PMID- 21584176 TI - Challenges in conducting psychiatry studies in India. AB - A large number of psychiatry studies are conducted in India. Psychiatry studies are complex and present unique challenges in the Indian setting. Ethical issues pertaining to the risk of worsening of illness, use of placebo and validity of informed consents are commonly faced. Site selection can be difficult due to the relative paucity of ICH-GCP (International Conference on Harmonisation - Good Clinical Practice) trained psychiatry investigators in India. Recruitment can be challenging due to issues such as strict eligibility criteria, (lack of) availability of caregiver, illness-related considerations, etc. Assessment of the consent capacity of patients is not simple, while structured assessments are not commonly employed. As the illness fluctuates, the consent capacity may change, thus requiring continued assessment of consent capacity. Study patients run the risk of worsening of illness and suicide due to exposure to inactive treatments; this risk is counterbalanced by use of appropriate study designs, as well as the indirect psychotherapeutic support received. Psychiatry studies are associated with a high placebo response. This necessitates conduct of placebo-controlled studies despite the attendant difficulties. Also, the high placebo response is often the cause of failed trials. Rating scales are essential for assessment of drug response. Some rating instruments as well as some rater training procedures may not be suitable for the Indian setting. Technological advancements may increase the procedural complexity but improve the quality of ratings. Psychiatry studies present monitors and auditors with unique scenarios too. Utilization of psychiatry specific training and expertise is recommended to ensure successful conduct of these studies in India. PMID- 21584177 TI - Phase 0 clinical trials in oncology new drug development. AB - Research focus of pharmaceutical industry has expanded to a larger extent in last few decades putting many more new molecules, particularly targeted agents, for the clinical development. On the other hand, researchers are facing serious challenges due to high failure rates of new molecules in clinical studies. The United States Food and Drug Administration (FDA) in combination with academia and industry experts identified many factors responsible for failures of new molecules, and with a vision of taking traditional drug development model toward an innovative paradigm shift, issued regulatory guidance on conduct of exploratory investigational new drug (exploratory IND) studies, often called as phase 0 clinical trials, requiring reduced preclinical testing, which has special relevance to life-threatening diseases such as cancer. Phase 0 trials, utilizing much lower drug doses, provide an opportunity to explore the clinical behavior of new molecules very early in the drug development pathway, helping to identify the promising candidates and eliminating non-promising molecules, thus improving the efficiency of overall drug development with significant savings of resources. Being non-therapeutic in nature, these studies, however, pose certain ethical challenges requiring careful study designing and informed consent process. This article reviews the insights and perspectives for the feasibility, utility, planning, designing and conduct of phase 0 clinical trials, in addition to ethical issues and industrial perspective focused at oncology new drug development. PMID- 21584178 TI - Adaptive designs in clinical trials. AB - In addition to the expensive and lengthy process of developing a new medicine, the attrition rate in clinical research was on the rise, resulting in stagnation in the development of new compounds. As a consequence to this, the US Food and Drug Administration released a critical path initiative document in 2004, highlighting the need for developing innovative trial designs. One of the innovations suggested the use of adaptive designs for clinical trials. Thus, post critical path initiative, there is a growing interest in using adaptive designs for the development of pharmaceutical products. Adaptive designs are expected to have great potential to reduce the number of patients and duration of trial and to have relatively less exposure to new drug. Adaptive designs are not new in the sense that the task of interim analysis (IA)/review of the accumulated data used in adaptive designs existed in the past too. However, such reviews/analyses of accumulated data were not necessarily planned at the stage of planning clinical trial and the methods used were not necessarily compliant with clinical trial process. The Bayesian approach commonly used in adaptive designs was developed by Thomas Bayes in the 18th century, about hundred years prior to the development of modern statistical methods by the father of modern statistics, Sir Ronald A. Fisher, but the complexity involved in Bayesian approach prevented its use in real life practice. The advances in the field of computer and information technology over the last three to four decades has changed the scenario and the Bayesian techniques are being used in adaptive designs in addition to other sequential methods used in IA. This paper attempts to describe the various adaptive designs in clinical trial and views of stakeholders about feasibility of using them, without going into mathematical complexities. PMID- 21584179 TI - Integrated monitoring: Setting new standards for the next decade of clinical trial practice. AB - The new age clinical research professional is now geared toward an "integrated monitoring" approach. A number of critical activities at the site level and at the sponsor's organization need convergence to harness rich dividends in early study start and quick close of the study. The field monitor needs full integration to ensure standard of care, train the site in protocol, select the right site, ensure regulatory support, ensure excellent project management skills, coach, support the logistics team, manage the vendor, ensure good documentation practices, develop patient recruitment and retention, lean the applicable process, as well as ensure effective site management amongst the myriad activities assigned toward developing the drug in the clinic. PMID- 21584180 TI - Quality assurance: Importance of systems and standard operating procedures. AB - It is mandatory for sponsors of clinical trials and contract research organizations alike to establish, manage and monitor their quality control and quality assurance systems and their integral standard operating procedures and other quality documents to provide high-quality products and services to fully satisfy customer needs and expectations. Quality control and quality assurance systems together constitute the key quality systems. Quality control and quality assurance are parts of quality management. Quality control is focused on fulfilling quality requirements, whereas quality assurance is focused on providing confidence that quality requirements are fulfilled. The quality systems must be commensurate with the Company business objectives and business model. Top management commitment and its active involvement are critical in order to ensure at all times the adequacy, suitability, effectiveness and efficiency of the quality systems. Effective and efficient quality systems can promote timely registration of drugs by eliminating waste and the need for rework with overall financial and social benefits to the Company. PMID- 21584182 TI - International regulatory agencies: Indian clinical trials. PMID- 21584181 TI - Use, abuse and misuse of notes to file. AB - A quick and easy solution to the absence of adequate documentation during clinical trial conduct is the use of notes to file. Over the years, the use of notes to file has evolved from a last resort solution to a common working practice amongst clinical teams, bordering on misuse and abuse of this tool. This article explores this evolution from the perspective of an independent observer. PMID- 21584183 TI - Microarray data analysis and mining tools. AB - Microarrays are one of the latest breakthroughs in experimental molecular biology that allow monitoring the expression levels of tens of thousands of genes simultaneously. Arrays have been applied to studies in gene expression, genome mapping, SNP discrimination, transcription factor activity, toxicity, pathogen identification and many other applications. In this paper we concentrate on discussing various bioinformatics tools used for microarray data mining tasks with its underlying algorithms, web resources and relevant reference. We emphasize this paper mainly for digital biologists to get an aware about the plethora of tools and programs available for microarray data analysis. First, we report the common data mining applications such as selecting differentially expressed genes, clustering, and classification. Next, we focused on gene expression based knowledge discovery studies such as transcription factor binding site analysis, pathway analysis, protein- protein interaction network analysis and gene enrichment analysis. PMID- 21584185 TI - Antimony resistance during Visceral Leishmaniasis: A possible consequence of serial mutations in ABC transporters of Leishmania species. AB - Visceral Leishmaniasis is a macrophage associated disorder for the treatment of which antimony based drugs like SAG and SSG were the first choice in the recent past. The clinical value of antimony therapy is now declined against VL because increasing cases of Sodium Antimony Gluconate (SAG) resistance have reached outstanding proportion in Bihar, India. Within this context we looked into the protein sequences of ABC transporters of Leishmania spp associated with Visceral Leishmaniasis that are known to play a crucial role in the development of multidrug resistance (MDR). Our studies consisting of ClustalW, Phylogeny and TCOFFEE have pinpointed that ABC transporters have enormously diverged during the process of evolution even within the identical species strains resulting in insignificant homology and subdued conservation amongst the aminoacid residues. Moreover these amino acid residues remain susceptible to mutations in evolutionary era as indicated by high frequency of variations by the variability studies. Hence we predict that during the process of evolution a series of frequent mutations might have led to changes in the ABC transporters favorable to effluxing the drug thereby making the Leishmania species prone to resistance against the efficient first line drug SAG, used for combating VL. This selection has made them to survive efficiently in the adverse circumstances of antimony based antileishmanial therapy regime. PMID- 21584184 TI - In silico studies on marine actinomycetes as potential inhibitors for Glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is considered to be the most common and often deadly disorder which affects the brain. It is caused by the over expression of proteins such as ephrin type-A receptor 2 (EphA2), epidermal growth factor receptor (EGFR) and EGFRvIII. These 3 proteins are considered to be the potential therapeutic targets for GBM. Among these, EphA2 is reported to be over-expressed in ~90% of GBM. Herein we selected 35 compounds from marine actinomycetes, 5 in vitro and in vivo studied drug candidates and 4 commercially available drugs for GBM which were identified from literature and analysed by using comparative docking studies. Based on the glide scores and other in silico parameters available in Schrodinger, two selected marine actinomycetes compounds which include Tetracenomycin D and Chartreusin exhibited better binding energy among all the compounds studied in comparative docking. In this study we have demonstrated the inhibition of the 3 selected targets by the two bioactive compounds from marine actinomycetes through in-silico docking studies. Furthermore molecular dynamics simulation were also been performed to check the stability and the amino acids interacted with the 3 molecular targets (EphA2 receptor, EGFR, EGFRvIII) for GBM. Our results suggest that Tetracinomycin D and Chartreusin are the novel and potential inhibitor for the treatment of GBM. PMID- 21584186 TI - Deciphering the key molecular and cellular events in neutrophil transmigration during acute inflammation. AB - Recruitment of leukocytes circulating in our blood to the sites of infection or tissue damage is the key phenomenon in the acute inflammatory response(s). Among the leukocytes, neutrophils are primarily recruited into the areas of acute inflammation. When neutrophils interact with activated endothelium of the blood vessels, they become migratory and cross the endothelial layer of the blood vessel wall in a process called as leukocyte extravasation. Identifying and understanding the gene regulation of this extravasation phenomenon is one of the key objective of biomedical research aimed at ameliorating or alleviating the symptoms of various diseases, such as rheumatoid arthritis, asthma, anaphylaxis, atherosclerosis, ulcerative colitis etc., that are exacerbated by inappropriate inflammatory stimuli. Here, we decipher and discuss the key genes implicated in the leukocyte transmigration using the acute inflammation model called as the Dextran Sulphate Sodium (DSS) induced Colitis in mice as a classic paradigm. PMID- 21584187 TI - Homology modeling of Ferredoxin-nitrite reductase from Arabidopsis thaliana. AB - Nitrogen is one of the major growth-limiting nutrients for plants: The main source of nitrogen in most of the higher plants is nitrate taken up through roots. Nitrate can be reduced both in the chloroplasts (photosynthetic tissues) and in proplastes (nonphotosynthetic tissues) such as roots. Ferredoxin-nitrite reductase (NiR) catalyses the reduction of nitrite to ammonium in the second step of the nitrate- assimilation pathway. Homology model of Ferredoxin-nitrite reductase has been constructed using the X-ray structure (PDB code: 2akj) a s a template and MODELLER 9v5 software. The resulting model assessed by PROCHECK, PROSAII and RMSD that showed the final refined model is reliable: has 81% of amino acid sequence identity with template, 0.2A as RMSD and has (-10.37) as Z scores, the Ramachandran plot analysis showed that conformations for 99.5 % of amino acid residues are within the most favored regions. The model could prove useful in further functional characterization of this protein. ABBREVIATIONS: PDB - Protein Data Bank, NMR - Nuclear Magnetic Resonance, NiR - Nitrite Reductase, RMSD - Root Mean Squared Deviation, Fd - ferredoxin. PMID- 21584188 TI - Meta analysis of Chronic Fatigue Syndrome through integration of clinical, gene expression, SNP and proteomic data. AB - We start by constructing gene-gene association networks based on about 300 genes whose expression values vary between the groups of CFS patients (plus control). Connected components (modules) from these networks are further inspected for their predictive ability for symptom severity, genotypes of two single nucleotide polymorphisms (SNP) known to be associated with symptom severity, and intensity of the ten most discriminative protein features. We use two different network construction methods and choose the common genes identified in both for added validation. Our analysis identified eleven genes which may play important roles in certain aspects of CFS or related symptoms. In particular, the gene WASF3 (aka WAVE3) possibly regulates brain cytokines involved in the mechanism of fatigue through the p38 MAPK regulatory pathway. PMID- 21584189 TI - PKSIIIexplorer: TSVM approach for predicting Type III polyketide synthase proteins. AB - PKSIIIexplorer, a web server based on 'transductive Support Vector Machine' allows fast and reliable prediction of Type III polyketide synthase proteins. It provides a simple unique platform to identify the probability of a particular sequence, being a type III polyketide synthases or not with moderately high accuracy. We hope that our method could serve as a useful program for the type III polyketide researchers. The tool is available at "http://type3pks.in/tsvm/pks3". ABBREVIATIONS: PKS - Polyketide synthase, CHS - Chalcone synthase, SVM - Support vector machine, MCC - Matthews Correlation Coefficient. PMID- 21584190 TI - A database of six eukaryotic hypothetical genes and proteins. AB - Assigning functions to proteins of unknown function is of considerable interest to the proteomic researchers as the genes encoding them are conserved over various species. Here, we describe HypoDB, a database of hypothetical genes and proteins in six eukaryotes. The database was collected and organized based on the number of entries in each chromosome with few annotations. Hypothetical protein database contains information related to gene and protein sequences, chromosome number and location, secondary and tertiary structure related data. AVAILABILITY: The database is available for free at http://www.trimslabs.com/database/hypodb/index.html. PMID- 21584191 TI - MTB-PCDB: Mycobacterium tuberculosis proteome comparison database. AB - The Mycobacterium tuberculosis Proteome Comparison Database (MTB-PCDB) is an online database providing integrated access to proteome sequence comparison data for five strains of Mycobacterium tuberculosis (H37Rv, H37Ra, CDC 1551, F11 and KZN 1435) sequenced completely so far. MTB-PCDB currently hosts 40252 protein sequence comparison data obtained through inter-strain proteome comparison of five different strains of MTB. 2373 proteins were found to be identical in all 5 strains using MTB H(37)Rv as reference strain. To enable wide use of this data, MTB-PCDB provides a set of tools for searching, browsing, analyzing and downloading the data. By bringing together, M. tuberculosis proteome comparison among virulent & avirulent strains and also drug susceptible & drug resistance strains MTB-PCDB provides a unique discovery platform for comparative proteomics among these strains which may give insights into the discovery & development of TB drugs, vaccines and biomarkers. AVAILABILITY: The database is available for free at http://www.bicjbtdrc-mgims.in/MTB-PCDB/ PMID- 21584192 TI - Information resource needs and preference of queensland general practitioners on complementary medicines: result of a needs assessment. AB - Objectives. To explore in a cohort of Queensland (Qld) GPs' their attitudes to; knowledge about; and practice behaviour regarding complementary medicines (CMs), and to identify their perceptions of need for information resources on CMs. Design. A faxed self-administered survey to a random sample of 800 GPs in Qld. Participants. 463 completed surveys were returned, representing a 58% response rate. Results. The majority of GPs had a positive attitude about incorporating CMs in their clinical practice; however, only 12% perceived they had adequate knowledge to be able to advise patients about CMs. GPs most preferred evidence based resources for receiving information on CMs (fact sheets, booklets, and journals) that contain clinical, pharmacological, and toxicological information. Most GPs perceived a need for an information resource on herbal medicines, vitamins, minerals, and trace elements, and nutritional supplements. Conclusion. GPs are open to integrating CMs into their clinical practice. They identify a current lack of knowledge coupled with a substantive level of interest to learn more. GPs perceive a high level of need for information resources on CMs. These resources should be developed and readily available to GPs to increase their knowledge about CMs and better equip them in communicating with patients about CMs use. PMID- 21584193 TI - Cytotoxicity Effects of Amoora rohituka and chittagonga on Breast and Pancreatic Cancer Cells. AB - Chemotherapeutic agents for cancer are highly toxic to healthy tissues and hence alternative medicine avenues are widely researched. Majority of the recent studies on alternative medicine suggested that Amoora rohituka possesses considerable antitumor and antibacterial properties. In this work, rohituka and chittagonga, fractionated with petroleum ether, dichloromethane, and ethanol, were explored for their anticancer potential against two breast cancer (MCF-7 and HTB-126) and three pancreatic cancer (Panc-1, Mia-Paca2, and Capan1). The human foreskin fibroblast, Hs68, was also included. Cytotoxicity of each extract was analyzed using the MTT assay and label-free photonic crystal biosensor assay. A concentration series of each extract was performed on the six cell lines. For MCF 7 cancer cells, the chittagonga (Pet-Ether and CH(2)Cl(2)) and rohituka (Pet Ether) extracts induced cytotoxicity; the chittagonga (EtoAC) and rohituka (MeOH) extracts did not induce cytotoxicity. For HTB126, Panc-1, Mia-Paca2, and Capan-1 cancer cells, only the chittagonga CH(2)Cl(2) extract showed a significant cytotoxic effect. The extracts were not cytotoxic to normal fibroblast Hs68 cells, which may be correlated to the specificity of Amoora extracts in targeting cancerous cells. Based on these results, further examination of the potential anticancer properties Amoora species and the identification of the active ingredients of these extracts is warranted. PMID- 21584195 TI - The Association between Traditional Chinese Dietary and Herbal Therapies and Uterine Involution in Postpartum Women. AB - Background. Traditional Chinese postpartum care is believed to help in the recovery of women after delivery. Objective. This study investigated the association of elements in dietary and herbal therapy with uterine involution. Methods. Indices of uterine involution were measured ultrasonographically in 127 postpartum women between 4-6 weeks after delivery. A self-reported retrospective questionnaire was used to query women about their frequencies of taking herbal medicines and consuming special diets during the first month after delivery. Correlation coefficients were calculated to identify the associations, then the regression models were used to identify the predictors. Result. Among the herbal medicines and diet, consumption of Eucommia ulmoides (E. ulmoides) negatively correlated with the AP diameter of the uterus and the cavity. E. ulmoides was also the only predictor of maximum AP diameter of the uterus, AP diameter of the uterus 5 cm from the fundus, and the maximum AP diameter of the cavity. Moreover, consumption of Sheng-hau-tang was significantly correlated with anteverted uterus and was a predictor of anteverted uterus. Conclusion. E. ulmoides and Sheng-hau tang positively correlated with the degree of uterine involution after delivery, implying that both therapies might possess the pharmacological efficacy of uterine contraction in postpartum women. PMID- 21584194 TI - Antinociceptive activities and the mechanisms of anti-inflammation of asiatic Acid in mice. AB - Asiatic acid (AA), a pentacyclic triterpene compound in the medicinal plant Centella asiatica, was evaluated for antinociceptive and anti-inflammatory effects. Treatment of male ICR mice with AA significantly inhibited the numbers of acetic acid-induced writhing responses and the formalin-induced pain in the late phase. In the anti-inflammatory test, AA decreased the paw edema at the 4th and 5th h after lambda-carrageenan (Carr) administration and increased the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the liver tissue. AA decreased the nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) levels on serum level at the 5th h after Carr injection. Western blotting revealed that AA decreased Carr-induced inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and nuclear factor-kappaB (NF-kappaB) expressions at the 5th h in the edema paw. An intraperitoneal (i.p.) injection treatment with AA also diminished neutrophil infiltration into sites of inflammation as did indomethacin (Indo). The anti-inflammatory mechanisms of AA might be related to the decrease in the level of MDA, iNOS, COX-2, and NF-kappaB in the edema paw via increasing the activities of CAT, SOD, and GPx in the liver. PMID- 21584196 TI - Aromatherapy benefits autonomic nervous system regulation for elementary school faculty in taiwan. AB - Workplace stress-related illness is a serious issue, and consequently many stress reduction methods have been investigated. Aromatherapy is especially for populations that work under high stress. Elementary school teachers are a high stress working population in Taiwan. In this study, fifty-four elementary school teachers were recruited to evaluate aromatherapy performance on stress reduction. Bergamot essential oil was used for aromatherapy spray for 10 minutes. Blood pressure and autonomic nervous system parameters were recorded 5 minutes before and after the application of the aroma spray. Results showed that there were significant decreases in blood pressure, heart rate, LF power percentage, and LF/HF while there were increases in heart rate variability and HF power percentage (P < .001(***)) after application of the aromatherapy spray. Further analysis was investigated by dividing subjects into three background variables (position variables, age variables, gender variables) and anxiety degree groups. All parameters were significantly different for most subgroups, except for the substitute teachers and the light-anxiety group. Parasympathetic nervous system activation was measured after aromatherapy in this study. It encouraged further study for other stress working population by aromatherapy. PMID- 21584197 TI - Hematuria after orthopedic tuina: a case report and brief review of literature. AB - We present a case of a 24-year-old man who presented hematuria after the orthopedic tuina, which has not been recorded previously in the literature. We review complications of tuina in the literature too. PMID- 21584198 TI - Application of a heat- and steam-generating sheet increases peripheral blood flow and induces parasympathetic predominance. AB - To promote the practical application of a Japanese traditional medical treatment, such as hot compresses, we developed a plaster-type warming device consisting of a heat- and steam-generating sheet (HSG sheet). First, we tested its effects when applied to the anterior abdominal wall or lumbar region of women complaining of a tendency towards constipation. Application of the sheet to either region produced a feeling of comfort in the abdomen, as assessed by a survey of the subjects. The significant increases in the total hemoglobin observed in these regions suggested an increase in peripheral blood flow, and significant increases in the HF component on ECG and in the amplitude of gastric motility suggested parasympathetic predominance. We concluded that application of the HSG sheet improves the peripheral hemodynamics and autonomic regulation, induces a feeling of comfort in the abdomen, and provides a beneficial environment for the improvement of gastrointestinal movements. PMID- 21584199 TI - High flexion total knee arthroplasty - mid-term follow up of 5 years. AB - Because of demographic changes, ever greater demands are made of knee replacement systems by patients and surgeons. To meet these demands, knee joint systems with increased flexion are currently being marketed. The main hypothesis of the present study was to evaluate the functional outcome of a high flexion TKA in amid-term follow up. 75 consecutive patients (29 men and 46 women) who had primary arthritis of the knee with similar deformity and range of motion undergo TKA using a NexGen Cr Flex mobile.Knee Society knee and functional scores and range of motion were assessed.The follow-up duration was 5 years. There was a highly significant improvement in comparison to the preoperative status (p<0.005). The maximum flexion was 122 degrees in mean and the mean KSS was 167 (SD: 21) at final follow up. Despite positive results in the first 5 postoperative years, the NexGen Cr Flex mobile TKA shows no advantages with regard to ROM and KSS compared to the recent literature. Long-term studies are needed to determine a superiority of high flexion knee implants versus traditional TKA's. PMID- 21584200 TI - Total elbow arthroplasty. AB - Total elbow arthroplasty has continued to evolve over time. Elbow implants may be linked or unlinked. Unlinked implants are attractive for patients with relatively well preserved bone stock and ligaments, but many favor linked implants, since they prevent instability and allow replacement for a wider spectrum of indications. Inflammatory arthropathies such as rheumatoid arthritis represent the classic indication for elbow arthroplasty. Indications have been expanded to include posttraumatic osteoarthritis, acute distal humerus fractures, distal humerus nonunions and reconstruction after tumor resection. Elbow arthroplasty is very successful in terms of pain relief, motion and function. However, its complication rate remains higher than arthroplasty of other joints. The overall success rate is best for patients with inflammatory arthritis and elderly patients with acute distal humerus fractures, worse for patients with posttraumatic osteoarthritis. The most common complications of elbow arthroplasty include infection, loosening, wear, triceps weakness and ulnar neuropathy. When revision surgery becomes necessary, bone augmentation techniques provide a reasonable outcome. PMID- 21584201 TI - Biomarkers in arthroplasty: a systematic review. AB - We performed a systematic review of all MEDLINE-published studies of biomarkers in arthroplasty. Thirty studies met the inclusion criteria; majority evaluated biomarkers for osteolysis, aseptic prosthetic loosening, and prosthetic infections. Four studies reported an elevated Cross-linked N-telopeptides of type I collagen (urine or serum) in patients with osteolysis or aseptic prosthetic loosening when compared to appropriate controls. Two or more studies each found elevated C-reactive protein, erythrocyte sedimentation rate, and interleukin-6 in patients with infected prosthetic joints compared to controls. Most other biomarkers were either examined by single studies or had inconsistent or insignificant associations with outcomes. We conclude that the majority of the biomarkers currently lack the evidence to be considered as biomarkers for arthroplasty outcomes. Further studies are needed. PMID- 21584202 TI - Total knee arthroplasty for post-traumatic proximal tibial bone defect: three cases report. AB - Bone stock deficiency in primary as well as in revision total knee arthroplasty (TKA) represents a difficult problem to surgeon with regard to maintaining proper alignment of the implant components and in establishing a stable bone-implant interface. Different surgical procedures are available in these situations, for instances the use of bone cement, prosthetic augments, custom implant, and wire mesh with morsellized bone grafting and structural bone allograft. Structural allograft offers a numerous advantages as easy remodeling and felling cavitary or segmental defects, excellent biocompatibility, bone stock restoration and potential for ligamentous reattachment. In this article we report a short term result of three cases affected by severe segmental medial post/traumatic tibial plateau defect in arthritic knee, for which massive structural allograft reconstruction and primary total knee replacement were carried. The heights of the bone defect were between 27-33 mm and with moderate medio-lateral knee instability. Pre-operative AKS score in three cases was 30, 34 and 51 points consecutively and improved at the last follow-up to 83, 78 and 85 consecutively. No acute or chronic complication was observed. Last radiological exam referred no signs of prosthetic loosening, no secondary resorption of bone graft and well integrated graft to host bone. These results achieved in our similar three cases have confirmed that the structural bone allograft is a successful biological material to restore hemi-condylar segmental tibial bone defect when total knee replacement is indicated. PMID- 21584204 TI - Combination of two cytokine inhibitors reduces nucleus pulposus-induced nerve injury more than using each inhibitor separately. AB - Although recent experimental studies indicate that disc-derived cytokines, as for instance TNF, seems to be intimately involved in the pathophysiology of sciatica and low back pain, the clinical studies performed do not provide conclusive data on TNF-inhibition as a useful complement for treatment of such conditions to existing modalities. Based on the fact that TNF is merely one component in a complex network it was assumed that the combination of a TNF-inhibitor and an IL 1beta-inhibitor could potentiate the effects in a pig model on nucleus pulposus induced nerve conduction velocity reduction. The data indicated that combination of two cytokine inhibitors seems to be more efficient in reducing the nucleus pulposus-induced effects on nerve conduction velocity than using each inhibitor separately. This may be considered if future clinical trials for the treatment of sciatica and low back pain using just a single inhibitor may continue to demonstrate inconclusive data. PMID- 21584203 TI - Seasonal trends in the incidence of hip osteoarthritis in Japanese patients. AB - PURPOSE: There is an association between winter birth and developmental dysplasia of the hip, formerly termed congenital dislocation of the hip. The purpose of this study was to clarify the relationship between the month and season of birth and hip osteoarthritis in Japanese patients who had undergone total hip arthroplasty or transpositional osteotomy of the acetabulum. METHODS: One thousand eight hundred and 52 female patients that presented for the surgical treatment of hip osteoarthritis between 1999 and 2005 were included in this study. Female out-patients who were seen at the initial visit during same period were used as controls to correct the bias of the month of birth. RESULTS: There was a significant deviation of the observed number of births from the expected values calculated on a monthly basis (p<0.001). A comparison by seasons (periods of 3 months) revealed more births than expected in winter (p<0.001). The risk of hip osteoarthritis was significantly associated with the month of birth. Namely, it was highest for births in January (p<0.001). CONCLUSIONS: These data clearly revealed that the prevalence of hip osteoarthritis was significantly higher in those patients born in winter. The seasonal trend in hip osteoarthritis might be due to the winter prevalence of congenital dislocation of the hip in childhood. PMID- 21584205 TI - Dynamic assessment in patients following bone-patellar tendon-bone autograft anterior cruciate ligament reconstruction. AB - BACKGROUND: The knee's passive movement is insufficient to determine function in patients following ACL reconstruction. HYPOTHESIS: We hypothesize that there are kinematic differences in the lower extremities (LE) during stair climbing and ground level walking following ACL surgery between the intact and reconstructed sides. STUDY DESIGN: This was a retrospective cohort study. Eleven patients with an average age of 15.3 years at the time of their ACL reconstructive surgery (BPTB autograft) participated in the study. METHODS: Patients were followed for at least 2 years post surgery. The subjects underwent a non-weight bearing ability test to reproduce predetermined knee joint positions. Their LE's velocity and joint kinematics were then measured during level ground walking and on a set of custom designed stairs as they ascended and descended. RESULTS: During level ground walking the maximum internal rotation at the ankle during the swing phase on the reconstructed side increased significantly from 2.3o to 19.9 o compared to the unreconstructed limb (P=0.04). The leading reconstructed knee during stair ascent exhibited less knee flexion as compared to the unreconstructed knee for each step (1(st) step: 74.2o vs 81.5o; 2(nd) step:93.6o vs 97.6o; 3(rd) step: 48o vs 53.5o; 4(th) step: 72.5o vs 78.1o; p<0.05). CONCLUSIONS: A two-year follow-up study in adolescents who had a bone-patellar tendon-bone autograft demonstrated that they had normal knee proprioception and 3D joint rotations of the LE, while showing an alteration of the ankle and knee kinematics during walking or ascending stairs. PMID- 21584206 TI - Total shoulder arthroplasty. AB - Shoulder arthroplasty has been the subject of marked advances over the last few years. Modern implants provide a wide range of options, including resurfacing of the humeral head, anatomic hemiarthroplasty, total shoulder arthroplasty, reverse shoulder arthroplasty and trauma-specific implants for fractures and nonunions. Most humeral components achieve successful long-term fixation without bone cement. Cemented all-polyethylene glenoid components remain the standard for anatomic total shoulder arthroplasty. The results of shoulder arthroplasty vary depending on the underlying diagnosis, the condition of the soft-tissues, and the type of reconstruction. Total shoulder arthroplasty seems to provide the best outcome for patients with osteoarthritis and inflammatory arthropathy. The outcome of hemiarthroplasty for proximal humerus fractures is somewhat unpredictable, though it seems to have improved with the use of fracture-specific designs, more attention to tuberosity repair, and the selective use of reverse arthroplasty, as well as a shift in indications towards internal fixation. Reverse shoulder arthroplasty has become extremely popular for patients with cuff tear arthropathy, and its indications have been expanded to the field of revision surgery. Overall, shoulder arthroplasty is a very successful procedure with predictable pain relief and substantial improvements in motion and function. PMID- 21584208 TI - Takotsubo cardiomyopathy vs acute myocardial infarction: diagnostic utility of subtle ECG differences. AB - The clinical findings of Takatsubo Cardiomyopathy and acute myocardial infarction can be very similar. While Takatsubo cardiomyopathy rarely leads to severe complications, acute myocardial infarction can be life threatening. Treatment of both these conditions is different and so it is imperative for clinicians to have a high index of suspicion for either. Several EKG differences between the two entities have been proposed. This article summarizes the EKG changes most likely seen in Takatsubo cardiomyopathy and compares them to those seen in Acute Myocardial infarction. PMID- 21584207 TI - Triangle tilt and steel osteotomy: similar approaches to common problems. AB - BACKGROUND: Each year, thousands of children worldwide suffer obstetric brachial plexus nerve injuries resulting not only in primary nerve injury, but also in development of secondary muscle and bone deformities of the shoulder. The triangle tilt surgery has been developed and shown to effectively address these deformities. The triangle tilt procedure was initially designed by the lead author (RKN) to follow the concepts of joint normalization featured in the Steel pelvic osteotomy used to correct developmental dysplasia of the hip joint, and indeed ultimately bears a striking resemblance to the Steel osteotomy. Prior to performing these bony surgical procedures, soft tissue procedures are performed to release the muscle contractures of the shoulder and hip. The purpose of this article is to compare and analyze the similarities between the indications, surgical techniques, involved anatomy, and outcomes of these operative procedures. METHODS: A literature review was conducted using PubMed to identify articles pertaining to triangle tilt surgery and the Steel pelvic osteotomy. Functional parameters and surgical strategies were compared. Pre- and post operative CTs were analyzed to compare anatomical results of the procedures. RESULTS: Similarities were found between both procedures in terms of indications, involved anatomy, surgical techniques, and outcomes. The triangle tilt surgery is indicated to correct the developmental dysplasia of the glenohumeral joint in obstetric brachial plexus injury patients. Steel pelvic osteotomy is performed to correct the subluxation and dislocation of the hip innominate bone in patients with congenital dysplasia, cerebral palsy myelodysplasia, and poliomyelitis. The involved anatomy of both procedures is similar in that both involve limb girdles and ball-and-socket joints, namely the shoulder and hip. Both procedures are also triple osteotomies, the triangle tilt involving the acromion, clavicle and scapula while the Steel osteotomy involves the iliac spine, ischial and pubic ramus of the innominate bone. Surgical techniques also bear likenesses in that both can theoretically be done percutaneously. Post-operative CT outcomes of both surgeries showed improved anatomical positioning of the ball-and-socket joint congruency, and therefore better functional outcomes. DISCUSSION: The similarities between the triangle tilt surgery and Steel pelvic osteotomy could potentially be useful as a model system in developing other procedures that involve the shoulder and hip. Future clinical applications include the development and implementation of new surgical procedures based on comparisons and adaptations from the hip to the shoulder and vice versa. PMID- 21584209 TI - Charcot's triad. AB - Biliary stones are usually found in the gallbladder, but about 10-20% may spontaneously migrate into the common bile duct where they either remain trapped or migrate subsequently via the papilla of Vater into the duodenal lumen. In some cases, biliary stones may form de novo in the common bile duct because of local precipitating factors. We here present a spectacular case of huge gallstones impacted in the common bile duct (empierrement of the common bile duct) that led to the development of acute cholangitis with septic shock. Urgent nocturnal percutaneous cholangiography permitted biliary drainage and resolution of the cholangitis while the stones were secondarily removed surgically because of the large size of the stones.Acute suppurative cholangitis may be fatal unless adequate biliary drainage is obtained in a timely manner. The association of fever and rapid onset of jaundice in elderly patients should always make physicians think of cholangitis. PMID- 21584210 TI - Abdominal imaging utilization in the emergency department: trends over two decades. AB - BACKGROUND: To assess patterns of use of abdominal imaging in the emergency department (ED) from 1990 to 2009. METHODS: We retrospectively reviewed data on adult ED patients treated between 1990 and 2009 at our university-affiliated quaternary care institution. Examinations were coded by abdominal imaging modality: x-ray, sonography, CT, or MRI. Proportional costs for each imaging modality were evaluated using relative value units (RVUs). Chi-square tests were used to assess for significant trends. RESULTS: The intensity of abdominal imaging per 1,000 ED visits increased 19.3% from 1990-2009 (p = 0.0050). The number of abdominal CT scans per 1,000 ED visits increased 17.5-fold (p < 0.0001). Similarly, the number of abdominal MRIs per 1,000 ED visits increased from 0 to 1.0 (p < 0.0001), and the number of abdominal sonographs per 1,000 ED visits increased 51.6% (p = 0.0198). However, the number of x-ray examinations per 1,000 ED visits decreased 81.6% (p < 0.0001). Abdominal imaging RVUs per 1,000 ED visits increased 2.7-fold (p < 0.0001), due primarily to CT imaging, which accounted for 14% of RVUs in 1990 and 76% of RVUs in 2009. CONCLUSIONS: The intensity of abdominal imaging examinations per 1,000 ED visits and the number of abdominal imaging RVUs increased significantly over a 20-year period. CT replaced x-ray as the most common abdominal imaging modality for evaluation of ED patients. In light of these increasing costs as well as the increased radiation exposure of CT, clinical decision rules and computerized decision support may be needed to ensure appropriate utilization of abdominal CT in the ED. PMID- 21584211 TI - Observation of nonspherical particle behaviors for continuous shape-based separation using hydrodynamic filtration. AB - Selection of particles or cells of specific shapes from a complex mixture is an essential procedure for various biological and industrial applications, including synchronization of the cell cycle, classification of environmental bacteria, and elimination of aggregates from synthesized particles. Here, we investigate the separation behaviors of nonspherical and spherical particles/cells in the hydrodynamic filtration (HDF) scheme, which was previously developed for continuous size-dependent particle/cell separation. Nonspherical particle models were prepared by coating the hemisphere of spherical polymer particles with a thin Au layer and by bonding the Janus particles to form twins and triplets resembling dividing and aggregating cells, respectively. High-speed imaging revealed a difference in the separation behaviors of spherical and nonspherical particles at a branch point; nonspherical particles showed rotation behavior and did not enter the branch channel even when their minor axis was smaller than the virtual width of the flow region entering the branch channel, w(1). The confocal laser high-speed particle intensity velocimetry system visualized the flow profile inside the HDF microchannel, demonstrating that the steep flow-velocity distribution at the branch point is the main factor causing the rotation behavior of nonspherical particles. As applications, we successfully separated spherical and nonspherical particles with various major/minor lengths and also demonstrated the selection of budding/single cells from a yeast cell mixture. We therefore conclude that the HDF scheme can be used for continuous shape-based particle/cell separation. PMID- 21584213 TI - Progression-free or overall... That is the question.... PMID- 21584212 TI - Assessment of narghile (shisha, hookah) smokers' actual exposure to toxic chemicals requires further sound studies. AB - Tobacco smoking is hazardous for health. However, not all forms of tobacco use entail the same risks and the latter should be studied and compared in a sound realistic way. Smoking machines for cigarettes (which are consumed in a few minutes) were early designed as a tool to evaluate the actual intake of toxic substances ('toxicants') by smokers. However, the yields (tar, nicotine, CO, etc.) provided by such machines poorly reflect the actual human smoking behaviour known to depend on numerous factors (anxiety, emotions, anthropological situation, etc.). In the case of narghile smoking, the problems are even more complex, particularly because of the much longer duration of a session. A recent study from the US-American University of Beirut was based on a field smoking topography and claimed consistency with a laboratory smoking machine. We offer a point by point critical analysis of such methods on which most of the 'waterpipe' antismoking literature since 2002 is based. PMID- 21584214 TI - The effect of rehabilitation on quality of life in female breast cancer survivors in Iran. AB - BACKGROUND: The purpose of this study was to compare the quality of life (Qol) of female breast cancer survivors who received rehabilitation intervention beside medical care and survivors who received medical care alone. MATERIALS AND METHODS: Fifty-seven female breast cancer survivors were assigned to usual medical care (control group) or to usual medical care plus rehabilitation intervention (experimental group). Qol of all patients was assessed before, 1 week and 3 months after intervention. The intervention consisted of physiotherapy, education and individual counseling. The authors used the European Organization for Research and Treatment of Cancer core questionnaire and breast module (EORTC QLQ-C30/BR23) for the assessment of Qol. RESULTS: Patients who received rehabilitation had significantly better Qol. Overall, mean of Qol scores improved gradually in experimental group from before to 1 week and 3 months after intervention. In contrast, minimal change was observed between pre/post and follow-up measures for control group. CONCLUSION: Rehabilitation after breast cancer treatment has the potential for physical, psychological and overall Qol benefits. PMID- 21584215 TI - Pesticides and brain cancer linked in orchard farmers of Kashmir. AB - BACKGROUND: The atmosphere of valley of Kashmir is ideal for fresh and dry fruit production. Millions of tons of pesticides, insecticides and fungicides (chemicals like chlorpyriphos, mancozeb, captan, dimethoate, phosalone, etc.) are being used by the orchard farmers to spray the plants, fruits and the leaves every year. The increasing trend in the incidence of primary malignant brain tumors in orchard farmers of Kashmir is alarming. AIM: To determine the relationship between the patients of primary malignant brain tumors and their occupation. MATERIALS AND METHODS: Retrospectively case files along with death certificates of 432 patients of primary malignant brain tumors and 457 controls (non-tumor neurologic diseases), admitted for treatment simultaneously over a period of 4 years from January 2005 to December 2008, to the Department of Neurosurgery, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Kashmir, were studied. Follow-up and family contact was established. The serum cholinesterase activity was measured by kinetic/DGKC calorimetric method and ethylenediaminetetraacetic acid (EDTA) samples were sent to the laboratory. The results are expressed in U/l which is U/l*1000. The laboratory at SKIMS, Srinagar, and Dr Lal PathLabs at New Delhi used a reference range for serum cholinesterase as 3167-6333 U/l. RESULTS: Analysis revealed that 90.04% (389 out of 432) patients were orchard-farm workers, orchard residents and orchard playing children exposed to the high levels of multiple types of neurotoxic and carcinogenic (chlorpyriphos, dimethoate, mancozeb and captan) chemicals for more than 10-20 years. About 31.9% (124 out of 389) of these from both sexes were younger than 40 years beginning exposure at an early age and had higher (<6334 U/l) serum cholinesterase (SCE) levels. The 9.96% (43 out of 432) patients were not exposed to pesticides. On the other hand, only 119 patients out of 457 controls had recorded history of pesticide exposure and 338 were unrelated to pesticides. Out of 389 patients, 71.7% (279 out of 389) were males and 28.3% (110 out of 389) including 7 members of three families, 6 were females and 1 male. CONCLUSION: All orchard-related 389 patients had high grade tumors as compared to the non-pesticide tumors. Mortality in pesticide exposed tumors was 12%. Higher levels of SCE were found in 31.9% (124 out of 389) patients and decreased levels in only 45.3% (176 out of 389) orchard-related patients. The significantcase/control odds ratio (OR) of 0.28, hospital control SCE OR of 1.1 and family control SCE OR of 1.5, points the finger of suspicion toward the link between pesticides and brain cancer. PMID- 21584216 TI - Quality of life as an outcome variable in the management of advanced cancer. AB - BACKGROUND AND OBJECTIVE: Though well recognized in the West, palliative care and quality of life are relatively newer concepts in a developing country like India. The aim of this study was to assess the effect of palliative care on pain and quality of life and to identify the association between the two. STUDY DESIGN: Observational prospective study. MATERIALS AND METHODS: Patients with advanced cancer, receiving palliative drug therapy, were recruited from a tertiary care hospital. City of Hope Medical Center Quality of Life Survey and visual analog scale (VAS) were used to assess the quality of life and cancer pain severity, respectively. RESULTS: A total of 100 patients were included in the study. Palliative drug therapy produced a significant reduction in pain scores expressed as mean +/- SD in VAS [7.13 +/- 2.2 vs. 2.62 +/- 2.1 (P<0.001) after 1 month in 93 patients; 7.06 +/- 2.1 vs. 2.47 +/- 2.1 (P<0.001) after 1 month and 2.02 +/- 1.9 (P<0.001) after 2 months in 51 patients]. Also, significant improvement in the quality of life scores [919.78 +/- 271.3 vs. 1280.65 +/- 306.8 (P<0.01) after 1 month in 93 patients; 950.39 +/- 238.2 vs. 1336.67 +/- 291 (P<0.01) after 1 month and 1405.49 +/- 368.3 (P<0.01) after 2 months in 51 patients] was obtained. There was a high correlation between the average change of pain intensity and quality of life scores (r= -0.53, P<0.02). Overall, a reduction in pain resulted in significant improvement in the quality of life (P<0.001). CONCLUSION: This study emphasizes the role of palliative care and, more importantly, pain management in improving the quality of life of advanced cancer patients. PMID- 21584217 TI - The role of bacteria in oral cancer. AB - Despite the widening interest in the possible association between bacteria and different stages of cancer development, our knowledge in its relation to oral cancers remains inadequate. The aim of this review article is to derive a better understanding on the role of various micro-organisms in the etiogenesis of oral cancers through all the available data on the pubmed. Different bacteria have been proposed to induce carcinogenesis either through induction of chronic inflammation or by interference, either directly or indirectly, with eukaryotic cell cycle and signaling pathways, or by metabolism of potentially carcinogenic substances like acetaldehyde causing mutagenesis. Studies have shown diversity of isolated bacterial taxa between the oral cancer tissue specimens and the control, with Exiguobacterium oxidotolerans, Prevotella melaninogenica, Staphylococcus aureus and Veillonella parvula being specific for tumorogenic tissues. Most isolates are saccharolytic and acid tolerant. Streptococcus anginosus, commonly linked with esophageal and pharyngeal cancers, is not of significance in oral cancers. Similarly, significant salivary specificity is noted for three bacteria, namely, Capnocytophaga gingivalis, P. melaninogenica, and Streptococcus mitis in oral cancer patients, making these species salivary markers for the early detection of oral cancers and thus improving the survival rate significantly. Also, such high degree of bacterial specificity in oral cancers has also provoked the designing of new treatment options for cancer prevention by way of vaccine delivery. However, for the success of these steps, a deeper exploration into this subject with a greater understanding is warranted. PMID- 21584218 TI - Targeting mTOR pathway: A new concept in cancer therapy. AB - This article highlights the current knowledge of mTOR biology and provides new insights into the role of mTOR in different cancers. An active mTOR coordinates a response in cell growth directly through its effects on cell cycle regulators and indirectly by sustaining nutrient supply into the cell through the production of nutrient transporters and also through the promotion of angiogenesis. A primary way that mTOR exerts its regulatory effects on cell proliferation is by controlling the production of cyclin D1. mTOR increases the translation of hypoxia-inducible factor 1 (HIF-1)/HIF-2. The HIF transcription factors drive the expression of hypoxic stress response genes, including angiogenic growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor beta (PDGF-beta), and transforming growth factor a (TGF-alpha). mTOR also increases the surface expression of nutrient transporters proteins. An increase in these proteins results in greater uptake of amino acids and other nutrients by the cell leading to adequate nutrient support to abnormal cell growth and survival. There is also emerging evidence that mTOR activation may play a role in promoting cell survival through the activation of antiapoptotic proteins that contribute to tumor progression. Given that the mTOR pathway is deregulated in a number of cancers, it is anticipated that mTOR inhibitors will have broad therapeutic application across many tumor types. Until now, no treatment demonstrated Phase III evidence after disease progression on an initial VEGF targeted therapy in advanced renal cell carcinoma. Everolimus is the first and only therapy with Phase III evidence after failure of VEGF-targeted therapy. Everolimus is a once-daily, oral inhibitor of mTOR (mammalian target of rapamycin) indicated for the treatment of advanced renal cell carcinoma in patients, whose disease has progressed on or after treatment with VEGF-targeted therapy. PMID- 21584220 TI - Bortezomib. PMID- 21584219 TI - Scope and limitations of minimal invasive surgery in practice of pediatric surgical oncology. AB - Management of Solid tumors in children needs a comprehensive multimodality protocol based treatment plan. Open surgical removal of the tumors occurring in any of the sites such as abdomen, thorax, chest wall, HFN (head, face, neck), brain and extremities, is the option which has been traditionally practiced even in the present era and in most of the centers. Nevertheless with the advances in science and technology and with ever increasing usage and expertise of laparoscopy in children, it's application has extended to treatment of solid tumors in children. A review of the scope of such intervention as well as the limitations of minimal invasive surgery in this specialized field of pediatric surgery has been attempted in this article. PMID- 21584221 TI - Role of immunohistochemistry in lymphoma. PMID- 21584222 TI - Staring secondaries, where is the primary? AB - An asymptomatic issueless young staff nurse underwent pre-employment health screening and USG abdomen showed multiple hypodense lesions in liver. Further screening with whole body positron emission tomography-computed tomography (PET CT) scan showed significantly FDG avid mass involving most of the right lobe of liver with multiple large FDG avid lymph nodal metastases. Unsuspected focal abnormal, FDG avid, hyperdense mural nodule was seen in uterus, which is the site of primary. PMID- 21584223 TI - Enhancing recruitment of African-American families into genetic research: lessons learned from Project SuGar. AB - Despite some recruitment success in biomedical research among minorities, participation by African-American families into research, specifically genetic research, is lower than Caucasian families (Bowen and Penchaszadeh Community Genet 11:189-190, 2008). Such low participation rates by African-Americans prevent the exploration of specific ethnic differences in patterns of diseases and diminish the identification of specific disease risks among ethnic groups (Bowen and Penchaszadeh Community Genet 11:189-190, 2008). Although African Americans are heterogeneous, few studies exist to describe effective recruitment strategies across diverse African-American populations, and even fewer studies share effective strategies for the enrollment of African-American families into genetic research. A process evaluation of recruitment strategies used by Project SuGar (a community-based genetic research study focusing on families affected by type 2 diabetes) to enroll African-American families into genetic research was conducted. Our goal was to enroll 400 affected African-American families, and our results yielded 672 families, (n=672). Our success can be attributed to the formation of a Citizen Advisory Committee, recruitment style, flexible protocol, and formal agreement with community health centers. We found that African American families will participate in research and that providing tangible benefits to the community and utilizing a sense of patience can enhance positive recruitment results. Data from this study may be used to recruit geographically isolated families into genetic research. PMID- 21584224 TI - From Basic Processes to Real-World Problems: How Research on Emotion and Emotion Regulation Can Inform Understanding of Psychopathology, and Vice Versa. AB - Research on emotion and emotion regulation is expected to improve our understanding of psychopathology. However, achieving this understanding requires overcoming several obstacles, including the paucity of objective markers of specific emotions or psychiatric diagnoses, and the fact that emotion regulation is a concept that can be difficult to operationalize. We review affective neuroscience research that has addressed these issues by focusing on psychological and neural mechanisms implicated in approach and avoidance behaviors, as revealed by studies of fear, anxiety, and reward processing. Dysfunction in these mechanisms may serve as risk markers for psychopathology, while emotion regulation research demonstrates that some of them are susceptible to volitional control. The conclusion acknowledges limitations of affective neuroscience and highlights goals for future work. PMID- 21584225 TI - Lower frequency of CD62L(high) and higher frequency of TNFR2(+) Tregs are associated with inflammatory conditions in type 1 diabetic patients. AB - Diabetes type 1 is a chronic autoimmune disease in which insulin-producing cells are gradually destroyed by autoreactive T cells. Human regulatory cells play important role in controlling autoimmunity, and their qualitative or quantitative dysfunctions may result in ineffective suppression of autoreactive T cells. CD62L is a surface molecule that plays role in homing capabilities of Tregs, and only cells with high expression of CD62L have high suppressive potential. Tregs are also characterized by the constant expression of TNFR2. The frequency of Tregs carrying TNFR2 is higher in inflammatory conditions. We investigated blood regulatory T cells with CD62L expression and regulatory T cells expressing TNFR2 in type 1 diabetic patients. We found differences in these populations when comparing to healthy individuals. We propose that these may be associated with inflammatory conditions that are present in patients with type 1 diabetes. The lower percentage of Tregs and Treg CD62L(high) may contribute to ineffective suppression of proinflammatory cytokines production during type 1 diabetes. PMID- 21584226 TI - Physical and leisure activity in older community-dwelling canadians who use wheelchairs: a population study. AB - Background. Physical and leisure activities are proven health promotion modalities and have not been examined in older wheelchair users. Main Objectives. Examine physical and leisure activity in older wheelchair users and explore associations between wheelchair use and participation in physical and leisure activity, and wheelchair use, physical and leisure activity, and perceived health. Methods. 8301 Canadians >=60 years of age were selected from the Canadian Community Health Survey. Sociodemographic, health-related, mobility-related, and physical and leisure activity variables were analysed using logistic regression to determine, the likelihood of participation in physical and leisure activity, and whether participation in physical and leisure activities mediates the relationship between wheelchair use and perceived health. Results. 8.3% and 41.3% older wheelchair users were physically and leisurely active. Wheelchair use was a risk factor for reduced participation in physical (OR = 44.71) and leisure activity (OR = 10.83). Wheelchair use was a risk factor for poor perceived health (OR = 10.56) and physical and leisure activity negatively mediated the relationship between wheelchair user and perceived health. Conclusion. There is a need for the development of suitable physical and leisure activity interventions for older wheelchair users. Participation in such interventions may have associations with health benefits. PMID- 21584227 TI - Effects of electroacupuncture on benign prostate hyperplasia patients with lower urinary tract symptoms: a single-blinded, randomized controlled trial. AB - We tested the effect of electroacupuncture (EA) on lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH) patients. A total of 42 BPH patients with LUTS were randomly assigned to either the EA group (EG), received 2 Hz EA for 20 min twice/week for a total of twelve treatments, or a sham EA group (CG), received sham EA. The increase of voiding volume, average flow rate, and maximal flow rate in the EG were 32.2 +/- 104.4 mL, 1.2 +/- 1.6 mL/sec, and 2.3 +/- 3.7 mL/sec, respectively, from baseline value (before EA) using the measurement of an uroflowmetry. These increases were greater than -37.9 +/- 120.4, -0.22 +/- 2.7, and -0.3 +/- 4.3, respectively, in the CG (P = .038, .026, and .030, resp.). The changes of prostate special antigen and international prostatic symptom score were not significantly different between two groups (P = .573, .175, resp.), suggesting the clinical improvement of 2 Hz EA was quite limited to the LUTS of patients with BPH. PMID- 21584229 TI - Effects of tai chi training on antioxidant capacity in pre- and postmenopausal women. AB - The risk of oxidative stress-related metabolic diseases increases with menopause and physical inactivity. We hypothesized that an 8-week Tai Chi (TC) training program (2 sessions in class; 2 sessions at home; 1-1:15/session) would improve antioxidant capacity and reduce cardiovascular risks in both pre- (n = 8) and postmenopausal (n = 7) sedentary women. Selected measures of physical fitness and blood parameters were analyzed before and after the program. Besides the well known effects of TC on balance, flexibility, and maximum leg extensor strength, TC (1) increased erythrocyte glutathione peroxidase activity-an aerobic training responsive antioxidant enzyme-and plasma total antioxidant status and (2) decreased plasma total homocysteine, a cardiovascular risk marker. In addition to being a low-velocity, low-impact, and relatively safe, TC is a suitable physical activity design for pre- and postmenopausal women to increase antioxidant defenses. Investigating breathing effects during TC movements would be an interesting area for further research in diseases prevention. PMID- 21584228 TI - The influence of MHC and immunoglobulins a and e on host resistance to gastrointestinal nematodes in sheep. AB - Gastrointestinal nematode parasites in farmed animals are of particular importance due to their effects on production. In Australia, it is estimated that the direct and indirect effects of parasite infestation cost the animal production industries hundreds of millions of dollars each year. The main factors considered by immunologists when studying gastrointestinal nematode infections are the effects the host's response has on the parasite, which immunological components are responsible for these effects, genetic factors involved in controlling immunological responses, and the interactions between these forming an interconnecting multilevel relationship. In this paper, we describe the roles of immunoglobulins, in particular IgA and IgE, and the major histocompatibility complex in resistance to gastrointestinal parasites in sheep. We also draw evidence from other animal models to support the involvement of these immune components. Finally, we examine how IgA and IgE exert their influence and how methods may be developed to manage susceptible animals. PMID- 21584230 TI - Helminth Community Dynamics in Populations of Blue-Winged Teal (Anas discors) Using Two Distinct Migratory Corridors. AB - The influence of spatially distinct host subpopulations on helminth community structure and pattern was examined in a migratory avian host species. Forty helminth species represented by 24,082 individuals were collected from 184 blue winged teal (Anas discors; BWT) from 2 primary migratory corridors in Florida (eastern migratory corridor; EMC) and Louisiana and Texas (western migratory corridor; WMC). Mean species richness was greater in BWT from the WMC (x+/-SE = 10.2 +/- 0.3 species) than the EMC (8.6 +/- 0.2). The helminth community from the WMC had higher abundances of 6 common/intermediate species. Corridor helminth communities were similar in species composition but less similar when incorporating abundances of those species. Overlapping distributions of phylogenetically related host species that share generalist helminth species across ecologically similar habitats seem to mitigate the isolating mechanisms that are necessary for the distinct coevolutionary pathways to develop between adjacent corridors. PMID- 21584231 TI - Protective Effects of Luteolin on Diabetic Nephropathy in STZ-Induced Diabetic Rats. AB - Diabetic nephropathy is a long-term complication of diabetic mellitus. Many experimental evidences suggest that persistent hyperglycaemia generates intracellular reactive oxygen species (ROS) and upregulates transforming growth factor-b1 and extracellular matrix expression in mesangial and tubular epithelial cells, which is involved of free radicals in the pathogenesis of diabetes and more importantly in the development of diabetic complications. Antioxidants effectively inhibit high-glucose- and H2O2-induced transforming growth factor-b1 and fibronectin upregulation, thus providing evidence that ROS play an important role in high glucose-induced renal injury. The flavonoid luteolin has been shown to possess direct antioxidant activity, therefore we hypothesize that it may be useful in treatment of many chronic disease associated with oxidative stress, such as diabetic nephropathy via its antioxidant properties. Our results suggested that protection against development of diabetic nephropathy by luteolin treatment involved changes in superoxide dismutase (SOD) activity, the malondialdehyde (MDA) content and expression of Heme Oxygenase-1 (HO-1) protein. PMID- 21584232 TI - Meaning and practice of palliative care for hospitalized older adults with life limiting illnesses. AB - Objective. To illustrate distinctions and intersections of palliative care (PC) and end-of-life (EOL) services through examples from case-centered data of older adults cared for during a four-year ethnographic study of an acute care hospital palliative care consultation service. Methods. Qualitative narrative and thematic analysis. Results. Description of four practice paradigms (EOL transitions, prognostic uncertainty, discharge planning, and patient/family values and preferences) and identification of the underlying structure and communication patterns of PC consultation services common to them. Conclusions. Consistent with reports by other researchers, study data support the need to move beyond equating PC with hospice or EOL care and the notion that EOL is a well-demarcated period of time before death. If professional health care providers assume that PC services are limited to assisting with and helping patients and families prepare for dying, they miss opportunities to provide care considered important to older individuals confronting life-limiting illnesses. PMID- 21584233 TI - Trypanosoma congolense Infections: Induced Nitric Oxide Inhibits Parasite Growth In Vivo. AB - Wild-type (WT) C57BL/6 mice infected intraperitoneally with 5 * 10(6) Trypanosoma congolense survive for more than 30 days. C57BL/6 mice deficient in inducible nitric oxide synthase (iNOS(-/-)) and infected with 10(3) or 5 * 10(6) parasites do not control the parasitemia and survive for only 14 +/- 7 or 6.8 +/- 0.1 days, respectively. Bloodstream trypanosomes of iNOS(-/-) mice infected with 5 * 10(6)T. congolense had a significantly higher ratio of organisms in the S+G2+M phases of the cell cycle than trypanosomes in WT mice. We have reported that IgM anti-VSG-mediated phagocytosis of T. congolense by macrophages inhibits nitric oxide (NO) synthesis via CR3 (CD11b/CD18). Here, we show that during the first parasitemia, but not at later stages of infection, T. congolense-infected CD11b( /-) mice produce more NO and have a significantly lower parasitemia than infected WT mice. We conclude that induced NO contributes to the control of parasitemia by inhibiting the growth of the trypanosomes. PMID- 21584234 TI - A randomised controlled single-blind trial of the efficacy of reiki at benefitting mood and well-being. AB - This is a constructive replication of a previous trial conducted by Bowden et al. (2010), where students who had received Reiki demonstrated greater health and mood benefits than those who received no Reiki. The current study examined impact on anxiety/depression. 40 university students-half with high depression and/or anxiety and half with low depression and/or anxiety-were randomly assigned to receive Reiki or to a non-Reiki control group. Participants experienced six 30 minute sessions over a period of two to eight weeks, where they were blind to whether noncontact Reiki was administered as their attention was absorbed in a guided relaxation. The efficacy of the intervention was assessed pre-post intervention and at five-week follow-up by self-report measures of mood, illness symptoms, and sleep. The participants with high anxiety and/or depression who received Reiki showed a progressive improvement in overall mood, which was significantly better at five-week follow-up, while no change was seen in the controls. While the Reiki group did not demonstrate the comparatively greater reduction in symptoms of illness seen in our earlier study, the findings of both studies suggest that Reiki may benefit mood. PMID- 21584236 TI - Cattle bile aggravates diclofenac sodium-induced small intestinal injury in mice. AB - Cattle bile (CB) has long been used in Japan as an ingredient of digestive medicines. Bile acids are major chemical constituents of CB, and CB ingestion is assumed to affect small intestinal injury induced by nonsteroidal anti inflammatory drugs (NSAIDs). Mice were fed a diet supplemented with or without CB for 7 days and treated with diclofenac sodium (DIF) to induce small intestinal injury. Lesion formation was enhanced, and PGE2 content and COX expression levels were elevated in the small intestine of DIF-treated mice fed the CB diet compared with those fed the control diet. The administration of a reconstituted mixture of bile acids found in CB enhanced lesion formation in DIF-treated mice. CB administration elevated the contents of CB-derived bile acids in the small intestine, some of which exhibited a high cytotoxicity to cultured intestinal epithelial cells. These results suggest that the elevated levels of CB-derived cytotoxic bile acids in the small intestine contribute to the aggravation of DIF induced small intestinal injury. The use of CB may be limited during the therapy of inflammatory diseases with NSAIDs. PMID- 21584235 TI - The importance of mitochondrial DNA in aging and cancer. AB - Mitochondrial dysfunction has been implicated in premature aging, age-related diseases, and tumor initiation and progression. Alterations of the mitochondrial genome accumulate both in aging tissue and tumors. This paper describes our contemporary view of mechanisms by which alterations of the mitochondrial genome contributes to the development of age- and tumor-related pathological conditions. The mechanisms described encompass altered production of mitochondrial ROS, altered regulation of the nuclear epigenome, affected initiation of apoptosis, and a limiting effect on the production of ribonucleotides and deoxyribonucleotides. PMID- 21584237 TI - Effect of Water Flooding on the Oviposition Capacity of Engorged Adult Females and Hatchability of Eggs of Dog Ticks: Rhipicephalus sanguineus and Haemaphysalis leachi leachi. AB - Effects of water flooding on the oviposition capacity of engorged adult females and hatchability of eggs of Rhipicephalus sanguineus and Haemaphysalis leachi leachi under laboratory conditions were investigated. The durations of time of water flooding were 1, 2, 4, 6, 12, 24, 48, 72, 96, and 120 hours. Engorged females of R. sanguineus and H. leachi leachi did not oviposit after being flooded for more than 48 and 6 hours, respectively. The preoviposition periods of both species were longer than those of their controls. The number of eggs laid were significantly lower (P < .05) and higher (P < .05) than their controls, respectively, for R. sanguineus and H. leachi leachi flooded for 1-4 hours. The hatchability of eggs of both species decreased as flooding time increased. The percentage of hatchability was negatively correlated with flooding time and was highly significant (r = -0.97; P < .10). It is concluded that R. sanguineus tolerated simulated water flooding more than H. leachi leachi. PMID- 21584238 TI - The Impact of Physical Activity on Disability Incidence among Older Adults in Mexico and the United States. AB - Evidence suggests that transitions among older adults towards healthy habits, such as physical activity, appear underway in developed countries such as the USA but not in developing countries such as Mexico. However, little is known about the potential benefit of physical activity in preventing disability among elders in countries at different stages of epidemiological transition. We explore the impact of physical activity on the disablement process among elders in Mexico compared to the USA. Data are from two waves of the Mexican Health and Aging Study and the Health and Retirement Study. We examine the impact of exercise on the transition from no disability to ADL limitations two years later. Findings indicate that exercise is more common in the U.S. than in Mexico. There is a positive effect of exercise on negative outcomes in both countries. However, the protective effect of exercise is stronger in the U.S. than in Mexico. PMID- 21584239 TI - Selective Interactions of Valeriana officinalis Extracts and Valerenic Acid with [H]Glutamate Binding to Rat Synaptic Membranes. AB - Although GABA neurotransmission has been suggested as a mechanism for Valeriana officinalis effects, CNS depression can also be evoked by inhibition of ionotropic (iGluR) and metabotropic glutamate receptors (mGluR). In this study, we examined if aqueous valerian extract interacted with glutamatergic receptors. Freshly prepared aqueous valerian extract was incubated with rat cortical synaptic membranes in presence of 20 nM [(3)H]Glutamate. Aqueous valerian extract increased [(3)H]Glutamate binding from 1 * 10(-7) to 1 * 10(-3) mg/mL. In the presence of (2S,1'S,2'S)-2-(Carboxycyclopropyl)glycine (LCCG-I) and (2S,2'R,3'R) 2-(2',3'-Dicarboxycyclopropyl)glycine (DCG-IV), Group II mGluR agents, valerian extract markedly decreased [(3)H]Glutamate binding, while (2S)-2-amino-3-(3,5 dioxo-1,2,4-oxadiazolidin-2-yl) propanoic acid) (quisqualic acid, QA), Group I mGluR agonist, increased [(3)H]Glutamate binding. At 0.05 mg/mL aqueous valerian extract specifically interacted with kainic acid NMDA and AMPA receptors. Valerenic acid, a marker compound for Valeriana officinalis, increased the [(3)H]Glutamate binding after 1.6 * 10(-2) mg/mL, and at 0.008 mg/mL it interacted only with QA (Group I mGluR). The selective interactions of valerian extract and valerenic acid with Group I and Group II mGluR may represent an alternative explanation for the anxiolytic properties of this plant. PMID- 21584240 TI - Energetic Cost of Ichthyophonus Infection in Juvenile Pacific Herring (Clupea pallasii). AB - The energetic costs of fasting and Ichthyophonus infection were measured in juvenile Pacific herring (Clupea pallasii) in a lab setting at three temperatures. Infected herring incurred significant energetic costs, the magnitude of which depended on fish condition at the time of infection (fat versus lean). Herring that were fed continually and were in relatively good condition at the time of infection (fat) never stored lipid despite ad libitum feeding. In feeding herring, the energetic cost of infection was a 30% reduction in total energy content relative to controls 52 days post infection. Following food deprivation (lean condition), infection caused an initial delay in the compensatory response of herring. Thirty-one days after re-feeding, the energetic cost of infection in previously-fasted fish was a 32% reduction in total energy content relative to controls. Body composition of infected herring subsequently recovered to some degree, though infected herring never attained the same energy content as their continuously fed counterparts. Fifty-two days after re-feeding, the energetic cost of infection in previously-fasted fish was a 6% reduction in total energy content relative to controls. The greatest impacts of infection occurred in colder temperatures, suggesting Ichthyophonus-induced reductions in body condition may have greater consequences in the northern extent of herring's range, where juveniles use most of their energy reserves to survive their first winter. PMID- 21584241 TI - Cognitive stimulation for apathy in probable early-stage Alzheimer's. AB - We studied changes in apathy among 77 community-dwelling older persons with mild memory loss in a randomized clinical trial comparing two nonpharmacological interventions over four weeks. The study used a pre-post design with randomization by site to avoid contamination and diffusion of effect. Interventions were offered twice weekly after baseline evaluations were completed. The treatment group received classroom style mentally stimulating activities (MSAs) while the control group received a structured early-stage social support (SS) group. The results showed that the MSA group had significantly lower levels of apathy (P < .001) and significantly lower symptoms of depression (P < .001). While both groups improved on quality of life, the MSA group was significantly better (P = .02) than the SS group. Executive function was not significantly different for the two groups at four weeks, but general cognition improved for the MSA group and declined slightly for the SS group which produced a significant posttest difference (P < .001). Recruitment and retention of SS group members was difficult in this project, especially in senior center locations, while this was not the case for the MSA group. The examination of the data at this four-week time point shows promising results that the MSA intervention may provide a much needed method of reducing apathy and depressive symptoms, while motivating participation and increasing quality of life. PMID- 21584242 TI - The Antiinfective Effects of Velvet Antler of Formosan Sambar Deer (Cervus unicolor swinhoei) on Staphylococcus aureus-Infected Mice. AB - We assayed the effects of velvet antler (VA) of Formosan sambar deer (Cervus unicolor swinhoei) and its extracts on the anti-infective activity against pathogenic Staphylococcus aureus in vitro and in vivo in this study. In vitro data indicated that the VA extracts stimulated the proliferation of resting splenocytes and macrophages in a dose-dependent manner up to the highest concentration used (150 MUg mL(-1)). The production of proinflammatory cytokines (TNF-alpha, IL-6, IL-12) by lipoteichoic acid was significantly suppressed after being cocultured with the VA extracts in a dose-dependent manner. Animal test in S. aureus-infected mice demonstrated that the numbers of bacteria determined in the kidneys and peritoneal lavage fluid of S. aureus-infected mice were significantly higher than those found in the same organs of mice pretreated with the VA samples. Moreover, the highly enhanced phagocytic activity of macrophages was further verified after in vitro treatment with the VA samples. The protective mechanisms of the VA samples might include an immune enhancer and an inflammatory cytokine suppressor. PMID- 21584243 TI - Helminth parasites and the modulation of joint inflammation. AB - There is an urgent need to develop better therapeutics for autoimmune and autoinflammatory diseases, of which musculoskeletal disorders such as rheumatoid arthritis are particularly prevalent and debilitating. Helminth parasites are accomplished masters at modifying their hosts' immune activity, and so attention has focused on rodent-helminth model systems to uncover the workings of the mammalian immune response to metazoan parasites, with the hope of revealing molecules and/or mechanisms that can be translated into better treatments for human autoimmune and idiopathic disorders. Substantial proof-of-principal data supporting the concept that infection with helminth parasites can reduce the severity of concomitant disease has been amassed from models of mucosal inflammation. Indeed, infection with helminth parasites has been tried as a therapy in inflammatory bowel disease, and there are case reports relating to other conditions (e.g., autism); however, the impact of infection with parasitic helminths on musculoskeletal diseases has not been extensively studied. Here, we present the view that such a strategy should be applied to the amelioration of joint inflammation and review the literature that supports this contention. PMID- 21584244 TI - The effectiveness of exercise interventions for the management of frailty: a systematic review. AB - This systematic review examines the effectiveness of current exercise interventions for the management of frailty. Eight electronic databases were searched for randomized controlled trials that identified their participants as "frail" either in the title, abstract, and/or text and included exercise as an independent component of the intervention. Three of the 47 included studies utilized a validated definition of frailty to categorize participants. Emerging evidence suggests that exercise has a positive impact on some physical determinants and on all functional ability outcomes reported in this systematic review. Exercise programs that optimize the health of frail older adults seem to be different from those recommended for healthy older adults. There was a paucity of evidence to characterize the most beneficial exercise program for this population. However, multicomponent training interventions, of long duration (>=5 months), performed three times per week, for 30-45 minutes per session, generally had superior outcomes than other exercise programs. In conclusion, structured exercise training seems to have a positive impact on frail older adults and may be used for the management of frailty. PMID- 21584245 TI - The In Vivo Antidiabetic Activity of Nigella sativa Is Mediated through Activation of the AMPK Pathway and Increased Muscle Glut4 Content. AB - The antidiabetic effect of N. sativa seed ethanol extract (NSE) was assessed in Meriones shawi after development of diabetes. Meriones shawi were divided randomly into four groups: normal control, diabetic control, diabetic treated with NSE (2 g eq plant/kg) or with metformin (300 mg/kg) positive control, both administered by daily intragastric gavage for 4 weeks. Glycaemia and body weight were evaluated weekly. At study's end, an Oral Glucose Tolerance Test (OGTT) was performed to estimate insulin sensitivity. Upon sacrifice, plasma lipid profile, insulin, leptin, and adiponectin levels were assessed. ACC phosphorylation and Glut4 protein content were determined in liver and skeletal muscle. NSE animals showed a progressive normalization of glycaemia, albeit slower than that of metformin controls. Moreover, NSE increased insulinemia and HDL-cholesterol, compared to diabetic controls. Leptin and adiponectin were unchanged. NSE treatment decreased OGTT and tended to decrease liver and muscle triglyceride content. NSE stimulated muscle and liver ACC phosphorylation and increased muscle Glut4. These results confirm NSE's previously reported hypoglycaemic and hypolipidemic activity. More significantly, our data demonstrate that in vivo treatment with NSE exerts an insulin-sensitizing action by enhancing ACC phosphorylation, a major component of the insulin-independent AMPK signaling pathway, and by enhancing muscle Glut4 expression. PMID- 21584246 TI - Identification of potential calorie restriction-mimicking yeast mutants with increased mitochondrial respiratory chain and nitric oxide levels. AB - Calorie restriction (CR) induces a metabolic shift towards mitochondrial respiration; however, molecular mechanisms underlying CR remain unclear. Recent studies suggest that CR-induced mitochondrial activity is associated with nitric oxide (NO) production. To understand the role of mitochondria in CR, we identify and study Saccharomyces cerevisiae mutants with increased NO levels as potential CR mimics. Analysis of the top 17 mutants demonstrates a correlation between increased NO, mitochondrial respiration, and longevity. Interestingly, treating yeast with NO donors such as GSNO (S-nitrosoglutathione) is sufficient to partially mimic CR to extend lifespan. CR-increased NO is largely dependent on mitochondrial electron transport and cytochrome c oxidase (COX). Although COX normally produces NO under hypoxic conditions, CR-treated yeast cells are able to produce NO under normoxic conditions. Our results suggest that CR may derepress some hypoxic genes for mitochondrial proteins that function to promote the production of NO and the extension of lifespan. PMID- 21584247 TI - Zingiber zerumbet (L.) Smith: A Review of Its Ethnomedicinal, Chemical, and Pharmacological Uses. AB - Zingiber zerumbet Sm., locally known to the Malay as "Lempoyang," is a perennial herb found in many tropical countries, including Malaysia. The rhizomes of Z. zerumbet, particularly, have been regularly used as food flavouring and appetizer in various Malays' cuisines while the rhizomes extracts have been used in Malay traditional medicine to treat various types of ailments (e.g., inflammatory- and pain-mediated diseases, worm infestation and diarrhea). Research carried out using different in vitro and in vivo assays of biological evaluation support most of these claims. The active pharmacological component of Z. zerumbet rhizomes most widely studied is zerumbone. This paper presents the botany, traditional uses, chemistry, and pharmacology of this medicinal plant. PMID- 21584249 TI - Dejian mind-body intervention improves the cognitive functions of a child with autism. AB - There has been increasing empirical evidence for the enhancing effects of Dejian Mind-Body Intervention (DMBI), a traditional Chinese Shaolin healing approach, on human frontal brain activity/functions, including patients with autism who are well documented to have frontal lobe problems. This study aims to compare the effects of DMBI with a conventional behavioural/cognitive intervention (CI) on enhancing the executive functions and memory of a nine-year-old boy with low functioning autism (KY) and to explore possible underlying neural mechanism using EEG theta cordance. At post-one-month DMBI, KY's inhibitory control, cognitive flexibility, and memory functioning have significantly improved from "severely-to moderately impaired" to "within-normal" range. This improvement was not observed from previous 12-month CI. Furthermore, KY showed increased cordance gradually extending from the anterior to the posterior brain region, suggesting possible neural mechanism underlying his cognitive improvement. These findings have implicated potential applicability of DMBI as a rehabilitation program for patients with severe frontal lobe and/or memory disorders. PMID- 21584250 TI - Concurrent Validity of the Cognitive Assessment of Minnesota in Older Adults with and without Depressive Symptoms. AB - Cognitive impairment represents a common mental health problem in community dwelling and institutionalized older adults, and the prevalence increases with age. Multidisciplinary teams are often asked to assess cognitive and functional impairment in this population. The Cognitive Assessment of Minnesota was created by occupational therapists for this purpose and is frequently used, but has not been extensively validated. This study examined the performance of the CAM and compared it to the MMSE with 113 outpatient clinic patients over the age of 60. Subgroups were established based on scores on a depression inventory to determine if the presence of depressed mood altered the relationship between the measures. Both measures demonstrated good internal consistency. The overall correlation between the two measures was high, statistically significant and remained high regardless of depression status. We offer recommendations about the utility of each measure in screening cognitive functioning for older adults. PMID- 21584248 TI - Physical activity and hip fracture disability: a review. AB - Objective. The present paper examines pertinent literature sources published in the peer-reviewed English language between 1980 and November 1, 2010 concerning hip fractures. The aim was to highlight potential intervention points to offset the risk of incurring a hip fracture and its attendant disability. Methods. An in depth search of the literature using the key terms: disability, epidemiology, hip fracture, prevention, and risk factors was conducted, along with data from the author's research base detailing the disability associated with selected hip fracture cases. All articles that dealt with these key topics were reviewed, and relevant data were tabulated and analyzed. Results. Hip fractures remain an important but potentially preventable public health problem. Among the many related remediable risk factors, low physical activity levels are especially important. Related determinants of suboptimal neuromuscular function also contribute significantly to hip fracture disability. Conclusion. Physical activity participation can help to reduce the prevalence and excess disability of hip fractures and should be encouraged. PMID- 21584251 TI - Pilot scheme of health policy in stroke adjuvant acupuncture therapy for acute and subacute ischemic stroke in taiwan. AB - To reduce the health care burden of strokes, the Taiwan Department of Health launched the Pilot Scheme of the Health Policy in Stroke Adjuvant Acupuncture Therapy (HPSAAT) in 2006. This cross-sectional, hospital-based, match-controlled study at Chang Gung Memorial Hospital-Kaohsiung Medical Center during 2006~2008 retrospectively evaluated the clinical characteristics of acute and subacute ischemic stroke patients who electively joined the HPSAAT. The study also evaluated the safety and clinical benefits of adjuvant acupuncture in treating acute and subacute ischemic stroke patients. Twenty-six HPSAAT participants and 52 age-sex matched random controls were enrolled. The stroke baseline of the HPSAAT participants was more severe than the non-HPSAAT controls. Although the stroke severity closely correlates to mortality and comorbidity, this study noted no significant complications in the HPSAAT participants during the acupuncture treatment course. Adjuvant acupuncture was considered safe at the acute and subacute stages of ischemic stroke. Due to uneven baseline severity, the clinical benefits in reducing neurological deficits and functional recovery were not concluded in this study. PMID- 21584252 TI - Traditional chinese medicines in treatment of patients with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) occurs in 95% of the diabetic populations. Management of T2DM is a challenge. Traditional Chinese medicines (TCM) are usually served as adjuvants used to improve diabetic syndromes in combination of routine antidiabetic drugs. For single-herb prescriptions, Ginseng, Bitter melon, Golden Thread, Fenugreek, Garlic, and Cinnamon might have antidiabetic effects in T2DM patients. Among 30 antidiabetic formulas approved by the State Food and Drugs Administrator of China, top 10 of the most frequently prescribed herbs are Membranous Milkvetch Root, Rehmannia Root, Mongolian Snakegourd Root, Ginseng, Chinese Magnoliavine Fruit, Kudzuvine Root, Dwarf Lilyturf Tuber, Common Anemarrhena Rhizome, Barbary Wolfberry Fruit, and India Bread, which mainly guided by the theory of TCM. Their action mechanisms are related to improve insulin sensitivity, stimulate insulin secretion, protect pancreatic islets, and even inhibit intake of intestinal carbohydrates. However, it is very difficult to determine antihyperglycemic components of TCM. Nevertheless, TCM are becoming popular complementary and alternative medicine in treatment of syndromes of T2DM. In the future, it requires further validation of phytochemical, pharmacological, and clinical natures of TCM in T2DM in the future studies, especially for those herbs with a high prescription frequency. PMID- 21584253 TI - Clinical Evidence of the Efficacy of a Mouthwash Containing Propolis for the Control of Plaque and Gingivitis: A Phase II Study. AB - The aim of this study was to evidence the clinical efficacy of an alcohol-free mouthwash containing 5.0% (W/V) Brazilian green propolis (MGP 5%) for the control of plaque and gingivitis. Twenty five subjects, men and women aging between 18 and 60 years old (35 +/- 9), were included in a clinical trials phase II study who had a minimum of 20 sound natural teeth, a mean plaque index of at least 1.5 (PI), and a mean gingival index of at least 1.0 (GI). They were instructed to rinse with 10 mL of mouthwash test for 1 minute, immediately after brushing in the morning and at night. After 45 and 90 days using mouthwash, the results showed a significant reduction in plaque and in gingival index when compared to samples obtained in baseline. These reductions were at 24% and 40%, respectively (P < .5). There were no important side effects in soft and hard tissues of the mouth. In this study, the MGP 5% showed evidence of its efficacy in reducing PI and GI. However, it is necessary to perform a clinical trial, double-blind, randomized to validate such effectiveness. PMID- 21584254 TI - Flourensia cernua: Hexane Extracts a Very Active Mycobactericidal Fraction from an Inactive Leaf Decoction against Pansensitive and Panresistant Mycobacterium tuberculosis. AB - The efficacy of decoction in extracting mycobactericidal compounds from Flourensia cernua (Hojase) leaves and fractionation with solvents having ascending polarity was compared with that of (i) ethanol extraction by still maceration, extraction with a Soxhlet device, shake-assisted maceration, or ultrasound-assisted maceration, followed by fractionation with n-hexane, ethyl acetate, and n-butanol; (ii) sequential extraction with n-hexane, ethyl acetate, and n-butanol, by still maceration, using a Soxhlet device, shake-assisted maceration, or ultrasound-assisted maceration. The in vitro mycobactericidal activity of each preparation was measured against drug-sensitive (SMtb) and drug resistant (RMtb) Mycobacterium tuberculosis strains. The results of which were expressed as absolute mycobactericidal activity (AMA). These data were normalized to the SigmaAMA of the decoction fraction set. Although decoction was inactive, the anti-RMtb normalized SigmaAMA (NAMA) of its fractions was comparable with the anti-RMtb NAMA of the still maceration extracts and significantly higher than the anti-SMtb and anti-RMtb NAMAs of every other ethanol extract and serial extract and fraction. Hexane extracted, from decoction, material having 55.17% and 92.62% of antituberculosis activity against SMtb and RMtb, respectively. Although the mycobactericidal activity of decoction is undetectable; its efficacy in extracting F. cernua active metabolites against M. tuberculosis is substantially greater than almost all pharmacognostic methods. PMID- 21584255 TI - Formulated Beta-Cyfluthrin Shows Wide Divergence in Toxicity among Bird Species. AB - It is generally assumed that the toxicity of pyrethroid insecticides to birds is negligible, though few species have been tested. The oral acute toxicity of formulated beta-cyfluthrin was determined for canaries (Serinus sp.), shiny cowbirds (Molothrus bonariensis), and eared doves (Zenaida auriculata). Single doses were administered to adults by gavage. Approximate lethal doses 50 (LD(50)) and their confidence intervals were determined by approximate D-optimal design. Canaries were found to be substantially more sensitive to formulated beta cyfluthrin (LD(50) = (170 +/- 41) mg/kg) than the other two species tested (LD(50) = (2234 +/- 544) mg/kg and LD(50) = (2271 +/- 433) mg/kg, resp.). The LD(50) obtained for canaries was also considerably lower than typical toxicity values available in the literature for pyrethroids. This study emphasizes the need for testing a broader range of species with potentially toxic insecticides, using modern up and down test designs with minimal numbers of birds. PMID- 21584256 TI - Brainstorm: a user-friendly application for MEG/EEG analysis. AB - Brainstorm is a collaborative open-source application dedicated to magnetoencephalography (MEG) and electroencephalography (EEG) data visualization and processing, with an emphasis on cortical source estimation techniques and their integration with anatomical magnetic resonance imaging (MRI) data. The primary objective of the software is to connect MEG/EEG neuroscience investigators with both the best-established and cutting-edge methods through a simple and intuitive graphical user interface (GUI). PMID- 21584257 TI - Slowing and Loss of Complexity in Alzheimer's EEG: Two Sides of the Same Coin? AB - Medical studies have shown that EEG of Alzheimer's disease (AD) patients is "slower" (i.e., contains more low-frequency power) and is less complex compared to age-matched healthy subjects. The relation between those two phenomena has not yet been studied, and they are often silently assumed to be independent. In this paper, it is shown that both phenomena are strongly related. Strong correlation between slowing and loss of complexity is observed in two independent EEG datasets: (1) EEG of predementia patients (a.k.a. Mild Cognitive Impairment; MCI) and control subjects; (2) EEG of mild AD patients and control subjects. The two data sets are from different patients, different hospitals and obtained through different recording systems. The paper also investigates the potential of EEG slowing and loss of EEG complexity as indicators of AD onset. In particular, relative power and complexity measures are used as features to classify the MCI and MiAD patients versus age-matched control subjects. When combined with two synchrony measures (Granger causality and stochastic event synchrony), classification rates of 83% (MCI) and 98% (MiAD) are obtained. By including the compression ratios as features, slightly better classification rates are obtained than with relative power and synchrony measures alone. PMID- 21584258 TI - Protective Effects of Liposomal N-Acetylcysteine against Paraquat-Induced Cytotoxicity and Gene Expression. AB - Paraquat (PQ) is a herbicide that preferentially accumulates in the lung and exerts its cytotoxicity via the generation of reactive oxygen species (ROS). There is no specific treatment for paraquat poisoning. Attempts have been made to increase the antioxidant status in the lung using antioxidants (e.g., superoxide dismutase, vitamin E, N-acetylcysteine) but the outcome from such treatments is limited. Encapsulation of antioxidants in liposomes improves their therapeutic potential against oxidant-induced lung damage because liposomes facilitate intracellular delivery and prolong the retention of entrapped agents inside the cell. In the present study, we compared the effectiveness of conventional N acetylcysteine (NAC) and liposomal-NAC (L-NAC) against PQ-induced cytotoxicity and examined the mechanism(s) by which these antioxidant formulations conferred cytoprotection. The effects of NAC or L-NAC against PQ-induced cytotoxicity in A549 cells were assessed by measuring cellular PQ uptake, intracellular glutathione content, ROS levels, mitochondrial membrane potential, cellular gene expression, inflammatory cytokine release and cell viability. Pretreatment of cells with L-NAC was significantly more effective than pretreatment with the conventional drug in reducing PQ-induced cytotoxicity, as indicated by the biomarkers used in this study. Our results suggested that the delivery of NAC as a liposomal formulation improves its effectiveness in counteracting PQ-induced cytotoxicity. PMID- 21584259 TI - Contrast sensitivity after zyoptix tissue saving LASIK and standard LASIK for myopia with 6-month followup. AB - This control-matched comparative study evaluated changes in contrast sensitivity after Zyoptix tissue-saving (TS) LASIK and Planoscan standard LASIK (Technolas 217z, Bausch & Lomb) for myopia 6 months postoperatively. 102 TS LASIK-treated eyes were matched with 102 standard LASIK-treated eyes (divided into low, moderate, and high groups). There were no significant differences in refraction outcomes between the groups postoperatively. In high group, a significant reduction in contrast sensitivity after TS LASIK was found at high spatial frequencies (P < .05) under photopic conditions and at middle to high spatial frequencies (P < .05) under mesopic conditions. And significant reduction was also found in standard LASIK at high spatial frequency (P < .05) under mesopic conditions. The reduction was significantly lower in TS LASIK than that in standard LASIK at high spatial frequencies (P < .05) under mesopic conditions. TS LASIK was prone to reduce mesopic contrast sensitivity of high myopia at high spatial frequencies. PMID- 21584260 TI - Intravitreal Bevacizumab (Avastin) for Diabetic Retinopathy: The 2010 GLADAOF Lecture. AB - This paper demonstrates multiple benefits of intravitreal bevacizumab (IVB) on diabetic retinopathy (DR) including diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) at 24 months of followup. This is a retrospective multicenter interventional comparative case series of intravitreal injections of 1.25 or 2.5 mg of bevacizumab for DME, PDR without tractional retinal detachment (TRD), and patients who experienced the development or progression of TRD after an intravitreal injection of 1.25 or 2.5 mg of bevacizumab before vitrectomy for the management of PDR. The results indicate that IVB injections may have a beneficial effect on macular thickness and visual acuity (VA) in diffuse DME. Therefore, in the future this new therapy could complement focal/grid laser photocoagulation in DME. In PDR, this new option could be an adjuvant agent to panretina photocoagulation so that more selective therapy may be applied. Finally, TRD in PDR may occur or progress after IVB used as an adjuvant to vitrectomy. Surgery should be performed 4 days after IVB. Most patients had poorly controlled diabetes mellitus associated with elevated HbA1c, insulin administration, PDR refractory to panretinal photocoagulation, and longer time between IVB and vitrectomy. PMID- 21584261 TI - The domestic cat as a large animal model for characterization of disease and therapeutic intervention in hereditary retinal blindness. AB - Large mammals, including canids and felids, are affected by spontaneously occurring hereditary retinal diseases with similarities to those of humans. The large mammal models may be used for thorough clinical characterization of disease processes, understanding the effects of specific mutations, elucidation of disease mechanisms, and for development of therapeutic intervention. Two well characterized feline models are addressed in this paper. The first model is the autosomal recessive, slowly progressive, late-onset, rod-cone degenerative disease caused by a mutation in the CEP290 gene. The second model addressed in this paper is the autosomal dominant early onset rod cone dysplasia, putatively caused by the mutation found in the CRX gene. Therapeutic trials have been performed mainly in the former type including stem cell therapy, retinal transplantation, and development of ocular prosthetics. Domestic cats, having large human-like eyes with comparable spontaneous retinal diseases, are also considered useful for gene replacement therapy, thus functioning as effective model systems for further research. PMID- 21584263 TI - A jackknife and voting classifier approach to feature selection and classification. AB - With technological advances now allowing measurement of thousands of genes, proteins and metabolites, researchers are using this information to develop diagnostic and prognostic tests and discern the biological pathways underlying diseases. Often, an investigator's objective is to develop a classification rule to predict group membership of unknown samples based on a small set of features and that could ultimately be used in a clinical setting. While common classification methods such as random forest and support vector machines are effective at separating groups, they do not directly translate into a clinically applicable classification rule based on a small number of features.We present a simple feature selection and classification method for biomarker detection that is intuitively understandable and can be directly extended for application to a clinical setting. We first use a jackknife procedure to identify important features and then, for classification, we use voting classifiers which are simple and easy to implement. We compared our method to random forest and support vector machines using three benchmark cancer 'omics datasets with different characteristics. We found our jackknife procedure and voting classifier to perform comparably to these two methods in terms of accuracy. Further, the jackknife procedure yielded stable feature sets. Voting classifiers in combination with a robust feature selection method such as our jackknife procedure offer an effective, simple and intuitive approach to feature selection and classification with a clear extension to clinical applications. PMID- 21584264 TI - A comparison of methods for data-driven cancer outlier discovery, and an application scheme to semisupervised predictive biomarker discovery. AB - A core component in translational cancer research is biomarker discovery using gene expression profiling for clinical tumors. This is often based on cell line experiments; one population is sampled for inference in another. We disclose a semisupervised workflow focusing on binary (switch-like, bimodal) informative genes that are likely cancer relevant, to mitigate this non-statistical problem. Outlier detection is a key enabling technology of the workflow, and aids in identifying the focus genes.We compare outlier detection techniques MOST, LSOSS, COPA, ORT, OS, and t-test, using a publicly available NSCLC dataset. Removing genes with Gaussian distribution is computationally efficient and matches MOST particularly well, while also COPA and OS pick prognostically relevant genes in their top ranks. Also our stability assessment is in favour of both MOST and COPA; the latter does not pair well with prefiltering for non-Gaussianity, but can handle data sets lacking non-cancer cases.We provide R code for replicating our approach or extending it. PMID- 21584262 TI - Dendritic spines and development: towards a unifying model of spinogenesis--a present day review of Cajal's histological slides and drawings. AB - Dendritic spines receive the majority of excitatory connections in the central nervous system, and, thus, they are key structures in the regulation of neural activity. Hence, the cellular and molecular mechanisms underlying their generation and plasticity, both during development and in adulthood, are a matter of fundamental and practical interest. Indeed, a better understanding of these mechanisms should provide clues to the development of novel clinical therapies. Here, we present original results obtained from high-quality images of Cajal's histological preparations, stored at the Cajal Museum (Instituto Cajal, CSIC), obtained using extended focus imaging, three-dimensional reconstruction, and rendering. Based on the data available in the literature regarding the formation of dendritic spines during development and our results, we propose a unifying model for dendritic spine development. PMID- 21584265 TI - Bioinformatic prediction of ultraviolet light mutagenesis sensitivity of human genes and a method for genetically engineering UVB resistance. AB - Living on earth, we are exposed to ultraviolet (UV) light as part of the solar radiation. UVB spectrum light exposure contributes to the development of skin cancer by interacting with pyrimidine pairs to create lesions called cyclobutane pyrimidine dimers. If these lesions are not removed by nucleotide excision repair, they often give rise to C to T transition mutations. Based on these observations, a bioinformatics approach was used to predict the vulnerability of human protein coding genes to UVB induced loss of function mutations. This data was used to evaluate in depth those genes associated with malignant melanoma. In addition, we demonstrate a method of genetically engineering genes that significantly improves resistance to UVB loss of function mutations. PMID- 21584266 TI - Associating GWAS Information with the Notch Signaling Pathway Using Transcription Profiling. AB - Genome-wide association studies (GWAS) have identified SNPs associated with breast cancer. However, they offer limited insights about the biological mechanisms by which SNPs confer risk. We investigated the association of GWAS information with a major oncogenic pathway in breast cancer, the Notch signaling pathway. We first identified 385 SNPs and 150 genes associated with risk for breast cancer by mining data from 41 GWAS. We then investigated their expression, along with 32 genes involved in the Notch signaling pathway using two publicly available gene expression data sets from the Caucasian (42 cases and 143 controls) and Asian (43 cases and 43 controls) populations. Pathway prediction and network modeling confirmed that Notch receptors and genes involved in the Notch signaling pathway interact with genes containing SNPs associated with risk for breast cancer. Additionally, we identified other SNP-associated biological pathways relevant to breast cancer, including the P53, apoptosis and MAP kinase pathways. PMID- 21584267 TI - Antiatherosclerotic Potential of Active Principle Isolated from Eugenia jambolana in Streptozotocin-Induced Diabetic Rats. AB - The aim of the present study was to investigate the antiatherosclerotic effect of active principle (FIIc) isolated from aqueous fruit pulp extract of Eugenia jambolana. Crude aqueous extract of E. jambolana was subjected to purification using chromatographic techniques which yielded purified active compound (FIIc). Purity of FIIc was tested by HPLC. Phytochemical investigation of FIIc by NMR, IR, and UV spectra showed that the purified compound is alpha-hydroxy succinamic acid. The streptozotocin- (STZ-) induced diabetic rats were fed atherosclerotic (Ath) diet containing 1.5 mL olive oil containing 8 mg (3, 20,000 IU) vitamin D(2) and 40 mg cholesterol for 5 consecutive days. The STZ-induced diabetic rats receiving Ath diet were orally administered FIIc at doses of 10, 15, and 20 mg/kg, and results were compared with reference drug, that is, glibenclamide (600 MUg/mg) and healthy control. 30-day treatment with FIIc resulted in significant (P < .001) improvement in blood glucose, serum lipid profile, apolipoproteins (Apo A(1) and apoB(100)), and endothelial dysfunction parameters. Histomorphological studies also confirmed biochemical findings. Our results showed that FIIc has protective effect on hyperglycemia-induced atherosclerosis. PMID- 21584268 TI - Immunohistochemical Evaluation of p63, E-Cadherin, Collagen I and III Expression in Lower Limb Wound Healing under Honey. AB - Honey is recognized traditionally for its medicinal properties and also appreciated as a topical healing agent for infected and noninfected wounds. This study evaluates impact of honey-based occlusive dressing on nonhealing (nonresponding to conventional antibiotics) traumatic lower limb wounds (n = 34) through clinicopathological and immunohistochemical (e.g., expression of p63, E cadherin, and Collagen I and III) evaluations to enrich the scientific validation. Clinical findings noted the nonadherence of honey dressing with remarkable chemical debridement and healing progression within 11-15 days of postintervention. Histopathologically, in comparison to preintervention biopsies, the postintervention tissues of wound peripheries demonstrated gradual normalization of epithelial and connective tissue features with significant changes in p63(+) epithelial cell population, reappearance of membranous E cadherin (P < .0001), and optimum deposition of collagen I and III (P < .0001). Thus, the present study for the first time reports the impact of honey on vital protein expressions in epithelial and connective tissues during repair of nonhealing lower limb wounds. PMID- 21584269 TI - Effect of the Japanese herbal kampo medicine dai-kenchu-to on postoperative adhesive small bowel obstruction requiring long-tube decompression: a propensity score analysis. AB - Adhesive small bowel obstruction (ASBO) is an adverse consequence of abdominal surgery. Although the Kampo medicine Dai-kenchu-to is widely used in Japan for treatment of postoperative ASBO, rigorous clinical studies for its use have not been performed. In the present retrospective observational study using the Japanese diagnosis procedure combination inpatient database, we selected 288 propensity-score-matched patients with early postoperative ASBO following colorectal cancer surgery, who received long-tube decompression (LTD) with or without Dai-kenchu-to administration. The success rates of LTD were not significantly different between Dai-kenchu-to users and nonusers (84.7% versus 78.5%; P = .224), while Dai-kenchu-to users showed a shorter duration of LTD (8 versus 10 days; P = .012), shorter duration between long-tube insertion and discharge (23 versus 25 days; P = .018), and lower hospital charges ($23,086 versus $26,950; P = .018) compared with Dai-kenchu-to nonusers. In conclusion, the present study suggests that Dai-kenchu-to is effective for reducing the duration of LTD and saving costs. PMID- 21584270 TI - Production of Active Nonglycosylated Recombinant B-Chain of Type-2 Ribosome Inactivating Protein from Viscum articulatum and Its Biological Effects on Peripheral Blood Mononuclear Cells. AB - Type-2 ribosome-inactivating proteins, composed of a toxic A-chain and lectin like B-chain, display various biological functions, including cytotoxicity and immunomodulation. We here cloned the lectin-like B-chain encoding fragment of a newly identified type-2 RIP gene, articulatin gene, from Viscum articulatum, into a bacterial expression vector to obtain nonglycosylated recombinant protein expressed in inclusion bodies. After purification and protein refolding, soluble refolded recombinant articulatin B-chain (rATB) showed lectin activity specific toward galactoside moiety and was stably maintained while stored in low ionic strength solution. Despite lacking glycosylation, rATB actively bound leukocytes with preferential binding to monocytes and in vitro stimulated PBMCs to release cytokines without obvious cytotoxicity. These results implicated such a B-chain fragment as a potential immunomodulator. PMID- 21584271 TI - Editorial: current concepts in arthroplasty. PMID- 21584272 TI - Diagnosis and management of infected total knee arthroplasty. AB - Infection following total knee arthroplasty can be difficult to diagnose and treat. Diagnosis is multifactorial and relies on the clinical picture, radiographs, bone scans, serologic tests, synovial fluid examination, intra operative culture and histology. Newer techniques including ultrasonication and molecular diagnostic studies are playing an expanded role. Two-stage exchange arthroplasty with antibiotic cement and 4-6 weeks of intravenous antibiotic treatment remains the most successful intervention for infection eradication. There is no consensus on the optimum type of interval antibiotic cement spacer. There is a limited role for irrigation and debridement, direct one-stage exchange, chronic antibiotic suppression and salvage procedures like arthrodesis and amputation. We examine the literature on each of the diagnostic modalities and treatment options in brief and explain their current significance. PMID- 21584273 TI - Flow-injection preconcentration of chloramphenicol using molecularly imprinted polymer for HPLC determination in environmental samples. AB - The residue of antibiotic chloramphenicol (CAP) is important issue for food quality control and also for the environmental monitoring. It is banned for use in food-producing animals and has very limited use in human medicine, because of its severe impact on human health. Determination of trace level of CAP in environmental samples requires a very sensitive analytical method and efficient preconcentration procedure. CAP can be efficiently preconcentrated in flow injection system using flow-through reactor packed with molecularly imprinted polymer (MIP), but determination of CAP in eluate from MIP requires the application of chromatographic separation, which was made in reversed-phase HPLC system with UV detection. In optimized conditions the limit of detection for 100 mL sample in HPLC with offline preconcentration on MIP was evaluated as 0.66 mg/L. In hyphenated FIA-HPLC system with zone sampling the LOD for developed method was evaluated as 15 ng/L, which indicates the possibility of using it for analysis of environmental samples. PMID- 21584274 TI - mRNA/microRNA Profile at the Metamorphic Stage of Olive Flounder (Paralichthys olivaceus). AB - Flatfish is famous for the asymmetric transformation during metamorphosis. The molecular mechanism behind the asymmetric development has been speculated over a century and is still not well understood. To date, none of the metamorphosis related genes has been identified in flatfish. As the first step to screen metamorphosis-related gene, we constructed a whole-body cDNA library and a whole body miRNA library in this study and identified 1051 unique ESTs, 23 unique miRNAs, and 4 snoRNAs in premetamorphosing and prometamorphosing Paralichthys olivaceus. 1005 of the ESTs were novel, suggesting that there was a special gene expression profile at metamorphic stage. Four miRNAs (pol-miR-20c, pol-miR-23c, pol-miR-130d, and pol-miR-181e) were novel to P. olivaceus; they were characterized as highly preserved homologies of published miRNAs but with at least one nucleotide differed. Representative 24 mRNAs and 23 miRNAs were quantified during metamorphosis of P. olivaceus by using quantitative RT PCR or stem-loop qRT PCR. Our results showed that 20 of mRNAs might be associated with early metamorphic events, 10 of mRNAs might be related with later metamorphic events, and 16 of miRNAs might be involved in the regulation of metamorphosis. The data provided in this study would be helpful for further identifying metamorphosis-related gene in P. olivaceus. PMID- 21584275 TI - Association of low-risk human papillomavirus infection with male circumcision in young men: results from a longitudinal study conducted in Orange Farm (South Africa). AB - BACKGROUND: Low-Risk Human Papillomavirus (LR-HPV) genotypes 6 and 11 cause genital warts. This study investigated the association of LR-HPV infection with male circumcision (MC). METHODS: We used data from the South African MC trial conducted among young men. Urethral swabs, collected among intervention (circumcised) and control (uncircumcised) groups, were analyzed using HPV linear array. Adjusted LR-HPV prevalence rate ratio (aPPR) and Poisson mean ratio (aPMR) of number of LR-HPV genotypes were estimated using log-Poisson regression, controlling for background characteristics, sexual behaviour, and HIV and HSV-2 statuses. RESULTS: Compared to controls, LR-HPV prevalence and mean number of genotypes were significantly lower among the intervention group ((8.5% versus 15.8%; aPRR: 0.54, P < .001) and (0.33 versus 0.18; aPMR: 0.54, P < .001), resp.). Mean number of LR-HPV genotypes increased with number of lifetime sexual partners and decreased with education level and consistent condom use. CONCLUSIONS: This study shows a reduction in LR-HPV infection among circumcised men. PMID- 21584277 TI - Epidemiology of knee and hip arthroplasty: a systematic review. AB - We present a systematic review of epidemiologic studies of Total Knee Arthroplasty (TKA) and Total Hip Arthroplasty (THA). The studies summarized in this systematic review provide us with estimates of arthroplasty utilization rates, underlying disease frequency and its trends and differences in utilization rates by age, gender and ethnicity among other factors. Among these, many studies are registry-based that assessed utilization rates using data from major orthopedic centers that may provide some understanding of underlying diagnosis and possibly time-trends. Several studies are population-based cross-sectional, which provide estimates of prevalence of TKA and THA. Population-based cohort studies included in this review provide the best estimates of incidence and utilization rates, time-trends and differences in these rates by important patient characteristics (age, gender, ethnicity and others). This article reviews the current published literature in the area and highlights the main findings. PMID- 21584276 TI - Glucagon-like peptide-1 receptor agonists and cardiovascular events: a meta analysis of randomized clinical trials. AB - OBJECTIVE: Data from randomized clinical trials with metabolic outcomes can be used to address concerns about potential issues of cardiovascular safety for newer drugs for type 2 diabetes. This meta-analysis was designed to assess cardiovascular safety of GLP-1 receptor agonists. DESIGN AND METHODS: MEDLINE, Embase, and Cochrane databases were searched for randomized trials of GLP-1 receptor agonists (versus placebo or other comparators) with a duration >=12 weeks, performed in type 2 diabetic patients. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for major cardiovascular events (MACE), on an intention-to-treat basis, excluding trials with zero events. RESULTS: Out of 36 trials, 20 reported at least one MACE. The MH-OR for all GLP-1 receptor agonists was 0.74 (0.50-1.08), P = .12 (0.85 (0.50-1.45), P = .55, and 0.69 (0.40-1.22), P = .20, for exenatide and liraglutide, resp.). Corresponding figures for placebo-controlled and active comparator studies were 0.46 (0.25 0.83), P = .009, and 1.05 (0.63-1.76), P = .84, respectively. CONCLUSIONS: To date, results of randomized trials do not suggest any detrimental effect of GLP-1 receptor agonists on cardiovascular events. Specifically designed longer-term trials are needed to verify the possibility of a beneficial effect. PMID- 21584278 TI - Phase I Clinical Study of the Dietary Supplement, Agaricus blazei Murill, in Cancer Patients in Remission. AB - Although many cancer patients use complementary and alternative medicine, including Agaricus blazei Murill (ABM), safety is not yet well understood. Cancer survivors took 1.8, 3.6, or 5.4 g ABM granulated powder (Kyowa Wellness Co., Ltd., Tokyo, Japan) per day orally for 6 months. Adverse events were defined by subjective/objective symptoms and laboratory data according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Seventy-eight patients were assessed for safety of ABM (30/24/24 subjects at 1/2/3 packs per day, resp.). Adverse events were observed in 9 patients (12%). Most were digestive in nature such as nausea and diarrhea, and one patient developed a liver dysfunction-related food allergy, drug lymphocyte product. However, none of these adverse events occurred in a dose-dependent manner. This study shows that ABM does not cause problems in most patients within laboratory parameters at the dosages tested over 6 months. This trial supports previous evidence that the ABM product is generally safe, excluding possible allergic reaction. PMID- 21584280 TI - Rapid and automated analytical methods for redox species based on potentiometric flow injection analysis using potential buffers. AB - Two analytical methods, which prove the utility of a potentiometric flow injection technique for determining various redox species, based on the use of some redox potential buffers, are reviewed. The first is a potentiometric flow injection method in which a redox couple such as Fe(III)-Fe(II), Fe(CN)(6) (3-) Fe(CN)(CN)(6) (4-), and bromide-bromine and a redox electrode or a combined platinum-bromide ion selective electrode are used. The analytical principle and advantages of the method are discussed, and several examples of its application are reported. Another example is a highly sensitive potentiometric flow injection method, in which a large transient potential change due to bromine or chlorine as an intermediate, generated during the reaction of the oxidative species with an Fe(III)-Fe(II) potential buffer containing bromide or chloride, is utilized. The analytical principle and details of the proposed method are described, and examples of several applications are described. The determination of trace amounts of hydrazine, based on the detection of a transient change in potential caused by the reaction with a Ce(IV)-Ce(III) potential buffer, is also described. PMID- 21584279 TI - Computational approaches in metabolic engineering. PMID- 21584281 TI - Effect of tumor necrosis factor-alpha on neutralization of ventricular fibrillation in rats with acute myocardial infarction. AB - The purpose of this study was to explore the effects of tumor necrosis factor alpha (TNF-alpha) on ventricular fibrillation (VF) in rats with acute myocardial infarction (AMI). Rats were randomly classified into AMI group, sham operation group and recombinant human tumor necrosis factor receptor:Fc fusion protein (rhTNFR:Fc) group. Spontaneous and induced VFs were recorded. Monophasic action potentials (MAPs) among different zones of myocardium were recorded at eight time points before and after ligation and MAP duration dispersions (MAPDds) were calculated. Then expression of TNF-alpha among different myocardial zones was detected. After ligation of the left anterior descending coronary artery, total TNF-alpha expression in AMI group began to markedly increase at 10 min, reached a climax at 20-30 min, and then gradually decreased. The time-windows of VFs and MAPDds in the border zone performed in a similar way. At the same time-point, the expression of TNF-alpha in the ischemia zone was greater than that in the border zone, and little in the non-ischemia zone. Although the time windows of TNF-alpha expression, the MAPDds in the border zone and the occurrence of VFs in the rhTNFR:Fc group were similar to those in the AMI group, they all decreased in the rhTNFR:Fc group. Our findings demonstrate that TNF-alpha could enlarge the MAPDds in the border zone, and promote the onset of VFs. PMID- 21584282 TI - The rs1014290 polymorphism of the SLC2A9 gene is associated with type 2 diabetes mellitus in Han Chinese. AB - AIMS: The SLC2A9 gene encodes the glucose transporter 9, with the abilities of transporting both glucose and uric acid and is involved in the pancreatic glucose stimulated insulin secretion. The single nucleotide polymorphisms (SNPs) of SLC2A9 accounted for 5% variance of serum uric acid (UA). UA was identified as a risk factor for type 2 diabetes mellitus (DM). We investigated whether the SLC2A9 gene variations are associated with type 2 DM in Han Chinese. METHODS: Three common SNPs of the SLC2A9, rs1014290, rs2280205, and rs3733591, were genotyped in 1003 Han Chinese randomly selected from Kaohsiung, Taiwan. RESULTS: The variant SNP rs1014290 is associated with decreased 0.12-fold risk of type 2 DM (P = .002). Per-copy increase in the minor C-allele results in 0.13 mmol/L (P = .037) and 10.03 MUmol/L (P = .016) decrease in serum glucose and UA, respectively. CONCLUSIONS: The SNP rs1014290 within the SLC2A9 gene is associated with type 2 DM in Han Chinese. PMID- 21584283 TI - Review of evidence suggesting that the fascia network could be the anatomical basis for acupoints and meridians in the human body. AB - The anatomical basis for the concept of meridians in traditional Chinese medicine (TCM) has not been resolved. This paper reviews the evidence supporting a relationship between acupuncture points/meridians and fascia. The reviewed evidence supports the view that the human body's fascia network may be the physical substrate represented by the meridians of TCM. Specifically, this hypothesis is supported by anatomical observations of body scan data demonstrating that the fascia network resembles the theoretical meridian system in salient ways, as well as physiological, histological, and clinical observations. This view represents a theoretical basis and means for applying modern biomedical research to examining TCM principles and therapies, and it favors a holistic approach to diagnosis and treatment. PMID- 21584285 TI - Zinc-binding proteins from boar seminal plasma -- isolation, biochemical characteristics and influence on spermatozoa stored at 4 degrees C. AB - Affinity chromatography on Chelating Sepharose Fast Flow Gel-Zn(2+) was used for fractionation of boar seminal plasma proteins. Approximately 30% of total boar seminal plasma proteins showed affinity for zinc ions (ZnBP fraction). Native electrophoresis (PAGE) of ZnBP revealed six protein fractions which separated into 27 bands under denaturing conditions (SDS/PAGE). Two-dimensional electrophoresis (2D PAGE) showed 148 polypeptides with isoelectric points mostly in the basic and neutral pH range. The zinc-binding proteins comprise mainly 10 20 kDa polypeptides which are probably members of the spermadhesin family. ZnBP present in the incubation mixture of spermatozoa stored for 1 or 24 h at 4 degrees C allowed preservation of a higher percentage of cells exhibiting linear motility in comparison to a control sample stored in PBS. Presented results indicate that proteins binding Zn(2+) ions have a shielding effect on the sperm plasma membrane and acrosome of spermatozoa, protecting these structures against consequences of cold shock. PMID- 21584284 TI - Investigation of a potential scintigraphic tracer for imaging apoptosis: radioiodinated annexin V-Kunitz protease inhibitor fusion protein. AB - Radiolabeled annexin V (ANV) has been widely used for imaging cell apoptosis. Recently, a novel ANV-Kunitz-type protease inhibitor fusion protein, ANV-6L15, was found to be a promising probe for improved apoptosis detection based on its higher affinity to phosphatidylserine (PS) compared to native ANV. The present paper investigates the feasibility of apoptosis detection using radioiodinated ANV-6L15. Native ANV and ANV-6L15 were labeled with iodine-123 and iodine-125 using Iodogen method. The binding between the radioiodinated proteins and erythrocyte ghosts or chemical-induced apoptotic cells was examined. ANV-6L15 can be radioiodinated with high yield (40%-60%) and excellent radiochemical purity (>95%). (123)I-ANV-6L15 exhibited a higher binding ratio to erythrocyte ghosts and apoptotic cells compared to (123)I-ANV. The biodistribution of (123)I-ANV 6L15 in mice was also characterized. (123)I-ANV-6L15 was rapidly cleared from the blood. High uptake in the liver and the kidneys may limit the evaluation of apoptosis in abdominal regions. Our data suggest that radiolabeled ANV-6L15 may be a better scintigraphic tracer than native ANV for apoptosis detection. PMID- 21584286 TI - Altered oxidative stress levels in Indian Parkinson's disease patients with PARK2 mutations. AB - The aim of this pilot study was to determine the baseline state of oxidative stress indices in patients with Parkinson's disease (PD). Peripheral blood samples of 15 PD subjects were analyzed and compared with ten age matched healthy controls. Patients with PARK2 mutations were also compared with PD patients without mutations. There was significant increase in malondialdehyde content and superoxide-dismutase (SOD) activity in peripheral blood parameters in PD patients (p < 0.05) in comparison to controls. These findings suggest an important role of oxidative stress in Parkinson's disease evolution and progress. No changes were observed in glutathione peroxidase and nitric oxide levels. We found significant correlation between SOD activity and lipid peroxidation when the biochemical data was further analyzed. In addition, significant increase in the levels of SOD among the PD patients with PARK2 mutations was observed, which can be ascribed to chronic oxidative stress induced by PARK2 mutations. PMID- 21584288 TI - Induction of the multixenobiotic/multidrug resistance system in HeLa cells in response to imidazolium ionic liquids. AB - The multixenobiotic/multidrug resistance (MXR/MDR) system controls transport of foreign molecules across the plasma membrane as a preventive measure before toxicity becomes apparent. The system consists of an efflux pump, ABCB1, and/or a member of the ABCC family. Ionic liquids are broadly used solvents with several unique properties such as wide liquid range, negligible vapor pressure, good thermal and chemical stability and extraordinary dissolution properties for organic and inorganic compounds. Ionic liquids containing imidazolium ring are frequently used as solvents in drug synthesis. Constitutive and induced amounts of ABCB1 and ABCC1 proteins were estimated here by Western blotting and quantified by flow cytometry in HeLa cells exposed to three homologous 1-alkyl-3 methylimidazolium and one benzyl ring substituted salts. Aliphatic substituents in position 1 of the salts caused a weak toxicity but 1-benzyl ring was strongly toxic. An 8-day long treatment with 10(-4) M 1-hexyl-3-methylimidazolium chloride resulted in an about 1.5-fold increase of ABCB1 level and over 2-fold increase of ABCC1 level. The amounts of both investigated ABC-proteins were linearly dependent on the length of the imidazolium ring side chain. Such distinctive changes of the amount of MXR/MDR proteins measured in cultured cells may be a useful marker when screening for potential toxicity of various chemicals. PMID- 21584287 TI - Cyclic enkephalin-deltorphin hybrids containing a carbonyl bridge: structure and opioid activity. AB - Six hybrid N-ureidoethylamides of octapeptides in which an N-terminal cyclic structure related to enkephalin was elongated by a C-terminal fragment of deltorphin were synthesized on MBHA resin. The synthetic procedure involved deprotection of Boc groups with HCl/dioxane and cleavage of the peptide resin with 45 % TFA in DCM. d-Lys and d-Orn were incorporated in position 2, and Lys, Orn, Dab, or Dap in position 5. The side chains of the dibasic amino function were protected with the Fmoc group. This protection was removed by treatment with 55 % piperidine in DMF, and cyclization was achieved by treatment with bis-(4 nitrophenyl)carbonate. Using various combinations of dibasic amino acids, peptides containing a 17-, 18-, 19- or 20-membered ring structure were obtained. The peptides were tested in the guinea-pig ileum (GPI) and mouse vas deferens (MVD) assays. Diverse opioid activities were observed, depending on the size of the ring. Extension of the enkephalin sequence at the C-terminus by a deltorphin fragment resulted in a change of receptor selectivity in favor of the delta receptor. The conformational propensities of selected peptides were determined using the EDMC method in conjunction with data derived from NMR experiments carried out in water. This approach allowed proper examination of the dynamical behavior of these small peptides. The results were compared with those obtained earlier with corresponding N-(ureidoethyl)pentapeptide amides. PMID- 21584289 TI - Nanoparticle and nanorod TiO2 composite photoelectrodes with improved performance. AB - A novel nanoparticle-nanorod composite TiO(2) photoelectrode is fabricated. A 3.20% efficiency is achieved by using a 2.1 MUm-thick as-prepared photoelectrode, which is about 3 times of that obtained by a nanorod array electrode (1.05%). The results demonstrate that the composite nanostructure can take advantage of both fast electron transport (nanorod) and high surface area (nanoparticle). PMID- 21584290 TI - Catalytic asymmetric conjugate boration of alpha,beta-unsaturated sulfones. AB - The alpha,beta-unsaturated sulfones are suitable activated olefins in catalytic asymmetric conjugate beta-boration. These substrates undergo smooth conjugate addition of bis(pinacolato)diboron [B(2)(pin)(2)] catalyzed by nonracemic Cu(I) diphosphine complexes to provide, upon subsequent oxidation, beta-hydroxy sulfones in good yields and high enantiocontrol. PMID- 21584291 TI - Spin-crossover in [Fe(3-bpp)2][BF4]2 in different solvents--a dramatic stabilisation of the low-spin state in water. AB - The temperature of spin-crossover in [Fe(3-bpp)(2)][BF(4)](2) (3-bpp = 2,6 di{pyrazol-3-yl}pyridine) tends to increase in associating solvents. In particular, T(1/2) shifts to 60-70 K higher temperature in water compared to organic solvents. PMID- 21584292 TI - Bio-inspired synthesis of chiral silver nanoparticles in mucin glycoprotein--the natural choice. AB - A method of synthesizing stable chiral Ag nanoparticles inside a natural mucin glycoprotein is demonstrated. The reaction is carried out without the help of an external reducing agent, by utilizing the reducing properties of the host mucin. A chiral spectrum is detected in the visible range, indicating the formation of a new type of chiral Ag nanoparticles-containing biomaterial. PMID- 21584293 TI - Anticancer gold(I)-phosphine complexes as potent autophagy-inducing agents. AB - A panel of anticancer gold(I)-phosphine complexes exhibit significant autophagy inducing properties in cancer cells. PMID- 21584294 TI - Proton transfer reactions and dynamics of sulfonic acid group in Nafion(r). AB - Proton transfer reactions and dynamics of the hydrophilic group (-SO(3)H) in Nafion(r) were studied at low hydration levels using the complexes formed from CF(3)SO(3)H, H(3)O(+) and nH(2)O, 1 <=n<= 3, as model systems. The equilibrium structures obtained from DFT calculations suggested at least two structural diffusion pathways at the -SO(3)H group namely, the "pass-through" and "pass-by" mechanisms. The former involves the protonation and deprotonation at the -SO(3)H group, whereas the latter the proton transfer in the adjacent Zundel complex. Analyses of the asymmetric O-H stretching frequencies (nu(OH)) of the hydrogen bond (H-bond) protons showed the threshold frequencies (nu(OH*)) of proton transfer in the range of 1700 to 2200 cm(-1). Born-Oppenheimer Molecular Dynamics (BOMD) simulations at 350 K anticipated slightly lower threshold frequencies (nu(A)(OH*,MD)), with two characteristic asymmetric O-H stretching frequencies being the spectral signatures of proton transfer in the H-bond complexes. The lower frequency (nu(A)(OH,MD))) is associated with the oscillatory shuttling motion and the higher frequency (nu(B)(OH,MD))) the structural diffusion motion. Comparison of the present results with BOMD simulations on protonated water clusters indicated that the -SO(3)H group facilitates proton transfer by reducing the vibrational energy for the interconversion between the two dynamic states (Deltanu), resulting in a higher population of the H-bonds with the structural diffusion motion. One could therefore conclude that the -SO(3)H groups in Nafion(r) act as active binding sites which provide appropriate structural, energetic and dynamic conditions for effective structural diffusion processes in a proton exchange membrane fuel cell (PEMFC). The present results suggested for the first time a possibility to discuss the tendency of proton transfer in H-bond using Deltanu(BA)(OH,MD)) and provided theoretical bases and guidelines for the investigations of proton transfer reactions in theory and experiment. PMID- 21584295 TI - Cu(I) catalysed cyclopropanation with enantiopure scorpionate type ligands derived from (+)-camphor or (-)-menthone. AB - One-pot syntheses of three new enantiopure heteroscorpionate ligands derived from (+)-camphor or (-)-menthone are described. The ligands are obtained by reacting pyrazoles derived from (+)-camphor or (-)-menthone with sodium hydride and thionyl chloride. Subsequent reactions with pyridine and various aldehydes afford the tripod ligands in multi-gram amounts. Especially the menthopyrazole based ligand 6 showed encouraging ee values up to 69% in the Cu(I) catalysed enantioselective cyclopropanation of styrene with ethyl diazoacetate. PMID- 21584296 TI - Anhydrous mono- and dinuclear tris(quinolinolate) complexes of scandium: the missing structures of rare earth metal 8-quinolinolates. AB - The first monomeric anhydrous scandium tris(8-quinolinolate) complex 1 with the 2 amino-8-quinolinolate ligands and the Sc(2)Q(6) dinuclear complex 2 with the unsubstituted 8-quinolinolate ligands have been synthesized and characterized by X-ray analysis and DFT calculations. The intramolecular hydrogen bonds appear to be responsible for the unique monomeric structure of complex 1. The DFT-based analysis of the electron density topology reveals the (3,-1) critical points corresponding to the O...H and N...H bonds. The two scandium atoms in compound 2 are inequivalent due to different ligand surroundings. They are coordinated by seven (5O, 2N) and eight (4O, 4N) ligand atoms. The increase in the coordination number is accompanied by a decrease in the positive charge of the metal atom as evidenced by the DFT calculations. PMID- 21584297 TI - Lanthanide complexes as imaging agents anchored on nano-sized particles of boehmite. AB - The synthesis of boehmite nanoparticles modified with lanthanides (Eu, Tb and Gd) is described. Their synthesis, characterization and in vitro assays with HeLa cells were performed. The nuclear magnetic relaxation dispersion (NMRD) profiles of the two chelating moieties were studied. Imaging data from laser scanning confocal fluorescence microscopy and flow cytometry revealed that the nanoscaffolds were taken up by the cells, distributed throughout the cytoplasm and showed no toxicity. This platform could represent an alternative to silica based inert matrices as imaging vehicles. PMID- 21584298 TI - A turn-on chemosensor for Hg2+ in aqueous media and its application in "MCT" imaging in living cells. AB - A turn-on chemosensor L1, which exhibits high selectivity and sensitivity toward Hg(2+) over other common metal ions in aqueous media under a physiological pH window via a 1:1 binding mode, had been synthesized and characterized. L1 provides good fluorescent imaging of Hg(2+) in living cells. Particularly, we adopted the "micro computed tomography (MCT)" technology, successfully demonstrating the method of Hg(2+) sensing by L1 in cell lines, also the cell permeability of L1 and its imaging position in the cells. PMID- 21584299 TI - Synthesis, crystal structure and living cell imaging of a Cu(2+)-specific molecular probe. AB - We report the development of a rhodamine chromene-based fluorescence probe to monitor the intracellular Cu(2+) level in living cells. The new fluorescent probe exhibits a fluorescence response towards Cu(2+) under physiological conditions with high sensitivity and selectivity, and facilitates the naked-eye detection of Cu(2+). The fluorescence intensity was significantly increased by about 40-fold with 10 equiv. of added Cu(2+). PMID- 21584300 TI - A straightforward synthesis of 2-aminobenzothiazoles from Herz compounds. AB - 2-Aminobenzothiazoles are readily synthesised from anilines, sulfur monochloride and isocyanides. The key step consists of an iodine-catalysed insertion of isocyanides into the S-S bond of hydrolysed Herz salts, with concomitant extrusion of sulfur monoxide. PMID- 21584301 TI - Alkenylphosphonates: unexpected products from reactions of methyl 2 [(diethoxyphosphoryl)methyl]benzoate under Horner-Wadsworth-Emmons conditions. AB - Methyl 2-[(diethoxyphosphoryl)methyl]benzoate reacts with several aldehydes to produce an alkenylphosphonate as the major product, together with varying amounts of the expected Horner-Wadsworth-Emmons product, a 1,2-disubstituted E-alkene. Use of a bulky aldehyde or the tert-butyl ester favours the normal HWE product. PMID- 21584302 TI - Design and synthesis of bile acid-peptide conjugates linked via triazole moiety. AB - A conjugation of bile acids with peptides via Cu(I)-catalyzed click chemistry has been described. Novel bile acid-peptide conjugates linked via a 1,2,3-triazole moiety based on cholic, deoxycholic and lithocholic acid derivatives were synthesized using Cu(I)-catalyzed 1,3-dipolar cycloaddition ("click" reaction). It was shown that up to three peptide fragments can be attached to a central steroid core, thus forming complex three-dimensional polyconjugate structures, which can find important applications in biochemistry, medicinal chemistry, and coordination chemistry. PMID- 21584303 TI - A predicted protein-protein interaction network of the filamentous fungus Neurospora crassa. AB - The filamentous fungus Neurospora crassa is a leading model organism for circadian clock studies. Computational identification of a protein-protein interaction (PPI) network (also known as an interactome) in N. crassa can provide new insights into the cellular functions of proteins. Using two well-established bioinformatics methods (the interolog method and the domain interaction-based method), we predicted 27,588 PPIs among 3006 N. crassa proteins. To the best of our knowledge, this is the first identified interactome for N. crassa, although it remains problematic because of incomplete interactions and false positives. In particular, the established PPI network has provided clues to further decipher the molecular mechanism of circadian rhythmicity. For instance, we found that clock-controlled genes (ccgs) are more likely to act as bottlenecks in the established PPI network. We also identified an important module related to circadian oscillators, and some functional unknown proteins in this module may serve as potential candidates for new oscillators. Finally, all predicted PPIs were compiled into a user-friendly database server (NCPI), which is freely available at . PMID- 21584304 TI - The saponins: polar isoprenoids with important and diverse biological activities. AB - Saponins are polar molecules that consist of a triterpene or steroid aglycone with one or more sugar chains. They are one of the most numerous and diverse groups of plant natural products. These molecules have important ecological and agronomic functions, contributing to pest and pathogen resistance and to food quality in crop plants. They also have a wide range of commercial applications in the food, cosmetics and pharmaceutical sectors. Although primarily found in plants, saponins are produced by certain other organisms, including starfish and sea cucumbers. The under explored biodiversity of this class of natural products is likely to prove to be a vital resource for discovery of high-value compounds. This review will focus on the biological activity of some of the best-studied examples of saponins, on the relationship between structure and function, and on prospects for synthesis of ''designer'' saponins. PMID- 21584305 TI - Synthesis and revision of stereochemistry of rubescensin S. AB - An effective two step transformation of oridonin to 15,16-seco-ent-kaurane skeleton is reported. We also achieved the conversion of one intermediate to natural product rubescensin S and revised its structure as a 13S configuration although 13R is reported in the literature. PMID- 21584306 TI - Estuarine mixing behavior of colloidal organic carbon and colloidal mercury in Galveston Bay, Texas. AB - Mercury (Hg) in estuarine water is distributed among different physical phases (i.e. particulate, colloidal, and truly dissolved). This phase speciation influences the fate and cycling of Hg in estuarine systems. However, limited information exists on the estuarine distribution of colloidal phase Hg, mainly due to the technical difficulties involved in measuring it. In the present study, we determined Hg and organic carbon levels from unfiltered, filtered (<0.45 MUm), colloidal (10 kDa-0.45 MUm), and truly dissolved (<10 kDa) fractions of Galveston Bay surface water in order to understand the estuarine mixing behavior of Hg species as well as interactions of Hg with colloidal organic matter. For the riverine end-member, the colloidal fraction comprised 43 +/- 11% of the total dissolved Hg pool and decreased to 17 +/- 8% in brackish water. In the estuarine mixing zone, dissolved Hg and colloidal organic carbon showed non-conservative removal behavior, particularly in the low salinity (<15 ppt) region. This removal may be caused by salt-induced coagulation of colloidal matter and consequent removal of dissolved Hg. The particle-water interaction, K(d) ([particulate Hg (mol kg(-1))]/[dissolved Hg (mol L(-1))]) of Hg decreased as particle concentration increased, while the particle-water partition coefficient based on colloidal Hg and the truly dissolved Hg fraction, K(c) ([colloidal Hg (mol kg( 1))]/[truly dissolved Hg (mol L(-1))]) of Hg remained constant as particle concentration increased. This suggests that the particle concentration effect is associated with the amount of colloidal Hg, increasing in proportion to the amount of suspended particulate matter. This work demonstrates that, colloidal organic matter plays an important role in the transport, particle-water partitioning, and removal of dissolved Hg in estuarine waters. PMID- 21584307 TI - An efficient synthesis of benzodiazepinyl phosphonates as clostripain inhibitors via FeCl3 catalyzed four-component reaction. AB - A novel one-pot route for the synthesis of benzodiazepinyl phosphonates (BDPs) has been achieved. FeCl(3) efficiently catalyzed four-component condensation of diamines, acetone and phosphites in the presence of molecular sieves to furnish BDPs as novel chemical entities with good yield. The synthesized BDPs have shown significant protease inhibition activity against clostripain, a disease model for gas gangrene, suggesting that these novel chemical entities could be further explored as cysteine protease inhibitors. PMID- 21584308 TI - Intrauterine growth restriction alters the metabonome of the serum and jejunum in piglets. AB - Intrauterine growth restriction (IUGR) is not only an underlying factor for stunted postnatal growth and newborn deaths, but also associated with disease prevalence, such as hypertension and diabetes, in both adult humans and animals. To investigate the metabolic status of IUGR, the differences in serum and jejunal tissue metabonome were examined in IUGR and normal weight 21 day old piglets. IUGR piglets had a significantly lower birth weight (785 +/- 42 g vs. 1451 +/- 124 g), weaned weight (3053 +/- 375 g vs. 6489 +/- 545 g) and average daily gain (108 +/- 16 g vs. 240 +/- 21 g) than normal weight piglets (p < 0.05). IUGR piglets also had a shorter villus height and smaller villus height to crypt depth ratio (p < 0.05) in jejunum. An NMR-based metabonomic study found that serum levels of glycoprotein, albumin and threonine were higher in IUGR than in normal weight piglets, while serum levels of HDL, lipids, unsaturated lipids, glycerophosphorylcholine, myo-inositol, citrate, glutamine and tyrosine were lower in IUGR piglets (p < 0.05). In addition, marked changes in jejunal metabolites, including elevated levels of lipids and unsaturated lipids, and decreased levels of valine, alanine, glutamine, glutamate, choline, glycerophosphorylcholine, trimethylamine-N-oxide, scyllo-inositol, lactate, creatine, glucose, galactose, phenylalanine, tyrosine, glutathione, inosine and taurine were observed in IUGR piglets (p < 0.05). These novel findings indicate that IUGR piglets have a distinctive metabolic status compared to normal weight piglets, including changes in lipogenesis, lipid oxidation, energy supply and utilization, amino acid and protein metabolism, and antioxidant ability; these changes could contribute to impaired growth and jejunal function. PMID- 21584309 TI - Efficient metabolic oligosaccharide engineering of glycoproteins by UDP-N acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) knock-down. AB - Improving the accessibility and functions of therapeutic and diagnostic glycoproteins is one of the major goals of glycobiotechnology. Here we present that stable knock-down of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme in the sialic acid biosynthetic pathway, dramatically increases incorporation of N-acetylmannosamine analogues into glycoproteins of HEK293 cells. By means of these GNE-deficient cells highly sialylated glycoproteins can efficiently be decorated with reactive functional groups, which can be employed in bioorthogonal functionalization strategies for fluorescence labelling or biotinylation. PMID- 21584311 TI - Towards new ligands of nuclear receptors. Discovery of malaitasterol A, an unique bis-secosterol from marine sponge Theonella swinhoei. AB - Malaitasterol A, an unprecedented bis-secosterol, was isolated from a Solomon collection of Theonella swinhoei. The structure was elucidated on the basis of a combination of comprehensive 1D and 2D NMR analysis, high-resolution mass spectrometry and DFT (13)C chemical shift calculations. The biological characterization of malaitasterol A provided evidence that this compound is a potent agonist of pregnane-X-receptor and its putative binding mode to PXR has been obtained through docking calculations. PMID- 21584310 TI - Discovery of peptidylarginine deiminase-4 substrates by protein array: antagonistic citrullination and methylation of human ribosomal protein S2. AB - Peptidylarginine deiminase (PAD) catalyzes the posttranslational citrullination of selected proteins in a calcium dependent manner. The PAD4 isoform has been implicated in multiple sclerosis, rheumatoid arthritis, some types of cancer, and plays a role in gene regulation. However, the substrate selectivity of PAD4 is not well defined, nor is the impact of citrullination on many other pathways. Here, a high-density protein array is used as a primary screen to identify 40 previously unreported PAD4 substrates, 10 of which are selected and verified in a cell lysate-based secondary assay. One of the most prominent hits, human 40S ribosomal protein S2 (RPS2), is characterized in detail. PAD4 citrullinates the Arg-Gly repeat region of RPS2, which is also an established site for Arg methylation by protein arginine methyltransferase 3 (PRMT3). As in other systems, crosstalk is observed; citrullination and methylation modifications are found to be antagonistic to each other, suggesting a conserved posttranslational regulatory strategy. Both PAD4 and PRMT3 are found to co-sediment with the free 40S ribosomal subunit fraction from cell extracts. These findings are consistent with participation of citrullination in the regulation of RPS2 and ribosome assembly. This application of protein arrays to reveal new PAD4 substrates suggests a role for citrullination in a number of different cellular pathways. PMID- 21584320 TI - Adsorption of n-alkane vapours at the water surface. AB - Monte Carlo simulations are reported here to predict the surface tension of the liquid-vapour interface of water upon adsorption of alkane vapours (methane to hexane). A decrease of the surface tension has been established from n-pentane. A correlation has been evidenced between the decrease of the surface tension and the absence of specific arrangement at the water surface for n-pentane and n hexane. The thermodynamic stability of the adsorption layer and the absence of film for longer alkanes have been checked through the calculation of a potential of mean force. This complements the work recently published [Ghoufi et al., Phys. Chem. Chem. Phys., 2010, 12, 5203] concerning the adsorption of methane at the water surface. The decrease of the surface tension has been interpreted in terms of the degree of hydrogen bonding of water molecules at the liquid-vapour interface upon adsorption. PMID- 21584321 TI - Reactivity, photolability, and computational studies of the ruthenium nitrosyl complex with a substituted cyclam fac-[Ru(NO)Cl2(kappa3N4,N8,N11(1 carboxypropyl)cyclam)]Cl.H2O. AB - Chemical reactivity, photolability, and computational studies of the ruthenium nitrosyl complex with a substituted cyclam, fac [Ru(NO)Cl(2)(kappa(3)N(4),N(8),N(11)(1-carboxypropyl)cyclam)]Cl.H(2)O ((1 carboxypropyl)cyclam = 3-(1,4,8,11-tetraazacyclotetradecan-1-yl)propionic acid)), (I) are described. Chloride ligands do not undergo aquation reactions (at 25 degrees C, pH 3). The rate of nitric oxide (NO) dissociation (k(obs-NO)) upon reduction of I is 2.8 s(-1) at 25 +/- 1 degrees C (in 0.5 mol L(-1) HCl), which is close to the highest value found for related complexes. The uncoordinated carboxyl of I has a pK(a) of ~3.3, which is close to that of the carboxyl of the non coordinated (1-carboxypropyl)cyclam (pK(a) = 3.4). Two additional pK(a) values were found for I at ~8.0 and ~11.5. Upon electrochemical reduction or under irradiation with light (lambda(irr) = 350 or 520 nm; pH 7.4), I releases NO in aqueous solution. The cyclam ring N bound to the carboxypropyl group is not coordinated, resulting in a fac configuration that affects the properties and chemical reactivities of I, especially as NO donor, compared with analogous trans complexes. Among the computational models tested, the B3LYP/ECP28MDF, cc-pVDZ resulted in smaller errors for the geometry of I. The computational data helped clarify the experimental acid-base equilibria and indicated the most favourable site for the second deprotonation, which follows that of the carboxyl group. Furthermore, it showed that by changing the pH it is possible to modulate the electron density of I with deprotonation. The calculated NO bond length and the Ru/NO charge ratio indicated that the predominant canonical structure is [Ru(III)NO], but the Ru-NO bond angles and bond index (b.i.) values were less clear; the angles suggested that [Ru(II)NO(+)] could contribute to the electronic structure of I and b.i. values indicated a contribution from [Ru(IV)NO(-)]. Considering that some experimental data are consistent with a [Ru(II)NO(+)] description, while others are in agreement with [Ru(III)NO], the best description for I would be a linear combination of the three canonical forms, with a higher weight for [Ru(II)NO(+)] and [Ru(III)NO]. PMID- 21584322 TI - Bacterial protein interaction networks: puzzle stones from solved complex structures add to a clearer picture. AB - Global scale studies of protein-protein interaction (PPI) networks have considerably expanded our view of how proteins act in the cell. In particular, bacterial "interactome" surveys have revealed that proteins can sometimes interact with a large number of protein partners and connect different cellular processes. More targeted, pathway-orientated PPI studies have also helped to propose functions for unknown proteins based on the "guilty by association" principle. However, given the immense repertoire of PPIs generated and the variability of PPI networks, more studies are required to understand the role(s) of these interactions in the cell. With the availability of bioinformatic analysis tools, transcriptomics and co-expression experiments for a given interaction, interactomes are being deciphered. More recently, functional and structural studies have been derived from these PPI networks. In this review, we will give a number of examples of how combining functional and structural studies into PPI networks has contributed to understanding the functions of some of these interactions. We discuss how interactomes now represent a unique opportunity to determine the structures of bacterial protein complexes on a large scale by the integration of multiple technologies. PMID- 21584323 TI - Strongly green-photoluminescent graphene quantum dots for bioimaging applications. AB - Strongly fluorescent graphene quantum dots (GQDs) have been prepared by one-step solvothermal method with PL quantum yield as high as 11.4%. The GQDs have high stability and can be dissolved in most polar solvents. Because of fine biocompatibility and low toxicity, GQDs are demonstrated to be excellent bioimaging agents. PMID- 21584324 TI - Pb(2+)-introduced activation of horseradish peroxidase (HRP)-mimicking DNAzyme. AB - A novel nucleic acid hairpin structure composed of Pb(2+)-dependent DNAzyme and HRP-mimicking DNAzyme was developed. This hairpin structure can be used as a sensor for the detection of Pb(2+) based on colorimetry. PMID- 21584325 TI - Single-molecule chemistry and physics explored by low-temperature scanning probe microscopy. AB - It is well known that scanning probe techniques such as scanning tunnelling microscopy (STM) and atomic force microscopy (AFM) routinely offer atomic scale information on the geometric and the electronic structure of solids. Recent developments in STM and especially in non-contact AFM have allowed imaging and spectroscopy of individual molecules on surfaces with unprecedented spatial resolution, which makes it possible to study chemistry and physics at the single molecule level. In this feature article, we first review the physical concepts underlying image contrast in STM and AFM. We then focus on the key experimental considerations and use selected examples to demonstrate the capabilities of modern day low-temperature scanning probe microscopy in providing chemical insight at the single molecule level. PMID- 21584326 TI - Separation of isomers of sulfophthalic acid by guest induced host framework formation with 4,4'-bipyridine. AB - The selective inclusion of aromatic guest molecules in host frameworks formed by 3-sulfophthalic acid or 4-sulfophthalic acid and 4,4'-bipyridine has been effectively utilized for the separation of sulfophthalic acid isomers. PMID- 21584327 TI - Phospholipids with a stimuli-responsive thermotropic liquid-crystalline moiety. AB - Lyotropic liquid-crystalline phospholipids having an electro- and/or light responsive mesogenic core were prepared. These LCs show lyotropic smectic A, smectic C, rectangular columnar, and nematic phases. We succeeded in the dynamic control of these LC phases by applying an electric field, which could lead to electrically switchable phospholipid bilayers. PMID- 21584328 TI - Atom arrangement strategy for designing a turn-on 1H magnetic resonance probe: a dual activatable probe for multimodal detection of hypochlorite. AB - The first dual activatable hypochlorite ((-)OCl)-sensing probe was developed, based on a new proof-of-concept design involving signal-activatable (1)H chemical probes using the triple-resonance NMR technique. The probe enabled fluorescence (1)H MR dual turn-on detection of (-)OCl in solution and in crude tissue extracts. PMID- 21584329 TI - Structural modifications of ionic liquid surfactants for improving the water dispersibility of carbon nanotubes: an experimental and theoretical study. AB - The 1-hexadecyl-3-vinylimidazolium bromide (hvimBr), a water-soluble long-chain imidazolium ionic liquid (IL) with surfactant properties, showed the ability to produce stable homogeneous aqueous dispersions of pristine Single-Walled Carbon Nanotubes (SWNTs). The purpose of this study is the improvement of SWNT dispersing ability by assessing the effect of different groups in position 3 of the imidazole ring. In this regard structural analogues were synthesized and, after characterization, their capability to dissolve SWNTs in water was investigated. Molecular Dynamics (MD) simulations have been performed to provide a semi-quantitative indication of the affinity of each dispersing agent toward SWNT and to attempt an explanation of the experimental results. PMID- 21584330 TI - Sensing through signal amplification. AB - The naked eye detection of single molecules in a complex mixture is the ultimate detection limit. Since a single molecule is unable to generate a strong enough signal, sensing methodologies able to reach that limit by necessity need to rely on signal amplification. This tutorial review describes various molecular approaches towards signal amplification in which a single analyte molecule affects the properties of a multitude of reporter molecules. Sensing by advanced instrumentation or changes in the physical properties of materials are excluded. The review is divided into four parts (catalysts, macromolecules, metal surfaces and supramolecular aggregates) depending on the species responsible for generating reporter molecules. Although on first sight apparently very diverse in nature, the majority of approaches rely on two key concepts: catalysis and multivalency. The ability of a catalyst to convert a multitude of substrate molecules into product (defined by the turn over number) makes a catalyst an intrinsic signal amplifier in case the chemical conversion of the substrate is accompanied by a measurable change in physical properties. For sensing purposes, catalytic activity must depend on the interaction between the analyte and the catalyst. Sensing using multivalent structures such as polymers and functionalized nanoparticles relies on the ability of a single analyte molecule to affect the properties of a multitude of reporter molecules collected in the multivalent structure. Chemical sensing systems will be discussed with detection limits that indeed go down to a few molecules and can rival the best biological assays. It will be shown that the most sensitive methods rely on a cascade of amplification mechanisms. PMID- 21584331 TI - Radiopharmaceuticals for imaging and therapy. PMID- 21584332 TI - Effects of sampling techniques on physical parameters and concentrations of selected persistent organic pollutants in suspended matter. AB - This study focusses on the effect of sampling techniques for suspended matter in stream water on subsequent particle-size distribution and concentrations of total organic carbon and selected persistent organic pollutants. The key questions are whether differences between the sampling techniques are due to the separation principle of the devices or due to the difference between time-proportional versus integral sampling. Several multivariate homogeneity tests were conducted on an extensive set of field-data that covers the period from 2002 to 2007, when up to three different sampling techniques were deployed in parallel at four monitoring stations of the River Rhine. The results indicate homogeneity for polychlorinated biphenyls, but significant effects due to the sampling techniques on particle-size, organic carbon and hexachlorobenzene. The effects can be amplified depending on the site characteristics of the monitoring stations. PMID- 21584333 TI - Development of highly effective three-component cytoprotective adjuncts for cisplatin cancer treatment: synthesis and in vivo evaluation in S180-bearing mice. AB - A series of chelants (3a-s) composed of a glucosyl tail, an amino acid side chain and a dithiocarbamate group were designed, synthesized, and evaluated. By co administering with cisplatin, 3a-s were able to decrease the accumulation of platinum in the organs, maintain the accumulation of platinum in the tumor tissues, and increase the urinary and fecal platinum, as well as increasing the voided volume of the treated S180-bearing mice. Compared to S180-bearing mice treated with cisplatin alone, the co-administered mice lost no spleen, kidney, liver, brain and heart weights, lost less body weight, and showed no increase in tumor weight. PMID- 21584334 TI - Multiplex digital PCR: breaking the one target per color barrier of quantitative PCR. AB - Quantitative polymerase chain reactions (qPCR) based on real-time PCR constitute a powerful and sensitive method for the analysis of nucleic acids. However, in qPCR, the ability to multiplex targets using differently colored fluorescent probes is typically limited to 4-fold by the spectral overlap of the fluorophores. Furthermore, multiplexing qPCR assays requires expensive instrumentation and most often lengthy assay development cycles. Digital PCR (dPCR), which is based on the amplification of single target DNA molecules in many separate reactions, is an attractive alternative to qPCR. Here we report a novel and easy method for multiplexing dPCR in picolitre droplets within emulsions-generated and read out in microfluidic devices-that takes advantage of both the very high numbers of reactions possible within emulsions (>10(6)) as well as the high likelihood that the amplification of only a single target DNA molecule will initiate within each droplet. By varying the concentration of different fluorogenic probes of the same color, it is possible to identify the different probes on the basis of fluorescence intensity. Adding multiple colors increases the number of possible reactions geometrically, rather than linearly as with qPCR. Accurate and precise copy numbers of up to sixteen per cell were measured using a model system. A 5-plex assay for spinal muscular atrophy was demonstrated with just two fluorophores to simultaneously measure the copy number of two genes (SMN1 and SMN2) and to genotype a single nucleotide polymorphism (c.815A>G, SMN1). Results of a pilot study with SMA patients are presented. PMID- 21584335 TI - Challenge of studies on the development of new Zn complexes (Zn(opt)2) to treat diabetes mellitus. AB - The number of worldwide patients suffering from diabetes mellitus (DM) is forecasted to increase over time. The development of compounds without severe side effects for type 2 DM is required not only to treat DM but also to improve the quality of life (QOL) of patients. In this paper, we have described the synthesis of novel first transition metal complexes with S2O2 coordination mode and discussed their anti-diabetic activities. Di(1-oxy-2-pyridinethiolato)Zn complex (Zn(opt)2) with Zn(S2O2) coordination mode displayed higher insulin mimetic with anti-diabetic activity, compared to the ZnCl2 or clinically used medicine (pioglitazone). In addition, Zn(opt)2 improved the insulin and adiponectine levels in the plasma. The gastrointestinal absorption of the Zn complex was found to be higher than that of ZnCl(2). Based on these results, we propose that the Zn(opt)2 complex with Zn(S2O2) coordination mode is a novel candidate for the treatment of type 2 DM; through oral administration. PMID- 21584336 TI - A mechanistic study of sialic acid mutarotation: implications for mutarotase enzymes. AB - The mutarotation of N-acetylneuraminic acid (Neu5Ac) proceeds by four kinetically distinct pathways: (i) the acid-catalyzed reaction of neutral Neu5Ac; (ii) the spontaneous reaction of the carboxylic acid (the kinetically equivalent acid catalyzed reaction on the anion being ruled out by the solvent deuterium kinetic isotope effect of 3.74 +/- 0.68); (iii) a spontaneous, water-catalyzed, reaction of the anion; and (iv) a specific-base catalyzed reaction of the anion. The magnitude of the solvent kinetic isotope effect, k(H2O)/k(D2O) = 4.48 +/- 0.74 is consistent with a ring-opening transition state in which a water molecule is deprotonating the anomeric hydroxyl group in concert with strengthening solvation of the ring oxygen atom. The mechanistic implications for Neu5Ac mutarotases are discussed. PMID- 21584337 TI - A dumbbell double nicked duplex dodecamer DNA with a PEG6 tether. AB - A hairpin dodecamer DNA motif with a dangling end composed of four bases was studied in order to find conditions which promote a dumbbell structure as the sole form in solution. It could be used as a model of a DNA duplex with two nicks on opposite strands, mimicking a target for topo II poisons. We have established two alternative means of obtaining a dumbbell in solution as the only form present at 0 degrees C. The first one is to use a relatively high concentration of a hairpin motif, ca. 3.5 mM, at low ionic strength, and second is to use a moderate hairpin motif concentration of ca. 2 mM at high ionic strength, 200 mM and 15% of methanol. An NMR-derived structure in a buffered water solution is presented. A representative structure ensemble of 10 structures was obtained from MD calculations utilizing the AMBER protocol and using NOESY-derived experiment cross peak volumes transferred to experimental restraints by the MARDIGRAS algorithm. PMID- 21584338 TI - Disulfuration and hydrosulfuration of an alkyne at a 1,2-dicarba-closo dodecaborane-thiolate ligand. AB - The reaction of the dinuclear cobalt compound [(CpCoS(2)C(2)B(10)H(10))(CpCoSC(2)B(10)H(11))(n-C(4)H(9)S)] (1) with HC=CC(O)Fc leads to the cobalt-free products (C(2)B(10)H(10))(SCH=CHCOFc)(2) (4-6), (S(2)C(2)B(10)H(10))(HC=CCOFc) (7), and (C(2)B(10)H(11))(SCH=CHCOFc) (8, 9). 4-6 are produced by hydrosulfuration of the alkyne at the 1,2-dicarba-closo dodecaborane-dithiolate ligand with the generated vinyl groups in Z/Z, Z/E and E/E configurations, respectively. In 7, the alkyne is added to 1,2-dicarba-closo dodecaborane-dithiolate at the two sulfur sites. 8 and 9 are the products of alkyne hydrosulfuration at the 1,2-dicarba-closo-dodecaborane-1-monothiolate ligand with the generated vinyl group in either Z or E configuration. The treatment of 1 with HC=CCO(2)Me gives rise to the parallel products (C(2)B(10)H(10))(SCH=CHCO(2)Me)(2) (10-12) and (C(2)B(10)H(11))(SCH=CHCO(2)Me) (13, 14). All of the new compounds have been characterized by IR, NMR, elemental analysis and mass spectroscopy. The structures of compounds 4, 7, and 8 have also been determined by single-crystal X-ray diffraction analysis. PMID- 21584339 TI - Ready synthesis of free N-H 2-arylindoles via the copper-catalyzed amination of 2 bromo-arylacetylenes with aqueous ammonia and sequential intramolecular cyclization. AB - A wide range of free N-H 2-arylindoles were synthesised via the copper(II) catalyzed amination of 2-bromo-arylacetylenes with aqueous ammonia and sequential intramolecular cyclization. The convenience and atom economy of aqueous ammonia, and the low cost of the copper catalytic system make this protocol readily superior in practical application. PMID- 21584340 TI - Calculated vibrational frequencies for FeMo-co, the active site of nitrogenase, bearing hydrogen atoms and carbon monoxide. AB - The intramolecular hydrogenation paradigm for the reducing actions of the enzyme nitrogenase postulates that the iron-molybdenum cofactor (FeMo-co, Fe(7)MoS(9)N(homocitrate)) as active site contains H atoms bound to Fe and S during the catalytic cycle, and that these H atoms are the reducing agents. The reduction of N(2) and of all other non-physiological substrates is strongly inhibited by carbon monoxide, except for the formation of H(2) from protons. It has been recently reported that vanadium nitrogenase and modified molybdenum nitrogenase reduce CO to hydrocarbons. Therefore many questions now arise about relationships between CO and H on the nitrogenase cofactors. In order to assist the interpretation of kinetic infrared spectral data, vibrational frequencies and modes have been calculated for a variety of possible structures in which FeMo-co bears H atoms, or CO ligands, or both. Fe-H stretching frequencies occur in the same spectral window as the C-O stretching frequencies, with lesser intensity, and both stretches are strongly coupled in some structures. Symmetrical bridging of CO between two Fe atoms of FeMo-co is destabilised by the presence of other ligands on Fe, and the reason for this is evident. Two results for bound formyl, HCO, are reported. These calculations of reference structures allow some interpretation of existing experimental spectra, but, more significantly, they suggest further kinetic infrared experiments to elucidate the chemical mechanism of catalysis by nitrogenase under normal turnover conditions. PMID- 21584341 TI - Proteomic analysis of pork meat in the production of cooked ham. AB - The industrial production of cooked ham from pork meat involves, as initial steps, the injection of brine and a prolonged meat massage. These processes strongly affect the quality of the final product because they determine the breakage of muscle cells and the release of their protein content. The produced dense exudates act as a glue in the final cooked ham. In order to exploit modern tools to direct the technological process, still mainly based on empirical observations and traditional recipes, we have carried out a comprehensive proteomic analysis of the exudates as a function of brine concentration, temperature, and length of meat massage. Each condition was found to generate specific protein patterns. Peptide mass fingerprinting analysis was applied allowing the identification of proteins, whose presence and/or quantity can be defined as biomarkers of meat processing, and, potentially, of final product quality. PMID- 21584342 TI - Implementing an OR-NOT (ORN) logic gate with components of the SOS regulatory network of Escherichia coli. AB - Whether biological or electronic, man-engineered computation is based on logic circuits assembled with binary gates that are interconnected to perform Boolean operations. We report here the rewiring of the SOS system of Escherichia in a fashion that makes the output of both the recA and lexA promoters to faithfully follow the pattern of a binary composite OR-NOT gate (ORN) in which the inputs are DNA damage (e.g. nalidixic acid addition) and IPTG as an exogenous signal. Unlike other non-natural gates whose implementation requires changes in genes and promoters of the genome of the host cells, this ORN was brought about by the sole addition of wild-type bacteria with a plasmid encoding a module for LacI(q) dependent expression of lexA. Specifically, we demonstrate that the interplay between native, chromosomally-encoded components of the SOS system and the extra parts engineered in such a plasmid made the desired performance to happen without any modification of the core DNA-damage response network. It is thus possible to artificially interface autonomous cell networks with a predetermined logic by means of Boolean gates built with regulatory elements already functioning in the recipient organism. PMID- 21584343 TI - Comparing dendritic and self-assembly strategies to multivalency--RGD peptide integrin interactions. AB - This paper compares covalent and non-covalent approaches for the organisation of ligand arrays to bind integrins. In the covalent strategy, linear RGD peptides are conjugated to first and second generation dendrons, and using a fluorescence polarisation competition assay, the first generation compound is demonstrated to show the most effective integrin binding, with an EC(50) of 125 MUM (375 MUM per peptide unit). As such, this dendritic compound is significantly more effective than a monovalent ligand, which does not bind integrin, even at concentrations as high as 1 mM. However, the second generation compound is significantly less effective, demonstrating that there is an optimum ligand density for multivalency in this case. In the non-covalent approach to multivalency, the same RGD peptide is functionalised with a hydrophobic C12 chain, giving rise to a lipopeptide which is demonstrated to be capable of self-assembly. This lipopeptide is capable of effective integrin binding at concentrations of 200 MUM. These results therefore demonstrate that covalent (dendritic) and non-covalent (micellar self assembly) approaches have, in this case, comparable efficiency in terms of achieving multivalent organisation of a ligand array. PMID- 21584344 TI - Survival of a cohort of women with cervical cancer diagnosed in a Brazilian cancer center. AB - OBJECTIVE: To assess overall survival of women with cervical cancer and describe prognostic factors associated. METHODS: A total of 3,341 cases of invasive cervical cancer diagnosed at the Brazilian Cancer Institute, Rio de Janeiro, southeastern Brazil, between 1999 and 2004 were selected. Clinical and pathological characteristics and follow-up data were collected. There were performed a survival analysis using Kaplan-Meier curves and a multivariate analysis through Cox model. RESULTS: Of all cases analyzed, 68.3% had locally advanced disease at the time of diagnosis. The 5-year overall survival was 48%. After multivariate analysis, tumor staging at diagnosis was the single variable significantly associated with prognosis (p<0.001). There was seen a dose-response relationship between mortality and clinical staging, ranging from 27.8 to 749.6 per 1,000 cases-year in women stage I and IV, respectively. CONCLUSIONS: The study showed that early detection through prevention programs is crucial to increase cervical cancer survival. PMID- 21584345 TI - Reliability study of the Behavioral Assessment of the Dysexecutive Syndrome adapted for a Brazilian sample of older-adult controls and probable early Alzheimer's disease patients. AB - OBJECTIVE: Ecological tests are useful in assessing executive function deficits and may be of value in appraising response to treatment in Alzheimer's disease patients. Our aims were to examine executive function using the Behavioral Assessment of the Dysexecutive Syndrome for a Brazilian sample of older-adult controls and probable early Alzheimer's disease patients, and verify the applicability of this test battery. METHOD: Forty-one older-adult controls were matched with mild Alzheimer's disease patients by age, education, and gender. RESULTS: There significant inter-group differences in overall profile and almost all subtests except temporal judgment, time spent on planning the first and second Zoo Map visit, number of errors when copying drawings, naming pictures and Six Modified Elements arithmetic, and dysexecutive questionnaire self-rating. The Behavioral Assessment of the Dysexecutive Syndrome item that best discriminated controls from patients was the Modified Six Elements - adapted (general index), with a sensitivity of 80% and specificity of 90%, (AUC = 0.91, p < 0.001). CONCLUSION: Behavioral Assessment of the Dysexecutive Syndrome was effective in detecting executive function deficits in mild Alzheimer's disease patients, particularly the task switching, time monitoring, and rule-shift subtests. PMID- 21584348 TI - Alcohol screening instruments in elderly male: a population-based survey in metropolitan Sao Paulo, Brazil. AB - OBJECTIVE: This study compares the efficacy of the AUDIT (gold standard) with the more easily and quickly applied instruments CAGE, TWEAK, and T-ACE for men aged > 60 using data from a representative stratified sample of the general population of metropolitan Sao Paulo. METHOD: The GENACIS questionnaire was administered to a total sample of 2,083 people aged over 18, with a response rate of 74.5%. The elderly male sample consisted of 169 men. Sensitivity, specificity, positive and negative predictive values, area under the receiver operating characteristic curve, and confidence intervals were calculated for each instrument (95% CI). RESULTS: Respondents were predominantly married (81.7%), had up to 11 years of education (61.3%) and a monthly per capita income of up to 300 US dollars. Current abstinence rate was high (61.6%) and 38% reported being former drinkers. There were no statistically significant differences among the instruments tested; however, the TWEAK had a higher area under the receiver operating characteristic curve (95% CI; 0.90-0.99). CONCLUSION: Research in the general population with screening instruments is scarce, especially among the elderly. However, it can provide specific information concerning this age group and be useful in the formulation of policies and prevention strategies. PMID- 21584351 TI - [The beginning of the disease]. AB - Originating from the ancient enzootic cycle of Trypanosoma cruzi, human Chagas disease (HCD) emerged focally in different points of America, in the Pre Christian period. Being slowly expanded as a consequence of internal migrations, HCD was settled in those locals where some vector species reached domiciliation and where different kinds of reservoirs entered in domestic environment , with major expression in the post Columbus era, particularly between the final of XIX Century and the middle of XX Century, when the maximum prevalence rates were attained. Originally, scarce evidences of acute cases, chronic cardiopathy and megacolon could be detected in different points of the Region, but the diagnosis of such clinical pictures was not easily ascertained. Nevertheless, the megaoesophagus picture proved to be the more specific marker of ancient HCD, with several descriptions of its occurrence in different Brazilian regions, mainly since the XVIII Century. The social burden of HCD depends basically of the presence of chronic cardiopathy, and only after its recognition, control actions of the disease were definitely lounged in endemic countries. PMID- 21584352 TI - [The beginning of Chagas disease control (homage to Dr. Emmanuel Dias, the pioneer of Chagas disease control, in the year of his birth centenary)]. AB - Very soon Carlos Chagas took into account the need of trypanosomiasis control, considering its great social impact and geographical dispersion The vector was considered the more vulnerable target and housing improvement the basic strategy to face the disease. In parallel, it was required a more clinical visibility for the disease, as an argument for its control. The first concrete tentative occurred in 1918 when Souza Araujo dedicating his efforts in Parana, trying housing improvement. He was followed by Ezequiel Dias et al, in 1921, employing chemical compounds against the vector, The chemical fight will be retaken by Emmanuel Dias in 1944, assaying several old compounds, fire thrower and cyanidric gas. In 1946, DDT showed to be ineffective, but one year later Dias & Pellegrino described the insecticide gammexane, highly effective against domestic triatomines. Working with Mario Pinotti, expanded trials occurred in Minas Gerais (Triangle Region), justifying the expansion of the campaign to other endemic regions, with the rationale of continuous work in contiguous areas. In 1957 Pedreira de Freitas proposed the selective spraying, which was the model for the future strategy of program evaluation, by SUVEN and SUCAN organizations. In 1975 the national program is reorganized, launching two national surveys (entomology and serology). In 1979 the new pyrethroid compounds are tried and im 1983 the national program is expanded. Transfusion transmitted Chagas Disease was studied since the 1950 by the Nussenzweig group in S. Paulo, showing to be vulnerable to chemoprophylaxis and blood donor pre transfusional serologic screening. Nevertheless, these preventive measures only were implemented in the 1980 decade, following the emergence of HIV/AIDS pandemic. Practically, since the pioneer essays, the control of Chagas Disease transmission showed to be efficient against vector and blood bank mechanisms, depending on continuity, educative support and political will. PMID- 21584353 TI - [Institutional insertion of Chagas' disease control]. AB - After the starting of the Center for studies and prophylaxis of Chagas disease in 1943, with the help of Oswaldo Cruz Foundation, in the city of Bambui, state of Minas Gerais, technological and methodological basis for the extensive control of the disease were conceived. A main step to achieve success was the introduction of a new insecticide (gammexane, P 530) and the demonstration of its efficacy in the vector control. A consequence of these improvements was the official inauguration of the first prophylactic campaign for Chagas disease in Brazil, held in Uberaba in May, 1950. Even with the knowledge of how to control the vectorial transmission, financial resources were not available by this time, at a necessary degree to make it both regularly and in all the affected area. The institutional allocation of these activities is useful to understand the low priority given to them at that time. Several national services were created in 1941, for diseases as malaria, pest, smallpox, among others, but Chagas was included in a group of diseases with lower importance, inside a Division of Sanitary Organization. In 1956, the National Department of Rural endemies (DNERu) allocate all the major endemic diseases in a single institution, however this was not translated in an implementation program for the control of Chagas disease. After profound changes at the Ministry of Health, in 1970, the Superintendencia de Campanhas de Saude Publica (SUCAM) was in charge of all rural endemies including Chagas disease, which now could compete with other diseases transmitted by vectors, formerly priorities, included in the National Division. With this new status, more funds were available, as well as redistribution of personnel and expenses from the malaria program to the vectorial control of Chagas disease. In 1991 the Health National foundation was created to substitute SUCAM in the control of endemic diseases and it included all the units of the Ministry of Health related to epidemiology and disease control. By this time a new tendency for decentralization of these programs was clear. In the case of diseases transmitted by vectors, this was a major difference from the campaign model so far employed. At the same time, the Initiative for the South Cone countries for the control of Chagas disease started, sharing techniques among the countries of this region, as well as establishing similar objectives and trends, what possible helped to maintain Chagas disease as a priority among all the public health issues. From 2003 on, all activities for control of the disease at a national level are under responsibility of the Secretary of Health Surveillance of the Ministry of Health. PMID- 21584354 TI - [Entomological survey (1975-1983)]. AB - After the systematization and re-dimension of the vectorial control in all the Country by 1975, it was considered necessary to have an up-to-date information on the distribution of vectors in Brazil, and differentiate precisely the role of each of the different species on the intra-domiciliary transmission of Chagas disease. For this purpose, sampling regional surveys for regions with non reliable information were performed, as well as, a house by house search for vectors on those areas considered at risk. For this last, 1,942 municipalities from 19 states were searched, as by the political division of the country by 1980, that was taken as a reference in this paper. These activities, that were implemented as part of the routine for intervention, were completed by 1983. Immediately after, this work was also extended for other areas considered targets for infected bugs. Results obtained, allowed to map the endemic area and the area under risk of vectorial transmission all over the country. Even more, with the results obtained it was possible to recognize those five species proved as vectors of the infection, among thirty already identified. These species, in order of importance, were: Triatoma infestans, Panstrongylus megistus, T. brasiliensis, T pseudomaculata and T. sordida. It was possible also to verify the increase in the dispersion of T. infestans, an aloctonous vector captured now in states of the North-east region, where it was not recognized previously. In relation with native species, a clear division of territories among them was found. Furthermore, P. megistus was found with a diffuse distribution, but T. brasiliensis and T. pseudomaculata were restricted to the semi-arid North-east. The most often captured bug was T. sordida, (mostly around houses) limited to the cerrado area, which is its origin. PMID- 21584355 TI - [Seroprevalence survey of human Chagas' infection (1975-1980)]. AB - The results of the Serological survey for the prevalence of chagasic infection in Brazil, 1975/1980, were published before (Camargo et al, 1984) but the detailed geographical distribution is described in this paper. This was an initiative of two governmental bodies: the Superintendencia de Campanhas de Saude Publica a Ministry of Health Division in charge of all public health policies, and, the Research National Council of the Ministry of Science and Technology through a program called Integrated Program for Endemic Diseases. Results obtained were extremely useful for a precise delimitation of the area with endemic transmission of Chagas disease, and hence, to direct the activities for vector control, which were implemented from 1975 onwards. This survey showed an estimated seroprevalence of 4.2% of T. cruzi infection in the rural population in the country. Only two federal units were not included, Sao Paulo and the Federal District (Brasilia) for which enough recent information was available. This survey included all the other federal units of Brazil, with the examination of 1,626,745 blood samples by indirect immunofluorescence. From them, 1,352,197 were validated for processing and statistical analysis, which were from 3,026 municipalities of 24 states, as by the political division of the country by this time. Overall results obtained, confirmed data that were well known, but some were non expected. These last were subject of further investigations, until confirmation, based also on entomological data and a better interpretation of the results obtained. PMID- 21584356 TI - [The electrocardiographic survey]. AB - In order to investigate the prevalence of chagasic heart disease in Brazil, a national electrocardiographic survey was carried out from 1977 to 1981. A total of 5,347 electrocardiograms (ECG) were performed and paired by age and gender. The results obtained in relation with the autochthonous cases, were distributed by Brazilian states, as follows: Rio Grande do Sul (1,078), Minas Gerais (760), Bahia (612), Parana (400), Paraiba (340), Piaui (218), Sergipe (216), Goias (176), Pernambuco (170), Ceara (136) and Alagoas 134. The higher proportions of altered ECGs among seropositive individuals were found in the States of Goias (63.6%), Minas Gerais (57.6%), Ceara (57.3%), Parana (54.5%), Piaui (53.2%) and Paraiba (52.3%). Among the control individuals, these proportions were respectively 25%, 25.7%, 25%, 12.5%, 22.9% and 26.5%. A significant statistical difference of altered ECGs between positive and negative individuals was verified in all the States, with a single exception (Alagoas). The estimation of the gradient showed to be higher in Parana State (42%), followed by Goias (38.6%), Ceara (32.3%), Minas Gerais (31.9%), Piaui (30.3%), Paraiba (25.8%), Pernambuco (22.3%), Bahia (18.9%), Sergipe (16.7%), Rio Grande do Sul (9.9%) and Alagoas (7.5%). Concerning the distribution of the electrocardiographical alterations found in the eleven states, the main alterations find among the seropositive group were: ventricular extrasystoles, complete right bundle branch block, left anterior fascicular block, the association of complete right bundle branch block with left anterior fascicular block and primary alterations of the ST segment and of the T wave. Furthermore, these ECG alterations were more prevalent in the group of infected individuals. PMID- 21584357 TI - [Summary of results from the national surveys]. AB - This article aims to correlate the main results of three large national surveys on Chagas disease (entomologic, seroprevalence and electrocardiographic) carried out in Brazil from late 1970's to early 1980's, which served as baseline for definition of the control measures adopted in the country. The proportion of infected people was much higher in areas where Triatoma infestans, the most efficient vector of Chagas disease among the five principal species involved in transmission at that time, was predominant. Similar result was observed in places where Triatoma sordida was dispersed, mainly in the country's central region, which corresponds to its native area. This finding is due to the coincidence observed in the geographic distribution of both vectors, since T. sordida is not considered to play an important role in transmission. In the Northeastern semi arid, endemic area for Triatoma brasiliensis and Triatoma pseudomaculata, rates of human infection were much lower, although both vectors may have some relevance in the maintenance of the disease. As for areas with Panstrongylus megistus, human infection varied according to the levels of domiciliation. Whenever domiciled, like in the humid northeastern coastal area, its involvement in transmission can be clearly demonstrated. In some parts of Bahia State it represented the exclusive vector of the disease. Based upon the results of the seroprevalence survey an electrocardiographic study was carried out in 11 Brazilian states, which showed marked differences in the presence of cardiac alterations when comparing different areas of the country. PMID- 21584358 TI - [The control of vectorial transmission]. AB - Between 1950 and 1951, the first Prophylactic campaign against Chagas Diseases was carried on in Brazil by the so existing Servico Nacional de Malaria. The actions involving chemical vector control comprehended 74 municipalities along the Rio Grande Valley, between the States of Sao Paulo and Minas Gerais. Ever since, until 1975, the activities were performed according the availability of resources, being executed with more or less regularity and coverage. At that time, Chagas disease did no represent priority, in comparison with other endemic diseases prevalent in the Country. Even so, taking into account the accumulated data along those 25 years, the volume of work realized cannot be considered despicable. Nevertheless, it was few consistent, in terms of its impact on disease transmission. In 1975, with an additional injection of resources surpassed from the malaria program, plus the methodological systematization of the activities, and with the results of two extensive national inquiries (entomologic and serologic), the activities for vector control could be performed regularly, following two basic principles: interventions in always contiguous areas, progressively enlarged, and sustainability (continuity) of the activities, until being attained determined requirements and purpose previously established. Such actions and strategies lead into the exhaustion of the populations of the principal vector species, Triatoma infestans, no autochthonous and exclusively domiciliary, as well as the control of the domiciliary colonization of autochthonous species important to disease transmission. Vector transmission today is being considered residual, by means of some few native and peridomestic species, such as Triatoma brasiliensis and Triatoma pseudomaculata. There is, also, the risk of progressive domiciliation of some species before considered sylvatic, such as Panstrongylus lutzi and Triatoma rubrovaria. Finally, there is the possibility of the occurrence of cases of human infection directly related to the enzootic cycle of the parasite. By all these reasons, it is still indispensable the maintenance of a strict epidemiological surveillance against Chagas Disease in Brazil. PMID- 21584359 TI - [Control of transfusional transmission]. AB - The high prevalence of chagasic blood donors in blood centers in Brazil (6.9%) and in Latin America (6.5%) in the 60's and 70's, together with the combat to the vector since the 70's have made transfusion Chagas disease the main mechanism of the disease transmission in the 80's. However, the highly favorable results achieved to eliminate the vector and the serologic screening of blood donors, reduced the prevalence of serum positivity to 0.2% and 1.3%, respectively and the rate of annual transmission through blood transfusion from 20.000 to 13 in four decades in Brazil. Nevertheless, despite outstanding advancements in endemic countries, Chagas disease reached, via migration, non-endemic countries in North America and Europe besides Japan and Australia, placing their blood recipients at risk and turning Chagas disease into a worldwide health problem. Transfusion safety through serologic selection raised another big issue i.e. high proportion of inconclusive reactions as well as two great challenges: the meaning of such exams and what guidelines to provide the donor. However, the strategies adopted by non-endemic countries and the advancements achieved by endemics so far forecast the highly wished vector and transfusion control of Chagas disease. PMID- 21584360 TI - [Prevention concerning the different alternative routes for transmission of Trypanosoma cruzi in Brazil]. AB - Vectorial, transfusion and congenital are considered the main transmission mechanisms in human Chagas disease. Alternative mechanisms are accidental, oral and by organ transplantation. Other hypothetic mechanisms could be by other vectors, sexual, criminal and by means of marsupial anal secretions. The present accorded strategies for prevention are: CONGENITAL: early case detection and immediate treatment. If possible, start during the pre natal period, throughout mothers serology, performing parasitological tests in the new born from positive women. For positive cases, immediate treatment; for those negative babies, conventional serology at the 8th month, treating specifically those with positive results. ACCIDENTAL TRANSMISSION: Rigorous training and utilization of protection equipments. IF accident occurs, immediate disinfection, conventional serology and beginning of specific treatment by ten days. Revision of the serology after 30 days: if positive, extend the treatment until the total dose (60 days or more). ORGAN TRANSPLANTATION: previous serology for donor and receptor. When the former is infected and the last negative, cancel the surgery or install the specific treatment by ten days before the surgery for the donor, followed by the receptor during ten days after the transplantation. ORAL TRANSMISSION: Specific measures are not available, food hygiene is recommended, including the cooking of meats delivered from possible reservoirs. Nowadays, the detection and immediate treatment of the case is recommended, followed by active research of new cases around the detected one. PMID- 21584361 TI - [Control Program of Chagas disease in Sao Paulo, Brazil: the control and surveillance of vector transmission]. AB - The control of the vectors of Chagas' disease in the State of Sao Paulo are discussed, mainly those activities that led to the elimination of Triatoma infestans. Secondary factors that helped the control such as rural exodus are also analyzed. The article shows that since 1965 the control became a campaign with different phases due to the epidemiological situation, the acquired knowledge and the entomological surveillance. After 25 years of work, the elimination of all the focus of Triatoma infestans was finally reached and the campaign was ended. However, due to the possibility of reintroduction of the vector in rural areas by passive transportation besides the presence of secondary vectors (Triatoma sordida and Panstrongylus megistus) in several localities, the vector control activities were not interrupted and the surveillance is continuous. PMID- 21584362 TI - [Chagas disease Control Program in the State of Sao Paulo, Brazil: seroepidemiological aspects of homogeneous geographic microregions]. AB - Between the years 1976 and 1980, the American trypanosomiasis was searched for among residents in two geographic microregions of the State of Sao Paulo: Campos de Itapetininga, in the region of Sorocaba, and Encosta Ocidental da Mantiqueira Paulista, in the region of Campinas. Both areas have in the past been colonized by Triatoma infestans. Campos de Itapetininga remained, until the beginning of the 1970s as a stronghold of this species in the State of Sao Paulo. Panstrongylus megistus has currently colonized in these areas, now classified as having serological titer profiles characteristic of low endemicity. Transmission of Chagas disease was interrupted earlier in the Encosta Ocidental. Intense exposure to the vector in Campos de Itapetininga can explain the seroreactivity frequencies observed in people born before 1956, aged more than 20 years. Among the residents in this region born between 1972 and 1977, a low positivity rate remains, which might also include cases of congenital transmission. The mean age of seroreagents resident in the Encosta indicates that they must have been born in the 1930s; positivity levels here vary in different municipalities according to their growth in capital goods. After 1984 new criteria were adopted for the use of serology in the Program for the Control of Chagas disease, the detection of seroreagents has not been statistically associated to notification of the occurrence of domestic triatomines in these regions. PMID- 21584363 TI - [Chagas disease Control Program in the State of Sao Paulo, Brazil: serological and entomological aspects of primary school-children surveys]. AB - Two serological surveys were carried out to evaluate the effectiveness of measures put into effect in the State of Sao Paulo (Brazil) to control Chagas disease vectors. The first one, during the period from 1968 to 1970; the complement fixation reaction was performed on serum samples from school-children resident in all municipalities of the State of Sao Paulo, with the exception of the Greater Sao Paulo. The second one, annually, from 1973 to 1983, involving school-children resident in municipalities with high trypanosomiasis prevalence values; the indirect immuno-fluorescence test was performed on filter paper total blood eluates. Data on the occurrence of triatomines and their infection with Trypanosoma cruzi in each municipality formed the basis of insight into the epidemiological situation associated with the school-children's dates of birth. Most positive serological results, as well as the highest proportion of autochthonous cases associated with Triatoma infestans were observed in the region of Sorocaba until the early 1970s, while the proportions of both autochthonous and imported cases were kept in equilibrium elsewhere. It has been inferred that as recently as 1974, vectorial transmission of Chagas disease could still be observed in the State of Sao Paulo. We emphasize that, even rather lacking in coverage, no seropositive cases have been observed in people inhabiting the regions included in the Control Program for the State of Sao Paulo and now aged less than 15 years. PMID- 21584364 TI - [The national survey of seroprevalence for evaluation of the control of Chagas disease in Brazil (2001-2008)]. AB - A survey for seroprevalence of Chagas disease was held in a representative sample of Brazilian individuals up to 5 years of age in all the rural areas of Brazil, with the single exception of Rio de Janeiro State. Blood on filter paper was collected from 104,954 children and screened in a single laboratory with two serological tests: indirect immunofluorescence and enzyme linked immunoassay. All samples with positive or indetermined results, as well as 10% of all the negative samples were submitted to a quality control reference laboratory, which performed both tests a second time, as well as the western blot assay of TESA (Trypomastigote Excreted Secreted Antigen). All children with confirmed final positive result (n = 104, prevalence = 0.1%) had a follow-up visit and were submitted to a second blood collection, this time a whole blood sample. In addition, blood samples from the respective mothers and familiar members were collected. The infection was confirmed in only 32 (0.03%) of those children. From them, 20 (0.025%) had maternal positive results, suggesting congenital transmission; 11 (0.01%) had non-infected mothers, indicating a possible vectorial transmission; and in one whose mother had died the transmission mechanism could not be elucidated. In further 41 visited children the infection was confirmed only in their mothers, suggesting passive transference of maternal antibodies; in other 18, both child and mother were negative; and in 13 cases both were not localized. The 11 children that acquired the infection presumably through the vector were distributed mainly in the Northeast region of Brazil (States of Piaui, Ceara, Rio Grande do Norte, Paraiba and Alagoas), in addition to one case in Amazonas (North region) and another in Parana (South region). Remarkably, 60% of the 20 cases of probably congenital transmission were from a single State, Rio Grande do Sul, with the remaining cases distributed in other states. This is the first report demonstrating regional geographical differences in the vertical transmission of Chagas disease in Brazil, which probably reflects the predominant Trypanosoma cruzi group IId and IIe (now TcV and TcVI) found in this state. Overall, these results show that the regular and systematic control programs against the transmission of Chagas disease, together with socioeconomic changes observed in Brazil in the last decades, interrupted the vectorial transmission in Brazil, resumed in the few cases found in this national survey. Furthermore they reinforce the need for maintenance of control programs for the consolidation of this major advance in public health. PMID- 21584365 TI - [New challenges and the future of control]. AB - The epidemiological situation of Chagas disease in Brazil was substantially altered in the last decades, partially as a consequence of the control measures implemented and partially due to the environmental, economical and social changes that took place in the country. Domicile vector transmission was interrupted when caused by Triatoma infestans and importantly controlled when associated with native species of the vector. Transfusion transmission is no longer a problem since generalized screening of blood donors came into routine. Congenital transmission, although still possible, mainly in some areas, also tends to disappear due to the control in the vector and transfusion transmission. The primordial mechanisms of transmission directly related to the enzootic cycle, as the one caused by vectors outside the homes, or by sporadic entrance of vectors in the domicile, in addition to the oral transmission, started to become relevant in the generation of new infections by Trypanosoma cruzi. The new challenges in facing Chagas disease include: a) to preserve the excellent level of control that was achieved; b) to develop new technologies and methods of surveillance and control capable of reducing the risk of cases associated to enzootic transmission; c) to provide adequate medical attention to patients with the infection or the disease in its chronic stage. PMID- 21584366 TI - Palliative care: challenges for the health systems. PMID- 21584367 TI - Virtual learning object for the simulated evaluation of acute pain in nursing students. AB - This study aimed to evaluate the results of the application of a virtual learning object for the simulated evaluation of acute pain in the learning of undergraduate nursing students and to verify the opinions of the students regarding the quality of the technology. This was a quasi-experimental, non randomized, before and after study performed with 14 students in the seventh phase of the undergraduate nursing course of the Federal University of Santa Catarina. The pre (8.84) and post-test (9.31) means revealed significant differences in learning after the intervention (p=0.03). In the qualitative evaluation the flexibility of access, access independent of time/place, freedom to decide the best learning route and the similarity with reality were highlighted. It constitutes a promising educational tool, an interactive experience, similar to reality, dynamic and constructive learning. The application of the technology has brought positive results for learning about pain evaluation, contributing to fill the gap in the teaching of the thematic. PMID- 21584368 TI - Impact of the clinical management of pain: evaluation of stress and coping among health professionals. AB - The specialist literature highlights that the clinical management of pain involves psychological difficulties associated with the pursuit of the alleviation of the suffering of patients. Therefore, an investigation was conducted into the perception of stress and coping strategies of 31 professionals of different categories from a severe burns care center (acute pain) and a pain control and palliative care unit (chronic pain). For this, a sociodemographic questionnaire, the Job Stress Scale (short version) and the Coping Strategies Inventory were applied. Compared to other categories, the nursing technicians indicated more stress factors. In compensation, they reported a greater diversity of coping strategies with significant differences between the services. These results corroborate previous studies, which warn of the adverse conditions that interfere in nursing practice. However, they also reveal the availability of protective factors, indicating perspectives of preventive intervention for the nursing team. PMID- 21584369 TI - The prevalence and characterization of self-medication for obtaining pain relief among undergraduate nursing students. AB - This study investigates the prevalence of self-medication among undergraduate nursing students seeking to relieve pain and characterizes the pain and relief obtained through the used medication. This epidemiological and cross-sectional study was carried out with 211 nursing students from a public university in Goias, GO, Brazil. A numerical scale (0-10) measured pain intensity and relief. The prevalence of self-medication was 38.8%. The source and main determining factor of this practice were the student him/herself (54.1%) and lack of time to go to a doctor (50%), respectively. The most frequently used analgesic was dipyrone (59.8%) and pain relief was classified as good (Md=8.5;Max=10;Min=0). The prevalence of self-medication was higher than that observed in similar studies. Many students reported that relief obtained through self-medication was good, a fact that can delay the clarification of a diagnosis and its appropriate treatment. PMID- 21584370 TI - Nursing professional education: implications of education for transpersonal care. AB - This study identifies the perceptions of undergraduate nursing students concerning their education to provide transpersonal care. This qualitative study was conducted in four public universities in Bahia, Brazil with 16 seniors (non probabilistic sampling) through semi-structured interviews, analyzed through the Collective Subject Discourse. The results expressed the students' feelings in the face of the challenge to provide transpersonal care; the psycho-cognitive competencies required by inter-subjective praxis; their perceptions concerning the curriculum in relation to the psycho-emotional dimension of being, untying critical knots; strategies suggested. The final reflections indicate the need to implement changes in the professional education of nurses in order to recover the humanistic view while preserving the scientific view. Undergraduate courses should develop an interactive methodology capable of supporting a more humane, sensitive and inter-subjective care praxis. PMID- 21584371 TI - Theoretical knowledge of nurses working in non-hospital urgent and emergency care units concerning cardiopulmonary arrest and resuscitation. AB - Non-Hospital Urgent and Emergency Care Units were created to deliver care to patients in chronic or acute situations and to coordinate the flow of urgent care. This descriptive study analyzed the theoretical knowledge of nurses working in these units concerning cardiopulmonary arrest and resuscitation. A questionnaire was applied to 73 nurses from 16 units in seven cities in the region of Campinas, SP, Brazil. The respondents displayed some gaps in their knowledge such as how to detect Cardiopulmonary Arrest (CPA), the ability to list the sequence of basic life support, and how to determine the appropriate compression to ventilation ratio (>60%). They also did not know: the immediate procedures to take after CPA detection (>70%); the rhythm pattern present in a CPA (>80%); and they only partially identified (100%) the medication used in cardiopulmonary resuscitation. The average score on a scale from zero to ten was 5.2 (+/- 1.4). The nurses presented partial knowledge of the guidelines available in the literature. PMID- 21584372 TI - Surgical site infection in patients submitted to orthopedic surgery: the NNIS risk index and risk prediction. AB - The applicability of the risk index for surgical site infection of the National Nosocomial Infection Surveillance (NNIS) has been evaluated for its performance in different surgeries. In some procedures, it is necessary to include other variables to predict. OBJECTIVE: to evaluate the applicability of the NNIS index for prediction of surgical site infection in orthopedic surgeries and to propose an alternative index. The study involved a historical cohort of 8236 patients who had been submitted to orthopaedic surgery. Statistical analysis was performed using multivariate logistic regression to fit the model. The incidence of infection was 1.41%. Prediction models were evaluated and compared to the NNIS index. The proposed model was not considered a good predictor of infection, despite moderately stratified orthopedic surgical patients in at least three of the four scores. The alternative model scored higher than the NNIS models in the prediction of infection. PMID- 21584373 TI - Cross-cultural adaptation and validation of a disease knowledge and self-care questionnaire for a brazilian sample of heart failure patients. AB - To adapt a questionnaire that assesses knowledge about heart failure (HF) and self-care and to analyze its content validity and reproducibility for use in Brazil. The questionnaire was validated through translation, summary, back translation, expert committee review, pretest and assessment of psychometric properties. The final version (14 questions) was applied at the university hospital to HF outpatients under multidisciplinary team care. Five questions showed total agreement; seven scored Kappa > 0.4; one Kappa = 0.4, and just one presented no agreement. A group of 153 patients within 1-4 years of outpatient follow-up was assessed (age 59+/-13, 61% male). In the knowledge assessment, right answers varied from 4 to 14 (average 9.9+/-2.1). Results indicate the validity of the questionnaire for use in Brazil. PMID- 21584374 TI - Health services users with diabetes mellitus: from knowledge to the use of healthcare rights. AB - This descriptive study with qualitative approach analyzes the knowledge of individuals with diabetes mellitus (DM) concerning their health rights. Open interviews were conducted with 12 individuals with DM in a university center in the interior of Sao Paulo, Brazil. Content analysis enabled the identification of two categories: the users' (lack of) knowledge concerning their rights and the unaware exercise of their rights. The results revealed that despite the legal advancements achieved in public policies, most users with DM are unaware of their rights, although they use the benefits that accrue from law in an unconscious way. Providing complete and sufficient information is essential so that individuals are able to make the best decision in relation to their treatment, preserving their autonomy. PMID- 21584375 TI - Evaluation of care for at-risk newborns from the perspective of a public health policy. AB - The aim was to evaluate the care for at-risk newborns under follow-up in their first year of life by the Growing Happily Program, developed in a city in inner Sao Paulo state. It is a population-based epidemiological health program evaluation study, which was based on the national guidelines of the Agenda of Commitments to Children and Child Mortality Reduction for data analysis. Results showed the program's institutional vulnerability, caused by problems related to its structure and process, with implications for its outcomes. Considering the adaptation of the criteria adopted by the Program for defining at-risk newborns, as well as the proposed interventions and strategies, in consonance with the Agenda of Commitments, the need for managers to make it a priority is appointed, by effectively including it in public health care policies to be developed in cities, in order to reverse the institutional vulnerability identified. PMID- 21584376 TI - The role of the nurse in the neonatal intensive care unit: between the ideal, the real and the possible. AB - The nurse is one of the professionals responsible for the care directed toward the physical, mental and social development of newborns in the Neonatal Intensive Care Unit. This study aimed to comprehend the experience of nurses working in a Neonatal Intensive Care Unit. Data collection was performed in 2008, through interviews with 12 nurses working in public and private hospitals of the city of Sao Paulo. The units of meaning identified were grouped into three categories: Developing actions; Perceiving their actions and Expectations. The analysis was based on social phenomenology. It was concluded that the overload of activities, the reduced number of staff, the lack of materials, equipment and the need for professional improvement are the reality of the work of the nurse in this sector. To supervise the care is the possible; integral care of the newborn, involving the parents, is the ideal desired. PMID- 21584377 TI - Association of the red reflex in newborns with neonatal variables. AB - The aim of this study was to investigate the results of the red reflex test and to associate these results with neonatal variables. This descriptive study was conducted with 190 newborns in a public maternity hospital. A total of 187 infants presented no alteration and three presented suspect results. Different shades of reflex color were observed: 50 (26.3%) presented red; 34 (17.9%) orange red, 92 (48.4%) orange, 11 (5.8%) light yellow and three (1.6%) milky white spots. Statistically significant associations between the color gradient instrument and neonatal variables were found: weight (p=0.03), gestational age (p=0.019) and oxygen therapy (p=0.024). Nurses trained to practice and evaluate this test may become professionals in the potential for the prevention of childhood blindness. PMID- 21584378 TI - Drugs use by adolescents and their perceptions about specialized treatment adherence and dropout. AB - Drugs use in adolescence is an important issue to be discussed, due to the early damage it causes. This study investigated adolescent drugs use, ranging from the first trial to perceptions about treatment adherence. Based on qualitative research, the researchers aimed to understand the problem from the subjects' viewpoint. Data were analyzed through thematic categorization. Fourteen teenagers were interviewed: mostly males, 14 to 19 years old and low education. Marijuana was the most used drug upon the first trial. Friends, free time and "parties" favored drugs use. Teenagers also used drugs to escape from conflicts and feelings. Different intrinsic and extrinsic factors were reported as favorable to treatment adherence and dropout. The findings can contribute to establish therapeutic intervention proposals for adolescent drug users. PMID- 21584379 TI - Colonization of nursing professionals by Staphylococcus aureus. AB - This cross-sectional study aimed to investigate the presence of Staphylococcus aureus in the saliva of the nursing team of a teaching hospital in the interior of Sao Paulo State. Three saliva samples were collected from 351 individuals with an interval of two months between each collection. All ethical aspects were considered. In 867 (82.3%) cultures there was no identification of Staphylococcus aureus in the saliva, in 88 (17.7%) cultures Staphylococcus aureus was isolated, 26 (2.5%) of which were resistant to methicillin. The prevalence of professionals colonized by Staphylococcus aureus was 41.0% (144/351), of which 7.1% (25/351) were characterized as methicillin-resistant Staphylococcus aureus. Transient carriers represented 81.2% and persistent carriers 18.8%. Resistance to mupirocin was 73.1% of MRSA and 9.3% of MSSA. The results demonstrate that it is the nurse and nursing technician that are the professional categories most susceptible to MRSA. Broader discussion on the thematic and interventions are needed. PMID- 21584380 TI - Analysis of accidents with organic material in health workers. AB - This retrospective and descriptive study with a quantitative design aimed to evaluate occupational accidents with exposure to biological material, as well as the profile of workers, based on reporting forms sent to the Regional Reference Center of Occupational Health in Florianopolis/SC. Data collection was carried out through a survey of 118 reporting forms in 2007. Data were analyzed electronically. The occurrence of accidents was predominantly among nursing technicians, women and the mean age was 34.5 years. 73% of accidents involved percutaneous exposure, 78% had blood and fluid with blood, 44.91% resulted from invasive procedures. It was concluded that strategies to prevent the occurrence of accidents with biological material should include joint activities between workers and service management and should be directed at improving work conditions and organization. PMID- 21584381 TI - Psychic workloads and strain processes in nursing workers of Brazilian university hospitals. AB - OBJECTIVE: To identify the work process, the psychic workloads and the strains generated in nursing workers. METHOD: The study was developed in five Brazilian university hospitals. The sample was composed by 62 nursing workers and the data collection was done by focal group technique, followed by the application of a collective inquire. The data were quantitatively described and systematized according to a thematic analysis. RESULTS: The study population represented 35,37% of the hospital workforce in national setting. The workers mentioned are exposure to several kinds of psychic workload and link them to with others workloads, highlighting the strain processes resulting from this kind of workload, such stress, fatigue, complaints of gastritis and headaches. CONCLUSIONS: Nursing workers are exposed to several workloads in the hospital environment, especially psychic workloads. This exposure starts strain processes that compromise the health and quality of life, signaling the necessity of interventions in this reality. PMID- 21584382 TI - Depression, anxiety and stress in primary health care users. AB - AIM: Describe levels of depression, anxiety and stress among users of an urban/rural health centre, analyse sex differences and comorbidity between depression, anxiety and stress. METHOD: Descriptive co-relational study with a Portuguese version of DASS-21; consecutive sample (n=343). RESULTS: 40.52%, 43.48% and 45.06% of individuals present some degree of depression, anxiety and of stress, respectively. Severe or very severe levels of disturbance were found in 20.87% (anxiety), 22.38% (stress) and 12.24% (depression) of individuals. Women present higher levels of depression, anxiety and stress. Depression, Anxiety and Stress are strongly and positively associated. CONCLUSION: These results show high point prevalence--higher than in other countries--and reveal differences in sex as well as comorbidity. They may allow for the development of a local and community intervention strategy for mental health promotion and disease prevention, particularly for women. PMID- 21584383 TI - Safety of nursing staff and determinants of adherence to personal protective equipment. AB - A qualitative study conducted in a teaching hospital with 15 nursing professionals. Attempted to analyze the reasons, attitudes and beliefs of nursing staff regarding adherence to personal protective equipment. Data were collected through focus groups, analyzed by the method of interpretation of meanings, considering Rosenstock's model of health beliefs as a reference framework. Data revealed two themes: Occupational safety and Interpersonal Relationship. We identified several barriers that interfere in matters of safety and personal protective equipment, such as communication, work overload, physical structure, accessibility of protective equipment and organizational and management aspects. Adherence to personal protective equipment is determined by the context experienced in the workplace, as well as by individual values and beliefs, but the decision to use the personal protective equipment is individual. PMID- 21584384 TI - Conflict in nursing management in the hospital context. AB - This qualitative study aimed to analyze how conflicts manifest in interpersonal relations and the dimensions they assume in nursing management in hospitals. Data were collected through semi-structured interviews with 13 nurse managers from hospitals in the interior of Rio Grande do Sul, Brazil. Content analysis was used to interpret the results. Among the results, it was highlighted that: a) 11 of the 13 nurses have been managers for more than 80% of their time since graduation and expressed that they had no idea about the management role before taking up this function; b) the nurses consider that conflicts are immanent in the organization, entailing the need to live and interact with them; c) internal conflicts showed to be the most determining for the managers. There is a need to understand the origin of conflicts and factors favoring their establishment, as well as to acknowledge the importance of an interdisciplinary response. PMID- 21584385 TI - Evaluation of single-use reprocessed laparoscopic instrument sterilization. AB - This experimental, comparative, laboratory study evaluated the effectiveness of the sterilization of single-use laparoscopic instruments--SULIs (grasper, dissector, scissors, Veress needle and electrosurgical probe system), after contamination-challenge with bacterial spores and sheep blood, and compared the results of the sterilization tests with those of the equivalent reusable instruments. The cleaning methods used were; ultrasonic washer with pulsatile water jet and enzymatic detergent, manual cleaning, cleaning with pressurized water and rinsing. The SULIs were sterilized with ethylene oxide and the reusable instruments in an autoclave. Sterility tests showed 100% negative results for recovery of contaminate microorganisms in both groups. It was concluded that, regarding the sterilization, that it is possible to reprocess SULIs. PMID- 21584386 TI - Adverse drug events in a sentinel hospital in the State of Goias, Brazil. AB - This was a retrospective, descriptive and documental study with the aim of identifying adverse drug events which occurred in the medication administration process and to classify these medication errors. This study was developed in the internal medicine unit of a general hospital of Goias, Brazil. Report books used by nursing staff from the period 2002 to 2007, were analyzed. A total of 230 medication errors were identified, most of which occurred in the preparation and administration of the medications (64.3%). Medication errors were of omission (50.9%), of dose (16.5%), of schedule (13.5%) and of administration technique (12.2%) and were more frequent with antineoplastic and immunomodulating agents (24.3%) and anti-infective agents (20.9%). It was found that 37.4% of drugs were high alert medications. Considering the medication errors detected it is important to promote a culture of safety in the hospital. PMID- 21584387 TI - Intersectorality and bonding in tuberculosis control in Family Health. AB - This is a qualitative study which aims to analyze the performance of the Family Health teams in the control of tuberculosis according to the relationship between bonding and the development of intersectoral actions in the metropolitan region of Joao Pessoa, Paraiba, Brazil. To construct the empirical material focus group techniques were used. Seven focus groups were conducted, involving 37 professionals of the Family Health teams. For analysis, the discourse analysis technique was used. It was concluded that the lack of intersectoral action weakens the bond between tuberculosis patients, their families and the Family Health team. It is noteworthy that intersectoral measures are fundamental in the development of integral care for tuberculosis patients in the context of Primary Health Care. PMID- 21584388 TI - The purpose of the communication process of group activities in the Family Health Strategy. AB - This study identified the purposes of the communication process in the group activities of the Family Health strategy from the perspective of nurses. Semi structured interviews were conducted and recorded with 60 nurses and non participant observation with 19 group activities, analyzed according to qualitative content analysis. Five categories emerged: Health education, Clinical follow-up, co-responsibilization of patients, Team-Community Interaction, and Work Organization. These categories revealed that the establishment of reciprocal interactions among professionals, patients and families favor health promotion because it encourages the exchange of knowledge among the participants concerning their health experiences. PMID- 21584389 TI - Traffic accidents with motorcycles and their relationship to mortality. AB - This study characterizes traffic accidents involving motorcycles according to local conditions, data concerning the type of accident, date and time, and identifies among these variables those associated with the death of victims. This retrospective study uses data from traffic collision reports from 2004 and death records from the institute of forensic medicine. A total of 99.4% of the events occurred in urban areas, where illumination (87.4%), weather conditions (80.6%); and traffic signs (70.6%) were satisfactory. Collisions between motorcycles and cars or pickup trucks prevailed (55.5%), followed by motorcycle falls (18.0%). In relation to the type of collision, the highest percentage was observed in broadside collision category (35.2%). There were differences between the groups of fatalities and survivors in relation to the area and illumination in the collision's site, in addition to the types of collision and impact. The conclusion is that local conditions and types of collision and impact stand out among the multiple variables defining the severity of accidents involving motorcycles. PMID- 21584390 TI - Movements of permanent health education triggered by the training of facilitators. AB - This study mapped the movements of Permanent Health Education in the region of Araraquara, Sao Paulo, Brazil, begun by the Permanent Health Education Facilitators program, promoted by the Ministry of Health and the National School of Public Health. This qualitative study was grounded on the theoretical framework of institutional and schizoanalysis. Data were collected from operative groups of individuals who finished the program. The results were grouped into two plans: micropolitics and organization. Micropolitics indicates the production of different concepts concerning permanent education and different ways to establish it. Autonomy and control and also a tenuous relationship between tutorship and autonomy were highlighted, in the plan of organization. In conclusion, the program was an important device that suffered captures/overcoding but also produced changes in practice. PMID- 21584391 TI - The construction process of pedagogical knowledge among nursing professors. AB - Didactic knowledge about contents is constructed through an idiosyncratic synthesis between knowledge about the subject area, students' general pedagogical knowledge and the teacher's biography. This study aimed to understand the construction process and the sources of Pedagogical Content Knowledge, as well as to analyze its manifestations and variations in interactive teaching by teachers whom the students considered competent. Data collection involved teachers from an undergraduate nursing program in the South of Brazil, through non-participant observation and semistructured interviews. Data analysis was submitted to the constant comparison method. The results disclose the need for initial education to cover pedagogical aspects for nurses; to assume permanent education as fundamental in view of the complexity of contents and teaching; to use mentoring/monitoring and the value learning with experienced teachers with a view to the development of quality teaching. PMID- 21584392 TI - Contributions of the nursing intervention in primary healthcare for the promotion of breastfeeding. AB - This study aimed to analyze the contributions of the Primary Healthcare nursing interventions, with primiparae in the promotion of breastfeeding. This is a quasi experimental, longitudinal study, with a sample consisting of 151 primiparae, who had less than 28 weeks of pregnancy, with the child living for at least six months after the birth, performed between 15 October 2007 and 29 February 2008. Almost all the women initiated breastfeeding, with a sharp decline verified in the prevalence at six months. The mean duration of breastfeeding was 123.8+/-68.9 days. The intervention that began in the prepartum and continued into the postpartum period, using various strategies (individual consultation, preparation courses for parenting/childbirth, and domicile visits) and intervention contexts (health services and domicile) had significant effects on the duration of breastfeeding, which was not verified in the prevalence. PMID- 21584393 TI - Integrative review of the nursing interventions used for the early detection of cervical uterine cancer. AB - In a national program to combat cervical uterine cancer (CUC) four basic elements should exist: primary prevention, early detection, diagnosis/treatment and palliative care. Of these, early detection is the most effective modality. One of the purposes of Evidence-Based Practice (EBP) is to encourage the use of research results with the assistance provided, reinforcing the importance of research for clinical practice. This study aimed to evaluate the evidence available in the literature regarding effective nursing interventions for the early detection of CUC. The selection of articles was performed in the databases: Scopus, PubMed, CINAHL, Lilacs and Cochrane. The sample of this review consisted of seven articles, with evidence levels 1, 2 or 3. The behavioral, cognitive and social interventions, showed positive effects in the early detection of CUC, especially the interactive cognitive interventions. It is suggested, when appropriate, to use a combination of interventions in order to obtain a more effective result. PMID- 21584394 TI - Climate change and its effects on terrestrial insects and herbivory patterns. AB - Climate change and extreme weather events affect plants and animals and the direct impact of anthropogenic climate change has been documented extensively over the past years. In this review, I address the main consequences of elevated CO2 and O3 concentrations, elevated temperature and changes in rainfall patterns on the interactions between insects and their host plants. Because of their tight relationship with host plants, insect herbivores are expected to suffer direct and indirect effects of climate change through the changes experienced by their host plants, with consequences to population dynamics, community structure and ecosystem functioning. PMID- 21584395 TI - Wolbachia screening in spiders and assessment of horizontal transmission between predator and prey. AB - Recent studies have revealed that the prevalence of Wolbachia in arthropods is attributable not only to its vertical transmission, but also to its horizontal transfer. In order to assess the horizontal transmission of Wolbachia between predator and prey, arthropods belonging to 11 spider families and six insect families were collected in the same field of rice. The distribution of Wolbachia in these arthropods was detected by diagnostic PCR amplification of the wsp (Wolbachia outer surface protein gene) and 16S rDNA genes. Nurscia albofasciata Strand (Araneae: Titanoecidae), Propylea japonica Thunberg (Coleoptera: Coccinellidae), Paederus fuscipes Curtis (Coleoptera: Staphylinidae), and Nilaparvata lugens Stal (Homoptera: Delphacidae) were infected with Wolbachia. This is the first report of infection of N. albofasciata and P. fuscipes by Wolbachia. No direct evidence indicated the existence of horizontal transmission of Wolbachia between predator and prey. PMID- 21584396 TI - Feeding patterns of the aquatic grasshopper Cornops aquaticum (Bruner) (Orthoptera: Acrididae) in the middle Parana river, Argentina. AB - The aquatic grasshopper Cornops aquaticum (Bruner) is native to South America and inhabits lowlands from southern Mexico to Central Argentina and Uruguay. This grasshopper is host-specific to aquatic plants of the genera Eichhornia and Pontederia. The objectives of this study were to analyze the feeding patterns of the aquatic grasshopper C. aquaticum in relationship to development stages and sex and to determine the food consumption rate in their host plant, Eichhornia crassipes. Samples were collected from April 2006 to May 2007 in different floodplain lakes of the Middle Parana River. The average consumption was greater in the females (0.127 g food/day +/- 0.051) than in the males (0.060 g food/day +/- 0.025). The feces of 361 nymphs and adults of this locust were examined and the most common tissue fragments found were of the water hyacinth (E. crassipes). In the initial nymphal stages (I, II and III), an exclusive consumption of E. crassipes was registered, while in the IV and V stages the choice included also other macrophytes. In summary, C. aquaticum presents polyphagy in the field, feeding on six macrophytes of different classes and families. PMID- 21584397 TI - The importance of odor in nest site selection by a lodger bee, Centris Bicornuta Mocsary (Hymenoptera: Apidae) in the dry forest of Costa Rica. AB - The more common lodger bee occurring in the dry forest of Costa Rica, Centris bicornuta Muscary), has been observed nesting in new nest cavities drilled into wooden blocks placed next to cavities used by another female within 2-3 days. In contrast, new nest cavities placed in similar areas with no nesting Centris nearby were not used for weeks. These observations suggest that the presence of nesting bees may play a role in nest site selection. To confirm our observations, new nest cavities were placed in areas with or without nesting. We found nest initiation in newly placed nest cavities only in areas where bees were actively nesting. To examine the possibility that nesting locations are not unique, we placed new nest cavities in new locations either with (a) a number of completed nest cavities or (b) placed alone. Within three days we only found bees nesting in the newly placed nest cavities in situation "a". The results suggested that odor might be involved. We next compared nesting in new cavities placed alone with cavities contaminated with either (a) nest entrance plug material, (b) nest nectar, (c) nest pollen or (d) a combination of pollen and nectar. Nesting was significantly low in cavities placed next to cavities with nest entrance plug material (a), and high in cavities placed next to cavities "b, c, or d". The results suggest that pollen and /or nectar odor play a role in the location of potential nest sites. PMID- 21584398 TI - Population dynamics, life stage and ecological modeling in Chrysomya albiceps (Wiedemann) (Diptera: Calliphoridae). AB - In this study we investigated the population dynamics of Chrysomya albiceps (Wiedemann) with laboratory experiments, employing survival analysis and stage structure mathematical models, emphasizing survival among life stages. The study also assessed the theoretical influence of density dependence and cannibalism during immature stages, on the population dynamics of the species. The survival curves were similar, indicating that populations of C. albiceps exhibit the same pattern of survival among life stages. A strong nonlinear trend was observed, suggesting density dependence, acting during the first life stages of C. albiceps. The time-series simulations produced chaotic oscillations for all life stages, and the cannibalism did not produce qualitative changes in the dynamic behavior. The bifurcation analysis shows that for low values for survival, the population reaches a stable equilibrium, but the cannibalism results in chaotic oscillations practically over all the parametric space. The implications of the patterns of dynamic behavior observed are discussed. PMID- 21584399 TI - Postembryonic development and food consumption of Dichroplus elongatus Giglio-Tos and Dichroplus maculipennis (Blanchard) (Orhtoptera: Acrididae: Melanoplinae) under laboratory conditions. AB - Dichroplus maculipennis (Blanchard) and D. elongatus Giglio-Tos are two of the most important melanoplines in Argentina, both ecologically and economically. The postembryonic development and forage loss (consumption of Bromus brevis Ness + fallen material) caused by older nymphs (instars IV, V, VI) and adults of both species were studied under controlled conditions (30oC, 14L:10D, 40% RH). Five nymphal instars were recorded in D. elongatus, and six in D. maculipennis. Total nymphal development was similar in both species (D. elongatus: 32 +/- 0.70 days; D. maculipennis: 34.5 +/- 0.37 days). Daily consumption increased from nymphal instars to pre-reproductive adult stage. In both species, pre-reproductive females had higher consumption rates than other stages considered (D. elongatus: 30.6 +/- 0.56 mg dry weight/day; D. maculipennis: 48.7 +/- 0.74 mg dry weight/day). In the reproductive stage, consumption decreased significantly in both sexes. When feeding, D. maculipennis let some plant material to drop, increasing total loss. The percentage of fallen material was greater in reproductive adults, representing 3.9% and 2.9% of the total daily loss for males and females, respectively. Females and males of D. maculipennis were heavier than those of D. elongatus (P < 0.05), and daily consumption was significantly higher (P < 0.05). Regardless sex and reproductive status, adults of D. maculipennis consumed 29.1 +/- 0.64 mg dry weight/day on average, while one of D. elongatus 20.0 +/- 0.3 mg dry weight/ day. PMID- 21584400 TI - Duration of feeding and superficial and in-depth damage to soybean seed by selected species of stink bugs (Heteroptera: Pentatomidae). AB - Laboratory studies were conducted to compare duration of feeding and superficial and in-depth damage to soybean (Glycine max) seeds by the Southern green stink bug, Nezara viridula (L.), the Neotropical brown stink bug, Euschistus heros (F.), the red-banded stink bug, Piezodorus guildinii (Westwood), and the green belly stink bug, Dichelops melacanthus (Dallas). Results indicated that feeding time was significantly longer for N. viridula (~ 133 min) compared to E. heros and D. melacanthus (~ 70 min), but not different from P. guildinii (~ 103 min). There was a positive correlation between feeding time and the resulting damage for E. heros, N. viridula and P. guildinii (R2 > 0.80, P < 0.0001), but not for D. melacanthus (R2 = 0.1011, P = 0.1493). The deepest seed damage (2.0 mm) was made by P. guildinii and the shallowest (0.5 mm) by D. melacanthus. The depth of the seed damage by E. heros and N. viridula (0.8, 1.2 mm, respectively) was intermediate in comparison to the other species studied. Feeding damage to the seed endosperm caused variable cell disruption and protein body dissolution, particularly when P. guildinii fed on seeds, suggesting that the deleterious action of salivary enzymes was greater for this bug compared to the others. PMID- 21584401 TI - [Population genetic structure of Bemisia tabaci (Hemiptera: Aleyrodidae) utilizing microsatellite markers]. AB - We aimed to characterize the population genetic structure within and among five Bemisia tabaci (Gennadius) populations collected from different host plants and geographic regions by using microssatelites as a molecular marker. Each population was represented by 19 specimens. The host plants and geographic origins of these populations were described as follows: Pop 1: Squash Barreiras (BA); Pop 2: Cotton Barreiras (BA); Pop 3: Soybean Campinas (SP); Pop 4: Tomato Cruz das Almas (BA); and Pop 5: Soybean Rondonopolis (MT). Six polymorphic loci were observed, which discriminated 31 different alleles in the studied populations, with a mean number of alleles per population of 3.30 (2.67 - 4.00). Using Fisher's Exact test, it was observed that at least three populations were in Hardy-Weinberg equilibrium for most of the studied loci (six). The dendrogram (UPGMA) separated populations into groups mainly related to the geographic origin of the samples. Only population 5 differed from the others at a 0.15 distance (74.5% group consistency). The most similar populations were 1 and 2, with a 0.01 distance (65.3%). This is in agreement with their geographic origins and it was not consistent with host specificity. The results suggest considerable gene flow (7.3%) among all whitefly populations and indicate that a better understanding of the gene flow in populations of B. tabaci associated with different hosts is required for the management of this insect. PMID- 21584402 TI - Morphometry and distribution of sensilla on the antennae of Anastrepha fraterculus (Wiedemann) (Diptera: Tephritidae). AB - Antennal sensilla of Anastrepha fraterculus (Wied.) were examined using scanning electron microscopy. In the flagellum, there are trichoid, basiconic, clavate type I and II, and styloconic sensilla and microtrichia. Only microtrichiae and chaetica sensilla were observed in the scape and pedicel. The number of sensilla in the flagellum was similar between sexes. At the apex there was a higher density of trichoid and an absence of clavate sensilla, while basiconic sensilla were more abundant in the proximal region. PMID- 21584403 TI - Phylogenetic relationships of the genus Hoplia Illiger (Scarabaeidae: Hopliinae). AB - Results of phylogenetic analysis based on 34 morphological characters of 24 species of 11 genera of Hopliinae from Europe, Japan, South Africa, Madagascar, North and Central America, indicates that the genus Hoplia is a monophyletic group with species distributed in Europe, Japan and America. Based in this analysis the Asiatic genus Ectinohoplia is the closest relative of the genus Hoplia, and the South American genus Barybas (Melolonthinae: Macrodactylini) is the sister group of Hopliinae. PMID- 21584404 TI - Ultrastructural and functional aspects of the spermatheca in the American harlequin bug, Murgantia histrionica (Hemiptera: Pentatomidae). AB - The spermatheca of Murgantia histrionica (Hahn) was investigated using fluorescence, scanning and transmission electron microscopy. The aim of the study was to elucidate the structure of this organ, pointing out differences between mated and unmated females. Results have shown an elaborated cuticular structure associated with muscular and glandular tissues. The spermatheca is joined with the common oviduct by the spermathecal duct, forming a thin saccular dilation through two consecutive invaginations. The distal part of the organ is formed by a series of two communicating cuticular chambers. The first cylindrical-shaped chamber, corresponding to the coiled region, is wrapped by longitudinal muscular fibers suspended between two cuticular flanges. The contractions of these fibers compress a deformable zone of the cylinder, pumping the sperm toward the spermathecal duct. Without contractions the cylinder results to be isolated from the proximal part of the spermatheca by means of a valve. The second chamber, corresponding to the spermatheca, is made of two parts: a truncated-conical sub chamber, with a constant cuticular thickness, bearing on itself the distal flange, where muscular fibers are attached. The second part is a bulb-like structure wrapped in a glandular epithelium. The secretory units are composed by two cells: a secretory cell and an associated duct cell. Every evacuating duct shows a little reservoir just after the terminal apparatus, and converge inside the distal bulb after a tortuous path. The functional implications of this structure in the reproductive biology of M. histrionica are discussed. PMID- 21584405 TI - A new genus and species of Euptychiina (Lepidoptera: Nymphalidae: Satyrinae) from southern Brazil. AB - This paper describes a new genus and a new species of Euptychiina from open grassland habitats (campos de cima da serra) in southern Brazil. The systematic position of this new taxon is discussed based on morphological and molecular data, and it is considered sister to Taydebis Freitas. Since the campos vegetation is considered endangered due to anthropogenic activities, this butterfly species deserves attention and should be included in future conservation plans for this biome. PMID- 21584406 TI - [Influence of Diaphania hyalinata (L.) (Lepidoptera: Crambidae) egg density on the parasitization capacity of Trichogramma exiguum Pinto & Platner and Trichogramma pretiosum Riley (Hymenoptera: Trichogrammatidae)]. AB - The effects of the egg density of Diaphania hyalinata (L.) on several biological parameters of Trichogramma exiguum Pinto & Platner and T. pretiosum Riley were investigated. For that, 24h-old egg masses were isolated in glass tubes (15 replicates; 1 egg mass = 1 replicate), and offered to parasitization by a newly emerged female of T. pretiosum or T. exiguum 24h at the proportion of one female to 5, 10, 15, 20, 25, 30, 35 and 40 eggs of D. hyalinata. The following parameters were evaluated: number of parasitized eggs, number of individuals per egg, viability and sex ratio. Trichogramma exiguum parasitized more eggs than T. pretiosum when more than 25 eggs were available per female. The percentage of emergence was satisfactory to T. pretiosum in densities up to 15 eggs/female and up to 20 eggs/female for T. exiguum. The number of individuals per egg was not statistically different in both species except in the density of 25 eggs/female. It can be concluded that T. exiguum performed better than T. pretiosum at larger clutch sizes, as T. exiguum parasitization capacity increased as a result of the size of the host clutch size. PMID- 21584407 TI - Laboratory and field evaluation of Metarhizium anisopliae var. anisopliae for controlling subterranean termites. AB - The efficacy of the Metarhizium anisopliae strain ARSEF 6911 was determined in the laboratory and field against two sugarcane pests, Microtermes obesi Holmgren and Odontotermes obesus Rambur (Termitidae: Isoptera). The susceptibility of both termite species to different conidial suspensions (1 * 10(10), 1 * 10(8), 1 * 10(6) and 1 * 10(4) conidia/ml) was determined in laboratory. All conidial suspensions were able to induce mortality. Termite mortality caused by the fungal suspensions was dose dependent. There were no significant differences in the LT50 values between species. Field evaluation of M. anisopliae alone or in combination with diesel oil and thiamethoxam was carried out in two growing seasons (autumn 2005 and spring 2006) at two sites located in Punjab, Pakistan. Dipping the sugarcane setts in these suspensions was tried to determine their effects on germination and percentage of bud damage to sugarcane setts. All treatments significantly reduced termite infestation compared to the untreated control. The combined treatment of M. anisopliae and diesel oil significantly reduced insect damage by attaining higher germination > 55% and lower bud damage < 5.50% at both sites in both seasons. The results suggest that the application of M. anisopliae and diesel oil in combination might be a useful treatment option for the management of termites in sugarcane. PMID- 21584408 TI - [Effect of the populations of Alabama argillacea (Hubner) (Lepidoptera: Noctuidae) on cotton crop at two sowing distances]. AB - The objective of this research was to evaluate the incidence of damage by the leafworm Alabama argillacea (Hubner) on yields of cotton grown under rows spaced 0.38 m and 0.76 m at the irrigation area of Santiago del Estero, Argentina. The period evaluated was extended from first flower to first open boll. Treatments were T1 - without control of larvae, T2 - with control of larvae, T3 - control since first flower to the end of effective blooming, and T4 - with larval control since the end of effective blooming to first open boll. The effect of injuries on the crop was evaluated trough boll cotton yield. Larvae were sampled in a weekly basis and insects were present from the first flower until harvest. Populations of A. argillacea decreased crop yields in the two distances tested, by decreasing the weight or number of open bolls. PMID- 21584409 TI - Sequential sampling of Aphis gossypii Glover (Hemiptera: Aphididae) and Frankliniella schultzei Trybom (Thysanoptera: Thripidae) on cotton crop. AB - The goal of this research was to use the sequential probability ratio test to establish a sequential sampling plan for Aphis gossypii Glover and Frankliniella schultzei Trybom infesting cotton. Field work was conducted at the agricultural experimental station of the Universidade Federal da Grande Dourados during the 2003/2004 and 2004/2005 agricultural years. Aphid colonies and individual thrips in the sampling area were counted and their numbers were recorded. The spatial distribution pattern of A. gossypii and F. schultzei in the cotton culture was aggregated. Sequential sampling plans were developed for aphids and thrips with type I and type II errors set at 0.1, common Kc = 0.6081 (aphids) and = 0. 9449 (thrips), and safety and management levels of 20% (aphids) and 40% (thrips) of infested plants. The sampling plans resulted in two decision boundaries for each species, as follows: the upper boundary, indicating when management (population control) is recommended: S1 = 4.6546 + 0.2849n (aphids), and S1 = 3.6514 + 0.1435n (thrips); and the lower boundary, indicating when population control is not necessary: S0 = -4.6546 + 0.2849n (aphids) and S0 = - 3.6514 + 0.1435n (thrips). The highest probability of error when making a decision was 3% for aphids and 2% for thrips, respectively. The maximum number of samples required to reach a decision was 63 for aphids and 95 for thrips. PMID- 21584410 TI - Insecticide resistance in populations of the diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae), from the state of Pernambuco, Brazil. AB - The diamondback moth Plutella xylostella (L.) has a great economic importance in Brassicaceae crops in many parts of the world. Recurrent infestations of this pest in growing areas of Pernambuco state, Brazil, have led farmers to frequently spray their crops with insecticides. However, control failures by several insecticides have been alleged by farmers. The objective of this study was to check whether resistance to insecticides could explain these control failures in P. xylostella. Populations of P. xylostella from Pernambuco were collected between January and April 2009. The resistance ratios of P. xylostella populations were compared among five different active ingredients: abamectin, methomyl, lufenuron, indoxacarb, and diafenthiuron by leaf dipping bioassays using foliar discs of kale leaves. Mortality data were submitted to probit analysis. The P. xylostella populations showed variable response and significant resistance to one or more insecticides. The population from Bezerros County exhibited the highest resistance ratios to indoxacarb (25.3 times), abamectin (61.7 times), and lufenuron (705.2 times), when compared to the reference population. The populations from Bonito and Jupi Counties were 33.0 and 12.0 times more resistant to lufenuron and abamectin, respectively, when compared with the reference population. Resistance to methomyl was the least common, but not less important, in at least four populations. These results indicated that control failures were associated with resistance by some of the evaluated insecticides, reinforcing the need for resistance management in areas of the state of Pernambuco. PMID- 21584411 TI - The effect of fragmentation on phlebotomine communities (Diptera: Psychodidae) in areas of ombrophilous forest in Sao Luis, state of Maranhao, Brazil. AB - The aim of this study was to determine whether an edge effect could be observed in the structure and composition of phlebotomine assemblages in five forest fragments on Sao Luis Island. The study also investigated whether there were any differences in species along the forest edge-to-interior gradient and in species richness and abundance between the fragments studied. To capture the insects a transect was defined in each fragment, and eight light traps were set up at 15 m intervals from the edge. Phlebotomines were found in all fragments, and a total of 2972 specimens (1188 males and 1784 females) belonging to 24 species were collected. Of these, the most abundant was Lutzomyia antunesi (Coutinho), followed by Brumptomyia avellari (Costa Lima), L. infraspinosa (Mangabeira), L. flaviscutellata (Mangabeira), L. claustrei Abonnenc, Leger & Fauran, L. wellcomei (Fraiha, Shaw & Lainson), L. sordellii (Shannon & Del Ponte) and L. paraensis (Costa Lima). No significant differences were observed in the number of individuals or species along the edge-to-interior gradient. However, a higher distribution of some species in certain regions of the forest could be observed graphically. There was no correlation between fragment size and the number of species or individuals. PMID- 21584412 TI - Does native bromeliads represent important breeding sites for Aedes aegypti (L.) (Diptera: Culicidae) in urbanized areas? AB - This study evaluates the importance of native bromeliads growing on rocky outcrops interspersed with urbanized areas as breeding sites for the Aedes aegypti (L.) in Vitoria, state of Espirito Santo, Brazil. Oviposition traps were installed in backyards of houses in two separate zones. In the first zone houses were up to 50 m away from the rocky outcrops, while in the second zone they were at least at 200 m from the rocky outcrops. Aedes aegypti was significantly more abundant in the latter zone. The finding was that rocky outcrops with native bromeliads, even with the greater availability of potential breeding sites, do not play an important role as breeding sites for A. aegypti. This conclusion supports the hypothesis that the macrobiota of native bromeliads plays an important role in the natural control of A. aegypti. Besides, the interspecific competition between species of mosquitoes and the attractiveness of bromeliads could also be important factors. PMID- 21584413 TI - New records, threatens and conservation status for Dichotomius schiffleri Vaz-de Mello, Louzada & Gavino (Coleoptera: Scarabaeidae): an endangered dung beetle species from Brazilian atlantic forest ecosystems. AB - Dichotomius schiffleri Vaz-de-Mello et al is often cited as endemic to the preserved coastal sandy-dune vegetation (restinga) of Guriri Island, Espirito Santo state, and is included in the Brazilian List of Endangered Fauna as "critically endangered" (CR). However, we recorded its occurrence in twelve additional sites along the coasts of Espirito Santo, Bahia, Sergipe and Pernambuco. The geographic distribution of D. schiffleri is limited to the coastal Atlantic Forest domain, mainly in preserved restinga patches. We recommend that D. schiffleri remains in the List of Endangered species, but in the "endangered" (EN) category, according to the IUCN criteria. PMID- 21584414 TI - First host record for Anteon pilicorne (Ogloblin) (Hymenoptera: Dryinidae), a parasitoid of Cicadellidae, including the corn leafhopper (Hemiptera: Cicadellidae). AB - For the first time the dryinid wasp Anteon pilicorne (Ogloblin) is recorded as a parasitoid of two Macrostelini leafhoppers: Balclutha rosea (Scott) and the corn leafhopper Dalbulus maidis (DeLong & Wolcott). New distributional records are presented. PMID- 21584415 TI - Occurrence of Scaptocoris castanea Perty (Hemiptera: Cydnidae) damaging Azadirachta indica (Meliaceae) seedlings in Brazil. AB - Neem (Azadirachta indica) seedlings were found infested by the brown burrower bug, Scaptocoris castanea Perty, in December 2009, in the county of Tupaciguara, Minas Gerais state. Symptoms observed varied from leaf yellowing and stem drying, reduction in root size and number to plant death. This is the first report of S. castanea attacking neem plants. PMID- 21584416 TI - Record of Diglyphus walker (Hymenoptera: Eulophidae) species in Brazil. AB - Leafminers (Diptera: Agromyzidae) are pests of various crops, mainly in greenhouses, and have Diglyphus spp. as important leafminer larval parasitoids. Until recently, only Diglyphus insularis (Gahan) had been reported in Brazil. In here we report the first records of Diglyphus begini (Ashmead), D. intermedius (Girault) and D. isaea (Walker) in Brazil. These parasitoids were found parasitizing leafminer larvae on cultivated and spontaneous plants in some areas of Minas Gerais state, Brazil. PMID- 21584417 TI - BiobadaBrasil: Brazilian biologic registry. PMID- 21584418 TI - Comorbidities in patients with osteoarthritis: frequency and impact on pain and physical function. AB - INTRODUCTION: As the prevalence of osteoarthritis (OA) increases with age, the coexistence of other chronic diseases is common. OBJECTIVES: To evaluate the frequency of comorbidities in OA patients and to measure their impact on pain and physical function of those patients. METHODS: Cross-sectional study in OA patients of a public rheumatology clinic. Pain was measured by use of the Visual Analogue Scale (VAS) and physical function by use of the Lequesne's and SACRAH indices. A screening for depression was performed, as were the following measurements: anthropometric data; blood pressure; fasting glycemia; and lipid profile. RESULTS: The study assessed 91 patients (mean age 59.3 years; 91.4% female). The metabolic syndrome frequency was 54.9%. Hypertension occurred in 75.8% of the patients, dyslipidemia in 52.6%, and obesity in 57.1%. The screening for depression was positive in 61.3% of patients. When comparing the metabolic syndrome components individually, patients with hypertension had higher SACRAH scores, with statistically significant differences (P = 0.035). For the other variables, no differences among the Lequesne's, SACRAH and VAS scores were observed. CONCLUSION: This group of OA patients showed a high frequency of depression, metabolic syndrome and its components in isolation, which can impact the pain and physical function of those patients. Such results showed the need for investigating and treating those comorbidities in OA patients. PMID- 21584419 TI - Bisphosphonates can reduce bone hunger after parathyroidectomy in patients with primary hyperparathyroidism and osteitis fibrosa cystica. AB - OBJECTIVE: To assess the effect of bisphosphonates on post-parathyroidectomy hypocalcemia in patients with osteitis fibrosa cystica. METHODS: Review of the medical records of six patients using bisphosphonates preoperatively. RESULTS: Mean age was 35.6 +/- 10.5 years; serum calcium = 13.51 + 0.87 mg/dL; iPTH = 1,389 + 609 pg/mL. The mean value of urine deoxypyridinoline (UDPD) of three patients was 131 +/- 183 nmol/mmol Cr, and of C-telopeptide (CTX), 2,253 +/- 1,587 pg/mL. The mean values of bone densitometry (T score) were as follows: 0.673 +/- 0.150 g/cm(2) (-4.42 +/- 1.23) in lumbar spine (L2-L4); 0.456 +/- 0.149 g/cm(2) (-5.58 +/- 1.79) in the femoral neck; and 0.316 +/- 0.055 g/cm(2) (-5.85 +/- 0.53) in radius 33. Patient 1 received oral alendronate, 30 mg/day for four weeks; his calcium decreased from 14 to 11.6 mg/dL, and his UDPD from 342 to 160 nmol/mmol Cr. Patient 2 received oral alendronate, 20 mg/day for six weeks; his calcium decreased from 14 to 11.0 mg/dL and his UDPD from 28.8 to 14 nmol/mmol Cr. Patient 3 received intravenous pamidronate, 90 mg prior to surgery. Patient 4 received oral alendronate, 140 mg/week for six weeks; her calcium decreased from 13.7 to 12.3 mg/dL and her CTX from 2,160 to 1,340 pg/mL. Patient 5 received oral alendronate, 140 mg/ week for six weeks; her calcium levels dropped from 14.3 to 14.1 mg/dL; her CTX did not change. Patient 6 received ibandronate, 150 mg, ten days prior to surgery; his CTX reduced by 62%. No patient developed severe hypocalcemia in the first postoperative week. One year after surgery, the mean gain in bone mineral density was 40% +/- 29% in L2-L4, 86 +/- 39% in the femoral neck, and 22% +/- 11% in radius 33. CONCLUSION: The preoperative use of bisphosphonates seems to attenuate bone hunger without preventing a significant increase in bone mass in the follow-up of parathyroidectomy. PMID- 21584420 TI - Liver toxicity is rare in rheumatoid arthritis patients using combination therapy with leflunomide and methotrexate. AB - OBJECTIVE: Some studies have reported that adding leflunomide (LEF) to the treatment of rheumatoid arthritis (RA) in patients who do not respond to methotrexate (MTX) improved efficacy but increased the risk of liver toxicity. This study aimed at assessing the incidence of liver toxicity in patients with active RA using the LEF and MTX combination therapy in comparison with that of patients on MTX monotherapy. METHODS: Between February and September 2009, 97 consecutive patients followed up at the University Hospital of the Universidade Federal de Santa Catarina, Brazil, were enrolled. RA patients on MTX alone or using the LEF and MTX combination had their medical records systematically reviewed. The alanine/aspartate aminotransferase enzymes were retrospectively analyzed since the beginning of treatment with MTX or MTX plus LEF. Hepatotoxicity was defined as an increase of at least two-fold the upper limits of normal of the liver enzymes. RESULTS: 71 RA patients were included in the study: 36.6% were using 20-25 mg/week of MTX alone and 63.4% were using 20-25 mg/week of MTX plus 20 mg/day of LEF. Of the patients on the combination therapy, 11.1% had abnormal levels of liver enzymes versus 11.5% of the patients on monotherapy (P = 1.0). Abnormal aminotransferase levels have been seen with both MTX and LEF monotherapies in patients with RA. In our study, no difference was found between the percentages of aminotransferase elevations of patients being treated with MTX alone or in combination with LEF. CONCLUSION: The combination of MTX and LEF in RA patients is generally safe and well tolerated. PMID- 21584421 TI - Brazilian biologic registry: BiobadaBrasil implementation process and preliminary results. AB - OBJECTIVES: The present study aimed at describing the implementation process of a national registry in a developing country (Brazil) and at reporting the main preliminary results of the BiobadaBrasil registry. MATERIAL AND METHODS: Through a PANLAR agreement, the Biobadaser protocol was used as a model for implementing the new registry in our country. During the first two years of this effort, the original protocol was adapted, translated, and presented to all Brazilian rheumatologists. For ten months, data of 1,037 patients (750 subjects treated with biological drugs and 287 control subjects) from 15 centers were collected. RESULTS: Most patients had rheumatoid arthritis (RA) (n = 723). Infliximab was the most frequently used anti-TNF agent, and the total exposure to biologic drugs was 2,101 patient-years. The most common reason for interrupting drug use was lack or loss of efficacy (50%), while 30% withdrew from the treatment arm due to adverse events. Three cases of tuberculosis were observed in the biologic group, with an incidence higher than that of the general Brazilian population. Infections were observed in 23% of the biologic group, and the upper respiratory tract was the most commonly affected site. Only one case of tuberculoid leprosy was observed. No deaths or malignancies attributed to drug effects were observed as of February 2010. CONCLUSIONS: The implementation of the BiobadaBrasil registry was successful, and, although recent, the registry has provided important data. PMID- 21584422 TI - Drug interactions: a contribution to the rational use of synthetic and biological immunosuppressants. AB - Drug interaction is a clinical event in which the effects of a drug are altered by the presence of another drug, phytochemical drug, food, beverage, or any environmental chemical agent. The incidence of adverse reactions caused by drug interactions is unknown. This lack of information is compounded by not knowing the number of patients who are prescribed combinations of drugs that can potentially interact. Patients who will or will not experience an adverse drug interaction cannot be clearly identified. Those with multiple diseases, with kidney or liver dysfunction, and those on many drugs are likely to be the most susceptible. Patients with autoimmune diseases are at higher risk for drug interactions. In addition to representing a risk for the patient and jeopardizing the health care provided by professionals, drug interactions can increase dramatically health care costs. This review article approached the clinically relevant interactions between the most used drugs in rheumatology (except for non steroidal anti-inflammatories and corticosteroids) aiming at helping rheumatologists to pharmacologically interfere in the disease processes, in the search for better outcomes for patients and lower costs with the complex therapy of chronic diseases they deal with. PMID- 21584423 TI - Informed consent in rheumatology care practice. AB - Informed consent is a mandatory document in human subject research protocols. Its principles have been recently established in the history of Medicine, and the first official document to establish the need for an informed consent from the research subject was the Nuremberg Code (1947). All following documents confirmed that the informed consent is mandatory in human subject research. However, the informed consent, which represents patients' autonomy or self-determination regarding their relationship with their physicians, took a while to be included in medical care practice and medical deontology codes. The convenience of using the informed consent in medical practice is widely discussed today, especially in rheumatology. Our opinion is that the obligation of a signed informed consent provided by the patient for every medical procedure is neither reasonable nor practical. It should be used for more invasive or risky therapeutic procedures. We understand that the informed consent does not guarantee that the patient has been fully informed, which is an essential condition for the current rheumatological practice. Its adoption in routine medical care practice would make medical intervention bureaucratic, and, thus, quite different from the Hippocratic view, which considered the trustful physician-patient relationship fundamental for an adequate medical care practice. PMID- 21584424 TI - Graves' disease associated with juvenile idiopathic arthritis. AB - The authors report the case of a 10-year-old girl with Graves' disease (GD), treated with propylthiouracil, who developed uveitis and polyarticular arthritis, and whose mother also had GD and discoid lupus. The differential diagnosis of inflammatory arthritis that appears in a child with autoimmune thyroid disease managed with antithyroid drugs is discussed. PMID- 21584425 TI - Treatment of mesenteric angina in patients with Takayasu's arteritis. AB - Takayasu's arteritis (TA) is an idiopathic chronic inflammatory disease of the connective tissue that affects mainly the aorta and its branches. Treatment is mainly based on corticosteroids and immunosuppressants. We report the case of a 33-year-old female complaining of malaise, fever, myalgia, severe pulsing holocranial headache resistant to analgesics, systemic arterial hypertension hard to control, right lower limb claudication, and severe abdominal pain that worsened after the meals. Angiotomography revealed aneurysm of the ascending aorta, and stenosis of the following vessels: right common iliac artery, renal arteries, and superior mesenteric artery. Those findings supported the diagnosis of mesenteric angina and the interventional approach by use of percutaneous transluminal angioplasty with stent placement. PMID- 21584426 TI - [Recommendations of Neuroendocrinology Department from Brazilian Society of Endocrinology and Metabolism for diagnosis and treatment of acromegaly in Brazil]. AB - Acromegaly is a disease associated with increased morbidity and reduced life expectancy. Because of its insidious character and its non-recognition, the diagnosis is often made with delay, which, along with the complications related to GH/IGF-I excess, determines high morbidity and mortality. However, an early diagnosis and an effective treatment reduce the morbidity and normalize the mortality rate. In this publication, the goal of Neuroendocrinology Department from Brazilian Society of Endocrinology and Metabolism is to disclose which clinical set should arouse the suspicious of acromegaly and how to diagnose it. Furthermore, we discuss the most effective and safe approach to perform the treatment of acromegaly, emphasizing that it must be carried out in reference centers. Therefore, based on data published in journals with recognized scientific level and authors' experience, recommendations are presented for diagnosis and treatment of the disease. PMID- 21584427 TI - [The role of vascular endothelial growth factor in angiogenesis and diabetic retinopathy]. AB - Diabetic retinopathy (DR), a DM microvascular complication, is the leading cause of blindness. Angiogenic factors such as vascular endothelial growth factor (VEGF) are involved in the pathogenesis of DR. VEGF-A is a potent, multifunctional cytokine that acts through the receptors VEGFR-1 and VEGFR-2 expressed in the vascular endothelium and causing increased vascular permeability and neovascularization stimulation in both physiological and pathological processes. The expression of VEGFR-1 is upregulated by hypoxia and is less responsive to VEGF compared to VEGFR-2 which is the main mediator mitogenic, angiogenic, and increased vascular permeability. VEGF polymorphisms have been studied in DR susceptibility and progression. Significant association between the polymorphism 634C / G and the presence of RD is reported mainly in relation to allele C. The homozygous CC is associated to proliferative RD and to increased vitreous and serum levels of VEGF suggesting that the presence of the C allele is an independent risk factor for RD. The knowledge of VEGF lead to the development of anti-VEGF drugs (pegaptanib, ranibizumab and bevacizumab) aiming to prevent pathological neovascularization. The anti-VEGF therapy is a reality in practice medical treatment of DR. PMID- 21584428 TI - [Body mass index to the cardiovascular disease risk screening in infancy]. AB - OBJECTIVE: To purpose news body mass index (BMI) cut offs to 7 to 12 years old scholars. SUBJECTS AND METHODS: 1.413 scholars of 7 to 12 years old selected of aleatory way. Were measured the BMI, total cholesterol (TC), and systolic (SBP) and diastolic blood pressure (DBP). To the date analyze were used the receiver operating characteristic curve (ROC curve) and the bivariate analyze. RESULTS: The BMI cut offs proposed at this study show adequate capacity to identify true positive and negative to the cardiovascular diseases (CVD) risk factors presence. Besides, these cut offs show higher and more balanced sensibility and specificity values than other cut offs proposals. CONCLUSIONS: The BMI proposed at this study configure with as the more adequate alternative to the screening for the scholars with increased chances to carry DCV risk factors. PMID- 21584429 TI - Lipid profile, apolipoprotein A-I and oxidative stress in professional footballers, sedentary individuals, and their relatives. AB - OBJECTIVE: To evaluate whether lipid profile (LP), apolipoprotein A-1 (apo A-I) and malondialdehyde (MDA) have any relationship with physical exercise by comparing the groups of footballers (FG) with sedentary individuals (CG) and their relatives (RFG and RCG). SUBJECTS AND METHODS: Twenty individuals from FG and CG, 60 from RFG, and 57 from RCG were studied. RESULTS: FG showed lower levels of total cholesterol (119.5 +/- 37.9 mg/dL), LDL-cholesterol fraction (53.6 +/- 30.3), apo A-I (116.7 +/- 11.9), and higher level of HDL-cholesterol fraction (HDLc) (49.7 +/- 8.5) compared to RFG (148.3 +/- 36.9, P = 0.02; 82.4 +/ 37.7, P < 0.01; 124.6 +/- 10.2, P = 0.03; and 42.7 +/- 7.7, P < 0.01; respectively). Moreover, FG had reduced levels of MDA (101.0 +/- 77.0 ng/mL) compared to CG (290.0 +/- 341.0, P = 0.03) and RFG (209.9 +/- 197.5, P = 0.04). CONCLUSIONS: These results suggest an association between physical exercise and lower levels of MDA in FG. Physical activity seems to promote beneficial effects on the LP regardless of the genetic influence considering HDLc levels. PMID- 21584430 TI - Prevalence of diabetes mellitus in the Japanese-Brazilian community of Mombuca, Guatapara, SP. AB - OBJECTIVE: To estimate the prevalence of type 2 diabetes mellitus (DM2) and impaired glucose tolerance (IGT) in the Japanese-Brazilian community of Mombuca in relation to risk factors (FR) for diabetes and cardiovascular disease. SUBJECTS AND METHODS: Cross-sectional study with 131 individuals of Japanese ancestry (69% first generation), aged 20 years or more, submitted to socio cultural, anthropometric, and biochemistry evaluation. RESULTS: Of the individuals studied (n = 131, age = 55.1 +/- 15.9 years), 58.8% were women. The prevalence of DM2 and IGT were 13.7% and 14.5%, respectively. Regarding RF, 76.3% presented dyslipidemia, 52.7% abdominal obesity, 48.1% arterial hypertension, and 42.3% whole body obesity. CONCLUSIONS: The prevalence of DM2, IGT, and RF in this Japanese-Brazilian community was higher than in the adult population of the city of Ribeirao Preto-SP, Brazil, suggesting an increase in risk conditions for these morbidities. PMID- 21584431 TI - [Impact of a lifestyle intervention program on metabolic, anthropometrical and dietary profile of Japanese-Brazilians with and without metabolic syndrome]. AB - OBJECTIVE: We evaluated the changes in biochemical and nutritional profiles of Japanese-Brazilians with and without metabolic syndrome after two years of participation in the intervention program. MATERIALS AND METHODS: It was a non controlled experimental study. The biochemical and clinical assessments were conducted at baseline (2005), after a year (2006) and after two years (2007) of intervention. On the present study, data of 360 individuals, who participated on the three assessments were considered. RESULTS: Both groups presented improvements on the anthropometric and metabolic profile, after two years of intervention. It was observed reduction in the intake of total fat, saturated fat, and dietary cholesterol, and increased intake of fiber among men without metabolic syndrome. It was observed reduction in the intake of total fat (p = 0,003) and monounsaturated fatty acid (p = 0,002). CONCLUSION: The results showed a positive impact of the lifestyle intervention program in metabolic and nutritional profile of Japanese-Brazilians with and without metabolic syndrome. PMID- 21584432 TI - [Adiponectin and low cardiometabolic risk in obese women]. AB - OBJECTIVE: To investigate the association between elevated levels of plasmatic adiponectin (AdipoQ) and low cardiometabolic risk (CMR) in obese women (O(b)W). SUBJECTS AND METHODS: Case-control study, matched by age, of 306 O(b)W, BMI > 30 kg/m2, with 66 cases (21.6%) - all non-hypertensive, normolipidemic, and non diabetic - conducted in SUS (Brazil's Public Health System) outpatient referral services for obesity in the City of Salvador, Brazil. Secondary data were collected from medical records; primary and complementary data were obtained from a clinical pathology laboratory. Values of AdipoQ > 10.00 ug/ml (> 3(rd) quartile) were considered elevated. Descriptive, bivariate, and conditional logistic regression analyses were performed. RESULTS: A statistically significant positive association between low CMR and AdipoQ > 10.00 ug/ml in physically active (AOR = 5.1; CI95%: 1.8-14.3), non-smoking (AOR = 3.6;CI95%: 1.6-8.4) O(b)W was found. CONCLUSION: This study suggests that physically active, non-smoking O(b)W, with higher AdipoQ levels, present greater chances of a low CMR. It becomes important to reinforce encouragement of the adoption of healthy behaviors, by means of public policies. PMID- 21584434 TI - Prevalence of metabolic syndrome and of its specific components among adolescents from Niteroi City, Rio de Janeiro State, Brazil. AB - OBJECTIVE: To compare the prevalence of metabolic abnormalities (MA) and metabolic syndrome (MS) assessed by different criteria among Brazilian adolescents. SUBJECTS AND METHODS: Weighted prevalence of MA and MS were estimated using criteria adapted from the International Diabetes Federation (IDF), National Cholesterol Education Program, Adult Treatment Panel III (NCEP/ATP III), and the World Health Organization (WHO) in a probabilistic sample of 577 students aged 12-19. RESULTS: The most prevalent MA was low concentration of HDL-C as per IDF (32.5%) and NCEP/ATP III (41.6%) criteria and hypertension as per the WHO's criterion (12.4%). Prevalence of MS using the NCEP/ATP III criterion (6.04%) was five times higher than the WHO's (1.1%) and the IDF's (1.6%) criteria. As expected, MS was significantly higher among overweight than among non-overweight adolescents. CONCLUSION: Low prevalence of MS but high prevalence of some MA were found. These findings suggest that the diagnosis of MA is more relevant in clinical practice especially in overweight adolescents. PMID- 21584433 TI - [Resistive training reduces inflammation in skeletal muscle and improves the peripheral insulin sensitivity in obese rats induced by hyperlipidic diet]. AB - OBJECTIVE: To determine if resistive exercise protocol can modulate Tnf-alpha, SOCS3 and glucose transporter GLUT4 genes expression in skeletal muscle, and peripheral insulin sensitivity in obese rats induced by hyperlipidic diet. MATERIALS AND METHODS: Wistar obese rats induced by hyperlipidic diet were subjected a resistive exercise protocol as jump squat. Insulin sensitivity and mRNA content of Tnf-alpha, SOCS3 and GLUT4 were assayed and compared among the groups: obese sedentary (OS) and exercised (OE), control sedentary (CS) and exercised (CE). RESULTS: The mRNA content of Tnf-alpha and SOCS3 has increased in skeletal muscle from OS and has decreased in OE group. The protein and GLUT4 mRNA contents were correlated but they did not change among the groups. Peripheral insulin sensitivity has increased in the OE compared to OS group. CONCLUSION: The resistive exercise reverses the peripheral insulin resistance and the inflammatory state in skeletal muscle from diet-induced obese rats. PMID- 21584435 TI - Sheehan's syndrome with central diabetes insipidus. AB - Sheehan's syndrome refers to the occurrence of hypopituitarism after delivery, usually preceded by postpartum hemorrhage. The condition still continues to be a common cause of hypopituitarism in developing countries like India. The disorder usually presents with anterior pituitary failure with preservation of posterior pituitary functions. Posterior pituitary dysfunction in the form of central diabetes insipidus is rare in patients with Sheehan's syndrome. We describe the clinical course of a young lady who after her sixth childbirth developed severe postpartum hemorrhage followed by development of panhypopituitarism which was confirmed by hormonal investigation and demonstration of empty sella on imaging. In addition, she developed Polyuria. The water deprivation test and response to vasopressin test results indicated central diabetes insipidus. She needed oral desmopressin on a continuous basis to control polyuria. PMID- 21584436 TI - [The environmental endocrine disruptors must receive the attention of Brazilian endocrinologists]. PMID- 21584437 TI - An HPLC-UV method for the measurement of permeability of marker drugs in the Caco 2 cell assay. AB - The Caco-2 cell line has been used as a model to predict the in vitro permeability of the human intestinal barrier. The predictive potential of the assay relies on an appropriate in-house validation of the method. The objective of the present study was to develop a single HPLC-UV method for the identification and quantitation of marker drugs and to determine the suitability of the Caco-2 cell permeability assay. A simple chromatographic method was developed for the simultaneous determination of both passively (propranolol, carbamazepine, acyclovir, and hydrochlorothiazide) and actively transported drugs (vinblastine and verapamil). Separation was achieved on a C18 column with step gradient elution (acetonitrile and aqueous solution of ammonium acetate, pH 3.0) at a flow rate of 1.0 mL/min and UV detection at 275 nm during the total run time of 35 min. The method was validated and found to be specific, linear, precise, and accurate. This chromatographic system can be readily used on a routine basis and its utilization can be extended to other permeability models. The results obtained in the Caco-2 bi-directional transport experiments confirmed the validity of the assay, given that high and low permeability profiles were identified, and P-glycoprotein functionality was established. PMID- 21584438 TI - Do whole-body vibration exercise and resistance exercise modify concentrations of salivary cortisol and immunoglobulin A? AB - A single bout of resistance exercise (RE) induces hormonal and immune responses, playing an important role in a long-term adaptive process. Whole-body vibration (WBV) has also been shown to affect hormonal responses. Evidence suggests that combining WBV with RE may amplify hormonal and immune responses due to the increased neuromuscular load. Therefore, the aim of this study was to evaluate salivary cortisol (Scortisol) and salivary IgA (SIgA) concentrations following a RE session combined or not with WBV. Nine university students (22.9 +/- 5.1 years, 175.8 +/- 5.2 cm, and 69.2 +/- 7.3 kg) performed five sets of squat exercise (70% one-repetition-maximum) combined (R+V30) or not (R) with WBV at 30 Hz. Saliva samples were obtained before and after exercise. Subjects also rated their effort according to the Borg CR-10 scale (RPE). Data were analyzed by a mixed model. RPE was higher after R+V30 (8.3 +/- 0.7) compared to R (6.2 +/- 0.7). However, Scortisol (pre: 10.6 +/- 7.6 and 11.7 +/- 7.6, post: 8.3 +/- 6.3 and 10.2 +/- 7.2 ng/mL for R and R+V30, respectively) and SIgA concentrations (pre: 98.3 +/- 22.6 and 116.1 +/- 51.2, post: 116.6 +/- 64.7 and 143.6 +/- 80.5 ug/mL for R and R+V30, respectively) were unaffected. No significant correlations were observed between Scortisol and RPE (r = 0.45, P = 0.22; r = 0.30, P = 0.42, for R and R+V30, respectively). On the basis of these data, neither protocol modified salivary cortisol or IgA, although RPE was higher after R+V30 than R. PMID- 21584439 TI - Characterization and analysis of the outcome of adults with acute myeloid leukemia treated in a Brazilian University hospital over three decades. AB - We evaluated the outcome of 227 patients with acute myeloid leukemia during three decades (period 1 - 1980's, N = 89; period 2 - 1990's, N = 73; period 3 - 2000's, N = 65) at a single institution. Major differences between the three groups included a higher median age, rates of multilineage dysplasia and co-morbidities, and a lower rate of clinical manifestations of advanced leukemia in recent years. The proportion of patients who received induction remission chemotherapy was 66, 75, and 85% for periods 1, 2, and 3, respectively (P = 0.04). The median survival was 40, 77, and 112 days, and the 5-year overall survival was 7, 13, and 22%, respectively (P = 0.01). The median disease-free survival was 266, 278, and 386 days (P = 0.049). Survival expectation for patients with acute myeloid leukemia has substantially improved during this 30-year period, due to a combination of lower tumor burden and a more efficient use of chemotherapy and supportive care. PMID- 21584440 TI - Effect of triiodothyronine on the maxilla and masseter muscles of the rat stomatognathic system. AB - The maxilla and masseter muscles are components of the stomatognathic system involved in chewing, which is frequently affected by physical forces such as gravity, and by dental, orthodontic and orthopedic procedures. Thyroid hormones (TH) are known to regulate the expression of genes that control bone mass and the oxidative properties of muscles; however, little is known about the effects of TH on the stomatognathic system. This study investigated this issue by evaluating: i) osteoprotegerin (OPG) and osteopontine (OPN) mRNA expression in the maxilla and ii) myoglobin (Mb) mRNA and protein expression, as well as fiber composition of the masseter. Male Wistar rats (~250 g) were divided into thyroidectomized (Tx) and sham-operated (SO) groups (N = 24/group) treated with T3 or saline (0.9%) for 15 days. Thyroidectomy increased OPG (~40%) and OPN (~75%) mRNA expression, while T3 treatment reduced OPG (~40%) and OPN (~75%) in Tx, and both (~50%) in SO rats. Masseter Mb mRNA expression and fiber type composition remained unchanged, despite the induction of hypo- and hyperthyroidism. However, Mb content was decreased in Tx rats even after T3 treatment. Since OPG and OPN are key proteins involved in the osteoclastogenesis inhibition and bone mineralization, respectively, and that Mb functions as a muscle store of O2 allowing muscles to be more resistant to fatigue, the present data indicate that TH also interfere with maxilla remodeling and the oxidative properties of the masseter, influencing the function of the stomatognathic system, which may require attention during dental, orthodontic and orthopedic procedures in patients with thyroid diseases. PMID- 21584441 TI - Effect of methylprednisolone on perivascular pulmonary edema, inflammatory infiltrate, VEGF and TGF-beta immunoexpression in the remaining lungs of rats after left pneumonectomy. AB - Pneumonectomy is associated with high rates of morbimortality, with postpneumonectomy pulmonary edema being one of the leading causes. An intrinsic inflammatory process following the operation has been considered in its physiopathology. The use of corticosteroids is related to prevention of this edema, but no experimental data are available to support this hypothesis. We evaluated the effect of methylprednisolone on the remaining lungs of rats submitted to left pneumonectomy concerning edema and inflammatory markers. Forty male Wistar rats weighing 300 g underwent left pneumonectomy and were randomized to receive corticosteroids or not. Methylprednisolone at a dose of 10 mg/kg was given before the surgery. After recovery, the animals were sacrificed at 48 and 72 h, when the pO(2)/FiO(2) ratio was determined. Right lung perivascular edema was measured by the index between perivascular and vascular area and neutrophil density by manual count. Tissue expression of vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-beta) were evaluated by immunohistochemistry light microscopy. There was perivascular edema formation after 72 h in both groups (P = 0.0031). No difference was observed between operated animals that received corticosteroids and those that did not concerning the pO(2)/FiO(2) ratio, neutrophil density or TGF-beta expression. The tissue expression of VEGF was elevated in the animals that received methylprednisolone both 48 and 72 h after surgery (P = 0.0243). Methylprednisolone was unable to enhance gas exchange and avoid an inflammatory infiltrate and TGF-beta expression also showed that the inflammatory process was not correlated with pulmonary edema formation. However, the overexpression of VEGF in this group showed that methylprednisolone is related to this elevation. PMID- 21584442 TI - Dynamics of immunosuppression in hamsters with experimental visceral leishmaniasis. AB - Immunosuppression has been reported to occur during active visceral leishmaniasis and some factors such as the cytokine profile may be involved in this process. In the mouse model of cutaneous leishmaniasis using Leishmania (Leishmania) major, the Th1 response is related to protection while the Th2 response is related to disease progression. However, in hamsters, which are considered to be an excellent model for the study of visceral leishmaniasis, this dichotomy is not observed. Using outbred 45- to 60-day-old (140 to 150 g) male hamsters infected intraperitoneally with 2 x 10(7) L. (L.) chagasi amastigotes, we evaluated the immune response of spleen cells and the production of cytokines. We used 3 to 7 hamsters per group evaluated. We detected a preserved response to concanavalin A measured by index of proliferation during all periods of infection studied, while a proliferative response to Leishmania antigen was detected only at 48 and 72 h post-infection. Messenger RNA from cytokines type 1 (IL-2, TNF-alpha, IFN-gamma) and type 2 (IL-4, IL-10 and TGF-beta) detected by reverse transcriptase polymerase chain reaction and produced by spleen cells showed no qualitative difference between control non-infected hamsters and infected hamsters during any period of infection evaluated. Cytokines were measured by the DNA band intensity on agarose gel using the Image Lab 1D L340 software with no differences observed. In conclusion, the present results showed an antigen-dependent immunosuppression in hamsters with active visceral leishmaniasis that was not related to the cytokine profile. PMID- 21584443 TI - Trends in adjuvant development for vaccines: DAMPs and PAMPs as potential new adjuvants. AB - Aluminum salts have been widely used in vaccine formulations and, after their introduction more than 80 years ago, only few vaccine formulations using new adjuvants were developed in the last two decades. Recent advances in the understanding of how innate mechanisms influence the adaptive immunity opened up the possibility for the development of new adjuvants in a more rational design. The purpose of this review is to discuss the recent advances in this field regarding the attempts to determine the molecular basis and the general mechanisms underlying the development of new adjuvants, with particular emphasis on the activation of receptors of innate immune recognition. One can anticipate that the use of these novel adjuvants will also provide a window of opportunities for the development of new vaccines. PMID- 21584444 TI - [Bioethics and research into mental health]. AB - This article discusses research in the field of mental health, examining the ethical is sues involved and the use of Informed Consent. In order to achieve these objectives two main approaches were used: (1) a brief history of the different treatments and research with patients with mental illness or disability; (2) theoretical and conceptual analysis of the main problems concerning the mental health field, namely the notion of vulnerability, responsibility and autonomy and the use of placebo control groups. Two main questions prompted the reflection on whether the patient with a mental disorder can sign an Informed Consent, and whether the use of a placebo is acceptable. The existence of antagonistic and contradictory positions indicates that mental health research is hampered by biases that are difficult to overcome. Ethical investigation that may contribute to the healing of mental disorders should not however be overlooked merely because of the difficulties involved in its implementation. It must be borne in mind that changes occurring in the context of Psychiatric Reform in Brazil are gradually altering archaic concepts about what constitutes mental illness and how this group should be understood and treated. PMID- 21584445 TI - Mental health research in Brazil: through the looking-glass. PMID- 21584446 TI - [Intersubjectivity in Mental Health care: narratives of nursing technicians at a Psychosocial Care Center]. AB - Psychosocial Care Centers (Caps) were established as a result of the demand for Mental Health care and were an attempt to update psychiatric treatment for those afflicted with severe mental disorders. This article seeks to analyze subjective repercussions of work conducted in Caps on mid-level professionals and to contribute to healthcare planning. Two focal groups were conducted with workers of a Caps III. The methodology applied to the analysis was based on the critical hermeneutical approach proposed by Ricoeur and espoused by Gadamerian philosophy. Lack of appreciation in the workplace was revealed as being the main cause of suffering. Several themes stood out including the difficulty of obtaining the cooperation of users'; relatives, the tenuous interconnection between Caps and the health network, the attribution of responsibility for the night shift, controversies regarding overnight-stay patients and an excessive workload. Adequate structural planning and institutional organization is proposed when opening new Caps in order to reduce the workload of technicians and improve the clinical performance of the team. PMID- 21584447 TI - [Qualitative assessment of the environment in a Psychosocial Care Center]. AB - This study is based on a cross-section of the study of Psychosocial Care Center (Caps) in the South of Brazil. OBJECTIVE: to conduct a qualitative assessment of the structure, in terms of environment, of a Caps in the interior of the State of Rio Grande do Sul. A case study was conducted on the Caps in Alegrete (RS) based on a fourth generation, constructivist and responsive assessment using a hermeneutic-dialectic approach. The data collection instruments were semi structured interviews with a team (26), users (11), and family members (14), defined as interest groups to make up the hermeneutic-dialectic circle and field observation (390 hours) establishing prior ethnography. The structure of the Alegrete Caps was a strong aspect in the environmental evaluation. The lack of human and material resources does not interfere directly in user satisfaction with the environment. PMID- 21584448 TI - [Challenges for Psychosocial Care Centers as alternative services: the new chronicity in question]. AB - This paper is part of a qualitatively oriented research project conducted in a Psychosocial Care Center (Caps) in Rio de Janeiro, Brazil. The goal of this work was to analyze the risks of a new chronicity in this service. The research was based on semi-structured interviews with professionals, patients and relatives, analyzing the data from a social constructionist perspective. The main conclusion of this study is that the people interviewed agree with the tendency of a new chronicity, an expression that was useful to analyze the operations, advances and challenges of this service. PMID- 21584449 TI - [Mental health care: perceptions of people with schizophrenia and their carers]. AB - The current study aims to discover the opinions of patients and their (informal and formal) carers concerning the mental health care of individuals with long term schizophrenic disorders within different contexts and cultures. It's a qualitative study with focus groups,in which 6 research centers (from Argentina, Brazil, Chile, Spain, England and Venezuela) participated. Eight focus groups were conducted in each center, totaling 303 individuals in 46 groups. The data were analyzed with the aid of the Qualitative Solutions and Research/Non numerical Unstructured Data Indexing program (QSR NUD*IST 4.0). The perception regarding the quality of care is influenced by the professional-patient relationship and the availability of resources. Poor quality of care is also perceived as discrimination. People with schizophrenia in general consider themselves to be ostracized by professionals and services and lacking in more humanized care. In the contexts in which community care is less advanced, the complaints center on resources and services that do not meet demands. On the other hand, in more developed contexts criticism centers more on the attitude of the professionals and the professional patient relationship. Over and above the need for resources and services, people with schizophrenia require more humanized health care. PMID- 21584450 TI - [Let them speak for themselves: reports from professionals about their experiences in therapeutic residency training]. AB - This paper deals with qualitative research conducted in the Therapeutic Residency Service in the municipality of Campina Grande, State of Paraiba, Brazil, the objective being to ascertain the difficulties encountered by the professionals in the healthcare practices defined by the aforementioned service and identify the prospects identified by them for the residents. A semi-structured interview routine was conducted with ten professionals for the data collection, along with analysis of field records and systematic observation. The main difficulties faced are of a structural nature, namely lack of human resources and/or training and social support. Social reintegration, insertion in the workplace and autonomy are the expectations singled out by the professionals. In light of the results, it can be affirmed that, in spite of the difficulties experienced, it is possible to see progress, such as the autonomy of some residents. Nevertheless, as it is a recent service, it needs to be constantly evaluated. PMID- 21584451 TI - [Cerebral palsy and Down syndrome: level of parental knowledge and information]. AB - The study sought to identify and analyze research related to knowledge and information received by parents of children with cerebral palsy or Down syndrome about these disabilities. It involves a bibliographical revision limited to the period from 1996 through 2008. Computerized data bases were used to collect information, using the following terms as key words: cerebral palsy, Down syndrome, knowledge and family. Fifty-seven studies were located from which 16 were selected; of these, seven were related to cerebral palsy, four to Down syndrome and five were related to sundry deficiencies. The parents receive little information from the healthcare staff and clearly have many doubts about cerebral palsy and Down syndrome. This makes it very difficult for the parents to assist in the treatment of their children, as well as interfering in educational practices and decision-making. There is a need for educational actions to change this reality. Only one research project sought to implement educational strategies which focused on broadening knowledge among family members about aspects related to Down syndrome. It was concluded that there is an urgent need to conduct research and develop actions that contribute to parents being better informed and more secure about their children's health care. PMID- 21584452 TI - Psychiatric care in the Brazilian context. AB - This study seeks to present an updated discussion concerning psychiatric care in Brazil. It is based upon a historical review of psychiatric knowledge and practices within the Brazilian context and knowledge about the phenomenon of madness. It discusses the appearance of modern medical science as an area of knowledge designed for the treatment and comprehension of mental suffering. It also presents a discussion on psychiatric reform, stressing how it is a movement that seeks to redefine the significance of knowledge and practices about the phenomenon of madness, by concentrating on the application of such knowledge and practices in the psychiatric hospital. This paper concludes with a brief critical reflection on prevailing mental healthcare in Brazil, singling out the potential and the difficulties faced within the scope of health policies and the day-to-day working life of professionals of the area. PMID- 21584453 TI - [Mental health and anxiety in community health agents in Uberlandia (MG, Brazil)]. AB - The scope of this research, carried out together with community-based health workers (ACS) was: (1) to evaluate the mental health of the ACS; (2) to describe the vital events in the last year of the ACS; (3) to inquire about the level of anxiety of the ACS; (4) to correlate mental health, vital events and anxiety of the ACS. PARTICIPANTS: 116 ACS. MEASUREMENTS: socio-demographic questionnaire, Goldberg General Health Questionnaire, The Life Events Inventory, State-Trait Anxiety Inventory. The majority of the ACS presented a moderate degree of anxiety and positive mental health; they reported having experienced few stressful events in the past year, even though the majority had experienced health problems. The fact that most of the ACS reported having experienced moderate anxiety levels suggests a probable interference of specific characteristics of the profession. However, the fact that the persons subjectively identified the presence of anxiety and classified it at a given level presupposes that they are using control strategies, which is a factor that assists in maintaining mental health. PMID- 21584454 TI - [Neuroimaging and the case of chronic fatigue syndrome]. AB - This article analyzes the use of neuroimaging in research into chronic fatigue syndrome. It reviews some works published in the 1990 s and investigates a specific aspect of these studies, namely the search for a cerebral abnormality, in the form of an altered activation pattern, which could provide a pattern for diagnosis and treatment of the disease. The understanding of chronic fatigue syndrome as a disease reduced to some cerebral findings is analyzed, arguing in favor of a broader vision of this disease that includes psychosocial elements of the patient's life as opposed to entirely somatic explanations. PMID- 21584455 TI - [Dimensions of the scope of work in a Psychosocial Care Center]. AB - This article presents partial results of evaluative research conducted in 2005 at a Psychosocial Care Center in Pelotas, in the Southern Brazilian State of Rio Grande do Sul. The study adopts a qualitative approach and utilizes the theoretical and methodological referential of the Fourth Generation Evaluation. The data collected contains observation and interviews with users, family members and professionals of the care center. The analysis was based on the Constant Comparative Method that made the definition of the thematic nuclei possible. One of them refers to the dimensions of the scope of work broken down into issues related to integrality, to old and new chronicities, to dealing with crises and to family involvement. Considering the inclusion of groups directly involved with the daily routine services, relevant issues have emerged from the evaluation in a context of change in the model of mental healthcare. PMID- 21584456 TI - [(Dis)satisfaction with mental healthcare work: a study in Psychosocial Care Centers]. AB - The scope of this article is to analyze satisfaction in the workplace of mental healthcare professionals who serve in Psychosocial Care Centers (Caps). The research is of a qualitative nature and the data-collecting medium was semistructured interviews with 19 workers of three Caps in Fortaleza, in the Northern Brazilian State of Ceara. The treatment of the empirical material was based upon the analysis of content with an emphasis on the thematic bias. The results revealed the determinants of (dis)satisfaction present in the daily routine of these workers. The relationships established with the users were singled out as the main source of satisfaction, whereas the work and wage conditions were the main motives for dissatisfaction. In addition to these aspects, consequences of (dis)satisfaction at work in the private, social and organizational field of the workers' life in the Caps were revealed, mainly in physical and mental health. Lastly, they emphasized the urgent need for implementation - on the part of public administration - of strategies that seek to reduce the precariousness of healthcare work, especially in mental health, with a view to mitigating damages potentially caused by such work. PMID- 21584457 TI - [The social experience of psychosis in the context of a Psychosocial Care Center]. AB - This study discusses the relations existing between the institutional aspects of a Psychosocial Care Center (Caps) and the experience of psychotic patients. Using the referential base of the social experience of psychosis, which is broader in scope than a description of the experience of symptoms, while considering cultural aspects of the experience, three case studies were conducted at two different times. All of the patients studied were interviewed in 1995 and again in 2003. In addition to interviews with the subjects themselves, open interviews were conducted with their families and their professional carers, thereby taking the social relationship networks of the patients into consideration. Three central aspects were emphasized: (1) study of the history of the illness; (2) study of the representations of the disease; and (3) description of the everyday life and social relationships of the patients. Aspects with respect to the treatment of psychotic patients included in Psychosocial Care Centers were conducted using an anthropological approach. PMID- 21584458 TI - [The sustainability of day-to-day life: a study of the social networks of users of mental healthcare service in the municipality of Santo Andre (SP, Brazil)]. AB - Studies into social networks show that relationships have a significant impact on people's lives. When associated with the population suffering from mental disorders, they serve as an important protection factor and a manager of resources and social support. However, studies show that people with mental disorders have impoverished social networks and few significant relationships. In this perspective, this research sought to characterize the social networks of users of NAPS II in Santo Andre (SP, Brazil). Conducted in 2006, the qualitative research adopted an ethnographic approach and used interviews by topics, participant observation and field notes. The results revealed that the group studied had an impoverished social network; the life histories of the subjects is related to this impoverishment, since the disruptions caused by situations of crisis or institutionalization removed them from the network of relationships, placing them in a situation of social vulnerability. An attempt was made to address the importance of intervention in the relationships and the role of the services in this process. PMID- 21584459 TI - [Prevalence of psychiatric disorders in juvenile offenders in the city of Rio de Janeiro (RJ, Brazil)]. AB - The prevalence of juvenile offenders in Brazil, mainly among young females, is on the increase. The literature on this issue indicates an increased incidence of mental disorders among young offenders in several countries, though studies in Brazil are lacking. The aim of this article is to study the prevalence of mental disorders in adolescents from a socio-educational standpoint, taking as a hypothesis the gender difference and the type of offense committed. The instrument used was the K-SADS-PL. As results, we found a high prevalence of psychiatric disorders among juvenile offenders, the most common being: attention deficit hyperactivity disorder (33.3%); behavioral disorder (77%); oppositional defiant disorder (50%), anxiety disorders (70%), depressive disorder (50%), illicit drug abuse/dependence (70%), and alcohol abuse/dependence (52%). Alcohol abuse/dependence caused a 2.4-fold increase in the probability of adolescents committing a violent offence. Public health authorities should concentrate on early diagnosis and treatment of psychiatric disorders in childhood to reduce future violations. It is also suggested that mental health treatment of detained juveniles should be a fundamental part of the recuperation and reintegration of young offenders into society. PMID- 21584460 TI - [The influence of Social Security legislation changes on the profile of the granting of disability benefits for mental disorders]. AB - This article is a preliminary study on possible influences of legal regulation changes (Copes and PP) on the result of initial expertise examination in Juiz de Fora (State of Minas Gerais, Brazil), following a request for social benefits due to a mental disorder. METHOD: retrospective analysis of data drawn from an official data bank (Dataprev) related to examinations concluded between July/2004 and December/2006. Four periods were considered: (1o) July/2004 to July/ 2005 before the legal regulation Copes took effect; (2o) August/2005 to November/2005, with Copes in effect and examinations by third part experts; (3o) December/2005 to April/2006, without third part experts; (4o) May/2006 to December/2006, with PP in effect. RESULTS: reduction on the frequency of benefit granting from 81.9% to 49.5% from 1o to 4o period. Increase of favorable conclusions on requests for re-evaluations (from 52.0% in 1o period to 75.3% after Copes) and reduction in 4o period (36.5%). Reduction on average number of benefit renewal (from 3.5 to 1.7, respectively in 1o and 4o periods). The mean period of work dismissal was longer in 1o period and shorter in 4o period (respectively 397.4 and 247.6 days). The results highlighted changes on the profile of benefits granted during the period of time in which the new regulations came into force. PMID- 21584461 TI - [The impact of professional activities on the physical and mental health of the civil and military police of Rio de Janeiro (RJ, Brazil)]. AB - In this article, we analyze the physical and mental stress and illness of military and civil police force officers in the State of Rio de Janeiro (Brazil) due to their working conditions and professional activities. The same methodology was used for the study of two categories, namely a quantitative approach (simple random sampling by conglomerates, involving a total of 1,458 civil police officers and 1,108 military police officers, who answered questionnaires anonymously) and a qualitative approach (focal groups involving 143 professionals and 18 interviews with managers of both police forces). The data presented here are all original. Disorders identified were: overweight and obesity in both forces but mainly in the Military Police; low frequency of physical exercise and high levels of cholesterol, especially in the Civil Police. The main health complaints are neck, back or spinal cord pain, eyesight complaints and headaches/ migraines. Sixteen point two per cent of officers of both forces reported physical lesions that were more prevalent in the Military Police, among whom psychic suffering was also more frequent (SRQ20). The need for changes in the individual and professional dimensions and in institutional aspects regarding the conditions and organization of work and of health services is emphasized. PMID- 21584462 TI - [Psychic experiences of women attended at public health centers in Teresina (PI, Brazil)]. AB - The scope of this article is to examine the findings of the psychic experiences of women attended at Primary Care level in public healthcare centers in Teresina, State of Piaui, Brazil. Qualitative research was conducted in order to assess emotional, social, family, sexual and workplace experiences from the standpoint of women who seek Family Healthcare services in Teresina. Semi-structured interviews and non-systematic observation carried out in the Municipal Health Unit itself were used to collect the data. The information gathered revealed psychic suffering that is intrinsic to everyday experiences, family relationships and situations involving betrayal, separation, unemployment, violence and sexual experiences. The importance of integrating mental healthcare and basic healthcare was identified, requiring in-depth dialogue, bringing together staff, family and communities that will undoubtedly benefit from this to tackle day-to-day problems permeated by violence, abuse, maltreatment and negligence. The proposal put forward is to train healthcare professionals and implement an interface between Family Healthcare and psychosocial treatment permitting integrated action geared to the individual as a whole. PMID- 21584463 TI - A growing role for gender analysis in air pollution epidemiology. AB - Epidemiologic studies of air pollution effects on respiratory health report significant modification by sex, although results are not uniform. Importantly, it remains unclear whether modifications are attributable to socially derived gendered exposures, to sex-linked physiological differences, or to some interplay thereof. Gender analysis, which aims to disaggregate social from biological differences between males and females, may help to elucidate these possible sources of effect modification. Studies of children suggest stronger effects among boys in early life and among girls in later childhood. The qualitative review describes possible sources of difference in air pollution response between women and men, which may vary by life stage, coexposures, hormonal status, or other factors. The sources of observed effect modifications remain unclear, although gender analytic approaches may help to disentangle gender and sex differences in pollution response. A framework for incorporating gender analysis into environmental epidemiology is offered, along with several potentially useful methods from gender analysis. PMID- 21584464 TI - [History and paradigms in Collective Health: record of a teaching experience]. AB - The paper describes a pedagogical experience at graduate level on the topic of History and Paradigms of Knowledge in Health. The experience originated in the first two courses at the Sergio Arouca National School of Public Health, at Oswaldo Cruz Foundation (Fiocruz) (19921993) and later at the School of Medical Sciences, State University of Campinas (Unicamp) (19942006). The article highlights the contents of the two courses and presents some considerations about the relevance of the subjects that deal with the historical character of the areas of knowledge and provides feedback for reflection on the field of knowledge as a whole and its specific aspects. PMID- 21584465 TI - [Exclusive breastfeeding among professionals in a Family Healthcare Program]. AB - Breastfeeding is considered an important strategy for survival in infancy. Consequently, strategies have been developed mainly directed towards health professionals. The scope of the study was to identify the frequency and duration of breastfeeding among professionals of a Family Health Program in the city of Recife, Pernambuco, Brazil. It is a transversal descriptive study conducted between September and November 2006 involving 37 workers and mothers of under five's in the Family Health Program of the IV Sanitary Health District of Recife. Of the 37 professionals, two refused to participate and were therefore excluded, meaning that 35 were effectively interviewed. The mean duration of breastfeeding was four months. Comparing the workers who breastfed exclusively with those that did not, it was found that mothers who breastfed exclusively for > 4 months, had no difficulties with breastfeeding (p=0.027). A tendency of statistical significance was found in relation to the use of pacifiers among children whose mothers did not breastfeed exclusively (p=0.051). The difficulties found during breastfeeding among the workers of the Family Health Program of the IV Sanitary Health District and the use of pacifiers among their children are problems that deserve attention, due to the fact that they represent a group that serves as a model for the community. PMID- 21584466 TI - [Risk Analysis applied to food safety in Brazil: prospects and challenges]. AB - The scope of this case study is to discuss the ideas of the Brazilian Codex Alimentarius Committee (CCAB) coordinated by National Institute of Metrology, Standardization and Industrial Quality (Inmetro), with respect to the Codex Alimentarius norm on Risk Analysis (RA) applied to Food Safety. The objectives of this investigation were to identify and analyze the opinion of CCAB members on RA and to register their proposals for the application of this norm in Brazil, highlighting the local limitations and potential detected. CCAB members were found to be in favor of the Codex Alimentarius initiative of instituting an RA norm to promote the health safety of foods that circulate on the international market. There was a consensus that the Brazilian government should incorporate RA as official policy to improve the country's system of food control and leverage Brazilian food exports. They acknowledge that Brazil has the technical-scientific capacity to apply this norm, though they stressed several political and institutional limitations. The members consider RA to be a valid initiative for tackling risks in food, due to its ability to improve food safety control measures adopted by the government. PMID- 21584467 TI - [Rehabilitation, ethics and technique]. AB - This paper initially includes the presentation of some ideas on the deficiency and the process of rehabilitation, whereby the latter is defined in its "condition" as a process. A few differences in relation to the idea of a program in the strict sense (defined as a fixed set of previously defined procedures or techniques) will be detected, as well as some ethical implications in the social, health or educational fields for professionals working with the disabled. Thus, the handling of the technique and the use of institutional measures will be discussed in this context, inasmuch as they are related to subjective and educational processes inherent to rehabilitation work. In so doing, we hope to contribute to a better understanding of the role pertaining to these professionals. PMID- 21584468 TI - [From the perception of powerlessness to the fight for justice in healthcare]. AB - The search for communicative settings for reflection concerning the exercise and practice of nursing based on bioethical frameworks sought to comprehend how participant nurses interpret the reality of their praxis vis-a-vis the observance of justice. The focal group technique was used for data collection and the latter was analyzed using Grounded Theory. Three phenomena were identified: conceptualizing a sense of justice; feeling powerless in living with inequities/injustice; and moving towards the fight for justice. From the inter relation of such phenomena, the core categories emerged, namely constructing mechanisms to overcome injustice and inequities which undermine quality in nursing care, and the experience of recently-graduated nurses in a public hospital in the interior of Sao Paulo State. Focal group strategy proved to be highly adequate for achieving the proposed objectives, and Grounded Theory made it possible to assess the movement undertaken by the nurses in this experience. PMID- 21584469 TI - [Obesity among the poor in Brazil: female vulnerability]. AB - The increase in obesity among women in the lower income bracket in Brazil has been singled out as a priority issue in the field of Public Health today. Concern about future repercussions of obesity in the less privileged groups calls for an in-depth theoretical approach and the energetic definition of public policy for prevention and control of the affliction in these segments. In this respect, the scope of this work is to attempt to pinpoint some analytical categories in the phenomenon of obesity among the underprivileged female population in Brazil. Biological, socioeconomic and cultural factors appear to interact in the dynamics of female obesity in the context of poverty revealing the complexity of this problem. Public policies of job creation, social inclusion and gender equality in the labor market would appear to be more promising ways of tackling obesity in underprivileged females in Brazil. PMID- 21584470 TI - [Are the drug prescription quality indicators of the World Health Organization still valid?]. AB - The scope of this article is to analyze the drug prescription quality indicators proposed by the World Health Organization in 1993 and suggest new indicators attuned to the new profile of illness of the population. For this purpose, a cross-sectional study was conducted by means of personal interviews and prescription analysis among 320 patients who were attended at Strategic Family Health Units located in a Brazilian municipality in the state of Rio Grande do Sul. The users were recruited by the consecutive nonprobabilistic sampling method. In accordance with the drug prescription quality indicators of the World Health Organization, the prescriptions can be considered adequate. However, analysis of those indicators shows that they may currently be inappropriate. Therefore, new indicators were created. Using the new, easily quantifiable and straightforward indicators proposed, it was possible to detect the problems in a drug prescription with a view to taking corrective action. PMID- 21584471 TI - [Dental treatment of pregnant women: the role of healthcare professionals]. AB - The scope of this article involved qualitative research conducted together with pregnant women attended by the Brazilian Unified Health System (SUS) and private services, seeking to identify the perception of these women on the role of health professionals in relation to dental care during pregnancy. The data were collected through recorded, semi-structured interviews based on a questionnaire and analyzed by assessment of thematic content. It was noted that some health professionals propagate and reinforce misconceptions and fears about dental care and oral health during pregnancy. The need for investment in education on dental care during pregnancy, both at undergraduate and graduate level, was clearly revealed, since knowledge on the subject can contribute to a review of concepts, and consequently the manifest behavior vis-a-vis this segment of the population. PMID- 21584472 TI - [Rural Internship in the professional training of pharmacists to serve in the Brazilian Unified Health System]. AB - In order to comply with Brazilian Syllabus requirements, some schools of Pharmacy included Rural Internships (RI) in the curriculum as a way of familiarizing students with the Unified Health System (SUS), thereby permitting the interaction of the students with pharmaceutical practices. This work assesses the knowledge about SUS and pharmaceutical activities of students who have taken the RI subject at the schools of Pharmacy of the UFMG. The information gathered was acquired by means of Focus Groups (FG), one before and another immediately after the field experience. Eight students participated in the FG at both stages. The questionnaire of the FG included: concept of the SUS, the activities of the professional in public health and the expectation of the students about the RI. The processing of the information was done by content analysis. It was revealed at both stages the students were unaware of the concepts and principles of SUS. However, after returning from the RI, the students used words like "access," "universal right" and "health promotion." Students were unaware of the activities of the pharmacist in the service and the pharmaceutical care was not mentioned. The data analysis revealed the low level of knowledge of the students about SUS. Nevertheless, they considered RI a motivational curriculum subject for future performance in SUS. PMID- 21584473 TI - [The control of babies' dental visits through the vaccines card: evaluating a pilot program developed at the Family Health Strategy at Ponta Grossa (PR, Brazil)]. AB - This study evaluated a concept-program developed in the area of a Family Health Unity, which monitored, for two years, the returns of infant children to regular attendance by the dentist, through their vaccines cards. A cross-sectional study was conducted, involving a convenience sample of 123 children aged 12 to 36 months, residents in the area. Data were collected during a campaign of immunization, in 2007, through a questionnaire answered by parents, vaccines cards checking, and clinical examination of children. The results showed that 81% of the examined children were registered in the FHU for dental care; from them, 95% had entered before reaching one year of life, having vaccines cards registration. It was also found that 50% of the children had visited the dentist more than once per year of life and 58% of them returned for dental appointments in the year before the survey. The prevalence of dental caries was lower in this group of children (17%), than in the group without frequent returns, or the one not registered in the FHU (26%). It was concluded that the vaccines card can be a useful tool for tracking the frequency of babies to dentist. PMID- 21584474 TI - [Dental care and oral hygiene practices in long-term geriatric care institutions]. AB - This study evaluated the activities of dentists, dental care and oral hygiene practices in the long-term care institutions of Belo Horizonte (Minas Gerais, Brazil). A semi-structured questionnaire was handed out to the coordinators of 37 philanthropic and 30 private institutions. The data was compared by the chi square and Fisher's Exact Tests. 81% of the questionnaires were answered. The majority of the private (74.2%) and philanthropic institutions (87%) do not have a dentist (p=0.21). The location, period of existence, type institution kind and number of residents weren't factors regarding the presence of a dentist (p>0.05). 67% of the philanthropic institutions with equipped consultation rooms had dentists, though there were none when there was no consultation room. Even without consultation rooms, 13% of the private institutions had dentists. When necessary, 69.6% of the philanthropic institutions refer the elderly to public health centers, while 58.1% of the private institutions refer them to their family dentists. A higher percentage of the private institutions adopted systematic oral hygiene procedures (p=0.01), with a considerable divergence of treatment reported. There is a need to include a dentist on the health staff in the institutions and for systematization of oral hygiene practices. PMID- 21584475 TI - [Calibration study of the Food Frequency Questionnaire for Adolescents (AFFQ)]. AB - In order to establish calibration factors of the Adolescent Food Frequency Questionnaire (AFFQ), 74 boys and girls from Piracicaba (SP, Brazil) with ages ranging from 10 to 14 took part in the study. Dietary intake (assessed by the food frequency questionnaire and 24-hour recall) was assessed and adjusted for energy intake. Descriptive statistics, variance analysis using one classification factor, Pearson's correlation coefficients and linear regression were performed. The average of two 24-hour recalls was used as a reference for calibration of data. Calibration coefficients (lambda) ranged from -0.07 (iron) to 0.40 (vitamin C) revealing substantial error in the dietary method tested, albeit similar to those observed in the literature. As these coefficients were low, they indicate the need for reformulating the instrument regarding some nutrients, though application was not considered advisable for correcting information on iron and retinol. The methodology used to calibrate dietary data can consider measurement error in the assessment when its assumptions are respected, since violations of these assumptions may lead to other errors that are difficult to predict. PMID- 21584478 TI - Growth-differentiation factor-15: a novel biomarker in patients with diastolic dysfunction? AB - BACKGROUND: Growth differentiation factor-15 (GDF-15), a stress-responsive transforming growth factor-beta-related cytokine, is elevated and independently related to an adverse prognosis in systolic heart failure. OBJECTIVE: This study aimed to investigate plasma levels of GDF-15 in patients with preclinical diastolic dysfunction or heart failure with normal ejection fraction (HFnEF). METHODS: We evaluated 119 patients with normal ejection fraction referred for an elective coronary angiography, 75 (63%) of whom had coronary artery disease. Subjects were classified as having either mild left ventricular diastolic dysfunction (LVDD grade I, n = 61), HFnEF (LVDD grade II or III, n = 38) or normal diastolic function (controls, n = 20). In a subgroup of 20 subjects, changes in cardiac output (CO) were measured by inert gas rebreathing (InnocorTM) in response to an orthostatic hemodynamic test. RESULTS: Growth differentiation factor-15 levels in HFnEF [median 1.08, interquartile range (0.88-1.30) ng/ml] were significantly higher than in controls [0.60 (0.50-0.71) ng/ml, p = 0.003] and in patients with LVDD grade I [0.78 (0.62-1.04) ng/ml, p < 0.001]. In addition, GDF-15 was significantly elevated in patients with LVDD grade I compared to controls (p = 0.003). Furthermore, GDF-15 was correlated with echocardiographic markers of diastolic dysfunction and was correlated with the magnitude of CO response to the change in body position from standing to supine (r = -0.67, p = 0.005). CONCLUSION: Growth differentiation factor-15 levels are elevated in subjects with HFnEF and can differentiate normal diastolic function from asymptomatic LVDD. In addition, GDF-15 is associated with a reduced cardiac output response in the orthostatic hemodynamic test. PMID- 21584479 TI - Heart rate variability in preterm and term neonates. AB - BACKGROUND: Several studies have demonstrated the importance of the autonomic nervous system through sympathetic and parasympathetic components in the management of the interaction between different parts of the body. These studies have applied linear and nonlinear techniques (Chaos Theory) for assessment in different situations, illnesses and age groups, using the heart rate variability (HRV). OBJECTIVE: To apply knowledge of linear and nonlinear dynamics in the assessment of preterm neonates (PTN), analyzing their HRV and comparing with healthy term neonates (NT). METHODS: Forty-eight premature neonates with different gestational ages had their heart rates assessed with the aid of a Polar Advanced S810i and HRV obtained by recording RR intervals. HRV was analyzed according to time (SDNN, RMSSD, SD1/SD2), frequency (VLF, LF, HF and LF/HF) and chaos (TAU and its standardization [TAU(n)], Lyapunov Exponent and Enthropy). PTN were compared with a group of 78 healthy NT with no perinatal events using Kruskal-Wallis nonparametric test. RESULTS: We detected a statistically significant difference between groups for all variables, both in time, frequency and chaos. CONCLUSION: Preterm Neonates have a less complex heart rate variability behavior than term neonates, which was evident in time, frequency and chaos. The study of heart rate variability in this group can be considered another tool in the evaluation of autonomic maturation and hence the progression to normality. PMID- 21584480 TI - Tissue doppler echocardiography in the diagnosis of heart transplantation rejection. AB - BACKGROUND: Endomyocardial biopsy (EMB) is the gold standard method for the diagnosis of cellular rejection (CR) after heart transplantation (HT). OBJECTIVE: To test the hypothesis that tissue Doppler imaging (TDI) could detect CR > 3A and add diagnostic information compared to conventional Doppler. METHODS: Fifty-four HT patients underwent 129 EMB and a TDI echocardiographic study within 24 hours. We compared HT patients with CR > 3A versus HT patients with CR < 3A, with a normal matched control group (13 patients). We measured TDI systolic (S), early diastolic (e'), late diastolic (a') velocities and e'/a' ratio in the left ventricular annulus, basal and medium (mid) segments of the septal (SEP), lateral (LAT), inferior (INF), anterior (ANT) walls; and in the right ventricular annulus. RESULTS: HT patients showed CR > 3A in 39/129 (30.2%) EMB. The best isolated predictor for CR diagnosis was a'LAT, with a sensitivity of 76.3%, specificity of 73.8% (p = 0.001). In the multivariate analysis, a'LAT (p = 0.001), a'SEP (p = 0.002), e'/a' LAT ratio (p = 0.006), e'Mitral/ e'LAT ratio (p = 0.014), SINF (p = 0.009) predicted CR > 3A. We obtained a score with a sensitivity of 88.2%, accuracy of 79.6% and negative predictive value of 92.9% to diagnose CR > 3A. Conventional Doppler (mitral and pulmonary venous flow) was not relevant to predict CR > 3A. CONCLUSION: TDI added diagnostic information to predict CR > 3A compared to conventional Doppler. A TDI-based model could become a potential method to detect CR > 3A after heart transplantation. PMID- 21584481 TI - Myocardial dysfunction and abnormalities in intracellular calcium handling in obese rats. AB - BACKGROUND: Several mechanisms have been proposed to contribute to cardiac dysfunction in obesity models, such as alterations in calcium (Ca2+) handling proteins and beta-adrenergic receptors. Nevertheless, the role of these factors in the development of myocardial dysfunction induced by obesity is still not clear. OBJECTIVE: The purpose of this study was to investigate whether obesity induced by hypercaloric diets results in cardiac dysfunction. Furthermore, it was evaluated whether this functional abnormality in obese rats is related to abnormal Ca2+ handling and the beta-adrenoceptor system. METHODS: Male 30-day-old Wistar rats were fed with standard food (C) and a cycle of five hypercaloric diets (Ob) for 15 weeks. Obesity was defined as increases in body fat percentage in rats. Cardiac function was evaluated by isolated analysis of the left ventricle papillary muscle under basal conditions and after inotropic and lusitropic maneuvers. RESULTS: Compared with the control group, the obese rats had increased body fat and glucose intolerance. The muscles of obese rats developed similar baseline data, but the myocardial responsiveness to post-rest contraction stimulus and increased extracellular Ca2+ were compromised. There were no changes in cardiac function between groups after beta-adrenergic stimulation. CONCLUSION: Obesity promotes cardiac dysfunction related to changes in intracellular Ca2+ handling. This functional damage is probably caused by reduced cardiac sarcoplasmic reticulum Ca2+ ATPase (SERCA2) activation via Ca2+ calmodulin kinase. PMID- 21584482 TI - Development of a new scale for perceived self-efficacy in manual wheeled mobility: a pilot study. AB - OBJECTIVE: To study the psychometric qualities of a perceived self-efficacy in wheeled mobility scale. DESIGN: Questionnaires. SUBJECTS: Forty-seven wheelchair basketball players with spinal cord injury (elite n=25, recreational n=22, from 6 different countries). METHOD: Based on the literature, and expert's and wheelchair user's comments, a new Self-Efficacy in Wheeled Mobility Scale (SEWM)1 was developed. Internal consistency (split-half and Cronbach's alpha) and concurrent validity (correlating the Self-Efficacy in Wheeled Mobility Scale with the Generalized Perceived Self-efficacy Scale (GSE) and the spinal cord injury Exercise Self-Efficacy Scale (ESES)) were assessed. To evaluate the construct validity, age, lesion level and completeness and time since injury between groups of participants and their total scores were compared statistically. RESULTS: Cronbach's alpha for the SEWM was 0.91, internal consistency was r=0.90. Significant correlations between pairs of scales of the entire sample (SEWM-ESES: 0.60; SEWM-GSE: 0.50 (p<0.05; n= 47, 2-tailed) and of the sub-group comparison (SEWM-ESES recreational r=0.61; elite r=0.73), demonstrated fair construct and concurrent validity of the SEWM. CONCLUSION: The SEWM was found to be reliable and valid in active spinal cord injury. A larger more diverse sample is needed to support the psychometric qualities of the SEWM scale. PMID- 21584483 TI - Performance of prioritized activities is not correlated with functional factors after grip reconstruction in tetraplegia. AB - OBJECTIVE: To investigate the correlation between perceived performance in prioritized activities and physical conditions related to grip reconstruction. DESIGN: Retrospective clinical outcome study. PATIENTS: Forty-seven individuals with tetraplegia were included in the study. Each participant underwent tendon transfer surgery in the hand between November 2002 and April 2009 and had a complete 1-year follow-up. METHODS: Functional characteristics and performance data were collected from our database and medical records. Patients' perceived performances in prioritized activities were recorded using the Canadian Occupational Performance Measurement. Preoperative data included age at surgery, time since injury, severity of injury, sensibility and hand dominance. At 1-year follow-up, grip strength, key pinch strength, finger pulp-to-palm distance, distance between thumb and index finger and wrist flexion were measured. Correlation rank coefficient was used to test the possible relationship between physical data and activity performance. RESULTS: There were improvements in both functional factors and in rated performance of prioritized activities after surgery. There was no correlation between performance change and any of the physical functions, the factors known before surgery, or the functional outcome factors. CONCLUSION: No correlation exists between a single functional outcome parameter and the patients' perceived performance of their prioritized goals in reconstructive hand surgery in tetraplegia. PMID- 21584484 TI - Novel application of lower body positive-pressure in the rehabilitation of an individual with multiple lower extremity fractures. AB - OBJECTIVE: Lower extremity fractures, if not treated appropriately, can increase the risk of morbidity. Partial weight-bearing after surgical repair is recommended; however, current methods of partial weight-bearing may cause excessive loads through the lower extremity. A new rehabilitation tool that uses lower body positive-pressure is described, that may allow partial weight-bearing while preventing excessive loads, thereby improving functional outcomes. METHODS: A patient with multiple lower extremity fractures underwent a 6-month rehabilitation programme using bodyweight support technology 3 times per week, post-surgery. RESULTS: The patient experienced a reduction in pain and an improvement in ankle range of motion (p=0.002), walking speed (p>0.05) and physical function (p=0.004), as assessed by the Foot and Ankle Module of the American Academy of Orthopaedic Surgeons Lower Limb Outcomes Assessment Instrument. Training did not appear to affect fracture healing, as was evident on radiograph. The effect of lower body positive-pressure on effusion, which has not previously been reported in the literature, was also investigated. No significant difference in effusion of the foot and ankle when using lower body positive pressure was found. CONCLUSION: Initial results suggest that this new technology may be a useful rehabilitation tool that allows partial weight-bearing during the treatment of lower extremity injuries. PMID- 21584485 TI - Circuit class therapy for improving mobility after stroke: a systematic review. AB - OBJECTIVE: To examine the effectiveness of group circuit class therapy for improving the mobility of adults after stroke. DESIGN: Cochrane systematic review. METHODS: A comprehensive search strategy was used to find randomized and quasi-randomized controlled trials of adults post-stroke receiving circuit class therapy. Two authors independently selected trials for inclusion, assessed the methodological rigor and extracted data. RESULTS: Six trials were included, involving 292 participants; most were community-dwelling survivors who were able to walk independently. Circuit class therapy was effective in improving walking ability (6-minute walk test mean difference, 76.6 m, 95% confidence interval 38.4 114.7, walking speed mean difference 0.12 m/s, 95% confidence interval 0-0.24) and balance (step test mean difference 3.0 steps, 95% confidence interval 0.08 5.9, activities specific balance confidence mean difference 7.76 points, 95% confidence interval 0.66-14.9). Other balance measures did not show a difference in effect. Results from two studies suggest that circuit class therapy can reduce length of hospital stay (mean difference -19.7 days, 95% confidence interval 35.4 to -4.0). Two studies measured adverse events (falls); all were minor. CONCLUSION: Circuit class therapy is safe and effective in improving mobility in people after stroke and, when provided as part of hospital-based rehabilitation, may reduce length of stay. PMID- 21584487 TI - ATPase family AAA domain containing 3A is an anti-apoptotic factor and a secretion regulator of PSA in prostate cancer. AB - In order to investigate the clinical value of ATPase family AAA domain containing 3A (ATAD3A), a potential anti-apoptotic factor in prostate cancer (PCa), immunohistochemistry was used to measure ATAD3A expression in pathological specimens from 86 Chinese patients and in 183 tissue-array samples from American patients. The effect of ATAD3A on the expression of prostate specific antigen (PSA) and drug resistance in PCa cell lines was determined by in vitro experiments. ATAD3A was detected in 74 of 86 (86.0%) Chinese specimens and in 145 of 183 (79.2%) American patient samples. No difference was found in ATAD3A expression between these two patient groups. In vitro, silencing of ATAD3A expression reduced PSA secretion and cisplatin resistance, suggesting that ATAD3A was associated with PSA secretion and drug resistance in PCa. PMID- 21584488 TI - Transcription factor decoy against NFATc1 in human primary osteoblasts. AB - The present study describes, for the first time, the removal of the nuclear factor of activated T cells cytoplasmic 1 (NFATc1) by a decoy approach in human primary osteoblasts (hOBs). hOBs with different NFATc1 expression levels were used. The functionality of endogenous NFAT proteins in our experimental model was analyzed by monitoring the transcriptional activity on a luciferase reporter construct driven by three copies of an NFAT response element (pNFAT-TA-luc). Cell treatment with the decoy against NFATc1 resulted in a significant increase in the expression of osteoblastic markers, including ERalpha and ColXV. On the contrary, the expression of Runx2, which is known to not be transcriptionally regulated by NFATc1, was not altered, indicating the specificity of the decoy effect. To our knowledge, this is the first time that transcription factor decoy has been successful in hOBs to allow the investigation of the role of NFATc1 in an experimental model that, compared to the use of cell lines, more closely resembles an in vivo model. In addition, by using chromatin immunoprecipitation we found that in vivo NFATc1 is recruited on the ColXV gene promoter. The specific role of NFATc1 in osteoblast differentiation is not well understood, however, our findings reinforce the action of NFATc1 in the transcriptional program of osteoblasts, also supporting the therapeutic potential for the proper manipulation of NFATc1-mediated events in different bone disorders. At the same time, our data add important information on the regulation of the expression of ColXV, which only recently has been proposed as an osteoblastic marker. PMID- 21584489 TI - Phosphorylation of beta-catenin results in lack of beta-catenin signaling in melanoma. AB - The Wnt/beta-catenin pathway is involved in differentiation events during embryonic development and is further described as a pathway often participating in tumor formation when aberrantly activated. Molecular studies concentrating on colorectal cancer revealed mutations of apc, ctnnbi, btrc and tcf-4 genes which mimic Wnt stimulation. However, such mutations are rarely found during melanoma development. Therefore, we analyzed the beta-catenin activity in this type of skin cancer. Interestingly, localization of beta-catenin protein was basically cytoplasmic in melanomas in vivo, which was in clear contrast to findings in colon carcinoma. Congruently, the transcriptional activity of beta-catenin regulating expression of beta-catenin target genes was not observed in several melanoma cell lines. Further, neither LiCl nor Wnt agonist treatment led to significant activation of beta-catenin signaling. This lack in functionality seems to depend on phosphorylation at threonine 41 and serine 45 of beta-catenin observed in several melanoma cell lines. However, this specific endogenous phosphorylation pattern led to upregulation of other signaling pathways resulting e.g. in induction of N-cadherin expression. In summary, this study suggests a cell type-specific regulation of beta-catenin function. This alternative beta catenin signaling pathway should be considered when thinking about targeting beta catenin in melanoma treatment. PMID- 21584490 TI - SNP rs1801157 significantly correlates with distant metastasis in CXCL12 expressing esophagogastric cancer. AB - We performed this study in order to evaluate the impact of the chemokine CXCL12 and its single-nucleotide polymorphism (SNP) rs1801157 on clinicopathological parameters and survival in patients undergoing surgery for esophagogastric cancer. The expression pattern of CXCL12 and its polymorphisms were analyzed by RT-PCR and PCR-RFLP in 69 consecutive fresh-frozen samples of human esophagogastric junction and gastric adenocarcinomas and statistically analyzed. Expression of the CXCL12 (SNP rs1801157) polymorphisms GA/AA significantly correlated with distant metastasis (P=0.026), but not with prognosis. However, CXCL12 expression was not significantly associated with the tumor infiltration depth, lymphatic metastasis and grading. As CXCL12 polymorphisms mediate tumor cell dissemination in esophagogastric cancer, they could represent a marker indicating advanced disease. Antagonists targeting the CXCL12/ CXCR4 axis may be a novel therapeutic option in this entity. PMID- 21584491 TI - Effects of affinity on binding of HER2-targeting Affibody molecules: model experiments in breast cancer spheroids. AB - Binding of a targeting agent in tumor tissue is influenced by many factors such as molecular weight, charge and affinity of the targeting agent and vascularization of the tumor. In this study, we analyzed tumor cell binding of three HER2-specific and radiolabeled Affibody molecules with different affinities. The Affibody molecules had affinities in the range of 0.12-3.8 nM. Cellular binding was analyzed, after 2 h of incubation, in tumor spheroids composed of BT474 breast cancer cells, which highly express HER2. Binding was, due to the binding-site barrier, limited to the outer 15 +/- 5 um rim of the spheroids, independent of affinity when the concentration of the substances was low. When the concentration was high, the binding site barrier was overcome and the binding occurred approximately 35 +/- 5 um into the spheroids for the two high affinity substances and 50 +/- 5 um for the low affinity substance. The lower affinity might allow for penetration into deeper regions due to less firm binding. We conclude that there is a binding site barrier within tumor spheroids which can be overcome by increased concentration of substance and modified by affinity. PMID- 21584492 TI - Production of free methylarginines via the proteasome and autophagy pathways in cultured cells. AB - omega-NG-monomethylarginine (MMA) and asymmetric omega-NG, omega-NG dimethylarginine (ADMA), are endogenous competitive inhibitors for three isoforms of nitric oxide synthase (NOS). Although free methylarginines are thought to be liberated through the intracellular proteolysis of proteins methylated by protein arginine methyltransferases (PRMTs), the degradation pathways of the arginine methylated proteins involved in the biosynthesis of free methylarginines have yet to be determined. In this study, the biosynthesis of free methylarginines with cultured cells was analyzed as follows: first, we established a method for quantifying trace amounts of free intracellular methylarginines by means of ultra high-performance liquid chromatography (UPLC). Second, we determined the type of methylation produced in the cultured cell lines using matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight tandem mass spectrometry (MALDI-QIT-TOF/MS). Finally, we investigated whether methylarginines are generated via the proteasome and autophagy pathways, the primary intracellular protein degradation systems. By using specific inhibitors for each pathway, we found that the blockade of proteasome activity reduced the amount of free ADMA and symmetric omega-NG, omega-N'G-dimethylarginine (SDMA), while the inhibition of autophagy significantly reduced cellular ADMA only. These results suggest that both the proteasome and autophagy pathways play an essential role in the production of free methylarginines. PMID- 21584493 TI - Differentially expressed microRNAs and their target genes in the hearts of streptozotocin-induced diabetic mice. AB - Persistent hyperglycemia in diabetic patients has been associated with cardiac hypertrophy, myocardial fibrosis and cardiac dysfunction. However, the underlying mechanisms of this association have yet to be fully elucidated. The aim of this study was to investigate the expression and function of microRNAs (miRNAs) in diabetic cardiomyopathy. miRNA expression profiles were examined by miRNA microarray analysis in heart tissue from streptozotocin (STZ)-induced diabetic mice and non-diabetic mice. The targets of the altered miRNAs were predicted using the Sanger database. Then, the targets RASA1, RAC1, TGFB3 and COL1A1, related to cardiac hypertrophy or myocardial fibrosis, were selected to analyze the miRNA level by real-time reverse transcription (RT-PCR). Gene Ontology (GO) was further applied to describe the function of each miRNA target gene and to elucidate their combined effects in diabetic cardiomyopathy. Up-regulated (n=10) and down-regulated (n=6) miRNAs were identified in diabetic cardiomyopathy. Target genes (n=192) were pooled from the Sanger database. Among the 192 targets, the mRNA expression of RASA1, RAC1, TGFB3 and COL1A1 was increased in diabetic cardiomyopathy. Thirty one GO functions were enriched in diabetic cardiomyopathy. These results demonstrate that miRNAs may mediate cardiac hypertrophy and myocardial fibrosis in diabetic cardiomyopathy via their targets, and provide insights into the pathogenesis of diabetic cardiomyopathy. PMID- 21584494 TI - Prenatal essential fatty acid deficiency in mice results in long-term gender specific effects on body weight and glucose metabolism. AB - Essential fatty acids are important for normal growth and development in early life. However, the long-term effects of prenatal essential fatty acid deficiency (EFAD) on the adult metabolism remain to be determined. The aim of this study was to investigate the effects of an EFAD diet given to mice during late gestation on body weight and body composition, and metabolism in the adult offspring. Pregnant dams were given an EFAD or a control diet during the last 10 days of gestation. After delivery, all mice were fed normal chow and the body weight of the offspring was measured weekly. Furthermore, food intake, energy expenditure and intraperitoneal glucose tolerance were analysed in the adult offspring in addition to body composition (analysed by dual-energy X-ray absorptiometry), plasma levels of leptin, triglycerides and cholesterol. The body weight was lower in the EFAD offspring as compared to the controls during the first 4 weeks of age, and remained lower in the females throughout the study. Lean body mass and plasma leptin levels were also lower in the female EFAD offspring as compared to the controls. Male EFAD offspring were found to have higher fasting glucose and insulin levels as well as higher insulin levels during the glucose tolerance test compared to the controls. However, no differences were found in blood lipids, food intake or energy expenditure between EFAD and control mice of either gender. These results demonstrate that an EFAD diet given during the last 10 days of gestation results in long-term gender-specific effects on body weight and insulin sensitivity in the adult offspring. PMID- 21584495 TI - Atorvastatin reduces lipopolysaccharide-induced expression of C-reactive protein in human lung epithelial cells. AB - Accumulating evidence suggests that statins possess anti-inflammatory properties and may decrease C-reactive protein (CRP) levels in plasma. However, no studies have as yet addressed whether or not statins regulate the expression of CRP in human lung epithelial cells (A549). In this study, we determined whether atorvastatin modulates the lipopolysaccharide (LPS)-induced expression of CRP in A549 cells. A549 cells were incubated in Dulbecco's modified Eagle's medium containing LPS in the absence or presence of various concentrations of atorvastatin. After incubation, the medium was collected and the amount of CRP was measured by an enzyme-linked immunosorbent assay. The cells were harvested and CRP messenger ribonucleic acid (mRNA) was analyzed by reverse transcription polymerase chain reaction. Incubation with LPS induced a significant time- and dose-dependent increase in CRP mRNA expression and CRP production in A549 cells, whereas atorvastatin significantly decreased LPS-induced CRP mRNA expression and CRP production in a dose-dependent manner. The present study revealed that A549 cells are capable of LPS-induced CRP expression, and that atorvastatin down regulates the LPS-induced expression of CRP in cultured A549 cells. Our results suggest that statins ameliorate lung inflammation by regulating CRP production in human lung epithelial cells. PMID- 21584496 TI - High chromogranin A cell density in the colon of patients with lymphocytic colitis. AB - Microscopic colitis (MC) is a chronic condition that is characterized by watery diarrhoea with normal appearance of the colonic mucosa. MC is subdivided into two distinctive entities: lymphocytic colitis (LC) and collagenous colitis (CC). The etiology and pathophysiology of LC remain to be determined. The present study included 9 female patients with LC, with an average age of 34 years. Subjects (n=25) who underwent colonoscopy were used as controls. The subjects underwent colonoscopy due to gastrointestinal bleeding, where the source of bleeding was identified as haemorrhoids, or due to health concerns. The control subjects included 18 females and 7 males, with an average age of 49 years. Colonoscopy was performed in both patient and control groups, and biopsies were obtained from different segments of the colon. The biopsies were immunostained with the avidin biotin complex method for human leucocytes CD45, collagen type III and chromogranin A (CgA). CgA was quantified by computer image analysis. The density of CgA-immunoreactive cells in patients with LC was significantly higher than that in controls. The high density of colonic CgA, a common marker for endocrine cells, indicates the possibility that colonic hormones are involved in the pathophysiology of LC. Serotonin-containing cells are the major endocrine cell type in the colon and constitute approximately 88% of the total endocrine cell population. It is likely that the increase in colonic CgA in LC patients accounts for an increase in serotonin cells. PMID- 21584497 TI - Molecular pathology of myelodysplastic syndromes: biology of medullary stromal and hematopoietic cells (review). AB - Myelodysplastic syndromes (MDS) have been defined as a disease entity based on clinical features and morphological findings. Despite similarities in clinical manifestations, genetic abnormalities occurring in hematopoietic cells are heterogeneous among the syndromes. However, recent investigations have revealed that there are common biological events in the bone marrow of MDS cases. Most notably, excessive apoptosis of hematopoietic cells was observed to be induced by the bone marrow microenvironment. The apoptosis was mediated by paracrine as well as autocrine factors, suggesting that medullary stromal and hematopoietic cells play a role in the pathology of disease. Pro-inflammatory cytokines, such as TNFalpha, in the bone marrow microenvironment are predominantly paracrine mediators of apoptosis. Regarding autocrine stimulation mechanisms, it has recently been shown that the deregulation of ribosomal protein is capable of initiating a stress response in the hematopoietic cell through a p53-mediated signaling pathway. Thus, both the stromal cells of the bone marrow microenvironment and hematopoietic cells themselves possess a common and characteristic biology in this heterogeneous disease entity. PMID- 21584499 TI - Polymorphism of the salt sensitivity gene angiotensinogen and gastric cancer risk. AB - A high-salt diet is a risk factor for gastric cancers other than those caused by Helicobacter pylori. The angiotensinogen (AGT) M235T polymorphism has been associated with salt sensitivity. The aim of the present study was to clarify the association between the AGT M235T polymorphism and gastric cancer. The AGT M235T polymorphism was genotyped using PCR-RFLP analysis in 206 gastric cancers and 210 control biopsies. A logistic-regression analysis was performed to identify an odds ratio to determine whether a correlation exists between genetic polymorphism and risk in patients with gastric cancer as compared to the control samples. Statistical significance was determined using the Mann Whitney U and Chi-square tests. The genotype distribution was found to be MM=9 (4.4%), MT=57 (27.7%), and TT=140 (67.9%) in samples from patients with gastric cancer and MM=8 (3.8%), MT=60 (28.6%) and TT=142 (67.6%) in the control samples. The odds ratio of gastric cancer of the MM genotype associated with the T carrier was 1.0 (0.4-2.7) (P=0.95). The distribution pattern of AGT M235T polymorphism in the gastric cancer cases and controls was not found to be significantly different in this study. Thus, it can be concluded that other sites of AGT polymorphism or other salt sensitivity genes may be associated with gastric cancer. PMID- 21584498 TI - Function of Aurora kinase A in Taxol-resistant breast cancer and its correlation with P-gp. AB - Breast cancer is one of the most common malignant diseases among women. In early and metastatic breast cancer, Taxane (Taxol) is widely used as an adjuvant and neoadjuvant therapies. Although breast cancer is initially responsive to Taxol, inherent or developed resistance to Taxol often limits the efficacy of the drug. The oncogene Aurora kinase A is frequently up-regulated in human cancer, and is associated with sensitivity to chemotherapy in certain types of cancer. In the present study, we aimed to clarify the functional role of Aurora kinase A in breast cancer resistance to Taxol, and to determine the means to overcome this resistance. The correlation between the expression levels of Aurora kinase A and chemoresistance to Taxol in breast cancer cells, and resistance to Taxol in a xenograft model were demonstrated. MTT assay was performed to determine cell viability. Subsequently, the relationship of Aurora kinase A with the expression and functional role of P-gp was clarified, as well as its relationship with p ERK2, which regulates the expression of P-gp. The expression of Aurora A was determined to be capable of enhancing the sensitivity of cells resistant to Taxol in vitro and in vivo using stable knockdown Aurora kinase A cells. We propose that this kinase may be used as a target for overcoming chemoresistance and enhancing the chemosensitivity of breast cancer to Taxol. PMID- 21584500 TI - FW523-3, a novel lipopeptide compound, induces apoptosis in cancer cells. AB - FW523-3, a new lipopeptide compound, was recently isolated and purified from the culture broth of a marine Micromonospora chalcea. FW523-3 was shown to inhibit the proliferation of certain cancer cells. However, the spectra and the underlying mechanism of its antitumor activity are unclear. In this study, the MTT and colony formation assays were employed to determine the antitumor spectra of FW523-3 and its effect on cell proliferation, respectively. Apoptosis was analyzed using DNA laddering assay and flow cytometry and the involved pathways were explored by Western blotting. Results revealed that FW523-3 exhibited cytotoxicity in a panel of tumor cell lines including esophageal squamous cell carcinoma cells (EC109), lung cancer cells (A549 and 95D), gastric cancer cells (SGC7901), uterine cervix cancer cells (HeLa) and hepatocellular carcinoma cells (HepG2). Based on these results, FW523-3 inhibited the colony formation ability of tumor cells. Moreover, FW523-3 induced apoptosis via activation of caspases 9, 7 and 3. FW523-3 also blocked the ERK and p38 signaling pathways. Taken together, we propose that FW523-3 acts as a broad-spectrum antitumor drug. FW523-3 inhibits tumor cell growth and induces tumor cell apoptosis via the mitochondrial and MAPK pathways. PMID- 21584501 TI - Association study between the -866G/A polymorphism in the promoter of uncoupling protein-2 gene and polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, chronic oligoanovulation and insulin resistance. A number of women with PCOS are obese and exhibit abnormal phenotypes, including high levels of androgens, an irregular menstrual cycle and increased hair growth. Studies on obese PCOS patients have proven the crucial role that obesity plays in insulin resistance and hyperinsulinemia. The uncoupling protein (UCP) gene is one of the genes known to have a strong association with obesity and insulin resistance. Thus, we analyzed the association between the -866G/A polymorphism in the promoter of UCP2 and PCOS. Genotyping was performed by polymerase chain reaction along with restriction fragment length polymorphism analysis, followed by an analysis of the genotype of the UCP2 polymorphism in PCOS and control subjects using HapAnalyzer. The study included samples from 277 PCOS patients and 152 healthy controls. P<0.05 was considered to be statistically significant. In conclusion, no association was found between the -866G/A single nucleotide polymorphism and PCOS (P=0.7168, OR=1.07, 95% CI). The present study showed that -866G/A, a UCP2 gene polymorphism, is not associated with the pathogenesis of PCOS. PMID- 21584502 TI - Fatal attraction - the fos-jun affair with nuclear receptors. AB - The modulation of cell physiology forms the basis of cellular growth and differentiation. Aberrant steps in this process are responsible for deregulated proliferation and constitute the molecular causes of tumorigenic development. Signal transduction events regulate gene expression by modulating the activity of transcription factors. Two principal pathways are used by the cell to convey signals to the nucleus. In one, cell surface receptors bind growth factors or peptide hormones and thereby activate intracellular signalling systems. In this case, transcription factors are targets for modification by transduction pathways. The other pathway involves nuclear receptors which bind to steroid and thyroid hormones, vitamin D and retinoic acid. In this case the nuclear receptors themselves are transcriptional regulators. PMID- 21584503 TI - Structure, biology and possible clinical-applications of carcinoma-associated mucins. AB - Mucins are large o-glycosylated proteins which are present on the surfaces of epithelial cells. These mucins are aberrantly expressed in malignancy, thus serving as useful markers. Since these molecules are extremely immunogenic in rodents, many antibodies to the mucin have been previously characterized and are clinically useful. We have isolated the cDNA coding for the mammary gland or milk mucin, MUC1 (Gendler S, Lancaster C, Taylor-Papadimitriou J. et al. J.Biol.Chem., 1990). This core protein was found to be identical to the mucin produced by the pancreas, although glycosylation varies considerably in content and quantity. The same core protein is also expressed on the apical surfaces of duct cells in die lung, ovary, stomach, salivary gland and kidney - simple secretory epithelial tissues. The MUC1 core protein is an integral membrane protein consisting of distinct domains: an amino terminal region containing a hydrophobic signal sequence, the largest domain consisting of from 30 to 125 well-conserved tandem repeats of twenty amino acids, a hydrophobic membrane spanning domain and a sixty nine amino acid cytoplasmic tail. The core protein is highly polymorphic in size due to the variable numbers of repeats with molecular weights from about 120,000 to >300,000 Da. The aberrant glycosylation of the core protein that occurs in malignancy exposes T cell epitopes, thus allowing for the possible use of the protein in immunotherapy of some carcinomas. Both syngeneic and transgenic systems have been developed to examine the immune response to PEM based immunogens. To look at function and the role in development more easily, the mouse homologue has been cloned. PMID- 21584504 TI - Vasoactive-intestinal-Peptide (vip) modulates the growth fraction of epithelial skin cells. AB - Using the human keratinocyte cell line HaCaT, modifications of the growth fraction due to vasoactive intestinal peptide (VIP) were determined by immunostaining with monoclonal antibody Ki67. In addition, the expression of VIP receptor and epidermal growth factor (EGF) receptor have been analysed. VIP (10 (7) to 10-(11) M) produced an almost doubling of the total number of Ki67 positive cells in cultures with 2% fetal calf serum (FCS), wheras it was ineffective in FCS-free and 10% FCS cultures. The nuclear Ki67-staining patterns were classified into four categories. In FCS-free cultures VIP induced a shift from type III (light nucleus, staining nuclei) to type II (multiple, intensely stained spots). In cultures with 2% FCS, VIP induced a shift from type II to type III. VIP receptor expression was facilitated by VIP, when cells were grown in a medium supplemented with 10% FCS. VIP increased EGF receptor expression in FCS free cultures but decreased the number EGF receptor-positive cells in experiments with 2% FCS. In conclusion, VIP is capable to modulate the growth fraction and receptor expression of HaCaT cells in vitro. The effects are dependent on the concentration of FCS within the culture medium. The findings might be of interest for keratinocyte pathology in general and dermatooncology in particular. PMID- 21584505 TI - Differentiation of glioma-cells by a pdgf-antagonist. AB - We previously reported that trapidil, a Platelet-derived Growth Factor (PDGF) antagonist, can inhibit the proliferation of PDGF-dependent glioma cells. In the current study, we explored the effect of trapidil on the differentiation of glioma cells by observing the morphological changes in glioma cells in control and trapidil-treated cultures under a phase contrast microscope. Most cells in the control cultures were flat, large, and irregularly shaped. On the other hand, most cells treated with trapidil formed several long cytoplasmic processes and exhibited fibrous morphology. Western blots and immunocytochemical analysis of glial fibrillary acidic protein (GFAP)-stained, trapidil-treated cultures revealed an increase in GFAP content over the control cultures. From these results we propose that trapidil induces the differentiation of glioma cells. PMID- 21584506 TI - Coinduction of hsp27 phosphorylation and drug-resistance in chinese-hamster cells. AB - Treatments of Chinese hamster fibroblasts with A23187, 2-deoxyglucose, tunicamycin, beta-mercaptoethanol or glucosamine induce an increase in cell resistance to doxorubicin and VM-26 that attains a maximum after 8 h of treatment. We tested the possibility that HSP27, a heat shock protein whose overexpression in cells was shown to confer thermoresistance and chemoresistance, might also be associated with this acquisition of drug resistance. [H-3]leucine incorporation and immunoblot analyses showed that the increased resistance was not accompanied by the synthesis or accumulation of HSP27 or other heat shock proteins. However, drug resistance promoting agents all stimulated protein kinase activities that phosphorylated HSP27 in vitro and stimulated incorporation of P 32 into HSP27 in vivo. HSP27 is thought to exert in unstressed cells functions linked with growth signal pathways. It is suggested that stimulation of HSP27 phosphorylation may modulate a protective function associated with the maintenance of signal transduction homeostasis. PMID- 21584507 TI - Functional implications of the growth-suppressor oncoprotein p53. AB - The nuclear phosphoprotein p53, named according to its apparent molecular weight on SDS-polyacrylamide gels is expressed, albeit at low levels, in a variety of cell types. In normal cells, it seems to be required for cell proliferation whereas in transformed cells it is frequently a target for mutations. Wild-type p53 has a growth-suppressor function which is completely abolished in mutant p53. However, there is ample evidence that mutant p53 has not only lost the suppressor activity but contributes as a dominant oncogene to tumorigenesis. In line with these observations wild-type p53 has a growth inhibitory function even when introduced in rapidly proliferating tumor cells whereas mutant p53 has a growth promoting function. Wild-type p53 and mutant p53 exhibit different DNA binding activities which may be implicated in transcriptional regulation and in DNA replication. Furthermore, both wild-type and mutant p53 play a role in controlling the transition of cells through at least two different restriction points of the cell cycle. Besides these functions in growth control p53 also plays an active role during embryonic development. Expression of p53 is high in cells predetermined to differentiate and decreases upon differentiation. Since embryonic cells express wild-type p53, a progressive role during differentiation has to be attributed to wild-type p53. Thus, this review will try to highlight some of the significant advances in the most rapidly evolving field of the functional implications of p53 in cell biology and tumorigenesis. PMID- 21584508 TI - Alveolar rhabdomyosarcoma - primary and recurrent metastatic tumor has chromosomal translocation t(2-13)(q37-q14), amplified N-myc and is tumorigenic in nude-mice. AB - Tissue specimens of primary and recurrent metastatic alveolar rhabdomyosarcoma (A RMS) from a 12 year old child were cultured and shown to contain A-RMS specific t(2;13) (q37;q14) chromosomal translocation and to be tumourigenic in nude mice. Whereas c-myc protooncogene was neither amplified nor grossly rearranged, both biopsy samples were demonstrated to have 5-fold amplification of N-myc gene sequence. N-myc gene was also amplified in cell cultures produced by primary and metastatic tumour biopsies. Such a model for A-RMS has not been previously available. PMID- 21584509 TI - Ras p21 expression in neuroblastomas and ganglio-neuroblastomas - correlation with patients prognosis. AB - Ras p21 expression was investigated in 28 cases of neuroblastomas and 12 cases of ganglio-neuroblastomas by the biotin-streptavidin immunoperoxidase method using the anti-ras p21 rat monoclonal antibody Y13-259. The results showed that 28% of neuroblastomas and 92% of ganglio-neuroblastomas demonstrated elevated ras p21 expression. However, in this series of patients 10 of 12 ganglio-neuroblastomas were staged as early disease (stage I or II) compared to 15 of 28 neuroblastomas, with similar staged disease. On analysing all of these tumours into early and late disease (i.e. stage I and II; and stage III and IV) a correlation was found between p21-ras overexpression and early disease (P<0.0001). As staging of neuroblastomas has been considered to be a prognostic indicator, it is argued that ras p21 over-expression maybe an indicator for a favourable prognosis in these patients. PMID- 21584510 TI - Reversible dissociation of a tumor-cell surface protease-inhibitor complex. AB - Tumour cell surfaces possess a cell surface protease (GB), which can be recognised by a cytoplasmic inhibitor protein prepared from cultured tumour cells. This enzyme inhibitor complex has been shown to be reversibly dissociated by 10-(4)M sodium dodecyl sulphate. Sections of frozen tumour tissue were used to provide cells with active GB and the successful recognition and inhibition of this GB was followed by fluorescence microscopy employing the competitive inhibitor 9-amino acridine as a fluorescent probe. PMID- 21584511 TI - Locally advanced breast-carcinoma - results of a multimodal therapy including alternating neoadjuvant chemotherapy, surgery and radiotherapy. AB - Thirty women with locally advanced breast cancer (LABC), but no evidence of distant metastases, were prospectively treated with four fixed cycles of neoadjuvant chemotherapy (CT). This regimen consisted of epidoxorubicin (Epi) alternated every 21 days with cyclophosphamide, methotrexate and 5-fluorouracil (CMF). After this induction CT, subsequent therapy was planned according to the response obtained as follows: (a) modified mastectomy with axillary dissection was performed in patients who had major objective response (complete or partial), followed by four doses of adjuvant CT and radiotherapy (RT); (b) debulking rescue surgery followed by RT and 2nd line CT with mitomycin C were given in patients with stable disease or minor response. The response rate to induction CT was 63% (19 of 30 patients) (95% confidence limits 46-80%). Overall, 43% of patients had no persistance of tumor at the end of the planned therapy. After a median follow up time of 36 months, disease-free survival (DFS) and overall survival (OS) were 35% and 47%, respectively. The median duration of DFS was 16 + months (4-52+ months). A significantly better OS was observed in complete responders compared to the others (77% versus 23.5%; p=0.01). Compliance to treatment was high, gastrointestinal and hematological toxicities were the most common side-effects. Thus, this multimodal approach is effective in reducing primary tumor size with acceptable morbidity. Five of the 11 (45%) patients non responsive to induction CT obtained a transient local control of disease after debulking surgery, RT and mitomycin C. To assess the role of alternating non cross resistant regimens as induction therapy in LABC vs conventional schedules, phase III comparative studies are warrented. PMID- 21584512 TI - Overexpression of C-fos and C-erbb1 encoded proteins in squamous-cell carcinomas of the lung of smokers. AB - Seventy-eight human squamous cell carcinomas of the lung of previously untreated patients were analyzed for expression of c-fos and c-erbB1 proteins by means of immunohistochemistry. Of the tumors investigated expression of c-fos protein was detected in 60% and of c-erbB1 protein in 77%. Carcinomas of smokers significantly express more frequently c-fos and c-erbB1 protein than carcinomas of non-smokers (p<0.05). PMID- 21584513 TI - Activation of the human multidrug resistance-1 (mdr1) gene promoter in response to inhibitors of DNA topoisomerases. AB - The multidrug resistance (MDR1) gene encodes a Mr 170,000 energy-dependent membrane efflux pump termed P-glycoprotein, and the P-glycoprotein is often expressed in various human tumors before and after cancer chemotherapy. In this study, we have established a human cancer KB cell line (Kst-6) which stably expressed the CAT gene (pMDRCAT1) driven by the human MDR1 promoter. Exposure to inhibitors of DNA topoisomerase I (camptothecin: CPT-11) and II (etoposide: VP-16 and teniposide: VM-26) could efficiently induce CAT activities in both time- and dose-dependent manners. However, CAT activity could not be significantly induced when treated with an ATP-antagoist, novobiocin. Northern blot analysis showed about 5-fold increase in CAT mRNA levels in Kst-6 cells treated with CPT-11 or VP 16, but not with novobiocin. Proximal MDR1 promoter-binding activities of transacting factor were augmented in nuclear extracts from KB cells treated with CPT-11, VM-26, and VP-16. PMID- 21584514 TI - Multiple phenotypes induced by mutant ha-ras in thyroid epithelial-cells - correlation with level of expression. AB - To investigate the role of ras mutations in thyroid epithelial tumorigenesis, we introduced wild-type or mutant v- or c-Ha-ras genes into a sub-cloned rat thyroid follicular epithelial cell line using retroviral vectors and a neutral selection method (G418 resistance). Mutant, but not wild-type, ras induced a spectrum of clonal phenotypes. Interestingly, many clones showed an unchanged phenotype despite ras expression at levels greater than that of the endogenous gene. Further increase in ras expression was associated with altered morphology, loss of thyroid-specific differentiation (thyroglobulin synthesis) and growth factor independence, but not. anchorage-independence or tumorigenicity. The mutation site (codon 12 or 61) did not have a significant influence. The results clearly emphasize the critical importance of expression level in determining the phenotypic effect of mutant ras on epithelial cells. PMID- 21584515 TI - Circumvention of Cisplatin resistance in h-ras transformed-nih/3t3 cells by suppressor mutant of h-ras. AB - The expression of H-ras oncogene, it has been shown, induces cisplatin resistance in vitro. Using two types of flat revertants (R1, F32/F33) which lost the transformed phenotypes, we studied the mechanism of the cisplatin resistance. R1 cells, which expressed an activated c-H-ras oncogene, exhibited increased cisplatin resistance. Further, F32/F33 cell lines, which were suppressed the H ras function by a suppressor mutant of H-ras, restored the cisplatin sensitivity. These results implicate that the cisplatin resistance was directly related to the expression of H-ras and can be circumvented by suppression of the H-ras functions. PMID- 21584516 TI - Growth-inhibition of ht29 cells exposed to N-methylformamide correlates with altered expression of alpha-6/beta-4 integrin. AB - The anticancer agent N-methylformamide (NMF) suppresses the expression of the c myc proto-oncogene in human colon carcinoma cells while increasing the doubling time and reducing tumorigenicity in these cells. However, the mechanism by which NMF exerts its effects has remained unclear. We compared the expression of c-myc and of other growth-regulated genes (p53, beta-actin) to that of the H3 histone gene, which is specifically expressed in S-phase cells, in HT29 human colon carcinoma cells maintained in vitro or in nude mice. The growth fraction of the cell populations in the presence or absence of NMF was also evaluated at different days of growth by flow cytometric analysis. To assess whether prolonged exposure to NMF might induce a different phenotype in human carcinoma cells, the expression of alpha6, beta1, and beta4 integrin subunits were evaluated. The data indicate that NMF treatment induces a reduction in the growth fraction of HT29 colon carcinoma cells accompanied by a reduction in c-myc, H3 histone, p53, and beta-actin gene expression, and that prolonged exposure to NMF induces elevated expresssion of alpha6/beta4 integrin receptor, These data suggest that NMF induced reduction of the proliferative capacity supports a different 'maturation status' of colon carcinoma cells which is defined by an elevated expression of the alpha6/beta4 integrin. PMID- 21584517 TI - Enzyme-linked-immunosorbent-assay for the detection of a novel 21-kda protein associated with the clinical course of patients with urogenital tumors. AB - A novel 21 kDa protein (p21) was detected in sera of patients with urogenital tumors by ELISA, using rabbit polyclonal antibodies generated against the p21 polypeptide. Eight out of 11 patients (72%) exhibited a 2-5 fold increase in pre treatment p21 serum levels as compared with 20 healthy individuals. A decrease of p21 levels was observed in 6 out of 8 patients in which a regression of the disease was shown post-treatment. An increase or no change in p21 levels was observed in 3 patients with no change or progression of the disease. The ELISA described herein may be useful for clinical monitoring of patients with urogenital tumors, some of which have no available tumor marker. PMID- 21584518 TI - Regional loss of the y-chromosome in urothelial carcinoma. AB - Specific chromosomal losses have been reported for various human tumors. We have now investigated ten cases of urothelial carcinoma and observed genomic alterations by a new method allowing detection of chromosomal losses directly in the tissue section. In 6 out of 8 male carcinomas, the Y-chromosome was lost either in single cells and isolated areas or in extended regions of the tumor sample. Presence of chromosome 1 served as an internal control. This new in situ method allows studies of chromosomal alterations in relation to their tumor topology and the observations constitute the first report on such localised tumor specific genomic changes. PMID- 21584519 TI - Proliferative activity of carcinoma of the papilla of vater - an immunohistochemical study demonstrating proliferating cell nuclear antigen (pcna). AB - The expression of proliferative cell nuclear antigen (PCNA) in carcinomas of the papilla of Vater were studied. The PCNA LI of the specimens ranged from 13.0 to 72.8% (mean +/- standard deviation=43.1 +/- 16.4%). The tumors with lymph node involvement had a higher PCNA LI than those without lymph node involvement. The PCNA LI of tumors extending to duodenum or pancreas was significantly higher than that of tumors restricted to the muscle of the sphincter of Oddi. These results indicate that PCNA LI is one of the important factors indicating spread of tumor, i.e., lymph node involvement and depth of invasion. PMID- 21584520 TI - Detection of hepatitis-B virus-DNA at high-frequency in liver neoplasias using a PCR technique. AB - Hepatocellular carcinoma is the most frequent liver cancer and hepatitis B virus is included among the risk factors for the development of this type of neoplasia. Direct detection of this virus is difficult due to the lack of a simple tissue culture system for growing the virus. Amplification of HBV nucleic acid sequences with the Polymerase Chain Reaction technique leads to the direct detection of the virus, but involves several critical steps and it is prone to false positive results due to inter sample contaminations. We overcame these shortcomings by using a simple boiling method for extracting DNA from histological slides of tissues coupled with double ('nested') PCR amplification. In this study we evaluated the frequency of presence of HBV nucleic acid sequences in samples of neoplastic liver tissues from patients in Greece. We studied 20 DNA samples from hepatocellular carcinomas and we found 11 positive for HBV DNA and 8 DNA samples from hepatoblastomas and we found 3 positive for the viral DNA. PMID- 21584521 TI - Synergistic potentiation of Cisplatin cytotoxicity by caffeine in a Cisplatin resistant rat ovarian tumor-cell line. AB - The combined cytotoxicity of cisplatin (DDP) and caffeine (CA) against DDP sensitive (O-342) and -resistant (O-342/DDP) rat ovarian tumor cell lines in vitro was investigated. 0-342/DDP cells showed a similar sensitivity to CA as O 342 cells did. Simultaneous administration of DDP and CA resulted in infra additive to additive cytotoxicity in O-342 cells, whereas in O-342/DDP cells, combination of DDP with CA produced effects from infra-additivity to synergism. The strength of this enhancement of DDP cytotoxicity by CA in both cell lines varied in a CA-dose dependent manner but inversely with DDP concentrations. ADP ribosyl transferase (ADPRT) activity was 2.6-fold in O-342/DDP cells compared to that in O-342 cells. CA (2.5 mM) caused 53.4% and 28.9% inhibition of ADPRT activity in control and DDP-treated O-342/DDP cells, respectively. This inhibitory effect, however, was not observed in 0-342 cells. Our results suggest that CA may have some potential in combination with DDP for treatment of DDP resistant malignancies in the clinic. One of the possible mechanisms involved in this process might be that CA inhibits ADPRT-associated DNA repair in the resistant cells. PMID- 21584522 TI - Further characterization of acquired-resistance to Cisplatin in a rat ovarian tumor-cell line. AB - The proliferation of a rat ovarian tumor cell line (O-342) was completely inhibited by a 2 h exposure to 20 muM cisplatin (DDP) in vitro up to 120 h after its removal, while in its DDP resistant subline (O-342/DDP), the same treatment only caused a transient growth inhibition within the first 24 h post the exposure, followed by the recovery of proliferation at a similar rate as the control cells. DNA interstrand cross links (ISCL) were maximally formed 12 h post DDP treatment in either O-342 or O-342/DDP cells, with a 2.8-fold increase in the sensitive cells at this time (262 vs. 95 rad eq.). After further 12 h incubation, however, 75% of DNA-ISCL was removed in O-342/DDP cells, while only 22% of them were repaired in O-342 cells. DNA single strand breaks (SSB) were produced to a similar extent in both lines but reached a maximum at 12 and 24 h in the resistant and the sensitive cells, respectively. ADP-ribosyl transferase (ADPRT) activity, a DNA repair-associated enzyme, was 2.6-fold higher in O-342/DDP cells compared to the sensitive subline. Following DDP treatment, the activity was stimulated in the sensitive cells with a maximum of about 1.5-fold at 24 h, whereas the inhibitory effect was observed in the resistant cells, although at 12 h it recovered almost to the control level. Flow cytometric analysis showed that there were at least two sub-populations (2n and 4n) in O-342 cells, while only 2n population was observed in O-342/DDP cells. Following DDP exposure, O-342/DDP cells progressed through the cell cycle with only a small and transient accumulation of cells in S-phase at 12 h and 24 h, while in the sensitive cells, it was impossible to distinguish cell-cycle distribution at 12 h due to severe damage, at 24 h most of the cells became arrested in G2-phases, which persisted until the end of the observation (48 h). Our results suggest that both reduced interaction of cellular DNA with DDP and increased DNA repair are contributing factors for development of DDP resistance, which might be directly or indirectly subsequent to alterations of poly (ADP-ribose) metabolism in the resistant cells. PMID- 21584523 TI - Simple and efficient chemosensitivity assay for human primary tumor-cells using contact-sensitive microtiter plates. AB - A simple and efficient chemosensitivity assay for human primary tumors has been developed using 96-well microtiter plates covered totally with lethally irradiated 3T3 monolayers termed cell mats, on which the proliferation of normal human fibroblasts is preferentially inhibited. Two days after the inoculation of tumor cells into the microtiter cell mat plates, the cells were treated with various anticancer drugs, and the cell numbers were assessed by radioactivity using a 96-well automatic scintillation counter after subsequent radiolabeling with H-3-deoxyuridine for 24h. In this manner, complete dose response curves of many anticancer drugs were available from one plate within 5 days. Drugs tested in triplicate were adriamycin, mitomycin C, cisplatin, etoposide, and 5 fluorouracil at 0.01, 0.1, and Ix the peak tolerated drug concentrations in serum. Clinically, of the 39 primary tumor specimens of different types received, 4 were contaminated. The remaining 35 samples were successfully cultured, with 5 cultures being abandoned due to an insufficient cpm. As a result, cell survival curves were obtained from 30 (77%) specimens. This high evaluable rate might be due to the feeder effect brought by cell mats. Although optimization of the assay system has yet to be determined, the ability to have multiple drug sensitivity per plate with short-term duration would make this system an efficient assay for chemosensitivity test of human primary tumor cells. PMID- 21584524 TI - Differential splicing of the neurofibromatosis type-1 gene in the rat - splice variants homologous with the human are expressed in rat-cells. AB - The GTPase activating protein-related domain (GRD) of the human neurofibromatosis type 1 gene (NF1) was shown to have two types of splice variants. Through polymerase chain reaction (PCR), we isolated and sequenced three types of splice variants in the rat NF1-GRD. Type I and II transcripts were highly homologous with the human transcripts. The type III NF1-GRD transcript, unidentified in the human, had an additional 41-bp insert immediately downstream from the 63-bp insert of the type II transcript. The type III transcript encoded for a protein that prematurely terminated its predicted amino acid sequence because of a stop codon, resulting in possible modification of the GAP activity. All three transcripts were found in the rat's liver, cerebral hemispheres, spinal cord, colon, and spleen, whereas the other organs examined had only type I and II transcripts. This differential splicing mechanism may regulate the activity or compartmentalization of the NF1 protein, resulting in modulation of the Ras related signal transduction pathway. PMID- 21584525 TI - Prognostic factors in breast-cancer (review). AB - The challenge in breast cancer (BC) is to confide the heterogenous nature of BC and to find out the best individual therapeutic alternatives for clinical use. Recently a wide scale of sophisticated methods like morphometry, DNA flow cytometry and oncogene products have been introduced to predict the outcome of BC, but many of them are currently unsuitable for clinical use. At present limited experience in clinical practice, technical difficulties, sources of variation, and low cost-benefit ratio limit their use. Axillary lymph node status, tumour diameter and histological grade are classic and relevant predictors, although they suffer from subjectivity of assessments. Together with hormone receptor status they build the ground for clinical decision making. New demands make us to reconsider the general philosophy of the treatment of BC and there are two special groups of BCs in which we have an urgent need to find out new accurate prognostic factors. About 25% of axillary lymph node negative (ANN) tumours behave aggressively but on the other hand a group of axillary lymph node positive patients run a more favorable course than might be expected. In these situations under- or overtreatment could be avoided by accurate prediction. Recent results suggest that morphometric prognostic index, S-phase fraction and mitotic indices might be used in the prediction of BC in these situations since the prognostic results by these methods have been more accurate than by conventional prognostic methods. PMID- 21584526 TI - Amphibian tissue regeneration - a model for cancer regulation (review). AB - This paper attempts to re-examine the tumor and carcinogenesis-regulating abilities of tissues of several urodele species that are able to regenerate. Regeneration-competent tissues seem refractory to chemical carcinogenesis while this is not the case with regeneration-incompetent tissues. Spontaneous tumors are not readily found and the ones that have been found have not been well characterized. The implications of such resistance to cancer formation at the molecular level are discussed. It is proposed that regulation of embryonic genes, including oncogenes, might be driven by unique events in the regenerating tissues of amphibia. In addtion expression patterns of two oncogenes are presented. PMID- 21584527 TI - Synergy of interleukin-5 with interleukin-2 in the generation of lymphokine activated killer-cells. AB - IL-5 synergies with IL-2 to produce increased LAK activity, although IL-5 alone induced little cytotoxic activity. The most dramatic synergy occurred with a suboptimal IL-2 concentration. The kinetics of LAK activity induced by IL-2 plus IL-5 were similar to those induced by IL-2. IL-5 exerted its effects during the late stage of IL-2 induced LAK generation. In the precursor phase, depletion of asialo-GM1+ cells preceding culture eliminated IL-2 plus IL-5 induced LAK activity. In the effector phase, IL-2 plus IL-5 induced LAK activity was eliminated by depletion of Thy1.2+ cells following culture. PMID- 21584528 TI - Binding of transcription factor sp1 to exon-1 of C-myc is altered in burkitts lymphoma. AB - In Burkitt's lymphoma (BL) a consistent chromosomal translocation involving the c myc proto-oncogene locus on chromosome 8 and one of the immunoglobulin loci located on chromosomes 14, 22 or 2 results in the aberrant expression of c-myc. In six out of ten published BL sequences the translocated c-myc gene contains mutations and/or deletions in an Spl site in the first exon. We show by competition gel mobility shift assays and association constant comparison that the binding of Spl to this site is altered in four of these clones. The affinity of Spl for this site is increased 5-10 fold in Burkitt's lymphoma BL22 and decreased approximately 5 fold in BL2. Mutations at this site in cell lines Raji and Daudi also show a decrease in Sp1 binding when compared with the wild type sequence. PMID- 21584529 TI - Subcutaneous ril-2 in advanced melanoma and kidney carcinoma. AB - The aim of the present study was to verify the efficacy and tolerability of a treatment protocol using subcutaneous administration of rIL-2. Eighteen patients with metastatic disease were treated: 10 with renal carcinoma and 8 with malignant melanoma. The drug was administered as follows: 9 million UI/mq twice daily for two days followed by 1.8 million UI/mq twice daily for five days/week for six consecutive weeks. Of the 15 patients evaluated for clinical response, all completed treatment without rIL-2 dose modifications. No complete response was obtained. One patient with malignant melanoma and 1 with renal carcinoma (13%) had partial response (soft tissue and lymph nodes respectively) which lasted 3 and 4 months. Six patients with renal carcinoma and 3 melanoma patients had stable disease (60%) which lasted 6 months (median). Toxicity was moderate and spontaneously reversing after stopping treatment. Haemato-immunological modifications and pharmacokinetic study of this modality of rIL-2 treatment were also examined. PMID- 21584530 TI - Differences in the tumor DNA analysis of a hepatocellular-carcinoma and a synchronous fibrolamellar variant. AB - A 60 year old man had two tumours resected from his liver which were shown histologically to be a well differentiated hepatocellular carcinoma and the fibrolamellar variant. Both are considered clinically distinct and of different pathogenesis and have not been previously reported occurring synchronously. DNA analysis revealed allele loss on chromosome 12 in the hepatocellular carcinoma which was not found in the fibrolamellar variant. This finding may suggest that hepatocellular carcinoma and fibrolamellar variant may have different molecular genetic mechanisms for the development, in addition to their clinico-pathological difference. PMID- 21584531 TI - Methodological aspects of phase-I studies of novel anticancer agents (review). AB - In the last 5 years we have performed 14 phase I studies in our department. Eight of these trials involved evaluation of both the clinical and the pharmacokinetic behaviour of novel anti-cancer agents. The remainder investigated various aspects of drug delivery, targetting or resistance modification with existing anti-cancer drugs. In total these studies have involved over 200 patients. In this review article we have drawn upon our experience to suggest guidelines for future studies. PMID- 21584532 TI - Clonal evolution and tumor progression in 2 human colorectal adenoma-derived cell lines invitro - the involvement of chromosome-1 abnormalities. AB - Two human colorectal adenoma cell lines, S/RG and S/AN, have been continuously passaged in vitro to determine whether they would immortalize and if specific cytogenetic changes were involved in immortalization and tumor progression. At passage 7, S/RG was highly aneuploid, but had no abnormalities of chromosome 1 (Paraskeva et al, Cancer Res 49: 1282-1286, 1989). With continued passage under two independent sets of growth conditions an isochromosome Iq and derivatives of this isochromosome occurred as specific abnormalities. S/AN was near-diploid at passage 10, with a deletion in lp and monosomy 18. The karyotype at passage 44 showed no change. The cell lines are stable in that they have remained anchorage dependent and non-tumorigenic after several years in culture and S/AN has retained a near diploid karyotype. These cell lines are therefore highly valuable for further studies of tumor progression in human colorectal carcinogenesis. PMID- 21584533 TI - Human and rodent fibroblasts - model systems for studying senescence and immortalization (review). AB - Normal mammalian fibroblasts cultured in vitro will not divide indefinitely but undergo senescence and give rise to cells that can no longer be induced to divide. It is possible to overcome this finite life span by either cellular mutation or by the exogenous introduction of some viral or cellular oncogenes. This review describes the characteristics of senescence and the different ways in which it can be overcome. PMID- 21584534 TI - Mutations in an alternatively spliced exon of h-ras are not associated with loss of heterozygosity on chromosome 11p15.5 in ovarian tumorigenesis. AB - There is evidence that an alternatively spliced exon of the H-ras gene, called idx is associated with down-regulation of H-ras activity. We tested the hypothesis that mutations in this exon play an important role in the development of ovarian carcinomas because loss of heterozygosity at the H-ras locus is frequently observed in these tumors. The idx sequence of 26 different ovarian carcinomas was amplified by PCR and the products were analyzed for possible mutations by single-stranded conformation polymorphism and DNA sequencing. The results showed no idx mutations, even in tumors with a demonstrable loss of one H ras allele. PMID- 21584535 TI - Constitutive expression of C-myc in nih 3t3 cells which coexpress the colony stimulating factor-I receptor and the catalytic domain of the gtpase-activating protein restores colony stimulating factor-I dependent mitogenic growth. AB - To begin to understand how ras p21 might be coupled to the human colony stimulating factor-1 receptor (CSF-IR), we compared the signaling properties of a CSF-IR containing a point mutation that converts the tyrosine at position 809 to a phenylalanine residue to signal transduction in cells that co-express the wild type receptor and the catalytic domain of the GTPase activating protein (GAP(C)). We find that modulation of the immediate early gene c-myc and a delayed early response represented by the retrotransposon NVL3 were selectively impaired in both situations. Further, constitutive expression of c-myc in cells that contain GAP(C) restored CSF-1-dependent signal transduction. The data suggest a model in which information important for mitogenic cell.growth flows from the region of the receptor containing tyrosine 809, through ras p21, to c-myc in the nucleus. PMID- 21584536 TI - Fludarabine phosphate selectively inhibits growth and modifies the antigenic phenotype of human glioblastoma-multiforme cells expressing a multidrug resistance phenotype. AB - Fludarabine phosphate (FLU), the 2-fluro derivative of Ara-A, 9-beta-D-arabino furanosyl-2-fluoroadenine, has been shown to display both in vitro and in vivo antiproliferative activity toward a variety of murine tumors and human lymphoid malignancies. In the present study, we have determined the effect of FLU, alone and in combination with recombinant human fibroblast interferon (IFN-B), on in vitro growth, gene expression and the antigenic phenotype of human glioblastoma multiforme (GBM) cells displaying a multidrug sensitive and a multidrug resistant (MDR) phenotype. FLU exhibited a marked differential toxicity toward GBM-MDR cells versus the multidrug sensitive GBM parental cell line. Growth of GBM-MDR cells for seven days in 2.5 to 7.5 muM FLU resulted in a dose-dependent reduction or elimination of growth which persisted after removal of this agent. In contrast, recovery from FLU-induced growth suppression was observed in parental multidrug sensitive GBM cells. Acquisition of increased FLU sensitivity in GBM MDR cells did not appear to result from selection for a subset of sensitive cells or an artifact associated with the DNA-transfection process. This conclusion is supported by the similar pattern of FLU resistance in GBM-18 clones isolated after transfection with a cloned hygromycin resistance gene and selection for resistance to hygromycin. The antiproliferative and toxic effect of FLU was increased in GBM-MDR cells by simultaneous growth in IFN-B and the toxic effect of FLU could be blocked in a dose-dependent manner by the simultaneous addition of deoxycytidine. In contrast, the toxicity of FLU toward GBM-MDR cells was not altered when cells were grown in the presence or absence of colchicine or by the administration of verapamil, which can reverse the MDR phenotype in GBM-MDR cells. The selective toxicity of FLU toward GBM-MDR versus GBM-18 cells was not associated with a consistent differential change in all of the GBM-18 MDR clones in the steady-state mRNA levels of a number of genes, including mdr-1, c-myc, c fos, JunB, C-jun, proliferative cell nuclear antigen (PCNA), interferon stimulated gene-15 (ISG-15), fibronectin, tenascin, Class I HLA antigen, intercellular adhesion molecule I (ICAM-1), beta-actin or GAPDH. A common change observed in both parental GBM-18 cells and MDR GBM-18 clones exposed to FLU was an increase in the steady-state mRNA levels of deoxycytidine kinase (DCT). Analysis of the antigenic phenotype in GBM and GBM-MDR cells by fluorescence activated cell sorter (FACS) analysis using specific monoclonal antibodies (MoAbs) recognizing ICAM-1, Class I HLA antigen and a high molecular weight melanoma associated antigen (HMW-MAA) indicated that FLU was generally more active as an immunomodulating agent in MDR versus non-MDR GBM cells. Although the mechanism underlying the differential effect of FLU toward GBM-MDR versus GBM cells is not presently known, the present findings indicate that the growth inhibitory and immunomodulatory effects of FLU are enhanced in cells expressing an MDR phenotype resulting from overexpression of a cell membrane localized 170,000 M(r) glycoprotein (P-glycoprotein). PMID- 21584537 TI - Induction of differentiation in human rhabdomyosarcomas. AB - The effectiveness of all presently employed cancer therapies is limited by tumour cell heterogeneity. In patients with rhabdomyosarcomas (RMS), differentiation seemed to be associated with poor prognosis and vice versa. In order to confirm the validity of this observation, we have developed in vitro and in vivo models of RMS wherein the degree of tumour cell differentiation could be manipulated. On subcutaneous implantation in nude mice, 4 of 8 alveolar rhabdomyosarcomas (A RMS), produced tumours. In 3 of these 4 tumours the N- myc gene was amplified. In contrast, 2 embryonal (E-RMS) lacked N-myc amplification and also failed to grow in nude mice. Two cell lines from E-RMS formed tumours in nude mice. In vitro, a reduction in bovine serum concentration or supplementation of the medium with horse serum induced marked differentiation in an A-RMS but not in an E-RMS. In vivo, subcutaneous xenografts of undifferentiated A-RMS could be induced to differentiate by intratumoural injection of horse serum or transplantation into the peritoneal cavity of rats. This dramatic degree of differentiation was detected by histology and immunocytochemical staining using 3 different markers, viz, desmin, vimentin and myoglobin. Somewhat remarkably, when these differentiated A-RMS growing in the peritoneal cavities of rats, were reinplanted into peritoneal cavities of other rats they failed to grow. On the other hand, if they were reimplanted subcutaneously in other rats they grew well and reverted to an undifferentiated morphology. In contrast, the E-RMS could not be induced to undergo differentiation by horse serum and also failed to grow in the peritoneal cavity of rats. PMID- 21584538 TI - Mutations in the p53 gene at codon 249 are rare in squamous-cell carcinoma of the head and neck. AB - Mutations in the p53 tumour suppressor gene are common in a wide range of human malignancies. In particular G-T transversions in the p53 gene occur at a high frequency in lung cancer tumours and as the same mutagens maybe responsible for p53 mutations in head and neck squamous cell carcinomas, a preliminary investigation was carried out to establish if this may be the case. Codon 249 of the p53 gene has been found to be a hot spot of G-T transversions in hepatocellular carcinomas, thus it was decided to initially investigate this site using specific primers and restricting the PCR product with the HaeIII restriction endonuclease. Fifty seven squamous cell carcinomas of the head and neck were investigated using this technique and no mutations were found at codon 249 in the p53 gene. In this study twenty six of the specimens were also examined immunohistochemically using a number of antibodies to p53 (PAb 421, PAb 1801 and CM-1), and 19 were found to have positive staining. Moreover as positive p53 staining is considered to be synonymous with p53 mutations, over two thirds of our earlier immunohistochemical study indicated p53 mutations in head and neck tumours. The technique used in this paper has the advantage of scanning a large number of tumours for mutations at suspect sites and maybe of use in the future if specific mutational hot spots are found in the p53 gene in head and neck cancers. In the meantime p53 mutations in these tumours are been investigated by conventional sequencing techniques. PMID- 21584539 TI - Kinase group protooncogenes in non-hodgkins-lymphomas and nonmalignant lymphoid tissues - analysis of their expression by insitu hybridization assays. AB - Expression of src related proto-oncogenes in non-Hodgkin's lymphomas and non malignant lymph nodes was analyzed by means of in situ hybridization assays with biotinylated DNA probes. In 36 cases of non-Hodgkin's lymphomas, both c-mos and c abl were expressed in 27 cases, and c-erbB and c-src were expressed in 15 cases and 7 cases, respectively. No case expressed c-fps or c-yes. On the contrary, in 11 cases of non-malignant lymph nodes c-erbB and c-mos was expressed in only 3 cases. No other proto-oncogenes were expressed. Lymphomas in general express multiple proto-oncogenes simultaneously. A variety of combinations of expressed proto-oncogenes were observed suggesting diversity among non-Hodgkin's lymphomas in biological characteristics. However, a clear association with the expression of a single proto-oncogene or the number of expressed proto-oncogenes with T cell / B cell types, or the histopathological classification of NHL, or disease prognosis was not observed. PMID- 21584540 TI - Proliferative activity in advanced gastric-cancer with ki-67 and propidium iodide - analysis by flow-cytometry. AB - By setting the cut-off line at the level as used in a negative control study without primary antibody in the same sample, the Ki-67 labeling rate was calculated by the Ki67-DNA dual fluorescence analysis. The mean Ki-67 labeling rate of 28 advanced gastric cancer was 45.1% (13.9-76.3%). The Ki-67 labeling rates were significantly higher for larger size tumor (p<0.05), peritoneal metastasis and advanced stage (p<0.01). This is the first report that cycling cells are calculated by setting the cut-off line for solid tumors. Use of this flow cytometric procedure substantially facilitates the quantification of proliferating cells in gastric cancer. PMID- 21584541 TI - Barretts carcinoma in a 25-year-old man with point mutation of the p53 tumor suppressor gene. AB - Barrett's esophagus is a recognized risk factor for adenocarcinoma of the esophagus. Dysplasia in Barrett's epithelium is considered a precursor to malignancy. Several tumor suppressor genes, including p53, have recently been implicated in the pathogenesis of esophageal adenocarcinoma. However, the interval between the development of Barrett's esophagus, dysplasia, and frank malignancy is usually very long. A case of adenocarcinoma of the esophagus arising from Barrett's esophagus in a 25-year-old man is discussed. Point mutation in exon 8 of p53 was discovered in this patient's tumor and surrounding dysplastic Barrett's mucosa. To our knowledge, this is the youngest reported case of Barrett's-associated esophageal adenocarcinoma in the medical literature. It suggests that acquired somatic mutations in tumor suppressor genes may occur early in life and that these mutations may contribute to the development of dysplasia and cancer in Barrett's esophagus. PMID- 21584542 TI - N1-substituted tetra-benzamidines - inhibition of DNA-protein interactions and invitro tumor-cell growth. AB - The pharmacological-mediated inhibition of the interaction between regulatory proteins and target DNA sequences could represent a potential experimental strategy to control growth of neoplastic cells, viral DNA replication and biological life cycle of infectious microorganisms. Aromatic polyamidines are powerful inhibitors of DNA-protein interactions, in vitro proliferation of tumor cell lines and in vivo growth of tumorigenic cells xenografted into nude mice. In order to obtain more detailed information on structure-activity relationships, we have analysed the effects of different aromatic polyamidines on the binding of a recombinant protein, the Epstein-Barr Virus (EBV) Nuclear Antigen 1 (EBNA-1) to the DNA target sequence of EBV, containing the 12 bp palindromic consensus TAGCATATGCTA sequence. The results obtained suggest that aromatic polyamidines differentially inhibit the interactions between DNA-binding proteins and target DNA sequences, leading to differential effects on tumor cell growth. PMID- 21584543 TI - Induction of endogenous tnf production by biological response modifiers and bacterial preparations. AB - This review summarizes experiments on the endogenous induction of tumor necrosis factor (TNF) in mice by various biological response modifiers and bacterial preparations, such as heat-killed Streptococcus pyogenes (OK-432) or Lactobacillus casei (LC). Intravenous administration of OK-432 or LC transiently elicited endogenous TNF in mice. The endogenous TNF production was significantly enhanced by priming (pretreatment) with high molecular-weight lignins or polysaccharides, but not by phenylpropenoid precursors or partially hydrolyzed products of glucans. When stimulated with lignins and OK-432, tumor-bearing and aged mice produced much lower amounts of TNF than normal and young mice. Endogenously produced TNF was concentrated more in serum, liver and lungs, than in other organs. On the other hand, a much lower concentration of IL-1alpha was induced in the serum fraction, whereas significant amounts of this cytokine were detected in liver and lungs. Histochemical examination revealed significant increase in the number and swelling of Kupffer cells and sinusoidal endothelium in the liver of the treated mice. The results suggest the possible efficacy of applying endogenous TNF production for the treatment of human cancer patients. PMID- 21584544 TI - Detrimental effect of neoadjuvant chemotherapy in patients with stage-iiib carcinoma of the cervix - results of a randomized trial. AB - With the objective of testing the value of neoadjuvant chemotherapy in patients with stage III B carcinoma of the cervix, we began in 1984 a randomized, phase III trial comparing BOMP chemotherapy followed by pelvic radiotherapy versus pelvic radiotherapy alone. Patients were stratified by age, extension of parametrial involvement, and lymphangiographic findings. Despite a higher complete response rate, the overall 5-year survival was significantly inferior in the combined therapy group (39% vs 23%, P=0.02). Toxicity was more pronounced in the chemoradiation arm and 4 patients developed fatal pulmonary complications. Patterns of failure were similar in both groups. The use of primary chemotherapy in advanced carcinoma of the cervix was detrimental to the patients and its use outside a protocol setting is discouraged. PMID- 21584545 TI - Characterization of the a431 tumor xenograft as an invivo model for testing epidermal growth factor-receptor antagonists. AB - The A431 tumor Xenograft was characterized as a model to test EGF-receptor antagonists. Removal of the EGF rich submandibular gland from athymic mice, or stimulation of EGF production in the submandibular gland by testosterone administration both failed to influence tumor growth. Infusion of EGF from alzet minipumps raised circulating EGF levels, however, A431 tumor growth was not significantly changed. Treatment on the other hand (IP every 4 days) with a monoclonal to the human EGF receptor (225 antibody) produced a dose (1-0.25 mg/inj) related inhibition of Subcutaneous (s.c.) implanted A431 tumor growth. Long term inhibition (> 114 days) of tumor growth was related to the number of doses of antibody administrated with 9/10 tumors not re-growing after 9 doses of 1 mg/mouse/inj given 4 days apart. A dose related inhibition of A431 tumor growth when implanted under the subrenal capsule (src) was also established for the EGF receptor antibody and tumor regression was frequently observed with doses greater than-or-equal-to 0.5mg/mouse/inj. These studies indicate that A431 tumor growth is insensitive to modulation of host EGF but can be inhibited by agents that block the EGF-receptor. The s.c. and src implanted A431 tumor models that have been established will now be used to evaluate the antitumor potential of EGF inhibitors identified from our screening programs. PMID- 21584546 TI - Quercetin and hyperthermia produce a synergistic inhibitory effect on primary human ovarian-cancer cells. AB - Quercetin (from 0.1 muM to 10 muM) produced a dose dependent inhibition of colony formation of cells from 4 primary ovarian tumors expressing type II estrogen binding sites (type II EBS).The combined effects of quercetin ( 10 muM) and hyperthermia (42-degrees-C) result in a significant synergistic action on three out of four tumors analyzed. Moreover, two other flavonoids tested, rutin and hesperidin, which do not bind to type II EBS, are ineffective in synergizing with hyperthermia. In conclusion our results suggest that hyperthermia could synergize the growth inhibitory activity of quercetin which is probably mediated by the flavonoid interaction with type II EBS. PMID- 21584547 TI - Monoclonal-antibodies to huifn-alpha species applied to the study of IFN-receptor interaction indicate that receptor down-regulation does not occur in daudi cells. AB - Monoclonal antibodies to HuIFN- alpha species were previously isolated and the reactive epitopes on HuIFN- alpha2 identified. When used in excess concentration the antibodies neutralise the antiviral activity of HuIFN- alpha and inhibit binding of IFN to its receptor on human and bovine cells. However, when used in equimolar concentrations the antibodies bind to IFN bound to its receptor on human but not on bovine cells. Radiolabelled antibodies and radiolabelled ligand have been used to study in detail IFN-receptor interactions in human cells. The use of the monoclonal antibodies has identified differences in the interaction in different cell lines not obvious from ligand binding studies alone. IFN receptors do not appear to be down-regulated in Daudi cells but remain on the cell surface complexed with bound IFN whereas down-regulation does occur in the human epithelial breast carcinoma cell line BT20. Although surface receptors are not decreased in Daudi cells exposed to IFN, the time course of association of radiolabelled IFN with these cells shows that cell associated radioactivity decreases after incubation for more than 1 hr at 37-degrees-C. This result cannot be explained by degradation of exogeneous IFN (which does not occur) and suggests that endogenous IFN may be involved in the interaction of HuIFN- alpha with Daudi cells. PMID- 21584548 TI - How the laboratory can help the clinician improve cure rates in invasive cervical cancer. AB - Cancer of the cervix is the most important female malignancy in the developing world and is mainly treated by radiotherapy. Treatment results may improve following the application of evolving laboratory techniques. Measurement of tumour radiosensitivity already seems possible using the Courtney-Mills assay. Unfortunately this requires about 5 weeks to produce clinically useful data. More rapid techniques such as the CAM assay and tests for DNA double strand breaks as predictors of radiosensitivity are being evaluated. Radiation dosage is limited by the probability of late normal tissue damage. The identification of individuals who may suffer excessive damage such as ataxia-telangiectasia hetorozygotes may enable higher doses to be given to the 'normal' majority. Cell kinetic studies have shown that repopulation is an important source of radioresistance and some tumours may respond better to accelerated hyperfractionated radiation schedules. Repair, proliferation capacity and radioresistance are all factors under genetic control. The search for the genes responsible remains a high priority. PMID- 21584549 TI - Surgical-management of carcinoma of the middle and distal bile-duct. AB - Forty patients underwent surgical resection for cancer of the middle and distal bile duct. Nineteen patients underwent a curative resection with 3- and 5-year survival rates of 63% and 48%, respectively. None of the patients who underwent a palliative resection survived two years. The factor most strongly associated with recurrence was the presence of tumor in the surgical margin. Recurrence was frequent in patients with disease in the middle portion of the bile duct who underwent extrahepatic biliary resection with choledochojejunostomy, while lower bile duct cancer was associated with peri-aortic or retroperitoneal recurrence. Pancreatoduodenectomy, with combined resection of the portal vein in middle bile duct cancer, regional lymphadenectomy, including peri-aortic lymph nodes and nerve plexus is required for curative resection of middle and distal biliary carcinoma beyond the early noninvasive stage. PMID- 21584550 TI - The flow cytometric nuclear-DNA content, tumor-origin, nuclear size and prognosis in squamous-cell lung-cancer. AB - We examined the relationships among nuclear DNA content, tumor origin, nuclear size, and prognosis in squamous cell lung cancer. Central tumors had significantly higher DNA aneuploidy (83%, p<0.01) and DNA indices (1.65+/-0.40, p<0.01) than did peripheral tumors (40%, 1.29+/-0.37, respectively). All six women in the study (five no smokers) had peripheral diploid tumors. Patients (15) with diploid tumors had significantly longer survival times (a 5-year survival rate of 63%) than did those (28) with aneuploid tumors (29%, p<0.01). Patients with tumors having both large nuclei (nuclei greater than 11 mum in mean diameter) and a DNA index of 1.0 had the longest survival times (a 5-year survival rate of 100%). This was followed by patients with large-nucleus tumors and a DNA index of more than 1.51 (71%). However, all patients with small-nucleus tumors (tumors with nuclei less than 10 mum in mean diameter) and a DNA index of more than 1.51 died within 30 months. These results suggested that the malignancy level of squamous cell lung cancer and the prognosis could be determined by studying the DNA content and the size of the tumor nuclei, and that there may be differences in the pathogenesis and/or malignancy of central and peripheral tumors. PMID- 21584551 TI - Immunohistochemical demonstration of epidermal growth-factor receptors in normal, benign and malignant thyroid tissues. AB - Human epidermal growth factor receptor (EGF-receptor) has been detected immunohistochemically in normal, benign and malignant human thyroid tissues. With a monoclonal antibody for EGF-receptor and avidin-biotin-peroxidase complex (ABC), the expression of EGF-receptor was evaluated in paraffin-embedded sections. Carcinomas of the thyroid showed a moderate to intense staining for EGF receptor in most cases. Apical cell surface and cytoplasmic staining was the most common pattern of immunoreactivity. Adenomas showed a variable positivity in the cytoplasm of th tumor cells, and their apical cell surface staining was generally negative to borderline. The follicular cells in Hashimoto's thyroiditis showed a weak to moderate cytoplasmic staining, but those in Graves' disease and normal thyroids showed an essentially negative cytoplasmic staining. Apical cell surface staining was essentially negative or borderline in these benign lesions. There were no significant correlations between EGF-receptor expression and tumor size, degree of invasion or cervical metastases in the thyroid carcinomas. The apical surface expression of EGF-receptor was characteristic to thyroid carcinomas and this feature may be useful in the differentiation of thyroid carcinomas from benign thyroid lesions. PMID- 21584552 TI - The effects of short-term treatment with levamisole on cytokines in volunteers and cancer-patients. AB - In search for clues to the potential immunomodulating mechanism of action of levamisole which might be used as monitoring parameters, we have determined a variety of cytokines in the peripheral blood of volunteers and carcinoma patients before and after a single or a 3-day-treatment with 150 mg/day. In cancer patients no changes could be detected 4 days after a 3-day-treatment course in the levels of TNF-alpha, IL-1beta, IL-2 or IL-6. In a placebo-controlled volunteer study the same treatment did not affect the levels of beta2 microglobulin, IL-1beta, IL-1alpha, IL-2 or IL-6. However, 24hr after the last treatment the concentration of neopterin was slightly but significantly increased and the concentration of soluble IL-2 receptors decreased. A single treatment failed to produce such an effect. It is suggested that the measurement of neopterin and soluble IL-2 receptors may provide useful information in future trials. PMID- 21584553 TI - Subcutaneous recombinant-human-erythropoietin prevents chemotherapy-related anemia in patients with advanced cancer. AB - Nineteen patients with advanced cancer were randomly allocated to receive: (i) rhEpo 150 UI/kg subcutanously three times/week starting 24 hours after the completion of cisplatin- or carboplatin-based chemotherapy; or (ii) normal saline. There were 17 patients with advanced head and neck carcinoma and 2 patients with small cell lung cancer. Patients were monitored for hemoglobin level, hematocrit, WBC, PLT and reticulocytes. Patients who received rhEpo overall showed a 7.2 +/- 6.3% mean increase in Hb level over their pretreatment values, while control patients had a 26.4 +/- 12% decrease. This difference was statistically significant (p<0.001). No patients in the rhEpo group required transfusion, while 4 patients in the control group received packed red cell transfusion. No significant side-effects attributable to rhEpo were recorded, but 1 patient showed a transitory increase in PLT count. In conclusion, subcutaneous rhEpo may be safely administered to patients with advanced cancer and effectively prevents cisplatin- or carboplatin-related anemia. PMID- 21584554 TI - Over-expression of cellular oncogenes in cystadenocarcinomas of the ovary. AB - A complex analysis of oncogene over-expression in ovarian cystadenocarcinomas of 20 patients was performed. Radioactively labelled cDNAs were synthesized from total cellular RNA from tumor cells and hybridized to dot blot filters. On each filter more than 20 different plasmids containing cloned oncogene fragments were immobilized. In concordance with published data fms was found over-expressed in 40% of the tumors. Elevated expression levels of the EGF receptor was also frequently detected. 35% of the tumors showed elevated N-ras mRNA levels. All those tumors' showed a highly dedifferentiated phenotype and were classified as G3-tumors. More over, simultaneous over-expression of different oncogenes correlated surprisingly strongly with tumor grading. PMID- 21584555 TI - Growth-factor content of benign and malignant ovaries - a comparison. AB - Epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) were estimated in extracts of 193 malignant ovarian samples, 42 benign ovarian samples and 71 normal ovaries. TGFalpha was present in 87% of malignant ovaries, 85.7% of benign ovarian tumours and 85.9% of normal ovaries. EGF was present in 30% of malignant ovaries, 35.7% of benign ovarian tumours and 12.7% of normal ovaries. TGFalpha was significantly elevated in both the malignant ovarian and benign ovarian extracts compared to normal ovaries. The median values for EGF was significantly elevated in the benign ovarian group compared to extracts from both malignant and normal ovaries. PMID- 21584556 TI - Chromatin and nuclear matrix in development and in carcinogenesis - a theory. AB - Sufficient evidence indicates that the nuclear matrix which organizes chromatin into loops or domains harbors origins of replication, homeodomain protein binding sites, and transcriptional enhancer sequences. Thus nuclear matrix might sculpture the crossroads of the differential gene expression and differential activation of origins of replication occurring during development. Nuclear matrix is also the site of transcription, replication, repair and recombination. These properties of the nuclear matrix are explored in the context of their implications in carcinogenesis. Many tumors result from abnormal translocations of DNA segments at other genomic sites via a recombination process involving some unusual DNA sequences at the breakpoints, such as Alu repetitive sequences or Z DNA. Translocations are predicted to occur more frequently on the nuclear matrix and to involve DNA sequences at the bases of chromatin loops. Other tumors may result from the overexpression of distinct genes whose transcription regulation occurs at their nuclear matrix attachment sites. Tumorigenesis connected with mutations at coding DNA sequences is also related to the nuclear matrix, since nuclear matrix governs repair activities in the nucleus and might also harbor the most vulnerable DNA sites to damage and the most refractory to repair. These novel, and the previously known, features of the nuclear matrix reveal a new approach in understanding carcinogenesis. PMID- 21584557 TI - Cyclic amp-responsive gene-transcription in cellular proliferation and transformation. AB - The proteins binding the cAMP responsive elements constitute a family of transcription factors (e.g. CREB 327/341, ATF, HB16, CREM) which operate as dimers and regulate positively and negatively gene expression upon interaction with the cAMP responsive motifs CRE/ATF. These proteins regulate transcription after cAMP- dependent phosphorylation (CREB), or interaction with the adenovirus E1A oncoprotein (ATF-2). Subtle modulation might be further attained by the cross talk between the different signal-transduction pathways and the heterodimerization of different classes of transcription factors. The CREB/ATF transcription factors therefore exert a pleiotropic action during the integration of extra/intra cellular signals in the resulting adaptation of cellular responses. Dysregulation might be associated with pathological situations related to the uncontrolled cell proliferation, oncogenic progression and metastasis. PMID- 21584558 TI - Mitotic indexes as indicators of malignancy in human tumors. AB - This review summarises recent prognostic results by mitotic indices in human tumours. The prognostic value of the mitotic indices is evaluated in breast carcinoma, in transitional cell bladder carcinoma, in ovarian carcinoma, in pancreatic carcinoma and in prostatic adenocarcinoma. The results show that mitotic indices can efficiently categorise particularly breast carcinomas, transitional cell bladder carcinomas and ovarian carcinomas into groups of distinctly different prognoses. The mitotic frequency 10 mitotic figures per mm2 of neoplastic tissue seems critical. The survival of patients with slowly proliferating tumours is significantly better than the survival of patients with a mitotic frequency over 10 mitotic fiqures per mm2 of neoplastic tissue. Methodological analyses also indicate that mitotic indices are reproducible and accordingly suitable for grading of tumours in clinical context. However, there are several variation factors related to mitosis counts like variation related to a delay in fixation, intratumoural variations, and variations related to observational reasons. Adequate standardization of fixation and measurement process probably improve the prognostic estimates based on mitosis counts. PMID- 21584559 TI - Sweat gland tumors of skin - immunohistochemistry with common antibodies in the paraffin section. AB - Adnexal tumors of skin are a group of relatively uncommon tumors. Their differential diagnosis is complicated by the fact, that in one lesion different lines of differentiation may be present, i.e. eccrine, apocrine or pilosebaceous. Immunohistochemistry can provide additonal informations on the cellular phenotype. In the present paper fifty-three sweat gland tumors have been investigated by immunohistochemistry in the paraffin section. The usefulness of commonly used 'marker antibodies' (S-100, CEA, Cam 5.2, Vim9(1)) has been challenged by the use of routine material and a comparison to other adnexal, vascular and epidermal tumors of skin (n = 22). Tumors with lumen formations, which express at least Cam 5.2 and CEA are highly suggestive for a differentiation related to the secretory coils of eccrine or to apocrine glands. Lumen forming tumors with the phenotype CEA-positive/ Cam 5.2-negative more closely resemble the eccrine duct. A myoepithelial phenotype is more suggestive, when cells are expressing vimentin and S-100. The histopathology, however, is an essential for the interpretation of immunohistochemical findings. PMID- 21584560 TI - Ras and p53 expression in non-small-cell lung-cancer patients - p53 over expression correlates with a poor prognosis. AB - Expression of the tumor suppressor gene p53 and the ras oncogene were examined in 46 tumor and nodal specimens of non-small cell lung cancer (NSCLC) using the antibodies p53 pAb 240 and ras Y13-259 respectively. p53 expression was elevated in 46% and ras p21 was over-expressed in 85% of the tumor specimens analyzed. Fifteen cases of benign lessions were also assessed for both ras p21 and p53 expression; all were found to have negative staining. p53 over-expression was found to correlate with a poor prognosis in both the tumor specimens (p<0.05) and in the nodal tissues (p<0.005). Ras p21 over-expression was found to be associated with survival (p<0.1) in both the tumor and the nodal specimens. Stage of the disease correlated with survival; similarly both p53 and ras p21 over expression correlated with stage. No correlations were found with the pathological grade of the tumors nor with a history of smoking or duration of smoking. No K-ras mutations at codon 12 were observed in a further 15 NSCLC specimens analyzed. These results indicate that the p53 gene in particular plays a role in the stages of NSCLC. PMID- 21584561 TI - Transformed murine leydig-cells in serum-free culture - useful model for analyses of steroid hormone-induced cell-growth and cell morphology (review). AB - A clonal cell line has been established from estrogen-induced testicular Leydig cell tumor of BALB/c mouse. This cell line termed as B-1F can be maintained in a serum-free culture condition without any authentic growth factor. The growth of B 1F cells is significantly enhanced by estrogen, androgen or retinoic acid. Biochemical and Northern blot analyses reveal that B-1F cells contain respective receptors for these stimulants, although estrogen receptor has an interesting mutation. The simultaneous addition of these stimulants in combination fails to elevate the maximum levels of B-1F cell growth, suggesting that these stimulants would share some common pathway to stimulate B-1F cell growth. One possible step affected by these stimulants is mapped to 5-lipoxygenase since inhibitors of this enzyme can stimulate B-1F cell growth and estrogen stimuli can lower its activity. B-1F cells grow in a serum-free medium as a cell clump irrespective of the presence of growth stimulants. Interestingly, the addition of low concentrations of elastase or trypsin in the medium changes the cell morphology from a round to well spreaded shape. Furthermore, treatment of conditioned medium from B-1F cell culture with trypsin or elastase results in an appearance of cell spreading activity. In addition, a relatively high concentration of elastase abolishes estrogen-induced enhancemant of B-1F cell growth. In conclusion, a serum-free culture of B-1F cells can provide us with a model system quite useful for studying the effects of physiologically active molecules on cancer cells. PMID- 21584562 TI - Human nm23-h1-protein and h2-protein have similar nucleoside diphosphate kinase activities. AB - The nucleoside diphosphate kinase activity of nm23-H1 and nm23-H2 proteins was examined. Full length nm23-H1 and nm23-H2 proteins were produced in E.coli in fusion form with a 26 kDa glutathione S-transferase (GST). Affinity purified nm23 H1 and nm23-H2 formed phosphoenzyme intermediates when incubated with [gamma-P 32]ATP. The formation of GTP from GDP was also demonstrated by these two proteins by thin layer chromatography. The 26 kDa GST alone did not show similar activity. Both nm23-H1 and nm23-H2 shared very similar biochemical characteristics, namely, time kinetics, pH, temperature and cation dependency for the formation of the phosphoenzyme intermediates. PMID- 21584563 TI - Genetic abnormalities and expression of p53 in human colon carcinomas. AB - Genetic alteration and expression of p53 was examined on matched pairs of tumor and nonneoplastic tissues of colon carcinomas and compared with clinicopathological findings. Loss of heterozygosity (LOH) of p53 locus was found in 83% (44/53) of carcinomas and the incidence of LOH increased as tumor stage progressed. Among LOH cases, 63% (5/8) showed p53 mutations, most of which occured at CpG site. Although the level of p53 mRNA in tumor tissues was lower than its nonneoplastic counterpart in 55% (6/11) of the cases, no obvious relation was detected between mRNA expression and gene alteration. Accumulation of p53 protein determined by immunohistochemistry was found in 47% (25/53) of cases regardless of allelic status nor mRNA level. p53 immunoreactivity showed a tendency to increase with tumor stage. These results indicate the diversity of p53 alterations in the development and progression of colon carcinoma. PMID- 21584564 TI - The safety and efficacy of gi endoscopy in patients with acute-leukemia - a review of 27 cases. AB - In the course of aggressive treatment for acute leukemia, the ensuing pancytopenia and intensive medical support may be accompanied by severe gastrointestinal (GI) complications. Therefore, to assess the safety and efficacy of GI endoscopy as a means of diagnosis, we analyzed the records of 16 patients undergoing 27 endoscopies a mean (+/-S.D.) of 18.4 +/- 11.9 days post chemotherapy. There were 6 procedures performed in patients with acute lymphocytic, 18 with acute myelogenous, including 3 with acute promyelocytic and 3 with blastic phase chronic myelogenous leukemia. 10/27 procedures were performed in patients with less than 1000 WBC/mm3 and 19/27 had less than 100,000 platelets. 15 patients had 25 upper endoscopies done for: bleeding (twenty-one), abdominal pain (two), and persistent vomiting (two). The principal bleeding sources were: esophagitis (eleven), Mallory Weiss tear (one), gastritis (three), gastric ulcer (one), duodenal ulcer (five). In the non-bleeding cases 2 exams were normal and the others had gastritis (one) and esophagitis (one). 15/25 procedures (64%) resulted in new diagnosis and 20/25 (80%) in additional therapies. 47% of patients undergoing upper GI endoscopy received specific new therapies as a result of that procedure. Nd: YAG laser photocoagulation was effective in stopping bleeding lesions in 4/6 cases. 10/12 bleeding patients had persistent or recurrent bleeding and 2 died from bleeding. None had surgery. Two patients underwent colonoscopy, both for colonic distention. One patient, who had been recently treated for Cl. difficile had submucosal petechiae. The other had non-specific colitis. No biopsies were done and both cases were successfully decompressed..No complications occurred from any GI endoscopy. We conclude that GI endoscopy can be safely performed in patients with acute leukemia, resulting in specific diagnoses and therapies. Esophagitis is a principal cause of GI bleeding in these patients. The role of therapeutic endoscopy in controlling bleeding is promising but requires further evaluation. PMID- 21584565 TI - Ondansetron versus metoclopramide in the prevention of chemotherapy-induced nausea and vomiting - a metaanalysis. AB - Nausea and vomiting remain important clinical problems occuring in 25 to 50% of patients receiving chemotherapy for cancer. Clinical trials comparing a new antiemetic drug, ondansetron, to metoclopramide have suggested improved control of nausea and vomiting but studies disagree on the magnitude of the treatment effect and its statistical significance. We combined evidence from randomized controlled trials in a meta-analysis of the efficacy and safety of ondansetron compared to metoclopramide in the prevention of acute (less-than-or-equal-to 24 hours) nausea and emesis associated with chemotherapy. Literature search identified six randomised controlled trials of ondansetron versus metoclopramide in an adult population. Study outcomes were the observed incidence of emesis (vomiting or retching) and patient-reponed grades of nausea after chemotherapy. For meta-analysis of each outcome we defined therapeutic success as complete protection (ie. zero episodes during 24 hours following chemotherapy). The relative odds of success (ondansetron/metoclopramide) was calculated for each trial and all trials combined. Results were expressed as a relative risk (RR) for zero emesis or nausea at 24 hours. The six trials reported on 705 patients (median age range 53-59 years; 57% female). Relative odds for complete control of emesis was greater than one in all trials but was nonsignificant (p>0.05) in two trials, including the largest trial. When trials were combined, summary odds ratios for control of emesis and nausea were greater than one (p<0.05). RR of zero emesis with ondansetron was 1.72 (95% CI 1.45 to 1.97) and was similar for nausea (RR= 1.78, 95% CI 1.39 to 2.13). In trials using high-dose cisplatin chemotherapy, higher rates of extrapyramidal affects and diarrhea were associated with metoclopramide (p<0.05) while headache was frequently associated with ondansetron (p<0.05). Combined clinical trial evidence supports the conclusion. that, relative to metoclopramide, ondansetron places patients at a much lower risk of nausea and emesis following chemotherapy with moderately or highly emetogenic regimens. PMID- 21584566 TI - Timing of induction of tgf-alpha in ras induced human bladder neoplastic progression. AB - Introduction of a H-ras oncogene into an SV-40 immortalized human urothelial cell lines (SV-HUC) results in morphologically altered cell clones which acquire tumorigenic potential following serial passaging in culture. Early and late passage cells, from individual ras transfected clones exhibiting different tumorigenic potential, display increased growth factor synthesis in mitogenic assays. Northern blot analysis revealed induction of TGF-alpha mRNA concomitant with the introduction of a H-ras oncogene with no modulation in EGF receptor expression observed throughout neoplastic progression. Consistent with completion of an autocrine loop, down modulation and activation of EGF receptors was observed in early passage cells coincident with TGF-alpha expression. In this human urothelial progression model TGF-alpha secretion follows the introduction of a H-ras oncogene prior to the acquisition of tumorigenic potential. PMID- 21584567 TI - Immunoglobulin gene sequence-analysis of B-1 (cd5+b) cell clones in a murine model of chronic lymphocytic-leukemia and richters syndrome. AB - The NZB mouse has recently been proposed as an animal model for the human malignancy chronic lymphocytic leukemia (CLL) because of the age-dependent onset of clonally expanded hyperdiploid B-1 cells these mice develop by one year of age. We have examined the immunoglobulin sequence of several NZB B-1 malignant clones and found these clones to have several common characteristics. The B-1 malignant clones all use unmuated VH genes and DFL16.1, a D region gene which pre dominates during fetal B cell development. In addition, no N base insertions were observed in the clones. A continually passaged line of murine CLL-like cells was examined in more detail. This line used a germline S107 VH gene that showed no evidence of accumulated somatic mutation over the course of five years of in vivo passage. The D gene (DFL16.1) was also unmutated with no evidence of non-germline diversity at the junction sites. The non-mutated state was maintained despite a continued transformation of the CLL-like cells into a more aggressive large cell lymphoma known as Richter's syndrome. Several years after the development of Richter's syndrome, the usage of a completely new VH gene family was detected. This second B-1 clone employing a new VH gene was expressed with similar characteristics as the initial B-1 clone, both employing DFL16.1 with no N base insertions at the junction sites. This demonstrates that B-1 cells which are destined to clonally expand have unique characteristics in the expression of surface immunoglobulin. Therefore, B-1 (CD5+ B) cells which undergo transformation in CLL are not randomly derived from the normal B-1 cell population but instead come from a subpopulation of B-1 cells which display these specific features of immunoglobulin expression. PMID- 21584568 TI - Histoculture and the immunodeficient mouse come to the cancer clinic - rational approaches to individualizing cancer-therapy and new drug-evaluation (review). AB - Originating from the experiments of Alexis Carrel, tissues in culture were originally grown in three dimensions and maintained important in vivo-like structural and functional properties. However, in modem times, monolayer cell culture methods have become predominant despite losses of structural and functional properties of the cells. Strangeways, Fell, Leighton, Sutherland and others have designed various methods of three-dimensional culture using cellulose supports, mesh supports, collagen gel or sponge supports and floatation that allow tissues to maintain many in vivo-like properties such as native architecture, differentiated functions, gene regulation, invasive properties and drug sensitivities which are very different than cells in monolayer cultures. Collagen-sponge-gel-supported histoculture has been shown to support the growth and native three-dimensional architecture of both tumor and normal tissue, often for long periods of time. This method of histoculture was utilized to develop a chemosensitivity assay for individual cancer patients by assessing the effects of drug on the patients' histocultured tumor. Various end points to measure drug response have been utilized in histoculture, including [H-3]thymidine incorporation measured by histological autoradiography and the use of vital dyes to indicate cell viability. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) end point was applied to the histoculture assay in an attempt to increase in vitro-in vivo correlation. The chemosensitivities of 16 human tumor lines were determined in vitro by the histoculture assay, and retrospectively correlated to their in vivo chemosensitivity as xenografts in nude mice. The overall correlation rate of the efficacy results of the drug response assay to in vivo chemosensitivities was 89.8%, with 90.0% true-positive and 89.7% true-negative rates, 81.7% sensitivity and 94.6% specificity, thereby indicating potential clinical use for tumor histoculture with the MTT end point. The data reviewed and analyzed here thus indicate that three-dimensional culture systems offer much more realistic model systems for evaluating potential new cancer agents and individualized treatment such as predictive drug-response testing. The 'MetaMouse' model developed in our laboratory allows direct 'onplantation' of intact patient surgical cancer specimens orthotopically to athymic 'nude' mice with high-level expression of local growth on the target organ and high metastatic potential. Eight MetaMouse human cancer models are reviewed including those for the colon, bladder, lung, stomach, prostate, ovary, pancreas and head and neck. The human tumors growing and metastasizing in the mice reflect the clinical situation and should be useful for new drug evaluation and development of strategies for individual treatment. The combined technologies of histoculture and MetaMouse thus offer an integrated in vitro-in vivo system for preclinical evaluation of experimental and standard cancer therapy. PMID- 21584569 TI - Presence of the mouse mammary-tumor virus (mmtv) pol gene in breast-cancer. AB - We have used the polymerase chain reaction (PCR) to detect sequences related to the mouse mammary tumor virus (MMTV) reverse transcriptase gene in DNA from breast cancer cell lines and an extensive series of breast tumors. Similar MMTV related sequences were observed in DNA from normal tissues. The segments amplified by PCR showed over 90% homology to the nucleotide sequence of the MMTV pol gene and no significant differences were noted between the DNA from normal or tumor tissue. When the amplified DNA was used to probe Southern blots, a unique restriction fragment indicative of a single copy locus was detected in all DNAs tested, but the high background of hybridization suggested that many closely related sequences may occur in the human genome. PMID- 21584570 TI - The role of endogenous proteins in the protein-free maintenance of 3 distinct tumor-cell lines invitro. AB - We established new two protein-free culture subclones from murine well characterized Ehrlich ascites carcinoma and P815 mastocytoma using intermittent protein-free culture performed previously for a protein-free subclone of fibrosarcoma (Gc-4 PF). The Ehrlich protein-free subclone (Ehrlich PF) grew much more slowly than the original cell line and showed a proliferative response to FCS. On the other hand, like Gc-4 PF, the P815 protein-free subclone (P815 PF) showed a similar growth rate to that of the original counterpart. Interestingly the original P815 mastocytoma cells also grew exponentially in protein-free medium. Although the protein-free culture exhibited cells that were more spheroid and spread less in each of these three cell lines, the major structure protein bands demonstrated on SDS-PAGE were virtually identical between the original and protein-free culture cells. In contrast to the structural peptides, the distribution of the secretory peptide differed among the three protein-free culture cell lines, which may reflect their state of differentiation. Growth inhibiting activities were detected from the supernatant of all three protein free culture cells, while no protein-free culture cells secreted predominantly growth-stimulating activity into their cultured media. These results suggest that autonomy in tumor cell proliferation may result from the acquisition of the ability to escape from negative control in multicellular organisms, as shown in monads, rather than an acquisition of further response to growth-stimulating control. PMID- 21584571 TI - Requirement for isoprenoid-dependent posttranslational modifications in the cell cycle progression of human breast-cancer cells. AB - Treatment with HMG CoA reductase inhibitors, i.e. 25-hydroxycholesterol and mevinolin, inhibited cell growth of the human breast cancer cell line MDA231 in a cell cycle-specific manner by blocking progression through G1. Since 25 hydroxycholesterol, as distinguished from mevinolin, also inhibits steps in mevalonate metabolism, exogenous mevalonate failed to overcome the 25 hydroxycholesterol-induced block. Using 25-hydroxycholesterol we investigated whether protein isoprenylation or protein glycosylation is rate-limiting for G1 progression in MDA231. We thereby found that 25-hydroxycholesterol was efficient in inhibiting N-linked glycosylation, measured by determining the glucosamine incorporation into cellular proteins. In contrast, 25-hydroxycholesterol did not depress the level of protein isoprenylation, measured as incorporation of mevalonate into cellular proteins. Furthermore, tunicamycin (an inhibitor of N linked glycosylation) inhibited G1-progression of MDA231 in a similar way to 25 hydroxycholesterol. Addition of trans-trans farnesol, which inhibits protein isoprenylation, did not result in any inhibitory effects on MDA231 growth. Our data suggest that N-linked protein glycosylation is rate-limiting in the isoprenoid-regulated cell cycle of human breast cancer cells. PMID- 21584572 TI - Subtraction hybridization - an approach to the isolation of genes differentially expressed in cancer and other biological-systems. AB - Subtraction hybridization allows for the isolation and identification of genes which are differentially expressed in different cell types. It allows for such isolation without any a priori knowledge of the sequence or function of the target gene. The only requirement is that there be a difference in the relative abundance of the nucleic acid (mRNA or genomic DNA) in the two cell types being compared. In contrast to differential hybridization, cDNA clones representing mRNAs of very low abundance (0.001% to 0.1%) can be discerned using subtraction hybridization. The concept, applications and techniques of performing subtraction hybridization is discussed. PMID- 21584573 TI - P53 and cathepsin-d are independent of established prognostic factors in breast cancer. AB - p53 and cathepsin D expression was investigated in 300 primary breast cancers by the avidin-biotin immunoperoxidase method using two murine monoclonal antibodies: PAb1801 and anti-procathepsin D, respectively. The frequency of p53- and cathepsin D-positive cells varied widely among different tumors and most tumors (82% and 86%) at least occasionally showed positive cells. The two biological markers were unrelated to one another, to cell proliferative rate and ploidy and were differently related to other biological and pathological features. In particular, p53 was directly related to tumor size and nodal involvement and inversely related to the presence of steroid receptors. Conversely, cathepsin D was directly related only to nodal involvement. PMID- 21584574 TI - Inhibition of viral mos gene-expression in transformed-cells restricts cell-cycle progression through g1-phase and g2-phase. AB - The c-mos protein is required for the activation of M-phase promoting factor (MPF) during oocyte maturation and for MPF stabilization in unfertilized eggs. To address the question whether v-Mos plays an important role during cell cycle progression in transformed somatic cells, we have utilized a temperature sensitive (ts) mutant of v-Mos. We examined NRK-6m2 cells chronically transformed by the ts mutant of Moloney murine sarcoma virus (MuSV ts110). NRK-6m2 cells transformed by MuSV ts 110 fail to express the viral mRNA for the heat-labile P85gag-mos protein at the restrictive temperature (39-degrees-C). To serve as controls for this study, two new transformation revertant cell lines, 6m3 and 6m4, were generated. 6m3 and 6m4 cells were found to express P85gag-mos maintained at both permissive (28-33-degrees-C) and restrictive temperatures. The growth rate of 6m2 cells at 37-degrees-C was significantly slower than either 6m3 or 6m4 cells at these same temperatures. To determine whether 6m2 cells maintained at 39-degrees-C were arrested at a specific phase in the cell cycle, flow cytometry analysis using double labeling was performed to quantitate cells in G0/G1, S- and G2/M-phases. The analyses indicated that 6m2 cells shifted to 39 degrees-C are arrested predominantly in the G1-phase of the cell-cycle. Of importance however, blocking v-mos expression also delayed progression through the G2-phase of the cell cycle. PMID- 21584575 TI - Alternative splicing of pvt-1 transcripts in murine lymphocytic-B neoplasms accompanies amplification and chromosomal translocation. AB - The Pvt-1 region lies approximately 260 kb 3' of the c-myc proto-oncogene on mouse chromosome 15. Chromosomal translocation or viral integration into the region of Pvt-1 in B-cell or T-cell neoplasms appears to up-regulate c-myc expression by some unknown mechanism. Recent isolations of Pvt-1-encoding cDNAs from both mouse and human tissues indicate that transcripts of Pvt-1 can be found in multiple forms. To elucidate the nature of these transcripts in the mouse, we have analyzed cDNAs from AJ9, an immortalized Ly-1+ B-lymphocytic cell line in which myc/Pvt-1 have been co-amplified, and from ABPC20, a plasmacytoma that contains a t(6;15) translocation in the region of Pvt-1. Alternatively spliced transcripts of Pvt-1 are evident, but a stretch of 57 bp makes up the amino terminus in each of these cDNAs. This region, designated Pvt-1a, is part of exon 1 and is also found within a 140 aa open reading frame (ORF), the longest Pvt-1 ORF established to date. Pvt-1a also shows homology at the amino acid level with two enzymes associated with transport in E. coli, glutamine permease operon protein glnQ and glycerophosphoryl diester phosphodiesterase glpQ. We predict that such chimeric mRNAs generated in mouse B-cell lymphomas and plasmacytomas with amplified or translocated Pvt-1 sequences may encode an in-frame segment of Pvt-1a. PMID- 21584576 TI - The usefulness of cytogenetic findings in differential-diagnosis of metastases of unknown origin. AB - Chromosomal abnormalities can be applied in the diagnosis and classification of some metastases of unknown origin. A selective search is most appropriate for treatable tumors, such as prostate, ovary, breast, small-cell lung cancer and germ cell tumors. Cytogenetic analysis may be particularly useful in these cases, since some of these tumors have been found to have specific chromosomal changes that are generally retained in the metastases. We discuss the usefulness of cytogenetic analysis in differentiating the origin of metastases and review the few cases reported in the literature. PMID- 21584577 TI - Determination of transrepression domains of the human N-myc protein. AB - The myc gene family, including c- and N-myc, is believed to play a critical role in the regulation of cell cycle and proliferation. The function of N-myc, in contrast to c-myc, is not clearly understood. Here we report that, using a N-myc expression vector in CAT and S1 nuclease protection assays, the N-myc protein trans-represses expression of the human N-myc, the mouse N-myc, and the human MHC class 1 antigen genes. The analysis of N-myc deletion mutants showed that the N terminal region where there are amino acid sequences highly conserved in the myc family and the central region where the acidic amino acids are concentrated, are necessary for trans-repression activity. Also, the region near the C-terminus is relevant for DNA-protein and protein-protein interaction; in particular, the basic region, helix-loop-helix, and leucine zipper are important for activity. PMID- 21584578 TI - Does mca contribute to the follow-up of breast-cancer patients by ca-15-3. AB - Mucin-like carcinoma-associated antigen (MCA) and CA 15-3 tumor markers were randomly assayed in 234 consecutive breast cancer patients. It was found that 45 patients (19.2%) had elevated MCA levels (cut-off level >14 U/ml) and normal CA 15-3 levels (cut off level >30 U/ml). In 14 of these 45 patients (31.1%), overt metastases were detected, although five had started their follow-up with no evidence of disease. In these five patients, the median lead time was nine months. In our limited experience, it was found that measuring MCA levels in the serum in the presence of normal CA15-3 levels contributes to early detection and monitoring of recurrences in follow-up of breast cancer patients. PMID- 21584579 TI - Comparison of flow cytometric DNA content in the primary tumor and in the corresponding lymph-node metastasis of patients with squamous cells carcinomas of the head and neck. AB - The clonal DNA content of the cell populations of primary tumors and corresponding lymph node metastases was analysed by DNA flow cytometry in 48 patients with squamous cell carcinoma of the oral cavity. Three primary tumors were diploid, two associated with diploid metastases, one showing an aneuploid cell line in the secondary lesion. Fourty-five cases were aneuploid in both the primary tumors and in the synchronous metastases, all characterized by nearly identical DNA indices of the corresponding primary and secondary lesions. With few exceptions, aneuploidy formation appears to take place prior to dissemination of metastatic cells. PMID- 21584580 TI - Preoperative radiotherapy for muscle-invading bladder-carcinoma. AB - One hundred five patients with clinical stage T2-T4 transitional cell bladder carcinoma who completed either low-dose (20-26 Gy) or high dose (40-50 Gy) preoperative radiotherapy (RT) followed by cystectomy were reviewed. Five-year actuarial survival was 42%, 52%, and 17% for stages T2, T3, and T4, respectively. Five-year local control rates for stages T2, T3, and T4 was 93%, 93% and 22%, respectively. Survival, local control, distant metastasis and complications were similar for both preoperative regimens. The high rates of local control support the use of preoperative RT in selected patients with bladder carcinoma. PMID- 21584581 TI - Invivo control of tumor-growth by lonidamine and radiations - influence of the timing and sequence of drug administration and irradiation treatment. AB - It has been well established that Lonidamine (LND), [1,(2,4 dichlorobenzyl)-1H indazol-3-carboxylic acid], affects tumor growth and enhances the effect of X-ray both in vitro and in vivo. Nevertheless, difficulties arise if the available experimental data should be utilized to design clinical trials since schedules, routes of administration as well as dosages greatly differ from those currently employed in the clinic. With the aim to overcome these difficulties, experiments with modalities similar to those employed in the current clinical practice have been undertaken to evaluate: (i) the influence of the LND dosage on the antitumor effect; (ii) the time lenght of its administration for the optimal effect; (iii) the best schedule of treatment when LND is associated with radiations. The results may be summarized as follows: (i) antitumor effectiveness of LND, in terms of growth delay, increases with LND dosage. Moreover, the drug administered from the day of transplant significantly decreases the tumor takes. (ii) to exert the antineoplastic effect LND must be administered continuosly because if the treatment is interrupted the tumor regrows like an untreated one. (iii) the maximal response of the association X-ray-LND is elicited when the drug is given after irradiation treatment. PMID- 21584582 TI - Binding of transferrin to membrane-associated proteoglycans in breast-cancer cells. AB - Cell surface associated proteoglycans were isolated from MCF-7 breast tumor cells by mild trypsin digestion, extraction by guanidine-hydrochloride and purification by ion-exchange chromatography. Immunological studies showed that transferrin can bind to membrane associated proteoglycans (MAPG). However, these MAPG are not recognized by anti-transferrin receptor antibodies either in an intact, or in a form stripped of glycosaminoglycan chains. Considering the possible involvement of secreted transferrin in proliferation or differentiation of breast tumor cells, we suggest that transferrin binding to MAPG may be related to a specific function of transferrin. PMID- 21584583 TI - Phosphorylation of wild-type and mutant phenotypes of p53 by an associated protein-kinase. AB - Immunopurified mutant mouse p53 from transformed cells is known to be tightly associated with a protein kinase which phosphorylates p53 in an in vitro kinase reaction. Wild-type p53 from a non-transformed cell line was not associated with a protein kinase whereas immunopurified wild-type p53 from a transformed cell line was tightly associated with a protein kinase which phosphorylated p53. In order to compare wild-type and mutant p53 in the same cellular environment both forms were cloned in a baculovirus expression system and in in vitro transcription/translation vectors and both p53 proteins were expressed in the two systems. Wild-type and mutant p53 from baculovirus infected insect cells were tightly associated with a protein kinase which phosphorylates p53. In contrast, immunopurified wild-type and mutant p53 from an in vitro transcription/translation reaction were not associated with a protein kinase but could be phosphorylated by added casein kinase II. Thus, in the present paper we demonstrate that the association of p53 with a protein kinase and the in vitro phosphorylation of p53 seems to depend on the surrounding cellular environment. PMID- 21584584 TI - Expression of individual ras proteins in normal and neoplastic colon. AB - In this study, we report the use of a panel of four ras antibodies in Western blot analysis which characterize the expression of individual ras members in different cell populations. The specificity of the different antibodies to H-, N- or K-ras proteins was established in a panel of NIH/3T3 transfectants and human cell lines harboring known ras oncogenic events. Localization of individual ras members in one dimensional gel electrophoresis revealed slower migration of K-ras p21 products, whilst H- and N-ras proteins co-migrated in this system. Identification of migrational differences between activated proto-oncogene products was facilitated using ras member specific probes. Application of this approach to normal gastrointestinal mucosa.revealed over-representation of K-ras p21 in both stomach and colon epithelium in the rat. This differential ras profile was maintained in normal human colon mucosa and colon tumors from the same individual. Use of such antibodies now enables dissection of ras proto oncoprotein expression in different tissues and compartments within tissue with the ability to characterize ras mutational events in neoplastic progression. PMID- 21584585 TI - Epidermal growth-factor receptor and erbb2 protein in colorectal tissue - comparison between cancer and normal mucosa. AB - Epidermal growth factor receptor (EGFr) and p185neu protein were measured in 55 samples of carcinoma and 55 of normal colorectal mucosa from the same patient, using a ligand binding assay and an ELISA method respectively. The binding characteristics of EGFr were similar in cancer and normal tissue. The concentrations of both EGFr and p185 showed gaussian distribution and were not significantly different between normal and cancer tissue, although a trend toward higher levels of EGFr in normal mucosa was found. Moreover, no significative variations were found in the ratios between cancer and normal tissue after desaturation of the EGFr. No correlations were found between EGFr and p185 and the main clinopathological parameters. PMID- 21584586 TI - Immunohistochemical study of neuron specific enolase expression in salivary-gland tumors. AB - The immunoreactivity of monoclonal anti-neuron-specific enolase (MoAb NSE) on 10% formalin-fixed sections of normal human salivary glands and tumors were examined by the avidin-biotin-peroxidase complex (ABC) method. MoAb NSE staining of ductal and acinar cells of the normal salivary glands were, negative, and peripheral nerve fiber in the gland tissue showed strongly positive staining. In salivary gland tumors, pleomorphic adenoma (34 in total 68), myoepithelioma (15 in 35), monomorphic adenoma (7 in 10), adenolymphoma (15 in 23), mucoepidermoid carcinoma (3 in 16), acinic cell carcinoma (1 in 7), adenoid cystic carcinoma (12 in 20) and sialocarcinoma (4 in 15), stained focally for MoAb NSE staining. Frequency of occurrence for positive NSE activity varies among benign and malignant salivary gland tumors. In addition to MoAb NSE, S-100 protein and GFAP also demonstrated positive reactions in pleomorphic adenoma (Simpson et al Cancer 54: 1364-1369, 1984). The outer layer cells and/or peripheral cells of tubulo-ductal structure as well as modified myoepithelial cells and the cells of solid structure coexpressed with NSE, S-100 protein and GFAP. It is postulated that the salivary gland tumors particularly pleomorphic adenoma may be neuroectodermal in origin, arising from stem cells in intercalated duct segments. PMID- 21584587 TI - Desensitization of human breast-cancer cells by interferon-alpha. AB - Continuous exposure of human breast cancer cells, MCF-7, to interferon-alpha (IFN) induces a state.of non-responsiveness termed as desensitization. mRNA 561 is transiently induced by IFN-alpha in MCF-7 cells, peak cytoplasmic levels are reached by six to twelve hours; the mRNA level declines steadily and is reduced to uninduced levels by forty eight hours. Induction of mRNA 561 was used as an index of responsiveness of cells to IFN-alpha and desensitization was characterized in MCF-7 cells and in MCF-7 cells transfected by the v-H-ras oncogene (MCF-7ras). The kinetics and degree of IFN-mediated induction of mRNA 561 was comparable in both the cell lines. Desensitization was observed in MCF-7 cells and not in MCF-7ras. It was a reversible event, requiring de novo protein synthesis as inclusion of cycloheximide inhibited desensitization. The cellular elements that mediate such a phenomena are elicited by IFNs during the initial phases of IFN action and may be polypeptides. The refractory period, the time after which MCF-7 cells become responsive, was determined to be five days. In conclusion, we demonstrate the use of mRNA 561 induction in evaluating desensitization. Inhibition of protein synthesis or transfection with ras blocks desensitization in MCF-7 cells. PMID- 21584588 TI - The treatment of colorectal hepatic metastases by continuous local infusion of interleukin-2. AB - Patients with hepatic metastases from colorectal cancer appear to be resistant to most forms of therapy. Recent reports suggest synergism between systemically administered recombinant interleukin-2 (rIL-2) and 5-fluorouracil (5-FU) with responses documented in the treatment of advanced colonic tumours albeit with significant toxicity. Local continuous infusion of rIL-2 into selected sites may reduce toxicity and increase efficacy. We have assessed the feasibility of continuously infusing rIL-2 into the region of a hepatic metastasis in 3 patients via a catheter placed within the liver under ultrasound guidance in a regimen including systemic rIL-2 and 5FU. PMID- 21584589 TI - Circulating levels of epithelial membrane antigen in patients with breast or colorectal-cancer. AB - Epithelial membrane antigen (EMA) is expressed by adenocarcinomas of the breast, ovary and colon and has been suggested as a circulating tumour marker. Serum EMA levels were measured in 126 patients, 31 with colorectal cancer, 52 with breast cancer and 43 age matched controls using a competitive binding radioimmunoassay and the rat anti-EMA monoclonal antibody (MAb) ICR2. The EMA levels in the control group varied widely from 90-3240ng/ml with a median value of 570ng/ml. This was not significantly different from the levels in patients with colorectal cancer (60-8530, median 580ng/ml) or those with breast cancer (210-13300, median 655ng/ml). However, the highest EMA levels (>5000ng/ml) were found in patients with cancer. The wide range of EMA levels in the control group prohibit its use for screening. PMID- 21584590 TI - Reliability of a primary culture system to test cytotoxic drug activity in human malignant melanoma. AB - Optimal conditions have been defined to grow primary cultures of malignant melanoma suitable for in vitro pharmacological studies. A feasibility of primary cultures was observed in 60% of 62 clinical melanoma lymph node metastases. The neoplastic nature of the cells grown in culture, as assessed by the highly specific monoclonal antibodies anti-S100 and HMB45, was confirmed in 100% and 65% of the cases, respectively. Flow cytometric analysis showed a high stability of DNA content profiles observed in clinical samples through all the methodologic steps used to obtain in vitro cultures. The intertumor variability of the degree of the antiproliferative effect of melphalan and its relation with DNA interstrand cross-links (DNA ISC) provided preliminary evidence of the reliability of the experimental system for in vitro evaluation of anticancer drug activity. PMID- 21584591 TI - Etanidazole as a modulator of combined modality therapy in the rat 9l gliosarcoma. AB - The use of chemotherapy has led to improved treatment outcome for some pediatric patients with medulloblastoma. We have used a pre-radiation chemotherapy regimen consisting of vincristine and CDDP. The 9L gliosarcoma implanted intracranially and subcutaneously in the same animals was used as a preclinical model system to assess the efficacy of treatment combinations including: vincristine, CDDP, cyclo phosphamide, etanidazole and radiation. The experimental endpoints were percent increase-in-lifespan, tumor growth delay and tumor cell survival. Both the tumor growth delay and percent increase-in-lifespan improved as the number of agents included in the chemotherapy regimen increased. so that the chemotherapy regimen including all four agents (ETA/VIN/CDDP/CTX) resulted in the greatest tumor growth delay (23.6 +/- 1.5 days) and the greatest increase-in-lifespan (35.8%). When radiation (20 Gray, single dose) was added to the treatment regimens the combinations of ETA/CTX/X-ray and ETA/VIN/CDDP/CTX/X-ray resulted in equivalent tumor growth delays (25.2 +/- 1.3 days and 25.8 +/- 1.7 days, respectively), while the greatest increase-in-lifespan (39.1%) was obtained with the five agent combination. The response of the 9L gliosarcoma to CDDP and cyclophosphamide over a dosage range was very similar to that of the murine FSaII fibrosarcoma. Our results indicate that etanidazole may be an effective chemosensitizer of combination chemotherapy and combined modality treatment regimens for brain tumors. PMID- 21584592 TI - Influence of nucleotides flanking the ggaa core sequence on ets1 and ets2 DNA binding activity and the mechanism of ets1 autoregulation. AB - The Ets family of genes encode nuclear proteins that activate transcription by binding to a specific purine-rich (GGAA) ets binding sequence (EBS) present in promoters/enhancers of various genes. We have previously shown that over expression of ets1 via transfection of ets1 expression vectors into NIH3T3 cells induced the expression of the endogenous Ets1 gene. Here we report that the autoregulation occurs as a result of the ets1 protein binding to the EBS-core located in its own promoter. In the present study, we have also identified Ets binding sites in the IL-4, G-CSF (granulocyte colony stimulating factor), and the 2'5' OAS (oligoadenylate synthetase) promoters by binding with Ets1 and Ets2 proteins using electrophoretic mobility shift assays. Interestingly, we have found that the EBS containing T nucleotides on either side of the GGAA core sequence, does not bind Ets1 or Ets2 proteins. Our findings demonstrate that the sequences surrounding the purine core - GGAA- have a profound influence on the binding of Ets proteins. PMID- 21584593 TI - DNA strand breaks occurring during apoptosis - their early insitu detection by the terminal deoxynucleotidyl transferase and nick translation assays and prevention by serine protease inhibitors. AB - The appearance of DNA strand breaks during apoptosis was detected in individual cells, in relation to the cell cycle phase, by a novel assay based on labeling 3' OH termini with biotinylated dUTP using exogenous terminal transferase or DNA polymerase. Apoptosis was induced in HL-60 cells by the DNA topoisomerase I and II inhibitors, and in rat thymocytes by prednisolone. Formation of strand breaks was prevented by the serine protease irreversible inhibitors diisopropyl fluorophosphate (DFP), L-1-tosylamido-2-phenylethyl chloromethyl ketone (TPCK), N p-tosyl-L-lysine chloromethyl ketone (TLCK) and by the substrates N-alpha-tosyl-L arginine methyl ester (TAME) and N-benzoyl-L-tyrosine ethyl ester (BTEE). The data indicate that initiation of DNA degradation during apoptosis is preceded by a proteolytic step and suggest that apoptosis starts with activation (e.g. by DNA lesions) of a serine protease which hydrolyses protein(s) associated with the internucleosomal linker DNA sections, thus increasing accessibility of linker DNA to the apoptosis-associated endonuclease. PMID- 21584594 TI - A circulating heat-resistant mucin-like antigen in patients with lung-cancer detected by a new murine monoclonal-antibody. AB - We discovered a circulating mucin-like antigen designated as CAM-14 detected by a new murine monoclonal antibody KL-14 (IgM). We found different heat resistant properties between serum CAM- 14 from normal individuals and from lung cancer patients. Heat treatment had less effect on the levels of CAM-14 in sera from lung cancer patients, whereas CAM-14 levels in sera from normal individuals were markedly decreased after heat treatment at tempratures > 65-degrees-C. As a serum tumor marker, CAM- 14 had only very low levels of false-positive values with a high specificity and effectively increased the positive rate for lung cancer patients when used together with carcinoembryonic antigen. PMID- 21584595 TI - Neoplastic response to dmba powder in mammary and interscapular tissues in wistar furth and copenhagen female rats. AB - To investigate genetic factors in local tumorigenesis, a dusting of 1 mg of 7,12 dimethylbenz(a)-anthracene (DMBA) powder was directly applied to exposed mammary tissue in 15 Wistar/Furth (WF), 20 Copenhagen (Cop), 19 (WF x Cop) F1, 16 backcross (BC) (F1 x WF) and 19 BC (F1 x Cop) females, at the age of 30 days. By 28 weeks after dusting, gross tumors were induced in 15 WF, 17 Cop, 12 (WF x Cop) F1, 11 BC (F1 x WF) and 14 BC (F1 x Cop) rats. Depending on their neoplastic response, carcinomatous response was 93% in WF, 5% in Cop, 16% in (WF x Cop) F1, 31% in BC (F1 x WF) and 0% in BC (Fl x Cop) rats, and sarcomatous response was 20% in WF, 85% in Cop, 58% in (WF x Cop) F1, 44% in BC (F1 x WF) and 73% in BC (F1 x Cop) rats. When dusting was performed on the interscapular fat tissue of 21 WF and 22 Cop females at 38 days of age, sarcomas were found in 67% of WF and 91% of Cop rats. Therefore, susceptibility and supressor gene(s) are suspected in mammary epithelial cells of the WF and Cop, respectively, for carcinogenesis, while co-dominant allele for sarcomagenesis exists in the Cop and WF mammary stromal cells. PMID- 21584596 TI - Regional intraarterial infusion chemotherapy without laparotomy for hepatic metastases of pancreatic-cancer. AB - The therapeutic effectiveness of regional infusional chemotherapy for treatment of hepatic metastases of pancreatic cancers was compared with systemic chemotherapy. Studies were made on 17 patients with unresectable pancreatic cancer with hepatic metastases. Regional infusion chemotherapy was performed after the insertion of an angiocatheter into the hepatic artery without laparotomy. This treatment significantly increased the rate of the partial response (40%) of the hepatic metastases, prolonged the survival and reduced the duration of the hospital stay. As hepatic infusion chemotherapy without laparotomy is also simple and inexpensive, it should be useful for treatment of hepatic metastases of pancreatic cancer. PMID- 21584597 TI - Multivariate-analysis of prognostic factors in 232 patients with clinical stage-I endometrial adenocarcinoma using the new figo surgical staging system. AB - A retrospective analysis is reported in 232 patients with clinical Stage I endometrial adenocarcinoma diagnosed between 1980 and 1988, treated with combined surgery and adjuvant irradiation. Tumors were restaged according to the FIGO (1988) surgical staging system (SSS) in order to assess the prognostic value of this revised classification and of the conventional clinico-pathological features (age, performance status, grade and depth of myometrial invasion). The 5-year relapse-free survival (RFS) and overall survival (OS) of the series was 85% and 90.8%, respectively. Both 5-year RFS and OS were not significantly different adopting the FIGO (1971) clinical Stage (Stage IA 93% and 88% vs Stage IB 88.5 and 82%. respectively) whereas they were significant by FIGO SSS (Stage IA 96% and 93% vs Stage IB 94% and 88.5% vs Stage IC 74% and 63%, respectively) (p=0.001 and p=0.0005, respectively). Other factors that significantly affected 5-year RFS or OS at univariate analysis were age (p=0.01 and p<0.0001, respectively), performance status (p=0.035 and p=0.001, respectively), grade (p=0.015 and p<0.0001, respectively) and myometrial invasion (p=0.0017 and p=0.0003, respectively). A multivariate analysis of these prognostic variables showed that FIGO SSS was the only significant and independent (p=0.01) indicator for recurrence. However, when therapy was added to the model, FIGO SSS failed to retain significance (p=0.11). Concerning OS age (p<0.0001), performance status (p=0.04) and FIGO SSS (p=0.05) were significant and independent prognosticators, also when therapy was included in the analysis. In conclusion, this study shows that the new FIGO SSS is a useful prognosticator as well as is age and performance status, in early Stage endometrial adenocarcinoma. PMID- 21584598 TI - Protooncogene expression in human glioma derived cell-lines. AB - Growth factor/ligand interactions have been shown to play an important role in various malignancies. Expression of two differentially spliced forms of SCF was detected in 20 of 24 glioma cell lines by RT-PCR. Northern blot analysis revealed expression of the corresponding receptor, c-kit (11/24), as well as PDGF alpha receptor (22/25 glioma cell lines), PDGF beta-receptor (22/25), TGF-alpha (13/24 ) and PDGF B/c-sis (7/16) expression. As determined by FACS analysis, expression of EGFR and p185HER2 was detected in 21 of 21 and 15 of 21 glioma cell lines, respectively. Four cell lines showed moderate EGFR overexpression (>90,000 receptors/cell) and in one cell line p 185HER2 expression exceeded EGFR levels. Loss of EGFR gene amplification during in vitro culturing was observed in 3 of 18 investigated cell lines by differential PCR. In summary, our work suggests the simultaneous activation of several different growth factor/receptor systems in human glioma cell lines. PMID- 21584599 TI - Plasminogen activators in breast-cancer cells. AB - This review summarizes recent experimental and clinical studies on plasminogen activator (PA) expression in breast cancer cells. The two PAs, urokinase-type (u PA) and tissue-type (t-PA), have quite different biological significance in breast cancer cells. Sufficient evidence indicates that t-PA production is regulated by estrogen via an estrogen receptor system and suggests the potential usefulness of this enzyme as a marker for estrogen action in breast cancer cells. On the other hand, u-PA has been implicated in cancer cell invasion and metastasis formation because this enzyme can degrade components of the extracellular matrices and basement membranes either directly through its enzyme activity or indirectly by activation of other proteinases. High levels of u-PA correlates with both shortened disease-free survival and overall survival in patients with breast cancer indicating that u-PA is a new prognostic marker in human breast cancer. In contrast to u-PA, t-PA is associated with a good prognosis. However, t-PA is involved in bone-only metastasis formation by its effects through the vertebral venous plexus. PMID- 21584600 TI - Increased resistance to Doxorubicin in human non-small-cell lung carcinomas with metallothionein expression. AB - Ninety-four human non-small cell lung carcinomas (NSCLC) of previously untreated patients were analyzed for the presence of metallothionein (MT) expression by means of immunohistochemistry. Of the tumors investigated, expression of MT was detected in 63%. The expression of MT was correlated with the results of doxorubicin resistance of the tumors in vitro. A significant relationship between MT expression and doxorubicin resistance was found (p=0.01). Significant correlations also exist between MT and P-glycoprotein or glutathione-S transferase-pi expression respectively (p<0.005). PMID- 21584601 TI - Ag-nor protein area in transitional cell bladder-cancer as measured by image analysis. AB - Nucleolar organizer regions were visualised in 50 transitional cell carcinomas by using the silver staining technique. The area occupied by the individual Ag-NOR dots and other structural features related to Ag-NORs were measured by image analyzer (IBAS 2) at a total magnification of x9500. The mean Ag-NOR area ranged between 0.37-0.53 mum2 and the mean Ag-NOR area was 0.47 mum2. The Ag-NOR area or other structural features were not related to clinical stage, WHO grade, papillary status, DNA ploidy, S-phase fraction, volume corrected mitotic index or Ag-NOR count. The Ag-NOR area had no prognostic value in terms of progression or survival. The results indicate that the area of individual Ag-NOR dots is relatively constant in transitional cell bladder cancer and the enumeration of the Ag-NORs has prognostic value. In case the Ag-NORs are packed together, the Ag NOR area reflects the number of individual Ag-NOR dots and may have prognostic value on that basis. PMID- 21584602 TI - Characterization of a glycoprotein associated with malignant proliferation of human mammary epithelial-cells. AB - A secretory product of human mammary epithelial cells (MEC), termed tumor associated antigen with an apparent molecular weight of 62 kilodaltons (TAA.62), was identified by a human monoclonal antibody. The study showed that TAA.62 was present at elevated levels in the cytoplasmic compartment of malignant as compared with normal or benign in tissue and non-tumorigenic immortalized MEC lines. A similar pattern of TAA.62 expression was also observed in cervix, colon, kidney, lung and stomach. The antigen was purified to homogeneity from the conditioned medium of malignant (tumorigenic) and immortalized (nontumorigenic) MEC lines and was termed TAA.62(T) and TAA.62(NT), respectively. Both TAA.62(T) and TAA.62(NT) were indistinguishable in terms of their sizes, sequence of their first twelve amino acid residues of the N-terminus and immunoreactivity with anti TAA.62 antibody. However, purified TAA.62(T) interacted in vitro specifically with a 160 kd cell-surface component on the malignant and immortalized MEC lines, whereas TAA.62(NT) did not. Interestingly, addition of the purified TAA.62(T) to the culture medium resulted in an enhanced growth of both the malignant and immortalized MEC lines, whereas no such effect was observed when TAA.62(NT) was added. Finally, addition of anti-TAA.62 antibody to culture medium neutralized the growth-stimulatory effect of exogenously added TAA.62(T). The results suggest that TAA.62(T) may interact as a ligand with a 160 kd-receptor, having a possible growth function. PMID- 21584603 TI - Magnetic-resonance-imaging of bone-marrow in lymphoma. AB - Magnetic resonance imaging provides a non-invasive method of obtaining high resolution images of the bone marrow. The signal obtained is dependent on bone marrow cellularity and the proportions of haemopoietic tissue, fat, tumour and fibrous tissue present. MRI is a sensitive method of detecting bone marrow involvement in Hodgkin's disease and high grade non-Hodgkin's lymphoma and provides a complimentary tool to conventional bone marrow trephine biopsy in assessing bone marrow involvement. PMID- 21584604 TI - The galactoside-specific lectin from mistletoe as biological response modifier. AB - Experience with herbal extracts can guide the isolation of substances that effectively amend aspects of the host's defence system against tumor growth and spread. This capacity appears to be conferred to mistletoe (Viscum album) extract by a rather small dose range of the galactoside-specific lectin (VAA). It is a biochemically characterized dimer, consisting of a toxic subunit that acts as a RNA N-glycosidase (depurination of A-4324 in 28S rRNA) and a carbohydrate-binding B-chain. The binding of this subunit to galactose-exposing glycoligands on mononuclear cells elicits cytokine secretion in vitro and antitumoral/antimetastatic capacity in vivo in lymphosarcoma/sarcoma model systems. Increases in NK cell number, the activity of peritoneal macrophages and NK cells as well as the response of splenic T cells to mitogens are detectable. Immunophenotyping of blood samples from lectin-treated patients reveals increases in the number of helper/inducer T cells, NK cells and CD25-positive cells. Since the response to the treatment is assumed to be dependent on the presence of lectin-specific ligands on inflammatory host cells, histopathological monitoring of tumor specimens with labelled lectin is conceivable to be one factor of relevance to predict a response to the treatment in animal models or within clinical trials. PMID- 21584605 TI - Aromatase fails to mediate the proliferative effects of adrenal androgens on cultured mcf-7 breast-cancer cells. AB - Dehydroepiandrosterone and 5-en-Androstene-3beta, 17beta-diol affect MCF-7 human breast cancer cell growth through estrogen receptor, as shown by Tamoxifen counteraction. To assess whether the aromatization of these adrenal androgens to classical estrogens is required to stimulate proliferation, we evaluated the aromatase activity of MCF-7 cells. Aromatase activity was determined in both whole cells grown as monolayer cultures and microsomal fraction of cell homogenates. The conversion of Androstendione to Estrone was very low in cell cultures. By contrast, a high aromatase activity was found in cell homogenates, indicating that in isolated microsomal fractions of MCF-7 cells aromatase is unveiled. Since in whole cultured MCF-7 cells the conversion of androgens to estrogens is negligible, we suggest that the stimulatory effect of DHEA and ADIOL on the 'in vitro' growth of MCF-7 does not involve the aromatase pathway. PMID- 21584606 TI - Membrane cholesterol content and sensitivity of human carcinoma-cells to antineoplastic ether phospholipids. AB - Ether phospholipids represent a new class of anti-cancer drugs which appear to exert their tumoricidal activity through a direct and indirect cytotoxic effect against tumor cells of different origins. The chemotherapeutic interest in these new drugs is based on the finding that, contrary to the majority of anti-cancer drugs, ether phospholipids do not interfere with DNA synthesis, are anti-invasive and induce tumor cell differentiation. There is increasing experimental evidence that the direct cytotoxic effect of these new drugs is mediated by the cell membrane. We have measured the lipid membrane composition of three human carcinoma cell lines that have been found to possess different sensitivity to the tumoricidal activity of four antitumor ether phospholipids. A statistically significant difference has been found in the membrane cholesterol content of the three cell lines and a positive correlation has been established between the membrane cholesterol level and the carcinoma cell sensitivity to ether phospholipids. These findings emphasize previous data obtained with leukemic cells and reinforce the interest in ether phospholipids whose cytotoxic properties may represent a new step towards a more promising anti-cancer chemotherapy. PMID- 21584607 TI - Characterization of kaposis sarcoma-derived cell-cultures from an epidemic and a classic case. AB - Cells derived from skin biopsies from two Kaposi's sarcoma patients, an elderly female with a sporadic non-AIDS form, and an AIDS-affected homosexual male, were established in culture. The classic patient had a few small lesions, while the epidemic case presented-large, disseminated, cutaneous and oral mucosa lesions. The cells obtained from both patients, termed IST-KS2 and AIDS-IST-KS3 respectively, had the characteristic spindle shape reported for Kaposi's sarcoma derived cells. By immunocytochemistry they were both found to express the smooth muscle specific isoform of alpha actin. The KS cells expressed the fibroblastic antigen TE-7, which is not expressed in endothelial cells. Furthermore both KS cultures were negative for the endothelium associated markers Factor VIII, EN4 and PAL-E. They were also negative for the leukocyte antigen CD45, but were positive for vimentin. Immunocytochemistry studies were therefore suggestive of a primitive mesenchymal cell. When the KS-derived cells were grown on a gel of reconstituted basement membrane, both cultures formed large branching colonies characteristic of malignant cells of mesenchymal origin. No differences were observed between HIV-related and the sporadic KS-derived cultures studied. Fibroblasts and smooth muscle cells did not form branching colonies, while endothelial cells on matrigel differentiated forming tube-like structures. Supernatants from both sporadic and AIDS-related KS cell cultures had similar effects on endothelial cell growth in vitro and were also found to stimulate chemotaxis and chemoinvasion of normal vascular endothelial cells in the Boyden chamber assay, showing angiogenic potential in vitro. Our results demonstrate that long term cultures of spindle shaped cells derived from either HIV associated and classic KS show the same histocytochemical phenotype, have invasiveness in matrigel similar to that of malignant sarcomas, and share in vitro angiogenic properties. Therefore, factors from the host are likely to be responsible for the divergent clinical picture of the classic and epidemic Kaposi's patients studied here. PMID- 21584608 TI - H-ras oncogene mutations in the urine of patients with bladder-tumors - description of a noninvasive method for the detection of neoplasia. AB - Bladder cancers are usually curable, by surgical or transurethral excision, if diagnosed at an early stage. Tumor derived mutations in oncogenes potentially provide specific markers for the detection of surgically resectable tumors. The detection of point mutations of H-ras oncogene correlated with this disease. DNA sequences produced by the Polymerase Chain Reaction (PCR) can be considered for this application, because theoretically bladder tumors should shed cells containing this mutation into the urine. We examined urine from 21 individuals with bladder cancer before any treatment, as well as tissue specimens from the excised tumor and we found 10 mutations of the H-ras gene at codon 12 in the urine (47.61%) and 14 mutations in the tumor specimens (66.66%). We were able to detect nearly 50% of the patients with bladder tumors using this method. We also studied two relapses; in one case (which presented the mutation in the original tumor and the urine) the relapse grade had progressed from II to III. In the other case the relapse grade stayed at III but it presented for the first time the studied mutation in the urine. These results provide the theoretical and technical basis for the detection of bladder tumors by a non-invasive method and possibly for the evaluation of the invasiveness of the disease. PMID- 21584609 TI - Chemosensitization of murine fibrosarcoma cells to drugs affected by the multidrug resistance phenotype by the antidepressant trazodone - an experimental model for the reversal of intrinsic drug-resistance. AB - A variety of resistance phenotypes to cytotoxic agents in bacteria, protozoa parasites and mammalian cells are mediated by evolutionarily conserved proteins of the mdr family. The finding that chloroquine resistance in the malarial parasite, Plasmodium falciparum, that is mediated by an mdr-1 gene product can be circumvented by tricyclic antidepressant drugs has stimulated the present study to assess whether this class of agents might also modulate the multidrug resistance (MDR) phenotype(s) in mammalian tumor cells. The possible chemosensitizing effects of nine antidepressant drugs have been tested against the UV-2237M murine fibrosarcoma line and its MDR variant. At nontoxic concentrations all nine antidepressants markedly enhanced the cytotoxicity of ADR against the parental cells but were much less effective against the MDR cells. The most active antidepressant, trazodone, also enhanced the cytotoxicities of vinblastine and vincristine, but not those of actinomycin D, mitomycin C, or 5 fluorouracil. The parental cells treated with trazodone exhibited an increased accumulation of intracellular ADR, but lacked detectable alterations in the expression and drug-binding activity of plasma membrane P-glycoprotein, and trazodone did not affect the activities of isolated protein kinase C and calmodulin. These data suggest that the antidepressant drug trazodone may be useful in the reversal of the intrinsic drug resistance of tumor cells that express low levels of P-glycoprotein. PMID- 21584610 TI - Methylation of chromosome 11p genes in wilms-tumor and kidney tissue. AB - Three genes on the short arm of chromosome 11 (WT1, IGF2 and HRAS) were hypomethylated in Wilms' tumour tissue compared to normal kidney tissue, and one (CALCA) was hypermethylated. IGF2 and HRAS showed evidence of allele-specific methylation, which may indicate genomic imprinting of the 11p15 region in some kidney cells. PMID- 21584611 TI - Cytogenetic and molecular analysis of synovial sarcoma. AB - We have carried out cytogenetic studies on a series of ten synovial sarcomas. Five of these tumours contained the characteristic reciprocal translocation t(X;18) (p11.2;q11.2) and a further two tumours contained complex rearrangements involving chromosomes X and 18. Secondary clonal alterations were seen in four tumours. Candidate genes at Xp11.2-p11.3 have been assessed for involvement in the translocation by Northern and Southern analysis: genes encoding transcription factors (ELK1 and TFE3), a metalloproteinase inhibitor (TIMP-1), a ubiquitin activating enzyme (UBE1), a serine-threonine kinase (ARAF1) and the neural cell phosphoprotein synapsin 1 (SYN1). We found no evidence of abnormal transcription or rearrangements of these genes in a panel of synovial sarcoma biopsies and cell lines, indicating that they are not directly involved in the t(X;18) chromosome translocation. PMID- 21584612 TI - Immunohistochemical evaluation of mam-3 and mam-6 antigens in squamous-cell carcinoma of the oral cavity. AB - MAM-3 and MAM-6 antigens of human milk fat globule membrane designated as human polymorphic epithelial mucin (PEM) were detected immunohistochemically in a total of 86 specimens from 39 cases of oral squamous cell carcinoma (SCC) and 6 cases of normal oral mucosa. The two antigens were identified by MoAbs 67D11 and 115G3 (MAM-3 antigen) and by MoAbs 115D8 and 115F5 (MAM-6 antigen) in paraffin sections. MoAb 115G3 staining was found in well keratinized foci; whereas, MoAb 115D8 and 115F5 staining was very low in keratinized tumor cells. The cytochemical distribution of the antigens was classified into 3 types; (i) cell membrane positive type, (ii) whole cell positive type and (iii) antigen negative type. Reduction and disappearance of the two antigens were correlated to the mode of tumor invasion and suggested that glycocalyx complex in cell membrane properties was changed for malignant transformation. PMID- 21584613 TI - Intracellular free Fatty-Acid release and lipid-peroxidation in cultured human breast-cancer cells in response to gamma-linolenic Acid with iron (gla + fe). AB - Intracellular free fatty acid (FFA) release and peroxidation of polyunsaturated fatty acid (PUFA) were studied in cultured human breast cancer cells (ZR-75-1) exposed to gamma-linolenic acid with iron (GLA + Fe). This treatment results in cell death. Increased intracellular FFA were observed in association with both the accelerated peroxidation of PUFA and the killing effect. Vitamin E reduced all three effects. The FFA were methyl esterified and analyzed by gas chromatography-mass spectrometry. The identified FFAs were 16: 0, 18: 3, 20: 3 and 20: 4 (numbers of carbons and double bonds indicated). These results suggest an association of intracellular FFA release with the peroxidation of PUFA and the cancer cell-killing by GLA in the presence of iron. PMID- 21584614 TI - Ha-ras oncogene induction of invasion and metastasis is associated with the activation and redistribution of protease(s) in rat-kidney cells. AB - To investigate the role of oncogenes in the development of metastatic ability, the Ha-ras oncogene was transfected into murine kidney cell line NRK and an alternative murine cell line C127 cells. The resulting transfectants, NRK-Ha and HC127, were assayed for their invasive capability in an in vitro invasion assay and compared with their parental cell lines. All transfected cells were demonstrated to express a 0.6 kb mRNA for the ras oncogene by Northern blot analysis. Using a modified Boyden chamber, we showed that the motile ability of the cell lines, transfected versus non-transfected, were not altered by the introduction of the Ha-ras oncogene. However, ras transfected NRK-Ha cells were able to penetrate and invade through an artificial basement membrane coated filter when compared with the non-transfected parental cell line. Neither the C127 cells nor its ras transfected HC127 cells were able to migrate or penetrate through an artificial basement membrane coated filter. Using immunoblot analyses, we determined that invasive NRK-Ha cells expressed a mature form of protease cathepsin B with a molecular weight between 25-28 kD. Furthermore, using subcellular fractionation and immunoblot, we localized this mature form of cathepsin B to the plasma membrane fraction of the invasive NRK-Ha cells. The plasma membrane fraction of invasive NRK-Ha cells was able to degrade basement membrane components such as fibronectin and the patterns seen were similar to those of purified cathepsin B degradation. Non-invasive NRK, C127 and HC127 cells had only the precursor form of cathepsin B with a molecular weight between 38-45 kD and were unable to degrade basement membrane components. We suggest that the presence and expression of the Ha-ras oncogene alone does not confer metastatic capability, but rather that the ras oncogene must signal specific intracellular redistribution of proteases such as cathepsin B in order to promote tumor cell invasiveness. PMID- 21584615 TI - A comparative immunohistochemical study of p53 and proliferating-cell nuclear antigen expression in microwave-fixed paraffin sections of colorectal tumors. AB - This paper reports on a comparative immunohistochemical study of p53 and proliferating-cell nuclear antigen (PCNA) performed on microwave (MW)-fixed paraffin sections of 24 colorectal carcinomas and 68 adenomas in order to investigate the relationship between p53 expression and proliferative activity. Nuclear p53 was detected in 12 cases out of 24 carcinomas and eight out of 68 adenomas were found to focally express p53. Examination of PCNA expression in the adjacent sections of carcinomas revealed that the incidence of PCNA expression was not affected by p53, and both p53-positive and p53-negative carcinomas exhibited a high level of PCNA expression that reached more than 75% of the cancer cells. In the colorectal adenomas, the incidence of PCNA expression averaged about 30% although highly heterogenous distribution of PCNA-positive cells in the section was observed. When we examined eight adenomas positive for p53, the incidence of PCNA expression in the p53-positive glands of each adenoma was significantly higher (52.1%) than that in the neighboring glands without p53 expression (36.5%) (p<0.05). The results indicate that the abnormal expression of p53 in colorectal adenomas may reflect a failure in the control of cell proliferation. Furthermore, lack of the association of p53 expression with proliferative activity in colorectal carcinomas implies that several gene alterations together with p53 may be responsible for the complete loss of the regulatory mechanism for cell proliferation. PMID- 21584616 TI - Invitro synergism between a novel amphibian oocytic ribonuclease (onconase(r)) and tamoxifen, lovastatin and Cisplatin, in human ovcar-3 ovarian-carcinoma cell line. AB - In vitro tumor cell growth inhibitory and cytotoxic synergisms between a novel amphibian oocytic ribonuclease (ONCONASE)(ONC) and tamoxifen (TMX), lovastatin (LVT) and cisplatin (CDDP), have been observed in the human, estrogen and androgen receptor positive, chemotherapy-resistant NIH-OVCAR-3 ovarian carcinoma cell line. In view of the fact that the resistance to the available systemic chemotherapy represents one of the most important causes of treatment failure in patients with advanced ovarian cancer, the observed various forms of combination therapy synergisms suggest that these regimens could be tested in vivo, including human clinical trials. Particularly important are findings of significant synergistic tumor cell growth inhibitory and cytotoxic activities exerted by the combination of ONC with CDDP; NIH-OVCAR-3 cells are reportedly resistant to the latter. Of specific interest are the observed synergisms between ONC and TMX and between ONC and LVT, an inhibitor of the 3-hydroxy-3- methyl-glutaryl-CoA reductase which is a rate-limiting enzyme in the mevalonate/cholesterol synthesis pathway. A facilitation of apoptosis-induction by the drug combinations presently studied is discussed as a possible mechanism of the observed synergisms. PMID- 21584617 TI - Liver adenosquamous carcinoma invading the esophagogastric junction - a case report and a review of the literature. AB - A case of adenosquamous carcinoma of the liver involving the esophago-gastric junction is reported. The preoperative diagnosis of a submucosal tumor of the cardia of the stomach was made following a barium meal study, gastrofiberscopy, ultrasonography, and computed tomography. At surgery, a tumor was found measuring 6x5 cm in diameter and involving the left lobe of the liver, lower esophagus and cardia of the stomach, and the origin of the tumor was unclear. Post-operative histopathology revealed that the tumor contained two different malignant components of glandular and squamous cells. An adenosquamous carcinoma originating in the liver was suspected, since the cancer cells did not involve the esophago-gastric mucosa and were mainly located in the S2 of the liver. Despite aggressive adjuvant chemotherapy, the patient died of a recurrence in the liver seven months later. This seems to be the first documentation of adenosquamous carcinoma of the liver invading the esophago-gastric junction. PMID- 21584618 TI - Changes in plasma iron levels following Carboplatin administration. AB - Carboplatin-induced changes in plasma iron levels and the related erythropoiesis impairment were investigated in 32 neoplastic patients for a total of 64 courses of chemotherapy. Iron showed a significant increase over pretreatment levels starting from day 1 after carboplatin administration (p< 0.001). Return to pre treatment levels was achieved on day 14. Hemoglobin decreased significantly on day 7 (p< 0.05) and further on days 14 and 21 (p< 0.001). In patients undergoing 3 consecutive cycles of chemotherapy, basal hemoglobin before the 2nd cycle was significantly lower than before the 1st (p< 0.05), whereas before the 3rd cycle the levels were similar to those before the 2nd. Hemoglobin time-course did not differ among the three cycles. No relationship was observed between maximum iron levels and hemoglobin at minimum levels, nor between pre-treatment hemoglobin levels and severity of chemotherapy-induced subacute anemia. These results suggest that neither pre-treatment hemoglobin nor the entity of iron increase are predictive of the need of blood transfusion. Moreover, the absence of correlation between iron increase and hemoglobin decrease suggests that the toxic block on erythroid maturation is not the only mechanism with which platinum compounds interfere with iron metabolism. It is possible that the bivalent platinum ion may displace competitively iron from its binding sites, either on proteins or on cells. PMID- 21584619 TI - Intraoperative radiation-therapy combined with hyperthermia for pancreatic carcinoma. AB - Seventeen patients with pancreatic carcinoma were treated with intraoperative radiation therapy (IORT) combined with hyperthermia. Their treatment results were compared with those of 56 patients treated with the IORT alone (control group). The pain relief rate and the local tumor control rate of the hyperthermia group were slightly better than the control group. The survival rate of all patients was 13.7% at one year, 1.4% at two years (median, 5.0 months). The survival of the hyperthermia group was marginally better than that of the control group. Only 29% of the patients of the hyperthermia group was successfully heated, and if hyperthermia were given successfully to all patients, their prognoses would have been possibly improved. PMID- 21584620 TI - Immunomodulation by adriamycin - effect on the production of cytotoxic and inflammatory antitumor immune-responses. AB - We have recently demonstrated in a mouse renal adenocarcinoma tumor system that the antitumor effect of adriamycin (ADM) in combination with interleukin-2 (IL2) is superior to treatment with either ADM or IL2 alone. Based on this observation we postulated that modulation of host's immune competence by ADM and/or IL2 may be partly responsible for the antitumor effects of the combination treatment. Indeed, pretreatment with ADM was found to potentiate the production of both cytotoxic and non-cytotoxic immune responses. A single dose of ADM significantly increased the number of nucleated cells in the spleen in a time related fashion. A small but selective increase in CD4+ cells without an apparent change in CD8+ subset of T cells was observed following treatment with ADM. ADM potentiated augmentation of NK activity by IL2, but had no effect on the production of lymphokine activated killer (LAK) cells by IL2. In contrast, treatment with a combination of ADM and IL2 resulted in increased LAK activity and the frequency of LAK-precursors in the spleen. ADM also enhanced the development of tumor specific inflammatory delayed hypersensitivity (DH) response. Mice expressing tumor specific DH were resistant to rechallenge with viable tumor cells and their spleen cells inhibited the tumor growth in a local adoptive transfer assay. Thus, antitumor effects of combined ADM/IL2 treatment may in part involve augmented production of cytotoxic and T cell-mediated inflammatory antitumor immune responses. PMID- 21584621 TI - Effects of inhibitors of topoisomerases-I and topoisomerases-ii on DNA methylation and DNA-synthesis in human colonic adenocarcinoma cells-invitro. AB - Exposure of human and animal cells to inhibitors of topoisomerase I or II has recently been shown to alter gene expression and induce differentiation in a number of experimental systems. We have previously shown that nalidixic acid and novobiocin, inhibitors of topoisomerase II, induce DNA hypomethylation. Since DNA hypomethylation is frequently associated with transcriptional activation, we wished to further explore the relationship between inhibition of DNA topoisomerases and enzymatic DNA methylation. When HT-29 human colonic adenocarcinoma cells were exposed to the specific topoisomerase II inhibitor teniposide (VM-26), a dose-dependent hypomethylation of DNA was observed during the window of drug treatment. Exposure to the topoisomerase I inhibitor camptothecin (CPT) produced a small but not statistically significant trend toward DNA hypomethylation. CPT-treated cells were found to have up to 19 fold increased levels of topoisomerase II protein, which may have compensated for decreased levels of non-drug-bound topoisomerase I. Both VM-26 and CPT were found to increase [H-3]thymidine incorporation into DNA when administered in low dose (0.5 muM VM-26; 8 nM CPT). Combination of VM-26 and CPT (0.5 muM and 8 nM, respectively) produced DNA hypomethyltion, a synergistic increase in [H 3]thymidine incorporation, and an increasing number of cells entering a higher DNA ploidy cycle. Since VM-26 interferes with the DNA strand breakage-reunion reaction by stabilizing a topoisomerase II-relaxed DNA complex, our results suggest that DNA existing in this form may be a poor substrate for DNA methylase. Topoisomerase inhibitor-induced DNA hypomethylation may offer a possible explanation for the induction of differentiation observed upon exposure to this family of drugs. Altered topoisomerase activity occurring during the process of tumor progression may also provide a link between the induction of polyploidy, DNA hypomethylation and aberrant gene expression frequently observed in tumor cells. PMID- 21584622 TI - Expression of her-2/neu oncogene in breast-cancer - correlation of quantitative immunocytochemistry and prognostic factors. AB - HER-2/neu oncogene expression by breast carcinomas (n = 208) was investigated on frozen sections using monoclonal anti-p185 HER-2/neu protein. Results were evaluated by computer-assisted image analysis and correlated with morphological prognostic factors, hormone receptor antigenic sites, Ki 67 antigen and cathepsin content, nuclear morphometry, DNA content and Ag NORs, which were also evaluated by image analysis. All tumors were anti-p185 HER-2/neu immunoreactive, but in 40% of the cases, less than 20% of the tumor cell surface was immunostained. In terms of both extent and intensity, immunostaining which was greatest in comedocarcinomas correlated with tumor size (p = 0.019) and Ki 67 (p = 0.0012) and cathepsin (p<0.0001) content. No correllation was found with tumor grade, axillary lymph node involvement, hormone receptor sites, nuclear DNA content and Ag NORs distribution and morphometry. PMID- 21584623 TI - Mitochondria as a target for combination cancer-chemotherapy. AB - The purpose of this study was to examine whether mitochondria could be used as a potential target for combination cancer chemotherapy. Mitochondrial specific agents, namely Dequalinium chloride and Rhodamine 123 were tested as single agent and in combination with cis-diammine dichloroplatinum (II). Combination of either cis-diammine dichloroplatinum (II) and Rhodamine 123 or cis-diammine dichloroplatinum (II) and Dequalinium chloride showed that there was a synergistic action. However, combination of Rhodamine 123 and Dequalinium chloride showed a slight antagonistic activity which could be due to competition for the same site. The data also show that a much lower dose of cisplatin is required to produce an equieffective-response when used in combination with Dequalinium chloride and thus may lower the cis-diammine dichloroplatinum (II) induced toxicities. PMID- 21584624 TI - The impact of light fingertip touch on haptic cortical processing during a standing balance task. AB - Availability of fingertip touch onto a stable surface reduces body sway for subjects standing with eyes closed. This is largely associated with sensory feedback from the fingertip when mechanical load is limited. Here, it is possible that the central nervous system facilitates cortical sensory processing to augment feedback to control upright stance. To test this, we compared cortical sensory excitability between tasks with and without light finger touch while standing. Subjects stood in tandem on a force plate with eyes closed while lightly touching a stable surface with the index finger. This was, in two different studies, compared to: (1) no haptic contact or (2) light touch on an object not referenced to balance. Throughout testing, the median nerve was stimulated and electroencephalography was used to measure somatosensory evoked potentials (SEPs). As expected, availability of stable light touch reduced medial lateral COP sway. Peak amplitudes for SEP components revealed reduced P100 (48%), but increased P50 (31%), N140 (80%), and P200 (20%) during stable touch versus no touch. The modulation of P50 and N140 was no longer present when comparing stable to control (touch), which suggested that attending to touch on either surface, regardless of stability reference, accounted for these changes. Conversely, P200 was increased (19%) when touching the stable surface. Our data show SEP modulation during a standing balance task related to hand contact. Facilitation of P200 in particular may indicate task-specific regulation of the cortical representation of fingertip afferent input when it is relevant to providing stable cues for static balance control. PMID- 21584625 TI - Electroencephalographic coherence, aging, and memory: distinct responses to background context and stimulus repetition in younger, older, and older declined groups. AB - The current study examines the EEG coherence of young, old, and old declined adults performing a visual paired-associates task. In order to examine the effects of encoding context and stimulus repetition, target pairs were presented on either detailed or white backgrounds and were repeatedly presented during both early and late phases of encoding. Younger adults were found to have lower levels of frontal-temporal and temporal-parietal coherence, but higher levels of frontal parietal coherence, particularly for the gamma frequency band. A number of differential coherence responses to background context and early- versus late encoding phases were also observed across the groups, particularly for lower alpha and upper alpha frequencies. Coherence-performance maps were generated to further explore topographical differences in the relationship between coherence and performance across groups. Results revealed a more diffuse pattern of negative coherence-performance relations in older declined adults. Results are discussed in light of the literature on age-related cognitive decline. PMID- 21584626 TI - Electrophysiological correlates of facial configuration and audio-visual congruency: evidence that face processing is a visual rather than a multisensory task. AB - Behavioural, neuroimaging and lesion studies show that face processing has a special role in human perception. The purpose of this EEG study was to explore whether auditory information influences visual face perception. We employed a 2 * 2 factorial design and presented subjects with visual stimuli that could be cartoon faces or scrambled faces where size changes of one of the components, the mouth in the face condition, was either congruent or incongruent with the amplitude modulation of a simultaneously presented auditory signal. Our data show a significant main effect for signal congruence at an ERP peak around 135 ms and a significant main effect of face configuration at around 200 ms. The timing and scalp topology of both effects corresponds well to previously reported data on the integration of non-redundant audio-visual stimuli and face-selective processing. Our analysis did not show any significant statistical interactions. This double disassociation suggests that the early component, at 135 ms, is sensitive to auditory-visual congruency but not to facial configuration and that the later component is sensitive to facial configuration but not to AV congruency. We conclude that facial configurational processing is not influenced by the congruence of simultaneous auditory signals and is independent from featural processing where we see evidence for multisensory integration. PMID- 21584627 TI - Multisensory adaptation of spatial-to-motor transformations in children with developmental coordination disorder. AB - Recent research has demonstrated that adaptation to a visuomotor distortion systematically influenced movements to auditory targets in adults and typically developing (TD) children, suggesting that the adaptation of spatial-to-motor transformations for reaching movements is multisensory (i.e., generalizable across sensory modalities). The multisensory characteristics of these transformations in children with developmental coordination disorder (DCD) have not been examined. Given that previous research has demonstrated that children with DCD have deficits in sensorimotor integration, these children may also have impairments in the formation of multisensory spatial-to-motor transformations for target-directed arm movements. To investigate this hypothesis, children with and without DCD executed discrete arm movements to visual and acoustic targets prior to and following exposure to an abrupt visual feedback rotation. Results demonstrated that the magnitudes of the visual aftereffects were equivalent in the TD children and the children with DCD, indicating that both groups of children adapted similarly to the visuomotor perturbation. Moreover, the influence of visuomotor adaptation on auditory-motor performance was similar in the two groups of children. This suggests that the multisensory processes underlying adaptation of spatial-to-motor transformations are similar in children with DCD and TD children. PMID- 21584628 TI - To use or to move: goal-set modulates priming when grasping real tools. AB - How we interact with objects depends on what we intend to do with them. In the current work, we show that priming and the kinematics of grasping depend on the goals of grasping, as well as the context in which tasks are presented. We asked participants to grasp familiar kitchen tools in order to either move them, grasp to-move (GTM), or to demonstrate their common use, grasp-to-use (GTU). When tasks were blocked separately (Experiment 1), we found that priming was only evident for the GTU task. However, when tasks were presented in the same block of trials (Experiment 2), we observed priming for both tasks. Independent of priming, differences in kinematics and reaction times according to task were evident for both Experiments. Longer reaction times for the GTU task indicate more extensive planning, and differences in grasping reflect the characteristics of subsequent actions. Priming of real grasping is determined by task goals as well as task setting, both of which are likely to modulate how object features (affordances) are perceived and influence the planning of future actions. PMID- 21584629 TI - In vitro and in vivo trypanocidal activity of native plants from the Yucatan Peninsula. AB - Ethanol extracts of Senna villosa, Serjania yucatanensis, Byrsonima bucidaefolia, and Bourreria pulchra were evaluated for their in vitro activity against epimastigotes and trypomastigotes of Trypanosoma cruzi. Results showed that the leaf extracts of S. yucatanensis and B. pulchra were the most active against epimastigotes (IC(100) = 100 MUg/mL) and trypomastigotes of T. cruzi (95% or more reduction in the number of parasites at 100 and 50 MUg/mL). However, only the leaf extract of S. yucatanensis showed significant trypanocidal activity when tested in vivo, reducing 75% of the parasitemia in infected mice at 100 mg/kg. This same extract inhibited the egress of trypomastigotes from infected cells and proved not to be cytotoxic (IC(50) = 318.8 +/- 2.3 MUg/mL). PMID- 21584630 TI - Spermiogenesis and spermatozoon ultrastructure of the bothriocephalidean cestode Clestobothrium crassiceps (Rudolphi, 1819), a parasite of the teleost fish Merluccius merluccius (Gadiformes: Merlucciidae). AB - Spermiogenesis and the ultrastructure of the spermatozoon of the bothriocephalidean cestode Clestobothrium crassiceps (Rudolphi, 1819), a parasite of the teleost fish Merluccius merluccius (Linnaeus, 1758), have been studied by means of transmission electron microscopy. Spermiogenesis involves firstly the formation of a differentiation zone. It is characterized by the presence of two centrioles associated with striated rootlets, an intercentriolar body and an electron-dense material in the apical region of this zone. Later, two flagella develop from the centrioles, growing orthogonally in relation to the median cytoplasmic process. Flagella then undergo a rotation of 90 degrees until they become parallel to the median cytoplasmic process, followed by the proximodistal fusion of the flagella with the median cytoplasmic process. The nucleus elongates and afterwards it migrates along the spermatid body. Spermiogenesis finishes with the appearance of the apical cone surrounded by the single helical crested body at the base of the spermatid. Finally, the narrowing of the ring of arched membranes detaches the fully formed spermatozoon. The mature spermatozoon of C. crassiceps is filiform and contains two axonemes of the 9 + "1" trepaxonematan pattern, a parallel nucleus, parallel cortical microtubules, and electron-dense granules of glycogen. The anterior extremity of the gamete exhibits a short electron-dense apical cone and one crested body, which turns once around the sperm cell. The first axoneme is surrounded by a ring of thick cortical microtubules that persist until the appearance of the second axoneme. Later, these thick cortical microtubules disappear and thus, the mature spermatozoon exhibits two bundles of thin cortical microtubules. The posterior extremity of the male gamete presents only the nucleus. Results are discussed and compared particularly with the available ultrastructural data on the former "pseudophyllideans". Two differences can be established between spermatozoa of Bothriocephalidea and Diphyllobothriidea, the type of spermatozoon (II vs I) and the presence/absence of the ring of cortical microtubules. PMID- 21584631 TI - Myxobolus harikensis sp. nov. (Myxozoa: Myxobolidae) infecting fins of Cirrhina mrigala (Ham.)--an Indian major carp in Harike Wetland, Punjab (India). AB - During a study of myxosporean parasites of freshwater fishes of Punjab Wetlands, India, one new myxosporean species, Myxobolus harikensis sp. nov. was recorded from the caudal fin of Cirrhina mrigala (Ham.) (Cypriniformes: Cyprinidae). Plasmodia are small, white, spherical-to-rounded and are present on the caudal fin (in between the fin rays) having two to five spores per plasmodium. Spores of M. harikensis measure 10.1 * 8.5 MUm in size, pyriform in valvular view and lenticular in sutural view pointing in the direction to the plane of slightly bent sutural line. Shell valves are thick, smooth, asymmetric and flattened at the sutural plane. Parietal folds are absent. Polar capsules are two, prominently unequal, broadly pyriform-to-rounded in shape and lie at different levels in the spore body cavity. The larger polar capsule is 5.0 * 3.1 MUm in size, placed anteriorly on the sutural plane and opening to the exterior anteriolaterally. The smaller polar capsule measures 1.7 * 1.4 MUm in size, placed posteriorly, perpendicular to the sutural plane and opening to the exterior mediolaterally. Spores of M. harikensis closely resembles to that of Myxobolus africanus in having polar capsules placed at different levels in the spore body cavity, however, are unique in having unequal polar capsules both discharging laterally. PMID- 21584632 TI - Modulation of mouse macrophage proteome induced by Toxoplasma gondii tachyzoites in vivo. AB - Toxoplasma gondii is an obligate intracellular protozoan parasite, which can invade and multiply within the macrophages of humans and most warm-blooded animals. Macrophages are important effector cells for the control and killing of intracellular T. gondii, and they may also serve as long-term host cells for the replication and survival of the parasite. In the present study, we explored the proteomic profile of macrophages of the specific pathogen-free Kunming mice at 24 h after infection with tachyzoites of the virulent T. gondii RH strain using two dimensional gel electrophoresis combined with matrix-assisted laser desorption ionization time-of-flight (TOF)/TOF tandem mass spectrometry. Totally, 60 differentially expressed protein spots were identified. Among them, 52 spots corresponded to 38 proteins matching to proteins of the mouse, including actin, enolase, calumenin, vimentin, plastin 2, annexin A1, cathepsin S, arginase-1, arachidonate 12-lipoxygenase, and aminoacylase-1. Functional prediction using Gene Ontology database showed that these proteins were mainly involved in metabolism, structure, protein fate, and immune responses. The findings provided an insight into the interactive relationship between T. gondii and the host macrophages, and will shed new lights on the understanding of molecular mechanisms of T. gondii pathogenesis. PMID- 21584633 TI - Reduced thrombin generation and soluble P-selectin after intravenous enoxaparin during PCI. AB - PURPOSE: The objective of our study was to identify changes in the coagulation and serum concentration of soluble P-selectin (sP-sel) after i.v. bolus of 0.75 mg/kg enoxaparin in a group of 33 patients during PCI. METHODS AND RESULTS: As compared to baseline, i.v. enoxaparin increased anti -Xa activity and FIIa inhibition together with APTT and thrombin time tests within 20 min, that persisted for 60 min. At 6 h, the results of all tests had returned to baseline. In contrast, the level of prothrombin fragments (F1 + 2) decreased persistingly for a period of 6 h (baseline 1.19 +/- 0.42 nmol/l, after 20 min 1.03 +/- 0.46 nmol/l, after 60 min 1.06 +/- 0.43 nmol/l, after 6 h 0.95 +/- 0.40 nmol/l, p < 0.001 vs. baseline for all values). In addition, i.v. enoxaparin decreased serum sP-sel level (baseline 111.80 +/- 37.05 ng/ml, after 20 min 87.80 +/- 33.17 ng/ml, after 60 min 86.45 +/- 29.15 ng/ml, after 6 h 92.24 +/- 31.34 ng/ml, p < 0.001 vs. baseline value for all). sP-sel level mildly correlated with both F Xa inhibition (r = -0.275, p < 0.05) and F1 + 2 level (r = 0.274, p < 0.05). CONCLUSION: Intravenous enoxaparin induced target F Xa inhibition (>0.6 IU/ml) for 60 min in 82% of study patients. During the 6 h of monitoring, a decrease of thrombin generation (F1 + 2) and sP-selectin levels were observed. PMID- 21584634 TI - Prognostic implications of tumor vascularity and its relationship to cytokeratin 19 expression in patients with hepatocellular carcinoma. AB - OBJECTIVE: Although hepatocellular carcinoma (HCC) demonstrates characteristic hypervascularity, some HCCs have a hypovascular pattern on computed tomography (CT). Cytokeratin 19 (CK19) is a marker for the biliary phenotype reflecting a poor prognosis. We assessed the prognostic implications of tumor vascularity and its association with CK19 expression in HCC. METHODS: Patients that underwent surgical resection for HCC were included. Tumor vascularity was evaluated according to the arterial enhancement patterns on CT scans and CK19 expression was evaluated by using tissue microarray methods. RESULTS: One hundred and forty patients were included. Their median follow-up duration was 55.0 months, and 92 (65.7%) patients had tumor recurrence. Forty-five patients (30.6%) had hypovascular HCC at the time of diagnosis, and they showed a significantly higher CK19 expression rate (32.5% vs. 8.2%, P = 0.001) and earlier recurrence rate within 6 months (hazard ratio (HR), 2.301; P = 0.025) compared to the patients with hypervascular HCCs. Hypovascularity (HR, 1.694; P = 0.045) was an independent risk factor for short overall survival. CONCLUSIONS: Hypovascular HCCs were associated with early recurrence and short overall survival, and CK19 was more frequently expressed in hypovascular HCC than in hypervascular tumors. Therefore, tumor vascularity on CT images might be utilized in determining the prognosis of patients with HCCs. PMID- 21584635 TI - Arterial therapies of non-colorectal cancer metastases to the liver (from chemoembolization to radioembolization). AB - Treatment of primary and secondary hepatic malignancies with transarterial chemoembolization (TACE) represents an essential component of interventional oncology known for many years and performed by many interventional radiologists first in primary liver tumors and nowadays even in metastases of different origins. Radioembolization (RE) has been introduced to the clinical arsenal of cytoreductive modalities in recent years. There is growing evidence for efficiency in liver tumors of various entities, with the most prominent ones being hepatocellular carcinoma, colorectal cancer, and neuroendocrine tumors. Hepatic metastases of other tumor entities (breast cancer, malignant melanoma, and pancreatic cancer) are treatment-sensitive. This article focuses on procedural and technical aspects for selection, preparation, and performance of treatment as well as the results in metastatic breast cancer, neuroendocrine tumors, melanoma, and pancreatic cancer giving an overview of the results after RE, transarterial embolization, or TACE. PMID- 21584636 TI - Peri-intraprocedural imaging: US, CT, and MRI. AB - Imaging in liver interventional oncology plays a key role in the entire process starting from patient selection, leading to patient treatment and continuing with patient follow-up. Pre-procedural imaging evaluation is aimed to determine the indication for interventional therapies according to the size, number, and location of hepatic lesions, to the presence of major vascular invasion, nodal disease, and distant metastases, and to choose the most suitable approach according to tumor histology. Ideal qualities of a targeting technique include clear delineation of the tumor tissue and the surrounding anatomy, coupled with real-time imaging, multiplanar, and interactive capabilities. Moreover, the modality of image guidance should visualize therapy effects during the intervention to assess coverage of the targeted tissue and to prevent unintended thermal injury to critical structures in the surroundings of the target. Post treatment imaging is then imperative to evaluate response to therapy by assessing for residual or recurrent disease, revising prognosis, and guiding future therapy. In this article, the role of imaging in patient selection and treatment planning will be discussed. Recently amended RECIST (mRECIST) for evaluation of tumor response in hepatocellular carcinoma and specific treatment-related findings after thermal ablation, trans-arterial chemoembolization, and radioembolization will be reviewed. PMID- 21584637 TI - New acquisition techniques: fields of application. AB - Conventional MR imaging of the liver has a central role in the assessment of liver diseases. Diffusion-weighted MR imaging, MR elastography, and time-resolved dynamic contrast-enhanced MR imaging improve the anatomical information provided by conventional MR imaging and add quantitative functional information in diffuse and focal liver diseases. Particularly, accurate detection and characterization of liver fibrosis are feasible with quantitative MR elastography, detection of liver tumors is increased with diffusion-weighted MR imaging and time-resolved dynamic contrast-enhanced MR imaging, characterization of tumors can be improved with quantitative diffusion-weighted MR imaging and MR elastography. These methods also have the potential to provide adequate biomarkers for assessing the response to treatment. Currently, the main limitations of quantitative MR imaging are related to reproducibility, standardization, and/or limited clinical data. It is important to improve and standardize the quantitative MR methods and validate their role in large multicenter trials. PMID- 21584638 TI - Laparoscopic sleeve gastrectomy: a guide to postoperative anatomy and complications. AB - The purpose of this pictorial essay is to review the surgical technique, postoperative anatomy, and potential complications of the laparoscopic sleeve gastrectomy. As the laparoscopic sleeve gastrectomy becomes an increasingly popular bariatric surgery, it is important for radiologists to familiarize themselves with the procedure and possible complications. PMID- 21584639 TI - Remediation of polycyclic aromatic hydrocarbon (PAH) contaminated soil through composting with fresh organic wastes. AB - INTRODUCTION: Composting may enhance bioremediation of PAH-contaminated soils by providing organic substrates that stimulate the growth of potential microbial degraders. However, the influence of added organic matter (OM) together with the microbial activities on the dissipation of PAHs has not yet been fully assessed. MATERIALS AND METHODS: An in-vessel composting-bioremediation experiment of a contaminated soil amended with fresh wastes was carried out. Four different experimental conditions were tested in triplicate during 60 days using laboratory scale reactors: treatment S (100% soil), W (100% wastes), SW (soil/waste mixture), and SWB (soil/waste mixture with inoculation of degrading microorganisms). RESULTS AND DISCUSSION: A dry mass loss of 35 +/- 5% was observed in treatments with organic wastes during composting in all the treatments except treatment S. The dissipation of the 16 USEPA-listed PAHs was largely enhanced from no significant change to 50.5 +/- 14.8% (for SW)/63.7 +/- 10.0% (for SWB). More obvious dissipation was observed when fresh wastes were added at the beginning of composting to the contaminated soil, without significant difference between the inoculated and non-inoculated treatments. Phospholipid fatty acid (PLFA) profiling showed that fungi and G-bacteria dominated at the beginning of experiment and were probably involved in PAH dissipation. Subsequently, greater relative abundances of G + bacteria were observed as PAH dissipation slowed down. CONCLUSIONS: The results suggest that improving the composting process with optimal organic compositions may be a feasible remediation strategy in PAH-contaminated soils through stimulation of active microbial populations. PMID- 21584640 TI - The effect of continuous exposure of copper on the properties and extracellular polymeric substances (EPS) of bulking activated sludge. AB - INTRODUCTION: This study investigated the effect of copper on chemical oxygen demand (COD) removal efficiency and on the properties (mainly settling and dewatering) and the composition of extracellular polymeric substances (EPS) when 20 mg/L Cu(II) was continuously dosed to a sequencing batch reactor (SBR) inoculated with activated sludge. MATERIALS AND METHODS: The results showed that the continuous addition of 20 mg/L Cu(II) seriously inhibited the removal of sodium benzoate (provided as a model organic pollutant) by activated sludge in a SBR. RESULTS AND DISCUSSION: After 40 days of acclimation, the removal efficiency presented a slight but unsteady recovery and the settling and dewatering properties improved, indicating that sludge bulking had been inhibited. Additionally, the proportion of loosely bound EPS in the total EPS increased with time and the relative composition of the total organics was polysaccharide > humic substances > protein > DNA. CONCLUSION: The effects of copper on the composition of EPS and the settling and dewatering properties of bulking activated sludge were also discussed for the first time in this paper. PMID- 21584641 TI - Are menstrual and nonmenstrual migraine attacks different? AB - Migraine is the second most common headache condition next to tension-type headache. Up to one fourth of all women have migraine, and 20% of them experience migraine without aura attack in at least two thirds of their menstrual cycles. The current literature is analyzed in response to the question of whether menstrual and nonmenstrual migraine attacks are different. The different studies provide conflicting results, so it is not possible to answer the question firmly. Future studies should be based on the general population. Collection of both prospective and retrospective data is warranted, and headache diagnosis base on interviews by physicians with interest in headache are more precise than lay interviews or questionnaires. PMID- 21584642 TI - Enhancement of the osseointegration of a polyethylene terephthalate artificial ligament graft in a bone tunnel using 58S bioglass. AB - PURPOSE: The aim of the study was to investigate whether a bioactive glass (BG) coating on the polyethylene terephthalate (PET) artificial ligament could enhance graft osseointegration by promoting bone regeneration at the interface between PET graft and bone tunnel. METHODS: Thirty New Zealand white rabbits underwent artificial ligament graft transplantation in proximal tibial tunnels bilaterally. One limb was implanted with a 58S BG-coated PET graft, and the contralateral limb was implanted with a non-BG-coated PET graft as a control. The rabbits were randomly sacrificed at three, six and 12 weeks after surgery for biomechanical and histological examinations. RESULTS: The maximum load to failures of the BG coated experimental group were significantly higher than those of the control group at 12 weeks (p = 0.0051). Histologically, at 12 weeks, the BG-coated PET graft induced great new bone formation between graft and host bone, and the average graft-bone interface width of the BG group became significantly lower than that of the control group. Furthermore, the BG coating on the ligament graft surface also stimulated greater expression of bone morphogenetic protein 2 (BMP 2) and vascular endothelial growth factor (VEGF) around the graft in vivo compared to the control group at three weeks (p < 0.05). CONCLUSIONS: This study has shown that a BG coating on the PET artificial ligament surface has a positive effect in the induction of artificial ligament osseointegration within the bone tunnel. PMID- 21584643 TI - First experiences with negative pressure wound therapy and instillation in the treatment of infected orthopaedic implants: a clinical observational study. AB - PURPOSE: Infections associated with orthopaedic implants remain a serious complication. The main objective in acute infection control is component retention, whereas this option is usually not considered for chronic infections. METHODS: This multi-centre prospective, non-randomised observational study investigated one possible treatment option for implant retention in combination with negative pressure wound therapy with instillation (NPWTi). Thirty-two patients with an infected orthopaedic implant were analysed. Twenty-two patients had an acute infection (< 8 weeks after implantation) and ten patients had a chronic infection (> 8 weeks and < 36 weeks after implant placement). Polyhexanide was used as the instillation solution in 31 of the 32 cases. RESULTS: Nineteen patients (86.4%) with an acute infection and eight patients (80%) with a chronic infection retained their implant at 4-6 months follow-up after treatment. CONCLUSIONS: Our study showed that NPWTi can be used as adjunctive therapy for salvage of acutely infected orthopaedic implants and may even be considered for early chronically infected implants. PMID- 21584645 TI - Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. PMID- 21584644 TI - Angiographic embolisation of pelvic ring injuries. Treatment algorithm and review of the literature. AB - PURPOSE: The purpose of this study was to evaluate the relation between pelvic fracture patterns and the angiographic findings, and to assess the effectiveness of the embolisation. METHODS: This retrospective study, included patients with pelvic fractures and angiographic evaluation. Demographics, Injury Severity Score (ISS), associated injuries, embolisation time, blood units needed, method of treatment and complications were recorded and analysed. Fractures were classified according to the Burgess system. RESULTS: Between 1998 and 2008, 34 patients with pelvic fractures underwent angiographic investigation. Twenty six were males. The mean age was 41 years. Twenty-seven were motor vehicle accidents and seven were falls. There were 11 anterior posterior (APC) fractures, 12 lateral compression (LC), eight vertical shear (VS) patterns and three with combined mechanical injuries. The median ISS was 33.1 (range 5-66). From the 34 who underwent angiography, 29 had positive vascular extravasations. From them, 21 had embolisation alone, two had vascular repair and embolisation, five required vascular repair alone and one patient died while being prepared for embolisation. Five cases were re-embolised. The findings suggested that AP fractures have a higher tendency to bleeding compared with LC fractures. Both had a higher chance of blood loss compared to VS and complex fracture patterns. We reported 57 additional injuries and 65 fractures. The complications were: one non lethal pulmonary embolism, one renal failure, one liver failure, one systemic infection, two deep infections and two psychological disorientations. Seven patients died in hospital. CONCLUSION: Control of pelvic fracture bleeding is based on the multidisciplinary approach mainly related to hospital facilities and medical personnel's awareness. The morphology of the fracture did not have a predictive value of the vascular lesion and the respective bleeding. PMID- 21584646 TI - Systemic therapy options for unresectable and metastatic chordomas. AB - Chordoma is an exceedingly rare tumor, marked by a slow growth rate. Surgery is the treatment of choice, but the most frequent sites of origin (spine and skull base) make treatment of primary disease challenging. Local relapses affect more than 50% of cases, with a minority of patients being cured by further surgery. Furthermore, metastases occur in at least 20% of patients. For residual or recurrent disease, high-dose radiation therapy may be indicated. Radiation therapy is currently the preferred local treatment when surgery is problematic, exploiting most recent techniques, including proton beams and carbon ions. However, systemic therapy is needed in patients non-amenable to surgery and/or radiation therapy. We reviewed systemic treatments currently available, and targets possibly druggable in the future in this orphan disease. PMID- 21584647 TI - Maxillary sinus floor elevation using BMP-2 and Nell-1 gene-modified bone marrow stromal cells and TCP in rabbits. AB - This study evaluated the synergistic osteogenic effect of bone morphogenetic protein-2 (BMP-2) and Nel-like molecule-1 (Nell-1) genes in a rabbit maxillary sinus floor elevation model. Bone marrow stromal cells (bMSCs) were cultured and transduced with AdEGFP, AdNell-1, AdBMP-2, or AdNell-1 + AdBMP-2 overexpression virus. These gene-modified autologous bMSCs were then combined with a beta tricalcium phosphate (beta-TCP) granule scaffold and used to elevate the maxillary sinus floor in rabbits. bMSCs cotransduced with AdNell-1 + AdBMP-2 demonstrated a synergistic effect on osteogenic differentiation as detected by real-time PCR analysis on markers of runt-related transcription factor-2, osteocalcin, collagen type 1, alkaline phosphatase activity, and calcium deposits in vitro. As for maxillary sinus floor elevation in a rabbit model in vivo, AdNell-1 + AdBMP-2 gene-transduced autologeous bMSCs/beta-TCP complex had the largest bone area and most mature bone structure among the groups, as detected by HE staining and immunohistochemistry at weeks 2 and 8 after implantation. Our data suggested that the BMP-2 and Nell-1 genes possessed a synergistic effect on osteogenic differentiation of bMSCs, while bMSCs modified with the BMP-2 and Nell 1 genes could promote new bone formation and maturation in the rabbit maxillary sinus model. PMID- 21584648 TI - Erasing injury-related cortical synaptic potentiation as a new treatment for chronic pain. AB - Synaptic plasticity in the spinal cord and the cortex is believed to be important for the amplification of painful information in chronic pain conditions. The investigation of molecular mechanism responsible for maintaining injury-related plastic changes, such as through the study of long-term potentiation in these structures, provides potential novel targets for designing new medicine for chronic pain. Recent studies using integrative neurobiological approaches demonstrate that protein kinase M zeta (PKMzeta) maintains pain-induced persistent changes in the anterior cingulate cortex (ACC), and inhibiting PKMzeta by zeta-pseudosubstrate inhibitory peptide produces analgesic effects in animal models of chronic pain. We propose that targeting PKMzeta, or its up- or downstream signaling proteins, in the ACC may provide novel clinical treatment for chronic pain. PMID- 21584649 TI - Synaptology of ventral CA1 and subiculum projections to the basomedial nucleus of the amygdala in the mouse: relation to GABAergic interneurons. AB - GABAergic neurons of the amygdala are thought to play a critical role in establishing networks for feedback and feedforward inhibition and in mediating rhythmic network activity patterns relevant for emotional behavior, determination of stimulus salience, and memory strength under stressful experiences. These functions are typically fulfilled in interplay of amygdala and hippocampus. Therefore, we explored the putative connectivity of GABAergic neurons with the hippocampo-amygdalar projection with the anterograde tracers Phaseolus vulgaris leucoagglutinin (Phal) and Miniruby injected to GAD67-GFP knock-in mice in which GABAergic neurons are labeled by the expression of the gene for green fluorescent protein (GFP) inserted to the GAD1 gene locus (Tamamaki et al. J Comp Neurol 467:60-79, 2003). We found that, while hippocampal axons target all nuclei of the amygdala, the densest fiber plexus was found in the posterior basomedial nucleus. Electron microscopy revealed that the vast majority of contacts in this nucleus were formed by thin fibers making small asymmetrical contacts, predominantly on GFP-negative profiles. However, several asymmetrical contacts could also be seen on GFP-positive profiles. A surprising result was the occasional occurrence of anterogradely labeled symmetrical synapses indicating a GABAergic contribution to the projection from the hippocampus to the amygdala. While hippocampal input to the amygdala appears to be largely excitatory and targets non-GABAergic neurons, our data provide evidence for a direct involvement of GABAergic neurons in the interplay of these regions, either as target in the amygdala or as projection neurons from the hippocampus. These particular "interface neurons" may be of relevance for the information processing in the amygdalo-hippocampal system involved in emotional behavior and memory formation. PMID- 21584651 TI - Eating disturbance in behavioural-variant frontotemporal dementia. AB - Behavioural-variant frontotemporal dementia (bvFTD) is a progressive neurodegenerative brain disorder, clinically characterised by changes in cognition, personality and behaviour. Marked disturbances in eating behaviour, such as overeating and preference for sweet foods, are also commonly reported. This paper reviews the current literature on eating abnormalities in bvFTD, their clinical characteristics and biological correlates, and the contribution of hypothalamus to eating regulation. Existing literature shows that disturbance in an orbitofrontal-insular-striatal brain network underlies the emergence of eating disturbance in bvFTD. In addition, recent evidence indicates that degeneration and consequent dysregulation within the hypothalamus relates to significant feeding disturbance in this disease. These findings could provide a basis for the development of therapeutic models in bvFTD. PMID- 21584650 TI - New approaches to Prunus transcriptome analysis. AB - The recent sequencing of the complete genome of the peach offers new opportunities for further transcriptomic studies in Prunus species in the called post-genomics era. First works on transcriptome analysis in Prunus species started in the early 2000s with the development of ESTs (expressed sequence tags) and the analysis of several candidate genes. Later, new strategies of massive analysis (high throughput) of transcriptomes have been applied, producing larger amounts of data in terms of expression of a large number of genes in a single experiment. One of these systems is massive transcriptome analysis using cDNA biochips (microarrays) to analyze thousands of genes by hybridization of mRNA labelled with fluorescence. However, the recent emergence of a massive sequencing methodology ("deep-sequencing") of the transcriptome (RNA-Seq), based on lowering the costs of DNA (in this cases complementary, cDNA) sequencing, could be more suitable than the application of microarrays. Recent papers have described the tremendous power of this technology, both in terms of profiling coverage and quantitative accuracy in transcriptomic studies. Now this technology is being applied to plant species, including Prunus. In this work, we analyze the potential in using this RNA-Seq technology in the study of Prunus transcriptomes and the development of genomic tools. In addition, the strengths and limitations of RNA-Seq relative to microarray profiling have been discussed. PMID- 21584652 TI - Variably protease-sensitive prionopathy: a novel disease of the prion protein. AB - Variably protease-sensitive prionopathy (VPSPr) is a novel disease involving the prion protein (PrP) that has clinical similarities with non-Alzheimer's dementias especially frontotemporal dementia, diffuse Lewis body disease, and normal pressure hydrocephalus. VPSPr can be distinguished from sporadic Creutzfeldt Jakob disease (sCJD) especially for the characteristics of the abnormal PrP. Furthermore, although VPSPr like sCJD affects patients with the three PrP genotypes as determined by the common methionine/valine polymorphism, the allelic prevalence is very different in the two diseases. These findings suggest that VPSPr is basically different from classical prion diseases such as sCJD being perhaps more akin to other neurodegenerative dementias. PMID- 21584653 TI - Aspirin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity in primary midbrain cultures. AB - Aspirin (ASA) is one of the most widely used nonsteroidal anti-inflammatory drugs. ASA has primarily been used to treat headaches, rheumatic pain, and inflammation, but its therapeutic effects have recently been demonstrated on a range of disorders, including those of the central nervous system. In this study, we investigated whether ASA is neuroprotective in inflammation-mediated neurodegenerative diseases. Pretreatment with ASA reduced the lipopolysaccharide (LPS)-induced degeneration of dopaminergic (DA) neurons in mesencephalic neuron glia cultures in a dose-dependent manner. The neuroprotective effect of ASA was attributed to the inhibition of microglial activation because of its observed inhibitory effects on LPS-stimulated nitric oxide, tumor necrosis factor-alpha, and superoxide production by microglial cells. Moreover, ASA increased the production of the anti-inflammatory cytokines transforming growth factor beta-1 and interleukin-10 in neuron-glia cultures after stimulation with LPS. Mechanistic studies revealed that the neuroprotective effects of ASA were mediated through the inhibition of nicotinamide adenine dinucleotide phosphate oxidase (PHOX), a key enzyme for superoxide production in microglia. These results suggest that ASA protects DA neurodegeneration by inhibiting the microglial-mediated oxidative stress/inflammatory response and by regulating the production of anti-inflammatory cytokines. PMID- 21584654 TI - Estimating the number of persons with frontotemporal lobar degeneration in the US population. AB - There are many challenges for determining the prevalence and incidence of frontotemporal lobar degenerations (FTLD). Consequently, the number of cases of behavioral variant frontotemporal dementia (bvFTD) or primary progressive aphasia (PPA) in the USA is unknown. Our objective was to derive a consensus estimate of bvFTD and PPA prevalence and thereby to estimate the total number of these syndromes in the USA. We identified five prevalence and three incidence studies of FTLD based on passive surveillance and seven studies of survival in FTLD. Data from these studies were used to estimate the number of cases of PPA or bvFTD in the USA. Because prevalence and incidence estimates outside of the 45-64-year age range were either not available or widely divergent, we used data from clinical and pathological series to estimate the proportion of FTLD cases aged <45 or >64 years. The prevalence estimates in the age categories of 45-64 years old have ranged from 15 to 22 per 100,000 person-years in studies where both bvFTD and PPA were identified. The incidence estimates for the same age group ranged from 2.7 to 4.1 per 100,000 person-years. Using a survival rate of 6 to 9 years from onset and rates from the incidence studies, a calculated prevalence estimate (prevalence = incidence * duration) was similar to the previously reported prevalence rates. We estimated that 10% of cases were less than age 45 years and 30% were 65 years and older. We estimate that there are approximately 20,000 to 30,000 cases of the cognitive syndromes of FTLD in the USA. The main threat to the accuracy of the estimates is the difficulty in diagnosing the clinical syndromes that comprise the FTLD group of disorders. PMID- 21584655 TI - alpha-Crystallin promotes rat axonal regeneration through regulation of RhoA/rock/cofilin/MLC signaling pathways. AB - Intravitreal injection of alpha-crystallin can promote axons from optic nerve regeneration after crushing in rats. We have previously demonstrated that alpha crystallin can counteract the effect of myelin inhibitory factors and stimulate neurite growth. And a common crucial signaling event for myelin inhibitory factors is the activation of RhoA. To investigate whether alpha-crystallin counteracts the inhibitory effect of myelin inhibitory factors through regulation of RhoA/Rock signaling pathway, alpha-crystallin (10(-4) g/L) was injected into rat vitreous at the time the optic nerve crushed. The RhoA protein activity and the expression of RhoA and Rock were evaluated after 3 days of optic nerve axotomy. Rock downstream effectors, phosphorylated cofilin, and phosphorylated myosin light chain were detected when retinal neurons were cultured for 3 days. Axonal regeneration and neurites growth of cultured cells were observed also. Our results showed that alpha-crystallin decreased the RhoA protein activity and the phosphorylation of both cofilin and myosin light chain, and promoted the axonal growth. However, the expression of RhoA and Rock was not affected by alpha crystallin. These findings indicated that alpha-crystallin could counteract the effect of myelin inhibitory factors through the regulation of RhoA/Rock signaling pathway. PMID- 21584656 TI - RNA integrity in post-mortem samples: influencing parameters and implications on RT-qPCR assays. AB - Messenger RNA (mRNA) profiling in post-mortem human tissue might reveal information about gene expression at the time point of death or close to it. When working with post-mortem human tissue, one is confronted with a natural RNA degradation caused by several parameters which are not yet fully understood. The aims of the present study were to analyse the influence of impaired RNA integrity on the reliability of quantitative gene expression data and to identify ante- and post-mortem parameters that might lead to reduced RNA integrities in post-mortem human brain, cardiac muscle and skeletal muscle tissues. Furthermore, this study determined the impact of several parameters like type of tissue, age at death, gender and body mass index (BMI), as well as duration of agony, cause of death and post-mortem interval on the RNA integrity. The influence of RNA integrity on the reliability of quantitative gene expression data was analysed by generating degradation profiles for three gene transcripts. Based on the deduced cycle of quantification data, this study shows that reverse transcription quantitative polymerase chain reaction (RT-qPCR) performance is affected by impaired RNA integrity. Depending on the transcript and tissue type, a shift in cycle threshold values of up to two cycles was observed. Determining RNA integrity number of 136 post-mortem samples revealed significantly different RNA qualities among the three tissue types with brain revealing significantly lower integrities compared to skeletal and cardiac muscle. The body mass index was found to influence RNA integrity in skeletal muscle tissue (M. iliopsoas). Samples originating from deceased with a BMI > 25 were of significantly lower integrity compared to samples from normal weight donors. Correct data normalisation was found to partly diminish the effects caused by impaired RNA quality. Nevertheless, it can be concluded that in post-mortem tissue with low RNA integrity numbers, the detection of large differences in gene expression activities might still be possible, whereas small expression differences are prone to misinterpretation due to degradation. Thus, when working with post mortem samples, we recommend generating degradation profiles for all transcripts of interest in order to reveal detection limits of RT-qPCR assays. PMID- 21584657 TI - Alternative surgical approaches in epilepsy. AB - The mainstay of epilepsy surgery is the resection of a presumed seizure focus or disruption of seizure propagation pathways. These approaches cannot be applied to all patients with medically refractory epilepsy (MRE). Since 1997, vagus nerve stimulation has been a palliative adjunct to the care of MRE patients. Deep brain stimulation (DBS) in select locations has been reported to reduce seizure frequency in small studies over the past three decades. Recently published results from the SANTE (Stimulation of the Anterior Nuclei of Thalamus for Epilepsy) trial-the first large-scale, randomized, double-blind trial of bilateral anterior thalamus DBS for MRE-demonstrate a significant reduction in seizure frequency with programmed stimulation. Another surgical alternative is the RNSTM System (NeuroPace, Mountain View, CA), which uses a closed-loop system termed responsive neurostimulation to both detect apparent seizure onsets and deliver stimulation. Recently presented results from the RNSTM pivotal trial demonstrate a sustained reduction in seizure frequency with stimulation, although comprehensive trial results are pending. PMID- 21584658 TI - Magnesium supplementation through seaweed calcium extract rather than synthetic magnesium oxide improves femur bone mineral density and strength in ovariectomized rats. AB - Commercially available seaweed calcium extract can supply high amounts of calcium as well as significant amounts of magnesium and other microminerals. The purpose of this study was to investigate the degree to which the high levels of magnesium in seaweed calcium extract affects the calcium balance and the bone status in ovariectomized rats in comparison to rats supplemented with calcium carbonate and magnesium oxide. A total of 40 Sprague-Dawley female rats (7 weeks) were divided into four groups and bred for 12 weeks: sham-operated group (Sham), ovariectomized group (OVX), ovariectomized with inorganic calcium and magnesium supplementation group (OVX-Mg), and ovariectomized with seaweed calcium and magnesium supplementation group (OVX-SCa). All experimental diets contained 0.5% calcium. The magnesium content in the experimental diet was 0.05% of the diet in the Sham and OVX groups and 0.1% of the diet in the OVX-Mg and OVX-SCa groups. In the calcium balance study, the OVX-Mg and OVX-SCa groups were not significantly different in calcium absorption compared to the OVX group. However, the femoral bone mineral density and strength of the OVX-SCa group were higher than those of the OVX-Mg and OVX groups. Seaweed calcium with magnesium supplementation or magnesium supplementation alone did not affect the serum ALP and CTx levels in ovariectomized rats. In summary, consumption of seaweed calcium extract or inorganic calcium carbonate with magnesium oxide demonstrated the same degree of intestinal calcium absorption, but only the consumption of seaweed calcium extract resulted in increased femoral bone mineral density and strength in ovariectomized rats. Our results suggest that seaweed calcium extract is an effective calcium and magnesium source for improving bone health compared to synthetic calcium and magnesium supplementation. PMID- 21584659 TI - Long-term selenium deficiency increases the pathogenicity of a Citrobacter rodentium infection in mice. AB - Citrobacter rodentium is a mouse pathogen that causes infectious colitis and shares characteristics with human enteropathogenic (EPEC) and enterohemorrhagic (EHEC) Escherichia coli, including the ability to cause attaching and effacing lesions in the colon and serves as a useful model to study the pathogenicity of these bacteria. In this study, mice were fed a selenium-deficient diet for 5 or 20 weeks and then infected with C. rodentium. Colonization of the colon by C. rodentium was similar in mice fed adequate or selenium-deficient diets, but total bacterial colonization of the spleen was elevated in mice fed selenium-deficient diet for 20 weeks. Infection-induced changes to the colon included inflammatory cell infiltration, gross changes in crypt architecture, and ulceration and denuding of the epithelial layer that were greatest in mice fed a selenium deficient diet for 20 weeks. Expression of pro-inflammatory genes was significantly higher 12-days post-infection in mice fed the selenium-deficient diet for 20 weeks compared to mice fed a selenium-adequate diet or selenium deficient diet for 5 weeks. Diarrhea was prevalent in mice fed the selenium deficient diet for 20 weeks but not 5 weeks, and this was associated with decreased expression of solute carrier family 26a3 and carbonic anhydrase IV, genes involved in ion transport. These results indicated that selenium played an important role in resistance to the pathological effects of a C. rodentium infection, and therefore, selenium status may be important in the expression of human disease caused by common food-borne bacteria. PMID- 21584660 TI - Immunohistochemical expression of neuroendocrine secretory protein-55 (NESP-55) in pituitary adenomas. AB - Neuroendocrine secretory protein-55 (NESP-55) is a recently described member of the chromogranin family and appears to be a marker of the constitutive secretory pathway in certain neural, neuroendocrine, and endocrine cell types. It has been shown to be selectively expressed in tumors differentiating towards the adrenal chromaffin and pancreatic islet cell phenotypes. The highest levels of NESP-55 expression, at least in animals, appear to be in the adrenal medulla and the pituitary gland. However, very little is known about the status of NESP-55 expression in pituitary adenomas. We therefore studied the immunohistochemical profile of NESP-55 expression in a series of 30 well-characterized pituitary adenomas (five each of FSH/LH and ACTH, four GH, three TSH, seven prolactin, and six null cells). All tumors were positive for one or more generic marker(s) (chromogranin A, synaptophysin, neuron-specific enolase) of neuroendocrine differentiation. All pituitary adenomas selected for study were stained for NESP 55 with appropriate positive and negative controls. NESP-55 immunoreactivity, seen as brown finely granular cytoplasmic staining of the tumor cells with prominent perinuclear accentuation, was graded as focal (<10% tumor cells staining), moderate (10-50% tumor cells staining), and diffuse (>50% tumor cell staining). Four of seven prolactinomas were positive for NESP-55 (one focal, two moderate, and one diffuse). Two of four GH adenomas were also positive (one focal and one diffuse) while only 1/5 FSH tumors showed a moderately intense immunoreactivity. All other pituitary adenomas were completely negative for NESP 55. Our results indicate that, in human pituitary adenomas, NESP-55 has a more restricted pattern of expression than that of chromogranins A and B. Since immunohistochemical expression of NESP-55 is largely confined to prolactinomas and GH adenomas, it raises the possibility that NESP-55 may somehow be involved in the secretory pathways of these specific cell types. PMID- 21584661 TI - Muscle-specific RING finger (MuRF) cDNAs in Atlantic salmon (Salmo salar) and their role as regulators of muscle protein degradation. AB - The selection of proteins destined for degradation by the ubiquitin-proteasome pathway is coordinated by E3 ubiquitin ligases (E3Ub). One group of E3Ubs is described as muscle-specific RING finger (MuRF) molecules. In mammals, these proteins are believed to be central to targetting of muscle proteins for degradation during physiological perturbations such as starvation and inflammatory responses. In fish, the diversity of MuRF sequences is unexplored as is the expression of their mRNAs. In this study, three MuRF1 cDNAs, denoted as MuRF1a, MuRF1b, and MuRF1c, and a single MuRF2 were identified and characterized in Atlantic salmon. The MuRF1 sequences are highly conserved and encode predicted proteins of 349, 350, and 353 amino acids, whereas MuRF2 encodes a longer protein of 462 amino acids. The evolutionary relationship of these sequences with other fish and mammalian molecules shows that MuRF1a and 1b may have arisen from a recent salmonid duplication. The mRNA of MuRFs was expressed in multiple tissues, with highest abundance in white muscle tissue followed by the heart. The expression of MuRFs was modulated after both starvation and immune challenge. Starvation increased expression of all MuRF mRNAs in white muscle, with the greatest increase found in MuRF1a. A proinflammatory stimulation increased expression of MuRF mRNA in muscle and other tissues indicating a role of these proteins in protein degradation during inflammation. PMID- 21584663 TI - Methicillin-resistant Staphylococcus aureus (MRSA) colitis--is there a problem? PMID- 21584662 TI - The biology and economics of coral growth. AB - To protect natural coral reefs, it is of utmost importance to understand how the growth of the main reef-building organisms-the zooxanthellate scleractinian corals-is controlled. Understanding coral growth is also relevant for coral aquaculture, which is a rapidly developing business. This review paper provides a comprehensive overview of factors that can influence the growth of zooxanthellate scleractinian corals, with particular emphasis on interactions between these factors. Furthermore, the kinetic principles underlying coral growth are discussed. The reviewed information is put into an economic perspective by making an estimation of the costs of coral aquaculture. PMID- 21584664 TI - Predictors of long-term survival in patients with colorectal liver metastases: a single center study and review of the literature. AB - PURPOSE: Prognosis after resection of liver metastases of colorectal cancer is influenced by a variety of clinical factors. For more than 20 years, efforts have been made to restructure and simplify prognostic parameters into clinical scores. We evaluated the influence of various clinical and pathological factors on survival and recurrence and developed a simple model for risk stratification. METHODS: We have analyzed a total of 13 prognostic factors in 382 consecutive and prospectively enrolled R0-resected patients and applied our data set to ten published prognostic scoring systems. Prognostic factors that influenced disease specific and disease-free survival were included into a model clinical risk score. RESULTS: The 5- and 10-year observed survival rates were 43% and 28%, respectively, for all 382 patients. The disease-specific 5- and 10-year survival rates were 49% and 37%, respectively; the 5- and 10-year recurrence rates were 68% and 70%, respectively. For patients with synchronous liver metastases, survival was not affected by the timing of liver resection. The prognosis after treatment of any recurrence was best after the accomplishment of a repeated R0 situation, independent of the location of the recurrence. In the multivariate analysis, the disease-specific survival and recurrence rates were statistically significantly influenced by more than three lymph node metastases of the primary tumor, more than two lesions within the liver, and the presence of extrahepatic tumor. CONCLUSIONS: From these data, we have developed a simple score for the risk stratification which may be useful for future studies on interdisciplinary management of colorectal liver metastases. PMID- 21584665 TI - Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway. AB - Mesenchymal stem cells (MSCs) play a critical role in promoting cancer progression. However, it is not clear whether MSCs are located in breast cancer tissues and correlated with tumor proliferation. The aim of this study was to investigate the presence of MSCs in breast cancer tissues and evaluate their interactions with cancer cells. We successfully isolated and identified MSCs from primary breast cancer tissues. Breast cancer-associated MSCs (BC-MSCs) showed homogenous immunophenotype, and possessed tri-lineage differentiation potential (osteoblast, adipocyte, and chondrocyte). When co-transplanted with cancer cells in a xenograft model in vivo, BC-MSCs significantly increased the volume and weight of tumors. We observed that BC-MSCs stimulated mammosphere formation in the transwell co-culture system in vitro. This effect was significantly suppressed by the EGF receptor inhibitor. We verified that BC-MSCs could secrete EGF and activate cancer cell's EGF receptors. Furthermore, our data showed that EGF derived from BC-MSCs could promote mammosphere formation via the PI3K/Akt signaling pathway. Our results confirmed the presence of MSC in primary breast cancer tissues, and they could provide a favorable microenvironment for tumor cell growth in vivo, partially enhance mammosphere formation via the EGF/EGFR/Akt pathway. PMID- 21584666 TI - Epirubicin and paclitaxel with G-CSF support in first line metastatic breast cancer: a randomized phase II study of dose-dense and dose-escalated chemotherapy. AB - An increased dose-intensity can be achieved by either higher dose of chemotherapy per cycle (dose-escalation) or by shortening the interval between cycles (dose dense). This multicenter randomized phase II study assessed the efficacy and safety of two different approaches: epirubicin 110 mg/m(2) combined with paclitaxel 200 mg/m(2) every 21 days and epirubicin 75 mg/m(2) combined with paclitaxel 175 mg/m(2) every 10 days, both supported with G-CSF. Patients with advanced breast cancer and without prior palliative chemotherapy were scheduled for 6 cycles. Evaluable for response were 101 patients and for toxicity 106 patients. Grade >= 3 toxicities occurred in 39% of patients in the dose-escalated arm and in 29% of the dose-dense arm, mainly febrile neutropenia, thrombocytopenia, neurotoxicity and (asymptomatic) cardiotoxicity. The median delivered cumulative doses for epirubicin/paclitaxel were 656/1194 and 448/1045 mg/m(2), treatment durations were 126 and 61 days, and delivered dose intensities were 36/67 and 51/120 mg/m(2)/week for the dose-escalated and dose-dense arm, respectively. Response rates were 75 and 70%, the progression-free survival 6 and 7 months, respectively. Dose-dense chemotherapy with a lower cumulative dose, a halved treatment time, but a higher dose-intensity may be as effective and safe as dose-escalated chemotherapy. The value of dose-densification over standard scheduled chemotherapy regimes yet needs to be determined. PMID- 21584667 TI - Effect of primary prophylactic G-CSF use on systemic therapy administration for elderly breast cancer patients. AB - Effective systemic therapy is vital for successful breast cancer treatment, but early onset toxicities like neutropenia hinder systemic therapy administration, especially in the elderly. Primary prophylactic use of granulocyte-colony stimulating factors (G-CSF) helps prevent neutropenia, and according to some clinical trials, facilitates chemotherapy completion. Nevertheless, evidence supporting the effectiveness of primary prophylactic G-CSF in the elderly is limited. Thus, the ASCO recommendations for primary prophylactic G-CSF use in the elderly are not explicit. This retrospective observational study examined the association between primary prophylactic G-CSF administration at the start of first course chemotherapy with adequate first course chemotherapy and radiation therapy administration in elderly breast cancer patients. The study analyzes newly diagnosed breast cancer patients receiving chemotherapy present in the SEER Medicare data from 1994 to 2003. To account for the non-random nature of the observational data, a non-parametric matching technique was used to pre-process the data before estimating the effect of primary prophylactic G-CSF on adequate chemotherapy and radiation therapy administration. Adequate chemotherapy was defined as administration of six or more cycles during the first course. Primary prophylactic G-CSF administered at the start of the first course chemotherapy was associated with a statistically significant increase in the probability of administration of six or more first course chemotherapy cycles by 29% [95% CI 7.7 50.6%] and any radiation therapy administration by 42% [95% CI 25.2-58.4%]. Primary prophylactic G-CSF use with the first course of chemotherapy is associated with improved chemotherapy completion rates and radiation therapy. These findings emphasize the clinical value of primary prophylactic G-CSF use for systemic therapy completion, and have implications for ASCO guidelines and medicare coverage policies. PMID- 21584668 TI - F-18 Fluorodeoxyglucose non-avid hepatosplenic T cell lymphoma: a diagnostic pitfall. PMID- 21584669 TI - Chronic lymphocytic leukemia developing in a patient with Janus kinase 2 V617F mutation positive myeloproliferative neoplasm. PMID- 21584670 TI - Intermediate intensity conditioning regimen containing FLAMSA, treosulfan, cyclophosphamide, and ATG for allogeneic stem cell transplantation in elderly patients with relapsed or high-risk acute myeloid leukemia. AB - Lower dosage of total body irradiation (TBI) and chemotherapy in reduced intensity conditioning (RIC) regimens prior to allogeneic stem cell transplantation have reduced the toxicity of the conditioning and non-relapse mortality. The FLAMSA-RIC protocol for high-risk patients with acute myeloid leukemia (AML) and myelodysplastic syndrome has shown promising results in refractory disease as well as in first complete remission. Still, the RIC protocol containing 4 Gy TBI/cyclophosphamide/anti-thymocyte globulin (ATG) implicates acute toxicity mainly due to TBI preventing its usage in patients with advanced age and/or severe co-morbidities. To increase feasibility and safety of the conditioning, we substituted TBI with treosulfan. Seventeen patients with relapsed or high-risk AML and either advanced age or concomitant disease were treated within a preparative regimen containing a 4-day course of chemotherapy (FLAMSA) followed by RIC comprising of treosulfan, cyclophosphamide, and ATG. After median follow-up of 12 months, the estimated incidences of relapse and non relapse mortality were 25% and 20%, respectively. One-year overall survival was 62%. In conclusion, FLAMSA-treosulfan/cyclophosphamide/ATG is an intermediate intensity conditioning regimen with acceptable non-relapse mortality for patients with relapsed or high-risk AML. Substituting TBI with treosulfan provides an alternative to treat elderly patients or patients with severe co-morbidities when TBI appears not feasible due to the potential of increased toxicity. PMID- 21584671 TI - International Staging System predicts prognosis of Chinese patients with multiple myeloma across different calendar periods with application of novel agents. AB - The applicability of the International Staging System (ISS) for Chinese patients with multiple myeloma (MM) has not been demonstrated, especially with respect to treatments with novel agents. Newly diagnosed MM patients at Taipei Veterans General Hospital were enrolled between 1996 and 2007. Data regarding clinical features, laboratory tests, and outcome at last follow-up were collected. A total of 389 MM patients (71% male) were enrolled, with median age of 71 years. At diagnosis, 72.7% had Durie-Salmon (DS) stage III disease, 56.2% had ISS stage III disease, and 34% had serum creatinine ?2.0 mg/dL. Compared with patients diagnosed in the first calendar period 1996-2001, the patients of the second calendar period 2002-2007 were older and more of these patients had received novel agents, especially thalidomide. The median overall survival period was 20.5 months, with a significant increase of patients in the second calendar period (15.3 and 28.2 months, respectively; P = 0.002), especially for those with ISS stages I and II. In the Cox proportion model, elevated serum beta(2) microglobulin at diagnosis (?3.5 mg/L), old age (?65 years), and impaired renal function were found to be independently associated with poor survival. Over the entire period, the ISS was found to be effective in providing an accurate prognosis with respect to different ages and calendar periods. This is the first study to show the applicability of ISS for Chinese patients with MM, especially for those who had received thalidomide. PMID- 21584673 TI - Hyperdense basilar artery sign-a reliable sign of basilar artery occlusion. AB - INTRODUCTION: We aimed to investigate the value of the hyperdense basilar artery (HBA) sign and of basilar artery (BA) attenuation measurements as predictors of basilar artery occlusion (BAO) on nonenhanced cranial CT (NECT). METHODS: Forty one consecutive patients with proven BAO in CT angiography, who had undergone NECT for initial evaluation (30 males, 11 females) were retrospectively included. Another 41 age-matched patients without BAO were included as a control group. The NECT scans of both groups were assessed by three independent blinded readers (staff, fellow, and resident) in a randomized reading order using a standardized semiquantitative questionnaire. Visual BA hyperdensity, including the presence of HBA sign (hyperdensity scores of 4 and 5/5), was assessed, quantitative BA attenuation was measured in a region of interest (ROI), and diagnosis of BAO was made before and after ROI measurements. For statistical analysis, multivariate mixed effects models, likelihood ratio tests, and receiver operating characteristics techniques were applied. RESULTS: HBA sign had a relatively low sensitivity (60.98-65.85%), specificity (70.73-90.24%), and accuracy (65.85 75.61%) for the presence/absence of BAO on NECT. Optimal cut-off points were 40 42 HU (sensitivity, 68.29-78.05%; specificity, 75.61-82.93%; accuracy, 74.39 80.49%). CONCLUSION: In basilar artery occlusion, quantitative measurement of BA attenuation can slightly improve the diagnostic predictiveness of NECT. However, even with optimal cut-off values, the sensitivity is too low to serve as the sole diagnostic decision-making tool. PMID- 21584674 TI - Segmentation of multiple sclerosis lesions in MR images: a review. AB - INTRODUCTION: Multiple sclerosis (MS) is an inflammatory demyelinating disease that the parts of the nervous system through the lesions generated in the white matter of the brain. It brings about disabilities in different organs of the body such as eyes and muscles. Early detection of MS and estimation of its progression are critical for optimal treatment of the disease. METHODS: For diagnosis and treatment evaluation of MS lesions, they may be detected and segmented in Magnetic Resonance Imaging (MRI) scans of the brain. However, due to the large amount of MRI data to be analyzed, manual segmentation of the lesions by clinical experts translates into a very cumbersome and time consuming task. In addition, manual segmentation is subjective and prone to human errors. Several groups have developed computerized methods to detect and segment MS lesions. These methods are not categorized and compared in the past. RESULTS: This paper reviews and compares various MS lesion segmentation methods proposed in recent years. It covers conventional methods like multilevel thresholding and region growing, as well as more recent Bayesian methods that require parameter estimation algorithms. It also covers parameter estimation methods like expectation maximization and adaptive mixture model which are among unsupervised techniques as well as kNN and Parzen window methods that are among supervised techniques. CONCLUSIONS: Integration of knowledge-based methods such as atlas-based approaches with Bayesian methods increases segmentation accuracy. In addition, employing intelligent classifiers like Fuzzy C-Means, Fuzzy Inference Systems, and Artificial Neural Networks reduces misclassified voxels. PMID- 21584675 TI - Image evaluation of HIV encephalopathy: a multimodal approach using quantitative MR techniques. AB - INTRODUCTION: A multimodal approach of the human immunodeficiency virus (HIV) encephalopathy using quantitative magnetic resonance (MR) techniques can demonstrate brain changes not detectable only with conventional magnetic resonance imaging (MRI). The aim of this study was to compare conventional MRI and MR quantitative techniques, such as magnetic resonance spectroscopy (MRS) and relaxometry and to determine whether quantitative techniques are more sensitive than conventional imaging for brain changes caused by HIV infection. METHODS: We studied prospectively nine HIV positive children (mean age 6 years, from 5 to 8 years old) and nine controls (mean age 7.3 years; from 3 to 10 years), using MRS and relaxometry. Examinations were carried on 1.5-T equipment. RESULTS: HIV positive patients presented with only minor findings and all control patients had normal conventional MR findings. MRS findings showed an increase in choline to creatine (CHO/CRE) ratios bilaterally in both frontal gray and white matter, in the left parietal white matter, and in total CHO/CRE ratio. In contrast, N acetylaspartate to creatine (NAA/CRE) ratios did not present with any significant difference between both groups. Relaxometry showed significant bilateral abnormalities, with lengthening of the relaxation time in HIV positive in many regions. CONCLUSION: Conventional MRI is not sensitive for early brain changes caused by HIV infection. Quantitative techniques such as MRS and relaxometry appear as valuable tools in the diagnosis of these early changes. Therefore, a multimodal quantitative study can be useful in demonstrating and understanding the physiopathology of the disease. PMID- 21584676 TI - Time in action contexts: learning when an action effect occurs. AB - Action effects do not occur randomly in time but follow our actions at specific delays. The ideomotor principle (IMP) is widely used to explain how the relation between actions and contingently following effects is acquired and numerous studies demonstrate robust action-effect learning. Yet, little is known about the acquisition of temporal delays of action effects. Here, we demonstrate that participants learn that action effects occur at specific delays. Participants responded slower to action effects that occurred earlier than usual. In addition, participants often prematurely responded before the effect when it occurred later than expected. Thus, in contrast to biases of time perception in action contexts (e.g., Haggard, Trends Cogn Sci 9:290-295, 2005; Stetson et al., Neuron 51:651 659, 2006), participants learn and exploit temporal regularities between actions and effects for behavioral control. PMID- 21584677 TI - Agrobacterium-mediated transformation of finger millet (Eleusine coracana (L.) Gaertn.) using shoot apex explants. AB - A new Agrobacterium-mediated transformation system was developed for finger millet using shoot apex explants. The Agrobacterium strain LBA4404 harboring binary vector pCAMBIA1301, which contained hygromycin phosphotransferase (hptII) as selectable marker gene and beta-glucuronidase (GUS) as reporter gene, was used for optimization of transformation conditions. Two finger millet genotypes, GPU 45 and CO 14, were used in this study. The optimal conditions for the Agrobacterium-mediated transformation of finger millet were found to be the co cultivation of explants obtained on the 16th day after callus induction (DACI), exposure of explants for 30 min to agrobacterial inoculum and 3 days of co cultivation on filter paper placed on medium supplemented with 100 MUM acetosyringone (AS). Addition of 100 MUM L: -cysteine in the selection medium enhanced the frequency of transformation and transgenic plant recovery. Both finger millet genotypes were transformed by Agrobacterium. A frequency of 19% transient expression with 3.8% stable transformation was achieved in genotype GPU 45 using optimal conditions. Five stably transformed plants were fully characterized by Southern blot analysis. A segregation analysis was also performed in four R(1) progenies, which showed normal Mendelian pattern of transgene segregation. The inheritance of transgenes in R(1) progenies was also confirmed by Southern blot analysis. This is the first report on Agrobacterium mediated transformation of finger millet. This study underpins the introduction of numerous agronomically important genes into the genome of finger millet in the future. PMID- 21584678 TI - Molecular approaches to improvement of Jatropha curcas Linn. as a sustainable energy crop. AB - With the increase in crude oil prices, climate change concerns and limited reserves of fossil fuel, attention has been diverted to alternate renewable energy sources such as biofuel and biomass. Among the potential biofuel crops, Jatropha curcas L, a non-domesticated shrub, has been gaining importance as the most promising oilseed, as it does not compete with the edible oil supplies. Economic relevance of J. curcas for biodiesel production has promoted world-wide prospecting of its germplasm for crop improvement and breeding. However, lack of adequate genetic variation and non-availability of improved varieties limited its prospects of being a successful energy crop. In this review, we present the progress made in molecular breeding approaches with particular reference to tissue culture and genetic transformation, genetic diversity assessment using molecular markers, large-scale transcriptome and proteome studies, identification of candidate genes for trait improvement, whole genome sequencing and the current interest by various public and private sector companies in commercial-scale cultivation, which highlights the revival of Jatropha as a sustainable energy crop. The information generated from molecular markers, transcriptome profiling and whole genome sequencing could accelerate the genetic upgradation of J. curcas through molecular breeding. PMID- 21584679 TI - The death of ouabain-treated renal epithelial C11-MDCK cells is not mediated by swelling-induced plasma membrane rupture. AB - This study examined the role of cell volume modulation in plasma membrane rupture and death documented in ouabain-treated renal epithelial cells. Long-term exposure to ouabain caused massive death of C11-MDCK (Madin-Darby canine kidney) epithelial cells, documented by their detachment, chromatin cleavage and complete loss of lactate dehydrogenase (LDH), but did not affect the survival of vascular smooth muscle cells (VSMCs) from the rat aorta. Unlike the distinct impact on cell survival, 2-h exposure to ouabain led to sharp elevation of the [Na+](i)/[K+](i) ratio in both cell types. A similar increment of Na+(i) content was evoked by sustained inhibition of Na+,K+-ATPase in K+-free medium. However, in contrast to ouabain, C11-MDCK cells survived perfectly during 24-h exposure to K+-free medium. At 3 h, the volume of ouabain-treated C11-MDCK cells and VSMCs, measured by the recently developed dual-image surface reconstruction technique, was increased by 16 and 12%, respectively, whereas 5-10 min before the detachment of ouabain-treated C11-MDCK cells, their volume was augmented by ~30-40%. To examine the role of modest swelling in the plasma membrane rupture of ouabain treated cells, we compared actions of hypotonic medium on volume and LDH release. We observed that LDH release from hypoosmotically swollen C11-MDCK cells was triggered when their volume was increased by approximately fivefold. Thus, our results showed that the rupture of plasma membranes in ouabain-treated C11-MDCK cells was not directly caused by cell volume modulation evoked by Na+,K+-ATPase inhibition and inversion of the [Na+](i)/[K+](i) ratio. PMID- 21584681 TI - Carbohydrate supplementation delays DNA damage in elite runners during intensive microcycle training. AB - The aim of this study was to evaluate the effect of carbohydrate supplementation on free plasma DNA and conventional markers of training and tissue damage in long distance runners undergoing an overload training program. Twenty-four male runners were randomly assigned to two groups (CHO group and control group). The participants were submitted to an overload training program (days 1-8), followed by a high-intensity intermittent running protocol (10 * 800 m) on day 9. The runners received maltodextrin solution (CHO group) or zero energy placebo solution as the control equivalent before, during, and after this protocol. After 8 days of intensive training, baseline LDH levels remained constant in the CHO group (before: 449.1 +/- 18.2, after: 474.3 +/- 22.8 U/L) and increased in the control group (from 413.5 +/- 23.0 to 501.8 +/- 24.1 U/L, p < 0.05). On day 9, LDH concentrations were lower in the CHO group (509.2 +/- 23.1 U/L) than in the control group (643.3 +/- 32.9 U/L, p < 0.01) post-intermittent running. Carbohydrate ingestion attenuated the increase of free plasma DNA post intermittent running (48,240.3 +/- 5,431.8 alleles/mL) when compared to the control group (73,751.8 +/- 11,546.6 alleles/mL, p < 0.01). Leukocyte counts were lower in the CHO group than in the control group post-intermittent running (9.1 +/- 0.1 vs. 12.2 +/- 0.7 cells/uL; p < 0.01) and at 80 min of recovery (10.6 +/- 0.1 vs. 13.9 +/- 1.1 cells/uL; p < 0.01). Cortisol levels were positively correlated with free plasma DNA, leukocytes, and LDH (all r > 0.4 and p < 0.001). The results showed that ingestion of a carbohydrate beverage resulted in less DNA damage and attenuated the acute post-exercise inflammation response, providing better recovery during intense training. PMID- 21584680 TI - New insights into the translocation route of enrofloxacin and its metalloantibiotics. AB - Probing drug/lipid interactions at the molecular level represents an important challenge in pharmaceutical research, drug discovery and membrane biophysics. Previous studies showed that enrofloxacin metalloantibiotic has potential as an antimicrobial agent candidate, since it exhibits antimicrobial effect comparable to that of free enrofloxacin but a different translocation route. These differences in uptake mechanism can be paramount in counteracting bacterial resistance. In view of lipids role in bacterial drug uptake, the interaction of these compounds with different Escherichia coli model membranes were studied by fluorescence spectroscopy. Partition coefficients determined showed that lipid/antibiotic interactions were sensitive to liposomes composition and that the metalloantibiotic had a higher partition than free enrofloxacin. These results corroborate the different mechanism of entry proposed and can be rationalized on the basis that an electrostatic interaction between the metalloantibiotic positively charged species, present at physiological pH, and the lipids negatively charged head groups clearly promotes the lipid/antimicrobial association. PMID- 21584683 TI - Acute and chronic loading of sodium bicarbonate in highly trained swimmers. AB - In the present study, 200-m swim time in highly trained male swimmers was measured on two consecutive days (Trial 1 and Trial 2) and under three conditions [(1) acute loading, AcL; (2) chronic loading, ChL; (3) Placebo, PLA]. No sodium bicarbonate (NaHCO(3)) was administered between Trial 1 and Trial 2 under each condition. Blood lactate concentration ([La(-)]), base excess of extracellular fluid (BE(ecf)), plasma bicarbonate concentration ([HCO(3) (-)]) and pH were determined before and after capsule administration as well as at 0, 3, 5, 15 and 30 min after each 200-m swim trial. Swim time was not different among AcL, ChL or PLA for Trial 1 or 2 and we observed no change in 200-m swim time from Trial 1 to 2 under any condition (F = 0.48, P = 0.80). [HCO(3) (-)], pH and BE(ecf) measured after capsule administration was higher during AcL and ChL when compared with PLA (P < 0.05). We did not observe any difference in blood [La(-)] between the three conditions at any stage post-exercise (P > 0.05). The results indicate that acute and chronic loading of NaHCO(3) does not improve 200-m swim time in highly trained male swimmers. PMID- 21584682 TI - Vitamin C prevents hyperoxia-mediated coronary vasoconstriction and impairment of myocardial function in healthy subjects. AB - Supplementary oxygen is commonly administered in current medical practice. Recently it has been suggested that hyperoxia causes acute oxidative stress and produces prompt and substantial changes in coronary resistance in patients with ischemic heart disease. In this report, we examined whether the effects of hyperoxia on coronary blood velocity (CBV) would be associated with a reduction in myocardial function. We were also interested in determining if the postulated changes in left ventricular (LV) function seen with tissue Doppler imaging (TDI) could be reversed with intravenous vitamin C, a potent, acute anti-oxidant. LV function was determined in eight healthy subjects with transthoracic echocardiography and TDI before and after hyperoxia and with and without infusing vitamin C. Hyperoxia compared with room air promptly reduced CBV by 28 +/- 3% (from 23.50 +/- 2.31 cm/s down to 17.00 +/- 1.79 cm/s) and increased relative coronary resistance by 34 +/- 5% (from 5.63 +/- 0.88 up to 7.32 +/- 0.94). Meanwhile, LV myocardial systolic velocity decreased by 11 +/- 6% (TDI). These effects on flow and function were eliminated by the infusion of vitamin C, suggesting that these changes are mediated by vitamin C-quenchable substances acting on the coronary microcirculation. PMID- 21584684 TI - Cardiac mechanisms underlying normal exercise tolerance: gender impact. AB - The aim of this study is to test our hypothesis that normal exercise tolerance differs according to gender and to identify potential functional cardiac relationships, which could explain those differences. A total of 44 healthy individuals with mean age of 49 +/- 12 years (28-74 years, 22 males) constituted the study cohort. All individuals underwent resting and exercise Doppler echocardiogram simultaneously with peak oxygen uptake analysis (pVO(2)). At equal pVO(2), males achieved higher peak exercise workload (p < 0.001) and females higher heart rate (p < 0.001) but the two groups maintained similar indexed left ventricular (LV) stroke volume (SV) and cardiac output. Indexed LV end-diastolic (LVDVI) and end-systolic volumes (LVSVI) were smaller in females (p < 0.001 and p < 0.01, respectively), but filling time (FT) was shorter (p < 0.001) and they had higher early diastolic (E) velocity (p = 0.004), E/E (m) (myocardial E velocity) (p < 0.001) and global longitudinal strain rate atrial velocity (GLSRa') (p = 0.02), compared to males. In males, workload (p < 0.01), LVDVI (p < 0.01), LVSVI (p < 0.05), SVI (p < 0.001) directly but LV myocardial isovolumic relaxation time (IVRTm) (p < 0.01) inversely correlated with pVO(2). In females, mitral E velocity (p < 0.01), GLSRs' (p < 0.05) positively and LVFT negatively (p < 0.05) correlated with pVO(2). In a multivariable analysis SVI in males (p < 0.01) and GLSRs' in females (p < 0.01) were the strongest predictors for pVO(2). Thus, normal exercise capacity as determined by pVO(2) is related to the indexed stroke volume in males and left atrial pressure in females. These native normal differences between genders may explain the known vulnerability of women to endurance exercise compared to men. PMID- 21584685 TI - Heart rate variability and baroreceptor sensitivity following exercise-induced hyperthermia in endurance trained men. AB - We evaluated the effect of exercise-induced hyperthermia (EIH) on autonomic nervous system (ANS) function in the early (<80 min) and late (24 and 48 h) stages of recovery. Eight males underwent three repeated 6 min 70 degrees head up tilts (HUT1, HUT2 and HUT3), each separated by 10-min supine rest in a non exercise/non-heat stress control state (NHS). On a separate day, three 6 min 70 degrees HUT were performed following EIH (esophageal temperature >= 40 degrees C) and repeated after 24 and 48 h of recovery. Heart rate, stroke volume (SV), mean arterial pressure and cardiac output ([Formula: see text]) were evaluated during the last min prior to a change in posture. Responses to 70 degrees HUT were compared to the same challenge performed without prior exercise and under a NHS condition. Relative to NHS, [Formula: see text] was maintained during the repeated HUT's following EIH, despite significant reductions in SV and sustained elevations in esophageal temperature (p < 0.05). The preserved [Formula: see text] appears to be due to increased HR (HUT1: NRS = 76 +/- 3 beats min(-1), EIH = 126 +/- 6 beats min(-1)) stemming from modulation of the ANS toward sympathetic dominance. Parasympathetic withdrawal was evidenced by a reduction in root mean squared successive difference (i.e., HUT1: NHS = 66 +/- 12 ms, EIH = 9 +/- 1 ms) of heart rate variability and paralleled by a reduction in baroreceptor sensitivity for all HUT's following EIH (p < 0.05). Despite significant modulation in ANS activity, Q is maintained and participants do not become orthostatic intolerant/syncopal during the short-term recovery period following EIH. Normal ANS and cardiovascular function is restored following 24 h of recovery. PMID- 21584686 TI - Cytokine production by monocytes, neutrophils, and dendritic cells is hampered by long-term intensive training in elite swimmers. AB - Elite level athletes seem to be prone to illness especially during heavy training phases. The aim of this study was to investigate the influence of long term intensive training on the functional features of innate immune cells from high competitive level swimmers, particularly the production of inflammatory mediators and the possible relationship with upper respiratory symptoms (URS) occurrence. A group of 18 swimmers and 11 healthy non athletes was studied. Peripheral blood samples were collected from athletes after 36 h of resting recovery from exercise at four times during the training season and at three times from non athletes. Samples were incubated in the presence or absence of LPS and IFN-gamma and the frequency of cytokine-producing cells and the amount produced per cell were evaluated by flow cytometry. In addition, plasma cortisol levels were measured and URS recorded through daily logs. The athletes, but not the controls, showed a decrease in the number of monocytes, neutrophils, and dendritic cell (DC) subsets and in the amount of IL-1beta, IL-6, IL-12, TNF-alpha, and MIP-1beta produced after stimulation, over the training season. Differences were most noticeable between the first and second blood collections (initial increase in training volume). Athlete's cortisol plasma levels partially correlated with training intensity and could help explain the reduced in vitro cell response to stimulation. Our results support the idea that long-term intensive training may affect the function of innate immune cells, reducing their capacity to respond to acute challenges, possibly contributing to an elevated risk of infection. PMID- 21584687 TI - Radiosurgery for intracranial dural arteriovenous fistulas (DAVFs): a review. AB - The management of intracranial dural arteriovenous fistulas (DAVFs) is complex and may require a combination of various treatment techniques. Endovascular embolization has recently emerged as the primary definitive treatment modality. However, an increasing body of literature has supported the use of stereotactic radiosurgery as the sole therapeutic modality or in combination with embolization and/or surgery. We review the rationale, results, and complications of stereotactic radiosurgery for intracranial DAVFs. PMID- 21584688 TI - Stand-alone 3D-ultrasound navigation after failure of conventional image guidance for deep-seated lesions. AB - Image guidance has proven to be an important tool in surgery for deep-seated or eloquently located cavernomas. However, neuronavigation depending on preoperative images can fail. Thus, the displayed anatomy might be distorted already during the approach. This report demonstrates the use of three-dimensional intraoperative ultrasound (3D-US) as a rescue tool, when conventional navigation is erroneous. Two patients with symptomatic cavernomas, the one located subcortically in the right peritrigonum, the other in the left thalamus, were operated in our clinic via an image-guided approach. An integrated ultrasound navigation system was used for neuronavigation. In both cases, navigation based on preoperative MRI failed after the craniotomy because patient-to-image registration was lost. In both cases, a simple registration of the patient's orientation was performed. Then a 3D-US volume was acquired and navigation was performed using the 3D-US data set. This is accurate as image acquisition and navigation are done in the same system. The cavernoma was visualized without difficulties in both cases. It could be reached directly via the ultrasound guided approach. Patients' symptoms improved postoperatively and a complete resection could be documented. Two cavernomas were successfully resected using 3D US guidance. In our experience, stand-alone 3D-US navigation is an effective option if conventional MRI-based navigation fails. PMID- 21584690 TI - What can we expect from long-acting formulations for schizophrenia? PMID- 21584689 TI - Blister-like aneurysms--a diagnostic and therapeutic challenge. AB - Blister-like internal carotid artery (ICA) aneurysms are known for their fragile and thin-walled morphology associated with a high risk of intraprocedural rupture. Neurosurgical and endovascular options are illustrated on three exemplary cases reviewing the diagnostic and therapeutic implications of these special aneurysms. A 49-year-old woman was admitted with subarachnoid hemorrhage (SAH) in which angiography showed a broad-based, small bulging ectasy of the terminal ICA segment. On the attempt of surgical clipping, the aneurysm ruptured leaving a tear in the ICA. After temporary clipping, the rims of the tear were approximated by sutures. Sufficient closure of the remaining leakage was achieved by circumferential wrapping which was secured by two clips. Postoperative angiography confirmed stenosis of the tightened ICA and patient recovered without neurological deficit. Surgical attempt on a second case with bulging of the C4 segment topped by a small aneurysm was fatal due to extensive laceration of the basal ICA intraoperatively. Endovascular stenting was the choice of treatment in a third SAH patient in which angiography was suspicious of a blister-like ICA aneurysm. Six-month follow-up was uneventful; the patient recovered well and further growth of bulging was not seen. Reviewing the literature, blister-like aneurysms tend to arise at uncommon sites not located at the arterial branches. Small and broad-based bulges with or without true saccular aneurysms have to be assessed as characteristic features of blister-like aneurysms. Rupture of the aneurysm involving the carrying artery has to be considered during therapeutic attempts, in which urgent strategies have to be kept in reserve preventing fatal outcome. Blister-like aneurysms is a hazardous affair for neurosurgeons and neuroradiologists as their fragile structure most likely will lead to intraoperative rupture. If endovascular treatment is not promising, wrapping and revascularization techniques come true to still be an important part of the neurosurgeons toolbox for reconstructing a vessel lumen and preserving a sufficient cerebral blood flow. PMID- 21584691 TI - Treatment of lupus nephritis. AB - The treatment of lupus nephritis has evolved over the past few decades. Standard practice is to define the first 6 months of therapy as an induction phase, during which the goal of therapy is to achieve renal remission, usually with bolus intravenous infusions of the cytotoxic cyclophosphamide or the immunosuppressant mycophenolate mofetil (MMF). Following induction, therapy is continued, with some decrease in aggressive dosing for a more prolonged period of time-typically 24 months-that is aimed at preventing renal flares and smoldering disease, which could lead to continuous deterioration of renal function. During maintenance, the usual therapeutic option is immunosuppression with MMF or azathioprine. In recent years, MMF has been increasingly replacing intravenous cyclophosphamide as an initial standard of care. The current paper reviews data on these treatment strategies and suggests a possible treatment algorithm for clinical care. PMID- 21584692 TI - Treatment of mild, moderate, and severe lupus erythematosus: focus on new therapies. AB - Despite large-scale efforts devoted to the conduct of clinical trials in systemic lupus erythematosus (SLE), no new therapy has been approved for treatment of this disease in more than 50 years. Increased understanding of the immunologic mechanisms underlying SLE has led to the development of a variety of biologic agents that target specific aspects of the adaptive and innate arms of the immune system, including B cells, T cells, dendritic cells, and various cytokines. One of these agents, belimumab, was the subject of two positive phase 3 trials in nonrenal lupus that have given us hope that a new therapy for SLE may be finally within our grasp. In addition to these newer therapies, recent studies of standard-of-care medications such as mycophenolate mofetil and hydroxychloroquine have better defined the efficacy and safety of these agents for the treatment of lupus nephritis and nonrenal lupus. This article provides a discussion of several novel biologic agents at different stages of development for the treatment of SLE, as well as an analysis of newer data on agents that have been used in the treatment of SLE for many years. PMID- 21584693 TI - Enterococcus faecalis affects the proliferation and differentiation of ovine osteoblast-like cells. AB - Enterococcus faecalis (E. faecalis) is a Gram-positive bacterium, mostly recovered from root-filled teeth with persistent periapical lesions. Bacterial contamination of root canals inevitably results in interaction between E. faecalis and periapical tissues during the dynamic process of periapical inflammation. This study investigated the impact of heat-inactivated endodontic E. faecalis on the proliferation and the differentiation of ovine osteoblast-like cells, in an attempt to elucidate its putative enhanced pathogenicity mechanisms. Therefore, two different concentrations of a heat-inactivated endodontic E. faecalis isolate (2 * 10(6) or 2 * 10(8) CFU/ml) were incubated with ovine osteoblast-like cells for 7 and 14 days, respectively. Cells without antigen served as control. The effects of antigen on cell growth were evaluated by a proliferation assay (EZ4U). Furthermore, the assessment of alkaline phosphatase (ALP) activity, calcium deposition, and osteocalcin (OCN) gene expression through quantitative real-time PCR determined the degree of osteogenic cell differentiation. Scanning electron microscopy (SEM) was also performed to detect alterations in cell morphology. Interestingly, although highly concentrated E. faecalis increased cellular reproduction after 14 days, ALP activity and OCN gene expression decreased in an antigen concentration-dependent and incubation time independent way. SEM images revealed E. faecalis adhesion on cells, a fact that might contribute to its virulence. These results suggest that E. faecalis stimulated cell multiplication, whereas it likely restrained cell differentiation of ovine osteoblast-like cells. In conclusion, the presence of E. faecalis in root canals may negatively affect periapical new bone formation, and thus, the healing of periapical lesions. PMID- 21584694 TI - Effect of coating Straumann Bone Ceramic with Emdogain on mesenchymal stromal cell hard tissue formation. AB - Periodontal tissue engineering requires a suitable biocompatible scaffold, cells with regenerative capacity, and instructional molecules. In this study, we investigated the capacity of Straumann Bone Ceramic coated with Straumann Emdogain, a clinical preparation of enamel matrix protein (EMP), to aid in hard tissue formation by post-natal mesenchymal stromal cells (MSCs) including bone marrow stromal cells (BMSCs) and periodontal ligament fibroblasts (PDLFs). MSCs were isolated and ex vivo-expanded from human bone marrow and periodontal ligament and, in culture, allowed to attach to Bone Ceramic in the presence or absence of Emdogain. Gene expression of bone-related proteins was investigated by real time RT-PCR for 72 h, and ectopic bone formation was assessed histologically in subcutaneous implants of Bone Ceramic containing MSCs with or without Emdogain in NOD/SCID mice. Alkaline phosphatase activity was also assessed in vitro, in the presence or absence of Emdogain. Collagen-I mRNA was up-regulated in both MSC populations over the 72-h time course with Emdogain. Expression of BMP-2 and the osteogenic transcription factor Cbfa-1 showed early stimulation in both MSC types after 24 h. In contrast, expression of BMP-4 was consistently down-regulated in both MSC types with Emdogain. Up-regulation of osteopontin and periostin mRNA was restricted to BMSCs, while higher levels of bone sialoprotein-II were observed in PDLFs with Emdogain. Furthermore, alkaline phosphatase activity levels were reduced in both BMSCs and PDLFs in the presence of Emdogain. Very little evidence was found for ectopic bone formation following subcutaneous implantation of MSCs with Emdogain-coated or -uncoated Bone Ceramic in NOD/SCID mice. The early up regulation of several important bone-related genes suggests that Emdogain may have a significant stimulatory effect in the commitment of mesenchymal cells to osteogenic differentiation in vitro. While Emdogain inhibited AP activity and appeared not to induce ectopic bone formation, longer-term studies are required to determine whether it promotes the final stages of osteoblast formation and mineralization at gene and protein levels. While used in clinical applications, whether Emdogain and other commercial preparations of EMPs truly possess the capacity to induce the regeneration of bone or other components of the periodontium remains to be established. PMID- 21584695 TI - Galectins as tools for glycan mapping in histology: comparison of their binding profiles to the bovine zona pellucida by confocal laser scanning microscopy. AB - Gene divergence has given rise to the galectin family of mammalian lectins. Since selective binding to distinct beta-galactosides underlies the known bioactivities of galectins, they could find application in cyto- and histochemistry. The pertinent question on the characteristics of their individual reactivity profiles therefore needs to be answered. Toward this end, comparative studies of a panel of galectins in defined systems are required. We here characterise the staining profiles of seven human lectins as well as five natural derivatives originating from proteolytic truncation and serine phosphorylation and one engineered variant. As test system, bovine germinal vesicle oocytes with their glycoprotein envelope (zona pellucida), which presents bi- to tetraantennary complex-type N glycans with N-acetyllactosamine repeats and core fucosylation, were processed. Technically, confocal laser scanning microscopy was used, first with plant lectins to map the sialylation status. Hereby, alpha2,3/6-sialylation was detected in the superficial filamentous meshwork of the zona pellucida, while sialic acid-free glycan chains were found to characterise the main inner part of the compact layer of the zona pellucida. Galectin staining was specific and non uniform. Significant differences in reactivity were detected for the superficial filamentous meshwork and the compact layer of the zona pellucida between galectins-1 to -4 versus galectins-8 and -9. The typical staining profiles intimate a spatially organised display of N-glycans in the different layers of the zona pellucida, underscoring the potential of galectins as cyto- and histochemical tools. Our results encourage further comparative analysis and research to trace the underlying structural and/or topological properties. PMID- 21584697 TI - Acute coronary syndrome in the Middle East. PMID- 21584696 TI - Antithrombotic management for transient ischemic attack and ischemic stroke (other than atrial fibrillation). AB - The new definition and risk stratification for transient ischemic attack (TIA) have clear implications for the urgency of evaluation and treatment. The optimal antithrombotic treatment for TIA is being intensively studied. New guidelines for prevention of non-cardioembolic stroke in patients with stroke or TIA recommend the use of antiplatelet agents rather than oral anticoagulation. New antiplatelet drugs are being used in cardiovascular patients, and their role in cerebrovascular patients is being studied. The impact of genetic CYP2C19 polymorphisms is becoming clarified in cardiovascular patients and it is likely these polymorphisms will affect the management of cerebrovascular patients. The results of trials of clopidogrel plus aspirin in patients with lacunar strokes and acute TIAs are forthcoming. The results of CLOSURE I, a study of a patent foramen ovale device closure trial for cryptogenic stroke or TIA, showed no differences in stroke or TIA at 2 years. PMID- 21584698 TI - The expression of damage-regulated autophagy modulator 2 (DRAM2) contributes to autophagy induction. AB - Autophagy is a membrane trafficking process involved in intracellular degradation and recycling in eukaryotic cells. DRAM2 (damage-regulated autophagy modulator 2) is a homologue of DRAM that regulates p53-mediated cell death. As its name implies, DRAM expression induces autophagy in a p53-dependent manner; however, the role of DRAM2 in autophagy is not clear. In this study, we report that DRAM2 expression contributes to autophagy induction. Overexpression of DRAM2 induces cytoplasmic GFP-LC3 punctuates, and increases the level of endogenous LC3-II. Moreover, the silencing of endogenous DRAM2 interferes with starvation-induced autophagy. Thus, we propose that DRAM2 as well as DRAM are involved in autophagy. PMID- 21584699 TI - Association between vitamin D receptor gene polymorphisms and type 1 diabetes mellitus in Iranian population. AB - Type 1 diabetes mellitus (T1DM) is one of the T-cell mediated autoimmune diseases and vitamin D suppresses activation of T-cell and has immunomodulatory effects. In this study the association between four vitamin D receptor (VDR) gene polymorphisms, at positions FokI, BsmI, ApaI and TaqI, and susceptibility to T1DM was investigated. We assessed 87 Iranian patients with T1DM and one hundred healthy controls with no history of diabetes or other autoimmune diseases. Our results demonstrated that genotypes frequency of the TaqI VDR polymorphism differed significantly between T1DM patients and controls, TT genotype and T allele was more frequent in healthy controls compared with TIDM patients (P = 0.003; OR = 0.51, 95% CI = 0.31-0.84). Therefore, allele t is the risk-allele for developing TIDM in this study. No significant association was observed between others VDR SNPs and disease susceptibility. In conclusion, our case-control study indicated that the VDR TaqI polymorphism is associated with TIDM in Iranian population. PMID- 21584700 TI - Cloning and characterization of beta-catenin gene in early embryonic developmental stage of Artemia sinica. AB - beta-Catenin plays a crucial role in embryonic development and responds to the activation of several signal transduction pathways. In this paper, in order to understand the functions of beta-catenin gene in early embryonic development of Artemia sinica, the complete cDNA sequence was cloned for the first time using RACE technology, then the sequence was analyzed by some bioinformatic methods. The expression of the beta-catenin gene was investigated at various stages during the embryonic development using quantitative real-time PCR and immunohistochemistry assay. Through the investigation, the result of real-time PCR illustrated that beta-catenin gene might relate to the response of A. sinica's immune system and osmotic pressure system in early embryonic developmental stage. Meanwhile, Immunohistochemistry assay demonstrated that during embryonic development, beta-catenin was mainly expressed in the cephalothorax. Besides, we discovered that beta-catenin might not be a maternal gene in A. sinica, and this new phenomenon may explain a constitutive and regional expression during the early embryonic development of A. sinica. PMID- 21584701 TI - An enzyme-coupled continuous spectrophotometric assay for glycogen synthases. AB - The metabolic pathways leading to the synthesis of bacterial glycogen involve the action of several enzymes, among which glycogen synthase (GS) catalyzes the elongation of the alpha-1,4-glucan. GS from Agrobacterium tumefaciens uses preferentially ADPGlc, although UDPGlc can also be used as glycosyl donor with less efficiency. We present here a continuous spectrophotometric assay for the determination of GS activity using ADP- or UDPGlc. When ADPGlc was used as the substrate, the production of ADP is coupled to NADH oxidation via pyruvate kinase (PK) and lactate dehydrogenase (LDH). With UDPGlc as substrate, UDP was converted to ADP via adenylate kinase and subsequent coupling to PK and LDH reactions. Using this assay, we determined the kinetic parameters of GS and compared them with those obtained with the classical radiochemical method. For this purpose, we improved the expression procedure of A. tumefaciens GS using Escherichia coli BL21(DE3)-RIL cells. This assay allows the continuous monitoring of glycosyltransferase activity using ADPGlc or UDPGlc as sugar-nucleotide donors. PMID- 21584702 TI - STR markers for detecting heterogeneity in Indian population. AB - Short tandem repeats are highly polymorphic sequences of nucleotides, which are abundant in eukaryotic genome. They form approximately 3% of the total human genome and occur on average in every 10, 000 nucleotides. Due to their small dimension, low mutation, and high level of polymorphism, these markers are intensely used as important genetic markers for mapping studies, disease diagnosis, and human identity testing. In the present study allelic distribution of four autosomal short tandem repeat markers (D21S2055, D21S11, D21S1435 and D21S1411) has been analyzed in Indian population. For determination of heterogeneity and their allelic frequency QF-PCR analysis have been done. All the loci were found highly polymorphic. Marker D21S1411 was the most informative (93.6%) and D21S1435 (70.1%) was the least informative marker in Indian population. PMID- 21584703 TI - [Supination external rotation lesions of the ankle joint in osteoporotic lower leg specimens. Experimental induction and review of the literature]. AB - BACKGROUND: Knowledge of the pathomechanism and the detailed extent of ankle joint lesions determines adequate therapy and success of treatment. MATERIAL AND METHODS: Supination external rotation lesions were induced in 29 human cadavera with a testing apparatus; 27 of these specimens were from elderly women. Bone mineral density was measured. The literature review includes experimental studies of this fracture entity. RESULTS: We induced stage II in 42%; applying an additional lateral force on the fibula raised the incidence. The syndesmosis stayed intact in 50% although the fibula fractured at the level of the tibial plafond. Stage IV lesions were registered in 25%. The overall low bone mineral density showed a positive correlation to the angle at which the fibula fracture occurred. CONCLUSIONS: We reproduced supination external rotation lesions according to Lauge-Hansen in osteoporotic ankles. There is a certain discrepancy between the obligatory lesion of the inferior anterior tibiofibular syndesmosis at stage II according to Lauge-Hansen, as we observed an intact syndesmosis in 50% at stage II. Stage IV defining medial malleolar fractures were reproduced after Lauge-Hansen and Michelson et al. PMID- 21584704 TI - [Coincidence of traumatic tracheal rupture accompanied by ARDS. Illustrated by the example of a 17-year-old patient with multiple injuries]. AB - Treatment and diagnosis of a traumatic tracheal rupture is a challenge. Due to the rarity of such injuries and the subtle and delayed clinical presentation it is difficult to diagnose. We present for the first time the successful management of a 17-year-old multiply injured patient with coincidental tracheal rupture and ARDS (acute respiratory distress syndrome) after a fall. Besides the case report and pathogenesis the essential diagnostic and therapeutic measures are mentioned and discussed. The circumstances surrounding the accident have to be balanced with the severity of the trauma to also exclude rare injuries with certainty. Finally level 1 trauma centers specialized in ARDS provide the best clinical setting for successful treatment of these life-threatening injuries. PMID- 21584706 TI - Needlescopic surgery for liver, gallbladder and spleen diseases. AB - BACKGROUND: We propose that needlescopic surgery (NS) should be considered as a way of improving the esthetic result and post-operative quality of life of patients and of reducing costs and stress on surgeons, and we have evaluated the results of NS. METHODS: We used NS in 157 patients between May 1998 and December 2010: cholecystectomy in 150 patients, marsupialization of splenic and hepatic cysts in 4 and splenectomy in 3, respectively. Under general anesthesia, one 12 mm and two or three 2- or 3-mm ports were introduced into the operative field. The specimen was retrieved from the 12-mm wound using a plastic bag. RESULTS: The procedures were successfully completed in all patients without conversion to an open procedure. In eight (5.3%) of 150 cholecystectomies a change to 5-mm instruments was required. The mean operation times and postoperative hospital stays for cholecystectomy, splenectomy, and marsupialization of splenic and hepatic cysts were 80.2 min and 3.2 days, 167 min and 5.6 days, 170 min and 7 days, and 120 min and 7 days, respectively. There were a few perioperative complications. The most important factor for reducing operation time and achieving a low conversion rate is the use of at least one 3- or 5-mm port for the grasping instruments in cholecystectomy. We recognized a residual cyst requiring splenectomy 62 months after marsupialization in one case. Technical points for performing safe procedures on solid organs were: no direct organ mobilization to avoid organ injuries, the rotation of the operating table and the utilization of organ gravity to create a better operative field, the minimum use of the needlescope to perform a safe maneuver and the improvement of bi-manual technique. CONCLUSIONS: NS is a safe and feasible procedure for achieving minimal invasive surgery. We should consider NS as a first choice to treat operable diseases in this laparoscopic era. PMID- 21584705 TI - [Treatment of peritrochanteric fractures: biomechanical considerations]. AB - Biomechanical considerations are relevant in the treatment of peritrochanteric fractures. Concomitant diseases and osteoporosis place high demands on the primary stability of the operative treatment. In the situation of unstable fractures (AO/ASIF 31-A2 and A3), even normal activities of life can easily exceed the critical limits of stability, which can result in implant failure. Both intramedullary and extramedullary implants are used successfully in the treatment of even unstable fractures. Different variations in the implant design and anchorage of the load carrier of the femoral neck are available and may have different biomechanical characteristics. Biomechanical tests show that new developments of implants can increase stability. Nevertheless, accurate reduction and operative technique is essential to ensure uneventful fracture healing. Although some supportive measures are very promising, such as augmentation, further research is required to increase stability in the unstable and osteoporotic fracture situation. PMID- 21584707 TI - Tri-iodothyronine enhances liver regeneration after living donor liver transplantation in rats. AB - BACKGROUND: Tri-iodothyronine (T3) has been shown to be a hepatic mitogen. The aim of this study was to evaluate the effect of T3 on liver regeneration after 50% partial liver transplantation (pLT) in rats. METHODS: Immediately after pLT, a single dose of T3 (4 mg/kg body weight) was administered. Liver/body weight ratio (LBWR), hepatocyte proliferation (Ki-67), biochemical parameters, and changes in cell cycle related proteins were evaluated. RESULTS: T3 promoted liver regeneration as shown by an increased liver/body weight ratio and Ki-67 proliferation index after pLT. On the transcriptional level, T3-treated rats had an increased expression of cyclin D1 and cyclin A as demonstrated by real time RT PCR and Western blot. CONCLUSIONS: Exogenous administration of T3 significantly improved liver regeneration after pLT, and therefore it may represent a promising strategy to improve the clinical outcome after living donor liver transplantation in the future. PMID- 21584708 TI - Clinical Immunology Society: the early years 1984-1989 : I. An introduction. PMID- 21584709 TI - About breaking barriers, the risk paradox, and other twists. PMID- 21584710 TI - Supplementation of zinc mitigates the altered uptake and turnover of 65Zn in liver and whole body of diabetic rats. AB - Diabetes is a life threatening disease and its onset is linked with both environmental and genetic factors. Zinc metabolism gets altered during diabetes and results in many complications. The present study was designed to elucidate the effects of zinc supplementation on the biokinetics of (65)Zn in whole body, liver and its biodistribution in diabetic rats. The animals were divided into four groups viz; normal control; diabetic (single intraperitoneal injection of alloxan 150 mg/kg body weight); zinc treated (227 mg/l in drinking water); and diabetic + zinc treated. To carry out biokinetics study, each rat was injected intraperitoneally with 0.74 MBq radioactivity of (65)Zn following 4 weeks of different treatments and the radioactivity was determined by using a suitably shielded scintillation counter. Alloxan induced diabetic rats showed a significant decrease in both the fast (Tb(1)) and slow (Tb(2)) components of biological half-life of (65)Zn which, however, were normalized in whole body (P > 0.05) following zinc supplementation. In case of liver, Tb(2) component was brought back to the normal but Tb(1) component was not increased significantly. The present study indicates that the paucity of zinc in the tissues of the diabetic animals was due to decreased retention of tissue zinc as evidenced by increased serum Zn, hyperzincuria and increased rate of uptake of (65)Zn by the liver. Zinc supplementation caused a significant improvement in the retention of zinc in the tissues and is therefore likely to be of benefit in the treatment of diabetes. PMID- 21584711 TI - Role of aluminum in red-to-blue color changes in Hydrangea macrophylla sepals. AB - Red, purple, and blue sepals on selected cultivars of Hydrangea macrophylla were analyzed for their aluminum content. This content was determined to be a function of the sepal color with red sepals possessing 0-10 MUg Al/g fresh sepal, purple sepals having 10-40 MUg Al/g fresh sepal, and blue sepals containing greater than 40 MUg Al/g fresh sepal. Accordingly, the threshold aluminum content needed to change H. macrophylla sepals from red to blue was about 40 MUg Al/g fresh sepal. Higher aluminum concentrations were incorporated into the sepals, but this additional aluminum did not affect the intensity or hue of the blue color. These observations agreed with a chemical model proposing that the concentration of the blue Al(3+)-anthocyanin complex reached a maximum when a sufficient excess of aluminum was present. In addition, the visible absorbance spectra of harvested red, purple, and blue sepals were duplicated by Al(3+) and anthocyanin (delphinidin-3-glucoside) mixtures in this model chemical system. PMID- 21584713 TI - Cerebrovascular disorders: nonfasting triglycerides and stroke, silent ischemia and thrombolysis, and pathogenesis of cervical artery dissection. PMID- 21584712 TI - Pathophysiology and pathogenesis of post-resuscitation myocardial stunning. AB - The prognosis for cardiac arrest victims remains dismal, as only 17% survives to hospital discharge. Post-resuscitation myocardial stunning is the mechanical dysfunction that persists after the restoration of spontaneous circulation. Our knowledge regarding myocardial stunning has grown dramatically over the years, and several hypotheses have been proposed in order to explain its pathophysiology; however, the interrelationships among various mechanisms remain unclear. This review deals primarily with the basic aspects of the pathophysiology of post-resuscitation myocardial stunning. Given the large number of relevant studies and the fragmented information, an effort was made to summarize current knowledge in order to present a comprehensive pathophysiological mechanism. In this review, the pathophysiological disturbances occurring from the onset of cardiac arrest until the restoration of spontaneous circulation are addressed. Then, the pathophysiology of myocardial stunning during the post-resuscitation period is critically reviewed in 4 parts, the immediate, the early, the intermediate, and the recovery post-arrest phase. This article covers a huge gap in the existing literature regarding the pathophysiology of post-resuscitation period and provides a better understanding of the pathophysiology and pathogenesis of post-resuscitation myocardial stunning. PMID- 21584714 TI - Treatment of cardiovascular diseases in cancer patients. AB - Cardiovascular diseases and cancer are the leading causes of death in the Western world. Cancer treatment has been associated with cardiovascular complications, among others cardiotoxicity of mediastinal radiation and certain chemotherapeutics. Identification of patients at high risk, prevention, early diagnosis, and treatment of cardiovascular diseases are emerging fields in cancer patients. Close interdisciplinary work between oncologists and cardiologists is pertinent for the treatment of cardiovascular diseases and complications in cancer patients. Diagnostics and treatment applied to the individual case should be based on the available evidence in terms of patient-centered management. Further clinical research focused on the pathogenesis and treatment of cardiovascular diseases in cancer patients is warranted to pave the way to guidelines for this nonhomogeneous patient group. PMID- 21584715 TI - Sorafenib-associated multivessel coronary artery vasospasm. AB - Cardiotoxicity associated with cancer treatment is an important field of interest especially as the new class of VEGF signaling pathway inhibitors (VSP) continues to grow. Small molecule tyrosine kinase inhibitors such as sorafenib, sunitinib, and pazopanib inhibit the downstream pathways of all three of the vascular endothelial growth factor receptors (VEGFR 1, 2, and 3). Other targets of these agents include kinases involved in vascular and myocardial homoeostasis. These agents are all known to frequently cause hypertension, their most common side effect. Myocardial ischemia has also been reported, but the frequency and etiology of VSP-related ischemia is poorly characterized. This manuscript describes the first reported case of sorafenib-associated multivessel coronary vasospasm in a 57-year-old patient with hepatocellular carcinoma. He underwent sorafenib treatment, a tyrosinase inhibitor, 400 mg twice a day. The vasospasm was reversible under nitroglycerin. Possible mechanisms are also discussed. PMID- 21584716 TI - Effect of Ganciclovir on murine cytomegalovirus-induced hearing loss in a mouse model. AB - We evaluated the effect of Ganciclovir on murine cytomegalovirus (MCMV)-induced hearing impairment in a mouse model by studying modulations in auditory brainstem response (ABR) and pathological changes in the inner ear. MCMV infection was established via trans-brain. For this purpose, 24 BALB/c newborn mice were randomly and equally divided into control group (10 MUl of sterile normal saline was injected); model group (10 MUl of MCMV TCID50-10(4) IU/0.1 ml was injected); and interfered group (Trans-brain MCMV; Ganciclovir at the rate of 60 mg/kg was intraperitoneally injected). ABR audiometry was performed after 14 days. Acoustic vesicles were obtained for MCMV-PCR analysis and histopathological examination. Comparing ABR in model group against controls, incubation period of wave was lengthened (F = 9.151, P = 0.011-0.05) and wave amplitude was cut down (F = 5.095, P = 0.043-0.05). Comparing ABR in model group against interfered group, incubation period and amplitude of wave were F = 13.797 (P = 0.003-0.05) and F = 14.587 (P = 0.002-0.05), respectively. Cochlear histopathological changes in model group included thickening of vestibular membrane, lymphocytic infiltration, and fibrous degeneration of cochlear duct. In Ganciclovir interfered group, however, these pathologic changes were less significant as compared with those of model group. We, therefore, conclude that Ganciclovir treatment at the early stage of MCMV-induced hearing impairment inhibits the disease progression in infected mice. PMID- 21584717 TI - Molecular characterization of two distinct strains of blueberry scorch virus (BlScV) in northern Italy. AB - During blueberry scorch virus (BlScV) surveys of highbush blueberries in Italy between 2005 and 2010, we initially discovered infected orchards only in Piedmont. Since 2009, however, three infected orchards have also been found in Trentino, where a new host species, Vaccinium ashei, was found to be infected by BlScV. Molecular characterization of isolates during the study period suggests that two very distinct epidemics are now present in Italy: the Piedmont isolates belong to a new BlScV strain, whereas the Trentino isolates are almost identical to the Washington State strain. PMID- 21584718 TI - Development of appropriate equations for physiologically based pharmacokinetic modeling of permeability-limited and flow-limited transport. AB - Although the implementation of a flow-limited, well-stirred tank (WST) single compartment tissue model in pharmacokinetics and toxicokinetics is widespread, its use is not always justified biophysically or physiologically. The WST model introduces a loss of biophysical detail, specifically the vascular space, which is present in the standard permeability-limited two-subcompartment (PLT) tissue model. To address this loss of detail when evaluating the in vivo kinetics of drugs, toxins, nutrients, and endogenous metabolites, a novel set of physiologically based pharmacokinetic tissue compartment equations is developed through application of an asymptotic approximation to a two-region vascular extravascular system to arrive at a permeability-limited two-region asymptotically reduced (P-TAR) model and a flow-limited (F-TAR) model. Development of the TAR modeling approach illustrates the importance of relative timescales in PBPK tissue compartment model selection and the conditions under which improved biophysical realism is advantageous. In the permeability-limited regime, the TAR model formulations enable drug or toxicant concentration to be modeled in the vascular and extravascular spaces equivalent to the PLT tissue model while invoking only one state variable to represent the vascular and extravascular spaces. In the flow-limited regime, the F-TAR model is more biophysically realistic than the WST model because it maintains the anatomical distinction between the vascular and extravascular spaces, and hence offers greater pharmacological and physiological insight than the WST model, without introducing additional computational complexity. PMID- 21584719 TI - Systematic review on cadaveric studies of anatomic anterior cruciate ligament reconstruction. AB - PURPOSE: One of the templates in the development of "anatomic" anterior cruciate ligament (ACL) reconstruction has been basic science studies focusing on comparing various aspects of ACL reconstruction in order to optimize surgical technique. However, often such papers lack necessary data in the methods section to ascertain the proposed surgical technique as anatomic. The goal of this systematic review was to evaluate basic science studies on anatomic ACL reconstruction. METHODS: A systematic electronic search was performed using the MEDLINE and EMBASE databases. Studies that were published from January 1995 to April 2009 were included. Only basic science studies on human cadavers that reported "anatomic" ACL reconstruction and written in English were included. Variation in surgical technique and reporting of surgical description were assessed. RESULTS: Eighteen studies were included in this systematic review. Only the fixation method, graft type and tension pattern were reported in the majority studies. Notchplasty and radiographic documentation were grossly underreported. Other surgical data were reported at best in two-thirds of the studies. There was a large variation in the reported surgical techniques among the included studies. Due to the aforementioned, it was not deemed possible to pool data of the included studies. CONCLUSION: For most variables in the surgical technique description, there was sizeable underreporting resulting in an inability to pool the outcomes. To provide literature that holds up to the current high level of medical research, authors are encouraged to report their surgical technique in a thorough manner, similar to high-level clinical trials. PMID- 21584720 TI - Reliability and reference values of two clinical measurements of dynamic and static knee position in healthy children. AB - PURPOSE: The purposes of this study were to evaluate reliability of the Single limb mini squat test (a dynamic measure of medio-lateral knee position) and the Quadriceps-angle (Q-angle) (a static measure of medio-lateral knee position), present paediatric reference values of the Q-angle, and evaluate the association between the tests. METHODS: Two hundred and forty-six healthy children (9-16 years) were included (intra/inter-rater reliability for Q-angle (n = 37/85) and for Single-limb mini squat test (n = 33/28)). Dynamic medio-lateral knee position was assessed by the Single-limb mini squat test. Static medio-lateral knee position was evaluated by the Q-angle. RESULTS: The reliability of the Single limb mini squat test was found to be moderate (kappa 0.48-0.57, 95% CI 0.16-0.85, 76-79% agreement). Fair to moderate reliability (ICC 0.35-0.42, 95% CI 0.11-0.66, SEM 1.4 degrees -1.9 degrees , n.s.) of the Q-angle measurements was found. Reference values for the Q-angle (mean 13.5 degrees (1.9)-15.3 degrees (2.8)) varies with age and gender. No associations were found between dynamic and static measures. CONCLUSIONS: The Single-limb mini squat test showed a moderate reliability and the Q-angle showed a fair to moderate reliability. A difference found for age and gender was lower than 5 degrees and may not be clinical significant. No association were found between the two tests, indicating dynamic and static knee position being two different concepts. In a clinical perspective, we suggest that the Single-limb mini squat test is a contribution to the available tool box for evaluation of dynamic medio-lateral knee position in children, although the Q-angle may not be used before more research has been done justifying its use. PMID- 21584721 TI - The role of psychosocial stress at work for the development of cardiovascular diseases: a systematic review. AB - PURPOSE: A systematic review was carried out to assess evidence for the association between different models of stress at work, and cardiovascular morbidity and mortality. METHODS: A literature search was conducted using five databases (MEDLINE, Cochrane Library, EMBASE, PSYNDEX and PsycINFO). Inclusion criteria for studies were the following: self-reported stress for individual workplaces, prospective study design and incident disease (myocardial infarction, stroke, angina pectoris, high blood pressure). Evaluation, according to the criteria of the Scottish Intercollegiate Guidelines Network, was done by two readers. In case of disagreement, a third reader was involved. RESULTS: Twenty six publications were included, describing 40 analyses out of 20 cohorts. The risk estimates for work stress were associated with a statistically significant increased risk of cardiovascular disease in 13 out of the 20 cohorts. Associations were significant for 7 out of 13 cohorts applying the demand-control model, all three cohorts using the effort-reward model and 3 out of 6 cohorts investigating other models. Most significant results came from analyses considering only men. Results for the association between job stress and cardiovascular diseases in women were not clear. Associations were weaker in participants above the age of 55. CONCLUSIONS: In accordance with other systematic reviews, this review stresses the importance of psychosocial factors at work in the aetiology of cardiovascular diseases. Besides individual measures to manage stress and to cope with demanding work situations, organisational changes at the workplace need to be considered to find options to reduce occupational risk factors for cardiovascular diseases. PMID- 21584724 TI - Clinical efficacy of carbapenems on hospital-acquired pneumonia in accordance with the Japanese Respiratory Society Guidelines for management of HAP. AB - Hospital-acquired pneumonia (HAP) is the second most common cause of hospital acquired infection and is the leading cause of death. In 2002, the Japanese Respiratory Society (JRS) published guidelines for the diagnosis and treatment of HAP (JRS GL 2002). In these guidelines, treatment with carbapenems is recommended for all disease types of HAP, excluding cases of mild or moderate pneumonia with no risk factors, and cases with early-onset ventilation-acquired pneumonia. To evaluate the efficacy of carbapenems on HAP in accordance with JRS GL 2002, we conducted a prospective study of HAP patients treated with carbapenems based on JRS GL 2002. The results of this study were also analyzed based on the revised guidelines published in June 2008 (JRS GL 2008), and the validity of the new guidelines was examined. Of the 33 subjects, 19 were judged as responders to the treatment, corresponding to a response rate of 57.6%. There were 3 deaths, corresponding to a mortality rate of 9.1%. The efficacy of carbapenems for the treatment of HAP based on JRS GL 2002 was confirmed. The severity rating system in JRS GL 2002 has a tendency to overestimate the severity of the cases and may lead to overtreatment in some cases. On the other hand, the severity rating system by JRS GL 2008 seemed to be more accurate and closely correlated with the efficacy of the treatment. It is suggested that JRS GL 2008 is more useful in clinical practice for accurately judging the severity of the disease and initiating appropriate subsequent antibiotic therapy. PMID- 21584725 TI - Recent trends in adult-onset septic arthritis of the knee and hip: retrospective analysis of patients treated during the past 50 years. AB - This study was a retrospective analysis of 53 adult patients with septic arthritis (SA) of the knee or hip treated during the years from 1955 to 2005 in Tottori University Hospital in Japan. Patients with postoperative infection, infection caused by trauma, and periprosthetic infection were excluded. The 50 year period between 1955 and 2005 was divided into five periods: there were 5 patients in the first decade, 9 in the second decade, 11 in the third decade, 10 in the fourth decade, and 18 in the fifth decade. All SA occurred in the knee until the fourth decade. Five cases of septic arthritis in the hip occurred in the fifth decade. In contrast to the decrease in direct infections (post intraarticular injection), hematogenous infections were observed to increase after 1986. The rate of SA caused by Staphylococcus aureus (including methicillin resistant Staphylococcus aureus, MRSA) had been highest during the 50 years. Infections caused by MRSA, comprising 22% of all staphylococcal infection, occurred in the fifth decade. The numbers of patients with comorbid conditions such as diabetes increased during the 50-year period. This study indicated that patients with SA have been increasing in number. Furthermore, hematogenous SA has been increasing. The increase in occurrence of SA could result from increase in opportunistic infection, occurrence of SA of the hip, and increase in MRSA infection. PMID- 21584726 TI - Multifocal mucosa-associated lymphoid tissue lymphoma associated with IgG4 related disease: a case report. PMID- 21584727 TI - Age-related changes in functional visual acuity in healthy individuals. AB - OBJECTIVES: To investigate the age-related alterations in functional visual acuity (FVA) in healthy individuals. DESIGN: A prospective non-comparative multi center study. SETTING AND PARTICIPANTS: Fifty-four eyes of 54 normal subjects with best corrected visual acuities better than 20/20 seen at the outpatient clinics of the Department of Ophthalmology at Keio University, Minamiaoyama Eye Clinic and Ishida Eye Clinic were studied. MEASUREMENTS: FVA measurements, Schirmer test, BUT, tear clearance rate and fluorescein vital staining scores were obtained. RESULTS: Schirmer test scores, BUT values and fluorescein vital staining scores did not show significant changes (p > 0.05), but there were significant differences in tear clearance rates among the age groups (p < 0.05). Tear function index, which is a value obtained from multiplying a Schirmer test score by the tear clearance rate, also showed significant differences in the age groups (p < 0.05). The mean logMAR FVA score decreased significantly in the older groups (p < 0.05), while the mean conventional VA score did not show significant differences among the age groups. Moreover, there were significantly more eyes with lower minimum VA scores in the older age groups (p < 0.05). LogMAR minimum VA appeared to be significantly related to the tear clearance rates in subjects 60 years and older (p < 0.05). CONCLUSIONS: FVA testing seems to be a useful method of assessing the age-related decline in dynamic visual and tear functions. PMID- 21584728 TI - Long-term impacts of genome-enabled selection. AB - The objective was to evaluate the effects of directional selection based on estimated genomic breeding values (GEBVs) for a quantitative trait. Selection affects GEBV prediction accuracy as well as genetic architecture via changes in allelic frequencies and linkage disequilibrium (LD), and the resulting changes are different from those in the absence of selection. How marker density affects long-term GEBV accuracy and selection response needs to be understood as well. Simulations were used to characterize the impact of selection based on GEBVs over generations. Single-nucleotide polymorphism (SNP) marker effects were estimated with the Bayesian Lasso method in the base generation, and these estimates were used to calculate the GEBVs in subsequent generations. GEBV accuracy decreased over generations of selection, and it was lower than under random selection, where a decay took place as well. In the long term, selection response tended to reach a plateau, but, at higher marker density, both the magnitude and duration of the response were larger. Selection changed quantitative trait loci (QTL) allele frequencies and generated new but unfavorable LD for prediction. Family effects had a considerable contribution to GEBV accuracy in early generations of selection. PMID- 21584729 TI - X inactivation testing for identifying a non-syndromic X-linked mental retardation gene. AB - The purpose of this study was to identify a gene causing non-syndromic X-linked mental retardation in an extended family, taking advantage of the X chromosome inactivation status of the females in order to determine their carrier state. X inactivation in the females was determined with the androgen receptor methylation assay; thereafter, the X chromosome was screened with evenly spaced polymorphic markers. Once initial linkage was identified, the region of interest was saturated with additional markers and the males were added to the analysis. Candidate genes were sequenced. Ten females showed skewed inactivation, while six revealed a normal inactivation pattern. A maximal lod score of 5.54 at theta = 0.00 was obtained with the marker DXS10151. Recombination events mapped the disease gene to a 17.4-Mb interval between the markers DXS10153 and DXS10157. Three candidate genes in the region were sequenced and a previously described missense mutation (P375L) was identified in the ACSL4/FACL4 gene. On the basis of the female X inactivation status, we have mapped and identified the causative mutation in a gene causing non-syndromic X-linked mental retardation. PMID- 21584730 TI - CCAAT/enhancer binding protein-beta negatively regulates the expression of glycerol-3-phosphate dehydrogenase 1 in pig PK-15 cells. AB - Soluble glycerol-3-phosphate dehydrogenase 1 (GPD1, EC 1.1.1.8) plays important roles in the synthesis of triacylglycerol and in the glycerol-3-phosphate shutter. Though GPD1 is expressed in most adult tissues, little is known about the regulation of its expression. In this study, we analyzed the characters, organization and core region of the promoter of pig GPD1 gene by in silico analysis and activity detection of deletion mutants. We also identified and testified the negative regulation effect of C/EBP beta on pig GPD1 gene by Chromatin immunoprecipitation (ChIP) assay and over-expression experiments in cultured pig kidney cells. Compared to that of human, pig GPD1 gene promoter has three conserved regions and one deletion region. In silico analysis indicated that pig GPD1 promoter was TATA-less with at least 3 CpG islands of over 200 bp in length and over 60% in GC content. The activity detection of deletion mutants suggested that the essential elements required for the optimal promoter activity scatter in the promoter region, while the core promoter region was from -422 bp to -1 bp. Chromatin immunoprecipitation (ChIP) assay results indicated that C/EBP beta had plenty of binding sites in pig GPD1 promoter with the common cis-element (5'- TKNNGCAAK -3'). The over-expression examination of C/EBP beta showed that the expression of GPD1 was negatively regulated by C/EBP beta in pig kidney cells. Overall, our study revealed that the pig GPD1 promoter is a TATA-less promoter, and in promoter region, the binding sites of C/EBP beta share common motif of (5'-TKNNGCAAK -3'). We also showed that pig GPD1 gene is regulated negatively by C/EBP beta in cultured kidney cells. PMID- 21584731 TI - Identification of the chromosome complement and the spontaneous 1R/1V translocations in allotetraploid Secale cereale * Dasypyrum villosum hybrids through cytogenetic approaches. AB - Genome modifications that occur at the initial interspecific hybridization event are dynamic and can be consolidated during the process of stabilization in successive generations of allopolyploids. This study identifies the number and chromosomal location of ribosomal DNA (rDNA) sites between Secale cereale, Dasypyrum villosum, and their allotetraploid S. cereale * D. villosum hybrids. For the first time, we show the advantages of FISH to reveal chromosome rearrangements in the tetraploid Secale * Dasypyrum hybrids. Based on the specific hybridization patterns of ribosomal 5S, 35S DNA and rye species-specific pSc200 DNA probes, a set of genotypes with numerous Secale/Dasypyrum translocations of 1R/1V chromosomes were identified in successive generations of allotetraploid S. cereale * D. villosum hybrids. In addition we analyse rye chromosome pairs using FISH with chromosome-specific DNA sequences on S. cereale * D. villosum hybrids. PMID- 21584732 TI - Self-esteem mediates the relationship between maladaptive perfectionism and depression in chronic fatigue syndrome. AB - Patients with chronic fatigue syndrome (CFS) often experience depression which may negatively affect prognosis and treatment outcome. Research has shown that depression in CFS is associated with maladaptive or self-critical perfectionism. However, currently, little is known about factors that may explain this relationship, but studies in nonclinical samples suggest that low self-esteem may be an important mediator of this relationship. The present study therefore examined whether self-esteem mediated the cross-sectional association between maladaptive perfectionism and severity of depression in 192 patients meeting Centres for Disease Control and Prevention criteria for CFS. Patients completed self-report measures of maladaptive perfectionism, self-esteem, depression, and fatigue. Regression analyses and more direct tests of indirect effects (i.e., the Sobel test and bootstrapping) were used to test for mediation. Congruent with expectations, we found that self-esteem fully mediated the relationship between maladaptive perfectionism and depression in CFS. Findings from this study suggest that self-esteem may explain the link between maladaptive perfectionism and depression in CFS, which may have important implications for the treatment and prevention of depression in these patients. PMID- 21584733 TI - [Evidence-based update in hip arthroplasty]. AB - The present manuscript provides an overview of current evidence-based data and new clinically relevant developments in the field of hip arthroplasty. A multitude of current clinical trials have focussed on tribology with special interest on metal-on-metal implants. Large trials from implant registries have defined specific risk factors for early implant failure and pseudotumors in surface replacement. Furthermore, new ceramic liners and femoral head implants have been investigated in randomized trials. Apart from other very interesting studies, the results of large meta-analyses are now available for laboratory values in periprosthetic infection, antibiotic prophylaxis, regional anesthesia, prevention of thromboembolism, implant fixation, navigation and clinical pathways to prevent complications. PMID- 21584734 TI - [Periprosthetic infections following total hip replacement with ESBL-forming bacteria: importance for clinical practice]. AB - Implant infections remain feared and severe complications after total hip replacement. An even higher rate of periprosthetic infections can be observed after revision surgery in comparison to primary total hip replacement. An additional threat for patients with artificial joints arises from the fact that bacteria resistant to a multitude of antibiotics are encountered with increasing frequency in the hospital setting.Among these the enterobacteria producing extended spectrum beta-lactamases (ESBL) are the second most frequent group of multiresistant pathogens. ESBLs are enzymes which possess the ability to hydrolyse third and fourth generation cephalosporins resulting in a distinctive resistance against these antibiotics. Even though ESBLs were first described in the early 1980's and now represent pathogens of utmost importance in intensive care units, they have been hardly considered in orthopedic and trauma surgery.In the present manuscript we provide an overview of the epidemiology and diagnostics of ESBL-expressing bacteria and demonstrate the difficulties in managing implant associated infections with resistant bacteria. Furthermore, we emphasize the importance of recognizing ESBL-positive bacteria as increasingly important pathogens which require special precautions and treatment. Clinical evaluations suggest that ESBLs in orthopedic and trauma surgery are not a rare phenomenon any more. PMID- 21584735 TI - [Heterotopic ossifications in total hip arthroplasty: prophylaxis and therapy]. AB - Heterotopic ossification (HO) is a frequent and occasionally severe complication after total hip arthroplasty. Clinical symptoms of this benign abnormal bone formation are loss of mobility and local pain. The etiology and pathomechanisms are not yet completely understood. Overexpression of bone morphogenetic proteins and dysregulation of prostaglandin metabolism seem to be relevant. Medication with non-steroidal anti-inflammatory drugs (NSAIDs) and perioperative single dose radiotherapy are used for prophylaxis, whereby radiotherapy should only be performed in patients with a history of HO or additionally after resection of HO. From currently available data selective cyclooxygenase-2 inhibitors seem to have a preventive efficacy equal to the classical NSAIDs diclofenac and indometacin. This work discusses current knowledge about the pathophysiology, risk factors and the clinical approach for prevention and treatment of HO. PMID- 21584737 TI - Cannabinoid WIN 55,212-2 inhibits TRPV1 in trigeminal ganglion neurons via PKA and PKC pathways. AB - Although the inhibitory effect of cannabinoids on transient receptor potential vanilloid 1 (TRPV1) channel may explain the efficacy of peripheral cannabinoids in antihyperalgesia and antinociceptive actions, the mechanism for cannabinoid induced inhibition of TRPV1 in primary sensory neurons is not understood. Therefore, we explored how WIN55,212-2 (WIN, a synthetic cannabinoid) inhibited TRPV1 in rat trigeminal ganglion neurons. A "bell"-shaped concentration-dependent curve was obtained from the effects of WIN on TRPV1 channel. The maximal inhibition on capsaicin-induced current (I (cap)) by WIN was at a concentration of 10(-9) M, and at this concentration I (cap) was reduced by 95 +/- 1.6%. When the concentration of WIN was at 10(-6) M, it displayed a stimulatory effect on I (cap). In this study, several intracellular signaling transduction pathways were tested to study whether they were involved in the inhibitory effects of WIN on I (cap). We found that the inhibitory effect of WIN on I (cap) was completely reversed by PKA antagonists H-89 and KT5720 as well as by PKC antagonists BIM and staurosporine. It was also found that the inhibitory effect was partly reversed by PKG antagonist PKGi, while G-protein antagonist GDP-betas/pertussis toxin (PTX) and PLC antagonist U-73122 had no effect on the inhibitory effect of WIN on I(cap). These results suggest that several intracellular signaling transduction pathways including PKA and PKC systems underlie the inhibitory effects of WIN on I (cap); however, G protein-coupled receptors CB1 or CB2 were not involved. PMID- 21584736 TI - Involvement of endothelial-derived relaxing factors in the regulation of cerebral blood flow. AB - Despite numerous researches and advances in the present times, delayed cerebral vasospasm remains a severe complication leading to a high mortality and morbidity in patients with subarachnoid hemorrhage (SAH). Since the discovery of endothelium-derived relaxing factor (EDRF) in 1980, its role in delayed cerebral vasospasm after SAH has been widely investigated as well as in regulation of basic cerebral blood flow, pathophysiology of vasoconstriction and application on prevention and treatment of cerebral vasospasm. Among all the EDRFs, nitric oxide has caught the most attention, and the other substances which display similar properties with characteristics of EDRF such as carbon monoxide (CO), hydrogen sulfide (H(2)S), hydrogen peroxide (H(2)O(2)), potassium ion (K(+)) and methane (CH(4)) have also evoked great interest in the research field. This review provides an overview of recent advances in investigations on the involvement of EDRFs in the regulation of cerebral blood flow, especially in cerebral vasospasm after SAH. Possible therapeutic measures and potential clinical implications for cerebral vasospasm are also summarized. PMID- 21584739 TI - Safety and tolerability of dapsone for the treatment of patients with drug resistant, partial-onset seizures: an open-label trial. AB - Dapsone has shown anti-convulsive properties in animal models of epilepsy. In the present study, we tested the safety and tolerability of dapsone as adjunctive therapy in adult patients with drug-resistant partial-onset seizures. Twenty-two adult patients with drug-resistant partial-onset seizures were included. After a 3-month baseline period, patients received dapsone 100 mg per day, for a 3-month evaluation period. Plasma concentrations of anti-epileptic drugs (AEDs) did not significantly change during the study. No alteration of mean clinical laboratory values was observed. The reported adverse events were: mild methemoglobinemia (50%), headache (31.8%), paleness (27.3%) and somnolence (4.5%).Sixteen of 22 patients reduced their seizure frequency in more than 50% as a result of dapsone treatment. Three subjects remained seizure-free during the entire dapsone treatment period. This open-label study of adjunctive dapsone therapy at 100 mg/day suggests that dapsone is safe, and well-tolerated in adults with drug resistant partial-onset seizures. PMID- 21584740 TI - Cognitive impairment and event-related potentials in paediatric multiple sclerosis: 2-year study. AB - Approximately, 3-10% of patients with multiple sclerosis (MS) present a disease onset before the age of 18 years. Although growing attention is dedicated to cognitive impairment and its functional consequences in paediatric MS, so far no study has explored possible neurophysiologic correlates. The study's aim was to describe event-related potentials in relationship with cognitive performance in children and adolescents with MS compared with demographically matched healthy controls (HC), providing two-year follow-up data. Six MS subjects aged between 9 and 17 years were assessed through an extensive neuropsychological battery at two time points. Event-related potentials with an odd-ball acoustic paradigm were also recorded in the patients and in nine HC. At baseline, four out of six patients failed three or more cognitive tasks and were classified as cognitively impaired. In all the cognitively impaired patients, we found abnormal latencies and amplitudes of the P300. After 2 years, five patients exhibited a deteriorating cognitive performance and a corresponding deterioration of the P300 parameters. In our group of children and adolescents with MS, changes in P300 parameters proceeded in parallel with deteriorating cognitive performance. P300 might represent an objective parameter to monitor cognitive changes in paediatric MS. PMID- 21584738 TI - Memantine effects on behaviour in moderately severe to severe Alzheimer's disease: a post-marketing surveillance study. AB - The aim of this study is to evaluate memantine effectiveness on behavioural and psychological symptoms of dementia (BPSD) in clinical practice and to identify variables that may predict the therapy effects. The effects of memantine on behaviour were analysed in the database of a post-marketing surveillance study promoted by the Lombardy Region Health Office and involving 43 Alzheimer's disease (AD) Units. From July to December 2005, 399 moderately severe-to-severe AD patients free of cholinergic medications were enrolled, treated with memantine and followed-up for 6 months. BPSD were assessed in a subgroup of 297 patients [mean age 77 +/- 8 years; 73% females; mean neuropsychiatric inventory (NPI) score 28 +/- 24] for whom the 12-item NPI subscores at baseline, and at 3 and 6 months were available. The 12 BPSD were clustered as follows: affect, physical behaviour, psychosis and hypomania. The main outcome measure was the proportion of individual cluster responders at 6 months of therapy. The proportion of individual cluster responders was 30% affect, 24% physical behaviour, 29% psychosis, 27% hypomania. Patients taking 20 mg memantine daily during the study period had a statistically significant higher probability to experience behavioural improvement than those who discontinued treatment or did not complete memantine titration (affect OR 9.0; 95% CI 3.8-21.6; physical behaviour OR 17.8; 95% CI 5.9-53.6; psychosis OR 23.6; 95% CI 5.1-110.8). The logistic regression analysis was not applicable to the hypomania subsyndrome because of the low cluster prevalence. The standard 20 mg daily memantine treatment regimen was found to be associated with a modest 6-month behavioural improvement in the affect, physical behaviour and psychosis domains in 24-30% of patients. PMID- 21584741 TI - Central pontine myelinolysis presented after prophylactic cranial irradiation in small cell lung cancer. AB - Prophylactic cranial irradiation (PCI) should now be considered as a part of the standard treatment of patients with small cell lung cancer (SCLC) in complete remission. The PCI has been offered in SCLC to reduce the incidence of brain metastasis and increase survival. The complications of PCI were reported brain necrosis, seizure or dementia. The complications were more frequent when chemotherapy was given at the time of cranial irradiation, or large radiation fraction size was employed. It is established that the pathophysiological reaction to irradiation in the normal brain tissue is necrosis, demyelinization, and diffuse changes due to wall thickening of the vascular structures. However, central pontine myelinolysis (CPM) of low dose irradiation like PCI is very rare. We report a patient with the classical syndrome of CPM following PCI for SCLC. The diagnosis was supported by typical features on magnetic resonance imaging. PMID- 21584743 TI - Open repair for massive rotator cuff tear with a modified transosseous-equivalent procedure: preliminary results at short-term follow-up. AB - BACKGROUND: Many surgical procedures have been reported for rotator cuff tears. We adopted the modified transosseous-equivalent procedure, also termed "surface holding repair with transosseous sutures," and demonstrated that this procedure has a biomechanical advantage regarding the concentration of stress on the tendon stump. This study aimed to evaluate the clinical and structural outcomes of this technique, which has been demonstrated by postoperative magnetic resonance imaging (MRI) to produce high intact rates. METHODS: Twenty-nine massive rotator cuff tears involving at least two tendons were treated by open repair using this procedure. Twenty-four patients were evaluated at an average of 43.2 months (range 24-71) postoperatively (the follow-up rate was 83.8%). The pre- and postoperative clinical outcomes were examined using the scoring system of the Japanese Orthopedic Association (JOA score). In an A-P radiograph, the presence of osteoarthritis (OA) of the glenohumeral joint and upward migration of the humeral head were compared pre- and postoperatively. The repair integrity of the cuff tendon was evaluated by applying Sugaya's classification to the postoperative MRIs. RESULTS: The JOA score improved from 42.8 points preoperatively to 89.3 points at final follow-up. Radiographic examination showed that OA progressed in 16.7% and upward migration of the humeral head progressed in 20.8%. Postoperative MRI scans revealed 14 shoulders with type 1 repair based on Sugaya's classification, 4 shoulders with type 2, 4 shoulders with type 3, 2 shoulders with type 4, and no shoulders with a type 5 repair. CONCLUSIONS: Although osteoarthritis of the glenohumeral joint and upward migration of the humeral head had both progressed postoperatively in some cases, postoperative MRI scans revealed that 91.7% of the repairs resulted in a continuous rotator cuff. Therefore, this technique produces a high healing rate. PMID- 21584742 TI - Expression of locus coeruleus mineralocorticoid receptor and glucocorticoid receptor in rats under single-prolonged stress. AB - The pathogenesis of the post-traumatic stress disorder (PTSD) may involve dysfunction of several brain structures, such as the amygdala, locus coeruleus, hippocampus, noradrenergic system as well as the hypothalamic-pituitary-adrenal (HPA) axis. The cortisol and locus coeruleus dysfunction may affect the secretion of corticosterone. The present study was designed to examine the expression of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the locus coeruleus in the rats treated with single-prolonged stress (SPS). The results showed that the expression of MR had a sharp decline on day 1, but gradually increased on days 4, 7, 14, and 28. The expression of GR gradually increased on days 1, 4, and 7, but decreased on days 14 and 28, respectively.MR and GR in the locus coeruleus may have a role in the development of long-term persistent neuropsychological sequelae in PTSD. PMID- 21584744 TI - Treatment of collagen-induced arthritis with recombinant plasminogen-related protein B: a novel inhibitor of angiogenesis. AB - BACKGROUND: We have previously reported that recombinant human plasminogen related protein B (rPRP-B), a putative 9-kDa protein that closely resembles the activation peptide of plasminogen, has shown significant inhibition of tumor growth through inhibition of angiogenesis. Based on recent reports suggesting a close relationship between rheumatoid arthritis (RA) and angiogenesis, we hypothesized that this compound would regulate inflammatory conditions in RA. The present study therefore tested the effects of rPRP-B in the treatment of collagen induced arthritis (CIA) to elucidate the mechanisms underlying these effects. METHODS: DBA/1J mice immunized with type II collagen to induce CIA were monitored to assess the effects of rPRP-B on clinical severity of the disease. Pathological changes in joints, including vessel formation and vascular endothelial growth factor (VEGF) production, were examined histologically. Bone destruction was radiologically evaluated. In vitro studies on the effects of rPRP-B on cell proliferation and production of VEGF in interleukin (IL)-1beta or basic fibroblast growth factor (bFGF)-stimulated human synoviocytes were also performed. RESULTS: Development of CIA was effectively inhibited by rPRP-B. Radiological examinations revealed that the protein reduced bone destruction in CIA. CIA-induced vessel formation and VEGF expression in vivo were also reduced. In vitro mechanistic studies demonstrated that rPRP-B affected human synoviocyte proliferation and VEGF production stimulated by IL-1beta and bFGF. CONCLUSIONS: Given the ability to effectively promote multistep anti-angiogenic activities, including cell growth inhibition and cytokine regulation, rPRP-B represents a promising candidate for a novel therapeutic agent against RA. PMID- 21584745 TI - Osteochondral impaction of the posterior acetabular surface without cortical fracture of any wall or column: an undescribed pattern of acetabular injury. AB - Surgical treatment of a unusual acetabular fracture is described. This fracture was characterized by impaction and breaking down of the posterior articular surface and comminution of lamina quadrilatera lower portion, without cortical fracture of both columns. The fracture was treated surgically through the Kocher Langenbeck approach. A small hole was created in the acetabulum posterior wall, the impacted fragment was reduced, and the bone defect was filled with autologous bone from the greater trochanter. A plate was shaped in order to fix both bone graft and fractured fragment. PMID- 21584747 TI - The understanding and operative treatment of cerebral palsy at the turn of the twentieth century: Harvey Cushing's early forays into pediatric neurosurgery. AB - INTRODUCTION: At the turn of the twentieth century, cerebral palsy and its treatment were not well understood, and a variety of treatment modalities were tested with only limited success. MATERIAL AND METHODS: Following IRB approval and through the courtesy of the Alan Mason Chesney Archives, we reviewed the Johns Hopkins Hospital surgical files from 1896-1912. Eight patients who received a diagnosis consistent with cerebral palsy and were treated surgically by Dr. Cushing were selected for further analysis and are described here. RESULTS: A total of eight patients underwent operative intervention for treatment of symptoms consistent with cerebral palsy. Of these, seven were male; the mean age was 4.9 years (range, 1.5 to 12). Five patients underwent decompressive craniotomies, one underwent tenotomies, one underwent transection of the spinal nerve roots, and one underwent primary transection of the spinal nerve roots with secondary tenotomies. Four representative cases are reported here. CONCLUSIONS: Cushing's contributions to pediatric neuro-oncology have been previously described, but his endeavors in non-oncologic realms remain largely unknown. Although Cushing employed previously described operative approaches for the treatment of cerebral palsy, parents brought their children to him from across the nation, in an era when long distance travel was tedious, and a financial burden. These cases serve to emphasize Cushing's interest in improving patient quality of life, and his broad contributions to pediatric neurosurgery. PMID- 21584746 TI - Web-based survey of resources for treatment and long-term follow-up for children with brain tumors in developing countries. AB - INTRODUCTION: Information about pediatric survivors of brain tumors in developing countries is scant. PURPOSE: In this study, we aimed to investigate the availability of resources for treatment and long-term follow-up of children with central nervous system tumors in developing countries. MATERIALS AND METHODS: A web-based questionnaire on available services and follow-up of brain tumor survivors was posted at www.cure4kids.org , and registered users were invited to participate. RESULTS: A total of 140 evaluable responses from developing countries (n = 103) and high-income countries (n = 37) were obtained. There was a significant correlation between gross national income and the availability of services for treatment and follow-up and between patient load and the availability of some services. CONCLUSION: The resources for treatment and long term follow-up of children with brain tumors need to be improved in developing countries. PMID- 21584748 TI - Leptin, leptin gene and leptin receptor gene polymorphism in heart failure with preserved ejection fraction. AB - Heart failure with a normal ejection fraction (HFNEF) is common in obesity and coronary artery disease (CAD). Both ischemia and reperfusion induce leptin (LEP) and leptin receptor (LEPR) gene expression. We aimed to investigate the possible associations of serum leptin, leptin gene and leptin receptor gene polymorphism with HFNEF in patients with CAD. 100 Egyptian CAD patients with HFNEF and 100 healthy subjects (the control group) were genotyped for LEP and LEPR polymorphism. Leptin levels were measured. Serum leptin levels were significantly increased in patients compared to the control group. There was a significant increase in the leptin gene (AA genotype) and the leptin receptor gene (RR genotype) in HFNEF patients compared to the control group. Leptin levels, leptin gene (AA genotype) and LEPR (RR genotype) were more associated with NYHA III than with NYHA I and II. We thus concluded that HFNEF is associated with increased serum leptin levels, and the LEP AA genotype or LEPR RR genotype carries at least a threefold increased risk of developing HFNEF. PMID- 21584749 TI - Steady-state B-type natriuretic peptide levels in patients with atrial fibrillation of various clinical backgrounds. AB - B-type natriuretic peptide level is increased in patients with atrial fibrillation. The aim of the present study was to present the distribution of steady-state B-type natriuretic peptide levels of various clinical backgrounds and to elucidate the usefulness of measuring them in patients with atrial fibrillation. B-type natriuretic peptide was measured in stable conditions in patients with atrial fibrillation (74 +/- 10 y/o, n = 473). The average B-type natriuretic peptide level was 161 +/- 202 (median 101) pg/ml. Multiple regression analysis showed that age, left ventricular ejection fraction, left atrial diameter, structural heart disease, chronic atrial fibrillation, and heart failure symptoms were independently associated with elevated B-type natriuretic peptide levels. However, in chronic atrial fibrillation patients without structural heart disease, B-type natriuretic peptide levels did not differ between those with and without heart failure symptoms. Notably, B-type natriuretic peptide levels were high (>= 150 pg/ml) in 41% of asymptomatic chronic atrial fibrillation without structural heart disease. Steady-state B-type natriuretic peptide levels of various clinical backgrounds were presented. Contributions of BNP elevation by clinical variables were somewhat different in different population. B-type natriuretic peptide was elevated in substantial percentage of asymptomatic chronic atrial fibrillation even without structural heart disease. PMID- 21584750 TI - Inhibition of cyclooxygenase-2 modulates phenotypic switching of vascular smooth muscle cells during increased aortic blood flow. AB - This study investigates the interactions between cyclooxygenase (COX-2) and vascular smooth muscle cell (VSMC) phenotypic switching, the two important coupling mechanisms of the vasculature on arterial remodeling in response to high laminal shear stress. High aortic blood flow was induced by creating a fistula in the abdominal aorta and the adjacent IVC of anesthetized rats. Celecoxib, a selective COX-2 inhibitor (25 mg/kg/day), was fed in the chow, and animals were killed 8 weeks later. Blood flow, vasoreactivity and morphological changes in the aorta proximal to the fistula were measured. Concentrations of collagen, expression of desmin and smooth muscle myosin heavy chain (SM-MHC)-II in the aorta were determined. Celecoxib significantly increased aortic blood flow and reduced the contraction responses of aorta. Decreased medial thickness, presence of intimal thickening and derangement of elastic lamina were found in the aortic section of celecoxib-treated animals. Celecoxib significantly reduced the tissue content of collagen and upregulated expression of SM-MHC-II and desmin in the high-flow aorta. Inhibition of COX-2 enzymatic activity in the aorta exposed to higher blood flow resulted in increased blood flow and vascular remodeling. These functional changes were accomplished by VSMC phenotypic switching and reduced biosynthesis of collagen. PMID- 21584751 TI - Off-pump surgery for the poor ventricle? AB - Severely decreased ejection-fraction is an established risk-factor for worse outcome after cardiac surgery. We compare outcomes of off-pump coronary artery bypass grafting (OPCAB) and on-pump CABG (ONCABG) in patients with severely compromised EF. From 2004 to 2009, 478 patients with a decreased EF <=35% underwent myocardial-revascularization. Patients received either OPCAB (n = 256) or ONCABG (n = 222). Propensity score (PS), including 50 preoperative risk factors, was used to balance characteristics between groups. PS adjusted logistic regression analysis was performed to assess mortality and major adverse cardiac and cerebrovascular events (MACCE). A composite endpoint for major non-cardiac complications such as respiratory failure, renal failure, rethoracotomy was applied. Complete revascularization (CR) was assumed when the number of distal anastomoses was larger than that of diseased vessels. There was no difference for mortality (2.3 vs. 4.1%; PS-adjusted odds ratio (PS-OR) = 1.05; p = 0.93) and MACCE (13.7 vs. 17.6%; PS-OR = 1.22; p = 0.50) including myocardial-infarction (1.4 vs. 4.9%; PS-OR = 0.39; p = 0.26), low cardiac output (2.3 vs. 4.7%; PS-OR = 0.75; p = 0.72) and stroke (2.3 vs. 2.7%; PS-OR = 0.69; p = 0.66). OPCAB patients presented with a trend to less frequent occurrence of the non-cardiac composite (12.1 vs. 22.1%; PS-OR = 0.54; p = 0.059) including renal dysfunction (PAOR = 0.77; 95% CI 0.31-1.9; p = 0.57), bleeding (PAOR = 0.42; 95% CI 0.14-1.20; p = 0.10) and respiratory failure (PAOR = 0.39; 95% CI 0.05-3.29; p = 0.39). The rate of complete revascularization was similar (92.2 vs. 92.8%; PS-OR = 0.75; p = 0.50). OPCAB in patients with severely decreased EF is safe and feasible. It may even benefit these patients in regard to non-cardiac complications and does not come at cost of less complete revascularization. PMID- 21584753 TI - ? PMID- 21584752 TI - Estradiol and triiodothyronine differentially modulate reproductive and thyroidal genes in male goldfish. AB - While the reproductive and thyroidal systems are extensively studied in fish, they are largely studied in isolation from one another, but there is evidence supporting cross-regulation between these two systems. To better understand hormone action and the potential cross-regulation between estrogen and thyroid hormones, we examined gene expression changes in estrogen receptor (ER) and thyroid receptor (TR) subtypes and key enzymes responsible for the local synthesis and availability of estrogen and thyroid hormones (aromatase B and deiodinase, respectively) in sexually regressed, adult, male goldfish in response to 3 days waterborne exposures to 17beta-estradiol (E2; 1 nM), triiodothyronine (T3; 20 and 100 nM), and co-treatments thereof. Treatments with E2 alone did not effect ER subtype transcripts in the liver, telencephalon, or testis; however, in the testis, 1 nM T3 decreased ERalpha and ERbeta1 and co-treatments of T3 and E2 decreased ERbeta1 levels. TRalpha-1 and TRbeta transcripts were not auto regulated by T3 or cross-regulated by E2. Although deiodinase type I levels were also unaffected, deiodinase type II decreased in response to T3 treatments. Liver deiodinase type III transcripts increased in response to T3 treatments, while E2 exhibited antagonistic effects on this T3-mediated induction. These results provide novel evidence of cross-talk between the reproductive and thyroid endocrine axes in a model teleost. PMID- 21584754 TI - Microbial activity and organic matter dynamics during 4 years of irrigation with treated wastewater. AB - The global changes in rainfall frequency and quantity have subjected arid and semi-arid regions to long periods of drought. As this phenomenon corresponds to increasing trend of water shortage, the use of treated wastewater (TWW) has been suggested as an alternative for irrigation of agricultural crops in these areas. The aim of the study was to investigate the short- and middle-term effects of TWW irrigation on the soil microbial activities and organic carbon content. The microbial community activity was measured every 1-3 months for 4 years in a persimmon (Diospyros kaki) orchard. These activities were used here as an indicator for the soil health. The hydrolysis activity (detected by fluorescein diacetate hydrolysis (FDA) assay) increased during the irrigation season and was significantly higher in soils irrigated with TWW compared to those irrigated with freshwater (FW). This activity was also negatively correlated with dissolved organic carbon (DOC) concentrations during the irrigation season, suggesting that the community degraded the DOC in the soils regardless of its origin. The irrigation season was also characterized by an increase in nitrification potential in both TWW- and FW-irrigated soils, which coincided with high concentrations of nitrate (50 mg kg(-1) soil). Overall, there was an increase in all measured activities during the irrigation season, and they were higher in the TWW soils. However, it appears that after each irrigation season, the potential activity of the community returned to levels similar to or even slightly lower than those of FW-irrigated soil during the wet season, suggesting that the periodic irrigation did not significantly change the soil microbial activity. PMID- 21584755 TI - Dynamics of bacterial communities in cockles (Cerastoderma edule) with respect to trematode parasite (Bucephalus minimus) infestation. AB - The bacterial communities associated with the cockle (Cerastoderma edule) were investigated at the individual level through a 10-month monitoring programme. Temporal changes and those changes associated with a common parasite of the cockle, Bucephalus minimus, were investigated by monthly sampling of individuals, selected based on their shell length (cohort monitoring). Cockle bacterial community abundance (CBCA) and diversity (CBCD) were estimated by epifluorescence microscopy counts and automated ribosomal intergenic spacer analysis, respectively. CBCA showed a temporal pattern peaking at 30 * 10(6) cells per gram of cockle flesh and intervalval liquid in October and a significant 1.8-fold increase linked with B. minimus occurrence. CBCD was characterized by 112 +/- 26 intergenic transcribed spacer (ITS) per individual and showed a relative homology between individuals (52 +/- 6%, Jaccard similarity) in spite of more than 30% of rare ITS. Consistent with an undisturbed evolution of the condition index of the studied cohort individuals as an estimate of their physiological state, neither temporal nor parasite-induced change in CBCA has been related to marked changes in CBCD. PMID- 21584757 TI - Autoclave decomposition method for metals in soils and sediments. AB - Leaching of partially leached metals (Fe, Mn, Cd, Co, Cu, Ni, Pb, and Zn) was done using autoclave technique which was modified based on EPA 3051A digestion technique. The autoclave method was developed as an alternative to the regular digestion procedure passed the safety norms for partial extraction of metals in polytetrafluoroethylene (PFA vessel) with a low constant temperature (119.5 degrees +/- 1.5 degrees C) and the recovery of elements were also precise. The autoclave method was also validated using two Standard Reference Materials (SRMs: Loam Soil B and Loam Soil D) and the recoveries were equally superior to the traditionally established digestion methods. Application of the autoclave was samples from different natural environments (beach, mangrove, river, and city soil) to reproduce the recovery of elements during subsequent analysis. PMID- 21584758 TI - Determination of heavy metals and metals levels in five fish species from Isikli Dam Lake and Karacaoren Dam Lake (Turkey). AB - The concentrations of heavy metals and metals (Zn, Pb, Bi, Cd, Ni, Co, Fe, Mn, Mg, Cu, Cr, Ca, Sr, Na, Li, K) were measured in muscle of five species Cyprinus carpio (from Isikli dam), Scardinius erythrophthalmus (from Isikli dam), Tinca tinca (from Isikli dam), C. carpio (from Karacaoren dam), Carassius carassius (from Karacaoren dam) caught from Isikli and Karacaoren. The highest metal was Na (466.95 MUg/g) in C. carassius, while the lowest levels were Fe (0.37 MUg/g) and Cu (0.37 MUg/g) in C. carpio from Isikli dam. The mean concentrations MUg/g d.w. some of heavy metals in muscle of C. carpio (from Isikli dam), S. erythrophthalmus (from Isikli dam), T. tinca (from Isikli dam), C. carpio (from Karacaoren dam), C. carassius (from Karacaoren dam) were as follows: Cd 2.00-2.10 1.95-2.06-2.27, Zn 4.36-2.64-13.13-13.33-24.47, Pb 1.65-1.24-1.90-2.37-2.41, Co 2.46-2.37-2.48-2.58-2.80, Mg 138.51-154.35-218.59-204.58-202.16, Fe 0.37-2.62 3.17-3.01-12.33, respectively. PMID- 21584756 TI - Bacterial diversity of terrestrial crystalline volcanic rocks, Iceland. AB - Bacteria inhabiting crystalline rocks from two terrestrial Icelandic volcanic lava flows of similar age and from the same geographical region, but differing in porosity and mineralogy, were characterised. Microarray (PhyloChip) and clone library analysis of 16S rRNA genes revealed the presence of a diverse assemblage of bacteria in each lava flow. Both methods suggested a more diverse community at the Domadalshraun site (rhyolitic/andesitic lava flow) than that present at the Hnausahraun site (basaltic lava flow). Proteobacteria dominated the clone library at the Domadalshraun site, while Acidobacteria was the most abundant phylum in the Hnausahraun site. Although analysis of similarities of denaturing gradient gel electrophoresis profiles suggested a strong correlation of community structure with mineralogy, rock porosity may also play an important role in shaping the bacterial community in crystalline volcanic rocks. Clone sequences were most similar to uncultured microorganisms, mainly from soil environments. Of these, Antarctic soils and temperate rhizosphere soils were prominent, as were clones retrieved from Hawaiian and Andean volcanic soils. The novel diversity of these Icelandic microbial communities was supported by the finding that up to 46% of clones displayed <85% sequence identities to sequences currently deposited in the RDP database. PMID- 21584759 TI - An evaluation of improvements in the air quality of Beijing arising from the use of new vehicle emission standards. AB - An innovative approach of mean emission by vehicle type was used in this paper to assess the impact of new vehicle emission standards in Beijing, China during the period of 2000-2005. It was found that CO and NO(x) emissions decreased by 48% and 23%, respectively, from Type O (before 2000) to Type I (year 2000) vehicles. The reductions from Type O to Type II (year 2002) vehicles were 85% and 73% for CO and NO(x), respectively. When all three types of vehicles (Types O, I and II) are combined, the annual per vehicle CO emissions decreased from 586 kg per vehicle per year in 2000 to 324 kg per vehicle per year in 2005, while that of NO(x) decreased from 66.9 to 43.4 kg per vehicle per year, which was mainly resulted from the impact of stringent new vehicle emission standards implemented in years 2000 and 2002. However, the vehicle population increased by 70% during the same time period, which offset the impact of cleaner vehicles. Thus, the total vehicle emission decreased little for CO (885,000 tons in 2000, 837,000 tons in 2005) and even increased slightly for NO(x) (101,000 and 112,000 tons in 2000 and 2005, respectively). The ambient concentrations of CO decreased significantly throughout 2000-2005, the same trend was not observed for NO(2). Correlation analysis (grey correlation and Pearson correlation) between the annual vehicle emissions and annual concentrations of CO, the annual NO(x) emission and annual NO(2) concentration indicated that the implementation of new vehicle emission standards was associated with the abatement of ambient CO and NO(2) concentrations in Beijing. PMID- 21584761 TI - Changes in transcription during recovery from heat injury in Salmonella typhimurium and effects of BCAA on recovery. AB - Mechanisms of recovery from heat injury in Salmonella typhimurium were elucidated. Recovery of the heat-injured S. typhimurium cells in TSB resulted in full recovery after 3 h of incubation at 37 degrees C. The DNA microarray analysis of 30- and 60-min recovering cells resulted in an increase in transcription of 89 and 141 genes, respectively. Among them, 15 genes, with known function, seemed to be somewhat involved in recovery. They encoded proteins involved in branched-chain amino acid (BCAA) transport (livJ, livH), cell envelope integrity (ddg), heat-shock response (cpxP, rrmJ), phage shock protein (pspA), ribosome modulation factor (rmf), virulence (sseB) transcriptional regulation (rpoE, rpoH, rseA, rseB, rseC) and ArcB signal transduction (sixA) and cytoplasmic membrane protein (fxsA). Among them, the effects of BCAA supplementation on recovery from heat injury were studied to confirm the importance of the BCAA transport liv genes during recovery. It was found that supplementation of TSB with 0.1% BCAA resulted in an enhanced recovery of injured cells in comparison to those recovered in TSB without BCAA. Supplementation of BCAA at 0.1% resulted in a cell count increase 4.4-fold greater than that of the control after 1 h incubation. It seems that BCAA promoted the recovery by promoting protein synthesis either directly through their use in translation or indirectly through stimulation of protein synthesis by activation of the Lrp protein. PMID- 21584760 TI - Wound healing activity of carbon monoxide liberated from CO-releasing molecule (CO-RM). AB - Wound microenvironment presents widespread oxidant stress, inflammation, and onslaught of apoptosis. Carbon monoxide (CO) exerts pleiotropic cellular effects by modulating intracellular signaling pathways which translate into cellular protection against oxidative stress, inflammation, and apoptosis. CO-releasing molecules (CO-RMs) deliver CO in a controlled manner without altering carboxyhemoglobin levels. This study observed a potential therapeutic value of CO in the wound healing by using tricarbonyldichlororuthenium (II) dimer (CO releasing molecule (CO-RM)-2), as one of the novel CO-releasing agent. The effect of CO-RM-2 treatment was studied on wound contraction, glucosamine, hydroxyproline levels, and mRNA of cytokines/adhesion molecule in rats using a full-thickness cutaneous wound model and angiogenesis in chick chorioallantoic membrane (CAM) model. CO-RM-2 treatment increased cellular proliferation and collagen synthesis as evidenced by the increase in wound contraction and hydroxyproline and glucosamine contents. The mRNA expression of cytokines endorsed fast healing, as was indicated by the inhibition of pro-inflammatory adhesion molecules such as ICAM-1 and cytokine TNF-alpha and upregulation of anti inflammatory cytokine IL-10. An ELISA assay of IL-10 and TNF-alpha cytokines revealed pro-healing modulation in excision wound by CO-RM-2 treatment. CO-RM significantly promoted the angiogenesis as compared to the iCO-RM group in vitro in CAM model demonstrating pro-angiogenic effects of CO-RM-2 in wound healing process. These results indicate that CO-RM-2 may have a potential application in the management of recalcitrant/obstinate wounds wherein, active wound healing is desired. This study also opens up a new area of research for the synthesis of novel CO-releasing molecules to be used for such purposes. PMID- 21584762 TI - Sound imaging of nocturnal animal calls in their natural habitat. AB - We present a novel method for imaging acoustic communication between nocturnal animals. Investigating the spatio-temporal calling behavior of nocturnal animals, e.g., frogs and crickets, has been difficult because of the need to distinguish many animals' calls in noisy environments without being able to see them. Our method visualizes the spatial and temporal dynamics using dozens of sound-to light conversion devices (called "Firefly") and an off-the-shelf video camera. The Firefly, which consists of a microphone and a light emitting diode, emits light when it captures nearby sound. Deploying dozens of Fireflies in a target area, we record calls of multiple individuals through the video camera. We conduct two experiments, one indoors and the other in the field, using Japanese tree frogs (Hyla japonica). The indoor experiment demonstrates that our method correctly visualizes Japanese tree frogs' calling behavior. It has confirmed the known behavior; two frogs call synchronously or in anti-phase synchronization. The field experiment (in a rice paddy where Japanese tree frogs live) also visualizes the same calling behavior to confirm anti-phase synchronization in the field. Experimental results confirm that our method can visualize the calling behavior of nocturnal animals in their natural habitat. PMID- 21584763 TI - Severe donor-related Candida keratitis after Descemet's stripping automated endothelial keratoplasty. PMID- 21584765 TI - Establishment and characterization of RNA-edited serotonin 2C receptor isoform cell models and alteration of amyloid precursor protein ectodomain secretion in HEK293 APPSwe cells. AB - RNA editing is a mechanism for generating molecular diversity by altering the genetic code at the level of RNA. The 5-HT(2C) receptor is the only G protein coupled receptor known to be edited. It has been reported that the non-edited 5 HT(2C) receptor stimulates secretion of the APP metabolite APP ectodomain (APPs). However, it remains unknown whether RNA-edited 5-HT(2C) receptors can also affect APPs secretion. In this study, cDNAs of five non-edited or partially/fully edited 5-HT(2C) receptor isoforms (INI, VNI, VNV, VSV and VGV) were stably transfected into HEK293APPSwe cells to detect the cell proliferation and APPs secretion. The results demonstrated that the overexpression of INI and VNI caused increased proliferation of host cells while VNV, VSV and VGV caused inverse effects (P < 0.01). Compared with both control and non-edited isoform INI, APPs levels were significantly increased in the four edited 5-HT(2C) receptor isoforms, VNI (P < 0.05), VNV (P < 0.05), VSV (P < 0.05) and VGV (P < 0.01). These results suggest that the RNA editing of the 5-HT(2C) receptor may affect APPs secretion through different signaling pathways related to cell growth and protein processing, and that these cell models will provide appropriate useful information to study the association between the RNA editing of the serotonin 5-HT(2C) receptor and APP metabolism. PMID- 21584764 TI - Recent studies provide an updated clinical perspective on blue light-filtering IOLs. AB - BACKGROUND: Recent reviews of blue light-filtering intraocular lenses (IOLs) have stated their potential risks for scotopic vision and circadian photoentrainment. Some authors have challenged the rationale for retinal photoprotection that these IOLs might provide. Our objective is to address these issues by providing an updated clinical perspective based on the results of the most recent studies. METHODS: This article evaluates the currently available published papers assessing the potential risks and benefits of blue light-filtering IOLs. It summarizes the results of seven clinical and two computational studies on photoreception, and several studies related to retinal photoprotection, all of which were not available in the previous reviews. These results provide a clinical risk/benefit analysis for an updated review for these IOLs. RESULTS: Most clinical studies comparing IOLs with and without the blue light-filtering feature have found no difference in clinical performance for; visual acuity, contrast sensitivity, color vision, or glare. For blue light-filtering IOLs, three comparative clinical studies have shown improved contrast sensitivity and glare reduction; but one study, while it showed satisfactory overall color perception, demonstrated some compromise in mesopic comparative blue color discrimination. Comparative results of two recent clinical studies have also shown improved performance for simulated driving under glare conditions and reduced glare disability, better heterochromatic contrast threshold, and faster recovery from photostress for blue light-filtering IOLs. Two computational and five clinical studies found no difference in performance between IOLs with or without blue light-filtration for scotopic vision performance and photo entrainment of the circadian rhythm. The rationale for protection of the pseudophakic retina against phototoxicity is discussed with supporting results of the most recent computational, in-vitro, animal, clinical, and epidemiological investigations. CONCLUSIONS: This analysis provides an updated clinical perspective which suggests the selection of blue light-filtering IOLs for patients of any age, but especially for pediatric and presbyopic lens exchange patients with a longer pseudophakic life. Without clinically substantiated potential risks, these patients should experience the benefit of overall better quality of vision, reduced glare disability at least in some conditions, and better protection against retinal phototoxicity and its associated potential risk for AMD. PMID- 21584766 TI - Emerging therapies for neurodegenerative lysosomal storage disorders - from concept to reality. AB - Lysosomal storage disorders are inherited metabolic diseases in which a mutation in a gene encoding a lysosomal enzyme or lysosome-related protein results in the intra-cellular accumulation of substrate and reduced cell/tissue function. Few patients with neurodegenerative lysosomal storage disorders have access to safe and effective treatments although many therapeutic strategies have been or are presently being studied in vivo thanks to the availability of a large number of animal models. This review will describe the comparative advancement of a variety of therapeutic strategies through the 'research pipeline'. Our goal is to provide information for clinicians, researchers and patients/families alike on the leading therapeutic candidates at this point in time, and also to provide information on emerging approaches that may provide a safe and effective treatment in the future. The length of the pipeline represents the significant and sustained effort required to move a novel concept from the laboratory into the clinic. PMID- 21584768 TI - Response to modeling and notation of DEA with strong and weak disposable outputs. PMID- 21584767 TI - Insulin therapy. AB - Insulin therapy is a vital hormone replacement therapy in type 1 diabetes mellitus. In type 2 diabetes, insulin is indicated if glycaemic goals are not reached by oral anti diabetics, as well as for metabolic detoriation, co morbidities, surgery, pregnancy or contradictions against oral anti diabetics. Insulin preparations are characterized by the onset of the insulin action, the peak profile and duration of action. Available are short acting, long-acting and premixed preparations of human insulin, and insulin analogues. The gold standard of insulin therapy in type 1 diabetes is functional insulin therapy with a basal bolus insulin regimen and control and adaption of the therapy by the patient. Various insulin regimens are available for treating patients with type 2 diabetes, including basal insulin supported oral therapy, supplementary mealtime injection of short acting insulin or insulin analogues, conventional insulin therapy or a basal bolus procedure. The various insulin preparations and regimens make it possible to adapt the therapy according to the patient's individual need. PMID- 21584769 TI - Modeling and notation of DEA with strong and weak disposable outputs. AB - Recent articles published in Health Care Management Science have described DEA applications under the assumption of strong and weak disposable outputs. As we confidently assume that these papers include some methodical deficiencies, we aim to illustrate a revised approach. PMID- 21584770 TI - Automated diagnosis of Alzheimer disease using the scale-invariant feature transforms in magnetic resonance images. AB - In this paper we present an automated method for diagnosing Alzheimer disease (AD) from brain MR images. The approach uses the scale-invariant feature transforms (SIFT) extracted from different slices in MR images for both healthy subjects and subjects with Alzheimer disease. These features are then clustered in a group of features which they can be used to transform a full 3-dimensional image from a subject to a histogram of these features. A feature selection strategy was used to select those bins from these histograms that contribute most in classifying the two groups. This was done by ranking the features using the Fisher's discriminant ratio and a feature subset selection strategy using the genetic algorithm. These selected bins of the histograms are then used for the classification of healthy/patient subjects from MR images. Support vector machines with different kernels were applied to the data for the discrimination of the two groups, namely healthy subjects and patients diagnosed by AD. The results indicate that the proposed method can be used for diagnose of AD from MR images with the accuracy of %86 for the subjects aged from 60 to 80 years old and with mild AD. PMID- 21584771 TI - Image analysis tools for evaluation of microscopic views of immunohistochemically stained specimen in medical research-a review. AB - The aim of this study is to review the methods being used for image analysis of microscopic views of immunohistochemically stained specimen in medical research. The solutions available range from general purpose software to commercial packages. Many studies have developed their own custom written programs based on some general purpose software available. Many groups have reported development of computer aided image analysis programs aiming at obtaining faster, simpler and cheaper solutions. Image analysis tools namely Aperio, Lucia, Metaview, Metamorph, ImageJ, Scion, Adobe Photoshop, Image Pro Plus are also used for evaluation of expressions using immunohistochemical staining. An overview of such methods used for image analysis is provided in this paper. This study concludes that there is good scope for development of freely available software for staining intensity quantification, which a medical researcher could easily use without requiring high level computer skills. PMID- 21584772 TI - A data-mining framework for transnational healthcare system. AB - Medical resources are important and necessary in health care. Recently, the development of methods for improving the efficiency of medical resource utilization is an emerging problem. Despite evidence supporting the use of order sets in hospitals, only a small number of health information systems have successfully equipped physicians with analysis of complex order sequences from clinical pathway and clinical guideline. This paper presents a data-mining framework for transnational healthcare system to find alternative practices, including transfusion, pre-admission tests, and evaluation of liver diseases. However, individual countries vary with respect to geographical location, living habits, and culture, so disease risks and treatment methods also vary across countries. To realize the difference, a service-oriented architecture and cloud computing technology are applied to analyze these medical data. The validity of the proposed system is demonstrated in including Taiwan and Mongolia, to ensure the feasibility of our approach. PMID- 21584773 TI - Conflicting effects of excitatory synaptic and electric coupling on the dynamics of square-wave bursters. AB - Using two-cell and 50-cell networks of square-wave bursters, we studied how excitatory coupling of individual neurons affects the bursting output of the network. Our results show that the effects of synaptic excitation vs. electrical coupling are distinct. Increasing excitatory synaptic coupling generally increases burst duration. Electrical coupling also increases burst duration for low to moderate values, but at sufficiently strong values promotes a switch to highly synchronous bursts where further increases in electrical or synaptic coupling have a minimal effect on burst duration. These effects are largely mediated by spike synchrony, which is determined by the stability of the in-phase spiking solution during the burst. Even when both coupling mechanisms are strong, one form (in-phase or anti-phase) of spike synchrony will determine the burst dynamics, resulting in a sharp boundary in the space of the coupling parameters. This boundary exists in both two cell and network simulations. We use these results to interpret the effects of gap-junction blockers on the neuronal circuitry that underlies respiration. PMID- 21584774 TI - Persistent membranous cross correlations due to the multiplicity of gates in ion channels. AB - Ion channels in excitable cells reveal spontaneous intermittent opening and closing. As the membrane area reduces, this stochasticity enables spontaneous firing and elevates the cell's ability to fire at weaker stimuli. A multiple number of gates are accommodated in each individual ion channel. Here we investigate the possible impact of that gate multiplicity on the cell's function specifically when the membrane area is of limited size. It is shown that a non trivially persistent correlation then takes place between the transmembrane voltage fluctuations (also between the fluctuations in the gating variables) and the component of open channel fluctuations attributed to the above gate multiplicity. This cross correlation persistency is found to be playing a major augmentative role in the elevation of the cell's excitability and spontaneous firing; without the persistency, the cell would be much less excitable. The cross correlation persistency is also found to enhance spike coherence. The stochastic Hodgkin-Huxley equations, put forward by Fox and Lu, are addressed in the context of their recognized failure to produce accurate enough statistics of spike generation. Our results indicate that the major source of that inaccuracy is the incapability of the stochastic Hodgkin-Huxley description to reflect the above cross correlation persistency. PMID- 21584775 TI - An information-geometric framework for statistical inferences in the neural spike train space. AB - Statistical inferences are essentially important in analyzing neural spike trains in computational neuroscience. Current approaches have followed a general inference paradigm where a parametric probability model is often used to characterize the temporal evolution of the underlying stochastic processes. To directly capture the overall variability and distribution in the space of the spike trains, we focus on a data-driven approach where statistics are defined and computed in the function space in which spike trains are viewed as individual points. To this end, we at first develop a parametrized family of metrics that takes into account different warpings in the time domain and generalizes several currently used spike train distances. These new metrics are essentially penalized L ( p ) norms, involving appropriate functions of spike trains, with penalties associated with time-warping. The notions of means and variances of spike trains are then defined based on the new metrics when p = 2 (corresponding to the "Euclidean distance"). Using some restrictive conditions, we present an efficient recursive algorithm, termed Matching-Minimization algorithm, to compute the sample mean of a set of spike trains with arbitrary numbers of spikes. The proposed metrics as well as the mean spike trains are demonstrated using simulations as well as an experimental recording from the motor cortex. It is found that all these methods achieve desirable performance and the results support the success of this novel framework. PMID- 21584776 TI - Unusual cause of acute chest pain. PMID- 21584777 TI - Impact of a bleeding care pathway in the management of acute upper gastrointestinal bleeding. AB - OBJECTIVES: Upper gastrointestinal (UGI) bleeding carries high morbidity and mortality. The use of a bleeding care pathway (BCP) may improve outcomes, but the results are inconsistent in various studies. METHODS: A BCP for patients with UGI bleed with admission in a bleeding care unit (BCU) has been in use at our hospital since 2005. Prior to this, a high dependency unit was used for management of all emergencies including UGI bleeding. We compared the length of stay in the bleeding care/high dependency unit, total hospital stay, time to UGI endoscopy after admission, and survival between pre-2005 and post-2005 patients. RESULTS: Five hundred and fifty-one patients were admitted with acute UGI bleed in the last 5 years; 121 belonged to pre-BCP (2004) period and 430 after implementation of the pathway (2005-2008). The mean (SD) time to UGI endoscopy improved from 21.3 (7.4) hours in the pre-BCU era to 9.4 (9.9) hours in BCU, p < 0.001. BCU stay was shorter from 2.41 (1.4) days pre-BCP to 1.93 (1.32) days post BCP, (p < 0.001). The total hospital stay in pre-BCU (4.0 [2.08] days) as compared to BCU (4.13 [2.62] days; p = 0.58) was similar; there was no impact of BCU on survival. CONCLUSION: A BCU implementation showed improvement in time to UGI endoscopy, and did not reduce BCU stay or impact survival. PMID- 21584778 TI - Cloning, sequencing, and identification using proteomic tools of a protease from Bromelia hieronymi Mez. AB - Fruits of Bromelia hieronymi, a tropical South American plant, possess a high content of peptidases with potential biotechnological uses. Total RNA was extracted from unripe fruits and peptidase cDNA was obtained by 3'RACE-PCR. The consensus sequence of the cysteine peptidase cDNA contained 875 bp, the 690 first ones codifying for a hypothetical polypeptide chain of the mature peptidase, named Bh-CP1 (molecular mass 24.773 kDa, pI 8.6, extinction molar coefficient 58,705 M(-1) cm(-1)). Bh-CP1 sequence shows a high percentage of identity with those of other cysteine plant proteases. The presence of highly preserved residues is observed, like those forming the catalytic site (Gln19, Cys25, His159, and Asn175, papain numbering), as well as other six Cys residues, involved in the formation of disulfide bounds. Molecular modeling results suggest the enzyme belongs to the alpha + beta class of proteins, with two disulfide bridges (Cys23-Cys63 and Cys57-Cys96) in the alpha domain, while the beta domain is stabilized by another disulfide bridge (Cys153-Cys203). Additionally, peptide mass fingerprints (PMFs) of the three peptidases previously isolated from B. hieronymi fruits (namely hieronymain I, II, and III) were performed and compared with the theoretical fingerprint of PMF of Bh-CP1, showing a partial matching between the in silico-translated protein and hieronymain II. PMID- 21584779 TI - Cow-specific risk factors for retained placenta, metritis and clinical mastitis in Holstein cows. AB - The objective of this study was to evaluate the association between cow-specific risk factors and the lactational incidence risks of retained placenta (RP), metritis (MET) and clinical mastitis (CM) in 57,301 dairy cows on 20 large dairy herds in Iran between January 2005 and June 2009. A multivariable logistic regression model was used to identify risk factors for MET, RP and CM and quantify their odds ratio (OR). The lactational incidences of MET, RP and CM were 8%, 5.2% and 18.9%, respectively, and significant risk factors for MET were dystocia (OR = 4.32), stillbirth (OR = 6.26), RP (OR = 27.74), twin births (OR = 6.57), primiparity (OR = 1.68), calving during winter season (OR = 2.45) and male calves (OR = 2.41). Significant risk factors for RP were dystocia (OR = 3.17), stillbirth (OR = 3.18), abortion (OR = 8.46), milk fever (OR = 3.66), twin births (OR = 2.76), pluriparity (OR = 2.69), calving during winter season (OR = 1.86) and shorter gestation length of dairy cows (OR = 3.82). Also, significant risk factors for CM were RP (OR = 9.45), milk fever (OR = 12.36), pluriparity (OR = 2.83), calving during winter season (OR = 1.68) and the first months of lactation (P < 0.001)) and SCC concentrations at previous lactation (OR = 1.82). The current study indicates that differentiation can be made among cows in the risk of having MET, RP and CM based on a combination of cow factors. These differences among cows could be useful to aid the better detection of these diseases in the dairy herds. PMID- 21584780 TI - Effect of maternal antibodies and pig age on the antibody response after vaccination against Glassers disease. AB - The influence of age and maternal antibodies on the development and duration of postvaccinal antibody response against Glasser's disease were investigated. Pigs born to immune (MDA-positive) and non-immune (MDA-negative) sows were vaccinated with inactivated vaccine. Vaccination was done according to three different protocols: at 1 and 4, at 2 and 5 or at 4 and 7 weeks of age. There were also two control groups for MDA-negative and MDA-positive pigs. The level of Haemophilus parasuis (Hps) specific antibodies were determined using commercial ELISA test. No serological responses were seen in any of the groups after the first vaccination. Maternally derived antibodies (MDA) against Hps were above the positive level until approximately 3 weeks of life in MDA-positive pigs. In those pigs the strongest postvaccinal humoral response was observed in piglets vaccinated at 4 and 7 weeks of age. In the remaining MDA-positive piglets only slight seroconversion was noted but levels of antibodies never exceeded values considered as positive. All MDA-negative pigs produced Hps-specific antibodies after the second vaccination. The results of the present study indicated that MDA may alter the development and duration of active postvaccinal antibody response. Age of pigs at the moment of vaccination was not associated with the significant differences in the magnitude of antibody response, however influenced the kinetics of decline of Hps-specific antibodies. PMID- 21584781 TI - Genetic manipulation of pathway regulation for overproduction of angucycline-like antibiotic auricin in Streptomyces aureofaciens CCM 3239. AB - The polyketide gene cluster aur1 is responsible for the production of the antibiotic auricin in Streptomyces aureofaciens CCM 3239. Auricin production is low and strictly regulated by two regulators, Aur1P and Aur1R. To improve auricin yield, we genetically manipulated S. aureofaciens CCM 3239 strain to overcome this strict regulation. A regulatory region including aur1R, aur1P, aur1O and the target biosynthetic aur1Ap promoter were replaced by the strong constitutive ermEp* promoter. However, auricin production was decreased in such a genetically manipulated strain. In the second strategy we placed the aur1P gene for auricin pathway-specific activator under the control of the ermEp* promoter. The resulting strain has been shown to produce 2.8-fold higher amount of auricin compared with the WT strain. PMID- 21584782 TI - Molecular evidence of Plesiomonas shigelloides as a possible zoonotic agent. AB - The most frequently used method for establishing epidemiological relationships between Plesiomonas shigelloides strains is O:H serotyping. However, a number of strains are not serotypeable and isolates from diverse sources can display the same serovar. Moreover, since the zoonotic nature of Plesiomonas has been suggested and this hypothesis is based on the identical serovars found in animals and humans, we intend to use four DNA-based techniques: random amplified polymorphic DNA-PCR, enterobacterial repetitive intergenic consensus-PCR, repetitive extragenic palindromic-PCR, and pulsed field gel electrophoresis in order to screen 24 strains belonging to nine O:H serovars isolated from humans, animals, and the environment. In general, P. shigelloides showed a high genetic heterogeneity. Three pairs of strains, each containing a human and an animal isolate, displayed similar genotypes. This is the first report that provides molecular evidence that P. shigelloides may be zoonotic. PMID- 21584783 TI - Vanishing prostate cancer on radical prostatectomy (RP) in the PSA era: incidence and follow-up data from a cohort of 1,060 patients between 1998 and 2010. PMID- 21584784 TI - Chest radiography is a poor predictor of left ventricular lead position in patients undergoing cardiac resynchronization therapy: comparison with multidetector computed tomography. AB - BACKGROUND: Optimal left ventricular (LV) lead position is thought to be a major predictor of response in patients undergoing cardiac resynchronization therapy (CRT). While the post-implant posterior-anterior (PA) and lateral chest X-ray (CXR) is commonly used to determine the position of the LV lead, the accuracy to which the CXR can correctly localize the LV lead is unknown. METHODS: We collected data on 47 consecutive patients (mean age 64 years, 60% men and LV ejection fraction 23%, 49% ischemic cardiomyopathy) that underwent CRT between 2004 and 2007, who had both a post-implant CXR as well as a contrast-enhanced multi-detector computed tomography (MDCT) of the chest for any reason. The positions of the LV lead on CXR and MDCT were interpreted in a blinded fashion, independent of each other. The accuracy of the CXR in localizing various LV lead positions, with MDCT as the gold standard, was recorded. RESULTS: On CXR, the LV lead tip position was as follows: basal (4%), mid-ventricular (66%), and apical (30%) and anterior (2%), lateral (34%), and posterior (64%). On MDCT, the LV tip position was: basal (28%), mid-ventricular (60%), and apical (13%) and anterior (13%), lateral (19%), and posterior (68%). Compared to the MDCT gold standard, the percentage of LV lead positions the CXR correctly classified correctly were: 100% basal, 39% mid-ventricular, and 29% apical and 0% anterior, 12% lateral, and 77% posterior. Taking both PA and lateral views into consideration, the LV lead position was misclassified by CXR in 62% cases. CONCLUSION: Using MDCT as a gold standard, the routine post-implant CXR performs very modestly in terms of accurate LV lead positioning. PMID- 21584787 TI - Can the capacity for isoprene emission acclimate to environmental modifications during autumn senescence in temperate deciduous tree species Populus tremula? AB - Changes in isoprene emission (Phi(isoprene)), and foliage photosynthetic (A) rates, isoprene precursor dimethylallyldiphosphate (DMADP), and nitrogen and carbon contents were studied from late summer to intensive leaf fall in Populus tremula to gain insight into the emission controls by temperature and endogenous, senescence-induced, modifications. Methanol emissions, characterizing degradation of cell wall pectins, were also measured. A rapid reduction in Phi(isoprene) and A of 60-70% of the initial value was observed in response to a rapid reduction of ambient temperature by ca. 15 degrees C (cold stress). Later phases of senescence were associated with further reductions in Phi(isoprene) and A, with simultaneous major decrease in nitrogen content. However, during episodes of temperature increase, A and in particular, Phi(isoprene) partly recovered. Variation in Phi(isoprene) during senescence was correlated with average temperature of preceding days, with the highest degree of explained variance observed with average temperature of 6 days. Throughout the study, methanol emissions were small, but a large burst of methanol emission was associated with leaf yellowing and abscission. Overall, these data demonstrate that the capacity for isoprene emission can adjust to environmental conditions in senescing leaves as well, but the responsiveness is low compared with mid-season and is also affected by stress. PMID- 21584788 TI - Prevalence of potentially inappropriate prescribing in an acutely ill population of older patients admitted to six European hospitals. AB - PURPOSE: Potentially inappropriate prescribing is common in older people presenting to hospital with acute illness in Ireland. The aim of this study was to determine if this phenomenon is unique to Ireland or whether it is a more widespread problem in hospitals across Europe. METHODS: Prospective data were collected from 900 consecutive older patients admitted to six university teaching hospitals (150 patients per centre) in Geneva (Switzerland), Madrid (Spain), Oostende (Belgium), Perugia (Italy), Prague (Czech Republic) and Cork (Ireland). Age, gender, comorbidity, cognitive status, prescription medicines taken before admission and baseline haematological, biochemical and electrocardiographic data were recorded. STOPP and Beers' criteria were applied to detect potentially inappropriate medicines (PIMs). START criteria were applied to detect potentially inappropriate prescribing omissions (PPOs). RESULTS: The overall PIM prevalence rate was 51.3% using STOPP criteria, varying from 34.7% in Prague to 77.3% in Geneva, and 30.4% using Beer's criteria, varying from 22.7% in Prague to 43.3% in Geneva. Using START criteria, the overall PPO prevalence rate was 59.4%, ranging from 51.3% in Cork to 72.7% in Perugia. Polypharmacy predicted the presence of PIMs using STOPP criteria [with >10 medications: odds ratio (OR) 7.22, 95% confidence interval (CI) 4.30-12.12, p < 0.001] and Beers' criteria (with >10 medications: OR 4.87, 95% CI 3.00-7.90, p < 0.001). Increasing co-morbidity (Charlson Index >=2) and age >=85 years significantly predicted PPOs. CONCLUSION: Potentially inappropriate drug prescribing and the omission of beneficial drugs are highly prevalent in acutely ill hospitalized older people in six European centres. PMID- 21584790 TI - [Neuromuscular signal transmission in adulthood. Current facets of acquired and hereditary disorders]. AB - The availability of early diagnosis and modern effective therapies has reduced mortality and disability linked to late-onset acquired or hereditary neuromuscular transmission disorders. Nevertheless, identification of the pathogenesis of these diseases remains a challenge. In addition to non-specific and fluctuating presenting symptoms current diagnostic work-up strategies include electrophysiology, antibody measurements and less frequently molecular genetics. For differential diagnostic purposes there is an increasing demand for improving awareness concerning late-onset congenital myasthenic syndromes (CMS) which are rare but nevertheless symptomatically treatable diseases. Especially in seronegative myasthenic syndromes, molecular genetic analyses of CMS genes should be integrated into the differential diagnostic work-up. Therefore, some facets of neuromuscular synaptogenesis in the context of seronegative acquired myasthenic syndromes and recently uncovered congenital myasthenic syndromes are reviewed. PMID- 21584791 TI - Screening for postpartum depression among low-income mothers using an interactive voice response system. AB - This study tested the feasibility of using an interactive voice response (IVR) phone system to screen for postpartum depression among low-income, English- and Spanish-speaking mothers. Newly delivered mothers were interviewed in the hospital. Consenting subjects completed a background questionnaire and were asked to call an automated phone system 7 days postpartum to complete an IVR version of the Edinburgh Postnatal Depression Screen (EPDS). During the phone screen, subjects were branched to different closing narratives based on their depression scores which were later posted to a password protected website. Logistic regression was used to assess relationships between demographic and psychosocial factors, IVR participation, and depression scores. Among 838 ethnically diverse, low income, postpartum mothers, 324 (39%) called into the automated phone screening system. Those who called were more likely to have at least a high school education (OR = 1.63, 95%CI: 1.23, 2.16), be employed (OR = 1.48, 95%CI: 1.08, 2.03) and have food secure households (OR = 1.50, 95%CI: 1.06, 2.13). There was no statistically significant difference between callers and non-callers in terms of marital status, race/ethnicity, parity, or self-reported history of depression. Postpartum depression symptoms were present in 17% (n = 55) and were associated with being single (AOR = 2.41, 95% CI: 1.29, 4.50), first time mother status (AOR = 2.43, 95% CI: 1.34, 4.40), temporary housing (AOR = 2.35, 95% CI: 1.30, 4.26), history of anxiety (AOR = 2.79, 95% CI: 1.69, 6.67), and history of self-harm (AOR = 2.66, 95% C: 1.01, 6.99). Automated phone screening for postpartum depression is feasible among disadvantaged mothers but those with the highest psychosocial risk factors may not choose or be able to access it. IVR could be used to supplement office- and home visit-based screening protocols and to educate patients about mental health resources. PMID- 21584789 TI - [Default mode network of the brain. Neurobiology and clinical significance]. AB - The resting state of the human brain is intrinsically organized by the so-called default mode network (DMN) which comprises cortical midline structure as well as lateral parietal and temporal areas. The activity of this system increases during self-oriented thinking, e.g. during a resting state but decreases during externally oriented attention and specific cognitive tasks. This review article provides a historical and methodological outline of the DMN model and describes its functional anatomy and putative functions. Based on the empirical literature the clinical implications of alterations of the DMN architecture and its role in various mental disorders are discussed. PMID- 21584792 TI - Depression and pregnancy stressors affect the association between abuse and postpartum depression. AB - To determine how psychosocial factors affect the association between a history of abuse and postpartum depression (PPD). Women at four urban hospitals in Utah were enrolled <= 48 h of delivering a live-born infant. At enrollment, pregravid history of physical or sexual abuse was obtained via self-report. Psychosocial covariates such as pregnancy stressors and depression were also collected. Pregnancy stressors were categorized using "stressor" questions from the Pregnancy Risk Assessment Monitoring System. The primary outcome measure, a pre specified Edinburgh Postnatal Depression Scale score of >= 12 was obtained 6-8 weeks postpartum. Among the 1,038 women studied, psychosocial risk factors were common: abuse history 11.7%, pregnancy stressors-financial 49.1%, emotional 35.0%, partner-associated 19.8%, and traumatic 10.3% and depression history 16.7%. While abuse was associated with a +PPD screen in a preliminary model [aOR 2.05 (1.28, 3.26)], adding psychosocial covariates reduced the unadjusted association of abuse and PPD [aOR 1.12 (0.66, 1.91)]. After adjustment, PPD was associated with depression history [aOR 2.85 (1.90, 4.28)], prepregnancy BMI [aOR 1.04 (1.01, 1.07)] multiple stressors [3 categories aOR 4.35 (2.00, 9.46)]; 4 categories [aOR 6.36 (2.07, 19.49)] and sum of stressors * history of abuse [aOR 1.50 (0.92, 2.46)]. Interestingly only women with a moderate number of stressors were sensitive to an abuse history. Abuse and pregnancy stressors are common and interact to influence the likelihood of screening positive for PPD. PMID- 21584793 TI - No evidence of an increased mortality risk associated with low levels of glycated haemoglobin in a non-diabetic UK population. AB - AIMS/HYPOTHESIS: There is debate about increased mortality risk associated with low levels of glycaemia. To address this issue, we examined the shape of the risk relationship between glycated haemoglobin and mortality in a UK population. METHODS: In 17,196 men and women aged 39-82 years participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study in Norfolk without known diabetes or cardiovascular disease, we estimated HRs for total and cause-specific mortality comparing categories of glycated haemoglobin (<4.5%, 4.5% to <5.0%, 5.0% to <5.5% [reference], 5.5% to <6.0%, 6.0% to <6.5%, and >=6.5%) using Cox regression. RESULTS: During a mean (+/-SD) follow-up of 11.2 (+/-2.1) years 1,953 participants died. The HR for all-cause mortality increased with categories of increasing glycated haemoglobin in adjusted analyses (HR 0.94 [95% CI 0.72-1.22], 0.99 [0.86-1.13], 1.00 [0.92-1.08], 1.10 [1.02-1.19], 1.29 [1.14-1.46] and 1.45 [1.16-1.80]). Spline regression suggested no increased risk at the low end of the distribution. Indeed, the HR for all-cause mortality was virtually constant in the low range and only started to rise when the level was approximately 5.5%. There were similar associations of glycated haemoglobin with cause-specific mortality, with the strongest association being seen for cardiovascular mortality. CONCLUSIONS/INTERPRETATION: Our findings in a large non diabetic population do not support the concern about increased mortality risk with low glycated haemoglobin. Differences in population characteristics might explain contrary results of earlier studies and need further exploration. PMID- 21584794 TI - Retraction of 'Angiotensin-II-induced oxidative stress elicits hypoadiponectinaemia in rats'. PMID- 21584795 TI - The impact of caveolin protein expression in tumor stroma on prognosis of breast cancer. AB - We aimed to investigate the expression of caveolin-1, -2, -3, and platelet derived growth factor (PDGF) beta receptor in breast cancer cells and stroma by immunohistochemistry and to analyze their implications. The expression rates of stromal caveolin-2 and PDGF beta receptor increased as the tumor progressed from ductal carcinoma in situ to microinvasive ductal carcinoma, intraductal component of invasive ductal carcinoma (IDC), and IDC (p<0.001). The expression loss of caveolin-1 in tumor stroma of IDC correlated with high tumor stage (p<0.001), high nodal stage (p=0.011), high cancer stage (p=0.005), estrogen receptor negativity (p=0.003), and tumor recurrence (p=0.003). In addition, the expression loss of caveolin-1 in tumor stroma was correlated with a shorter disease-free survival and an overall survival (p<0.001). In conclusion, the loss of stromal caveolin-1 is related to poor prognosis in IDC. PMID- 21584796 TI - [Best article of continuing education. Springer CME-Award Der Internist granted for the seventh time]. PMID- 21584797 TI - [Therapeutic strategies in rheumatology. New concepts, new agents, observance of comorbidities]. PMID- 21584798 TI - Three-dimensional echocardiography for left ventricular quantification: fundamental validation and clinical applications. AB - One of the earliest applications of clinical echocardiography is evaluation of left ventricular (LV) function and size. Accurate, reproducible and quantitative evaluation of LV function and size is vital for diagnosis, treatment and prediction of prognosis of heart disease. Early three-dimensional (3D) echocardiographic techniques showed better reproducibility than two-dimensional (2D) echocardiography and narrower limits of agreement for assessment of LV function and size in comparison to reference methods, mostly cardiac magnetic resonance (CMR) imaging, but acquisition methods were cumbersome and a lack of user-friendly analysis software initially precluded widespread use. Through the advent of matrix transducers enabling real-time three-dimensional echocardiography (3DE) and improvements in analysis software featuring semi automated volumetric analysis, 3D echocardiography evolved into a simple and fast imaging modality for everyday clinical use. 3DE provides the possibility to evaluate the entire LV in three spatial dimensions during the complete cardiac cycle, offering a more accurate and complete quantitative evaluation the LV. Improved efficiency in acquisition and analysis may provide clinicians with important diagnostic information within minutes. The current article reviews the methodology and application of 3DE for quantitative evaluation of the LV, provides the scientific evidence for its current clinical use, and discusses its current limitations and potential future directions. PMID- 21584799 TI - Very late dehiscence of a Bentall prosthesis. PMID- 21584800 TI - GRACE and TIMI risk scores but not stress imaging predict long-term cardiovascular follow-up in patients with chest pain after a rule-out protocol. AB - OBJECTIVE: To determine the long-term prognostic value of stress imaging and clinical risk scoring for cardiovascular mortality in chest pain patients after ruling out acute coronary syndrome (ACS). METHODS: A standard rule-out protocol was performed in emergency room patients with a normal or non-diagnostic admission electrocardiogram (ECG) within 6 h of chest pain onset. ACS patients were identified by troponin T, recurrent angina and serial ECG. Dobutamine stress echocardiography (DSE) was performed after ACS was ruled out. Myocardial perfusion scintigraphy (MPS) was performed within 6 months in an outpatient setting according to the physician's discretion. RESULTS: 524 patients were included. GRACE and TIMI risk scores were 75 (57-96) and 1 (0-2) in the rule-out ACS group, and 89 (74-107) and 2 (1-3) in the ACS group, respectively (median, interquartile range). Follow-up (median 9.4 (8.9-10.0) years) was complete in 96%. 350 of 379 rule-out ACS patients had an interpretable DSE and 52 patients underwent an MPS. 21 of the rule-out ACS patients (6%) died of a cardiovascular cause compared with 24 (17%) ACS patients (p < 0.001). For rule-out ACS patients, C-statistics were 0.829 and 0.803 for the GRACE and TIMI scores. In these patients, DSE and MPS outcome did not predict long-term cardiovascular mortality. In multivariate analysis, known chronic heart failure, ACE inhibitor use, and GRACE score were independent predictors of cardiovascular mortality. CONCLUSIONS: TIMI and GRACE score but not DSE and MPS are accurate predictors of long-term cardiovascular mortality, even in chest pain patients with a normal or non diagnostic electrocardiogram undergoing a rule-out protocol. PMID- 21584801 TI - An undulating giant left ventricular apical thrombus after myocardial infarction. PMID- 21584802 TI - Haemodynamic bradycardia in tachycardiomyopathy. PMID- 21584803 TI - Left ventricular aneurysm with massive myocardial calcification. PMID- 21584804 TI - Patent ductus arteriosus in adults - indications and possibilities for closure. AB - Patent ductus arteriosus (PDA) is a rare diagnosis in adults, since symptoms and signs usually occur in infancy and most cases are treated shortly after diagnosis. We present two patients who were first diagnosed with PDA during adulthood. The first case represents a more severe form of PDA, where the need for closure of the PDA is obvious. In the second case the sequelae of the PDA are less clear. In both patients, closure of the PDA (surgically in one case, percutaneously in the other) was successful. PMID- 21584805 TI - J deflections on ECG in severe hypothermia and hypokalaemia: a case report. AB - The J wave, also known as Osborn wave, is a deflection that can be observed on the surface ECG as a late delta wave, seen at the end of the QRS complex. In this case, a 75-year-old woman, after 1 day of continuous haemodialysis, showed a marked hypothermia (28.5 degrees C) and severe hypokalaemia (1.7 mEq/l). Bradycardia was seen on the monitor and J waves were recognised on the ECG recording. After appropriate replacement of potassium and treatment of hypothermia, the J waves disappeared spontaneously. PMID- 21584806 TI - Histone deacetylase inhibitors augment doxorubicin-induced DNA damage in cardiomyocytes. AB - Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutics with suberoylanilide hydroxamic acid (Vorinostat) and depsipeptide (Romidepsin) already being approved for clinical use. Numerous studies have identified that histone deacetylase inhibitors will be most effective in the clinic when used in combination with conventional cancer therapies such as ionizing radiation and chemotherapeutic agents. One promising combination, particularly for hematologic malignancies, involves the use of histone deacetylase inhibitors with the anthracycline, doxorubicin. However, we previously identified that trichostatin A can potentiate doxorubicin-induced hypertrophy, the dose-limiting side-effect of the anthracycline, in cardiac myocytes. Here we have the extended the earlier studies and evaluated the effects of combinations of the histone deacetylase inhibitors, trichostatin A, valproic acid and sodium butyrate on doxorubicin-induced DNA double-strand breaks in cardiomyocytes. Using gammaH2AX as a molecular marker for the DNA lesions, we identified that all of the broad-spectrum histone deacetylase inhibitors tested augment doxorubicin-induced DNA damage. Furthermore, it is evident from the fluorescence photomicrographs of stained nuclei that the histone deacetylase inhibitors also augment doxorubicin-induced hypertrophy. These observations highlight the importance of investigating potential side-effects, in relevant model systems, which may be associated with emerging combination therapies for cancer. PMID- 21584807 TI - Hypoxia in the regulation of neural stem cells. AB - In aerobic organisms, oxygen is a critical factor in tissue and organ morphogenesis from embryonic development throughout post-natal life, as it regulates various intracellular pathways involved in cellular metabolism, proliferation, survival and fate. In the mammalian central nervous system, oxygen plays a critical role in regulating the growth and differentiation state of neural stem cells (NSCs), multipotent neuronal precursor cells that reside in a particular microenvironment called the neural stem cell niche and that, under certain physiological and pathological conditions, differentiate into fully functional mature neurons, even in adults. In both experimental and clinical settings, oxygen is one of the main factors influencing NSCs. In particular, the physiological condition of mild hypoxia (2.5-5.0% O(2)) typical of neural tissues promotes NSC self-renewal; it also favors the success of engraftment when in vitro-expanded NSCs are transplanted into brain of experimental animals. In this review, we analyze how O(2) and specifically hypoxia impact on NSC self-renewal, differentiation, maturation, and homing in various in vitro and in vivo settings, including cerebral ischemia, so as to define the O(2) conditions for successful cell replacement therapy in the treatment of brain injury and neurodegenerative diseases. PMID- 21584808 TI - Fluorescence spectroscopy and molecular dynamics simulations in studies on the mechanism of membrane destabilization by antimicrobial peptides. AB - Since their initial discovery, 30 years ago, antimicrobial peptides (AMPs) have been intensely investigated as a possible solution to the increasing problem of drug-resistant bacteria. The interaction of antimicrobial peptides with the cellular membrane of bacteria is the key step of their mechanism of action. Fluorescence spectroscopy can provide several structural details on peptide membrane systems, such as partition free energy, aggregation state, peptide position and orientation in the bilayer, and the effects of the peptides on the membrane order. However, these "low-resolution" structural data are hardly sufficient to define the structural requirements for the pore formation process. Molecular dynamics simulations, on the other hand, provide atomic-level information on the structure and dynamics of the peptide-membrane system, but they need to be validated experimentally. In this review we summarize the information that can be obtained by both approaches, highlighting their versatility and complementarity, suggesting that their synergistic application could lead to a new level of insight into the mechanism of membrane destabilization by AMPs. PMID- 21584810 TI - Host-defense peptides: from biology to therapeutic strategies. AB - Primitive innate defense mechanisms in the form of gene-encoded antimicrobial peptides are now considered as potential candidates for the development of new therapeutics. They are well known for their function as the first protective barrier of all organisms against microbial infections. In addition, emerging studies reveal that they assist in modulating the host immune system. The biological properties of these host-defense peptides, their role in human health, their cell selectivity and related molecular mechanisms are discussed in this multi-author review along with the strategies to transform them or their peptidomimetics into clinically usable drugs. PMID- 21584809 TI - Role of host-defence peptides in eye diseases. AB - The eye and its associated tissues including the lacrimal system and lids have evolved several defence mechanisms to prevent microbial invasion. Included among this armory are several host-defence peptides. These multifunctional molecules are being studied not only for their endogenous antimicrobial properties but also for their potential therapeutic effects. Here the current knowledge of host defence peptide expression in the eye will be summarised. The role of these peptides in eye disease will be discussed with the primary focus being on infectious keratitis, inflammatory conditions including dry eye and wound healing. Finally the potential of using host-defence peptides and their mimetics/derivatives for the treatment and prevention of eye diseases is addressed. PMID- 21584811 TI - Visualizing odor representation in the brain: a review of imaging techniques for the mapping of sensory activity in the olfactory glomeruli. AB - The brain transforms clues from the external world, the sensory stimuli, into activities in neuroglial networks. These circuits are activated in specialized sensory cortices where specific functional modules are responsible for the spatiotemporal coding of the stimulus. A major challenge in the neuroscience field has been to image the spatial distribution and follow the temporal dynamics of the activation of such large populations in vivo. Functional imaging techniques developed in the last 30 years have enabled researchers to solve this critical issue, and are reviewed here. These techniques utilize sources of contrast of radioisotopic, magnetic and optical origins and exploit two major families of signals to image sensory activity: the first class uses sources linked to cellular energy metabolism and hemodynamics, while the second involves exogenous indicators of neuronal activity. The whole panel of imaging techniques has fostered the functional exploration of the olfactory bulb which is one of the most studied sensory structures. We summarize the major results obtained using these techniques that describe the spatial and temporal activity patterns in the olfactory glomeruli, the first relay of olfactory information processing in the main olfactory bulb. We conclude this review by describing promising technical developments in optical imaging and future directions in the study of olfactory spatiotemporal coding. PMID- 21584812 TI - Vgamma9Vdelta2 T cell-based immunotherapy in hematological malignancies: from bench to bedside. AB - Many hematological malignancies consist of tumor cells that are spontaneously recognized and killed by Vgamma9Vdelta2 T cells. These tumor cells generate high amounts of intracellular phosphorylated metabolites mimicking the natural ligands and display a wide range of stress-induced self-ligands that are recognized by Vgamma9Vdelta2 T cells via TCR-dependent and TCR-independent mechanisms. The intrinsic features of Vgamma9Vdelta2 T cells and that of tumor cells of hematological origin constitute an ideal combination from which to develop Vgamma9Vdelta2 T cell-based immune interventions. In this review, we will discuss the rationale, preclinical and clinical data in favor of this therapeutic strategy and the future perspectives of its development. PMID- 21584814 TI - Introduction: studies on the learning process in the one-day, one-problem approach to problem-based learning. PMID- 21584813 TI - Dynamics of the interaction of gammadelta T cells with their neighbors in vivo. AB - gammadelta T cells are a diverse component of the immune system in humans and mice with presumably important but still largely unknown functions. Understanding the dynamic interaction of gammadelta T cells with their neighbors should help to understand their physiological role. This review addresses recent advances and strategies to visualize the dynamic interactions of gammadelta T cells with their neighbors in vivo. Current knowledge regarding the dynamic contacts of tissue resident gammadelta T cells and epithelial cells, but also of the communication between circulating gammadelta T cells and DCs, monocytes and FoxP3(+) regulatory T cells is revisited with emphasis on the role of gammadelta T cell motility. PMID- 21584815 TI - The trade-off between formal and informal care in Spain. AB - Understanding the factors that determine the type and amount of formal care is important for predicting use in the future and developing long-term policy. In this context, we jointly analyze the provision of care at both the extensive (choice of care) and the intensive margin (number of hours of care received). In particular, we estimate and test, for the first time in this area of research, a sample selection model with the particularities that the first step is a multinomial logit model and the hours of care is an interval variable. Our results support the complementary and task-specific models which evidence has been found in other countries. Furthermore, we obtain evidence of substitution between formal and informal care for the male, young, married and unmarried subsamples. Regarding the hours of care, we find significant biases in predicted hours of care when sample selection is not taken into account. For the whole sample, the average bias is 2.77% for total hours and 3.23% for formal care hours. However, biases can be much larger (up to 10-15%), depending on the subsample and the type of care considered. PMID- 21584816 TI - Peritoneal volume is predictive of tension-free fascia closure of large incisional hernias with loss of domain: a prospective study. AB - INTRODUCTION: The surgical treatment of large incisional hernias with loss of domain (LIHLD) carries the risk of fascia closure under tension and, thus, abdominal compartment syndrome. We investigated volume measurements as a predictive factor for tension-free fascia closure. PATIENTS AND METHODS: From September 2004 to July 2008, we prospectively included 17 patients with LIHLD. The operation was prepared by a progressive preoperative pneumoperitoneum (PPP) technique known as the Goni Moreno procedure. The patient's age and body mass index (BMI), the incisional hernia's width, length and surface area, and the incisional hernia volume (IHV)/peritoneal volume (PV) ratio <20% were evaluated as predictive factors for tension-free fascia closure. A tension-free closure was defined as a closure in which the use of a surgical device for avoiding postoperative compartment syndrome was not required. RESULTS: The mean PPP volume introduced was 12.7 +/- 4.4 l (range 4.5-19.2) over a period of 11 +/- 6 days (range 4-24). The mean width, height and surface area of the incisional hernia after PPP were 11.3 +/- 4.7 cm (range 4.5-19), 13.4 +/- 7.8 cm (range 4.4-30) and 165 +/- 101 cm(2) (range 19-304), respectively. The mean IHV after PPP was 2,374 +/- 1,356 cc (range 517-4,802) and the mean abdominal cavity volume was 9,558 +/- 4,106 cc (range 4,785-21,782). The mean IHV/PV ratio was 16.3 +/- 10.4% (range 4.4-34). In a univariate analysis, the BMI and the IHV/PV ratio were predictive of tension-free fascia closure. In a multivariate analysis, only an IHV/PV ratio <20% was a significant predictive factor. CONCLUSIONS: The IHV/PV ratio is predictive of tension-free fascia closure for hernias or incisional hernias with loss of domain. Simplification of the volumetry method is necessary. PMID- 21584817 TI - Recurrent perineal hernia repair: a novel approach. AB - PURPOSE: Postoperative perineal hernias are rare complications from procedures, which compromise the pelvic floor, mainly abdominoperineal resection, proctocolectomy, and partial or total pelvic exenteration. Surgical repair can be accomplished through abdominal, laparoscopic, or transperineal approaches. METHODS: We present a case report of a 70-year-old man who underwent two prior operations for recurrent perineal hernia and was ultimately successfully treated with a third operation, a synthetic mesh redo procedure that utilized a synthetic mesh system marketed for women with pelvic organ prolapse. RESULTS: Although there is no "gold standard" for perineal hernia repair, our patient had multiple surgeries employing a variety of approaches. Final success was achieved using a mesh system with improved fixation to secure pelvic ligaments, using an exclusive perineal approach. Now, more than five years following the final surgery, the patient remains symptom free with no clinical evidence of perineal hernia recurrence. CONCLUSIONS: To date, this is the only report of using this mesh system in a male. The advantages of using this mesh system are (1) exclusive perineal approach without the accompanying risks of abdominal or laparoscopic approach; (2) improved fixation of mesh to secure pelvic ligaments; and (3) lightweight, flexible, and large mesh shape that can easily be trimmed to allow versatility in procedures. PMID- 21584818 TI - HIV among military personnel in the Niger Delta of Nigeria. AB - The military community is considered a high-risk environment for HIV transmission. In this study, a total of One hundred and fifty military personnel aged between 20 and 55 years attending the Nigerian army Hospital, Air Force Clinic and Police Clinic in the Niger Delta of Nigeria were randomly recruited for the study. Samples were tested for HIV using an immunochromatographic assay. The CD4 cell count was estimated using the Partec Cyflow Counter (Partec, Germany). Results of the study showed an overall HIV prevalence rate of 14.67%. The prevalence of HIV was significantly higher among subjects in the >=40 years age group (P = 0.03). The HIV prevalence was higher among female subjects compared to male military personnel (P = 0.05). Also, there was a significant negative correlation between the CD4 count and HIV positivity (r = -0.443, P<0.01). Out of the 22 subjects positive for HIV, 9.1% were severely immune compromised with CD4 count below<200 cells/MUL while 72.7 and 18.2% had CD4 count of 200-350 and 350-500 cells/MUL respectively. There is need for the development of a strategic plan that integrates HIV/AIDS and other STIs programs into existing systems and structures to foster behavior change through information dissemination. Policies should be instituted to make condoms regularly available and freely distributed, with the goal of achieving a 100%-condom-use rate. There is the need for an effective voluntary counseling and testing (VCT) and sentinel surveillance survey in the Nigerian military. Also critical is the establishment of a fully integrated and comprehensive care and support system including universal access of antiretroviral treatment for infected people. PMID- 21584819 TI - Overexpression of Aurora-A promotes laryngeal cancer progression by enhancing invasive ability and chromosomal instability. AB - The purpose of the study was to investigate the expression of Aurora-A in human laryngeal squamous cell carcinoma (LSCC) and to explore the effects of Aurora-A silencing on invasion and chromosomal instability in laryngeal cancer HEp-2 cells. The expression of Aurora-A mRNA and protein were studied using reverse transcription-PCR and Western blot in LSCC tissues and corresponding normal epithelium, respectively. In addition, the correlation between Aurora-A expression and clinicopathologic characteristics was analyzed in LSCC patients. Furthermore, HEp-2 cells were transfected with Aurora-A short hairpin RNA and the effects of knockdown of Aurora-A on tumor invasion and chromosomal instability were investigated. The results showed that expression of Aurora-A mRNA was significantly upregulated in laryngeal tumor tissue compared with that in normal tissue (P = 0.001), and overexpression of Aurora-A was found in 64.0% (16 of 25) of the patients by Western blotting. Upregulation of Aurora-A mRNA was significantly correlated with regional lymph node metastasis (P = 0.007) and clinical stage III/IV (P = 0.022). Overexpression of Aurora-A was significantly associated with lymph node metastasis (P = 0.027). Furthermore, disruption of Aurora-A using RNA interference technique suppressed invasive ability and chromosomal instability in HEp-2 cells. In conclusion, Aurora-A expression is elevated in human LSCC and associated with regional lymph node metastasis and late clinical stage. Overexpression of Aurora-A may contribute to LSCC carcinogenesis and progression partially due to enhancement of invasion ability and chromosomal instability. PMID- 21584820 TI - Emerging ideas: can erythromycin reduce the risk of aseptic loosening? AB - BACKGROUND: Persistent inflammatory reaction to wear debris causes periprosthetic osteolysis and loosening. Some authors have advocated pharmaceutical approaches to reduce the inflammatory reaction. Erythromycin has antiinflammatory effects independent of its antimicrobial properties. Although oral erythromycin reportedly inhibits periprosthetic tissue inflammation in patients with aseptic loosening, long-term systematic erythromycin treatment is not recommended owing to its side effects. Therefore, it would be advantageous to restrict erythromycin delivery to the inflammatory periprosthetic tissue without causing side effects. QUESTIONS/HYPOTHESES: Erythromycin eluted from hydroxyapatite-coated titanium (Ti) pins inhibits periprosthetic tissue inflammation and osteolysis. METHOD OF STUDY: We propose restricting erythromycin delivery to the inflammatory periprosthetic site. A previously described rat model of ultrahigh molecular weight polyethylene (UHMWPE) particle-induced periprosthetic tissue inflammation and osteolysis will be used to test the effect of local delivery of erythromycin via Peri-Apatite(TM)-coated Ti implants. The outcome measures will include bone ingrowth (MUCT), implant stability (pullout test), and histologic analysis of periprosthetic tissues. SIGNIFICANCE: Pharmacologic intervention aimed at slowing, preventing, or reversing the aseptic loosening process would represent an advance in the management of joint replacement. Erythromycin may be appropriate for prophylactically treating patients who have repeated revision surgery and/or show early signs of progressive osteolysis after arthroplasty. PMID- 21584821 TI - Clinicopathologic characteristics and outcomes of patients with obstructive colorectal cancer. AB - PURPOSE: The aim of this retrospective study was to analyze the clinicopathologic characteristics and short-term and long-term outcomes of colorectal cancer patients with obstruction compared to those of non-obstructive colorectal cancer patients. METHODS: Between January 1998 and December 2005, 1,672 colorectal cancer patients undergoing operation were enrolled in this study. Patients were classified into two groups according to the presentation: patients with complete obstructive colorectal cancer (COC, n = 215) receiving emergency procedures and patients with non-obstructive colorectal cancer (NOC, n = 1,457) receiving elective procedures. The data on the clinicopathologic characteristics and short term and long-term outcomes of patients were analyzed retrospectively. RESULTS: Among 1,672 colorectal cancer patients, 215 cases presented with complete obstruction. The distribution of tumor location and size, macroscopic type, depth of invasion, liver metastasis, peritoneal carcinomatosis, and TNM stage were found to be different between the COC and NOC groups. Logistic regression analysis showed that tumor location, depth of invasion, and peritoneal carcinomatosis were independent factors associated with obstruction. Patients with obstruction had an increased risk of death by a factor of 2.251 compared to patients without obstruction. Peritoneal carcinomatosis and TNM stage were independent factors for the survival of the COC group. Obstruction, peritoneal carcinomatosis, tumor macroscopic type, and TNM stage were independent indicators for postoperative recurrence. Postoperative mortality was significantly higher in the COC group than the NOC group. The overall 5- and 10-year survival rates in the COC group were 47.8% and 42.8%, respectively, compared to 67.2% and 59.8% in the NOC group, respectively (p < 0.05). The postoperative recurrence rates were 43.1% in the COC group and 32.8% in the NOC group (p < 0.05). CONCLUSIONS: Obstruction is an independent indicator for the survival and postoperative recurrence for patients with colorectal cancer. Patients in the COC group have worse overall survival with high postoperative recurrence rate compared to those in the NOC group. PMID- 21584822 TI - Therapeutic management of hemorrhage from visceral artery pseudoaneurysms after pancreatic surgery. AB - INTRODUCTION: Hemorrhage from pseudoaneurysms after pancreatic surgery is a rare but life-threatening and complicated complication. The study presents our experience to provide therapeutic management for this rare condition. METHODS: Between February 1994 and January 2011, 35 patients experienced hemorrhage from pseudoaneurysms in our hospital. Medical data of this rare complication were analyzed retrospectively. RESULTS: The prevalence of hemorrhage from pseudoaneurysms was 3.2% (35/1,102). Sixteen patients (45.7%) experienced sentinel bleeding. Pancreatic fistula (74.3%) and intra-abdominal abscess (57.1%) were two common complications prior to hemorrhage. Of 35 patients, 20 underwent endovascular intervention, 14 received surgical re-laparotomy, and bleeding stopped spontaneously in one. The overall mortality rate was 22.9%. Technical success rate of endovascular treatment was 87%. There were significant differences in the mortality rate (10.0% vs 42.9%), operation time (72.8 vs 123.9 min), estimated blood loss (1,835 vs 3,000 ml), and intensive care unit stay (3.6 vs 8.6 days) between endovascular and surgical treatment. Mean follow-up was 19.2 +/- 17.0 (range, 5-63 months). CONCLUSION: Endovascular intervention represents the first-line treatment for hemorrhage from pseudoaneurysms after pancreatic surgery. Endovascular embolization or stent-graft placement should be selected individually depending on the involved artery and its vascular anatomy. PMID- 21584823 TI - Laparo-endoscopic single-site (LESS) with transanal natural orifice specimen extraction (NOSE) sigmoidectomy: a new step before pure colorectal natural orifices transluminal endoscopic surgery (NOTES(r)). AB - INTRODUCTION: We present the first human case of laparo-endoscopic single-site sigmoidectomy with transanal natural orifice specimen extraction. DISCUSSION: This technical achievement is a new step toward pure colorectal Natural Orifices Transluminal Endoscopic Surgery. It is the product of a gradual development with critical steps being conceived and standardised in years of experimental and clinical procedures. PMID- 21584824 TI - A focal mass-forming autoimmune pancreatitis mimicking pancreatic cancer with obstruction of the main pancreatic duct. AB - INTRODUCTION AND BACKGROUND: Autoimmune pancreatitis (AIP) is a rare disease that closely mimics pancreatic cancer (PC) in its presentation. It is very important for clinicians to distinguish one from the other because their treatment and prognosis are vastly different. Typical radiological imaging findings, in particular observation of diffusely or segmentally narrowed main pancreatic duct (MPD) with an irregular wall by endoscopic retrograde cholangiopancreatography (ERCP), are essential for making the diagnosis of AIP. On the other hand, MPD obstruction is one of the most frequent features on ERCP. CASE REPORT: We report a rare case of a patient with focal mass-forming AIP strongly suspected of being PC because of MPD obstruction on ERCP. CONCLUSION: It was difficult to distinguish PC from AIP with current diagnostic modalities. We will continue to make an effort to distinguish between the two disorders to prevent unnecessary surgery. PMID- 21584825 TI - Robotic-assisted laparoscopic side-to-side lateral pancreaticojejunostomy. PMID- 21584826 TI - [Urology needs health services research: the case of small renal tumours]. AB - The central tasks of health services research include the description and analysis of health care under everyday conditions as well as the development and evaluation of new concepts. As a first step, the reality of the health services' situation should be assessed using representative data. For that, registries, claims data of health insurance funds or observational studies are suitable. To investigate specific patterns or decisions, qualitative methods are of importance. To evaluate the effectiveness of health care concepts or structures, pragmatic randomized, controlled trials are considered to provide the best evidence. In this paper we discuss these questions on the basis of treatment for patients with small renal masses. Although recent guidelines recommend nephron sparing surgery instead of radical nephrectomy for these patients, international studies suggest that there is a significant underuse of nephron-sparing procedures. However, national data describing the situation in Germany are necessary to analyse reasons and to develop new concepts which subsequently have to be tested in randomized trials. Therefore, the aim of health services research is to create a scientific basis for continuous improvements in health care. Urology needs health services research and we should find ways to overcome barriers to improve quality of care. PMID- 21584827 TI - [AUO study AP 59/10: first-line therapy of castration-resistant prostate cancer]. PMID- 21584828 TI - Stability and change in sexual orientation identity over a 10-year period in adulthood. AB - We examined reports of sexual orientation identity stability and change over a 10 year period drawing on data from the National Survey of Midlife Development in the United States (MIDUS I and II) and tested for three patterns: (1) heterosexual stability, (2) female sexual fluidity, and (3) bisexual fluidity. Fifty-four percent of the 2,560 participants were female and the average age was approximately 47 years. At Wave 1, 2,494 (97.42%) reported a heterosexual identity, 32 (1.25%) a homosexual identity, and 34 (1.33%) a bisexual identity and somewhat more than 2% reported a different sexual orientation identity at Wave 2. Although some support for each hypothesis was found, initial sexual orientation identity interacted with gender to predict a more complex pattern. For the sample as a whole, heterosexuality was the most stable identity. For women, bisexuality and homosexuality were equally unstable and significantly less stable than heterosexuality, suggesting that sexual orientation identity fluidity is a pattern that applies more to sexual minority women than heterosexual women. For men, heterosexuality and homosexuality were both relatively stable compared to bisexuality, which stood out as a particularly unstable identity. This pattern of results was consistent with previous findings and helps to address methodological limitations of earlier research by showing the characteristics of a population-based sample of heterosexual, homosexual, and bisexual identified men and women over time. PMID- 21584829 TI - When a chance to cut is not a chance to cure: a future for palliative surgery? AB - In the context of healthcare reform, Surgery stands at a critical juncture. Attempting to rein in healthcare spending, legislators and payers can be expected to closely examine the legitimacy and necessity of a variety of medical treatments, including surgical procedures. Among these procedures, the most at risk for dismissal based on perceived ineffectiveness or lack of need may be those performed near the end of life, when the potential benefit of surgical intervention may seem negligible. While procedures may be performed for a variety of reasons toward the end of life--some indeed being inappropriate and/or unnecessary--palliative surgery plays an important role in the management of incurable disease. The purposes of this article are to: describe the place for palliative surgery in the armamentarium of palliative care; discuss potential challenges to patients' access to palliative surgery that may arise from health policy or quality initiatives based on poor evidence; and outline a strategy for (a) systematically differentiating palliative surgeries from other, potentially expendable surgeries performed near the end of life, and (b) defining a plan for generating the evidence base to support best practice. PMID- 21584830 TI - Long-term experience in sentinel node biopsy for early oral and oropharyngeal squamous cell carcinoma. PMID- 21584831 TI - Significance of tumor necrosis for outcome of patients with hepatocellular carcinoma receiving locoregional therapy prior to liver transplantation. AB - BACKGROUND: Locoregional therapy has been advocated as an effective treatment for patients with unresectable hepatocellular carcinoma (HCC), and the majority of patients with HCC receive locoregional therapy prior to liver transplantation (LT). We herein aim to determine the prognostic factors affecting the outcome in patients who receive pretransplantation therapy. METHODS: We conducted a retrospective study of the prospective data of patients who received locoregional therapy before undergoing LT for HCC. The clinicopathologic features of the patients were studied using univariate and multivariate analysis to determine prognostic factors. RESULTS: Univariate and multivariate analysis of clinicopathologic features identified mean tumor necrosis (TN) >=60% as the sole independent factor associated with lower HCC recurrence following LT. Further, the groups of patients with mean TN >=60% who were within the University of California, San Francisco (UCSF) criteria and whose tumors beyond UCSF criteria were downstaged by TN following locoregional therapy had significantly better survival rates than the opposite groups. In-depth exploration of treatment modalities and pathological features indicated that HCC showed marked TN, while tumor nodules were well treated by locoregional therapy, and no viable tumors could be detected on radiological examination. CONCLUSIONS: Mean TN >=60% of tumor by locoregional therapy could offer better outcomes for patients with HCC undergoing LT. Therefore, locoregional therapy should be considered for patients with HCC awaiting LT or potential candidates for LT in order to induce TN as well as leading to diminished viable tumor burden and reducing the odds of HCC recurrence following LT. PMID- 21584832 TI - CXCR4 expression predicts patient outcome and recurrence patterns after hepatic resection for colorectal liver metastases. AB - BACKGROUND: The purpose of this study was to determine if the expression of the chemokine receptors, CXCR4 and CCR7, and the chemokine ligand, CXCL12, in completely resected colorectal cancer hepatic metastases are predictive of disease-specific survival, recurrence-free survival and patterns of recurrence. METHODS: Immunohistochemical analysis of CXCR4, CCR7 and CXCL12 expression within resected hepatic metastases was performed and correlated with clinicopathological variables, disease-specific survival, recurrence-free survival and patterns of recurrence. RESULTS: Seventy-five patients who underwent partial hepatectomy with curative intent were studied. CXCR4 expression (hazard ratio [HR] 3.6, 95% confidence interval [95% CI] 1.4-9.1) and clinical risk score >2 (HR 2.3, 95% CI 1.1-4.7) were independently associated with disease-specific survival by multivariate analysis. The 5-year estimated disease-specific survival rates for positive and negative CXCR4 tumor expression were 44 and 77%, respectively (P = 0.005). CXCR4 expression (HR 2.2, 95% CI 1.2-4.2) and clinical risk score >2 (HR 1.9, 95% CI 1.1-3.4) were independently associated with recurrence-free survival by multivariate analysis. The five year estimated recurrence-free survival rates for positive and negative CXCR4 tumor expression were 20 and 50%, respectively (P = 0.004). Neither CXCL12 nor CCR7 expression in tumors predicted disease-specific survival or recurrence-free survival. Forty-nine patients (65%) developed recurrent disease after initial hepatectomy. Negative CXCR4 tumor expression was associated with favorable recurrence patterns amenable to salvage resection and/or ablation. CONCLUSIONS: Negative CXCR4 expression in resected colorectal cancer hepatic metastases is independently associated with improved disease specific and recurrence-free survival and favorable patterns of recurrence. PMID- 21584833 TI - Clinicopathological significance of ZEB1 protein in patients with hepatocellular carcinoma. AB - BACKGROUND: ZEB1, a member of the ZFH family of proteins (zinc-finger E-box binding homeobox), plays a central role in epithelial-mesenchymal transition (EMT) during carcinogenesis. In this study, we investigated the expression of ZEB1 in patients with hepatocellular carcinoma (HCC) and its clinical effects with underlying mechanisms. METHODS: Expression levels of ZEB1 were assessed by Western blot in 5 HCC cell lines and in paired cancerous and noncancerous tissues from 110 patients with HCC. Short-hairpin RNA (shRNA) interference for ZEB1 was performed in MHCC-97H cell line. RESULTS: ZEB1 protein was detected at a relatively high level in metastatic human HCC cell lines (MHCC-97L and MHCC-97H) when compared with that in nonmetastatic HCC cell lines (Hep3B, PLC and Huh-7). ZEB1 was expressed at high levels in 72 of 110 HCC patients (65.4%) and correlated with advanced TNM stage, tumor size >5 cm, intrahepatic metastasis, vascular invasion, and frequent early recurrence. The results of multivariate analysis revealed that ZEB1 high expression was a significant prognostic factor for poor overall and disease-free survivals. Silencing ZEB1 resulted in significant suppression of motility of MHCC-97H cell line, which was accompanied with increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers N-cadherin and vimentin. Furthermore, silencing ZEB1 prevented the spread of intrahepatic metastasis and increased overall survival in mouse orthotopic tumor models. CONCLUSIONS: This study shows that ZEB1 high expression was correlated with HCC malignant progression and subsequent poor patient survival by induction of EMT changes. PMID- 21584834 TI - Mechanisms of improved outcomes for breast cancer between surgical oncologists and general surgeons. AB - BACKGROUND: Prior multi-institutional studies have reported a survival benefit of breast cancer treatment by surgical oncologists (SO) over general surgeons (GS). METHODS: Retrospective review tumor registry data of all breast cancer patients receiving primary treatment at a single institution from January 1, 1995, to December 31, 2008. RESULTS: During the time period, there were 2192 patients who received primary breast cancer treatment at this institution. The mean age was 57 years and the mean follow-up was >55 months. Stage distribution was similar between GS and SO. Overall survival (SO 83.8% vs. GS 75.6%) and disease-free survival (SO 80.7% vs. GS 72.0%) was highly statistically significant (P<0.0001). For stages 1, 2a, 2b, 3a, and 3b there were statistically significant (P<0.05) differences for overall and disease-free survival. Overall, the use of breast conservation was more likely by SO-52.6 vs. 38.3% all stages and 65.8 vs. 54.0% for stage 0-2. The compliance with all systemic therapies (chemotherapy and hormone therapy) was more likely if being treated by SO-77.3 vs. 68.5% (P<0.02). The use of radiotherapy for breast conservation and in stage 3 mastectomy patients was higher for SO (P<0.001). Participation in clinical trials was far higher for SO patients-56.2 vs. GS 7.0% (P<0.001). CONCLUSIONS: The value added by having primary breast cancer treatment by a SO seems to arise from the more successful completion of multidisciplinary care in a timely fashion and higher rates of clinical trial involvement. PMID- 21584835 TI - Neoadjuvant intraperitoneal and systemic chemotherapy for gastric cancer patients with peritoneal dissemination. AB - BACKGROUND: The present study was designed to assess the feasibility and efficiency of intraperitoneal and intravenous neoadjuvant chemotherapy in gastric cancer patients with peritoneal dissemination. METHODS: The study subjects were 25 treatment-naive patients with gastric cancer. Patients with positive cytology or with peritoneal carcinomatosis received neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), comprising intraperitoneal (i.p.) mitomycin C (MMC) and cisplatin (CDDP), followed by two cycles of intravenous triplet chemotherapy of docetaxel, 5-fluorouracil (5-FU), and CDDP. Gastrectomy with lymph node dissection was performed after NIPS in patients free of peritoneal deposits, confirmed by staging laparoscopy. RESULTS: Seventeen patients had measurable lymph node metastases by the RECIST criteria. CT examination showed response to the treatment in ten (59%, 0 complete response, 10 partial response). Of the 25 patients, 14 (56%) showed negative results on peritoneal cytology with no macroscopic peritoneal metastasis, whereas the remaining 11 were cancer cell positive on peritoneal cytology or macroscopic peritoneal metastasis even after NIPS. The median survival time for all 25 patients was 16.7 months. Prognosis was better in patients who showed negative cytology and disappearance of peritoneal cancer metastases after NIPS than in those with positive cytology or existing peritoneal deposits (P < 0.0001). The predominant toxicity was myelosuppression and grade 3-4 leukopenia and neutropenia occurred in 20 (80%) patients, which were manageable. No treatment-related mortality was observed during and after NIPS and surgery. CONCLUSIONS: The results of this prospective phase II study indicated that the newly designed NIPS was highly effective and well tolerated in patients with advanced gastric cancer and peritoneal dissemination. PMID- 21584836 TI - Splenic artery invasion in pancreatic adenocarcinoma of the body and tail: a novel prognostic parameter for patient selection. AB - BACKGROUND: The value of splenic vessels invasion (which identified T3 tumors) in prognosis after resection for pancreatic ductal adenocarcinoma (PDA) of the body and tail has not been extensively investigated. The goal of this study was to evaluate prognostic factors in PDA of the body/tail, emphasizing the role of splenic vessels infiltration. METHODS: Between 1990 and 2008, 87 patients who underwent distal pancreatectomy (DP) for histologically proven PDA of the body and tail were analyzed. Clinicopathological prognostic factors for survival were evaluated. Univariate and multivariable analyses were performed. RESULTS: Postoperative morbidity was 31% with no mortality. The 1-, 3-, and 5-year overall survival rates were 77%, 48%, and 24.5%, respectively. Invasion of the splenic artery (SA) was observed in 19 patients (22%). Patients with SA invasion had a significantly poorer prognosis compared with those without SA invasion (median survival: 15 vs. 39 months, P = 0.014). On multivariable analysis, adjuvant therapy, poor differentiation (G3/G4), R2 resection, the presence of lymph node metastases, and SA invasion were independent predictors of survival. CONCLUSIONS: Along with other well-known prognostic factors, invasion of SA is an independent predictor of poor survival in PDA of the body/tail. In case of the presence of SA infiltration, neoadjuvant treatment should be considered. SA infiltration might be reclassified from a T3 to T4 tumor. PMID- 21584837 TI - Rates of venous thromboembolism among patients with major surgery for cancer. AB - BACKGROUND: Previous studies have reported VTE rates during surgical stays in hospitals or by diagnoses over extended periods without being linked to specific surgical events. The purpose of this project was to assess the potential rate of venous thromboembolism in patients with cancer after a surgical procedure within the immediate posthospital admission period of 30 days, with special emphasis in increased sensitivity of detection. METHODS: Patients with cancer who had a major surgery were identified in a large commercial (non-Medicare) database containing data from more than 22 million patients in the United States. Those with a new diagnosis of VTE within 30 days postadmission for surgery were identified. Additional drug-based criteria were used to vary the VTE definition in a sensitivity analysis. VTE rates are reported for each of the surgical procedure group and overall. RESULTS: The overall 30-day VTE rate was 3.5% with a diagnosis based definition, with rates ranging by procedure from 1.8 to 13.2%. Esophageal resection patients have a VTE rate of 13.2% (95% confidence interval (CI), 8.8 18.9%), whereas prostatectomy patients have a VTE rate of 1.8% (95% CI, 1.5 2.1%). Of the 3.5% of patients with a VTE diagnosis on or before postoperative day 30, 73% of those have the VTE diagnosis by day 14. Another 1.15% is added to the overall VTE rate as the definition sensitivity is increased with outpatient pharmacy claims data. CONCLUSIONS: Using administrative data from large populations provides valuable insight into the potential VTE rates that occur within the 30-day post period after various cancer-related surgeries. The information can be used by surgeons as one component of the benefit-risk decision regarding postoperative VTE prophylaxis in surgical patients. PMID- 21584838 TI - Mungbean plants expressing BjNPR1 exhibit enhanced resistance against the seedling rot pathogen, Rhizoctonia solani. AB - Mungbean, Vigna radiata (L.) Wilczek is an important pulse crop that is widely cultivated in semi- arid tropics. The crop is attacked by various soil-borne pathogens like Rhizoctonia solani, which causes dry rot disease and seriously affects its productivity. Earlier we characterized the non-expressor of pathogenesis related gene-1(BjNPR1) of mustard, Brassica juncea, the counterpart of AtNPR1 of Arabidopsis thaliana. Here, we transformed mungbean with BjNPR1 via Agrobacterium tumefaciens. Because of the recalcitrant nature of mungbean, the effect of some factors like Agrobacterium tumefaciens strains (GV2260 and LBA4404), pH, L: -cysteine and tobacco leaf extract was tested in transformation. The transgenic status of 15 plants was confirmed by PCR using primers for nptII. The independent integration of T-DNA in transgenic plants was analyzed by Southern hybridization with an nptII probe and the expression of BjNPR1 was confirmed by RT-PCR. Some of the T(0) plants were selected for detached leaf anti fungal bioassay using the fungus Rhizoctonia solani, which showed moderate to high level of resistance depending on the level of expression of BjNPR1. The seedling bioassay of transgenic T(2) plants indicated resistance against dry rot disease caused by R. solani. PMID- 21584839 TI - Healthcare consumers' attitudes towards physician and personal use of health information exchange. AB - BACKGROUND: Health information exchange (HIE), the electronic transmission of patient medical information across healthcare institutions, is on the forefront of the national agenda for healthcare reform. As healthcare consumers are critical participants in HIE, understanding their attitudes toward HIE is essential. OBJECTIVE: To determine healthcare consumers' attitudes toward physician and personal use of HIE, and factors associated with their attitudes. DESIGN: Cross-sectional telephone survey. PARTICIPANTS: English-speaking residents of the Hudson Valley of New York. MAIN MEASURE: Consumer reported attitudes towards HIE. KEY RESULTS: Of 199 eligible residents contacted, 170 (85%) completed the survey: 67% supported physician HIE use and 58% reported interest in using HIE themselves. Multivariate analysis suggested supporters of physician HIE were more likely to be caregivers for chronically ill individuals (OR 4.6, 95% CI 1.06, 19.6), earn more than $100,000 yearly (OR 3.5, 95% CI 1.2, 10.0), and believe physician HIE would improve the privacy and security of their medical records (OR 2.9, 95% CI 1.05, 7.9). Respondents interested in using personal HIE were less likely to be female (OR 0.4, 95% CI 0.1, 0.98), and more likely to be frequent Internet-users (OR 3.3, 95% CI 1.03, 10.6), feel communication among their physicians was inadequate (OR 6.7, 95% CI 1.7, 25.3), and believe personal HIE use would improve communication with their physicians (OR 4.7, 95% CI 1.7, 12.8). CONCLUSIONS: Consumer outreach to gain further support for ongoing personal and physician HIE efforts is needed and should address consumer security concerns and potential disparities in HIE acceptance and use. PMID- 21584840 TI - Chemotherapy for endometrial carcinoma (GOGO-EM1 study): TEC (paclitaxel, epirubicin, and carboplatin) is an effective remission-induction and adjuvant therapy. AB - BACKGROUND: TAP chemotherapy (paclitaxel, doxorubicin, and cisplatin) is effective for advanced and recurrent endometrial carcinoma, but has occasional severe toxicity. TEC chemotherapy (paclitaxel, epirubicin, and carboplatin) has been suggested to have less toxicity; however, the optimal dosage has yet to be determined. PATIENTS AND METHODS: Phase I/II prospective study for TEC therapy was performed. A retrospective comparison of the prognosis between adjuvant TEC therapy and radiation for completely resected cases with risk factors was also performed. RESULTS: The recommended dose of TEC therapy was determined to be paclitaxel 150 mg/m(2), epirubicin 50 mg/m(2), and carboplatin AUC 4. A TEC regimen at this dose level was shown to be tolerable. The response rate and median overall survival were 74% and 37 months for those with advanced primary disease (Group B) and 50% and 26 months for recurrent tumors (Group C), respectively. A retrospective comparison showed that adjuvant TEC therapy for completely resected stage III cases improved their prognosis when compared to an adjuvant radiation therapy. CONCLUSION: TEC therapy was demonstrated to be a tolerable and effective treatment, not only as a remission-induction therapy for advanced and recurrent endometrial carcinomas but also as the adjuvant therapy. PMID- 21584841 TI - Unenhanced MR angiography of uterine and ovarian arteries after uterine artery embolization: differences between patients with incomplete and complete fibroid infarction. AB - PURPOSE: To compare the status of uterine and ovarian arteries after uterine artery embolization (UAE) in patients with incomplete and complete fibroid infarction via unenhanced 3D time-of-flight magnetic resonance (MR) angiography. MATERIALS AND METHODS: Thirty-five consecutive women (mean age 43 years; range 26 52 years) with symptomatic uterine fibroids underwent UAE and MR imaging before and within 2 months after UAE. The patients were divided into incomplete and complete fibroid infarction groups on the basis of the postprocedural gadolinium enhanced MR imaging findings. Two independent observers reviewed unenhanced MR angiography before and after UAE to determine bilateral uterine and ovarian arterial flow scores. The total arterial flow scores were calculated by summing the scores of the 4 arteries. All scores were compared with the Mann-Whitney test. RESULTS: Fourteen and 21 patients were assigned to the incomplete and complete fibroid infarction groups, respectively. The total arterial flow score in the incomplete fibroid infarction group was significantly greater than that in the complete fibroid infarction group (P=0.019 and P=0.038 for observers 1 and 2, respectively). In 3 patients, additional therapy was recommended for insufficient fibroid infarction. In 1 of the 3 patients, bilateral ovarian arteries were invisible before UAE but seemed enlarged after UAE. CONCLUSION: The total arterial flow from bilateral uterine and ovarian arteries in patients with incomplete fibroid infarction is less well reduced than in those with complete fibroid infarction. Postprocedural MR angiography provides useful information to estimate the cause of insufficient fibroid infarction in individual cases. PMID- 21584842 TI - Comparison of the anti-tumor effects of two platinum agents (miriplatin and fine powder cisplatin). AB - PURPOSE: This study was designed to evaluate the anti-tumor effects of miriplatin lipidol and fine-powder cisplatin-lipiodol suspensions. METHODS: Assessment of the cytotoxicity of two drugs was performed: a soluble derivative of miriplatin (DPC) and fine-powder cisplatin. We randomly divided 15 rabbits with transplanted VX2 liver tumors into three equal groups. They were infused via the proper hepatic artery with a miriplatin-lipiodol suspension (ML), a fine-powder cisplatin-lipiodol suspension (CL), or saline (control) and the tumor growth rate was determined on MR images acquired before and 7 days after treatment. The concentration of platinum (PCs) in blood was assayed immediately, and 10, 30, and 60 min, and 24 h and 7 days after drug administration. Its concentration in tumor and surrounding normal liver tissues was determined at 7 days postadministration. RESULTS: At high concentrations, fine-powder cisplatin exhibited stronger cytotoxicity than DPC. At low concentrations, both agents manifested weak cytotoxicity. While there was no difference between the tumor growth rate of the ML and the CL groups, the difference between the controls and ML- and CL-treated rabbits was significant. The blood PCs peaked at 10 min and then gradually decreased over time. On the other hand, no platinum was detected at any point after the administration of ML. There was no difference between the ML and CL groups in the PCs in tumor tissues; however, in normal hepatic tissue, the PCs were higher in ML- than CL-treated rabbits. CONCLUSIONS: We confirmed the anti tumor effect of ML and CL. There was no significant difference between the anti tumor effect of ML and CL at 7 days postadministration. PMID- 21584843 TI - The evolution of the manufacturing science and the pharmaceutical industry. PMID- 21584844 TI - Improvement of cerebral metabolism mediated by Ro5-4864 is associated with relief of intracranial pressure and mitochondrial protective effect in experimental brain injury. AB - PURPOSE: To investigate the possible impact of reduction of mitochondrial membrane permeabilization by modulation of the 18 kDa translocator protein mediated by Ro5-4864 over post-traumatic cerebral edema and metabolic crisis. METHODS: Cerebral microdialysis and intracranial pressure (ICP) monitoring were performed in Sprague-Dawley rats treated by intraperitoneal injection of either dimethylsulfoxide (vehicle) or Ro5-4864 following cortical contusion and further correlated with quantitative assessment of mitochondrial damage, water content in the injured tissue, modified neurological severity score, and lesion size. RESULTS: Ro5-4864 resulted in a profound decrease in ICP that correlated with improved cerebral metabolism characterized by significantly higher glucose and pyruvate and lower lactate concentrations in the pericontusional area in comparison with vehicle-treated animals. Reduced ICP correlated with reduced water content in the injured tissue; improved metabolism was associated with reduced mitochondrial damage evidenced by electron microscopy. Both effects were associated with a profound and significant reduction in glycerol release and lesion size, and correlated with improved neurological recovery. CONCLUSIONS: The present study shows that Ro5-4864 has a favorable effect on the fate of injured brain, presumably mediated by improvement of metabolism. It further suggests that improvement of metabolism may contribute to ICP relief. PMID- 21584845 TI - Turbidity spectroscopy for characterization of submicroscopic drug carriers, such as nanoparticles and lipid vesicles: size determination. AB - PURPOSE: To apply UV/Vis spectrometry for characterization of submicroscopic drug carriers, such as nanoparticles and lipid vesicles. METHODS: We first investigated theoretically, within the framework of the Rayleigh-Gans-Debye approximation (RGDA), parameters affecting turbidity spectrum, tau(lambda), of nanosized light scatterers. We then analyzed, within the framework of the RGDA, experimental turbidity spectra (lambda = 400-600 nm) of extruded unilamellar vesicle (70 nm <= 2r <= 110 nm) suspensions to derive vesicle size, using dynamic light scattering results for comparison. We similarly studied the preparations polydispersity and lamellarity and monitored vesicle size changes. RESULTS: Turbidimetry suffices for accurate, fast, and viscosity-independent characterization of submicroscopic particles. Analysis of turbidity spectra, or more precisely wavelength exponent spectra (derivatives of logarithmic turbidity spectra), yielded similar average radii (r = 54.2 +/- 0.2 nm; 46.0 +/- 0.2 nm; 35.5 +/- 0.1 nm) as dynamic light scattering (r = 55.9 +/- 1.5 nm; 46.1 +/- 0.4 nm; 36.1 +/- 0.4 nm). Both methods also revealed similar suspension polydispersity and cholate-induced vesicle size changes in a few nanometer range. CONCLUSION: Despite its experimental simplicity, the widely accessible turbidimetric method provides accurate size values and is suitable for (continuous) monitoring size stability, or sameness, of submicroscopic drug carriers. PMID- 21584846 TI - Bone mineral density, quantitative ultrasound parameters and bone metabolism in postmenopausal women with depression. AB - Low bone mineral density, which increases the risk of stress fragility fractures, is a frequent, often persistent finding in patients with major depressive disorder (MDD). The clinical association between major depressive disorder and osteopenia is still unclear, although several factors are associated with a loss of bone mass. The aim of our study, therefore, was to evaluate bone mineral density and bone metabolism in patients with MDD. Bone mineral density was evaluated in fifty postmenopausal women with MDD, and in 50 matched postmenopausal control women by dual-energy X-ray absorptiometry of the lumbar spine and femur, and by ultrasonography of the calcaneus and phalanges. Serum levels of 25-hydroxivitamin D, parathyroid hormone, Osteoprotegerin/Receptor Activator for Nuclear Factor kappaB Ligand ratio, bone turnover markers, serum and urinary cortisol were examined. Bone mineral density of the lumbar spine (BMD: 0.72 +/- 0.06 vs. 0.82 +/- 0.09 g/cm(2), p < 0.001), femoral neck (BMD: 0.58 +/- 0.04 vs. 0.71 +/- 0.07 g/cm(2), p < 0.001) and total femur (BMD 0.66 +/- 0.09 vs. 0.54 +/- 0.06 g/cm(2), p < 0.001); and ultrasound parameters at calcaneus (SI: 81.30 +/- 6.10 vs. 93.80 +/- 7.10, p < 0.001) and phalanges (AD SOS: 1915.00 +/- 37.70 vs. 2020.88 +/- 39.46, p < 0.001; BTT : 1.30 +/- 0.8 vs. 1.45 +/- 0.9, p < 0.001) are significantly lower in patients with MDD compared with controls. Moreover bone turnover markers, parathyroid hormone levels and Receptor Activator for Nuclear Factor kappaB Ligand are significantly higher in MDD patients compared with controls, while serum levels of 25-hydroxivitamin D and osteoprotegerin are significantly lower. There are no differences in urinary excretion and serum cortisol between groups. Postmenopausal women with depressive disorder have an elevated risk for osteoporosis. Our data suggest that a high level of parathyroid hormone may play a role in the pathogenetic process underlying osteopenia in these patients. PMID- 21584847 TI - Age and gender specific cut-off values to improve the performance of D-dimer assays to predict the risk of venous thromboembolism recurrence. AB - The Prolong study shows that continuing vitamin K antagonists (VKA) in patients with abnormal D-dimer (evaluated by a qualitative assay, Clearview Simplify D dimer) results in a significant reduction of venous thromboembolism (VTE) recurrence. The present study retrospectively analyzes a subgroup of patients enrolled in the Prolong study with a view to calculate cut-off values for six quantitative D-dimer methods to predict the risk of VTE recurrence. We measured D dimer levels by VIDAS D-dimer Exclusion (bioMerieux), STA Liatest D-dimer (DiagnosticaStago), HemosIL D-dimer and HemosIL D-dimer HS (Instrumentation Laboratory), Innovance D-dimer (Siemens) and AutoDimer (Trinity Biotech) in frozen plasma aliquots sampled 30 +/- 10 days after VKA cessation in 390 patients enrolled in the Prolong study. During follow-up (562.7 years), 28 patients had recurrent VTE (7.2%, 5.0% person-years). Since D-dimer levels are positively correlated with age and significantly lower in men, we calculated method-specific cut-off values according to age and gender. The HRs for VTE recurrence calculated using method-specific cut-off values based on age and gender are higher than those using cut-off values indicated by the manufacturers for VTE exclusion in symptomatic outpatients. These data suggest that method-specific cut-off values calculated according to patient age and gender can be more accurate in identifying patients at a higher risk for VTE recurrence. These method-specific cut-off values are being evaluated in the ongoing prospective management multicenter DULCIS study. PMID- 21584848 TI - Fractures in individuals with and without a history of infantile autism. A Danish register study based on hospital discharge diagnoses. AB - We compared the prevalence and types of fractures in a clinical sample of 118 individuals diagnosed as children with infantile autism (IA) with 336 matched controls from the general population. All participants were screened through the nationwide Danish National Hospital Register. The average observation time was 30.3 years (range 27.3-30.4 years), and mean age at follow-up was 42.7 years (range 27.3-57.3 years). Of the 118 individuals with IA, 14 (11.9%) were registered with at least one fracture diagnosis against 83 (24.7%) in the comparison group (p = 0.004; OR = 0.41; 95%CI 0.22-0.76), but the nature of their fractures seems somewhat different. Epilepsy was a risk factor, but only in the comparison group. Our results lend no support to the notion that fracture is a common comorbid condition in a population of people diagnosed with IA as children. PMID- 21584850 TI - Predictive and concurrent validity of parent concern about young children at risk for autism. AB - Parents' concerns about their children's development were examined prospectively at 14, 24, and 36 months for 89 younger siblings of a child with autism. Parent reported concern was high at all ages (40-75%) and was higher at 24 and 36 months in children with ASD than non-ASD outcomes (p < .05). Communication concerns were reported most frequently. Parent concern compared to impairment classification based on concurrent standardized tests provided better specificity than sensitivity, and was better for communication than social functioning. Parent communication concern (but not social concern) at 24 months and 36 months predicted ASD versus non-ASD outcome; however, children's impairment on standardized tests yielded greater predictive value at all ages (p < .001). Close monitoring of this at risk group is warranted. PMID- 21584849 TI - Evidence-based behavioral interventions for repetitive behaviors in autism. AB - Restricted and repetitive behaviors (RRBs) are a core symptom of autism spectrum disorders (ASD). There has been an increased research emphasis on repetitive behaviors; however, this research primarily has focused on phenomenology and mechanisms. Thus, the knowledge base on interventions is lagging behind other areas of research. The literature suggests there are evidence-based practices to treat "lower order" RRBs in ASD (e.g., stereotypies); yet, there is a lack of a focused program of intervention research for "higher order" behaviors (e.g., insistence on sameness). This paper will (a) discuss barriers to intervention development for RRBs; (b) review evidence-based interventions to treat RRBs in ASD, with a focus on higher order behaviors; and (c) conclude with recommendations for practice and research. PMID- 21584851 TI - So you think you can safely extubate your patient? PMID- 21584852 TI - More is not always better: paradoxical effects of repetition on semantic accessibility. AB - Repetition normally enhances memory. While in some cases the benefit of added repetition may be incremental, few would expect that massed repetition could actually reverse the benefits of brief repetition. Here we report two experiments that document a clear example of a paradoxical effect of massed repetition. Subjects first repeated words (e.g., "sheep") aloud one at a time for 0, 5, 10, 20, or 40 s. A free association phase followed in which cues could be completed with repeated words (e.g., "herd s___" for "sheep") or with semantically associated words (e.g., "fabric w___" for "wool"). Brief periods of repetition (5 10 s) resulted in priming, as would be expected based on research on repetition priming and spreading activation. Longer periods of repetition (20-40 s), however, abolished priming. Interestingly, this massed-repetition decrement was particularly robust for semantic associates of repeated words, and was evident after a 15-min delay. These findings document a paradoxical feature of the effects of rehearsal on memory: When ideas are repeated often enough, the benefits of rehearsal can actually be reversed. PMID- 21584853 TI - Dissociative effects of orthographic distinctiveness in pure and mixed lists: an item-order account. AB - We apply the item-order theory of list composition effects in free recall to the orthographic distinctiveness effect. The item-order account assumes that orthographically distinct items advantage item-specific encoding in both mixed and pure lists, but at the expense of exploiting relational information present in the list. Experiment 1 replicated the typical free recall advantage of orthographically distinct items in mixed lists and the elimination of that advantage in pure lists. Supporting the item-order account, recognition performances indicated that orthographically distinct items received greater item specific encoding than did orthographically common items in mixed and pure lists (Experiments 1 and 2). Furthermore, order memory (input-output correspondence and sequential contiguity effects) was evident in recall of pure unstructured common lists, but not in recall of unstructured distinct lists (Experiment 1). These combined patterns, although not anticipated by prevailing views, are consistent with an item-order account. PMID- 21584854 TI - Spatial memory in the real world: long-term representations of everyday environments. AB - When people learn an environment, they appear to establish a principle orientation just as they would determine the "top" of a novel object. Evidence for reference orientations has largely come from observations of orientation dependence in pointing judgments: Participants are most accurate when asked to recall the space from a particular orientation. However, these investigations have used highly constrained encoding in both time-scale and navigational goals, leaving open the possibility that larger spaces experienced during navigational learning depend on a different organizational scheme. To test this possibility, we asked undergraduates to perform judgments of relative direction on familiar landmarks around their well-learned campus. Participants showed clear evidence for a single reference orientation, generally aligned along salient axes defined by the buildings and paths. This result argues that representing space involves the establishment of a reference orientation, a requirement that endures over repeated exposures and extensive experience. PMID- 21584855 TI - Percutaneous treatment of thoracic duct injuries. AB - BACKGROUND: Major thoracic or neck surgery or penetrating trauma can cause injury to the thoracic duct and development of a chylothorax. Chylothorax results in metabolic and immunologic disorders that can be life threatening, with a mortality rate reaching 50%. The management of chyle leaks is dependent on the etiology and daily output. Interventions are used to treat only leaks unresponsive to medical management or those with an output exceeding 1,000 ml/day. METHODS: This study reviewed the existing literature on the percutaneous management of chyle leaks. The authors evaluated five case series and three case reports inclusive of 90 patients in which percutaneous treatment for chylothorax was attempted between 1998 and 2004. RESULTS: For 71 patients, percutaneous treatment was technically successful, and chylothorax resolved in 49 of the patients (69%). Percutaneous treatment of chylothorax was associated with a 2% morbidity rate and no mortality. For 19 patients whose percutaneous approach failed, either surgical ligation or pleurodesis was performed. CONCLUSIONS: The percutaneous management of chyle leak is feasible, with low morbidity and mortality rates and a high rate of effectiveness. This approach should be considered before more invasive procedures. PMID- 21584856 TI - Pharmacokinetics, efficacy, and safety evaluation of docetaxel/hydroxypropyl sulfobutyl-beta-cyclodextrin inclusion complex. AB - Hydroxypropyl-sulfobutyl-beta-cyclodextrin (HP-SBE-beta-CD) inclusion complex was developed and used as a drug delivery system for DTX (DTX/HP-SBE-beta-CD). The objective of the present study was to evaluate and compare the biological properties of DTX/HP-SBE-Beta-CD with Taxotere(r). The pharmacokinetics, biodistribution, antitumor efficacy in vivo and in vitro, and safety evaluation of DTX/HP-SBE-beta-CD were studied. The most significant finding was that it was possible to prepare a Polysorbate-80-free inclusion complex for DTX. Studies based on pharmacokinetics, biodistribution, and antitumor efficacy indicated that DTX/HP-SBE-beta-CD had similar pharmacokinetic properties and antitumor efficacy both in vitro and in vivo as Taxotere(r). Fortunately, this new drug delivery system attenuated the side effects when used in vivo. As a consequence, DTX/HP SBE-beta-CD may be a promising alternative to Taxotere(r) for cancer chemotherapy treatment with reduced side effects. The therapeutic potential against a variety of human tumors and low toxicity demonstrated in a stringent study clearly warrant clinical investigation of DTX/HP-SBE-beta-CD for possible use against human tumors. PMID- 21584857 TI - [Contrast-enhanced ultrasound imaging of the carotid artery]. AB - A conventional grey scale, Doppler sonography and color-coded Doppler ultrasound examination should be the first step in the diagnosis of the vessels supplying the brain and have a major impact in diagnostic imaging. This ultrasound examination allows the simultaneous acquisition of morphologic and hemodynamic information with high spatial and temporal resolution. Most of the pathological changes of the extracranial arteries can thus be reliably detected. Contrast enhanced ultrasound (CEUS) is a promising new non-invasive method for the diagnosis and follow-up of complex carotid abnormalities. In addition to improving current carotid structural scans, CEUS has the potential to improve or provide additional information on carotid arterial diseases, such as the reliable differentiation between internal carotid artery (ICA) occlusion and pseudo occlusion, improved visualization of in-stent stenosis, extracranial ICA aneurysms and carotid dissection.In this article the contribution of color-coded duplex ultrasound and CEUS in assessing various pathologies of the carotid artery will be addressed. PMID- 21584858 TI - Expression and beta-glucan binding properties of Scots pine (Pinus sylvestris L.) antimicrobial protein (Sp-AMP). AB - Scots pine (Pinus sylvestris) secretes a number of small, highly-related, disulfide-rich proteins (Sp-AMPs) in response to challenges with fungal pathogens such as Heterobasidion annosum, although their biological role has been unknown. Here, we examined the expression patterns of these genes, as well as the structure and function of the encoded proteins. Northern blots and quantitative real time PCR showed increased levels of expression that are sustained during the interactions of host trees with pathogens, but not non-pathogens, consistent with a function in conifer tree defenses. Furthermore, the genes were up-regulated after treatment with salicylic acid and an ethylene precursor, 1 aminocyclopropane-1-carboxylic-acid, but neither methyl jasmonate nor H(2)O(2) induced expression, indicating that Sp-AMP gene expression is independent of the jasmonic acid signaling pathways. The cDNA encoding one of the proteins was cloned and expressed in Pichia pastoris. The purified protein had antifungal activity against H. annosum, and caused morphological changes in its hyphae and spores. It was directly shown to bind soluble and insoluble beta-(1,3)-glucans, specifically and with high affinity. Furthermore, addition of exogenous glucan is linked to higher levels of Sp-AMP expression in the conifer. Homology modeling and sequence comparisons suggest that a conserved patch on the surface of the globular Sp-AMP is a carbohydrate-binding site that can accommodate approximately four sugar units. We conclude that these proteins belong to a new family of antimicrobial proteins (PR-19) that are likely to act by binding the glucans that are a major component of fungal cell walls. PMID- 21584859 TI - Intron hairpin and transitive RNAi mediated silencing of orfH522 transcripts restores male fertility in transgenic male sterile tobacco plants expressing orfH522. AB - The present work was aimed at developing vector construct(s) suitable for restoring fertility in transgenic male sterile tobacco plants expressing male sterility-inducing ORFH522 in tapetal cell layer (Nizampatnam et al. Planta 229:987-1001, 2009). PTGS vectors that could produce either intron spliced hairpin RNA against the orfH522 or induce silencing of orfH522 by heterologous 3'UTR region were developed using the selected 316 bp (orf316) fragment of orfH522. The constructs were independently mobilized into Agrobacterium and used for transforming tobacco. The T(1) generation plants carrying the restorer gene cassettes in homozygous condition were identified and crossed with the male sterile transgenic tobacco plants to obtain the hybrid seeds. PCR analysis of hybrid plants indicated segregation for the sterility inducing cassette while all the plants carried the restorer cassette. Hybrid plants produced fertile pollen grains and formed normal capsules upon selfing. Further molecular analyses of these hybrid plants with RT-PCR, Northern blotting and siRNA detection, revealed that intron interrupted hairpin RNA (ihp-RNA) mediated gene silencing was more effective compared to silencing by heterologous 3'UTR (SHUTR) as indicated by the complete degradation of orfH522 transcripts and formation of higher levels of orf316 specific siRNA molecules in plants carrying ihp-RNA restorer construct. Segregation analyses of F(2) (selfed hybrid) plants confirmed the co-segregation of gene cassettes and the traits in Mendelian di-hybrid ratio (9:3:3:1). Taken together, the results established that intron hairpin and transitive RNAi mediated silencing of orfH522 transcripts restored fertility in transgenic male sterile tobacco plants expressing orfH522 and ihp-RNA was more efficient in silencing orfH522 transcripts. PMID- 21584860 TI - Stress response of transgenic tobacco plants expressing a cyanobacterial ferredoxin in chloroplasts. AB - Expression of the chloroplast electron shuttle ferredoxin is induced by light through mechanisms that partially depend on sequences lying in the coding region of the gene, complicating its manipulation by promoter engineering. Ferredoxin expression is also down-regulated under virtually all stress situations, and it is unclear if light-dependent induction and stress-dependent repression proceed through the same or similar mechanisms. Previous reports have shown that expression of a cyanobacterial flavodoxin in tobacco plastids results in plants with enhanced tolerance to adverse environmental conditions such as drought, chilling and xenobiotics (Tognetti et al. in Plant Cell 18:2035-2050, 2006). The protective effect of flavodoxin was linked to functional replacement of ferredoxin, suggesting the possibility that tolerant phenotypes might be obtained by simply increasing ferredoxin contents. To bypass endogenous regulatory constraints, we transformed tobacco plants with a ferredoxin gene from Anabaena sp. PCC7120, which has only 53% identity with plant orthologs. The cyanobacterial protein was able to interact in vitro with ferredoxin-dependent plant enzymes and to mediate NADP(+) photoreduction by tobacco thylakoids. Expression of Anabaena ferredoxin was constitutive and light-independent. However, homozygous lines accumulating threefold higher ferredoxin levels than the wild-type failed to show enhanced tolerance to oxidative stress and chilling temperatures. Under these adverse conditions, Anabaena ferredoxin was down-regulated even faster than the endogenous counterparts. The results indicate that: (1) light- and stress dependent regulations of ferredoxin expression proceed through different pathways, and (2) overexpression of ferredoxin is not an alternative to flavodoxin expression for the development of increased stress tolerance in plants. PMID- 21584862 TI - Prism adaptation in left-handers. AB - Two experiments with left-handers examined the features of prism adaptation established by previous research with right-handers. Regardless of handedness, (1) rapid adaptation occurs in exposure pointing with developing error in the opposite direction after target achievement, especially with early visual feedback in target pointing; (2) proprioceptive or visual aftereffects are larger, depending on whether visual feedback is available early or late, respectively, in target pointing; (3) the sum of these aftereffects is equal to the total aftereffect for the eye-hand coordination loop; (4) intermanual transfer of visual aftereffects occurs only for the dominant hand; and (5) visual aftereffects are larger in left space when the dominant hand is exposed to leftward displacement. A notable handedness difference is that, while transfer of proprioceptive aftereffects only occurs to the nondominant hand in right-handers, transfer occurs in both directions for left-handers, but regardless of handedness, such transfer only occurs when the exposed hand is tested first after exposure. A discussion then focuses on the implications of these data for a theory of handedness. PMID- 21584861 TI - Effect of acute xanthine oxidase inhibition on myocardial energetics during basal and very high cardiac workstates. AB - Myocardial ischemia is associated with reduced myocardial adenosine triphosphate (ATP) and increased free adenosine diphosphate (ADP) similar to the normal heart at very high cardiac workstates (HCW). We examined whether acute xanthine oxidase inhibition (XOI) in vivo can decrease myocardial free ADP in normal hearts functioning at basal cardiac workstates (BCW) or very HCW (catecholamine induced). Myocardial high-energy phosphate ((31)P magnetic resonance spectroscopy), blood flow (radioactive microspheres), and oxygen consumption (MVO(2)) were measured in an open-chest canine model before and after infusion of vehicle or an XO inhibitor (allopurinol or febuxostat; n = 10 in each group) during BCW and infusion of dobutamine + dopamine to induce a very HCW. During BCW, both allopurinol and febuxostat resulted in higher phosphocreatine (PCr)/ATP, corresponding to lower ADP levels. During vehicle infusion, HCW caused a decrease of PCr/ATP and an increase in myocardial free ADP. Although XOI did not prevent an increase in free ADP during catecholamine infusion, the values in the allopurinol or febuxostat groups (0.141 +/- 0.012 and 0.136 +/- 0.011 MUmol/g dry wt, respectively) remained significantly less than in the vehicle group (0.180 +/- 0.017; P < 0.05). Thus, at a given rate of ATP synthesis, XOI decreased the free ADP level needed to drive ATP synthesis, suggesting a more energy-efficient status. As contractile dysfunction in ischemia is characterized by increase of myocardial free ADP and energy deficiency, the data suggest that XOI might be a potential therapy for improving energy efficiency during myocardial ischemia. PMID- 21584864 TI - Requirement of alpha7 nicotinic acetylcholine receptors for amyloid beta protein induced depression of hippocampal long-term potentiation in CA1 region of rats in vivo. AB - The high density of senile plaques with amyloid beta protein (Abeta) and the loss of cholinergic neurons in the brain are the dominated pathological characteristics of Alzheimer's disease (AD). However, the active center of Abeta, especially the cholinergic mechanism underlying the Abeta neurotoxicity, is mostly unknown. This study examined the effects of different Abeta fragments on hippocampal long-term potentiation (LTP) and investigated its probable alpha7 nicotinic acetylcholine receptors (nAChRs) mechanism. The results show that: (1) intracerebroventicular injection of Abeta25-35 or Abeta31-35 significantly and similarly suppressed hippocampal LTP in CA1 region in rats; (2) choline, a selective alpha7 nAChR agonist, did not affect the LTP induction but enhanced LTP suppression induced by Abeta31-35; and (3) methyllycaconitine, a specific alpha7 nAChR antagonist, slightly suppressed hippocamal LTP but effectively prevented against Abeta31-35-induced LTP depression in the presence of Abeta31-35. These results indicate that: (1) the amino acid sequence 31-35 of the Abeta peptide might be a shorter active sequence in the full length molecule; (2) alpha7 nAChRs are required for the Abeta-induced suppression of hippocampal LTP. Thus, this study not only provides a new insight into the mechanism by which Abeta impairs synaptic plasticity but also strongly suggests that sequence 31-35 in Abeta molecule and alpha7 nAChRs in the brain might be potential therapeutic targets for the treatment of AD. PMID- 21584863 TI - D-cycloserine facilitates extinction of cocaine self-administration in C57 mice. AB - INTRODUCTION: Cocaine is a highly addictive drug of abuse for which there are currently no medications. In rats and mice d-cycloserine (DCS), a partial NMDA agonist, accelerates extinction of cocaine seeking behavior. Since cues delay extinction here, we evaluated the effects d-cycloserine in extinction with and without the presence of cues. METHODS: Two doses of DCS (15 and 30 mg/kg) were studied in C57 mice. Mice self-administered cocaine (1 mg/kg) for 2 weeks and then underwent a 20-day extinction period where DCS was administered i.p. immediately following each daily session. Extinction was conducted in some mice with the presence of cocaine-paired cues; while others were in the absence of these cues. RESULTS: DCS treated mice (either dose) showed significantly reduced lever pressing during extinction with cue exposures when compared with vehicle treated mice. Without cues, animals showed much lower levels of lever pressing but the differences between vehicle and DCS were not significant. CONCLUSION: DCS accelerated extinction with the presence of cues, but there were no differences on extinction without cues as compared with vehicle. These findings are consistent with DCS disrupting the memory process associated with the cues. Since drug cues are significantly involved in relapse, these findings support research to assess the therapeutic potential of DCS in cocaine addiction. PMID- 21584865 TI - Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine induced dopamine and serotonin neurotoxicity. AB - Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex. PMID- 21584866 TI - Involvement of NMDA receptors in ryanodine receptor expression in dopaminergic neurons in the ventral tegmental area of mice with intermittent methamphetamine treatment. AB - Excitatory synapses on dopaminergic neurons of the ventral tegmental area (VTA) represent an important role in psychostimulant-induced rewarding effect. This study investigated the regulation of ryanodine receptor (RyR) and N-methyl-D aspartate (NMDA) receptor expression in mice under intermittent methamphetamine (METH) treatment using a place preference procedure. RyR-1 and -2 significantly increased in the VTA of mice with METH-induced place preference, whereas RyR-3 showed no changes. In addition, the levels of NR1, NR2A, and NR2B subunits were increased in the VTA. The METH-induced place preference was inhibited by intracerebroventricular pretreatment with MK-801, a noncompetitive NMDA receptor antagonist, and ifenprodil, a selective NR2B subunit-containing NMDA receptor antagonist, in a dose-dependent manner. Under these conditions, the increase of RyR-1 and -2 in the VTA was significantly blocked by ifenprodil. The immunohistochemical analysis revealed the colocalization of RyR-1 and -2 with NR2B subunits in dopaminergic neurons in the mouse VTA. These findings suggest that RyRs could be involved in the development of METH-induced place preference and that NR2B subunit-containing NMDA receptors in mice showing METH-induced place preference play an important role in expression of RyRs. PMID- 21584867 TI - Inhibition of the serotonin transporter induces microglial activation and downregulation of dopaminergic neurons in the substantia nigra. AB - Drugs that selectively inhibit the serotonin transporter (SERT) are widely used in the treatment of depression and anxiety disorders. These agents are associated with a range of extrapyramidal syndromes such as akathisia, dystonia, dyskinesia and parkinsonism, suggesting an effect on dopaminergic transmission. We studied the time course of changes in dopaminergic neurons in the substantia nigra (SN) after initiation of two different SERT inhibitors, citalopram and fluoxetine. In the first experiment, groups of Sprague-Dawley rats received daily meals of rice pudding either alone (N = 9) or mixed with citalopram 5 mg/kg/day (N = 27). Rats were sacrificed after 24 h, 7 days or 28 days of treatment. Sections of SN were processed for tyrosine hydroxylase (TH) immunohistochemistry. Citalopram induced a significant decrease in TH-positive cell counts at 24 h (44%), 7 days (38%) and 28 days (33%). No significant differences among the citalopram treatment groups were observed in the SN. To determine whether these changes would occur with other SERT inhibitors, we conducted a second experiment, this time with a 28 day course of fluoxetine. As was observed with citalopram, fluoxetine induced a significant 21% reduction of TH cell counts in the SN. Immunoblot analysis showed that fluoxetine also induced a 45% reduction of striatal TH. To investigate a possible role for the innate immune system in mediating these changes, we also studied the microglial marker OX42 after administration of fluoxetine and noted a significant 63% increase in the SN of fluoxtine-treated animals. These results indicate that SERT inhibition can activate microglia and alter the regulation of TH, the rate limiting enzyme for dopamine biosynthesis. These changes may play a role in mediating the extrapyramidal side effects associated with SERT inhibitors. PMID- 21584868 TI - Impact of isoflurane anesthesia on D2 receptor occupancy by [18F]fallypride measured by microPET with a modified Logan plot. AB - In the previous work, we reported a method that utilized imaging data collected from 60 to 120 min following [(18) F]fallypride administration to estimate the distribution volume ratio DVR' (DVR' ? DVR; DVR = 1 + BP(ND) , where BP(ND) is a measure of receptor density, DA D2 in this case). In this work, we use this method to assess the effects of isoflurane anesthesia on [(18) F]fallypride DVR'. METHODS: Rats were injected with [(18) F]fallypride either unconsciously under ~1.5% isoflurane via the tail vein (Group 1) or consciously via a catheter inserted either in the jugular vein (Group 2) or the tail vein (Group 3). After about 1 h of free access to food and water the rats were anesthetized with 1.5% isoflurane and imaged in a microPET for 60 min. The rats that were injected consciously (Groups 2 and 3) were placed in a rat restrainer during [(18) F]fallypride injection. They were habituated in that restrainer for 3 days prior to the experiment day to minimize restraint-related stress. For comparison, a control group of rats was imaged for 120 min simultaneously with the administration of [(18) F]fallypride i.v. while under 1.5% isoflurane. The DVR' estimates from the 60 min acquisitions were compared with the DVR' from the last 60 min of the 120 min acquisitions (after neglecting the first 60 min). In addition, the striatal time-activity curves were fit with a 2-tissue + plasma compartment model using an arbitrary simulated plasma input function to obtain k(3) /k(4) (~ BP(ND) ) for the 60 and 120 min acquisitions. RESULTS: Isoflurane anesthesia caused a significant reduction, up to 22%, in the DVR' estimates, which were 15.7 +/- 0.3 (mean +/- SE) for the controls, 17.7 +/- 0.3 for Group 1, 19.2 +/- 0.4 for Group 2, and 18.8 +/- 0.7 for Group 3. The compartmental model fit produced similar results, ~30% reduction in k(3) /k(4) for the 120-min acquisitions compared with the 60-min acquisitions (initial conscious uptake of the radiotracer). CONCLUSION: The results of this study demonstrate that isoflurane anesthesia significantly decreases striatal [(18) F]fallypride BP(ND) in rats. Of similar importance, this work demonstrates the effectiveness of delayed scans following radiotracer injection and the implication that different types of studies can be conducted simultaneously with this method, including studies of behavioral and environmental impact on brain receptors. PMID- 21584869 TI - The evolutionary origins of glia. AB - The evolutionary origins of glia are lost in time, as soft tissues rarely leave behind fossil footprints, and any molecular footprints they might have been left we have yet to decipher. Nevertheless, because of the growing realization of the importance glia plays in the development and functioning of the nervous system, lessons we can draw about commonalities among different taxa (including vertebrates) brought about either from a common origin, or from common adaptational pressures, shed light on the roles glia play in all nervous systems. The Acoelomorpha, primitive interstitial flatworms with very simple cellular organization and currently at the base of the bilaterian phylogeny, possess glia like cells. If they indeed represent the ancestors of all other Bilateria, then it is possible that all glias derive from a common ancestor. However, basal taxa lacking convincing glia are found in most major phyletic lines: urochordates, hemichordates, bryozoans, rotifers, and basal platyhelminths. With deep phylogenies currently in flux, it is equally possible that glia in several lines had different origins. If developmental patterns are any indication, glia evolved from ectodermal cells, possibly from a mobile lineage, and even possibly independently in different regions of the body. As to what functions might have brought about the evolution of glia, by-product removal, structural support, phagocytic needs, developmental programming, and circuit modulation may be the more likely. Explaining possible cases of glial loss is more difficult, as once evolved, glia appears to keep inventing new functions, giving it continued value even after the original generative need becomes obsolete. Among all the uncertainties regarding the origin of glia, one thing is certain: that our ideas about those origins will change with every rearrangement in deep phylogeny and with continued advances in invertebrate molecular and developmental areas. PMID- 21584870 TI - Inhibitory effects of secoiridoids from the roots of Gentiana straminea on stimulus-induced superoxide generation, phosphorylation and translocation of cytosolic compounds to plasma membrane in human neutrophils. AB - Gentiana straminea Maxim. has been used widely as a traditional Chinese medicine for the treatment of rheumarthritis, icterepatitis, constipation, pain and hypertension. Five secoiridoids, gentiopicroside (GTP), 6'-O-(2-hydroxy-3-O-beta D-glucopyranosyl-benzoyl)-sweroside (HGBS), 6'-O-beta-D-glucosylgentiopicroside (GGTP), sweroside (SW) and swertiamarin (STM) were isolated from the roots of G. straminea. The effect of these secoiridoids on stimulus-induced superoxide generation in human neutrophils was assayed by measuring the reduction of ferricytochrome c. Tyrosyl or serine/threonine phosphorylation of neutrophil proteins, and translocation of the cytosolic compounds to the cell membrane were also investigated using specific monoclonal antibodies. The five secoiridoids used in the present experiment suppressed N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide generation in a concentration dependent manner. GTP and HGBS also suppressed phorbol 12-myristate 13-acetate (PMA) and arachidonic acid (AA)-induced superoxide generation. However, the other three secoiridoids showed no effect on PMA- and AA-induced superoxide generation. fMLP-, PMA- and AA induced tyrosyl or serine/threonine phosphorylation and translocation of the cytosolic proteins to the cell membrane were suppressed in parallel with the suppression of the stimulus-induced superoxide generation. PMID- 21584871 TI - Curcumin inhibits melanogenesis in human melanocytes. AB - Plant derived compounds, as potentially safe and effective skin lightening agents (SLAs), have attracted great attention from many researchers. Curcumin is a plant derived polyphenol, which has been reported to suppress melanogenesis in B16 melanoma cells. However, little is known about whether curcumin affects melanogenesis in cultured human melanocytes. In addition, the molecular mechanism for the antimelanogenic effects of curcumin remains largely unknown. The present study assessed the effects of curcumin on melanin synthesis, cellular tyrosinase activity, the expression of melanogenesis-related proteins (microphthalmia associated transcription factor (MITF), tyrosinase, tyrosinase-related protein 1 and 2 (TRP-1, TRP-2)), and activation of melanogenesis-regulating signals including phosphatidylinositol 3-kinase (PI3K)/Akt/ glycogen synthase kinase 3 (GSK 3beta), extracellular signal-regulated kinase (ERK) and p38 MAPK in human melanocytes. The results showed that the melanin content and tyrosinase activity, as well as the expression of melanogenesis-related proteins in human melanocytes, were significantly inhibited by curcumin in a dose dependent manner. In addition, PI3K/Akt/ GSK 3beta, ERK and p38 MAPK were activated by curcumin, while inhibitors of these signals attenuated the inhibitory effects of curcumin on melanogenesis. These results suggest that curcumin inhibits melanogenesis in human melanocytes through activation of Akt/GSK 3beta, ERK or p38 MAPK signaling pathways. PMID- 21584872 TI - Prevention of chemically induced diabetes mellitus in experimental animals by virgin argan oil. AB - The argan tree plays an important socioeconomic and ecologic role in South Morocco. Moreover, there is much evidence for the beneficial effects of virgin argan oil (VAO) on human health. Thus, this study investigated whether administering VAO to rats can prevent the development of diabetes. VAO extracted by a traditional method from the almonds of Argania spinosa (2 mL/kg) was administered orally (for 7 consecutive days) to rats before and during intraperitoneal alloxan administration (75 mg/kg for 5 consecutive days). An alloxan diabetic-induced untreated group and treated by table oil were used as control groups. Body mass, blood glucose and hepatic glycogen were evaluated. In the present study, subchronic treatment with VAO at a dose of 2 mL/kg, before the experimental induction of diabetes, prevented the body mass loss, induced a significant reduction of blood glucose and a significant increase of hepatic glycogen level (p < 0.001) compared with the untreated diabetic group. In conclusion, the present study shows that argan oil should be further investigated in a human study to clarify its possible role in reducing weight loss in diabetics, and even in inhibiting the development or progression of diabetes. This antidiabetic effect could be due to the richness of VAO in tocopherols, phenolic compounds and unsaturated fatty acids. PMID- 21584874 TI - New avenues for phage-display library to produce a Cryptococcus-specific anti idiotypic antibody of HM-1 killer toxin. AB - Existing antifungal drugs are notable for their inability to act rapidly, as well as their toxicity and limited spectrum. The identification of fungal-specific genes and virulence factors would provide targets for new and influential drugs. The display of repertories of antibody fragments on the surface of filamentous phage offers a new way to produce immunoreagents as defined specificities. Here we report the selection of Cryptococcus-specific targets by using phage-display panning from a cDNA library, where bactericidal antibodies have been developed against conserved surface-exposed antigens. A single-chain variable fragment (scFv) phage library was constructed from splenocyte of an immunized mouse by idiotypic vaccination with HM-1 killer toxin (HM-1) neutralizing monoclonal antibody (nmAb-KT) that was used for selection against Cryptococcus neoformans membrane fraction (CnMF). Key elements were the selection against antigen (nmAb KT and CnMF) and the release of bound phages using competitive panning elution with CnMF at neutral pH condition. Isolated scFvs react specifically with C. neoformans and some other pathogenic and non-pathogenic fungal strain's cell wall receptors by exerting strong antifungal activity in vitro. A high affinity clone, designated M1 was selected for detailed characterization and tested anti cryptococcal activity with IC(50) values at 5.33 * 10(-7) to 5.56 * 10(-7) M against C. neoformans. The method described here is a new technique for the isolation of cell membrane specific immunoreactive phages in the form of scFv using CnMF that contained cell membrane associated proteins. PMID- 21584875 TI - A new paradigm in molecular recognition? Specific antibody binding to membrane inserted HIV-1 epitopes. AB - The conserved membrane proximal external region (MPER), adjacent to the transmembrane domain (TMD) of human immunodeficiency virus type-1 (HIV-1) gp41 glycoprotein subunit, is accessible to the broadly neutralizing 4E10 and 2F5 monoclonal antibodies (mAbs) and, therefore, constitutes a potential target for vaccine design. This gp41 domain is postulated to be functional during the Env glycoprotein-mediated fusion reaction by destabilizing the highly rigid viral envelope. To perform this task, the aromatic-rich MPER is believed to insert into the interfacial region of the viral membrane external monolayer, thereby inducing the restructuring of the lipid bilayer required for fusion-pore opening. This model predicts that: (i) 2F5 and 4E10 mAbs are capable of binding epitopes inserted into the membrane interface; (ii) in-membrane binding will result in effective blocking of MPER membrane activity; and (iii) both processes, in membrane recognition and blocking of membrane activity, can be modulated by altering both the lipid composition and the MPER amino acid sequence. We review here recently reported experimental data consistent with those predictions, and further speculate on their relevance for prospective anti-HIV vaccine development. PMID- 21584876 TI - Systematic analysis of tropomodulin/tropomyosin interactions uncovers fine-tuned binding specificity of intrinsically disordered proteins. AB - An intriguing regulatory mechanism is the ability of some proteins to recognize their binding partners in an isoform-specific manner. In this study we undertook a systematic analysis of the specificity of the tropomodulin (Tmod) interaction with tropomyosin (TM) to show that affinities of different Tmod isoforms to TM are isoform-dependent. Intrinsic disorder predictions, alignment of sequences, and circular dichroism were utilized to establish a structural basis for these isoform-specific interactions. The affinity of model peptides derived from the N terminus of different TM isoforms to protein fragments that correspond to the two TM-binding sites of different Tmod isoforms were analyzed. Several residues were determined to be responsible for the isoform-dependent differences in affinity. We suggest that changing a set of residues rather than a single residue is needed to alter the binding affinity of one isoform to mimic the affinity of another isoform. The general intrinsic disorder predictor, PONDR(r) VLXT, was shown to be a useful tool for analyzing regions involved in isoform-specific binding and for predicting the residues important for isoform differences in binding. Knowing the residues responsible for isoform-specific affinity creates a tool suitable for studying the influence of Tmod/TM interactions on sarcomere assembly in muscle cells or actin dynamics in non-muscle cells. PMID- 21584877 TI - Structural, thermodynamic, and kinetic basis for the activities of some nucleic acid repair enzymes. AB - X-ray structural analysis provides no quantitative estimate of the relative contribution of specific and nonspecific or strong and weak interactions to the total affinity of enzymes for nucleic acids. We have shown that the interaction between enzymes and long nucleic acids at the molecular level can be successfully analyzed by the method of stepwise increase in ligand complexity (SILC). In the present review we summarize our studies of human uracil DNA glycosylase and apurinic/apyrimidinic endonuclease, E. coli 8-oxoguanine DNA glycosylase and RecA protein using the SILC approach. The relative contribution of structural (X-ray analysis data), thermodynamic, and catalytic factors to the discrimination of specific and nonspecific DNA by these enzymes at the stages of complex formation, the following changes in DNA and enzyme conformations and especially the catalysis of the reactions is discussed. PMID- 21584878 TI - Receptor-attached amphiphilic terpolymer for selective drug recognition in aqueous solutions. AB - In the present work, a combination of binding studies and molecular docking were employed to demonstrate drug encapsulation and host-guest chemistry in self assembled micelles consisting of amphiphilic terpolymers. The terpolymer is composed of poly(3-sulfopropyl methacrylate), as the hydrophilic component, poly(n-dodecyl acrylate), as the hydrophobic component and poly(barbiturate receptor), as the component for drug recognition. The combined approach was tested on four model compounds from the family of barbiturates, phenobarbital, mephobarbital, secobarbital, and thiopental, chosen based on their differential hydrogen bonding capabilities. Drug encapsulation and hydrogen-bonding based recognition within the micellar core of the receptor-terpolymer was demonstrated by micellar electrokinetic chromatography. The resulting trends in the binding affinity of the barbiturates to the receptor-terpolymer, were correlated to the trends obtained from computational docking simulations. This receptor-modified polymeric micelle is intended to serve as a model for the design of novel, versatile, and highly selective molecular scaffolds that will provide suitable environment for host-guest chemistry and act as simplified mimics to more complex biological systems. PMID- 21584879 TI - Identification of the epitope for anti-cystatin C antibody. AB - Human cystatin C (hCC), like many other amyloidogenic proteins, has been shown to form dimers by exchange of subdomains of the monomeric protein. Considering the model of hCC fibrillogenesis by propagated domain swapping, it seems possible that inhibition of this process should also suppress the entire process of dimerization and fibrillogenesis which leads to specific amyloidosis (hereditary cystatin C amyloid angiopathy (HCCAA)). It was reported that exogenous agents like monoclonal antibody against cystatin C are able to suppress formation of cystatin C dimers. In the effort to find a way of controlling the cystatin fibrillization process, the interactions between monoclonal antibody Cyst-13 and cystatin C were studied in detail. The present work describes the determination of the epitope of hCC to a monoclonal antibody raised against cystatin C, Cyst 13, by MALDI mass spectrometry, using proteolytic excision of the immune complex. The shortest epitope sequence was determined as hCC(107-114). Affinity studies of synthetic peptides revealed that the octapeptide with epitope sequence does not have binding ability to Cyst-13, whereas its longer counterpart, hCC(105-114), binds the studied antibody. The secondary structure of the peptides with epitope sequence was studied using circular dichroism and NMR spectroscopy. PMID- 21584880 TI - Molecularly imprinted polyaniline film for ascorbic acid detection. AB - Molecularly imprinted polyaniline (PANI) film (~ 100 nm thick) has been electrochemically fabricated onto indium-tin-oxide (ITO) coated glass plate using ascorbic acid (AA) as template molecule. Fourier transform infra-red spectroscopy, scanning electron microscopy, cyclic voltammetry and differential pulse voltammetry (DPV) studies indicate the presence of AA in PANI matrix, which also acts as a dopant for PANI. Further, the AA selective molecularly imprinted PANI electrode (AA-MI-PANI/ITO) has been developed via over-oxidation of AA doped PANI electrode which leads to the removal of AA moieties from PANI film. The response studies using DPV technique have revealed that this molecularly imprinted AA-MI-PANI/ITO electrode can detect AA in the range of 0.05-0.4 mM with detection limit of 0.018 mM and sensitivity of 1.2 * 10(-5) AmM(-1). Interestingly, this AA-MI-PANI/ITO electrode shows excellent reusability, selectivity and stability. PMID- 21584881 TI - Azurin modulates the association of Mdm2 with p53: SPR evidence from interaction of the full-length proteins. AB - The tumour suppressor p53 plays a crucial role in cell stress response and its anticancer activity is mainly down-regulated by the oncoprotein Mdm2 that, upon binding to p53, blocks its transcriptional activity and promotes its ubiquitin dependent degradation. Targeting Mdm2-p53 interaction is believed to be the most direct of all p53-activating strategies to treat tumours in which p53 has retained its wild-type function. The bacterial protein Azurin has been shown to bind p53, inhibiting cancer cell proliferation likely through a post translational increasing of the p53 level. This apparent antagonist action with respect to the Mdm2-p53 functional interaction suggests that binding of Azurin to p53 might interfere with the Mdm2-p53 association and, thus, preventing p53 from degradation. Toward this end, a detailed kinetic characterization of the binding interaction of these three proteins has been performed by surface plasmon resonance. The occurrence of specific binary interactions of both Azurin and Mdm2 with p53, as investigated more appropriately in their full-length conformation, is ascertained and the corresponding association and dissociation rate constants are measured. Interestingly enough, the three proteins are likely engaged in a ternary interaction, whose kinetics points out that binding of Azurin to p53 causes a significant decrease of the Mdm2-p53 association rate constant and binding affinity, without hindering the accessibility of Mdm2 to the binding pocket of p53. The Azurin-induced p53 conformational change, as demonstrated by circular dichroism, suggests that the protein may affect Mdm2-p53 association through an allosteric mechanism, which could give an useful insight into designing new anticancer drugs. PMID- 21584882 TI - Mechanically enforced bond dissociation reports synergistic influence of Mn2+ and Mg2+ on the interaction between integrin alpha7beta1 and invasin. AB - Integrins require the divalent ions magnesium and manganese for ligand recognition. Here we mechanically enforced bond dissociation to explore the influence of these ions on the mechanical strength of the specific bond between alpha(7) beta(1) integrin and its pathologically relevant ligand invasin. Upon addition of these cations to the measurement buffer, we observe a pronounced increase in the force necessary to separate integrin and invasin coated beads. Both ions were found to work synergistically. With free invasin in the measurement buffer we furthermore observe that competitive blocking of binding sites overrides the increase in binding strength of individual beads. We show that this is due to a very strong dependence of bond affinity on divalent ions. Our study illustrates the importance of divalent ions for the regulation of force transmission by integrin ligand bonds on the molecular level. PMID- 21584883 TI - Characterization of hyaluronic acid interaction with calcium oxalate crystals: implication of crystals faces, pH and citrate. AB - Interaction between hyaluronic acid (HA) present at the surface of tubular epithelial cells and calcium oxalate monohydrate (COM) crystals is thought to play an important role in kidney stone formation. AFM-based force spectroscopy, where HA is covalently attached to AFM-probes, was used to quantify the interaction between HA and the surfaces of COM crystals. The work of adhesion of the HA-probe as well as the rupture force of single HA molecules were quantified in order to understand the molecular regulation of HA binding to COM crystals. Our results reveal that HA adsorbs to the crystal surface in physiological conditions. We also observed increased adhesion when the pH is lowered to a value that increases the risk of kidney stone formation. HA adhesion to the COM crystal surface can be suppressed by citrate, a physiological inhibitor of stone retention currently used in the treatment and prevention of kidney stone formation. Interestingly, we also observed preferential binding of HA onto the [100] face versus the [010] face, suggesting a major contribution of the [100] faces in the crystal retention process at the surface of tubular epithelial cells and the promotion of stone formation. Our results clearly establish a direct role for the glycosaminoglycan HA present at the surface of kidney tubular epithelium in the process of COM crystal retention. PMID- 21584884 TI - Female external genitalia on fetal magnetic resonance imaging. AB - OBJECTIVES: To characterize the normal development of the female external genitalia on fetal magnetic resonance imaging (MRI). METHODS: This retrospective study included MRI examinations of 191 female fetuses (20-36 gestational weeks) with normal anatomy or minor abnormalities, following suspicion of anomalies on prenatal ultrasound examination. Using a 1.5-Tesla unit, the bilabial diameter was measured on T2-weighted sequences. Statistical description, as well as correlation and regression analyses, was used to evaluate bilabial diameter in relation to gestational age. MRI measurements were compared with published ultrasound data. The morphological appearance and signal intensities of the external genitalia were also assessed. RESULTS: Mean bilabial diameters, with 95% CIs and percentiles, were defined. The bilabial diameter as a function of gestational age was expressed by the regression equation: bilabial diameter = - 11.336 + 0.836 * (gestational age in weeks). The correlation coefficient, r = 0.782, was statistically significant (P < 0.001). Bilabial diameter on MRI was not significantly different from that on ultrasound (P < 0.001). In addition, on MRI we observed changes in morphology of the external genitalia and in signal intensities with increasing gestational age. CONCLUSIONS: We have provided a reference range of fetal bilabial diameter on MRI, which, in addition to ultrasound findings, may be helpful in the identification of genital anomalies. PMID- 21584885 TI - Cervical blood perfusion assessed using power Doppler-derived estimation of fractional moving blood volume: a reproducibility study. AB - OBJECTIVE: To evaluate the reproducibility of estimation of power Doppler-derived fractional moving blood volume (FMBV) in the uterine cervix of women with uncomplicated pregnancies. METHODS: Two experienced operators evaluated 30 uncomplicated singleton pregnancies at 20-24 weeks of gestation. The PDU box was positioned in a mid-sagittal view of the cervix, including the internal os and external os, in the same plane as that in which cervical length is measured. Two consecutive examinations were performed by each operator, in each of which the cervical length was measured and five consecutive good-quality images with PDU information were obtained. The region of interest (ROI) (cervix) was delineated offline and FMBV, which expresses the percentage of blood occupying the ROI, was calculated with purpose-designed software. Intra- and interobserver intraclass correlation coefficients (ICCs) and mean differences with 95% limits of agreement (LOA) were calculated. RESULTS: The median gestational age at examination was 22 + 0 weeks. Measurements (median +/- SD) obtained for cervical length and FMBV were as follows: Operator A: 37 +/- 7.4 mm and 8.11 +/- 2.9%; Operator B: 37.5 +/ 9.3 mm and 7.9 +/- 3.3%, respectively. The intra- and interobserver ICCs for FMBV were 0.88 (95% CI, 0.75-0.94) and 0.82 (95% CI, 0.64-0.94), respectively. There was a mean difference in FMBV measurement between operators of - 0.2 +/- 1.75% (95% LOA, - 3.7 to 3.2%). CONCLUSIONS: Reproducible assessment of cervical blood perfusion through estimation of FMBV can be achieved while cervical length is being measured. PMID- 21584886 TI - Prenasal thickness-to-nasal bone length ratio: a strong and simple second- and third-trimester marker for trisomy 21. AB - OBJECTIVES: To study the ratio of prenasal thickness (PT) to nasal bone length (NBL) in normal and trisomy-21 fetuses in the second and third trimesters of pregnancy. METHODS: The PT and NBL were measured retrospectively in 106 normal fetuses (in three-dimensional (3D) volumes) and in 30 fetuses with trisomy 21 (10 on two-dimensional (2D) images and 20 in 3D volumes). RESULTS: In normal fetuses the mean PT and NBL increased between 15 and 33 weeks' gestation from 2.3 to 6.1 mm (r = 0.85, P < 0.001) and from 3.3 to 9.6 mm (r = 0.87, P < 0.001), respectively. The PT : NBL ratio was stable throughout gestation, with a mean of 0.61 (95% CI, 0.59-0.63; r = - 0.04, P = 0.7). The 5(th) and 95(th) percentiles were 0.48 and 0.80, respectively. In trisomy-21 fetuses the mean PT and NBL increased between 14 and 34 weeks from 3.0 to 9.2 mm (r = 0.86, P < 0.001) and from 1.9 to 7.8 mm (r = 0.85, P < 0.001), respectively. The PT : NBL ratio was significantly higher than in normal fetuses (P < 0.001) but also stable throughout gestation, with a mean of 1.50 (95% CI, 1.20-1.80; r = - 0.35, P = 0.07). Twenty-three (77%) of the 30 fetuses with trisomy 21 had a PT above the 95(th) percentile and 20 (67%) had an NBL below the 5(th) percentile. All the trisomy-21 fetuses had a PT : NBL ratio above the 95(th) percentile. When the 95(th) percentile of the PT : NBL ratio was used as a cut-off value the detection and false positive rates for trisomy 21 were 100 (95% CI, 89-100)% and 5 (95% CI, 2-11)%, respectively. The positive likelihood ratio was 21.2. CONCLUSIONS: The PT : NBL ratio is stable in the second and third trimesters of pregnancy in both normal and trisomy-21 fetuses, but all trisomy-21 fetuses in this series had a PT : NBL ratio above the 95(th) percentile. The ratio is therefore a strong marker for trisomy 21. PMID- 21584887 TI - Experimental treatment of bilateral fetal chylothorax using in-utero pleurodesis. AB - OBJECTIVE: To assess the use and efficacy of in-utero pleurodesis for experimental treatment of bilateral fetal chylothorax. METHODS: This was a study of 78 fetuses with bilateral pleural effusion referred to three tertiary referral centers in Taiwan between 2005 and 2009. Fetuses were karyotyped following amniocentesis and the lymphocyte ratio in the pleural effusion was determined following thoracocentesis. Forty-nine (62.8%) fetuses had a normal karyotype and were recognized to have fetal chylothorax; of these, 45 underwent intrapleural injection of 0.1KE OK-432 per side per treatment. We evaluated clinical (hydrops vs. no hydrops) and genetic (mutations in the reported lymphedema-associated loci: VEGFR3, PTPN11, FOXC2, ITGA9) parameters, as well as treatment outcome. Long-term survival was defined as survival to 1 year of age. RESULTS: The overall long-term survival rate (LSR) was 35.6% (16/45); the LSR for non-hydropic fetuses was 66.7% (12/18) and for hydropic fetuses it was 14.8% (4/27). If we included only fetuses with onset of the condition in the second trimester, excluding those with onset in the third trimester, the LSR decreased to 29.4% (10/34). Notably, 29.6% (8/27) of hydropic fetuses had mutations in three of the four loci examined. CONCLUSIONS: OK-432 pleurodesis appeared to be an experimental alternative to the gold-standard technique of thoracoamniotic shunting in non hydropic fetal chylothorax. In hydropic fetuses, pleurodesis appeared less effective. PMID- 21584888 TI - Preoperative assessment of submucous fibroids by three-dimensional saline contrast sonohysterography. AB - OBJECTIVE: Submucous fibroids are a common cause of menstrual disturbance that can be treated by hysteroscopic resection. Preoperative patient selection is critical for the success of surgery and it is usually based on hysteroscopic assessment of fibroid protrusion into the uterine cavity. Three-dimensional saline contrast sonohysterography (3D-SCSH) provides additional information about the size and location of submucous fibroids, but it has not yet been evaluated for its usefulness in preoperative assessment. The aim of this study was to examine the potential value of various demographic and ultrasound variables for the prediction of successful submucous fibroid resection. METHODS: This was a prospective study of symptomatic women diagnosed with submucous fibroids who underwent 3D-SCSH prior to hysteroscopic resection. The women's age and parity and fibroid position, diameter, protrusion ratio, size of the intramural component and distance from the internal cervical os were all recorded. The outcome measure was success of a single hysteroscopic resection in achieving a complete excision of the fibroid. Univariate analysis and multivariate logistic regression analysis using a training set and a testing set were performed to investigate the prediction of successful fibroid resection. RESULTS: A total of 61 women with 67 fibroids were included in the study. There was a statistically significant difference between women who had complete and those who had incomplete resection in the mean protrusion ratio (67.8 (SD 14.5)% vs. 47.0 (SD 17.8)%; P = 0.001), the median maximum fibroid diameter (24.0 (interquartile range (IQR), 19.0-30.5) mm vs. 45.0 (IQR, 28.8-51.3) mm; P = 0.001) and the median size of the intramural component of the fibroid (8.0 (IQR, 4.0-11.5) mm vs. 16.5 (IQR, 12.5-29.3) mm; P = 0.001). Stepwise multivariate logistic regression analysis retained size of intramural component (odds ratio (OR) 0.511), parity (OR 0.002) and fibroid diameter (OR 0.843) as significant independent predictors of a complete fibroid resection. The model had an area under the receiver-operating characteristics curve of 0.975 (SE 0.039) for the training set (n = 39) and 0.864 (SE 0.090) for the testing set (n = 28). CONCLUSION: Submucous fibroid protrusion ratio, fibroid diameter and size of the fibroid's intramural component are significantly associated with the likelihood of successful fibroid resection. A logistic regression model can calculate individual probability of complete resection and may improve preoperative counseling of patients. PMID- 21584889 TI - Fetal optic nerve sheath measurement as a non-invasive tool for assessment of increased intracranial pressure. AB - OBJECTIVES: To describe the sonographic technique for assessment of the fetal optic nerve sheath and to report on three fetuses with intracranial lesions and enlarged optic nerve sheath diameter (ONSD) compared with normal controls matched for gestational age (GA). METHODS: In this cross-sectional study ONSD was measured sonographically in three fetuses (aged 23, 24 and 35 gestational weeks) with intracranial findings associated with increased intracranial pressure (ICP; dural thrombosis and intracranial tumors) as well as 42 healthy controls matched for GA +/- 1 week (aged 22-25 and 34-36 weeks). For fetal eye assessment, transabdominal and transvaginal routes and high-resolution transducers were used for optimal visualization depending on fetal position. Measurements were made using an axial view at the level of the orbits, with the fetal face positioned towards the transducer. The ONSD was measured 1.5 or 2 mm behind the papilla (depending on GA) in all fetuses. Mean +/- 2 SD ONSD of controls were calculated for each GA and compared with data from the three fetuses with intracranial pathology. RESULTS: In the 42 normal fetuses, ONSD increased from 1.2 mm at 23 weeks to 2.6 mm at 36 weeks. The measurements at 36 weeks correlated well with those observed in newborns. ONSD measurements of the three cases were above mean + 2 SD of values obtained from healthy controls at the same GA and also exceeded values of fetuses that were 1 week older. CONCLUSIONS: Fetal ONSD measurement is feasible using a technique similar to that used in adults and children. ONSD enlargement was observed in all three fetuses with intracranial lesions and may be an early tool with which to diagnose increased ICP. PMID- 21584890 TI - Power Doppler of the endometrium in patients with postmenopausal bleeding. PMID- 21584891 TI - Outcome of prenatally diagnosed bronchial atresia. PMID- 21584892 TI - Ultrasound in pregnancy and non-right handedness: meta-analysis of randomized trials. AB - OBJECTIVE: To study the association between exposure to ultrasound in pregnancy and non-right handedness in children with available data from randomized trials. METHODS: Follow-up data of 8865 children aged 8-14 years from three randomized trials on routine ultrasonography at 15-20 weeks' gestation were available. Handedness was assessed through questionnaires to the parents and classified according to five, 10 or 11 questions. Children not classified as right handed were regarded as non-right handed. RESULTS: There was a statistically significant increased prevalence of non-right handedness in ultrasonographically screened children compared with controls (odds ratio (OR) 1.15; 95% CI, 1.03-1.29). The results in subgroups according to gender are consistent with the overall results, with no significant differences between boys and girls. Among boys, the association became stronger when an exploratory analysis according to ultrasound exposure before 19-22 weeks' gestation was done (OR 1.30; 95% CI, 1.10-1.53). CONCLUSION: There is a statistically significant-albeit weak-association between ultrasound screening during pregnancy and being non-right handed later in life. PMID- 21584893 TI - Quality of life for patients requiring surgical resection and reconstruction for mandibular osteoradionecrosis: 10-year experience at the University of California San Francisco. AB - BACKGROUND: Mandibular osteoradionecrosis is the most devastating complication after radiation therapy for head and neck malignancies. Quality of life (QOL) after surgical treatment is unclear. METHODS: A retrospective cohort analysis (1997-2007) was conducted of all patients treated at our institution for stage II and III mandibular osteoradionecrosis. Nineteen of 35 patients responded to a modified University of Washington QOL questionnaire. Twenty had undergone reconstruction using free flaps, and the remainder with plates, plates and local flaps, or debridement alone. RESULTS: Complications included 3 infections, 5 with hardware, 5 flap-specific, and 1 nonunion. Four patients had recurrent squamous cell carcinoma (SCC). The factors of greatest concern to patients were appearance, swallowing, and chewing. Average overall QOL was good to very good, and very good compared to preoperative. CONCLUSION: Despite a 37% complication rate, a multidisciplinary team approach with adequate debridement, resection, and reconstruction can greatly improve QOL. PMID- 21584894 TI - Endonasal transpterygoid approach to the infratemporal fossa: correlation of endoscopic and multiplanar CT anatomy. AB - BACKGROUND: The infratemporal fossa anatomy, from an endoscopic standpoint, is poorly understood. Our purpose was to design an anatomic model that illustrates the anatomy of the infratemporal fossa from the endoscopic standpoint and serves as a training model for surgeons interested in pursuing this endeavor. METHODS: Red and blue silicone dyes were respectively injected into the great vessels of the neck. Digital data acquired from a high resolution CT scan was imported to a navigational system. An endoscopic endonasal dissection of the infratemporal fossa was completed under conditions that mimicked our operating suite. RESULTS: A detailed anatomic dissection of the infratemporal fossa was correlated to the image guidance (navigation) system. This provided a surgical map highlighting critical neurovascular structures and illustrating the potential surgical corridors. CONCLUSION: A thorough understanding of the anatomy of infratemporal fossa from the endoscopic perspective allows the surgeon to plan an adequate corridor. PMID- 21584895 TI - Pedicled mandible myo-osseous flaps combined with free skin flaps for reconstruction of complex lateral mandibular defects. AB - BACKGROUND: This study presents an alternative in reconstruction, using free skin flaps in combination with pedicled mandible bone flaps for complex lateral mandibular defects. METHODS: In all, 13 patients were included in this prospective study. Pedicled mandible myo-osseous flaps were used for reconstruction of bone defects of the lateral mandible in combination with free skin flaps, including radial forearm flaps (n = 3), anterolateral thigh (ALT) flaps (n = 9), and local tongue flap (n = 1). Postoperatively, a (99m)Tc-methyl diphosphonate bone scan was performed to assess bone flap viability. RESULTS: All patients had acceptably contoured mandibles. The major complications consisted of 1 failed ALT flap and 2 nonviable bone flaps. The bone scan confirmed viable bone flaps in 11 cases. Ten patients (77%) were able to resume soft to full diets. CONCLUSIONS: For complex lateral mandibular defects (<=6 cm), a combination of the pedicled mandible myo-osseous flaps and free skin flaps is an alternative in reconstruction. PMID- 21584896 TI - Modulation of the opioid growth factor ([Met(5)]-enkephalin)-opioid growth factor receptor axis: novel therapies for squamous cell carcinoma of the head and neck. AB - BACKGROUND: The opioid growth factor (OGF)-OGF receptor (OGFr) axis is a constitutively expressed biologic pathway regulating cell proliferation of squamous cell carcinoma of the head and neck (SCCHN). This study investigated modulation of the OGF-OGFr system by (1) exogenous OGF, (2) upregulation of OGFr using imiquimod, or (3) intermittent opioid receptor blockade with a low dose of naltrexone on progression of established SCCHN. METHODS: Nude mice with visible human SCCHN SCC-1 tumors received (1) OGF or low-dose naltrexone either 1, 3, or 7 times/week or (2) imiquimod 1 or 3 times/week. Tumor growth and DNA synthesis were monitored. RESULTS: OGF and low-dose naltrexone increased the latency from visible to measurable tumors up to 1.6-fold. OGF, low-dose naltrexone, and imiquimod treatment markedly reduced tumor volume and weight, and decreased DNA synthesis in tumors. CONCLUSIONS: Modulation of the native OGF-OGFr regulatory network in SCCHN represents a novel nontoxic and highly efficacious approach for treatment of SCCHN. PMID- 21584897 TI - Craniopharyngioma: a pathologic, clinical, and surgical review. AB - Craniopharyngioma is a rare and mostly benign epithelial tumor of the sellar and suprasellar region. Two principal patterns of craniopharyngioma are recognized: papillary and adamantinomatous. Papillary craniopharyngiomas are encountered in adults and may lack the cystic spaces filled with "motor oil" as well as the palisading peripheral rows of epithelial cells, keratinization, or calcification typical of pediatric adamantinomatous craniopharyngioma. Secondary to their anatomic location, craniopharyngiomas may present with endocrinologic dysfunction and visual disturbances. Differential diagnosis includes Rathke's cleft cyst, pituitary adenoma, dermoid/epidermoid cysts, and other rare sellar/suprasellar lesions as pituicytomas. Many controversies exist concerning the preferred surgical approach for these tumors. Endoscopic endonasal surgery is no longer reserved only for sellar or small cystic suprasellar lesions. Prechiasmatic/preinfundibular lesions are effectively removed using an endonasal transtuberculum/transplanum approach; subchiasmatic/transinfundibular tumors require the addition of a transellar approach with inferior pituitary transposition; and retrochiasmatic/retroinfundibular lesions are better accessed performing an endonasal superior pituitary transposition. Compared with well established trancranial approaches (pterional, subfrontal, presigmoid), endoscopic endonasal surgery combines the virtues of the caudocranial and midline approaches, allowing for appropriate infrachiasmatic exposure without the need for manipulation of surrounding neurovascular structures to access the tumor. This anatomic advantage, combined with high-definition wide-angle visualization, exquisite endonasal microsurgical techniques, and devoted instrumentation facilitates a high rate of endocrine function preservation and visual improvement, while concurrently achieving comparable resections. Endoscopic skull base reconstruction with the vascularized nasoseptal flap has dramatically reduced the incidence of cerebrospinal fluid leak, consolidating endoscopic endonasal surgery as an effective and safe alternative for the treatment of these challenging tumors. PMID- 21584898 TI - A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. AB - The classification of epithelioid vascular tumors remains challenging, as there is considerable morphological overlap between tumor subtypes, across the spectrum from benign to malignant categories. A t(1;3)(p36.3;q25) translocation was reported in two cases of epithelioid hemangioendothelioma (EHE), however, no follow-up studies have been performed to identify the gene fusion or to assess its prevalence in a larger cohort of patients. We undertook a systematic molecular analysis of 17 EHE, characterized by classic morphological and immunophenotypic features, from various anatomical locations and with different malignant potential. For comparison, we analyzed 13 epithelioid hemangiomas, five epithelioid angiosarcomas, and four epithelioid sarcoma-like EHE. A fluorescence in situ hybridization (FISH) positional cloning strategy, spanning the cytogenetically defined regions on chromosomes 1p36.3 and 3q25, confirmed rearrangements in two candidate genes from these loci in all EHE cases tested. None of the other benign or malignant epithelioid vascular tumors examined demonstrated these abnormalities. Subsequent reverse transcription-polymerase chain reaction (RT-PCR) confirmed in three EHE the WWTR1-CAMTA1 fusion product. CAMTA1 and WWTR1 have been previously shown to play important roles in oncogenesis. Our results demonstrate the presence of a WWTR1-CAMTA1 fusion in all EHE tested from bone, soft tissue, and visceral location (liver, lung) in keeping with a unique and specific pathological entity. Thus, FISH or RT-PCR analysis for the presence of WWTR1-CAMTA1 fusion may serve as a useful molecular diagnostic tool in challenging diagnoses. PMID- 21584900 TI - Relative 8q gain predicts disease-specific survival irrespective of the TMPRSS2 ERG fusion status in diagnostic biopsies of prostate cancer. AB - Screening tools have greatly improved prostate cancer (PCa) detection, but the disease course is heterogeneous, and standard clinicopathological parameters do not fully discriminate aggressive from indolent tumors. To evaluate the prognostic value of the TMPRSS2-ERG fusion gene combined with chromosome arm 8q relative gain in diagnostic biopsies of PCa, we studied a consecutive series of 200 diagnostic needle biopsies from patients with 10-year disease-specific survival data. TMPRSS2-ERG fusion gene status and relative 8q gain were assessed by fluorescent in situ hybridization in whole formalin fixed paraffin-embedded biopsies. The TMPRSS2-ERG fusion gene was detected in 43.5% of PCa and was associated with lower Gleason score (P = 0.045), whereas relative 8q gain was present in 48% of PCa and was associated in high-Gleason score (P < 0.001). ERG rearrangement alone was not associated with clinical outcome, whereas relative 8q gain predicted worse disease-specific survival in PCa patients both with and without the TMPRSS2-ERG fusion gene (P < 0.001), independently of Gleason score, clinical stage, and treatment modality. We conclude that relative 8q gain in diagnostic needle biopsies is a poor prognostic factor independent of the TMPRSS2 ERG fusion gene status and of standard clinicopathological parameters. PMID- 21584899 TI - Germline and somatic DNA methylation and epigenetic regulation of KILLIN in renal cell carcinoma. AB - We recently identified germline methylation of KILLIN, a novel p53-regulated tumor suppressor proximal to PTEN, in >1/3 Cowden or Cowden syndrome-like (CS/CSL) individuals who are PTEN mutation negative. Individuals with germline KILLIN methylation had increased risks of renal cell carcinoma (RCC) over those with PTEN mutations. Therefore, we tested the hypothesis that KILLIN may be a RCC susceptibility gene, silenced by germline methylation. We found germline hypermethylation by combined bisulfite restriction analysis in at least one of the four CpG-rich regions in 23/41 (56%) RCC patients compared to 0/50 controls (P < 0.0001). Of the 23, 11 (48%) demonstrated methylation in the -598 to -890 bp region in respect to the KILLIN transcription start site. Furthermore, 19 of 20 advanced RCC showed somatic hypermethylation upstream of KILLIN, with the majority hypermethylated at more than one CpG island (13/19 vs. 3/23 with germline methylation, P < 0.0001). qRT-PCR revealed that methylation significantly downregulates KILLIN expression (P = 0.05), and demethylation treatment by 5-aza-2'deoxycytidine significantly increased KILLIN expression in all RCC cell lines while only increasing PTEN expression in one line. Furthermore, targeted in vitro methylation revealed a significant decrease in KILLIN promoter activity only. These data reveal differential epigenetic regulation by DNA promoter methylation of this bidirectional promoter. In summary, we have identified KILLIN as a potential novel cancer predisposition gene for nonsyndromic clear-cell RCC, and the epigenetic mechanism of KILLIN inactivation in both the germline and somatic setting suggests the potential for treatment with demethylating agents. PMID- 21584901 TI - Maffucci syndrome: a genome-wide analysis using high resolution single nucleotide polymorphism and expression arrays on four cases. AB - Ollier disease and Maffucci syndrome are rare, nonhereditary skeletal disorders characterized by the presence of multiple enchondromas with (Maffucci) or without (Ollier) co-existing multiple hemangiomas of soft tissue. Enchondromas can progress toward central chondrosarcomas. PTH1R mutations are found in a small subset of Ollier patients. The genetic deficit in Maffucci syndrome is unknown. Here, we report the first genome-wide analysis using Affymetrix SNP 6.0 array on Maffucci enchondromas (n = 4) and chondrosarcomas (n = 2) from four cases. Results were compared to a previously studied cohort of Ollier patients (n = 37). We found no loss of heterozygosity (LOH) or common copy number alterations shared by all enchondromas, with the exception of some copy number variations. As expected, chondrosarcomas were found to have multiple genomic imbalances. This is similar to conventional solitary and Ollier-related enchondromas and chondrosarcomas and supports the multistep genetic progression model. Expression profiling using Illumina BeadArray-v3 chip revealed that cartilaginous tumors in Maffucci patients are more similar to such tumors in Ollier patients than to sporadic cartilage tumors. Point mutations in a single gene or other copy number neutral genomic changes might play a role in enchondromagenesis. PMID- 21584902 TI - Identification of genetic disparity between primary and metastatic melanoma in human patients. AB - It is commonly accepted that cancer cell progression is accompanied by accumulation of genetic changes. Here we searched for copy number variations in melanoma and asked whether homozygous losses always cumulate during tumor cell progression. Therefore we investigated either melanoma cell lines or tissue derived from the primary lesion and from the lymph node metastasis of the same individual patient. In vitro studies of melanoma cell lines revealed high migratory and anchorage independent growth of metastasis-derived cells. Surprisingly, whole genome DNA analysis of a primum-derived cell line revealed a total of 10 homozygous losses, whereas the matched metastasis-derived cell line only shared five of those losses. We further tested these cells in a mouse model for intradermal melanoma growth and detected fast growth of the metastasis derived cell line and no growth of primum-derived cells. Additionally, we screened matched pairs of patient-derived melanoma primum and metastasis samples and we could also identify a case with homozygous deletions exclusively present in the primary lesion. Therefore, we suggest that tumor cell progression at the metastatic niche can occur parallel and independently from the primary tumor. We propose that for mutation-targeted therapy genotyping should be performed not only from primary, but also from metastatic melanoma. PMID- 21584904 TI - The hippocampus is involved in mental navigation for a recently learned, but not a highly familiar environment: a longitudinal fMRI study. AB - Functional magnetic resonance imaging (MRI) was used to investigate the hypothesis that memory for a large-scale environment is initially dependent on the hippocampus but is later supported by extra-hippocampal structures (e.g., precuneus, posterior parahippocampal cortex, and lingual gyrus) once the environment is well-learned. Participants were scanned during mental navigation tasks initially when they were newly arrived to the city of Toronto, and later after having lived and navigated within the city for 1 yr. In the first session, activation was observed in the right hippocampus, left precuneus, and postcentral gyrus. The second session revealed activation in the caudate and lateral temporal cortex, but not in the right hippocampus; additional activation was instead observed in the posterior parahippocampal cortex, lingual gyrus, and precuneus. These findings suggest that the right hippocampus is required for the acquisition of new spatial information but is not needed to represent this information when the environment is highly familiar. PMID- 21584903 TI - Chromosomal copy number alterations are associated with tumor response to chemoradiation in locally advanced rectal cancer. AB - Rectal cancer response to chemoradiation (CRT) varies from no response to a pathologic complete response (pCR). Identifying predictive biomarkers of response would therefore be useful. We assessed whether chromosomal copy number alterations (CNAs) can assist in predicting pCR. Pretreatment tumor biopsies and paired normal surgical tissues from the proximal resection margin were collected from 95 rectal cancer patients treated with preoperative CRT and total mesorectal excision in a prospective Phase II study. Tumor and control DNA were extracted, and oligonucleotide array-based comparative genomic hybridization (aCGH) was used to identify CNAs, which were correlated with pCR. Ingenuity pathway analysis (IPA) was then used to identify functionally relevant genes in aberrant regions. Finally, a predictive model for pCR was built using support vector machine (SVM), and leave-one-out cross validation assessed the accuracy of aCGH. Chromosomal regions most commonly affected by gains were 20q11.21-q13.33, 13q11.32-23, 7p22.3 p22.2, and 8q23.3-q24.3, and losses were present at 18q11.32-q23, 17p13.3-q11.1, 10q23.1, and 4q32.1-q32.3. The 25 (26%) patients who achieved a pCR had significantly fewer high copy gains overall than non-pCR patients (P = 0.01). Loss of chromosomal region 15q11.1-q26.3 was significantly associated with non pCR (P < 0.00002; Q-bound < 0.0391), while loss of 12p13.31 was significantly associated with pCR (P < 0.0003; Q-bound < 0.097). IPA identified eight genes in the imbalanced chromosomal regions that associated with tumor response. SVM identified 58 probes that predict pCR with 76% sensitivity, 97% specificity, and positive and negative predictive values of 91% and 92%. Our data indicate that chromosomal CNAs can help identify rectal cancer patients more likely to develop a pCR to CRT. PMID- 21584905 TI - Partially redundant functions of Adamts1 and Adamts4 in the perinatal development of the renal medulla. AB - Adamts4 encodes a widely-expressed proteinase thought to be involved in processes ranging from cartilage metabolism to ovarian follicle development. To study its physiological roles, Adamts4-null mice were created by gene targeting. Unexpectedly, these were found to be phenotypically normal, suggesting that other gene(s) may compensate for its loss. Adamts4(-/-) mice were, therefore, crossed with a strain lacking Adamts1, whose pattern of expression and substrate specificity overlap that of Adamts4. Most (>95%) Adamts1(-/-) ;Adamts4(-/-) mice died within 72 hr after birth with a marked thinning of the renal medulla. The renal defect was not observed in embryonic Adamts1(-/-) ;Adamts4(-/-) kidneys, but became apparent around birth. The few (<5%) Adamts1(-/-) ;Adamts4(-/-) animals to reach adulthood had the same renal phenotype seen in newborns. This study is thus the first to report Adamts4 expression and function in the mammalian kidney, and to demonstrate that Adamts1 and Adamts4 play redundant and essential roles in perinatal kidney development. PMID- 21584906 TI - Cell adhesion molecule cadherin-6 function in zebrafish cranial and lateral line ganglia development. AB - Cadherins regulate the vertebrate nervous system development. We previously showed that cadherin-6 message (cdh6) was strongly expressed in the majority of the embryonic zebrafish cranial and lateral line ganglia during their development. Here, we present evidence that cdh6 has specific functions during cranial and lateral line ganglia and nerve development. We analyzed the consequences of cdh6 loss-of-function on cranial ganglion and nerve differentiation in zebrafish embryos. Embryos injected with zebrafish cdh6 specific antisense morpholino oligonucleotides (MOs, which suppress gene expression during development; cdh6 morphant embryos) displayed a specific phenotype, including (i) altered shape and reduced development of a subset of the cranial and lateral line ganglia (e.g., the statoacoustic ganglion and vagal ganglion) and (ii) cranial nerves were abnormally formed. These data illustrate an important role for cdh6 in the formation of cranial ganglia and their nerves. PMID- 21584907 TI - Construction and factorial validation of a short form of the Self-Compassion Scale. AB - The objective of the present study was to construct and validate a short-form version of the Self-Compassion Scale (SCS). Two Dutch samples were used to construct and cross-validate the factorial structure of a 12-item Self-Compassion Scale-Short Form (SCS-SF). The SCS-SF was then validated in a third, English sample. The SCS-SF demonstrated adequate internal consistency (Cronbach's alpha >= 0.86 in all samples) and a near-perfect correlation with the long form SCS (r >= 0.97 all samples). Confirmatory factor analysis on the SCS-SF supported the same six-factor structure as found in the long form, as well as a single higher order factor of self-compassion. The SCS-SF thus represents a reliable and valid alternative to the long-form SCS, especially when looking at overall self compassion scores. PMID- 21584908 TI - Dysfunctional beliefs in the process of change of cognitive treatment in obsessive compulsive checkers. AB - Cognitive behaviour therapy (CBT) is considered to be effective in the reduction of obsessive compulsive symptoms. However, questions remain as to how CBT works. Cognitive-behavioural models postulate that negative appraisals of intrusive thoughts and dysfunctional beliefs that give rise to them underlie the development and maintenance of obsessive-compulsive disorder (OCD). The current study aimed to study this hypothesis by investigating the processes of change over the course of cognitive treatment for OCD. Furthermore, a new theoretical approach and method for studying processes of change was presented. The participants were seven patients suffering from OCD with predominantly checking symptoms. Process variables (beliefs, anxiety and compulsions) were measured using idiosyncratic diaries and were analysed on an intra- and inter-individual level using dynamic systems methods. Results showed significant decreases in credibility of dysfunctional beliefs in six out of the seven participants, which is in line with the cognitive-behavioural model. Associations between process variables were in general medium to high. However, the actual patterns of change showed important intra- and interpersonal differences. Results indicated that different paths can lead to clinical recovery, and it was concluded that process studies that focus on individual trajectories of change can contribute to our understanding of OCD and its treatment. Furthermore, dynamic systems methods provide insight into intra-individual processes and shed a new light on variability. PMID- 21584909 TI - The capacity to see things from the child's point of view--assessing insightfulness in mothers with and without a diagnosis of depression. AB - Insightfulness is seen as the mental capacity that provides the context for a secure child-parent attachment. It involves the ability to see things from the child's perspective and is based on insight into the child's motives, a complex view of the child and openness to new information about the child. To test our hypothesis that maternal insightfulness is related to maternal depression, we utilized the Insightfulness Assessment (IA) developed by Oppenheim and Koren Karie to conduct and analyse interviews in which mothers discussed their perceptions of video segments of their interactions with their children. We compared the results of a control group of 30 mothers without a diagnosis of depression with a sample of 23 mothers diagnosed with depression (International Classification of Diseases, 10th Revision). As expected, depression was negatively related to maternal insightfulness. Oppenheim and Koren-Karie have argued that the IA might be used as a diagnostic instrument; our work suggests that the IA might show ways of aiding mothers in improving the quality of mother infant interaction while they are being treated for depression. KEY PRACTITIONER MESSAGE: Insightfulness is seen as the mental capacity that provides the context for a secure child-parent attachment. Maternal depression was negatively related to maternal insightfulness. The Insightfulness Assessment might be used as a diagnostic instrument. The Insightfulness Assessment might show ways of aiding mothers in improving the quality of mother-infant interaction while they are being treated for depression. PMID- 21584910 TI - Exercise in the eating disorders: terms and definitions. PMID- 21584911 TI - Compulsive exercise and eating disorders. AB - The aim of this review was to develop an empirically supported cognitive behavioural model of compulsive exercise within the context of the eating disorders. A systematic review of the correlates and predictors of compulsive exercise among eating disordered patients identified four key correlates. These were subsequently validated by a second review, incorporating both the clinical and non-clinical as well as the exercise science literatures. A proposed model is presented which is both evidence-based and testable. PMID- 21584912 TI - Eating disordered behaviours in Portuguese athletes: the influence of personal, sport, and psychological variables. AB - OBJECTIVE: This study describes eating disordered behaviours in a sample of Portuguese elite athletes and analyses the impact of personal and sports factors on those eating disordered behaviours. METHOD: Two hundred and ninety athletes (51.7% males) practicing collective (64.8%) and individual sports have been included. The evaluation protocol included the Eating Disorder Examination Questionnaire; the Sport Condition Questionnaire; the Sport Anxiety Scale; the Task and Ego Orientation in Sport Questionnaire; the Cognitive Evaluation of Sport-Threat Perceptions and the Self-Presentation Exercise Questionnaire. RESULTS: Females, athletes with a higher body mass index, and those with a desire to weigh less, reported more eating disordered behaviours. No relation with sports variables was found. Finally, a higher prevalence of eating disorders behaviour was predicted by lower satisfaction in terms of body shape and physical appearance, higher anxiety and impression motivation. CONCLUSION: Personal characteristics of athletes, as well as their body satisfaction, anxiety, impression motivation and threat perception and coach comments on their weight, represent dimensions that could raise the risk for eating disorders. PMID- 21584913 TI - Contextual body image and athletes' disordered eating: the contribution of athletic body image to disordered eating in high performance women athletes. AB - The present study investigated the contribution of a contextual body image perspective to understanding disordered eating in high performance women athletes. Because existing questionnaires were not suitable for measuring body image in the contexts of sport and daily life, we developed the 'Contextual Body Image Questionnaire for Athletes' (CBIQA) in which body image is divided into 'appearance', 'muscularity', 'thin-fat self-evaluations' and 'thin-fat perceived opinions of others', in both contexts. In Study 1, the internal validity and reliability of this questionnaire was established in a general, heterogeneous sample of female sport participants and exercisers. In Study 2, the external validity was determined in a sample of 52 high performance women athletes who mainly participated in aesthetic or endurance sports, 19 of which were classified with and 33 without disordered eating. The results of Study 2 showed that both 'thin-fat self' and 'thin-fat opinions of others' in sport made significant unique contributions to explaining eating disorder variance, indicating the important role of athletic body image. In conclusion, the contextual body image approach seems to be a promising framework for a better understanding of athletes' disordered eating. PMID- 21584914 TI - Eating disorders and exercise: a structural equation modelling analysis of a conceptual model. AB - OBJECTIVE: Despite the well-established health benefits of physical activity, the role of exercise for eating disorders (ED) is controversial; thus dictating a need for a better understanding of the mechanisms of exercise and ED. The purpose of our study was to examine a conceptual model that hypothesizes regular exercise without psychological compulsion might impart beneficial effects for preventing and treating ED. METHOD: University students (N = 539) completed self-report assessments of quality of life, exercise level, ED risk and exercise dependence symptoms. Structural equation modelling analysis was undertaken to examine the conceptual model's proposed relationships. RESULTS: Mediation analysis and model comparison tests showed that the partially mediated model without the physical well-being latent construct fit the data best. DISCUSSION: Our results provided initial support for the conceptual model by showing that the psychological benefits, but not the physical benefits, conveyed by exercise were associated with reduced ED risk. PMID- 21584915 TI - Beliefs about excessive exercise in eating disorders: the role of obsessions and compulsions. AB - OBJECTIVE: This study aimed to develop an understanding of excessive exercise in eating disorders by exploring the role of exercise beliefs, obsessive beliefs and obsessive-compulsive behaviours. METHOD: Sixty-four women were recruited from eating disorder services and 75 non-clinical women were recruited from a university. Exercise beliefs and behaviours, obsessive beliefs and behaviours and eating disorder psychopathology were assessed using self-report questionnaires. RESULTS: There was an association between exercise beliefs, obsessive beliefs and obsessive-compulsive behaviours in the eating-disordered group, but not in the non-eating-disordered group. In the eating-disordered group obsessive beliefs and obsessive-compulsive behaviours were associated with a significant proportion of variance in exercise beliefs after controlling for eating disorder psychopathology and BMI. In the non-eating-disordered group obsessive beliefs and behaviours were associated with beliefs about exercise as a method of affect regulation after controlling for BMI. CONCLUSION: The results are compatible with a model in which obsessive beliefs and exercise beliefs could maintain exercise in eating disorders. This has implications for the assessment and treatment of excessive exercise. Further research is necessary to determine the causality of these relationships. PMID- 21584916 TI - Excessive exercise: from quantitative categorisation to a qualitative continuum approach. AB - Researchers have yet to reach a consensus on the definition of excessive exercise, and many questions remain about the relationship between excessive exercise and eating disorders. Understanding of excessive exercise may be furthered by adoption of a broader, dimensional perspective. The current qualitative (grounded theory) study explored the continuum of women's exercise experiences, ranging from casual to more extreme regimens. Thirty-two women were interviewed, aged 16-77. Participants described stages in a continuum of exercise experiences. Overlaps were described between participant perceptions of 'normal' exercise, excessive exercise and exercise addiction. Excessive exercise and disturbed eating were described as arising from common concerns about the need to control the body, with exercise viewed as a more acceptable alternative to disturbed eating. The results provide support for a continuum approach to the understanding of excessive exercise, and highlight the utility of qualitative methods in this area. PMID- 21584917 TI - Exercise dependence score in patients with longstanding eating disorders and controls: the importance of affect regulation and physical activity intensity. AB - OBJECTIVE: To examine associations among exercise dependence score, amount of physical activity and eating disorder (ED) symptoms in patients with longstanding ED and non-clinical controls. METHODS: Adult female inpatients (n = 59) and 53 age-matched controls participated in this cross sectional study. Assessments included the eating disorders examination, eating disorders inventory, exercise dependence scale, reasons for exercise inventory, and MTI Actigraph accelerometer. RESULTS: Positive associations were found among vigorous, not moderate, physical activity, exercise dependence score and ED symptoms in patients. In the controls, ED symptoms were negatively associated with vigorous physical activity and not correlated with exercise dependence score. Exercise for negative affect regulation, not weight/appearance, and amount of vigorous physical activity were explanatory variables for exercise dependence score in both groups. CONCLUSIONS: The positive associations among exercise dependence score, vigorous physical activity and ED symptoms need proper attention in the treatment of longstanding ED. PMID- 21584918 TI - Disordered eating and exercise: development and preliminary validation of the compulsive exercise test (CET). AB - OBJECTIVE: The Compulsive Exercise Test (CET) was developed to assess the primary factors operating in the maintenance of excessive exercise. METHODS: A total of 367 young female exercisers were recruited from University campuses. Across three separate studies, the participants completed either the CET alone, or the CET and other standard self-report measures of excessive exercise and eating psychopathology. RESULTS: Factor analyses yielded five factors from which a final 24-item, five subscale measure was constructed. The CET demonstrated high internal consistency across the three samples. Supporting the concurrent and convergent validity of the scale, the CET correlated in the expected direction with existing measures of excessive exercise and eating pathology. As expected, the CET explained greater variance in eating pathology than existing measures of excessive exercise. DISCUSSION: The resulting subscales of the CET are consistent with a cognitive-behavioural maintenance model of excessive exercise and support the multidimensionality of the excessive exercise construct. Further research is required to validate the instrument within a sample of eating disordered women. PMID- 21584919 TI - Psychometric evaluation of the compulsive exercise test (CET) in an adolescent population: links with eating psychopathology. AB - OBJECTIVE: Compulsive exercise describes a rigid, driven urge to exercise that has been reported in different populations, including eating disorder patients. This compulsion can develop at an early age and yet the measurement of compulsive exercise in adolescents is limited by inappropriate assessment techniques. This study aimed to psychometrically evaluate the Compulsive Exercise Test (CET) in a sample of adolescents. METHODS: The sample consisted of 1012 adolescents aged 12 14 years old, who completed the CET, the Commitment to Exercise Scale (CES), and selected subscales from the Eating Disorder Inventory-2 (EDI-2). RESULTS: Results confirmed the original five-factor solution of the CET. The CET's concurrent validity with the CES, as well as the convergent validity with the EDI-2, was established. The CET was not strongly related to exercise frequency. CONCLUSION: The CET appears to be valid and reliable for use with adolescents. Replication with an adolescent clinical eating disorder sample is now required. PMID- 21584920 TI - Psychosocial consequences of disordered eating attitudes in elite female figure skaters. AB - The purpose of this study was to test a model of the effects of athletes' eating disorders on coach, sport friend and parent social relationships and peer social acceptance through physical self-perceptions (i.e. perceived physical appearance and perceived physical ability). The sample comprised 199 elite female figure skaters. The data were analysed using structural equation modelling. Our results showed that the effects of athletes' eating disorders on social relationships were not mediated by physical self-perceptions. Athletes' eating disorders directly negatively influenced the quality of the parent-athlete relationship, thus confirming previous findings in young adults. Contrary to the literature, eating disorders were positively related to perceived physical ability. This paradoxical finding is discussed in relation to achievement theories and the particularity of the sport context. PMID- 21584921 TI - Tracing of islet graft survival by way of in vivo fluorescence imaging. AB - BACKGROUND: To increase the success rate in xenogeneic islet transplantation, proper assessment of graft mass is required following transplantation. For this reason, we aimed to develop a suitable fluorescence imaging system to monitor islet xenograft survival in diabetic mice. METHODS: Adenovirus vector encoding enhanced green fluorescent protein-transduced rat pancreatic islets were transplanted under the renal capsule of streptozotocin-induced diabetic mice and the fluorescence signal was quantified over time using a cooled charge-coupled device. Non-fasting blood glucose levels were recorded during the same period. Insulin release from transduced and control islets was detected via enzyme-linked immunosorbent assay. RESULTS: Adenovirus vector encoding enhanced green fluorescent protein infection did not alter the function or survival of pancreatic islets post transduction. A direct correlation was found between the number of islets (250-750) transplanted under the kidney capsule and the blood glucose recovery. CONCLUSIONS: Fluorescence imaging appears to be a useful tool for quantitative assessment of islet cell viability post transplantation and could permit earlier detection of graft rejection. PMID- 21584922 TI - Benefits of a simple glycaemic protocol in an orthopaedic surgery ward: a randomized prospective study. AB - BACKGROUND: Hyperglycaemia and diabetes mellitus are common in patients hospitalized in the orthopaedic surgery ward. However, glycaemic control obtained during hospitalization is often suboptimal. No method for achieving adequate glycaemic control in this population has been validated in an in-hospital setting. INTERVENTION: An intervention including an intensive subcutaneous insulin protocol in the orthopaedic department. METHODS: All diabetic patients admitted to the Department of Orthopaedic Surgery were prospectively randomized during a 6-month period. One group (n = 30) received standard care with sliding scale insulin and the other group (n = 35) received the intervention protocol. During the intervention period, the staff was briefed on the importance of glucose monitoring and control. An intensive multiple-injection protocol consisting of four daily regular/neutral protamine hagedorn (NPH) insulin injections was initiated in diabetic patients. The programme was followed up by a consulting diabetologist. RESULTS: Mean blood glucose levels throughout the hospitalization were 161.48 +/- 3.8 mg/dL in the intervention group versus 175.29 +/- 2.3 mg/dL in the control group (p < 0.0005). Hospitalization was shorter by 2 days in the intervention group (p < 0.05). The number of severe hyperglycaemic events (blood glucose level above 400 mg%) was significantly lower (p < 0.05) in the intervention group. There was no significant difference in the number of hypoglycaemic events. CONCLUSIONS: The suggested four-step intervention regimen improved glycaemic control of hospitalized patients in the orthopaedic department and simplified the 'in-house' treatment of the diabetic patient. Hospital stays were reduced on average by two days (p < 0.05). PMID- 21584923 TI - Effect of duration of hemostatic compression on radial artery occlusion after transradial access. AB - OBJECTIVES: To evaluate the effect of duration of hemostatic compression on the incidence of radial artery occlusion (RAO) after transradial coronary intervention. BACKGROUND: RAO occurs in 2-10% of patients after transradial access. The effect of duration of hemostatic compression on occurrence of RAO is unknown. METHODS: Four hundred consecutive patients undergoing transradial coronary intervention were retrospectively analyzed. Group I (n = 200) patients received hemostatic compression for 6 hr after completion of the procedure, and group II (n = 200) patients for 2 hr after completion of the procedure. TR band was used for hemostasis. Demographic and procedural variables as well as early (24 hr) and chronic (30 days) RAO as well as bleeding events were recorded. RESULTS: Demographic as well as procedural variables were similar between group I and group II. Early radial artery occlusion (ERAO) occurred in 12% of patients in group I and 5.5% of patients in group II, the difference was statistically significant (P = 0.025). Chronic radial artery occlusion (CRAO) occurred in 8.5% of patients in group I and 3.5% of patients in group II, the difference was statistically significant (P = 0.035). Occlusive compression was the only independent predictor of radial artery occlusion [Odds ratio = 13.1, P = 0.001]. Two patients in group I and one in group II developed small hematoma (P = 0.161). CONCLUSIONS: Shorter duration of hemostatic compression is associated with a lower incidence of early and chronic RAO, without increase in bleeding complications, although maintaining radial patency during hemostatic compression, eliminates the adverse effect of duration of compression. PMID- 21584924 TI - Highlighted article: "C. elegans meg-1 and meg-2 differentially interact with nanos family members to either promote or inhibit germ cell proliferation and survival" by W.S. Kapelle and V. Reinke. PMID- 21584925 TI - Synphilin suppresses alpha-synuclein neurotoxicity in a Parkinson's disease Drosophila model. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder in humans. It affects 1% of the population over 65-years old. Its causes are environmental and genetic. As the world population ages, there is an urgent need for better and more detailed animal models for this kind of disease. In this work we show that the use of transgenic Drosophila is comparable to more complicated and costly animal models such as mice. The Drosophila model behaves very similar to the equivalent transgenic mice model. We show that both Synphilin-1 and alpha synuclein are toxic by themselves, but when co-expressed, they suppress their toxicity reciprocally. Importantly, the symptoms induced in the fly can be treated and partially reverted using standard PD pharmacological treatments. This work showcases Drosophila as a detailed and multifaceted model for Parkinson's disease, providing a convenient platform in which to study and find new genetic modifiers of PD. genesis 49:392-402, 2011. PMID- 21584926 TI - Tools for monitoring patients with hepatocellular carcinoma on the waiting list and after liver transplantation. PMID- 21584927 TI - Does a patient qualify for liver transplantation after the down-staging of hepatocellular carcinoma? PMID- 21584928 TI - Which matters most: number of tumors, size of the largest tumor, or total tumor volume? PMID- 21584929 TI - Use of an upper midline incision for living donor partial hepatectomy: a series of 143 consecutive cases. AB - Over a period of 2 years, we used an upper midline incision (UMI) without laparoscopic assistance in 143 consecutive living donor partial hepatectomy (LDPH) procedures, regardless of the graft type or the donor age, sex, body mass index, or body shape. Here we report surgical recommendations based on our experience with the use of UMIs in this context. The celiac axis (CA) depth ratio (the depth-to-width ratio for the trunk at the CA) was measured to define the shape of the abdominal cavity. A questionnaire was used to assess satisfaction and cosmetic outcomes in this population of donors. One hundred forty-one of the grafts (98.6%) were right grafts or extended right grafts; there were no donor deaths. The mean time of the operation up to graft retrieval in 141 right side grafts was 3 hours 1 minute. All donors recovered fully and returned to their previous activities. Major complications occurred in 9 patients (6.4%) and included reoperation due to bleeding (4), the insertion of a percutaneous drain (4), and rhabdomyolysis (1). Male sex, a large graft (>900 kg), a fatty liver (large fatty changes >= 10%), and a deep truncal cavity (a CA depth ratio > 0.35) were significant risk factors for a long graft retrieval time. The use of a wound protector significantly reduced wound complications. The cosmetic outcomes were more satisfactory when a UMI preceded partial hepatectomy instead of a conventional J-shaped incision (P = 0.01). In conclusion, a UMI without laparoscopic assistance can be safely used for LDPH, regardless of the graft type or the donor characteristics. However, the procedure after a UMI is more difficult in male donors with large fatty livers and deep truncal cavities. Accordingly, these features can be used as exclusion criteria for surgeons not accustomed to this modified procedure. PMID- 21584930 TI - Non-palpable splenic enlargement as the etiology of abdominal pain in an adolescent with hemoglobin SC disease. PMID- 21584931 TI - Sustained response to intrathecal rituximab in EBV associated Post-transplant lymphoproliferative disease confined to the central nervous system following haematopoietic stem cell transplant. AB - Post-transplant lymphoproliferative disorder (PTLD) in the central nervous system (CNS) is a very rare complication of haematopoietic stem cell transplant (HSCT) and has a dismal prognosis. We report the successful treatment of this disorder with intrathecal rituximab therapy in two children who developed isolated CNS PTLD after HSCT. These children had failed to respond to standard chemotherapy, intravenous rituximab and EBV specific cellular therapy. PMID- 21584932 TI - Sustained remission of Chronic Immune Thrombocytopenic Purpura with low dose hydroxyurea. PMID- 21584933 TI - Reporting health-related quality of life scores to physicians during routine follow-up visits of pediatric oncology patients: is it effective? AB - BACKGROUND: The aim of the current study is to investigate the effectiveness of an intervention that provides health-related quality of life (HRQOL) scores of the patient (the QLIC-ON PROfile) to the pediatric oncologist. PROCEDURE: Children with cancer participated in a sequential cohort intervention study: intervention N = 94, control N = 99. Primary outcomes of effectiveness were communication about HRQOL domains (t-test, Mann-Whitney U-test) and identification of HRQOL problems (chi-squared test). Secondary outcomes were satisfaction (multilevel analysis), referrals (chi-squared test), and HRQOL (multilevel analysis). RESULTS: The QLIC-ON PROfile increased discussion of emotional functioning (control M = 32.9 vs. intervention M = 47.4, P < 0.05) and psychosocial functioning (M = 56.9 vs. M = 63.8, P < 0.05). Additionally more emotional problems remained unidentified in the control compared to the intervention group, for example, anger (control 26% vs. intervention 3%, P < 0.01), fear (14% vs. 0%, P < 0.01), and sadness (26% vs. 0%, P < 0.001). The intervention had no effect on satisfaction and referrals, but did improve HRQOL of patients 5-7 years of age with respect to self-esteem (P < 0.05), family activities (P < 0.05), and psychosocial functioning (P < 0.01). CONCLUSIONS: We conclude that a PRO is a helpful tool for systematic monitoring HRQOL of children with cancer, without lengthening the duration of the consultation. It is recommended to be implemented in clinical practice. PMID- 21584934 TI - Autologous purified peripheral blood stem cell transplantation compare to chemotherapy in childhood acute lymphoblastic leukemia after low-risk relapse. AB - BACKGROUND: The treatment of childhood B-cell precursor acute lymphoblastic leukemia (ALL) after isolated extramedullary or late relapse is mostly based on chemotherapy or allogeneic transplantation. The aim of this study is to provocatively assess the role of purified autologous transplantation compared with best chemotherapy results in the same setting. PROCEDURE: We reported a series of 30 pediatric patients who underwent purified peripheral blood autologous transplantation for ALL in CR2, after isolated extramedullary (7), or late medullary (23) relapse from January 1997 and March 2004. Among 246 patients treated with chemotherapy within Berlin-Frankfurt-Munster relapse protocols during the same period, we found 103 controls who matched our 30 cases, according to site of relapse, CR1 duration, time elapsed in CR2, and period of relapse. RESULTS: Event-free survival and survival at 5 years after relapse were 73.3% (SE 8.1) and 86.5% (SE 8.2) for auto-transplanted cases and 40.0% (SE 9.7) and 62.5%(SE 9.6) for chemotherapy-treated controls (P-values: 0.012 and 0.025, respectively). The risk of relapse after auto-transplantation at 1 and 4 years was approximately half and one-fifth, respectively, of the same risk obtained with chemotherapy. CONCLUSIONS: This matched analysis showed an advantage of purified autologous transplantation compared with chemotherapy in low-risk relapsed ALL, possibly explained by the single-center effect, the myeloablation of total body irradiation, the documented low tumor burden at mobilization and the stem cell isolation procedure. PMID- 21584935 TI - Comparison of propofol versus propofol-ketamine combination in pediatric oncologic procedures performed by non-anesthesiologists. AB - BACKGROUND: Limited data are available on the best option (short acting sedatives, opioids, or ketamine) in oncologic procedural sedation performed by non-anesthesiologists. The aim of the present prospective study is to compare the safety and efficacy of propofol-ketamine versus propofol alone, managed by trained pediatricians, in children with cancer undergoing painful procedures. PROCEDURES: Data on 121 children with acute lymphatic leukemia (ALL) undergoing procedural sedations (lumbar punctures and bone marrow aspirations) were prospectively collected and included drug doses, side effects, pain assessment, and sedation degree. Children were randomly assigned to one of the two groups: P (n = 62) receiving propofol alone and K (n = 59) in whom a ketamine-propofol combination was used. RESULTS: In group K, the total dose of propofol required was significantly lower than in group P (3.9 +/- 3.6 mg/kg vs. 5.1 +/- 3.6 mg/kg; P < 0.001). The incidence of hypotension was also significantly lower (11% vs. 39%; P < 0.001). Major O(2) desaturations (defined as SatO(2) < 88%) occurred principally in group P (7 vs. 1; P = 0.05). Both best analgesia and shorter recovery time were obtained with the propofol-ketamine association. No differences were observed in the degree of sedation and in the awakening quality score between the two groups. CONCLUSIONS: The combination of propofol and ketamine produced statistically significant clinical advantages combined with a higher profile of safety in children with cancer undergoing painful procedures. PMID- 21584936 TI - Increased prevalence of false positive hemoglobinopathy newborn screening in premature infants. AB - BACKGROUND: The objective was to investigate the specificity of the hemoglobinopathy newborn screening in premature neonates as compared to term neonates. PROCEDURE: The screening results from infants suspected to have hemoglobinopathy disease identified by the Florida Newborn Screening Program for years 2002-2007 were compared to the corresponding confirmatory testing. The risks for false positives for preterm and full term newborns were calculated by Chi-square or the Cochran-Armitage test for trend. Isoelectric focusing and HPLC were the methods of hemoglobin screening. RESULTS: Over 2,300 neonates (1/576 neonates born in Florida) were suspected to have hemoglobinopathy. The most common abnormal pattern in term and preterm infants (gestational age 22-36 weeks) suggesting disease at screening was FS. Overall, 93% of the children who screened positive for FCA and 64% of infants identified with FSA were later confirmed with trait. FSC was confirmed in 96% of the cases in both preterm and term infants. Compared to term newborns, preterm newborns were more likely to have a false positive result for FS or FC at screening. Twenty-three percent of preterms with FS and 59% of preterms with FC were diagnosed as traits by confirmatory testing, compared to only 2% and 6% for term infants (P < 0.001). CONCLUSIONS: As compared to term newborns, more preterm newborns with trait were misidentified as having sickle cell anemia or hemoglobin C at screening. We speculate that abnormal hemoglobins may precede the development of hemoglobin A during fetal life. PMID- 21584938 TI - High resource hospitalizations among children with vaso-occlusive crises in sickle cell disease. AB - BACKGROUND: Vaso-occlusive crises (VOCs) contribute to frequent hospitalizations among children with sickle cell disease (SCD). The objective of this study was to identify factors associated with high resource utilization during hospitalizations for VOC. PROCEDURE: We analyzed pediatric discharges 0-18 years of age with a primary diagnosis of SCD with crisis from the 2006 Kids' Inpatient Database, a nationally representative sample of pediatric hospital discharges. High resource hospitalizations were defined as those in the highest decile for total charges. We conducted sample-weighted regression analyses to determine associations between independent variables (patient demographics, hospital characteristics, illness severity) and high resource use. RESULTS: There were 9,893 (0.371%) discharges for children with VOCs. Median total hospitalization charges were $10,691. In multivariate analysis, children 15-18 years of age (odds ratio [OR] 3.39, 95% confidence interval [CI] 2.54-4.53), 10-14 years of age (OR 2.72, 95% CI 2.07-3.59), and 5-9 years of age (OR 1.74, 95% CI 1.30-2.34) had higher odds of high resource hospitalizations compared to children 0-4 years of age. Care in a children's hospital had three times the odds of high resource use compared to care in a general hospital. Discharges with secondary diagnoses including pneumonia (OR 2.46, 95% CI 1.96-3.09) and constipation (OR 1.78, 95% CI 1.31-2.40) were also associated with high resource use. CONCLUSIONS: Older age and secondary diagnoses were associated with high resource use during VOC hospitalizations. These findings suggest the need to improve adherence to comprehensive care among older children to prevent VOCs and standardize protocols to manage VOC complications. PMID- 21584939 TI - A longitudinal study of pulmonary function after stem cell transplantation, from childhood to young adulthood. AB - BACKGROUND: Impairment of pulmonary function after stem cell transplantation (SCT) in childhood has been reported before. However, long-term longitudinal studies are scarce. PROCEDURE: We measured lung volumes and performed dynamic spirometry serially in 18 patients after SCT. At the last investigation, a median of 18.2 years after SCT, the patients were compared with 18 matched controls. The diffusing capacity (DLCO) was only compared cross-sectionally. RESULTS: There was a significant increase in the prevalence of restrictive lung disease (RLD, total lung capacity <80% of that predicted) from 7% (1/14) before SCT to 28% (5/18) 5 years after SCT, and 61% (11/18) a median of 18.2 years after SCT (P = 0.002). In comparison, none of the controls had RLD (61% vs. 0%, P = 0.001). Before SCT, no patient had obstructive lung disease (OLD, forced expiratory volume in 1 sec/vital capacity <70). OLD was found in one of 18 patients (6%) 5 years after SCT but in none of the patients a median of 18.2 years after SCT. Three of the controls had OLD (P = 0.25). Eleven patients had diffusion impairment (DLCO <80% of that predicted), as opposed to none of the controls (P = 0.001). The DLCO corrected for alveolar volume was decreased in only two patients. CONCLUSION: We documented an increase in the prevalence of RLD, but not of OLD, after SCT. At the last investigation, only two patients had diffusion impairment after correction for alveolar volume. PMID- 21584937 TI - Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program. AB - BACKGROUND: The centromere kinesin motor protein CENP-E plays a crucial role in mitosis, and is an appealing molecular target in cancer. GSK923295A is an allosteric inhibitor of CENP-E that is undergoing clinical evaluation. PROCEDURES: GSK923295A was evaluated against the 23 cell lines in the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hr exposures to concentrations ranging from 1.0 nM to 10.0 uM. GSK923295A was also tested in vivo against the PPTP acute lymphoblastic leukemia (ALL) and solid tumor xenograft panels using a days 1-3 and 8-10 schedule that was repeated at day 21. The agent was administered via the intraperitoneal (i.p.) route at a daily dose of 125 mg/kg. RESULTS: The median IC(50) for all PPTP cell lines was 27 nM, with the median IC(50) for the ALL panel being the lowest (18 nM) and for the neuroblastoma panel the highest (39 nM). Excessive toxicity was observed for each of the 8 xenografts of the ALL panel in NOD/SCID mice. Thirty-five solid tumor xenograft models were considered evaluable. GSK923295A induced significant differences in event-free survival distribution compared to controls in 32 of 35 evaluable solid tumor xenografts tested. Objective responses were noted in 13 of 35 solid tumor xenografts, including 9 with maintained complete responses, and 3 with complete response (CR). CONCLUSIONS: GSK923295A demonstrated significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts. These results suggest that CENP-E may be a valuable therapeutic target in pediatric cancer. PMID- 21584940 TI - Proteomic analysis of the coagulation reaction in plasma and whole blood using PROTOMAP. AB - Proteases are critical in many physiological processes and the human genome encodes for 566 predicted proteolytic enzymes. Therefore, there is great interest in identifying and characterizing physiologic protease-substrate relationships. The coagulation cascade is a well-described network of serine proteases. However, new interactions of the coagulation cascade with other biological pathways have been discovered only recently. Therefore, we hypothesized that a non-biased protease degradomics analysis of the physiologic coagulation reaction would identify new interactions between the coagulation cascade and other pathways. We used the recently described PROTOMAP technique to profile the complete coagulation degradome. This analysis detected virtually all of the proteins of the coagulation cascade and identified a majority of the expected proteolytic events, suggesting significant coverage of the coagulation degradome. Multiple potential new proteolytic cleavages were detected, including two of transmembrane proteins that may be shed from the surface of blood cells. In addition, this analysis was able to identify several new potentially secreted proteins. A significant majority of the newly identified events were of proteins involved in innate immunity (complement and inflammation). This highlights potential new areas of crosstalk between these linked systems. Future studies will elucidate the details and functional consequences of these proteolytic events during coagulation. PMID- 21584941 TI - Citrulline-modified phage display: a novel high-throughput discovery approach for the identification of citrulline-containing ligands. AB - Phage display is a high-throughput technology used to identify ligands for a given target. A drawback of the approach is the absence of PTMs in phage displayed peptides. The applicability of phage display could be broadened considerably by the implementation of PTMs in this system. The aim of this study was to investigate the possible application of citrullination, a PTM of an arginine into a citrulline amino acid, in filamentous (M13) and lytic (T7) phage display. After in vitro citrullination of T7 and M13 phages, citrullination was confirmed and the infectivity of both citrullinated and non-citrullinated phage was compared by titer determination. We demonstrated the successful in vitro citrullination of T7 and M13 phage-displayed peptides. This in vitro modification did not affect the viability or infectivity of the T7 virions, a necessary prerequisite for the implementation of this approach in T7 phage display. For M13 phage, however, the infecting phage titer decreased five-fold upon citrullination, limiting the use of this modification in M13 phage display. In conclusion, in vitro citrullination can be applied in T7 phage display giving rise to a high-throughput and sensitive approach to identify citrulline containing ligands by the use of the strengths of phage display technology. PMID- 21584942 TI - Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. AB - OBJECTIVE: To compare the efficacy, safety, and tolerability of 4 doses of oral tofacitinib (CP-690,550) with placebo in Japanese patients with active rheumatoid arthritis (RA) receiving stable background methotrexate (MTX) who had an inadequate response to MTX alone. METHODS: A total of 140 patients were randomized to receive tofacitinib 1, 3, 5, and 10 mg twice a day or placebo in this 12-week, phase II, double-blind study. All patients remained on background MTX. Efficacy and safety were assessed at weeks 1, 2, 4, 8, and 12. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS: ACR20 response rates at week 12 were significant (P < 0.0001) for all tofacitinib treatment groups: 1 mg twice a day, 64.3%; 3 mg twice a day, 77.8%; 5 mg twice a day, 96.3%; and 10 mg twice a day, 80.8% versus placebo, 14.3%. A significant dose-response relationship for the ACR20 was observed (P < 0.0001). Low disease activity was achieved by 72.7% of patients with high baseline disease activity for tofacitinib 10 mg twice a day at week 12 (P < 0.0001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, and Disease Activity Score 28-3 (C reactive protein) were also reported. The most commonly reported adverse events (AEs) were nasopharyngitis (n = 13) and increased alanine aminotransferase (n = 12) and aspartate aminotransferase (n = 9) levels. These AEs were mild or moderate in severity. Serious AEs were reported by 5 patients. No deaths occurred. CONCLUSION: In Japanese patients with active RA with an inadequate response to MTX, tofacitinib in combination with MTX over 12 weeks was efficacious and had a manageable safety profile. PMID- 21584943 TI - Experience of intravenous immunoglobulin therapy in neuropathy associated with primary Sjogren's syndrome: a national multicentric retrospective study. AB - OBJECTIVE: Sjogren's syndrome (SS)-related peripheral neuropathy is responsible for disability, but no treatment has been shown to improve its outcome. In some cases, intravenous immunoglobulin (IVIG) therapy has been associated with some benefit. In this study, we investigated the effectiveness of IVIG in SS-related peripheral neuropathy. METHODS: We assessed the efficacy and tolerance of IVIG in 19 patients with primary SS-related neuropathy without any necrotizing vasculitis in a retrospective national multicentric study. The evaluation of the response was assessed using the disability Modified Rankin Scale (MRS) and a global evaluation by the practitioner. RESULTS: Eight patients (42%) exhibited a decrease of the MRS score corresponding to a clinical improvement, 10 patients (52%) exhibited a stable MRS score, and 1 patient (6%) showed an increase of MRS score. According to the global evaluation by the practitioner, 9 (47%) of the 19 patients were improved, 6 patients (31%) were stable, and 4 patients (21%) worsened. All the patients with sensorimotor (n = 5) or nonataxic sensory neuropathy (n = 4) were improved or stabilized. However, among the patients with ataxic neuropathy (n = 9), only 2 improved and 4 worsened. Ten of the 13 patients treated with corticosteroids could have had the prednisone dosage decreased from 15 mg/day (range 7.5-60) to 10 mg/day (range 5-20) with IVIG. Only 1 patient stopped the treatment after 1 dose because of a minor side effect and lack of initial efficacy. CONCLUSION: IVIG may be useful in the treatment of SS associated sensorimotor neuropathies or nonataxic sensory neuropathy without any necrotizing vasculitis. The benefit of such therapy in the SS-related ataxic neuropathy seems less clear. PMID- 21584944 TI - Characteristics of the arthropathy described in hereditary hemochromatosis. PMID- 21584945 TI - A structured literature review of the direct costs of adult systemic lupus erythematosus in the US. AB - OBJECTIVE: A structured review of the literature was undertaken to examine the direct costs of adult systemic lupus erythematosus (SLE) in a US population. METHODS: English-language studies published from January 2000 to April 2010 were systematically reviewed from both Medline's PubMed and the Cochrane databases. Studies were included if they reported direct medical costs of SLE among adults in the US. RESULTS: Seven studies published since January 2000 that reported direct medical costs associated with SLE in the US were identified. Studies examined main cost categories of inpatient, outpatient, and pharmacy services; each contributed substantially to total costs. Wide SDs were reported, consistent with variability in disease manifestation. Mean annual direct costs of SLE patients ranged from $13,735-$20,926; the costs of those with and without nephritis ranged from $29,034-$62,651 and $12,273-$16,575, respectively. Across studies of a general SLE population, pharmaceutical costs composed 19-30% of total expenditures, with inpatient costs accounting for 16-50% and outpatient costs accounting for 24-56% of overall costs. Methodologies varied across studies, with patient self-reported resource utilization generating the lowest estimates versus claims-based analyses; Medicaid claims analyses generated lower incremental cost estimates for SLE patients versus control patients compared to estimates based on commercial claims analysis. CONCLUSION: SLE is associated with substantial annual direct cost burden in the US; however, little research has been done examining costs associated with specific treatments or cost variation by disease severity and disease manifestations. Future research elucidating the causes in variation of costs will help in the appraisal of emerging therapies and in developing clinical management strategies. PMID- 21584947 TI - Systemic and immune manifestations in myelodysplasia: a multicenter retrospective study. AB - OBJECTIVE: The presence of systemic and/or immune manifestations in myelodysplasia has been currently reported. The influence of these manifestations on the natural outcome of myelodysplastic syndrome has to be considered. We present a multicenter retrospective study (2002-2009) of patients with myelodysplastic syndrome disclosing systemic and/or immune manifestations. METHODS: Forty-six patients with myelodysplasia presenting with systemic and/or immune manifestations were compared in terms of survival with 189 patients with myelodysplasia lacking these features. RESULTS: The clinical picture in these cases consisted of fever (13%), arthralgia or arthritis (13%), and cutaneous manifestations (67%). Four cases of systemic vasculitis have been reported in our series, and they have a worse prognosis. Immune anomalies were recorded in 29% of the cases, and the presence of cryoglobulins was also associated with a worse prognosis. CONCLUSION: A difference in survival between patients with myelodysplastic syndrome with systemic manifestations and patients lacking these manifestations has been observed in the presence of systemic vasculitis and/or cryoglobulins. PMID- 21584948 TI - A cumulative dose, safety and tolerability study of arformoterol in pediatric subjects with stable asthma. AB - PURPOSE: Short-acting beta(2) -agonists (SABAs) are recommended for treating acute pediatric asthma. The long-acting beta(2) -agonist (LABA) arformoterol is approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Arformoterol acts rapidly, is delivered via nebulization, and, as such, raises concerns from the FDA over possible off-label use in acute asthma in children. As a step to investigate this issue, this study evaluated the safety and tolerability of three consecutive doses of arformoterol administered over 1 hr in children with stable asthma. METHODS: This study consisted of a double blind, crossover period in which subjects (ages 2-11 years) with stable asthma were randomized to three consecutive nebulized doses of arformoterol (7.5 ug/dose) or levalbuterol (0.63 mg/dose) administered over 1-hr (0, 30, and 60 min) followed by an open-label period with three consecutive doses of arformoterol (15 ug/dose) administered over 1 hr. Endpoints were change in heart rate, blood pressure, and serum potassium and glucose levels. Other endpoints included adverse events and pulmonary function. RESULTS: There were no clinically important mean changes from pre-dose in heart rate, blood pressure, or serum glucose levels, across treatment groups. Substantial declines in serum potassium levels were observed both 2 and 6 hr post-dosing. Two subjects had declines to 2.8 mEq/L and 2.9 mEq/L 2-hr post-dosing. Adverse events were infrequent and differences in forced expiratory volume in 1 sec and peak expiratory flow across treatment groups were not clinically meaningful. CONCLUSION: In this study, in children with stable asthma, three consecutive doses of arformoterol (7.5 and 15 ug) and levalbuterol were overall well tolerated. Nonetheless, serum potassium levels demonstrated substantial mean declines after dosing. These findings do not address or support the safety and tolerability of arformoterol use in acute exacerbations of asthma in children. PMID- 21584946 TI - Brief index of lupus damage: a patient-reported measure of damage in systemic lupus erythematosus. AB - OBJECTIVE: To develop and test the Brief Index of Lupus Damage (BILD), an interviewer-administered measure of damage in systemic lupus erythematosus (SLE), for use in epidemiologic studies in which administration of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) by trained physicians is not possible or feasible. In addition, we compared the BILD to another recently developed patient-reported measure, the Lupus Damage Index Questionnaire (LDIQ), which was designed as a written survey. METHODS: A sample of 81 patients from 2 university-affiliated SLE clinics was used to test the criterion validity of the BILD and the LDIQ. A second sample, the Lupus Outcomes Study (n = 728), was used to ascertain the construct validity of the BILD. RESULTS: We found good agreement between most BILD items and corresponding SDI items, and moderately high overall Spearman's rank correlations for SDI with BILD (0.64) and with LDIQ (0.54). BILD scores were higher among older individuals, those with longer disease duration, and those with higher mean disease activity in the preceding 4 years. In addition, higher BILD scores were associated with poorer self-rated health and functional status, greater unemployment and work disability, and increased health care utilization. CONCLUSION: We developed and performed a preliminary validation study demonstrating content, criterion, and construct validity of a new practical patient-reported instrument of SLE disease damage. Although further studies are needed to examine reliability and to document psychometric properties in other populations, the BILD appears to represent a promising tool for studies of SLE outside the clinical setting. PMID- 21584949 TI - Polymer-based microparticles in tissue engineering and regenerative medicine. AB - Different types of biomaterials, processed into different shapes, have been proposed as temporary support for cells in tissue engineering (TE) strategies. The manufacturing methods used in the production of particles in drug delivery strategies have been adapted for the development of microparticles in the fields of TE and regenerative medicine (RM). Microparticles have been applied as building blocks and matrices for the delivery of soluble factors, aiming for the construction of TE scaffolds, either by fusion giving rise to porous scaffolds or as injectable systems for in situ scaffold formation, avoiding complicated surgery procedures. More recently, organ printing strategies have been developed by the fusion of hydrogel particles with encapsulated cells, aiming the production of organs in in vitro conditions. Mesoscale self-assembly of hydrogel microblocks and the use of leachable particles in three-dimensional (3D) layer-by layer (LbL) techniques have been suggested as well in recent works. Along with innovative applications, new perspectives are open for the use of these versatile structures, and different directions can still be followed to use all the potential that such systems can bring. This review focuses on polymeric microparticle processing techniques and overviews several examples and general concepts related to the use of these systems in TE and RE applications. The use of materials in the development of microparticles from research to clinical applications is also discussed. PMID- 21584950 TI - Synthesis, biophysical properties, and oxygenation potential of variable molecular weight glutaraldehyde-polymerized bovine hemoglobins with low and high oxygen affinity. AB - In a recent study, ultrahigh molecular weight (Mw ) glutaraldehyde-polymerized bovine hemoglobins (PolybHbs) were synthesized with low O2 affinity and exhibited no vasoactivity and a slight degree of hypertension in a 10% top-load model.(1) In this work, we systematically investigated the effect of varying the glutaraldehyde to hemoglobin (G:Hb) molar ratio on the biophysical properties of PolybHb polymerized in either the low or high O2 affinity state. Our results showed that the Mw of the resulting PolybHbs increased with increasing G:Hb molar ratio. For low O2 affinity PolybHbs, increasing the G:Hb molar ratio reduced the O2 affinity and CO association rate constants in comparison to bovine hemoglobin (bHb). In contrast for high O2 affinity PolybHbs, increasing the G:Hb molar ratio led to increased O2 affinity and significantly increased the CO association rate constants compared to unmodified bHb and low O2 affinity PolybHbs. The methemoglobin level and NO dioxygenation rate constants were insensitive to the G:Hb molar ratio. However, all PolybHbs displayed higher viscosities compared to unmodified bHb and whole blood, which also increased with increasing G:Hb molar ratio. In contrast, the colloid osmotic pressure of PolybHbs decreased with increasing G:Hb molar ratio. To preliminarily evaluate the ability of low and high O2 affinity PolybHbs to potentially oxygenate tissues in vivo, an O2 transport model was used to simulate O2 transport in a hepatic hollow fiber (HF) bioreactor. It was observed that low O2 affinity PolybHbs oxygenated the bioreactor better than high O2 affinity PolybHbs. This result points to the suitability of low O2 affinity PolybHbs for use in tissue engineering and transfusion medicine. Taken together, our results show the quantitative effect of varying the oxygen saturation of bHb and G:Hb molar ratio on the biophysical properties of PolybHbs and their ability to oxygenate a hepatic HF bioreactor. We suggest that the information gained from this study can be used to guide the design of the next generation of hemoglobin-based oxygen carriers (HBOCs) for use in tissue engineering and transfusion medicine applications. PMID- 21584951 TI - Visualization of human immunodeficiency virus protease inhibition using a novel Forster resonance energy transfer molecular probe. AB - The in vivo high-throughput screening (HTS) of human immunodeficiency virus (HIV) protease inhibitors is a significant challenge because of the lack of reliable assays that allow the visualization of HIV targets within living cells. In this study, we developed a new molecular probe that utilizes the principles of Forster resonance energy transfer (FRET) to visualize HIV-1 protease inhibition within living cells. The probe is constructed by linking two fluorescent proteins: AcGFP1 (a mutant green fluorescent protein) and mCherry (a red fluorescent protein) with an HIV-1 protease cleavable p2/p7 peptide. The cleavage of the linker peptide by HIV-1 protease leads to separation of AcGFP1 from mCherry, quenching FRET between AcGFP1 and mCherry. Conversely, the addition of a protease inhibitor prevents the cleavage of the linker peptide by the protease, allowing FRET from AcGFP1 to mCherry. Thus, HIV-1 protease inhibition can be determined by measuring the FRET signal's change generated from the probe. Both in vitro and in vivo studies demonstrated the feasibility of applying the probe for quantitative analyses of HIV-1 protease inhibition. By cotransfecting HIV-1 protease and the probe expression plasmids into 293T cells, we showed that the inhibition of HIV-1 protease by inhibitors can be visualized or quantitatively determined within living cells through ratiometric FRET microscopy imaging measurement. It is expected that this new probe will allow high-content screening (HCS) of new anti HIV drugs. PMID- 21584952 TI - [The influence of radon baths on the lipid profile of patients with cardiovascular diseases and dyslipidemia]. AB - The present study included 82 patients at the age from 28 to 60 years (46 women and 36 men). Radiotherapy was given to 44 patients of whom 27 presented with cardiovascular diseases (CVD) and 17 with diseases of the locomotor apparatus (LA) and concomitant dislipoproteinemia (DLP). The control group was comprised of 38 subjects (27 with CVD and 11 with LA disease + DLP). The patients received radiotherapy every other day as a series of 8-9 radon baths (water temperature 36 37 degrees C) for 10-15 min each at a radon concentration of 20-40 nCi/l (total dose 1.2 mSv). The treatment caused a significant increase of serum cholesterol (CL) and high-density lipoproteide (HDLP) levels with simultaneous reduction of the atherogenicity index and a tendency towards a decrease in the levels of total cholesterol, cholesterol of low density lipoproteides (LDLP), and triglicerides. Clinically, the desired level of arterial pressure was reached in 77.2% of the patients. PMID- 21584953 TI - [Application of physical factors for the hospital-based rehabilitation of patients with combined cardiovascular and bronchopulmonary diseases]. AB - The hospital-based rehabilitative treatment was given to 36 patients presenting with combined cardiopulmonary pathology. It included electrophoresis of the the salt sediment from Amurskaya-2 mineral water and the assessment of its efficacy in clinical, functional, and laboratory studies. It was shown that this therapeutic modality had positive influence on lipid metabolism and improved the functional state of myocardium. Overall, the rehabilitative potential of the treatment increased. PMID- 21584954 TI - [Certain changes in mineral metabolism of patients with osteoarthrosis and osteoporosis under the influence of combined treatment]. AB - Disturbances of calcium and phosphorus metabolism in patients with articular disorders are gender-dependent and related to the presence of osteoporosis. Concomitant abnormalities in collagen synthesis are more pronounced in women than in men and especially in patients with osteoporosis, in agreement with their altered hormonal status. Combined balneo-physiotherapeutic treatment including mid-wavelength ultraviolet irradiation partially normalizes calcium and phosphorus metabolism but fails to significantly decrease the enhanced activity of alkaline phospatase and elevated blood oxyproline level that collectively account for the low regenerative potential of osteoblasts. PMID- 21584955 TI - [Dynamics of tumour necrosis factor-alpha and clinical signs of osteoarthrosis during the treatment with alflutop in combination with peloid applications under conditions of health resort]. AB - The objective of the present work was to develop indications for the combined treatment of patients presenting with osteoarthrosis including the use of peloid applications and intramuscular injections of alflutop. The study was based at Yakty-Kul' health resort and included 94 patients at the age from 40 to 59 years. The proposed method was shown to have beneficial effect on the patients' clinical conditions. In addition, the treatment caused a decrease in the level of tumour necrosis factor-alpha (TNF-alpha) that turned out to be related to the articular index. PMID- 21584956 TI - [Combined physiotherapy of patients with dorsopathies and concomitant osteoarthrosis]. AB - The combined treatment of patients presenting with dorsopathies and concomitant osteoarthrosis using magnetic stimulation, ultrasonic and peloidotherapy was shown to promote the recovery of the locomotor function of the vertebral column and the affected limb joints, alleviate pain sensation, and exert anti inflammatory effect. Moreover, it contributed to the improvement of the overall orthopedic situation in the region. The inclusion of vibrotraction in the combined treatment of patients presenting with dorsopathies and concomitant osteoarthrosis resulted in a marked decrease of the severity of static and dynamic disturbances of the spine, increase in the activity of spinal muscles, extension of the range of locomotor movements, and improvement of working ability of the patients. PMID- 21584957 TI - [The influence of hirudotherapy on the biochemical status of patients with gonarthrosis]. AB - The results of conservative treatment with the use of hirudotherapy of patients presenting with bilateral gonarthrosis were evaluated by biochemical analysis of their serum and urine samples. The study revealed changes of mineral, carbohydrate, and lipid metabolism suggestive of the positive homeostatic effect of hirudotherapy at the local and systemic levels. This finding gives reason to recommend hirudotherapy for the treatment and prevention of osteoarthrosis. PMID- 21584958 TI - [Thalassotherapy: long-term developments]. AB - The currently available medical technologies for the rehabilitative and balneological treatment of osteoarthrosis enable specialists to significantly suppress the activity of inflammatory and destructive process, reduce severity of pain syndrome, improve functional abilities of the patients, prevent the further development of the disease, and increase the overall efficiency of health resort based therapy by 18-20%. PMID- 21584960 TI - [Let's apply the Leonetti's law at every care setting]. PMID- 21584959 TI - [Silicon-carbonate baths in the rehabilitation and secondary prophylaxis of the associated cardiological diseases. Medical technology]. PMID- 21584961 TI - [Management of handicapped patients, towards more suitable medical training]. PMID- 21584962 TI - [2011, the year of patients and their rights is launched]. PMID- 21584963 TI - [Difficult to understand the fear of freedom of choice in health care]. PMID- 21584964 TI - [Prevention of atherosclerosis. The positional specificity of blood triglycerides and lipases, the particular milk lipids, and the modification of the fatty acids of vegetable oils and animal fats]. AB - Milk is a biological medium that bears no resemblance to any of the biological fluids and tissues in primates and mammals in the positional composition of fatty acids (FA) in triglycerides. This is determined by the fact that at the very early phylogenesis of mammals, milk is to ensure a high postnatal bioavailability (absorption) of saturated palmitic FA, a substrate for neonatal energy supply despite all obstacles that are formed in the baby's intestine in vivo. Milk is destined for infant nutrition in the biology-destined period (not more than a year); assimilation of triglycerides that are so structurally unusual requires a) high isomerization activity in the enterocytes and b) the ability of blood lipases to hydrolyze palmitate-oleate-palmitate triglycerides as a component of oleic very-low-density lipoproteins. After the period permitted by nature, there is virtually no possibility to physiologically consume milk that contains structurally unusual triglycerides. The use of whole milk and its products by adults impairs the active, receptor cell absorption of FAs as ligand lipoproteins via apoE/B-100-endocytosis and enhances the generation of small, dense low density lipoproteins as biological debris. The impaired biological function of endoecology and the debris accumulation of the intercellular medium lead to the activation of atheromatosis, atherothrombosis, and coronary sclerosis. Nature has given no sanction for turning the mammals that are not on milk to those on milk for whole life. Up to one year of age, the baby has in vivo conditions for the absorption and hydrolysis of triglycerides with palmitic FA at the sn-2 position. After one year of age, the expression of these lipases and coenzymes is over; re expression occurs only with the activation of the biological function of locomotion - long-term strenuous physical activity. High physical activity expresses other genes, enzymes, coenzymes, and carrier proteins, which activate the hydrolysis of triglycerides high in palmitic FA. These mechanisms are similar to those activated in vivo during the early postnatal period. PMID- 21584965 TI - [Serum lactoferrin levels in children with viral hepatitis A]. AB - Serum lactoferrin levels were studied in 79 healthy children and 80 children with viral hepatitis A in the Republic of Tyva. No statistically significant age- and gender-related differences were found in the healthy children. In viral hepatitis A, the level of the protein was shown to decrease with disease severity and to return to the normal values after 6 months. PMID- 21584966 TI - [Current methods for preparing samples on working with hematology analyzers]. AB - The paper raises a problem of preparing samples in hematology. It considers whether the preanalytical stage is of importance in hematological studies. The use of disposal vacuum blood collection systems is shown to solve the problem in the standardization of a blood sampling procedure. The benefits of the use of close tube hematology analyzers are also considered. PMID- 21584967 TI - [Effect of fibrin monomer on spontaneous platelet aggregation]. AB - Fibrin monomer (FM) was shown to cause a considerable increase in artificial shear-induced platelet aggregation. The aggregatory effect of FM was found to be tangibly higher than that in fibrinogen. The mechanism of action of FM on platelet aggregation is hypothesized. PMID- 21584968 TI - [Use of the granulocytic myeloperoxidase release reaction to diagnose food additive allergies]. AB - Adverse reactions to food additives are difficult to diagnose due to the diversity of mechanisms involved in their realization and to the absence of reasonably reliable methods for their determination. Eighty-three patients with allergic diseases were examined using the granulocytic myeloperoxidase release reaction (MRR) to diagnose intolerance reactions to food additives (E102, E122, E124, E132, E110, E2111). MRR revealed leukocyte hypersensitivity to tartrazine in 10.8%, sunset yellow in 4.8%, ponceau in 13.2%, indigo carmine in 8.4%, carmoisine and benzoate in 9.6%. The findings were correlated with history data and the levels of IgE antibodies to these dyes. The practical use of the proposed MRR method makes it possible to enhance the accuracy of diagnosis of allergy to food additives. PMID- 21584969 TI - [The development and testing of a molecular biological test system for DNA detection of anthrax pathogen by real-time polymerase chain reaction assay]. AB - The paper presents the results of the development and testing of a molecular biological test system for DNA detection of anthrax pathogen (Bacillus anthracis) by real-time polymerase chain reaction assay. The test system has shown high sensitivity, specificity, and reproducibility of results of analysis, as exemplified by aqueous suspensions of daily agar cultures of Bacillus anthracis strains, related and heterologous species of microorganisms, and clinical materials of experimental animals. There is evidence for the persistence of the basic characteristics of the test system when stored at 22 +/- 2 degrees C for 12 months. PMID- 21584970 TI - [An experimental comparative study of the efficiency of three methods for measurement of the resolution of digital radiographic systems]. PMID- 21584971 TI - [A device for metrological support of medical techniques for diagnostic contact thermography]. PMID- 21584973 TI - 'Smart' biomaterials and osteoinductivity. PMID- 21584974 TI - Infectious diseases burden in South Sudan. PMID- 21584975 TI - Road use pattern and risk factors for non-fatal road traffic injuries among children in urban India. AB - OBJECTIVE: We assessed the road use pattern and incidence and risk factors of non fatal road traffic injuries (RTI) among children aged 5-14 years in Hyderabad, India. METHODS: In a cross-sectional population-based survey, data were collected on 2809 participants aged 5-14 years (98.4% participation) selected using multi stage cluster sampling. Participants recalled non-fatal RTI during the previous 3 and 12 months. RTI was defined as an injury resulting from a road traffic crash irrespective of severity and outcome. RESULTS: Boys (11.5) had a higher mean number of road trips per day than girls (9.6), and the latter were more likely to walk and less likely to use a cycle (p < 0.001). With increasing household income quartile,the proportion of trips using cycles or motorised two-wheeled vehicles increased while trips as pedestrians decreased (p < 0.001). Based on the 3-month recall period, the age-sex-adjusted annual rate of RTI requiring recovery period of >7 days was 5.8% (95% CI 4.9-6.6). Boys and girls had similar RTI rates as pedestrians but boys had a three times higher rate as cyclists. Considering the most recent RTI in the last 12 months, children of the highest household income quartile were significantly less likely to sustain pedestrian RTI (0.26, 95% CI 0.08-0.86). The odds of overall RTI were significantly higher for those who rode a cycle (2.45, 95% CI 1.75-3.42) and who currently drove a motorised two-wheeled vehicle (2.83,95% CI 1.60-5.00). CONCLUSION: These findings can assist in planning appropriate road safety initiatives to reduce cycle and pedestrian RTI among children to reduce RTI burden in India. PMID- 21584977 TI - Expert Commentary on New Daily Persistent Headache. PMID- 21584976 TI - Crashes involving motorised rickshaws in urban India: characteristics and injury patterns. AB - INTRODUCTION: Motorised three-wheeled vehicles (motorised rickshaw) are popular in Asian countries including India. This study aims to describe the crash characteristics and injury patterns for motorised rickshaw occupants and the road users hit-by-motorised rickshaw in urban India. METHODS: Consecutive cases of road traffic crashes involving motorised rickshaw, irrespective of injury severity, whether alive or dead, presenting to the emergency departments of two large government hospitals and three branches of a private hospital in Hyderabad city were recruited. Crash characteristics,details of injuries, injury severity parameters and outcome were documented in detailed interviews. RESULTS: A total of 139 (18%) of the 781 participants recruited were injured as a motorised rickshaw occupant (11%) or were hit by a motorised rickshaw (7%) in 114 crashes involving motorised rickshaw. Amongst motorised rickshaw occupants, single vehicle collisions (54%) were more frequent than multivehicle collisions (46%), with overturning of motorised rickshaw in 73% of the single-vehicle collisions.Mortality (12%), the mean Injury Severity Score (5.8) and rate of multiple injured (60%) indicated a substantial trauma load. No significant differences in injury pattern were found between motorised rickshaw occupants and hit-by-motorised rickshaw subjects, with the pattern being similar to that of the pedestrians and two-wheeled vehicle users. With bivariate analysis for motorised rickshaw occupants,the risk of fatal outcome (odds ratio (OR) 2.60, 95% confidence interval (CI): 0.64-10.54), upper limb injury (OR 2.25, 95% CI: 0.94 5.37) and multiple injuries (OR 2.03, 95% CI 0.85-4.83) was high, although not statistically significant in multi-motorised-vehicle collisions as compared with the single-vehicle collisions or overturning. The risk of having multiple injuries (OR 4.55, 95% CI: 1.15-17.95) was significantly higher in motorised rickshaw occupants involved in front collisions. Being a front-seat motorised rickshaw passenger in a vehicle collision increased the risk of having a fatal outcome (OR 7.37,95% CI: 0.83-65.66) and a Glasgow coma score 12 (OR 2.21, 95% CI: 0.49-9.89), although not significantly when compared to the back-seat passengers. CONCLUSION: These findings can assist with planning to deal with the consequences and prevention of road traffic injuries due to crashes involving motorised rickshaw, given the high use of these and substantial morbidity of related injuries in India. The need for improved understanding of the risk characteristics of motorised rickshaw is highlighted. PMID- 21584978 TI - A cytosolic protein-tyrosine phosphatase PTP1B specifically dephosphorylates and deactivates prolactin-activated STAT5a and STAT5b. PMID- 21584979 TI - J. Craig Venter--The Human Genome Project. PMID- 21584980 TI - Stromules: bona fide chloroplast structures. PMID- 21584981 TI - The temporary permanence of Dominican bodegueros in Philadelphia: neighbourhood development in an era of transnational mobility. AB - The relationship between "neighbourhood" and "community" is contentious: while neighbourhoods are spatially based, communities are more amorphous institutions that are connected to local places through far-flung transnational networks. Dominican corner-store owners (bodegueros) in Philadelphia, USA, understand their role in their local neighbourhood community as a form of "temporary permanence" because their economic development model involves building networks between the US and the Dominican Republic. The mobility practices of grocers and interviews with community leaders in Philadelphia are used to make two propositions about constructions of place-based "neighbourhood communities" in the US: the mobility of the grocers highlights the spatial entrapment experienced by other urban residents and thus their embrace of place-based communities; and, in the mobility of the grocers and conversations with some neighbourhood leaders, we see actualised a more fluid and expansive understanding of the concept of a "neighbourhood community" which is embedded in transnational networks. PMID- 21584982 TI - Residential outcomes of forced relocation: lifting a corner of the veil on neighbourhood selection. AB - Fear of the detrimental effects of ethnic segregation has pervaded the debate on the population composition of cities and neighbourhoods. However, little is known about mechanisms underlying the spatial sorting of ethnic minorities. Hence, policies aimed at desegregation may result in exactly the opposite - that is, new ethnic concentrations and segregation. This paper studies the residential outcomes of 658 forced movers from urban restructuring areas in The Hague. Compared with "native" Dutch (those with both parents born in the Netherlands), ethnic minorities report neighbourhood improvement less often and are more likely to stay within or move into other ethnically concentrated neighbourhoods. These differences are not fully explained by differences in individual characteristics, resources, institutional factors, pre-relocation preferences or other relocation outcomes. Ethnic specificities in neighbourhood choices thus remain a pressing issue for further research. PMID- 21584984 TI - Optimisation of city size. AB - Club theoretical analysis of migration between asymmetrical cities shows that centralised policy intervention is necessary to ensure the efficient allocation of people between cities. Administrative and economic measures are compared as policy instruments of central government. These instruments are found to differ in their effects on residential allocation and welfare. In particular, a lump-sum tax-transfer programme pools the welfare-creating potentials of cities, thus affecting the efficiency condition. Therefore, lump-sum tax-transfers are superior to both quantity rationing and Pigouvian taxes, and they also activate, rather than stabilise, migration. PMID- 21584983 TI - The politicisation of suburbanisation in Belgium: towards an urban-suburban divide. AB - The electoral and political consequences of suburbanisation recently regained interest in the Anglo-Saxon literature, pointing to a growing polarisation between city and suburban fringe. This paper analyses these processes in the Antwerp urban region and shows the development of a similar electoral divide that is supported by the political parties involved. These observations add to the existing evidence that city-suburban polarisation in Belgium cannot be simply equated with the Anglo-Saxon experience, where a complete suburban fencing off from the city is observable. Rather, because of the comparatively limited development of functions in the Belgian suburbs, a suburban discourse emerges that focuses on safe and accessible cities for the suburban user, yet without much reference to its present inhabitants. PMID- 21584985 TI - Searching for economic rationale behind gated communities: a public choice approach. AB - As millions of people world-wide now live in residential areas with restricted access to the public, the ascent of gated communities can no longer be attributed to incidental or deviant development. Hence this paper makes an attempt to discover the economic rationale behind the gated community phenomenon; it discusses the mainstream theses and outlines 10 theorems for an alternative proposition based on theories of public choice and fiscal federalism. The core theorem asserts that a centrally featured system of government diminishes the ability of local municipalities properly to reflect citizens' demands for local public goods and services, and that this constitutes a strong incentive for people to move into gated communities. In particular, gated and guarded residential developments represent an exit option when local municipalities fail to deploy vital governmental rules and instruments, such as fiscal equivalence and benefit taxation. PMID- 21584986 TI - From convicts to colonists: the health of prisoners and the voyage to Australia, 1823-53. AB - From 1815, naval surgeons accompanied all convict voyages from Britain and Ireland to the Australian colonies. As their authority grew, naval surgeons on convict ships increasingly used their medical observations about the health of convicts to make pointed and sustained criticisms of British penal reforms. Beyond their authority at sea, surgeons' journals and correspondence brought debates about penal reform in Britain into direct conversation with debates about colonial transportation. In the 1830s, naval surgeons' claims brought them into conflict with their medical colleagues on land, as well as with the colonial governor, George Arthur. As the surgeons continued their attempts to combat scurvy, their rhetoric changed. By the late 1840s, as convicts' bodies betrayed the disturbing effects of separate confinement as they boarded the convict ships, surgeons could argue convincingly that the voyage itself was a space that could medically, physically and spiritually reform convicts. By the mid-1840s, surgeons took the role of key arbiters of convicts' potential contribution to the Australian colonies. PMID- 21584987 TI - Bad blood: poverty, psychopathy and the politics of transgression in Kenya Colony, 1939-59. AB - This article examines the inter-relationship between psychiatry and sex, both fertile fields within the recent historiography of colonialism and empire. Using a series of case files pertaining to European patients admitted to the Mathari Mental Hospital in Nairobi during the 1940s and 1950s, this article shows how sexual transgression among colonial Europeans precipitated, and was combined with, mental distress. Considering psychiatric treatment as a form of social control, the article investigates a number of cases in which a European patient had been perceived to have transgressed the normative sexual behaviour codes of settler society in Kenya. What these files suggest is that transgressive sexuality in Kenya was itself framed by indices, as insistent as they were uncertain, of gender, race and class. While psychiatry as social control has some degree of purchase here, more valuable is an attempt to discern the particular ways in which certain forms of sexual behaviour were understood in diagnostic terms. Men who had sex with Africans, we see, tended to be diagnosed as 'depressed' on arrival at the hospital but were judged to be mentally normal consequently. Women, by contrast, were liable to be diagnosed as psychopathic, a diagnosis, I argue, that helped to explain the uniquely transgressive status of impoverished European women living alone in the margins of white society. Unlike white men, moreover, women did not have to have sex with non-Europeans to transgress sexual codes: this is because female poverty was a sexual problem in a way that male poverty decidedly was not. Poor white women were marked by uncertainty over their sexual behaviour-and dubious racial identity in its turn and the problem of social contamination was described by reference both to the polluted racial ancestry of an individual and to the prospective contamination of healthy racial stocks. This article aims to address current historical debates around sex and empire, 'white subalternity' and the social history of psychiatry and mental health. All names have been changed to protect patient anonymity. PMID- 21584988 TI - Millennium Development Goal 1: poverty, hunger and decent work in Southeast Asia. AB - This article considers three questions: 1) what progress has been made in achieving MDG1 targets?; 2) what challenges remain?; and 3) what more could and should be done? To examine these questions, the article assesses the progress of Southeast Asia in seeking to achieve MDG1. It argues that the region is 'on track' to achieve MDG 1 targets, although significant challenges such as inequality remain. Economic growth, significant structural change and incorporation into global value chains have contributed to MDG progress. However, this is a double-edged sword as exposure to global economic turbulence can increase. The longer-term reduction of poverty, inequality and social exclusion is a question of empowerment of local producers within value chains-a shift in economic power and control through pro-poor strategies strong enough to effect substantive structural change. The article outlines key concepts; identifies the main characteristics of Southeast Asian poverty; outlines what more needs to be done; and concludes by reprising the article's findings and weighing the prospects for 2010-15 and beyond. PMID- 21584989 TI - Military morality transformed: weapons and soldiers on the nineteenth-century battlefield. AB - The increased lethality of nineteenth-century "arms of precision" caused military formations to disperse in combat, transforming the ordinary soldier from a near automaton, drilled to deliver random fire under close supervision, into a moral agent who exercised a degree of choice about where, when, and how to fire his weapon. The emerging autonomy of the soldier became a central theme in contemporary tactical debates, which struggled to reconcile the desire for discipline with the individual initiative necessary on the battlefield. This tactical conundrum offers revealing insights about human aggression and mass violence. Its dark legacy was the propagation of military values into civilian society, thus paving the way for the political soldiers of the twentieth century. PMID- 21584990 TI - [Working despite having diseases: Endocrine system diseases and metabolic diseases]. PMID- 21584991 TI - [Working despite having diseases: Nervous system diseases]. PMID- 21584992 TI - [Working despite having diseases: Hemic and lymphatic diseases]. PMID- 21584993 TI - [Working despite having diseases: Autoimmune diseases]. PMID- 21584994 TI - [Working despite having diseases: Infectious diseases]. PMID- 21584995 TI - [Working despite having diseases: Skin diseases]. PMID- 21584996 TI - [Working despite having diseases: Wounds and injuries]. PMID- 21584997 TI - [Working despite having diseases: Pregnancy and female urogenital diseases]. PMID- 21584998 TI - [Working despite having diseases: Eye diseases]. PMID- 21584999 TI - [Working despite having diseases: Ear diseases and nose diseases]. PMID- 21585000 TI - Research. Survey shows decline in HIV/AIDS knowledge in U.K. adults. PMID- 21585001 TI - Vaginal care may affect likelihood of HIV transmission. PMID- 21585003 TI - Testing. Claims by man who falsely thought he had HIV may proceed. PMID- 21585002 TI - SSI. Man's records do not support finding of disability. PMID- 21585004 TI - [Genital chlamydia infections--recommended management]. PMID- 21585005 TI - [Integrative pediatrics and personalized at the National Institute of Pediatrics]. PMID- 21585006 TI - [Prognostic factors in renal-cell carcinoma treated surgically: analysis of a cohort of 345 cases]. AB - OBJECTIVE: To assess the prognostic role of clinical and pathological variables in patients with renal-cell carcinoma (RCC) treated surgically. MATERIAL AND METHODS: We retrospectively analyzed our database of 394 consecutive patients with renal tumors. We excluded those with hereditary conditions, benign tumors or histological diagnosis other than RCC. The variables evaluated were weight loss, performance status, thrombocytosis, tumor diameter, nuclear grade, lymph node invasion and metastases. The main endpoint was cancer-specific survival (CSS). We performed univariate and multivariate analysis to determine prognostic factors. RESULTS: We identified 345 patients with RCC treated surgically between 1980 and 2009. After a median follow-up of 32 months, 23% died from cancer; they had larger tumors (p<0.0001), higher nuclear grade (p<0.0001) and lymphovascular invasion (p<0.0001). The 5- and 10-year CSS was 97.6 and 97.6% for stage I, 75.3 and 63.8% for stage II; 62.3 and 55.5% for stage III; 16.5 and 11.0% for stage IV (p<0.0001). All variables were associated with CSS on univariate analysis. On multivariate analysis tumor size, thrombocytosis, nuclear grade, lymph node invasion and metastases were independently associated with cancer-related mortality. CONCLUSION: Our findings confirm the potential role of tumor size, nuclear grade, lymph node invasion and metastases. Thrombocytosis also has a prognostic role in patients with renal-cell carcinoma. PMID- 21585007 TI - [Diagnostic validity of coronary angiotomography]. AB - BACKGROUND: Coronary arterial disease is the main cause of morbidity in western countries and coronary angiography is the most important diagnosis test. Lately, coronary angiotomography has been introduced for studying coronary arteries in a non-invasive way. Our goal was to assess the diagnostic accuracy of coronary angiotomography in the diagnosis of coronary arterial disease. MATERIAL AND METHODS: Cross-sectional study for assessing diagnostic test comparing coronary angiotomography to invasive angiography in patients without previous coronary disease. All the patients underwent both tests consecutively in a blind way. Coronary arteries were studied according to the modified reference model of coronary segmentary analysis of the American Heart Association. Tomography validity indexes (sensitivity, specificity, positive--PPV--and negative--NPV- predictive values and global value) by patient, artery, and segment were calculated. RESULTS: We studied 121 patients (47 females--38.8%--and 74 males- 61.2%-). Prevalence of coronary arterial disease was 38%. The most frequent risk factor detected was hypertension. We obtained a 100% sensitivity and NPV studying patients as a whole by patient, a specificity of 92% (95% CI: 86.0-99.0) and a global value of 94% (95% CI: 89.0-99.0). The higher validity by artery was for anterior descending artery with a specificity of 98% (CI95%: 90.0-96.0) and NPV of 97% (IC95%: 96.0-100). The segment with higher validity was distal right coronary artery with 100% specificity and PPV. CONCLUSION: A high diagnostic validity of coronary angiotomography was obtained and it could be considered as another diagnostic test for studying coronary arterial disease. PMID- 21585008 TI - [Prevalence, risk factors and consecuences of late nephrology referral]. AB - BACKGROUND: Late referral of patients with chronic kidney disease (CKD) to specialized care by the nephrologist is associated with worse patient outcomes while on dialysis. OBJECTIVES: To determine the prevalence, risk factors, and consequences of late nephrology referral at a Mexican tertiary care hospital. MATERIAL AND METHODS: Retrospective chart review of all adult patients who began chronic hemodialysis between 2002 and 2006 at the National Institute of Cardiology "Ignacio Chavez" (NICICh), Mexico City. Timing of referral to Nephrology Department was classified as early, late or very late if the time elapsed between referral and initiation of dialysis was < 1 month, between 1-6 months or > or = 6 months, respectively. Socio-demographic, clinical, laboratory and echocardiographic characteristics were compared according to timing of referral. RESULTS: Eighty four out of 150 patients were included in the analysis. Of these, 56% were referred < 1 month, and an additional 15% between 1-6 months prior to the initiation of chronic hemodialysis. In univariate analysis, being referred by a relative or friend was associated with a higher risk (p = 0.04), and being employed with a lower risk of late referral (p = 0.05). Late referred patients were more likely to require emergency dialysis and hospitalization, and of not having a permanent vascular access for their first dialysis. They also had a higher prevalence of severe anemia (hematocrit < 28%) and of residual kidney function (estimated glomerular filtration rate < 5 mL/min/1.73 m2), as well as increased left ventricular mass. CONCLUSIONS: Late nephrology referral is highly prevalent in our population and is associated with markers of suboptimal predialysis care at the onset of chronic dialysis. PMID- 21585009 TI - [A case-control study of the impact of tuberculosis on the quality of life of patients]. AB - A prospective study was conducted on 72 patients of pulmonary tuberculosis (TB) and 201 healthy controls in a third level hospital. The HRQoL questionnaire (12 Item Short Form Health Survey, SF-12) was used to assess the QoL at the onset of treatment DOTS. Patients with TB had significantly lower mean scores than controls for overall QoL (51.1 +/- SD 22.6) versus 75.9 (+/- SD 17.6), p < 0.0001. The most affected domains were physical and psychological. Active TB patients shown difficulties in activities of daily living and alterations of the psychological state. PMID- 21585010 TI - [Laser ablation of the placental vascular anastomoses for the treatment of twin to-twin transfusion syndrome]. AB - AIM: To report the experience of the intrauterine treatment of monochorionic biamnotic (MC/BA) twin pregnancies complicated with twin-to-twin transfusion syndrome (TTTS) applying laser ablation of the placental vascular anastomoses (LAPVA). MATERIAL AND METHODS: During 18 months period 35 MC/BA twin pregnancies were treated. TTTS was diagnosed based on the discrepancies in amniotic fluid and bladder size between both twins. Severity of TTTS was classified according to the hemodynamic changes in both twins. LAPVA was performed between 16-26 weeks of gestation using a rigid straight fetoscope and a YAG (neodymium: yttrium aluminium garnet) laser equipment. Survival was considered when the neonate was home discharged. RESULTS: Overall survival was 62.8% (44/70 fetuses). In 77% of pregnancies (27/35) at least one twin survived, and in 48.5% (17/35) of cases both twins survived. Bleed was the most frequent complication (12/35; 34%). In 5 cases there was severe bleeding leading to late premature rupture of membranes and death of both twins. Median time stay in the neonatal intensive care unit was 20 days (range, 7-120). There were no signs of brain damage at the time of discharge. CONCLUSION: These results are similar to those already published. Bleeding was the most frequent complication, however as the experience improved it was less frequent. Overall success is highly associated with a good neonatal care support. PMID- 21585011 TI - [Acute coronary syndrome. Physiopathology and genetics]. AB - The acute coronary syndrome (ACS) is characterized by a spectrum of arterial diseases that include unstable angina and myocardial infarction. In the last 10 years, ACS has become the cause of up to 29% of deaths in the industrialized countries, becoming the main cause of death, and it will most probably stay that way for the year 2020. The physiopathogenesis of ACS include oxidative, inflammatory, and thrombotic processes. Diverse molecules participate in the processes, increasing of decreasing the damage. The genes that encode these molecules have been associated with the disease. However, in some cases inconsistent results in different populations have been reported. In this review the physiopathogenesis and the role of several candidate genes involved in the pathogenesis of ACS are discussed. PMID- 21585012 TI - [Deficiency of adenosine desaminase (ADA): clinical, biochemical, molecular and treatment aspects]. AB - Adenosine Desaminase (ADA) deficiency, is a purine metabolic disorder that cause severe combined immunodeficiency (SCID) due to the accumulation of toxic metabolites that primarily affects development, differentiation and function of T and B lymphocytes. In addition, some patients show neurological, renal and liver abnormalities, delayed in development, deafness and seizures. If the immune response is not restored, children with this disorder rarely survive; therefore, ADA deficiency must be suspected when difficulty gaining weight, recurrent infections and skeletal abnormalities are present. The ADA deficiency has clinical and immunological characteristics not seen in other immunodeficiencies, data that helps to guide the diagnosis and therapy. This review summarizes clinical, pathological, molecular and treatment findings described in this disease. PMID- 21585013 TI - [On the vaccination before and after Jenner]. AB - The expression "inoculation" of smallpox was first employed by doctor Emanuel Timone, native of the Greek island of Chios and graduated from the Universities of Padua and Oxford. This method was largely employed in the XVIII century. Nevertheless, in 1798, the English physician Edward Jenner published the results of his observartions and his own experience with "vaccination", i. e. the inoculation of cowpox. These were exposed in his book "Inquiry into the causes and effects of the variolae vaccinae". This method soon substituted the variolization. However it must to be mentioned that, starting from 1770, vaccination was already performed in northern Europe by non medical personnel as for example the school teacher Peter Plett. Notwithstanding some initial opposition, vaccination quickly spreaded throughout Europe. It arrived to Spain in 1801 and thence was transferred to Spanish America and Philippines Islands with the expedition leaded by doctor Francisco Xavier Balmis. This expedition reached New Spain in June 1804, and remained there until February 1805 when embarked addressing to Philippines Islands. The other expeditionary group, leaded by doctor Jose Salvani, addressed toward Colombia, Peru and Bolivia, where Salvani died. PMID- 21585014 TI - [Sleep medicine: development, contributions and perspectives. Report of the work group on sleep medicine]. AB - Sleep is a basic biological process that has an impact on all the functions of the body, and interacts bidirectionally with virtually all of the body systems, so that the sleep disorders are associated with disturbances in other systems, either respiratory, neurological, cardiovascular, endocrine, immune, etc., and vice versa. The complexity of the regulatory mechanisms of sleep and the variety of their disorders, together with the clinical evidence accumulated in recent decades, have led to the birth of a new branch in medicine: the Sleep Medicine, with well defined intrinsic disorders. The consequences of sleep deprivation or fragmentation induced by changes in social and work dynamics, as well as sleep disorders have harmful effects on individuals in the short and long-term, the most important are an elevated risk for vehicular and occupational accidents, cardiovascular damage, cognitive impairment, obesity, diabetes mellitus, among others, impacting individuals of all ages. The sleep clinics and laboratories in Mexico, have made significant contributions, at both the basic and clinical levels, for the diagnosis and treatment of sleep disorders; however, without a specific health policy, we will continue to commit resources only on the attention of its effects and not on prevention, making the impact on the economy and quality of life of patients with sleep disorders, much higher than in developed countries. It is necessary to build a program of medical care to incorporate the Sleep Medicine in the priorities of medical care in the National Institutions of Health at all levels. Solutions and guides to optimize the achievement of the proposed results, and increase efficiency and effectiveness of the resources applied in this new field of Medicine are offered. PMID- 21585015 TI - [Management of obesity in medical units: a reflection on leadership in nutritional surveillance programs]. PMID- 21585016 TI - [Research strategy on molecular identification of animal medical material]. AB - This paper summarized and analyzed the status quo and problems about molecular identification of animal medical material, based on the facts, we proposed some research strategies, including uniting to tackle key problems, expanding the research species, accelerating manufacture and generalization of molecular identification kit, priming the research project of DNA barcoding, and establishing standard database on animal medical material. PMID- 21585017 TI - [Molecular methods for authentication of Chinese medicinal materials]. AB - The resource authentication is required for quality assurance and control of Chinese medicine. This review provides an informative introduction to molecular methods used for authentication of Chinese medicinal materials. The technical features of the methods based on sequencing, polymerase chain reaction (PCR) and hybridization are described, merits and demerits and development of the molecular methods in identification of Chinese medicinal materials are discussed. PMID- 21585018 TI - [Application of digital earth technology in research of traditional Chinese medicine resources]. AB - This paper describes the digital earth technology and its core technology-"3S" integration technology. The advance and promotion of the "3S" technology provide more favorable means and technical support for Chinese medicine resources survey, evaluation and appropriate zoning. Grid is a mature and popular technology that can connect all kinds of information resources. The author sums up the application of digital earth technology in the research of traditional Chinese medicine resources in recent years, and proposes the new method and technical route of investigation in traditional Chinese medicine resources, traditional Chinese medicine zoning and suitability assessment by combining the digital earth technology and grid. PMID- 21585019 TI - [Process on researching methods of ecology of Chinese traditional medicine resources]. AB - Though the study on ecology of Chinese traditional medicinal resources methods has achieved great progress in recent years, it is not able to catch the pace of the development of ecology science. Based on the analysis of recent literatures about ecology development trend and Chinese traditional medicinal ecology methods, the progress of Chinese traditional medicinal ecology methods was reviewed, and future study trend was discussed. PMID- 21585020 TI - [AM and its application in plant disease prevention of Chinese medicinal herbs cultivation]. AB - To study the beneficial effect of AMF from the utilization achievement in the agroforestry research, we discuss the application of AM in medicinal plant disease prevention and control. This paper summarized the type of medicinal plant disease, the influence of plant disease and the commonly used prevention method in production. As for the adverse consequences caused by plant's non-infectious and infectious diseases, AM has some improvement function. Something will affect the function of AM in the prevention of medicinal plant disease, for example, the relationship between AMF and the plants, the quantity, the time and the environmental factors about AMF inoculation and so on. In order to achieve the useful effect of AM in the prevention of medicinal plant disease, we should choose the suitable condition during production in practice to carry on the vaccination. PMID- 21585021 TI - [Effect of elicitors on induction and manipulation of secondary metabolic effective ingredients in Salvia miltiorrhiza]. AB - The application of elicitors, which is currently the focus of research, has been considered as one of the most effective methods to improve the synthesis of secondary metabolites in medicinal plants. Biotic and abiotic elicitors can regulate the secondary metabolic pathways of effective ingredients in Salvia miltiorrhiza. This paper has introduced the research progress about the induction and the regulation mechanism of S. miltiorrhiza by elicitors. PMID- 21585022 TI - [Novel method for dynamic monitoring and early-warning on wild resources of traditional Chinese medicines based on price ratio between drug and foodstuff]. AB - OBJECTIVE: To probe into the new idea along with establishment of a novel method for dynamic monitoring and early-warning on the wild resources of traditional Chinese medicines (TCMs). METHOD: The alterations of wild traditional Chinese medicinal resources were assessed through the price ratio between drug and foodstuff (PRDF) indicating the balance between supply and demand of the specific TCMs, referred to the price ration between pork to foodstuff which is used in national monitoring to the balance between pork supply and demand. RESULT: Since the price of rice was tightly controlled by government, it was selected as a relatively stable reference to build the PRDF in order to take away the non marketing influence to TCMs price such as CPI and inflation rate. The modified relative alteration trend of TCMs price had been researched through comparing different formulae to build PRDF, including absolute average month price of TCMs, month average price ratio of TCMs to foodstuff (rice) , month-on-month change of TCMs to rice, year-on-year change of TCMs to rice, and difference in value of period-on-period change (DVPPC). In the research, Cordyceps, Glycyrrhiza and totally five herbs were selected as model drugs and the price data were collected from 2002 to 2008. The results showed that DVPPC calculated of relative long time window was more sensitive and stable to reflect the relative alteration trend of TCMs price. For instance, the DVPPC of Ligustici showed continuously increase trend in recent years. This suggested appearance of unbalance between supply and demand of Ligustici, and forced policy intervention to maintain reasonable and continuable utilization of Ligustici resource. CONCLUSION: The proposed method and the formula of DVPPC revealed some useful guidance for dynamic monitoring the wild resources of TCMs. PMID- 21585023 TI - [Species diversity and host of Thesium chinense community]. AB - OBJECTIVE: To study species diversity and the host of Thesium chinense community. METHOD: The investigation on phytocoenology was carried out on the T. chinense community in 7 areas of Anhui Province and Jiangsu Province. The correlation between species diversity of community and T. chinense abundance was analyzed regarding to the abundance of species, the abundant index of species, species diversity index and community even index. RESULT AND CONCLUSION: The results showed that T. chinense liked light, warm climate, liked acidic to neuter soil. The majority of T. chinense distributed in the humid wasteland and herbaceous community. There was a positive correlation between the abundance of T. chinense and the unity numbers of community, and a negative correlation between the abundance of T. chinense and the abundance, coverage, diversity index, Pielou even index of community. T. chinense host species was various. This investigation found 28 host species belong to 11 Families, among them 5 Families and 18 species were found for the first time. PMID- 21585024 TI - [Growth curve of Siraitia grosvenorii and correlative analysis of seed and growth of fruit]. AB - OBJECTIVE: To establish the growth curve of Siraitia grosvenorii and analyze the correlation between seed and growth of fruit. METHOD: The growth curve fitting function was applied for the study of correlation between seed and fruit growth. RESULT: The significant positive correlation existed between seed and horizontal diameter x vertical diameter, not between seed and flesh weight of single fruit. CONCLUSION: The growth curve is a reciprocal function, and seed is one of major factors to influencing the size of fruits and the shape of fruit. PMID- 21585025 TI - [Construction and analysis of suppression subtractive cDNA libraries of continuous monoculture Rehmannia glutinosa]. AB - OBJECTIVE: To explore the molecular mechanism of continuous monoculture problem by constructing the cDNA libraries of continuous monoculture Rehmannia glutinosa. METHOD: To use the suppression subtractive hybridization (SSH) technique to construct the forward and reverse subtractive cDNA libraries of continuous monoculture R. glutinosa to adopt blue-white colony screening and PCR to detect the positive clones which would be sequenced and analyzed by bioinformatics. RESULT: The subtracted cDNA libraries of continuous monoculture R. glutinosa. were successfully constructed, and the result showed that the forward and reverse subtracted libraries obtained 300 positive clones, respectively. The forward and reverse libraries got different ESTs, and produced 232 (forward library) and 214 (reverse library) unique ESTs by sequencing. Based on homology search of BLASTX and BLASTN in NCBI, 200 and 195 of unique ESTs were homologous to known genes in the forward and reverse libraries, respectively. Categories of orthologous group (COG) showed that the forward and reverse libraries got 60 and 61 ESTs with the corresponding gene annotation, involving 21 metabolic pathways. CONCLUSION: The information of differential expression genes in continuous monoculture R. glutinosa, and their functional annotation of differentially expressed genes indicate that continuous monoculture has a profound effect on expression of the genes in R. glutinosa. Furthermore, the research analyzed several key genes in response to replant problem, which provided a foundation for revealing the molecular mechanism of continuous monoculture R. glutinosa. PMID- 21585026 TI - [Instantaneous expression aFGF-GFP fusion gene in safflower]. AB - OBJECTIVE: To study the instantaneous expression aFGF-GFP fusion gene in Carthamus tinctorius. METHOD: Molecular biology methods were applied to construct aFGF and GFP fusion gene vector, it is transformed into C. tinctorius by Agrobacterium tumefaciens, forming the resistant callus, fluorescence microscopy was used for detection. RESULT: aFGF gene and GFP gene were amplified by PCR reaction. It was successfully constructed plant fluorescence expression vector pCAMBIA1390: :35S: :aFGF-GFP, it was used to transform C. tinctorius, and the acquired resistance calli showed strong green fluorescence under UV light. CONCLUSION: The expression of GFP in resistance C. tinrictorius calli is good, it is indicated that aFGF gene in plant cells has also been expressed. PMID- 21585027 TI - [Study on allelopathy effect of pericarp extract of Phellodendron amurense]. AB - Through the study of allelopathy of the pericarp of Phellodendron amurense, the role of self-regeneration barriers was investigated in order to find ways and means for the protection of wild populations of P. amurense. Solution preparation: soaked pericarp of P. amurense in distilled water at 4 degrees C to get solution A, and reflux extraction of pericarp with distilled water at 100 degrees C to get solution B. Both of the solution A and solution B were used in the experiment of seed germination and seedling growth with the seeds of cabbage and wheat. The results showed that 20 g x L(-1) concentration of solution A and solution B inhibited significantly seed germination of cabbage and wheat, while 100 g x L(-1) concentration of solution A even completely inhibited the seed germination of wheat. 20 g x L(-1) concentration of solution A significantly inhibited the cabbage and wheat seedling growth, completely inhibited the root growth of cabbage, while 100 g x L(-1) concentrations of solution A completely inhibited seedling growth of cabbage and wheat. Comparing to solution A, the intensity of solution B are diminished on seed germination and seedling growth. It is concluded that the allelopathy of pericarp of P. amurense is multi-material role in the results, some of allelochemicals are easily degradable when exposed to heat. Overall, the allelopathy of pericarp of P. amurense can affect the seed germination and seedling growth. It is supposed that allelochemicals existed in the pericarp of P. amurense is one of the reason leading to difficulties in self regeneration of its population. PMID- 21585028 TI - [New analysis of EST-SSR distribution and development of EST-SSR markers in Salvia miltiorrhiza]. AB - OBJECTIVE: To establish the new EST-SSR markers for analyzing the genetic variation of different population of Salvia miltiorrhiza. METHOD: It was dealt with ESTs newly downloaded from Genbank and that of acquired from HMPL lab EGassembler software, and then carried out SSR loci search and SSR type analysis by SSRIT software. After that, it was designed the EST-SSR primer pairs for PCR amplification condition optimization. RESULT: Abundant and high coverage of SSR loci distribution were found in S. miltiorrhiza with having one SSR per 5.8 kb ESTs. Among them, the occurrences of different repeat units were mainly the di- (63.0%) and tri- (35.5%). The CT/AG was the most frequent motif in dinucleotide motif type and the GAA/TCC was the most frequent motif in trinucleotide repeats. Out off 36 primer pairs, 29 primer pairs (80.5%) were successfully amplified in all samples of S. miltiorrhiza while the rest failed to give PCR products at various annealing temperature and Mg2+ concentrations. The selected primer pairs also showed the polymorphism in samples from different S. miltiorrhiza populations. CONCLUSION: The newly establishment of EST-SSR markers showed high SSR loci coverage and genetic polymorphisms in S. miltiorrhiza population. It could be used for genetic variation analysis. PMID- 21585029 TI - [Distribution and variation of paclitaxel and cephalomannine contents in wild Taxus cuspidata]. AB - Paclitaxel and cephalomannine contents in wild Taxus cuspidata were determined by HPLC. The results indicated that paclitaxel and cephalomannine contents in T. cuspidate at the sunny side were slightly higher than that at the shadow side in the current-year and biennial branches. Paclitaxel and cephalomannine contents had no obvious regularity in leaves. Paclitaxel and cephalomannine contents were both the highest in the bark, then in the current-year branches, lower in the current-year leaves, and the lowest in the fruits. There were no remarkable correlation between stem diameter and paclitaxel and cephalomannine contents in the current-year branches and leaves. Significant difference was observed among samples collected in different period, and higher paclitaxel and cephalomannine concentrations were detected at the dormancy stage than that at the flower and fruit stages. PMID- 21585030 TI - [Classification of Pueraria lobata in different geographical regions]. AB - OBJECTIVE: To classify Pueraria lobata originated from different geographical regions based on ITS,psbK-psbI and trnH-psbA information. METHOD: Twenty-four samples of P. lobata were collected from northeast China, north China, central China and northwest China. DNA extraction, PCR, sequence and genotypes/haplotypes analysis were performed . RESULT: ITS1, 5.8S and ITS2 varied only 1 bp respectively, psbK-psbI 2 bps; trnH-psbA varied 1 bp and 10 bp deletion. CONCLUSION: Based on the variation of ITS,psbK-psbI and trnH-psbA, 4 genotypes and 2 haplotypes were identified, respectively. PMID- 21585031 TI - [Effect of PEG stress on plantlets of Chrysanthemum morifolium induced by endophytic botrytis sp. (C1) and Chaetomium globosum (C4)]. AB - The effect of the endophytic fungi Botrytis sp. (C1) or Chaetomium globosum (C4) on the drought resistance of Chrysanthemum morifolium was studied. Ch. morifolium plantlets were inoculated with C1, C4 and cultured in the pots for 60 days, then the plantlets were stressed by 0%, 10%, 20%, 30%, 40% PEG6000 respectively in order to simulate different drought conditions. Biomass, the activities of SOD, POD, PAL, the contents of MDA and soluble protein of each group were determined. The results showed that endophytic fungi groups grew better than the control (without inoculation endophytic fungi). With the increasing of the concentration of PEG6000, the biomass of Ch. morifolium of each groups decreased, while the biomass of fungi groups was significantly higher than that of control, moreover C4 group higher than C1 group. With the concentration of PEG increasing, the content of MDA of each group increased too, while POD activity and soluble protein content of all treatments increased at first and then decreased. SOD activity and PAL activity of the control were increased with the increase of PEG concentration, but SOD activity of the two fungi groups were stable. After been stressed by different concentrations of PEG, MDA content of two fungi groups were always lower than the control, while SOD activity, POD activity, PAL activity and soluble protein content were higher. In conclusion, endophytic fungi can increase the drought resistance of Ch. morifolium. PMID- 21585032 TI - [Pollen viability and stigma receptivity of Cistanche deserticola]. AB - OBJECTIVE: To study the characteristics of pollen viability and stigma receptivity of C. deserticola and provide theory basis for seed production and breeding of C. deserticola. METHOD: Different physiological measurement methods were applied to evaluate pollen viability and stigma receptivity. The results of different methods were compared with the seed setting percentage of the cross pollination in the field test and pollen germination percentage by fluoroscope observation methods. The changes of pollen vitality and stigma receptivity in different conditions were tested using proper methods. RESULT: The optimum methods on pollen viability and stigma receptivity detection were MTT-test and Benzidine-Hydrogen Peroxide method respectively. Results showed that the mean pollen viability and stigma receptivity were both the highest in inchoate anthesis with pollen germination percentage up to 95%, and can maintain viable for 4-5 d, but at the lower temperature of 4 degrees C, the pollen can be stored up to 10 days. CONCLUSION: The physiological characteristics of pollen and stigma of C. deserticola displayed good ecological adaptation, which are much more adaptive to the large area of cultivation condition. PMID- 21585033 TI - [Ecology suitability of Polygonum capitatum in Guizhou province based on topographical conditions]. AB - OBJECTIVE: To study ecology suitability rank dividing of Polygonum capitatum for selecting artificial planting base and high-quality industrial raw material in Guizhou province. METHOD: Based on the investigation of PCB and DEM data of Guizhou province, the relationship between the gallic acid content in P. capitatum and topographical conditions was analyzed by statistical analysis. The geographic information systems (GIS)-based assessment and landscape ecological principles were applied to assess ecology suitability areas of P. capitatum in Guizhou. RESULT AND CONCLUSION: slope, aspect and altitude are main topographical factors that affect the content of gallic acid in P. capitatum. The gallic acid content of P. capitatum is higher in the lower altitude, shady slope and smaller slope areas. The gallic acid content is higher in the eastern areas of Guizhou province. PMID- 21585034 TI - [Differential display of mRNA from microtubers of Pinellia ternata in vitro]. AB - OBJECTIVE: To study mRNA differential expression from microtubes of Pinellia ternata in vitro, and give more information of the molecular mechanism in the formation of microtubers. METHOD: DDRT-PCR was used to identify the expressed gene fragments related to the microtubers development of P. ternata in vitro. RESULTS AND CONCLUSION: Fifteen cDNA fragments differentially expressed in the induction of microtubers of P. ternata in vitro were identified and characterized by using mRNA differential display DDRT-PCR. The deduced amino-acid sequences of six fragments of cDNA showed no significant homology with ESTs and genes in the Genbank databases, and they could be new cDNA fragments. However, the remaining three showed significant homologies with sequences encoding components of eukaryotic translation initiation factor 3 subunit H, MADS-box protein and ethylene signal transcription factor, respectively. Their differential expression patterns were confirmed by semi-quantitative RT-PCR analysis. And the expression level of the induction of microtubers of P. ternata in vitro was different. PMID- 21585036 TI - [Effect of nitrogen, phosphorus and potassium deficiency on content of phenolic compounds in exudation of American ginseng]. AB - OBJECTIVE: Some of the phenolic compounds detected in the soil of commercially cultivated American ginseng could inhibit the seed germination and seedling growth of American ginseng. In this paper we studied the root exudation of American ginseng induced by deficiency of nitrogen, phosphorus and potassium on the content of phenolic compounds. METHOD: Two years old American ginsengs were cultured in hydroponic culture with different nutrient solution. The culture solution was collected after 14 days. The exudations of different polarities in the culture solution were enriched by the amberlite XAD4 and XAD7. The content of the total phenolic acids in the exudation was analyzed by Folin-Ciocalteu colorimetry; the contents of vanillic acid, p-coumaric acid and trans-cinnamic acid were detected and quantified by HPLC. RESULT: Both in the situation of nitrogen and potassium deficiency, the concentration of total phenolic compounds increased significantly in the exudation of American ginseng comparing with the complete nutrient solution (P < 0.05) , while decreased significantly under phosphorus deficient conditions (P < 0.05). The contents of the 3 autotoxic phenolic acids decreased significantly under nitrogen, phosphorus and potassium deficient conditions (P < 0.05). CONCLUSION: The contents of total phenolic compounds and the 3 autotoxic phenolics in the root exudation of American ginseng altered variously in the deficiency of nitrogen, phosphorus and potassium. PMID- 21585035 TI - [Effects of soil water content on seedlings growth and active ingredients of Salvia miltiorrhiza]. AB - OBJECTIVE: In order to provide a scientific water management for the standardized cultivation, the effects of soil water content on the seedlings growth and active ingredients of S. miltiorrhiza were studied. METHOD: A water stress experiment with pot culture was applied to study the effects of different soil water content on the seedlings growth, biomass and the accumulation of tanshinone, salvianolic acid B and mineral nutrition of S. miltiorrhiza. RESULT: Soil water content had serious influence on the growth, yield, outer appearance and inner quality of S. miltiorrhiza when the soil was under severe drought or with too much water. But the shoot and root biomass of S. miltiorrhiza was increased significantly under mild drought. As well as the content and cumulant of dihydrotanshinone I , cryptotanshinone, tanshinone I , tanshinone IIA and salvianolic acid B in root of mild drought were increased. It also enhanced the P, K, Ca, Mg, Mn, Zn, Cu and Fe contents of S. miltiorrhiza under mild drought. CONCLUSION: The overall results from the experiment suggest that the appropriate soil water content is 55% to 60% in seedling stage of S. miltiorrhiza. And it will be strongly recommended that the ridge culture and suitable soil moisture management must be carry out in production of S. miltiorrhiza in order to improve the yield and quality of medicinal materials. PMID- 21585037 TI - [AFLP analysis of genetic diversity of Alpinia officinarum]. AB - OBJECTIVE: To explore the genetic diversity and relationship of different Alpinia officinarum germplasm. METHOD: Amplified fragment length polymorphism (AFLP) markers were developed to analyze genetic polymorphism in A. officinarun from eight resources. The amplified fragments were used as primary matrix with NTSYSpc 2.11F software to analyze the similarity between the A. officinarum germplasm and to construct the genetic phylogenetic tree. RESULT: A total of 1,120 fragments were genotyped using AFLP with eight prime combinations. Analysis identified 1,044 polymorphic fragments, accounting for 92.57% of the total detected variation. Genetic phylogenetic tree analysis indicates that three categories can be divided among the eight resources of A. officinanrum. CONCLUSION: Significant polymorphism and genetic diversity can be observed among A. officinarum germplasm resources. PMID- 21585038 TI - [Analysis of genetic diversity of gemplasm of Pinellia ternata based on SRAP]. AB - OBJECTIVE: To assess population genetic diversity of Pinellia ternata with different phenotype and from different habitat by sequence-related amplified polymorphism (SRAP) technique. METHOD: Fourteen appropriate primer pairs were selected out from a total of 80 pairs for SRAP PCR amplification. A Jaccard's genetic similarity matrix and a dendrogram were established using SPSS 16.0 software. RESULT: The 14 primer pairs could amplify 171 bands, and the percentage of polymorphic bands was 15.8%. Based on the dendrogram, P. ternata in the same habitat clustered in a clade. CONCLUSION: These results suggested that SRAP markers could be used as an effective molecular technique for the diversity study of P. ternata and the habitat was more important than the phenotype in identification of P. ternata germplasm resource. PMID- 21585039 TI - [Identification of traditional medicine "Fructus Arctii" by nuclear ribosomal DNA ITS sequences]. AB - OBJECTIVE: To identify the traditional medicine Fructus Arctii from its adulterants by ITS. METHOD: Twenty-six samples of the different Fructus Arctii materials and 10 samples of the adulterants of the fruits of A. tomentosum, Onopordum acantium, Silybum marianum, and Amorpha fruticosa were collected. The total DNA of the samples were extracted, amplified cloned and sequenced. RESULT: ITS sequences were obtained from 26 samples respectively, there were Fructus Arctii 641 bp, A. tomentosum 641 bp, Onopordum acantium 639 bp, Silybum marianum 630-631 bp, Amorpha fruticosa 625-626 bp, which were registered in the GenBank. The similarity in ITS sequences between Fructus Arctii and the adulterants was less than 95%. In contrast, the similarity between any pair of Fructus Arctii was greater than 99%. The similarity was 98.29%-99.22% between Fructus Arctii and A. tomentosum. Phylogeny tree reconstruction using UPGMA analysis based on ITS nucleotide sequences can effectively distinguish Fructus Arctii from adulterants. CONCLUSION: ITS sequences can be used as a reliable molecular marker for the identification of Fructus Arctii. PMID- 21585040 TI - [Analysis on chloroplast DNA sequences of Polygonum capitatum of different geographical population]. AB - OBJECTIVE: To investigate the relationship between the variation of chloroplast DNA gene sequences and the geographical origins of Polygonum capitatum in order to provide the molecular evidence for its excellent germplasm resources. METHOD: PCR direct sequencing was applied to detect the chloroplast psbA-trnH, trnL-trnF gene sequence of 11 samples collected from 11 populations of P. capitatum. RESULT: The psbA-trnH gene sequence of P. capitatum from different populations was 402 bp in length, there were 6 variable sites. TrnL-F gene sequence was 875 bp, there were 5 variable sites. The clusters diagram by UPGMA method showed that P. capitatum groups in Yunnan and Guizhou existed a considerable variation. CONCLUSION: P. capitaturni which is located in the east of Yunnan and the west of Guizhou is helpful of screening the germplasm resources. PMID- 21585041 TI - [Cloning, molecular characterization and expression of acireductone dioxygenase (ARD) gene from Salvia miltiorrhiza]. AB - OBJECTIVE: To study the acireductone dioxygenase (designated as SmARD) gene of Salvia miltiorrhiza through bioinformatics and characterization of its tissue expression and response expression on stress in shoot. METHOD: SmARD gene was obtained by sequencing cDNA library constructed by us. BLAST was used for alignment, ORF finder software was applied to find open reading frame, prosite was used to analyze the protein characterization. Semi-quantitative RT-PCR was used to detect the gene expression level. RESULT: The full -length cDNA of SmRAD was 688 bp long with a 591 bp ORF (open reading frame) that putatively encoded a polypeptide of 196 amino acids; with a predicted molecular mass of 23.27 kDa. The deduced amino acid sequence of SmRAD of gene shared high homology with other known RADs. Semi-quantitative RT-PCR analysis indicated that SmRAD was constitutively expressed in roots, stems, flower and leaves of S. miltiorrhiza, with the high expression in roots. In addition, SmRAD expression level under different stress condition was also analyzed in root, including signaling components for plant defence responses, such as methyl jasmonate, salicylic acid and ABA, as well as drought, cold and salt abiotic stress. The expression of SmRAD was suppressed by water deficit treatment for 3 d, 150 mmol x L(-1) NaCl, 4 degrees C cold and 100 mmol x L(-1) ABA treatment for 1 d, but induced by 100 mmol x L(-1) MJ and 10 mmol x L(-1) ETH. CONCLUSION: A novel SmARD gene was cloned from S. miltiorrhiza. This study will enable us to further understand the role of SmARD in the defense response under different abiotic stress and in synthesis of active cmpounds in S. miltiorrhiza at molecular level. PMID- 21585042 TI - [Biotransformation of daphnetin by suspension transgenic hairy roots of Polygonum multiflorum]. AB - OBJECTIVE: To investigate the biotransformation of daphnetin by suspension transgenic hairy root of Polygonum multiflorum and provide a biotechnological method for large-scale production of the daphnetin-8-O-beta-D-glucoside using this new culture system. METHOD: Daphnetin was added into the media of suspension to culture 36 h. The biotransformation product was detected with TLC and HPLC, and isolated by various chromatographic methods. The influence of co-cultured time on conversion ratio, content of degradation product and the reason for the degradation of product II were investigated using HPLC. RESULT: One biotransformation product, daphnetin-8-O-beta-D-glucoside, was obtained, the optimal co-cultured time in suspension hairy root of P. multiflorum was 36 h with the highest biotransformation molar ratio of 32.11%, the sucrose medium (sucrose only) can increase the biotransformation molar ratio to 72.44%. The result demonstrated that the degradation products of the product II was induced by the MS medium. CONCLUSION: The potential application of suspension transgenic hairy root of P. multflorum in the sucrose-only medium on generating daphnetin-8-Obeta D- glucoside could be prospective. PMID- 21585043 TI - [Study on 11 metal [correction of mental] element contents in Dendrobium officinale]. AB - OBJECTIVE: To find out the variation of 11 mental element contents in Dendrobium officinale with different germplasms and harvesting ages, the results can provide scientific basis for the quality evaluation and the breeding of D. officinale. METHOD: 32 samples with 1-3 ages were collected from cultivated fields of Zhejiang and 11 samples were collected from markets. The 11 mental element contents of samples were determined by ICP-MS or AAS. RESULT: The average contents of K, Ca, Mg, Mn, Zn, Cr, and Cu were 1,205.23, 766.82, 158.25, 31.06, 4.28, 8.28, and 0.97 mg x kg(-1), the contents of As, Hg, Pb, and Cd were all in limits except Cd content of one sample exceeded the standard limit 0.07 mg x kg( 1); germplasms and physiological ages impacted mental elements contents accumulation significantly. CONCLUSION: There were rich essential mental elements in D. officinale. D. officinale from Zhejiang province and medical materials from market were all safe; the breeding of D. officinale can increase the contents of essential mental elements and reduce contents of heavy mental elements; the effect of physiological age on metal elements contents was related to each element's physiological and biochemical function. PMID- 21585044 TI - [Preliminary functional analysis of intron in chalcone synthase gene from Scutellaria baicalensis]. AB - OBJECTIVE: To study the function of the chalcone synthese gene introns in Scutellaria baicalensis, and clarify preliminarily their role in abiotic stress. METHOD: The CHS introns with specific primers were cloned and bioinformatic method was applied to predict the cis-elements in the intron of CHS. The introns were subcloned into binary vector, pCAMBIA-1301 before being transferred to tobacco. Then the activity of GUS of the transgenic tobacco seeds was analyzed. RESULT: Seven cis-elements were found in the introns. Under the dark and high temperature GUS expression rose at the first (3 h), but then declined (9 h). ABA and MeJA regulated insignificantly the GUS activity in normal temperature; treatment of 10% PEG induced GUS expression. CONCLUSION: CHS introns could be play a role in the regulation of S. baicalensis phenylpropanoid biosynthetic pathway. PMID- 21585045 TI - [Establishment of ARDRA system for Panax ginseng cultivated soil microbial community study]. AB - In this study, ARDRA system was established for Panax ginseng cultivated soil microbial community analysis. In the process of soil analysis we found that, ARDRA can not only distinguish soil microbial communities, proportion of each microbial type in total microorganisms can be calculated based on profiles of restricted enzyme digested 16S rDNA, also. Results indicated that, ARDRA system established was able to analyze microbial communities of P. ginseng cultivated soil samples. PMID- 21585046 TI - [Investigate of DNA extraction of os cervi]. AB - OBJECTIVE: To establish a convenient, practical and high efficient method of DNA extraction of os cervi, and lay the foundation of identification of animal bones. METHOD: The bones of sika deer, red deer, cattle, dog and pig were used to extract DNA under different decalcification time (24,48,72 h) and decalcification temperature (4,25,37,56,70 degrees C), and extract method. RESULT: It proved by experiments that demineralization process promotes the cracking of osteocyte. In a broad of decalcification time and temperature, DNA could be extracted from all bone samples successfully while the quantity varied slightly. CONCLUSION: Samples (about 0.1 g) decalcify with 0. mol x L(-1) EDTA at 4 degrees C for 24 h, then water-bath for 1 h after lysis buffer added, DNA extracted via the method above is of high quality and can be used for PCR. PMID- 21585047 TI - [Water cultured propagation of Polygonum multiflorum and dynamic changes of physiological and biochemical characteristics during adventitious roots formation]. AB - Water cultured propagation technology of Polygonum multiflorum was investigated with Rooting Powder No. 2 (ABT 2) comparison experiments, and the dynamic changes of endogenous hormones including indole acetic acid (IAA), abscisic acid (ABA), zeatin riboside (ZRs) contents and activities of indoleacetic acid oxidase (IAAO), polyphenol oxidase (PPO) were analyzed during rooting period. The results showed that rooting percentage of softwood cutting with 50 mg x L(-1) ABT2 and 10 mg x L(-1) ABT2 + 0.2% Urea + 0.2% KH2PO4 treatments was 94%, rooting percentage of softwood cuttings of control was 46% only. The adventitious rooting displayed three distinct phases i. e. root-inducing, root formation and root-elongating phases. The dynamic changes of contents of endogenous plant hormones (IAA, ABA, ZRs) and activities of IAAO, PPO tested were tightly related to the rooting process of soft-wood cuttings in P. multiflorum. During root-inducing phase the contents of IAA, ABA and ZRs decreased sharply, whereas ZRs content and IAAO activity kept higher level. IAA content reached the peak and PPO activity increased obviously during root formation phase, while IAAO activities and ABA, ZRs contents declined to minimum. During root-elongating phase PPO, IAAO activities were higher and IAA, ABA, ZRs contents kept steady. During rooting ABT2 (50 mg x L(-1)) treatment increased the content of IAA and PPO activity in cuttings, while the opposite result occurred in contents of ZRs, ABA and IAAO activity. PMID- 21585048 TI - [Quantitative study on ecological suitability of Chinese herbal medicine based on GIS]. AB - The quality of Chinese herbal medicine is closely related to its producing region. In order to apply mathematical models to do a quantitative study on the suitability of Chinese herbal medicine, it is necessary to study on the ecological factors and the interpolation of climatic data, which influence the Chinese herbal medicine growth. The paper firstly studied the judgment standard of ecological index from the points of ecology and statistics, and how to calculate the optimum range values and the weight of each ecological factor. Secondly, meteorological element data is essential data in analyzing the suitable region of Chinese herbal medicine, and the spatial distribution of meteorological elements is closely related to terrain environment, so, in order to make the results close to true value by the greatest degree. The paper adopted multiple linear regression interpolation method which based on DEM. The paper distinguished the factor system of suitable region and interpolation on the point of datumization, and made a study on it about some key issues. PMID- 21585049 TI - [Exploration and practice of open experiment in molecular pharmacognosy]. AB - In order to improve quality of molecular pharmacognosy teaching, the open experiment is applied. Under the guidance of tutors, students conduct the whole experiment independently. Students' abilities of independent thinking and comprehensive-experimental conduction were enhanced in the open experiment. Meanwhile, the authors discuss the problems of open experiment and propose some reflection and suggestions. PMID- 21585051 TI - [Effect of "Xiusanzhen"on expression of hippocampal Bcl-2 and Bax proteins in Alzheimer disease rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Xiusanzhen" [3 acupoints, i.e., bilateral "Yingxiang" (LI 20) and "Yintang" (EX-HN 3)] on expression of B-cell lymphoma/leukemia-2 (Bcl-2, an antiapoptosis protein) and Bax (a protein for promoting apoptosis) in the hippocampus in Alzheimer disease (AD) rats, so as to explore its clinical mechanisms underlying relieving AD. METHODS: A total of 40 Sprague Dawley rats were randomly divided into normal control, AD model, EA and olfactory nerve transaction(ONT) + EA groups, with 10 rats in each. AD model was established by injection of beta-amyloid (Abeta)(1-40) (2 microL containing 10 microg) into the hippocampus (Bregma: 3.5 mm, L: 2.0 mm, H: -2.8 mm below dura), and the ON was sectioned by using a fine needle. EA (80 100 Hz, 1-3 mA) was applied to bilateral LI 20 and EX-HN 3 for 10 min, once daily (except Saturdays and Sundays) for 6 weeks. The expression of Bcl-2 and Bax of hippocampus was measured by immunohisto-chemistry. RESULTS: Compared with the normal control group, the expression of Bcl-2 of hippocampus was significantly lower in the AD model group (P<0.05), and that of Bax in AD model group was much higher (P<0.01). In comparison with the model group, the expression of hippocampal Bcl-2 was up-regulated significantly (P<0.01), and that of hippocampal Bax protein downregulated considerably in the EA group (P<0.01). No significant differences were found between AD model and ONT + EA groups in the expression of hippocampal Bcl-2 and Bax proteins (P>0.05), suggesting a necessary premise condition for EA in regulating hippocampal Bcl-2 and Bax expression. CONCLUSION: "Xiusanzhen" can regulate the expression of hippocampal Bcl-2 and Bax proteins in AD rats, which may contribute to its clinical effect in relieving AD, and the therapeutic effect depends on the integrity of the olfactory nerve pathway. PMID- 21585050 TI - [Influence of electroacupuncture on efficacy of estrogen in regulating hypothalamic reproductive endocrine activity in rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on the efficacy of estrogen-induced regulation of reproductive endocrine in ovariectomized (OVX) rats. METHODS: Thirty SD rats were randomly divided into control, model (OVX), EA Guanyuan(CV 4), Estrogen (E) and EA+ E groups (n = 6 in each group). OVX model was duplicated by removing the bilateral ovaries. EA (5 Hz/20 Hz, 1- 2 mA) was applied to "Guanyuan" (CV 4) for 30 min, once every other day and for 3 sessions. Estrogen at doses of 0.5 mg/kg and 0. 25 mg/kg was intraperitonealy given to rats in the E group and EA+ E group, respectively. Serum estrogen and cortisol contents were assayed by enzyme linked immunosorbent assay and the expression of hypothalamic gonadotrophin releasing hormone(GnRH)mRNA, G protein-coupled receptor 54(GPR 54)mRNA, kisspeptin-1 (Kiss-l) mRNA and corticotropin releasing hormone (CRH) mRNA were detected by using real time polymerase chain reaction (RT PCR). RESULTS: Compared with the control group, the expression levels of GnRH mRNA, GPR 54 mRNA and Kiss-1 mRNA in hypothalamus in the model group were increased significantly (P<0. 05), while the expression of hypothalamic CRH mRNA was down-regulated obviously (P<0. 05), and serum cortisol and estrogen levels were reduced significantly (P<0. 05). In comparison with the model group, the expression levels of hypothalamic GnRH mRNA in the EA, E and EA+ E groups, and those of hypothalamic GPR 54 mRNA and Kiss-1 mRNA in the E and EA+ E groups were down-regulated considerably (P<0. 05); whereas hypothalamic CRH mRNA expression levels in the E and EA+ E groups were up-regulated obviously (P<0. 05),and serum cortisol and estrogen contents in the E and EA+ E groups were increased remarkably (P<0.05). Comparison among the EA and EA+ E groups showed that the effects of EA+ E group were significantly superior to those of EA group in down regulating hypothalalmic GnRH mRNA and GPR 54 mRNA expression, and in up regulating hypothalamic CRH mRNA expression and serum cortisol and estrogen contents (P<0.05). No significant differences were found between E and EA + E groups in down-regulating hypothalamic GnRH mRNA, GPR 54 mRNA and Kiss-1 mRNA expression, and in up-regulating hypothalamic CRH mRNA expression and serum cortisol and estrogen levels (P>0. 05). CONCLUSION: EA-CV 4 is able to potentiate the effects of low-dose of estrogen in down-regulating hypothalamic GnRH mRNA,GPR 54 mRNA and Kiss-1 mRNA expression, and up-regulating hypothalamic CRH mRNA expression and raising serum cortisol and estrogen contents in OVX rats, showing a favorable modulation effect on reproductive endocrine activity. PMID- 21585052 TI - [Effect of electroacupuncture on the uterine microcirculation in dysmenorrhea rats]. AB - OBJECTIVE To observe the effect of electroacupuncture (EA) on uterine microcirculation in dysmenorrhea rats so as to investigate its mechanism underlying relieving primary dysmenorrheal (PD). METHODS: Female SD rats undergoing diestrus were randomly divided into saline control, model, Sanyinjiao(SP 6), Xuanzhong(GB 39) and non-acupoint groups, with 6 rats in each. PD model was established by subcutaneous injection of estradiol benzoate for 10 days and intra-peritoneal injection of oxytocin (2 U) 1 h after the last estradiol injection. EA (2 Hz/100 Hz, 1- 1.5 mA) was applied to the above mentioned acupoints and non-acupoint area for 20 minutes. Numbers and diameters of the uterine microvessels (11-100 microm) and capillaries (< or =10 microm), and the state of the uterine microcirculation were observed by using a Cold Light Microcirculation Detector. RESULTS: In comparison with the saline control group, the numbers and diameters of uterine microvessels and capillaries at the corresponding time-points 5 min, 10 min and 20 min were decreased significantly in the model group (P<0. 05,P<0. 01). While compared with the model group, the numbers and diameters of uterine microvessels and capillaries at 20 min after EA in the SP 6 group were increased significantly (P<0. 05). The diameter of uterus capillaries of SP 6 group was significantly bigger than that of the non-acupoint group at the time-point 20 min (P<0. 05). No significant differences were found among the SP 6, GB 39 and non-acupoint groups in the diameter of uterine microvessels (P>0. 05). CONCLUSION: EA of SP 6 can effectively increase the number of uterine microvessels and capillaries and the diameter of the uterine microvessels and capillaries in PD rats, which may contribute to its effect in relieving dysmenorrhea by improving uterine microcirculation. PMID- 21585053 TI - [Effects of repeated electroacupuncture on gene expression of cannabinoid receptor-1 and dopamine 1 receptor in nucleus accumbens-caudate nucleus region in inflammatory-pain rats]. AB - OBJECTIVE: To observe the effect of repeated electroacupuncture (EA) on the expression of cannabinoid receptor-1 (CB 1) mrRNA and dopamine 1 receptor (D 1) mRNA in Nucleus Accumbens (NAC)-Caudate Nucleus (CN) region in inflammatory-pain rats, so as to study its underlying mechanism in analgesia. METHODS: A total of 30 SD rats were randomized into normal control, model, EA, EA+ AM 251 and WIN 55212-2 groups, with 6 cases in each group. EA (2 Hz/100 Hz, 1 -3 mA) was applied to "Zusanli"(ST 36) and "Kunlun"(BL 60) for 30 min, once every other day, and 4 sessions all together. Arthritis model was established by injection of Freund's complete adjuvant 0.05 mL in the rat's left ankle. Thermal pain threshold (paw withdrawal latency, PWL) was detected before and after modeling and after repeated EA and/or intraperitoneal injection of AM 251(an inverse antagonist at the CB 1 cannabinoid receptor, 0. 1 mg/100 g) and WIN 55212-2 (a potent cannabinoid receptor agonist, 0. 2 mg/100 g). The expression of CB 1 receptor mRNA and D 1 receptor mRNA in the NAC-CN region was measured by real time fluorescence quantitative-polymerase chain reaction. RESULTS: Compared with the control group, the pain threshold values of the model group was decreased significantly (P<0.01). In comparison with the model group, the pain threshold values of the EA group and WIN 55212-2 group were increased considerably on day 10 (P<0. 01). No significant differences were found between the EA+ AM 251 and model groups and between the EA and WIN 55212-2 groups in PWL after the treatment (P>0.05). Compared with the control group, both CB 1 R mRNA and D 1 R mRNA expression levels in the model group were increased slightly, while in comparison with the model group and EA+ AM 251 group, CB 1 R mRNA and D 1 R mRNA expression levels in the EA group and WIN 55212-2 group were upregulated obviously. No significant differences were found between the EA + AM 251 and model groups and between the EA and WIN 55212-2 groups in CB 1 R mRNA and D 1 R mRNA expression levels. PMID- 21585054 TI - [Effects of electroacupuncture on expression of tyrosine hydroxylase and c-fos in hippocampal CA 1 area in ketamine-addiction rats]. AB - OBJECTIVE: To explore the morphological basis of electroacupuncture (EA) in relieving addiction of ketamine. METHODS: Forty Sprague-Dawley rats were randomized into normal control, normal saline (10 mL/kg), model and ketamine+ EA groups. Ketamine-addiction model was established by intraperitoneal administration of ketamine (100 mg/kg) , once a day for 7 days. EA (2 Hz) was applied to "Zusanli" (ST 36) and "Sanyinjiao"(SP 6) for 30 min, once a day for 7 days. The expression of tyrosine hydroxylase (TH) and c-fos in the hippocampal CA 1 region was detected by immunohistochemistry. RESULTS: In comparison with the normal control group and normal saline group, the numbers of both TH immune reaction (IR)-positive and c-fos IR-positive neurons in the hippocampal region in the model group were increased significantly (P<0. 05, P<0. 01). Correspondingly, the expression of both TH IR-positive and c-fos IR-positive products in the hippocampal CA 1 region in the model group was upregulated evidently (P<0. 05, P<0. 01). After EA of "Zusanli" (ST 36)-"Sanyinjiao" (SP 6), compared with the model group, the expression of both TH IR-positive and c-fos IR-positive products was downregulated considerably (P<0. 01). CONCLUSION: EA of "Zusanli"(ST 36) "Sanyinjiao" (SP 6) can downregulate ketamine-addiction induced increase of expression of tyrosine hydroxylase and c-fos in the hippocampal CA 1 region in ketamine-addiction rats, which may contribute to its effect in relieving ketamine addiction symptoms in clinic. PMID- 21585055 TI - [Warm-needle moxibustion therapy may reduce aspirin-induced gastric mucosal injury in rats]. AB - OBJECTIVE: To observe the effect of warm-needle moxibustion on the gastric mucosal injury caused by anti-rheumatic dose of Aspirin. METHODS: Forty SD rats were equally randomized into blank group, model group, warm needling group and Omeprazole (for relieving peptic ulcer) group, with 10 rats in each. The rats were forced to undergo 12 hours' fasting and 4 hours' water-deprivation before the experiments. Normal saline (10 mL/kg) was given to the rats in the blank group. Gastric mucosa lesion model was established by intragastric infusion of aspirin (420 mg/kg). Warm needling was applied to "Zhong-wan" (CV 12), "Xiawan" (CV 10), "Zusanli" (ST 36) and "Neiguan" (PC 6) for 30 min, once a day for 7 days. The rats of the Omeprazole group were fed with Omeprazole( 10 mg/100 g body weight) once a day for 7 days. According to Guth's method, the ulcer index (UI) of the gastric mucosa was calculated following killing the rats. The activity of superoxide dismutase (SOD) and the levels of malondialdehyde (MDA) in the serum and gastric mucosa were detected with hydroxylamine method and thiobarbituric acid method, respectively. RESULTS: Compared with the blank group, the gastric UI, MDA levels of both serum and gastric mucosa in the model group were increased obviously (P<0. 01), while serum and gastric mucosal SOD activity in the model group were decreased considerably (P<0. 01). In comparison with the model group, the gastric UI, and both serum and gastric mucosal MDA contents in the warm needling group and Omeprazole group were down-regulated significantly (P<0. 01), whereas both serum and mucosal SOD activity in the warm needling group and serum SOD activity in the Omeprazole group were up-regulated significantly (P<0. 01). Comparison between the warm needling group and Omeprazole group showed that the UI, both serum and gastric mucosal SOD activity, and serum MDA level of the former group were evidently higher than those of the Omeprazole group (P<0. 05), but gastric mucosal MDA level of the warm needling group was apparently lower than that of the Omeprazole group (P<0.05). CONCLUSION: Warm-needle moxibustion can reduce the gastric lesion (ulcer) caused by aspirin in the rat, which may be closed associated with its effects in up-regulating both serum and gastric mucosal SOD activity and down-regulating both serum and gastric mucosal MDA levels. PMID- 21585056 TI - [Effect of moxibustion on hepatic glycogen and ultrastructure of exercise-induced fatigue rats]. AB - OBJECTIVE: To observe the effect of moxibustion of "Zusanli" (ST 36) on hepatic glycogen-level and ultrastructure changes in exercise-induced fatigue rats. METHODS: Thirty-three SD rats were randomly and equally divided into control, model and moxibustion groups. The fatigue model was established by forcing the rat to have a loaded exhaustion swim, once daily for 21 days. Moxibustion was applied to bilateral "Zusanli" for about 30 min, once every other day for 11 times. The hepatic glycogen content was detected by chromatometry and the hepatic ultrastructure was observed by using transmission electron microscope. RESULTS: The hepatic glycogen content in the fatigue model group decreased significantly compared with the control group(P<0. 01), and that in the moxibustion group was increased significantly compared with the model group(P<0. 05). Under transmission electron microscope , it was found that the glycogen in the hypatocytes of the model was decreased and the ultrastructure of mitochondria and rough endoplasmic reticulum was unclear in outline. In moxibustion group, more glycogen granules were found in hepatocytes, and the structure of mitochondria and rough endoplasmic reticulum was basically clear. CONCLUSION: Moxibustion may increase hepatic glycogen content and improve ultrastructure of hypatocytes in fatigue rats, which may be part of its mechanism underlying relieving exercise induced fatigue. PMID- 21585057 TI - [Effect of moderate acupuncture-stimulation of "Taichong" (LR 3) on blood pressure and plasma endothelin-1 levels in spontaneous hypertension rats]. AB - OBJECTIVE: To observe the effect of different strength of acupuncture stimulation on blood pressure and plasma endothelin (E)-1 in spontaneous hypertension rats (SHR) ,so as to seek a better acupuncture parameter for clinical treatment of hypertension. METHODS: Twenty-eight 9-week-old SHRs were randomized into mild stimulation group, moderate-stimulation group, strong-stimulation group and model group (n = 7 in each group). Seven normotensive SD rats served as a normal control group. Acupuncture stimulation with mild, moderate and strong stimulation was applied to bilateral "Taichong" (LR 3) for 5 min, once daily for 7 days. Blood pressure (BP) was determined by using a non-invasive BP-6 detection system. Plasma ET-1 was assayed by radioimmunoassay. RESULTS: Compared with the model group, the systolic pressure of the moderate-stimulation group on the 6th and 7th day was decreased significantly after acupuncture of "Taichong" (LR 3) (P<0. 01), being significantly lower than that of the mild- and strong-stimulation groups (P<0. 01). In comparison with the normal control group, plasma ET-1 level in the model group was increased significantly (P<0.01), while compared with the model group, only that in the moderate-stimulation group was down-regulated considerably (P<0. 01). No significant differences were found between the mild stimulation and model groups, between the strong-stimulation and model groups, and between the mild-stimulation and strong-stimulation groups in plasma ET-1 level (P>0. 05). CONCLUSION: Moderate-stimulation of "Taichong" (LR 3) can lower blood pressure and plasma EA-1 level in spontaneous hypertension rats. The reduced level of plasma ET-1 may be one of its mechanisms underlying improving hypertension. PMID- 21585058 TI - [Influence of acupoint-catgut-implantation on blood pressure and cardiac function in chronic congestive heart failure rats]. AB - OBJECTIVE: To observe the effect of acupoint-catgut-implantation on blood pressure and cardiac function in chronic heart failure (CHF) rats. METHODS: A total of 60 SD female rats were randomly divided into sham-operation group (sham), CHF model group, catgut-implantation group, Captopril group. CHF model was established by suprarenal abdominal artery constriction. Surgical catgut (No. 3-0, 2-3 mm length piece) was implanted into bilateral "Neiguan" (PC 6), "Xinshu" (BL 15) and "Zusanli" (ST 36) twice for 7 weeks. Rats of the Captopril group were treated with intragastric infusion of Captopril from the 50= day on after the operation, once daily for 7 weeks. Blood pressure (BP) including the systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP), heart rate (HR) and the left ventricular ejection fraction (LVEF) were detected respectively by cardiac sonography. RESULTS: On the 14th week after modeling, in comparison with the sham group, the SBP, DBP, MBP and HR in rats of the model group were increased significantly (P<0. 01, P<0. 05), while LVEF of the model group was decreased considerably (P<0. 01). Compared with the model group, the SBP, DBP, MBP and HR after 7 weeks' treatment in rats of the catgut implantation and Captopril groups were decreased considerably (P<0. 01), while the LVEF of the catgut-implantation group was increased evidently (P<0. 05). No significant differences were found between the catgut-implantation and Captopril groups in the SBP, DBP, MBP and HR levels, and between the model and Captopril groups in LVEF values (P>0. 05). CONCLUSION: Acupoint-catgut-implantation can down-regulate BP and HR, and increase LVEF in chronic congestive heart failure rats, which may contribute to its effect in ameliorating the cardiac function. PMID- 21585059 TI - [Characteristics of PET cerebral functional imaging during "Deqi" of acupuncture in healthy volunteers]. AB - OBJECTIVE: To observe the characteristics of needling sensation of "Deqi" (feelings of soreness, numbness, distending and heaviness, SNDH) by using positron emission tomography (PET) based on changes of glucose metabolism in different functional brain areas. METHODS: Eighteen normal volunteers [9 men and 9 women, mean age (23.23-1- 3. 32) years] were randomly divided into control, Waiguan (SJ 5) and non-acupoint groups (n=6 in each group). SJ 5 and non-acupoint (the midpoint between SJ 5 and the running course of the Small Intestine Meridian on the right forearm) were punctured by using a sterilized filiform needle. PET scan of the brain began 40 min after intravenous 18 F-fluorodeoxyglucose (FDG) injection (0. 11 mCi/kg body weight, left opisthenar vein). Needling sensations including "Deqi"(n= 5), tingling (n 5) and no-apparently-specific-feeling (NASF) were acquired by acupuncture stimulation and grouped. The needling sensations were evaluated by using Visual Analog Scale(VAS). The acquired image data of different needling-sensation groups were analyzed using SPM 2. 0 software in the Matlab Platform. RESULTS: After receiving acupuncture stimulation of SJ 5, 5 volunteers in the Waiguan (SJ 5) group experienced fee- lings of SNDH, with the mean VAS score being 4.23 +/- 1. 50, and 5 volunteers of the non-acupoint group had a tingling feeling, with the mean VAS score being 5.73 2.40. The VAS score of the tingling group was significantly higher than that of SNDH group (P<0. 05). Compared with the NASF control group, the activated cerebral areas were Brodmann area (BA) 7, 13, 20, 22, 39, 42 and BA 45 in the SNDH group, mainly involving the left temporal lobe, superior temporal gyrus, etc. and being obviously different to those of the control group (P<0. 001,k>10 voxels). The activated cerebral areas in the tingling group were BA 18, 19, 22, 24, 25, 32, 36, 40 and BA 45, predominantly involving the left limbic lobe, hippocampal gyrus, etc. and being apparently different to those of the control group (P<0. 001,k> 10 voxels). CONCLUSION: Acupuncture of Waiguan (SJ 5) mainly produces feelings of soreness, numbness, distending and heaviness, and the activated cerebral areas mainly involve the left temporal lobe, superior temporal gyrus, etc. ; while acupuncture of its neighboring non-acupoint chiefly induces a feeling of tingling in the healthy subjects, and the activated regions predominately involve the left limbic lobe, hippocampal gyrus, etc. PMID- 21585060 TI - [Effect of acupoint-catgut-embedment on mammary gland hyperplasia]. AB - OBJECTIVE: To evaluate the clinical therapeutic effect of acupoint-catgut embedment therapy in the treatment of mammary gland hyperplasia (MGH). METHODS: Eighty MGH patients were equally randomized into acupoint-catgut-embedment (ACE) group and medication (Rupixiao, a herbal patent drug for relieving MGH) group according to odd-numbered days or even-numbered days of visiting. Subcutaneous catgut-embedment was performed in Wuyi (ST 15), Rugen (ST 18), Tanzhong (CV 17), Xuehai (SP 10), Zusanli (ST 36) and Yanglingquan (GB 34), once every 15 days for 3 months. Patients of the medication group were treated by oral administration of Rupixiao (3 tablets, 3 times per day, 3 months altogether). The degree of breast pain and the size of the hyperplastic lump were observed before and after the treatment. Serum estrodiol, progesterone and prolactin contents on day 1 to day 3 of menstruation were detected by using an automation chemiluminescence immune analysator. RESULTS: After the treatment, of the two 40 MGH patients in the ACE and medication groups, 16 (40. 0%) and 5 (12. 5%) were cured basically, 8 (20. 0%) and 8 were improved markedly in their symptoms and signs, 16 (40. 0%) and 22 (55. 0%) were effective, and 0 and 5 (12. 5%) failed in the treatment, with the effective rates being 100% and 87.5%, respectively. The therapeutic effect of the ACE group was significantly better than that of the medication group (P<0. 05). In comparison with the pretreatment, the pain grades and the size of the hyperplastic lump in both ACE and medication groups decreased significantly after immediate termination of the treatment and 6 months after the treatment (P<0.01), and the therapeutic effects of the ACE group were significantly superior to those of the medication group in reducing pain grade and hyperplastic lump size (P<0. 01). After the treatment, serum estrodiol and progesterone contents were decreased evidently in both ACE and medication groups (P<0. 01, P<0. 05). Type-B ultrasonic examination showed that of the two 40 MGH patients in the ACE and medication groups, 16 and 5 cases turned to normal in their mammary glands, and the cure rate of the ACE group was evidently higher than that of the medication group (P<0. 01). CONCLUSION: Acupoint-catgut-embedment is effective in relieving MGH, and its therapeutic effect is apparently superior to that of medication (oral administration of Rupixiao). PMID- 21585061 TI - [Treatment of vocal cord submucosal bleeding with pricking therapy]. AB - OBJECTIVE: To observe the clinical efficacy of pricking bleeding of 3 points of the thumb tip, and 3 points of the auricular helix for treatment of vocal cord submucosal bleeding (VCSB), so as to provide a better therapy for it. METHODS: Sixty VCSB patients were equally randomized into pricking bleeding group and ultrasonic atomizing inhalation (UAI) group. Pricking bleeding was applied to Shaoshang (LU 11, 0. 1 cun to the nail on the radial side), Zhongshang (the center of the thumb back, 0. 1 cun to the nail), Laoshang (0. 1 cun to the nail on the ulnar side), Lun 1, 3 and 5 (MA-H) of the helix, once daily for 7 days. Ultrasonic atomizing inhalation treatment was given to patients of the UAI group for 15 min every time, once daily for 7 days. The scores of symptoms and signs and their difference values were calculated before and after the treatment. The acoustical parameters maximum phonation time (MPT), frequency perturbation quotient (FPQ), amplitude perturbation quotient (APQ), ratio of harmonic to noise (H/N) were detected by using a USSA Computer Language Phonetic Spectrum Analysis System. RESULTS: Of the two 30 cases of VCSB patients in the pricking bleeding and UAI groups, 20 (66.67%) and 12(40.00%)were cured, 7 (23.33%) and 6 (20.00%) were improved remarkably, 3 (10.00%) and 8 (26.67%) improved, and 0 and 4 (13.33%) failed, with the cure plus markedly effective rates being 90% and 60%, respectively. The cure plus markedly effective rate of the pricking bleeding group was significantly superior to that of the UAI group (P<0. 01). The difference values between pre-treatment and post-treatment in hoarseness, laryngalgia, throat dryness, throat burning sensation, throat clearing, vocal bleeding, glottis dysraphism, and total score were significantly higher in the pricking bleeding group than those in the UAI group (P<0.05). In comparison with the pre-treatment, MPT and H/N values were increased obviously (P<0. 05), and FPQ and APQ decreased clearly in the two groups after the treatment (P<0.05), suggesting an improvement of the acoustical parameters after the treatment. But, no significant differences were found between the two groups (P>0. 05). CONCLUSION: Pricking bleeding therapy is effective in relieving submucosal bleeding of the vocal cord and can improve its clinical symptoms and signs. PMID- 21585062 TI - [Randomized controlled trials for treatment of 30 cases of ordinary psoriasis by acupuncture and moxibustion]. AB - OBJECTIVE: To observe the therapeutic effect of acu-moxibustion for ordinary psoriasis, so as to find a better curative method for it. METHODS: A total of 60 cases of psoriasis were equally randomized into medication group[(8. 67 - 6. 53) months in duration of disease, (39. 25+/- 10. 21) years in age] and acu moxibustion group [(9. 16 7. 37) months in duration of disease, and (37. 38 +/- 11. 36) years in age] according to a random number table. For patients of acu moxibustion group, main acupoints used were Feishu (BL13), Geshu (BL17), Ganshu (BL18), Pishu (BL 20) and Shenshu (BL 23), combined with other acupoints [Hegu (LI 4), Weizhong (BL 40), etc. ] according to the affected part of the body. Moxibustion was applied to Shenshu (BL 23) and the injured skin area for about 3 min every time. Acu-moxibustion treatment was given once every other day continuously for 12 weeks. Patients of the medication group were treated with oral administration of Acitretin capsules (20 mg/d, for 12 weeks). The therapeutic effect was evaluated by using psoriasis area and severity index (PASI) scoring method. Results After the treatment, the integrative scores of PASI in both medication and acu-moxibustion groups decreased significantly (P<0. 01), and that of the acu-moxibustion group was significantly lower than that of the medication group (P<0. 05). Of the both 30 psoriasis patients in the medication and acu-moxibustion groups, 1 (3. 33%) and 4 (13. 33%) were cured basically, 15 (50. 00%) and 17 (56. 67%) were improved significantly, 12 (40. 00%) and 6 (20. 00%) were effective, and 2 (6. 67%) and 3 (10. 00%) invalid, with the effective rates being 93. 33% and 90. 00%, respectively. The cured plus markedly effective rate of the acu-moxibustion group was significantly higher than that of the medication group (P<0. 05). CONCLUSION: Acu-moxibustion therapy is effective in the treatment of psoriasis and is remarkably superior to that of medication. PMID- 21585063 TI - [A proportional bone measurement of acupuncture in 100 healthy volunteers]. AB - OBJECTIVE: To compare the difference of bone proportional cun of acupuncture between the description in book Lingshu Gudu (Miraculous Pivot Proportional Bone Measurement) and the current National Standard for Locating the Acupoint ("National Standard" in short), so as to determine the proportional relationship of the distance between two positions of the human body in terms of bone proportional cun. METHODS: A total of 100 volunteers [age: 18 - 25 years, body weight: (64.0 +/- 8.2)kg, and height: (169. 3 +/- 5.7)cm] were enlisted in the present study. The distances of the bilateral isonym acupoints [Touwei (ST 8), Yunmen (LU 2), etc. ,] or two sites on the body surface such as the bilateral nipples, Tiantu (CV 22)-umbilicus, etc., were detected by using a soft ruler or a detector in accordance with the Methods of Anthropometry for Locating Acupuncture Points (GB/T 23237-2009, "National Standard"). RESULTS: 1) The distances between the bilateral Touwei (ST 8) and bilateral Wangu (GB 12) were (134. 54 +/- 14. 72) mm and (161. 73 +/- 25. 05) mm respectively, both being different to the conventional equal lengths used nowadays. 2) The ratios of a) the distance between the bilateral Yunmen (LU 2) and that between the bilateral nipples, and b) the distance between Tiantu (CV 22) and the umbilicus center and that between the umbilicus center and the superior margin of the pubic symphysis were 233.28 : 194.46, and 398. 09 : 153.45, respectively, being identical to the descriptions of book Lingshu Gudu, but being different to those of the current "National Standard". 3) The distances between the anterior axillary fold and the cubital transverse crease, between the posterior axillary fold and the cubital transverse crease, and between Jianyu (LI 15) and the cubital transverse crease were (203. 89 +/- 32. 39) mm, (194.31 +/- 64.06) mm, and (286.45 +/-21. 16) mm respectively. In terms of proportional bone-length, the distance between the anterior axillary fold and the cubital transverse crease was converted to be 12 cun, being bigger than 9 cun recorded in the "National Standard". 4) The distances between the superior border of the pubic symphysis and the superior border of patella, and between the superior border of patella and the patella apex were (439. 96 +/- 801. 51) mm, and (48. 41 +/- 9. 40) mm, separately. When converted to the proportional bone- length, they are identical to the 18. 0 cun and 2. 0 cun recorded in the current "National Standard". CONCLUSION: The real distances between bilateral Touwei (ST 8) and between two nipples are not equal, the ratio of the distance between Tiantu (CV 22) and the umbilicus center and that between the umbilicus and the superior margin of the pubic symphysis, and the converted proportional bone-length of the distance between the anterior axillary fold and the cubital crease are not identical to the descriptions in current "National Standard" on acupoints location. PMID- 21585064 TI - [Comments on methodological quality of systematic review/meta-analysis on acupuncture therapy in China]. AB - Along with the development of evidence-based medicine, more and more systematic review/Meta-analysis papers on acupuncture therapy have been published in China. Most researches have played an important part in guiding clinical study and practice on acupuncture. However, low quality researches may mislead the users. In the present paper, we analyze shortcomings of the published papers in China about systemic review/Meta-analysis on acupuncture therapy from the methodological quality according to the assessment tool: Oxman-Guyatt Overview Quality Assessment Questionnaire(OQAQ). Moreover, we also analyze some possible factors affecting the quality of systemic review/Meta-analysis and put forward a few of measures for improving the quality of systemic review. PMID- 21585065 TI - [Research thoughts and methodology on efficacy specificity of needling and moxibustion methods based upon data mining]. AB - The method for needling and moxibustion is an indispensable component of acupuncturology. In clinical practice of acupuncture and moxibustion, efficacy specificity of different needling and moxibustion methods for different clinical conditions or different phases of a disease exists objectively, which is in a close relation with the results of clinical interventions. Starting with the correlation between the efficacy specificity of different needling and moxibustion methods and different clinical conditions or syndromes, the authors of the present paper put forward to collect abundant literature on needling and moxibustion methods, extract and analyze standard formats of information, establish literature database on needling and moxibustion methods and then design literature data application platform. On the basis of those mentioned above, a data mining model of needling and moxibustion methods will be established for revealing the potential knowledge and regularities about application of needling and moxibustion methods from the related abundant fuzzy and incomplete literature data according to data analysis and designed research program on efficacy specificity. PMID- 21585066 TI - [A good start for a better quality of life]. PMID- 21585067 TI - [Lack of professional knowledge!]. PMID- 21585068 TI - [Admissions to study dentistry should be chosen based on suitability in stead of through lottery. Yes]. PMID- 21585069 TI - [Admissions to study dentistry should be chosen based on suitability in stead of through lottery. No]. PMID- 21585070 TI - [Angioma with aging]. PMID- 21585071 TI - [Treatment of dental phobia and quality of life]. AB - Phobia for dental treatment often has a considerable influence on a person's perceived quality of life. In this research project, the relationship and interactions between dental anxiety, oral health and quality of life were studied. Scores on the basis of several parameters of these factors were analyzed prior to and following dental treatment. It appeared that quality of life was associated with both dental anxiety and oral health. When improvement in quality of life was investigated, it appeared that this was only statistically correlated with a reduction in dental anxiety. These findings suggest that treatment of dental phobia patients should focus not only on making patients treatable (pharmacologically), but also on reducing anxiety. PMID- 21585072 TI - [Orthodontics and quality of life]. AB - The impact of oral health on quality of life among orthodontic patients was assessed using the Child Oral Health Impact Profile. Responses of parents and children to questions about the quality of life of the child were very similar, suggesting that the parents were quite well able to assess the oral health related quality of life of their children. Girls experienced more adverse effects on their quality of life due to oral health problems as compared to boys. Subscales of the Child Oral Health Impact Profile appeared to have little predictive value with respect to the general feeling of healthiness among orthodontic patients. PMID- 21585073 TI - [Quality of life in patients with craniofacial disorders]. AB - Children with a serious congenital craniofacial disorder experience a variety of problems. Research on quality of life in these children has commenced relatively late. A specially developed questionnaire, the Child Oral Health Impact Profile, was used for a group of cleft lip and palate children and their parents. The study set out to determine the extent to which the answers given by the children corresponded to those of their parents. The children's perception of oral health related quality of life appeared to differ from that of their parents. PMID- 21585074 TI - [Periodontal disease and quality of life]. AB - In order to gain insight into the degree to which periodontal disease is related to quality of life, research was carried out among 85 patients with moderate or severe periodontal disease in which they were asked to complete the Oral Health Impact Profile-NL49. Their scores on this questionnaire were compared with the scores of 85 control subjects of comparable age and gender. The patients with periodontal disease demonstrated significantly worse scores compared to the control group and patients with severe periodontal disease had scores which were statistically significantly worse than patients with moderate periodontal disease. The results of this study suggest a causal negative association of periodontal disease with quality of life. PMID- 21585075 TI - [The accidental detection of apical periodontitis]. AB - Accidental detection of an asymptomatic apical periodontitis raises the question whether this lesion should be treated or not. Arguments favouring treatment are that the inflammation may cause pain in the future, may enlarge or may negatively affect the host's resistance. Reasons for not treating may be that treatment weakens the tooth, may cause iatrogenic damage and that treatment is expensive and burdensome for the patient and does not lead in all cases to complete healing. Scientific evidence supporting either choice, whether treating the lesion or not, is lacking. In making such decisions, therefore, personal judgments by the patient and the dentist concerning the impact on the quality of life of the patient play an important role. PMID- 21585076 TI - [Quality of life associated with tooth loss and tooth replacement]. AB - Tooth loss leads, depending on the number and location of missing teeth, to a certain degree of loss of function. This loss of function might lead to an impairment of oral health-related quality of life. The literature provides fairly strong evidence that tooth loss is associated with impaired oral health-related quality of life. The locations where teeth are missing and the distribution in the tooth arch of the teeth that still remain have an effect on the degree to which oral health-related quality of life is impaired. These findings are independent of the context and the measurement instrument used. With respect to tooth replacement no direct evidence exists concerning which type of replacement for which cases of tooth reduction have the largest positive effect. Research in this area is still in its infancy. PMID- 21585077 TI - [Quality of life in gerodontology]. AB - In clinical decision-making on whether or not to treat an oral disease and on making a choice from the spectrum of treatment options, the influence of the treatment on the physical and psycho-social well-being of the patient should play a crucial role. This awareness originates from gerodontology. To assess the value of a potential treatment, the concept quality of life has been advanced and various related questionnaires have been developed and employed. In the meantime, doubts have arisen about the value of these questionnaires. The present-day trend is to return to so-called qualitative research, which consists of systematic interviews of groups of older people using open-ended questions without making use of structured response options. PMID- 21585078 TI - [Quality of life related to oral health among addicts]. AB - In this study, the impact of oral health on the daily functioning of a group of individuals addicted to alcohol and/or drugs that were being treated at a centre for specialized dentistry in Amsterdam was investigated. Every new patient who reported to the clinic received the OHIP-14-questionnaire at home by post with the request that it be filled in and returned. A total of 110 usable questionnaires were returned (response 27.5%). The average OHIP-score (40.6; standard deviation 12.9) can be termed substantial when compared to other patient groups. On the subcategories 'physical pain', 'psychological discomfort' and 'psychological disability; the patients scored highest, and on the subcategory functional limitations' the lowest. The poor oral health of the patient group studied has a substantial impact on daily functioning. These baseline results will be used for measuring the effect of dental health treatment at this centre for specialized dentisty. PMID- 21585079 TI - [Treatment of malaria in Sub-Saharan Africa: significant progress but measures not always applicable]. PMID- 21585080 TI - [Giant retroperitoneal hydatid cyst in a traveller]. AB - INTRODUCTION: Giant hydatid cyst located in the retroperitoneal space is rare. The purpose of this report is to present a case cured by surgery in an adult traveller. CASE REPORT: In August 2009, a 67-year-old female who traveled frequently to Lebanon was admitted for assessment of a giant retroperitoneal hydatid cyst discovered coincidentally following palpation of an abdominal mass in 1997. From 1966 to 1975, the patient had undergone several surgical procedures for pulmonary and hepatic hydatidosis, complicated by vomica and anaphylactic shock. In 1997, computed tomography showed that the retroperitoneal cyst measured 100 mm at the widest point. At that time, the patient refused to undergo further surgery and was treated medically using albendazole initially in association with praziquantel. In 2009, the cyst had expanded to 180 mm at the widest point and the patient finally consented to perikystectomy. Excision was total and recovery was uneventful. Histology examination confirmed the viability of the cyst. Follow up examination at 12 months indicated no relapse. COMMENTS: The retroperitoneal space is a rare location for hydatidosis. Occurrence in this location is generally primary. In case of discovery of a liquid-filled retroperitoneal mass, a history of travel to an endemic area for hydatid disease should be elicited. Diagnosis relies on radiological findings and positive serology. Since retroperitoneal cysts are often giant, they respond poorly to medical treatment. Similarly radiological treatment is difficult due to retroperitoneal location. Surgery, preferably perikystectomy, is the treatment of choice. PMID- 21585081 TI - [Upper airway management during anesthesia for reconstructive surgery in patients with noma]. AB - Noma causes tissue degeneration of the face resulting in impaired mouth opening with secondary malnutrition and metabolic disorders. Reconstructive plastic surgery for noma can be lifesaving but requires special airway and ventilation techniques because of limited mouth opening. In addition, the African context imposes logistic and budgetary constraints. The purpose of this article is to describe an upper airway management strategy that takes into account disease factors and available resources. PMID- 21585082 TI - [Tuberculous gumma in sporotrichoid pattern]. PMID- 21585083 TI - [Pharo School - Le Pharo]. PMID- 21585084 TI - [The contribution of biology laboratories to keep immunization recommendations up to date: the example of the Centre Pasteur of Cameroon in the fight against meningococcal meningitis in North-Cameroon]. AB - The Centre Pasteur of Cameroon, Annex of Garoua, studied since 2007 meningococcus of meningitidis in the North of Cameroon. The serogroup A meningococcus completely seem to have disappeared with the profit from the serogroup W135 meningococcus. Current measurements of answers to an epidemic, based between others on reactive vaccination will have to take into account these new data to remain effective. Trivalent vaccine ACW135, placed at the disposal by WHO, should logically be able to be used in the event of epidemic, under reserve of an identification of the germ by a laboratory. The diffusion of the results of the circulation of serogroup W135 meningococcus supported vaccination by the tetravalent vaccine, but this one remains very expensive and, so held for a negligible minority of the population of North-Cameroon. It is part from now on of the recommendations to the travellers. PMID- 21585085 TI - [Benzonidazole: one of the rare treatment for Chagas disease]. AB - Benznidazole is indicated in the treatment of Chagas' disease, which is endemic in Latin America. However, it has numerous adverse effects and is effective only at certain disease stages. Because of these drawbacks and the appearance of resistance to benzinidazole, there is ongoing research for alternative therapeutic strategies and new drugs. PMID- 21585086 TI - [Drug utilization and HIV in West Africa Raguin G et al. published in issue No. 4/70 (Med Trop 2010; 70:319-20)]. PMID- 21585087 TI - [Prescription errors in a pediatric hospital department in Dakar, Senegal]. AB - Prescription is the main source of medication error in daily medical practice. The purpose of this study was to determine the distribution and cost of drugs used and causes of prescription errors in one department of the Albert Royer National Children's Hospital Center in Dakar, Senegal. Study was focused on patients admitted from December 1 to March 3, 2009. Based on 792 expected hospitalizations, 1 out of 2 patients was randomly selected to obtain a cohort of 400 patients for whom a total of 1267 prescriptions were written by pediatricians and interns on duty. Prescriptions were evaluated by pediatric professors to identify errors. The types of errors taken into account in this study involved indication, dosage schedule, and treatment duration. A total of 216 (17.0%) errors were identified including 121 cases (9.5%) involving indication mainly for antibiotics (30.5%) and antimalarial drugs (28.9%). Dosage schedule errors were observed in 58 cases (4.5%) involving antibiotics (24.1%) and antifungals (25.8%). These findings confirm the need for an intensive information campaign to prevent medication misuse in countries such as Senegal. Campaigns should be based on training of relevant therapeutic staff to optimize health care and improve availability for everyone. PMID- 21585088 TI - [Incidence of malaria among United Nations troops deployed in the Ituri district of Democratic Republic of Congo (ex-Zaire) during a 12-month period spanning 2005 and 2006]. AB - The purpose of this study was to determine the incidence of malaria in United Nations (UN) troops deployed in northeastern Democratic Republic of Congo (ex Zaire). A one-year study was conducted from June 2005 to May 2006. The study was retrospective for the first six months and prospective for the second. During the study period, a total of 99 cases of malaria requiring hospitalization at the UN Level II Hospital in the town of Bunia, Democratic Republic of Congo were recorded among UN troops. Malaria accounted for approximately 36% of all hospitalizations for medical diseases. The offending species in 98% of cases was Plasmodium falciparum. Transmission was highest from April to September. There were no deaths. Parasitemia was less than or equal to 2% in 91% of cases. PMID- 21585089 TI - [Air pollution and respiratory disease in a tropical urban setting in Cotonou, Benin]. AB - PURPOSE: To assess the impact of air pollution inside and outside housing on respiratory function in people living around traffic intersections. METHODS: A descriptive analytical study was carried out from February 5 to July 5, 2006. Carbon monoxide (CO), sulfur dioxide (SO2), and nitric dioxide (NO2) were measured over an 8-hour period inside and outside 60 houses near intersections during periods of heavy and light traffic. Spirometry was performed on residents of the same houses. RESULTS: CO levels were higher during heavy than light traffic both inside houses: 65 ppm vs. 43.2 ppm and outside houses: 160 ppm vs. 115 ppm. Similar results were observed for SO2, i.e., 2.8 ppm vs. 0.49 ppm inside houses and 4.3 ppm vs. 0.83 ppm outside houses. Measurements for NO2 were consistently nil. Respiratory symptoms were more frequent during heavy than light traffic: p = 0.0001; odds ratio (OR), 4.73; confidence interval (CI), 2.13-10.51. The frequency of spirometric abnormalities was higher in heavy than light traffic: p = 0.004; OR, 5.78; CI, 1.43-27.10. CONCLUSION: Indoor pollution level is higher during heavy traffic than light traffic. Respiratory symptoms were greater during heavy than light traffic. PMID- 21585090 TI - [Water quality and personal hygiene in rural areas of Senegal]. AB - INTRODUCTION: The high prevalence of diarrhea in developing countries is mostly due to poor water quality and hygiene practices. The purpose of this study was to assess water quality as well as hygiene practices and their determinants in Ngohe, i.e., a rural community (RC) in Senegal. METHOD: A combined approach consisting of a cross-sectional descriptive survey and bacterial analysis of water was used. Study was conducted in 312 randomly selected households. Data was collected through individual interviews with the assistance of a guide. Water for bacteriological analysis was collected from various sources, i.e., 3 modem borehole wells, 2 protected wells, and 10 traditional wells. Study points included home water treatment, drinking water source, latrine use, hand washing habits, and bacteria identified in water. A multiple regression model was used for data analysis. RESULTS: The household survey population was 59% male, 61% illiterate, and 93% married. Mean age was 44.8 +/- 18.1 years. Chlorination technique was inadequate in 62% of cases. Latrines were not restricted to adult use in 76% of homes. Hand washing was not performed at critical times in 94%. Drinking water was drawn from traditional wells in 48% of households, modem borehole wells in 45% and protected wells in 7%. Escherichia coli was found in water from all three sources and Vibrio cholerae was found in two traditional wells. Level of education, average monthly income, knowledge about chlorination techniques, and source of the water consumed were the main behavioral determinants (p < 0.05). CONCLUSION: Water treatment at the source and in the home as well as protection of water sources is necessary to ensure water quality. This will require effective public education campaigns and financial support for improvement of sanitary facilities. PMID- 21585091 TI - [Bacterial profile of surgical site infections at Souro Sanou National Hospital Center in Bobo Dioulasso, Burkina Faso]. AB - OBJECTIVE: The purpose of this study was to evaluate the bacterial profile and antimicrobial susceptibility of surgical site infection (SSI) as a basis for optimizing probabilistic antibiotherapy. MATERIALS AND METHODS: A 6-month transversal retrospective study was carried out at the Souro Sano Hospital Laboratory from November 1st, 2006 to April 30th, 2007. All positive pus samples collected for etiologic diagnosis of SSI were included. RESULTS: In a series of 681 patients who underwent surgery at the hospital, SSI was observed in 159 cases for an incidence of 23.4%. Pus samples for etiologic diagnosis were collected from 112 patients and led to identification of 103 bacterial strains. The most common strains were enterobacteriaceae in 54.0%, gram-positive cocci in 29.0% and non-fermenting Gram-negative bacilli in 16.5%. Escherichia coli was the most common species (30%) followed by Staphylococcus aureus (16.5%) and Pseudomonas aeroginosa (12.0%). Enterobacteriaceae resistance rates were 71% to amoxicillin, 64% to clavulanic acid-amoxicillin and 15% to third generation cephalosporin. Most S. aureus isolates (85%) were sensitive to methicillin. Non-fermenting Gram negative bacilli resistance rates were 68.5% to carboxypenicillin and 56% to fluoroquinolones. CONCLUSION: These findings indicate that SSI can be treated using third generation cephalosporin-aminosides in combination with oral fluoroquinolones. PMID- 21585092 TI - [Micronecta sp (Corixidae) and Diplonychus sp (Belostomatidae), two aquatic Hemiptera hosts and/or potential vectors of Mycobacterium ulcerans (pathogenic agent of Buruli ulcer) in Cote d'Ivoire]. AB - Buruli ulcer is currently a major public health problem in Cote d'Ivoire. It is a neglected tropical disease closely associated with aquatic environments. Aquatic insects of the Hemiptera order have been implicated in human transmission of Mycobacterium ulcerans, the pathogenic agent of Buruli ulcer. The purpose of this preliminary study using the polymerase chain reaction (PCR) method was to evaluate aquatic insects in Sokrogbo, a village in the Tiassale sanitary district where Buruli ulcer is endemic. Findings identified two water bugs hosting Mycobacterium ulcerans, i.e., one of the Micronecta genus in the Corixidae family and another of the Diplonychus genus in the Belostomatidae family. The PCR technique used revealed the molecular signatures of M. ulcerans in tissue from these two insects. Based on these findings, these two water bugs can be considered as potential hosts and/or vectors of M. ulcerans in the study zone. Unlike Diplonychus sp., this is the first report to describe Micronecta sp as a host of M. ulcerans. Further investigation will be needed to assess the role of these two water bugs in human transmission of M. ulcerans in Cote d'Ivoire. PMID- 21585093 TI - [Cutaneous tuberculosis: a 36-case series from Morocco]. AB - Tuberculosis is still endemic in Morocco. Cutaneous tuberculosis is the fifth most common form after pleuropulmonary, glandular, digestive and urogenital tract tuberculosis. The purpose of this single-center prospective study is to describe all cases of cutaneous tuberculosis treated between May 2006 and June 2009. Diagnosis was suspected based on clinical, immunological and histological features. The main clinical presentations, i.e., scrofuloderma and gumma, were consistent with endemicity of tuberculosis in Morocco. Since definitive diagnosis by detection of the tubercle bacillus was rarely possible, therapy was usually undertaken presumptively based on clinical and laboratory findings and therapeutic response. PMID- 21585095 TI - [Determination of prevalence and etiology of anemia during pregnancy in southern Benin, in conjunction with revision of national management policy]. AB - BACKGROUND: Anemia during pregnancy is a serious public health problem. Control requires identification of the underlying etiology. The objective of this study carried out in conjunction with revision of the national policy for the protection of pregnant women in Benin was to determine the prevalence and etiology of anemia. METHODS: From October 2006 to April 2007, 300 pregnant women were examined at two maternities in Ouidah, Benin. Sociodemographic and environmental characteristics, dietary data, behavioral practices, and history of malaria infection during pregnancy were collected. Blood and stool samples were tested for the presence of malaria parasites and intestinal worms respectively. Hemoglobin and ferritinemia levels were also determined. RESULTS: The prevalence of anemia (Hb < 11 g/dL) was 65.7% while that of malaria and intestinal worms was 4.3% and 8% respectively. Iron deficiency was not found. A borderline significant correlation was found between helminthiasis and anemia. No correlation was found between anemia and malaria. These findings indicate that kits progressively introduced by the health system during the study period provided relatively effective care. CONCLUSION: This study demonstrates a high prevalence of moderate anemia during pregnancy and suggests that it is mainly due to intestinal helminthiasis. These findings underline the importance of preventive antihelminthic treatment during pregnancy. PMID- 21585094 TI - [Infectious arthritis in hospital patients in Lome, Togo]. AB - OBJECTIVE AND METHODS: The purpose of this study was to determine the frequency and semiological profile of infectious arthritis in the outpatient clinic of the Tokoin University Hospital Center in Lome, Togo. PATIENTS AND METHODS: This study was based on a review of the charts of patients hospitalized in the rheumatology department over a period of 16 years. RESULTS: During the 16-year study period, 198 of the 13517 patients (1.5%) examined were hospitalized for infectious arthritis. There were 100 women and 98 men with a mean age of 36.3 +/- 17.5 years. Mean disease duration was 9.3 +/- 9.8 months. Diagnosis was banal germ arthritis in 157 cases (79.3%) and likely tuberculosis arthritis in 41 (20.7%). The knee was the most common location (34.3%). Arthritis affected a single joint in 159 cases (80.3%). Isolation of offending microorganism was achieved in 39 patients (19.7%). The most frequently identified agent was Staphylococcus aureus (42.5%). In addition to underdevelopment and poor hygiene observed in most patients in this series, risk factors included human immunodeficiency virus infection in 28 cases, alcoholism in 10, sickle cell anemia in 8, cancer in 3, and diabetes mellitus in 2. Outcome was favorable in 181 patients (88.7%). Four patients died. CONCLUSION: The frequency of infectious arthritis is correlated with underdevelopment and poor hygiene in black Africa. PMID- 21585096 TI - [Prevalence of methicillin-resistant Staphylococcus aureus in community-acquired skin infections in Lome, Togo]. AB - PURPOSE: To determine the prevalence of methicillin-resistant Staphylococcus aureus in community-acquired skin infections in Lome, Togo. PATIENTS AND METHODS: A prospective study including 90 cases of skin infection observed in dermatological outpatients at the teaching Hospital of Lome was carried out from 1st June 2003 to 30th May 2005. A bacteriological sample with antibiograms was obtained from all patients. RESULTS: Mean patient age was 21 years (extremes, 6 months to 78 years). The male-to- female ratio was 0.84. Infection was primary in 80% of cases including impetigo in 42.2%, follicular infection in 28.9%, and abscess in 8.9% and secondary in 20% of cases including eczema in 8.9%, mycosis in 3.3%, and other in 7.8%. Staphylococcus aureus strains were isolated in a total of 84 cases (93.3%). Staphylococcus aureus occurred alone in 79 cases (87.8%) or in association with other bacteria in 5. A total of 30 of the 84 Staphylococcus aureus strains (35.7%) isolated were methicillin-resistant. Resistant strains were associated with primary infection in 24 cases and secondary infection in 6. CONCLUSION. Staphylococcus aureus is the most common cause of community-acquired skin infections in Lome. One third of Staphylococcus aureus strains are methicillin-resistant. These findings should be taken into account in daily practice for prescription of antibiotics to patients presenting these infections. PMID- 21585097 TI - [HIV/AIDS-related digestive tract emergencies in the Department of Gastroenterology of the Campus University Hospital in Lome, Togo]. AB - The purpose of this study was to describe digestive tract emergencies observed in adult HIV-infected patients at the Campus Teaching Hospital in Lome, Togo. The files of patients admitted in emergency to the Gastroenterology Department of the Lome Campus Teaching Hospital from January 2005 to December 2009 were retrospectively reviewed. All patients over the age of 15 years with positive HIV serology were included in the study group. Out of a total of 842 files reviewed, 70 involved patients who were positive for HIV (8.31%). Mean patient age was 38 years and the sex ratio was 0.89. The most frequent reasons for admission were weight lost (75.7%), diarrhea (45.7%), and vomiting (41.4%). The main clinical signs were deterioration of general state (78.6%), conjunctive paleness (54.3%), fever (50%), and dehydration (17.1%). Digestive tract manifestations included thrush (37.1%), abdominal pain (21.4%) and ascites (18.6%). The most frequent diagnoses were infectious diarrhea (47.14%), digestive candidiasis (40%), and peritoneal tuberculosis (18.6%). The death rate during emergency treatment was 18.6%. These results demonstrate the high frequency and severity of digestive tract complications in HIV patients and underline the need for early management. PMID- 21585098 TI - [Chronic kidney failure in Togo: clinical, laboratory, and etiological aspects]. AB - OBJECTIVES: Determine clinical, laboratory, and etiological aspects of chronic kidney failure (CKF) in Togo. PATIENTS AND METHODS: This retrospective study was focused on the 11-year period from 1st January 1995 to 31st December 2005. Review was carried out on the medical files of 398 patients hospitalized for CKF in various departments of Lome-Tokoin University Hospital. For lack of kidney biopsy findings, nephropathy was classified on the basis of semiological criteria. RESULTS: Male predominance with a sex ratio of 1.34 was noted. Mean age was 42.6 years. Most patients presented extrarenal signs including hematological changes (94.5%), digestive tube manifestations (68.3%), and cardiovascular disease (55%). Most patients (75.5%) had end-stage disease with creatinine clearance below 10 ml/min. Ultrasound demonstrated stage III kidney damage in 42.8% of cases. Chronic glomerulonephritis (40.2%) was the main etiology, followed by chronic interstitial kidney failure (20.9%) and nephroangioscerosis (17.6%). CONCLUSION: The clinical and laboratory presentation of CKF in Togo is unremarkable but has a rich semiological background. PMID- 21585099 TI - [Human rabies: diagnostic pitfalls]. AB - The purpose of this report is to describe two cases of human rabies in Senegal that illustrate possible diagnostic and therapeutic pitfalls even in an endemic area. Although outcome is almost always fatal and interhuman transmission is uncommon, prompt diagnosis of rabies is important since delay increases the risk of exposure to the virus for the entourage. PMID- 21585100 TI - [Acute pericarditis associated with Plasmodium ovale malaria]. AB - The purpose of this report is to describe a rare case of benign acute pericarditis associated with recurrent Plasmodium ovale malaria. It was observed in a 33-year-old soldier who was stationed in Djibouti after serving several previous stints in West Africa. A favorable clinical outcome was achieved using chloroquin (30 mg/kg on 6 days) in association with NSAID followed by salicylates for one month. Re-examination at one year showed no recurrence. This case shows that Plasmodium ovale malaria must be considered as a potential etiology for acute benign pericarditis in patients with a history of travel to endemic countries. PMID- 21585101 TI - [Role of eldest in a destructured family context: clinical case report from Fann Hospital in Dakar, Senegal]. AB - In a Senegalese family, the role of the eldest, i.e. the one who must lead the way, is particularly difficult. The eldest is the only one required to excel and wield power in the family. To ensure his status and maintain his identity, the elder must be acknowledged as such by the father, mother, and younger siblings. The purpose of this report is to describe a case demonstrating the psychological frailness associated with elder status. The patient developed depressive breakdown when his mother dismayed by his professional failure ceased to acknowledgement his status and implicitly disqualified him. Discussion includes the psychopathological dimension revolving mainly around an Oedipal relationship with the father. PMID- 21585102 TI - [Human rhinomyiasis due to Oestrus ovis: case report in Morocco]. AB - The purpose of this report is to describe a case of human nasal myiasis caused by Oestrus ovis diagnosed in our laboratory in Morocco. Oestrus ovis is an obligate parasite of nasal cavities and sinuses. It is usually found in sheep and goats in the Mediterranean basin. Oestrosis is a rare finding in man. PMID- 21585103 TI - [Ulceration of the heel in a woman from Djibouti: squamous cell carcinoma with carcinomatous lymphangitis]. AB - The purpose of this report is to describe a case in which a heel ulcer with atypical features, i.e., large size and rapid progression, led to diagnosis of squamous cell carcinoma. Patient management was based on specialist advice obtained by "tele-dermatology" based on pictures and comments transmitted over the Internet. However, due to the risk of spreading and impossibility of providing other medical treatment (radiotherapy-chemotherapy), the lower limb was amputated at the top of the thigh. PMID- 21585104 TI - [Sciatica in a Tunisian teenager: pelvic hydatid cyst]. AB - The purpose of this report is to describe the case of a 13-year-old boy presenting typical sciatica leading to the discovery of primary pelvic hydatid cyst extending to the ischiatic bone. Diagnosis was suspected based on echography and magnetic resonance imaging and confirmed by surgical exploration. PMID- 21585105 TI - [Post-partum thunderclap headaches in a patient from Burkina Faso: reversible cerebral vasoconstriction syndromes]. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is considered as rare but is probably under-recognized. It is characterized by the association of acute severe headache and/or focal neurological deficits and/or seizures and segmental vasoconstriction of cerebral arteries that resolve within one to three months. The purpose of this report is to describe the first case of post-partum RCVS from Burkina Faso. Diagnosis of RCVS was based on clinical setting (post-partum), absence of vascular risk factor, sudden onset, rapid resolution of signs and symptoms within eight days, brain scan findings (spontaneous bilateral posterior low density areas of cerebral ischemia), and elimination of other possible causes, i.e., meningeal or cerebellar hemorrhage, cerebral venous thrombosis, HELLP syndrome. PMID- 21585106 TI - [Malaria and life at sea: prophylactic regimens on merchant ships]. AB - The purpose of this article is to describe requirements for protection/treatment of malaria on merchant ships. The first part of the article reviews recent data on the incidence of malaria in seagoing personnel. The second part provides advice on mosquito-bite prevention on merchant ships. The third part presents the most important information on prophylaxis for seafarers working in malarial risk areas. Several regimens are proposed. The last part of the article discusses curative treatment for malaria on merchant ships. PMID- 21585107 TI - [Hypertensive emergencies at the University Hospital Center in Brazzaville, Congo]. AB - The purpose of this retrospective study conducted in the emergency department of the University Hospital Center in Brazzaville, Congo was to determine the prevalence and clinical characteristics of hypertensive emergencies. With a total of 76 patients admitted during the study period, the prevalence of hypertensive emergency was 4%. The sex ratio was 1 and mean patient age was 57.3 years (range, 30 to 80 years). Risk factors included obesity in 62 cases (81.6%), history of hypertension in 65 (85.5%) and low socioeconomic level in 58 (76.3%). Mean delay for consultation was 50 hours (range, 1 to 240 hours). The disease underlying the hypertensive emergency was stroke with 38 cases (50%), heart failure in 20 (26.3%), hypertensive encephalopathy in 11 (14.4%), malignant hypertension in 9 (11.8%), and renal failure in 10 (13.1%). The mean length of emergency treatment was 14.7 hours (range, 5 to 48 hours). Eight deaths (10.5%) occurred during hospitalization in the emergency department. PMID- 21585108 TI - [Spondylodiscitis in Cote d'Ivoire: findings of computed tomography scan in 18 cases]. AB - The aim of this study was to document computed tomography (CT) scan findings and nosological characteristics in patients managed for spondylodiscitis in Abidjan, Cote d'Ivoire. This retrospective study was carried out over a two-year period (January 2006 to December 2007). A total of 18 cases of spondylodiscitis assessed in the radiology department of Yopougon Teaching Hospital in Abidjan were included. Mean patient age was 39.4 years. Seven patients (38.9%) had positive HIV serology. Mycobacterium tuberculosis was the main causative agent of spondylodiscitis accounting for 94.4% of cases. Only one case (5.6%) of pyogenic spondylodiscitis (staphylococcus aureus) was observed. The upper back was the preferential location (55.6%) of spondylodiscitis. Both discs and vertebral bodies were involved in all cases. Associated manifestations included balance impairment (dorsal kyphosis) (11.2%), soft tissue abscess (44.4%), vertebral compression (11.2%), epiduritis (16.7%), and medullar compression (16.7%). This study shows that CT scan not only plays a decisive role in early positive diagnosis of spondylodiscitis but also contributes to therapy by guiding biopsy to obtain samples necessary to identify the causal germ and assess disco vertebral involvement. Findings also show that most cases of spondylodiscitis in Abidjan are related to tuberculosis and located in the upper back. PMID- 21585109 TI - [Heterogeneous testicle on ultrasonography: consider tuberculosis after cancer in endemic zone]. AB - The purpose of this report is to describe findings of clinical examination and imaging in a 27-year-old man admitted for nonpainful left testicular enlargement. Initial diagnosis was testicular cancer based on ultrasonography and association with pulmonary metastasis. This diagnosis was revised after histological study demonstrated testicular tuberculosis. PMID- 21585110 TI - [Update on toxoplasmosis prevalence based on serological tests in pregnant women in Dakar, Senegal from 2002 to 2006]. AB - The purpose of this study was to update data on toxoplasmosis antibody prevalence based on antenatal surveillance tests in pregnant women in Dakar, Senegal. The study population consisted of 941 pregnant women referred for diagnosis of toxoplasmosis in the Laboratory of Parasitology and Mycology at Le Dantec University Hospital Center from 2002 to 2006. Two tests using the solid-phase immunoenzymatic method were performed on venous blood samples collected at 3 weeks of interval (S1 and S2). This double testing technique was designed to detect increases in IgM and IgG antibody levels in order to confirm diagnosis of toxoplasmosis by ruling out immune response, acquired immunity or nonspecific antibody fixation. Comparison of S1 and S2 results in the 941 patients indicated a prevalence of 7.7% and 0% respectively for IgM+IgG- cases, 23.3% and 24.3% respectively for IgM+IgG-cases, and 11.3% and 10.2% respectively for IgM+IgG+ cases. The overall prevalence of toxoplasmosis antibodies was 34.5%. These data showing a high prevalence of toxoplasmosis among pregnant women in Dakar underscore the need to improve serological screening and follow up. PMID- 21585111 TI - [Evaluation of the quality of malaria management during the transition period of political change in Benin]. AB - The purpose of this retrospective study in 2006 was to evaluate the impact of control activities implemented within the framework of "Roll Back Malaria (RBM) program" on the medical indicators. Study was based on review of the files of children between 0 and 14 years treated in pediatric outpatient or hospital facilities for malaria confirmed by the thick drop smears from January 1, 2001 to December 31, 2005. A total of 1589 files were reviewed. Data was collected using a standardized form. From 2001 to 2005, the number of children treated for uncomplicated malaria seesawed while the number treated for complicated malaria increased. Proper treatment of uncomplicated malaria went from 58.78% in 2001 to 15.38% in 2005. In all study years, quinine was the most-used drug for uncomplicated malaria. Treatment of complicated malaria also improved from 40% in 2001 to 90.61% in 2005. Although malaria-related mortality remained low (< 2%), the death rate increased from 2001 to 2005. Proper treatment of uncomplicated malaria still poses a challenge using quinine indicated in complicated malaria cases. Based on these findings, it appears urgent for the MNCP to intensify training activities at the medical facilities. This is the only means of achieving the strategic goals of "initiative RBM". PMID- 21585112 TI - [Visceral leishmaniasis, pemphigus and immunosuppressive treatment: case report from Morocco]. AB - Atypical forms of visceral leishmaniasis associated with immunosuppressive treatment are difficult to diagnose and cause high mortality. The purpose of this report is to describe a case involving a 42-year-old patient living in a leishmaniasis-endemic area, who was undergoing immunosuppressive treatment using corticosteroids and methotrexate for pemphigus. Despite clinical and laboratory findings consistent with visceral leishmaniasis, detection of Leishmania bodies was a coincidental finding of cytological examination of bone marrow during workup for pancytopenia and associated clinical signs. This case argues in favor of systematic screening for this opportunistic parasitic disease before undertaking immunosuppressive treatment in patients presenting risk factors and consistent clinical/laboratory findings. PMID- 21585114 TI - When the research subject is you. PMID- 21585115 TI - Focus Factor fiction? PMID- 21585116 TI - Intercomparison of gamma scattering, gammatography, and radiography techniques for mild steel nonuniform corrosion detection. AB - This paper focuses on the mild steel (MS) corrosion detection and intercomparison of results obtained by gamma scattering, gammatography, and radiography techniques. The gamma scattering non-destructive evaluation (NDE) method utilizes scattered gamma radiation for the detection of corrosion, and the scattering experimental setup is an indigenously designed automated personal computer (PC) controlled scanning system consisting of computerized numerical control (CNC) controlled six-axis source detector system and four-axis job positioning system. The system has been successfully used to quantify the magnitude of corrosion and the thickness profile of a MS plate with nonuniform corrosion, and the results are correlated with those obtained from the conventional gammatography and radiography imaging measurements. A simple and straightforward reconstruction algorithm to reconstruct the densities of the objects under investigation and an unambiguous interpretation of the signal as a function of material density at any point of the thick object being inspected is described. In this simple and straightforward method the density of the target need not be known and only the knowledge of the target material's mass attenuation coefficients (composition) for the incident and scattered energies is enough to reconstruct the density of the each voxel of the specimen being studied. The Monte Carlo (MC) numerical simulation of the phenomena is done using the Monte Carlo N-Particle Transport Code (MCNP) and the quantitative estimates of the values of signal-to-noise ratio for different percentages of MS corrosion derived from these simulations are presented and the spectra are compared with the experimental data. The gammatography experiments are carried out using the same PC controlled scanning system in a narrow beam, good geometry setup, and the thickness loss is estimated from the measured transmitted intensity. Radiography of the MS plates is carried out using 160 kV x-ray machine. The digitized radiographs with a resolution of 50 MUm are processed for the detection of corrosion damage in five different locations. The thickness losses due to the corrosion of the MS plate obtained by gamma scattering method are compared with those values obtained by gammatography and radiography techniques. The percentage thickness loss estimated at different positions of the corroded MS plate varies from 17.78 to 27.0, from 18.9 to 24.28, and from 18.9 to 24.28 by gamma scattering, gammatography, and radiography techniques, respectively. Overall, these results are consistent and in line with each other. PMID- 21585117 TI - SCOT Data: Deceased heart beating donor and organ transplantation in Saudi Arabia. PMID- 21585118 TI - NAMI documents large cuts in state mental health budgets, 2009 to 2011. PMID- 21585119 TI - Improved efficacy of prebiotic by flaxseed oil and horse chestnut in experimental colon cancer. AB - OBJECTIVES: This experimental work was designed to investigate the efficacy of prebiotic by itself and in combination with Hyppocastani extractum siccum, and Lini oleum virginale on selected parameters in rats with dimethylhydrazine induced colon cancer. METHODS: Rats were randomly divided into 5 experimental groups of 12 rats each. Rats were fed with high fat (HF) diet containing 10 % of fat, supplemented by prebiotic at a dose of 2 % of HF diet itself and in combination with Hyppocastani extractum siccum at a dose of 1 % of diet and Lini oleum virginale at a dose of 2 % of diet. Two weeks after the start of the diet dimethylhydrazine injections in dose 20 mg/kg b.w. were applied (DMH, Merck, DE), two times at week interval. The activity of beta-glucuronidase, concentration of lipid parameters, bile acids and short chain fatty acids were determined. RESULTS: Prebiotic and its combinations with selected substances significantly decreased the activity of bacterial enzyme beta-glucuronidase (p<0.001). Bile acids concentration was significantly decreased (p<0.01) excepting combination of prebiotic with Horse chestnut. Self applied prebiotic decreased (p<0.001) lipids parameters (total cholesterol and triacylglycerols), and enhanced short chain fatty acids production. CONCLUSION: Prebiotics have protective effect and may be the useful candidate agents for colon cancer prevention and treatment. The application of selected bioactive food components supported the effect of prebiotics (Tab. 2, Fig. 1, Ref. 16). Full Text in free PDF www.bmj.sk. PMID- 21585120 TI - Risk factor analysis for early mortality and morbidity following pneumonectomy for non-small cell lung cancer. AB - OBJECTIVES: The purpose of this report is to analyze factors affecting morbidity and mortality following pneumonectomy for non-small cell lung cancer (NSCLC). METHODS: We reviewed our institutional experience with all consecutive patients undergoing pneumonectomy for NSCLC from 1998 to 2010. Patients were analyzed with regard to hospital mortality and morbidity and long-term outcome. RESULTS: There were 310 patients following pneumonectomy. Overall 30-day mortality rate was 5.5 %. Chronic obstructive pulmonary disease, induction therapy, smoking habits and obesity had no statistical influence on short-term outcome. Coronary artery disease and respiratory failure were identified as risk factors for increased 30 day mortality (p<0.01). Right pneumonectomy and presence of respiratory failure with mechanical ventilation increases the incidence of bronchopleural fistula (p<0.01). CONCLUSIONS: Patients with right pneumonectomies are at increased risk. Coronary artery disease and respiratory failure adversely affect morbidity and mortality after this procedure (Tab. 3, Ref. 19). Full Text in free PDF www.bmj.sk. PMID- 21585121 TI - Preoperative staging of colon cancer patients: ultrasound can be a valuable alternative to computed tomography. AB - OBJECTIVE: The aim of this study was to compare the results of ultrasound and CT assessment in preoperative staging of colonic cancer, and to determine whether CT offers any benefits beyond ultrasound. PATIENTS AND METHODS: Sixty-one cases of intraperitoneal colon cancer were assessed by preoperative abdominal ultrasound and CT. The ultrasound and CT findings were assessed for ascites, hepatic and peritoneal metastases, invasion of adjacent organs, and findings of other diseases. RESULTS: The sensitivity rates of CT for liver metastases, adjacent organ invasion, ascites and peritoneal metastases were 81 %, 25 %, 29 % and 20 % respectively, while those of ultrasound were 69 %, 6 %, 43 % and 0%, respectively. Both methods had similar sensitivity, specificity and accuracy rates regarding the detection of all criteria. Ultrasound was more sensitive for detecting ascites and liver metastasis when compared to peritoneal metastasis and invasion (p<0.05). CT allowed the detection of liver metastasis to be more sensitive when compared to the other three criteria (p<0.05). In addition to ultrasound, CT gave no more additional knowledge indicating the necessity of altering the clinical management in patients. CONCLUSION: The first-line scanning technique should be the ultrasound and there is no need for CT scan, should no abnormalities be found upon ultrasound examination. CT investigation plays a role in cases where the ultrasound findings are suspicious (Tab. 1, Ref. 16). Full Text in free PDF www.bmj.sk. PMID- 21585122 TI - Time trend in the surgical therapy of lung cancer. AB - BACKGROUND: The purpose of our study was to clarify results of surgery for non small cell lung cancer (NSCLC) and its time trends. METHODS: We retrospectively reviewed our prospective database of patients who underwent surgery for NSCLC between 1998 and 2009 in our institution. Patients were divided into two equal 6 year periods according to the year of surgery (1998-2003 and 2004-2009). RESULTS: One thousand, four hundred and twelve patients underwent operation for NSCLC. We performed 985 lobectomies with 30-days mortality of 1.8 % and 300 pneumonectomies with 30-days mortality of 5.7 %. Median of survival of all 1412 patients was 4.3 year and 5-year survival was 45 %. The percentage of female patients, lobectomies and adenocarcinomas increased over time, as well as the age of our patients. Outcome improved over time, with significant decrease in a 30-days mortality after pneumonectomy (8.2 % vs 2.3 %, p=0.029). The overall 3-year survival improved in patients with stage III (30 % vs 40 %, p=0.012). CONCLUSION: Outcomes of lung resection for NSCLC improved over time despite a worsening of some elements of preoperative status. The shift in histological distribution was associated with an increasing proportion of patients with stage I, a lower operative mortality and better 3- and 5-year survival. These trends are due to improvement of preoperative evaluation, preoperative and postoperative care (Tab. 1, Fig. 2, Ref. 9). Full Text in free PDF www.bmj.sk. PMID- 21585123 TI - Influence of infection on clinical picture of diabetic foot syndrome. AB - The aim of our study was to analyse the foot infections in diabetic patients. We analysed foot ulcerations in 124 diabetics who attended outpatient foot clinic, or were hospitalized in the period from 1996 to 2006. Basic neuropathy screening examination was made with cotton wisp, pin-prick, tuning fork, and monofilament. For evaluation of leg ischemia, besides the evaluation of the presence of pedal pulses, the ankle-brachial pressure index was measured. If the infection of foot ulceration was clinically present, bacteriology examinations was performed. In the case of deep wound infection, x-ray examination was made. If bone destruction was present, osteomyelitis was diagnosed by technecium bone scanning and by technecium-labelled leukocyte scan. Deformation and destruction of the bone without infection was appoited as Charcot neuroarthropathy. Foot ulcer infection was found in 58 % diabetic patients, wounds were more often deep (80 %). Infection was not associated with special location of foot ulcer. Two-third of the total infected wounds were associated with leg ischemia and 30.6 % of infected ulcer ended with leg amputation. More foot ulcer infections were found in the diabetics with HbAlc over 8 %. Infection was coupled with diabetic retinopathy (in 63 % patients) (p=0.023), and also with diabetic nephropathy (in 66 % patients) (p=0.012). Bacteriology examination revealed most often Staphylococci (45.8 %), antibiotic therapy was made most often with chinolones. Osteomyelitis was present in 34.7 % of foot ulcer infections. In 14 diabetics (56 %) after antibiotic therapy it was not necessary to perform a leg amputation. HbAlc seems to be a significant predictor of osteomyelitis (p<0.02; OR=1.76). In conclusion, we confirmed that diabetic foot infections, especially on ischemic leg, in diabetics with poor metabolic control and chronic diabetic microvascular complications, are associated with a higher risk of leg amputations. Further, it is possible to cure osteomyelitis successfully without surgery in more than half the cases (Tab. 1, Ref. 24). Full Text in free PDF www.bmj.sk. PMID- 21585124 TI - DNA analysis of Y chromosomal AZF region in Slovak population with fertility disorders. AB - BACKGROUND: The Y chromosome is characterized by a low number of functional genes, relatively high number of repetitive sequences and the ability of recombination purely by short arms of telomeres PAR1 and PAR2. The long arm contains an AZF region with genes participating in spermatogenesis. Microdeletions of three subregions, namely AZFa,b,c and their mutual combinations are responsible for male infertility and the resulting azoospermia and oligospermia. OBJECTIVES: The aim of this study based on evaluating 822 patients during a period of ten years was to analyse types of microdeletions in men with fertility disorders in Slovakia. METHODS: For detecting the microdeletions in Y chromosomal AZF region and for identifying the Y-specific sequences we used PCR while using three different sets of sY sequences. REPORTS: We reported 38 cases of deletions in AZF region, namely 18 cases when using the first set of sequences, 12 cases when using the second set, and finally 8 cases when using the third set. When using the last set of sequences according to the European Academy of Andrology and European Molecular Genetics Quality Network, we detected deletions only in patients with azoospermia. In addition to deletions in each of AZF a,b,c subregions we recorded also a complete deletion of the whole AZF region. In the AZFa subregion, we recorded a deletion of sequence sY86. CONCLUSION: The study has confirmed that the detection of microdeletions of AZF region is significant from the diagnostic and prognostic views (Tab. 5, Ref. 21). Full Text in free PDF www.bmj.sk. PMID- 21585125 TI - Previous pregnancy history, parity, maternal age and risk of pregnancy induced hypertension. AB - OBJECTIVE: The influence of antepartal, intrapartal and early neonatal risk factors, are very important during the pregnancy and the pregnancy outcome, also for the early neonatal period and the forthcoming children development. Our aim is to detect the risks groups of pregnant women that later develop Pregnancy Induced Hypertension (PIH) and risk factors that precede its appearance. PATIENTS AND METHODS: We examined 67 preeclamptic and 129 normotensive pregnancies. In research are included only single pregnancies and the following parameters: maternal age, parity and previous pregnancy history. RESULTS: Average age is 25.73+/-5.77 years. After all, the largest number of primipara with preeclampsia is in category from 20 years (p<0.01). Considering the multipara we noticed that preeclampsia is most commonly developed in age between 31-35 years (p<0.01). Biggest number of pregnancies in normotensive group had previous normal pregnancies (59.15 %), while in hypertensive group only 30.77 % patients had normal pregnancies (p<0.05). CONCLUSIONS: PIH is most frequently appearing in young primiparas and adult multiparas. Pregnancies with PIH, really often there were negative ending of previous pregnancies (Tab. 5, Ref. 20). Full Text in free PDF www.bmj.sk. PMID- 21585126 TI - Clinical value of cystatin c determination in children with lymphoma. AB - Cystatin, a proteinase inhibitor, is involved in the intracellular catabolism of proteins. We investigated the change in concentration of serum Cystatin C (CysC) in children with lymphomas and its diagnostic utility. Twenty-eight newly diagnosed patients with lymphoma were included in this study. The male/female ratio was 20/8, with a median age of 8.5 years (range 3-17 years). Thirteen patients had Hodgkin's lymphoma (HL) and 15 had non-Hodgkin's lymphoma (NHL). Cystatin C concentration was determined at the time of diagnosis and during remission. In the entire group, CysC concentrations at diagnosis and during remission were 0.87+/-0.29 mg/L and 0.86+/-0.21 mg/L, respectively (p=0.93). In the NHL group, CysC concentrations at diagnosis and remission were 0.89+/-0.32 mg/L and 0.85+/-0.23 mg/L, respectively (p=0.73). The CysC concentrations in the HL group at diagnosis and remission were 0.88+/-0.36 mg/L and 0.88+/-0.18 mg/L, respectively (p=0.73). No significant difference was observed between CysC concentrations in the HL (0.88+/-0.36 mg/L) and NHL (0.89+/-0.32 mg/L) groups. Cystatin C concentrations in all the patients with localized versus those with advanced disease were 0.91+/-0.41 mg/L and 0.88+/-0.3 mg/L, respectively (p=0.83). Cystatin C concentrations of the patients with localized and advanced HL were 0.95+/-0.45 mg/L and 0.77+/-0.14 mg/L, respectively, (p=0.41). Cystatin C level was higher in patients with localized disease, in those without B symptoms, and, at diagnosis, in those with an unfavorable response (Tab. 2, Ref. 20). Full Text in free PDF www.bmj.sk. PMID- 21585127 TI - The effect of medication costs on physicians' drug selection. AB - BACKGROUND: To determine the physicians' knowledge of medication costs and its effect on drug selection. METHODS: The study was conducted between April 2007 and June 2007 on 245 physicians providing healthcare at outpatient clinics of different institutes at the city center of Ankara, Turkey. The data were collected by using questionnaires designed to obtain demographic characteristics of physicians, and assess factors affecting their drug selection based on knowledge of substances, producers and costs of five commonly prescribed commercial drugs. RESULTS: A total of 245 physicians responded, while 53 (21.6 %) were general practitioners, 145 (59.2 %) were resident physicians and 47 (19.2 %) were specialists. Of 1,225 medications that were commonly prescribed, the physicians knew the substance of 1,072 (87.5 %) medications and producers of 565 (46.1) medications. The costs of all drugs were overestimated or underestimated by physicians with a difference of 21.9 %. The factor most significantly affecting the drug selection was drug efficiency (39.4 %) whereas its cost had little effect (11.6 %). A significant difference was found among physicians in respect of the effect of insurance/legal limitations and producer of medication on drug selection (p=0.002, p=0.004, respectively). There were also significant differences in drug selection among institutes. CONCLUSIONS: It was determined that the physicians did not pay attention to the cost of drugs, were unaware of their prices, and prescribed expensive drugs instead of cheap ones even though the latter were available (Tab. 3, Ref. 16). Full Text in free PDF www.bmj.sk. PMID- 21585128 TI - Treatment approaches in tubo-ovarian abscesses according to scoring system. AB - BACKGROUND: The aim of this study was to define treatment modalities in tubo ovarian abscesses (TOA) using a scoring system. As there is no scoring system for TAO there is still a controversy on the management. In our opinion, as there is no evidence based TAO management strategy, a scoring system is needed in the management of these patients. For this purpose we prospectively tried to define that may be useful for favoring a treatment modality and the effects of the parameters on the outcome. METHODS: The study group comprised of hundred and eighty-four patients hospitalized between May 2001 and June 2008. Patients were divided in three groups according to the treatment modality--laparotomy (group 1, n: 122), medical treatment, (group 2, n: 34), and laparoscopic surgery (group 3, n: 28). Antibiotic regimens or other means of treatment strategies were directed according to our scoring system. RESULTS: Of the patients, 122 underwent laparatomy, 34 received medical treatment and 28 had operative laparoscopy. Intraoperative complications in the group of 122 patients who underwent laparatomy were bowel injury in 8 patients (6.5%) and ureteral injury in six (4.9 %). Fourteen patients (11.4 %) in the laparatomy group suffered from morbidity related to abdominal incision. In the laparoscopy group two patients (7.1 %) had bowel injury. CONCLUSION: With this study, we propose a scoring system in TOA cases and define treatment strategies accordingly. According to the results of our study, laparoscopy serves the best treatment option. Medical treatment, despite longer follow up, may be suitable in well-selected cases (Tab. 3, Ref. 39). Full Text in free PDF www.bmj.sk. PMID- 21585129 TI - The efficacy of supervised physiotherapy for the treatment of adhesive capsulitis. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy of supervised physiotherapy supplemented with non-steroidal antiinflammatory drugs (NSAIDs) for treating adhesive capsulitis. BACKGROUND: Even though adhesive capsulitis is a common disorder, literature on its treatment is still limited. METHODS: Forty five patients with adhesive capsulitis treated between 2004 and 2007 were reviewed retrospectively and 29 patients were enrolled in the study. All patients received a supervised physiotherapy program supplemented with NSAIDs. The outcome variables were determined as passive range of motion (ROM) values and intensity of shoulder pain. The clinical assessment was performed at the initial visit and immediately after physiotherapy. One to four years after the supervised physiotherapy, the resolved patients were reevaluated. RESULTS: The mean age of patients was 55.4+/-9.2 years. Fifteen patients (51.7 %) were women and 14 (48.3 %) were men. The average length of supervised physiotherapy was 3.5+/-0.5 weeks. After physiotherapy, the shoulder flexion, abduction and external rotation significantly increased (p<0.001) compared with the initial values. Additionally, shoulder pain significantly decreased (p<0.001). In the follow-up, 25 (86.2 %) of 29 patients were resolved with physiotherapy, whereas 4 (13.8 %) patients required capsular release operation because of residual functional impairment. As to long-term results of patients resolved with physiotherapy, 45.4 % of cases were cured with less than a 10 % loss in total passive ROM of the shoulder, 22.7 % of cases with a total ROM loss between 10 and 20 %, 18.1 % of cases with a total ROM loss from 20 to 30 %, and lastly, 13.6% of cases with a total ROM loss up to 40 %. CONCLUSIONS: Supervised physiotherapy supplemented with NSAIDs improves the ROM values in most of patients with adhesive capsulitis. A small percentage of patients may require operative treatment (Tab. 2, Fig. 1, Ref. 23). Full Text in free PDF www.bmj.sk. PMID- 21585130 TI - Immunologic and psychosocial status in chronic fatigue syndrome. AB - OBJECTIVE: The aim of the study was to investigate the immunologic functions and psychosocial status in patients with chronic fatigue syndrome (CFS). METHODS: Twenty-five patients with CFS diagnosed by the international CFS definition criteria and 20 age- and gender-matched healthy controls were recruited. Depression was assessed by Beck Depression Inventory (BDI) and health status was assessed by Nottingham Health Profile (NHP). Monoclonal antibodies (MAbs) were measured to identify the following NK cell subsets: CD3, CD4, CD8 and CD56 and cytokine measurements were performed for IL2r, IL6 and IL8 in both patients and control subjects. RESULTS: The BDI and NHP scores of CFS group were found to be significantly higher than in the control group. The absolute numbers of CD56 cell were also significantly decreased in the patients with CFS compared with the healthy controls. There were no other significant differences of NK cell activity (CD3, CD4 and CD8) and there were significant differences in IL6 and IL2r levels between patients and controls. There were significant correlations between serum IL-6 level and sleep, social isolation and physical ability NHP subscores, and betweenCD56 NK cell activity and emotional reaction NHP sub score in CFS patients. CONCLUSION: Significantly higher ratios of psychological and physical disturbances were found in patients with CFS. Decreased CD56 NK cell activity and increased IL2r levels seem to be important immunopathologic changes in CFS. IL-6 and CD 56 NK cell activity may play an important role in sleep, physical, social, and physicological manifestations of CFS (Tab. 3, Fig. 1, Ref. 36). Full Text in free PDF www.bmj.sk. PMID- 21585131 TI - Daily timing of salivary cortisol responses and aerobic performance in lean and obese active females. AB - The main aim of the present study was to study the effects of morning and afternoon physical activities on cortisol responses in obese and lean women. Twenty women volunteered to participate in this study. Subjects were divided into an obese group (BMI =29.1 kg/m2) and a lean group (BMI =19 kg/m2). All subjects participated in an exercise program consisting of treadmill running at 65+/-2 % VO2max until exhaustion. In order to study effects of circadian rhythm, exercise was performed at a similar intensity and in similar environmental conditions at both 8:00 AM and 4:00 PM. Saliva specimens were collected at rest 20 minutes before activity and then immediately after the exercise in both morning and afternoon sessions. Morning and afternoon exercise resulted in a significant increase in salivary cortisol concentrations compared to basal levels in both lean and obese women (p<0.05), though the change in cortisol concentrations were higher in lean. The aerobic function of lean and obese women in the morning and afternoon showed a significant increase of 13.8 % and 5.9 %; respectively, with lean being consistently higher than obese. In conclusion, the stress response to exercise is related to circadian rhythm and individual's body weight. Based on the results of this study, it is suggested that overweight women perform exercises in the afternoon to minimize the stress response for the exercise volume performed (Tab. 1, Fig. 3, Ref. 39). Full Text in free PDF www.bmj.sk. PMID- 21585132 TI - Exogenous surfactant as a component of complex non-ECMO therapy of ARDS caused by influenza A virus (2009 H1N1). AB - During the pandemy caused by novel influenza A virus (subgroup H1N1), a significant number of patients became critically ill from respiratory failure. In the most severe cases of primary pneumonia, patients develop refractory hypoxemic acute respiratory distress syndrome (ARDS) with typical computed tomographic findings of multi-lobar alveolar opacities and extremely reduced pulmonary airspace. To reduce the risk of injurious ventilation and promote survival, some authors recommend the use of extracorporeal membrane oxygenation (ECMO). Unfortunately, ECMO is expensive, associated with serious complications, and available at very few centers. Other therapeutic options are clearly needed. Here we report three patients with severe influenza pneumonia who recovered following treatment with porcine surfactant (Tab. 1, Fig. 3, Ref. 6). Full Text in free PDF www.bmj.sk. PMID- 21585134 TI - Communication key to reducing disruptive behaviors. PMID- 21585133 TI - Effects of cardiac resynchronization therapy on sleep apnea, quality of sleep and daytime sleepiness in patients with chronic heart failure. AB - BACKGROUND: Sleep-related breathing disorders are common in patients with chronic heart failure (CHF) and contribute to exacerbation of CHF. The effects of biventricular stimulation (CRT) seem to exceed the improvement of mechanical heart performance and are likely to affect other aspects of CHF pathophysiology. The aim of the study was to assess the influence of CRT on subjective and objective sleep features. MATERIAL AND METHODS: Twenty seven consecutive patients (aged 67.7 +/- 8.7 years, 23 men - 85%) with chronic heart failure (62.9% with ischaemic background and 37.1% of non-ischaemic etiology) in stable for at least 3 months NYHA class III - IV despite optimized pharmacotherapy, with left ventricular end-diastolic diameter (LVEDd) > 55 mm, left ventricular ejection fraction (LVEF) < or = 35% and wide QRS complex (> or = 120 ms) were appraised before and 12-16 weeks after CRT introduction clinically (including 6-minute walk test--6-MWT), echocardiographically and in polisomnography. The apnea-hypopnea index (AHI) and apnea indexes (AI) of central, obstructive and mixed types were calculated. The sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI), daytime sleepiness with the Epworth Sleepiness Scale (ESS). RESULTS: LVEF increased, 6-MWT distance rose. Left ventricular diameters and left ventricular end-systolic volume decreased. PQSI and ESS fell (9.3 +/- 4.2 vs 6.2 +/- 3.2, p < 0.001 and 8.4 +/- 4.1 vs 7.0 +/- 3.4, p < 0.001, respectively). AHI, obstructive AL and mixed AL did not alter but significant reduction of central AL was noted (9.6 +/- 13.0 vs 3.7 +/- 6.2, p = 0.023). CONCLUSIONS: CRT decreases central sleep apnea and improves quality of sleep and daytime sleepiness in patients with CHF. PMID- 21585135 TI - How to measure success of communication. PMID- 21585136 TI - The new push for reliability. PMID- 21585137 TI - Accreditation field report. PMID- 21585138 TI - Readmissions costly, impact quality of life. PMID- 21585139 TI - A technical platform for future success. AB - Authorising Engineers (Decontamination), a group of highly skilled individuals acknowledged as lacking an effective representative professional body over the past decade by Graham Stanton, the chairman of a new IHEEM Decontamination Technical Platform (DTP) established recently to promote their professional interests, have much both to contribute to, and to gain from, the new Platform, he, and the body's secretary, Brian Kirk, explained to HEJ editor Jonathan Baillie at a recent meeting in London. PMID- 21585140 TI - Landfill alternative offers powerful case. AB - With many of Europe's landfill sites now close to capacity, and the EU Landfill Directive requiring that, by 2020, the amount of waste sent to landfill should be just 35% of the volume similarly disposed of in 1995, pressure is mounting to find environmentally acceptable waste disposal alternatives. At a recent IHEEM waste seminar, Gary Connelly, a technical consultant at environmental technology consultancy the Cameron Corporation, described a technology which he explained can effectively convert 85% of the European Waste Catalogue of materials into an inert residue, is "cleaner and cheaper" than incineration, and can generate both electricity an waste heat. As HEJ editor Jonathan Baillie reports, a key target market is healthcare facilities. PMID- 21585113 TI - Detecting non-maxwellian electron velocity distributions at JET by high resolution Thomson scattering. AB - The present work is motivated by a long standing discrepancy between the electron temperature measurements of Thomson scattering (TS) and electron cyclotron emission (ECE) diagnostics for plasmas with strong auxiliary heating observed at both JET and TFTR above 6-7 keV, where in some cases the ECE electron temperature measurements can be 15%-20% higher than the TS measurements. Recent analysis based on ECE results at JET has shown evidence of distortions to the Maxwellian electron velocity distribution and a correlation with the TS and ECE discrepancies has been suggested. In this paper, a technique to determine the presence of non-Maxwellian behavior using TS diagnostics is outlined. The difficulties and limitations of modern TS system designs to determine the electron velocity distribution are also discussed. It is demonstrated that small deviations such as those suggested by previous ECE analysis could be potentially detected, depending on the spectral layout of the TS polychromators. The spectral layout of the JET high resolution Thomson scattering system is such that it could be used to determine these deviations between 1 and 6 keV, and the results presented here indicate that no evidence of non-Maxwellian behavior is observed in this range. In this paper, a modification to the current polychromator design is proposed, allowing non-Maxwellian distortions to be detected up to at least 10 keV. PMID- 21585141 TI - Authorising engineer's 'pivotal role' explained. AB - Graeme Dunn, engineer, Design and Engineering at Atkins, who serves as an Authorising Engineer (MGPS) for both NHS clients and healthcare providers throughout the UK, Ian Sandford, a medical gas consultant (associate) at Hulley Specialist Gas Services, a specialist division of consulting engineers Hulley and Kirkwood, and Alex Black, an experienced technical consultant and AE (MGPS), of Alex Black and Associates, examine how the AE (MGPS) role developed, and highlight what they describe as its "pivotal importance" today. PMID- 21585142 TI - Sloping site proves bonus, not barrier. AB - Speed of construction, with significantly less disruption to on-site activity, and continuity of a wide range of orthopaedic surgery, coupled with excellent prior experience of the modular build specialist's expertise at the site, led the project team for a suite of four new orthopaedic operating theatres at the Leicester General Hospital to again select Stockport-based MTX Contracts for the job. As HEJ editor Jonathan Baillie reports, last November's completion of the pound 6.5 million theatre complex means the University Hospitals of Leicester NHS Trust will no longer, in the face of growing demand, need to send some 600 patients annually to private hospitals in the area for their operation. PMID- 21585143 TI - Mapping out a 'greener' future. AB - Addressing a 220-strong audience at London's Barts Hospital at the launch of a new NHS Sustainable Development Unit (NHS SDU) publication, Route Map for Sustainable Health, senior NHS and NHS SDU speakers highlighted the magnitude of the challenge faced by the service over the next 5-40 years in meeting its carbon reduction targets, and set out how the new "Route Map" could provide important pointers to help all in the healthcare arena operate more sustainably in the broadest sense. HEJ editor Jonathan Baillie reports. PMID- 21585144 TI - Inspiring facility fuses a century of change. AB - Creating a 21st Century mental healthcare facility which would soon be world renowned both for its quality of care, and for the high standard of its buildings, was the overriding goal of the project team behind the new pound 75 million, 312-bed Roseberry Park mental healthcare facility in Middlesbrough. HEJ editor Jonathan Baillie visited the new PFI facility to discover more about the sizeable new mental healthcare "village", which was highly commended at the 2010 Building Better Healthcare Awards, from MAAP Architects lead designer and director Raechal Ferguson, and project director at the Tees, Esk and Wear Valleys (TEWV) NHS Foundation Trust John Ord. PMID- 21585145 TI - Fund offers support and expertise. AB - Clive Nattrass, programme director for the Carbon and Energy Fund (CEF), describes how the Fund can potentially help NHS Trusts seeking to upgrade and improve their infrastructure to reduce their carbon footprint, and thus make useful energy savings, to secure the necessary finance. He outlines the steps that Trusts interested in obtaining CEF funding need to take, and explains the key timelines over the next 3-4 years. PMID- 21585146 TI - Keeping a cool head over medicine storage. AB - Many medicines can be destroyed by storage and transportation at the wrong temperature. Joe Fudge, service manager at ABB Measurement Products, examines how proper monitoring supports best practice. PMID- 21585147 TI - Microfibre barrier laundry adds value. AB - London's Guy's and St Thomas' NHS Foundation Trust has installed a complete barrier laundry system from Electrolux Professional at its St Thomas' Hospital location for specialist washing of an estimated 7,000 microfibre cloths and 5,000 microfibre mops each day from both the St Thomas' and Guy's Hospital sites. Since the installation, as Electrolux Professional national account manager Kurt Fryer reports, the "cost-effective" equipment's high performance has seen laundry staff achieve a significant increase in productivity. PMID- 21585148 TI - Mid-term clinical outcome of critical limb ischemia after infrapopliteal bypass surgery. AB - OBJECTIVE: Critical limb ischemia caused by peripheral arterial occlusive disease of the infrapopliteal segment is best managed by bypass surgery with an autogenous vein conduit. Yet there remains confusing heterogeneity in the strategy, utilization, techniques, and outcomes in current practice. We reviewed our 7-year experience of infrapopliteal bypass surgery to analyze early and mid term clinical outcomes. METHODS: From May 2003 through May 2010, 63 bypasses to the infrapopliteal artery were performed in 59 patients. This comprised 32.4% of the 194 infrainguinal arterial reconstructions performed during that period. RESULTS: Of the 63 bypasses, 57 were performed with an autologous vein and 6 with a composite graft. For the autologous vein bypasses, a single-segment great saphenous vein (GSV) was used in 39 bypasses, which included 23 reversed, 5 in situ, and 11 non-reversed free grafts. "Spliced" vein grafts, constructed by splicing the GSV or lesser saphenous veins (LSV) together, were utilized in 18 bypasses. No deaths occurred within 30 days of surgery. Two patients (3.5%) died while hospitalized . Five grafts failed within 30 days of surgery due to thrombosis or bleeding. The primary graft patency, secondary graft patency, amputation-free survival (AFS) and overall survival were 73.7%, 82.4%, 84.7%, 88.1%, respectively at 1 year and 65.4%, 76.3%, 71.0%, 74.6% at 3 years. When patients were divided into groups based on the presence of end-stage renal disease on hemodialysis (HD), the 3-year secondary patency, AFS, and overall survival were 82.5%, 49.2, 49.2% in the HD group and 74.1%, 84.2%, 88.8% in the non-HD group. The overall survival in the HD group was significantly worse compared with the non-HD group. CONCLUSION: Infrapopliteal arterial bypass is a safe, durable and highly effective procedure in patients with CLI, with excellent mid-term patency and amputation-free survival. Renal insufficiency may be associated with a poorer limb salvage rate and long-term survival. PMID- 21585149 TI - Minimally invasive thyroid surgery in children. AB - OBJECTIVES: As the prevalence of thyroid nodules and thyroid cancer increases, thyroid surgery is being performed in a growing number of pediatric patients. Minimally invasive thyroid surgery may be particularly beneficial in this patient population. Smaller incisions result in improved cosmesis in this young, predominantly female group, and minimal-access techniques better preserve tissue planes--an advantage, because of younger patients' higher lifetime likelihood of reoperation. METHODS: For this case series with planned data collection, Institutional Review Board approval was obtained to analyze a prospective database and assess outcome data. The outcome measures included pathologic classification, cosmetic results, rates of complications (especially hypocalcemia), true vocal fold paralysis, and the need for admission or readmission. RESULTS: We performed 495 thyroidectomy procedures during the study period (February 2003 to May 2008). Of these, 23 were in patients less than 21 years of age. The mean incision length was 3.3 +/- 1.0 cm (range, 1.5 to 5.0 cm), and 12 of the incisions (52.2%) were 3 cm or shorter. Nine patients (41%) had thyroid cancer, most commonly papillary carcinoma (compared with 21.9% of the adult population). There were no hematomas and no cases of permanent true vocal fold paralysis or permanent hypocalcemia. Two patients (8.7%) had temporary hypocalcemia, and both required readmission. CONCLUSIONS: Minimally invasive thyroid surgery has benefits over conventional thyroid surgery, particularly in a pediatric population. Among its many potential advantages, the social stigma of a large incision is reduced and preservation of tissue planes is improved. PMID- 21585150 TI - Eustachian tube function in adults without middle ear disease. AB - OBJECTIVES: We sought to develop normative values for 5 eustachian tube function (ETF) test protocols in adults without otitis media (OM). METHODS: Twenty adults (19 to 48 years of age) without a recent history of OM (5 had OM in childhood) underwent unilateral myringotomy and were evaluated for ETF by use of the forced response, inflation, deflation, forcible "sniff", and Valsalva test protocols. When possible, these tests were repeated on a second day. RESULTS: Normative values for the parameters of these protocols in adult subjects without a recent history of OM were developed. Between-day data for the forced response test were highly correlated. A percentage of these tests showed eustachian tube "constriction" during swallowing--an abnormal condition. The percent reduction in applied pressures for the inflation and deflation tests was high, indicative of good ETF. Few subjects had a positive "sniff" test, whereas most had a positive Valsalva test, and the results for both tests were effort-dependent. CONCLUSIONS: Results of ETF tests in adults with and without recent OM have not been published. Normative data are now available for comparison with ETF test results in adults with OM. These protocols will be used to evaluate the efficacy of surgical procedures designed to improve ETF. PMID- 21585151 TI - Prevalence of insomnia and impact on quality of life among community elderly subjects with tinnitus. AB - OBJECTIVES: We sought to determine the prevalence of insomnia and its impact on the quality of life (QoL) among community elderly subjects (at least 65 years of age) with subjective tinnitus. METHODS: After household selection with multistage stratified area probability sampling, face-to-face interviews were used to obtain self-reports of subjective tinnitus and insomnia, and QoL was assessed with the WHOQoL-Bref instrument. RESULTS: Among 1302 elderly subjects, there were 183 subjects (109 female and 74 male) with tinnitus. Among those with tinnitus, insomnia was encountered in 95 (51.9%) and was found to be significantly more common among those with tinnitus than among those without (378 of 1119, or 33.8%; p = 0.002). The insomnia symptoms included difficulty in maintaining sleep in 73.4% of subjects, difficulty in falling asleep in 70.0%, early morning wakefulness in 64.3%, nonrestorative sleep in 35.1%, and daytime sleepiness in 34.7%. Univariate analysis revealed difficulty with falling asleep (p = 0.01) and early morning wakefulness (p = 0.05) to be significantly associated with tinnitus among the symptoms. Student's t-test and logistic regression analysis revealed significant deterioration in the total QoL and in the physical, psychological, social, and environmental QoL domains among elderly subjects who had tinnitus with insomnia as compared with those without insomnia. CONCLUSIONS: We believe that insomnia is significantly more common among elderly subjects with tinnitus than among those without, and that its presence further depreciates the QoL in these elderly individuals. PMID- 21585152 TI - Analysis of functional and anatomic success following endonasal dacryocystorhinostomy. AB - OBJECTIVES: The aim of this study was to assess the concomitant perioperative procedures, the causes of nasolacrimal duct obstruction, the success rate, and the complications associated with endonasal dacryocystorhinostomy (ENDCR). METHODS: In this single-center retrospective study, 98 patients underwent 104 ENDCRs between January 1994 and February 2006. There were 78 patients with 84 nasolacrimal duct obstructions who were included in this study. RESULTS: The overall functional success rate with improvement in symptoms was 94.9% for primary surgery (59 of 84 obstructions) and 63.6% for salvage surgery after failure of primary surgery performed in another hospital (25 of 84 obstructions). The mean follow-up time was 36.8 +/- 17.11 months. Primary surgery showed better results, with a complete success rate of 93.2%, than did salvage surgery, with a success rate of only 68%. Persistent symptoms, despite an open rhinostomy, were found in 1.7% of patients with primary surgery and in 12% of those with salvage surgery. Failure of ENDCR was observed in 3.4% of patients after primary surgery and in 20% after salvage surgery. We encountered only minimal perioperative complications, and these were essentially related to lacrimal intubation. CONCLUSIONS: Because of the possibility of treating concomitant sinonasal disorders, the cosmetic advantages, and the excellent results, ENDCR represents the procedure of choice for treating nasolacrimal duct obstructions. The main challenge lies in the exact preoperative assessment, as well as postoperative evaluation in case of failure. PMID- 21585153 TI - Vibratory asymmetry in mobile vocal folds: is it predictive of vocal fold paresis? AB - OBJECTIVES: The purpose of this study was to determine whether the videostroboscopic finding of vibratory asymmetry in mobile vocal folds is a reliable predictor of vocal fold paresis. In addition, the ability of experienced reviewers to predict the distribution (left/right/bilateral) of the paresis was investigated. METHODS: This is a retrospective chart review of all patients who presented to our clinic during a 3-year period with symptoms suggestive of glottal insufficiency (vocal fatigue or reduced vocal projection) accompanied by the videostroboscopic findings of bilateral normal vocal fold mobility and vibratory asymmetry. Twenty-three of these patients underwent diagnostic laryngeal electromyography of the thyroarytenoid and cricothyroid muscles to determine the presence of vocal fold paresis. RESULTS: Nineteen of the 23 patients (82.6%) were found to have electrophysiological evidence of vocal fold paresis, either unilaterally or bilaterally, when videostroboscopic asymmetry was present in mobile vocal folds. However, the three expert reviewers' ability to predict the distribution (left/right/bilateral) of the paresis was poor (26.3%, 36.8%, and 36.8%, respectively). CONCLUSIONS: The videostroboscopic finding of vibratory asymmetry in mobile vocal folds is a reliable predictor of vocal fold paresis in most cases. However, the ability of expert reviewers to determine the distribution (left/right/bilateral) of the paresis using videostroboscopic findings is poor. This study highlights the value of laryngeal electromyography in arriving at a correct diagnosis in this clinical situation. PMID- 21585154 TI - Audioprofile-directed successful mutation analysis in a DFNA2/KCNQ4 (p.Leu274His) family. AB - OBJECTIVES: We undertook to show that in a family with nonsyndromic autosomal dominant sensorineural hearing loss, genetic analysis can be successful when there is a match with a specific DFNA audioprofile. We also provide an update of relevant DFNA2/KCNQ4 audioprofiles and report the results of automatic audioprofile analysis using the Internet program AudioGene. METHODS: Audiometric data and blood samples were obtained from the family W08-0384. Based on the audiograms of the affected participants, mutation analysis of KCNQ4 was started. Original audiometric threshold data were collected for all identified KCNQ4 related DFNA2 families. The Internet computer program AudioGene, recently developed for automatic audioprofile analysis, was accessed. RESULTS: The family's audioprofile and the program AudioGene predicted the DFNA2/KCNQ4 locus. Mutation analysis of KCNQ4 revealed a c.821T>A (p.Leu274His) mutation of the KCNQ4 gene. This mutation has been previously identified in a Dutch family. Genetic analysis revealed a common haplotype in these two families over a region including the KCNQ4 gene. CONCLUSIONS: Familiarity with the audioprofiles of DFNA traits may lead to successful mutation analysis of the gene involved, even in a small family in which genetic linkage analysis is not an option. Alternatively, the specially developed program AudioGene can be accessed on the Internet to perform automatic audioprofile analysis of a family's (audiological) phenotype. PMID- 21585155 TI - Potential nerve damage following contact with a piezoelectric device. AB - OBJECTIVES: The aim of the study was to assess the extent of the potential nerve damage following prolonged contact with a piezoelectric device. METHODS: The study was conducted with 30 patients; all of the patients had cervical metastatic lymph nodes at levels II, III, and IV (N2b) and a negative evaluation for metastatic disease (MO). The patients underwent radical neck dissection. After its skeletonization, the spinal nerve was exposed directly to ultrasonic activation with a piezoelectric device for various times (5, 10, and 20 seconds) and with different inserts (OP3 insert and OT7 insert). The axonal damage was graded from 0 to 3 as follows: 0, no damage; 1, minor axonal damage; 2, severe axonal damage but not covering the entirety of the nerve fascicles; 3, severe axonal damage covering the entirety of the nerve fascicles. RESULTS: Histologic examination showed no evidence of damage to the perineurium and axons after 5 and 10 seconds of exposure to ultrasonic activation with each insert. CONCLUSIONS: Our histologic data highlight the selective action of the piezoelectric device, which reduces the risk of accidental nerve damage in otolaryngological bone surgery. PMID- 21585156 TI - Comparative case series of exostoses and osteomas of the internal auditory canal. AB - Exostoses and osteomas are benign bony lesions of the auditory canal. Although common in the external auditory canal, they are rare and difficult to distinguish in the internal auditory canal (IAC). In this literature review and case presentation, we define radiologic and histologic criteria to differentiate exostoses from osteomas of the IAC. Two patients with exostoses and 1 patient with an osteoma of the IAC are described here. Patient 1 presented with disabling vertigo and was found to have bilateral exostoses with nerve impingement on the right. After removal of the right-sided exostoses via retrosigmoid craniotomy, the patient had complete resolution of her symptoms over 1 year. Patient 2 presented with bilateral pulsatile tinnitus and vertigo and was found to have bilateral IAC exostoses. Patient 3 presented with hearing loss and tinnitus, and a unilateral IAC osteoma was ultimately discovered. Because of the mild nature of their symptoms, patients 2 and 3 were managed without surgery. We show that IAC osteomas can be differentiated from exostoses by radiographic evidence of bone marrow in high-resolution computed tomography scans, or by the presence of fibrovascular channels on histologic analysis. Management of these rare entities is customized on the basis of patient symptoms. PMID- 21585157 TI - Facial nerve dehiscence and cholesteatoma. AB - OBJECTIVES: We evaluated the incidence of facial nerve dehiscence in a group of patients with cholesteatoma who underwent otologic surgery. METHODS: We performed a retrospective study in a tertiary referral hospital of 336 patients (298 adults, 38 children) with cholesteatoma who underwent surgery in the years 1998 to 2008. Using intraoperative findings, we assessed the incidence of facial nerve dehiscence in a group of patients with cholesteatoma. We quantified, in adult versus pediatric patients and in primary versus revision surgeries, the occurrence of facial nerve dehiscence, the predisposed anatomic sites, and the coexistence of semicircular canal fistula. In a selected group of 67 patients, preoperative 0.55-mm collimation computed tomography (CT) scans were compared with the intraoperative findings. RESULTS: The frequency of facial nerve dehiscence in this group of patients was 27.1%. The dehiscence was detected in 29.5% of the adults, but in only 7.8% of the patients 16 years and younger. Dehiscence was present in 42.3% of the patients who underwent revision surgery. The most common site of dehiscence (92.3%) was the tympanic segment. The sensitivity and specificity of CT were 69% and 87%, respectively. CONCLUSIONS: Dehiscence of the facial nerve was found in 27.1% of patients with cholesteatoma, with a significant difference between patients of pediatric and adult ages. A dehiscent facial nerve was more commonly seen during revision surgery and more frequent in patients older than 16 years. The site of dehiscence most frequently involved by cholesteatoma was the tympanic segment. The presence of a semicircular canal fistula increases the risk of facial nerve dehiscence. Finally, the results of preoperative CT scans are encouraging for the use of CT in predicting facial nerve dehiscence. PMID- 21585158 TI - School performance and behavior of Korean elementary school students with sleep disordered breathing. AB - OBJECTIVES: It is known that children with sleep-disordered breathing (SDB) often have accompanying growth retardation and learning and behavior disabilities. However, these results are based mainly on studies of children from European and North American countries. The objective of this study was to investigate the school performance and behavior of Korean children with SDB. METHODS: We enrolled 302 third-grade elementary students from an elementary school in Seoul. A survey was conducted, using information from the children's parents for the diagnosis of SDB. The children's height, weight, midterm examination scores, and behavioral disturbances were analyzed. RESULTS: Overall, 299 parents returned the survey. Of the 299 students, 29 (9.7%) were considered to have SDB. They showed no difference from the control in terms of body mass index. The mean examination score was higher in the control group than in the SDB group. However, there was a statistical difference only in social science. The prevalences of students who were inattentive (58.6% versus 23.7%) and lacking in self-control (44.8% versus 14.1%) were significantly higher among students with SDB. CONCLUSIONS: SDB is not closely associated with poor school performance among Korean elementary students. However, behavioral disturbance is more frequent among the students with SDB than in those without. PMID- 21585159 TI - Olfactory ensheathing cells in a rat model of laryngeal reinnervation. AB - OBJECTIVES: Olfactory ensheathing cells have been used successfully for recovery of nervous system lesions. The aim of our study was to determine whether olfactory ensheathing cells from the olfactory bulb or olfactory mucosa were able to improve functional recovery in a laryngeal reinnervation animal model. METHODS: Fifty-nine rats were divided into 6 groups. A group without nerve section (group 1; n=10) and a group without anastomosis (group 2; n=11) served as controls. Right vagus nerve section and immediate anastomosis (nonselective reinnervation) was performed in 4 other groups, as follows. In group 3 (n=10), there was selective reinnervation without any addition of substance; groups 4 (n=10), 5 (n=10), and 6 (n=8) received, on the section and anastomosis site, and at the same time, cultivated olfactory bulb, cultivated olfactory mucosa, and noncultivated olfactory mucosa from inbred rats, respectively. Three months later, videolaryngoscopy with vocal fold movement measurements, electromyography, and histologic examination were performed. RESULTS: The best right vocal fold angular movement (3.05 degrees +/- 1.14 degrees) was observed in group 5 with cultivated olfactory mucosa, versus group 3 (-0.28 degrees +/- 1.51 degrees; p = 0.06). The relative angular vocal fold movement was better in group 5 (p = 0.05). The mobility score was 0.6 +/- 0.27 for group 3 and 1.4 +/- 0.31 for group 5 (p = 0.07). Less synkinesis was observed in the reinnervated groups with cell addition, particularly with noncultivated olfactory mucosa (group 6; p = 0.05). CONCLUSIONS: Olfactory ensheathing cells obtained from olfactory mucosa cultures seem to improve functional laryngeal reinnervation in a rat model of nonselective vagus nerve section and anastomosis. PMID- 21585160 TI - Crystal/cell interaction and nephrolithiasis. AB - Crystals of calcium oxalate (CaOx), the major constituents of most urinary stones, are injurious to cells, create oxidative stress and evoke an inflammatory response. Renal injury results in cell damage. The damaged and dead cells are released into the urine and are capable of promoting crystal nucleation at much lower supersaturations. Damaged cell membranes also provide sites for crystal attachment and eventual retention within the kidneys. Renal epithelial damage may assist in movement of crystals from the intratubular to interstitial location and perhaps in the formation of apatitic Randall's plaques. Inflammatory response may be responsible for Randall's plaques ulceration to the renal papillary surface. PMID- 21585161 TI - Treatment of small lower pole calculi--SWL vs. URS vs. PNL? AB - According to current guideline recommendations extracorporeal shock wave lithotripsy (SWL) remains the first choice treatment for small and mid-sized renal calculi. However, the results of SWL treatment for lower pole stones can be disappointing whilst more invasive endoscopic modalities, such as flexible ureterorenoscopy (fURS) and percutaneous nephrolithotomy (PNL) are often considered more effective. This article summarizes a point-counterpoint discussion at the 9th eULIS symposium in Como, Italy, and discusses the potential advantages and disadvantages of the different therapeutic approaches. PMID- 21585162 TI - Ureteral stones: SWL treatment. AB - When stone removal is indicated SWL (Shock Wave Lithotripsy) and ureteroscopy (URS) are the two most commonly offered interventional procedures and they are both acceptable as first-line treatment. The choice of the procedure depends on several factors, including local experience, patient preference, available equipment, and associated costs. The meta-analysis by the EAU/AUA Guideline Panel in 2007 analysed SWL stone-free results for three locations in the ureter (proximal, mid, distal) and reported an overall stone-free rate for proximal ureteral stones of 82%, with no difference in stone-free rate from URS results. However, for stones < 10 mm SWL, at 90%, had a higher stone-free rate than URS and even for mid and distal ureter it reached a stone-free rate of 84% and 86% respectively. It does appear that SWL may be more effective in the paediatric subset than in the overall population, particularly in the mid and lower ureter with a stone free rate of 82% and 80% respectively. In fact, children appear to pass stone fragments after SWL more readily than adults. SWL is a safe method to treat ureteral stones and serious complications occur very rarely when proper indications are followed. A few published studies addressed the role of SWL in acute renal colic. The available data suggest that is a safe procedure, with an overall success of 70-80% and a need for further intervention in 2-20%. In choosing the optimal therapy for an individual patient, several factors that might affect the outcome should be considered to identify the best candidate for SWL. A superior success rate for proximal ureteral stones was reported in the EAU/AUA meta-analysis but stone size over 10 mm appears negatively correlated with the stone-free rate. About composition, calcium oxalate monohydrate, brushite, cystine and matrix are unfavourable compositions for SWL. Finally, impacted stones are often more resistant to fragmentation. Whether hydronephrosis affects the outcome of SWL remains controversial. A body mass index of over 30 has been found to be an independent factor in predicting failure of SWL treatment in ureteral stones. A number of treatment strategies have been proposed to increase SWL efficacy: a promising suggestion to improve SWL outcome is to reduce the shock wave rate. There have also been attempts to improve shock wave efficiency of stone fragmentation with new shock wave lithotriptor devices. But although these innovation are promising, no advantage in stone-free rate or retreatment rate have yet been proven. Acoustic coupling is a key factor affecting the efficacy of shock wave lithotripsy. An accurate pre-treatment assessment of stone burden and composition with unenhanced CT scan provides useful information to discern which treatment strategy should be favoured and may reduce SWL failure. The real cost for SWL and URS varies considerably from one centre to another, as a result of different internal organisations and also due to the principles of reimbursement from the health care system. CONCLUSIONS: SWL is the first treatment choice for stones smaller than 1 cm in the proximal ureter With a lower grade of invasiveness and the possibility to complete the treatment with only analgesics and sedation on an outpatient basis, SWL still appears an excellent alternative for removing ureteral stones and these properties compensate for the higher need for repeated treatments. An accurate pre-treatment assessment of stone and clinical factors to select the best candidates for SWL could improve the stone-free rate and reduce retreatments. PMID- 21585163 TI - Predicting five-year recurrence rates of kidney stones: an artificial neural network model. AB - OBJECTIVE: Due to high recurrence rates of urolithiasis, many attempts have been performed to identify tools for predicting the risk of stone formation. The application of Artificial Neural Networks (ANNs) seems to be a valid candidate for reaching this endpoint. The aim of this study was to find a set of parameters able to predict recurrence episodes immediately after clinical and metabolic evaluation performed at the first visit in a 5-year window. MATERIAL AND METHODS: Data were collected from 80 outpatients who presented idiopathic calcium stone disease both at baseline and after 5 years; patients underwent treatment including both general measures and medical therapy. After 5 years, patients were classified into two subsets, namely SSFs (without recurrence episodes), consisting of 45 subjects (56.25%) and RSFs, with at least one episode of recurrence after the baseline, consisting of 35 subjects (43.75%). Helped by conventional statistics (One-way ANOVA and three Discriminant Analyses: standard, backward stepwise and forward stepwise), an Artificial Neural Network (ANN) approach was used to predict recurrence episodes. RESULTS: An optimal set of 6 parameters was identified from amongst the different combinations in order to efficiently predict the outcome of stone recurrence in approximately 90% of cases. This set consist of serum Na and K as well as Na, P, Oxalate and AP (CaP) index from urine. The results obtained with ANN seem to suggest that some kind of relationship is present between the identified parameters and future stone recurrence. This relationship is probably very complex (in the mathematical sense) and non-linear In fact, a Logistic Regression was built as a comparative method and performed less good results at least in terms of accuracy and sensitivity. CONCLUSIONS: The application of ANN to the database led to a promising predicting algorithm and suggests that a strongly non-linear relationship seems to exist between the parameters and the recurrence episodes. In particular, the ANN approach identifies as optimal parameters serum concentration of Na and K as well as urinary excretion of Na, P, Oxalate and AP (CaP) index. This study suggest that ANNs could potentially be a useful approach because of their ability to work with complex dynamics such as recurrent stone formation seems to have. PMID- 21585164 TI - Prognostic estimation of chemical composition of recurrent urinary stones. AB - We conducted a retrospective study of the course of recurrent urolithiasis in 127 patients (63 women, 64 men aged from 27 to 58) who were under close and regular outpatient follow-up for up to 15 years and who did not receive conservative prophylactic therapy due to different reasons. The group consisted of 33 patients with uric acid lithiasis, 52 patients with calcium oxalate lithiasis, 42 patients with magnesium-ammonium-phosphate lithiasis. By the start of follow-up not a single patient had had urinary stones detected by ultrasound and X-ray. For the period of observation there were up to 7 recurrences diagnosed in each patient and we studied the chemical composition not only of the primary stones but also of 352 recurrent stones by means of infrared spectrophotometry and X-ray diffraction. In our investigation we also performed biochemical and microbiological analysis and urinalysis. We established the chance and we found prognostic factors of changes in the type of stone formation in patients with different chemical forms of the disease. In patients with uric acid lithiasis recurrent stones can be composed of calcium-oxalate or phosphate, in patients with calcium-oxalate lithiasis recurrent stones could be composed of phosphate, and patients with magnesium-ammonium-phosphate stones may develop stones of uric acid or calcium-oxalate. PMID- 21585165 TI - The role of long-term loading of cholesterol in renal crystal formation. AB - We studied the effects of cholesterol load on urinary stone in rats receiving a standard diet or a high fat diet. Sixty male rats were randomized to two groups and were fed either a standard diet (SD group) or a high fat diet (HFD group) for 8 weeks. Then the two groups were further divided into four groups. SD group, HFD group, SD + EG group (with standard diet + ethylene glycol administration for two weeks), and HFD + EG group (with high fat diet + ethylene glycol administration). The starting date of EG administration was considered to be week 0. Twenty-four hour urine samples were collected in week 0, week 1, and week 2, and oxalate excretion and citrate excretion were measured by capillary electrophoresis analyzer The excretion of phosphorus, magnesium, and creatinine for 24 hours was measured using an automated analyzer Serum sodium, potassium, chloride, calcium, phosphate, magnesium, creatinine, total cholesterol, triglyceride, HDL cholesterol and glucose were determined using an automated analyzer The kidney tissues were obtained to perform hematoxyline-eosine staining and Pizzolato's staining to detect oxalate-containing crystals. The average body weight in HFD groups and HFD + EG group in week 0 was significantly higher than that of SD group and SD + EG group. The calcium oxalate crystal deposition was not observed in all groups in week 0. HFD + EG group in week 1 had sporadically calcium oxalate crystal deposition in renal distal tubular cells and tubular lumens. In week 2, the number of crystal deposition in HFD + EG group was increased remarkably. The crystals were slightly observed in SD + EG group in week 2. The excretion of urinary calcium and phosphate in HFD group and HFD + EG group was significantly higher than that of the SD group and SD + EG group in week 0. The amount of urinary citrate excretion in the SD group and SD + EG group showed a significantly higher value compared with that of the HFD group and HFD + EG group in week 0. The level of serum total cholesterol in the HFD group and HFD + EG group was higher compared to that in the SD group and SD + EG group. The serum triglyceride level was not significantly different in the four groups in week 0. Interestingly, the level of triglyceride of EG administration groups (SD + EG and HFD + EG group) was significantly higher than that in EG no-administration groups (SD group and HFD group) in week 1 and week 2. The serum glucose level in the HFD group and HFD + EG group was significantly higher than that in the SD group and SD + EG group in week 0. In week 2, the glucose level of EG administration groups (HDF + EG group and SD + EG group) was significantly lower than that of EG no administration groups (HFD group and SD group). In conclusion, this result suggested that long-term loading of cholesterol could increase renal calcium stone formation. PMID- 21585166 TI - Effect of sex hormones on crystal formation in a stone-forming rat model. AB - Sex hormones have substantial effects on crystal formation in the rat kidney through oxalate metabolism and oxidative cell damage. Testosterone is a promoter and estradiol an inhibitor of such crystal formation. The development of new medications related to sex hormones or GO are anticipated for sufferers of recurrent urolithiasis. PMID- 21585167 TI - The role of functional urodynamic disorders in the pathogenesis of urolithiasis. AB - OBJECTIVE: The aim of this study was to analyze the functional urodynamic parameters, which affect renal function and can promote stone formation. MATERIALS AND METHODS: We examined sixty consecutive patients with renal and ureteral stones and indication to urinary diversion by nephrostomy tube or indwelling catheter In upper urinary tract, urodynamics was assessed with the help of electromanometry and multichannel impedance ureterography. To measure ureteral peristalsis, a probe equipped with 9 successively incorporated electrodes was indwelled retrogradely into distal ureter through a urethroscope. The documented data included renal pelvic pressure (RPP) and the number of ureteric contractility parameters such as peristalsis amplitude, peristalsis rate, the ureteral wall tone, the characteristics of contractile waveform and its direction (antegrade or retrograde). Urinary biochemistry and enzymuria were studied in order to characterize the lithogenic activity and renalfunction. The patients were divided into three groups: group 1 included patients with acute pyelonephritis caused by unilateral stone obstruction (n = 24), group 2 patients with stones and non-acute latent chronic pyelonephritis (n = 31) and group 3 unobstructed patients without signs of inflammation (n = 5). RESULTS: In the three groups of patients, the mean baseline RPP values were, respectively 28.7 +/ 2.6 (range 20.0-32.4); 15.6 +/- 1.9 (range 3.5-29.0); and 3.6 +/- 1.4 (range 0 8) cm H2O. The ratio of GGT to urinary creatinine changed similarly: it was elevated during acute inflammation, moderately enhanced during the chronic process, but significantly decreased after stone removal and resolution of inflammation (11.5 +/- 3.2; 8.1 +/- 2.0, and 1.6 +/- 0.5 unit/L). Biochemical evaluation revealed 54% patients with enhanced lithogenic activity assessed by elevated calcium and oxalates in the urine (4.95 +/- 0.25 mM and 504 +/- 35 microM, correspondingly) and low level of citrates (2.5 +/- 0.1 mM). In a subgroup of 11 patients with urolithiasis the baseline RPP values were assessed in relation to ureteral contractile activity in the distal region of ureter. Low RPP was found in a patient (9%) with strong ureteral contractions and a low tone while RPP was moderately higher in another patient (9%) with moderate mean peristaltic amplitude value but with elevated tone of ureteral wall. In the majority of examined patients with significantly elevated mean RPP value (45%), peristalsis of distal ureter was characterized by weak long-term and frequent contractions as well as increased tone with respect to the patients with normal RPP. The patients (36%) with moderately increased RPP demonstrated strong frequent contractions in the distal ureter and low ureteral wall tone. Changes in urodynamic parameters in patients examined before and immediately after ureteroscopy and lithotripsy procedures were observed. Factors affecting the ureteral wall tone were duration of stone disease, location and disposition of stones. CONCLUSIONS: Our clinical observations obtained with the help of physiological methods revealed various factors modulating the urodynamic disorders in renal pelvis: temporary or persistent elevation of pelvic pressure; peculiarities of contractile function in distal ureter manifested by the tonic changes and variations in contractile amplitude, and certain abnormalities in propagation of contractile wave in the upper urinary tract. The reported urodynamic changes in patients with stone disease can be supplementary pathogenic factors causing deterioration of renal function probably followed by stone formation. PMID- 21585168 TI - Evaluation of methods for urine inhibitory potential for precipitation of calcium oxalate. AB - Renal lithiasis is a significant medical and social problem. Worldwide recurrence is anywhere from 3% to 5%. Objective of this paper is to evaluate two methods for distinguishing between stone formers and non-stone formers. Urine samples were titrated with calcium and seed crystals were added to facilitate precipitation. Ionic calcium levels were monitored and compared between the two groups. Stone formers showed impaired tolerance to the calcium added and increased precipitation on seed crystals. Both methods discriminated between stone formers and non-stone formers. Further evaluations are needed to establish the better of the two for wider clinical use. PMID- 21585169 TI - Nephrolithiasis in medullary sponge kidney. AB - Seventy-one patients with documented Medullary Sponge Kidney (MSK) and nephrolithiasis underwent complete metabolic evaluation. These patients constituted 7.3% of our calcium stone-forming population Metabolic anomalies (hypercalciuria, hyperoxaluria, hypocitraturia and hyperuricosuria) were observed in 82% of patients. No patient was hypercalcemic and none had hyperparathyroidism. Thus the patients with medullary sponge kidney and renal stones had the same spectrum of metabolic anomalies as the overall population of idiopathic stone formers. Although these patients may have anatomic anomalies which determine stasis of urine and infection causing stone formation, they should be evaluated and treated appropiately for any metabolic defect. PMID- 21585170 TI - Increasing water intake by 2 liters reduces crystallization risk indexes in healthy subjects. AB - OBJECTIVE: The objective of the present study was to evaluate the effects of drinking 2 additional litres of water/day on several urinary risk factors for lithiasis in healthy subjects, through measurement of crystallization risk indices (Tiselius CRI). MATERIALS AND METHODS: 48 healthy subjects, aged 25 to 50 were studied for urinary parameters including CRI in the laboratory ward, for 24 hours. After this first period, they were randomized either to a 2L/d additional water intake (treated group) or usual fluid consumption (control group) for a 6 days period, which ended by a second measurement period in the laboratory ward for 24 hours. RESULTS: Total additional water intake was actually 1.3L/d on average in treated subjects, because subjects decreased other usual sources of fluid intake. In 24 hour urine, Tiselius CRI varied differently among treated subjects and controls between the 2 periods; male controls subjects experienced much higher values (above 2 in average in first morning urine sample) in the second period (p = 0.05). Of interest, in a transversal analysis, we observed a positive relation between BMI or waist circumference on the one hand, and with 24 hour urea excretion or osmotic load on the other hand. CONCLUSION: These results show a beneficial effect of a final 1.3L additional water intake on Tiselius CRI in healthy subjects. PMID- 21585171 TI - Ureterolithiasis in children. AB - The aim of our work is to present our own experience in the field of urolithiasis treatment in children using ureteroscopic lithotripsy. PMID- 21585172 TI - Diagnostic difficulties with estimation of the cause of nephrolithiasis. Case presentation. AB - In some patients with recurrent urolithiasis we cannot identify the cause of stone formation. A 18 years old girl was evaluated for recurrent urolithiasis. Analysis of her stones demonstrated: calcium oxalate and 10% cystine; calcium phosphate and traces of magnesium and chloride, calcium phosphate and traces of potassium and calcium oxalate and ammonium-magnesium phosphate. We failed to make a correct etiological diagnosis despite of a very broad spectrum of laboratory investigations. PMID- 21585173 TI - Stenting after ureteroscopy for ureteral lithiasis: results of a retrospective study. AB - OBJECTIVES: Routine ureteral stenting after ureteroscopy for stone removal is common. However ureteral stent negatively impact quality of life and can cause significant morbidity. This study was carried out to report our experience. MATERIALS AND METHODS: A total of 529 patients underwent ureteroscopy for the treatment of ureteral stones. In 436 pts (82%) a stent was placed, in 281 double J (removed within 2-4 weeks) and in 155 mono J (removed within 24 h). Ninethy three did not received stenting. At 24 hour the mesaured outcomes were post operative pain, fever and hematuria, at 4 weeks need for hospital care (readmission or visit in the clinic) for lower urinary tract symptoms (LUTS), hematuria, fever or pain. RESULTS: No significant difference was observed between two groups regarding the complications at 24 hour after the treatment ( pain p = 0.6, fever = 0.7, hematuria p = 0.8). At 4 weeks after the ureteroscopy the incidence of LUTS, hematuria, pain and fever requiring the need for hospital care (readmission or visit in the clinic) was higher in the group with double J stent respect to the group with mono J stent (p < 0.05). At 3 months follow-up no difference was oberved between the two groups regarding stone-free rate and incidence of ureteral stricture formation. CONCLUSIONS: Routine stenting is necessary after ureteroscopy for ureteral lithiasis to prevent pain and fever without difference in stone free rate and incidence of stricture formation rate between the two groups. LUTS, hematuria and/or pain needing for hospital care were more frequent in the group with double J stent in spite of high stone free rate and low incidence of stricture formation. Further prospective randomized studies are needed to assess the role of using "short" and "long-term" stenting after ureteroscopy lithotripsy, considering that the choice actually depends on the surgeon's intraoperative judgment. PMID- 21585174 TI - The management of erectile dysfunction: innovations and future perspectives. AB - Phosphodiesterase 5 (PDE5) inhibitors are recommended as first line therapy for the treatment of erectile dysfunction (ED). To date, three PDE5 inhibitors are on the market: sildenafil, vardenafil and tadalafil. These compounds are available as oral tablets; they are rapidly absorbed in the gastrointestinal tract and are excreted mainly in the fces and to a lexer extent in the urine. Recently, an orodisnersible formulation of feces and, to a lesser extent, in the urine. Recently, an orodispersible formulation of vardenafil (vardenafil ODT) has been developed, which is able to dissolve in the mouth within seconds, releasing a minty flavor, without the need of being swallowed with water. The clinical studies so far performed showed that vardenafil ODT has a bioavailability superior to the traditional film-coated tablet. Among the other PDE5 inhibitors under development we report mirodenafil, lodenafil carbonate, avalafil and SLx 2101 It is likely that in the future molecules that act on pathways other than the one of NO/cGMP will be available. Such as Rho-kinase inhibitors, which inhibit the mechanism that leads to smooth muscle contraction thus allowing erection and hydrogen sulphide (H2S), an endogenous molecule synthesized from cysteine that can be both a vasodilator and a vasoconstrictor according to its concentration. PMID- 21585175 TI - Prostate cancer and androgen deprivation: optimal castration? Prospects and developments. AB - Prostate cancer (PCa) therapy has always been connected with the problem of what optimal male castration is and how to achieve and control it. Optimal medical castration should follow quite the same characteristics as surgical castration, then it should allow testosterone levels to be quickly and permanently reduced to levels ranging between 12 and 20 ng/dl. It should also be pointed out that using luteinizing hormone-releasing hormone (LHRH) agonists does not result in immediate castration; castration occurs 2-4 weeks after the first injection. Furthermore testosterone levels could also increase after subsequent injections if the depot formulation does not adequately cover the period between injections, as some LHRH receptors can remain free. This results in a new testosterone surge in conjunction with the following injections. Such episodes of increased testosterone levels in vicinity with injections are known as "miniflares". Yet, also persistently increased testosterone levels (> 50 ng/dl) might be shown, even under continuous treatment with LHRH analogues. Such increases are known as "late breakthrough escapes". A depot formulation of leuprolide acetate using a novel delivery system provides steady blood levels above the threshold of 0.1 mg/ml and completely suppresses pituitary gonadotropin secretion. PMID- 21585176 TI - Electrophysiological assessment of cognitive processes in young healthy adults with different level of physical activity. AB - AIM: Physical activity has been promoted as a factor that has beneficial influence on brain functions, including cognition. The aim of this study was to detect whether subjects with different levels of physical activity (PA) have different electrophysiological response during cognitive paradigm that includes the processes of expectation, attention and learning. MATERIAL AND METHODS: The study comprised 100 subjects, aged between 17 and 28 years, who were divided into three groups according to the level of general physical activity: with low, moderate and high level of PA. Electroexpectogram (EXG) paradigm is a dynamic CNV paradigm in which the registered evoked potential is a neurophysiological measure of the level of attention and cognitive performance during the paradigm. Parameters derived from these tests are the general EXG parameters that refer to the entire paradigm (number of EXG cycles, maximal and minimal amplitude of the CNV potential and reaction time) and specific EXG parameters that refer to the characteristics of each and every EXG cycle, their amplitude and duration (expressed in number of trials). RESULTS: Subjects with high and moderate level of PA created EXG curves with a greater number of cycles than subjects with a low level of PA. The mean value of the number of created EXG cycles (Low PA = 2.27; moderate PA = 2.73; high PA = 3.8) and maximal amplitude of CNV (Low PA = 9.42 microV; moderate PA = 10.3 microV; high PA = 10.43 microV) was not statistically significant in subjects with different level of PA. The participants with a high and a moderate level of PA showed a distinct tendency of decreasing the dimensions of the EXG cycles: after the long and high first cycle, all subsequent cycles gradually shortened in duration (number of trials) and in height (CNV amplitude). The results of this investigation have emphasized the specific EXG parameters as sensitive indices for successful cognitive adaptation in a dynamic electrophysiological setting created by the EXG paradigm. PMID- 21585177 TI - The role of predictor factors in patients with non Hodgkin lymphoma in relation to the applied therapy. AB - Lymphoma are defined as malignant neoplasms of immune system, or in other words the neoplasms of lymphocytes and their precursory cells which form the basic cellular elements of the immune system. The heterogeneity of lymphoma from the aspect of morphology and the aspect of clinical manifestations demanded the identification of all possible parameters which could influence the course and outcome of the disease on every single level. The aim of our study was to investigate which of the prognostic factors confirms the statistical importance of the remission state and overall survival and if the patients treated with standard PHT (poly chemotherapy) protocols with the addition of anti-CD20 antibody show more clinical benefit. PATIENTS AND METHODS: Considering the applied protocol, patients were divided in two groups: group of patients treated with PHT protocol CHOP (Cyclophosphamide, Adriamycin, Oncovin, Pronison) and the group treated with PHT protocol with the addition of anti-CD20 antibody (Rituximab). RESULTS: There was no statistically significant difference in values of Karnofsky score between patients in CHOP and CHOP+R groups before the therapy (U=133; Z = -1.87; p = 0.06), although this difference was on the border of statistical significance. The values of Karnofsky score before and after the therapy in CHOP group showed no significant difference (Wilcoxon Z = -1.62; p = 0.11), but CHOP+R group pointed significant differences before and after the treatment, (Wilcoxon Z = -2.34; p = 0.02) with generally higher values after the therapy. Looking from the aspect of B-symptomatology in CHOP group, there was a significant reduction of B-symptoms (50%; %95 CI = 19-50; p = 0.002) after the therapy (7/20; 35%) in comparison with patients before the therapy (17/20; 85%). According to those results, the reduction of symptoms in CHOP +R group was more evident (60%; 95% CI = 28-60; p < 0.001) after the therapy (3/20; 15%) comparing to the state before the therapy (15/20; 75%). Comparison of LDH values in the complete sample demonstrated that the value of LDH before the therapy was significantly higher (Z = -3.76; p < 0.001). There was a significant difference in number of patients in relation to the category of IPI prognostic index (chi2 = 10.38; df=3; p < 0.02), pointing out most of the patients with low intermediary risk in CHOP+R group, and largest number of patients with high and high intermediary risk in CHOP group. PMID- 21585178 TI - The frequency of complications of pseudoaneurysms after cardiac interventional diagnostic and therapeutic interventions. AB - Pseudo aneurysms as complications are a major source of morbidity after cardiac catheterization. Their incidence varies in the literature due to different definitions, methods of interrogation and presence of certain complications. We found in the literature that post-catheterization lesions occur in approximately 0.05% of treated patients after diagnostic catheterization and up to 1.2% after more complex procedures. The aim of this retrospective study was to determine the incidence of pseudo aneurysm after cardiac catheterization using the physical findings and color Doppler ultrasound. In the study, which encompasses the period of 2009-2010, there were 400 coronary angiography with trans femoral catheterization. After compression hemostasis was carried out, each patient was checked after 24 hours and again after 48 hours. Diagnostic coronary angiography was made in 400 patients (100%), out of which, 110 patients (27,5%) had a percutaneous coronary intervention with stent placement (PCI), Color Doppler ultrasound of femoral artery was normal in 384 (96.3%), local hematoma was found in 360 (90%), pseudo aneurysm in 14 (3.7%), AV fistula in 1 (0.25%) and dissection of the femoral artery in 1 (0.25%) patient. Complications in 16 patients were treated surgically, in 7 patients they were treated conservatively and in 1 case thrombin was applied within pseudo aneurism. Patients with complications were more often present with concomitant use of anticoagulant and anti platelet tablets than patients without complications (P = 0.003). Prevention of post catheterization pseudo aneurysm can be achieved by proper puncture technique, choosing the right place and right post interventional hemostatic compression with or without external devices. Special attention should be paid to the use of anti platelet drugs and anticoagulant and combinations thereof. PMID- 21585179 TI - APACHE II scoring system is superior in the prediction of the outcome in critically ill patients with perforative peritonitis. AB - BACKGROUND: There are several scoring systems used in the prediction of outcome in critically ill patients. This study was undertaken to evaluate APACHE II, SAPS I, Sepsis score, MOF, TISS-28 and MPI scoring systems in prediction of the outcome in patients with perforative peritonitis. PATIENTS AND METHODS: The prospective study of 145 patients of both sexes with perforative peritonitis was performed. The main outcome of study was peritonitis-related death. Variables necessary for calculation of the scoring systems were recorded at the initial admission to the hospital and the third and seventh day of hospitalization, except Mannheim Peritonitis Index, which was calculated during the first 24 hours after hospitalization. Cut-off points were specified and all values greater than cut-off points were taken to predict death. Sensitivity and specificity are graphically shown for the different values of cut-off points and represented with the receiver-operating characteristic curve. The difference in the area below the curve between scoring systems was statistically compared. RESULTS: The area under the curve for the first postoperative day was 0.87 for TISS-28 score, 0.86 for APACHE II score, 0.83 for MOF and SAPS I, 0.72 for MPI and 0.70 for Sepsis score. This demonstrated that TISS-28 and APACHE II are significantly better than other systems (p < 0.01). In addition, this discriminatory ability remained on the third and seventh postoperative day as well. The highest rate of correlation between the observed and the expected mortality rate for the first (Kendall's tau correlation 0.964) and the third day (Kendall's scorrelation 0.810) was in APACHE II system. CONCLUSION: APACHE II is superior in prediction of the outcome to other tested scoring systems. PMID- 21585180 TI - Extracorporeal shock wave lithotripsy and intravenous contrast media application for localization of radiolucent calculi. AB - BACKGROUND AND PURPOSE: The present study was carried out to compare the efficacy of ESWL treating radiolucent ureteric calculi visible in the ureter after application of contrast media. MATERIAL AND METHODS: Medical records of 47 patients who had verified ureteric calculi by intravenous urography and retrograde pyelography were included in this study. Patients had undergone ESWL treatment after application of contrast media. Patients were divided in two groups, different in focusing the shock waves either at the end and below contrast shadows of the column of contrast medium visible in the ureter. 23 patients from group 1 were treated with shock waves focused on the end of contrast medium column and 24 patients from group 2 were treated with shock waves focused below contrast shadow of the contrast column. RESULTS: The stone free rate after 1 month were 9% and after 3 months were 14% greater in group 2 (89%) than in group 1 (75%). There were no allergic reactions to the contrast medium. Distributions of age, gender, treatment and diagnostic methods had been in both groups compared. CONCLUSION: ESWL of radiolucent ureteric calculi with application of contrast media is effective and safe. Shock waves focused below contrast shadow of the contrast column had better stone free rate than focusing at the end of the column. PMID- 21585181 TI - Follow-up of acute aortic dissection. AB - INTRODUCTION: Aortic dissection is a tear in the wall of the aorta. It is a medical emergency. If left untreated the mortality rate is extremely high. Aortic dissection is divided into two types, A and B. Primary, because of low suspicion the diagnosis can delay. The natural history is poorly understood. OBJECTIVES: Our objectives were to improve diagnosis of aortic dissection. To encourage use of trans esophageal echo cardiography in emergency room. To clarify the role of prompt treatment in prognosis of aortic dissection. METHODS: This study was approved by the Committee of Ethics. All of the patients signed a informed consent. Clinical evaluation was performed by expert cardiologists, using different modalities. A complete medical history and physical examination were performed. The follow-up time of patients was 24 months. RESULTS: Eleven patients were included in this study. Male/female ratio was 2.7:1. Type A was present in 7 patients, hypertension in 9. All patients were symptomatic. Three patients died, two in the emergency center, one after surgery. Surgery was performed in five patients, all with type A dissection. Four survived patients after operation and all patients with type B dissection survived follow-up time of 24 months. CONCLUSION: Most crucial step in aortic dissection diagnosis remain clinical suspicion. It should be confirmed rapidly since it is lifesaving. We want to emphasize that the trans esophageal echo cardiography is very useful exam to make the diagnosis which is the key for correct treatment and for follow-up. It must be widely available in the emergency centre. PMID- 21585182 TI - The effect of loneliness on malnutrition in elderly population. AB - INTRODUCTION: The clinical and epidemiological data show that proper nutrition plays an important role in maintaining health and combating the danger of developing some chronic diseases in the elderly population. Nutrition is an important factor in many physiological and pathological changes that accompany the aging process. More than 50% of elderly patients are suffering from malnutrition which is information that concerns. Due to various factors, older people are potentially vulnerable groups at risk of malnutrition. Loneliness, isolation from society and neglect of parents by children is a big problem to many people in old age. OBJECTIVE: To determine differences in nutritional status of elderly people living alone compared to those who live in family surroundings. SUBJECT AND METHODS: The study was conducted in the municipality of Tuzla in 2009 2010, in outpatient family medicine Simin Han. The survey covered a total of 200 elderly subjects (age >65 years). Subject group consisted of 45% of people living alone, and 55% control group consisted of elderly patients who live in traditional family surroundings. Questionnaires used in this study are General geriatric assessment questionnaire and Mini nutritional status. RESULTS: The average age (+/- SD) was 75.4 +/- 6.2 years in subject group, while the same in the control group was 74.9 +/- 5.6 years. In subject group significantly more patients are on the verge of poverty. There are significant differences in the classification of financial status, according to the groups (p = 0.043). Members of subject groups have significantly lower BMI categories (p = 0.03) compared with the control group. In our study, people who live alone are at increased risk of malnutrition (p = 0030), have reduced the number of daily meals, significantly lower daily intake of protein, fruits and vegetables in the diet in relation to persons living in a family environment. Significantly more patients with loss of appetite live alone. According to the existence of self-reported food problems significantly more people are in subject group. There is a difference value score "Small assessment of nutrition" between the two groups (p = 0.001). About 22% of the total number of respondents said they have not so good health status compared to others. CONCLUSIONS: Loneliness is a significant predictor of anorexia nervosa, the risk of malnutrition and malnutrition. Results indicate that it is necessary to work on improving the status and protection of elderly. PMID- 21585183 TI - Comparison of the diagnostic capabilities of noninvasive methods for early detection of coronary artery disease. AB - Early detection of coronary artery disease is one of the prerequisites for adequate and successful treatment of patients and because of that it is important to assess which diagnostic method in a certain time gives the most reliable data to define the optimal medical treatment. The study included 100 subjects. All subjects underwent the electrocardiogram, electrocardiographic stress test, ultrasound examination of the heart without a load, SPECT stress/rest myocardial perfusion scintigraphy and coronary angiography. Coronary angiography as an invasive method has been used as a gold standard with which are compared the results of conducted diagnostic noninvasive examinations, and determined their specificity and sensitivity. The results were statistically analyzed using the recipient operating curve-ROC. Discussed are the diagnostic features of each method and conclusions that brought complementary radiological and nuclear medical imaging can provide very important information about coronary heart disease before making a decision on coronary angiography. PMID- 21585184 TI - Influence of surgical therapy on serum values of alpha 1-antitrypsin in patients with head and neck tumors. AB - INTRODUCTION AND AIM: The aim of this study was to quantitatively evaluate serum concentration of alpha 1-antitrypsin (A1AT) in patients undergoing surgery of head and neck malignant tumors. PATIENTS AND METHODS: Fifty patients undergoing surgery because of head and neck tumors in the years 2007-2008 were analyzed. Serial determinations were performed in all patients in three times: preoperative day--A1AT1; first postoperative day--A1AT2, and thirtieth postoperative day- A1AT3. Concentrations of A1AT were determined by nephelometry method. RESULTS: The patients' age varied from 39 to 86 years, 46 male and 4 females. Serum values of A1AT in patients with stage III and IV are statistically significant elevated after operation (and after one month), but in patients with lower stages (I and II) there were not. In patients with laryngeal malignancies recorded statistical significant elevation of serum values of A1AT postoperatively (and after one month). Other tumor locations did not recorded the same results. CONCLUSION: The above results suggest that measurements of A1AT may have an ancillary role in the diagnosis and monitoring of head and neck tumors. PMID- 21585185 TI - Polypharmacy and decreased cognitive abilities in elderly patients. AB - GOAL: To estimate the prevalence of poly pharmacy and poly pharmacy effect on decline in cognitive abilities of randomly selected group of people over 65. METHODOLOGY: A preliminary pilot study was based on the results of other researchers. 54 patients over 65 were randomly interviewed. Poly pharmacy was defined as using 23 drugs. "A short portable mental status questionnaire" was used in estimating decline of cognitive abilities. RESULTS: According to the study results it was concluded that prevalence of poly pharmacy by the elderly is significant--48.1%. Most present drugs are the ones treating cardiovascular disease, anti diabetic, anti-inflammatory drugs, long acting benzodiazepines, antihistamines. Of the total respondents 33.3% of them live alone and do not have adequate supervision. We have found that poly pharmacy resulted in decline of cognitive abilities in 23 of 54 patients tested in rapid mental status check. CONCLUSION: It is necessary to conduct future research on this issue. PMID- 21585186 TI - The recovery of motor function in post stroke patients. AB - PURPOSE: The purpose of the paper was to assess physical recovery in post stroke patients. WORK METHOD: Prospective cohort study was conducted. The study involved 30 post stroke patients from the city of Nis, aged 40-69. To assess the functional status of the Barthel index (BI) was used. Functional status and BI scores were determined by two times, on admission to the Clinic for rehabilitation and three months after discharge from the Clinic. WORK RESULTS: A total number of patients was 30 (20 men and 10 women). There were twice more men than women (66.7% vs 33.3%, p < 0.001). The average age of all patients was 58.93 +/- 6.86. The majority of patients, were from the age group 60 to 69 years. Left side hemiparesis had 23(77.%) of all patients (16 men and 7 women). Right-side hemiparesis had 7 (23%) patients (4 men and 3 women). Ischemic as a cause of stroke was found in 92% of patients and hemorrhage in 8%. The values of BI score on admission ranged from 30 to 100, with a mean BI score in all patients on admission to the Clinic was the 57. Three months after discharge from rehabilitation in all patients there was an increase in BI score in relation to the value of BI on admission. The average value of BI score was 79. The determined difference is statistically significant (p < 0.01). DISCUSSION: All the patients achieved an increase in BI score indicating their improved status after the applied rehabilitation treatment. CONCLUSION: At the end of the study 57% of the patients could move independently. Patients with a left-sided lesions had better self care of patients with right-sided lesions. Mobility was better in patients with left-sided lesions at the start of rehabilitation. On completion of the rehabilitation, patients with right-sided lesions still needed external help. PMID- 21585187 TI - Prostate cancer detection rate and the importance of premalignant lesion in rebiopsy. AB - OBJECTIVE: Establish the prostate cancer (PCa) detection rate and the premalignant lesion incidence, as well as their importance in cancer detection at the first rebiopsy. MATERIALS AND METHODS: In the period 2006-2008, at the CCUS Urology Clinic, there were 585 prostate biopsies performed in 515 patients. 12% of the patients underwent the first biopsy due to premalignant lesion findings. The main characteristics of the patients--age, prostate specific antigen (PSAt) total and PSA ratio (PSAr), the number of needle biopsies, Gleason score and the role of premalignant lesions in diagnosis of PCa at the first rebiopsy were processed retrospectively. RESULTS: Primarily detected PCa amounted to 32.4% (167/515), while the rebiopsy showed the detection rate of 35.7% (25/70). No statistically significant age or PSAt and PSAr difference was observed, while there was, however, a difference in the number of biopsy samples, 11 (6-18) vs. 12 (8-20) and in the Gleason score (6.5 vs. 5.9) among the observed groups (p < 0.05). Atypical small acinar proliferation (ASAP) and high grade intra epithelial neoplasia (HGPIN), were found in 4.95% and 7.2% of the cases, while the ASAP + HGPIN combination was found in 1.5% of the cases. The PCa detection rate at the first rebiopsy in patients with ASAP, HGPIN and ASAP + HGPIN lesions was 50%, 23.6% and 50%, respectively. The ANOVA test showed a statistically significant shorter time period for rebiopsy in ASAP+HGPIN patients than that of patients with ASAP and HGPIN lesions. CONCLUSION: A repeated positive biopsy establishes PCa in patients with lower PSAt values and the Gleason score, which is followed by an increased number of biopsy samples. ASAP and ASAP + HGPIN lesions carry a higher specificity of75% and 91%, respectively, while the PPV in prostate cancer detection for HGPIN is low (24%). PMID- 21585188 TI - Non-invasive ultrasound guided compression repair of post puncture femoral pseudoaneurysm. AB - BACKGROUND: Pseudo aneurysm (PSA) of femoral artery is the second common post puncture complication. If PSA is less than 18 mm, it can be closed spontaneously and it can be asymptomatic. If not, it needs treatment. The most common non invasive method used in the treatment is ultrasound guided compression (UGC) with duplex color Doppler. In the treatment of PSA, other options are available, such as thrombin and collagen injection in the PSA sack, application of stent, but they are more invasive, with more complications than UGC. MATERIAL AND METHOD: Retrospective study was performed in the period from 2005-2010. During this period, 4575 punctions of femoral artery were performed. Because of suspected PSA of femoral artery, we examined and diagnosed 28 PSA in the ward of ultrasound diagnostic. Data regarding the location and morphologic characteristics of PSA, morbid disease were documented. RESULTS: UGC was performed in 22 PSA patients, 12 men and 9 women, with average age of 48 years. 20 PSA were obliterated, while 2 remained persistent even after second attempt, and they were surgically treated. Efficacy of this method was 90%. Control examination was performed after 12 and 24 hours, and after 1 and 3 months. Intra- and after procedural complications were not observed. CONCLUSION: Non invasive treatment of PSA with UGC is cheap, efficient and easy to perform, with minor complications in well selected patients. PMID- 21585189 TI - Depression in multiple sclerosis patients. AB - INTRODUCTION: Multiple sclerosis (MS) manifests also with the symptoms of affective disorders. Depression is the most common mental disorder among patients with MS and it has negative impact on their working ability, social relations and quality of life. The aim of this study is to investigate gender, age, marital status, education level and employment related to patients with depressive symptoms in population of MS, treated at the Department of Neurology, Clinical Center University of Sarajevo. METHOD: In the study it was analyzed 50 randomly selected patients with various types of multiple sclerosis. Severity of depression was evaluated using the Beck Depression Inventory (BDI). RESULTS: The study included 33 female and 17 male patients aged 21 to 60 years. In the sample of MS patients there were 56% with depressive disorder. There is no statistically significant difference between patients gender. Depression is more frequent among younger and middle age patients, while all the patients older than 51 years are in a normal mood (total 31.9%). Significantly higher percentage of non-depressive patients (72.2%) are married, while depression is present among all divorced patients (10.7%), majority of single (35.8%) and widowers (21.4%). Taking into consideration level of education, there is a statistically significant difference as follows: depression is more frequent among patients who graduated university (46.4%) and secondary school (50%) compared to ones who finished only primary school (3.6%). There is significantly higher number of unemployed and retired patients with depressive symptoms (75%) in comparison to the employed ones. CONCLUSION: Depression occurs more frequently among MS patients who are younger, unemployed, highly educated and without spouse. There is no statistically significant difference between male and female patients. PMID- 21585190 TI - How to make assisted reproductive technologies (ART) affordable in Bosnia and Herzegovina: experience after the first 105 cycles. AB - OBJECTIVE: Evaluation of the results after the first 105 cycles in private IVF centres in Bosnia and Herzegovina. STUDY DESIGN: Retrospective analysis of one hundred and five infertile couples who underwent IVF procedures. RESULTS: The mean age of women who underwent IVF/ ICSI was 34.1 +/- 5.1. The male factor was the cause of infertility in 50 (47.6%), tubal factor in 24 (22.2%), idiopathic infertility in 14 (13.3%), advanced age in 14 (13.3%) and PCOS in 4 (3.8%) infertile couples. The average number of retrieved oocyte was 7.84 +/- 5.30. In 96.2% cycles ICSI was performed and in 3.8% IVF/ICSI. The average number of transferred embryos per cycle was 2.49 +/- 0.9. The pregnancy rate per aspiration was 26.7%. The clinical pregnancy rate per transfer was 26.3%. The percentage of live births per transfer to date was 13.1% and 7 of them are still pregnant. In the entire group of pregnant women 40% had twin pregnancies, 1 of them had an ectopic pregnancy (1.01%) and 4 (4.04%) had spontaneous abortions. CONCLUSIONS: The pregnancy and delivery rates are not satisfactory. The twin pregnancy rate is higher than is acceptable. Low-cost hormonal stimulation, natural cycles and freezing of embryos could be a possible way to make IVF affordable to a larger number of infertile couples. PMID- 21585191 TI - Treatment of anterior encephaloceles over 24 years in Kosova. AB - INTRODUCTION: In the present study we report 36 cases of anterior encephaloceles treated at Clinic of Neurosurgery in the University Clinical Center of Kosova over a 24 year period. MATERIALS AND METHODS: All 36 children were included in this retrospective study (1986 through 2009). Their ages ranged from 1 day to 10 years (mean 13 months); 20 were boys and 16 were girls. The commonest type of anomaly seen was nasofrontal 17 patients, 12 nasoethmoidal, and 7 nasoorbital. The size of the lesion varied from 2.5 cm to 28 cm. Hypertelorism occurred in 12 patients. Hydrocephalus was present in 11 patients and in 8 of them was progressive. RESULTS: 1 patient died on 10th postoperative day due to fulminant meningitis. Cosmetic results were judged from parents as excellent in 16 patients, good in 12 patients, average in 6 patients and poor in 2 patients. None of patients were lost to follow-up. DISCUSSION: Histologic examination of the herniated tissue can vary between normal brain to fibrous atrophic nonviable tissue. No familial cases have been reported in the literature, we also have similar experience. In our study we have found that the prevalence is higher among patients coming from rural parts of our country with pore living conditions, malnutrition and so on. We have avoided surgery in very young children until body weight is around 5-6 kg because of complication from blood lose and hypothermia. CONCLUSION: The aim of treatment is early removal of the meningoencephalocele to allow normal growth forces to be re-established. In patients with hypertelorism, correction surgery is done in the same session. Ifhydrocephalus is not treated before corrective surgery for encephalocele, the risk of postoperative CSF is very high. With one stage surgery excellent results can be achieved. PMID- 21585192 TI - Laparoscopic appendectomy is safe procedure in the pregnant patients in second trimester. AB - Optimal approach to appendicitis in pregnancy remains controversial issue. There is also some concern that laparoscopy during pregnancy may cause fetal injury and alter fetal perfusion. Supporters of laparoscopy claim that minimally invasive approach even in pregnant state possesses several advantages, including fewer wound complications and less postoperative pain, producing faster return to normal activities and early hospital discharge, with no increased fetal risk. We present our series of pregnant patients who underwent laparoscopic appendectomy that shows that in the hands of an experienced surgeon, this method is a safe option in pregnant patients in the second trimester. PMID- 21585193 TI - How does the QB site influence propagate to the QA site in photosystem II? AB - The redox potential of the primary quinone Q(A) [E(m)(Q(A))] in photosystem II (PSII) is lowered by replacement of the native plastoquinone (PQ) with bromoxynil (BR) at the secondary quinone Q(B) binding site. Using the BR-bound PSII structure presented in the previous Fourier transform infrared and docking calculation studies, we calculated E(m)(Q(A)) considering both the protein environment in atomic detail and the protonation pattern of the titratable residues. The calculated E(m)(Q(A)) shift in response to the replacement of PQ with deprotonated BR at the Q(B) binding site [DeltaE(m)(Q(A))(PQ->BR)] was -55 mV when the three regions, Q(A), the non-heme iron complex, and Q(B) (Q(B) = PQ or BR), were treated as a conjugated supramolecule (Q(A)-Fe-Q(B)). The negative charge of BR apparently contributes to the downshift in DeltaE(m)(Q(A))(PQ->BR). This downshift, however, is mostly offset by the influence of the residues near Q(B). The charge delocalization over the Q(A)-Fe-Q(B) complex and the resulting H bond strength change between Q(A) and D2-His214 are crucial factors that yield a DeltaE(m)(Q(A))(PQ->BR) of -55 mV by (i) altering the electrostatic influence of the H-bond donor D2-His214 on E(m)(Q(A)) and (ii) suppressing the proton uptake events of the titratable residues that could otherwise upshift DeltaE(m)(Q(A))(PQ >BR) during replacement of PQ with BR at the Q(B) site. PMID- 21585194 TI - Antifouling poly(beta-peptoid)s. AB - A new type of polymer highly resistant to nonspecific protein adsorption is reported. Poly(N-methyl-beta-alanine) (PMeA) and poly(N-ethyl-beta-alanine) (PEtA) synthesized via cobalt-catalyzed carbonylative polymerization of N methylaziridine and N-ethylaziridine were end-functionalized with thiol groups and grafted onto Au surfaces. Protein adsorption was studied by the surface plasmon resonance (SPR) method. The amounts of representative single proteins adsorbed onto the PMeA- and PEtA-grafted surfaces were below the detection limit of SPR at the pg/mm(2) level. After exposure to full blood plasma and serum for 10 min, protein adsorption was at the level of ~ 100 pg/mm(2), similar to the level of protein adsorption on poly(ethylene glycol) surfaces subjected to identical conditions. These poly(beta-peptoid)s therefore provide excellent protein resistance comparable to the best antifouling materials known to date. The strong proton-accepting ability when forming hydrogen bonds is suggested to be an important attribute for these poly(beta-peptoid)s as well as other poly(tertiary amide)s as antifouling materials. PMID- 21585195 TI - High photoluminescent metal-organic frameworks as optical markers for the identification of gunshot residues. AB - Gunshot residue (GSR) are solid particles produced when a firearm is discharged, and its detection is important evidence in forensic investigations. Currently, scanning electron microscopy coupled to energy dispersive spectroscopy (SEM-EDS) is the standard technique adopted for the analysis and identification of GSR; however, this methodology is inefficient for lead-free ammunition. Herein, we report the inclusion of high photoluminescent metal-organic frameworks in ammunition to allow for the visual detection of GSR. The tests indicated that marked GSR is easily visible in proportions above 5.0 wt %. A total of 1 g of marker suffices to tag 100 0.38 mm bullets or 62 0.40 mm bullets. PMID- 21585197 TI - Isomerization mechanism in hydrazone-based rotary switches: lateral shift, rotation, or tautomerization? AB - Two intramolecularly hydrogen-bonded arylhydrazone (aryl = phenyl or naphthyl) molecular switches have been synthesized, and their full and reversible switching between the E and Z configurations have been demonstrated. These chemically controlled configurational rotary switches exist primarily as the E isomer at equilibrium and can be switched to the protonated Z configuration (Z-H(+)) by the addition of trifluoroacetic acid. The protonation of the pyridine moiety in the switch induces a rotation around the hydrazone C=N double bond, leading to isomerization. Treating Z-H(+) with base (K(2)CO(3)) yields a mixture of E and "metastable" Z isomers. The latter thermally equilibrates to reinstate the initial isomer ratio. The rate of the Z -> E isomerization process showed small changes as a function of solvent polarity, indicating that the isomerization might be going through the inversion mechanism (nonpolar transition state). However, the plot of the logarithm of the rate constant k vs the Dimroth parameter (E(T)) gave a linear fit, demonstrating the involvement of a polar transition state (rotation mechanism). These two seemingly contradicting kinetic data were not enough to determine whether the isomerization mechanism goes through the rotation or inversion pathways. The highly negative entropy values obtained for both the forward (E -> Z-H(+)) and backward (Z -> E) processes strongly suggest that the isomerization involves a polarized transition state that is highly organized (possibly involving a high degree of solvent organization), and hence it proceeds via a rotation mechanism as opposed to inversion. Computations of the Z <-> E isomerization using density functional theory (DFT) at the M06/cc-pVTZ level and natural bond orbital (NBO) wave function analyses have shown that the favorable isomerization mechanism in these hydrogen-bonded systems is hydrazone-azo tautomerization followed by rotation around a C-N single bond, as opposed to the more common rotation mechanism around the C=N double bond. PMID- 21585198 TI - Novel thieno-[3,4-b]-pyrazines cored dendrimers with carbazole dendrons: design, synthesis, and application in solution-processed red organic light-emitting diodes. AB - A series of novel red-emitting thieno-[3,4-b]-pyrazine-cored molecules containing oligo-carbazole dendrons (called C1-TP, C2-TP) are synthesized. Their photophysical, electrochemical, and electroluminescent properties are investigated. The peripheral carbazolyl units facilitate the hole transporting ability and inhibit the intermolecular interactions, but quench the fluorescence of the thieno-[3,4-b]-pyrazine core through Intramolecular Charge Transfer (ICT). Introduction of a polyphenyl spacer between the core and the first generation carbazole dendrons, i.e., C-DTP, decreases the ICT efficiency. In addition to providing the site-isolation effect on the planar emissive core, these bulky dendrons enable these molecules to be solution processable. As a result, efficient OLEDs with saturated red emission are fabricated by spin coating technique using these dendritic materials as nondoped emitting layer. C-DTP exhibits much better device performance than C1-TP and C2-TP, while the small molecular reference compound containing neither the spacer nor the carbazole dendrons (TP) fails to transmit pure red emission under identical conditions. A brightness of 925 cd m(-2) and a luminous efficiency of 0.53 cd A(-1) are obtained for C-DTP, which are comparable with OLEDs fabricated from thieno-[3,4 b]-pyrazine-based counterparts by the vacuum deposition method or those assembled with other red fluorescent dendrimers via the solution processing method. PMID- 21585196 TI - Targeted cleavage of HIV RRE RNA by Rev-coupled transition metal chelates. AB - A series of compounds that target reactive metal chelates to the HIV-1 Rev response element (RRE) mRNA have been synthesized. Dissociation constants and chemical reactivity toward HIV RRE RNA have been determined and evaluated in terms of reduction potential, coordination unsaturation, and overall charge associated with the metal-chelate-Rev complex. Ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), diethylenetriaminepentaacetic acid (DTPA), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were linked to a lysine side chain of a Rev-derived peptide by either EDC/NHS or isothiocyanate coupling. The resulting chelate-Rev (EDTA-Rev, DTPA-Rev, NTA-Rev, and DOTA-Rev) conjugates were used to form coordination complexes with Fe(2+), Co(2+), Ni(2+), and Cu(2+) such that the arginine-rich Rev peptide could mediate localization of the metal chelates to the Rev peptide's high-affinity mRNA binding partner, RRE stem loop IIB. Metal complexes of the extended peptides GGH Rev and KGHK-Rev, which also contain N-terminal peptidic chelators (ATCUN motifs), were studied for comparison. A fluorescence titration assay revealed high-affinity RRE RNA binding by all 22 metal-chelate-Rev species, with K(D) values ranging from ~0.2 to 16 nM, indicating little to no loss of RNA affinity due to the coupling of the metal chelates to the Rev peptide. Dissociation constants for binding at a previously unobserved low-affinity site are also reported. Rates of RNA modification by each metal-chelate-Rev species were determined and varied from ~0.28 to 4.9 nM/min but were optimal for Cu(2+)-NTA Rev. Metal-chelate reduction potentials were determined and varied from -228 to +1111 mV vs NHE under similar solution conditions, allowing direct comparison of reactivity with redox thermodynamics. Optimal activity was observed when the reduction potential for the metal center was poised between those of the two principal co-reagents for metal-promoted formation of reactive oxygen species: E degrees (ascorbate/ascorbyl radical) = -66 mV and E degrees (H(2)O(2)/hydroxyl radical) = 380 mV. Given the variety of oxidative activities of these metal complexes and their high-affinity binding to the targeted RRE mRNA following coupling to the Rev peptide, this class of metal-chelate-Rev derivatives constitutes a promising step toward development of multiple-turnover reagents for selective eradication of HIV-1 RRE mRNA. PMID- 21585199 TI - Suitable labels for molecular imaging--influence of dye structure and hydrophilicity on the spectroscopic properties of IgG conjugates. AB - Aiming at the design of highly brilliant NIR emissive optical probes, e.g., for in vivo near-infrared fluorescence imaging (NIRF), we studied the absorption and fluorescence properties of the asymmetric cyanines Dy678, Dy681, Dy682, and Dy676 conjugated to the model antibody IgG. The ultimate goal was here to derive general structure-property relationships for suitable NIR fluorescent labels. These Dy dyes that spectrally match Cy5 and Cy5.5, respectively, were chosen to differ in chromophore structure, i.e., in the substitution pattern of the benzopyrylium end group and in the number of sulfonic acid groups. Spectroscopic studies of the free and IgG-bound fluorophores revealed a dependence of the obtained dye-to-protein ratios on dye hydrophilicity and control of the fluorescence quantum yields (Phi(f)) of the IgG conjugates by the interplay of different fluorescence reduction pathways like dye aggregation and fluorescence resonance energy transfer (FRET). Based upon aggregation studies with these dyes, the amount of dye dimers in the IgG conjugates was determined pointing to dye hydrophilicity as major parameter controlling aggregation. To gain further insight into the exact mechanism of dye dimerization at the protein, labeling experiments at different reaction conditions but constant dye-to-protein ratios in the reaction solution were performed. With Dy682 that displays a Phi(f) of 0.20 in PBS and 0.10 for moderate dye-to-protein ratio of 2.5, a low aggregation tendency, and a superior reactivity in IgG labeling, we identified a promising diagnostic tool for the design of NIR fluorescent probes and protein conjugates. PMID- 21585200 TI - Quantum features of a barely bound molecular dopant: Cs2(3Sigmau) in bosonic helium droplets of variable size. AB - We present in this work the study of small (4)He(N)-Cs(2)((3)Sigma(u)) aggregates (2 <= N <= 30) through combined variational, diffusion Monte Carlo (DMC), and path integral Monte Carlo (PIMC) calculations. The full surface is modeled as an addition of He-Cs(2) interactions and He-He potentials. Given the negligible strength and large range of the He-Cs(2) interaction as compared with the one for He-He, a propensity of the helium atoms to pack themselves together, leaving outside the molecular dopant is to be expected. DMC calculations determine the onset of helium gathering at N = 3. To analyze energetic and structural properties as a function of N, PIMC calculations with no bosonic exchange, i.e., Boltzmann statistics, at low temperatures are carried out. At T = 0.1 K, although acceptable one-particle He-Cs(2) distributions are obtained, two-particle He-He distributions are not well described, indicating that the proper symmetry should be taken into account. PIMC distributions at T = 1 K already compare well with DMC ones and show minor exchange effects, although binding energies are still far from having converged in terms of the number of quantum beads. As N increases, the He-He PIMC pair correlation function shows a clear tendency to coincide with the experimental boson-liquid helium one at that temperature. It supports the picture of a helium droplet which carries the molecular impurity on its surface, as found earlier for other triplet dimers. PMID- 21585202 TI - Solid-phase synthesis, thermal denaturation studies, nuclease resistance, and cellular uptake of (oligodeoxyribonucleoside)methylborane phosphine-DNA chimeras. AB - The major hurdle associated with utilizing oligodeoxyribonucleotides for therapeutic purposes is their poor delivery into cells coupled with high nuclease susceptibility. In an attempt to combine the nonionic nature and high nuclease stability of the P-C bond of methylphosphonates with the high membrane permeability, low toxicity, and improved gene silencing ability of borane phosphonates, we have focused our research on the relatively unexplored methylborane phosphine (Me-P-BH(3)) modification. This Article describes the automated solid-phase synthesis of mixed-backbone oligodeoxynucleotides (ODNs) consisting of methylborane phosphine and phosphate or thiophosphate linkages (16 mers). Nuclease stability assays show that methylborane phosphine ODNs are highly resistant to 5' and 3' exonucleases. When hybridized to a complementary strand, the ODN:RNA duplex was more stable than its corresponding ODN:DNA duplex. The binding affinity of ODN:RNA duplex increased at lower salt concentration and approached that of a native DNA:RNA duplex under conditions close to physiological saline, indicating that the Me-P-BH(3) linkage is positively charged. Cellular uptake measurements indicate that these ODNs are efficiently taken up by cells even when the strand is 13% modified. Treatment of HeLa cells and WM-239A cells with fluorescently labeled ODNs shows significant cytoplasmic fluorescence when viewed under a microscope. Our results suggest that methylborane phosphine ODNs may prove very valuable as potential candidates in antisense research and RNAi. PMID- 21585201 TI - A selective inhibitor and probe of the cellular functions of Jumonji C domain containing histone demethylases. AB - Histone methylations are important chromatin marks that regulate gene expression, genomic stability, DNA repair, and genomic imprinting. Histone demethylases are the most recent family of histone-modifying enzymes discovered. Here, we report the characterization of a small-molecule inhibitor of Jumonji C domain-containing histone demethylases. The inhibitor derives from a structure-based design and preferentially inhibits the subfamily of trimethyl lysine demethylases. Its methyl ester prodrug, methylstat, selectively inhibits Jumonji C domain containing his-tone demethylases in cells and may be a useful small-molecule probe of chromatin and its role in epigenetics. PMID- 21585203 TI - A protein tyrosine phosphatase 1B activity inhibitor from the fruiting bodies of Ganoderma lucidum (Fr.) Karst and its hypoglycemic potency on streptozotocin induced type 2 diabetic mice. AB - Inhibition of protein tyrosine phosphatase 1B (PTP1B) activity has been considered to be a promising therapy approach to treat type 2 diabetes. In this work, a novel PTP1B activity inhibitor, named FYGL (Fudan-Yueyang-G. lucidum), was screened from the fruiting bodies of Ganoderma lucidum and showed an efficient PTP1B inhibitory potency with IC50 = 5.12 +/- 0.05 MUg/mL. FYGL is a water-soluble macromolecular proteoglycan with a protein to polysaccharide ratio of 17:77 and a viscosity-average molecular weight (M(eta)) of 2.6 * 105. The type 2 diabetic mice treated orally by FYGL showed an obvious decrease in plasma glucose level compared with the diabetic controls without drug treatment, comparable with that of diabetic mice treated with metformin, a clinical drug. The toxicity of FYGL is very low. The results indicate that FYGL may serve as a drug candidate or a health-care food for diabetic therapy or protection. PMID- 21585204 TI - Influenza virus neuraminidase inhibitory activity of phlorotannins from the edible brown alga Ecklonia cava. AB - Influenza A virus infections continue to pose a major threat to humans and several animal species. Neuraminidase (NA) is one of the most promising targets for the development of drugs against influenza viruses because of its critical role in the viral life cycle. During the course of a search for NA inhibitors from edible natural sources, we found that the ethyl acetate layer of ethanol extracts of Ecklonia cava showed extremely high NA-inhibitory activity (72.1% inhibition at 30 MUg/mL). Bioactivity-guided fractionation of the ethyl acetate layer yielded five phlorotannins, identified as phloroglucinol (1), eckol (2), 7 phloroeckol (3), phlorofucofuroeckol (4), and dieckol (5). The inhibitory activities of these compounds (1-5) against NAs from group-1 (A/Bervig_Mission/1/18 [H1N1], A/PR/8/34 [H1N1]) and group-2 (A/Hong Kong/8/68 [H3N2], A/Chicken/Korea/MS96/96 [H9N2]) influenza A were evaluated to determine potencies and kinetic behavior. Analyses using various in vitro influenza A virus NA assays showed that all five phlorotannin derivatives were selective NA inhibitors. Of the phlorotannins, phlorofucofuroeckol (4) exhibited the most potent inhibitory activities toward group-1 NAs (IC50 values, 4.5 and 14.7 MUM), whereas dieckol (5) potently inhibited group-2 NAs. Kinetic analyses indicated that compounds 1-5 were all noncompetitive. Notably, these noncompetitive inhibitors synergized with oseltamivir to enhance the NA-inhibitory effects of oseltamivir. PMID- 21585205 TI - The controlled display of biomolecules on nanoparticles: a challenge suited to bioorthogonal chemistry. AB - Interest in developing diverse nanoparticle (NP)-biological composite materials continues to grow almost unabated. This is motivated primarily by the desire to simultaneously exploit the properties of both NP and biological components in new hybrid devices or materials that can be applied in areas ranging from energy harvesting and nanoscale electronics to biomedical diagnostics. The utility and effectiveness of these composites will be predicated on the ability to assemble these structures with control over NP/biomolecule ratio, biomolecular orientation, biomolecular activity, and the separation distance within the NP bioconjugate architecture. This degree of control will be especially critical in creating theranostic NP-bioconjugates that, as a single vector, are capable of multiple functions in vivo, including targeting, image contrast, biosensing, and drug delivery. In this review, a perspective is given on current and developing chemistries that can provide improved control in the preparation of NP bioconjugates. The nanoscale properties intrinsic to several prominent NP materials are briefly described to highlight the motivation behind their use. NP materials of interest include quantum dots, carbon nanotubes, viral capsids, liposomes, and NPs composed of gold, lanthanides, silica, polymers, or magnetic materials. This review includes a critical discussion on the design considerations for NP-bioconjugates and the unique challenges associated with chemistry at the biological-nanoscale interface-the liabilities of traditional bioconjugation chemistries being particularly prominent therein. Select bioorthogonal chemistries that can address these challenges are reviewed in detail, and include chemoselective ligations (e.g., hydrazone and Staudinger ligation), cycloaddition reactions in click chemistry (e.g., azide-alkyne cyclyoaddition, tetrazine ligation), metal-affinity coordination (e.g., polyhistidine), enzyme driven modifications (e.g., HaloTag, biotin ligase), and other site-specific chemistries. The benefits and liabilities of particular chemistries are discussed by highlighting relevant NP-bioconjugation examples from the literature. Potential chemistries that have not yet been applied to NPs are also discussed, and an outlook on future developments in this field is given. PMID- 21585206 TI - Imaging of specific activation of photodynamic molecular beacons in breast cancer vertebral metastases. AB - Breast cancer is the second leading cause of cancer-related death in women. Approximately 85% of patients with advanced cases will develop spinal metastases. The vertebral column is the most common site of breast cancer metastases, where overexpression of matrix metalloproteinases (MMPs) promotes the spread of cancer. Current therapies have significant limitations due to the high associated risk of damaging the spinal cord. An attractive alternative is photodynamic therapy providing noninvasive and site-selective treatment. However, current photosensitizers are limited by their nonspecific accumulation. Photodynamic molecular beacons (PP(MMP)B), activated by MMPs, offer another level of PDT selectivity and image-guidance preserving criticial tissues, specifically the spinal cord. Metastatic human breast carcinoma cells, MT-1, were used to model the metastatic behavior of spinal lesions. In vitro and in vivo evidence demonstrates MMP specific activation of PP(MMP)B in MT-1 cells. Using a clinically relevant metastatic model, fluorescent imaging establishes the specific activation of PP(MMP)B by vertebral metastases versus normal tissue (i.e., spinal cord) demonstrating the specificity of these beacons. Here, we validate that the metastasis-selective mechanism of PP(MMP)Bs can specifically image breast cancer vertebral metastases, thereby differentiating tumor and healthy tissue. PMID- 21585207 TI - Real-time monitoring of actin polymerization in living cells using split luciferase. AB - Real-time monitoring of actin polymerization in living cells is beneficial for characterizing cellular activities such as migration, proliferation, and death. We developed new bioluminescence-based probe proteins that enable the monitoring of actin polymerization in living cells. Unlike other ordinary split luciferase probes, our probes were incorporated in endogenous actin filament that enabled it to measure the actin polymerization quantitatively. The probe proteins exhibited a dose-responsive decrease in photon emission intensity in response to the filamentous (F)-actin-disrupting agent latrunculin A. This technique has a high sensitivity with a high signal-to-noise ratio and is nontoxic compared with other methods of monitoring actin polymerization in living cells. Using this technique, we succeeded in monitoring the F-actin level in living cells during apoptosis progression induced by UV irradiation continuously for 12 h. F-actin was transiently upregulated after UV irradiation. Since UV-induced cell death was enhanced by treatment with latrunculin A during the period which F-actin is increased, transient upregulation of F-actin after UV is likely a protective reaction against UV-induced cell death. Our novel technique is an effective tool for investigating actin polymerization in living cells. PMID- 21585209 TI - Influence of carbohydrate biological vectors on the two-photon resonance of porphyrin oligomers. AB - We propose a spectroscopic study of pi-conjugated porphyrin dimers and a triphenylamine centered trimer bearing monoethyleneglycol-peracetylated alpha mannose targeting moieties, which were synthesized for application to two-photon absorption photodynamic therapy (2PA-PDT). The collected spectroscopic data are explained through comparison with previous results obtained on similar nonvectorized analogues. It appears that the different shifts and variations in linear and nonlinear absorption and emission bands are mainly due to an increased twist between the tetrapyrrolic units. The 2PA properties of the triphenylamine centered trimer have been studied, and two fluorescence emission bands are observed that seem to originate from two different 2PA excitation pathways. These results have important implication for the design of new vectorized photosensitizers for 2PA-PDT. PMID- 21585208 TI - Identification of two imidazole binding sites and key residues for substrate specificity in human primary amine oxidase AOC3. AB - Human membrane primary amine oxidase (hAOC3; also known as vascular adhesion protein-1, VAP-1) is expressed upon inflammation in most tissues, where its enzymatic activity plays a crucial role in leukocyte trafficking. We have determined two new structures of a soluble, proteolytically cleaved form of hAOC3 (sAOC3), which was extracted from human plasma. In the 2.6 A sAOC3 structure, an imidazole molecule is hydrogen bonded to the topaquinone (TPQ) cofactor, which is in an inactive on-copper conformation, while in the 2.95 A structure, an imidazole molecule is covalently bound to the active off-copper conformation of TPQ. A second imidazole bound by Tyr394 and Thr212 was identified in the substrate channel. We furthermore demonstrated that imidazole has an inhibitory role at high concentrations used in crystallization. A triple mutant (Met211Val/Tyr394Asn/Leu469Gly) of hAOC3 was previously reported to change substrate preferences toward those of hAOC2, another human copper-containing monoamine oxidase. We now mutated these three residues and Thr212 individually to study their distinct role in the substrate specificity of hAOC3. Using enzyme activity assays, the effect of the four single mutations was tested with four different substrates (methylamine, benzylamine, 2-phenylethylamine, and p tyramine), and their binding modes were predicted by docking studies. As a result, Met211 and Leu469 were shown to be key residues for substrate specificity. The native structures of sAOC3 and the mutational data presented in this study will aid the design of hAOC3 specific inhibitors. PMID- 21585211 TI - New insights in the atmospheric HONO formation: new pathways for N2O4 isomerization and NO2 dimerization in the presence of water. AB - Isomerization of N(2)O(4) and dimerization of NO(2) in thin water films on surfaces are believed to be key steps in the hydrolysis of NO(2), which generates HONO, a significant precursor to the OH free radical in lower atmosphere and high energy materials. Born-Oppenheimer molecular dynamics simulations using the density functional theory are carried out for NO(2)(H(2)O)(m), m <= 4, and N(2)O(4)(H(2)O)(n) clusters, n <= 7, used to mimic the surface reaction, to investigate the mechanism around room temperature. The results are (i) the NO(2) dimerization and N(2)O(4) isomerization reactions occur via two possible pathways, the non-water-assisted and water-assisted mechanisms; (ii) the NO(2) dimerization in the presence of water yields either ONONO(2)(H(2)O)(m) or NO(3)( )NO(+)(H(2)O)(m) clusters, but it is also possible to form the HNO(3)(NO(2)( ))(H(3)O(+))(H(2)O)(m-2) transition state to form HONO and HNO(3), directly; (iii) the N(2)O(4) isomerization yields the NO(3)(-)NO(+)(H(2)O)(n) cluster, but it does not hydrolyze faster than the NO(2)(+)NO(2)(-)(H(2)O)(n) hydrolysis to directly form the HONO and HNO(3). New insights for hydrolysis of oxides of nitrogen in and on thin water films on surfaces in the atmosphere are discussed. PMID- 21585210 TI - Pressure effect on the nonradiative process of thioflavin-T. AB - Time-resolved emission techniques were employed to study the nonradiative process of thioflavin-T (ThT) in 1-propanol, 1-butanol, and 1-pentanol as a function of the hydrostatic pressure. Elevated hydrostatic pressure increases the alcohol viscosity, which in turn strongly influences the nonradiative rate of ThT. A diamond-anvil cell was used to increase the pressure up to 2.4 GPa. We found that the nonradiative rate constant, k(nr), decreases with pressure. We further found a remarkable linear correlation between a decrease in k(nr) (increase in the nonradiative lifetime, tau(nr)) and an increase in the solvent viscosity. The viscosity was varied by a factor of 1000 and k(nr) was measured at high pressures, at which the nonradiative rate constant of the molecules decreased from (7 ps)(-1) to (13 ns)(-1), (13 ps)(-1) to (17 ns)(-1) and (17 ps)(-1) to (15 ns)(-1) for 1-propanol, 1-butanol, and 1-pentanol, respectively. The viscosity dependence of k(nr) is explained by the excited-state rotation rate of the two ring systems, with respect to each other. PMID- 21585212 TI - Charge transport and electrochemical response of poly(3,4-ethylenedioxypyrrole) films improved by noble-metal nanoparticles. AB - Charge-transport phenomena and redox switching of poly(3,4-ethylenedioxypyrrole) (PEDOP) films embedded with Au and Ag nanoparticles have been investigated. In the bulk, charge transport can be described by an ohmic regime at low voltages and a space-charge-limited current regime at high voltages in PEDOP-Au, which is in contrast to trap-filled domains deduced for neat PEDOP and PEDOP-Ag nanocomposites, all indicating transitions driven by an external bias. This also allowed a direct estimation of a fairly high charge-carrier mobility at room temperature in PEDOP-Au, in addition to a higher donor density, which are advantageous for device applications. X-ray photoelectron spectroscopy and high resolution transmission electron microscopy affirmed the prevalence of Au/Ag nanoparticles as nonleachable entities in PEDOP, thus allowing the movement of electrons through the conducting nanoaparticles during electrochemical switching, an effect that is absent in the neat PEDOP film. Valence-band spectra and optical studies revealed that nanoparticles narrowed the band gap and increased the absorption coefficient of PEDOP, which enhanced the electrochromic switching ability of PEDOP. A coloration efficiency enhancement by an order of magnitude, higher electrochemical charge intercalation capacity, and higher diffusion rates reflect the role of noble-metal nanoparticles in improving the conduction and electrochemical activity of PEDOP. PMID- 21585213 TI - Thermodynamics and activity coefficients at infinite dilution measurements for organic solutes and water in the ionic liquid N-hexyl-3-methylpyridinium tosylate. AB - The activity coefficients at infinite dilution, gamma13(infinity), for 44 solutes, including alkanes, cycloalkanes, alkenes, alkynes, aromatic hydrocarbons, alcohols, water, thiophene, tetrahydrofuran, ethers, and ketones in the ionic liquid (IL) N-hexyl-3-methylpyridinium tosylate (p-toluenesulfonate), [HM3Py][TOS], were determined by gas-liquid chromatography at temperatures from 338.15 to 368.15 K. The densities of [HM3Py][TOS] as a function of temperature have been measured at temperatures higher than the melting temperature and were extrapolated to T = 298.15 K. The gas-liquid partition coefficients, K(L) were calculated for all solutes. The partial molar excess Gibbs energies DeltaG1(E,infinity), enthalpies DeltaH1(E,infinity), and entropies DeltaS1(E,infinity) at infinite dilution were calculated from the experimental gamma13(infinity) values obtained over the temperature range. The selectivities for different separation problems including n-heptane/benzene, cyclohexane/benzene, and n-heptane/thiophene were calculated from gamma13(infinity) and compared to literature values for tosylate-based ILs, or hexyl-substituted cations of ILs, or pyridynium-based IL, or N-methyl-2 pyrrolidinone (NMP), and sulfolane. PMID- 21585214 TI - Synergistic antibacterial brilliant blue/reduced graphene oxide/quaternary phosphonium salt composite with excellent water solubility and specific targeting capability. AB - A water-soluble brilliant blue/reduced graphene oxide/tetradecyltriphenylphosphonium bromide composite (BB-rGO-TTP) was prepared by using noncovalent brilliant blue-functionalized reduced graphene oxide (BB rGO) as the tetradecyltriphenylphosphonium bromide (TTP) carrier. Antibacterial performance of this novel composite was investigated for both Gram-positive and Gram-negative bacteria. The results showed that the novel BB-rGO-TTP, combing the advantages of graphene and TTP, displayed excellent synergistic antibacterial activity, specific targeting capability, water solubility, and mild cytotoxicity, suggesting the great potential application as sprayable graphene-based antibacterial solutions. PMID- 21585215 TI - Hydration free energies using semiempirical quantum mechanical Hamiltonians and a continuum solvent model with multiple atomic-type parameters. AB - To build the foundation for accurate quantum mechanical (QM) simulation of biomacromolecules in an aqueous environment, we undertook the optimization of the COnductor-like Screening MOdel (COSMO) atomic radii and atomic surface tension coefficients for different semiempirical Hamiltonians adhering to the same computational conditions recently followed in the simulation of biomolecular systems. This optimization was achieved by reproducing experimental hydration free energies of a set consisting of 507 neutral and 99 ionic molecules. The calculated hydration free energies were significantly improved by introducing a multiple atomic-type scheme that reflects different chemical environments. The nonpolar contribution was treated according to the scaled particle Claverie Pierotti formalism. Separate radii and surface tension coefficient sets have been developed for AM1, PM3, PM5, and RM1 semiempirical Hamiltonians, with an average unsigned error for neutral molecules of 0.64, 0.66, 0.73, and 0.71 kcal/mol, respectively. Free energy calculation of each molecule took on average 0.5 s on a single processor. The new sets of parameters will enhance the quality of semiempirical QM calculations using COSMO in biomolecular systems. Overall, these results further extend the utility of QM methods to chemical and biological systems in the condensed phase. PMID- 21585216 TI - Ionization of doped helium nanodroplets: residual helium attached to diatomic cations and their clusters. AB - Electron impact ionization of helium nanodroplets containing a dopant, M, can lead to the detection of both M(+) and helium-solvated cations of the type M(+).He(n) in the gas phase. The observation of helium-doped ions, He(n)M(+), has the potential to provide information on the aftermath of the charge transfer process that leads to ion production from the helium droplet. Here we report on helium attachment to the ions from four common diatomic dopants, M = N(2), O(2), CO, and NO. For experiments carried out with droplets with an average size of 7500 helium atoms, the monomer cations show little tendency to attach and retain helium atoms on their journey out of the droplet. By way of contrast, the corresponding cluster cations, M(n)(+), where n >= 2, all show a clear affinity for helium and form He(m)M(n)(+) cluster ions. The stark difference between the monomer and cluster ions is attributed to more effective cooling of the latter in the aftermath of the ionization event. PMID- 21585217 TI - Bifunctional silver nanoparticle cathode in microbial fuel cells for microbial growth inhibition with comparable oxygen reduction reaction activity. AB - Organic contamination of water bodies in which benthic microbial fuel cells (benthic MFCs) are installed, and organic crossover from the anode to the cathode of membraneless MFCs, is a factor causing oxygen depletion and substrate loss in the cathode due to the growth of heterotrophic aerobic bacteria. This study examines the possible use of silver nanoparticles (AgNPs) as a cathodic catalyst for MFCs suffering from organic contamination and oxygen depletion. Four treated cathodes (AgNPs-coated, Pt/C-coated, Pt/C+AgNPs-coated, and plain graphite cathodes) were prepared and tested under high levels of organics loading. During operation (fed with 50 mM acetate), the AgNPs-coated system showed the highest DO concentration (0.8 mg/L) in the cathode area as well as the highest current (ranging from 0.04 to 0.12 mA). Based on these results, we concluded that (1) the growth of oxygen-consuming heterotrophic microbes could be inhibited by AgNPs, (2) the function of AgNPs as a bacterial growth inhibitor resulted in a greater increase of DO concentration in the cathode than the other tested cathode systems, (3) AgNPs could be applied as a cathode catalyst for oxygen reduction, and as a result (4) the MFC with the AgNPs-coated cathode led to the highest current generation among the tested MFCs. PMID- 21585218 TI - Fraudulent and substandard medicines: getting away with murder? PMID- 21585219 TI - A benefit-risk assessment of dabigatran in the prevention of venous thromboembolism in orthopaedic surgery. AB - Dabigatran etexilate is a novel orally administered anticoagulant that exerts its action through reversible direct thrombin inhibition. This anticoagulant has been approved for prophylaxis against venous thromboembolism (VTE) after hip or knee arthroplasty, and in a few countries also for atrial fibrillation. This article reviews the efficacy and safety of dabigatran for the prophylaxis of VTE indication compared with data on the most common current regimen with low molecular-weight heparin (LMWH), specifically enoxaparin. Alternative prophylactic agents are also discussed. The results regarding efficacy and safety are very similar for dabigatran and LMWH. Bleeding and gastrointestinal reactions are the most frequently reported adverse events with a comparable incidence on LMWH and are probably the result of surgery and anaesthaesia. No adverse event that is specific for dabigatran has been observed in these studies, although dyspepsia has been reported as significantly more frequent than warfarin in long term studies on other indications. The fact that dabigatran has no antidote has so far not been a problem in patients undergoing orthopaedic surgery. The use of the lower dose of dabigatran (150 mg) appears beneficial to reduce the risk of bleeding in patients over 75 years of age and in those with moderate renal impairment to avoid drug accumulation. The convenience of oral administration is an advantage for dabigatran over LMWH, particularly for extended prophylaxis up to 1 month after surgery. In conclusion, the benefit-risk profile of dabigatran is favourable for use as prophylaxis against VTE after major orthopaedic surgery with its convenient oral administration without need for laboratory monitoring and a low risk of bleeding or other adverse events. PMID- 21585220 TI - Quinolones: review of psychiatric and neurological adverse reactions. AB - Quinolones are a class of antibacterial agents for the treatment of several infectious diseases (e.g. urinary and respiratory tract infections). They are used worldwide due to their broad spectrum of activity, high bioavailability and good safety profile. The safety profile varies from quinolone to quinolone. The aim of this article was to review the neurological and psychiatric adverse drug reaction (ADR) profile of quinolones, using a literature search strategy designed to identify case reports and case series. A literature search using PubMed/MEDLINE (from inception to 31 October 2010) was performed to identify case reports and case series related to quinolone-associated neurological and psychiatric ADRs. The search was conducted in two phases: the first phase was the literature search and in the second phase relevant articles were identified through review of the references of the selected articles. Relevant articles were defined as articles referring to adverse events/reactions associated with the use of any quinolone. Abstracts referring to animal studies, clinical trials and observational studies were excluded. Identified case reports were analysed by age group, sex, active substances, dosage, concomitant medication, ambulatory or hospital-based event and seriousness, after Medical Dictionary for Regulatory Activities (MedDRA(r)) coding. From a total of 828 articles, 83 were identified as referring to nervous system and/or psychiatric disorders induced by quinolones. 145 individual case reports were extracted from the 83 articles. 40.7% of the individual case reports belonged to psychiatric disorders only, whereas 46.9% related to neurological disorders only. Eight (5.5%) individual case reports presented both neurological and psychiatric ADRs. Ciprofloxacin, ofloxacin and pefloxacin were the quinolones with more neurological and psychiatric ADRs reported in the literature. Ciprofloxacin has been extensively used worldwide, which may explain the higher number of reports, while for ofloxacin and pefloxacin, the number of reports may be over-representative. A total of 232 ADRs were identified from the selected articles, with 206 of these related to psychiatric and/or neurological ADRs. The other 26 were related to other body systems but were reported together with the reactions of interest. Mania, insomnia, acute psychosis and delirium were the most frequently reported psychiatric adverse events; grand mal convulsion, confusional state, convulsions and myoclonus were the most frequently reported neurological adverse events. Several aspects should be taken into account in the development of CNS adverse effects, such as the pharmacokinetics of quinolones, chemical structure and quinolone uptake in the brain. These events may affect not only susceptible patients but also 'healthy' patients. PMID- 21585221 TI - Impact of a pharmacotherapeutic programme on control and safety of long-term anticoagulation treatment: a controlled follow-up study in Spain. AB - BACKGROUND: In patients undergoing oral anticoagulation treatment, correct control of the international normalized ratio (INR) is necessary. This study sought to assess the effectiveness of a pharmacotherapeutic follow-up programme (PTP) on achieving an optimal INR range, reducing the need for rescue medications and for monitoring the development of possible adverse events associated with poor oral anticoagulation therapy control (haemorrhagic events and thromboembolic disease). OBJECTIVE: The aim of this study was to evaluate the effectiveness of a PTP targeted at the anticoagulated patient to ensure proper self-control of anticoagulation. METHODS: This was a prospective, controlled, multicentre cohort study conducted at four primary care centres in Galicia (northwest Spain), covering a group of patients receiving anticoagulation treatment exposed to pharmacotherapeutic follow-up by a primary care pharmacist (n = 272), and a concurrent control group (n = 460). The intervention consisted of a patient health-education programme plus activities involving collaboration with the physician. The educational intervention exposure period was 12 months (starting from February 2006 and finishing in February 2007), during which time a minimum of one INR determination per month was performed. To assess the quality of haematological control, the British Committee for Standards in Haematology criteria were used, namely (i) 50% or more determinations per patient within a range of 0.5 units above or below the target INR; and (ii) 80% or more determinations per patient within a range of 0.75 units above or below the target INR. As an indicator of correct control of coagulation, we also assessed the occurrence of oral anticoagulation therapy-related adverse events, such as active bleeding, haematomas (jointly referred to as haemorrhagic events) and thromboembolic events. Depending on the type of response variable, negative binomial regression or Cox proportional risks models were fitted. RESULTS: Compared with the control group, the PTP managed to improve correct INR ranges by (i) 25% (relative risk [RR] = 0.75; 95% CI 0.69, 0.82) in terms of the number of patients who had their determinations within +/-0.5 units of the target range; and (ii) 26% (RR = 0.74; 95% CI 0.67, 0.81) in terms of the number of patients who had their determinations within +/-0.75 units of the target range. Patients belonging to the intervention group registered a 75% reduction in bleeding (hazard ratio [HR] = 0.25; 95% CI 0.18, 0.36). For every 3.27 patients exposed to the PTP, one event would be prevented (number needed to treat = 3.27; 95% CI 2.73, 4.07). CONCLUSIONS: Including patients receiving oral anticoagulant treatment in a PTP enhances INR control, efficacy and safety of treatment, and efficiency of primary healthcare services. PMID- 21585222 TI - Risk of depressive episodes with rimonabant: a before and after modified prescription event monitoring study conducted in England. AB - BACKGROUND: Marketing authorization for rimonabant was withdrawn in October 2008, mainly because the psychiatric adverse effects could not be addressed by further risk minimization. OBJECTIVE: The aim of the study was to compare the risk of major and minor depressive episodes in the 6 months prior to and the 6 months after starting treatment with rimonabant. METHODS: We conducted a before and after study using the observational cohort technique of Modified Prescription Event Monitoring to compare the risk of major and minor depressive episodes in new users of rimonabant reported in the 6 months before to the 6 months after starting treatment with rimonabant. Patients were identified from dispensed prescriptions issued by primary care physicians from June 2006 to October 2008. Patient demographics and information on depressive episodes were requested 6 months after the date of the first prescription for each patient. Risk ratios (RR) were calculated by comparing before and after events using a matched analysis. RESULTS: The cohort comprised 10,011 patients. The number of patients who had major depressive episodes before and after starting treatment were 147 and 168, respectively (RR 1.14; 95% CI 0.94, 1.39) and the number of patients who had minor depressive episodes were 825 and 829, respectively (RR 1.00; 95% CI 0.93, 1.10). For patients who had a previous history of psychiatric illness (n = 1132), 91 and 73, respectively, experienced major depressive episodes (RR 0.80; 95% CI 0.62, 1.03), and 367 and 220, respectively, experienced minor depressive episodes (RR 0.59; 95% CI 0.53, 0.68). For patients without a previous history of psychiatric illness (n = 8879), 56 and 95, respectively, experienced major depressive episodes (RR 1.7; 95% CI 1.2, 2.3), and 458 and 609, respectively, experienced minor depressive episodes (RR 1.33; 95% CI 1.20, 1.48). CONCLUSIONS: When comparing all patients in the cohort, there was no increased risk of developing a depressive episode whilst taking rimonabant. However, when considering subsets of patients with and without a previous history of psychiatric illness, the risk profiles were different. In patients without a previous history of psychiatric illness, there were more depressive episodes in the 6 months after starting treatment compared with the 6 months before starting treatment with rimonabant. PMID- 21585224 TI - The new EU legislation on pharmacovigilance and changing models for drug development. PMID- 21585223 TI - Prescription patterns in asthma patients initiating salmeterol in UK general practice: a retrospective cohort study using the General Practice Research Database (GPRD). AB - BACKGROUND: An association between salmeterol, a long-acting beta(2)-agonist (LABA), use and rare serious asthma events or asthma mortality was observed in two large clinical trials. This has resulted in heightened scrutiny of LABAs and comprehensive reviews by regulatory agencies. OBJECTIVE: The aim of this retrospective observational cohort study was to better characterize salmeterol medication use patterns in the UK. We describe asthma prescription patterns in a cohort of patients (n =17,745) in the General Practice Research Database who initiated treatment with salmeterol-containing prescriptions between 2003 and 2006, including salmeterol and salmeterol/fluticasone propionate in a single device. METHODS: Prescriptions patterns by medication class, including concurrent prescription of salmeterol with inhaled corticosteroids (ICS), were described using 6-month intervals in the 1-year period before and after the salmeterol containing index prescription. RESULTS: In the 0- to 6-month and 7- to 12-month periods prior to initiation of the salmeterol-containing prescription, the cohort experienced worsening of asthma, measured by an increase in the proportion of patients with prescriptions for short-acting beta-agonists [SABA] (73-89%), ICS (70-81%) and systemic corticosteroids (14-28%). Nearly all patients prescribed salmeterol were concurrently prescribed ICS (>=95% within 90 days). In the 12 months following initiation of the salmeterol-containing prescription, a decrease in asthma prescriptions was observed. DISCUSSION: These results support the appropriate prescribing of salmeterol-containing medications, as per recommendations in asthma treatment guidelines in the UK. CONCLUSION: Salmeterol was consistently prescribed as an add-on asthma-controller with an ICS for most patients, and was associated with improvements in asthma control, as indicated by decreases in SABA and systemic corticosteroid prescriptions following salmeterol introduction. PMID- 21585227 TI - Pre-hospital care of spinal cord injury in a rural Indian setting. PMID- 21585226 TI - Cost estimation of cardiovascular disease events in the US. AB - BACKGROUND: In this study, we developed cost prediction equations that facilitate estimation of the costs of various cardiovascular events for patients of specific demographic and clinical characteristics over varying time horizons. METHODS: We used administrative claims data and generalized linear models to develop cost prediction equations for selected cardiovascular events, including myocardial infarction (MI), angina, strokes and revascularization procedures. Separate equations were estimated for patients with events and for their propensity score matched controls. Attributable costs were estimated on a monthly basis for the first 36 months after each event and annually thereafter, with differences in survival between cases and controls factored into the longitudinal cost calculations. The regression models were used to estimate event costs ($US, year 2007 values) for the 'average' patient in each event group, over various time periods ranging from 1 month to lifetime. RESULTS: When the equations are run for the average patient in each event group, attributable costs of each event in the acute phase (i.e. first 3 years) are substantial (e.g. MI $US 73 300; hospitalization for angina $US 36 000; non-fatal haemorrhagic stroke $US 71 600). Furthermore, for most events, cumulative costs remain substantially higher among cases than among controls over the remaining lifetime of the patients. CONCLUSIONS: This study provides updated estimates of medical care costs of cardiovascular events among a managed care population over various time horizons. Results suggest that the economic burden of cardiovascular disease is substantial, both in the acute phase as well as over the longer term. PMID- 21585228 TI - Colorectal cancer screening in rural and remote areas: analysis of the National Bowel Cancer Screening Program data for South Australia. AB - INTRODUCTION: In Australia, colorectal cancer is the second most commonly diagnosed cancer and cause of death from malignant diseases, and its incidence is rising. The aim of this article was to present an analysis of National Bowel Cancer Screening Program (NBCSP) data for rural and remote South Australia (SA), in order to identify geographical areas and population groups that may benefit from targeted approaches to increase participation rates in colorectal cancer screening. METHODS: De-identified data from the NBCSP (February 2007 to July 2008) were provided by Medicare Australia. Mapping and analysis of the NBCSP data was performed using ESRI ArcGIS (http://www.esri.com/software/arcgis/index.html) and MapInfo (http://slp.pbinsight.com/info/mipro-sem-au). Data were aggregated to postcode and Accessibility/Remoteness Index of Australia (ARIA) and participation was then mapped according to overall participation rates, sex, age, Indigenous status and Socio-Economic Indexes for Areas (SEIFA)-Index of Relative Socio Economic Disadvantage (IRSD). The participants were South Australians who turned 55 and 65 years between 2007 and 2008 who returned the completed NBCSP test sent to them by Medicare Australia. RESULTS: The overall participation rate was 46.1% in rural and remote SA, although this was statistically significantly different (p<.001) according to sex (46.7% for males and 53.3% for females), age (45.2% for those 55 years, and 52% for those 65 years), socio-economic status (from 43% in 'most deprived' quintile to 50% in 'most affluent' quintile) and remoteness (45.6% for metropolitan, 46% for remote and 48.6% for rural areas). Indigenous participation was 0.5%. CONCLUSIONS: The findings of this study suggest lower NBCSP participation rates for people from metropolitan and remote areas, compared with those from rural areas. The uptake of cancer screening is lower for older rural and remote residents, men, Indigenous people, lower socioeconomic groups and those living in the Far North subdivision of SA. PMID- 21585229 TI - Antiangiogenic anticancer strategy based on nanoparticulate systems. AB - INTRODUCTION: Angiogenesis is a process that provides a blood supply for cancer cells. The discovery that the blockade of this blood supply results in the inhibition of cancer cell growth has been applied in cancer treatment. This antiangiogenic strategy is mainly directed at the inhibition of the binding process between proangiogenic growth factors and their receptors or the inhibition of the activity of proteolytic enzymes of the extracellular matrix. The toxicity of some antiangiogenic agents, such as small-molecule inhibitors, and the instability of antiangiogenic proteins require their formulation in an appropriate delivery system. On the other hand, active drug targeting to selective markers expressed on tumor vasculature could improve antiangiogenic treatment. AREAS COVERED: The present review focuses on nanoparticulate systems (nanoparticles, liposomes, polymeric micelles, etc.) because their properties could enable both the targeting of endothelial cells and the efficient delivery of antiangiogenic agents. The most important properties of nanoparticles that influence both processes, such as their size, charge and surface modification, are also discussed. Various examples illustrating the targeting ability of nanoparticles are reported, in particular conjugated nanoparticles targeting VEGF and its receptors, fibroblast growth factor and its receptors, EGFRs, MMPs, tubulin function and so on. EXPERT OPINION: Targeting of nanoparticles (e.g., by tumor-penetrating peptides) allows the co-administration of antiangiogenic and anticancer drugs, facilitates drug penetration into extravascular tumor tissue and improves the therapeutic effect at reduced drug doses. PMID- 21585235 TI - Ethnic differences in the metabolism, toxicology and efficacy of three anticancer drugs. AB - INTRODUCTION: Large inter-individual and inter-ethnic differences are observed in efficacies and toxicities of medical drugs. To improve the predictability of these differences, pharmacogenetic information has been applied to clinical situations. Expanding pharmacogenetic information would be a valuable tool to the medical community as well as the patient to fulfill the promise of personalized anticancer drug therapy. AREAS COVERED: This review highlights genetic polymorphisms and ethnic differences of genes, UGT1As, CYP3A4, CES1As, ABCB1, ABCC2, ABCG2, SLCO1B1, CDA and CYP2D6, involved in metabolism and disposition of three anticancer drugs: irinotecan, gemcitabine and tamoxifen. EXPERT OPINION: Recent pharmacogenetic studies have successfully identified distinct ethnic differences in genetic polymorphisms that are potentially involved in efficacies and toxicities of anticancer drugs. This achievement has led to personalized irinotecan therapy, reflecting ethnic differences in UGT1A1 genotypes, and possible benefits of genetic testing have also been suggested for gemcitabine and tamoxifen therapy, which still requires further validation. The ultimate goal for patients is a high rate or even perfect prediction of efficacies and toxicities of anticancer drugs in each ethnic population. For this challenge, more clinical studies combined with comprehensive omics approaches are necessary to further advance the field. PMID- 21585238 TI - Connexins as therapeutic targets in lung disease. AB - INTRODUCTION: The lung is a mechanically active system exposed to the external environment and is particularly sensitive to injury and inflammation. Studies have identified intercellular communication pathways that promote proper lung function in response to injury and disease. These pathways involve connexins (Cxs) and gap junctional intercellular communication (GJIC). AREAS COVERED IN THIS REVIEW: The functional expression of Cxs in airway epithelium and vasculature, under normal and pathological conditions, is reviewed. Inhibition of GJIC and/or silencing of Cxs have been shown to modulate the course of disease development. Cx-based channels: i) coordinate ciliary beating and fluid transport to promote clearance of particulates, ii) regulate secretion of pulmonary surfactant, in response to deep inhalation by interconnecting type I and type II alveolar epithelial cells, and iii) are key mediators of pro- and anti inflammatory signalling by the pulmonary endothelium, in order to modulate leukocyte recruitment from the circulation. EXPERT OPINION: Cx-based channels play several central roles in promoting a regulated inflammatory response and facilitating lung repair, thus enabling the pulmonary epithelium and vasculature to behave as integrated systems. Several pathologies can disrupt the normal communication pathways required for proper lung function, including acute lung injury, asthma, cystic fibrosis, pulmonary fibrosis and cancer. PMID- 21585239 TI - Emerging pharmacotherapeutic strategies for cholangiocarcinoma. AB - INTRODUCTION: Although of limited clinical benefit, chemotherapy represents the cornerstone of management for patients with inoperable cholangiocarcinoma. The literature on chemotherapy in advanced cholangiocarcinoma is difficult to interpret because of the heterogeneity of cholangiocarcinoma, the use of various chemotherapeutic agents in different combinations and dosing regimens, and the small size of existing patient cohorts. AREAS COVERED: The authors discuss the major advances in the therapy of cholangiocarcinoma over the past decade. The audience will become familiarized with the contemporary medical management of cholangiocarcinoma and potentially useful agents/combinations for the therapy of this entity in the future. EXPERT OPINION: In recent years, gemcitabine-based chemotherapy has improved overall survival in advanced cholangiocarcinoma. Although gemcitabine-cisplatin combination represents the largely accepted standard for biliary cancers at present, very few studies so far have looked at the results in cholangiocarcinoma patients only. Therefore, large multicenter, randomized clinical trials are essential to identify the optimal treatment strategy for this rare tumor. In addition, regimens employing gemcitabine with oxaliplatin and/or fluoropyrimidines have shown promising results and warrant additional investigation in cholangiocarcinoma. The efficacy of a variety of newer agents is also now being tested in clinical trials. PMID- 21585237 TI - Lung-derived mesenchymal stromal cell post-transplantation survival, persistence, paracrine expression, and repair of elastase-injured lung. AB - While multipotent mesenchymal stromal cells have been recently isolated from adult lung (L-MSCs), there is very limited data on their biological properties and therapeutic potential in vivo. How L-MSCs compare with bone marrow-derived MSCs (BM-MSCs) is also unclear. In this study, we characterized L-MSC phenotype, clonogenicity, and differentiation potential, and compared L-MSCs to BM-MSCs in vivo survival, retention, paracrine gene expression, and repair or elastase injury after transplantation. L-MSCs were highly clonogenic, frequently expressed aldehyde dehydrogenase activity, and differentiated into osteocytes, chondrocytes, adipocytes, myofibroblasts, and smooth muscle cells. After intravenous injection (2 h), L-MSCs showed greater survival than BM-MSCs; similarly, L-MSCs were significantly more resistant than BM-MSCs to anchorage independent culture (4 h) in vitro. Long after transplantation (4 or 32 days), a significantly higher number of CD45(neg) L-MSCs were retained than BM-MSCs. By flow cytometry, L-MSCs expressed more intercellular adhesion molecule-1 (ICAM-1), platelet derived growth factor receptor alpha (PDGFRalpha), and integrin alpha2 than BM-MSCs; these proteins were found to modulate endothelial adherence, directional migration, and migration across Matrigel in L-MSCs. Further, L-MSCs with low ICAM-1 showed poorer lung retention and higher phagocytosis in vivo. Compared with BM-MSCs, L-MSCs expressed higher levels of several transcripts (e.g., Ccl2, Cxcl2, Cxcl10, IL-6, IL-11, Hgf, and Igf2) in vitro, although gene expression in vivo was increased by L-MSCs and BM-MSCs equivalently. Accordingly, both L-MSCs and BM-MSCs reduced elastase injury to the same extent. This study demonstrates that tissue-specific L-MSCs possess mechanisms that enhance their lung retention after intravenous transplantation, and produce substantial healing of elastase injury comparable to BM-MSCs. PMID- 21585240 TI - Linezolid in the central nervous system: comparison between cerebrospinal fluid and plasma pharmacokinetics. AB - BACKGROUND: Linezolid is effective against methicillin-resistant Staphylococcus aureus, which may cause central nervous system (CNS) infections, but drug concentrations in plasma are characterized by a large inter-patient variability. Therefore, the present study was aimed at evaluating linezolid pharmacokinetics in plasma and cerebrospinal fluid (CSF) in 7 patients with external ventricular drainage, who received linezolid 600 mg twice daily as 1-h intravenous infusion to prevent CNS infections. METHODS: Plasma and CSF linezolid concentrations were measured by high-performance liquid chromatography (HPLC) after the 1(st) and 5(th) dose, and pharmacokinetics were evaluated by non-compartmental analysis. RESULTS: Values of the CSF area under the time/concentration curve (AUC) (range 18.2-85.5 and 19.6-160.5 h * mg/l at the 1st and 5th dose, respectively) were lower than those calculated in plasma (range 27.6-224.0 and 27.5-166.1 h * mg/l, respectively). For minimum inhibitory concentration (MIC) = 1 mg/l, CSF AUC/MIC values were nearly equal to or greater than 100 only in 2 subjects after the 1st and 5th dose, whereas mean time above the MIC (T > MIC) values were higher than 75% in only 3 patients. Similar results were obtained when pharmacokinetic/pharmacodynamic parameters were evaluated in plasma. CONCLUSION: The present results suggest that changes in linezolid doses and measurement of drug concentrations should be considered as useful strategies to optimize treatment in some patients. PMID- 21585241 TI - Evidence of simian virus 40 infection in multiple organ transplant recipients with renal dysfunction. AB - Electron microscopy (EM), real-time polymerase chain reaction (PCR) and conventional PCR were used to identify viruses associated with infection in 2 transplantation patients. An autologous haematopoietic stem cell, liver and renal transplant recipient was found to be positive for simian virus 40 (SV40). Dual BK virus and SV40 infection was found in a heart and renal transplantation patient. SV40 infection can occur in immunocompromised patients. PMID- 21585242 TI - Travel and vaccination patterns: a report from a travel medicine clinic in northern Sweden. AB - BACKGROUND: The Travel Medicine Clinic in Umea is one of Sweden's largest public providers of vaccination and counselling prior to international travel. During the study period it was the only travel medicine clinic in Umea. This study describes the demography of the visitors to the clinic and travel destinations and durations, as well as vaccinations administered. METHODS: This was a retrospective study for the period January 2005 to April 2008 based on pre-travel consultation questionnaires and on vaccine expenditure data. A 10% sample of 16,735 first visits prior to international travel was consecutively selected according to the chronology of the visits. RESULTS: Data on 1698 travellers were included in the study. Thailand was the most common destination among visitors, accounting for one third of all destinations. Medical problems affecting pre travel health planning were rare. Four out of 5 visitors (79%) received only 1 vaccination, mainly for hepatitis A. Travellers to Thailand more often sought travel health advice compared to travellers to Turkey, despite the fact that the 2 destinations were almost equally distributed among travellers from Umea. We found differences between men and women in money spent on vaccines and in particular in vaccination against Japanese encephalitis. CONCLUSIONS: To assess the optimal vaccination level at a travel medicine clinic is difficult. Decisions are affected by general recommendations and the risk perception of the travel medicine practitioner, as well as the risk perception of the traveller. The sex difference found in this study might be due to gender differences in risk perception and should be further investigated. PMID- 21585243 TI - General practitioners' views on the use of the levonorgestrel-releasing intrauterine system in young, nulligravid women, in London, UK. AB - BACKGROUND AND OBJECTIVES: The levonorgestrel-releasing intrauterine system (LNG IUS, Mirena(r)) is one of the most reliable and cost-effective methods of contraception. In the UK, uptake of this method among nulligravid women under 25 years of age is very low. This study surveyed the knowledge and attitudes of general practitioners (GPs) towards the use of the LNG-IUS by young nulligravidae. METHOD: A questionnaire containing 15 multiple choice questions was sent to GPs in City and Hackney Primary Care Trust, in London, in 2008. RESULTS: Seventy-one GPs responded (38%). None would opt for the LNG-IUS as their first choice contraceptive method for nulligravid women under 25 years of age. Ninety-two percent stated that an oral contraceptive was their first choice, whilst only 8% chose a long-acting reversible contraceptive (LARC). Seventeen percent considered that the LNG-IUS was associated with an increased risk of pelvic inflammatory disease (PID), and 23% stated it was associated with an increased risk of ectopic pregnancy. CONCLUSIONS: The LNG-IUS was not widely promoted or provided to young nulligravid women by GPs participating in this survey. Misconceptions relating to PID and risk of ectopic pregnancy and perceived difficulty of insertion in nulligravidae may contribute to the low use of this contraceptive. PMID- 21585244 TI - Female sex bias in human embryonic stem cell lines. AB - The factors limiting the rather inefficient derivation of human embryonic stem cells (HESCs) are not fully understood. The aim of this study was to analyze the sex ratio in our 42 preimplantation genetic diagnosis (PGD)-HESC lines, in an attempt to verify its affect on the establishment of HESC lines. The ratio between male and female PGD-derived cell lines was compared. We found a significant increase in female cell lines (76%). This finding was further confirmed by a meta-analysis for combining the results of all PGD-derived HESC lines published to date (148) and all normal karyotyped HESC lines derived from spare in vitro fertilization embryos worldwide (397). Further, gender determination of embryos demonstrated that this difference originates from the actual derivation process rather than from unequal representation of male and female embryos. It can therefore be concluded that the clear-cut tendency for female preponderance is attributed to suboptimal culture conditions rather than from a true gender imbalance in embryos used for derivation of HESC lines. We propose a mechanism in which aberrant X chromosome inactivation and/or overexpression of critical metabolic X-linked genes might explain this sex dimorphism. PMID- 21585245 TI - Interleukin-23: a key cytokine in inflammatory diseases. AB - Interleukin-23 (IL-23) is a pro-inflammatory cytokine composed of two subunits, p19 and p40. The p40 subunit is shared with IL-12. IL-23 and IL-12 have different receptors and different effects. Whereas IL-12 induces development of Th1 cells, which produce interferon-gamma, IL-23 is involved in differentiation of Th17 cells in a pro-inflammatory context and especially in the presence of TGF-beta and IL-6. Activated Th17 cells produce IL-17A, IL-17F, IL-6, IL-22, TNF-alpha, and GM-CSF. Inflammatory macrophages express IL-23R and are activated by IL-23 to produce IL-1, TNF-alpha, and IL-23 itself. These effects identify IL-23 as a central cytokine in autoimmunity and a highly promising treatment target for inflammatory diseases. IL-23 is found in the skin of patients with psoriasis, in the bowel wall of patients with chronic inflammatory bowel disease, and in synovial membrane of patients with rheumatoid arthritis. IL-23 is involved in osteoclastogenesis, independently from IL-17, via induction of RANKL expression. Debate continues to surround the role for IL-23 in the pathophysiology of inflammatory joint diseases (rheumatoid arthritis and spondyloarthritis). Ustekinumab, which inhibits IL-12 and IL-23 by blocking p40, has been found effective in cutaneous psoriasis and psoriatic arthritis, as well as in Crohn's disease. Treatments that specifically target IL-23 (antibodies to p19) are being developed. PMID- 21585246 TI - High blood hemoglobin concentration as risk factor of major atherosclerotic cardiovascular events in 114,159 healthy men and women in the apolipoprotein mortality risk study (AMORIS). AB - BACKGROUND: Few studies have tested differences in relationships between hemoglobin (Hb) and long-term risk of major cardiovascular diseases according to age and gender in healthy subjects as opposed to anemia. AIMS: Such relationships were examined and risk-tested in relation to Hb values in the Apolipoprotein MOrtality RISk (AMORIS) Study. METHODS: Using data from AMORIS and the Swedish hospital discharge and mortality registers, a prospective cohort study of 114,159 subjects with mean follow-up of 11.8 years, the association between Hb and risk of acute myocardial infarction (AMI), ischemic stroke (IS), and congestive heart failure (CHF) by Cox regression analysis according to age and gender was studied. RESULTS: Elevated Hb levels were associated to acute myocardial infarction (AMI) (HR 1.10 (1.06-1.13) per SD change), mostly confined to men and younger subjects but with greater sex similarity trends for CHF. Slightly increased risks were seen for the lowest Hb levels in the elderly and in females. IS risk was positively and more linearly associated to Hb. INTERPRETATION: In AMORIS the highest AMI and CHF risks were found in the upper region of the distribution, but different shapes of relationships according to age and gender were found. IS associated positively with Hb. Key words: PMID- 21585247 TI - Golgi pH, its regulation and roles in human disease. AB - Most organelles within the exocytic and endocytic pathways typically acidify their interiors, a phenomenon that is known to be crucial for their optimal functioning in eukaryotic cells. This review highlights recent advances in our understanding of how Golgi acidity is maintained and regulated, and how its misregulation contributes to organelle dysfunction and disease. Both its biosynthetic products (glycans) and protein-sorting events are highly sensitive to changes in Golgi luminal pH and are affected in certain human disease states such as cancers and cutis laxa. Other potential disease states that are caused by, or are associated with, Golgi pH misregulation will also be discussed. PMID- 21585248 TI - Ixabepilone for the treatment of breast cancer. AB - Patients with breast cancer that becomes resistant to taxanes and anthracyclines experience considerable morbidity and mortality. The Food and Drug Administration has approved the use of ixabepilone for the treatment of patients with locally advanced or metastatic breast cancer that is refractory or resistant to taxanes and anthracyclines. The purpose of this review is to summarize the evidence from published studies on the pharmacological data and clinical activity of ixabepilone in patients with breast cancer. The conclusion of this review is that ixabepilone demonstrated a high efficacy in combination with capecitabine and as a single agent in breast cancer refractory to taxanes and anthracyclines. The clinical activity of ixabepilone combined with bevacizumab for advanced breast cancer was very promising. PMID- 21585249 TI - The incremental value of brachial flow-mediated dilation measurements in risk stratification for incident cardiovascular events: a systematic review. AB - Abstract Adequate risk assessment for cardiovascular disease (CVD) is essential as a guide to initiate drug treatment. Current methods based on traditional risk factors could be improved considerably. Although brachial flow-mediated dilation (FMD) predicts subsequent cardiovascular events, its predictive value on top of traditional risk factors is unknown. We performed a systematic review to evaluate the incremental predictive value of FMD on top of traditional risk factors in asymptomatic individuals. Using PubMed and reference tracking, three studies were identified that reported on the incremental value of FMD using change in the area under the curve (AUC). Two large cohort studies found no improvement in AUC when FMD was added to traditional risk prediction models, whereas one small case control study found an improvement. One study used the net reclassification improvement (NRI) to assess whether FMD measurement leads to correct risk stratification in risk categories. Although this study did not find an improvement in AUC, the NRI was statistically significant. Based on the reclassification results of this study, FMD measurement might be helpful in risk prediction. Evidence supporting the use of FMD measurement in clinical practice for risk stratification for CVD on top of traditional risk factors is limited, and future studies are needed. PMID- 21585250 TI - Inherited disorders of blood coagulation. AB - Hemostasis is traditionally defined as a physiological response to blood vessel injury and bleeding, which entails a co-ordinated process involving the blood vessel, platelets, and blood clotting proteins (i.e. coagulation factors). Hemostasis can be divided into primary and secondary components. The former rapidly initiates after endothelial damage and is characterized by vascular contraction, platelet adhesion, and formation of a soft aggregate plug. The latter is initiated following the release of tissue factor and involves a complex sequence of events known as the blood coagulation cascade, encompassing serial steps where each coagulation factor activates another in a chain reaction that culminates in the conversion of fibrinogen to fibrin. Patients carrying abnormalities of the coagulation cascade (i.e. deficiencies of coagulation factors) have an increased bleeding tendency, where the clinical severity is mostly dependent upon the type and the plasma level of the factor affected. These disorders also impose a heavy medical and economic burden on individual patients and society in general. The aim of this article is to provide a general overview on the pathophysiology, clinics, diagnostics, and therapy of inherited disorders of coagulation factors. PMID- 21585252 TI - Development and reliability of performance indicators for measuring adherence to a guideline for depression by insurance physicians. AB - INTRODUCTION: We wanted to measure adherence to the guideline for depression in disability assessments. The research questions we addressed were: How can we develop performance indicators (PIs) for adherence to the Dutch guideline for disability assessment of patients with depression and how can we measure the quality of the scores? What is the inter-rater reliability of these PIs? What is the quality of the PI scores? METHODS: PIs, developed by the researchers, were reviewed on various aspects, by a panel of seven experts in several consulting rounds. After adjustments, senior insurance physicians (IPs) attended two training sessions and scored the PIs on 10 different simulated case reports. Two researchers developed proxy 'gold standard' scores for these 10 case reports. To assess the inter-rater reliability and the quality of the scores, we calculated the intra-class correlations (ICC) and 95% confidence intervals (CI) of the PI scores and of the PI scores compared to the proxy 'gold standard', respectively. RESULTS: Six specific and relevant PIs resulted from the consultation of the panel of experts. The PI scores for the 10 case reports, rated by seven (of the eight) senior IPs who completed both training sessions, showed that the PIs were not reliable at individual level (ICC = 0.543; 95% CI 0.426-0.642). However, the ICC became more reliable as an average of two raters was calculated (ICC = 0.704). The ICC of the PI scores with the proxy 'gold standard' was 0.538 (95% CI 0.419-0.640), but the quality was higher when calculated as an average of two raters (ICC = 0.700). CONCLUSION: The PIs for adherence to the guideline were sufficiently reliable, and the quality of their scores was adequate if at least two well-trained raters were involved. The senior IPs evaluated the feasibility of the PIs as good, with a prerequisite of sufficient training. This method may be interesting for measuring guideline adherence and quality of disability assessments in general. PMID- 21585251 TI - Human Schwann cells retain essential phenotype characteristics after immortalization. AB - Schwann cells (SCs) play an important role in the pathogenesis of peripheral nerve diseases and represent a potential target for development of therapies. However, use of primary human SCs (hSCs) for in vitro models is limited because these cells are difficult to prepare and maintain in high yield and purity under common cell culture conditions. To circumvent this obstacle, we immortalized primary human fetal SCs using the SV40 large T-antigen and human telomerase reverse transcriptase expression vectors. After cloning, selection, and purification, we evaluated several immortalized SC lines for their ability to express extracellular matrix (ECM) molecules and myelinate embryonic rat sensory axons. In addition, we established a gene expression profile and explored their sensitivity to oxidative stress in a simple in vitro assay. Immortalized hSC clones expressed common glial markers and a broad variety of growth factors, receptors, and ECM molecules as determined by immunocytochemistry, microarray, and quantitative reverse transcription-polymerase chain reaction. In neuron-SC co cultures, these cells were able to myelinate rat dorsal root ganglia neurons, although their effectiveness was lower in comparison to primary rat SCs. In toxicity assays, immortalized hSCs remain susceptible to oxidative stress induced by H(2)O(2). This study shows that, using specific immortalization techniques, it is possible to establish hSC lines that retain characteristics of typical primary hSCs. These cells are particularly useful for drug screening and studies aimed at disease mechanisms involving SCs. PMID- 21585253 TI - Rehabilitation outcomes for orthopaedic trauma individuals as measured by the INTERMED. AB - PURPOSE: Bio-psychosocial characteristics of patients after orthopaedic traumas may be a strong predictor of poor outcome. The objective of this prospective study was to assess whether the INTERMED, a measure of bio-psychosocial complexity, identifies complex inpatients during rehabilitation including vocational aspects with a poor outcome 1 year after discharge. METHOD: At entry, the INTERMED scores of 118 inpatients were used to assign patients to the high or low complexity group. A questionnaire evaluated 1 year after discharge whether patients: (1) returned to work, (2) still have therapies, (3) take psychoactive drugs, (4) take medication against pain and (5) were satisfied with vocational therapy. Univariate logistic regressions identified which variables predict INTERMED case complexity during hospitalisation as well as predictors (i.e. INTERMED case complexity, French as preferred language, duration of the disability, accident at work, work qualification, severity of the injury, psychiatric co-morbidities, pain) of the five measured outcomes 1 year after discharge. RESULTS: During hospitalisation, the high complexity group was associated with a high prevalence of psychiatric co-morbidities, a higher level of pain and a weaker perception of treatment effects. One year after discharge, the INTERMED was the sole variable to predict all outcomes. CONCLUSION: The INTERMED identifies complex patients during vocational rehabilitation after orthopaedic trauma and is a good predictor of poor outcome 1 year after discharge. PMID- 21585254 TI - Reflections on screening blood donors for the presence of virus infections in England. PMID- 21585256 TI - Translocation of effectors: revisiting the injectosome model. PMID- 21585257 TI - Antibiotic treatment of acute otitis media in pediatrics. PMID- 21585258 TI - Does Staphylococcus aureus nasal colonization involve biofilm formation? AB - The human anterior nares are used by Staphylococcus aureus as the major colonization site in 20-30% of the human population. Eradication of S. aureus carriage can significantly reduce the numbers of nosocomial infections. However, the interactions governing the colonization process have remained elusive and it has been debated whether S. aureus adopts a biofilm-like state in the nose. We summarize recent studies on staphylococcal living conditions during nasal colonization, which favour a dispersed rather than a biofilm-related mode of growth during S. aureus nasal colonization. This notion is of major importance for future directions in the development of new decolonization strategies. PMID- 21585259 TI - Clinical impact and molecular basis of antimicrobial resistance in non-baumannii Acinetobacter. AB - Species of Acinetobacter other than Acinetobacter baumannii are involved in nosocomial infections. Acinetobacter lwoffii, Acinetobacter genomospecies 3 and Acinetobacter genomospecies 13TU are found in community- and nosocomial-acquired infections as well as in neonatal intensive care units. The non-baumannii Acinetobacter are normally highly susceptible to ciprofloxacin, ampicillin/sulbactam, gentamicin and tigecycline. Carbepenems show good activity although resistant isolates have been reported. Resistance to beta-lactams other than carbapenems is associated with overexpression of chromosomal cephalosporinases and extended-spectrum beta-lactamase acquisition, whereas resistance to carbapenems involves acquisition of carbapenemases. Quinolone resistance is related to gyrA and/or parC mutations but overexpresion of efflux proteins also plays an important role. With the development of novel and more accurate typing methodologies, an increase in infections caused by non-baumannii Acinetobacter might be observed in the future. PMID- 21585260 TI - Epidemiology and virulence insights from MRSA and MSSA genome analysis. AB - Staphylococcus aureus is a major human pathogen responsible for a wide diversity of infections ranging from localized to life threatening diseases. From 1961 and the emergence of methicillin-resistant S. aureus (MRSA), this bacterium has shown a particular capacity to survive and adapt to drastic environmental changes and since the beginning of the 1990s it has spread worldwide. Until recently, S. aureus was considered as the prototype of a nosocomial pathogen but it has now been recognized as an agent responsible for outbreaks in the community. Several recent reports suggest that the epidemiology of MRSA is changing. Understanding of pathogenicity, virulence and emergence of epidemic clones within MRSA populations is not clearly defined, despite several attempts to identify common molecular features between strains that share similar epidemiological and/or virulence behavior. These studies included: pattern profiling of bacterial adhesins, analysis of clonal complex groups, molecular genotyping and enterotoxin content analysis. To date, all approaches failed to find a correlation between molecular determinants and clinical outcomes. We hypothesize that the capacity of the bacterium to become more invasive or virulent is determined by genetics. The utilization of massively parallel methods of analysis is therefore ideal to study the contribution of genetics. Therefore, this article focuses on the entire genome including coding sequences as well as noncoding sequences. This high resolution approach allows the monitoring micro- and macroevolution of MRSA and identification of specific genomic markers of evolution of invasive or highly virulent phenotypes. PMID- 21585261 TI - Leprosy susceptibility: genetic variations regulate innate and adaptive immunity, and disease outcome. AB - The past few years have been very productive concerning the identification of genes associated with leprosy. Candidate gene strategies using both case-control and family-based designs, as well as large-scale approaches such as linkage and gene-expression genomic scans and, more recently, genome-wide association studies, have refined and enriched the list of genes highlighting the most important innate and adaptive immune pathways associated with leprosy susceptibility or resistance. During the early events of host-pathogen interaction identified genes are involved in pattern recognition receptors, and mycobacterial uptake (TLRs, NOD2 and MRC1), which modulate autophagy. Another gene, LTA4H, which regulates the levels of lipoxin A4 and possibly interacts with lipid droplet-related events, also plays a role in the early immune responses to Mycobacterium leprae. Together, the activation of these pathways regulates cellular metabolism upon infection, activating cytokine production through NF kappaB and vitamin D-vitamin D receptor pathways, while PARK2 and LRRK2 participate in the regulation of host-cell apoptosis. Concomitantly, genes triggered to form and maintain granulomas (TNF, LTA and IFNG) and genes involved in activating and differentiating T-helper cells (HLA, IL10, as well as the TNF/LTA axis and the IFNG/IL12 axis) bridge immunological regulation towards adaptive immunity. Subtle variations in these genes, mostly single nucleotide polymorphisms, alter the risk of developing the disease or the severity of leprosy. Knowing these genes and their role will ultimately lead to better strategies for leprosy prevention, treatment and early diagnosis. Finally, the same genes associated with leprosy were also associated with autoimmune (Crohn's disease, rheumathoid arthritis, psoriasis) or neurodegenerative diseases (Parkinson's and Alzheimer's). Thus, information retrieved using leprosy as a model could be valuable to understanding the pathogenesis of other complex diseases. PMID- 21585263 TI - Lactobacilli at the front line of defense against vaginally acquired infections. AB - Probiotics are microorganisms that provide a health benefit to the host and are promoted as alternatives for the treatment and prevention of infectious diseases and other conditions. One of the most rapidly developing areas of probiotic research is in the management of vaginally acquired infections. Several Lactobacillus species produce compounds that kill or inhibit the growth of vaginally acquired pathogens. Other lactobacilli reduce the adherence of pathogens to urogenital epithelial cells in culture. This article discusses the mechanisms by which vaginal lactobacilli prevent pathogen colonization of the urogenital tract, and potential mechanisms that warrant investigation. Animal models and clinical studies, while limited, are discussed with the idea that these are the next critical steps to advance the study of probiotics for the treatment and prevention of vaginally acquired infections. PMID- 21585262 TI - Viral myocarditis: potential defense mechanisms within the cardiomyocyte against virus infection. AB - Virus infection can inflict significant damage on cardiomyocytes through direct injury and secondary immune reactions, leading to myocarditis and dilated cardiomyopathy. While viral myocarditis or cardiomyopathy is a complication of systemic infection of cardiotropic viruses, most individuals infected with the viruses do not develop significant cardiac disease. However, some individuals proceed to develop severe virus-mediated heart disease. Recent studies have shown that viral infection of cardiomyocytes is required for the development of myocarditis and subsequent cardiomyopathy. This suggests that viral infection of cardiomyocytes can be an important step that determines the pathogenesis of viral myocarditis during systemic infection. Accordingly, this article focuses on potential defense mechanisms within the cardiomyocyte against virus infection. Understanding of the cardiomyocyte defense against invading viruses may give us novel insights into the pathophysiology of viral myocarditis, and enable us to develop innovative strategies of diagnosis and treatment for this challenging clinical entity. PMID- 21585265 TI - Eggerthella lenta bacteremia in a Crohn's disease patient after ileocecal resection. AB - Eggerthella lenta is an anaerobic, nonspore-forming Gram-positive rod and is a common gut commensal. Bacteremia from this organism is rare but when present is always clinically significant. Gastrointestinal disease and malignancy are the most common causes for bacteremia from this organism. Eggerthella species have been isolated in feces from patients with inflammatory bowel disease, but bacteremia has not been reported to the best of our knowledge. Here we report the case of a young African-American female with Crohn's disease who developed Eggerthella lenta bacteremia after ileocaecal resection. PMID- 21585264 TI - Lactobacilli producing bispecific llama-derived anti-rotavirus proteins in vivo for rotavirus-induced diarrhea. AB - AIMS: Using genetically engineered lactobacilli, producing high avidity llama VHH domains (referred to as anti-rotavirus proteins; ARPs), to test the effect of multimeric antibody fragments as prophylaxis and therapy against rotavirus infection. METHODS: Two ARPs, ARP1 and ARP3, shown to bind to different epitopes and act synergistically against rotavirus, were displayed on the surface of Lactobacillus paracasei as monovalent or bivalent proteins (mono- or bi specific). RESULTS: Although a nonsignificant difference was observed between lactobacilli producing bispecific ARP3-ARP1 and monomeric ARPs, lactobacilli producing bispecific ARP3-ARP1 were superior at reducing the rate of diarrhea when used for prophylactic and therapeutic intervention in a mouse model of rotavirus infection in comparison to nontreated animals. CONCLUSION: Expression of bispecific antibodies in lactobacilli resulted in slight improvement of their efficacy. Furthermore, increasing the specificity would theoretically reduce the rate of appearance of viral escape mutants and would have a broader capacity to be effective against a range of viral serotypes. PMID- 21585268 TI - Control of Tobacco mosaic virus by PopW as a result of induced resistance in tobacco under greenhouse and field conditions. AB - In a previous study, we isolated a new harpin protein, PopW, from the bacterium Ralstonia solanacearum ZJ3721 that can induce a hypersensitive response in tobacco, Nicotiana tabacum, leaves. In the current study, we demonstrate that, in a greenhouse experiment, PopW induced tobacco-acquired resistance against the Tobacco mosaic virus (TMV) with a biocontrol efficacy of 80.9 to 97.4% at a concentration as low as 25 MUg/ml in both PopW-treated and neighboring leaves. The resistance induced by PopW is systemic acquired resistance mediated by salicylic acid, which was certified by the development of resistance being accompanied by the expression of the pathogenesis-related-1 gene (PR1) 8 h after PopW was sprayed onto the tobacco leaves. In addition, hydrogen peroxide began to accumulate 10 h after PopW spraying, peaking at 24 h with a maximum concentration of 1.97 MUM/g fresh weight. The activities of phenylalanine ammonia lyase (EC4.3.1.5), polyphenoloxidase (EC1.14.18.1), and peroxidase (EC1.11.1.7) also increased, peaking at different times in the PopW-treated tobacco leaves. PopW also reduced the level of TMV disease in field trials with a biocontrol efficacy of 45.2%. Furthermore, PopW both increased tobacco yield (by 30.4 more than in control plants) and improved tobacco foliar quality, with an increase of 50.2% in the number of first-class tobacco leaves from treated compared with untreated plants. All of these results indicate that the new harpin protein PopW has the potential to be an effective biocontrol agent against TMV in tobacco. PMID- 21585269 TI - Transformed hairy roots of Discaria trinervis: a valuable tool for studying actinorhizal symbiosis in the context of intercellular infection. AB - Among infection mechanisms leading to root nodule symbiosis, the intercellular infection pathway is probably the most ancestral but also one of the least characterized. Intercellular infection has been described in Discaria trinervis, an actinorhizal plant belonging to the Rosales order. To decipher the molecular mechanisms underlying intercellular infection with Frankia bacteria, we set up an efficient genetic transformation protocol for D. trinervis based on Agrobacterium rhizogenes. We showed that composite plants with transgenic roots expressing green fluorescent protein can be specifically and efficiently nodulated by Frankia strain BCU110501. Nitrogen fixation rates and feedback inhibition of nodule formation by nitrogen were similar in control and composite plants. In order to challenge the transformation system, the MtEnod11 promoter, a gene from Medicago truncatula widely used as a marker for early infection-related symbiotic events in model legumes, was introduced in D. trinervis. MtEnod11::GUS expression was related to infection zones in root cortex and in the parenchyma of the developing nodule. The ability to study intercellular infection with molecular tools opens new avenues for understanding the evolution of the infection process in nitrogen-fixing root nodule symbioses. PMID- 21585270 TI - The transcriptome of Fusarium graminearum during the infection of wheat. AB - Fusarium graminearum causes head blight disease in wheat and barley. To help understand the infection process on wheat, we studied global gene expression of F. graminearum in a time series from 24 to 196 h after inoculation, compared with a noninoculated control. The infection was rapid and, after 48 h, over 4,000 fungal genes were expressed. The number of genes expressed increased over time up to 96 h (>8,000 genes), and then declined at the 144- and 192-h post-inoculation time points. After subtraction of genes found expressed on complete medium, during carbon or nitrogen starvation, and on barley, only 355 were found exclusively expressed in wheat, mostly genes with unknown function (72.6%). These genes were mainly found in single-nucleotide polymorphism-enriched islands on the chromosomes, suggesting a higher evolutionary selection pressure. The annotated genes were enriched in functional groups predicted to be involved in allantoin and allantoate transport, detoxification, nitrogen, sulfur and selenium metabolism, secondary metabolism, carbohydrate metabolism, and degradation of polysaccharides and ester compounds. Several putative secreted virulence factors were also found expressed in wheat. PMID- 21585271 TI - The ectopic expression of a pectin methyl esterase inhibitor increases pectin methyl esterification and limits fungal diseases in wheat. AB - Cell wall pectin methyl esterification can influence plant resistance because highly methyl-esterified pectin can be less susceptible to the hydrolysis by pectic enzymes such as fungal endopolygalacturonases (PG). Pectin is secreted into the cell wall in a highly methyl-esterified form and, here, is de-methyl esterified by pectin methyl esterase (PME). The activity of PME is controlled by specific protein inhibitors called PMEI; consequently, an increased inhibition of PME by PMEI might modify the pectin methyl esterification. In order to test the possibility of improving wheat resistance by modifying the methyl esterification of pectin cell wall, we have produced durum wheat transgenic lines expressing the PMEI from Actinidia chinensis (AcPMEI). The expression of AcPMEI endows wheat with a reduced endogenous PME activity, and transgenic lines expressing a high level of the inhibitor showed a significant increase in the degree of methyl esterification. These lines showed a significant reduction of disease symptoms caused by the fungal pathogens Bipolaris sorokiniana or Fusarium graminearum. This increased resistance was related to the impaired ability of these fungal pathogens to grow on methyl-esterified pectin and to a reduced activity of the fungal PG to hydrolyze methyl-esterified pectin. In addition to their importance for wheat improvement, these results highlight the primary role of pectin despite its low content in the wheat cell wall. PMID- 21585272 TI - Secretion of arsenic, cholesterol, vitamin E, and zinc from the site of arsenical melanosis and leucomelanosis in skin. AB - BACKGROUND: Melanosis and leucomelanosis with or without keratosis are the earliest symptoms of arsenicosis. Uneven distribution of arsenical melanosis and leucomelanosis in skin led us to investigate the possibility of preferential secretion of arsenic and three constituents of sweat; cholesterol, vitamin E, and zinc. METHODS: Twenty-four-hour skin secretion was collected from skin lesions and unaffected sites of 20 patients. Skin secretions were collected from 20 people exposed to arsenic-contaminated drinking water and 20 healthy, unexposed individuals. RESULTS: The secretion of arsenic from the skin of healthy controls (mean +/- SE; unit: MUg/in.(2) of skin/24 h; chest: 0.6 +/- 0.2; back: 0.3 +/- 0.1; abdomen: 0.5 +/- 0.2) was increased several folds in arsenic-exposed controls (chest: 8.4 +/- 1.8; back: 8.3 +/- 1.9; abdomen: 6.7 +/- 1.8) and patients (chest: 9.2 +/- 1.3; back: 7.8 +/- 1.3; abdomen: 5.2 +/- 1.0). There was no difference in the skin lesions and unaffected sites in patients. However, the secretion of cholesterol was significantly lower in the chest of patients (190 +/ 36) and healthy controls (686 +/- 100) (p < 0.001). Secretions of vitamin E were low in healthy controls (chest: 8.5 +/- 3.1; back: 5.2 +/- 1.7; and abdomen: 8.7 +/- 2.4), higher in arsenic-exposed controls (chest: 30.2 +/- 8.1; back: 16.3 +/- 8.9; and abdomen: 24.8 +/- 9.3), and highest in patients [chest: 91.4 +/- 14.9 (p < 0.0001 vs. control); back: 72.4 +/- 13.2 (p < 0.001 vs. control); and abdomen: 46.8 +/- 12.9]. Chronic intake of arsenic led to several folds higher secretion of zinc both in patients and in arsenic-exposed controls. One molecule of arsenic appears to be co-secreted with two molecules of zinc. CONCLUSION: Arsenic skin lesions showed no alteration in secretion of arsenic, although the secretion of cholesterol, vitamin E, and zinc was changed. Potential implications are discussed. PMID- 21585273 TI - The range and clinical impact of cognitive impairment in French patients with ALS: a cross-sectional study of neuropsychological test performance. AB - Our objective was to assess the spectrum and clinical associations of cognitive impairment in French patients with ALS, and determine the effect of cognitive impairment on survival in this population. One hundred and thirty-one patients were enrolled in a cross-sectional cohort study of neuropsychological test performance. ANOVA and chi(2) tests assessed differences in clinical characteristics between impaired and unimpaired patients; multiple regression determined which features contributed most strongly to cognitive status, and Cox models compared survival. Fifty-three patients (40%) were categorized as cognitively impaired based on test performance. Thirteen (10%) patients had frontotemporal dementia (FTD) clinically; all scored in the moderate to severely impaired range on testing. Impaired patients had less education (p = 0.001), and severely impaired patients were more likely to have bulbar onset than unimpaired patients (p < 0.001). Severe cognitive impairment predicted shorter survival (p = 0.007), even when controlled for motor severity (p = 0.001). In summary, 10% of a consecutive series of French ALS patients had overt dementia and 40% were cognitively impaired by neuropsychological testing. We conclude that lower education level and possibly bulbar-onset ALS were associated with impairment. As in other causes of dementia, higher education attainment may protect against clinical cognitive deterioration in ALS. French patients with severe cognitive impairment have shorter survival time. PMID- 21585275 TI - Developing a balanced business model for gene therapy. PMID- 21585274 TI - Brain iron levels in attention-deficit/hyperactivity disorder: a pilot MRI study. AB - OBJECTIVE: Brain iron deficiency has been supposed to be involved in the pathophysiology of ADHD. Available studies assessing iron in ADHD are based on serum ferritin, a peripheral marker of iron status. To what extent serum ferritin correlates with brain iron (BI) is unclear. The main aim of this study was to compare BI, estimated with magnetic resonance imaging (MRI) in the putamen, pallidum, caudate, and thalamus, between children with and without ADHD. The secondary aim was to assess the correlation between serum ferritin and BI levels. METHODS: Thirty-six children (18 with and 18 without ADHD, the latter including nine healthy controls and nine psychiatric controls) completed MRI and blood sampling. Brain iron levels were estimated by imaging T2*. RESULTS: Children with ADHD showed significantly lower estimated BI in right and left thalamus compared to healthy controls. Estimated BI did not differ significantly between children with ADHD and psychiatric controls. Children with ADHD had significantly lower levels of serum ferritin than healthy as well as psychiatric controls. Serum ferritin and T2* values did not correlate significantly in most regions. CONCLUSIONS: Low iron in the thalamus may contribute to ADHD pathophysiology. PMID- 21585276 TI - Identification of candidate genes for histiocytoid cardiomyopathy (HC) using whole genome expression analysis: analyzing material from the HC registry. AB - Histiocytoid cardiomyopathy (HC) is a rare but distinctive arrhythmogenic disorder characterized by incessant ventricular tachycardia, cardiomegaly, and often sudden death by age 2 years. The underlying genetic mechanism of HC has eluded researchers for decades. To further identify the potential molecular genetic bases of HC, molecular analyses of HC hearts and hearts of age-matched controls were performed. Total RNA and genomic DNA were prepared from formalin fixed, paraffin-embedded cardiac tissue from 12 cases of HC and 12 age-matched controls. To identify genes differentially expressed in HC, whole genome cDNA mediated annealing, selection, extension, and ligation profiling was performed. TaqMan quantitative polymerase chain reaction confirmed changes in RNA expression. DNA copy number changes were measured by TaqMan copy number variant analysis. Analysis of differential gene expression in HC cases identified 2 significantly downregulated gene sets aligned sequentially along the genome. The 1st gene cluster consisted of genes S100A8 , S100A9 , and S100A12 at 1q21.3c, and the 2nd cluster consisted of genes IL1RL1 ( ST2 ), IL18R1 , and IL18RAP at 2q12.1a. Strong decreases in interleukin 33 expression were also observed. Decreases in copy number of the S100A genes were confirmed by TaqMan copy number variant assays. S100A genes are downstream of the p38-MAPK pathway that can be activated by interleukin 33 signaling. These data suggest a model in which the interleukin 33-IL1RL1/p38-MAPK/ S100A8-S100A9 axis is downregulated in HC cardiac tissue and provide several candidate genes on 1q21.3c and 2q12.1a for inherited mutations that may predispose individuals to HC. PMID- 21585277 TI - Characterization of a plant-transformation-ready large-insert BIBAC library of Arabidopsis and bombardment transformation of a large-insert BIBAC of the library into tobacco. AB - Plant-transformation-ready, large-insert binary bacterial artificial chromosome (BIBAC) libraries are of significance for functional and network analysis of large genomic regions, gene clusters, large-spanning genes, and complex loci in the post-genome era. Here, we report the characterization of a plant transformation-ready BIBAC library of the sequenced Arabidopsis genome for which such a library is not available to the public, the transformation of a large insert BIBAC of the library into tobacco by biolistic bombardment, and the expression analysis of its containing genes in transgenic plants. The BIBAC library was constructed from nuclear DNA partially digested with BamHI in the BIBAC vector pCLD04541. It contains 6144 clones and has a mean insert size of 108 kb, representing 5.2* equivalents of the Arabidopsis genome or a probability of greater than 99% of obtaining at least one positive clone from the library using a single-copy sequence as a probe. The transformation of the large-insert BIBAC and analyses of the transgenic plants showed that not only did transgenic plants have intact BIBAC DNA, but also could the BIBAC be transmitted stably into progenies and its containing genes be expressed actively. These results suggest that the large-insert BIBAC library, combined with the biolistic bombardment transformation method, could provide a useful tool for large-scale functional analysis of the Arabidopsis genome sequence and applications in plant-molecular breeding. PMID- 21585278 TI - Occult androgenetic-biparental mosaicism and sporadic hepatic mesenchymal hamartoma. AB - The incidence of hepatic mesenchymal hamartoma (HMH) is increased in patients with placental mesenchymal dysplasia (PMD), which appears to be caused by androgenetic-biparental mosaicism (ABM). We hypothesized that occult ABM might underlie cases of HMH with no known history of PMD. Formalin-fixed, paraffin embedded HMH specimens from 10 such patients and liver specimens from 6 non-HMH controls were identified retrospectively from the surgical pathology records of a pediatric hospital. The relative abundance of maternal and paternal alleles was assessed by quantitative polymerase chain reaction amplification of polymorphic short tandem repeats and single nucleotide polymorphisms located on 15 different chromosomes. Androgenetic-biparental mosaicism was diagnosed in one patient based on global allelic imbalances at all informative loci. In that patient, the greatest imbalances were observed in stroma-rich portions of the hamartoma, with no significant imbalance in histologically normal liver or epithelium-rich portions of the hamartoma. A retrospective, unbiased review of the histology and clinical records from all 10 patients revealed no morphologic or clinical correlates to distinguish the affected patient, except that she had multiple cutaneous hemangiomas, which like HMH, appear to be more common in patients with PMD. Our findings suggest that other patients with apparently sporadic HMH, hemangioma, or other lesions seen more frequently with PMD may harbor occult ABM. Recognition of ABM may be important because its long-term consequences are unknown but may be significant. PMID- 21585279 TI - Successful treatment of angioimmunoblastic T-cell lymphoma with the retinoid X receptor agonist, bexarotene. PMID- 21585280 TI - Clinical dissection of multicentric Castleman disease. AB - This study investigated the prognostic factors of Castleman disease (CD) and focused specifically on multicentric CD (MCD). Seventy patients with CD were studied. Forty-three patients (61.5%) had unicentric CD (UCD) and 27 patients (38.5%) had MCD. Thirty-six patients with UCD (83.7%) underwent surgical excision, and 25 patients with MCD (92.6%) received systemic treatment, including corticosteroids and combination chemotherapy. In the patients with MCD, age >60 years and the presence of splenomegaly were prognostic factors for progression free survival (hazard ratio [HR] 9.01, 95% confidence interval [CI] 2.64-30.83 and HR 4.32, 95% CI 1.16-16.09) as well as overall survival (OS) in MCD (HR 8.7, 95% CI 2.83-26.84 and HR 2.9, 95% CI 0.95-9.02, respectively). Patients <= 60 years old without splenomegaly showed better OS than patients > 60 years old or with splenomegaly (71.4% vs. 10.8% for 5-year OS). MCD might be dissected clinically by the simple parameters of age and presence of splenomegaly. PMID- 21585281 TI - Hypoglycemia and glycemic variability among children with acute lymphoblastic leukemia during maintenance therapy. AB - Symptomatic, chemotherapy-related hypoglycemia is a rare complication associated with the administration of purine analogs. The aim of the study was to evaluate 24 h glucose variability and frequency of hypoglycemia among patients with acute lymphoblastic leukemia (ALL) during maintenance therapy (MT). Eighteen children with ALL underwent continuous glucose monitoring (CGM). The number of episodes of hypoglycemia and glucose variability were analyzed. Serum alanine aminotransferase, asparagine aminotransferase, and gamma-glutamyl transferase levels were measured as liver function markers. The mean glucose level in CGM equaled 105 +/- 13 mg/dL, with standard deviation (SD) 13.8 +/- 6.1 mg/dL, and the mean amplitude of glycemic excursions (MAGE) equaled 44.7 +/- 19.9 mg/dL. Eight patients had at least one measurement below 70 mg/dL while four patients had measurements below 50 mg/dL. Children with hypoglycemia in CGM examination had a lower median body mass index standard deviation score (BMI Z-score) (-0.65 [-0.94 to -0.27] vs. -0.14 [-0.29 to 0.35]; p = 0.05) and shorter duration of MT (6.5 [4-15] vs. 22.5 [16.5-28] weeks; p = 0.004). Glucose variability parameters were strongly correlated with BMI Z-score and liver function enzymes. Hypoglycemia, particularly at night-time, may develop as a complication of MT in children with ALL. The risk factors for low glucose level are low BMI Z-score and initiation of MT. PMID- 21585282 TI - Leukemic phase of follicular lymphomas: an atypical presentation. AB - Follicular lymphomas (FLs) are frequent B-cell derived malignancies, generally demonstrating an indolent evolution. Although circulating FL cells may be detected by high-resolution analysis, bloodstream involvement by FL cells is unusual. We observed in 10 patients a leukemic phase of FL at the onset of the disease. Six of them had concomitant lymph node involvement and all of them required treatment at diagnosis due to a high tumor burden, whereas four patients had pure FL-cell leukemia, which was associated with a more indolent clinical outcome. The detection of a leukemic phase should therefore be studied as a potential prognosis marker in further studies. PMID- 21585285 TI - Type V collagen-induced upregulation of capn2 (large subunit of m-calpain) gene expression and DNA fragmentation in 8701-BC breast cancer cells. AB - Type V collagen is known to be over-deposited in the stroma of ductal infiltrating carcinomas of the breast. When used as a substrate, type V collagen restrains growth and invasion, and affects gene expression of 8701-BC ductal infiltrating carcinomas cells. Here we supplement existing data by demonstrating type V collagen dependent upregulation of capn2 gene expression in 8701-BC cells through differential display-PCR and Western blot assays. Furthermore, we suggest that our data obtained by centrifugal sedimentation and electrophoresis strongly suggest a correlation between calpain overproduction and DNA fragmentation, since the incubation with calpain inhibitor partly reverts the latter. PMID- 21585286 TI - Cathepsins S, B and L with aminopeptidases display beta-secretase activity associated with the pathogenesis of Alzheimer's disease. AB - beta-site APP-cleaving enzyme (BACE1) cleaves the wild type (WT) beta-site very slowly (k(cat)/K(m): 46.6 m(-1) s(-1)). Therefore we searched for additional beta secretases and identified three cathepsins that split the WT beta-site much faster. Human cathepsin S cleaves the WT beta-site (k(cat)/K(m): 54 700 m(-1) s( 1)) 1170-fold faster than BACE1 and cathepsins B and L are 440- and 74-fold faster than BACE1, respectively. These cathepsins split two bonds flanking the WT beta-site (K-MD-A), where the K-M bond (85%) is cleaved more efficiently than the D-A bond (15%). Cleavage at the major K-M bond yields Abeta (amyloid beta peptide) extended by N-terminal Met that should be removed to generate Abeta initiated by Asp1. The activity of cytosol and microsomal aminopeptidases on relevant peptides revealed rapid removal of N-terminal Met but not N-terminal Asp. Brain aminopeptidases showed similar specificity. Thus, aminopeptidases would convert Abeta extended by Met into regular Abeta (Asp1) found in amyloid plaques. Earlier studies indicate that Abeta is likely produced in the endosome and lysosome system where cathepsins S, B and L are localized and cysteine cathepsin inhibitors reduce the level of Abeta in cells and animals. Taken together, cathepsins S, B and L deserve further evaluation as therapeutic targets to develop disease modifying drugs to treat Alzheimer's disease. PMID- 21585287 TI - Development and characterization of a bead-based, multiplex assay for estimation of recent HIV type 1 infection. AB - Estimation of HIV-1 incidence is an important public health tool for understanding the status of the epidemic, identifying high-risk populations, and assessing various intervention strategies. Several laboratory-based methods have been developed for distinguishing recent from long-term HIV-1 infection; however, each exhibits some degree of misclassification, particularly among AIDS patients and those taking antiretroviral therapy (ART). To improve upon the limitations associated with measuring responses to a single analyte, we have developed a bead based, multiplex assay for determination of HIV recent infection based on total antibody binding and antibody avidity to multiple analytes. An HIV-specific, multiplex panel was created by coupling the recombinant HIV-1 proteins p66, gp120, gp160, and gp41 to Bio-Plex COOH microspheres. Longitudinal plasma specimens from recent seroconverters were tested for reactivity to the coupled microspheres using the Bio-Plex 200 System. For each analyte, HIV-specific antibody binding and avidity increased for 1-2 years post-seroconversion, leading to a significant difference in reactivity between recent and long-term specimens. While the potential for misclassification of individuals diagnosed with AIDS or receiving ART appears to be minimal with avidity measures, the impact on total antibody binding was variable, depending on the individual analyte. This bead based, HIV-specific multiplex assay measures several distinct immune responses in a single assay plate, allowing for sampling of multiple analytes in the determination of recent infection, which could aid in the development of improved statistical methods or algorithms that will more accurately estimate HIV incidence. PMID- 21585288 TI - Supra-therapeutic doses of roflumilast have no effect on cardiac repolarization in healthy subjects. AB - OBJECTIVE: This study assesses the potential of the phosphodiesterase 4 inhibitor roflumilast to affect cardiac repolarization. METHODS: In this randomized, placebo-controlled study (n = 80), 40 healthy subjects received moxifloxacin 400 mg p.o. (positive control for prolongation of QT/heart-rate corrected QT [QTc]) and another 40 received placebo. After a 1-day washout, subjects received placebo or ascending doses of roflumilast 500 (therapeutic dose), 750 or 1000 MUg/day p.o., for 14, 7 and 14 days, respectively. QT intervals were measured and corrected for heart rate with a Fridericia algorithm (QTc(F)). The primary endpoint was the largest mean time-matched change in QTc(F) from baseline (day 1). Safety and tolerability were monitored. RESULTS: Moxifloxacin gave a maximum time-matched change in QTc(F) versus baseline of 6.79 ms. Repeated administration of roflumilast 500 and 1000 MUg resulted in maximum QTc(F) changes from baseline of -3.23 and -4.81 ms, respectively, confirming the absence of any QT/QTc prolongation at therapeutic and supra-therapeutic dosing. There were no changes in other electrocardiographic variables or time intervals, and roflumilast was well tolerated. CONCLUSIONS: Repeated administration of roflumilast at doses <= 1000 MUg/day had no effect on cardiac repolarization or overall cardiac safety evaluations in healthy subjects. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN63818313 PMID- 21585289 TI - HMGB1, TLR and RAGE: a functional tripod that leads to diabetic inflammation. AB - INTRODUCTION: Despite advances in treatment of diabetes mellitus, its prevalence continues to rise globally. Medications available are unable to control the vascular complications. Proposals for new therapeutic targets must take into account the hyperglycemia-induced signaling pathways that give rise to the inflammatory profile of the disease. AREAS COVERED: How high-mobility-group box-1 (HMGB1) protein, acting as an activator of Toll-like receptors (TLR) and receptors for advanced glycation end products (RAGE), creates a functional tripod that contributes to increased production of pro-inflammatory mediators, and sustains the chronic inflammatory state associated with diabetes. The interaction of TLR2 and TRL4 with host-derived ligands, which links diabetic complications with the innate immune response, and the activation of RAGE, which induces a cascade of metabolic responses, leading to the production and secretion of pro inflammatory cytokines. EXPERT OPINION: Considering the involvement of the innate immune system, in association with the role of HMGB1 as an activator of TLR and RAGE, diabetes should be considered and treated as a metabolic and immunological disease, triggered by hyperglycemia. HMGB1 plays a central role in mediating injury and inflammation, and interactions involving HMGB1-TLR-RAGE constitute a tripod that trigger NF-kappaB activation. Blockade or downregulation of HMGB1, and/or control of the inflammatory tripod, represent a promising therapeutic approach for the treatment of diabetes. PMID- 21585290 TI - Cerebrospinal fluid levels of a proliferation-inducing ligand (APRIL) are increased in patients with neuropsychiatric systemic lupus erythematosus. AB - OBJECTIVES: A proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are B-cell stimulation and survival molecules. We have investigated whether APRIL and/or BAFF activity is enhanced in the systemic and/or intrathechal compartment of patients with neuropsychiatric systemic lupus erythematosus (NPSLE). In particular, the association between fatigue and APRIL/BAFF activity was investigated. METHODS: Twenty-eight NPSLE patients were evaluated clinically, with sampling of cerebrospinal fluid (CSF) and blood, and magnetic resonance imaging (MRI). CSF and blood samples from 13 multiple sclerosis (MS) patients and 17 patients with other neurological diseases (OND) were used as controls. Protein levels of BAFF and APRIL were quantified in CSF and plasma, mRNA expression levels of BAFF and APRIL were determined in peripheral blood (PBMC) and CSF mononuclear cells (CSF-MC). The Fatigue Severity Scale (FSS) was used to quantify the degree of fatigue. RESULTS: NPSLE patients had higher levels of APRIL in CSF as compared to OND (p < 0.01). No corresponding increase in APRIL mRNA levels was detected in CSF-MC. BAFF levels in plasma were higher in NPSLE than in OND (p < 0.001). BAFF mRNA expression in PBMC was also higher in NPSLE patients than in controls (p < 0.05). FSS scores in patients with NPSLE correlated significantly with APRIL levels in CSF. CONCLUSIONS: Protein levels of APRIL in CSF were increased in NPSLE as compared to OND. Moreover, there was a positive correlation between CSF APRIL levels and fatigue. Our results suggest that APRIL and possibly also BAFF may be involved in the pathogenesis of NPSLE and in SLE-related fatigue. PMID- 21585291 TI - Pain management in the 21st century: utilization of pharmacogenomics and therapeutic drug monitoring. AB - INTRODUCTION: Anesthesiologists and pain management physicians recognize that the key to clinical success is the ability to effectively control pain and related symptoms in patients without causing excess side effects from prescribed medications. The use of opioids for pain management is broadly accepted by regulatory bodies, professional organizations (i.e., the WHO) and physicians, as is the wide range of patient responses to these medications. Pharmacogenomics and therapeutic drug monitoring are two underutilized tools which can be implemented to best predict and monitor which opioid and dose may be the most appropriate for an individual patient. AREAS COVERED: This review summarizes and discusses evidence for the use of genetic analysis to guide the selection and modification of opioid therapy along with the use of therapeutic drug monitoring to objectively check therapeutic outcomes and compliance. The reader will gain an understanding of the most notable genetic polymorphisms that can affect a patient's response to commonly prescribed opioids, along with the clinical benefits of genotyping and performing therapeutic drug monitoring. EXPERT OPINION: In the end, the authors strongly believe that objective tools such as pharmacogenomics and therapeutic drug monitoring provide added benefit (minimizing adverse effects, while maximizing efficacy) and will ultimately advance the practice of pain management by incorporating these tools into the standard of care. PMID- 21585295 TI - Bioanalysis in Latin America: where are we and where are we going? PMID- 21585296 TI - Bioimaging of elements and small molecules using MS. PMID- 21585298 TI - The 27th Montreux Symposium on LC-MS. AB - The recent Montreux Symposium on LC-MS held in 2010 provided an insight into the key areas of present achievements and future developments in LC-MS. This domain is rapidly changing from a technology- to an application-driven enterprise. New demands for advanced options are coming from (medical) biology, biotechnology, pharmaceutical and nutrition research. In particular, new diagnostic options based on -omics technologies, miniaturization and advanced data handling are rapidly being developed in relation to questions coming from personalized medicine, claim support in nutritional research, biotechnology production support and the human microbiome. PMID- 21585299 TI - 6th Annual Bioanalysis in Clinical Research conference. AB - The 6th Annual Bioanalysis in Clinical Research conference held recently in London, UK, targeted numerous themes of significant current interest within the discipline of bioanalysis. The conference invited a diverse speaker panel and attracted an audience consisting of researchers from the pharmaceutical industry, CROs and academia. The range of topics presented covered LC-MS and ligand-binding assays, small- and large-molecule quantification, regulatory issues and concerns and new technologies. Within the scope of LC-MS bioanalysis, presentation topics included new developments in dried blood spot technologies, the use of direct analysis MS techniques, eliminating matrix effects through direct-electron ionization MS, and the complications of developing and validating LC-MS methods for the quantitative determination of endogenous biomarkers. With respect to ligand binding, the importance of assay validation being a continuous process, extending into study analysis, was a recurrent theme in several presentations along with the hot topic of immunogenicity. Of relevance to both analytical disciplines were the presentations on regulatory topics covering the EMA guidelines on method validation and bioanalysis within bioequivalence clinical studies. PMID- 21585302 TI - Diagnosis of crystal-associated disease: where do we stand? PMID- 21585300 TI - Research in bioanalysis and separations at the University of Nebraska - Lincoln. AB - The Chemistry Department at the University of Nebraska - Lincoln (UNL) is located in Hamilton Hall on the main campus of UNL in Lincoln, NE, USA. This department houses the primary graduate and research program in chemistry in the state of Nebraska. This program includes the traditional fields of analytical chemistry, biochemistry, inorganic chemistry, organic chemistry and physical chemistry. However, this program also contains a great deal of multidisciplinary research in fields that range from bioanalytical and biophysical chemistry to nanomaterials, energy research, catalysis and computational chemistry. Current research in bioanalytical and biophysical chemistry at UNL includes work with separation methods such as HPLC and CE, as well as with techniques such as MS and LC-MS, NMR spectroscopy, electrochemical biosensors, scanning probe microscopy and laser spectroscopy. This article will discuss several of these areas, with an emphasis being placed on research in bioanalytical separations, binding assays and related fields. PMID- 21585303 TI - New approaches in the detection of calcium-containing microcrystals in synovial fluid. AB - BACKGROUND: The presence of calcium phosphate crystals such as basic calcium phosphate and calcium pyrophosphate dihydrate in intra-articular fluid is linked to a number of destructive arthropathies and detection of these deposits is often pivotal for early diagnosis and appropriate management of such disease. RESULTS: We describe the use of a calcium-sensitive dye, Fluo-4, to selectively label calcium-containing mineral deposits in synovial fluid, which can then be easily visualized using a standard fluorescence microscope. Furthermore, we have combined the fluorescent properties of the tagged crystals with flow cytometry as a fast and semi-quantitative method of detection. CONCLUSION: Dot-plots were used to quantify differences between various types of arthropathies and confirmed by visual observation of the crystals under a fluorescence microscope. PMID- 21585304 TI - Clinical evaluation of the determination of plasma concentrations of darunavir, etravirine, raltegravir and ritonavir in dried blood spot samples. AB - BACKGROUND: Measurement of drug levels in plasma is currently the gold standard for pharmacological studies. However, venous sampling is not feasible in some populations (e.g., neonates) or may be difficult in certain situations, such as nonhospital-based settings. Dried blood spots (DBS) can be obtained by a simple fingerprick and the subsequent collection of blood on a filter card, allowing patient-friendly sample collection in non-hospital-based settings. Despite these advantages, thus far no clinical evaluation has been performed for the use of DBS concentrations as surrogates for plasma levels. Our purpose was to clinically evaluate DBS sampling for the determination of plasma concentrations for the novel antiretroviral drugs etravirine, darunavir/ritonavir and raltegravir. RESULTS: DBS concentrations were measured in 11 HIV-infected patients using LC MS/MS. DBS concentrations were proportional to plasma concentrations. All drug concentrations were higher in DBS than in plasma samples. The plasma:DBS ratio and the respective relative standard error of estimate (RSE) of darunavir, etravirine, raltegravir and ritonavir were 0.632 (4.97% RSE), 0.523 (4.84% RSE), 0.617 (14.9% RSE) and 0.592 (2.99% RSE), respectively. Hematocrit did not explain variability in our study. CONCLUSIONS: DBS are reproducibly correlated to plasma levels and can be used for monitoring antiretroviral drug exposure in HIV infected patients. PMID- 21585305 TI - Dried blood spot sampling: practical considerations and recommendation for use with preclinical studies. AB - At present it is necessary to use animals to generate toxicokinetic data as part of preclinical safety studies. However, ethical standards require animal use to be carefully monitored and the principles of the 3Rs: replacement, reduction and refinement, to be considered and applied. Use of dried blood spot (DBS) samples, typically 10 to 20 ul, rather than the larger blood volumes required to obtain plasma samples, fully embraces the latter two principles of reduction and refinement. The use of DBS sampling enables the number of rodents per study to be reduced whilst also refining the way blood samples are taken from both rodents and non-rodents. The recent changes to the European Directive on the protection of animals used for scientific purposes favor DBS sampling becoming the standard for generation of toxicokinetic data, and imply that pharmaceutical companies will have to justify why plasma samples (and therefore larger blood volumes) are required for bioanalysis. Use of DBS samples has been, and is being, discussed widely within the pharmaceutical industry as the move away from taking large blood volumes becomes inevitable. PMID- 21585306 TI - Advantages of ion-exchange chromatography for oligonucleotide analysis. AB - The rapid development of therapeutic oligonucleotides (ONs) has created a need for in-depth characterization of ONs, beyond previous requirements. The natural migration to LC-MS requires the use of chromatography with MS-compatible eluents to introduce the large, highly charged biopolymers into the mass spectrometer. Most frequently this employs ion-pair reversed-phase liquid chromatography, which may leave gaps in the characterization, but these can be filled with the use of high-resolution ion-exchange chromatography. Several classes of isobaric isomers are among the impurities that will require further separation prior to MS analysis. This review shows how the use of ion exchange as an additional orthogonal analytical method can be used as standalone or interfaced with MS to achieve the highest possible analytical coverage in the characterization and quantification of impurities present in single- and double-stranded ON formulations. Some of these techniques have been in use for some time and the importance of others is just being recognized. PMID- 21585307 TI - Current strategies in the discovery of small-molecule biomarkers for Alzheimer's disease. AB - With the number of patients suffering from Alzheimer's disease rapidly increasing, there is a major requirement for an accurate biomarker capable of diagnosing the disease early. Much of the research is focused on protein and genetic approaches; however, small molecules may provide viable marker molecules. Examples that support this approach include known abnormalities in lipid metabolism, glucose utilization and oxidative stress, which have been demonstrated in patients suffering from the disease. Therefore, by-products of this irregular metabolism may provide accurate biomarkers. In this review we present the current approaches previously published in the literature used to investigate potential small-molecule and metabolite markers, and report their findings. A wide range of techniques are discussed, including separation approaches (LC, GC and CE), magnetic resonance technologies (NMR and magnetic resonance spectroscopy), and immunoassays. PMID- 21585308 TI - Metabolomics: a second-generation platform for crop and food analysis. AB - The combined factors of financial and food security, a rapidly increasing population and the associated requirement for food generated sustainably in a changing environment have brought food swiftly to the top of most government agendas. The consequence of this is that we need to produce more food at an equivalent or higher quality with lower inputs. These aims are achievable using conventional breeding, but not in the required timelines, and thus state-of-the art genetic and analytical technologies are coming to the forefront. The concept of metabolomics, underpinned by mainstream (GC-MS, LC-MS, NMR) and specialist (MALDI-TOF-MS) analytical technologies addressing broad chemical (class) targets and dynamic ranges, offers significant potential to add significant value to crop and food science and deliver on future food demands. Metabolomics has now found a home in the food analytical toolbox with raw material quality and safety the major quality areas, although, as we will show, it is translating beyond this into food storage, shelf-life and post-harvest processing. PMID- 21585310 TI - Dietary intake among adults in Trinidad and Tobago and development of a quantitative food frequency questionnaire to highlight nutritional needs for lifestyle interventions. AB - PRIMARY OBJECTIVE: To create a food list and develop a draft quantitative food frequency questionnaire (QFFQ) for Trinidad and Tobago. METHODS AND PROCEDURES: A mixed sampling method was used to obtain a representative sample and trained interviewers administered 24-h dietary recalls. Portion sizes were assessed and the most frequently reported foods were tabulated. MAIN OUTCOMES AND RESULTS: Results are from 155 men and 169 women aged 21-64 years. The most frequently reported food items were: full-cream milk (64%), rice (61%), and sweetened fruit drinks (50%). Carbonated drinks were consumed by 28%. The most frequently consumed fruits were banana (23%) and citrus (22%); < 20% consumed a vegetable food item. The final QFFQ contains 146 items: 19 breads/cakes/cereals; seven rice/pastas/noodles; 12 dairy; 26 meats/poultry/fish/soy products; 15 fruits; 34 vegetables; six legumes; 11 other; 12 drinks; four alcoholic drinks. CONCLUSIONS: A list of commonly consumed foods in Trinidad and Tobago was obtained and a draft QFFQ was prepared. PMID- 21585312 TI - Effects of inducible nitric oxide synthase inhibition in bronchial vascular remodeling-induced by chronic allergic pulmonary inflammation. AB - Vascular remodeling is an important feature in asthma pathophysiology. Although investigations suggested that nitric oxide (NO) is involved in lung remodeling, little evidence established the role of inducible NO synthase (iNOS) isoform in bronchial vascular remodeling. The authors investigated if iNOS contribute to bronchial vascular remodeling induced by chronic allergic pulmonary inflammation. Guinea pigs were submitted to ovalbumin exposures with increasing doses (1~5 mg/mL) for 4 weeks. Animals received 1400W (iNOS-specific inhibitor) treatment for 4 days beginning at 7th inhalation. Seventy-two hours after the 7th inhalation, animals were anesthetized, mechanical ventilated, exhaled NO was collected, and lungs were removed and submitted to picrosirius and resorcin fuchsin stains and to immunohistochemistry for matrix metalloproteinase-9 (MMP 9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and transforming growth factor-beta (TGF-beta). Collagen and elastic fiber deposition as well as MMP-9, TIMP-1, and TGF-beta expression were increase in bronchial vascular wall in ovalbumin-exposed animals. The iNOS inhibition reduced all parameters studied. In this model, iNOS inhibition reduced the bronchial vascular extracellular remodeling, particularly controlling the collagen and elastic fibers deposition in pulmonary vessels. This effect can be associated to a reduction on TGF-beta and on metalloproteinase-9/TIMP-1 vascular expression. It reveals new therapeutic strategies and some possible mechanism related to specific iNOS inhibition to control vascular remodeling. PMID- 21585311 TI - AID dysregulation in lupus-prone MRL/Fas(lpr/lpr) mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations: modulation by HoxC4. AB - Immunoglobulin gene somatic hypermutation (SHM) and class switch DNA recombination (CSR) play important roles in the generation of autoantibodies in systemic lupus erythematosus. Systemic lupus is characterized by the production of an array of pathogenic high-affinity mutated and class-switched, mainly IgG, antibodies to a variety of self-antigens, including nuclear components, such as dsDNA, histones, and chromatin. We previously found that MRL/Fas(lpr/lpr) mice, which develop a systemic autoimmune syndrome sharing many features with human lupus, display greatly upregulated CSR, particularly to IgG2a, in B cells of the spleen, lymph nodes, and Peyer's patches. In MRL/Fas(lpr/lpr) mice, the significant upregulation of CSR is associated with increased expression of activation-induced cytidine deaminase (AID), which is critical for CSR and SHM. We also found that HoxC4 directly activates the promoter of the AID gene to induce AID expression, CSR and SHM. Here, we show that in both lupus patients and lupus-prone MRL/Fas(lpr/lpr) mice, the expression of HoxC4 and AID is significantly upregulated. To further analyze the role of HoxC4 in lupus, we generated HoxC4(-/-) MRL/Fas(lpr/lpr) mice. In these mice, HoxC4-deficiency resulted in reduced AID expression, impaired CSR, and decreased serum anti-dsDNA IgG, particularly IgG2a, autoantibodies, which were associated with a reduction in IgG deposition in kidney glomeruli. In addition, consistent with our previous findings in MRL/Fas(lpr/lpr) mice that upregulated AID expression is associated with extensive DNA lesions, comprising deletions and insertions in the IgH locus, we found that c-Myc to IgH (c-Myc/IgH) translocations occur frequently in B cells of MRL/Fas(lpr/lpr) mice. The frequency of such translocations was significantly reduced in HoxC4(-/-) MRL/Fas(lpr/lpr) mice. These findings suggest that in lupus B cells, upregulation of HoxC4 plays a major role in dysregulation of AID expression, thereby increasing CSR and autoantibody production and promoting c Myc/IgH translocations. PMID- 21585314 TI - Nonopioid effect of beta-endorphin. AB - This review presents the generalized literature data and the results of our own research of the nonopioid effect of beta-endorphin, an opioid neuropeptide interacting not only with opioid but also with nonopioid (insensitive to the opioid antagonist naloxone) receptors. The roles of the hormone and its receptors in regulation of the immune, nervous, and endocrine systems are discussed. The effect of neuromediator on the immune system mediated by both opioid and nonopioid receptors is considered in detail. The data on distribution and function of the nonopioid beta-endorphin receptor in human and animal organisms are presented. All available data on the characteristics of the nonopioid beta endorphin receptor obtained by means of radioligand analysis are given. The discussed information is supposed to extend our conceptions of the role of beta endorphin in mammals and to be of extensive use in medicine and pharmacology. PMID- 21585315 TI - Functional properties of extracellular domains of transducer receptor gp130. AB - Cytokine receptor molecules have been shown to have extracellular domains of complex structure and a multi-step activation system. Glycoprotein gp130 is a typical transducer of cytokine signal; it functions by forming multicomponent receptor complexes and transferring signals of tens of cytokines from the IL-6 family. Structural organization and basic functioning principles of gp130 are well known, as well as related signal pathways, which function during normal differentiation and are involved in pathogenesis of many tumors. The role of gp130 in IL-6-dependent tumors is best studied. In this review, based on extensive accumulated data, we examine the functional significance of certain parts of gp130 extracellular domains. Potentials of a recently developed method for estimation of receptor activation at the level of epitope structure are discussed. PMID- 21585313 TI - Laser printing of three-dimensional multicellular arrays for studies of cell-cell and cell-environment interactions. AB - Utilization of living cells for therapies in regenerative medicine requires a fundamental understanding of the interactions between different cells and their environment. Moreover, common models based on adherent two-dimensional cultures are not appropriate to simulate the complex interactions that occur in a three dimensional (3D) cell-microenvironment in vivo. In this study, we present a computer-aided method for the printing of multiple cell types in a 3D array using laser-assisted bioprinting. By printing spots of human adipose-derived stem cells (ASCs) and endothelial colony-forming cells (ECFCs), we demonstrate that (i) these cell spots can be arranged layer-by-layer in a 3D array; (ii) any cell-cell ratio, cell quantity, cell-type combination, and spot spacing can be realized within this array; and (iii) the height of the 3D array is freely scalable. As a proof of concept, we printed separate spots of ASCs and ECFCs within a 3D array and observed cell-cell interactions in vascular endothelial growth factor-free medium. It has been demonstrated that direct cell-cell contacts trigger the development of stable vascular-like networks. This method can be applied to study complex and dynamic relationships between cells and their local environment. PMID- 21585316 TI - Mechanism of the Nrf2/Keap1/ARE signaling system. AB - Nrf2 regulates expression of genes containing antioxidant-respons(iv)e element (ARE) in their promoters and plays a pivotal role among all redox-sensitive transcription factors. Nrf2 is constitutively controlled by repressor protein Keap1, which acts as a molecular sensor of disturbances in cellular homeostasis. These molecular patterns are in close interconnection and function as parts of the integrated redox-sensitive signaling system Nrf2/Keap1/ARE. Depending on cellular redox balance, activity of this signaling system changes at the levels of transcription, translation, posttranslational modification, nuclear translocation of transcription factor, and its binding to ARE-driven gene promoters. This review summarizes current conceptions of Nrf2/Keap1/ARE induction and inactivation. PMID- 21585317 TI - Effect of glutathione on growth of the probiotic bacterium Lactobacillus reuteri. AB - Glutathione (GSH) is an abundant nonprotein thiol that plays numerous roles within the cell. Previously, we showed that Lactobacillus salivarius has the capacity to mount a glutathione-mediated acid-tolerance response. In the present work we provide evidence of a requirement for GSH by Lactobacillus reuteri and have studied the role of GSH during cell growth. Medium supplementation with 0.5 mM GSH as the sole sulfur source enhanced cell growth, resulting in an increase in glucose consumption, and increased cell GSH and protein contents compared with levels seen in the absence of supplementation. Moreover, L. reuteri showed enhanced amino acid consumption when grown with 0.5 mM GSH. These findings indicate that glutathione is a nutrient for bacterial growth. PMID- 21585318 TI - Regulation of cyclic electron transport through photosystem I in cyanobacterium Synechocystis sp. PCC 6803 mutants deficient in respiratory dehydrogenases. AB - The rate of PSI mediated cyclic electron transport was studied in wild type and mutant cells of Synechocystis sp. PCC 6803 deficient in NDH-1 (M55) or succinate dehydrogenase (SDH(-)) that are responsible for the dark reduction of the plastoquinone pool. Kinetics of P700 photooxidation and P700(+) dark reduction in the presence of 5.10(-5) M 3-(3,4-dichlorophenyl)-1,1-dimethylurea have been registered as light induced absorbance changes at 810 nm resulting from illumination of cells with 730-nm actinic light for 1 sec. It is shown that in the absence of dehydrogenases the rate of dark reduction of P700(+) in both mutants did not decrease but even increased in NDH-1-less mutant cells as compared with the rate in wild type cells. Dibromothymoquinone drastically reduced the rate of P700(+) dark reduction both in wild type and in mutant cells. Thus, the cyclic electron transfer from ferredoxin through the plastoquinone pool to P700(+), which is independent from dehydrogenases, takes place in all the types of cells. Preillumination of cells of wild type and both mutants for 30 min or anaerobic conditions resulted in delay of P700 photooxidation and acceleration of P700(+) dark reduction, while the level of photosynthesis and respiration terminal acceptors (NAD(P)(+) and oxygen) decreased. It appears that the rate of P700 photooxidation and P700(+) dark reduction in cyclic electron transport in Synechocystis wild type and mutant cells is determined by the level of NADP+ and oxygen in stroma. A possible approach to evaluation of the levels of these acceptors in vivo is proposed, based on kinetic curve parameters of P700 photoconversions induced by 730-nm light with 1-sec duration. PMID- 21585319 TI - Purification of a lectin from fruit bodies of Lactarius pergamenus (Fr.) Fr. and studies of its properties. AB - A lectin was purified from fruit bodies of the milk mushroom Lactarius pergamenus (Fr.) Fr. by a combination of ethanol precipitation, affinity chromatography on copolymer of polyvinyl alcohol and human blood B-group-specific substance, and ion-exchange chromatography on DEAE-Toyopearl. The lectin yield was 3 mg/kg of fresh mushrooms. Considerable loss of primary activity was observed during its purification, which, presumably, could be explained by disintegration of the lectin molecule, which consisted of six subunits, first to two molecules of three subunits, and then to individual subunits. There was a reverse tendency to aggregation during concentration of lectin solutions. Similar processes can take place in nature because of considerable individual variations of the lectin activity during growth of mushroom fruit bodies. The lectin weakly interacts with DGalNAc, while DGalbeta1-3DGalNAc and DGalbeta1-3DGlcNAc are the most probable candidates for ligands, with which the L. pergamenus lectin interacts at disaccharides level. The purified lectin may find application in histochemical research. PMID- 21585320 TI - Properties of Rhodobacter sphaeroides photosynthetic reaction center with double amino acid substitution I(L177)H+H(M182)L. AB - Histidine M182 in the reaction center (RC) of Rhodobacter sphaeroides serves as the fifth ligand of the bacteriochlorophyll (BChl) B(B) Mg atom. When this His is substituted by an amino acid that is not able to coordinate Mg, bacteriopheophytin appears in the B(B) binding site instead of BChl (Katilius, E., et al. (1999) J. Phys. Chem. B, 103, 7386-7389). We have shown that in the presence of the additional mutation I(L177)H the coordination of the BChl B(B) Mg atom in the double mutant I(L177)H+H(M182)L RC still remains. Changes in the double mutant RC absorption spectrum attributed to BChl absorption suggest that BChl B(B) Mg atom axial ligation might be realized not from the usual alpha-side of the BChl macrocycle, but from the opposite, beta-side. Weaker coordination of BChl B(B) Mg atom compared to the other mutant RC BChl molecules suggests that not an amino acid residue but a water molecule might be a possible ligand. The results are discussed in the light of the structural changes that occurred in the RC upon Ile/His substitution in the L177 position. PMID- 21585321 TI - Heat shock protein DnaK--substrate of actin-specific bacterial protease ECP32. AB - It has been found that actin-specific bacterial protease ECP32 cleaves prokaryotic heat shock protein DnaK, which belongs to the family of heat shock proteins with molecular weight 70 kDa. We propose a new one-step method for DnaK purification using heat treatment. The technique yields ~1 mg of partially purified DnaK from 25 g of wet bacterial biomass. Polyclonal antibodies against DnaK were obtained. The degree of ECP32 catalyzed proteolysis of partially purified DnaK and that of DnaK in initial cell extracts was compared. PMID- 21585322 TI - Correlation between influence of polysaccharides on hydrolase activity and their antiviral effect in tobacco leaves. AB - The activities of hydrolases (acid phosphatase, RNase, and proteases) in healthy and tobacco mosaic virus-infected leaves of Nicotiana tabacum L. var. Samsun, both untreated and treated with polysaccharides (PS) (1,3;1,6-beta-D-glucan, fucoidan, and kappa/beta-carrageenan), were determined. The PS lead to substantial increase in the hydrolase level. The percentage of viral particles undergoing destructive change also increases in leaves treated with PS 24 h before infection. We suppose that the PS-mediated hydrolase activation promotes intracellular destruction of the viral particles and, thus, comprises one of the PS-induced protective mechanisms limiting intracellular viral accumulation. PMID- 21585323 TI - Effect of homocysteine on properties of neutrophils activated in vivo. AB - We have found that neutrophils begin to express NMDA receptors on their membranes after in vivo activation. These receptors are the target for action of homocysteine (HC). After incubation of activated neutrophils with HC, the degranulation process is stimulated and generation of reactive oxygen species is increased. We conclude that expression of NMDA receptors on neutrophil membrane makes neutrophils sensitive to HC. Thus, hyperhomocysteinemia may induce additional stimulation of immune competent cells. PMID- 21585324 TI - Cyanines as efficient photosensitizers in photodynamic reaction: photophysical properties and in vitro photodynamic activity. AB - The purpose of the present study was to explore the potential application of cyanines in photodynamic treatment. The photophysical features of four cyanines (KF570, HM118, FBF-749, and ER-139) were investigated by elemental and spectral analyses. Two malignant cell lines (MCF-7/WT and MCF-7/DOX) were used to test the potential for use in the photodynamic therapy. The cytotoxic effects of these dyes were determined by the MTT assay after 4 and 24 h of incubation with the cyanine. KF570 and HM118 were irradiated with red light (630-nm filter) and FBF 749 and ER-139 with green light (435-nm filter). The results showed that the cyanine HM118 demonstrated a major phototoxic effect. It was also noted that the efficiency of photodynamic therapy was higher in the doxorubicin-resistant cell line (MCF-7/DOX). PMID- 21585325 TI - Oligopeptidase B from Serratia proteamaculans. II. Enzymatic characteristics: substrate analysis, influence of calcium ions, pH and temperature dependences. AB - Enzymatic properties of a novel oligopeptidase B from psychrotolerant gram negative microorganism Serratia proteamaculans (PSP) were studied. The substrate specificity of PSP was analyzed using p-nitroanilide substrates, and the influence of calcium ions on the enzyme activity was studied. Hydrolysis of oligopeptides by PSP was studied using melittin as the substrate. Optimal conditions for the PSP activity (pH and temperature) have been established. It was found that PSP shares some properties with oligopeptidases B from other sources containing two Asp/Glu residues in the S2 site, but it differs significantly in some characteristics. The S2 site of PSP contains only one Asp460 residue. The secondary specificity of PSP has a number of specific features: an unusual substrate inhibition by peptides with hydrophobic residues at the P2 position, as well as the drastic influence of calcium ions on substrate characteristics of the enzyme. It is assumed that the PSP molecule contains a large hydrophobic substrate-binding site, and significant conformational rearrangements of the enzyme active site are induced by Ca(2+) binding and by the formation of the enzyme-substrate complex. The temperature characteristics of PSP (high activity at low temperature as well as low apparent temperature optimum (25 degrees C)) confirm that PSP is a psychrophilic enzyme. PMID- 21585326 TI - Quasi-equilibrium assumption for arbitrary mechanism of enzymatic reaction. Criteria for existence of equilibrium segments. AB - The possible application of the quasi-equilibrium assumption for an arbitrary mechanism of enzymatic reaction is considered. It is shown at what ratios of kinetic constants a segment consisting of two, three, and four intermediates may be considered as an equilibrium one. Expressions for evaluation of accuracy of distribution of intermediate concentrations inside the equilibrium segment and accuracy of determination of intermediate concentrations inside and outside the equilibrium segment as a function of the ratio of kinetic constants are derived. A method for determination of the limitations on the ratio of rate constants for an equilibrium segment of arbitrary structure is suggested. PMID- 21585327 TI - Patented in vitro blood-brain barrier models in CNS drug discovery. AB - The blood-brain barrier (BBB) is a regulatory interface between the circulation and the central nervous system (CNS). Therapy of neurological diseases is limited due to restricted penetration of pharmacons across the BBB. Models for screening the brain penetration of drug candidates are needed early in drug discovery. Culture-based models are useful tools for both basic research on BBB, and testing the permeability of new therapeutical molecules. This review focuses on patented in vitro BBB models and their potential application in CNS drug discovery. Cell culture models using primary and immortalized brain endothelial cells of non human and human origin, in co-culture or mono-culture setting, in static or dynamic conditions are discussed, as well as methods to induce BBB properties in such in vitro models. The aim of these models is to reproduce as many aspects as possible of the in vivo BBB. All models should show some elements of general endothelial and specific BBB properties, like physiologically realistic cell architecture, restrictive paracellular pathway, and functional expression of transport mechanisms. Though no "ideal in vitro BBB model" has been constructed yet, the currently available models provide valuable information on BBB permeability and are useful tools in CNS drug discovery. PMID- 21585329 TI - BACE inhibitors as potential drugs for the treatment of Alzheimer's disease: focus on bioactivity. AB - Current drug development for the treatment of Alzheimer's Disease is principally based on the amyloid cascade theory, and aims to reduce the levels of Abeta amyloid peptide in the brain. This can be achieved, either by decreasing peptide production through inhibition of beta-secretase (also known as BACE-1) or gamma secretase, or by interfering with Abeta aggregation, or by promoting Abeta clearance. Targeting BACE-1, the proteolytic enzyme that initiates Abeta formation, has generated a lot of research interest recently and is currently thought to be one of the most promising therapeutic approaches. In this review, we summarize and discuss the latest patents and publications describing BACE-1 inhibitors, principally focussing on their drug properties and performance in preclinical trials. PMID- 21585328 TI - Potential drugs and methods for preventing or delaying the progression of Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant inherited and progressive neurodegenerative disorder with motor dysfunction and cognitive deficits. Although there are no treatments to delay the appearance and the progression of HD, there are potential drugs currently in preclinical and clinical trials that are focused on HD therapy. The signaling pathways involved in HD are not yet clearly elucidated; however, expression of mutant huntingtin protein is considered a key factor in the induction and/or progression of HD. The demonstration that the onset and progression of HD in models of transgenic mice, in particular, are delayed or improved by the application of neurotrophic factors has emphasized their importance in neuroprotection in HD. In addition, other compounds targeting the HD gene or mutant huntingtin protein are currently in preclinical and clinical testing and may show promising neuroprotective effects. There are current patented drugs that are currently being considered as potential therapeutics for HD. These patented drugs may provide promising therapy for HD. PMID- 21585330 TI - Metoclopramide as an analgesic in severe migraine attacks: an open, single-blind, parallel control study. AB - Metoclopramide is a well-known anti-emetic drug with central and peripheral pharmacological effects. Some authors have reported metoclopramide as an adjunct therapy to other analgesics in patients with migraine attacks. Treatment of migraine headache using a mix of metoclopramide and an NSAID has been patented (European Patent EP1014961) as well as a short series showing great efficacy and tolerability of metoclopramide in patients wtih migraine attacks. We decided to conduct an open, single-blind, parallel control study in the emergency department to evaluate the efficacy and tolerability of metoclopramide in patients with severe migraine attacks. 93 consecutive patients with severe migraine attacks were randomized into two groups (groups A and B). Patients in group A received 10mg of intravenous metoclopramide and patients in group B received 1 g of intravenous paracetamol. Patients were evaluated 5 minutes before (baseline), 15, 30, 60 and 120 minutes after drug delivery, and before being discharged from the emergency department They were then contacted by phone 48 hours after being discharged from the hospital (phone questionnaire). Patients treated with either metoclopramide or paracetamol showed a significant reduction in the intensity of pain at the 120 minute time point, with an 86% and 82% improvement respectively. However, patients treated with metoclopramide showed a more rapid improvement at the 15 and 30 minute evaluations. Patients with severe migraine attacks treated with metoclopramide as monotherapy showed a significant improvement in terms of pain relief and a faster improvement in pain intensity compared to those treated with paracetamol. Metoclopramide and other dopamine antagonistic drugs should be considered a therapeutic option in severe migraine headache attacks. PMID- 21585332 TI - Prospective observation for seven-year's highly active antiretroviral therapy in Chinese HIV-1 infected patients. AB - To prospectively observe the efficacy, tolerability, immune reconstitution and toxicity of long-term highly active antiretroviral therapy (HAART) in Chinese patients infected HIV. 437 cases originally received two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) during a mean period of 4.3 years (3.1-7.3). Patients were followed up by HIV RNA levels, T lymphocyte subsets, blood routine test, and biochemical parameters. If active opportunistic infections, apparent side effects or virological failure appeared, appropriate treatment would be taken immediately. 30 patients (6.86%) died, most in the first 6 months of HAART. The proportion of subjects with HIV-1 RNA <500 copies/ml was 90.8%, 63.5%, 69.4%, 70.0% and 72.2% at 1, 4, 5, 6 and 7 year. The CD4+ T cell count was 115, 246, 301, 334, 363, 356,386 and 373 cells/ul at 0, 1, 2, 3, 4, 5, 6 and 7 year. 67.9% showed various drug-related side effects, most including gastrointestinal side effects, nervous disorder, myelotoxicity and abnormal liver function, rashes, serum cholesterol elevation, mostly appearing in the first 12 months. Grade 3 and Grade 4 adverse events occurred in 41 cases. This is the first to report results from the prospectively 7-year follow-up of Chinese patients infected HIV taking HAART. It demonstrates that two NRTIs and one NNRTI regimens may persistently suppress HIV viremia and continuously induce CD4 cell increase, with good safety and tolerance. The majority took first-line regimens effectively. 19.2% changed to other first-line drug due to drug-related side effects, 10.2% switched to second-line regimens due to viral resistance. Some discontinued or got virological failure because of poor compliance. PMID- 21585333 TI - Liver-related factors associated with low vitamin D levels in HIV and HIV/HCV coinfected patients and comparison to general population. AB - OBJECTIVES: Low 25-Hydroxyvitamin D (25[OH]D) was associated with severe fibrosis and low sustained virological response (SVR) after interferon (IFN)-based therapy in chronic hepatitis C. Furthermore, hypovitaminosis D was reported in HIV infected individuals, but its role in liver disease progression in HIV/HCV coinfection is unknown. METHODS: 25(OH)D was retrospectively measured in 237 HIV infected patients (93 with HCV coinfection) and 76 healthy controls. Multivariate analysis included season, immuno-virological data, combined antiretroviral therapy (cART) and, in a subgroup of 51 HIV/HCV-genotype 1 coinfected patients, factors influencing SVR to pegylated-IFN and ribavirin. In a group of 20 patients, liver expression of cytochrome (CY)-P27A1 and CYP2R1, 25-hydroxylating enzymes, was assessed by immunohistochemistry. RESULTS: Median 25(OH)D levels were 23.4 (interquartile range 16.7-33.7) ng/mL in the HIV-infected population and 24 ng/mL (18.3-29.5) in healthy controls (p=0.9). At multiple regression analysis, only winter/spring measurements correlated with lower 25(OH)D levels. No correlation with HCV coinfection, nor with cART regimens was found. Low 25(OH)D was independently associated with advanced fibrosis in HIV/HCV coinfected patients (p=0.023), whereas no association emerged with SVR to IFN-based therapy. CYP27A1 and CYP2R1 expression was associated neither with 25(OH)D serum levels nor with HCV-infection, liver histology, or cART. CONCLUSIONS: In our experience, despite the high prevalence of 25(OH)D insufficiency, HIV and HCV-infection did not seem to influence vitamin D status. The role of HIV, HCV and cART on hypovitaminosis D needs further validation in larger cohorts that account for the vitamin levels in general populations and for seasonal and regional variability. PMID- 21585331 TI - Analgesic and antineuropathic drugs acting through central cholinergic mechanisms. AB - The role of muscarinic and nicotinic cholinergic receptors in analgesia and neuropathic pain relief is relatively unknown. This review describes how such drugs induce analgesia or alleviate neuropathic pain by acting on the central cholinergic system. Several pharmacological strategies are discussed which increase synthesis and release of acetylcholine (ACh) from cholinergic neurons. The effects of their acute and chronic administration are described. The pharmacological strategies which facilitate the physiological functions of the cholinergic system without altering the normal modulation of cholinergic signals are highlighted. It is proposed that full agonists of muscarinic or nicotinic receptors should be avoided. Their activation is too intense and un-physiological because neuronal signals are distorted when these receptors are constantly activated. Good results can be achieved by using agents that are able to a) increase ACh synthesis, b) partially inhibit cholinesterase activity c) selectively block the autoreceptor or heteroreceptor feedback mechanisms. Activation of M(1) subtype muscarinic receptors induces analgesia. Chronic stimulation of nicotinic (N(1)) receptors has neuronal protective effects. Recent experimental results indicate a relationship between repeated cholinergic stimulation and neurotrophic activation of the glial derived neurotrophic factor (GDNF) family. At least 9 patents covering novel chemicals for cholinergic system modulation and pain control are discussed. PMID- 21585334 TI - Cervical squamous intraepithelial lesions among HIV-positive women on antiretroviral therapy in Kenya. AB - BACKGROUND: The prevalence of cervical squamous intraepithelial lesions (SIL) among HIV-infected women on antiretroviral therapy in sub-Saharan Africa has not been well described. METHODS: HIV-infected women enrolled in an HIV treatment clinic in Nairobi, Kenya were offered free cervical screening with Papanicolaou (Pap) smear testing if they were 30 to 39 years of age and on antiretroviral therapy. Women with SIL were compared to those without SIL with univariate analyses and logistic regression. RESULTS: Of 595 eligible women, 267 accepted Pap testing and had available cytology results, of whom 258 (97%) were on a non nucleoside reverse transcriptase inhibitor (NNRTI) based regimen. Median duration of antiretroviral therapy was 13 months [interquartile range (IQR), 8-19]. Abnormal cytology was found in 123 women (46%) with 70 women (26%) having low grade squamous intraepithelial lesions (LSIL), 22 (8%) high grade squamous intraepithelial lesions (HSIL), 30(11%) atypical squamous cells of unknown significance (ASCUS) and 1 (0.4%) atypical glandular cells (AGC). Women with SIL had lower median CD4 cell count (239 vs 287 cells/mm3; P=0.02), lower income (<70 USD per month: 57% vs 38%; P=0.01), and less regular condom use (24% vs 40%; P=0.02) compared to those with no SIL. Duration and type of antiretroviral regimen were not significantly associated with SIL. CONCLUSION: SIL is prevalent among women on antiretroviral therapy and is associated with immunosuppression, low income, and less frequent condom use. Cervical cancer screening and counseling on condom use should be routinely offered to HIV-infected women in antiretroviral treatment clinics in Africa. PMID- 21585335 TI - Neutral actions of Raltegravir on adipogenesis, glucose metabolism and lipolysis in 3T3-L1 adipocytes. AB - Raltegravir (RAL) has been shown to be virologically effective in both treatment naive and triple class resistant patients. A more favourable metabolic profile associated with RAL in comparison with other antiretroviral drugs has also been observed. The aim of this study was to investigate the molecular mechanisms that could explain the lack of toxicity of this drug in metabolism. Thus, the effects of RAL on adipogenesis and adipocyte metabolism were analyzed using 3T3-L1 cells, a very adequate and convenient cell culture model for the investigation of adipose differentiation and metabolism. The effects of RAL on adipogenesis were evaluated by the Oil Red O staining after 8 days of induction of differentiation. Several adipogenic genes (C/EBP, PPAR, Pref-1 and AP2) were analyzed by real time PCR. Fully differentiated adipocytes were also incubated with RAL for 24 hours and glucose utilization, lactate production and glycerol release were analyzed. Thus, minimal effects of RAL on murine adipocyte differentiation were observed. Basal glucose uptake and lactate production were not affected by RAL at any of the concentrations used. No effects were also found on the percentage of glucose that is metabolized to lactate. Lipolysis was only slightly inhibited by Raltegravir (-10%) at the highest concentration used (50 uM), while no effects were observed with lower doses. Our results suggest that the absence of significant actions of RAL on adipogenesis and glucose and lipid metabolism in adipocytes could explain, at least in part, the neutral metabolic effects of RAL in clinical studies. PMID- 21585336 TI - Adenosine 5'-phosphosulfate reductase (APR2) mutation in Arabidopsis implicates glutathione deficiency in selenate toxicity. AB - APR2 is the dominant APR (adenosine 5'-phosphosulfate reductase) in the model plant Arabidopsis thaliana, and converts activated sulfate to sulfite, a key reaction in the sulfate reduction pathway. To determine whether APR2 has a role in selenium tolerance and metabolism, a mutant Arabidopsis line (apr2-1) was studied. apr2-1 plants had decreased selenate tolerance and photosynthetic efficiency. Sulfur metabolism was perturbed in apr2-1 plants grown on selenate, as observed by an increase in total sulfur and sulfate, and a 2-fold decrease in glutathione concentration. The altered sulfur metabolism in apr2-1 grown on selenate did not reflect typical sulfate starvation, as cysteine and methionine levels were increased. Knockout of APR2 also increased the accumulation of total selenium and selenate. However, the accumulation of selenite and selenium incorporation in protein was lower in apr2-1 mutants. Decreased incorporation of selenium in protein is typically associated with increased selenium tolerance in plants. However, because the apr2-1 mutant exhibited decreased tolerance to selenate, we propose that selenium toxicity can also be caused by selenate's disruption of glutathione biosynthesis leading to enhanced levels of damaging ROS (reactive oxygen species). PMID- 21585337 TI - Transforming growth factor-beta2 promotes Snail-mediated endothelial-mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling. AB - EndMT (endothelial-mesenchymal transition) is a critical process of cardiac development and disease progression. However, little is know about the signalling mechanisms that cause endothelial cells to transform into mesenchymal cells. In the present paper we show that TGF-beta2 (transforming growth factor-beta2) stimulates EndMT through the Smad, MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase], PI3K (phosphinositide 3-kinase) and p38 MAPK signalling pathways. Inhibitors of these pathways prevent TGF-beta2-induced EndMT. Furthermore, we show that all of these pathways are essential for increasing expression of the cell-adhesion-suppressing transcription factor Snail. Inhibition of Snail with siRNA (small interfering RNA) prevents TGF-beta2-induced EndMT. However, overexpression of Snail is not sufficient to cause EndMT. Chemical inhibition of GSK-3beta (glycogen synthase kinase-3beta) allows EndMT to be induced by Snail overexpression. Expression of a mutant Snail protein that is resistant to GSK-3beta-dependent inactivation also promotes EndMT. These results provide the foundation for understanding the roles of specific signalling pathways in mediating EndMT. PMID- 21585338 TI - The DLK gene is a transcriptional target of PPARgamma. AB - DLK (dual leucine zipper-bearing kinase) is a key regulator of development, cell differentiation and apoptosis. Interestingly, recent studies have shown that DLK expression is up-regulated in 3T3-L1 cells induced to differentiate into adipocytes and that DLK knockdown impairs the expression of PPARgamma (peroxisome proliferator-activated receptor gamma), a master regulator of adipogenesis. Because the PPARgamma agonist rosiglitazone was found to increase DLK expression in 3T3-L1 cells, we hypothesized that PPARgamma is required for the transcriptional activation of the DLK gene. To test this hypothesis, we first examined the effects of pharmacological inhibition or shRNA (small-hairpin RNA) mediated depletion of PPARgamma on DLK accumulation in 3T3-L1 cells undergoing differentiation. In addition to blocking adipocyte conversion of 3T3-L1 cells, inhibition of PPARgamma suppressed DLK expression at both the mRNA and protein levels. Moreover, supporting a role for PPARgamma in DLK regulation, two potential PPARgamma-binding sites identified by bioinformatic tools at positions 611 and -767 upstream of the DLK gene transcriptional start site were shown by electrophoretic mobility-shift assay and chromatin immunoprecipitation to bind PPARgamma and its essential heterodimer partner retinoid X receptor as differentiation proceeds. Collectively, these results show that DLK is a novel transcriptional target of PPARgamma with functional PPARgamma-binding sites in its promoter. PMID- 21585339 TI - Identification of the VIL2 enhancer in human embryonic kidney cells. AB - We previously demonstrated that the VIL2 -87/+134 region exhibited promoter activity in some human cells, and a region further upstream of this promoter might contain an enhancer. However, the properties and location of this VIL2 enhancer remain unclear. In this study, we cloned the VIL2 -1541/-706 segment and investigated its transcriptional regulatory properties via luciferase assays in transiently transfected HEK-293 cells (human embryonic kidney cells). The VIL2 1541/-706 was found to exhibit promoter activity. Furthermore, when this segment was located upstream of the VIL2 or SV40 (simian virus 40) promoters in the forward orientation, the expression levels of luciferase were dramatically enhanced. However, this transcriptional enhancement disappeared when this segment was located upstream of the promoter in the reverse orientation or downstream of the reporter gene in the forward or reverse orientation. In deletion experiments, we found several potential regulatory regions within the VIL2 -1541/-706. When these regions were separately located upstream of the VIL2 or SV40 promoters, only the -1297/-1186 considerably enhanced the activity of these promoters. Although the other regulatory regions exhibited significant transcriptional regulation in deletion experiments, they weakly enhanced VIL2 promoter activity and/or did not regulate SV40 promoter activity. These results suggest that the DNA sequence upstream of the VIL2 promoter functions as an enhancer in a position and orientation-dependent manner, and the VIL2 -1297/-1186, which acts as a key enhancer, probably regulates VIL2 transcription in combination with other potential regulatory regions located upstream of the VIL2 promoter. PMID- 21585340 TI - Demonstration that endoplasmic reticulum-associated degradation of glycoproteins can occur downstream of processing by endomannosidase. AB - During quality control in the ER (endoplasmic reticulum), nascent glycoproteins are deglucosylated by ER glucosidases I and II. In the post-ER compartments, glycoprotein endo-alpha-mannosidase provides an alternative route for deglucosylation. Previous evidence suggests that endomannosidase non-selectively deglucosylates glycoproteins that escape quality control in the ER, facilitating secretion of aberrantly folded as well as normal glycoproteins. In the present study, we employed FOS (free oligosaccharides) released from degrading glycoproteins as biomarkers of ERAD (ER-associated degradation), allowing us to gain a global rather than single protein-centred view of ERAD. Glucosidase inhibition was used to discriminate between glucosidase- and endomannosidase mediated ERAD pathways. Endomannosidase expression was manipulated in CHO (Chinese-hamster ovary)-K1 cells, naturally lacking a functional version of the enzyme, and HEK (human embryonic kidney)-293T cells. Endomannosidase was shown to decrease the levels of total FOS, suggesting decreased rates of ERAD. However, following pharmacological inhibition of ER glucosidases I and II, endomannosidase expression resulted in a partial switch between glucosylated FOS, released from ER-confined glycoproteins, to deglucosylated FOS, released from endomannosidase processed glycoproteins transported from the Golgi/ERGIC (ER/Golgi intermediate compartment) to the ER. Using this approach, we have identified a previously unknown pathway of glycoprotein flow, undetectable by the commonly employed methods, in which secretory cargo is targeted back to the ER after being processed by endomannosidase. PMID- 21585341 TI - Aldo-keto reductase family 1, member B10 is secreted through a lysosome-mediated non-classical pathway. AB - AKR1B10 (aldo-keto reductase family 1, member B10) protein is primarily expressed in normal human small intestine and colon, but overexpressed in several types of human cancers and considered as a tumour marker. In the present study, we found that AKR1B10 protein is secreted from normal intestinal epithelium and cultured cancer cells, as detected by a newly developed sandwich ELISA and Western blotting. The secretion of AKR1B10 was not affected by the protein-synthesis inhibitor cycloheximide and the classical protein-secretion pathway inhibitor brefeldin A, but was stimulated by temperature, ATP, Ca(2+) and the Ca(2+) carrier ionomycin, lysosomotropic NH(4)Cl, the G-protein activator GTPgammaS and the G-protein coupling receptor N-formylmethionyl-leucyl-phenylalanine. The ADP ribosylation factor inhibitor 2-(4-fluorobenzoylamino)-benzoic acid methyl ester and the phospholipase C inhibitor U73122 inhibited the secretion of AKR1B10. In cultured cells, AKR1B10 was present in lysosomes and was secreted with cathepsin D, a lysosomal marker. In the intestine, AKR1B10 was specifically expressed in mature epithelial cells and secreted into the lumen at 188.6-535.7 ng/ml of ileal fluids (mean=298.1 ng/ml, n=11). Taken together, our results demonstrate that AKR1B10 is a new secretory protein belonging to a lysosome-mediated non-classical protein-secretion pathway and is a potential serum marker. PMID- 21585342 TI - Prevalence of human papillomavirus in spontaneously aborted products of conception. AB - OBJECTIVE: To compare the prevalence of human papillomavirus (HPV) in placentas from women with spontaneous abortions and from control women after term delivery. DESIGN: Cross-sectional study. SETTING: Department of Obstetrics and Pathology of Pregnancy, Medical University of Lublin (Poland). POPULATION: Patients whose spontaneous abortions occurred between the 6th and the 16th week of pregnancy (n=51), and women after term delivery (n=78). METHOD: Polymerase chain reaction (PCR). MAIN OUTCOME MEASURES: HPV DNA prevalence rate and the fraction of HPV 16/18 infections in aborted products of conception and placentas. RESULTS: Patients with spontaneous abortion did not differ from the controls in terms of mean age and the fraction of primiparas. The DNA of HPV was detected in 17.7% of aborted products of conception and in 24.4% of placentas from term deliveries. The aborted products of conception and full-term placentas were positive for HPV 16/18 in 11.8 and 12.8% cases, respectively. Patients whose material was positive for HPV DNA or those with confirmed HPV 16/18 did not differ significantly from HPV-negative women in terms of mean age and the fraction of primiparas. CONCLUSIONS: The HPV 16/18 infection rate does not seem be higher in cases of spontaneous abortions. Nevertheless, further study of the consequences of HPV infection in pregnancy is still needed. PMID- 21585343 TI - The plant sterol brassicasterol as additional CSF biomarker in Alzheimer's disease. AB - OBJECTIVE: Plant sterols (sitosterol, campesterol, stigmasterol and brassicasterol) are solely dietary-derivable sterols that are structurally very similar to cholesterol. In contrast to peripheral cholesterol, plant sterols can cross the blood-brain barrier and accumulate within mammalian brain. As an impaired function of the cerebrospinal fluid (CSF)-blood barrier is linked to neurodegenerative disorders, i.e. Alzheimer's disease (AD), we investigated whether this results in altered plant sterol concentrations in CSF. METHOD: Applying gas chromatography/mass spectrometry analysis, plant sterol concentrations were measured in plasma and CSF of patients with AD (n = 67) and controls (n = 29). Age, gender, plasma-to-CSF albumin ratio, CSF Abeta(42) , CSF pTau, APOE4 genotype, and serum creatinine were applied as covariates in the statistical analysis for individual plant sterols in order to compare plasma and CSF plant sterol concentrations between patients with AD and controls. RESULTS: Albumin quotient was a consistent predictor in CSF for cholesterol and methyl plant sterols campesterol and brassicasterol. Comparison of lipid parameters per diagnosis based on relevant predictors revealed significantly lower concentrations of brassicasterol (P < 0.001) in CSF of patients with AD. Binary logistic regression analysis revealed that brassicasterol improved the predictive value when added to pTau and Abeta42 in a biomarker model. CONCLUSION: Brassicasterol might be a relevant additional biomarker in AD. PMID- 21585344 TI - Sinomenine protects against ischaemic brain injury: involvement of co-inhibition of acid-sensing ion channel 1a and L-type calcium channels. AB - BACKGROUND AND PURPOSE: Sinomenine (SN), a bioactive alkaloid, has been utilized clinically to treat rheumatoid arthritis in China. Our preliminary experiments indicated that it could protect PC12 cells from oxygen-glucose deprivation reperfusion (OGD-R), we thus investigated the possible effects of SN on cerebral ischaemia and the related mechanism. EXPERIMENTAL APPROACH: Middle cerebral artery occlusion in rats was used as an animal model of ischaemic stroke in vivo. The mechanisms of the effects of SN were investigated in vitro using whole-cell patch-clamp recording, calcium imaging in PC12 cells and rat cortical neurons subjected to OGD-R. KEY RESULTS: Pretreatment with SN (10 and 30 mg.kg(-1) , i.p.) significantly decreased brain infarction and the overactivation of calcium mediated events in rats subjected to 2 h ischaemia followed by 24 h reperfusion. Extracellular application of SN inhibited the currents mediated by acid-sensing ion channel 1a and L-type voltage-gated calcium channels, in the rat cultured neurons, in a concentration-dependent manner. These inhibitory effects contribute to the neuroprotection of SN against OGD-R and extracellular acidosis-induced cytotoxicity. More importantly, administration of SN (30 mg.kg(-1) , i.p.) at 1 and 2 h after cerebral ischaemia also decreased brain infarction and improved functional recovery. CONCLUSION AND IMPLICATIONS: SN exerts potent protective effects against ischaemic brain injury when administered before ischaemia or even after the injury. The inhibitory effects of SN on acid-sensing ion channel 1a and L-type calcium channels are involved in this neuroprotection. PMID- 21585345 TI - Maternal nicotine exposure and fetal programming of vascular oxidative stress in adult offspring. AB - Despite the well-known harmful effects, many women continue to smoke throughout pregnancy. Consequently, nicotine replacement therapy (NRT) - which has been developed as a pharmacotherapy for smoking cessation - has been used as an alternative to smoking during pregnancy. However, like cigarette smoking, NRT results in biologically significant levels of nicotine crossing the placenta, leading to both fetal and neonatal exposure to nicotine, and yet, NRT safety during pregnancy has not been extensively evaluated. There is now evidence from studies in rats that maternal nicotine exposure throughout gestation results in fetal programming of vascular oxidative stress in the offspring during adulthood. This phenomenon involves vascular dysfunction mediated by reactive oxygen species in association with decreased superoxide dismutase activity and increased Nox2 NADPH oxidase expression in the vascular wall. If this phenomenon also occurs in humans, either smoking or NRT use during pregnancy may represent a novel risk factor for the unborn that results in accelerated cardiovascular disease in their adulthood. PMID- 21585346 TI - Antidepressant-like effect induced by systemic and intra-hippocampal administration of DNA methylation inhibitors. AB - BACKGROUND AND PURPOSE: Epigenetic modifications are thought to play an important role in the neurobiology of depression. Antidepressant treatment induces histone acetylation in the hippocampus, which is associated with transcriptional activation, whereas stress increases DNA methylation, which is associated with transcriptional repression. Because the specific involvement of DNA methylation in the regulation of depressive-like behaviours is not yet known, we have investigated the effects induced by systemic or intra-hippocampal administration of inhibitors of DNA methyltransferase (DNMT) in rats submitted to a range of behavioural tests. EXPERIMENTAL APPROACH: Rats received i.p. injections of 5-aza 2-deoxycytidine (5-azaD, 0.1-0.8 mg.kg(-1) ), 5-azacytidine (5-azaC, 0.4-3.2 mg.kg(-1) ), imipramine (15 mg.kg(-1) ) or vehicle and were submitted to the forced swimming test (FST) or open field test (OFT). Other groups of rats received intra-hippocampal injection of DNMT inhibitors. KEY RESULTS: Systemic administration of DNMT inhibitors induced a dose-dependent antidepressant-like effect, which was followed by decreased DNA methylation and increased brain derived neurotrophic factor (BDNF) levels in the hippocampus. Hippocampal inhibition of DNA methylation induced similar behavioural effects. No treatment induced any locomotor effects in the OFT. Antidepressant-like effects of 5-azaD were confirmed in mice submitted to the FST or the tail suspension test. CONCLUSIONS AND IMPLICATIONS: Systemic, as well as hippocampal, inhibition of DNA methylation induced antidepressant-like effects. These effects could be associated with increased hippocampal expression of BDNF. Our data give further support to the hypothesis that DNA methylation is an important epigenetic mechanism involved in the development of depressive-like behaviours. PMID- 21585348 TI - Modulation of presynaptic GABA(A) receptors by endogenous neurosteroids. AB - BACKGROUND AND PURPOSE: Although 3alpha-hydroxy, 5alpha-reduced pregnane steroids, such as allopregnanolone (AlloP) and tetrahydrodeoxycorticosterone, are endogenous positive modulators of postsynaptic GABA(A) receptors, the functional roles of endogenous neurosteroids in synaptic transmission are still largely unknown. EXPERIMENTAL APPROACH: In this study, the effect of AlloP on spontaneous glutamate release was examined in mechanically isolated dentate gyrus hilar neurons by use of the conventional whole-cell patch-clamp technique. KEY RESULTS: AlloP increased the frequency of glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs) in a dose-dependent manner. The AlloP-induced increase in sEPSC frequency was completely blocked by a non-competitive GABA(A) receptor blocker, tetrodotoxin or Cd(2+) , suggesting that AlloP acts on presynaptic GABA(A) receptors to depolarize presynaptic nerve terminals to increase the probability of spontaneous glutamate release. On the other hand, gamma-cyclodextrin (gamma-CD) significantly decreased the basal frequency of sEPSCs. However, gamma-CD failed to decrease the basal frequency of sEPSCs in the presence of a non-competitive GABA(A) receptor antagonist or tetrodotoxin. In addition, gamma-CD failed to decrease the basal frequency of sEPSCs after blocking the synthesis of endogenous 5alpha-reduced pregnane steroids. Furthermore, gamma-CD decreased the extent of muscimol-induced increase in sEPSC frequency, suggesting that endogenous neurosteroids can directly activate and/or potentiate presynaptic GABA(A) receptors to affect spontaneous glutamate release onto hilar neurons. CONCLUSIONS AND IMPLICATIONS: The modulation of presynaptic GABA(A) receptors by endogenous neurosteroids might affect the excitability of the dentate gyrus-hilus-CA3 network, and thus contribute, at least in part, to some pathological conditions, such as catamenial epilepsy and premenstrual dysphoric disorder. PMID- 21585347 TI - Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARalpha agonist. AB - BACKGROUND AND PURPOSE: Adipose triglyceride lipase (ATGL) has been identified as a rate-limiting enzyme of mammalian triglyceride catabolism. Deletion of the ATGL gene in mice results in severe lipid accumulation in a variety of tissues including the heart. In the present study we investigated cardiac function in ATGL-deficient mice and the potential therapeutic effects of the PPARalpha and gamma agonists Wy14,643 and rosiglitazone, respectively. EXPERIMENTAL APPROACH: Hearts isolated from wild-type (WT) mice and ATGL(-/-) mice treated with Wy14,643 (PPARalpha agonist), rosiglitazone (PPARgamma agonist) or vehicle were perfused at a constant flow using the Langendorff technique. Left ventricular (LV) pressure-volume relationships were established, and the response to adrenergic stimulation was determined with noradrenaline (NA). KEY RESULTS: Hearts from ATGL(-/-) mice generated higher LV end-diastolic pressure and lower LV developed pressure as a function of intracardiac balloon volume compared to those from WT mice. Likewise, passive wall stress was increased and active wall stress decreased in ATGL(-/-) hearts. Contractile and microvascular responses to NA were substantially reduced in ATGL(-/-) hearts. Cardiac contractility was improved by treating ATGL(-/-) mice with the PPARalpha agonist Wy14,643 but not with the PPARgamma agonist rosiglitazone. CONCLUSIONS AND IMPLICATIONS: Our results indicate that lipid accumulation in mouse hearts caused by ATGL gene deletion severely affects systolic and diastolic function, as well as the response to adrenergic stimulation. The beneficial effects of Wy14,643 suggest that the cardiac phenotype of these mice is partially due to impaired PPARalpha signalling. PMID- 21585350 TI - Prematurity: is it a risk factor for striae distensae? AB - BACKGROUND: Although the causes of striae distensae (SD) remain to be elucidated, the condition is known to relate to changes in the structures that provide the skin with its tensile strength and elasticity. OBJECTIVE: This study was conducted to evaluate whether premature birth is a risk factor for SD. METHODS: A total of 15,475 parous women ranging in age from 18-45 years were interviewed between January 2007 and June 2009. After exclusion criteria were applied, a total of 1336 women were included in the study. Group 1 consisted of 1231 women of reproductive age who had been born at term. Group 2 included 105 women of reproductive age who had been born prematurely. The main outcome measure was the prevalence of SD. RESULTS: The overall prevalence of SD was 34.6% (462/1336). Mild SD was significantly more common (P < 0.01) in women who had been born prematurely (49.5%) than in women who had been born at term (31.8%). A multivariate analysis using backward stepwise logistic regression analysis identified that height, weight, gravidity, parity and abortion were found to be significantly associated with SD. CONCLUSIONS: Striae distensae was significantly more common in women who had been born prematurely than in women who had been born at term. PMID- 21585349 TI - Retinol-binding protein 4 : a possible role in cardiovascular complications. AB - BACKGROUND AND PURPOSE: Retinol-binding protein 4 (RBP4) is an adipocyte-secreted hormone proposed to link obesity with insulin resistance. However, the role of RBP4 in cardiovascular complications is yet to be fully understood. The present study is aimed to decipher the association between RBP4 with pro-inflammatory cytokines and low-density lipoprotein (LDL) cholesterol in diet-induced obese and hyperlipidaemic mice. To understand the correlation, rimonabant, an anti-obesity drug, has been used to relieve the atherosclerotic predisposition. EXPERIMENTAL APPROACH: Adipose and/or aortic tissue expressions of RBP4, pro-inflammatory cytokine genes and circulating LDL levels were measured in high fat (HF)-fed female C57BL/6 and high cholesterol (HC)-fed apolipoprotein E3 (ApoE3) Leiden mice. KEY RESULTS: Mice fed a HF diet had a significantly increased adipose expression of RBP4, TNF-alpha and monocyte chemoattractant protein 1 (MCP-1) and down-regulated adiponectin mRNA levels. A significant increase in aortic RBP4 and MCP-1 expression and circulating levels of LDL and C-reactive protein (CRP) was found in the ApoE3 mice fed a HC diet. Interestingly, rimonabant treatment lowered the elevated aortic RBP4, MCP-1 expressions and significantly reduced the serum levels of LDL, CRP, RBP4 and MCP-1. CONCLUSION AND IMPLICATIONS: Our results indicate that RBP4 is positively associated with markers of inflammation in obese and pro-atherogenic conditions and could play a role in a predisposition to atherosclerosis. Furthermore, our results indicate that rimonabant may improve vascular function by modulating RBP4 along with pro-inflammatory cytokines. PMID- 21585351 TI - Social amoeba and the origin of multicellularity. PMID- 21585353 TI - Cell-cycle checkpoint for transition from cell division to differentiation. AB - In general, growth and differentiation are mutually exclusive, but they are cooperatively regulated during the course of development. Thus, the process of a cell's transition from growth to differentiation is of general importance for the development of organisms, and terminally differentiated cells such as nerve cells never divide. Meanwhile, the growth rate speeds up when cells turn malignant. The cellular slime mold Dictyostelium discoideum grows and multiplies as long as nutrients are supplied, and its differentiation is triggered by starvation. A critical checkpoint (growth/differentiation transition or GDT point), from which cells start differentiating in response to starvation, has been precisely specified in the cell cycle of D. discoideum Ax-2 cells. Accordingly, integration of GDT point-specific events with starvation-induced events is needed to understand the mechanism regulating GDTs. A variety of intercellular and intracellular signals are involved positively or negatively in the initiation of differentiation, making a series of cross-talks. As was expected from the presence of the GDT point, the cell's positioning in cell masses and subsequent cell-type choices occur depending on the cell's phase in the cell cycle at the onset of starvation. Since novel and multiple functions of mitochondria in various respects of development including the initiation of differentiation have been directly realized in Dictyostelium cells, they are also reviewed in this article. PMID- 21585352 TI - Evolution of developmental cyclic adenosine monophosphate signaling in the Dictyostelia from an amoebozoan stress response. AB - The Dictyostelid social amoebas represent one of nature's several inventions of multicellularity. Though normally feeding as single cells, nutrient stress triggers the collection of amoebas into colonies that form delicately shaped fruiting structures in which the cells differentiate into spores and up to three cell types to support the spore mass. Cyclic adenosine monophosphate (cAMP) plays a very dominant role in controlling morphogenesis and cell differentiation in the model species Dictyostelium discoideum. As a secreted chemoattractant cAMP coordinates cell movement during aggregation and fruiting body morphogenesis. Secreted cAMP also controls gene expression at different developmental stages, while intracellular cAMP is extensively used to transduce the effect of other stimuli that control the developmental program. In this review, I present an overview of the different roles of cAMP in the model D. discoideum and I summarize studies aimed to resolve how these roles emerged during Dictyostelid evolution. PMID- 21585355 TI - Collective oscillations in developing cells: insights from simple systems. AB - From hormonal secretion to gene expression, multicellular dynamics are rich in oscillatory regulation. When organized in space and time, periodic cell-cell signaling can give rise to long-range coordination of gene expression and cell movement in tissues. Lack of synchrony of the oscillations on the other hand can serve as a source of initial divergence of cell fate in stem cells. How properties of individual cells can account for collective rhythmic behaviors at the tissue level remains elusive in most cases. Recently, studies in chemical reactions, synthetic gene circuits, yeast and social amoeba Dictyostelium have greatly enhanced our view of collective oscillations in cell populations. From these relatively simple systems, a unified view of how excitable and oscillatory regulations could be tuned and coupled to give rise to tissue-level oscillations is emerging. The review focuses on recent progress in cyclic adenosine monophosphate oscillations in Dictyostelium and highlights similarities and differences with other systems. We will see that the autonomy of single-cell level oscillations and different ways in which cells are coupled influence how group-level information can be encoded in collective oscillations. PMID- 21585354 TI - Signaling mechanisms for chemotaxis. AB - Cells recognize external chemical gradients and translate these environmental cues into amplified intracellular signaling that results in elongated cell shape, actin polymerization toward the leading edge, and movement along the gradient. Mechanisms underlying chemotaxis are conserved evolutionarily from Dictyostelium amoeba to mammalian neutrophils. Recent studies have uncovered several parallel intracellular signaling pathways that crosstalk in chemotaxing cells. Here, we review these signaling mechanisms in Dictyostelium discoideum. PMID- 21585356 TI - Regulation of spatiotemporal expression of cell-cell adhesion molecules during development of Dictyostelium discoideum. AB - The social amoeba Dictyostelium discoideum is a simple but powerful model organism for the study of cell-cell adhesion molecules and their role in morphogenesis during development. Three adhesive systems have been characterized and studied in detail. The spatiotemporal expression of these adhesion proteins is stringently regulated, often coinciding with major shifts in the morphological complexity of development. At the onset of development, amoeboid cells express the Ca(2+) -dependent cell-cell adhesion molecule DdCAD-1, which initiates weak homophilic interactions between cells and assists in the recruitment of individuals into cell streams. DdCAD-1 is unique because it is synthesized as a soluble protein in the cytoplasm. It is targeted for presentation on the cell surface by an unconventional protein transport mechanism via the contractile vacuole. Concomitant with the aggregation stage is the expression of the contact sites A glycoprotein csA/gp80 and TgrC1, both of which mediate Ca(2+) /Mg(2+) independent cell-cell adhesion. Whereas csA/gp80 is a homophilic binding protein, TgrC1 binds to a heterophilic receptor on the cell. During cell aggregation, csA/gp80 associates preferentially with lipid rafts, which facilitate the rapid assembly of adhesion complexes. TgrC1 is synthesized at low levels during aggregation and rapid accumulation occurs initially in the peripheral cells of loose mounds. The extracellular portion of TgrC1 is shed and becomes part of the extracellular matrix. Additionally, analyses of knockout mutants have revealed important biological roles played by these adhesion proteins, including size regulation, cell sorting and cell-type proportioning. PMID- 21585357 TI - Cell migration in multicellular environments. AB - Most experiments observing cell migration use planar plastic or glass surfaces despite these conditions being considerably different from physiological ones. On such planar surfaces, cells take a dorsal-ventral polarity to move two dimensionally. Cells in tissues, however, interact with surrounding cells and the extracellular matrix such that they transverse three-dimensionally. For this reason, three-dimensional matrices have become more and more popular for cell migration experiments. In addition, recent developments in imaging techniques have enabled high resolution observations of in vivo cell migration. The combination of three-dimensional matrices and such imaging techniques has revealed motile mechanisms in tissues not observable in studies using planar surfaces. Regarding models for such cell migration studies, the cellular slime mould Dictyostelium discoideum is ideal. Single amoeboid cells aggregate into hemispherical mound structures upon starvation to begin a multicellular morphogenesis. These tiny and simple multicellular bodies are suitable for observing the behaviors of individual cells in multicellular structures. Furthermore, the unique life cycle can be exploited to identify which genes are involved in cell migration in multicellular environments. Since mutants lacking such genes are expected to fail to undergo morphogenesis, easy and systematic gene screening is possible by isolating mutants whose developments arrest around the mound stage, which is the case for several mutants lacking specific cytoskeletal proteins. In this article, I discuss the basic elements required for cell migration in multicellular environments and how Dictyostelium can be used to elucidate them. PMID- 21585358 TI - Control of prestalk-cell differentiation by transcription factors. AB - Transcriptional control of developmental genes is important for cell differentiation and pattern formation. Developing Dictyostelium discoideum cells form a multicellular structure in which individual cells differentiate into either stalk cells or spores. This simplicity makes the organism an attractive model for studying fundamental problems in developmental biology. However, the morphogenetic process of forming a stalked fruiting body conceals a certain degree of complexity. This is reflected in the presence of multiple prestalk subtypes that have individual roles to generate the fruiting body. This review describes recent advances in understanding the molecular mechanisms, mediated by transcription factors that generate prestalk-cell heterogeneity. PMID- 21585359 TI - Non-genetic heterogeneity and cell fate choice in Dictyostelium discoideum. AB - From microbes to metazoans, it is now clear that fluctuations in the abundance of mRNA transcripts and protein molecules enable genetically identical cells to oscillate between several distinct states (Kaern et al. 2005). Since this cell cell variability does not derive from physical differences in the genetic code it is termed non-genetic heterogeneity. Non-genetic heterogeneity endows cell populations with useful capabilities they could never achieve if each cell were the same as its neighbors (Raj & van Oudenaarden 2008; Eldar & Elowitz 2010). One such example is seen during multicellular development and "salt and pepper" cell type differentiation. In this review, we will first examine the importance of non genetic heterogeneity in initiating "salt and pepper" pattern formation during Dictyostelium discoideum development. Second, we will discuss the various ways in which non-genetic heterogeneity might be generated, as well as recent advances in understanding the molecular basis of heterogeneity in this system. PMID- 21585360 TI - Nuclear organization and transcriptional dynamics in Dictyostelium. AB - The Dictyostelium model has a set of features uniquely well-suited to developing our understanding of transcriptional control. The complete Dictyostelium discoideum genome sequence has revealed that many of the molecular components regulating transcription in larger eukaryotes are conserved in Dictyostelium, from transcription factors and chromatin components to the enzymes and signals that regulate them. In addition, the system permits visualization of single gene firing events in living cells, which provides a more detailed view of transcription and its relationships to cell and developmental processes. This review will bring together the available knowledge of the structure and dynamics of the Dictyostelium nucleus and discuss recent transcription imaging studies and their implications for stability and accuracy of cell decisions. PMID- 21585361 TI - Plasticity in the development and dedifferentiation of Dictyostelium discoideum. AB - Dictyostelium discoideum has served as a model for development and differentiation for over 70 years. Also regulated in Dictyostelium is the process of dedifferentiation, which consists of multiple cellular events that are separately regulated, providing an excellent model system for studying the return of partially differentiated cells to a more pluripotent state. An interesting aspect of Dictyostelium development is the plasticity between growth and development. Reversibility of the processes of differentiation and dedifferentiation exist, allowing Dictyostelium to adjust to changing conditions by reverting to the growth phase during differentiation or reinitiating development during dedifferentiation. This ability of cells to respond to environmental cues is mediated by the checkpoint-like events "commitment" and "erasure," which occur during differentiation and dedifferentiation, respectively. Our review will discuss the current state of knowledge regarding dedifferentiation and the plasticity of the developmental process in both the forward and reverse directions. PMID- 21585362 TI - How social evolution theory impacts our understanding of development in the social amoeba Dictyostelium. AB - Dictyostelium discoideum has been very useful for elucidating principles of development over the last 50 years, but a key attribute means there is a lot to be learned from a very different intellectual tradition: social evolution. Because Dictyostelium arrives at multicellularity by aggregation instead of through a single-cell bottleneck, the multicellular body could be made up of genetically distinct cells. If they are genetically distinct, natural selection will result in conflict over which cells become fertile spores and which become dead stalk cells. Evidence for this conflict includes unequal representation of two genetically different clones in spores of a chimera, the poison-like differentiation inducing factor (DIF) system that appears to involve some cells forcing others to become stalk, and reduced functionality in migrating chimeras. Understanding how selection operates on chimeras of genetically distinct clones is crucial for a comprehensive view of Dictyostelium multicellularity. In nature, Dictyostelium fruiting bodies are often clonal, or nearly so, meaning development will often be very cooperative. Relatedness levels tell us what benefits must be present for sociality to evolve. Therefore it is important to measure relatedness in nature, show that it has an impact on cooperation in the laboratory, and investigate genes that Dictyostelium uses to discriminate between relatives and non-relatives. Clearly, there is a promising future for research at the interface of development and social evolution in this fascinating group. PMID- 21585363 TI - Ethylene as a potent inducer of sexual development. AB - A novel and critical function of ethylene, a potent plant hormone, has been well documented in Dictyostelium, because it leads cells to the sexual development (macrocyst formation) by inducing zygote formation. Zygote formation (sexual cell fusion) and the subsequent nuclear fusion are the characteristic events occurring during macrocyst formation. A novel gene, zyg1 was found to be predominantly expressed during the sexual development, and its enforced expression actually induces zygote formation. As expected, the zygote inducer, ethylene enhances the expression of zyg1. Thus the function of ethylene has been verified at all of individual (macrocyst formation), cellular (zygote formation), and molecular levels (zyg1 expression). Based on our recent studies concerning the behavior and function of the zyg1 product (ZYG1 protein), the signal transduction pathways involved in zygote formation are proposed in this review. PMID- 21585364 TI - Impairment in non-word repetition: a marker for language impairment or reading impairment? AB - AIM: A deficit in non-word repetition (NWR), a measure of short-term phonological memory proposed as a marker for language impairment, is found not only in language impairment but also in reading impairment. We evaluated the strength of association between language impairment and reading impairment in children with current, past, and no language impairment and assessed any differential impairment of NWR, compared with two other tests of verbal memory in children with language impairment with and without reading impairment. METHOD: Our sample comprised children aged 6-16y 11mo participating in a study of the genetics of language impairment: 78 children from 68 families (53 males, 25 females) with current language impairment (C-LI), compared with their 74 siblings: 25 children (18 males, seven females) with a past history of language impairment and 49 children (27 males, 22 females) who had never had a language impairment. The tests used were the Clinical Evaluation of Language Fundamentals (CELF III), the Children's Test of Non-word Repetition (CN-Rep), the Wide Range Assessment of Memory and Learning (WRAML) verbal memory index, the Wechsler Intelligence Scale for Children-III (WISC-III) digit span, and the Wechsler Objective Reading Dimensions (WORD(UK) ). RESULTS: Reading impairment was present in two-thirds of the children with current language impairment. NWR deficits were significantly worse in children with language impairment who had reading impairment in reading decoding (p=0.007 and 0.004 - average group compared with borderline and definitely impaired groups respectively) or spelling (p=0.002 and 0.005 - average group compared with borderline and severely impaired groups respectively) (not correlated with severity of language impairment) but not comprehension impairment. In contrast, WISC digit span and WRAML verbal memory were impaired in all children with language impairment and did not differentiate those who also had reading impairment. INTERPRETATION: We suggest that current NWR ability may be a marker of a process specifically underlying language impairment, co occurring with reading impairment involving reading decoding and spelling, rather than a generic correlate of language impairment. Other verbal memory deficits appear to be pervasive in children with language impairment. PMID- 21585365 TI - Effect of osmotic-release oral system methylphenidate on different domains of attention and executive functioning in children with attention-deficit hyperactivity disorder. AB - AIM: This study investigated whether components of attention and executive functioning improve when children with attention-deficit-hyperactivity disorder (ADHD) are treated with osmotic-release oral system (OROS) methylphenidate. METHOD: Thirty children (24 males, six females; mean age 8y 6mo, SD 1y 11mo; range 6y 5mo -12y 6mo) with ADHD combined type participated in a double-blind, placebo-controlled crossover trial with the child's clinically most effective dose as identified with a systematic open-label titration procedure. After 1 week on each treatment (placebo and OROS methylphenidate), a neuropsychological battery that assessed sustained attention, selective attention, attentional control, response inhibition, and working memory was administered. This battery included the Gordon Diagnostic System, seven subtests of the Test of Everyday Attention for Children, and two tests of working memory. RESULTS: Performance on two of three tests of response inhibition improved on OROS methylphenidate compared with placebo (p<0.01). Performance on one of two tasks assessing attentional control and one of five measures assessing sustained attention demonstrated clear improvement. There was no improvement on the two tasks assessing selective attention or the two tasks assessing working memory. INTERPRETATION: When OROS methylphenidate was used to treat children with ADHD at the clinically most effective dose, general improvement was noted on tasks requiring response inhibition; response to treatment in other domains was either variable or not demonstrated. PMID- 21585366 TI - Towards a more palatable treatment for Glut1 deficiency syndrome. PMID- 21585367 TI - Does loss of spasticity matter? A 10-year follow-up after selective dorsal rhizotomy in cerebral palsy. AB - AIM: The aim of this study was to evaluate the long-term effects of selective dorsal rhizotomy (SDR) in children with cerebral palsy (CP). METHOD: Nineteen children (four females, 15 males; mean age 4y 7mo, SD 1y 7mo) with bilateral spastic CP, were prospectively assessed at baseline and 18 months, 3 years, and 10 years after SDR. Assessments included the Modified Ashworth Scale for spasticity, the Gross Motor Function Measure 88 (GMFM-88) and the Wilson gait scale for ambulation, neurological investigations, and passive joint range of motion assessment. A 10-year retrospective chart review was added for orthopaedic surgery after SDR. RESULTS: Baseline muscle tone at the hip, knee, and ankle level displayed a high degree of spasticity that normalized after SDR. After 10 years there was a slight recurrence of spasticity at the knee and ankle. Joint range of motion declined from a maximum at 3 years after SDR to the 10-year follow-up. Median ambulatory status was best 3 years after SDR and then declined. The GMFM-88 score increased from the median baseline value of 51 to 66 (p=0.002) and 76 (p<0.001) at the initial follow-ups. After 10 years there was a decline in gross motor function with a reduction in the GMFM-88 score to 62 (p=0.022). Within 10 years, 16 out of 19 patients had a mean of three orthopaedic surgeries (SD 2.8), soft tissue surgery being the most common. INTERPRETATION: The spasticity-reducing effect of SDR, although pronounced, did not seem to improve long-term functioning or prevent contractures. This suggests that contracture development in CP is not mediated by spasticity alone. PMID- 21585368 TI - 10-year follow-up after selective dorsal rhizotomy in cerebral palsy. PMID- 21585369 TI - Do all inter-patch movements represent dispersal? A mixed kernel study of butterfly mobility in fragmented landscapes. AB - 1. In times of ongoing habitat fragmentation, the persistence of many species is determined by their dispersal abilities. Consequently, understanding the rules underlying movement between habitat patches is a key issue in conservation ecology. 2. We have analysed mark-release-recapture (MRR) data on inter-patches movements of the Dusky Large Blue butterfly Maculinea nausithous in a fragmented landscape in northern Bavaria, Germany. The aim of the analysis was to quantify distance dependence of dispersal as well as to evaluate the effect of target patch area on immigration probability. For statistical evaluation, we apply a 'reduced version' of the virtual migration model (VM), only fitting parameters for dispersal distance and immigration. In contrast to other analyses, we fit a mixed dispersal kernel to the MRR data. 3. A large fraction of recaptures happened in other habitat patches than those where individuals were initially caught. Further, we found significant evidence for the presence of a mixed dispersal kernel. The results indicate that individuals follow different strategies in their movements. Most movements are performed over small distances, nonetheless involving travelling between nearby habitat patches (median distance c. 480 m). A small fraction (c. 0.025) of the population has a tendency to move over larger distances (median distance c. 3800 m). Further, immigration was positively affected by patch area (I~A(zeta) ), with the scaling parameter zeta = 0.5. 4. Our findings should help to resolve the long-lasting dispute over the suitability of the negative exponential function vs. inverse-power one for modelling dispersal. Previous studies on various organisms found that the former typically gives better overall fit to empirical distance distributions, but that the latter better represents long-distance movement probabilities. As long distance movements are more important for landscape-level effects and thus, e.g. for conservation-oriented analyses like PVAs, fitting inverse-power kernels has often been preferred. 5. We conclude that the above discrepancy may simply stem from the fact that recorded inter-patch movements are an outcome of two different processes: daily routine movements and genuine dispersal. Consequently, applying mixed dispersal kernels to disentangle the two processes is recommended. PMID- 21585370 TI - Amyloid-beta peptide(1-40) elimination from cerebrospinal fluid involves low density lipoprotein receptor-related protein 1 at the blood-cerebrospinal fluid barrier. AB - Amyloid-beta peptide (Abeta) concentration in CSF is potentially a diagnostic and therapeutic target for Alzheimer's disease (AD). The purpose of this study was to clarify the elimination mechanism of human Abeta(1-40) [hAbeta (1-40)] from CSF. After intracerebroventricular (ICV) administration, [(125) I]hAbeta(1-40) was eliminated from the rat CSF with a half-life of 17.3 min. The elimination of [(125) I]hAbeta(1-40) was significantly inhibited by human receptor-associated protein (RAP) and the elimination was attenuated in either anti-low-density lipoprotein receptor-related protein (LRP)1 antibody-treated or RAP-deficient mice, suggesting that a member(s) of the low-density lipoprotein receptor gene family is involved in the elimination of hAbeta(1-40) from CSF. The amounts of LRP1 and LRP2 proteins were determined by means of liquid chromatography-tandem mass spectrometry, and the LRP1 content in rat choroid plexus was determined to be 3.7 fmol/MUg protein, whereas the LRP2 content was below the detection limit (<0.2 fmol/MUg protein). Conditionally, immortalized rat choroid plexus epithelial cells exhibited predominant apical-to-basal and apical-to-cell transport of [(125) I]hAbeta(1-40). These results indicated that hAbeta(1-40) is actively eliminated from CSF and this process is at least partly mediated by LRP1 expressed at choroid plexus epithelial cells, which therefore play a role in determining CSF concentrations of hAbeta(1-40). PMID- 21585371 TI - Should topical opioid analgesics be regarded as effective and safe when applied to chronic cutaneous lesions? AB - OBJECTIVES: The induction of analgesia for many chronic cutaneous lesions requires treatment with an opioid analgesic. In many patients suffering with these wounds such drugs are either contraindicated or shunned because of their association with death. There are now case reports involving over 100 patients with many different types of chronic superficial wounds, which suggest that the topical application of an opioid in a suitable gel leads to a significant reduction in the level of perceived pain. KEY FINDINGS: Some work has been undertaken to elucidate the mechanisms by which such a reduction is achieved. To date there have been no proven deleterious effects of such an analgesic system upon wound healing. Although morphine is not absorbed through the intact epidermis, an open wound provides no such barrier and for large wounds drug absorption can be problematic. However, for most chronic cutaneous lesions, where data has been gathered, the blood levels of the drug applied ranges from undetectable to below that required for a systemic effect. SUMMARY: If proven, the use of opioids in this way would provide adequate analgesia for a collection of wounds, which are difficult to treat in patients who are often vulnerable. Proof of this concept is now urgently required. PMID- 21585372 TI - Amphiphilic polylactic acid-hyperbranched polyglycerol nanoparticles as a controlled release system for poorly water-soluble drugs: physicochemical characterization. AB - OBJECTIVES: Quercetin was applied as a model drug to evaluate the potential application of amphiphilic polylactic acid-hyperbranched polyglycerol (HPG-PLA) nanoparticles as carriers for poorly water-soluble drugs. METHODS: The drug delivery systems were characterized by dynamic light scattering, powder X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR) and so forth. KEY FINDINGS: The results showed the particle sizes ranged from 205.3 to 433.3 nm with low polydispersity index. XRD and FTIR demonstrated that the crystal of the drug was converted to an amorphous state in the matrices and formed intermolecular interaction with carriers. The drug encapsulation efficiency and drug loading could reach 91.8% and 21.0%, respectively. Cell viability assay suggested the nanoparticles had good cytocompatibility. The in vitro drug release profiles showed a sustained quercetin release up to 192 h, indicating the suitability of nanoparticles in sustained drug release. Furthermore, the influence of many factors on release profiles could also be evaluated for the potential of using nanoparticles as controlled release systems. CONCLUSIONS: This system may be of clinical importance in both stabilizing and delivering hydrophobic drugs for the treatment of many diseases. PMID- 21585373 TI - Novel sulfobutyl ether cyclodextrin gradient leads to highly active liposomal irinotecan formulation. AB - OBJECTIVES: Liposomal delivery of irinotecan could provide protection against drug hydrolysis, deliver more active lactone form to tumours and prolong irinotecan exposure time. Nevertheless, conventional drug-loading technologies have typically resulted in undesired drug retention properties. To resolve the problem, a modified gradient loading method was developed and the resulting formulations were evaluated in a systemic manner. METHODS: Irinotecan was loaded into liposomes using a novel sulfobutyl ether beta-cyclodextrin (sbe-CD) gradient. The effect of drug-to-lipid ratio (D/L) and polyethylene glycol (PEG) grafting density were investigated. Drug release experiments were performed in ammonium-containing medium based on the fluorescence dequenching phenomenon of irinotecan. Pharmacokinetic studies were performed in normal balb/c mice treated with different formulations. To compare the anti-tumour effect of different formulations, an RM-1 prostate cancer model was used. Acute toxicity studies were performed in healthy female c57 mice. KEY FINDINGS: Irinotecan could be encapsulated into liposomes with >90% loading efficiency at a high drug-to-lipid mass ratio (>0.5). In-vitro release experiments revealed that sbe-CD anion was more able to retain irinotecan than sulfate. Moreover, the elevated D/L ratio elicited decreased drug release kinetics. Both trends had also been observed when the effects of anions and D/L ratio on half-life of irinotecan were assessed. Pegylated liposomal irinotecan loaded with sbe-CD/triethylammonium gradient had irinotecan half-life values ranging from 9.4 to 13.1 h, surpassing vesicles prepared by the triethylammonium sulfate method (~4.5 h). In the RM-1 tumour model, all the liposomal irinotecan formulations were more therapeutically active than free irinotecan and the formulation with a high D/L ratio was the most efficacious. Moreover, the high D/L formulation might be less toxic than free irinotecan based on acute toxicity studies. CONCLUSIONS: The novel sbe-CD gradient could mediate effective irinotecan loading and improve irinotecan retention, thus resulting in highly active liposomal irinotecan formulations. The improvement in drug retention might be associated with the formation of complicated aggregates inside vesicles. PMID- 21585374 TI - Effective in-vivo utilization of lipid-based nanoparticles as drug carrier for carvedilol phosphate. AB - OBJECTIVES: Lipid nanoparticles as carrier for oral drug administration improve gastrointestinal solubility of poorly soluble drugs and thus enhance bioavailability. However, basic drugs may undergo rapid dissolution from such solid dispersions in the stomach and precipitate in the intestine due to their higher solubility in acidic medium. Therefore, the objective of this work was to study the enhancement in bioavailability of carvedilol phosphate (basic drug) by providing an alkaline gastric environment to drug-loaded solid lipid nanoparticles. METHODS: An alkaline gastric environment in rats was created and maintained with oral administration of an antacid suspension 5 min before and 30 min post dosing. KEY FINDINGS: The formulation administered orally exhibited enhanced bioavailability (~27%) when compared with drug suspension and sustained release behaviour when compared with formulation under ideal gastric conditions. The enhanced bioavailability is due to the presence of lipid nanoparticles as drug carrier while the sustained-release characteristic may be attributed to the presence of antacid, which resulted in elevation of gastric pH and reduced the drug's solubility. CONCLUSIONS: It may be concluded that although lipid nanoparticles can be instrumental in improving bioavailability, additional sustained release may be achieved by targeting intestinal release of basic drugs from lipid vehicles, which is possible by incorporating them into suitable enteric-coated formulations. PMID- 21585375 TI - In-vivo evaluation of prolonged release bilayer tablets of anti-Parkinson drugs in Gottingen minipigs. AB - OBJECTIVES: Patients with Parkinson's disease can benefit from controlled released levodopa dosage forms since there is a clear clinical advantage in obtaining sustained plasma concentrations. The purpose of this study was to obtain a tablet that prolonged the release of levodopa. METHODS: A novel bilayer tablet, consisting of an immediate release layer containing nebicapone (100 mg) and an erosion-matrix type prolonged release layer containing levodopa (100 mg) and carbidopa (25 mg) was developed (LCN PR). A pharmacokinetic study in Gottingen minipigs was performed to evaluate this formulation. KEY FINDINGS: LCN PR tablets prolonged the in-vitro release of levodopa in HCl 0.1 m for more than 3 h. In-vivo plasma levodopa levels peaked at a later time point with LCN PR tablets as compared with that obtained with Sinemet 100/25 (2.7 vs 0.5 h). Nebicapone increased the maximum plasma concentration and area under the plasma concentration-time curve values for levodopa. CONCLUSIONS: The results obtained suggested that LCN PR tablets may have decreased the number of tablets and daily intake in the treatment of patients with Parkinson's disease. PMID- 21585376 TI - Development of effervescent tablets containing benzonidazole complexed with cyclodextrin. AB - OBJECTIVES: Benznidazole (BNZ), the primary chemotherapy agent used to treat Chagas disease, has poor aqueous solubility, which results in low bioavailability. The purpose of this work was to develop stable effervescent tablets using an inclusion complex of BNZ with cyclodextrin (CD). METHOD: In the first phase, different CDs were evaluated according to their ability to improve the aqueous solubility of BNZ. Then, inclusion complexes of BNZ in the solid state were produced by the kneading method and the complexes were evaluated using several physical-chemical assays. Finally, effervescent tablets were prepared according to a complete 3(2) factorial design. The effects of the concentration of CD and effervescent mixture on the dissolution rate and physical stability of tablets were evaluated. KEY FINDINGS: Hydroxypropyl-beta-cyclodextrin produced the greatest improvement in the aqueous solubility of BNZ, almost 20-times greater than the water system. Solid systems produced with BNZ and CD showed physical-chemical interactions and increased the drug dissolution rate, suggesting the formation of a true solid inclusion complex. Moreover, the effervescent matrix of the tablets was effective in improving the dissolution behaviour of BNZ complexed with CD. CONCLUSIONS: Effervescent tablets produced using an inclusion complex of BNZ with CD suggest a possible improvement in the bioavailability of BNZ, and this could represent a relevant advance in Chagas therapy. PMID- 21585377 TI - A novel tri-layered buccal mucoadhesive patch for drug delivery: assessment of nicotine delivery. AB - OBJECTIVES: The aim of this study was to assess the potential of a novel delivery device for administering drugs that suffer from a high degree of first-pass metabolism. METHODS: A tri-layered buccal mucoadhesive patch, comprising a medicated dry tablet adhered to a mucoadhesive film, was prepared and characterized by its physicochemical properties and mucoadhesive strength. Nicotine was used as a model drug for the characterization of drug release and drug permeation. The influence of different adsorbents on the release of nicotine base from the patches was evaluated in vitro. Different molecular forms of nicotine (base and complex salt) were evaluated for their effect on release performance and permeation in vitro. KEY FINDINGS: Results demonstrated acceptable physicochemical and mucoadhesive properties for the tri-layered patch. Rapid release of nicotine was observed when nicotine base was incorporated with calcium sulfate dihydrate as the adsorbent. Patches incorporating nicotine base showed distinct advantages over those containing nicotine polacrilex, in terms of drug release (complete drug release achieved at 30 vs 60 min) and transmucosal permeation (37.28 +/- 4.25 vs 2.87 +/- 0.26% of the dose permeating through mucosa within 120 min). CONCLUSIONS: The novel tri-layered patch can effectively adhere to, and deliver an active ingredient through the buccal mucosa, confirming its potential for buccal mucoadhesive drug delivery. PMID- 21585378 TI - Prevention of benzyl alcohol-induced aggregation of chymotrypsinogen by PEGylation. AB - OBJECTIVES: Addition of the antimicrobial preservative benzyl alcohol to reconstitution buffer promotes the formation of undesirable aggregates in multidose protein formulations. Herein we investigated the efficiency of PEGylation (attachment of poly(ethylene glycol)) to prevent benzyl alcohol induced aggregation of the model protein alpha-chymotrypsinogen A (aCTgn). METHODS: Various PEG-aCTgn conjugates were prepared using PEG with a molecular weight of either 700 or 5000 Da by varying the PEG-to-protein ratio during synthesis and the formation of insoluble aggregates was studied. The effect of benzyl alcohol on the thermodynamic stability and tertiary structure of aCTgn was also examined. KEY FINDINGS: When the model protein was reconstituted in buffer containing 0.9% benzyl alcohol, copious amounts of buffer-insoluble aggregates formed within 24 h (>10%). Benzyl alcohol-induced aggregation was completely prevented when two or five molecules of PEG with a molecular weight of 5000 Da were attached to the protein, whereas two or four molecules of bound 700 Da PEG were completely inefficient in preventing aggregation. Mechanistic investigations excluded prevention of structural perturbations or increased thermodynamic stability by PEGylation from being responsible for the prevention of aggregation. Simple addition of PEG to the buffer was also inefficient and PEG had to be covalently linked to the protein to be efficient. CONCLUSIONS: The most likely explanation for the protective effect of the 5000 Da PEG is shielding of exposed hydrophobic protein surface area and prevention of protein-protein contacts (molecular spacer effect). PMID- 21585379 TI - Investigation into drug release from colon-specific azoreductase-activated steroid prodrugs using in-vitro models. AB - OBJECTIVES: The aim of this study was to investigate drug release from a double steroid prodrug, OPN501, which incorporates a phenylpropionate linker, and its phenylacetate analogue. The prodrugs, which were designed to deliver prednisolone to the colon for the treatment of inflammatory bowel disease, are based on a novel design that requires sequential azoreductase activity and cyclization of an amino ester to trigger drug release. We sought to explain the divergent effects of the two compounds in anti-inflammatory models and to justify the selection of OPN-501 for clinical development. METHODS: The compounds were incubated in mouse colonic contents (10%) fermented in brain heart infusion under anaerobic conditions. The disappearance of the prodrugs and release of prednisolone was monitored by HPLC. We then developed a method for assessment of prodrug activation using suspensions of Clostridium perfringens, an anaerobe from the human colon. The cyclization of the compounds was studied in various media, assessing the influence of pH and bulk solvent polarity on cyclization rate using HPLC and NMR. KEY FINDINGS: The prodrugs were activated via multiple pathways releasing prednisolone in mouse colonic ferment. The compounds released prednisolone by reduction-cyclization in C perfringens suspension. The active OPN 501 generated a stoichiometric amount of prednisolone following azoreductase activation, whereas its analogue did not. The pH rate profile for the cyclization of the amino intermediates of the two compounds revealed significant differences in rate at pH values relevant to the inflamed colon, which explain in part the different amounts of drug produced. CONCLUSIONS: The steroid prodrug OPN-501 has optimal drug release characteristics for colon targeting because of a kinetic advantage of a six-membered ring formation in the aminolysis reactions of anilides. The results are relevant to the development of OPN-501 but also to cyclization strategies in prodrug design especially for colon targeting. PMID- 21585380 TI - Effect of bile on the oral absorption of halofantrine in polyethylene glycol 400 and polysorbate 80 formulations dosed to bile duct cannulated rats. AB - OBJECTIVES: The aim of this study was to examine the effects of bile on the oral absorption of the poorly water-soluble compound, halofantrine, when administered to rats in vehicles consisting of the co-solvent polyethylene glycol 400 (PEG 400) alone or in mixtures with the surfactant polysorbate 80 (PS 80) (95:5; 85:15; 75:25 PEG 400:PS 80). METHODS: Halofantrine (17.5 mg/kg) was administered to bile duct cannulated (BDC) and sham-operated rats in a fixed vehicle volume of 5 ml/kg. KEY FINDINGS: The bioavailability of halofantrine was significantly lower in BDC rats when dosed with 0-5% PS 80 in PEG 400 compared with BDC rats dosed with >15% PS 80. Increasing the concentration of PS 80 to 15-100% eliminated this difference. A possible explanation for the lower bioavailability of halofantrine in BDC rats when dosed in pure PEG 400 could be the dilution of the vehicle by intestinal fluids, decreased transit time and precipitation in the gastrointestinal tract upon dilution of PEG 400. CONCLUSIONS: The addition of PS 80 to the formulation increased its solubilising power upon dilution and may have inhibited precipitation and substituted the absence of bile above a certain level. Adjusting the level of surfactant in drug formulations could therefore be used to minimise variability in the bioavailability from co-solvent systems based upon differences in bile concentration between individuals. PMID- 21585381 TI - Isolation of a polysaccharide with antiproliferative, hypoglycemic, antioxidant and HIV-1 reverse transcriptase inhibitory activities from the fruiting bodies of the abalone mushroom Pleurotus abalonus. AB - OBJECTIVE: The intent of this study was to purify and characterize a polysaccharide named LA from the fruiting bodies of the edible mushroom Pleurotus abalones. METHODS: The 120-kDa polysaccharide was obtained by extraction with boiling water, ethanol precipitation, ion exchange chromatography on Diethylaminoethyl-cellulose and gel filtration on Sephadex G-200. KEY FINDINGS: The LA was composed of glucose, rhamnose, glucuronic acid, xylose, galactose and arabinose in the molar ratio of 26.3:2.7:1:1.4:1.8:1.2. The FITR and 1H-NMR spectrum of LA disclosed that it was a saccharide with an alpha-configuration. Its 13C-NMR spectrum revealed that its main chain was [->6)-alpha-D-Gly(1->]n. The LA exhibited antioxidant activities, especially in scavenging 1,1- diphenyl-2 picryl-hydrazyl radicals and hydroxyl radicals. It manifested antiproliferative activity towards breast cancer MCF7 cells with an IC50 of 3.7 um, and also exerted some antiproliferative activity against HepG2 cells. It manifested a hypoglycemic action on diabetic mice. It inhibited HIV-1 reverse transcriptase with an IC50 of 8.7 * 10(-2) um. CONCLUSIONS: The polysaccharide from the abalone mushroom. PMID- 21585382 TI - Influence of atorvastatin on fractional and subfractional composition of serum lipoproteins and MMP activity in mice with Triton WR 1339-induced lipaemia. AB - OBJECTIVES: The effects of atorvastatin on the atherogenic and anti-atherogenic lipoprotein-cholesterol (C-LP) and lipoprotein-triglyceride (TG-LP) fractions and subfractions at the early stage of murine acute hyperlipidaemia, and its pleiotropic anti-inflammatory effects via the activity of matrix metalloproteinases (MMPs) were studied. METHODS: Atorvastatin (75 mg/kg) was administered to ICR mice with acute lipaemia induced by a single injection of Triton WR 1339 (500 mg/kg). A novel small-angle X-ray scattering (SAXS) method was used for the determination of the fractional and subfractional composition of C-LP and TG-LP. KEY FINDING: In Triton WR 1339-treated mice, there was a drastic increase in the atherogenic low-density C-LP (C-LDL) fraction, intermediate density lipoprotein-cholesterol (C-IDL) subfraction, and very low-density C-LP (C VLDL) fractions (C-VLDL(3-5) subfraction). Additionally, there was an increase in the C-HDL(3) subfraction. Treatment of lipaemia with atorvastatin resulted in the normalization of the atherogenic C-LDL fraction and the C-IDL subfraction. A decrease in C-VLDL (C-VLDL(3-5) subfraction), total cholesterol and, especially, triglyceride (TG) concentrations was also demonstrated. Similar results were obtained with the TG-LP fractions and subfractions. Additionally, atorvastatin treatment resulted in an increase in the serum and liver MMP activity. CONCLUSION: High-dose atorvastatin therapy exerts its rapid lipid-lowering and pleiotropic effect(s) in the early stages of acute lipaemia induced with Triton WR-1339. PMID- 21585383 TI - Inhibitory effect of phytoglycoprotein (24 kDa) on hepatocarcinogenesis in N nitrosodiethylamine-treated ICR mice. AB - OBJECTIVES: Hepatocellular carcinoma (HCC) is becoming one of the most prominent types of cancer in the world. For a long time in Korea Zanthoxylum piperitum DC (ZPDC) has been used in folk medicine to cure several cancers and inflammation. This study was designed to investigate whether ZPDC glycoprotein protected liver tissues against hepatocarcinogenic compounds such as N-nitrosodiethylamine (DEN). METHODS: To study the chemopreventive effect of ZPDC glycoprotein on hepatocarcinogenesis, ICR mice were injected intraperitoneally with DEN (50 mg/kg) for four weeks. We evaluated the indicators of liver tissue damage (the activity of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT), and thiobarbituric acid-reactive substances (TBARS)), antioxidative enzymes (activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx)), hepatocarcinogenic indicator (heat shock protein (HSP) 70) and hepatocarcinogenic signals (activity of nuclear factor (NF)-kappaB, cyclooxygenase (COX)-2, and matrix metalloproteinase (MMP)-9) using biochemical methods and immunoblot analysis. KEY FINDINGS: The results obtained from this study revealed that ZPDC glycoprotein (20 mg/kg) decreased the levels of LDH, ALT, and TBARS, whereas the activity of SOD and GPx increased in the DEN-treated ICR mice. With respect to the hepatocarcinogenic indicator and hepatocarcinogenic signals, HSP70, NF kappaB, COX-2, and MMP-9 activity decreased. CONCLUSION: The findings suggested that ZPDC glycoprotein prevented damage to liver tissue caused by DEN in the experimental mouse model. PMID- 21585384 TI - Chemical study and anti-inflammatory, analgesic and antioxidant activities of the leaves of Aristotelia chilensis (Mol.) Stuntz, Elaeocarpaceae. AB - OBJECTIVES: Aristotelia chilensis leaves (Elaeocarpaceae) are used in Chilean folk medicine to treat pain and inflammation. A bioguided study was carried out on serial extracts (hexane, dichloromethane, methanol, aqueous extract (INFU) and a crude mixture of alkaloids (ALK-MIX). All extracts were evaluated for (1) topical administration against both arachidonic acid and 12-deoxyphorbol-13 decanoate (TPA)-induced inflammation in mice and (2) per-os administration against inflammation by lambda-carrageenan-induced paw oedema in guinea-pigs and (3) topical analgesia in tail flick and formalin models and per-os writhing test in mice. METHODS: Greater anti-inflammatory effects were obtained against TPA with dichloromethane extract and methanol extract (63.9 and 66.0%, respectively). INFU showed the most potent effect (56.2%) against arachidonic acid. Greater effects were obtained in the writhing test with hexane and dichloromethane extracts (89.2% both). In the topical analgesia models, all the extracts and ALK MIX were active with exception of the hexane extract in the formalin assay. In tail flick test, ALK-MIX and the methanol extract were the most active (58.2 and 55.2%, respectively). In relation to the tail formalin assay, the methanol extract (74.1%) was the most active. Concerning antioxidant activity, both INFU and the methanol extract were the most active either in the inhibition of xanthine oxidase (52.9 and 62.7%, respectively) or in the DPPH free radical scavenging activity (EC50 (concentration that produced 50% of activity) = 12.1 and 9.7 ug/ml, respectively). KEY FINDINGS: Aristoteline, aristone, serratoline and hobartinol were isolated from ALK-MIX. Ursolic acid, friedelin and quercetin 5,3'-dimethyl ether were present in the dichloromethane extract while quercetin 3 O-beta-D-glucoside and kaempferol were present in the methanol extract. From INFU were isolated protopine, aristoteline and caffeic and ferulic acids. CONCLUSIONS: The effects of A. chilensis are herein demonstrated, validating its use in traditional medicine. Protopine is reported for the first time in Elaeocarpaceae. PMID- 21585385 TI - Suppression of inflammatory response and endothelial nitric oxide synthase downregulation in hyperlipidaemic C57BL/6J mice by eugenosedin-A. AB - OBJECTIVES: Eugenosedin-A has been found to ameliorate high-fat diet (HFD) induced hyperglycaemia and hyperlipidaemia in C57BL/6J mice. This study aimed to investigate the mechanisms of action of eugenosedin-A on endothelial function and inflammation in hyperlipidaemic mice. METHODS: C57BL/6J mice were randomly divided into two control groups and two treatment groups. The control mice received either a regular diet or HFD, and the treatment groups were fed HFD with either 5 mg/kg eugenosedin-A or atorvastatin for eight weeks. KEY FINDINGS: Mice fed a HFD had higher concentrations of nitrate (NO) but not prostaglandin E2 (PGE2), increased tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) mRNA and inducible nitric oxide synthase (iNOS) proteins, but decreased endothelial nitric oxide synthase (eNOS) proteins. HFD-induced upregulation of iNOS is associated with p38, extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK), PI3K and Akt/IKKalpha/p65. Eugenosedin-A and atorvastatin reduced HFD-induced TNF-alpha and IFN-gamma mRNA, NO generation, upregulation of iNOS protein, and down-regulation of eNOS protein. Both agents inhibited p38, ERK, JNK and Akt/IKKalpha/p65 protein levels in the aorta. However, eugenosedin-A did not significantly reduce p38 in the liver. CONCLUSIONS: Our results showed an association between obesity-induced inflammation and altered levels of TNF-alpha, IFN-gamma, p38, ERK, JNK and Akt/IKKalpha/p65. Eugenosedin-A, like atorvastatin, could inhibit p38, ERK, JNK, Akt/IKKalpha/p65 proteins, as well as TNF-alpha and IFN-gamma mRNA during the regulation of the obesity-induced inflammatory process. PMID- 21585386 TI - Possible mechanism of the antidepressant effect of 3,6'-disinapoyl sucrose from Polygala tenuifolia Willd. AB - OBJECTIVE: The present study was designed to observe the effects of 3,6' disinapoyl sucrose (DISS), an active oligosaccharide ester component obtained from the roots of Polygala tenuifolia Willd., on behavioral and biochemical aspects of depression induced by chronic mild stress (CMS) in rats. It is the first exploration of the possible association between DISS's antidepressant-like effects and biochemical markers of depression, and involved measuring monoamine oxidase (MAO) activity, cortisol levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. METHODS: Rats were exposed to stressor once daily for consecutive 5 weeks. DISS and a positive control drug, fluoxetine, were administered via gastric intubation to once daily for consecutive 3 weeks from the third week. KEY FINDINGS: The results showed that rats subjected to CMS exhibit a reduction in sucrose intake. Conversely, brain MAO-A and MAO-B activity, plasma cortisol levels, and MDA levels were increased, while SOD activity was decreased following CMS exposures. DISS significantly inhibited MAO A and MAO-B activity and blocked plasma elevated cortisol level, an indicator of the hypothalamic-pituitary-adrenal (HPA) axis. In addition, DISS increases SOD activity, inhibits lipid peroxidation, and lessens production of MDA. CONCLUSION: These results suggest that DISS may possess potent and rapid antidepressant properties, which are mediated via MAO, the HPA axis and oxidative systems. These antidepressant actions make DISS a potentially valuable drug for the treatment of depression. PMID- 21585387 TI - Vasorelaxant and hypotensive effects of the extract and the isolated flavonoid rutin obtained from Polygala paniculata L. AB - OBJECTIVES: This study aimed to investigate the in-vitro and in-vivo cardiovascular effects of the crude hydroalcoholic extract from Polygala paniculata (HEPP) in rats. METHODS: The procedures were performed on aortic rings and on normotensive anaesthetized rats. KEY FINDINGS: When tested in endothelium intact aorta rings, HEPP (30-1000 ug/ml) produced a significant non-concentration dependent relaxing effect (~40%), which was completely prevented by incubation with L-NAME (nitric oxide synthase inhibitor), ODQ (soluble guanylate cyclase inhibitor) and partially inhibited by tetraethylammonium (TEA; a non-selective potassium channel blocker) and charybdotoxin (a large- and intermediate conductance calcium-activated potassium channel blocker). In contrast, atropine (a muscarinic receptor antagonist) or pyrilamine(a histamine H1 receptor antagonist) had no effect. Furthermore, oral administration of HEPP (30-300 mg/kg) in anaesthetized rats caused a dose-dependent and sustained hypotensive action. This effect was unchanged by atropine or TEA, but was strongly reduced in rats continuously infused with L-NAME or methylene blue. Moreover, rutin (1-3 mg/kg) administered by an intravenous route also caused a dose-dependent hypotensive effect in rats. CONCLUSIONS: Our results demonstrated that the extract obtained from P. paniculata induces potent hypotensive and vasorelaxant effects that are dependent on the nitric oxide/guanylate cyclase pathway. These effects could be related, at least in part, to the rutin contents in this extract. PMID- 21585388 TI - OsSFR6 is a functional rice orthologue of SENSITIVE TO FREEZING-6 and can act as a regulator of COR gene expression, osmotic stress and freezing tolerance in Arabidopsis. AB - The Arabidopsis protein SENSITIVE TO FREEZING-6 (AtSFR6) is required for cold- and drought-inducible expression of COLD-ON REGULATED (COR) genes and, as a consequence, AtSFR6 is essential for osmotic stress and freezing tolerance in Arabidopsis. Therefore, orthologues of AtSFR6 in crop species represent important candidate targets for future manipulation of stress tolerance. We identified and cloned a homologue of AtSFR6 from rice (Oryza sativa), OsSFR6, and confirmed its orthology in Arabidopsis. OsSFR6 was identified by homology searches, and a full length coding region isolated using reverse transcription polymerase chain reaction (RT-PCR) from Oryza sativa cDNA. To test for orthology, OsSFR6 was expressed in an Arabidopsis sfr6 loss-of-function mutant background, and restoration of wild-type phenotypes was assessed. Searching the rice genome revealed a single homologue of AtSFR6. Cloning and sequencing the OsSFR6 coding region showed OsSFR6 to have 61.7% identity and 71.1% similarity to AtSFR6 at the predicted protein sequence level. Expression of OsSFR6 in the atsfr6 mutant background restored the wild-type visible phenotype, as well as restoring wild type levels of COR gene expression and tolerance of osmotic and freezing stresses. OsSFR6 is an orthologue of AtSFR6, and thus a target for future manipulation to improve tolerance to osmotic and other abiotic stresses. PMID- 21585389 TI - Transition from wind pollination to insect pollination in sedges: experimental evidence and functional traits. AB - Transitions from wind pollination to insect pollination were pivotal to the radiation of land plants, yet only a handful are known and the trait shifts required are poorly understood. We tested the hypothesis that a transition to insect pollination took place in the ancestrally wind-pollinated sedges (Cyperaceae) and that floral traits modified during this transition have functional significance. We paired putatively insect-pollinated Cyperus obtusiflorus and Cyperus sphaerocephalus with related, co-flowering, co-occurring wind-pollinated species, and compared pairs in terms of pollination mode and functional roles of floral traits. Experimentally excluding insects reduced seed set by 56-89% in putatively insect-pollinated species but not in intermingled wind-pollinated species. The pollen of putatively insect-pollinated species was less motile in a wind tunnel than that of wind-pollinated species. Bees, beetles and flies preferred inflorescences, and color-matched white or yellow models, of putatively insect-pollinated species over inflorescences, or color-matched brown models, of wind-pollinated species. Floral scents of putatively insect-pollinated species were chemically consistent with those of other insect-pollinated plants, and attracted pollinators; wind-pollinated species were unscented. These results show that a transition from wind pollination to insect pollination occurred in sedges and shed new light on the function of traits involved in this important transition. PMID- 21585390 TI - Plant resistance to mechanical stress: evidence of an avoidance-tolerance trade off. AB - External mechanical forces resulting from the pressure exerted by wind or water movement are a major stress factor for plants and may cause regular disturbances in many ecosystems. A plant's ability to resist these forces relies either on minimizing the forces encountered by the plant (avoidance strategy), or on maximizing its resistance to breakage (tolerance strategy). We investigated plant resistance strategies using aquatic vegetation as a model, and examined whether avoidance and tolerance are negatively correlated. We tested the avoidance tolerance correlation across 28 species using a phylogenetically corrected analysis, after construction of a molecular phylogeny for the species considered. Different species demonstrated contrasting avoidance and tolerance and we demonstrated a significant negative relationship between the two strategies, which suggests an avoidance-tolerance trade-off. Negative relationships may result from costs that each strategy incurs or from constraints imposed by physical laws on plant tissues. The existence of such a trade-off has important ecological and evolutionary consequences. It would lead to constraints on the evolution and variation of both strategies, possibly limiting their evolution and may constrain many morphological, anatomical and architectural traits that underlie avoidance and tolerance. PMID- 21585391 TI - Influence of cultivated landscape composition on variety resistance: an assessment based on wheat leaf rust epidemics. AB - In plant pathology, the idea of designing variety management strategies at the scale of cultivated landscapes is gaining more and more attention. This requires the identification of effects that take place at large scales on host and pathogen populations. Here, we show how the landscape varietal composition influences the resistance level (as measured in the field) of the most grown wheat varieties by altering the structure of the pathogen populations. For this purpose, we jointly analysed three large datasets describing the wheat leaf rust pathosystem (Puccinia triticina/Triticum aestivum) at the country scale of France with a Bayesian hierarchical model. We showed that among all compatible pathotypes, some were preferentially associated with a variety, that the pathotype frequencies on a variety were affected by the landscape varietal composition, and that the observed resistance level of a variety was linked to the frequency of the most aggressive pathotypes among all compatible pathotypes. This data exploration establishes a link between the observed resistance level of a variety and landscape composition at the national scale. It illustrates that the quantitative aspects of the host-pathogen relationship have to be considered in addition to the major resistance/virulence factors in landscape epidemiology approaches. PMID- 21585392 TI - The psychological neuroscience of depression: implications for understanding effects of deep brain stimulation. AB - In this article it is suggested that current psychological theories of depression presuppose that this condition will develop as a result of a vicious circle involving negatively biased communication between systems of emotional stress /alarm-signaling, executive functions and mood regulation. These systems may from a neuroanatomical point of view be located in the limbic system, the orbitofrontal and lateral prefrontal cortex and the hypothalamus-pituitary adrenal (HPA-) axis respectively. The theoretical and practical implications of this model for the understanding of pharmacological treatments of depression are briefly discussed and this theory is related to the catecholamine hypothesis of depression. The model is furthermore discussed in relation to deep brain stimulation (DBS) of treatment resistant major depression. Similarities and differences between this perspective and the one advocated by the "homeostatic theory" of depression are discussed. It is concluded that a topographical psychological theory may offer a useful heuristic in thinking about depression and that it offers several testable predictions about treatments of the disorder. PMID- 21585393 TI - Deliberate self-harm and psychological problems in young adolescents: evidence of a bidirectional relationship in girls. AB - The purpose of this study was to test the hypotheses that there is a bidirectional prospective relationship between mental health and deliberate self harm, in the sense that (1) psychological problems are a risk factor for the development of self-harm; (2) self-harm is a risk factor for the development of psychological problems; and (3) the relative absence of psychological problems is a protective factor against the continued use of self-harm in adolescents who have started to harm themselves. This was studied in a community sample of 879 young adolescents by means of a 2-wave longitudinal design with a one-year interval, with self-harm measured by a nine-item version of the Deliberate Self Harm Inventory (DSHI-9r) and psychological problems by the self-report version of the Strengths and Difficulties Questionnaire (SDQ). The hypothesis of bidirectional relationship between psychological problems and self-harm was supported among girls, but not among boys - although there was evidence of psychological problems as a risk factor of self-harm in boys, the converse was not the case. The relative absence of psychological problems was found to be a protective factor against self-harm only among boys, but not among girls. The results are discussed in terms of self-harm having a different role in the development of psychopathology among girls than among boys. PMID- 21585394 TI - Emotional difficulties in seventh grade children in Denmark. AB - The present study investigates the prevalence of emotional difficulties and quality of life in a sample of 834 children from 56 seventh grade (aged 12-14 years) classes. Data was derived from a study of mental well-being developed by the National Council for Children, Denmark. The sample selection ensured that the children were nationally representative. Data was collected using the Strength and Difficulties Questionnaire (SDQ) and the Health Behaviour in School-aged Children (HBSC). Results indicated that 10.8% of children had concerns regarding emotional difficulties (6.6% definite concern; 4.2% some concern), and that significantly more girls than boys (44 girls and 10 boys) reported this concern. A novel finding was that emotional difficulties were related to children's perception of having low quality of life. Findings furthermore suggested that children's perception of a low home economy, less time spent on leisure activities, and female gender were all associated with emotional difficulties. PMID- 21585395 TI - Red blood cell transfusion practice in patients presenting with acute upper gastrointestinal bleeding: a survey of 815 UK clinicians. AB - BACKGROUND: Acute upper gastrointestinal bleeding (AUGIB) accounts for 14% of all red blood cell (RBC) transfusions in the United Kingdom, despite little evidence to guide optimal blood transfusion strategies and few data on the variation in practice. We aimed to survey UK clinicians about their RBC transfusion practice in AUGIB. STUDY DESIGN AND METHODS: A survey describing six clinical vignettes of AUGIB was sent to practicing gastroenterologists, acute care physicians, and upper gastrointestinal surgeons. Respondents were asked to select a hemoglobin (Hb) trigger at which they would ordinarily transfuse RBCs. RESULTS: The response rate was 48% (815/1709). Transfusion triggers differed significantly between all six cases (p < 0.001). There was significant variation in the selected Hb trigger between different clinical specialties for five of the six scenarios. Surgeons were more likely to select a lower Hb transfusion trigger than physicians across all six scenarios (p < 0.005), as were clinicians who had graduated more recently (p < 0.05 for Scenarios 1-3). The responses suggested the belief that restrictive use of RBCs is appropriate, which is in part discordant with actual observed practice. Only 70% of respondents reported familiarity with national guidelines for AUGIB. CONCLUSIONS: There is significant variation in the reported approach to transfusion practice among clinicians caring for patients with AUGIB, with both patient- and clinician-related factors accounting for these differences. Further studies are needed to evaluate the safety and efficacy of differing blood transfusion strategies in patients presenting with AUGIB. PMID- 21585396 TI - Glycophorin in red blood cell membranes of healthy and diseased carp, Cyprinus carpio L. PMID- 21585397 TI - Signalling through the IL-2 receptor gamma(c) peptide (CD132) is essential for the expression of immunity to Plasmodium chabaudi adami blood-stage malaria. AB - A genetic dissection approach was employed to determine whether the IL-2 receptor complex (IL-2R) comprised of alpha, beta and gamma chains is required for the suppression of Plasmodium chabaudi adami parasitemia. Blood-stage infections in IL-2Rgamma(c)(-/y) mice failed to cure with parasitemia remaining elevated for > 50 days indicating the IL-2Rgamma(c) through which all members of the gamma(c) family of cytokines signal has an essential role in protective immunity against blood-stage malarial parasites. In contrast, the curing of parasitemia in IL 2/15Rbeta-/- mice, deficient in both IL-2 and IL-15 signalling was significantly delayed but did occur, indicating that neither cytokine plays an essential role in parasite clearance. Moreover, the observation that the time course of parasitemia in IL-15-/- mice was nearly identical to that seen in controls suggests that the parasitemia-suppressing role of stimulating through the IL 2/15Rbeta chain is owing to IL-2 signalling and not a redundant function of IL 15. PMID- 21585398 TI - Antibodies directed against merozoite surface protein-6 are induced by natural exposure to Plasmodium falciparum in a low transmission environment. AB - Malaria caused by Plasmodium falciparum is a major cause of global infant mortality, and there is currently no licensed vaccine that provides protection against infection or disease. Several P. falciparum vaccine targets have undergone early testing, but many more candidates remain with little data to support their development. Plasmodium falciparum Merozoite Surface Protein 6 (PfMSP6) is a candidate of particular interest because it is a member of the PfMSP3 multi-gene family, raising the possibility that vaccine-induced immune responses could cross-react across multiple family members. However, few immunoepidemiological studies of PfMSP6 have been carried out to measure domain specific anti-PfMSP6 responses. This study investigated anti-PfMSP6 responses in P. falciparum-infected individuals from the Peruvian Amazon, using two different PfMSP6 N-terminal allele antigens and a single C-terminal domain antigen, and compared the responses with both PfMSP6 genotyping data and anti-PfMSP3 response data that had been previously generated for the same samples. Anti-PfMSP6 responses were detected despite the low transmission setting, but were less frequent and of considerably lower intensity than anti-PfMSP3 responses. There was a positive correlation between anti-PfMSP3 and PfMSP6 responses, suggesting that the possibility that PfMSP3 family antigens could induce cross-reactive responses requires further detailed investigation. PMID- 21585399 TI - Arginase-1-expressing macrophages are dispensable for resistance to infection with the gastrointestinal helminth Trichuris muris. AB - Alternatively activated macrophages (AAMs) have key roles in the immune response to a variety of gastrointestinal helminths such as Heligmosomoides bakeri and Nippostrongylus brasiliensis. In addition, AAMs have been implicated in the resolution of infection-induced pathology in Schistosoma mansoni infection. AAMs exert their activity in part via the enzyme arginase-1 (Arg1), which hydrolyses L arginine into urea and ornithine, and can supply precursor substrate for proline and polyamine production. Trichuris muris is a worm that resides in the large intestine with resistance being characterized by a Th2 T-cell response, which drives alternatively activated macrophage production in the local environment of the infection. To investigate the role of AAMs in T. muris infection, we used independent genetic and pharmacologic models of arginase deficiency. In acute infection and Th2-dominated immunity, arginase-deficient models expelled worms normally. Macrophage-Arg1-deficient mice showed cytokine and antibody levels comparable to wild-type animals in acute and chronic infection. We also found no role for AAMs and Arg1 in infection-induced pathology in the response to T. muris in either chronic (Th1 dominated) or acute (Th2 dominated) infections. Our data demonstrate that, unlike other gastrointestinal helminths, Arg1 expression in AAMs is not essential for resistance to T. muris in effective resolution of helminth-induced inflammation. PMID- 21585400 TI - Utilizing hydroglycolic extract from myrobalan fruits to counteract reactive oxygen species. AB - The hydroglycolic (HG) extract from 70% propylene glycol (PG) extraction of myrobalan fruits showed the most appreciable antioxidant efficiency towards 1,1 diphenyl-2-picrylhydrazyl (DPPH) in comparison to the extracts from 30, 50, 70 and 100% ethyl alcohol (EA), and 30, 50 and 100% PG . Its total polyphenols were also higher than others. The additional analysis of antioxidant power revealed that this HG extract was able to counteract the induced oxidation caused by hydrogen peroxide (H(2) O(2) ) and 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). The quantification for the antioxidant capacity of the extract showed it was equivalent to 93.78 mg of 6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylic acid (Trolox) g(-1) by 2,2'-azino-bis(3-ethylbenzthiazoline-6-suphonic acid) diammonium (ABTS) assay, and was 140.17 mg ascorbic acid (AA) equivalent g(-1) and 107.50 mg Trolox equivalent g(-1) by photochemiluminescence (PCL) assay. The incorporation of the HG myrobalan extract into lotion and sunscreen lotion rendered these products to provide the similar antioxidant power as the extract alone. PMID- 21585401 TI - The influence of alkane chain length on the skin irritation potential of 1,2 alkanediols. AB - Several studies have reported that 1,2-alkanediols show increasing anti-microbial activity as their alkane chain length increases. However, there are no reports on the influence of alkane chain length on the skin irritation potential of 1,2 alkanediols. To investigate the influence of alkane chain length on the skin irritation potential of 1,2-alkanediols. The objective and subjective (sensory) skin irritation potentials of five 1,2-alkanediols - 1,2-butanediol, 1,2 pentanediol, 1,2-hexanediol, 1,2-octanediol and 1,2-decanediol - were evaluated. We also estimated percutaneous absorption by measuring in vitro skin penetration using a Franz diffusion cell system. Like anti-microbial activity, sensory irritation potential increased as alkane chain length increased, most likely due to increasing membrane interference and/or intrinsic toxicity of 1,2-alkanediols. 1,2-Hexanediol showed the lowest objective skin irritation potential, which increased when the alkane chain length decreased or increased. Furthermore, percutaneous absorption negatively correlated with the alkane chain length of 1,2 alkanediols. These results show that a lower skin absorption potential is not indicative of a low skin irritation potential. Our results suggest that the factors and processes involved in skin irritation potential are complex and that skin irritation potential is influenced by intrinsic toxicity and the potential for penetration or integration in the lipid bilayer. PMID- 21585403 TI - Development of associations between microalgae and denitrifying bacteria in streams of contrasting anthropogenic influence. AB - We compared the development of microalgal and bacterial-denitrifier communities within biofilms over 28 days in a restored-prairie stream (RP) and a stream receiving treated wastewater effluent (DER). Inorganic nutrient concentrations were an order of magnitude greater in DER, and stream waters differed in the quality of dissolved organics (characterized via pyrolysis-GC/MS). Biofilm biomass and the densities of algae and bacteria increased over time in both systems; however, algal and denitrifier community composition and the patterns of development differed between systems. Specifically, algal and denitrifier taxonomic composition stabilized more quickly in DER than RP, whereas the rates of algal and denitrifier succession were more closely coupled in RP than DER. We hypothesize that, under unenriched conditions, successional changes in algal assemblages influence bacterial denitrifiers due to their dependence on algal exudates, while under enriched conditions, this relationship is decoupled. Between-system differences in organic signatures supported this, as RP biofilms contained more labile, aliphatic compounds than DER. In addition, potential denitrification rates (DNP) were negatively correlated with the percentage of aromatic compounds within the biofilm organic signatures, suggesting a significant relationship between algal exudate composition and denitrification. These results are significant because anthropogenic factors that affect biofilm community composition may alter their capacity to perform critical ecosystem services. PMID- 21585402 TI - Diversity and dynamics of free-living and particle-associated Betaproteobacteria and Actinobacteria in relation to phytoplankton and zooplankton communities. AB - The diversity of attached and free-living Actinobacteria and Betaproteobacteria, based on 16S rRNA gene sequences, was investigated in a mesotrophic lake during two periods of contrasting phytoplankton dominance. Comparison analyses showed a phylogenetic difference between attached and free-living communities for the two bacterial groups. For Betaproteobacteria, the betaI clade was detected at all sampling dates in free-living and attached bacterial communities and was the dominant clade contributing to 57.8% of the total retrieved operational taxonomic units (OTUs). For Actinobacteria, the acIV cluster was found to be dominant, followed by acI contributing to 45% and 25% of the total retrieved OTUs, respectively. This study allows the determination of eight new putative clades among the Betaproteobacteria termed lbI-lbVIII and a new putative clade named acLBI belonging to the Actinobacteria. The seasonal dynamics of phytoplankton and zooplankton communities have been reflected as changes in distinct bacterial phylotypes for both attached and free-living communities. For attached communities, relationships were observed between Actinobacteria and Chrysophyceae, and between Betaproteobacteria and Dinophyceae and Chlorophyceae biomass. On the other hand, within free-living communities, few actinobacterial clades were found to be dependent on either nutrients or phytoplankton communities, whereas Betaproteobacteria were mainly associated with biological parameters (i.e. phytoplankton and copepod communities). PMID- 21585404 TI - Comparison of four enrichment broths for the detection of non-O157 Shiga-toxin producing Escherichia coli O91, O103, O111, O119, O121, O145 and O165 from pure culture and food samples. AB - AIMS: We compared the efficiency of universal pre-enrichment broth (UPB), modified Escherichia coli broth containing novobiocin (mEC + n), modified Tryptic Soy Broth (mTSB) and mTSB with novobiocin (mTSB + n) for the enrichment of non O157 Shiga-toxin-producing E. coli (STEC). METHODS AND RESULTS: Freeze-injured and control non-O157 STEC (O91, O103, O111, O119, O121, O145 and O165) strains were used to artificially contaminate beef and radish sprout samples, which were then cultivated in each of the four enrichment media. After incubation, STEC strains were detected by loop-mediated isothermal amplification (LAMP) and plating assays. Enrichment in mEC + n was least effective for facilitating the detection of uninjured STEC strains in radish sprouts, while mTSB + n was least effective for enriching freeze-injured non-O157 STEC strains from beef samples for detection by LAMP assay. UPB and mTSB were superior to mEC + n and mTSB + n for the enrichment of non-O157 STEC from food samples. CONCLUSIONS: The enrichment of non-O157 STEC was negatively affected by the addition of novobiocin to enrichment broths. SIGNIFICANCE AND IMPACT OF THE STUDY: Novobiocin should not be added to media used for the enrichment of non-O157 STEC in food when cell injury is anticipated. PMID- 21585405 TI - Comparative evaluation of chromogenic agar CM1046 and mFC agar for detection of E. coli and thermotolerant coliform bacteria from water samples. AB - AIMS: The equivalence of Oxoid (CM 1046) Brilliance((TM)) E. coli/coliform selective agar to mFC agar, as used in the Australian/New Zealand Standard Method to detect thermotolerant coliforms and Escherichia coli in water samples, was assessed. METHODS AND RESULTS: A total of 244 water samples were analysed in parallel over a 5-month period. Sewage effluent samples (n = 131, sites = 43), freshwater (n = 62, sites = 18) and marine/brackish water samples (n = 51, sites = 23) were analysed. The Wilcoxon matched-pairs signed-ranks test showed a varying degree of statistical difference between the two methods. All matrices had a higher recovery in the trial method. Enterococci faecalis, Aeromonas spp. and Vibrio spp. did not grow on the CM1046 agar, and Pseudomonas aeruginosa and Enterobacter aerogenes were inhibited. CONCLUSIONS: The use of CM 1046 for the detection and enumeration of E. coli and thermotolerant coliforms in water samples is a suitable alternative to the AS/NZS Standard Method. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of CM1046 agar was less labour intensive and time consuming, as no secondary confirmation steps were required. Confirmed results could be reported within 24 h of sample analysis, as compared to 48 h with the reference method. Public health concerns can be addressed in a more efficient manner. PMID- 21585406 TI - Temperature dependency of Clostridium botulinum C and D toxin production from anaerobically enriched bovine gastrointestinal samples. AB - AIMS: To determine whether Clostridium botulinum neurotoxin (BoNT) production in anaerobic culture was affected by temperature and could influence the sandwich ELISA (sELISA) detection of group III toxins in pre-enriched gastrointestinal (GI) contents from clinically suspect cattle botulism cases. METHODS AND RESULTS: Bovine post-mortem GI samples taken from 124 and 96 animals with suspect and nonsuspect botulism, respectively, were pre-enriched anaerobically at 30 and 37 degrees C prior to testing by sELISA. After enrichment at 37 degrees C, BoNT was demonstrated in all clinically suspect bovine botulism cases that had been identified by the mouse bioassay, and enrichment by both temperatures enabled BoNT detection in a number of mouse bioassay-negative suspect cases. CONCLUSIONS: Culture temperature does influence the production of group III BoNT, and incubation at both 30 and 37 degrees C is required for optimum detection. SIGNIFICANCE AND IMPACT OF THE STUDY: The in vitro assay defined in this study has the potential of improving the confirmation rate of clinically suspect cattle botulism cases whilst reducing the use of the costly and ethically sensitive mouse bioassay, the current diagnostic gold standard for BoNT testing. PMID- 21585407 TI - Optimising the care of patients with cirrhosis and gastrointestinal haemorrhage: a quality improvement study. AB - BACKGROUND: Patients with cirrhosis and gastrointestinal haemorrhage are a complex group with high thirty-day mortality rates. AIM: To evaluate the quality of care delivered to patients admitted with gastrointestinal (GI) haemorrhage to a tertiary care centre before and after implementing a quality improvement initiative for better adherence to practice standards. METHODS: This is a prospective cohort study. All patients admitted to a tertiary care centre with a GI haemorrhage and known or suspected chronic liver disease were evaluated before and after the quality improvement initiative was implemented. Interventions to improve quality of care included the delivery of educational sessions for medical practitioners, and creation and implementation of standardised admission order sets. Quality of care measures included delivery of prophylactic antibiotics (PAs) within 24 h of admission, delivery of a somatostatin analogue (SA) and use of a proton pump inhibitor (PPI); optimal care was defined as receiving all three. Secondary outcomes included hospital length of stay (LOS) and 30-day readmission rate. RESULTS: In comparing the preintervention and postintervention groups, we found significant gains in delivering PAs (57% vs. 75%, P=0.05), SAs (54% vs. 76%, P=0.013) and overall optimal care (41% vs. 65%, P=0.008). Use of PPIs did not change and remained in accordance with guidelines (90% vs. 87%, P=0.67). Hospital LOS remained similar between the two groups (6.8 vs. 7.1, P=0.88), whereas the 30-day readmission decreased (41% vs. 13%, P=0.001). CONCLUSION: Implementation of quality improvement initiatives, such as targeted educational efforts and standardised order sets, can improve the quality of care delivered and patient outcomes in patients with cirrhosis and GI haemorrhage. PMID- 21585408 TI - Long-term results of treatment of malignant carcinoid syndrome with prolonged release Lanreotide (Somatuline Autogel). AB - BACKGROUND: Somatostatin analogues are the mainstay of therapy for malignant carcinoid syndrome. There is clear evidence that the once monthly intramuscular formulation, Octreotide LAR, controls symptoms of carcinoid syndrome, and recent data also suggests an antitumour effect. There is limited data on prolonged release Lanreotide (Somatuline Autogel, Ipsen Pharma Biotech, Signes, France) and no long-term data to date. AIM: To present long-term results of prolonged release Lanreotide in a large cohort of patients with malignant carcinoid syndrome, assessing clinical and objective response and tolerance. METHODS: Seventy six patients with metastatic midgut neuroendocrine tumours and carcinoid syndrome were included in this 9-year retrospective study. Clinical response was based on symptom score with radiological assessment based on RECIST (Response Evaluation Criteria In Solid Tumours). RESULTS: Data were available in 69 patients. Ninety four percent achieved symptomatic response at first follow-up visit. Forty six percent had loss of symptomatic response, but 44% of these achieved control with an increase in dose of prolonged release Lanreotide. Overall, symptoms were well controlled throughout the study period with prolonged release Lanreotide alone in 74% of patients. Twenty six percent required additional treatment despite good initial response. Only 30% demonstrated radiological progression. Eleven patients who were switched from Octreotide LAR had return of symptomatic control. No significant adverse effects were experienced. CONCLUSIONS: Prolonged release Lanreotide provides good symptomatic control of diarrhoea and flushing as well as tumour stability in patients with malignant carcinoid syndrome. PMID- 21585409 TI - Validation of the non-alcoholic fatty liver disease activity score. AB - BACKGROUND: The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) is a scoring system designed by the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) to encompass the spectrum of NAFLD and evaluate histological changes. However, the NAS and the correlation between the NAS and a diagnosis of NASH have not been validated outside the NASH CRN. AIM: To validate the NAS outside the NASH CRN. METHODS: This study retrospectively examined liver biopsies from adults with NAFLD or steatohepatitis obtained from January 2003 to May 2010. Biopsy specimens were evaluated twice in a blinded manner by a single hepatopathologist, once to determine a diagnosis (steatohepatitis or steatosis/not-steatohepatitis), and a second time to determine the NAS. RESULTS: A total of 386 liver biopsies were evaluated. Mean age of patients at time of biopsy was 49.9+/-10.2years. NASH was found in 51% of the patients. For NAS >=5 as a diagnosis of steatohepatitis and NAS <5 for not-steatohepatitis, the sensitivity was 57%, specificity: 95%, negative predictive value (NPV): 68% and positive predictive value (PPV): 93%. Lowering the NAS to >=4 as a diagnosis of steatohepatitis increased the sensitivity to 85% with a decrease in specificity to 81%; NPV: 84%, PPV: 82% and Cohen's kappa 0.658. CONCLUSIONS: The NAFLD activity score is a valid scoring system encompassing the spectrum of NAFLD with an excellent level of agreement between the histological diagnosis and the NAFLD activity score. A NAFLD activity score >=4 has optimal sensitivity and specificity for predicting steatohepatitis, and is the recommended value for admission into an interventional trial for NASH. PMID- 21585410 TI - Randomised clinical trial: a 'nudge' strategy to modify endoscopic sedation practice. AB - BACKGROUND: In behavioural economics, a 'nudge' describes configuration of a choice to encourage a certain action without taking away freedom of choice. AIM: To determine the impact of a 'nudge' strategy - prefilling either 3mL or 5mL syringes with midazolam - on endoscopic sedation practice. METHODS: Consecutive patients undergoing sedation for EGD or colonoscopy were enrolled. On alternate weeks, midazolam was prefilled in either 3mL or 5mL syringes. Preprocedure sedation was administered by the endoscopist to achieve moderate conscious sedation; dosages were at the discretion of the endoscopist. Meperidine was not prefilled. RESULTS: Overall, 120 patients received sedation for EGD [59 (5mL), 61 (3mL)] and 86 patients were sedated for colonoscopy [38 (5mL), 48 (3mL)]. For EGDs, average midazolam dose was significantly higher in the 5-mL group (5.2mg) vs. 3-mL group (3.3mg), (P<0.0001); for colonoscopies, average midazolam dose was also significantly higher in the 5-mL group (5.1mg) vs. 3-mL group (3.3mg), (P<0.0001). There was no significant difference in mean meperidine dose (42.1mg vs. 42.8mg, P=0.9) administered to both colonoscopy groups. No adverse sedation related events occurred; no patient required reversal of sedation. CONCLUSIONS: These findings demonstrate that 'nudge' strategies may hold promise in modifying endoscopic sedation practice. Further research is required to explore the utility of 'nudges' in impacting other aspects of endoscopic practice. PMID- 21585411 TI - Meta-analysis of the comparative efficacy and safety of pitavastatin and atorvastatin in patients with dyslipidaemia. AB - WHAT IS KNOWN AND OBJECTIVE: Pitavastatin is the latest available statin. It has been shown to be effective in the treatment of dyslipidaemia. This meta-analysis was aimed at evaluating the effects of pitavastatin on lipid profiles in patients with dyslipidaemia compared with atorvastatin. METHODS: Clinical trials were identified through electronic searches (MEDLINE, CINAHL, EBM review, and the Cochrane Library) up to January 2011 and historical searches of relevant articles. Studies were included in the meta-analysis if they were (i) randomized controlled trials that evaluated pitavastatin at the recommended dose vs. atorvastatin in patients with dyslipidaemia, (ii) lasting at least 6weeks, (iii) reporting total cholesterol (TC), LDL-C, HDL-C or triglyceride (TG) levels and (iv) published in English. Treatment effect was estimated with the mean difference in the per cent changes in lipid profiles from baseline to final assessment between pitavastatin and atorvastatin. RESULTS: Seven trials involving 1529 patients were included. Pitavastatin reduced LDL-C level as effectively as atorvastatin (mean difference 0.97%, 95% CI -0.48% to 2.42%). The reductions in TC and TG levels were also comparable between the two drugs. The mean differences were 1.22% (95% CI -0.55% to 2.99%) and 2.3% (95% CI -1.06% to 5.65%), respectively. However, HDL-C levels increased significantly more with pitavastatin than with atorvastatin (mean difference 1.78%, 95% CI 0.20-3.36%, P=0.03). WHAT IS NEW AND CONCLUSIONS: Pitavastatin was as effective as atorvastatin in lowering LDL-C, TC and TG levels. Pitavastatin was marginally superior to atorvastatin in increasing HDL-C levels. PMID- 21585414 TI - Support as a complement, intrusion and right--evidence from ageing and disability support service users in Sweden and Australia. AB - How service users conceptualise their personal support services is under researched, even though this understanding is important for responsive policy development and service implementation. This paper tests the proposition that service users understand formal support in three ways: support is a complement to their other arrangements, an intrusion into their personal life and a right. These three concepts were identified using discourse analysis in a Swedish study of older people wanting in-home support services. To test generalisability of these concepts, they were applied to data from an Australian study of people using disability personal support. The analysis found that the three concepts were core to people's views of their support, although the construction of the concepts differed in the two countries. Service users in Sweden asserted their right to services more forcefully than those in Australia, and they had higher expectations that their support needs would be met. These differences reflect the impact of each country's social policy environment on service users' expectations. The analysis suggests that service users and their families want to control their formal support arrangements to complement their informal care and their life preferences and to minimise the intrusive aspects of formal support. The findings imply that the three concepts have utility for theorising service users' perspectives, informing policy and developing implementation strategies which enhance peoples' quality of life. PMID- 21585415 TI - Nutritional care in inflammatory bowel disease--a literature review. AB - AIM AND METHOD: During recent years, an increasing number of young adults have developed inflammatory bowel disease (IBD). The caring perspective on IBD is now changing to adapt to the development of the illness and prescribing new health promotion methods of care, with a focus on nutrition, education and patient supervision. IBD, immunology and nutrition are the main focus in the selected articles, with presentation of possible connections to contribute to broader understanding of the illness. This present article is part of an empirical research project and is providing an overview of the current research knowledge in this field. The article is based on an extensive, systematic survey of literature comprising 28 review and original articles from June 2008 to July 2009. The important topics are emphasized and described. RESULTS: Two areas of knowledge are considered instrumental in inter-disciplinary health-promoting work with IBD patients: a focus on gut immunology and stress, nutritional care and diet. Healing damage to the gut wall by introducing an individually prescribed diet may take time, but will reduce internal stress on the body. Documentation shows that use of probiotics, fatty acids and antioxidants has been effective in a number of clinical scenarios relating to IBD. Individually prescribed nutrition, primarily through the diet, may be decisive in terms of a sustainable improvement in outcomes for patients with IBD. CONCLUSIONS: Addressing the educational challenges in caring to cure suffering from IBD is crucial. Emergency medical treatment helps patients during the acute phase of the disease. Once the acute phase is passed, the recommendation is a focus on investigating the environmental factors that could act as triggers for IBD in humans. Diet is the most important environmental factor in terms of the gut. Proper nutrition and micronutrients assist the body by subtly strengthening its capacity for self healing and regeneration. Education, confirmation, and a reflection into ones illness, create insight and a basis for coping. PMID- 21585416 TI - Increased self-awareness in the process of returning to work. AB - BACKGROUND: A group of employees on sick leave, living in the Oslo area, Norway, was offered participation in a counselling programme, based on Gestalt theory, mindfulness and phenomenological understanding of the body. AIMS: To explore the participants' processes of change related to their increased ability to work. METHOD DESIGN: This qualitative study is based on modified grounded theory. METHOD: A total of 12 female employees, all who had increased work ability 1 year after the programme, participated in open focus-group interviews at the end of the programme. FINDINGS: The participants' experiences from processes of change are described through the following categories: becoming more aware of one's own thoughts, emotions and bodily reactions; taking oneself seriously and accepting oneself; being secure enough to face being challenged; realizing new possibilities and choices and trying out new ways of acting. The participants further described what had been helpful in these processes. Experience of a secure setting and open-minded listening seemed important for getting the courage to open up to all reactions. Then, they could explore new ways of thinking, communicating and behaving. Discussing existential issues such as their core values was important. This, together with being allowed to take their own emotions seriously and being challenged by the counsellors, had encouraged the processes of change. CONCLUSIONS: The women described how experiences of increased awareness contributed to reconstruction of their self-understanding and opened up for new possibilities. This seemed to have provided them with new ways of communicating and acting, which enhanced participation in work. The context of the learning programme, the existential issues and counselling challenges appeared as essential in these processes of change. The findings give insights into aspects that may be important when designing rehabilitation programmes. PMID- 21585417 TI - Lithuanian nurses' assessments of their empowerment. AB - AIMS AND OBJECTIVES: The aim was to explore nurse empowerment and the factors associated with it from the viewpoint of surgical nurses. DESIGN: A multicentre cross-sectional, descriptive, correlational study design was used. SETTING AND PARTICIPANTS: The data were collected from 11 units of seven largest Lithuanian hospitals located in three major cities during the period of 11/2007 to 01/2008. All the nurses (N = 270) working in the abdominal perioperative settings were invited to participate in the study; 247 questionnaires were returned giving the response rate of 91 %. The data were analyzed on the basis of 218 responses. The statistical analysis was performed by SPSS (12.0 version). INSTRUMENTS: Two instruments, both originally developed in Finland and adapted to the Lithuanian cultural context, were used: Nurse Empowerment Scale (NES) and Good Nursing Care Scale for Nurses (GNCS-N). RESULTS: Surgical nurses evaluated their work empowerment positively. Several background factors were associated with nurse empowerment, such as nurse education, type of nurse license (working area), the continuing nurse education (completed courses during last 5 years), the workload at hospital, the work independence, and work satisfaction. The connection between nurse empowerment and quality of nursing care was also identified (r = 0.139 0.525, p < 0.01). CONCLUSIONS: Surgical nurses feel empowered at their work when they have higher education and have completed the continuing education courses. Nurses should have possibility to continue their studies at the university. Independent at work, satisfied, and motivated nurses have more power at their work in the surgical units in Lithuania. However, further research is needed to explore nurse empowerment in other fields of nursing care nationally and internationally. PMID- 21585418 TI - What is the best long-term management strategy for patients with primary adrenal insufficiency? AB - Primary adrenal insufficiency is treated with glucocorticoid and mineralocorticoid replacement therapy. Recent data revealed that health-related quality of life in adrenal insufficiency is impaired in many patients and that patients with adrenal insufficiency are also threatened by an increased mortality and morbidity. This may be caused by inadequate glucocortiocid therapy and adrenal crisis. Therefore, the optimization of hormone replacement therapy remains one of the most challenging tasks in endocrinology because it is largely based on clinical grounds because of the lack of objective assessment tools. This article provides answers to the important daily clinical questions, such as correct dose finding, dose adaptation in special situations, e g, pregnancy, improvement of quality of life and measures for protection from adrenal crisis. Other important aspects discussed are side effects of glucocortiocid replacement therapy and interactions with other drugs. PMID- 21585419 TI - Self-help parenting interventions for childhood behaviour disorders: a review of the evidence. AB - The use of self-help interventions for parents of children with behaviour problems is becoming more prevalent. This review critically evaluated the evidence supporting the efficacy of such programmes for children with behaviour problems. Using a systematic literature search, two modes of delivery were evaluated, namely bibliotherapy and multimedia. Programmes that included minimal therapist support were also included. Overall, there is good evidence supporting the efficacy of self-help programmes in improving child behaviour, over the short and longer term. Self-help programmes led to outcomes similar to those achieved with more intensive therapist input. Including minimal levels of therapist support in addition to self-help materials enhances child and parent outcomes. Parents view self-help favourably but significantly less so than programmes including some form of therapist input. The future directions for self-help parent programmes include the need for longer-term follow-ups, the identification of moderators of outcome and economic evaluations of self-help programmes. PMID- 21585420 TI - Indomethacin abolishes core temperature, but not cardiovascular or renal, responses to lipopolysaccharide in conscious lambs. AB - 1. Core temperature (Tc), cardiovascular and renal responses to lipopolysaccharide (LPS), as well as the role of endogenously produced prostaglandins (PG) in influencing these responses, were investigated in the present study in conscious, chronically instrumented lambs. 2. Core temperature, mean arterial pressure, heart rate (HR), renal blood flow (RBF) and several parameters of renal function were measured for 30 min before and for 5 h after intravenous injection of 0.03 MUg/kg of the LPS Salmonella abortus equi (n = 9) or saline vehicle (n = 9). 3. After injection of LPS, Tc increased with a latency of 40 min, duration of 130 min and magnitude of 1.5 degrees C. Mean arterial pressure increased within 110 min of LPS injection and then decreased below baseline within 5 h, concomitant with an increase in HR. There was a sustained increase in RBF after LPS injection and a significant increase in urinary flow rate, as well as Na(+) and Cl(-) excretion. 4. To determine the role of PGs in the responses to LPS observed, additional experiments were performed in another group of conscious lambs that had been pretreated with the non-selective cyclo oxygenase inhibitor indomethacin (10 mg/kg; n = 6). 5. Although indomethacin abolished the Tc response to LPS, it had no significant effect on the cardiovascular and renal responses to LPS. There were no effects of saline vehicle on any of the variables measured. 6. These data provide evidence that, in conscious young lambs, cardiovascular and renal responses to LPS do not appear to be mediated by endogenously produced PGs and that they are independent of pyrogen induced changes in Tc. PMID- 21585421 TI - Leukaemia inhibitory factor is expressed in rat gastrocnemius muscle after contusion and increases proliferation of rat L6 myoblasts via c-Myc signalling. AB - 1. Leukaemia inhibitory factor (LIF) has been shown to have an important role during muscle regeneration. The regenerative capacity of muscles after contusion injury in LIF-knockout mice is impaired compared with that of wild-type mice. 2. To clarify whether LIF modulates muscle regeneration by regulating myogenic precursor cell activity, we studied LIF expression and myogenic precursor cell activity in gastrocnemius muscles from Wistar rats at various times after contusion injury using immunohistochemistry and the direct effect of LIF on a rat myoblast cell line (L6). 3. After contusion injury, transient upregulation of the mRNA expression of LIF, LIF receptors and signal transducer and activator of transcription (STAT) 3, downstream of LIF and involved in enhanced cell proliferation, was observed. A marked increase in LIF protein in the cytosol of damaged myofibres was strongly correlated with a significant increase in the number of myogenic precursor cells (MyoD-positive cells) by 12 h after contusion. In addition, coexpression of LIF and MyoD protein in control and injured muscles after contusion injury from 3 h to 7 days was evident. 4. Treatment of L6 cells with LIF (1 ng/mL) in serum-free medium enhanced proliferation (bromodeoxyuridine incorporation) by 24 h. This was accompanied by increased expression of c-Myc protein within 12 h and was abolished by short interference RNA against c-Myc mRNA. 5. Together, the results of the present study suggest that LIF acts via paracrine and autocrine actions to regulate myogenic precursor cell activity during muscle regeneration after contusion injury and that the proliferative effect of LIF on L6 cells occurs via c-Myc signalling. PMID- 21585423 TI - The mucinous variant of columnar cell lesions. AB - AIMS: Mucin-producing columnar cell lesions (CCL) are a rare, new entity in the breast. The aim of this study was to describe the incidence and follow-up of mucinous CCLs. METHODS AND RESULTS: Of 4164 breast core needle biopsies (CNBs), 291 showed a CCL and 21 atypical ductal hyperplasia (ADH) originating in a CCL (ADH-CCL). Mucin production was present in 17 of 291 (5.8%) CCLs and three of 21 (14.3%) ADH-CCLs, together concerning 0.5% of all CNBs. The most common mucinous CCL pattern was a columnar cell change without atypia, and almost all were detected with microcalcifications as an abnormality at mammography. During a median follow-up of 3.1 years, no invasive carcinoma or ductal carcinoma in situ was detected. MUC2 was expressed in intraluminal mucin in 12 of 15 (80%) mucinous CCLs, and showed cytoplasmic expression in five of 15 (33%) mucinous CCLs seen in CNBs. Moreover, mucinous CCLs were significantly more common in association with 46 mucinous carcinomas than in 46 ductal carcinomas (28% versus 9%). CONCLUSIONS: Mucinous CCLs are rare lesions, with an incidence of about 0.5% in breast CNBs, usually presenting with microcalcifications. Although these lesions might play a role in the mucinous progression spectrum, the short-term risk of progression to more advanced lesions seems to be low. PMID- 21585422 TI - Role of mineralocorticoid action in the brain in salt-sensitive hypertension. AB - 1. The mechanisms by which excessive salt causes hypertension involve more than retention of sodium and water by the kidneys and are far from clear. Mineralocorticoids act centrally to increase salt appetite, sympathetic drive and vasopressin release, resulting in hypertension that is prevented by the central infusion of mineralocorticoid receptor (MR) antagonists. The MR has similar affinity for aldosterone and the glucocorticoids corticosterone or cortisol. Specificity is conferred in transport epithelia by the colocalization of the MR with 11beta-hydroxysteroid dehydrogenase Type 2. Coexpression also occurs in some neurons, notably those of the nucleus tractus solitarius that are activated by sodium depletion and aldosterone and mediate salt-seeking behaviour. 2. The salt induced hypertension of the Dahl salt-sensitive rat is mitigated by the central infusion of a mineralocorticoid antagonist even though circulating aldosterone is normal or reduced in salt-sensitive (SS). Contrary to reports that salt appetite in the Dahl salt-sensitive rat is depressed, we found that it is increased compared with that in Spraque-Dawley rats. 3. Extra-adrenal aldosterone synthesis in the brain occurs in minute amounts that could only be relevant locally. Expression of aldosterone synthase mRNA and aldosterone concentrations in the brain of Dahl salt-sensitive rats are increased compared with Spraque-Dawley rats. The central infusion of inhibitors of aldosterone synthesis lowers salt induced hypertension in the Dahl salt-sensitive rat, suggesting a role for excessive Dahl salt-sensitive synthesis in the brain. Brain MR, particularly those in the paraventricular nuclei, regulate inflammatory processes that are exacerbated by sodium and lead to cardiovascular dysfunction. PMID- 21585424 TI - Divergent behaviour of oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (HNE) in breast carcinogenesis. AB - AIMS: To clarify the role of oxidative stress during breast carcinogenesis by studying the expression of 8-hydroxydeoxyguanosine (8-OHdG) (a marker of oxidative DNA damage) and 4-hydroxy-2-nonenal (HNE) (a marker of lipid peroxidation) during the different phases of breast carcinogenesis. METHODS AND RESULTS: The study material consisted of a total of 219 patients: 31 with usual ductal hyperplasia (UDH), 25 with atypical ductal hyperplasia (ADH), 30 with ductal carcinoma in situ (DCIS) and 133 with invasive carcinoma. The expression of 8-OHdG and HNE were evaluated immunohistochemically. Both 8-OHdG (77.4%) and HNE (45.8%) expression was already seen in UDH lesions. Interestingly, the trend of these two immunostainings during breast carcinogenesis was diverse. 8-OHdG expression diminished significantly in invasive breast carcinomas compared to non invasive lesions (P < 0.005 when set against non-invasive cohorts). Also within the same lesions, 8-OHdG expression was the most intensive in benign cells. Conversely, HNE immunostaining was strongest in invasive breast carcinomas (UDH versus invasive cohort, P = 0.015). CONCLUSIONS: 4-hydroxy-2-nonenal as a marker of lipid peroxidation increases during breast carcinogenesis, reflecting the role of oxidative stress in the pathogenesis of breast cancer. However, 8-OHdG shows diminished levels in carcinomas, possibly resulting from the induction of DNA repair in these invasive lesions. PMID- 21585425 TI - Diagnosis of the sentinel lymph node in breast cancer: a reproducible molecular method: a multicentric Spanish study. AB - AIMS: Standardization of the sentinel node (SN) as a diagnostic tool has not yet been achieved, because the protocol for histopathological study is highly variable between centres. We compared the results of a new method with conventional histological tests and evaluated its feasibility for intra-operative evaluation, and propose it as a method to standardize the sentinel node evaluation procedure. METHODS AND RESULTS: Trial 1 included 181 cases; in parallel, 2-mm-thick sections of the SN were processed alternately for histological analysis and for the one-step nucleic acid amplification (OSNA) procedure. A final concordance of 99.45% was observed in the first trial of our study. For trial 2, the timing of every procedural step was recorded in an electronic database in order to discern the time spent for each step, the total SN evaluation time and to identify areas of improvement. In the second trial, after a learning period and feedback on data recorded, we spent a mean of 31 min for the entire SN evaluation procedure. CONCLUSION: Our multi-centric trial using the OSNA assay for sentinel node evaluation in breast cancer demonstrates that this is a highly sensitive, specific and reproducible technique that allows for standardization of the SN diagnostic procedure, a necessary, and until now unresolved, issue. PMID- 21585426 TI - Lymphangiogenesis is a predictor of nodal metastasis in extramammary Paget's disease. AB - AIMS: The depth of dermal invasion, lymphatic invasion and tumour formation are thought to be predictors of nodal metastasis in extramammary Paget's disease (EPD). This study investigated the relationship between lymphangiogenesis and nodal metastasis in EPD. METHODS AND RESULTS: Fifty cases (12 females and 38 males) with primary EPD of the external genitalia whounderwent surgical resection were studied. In 23 cases, inguinal lymph node dissection was performed, and nodal metastasis was found in eight cases. Lymphatic invasion and lymphangiogenesis were evaluated by D2-40 immunostain. Lymphangiogenesis was observed in 25 cases (50%). There were significant differences in the presence or absence of dermal invasion, depth of invasion, lymphatic invasion and nodal metastasis between the lymphangiogenesis group and non-lymphangiogenesis group. CONCLUSION: Dermal invasion and depth of dermal invasion are predictors for nodal metastasis in EPD. However, in the current study, we demonstrate that lymphangiogenesis is also a predictor of nodal metastasis in EPD. PMID- 21585427 TI - Angiogenesis and host immune response contribute to the aggressive character of non-melanoma skin cancers in renal transplant recipients. AB - AIMS: The aim of this study was to determine the contribution of tumour angiogenesis to the aggressive growth of non-melanoma skin cancers (NMSCs) in renal transplant recipients (RTRs). METHODS AND RESULTS: The study cohort included RTRs (n = 38) with formalin-fixed paraffin-embedded tumour samples available from first post-transplant NMSC (NMSC1) surgically excised at Christchurch Hospital, New Zealand, from 1997 to 2007. Comparable samples excised from immunocompetent individuals (ICIs) (n = 36) were selected to accommodate confounding factors. Markers of tumour angiogenesis were evaluated by immunohistochemistry, and analysed for associations with clinicopathological variables. As compared with ICIs, RTRs had a higher proportion of tumours with high microvessel density (P = 0.008), high proliferating capillary index (P < 0.0001) and low microvessel pericyte coverage index (P < 0.0001), and RTRs had a shorter cumulative second NMSC (NMSC2)-free interval (P < 0.0001). ICIs had a higher proportion of tumours with a 'marked' number of vascular endothelial growth factor (VEGF)-A-positive leukocytes than RTRs (P = 0.04), and RTRs with a 'moderate/marked' number of VEGF-A-positive leukocytes had longer cumulative NMSC2-free intervals than those with a 'minimum' number (P = 0.02). CONCLUSIONS: This study demonstrates increased tumour angiogenesis in NMSC in RTRs, and suggests a role for VEGF-A-positive peritumoural leukocytes in suppressing NMSC development. PMID- 21585428 TI - Differentiated precursor lesions and low-grade variants of squamous cell carcinomas are frequent findings in foreskins of patients from a region of high penile cancer incidence. AB - AIMS: About 10-20% of all penile squamous cell carcinomas (SCCs) originate in the foreskin, but knowledge about preputial precursor and associated lesions is scant. The aims of the present study were to determine the prevalence of various precancerous and cancerous lesions exclusively affecting the foreskin, and to describe their pathological features. METHODS AND RESULTS: One hundred consecutive circumcision specimens from symptomatic patients living in a region of high penile cancer incidence were analysed. Clinical diagnoses included mostly phimosis and chronic balanoposthitis (40 and 35 cases, respectively), but also a tumour mass (11 cases). Histopathological lesions found included: squamous hyperplasia in 61 cases; lichen sclerosus in 53 cases; penile intraepithelial neoplasia (PeIN) in 30 cases (all differentiated PeIN, with two cases showing multicentric foci of basaloid and warty-basaloid PeIN); and invasive SCC in 11 cases (three usual, three pseudohyperplastic, two verrucous-pseudohyperplastic, and one case each of basaloid, papillary and mixed usual-basaloid carcinomas). Lichen sclerosus was present in all low-grade SCC cases. Patients with no lesions were younger (mean age 44 years) than those with precursor lesions (mean age 54 years) or with invasive SCC (mean age 68 years). Immunohistochemistry for p16(INK4a) was performed in 19 precancerous lesions. All differentiated PeINs (18 lesions) were negative, and one basaloid PeIN was positive. CONCLUSIONS: The frequent coexistence of lichen sclerosus, squamous hyperplasia, differentiated PeIN and low-grade SCC suggests a common non-human papillomavirus related pathogenic pathway for preputial lesions, and highlights the importance of circumcision in symptomatic patients for the prevention of penile cancer. PMID- 21585429 TI - Heparanase expression in head and neck squamous cell carcinomas is associated with reduced proliferation and improved survival. AB - AIMS: Cellular expression of heparanase, a degrading enzyme of the extracellular matrix, is associated with poorer prognosis in several cancers. The present analysis, has studied the role of heparanase in tumour growth and clinical outcome in patients with head and neck squamous cell carcinoma (HNSCC). METHODS AND RESULTS: We analysed the cellular expression of the active form of heparanase in 71 human HNSCCs, using immunohistochemistry. The results were compared with clinicopathological data and, in 65 cases with immunoreactivity for the proliferation marker, MIB1. Cellular heparanase expression was detected in 41 of 71 (57.74%) cases; in particular, UICC IV-stage tumours showed high heparanase levels. Heparanase was localized mainly in the cytoplasm and, to a lesser extent, at the cell membrane. High levels of heparanase were significantly correlated with an almost four-fold decrease in MIB1 labelling (P = 0.006). Comparison with clinical outcome by multivariate analysis revealed that patients with high-level heparanase expression had prolonged overall survival (P = 0.029). CONCLUSIONS: Although heparanase was mainly found in late-stage HNSCCs, cellular heparanase expression in HNSCCs was associated with prolonged overall survival. We propose that the proliferation-reducing effect of high heparanase levels might outweigh the tumour-promoting effects of heparanase, especially in advanced tumours. PMID- 21585430 TI - Inter-observer variation in the histological diagnosis of polyps in colorectal cancer screening. AB - AIM: To determine the inter-observer variation in the histological diagnosis of colorectal polyps. METHODS AND RESULTS: Four hundred and forty polyps were randomly selected from a colorectal cancer screening programme. Polyps were first evaluated by a general (324 polyps) or expert (116 polyps) pathologist, and subsequently re-evaluated by an expert pathologist. Conditional agreement was reported, and inter-observer agreement was determined using kappa statistics. In 421/440 polyps (96%), agreement for their non-adenomatous or adenomatous nature was obtained, corresponding to a very good kappa value of 0.88. For differentiation of adenomas as non-advanced and advanced, consensus was obtained in 266/322 adenomas (83%), with a moderate kappa value of 0.58. For the non adenomatous or adenomatous nature, both general and expert pathologists, and expert pathologists between each other, showed very good agreement {kappa values of 0.89 [95% confidence interval (CI) 0.83-0.95] and 0.86 (95% CI 0.73-0.98), respectively}. For categorization of adenomas as non-advanced and advanced, moderate agreement was found between general and expert pathologists, and between expert pathologists [kappa values of 0.56 (95% CI 0.44-0.67) and 0.64 (95% CI 0.43-0.85), respectively]. CONCLUSIONS: General and expert pathologists demonstrate very good inter-observer agreement for differentiating non-adenomas from adenomas, but only moderate agreement for non-advanced and advanced adenomas. The considerable variation in differentiating non-advanced and advanced adenomas suggests that more objective criteria are required for risk stratification in screening and surveillance guidelines. PMID- 21585431 TI - Hepatoma-derived growth factor is a novel prognostic factor for cervical squamous cell carcinoma. PMID- 21585432 TI - Expression of the helicase-like transcription factor and its variants during carcinogenesis of the uterine cervix: implications for tumour progression. PMID- 21585433 TI - Overexpression of c-KIT (CD117) occurs infrequently in squamous cell carcinoma of the uterine cervix. PMID- 21585434 TI - Opposed roles of follicle-stimulating hormone and luteinizing hormone receptors in ovarian cancer survival. PMID- 21585435 TI - CD56 immunohistochemistry does not discriminate between cortisol-producing and aldosterone-producing adrenal cortical adenomas. PMID- 21585436 TI - Peribronchial lymph node metastasis from prostate cancer in pulmonary lobectomy for primary lung adenocarcinomas: a possible source of pitfall with therapeutic consequences. PMID- 21585437 TI - The tractable cognition thesis. AB - The recognition that human minds/brains are finite systems with limited resources for computation has led some researchers to advance the Tractable Cognition thesis: Human cognitive capacities are constrained by computational tractability. This thesis, if true, serves cognitive psychology by constraining the space of computational-level theories of cognition. To utilize this constraint, a precise and workable definition of "computational tractability" is needed. Following computer science tradition, many cognitive scientists and psychologists define computational tractability as polynomial-time computability, leading to the P Cognition thesis. This article explains how and why the P-Cognition thesis may be overly restrictive, risking the exclusion of veridical computational-level theories from scientific investigation. An argument is made to replace the P Cognition thesis by the FPT-Cognition thesis as an alternative formalization of the Tractable Cognition thesis (here, FPT stands for fixed-parameter tractable). Possible objections to the Tractable Cognition thesis, and its proposed formalization, are discussed, and existing misconceptions are clarified. PMID- 21585438 TI - Humor, abstraction, and disbelief. AB - We investigated humor as a context for learning about abstraction and disbelief. More specifically, we investigated how parents support humor understanding during book sharing with their toddlers. In Study 1, a corpus analysis revealed that in books aimed at 1-to 2-year-olds, humor is found more often than other forms of doing the wrong thing including mistakes, pretense, lying, false beliefs, and metaphors. In Study 2, 20 parents read a book containing humorous and non humorous pages to their 19-to 26-month-olds. Parents used a significantly higher percentage of high abstraction extra-textual utterances (ETUs) when reading the humorous pages. In Study 3, 41 parents read either a humorous or non-humorous book to their 18-to 24-month-olds. Parents reading the humorous book made significantly more ETUs coded for a specific form of high abstraction: those encouraging disbelief of prior utterances. Sharing humorous books thus increases toddlers' exposure to high abstraction and belief-based language. PMID- 21585439 TI - Audience-contingent variation in action demonstrations for humans and computers. AB - People may exhibit two kinds of modifications when demonstrating action for others: modifications to facilitate bottom-up, or sensory-based processing; and modifications to facilitate top-down, or knowledge-based processing. The current study examined actors' production of such modifications in action demonstrations for audiences that differed in their capacity for intentional reasoning. Actors' demonstrations of complex actions for a non-anthropomorphic computer system and for people (adult and toddler) were compared. Evidence was found for greater highlighting of top-down modifications in the demonstrations for the human audiences versus the computer audience. Conversely, participants highlighted simple perceptual modifications for the computer audience, producing more punctuated and wider ranging motions. This study suggests that people consider differences in their audiences when demonstrating action. PMID- 21585440 TI - Do Humans Really Learn A(n) B(n) Artificial Grammars From Exemplars? AB - An important topic in the evolution of language is the kinds of grammars that can be computed by humans and other animals. Fitch and Hauser (F&H; 2004) approached this question by assessing the ability of different species to learn 2 grammars, (AB)(n) and A(n) B(n) . A(n) B(n) was taken to indicate a phrase structure grammar, eliciting a center-embedded pattern. (AB)(n) indicates a grammar whose strings entail only local relations between the categories of constituents. F&H's data suggest that humans, but not tamarin monkeys, learn an A(n) B(n) grammar, whereas both learn a simpler (AB)(n) grammar (Fitch & Hauser, 2004). In their experiments, the A constituents were syllables pronounced by a female voice, whereas the B constituents were syllables pronounced by a male voice. This study proposes that what characterizes the A(n) B(n) exemplars is the distributional regularities of the syllables pronounced by either a male or a female rather than the underlying, more abstract patterns. This article replicates F&H's data and reports new controls using either categories similar to those in F&H or less salient ones. This article shows that distributional regularities explain the data better than grammar learning. Indeed, when familiarized with A(n) B(n) exemplars, participants failed to discriminate A(3) B(2) and A(2) B(3) from A(n) B(n) items, missing the crucial feature that the number of As must equal the number of Bs. Therefore, contrary to F&H, this study concludes that no syntactic rules implementing embedded nonadjacent dependencies were learned in these experiments. The difference between human linguistic abilities and the putative precursors in monkeys deserves further exploration. PMID- 21585441 TI - The relative success of recognition-based inference in multichoice decisions. AB - The utility of an "ecologically rational" recognition-based decision rule in multichoice decision problems is analyzed, varying the type of judgment required (greater or lesser). The maximum size and range of a counterintuitive advantage associated with recognition-based judgment (the "less-is-more effect") is identified for a range of cue validity values. Greater ranges of the less-is-more effect occur when participants are asked which is the greatest of m choices (m > 2) than which is the least. Less-is-more effects also have greater range for larger values of m. This implies that the classic two-alternative forced choice task, as studied by Goldstein and Gigerenzer (2002), may not be the most appropriate test case for less-is-more effects. PMID- 21585442 TI - The relation between essentialist beliefs and evolutionary reasoning. AB - Historians of science have pointed to essentialist beliefs about species as major impediments to the discovery of natural selection. The present study investigated whether such beliefs are impediments to learning this concept as well. Participants (43 children aged 4-9 and 34 adults) were asked to judge the variability of various behavioral and anatomical properties across different members of the same species. Adults who accepted within-species variation-both actual and potential-were significantly more likely to demonstrate a selection based understanding of evolution than adults who denied within-species variation. The latter demonstrated an alternative, incorrect understanding of evolution and produced response patterns that were both quantitatively and qualitatively similar to those produced by preschool-aged children. Overall, it is argued that psychological essentialism, although a useful bias for drawing species-wide inductions, leads individuals to devalue within-species variation and, consequently, to fail to understand natural selection. PMID- 21585443 TI - Moving to the speed of sound: context modulation of the effect of acoustic properties of speech. AB - Suprasegmental acoustic patterns in speech can convey meaningful information and affect listeners' interpretation in various ways, including through systematic analog mapping of message-relevant information onto prosody. We examined whether the effect of analog acoustic variation is governed by the acoustic properties themselves. For example, fast speech may always prime the concept of speed or a faster response. Alternatively, the effect may be modulated by the context dependent interpretation of those properties; the effect of rate may depend on how listeners construe its meaning in the immediate linguistic or communicative context. In two experiments, participants read short scenarios that implied, or did not imply, urgency. Scenarios were followed by recorded instructions, spoken at varying rates. The results show that speech rate had an effect on listeners' response speed; however, this effect was modulated by discourse context. Speech rate affected response speed following contexts that emphasized speed, but not without such contextual information. PMID- 21585444 TI - Zipf's Law and Avoidance of Excessive Synonymy. AB - Zipf's law states that if words of language are ranked in the order of decreasing frequency in texts, the frequency of a word is inversely proportional to its rank. It is very reliably observed in the data, but to date it escaped satisfactory theoretical explanation. This article suggests that Zipf's law may result from a hierarchical organization of word meanings over the semantic space, which in turn is generated by the evolution of word semantics dominated by expansion of meanings and competition of synonyms. A study of the frequency of partial synonyms in Russian provides experimental evidence for the hypothesis that word frequency is determined by semantics. PMID- 21585445 TI - Spatial reasoning with external visualizations: what matters is what you see, not whether you interact. AB - Three experiments examined the effects of interactive visualizations and spatial abilities on a task requiring participants to infer and draw cross sections of a three-dimensional (3D) object. The experiments manipulated whether participants could interactively control a virtual 3D visualization of the object while performing the task, and compared participants who were allowed interactive control of the visualization to those who were not allowed control. In Experiment 1, interactivity produced better performance than passive viewing, but the advantage of interactivity disappeared in Experiment 2 when visual input for the two conditions in a yoked design was equalized. In Experiments 2 and 3, differences in how interactive participants manipulated the visualization were large and related to performance. In Experiment 3, non-interactive participants who watched optimal movements of the display performed as well as interactive participants who manipulated the visualization effectively and better than interactive participants who manipulated the visualization ineffectively. Spatial ability made an independent contribution to performance on the spatial reasoning task, but did not predict patterns of interactive behavior. These experiments indicate that providing participants with active control of a computer visualization does not necessarily enhance task performance, whereas seeing the most task-relevant information does, and this is true regardless of whether the task-relevant information is obtained actively or passively. PMID- 21585446 TI - Optimal predictions in everyday cognition: the wisdom of individuals or crowds? AB - Griffiths and Tenenbaum (2006) asked individuals to make predictions about the duration or extent of everyday events (e.g., cake baking times), and reported that predictions were optimal, employing Bayesian inference based on veridical prior distributions. Although the predictions conformed strikingly to statistics of the world, they reflect averages over many individuals. On the conjecture that the accuracy of the group response is chiefly a consequence of aggregating across individuals, we constructed simple, heuristic approximations to the Bayesian model premised on the hypothesis that individuals have access merely to a sample of k instances drawn from the relevant distribution. The accuracy of the group response reported by Griffiths and Tenenbaum could be accounted for by supposing that individuals each utilize only two instances. Moreover, the variability of the group data is more consistent with this small-sample hypothesis than with the hypothesis that people utilize veridical or nearly veridical representations of the underlying prior distributions. Our analyses lead to a qualitatively different view of how individuals reason from past experience than the view espoused by Griffiths and Tenenbaum. PMID- 21585447 TI - Computer simulations of developmental change: the contributions of working memory capacity and long-term knowledge. AB - Increasing working memory (WM) capacity is often cited as a major influence on children's development and yet WM capacity is difficult to examine independently of long-term knowledge. A computational model of children's nonword repetition (NWR) performance is presented that independently manipulates long-term knowledge and WM capacity to determine the relative contributions of each in explaining the developmental data. The simulations show that (a) both mechanisms independently cause the same overall developmental changes in NWR performance, (b) increase in long-term knowledge provides the better fit to the child data, and (c) varying both long-term knowledge and WM capacity adds no significant gains over varying long-term knowledge alone. Given that increases in long-term knowledge must occur during development, the results indicate that increases in WM capacity may not be required to explain developmental differences. An increase in WM capacity should only be cited as a mechanism of developmental change when there are clear empirical reasons for doing so. PMID- 21585448 TI - Space between languages. AB - What aspects of spatial relations influence speakers' choice of locative? This article presents a study of static spatial descriptions from 24 languages. The study reveals two kinds of spatial terms evident cross-linguistically: specific spatial terms and general spatial terms (GSTs). Whereas specific spatial terms including English prepositions-occur in a limited range of situations, with concomitant specificity in their meaning, GSTs occur in all spatial descriptions (in languages that employ them). Because of the extreme differences in range of application, the two are considered separately. A multidimensional scaling analysis is used with specific spatial terms to extract statistically valid similarities across the languages sampled. For GSTs, which have not been previously analyzed in the literature, a semantic analysis is proposed and experimentally validated. The results suggest the importance of geometry, function, and qualitative physics to the meanings of both kinds of spatial terms, although the details differ. PMID- 21585449 TI - Body parts and early-learned verbs. AB - This article reports the structure of associations among 101 common verbs and body parts. The verbs are those typically learned by children learning English prior to 3 years of age. In a free association task, 50 adults were asked to provide the single body part that came to mind when they thought of each verb. Analyses reveal highly systematic and structured patterns of associations that are also related to the normative age of acquisition of the verbs showing a progression from verbs associated with actions by the mouth, to verbs strongly associated with actions by hand and arm, to verbs not so strongly associated with any one body part. The results have implications for proposals about embodied verb meaning and also for processes of early verb learning. PMID- 21585450 TI - The Pervasiveness of 1/f Scaling in Speech Reflects the Metastable Basis of Cognition. AB - Human neural and behavioral activities have been reported to exhibit fractal dynamics known as 1/f noise, which is more aptly named 1/f scaling. Some argue that 1/f scaling is a general and pervasive property of the dynamical substrate from which cognitive functions are formed. Others argue that it is an idiosyncratic property of domain-specific processes. An experiment was conducted to investigate whether 1/f scaling pervades the intrinsic fluctuations of a spoken word. Ten participants each repeated the word bucket over 1,000 times, and fluctuations in acoustic measurements across repetitions generally followed the 1/f scaling relation, including numerous parallel yet distinct series of 1/f fluctuations. On the basis of work showing that 1/f scaling is a universal earmark of metastability, it is proposed that the observed pervasiveness of 1/f fluctuations in speech reflects the fact that cognitive functions are formed as metastable patterns of activity in brain, body, and environment. PMID- 21585451 TI - Interpreting Pitch Accents in Online Comprehension: H* vs. L+H*. AB - Although the presence or absence of a pitch accent clearly can play an important role in signaling the discourse and information structure of an utterance, whether the form of an accent determines the type of information it conveys is more controversial. We used an eye-tracking paradigm to investigate whether H*, which has been argued to signal new information, evokes different eye fixations than L+H*, which has been argued to signal the presence of contrast. Our results demonstrate that although listeners interpret these accents differently, their interpretive domains overlap. L+H* creates a strong bias toward contrast referents whereas H* is compatible with both new and contrast referents. PMID- 21585452 TI - Introduction to the special issue. PMID- 21585453 TI - A survey of model evaluation approaches with a tutorial on hierarchical bayesian methods. AB - This article reviews current methods for evaluating models in the cognitive sciences, including theoretically based approaches, such as Bayes factors and minimum description length measures; simulation approaches, including model mimicry evaluations; and practical approaches, such as validation and generalization measures. This article argues that, although often useful in specific settings, most of these approaches are limited in their ability to give a general assessment of models. This article argues that hierarchical methods, generally, and hierarchical Bayesian methods, specifically, can provide a more thorough evaluation of models in the cognitive sciences. This article presents two worked examples of hierarchical Bayesian analyses to demonstrate how the approach addresses key questions of descriptive adequacy, parameter interference, prediction, and generalization in principled and coherent ways. PMID- 21585454 TI - Measuring model flexibility with parameter space partitioning: an introduction and application example. AB - A primary criterion on which models of cognition are evaluated is their ability to fit empirical data. To understand the reason why a model yields a good or poor fit, it is necessary to determine the data-fitting potential (i.e., flexibility) of the model. In the first part of this article, methods for comparing models and studying their flexibility are reviewed, with a focus on parameter space partitioning (PSP), a general-purpose method for analyzing and comparing all classes of cognitive models. PSP is then demonstrated in the second part of the article in which two connectionist models of speech perception (TRACE and ARTphone) are compared to learn how design differences affect model flexibility. PMID- 21585455 TI - Ability, breadth, and parsimony in computational models of higher-order cognition. AB - Computational models will play an important role in our understanding of human higher-order cognition. How can a model's contribution to this goal be evaluated? This article argues that three important aspects of a model of higher-order cognition to evaluate are (a) its ability to reason, solve problems, converse, and learn as well as people do; (b) the breadth of situations in which it can do so; and (c) the parsimony of the mechanisms it posits. This article argues that fits of models to quantitative experimental data, although valuable for other reasons, do not address these criteria. Further, using analogies with other sciences, the history of cognitive science, and examples from modern-day research programs, this article identifies five activities that have been demonstrated to play an important role in our understanding of human higher-order cognition. These include modeling within a cognitive architecture, conducting artificial intelligence research, measuring and expanding a model's ability, finding mappings between the structure of different domains, and attempting to explain multiple phenomena within a single model. PMID- 21585456 TI - Using FMRI to test models of complex cognition. AB - This article investigates the potential of fMRI to test assumptions about different components in models of complex cognitive tasks. If the components of a model can be associated with specific brain regions, one can make predictions for the temporal course of the BOLD response in these regions. An event-locked procedure is described for dealing with temporal variability and bringing model runs and individual data trials into alignment. Statistical methods for testing the model are described that deal with the scan-to-scan correlations in the errors of measurement of the BOLD signal. This approach is illustrated using a "sacrificial" ACT-R model that involves mapping 6 modules onto 6 brain regions in an experiment from Ravizza, Anderson, and Carter (in press) concerned with equation solving. The model's visual encoding predicted the BOLD response in the fusiform gyrus, its controlled retrieval predicted the BOLD response in the lateral inferior prefrontal cortex, and its subgoal setting predicted the BOLD response in the anterior cingulate cortex. On the other hand, its motor programming failed to predict anticipatory activation in the motor cortex, its representational changes failed to predicted the pattern of activity in the posterior parietal cortex, and its procedural component failed to predict an initial spike in caudate. The results illustrate the power of such data to direct the development of a theory of complex problem solving, both at the level of a specific task model as well as at the level of the cognitive architecture. PMID- 21585457 TI - Parameters, Predictions, and Evidence in Computational Modeling: A Statistical View Informed by ACT-R. AB - Model validation in computational cognitive psychology often relies on methods drawn from the testing of theories in experimental physics. However, applications of these methods to computational models in typical cognitive experiments can hide multiple, plausible sources of variation arising from human participants and from stochastic cognitive theories, encouraging a "model fixed, data variable" paradigm that makes it difficult to interpret model predictions and to account for individual differences. This article proposes a likelihood-based, "data fixed, model variable" paradigm in which models are treated as stochastic processes in experiments with participant-to-participant variation that can be applied to a broad range of mechanistic cognitive architectures. This article discusses the implementation and implications of this view in model validation, with a concrete focus on a simple class of ACT-R models of cognition. This article is not intended as a recipe for broad application of these preliminary, proof-of-concept methods, but as a framework for communication between statisticians searching for interesting problems in the cognitive modeling sphere, and cognitive modelers interested in generalizing from deterministic to stochastic model validation, in the face of random variation in human experimental data. PMID- 21585458 TI - Comparison of decision learning models using the generalization criterion method. AB - It is a hallmark of a good model to make accurate a priori predictions to new conditions (Busemeyer & Wang, 2000). This study compared 8 decision learning models with respect to their generalizability. Participants performed 2 tasks (the Iowa Gambling Task and the Soochow Gambling Task), and each model made a priori predictions by estimating the parameters for each participant from 1 task and using those same parameters to predict on the other task. Three methods were used to evaluate the models at the individual level of analysis. The first method used a post hoc fit criterion, the second method used a generalization criterion for short-term predictions, and the third method again used a generalization criterion for long-term predictions. The results suggest that the models with the prospect utility function can make generalizable predictions to new conditions, and different learning models are needed for making short-versus long-term predictions on simple gambling tasks. PMID- 21585460 TI - Acknowledgment: guest reviewers. PMID- 21585459 TI - Exemplars, prototypes, similarities, and rules in category representation: an example of hierarchical bayesian analysis. AB - This article demonstrates the potential of using hierarchical Bayesian methods to relate models and data in the cognitive sciences. This is done using a worked example that considers an existing model of category representation, the Varying Abstraction Model (VAM), which attempts to infer the representations people use from their behavior in category learning tasks. The VAM allows for a wide variety of category representations to be inferred, but this article shows how a hierarchical Bayesian analysis can provide a unifying explanation of the representational possibilities using 2 parameters. One parameter controls the emphasis on abstraction in category representations, and the other controls the emphasis on similarity. Using 30 previously published data sets, this work shows how inferences about these parameters, and about the category representations they generate, can be used to evaluate data in terms of the ongoing exemplar versus prototype and similarity versus rules debates in the literature. Using this concrete example, this article emphasizes the advantages of hierarchical Bayesian models in converting model selection problems to parameter estimation problems, and providing one way of specifying theoretically based priors for competing models. PMID- 21585461 TI - The repetition-break plot structure: a cognitive influence on selection in the marketplace of ideas. AB - Using research into learning from sequences of examples, we generate predictions about what cultural products become widely distributed in the social marketplace of ideas. We investigate what we term the Repetition-Break plot structure: the use of repetition among obviously similar items to establish a pattern, and then a final contrasting item that breaks with the pattern to generate surprise. Two corpus studies show that this structure arises in about a third of folktales and story jokes. An experiment shows that jokes with this structure are more interesting than those without the initial repetition. Thus, we document evidence for how a cognitive factor influences the cultural products that are selected in the marketplace of ideas. PMID- 21585462 TI - A causal model theory of the meaning of cause, enable, and prevent. AB - The verbs cause, enable, and prevent express beliefs about the way the world works. We offer a theory of their meaning in terms of the structure of those beliefs expressed using qualitative properties of causal models, a graphical framework for representing causal structure. We propose that these verbs refer to a causal model relevant to a discourse and that "A causes B" expresses the belief that the causal model includes a link from A to B. "A enables/allows B" entails that the model includes a link from A to B, that A represents a category of events necessary for B, and that an alternative cause of B exists. "A prevents B" entails that the model includes a link from A to B and that A reduces the likelihood of B. This theory is able to account for the results of four experiments as well as a variety of existing data on human reasoning. PMID- 21585463 TI - Language encodes geographical information. AB - Population counts and longitude and latitude coordinates were estimated for the 50 largest cities in the United States by computational linguistic techniques and by human participants. The mathematical technique Latent Semantic Analysis applied to newspaper texts produced similarity ratings between the 50 cities that allowed for a multidimensional scaling (MDS) of these cities. MDS coordinates correlated with the actual longitude and latitude of these cities, showing that cities that are located together share similar semantic contexts. This finding was replicated using a first-order co-occurrence algorithm. The computational estimates of geographical location as well as population were akin to human estimates. These findings show that language encodes geographical information that language users in turn may use in their understanding of language and the world. PMID- 21585464 TI - Lexically restricted utterances in Russian, german, and english child-directed speech. AB - This study investigates the child-directed speech (CDS) of four Russian-, six German, and six English-speaking mothers to their 2-year-old children. Typologically Russian has considerably less restricted word order than either German or English, with German showing more word-order variants than English. This could lead to the prediction that the lexical restrictiveness previously found in the initial strings of English CDS by Cameron-Faulkner, Lieven, and Tomasello (2003) would not be found in Russian or German CDS. However, despite differences between the three corpora that clearly derive from typological differences between the languages, the most significant finding of this study is a high degree of lexical restrictiveness at the beginnings of CDS utterances in all three languages. PMID- 21585465 TI - Sunk-cost effects on purely behavioral investments. AB - Although the sunk-cost effect is a well-documented psychological phenomenon in monetary investments, existing literature investigating behavioral investments (e.g., time, effort) has not replicated this effect except when such investments relate to monetary values. The current explanation for this discrepancy proposes that purely behavioral sunk-cost effects are unlikely to be observed because they are difficult to book, track, and balance in a mental account. Conversely, we argue that, through an effort-justification mechanism, people account for the amount of behavioral resources invested when selecting an alternative, in which case they may fall prey to purely behavioral sunk-cost effects. The results of two experiments support this prediction. Because many decisions involve behavioral investments, behavioral sunk-cost effects should be pervasive psychological phenomena. PMID- 21585466 TI - The semantics of prosody: acoustic and perceptual evidence of prosodic correlates to word meaning. AB - This investigation examined whether speakers produce reliable prosodic correlates to meaning across semantic domains and whether listeners use these cues to derive word meaning from novel words. Speakers were asked to produce phrases in infant directed speech in which novel words were used to convey one of two meanings from a set of antonym pairs (e.g., big/small). Acoustic analyses revealed that some acoustic features were correlated with overall valence of the meaning. However, each word meaning also displayed a unique acoustic signature, and semantically related meanings elicited similar acoustic profiles. In two perceptual tests, listeners either attempted to identify the novel words with a matching meaning dimension (picture pair) or with mismatched meaning dimensions. Listeners inferred the meaning of the novel words significantly more often when prosody matched the word meaning choices than when prosody mismatched. These findings suggest that speech contains reliable prosodic markers to word meaning and that listeners use these prosodic cues to differentiate meanings. That prosody is semantic suggests a reconceptualization of traditional distinctions between linguistic and nonlinguistic properties of spoken language. PMID- 21585467 TI - Probabilistically Valid Inference of Covariation From a Single x,y Observation When Univariate Characteristics Are Known. AB - Participants were asked to draw inferences about correlation from single x,y observations. In Experiment 1 statistically sophisticated participants were given the univariate characteristics of distributions of x and y and asked to infer whether a single x, y observation came from a correlated or an uncorrelated population. In Experiment 2, students with a variety of statistical backgrounds assigned posterior probabilities to five possible populations based on single x, y observations, again given knowledge of the univariate statistics. In Experiment 3, statistically naive participants were given a problem analogous to that given in Experiment 1, framed verbally. Experiment 4 replicated Experiment 3 but added an "impossible to determine" response option. Models that rely on computing sample correlations make no predictions about these investigations. From a Bayesian perspective, participants' inferences in all four experiments tended to make probabilistically valid inferences as long as the single datum was directional. The results are discussed in light of the Brunswikian notion of vicarious functioning. PMID- 21585468 TI - Computational models for the combination of advice and individual learning. AB - Decision making often takes place in social environments where other actors influence individuals' decisions. The present article examines how advice affects individual learning. Five social learning models combining advice and individual learning-four based on reinforcement learning and one on Bayesian learning-and one individual learning model are tested against each other. In two experiments, some participants received good or bad advice prior to a repeated multioption choice task. Receivers of advice adhered to the advice, so that good advice improved performance. The social learning models described the observed learning processes better than the individual learning model. Of the models tested, the best social learning model assumes that outcomes from recommended options are more positively evaluated than outcomes from nonrecommended options. This model correctly predicted that receivers first adhere to advice, then explore other options, and finally return to the recommended option. The model also predicted accurately that good advice has a stronger impact on learning than bad advice. One-time advice can have a long-lasting influence on learning by changing the subjective evaluation of outcomes of recommended options. PMID- 21585469 TI - Similarity and rules United: similarity- and rule-based processing in a single neural network. AB - A central controversy in cognitive science concerns the roles of rules versus similarity. To gain some leverage on this problem, we propose that rule- versus similarity-based processes can be characterized as extremes in a multidimensional space that is composed of at least two dimensions: the number of features (Pothos, 2005) and the physical presence of features. The transition of similarity- to rule-based processing is conceptualized as a transition in this space. To illustrate this, we show how a neural network model uses input features (and in this sense produces similarity-based responses) when it has a low learning rate or in the early phases of training, but it switches to using self generated, more abstract features (and in this sense produces rule-based responses) when it has a higher learning rate or is in the later phases of training. Relations with categorization and the psychology of learning are pointed out. PMID- 21585470 TI - Lexical and sublexical units in speech perception. AB - Saffran, Newport, and Aslin (1996a) found that human infants are sensitive to statistical regularities corresponding to lexical units when hearing an artificial spoken language. Two sorts of segmentation strategies have been proposed to account for this early word-segmentation ability: bracketing strategies, in which infants are assumed to insert boundaries into continuous speech, and clustering strategies, in which infants are assumed to group certain speech sequences together into units (Swingley, 2005). In the present study, we test the predictions of two computational models instantiating each of these strategies i.e., Serial Recurrent Networks: Elman, 1990; and Parser: Perruchet & Vinter, 1998 in an experiment where we compare the lexical and sublexical recognition performance of adults after hearing 2 or 10 min of an artificial spoken language. The results are consistent with Parser's predictions and the clustering approach, showing that performance on words is better than performance on part-words only after 10 min. This result suggests that word segmentation abilities are not merely due to stronger associations between sublexical units but to the emergence of stronger lexical representations during the development of speech perception processes. PMID- 21585471 TI - The role of moral commitments in moral judgment. AB - Traditional approaches to moral psychology assumed that moral judgments resulted from the application of explicit commitments, such as those embodied in consequentialist or deontological philosophies. In contrast, recent work suggests that moral judgments often result from unconscious or emotional processes, with explicit commitments generated post hoc. This paper explores the intermediate position that moral commitments mediate moral judgments, but not through their explicit and consistent application in the course of judgment. An experiment with 336 participants finds that individuals vary in the extent to which their moral commitments are consequentialist or deontological, and that this variation is systematically but imperfectly related to the moral judgments elicited by trolley car problems. Consequentialist participants find action in trolley car scenarios more permissible than do deontologists, and only consequentialists moderate their judgments when scenarios that typically elicit different intuitions are presented side by side. The findings emphasize the need for a theory of moral reasoning that can accommodate both the associations and dissociations between moral commitments and moral judgments. PMID- 21585472 TI - Indirect evidence and the poverty of the stimulus: the case of anaphoric one. AB - It is widely held that children's linguistic input underdetermines the correct grammar, and that language learning must therefore be guided by innate linguistic constraints. Here, we show that a Bayesian model can learn a standard poverty-of stimulus example, anaphoric one, from realistic input by relying on indirect evidence, without a linguistic constraint assumed to be necessary. Our demonstration does, however, assume other linguistic knowledge; thus, we reduce the problem of learning anaphoric one to that of learning this other knowledge. We discuss whether this other knowledge may itself be acquired without linguistic constraints. PMID- 21585473 TI - Causal-based property generalization. AB - A central question in cognitive research concerns how new properties are generalized to categories. This article introduces a model of how generalizations involve a process of causal inference in which people estimate the likely presence of the new property in individual category exemplars and then the prevalence of the property among all category members. Evidence in favor of this causal-based generalization (CBG) view included effects of an existing feature's base rate (Experiment 1), the direction of the causal relations (Experiments 2 and 4), the number of those relations (Experiment 3), and the distribution of features among category members (Experiments 4 and 5). The results provided no support for an alternative view that generalizations are promoted by the centrality of the to-be-generalized feature. However, there was evidence that a minority of participants based their judgments on simpler associative reasoning processes. PMID- 21585474 TI - An empirical and computational investigation of perceiving and remembering event temporal relations. AB - Events have beginnings, ends, and often overlap in time. A major question is how perceivers come to parse a stream of multimodal information into meaningful units and how different event boundaries may vary event processing. This work investigates the roles of these three types of event boundaries in constructing event temporal relations. Predictions were made based on how people would err according to the beginning state, end state, and overlap heuristic hypotheses. Participants viewed animated events that include all the logical possibilities of event temporal relations, and then made temporal relation judgments. The results showed that people make use of the overlap between events and take into account the ends and beginnings, but they weight ends more than beginnings. Neural network simulations showed a self-organized distinction when learning temporal relations between events with overlap versus those without. PMID- 21585475 TI - Argumentation and Explanation in Conceptual Change: Indications From Protocol Analyses of Peer-to-Peer Dialog. AB - In this paper we attempt to identify which peer collaboration characteristics may be accountable for conceptual change through interaction. We focus on different socio-cognitive aspects of the peer dialog and relate these with learning gains on the dyadic as well as the individual level. The scientific topic that was used for this study concerns natural selection, a topic for which students' intuitive conceptions have been shown to be particularly robust. Learning tasks were designed according to the socio-cognitive conflict instructional paradigm. After receiving a short instructional intervention on natural selection, paired students were asked to collaboratively construct explanations for certain evolutionary phenomena while engaging in dialectical argumentation. Two quantitative coding schemes were developed, each with a different granularity. The first assessed discrete dialog moves that pertained to dialectical argumentation and to consensual explanation development. The second scheme characterized the dialog as a whole on a number of socio-cognitive dimensions. Results from analyses on the dyadic as well as the individual level revealed that the engagement in dialectical argumentation predicted conceptual learning gains, whereas consensual explanation development did not. These findings open up new venues for research on the mechanisms of learning in and from peer collaboration. PMID- 21585476 TI - Representation of principled connections: a window onto the formal aspect of common sense conception. AB - Nominal concepts represent things as tokens of types. Recent research suggests that we represent principled connections between the type of thing something is (e.g., DOG) and some of its properties (k-properties; e.g., having four legs for dogs) but not other properties (t-properties; e.g., being brown for dogs). Principled connections differ from logical, statistical, and causal connections. Principled connections license (i) the expectation that tokens of the type will generally possess their k-properties, (ii) formal explanations (i.e., explanation of the presence of k-properties in tokens of a type by reference to the type of thing it is), and (iii) normative expectations concerning the presence of k properties in tokens of the type. The present paper investigates the hypothesis that representing principled connections requires representing properties as aspects of being the relevant kind of thing (Aspect Hypothesis). Experiment 1 provides a direct test of the Aspect Hypothesis. Experiments 2 and 3 provide indirect tests of the Aspect Hypothesis. All three experiments provide support for the Aspect Hypothesis. Experiment 4 investigates a prediction of the Aspect Hypothesis concerning the manner in which formal explanations are licensed by principled connections. Finally, Experiment 5 investigates a prediction of the Aspect Hypothesis concerning the nature of the normative expectations licensed by principled connections. Together these results provide strong evidence for the idea that representing principled connections involves representing a property as being an aspect of being a given kind of thing. The results also help clarify the manner in which formal explanation differs from other modes of explanation. Finally, the results of the experiments are used to motivate a proposal concerning the formal structure of the conceptual representations implicated by principled connections. This structure provides a domain-general way of structuring our concepts and embodies the perspective we take when we think and talk of things as being instances of a kind. PMID- 21585477 TI - Learning to attend: a connectionist model of situated language comprehension. AB - Evidence from numerous studies using the visual world paradigm has revealed both that spoken language can rapidly guide attention in a related visual scene and that scene information can immediately influence comprehension processes. These findings motivated the coordinated interplay account (Knoeferle & Crocker, 2006) of situated comprehension, which claims that utterance-mediated attention crucially underlies this closely coordinated interaction of language and scene processing. We present a recurrent sigma-pi neural network that models the rapid use of scene information, exploiting an utterance-mediated attentional mechanism that directly instantiates the CIA. The model is shown to achieve high levels of performance (both with and without scene contexts), while also exhibiting hallmark behaviors of situated comprehension, such as incremental processing, anticipation of appropriate role fillers, as well as the immediate use, and priority, of depicted event information through the coordinated use of utterance mediated attention to the scene. PMID- 21585478 TI - Fishing for the right words: decision rules for human foraging behavior in internal search tasks. AB - Animals depleting one patch of resources must decide when to leave and switch to a fresh patch. Foraging theory has predicted various decision mechanisms; which is best depends on environmental variation in patch quality. Previously we tested whether these mechanisms underlie human decision making when foraging for external resources; here we test whether humans behave similarly in a cognitive task seeking internally generated solutions. Subjects searched for meaningful words made from random letter sequences, and as their success rate declined, they could opt to switch to a fresh sequence. As in the external foraging context, time since the previous success and the interval preceding it had a major influence on when subjects switched. Subjects also used the commonness of sequence letters as a proximal cue to patch quality that influenced when to switch. Contrary to optimality predictions, switching decisions were independent of whether sequences differed little or widely in quality. PMID- 21585480 TI - Introduction to the 2007 rumelhart prize special issue honoring jeff elman. PMID- 21585479 TI - Exploration and exploitation during sequential search. AB - When we learn how to throw darts we adjust how we throw based on where the darts stick. Much of skill learning is computationally similar in that we learn using feedback obtained after the completion of individual actions. We can formalize such tasks as a search problem; among the set of all possible actions, find the action that leads to the highest reward. In such cases our actions have two objectives: we want to best utilize what we already know (exploitation), but we also want to learn to be more successful in the future (exploration). Here we tested how participants learn movement trajectories where feedback is provided as a monetary reward that depends on the chosen trajectory. We mathematically derived the optimal search policy for our experiment using decision theory. The search behavior of participants is well predicted by an ideal searcher model that optimally combines exploration and exploitation. PMID- 21585481 TI - Lexical organization and competition in first and second languages: computational and neural mechanisms. AB - How does a child rapidly acquire and develop a structured mental organization for the vast number of words in the first years of life? How does a bilingual individual deal with the even more complicated task of learning and organizing two lexicons? It is only until recently have we started to examine the lexicon as a dynamical system with regard to its acquisition, representation, and organization. In this article, I outline a proposal based on our research that takes the dynamical approach to the lexicon, and I discuss how this proposal can be applied to account for lexical organization, structural representation, and competition within and between languages. In particular, I provide computational evidence based on the DevLex model, a self-organizing neural network model, and neuroimaging evidence based on functional magnetic resonance imaging (fMRI) studies, to illustrate how children and adults learn and represent the lexicon in their first and second languages. In the computational research, our goal has been to identify, through linguistically and developmentally realistic models, detailed cognitive mechanisms underlying the dynamic self-organizing processes in monolingual and bilingual lexical development; in the neuroimaging research, our goal has been to identify the neural substrates that subserve lexical organization and competition in the monolingual and the bilingual brain. In both cases, our findings lead to a better understanding of the interactive dynamics involved in the acquisition and representation of one or multiple languages. PMID- 21585482 TI - Labels as features (not names) for infant categorization: a neurocomputational approach. AB - A substantial body of experimental evidence has demonstrated that labels have an impact on infant categorization processes. Yet little is known regarding the nature of the mechanisms by which this effect is achieved. We distinguish between two competing accounts: supervised name-based categorization and unsupervised feature-based categorization. We describe a neurocomputational model of infant visual categorization, based on self-organizing maps, that implements the unsupervised feature-based approach. The model successfully reproduces experiments demonstrating the impact of labeling on infant visual categorization reported in Plunkett, Hu, and Cohen (2008). It mimics infant behavior in both the familiarization and testing phases of the procedure, using a training regime that involves only single presentations of each stimulus and using just 24 participant networks per experiment. The model predicts that the observed behavior in infants is due to a transient form of learning that might lead to the emergence of hierarchically organized categorical structure and that the impact of labels on categorization is influenced by the perceived similarity and the sequence in which the objects are presented. The results suggest that early in development, say before 12 months old, labels need not act as invitations to form categories nor highlight the commonalities between objects, but they may play a more mundane but nevertheless powerful role as additional features that are processed in the same fashion as other features that characterize objects and object categories. PMID- 21585483 TI - Explanatory pluralism in cognitive science. AB - This brief commentary has three goals. The first is to argue that "framework debate" in cognitive science is unresolvable. The idea that one theory or framework can singly account for the vast complexity and variety of cognitive processes seems unlikely if not impossible. The second goal is a consequence of this: We should consider how the various theories on offer work together in diverse contexts of investigation. A final goal is to supply a brief review for readers who are compelled by these points to explore existing literature on the topic. Despite this literature, pluralism has garnered very little attention from broader cognitive science. We end by briefly considering what it might mean for theoretical cognitive science. PMID- 21585484 TI - They do what they are told to do: the influence of instruction on (chess) expert perception-commentary on linhares and brum (2007). AB - Linhares and Brum (2007) argue that they provide evidence for analogy as the main principle behind experts' acquisition of perceptual knowledge. However, the methodology they used-asking players to pair positions using abstract similarity raises the possibility that the task reflects more the effect of directional instructions than the principles underlying the acquisition of knowledge. Here we replicate and extend Linhares and Brum's experiment and show that the matching task they used is inadequate for drawing any conclusions about the nature of experts' perception. When expert chess players were instructed to match problems based on similarities at the abstract level (analogy), they produced more abstract pairs than pairs based on concrete similarity. However, the same experts produced more concrete pairs than abstract ones when instructed to match the problems based on concrete similarity. Asking experts to match problems using explicit instructions is not an appropriate way to show the importance of either analogy or similarity in the acquisition of expert knowledge. Experts simply do what they are told to do. PMID- 21585485 TI - How can experts see the invisible? Reply to bilalic and gobet. AB - Experts in all fields are able to see what is invisible to others. Experts are also able to see what is visible to all-and this is explored by Bilalic and Gobet. We question the method of normalizing all subjects in an experimental condition, and asking experts to behave as if they were novices. We claim that method leads Bilalic and Gobet to a nonsequitur. PMID- 21585486 TI - From exemplar to grammar: a probabilistic analogy-based model of language learning. AB - While rules and exemplars are usually viewed as opposites, this paper argues that they form end points of the same distribution. By representing both rules and exemplars as (partial) trees, we can take into account the fluid middle ground between the two extremes. This insight is the starting point for a new theory of language learning that is based on the following idea: If a language learner does not know which phrase-structure trees should be assigned to initial sentences, s/he allows (implicitly) for all possible trees and lets linguistic experience decide which is the "best" tree for each sentence. The best tree is obtained by maximizing "structural analogy" between a sentence and previous sentences, which is formalized by the most probable shortest combination of subtrees from all trees of previous sentences. Corpus-based experiments with this model on the Penn Treebank and the Childes database indicate that it can learn both exemplar-based and rule-based aspects of language, ranging from phrasal verbs to auxiliary fronting. By having learned the syntactic structures of sentences, we have also learned the grammar implicit in these structures, which can in turn be used to produce new sentences. We show that our model mimicks children's language development from item-based constructions to abstract constructions, and that the model can simulate some of the errors made by children in producing complex questions. PMID- 21585487 TI - A probabilistic model of semantic plausibility in sentence processing. AB - Experimental research shows that human sentence processing uses information from different levels of linguistic analysis, for example, lexical and syntactic preferences as well as semantic plausibility. Existing computational models of human sentence processing, however, have focused primarily on lexico-syntactic factors. Those models that do account for semantic plausibility effects lack a general model of human plausibility intuitions at the sentence level. Within a probabilistic framework, we propose a wide-coverage model that both assigns thematic roles to verb-argument pairs and determines a preferred interpretation by evaluating the plausibility of the resulting (verb, role, argument) triples. The model is trained on a corpus of role-annotated language data. We also present a transparent integration of the semantic model with an incremental probabilistic parser. We demonstrate that both the semantic plausibility model and the combined syntax/semantics model predict judgment and reading time data from the experimental literature. PMID- 21585488 TI - Multitimescale dynamical interactions between speech rhythm and gesture. AB - Temporal patterns in human movement, and in speech in particular, occur on multiple timescales. Regularities in such patterns have been observed between speech gestures, which are relatively quick movements of articulators (e.g., tongue fronting and lip protrusion), and also between rhythmic units (e.g., syllables and metrical feet), which occur more slowly. Previous work has shown that patterns in both domains can be usefully modeled with oscillatory dynamical systems. To investigate how rhythmic and gestural domains interact, an experiment was conducted in which speakers performed a phrase repetition task, and gestural kinematics were recorded using electromagnetic articulometry. Variance in relative timing of gestural movements was correlated with variance in rhythmic timing, indicating that gestural and rhythmic systems interact in the process of planning and producing speech. A model of rhythmic and gestural planning oscillators with multifrequency coupling is presented, which can simulate the observed covariability between rhythmic and gestural timing. PMID- 21585489 TI - Sleep deprivation and sustained attention performance: integrating mathematical and cognitive modeling. AB - A long history of research has revealed many neurophysiological changes and concomitant behavioral impacts of sleep deprivation, sleep restriction, and circadian rhythms. Little research, however, has been conducted in the area of computational cognitive modeling to understand the information processing mechanisms through which neurobehavioral factors operate to produce degradations in human performance. Our approach to understanding this relationship is to link predictions of overall cognitive functioning, or alertness, from existing biomathematical models to information processing parameters in a cognitive architecture, leveraging the strengths from each to develop a more comprehensive explanation. The integration of these methodologies is used to account for changes in human performance on a sustained attention task across 88 h of total sleep deprivation. The integrated model captures changes due to time awake and circadian rhythms, and it also provides an account for underlying changes in the cognitive processes that give rise to those effects. The results show the potential for developing mechanistic accounts of how fatigue impacts cognition, and they illustrate the increased explanatory power that is possible by combining theoretical insights from multiple methodologies. PMID- 21585490 TI - Cognitive models of choice: comparing decision field theory to the proportional difference model. AB - People often face preferential decisions under risk. To further our understanding of the cognitive processes underlying these preferential choices, two prominent cognitive models, decision field theory (DFT; Busemeyer & Townsend, 1993) and the proportional difference model (PD; Gonzalez-Vallejo, 2002), were rigorously tested against each other. In two consecutive experiments, the participants repeatedly had to choose between monetary gambles. The first experiment provided the reference to estimate the models' free parameters. From these estimations, new gamble pairs were generated for the second experiment such that the two models made maximally divergent predictions. In the first experiment, both models explained the data equally well. However, in the second generalization experiment, the participants' choices were much closer to the predictions of DFT. The results indicate that the stochastic process assumed by DFT, in which evidence in favor of or against each option accumulates over time, described people's choice behavior better than the trade-offs between proportional differences assumed by PD. PMID- 21585491 TI - Do the weak stand a chance? Distribution of resources in a competitive environment. AB - When two agents of unequal strength compete, the stronger one is expected to always win the competition. This expectation is based on the assumption that evaluation of performance is complete, hence flawless. If, however, the agents are evaluated on the basis of only a small sample of their performance, the weaker agent still stands a chance of winning occasionally. A theoretical analysis indicates that, to increase the chance of this happening the weaker agent ought to give up on enough occasions so that he or she can match the stronger agent on the remaining ones. We model such a competition in a game, present its game-theoretic solution, and report an experiment, involving 144 individuals, in which we tested whether players (both weak and strong) are actually sensitive to their relative strengths and know how to allocate their resources accordingly. Our results indicate that they do. PMID- 21585492 TI - Learning harmony: the role of serial statistics. AB - How do listeners learn about the statistical regularities underlying musical harmony? In traditional Western music, certain chords predict the occurrence of other chords: Given a particular chord, not all chords are equally likely to follow. In Experiments 1 and 2, we investigated whether adults make use of statistical information when learning new musical structures. Listeners were exposed to a novel musical system containing phrases generated using an artificial grammar. This new system contained statistical structure quite different from Western tonal music. Our results suggest that learners take advantage of the statistical patterning of chords to acquire new musical structures, similar to learning processes previously observed for language learning. PMID- 21585493 TI - The Wisdom of Individuals: Exploring People's Knowledge About Everyday Events Using Iterated Learning. AB - Determining the knowledge that guides human judgments is fundamental to understanding how people reason, make decisions, and form predictions. We use an experimental procedure called ''iterated learning,'' in which the responses that people give on one trial are used to generate the data they see on the next, to pinpoint the knowledge that informs people's predictions about everyday events (e.g., predicting the total box office gross of a movie from its current take). In particular, we use this method to discriminate between two models of human judgments: a simple Bayesian model (Griffiths & Tenenbaum, 2006) and a recently proposed alternative model that assumes people store only a few instances of each type of event in memory (MinK; Mozer, Pashler, & Homaei, 2008). Although testing these models using standard experimental procedures is difficult due to differences in the number of free parameters and the need to make assumptions about the knowledge of individual learners, we show that the two models make very different predictions about the outcome of iterated learning. The results of an experiment using this methodology provide a rich picture of how much people know about the distributions of everyday quantities, and they are inconsistent with the predictions of the MinK model. The results suggest that accurate predictions about everyday events reflect relatively sophisticated knowledge on the part of individuals. PMID- 21585494 TI - Weighted constraints in generative linguistics. AB - Harmonic Grammar (HG) and Optimality Theory (OT) are closely related formal frameworks for the study of language. In both, the structure of a given language is determined by the relative strengths of a set of constraints. They differ in how these strengths are represented: as numerical weights (HG) or as ranks (OT). Weighted constraints have advantages for the construction of accounts of language learning and other cognitive processes, partly because they allow for the adaptation of connectionist and statistical models. HG has been little studied in generative linguistics, however, largely due to influential claims that weighted constraints make incorrect predictions about the typology of natural languages, predictions that are not shared by the more popular OT. This paper makes the case that HG is in fact a promising framework for typological research, and reviews and extends the existing arguments for weighted over ranked constraints. PMID- 21585495 TI - Perception with compensatory devices: from sensory substitution to sensorimotor extension. AB - Sensory substitution devices provide through an unusual sensory modality (the substituting modality, e.g., audition) access to features of the world that are normally accessed through another sensory modality (the substituted modality, e.g., vision). In this article, we address the question of which sensory modality the acquired perception belongs to. We have recourse to the four traditional criteria that have been used to define sensory modalities: sensory organ, stimuli, properties, and qualitative experience (Grice, 1962), to which we have added the criteria of behavioral equivalence (Morgan, 1977), dedication (Keeley, 2002), and sensorimotor equivalence (O'Regan & Noe, 2001). We discuss which of them are fulfilled by perception through sensory substitution devices and whether this favors the view that perception belongs to the substituting or to the substituted modality. Though the application of a number of criteria might be taken to point to the conclusion that perception with a sensory substitution device belongs to the substituted modality, we argue that the evidence leads to an alternative view on sensory substitution. According to this view, the experience after sensory substitution is a transformation, extension, or augmentation of our perceptual capacities, rather than being something equivalent or reducible to an already existing sensory modality. We develop this view by comparing sensory substitution devices to other "mind-enhancing tools" such as pen and paper, sketchpads, or calculators. An analysis of sensory substitution in terms of mind-enhancing tools unveils it as a thoroughly transforming perceptual experience and as giving rise to a novel form of perceptual interaction with the environment. PMID- 21585496 TI - Building to discover: a common coding model. AB - I present a case study of scientific discovery, where building two functional and behavioral approximations of neurons, one physical and the other computational, led to conceptual and implementation breakthroughs in a neural engineering laboratory. Such building of external systems that mimic target phenomena, and the use of these external systems to generate novel concepts and control structures, is a standard strategy in the new engineering sciences. I develop a model of the cognitive mechanism that connects such built external systems with internal models, and I examine how new discoveries, and consensus on discoveries, could arise from this external-internal coupling and the building process. The model is based on the emerging framework of common coding, which proposes a shared representation in the brain between the execution, perception, and imagination of movement. PMID- 21585497 TI - Specialization effect and its influence on memory and problem solving in expert chess players. AB - Expert chess players, specialized in different openings, recalled positions and solved problems within and outside their area of specialization. While their general expertise was at a similar level, players performed better with stimuli from their area of specialization. The effect of specialization on both recall and problem solving was strong enough to override general expertise-players remembering positions and solving problems from their area of specialization performed at around the level of players 1 standard deviation (SD) above them in general skill. Their problem-solving strategy also changed depending on whether the problem was within their area of specialization. When it was, they searched more in depth and less in breadth; with problems outside their area of specialization, the reverse. The knowledge that comes from familiarity with a problem area is more important than general purpose strategies in determining how an expert will tackle it. These results demonstrate the link in experts between problem solving and memory of specific experiences and indicate that the search for context-independent general purpose problem-solving strategies to teach to future experts is unlikely to be successful. PMID- 21585498 TI - The role of color in human face detection. AB - Significant advances have been made in understanding human face recognition. However, a fundamental aspect of this process, how faces are located in our visual environment, is poorly understood and little studied. Here we examine the role of color in human face detection. We demonstrate that detection performance declines when color information is removed from faces, regardless of whether the surrounding scene context is rendered in color. Furthermore, faces rendered in unnatural colors are hard to detect, suggesting a role beyond simple segmentation. When faces are presented such that half the surface is colored appropriately, and half unnaturally, performance declines. This suggests that observers are not simply using the presence of skin color "patches" to detect faces. Rather, our data suggest that detection operates via a face template combining diagnostic color and face-shape information. These findings are consistent with color-template approaches used in some computer-based face detection systems. PMID- 21585499 TI - Spatial representations elicit dual-coding effects in mental imagery. AB - Spatial aspects of words are associated with their canonical locations in the real world. Yet little research has tested whether spatial associations denoted in language comprehension generalize to their corresponding images. We directly tested the spatial aspects of mental imagery in picture and word processing (Experiment 1). We also tested whether spatial representations of motion words produce similar perceptual-interference effects as demonstrated by object words (Experiment 2). Findings revealed that words denoting an upward spatial location produced slower responses to targets appearing at the top of the display, whereas words denoting a downward spatial location produced slower responses to targets appearing at the bottom of the display. Perceptual-interference effects did not obtain for pictures or for words lacking a spatial relation. These findings provide greater empirical support for the perceptual-symbols system theory (Barsalou, 1999, 2008). PMID- 21585500 TI - Holistic processing is tuned for in-group faces. AB - Past research has found that mere in-group/out-group categorizations are sufficient to elicit biases in face memory. The current research yields novel evidence that mere social categorization is also sufficient to modulate processes underlying face perception, even for faces for which we have strong perceptual expertise: same-race (SR) faces. Using the composite face paradigm, we find that SR faces categorized as in-group members (i.e., fellow university students) are processed more holistically than are SR faces categorized as out-group members (i.e., students at another university). Hence, holding perceptual expertise with faces constant, categorizing an SR target as an out-group member debilitates the strong holistic processing typically observed for SR faces. PMID- 21585501 TI - Learning representations of wordforms with recurrent networks: comment on sibley, kello, plaut, & elman (2008). AB - Sibley et al. (2008) report a recurrent neural network model designed to learn wordform representations suitable for written and spoken word identification. The authors claim that their sequence encoder network overcomes a key limitation associated with models that code letters by position (e.g., CAT might be coded as C-in-position-1, A-in-position-2, T-in-position-3). The problem with coding letters by position (slot-coding) is that it is difficult to generalize knowledge across positions; for example, the overlap between CAT and TOMCAT is lost. Although we agree this is a critical problem with many slot-coding schemes, we question whether the sequence encoder model addresses this limitation, and we highlight another deficiency of the model. We conclude that alternative theories are more promising. PMID- 21585502 TI - Solving geometric analogy problems through two-stage analogical mapping. AB - Evans' 1968 ANALOGY system was the first computer model of analogy. This paper demonstrates that the structure mapping model of analogy, when combined with high level visual processing and qualitative representations, can solve the same kinds of geometric analogy problems as were solved by ANALOGY. Importantly, the bulk of the computations are not particular to the model of this task but are general purpose: We use our existing sketch understanding system, CogSketch, to compute visual structure that is used by our existing analogical matcher, Structure Mapping Engine (SME). We show how SME can be used to facilitate high-level visual matching, proposing a role for structural alignment in mental rotation. We show how second-order analogies over differences computed via analogies between pictures provide a more elegant model of the geometric analogy task. We compare our model against human data on a set of problems, showing that the model aligns well with both the answers chosen by people and the reaction times required to choose the answers. PMID- 21585503 TI - Fear conditioning and social groups: statistics, not genetics. AB - Humans display more conditioned fear when the conditioned stimulus in a fear conditioning paradigm is a picture of an individual from another race than when it is a picture of an individual from their own race (Olsson, Ebert, Banaji, & Phelps, 2005). These results have been interpreted in terms of a genetic "preparedness" to learn to fear individuals from different social groups (Ohman, 2005; Olsson et al., 2005). However, the associability of conditioned stimuli is strongly influenced by prior exposure to those or similar stimuli. Using the Kalman filter, a normative statistical model, this article shows that superior fear conditioning to individuals from other groups is precisely what one would expect if participants perform optimal, Bayesian inference that takes their prior exposures to the different groups into account. There is therefore no need to postulate a genetic preparedness to learn to fear individuals from other races or social groups. PMID- 21585504 TI - Insights into knowledge representation: the influence of amodal and perceptual variables on event knowledge retrieval from memory. AB - Event sequences or scripts are the conceptual representations of activities in memory. Traditional views hold that events are represented in amodal networks and are retrieved by associative strategies. The embodied cognition approach holds that knowledge is grounded in perception and retrieved by mental simulation. We used a script generation task where event sequences of activities had to be produced. Activities varied in their degree of familiarity. In a regressional design we investigated whether amodal or perceptual variables best predicted knowledge retrieval to gain insight into the underlying representation. Retrieval depended on the familiarity of the activity. While novel activities mainly relied on perception-based simulation and to a lesser extent on associative strategies, moderately familiar activities showed the opposite pattern, and events of familiar activities were retrieved by association alone. We conclude that amodal structures exist in all representations that become stronger with increasing frequency and finally prevail over perceptual structures. PMID- 21585505 TI - Cue effects on memory for location when navigating spatial displays. AB - Participants maneuvered a rat image through a circular region on the computer screen to find a hidden target platform, blending aspects of two well-known spatial tasks. Like the Morris water maze task, participants first experienced a series of learning trials before having to navigate to the hidden target platform from different locations and orientations. Like the dot-location task, they determined the location of a position within a two-dimensional circular region. This procedure provided a way to examine how the number of surrounding cues (1, 2, or 3) affects the memory for spatial location in navigation. Memory performance was better when there were more cues and when targets were close to cues, consistent with the idea that cues bolster fine-grain memory, especially in proximal regions. Early and late measures of bias in memory reflected biases in a direction toward the nearest cue, implicating a cue-based category structure of the navigational space. Collectively, results suggest cue-based spatial memory representations that have been inferred from the dot-location task generalize to a navigation task within a simple, computer-based environment, as demonstrated by the good fits of the spatial model developed for the dot-location task (Fitting, Wedell, & Allen, 2005, 2007). PMID- 21585506 TI - A semantics-based approach to the "no negative evidence" problem. AB - Previous studies have shown that children retreat from argument-structure overgeneralization errors (e.g., *Don't giggle me) by inferring that frequently encountered verbs are unlikely to be grammatical in unattested constructions, and by making use of syntax-semantics correspondences (e.g., verbs denoting internally caused actions such as giggling cannot normally be used causatively). The present study tested a new account based on a unitary learning mechanism that combines both of these processes. Seventy-two participants (ages 5-6, 9-10, and adults) rated overgeneralization errors with higher (*The funny man's joke giggled Bart) and lower (*The funny man giggled Bart) degrees of direct external causation. The errors with more-direct causation were rated as less unacceptable than those with less-direct causation. This finding is consistent with the new account, under which children acquire-in an incremental and probabilistic fashion the meaning of particular constructions (e.g., transitive causative = direct external causation) and particular verbs, rejecting generalizations where the incompatibility between the two is too great. PMID- 21585507 TI - Relationships between language structure and language learning: the suffixing preference and grammatical categorization. AB - It is a reasonable assumption that universal properties of natural languages are not accidental. They occur either because they are underwritten by genetic code, because they assist in language processing or language learning, or due to some combination of the two. In this paper we investigate one such language universal: the suffixing preference across the world's languages, whereby inflections tend to be added to the end of words. A corpus analysis of child-directed speech in English found that suffixes were more accurate at cuing the grammatical category of the root word than were prefixes. An artificial language experiment found that there was a learning advantage for suffixes over prefixes in terms of grammatical categorization within an artificial language. The results are consistent with an account of language universals that originate in general purpose learning mechanisms. PMID- 21585508 TI - The effect of psychological distance on perceptual level of construal. AB - Three studies examined the effect of primed psychological distance on level of perceptual construal, using Navon's paradigm of composite letters (global letters that are made of local letters). Relative to a control group, thinking of the more distant future (Study 1), about more distant spatial locations (Study 2), and about more distant social relations (Study 3) facilitated perception of global letters relative to local letters. Proximal times, spatial locations, and social relations had the opposite effect. The results are discussed within the framework of Construal Level Theory of psychological distance (Liberman & Trope, 2008; Trope & Liberman, 2003). PMID- 21585509 TI - Reviving inert knowledge: analogical abstraction supports relational retrieval of past events. AB - We present five experiments and simulation studies to establish late analogical abstraction as a new psychological phenomenon: Schema abstraction from analogical examples can revive otherwise inert knowledge. We find that comparing two analogous examples of negotiations at recall time promotes retrieving analogical matches stored in memory-a notoriously elusive effect. Another innovation in this research is that we show parallel effects for real-life autobiographical memory (Experiments 1-3) and for a controlled memory set (Experiments 4 and 5). Simulation studies show that a unified model based on schema abstraction can capture backward (retrieval) effects as well as forward (transfer) effects. PMID- 21585510 TI - Representation recovers information. AB - Early agreement within cognitive science on the topic of representation has now given way to a combination of positions. Some question the significance of representation in cognition. Others continue to argue in favor, but the case has not been demonstrated in any formal way. The present paper sets out a framework in which the value of representation use can be mathematically measured, albeit in a broadly sensory context rather than a specifically cognitive one. Key to the approach is the use of Bayesian networks for modeling the distal dimension of sensory processes. More relevant to cognitive science is the theoretical result obtained, which is that a certain type of representational architecture is necessary for achievement of sensory efficiency. While exhibiting few of the characteristics of traditional, symbolic encoding, this architecture corresponds quite closely to the forms of embedded representation now being explored in some embedded/embodied approaches. It becomes meaningful to view that type of representation use as a form of information recovery. A formal basis then exists for viewing representation not so much as the substrate of reasoning and thought, but rather as a general medium for efficient, interpretive processing. PMID- 21585511 TI - Two routes to face perception: evidence from psychophysics and computational modeling. AB - The aim of this study was to separately analyze the role of featural and configural face representations. Stimuli containing only featural information were created by cutting the faces into their parts and scrambling them. Stimuli only containing configural information were created by blurring the faces. Employing an old-new recognition task, the aim of Experiments 1 and 2 was to investigate whether unfamiliar faces (Exp. 1) or familiar faces (Exp. 2) can be recognized if only featural or configural information is provided. Both scrambled and blurred faces could be recognized above chance level. A further aim of Experiments 1 and 2 was to investigate whether our method of creating configural and featural stimuli is valid. Pre-activation of one form of representation did not facilitate recognition of the other, neither for unfamiliar faces (Exp. 1) nor for familiar faces (Exp. 2). This indicates a high internal validity of our method for creating configural and featural face stimuli. Experiment 3 examined whether features placed in their correct categorical relational position but with distorted metrical distances facilitated recognition of unfamiliar faces. These faces were recognized no better than the scrambled faces in Experiment 1, providing further evidence that facial features are stored independently of configural information. From these results we conclude that both featural and configural information are important to recognize a face and argue for a dual mode hypothesis of face processing. Using the psychophysical results as motivation, we propose a computational framework that implements featural and configural processing routes using an appearance-based representation based on local features and their spatial relations. In three computational experiments (Experiments 4-6) using the same sets of stimuli, we show how this framework is able to model the psychophysical data. PMID- 21585512 TI - Conversation, gaze coordination, and beliefs about visual context. AB - Conversation is supported by the beliefs that people have in common and the perceptual experience that they share. The visual context of a conversation has two aspects: the information that is available to each conversant, and their beliefs about what is present for each other. In our experiment, we separated these factors for the first time and examined their impact on a spontaneous conversation. We manipulated the fact that a visual scene was shared or not and the belief that a visual scene was shared or not. Participants watched videos of actors talking about a controversial topic, then discussed their own views while looking at either a blank screen or the actors. Each believed (correctly or not) that their partner was either looking at a blank screen or the same images. We recorded conversants' eye movements, quantified how they were coordinated, and analyzed their speech patterns. Gaze coordination has been shown to be causally related to the knowledge people share before a conversation, and the information they later recall. Here, we found that both the presence of the visual scene, and beliefs about its presence for another, influenced language use and gaze coordination. PMID- 21585513 TI - On leveraged learning in lexical acquisition and its relationship to acceleration. AB - Children at about age 18 months experience acceleration in word learning. This vocabulary explosion is a robust phenomenon, although the exact shape and timing vary from child to child. One class of explanations, which we term collectively as leveraged learning, posits that knowledge of some words helps with the learning of others. In this framework, the child initially knows no words and so learning is slow. As more words are acquired, new words become easier and thus it is the acquisition of early words that fuels the explosion in learning. In this paper we examine the role of leveraged learning in the vocabulary spurt by proposing a simple model of leveraged learning. Our results show that leverage can change both the shape and timing of the acceleration, but that it cannot create acceleration if it did not exist in the corresponding model without leveraging. This model is then applied to the Zipfian distribution of word frequencies, which confirm that leveraging does not create acceleration, but that the relationship between frequency and the difficulty of learning a word may be complex. PMID- 21585515 TI - Does aposymbiotically cultivated fungus Ramalina produce isolichenan? AB - The main alpha-glucan synthesized by lichens of the genera Ramalina in the symbiotic state is isolichenan. This polysaccharide was not found in the aposymbiotically cultivated symbionts. It is still unknown if this glucan is produced by the mycobiont only in the presence of a photobiont, in a lichen thallus, or if the isolichenan suppression is influenced by the composition of culture medium used in its aposymbiotic cultive. Consequently, the latter hypothesis is tested in this study. Cultures of the mycobiont Ramalina complanata were obtained from germinated ascospores and cultivated on 4% glucose Lilly and Barnett medium. Freeze-dried colonies were defatted and their carbohydrates extracted successively with hot water and aqueous 10% KOH, each at 100 degrees C. The polysaccharides nigeran, laminaran and galactomannan were liberated, along with a lentinan-type beta-glucan and a heteropolysaccharide (Man : Gal : Glc, 21 : 28 : 51). Nevertheless, the alpha-glucan isolichenan was not found in the extracts. It follows that it was probably a symbiotic product, synthesized by the mycobiont only in this particular microenvironment, in the presence of the photobiont in the lichen thallus. A discussion about polysaccharides found in the symbiotic thallus as well as in other aposymbiotic cultivated Ramalina mycobionts is also included. PMID- 21585516 TI - The cost of growing old--can we meet it? PMID- 21585518 TI - Candida albicans biofilm formation on soft denture liners and efficacy of cleaning protocols. AB - OBJECTIVE: The aim of this study was to investigate Candida albicans biofilm formation on denture liners and to analyse the efficacy of cleaning protocols. MATERIAL AND METHODS: Specimens were prepared from four silicone-based soft denture liners. After artificial ageing and surface free energy determination, specimens were incubated with saliva (2 h) and Candida albicans ATCC 10231 for either short- (2.5 h) or long-term (24 h) biofilm formation. Adherent cells were determined either after incubation of specimens with Candida albicans or after treatment with different denture cleaning protocols. Statistical analysis was performed using one-way anova and the Games-Howell test (alpha = 0.05). RESULTS: For both short- and long-term biofilm formation, similar amounts of Candida albicans cells were found on the surface of the different liners (p = 0.295 and 0.178, respectively). For both short- and long-term biofilm formation, the highest cleaning efficacy was observed for sodium hypochlorite (NaOCl; p < 0.01). The efficacy of the chemical denture cleaner in removing long-term Candida albicans biofilms was significantly lower than the efficacy of removal by brushing (p < 0.001). CONCLUSION: Different silicone-based soft denture liners yield similar Candida albicans biofilm formation on their surface. The highest efficacy for the removal of Candida albicans biofilms was identified for NaOCl. Chemical denture cleaners appear to have rather low efficacy to remove mature Candida albicans biofilms. PMID- 21585519 TI - Protective role of melatonin in progesterone production by human luteal cells. AB - This study investigated whether melatonin protects luteinized granulosa cells from reactive oxygen species (ROS) as an antioxidant to enhance progesterone production in the follicle during ovulation. Follicular fluid was sampled at the time of oocyte retrieval in women undergoing in vitro fertilization and embryo transfer (IVF-ET). Melatonin concentrations in the follicular fluid were positively correlated with progesterone concentrations (r = 0.342, P < 0.05) and negatively correlated with the concentration of 8-hydroxy-2'-deoxyguanosine (8 OHdG), an oxidative stress marker (r = -0.342, P < 0.05). The progesterone and 8 OHdG concentrations were negatively correlated (r = -0.246, P < 0.05). Luteinized granulosa cells were obtained at the time of oocyte retrieval in women undergoing IVF-ET. Cells were incubated with H(2)O(2) (30, 50, 100 MUm) in the presence or absence of melatonin (1, 10, 100 MUg/mL). Progesterone production by luteinized granulosa cells was significantly inhibited by H(2)O(2). Melatonin treatment overcame the inhibitory effect of H(2) O(2) . Twenty-five patients who had luteal phase defect (serum progesterone concentrations <10 ng/mL during the mid-luteal phase) were divided into two groups during the next treatment cycle: 14 women were given melatonin (3 mg/day at 22:00 hr) throughout the luteal phase and 11 women were given no medication as a control. Melatonin treatment improved serum progesterone concentrations (>10 ng/mL during the mid-luteal phase) in nine of 14 women (64.3%), whereas only two of 11 women (18.1%) showed normal serum progesterone levels in the control group. In conclusion, melatonin protects granulosa cells undergoing luteinization from ROS in the follicle and contributes to luteinization for progesterone production during ovulation. PMID- 21585520 TI - From vineyard to glass: agrochemicals enhance the melatonin and total polyphenol contents and antiradical activity of red wines. AB - Resistance inducers are a class of agrochemicals, including benzothiadiazole and chitosan, which activate the plant own defence mechanisms. In this work, open field treatments with plant activators were performed on two red grape (Vitis vinifera L.) varieties cultivated in different localities, Groppello (Brescia, Lombardia, Italy) and Merlot (Treviso, Veneto, Italy). Treatments were carried out every 10 days until the veraison and, after harvesting, experimental wines (microvinificates) were prepared. In general, both melatonin and total polyphenol content, determined by mass spectrometry and Folin-Ciocalteu assay, respectively, were higher in wines produced from grapes treated with resistance inducers than in those obtained from untreated control and conventional fungicide-treated grapes. Accordingly, antiradical power of wines derived from plant activator treated grapes, measured by both DPPH (2,2-diphenyl-1-picrylhydrazyl) and the ABTS [(2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)] radical-scavenging assay, was higher than in their counterparts. To the best of our knowledge, this is the first report on the effects of agrochemicals on the melatonin content of red wine. PMID- 21585521 TI - Synergism between melatonin and atorvastatin against endothelial cell damage induced by lipopolysaccharide. AB - The beneficial effects of atorvastatin are based on both cholesterol-dependent and independent mechanisms. The latter probably include the ability of the estatin to enhance the expression of endothelial nitric oxide synthase (eNOS) and to cause a vasodilatation. In turn, the antioxidant and anti-inflammatory actions of melatonin are related to its vascular protection. In the present study, we investigated the efficacy of the combination of melatonin plus atorvastatin against endothelial cell damage induced by inflammation and oxidative stress injury. Human umbilical vein endothelial cells (HUVEC) were cultured with bacterial lipopolysaccharide (LPS) in the presence or absence of melatonin and/or atorvastatin. LPS inhibited eNOS mRNA and protein expression, which was reversed by atorvastatin and, to a lesser extent, by melatonin. Together, melatonin + atorvastatin induced higher eNOS protein expression than either compound alone. Melatonin, but not atorvastatin, reduced free radical generation, lipid peroxidation, and interleukin-6 levels induced by LPS. In the presence of atorvastatin, the effects of melatonin were maintained or even improved. These data suggest that melatonin improves the beneficial effects of atorvastatin and reduces its side effects in endothelial cells during inflammation and under conditions of oxidative stress. PMID- 21585522 TI - Melatonin inhibits insulin secretion in rat insulinoma beta-cells (INS-1) heterologously expressing the human melatonin receptor isoform MT2. AB - Melatonin exerts some of its effects via G-protein-coupled membrane receptors. Two membrane receptor isoforms, MT1 and MT2, have been described. The MT1 receptor is known to inhibit second messenger cyclic adenosine monophosphate (cAMP) signaling through receptor-coupling to inhibitory G-proteins (G(i) ). Much less is known about the MT2 receptor, but it has also been implicated in signaling via G(i) -proteins. In rat pancreatic beta-cells, it has recently been reported that the MT2 receptor plays an inhibitory role in the cyclic guanosine monophosphate (cGMP) pathway. This study addresses the signaling features of the constitutively expressed human recombinant MT2 receptor (hMT2) and its impact on insulin secretion, using a rat insulinoma beta-cell line (INS-1). On the basis of a specific radioimmunoassay, insulin secretion was found to be more strongly reduced in the clones expressing hMT2 than in INS-1 controls, when incubated with 1 or 100 nm melatonin. Similarly, cAMP and cGMP levels, measured by specific enzyme-linked immunosorbent assays (ELISAs), were reduced to a greater extent in hMT2 clones after melatonin treatment. In hMT2-expressing cells, the inhibitory effect of melatonin on insulin secretion was blocked by pretreatment with pertussis toxin, demonstrating the coupling of the hMT2 to G(i) -proteins. These results indicate that functional hMT2 expression leads to the inhibition of cyclic nucleotide signaling and a reduction in insulin release. Because genetic variants of the hMT2 receptor are considered to be risk factors in the development of type 2 diabetes, our results are potentially significant in explaining and preventing the pathogenesis of this disease. PMID- 21585523 TI - A proof-of-concept, randomized, placebo-controlled, multiple cross-overs (n-of-1) study of naftazone in Parkinson's disease. AB - To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson's disease (PD). Proof-of-concept, randomized, double blind, placebo-controlled, multiple-cross-over n-of-1 study in patients with PD with wearing-off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single-blind dose-finding phase. Seven patients entered the placebo controlled phase (four consecutive 28-day cross-overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48-h ON-OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven-point Likert scale to assess "patients' discomfort caused by dyskinesias" (Q1) and 'disability during OFF-periods' (Q2). A 'responder' analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross-over periods) was used. Treatment effects were derived from mixed-effects anova. On diaries, 5/7 patients responded to naftazone for 'ON-time with troublesome dyskinesia' (reduced time, treatment effect: -49 [95% CI: -93/-4] min, P = 0.03), 6/7 regarding 'ON-time without troublesome dyskinesia' (increased time, treatment effect: 35 [-19/88], P = 0.2). No trend was observed for 'OFF' time. There were 7/7 'responders' regarding UPDRSIII (reduced score, treatment effect: -2.1[-4.5/0.2], P = 0.08). The 7-point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation. PMID- 21585524 TI - The future of nursing. PMID- 21585525 TI - A "boots on the ground" perspective of caring for the women and children in Afghanistan. AB - In 1972 Margarete V. Silberberg wrote about her nursing experience when caring for women at a Kabul, Afghanistan, hospital. Based on my experience during a recent deployment to Afghanistan, I describe providing health care to Afghan women and children as a military Women's Health Nurse Practitioner. Delivering health care presented the threat of physical harm for the health care team and those who received the care. Afghan women and children continue to experience significant cultural, religious, and social circumstances that limit their education, personal development, protection from abuse, and access to health care. PMID- 21585526 TI - Noninstitutional births and newborn care practices among adolescent mothers in Bangladesh. AB - OBJECTIVE: To describe home-based newborn care practices among adolescent mothers in Bangladesh and to identify sociodemographic, antenatal care (ANC), and delivery care factors associated with these practices. DESIGN: The 2007 Bangladesh Demographic Health Survey, conducted from March 24 to August 11, 2007. SETTING: Selected urban and rural areas of Bangladesh. PARTICIPANTS: A total of 580 adolescent women (aged 15-19 years) who had ever been married with noninstitutional births and having at least one child younger than 3 years of age. METHODS: Outcomes included complete cord care, complete thermal protection, initiation of early breastfeeding, and postnatal care within 24 hours of birth. Descriptive statistics and multivariate logistic regression methods were employed in analyzing the data. RESULTS: Only 42.8% and 5.1% newborns received complete cord care and complete thermal protection. Only 44.6% of newborns were breastfed within 1 hour of birth. The proportion of the newborns that received postnatal care within 24 hours of birth was 9%, and of them 11% received care from medically trained providers (MTP). Higher level of maternal education and richest bands of wealth were associated with complete thermal care and postnatal care within 24 hours of birth but not with complete cord care and early breastfeeding. Use of sufficient ANC and assisted births by MTP were significantly associated with several of the newborn care practices. CONCLUSIONS: The association between newborn care practices of the adolescent mothers and sufficient ANC and skilled birth attendance suggest that expanding skilled birth attendance and providing ANC may be an effective strategy to promote essential and preventive newborn care. PMID- 21585527 TI - Birth outcomes following self-inflicted poisoning during pregnancy, California, 2000 to 2004. AB - OBJECTIVE: To describe birth outcomes following intentional acute poisoning during pregnancy. SETTING: California Linked Vital Statistics-Patient Discharge Database, 2000 to 2004. PARTICIPANTS: Pregnant women age 15 to 44, who had a singleton live birth or fetal death that occurred between gestational ages 20 and 42 weeks who were discharged from the hospital for an intentional poisoning were compared to pregnant women discharged from the hospital for any nonpoisoning diagnosis. Intentional acute poisoning hospital discharges were identifed by the presence of an ICD-9-CM E-Codes E950-E952 (suicide, attempted suicide and self inflicted injuries specified as intentional.) METHODS: Through a retrospective cohort design, birth outcomes including low birth weight; preterm birth; fetal, neonatal, and infant death; and congenital anomalies were identified by the presence of ICD-9-CM diagnosis codes or by notation in the dataset. RESULTS: There were 430 hospital discharges for an intentional poisoning during pregnancy documented in the dataset (rate=25.87/100,000 person years). The rate of intentional poisoning was greatest in the first weeks of gestation and declined with increasing gestational age. Analgesics, antipyretics, and antirheumatics were most commonly implicated. Adverse birth outcomes associated with intentional poisoning included preterm birth (odds ratio [OR]=1.34; 95% Confidence Interval [CI] [1.01, 1.77]), low birth weight (OR=1.49; 95% CI [1.04, 2.12]), and circulatory system congenital anomalies (OR=2.17; 95% CI [1.02, 4.59]). CONCLUSION: Intentional acute poisoning during pregnancy was associated with several adverse birth outcomes; however, these relationships may be confounded by concomitant maternal substance abuse. PMID- 21585529 TI - Evaluation of an infant simulator intervention for teen pregnancy prevention. AB - OBJECTIVE: To evaluate the effectiveness of simulation as a strategy to influence teens' perceptions of pregnancy and parenting. DESIGN: This pilot study was a preexperimental, one group pre/posttest design. SETTING: The school-based wellness center of a high school was the setting for the weekly sessions and the pre/posttest administration. PARTICIPANTS: Sample members participated in 6 weekly Baby Think it Over (BTIO) classes and an infant simulator experience. The final sample included 79 teens age 14 to 18 years who attended one of eight BTIO sessions. METHODS: We used the Thoughts on Teen Parenting Survey (TTPS) to assess the perceptions of teens with regard to the costs and rewards associated with teen parenting. The TTPS yields a composite score of the teen attitudes toward the teen parenting experience and eight subscale scores that assess different areas of teen life. RESULTS: No significant differences were found in the mean pre/posttest scores or in correlations of the demographic data and mean scores. Two significant differences in pre/posttest subscale scores were in the areas of friends and personal characteristics. CONCLUSIONS: The results of this study suggest that the effectiveness of using infant simulators to influence the perceptions of teens about the reality of teen parenting is minimal. PMID- 21585531 TI - A modified technique of left ventricular restoration: endoventricular spiral plication. AB - We describe a modified technique of left ventricular restoration after anterior myocardial infarction, referred to as endoventricular spiral plication (ESP). This technique was designed for surgical ventricular restoration with a modified spiral stitch and no patch plasty. A continuous spiral stitch can reconstruct the left ventricular shape both at the short and long axis, and appropriate restoration can be achieved by adjusting the tension of the string and the degree of spiral rotation. PMID- 21585528 TI - Attitudes toward physical activity of white midlife women. AB - OBJECTIVE: To explore attitudes toward physical activity of White midlife women in the United States using a feminist perspective. DESIGN: A cross-sectional qualitative study using a thematic analysis. SETTING: Internet communities for midlife women. PARTICIPANTS: Twenty-nine White midlife women in the United States recruited using a convenience sampling method. METHODS: We used 17 topics on attitudes toward physical activity and ethnic-specific contexts to administer an online forum. We analyzed the data using thematic analysis. RESULTS: We found three themes: thinking without action, gendered and sedentary culture, and motivating myself. The women knew and understood the necessity of physical activity for their physical and mental health but in most cases had not been able to take action to increase their physical activities. Although the culture that circumscribed the women's physical activity was sedentary in nature, the women tried to motivate themselves to increase their physical activities through several creative strategies. CONCLUSION: The findings strongly suggest that although women were doing their best, American culture itself needs to be changed to help women increase physical activity in their daily lives. PMID- 21585532 TI - Mitral valve repair, tricuspid valve annuloplasty, and ligation of coronary artery-pulmonary trunk fistula in a patient with arrhythmogenic right ventricular cardiomyopathy. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiac disorder characterized by replacement of myocytes with adipose and fibrous tissue and often presents with ventricular arrhythmia, heart failure, and sudden death. This report describes a 67-year-old man with ARVC complicated with severe mitral regurgitation, dilated annulus of the tricuspid valve, and coronary artery pulmonary artery fistula. Mitral valve repair, tricuspid valve annuloplasty, and ligation of the coronary artery-pulmonary artery fistula were performed. The postoperative course was uneventful, and the patient was discharged on postoperative day 15. PMID- 21585533 TI - Testicular germ cell tumor metastatic to the right atrium. AB - We describe a right atrial metastasis of a testicular germ cell tumor, which was successfully removed from the tricuspid valve and subvalvular apparatus without the need for valve replacement. PMID- 21585534 TI - Primary myxoma of the pulmonary artery. AB - Cardiac myxomas are most commonly found within the left atrium. We now report a patient presenting with dyspnea, palpitation, and chest pain who was found to have myxoma arising from the pulmonary valve commissure. Urgent surgical treatment is curative and warranted for these lesions, in order to prevent outflow obstruction and thromboembolic phenomena. PMID- 21585535 TI - Primary fibrosarcoma of the mitral valve. AB - A case of primary fibrosarcoma of the mitral valve is reported, which was resected and the valve was replaced. Adjuvant chemotherapy was admisinistered, and at one year the patient remains symptom free without evidence of recurrent disease. PMID- 21585536 TI - Extensive local spread of rhabdomyosarcoma. PMID- 21585537 TI - A massive right atrial cavernous hemangioma. PMID- 21585538 TI - Combined endovascular and open surgical approach for the management of subclavian artery occlusion due to thoracic outlet syndrome. AB - A 32-year-old male with arterial thoracic outlet syndrome (TOS) underwent endovascular treatment for the chronic total occlusive lesion from the subclavian to the brachial artery after resection of the first rib and cervical rib. A combined endovascular and surgical treatment represents an attractive alternative to the traditional surgical approach for the treatment of complicated arterial TOS. PMID- 21585539 TI - Combined resection of coronary and innominate artery aneurysms. AB - Coexistent aneurysms of the coronary and inominate arteries are extremely rare. We present the case of a 28-year-old male with an aneurysm of the left anterior descending coronary artery and an aneurysm of the inominate artery presenting with hoarseness and severely depressed left ventricular function (ejection fraction of 25%). He underwent successful surgical resection of both aneurysms. The inominate artery aneurysm was excised and the brachiocephalic trunk was reconstructed off-pump. The coronary artery aneurysm was excised and distal aorto coronary bypass grafting was done on cardiopulmonary bypass. PMID- 21585540 TI - Right coronary artery stenosis following the repair of an ascending aortic dissection. PMID- 21585541 TI - Extension of coronary artery with double flap technique in a complicated arterial switch operation. AB - The increased distance between the coronary ostium and the reimplantation site poses technical challenges in older patients with transposition of the great arteries (TGA) and complex coronary artery anomalies. In this report, we describe a technique for coronary artery reimplantation using a pedicle flap on the pulmonary artery (PA) to create a tunnel resulting in an extension of the coronary button. PMID- 21585542 TI - Infected mass on cardiac defibrillator lead. PMID- 21585543 TI - Severe tracheal compression due to cervical aortic arch aneurysm. AB - We report a left-sided cervical aortic arch (CAA) aneurysm that severely compressed the trachea resulting in respiratory insufficiency. A 59-year-old man was referred to our hospital because of a few years history of inspiratory obstruction without dysphagia. Enhanced computed tomography revealed severe tracheal stenosis caused by a large CAA aneurysm. As the location of the aneurysm was located between the left carotid artery and the left subclavian artery, we planned to approach the aneurysm resection via a median sternotomy extending to the bilateral supraclavicular region. Total arch replacement was performed and the tracheal compression was relieved. The postoperative course was uneventful and the tracheal stenosis was gradually decreased by 12 months after surgery. PMID- 21585544 TI - Use of a single Q guide catheter for complete assessment and treatment of both coronary arteries via radial access during acute ST elevation myocardial infarction: a review of 40 consecutive cases. AB - BACKGROUND: It is normally necessary to use more than 1 coronary catheter in primary percutaneous coronary intervention (PPCI) for ST elevation myocardial infarction (STEMI). We explored the utility of a single guide catheter (Q) strategy for complete coronary assessment and treatment in PPCI. METHODS: Fifty seven consecutive STEMI cases undergoing invasive management were included. Radial access was the default route (6 cases via femoral access). Among radial cases, a TIG catheter was used first on 6 occasions (perceived low likelihood of subsequent PCI) and a Judkins right followed by an EBU catheter on three occasions (stock issue). A Q guide was used as initial default in the remaining 42 cases. Two anterior STEMI cases had recently undergone angiography and did not require right coronary reinspection. Procedural and outcomes data were recorded prospectively. RESULTS: The Q catheter allowed complete assessment and treatment in 33 cases, 6 cases requiring a second catheter and one patient dying prior to right coronary imaging. Territories of infarction were: anterior (n = 18), inferior (n = 14), inferoposterior (n = 3), lateral (n = 1), inferolateral (n = 2), inferoposterolateral (n = 2). Sixty-three out of 65 lesions were treated successfully. Median catheterization laboratory door to balloon time was 18 minutes (IQR 15-21 minutes). There were no catheter-related complications. CONCLUSIONS: A default Q guide catheter allows rapid effective imaging and treatment of both left and right coronaries in the majority of STEMI cases suitable for radial access PPCI. PMID- 21585545 TI - Feasibility and safety of 7-Fr radial approach for complex PCI. AB - BACKGROUND: Although the transradial approach is well established for percutaneous coronary intervention (PCI), it is perceived as being not suitable for 7-Fr complex PCI, which is traditionally performed from the femoral approach. OBJECTIVE: To evaluate the procedural success and outcome of 7-Fr transradial complex PCI. METHOD: Retrospective review and analysis of all patients undergoing 7-Fr transradial complex PCI from August 2008 until October 2010 in a tertiary cardiac center setting. RESULTS: Transradial 7-Fr complex PCI was performed in 77 patients after manual assessment of the radial pulse and size. The radial access was obtained successfully in all 77 patients. The age range was 39-88 years with 16 patients (23.4%) over 80 years of age and 14 females (18.1%). There were 30 left main stem PCI (39%), 31 (40.2%) chronic total occlusion (CTO), and 13 (16.8%) rotational atherectomy. Intravascular ultrasound (IVUS) was used in 17 (22%) cases, cutting balloons in 16 (20.7%), and LASER PCI in 2 (2.6%) cases. Procedural success was achieved in 76 of 77 (98.7%) with 1 failure to canalize a CTO. There was 1 patient with type I coronary perforation managed conservatively. There was no in-hospital mortality. All radial pulses were present 6 hours after the procedure and only 23 patients were seen for follow-up, and all had patent radial artery 4-6 months following the procedure. CONCLUSION: A 7-Fr transradial complex PCI is feasible and can be carried out safely and successfully with excellent results. In suitable patients, male or female, complex PCI need not always be performed from the femoral approach. PMID- 21585546 TI - Iatrogenic coronary dissection causing flush side branch occlusion: use of intravascular ultrasound to reopen vessel. AB - Iatrogenic complications present a major challenge to the interventional cardiologist. We describe a case of extensive right coronary artery dissection caused by engagement of a 0.035" guidewire. Attempts to reopen the flush-occluded posterior descending artery using conventional methods were unsuccessful. However, the vessel was successfully restored with the use of intravascular ultrasound guidance and we describe the steps involved in this technique. PMID- 21585547 TI - Risk stratification of kidneys from donation after cardiac death donors and the utility of machine perfusion. AB - There has been a dramatic increase in the utilization of kidneys from donors after cardiac death (DCD). While these organs represent an opportunity to expand the donor pool, the assessment of risk and optimal perioperative management remains unclear. Our primary aim was to identify risk factors for objective outcomes, and secondarily, we sought to determine what impact pulsatile machine perfusion (PMP) had on these outcomes. From 1993 to November 2008, 6057 DCD kidney transplants were reported to the Organ Procurement and Transplantation Network database, with complete endpoints for delayed graft function (DGF) and graft survival (GS). Risk factors were identified using a multivariable regression analysis adjusted for recipient factors. Age (50 yr) [OR 1.81, p < 0.0001] and cold ischemia time (CIT) (>30 h) [OR 3.22, p < 0.0001] were the strongest predictors of DGF. The use of PMP decreased the incidence of DGF only when donor age was >60 yr and improved long-term graft survival when donor age was >50 yr. Donor warm ischemia time >20 min was also found to correlate with increased DGF. While the incidence of DGF in DCD kidneys is significantly higher, the only factors the transplant surgeon can control are CIT and the use of PMP. The data suggest that the use of PMP in DCD kidneys <50 yr old provides little clinical benefit and may increase CIT. PMID- 21585548 TI - Are informed consent forms for organ transplantation and donation too difficult to read? AB - Informed consent for organ transplantation and donation is an ethical obligation, legally required, and considered as part of the Patient's Rights Condition of Medicare Participation for hospitals. National policy-makers recommend that informed consent forms and patient education materials be written at a low reading level (5th-8th grade level) to facilitate patient comprehension. We assessed reading levels of informed consent forms (CFs) for adult organ transplant recipients and living organ donors across US transplant centers. CFs were analyzed using three measures of reading level: Lexile Measure, Flesch Kincaid Grade Level, and the Gunning Fog Index. Of active transplant centers contacted (N=209), 75 (36%) sent a total of 332 CFs. CFs were written, on average, at the college level, which is a considerably higher reading level than the standards set by policy-makers. CF reading levels were negatively correlated with transplant center volume (r=-0.119; p<0.03). CFs for intestine transplantation and for evaluation/listing were the easiest to read, while consent forms for liver transplantation/donation and pre-transplant agreements were the most difficult to read. Reducing CFs' reading level may help to increase patient comprehension for adequate informed consent. PMID- 21585549 TI - Lung transplantation after hematopoietic stem cell transplantation. AB - INTRODUCTION: Pulmonary insufficiency following bone marrow transplant (BMT) is common and has significant associated mortality. Lung transplantation (LTX) is the only viable treatment for patients with end-stage pulmonary disease, but LTX after BMT is an uncommon event given the medical candidacy of the potential recipients. We sought to evaluate the short- and long-term outcomes of LTX in BMT recipients. METHODS: We performed a retrospective evaluation of our institution's longitudinal LTX and BMT databases. Demographic and outcomes variables were collected. RESULTS: We identified 639 LTX from January 1, 1988, through December 31, 2009, and 5525 BMT from program inception, March 21, 1974, through December 31, 2009. From the cross-referenced cohort, we identified four patients who had BMT followed by LTX. Our series was composed of two men and two women, with a mean age of 32.3 yr (range, 20-59 yr). Single LTX were performed in two recipients (50%). All patients had significant and expected morbidities related to their transplant immunosuppression. Three patients (75%) required cardiopulmonary bypass at the time of LTX. The two recipients who underwent bilateral LTX required open chest management and subsequent tracheostomy. All patients are still alive at follow-up (range, 19-119 months, median 39.5). CONCLUSION: Our study demonstrates that LTX in the setting of BMT is a high-risk operation with the potential for a tumultuous perioperative course. Despite this, good outcomes and survival are obtainable in carefully selected patients. Selection factors include clinically stable patients without active sepsis and preoperative optimization of nutrition in anticipation of a prolonged recovery. An experienced multidisciplinary team approach and a protocol-driven management plan are paramount for successful outcomes in this challenging population. PMID- 21585550 TI - LabMELD-based organ allocation increases total costs of liver transplantation: a single-center experience. AB - INTRODUCTION: In 2006, model for end-stage liver disease (MELD)-based allocation was implemented in the Eurotransplant (ET) region. Sick patients, who in general require more resources, are prioritized. In this analysis, the effect of MELD on costs for liver transplantation (LTx) was assessed. METHODS: Total costs for LTx before and after implementation of MELD were identified in 256 patients from January 2005-December 2007. Forty-nine patients (Re-LTx, HU listings, and 30-d mortality) were excluded from further analysis. The costs of LTx in 207 patients have been correlated with their corresponding labMELD; 84 and 123 LTx before and after implementation of MELD were compared, and patient survival was monitored. RESULTS: A positive correlation exists between labMELD and costs (r(2) = 0.28; p < 0.05). Only nominal correlation existed between the Child-Pugh classification and costs. The labMELD scores can be stratified into four groups (I: 6-10, II: 11 18, III: 19-24, and IV: >24), with an increase of ?15.672 +/- 2.233 between each group (p < 0.05). Recipients' labMELD at the time of LTx increased significantly in the MELD-based allocation system. Costs increased by ?11.650/patient (p < 0.05), while median survival decreased from 1219 to 869 d (p < 0.05). CONCLUSION: LabMELD-based allocation increased total costs of LTx. In accordance with other studies, the sickest patients need the most resources. PMID- 21585551 TI - Co-occurrence of toxic bacterial and fungal secondary metabolites in moisture damaged indoor environments. AB - Toxic microbial secondary metabolites have been proposed to be related to adverse health effects observed in moisture-damaged buildings. Initial steps in assessing the actual risk include the characterization of the exposure. In our study, we applied a multi-analyte tandem mass spectrometry-based methodology on sample materials of severely moisture-damaged homes, aiming to qualitatively and quantitatively describe the variety of microbial metabolites occurring in building materials and different dust sample types. From 69 indoor samples, all were positive for at least one of the 186 analytes targeted and as many as 33 different microbial metabolites were found. For the first time, the presence of toxic bacterial metabolites and their co-occurrence with mycotoxins were shown for indoor samples. The bacterial compounds monactin, nonactin, staurosporin and valinomycin were exclusively detected in building materials from moist structures, while chloramphenicol was particularly prevalent in house dusts, including settled airborne dust. These bacterial metabolites are highly bioactive compounds produced by Streptomyces spp., a group of microbes that is considered a moisture damage indicator in indoor environments. We show that toxic bacterial metabolites need to be considered as being part of very complex and diverse microbial exposures in 'moldy' buildings. PRACTICAL IMPLICATIONS: Bacterial toxins co-occur with mycotoxins in moisture-damaged indoor environments. These compounds are measurable also in settled airborne dust, indicating that inhalation exposure takes place. In attempts to characterize exposures to microbial metabolites not only mycotoxins but also bacterial metabolites have to be targeted by the analytical methods applied. We recommend including analysis of samples of outdoor air in the course of future indoor assessments, in an effort to better understand the outdoor contribution to the indoor presence of microbial toxins. There is a need for a sound risk assessment concerning the exposure to indoor microbial toxins at concentrations detectable in moisture-damaged indoor environments. PMID- 21585552 TI - CFD and ventilation research. AB - There has been a rapid growth of scientific literature on the application of computational fluid dynamics (CFD) in the research of ventilation and indoor air science. With a 1000-10,000 times increase in computer hardware capability in the past 20 years, CFD has become an integral part of scientific research and engineering development of complex air distribution and ventilation systems in buildings. This review discusses the major and specific challenges of CFD in terms of turbulence modelling, numerical approximation, and boundary conditions relevant to building ventilation. We emphasize the growing need for CFD verification and validation, suggest ongoing needs for analytical and experimental methods to support the numerical solutions, and discuss the growing capacity of CFD in opening up new research areas. We suggest that CFD has not become a replacement for experiment and theoretical analysis in ventilation research, rather it has become an increasingly important partner. PRACTICAL IMPLICATIONS: We believe that an effective scientific approach for ventilation studies is still to combine experiments, theory, and CFD. We argue that CFD verification and validation are becoming more crucial than ever as more complex ventilation problems are solved. It is anticipated that ventilation problems at the city scale will be tackled by CFD in the next 10 years. PMID- 21585553 TI - Survivin in skin pathologies. AB - Survivin is a member of the inhibitor of apoptosis (IAP) protein family acting at the intersection between proliferation and cell survival. This protein exhibits low or undetectable expression in most adult tissues but is increased in the majority of cancers. Suggested to be one of the most cancer-specific proteins identified to date, survivin acts as a signalling node in tumour maintenance and, after first promising results, is now attracting increasing attention as a target in anti-cancer therapy. In the skin, survivin has been implicated in a number of pathological conditions such as psoriasis and tumours of melanocytic and epithelial origin. Its expression can correlate with tumour severity, metastasis and decreased patient survival and has been inversely correlated with the sensitivity to cytotoxic agents used in anti-cancer therapy. Survivin may also be of importance for normal epidermal homeostasis possibly supporting self-renewal of epidermal stem cells. In this review, the authors summarize and discuss current data of survivin in skin biology and provide a comprehensive compilation of survivin expression in skin pathologies with focus on future therapeutical use. PMID- 21585554 TI - Morphological and functional differences in coculture system of keratinocytes and dorsal-root-ganglion-derived cells depending on time of seeding. AB - Previous study indicated that in a coculture system of keratinocytes and dorsal root-ganglion-derived (DRG) cells, mechanical stimulation of keratinocytes induced ATP-mediated calcium propagation and excitation of DRG cells. Here, we examined two different coculture systems of keratinocytes and DRG cells. In one, we seeded keratinocytes first and then seeded DRG cells on the keratinocytes. In this system, nerve fibres from DRG cells passed between keratinocytes. Mechanical stimulation of keratinocytes did not induce excitation of DRG cells. In the other, we seeded both cell types together. At first, each cell type grew separately, forming cell aggregates. Then, nerve fibres grew out from the DRG cell aggregates to keratinocyte aggregates and penetrated into them. In this system, mechanical stimulation of keratinocytes induced excitation of the nerve fibres, but the excitation was not completely blocked by apyrase, an ATP degrading enzyme. These results suggest that coculture of keratinocytes and DRG can generate a variety of structures, depending on the seeding conditions. PMID- 21585555 TI - PTPN22 1858T is not a risk factor for North American pemphigus vulgaris. AB - Alterations in the protein tyrosine phosphatase N22 (PTPN22) gene affect the threshold for lymphocyte activation. The PTPN22 1858T polymorphism leads to uninhibited T-cell receptor cascade propagation. An elevated PTPN22 1858C/T genotype frequency has been correlated with several autoimmune disorders which have T-cell and humoral components. However, a recent Tunisian report demonstrated no association between PTPN22 1858T and patients with Pemphigus vulgaris (PV), an autoantibody-associated blistering disorder. Because PTPN22 1858T allele frequency is known to vary across ethnic populations, we conducted a case-control study investigating the relationship between PTPN22 1858T and PV in North American patients of either Ashkenazi Jewish or Caucasian (non-Ashkenazi) decent. Participant genotype was determined in 102 PV patients and 102 healthy controls by restriction fragment length polymorphism-polymerase chain reaction genotyping. Relationships were calculated using Fisher's exact tests and chi squared tests. We report that the PTPN22 1858C/T genotype is not significantly associated with PV in either Caucasians (P = 0.83) or Ashkenazi Jews (P = 0.60). Further stratification of the patient population by gender, age of disease onset, HLA-type, family history of autoimmune disease, history of anti-desmoglein (anti Dsg) 3 or anti-Dsg1 antibody response, history of lesion morphology, and disease duration did not uncover significant associations between the PTPN22 1858T allele and PV subgroups. Our data indicate that the PTPN22 1858T mutation is not associated with PV in the North American population. We do observe an elevation of PTPN22 1858C/T genotype frequency in male PV patients. Further investigation will be required to determine if this trend reaches significance in larger studies. PMID- 21585556 TI - Gene expression analysis of leprosy by using a multiplex branched DNA assay. AB - Leprosy is caused by Mycobacterium leprae, and the global registered prevalence of leprosy at the beginning of 2009 stood at 213,036 cases. It has long been thought that leprosy has a strong genetic risk. Recently, we have identified significant associations (P < 1.00 * 10(-10)) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR and RIPK2 and a trend towards an association (P = 5.10 * 10(-5)) with a SNP in LRRK2. Here, we investigated the expression of these seven genes in formalin-fixed, paraffin-embedded skin tissues of leprosy and matched normal tissues using branched DNA technology. This technology allows for direct measurement of targeted mRNA within cellular lysate using a 96-well plate format in a time frame compared to a reporter gene assay. The clear upregulation of all seven genes was found in leprosy tissues compared to normal tissues, which further supports our genome-wide association study results. PMID- 21585557 TI - From skin to the treatment of diseases--the possibilities of iPS cell research in dermatology. AB - Induced pluripotent stem cells (iPSCs) can be generated from different somatic cell types through ectopic expression of a set of transcription factors. iPSCs acquire all the features of embryonic stem cells (ESCs) including pluripotency and can thus give rise to any cell type of the body. iPSCs comparable with ESCs are amenable for the correction of gene mutations by homologous recombination. Patient-derived iPSCs may thus be an ideal source for studying diseases in vitro and for treating different disorders in the clinic. In this review, we summarize recent advances and possibilities of iPSC research with focus on the field of dermatology. PMID- 21585558 TI - Characterization of a new acne vulgaris treatment device combining light and thermal treatment methods. AB - BACKGROUND/PURPOSE: Conventional treatment methods for acne vulgaris have various side effects such as the development of bacterial resistance, phototoxicity, vertigo, gastro-intestinal problems, and drug eruptions. To minimize such side effects, light and thermal methods have been alternately suggested. This study characterized a new acne vulgaris treatment device (AVTD) that combines both light and thermal methods and evaluated its clinical efficacy. METHODS: We characterized the thermal and light properties of the AVTD itself and evaluated its thermal characteristics in ex vivo porcine skin samples. The Arrhenius equation was used to calculate the skin thermal injury coefficient to confirm the skin safety of the AVTD. Finally, the clinical efficacy of the AVDT was evaluated by analyzing cross-polarization and erythema index images, which were obtained from 13 volunteers undergoing treatment with the AVTD. RESULTS: The temperature of the AVTD itself was maintained at 49.1 degrees C on the tip and 39.7 degrees C in the porcine skin samples. The peak intensity of the light-emitting diode (LED) light was observed at 468 nm. The skin safety of the AVTD was confirmed and 84.2% of the volunteers presented positive treatment results. CONCLUSION: The treatment of acne using the AVTD resulted in a high treatment rate in a clinical study, minimizing side effects. On the basis of these results, we can be sure that the AVTD may be effectively used for the treatment of acne vulgaris. PMID- 21585559 TI - A novel influenza a (H1N1) virus as a possible cause of pityriasis rosea? A comment. PMID- 21585560 TI - Association of SPINK5 gene polymorphisms with atopic dermatitis in Northeast China. AB - BACKGROUND: Defect in the SPINK5 gene is known to be implicated in Netherton syndrome (NS), and has been suggested to be a locus predisposing to atopy in general. Coding polymorphisms in SPINK5 exons 13, 14 and 26 have been reported to be associated with atopic dermatitis (AD), asthma and high level of IgE. OBJECTIVES: To examine whether the SPINK5 gene polymorphisms are associated with AD in Northeast China, and to assess how variants influence selected phenotypic traits. METHODS: A case-control study was conducted on four non-synonymous polymorphisms in the coding region of SPINK5 in AD and controls. The SPINK5 gene polymorphisms were analyzed using the PCR and RFLP methods. RESULTS: For the four non-synonymous SNPs, A1103G(Asn368Ser), G1156A(Asp386Asn), G1258A(Glu420Lys), G2475T(Glu825Asp) in SPINK5, the allelic frequencies in the AD cohort were 0.55 for 1103G, 0.57 for 1156A, 0.54for 1258A, 0.62 for 2475T, consistent with those already published in the original British and Japanese cohorts. The T allele of SNP 2475G > T was found to be significantly associated with AD. There were significant differences in genotype frequencies for G1258A(Glu420Lys) and G2475T(Glu825Asp) but not for A1103G(Asn368Ser) and G1156A(Asp386Asn). Genotypes GA(420Glu/Lys), TT (2475Asp/Asp) and GT(2475Glu/Asp) were significantly more frequent in AD. However, the SPINK5 gene polymorphisms was found not to be associated with AD in regard to either serum IgE levels, concurrent allergic asthma or early onset of AD. CONCLUSIONS: Our study confirms the association between SPINK5 and AD. PMID- 21585561 TI - Clinical and dermoscopic characteristics of amelanotic melanomas that are not of the nodular subtype. AB - BACKGROUND: Amelanotic melanomas remain challenging to diagnose. OBJECTIVE: To analyze and describe the clinical and dermoscopic characteristics of amelanotic melanomas that are not of the nodular subtype. PATIENTS/METHODS: We conducted a retrospective review of 20 consecutively diagnosed amelanotic melanomas. The clinical and dermoscopic images of pathologically confirmed amelanotic melanomas that were not of the nodular subtype were analyzed. In addition, the clinical diagnosis and the reasons why these lesions were biopsied were examined. RESULTS: All 20 amelanotic melanomas were erythematous and lacked any of the clinical ABCD features commonly attributed to melanoma. The lesions appeared clinically to be relatively symmetric with regular borders and manifesting a circular to oval morphology. Dermoscopically, all lesions manifested polymorphous vascular pattern. CONCLUSIONS: Amelanotic melanomas that are not of the nodular subtype often present as clinically symmetric erythematous lesions. Therefore, it is important to consider AMs in the differential diagnosis of isolated and persistent erythematous outlier lesions, even if they are symmetric in appearance. Additionally, the presence of a polymorphous vascular pattern seen with dermoscopy can facilitate in correctly identifying these melanomas. PMID- 21585562 TI - Human parvovirus B19: general considerations and impact on patients with sickle cell disease and thalassemia and on blood transfusions. AB - Human parvovirus B19 (B19V) is a small (22-24 nm) nonenveloped DNA virus belonging to the genus Erythrovirus (family Parvoviridae). Although it generally causes self-limiting conditions in healthy people, B19V infection may have a different outcome in patients with inherited hemolytic anemias. In such high-risk individuals, the high-titer replication may result in bone marrow suppression, triggering a life-threatening drop of hemoglobin values (profound anemia, aplastic crisis). To date there is no consensus concerning a B19V screening program either for the blood donations used in the hemotherapy or for high-risk patients. Moreover, questions such as the molecular mechanisms by which B19V produces latency and persistent replication, the primary site (sites) of B19V infection and B19V immunopathology are far from being known. This review summarizes general aspects of B19V molecular characteristics, pathogenesis and diagnostic approaches with a focus on the role of this pathogen in blood transfusions and in patients with some hemoglobinopathies (sickle-cell disease, thalassemia). PMID- 21585563 TI - Feed consumption, nutrient utilization and serum metabolite profile of captive blackbucks (Antelope cervicapra) fed diets varying in crude protein content. AB - A feeding trial was conducted to determine the optimum level of crude protein (CP) in the diet of captive blackbuck (Antelope cervicapra) in which feed consumption and nutrient utilization are maximal. Fifteen blackbucks (BW 25-34 kg) were distributed into three groups of five each in an experiment of 75-days duration including a digestion trial of 5-day collection period. All the animals were offered 200 g of concentrates and fresh maize fodder ad libitum. The overall CP content of the three respective diets was 6.9%, 10.4% and 12.7%. Blood samples were collected on the last day of the experiment. Intake and digestibility of CP increased (p < 0.01) with the increased level of CP in the diet. Feed consumption and nutrient intake were not significantly different among the groups. However, digestibilities of most of the nutrients were higher in the 10.4% CP diet than in the 6.9% CP diet. The endogenous loss of nitrogen was similar among the groups. Based on the endogenous losses, minimum N requirement was calculated to be 776 mg/kg BW(0.75) /day, and to meet this requirement, diet must contain at least 8.27% CP. Serum urea nitrogen concentration increased (p < 0.01) with increased level of dietary CP. Serum level of glutamate oxaloacetate transaminase and glutamate pyruvate transaminase was higher (p < 0.05) in the group fed 6.9% CP diet. Animals in the group fed low protein diet also lost body mass during the experimental period. It was concluded that a diet containing 10.4% CP was optimum for maximizing nutrient utilization without any adverse effect on voluntary feed consumption and serum metabolite profile of blackbucks. PMID- 21585564 TI - Effects of dietary inclusion of Rhus coriaria on internal milieu of rabbits. AB - The aim of the present work was to investigate the effect of Rhus coriaria L. inclusion to the diet on some biochemical, haematological parameters and the level of antioxidant status of male rabbits. Adult rabbits were divided into five groups: one control (C) and four experimental groups. Experimental animals received sumac per os in feed in various doses (0.50%, 0.75%, 1.00% and 1.50%) for 90 days. Significant increase in PDWc (platelet distribution width) in E3 group when compared with control group was recorded. Sumac administration resulted in decreased cholesterol levels in all experimental groups vs. control group. Significantly lower level of cholesterol was found in E4 group with highest dose of sumac (1.50%). Higher values of total antioxidant status (TAS) and albumins were observed in all experimental groups in comparison with control group. A significant increase in TAS was detected in group E1 and E4. Concentrations of albumins were significantly higher in groups E3 and E4 vs. control group. Sumac administration had no significant effect on bilirubin content. In conclusion, these results show a positive effect of sumac consumption on antioxidant status and cholesterol level in adult male rabbits. PMID- 21585565 TI - The N-terminal part of Als1 protein from Candida albicans specifically binds fucose-containing glycans. AB - The opportunistic pathogen Candida albicans expresses on its surface Als (Agglutinin like sequence) proteins, which play an important role in the adhesion to host cells and in the development of candidiasis. The binding specificity of these proteins is broad, as they can bind to various mammalian proteins, such as extracellular matrix proteins, and N- and E-cadherins. The N-terminal part of Als proteins constitutes the substrate-specific binding domain and is responsible for attachment to epithelial and endothelial cells. We have used glycan array screening to identify possible glycan receptors for the binding domain of Als1p N. Under those conditions, Als1p-N binds specifically to fucose-containing glycans, which adds a lectin function to the functional diversity of the Als1 protein. The binding between Als1p-N and BSA-fucose glycoconjugate was quantitatively characterized using surface plasmon resonance, which demonstrated a weak millimolar affinity between Als1p-N and fucose. Furthermore, we have also quantified the affinity of Als1p-N to the extracellular matrix proteins proteins fibronectin and laminin, which is situated in the micromolar range. Surface plasmon resonance characterization of Als1p-N-Als1p-N interaction was in the micromolar affinity range. PMID- 21585566 TI - The SLH-domain protein BslO is a determinant of Bacillus anthracis chain length. AB - The Gram-positive pathogen Bacillus anthracis grows in characteristic chains of individual, rod-shaped cells. Here, we report the cell-separating activity of BslO, a putative N-acetylglucosaminidase bearing three N-terminal S-layer homology (SLH) domains for association with the secondary cell wall polysaccharide (SCWP). Mutants with an insertional lesion in the bslO gene exhibit exaggerated chain lengths, although individual cell dimensions are unchanged. Purified BslO complements this phenotype in trans, effectively dispersing chains of bslO-deficient bacilli without lysis and localizing to the septa of vegetative cells. Compared with the extremely long chain lengths of csaB bacilli, which are incapable of binding proteins with SLH-domains to SCWP, bslO mutants demonstrate a chaining phenotype that is intermediate between wild-type and csaB. Computational simulation suggests that BslO effects a non-random distribution of B. anthracis chain lengths, implying that all septa are not equal candidates for separation. PMID- 21585567 TI - Body mass index and obesity in adolescents in a psychiatric medium secure service. AB - BACKGROUND: Obesity is more prevalent in adults with severe mental illness than in the general population. Little is known about the prevalence of obesity in mentally ill adolescents. The present study aimed to determine the prevalence of obesity and its complications among inpatients in a psychiatric medium secure service for adolescents and young people. METHODS: The study comprised a cross sectional survey of routinely collected data, including body mass index (BMI) both currently and 3 months previously, serum cholesterol and psychotropic prescription data, as well as the number of patients known to have type II diabetes mellitus and hypertension. RESULTS: Of the 95 patients studied, 33 (34.7%) were overweight and 45 (47.4%) were obese. Twenty-six (56.5%) females were obese, including seven who were morbidly obese. Nineteen (38.8%) males were obese, one of whom was morbidly obese. Prescription of antipsychotics was associated with obesity and the total percentage dose of antipsychotic correlated with BMI. Two patients had type 2 diabetes mellitus and two had hypertension. Seventeen patients had a serum cholesterol of over 5 mm. CONCLUSIONS: Being overweight and obesity were very common in the young people studied and appeared to be related to the prescription of antipsychotics. Interventions are needed to reduce unhealthy raised BMI and prevent the physical complications of obesity. PMID- 21585568 TI - Impact of protected mealtimes on ward mealtime environment, patient experience and nutrient intake in hospitalised patients. AB - BACKGROUND: Malnutrition is a common problem in hospitalised inpatients, resulting in a range of negative clinical, patient-centred and economic sequelae. Protected mealtimes (PM) aim to enhance the quality of the mealtime experience and maximise nutrient intake in hospitalised patients. The present study aimed to measure mealtime environment, patient experience and nutrient intake before and after the implementation of PM. METHODS: PM were implemented in a large teaching hospital through a range of different approaches. Direct observations were used to assess ward-level mealtime environment (e.g. dining room use, removal of distractions) (40 versus 34 wards) and individual patient experience (e.g. assistance with eating, visitors present) (253 versus 237 patients), and nutrient intake was assessed with a weighed food intake at lunch (39 versus 60 patients) at baseline and after the implementation of PM, respectively. RESULTS: Mealtime experience showed improvements in three objectives: more patients were monitored using food/fluid charts (32% versus 43%, P = 0.02), more were offered the opportunity to wash hands (30% versus 40%, P = 0.03) and more were served meals at uncluttered tables (54% versus 64%, P = 0.04). There was no difference in the number of patients experiencing mealtime interruptions (32% versus 25%, P = 0.14). There was no difference in energy intake (1088 versus 837 kJ, P = 0.25) and a decrease in protein intake (14.0 versus 7.5 g, P = 0.04) after PM. CONCLUSIONS: Only minor improvements in mealtime experience were made after the implementation of PM and so it is not unexpected that macronutrient intake did not improve. The implementation of PM needs to be evaluated to ensure improvements in mealtime experience are made such that measurable improvements in nutritional and clinical outcomes ensue. PMID- 21585569 TI - The THEMA study: a sociodemographic survey of hypercholesterolaemic individuals. AB - BACKGROUND: Hypercholesterolaemia is estimated to affect 20% of the population, although little sociodemographic information is available on affected individuals. The present study aimed to gather relevant information and investigate social determinants of dietary compliance. METHODS: A telephone survey was carried out on a representative population sample. Quotas were applied for gender, geography and degree of urbanisation. Individuals were eligible if they were hypercholesterolaemic, and were being followed by a doctor. Sociodemographic, socioeconomic and health data were collected, as well as information about the individuals' perception of the disease, their relationship and beliefs surrounding food, and their food behaviour (shopping, cooking, eating out, deviation from prescribed diet). The association between compliance with diet and medication was investigated. RESULTS: Overall, 802 individuals were included, representing 8% of those contacted, as opposed to the expected 20%. Mean (SD) age was 60 (14.2) years, with 51% of individuals living as a couple; 48% had a good level of physical activity; 44% considered that the hypercholesterolaemia was inherited; 31% felt that the disease was normal beyond the age of 45 years. The functional and convivial aspects of eating were of more importance than that of health maintenance. Cheese was particularly likely to be eaten in dietary lapses. Of a subgroup of 729 individuals, 476 (65%) took medication; of these 476 individuals, 51% complied with dietary recommendations (P < 0.05). CONCLUSIONS: The key factors associated with dietary compliance in hypercholesterolaemic individuals were identified: age, sex, the perceptions of hypercholesterolaemia, and the sociocultural aspects of food. By contrast to general assumptions, both dietary and medicinal measures are practised fairly well by a large proportion of these individuals. PMID- 21585570 TI - Suppression of the rice heterotrimeric G protein beta-subunit gene, RGB1, causes dwarfism and browning of internodes and lamina joint regions. AB - In the present study, we investigated the function of the heterotrimeric G protein beta-subunit (Gbeta) gene (RGB1) in rice. RGB1 knock-down lines were generated in the wild type and d1-5, a mutant deficient for the heterotrimeric G protein alpha-subunit (Galpha) gene (RGA1). Both transgenic lines showed browning of the lamina joint regions and nodes that could be attributed to a reduction of RGB1 function, as the abnormality was not observed in d1-5. The RGB1 knock-down lines generated in d1-5 were shorter, suggesting RGB1 to be a positive regulator of cellular proliferation, in addition to RGA1. The number of sterile seeds also increased in both RGB1 knock-down lines. These results suggest that Gbetagamma and Galpha cooperatively function in cellular proliferation and seed fertility. We discuss the potential predominant role of RGB1 in G protein signaling in rice. PMID- 21585571 TI - The transcription factor EMISSION OF BENZENOIDS II activates the MYB ODORANT1 promoter at a MYB binding site specific for fragrant petunias. AB - Fragrance production in petunia flowers is highly regulated. Two transcription factors, ODORANT1 (ODO1) and EMISSION OF BENZENOIDS II (EOBII) have recently been identified as regulators of the volatile benzenoid/phenylpropanoid pathway in petals. Unlike the non-fragrant Petunia hybrida cultivar R27, the fragrant cultivar Mitchell highly expresses ODO1. Using stable reporter lines, we identified the 1.2-kbp ODO1 promoter from Mitchell that is sufficient for tissue specific, developmental and rhythmic expression. This promoter fragment can be activated in non-fragrant R27 petals, indicating that the set of trans-acting factors driving ODO1 expression is conserved in these two petunias. Conversely, the 1.2-kbp ODO1 promoter of R27 is much less active in Mitchell petals. Transient transformation of 5' deletion and chimeric Mitchell and R27 ODO1 promoter reporter constructs in petunia petals identified an enhancer region, which is specific for the fragrant Mitchell cultivar and contains a putative MYB binding site (MBS). Mutations in the MBS of the Mitchell promoter decreased overall promoter activity by 50%, highlighting the importance of the enhancer region. We show that EOBII binds and activates the ODO1 promoter via this MBS, establishing a molecular link between these two regulators of floral fragrance biosynthesis in petunia. PMID- 21585575 TI - Using multiple data sources to answer patient safety-related research questions in hospital inpatient settings: a discursive paper using inpatient falls as an example. AB - AIM AND OBJECTIVES: This education-focused paper presents a discussion of possible data sources used in patient safety issues specific to fall reduction in hospital inpatient care settings. BACKGROUND: Although hospitals and clinicians in the USA have been implored to improve care and reduce events that harm patients (falls), studies to date have failed to clearly address the facility system-level factors for falls. Making meaningful approaches to modify risk factors is clearly overdue. DESIGN: Discursive paper. METHOD: Possible data sources for answering patient fall-related research questions in hospital settings are categorised as: (1) archived hospital data, (2) surveys of patients/families/clinicians, (3) interviews and focus groups of patients/families/clinicians, (4) publicly available data sets and (5) published legal cases. The complexities of research in fall prevention are illustrated using the conceptual models. Examples were included to illustrate the use of these data sources. DISCUSSION: Data-related issues include: (1) unit of analysis, (2) computer data processing capabilities, (3) merging data sets from different sources and (4) data abstraction, aggregation and data analytic techniques. CONCLUSIONS: The trend to use multiple data sources to answer research questions is gradually emerging. To demonstrate effective fall prevention efforts across hospitals, publicly available data sets can be reliable sources for analyses to inform policymakers about meaningful fall prevention programmes that result in positive outcomes. RELEVANCE TO CLINICAL PRACTICE: Challenges to develop and evaluate any interventions to eliminate risk factors for falls often relate to selecting feasible interventions and whether staff members accept the interventions and adhere to adopting the intervention. Using multiple data sources with time factors to cross-validate the sufficiency of nurses' knowledge with their practice patterns may be more productive. This need further supports the importance of this paper about possible data sources used in the research on patient safety specific to fall reduction for adults in hospital inpatient care settings. PMID- 21585576 TI - Development of an evidence-based scoring system (HF-IS) to assess the quality of heart failure programmes for patients postdischarge from hospital. AB - AIM: The aim of this study was to develop a potential scoring algorithm for interventions in a chronic heart failure management programme--the Heart Failure Intervention Score--to facilitate quality improvement and programme auditing. BACKGROUND: The overall efficacy of chronic heart failure management programmes has been demonstrated in several meta-analyses. However, meta-analyses did not determine individual interventions in a programme that resulted in beneficial patient outcomes. DESIGN: A prospective cross-sectional survey design. METHOD: All chronic heart failure management programmes in Australia (n = 62), identified by a national register, were surveyed to determine programme characteristics and interventions. RESULTS: Of the 62 national chronic heart failure management programmes, 48 (77%) completed the survey and 27 individual interventions were identified. Variability in the use of the key interventions was common among the programmes. Each intervention was given an arbitrary weighted score according to the level of supportive evidence available and a total score calculated. Programmes were then categorised into low or high complexity based on several interventions implemented and their weighted score. A total score of >=190 (median = 178, interquartile range 176-195) was used to divide programmes into two groups. Nine programmes were categorised into high Heart Failure Intervention Score group and majority of these were based in the acute hospital setting (78%). In the low Heart Failure Intervention Score group, there were 39 programmes of which there were a higher proportion of community-based programmes (38%) and programmes in small community hospitals (10%). CONCLUSION: The Heart Failure Intervention Score provides a potential evidence-based quality improvement tool through which a set of minimum standards can be developed. Implementation of the Heart Failure Intervention Score provides guidance to programme coordinators to enable monitoring of standards of heart failure programmes, which may potentially result in better patient outcomes. RELEVANCE TO CLINICAL PRACTICE: The Heart Failure Intervention Score is an evidence-based tool that can be easily used by heart failure programme coordinators to ensure that their programme is evidence based, which will improve the quality of their programme and potentially programme outcomes. PMID- 21585577 TI - Assessing quality of life of older people with dementia in long-term care: a comparison of two self-report measures. AB - AIMS AND OBJECTIVES: This study sought to compare two well-known and well-used self-report quality of life questionnaires in terms of completion rates, reliability and assessment of quality of life. BACKGROUND: People with dementia have a meaningful experience of quality of life and several disease-specific instruments have been designed to capture self-report assessments. DESIGN: A quantitative survey design, with a convenience sample of older people with dementia from four long-term care facilities. METHOD: Sixty-one participants were recruited for survey on the Dementia Quality of Life questionnaire and the Quality of Life in Alzheimer's Disease questionnaire. RESULTS: The Quality of Life in Alzheimer's Disease questionnaire had a higher rate of completion (98.4%) than the Dementia Quality of Life questionnaire (68.9%). Those unable to complete the latter measure had significantly greater cognitive impairment (F(1,59) = 30.35, p < 0.001) than those completing the measure. Internal reliability was good for the Quality of Life in Alzheimer's Disease questionnaire (0.86), but there were varying levels found for the five Dementia Quality of Life questionnaire subscales (0.79-0.48). The Quality of Life in Alzheimer's Disease questionnaire was significantly correlated with all the Dementia Quality of Life questionnaire subscales and overall item. CONCLUSIONS: Although it is recognised that there is no superior instrument in assessing quality of life, this study found both the Quality of Life in Alzheimer's Disease questionnaire and Dementia Quality of Life questionnaire to be useful self-report instruments. RELEVANCE TO CLINICAL PRACTICE: Assessment of quality of life should include the perspective of the person with dementia. The Quality of Life in Alzheimer's Disease questionnaire and Dementia Quality of Life questionnaire appear to measure similar aspects of quality of life. Where assessments are sought from participants with more advanced cognitive and functional impairment, it may be favourable to employ the Quality of Life in Alzheimer's Disease questionnaire. PMID- 21585578 TI - Influence of helix 12 of Ultraspiracle on Drosophila melanogaster ecdysone receptor function. AB - Although it has no ligand, helix 12 in the ligand binding domain of Ultraspiracle (USP) is locked in an antagonistic position. To investigate whether this position is of functional importance, we enhanced the flexibility of helix 12 by mutating two amino acids (259, located in L1-3 and F491 in helix 12). Mutated USP reduces the stability of USP and all isoforms of the ecdysone receptor (EcR) and impairs nuclear localization and DNA binding of EcR/USP(L259A/F491/A), resulting in lower levels of basal transcriptional activity. Although the affinity of the ligand ponasterone A to EcR/USP(L259/F491) is moderately diminished, hormone-induced stimulation of transcriptional activity is normal. Potentiation of the ecdysone response by juvenile hormone (JH) is selectively increased in mutated heterodimers with EcR-B1, demonstrating that the antagonistic position impairs functional interaction of the EcR complex with JHIII. PMID- 21585579 TI - beta-Thymosin is upregulated by the steroid hormone 20-hydroxyecdysone and microorganisms. AB - Thymosins have diverse biological activities including actin-sequestering and tissue repair in vertebrates, however, there is little information about the function of thymosins in invertebrates. We isolated a beta-thymosin gene in Helicoverpa armigera. It has two transcript variants, HaTHY1 and HaTHY2, encoding 19.0 kDa and 14.5 kDa peptides, respectively. HaTHY1 was mainly transcribed in the integument and midgut, while HaTHY2 was principally presented in the fat body and haemocytes. The transcript levels of HaTHY2 showed some fluctuation; there was an obvious increase at the metamorphic stage in the integument or fat body. HaTHY was able to be upregulated by 20-hydroxyecdysone or by bacterial and viral challenge. These data suggest that HaTHY is upregulated by the steroid hormone and by responses to microorganism infection. PMID- 21585580 TI - Genetic structuring and recent demographic history of red pandas (Ailurus fulgens) inferred from microsatellite and mitochondrial DNA. AB - Clarification of the genetic structure and population history of a species can shed light on the impacts of landscapes, historical climate change and contemporary human activities and thus enables evidence-based conservation decisions for endangered organisms. The red panda (Ailurus fulgens) is an endangered species distributing at the edge of the Qinghai-Tibetan Plateau and is currently subject to habitat loss, fragmentation and population decline, thus representing a good model to test the influences of the above-mentioned factors on a plateau edge species. We combined nine microsatellite loci and 551 bp of mitochondrial control region (mtDNA CR) to explore the genetic structure and demographic history of this species. A total of 123 individuals were sampled from 23 locations across five populations. High levels of genetic variation were identified for both mtDNA and microsatellites. Phylogeographic analyses indicated little geographic structure, suggesting historically wide gene flow. However, microsatellite-based Bayesian clustering clearly identified three groups (Qionglai-Liangshan, Xiaoxiangling and Gaoligong-Tibet). A significant isolation by-distance pattern was detected only after removing Xiaoxiangling. For mtDNA data, there was no statistical support for a historical population expansion or contraction for the whole sample or any population except Xiaoxiangling where a signal of contraction was detected. However, Bayesian simulations of population history using microsatellite data did pinpoint population declines for Qionglai, Xiaoxiangling and Gaoligong, demonstrating significant influences of human activity on demography. The unique history of the Xiaoxiangling population plays a critical role in shaping the genetic structure of this species, and large-scale habitat loss and fragmentation is hampering gene flow among populations. The implications of our findings for the biogeography of the Qinghai-Tibetan Plateau, subspecies classification and conservation of red pandas are discussed. PMID- 21585581 TI - 'Doubly deprived': a post-death qualitative study of primary carers of people who died in Western Australia. AB - This paper explores the daily experiences and occupational needs of family carers of people who were dying, with particular reference to their daily routines and ability to undertake other varied activities during the period of care. The impact of the caring experience on these occupations was then examined to determine how, and if, these occupational needs were addressed in the community using potential and available services. An exploratory approach using grounded theory was employed to examine these experiences. Participants were recruited from metropolitan (n = 10) and rural (n = 4) locations across Western Australia between February and June 2009, using a purposive sampling method. A semi structured interview guide was developed following consultation with the literature, expert opinion and piloting. Interviews were conducted in participants' homes and questions were asked about their experiences as a carer including routines, engagement in usual activities and the impact of the caring role on their daily life during and after the period of care. Each interview was transcribed verbatim and analysed to determine potential themes. Two important themes were identified: (1) Carers experienced disengagement and deprivation from their usual occupations during and after the period of care; and (2) Participants described significant disempowerment in their role as carer. Carers are 'doubly disadvantaged' as a result of their caring role; they are unable to participate in their usual occupations and they are not recognised for their contributions as carers. Carers experienced disengagement and deprivation from their usual occupations, contributing to physical, psychological and emotional difficulties and this may result in long term consequences for health and well-being. In addition, the current services and support available for carers in the community are deemed inadequate; placing further stress on a health care system which needs to cope with increasing demands as a result of the ageing population in Australia. PMID- 21585582 TI - Healthcare-seeking patterns among immigrants in Portugal. AB - Equity of access to health services is a major concern as it is an important precondition for positive health outcomes. However, inequities in use of health services among immigrant populations persist. Despite the increasing research in the field, patterns of healthcare seeking among immigrant populations and its associated factors are not fully understood. This study aimed to investigate healthcare-seeking patterns among immigrants in Portugal and identify factors associated with utilisation of health services. A cross-sectional study was conducted between October 2008 and May 2009 with a sample of 1,375 immigrants residing in the Lisbon region. Data were collected through a structured questionnaire applied by trained interviewers. Two stepwise logistic regressions were conducted to identify which factors were associated with utilisation of the National Health Service (NHS) and with healthcare seeking for the first time in Portugal at the Primary Health Care service, estimated by calculating odds ratios and 95% confidence intervals. Among participants, around 77% reported having used the NHS; 50% sought health-care for the first time at the Primary Health Care service and 33% at the emergency room. Lower odds of having used the NHS were associated with being male, Brazilian or eastern European compared with being African, and undocumented. Lower odds of having sought health-care for the first time at the Primary Health Care service were associated with being male and undocumented. These results suggest that further efforts are needed to tackle inequalities in access to care and promote the utilisation of health services, particularly among the more vulnerable immigrant groups. Increasing appropriate utilisation of health services, including the primary and preventive care services, may lead to better health outcomes. Immigrants' involvement and participation should be incorporated into the development of health strategies to improve access and utilisation of healthcare services. PMID- 21585583 TI - Fecundity selection on ornamental plumage colour differs between ages and sexes and varies over small spatial scales. AB - Avian plumage colours are some of the most conspicuous sexual ornaments, and yet standardized selection gradients for plumage colour have rarely been quantified. We examined patterns of fecundity selection on plumage colour in blue tits (Cyanistes caeruleus L.). When not accounting for environmental heterogeneity, we detected relatively few cases of selection. We found significant disruptive selection on adult male crown colour and yearling female chest colour and marginally nonsignificant positive linear selection on adult female crown colour. We discovered no new significant selection gradients with canonical rotation of the matrix of nonlinear selection. Next, using a long-term data set, we identified territory-level environmental variables that predicted fecundity to determine whether these variables influenced patterns of plumage selection. The first of these variables, the density of oaks within 50 m of the nest, influenced selection gradients only for yearling males. The second variable, an inverse function of nesting density, interacted with a subset of plumage selection gradients for yearling males and adult females, although the strength and direction of selection did not vary predictably with population density across these analyses. Overall, fecundity selection on plumage colour in blue tits appeared rare and inconsistent among sexes and age classes. PMID- 21585584 TI - Signature of selection on the rhodopsin gene in the marine radiation of American seven-spined gobies (Gobiidae, Gobiosomatini). AB - In comparison with terrestrial and freshwater ecosystems, information about speciation modes and the role of selection in marine environments is scarce. Recent studies have indicated that spectral adaptation could play an important role in the diversification of marine species flocks. Natural selection influences specific amino acids (AAs) that are involved in the spectral tuning mechanism of visual pigment genes. To study the wider occurrence and the characteristics of spectral adaptation in marine radiations, a reinterpretation of the rhodopsin (RH1) data of American seven-spined gobies (genus Elacatinus; Gobiidae; Teleostei) was carried out. Reanalysis revealed that some AAs, which are well known in the literature as spectral tuning sites, are variable in Elacatinus. Those crucial AA substitutions originated polyphyletically, indicating convergent evolution within the genus Elacatinus. Moreover, statistical tests based on the d(N)/d(S) ratio detected selection in several phylogenetic lineages and at specific AAs. Many of these AAs were previously shown to be under selection in other marine radiations. Therefore, the current phylogenetic approach provided an extended list of AAs that are probably involved in spectral tuning, and which should be validated by mutagenic experiments. PMID- 21585585 TI - Direct fitness for dynamic kin selection. AB - The direct-fitness approach to modelling the evolution of social traits is an alternative to the classical inclusive-fitness-based approach. Despite both its utility and popularity, the direct-fitness approach has not yet been extended to include the analysis of dynamic traits, i.e. traits whose level of expression may vary over time. In this article, I apply the direct-fitness approach to cope with the evolution of a dynamic resource-allocation behaviour when this behaviour influences the fitness of relatives. I am able to implement the direct-fitness approach using components (reproductive value, fitness changes and measures of relatedness) found in standard, social-evolutionary models. I illustrate the modified direct-fitness model with an example studied by previous authors, and I show how the direct-fitness perspective can aid the validation of analytical results by means of a genetic algorithm. PMID- 21585586 TI - Evidence of multiple paternity and mate selection for inbreeding avoidance in wild eastern chipmunks. AB - Mate selection for inbreeding avoidance is documented in several taxa. In mammals, most conclusive evidence comes from captive experiments that control for the availability of mates and for the level of genetic relatedness between mating partners. However, the importance of mate selection for inbreeding avoidance as a determinant of siring success in the wild has rarely been addressed. We followed the reproduction of a wild population of eastern chipmunks (Tamias striatus) during five breeding seasons between 2006 and 2009. Using molecular tools and parentage assignment methods, we found that multiple paternity (among polytocous litters) varied from 25% in an early-spring breeding season when less than a quarter of females in the population were reproductively active to 100% across three summer breeding seasons and one spring breeding season when more than 85% of females were reproductively active. Genetically related parents were common in this population and produced less heterozygous offspring. Furthermore, litters with multiple sires showed a higher average relatedness among partners than litters with only a single sire. In multiply sired litters, however, males that were more closely related to their partners sired fewer offspring. Our results corroborate findings from captive experiments and suggest that selection for inbreeding avoidance can be an important determinant of reproductive success in wild mammals. PMID- 21585587 TI - Effect of engaging abutment position in implant-borne, screw-retained three-unit fixed cantilevered prostheses. AB - PURPOSE: To investigate the effects of internally connected engaging component position in screw-retained fixed cantilevered prostheses. MATERIALS AND METHODS: Twenty-one three-unit fixed dental prostheses (FDPs) were cast in high-palladium alloy in three groups. In group A, engaging components were incorporated into the units away from the cantilevered segment; proximal units received nonengaging components. In group B, these positions were reversed. Control specimens were fabricated using all nonengaging components. Specimens were attached to internally connected 3.5 (diameter) * 13 mm (length) implants, torqued to 32 Ncm, and embedded into epoxy resin. Specimens were tested in cyclic fatigue with a 2 Hz sine wave and 0.1 min/max load ratio. Load amplitude started at 1.8 N and increased by 1.8 N every 60 cycles until fracture. Log-rank statistic, ANOVA, Spearman's correlation, and LIFETEST procedures were used to evaluate level of statistical significance within the results. RESULTS: In the control group, the mean number of cycles to fracture was 31,205 +/- 2639. Mean axial force at fracture was 932 +/- 78 N. In group A, these numbers were 38,160 +/- 4292 and 1138 +/- 128 N, and in group B, 31,810 +/- 3408 and 949 +/- 101 N. Statistical significance levels for number of cycles to fracture were: Control versus group A, p = 0.0117, and groups A versus B, p = 0.0156 (statistically significant). Control versus group B, p = 0.357 (not statistically significant). Log-rank statistic for the survival curves is greater than would be expected by chance; there was a statistically significant difference between survival curves (p = 0.012). The location and mode of failure were noteworthy (always in the abutment screw). CONCLUSIONS: The position of the engaging component had significant effects on the results. Within the limitations of this investigation, it can be concluded that using an engaging abutment in a screw-retained fixed cantilevered FDP provides a mechanical advantage, and engaging the implant furthest from the cantilever when designing a screw-retained cantilever FDP increased resistance to fracture of the distal abutment screw. PMID- 21585588 TI - Condylar paths during protrusion in edentulous patients: analysis with electronic axiography. AB - PURPOSE: The aim of this study was to determine the condylar form, incline, and movement characteristics during protrusive movement in fully edentulous complete denture wearers. The study went on to analyze the occlusal consequences on the setup of artificial posterior teeth and the occlusal grinding phase. MATERIALS AND METHODS: The study included 60 complete denture wearers (aged 58 to 74 years), who received a new set of complete dentures for this study. The patients did not present signs of muscular or articular pain. Protrusive movements were recorded by a SAM((r)) electronic axiography system. RESULTS: Condylar paths exhibited fairly specific characteristics in the completely edentulous patients, particularly path forms, which had highly specific patterns. Three condylar path forms were determined: the classic form following a convex curve (41% of cases), a sinusoidal form that flattened out in the first 2 mm before following a convex curve (51%), and a rectilinear path (9%). The mean condylar angles also exhibited specific patterns. The mean started in the first millimeter of protrusive movement, at 32.2 degrees +/- 14.9 degrees , and then increased in the second millimeter to 40.4 degrees +/- 11.9 degrees , reaching 44.5 degrees +/- 9 degrees at 5 mm. CONCLUSION: During protrusive movement in completely edentulous patients, the condylar path patterns were different than conventionally described patterns. In particular, the sinusoidal form was frequently found, and the incline of the condylar slope was low. These factors need to be taken into account during the final occlusal selective grinding for new sets of complete dentures. PMID- 21585589 TI - A new technique for nasal stent fabrication for atrophic rhinitis: a clinical report. AB - Atrophic rhinitis is a chronic nasal disease characterized by progressive atrophy of the nasal mucosa accompanied by the formation of foul-smelling thick, dry crusts in the nasal cavities. Mild conditions of atrophic rhinitis can be treated by nasal irrigations and prescription of intravenous or topical aminoglycosides. In severe conditions, surgery can close the airways. The problem can also be managed by prosthodontic measures which include the fabrication of a poly methyl methacrylate acrylic resin nasal stents. This article describes a new procedure for fabricating a clear acrylic nasal stent with an alternative laboratory technique using small cylinders of soft putty as spacers for maintaining a 3-mm restricted nasal airway during processing. PMID- 21585590 TI - Treatment of maxillary jaws with dental implants: guidelines for treatment. AB - Maxillary implant prosthetic treatments may be considerably more difficult to accomplish when compared to the corresponding treatments for patients with edentulous or partially edentulous jaws. The objectives of this article include descriptions of diagnostic records and their impact on treatment success, and criteria clinicians should use to determine whether fixed or removable prostheses are the treatment of choice in any given situation. Specific criteria and clinical guidelines will be identified for use in the treatment planning process. Determination of optimal tooth positions and their relationships to residual ridges or extraction sites are one of the critical factors in determining designs for maxillary implant prostheses. Prosthetic designs (fixed or removable) should be determined by clinicians prior to placing implants; removable prostheses should not be considered to be the "fall-back" treatment option if fixed treatments become unavailable secondary to loss of implants or other clinical complications. Inherent differences between fixed and removable prosthetic treatments are critical for clinicians to understand, as they often include key points for clinicians explaining the features of fixed/removable-implant prostheses to patients. Appreciation of the differences between fixed and removable prostheses is critical for patients and clinicians to make informed decisions. PMID- 21585591 TI - Student-perceived factors for an enhanced advanced education program in prosthodontics recall system. AB - PURPOSE: A qualitative study of Advanced Education Programs in Prosthodontics (AEPPs) students was conducted to identify best practices to effectively promote ongoing health and student learning within the context of a patient-centered recall system. MATERIALS AND METHODS: Ten students from seven AEPPs nationwide were invited to participate in a focus group on recall systems within AEPPs. The discussion first identified whether an active recall program existed and then delved into benefits for patients and students, positive and negative features of existing recall systems, and factors that can be improved upon for an enhanced recall system. RESULTS: Participants advocated the highest standard of patient care, including regular ongoing care once restorative therapy is complete. Discussion indicates that not only does regular patient recall lead to health promotion, disease prevention, and monitoring of existing prostheses for the patient, but also provides for an enhanced learning experience for the students. Recognizing this, several students from AEPPs lacking an official recall system have established a "makeshift" system, encompassing a treatment completion letter, final intraoral photographs, patient education, and regular prosthetic evaluations, for their existing patients. CONCLUSIONS: Prosthodontic program students perceived their program's recall effectiveness could be improved. Due to the numerous potential benefits of an active recall system for both patients and students, some perceived factors to be improved upon include treatment completion protocol, patient education, and establishment of a patient-centered recall system managed by a team of hygienists, receptionists, attending faculty, and residents. PMID- 21585592 TI - The operative management of melanoma: where does Mohs surgery fit in? AB - BACKGROUND: Melanoma is a life-threatening malignancy. Surgery is the primary management for melanoma, and management guidelines have evolved gradually over a century from radical surgery with lymph node dissection to conservative margin surgery. There are specific rationales and problems with Mohs micrographic (MMS) surgery for managing melanoma. OBJECTIVE: To review the literature for the surgical management of melanoma and to understand where MMS fits in this spectrum of management options. CONCLUSIONS: MMS should be considered as an option for melanoma surgery, especially when the tumor is found in photodamaged skin. Further randomized prospective clinical trials are needed to select the best therapeutic approach for the treatment of melanoma. Until then, careful margin control is the key for successful tumor removal whether it is standard excision, staged excision, or MMS. PMID- 21585593 TI - Electrosurgery and implantable electronic devices: review and implications for office-based procedures. PMID- 21585594 TI - Aesthetic dermatology for aging ethnic skin. AB - BACKGROUND: Dark-skinned patients manifest the signs of skin aging differently than their fair-skinned counterparts in that the former exhibit more intrinsic facial aging, whereas the later shows more photodamage. Nevertheless, common cosmetic procedures can be used in skin of color to treat the signs of aging. OBJECTIVE: To provide updated clinical information on the use of cosmetic procedures for skin aging in darker phototypes for the safe treatment of this population. METHODS: A Medline literature search was performed for publications on the safety and efficacy of botulinum toxin, dermal fillers, chemical peels, laser and light-based devices, and microdermabrasion for the treatment of skin aging specifically in ethnic populations. RESULTS: Similarly to light-skinned patients, botulinum toxin and dermal fillers provide fast, effective results in skin of color, with fewer complications than with traditional surgery and no downtime. More-invasive procedures, such as chemical peeling, laser resurfacing, and microdermabrasion, can also be effective, but it is important to exercise caution and remain within certain parameters given the greater risk of dyschromias in this population. CONCLUSION: With the proper knowledge of how to treat aging skin of color, these patients can experience the benefits of cosmetic procedures while minimizing the risks. PMID- 21585596 TI - Eyebrow epilation by threading: an increasingly popular procedure with some less popular outcomes--a comprehensive review. PMID- 21585597 TI - Efficacy of 694-nm Q-switched ruby fractional laser treatment of melasma in female Korean patients. AB - BACKGROUND: Melasma is a common acquired symmetrical hypermelanosis of sun exposed areas of the skin. Although the classical Q-switched ruby laser (QSRL) has been used successfully for the removal of tattoos and for the treatment of cutaneous pigmented lesions, its efficacy for melasma remains controversial. OBJECTIVE: We used repeat low-dose fractional QSRL treatment for melasma and analyzed the clinical results. METHODS: Fifteen Korean women with melasma were enrolled. Each patient received six low-dose fractional QSRL treatments to the face at 2-week intervals. Two investigators independently evaluated Melasma Area and Severity Index (MASI) scores before each session and 4 and 16 weeks after the final session. The intensities of pigmentation and erythema were assessed by measuring skin reflectance using a tristimulus color analyzer. RESULTS: Mean MASI score decreased from 15.1 +/- 3.3 before treatment to 10.6 +/- 3.9 16 weeks after the final treatment. The lightness of pigmentation (L-value) increased from 56.6 +/- 3.5 before treatment to 59.9 +/- 2.8 16 weeks after the final treatment. CONCLUSIONS: Multiple treatment sessions of low-dose fractional QSRL may be an effective strategy for the treatment of dermal or mixed-type melasma. PMID- 21585598 TI - Facilitated scalp measuring using phototrichogram with a headband and tapeline. PMID- 21585599 TI - Technical feasibility and early results of radiologically guided foam sclerotherapy for treatment of varicose veins. AB - BACKGROUND: Duplex ultrasound guidance of foam sclerotherapy has been established as a routine and standard treatment of varicose veins, but duplex-guided technique is not perfect because of its inherent shortcomings, and correlative complications have been reported. Moreover, not every country or region of the world can use duplex ultrasound guidance for foam sclerotherapy. OBJECTIVE: To describe an original technique of using radiologically guided foam sclerotherapy for the treatment of leg varicose veins and to evaluate the technical feasibility and early results. MATERIALS AND METHODS: Fifty-nine legs of 41 patients (23 male, 18 female; median age 47, range 25-75) with leg varicose veins treated using radiologically guided foam sclerotherapy were assessed. Polidocanol 1% was foamed 1:4 with air using the Tessari method. Foam sclerotherapy of the superficial varicosities and the great saphenous veins (GSVs) were performed using the filling-defects technique under radiologic guidance. Postoperative compression was maintained for 15 days. Clinical outcome was assessed according to clinical criteria. RESULTS: The procedure was technically successful in all 59 legs. At a median 9.0 months (range 6-12 months) of follow-up, the clinical outcome was full success in 53 legs (89.8%), and partial success in six legs (10.2%). There was no evidence of recurrence of varices or GSV reflux during follow-up. Minor complications included skin pigmentation in 27 legs (45.8%), and superficial thrombophlebitis in 18 legs (30.5%). No major complications or systemic events occurred. CONCLUSIONS: Radiologically guided foam sclerotherapy could be a safe, effective, and technically feasible treatment for varicose veins. PMID- 21585600 TI - Hair transplantation for reconstruction of scalp defects using artificial dermis. PMID- 21585603 TI - Genome-wide DNA methylation profiles in noncancerous gastric mucosae with regard to Helicobacter pylori infection and the presence of gastric cancer. AB - BACKGROUND AND AIMS: To determine genome-wide DNA methylation profiles induced by Helicobacter pylori (H. pylori) infection and to identify methylation markers in H. pylori-induced gastric carcinogenesis. METHODS: Gastric mucosae obtained from controls (n = 20) and patients with gastric cancer (n = 28) were included. A wide panel of CpG sites in cancer-related genes (1505 CpG sites in 807 genes) was analyzed using Illumina bead array technology. Validation of the results of Illumina bead array technique was performed using methylation-specific PCR method for four genes (MOS, DCC, CRK, and PTPN6). RESULTS: The Illumina bead array showed that a total of 359 CpG sites (269 genes) were identified as differentially methylated by H. pylori infection (p < .0001). The correlation between methylation-specific PCR and bead array analysis was significant (p < .0001, Spearman coefficient = 0.5054). Methylation profiles in noncancerous gastric mucosae of the patients with gastric cancer showed quite distinct patterns according to the presence or absence of the current H. pylori infection; however, 10 CpG sites were identified to be hypermethylated and three hypomethylated in association with the presence of gastric cancer regardless of H. pylori infection (p < .01). CONCLUSIONS: Genome-wide methylation profiles showed a number of genes differentially methylated by H. pylori infection. Methylation profiles in noncancerous gastric mucosae from the patients with gastric cancer can be affected by H. pylori-induced gastritis. Differentially methylated CpG sites in this study needs to be validated in a larger population using quantitative methylation-specific PCR method. PMID- 21585602 TI - Vaccine-induced immunity against Helicobacter pylori in the absence of IL-17A. AB - BACKGROUND: Helicobacter pylori (H. pylori) is a gram negative bacterium that can cause diseases such as peptic ulcers and gastric cancer. IL-17A, a proinflammatory cytokine that can induce the production of CXC chemokines for neutrophil recruitment, has recently been shown to be elevated in both H. pylori infected patients and mice. Furthermore, studies in mouse models of vaccination have reported levels significantly increased over infected, unimmunized mice and blocking of IL-17A during the challenge phase in immunized mice reduces protective immunity. Because many aspects of immunity had redundant or compensatory mechanisms, we investigated whether mice could be protectively immunized when IL-17A function is absent during the entire immune response using IL-17A and IL-17A receptor knockout (KO) mice immunized against H. pylori. MATERIALS AND METHODS: Gastric biopsies were harvested from naive, unimmunized/challenged, and immunized/challenged wild type (WT) and KO mice and analyzed for inflammation, neutrophil, and bacterial levels. Groups of IL-17A KO mice were also treated with anti-IFNgamma or control antibodies. RESULTS: Surprisingly, all groups of immunized KO mice reduced their bacterial loads comparably to WT mice. The gastric neutrophil counts did not vary significantly between IL-17A KO and WT mice, whereas IL-17RA KO mice had on average a four-fold decrease compared to WT. Additionally, we performed an immunization study with CXCR2 KO mice and observed significant gastric neutrophils and reduction in bacterial load. CONCLUSION: These data suggest that there are compensatory mechanisms for protection against H. pylori and for neutrophil recruitment in the absence of an IL-17A-CXC chemokine pathway. PMID- 21585604 TI - Helicobacter pylori exhibits a fur-dependent acid tolerance response. AB - BACKGROUND: Helicobacter pylori colonizes the acid environment of the gastric mucosa. Like other enteric bacterial pathogens, including Salmonella enterica, which must survive a brief exposure to that environment, H. pylori displays a rapid response to subtle changes in pH, which confers an increased ability to survive at more extreme acidic pH. This two-step acid tolerance response (ATR) requires de novo protein synthesis and is dependent on the function of the global regulatory protein Fur. OBJECTIVE: We have explored the physiological bases of the ATR in H. pylori. MATERIALS AND METHODS: Proteomic analysis of phenotypes of H. pylori and fur mutant strains show that subtle pH changes elicit significant changes in the pattern of proteins synthesized. RESULTS: A loss-of-function mutation in the fur gene, obtained by insertion of an antibiotic resistance cassette, indicated that Fur regulates the expression of a fraction of H. pylori proteins. CONCLUSION: A subset of proteins is involved in the ATR and confer a negative ATR phenotype. PMID- 21585605 TI - Identification of Helicobacter pylori strain cagPAI+ and cagPAI- Antigens by IgG antibodies from sera of experimentally colonized meriones unguiculatus (Mongolian gerbils). AB - BACKGROUND: Mongolian gerbils that are experimentally infected with Helicobacter pylori develop a chronic inflammation that is similar to natural infections in humans. The aim of this study was to compare the antigens of H. pylori cagPAI+ and cagPAI- strains that are expressed during Meriones unguiculatus colonization. MATERIALS AND METHODS: We identified H. pylori cagPAI+ and cagPAI- strain antigens via Western blotting of samples from Mongolian gerbils that were subjected to unique, mixed, and sequential bacterial infections. RESULTS: The antigens from the J99/CG3 (cagPAI+) strain had a lower molecular weight than the antigens from the 251F/CG3 (cagPAI-) strain. There were fewer identified antigens in the single unique infections compared with the mixed and sequential infections. The number of recognized antigens that had a frequency of recognition >60% was higher for the simultaneous and sequential infection groups compared with the single infection group. A 57-kDa antigen was present in >60% of the samples and four of the five experimental groups. Antigens specific to each bacterial strain were identified; the 190- and 158-kDa antigens appear to be specific for cagPAI-, and the 70-kDa antigen appears to be specific for cagPAI+. CONCLUSIONS: In this study, we identified antigens that are common and specific to the H. pylori cagPAI+ and cagPAI- strains. PMID- 21585606 TI - Clinicopathological analysis of early-stage gastric cancers detected after successful eradication of Helicobacter pylori. AB - BACKGROUND AND AIMS: The results of a randomized controlled study and meta analysis study have recently proved that Helicobacter pylori eradication has a preventive effect against the development of metachronous and primary gastric cancer. However, gastric cancer is sometimes detected after successful eradication. There is a lack of study about gastric cancers in eradicated patients. To clarify the characteristics of gastric cancers detected after H. pylori eradication, we analyzed the clinicopathological features of these cancers. METHODS: The subjects were 18 early-stage gastric cancer specimens resected from 17 patients who had received successful eradication of H. pylori from February 1995 to March 2009. The control group consisted of 36 specimens from noneradicated patients with persistent H. pylori infection who were matched with the subjects in age, sex, and depth of invasion. Clinicopathological features and mucin phenotypes of gastric cancer were clinically and immunohistologically evaluated. RESULTS: The average diameter of gastric cancer was smaller and Ki-67 index was lower in the eradication group. The morphological distribution of depression types was significantly lower in the control group. Immunohistochemical phenotyping revealed that 72.2% of the lesions in the eradicated group were complete gastric type or gastric predominant mixed type, whereas the percentages of gastric type and intestinal type in the control group were similar. CONCLUSION: Our findings indicate that the clinicopathological characteristics of gastric cancers detected after H. pylori eradication are different from those of gastric cancers in patients with persistent H. pylori infection. H. pylori eradication may suppress intestinalization during the development of gastric cancer. PMID- 21585607 TI - Increased gastric osteopontin expression by Helicobacter pylori Infection can correlate with more severe gastric inflammation and intestinal metaplasia. AB - BACKGROUND: Osteopontin (OPN) is involved in the gastric cancer progression. The study validated whether OPN expressions correlate with Helicobacter pylori related chronic gastric inflammation and the precancerous change as intestinal metaplasia (IM). METHODS: This study included 105 H. pylori-infected patients (63 without and 42 with IM) and 29 H. pylori-negative controls. In each subject, the gastric OPN expression intensity was evaluated by immunohistochemistry, and graded from 0 to 4 for the epithelium, lamina propria, and areas with IM, respectively. For the H. pylori-infected subjects, the gastric inflammation was assessed by the Updated Sydney System. Forty-nine patients received follow-up endoscopy to assess OPN change on gastric mucosa after H. pylori eradication. The in vitro cell-H. pylori coculture were performed to test the cell origin of OPN. RESULTS: The H. pylori-infected patients had higher gastric OPN expression than the noninfected controls (p < .001). For the H. pylori-infected patients, an increased OPN expression correlated with more severe chronic gastric inflammation (p < .001) and the presence of IM (OR: 2.6, 95% CI: 1.15-5.94, p = .02). Within the same gastric bits, lamina propria expressed OPN stronger than epithelium (p < .001), suggesting OPN predominantly originates from inflammatory cells. The in vitro assay confirmed H. pylori stimulate OPN expression in the monocytes, but not in the gastric epithelial cells. After H. pylori eradication, the gastric OPN expression could be decreased only in areas without IM (p < .05). CONCLUSIONS: Increased gastric OPN expression by H. pylori infection can correlate with a more severe gastric inflammation and the presence of IM. PMID- 21585608 TI - A new modified concomitant therapy for Helicobacter pylori eradication in Turkey. AB - BACKGROUND: Helicobacter pylori eradication rates have tended to decrease recently, mostly due to antibiotic resistance. In the present study, our aim was to determine Hp eradication rate with the LAC plus tid metronidazole regimen and the secondary objective of this study was to identify an effective regimen for our population. METHODS: Eighty-four Hp-positive patients with non-ulcer dyspepsia were assigned into the same group. Patients were administered the classical LAC protocole (lansoprazole 30 mg bid, amoxicillin 1 g bid and claritromycin 500 mg bid for 14 days) plus metronidazole 500 mg tid for 14 days. Gastroscopy and histopathological assessment were performed before enrollment and C(14) urea breath test and stool antigen test were performed 6 weeks after treatment. RESULTS: All 84 patients completed the study. No patient left the study because of drug side effect. Total eradication rate was 75% (63/84). CONCLUSION: Although LAC plus tid metronidazole regimen achieved a much better eradication rate compared with the standard LAC regimen; this is the first study that has a relatively low success with a concomitant therapy. So in areas of high resistance like Turkey, one cannot expect a high success with any clarithromycin containing regimen and those should be avoided. PMID- 21585609 TI - High eradication rates of Helicobacter pylori infection following sequential therapy: the Israeli experience treating naive patients. AB - BACKGROUND: Helicobacter pylori eradication rates following triple therapy are decreasing. Cure rates as low as 57%, mainly to claritromycin resistance, have been reported in Israel. Studies performed in Italy have shown eradication rates of 93%, following sequential therapy. Our aim was to evaluate the effect of sequential therapy on eradication rates of H. pylori in naive Israeli patients. MATERIAL AND METHODS: Consecutive patients referred for esophagogastroduodenoscopy with a positive rapid urease test and positive (13) C urea breath test were included. Patients received omeprazole 20 mg bid and amoxicillin 1 g bid for 5 days followed by omeprazole 20 mg bid, clarithromycin 500 mg bid and tinidazole 500 mg bid for the subsequent 5 days. A second (13) C urea breath test was performed at least 4 weeks after completion of therapy. Patients were asked to avoid antibiotics, bismuth compounds or proton pump inhibitor until after the second (13) C urea breath test. Adverse effects were documented by a questionnaire. RESULTS: One hundred and twenty-four patients (mean age 56.1 +/- 12.5 years, 55.6% women) were included; 120/124 (96.8%) completed treatment and performed the second (13) C urea breath test. Two patients (1.6%) were lost to follow-up; 2 (1.6%) were noncompliant with study regulations. One hundred and fifteen patients achieved eradication of H. pylori. The eradication rate was 95.8% by per protocol analysis and 92.7% by intention to treat analysis. CONCLUSION: The sequential regimen attained significantly higher eradication rates in naive patients than usually reported for conventional triple therapy. Sequential therapy may be an alternative first-line therapy in eradicating H. pylori in Israel. PMID- 21585610 TI - Efficacy of 2-week, second-line Helicobacter pylori eradication therapy using rabeprazole, amoxicillin, and metronidazole for the Japanese population. AB - BACKGROUND: Following the failure of first-line Helicobacter pylori eradication therapy using a proton pump inhibitor, amoxicillin, and clarithromycin, second line therapy is conducted for 1 week using metronidazole instead of clarithromycin in Japan. Recent studies indicate that metronidazole-containing therapy has a higher eradication rate with prolonged treatment duration, even with metronidazole resistance. The aim of this study was to reveal the efficacy of 2-week metronidazole-containing second-line therapy. METHODS: Eighty-two consecutive outpatients who had failed in the first-line eradication therapy were enrolled and second-line therapy was initiated with 10 mg rabeprazole, 750 mg amoxicillin, and 250 mg metronidazole twice daily. After they had been screened by hematological examination 1 week after initiation, the treatment was continued for 2 weeks after initiation in patients without hematological abnormality. Cure was essentially confirmed by the urea breath test. RESULTS: After one patient was lost, hematological examination showed elevated serum aminotransferase in 14 of 81 patients. Although it was mild without clinical issues, they were ethically excluded from this study. In the remaining 67 patients and the lost patient, the eradication rate with 2-week therapy was 65/68 (96%, 95% confidence interval: 88 98%) by intention to treat analysis and 65/65 (100%, 94-100%) by per protocol analysis. The main adverse event was soft stools (39%), and no serious adverse event was observed. CONCLUSION: This 2-week metronidazole-containing second-line therapy provides high efficacy in Japan where metronidazole resistance is rare. PMID- 21585611 TI - High Helicobacter pylori resistance to metronidazole but zero or low resistance to clarithromycin, levofloxacin, and other antibiotics in Malaysia. AB - OBJECTIVE: Bacterial resistance to antibiotics is the single most important determinant of treatment success. The objective of this study was to determine the prevalence of Helicobacter pylori resistance to clarithromycin, amoxicillin, metronidazole, tetracycline, levofloxacin, rifabutin, and furazolidone in our local bacterial strains. METHODS: Samples from consecutive ninety patients were obtained for culture and sensitivity testing. Resistance to individual antibiotics were tested using the E-test and MIC(90) read from the strips. Resistance to rifampicin and nitrofurantoin were used as a surrogate for rifabutin and furazolidine. RESULTS: There was a high prevalence of resistance to metronidazole 68/90 (75.5%). No male (34/45 (75.5%) versus female (35/45 (77.7%) difference in frequency of metronidazole resistance was noted (p = 1.000). There was zero resistance (0) to clarithromycin, levofloxacin, amoxicillin, and nitrofurantoin/furazolidone. Resistance to rifampicin/rifabutin was for breakpoints of 1 and 4 MUg/mL of 14.4 and 2.2% respectively. CONCLUSIONS: Although there was high bacterial resistance to metronidazole, the absence of resistance particularly to the key antibiotics used in H. pylori eradication therapy: clarithromycin and levofloxacin is reassuring to note. Continued monitoring of antibiotic resistance should be carried out. PMID- 21585612 TI - IL-1 polymorphisms in children with peptic symptoms in South China. AB - BACKGROUND: Polymorphisms of IL-1 gene cluster are reported to be associated with histological changes and IL-1beta expression in the gastric mucosa in adults, especially in Helicobacter pylori-infected subjects. As H. pylori infecting adults and children own different virulence genotypes, the aim of this study was to investigate whether IL-1 polymorphisms are risk factors in young children in South China. MATERIALS AND METHODS: A total of 128 children with peptic symptoms were enrolled in this study. Polymorphisms of IL-1B-511 and IL-1B-31 were identified by dual fluorescence PCR. Variable number of tandem repeat region in IL-1RN was detected by conventional PCR and IL-1beta mRNA expression by real-time PCR ddCT assay. RESULTS: IL-1B-31T and IL-1B-511C were completely linked in this study. Significant differences of IL-1B-511/-31 genotypes were observed among different clinical outcomes (p = .001). The IL-1B-511TT/-31CC was mostly found in the moderate gastritis and the above (severe gastritis or gastric ulcer) groups, with percentage of 60.7%. While no association was observed between IL-1RN genotypes and the gastric mucosal histological changes (p = .128). Also no relationships were found between IL-1 polymorphisms and H. pylori infection or gastric mucosal IL-1beta mRNA expression level. CONCLUSION: Children with IL-1B 511TT/-31CC may have a risk to develop relatively severe gastric mucosal histological changes in South China. PMID- 21585613 TI - Maintaining and shipping Helicobacter pylori on agar stabs. PMID- 21585614 TI - Postoperative hyponatremia following calvarial vault remodeling in craniosynostosis. AB - BACKGROUND: The incidence, severity, and risk factors for the development of hyponatremia in patients undergoing craniosynostosis surgery are not well known. OBJECTIVE: To determine the incidence and severity of hyponatremia as a complication in surgical correction of craniosynostosis and to identify risk factors for postoperative hyponatremia. METHODS: A retrospective medical record review for 2003-2008 of the Cleft and Craniofacial Database was made. Specific data collected included sodium values, age, weight, type of surgery, duration of surgery, administration of DDAVP, composition and volume of pre-operative, intra operative, postoperative parenteral fluids, volume of blood, colloid, and crystalloid transfused, estimated blood loss (EBL), medications, comorbidities, pre-operative signs of elevated intracranial pressure (ICP), syndromic vs nonsyndromic craniosynostosis, and the complications associated with hyponatremia. RESULTS: A total of 72 records were reviewed. The incidence of postoperative hyponatremia was 30.6%. There was no intra-operative hyponatremia. While hospital stay was not prolonged, ICU stay was significantly longer (1.9 vs 2.9 days, P = 0.001). Elevated ICP was significantly associated with hyponatremia (P < 0.002). A greater volume of blood loss (EBL) was associated with postoperative hyponatremia (P = 0.019). Patients with normal pre-operative ICP were more likely to become hyponatremic if they were female (relative risk = 2.43; P < 0.05). The average decrease in sodium was greater in patients receiving hyponatremic (hypotonic) vs normonatremic (isotonic) postoperative IVF's (5.5 vs 3.2 mEq.l(-1), P = 0.039). There were no postoperative complications related to hyponatremia. CONCLUSIONS: The incidence of postoperative hyponatremia after calvarial vault remodeling was determined to be 30.6%. Hyponatremia was significantly associated with increased pre-operative ICP, blood loss, and female gender (normal pre-operative ICP). The average decrease in sodium was greater in patients receiving hyponatremic postoperative IVF's. PMID- 21585615 TI - Time-dependent perioperative anesthetic management and outcomes of the first 100 consecutive cases of spring-assisted surgery for sagittal craniosynostosis. AB - BACKGROUND: The anesthetic risks and outcomes of the first 100 consecutive spring-assisted surgeries (SAS) for cranial expansion from a single institution are reported. The effect of number of procedures was also tested on hematocrit postoperative day 1 (POD1), anesthesia time, and surgery time of the first procedure. METHODS: The records of 100 consecutive patients undergoing SAS were reviewed. Anesthesia management and related complications are presented. Time series linear regression analysis was performed on hematocrit POD1, anesthesia time, and surgery time of the first procedure. RESULTS: The average age of the first insertion procedure was 4.4 and 9.0 months for the second removal procedure. Two patients were inadvertently extubated during positioning. Thirty eight children had a decrease in blood pressure >20% from baseline. No child was admitted to the intensive care unit. No patient received any blood or blood product transfusion. Anesthesia time, surgery time, and hematocrit POD1 were correlated with procedure number or experience. CONCLUSIONS: Changes in anesthetic management resulted from changing the procedure. The reduction in volume resuscitation reduces the need for invasive monitoring. Facility and comfort with the surgical procedure increase with time and number of procedures performed. This experience further reduces blood loss and risk of transfusion. PMID- 21585616 TI - Pediatric sedation--evolution and revolution. AB - Pediatric sedation continues to change in terms of the professionals who provide this care, those who produce original research on this topic, guidelines and literature concerning risk, medications employed, and methods for training for new providers. Some of the changes could be categorized as 'evolutionary' or gradual in nature and predictable - such as the changing role of anesthesiologists in the field of pediatric sedation and the use of the well established dissociative sedative, ketamine. Other changes in pediatric sedation are more radical or 'revolutionary'. They include reconsideration of what is defined as an 'adverse event' during sedation, the use of propofol or dexmedetomidine, and the application of human patient simulation for training. This review will highlight the ongoing changes in the dynamic field of pediatric sedation by focusing on some of the important progress (both evolutionary and revolutionary) that has occurred across the varied specialties that provide this care. PMID- 21585617 TI - Heat shock protein 27 and cyclophilin A associate with the pathogenesis of COPD. AB - BACKGROUND AND OBJECTIVE: COPD is a global disease characterized by chronic bronchitis and obstructive emphysema. Its pathogenesis is not fully understood. This study aimed to use proteomics to provide new insights into the mechanisms of COPD. METHODS: Protein lysates were prepared from lung tissue samples harvested from never-smokers, non-COPD smokers and COPD smokers, and were analysed using 2 dimensional gel electrophoresis. Differentially expressed proteins were identified using mass spectrometry. The differential expression of heat shock protein 27 (Hsp27) and cyclophilin A (CyPA) was validated by immunohistochemistry and western blotting. RESULTS: Twenty-four proteins were identified by mass spectrometry as being differentially expressed among the three groups of subjects. The main functions of these proteins involve basic metabolism, oxidation/reduction, coagulation/fibrinolysis, protein degradation, signal transduction, inflammation and cell growth/differentiation/apoptosis. Proteomic analysis revealed that the expression of Hsp27 and CyPA was upregulated in smokers, and this upregulation was particularly marked in COPD smokers. The variation in expression of Hsp27 and CyPA between the groups was confirmed by immunohistochemistry and western blotting. CONCLUSIONS: Hsp27 and CyPA are associated with the pathogenesis of COPD, and smoking contributes to the overexpression of these proteins. PMID- 21585618 TI - Promoter hypermethylation of the CFTR gene and clinical/pathological features associated with non-small cell lung cancer. AB - BACKGROUND AND OBJECTIVE: The exact role of the cystic fibrosis transmembrane conductance regulator (CFTR) in pathophysiology, and the mechanisms regulating its expression are poorly understood. The CFTR gene is known to be genetically or epigenetically associated with several cancers. In the present study, the methylation status of the promoter region of the CFTR gene and its expression in primary non-small cell lung cancer (NSCLC) were investigated. METHODS: The methylation status of the promoter region of the CFTR gene in NSCLC tissue was assessed by pyrosequencing and methylation-specific PCR. Expression of the CFTR gene was analysed by real-time PCR, and CFTR gene reactivation was investigated using 5-aza-2'-deoxycytidine. The correlation between methylation of the CFTR gene and the clinical features of the patients was assessed. RESULTS: Methylation of the CFTR gene in NSCLC was quantitatively high by pyrosequencing analysis and qualitatively frequent by methylation-specific PCR analysis. Expression of the CFTR gene was significantly lower in NSCLC compared with normal lung tissue. In addition, the demethylating agent 5-aza-2'-deoxycytidine increased CFTR gene expression. Methylation of the CFTR gene was significantly greater in squamous cell carcinomas than in adenocarcinomas. CFTR gene methylation was associated with significantly poorer survival in young patients, but not in elderly patients. CONCLUSIONS: These findings suggest that DNA methylation may be important for downregulation of CFTR gene expression in lung cancer. Promoter hypermethylation of the CFTR gene may be an important prognostic factor in younger patients with NSCLC. PMID- 21585619 TI - Phase I trial of gemtuzumab ozogamicin in intensive combination chemotherapy for relapsed or refractory adult acute myeloid leukemia (AML): Japan Adult Leukemia Study Group (JALSG)-AML206 study. AB - In order to investigate better molecular-target therapy for acute myeloid leukemia (AML), we conducted a phase I trial of a combination of gemtuzumab ozogamicin (GO) with conventional chemotherapy. Between January 2007 and December 2009, a total of 19 adult Japanese patients with relapsed or refractory CD33 positive AML (excluding acute promyelocytic leukemia) were enrolled. All registered patients received a standard dose of cytarabine (Ara-C) (100 mg/m(2) * 7 days), combined with either idarubicin (IDR) (10-12 mg/m(2) * 3 days) or daunorubicin (DNR) (50 mg/m(2) * 3-5 days), and then GO (3-5 mg/m(2) ), which was administered 1 day after the last infusion of IDR (IAG regimen) or DNR (DAG regimen). While doses of both GO and IDR and the administration period of only DNR were increased, the dose-limiting toxicity (DLT) was assessed. Among 19 patients (nine in the IAG regimen, 10 in the DAG regimen), the median age was 59 years (range 33-64), and the relapsed/refractory ratio was 13/6. In the therapy using 3 mg/m(2) GO in the IAG or DAG regimen, grade 3/4 leukopenia and neutropenia were observed in all patients, but none had grade 3/4 non hematological toxicities, except febrile neutropenia. Three patients in the IAG regimen who were administered 5 mg/m(2) GO showed DLT. No patients had veno occlusive disease or sinusoidal obstructive syndrome. In conclusion, 3 mg/m(2) GO combined with Ara-C and IDR or DNR can be safely administered, and phase II trials should be conducted to investigate the clinical efficacy of the combination therapy. PMID- 21585620 TI - Prognostic significance of tumor/stromal caveolin-1 expression in breast cancer patients. AB - Caveolin-1 (Cav-1) has been extensively characterized in cancer biological research. However, the role of Cav-1 in the interaction between tumor and stromal cells remains unclear. In the present study, we examined Cav-1 expression in tumor cells and stromal cells in breast cancer tissue by immunohistochemical analysis and evaluated its prognostic value in a training cohort. Immunohistochemical analysis of Cav-1 expression was scored as (++), (+) or (-) according to the proportion of positively stained tumor cells (T) and stromal cells (S). Correlation analysis between tumor/stromal Cav-1 expression and clinicopathological parameters revealed that only T(++) Cav-1 status was positively associated with tumor size and histological nodal status (P = 0.019 and 0.021, respectively). Univariate analysis revealed that combined T(++)/S(-) status was significantly correlated with unfavorable prognostic outcomes (P < 0.001). Multivariate analysis demonstrated that this combined status is an independent prognostic factor for primary breast cancer (P = 0.002). Clinical outcomes in different subgroups of breast cancer patients were also strictly dependent on this combined status (P < 0.05). The prognostic value of T(++)/S(-) Cav-1 status was also validated in the testing cohort. Collectively, our data indicate that high Cav-1 expression in tumor cells and lack of this expression in stromal cells could help identify a particular subgroup of breast cancer patients with potentially poor survival. Further studies are required to understand the regulatory mechanism of Cav-1 in the tumor microenvironment. PMID- 21585621 TI - Pharmacological characterization of purinergic inhibitory neuromuscular transmission in the human colon. AB - BACKGROUND: In the present study, we further characterize the purinergic receptors mediating the inhibitory junction potential (IJP) and smooth muscle relaxation in the human colon using a new, potent and selective agonist (MRS2365), and antagonists (MR2279 and MRS2500) of the P2Y(1) receptor. The P2Y(12) antagonist AR-C66096 was tested as well. Using this pharmacological approach, we tested whether beta-nicotinamide adenine dinucleotide (beta-NAD) fulfilled the criteria to be considered an inhibitory neurotransmitter in the human colon. METHODS: We carried out muscle bath and microelectrode experiments on circular strips from the human colon and calcium imaging recordings on HEK293 cells, which constitutively express the human P2Y(1) receptor. KEY RESULTS: Both the fast component of IJP and non-nitrergic relaxation was concentration dependently inhibited by MRS2279 and MRS2500. This antagonism was confirmed in HEK293 cells. However, AR-C66096 did not modify either inhibitory response. Adenosine 5'-Omicron-2-thiodiphosphate and MRS2365 caused a smooth muscle hyperpolarization and transient inhibition of spontaneous motility that was antagonized by MRS2279 and MRS2500. beta-Nicotinamide adenine dinucleotide inhibited the spontaneous motility (IC(50) = 3.3 mmol L(-1) ). Nevertheless, this effect was not antagonized by high concentrations of P2Y(1) antagonists. CONCLUSIONS & INFERENCES: Inhibitory purinergic neuromuscular transmission in the human colon was pharmacologically assessed by the use of new P2Y(1) receptor antagonists MRS2179, MRS2279, and MRS2500. The rank order of potency of the P2Y(1) antagonists is MRS2500 > MRS2279 > MRS2179. We found that beta-NAD partially fulfills the criteria to be considered an inhibitory neurotransmitter in the human colon, but the relative contribution of each purine (ATP/ADP vsbeta NAD) requires further studies. PMID- 21585622 TI - Immunoreactivity for Ano1 detects depletion of Kit-positive interstitial cells of Cajal in patients with slow transit constipation. AB - BACKGROUND: Depletion of interstitial cells of Cajal (ICC) is associated with several gastrointestinal (GI) motility disorders. Changes in ICC networks are usually detected by immunolabeling for the receptor tyrosine kinase Kit. Ano1 (DOG1 or TMEM16A) was recently described as a marker of ICC in GI tract. Our aim was to determine whether Ano1 immunoreactivity can be used as a reliable marker for ICC in tissues from patients with motility disorders. METHODS: Four tissues from patients with normal ICC numbers and four tissues from patients with slow transit constipation and loss of Kit-positive ICC were studied. Interstitial cells of Cajal were detected by double labeling using antisera to Kit and Ano1. KEY RESULTS: Both the processes and cell bodies of ICC in tissue from controls and slow transit constipation were immunoreactive for Ano1. There was a near complete overlap between Kit and Ano1 immunoreactivity. Tissues from patients with slow transit constipation contained significantly fewer Ano1-positive ICC than control tissues. The numbers of ICC identified by Ano1 and Kit immunoreactivity were nearly identical across the range of ICC numbers from an average of 1.64 to 7.05 cells per field and correlated with an R(2) value of 0.99. CONCLUSIONS & INFERENCES: Ano1 is a reliable and sensitive marker for detecting changes in ICC networks in humans. Labeling with antibodies selective for Ano1 reproducibly detects depletion of Kit-positive ICC in tissues from patients with slow transit constipation. PMID- 21585623 TI - Insulin-like growth factor (IGF)-I and IGF-binding protein-3 serum levels in relapsing-remitting and secondary progressive multiple sclerosis patients. AB - BACKGROUND: Insulin-like growth factor (IGF)-I has a role in remyelination, and insulin-like growth factor-binding protein-3 (IGFBP-3) might reduce its bioavailability. A role of IGFBP-3 in multiple sclerosis (MS) progression was hypothesized in patients with primary progressive (PP) MS. OBJECTIVE: To evaluate serum levels of IGF-I and IGFBP-3 in patients with relapsing-remitting (RR) and secondary progressive (SP) MS and their correlations with disease activity and progression. METHODS: Sixty-three (41 RR and 22 SP) 'naive' MS patients and 60 age-matched healthy controls were enrolled. Patients were assessed through clinical [Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), number of relapses] and laboratory investigations. IGF-I and IGFBP 3 were measured by ELISA. RESULTS: Levels of IGF-I and IGFBP-3 were similar in the two MS groups. IGFBP-3 levels were higher in patients with MS than in controls (P < 0.001), with a reduction in IGF-I/BP3 ratio (P < 0.001). Patients showing IGFBP-3 levels higher than 2SD of the normal population had a higher EDSS (mean EDSS 3.7 vs. 2.8, P = 0.021). MSSS was not related to IGF-I or IGFBP-3 serum levels. CONCLUSIONS: Our patients showed high IGFBP-3 serum levels respect to controls and higher serum levels were associated with a higher EDSS, despite of comparable disease duration. Therefore, MS and higher disability seem to be associated with a reduction in bioavailability of IGF-I. MSSS score was not related to IGFBP-3 levels, suggesting that IGFBP-3 might not have the pathogenetic role previously suggested for PP MS, in the mechanism of progression in the SP form of disease. PMID- 21585624 TI - Association of haplotype combination of serotonin transporter gene polymorphisms with monthly headache days in MOH patients. AB - OBJECTIVES: To evaluate the role of 5-HTTLPR, STin2 VNTR, and rs1042173T>G polymorphisms of the serotonin transporter gene (SLC6A4) as susceptibility factors for medication overuse headache (MOH) and to assess their value as predictors of the number of headache days per month, a potential marker of disease severity. METHODS: Genotyping was performed by PCR and PCR-RFLP on genomic DNA extracted from peripheral blood of 227 MOH patients and 312 control subjects. Logistic regression analysis was used to evaluate the association between the SL6A4 gene polymorphisms and MOH risk. The association between polymorphic variants and monthly headache days was evaluated by linear regression analysis. RESULTS: Logistic regression analysis, adjusted for age and gender, revealed a nominal association between rs1042173T>G and MOH risk (TT vs. TG + GG, OR: 1.58 95% CI: 1.05-2.37, P = 0.028). In the linear regression analysis adjusted for age, gender, primary headache diagnosis, acute drug overused and monthly drug number, STin2 VNTR was found nominally associated with monthly headache days (12/12 vs. others, difference: 1.55 days, 95% CI: 0.01-3.08, P = 0.050). When STin2 VNTR and rs1042173T>G were analyzed in haplotypic combination, a global haplotype association emerged with monthly headache days which remained significant after Bonferroni correction for multiple comparisons (global haplotype association P = 0.0056). CONCLUSION: Although a minor contribution of SLC6A4 variants in the genetic liability of MOH cannot be excluded, haplotype based analysis of STin2 VNTR and rs1042173T>G polymorphisms allowed to identify a subgroup of MOH patients with a higher number of monthly headache and, possibly, with a more severe disease. PMID- 21585625 TI - Tuberculosis treatment default among HIV-TB co-infected patients in urban Uganda. AB - OBJECTIVE: To identify health facility and patient-specific factors associated with TB treatment default in HIV-infected patients, in a TB clinic on the campus of Mulago National Referral Hospital in Kampala, Uganda. METHODS: Unmatched case control study between March and May 2009. Cases were TB patients known to have defaulted on their anti-TB treatment, defined as a TB patient who had documented discontinuation of TB medication for two or more consecutive months due to reasons other than physician's advice and who did not access care at another facility. Controls were TB patients who completed 8 months of anti-TB treatment without interruption of two or more months. Data on health facility-specific factors and individual characteristics were collected using semi-structured questionnaires. RESULTS: Factors associated with defaulting from TB treatment were: distance from home to clinic (OR 2.22; 1.21-4.06); long waiting time at the clinic (OR 4.18; 2.18-8.02); poor drug availability (OR 4.75; 2.29-9.84); conduct of staff (OR 2.72; 1.02-7.25); lack of opportunity to express feelings (OR 3.47; 1.67-7.21). Other patient-related factors were lack of health education, i.e. not being aware of the duration of treatment or the risk of discontinuing it (OR 5.31; 1.94-14.57); not knowing that TB can be cured (OR 44.11; 13.66-142.41); length of TB treatment (OR 10.77; 5.18-22.41), and side effects of treatment OR 5.53 (2.25-13.61). CONCLUSIONS: Defaulting is influenced by health systems, staff factors, and patient misinformation. Health education on TB directed at patients combined with staff sensitization could help to improve adherence to TB treatment. PMID- 21585626 TI - Recommendation of lamivudine-to-entecavir switching treatment in chronic hepatitis B responders: Randomized controlled trial. AB - AIM: In the 2007-2008 guidelines of the study group (Ministry of Health, Labor and Welfare of Japan), lamivudine (LAM)-continuous treatment was recommended in patients treated with LAM for more than 3 years who maintained hepatitis B virus (HBV) DNA less than 2.6 log copies/mL, because in these patients LAM resistance might exist and switching treatment to entecavir (ETV) might cause ETV resistance. However, there was no evidence on whether switching treatment to ETV- or LAM-continuous treatment was better in those patients. In the present study, we performed a randomized controlled trial of LAM-to-ETV switching treatment. METHODS: Twenty-seven patients treated with LAM for more than 3 years whose HBV DNA levels were less than 2.6 log copies/mL were enrolled and randomly divided into two groups, LAM-continued group or switching to ETV group. Then, we examined incidence of virological breakthrough (VBT) and breakthrough hepatitis (BTH) in each group. RESULTS: There was no BTH in any of the patients. VBT was observed in six patients of the LAM group (6/15, 40%), and no patient of the ETV group (0/11, 0%) (P = 0.02). The differences of the proportion of cumulated VBT using a log-rank test with Kaplan-Meier analysis were significant between the LAM and ETV groups (P = 0.025). CONCLUSION: In patients treated with LAM for more than 3 years maintaining HBV DNA less than 2.6 log copies/mL, switching treatment to ETV is recommended at least during the 2 years' follow-up period. PMID- 21585627 TI - Living donor liver transplantation for ornithine transcarbamylase deficiency. AB - Ornithine transcarbamylase deficiency, the most common urea cycle disorder, causes hyperammonemic encephalopathy and has a poor prognosis. Recently, LT was introduced as a radical OTCD treatment, yielding favorable outcomes. We retrospectively analyzed LT results for OTCD at our facility. Twelve children with OTCD (six boys and six girls) accounted for 7.1% of the 170 children who underwent LDLT at our department between May 2001 and April 2010. Ages at LT ranged from nine months to 11 yr seven months. Post-operative follow-up period was 3-97 months. The post-operative survival rate was 91.7%. One patient died. Two patients who had neurological impairment preoperatively showed no alleviation after LT. All patients other than those who died or failed to show recovery from impairment achieved satisfactory quality-of-life improvement after LT. The outcomes of LDLT as a radical OTCD treatment have been satisfactory. However, neurological impairment associated with hyperammonemia is unlikely to subside even after LT. It is desirable henceforth that more objective and concrete guidelines for OTCD management be established to facilitate LDLT with optimal timing while avoiding the risk of hyperammonemic episodes. PMID- 21585628 TI - Laparoendoscopic single-site (LESS) bilateral nephrectomy in the pretransplant pediatric population. AB - End-stage renal failure management in children may require bilateral kidney removal prior to transplantation secondary to recurrent urinary tract infections, renin-dependent hypertension, vesicoureteral reflux, proteinuria, risk of malignancy (Denys-Drash), or high output renal failure. Conventional laparoscopy or open nephrectomy has been employed to date. However, we present our method of bilateral nephrectomy in four patients via the SILS Covidien (c) system. Patient age ranged from 18 months to 18 years. Operative time ranged from 308 to 370 minutes. Estimated blood loss was minimal, all cases were completed via the single incision and no cases were converted to open. Laparoendoscopic single-site bilateral nephrectomy is safe and feasible in children and well-suited for the pre-transplant population. PMID- 21585630 TI - Long-term follow-up in adult living donors for combined liver/bowel transplant in pediatric recipients: a single center experience. AB - Pediatric candidates for combined liver/bowel transplant (LBTx) experience a very high mortality on the cadaver waiting list. Our transplant center has successfully used adult living donors to treat pediatric candidates for LBTx. We report the long-term follow-up of this unique cohort of organ donors. The charts of six adult donors for LBTx performed between 2004 and 2007 were reviewed. All the pertinent clinical data were carefully reviewed and integrated with phone interviews of all donors. A total of six children (average age 13.5 months) received living donor LBTx. Average follow-up for the donors was 42 months (range 29-51). The donors' median age was 25 yr (19-32); five women and one man. The average median hospital stay was nine days. There were no peri-operative complications. At present all donors remain in good health. Three of the five mothers became pregnant after donation. Five of the six children are currently alive and well whereas one died with functioning grafts six months post transplant due to plasmoblastic lymphoma. Living donor LBTx is an effective therapy for combined hepatic and intestinal failure in children less than five yr. The donor operation can be performed with minimal morbidity. PMID- 21585629 TI - Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose fingolimod (FTY720) in adolescents with stable renal transplants. AB - Oral fingolimod signals the sphingosine 1-phosphate receptor and this in turn mediates immunomodulatory activity. No data of fingolimod in any pediatric population existed before this study. We put our study results in perspective against data from adult renal transplant patients. We investigated pharmacokinetics and pharmacodynamics of single-dose fingolimod (0.07 mg/kg) and its effects on lymphocytes and heart rate in seven adolescents (14.1 +/- 1.6 yr) with stable renal transplants. Blood samples for pharmacokinetics and lymphocytes were collected at screening, baseline, and up to 28 days post-dosing. Cardiac monitoring included 12-lead ECG, 24-h Holter monitoring, and echocardiography. A fingolimod dose of 0.07 mg/kg resulted in mean AUC of 731 +/- 240 ng.h/mL and C(max) of 3.6 +/- 0.6 ng/mL. Drug exposure was nearly identical to adults receiving the same dose. Absolute lymphocyte count decreased 85% from baseline; average nadir occurred by six h post-dose. Heart rate decreased from 74 bpm (predose mean) to 53 bpm (nadir) three h post-dose. Mean heart rates recovered by Day 14 (75 bpm). Weight-adjusted doses of fingolimod in adolescents resulted in drug exposure similar to adults. Adolescents and adults shared comparable negative chronotropic effects and decreased lymphocyte count. Recovery trajectories of these parameters back to baseline were similar between age groups. PMID- 21585631 TI - Perioperative renal failure in pediatric heart transplant recipients: outcome and risk factors. AB - PRF is encountered in 10-13% of adult heart transplants. Only one study of a single center's experience with PRF has been reported in pediatric patients. This study examines the effect of PRF on pediatric heart transplant outcome using the UNOS database. A total of 3598 patients met inclusion criteria, of whom 254 (7%) had PRF. The PRF group comprised 31 recipients requiring PRE and 223 recipients requiring POST. Compared with No-PRF patients, PRE patients had similar survival rate and POST patients had decreased survival rate at 30 days, one, five, and 10 yr post-transplant (p < 0.001). PRF patients also had significantly lower graft survival at one, five, and 10 yr (p < 0.001). Risk factors for developing PRF included ECMO, ventilator, and inotropic support at listing and CHD as the listing diagnosis. PRF increased the duration of hospital stay and the incidence of chronic severe renal dysfunction. PRF that requires POST (whether or not it began pretransplant) has a significant negative impact on pediatric heart transplant outcome. Specific characteristics identify patients at particular high risk of developing PRF. PMID- 21585632 TI - Long-term results of the percutaneous transhepatic venoplasty of portal vein stenoses after pediatric liver transplantation. AB - This paper has the objective to evaluate retrospectively the long-term results of transhepatic treatment of PV stenoses after pediatric LT. During an eight-yr period, 15 children with PV stenoses underwent PTA with balloon dilation or stent placement in case of PTA failure after LT. Patients' body weights ranged from 9.3 to 46kg (mean, 15.5kg). PV patency was evaluated in the balloon dilation and in the stent placement groups. Technical and clinical successes were achieved in all cases with no complication. Eleven patients (11/15; 73.3%) were successfully treated by single balloon dilation. Four patients (4/15; 26.7%) needed stent placement. One patient was submitted to stent placement during the same procedure because of PTA failure. The other three developed clinical signs of portal hypertension because of PV restenoses two, eight, and twenty-eight months after the first PTA. They had to be submitted to a new procedure with stent placement. The follow-up time ranged from 3 to 8.1 yr (mean, 6.3 yr). In conclusion, transhepatic treatment of PV stenoses after pediatric LT with balloon dilation or stent placement demonstrated to be a safe and effective treatment that results in long-term patency. PMID- 21585633 TI - Tetramer monitoring to assess risk factors for recurrent cytomegalovirus reactivation and reconstitution of antiviral immunity post allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: Reactivation of cytomegalovirus (CMV) is a major cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). In healthy individuals, virus-specific T cells (CMV-CTL) control the reactivation of latent CMV. The monitoring of virus-epitope-binding CD8(+) T cells using major histocompatibility complex-I-peptide complexes (tetramers) has recently been established, allowing assessment of the reconstitution of CMV-CTL post HSCT. PATIENTS AND METHODS: In order to study immune reconstitution and reactivation control through CMV-CTL, we regularly monitored all patients undergoing allogeneic HSCT in our department for 2 years, who matched at least 1 of 6 commercially available tetramers for common human leukocyte antigen (HLA) types. To verify risk factors for CMV reactivations in our cohorts, clinical characteristics of all patients transplanted within the last 10 years were included in statistical analyses determining the relative risk for single and recurrent CMV reactivations. RESULTS: As expected, CMV serostatus, HLA match, and donor source significantly influenced the risk of recurrent CMV reactivation. Applying CMV-CTL tetramer monitoring for 2 years allowed the monitoring of 114 (85%) of 134 patients, by testing a set of tetramers representing 6 epitopes from 3 different CMV proteins. The presence of CMV-CTL before day + 50 and their expansion post reactivation seem to protect against recurrent CMV reactivations. The mean number of CMV-CTL by day +100 was >5-fold higher in the recipient CMV positive/donor-positive (R +/D +) group (91/MUL) compared with the R +/ D- (13/MUL) and the R -/D +(2/MUL) group. Seventy-nine percent of patients from the R +/D + setting recovered >10 CMV-CTL per MUL by day + 100, while almost 50% of the other groups failed to mount a CMV-specific response by that time (R +/D -: 58%; R -/D +: 43%). CONCLUSION: Tetramer monitoring can help to predict (recurrent) CMV reactivation and is a useful approach to monitor individual patients with increased risk for recurrent reactivation post HSCT; thus, it could help to identify patients in need of adoptive transfer of CMV-CTL or to optimize the use of antiviral drugs. PMID- 21585635 TI - The unconventional secretory machinery of fibroblast growth factor 2. AB - Unconventional secretory proteins represent a subpopulation of extracellular factors that are exported from eukaryotic cells by mechanisms that do not depend on the endoplasmic reticulum and the Golgi complex. Various pathways have been implicated in unconventional secretion including those involving intracellular membrane-bound intermediates and others that are based on direct protein translocation across plasma membranes. Interleukin 1beta (IL1beta) and fibroblast growth factor 2 (FGF2) are classical examples of unconventional secretory proteins with IL1beta believed to be present in intracellular vesicles prior to secretion. By contrast, FGF2 represents an example of a non-vesicular mechanism of unconventional secretion. Here, the author discusses the current knowledge about the molecular machinery being involved in FGF2 secretion. To reveal both differential and common requirements, this review further aims at a comprehensive comparison of this mechanism with other unconventional secretory processes. In particular, a potentially general role of tyrosine phosphorylation as a regulatory signal in unconventional protein secretion will be discussed. PMID- 21585634 TI - Mammalian target of rapamycin signal inhibitors could play a role in the treatment of BK polyomavirus nephritis in renal allograft recipients. AB - BK virus (BKV) nephropathy is a common viral infection in renal transplant patients, with a prevalence of 1-9% at approximately 12 months after surgery. While it is widely agreed that reduction of immunosuppression should be the first intervention after diagnosis of BKV infection, there is no consensus on whether calcineurin inhibitors or antiproliferative drugs should be reduced first. Furthermore, target levels of immunosuppressive drugs are poorly defined, as are criteria for replacing one immunosuppressive agent with another. RESULTS: We report our series of 15 renal transplant patients who underwent surgery between September 2004 and March 2010 and who developed BKV infection. The first 8 patients were treated with reduction of immunosuppression; 7 of these patients received cidofovir and 6 received intravenous immunoglobulin. The remaining 7 renal transplant recipients received mammalian target of rapamycin inhibitors (imTOR). In this group, we observed faster and more efficacious BKV clearance in plasma and urine and a steady improvement in allograft function, with no episodes of acute allograft rejection during follow-up. The polymerase chain reaction assay for BKV in urine became positive in 2 patients in whom imTOR were stopped due to severe side effects. CONCLUSIONS: The use of imTOR should be considered a first step in the treatment of renal transplant recipients with BKV infection. In our experience, this change in treatment was safe and resulted in viral clearance. PMID- 21585636 TI - Intramembrane proteolysis in regulated protein trafficking. AB - Regulated intramembrane proteolysis is an evolutionarily conserved mechanism by which membrane-anchored bioactive molecules are released from cellular membranes. In eukaryotic cells, intramembrane proteases are found in different cellular organelles ranging from the endosomal system to mitochondria and chloroplasts. These proteases function in diverse processes such as transcription control, regulated growth factor secretion and recently even a role in the control of mitophagy has been suggested. Genomic annotation has predicted 13 different intramembrane proteases in humans. Apart from few studied examples, very little is known about their function. This review describes emerging principles of how intramembrane proteases contribute to the regulation of cellular protein trafficking in eukaryotic cells and raises the important question of how their activity is controlled. PMID- 21585637 TI - Placental weight and excess postpartum haemorrhage: a population study of 308,717 pregnancies. AB - OBJECTIVE: To investigate whether placental weight may be positively associated with the prevalence of excess postpartum haemorrhage because large placentas have large surface areas. DESIGN: Registry-based cross-sectional study. SETTING: Population study. POPULATION: All singleton deliveries after 21 weeks of gestation in Norway during 1999-2004 (n = 308,717). METHODS: Data were obtained from the Medical Birth Registry of Norway, which is based on compulsory notification of births by the midwife or doctor in charge of the delivery. MAIN OUTCOME MEASURE: Excess postpartum haemorrhage was defined as bleeding of 500 ml or more within 2 hours of delivery. RESULTS: There was a gradual increase in the prevalence of excess postpartum haemorrhage with increasing placental weight (test for trend, P < 0.05). Having a placenta of 1100 g or more was associated with 2.5 times (odds ratio 2.54, 95% CI 2.31-2.79) higher prevalence than having a placenta of 300-499 g, after adjustment for offspring birthweight, parity, caesarean section and placenta-related and delivery-related complications. A large placenta relative to birthweight was also associated with higher prevalence of excess postpartum haemorrhage. CONCLUSION: The size of the placental surface may explain the positive association of placental weight with the prevalence of postpartum haemorrhage. In pregnancies with a large placenta relative to offspring birthweight, other factors that enhance bleeding may also play a role. PMID- 21585638 TI - Perinatal mortality and mode of delivery in monochorionic diamniotic twin pregnancies >= 32 weeks of gestation: a multicentre retrospective cohort study. AB - OBJECTIVE: To study perinatal mortality rates in a cohort of 465 monochorionic (MC) twins without twin-twin transfusion syndrome (TTS) born at 32 weeks of gestation or later since reported interauterine fetal death (IUFD) rates >32 weeks of gestations in the literature vary, leading to varying recommendations on the optimal timing of delivery, and to investigate the relation between perinatal mortality and mode of delivery. DESIGN: Multicentre retrospective cohort study. SETTING: Ten perinatal referral centres in the Netherlands. POPULATION: All MC twin pregnancies without TTTS delivered at >= 32 weeks of gestation between January 2000 and December 2005. METHODS: The medical records of all MC twin pregnancies without TTTS delivered at the ten perinatal referral centres in the Netherlands between January 2000 and December 2005 were reviewed. MAIN OUTCOME MEASURES: Perinatal mortality in relation to gestational age and mode of delivery at >= 32 weeks of gestation. RESULTS: After 32 weeks of gestation, five out of 930 fetuses died in utero and there were six neonatal deaths (6 per 1000 infants). In women who delivered >= 37 weeks, perinatal mortality was 7 per 1000 infants. Trial of labour was attempted in 376 women and was successful in 77%. There were three deaths in deliveries with a trial of labour (8 per 1000 deliveries), of which two were related to mode of delivery. Infants born by caesarean section without labour had an increased risk of neonatal morbidity and respiratory distress syndrome. CONCLUSIONS: In MC twin pregnancies the incidence of intrauterine fetal death is low >= 32 weeks of gestation. Therefore, planned preterm delivery before 36 weeks does not seem to be justified. The risk of intrapartum death is also low, at least in tertiary centres. PMID- 21585639 TI - Placental expression of a novel primate-specific splice variant of sFlt-1 is upregulated in pregnancies complicated by severe early onset pre-eclampsia. AB - sFlt-1 is increased in the placenta and serum of women with pre-eclampsia. A novel primate-specific splice variant has recently been discovered, but its expression in severe pre-eclampsia has yet to be reported. We investigated placental expression of the previously described variant, sFlt-1/sFlt-i13, and the novel variant, sFlt-e15a, in pregnancies complicated by severe early onset pre-eclampsia (n = 14) and HELLP (haemolysis, elevated liver enzymes and a low platelet count) syndrome (n = 8). There was significant upregulation of both variants in pre-eclampsia and HELLP syndrome compared with normotensive term (n = 35) and preterm controls (n = 8). We conclude that the novel primate-specific splice variant of sFlt-1 is highly expressed in both severe pre-eclampsia and HELLP. PMID- 21585640 TI - Placenta accreta is associated with IVF pregnancies: a retrospective chart review. AB - OBJECTIVE: To study the association between placenta accreta (PA) and in vitro fertilisation (IVF) pregnancies. DESIGN: Retrospective chart review. SETTING: Tertiary care centre in Jerusalem, Israel. SAMPLE: During January 2004-February 2009, 25,193 deliveries occurred in our hospital, including 752 (3%) deliveries of IVF pregnancies. METHODS: Placenta accreta was only diagnosed when there were histological findings from the placenta associated with the suitable clinical course. Demographic, obstetrical and fertility characteristics of these patients were retrieved from hospital files. MAIN OUTCOME MEASURE: Rates of PA in pregnancies achieved with IVF versus rates of PA in spontaneous pregnancies. RESULTS: The rate of PA in the IVF group was 12/752 (16/1000) pregnancies, compared with 30/24,441 (1.2/1000) among spontaneous pregnancies (P < 0.0001; OR 13.2; 95% CI 6.7-25.8). Among the variables examined, parity, rate of caesarean delivery in the index pregnancy, and birthweight differed significantly between IVF and spontaneous pregnancies. CONCLUSIONS: The odds of developing PA are significantly higher in IVF pregnancies than in spontaneous pregnancies. These differences may stem from differences in the endometrial environment, or from changes to the endometrium wrought by IVF treatment protocols. PMID- 21585642 TI - A maternal dietary pattern characterised by fish and seafood in association with the risk of congenital heart defects in the offspring. AB - OBJECTIVE: To identify maternal dietary patterns related to biomarkers of methylation and to investigate associations between these dietary patterns and the risk of congenital heart defects (CHDs) in the offspring. DESIGN: Case control study. SETTING: Western part of the Netherlands, 2003-08. POPULATION: One hundred and seventy-nine mothers of children with CHD and 231 mothers of children without a congenital malformation. METHODS: Food intake was obtained by food frequency questionnaires. The reduced rank regression method was used to identify dietary patterns related to the biomarker concentrations of methylation in blood. MAIN OUTCOME MEASURES: Dietary patterns, vitamin B and homocysteine concentrations, biomarkers of methylation (S-adenosylmethionine [SAM] and S adenosylhomocysteine [SAH]) and the risk of CHD estimated by odds ratios and 95% confidence intervals. RESULTS: The one-carbon-poor dietary pattern, comprising a high intake of snacks, sugar-rich products and beverages, was associated with SAH (beta = 0.92, P < 0.001). The one-carbon-rich dietary pattern with high fish and seafood intake was associated with SAM (beta = 0.44, P < 0.001) and inversely with SAH (beta =-0.08, P < 0.001). Strong adherence to this dietary pattern resulted in higher serum (P <0.05) and red blood cell (P < 0.01) folate and a reduced risk of CHD in offspring: odds ratio, 0.3 (95% confidence interval, 0.2 0.6). CONCLUSIONS: The one-carbon-rich dietary pattern, characterised by the high intake of fish and seafood, is associated with a reduced risk of CHD. This finding warrants further investigation in a randomised intervention trial. PMID- 21585641 TI - Varicella-zoster virus (chickenpox) infection in pregnancy. AB - Congenital varicella syndrome, maternal varicella-zoster virus pneumonia and neonatal varicella infection are associated with serious fetomaternal morbidity and, not infrequently, mortality. Vaccination against varicella-zoster virus can prevent the disease, and outbreak control limits the exposure of pregnant women to the infectious agent. Maternal varicella-zoster immunoglobulin administration before rash development, with or without antiviral medication, can modify the progression of the disease. PMID- 21585643 TI - Rapid versus stepwise application of negative pressure in vacuum extraction assisted vaginal delivery: a multicentre randomised controlled non-inferiority trial. AB - OBJECTIVE: To evaluate whether the application of rapid negative pressure for vacuum-assisted delivery is as effective and safe as the stepwise method. DESIGN: Randomised controlled trial. SETTING: Six centres, including university, secondary and tertiary hospitals, in Thailand. SAMPLE: In total, 662 women were randomised to rapid and stepwise groups, with 331 women in each group. METHODS: Vacuum extraction was performed by applying a metal cup (Malmstrom) connected to an electric pump to the fetal head. The stepwise method consisted of four incremental steps of 0.2 kg/cm2 every 2 minutes to obtain a final negative pressure of 0.8 kg/cm2. In the rapid method the negative pressure of 0.8 kg/cm2 was applied in one step in < 2 minutes. MAIN OUTCOME MEASURES: Success rate of vacuum extraction, vacuum cup detachment rate, duration of vacuum extraction, and maternal and neonatal complications. RESULTS: There were no significant differences in detachment rates (RD 0.3%, 95% CI -3.1 to 2.4). The overall success rates were identical, at 98.2%. There were significant reductions in the time between applying the vacuum cup and attaining maximum negative pressure (MD 4.6 minutes; 95% CI -4.4 to -4.8 minutes), and in the time between applying the cup and delivery (MD -4.4 minutes; 95% CI -4.8 to -4.0 minutes). There was a significantly higher rate of perineal suture in the rapid method group (RD 4.5%; 95% CI 1.1-8.2). There were no significant differences in maternal and fetal morbidities. CONCLUSIONS: Rapid negative pressure vacuum extraction could be performed as effectively and safely as the stepwise method, in a shorter period of time. PMID- 21585644 TI - Analysis of 'count-to-ten' fetal movement charts: a prospective cohort study. AB - OBJECTIVE: We aimed to describe patterns of maternally perceived fetal movement (FM) counts in normal third-trimester pregnancies and present associations between published limits of decreased fetal movement (DFM) and FM patterns in the total population. DESIGN: Prospective cohort study. SETTING: Norway, in 2005-2007 and 2007-2009. POPULATION: The total population of women with singleton pregnancies. METHODS: Using a 'count-to-ten' approach, women counted FMs daily from pregnancy week 28 until delivery. Data on maternal characteristics and birth outcomes were obtained from the Medical Birth Registry of Norway and hospital records. We measured the observed mean counting time and used chi-square and Mann Whitney U-tests to examine differences between normal pregnancies and pregnancies with suboptimal outcomes. MAIN OUTCOME MEASURES: Fetal movements in normal pregnancies and in pregnancies ending in a small-for-gestational-age baby, preterm birth or non-elective caesarean section. RESULTS: A total of 1786 women were included. The mean time to perceive ten movements was approximately 10 minutes in normal pregnancies, with a <2-minute increase in the mean towards term. Fixed limits for DFMs had low predictive values. Overall, the mean counting time in pregnancies with suboptimal outcomes did not differ markedly from normal pregnancies. CONCLUSIONS: This study does not support the notion that FM counts decrease at term in normal pregnancies. A standard approach to FM counting, applying the currently best-founded definition of DFM, was not useful as a screening tool for at-risk pregnancies in this population. Further research is needed to improve measurements of DFM. PMID- 21585645 TI - Maternal deaths associated with H1N1 influenza virus infection in Turkey: a whole of-population report. AB - OBJECTIVE: To review the clinical and demographic characteristics of pregnant and postpartum women who died as a consequence of influenza A H1N1 (2009) infection in Turkey. DESIGN: A review of the records for pregnant and postpartum women who died as a consequence of H1N1 influenza virus infection. SETTING: Nationwide in Turkey. POPULATION: Thirty-six pregnant or postpartum women who died as a result of confirmed pandemic H1N1 influenza virus infection. METHODS: Using the General Directorate of Mother and Child Health and Family Planning (MCHFP) Registry of the Ministry of Health of Turkey, we identified all pregnant and postpartum women who died as a result of confirmed influenza A H1N1 (2009) infection between 29 October and 31 December 2009. MAIN OUTCOME MEASURE: Maternal mortality as a result of H1N1 virus infection. RESULTS: The average time from symptom onset to initial presentation for health care was approximately 2.5 days, and the mean time from symptom onset to the receipt of antiviral medication was approximately 5.5 days. Only one-fifth of all women received early antiviral treatment (administered 2 days or less after symptom onset) and only one woman was vaccinated for H1N1 influenza 1 week before the onset of symptoms. The cause specific maternal mortality ratio for H1N1 influenza infection in Turkey was estimated to be 3.01. The calculated risk of death associated with H1N1 influenza virus infection was approximately four times higher in pregnant and postpartum women than in the general population (relative risk, 3.88; 95% confidence interval, 2.77-5.43). CONCLUSIONS: Pregnant women are at increased risk for complications of, and death from, H1N1 influenza infection. Prompt evaluation and antiviral treatment of influenza-like illness should be considered in such women. Vaccination for H1N1 influenza may reduce the total number of deaths in pregnant and postpartum women. The high cause-specific maternal mortality rate suggests that H1N1 influenza virus infection may have increased the 2009 maternal mortality ratio in Turkey. PMID- 21585646 TI - Is first-trimester crown-rump length associated with birthweight? AB - OBJECTIVE: To evaluate the relationship between first-trimester crown-rump length (CRL) and birthweight (BW) Z scores. DESIGN: Retrospective cohort study. SETTING: Two tertiary centres in France. POPULATION: Three hundred and seventeen pregnancies conceived through assisted reproductive techniques between April 2001 and December 2008. METHODS: We used CRL and worked forward to BW. Only pregnancies examined during the first trimester by an Fetal Medicine Foundation certified operator were included. CRL was expressed as Z scores, and BW was transformed into Z scores by taking gestational age and gender into account. The influence of abnormal first-trimester CRL Z scores on BW was examined. MAIN OUTCOME MEASURES: Weight and gestational age at birth. RESULTS: Birth weight was significantly greater in babies with larger CRL: BW Z scores (+/- SD) were -0.36 (+/- 1.05), -0.27 (+/- 0.97), -0.10 (+/- 1.04) and 0.13 (+/- 0.96) in the first, second, third and fourth quartiles of CRL Z scores, respectively (P = 0.01). In contrast, there was no difference in gestational length according to the quartiles of the CRL Z scores. The CRL Z score was a significant predictor of the BW Z score (beta = 0.17, P = 0.001). After adjustment for maternal body mass index, a one-point increase in the first-trimester CRL Z score (i.e. 3.6 mm) was associated with a 39% decrease, 64% increase, 114% increase and 62% increase in the risk of having a BW below the 10th centile [odds ratio (OR), 0.61; 95% confidence intervals (95% CI), 0.39; 0.95; P=0.03], above the 90th centile (OR, 1.64; 95% CI, 1.03; 2.60; P = 0.02), above the 95th centile (OR, 2.14; 95% CI, 1.25; 3.68; P = 0.006) and above 4000 g (OR, 1.62; 95% CI, 1.04; 2.51; P = 0.04), respectively. CONCLUSIONS: Variations in BW may be partly explained by differences in growth trajectories that may express as early as the first trimester. PMID- 21585647 TI - Incidence of chronic kidney disease in patients with atrial fibrillation and its relevance for prescribing new oral antithrombotic drugs. PMID- 21585648 TI - Migraineurs show a high prevalence of antiphospholipid antibodies. AB - BACKGROUND: It has been observed that migraineurs show a higher risk of thrombosis and that the most frequent symptom reported by patients with antiphospholipid syndrome is headache, especially migraine. OBJECTIVES: The aim of our research was to evaluate the prevalence of antiphospholipid antibodies (aPL) in a random cohort of migraineurs. PATIENTS/METHODS: This analytic, comparative case study was performed to evaluate the prevalence of antiphospholipid antibodies by comparing a population of migraineurs with and without aura with sex- and age-matched controls. Both the diagnosis of migraine and the laboratory diagnosis of aPL positivity were made on the basis of the most recent international guidelines. RESULTS: Between September 2008 and August 2009, we recruited 284 consecutive patients (225 women and 59 men, 203 without aura and 81 with aura) and 225 controls (174 women and 51 men). Positivity for at least one test for aPL (LAC, ACA IgG or antibeta2GLP1 IgG) was detected and confirmed in 12% (n = 33) of patients and in 3% (n = 7) of controls (odds ratio, 4.08; confidence interval, 1.77-9:39; P = 0.0004). Two of the patients had triple positivity for aPL (LAC, ACA and antibeta2GLP1) and one had double positivity (LAC and antibeta2GLP1); none of the controls showed multiple positivity. CONCLUSIONS: Our data show that migraineurs have a significantly higher prevalence of antiphospholipid antibodies, and point towards the fact that the two conditions may be comorbid or even that migraine may be an early sign for identifying patients with aPL positivity. PMID- 21585649 TI - Towards standardization of in vivo thrombosis studies in mice. PMID- 21585651 TI - ADH1 expression inversely correlates with CDR1 and CDR2 in Candida albicans from chronic oral candidosis in APECED (APS-I) patients. AB - Expression of the alcohol dehydrogenase gene ADH1, which converts ethanol into carcinogenic acetaldehyde, significantly inversely correlated with the expression of CDR1 and CDR2, genes linked to azole resistance in Candida albicans isolated from chronic oral candidosis in autoimmune polyendocrinopathy-candidosis ectodermal dystrophy (APECED, APS-I) patients. This is a novel link between candidal two-carbon metabolism genes and azole resistance. PMID- 21585650 TI - Induction of tolerance to factor VIII by transient co-administration with rapamycin. AB - BACKGROUND: Formation of inhibitory antibodies is a frequent and serious complication of factor (F) VIII replacement therapy for the X-linked bleeding disorder hemophilia A. Similarly, hemophilia A mice develop high-titer inhibitors to recombinant human FVIII after a few intravenous injections. OBJECTIVE: Using the murine model, the study sought to develop a short regimen capable of inducing tolerance to FVIII. METHODS: A 1-month immunomodulatory protocol, consisting of FVIII administration combined with oral delivery of rapamycin, was developed. RESULTS: The protocol effectively prevented formation of inhibitors to FVIII upon subsequent intravenous treatment (weekly for 3.5 months). Control mice formed high-titer inhibitors and had CD4(+) T effector cell responses characterized by expression of IL-2, IL-4 and IL-6. Tolerized mice instead had a CD4(+)CD25(+)FoxP3(+) T cell response to FVIII that suppressed antibody formation upon adoptive transfer, indicating a shift from Th2 to Treg if FVIII antigen was introduced to T cells during inhibition with rapamycin. CD4(+) T cells from tolerized mice also expressed TGF-beta1 and CTLA4, but not IL-10. The presence of FVIII antigen during the time of rapamycin administration was required for specific tolerance induction. CONCLUSIONS: The study shows that a prophylactic immune tolerance protocol for FVIII can be developed using rapamycin, a drug that is already widely in clinical application. Immune suppression with rapamycin was mild and highly transient, as the mice regained immune competence within a few weeks. PMID- 21585652 TI - The Saccharomyces cerevisiae fermentation stress response protein Igd1p/Yfr017p regulates glycogen levels by inhibiting the glycogen debranching enzyme. AB - Wine fermentation imposes a number of stresses on Saccharomyces cerevisiae, and wine yeasts respond to this harsh environment by altering their transcriptional profile (Marks et al., 2008). We have labeled this change in gene expression patterns the fermentation stress response (FSR). An important component of the FSR is the increased expression of 62 genes for which no function has been identified for their protein products. We hypothesize that a function for these proteins may only be revealed late in grape must fermentation, when the yeast cells are facing conditions much more extreme than those normally encountered in laboratory media. We used affinity copurification to identify interaction partners for the FSR protein Yfr017p, and found that it interacts specifically with the glycogen debranching enzyme (Gdb1p). The expression of both of these proteins is strongly induced during wine fermentation. Therefore, we investigated the role of Yfr017p in glycogen metabolism by constructing wine yeast strains that lack this protein. These YFR017C null cells displayed a significant reduction in their ability to accumulate glycogen during aerobic growth and fermentation. Moreover, Yfr017p inhibits Gdb1p activity in vitro. These results suggest that Yfr017p functions as an inhibitor of Gdb1p, enhancing the ability of yeast cells to store glucose as glycogen. Therefore, we propose IGD1 (for inhibitor of glycogen debranching) as a gene name for the YFR017C ORF. PMID- 21585653 TI - Therapy of psoriasis in childhood and adolescence - a German expert consensus. AB - Psoriasis of childhood shows an annual prevalence of 0.71 % and accordingly has to be regarded as a frequent chronic inflammatory skin disorder of this age. The impact on the quality of life as well as development of the afflicted children and their parents is evident. On the other side, therapy is demanding with regard to the specific juvenile metabolism, physical development and skin penetration of topical drugs. Long-term treatment at an early age has to be critically judged regarding the chronicity of the disease. Topical corticosteroids, alternatively dithranol may be used first-line, followed by vitamin D derivatives. A combination with UV-light, preferably UV-B, has to be decided on an individual basis. Systemic treatment may be initiated in recalcitrant disease with methotrexate and cyclosporine where long-term experience is available from juvenile rheumatology and transplantation medicine. Alternatively fumaric acid esters or retinoids are available. Rehabilitation procedures will help the children and their parents to cope with the disease and its treatment. The different treatment options are presented here as a German expert consensus, as clinical studies are hardly available and only a few therapeutics are licensed for this age. In any case the therapy has to be individually planned and decided together with the patients and their parents to gain maximal safety, comfort and success. PMID- 21585654 TI - Modes of action of diclofenac 3%/hyaluronic acid 2.5% in the treatment of actinic keratosis. AB - BACKGROUND: The efficacy of topically applied diclofenac 3 % in combination with hyaluronic acid 2.5 % in the treatment of actinic keratoses (AKs) has been demonstrated in several clinical studies, but the exact mode of action is still unclear. This study evaluates the potential molecular and cellular main modes of action of topically applied diclofenac in the treatment of AKs. PATIENTS AND METHODS: In this prospective study 20 male patients with AKs were treated for 90 days with topically applied diclofenac 3 %/hyaluronic acid 2.5 %. Before and after treatment, skin biopsies were taken from the treatment area and were investigated histologically and immunohistochemically as well as compared to healthy skin. For this purpose, markers for inflammation (COX-2, CD3, CD8), apoptosis (p53), cell cycle arrest (p53, p21), proliferation (Ki67), and angiogenesis (CD31) were examined. RESULTS: The immunohistochemical analysis demonstrated a significant decrease in expression of COX-2, CD3 and CD8. Furthermore, there was a clear reduction of CD31 expression as a marker for angiogenetic processes. Additionally, there was a tendency toward a reduction in markers for proliferation and apoptosis. CONCLUSIONS: The efficacy of diclofenac 3 %/hyaluronic acid 2.5 % in the treatment of AKs is probably due to anti inflammatory and anti-angiogenic effects, potentially associated with anti proliferative and apoptosis-inducing underlying mechanisms. PMID- 21585655 TI - Do bacterial genotoxins contribute to chronic inflammation, genomic instability and tumor progression? AB - Cytolethal distending toxin, produced by several Gram-negative bacteria, and colibactin, secreted by several commensal and extraintestinal pathogenic Escherichia coli strains, are the first bacterial genotoxins to be described to date. Exposure to cytolethal distending toxin and colibactin induces DNA damage, and consequently activates the DNA damage response, resulting in cell cycle arrest of the intoxicated cells and DNA repair. Irreversible DNA damage will lead to cell death by apoptosis or to senescence. It is well established that chronic exposure to DNA damaging agents, either endogenous (reactive oxygen species) or exogenous (ionizing radiation), may cause genomic instability as a result of the alteration of genes coordinating the DNA damage response, thus favoring tumor initiation and progression. In this review, we summarize the state of the art of the biology of cytolethal distending toxin and colibactin, focusing on the activation of the DNA damage response and repair pathways, and discuss the cellular responses induced in intoxicated cells, as well as how prolonged intoxication may lead to chronic inflammation, the accumulation of genomic instability, and tumor progression in both in vitro and in vivo models. PMID- 21585656 TI - Nautilin-63, a novel acidic glycoprotein from the shell nacre of Nautilus macromphalus. AB - In molluscs, and more generally in metazoan organisms, the production of a calcified skeleton is a complex molecular process that is regulated by the secretion of an extracellular organic matrix. This matrix constitutes a cohesive and functional macromolecular assemblage, containing mainly proteins, glycoproteins and polysaccharides that, together, control the biomineral formation. These macromolecules interact with the extruded precursor mineral ions, mainly calcium and bicarbonate, to form complex organo-mineral composites of well-defined microstructures. For several reasons related to its remarkable mechanical properties and to its high value in jewelry, nacre is by far the most studied molluscan shell microstructure and constitutes a key model in biomineralization research. To understand the molecular mechanism that controls the formation of the shell nacreous layer, we have investigated the biochemistry of Nautilin-63, one of the main nacre matrix proteins of the cephalopod Nautilus macromphalus. After purification of Nautilin-63 by preparative electrophoresis, we demonstrate that this soluble protein is glycine-aspartate-rich, that it is highly glycosylated, that its sugar moieties are acidic, and that it is able to bind chitin in vitro. Interestingly, Nautilin-63 strongly interacts with the morphology of CaCO(3) crystals precipitated in vitro but, unexpectedly, it exhibits an extremely weak ability to inhibit in vitro the precipitation of CaCO(3) . The partial resolution of its amino acid sequence by de novo sequencing of its tryptic peptides indicates that Nautilin-63 exhibits short collagenous like domains. Owing to specific polyclonal antibodies raised against the purified protein, Nautilin-63 was immunolocalized mainly in the intertabular nacre matrix. In conclusion, Nautilin-63 exhibits 'hybrid' biochemical properties that are found both in the soluble and insoluble proteins, rendering it difficult to classify according to the standard view on nacre proteins. DATABASE: The protein sequences of N63 appear on the UniProt Knowledgebase under accession number P86702. PMID- 21585658 TI - Haemodynamic effects of negative pressure wound therapy when using a rigid barrier to prevent heart rupture. AB - Right ventricular heart rupture is a devastating complication associated with negative pressure wound therapy (NPWT) in cardiac surgery. The use of a rigid barrier has been suggested to offer protection against this lethal complication by preventing the heart from being drawn up and damaged by the sharp sternum bone edges. The aim of this study was to investigate the haemodynamic effects of placing a rigid barrier over the heart to protect it from rupture during NPWT. Eight pigs underwent median sternotomy followed by NPWT at --70 and --120 mmHg, using foam, with or without a rigid plastic disc between the heart and the sternal edges. The heart frequency, cardiac output, mean systemic arterial pressure, mean pulmonary artery pressure, central venous pressure and left atrial pressure were recorded. Cardiac output was not affected by NPWT, regardless of whether a rigid barrier was used. Heart frequency decreased during NPWT without a disc, and showed a tendency towards a decrease when using a rigid disc. The blood pressure decreased during NPWT without a disc, and showed only a tendency towards a decrease when a disc was inserted between the heart and the sternum. In conclusion, the results of this haemodynamic study show that a rigid disc can safely be placed over the heart during NPWT, to prevent heart rupture. The haemodynamic effects of NPWT in sternotomy wounds are slightly reduced by the presence of the rigid disc. PMID- 21585659 TI - Letter: a cheap and simple method for prevention of air leaks in vacuum-assisted closure therapy. PMID- 21585657 TI - A guide to taming a toxin--recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancer. AB - Pseudomonas exotoxin A (PE) is a highly toxic protein secreted by the opportunistic pathogen Pseudomonas aeruginosa. The modular structure and corresponding mechanism of action of PE make it amenable to extensive modifications that can redirect its potent cytotoxicity from disease to a therapeutic function. In combination with a variety of artificial targeting elements, such as receptor ligands and antibody fragments, PE becomes a selective agent for the elimination of specific cell populations. This review summarizes our current understanding of PE, its intoxication pathway, and the ongoing efforts to convert this toxin into a treatment for cancer. PMID- 21585660 TI - The influence on wound contraction and fluid evacuation of a rigid disc inserted to protect exposed organs during negative pressure wound therapy. AB - The use of a rigid disc as a barrier between the wound bed and the wound filler during negative pressure wound therapy (NPWT) has been suggested to prevent damage to exposed organs. However, it is important to determine that the effects of NPWT, such as wound contraction and fluid removal, are maintained during treatment despite the use of a barrier. This study was performed to examine the effect of NPWT on wound contraction and fluid evacuation in the presence of a rigid disc. Peripheral wounds were created on the backs of eight pigs. The wounds were filled with foam, and rigid discs of different designs were inserted between the wound bed and the foam. Wound contraction and fluid evacuation were measured after application of continuous NPWT at -80 mmHg. Wound contraction was similar in the presence and the absence of a rigid disc (84 +/- 4% and 83 +/- 3%, respectively, compared with baseline). Furthermore, the rigid disc did not affect wound fluid removal compared with ordinary NPWT (e.g. after 120 seconds, 71 +/- 4 ml was removed in the presence and 73 +/- 3 ml was removed in the absence of a disc). This study shows that a rigid barrier may be placed under the wound filler to protect exposed structures during NPWT without affecting wound contraction and fluid removal, which are two crucial features of NPWT. PMID- 21585661 TI - Marjolin ulcer: an overlooked entity. AB - Marjolin ulcer is a well-defined, but uncommon malignant ulcer that occurs in chronic wounds and cutaneous scars. Jean-Nicolas Marjolin was credited with describing this phenomenon in 1828. This entity is frequently overlooked and therefore inadequately treated leading to a poor prognosis. The malignant transformation of an ulcer is most commonly associated with burn scars, but has been reported in many other types of chronic, non healing wounds such as traumatic wounds, venous stasis and chronic pressure ulcers, fistulas, lacerations and leprosy ulcers. Development of malignancy tends to be slow with an average time of approximately 25 years. Various theories concerning pathogenesis of Marjolin ulcer have been proposed. Well-differentiated squamous cell carcinoma (SCC) is the most common histological type of Marjolin ulcer. Biopsy with histopathologic interpretation remains the gold standard for the diagnosis, with radical surgical excision being the treatment of choice. A high index of suspicion should be held by any health care provider when evaluating a chronic, non healing wound. This is a case report of a Marjolin ulcer arising on the left buttock of a patient with a long-standing history of a traumatic wound. PMID- 21585662 TI - Making it matter. PMID- 21585663 TI - Learning safe prescribing during post-take ward rounds. AB - BACKGROUND: As the main tool through which doctors treat the medically unwell, prescribing is a practice that is undervalued and under-taught within modern medicine. Paradoxically prescribing not only has the potential to cure, it also has the potential to cause great harm if carried out incorrectly and unsafely. CONTEXT: Prescribing errors have remained an issue in patient safety for many years, yet education in safe prescribing at both undergraduate and postgraduate level appears to be lacking. INNOVATION: 'Check and Correct' is an innovation developed at Worthing Hospital in West Sussex to educate both medical students and junior doctors on the importance of safe prescribing. As a final-year medical student I used 'Check and Correct' on busy post-take ward rounds for 2 weeks. The aim was to research the main areas where prescribing standards set by the hospital had not been met, whilst improving awareness in safe prescribing for both myself and the post-take team. The process involved checking the drug chart of every patient seen on the post-take round and addressing errors on the chart with the team for correction at the bedside. IMPLICATIONS: 'Check and Correct' reaffirms the assertion that further education is required in safe prescribing. The success of the process is highly dependent on the consultant leading the ward round ensuring that errors are vocalised and addressed. If conducted correctly, this exercise can educate doctors and medical students by addressing errors and emphasising the importance of prescribing, whilst ensuring the safety and care of patients. PMID- 21585664 TI - Paramedic preceptor: work readiness in graduate paramedics. AB - BACKGROUND: The paramedic profession is growing within Australia, and is undergoing change both in the nature of its roles in health care and in the nature of the education systems that produce paramedic graduates. CONTEXT: Within Australia there are two educational models for paramedic education: the post employment vocational model and the pre-employment university model. With the progressive phasing out of the vocational model and the rising number of paramedic students there is increasing demand on paramedic preceptors. This increase in demand raises questions about the education of paramedics to perform the teaching role and their work readiness. INNOVATION: This article explores issues associated with the work readiness of paramedic graduates from the perspective of the preceptor role. Links are drawn to the industry competency standards for paramedic graduates. IMPLICATIONS: This article identifies the need for further research into the role of the paramedic preceptor and the work readiness of paramedic graduates to undertake this role. PMID- 21585665 TI - Changing the learning environment: the medical student voice. AB - BACKGROUND: Students' perceptions of their learning environment influence both how they learn and the quality of their learning outcomes. The clinical component of undergraduate medical courses takes place in an environment designed for clinical service and not teaching. Tension results when these two activities compete for resources. An impending increase in medical student numbers led us to assess the learning environment with a view to planning for the future. METHODS: An open ended question 'If you could change three things about medical school, what would they be?' was added to the Dundee Ready Educational Environment Measure (DREEM). This was used to assess the learning environment of students in years 4 and 5. Allowing students to actively voice their views about changes in the curriculum was considered a useful extension to the DREEM questionnaire. RESULTS: The findings indicated commonalities over the two years of clinical teaching. The areas of commonality included the need for: more clinical exposure early in the curriculum; fewer lectures; greater consistency in terms of assessment; and more constructive relationships. Fourth-year students tended to voice more concerns around resourcing, and sought more clarification about roles and learning outcomes. DISCUSSION: There is a need to address concerns raised by students in the areas of curricula, assessments and access to earlier clinical training. Concerns that can be addressed are increasing resource access, implementation of clearer objectives, consistency of teaching and assessments across sites, more formative assessments, and engaging feedback. Students would also benefit from substantive mentoring and role-modelling. PMID- 21585666 TI - Maximising student preparation for clinical teaching placements. AB - BACKGROUND: With the increasing emphasis on ambulatory health care, clinical educators need to ensure that students are sufficiently prepared to maximise learning opportunities during placements in ambulatory settings. CONTEXT: This study focuses on third-year medical students entering urban or rural clinical placements at an Australian graduate entry medical school. INNOVATION: All rural and a subset of urban students received intensive training in taking Papanicolaou (Pap) smears prior to starting the clinical placement. Training involved gynaecological teaching associates, active practice and real-time feedback. Evaluation included workshop feedback, reflection on effectiveness during the placement, and comparison of trained and untrained students' recorded clinical experience of taking Pap smears. IMPLICATIONS: Students given pre-placement training praised their learning experience, and on average took more Pap smears during their placement than did their untrained peers. The difference, however, did not reach statistical significance. The pre-placement teaching workshop on a difficult skill was popular and worthy of further study regarding other challenging clinical skills. PMID- 21585667 TI - Tips for teaching in longitudinal clerkships. AB - BACKGROUND: Longitudinal clinics (LCs) are increasingly common learning settings for North American medical students. However, the structure of an LC is distinct from a traditional block rotation, and requires different teaching strategies to maximise opportunities for learning. CONTEXT: The length of the relationship between student and teacher in an LC allows the teacher to focus on the basics of orientation early in the year, and to gradually entrust the student with more responsibility. The trajectory of learning can be anticipated by a teacher and used to guide the student's development over time. INNOVATION AND IMPLICATIONS: We gathered feedback from students and teachers who participated in a year-long LC, and offer four tips for effective workplace learning. By using these tips, teachers can ease the transition into a complex work environment and maximise learning from clinical encounters. PMID- 21585668 TI - A novel objective structured clinical examination for the assessment of transfusion practice in anaesthesia. AB - BACKGROUND: In 2008 there were 262 episodes of incorrect blood component transfusion. Safer Practice Notice 14, Right patient, right blood, introduced a mandatory requirement for all clinical staff involved in the blood transfusion process to be assessed against competencies developed on a national basis. It was recommended that the assessment should be an observed, formalised process. The National Patient Safety Agency (NPSA) produced an assessment framework, but this has never been validated. We developed the Nottingham Anaesthesia Transfusion OSCE (NATO). This consists of an interactive clinical scenario that examines the key aspects of transfusion medicine. METHODS: After gaining informed consent, the NATO assessments of 12 anaesthetists were filmed. Three experienced assessors independently viewed the recorded material and scored the candidates. Cronbach's alpha was subsequently calculated. All participants were asked to complete a feedback form. RESULTS: The pass rate during the study was 58 percent (7/12). Cronbach's alpha for NATO was 0.929. Seventy-five percent of candidates judged NATO to be a fair assessment of transfusion competency. DISCUSSION: NATO allows the objectives detailed by the NPSA to be assessed formally in a format that is pertinent to anaesthetic practice. Internal reliability and face validity evaluation are the first steps in utility assurance of this assessment tool. PMID- 21585669 TI - Men's health: it is imperative to teach scrotal and rectal examination. AB - BACKGROUND: Men's health has been a neglected area. Both their general health and their sexual health impact on morbidity and mortality. To improve this situation we need to educate men to attend their doctor and discuss their concerns. But, we also need medical professionals who are both competent and confident in initiating discussions and dealing with men's concerns. CONTEXT: Studies of graduating students in both Australia and Ireland show that they have had little experience in performing rectal examinations, and have little confidence in their findings when they do perform them. INNOVATION: We decided to implement a pilot study of a Urological Teaching Associate (UTA) Programme, aiming to teach students during their urological rotation the technique and communication skills of hernia, genital and rectal examinations. We recruited men from the community, trained them in these skills, and in feedback skills, and the UTAs then teach the students whilst being examined themselves. Each tutorial begins with an introduction followed by a demonstration by the UTAs, where one plays the role of the doctor and the other plays the patient. The students then have a turn at examining a UTA, obtaining feedback from UTAs on their performance. The students complete an evaluation form before and after the tutorial. Part of this is to assess their confidence in performing these examinations. The results show a dramatic increase in confidence in performing these examinations after the tutorial. IMPLICATIONS: If these results are confirmed by a larger study then consideration needs to be given to these programmes becoming a standard part of the curriculum. PMID- 21585670 TI - Integration of high-fidelity simulator in third-year paediatrics clerkship. AB - BACKGROUND: Simulation in medicine is a useful tool for assessing clinical competencies. The liaison committee on medical education expects students to have simulation experiences in the curriculum. The integration of simulators has been encouraged for clinical clerkships. The use of the human simulator in a safe environment should result in enhanced teamworking, communication and critical thinking skills. CONTEXT: During the academic year 2007-08, a formative activity using the simulator was implemented in the paediatrics clerkship. The objectives included exposing students to an emergent general paediatric medical scenario using the human simulator. It was imperative that students would adequately go through the critical thinking process. INNOVATION: The paediatrics clerkship has incorporated a formative activity using the high-fidelity simulator. A faculty member debriefed the students, and feedback was offered. A total of 124 students participated in the activity. Ninety-eight percent agreed that the use of the simulator in a scenario such as the one presented allowed for a better understanding of the clinical issues studied in the clerkship. More than 85 percent of the students recommended the integration of the simulator in other major clinical clerkships. Performance in the objective structured clinical exam (OSCE) at the end of the clerkship has improved after the implementation of this formative activity. IMPLICATIONS: The use of the high-fidelity simulator during the paediatrics clerkship has been identified as an excellent teaching tool. This formative activity has been deemed successful by the students, who feel that it serves as an extra tool to strengthen learned concepts and skills. PMID- 21585671 TI - Over the counter clinical skills for pharmacists. AB - BACKGROUND: This paper describes the development, implementation and evaluation of a clinical skills course for pharmacist independent and supplementary prescribers. The aim of the course was to develop the clinical and procedural skills of pharmacists to enable safe practice at an advanced level, in conjunction with their prescribing role. METHODS: The development of the programme used qualitative data from interviews with practising pharmacists, senior pharmacists and clinical skills teachers to identify the list of procedural skills to be learned and practised. On completion of the programme participants were asked to provide written feedback on the content, learning and reaction in practice. RESULTS: Feedback from the participants was positive, with high satisfaction reported in terms of workshop organisation, content, teaching and skills practice. Participants completed an objective structured clinical examination (OSCE) at the end of the workshop, and the results for each of the five skill stations tested were good. Participants also kept a reflective logbook in practice, detailing when and how they used the skills learned during the workshop. INNOVATION: This is the first national clinical skills assessment course of its kind to be undertaken in support of the development of a standardised approach to clinical and procedural skills. The use of structured learning with simulation, simulated and real patients, standardised procedural checklists, and peer learning and support has led to a very successful course for participants across Scotland. IMPLICATIONS: The clinical skills assessment course is easily transferable across professions, and could be used to develop safe and effective clinical skills practice in a wide range of settings. PMID- 21585672 TI - A proposal to incorporate a public health perspective into clinical teaching. AB - BACKGROUND: In medicine today the 'whole person with an illness' struggles for attention in a health system dominated by a specific focus on disease. A reductionist approach alone is inadequate. CONTEXT: Efforts to broaden the medical curriculum through integrating public health into clinical practice have been numerous, yet the clinical application of a broad public health perspective in medical education has been frustrated by a number of factors. INNOVATION: This paper is a proposal to incorporate a public health perspective into clinical decision making, in order to assist the student to develop a comprehensive approach to clinical assessment. The proposed framework formalises the assessment of the patient's personal and social context, which is used to complement disease assessment and diagnosis. My suggestion is to use the SOAP format (subjective, objective, assessment and plan) as the framework for clinically processing a public health perspective of the patient. I have classified the public health perspective in terms of seven categories of the patient's context (cultural, social context, psychological context, population health context, social determinants, health services context and the information context). Within each of these categories the student clinician gathers subjective and objective public health data, which is used in combination with diagnostic clinical data to formulate the whole-patient assessment and plan. IMPLICATIONS: The next step is to trial and evaluate the effectiveness of the proposal in promoting the assessment of the whole person with an illness. PMID- 21585673 TI - Homemade laparoscopic simulators for surgical trainees. AB - BACKGROUND: Laparoscopic surgery has become increasingly popular in recent times. Laparoscopic skills and dexterity can be improved by using simulators. We provide a step-by-step guide with diagrams to build an individual homemade laparoscopic trainer box, which is easily available and affordable. METHODS: We collected the required material for our homemade trainer box from a local DIY shop and purchased a high-definition (HD) webcam online. We used a 12-litre plastic storage box and mounted the webcam inside the lid of the plastic box. The ultraslim energy-saving fluorescent light was mounted behind the webcam. Holes were made in the plastic lid and patched with circular pieces of Neoprene to accommodate the insertion of laparoscopic instruments. RESULTS: The trainer box can be built in 3 hours. The trainer box weighs 1.2 kg with a light source, and is easily portable. It was demonstrated to a cohort of surgical trainees and they were very receptive, and liked the idea of an easy to assemble, low-cost trainer box with high-quality images. DISCUSSION: Our homemade trainer box offers HD vision that can be viewed on a personal computer, and the webcam is adjustable so it gives hands-free stability. It is built with a lightweight plastic box so it can be easily carried around by a trainee. This simple, inexpensive, easy-to build trainer box makes a perfect solution for individuals who want to practise basic laparoscopic skills at home or in the workplace. PMID- 21585674 TI - Medical students as observers in theatre: is an explicit consent necessary? AB - BACKGROUND: Obtaining consent before engaging patients in teaching activities is essential. The presence of medical students as observers in the operating theatre is sometimes overlooked as a form of teaching activity, in which patients could have become unwitting or unwilling participants. PURPOSE: To investigate patients' attitudes towards student observers in theatre. METHOD: A cross sectional, voluntary, guided questionnaire survey on 225 general surgical patients at a teaching hospital. RESULTS: Over two-thirds of patients would accept student observers, and regard a prior consent process as essential. Gender, level of education, subjective state of health and the perceived risk of surgery were not found to influence their decisions. Younger patients were more likely to refuse observers. Close to 10 percent of patients who were happy to participate in bedside teaching would not accept theatre observers, whereas 25 percent who were not happy to participate in bedside teaching would accept theatre observers. CONCLUSION: An explicit consent process is essential for theatre-based teaching, even when students are simply acting as observers. Patients who are willing to participate in ward-based teaching should not be presumed to accept theatre observers. PMID- 21585675 TI - Emergency operative training and peer learning in practice. PMID- 21585676 TI - First footprints of an expedition doctor. PMID- 21585677 TI - How do you tell a student that they smell? PMID- 21585684 TI - The negatives of e-learning. PMID- 21585685 TI - School was more difficult than studying medicine. PMID- 21585687 TI - Perioperative therapy for resectable gastric cancer: what does the future hold? PMID- 21585688 TI - Evidence on the economic value of psychosocial interventions to alleviate anxiety and depression among cancer survivors: a systematic review. AB - AIM: With cancer cases expected to rise in the coming decades, increased demands will be placed on our health system to address the psychosocial care of patients affected by cancer. The objective of this study was to review the evidence on the cost effectiveness of psychological interventions for individuals with cancer. METHODS: A systematic review was undertaken to assess the cost effectiveness of psychosocial approaches specifically treating depression or anxiety, or both, in patients with cancer. Major medical databases were searched together with reference lists from eligible articles. A narrative approach was used to synthesise the findings and quality assessment was guided by recommendations by Drummond's 10-point checklist for reporting health economic evaluations. RESULTS: The review yielded five cost-effectiveness studies. Most interventions showed improvements in some psychological outcomes. Three studies reported slightly but not significantly higher health-care costs for their intervention than their comparison groups. Costs of the interventions ranged from US$47 to $629 per patient. One study of patients with mixed cancer diagnoses used the preferred outcome "quality-adjusted life years" (QALY) and found a cost-effective investment for an intensive nurse-led program with reported incremental costs of L5278 per QALY gained. No study undertook a comprehensive sensitivity analysis although two studies performed simple one-way sensitivity analyses. CONCLUSION: Current results are inconclusive due to study heterogeneity and inadequate analyses but suggest that psychosocial interventions are inexpensive on a per patient basis. Future studies should routinely include preference-based utility instruments to capture psychological distress in economic evaluation. PMID- 21585689 TI - Clinical guidance on the perioperative use of targeted agents in solid tumor oncology. AB - The use of targeted anti-cancer agents is increasing. It is common to utilize a multi-modal treatment approach towards solid tumors, often including surgical resection, and it has become apparent that some targeted agents can impair wound healing or cause an increased risk of perioperative complications. This article reviews targeted agents used in solid tumor oncology with an emphasis on clinically relevant details. Overall, the evidence of targeted agents causing surgical complications is limited. The greatest amount of evidence exists for bevacizumab causing perioperative complications, possibly due to its extended half-life. There are limited data for cetuximab, sorafenib and sunitinib and very little for other solid tumor targeted agents. Our findings suggest that there should be heightened pharmacovigilence around targeted agents with respect to perioperative complications and increased post-surgical support for patients to aid early detection of postoperative complications until definitive data become available. PMID- 21585690 TI - Decision aids for breast and nodal surgery in patients with early breast cancer: development and a pilot study. AB - AIM: As survival rates for aggressive and conservative breast and lymph node surgery are similar, surgical treatment decisions for patients with early-stage breast cancer should take patient preference into account. Decision aids have been demonstrated to increase patient knowledge and satisfaction with decision making, while decreasing decisional conflict. Hundreds of decision aids exist; however, few address lymph node surgery in any detail, and none acknowledge that there is a choice comparable to that between mastectomy and breast-conserving therapy. METHODS: A systematic process was employed to develop decision aids for mastectomy versus breast-conserving therapy, axillary dissection versus sentinel node biopsy, and options following a positive sentinel node biopsy. The first two of these decision aids were evaluated in a small pilot study. Choice of operation, knowledge and decisional conflict and satisfaction were compared with outcomes in an historical control group. RESULTS: Women reported favorably on the decision aids. The numbers in the pilot group were too small to allow definitive conclusions to be drawn, but suggested a possible reduction in decisional conflict, and possibly increase in decisional satisfaction, knowledge and choice of axillary clearance (rather than sentinel node biopsy) in the intervention group. CONCLUSION: These decision aids could improve decision making for the surgical treatment of early breast cancer. A prospective randomized, control trial is needed to further evaluate the impact of these decision aids, particularly in the case of nodal surgery. PMID- 21585691 TI - Access to assisted reproductive technology for cancer patients in Australia. AB - AIM: To evaluate patterns of care and equity of access to assisted reproductive technology (ART) for cancer patients in Australia. METHODS: A review of state and national legislation and Medicare numbers relevant to ART and phone interviews with representative fertility facilities in each State and Territory. RESULTS: There appears to be little legal restriction to ART for cancer patients although in some states, clinical practice is in fact contrary to legislation. The cost of ART is influenced by Medicare rebates and the overall cost of fertility treatments as set out by the specific fertility unit. There is no rebate for embryo and sperm storage. Costs of receiving an ART intervention vary greatly. Out-of-pocket costs ranged from nil to approximately $3000 per year for an in vitro fertilization or intracytoplasmic sperm injection cycle, from nil to $700 for embryo storage and from nil to $1500 for embryo transfer. All but two of the fertility clinics felt that the numbers of oncology patients accessing ART were low. The most common barrier to access identified by the fertility clinics interviewed was time restriction in a setting where there is a time pressure for a patient to commence anti-cancer treatment. CONCLUSION: Legislation is unlikely to be a barrier to the use of ART by cancer patients. The main reasons for limited access to ART may be cost or other factors including time pressure, the lack of a partner and age. Further research in this area is warranted. PMID- 21585692 TI - How do we apply adjuvant FOLFOX to Japanese patients with curatively resected colorectal cancer? AB - AIM: In Japan the combination of fluorouracil (5-FU), leucovorin and oxaliplatin (FOLFOX) was approved as adjuvant therapy for stage III or high-risk stage II colon cancer only in September 2009. In this study we evaluated the safety and efficacy of FOLFOX as adjuvant chemotherapy for stage IIIb or IV colorectal cancer (CRC) patients in a Japanese group at a single institute. METHODS: A total of 45 consecutive patients received 12 cycles of adjuvant FOLFOX for stage IIIb (n = 31) or IV (n = 14) CRC. Toxicity and disease-free survival (DFS) were analyzed retrospectively. RESULTS: The median dose intensities of oxaliplatin and 5-FU were 0.7 and 0.74, respectively. Oxaliplatin was discontinued in 10 (22%) patients due to an allergic reaction in five, neurotoxicity in four and gastrointestinal toxicity in one. No severe neurotoxicity occurred. The median duration from completion of treatment until complete recovery from peripheral neuropathy was 582 days (95% CI, 486-678). Two-year DFS for stages IIIb and IV was 56.9% and 56.3%, respectively (log-rank, P = 0.533). Univariate analysis revealed that severe vessel invasion, liver metastasis and higher baseline levels of CA19-9 were associated with shorter DFS in stage IV patients. Multivariate analysis including the selected biomarkers revealed none as a significant prognostic factor. CONCLUSION: Adjuvant FOLFOX was well tolerated in a Japanese cohort of both stage IIIb and IV CRC patients. PMID- 21585693 TI - Radioimmunotherapy with (131)I-rituximab for patients with relapsed/refractory B cell non-Hodgkin's lymphoma (NHL). AB - AIM: To evaluate the efficacy and safety of radioimmunotherapy (RIT) with radioiodinated human/murine chimeric anti-CD20 monoclonal antibody rituximab ((131)I-rituximab) for treating Korean patients with relapsed or refractory B cell non-Hodgkin's lymphomas (NHL). METHODS: All patients received unlabeled rituximab 70 mg immediately prior to the administration of a therapeutic dose (median dose: 7.3 GBq) of (131)I-rituximab. The tumor response was evaluated 1 month later by contrast enhanced (18) F-fludeoxyglucose positron emission tomography-computed tomography. RESULTS: Between May 2004 and October 2006, 24 patients received single treatment with (131)I-rituximab. The overall response rate (ORR) was 29%; 46% (three complete responses, two partial responses (PR) for patients with low grade B-cell NHL (LGL) and 9% (one PR) for patients with diffuse large B-cell lymphoma (DLBCL). After a median follow-up of 55 months, the median progression-free survival (PFS) for all the patients was 2.2 months. The median overall survival (OS) was 11.3 months. There were statistically significant differences between the LGL and the DLBCL for the median PFS (4.5 months vs 1.3 months, respectively, P = 0.0007) and the median OS (30.3 months vs 6.5 months, respectively, P = 0.0295). Grades 3-4 thrombocytopenia and neutropenia occurred in 33% (8/24) and 21% (5/24) of the patients, respectively. CONCLUSION: RIT with (131)I-rituximab seems to be effective and tolerable for patients with refractory LGL, although this treatment had modest activity in patients with refractory DLBCL. Further studies are warranted to determine the efficacy of (131)I-rituximab for treating the patients with DLBCL. PMID- 21585694 TI - Changes in medical oncology admissions for the management of breast cancer complications: an Australian institution's experience. AB - AIMS: There is a scarcity of data regarding medical hospitalizations for breast cancer. The aim was to determine whether the burden of inpatient care for breast cancer was declining. METHODS: A retrospective study was conducted of all admissions to a single medical oncology inpatient unit in 1996 and 2006 related to the treatment of breast cancer. The total number of hospitalizations, patients' length of stay in hospital, clinical indications for hospitalization and utilization of inpatient services were determined. Data analysis involved pairwise comparisons between the cohorts. RESULTS: The total number of breast cancer hospitalizations was similar in 1996 and 2006. However, the number of hospitalizations for adjuvant treatment complications was 50% lower in 2006, attributable to a lower rate of chemotherapy-associated febrile neutropenia. Acute clinical problems necessitating inpatient care differed between 1996 and 2006. Fewer hospitalizations for symptomatic hypercalcemia, uncontrolled pain and chemotherapy toxicity were required in 2006 but a significant increase was seen in central nervous system complications. Recent practice involved greater inpatient consultation of other medical and surgical teams. There was a trend towards a shorter duration of admissions in 2006 in both adjuvant and metastatic patients. CONCLUSION: Although total annual breast cancer admission numbers and length of stay did not change significantly, hospitalization for treatment related complications was less frequent in 2006. The clinical manifestations of metastatic breast cancer appear to be changing, and in our institution are being managed with broader multidisciplinary care. PMID- 21585695 TI - The impact of cytology screening and HPV vaccination on the burden of cervical cancer. AB - AIM: To evaluate the impact of different strategies of human papillomavirus (HPV) vaccination on the burden of cervical cancer in Singapore. METHODS: The incidence of cervical cancer was calculated using a Markov model with inputs based on Singapore data for the prevalence of HPV infection, socioeconomic characteristics and screening prevalence. The evaluation was performed for 10 scenarios: no screening, current opportunistic cytology screening, ideal optimal screening, universal adolescent HPV vaccination at 12-years old alone and with catch-up cohorts and combinations of screening and vaccination. RESULTS: (1) The model prediction showed that cervical cancer cases were reduced by 6.5% using opportunistic screening, by 34.3% using optimized screening and by 63.9% with a universal HPV vaccination at 12 years of age. (2) Adding optimized screening, but not opportunistic screening, to a universal adolescent HPV vaccination program caused a moderate further reduction in cervical cancer cases. (3) No difference was discernable in the impact of vaccination introduction between the age groups <20, 20-24 and 25-29 years old. (4) The time required to halve the incidence of cervical cancer was 42 years for universal vaccination at the age of 12 but could be shortened by including catch-up cohorts of women up to 40-years old. CONCLUSION: A universal HPV vaccination program introduced between the ages of 12 29 is superior to cytology screening in reducing the burden of cervical cancer. However, in the next four decades of post-vaccination era, optimizing the screening program remains the most important measure for cervical cancer prevention. PMID- 21585696 TI - Knowledge of Pap smear, HPV and the HPV vaccine and the acceptability of the HPV vaccine by Thai women. AB - AIMS: The primary prevention for cervical cancer, a human papilloma virus (HPV) vaccine, has been available in Thailand for almost 3 years. The present study evaluates knowledge about the Papanicolaou (Pap) smear, HPV and the HPV vaccine and focuses on identifying predictors for the acceptability of the HPV vaccine. METHODS: A sample of 764 women attending the gynecology clinic at Ramathibodi Hospital, Bangkok, was asked to answer a questionnaire on their personal background, their knowledge of the Pap smear and HPV and the HPV vaccine and the acceptability of the HPV vaccine for themselves and their daughters. RESULTS: Knowledge of the Pap smear (96%) is higher than that of HPV (41%) and the HPV vaccine (36%). Only 40% of participants had previously heard about HPV. The acceptability of the HPV vaccine for participants and their daughters was high, 77% and 84%, respectively. Knowing about HPV increases acceptance for the HPV vaccine (adjusted OR = 1.7, 95% CI = 1.2-2.5, in the participants and OR = 2.3, 95% CI = 1.5-3.6 in their daughters). Participants younger than 45 years old (OR = 2.3 and 95% CI = 1.6-3.4 for themselves; OR = 2.2 and 95% CI = 1.4-3.3 for their daughters) were more likely to accept the vaccination than those aged 45 years old and above. CONCLUSION: Knowledge about HPV and the HPV vaccine is generally poor in Thai women. However, the acceptability of the HPV vaccine is good. Knowing about HPV and age under 45 years predict the acceptability of the HPV vaccine. PMID- 21585697 TI - Zoledronic acid to prevent bone loss in Chinese men receiving androgen deprivation therapy for prostate cancer. AB - AIM: To explore the bone mineral density (BMD) preservation effect of zoledronic acid and its renal safety and tolerability in Chinese patients with prostate cancer on androgen deprivation therapy (ADT). METHODS: Overall 26 prostate cancer patients with ADT were given zoledronic acid 4 mg by a 15-min i.v. infusion every 3 months for up to 12 months. Assessment was made at baseline and at 3, 6, 9 and 12 months. Dual-energy X-ray absorptiometry was used to measure the BMD of the lumbar spine and the femoral neck at baseline and 12 months. RESULTS: A total of 23 of 26 recruited patients completed the study. Seven patients had bone metastases. The overall mean increase in BMD (T-score) of the lumbar spine and femoral head from baseline to follow up at 12 months was significant (-2.32 +/- 0.98 to -2.03 +/- 1.08, P = 0.02 and -1.77 +/- 0.72 to -1.63 +/- 0.76, P = 0.01, respectively). In subgroup analyses, significant BMD improvement was observed independent of the status of bone metastasis and the means of ADT. Zoledronic acid had no adverse effect on renal function. Adverse events related to zoledronic acid were minimal. CONCLUSION: Zoledronic acid administered every 3 months significantly increased BMD in prostate cancer patients receiving ADT. It had a satisfactory adverse event profile and imposed minimal risk on patients' renal function. PMID- 21585698 TI - Bevacizumab in combination with oxaliplatin and doxorubicin or liposomal doxorubicin for hepatocellular cancer: a case series. AB - AIMS: Despite the emergence of sorafenib as the standard treatment for patients with advanced hepatocellular cancer (HCC), therapy remains sub-optimal and toxic. METHODS: We report on five patients with advanced HCC treated with bevacizumab, oxaliplatin and doxorubicin or liposomal doxorubicin. RESULTS: Of the five patients, four had cirrhosis; two patients had Child-Pugh A cirrhosis, while one each had Child-Pugh B and C cirrhosis. Grade 3/4 toxicity was uncommon. Four patients had a decrease of >=50% in alpha-fetoprotein levels following therapy and one patient each had a radiographic complete response and stable disease. CONCLUSION: These data add to the growing phase II data that bevacizumab containing regimens are active in advanced HCC patients. Further evaluation of regimens containing bevacizumab with oxaliplatin and/or doxorubicin may be warranted. PMID- 21585699 TI - Small cell lung cancer presenting with paraneoplastic limbic encephalitis. AB - We report two cases of the rare neurological paraneoplastic syndrome, limbic encephalitis, as the initial presentation of small cell lung cancer. The first case responded to treatment of the underlying malignancy, while the second required more acute treatment in the intensive care setting. In this case, initial treatment was with immunosuppression to achieve a degree of stability before the underlying malignancy could be treated. Both cases had significant improvement in neurological function. These cases highlight the importance of directed investigation to try and identify an underlying malignancy in patients in whom a diagnosis of limbic encephalitis is made, and the difficulty in managing such patients. PMID- 21585700 TI - Childhood acute lymphoblastic leukemia with hyperleukocytosis at presentation: perspective and lessons from a tertiary care institution in India. PMID- 21585702 TI - Bevacizumab in the treatment of non-small cell lung cancer: focus on East Asia. PMID- 21585703 TI - Efficacy of bevacizumab with cisplatin and gemcitabine in Asian patients with advanced or recurrent non-squamous non-small cell lung cancer who have not received prior chemotherapy: a substudy of the Avastin in Lung trial. AB - AIM: The phase III AVAiL study evaluated the efficacy and safety of the anti vascular epidermal growth factor agent bevacizumab combined with platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC). We report the results of a preplanned analysis of Asian patients enrolled in AVAiL. METHODS: Patients with recurrent or advanced non squamous NSCLC were randomized to receive bevacizumab 7.5 mg/kg, bevacizumab 15 mg/kg or placebo, plus cisplatin 80 mg/m(2) and gemcitabine 1250 mg/m(2) for up to six cycles, followed by bevacizumab or placebo until disease progression. An exploratory analysis was undertaken to assess efficacy and safety in an Asian subgroup. RESULTS: Of the 1043 patients enrolled, 105 were Asian and were included in the subgroup analysis. Progression-free survival was 8.5 months (95% CI 7.3-10.8) in the bevacizumab 15-mg/kg group, 8.2 (95% CI 6.6-11.7) in the 7.5 mg/kg group and 6.1 (95% CI 5.1-8.0) in the placebo group. Median overall survival in the 7.5-mg/kg bevacizumab group was prolonged compared with placebo group (HR 0.46; 95% CI 0.22-0.97). Nausea was the most common adverse event, occurring at similar rates (ranging from 69-76%) in all study groups. Hypertension was the most common adverse event of special interest, seen in 29, 55 and 16% of patients in the 7.5-mg/kg and 15-mg/kg bevacizumab and placebo groups, respectively. CONCLUSION: Study results strongly suggest that bevacizumab at a dose of 7.5 mg/kg improves the duration of overall survival when combined with cisplatin-gemcitabine in Asian patients. Bevacizumab was well tolerated in this patient group. PMID- 21585704 TI - An indirect comparison of bevacizumab plus cisplatin-gemcitabine and cisplatin plus pemetrexed treatment for patients with advanced first-line non-squamous non small cell lung cancer in East Asia. AB - AIMS: To compare the relative efficacy of bevacizumab plus cisplatin-gemcitabine chemotherapy (BevCG) with cisplatin plus pemetrexed (CP) in the first-line treatment of advanced or recurrent non-small cell lung cancer (NSCLC) in East Asian patients. In the absence of evidence from head-to-head trials, an adjusted indirect treatment comparison (ITC) approach was selected to compare these treatments. METHODS: BevCG and CP treatments have been compared in their relative effects versus their common comparator, the CG treatment. Outcomes from the ITC were used in a statistical model to estimate progression-free survival (PFS) and overall survival (OS) of the two treatments. The non-proportional hazards log logistic, accelerated failure time model was selected as it provided the best fit. The ITC hazard ratio (HR) was conservatively adjusted to match what was observed between the cumulative hazard functions until the end of the Avastin in Lung trial follow-up period. RESULTS: The ITC analysis suggests that patients treated with Bev-based treatment can expect more favorable outcomes in terms of both PFS and OS (PFS HR=0.71 and OS HR=0.41). Probabilistic sensitivity analyses of PFS and OS HR showed that HR values below 1 are likely to occur in 82% of patients for PFS HR and in 94% of patients for OS HR. CONCLUSION: BevCG can be considered a more effective therapy than CP for NSCLC patients in East Asia. PMID- 21585705 TI - Cost-effectiveness of bevacizumab-based therapy versus cisplatin plus pemetrexed for the first-line treatment of advanced non-squamous NSCLC in Korea and Taiwan. AB - AIMS: The aim of this analysis is to investigate the mean incremental costs and life expectancy associated with two first-line treatments for advanced non squamous non-small cell lung cancer (NSCLC) in Korea and Taiwan; bevacizumab plus cisplatin and gemcitabine (BevCG) and cisplatin plus pemetrexed (CP). METHODS: A health economic (area under curve) model with three health states was developed to assess health outcomes (life-years gained [LYG]), direct costs, and incremental cost-effectiveness ratio (ICER). Progression-free survival (PFS) and overall survival (OS) were derived from randomized clinical trials and used in an indirect comparison in order to estimate their cost effectiveness. A life-time horizon was used. Costs and outcomes were discounted yearly by 5% in Korea and by 3% in Taiwan. RESULTS: The incremental LYG for the BevCG patients compared with patients treated with CP were 1.10 (13.2 months) in Korea and 1.19 (14.3 months) in Taiwan. The incremental costs were 37,439,968 ($ 33,322) in Korea and NT$ 1,910,615 ($ 64,541) in Taiwan. The incremental cost-effectiveness ratio was 34,064,835 ($ 30,318) in Korea and NT$ 1,607,960 ($ 54,317) in Taiwan. The inputs tested in one-way sensitivity analyses had very little impact on the overall cost effectiveness. CONCLUSION: This analysis shows that BevCG is more costly but is also associated with additional life-years in Korea and Taiwan. The ICER per LYG suggests that BevCG is a cost-effective therapy when compared to CP for patients with advanced NSCLC in Korea and Taiwan. PMID- 21585707 TI - Analysis for complete genomic sequence of HLA-B and HLA-C alleles in the Chinese Han population. AB - In the present study, we have determined the complete genomic sequence and analysed the intron polymorphism of partial HLA-B and HLA-C alleles in the Chinese Han population. Over 3.0 kb DNA fragments of HLA-B and HLA-C loci were amplified by polymerase chain reaction from partial 5' untranslated region to 3' noncoding region respectively, and then the amplified products were sequenced. Full-length nucleotide sequences of 14 HLA-B alleles and 10 HLA-C alleles were obtained and have been submitted to GenBank and IMGT/HLA database. Two novel alleles of HLA-B*52:01:01:02 and HLA-B*59:01:01:02 were identified, and the complete genomic sequence of HLA-B*52:01:01:01 was firstly reported. Totally 157 and 167 polymorphism positions were found in the full-length genomic sequence of HLA-B and HLA-C loci respectively. Our results suggested that many single nucleotide polymorphisms existed in the exon and intron regions, and the data can provide useful information for understanding the evolution of HLA-B and HLA-C alleles. PMID- 21585706 TI - Comparative effectiveness of bevacizumab plus cisplatin-based chemotherapy versus pemetrexed plus cisplatin treatment in East Asian non-squamous non-small cell lung cancer patients applying real-life outcomes. AB - AIM: To indirectly compare real-life clinical effectiveness of bevacizumab + cisplatin-based therapy from the Safety of Avastin in Lung (SAiL) phase IV clinical trial with published evidence from the phase III clinical trial for pemetrexed + cisplatin among East Asian patients with non-squamous metastatic or recurrent non-small cell lung cancer (NSCLC). METHODS: Survival outcomes were compared between subgroups of East Asian patients receiving treatments of either bevacizumab + cisplatin-based chemotherapy or pemetrexed + cisplatin using a matching-adjusted indirect comparison approach. Patient-level data were used to derive a new group with similar characteristics compared to those reported in a phase III clinical trial evaluating pemetrexed + cisplatin therapy. Exclusions to the SAiL data included those with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, those with mixed cell histology, non-East Asians and those who did not receive cisplatin-based chemotherapy. In total 1000 samples of the pre-matched analysis set of the SAiL data were selected that resulted in equal distributions of the ECOG PS and gender matching variables selected and evaluated for a progression-free survival (PFS) outcome. RESULTS: Median PFS was longer for patients treated with bevacizumab-based therapy (7.4 months; 95% confidence interval [CI]: 6.7-8.2) versus pemetrexed + cisplatin (6.4 months; 95% CI N/A) among non-squamous East Asian NSCLC patients. CONCLUSION: The results suggest that East Asian non-squamous NSCLC patients treated with bevacizumab based therapy have a trend toward improved PFS outcomes compared to those treated with pemetrexed + cisplatin, even after adjusting for differences between the two trial groups. PMID- 21585708 TI - Structure-based design, synthesis, and antifungal activity of new triazole derivatives. AB - A series of new antifungal triazole derivatives with phenylacetamide side chain were rational designed and synthesized on the basis of the structural information of lanosterol 14-demethylase (CYP51). In vitro antifungal activity assay indicated that several compounds showed higher activity than fluconazole. Especially, compound 8h showed excellent inhibitory activity against Candida albicans and Cryptococcus neoformans (MIC=0.0156 MUg/mL), suggesting that it is a promising lead for the development of novel antifungal agents. The binding mode of compound 8h was investigated by flexible molecular docking. It interacted with CACYP51 through hydrophobic and van der Waals interactions. PMID- 21585709 TI - Molecular modeling studies on benzimidazole carboxamide derivatives as PARP-1 inhibitors using 3D-QSAR and docking. AB - Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP-1 inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. To understand the structure activity correlation of cyclic amine-containing benzimidazole carboxamide-based PARP-1 inhibitors, we have carried out a combined molecular docking and three dimensional quantitative structure-activity relationship (3D-QSAR) modeling study. Two types of satisfactory substructure-based 3D-QSAR models were built, including the comparative molecular field analysis (CoMFA) model (r(2) , 0.913; q(2) , 0.743) and comparative molecular similarity indices analysis (CoMSIA) model (r(2) , 0.869; q(2) , 0.734), to predict the biologic activity of new compounds. Docking studies were performed to explore the binding mode between all of the inhibitors and the PARP-1 and produce the bioactive conformation of each compound in the whole data set. The docked conformer-based alignment strategy gave the best 3D-QSAR models, CoMFA model (r(2) , 0.899; q(2) , 0.712) and CoMSIA model (r(2) , 0.889; q(2) , 0.744), respectively. The structural insights obtained from both the 3D-QSAR contour maps and molecular docking help to better interpret the structure-activity relationship. The information obtained from molecular modeling studies helped us to predict the activity of new inhibitors and further design some novel and potent PARP-1 enzyme inhibitors. PMID- 21585710 TI - Assessing protein kinase selectivity with molecular dynamics and mm-pbsa binding free energy calculations. AB - An application of molecular dynamics and molecular mechanics Poisson-Boltzmann surface area techniques to the prediction of protein kinase inhibitor selectivity is presented. A highly active and selective ERK2 inhibitor was placed in equivalent orientations in five different protein kinases (SRC, LCK, GSK3, JNK3 and Aurora-A). Binding free energies were then computed with the molecular mechanics Poisson-Boltzmann surface area approach using 15 nanosecond fully solvated molecular dynamics trajectories of the corresponding protein-ligand complexes. The results show correlation with experimentally determined selectivities and provide useful insights into the underlying structural determinants for selectivity. PMID- 21585711 TI - Designing and engineering of a site-specific incorporation of a keto group in uricase. AB - Urate oxidase is a potential therapeutic protein in the prevention and treatment of tumor lysis syndrome and hyperuricemia. However, its severe immunogenicity limits its clinical application. In our work, several strides have been made toward engineering site-specific modifications of keto groups in urate oxidase by using evolved Methanocaldococcus jannaschii aminoacyl-tRNA synthetase(s)/suppressor tRNA pairs to reduce its antigenicity. Our approach, described here, consisted of designing a M. jannaschii tyrosyl-tRNA synthetase library based on the homology modeling and molecular docking model of the species specific TyrRS-Tyr complex. The active mutation was picked, and pBR-RS series vectors were constructed to define the relationship between the expression of aaRS and the efficiency of the orthogonal amber suppressor tRNA/synthetase system. Two sites based on the 3D structure of the Candida utilis uricase, Lys21 and Lys248, were substituted for p-acetyl-l-phenylalanine, and the yields were optimized. The products were purified, and their enzyme activities and antigenic properties were analyzed. The mutated uricase exhibited decreased antigenic properties, while its catalytic activities remained unchanged. This method imparts new insights into structure-function relationship research and provides a means by which site-specific modifications may be achieved by using PEG derivates to improve pharmacological properties of urate oxidase. PMID- 21585712 TI - Editorial. PMID- 21585713 TI - Sequencing breakthroughs for genomic ecology and evolutionary biology. AB - Techniques involving whole-genome sequencing and whole-population sequencing (metagenomics) are beginning to revolutionize the study of ecology and evolution. This revolution is furthest advanced in the Bacteria and Archaea, and more sequence data are required for genomic ecology to be fully applied to the majority of eukaryotes. Recently developed next-generation sequencing technologies provide practical, massively parallel sequencing at lower cost and without the requirement for large, automated facilities, making genome and transcriptome sequencing and resequencing possible for more projects and more species. These sequencing methods include the 454 implementation of pyrosequencing, Solexa/Illumina reversible terminator technologies, polony sequencing and AB SOLiD. All of these methods use nanotechnology to generate hundreds of thousands of small sequence reads at one time. These technologies have the potential to bring the genomics revolution to whole populations, and to organisms such as endangered species or species of ecological and evolutionary interest. A future is now foreseeable where ecologists may resequence entire genomes from wild populations and perform population genetic studies at a genome, rather than gene, level. The new technologies for high throughput sequencing, their limitations and their applicability to evolutionary and environmental studies, are discussed in this review. PMID- 21585714 TI - Feeding ecology of Xenoturbella bocki (phylum Xenoturbellida) revealed by genetic barcoding. AB - The benthic marine worm Xenoturbella is frequently contaminated with molluscan DNA, which had earlier caused confusion resulting in a suggested bivalve relationship. In order to find the source of the contaminant, we have used molluscan sequences derived from Xenoturbella and compared them to barcodes obtained from several individuals of the nonmicroscopic molluscs sharing the same environment as Xenoturbella. Using cytochrome oxidase 1, we found the contaminating sequences to be 98% similar to the bivalve Ennucula tenuis. Using the highly variable D1-D2 region of the large ribosomal subunit in Xenoturbella, we found three distinct species of contaminating molluscs, one of which is 99% similar to the bivalve Abra nitida, one of the most abundant bivalves in the Gullmarsfjord where Xenoturbella was found, and another 99% similar to the bivalve Nucula sulcata. These data clearly show that Xenoturbella only contains molluscan DNA originating from bivalves living in the same environment, refuting former hypotheses of a bivalve relationship. In addition, these data suggest that Xenoturbella feeds specifically on bivalve prey from multiple species, possibly in the form of eggs and larvae. PMID- 21585715 TI - A ribosomal DNA-based framework for the detection and quantification of stress sensitive nematode families in terrestrial habitats. AB - Indigenous communities of soil-resident nematodes have a high potential for soil health assessment as nematodes are diverse, abundant, trophically heterogeneous and easily extractable from soil. The conserved morphology of nematodes is the main operational reason for their under-exploitation as soil health indicators, and a user-friendly biosensor system should preferably be based on nonmorphological traits. More than 80% of the most environmental stress-sensitive nematode families belong to the orders Mononchida and Dorylaimida. The phylogenetic resolution offered by full-length small subunit ribosomal DNA (SSU rDNA) sequences within these two orders is highly different. Notwithstanding several discrepancies between morphology and SSU rDNA-based systematics, Mononchida families (indicated here as M1-M5) are relatively well-supported and, consequently, family-specific DNA sequences signatures could be defined. Apart from Nygolaimidae and Longidoridae, the resolution among Dorylaimida families was poor. Therefore, a part of the more variable large subunit rDNA (~ 1000 bp from the 5'-end) was sequenced for 72 Dorylaimida species. Sequence analysis revealed a subclade division among Dorylaimida (here defined as D1-D9, PP1-PP3) that shows only distant similarity with 'classical' Dorylaimid systematics. Most subclades were trophically homogeneous, and - in most cases - specific morphological characteristics could be pinpointed that support the proposed division. To illustrate the practicability of the proposed molecular framework, we designed primers for the detection of individual subclades within the order Mononchida in a complex DNA background (viz. in terrestrial or freshwater nematode communities) and tested them in quantitative assays (real-time polymerase chain reaction). Our results constitute proof-of-principle for the concept of DNA sequence signatures based monitoring of stress sensitive nematode families in environmental samples. PMID- 21585716 TI - Using the dog genome to find single nucleotide polymorphisms in red foxes and other distantly related members of the Canidae. AB - Single nucleotide polymorphisms (SNP) are the ideal marker for characterizing genomic variation but can be difficult to find in nonmodel species. We explored the usefulness of the dog genome for finding SNPs in distantly related nonmodel canids and evaluated so-ascertained SNPs. Using 40 primer pairs designed from randomly selected bacterial artificial chromosome clones from the dog genome, we successfully sequenced 80-88% of loci in a coyote (Canis latrans), grey fox (Urocyon cinereoargenteus), and red fox (Vulpes vulpes), which compared favourably to a 60% success rate for each species using 10 primer pairs conserved across mammals. Loci were minimally heterogeneous with respect to SNP density, which was similar, overall, in a discovery panel of nine red foxes to that previously reported for a panel of eight wolves (Canis lupus). Additionally, individual heterozygosity was similar across the three canids in this study. However, the proportion of SNP sites shared with the dog decreased with phylogenetic divergence, with no SNPs shared between red foxes and dogs. Density of interspecific SNPs increased approximately linearly with divergence time between species. Using red foxes from three populations, we estimated F(ST) based on each of 42 SNPs and 14 microsatellites and simulated null distributions conditioned on each marker type. Relative to SNPs, microsatellites systematically underestimated F(ST) and produced biased null distributions, indicating that SNPs are superior markers for these functions. By reconstituting the frequency spectrum of SNPs discovered in nine red foxes, we discovered an estimated 77-89% of all SNPs (within the region screened) present in North American red foxes. In sum, these findings indicate that information from the dog genome enables easy ascertainment of random and gene-linked SNPs throughout the Canidae and illustrate the value of SNPs in ecological and evolutionary genetics. PMID- 21585717 TI - Sperm contamination in archived and contemporary herring samples. AB - Studies using archived scales and otoliths to examine ancient fish populations have become increasingly common, despite many methodological challenges in ancient DNA research. Here, we describe a case of DNA contamination in both modern and historical samples of Pacific herring (Clupea pallasii), where the source of the contamination is likely from milt spillage during collection. We describe a series of experiments to remove contamination using pre-extraction wash treatments. Though contamination was easily removed from contemporary fin clippings, no method was successful at removing contamination from historical scales. We discuss the implications of our findings to the genetic analysis of archived samples. PMID- 21585718 TI - Nondestructive DNA extraction from blackflies (Diptera: Simuliidae): retaining voucher specimens for DNA barcoding projects. AB - A nondestructive, chemical-free method is presented for the extraction of DNA from small insects. Blackflies were submerged in sterile, distilled water and sonicated for varying lengths of time to provide DNA which was assessed in terms of quantity, purity and amplification efficiency. A verified DNA barcode was produced from DNA extracted from blackfly larvae, pupae and adult specimens. A 60 second sonication period was found to release the highest quality and quantity of DNA although the amplification efficiency was found to be similar regardless of sonication time. Overall, a 66% amplification efficiency was observed. Examination of post-sonicated material confirmed retention of morphological characters. Sonication was found to be a reliable DNA extraction approach for barcoding, providing sufficient quality template for polymerase chain reaction amplification as well as retaining the voucher specimen for post-barcoding morphological evaluation. PMID- 21585719 TI - Single nucleotide sequence analysis: a cost- and time-effective protocol for the analysis of microsatellite- and indel-rich chloroplast DNA regions. AB - We present a simple method to screen for DNA sequence variation in microsatellite and indel-rich regions of the chloroplast genome. The single nucleotide sequence (SNS) analysis provides a trade-off between the time- and cost-effective, but less informative and homoplasy-sensitive electrophoretic detection of microsatellite and indel size variation on the one hand, and more costly, but also more accurate methods like DNA sequencing on the other. The principle of the SNS method is to sequence one instead of all four nucleotides of a target region amplified by polymerase chain reaction. By careful selection of the respective nucleotide, almost the same amount of information can be retrieved from these partial sequences as could be from complete sequences; however, only a third to a fourth of the money and time resources are needed. PMID- 21585720 TI - Simple identification of mitochondrial lineages in contact zones based on lineage selective primers. AB - A variety of research projects focus on genetic variation among and within maternal lineages as encompassed by mitochondrial DNA (mtDNA). While mtDNA often differs substantially between species, large differences may also be found within species. The evaluation of such divergent lineages, for example in intraspecific contact zones (hybrid zones), commonly involves sequencing numerous individuals. Large-scale sequencing is both expensive and labour-intensive. Based on sequences from 15 individuals, we devised a simple and quick polymerase chain reaction assay for identification of divergent mtDNA lineages in a secondary contact zone of the side-blotched lizard (Uta stansburiana). The application uses lineage selective primers to amplify a lineage-diagnostic product, and is based on each group of mtDNA haplotypes being a monophyletic assemblage of haplotypes sharing the same maternal ancestry, deeply divergent from the other group. The assay was tested on a larger sample (n = 147) of specimens from the contact zone, confirming its usefulness in quick and reliable identification of mtDNA lineages. This approach can be modified for other species, provided diagnostic lineage variation is available, and may also be performed in simple laboratory settings while conducting fieldwork. PMID- 21585721 TI - The importance of setting the right genetic distance threshold for identification of clones using amplified fragment length polymorphism: a case study with five species in the tropical plant genus Piper. AB - Amplified fragment length polymorphism (AFLP) has been widely used for clone identification, but numerous studies have shown that clonemates do not always present identical AFLP fingerprints. Pairwise AFLP distances that distinguish known clones from nonclones have been used to identify a threshold genetic dissimilarity distance below which samples are considered to represent a single clone. Most studies to date have reported threshold values between 2% and 4%. Here, I determine the consistency of the clonal threshold across five species in the tropical plant genus Piper, and evaluate the sensitivity of genetic diversity indices and estimates of frequency of clonal reproduction to the threshold value selected. I sampled multiple ramets per individual from widely distributed plants for each of the five Piper species to set a threshold at the point where the error rate of clonal assignments was lowest. I then sampled all individuals of each shade-tolerant species in a 1-ha plot, and of each light-demanding species in 25 * 35-m plot, to estimate the frequency of asexual recruitment in natural populations using a series of different thresholds including the threshold set with the preliminary sampling. Clonal threshold values for the different species ranged from 0% to 5% AFLP genetic dissimilarity distance. To determine the sensitivity of estimates of clonal reproduction, I calculated several clonal diversity indexes for the natural populations of each of the five species guided by the range in clonal threshold values observed across the five Piper species. I show that small changes in the value of the clonal threshold can lead to very different conclusions regarding the level of clonal reproduction in natural populations. PMID- 21585722 TI - High throughput tissue preparation for large-scale genotyping experiments. AB - A fast, efficient technique is described for the extraction of DNA from a large number of samples. The applications of this method include population genetics, plant breeding, and genetic screening. In the field, samples are collected in premeasured silica gel aliquots in polypropylene blocks, which are later used to grind the dried tissue. This permits naturalists, breeders, and collaborators to collect a large number of samples in a short amount of time and allows the samples to dry quickly during shipping. No phenol or chloroform steps are required to obtain high-quality DNA. Samples representing 12 plant families, three invertebrates, and a mammal were included. Quantities of DNA obtained were consistent with or better than other techniques. The quality of samples was tested by amplification of the internal transcribed spacer region. Test amplifications were successful, confirming the quality of extracted DNA. PMID- 21585723 TI - geophylobuilder 1.0: an arcgis extension for creating 'geophylogenies'. AB - Evolution is inherently a spatiotemporal process; however, despite this, phylogenetic and geographical data and models remain largely isolated from one another. Geographical information systems provide a ready-made spatial modelling, analysis and dissemination environment within which phylogenetic models can be explicitly linked with their associated spatial data and subsequently integrated with other georeferenced data sets describing the biotic and abiotic environment. geophylobuilder 1.0 is an extension for the arcgis geographical information system that builds a 'geophylogenetic' data model from a phylogenetic tree and associated geographical data. Geophylogenetic database objects can subsequently be queried, spatially analysed and visualized in both 2D and 3D within a geographical information systems. PMID- 21585724 TI - msatcommander: detection of microsatellite repeat arrays and automated, locus specific primer design. AB - msatcommander is a platform-independent program designed to search for microsatellite arrays, design primers, and tag primers using an automated routine. msatcommander accepts as input DNA sequence data in single-sequence or concatenated, fasta-formatted files. Search data and locus-specific primers are written to comma-separated value files for subsequent use in spreadsheet or database programs. Binary versions of the graphical interface for msatcommander are available for Apple OS X and Windows XP. Users of other operating systems may run the graphical interface version using the available source code, provided their environment supports at least Python 2.4, Biopython 1.43, and wxPython 2.8. msatcommander is available from http://code.google.com/p/msatcommander/. PMID- 21585725 TI - ribosort: a program for automated data preparation and exploratory analysis of microbial community fingerprints. AB - ribosort is a computer package for convenient editing of automated ribosomal intergenic spacer analysis (ARISA) and terminal restriction fragment length polymorphism (TRFLP) data. It is designed to eliminate the labourious task of manually classifying community fingerprints in microbial ecology studies. This program automatically assigns detected fragments and their respective relative abundances to appropriate ribotypes. It permits simultaneous sorting of multiple profiles and facilitates direct workflow from TRFLP and ARISA output through to community analyses. ribosort also provides several options to merge repeat profiles of a sample into a single composite profile. By creating a 'ribotypes by samples' matrix ready for statistical analyses, use of the package saves time and simplifies the preparation of DNA fingerprint data sets for statistical analysis. In addition, ribosort performs exploratory analysis on the data by creating multidimensional scaling plots that compare the similarity of sample profiles using the statistical software r. PMID- 21585726 TI - phylochipanalyser - a program for analysing hierarchical probe sets. AB - The recent introduction of phylochips that contain molecular probes facilitates environmental microbial identification in a single experiment without previous cultivation. A set of probes recognizing species at different taxonomic levels is denoted as a hierarchical set. Application of hierarchical probe sets on a DNA microarray allows the assessment of biodiversity with different resolutions. It significantly increases the robustness of the results retrieved from phylochip experiments because of the possible consistency checks of hybridization across different taxonomic levels. Here, we present a computer program, phylo chipanalyser, for the hierarchy editing and the evaluation of phylochip data generated from hierarchical probe sets. PMID- 21585727 TI - genepop'007: a complete re-implementation of the genepop software for Windows and Linux. AB - This note summarizes developments of the genepop software since its first description in 1995, and in particular those new to version 4.0: an extended input format, several estimators of neighbourhood size under isolation by distance, new estimators and confidence intervals for null allele frequency, and less important extensions to previous options. genepop now runs under Linux as well as under Windows, and can be entirely controlled by batch calls. PMID- 21585728 TI - cid: a rapid and efficient bioinformatic tool for the detection of SSRs from genomic libraries. AB - cid is a computational tool developed in the Web environment to process cloned DNA fragments with the objective of masking the vector and adaptor regions, detecting the presence of microsatellites and designing the most appropriate primer pairs for the amplification of the identified repetitive sequences. This entire process is executed by the user in a simple and automated manner with the data input as a Zip file of chromatograms or a multiFASTA file. Thus, it is possible to analyse dozens of sequences at the same time, optimizing data processing and the search for the information of interest. cid is freely available on http://www.shrimp.ufscar.br/cid/index.php. PMID- 21585729 TI - Isolation and characterization of microsatellite markers for red elm (Ulmus rubra Muhl.) and cross-species amplification with Siberian elm (Ulmus pumila L.). AB - Ulmus pumila is an elm species, non-native to the USA that hybridizes with Ulmus rubra. In order to study the genetic structure and hybridization patterns between these two elm species, we developed 15 primer pairs for microsatellite loci in U. rubra and tested their cross-amplification in U. pumila. All 15 primers amplified in both species, 11 of which possessed species-specific alleles. Eight loci were polymorphic in U. pumila and eight in U. rubra, each with two to eight alleles per locus. In addition, five primer pairs previously developed in U. laevis and U. carpinifolia (syn. U. minor) cross-amplified and showed polymorphic loci in U. pumila and/or U. rubra. These markers will facilitate the study of genetic structure and gene flow between U. rubra and exotic, invasive U. pumila. PMID- 21585730 TI - Novel microsatellite markers for the saltmarsh sharp-tailed sparrow, Ammodramus caudacutus (Aves: Passeriformes). AB - We have developed eight high-quality microsatellite DNA loci for the saltmarsh sharp-tailed sparrow and one additional locus with evidence of null alleles. In a sample of 250-350 individuals, the average number of alleles per locus was 14.7 and average observed heterozygosity was 0.80. These loci were tested in three additional species of emberizid sparrows, indicating that more than half of the loci could be useful in other sparrows. PMID- 21585731 TI - Development, characterization and transferability of microsatellite markers for the plant genus Phlox (Polemoniaceae). AB - In order to study diversification and microevolution in Phlox, we developed nine polymorphic microsatellite loci. In 20 individuals of Phlox pilosa from a single population, the average number of alleles per locus was 10.0 +/- 5.1, and average observed and expected heterozygosities were 0.611 +/- 0.234 and 0.769 +/- 0.170, respectively. Most of these markers amplified successfully in 11 additional species of Phlox, representing a broad diversity of the genus, and some also amplified in more distantly related members of the Polemoniaceae. These microsatellite markers will be valuable for investigation of evolutionary processes in this important study system. PMID- 21585732 TI - Characterization of microsatellite markers in mandarin orange (Citrus reticulata Blanco). AB - A dinucleotide-enriched genomic library was obtained from mandarin orange (Citrus reticulata Blanco). A subset of 101 positive clones was sequenced and primers were designed. The loci were screened for levels of variation using 26-29 wild mandarin oranges collected in Vietnam. Forty-three loci were polymorphic with the number of alleles ranging from two to 18. The observed heterozygosity (H(O) ) and expected heterozygosity (H(E) ) were from 0.03 to 0.96 and from 0.03 to 0.92, respectively. PMID- 21585733 TI - Isolation and characterization of nine polymorphic microsatellite loci in the rock carp, Procypris rabaudi (Tchang). AB - Nine highly polymorphic microsatellite loci were isolated from AC- and GATA repeat microsatellite enrichment DNA libraries in the rock carp, Procypris rabaudi (Tchang). The number of alleles for these loci ranged from eight to 18 in tested individuals. Polymorphism information content ranged from 0.712 to 0.908 with an average of 0.837. Average observed and expected heterozygosities were 0.719 and 0.870, respectively. These molecular markers will be useful for the assessment of genetic diversity and analysis of population structure in wild rock carp. PMID- 21585734 TI - Development of 15 polymorphic microsatellite markers in the Atlantic tarpon (Megalops atlanticus) for capture-recapture studies. AB - Fifteen polymorphic microsatellite DNA loci for Atlantic tarpon, Megalops atlanticus, were isolated by using PIMA, a polymerase chain reaction-based technique. The number of alleles at each locus ranged from two to 24 (mean = 7.7) in 65 specimens from Tampa Bay, Florida. Observed and expected heterozygosities ranged from 0.27 to 0.92 (mean = 0.60) and from 0.28 to 0.95 (mean = 0.62), respectively. Genotypes at one locus deviated significantly from Hardy-Weinberg equilibrium. In exact tests for genotypic disequilibrium, there was no evidence of associations between any pair of loci. Overall, loci were well resolved and highly polymorphic, confirming their suitability for DNA fingerprinting applications and other genetic studies. PMID- 21585735 TI - Isolation and characterization of microsatellite loci in the Guanacaste tree, Enterolobium cyclocarpum. AB - We isolated nine microsatellite loci from the Guanacaste tree (Enterolobium cyclocarpum) and optimized them for future research on breeding populations of this species. Loci were screened across 53 individuals from one population and were shown to be variable with the number of alleles per locus ranging from five to 15. Polymorphic information content ranged from 0.420 to 0.900 and observed heterozygosity ranged from 0.547 to 0.906. PMID- 21585736 TI - Development and characterization of 12 microsatellite markers from the deep-sea hydrothermal vent siboglinid Riftia pachyptila. AB - Ecological processes at deep-sea hydrothermal vents on fast-spreading mid-ocean ridges are punctuated by frequent physical disturbance, often accompanied by a high occurrence of population turnover. To persist through local extinction events, sessile invertebrate species living in these geologically and chemically dynamic habitats depend on larval dispersal. We characterized 12 polymorphic microsatellite loci from one such species, the siboglinid tubeworm Riftia pachyptila. All loci conformed to Hardy-Weinberg expectations without linkage (mean H(E) = 0.9405, mean N(A) = 20.25). These microsatellites are being employed in the investigation of spatial and temporal population genetic structure in the eastern Pacific Ocean. PMID- 21585737 TI - Isolation, characterization and cross-amplification of polymorphic microsatellite loci in Laelia speciosa (Orchidaceae). AB - Laelia speciosa is an endangered epiphytic orchid endemic to central Mexico. Here, we report on the development of 14 perfect and imperfect microsatellite repeat loci for this species. Numbers of alleles ranged from two to 16 and levels of observed heterozygosities among the 14 loci ranged from 0.28 to 1.00 across two widely divergent populations. All loci were also tested for cross amplification in four other Laelia species and other selected genera of the subtribe Laeliinae. PMID- 21585738 TI - Isolation of microsatellite loci from the coqui frog, Eleutherodactylus coqui. AB - Thirteen microsatellite loci were isolated from the coqui frog (Eleutherodactylus coqui) and optimized for future research. The loci were screened across 37 individuals from two Puerto Rican populations. Loci were variable with the number of alleles per locus ranging from three to 38. Polymorphic information content ranged from 0.453 to 0.963 and observed heterozygosity for each population ranged from 0.320 to 0.920. PMID- 21585739 TI - Isolation, characterization and multiplex polymerase chain reaction of novel microsatellite loci for the avian parasite Philornis downsi (Diptera: Muscidae). AB - An enrichment technique was used to isolate 11 di-, tri-, and tetra microsatellites for the parasitic fly Philornis downsi (Diptera: Muscidae). These loci were polymerase chain reaction amplified in singleplexes or two-plexes for P. downsi. The loci showed low to moderate polymorphism, exhibited between three and four alleles, and observed heterozygosity ranged from 0.05 to 0.86. These new markers will be useful for population-level and paternity analyses and will provide valuable information about the ecology of this high-impact parasite of vulnerable bird species. PMID- 21585740 TI - Isolation and characterization of 39 microsatellite loci in the endangered Japanese loach Leptobotia curta. AB - A microsatellite-enriched genomic library was obtained for the endangered Japanese loach Leptobotia curta, and 39 dinucleotide markers were successfully isolated and characterized. These markers had between one and nine alleles, with expected heterozygosity ranging from 0 to 0.839, in a population from the Lake Biwa-Yodo River system of Japan. Linkage equilibrium was observed in most loci, and only one locus showed significant deviation from Hardy-Weinberg equilibrium. These microsatellite markers will be useful for genetic diversity studies of wild and captive L. curta populations. PMID- 21585741 TI - Isolation and identification of eight microsatellite loci in the Cherokee darter (Etheostoma scotti) and their variability in other members of the genera Etheostoma, Ammocrypta, and Percina. AB - The Cherokee darter Etheostoma scotti is a federally threatened fish endemic to the Etowah River system of northwest Georgia. In order to analyse the population structure and genetic diversity of this fish, eight tetranucleotide microsatellite genetic markers were developed. The marker set was applied to 13 additional darter species to test cross-species amplification and polymorphism. Successful amplification was obtained for all eight loci in each of the 13 other species of darters, with between seven and eight polymorphic loci per species. PMID- 21585742 TI - Development of expressed sequence tag-derived microsatellite markers for the sea urchin Hemicentrotus pulcherrimus. AB - The first set of 15 expressed sequence tag-simple sequence repeat markers was developed in sea urchin Hemicentrotus pulcherrimus. Number of alleles per locus ranged from two to 17. The observed and expected heterozygosities ranged from 0.022 to 0.911 and from 0.022 to 0.916, respectively. These informative marker loci will be useful for the assessment of genetic variation and population structure of this species. PMID- 21585743 TI - Isolation and characterization of microsatellite loci from Weigela coraeensis (Caprifoliaceae). AB - Weigela coraeensis var. coraeensis is a deciduous shrub species distributed in Japan on the mainland, Honshu, whereas its variety W. coraeensis var. fragrans is endemic to the Izu Islands located south of Honshu. We isolated eight polymorphic microsatellite loci from the species and characterized these loci for 20 individuals from a population in Honshu. The number of alleles per locus ranged from 7 to 15 and the observed and expected heterozygosities ranged from 0.60 to 0.90 and from 0.65 to 0.90, respectively. These eight polymorphic microsatellites will be useful for examining intraspecific genetic differentiation in W. coraeensis. PMID- 21585744 TI - Development of 16 microsatellite markers for the European cockchafer, Melolontha melolontha. AB - Sixteen polymorphic microsatellite markers were isolated from the European cockchafer, Melolontha melolontha L., based on enriched genomic libraries. Allelic variability was assessed in a collection of 30 individuals obtained from a field in eastern Switzerland. The number of detected alleles ranged from three to 13 with a mean of 6.69 and average observed and expected heterozygosities were 0.52 and 0.66, respectively. The 16 highly polymorphic microsatellite markers represent a powerful molecular tool, which will allow for detailed population genetic analyses on this important pest insect. PMID- 21585745 TI - A set of primers for plastid indels and nuclear microsatellites in the invasive plant Heracleum mantegazzianum (Apiaceae) and their transferability to Heracleum sphondylium. AB - This study reports the isolation and polymorphism characterization of four plastid indels and six nuclear microsatellite loci in the invasive plant Heracleum mantegazzianum. These markers were tested in 27 individuals from two distant H. mantegazzianum populations. Plastid indels revealed the presence of five chlorotypes while five nuclear microsatellite loci rendered polymorphism. Applications of these markers include population genetics and phylogeography of H. mantegazzianum. A very good transferability of markers to Heracleum sphondylium was demonstrated. PMID- 21585746 TI - Characterization of microsatellite loci for the endangered cactus Echinocactus grusonii, and their cross-species utilization. AB - Echinocactus grusonii is common in trade but critically endangered in its natural habitat. With the ultimate aim of developing a certification scheme to aid in the conservation of this species, we have isolated E. grusonii microsatellites from a nonenriched library. Fifty-seven sequences contained a microsatellite array, of which 12 were polymorphic among 30 individuals from a single wild population. All 12 microsatellite primer pairs amplified product in one or more species in a screen of 27 other cactus species. PMID- 21585747 TI - Development of microsatellite markers in Gonystylus bancanus (Ramin) useful for tracing and tracking of wood of this protected species. AB - Ten polymorphic microsatellite markers have been developed for Gonystylus bancanus (Ramin), a protected tree species of peat swamp forests in Malaysia and Indonesia. Eight markers were also shown to be polymorphic in other Gonystylus species. The markers will enable assessing the amount of genetic variation within and among populations and the degree of population differentiation, such that donor populations can be selected for reforestation projects. They may be used for tracing and tracking of wood in the production chain, so that legal trade in this Convention on International Trade in Endangered Species of Wild Fauna and Flora-protected timber species, derived from specifically described origins, can be distinguished from illegally logged timber. PMID- 21585748 TI - Microsatellite markers for leatherside chubs Lepidomeda aliciae and Lepidomeda copei. AB - We report the isolation and characterization of eight microsatellite markers in a rare desert cyprinid fish, the leatherside chub. This taxon has recently been divided into two species (Lepidomeda aliciae and Lepidomeda copei) based on genetic, ecological and morphological data, and we explore the utility of these microsatellite loci in both species. All eight loci show promise as highly polymorphic markers in L. aliciae, but only three of the markers appear to be useful in L. copei. PMID- 21585749 TI - Isolation and characterization of dinucleotide microsatellite loci in the Asian elephant (Elephas maximus). AB - The endangered Asian elephant is found today primarily in protected areas. We characterized 18 dinucleotide microsatellite loci in this species. Allelic diversity ranged from three to eight per locus, and observed heterozygosity ranged from 0.200 to 0.842 in a wild population. All loci were in Hardy-Weinberg equilibrium, but linkage disequilibrium was detected between two loci in the wild, but not in the zoo elephants. These loci will be useful for the population level studies of this species. PMID- 21585750 TI - Isolation and characterization of microsatellite loci for Florida largemouth bass, Micropterus salmoides floridanus, and other micropterids. AB - We isolated and characterized 52 novel microsatellite markers from Florida largemouth bass, Micropterus salmoides floridanus, for use in conservation, management and population genetic studies. Markers were assessed in M. s. floridanus from peninsular Florida (n = 30) and averaged eight alleles per locus with observed heterozygosity of 0.57 (range 0-0.97). Cross-taxa amplification was successful among 88% of tested congeners. These polymorphic and potentially taxon diagnostic markers contribute to the limited number of microsatellites currently available for micropterids and specifically M. s. floridanus. PMID- 21585751 TI - Isolation and characterization of microsatellite markers from the hosta species Hosta albomarginata (Liliaceae). AB - Hostas are very popular ornamental plants in gardens in the United States, Europe, and East Asia. We have developed nine microsatellite loci from an enrichment library of genomic DNA in Hosta albomarginata. We characterized these nine microsatellite loci for 20 individuals from a population of H. albomarginata. The primers developed in this study yielded an average of 12.4 alleles per locus (range five to 20) and an average expected heterozygosity of 0.86 (range 0.65 to 0.95). These markers will be powerful tools for breeding programmes of hosta cultivars, studies of population genetics, and the conservation of wild hosta species. PMID- 21585752 TI - A set of novel DNA polymorphisms within candidate genes potentially involved in ecological divergence between Populus alba and P. tremula, two hybridizing European forest trees. AB - We have identified 53 DNA (single nucleotide, microsatellite, and insertion deletion) polymorphisms within 12 candidate genes potentially involved in ecological differences between Populus alba and P. tremula, two hybridizing European forest trees. The genes represent candidates for functional roles associated with abiotic or biotic stress response, cross-talk, phenology, and leaf development. Distributions within sequences, intraspecific levels of diversity, and genetic divergence (F(ST) ) between species are reported for each polymorphism, as are haplotype frequencies for each gene. The markers will be used for population genomic studies of the barrier to gene flow between these two ecologically divergent forest trees. PMID- 21585753 TI - Development and characterization of microsatellite markers for the invasive weed Mikania micrantha (Asteraceae). AB - Mikania micrantha is a successful invasive weed in many parts of the world. Twelve polymorphic microsatellite loci were isolated and characterized from an AC enriched genomic library of this species. Twenty-eight individuals from one population in Dongguan were tested for polymorphism. The average allele number of these microsatellites was three per locus, ranging from two to five. The expected and observed heterozygosities ranged from 0.275 to 0.742, and from 0.250 to 1.000, respectively. These microsatellite markers can be applied to study the population genetics in the native and invasive ranges of this species, and to trace its invasion history. PMID- 21585754 TI - Development of 10 microsatellite loci for Yellow-billed Magpies (Pica nuttalli) and corvid ecology and West Nile virus studies. AB - We developed 10 polymorphic microsatellite loci for Yellow-billed Magpies (Pica nuttalli). The primers were tested across a population of 57 Central California Yellow-billed Magpies and displayed an average of 3.9 alleles per locus. Forty one American Crows (Corvus brachyrhynchos) from California were polymorphic for seven of the loci with an average of 2.9 alleles per locus. One additional microsatellite-containing locus displayed diagnostic allele sizes and may be useful to distinguish between the two species. These corvid specific microsatellites will aid ecological studies of the population-level effects of diseases, such as West Nile virus. PMID- 21585755 TI - Isolation and characterization of polymorphic microsatellite loci in the raccoon (Procyon lotor). AB - We report the isolation and characterization of 17 polymorphic microsatellite loci in the North American raccoon (Procyon lotor). These loci exhibit high levels of allelic diversity, with between four and 13 alleles per locus, and heterozygosity, with observed values of 0.500-1.000 in a sample of 20 individuals. All genotypes conformed to Hardy-Weinberg expectations and there were no instances of linkage disequilibrium detected. PMID- 21585756 TI - Isolation and characterization of polymorphic microsatellite loci from RAPD product in half-smooth tongue sole (Cynoglossus semilaevis) and a test of cross species amplification. AB - Eleven polymorphic microsatellite loci have been isolated and characterized from random amplified polymorphic DNA product in half-smooth tongue sole, Cynoglossus semilaevis. Twenty-one microsatellites were selected for designing microsatellite primers, of which 11 gave working primer pairs. They had between three and 12 alleles. Observed and expected heterozygosities varied from 0.53 to 0.93, and from 0.52 to 0.80, respectively. Five additional fish species assessed for cross species amplification revealed between one and three positive amplifications and between zero and three polymorphic loci per species. PMID- 21585757 TI - Eighteen trinucleotide microsatellite loci for the solitary vespid wasp Monobia quadridens. AB - We identified 18 polymorphic, trinucleotide microsatellite loci for the solitary vespid wasp Monobia quadridens. These markers are to be used for parentage assessment and for studying population structure and inbreeding. Forty-eight diploid females from Southwest Michigan, USA were screened for allelic variation at each locus. Observed heterozygosities ranged from 0.50 to 0.88. The primers were also tested on two other solitary vespid wasps Ancistrocerus adiabatus and Ancistrocerus antilope. PMID- 21585758 TI - Characterization of polymorphic microsatellite markers for the blowfly Chrysomya albiceps (Diptera: Calliphoridae). AB - Chrysomya albiceps is a blowfly of great medical, sanitary and forensic importance widely distributed in the Afrotropical, southern Palaearctic, northern Oriental regions and, recently, in Central and South Americas. Here, we report the characterization of 13 polymorphic microsatellite markers for C. albiceps. The number of alleles ranged from three to 13 alleles with expected heterozygosities ranging from 0.4668 to 0.8408. These markers will be extremely useful for investigating many important aspects of this species such as population structure, dispersal and colonization dynamics. PMID- 21585759 TI - Novel nuclear intron-spanning primers for Arecaceae evolutionary biology. AB - In this study, 96 nuclear 'conserved intron-scanning primers' were screened across subfamilies the Arecaceae (palms) for potential use in research focused on palm evolutionary biology. Primers were evaluated based on their ability to amplify single polymerase chain reaction products in Arecaceae, the clarity of sequencing reads, and the interspecific variability observed. Ultimately, the results suggest that: (i) seven of the loci are likely to be suitable when comparing non-Arecaceae outgroups and Arecaceae ingroups; (ii) seven loci may be of use when comparing subfamilies of Arecaceae; and (iii) four of the loci may be of use when comparing closely related genera. PMID- 21585760 TI - Isolation and characterization of microsatellite markers from the white-ruffed manakin Corapipo altera (Aves, Pipridae). AB - We describe 15 polymorphic microsatellite loci from the white-ruffed manakin Corapipo altera, a common understory bird of Neotropical lowland and montane evergreen forests from eastern Honduras to northwestern Colombia. These markers were developed in order to assess population structure and genetic diversity in a fragmented landscape, and to study gene flow between forest fragments. Primers were tested on a population of 159 individuals from the Coto Brus region of southwestern Costa Rica. We found between four and 23 alleles per locus, and observed heterozygosities ranging from 0.23 to 0.93. PMID- 21585761 TI - Thirteen polymorphic microsatellite DNA loci from whiptails of the genus Aspidoscelis (Teiidae: Squamata) and related cnemidophorine lizards. AB - We describe polymerase chain reaction primers and amplification conditions for 13 microsatellite DNA loci isolated from two bisexual species of whiptail lizards Aspidoscelis costata huico and Aspidoscelis inornata. Primers were tested on either 16 or 48 individuals of A. c. huico and/or 26 individuals of A. inornata. Ten of the 13 primers were also tested against a panel of 31 additional whiptail taxa. We detected three to nine alleles per locus in A. c. huico and four to 19 alleles per locus in A. inornata, with observed heterozygosity ranging from 0.60 to 0.87 and from 0.15 to 1.00, respectively. These primers will be an important resource for surveys of genetic variation in these lizards. PMID- 21585762 TI - Development and characterization of microsatellites markers from the macaw. AB - Macaw (Acrocomia aculeata) is a native palm tree from tropical forests, highly abundant in Brazil and cited as one of the principal sources of plant oil, thus presenting a high potential for biodiesel production. We have optimized and utilized a set of eight polymorphic microsatellite markers for A. aculeata from an enriched genomic library. Automatic sequencing and fluorescence detection were employed to analyse 43 individuals from natural populations. In this study, we have obtained an average number of five alleles per locus. These loci will be employed in future studies of population genetics by providing subsidy information for the species conservation and genetic breeding. PMID- 21585763 TI - Isolation and characterization of microsatellite loci in Psilopeganum sinense Hemsl (Rutaceae), an endangered herb endemic to Yangtze River valley. AB - Twenty-nine primer pairs flanking microsatellite repeats were designed from an AC enriched genomic library of Psilopeganum sinense and tested using 24 individuals derived from a natural population. A total of 11 microsatellite loci were found polymorphic. The number of alleles per locus varied from two to eight, with an average value of 3.7. The ranges of observed and expected heterozygosities were 0.000-0.750 and 0.365-0.800, respectively. These microsatellite loci have been directly applied to the ongoing conservation genetic studies of P. sinense. PMID- 21585764 TI - Isolation and characterization of microsatellite loci in Aspergillus sydowii, a pathogen of Caribbean sea fan corals. AB - Here we report on nine microsatellite loci designed for Aspergillus sydowii, a widely distributed soil saprobe that is also the pathogenic agent of aspergillosis in Caribbean sea fan corals. Primers were tested on 20 A. sydowii isolates from the Caribbean, 17 from diseased sea fans and three from environmental sources. All loci were polymorphic and exhibited varying degrees of allelic diversity (three to nine alleles). Gene diversity (expected heterozygosity) ranged from 0.353 to 0.821. These primers will enable future research into the epidemiology of A. sydowii as an emergent infectious disease. PMID- 21585765 TI - DNA BARCODING: CO1 DNA barcoding amphibians: take the chance, meet the challenge. AB - Although a mitochondrial DNA barcode has been shown to be of great utility for species identification and discovery in an increasing number of diverse taxa, caution has been urged with its application to one of the most taxonomically diverse vertebrate groups - the amphibians. Here, we test three of the perceived shortcomings of a CO1 DNA barcode's utility with a group of Holarctic amphibians: primer fit, sequence variability and overlapping intra- and interspecific variability. We found that although the CO1 DNA barcode priming regions were variable, we were able to reliably amplify a CO1 fragment from degenerate primers and primers with G-C residues at the 3' end. Any overlap between intra- and interspecific variation in our taxonomic sampling was due to introgressive hybridization (Bufo/Anaxyrus), complex genetics (Ambystoma) or incomplete taxonomy (Triturus). Rates of hybridization and species discovery are not expected to be greater for amphibians than for other vertebrate groups, and thus problems with the utility of using a single mitochondrial gene for species identification will not be specific to amphibians. Therefore, we conclude that there is greater potential for a CO1 barcode's use with amphibians than has been reported to date. A large-scale effort to barcode the amphibians of the world, using the same primary barcode region of CO1, will yield important findings for science and conservation. PMID- 21585766 TI - DNA BARCODING: Barcoding corals: limited by interspecific divergence, not intraspecific variation. AB - The expanding use of DNA barcoding as a tool to identify species and assess biodiversity has recently attracted much attention. An attractive aspect of a barcoding method to identify scleractinian species is that it can be utilized on any life stage (larva, juvenile or adult) and is not influenced by phenotypic plasticity unlike morphological methods of species identification. It has been unclear whether the standard DNA barcoding system, based on cytochrome c oxidase subunit 1 (COI), is suitable for species identification of scleractinian corals. Levels of intra- and interspecific genetic variation of the scleractinian COI gene were investigated to determine whether threshold values could be implemented to discriminate conspecifics from other taxa. Overlap between intraspecific variation and interspecific divergence due to low genetic divergence among species (0% in many cases), rather than high levels of intraspecific variation, resulted in the inability to establish appropriate threshold values specific for scleractinians; thus, it was impossible to discern most scleractinian species using this gene. PMID- 21585767 TI - TECHNICAL ADVANCES: A maximum-likelihood relatedness estimator allowing for negative relatedness values. AB - Previously reported maximum-likelihood pairwise relatedness (r) estimator of Thompson and Milligan (M) was extended to allow for negative r estimates under the regression interpretation of r. This was achieved by establishing the equivalency of the likelihoods used in the kinship program and the likelihoods of Thompson. The new maximum-likelihood (ML) estimator was evaluated by Monte Carlo simulations. It was found that the new ML estimator became unbiased significantly faster compared to the original M estimator when the amount of genotype information was increased. The effects of allele frequency estimation errors on the new and existing relatedness estimators were also considered. PMID- 21585768 TI - TECHNICAL ADVANCES: New strategies for telomere-based age estimation. AB - Telomere dynamics link molecular and cellular mechanisms with organismal processes and therefore may explain variation in a number of important life history traits. Telomere length has been used to estimate age in free-living populations of animals. Such estimation is a potentially powerful tool in the context of population dynamics and management, as well as the study of life history trade-offs. The number of studies utilizing telomere restriction fragment assays in the fields of ecology and evolution is steadily growing. However, the field lacks methodological and analytical standardization resulting in considerable variation in telomere length and therefore in the usefulness of these techniques. Here, we illustrate new laboratory and analytical methods to reliably measure telomere length from blood erythrocytes and accurately assess the relationship between telomeres and age. We demonstrate the importance of analysing those telomeres most relevant to age-related studies: the shortest telomeres. We present a reliable method to quickly identify an analysis window (the telomere optimal estimate, TOE) which approaches the optimal window for age estimation. Because the TOE focuses on the shortest telomeres - those telomeres which signal cellular senescence and ageing - TOE can also be used to compare telomeres in age-matched individuals. We also compare constant- and pulsed-field gel electrophoresis to show how each can influence telomere measurement. The use of TOE should provide powerful telomere-based age estimation and enable organismal biologists to readily uncover individual and longitudinal differences with regard to telomere dynamics. PMID- 21585769 TI - TECHNICAL ADVANCES: A microarray for large-scale genomic and transcriptional analyses of the zebra finch (Taeniopygia guttata) and other passerines. AB - The microarray technology has revolutionized biological research in the last decade. By monitoring the expression of many genes simultaneously, microarrays can elucidate gene function, as well as scan entire genomes for candidate genes encoding complex traits. However, because of high costs of sequencing and design, microarrays have largely been restricted to a few model species. Cross-species microarray (CSM) analyses, where microarrays are used for other species than the one they were designed for, have had varied success. We have conducted a CSM analysis by hybridizing genomic DNA from the common whitethroat (Sylvia communis) on a newly developed Affymetrix array designed for the zebra finch (Taeniopygia guttata), the Lund-zf array. The results indicate a very high potential for the zebra finch array to act as a CSM utility in other passerine birds. When hybridizing zebra finch genomic DNA, 98% of the gene representatives had higher signal intensities than the background cut-off, and for the common whitethroat, we found the equivalent proportion to be as high as 96%. This was surprising given the fact that finches and warblers diverged 25-50 million years ago, but may be explained by a relatively low sequence divergence between passerines (89 93%). Passerine birds are widely used in studies of ecology and evolution, and a zebra finch array that can be used for many species may have a large impact on future research directions. PMID- 21585770 TI - TECHNICAL ADVANCES: Effects of genotyping protocols on success and errors in identifying individual river otters (Lontra canadensis) from their faeces. AB - In noninvasive genetic sampling, when genotyping error rates are high and recapture rates are low, misidentification of individuals can lead to overestimation of population size. Thus, estimating genotyping errors is imperative. Nonetheless, conducting multiple polymerase chain reactions (PCRs) at multiple loci is time-consuming and costly. To address the controversy regarding the minimum number of PCRs required for obtaining a consensus genotype, we compared consumer-style the performance of two genotyping protocols (multiple tubes and 'comparative method') in respect to genotyping success and error rates. Our results from 48 faecal samples of river otters (Lontra canadensis) collected in Wyoming in 2003, and from blood samples of five captive river otters amplified with four different primers, suggest that use of the comparative genotyping protocol can minimize the number of PCRs per locus. For all but five samples at one locus, the same consensus genotypes were reached with fewer PCRs and with reduced error rates with this protocol compared to the multiple-tubes method. This finding is reassuring because genotyping errors can occur at relatively high rates even in tissues such as blood and hair. In addition, we found that loci that amplify readily and yield consensus genotypes, may still exhibit high error rates (7-32%) and that amplification with different primers resulted in different types and rates of error. Thus, assigning a genotype based on a single PCR for several loci could result in misidentification of individuals. We recommend that programs designed to statistically assign consensus genotypes should be modified to allow the different treatment of heterozygotes and homozygotes intrinsic to the comparative method. PMID- 21585771 TI - COMPUTER PROGRAMS: d-novl: a program to simulate overlap between two niche-based distribution models. AB - d-novl is a Monte Carlo program designed to generate a null expectation of overlap between two niche-based distribution models. The user may choose between two growth algorithms: the separated algorithm grows a random number of disjointed growth areas, whereas the number of islands algorithm allows the user to input the desired number of growth areas. The latter algorithm can also be used to grow a single growth area. The resulting probability distribution of expected overlap values can be exported into a spreadsheet for further analysis. d-novl is freely available for Mac and Windows platforms at http://www.mygalomorphae.org. PMID- 21585772 TI - COMPUTER PROGRAMS: nessi: a program for numerical estimations in sporophytic self incompatibility genetic systems. AB - nessi is a computer program generating predictions about allelic and genotypic frequencies at the S-locus in sporophytic self-incompatibility systems under finite and infinite populations. For any pattern of dominance relationships among self-incompatibility alleles, nessi computes deterministic equilibrium frequencies and estimates distributions in samples from finite populations of the number of alleles at equilibrium, allelic and genotypic frequencies at equilibrium and allelic and genotypic frequency changes in a single generation. These predictions can be used to rigorously test the impact of negative frequency dependent selection on diversity patterns in natural populations. PMID- 21585773 TI - COMPUTER PROGRAMS: onesamp: a program to estimate effective population size using approximate Bayesian computation. AB - The estimation of effective population size from one sample of genotypes has been problematic because most estimators have been proven imprecise or biased. We developed a web-based program, onesamp that uses approximate Bayesian computation to estimate effective population size from a sample of microsatellite genotypes. onesamp requires an input file of sampled individuals' microsatellite genotypes along with information about several sampling and biological parameters. onesamp provides an estimate of effective population size, along with 95% credible limits. We illustrate the use of onesamp with an example data set from a re introduced population of ibex Capra ibex. PMID- 21585774 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of nine microsatellite loci from the chub mackerel, Scomber japonicus (Perciformes, Scombridae). AB - The stock abundance of the chub mackerel Scomber japonicus - a very important species for fisheries, particularly in Japan - in the Pacific Ocean off Japan has remained at a low level. For studying the population genetics of the chub mackerel, we isolated nine polymorphic microsatellite loci (12-31 alleles/locus; expected heterozygosity, 0.762-0.983) from this species. Cross-species amplification indicated that eight of the nine microsatellite loci in the blue mackerel S. australasicus were polymorphic and functional. PMID- 21585775 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of polymorphic trinucleotide and dinucleotide microsatellite loci for the ice goby, Leucopsarison petersii. AB - Eleven microsatellite markers were isolated and characterized for the ice goby, Leucopsarion petersii, from genomic libraries enriched for (ATG)(9) and (CA)(16) . Twenty individuals from a single population were used to screen polymorphism in these loci. The number of alleles per locus and observed heterozygosity ranged from four to 22 and from 0.35 to 1.00, respectively. All loci did not significantly deviated from Hardy-Weinberg equilibrium, and there was no evidence of linkage disequilibrium between all loci-pairs. These loci showed Mendelian inheritance in a full-sib family. The high level of polymorphism of these loci will be useful for studies of population genetics. PMID- 21585776 TI - PERMANENT GENETIC RESOURCES: Fifteen polymorphic microsatellite DNA loci from Hawaii's Metrosideros polymorpha (Myrtaceae: Myrtales), a model species for ecology and evolution. AB - We developed 15 polymorphic microsatellite loci from the Hawaiian tree Metrosideros polymorpha. These loci were screened against two varieties from several populations and from 23 individuals from one mid-elevation population on Hawaii Island. Loci were variable with the number of alleles per locus ranging from three to 24. Polymorphic information content ranged from 0.222 to 0.941, and observed heterozygosity ranged from 0.261 to 0.955. PMID- 21585777 TI - PERMANENT GENETIC RESOURCES: Development of polymorphic microsatellite loci for the endangered Topeka shiner, Notropis topeka. AB - We have developed a set of eight polymorphic microsatellite markers for the endangered Topeka shiner, Notropis topeka. Allelic diversity at each of these loci was assessed in a single isolated population from eastern South Dakota, USA. The allelic diversity ranged from four to 15 alleles. These are the first microsatellite markers to be reported for this species. These markers are being used in a more thorough study of the population structure throughout the remaining range of this species. PMID- 21585778 TI - PERMANENT GENETIC RESOURCES: Development and characterization of 14 polymorphic microsatellite loci in the endangered tree Euptelea pleiospermum (Eupteleaceae). AB - Fourteen polymorphic microsatellite loci were developed and characterized for the endangered and tertiary relict tree, Euptelea pleiospermum. A genomic DNA enrichment protocol was used to isolate microsatellite loci and polymorphism was explored using 32 individuals from one natural population. The observed number of alleles ranged from two to nine. The ranges of observed and expected heterozygosities were 0.25-1.00 and 0.22-0.85, respectively. These microsatellite markers provide powerful tools for the ongoing conservation genetic studies of E. pleiospermum. PMID- 21585779 TI - PERMANENT GENETIC RESOURCES: Development of 52 new polymorphic SSR markers from cherimoya (Annona cherimola Mill.): transferability to related taxa and selection of a reduced set for DNA fingerprinting and diversity studies. AB - Fifty-two single locus polymorphic microsatellites were developed using two genomic libraries digested with HaeIII and RsaI of cherimoya cv. Fino de Jete enriched in CT/AG repeats. A total of 222 alleles were detected with the selected simple sequence repeats (SSRs). The observed and expected heterozygosities ranged from 0.08 to 0.73 and from 0.20 to 0.84, respectively. Most of the SSRs were transferable to other species in the Annonaceae. A set of 20 microsatellites was selected to facilitate the exchange of data among laboratories. PMID- 21585780 TI - PERMANENT GENETIC RESOURCES: Development of microsatellite markers of the Mexican understorey palm Chamaedorea elegans, cross-species genotyping, and amplification in congeners. AB - With striking morphological diversity and adaptability, Chamaedorea palms constitute an ecologically and economically important understorey component of Neotropical forests. Nine loci developed for Chamaedorea elegans evaluated in three Veracruz populations resulted in a large number of alleles (8-18), and high expected heterozygosity (0.49-0.92), but low observed (0.27-0.65) heterozygosity. Deviations from Hardy-Weinberg and high inbreeding suggest a lack of panmixia. Eight loci optimized for Chamaedorea ernesti-augustii showed similar patterns of variation. All nine multiplexing loci amplified in other five congeneric species, which will facilitate comparisons within the genus and contribute to the conservation of its genetic resources. PMID- 21585781 TI - PERMANENT GENETIC RESOURCES: Twelve new microsatellite markers for the Chinese shrimp Fenneropenaeus chinensis. AB - Twelve new microsatellite markers were isolated by sequencing random clones from a genomic library of Fenneropenaeus chinensis. The number of alleles per locus ranged from five to 15. The polymorphism information content ranged from 0.568 to 0.898, and observed and expected heterozygosities from 0.344 to 0.882 and from 0.691 to 0.915, respectively. All loci except one conformed to Hardy-Weinberg equilibrium. These markers, described here for Chinese shrimp, will be further used to analyse the species' population genetics. PMID- 21585782 TI - PERMANENT GENETIC RESOURCES: Eighteen new polymorphic microsatellite markers for the endangered Florida manatee, Trichechus manatus latirostris. AB - Here we describe 18 polymorphic microsatellite loci for Trichechus manatus latirostris (Florida manatee), isolated using a polymerase chain reaction-based technique. The number of alleles at each locus ranged from two to four (mean = 2.5) in specimens from southwest (n = 58) and northeast (n = 58) Florida. Expected and observed heterozygosities ranged from 0.11 to 0.67 (mean = 0.35) and from 0.02 to 0.78 (mean = 0.34), respectively. Departures from Hardy-Weinberg equilibrium occurred at two loci. There was no evidence of genotypic disequilibrium for any pair of loci. For individual identification, mean random mating and theta-corrected match probabilities were 9.36 * 10(-7) and 1.95 * 10( 6) , respectively. PMID- 21585783 TI - PERMANENT GENETIC RESOURCES: Isolation, characterization and multiplex genotyping of 11 autosomal and four sex-linked microsatellite loci in the reed bunting, Emberiza schoeniclus (Emberizidae, Aves). AB - Fifteen highly polymorphic microsatellite loci were characterized in the reed bunting, Emberiza schoeniclus. Eleven loci were autosomal and four linked to the Z chromosome. All loci were characterized and tested in 45 unrelated reed buntings from a Swiss population. Autosomal loci displayed seven to 17 and sex linked loci displayed four to 13 alleles with heterozygosities ranging from 0.756 to 0.933 and from 0.478 to 0.957, respectively. These loci will be used in population genetic and mating system studies of reed buntings. PMID- 21585784 TI - PERMANENT GENETIC RESOURCES: Microsatellite DNA primers for the candy darter, Etheostoma osburni and variegate darter, Etheostoma variatum, and cross-species amplification in other darters (Percidae). AB - In order to investigate a potential hybrid zone between the candy darter, Etheostoma osburni, and variegate darter, Etheostoma variatum, and examine population variation within E. osburni, a suite of primers for 15 polymorphic microsatellite loci were developed. The average number of alleles per locus was 5.5 in E. osburni and 7.6 in E. variatum, and the average observed heterozygosities were 62.5% and 71.4%, respectively. There were no deviations from Hardy-Weinberg equilibrium and no observed linkage disequilibrium after Bonferroni correction. The utility of these primers was also tested in 11 species of darters representing all four genera of darters. Success of cross-species amplification was largely consistent with phylogenetic relationships of darters. PMID- 21585785 TI - PERMANENT GENETIC RESOURCES: Development of polymorphic microsatellite markers in Acer mono Maxim. AB - Thirteen polymorphic microsatellite markers were developed for Acer mono Maxim., one of the major components of deciduous forests in Japan. An average of 13.8 alleles were found, with expected heterozygosity ranging from 0.140 to 0.945 in 34 A. mono individuals from the Ogawa Forest Reserve in Ibaraki Prefecture, Japan. This set of microsatellite markers can be used to analyse mating patterns and gene flow in A. mono populations. PMID- 21585786 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of 10 tetranucleotide microsatellite loci in an enigmatic East African bird, the spot-throat (Modulatrix stictigula). AB - We describe the isolation of 10 tetranucleotide microsatellites from the spot throat using an enrichment protocol. All loci were highly variable with the number of alleles ranging from six to 20 and observed heterozygosity ranging from 0.410 to 0.940. Although all loci were in Hardy-Weinberg equilibrium, locus Mst95 showed significant homozygote excess in both surveyed populations, possibly a consequence of the presence of null alleles at this locus. These loci will be used to determine the extent to which spot-throat populations are isolated in order to help set conservation priorities for this ancient African lineage. PMID- 21585787 TI - PERMANENT GENETIC RESOURCES: Characterization of eight microsatellite loci in the woolly mouse opossum, Micoureus paraguayanus, isolated from Micoureus demerarae. AB - Eight novel microsatellite markers were isolated from the woolly mouse opossum from the Amazon Forest in Peru, Micoureus demerarae, using a partial genomic DNA library and an enrichment protocol. These loci were polymorphic in M. demerarae and Micoureus paraguayanus populations from the Atlantic Forest in Brazil with the number of alleles ranging from two to 23. Those eight loci plus another five already described for M. paraguayanus will allow for the evaluation of genetic diversity of populations from the 'Rio Doce' Park, one of the last Atlantic Forest fragments in Minas Gerais state, Brazil. PMID- 21585788 TI - PERMANENT GENETIC RESOURCES: Development of microsatellite markers for the guava rust fungus, Puccinia psidii. AB - We developed and characterized 15 polymorphic microsatellite markers present in the genome of the guava rust fungus, Puccinia psidii. The primers for these microsatellite markers were designed by sequencing clones from a genomic DNA library enriched for a simple sequence repeat (SSR) motif of (AG). All these 15 primer pairs successfully amplified DNA fragments from a sample of 22 P. psidii isolates, revealing a total of 71 alleles. The observed heterozygosity at the 15 loci ranged from 0.05 to 1.00. The SSR markers developed would be useful for population genetics study of the rust fungus. PMID- 21585789 TI - PERMANENT GENETIC RESOURCES: A set of 12 microsatellite loci for genetic studies of Leishmania braziliensis. AB - Twelve microsatellite loci of Leishmania braziliensis were examined, nine of which were developed in this work. Fifty-six Leishmania braziliensis were genotyped with these microsatellite loci. The 12 loci studied were polymorphic with the number of alleles ranging from five to 19, with a mean of 9.7 +/- 4.1 and the observed heterozygosity averaging 0.425 +/- 0.202. The important heterozygote deficits we observed (F(IS) = 0.41, P value = 0.004) appear incompatible with the heterozygote excess expected in clonal diploids. This last result could revive the clonality/sexuality debate regarding Leishmania. This work validates the potential use of these microsatellites for population genetics analysis. PMID- 21585790 TI - PERMANENT GENETIC RESOURCES: Twelve polymorphic microsatellite markers for the bonefish, Albula vulpes and two congeners. AB - Twelve polymorphic microsatellite loci were isolated for the bonefish, Albula vulpes using a polymerase chain reaction-based procedure. The number of alleles ranged from two to 23 (mean = 8.8) in 37 specimens from south Florida. Observed and expected heterozygosities ranged from 0.07 to 0.77 (mean = 0.42) and from 0.07 to 0.84 (mean = 0.48), respectively. There were no significant departures from Hardy-Weinberg equilibrium and no evidence of genotypic disequilibrium between any pair of loci. In a cross-amplification test, all markers yielded appropriately sized alleles for specimens of the provisional Albula sp. B and 11 of the 12 loci amplified for those of Albula glossodonta. PMID- 21585791 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of microsatellite loci from the Arctic cisco (Coregonus autumnalis). AB - Eight polymorphic microsatellite loci were isolated and characterized for the Arctic cisco, Coregonus autumnalis. Loci were evaluated in 21 samples from the Colville River subsistence fishery. The number of alleles per locus ranged from two to 18. Observed heterozygosity of loci varied from 0.10 to 1.00, and expected heterozygosity ranged from 0.09 to 0.92. All eight microsatellite markers were in Hardy-Weinberg equilibrium. The loci presented here will be useful in describing population structure and exploring populations of origin for Arctic cisco. PMID- 21585792 TI - PERMANENT GENETIC RESOURCES: Ten polymorphic microsatellite markers for the pygmy rabbit (Brachylagus idahoensis). AB - We developed 10 polymorphic microsatellite loci for the pygmy rabbit (Brachylagus idahoensis). Nine of the 10 loci amplified reliably and had a low frequency of null alleles. Number of alleles per locus ranged from four to 12, and observed and expected heterozygosities ranged from 0.26 to 0.89 and from 0.63 to 0.88, respectively. These loci will be useful in determining population genetic structure and assessing patterns of gene flow in the pygmy rabbit. PMID- 21585793 TI - PERMANENT GENETIC RESOURCES: Isolation, characterization and cross-species amplifications of microsatellite loci from Conradina (Lamiaceae). AB - We report the isolation of microsatellite loci from three species in the genus Conradina (Lamiaceae). To ensure their utility for multiple species, loci were screened for amplification and variability in all six Conradina species; 11 loci demonstrated high levels of amplification and polymorphism in most species. These 11 loci were characterized in 20 individuals from one population of Conradina brevifolia; alleles per locus ranged from five to 15, and observed heterozygosity ranged from 0.30 to 0.90. These microsatellites will be used to clarify species limits, detect interspecific hybridization, and understand the partitioning of genetic variation in each species of Conradina. PMID- 21585794 TI - PERMANENT GENETIC RESOURCES: Isolation of microsatellite loci from the endangered plant Sibara filifolia (Brassicaceae). AB - Sibara filifolia (Brassicaceae) is a federally endangered annual herb found on two of the California Channel Islands. Previous studies based on allozymes revealed little genetic variability on San Clemente Island. Nine polymorphic microsatellite loci were isolated from individuals on San Clemente Island. We found low levels of allelic variation (mean N(A) = 2.3), with seven loci exhibiting significant deviations from Hardy-Weinberg equilibrium (P < 0.01) and 10 pairs of loci exhibiting significant linkage disequilibrium (P < 0.01). Most of the observed variability (mean H(O) = 0.003) occurred among populations or in rare homozygous individuals. PMID- 21585795 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of microsatellite loci in the Mediterranean shore crab Carcinus aestuarii (Decapoda, Portunidae). AB - We characterized nine polymorphic microsatellites in the Mediterranean shore crab Carcinus aestuarii (Decapoda: Portunidae). Microsatellites were isolated from a partial genomic library enriched for multiple motifs. All loci were polymorphic, with number of alleles ranging from two to 16 and a mean observed heterozygosity of 0.75. Seven loci were in Hardy-Weinberg equilibrium, and two showed weak heterozygote deficiency. No linkage disequilibrium was found between loci. In addition, we tested Hardy-Weinberg and linkage equilibrium of three Carcinus maenas loci, already reported to cross-amplify in C. aestuarii. These molecular markers will be potentially useful to investigate genetic structure of this species. PMID- 21585796 TI - PERMANENT GENETIC RESOURCES: Polymorphic microsatellite loci for Diachasma alloeum (Hymenoptera: Braconidae). AB - Here, we report the isolation of 21 novel primers for amplification of microsatellite loci in Diachasma alloeum (Hymenoptera: Braconidae). Diachasma alloeum is a larval parasitoid of the apple maggot fly (Rhagoletis pomonella), which is an economically significant agricultural pest species and a textbook example of sympatric speciation via host-plant shifting. These microsatellite markers will prove useful both for assessing genetic relationships between different host-associated populations of D. alloeum, as well as for future R. pomonella biological control programmes. We also report the cross-species amplification of several loci for Diachasmimorpha mellea and Diachasma ferrugineum, parasitoids of R. pomonella and R. cingulata, respectively. PMID- 21585797 TI - PERMANENT GENETIC RESOURCES: Development of microsatellite markers for two nonviviparous mangrove species, Acanthus ilicifolius and Lumnitzera racemosa. AB - Eight and nine of microsatellite loci were isolated from two nonviviparous mangrove species, Acanthus ilicifolius and Lumnitzera racemosa, respectively. The number of alleles per locus ranged from two to eight in A. ilicifolius and two to nine in L. racemosa. The observed heterozygosities ranged from 0.200 to 0.875 in A. ilicifolius and from 0.025 to 0.350 in L. racemosa. These loci would be effective for analysing genetic diversity and population genetic structure of these two mangrove species. PMID- 21585798 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of microsatellite DNA loci from the southern flounder, Paralichthys lethostigma. AB - Paucity of polymorphic molecular markers in southern flounder (Paralichthys lethostigma) has been a major limitation in genetic improvement of this important economic fish. Hence, we constructed a repeat-enriched genomic library from P. lethostigma. A total of 39 new microsatellites were identified, for which 33 primer pairs were designed. After validating and scoring, 10 of these loci were polymorphic in a test population with the range of alleles from two to nine per locus. The observed and expected heterozygosities ranged from 0.2500 to 0.9000 and from 0.4469 to 0.8514, respectively. These polymorphic microsatellites will be useful for genetic diversity analysis and linkage map construction for P. lethostigma. PMID- 21585799 TI - PERMANENT GENETIC RESOURCES: Development of microsatellite markers in Rhinanthus angustifolius and cross-species amplification. AB - Fifteen polymorphic microsatellite loci were developed from an enriched genomic library of the annual plant Rhinanthus angustifolius and characterized using 36 individuals. These markers provided high polymorphism ranging from two to 15 alleles per locus. Four loci showed significant departure from Hardy-Weinberg equilibrium, probably because of the occurrence of null alleles. No significant linkage disequilibrium was detected between pairs of loci. Tests of cross-species transferability were performed on four congeners with a success rate of 100% in Rhinanthus minor, 93% in R. mediterraneus and R. glacialis, and 80% in R. alectorolophus. These microsatellite loci will be useful tools to study mating system, gene flow and hybridization in the genus Rhinanthus. PMID- 21585800 TI - PERMANENT GENETIC RESOURCES: Isolation of 60 polymorphic microsatellite loci in EST libraries of four sibling species of the phytopathogenic fungal complex Microbotryum. AB - We report the development of 60 microsatellite markers on four species of the fungal complex Microbotryum, causing anther smut of the Caryophyllaceae. Microsatellites were found in four expressed sequence tag (EST) libraries, built from isolates of M. lychnis-dioicae, M. violaceum sensus stricto, M. lagerheimii and M. dianthorum, collected, respectively, from the plants Silene latifolia, S. nutans, S. vulgaris and Dianthus carthusianorum. Intrapopulation polymorphism was investigated using 24 isolates, and cross-amplification was explored using 23 isolates belonging to at least 10 different Microbotryum species. This study provides numerous microsatellite markers for population genetics and mapping studies. PMID- 21585801 TI - PERMANENT GENETIC RESOURCES: PCR primers for 100 microsatellites in red drum (Sciaenops ocellatus). AB - One hundred nuclear-encoded microsatellites from a genomic library of red drum (Sciaenops ocellatus) were isolated and characterized. Eight microsatellites had tetranucleotide motifs; 92 had dinucleotide motifs. The average number of alleles per microsatellite (sample of 22-24 fish) was 17.7 (range = 2-30); gene diversity averaged 0.796 (range = 0.227-1.000). Following Bonferroni correction, genotype frequencies at 90 microsatellites did not deviate significantly from Hardy Weinberg equilibrium expectations. Occurrence of null alleles was inferred at 15 microsatellites; alleles differing by only a single base were observed at 11 microsatellites. The microsatellites developed should prove useful for population genetic studies of 'wild' red drum and in construction of a genetic map. PMID- 21585802 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of microsatellite loci in the North Island brown kiwi, Apteryx mantelli. AB - We report the isolation and characterization of eight polymorphic and five monomorphic microsatellites in North Island brown kiwi (NIBK, Apteryx mantelli), using two polymerase chain reaction (PCR) techniques employing either short tandem repeat primers (STR method) or random PCR-based isolation of microsatellite arrays (PIMA method). Microsatellite polymorphism was subsequently determined using 65 individuals. There were two to seven alleles for each polymorphic locus with heterozygozity ranging between 0.04 and 0.86. These primers will be used in future studies to determine the level of extra-pair copulation, dispersal patterns, and genetic diversity within and between wild populations of NIBK. PMID- 21585803 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of microsatellite markers in the white-faced capuchin monkey (Cebus capucinus) and cross-species amplification in other New World monkeys. AB - Seventeen polymorphic microsatellite loci were identified for white-faced capuchin monkeys from an enriched genomic library in addition to one locus found through cross-species comparisons. In a sample of 187 wild individuals, these loci exhibited an average of five alleles and an observed heterozygosity of 0.62. The combined probability of exclusion of a random individual from parentage was 0.99. These loci were screened in 23 other New World monkeys and an average of seven loci was variable per species, suggesting that these loci could be of use in studies of other Neotropical primates. PMID- 21585804 TI - PERMANENT GENETIC RESOURCES: Isolation of microsatellite loci from the kelp, Saccorhiza polyschides (Heterokontophyta, incertae sedis). AB - Kelps are ecologically important seaweeds that dominate the subtidal zones of rocky coasts. In Northern Europe, Saccorhiza polyschides is a pioneer species suspected of outcompeting the harvested kelp, Laminaria digitata. To examine how the process of species competition affects species distribution and genetic diversity in coastal environments, we developed 10 polymorphic microsatellite markers for S. polyschides using an enriched library (microsatellites are already available for L. digitata). These loci showed from three to 24 alleles with heterozygosities ranging from 0.36 to 0.92. This polymorphism is high enough for fine-scale population analyses including assignment tests to determine the origin of recruits. PMID- 21585805 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of microsatellite loci from the European corn borer, Ostrinia nubilalis (Hubner) (Insecta: Lepidoptera: Crambidae). AB - Few useful microsatellites are available for population studies of the European corn borer, Ostrinia nubilalis (Hubner). An enrichment strategy was used to develop microsatellite markers for O. nubilalis, and over 500 positive clones were isolated. Seventy-five contained unique microsatellites, 10 of which were polymorphic with discernable polymerase chain reaction products. The 10 loci were surveyed for variability in 72 wild individuals from central Iowa. Five loci showed no deviation from Hardy-Weinberg proportions, and all were successfully cross-amplified in the related Asian corn borer, Ostrinia furnacalis. These loci represent a significant addition to microsatellites appropriate for population studies of O. nubilalis. PMID- 21585806 TI - PERMANENT GENETIC RESOURCES: A set of primer pairs for amplifying the complete mitochondrial DNA of endangered Chinese egret (Aves, Ardeidae, Egretta eulophotes). AB - The Chinese egret is a globally endangered species. Here we describe a set of primer pairs to amplify its entire mtDNA. The polymerase chain reaction products (1000-2000 bp) were successfully amplified by using this primer set and were then sequenced and aligned. The contiguous mtDNA sequences of the Chinese egret were assembled to be a circular molecule (17 579 bp). This primer set was also confirmed to be useful for six other species of ardeid birds. The versatility of this primer set will provide a groundwork for further studies on the genetic structure and molecular evolution of the ardeid species. PMID- 21585807 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of 12 microsatellite markers in the middle-spotted woodpecker (Dendrocopos medius). AB - Twelve polymorphic microsatellite loci were developed for Dendrocopos medius. Polymorphism was assessed for 27 individuals from the southwesternmost population of this woodpecker species. The number of alleles per locus ranged from three to seven, with observed heterozygosity values from 0.444 to 0.852. Genotypic frequencies conformed to Hardy-Weinberg equilibrium, and no evidence for linkage disequilibrium was observed. Multilocus genotypes resulting from this set of markers will be useful to determine genetic diversity and differentiation within and among habitat patches inhabited by D. medius. Three of the loci were polymorphic for Picoides articus. PMID- 21585808 TI - PERMANENT GENETIC RESOURCES: Microsatellite markers for the threatened Bliss Rapids snail (Taylorconcha serpenticola) and cross-amplification in its congener, T. insperata. AB - We developed and tested microsatellite markers to investigate population structure of a threatened North American freshwater gastropod, Taylorconcha serpenticola. Of the 21 primer pairs that were evaluated, 11 were readily optimized and scored, providing amplification of 12 loci that were screened for 820 specimens from 29 populations. The number of alleles across 11 of these polymorphic loci ranged from three to 20 and the observed heterozygosity varied from 0.0061 to 0.7561. All loci yielded suitable amplification products in the second species of Taylorconcha (T. insperata) and three proved to be diagnostic for these congeners, demonstrating that these markers are also useful for species identification studies. PMID- 21585809 TI - PERMANENT GENETIC RESOURCES: Polymorphic microsatellite loci and interspecific cross-amplification in the parasitoid wasps Megastigmus stigmatizans and Megastigmus dorsalis. AB - We isolated and characterized 19 polymorphic microsatellite loci in the congeneric parasitoid wasps Megastigmus stigmatizans and Megastigmus dorsalis associated with cynipid oak galls. Loci isolated from species-specific libraries showed extensive cross-amplification, resulting in a total of 15 polymorphic loci for M. stigmatizans and 13 for M. dorsalis. PMID- 21585810 TI - PERMANENT GENETIC RESOURCES: Characterization of microsatellite markers for the almendro (Dipteryx panamensis), a tetraploid rainforest tree. AB - The almendro (Dipteryx panamensis, Fabaceae) is a tetraploid tree native to the Atlantic lowland rainforests of Central America. We present nine microsatellite primer pairs amplified in three multiplexed reactions for 549 individuals from four sites in Costa Rica. All loci were polymorphic, ranging from three to 13 alleles per locus. Expected heterozygosity was estimated with the program tetrasat, and ranged from 0.21 to 0.74 across loci. These markers will be used for estimating pollen dispersal, seed dispersal, genetic structure and genetic diversity in fragmented landscapes. PMID- 21585811 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of microsatellite loci in the cichlid fish in Lake Victoria, Haplochromis chilotes. AB - Twelve short tandem repeat markers were successfully isolated from a cichlid, Haplochromis chilotes, in Lake Victoria, and characterized in Haplochromis pyrrhocephalus. The microsatellite regions of these markers were found to have between two and 48 alleles with heterozygosity ranging from 0.07 to 0.97. No loci showed significant departures from the Hardy-Weinberg or linkage equilibrium after the Bonferroni correction (P > 0.05). Cross-species amplification in other cichlids of Lake Victoria, Haplochromis laparogramma, Lithochromis rubripinnis, L. rufus and Haplochromis sp. 'rockkribensis', was successful. PMID- 21585812 TI - PERMANENT GENETIC RESOURCES: Characterization of tri- and tetranucleotide microsatellite loci for the slatey-grey snake (Stegonotus cucullatus, Colubridae). AB - We characterized nine polymorphic microsatellite (six trinucleotides and three tetranucleotides) loci for the slatey-grey snake (Stegonotus cucullatus) from Australia, in order to study the mating system of this species. Based on a total of 100 samples, the number of alleles per locus ranged from three to 10, and the observed and expected heterozygosities ranged from 0.62 to 0.86 and from 0.53 to 0.83, respectively. PMID- 21585813 TI - PERMANENT GENETIC RESOURCES: Isolation and characterization of polymorphic microsatellite loci in common evening primrose (Oenothera biennis). AB - We developed nine polymorphic microsatellite loci for evening primrose (Oenothera biennis). These loci have two to 18 alleles per locus and observed heterozygosities ranging from 0 to 0.879 in a sample of 34 individuals. In a pattern consistent with the functionally asexual reproductive system of this species, 17/36 pairs of loci revealed significant linkage disequilibrium and three loci showed significant deviations from Hardy-Weinberg equilibrium. The loci will be informative in identifying genotypes in multigenerational field studies to assess changes in genotype frequencies. PMID- 21585814 TI - PERMANENT GENETIC RESOURCES: Identification of nuclear microsatellite loci for Ipomopsis aggregata and the distribution of pairwise relatedness in a natural population. AB - Nine microsatellite loci were developed from enriched libraries of scarlet gilia (Ipomopsis aggregata). A screen of 160 individuals from a population identified reduced levels of heterozygosity, low levels of relatedness, and weak spatial genetic patterns. The population inbreeding coefficient was calculated to be 0.19 (SE = 0.04). These patterns are consistent with those expected from low levels of biparental inbreeding in an obligate outcrosser and extensive seed and pollen dispersal. These preliminary data confirm the usefulness of microsatellite markers for breeding system studies of I. aggregata. PMID- 21585815 TI - PERMANENT GENETIC RESOURCES: Development of polymorphic microsatellite loci for the common vampire bat, Desmodus rotundus (Chiroptera: Phylostomidae). AB - The common vampire bat (Desmodus rotundus) is one of three haematophagous species of bats and the only species in this genus. These New World bats prey on mammals and create significant economic impacts through transmission of rabies in areas where livestock are prevalent. Furthermore, in some portions of their range, it is not uncommon for them to prey upon humans. It is critical to the management of this species and for understanding the spread of bat rabies that detailed studies of D. rotundus population structure be conducted. To further such studies, we have characterized 12 microsatellite loci for this species. PMID- 21585816 TI - PERMANENT GENETIC RESOURCES: Development of microsatellite markers and analysis of their inheritance in the Australian reptile tick, Bothriocroton hydrosauri. AB - Despite long-term study, the mechanism explaining the parapatric distribution of two Australian reptile tick species is not understood. We describe the development of primers amplifying 10 microsatellite Bothriocroton hydrosauri loci, for the study of population structure and dispersal patterns of this tick. The numbers of alleles per locus ranged from two to seven in ticks from the study site, and the observed heterozygosity between 0.28 and 0.69. Pedigree analysis indicates that one locus is inherited in a non-Mendelian manner in three families, which was not explained by null allele presence. PMID- 21585817 TI - PERMANENT GENETIC RESOURCES: Identification and characterization of 14 polymorphic microsatellite loci in the argasid tick Ornithodoros coriaceus. AB - Fourteen polymorphic microsatellite loci (di, tetra and di-tetra complexes) were developed for the argasid tick Ornithodoros coriaceus. Polymorphism was assessed for 56 individuals from two populations separated by ~95 km. All loci were polymorphic (X = 7, range 3-17 alleles). All loci were in Hardy-Weinberg equilibrium except for one locus (OrC 8) in a single population (P < 0.00119, after Bonferroni correction for multiple tests). PMID- 21585818 TI - PERMANENT GENETIC RESOURCES: Development of microsatellite markers for the ecosystem bioengineer mussel Perumytilus purpuratus and cross-priming testing in six Mytilinae genera. AB - Eight microsatellite markers have been characterized from the Perumytilus purpuratus genome. Their gene diversity ranged from 0.057 to 0.873 and significant interpopulation genic heterogeneity was observed between two populations of southeastern Pacific (Chile) and southwestern Atlantic (Argentine). Distinct cross-priming amplification rates were recovered on nine additional species belonging to six Mytilinae genera. The microsatellites developed herein would likely be a powerful intraspecific genetic tool to undertake fine population studies in the intertidal ecosystem bioengineer P. purpuratus along the South American shoreline. PMID- 21585819 TI - PERMANENT GENETIC RESOURCES: Cross-family amplification: microsatellites isolated from Macropodidae are polymorphic in Potoroidae. AB - The superfamily Macropodoidea consists of two families - the Macropodidae and Potoroidae. Cross-species amplification and polymorphism of microsatellite loci is widely recognized within the macropodid family; however, the success of macropodid loci in potoroid species has not been as widely published. In this study, we tested the amplification and polymorphism of 17 cross-species microsatellite loci isolated from macropodids and potoroids in Bettongia lesueur (a potoroid). Success varied between loci and was not predicted by genetic distance from the species of isolation. PMID- 21585820 TI - PERMANENT GENETIC RESOURCES: Consensus primers of cyp73 genes discriminate willow species and hybrids (Salix, Salicaceae). AB - Consensus primers, based on exon sequences of the cyp73 gene family coding for cinnamate 4-hydroxylase (C4H) of the lignin biosynthesis pathway, were designed for the tetraploid willow species Salix alba and Salix fragilis. Diagnostic alleles at species level were observed among introns of three cyp73 genes and allowed unambiguous detection of the first generation and introgressed hybrids in populations. Progeny analysis of a female S. alba with a male introgressed hybrid confirmed the codominant inheritance of each intron. Sequences of the diagnostic alleles of both species were similar to those found in the hybrids. PMID- 21585821 TI - PERMANENT GENETIC RESOURCES: Ten novel polymorphic dinucleotide microsatellite loci cloned from the Antarctic fur seal Arctocephalus gazella. AB - Ten new dinucleotide microsatellite loci were isolated from the Antarctic fur seal Arctocephalus gazella. These markers should prove useful for studying the reproductive ecology of Antarctic fur seals and other related pinniped species. PMID- 21585822 TI - PERMANENT GENETIC RESOURCES: Identification of microsatellite loci for parentage analysis in roach Rutilus rutilus and eight other cyprinid fish by cross-species amplification, and a novel test for detecting hybrids between roach and other cyprinids. AB - In order to identify microsatellite loci for parentage analysis in roach Rutilus rutilus, 59 published primer sets were tested on roach and eight other cyprinid fish. Twenty polymorphic loci were identified for roach, of which the polymerase chain reaction products of seven could be pooled for sequencer analysis. Together, these seven loci have an exclusion probability of 0.997 for parentage, when no parents are known. We also describe a novel test for hybrids between roach and four other cyprinids, based on intraspecies length differences of internal transcribed spacer region 1. PMID- 21585823 TI - PERMANENT GENETIC RESOURCES: Development of microsatellite markers in the Japanese common squid Todarodes pacificus (Ommastrephidae). AB - Todarodes pacificus is an important species for commercial fisheries, but its reproductive biology has been little understood. We isolated 11 polymorphic microsatellite loci from this species. These loci provided highly polymorphic microsatellite markers with four to 26 alleles per locus. The observed and expected heterozygosities ranged from 0.150 to 1.000, and from 0.660 to 0.974, respectively. These markers will be useful for research about the mating systems and genetic diversity of T. pacificus. PMID- 21585824 TI - DNA barcoding in surveys of small mammal communities: a field study in Suriname. AB - The performance of DNA barcoding as a tool for fast taxonomic verification in ecological assessment projects of small mammals was evaluated during a collecting trip to a lowland tropical rainforest site in Suriname. We also compared the performance of tissue sampling onto FTA CloneSaver cards vs. liquid nitrogen preservation. DNA barcodes from CloneSaver cards were recovered from 85% of specimens, but DNA degradation was apparent, because only 36% of sequence reads were long (over 600 bp). In contrast, cryopreserved tissue delivered 99% barcode recovery (97% > 600 bp). High humidity, oversampling or tissue type may explain the poor performance of CloneSaver cards. Comparison of taxonomic assignments made in the field and from barcode results revealed inconsistencies in just 3.4% of cases and most of the discrepancies were due to field misidentifications (3%) rather than sampling/analytical error (0.5%). This result reinforces the utility of DNA barcoding as a tool for verification of taxonomic identifications in ecological surveys, which is especially important when the collection of voucher specimens is not possible. PMID- 21585825 TI - Testing candidate plant barcode regions in the Myristicaceae. AB - The concept and practice of DNA barcoding have been designed as a system to facilitate species identification and recognition. The primary challenge for barcoding plants has been to identify a suitable region on which to focus the effort. The slow relative nucleotide substitution rates of plant mitochondria and the technical issues with the use of nuclear regions have focused attention on several proposed regions in the plastid genome. One of the challenges for barcoding is to discriminate closely related or recently evolved species. The Myristicaceae, or nutmeg family, is an older group within the angiosperms that contains some recently evolved species providing a challenging test for barcoding plants. The goal of this study is to determine the relative utility of six coding (Universal Plastid Amplicon - UPA, rpoB, rpoc1, accD, rbcL, matK) and one noncoding (trnH-psbA) chloroplast loci for barcoding in the genus Compsoneura using both single region and multiregion approaches. Five of the regions we tested were predominantly invariant across species (UPA, rpoB, rpoC1, accD, rbcL). Two of the regions (matK and trnH-psbA) had significant variation and show promise for barcoding in nutmegs. We demonstrate that a two-gene approach utilizing a moderately variable region (matK) and a more variable region (trnH psbA) provides resolution among all the Compsonuera species we sampled including the recently evolved C. sprucei and C. mexicana. Our classification analyses based on nonmetric multidimensional scaling ordination, suggest that the use of two regions results in a decreased range of intraspecific variation relative to the distribution of interspecific divergence with 95% of the samples correctly identified in a sequence identification analysis. PMID- 21585826 TI - DNA barcode discovers two cryptic species and two geographical radiations in the invasive drosophilid Zaprionus indianus. AB - Comparing introduced to ancestral populations within a phylogeographical context is crucial in any study aiming to understand the ecological genetics of an invasive species. Zaprionus indianus is a cosmopolitan drosophilid that has recently succeeded to expand its geographical range upon three continents (Africa, Asia and the Americas). We studied the distribution of mitochondrial DNA (mtDNA) haplotypes for two genes (CO-I and CO-II) among 23 geographical populations. mtDNA revealed the presence of two well-supported phylogenetic lineages (phylads), with bootstrap value of 100%. Phylad I included three African populations, reinforcing the African-origin hypothesis of the species. Within phylad II, a distinct phylogeographical pattern was discovered: Atlantic populations (from the Americas and Madeira) were closer to the ancestral African populations than to Eastern ones (from Madagascar, Middle East and India). This means that during its passage from endemism to cosmopolitanism, Z. indianus exhibited two independent radiations, the older (the Eastern) to the East, and the younger (the Atlantic) to the West. Discriminant function analysis using 13 morphometrical characters was also able to discriminate between the two molecular phylads (93.34 +/- 1.67%), although detailed morphological analysis of male genitalia using scanning electron microscopy showed no significant differences. Finally, crossing experiments revealed the presence of reproductive barrier between populations from the two phylads, and further between populations within phylad I. Hence, a bona species status was assigned to two new, cryptic species: Zaprionus africanus and Zaprionus gabonicus, and both were encompassed along with Z. indianus and Zaprionus megalorchis into the indianus complex. The ecology of these two species reveals that they are forest dwellers, which explains their restricted endemic distribution, in contrast to their relative cosmopolitan Z. indianus, known to be a human-commensal. Our results reconfirm the great utility of mtDNA at both inter- and intraspecific analyses within the frame of an integrated taxonomical project. PMID- 21585827 TI - New evidence on the systematic and phylogenetic position of Parides burchellanus (Lepidoptera: Papilionidae). AB - Parides burchellanus is considered a rare and threatened swallowtail species restricted to central Brazil. It shows considerable morphological similarity to Parides panthonus jaguarae, with which it shares both geographical range and larval host plant. At present, P. burchellanus and P. panthonus are believed to be distinct species, based on minor differences in male genitalia. In this study, the phylogenetic and systematic position of P. burchellanus in relation to three subspecies of P. panthonus (P. p. jaguarae, P. p. lysimachus and P. p. aglaope) was evaluated using molecular evidence: the complete sequence of the mtDNA genes COI and COII and of the nuclear gene EF-1alpha (c. 3300 bp). In addition, the informativeness of the 'barcode' region next to the 5' end of COI (c. 650 bp) was evaluated for delimiting these taxa. Individual analysis by neighbour-joining, using Kimura 2-parameter distance model, and by maximum parsimony showed that P. p. jaguarae + P. p. lysimachus + P. p. aglaope + P. burchellanus form a strongly supported monophyletic clade, and all molecular regions consistently recovered P. p. jaguarae and P. burchellanus as sister species. The genetic divergence among the subspecies of P. panthonus and P. burchellanus is equivalent to the divergence among conspecifics of other species of Parides, and smaller than the interspecific divergence among different sister species of this genus. The results support the proposal that P. p. jaguarae and P. burchellanus are likely to be synonymous, and suggest that P. burchellanus can be considered conspecific with P. panthonus. The taxonomic classification of P. burchellanus should be revised on the basis of the molecular data. PMID- 21585828 TI - Gut content identification of larvae of the Anopheles gambiae complex in western Kenya using a barcoding approach. AB - Although larvae feeding and food source are vital to the development, survival and population regulation of African malaria vectors, the prey organisms of Anopheles gambiae larvae in the natural environment have not been well studied. This study used a molecular barcoding approach to investigate the natural diets of Anopheles gambiae s.l. larvae in western Kenya. Gut contents from third- and fourth-instar larvae from natural habitats were dissected and DNA was extracted. The 18S ribosomal DNA gene was amplified, the resulting clones were screened using a restriction fragment length polymorphism method and nonmosquito clones were sequenced. Homology search and phylogenetic analyses were then conducted using the sequences of non-mosquito clones to identify the putative microorganisms ingested. The phylogenetic analyses clustered ingested microorganisms in four clades, including two clades of green algae (Chlorophyta, Chlorophyceae Class, Chlamydomonadales and Chlorococcales families), one fungal clade, and one unknown eukaryote clade. In parallel, using the same approach, an analysis of the biodiversity present in the larval habitats was carried out. This present study demonstrated the feasibility of the barcoding approach to infer the natural diets of Anopheles gambiae larvae. Our analysis suggests that despite the wide range of microorganisms available in natural habitats, mosquito larvae fed on specific groups of algae. The novel tools developed from this study can be used to improve our understanding of the larval ecology of African malaria vectors and to facilitate the development of new mosquito control tools. PMID- 21585829 TI - New and improved molecular sexing methods for museum bird specimens. AB - We present two new avian molecular sexing techniques for nonpasserine and passerine birds (Neognathae), which are more suitable for use with museum specimens than earlier methods. The technique for nonpasserines is based on a new primer (M5) which, in combination with the existing P8 primer, targets a smaller amplicon in the CHD1 sex-linked gene than previously. Primers targeting ATP5A1, an avian sex-linked gene not previously used for sex identification, were developed for passerines. Comprehensive testing across species demonstrated that both primer pairs sex a range of different species within their respective taxonomic groups. Rigorous evaluation of each method within species showed that these permitted sexing of specimens dating from the 1850s. For corn bunting museum specimens, the ATP5A1 method sexed 98% of 63 samples (1857-1966). The M5/P8 CHD1 method was similarly successful, sexing 90% of 384 moorhen specimens from six different museum collections (1855-2001). In contrast, the original P2/P8 CHD1 sexing method only identified the sex of less than half of 111 museum moorhen samples. In addition to dried skin samples, these methods may be useful for other types of material that yield degraded or damaged DNA, and are hence potential new sexing tools for avian conservation genetics, population management and wildlife forensics. PMID- 21585830 TI - A microarray system for Y chromosomal and mitochondrial single nucleotide polymorphism analysis in chimpanzee populations. AB - Chimpanzee populations are diminishing as a consequence of human activities, and as a result this species is now endangered. In the context of conservation programmes, genetic data can add vital information, for instance on the genetic diversity and structure of threatened populations. Single nucleotide polymorphisms (SNP) are biallelic markers that are widely used in human molecular studies and can be implemented in efficient microarray systems. This technology offers the potential of robust, multiplexed SNP genotyping at low reagent cost in other organisms than humans, but it is not commonly used yet in wild population studies. Here, we describe the characterization of new SNPs in Y-chromosomal intronic regions in chimpanzees and also identify SNPs from mitochondrial genes, with the aim of developing a microarray system that permits the simultaneous study of both paternal and maternal lineages. Our system consists of 42 SNPs for the Y chromosome and 45 SNPs for the mitochondrial genome. We demonstrate the applicability of this microarray in a captive population where genotypes accurately reflected its large pedigree. Two wild-living populations were also analysed and the results show that the microarray will be a useful tool alongside microsatellite markers, since it supplies complementary information about population structure and ecology. SNP genotyping using microarray technology, therefore, is a promising approach and may become an essential tool in conservation genetics to help in the management and study of captive and wild living populations. Moreover, microarrays that combine SNPs from different genomic regions could replace microsatellite typing in the future. PMID- 21585831 TI - A robotic molecular method for in situ detection of marine invertebrate larvae. AB - Knowledge of the temporal and spatial abundance of invertebrate larvae is critical to understanding the dispersal capabilities and recruitment potential of marine and aquatic organisms. Traditional microscopic analyses are time-consuming and difficult given the diversity of larval species and a frequent lack of discriminating morphological characteristics. Here, we describe a sensitive rRNA targeted sandwich hybridization assay (SHA) that uses oligonucleotide probes to detect and enumerate the larvae of invasive green crabs (Carcinus maenas), native blue mussels (Mytilus), native barnacles (Balanus) and polychaetes (Osedax and Ophelia) that occur in the Monterey Bay National Marine Sanctuary, California. Laboratory-based assays demonstrate specificity, high sensitivity, and a quantitative response to cultured samples from three of the target organisms. Oligonucleotide probes were then printed in arrays on nitrocellulose membranes and deployed in our robotic Environmental Sample Processor (ESP) to detect larvae in situ and autonomously. We demonstrate that the SHA-detection method and ESP robot can be used for near real-time, in situ detection of larval species in the marine environment. PMID- 21585832 TI - Extracting DNA from museum bird eggs, and whole genome amplification of archive DNA. AB - We present a comprehensive protocol for extracting DNA from egg membranes and other internal debris recovered from the interior of blown museum bird eggs. A variety of commercially available DNA extraction methods were found to be applicable. DNA sequencing of polymerase chain reaction (PCR) products for a 176 bp fragment of mitochondrial DNA was successful for most egg samples (> 78%) even though the amount of DNA extracted (mean = 14.71 +/- 4.55 ng/uL) was significantly less than that obtained for bird skin samples (mean = 67.88 +/- 4.77 ng/uL). For PCR and sequencing of snipe (Gallinago) DNA, we provide eight new primers for the 'DNA barcode' region of COI mtDNA. In various combinations, the primers target a range of PCR products sized from 72 bp to the full 'barcode' of 751 bp. Not all possible combinations were tested with archive snipe DNA, but we found a significantly better success rate of PCR amplification for a shorter 176-bp target compared with a larger 288-bp fragment (67% vs. 39%). Finally, we explored the feasibility of whole genome amplification (WGA) for extending the use of archive DNA in PCR and sequencing applications. Of two WGA approaches, a PCR-based method was found to be able to amplify whole genomic DNA from archive skins and eggs from museum bird collections. After WGA, significantly more archive egg samples produced visible PCR products on agarose (56.9% before WGA vs. 79.0% after WGA). However, overall sequencing success did not improve significantly (78.8% compared with 83.0%). PMID- 21585833 TI - Optimizing the use of shed feathers for genetic analysis. AB - Shed feathers obtained by noninvasive genetic sampling (NGS) are a valuable source of DNA for genetic studies of birds. They can be collected across a large geographical range and facilitate research on species that would otherwise be extremely difficult to study. A limitation of this approach is uncertainty concerning the quality of the extracted DNA. Here we investigate the relationship between feather type, feather condition and DNA quality (amplification success) in order to provide a simple, cost-effective method for screening samples prior to genetic analysis. We obtained 637 shed feathers of the powerful owl (Ninox strenua) from across its range in southeastern Australia. The extracted DNA was amplified using polymerase chain reaction for a range of markers including mitochondrial DNA, ND3 and nuclear DNA, a simple sequence repeat (Nst02) and a portion of the CHD-1 gene (P2/P8). We found that feather condition significantly influenced the amplification success of all three loci, with feathers characterized as 'good' having greater success. Feather type was found to be of lower importance, with good quality feathers of all types consistently producing high success for all three loci. We also found that the successful amplification of multilocus genotypes was dependant on the condition of the starting material and was highly correlated with successful amplification of the sex-linked CHD-1 locus. Samples with low DNA quality have a higher probability of amplification failure and are more likely to produce incorrect genotypes; therefore, identifying samples with high DNA quality can save substantial time and cost associated with the genetic analysis of NGS. As a result, we propose a method for screening shed feathers in order to provide a subset of samples which will have a greater probability of containing high quality DNA suitable for the amplification of multilocus genotypes. PMID- 21585834 TI - bels: backward elimination locus selection for studies of mixture composition or individual assignment. AB - Methods of evaluating loci in studies of mixture composition or individual assignment are largely based on performance characteristics of individual loci. Synergisms between loci are not exploited. Loci are often evaluated based on their ability to resolve individual populations, even though multipopulation aggregations are more commonly of interest. In addition, measures of locus performance may indirectly relate to investigative objectives. A new computer program, bels, offers an alternative that addresses these limitations and may be preferable to existing methods in some applications. The algorithm is illustrated using Yukon River chum salmon (Oncorhynchus keta) data. PMID- 21585835 TI - combi.pl: a computer program to combine data sets with inconsistent microsatellite marker allele size information. AB - Combining two data sets with allele information from overlapping microsatellite markers is often desirable, particularly in population genetic studies where a substantial body of published data exists. When genotyping is performed in different laboratories, allele size calling may not be presumed to be consistent. Our approach solves this problem by assigning allele sizes across studies using maximum-likelihood theory. Using data overlaps in samples and markers, allele shifts between two studies are calculated for each overlapping marker and a single file containing allele frequencies of consistent alleles is produced. The program (combi.pl) is written in PERL and available at http://data40.uni tz.gwdg.de/~htaeube. PMID- 21585836 TI - cisprimertool: software to implement a comparative genomics strategy for the development of conserved intron scanning (CIS) markers. AB - The availability of complete, annotated genomic sequence information in model organisms is a rich resource that can be extended to understudied orphan crops through comparative genomic approaches. We report here a software tool (cisprimertool) for the identification of conserved intron scanning regions using expressed sequence tag alignments to a completely sequenced model crop genome. The method used is based on earlier studies reporting the assessment of conserved intron scanning primers (called CISP) within relatively conserved exons located near exon-intron boundaries from onion, banana, sorghum and pearl millet alignments with rice. The tool is freely available to academic users at http://www.icrisat.org/gt-bt/CISPTool.htm. PMID- 21585837 TI - create: a software to create input files from diploid genotypic data for 52 genetic software programs. AB - create is a Windows program for the creation of new and conversion of existing data input files for 52 genetic data analysis software programs. Programs are grouped into areas of sibship reconstruction, parentage assignment, genetic data analysis, and specialized applications. create is able to read in data from text, Microsoft Excel and Access sources and allows the user to specify columns containing individual and population identifiers, birth and death data, sex data, relationship information, and spatial location data. create's only constraints on source data are that one individual is contained in one row, and the genotypic data is contiguous. create is available for download at http://www.lsc.usgs.gov/CAFL/Ecology/Software.html. PMID- 21585838 TI - Isolation and characterization of 12 dinucleotide microsatellite loci in the anadromous fish Osmerus eperlanus (L.). AB - A subtractive hybridization method was used to isolate 12 dinucleotide microsatellite loci for the anadromous European smelt, Osmerus eperlanus (L.). Three to 17 (mean 8.08) alleles per locus were identified in the two populations screened, and observed heterozygosity ranged from 0.067 to 0.933. Loci in both populations showed significant deviations from Hardy-Weinberg expected frequencies. These 12 loci provide a good basis for investigation of O. eperlanus population structure. PMID- 21585839 TI - Isolation and characterization of microsatellite markers in black muntjac (Muntiacus crinifrons). AB - The black muntjac (Muntiacus crinifrons) is a vulnerable species found in the mountains of eastern China, about which little is known. Here we develop 11 polymorphic microsatellite loci from a (CA)(n) -enrichment library for the animal. In the analyses of 25 individuals sampled, unbiased expected heterozygosity levels varied from 0.686 to 0.876 and the number of alleles per locus varied from five to nine. Results that 11 microsatellite loci were highly polymorphic indicated that these markers are sufficiently powerful to address such questions as parentage, mating system and population genetic structure of M. crinifrons. PMID- 21585840 TI - Microsatellite loci isolated from the scleractinian coral, Acropora nobilis. AB - We report the isolation and characterization of eight microsatellite loci from the scleractinian coral, Acropora nobilis. The microsatellite loci were obtained using compound SSR primers or an enrichment protocol. All the loci were polymorphic with four to eight alleles per locus and observed heterozygosities ranging from 0.22 to 0.76. Some of the primers developed for the two congeners, Acropora palmata and Acropora millepora were applicable to A. nobilis. These loci are useful for studying the connectivity among A. nobilis populations in Okinawa, southern Japan. PMID- 21585841 TI - Microsatellite markers for the Eucalyptus stem canker fungal pathogen Kirramyces gauchensis. AB - Ten microsatellite markers were developed for the fungus Kirramyces gauchensis, which causes an important stem canker disease of Eucalyptus trees in plantations. Primers for 21 microsatellite regions were designed from cloned fragments. Fourteen of the primer pairs provided single amplicons and 10 of these were polymorphic for K. gauchensis. Allelic diversity ranged from 0.21 to 0.76 with a total of 30 alleles. None of the markers was able to amplify in the phylogenetically distinct but morphologically similar species Kirramyces zuluensis. The 10 characterized polymorphic microsatellite regions will be studied to determine the population structure of K. gauchensis in plantations of different countries. PMID- 21585842 TI - Isolation of polymorphic tri- and tetranucleotide microsatellite loci for the highly endangered Baw Baw frog (Philoria frosti). AB - We isolated 15 polymorphic microsatellite loci for the Baw Baw frog, Philoria frosti, from a genomic library enriched for (AAC)(n) and (AAAG)(n) repetitive elements. The number of alleles ranges from two to 14 per locus with the observed heterozygosity ranging from 0.04 to 0.96. PMID- 21585843 TI - Characterization of polymorphic microsatellite loci for two species of phyllostomid bats from the Greater Antilles (Erophylla sezekorni and Macrotus waterhousii). AB - We developed 12 polymorphic microsatellite loci for the buffy flower bat (Erophylla sezekorni) and 10 loci for Waterhouse's big-eared bat (Macrotus waterhousii). In E. sezekorni, we tested 65 individuals from three islands, Cuba, Exuma, and Abaco. Mean number of alleles per locus was 10.7 (range 5-20). In M. waterhousii, we tested 39 individuals from one island, Exuma. Mean number of alleles per locus was 6.9 (range 4-13). We will use these markers to study the phylogeography and mating system of these species. PMID- 21585844 TI - Identification and characterization of simple sequence repeat markers from a glandular Origanum vulgare expressed sequence tag. AB - Oregano (Origanum vulgare) and marjoram (Origanum majorana) are two sensorial distinct spices within the genus Origanum (Lamiaceae). Simple sequence repeat (SSR) markers were developed from expressed sequence tags (ESTs) of essential oil glands of O. vulgare. Thirteen EST-SSR loci were evaluated using 20 individual plants of O. vulgare and 19 plants of Origanum majorana. The number of alleles per locus ranged from one to four. All loci developed from O. vulgare successfully cross-amplified in O. majorana. PMID- 21585845 TI - Eleven polymorphic microsatellite markers in Cory's shearwater, Calonectris diomedea, and cross-species amplification on threatened Procellariiformes. AB - For the first time, we describe 11 variable dinucleotide microsatellites and the conditions for multiplexing and simultaneous genotyping sets of loci in Cory's shearwater, Calonectris diomedea. Microsatellite variability was assessed in a colony from the Azores archipelago (Atlantic Ocean). Two to eight alleles were detected per locus, the mean gene diversity being 4.5. Cross-species amplification in three other seabirds (Diomedea exulans, Procellaria aequinoctialis and Bulweria bulwerii) revealed some variability at one, two and eight loci, respectively. PMID- 21585846 TI - Isolation and characterization of polymorphic microsatellite markers in the red snow crab (Chionoecetes japonicus). AB - A total of 12 polymorphic microsatellite DNA loci were isolated from the red snow crab, Chionoecetes japonicus (Brachyura: Majidae), one of important fisheries resources in the Far East. The number of alleles observed at each locus ranged from two to 19, with the observed and expected heterozygosities of 0.125-0.875 and 0.156-0.949, respectively, suggesting these loci to be a useful molecular marker for population analysis in this species. Of the 12 loci, seven also were available for genotyping of the snow crab, Chionoecetes opilio, implying these loci as a useful molecular marker in the genus Chionoecetes. PMID- 21585847 TI - Beta SSR loci cross-amplify in five Salsola taxa. AB - We investigated 20 previously developed Beta SSR markers for their utility in the cross-genera amplification of five morphologically distinct invasive tumbleweed (Salsola) taxa. Of these markers, 17 loci had successful amplification within Salsola taxa. Six loci were polymorphic and were useful in confirming the presence of five genetically distinct Salsola taxa. PMID- 21585848 TI - Characterization of 25 microsatellite loci in bowhead whales (Balaena mysticetus). AB - Bowhead whales (Balaena mysticetus) experienced a severe demographic population bottleneck caused by commercial whaling that ceased in 1914. Aboriginal subsistence whale harvests have continued and are managed by the International Whaling Commission. In an effort to provide management advice for bowhead whales, 25 microsatellite loci were isolated from genomic DNA libraries. This panel of markers will be utilized to analyse stock structure hypotheses of current bowhead whale populations. PMID- 21585849 TI - Isolation and characterization of microsatellite loci in the beaver (Castor canadensis). AB - We have isolated and characterized 10 microsatellite loci in the beaver (Castor canadensis). Sixty individuals from southern and central Illinois were screened at each locus. All loci exhibited moderate levels of polymorphism, ranging from five to 13 alleles per locus with average heterozygosity ranging from 0.317 to 0.867. Locus Cca5 deviated significantly from HWE (P < 0.001). The locus pair Cca4/Cca5 was shown to be in linkage disequilibrium in southern Illinois, but not in the central Illinois population. The remaining eight loci will be useful in investigations of mating and kinship patterns in beaver populations in Illinois. PMID- 21585850 TI - Ten polymorphic STR loci in the cosmopolitan reef coral, Pocillopora damicornis. AB - We report the development of 10 polymorphic molecular markers containing short tandem repeats in the cosmopolitan reef-building coral, Pocillopora damicornis, an important model species for coral health, physiology, ecology, and genetics. The availability of polymorphic DNA markers in P. damicornis can act as impetus for investigations into inheritance and population genetics, as well as novel investigations into host-symbiont ecology and evolution. Coral bleaching and gene flow studies performed with these markers can have direct conservation implications. PMID- 21585851 TI - Isolation and characterization of 10 tetranucleotide microsatellite loci from the yellow-streaked greenbul (Phyllastrephus flavostriatus) and cross-species amplification in four closely related taxa. AB - We describe the isolation of 10 tetranucleotide microsatellite loci from the yellow-streaked greenbul using an enrichment protocol. All loci were highly variable with the number of alleles ranging from 8 to 13, and observed heterozygosity ranging from 0.652 to 0.870. All loci were in Hardy-Weinberg equilibrium; however, loci Pfl12 and Pfl54 showed significant linkage disequilibrium. All 10 loci successfully amplified and were polymorphic in at least one of four related Phyllastrephus species. These loci should prove to be widely applicable to studies of phylogeography, hybridization and paternity in African greenbuls. PMID- 21585852 TI - Microsatellite markers isolated from the flightless cormorant (Phalacrocorax harrisi). AB - Eight polymorphic microsatellite DNA loci were isolated from the flightless cormorant (Phalacrocorax harrisi) for future population genetic studies. Genetic variability was assessed using at least 38 individuals from two populations. Allele numbers ranged from three to nine per locus. Mean observed heterozygosity varied from 0.27 to 0.78. No locus deviated from Hardy-Weinberg (HW) or linkage equilibria in either population. The high levels of detected polymorphism indicate the utility of these markers for population genetic studies of this Galapagos species. PMID- 21585853 TI - Identification of 11 polymorphic simple sequence repeat loci in the phytopathogenic fungus Fusarium pseudograminearum as a tool for genetic studies. AB - Simple sequence repeat (SSR) markers for Fusarium pseudograminearum with 2 to 3 bp repeat motifs were identified by screening the genome database of the related species Fusarium graminearum. Twelve SSRs amplified single loci in both F. graminearum and F. pseudograminearum. Forty F. pseudograminearum and six F. graminearum individual isolates were screened to determine levels of polymorphism, with all SSRs displaying three to 14 alleles across all isolates. Eleven SSRs were polymorphic across F. pseudograminearum isolates tested proving the usefulness of genome databases of closely related species in identifying genetic markers. PMID- 21585854 TI - Polymorphic microsatellite markers for the lizard Psammodromus algirus (Squamata: Lacertidae). AB - Eight microsatellite loci are described for the lizard Psammodromus algirus, a species widely used as a model in behavioural and ecological studies. All loci were highly polymorphic (six alleles or more per locus) in a sample of 24 individuals from a single site near Navacerrada (central Spain). Observed heterozygosity ranged from 0.29 to 0.96. These markers will be used to study mating strategies and determinants of reproductive success in this species. PMID- 21585855 TI - Characterization of nine microsatellite loci in the sea star Astropecten aranciacus and cross-species amplification for related taxa. AB - So far, only few microsatellite markers have been developed and extensively tested for echinoderms. To study the population genetic structure of the sea star Astropecten aranciacus, we developed primers for nine polymorphic microsatellite loci and tested them on two populations from Faro in Portugal (N = 25) and from La Herradura in Spain (N = 20). Within populations, allele numbers varied from four to 20, while expected and observed heterozygosities ranged from 0.593 to 0.936 and from 0.222 to 0.900, respectively. Additional cross-species amplifications were polymorphic at some loci, indicating their potential usefulness for related taxa. PMID- 21585856 TI - Microsatellite DNA markers for the snow vole (Chionomys nivalis). AB - A total of 14 dinucleotide microsatellite loci were characterized in the snow vole (Chionomys nivalis). Allelic polymorphism across all loci and 28 individuals representing a single population in the Swiss Alps was high (mean = 10.1 alleles). No significant linkage disequilibrium between pairs of loci and no departure from Hardy-Weinberg equilibrium were found. These loci will be useful for describing mating systems and population structure and to investigate the genetic consequences of a species living in a highly fragmented habitat. PMID- 21585857 TI - Fourteen microsatellite loci for the Chinese medicinal plant Epimedium sagittatum and cross-species application in other medicinal species. AB - Epimedium sagittatum is a well-known medicinal plant as well as potential ground cover and ornamental plant. A total of 14 polymorphic microsatellite markers were developed for use in taxonomy, phylogenetics and conservation genetics. Markers were presented between two and eight alleles per locus. The observed heterozygosity (H(O) ) and expected heterozygosity (H(E) ) ranged from 0.03 to 0.81 and from 0.05 to 0.81, respectively. Cross-amplification among other four medicinal species revealed promising results in three to six polymorphic loci. These microsatellite loci contributed to the limited number of useful markers currently available for E. sagittatum. PMID- 21585858 TI - Thirteen nuclear microsatellite loci for butternut (Juglans cinerea L.). AB - Butternut (Juglans cinerea L.) is an eastern North American forest tree severely threatened by an exotic fungal pathogen, Sirococcus clavigignenti-juglandacearum. We report here 13 nuclear microsatellites for genetic evaluation of the remaining natural populations. Summary statistics are reported for individuals from a population of butternuts in central Kentucky (N = 63). All markers were polymorphic, with an average of 13.7 alleles per locus observed. Four loci exhibited significantly fewer heterozygotes than expected under Hardy-Weinberg equilibrium (P < 0.05). PMID- 21585859 TI - Isolation and characterization of the first polymorphic microsatellite markers for Schistosoma haematobium and their application in multiplex reactions of larval stages. AB - The ability of microsatellite loci to reveal genetic diversity within the trematode Schistosoma haematobium is demonstrated for the first time. Nine novel polymorphic microsatellite markers were isolated and their viability assessed on 36 S. haematobium adult worm individuals from three geographical populations. Allelic diversity and gene diversity ranged from two to seven and from 0.29 to 0.76, respectively, suggesting high variability between individuals and between unrelated populations. Three primers also amplified Schistosoma mansoni and two Schistosoma japonicum. The results suggest these primers are useful for population genetic analyses of S. haematobium. PMID- 21585860 TI - Ten di- and trinucleotide microsatellite loci in the Caribbean spiny lobster, Panulirus argus, for studies of regional population connectivity. AB - We describe 10 microsatellite loci for Panulirus argus (Caribbean spiny lobster). The number of alleles at each locus ranged from four to 39 (mean = 21.8) in 89 juvenile specimens collected at two different times at a recruitment site in south Florida. Levels of expected and observed heterozygosities ranged from 0.48 to 0.96 (mean = 0.83) and from 0.32 to 0.98 (mean = 0.71), respectively. Significant departures from Hardy-Weinberg equilibrium were observed at two loci. There was no evidence of genotypic disequilibrium for any pair of loci. Overall, the loci were well resolved, highly polymorphic and independently segregating, confirming their utility for population genetic studies. PMID- 21585861 TI - Polymorphic nuclear microsatellite loci for studies of brown crab, Cancer pagurus L. AB - Twelve polymorphic microsatellite DNA loci were isolated from the brown crab, Cancer pagurus L., by construction of microsatellite-enriched genomic libraries. Genotyping of 40 individuals from Norfolk (UK) revealed variable levels of locus polymorphism with an average of 7.75 alleles per locus (range 2-22). The observed and expected heterozygosities per locus ranged from 0.025 to 0.868 and from 0.025 to 0.947, respectively. No evidence of linkage disequilibrium was detected between pairs of loci and genotype proportions at all loci conformed to Hardy Weinberg equilibrium expectations. The microsatellite loci developed constitute a suite of genetic markers applicable to numerous areas of C. pagurus research. PMID- 21585862 TI - Sixteen polymorphic microsatellites in bighead carp (Aristichthys nobilis) and cross-amplification in silver carp (Hypophthalmichthys molitrix). AB - A (GT)(n) enriched partial genomic library of bighead carp (Aristichthys nobilis) was constructed by employing the (fast isolation by AFLP of sequences containing repeats) FIASCO protocol. Sixteen loci exhibited polymorphism with two to seven alleles/locus (mean 3.263) in a test population and the observed heterozygosity ranging from 0.100 to 0.690 (mean 0.392). Eleven of the 16 bighead carp microsatellites were found to be also polymorphic in silver carp. These polymorphic loci should provide sufficient level of genetic diversity to evaluate population structure of bighead carp. PMID- 21585863 TI - Isolation of 15 single nucleotide polymorphisms from coastal steelhead, Oncorhynchus mykiss (Salmonidae). AB - We describe 15 single nucleotide polymorphisms (SNPs) isolated in coastal California populations of steelhead (Oncorhynchus mykiss). SNP loci were developed using a 'gene-targeted' approach, which involved the development of primers from functional genes in O. mykiss that were deposited in GenBank or in the published literature. These markers show a wide range of variability in three coastal steelhead populations, and will be useful in population genetic studies and in pedigree reconstruction. Potential applications include evaluation of population structure, introgression between native and hatchery trout, and evaluating reproductive success. PMID- 21585864 TI - Characterization of microsatellite markers for Thoropa taophora (Anura, Cycloramphidae), a frog endemic to the Brazilian Atlantic Rain Forest. AB - Here we characterize nine microsatellite loci for Thoropa taophora collected from a coastal and an island population in southeastern Brazil. The number of alleles per locus ranged from three to 11 for the coastal population and from two to eight for the island population. Observed heterozygosities ranged from 0.308 to 0.778 for the coastal population and from zero to 0.737 for the island population. One locus did not conform to Hardy-Weinberg expectations on the coast, while two were in disequilibrium on the island. These markers are currently being used to examine genetic differentiation and patterns of dispersal in T. taophora. PMID- 21585865 TI - Highly polymorphic microsatellite loci for the Gran Canarian skink (Chalcides sexlineatus) and their applicability in other Canarian Chalcides. AB - The scincid lizard Chalcides sexlineatus is endemic to the island of Gran Canaria, within which it shows a pronounced phylogeographical pattern. Understanding the maintenance of this pattern requires knowledge of nuclear DNA structuring. Eleven polymorphic tetranucleotide microsatellite loci were isolated from a library constructed from genomic DNA enriched for AAAG repeat sequence. The number of alleles per locus ranged from 12 to 19, and expected heterozygosities spanned from 0.738 to 0.933 (n = 30). The majority of these could be cross-amplified in other endemic Canarian Chalcides. The loci will be used to investigate gene flow between the principal mitochondrial clades within C. sexlineatus. PMID- 21585866 TI - A PCR assay for gender assignment in dugong (Dugong dugon) and West Indian manatee (Trichechus manatus). AB - Gender assignment for some aquatic mammals in the field is difficult. Molecular sexing from tissue biopsies is possible as males are heterogametic. Here we describe a multiplex PCR assay that amplifies the male specific SRY gene and differentiates ZFX and ZFY gametologues in two sirenian species, dugong (Dugong dugon) and West Indian manatee (Trichechus manatus). The assay was validated with animals of known gender and proved accurate and robust to experimental failure. PMID- 21585867 TI - Isolation, characterization, and cross-amplification of polymorphic microsatellite loci in Guaiacum coulteri (Zygophyllaceae). AB - Guaiacum coulteri is a dry forest hardwood species of conservation concern endemic to the Pacific coast of Mexico. Fifteen microsatellite markers were developed which show high levels of polymorphism across two populations with the number of alleles ranging from four to 21. Most loci additionally exhibited consistent multiple banding patterns, indicating the likely polyploidy of this species. All loci were tested for cross-amplification with most found to amplify well across the genus Guaiacum, although amplification in other related genera of the Zygophyllaceae was limited. PMID- 21585868 TI - A set of primers conserved in genus Parnassius (Lepidoptera, Papilionidae) for amplification and sequencing of 1016 bp fragment of cytochrome oxidase subunit I from museum specimens. AB - Four short, overlapping amplicons covering a 1016 bp fragment of mitochondrial cytochrome oxidase subunit I were developed. All four fragments were successfully amplified and sequenced in eight species of butterflies belonging to the genus Parnassius including over 100-year-old DNA from pinned museum specimens. The fragment contains sufficient variation for both inter- and intraspecific analyses. A total of 105 sites were polymorphic within 52 haplotypes found in 186 samples from Parnassius mnemosyne. PMID- 21585869 TI - Group-specific primers for DNA-based detection of springtails (Hexapoda: Collembola) within predator gut contents. AB - Group-specific, degenerate polymerase chain reaction primers for DNA-based detection of springtails (Hexapoda: Collembola) within predator gut contents have been developed for the first time. Primers were designed from 18S rDNA and amplified fragments of 272 bp and 177 bp from 17 springtail species collected in agricultural habitats. Specificity tests against 41 nontarget species revealed no cross-reactivity. Group-specific polymerase chain reaction is advantageous when working in species-rich habitats and these primers could facilitate studies of trophic links between springtails and generalist arthropod predators worldwide. PMID- 21585870 TI - Development of polymorphic markers from expressed sequence tags of Manihot esculenta Crantz. AB - In this study, 49 primers were designed from sequences containing di-, tri-, tetra-, penta- and hexanucleotide motifs with a minimum of four repeats and presence of motif size polymorphisms (insertion/deletion) from cassava (Manihot esculenta Crantz) expressed sequence tags deposited in public sequence database. Each locus was subsequently screened on 29 M. esculenta Crantz obtained from 15 different countries. Cross-amplification was tested with M. esculenta Crantz (ssp. flabellifolia) and four different Manihot species, M. chlorosticta, M. carthaginensis, M. filamentosa and M. tristis. Of these, nine loci showed polymorphic profiles within M. esculenta Crantz, which revealed two to four alleles per locus. The average unbiased and direct count heterozygosities were 0.4901 and 0.5674, respectively. PMID- 21585871 TI - Highly polymorphic microsatellite loci in the rice- and maize-infecting fungal pathogen Rhizoctonia solani anastomosis group 1 IA. AB - Ten polymorphic microsatellite loci were isolated and characterized from the rice and maize-infecting Basidiomycete fungus Rhizoctonia solani anastomosis group AG 1 IA. All loci were polymorphic in two populations from Louisiana in USA and Venezuela. The total number of alleles per locus ranged from four to eight. All 10 loci were also useful for genotyping soybean-infecting R. solani AG-1 isolates from Brazil and USA. One locus, TC06, amplified across two other AG groups representing different species, showing species-specific repeat length polymorphism. This marker suite will be used to determine the global population structure of this important pathogenic fungus. PMID- 21585872 TI - Development of polymorphic microsatellite markers for the sorghum plant bug, Stenotus rubrovittatus (Heteroptera: Miridae). AB - Nine polymorphic microsatellite DNA markers from the sorghum plant bug, Stenotus rubrovittatus, were isolated and characterized. These markers were used to analyse 22 individuals from a single field population. The number of alleles at these nine loci ranged from two to 28 (mean = 11.4) and heterozygosity ranged from 0.27 to 0.86 (mean = 0.58). Stenotus rubrovittatus has shown rapid population growth in the decades since the first report in the 1980s of serious damage to a rice crop. These microsatellite markers will be of value for studying both the population genetics and population dynamics of S. rubrovittatus. PMID- 21585873 TI - Polymorphic microsatellite DNA markers in the penduline tit, Remiz pendulinus. AB - To describe the exceptional mating system of the penduline tit, Remiz pendulinus, we aim to combine field observation records with DNA analysis based on polymorphic microsatellite DNA markers. Here we describe features of nine loci and their corresponding polymerase chain reaction primers. The observed number of alleles varied from four to seven and the observed heterozygosity ranged from 0.419 to 0.802. Neither of the loci is sex-linked and as linkage disequilibrium analysis showed they assort independently. Seven of the nine loci were polymorphic in the Cape penduline tit, Anthoscopus minutus. PMID- 21585874 TI - Characterization of microsatellite loci in the lesser dawn bat (Eonycteris spelaea). AB - We constructed a genomic DNA library enriched for CA repeat motifs in Eonycteris spelaea. Nine microsatellite loci were isolated and tested on a population of 39 samples from Yunnan Province, China. These nine loci had three to 22 alleles per locus. Observed and expected heterozygosity values ranged from 0.079 to 0.963 and from 0.078 to 0.959. Two loci revealed significant departure from Hardy-Weinberg equilibrium and no linkage disequilibrium was found between loci pairs. These microsatellites can be a powerful molecular tool for population-level studies of E. spelaea. PMID- 21585875 TI - Microsatellite loci for the small hive beetle, Aethina tumida, a nest parasite of honey bees. AB - Aethina tumida, a beetle parasite of honey bee colonies, has recently and dramatically expanded its range and now parasitizes honey bees on three continents. Polymorphic microsatellite loci for this beetle species will help map this continuing range expansion, and will also prove useful for exploring the mating system and local gene flow patterns for this important parasite. We describe 15 loci that are polymorphic in both the native and introduced ranges of this species, showing from two to 22 alleles. PMID- 21585876 TI - Isolation and cross-amplification of microsatellites in pink abalone (Haliotis corrugata). AB - Ten novel microsatellite loci were isolated in pink abalone, Haliotis corrugata, using (GT)(15) and (CT)(15 ) enriched genomic libraries. Two previously reported Haliotis kamtschatkana microsatellites cross-amplified in H. corrugata. A set of 12 polymorphic microsatellites were evaluated in a wild population sample (N = 49). The number of alleles ranged from two to 55, and the observed and expected heterozygosities ranged from 0.104 to 0.939 and from 0.213 to 0.982, respectively. Significant deviations from Hardy-Weinberg equilibrium at three loci and no linkage disequilibrium were observed. Haliotis corrugata microsatellites cross-amplified in other abalone species, two in H. fulgens, and seven in H. rufescens. PMID- 21585877 TI - Characterization of 13 polymorphic microsatellite loci for two land snail species, Trochulus villosus and T. sericeus (Gastropoda: Pulmonata: Hygromiidae). AB - Thirteen new microsatellite loci were isolated and tested on two land snail species, Trochulus villosus and T. sericeus (Pulmonata: Hygromiidae), resulting in a set of eight polymorphic markers for each species. The expected heterozygosity was high for all loci and species (between 0.616 and 0.944). Such levels of variability will allow detailed insights into the population genetic structure of some Trochulus species. PMID- 21585878 TI - Polymorphic microsatellite loci from northern and Mexican corn rootworms (Insecta: Coleoptera: Chrysomelidae) and cross-amplification with other Diabrotica spp. AB - The northern corn rootworm (Diabrotica barberi) and Mexican corn rootworm (Diabrotica virgifera zeae) are significant agricultural pests. For the northern corn rootworm, and to a lesser extent, the Mexican corn rootworm, high resolution molecular markers are needed. Here we present 14 polymorphic microsatellite loci isolated from libraries constructed using pooled northern and Mexican corn rootworm genomic DNA. Polymorphism in other Diabrotica, including the banded cucumber beetle, southern corn rootworm and western corn rootworm, is described. PMID- 21585879 TI - Identification of 'extinct' freshwater mussel species using DNA barcoding. AB - Freshwater mollusks are highly imperiled, with 70% of the North American species extinct, endangered, or at risk of extinction. Impoundments and other human impacts on the Coosa River of Alabama, Georgia and Tennessee of the southeastern USA alone are believed to have caused 50 mollusk species extinctions, but uncertainty over boundaries among several putatively closely related species makes this number preliminary. Our examination of freshwater mussels collected during an extensive survey of the upper-drainage basin, DNA barcoding and molecular phylogenetic analyses confirm the rediscovery of four morphospecies in the genus Pleurobema (Unionidae) previously thought to be extinct from the upper Coosa basin. A fifth 'extinct' form was found in an adjoining basin. Molecular data show that the Coosa morphologies represent at least three species-level taxa: Pleurobema decisum, P. hanleyianum and P. stabile. Endemism is higher than currently recognized, both at the species level and for multispecies clades. Prompt conservation efforts may preserve some of these taxa and their ecosystem. PMID- 21585880 TI - An objective, rapid and reproducible method for scoring AFLP peak-height data that minimizes genotyping error. AB - Amplified fragment length polymorphism (AFLP) fingerprint data are now commonly collected using DNA sequencers. AFLP genotypes are still often scored by eye from such data - a time-consuming, error-prone and subjective process. We present a semi-automated method of genotyping sequencer-collected AFLPs at predefined fragment locations (loci) within the fingerprint. Our method uses thresholds of AFLP-polymerase chain reaction-product fluorescence intensity (peak height) in order to: (i) exclude AFLP loci that are likely to contribute high rates of error to data sets, and (ii) determine the AFLP phenotype (fragment presence or absence) at the retained loci. Error rate analysis is an integral part of this process and is used to determine optimal thresholds that minimize genotyping error, while maximizing the numbers of retained loci. We show that application of this method to a large AFLP data set allows genotype calls that are rapid, objective and repeatable, facilitating the extraction of reliable genotype data for molecular ecological studies. PMID- 21585881 TI - A high-throughput protocol for extracting high-purity genomic DNA from plants and animals. AB - DNA extraction techniques that employ the reversible binding of DNA to silica via chaotropic salts can deliver high-quality genomic DNA from plant and animal tissues, while avoiding the use of toxic organic solvents. Existing techniques that use this method are either prohibitively expensive, or are applicable to only a restricted set of taxa. Here we describe a cost-effective DNA extraction technique suitable for a wide range of plant and animal taxa that yields microgram quantities of high-molecular-weight genomic DNA at a throughput of 192 samples per day. Our technique is particularly robust for tissue samples that are insoluble or are rapidly discoloured or oxidized in standard DNA extraction buffers. We demonstrate the quality of DNA extracted using this method by applying the amplified fragment length polymorphism technique to plant species. PMID- 21585882 TI - Increasing ecological inference from high throughput sequencing of fungi in the environment through a tagging approach. AB - High throughput sequencing methods are widely used in analyses of microbial diversity, but are generally applied to small numbers of samples, which precludes characterization of patterns of microbial diversity across space and time. We have designed a primer-tagging approach that allows pooling and subsequent sorting of numerous samples, which is directed to amplification of a region spanning the nuclear ribosomal internal transcribed spacers and partial large subunit from fungi in environmental samples. To test the method for phylogenetic biases, we constructed a controlled mixture of four taxa representing the Chytridiomycota, Zygomycota, Ascomycota and Basidiomycota. Following cloning and colony restriction fragment length polymorphism analysis, we found no significant difference in representation in 19 of the 23 tested primers. We also generated a clone library from two soil DNA extracts using two primers for each extract and compared 456 clone sequences. Community diversity statistics and contingency table tests applied to counts of operational taxonomic units revealed that the two DNA extracts differed significantly, while the pairs of tagged primers from each extract were indistinguishable. Similar results were obtained using UniFrac phylogenetic comparisons. Together, these results suggest that the pig-tagged primers can be used to increase ecological inference in high throughput sequencing projects on fungi. PMID- 21585883 TI - ldne: a program for estimating effective population size from data on linkage disequilibrium. AB - ldne is a program with a Visual Basic interface that implements a recently developed bias correction for estimates of effective population size (N(e) ) based on linkage disequilibrium data. The program reads genotypic data in standard formats and can accommodate an arbitrary number of samples, individuals, loci, and alleles, as well as two mating systems: random and lifetime monogamy. ldne calculates separate estimates using different criteria for excluding rare alleles, which facilitates evaluation of data for highly polymorphic markers such as microsatellites. The program also introduces a jackknife method for obtaining confidence intervals that appears to perform better than parametric methods currently in use. PMID- 21585884 TI - SIMIL: an r (CRAN) scripts collection for computing genetic structure similarities based on structure 2 outputs. AB - The emergence of comparative phylogeography requires tools that allow comparing quantitatively the genetic structures between species. Whereas numerous methods have been developed to compare trees inferred from two species, comparison methods involving population structures issued from Bayesian inferences or maximum likelihood criterion have been poorly investigated. Here, we present a method implemented in an r (CRAN) scripts collection, SIMIL, based on the mean absolute differences computed from structure 2 outputs. The scripts collection is illustrated by the computation of unweighted and weighted genetic-structure similarity (GSS) indices in three alpine plants. Different weighting procedures - taking into account the level of overlap between the species sampling areas - are compared among the different species pairs and among the different numbers of gene pools considered in structure. PMID- 21585885 TI - incor: a computer program for testing differences among independent correlations. AB - An interactive fortran program (incor) performs the Paul (1989) procedure for testing the null hypothesis that more than two independent population correlations are equivalent. The program also performs subsequent range tests for comparing all possible pairwise correlations. PMID- 21585886 TI - p-loci: a computer program for choosing the most efficient set of loci for parentage assignment. AB - Determining how many and which codominant marker loci are required for accurate parentage assignment is not straightforward because levels of marker polymorphism, linkage, allelic distributions among potential parents and other factors produce differences in the discriminatory power of individual markers and sets of markers. p-loci software identifies the most efficient set of codominant markers for assigning parentage at a user-defined level of success, using either simulated or actual offspring genotypes of known parentage. Simulations can incorporate linkage among markers, mating design and frequencies of null alleles and/or genotyping errors. p-loci is available for windows systems at http://marineresearch.oregonstate.edu/genetics/ploci.htm. PMID- 21585887 TI - New polymorphic dinucleotide and trinucleotide microsatellite loci for hop Humulus lupulus L. AB - One hundred and thirty-five microsatellite markers were developed for hop Humulus lupulus L. from di- and trinucleotide-enriched libraries. Seventy-eight primers showed amplification in two tested genotypes. Twenty-four loci were further characterized on a population of 34 hop samples and the number of alleles per locus, observed heterozygosity and expected heterozygosity ranged from two to 20 (9.7 on average), from 0.0294 to 0.9412 (0.6234 on average) and from 0.0294 to 0.9170 (0.6720 on average), respectively. These microsatellite markers will be further used for studying population structures and relationships and for identifying important qualitative and quantitative loci of hop. PMID- 21585888 TI - Characterization of 21 microsatellites developed from Propithecus deckeni deckeni. AB - Decken's sifaka (Propithecus deckeni deckeni) is found between the Mahavavy and Manambolo Rivers, in western Madagascar. Twenty-one polymorphic nuclear microsatellite loci were isolated from genomic DNA derived from a P. d. deckeni, from Tsingy de Bemaraha National Park. Population genetic parameters were estimated on 10 individuals each, sampled from Tsingy de Bemaraha National Park and Tsiombikibo Classified Forests. Significant null alleles were detected in seven loci which were dropped before population genetic parameters were re estimated and compared to the full marker suite. PMID- 21585889 TI - Isolation and characterization of polymorphic microsatellite markers from Australia short-finned eel (Anguilla australis Richardson). AB - Seventeen microsatellite DNA loci from the Australian short-finned eel (Anguilla australis Richardson) were isolated and their amplification characteristics were described. The polymerase chain reaction primers were tested on 40 eel individuals. The primers amplified loci with relatively high numbers of alleles, ranging from five to 14 with an average of nine per locus. Mean observed heterozygosity (H(O) ) and expected heterozygosity (H(E) ) were 0.6779 and 0.7374, respectively, indicating that these markers would be useful for population studies. No loci deviated significantly from Hardy-Weinberg equilibrium (P = 0.05) and no evidence was found for genotypic disequilibrium among loci at a 5% significance level. PMID- 21585890 TI - Microsatellites from kousa dogwood (Cornus kousa). AB - Microsatellite loci were identified from Cornus kousa'National'. Primer pairs for 86 loci were developed and of these, eight were optimized and screened using genomic DNA from 22 kousa cultivars. All optimized loci were polymorphic and the number of alleles per locus ranged from three to 17. Observed heterozygosity ranged from 0 to 0.3 and expected heterozygosity ranged from 0.38 to 0.91. These microsatellites will be useful in population studies, and a breeding programme for cultivar development of Cornus species. PMID- 21585891 TI - Development of novel microsatellites from Moniliophthora perniciosa, causal agent of the witches' broom disease of Theobroma cacao. AB - Moniliophthora perniciosa is the causal agent of the witches' broom disease of cacao. Based on available genomic sequences, we identified 30 new microsatellite loci, which were analysed using 50 isolates from four populations sampled over a wide geographical area in Brazil, including three populations from the Amazon, the fungal putative centre of diversity, plus one from Bahia. Nine loci were polymorphic, with an average of 2.9 alleles per locus. The level of polymorphism observed was low, but these markers may allow the evaluation of pathogen diversity and the establishment of molecular standards for isolate fingerprinting to support cacao breeding. PMID- 21585892 TI - Development of cytochrome b primers for mitotyping of barbels (Barbus spp.). AB - Primers were developed that allow for rapid, reliable and inexpensive screening of cytochrome b by analysis of single-stranded conformational polymorphisms. Twenty different haplotypes were identified from six species of Iberian Barbus. These primers proved useful for population and species level studies, and could also be valuable in population genetic and phylogenetic studies of other cyprinin fishes. PMID- 21585893 TI - Accurate methods of DNA extraction and PCR-based genotyping for single scallop embryos/larvae long preserved in ethanol. AB - Marine scallops are sessile as adult but have a long planktonic larval phase showing great possibility to migrate in marine realm lacking of obvious barriers. Genetic analysis of scallop embryos/larvae based on molecular markers is very essential to clarify the spatial and temporal gene flow and the unique population and community structure. However, the technical challenges, such as single embryos/larvae isolation and low quantity and poor quality of DNA extracted, make genotyping for a single embryo/larva long preserved in ethanol to be a really difficult task. In this study, we analysed the factors that might affect the DNA quantity and quality for simple sequence repeat-based genotyping for single embryos/larvae. Based on the factors analysed, we developed a LoTEPA buffer-based method, of which the accuracy, stability and reproducibility were evaluated by controlled inter- and intraspecies and self-fertilized scallop families. The genotyping results showed the high success rate of more than 90% in total for embryos/larvae preserved in ethanol for 1-5 years. Furthermore, the successful genotyping for the larvae sampled from a natural habitat well demonstrated the potential use of this method in practical ecological analysis. PMID- 21585894 TI - Eleven polymorphic microsatellites isolated from red swamp crayfish, Procambarus clarkii. AB - Eleven microsatellites were isolated from a genomic DNA library enriched for CA- and GA-repeats, and were characterized in 48 individuals of red swamp crayfish Procambarus clarkii. All 11 microsatellites were polymorphic with an average of allele number of 6.6 per locus. Genotypic distributions of these 11 markers were found to be in conformance with the expectations of Hardy-Weinberg equilibrium. All 11 markers were unlinked. These markers are being used to study the invasion routine, genetic diversity and population structure of the species P. clarkii. PMID- 21585895 TI - Isolation and characterization of microsatellite loci in the long-fingered bat Miniopterus fuliginosus. AB - We isolated and characterized 10 microsatellite loci in the long-fingered bat Miniopterus fuliginosus. These loci were tested on 48 individuals from Anhui Province of China, and all loci were highly polymorphic. The mean number of observed alleles per locus was 13.6 (range from six to 27). Observed and expected heterozygosity values ranged from 0.364 to 0.957, and from 0.676 to 0.951, respectively. After Bonferroni correction, four loci deviated significantly from Hardy-Weinberg equilibrium. No pairs of loci were in linkage disequilibrium. These polymorphic markers will be used to examine population structure and genetic diversity in this species. PMID- 21585896 TI - Isolation and characterization of microsatellite markers for Casearia sylvestris Sw. (Salicaceae), a neotropical medicinal tree. AB - Casearia sylvestris Sw. is a widespread neotropical tree utilized in popular medicine. Recent research ranked Casearia as one of the most promising genus in the search of drugs against cancer. Despite its wide distribution and pharmacological importance, no microsatellite markers have yet been developed for this genus. In this study, we provide 10 polymorphic microsatellite loci specifically designed for C. sylvestris, used to analyse 90 individuals distributed in two populations from Sao Paulo state, Brazil. On average, 12.3 alleles per locus were identified, showing the ability of the markers to detect microsatellite polymorphism in this species. PMID- 21585897 TI - Characterization of eight polymorphic microsatellite loci for the giant grouper (Epinephelus lanceolatus Bloch). AB - Eight polymorphic microsatellite loci were isolated and characterized using a small insert genomic DNA library for the giant grouper (Epinephelus lanceolatus Bloch, 1790), a commercially valuable marine fish in tropical waters. They showed polymorphism information content ranging from 0.177 to 0.775, allele numbers ranging from two to 10, effective allele numbers ranging from 1.227 to 5.012, and observed and expected heterozygosities from 0.2 to 0.733 and from 0.185 to 0.801, respectively, which we anticipate will be useful for population genetic studies of the giant grouper. PMID- 21585898 TI - Isolation and characterization of eight polymorphic microsatellite loci in the endangered Hawaiian tree snail, Achatinella sowerbyana. AB - Achatinella is a genus of highly endangered native Hawaiian tree snails. Eight polymorphic microsatellite markers were isolated for one species, Achatinella sowerbyana, to be used in assessing remaining genetic diversity and gene flow in the often small and isolated populations. All loci amplified consistently in every individual tested. The number of alleles per locus in a sample of 40 individuals varied from three to 13, and the observed heterozygosity ranged from 0.308 to 0.846. These markers will be used to assist in the development of conservation and management plans. PMID- 21585899 TI - Development of new microsatellite loci and multiplex reactions for muskellunge (Esox masquinongy). AB - The muskellunge (Esox masquinongy) is a valued fisheries species throughout its native range. Numerous studies have documented performance and phenotypic differences among muskellunge populations, but genetic markers for assessment have been lacking. We characterized 14 microsatellite loci and developed five multiplex polymerase chain reactions. Successful amplification of northern pike (Esox lucius) was observed for seven loci. These microsatellites will be useful for analysing population structure, performance characteristics of propagated strains, and helping to develop and monitor hatchery management guidelines for muskellunge. PMID- 21585900 TI - Isolation of compound microsatellite loci in the herbaceous perennial Cirsium purpuratum (Maxim.) Matsum. AB - The herbaceous perennial Cirsium purpuratum is a pioneer on the southeast side of Mount Fuji in Japan. For genetic analysis of reproduction in this species, we developed polymorphic compound microsatellite markers using an adaptor-ligated library method and a simpler method called the intercompound microsatellite method. The latter method was an effective method for developing compound simple sequence repeat markers. In total, 11 polymorphic, codominant microsatellite markers were developed and characterized for this species. These polymorphic markers had three to 20 alleles per locus, a range of observed heterozygosity from 0.25 to 0.90, and were considered effective for genetic analysis. PMID- 21585901 TI - Isolation and characterization of microsatellite markers from the marine isopods Serolis paradoxa and Septemserolis septemcarinata (Crustacea: Peracarida). AB - This study reports the successful isolation of highly informative microsatellite marker sets for two marine serolid isopod species. For Serolis paradoxa (Fabricius, 1775), 13, and for Septemserolis septemcarinata (Miers, 1875), eight polymorphic microsatellite markers were isolated using the reporter genome enrichment protocol. The number of alleles per locus (N(A) ) and the observed heterozygosity (H(O) ) encompass a wide range of variation within S. paradoxa (N(A) 3-31, H(O) 6-89%) and S. septemcarinata (N(A) 2-18, H(O) 9-94%). The suitability of the newly isolated markers for population genetic studies is evaluated. PMID- 21585902 TI - Isolation and characterization of new microsatellite markers in shea tree (Vitellaria paradoxa C. F. Gaertn). AB - Vitellaria paradoxa is one of the major components of African parkland agroforestry systems. In order to assess the genetic diversity and population structure of this species, we isolated and characterized 14 polymorphic nuclear microsatellite loci. Primers developed to amplify these loci were used to analyse 200 individuals of a shea tree population in Mali. Loci have shown a high number of alleles ranging from four to 26, and display an observed level of heterozygosity between 0.37 and 0.85. These new very polymorphic microsatellite markers will be useful for genetic and ecological studies of V. paradoxa. PMID- 21585903 TI - Development and characterization of 11 microsatellite loci for the Mona Island iguana (Cyclura cornuta stejnegeri). AB - We isolated and characterized 11 microsatellite loci in the Mona Island iguana (Cyclura cornuta stejnegeri). Eleven loci exhibit moderate to high allelic diversity (two to 12 alleles, mean = 4.5) and polymorphism (mean observed heterozygosity, 0.56; range, 0.26 to 0.78) in 41 adults. This marker set has low probability of identity and high parentage exclusion power and will be suitable for studies of paternity, social organization and relatedness in this species. PMID- 21585904 TI - Characterization of 12 highly variable tetranucleotide microsatellite loci for Arctic grayling (Thymallus arcticus) and cross amplification in other Thymallus species. AB - We describe the isolation and development of 12 polymorphic tetranucleotide microsatellite loci for Arctic grayling (Thymallus arcticus). In a sample of 46 fish, we observed between three and 20 alleles per locus. All 12 of these loci were also polymorphic in at least one of the following Thymallus species and subspecies: T. burejensis, T. amurensis, T. thymallus, T. brevirostris, T. grubii, T. arcticus baicalensis and T. arcticus pallasi. These loci will aid in our understanding of the population genetics, behaviour and conservation of grayling species throughout the northern hemisphere. PMID- 21585905 TI - Microsatellite markers for the endangered Roanoke logperch, Percina rex (Percidae) and their potential utility for other darter species. AB - The Roanoke logperch (Percina rex Jordan and Evermann), an endangered fish, occurs in only six watersheds in the Roanoke and Chowan river drainages of Virginia, USA. The species' population genetic structure is poorly known. We developed 16 microsatellite markers that were reliably scorable and polymorphic P. rex. Markers were also screened in seven other darter species of the genus Percina. Most markers exhibited successful amplification and polymorphism in several species. These markers may therefore prove useful for population genetic studies in other darters, a diverse but highly imperiled group. PMID- 21585906 TI - Cross-species amplification and optimization of microsatellite markers for use in six Neotropical parrots. AB - Short amplicon primers were redesigned for 17 microsatellite loci developed in St. Vincent's Amazon and six loci developed in blue-and-yellow macaw and tested using six species of Neotropical parrot. Polymorphism was observed at 12 loci in blue-and-yellow macaw, 10 in red-and-green macaw, 11 in scarlet macaw, 10 in chestnut-fronted macaw, 11 in red-bellied macaw and 16 in mealy parrot. Number of alleles per locus ranged from two to 23 and expected heterozygosity ranged from 0.05 to 0.95. The resulting multiplexed loci will be useful in evaluating genetic diversity, genetic structure and mating system in Neotropical parrots. PMID- 21585907 TI - Development of 17 microsatellite markers for Ceratosolen constrictus, the pollinating fig wasp of Ficus fistulosa. AB - The obligate mutualism between figs (Ficus) and fig pollinating wasps (Agaonidae) is regarded as a classic example of mutualism. Seventeen polymorphic microsatellite loci were developed for Ceratosolen constrictus, the pollinating wasp of the dioecious fig Ficus fistulosa. The number of alleles per locus ranged from two to 15 and the observed and expected heterozygosities ranged from 0.040 to 0.846 and from 0.040 to 0.916, respectively. These microsatellite loci offer a powerful tool for evolutionary and population genetic studies in C. constrictus, and gene flow of F. fistulosa. PMID- 21585908 TI - Eleven novel microsatellite markers for the Asian oyster Crassostrea ariakensis. AB - Clones from four partial genomic libraries of the Asian oyster Crassostrea ariakensis were screened to reveal 64 microsatellite-containing sequences. Polymerase chain reaction primers were designed for 34 of these loci. Reactions were optimized for 11 primer pairs and markers were evaluated in eight family crosses and one wild population from northern China. Zero to three null alleles per locus were identified in family crosses, and two of the 11 loci showed allele frequency deviations from Hardy-Weinberg equilibrium in the wild population. These markers have proven useful for genetic studies of C. ariakensis. PMID- 21585909 TI - Identification of 20 polymorphic microsatellite loci in European crow (Corvus corone) from existing passerine loci. AB - The European crow (Corvus corone) occurs in two subspecies (or species) with distinct plumage coloration: the black carrion crow (C. c. corone) and the grey and black hooded crow (C. c. cornix). We tested 42 passerine microsatellite loci for amplification in the European crow and identified 20 loci that were both polymorphic and easy to score. In 50 individuals sampled in the Danish part of the species' pan-European hybrid zone, the number of alleles ranged between two and 21. One locus deviated from Hardy-Weinberg equilibrium and had a high estimated null allele frequency. These 20 loci were highly successful in amplifying polymorphic products also in other crow populations and in another Corvidae species, the rook (Corvus frugilegus). PMID- 21585910 TI - Ten new microsatellite markers for the buttonwood mangrove (Conocarpus erectus L., Combretaceae). AB - We present 10 microsatellite markers for the buttonwood mangrove, Conocarpus erectus, a wide-range mangrove associate species. Polymorphism was assessed among individuals from six different populations along the Pacific Coast of Mexico and Costa Rica, as well as in two individuals from the Yucatan Peninsula in the Atlantic. The number of alleles detected in the Pacific ranged from two to five. All loci amplified in the Yucatan samples and seven loci revealed a unique Atlantic allele. These markers will be useful for studies in the conservation of the species and to study the basic biology of C. erectus. PMID- 21585911 TI - Isolation and characterization of microsatellite loci in Coccoloba cereifera (Polygonaceae), an endangered species endemic to the Serra do Cipo, Brazil. AB - Microsatellite primers were isolated from the microendemic and threatened species Coccoloba cereifera, a shrub known only from a small region in the Serra do Cipo, Brazil. Thirteen primer pairs amplifying perfect and imperfect microsatellite regions were tested in 40 individuals from the one known occurrence of the species. Number of alleles ranged from two to six and levels of observed heterozygosities ranged from 0.21 to 0.95. These markers will be useful for the analysis of questions concerning population genetic structure and will assist in providing information for future conservation management programmes. PMID- 21585912 TI - Development of polymorphic microsatellite markers for the livebearing fish Poecilia parae. AB - We developed 16 novel polymorphic tetranucleotide microsatellite markers for Poecilia parae, a livebearing fish used in evolutionary studies because of its Y linked colour and size polymorphism. A set of 199 clones was sequenced out of an enriched genomic library, and we achieved an enrichment efficiency of nearly 80%. Primers were designed for 16 pure repeats, and 59 P. parae were screened for polymorphism. Cross-amplification was tested on Poecilia picta and Poecilia reticulata, the guppy. The new microsatellite markers showed an exceptionally high allelic diversity and low stutter formation, proving their suitability for a broad range of applications in these species. PMID- 21585913 TI - Characterization of nine polymorphic microsatellite markers in sprat (Sprattus sprattus L.). AB - Nine polymorphic microsatellites were isolated from sprat (Sprattus sprattus) using a microsatellite enrichment protocol and selective hybridization with a biotinylated (AC)(12) probe. The loci showed different variation patterns in a Baltic Sea population (44 individuals) with mean number of alleles at 12.7 and mean observed heterozygosity at 0.78. These microsatellite loci are expected to be used for taxonomic considerations in sprat, stock differentiation and population genetic analysis. PMID- 21585914 TI - Isolation and characterization of polymorphic microsatellite loci in yellowtail catfish, Pangasius pangasius (Hamilton, 1822). AB - A total of nine polymorphic microsatellite loci were obtained from a genomic library of Pangasius pangasius (order Siluriformes, family Pangasiidae). Samples from rivers Bhagirathi (n = 22) and Mahanadi (n = 20) were genotyped for each of the nine microsatellite loci to determine genetic variation. The mean number of alleles per locus was 5.22 in Bhagirathi and 5.78 in Mahanadi; and expected heterozygosity ranged from 0.567 (Bhagirathi) to 0.578 (Bhagirathi). Significant deviation (P < 0.003) from Hardy-Weinberg expectations was evident at three loci, Ppa2 (Bhagirathi), Ppa14 (Mahanadi) and Ppa28 (Bhagirathi and Mahanadi). The identified microsatellite loci were found to be promising for population genetics studies of P. pangasius. PMID- 21585915 TI - Isolation and characterization of polymorphic microsatellite loci from Tetratheca ericifolia (Elaeocarpaceae). AB - We identified 11 informative microsatellite loci in Tetratheca ericifolia from an (AG)(n) -enriched library. Using these loci on 32 individuals from two populations (16 individuals from each), we detected an average of 11.3 alleles per locus (range of five to 21, average expected heterozygosity of 0.728), of which 56% were unique to one population or the other. All loci were amplifiable in seven to 12 of a further 12 species of Tetratheca under the same reaction conditions. The markers will be useful tools for evolutionary studies of this Australian endemic group. PMID- 21585916 TI - Fifteen new microsatellite markers for the reef coral Favia fragum and a new Symbiodinium microsatellite. AB - Sixteen new microsatellite loci were isolated from the Tropical Atlantic coral Favia fragum. One locus amplified with pure zooxanthellae DNA template, revealing a symbiont (Symbiodinium) origin. We genotyped 48 short and 45 tall ecomorphs of F. fragum from the Bocas del Toro region of Panama. For 15 host loci, allelic diversity ranged from three to 23 with an average of 5.75 alleles per locus. Analysis of genotypic data revealed significant heterozygote deficits at all loci and linkage disequilibrium between loci, as did a previous study of the two ecomorphs with allozymes. We found evidence for null alleles at four of the host loci in the form of locus-specific polymerase chain reaction failure; however, extreme inbreeding via self-fertilization is likely to explain the large departures from Hardy-Weinberg equilibrium. PMID- 21585917 TI - Seventy new microsatellites for the pied flycatcher, Ficedula hypoleuca and amplification in other passerine birds. AB - The pied flycatcher (Ficedula hypoleuca) is a small migratory passerine bird commonly distributed across Europe which has been the focus of considerable ecological and evolutionary research. Here, we present details of 70 microsatellite markers for the species adding to the six which are currently available. Sixty-six markers were also polymorphic in the closely related collared flycatcher (Ficedula albicollis), while 54 were polymorphic in another related passerine, the bluethroat (Luscinia svecica), and 12 were polymorphic in the more distantly related Siberian jay (Perisoreus infaustus). PMID- 21585918 TI - Isolation and characterization of polymorphic microsatellite and COI loci from the whelk Kelletia kelletii. AB - There is considerable interest in the genetic structure of Kelletia kelletii because of its economic, ecological and scientific importance. To that end, we developed species-specific primers which amplify mitochondrial cytochrome c oxidase subunit I as well as 13 hypervariable nuclear microsatellite loci. Using dye-labelled primers, the microsatellite loci can be co-amplified in two multiplex polymerase chain reactions and scored simultaneously on an automated sequencer. PMID- 21585919 TI - Isolation and characterization of microsatellite loci from the endangered New Zealand takahe (Gruiformes; Rallidae; Porphyrio hochstetteri). AB - Nineteen polymorphic microsatellite loci were characterized from the endangered takahe (Porphyrio hochstetteri). Like many of New Zealand's other native avian species, levels of polymorphism were low, with variation detected at only 19 of 110 (17.3%) loci, and most polymorphic loci (78.9%) were diallelic (mean number of alleles = 2.3). Despite these low levels of variation, the microsatellites developed here will be useful for parentage assignment for confirming pedigrees, and investigating relationships between genetic variation, pedigree-based inbreeding and reproductive success in this highly endangered species. PMID- 21585920 TI - Development of highly polymorphic tetranucleotide microsatellite markers in Austrocedrus chilensis. AB - An enriched genomic library was constructed and 9 novel polymorphic tetranucleotide microsatellite markers developed for Austrocedrus chilensis, the most economically important native conifer in the Andean Patagonian region. Polymorphism was investigated for these markers in 48 individuals from two populations. Numbers of alleles ranged from 3 to 19 and levels of observed heterozygosity among the 9 loci ranged from 0.32 to 0.95. No locus combinations exhibited linkage disequilibrium. These polymorphic markers will be useful tools for the study of demography and gene flow and more in general for population and conservation genetics of this species. PMID- 21585921 TI - Microsatellite development suggests evidence of polyploidy in the social sponge dwelling snapping shrimp Zuzalpheus brooksi. AB - We isolated and characterized 33 novel, polymorphic microsatellite loci from the social sponge-dwelling snapping shrimp Zuzalpheus brooksi. We screened all 33 loci in approximately 31 individuals from a population of Z. brooksi from the Florida Keys, USA and found an average of 16 alleles per locus. Approximately 25% of the loci showed more than two bands per individual, suggesting evidence of high gene duplication, or more likely, polyploidy, which is common in crustaceans. The 25 disomic loci had an observed heterozygosity of 0.57 (range = 0.03-1.00) and will be useful for studying the social organization in Zuzalpheus shrimp. PMID- 21585922 TI - Isolation and characterization of 19 microsatellite markers in a tropical and warm subtropical birch, Betula alnoides Buch.-Ham. ex D. Don. AB - Betula alnoides is an ecologically and economically important species in the tropics and warm subtropics. Nineteen polymorphic microsatellite markers were isolated from this species, which displayed three to 12 alleles per locus. The observed heterozygosities ranged from 0.100 to 0.905, and the expected heterozygosities from 0.510 to 0.893. These markers would be useful tools in genetic resource assessment, molecular marker-assistant breeding, parentage analysis and genetic diversity studies for this species. PMID- 21585923 TI - Cross-amplification and characterization of 13 tetranucleotide microsatellites in multiple species of Neotropical canids. AB - We tested 47 tetranucleotide microsatellite loci developed for the domestic dog in four species of Neotropical canids, aiming to produce a standardized set that could be successfully used even in noninvasive samples across this group. We identified 13 suitable loci, nine of which constitute a standardized set for all species. Considering only the ideal panel of nine loci, the mean expected heterozygosity (averaged across species) per locus ranged from 0.58 to 0.92 (overall mean 0.76), and the maximum probability of identity value was 1.3 * 10( 9) . This set of loci has a great potential for application in evolutionary, ecological and conservation studies. PMID- 21585924 TI - Microsatellite markers for the drought-resistant earthworm Hormogaster elisae. AB - We developed and characterized 10 highly polymorphic microsatellite loci from a simple sequence repeat-enriched genomic DNA library of the earthworm Hormogaster elisae. Characterization of these loci using 26 individuals revealed eight to 25 alleles per locus and high levels of heterozygosity. These loci will be used for paternity analysis and population genetic studies. PMID- 21585925 TI - Development and characterization of eight polymorphic microsatellite loci from Pistacia lentiscus L. (Anacardiaceae). AB - We have developed a set of eight polymorphic nuclear microsatellite markers for the Mediterranean shrub Pistacia lentiscus by means of an enriched library method. Characterization for the eight loci was carried out on 42 individuals from two populations sampled in southern Spain. The overall number of alleles detected was 59, ranging from three to 13 per locus. Expected heterozygosity per locus and population ranged from 0.139 to 0.895. Two loci albeit only in one population (Seville) departed significantly from Hardy-Weinberg equilibrium expectations and no linkage disequilibrium between pairs of loci was detected. These markers will be used in studies of gene flow across a fragmented landscape. PMID- 21585926 TI - Isolation and characterization of 13 microsatellite loci for Percichthys trucha (Percichthyidae). AB - Thirteen polymorphic microsatellite loci are described for the South American freshwater fish Percichthys trucha. Number of alleles per locus ranged from two to 21 and observed heterozygosities ranged from 0.304 to 0.915 in a sample of 47 individuals from four different sampling locations. PMID- 21585927 TI - Fourteen polymorphic microsatellite markers for the fungal banana pathogen Mycosphaerella fijiensis. AB - Fourteen polymorphic microsatellite markers were developed for Mycosphaerella fijiensis, a fungus causing the black sigatoka disease in banana. The sequenced genome of M. fijiensis was screened for sequences with single sequence repeats (SSRs) using a Perl script. Fourteen SSR loci, evaluated on 48 M. fijiensis isolates from Hawaii, were identified to be highly polymorphic. These markers revealed two to 19 alleles, with an average of 6.43 alleles per locus. The estimated gene diversity ranged from 0.091 to 0.930 across the 14 microsatellite loci. The SSR markers developed would be useful for population genetics studies of M. fijiensis. PMID- 21585928 TI - Isolation and characterization of microsatellite markers for Cycas debaoensis Y. C. Zhong et C. J. Chen (Cycadaceae). AB - Cycas debaoensis is one of the critically endangered cycad species endemic to China. In this study, we described the development of six microsatellite markers from the genome of C. debaoensis using the protocol of fast isolation by AFLP of sequences containing repeats (FIASCO) and two microsatellite markers derived from the database of expressed sequence tags (dbEST). Polymorphism of each locus was assessed in 60 adult individuals of the cycad. The average allele number of the microsatellites was 2.6 per locus, ranging from two to five. The observed and expected heterozygosities varied from 0.0833 to 0.7333 and from 0.0805 to 0.7188, respectively. Despite its rarity, only one locus (Y177) deviated from Hardy Weinberg equilibrium due to the excessive homozygosity. The marker transferability of the eight primer pairs was tested on other four congeneric species that also occur in China. PMID- 21585929 TI - Isolation and characterization of microsatellites in Rattus rattus. AB - We isolated and characterized 10 microsatellite loci in the black rat Rattus rattus (Muridae, Rodentia), a widespread invasive species largely known to cause serious problems in agriculture and human health. Polymorphism was studied in two populations, one from Madagascar and one from Senegal. It ranged from three to 12 alleles in Madagascar, and from two to five alleles in Senegal. Together with the loci previously adapted from Rattus norvegicus, this set of markers should allow the conduct of thorough studies on the genetic structure of natural populations of R. rattus. PMID- 21585930 TI - Isolation and characterization of microsatellite loci from the invasive ant Pheidole megacephala. AB - We report the characterization of eight microsatellite markers in the big-headed ant Pheidole megacephala, a pest ant registered in the list of '100 of the world's worst invasive alien species'. An enrichment protocol was used to isolate microsatellite loci, and polymorphism was explored with 36 individuals collected in an invasive population from Australia and 20 individuals collected in a population from the native mainland location in South Africa. These primers showed a number of alleles per locus ranging from two to 10, and expected heterozygosities ranging from 0.083 to 0.826. Moreover, results of cross-species amplification are reported in five other Pheidole species and in seven other ants of the subfamily Myrmicinae. PMID- 21585931 TI - Isolation and characterization of microsatellite loci from the coppertail skink (Ctenotus taeniolatus). AB - We report on the isolation and characterization of eight microsatellite markers for the coppertail skink (Ctenotus taeniolatus). From a sample of 27 individuals, the number of alleles per locus ranged from seven to 13 and observed and expected heterozygosities ranged from 0.714 to 0.818 and from 0.738 to 0.899, respectively. These loci will be used to assess anthropogenic disturbance on coppertail skink populations. These are the first microsatellites reported for the genus Ctenotus, despite being the most speciose genus of lizards in Australia. PMID- 21585932 TI - New polymorphic microsatellite markers for the limpet Patella rustica and cross priming testing in four Patella species. AB - Eighteen microsatellite markers have been characterized from the Patella rustica genome. An average of 10 alleles per locus and an expected heterozygosity ranging from 0.054 to 0.937 were observed in a sample of 32 wild individuals from Viana do Castelo, Portugal. Distinct cross-priming amplification rates were recovered on four additional Patella species. Three monomorphic P. rustica loci were polymorphic in other Patella species. The microsatellites developed herein could be a useful intraspecific genetic tool to undertake fine population studies in the genus Patella. PMID- 21585933 TI - Identification of 21 polymorphic microsatellites in the African parasitoid wasp, Psyttalia lounsburyi (Silvestri) (Hymenoptera: Braconidae). AB - We have developed 21 dinucleotide repeat microsatellite loci from African populations of Psyttalia lounsburyi (Silvestri) (Hymenoptera: Braconidae), a parasitoid wasp of the olive fruit fly, as part of a study assessing the role of introgression/hybridization in the success of a biological control introduction. We proposed suitable conditions for polymerase chain reaction multiplexing. All 21 loci were polymorphic with two to 21 alleles per locus within the Kenyan and South African populations tested. Most of them were successfully amplified in two other Psyttalia species. PMID- 21585934 TI - Development of microsatellite markers for parentage analysis in the great tinamou (Tinamus major). AB - Eighteen microsatellite loci were isolated from great tinamous (Tinamus major), which are large terrestrial birds found in the Neotropics. These are the first primers developed for the Order Tinamiformes. Paternity analyses are possible because the levels of heterozygosity are sufficiently high (0.29-0.90). PMID- 21585935 TI - Newly developed polymorphic microsatellite markers for frogs of the genus Ascaphus. AB - Thirteen polymorphic microsatellite loci were identified and developed for the coastal tailed frog, Ascaphus truei, from sites within the Olympic Peninsula of Washington, USA. These tetranucleotide repeat loci were highly variable, averaging 19 alleles per locus and expected heterozygosity of 0.91. In addition, these loci cross-amplify in the sister species, Ascaphus montanus. These markers will prove useful in identifying fine-scale genetic structure, as well as provide insight into the evolution and conservation of this group across fragmented landscapes. PMID- 21585936 TI - Isolation and characterization of 30 polymorphic microsatellite loci from the mycophagous fly Drosophila innubila. AB - Drosophila innubila is a mushroom-feeding member of the quinaria group, found in the woodlands and forests of the 'sky islands' in Arizona and New Mexico and extending south into central Mexico. Here, we describe and characterize 30 polymorphic microsatellite loci from D. innubila collected in the Chiricahua Mountains in Arizona. The number of alleles ranged from three to 21, and observed heterozygosity ranged from 0.0513 to 0.9737. Six loci were putatively X-linked, six departed from Hardy-Weinberg equilibrium, seven had evidence of null alleles, and six showed evidence of linkage disequilibrium. These markers will be useful for examining population structure of D. innubila and its association with male killing Wolbachia. PMID- 21585937 TI - Isolation and characterization of highly polymorphic microsatellites in the chokka squid, Loligo reynaudii. AB - The chokka squid, Loligo reynaudii, is the target of a commercially valuable fishery in South Africa, but little information is available on population structure and mating system. We developed 11 polymorphic microsatellite markers using both standard nonenrichment and enrichment protocols. Numbers of alleles per locus ranged from 11 to 30, and levels of expected heterozygosity ranged between 0.77 and 0.98. Three loci developed using an enriched library displayed significant departure from Hardy-Weinberg genotype proportions suggesting high frequencies of null alleles. The remaining loci should prove useful for population and parentage studies. PMID- 21585938 TI - Unravelling below-ground plant distributions: a real-time polymerase chain reaction method for quantifying species proportions in mixed root samples. AB - Knowledge on below-ground plant distributions is almost lacking to date, despite the fact that such information would be very valuable in understanding below ground competition and species-specific interactions, processes that are expected to shape community structure. Methods available so far for below-ground species determination have drawbacks that we tried to challenge. Some methods make use of differences in the chemical composition between species, but this is highly variable upon environmental factors. DNA-based techniques - far less dependent on chemical composition - such as polymerase chain reaction on internal transcribed spacer (ITS) primers can so far only determine presence-absence of a species in a mixed root sample. Here, we present a quantitative DNA-based technique that allows investigation of relative species abundances in experimental mixed root samples. We used quantitative real-time polymerase chain reaction (PCR) on species-specific markers obtained from intersimple sequence repeat (ISSR) analyses in root samples. This molecular technique is novel in the field of root ecology and its development overcame three challenges: (i) determination of species-specific DNA fragments, (ii) development and optimization of the real time PCR protocol, (iii) designing a data treatment method based on a modified delta-delta-cycle threshold (CT) analysis. The method gained robustness from using relative DNA abundances in species mixtures rather than absolute concentration readings. This requires accurate multispecies reference series as a calibration. Test samples with different known biomass ratios of all species showed proof of concept of this method. The pro's and contra's of this method are discussed in the light of its contribution to advancing ecological research on below-ground plant-plant interactions. PMID- 21585939 TI - clonality V.0.4: a randomization-based program to test for heterozygosity-genet size relationships in clonal organisms. AB - clonality V.0.4 is a program for testing heterozygosity-genet size relationships in clonal organisms using a randomization procedure. The software has been developed under the Borland Delphi developing environment and a Windows executable version is freely downloadable from http://gemi.mpl.ird.fr/SiteSGASS/Prugnolle/ClonalityPage.html. The program compares the observed F(IS) of the population with the F(IS) expected if genets (multilocus genotypes present in multiple copies within the population) were chosen randomly from the set of different multilocus genotypes. The randomization procedure is performed with the same number of genets and the same number of repetitions per genet as what is observed in the original data set. PMID- 21585940 TI - Spatial analysis method (sam): a software tool combining molecular and environmental data to identify candidate loci for selection. AB - sam is a Windows program designed to detect candidate loci for selection in whole genome scans. It also gives valuable clues as regards the ecological factors at stake in the selection process. The method used is based on multiple univariate logistic regression models to test for association between allelic frequencies at marker loci and environmental variables. The software reads matrices constituted of presence/absence of molecular markers, and of the corresponding environmental parameters at sampling locations. It provides dynamic analysis tables to process the results. The tool is freely available for download at http://www.econogene.eu/software/sam/. PMID- 21585941 TI - Isolation and characterization of polymorphic microsatellite markers from the velvet tree, Miconia calvescens DC. (Melastomataceae). AB - Nine polymorphic microsatellite loci were isolated and characterized from the invasive velvet tree (Miconia calvescens DC.), a serious forest invader in tropical Pacific oceanic islands. These loci provided markers with polymorphism of three to 10 alleles per locus within 95 individuals. The expected and observed heterozygosities ranged from 0.0367 to 0.5053 and from 0.0370 to 0.2473, respectively. These markers should be useful to study dispersal and the invasion genetics of the velvet tree. PMID- 21585942 TI - Isolation and characterization of microsatellite loci for eastern foxsnakes (Elaphe gloydi). AB - New statistical techniques and software have improved our ability to quantify fine-scale population structure. We isolated 11 microsatellite markers for eastern foxsnakes (Elaphe gloydi) and surveyed the variability of each using 115 136 individuals from one population in southwestern Ontario. We determined that all loci were variable and conformed to Hardy-Weinberg expectations and that no locus demonstrated linkage disequilibrium. We are using these markers to quantify the scale of gene flow, and to assess the effect of variable landscapes on connectivity and genetic diversity of three disjunct regional populations in the northern portion of the species' range. PMID- 21585943 TI - Microsatellite loci for the invasive colonial hydrozoan Cordylophora caspia. AB - Cordylophora caspia, a colonial hydrozoan native to the Ponto-Caspian region, has become a common invader of both fresh and brackish water ecosystems of North America and Europe. We describe 11 polymorphic microsatellite loci for this species. Preliminary analyses indicate that population substructure may contribute to departures from Hardy-Weinberg equilibrium. In addition, new loci failed to consistently amplify Cordylophora samples known to be genetically distant from those utilized in this study, indicating the presence of cryptic diversity within the taxon. PMID- 21585944 TI - Isolation and characterization of polymorphic microsatellite loci for the horn fly, Haematobia irritans (L.) (Diptera: Muscidae). AB - The horn fly, Haematobia irritans (L.) (Diptera: Muscidae), is a cosmopolitan livestock pest that has caused a great negative impact on the animal production sector throughout the world. Here, we describe 10 polymorphic microsatellite loci isolated from H. irritans. The number of alleles found ranged from two to eight per locus and the expected heterozygosity from 0.1421 to 0.7702. These loci are potentially useful for the fine-scale genetic characterization of horn fly populations and provide fundamental information for pest management and planning of control programs. PMID- 21585945 TI - Characterization of 12 single nucleotide polymorphisms (SNPs) in Pacific abalone, Haliotis discus hannai. AB - We report here for the first time 12 polymorphic single nucleotide polymorphisms (SNPs) in a commercially important gastropod, Pacific abalone (Haliotis discus hannai) that were identified by searching expressed sequence tag database. These SNP loci (seven nuclear and five mitochondrial SNPs) were polymorphic among 37 wild abalone individuals, based on a four-primer allele-specific polymerase chain reaction analysis. All loci had two alleles and the minor allele frequency ranged from 0.027 to 0.473. For the seven nuclear SNPs, the expected and observed heterozygosities ranged from 0.053 to 0.499 and from 0.054 to 0.811, respectively. PMID- 21585946 TI - Isolation and characterization of 21 microsatellite markers in the barn owl (Tyto alba). AB - We report 21 new polymorphic microsatellite markers in the European barn owl (Tyto alba). The polymorphism of the reported markers was evaluated in a population situated in western Switzerland and in another from Tenerife, Canary Islands. The number of alleles per locus varies between two and 31, and expected heterozygosity per population ranges from 0.16 to 0.95. All loci are in Hardy Weinberg equilibrium and no linkage disequilibrium was detected. Two loci exhibit a null allele in the Tenerife population. PMID- 21585947 TI - Isolation and characterization of microsatellite loci in Pitcairnia albiflos (Bromeliaceae), an endemic bromeliad from the Atlantic Rainforest, and cross amplification in other species. AB - Eight microsatellite markers were isolated from Pitcairnia albiflos, an endangered endemic bromeliad species restricted to 'inselberg' rock outcrops in the state of Rio de Janeiro, Brazil. The number of alleles observed for each locus ranged from two to 12. Average observed and expected heterozygosities were 0.408 and 0.663, respectively. The cross-amplification test in 16 taxa suggests that the markers will be useful in numerous related bromeliad species. The loci will be used to study genetic structure and reproductive biology in fragmented inselberg populations and the origin and maintenance of barriers to gene flow between sympatric Pitcairnia species. PMID- 21585948 TI - Isolation and characterization of microsatellite loci in the Malaysian giant freshwater prawn, Macrobrachium rosenbergii. AB - Eight single locus microsatellite markers were developed to characterize the Malaysian giant freshwater prawn, Macrobrachium rosenbergii. These microsatellites were isolated from an enriched genomic library contained by using a 5'-anchored polymerase chain reaction technique. Primers were designed to flank the repeat sequences and subsequently used to characterize 30 unrelated individuals of the giant freshwater prawn. The polymerase chain reaction amplification products of these eight microsatellite loci were polymorphic with the number of alleles ranging from two to 10 alleles per locus while the levels of heterozygosity ranged from 0.6333 to 0.8667. PMID- 21585949 TI - Twelve polymorphic microsatellites in Oriental river prawn, Macrobrachium nipponense. AB - Oriental river prawn, Macrobrachium nipponense, is a commercially important freshwater prawn species in China, Japan, Korea and Vietnam. Due to overfishing for food, the wild stocks M. nipponense are endangered. Twenty microsatellite loci were isolated from the M. nipponense. Twelve of these loci were polymorphic (seven to 16 alleles per locus), with expected heterozygosity ranging from 0.68 to 0.86 (n = 48). These polymorphic loci provide a valuable tool for assessing genetic diversity of wild and cultured populations. PMID- 21585950 TI - Development of microsatellite markers in Cordia bifurcata (Boraginaceae) and cross-species amplification in Cordia inermis and Cordia pringlei. AB - We developed 16 microsatellite markers in Cordia bifurcata, a Central and South American shrub. The markers show low polymorphism in C. bifurcata, a species suspected of self-fertilization or apomixis. Of four polymorphic loci, three had only two alleles. However, current research indicates that these markers hold value for interpopulational comparisons of C. bifurcata and for analyses of congeners. In Cordia inermis, a dioecious or subdioecious shrub, seven of the markers produced interpretable amplification products of which five showed polymorphism. In Cordia pringlei, a distylous shrub, nine of the markers produced interpretable amplification products of which six showed polymorphism. PMID- 21585951 TI - Isolation and characterization of microsatellite loci in the deep-sea marine fish, the roundnose grenadier (Coryphaenoides rupestris). AB - We developed polymerase chain reaction primers for eight dinucleotide microsatellite loci in the marine deep sea fish, roundnose grenadier (Coryphaenoides rupestris). All markers were obtained from a partial genomic DNA library, and characterized in 90 unrelated individuals from one putative population sampled on the Mid-Atlantic Ridge. The number of alleles ranged from two to 61 with an average of 21 per locus. The observed heterozygosity levels ranged from 0.301 to 0.987 with an average of 0.672. Several of the markers amplified multiple alleles from either the Atlantic cod (Gadus morhua) or the deep-sea fish roughhead grenadier (Macrourus berglax). PMID- 21585952 TI - Development of microsatellite markers in a large perennial herb, Veratrum album ssp. oxysepalum. AB - We developed 11 polymorphic microsatellite [simple sequence repeat (SSR)] loci from genomic DNA of Veratrum album ssp. oxysepalum using a dual-suppression polymerase chain reaction technique and an improved method. These markers, with four to 17 alleles per locus, identified 47 genotypes in 48 samples collected from a population in Hokkaido, Japan. The observed and expected heterozygosities ranged from 0.042 to 0.938 and from 0.448 to 0.909, respectively. These SSR markers will be available to identify genets and evaluate genetic diversity of V. album ssp. oxysepalum. PMID- 21585953 TI - Isolation and characterization of microsatellite markers in Acca sellowiana (Berg) Burret. AB - Acca sellowiana has commercial potential due to the quality and the unique flavor of its fruit. Conservation of natural populations and management of breeding programmes would benefit from the availability of molecular markers that could be used to characterize levels and distribution of genetic variability. Thus, 13 microsatellite markers were developed from an enriched genomic library of A. sellowiana. They were characterized using 40 samples. The expected and observed heterozygosities ranged from 0.513 to 0.913 and from 0.200 to 0.889, respectively. These are the first microsatellite loci characterized from A. sellowiana that will contribute to improve researches on its genetic conservation, characterization and breeding. PMID- 21585954 TI - Development of nine polymorphic microsatellite loci in the spined loach, Cobitis taenia, and cross-species amplification in the related species C. elongatoides, C. taurica and C. tanaitica. AB - Nine polymorphic microsatellite loci were developed for the spined loach, Cobitis taenia (Teleostei: Cobitidae). The loci were validated using 50 individuals from a population in Belgium. Moderate to high levels of polymorphism were detected (two to 11 alleles). In addition, most markers amplified successfully in three closely related taxa that are known to hybridize with C. taenia: C. elongatoides, C. taurica and C. tanaitica. Some of the loci are most likely diagnostic among species. These markers will be valuable for the study of the historical and contemporary interactions within C. taenia and the Cobitis species complex. PMID- 21585955 TI - Twelve new polymorphic microsatellite loci and PCR multiplexing in the whitefly, Bemisia tabaci. AB - Twelve new dinucleotide microsatellite loci of the whitefly, Bemisia tabaci, were obtained from enriched genomic libraries. Three polymerase chain reaction multiplex sets comprising three, five and four loci were optimized and characterized across 133 B. tabaci females from Israeli rearings and natural populations collected in four Mediterranean countries (Tunisia, France, Spain and Morocco). There were three to 24 alleles per locus and the observed heterozygosity was from 0.084 to 0.420. Deviation from Hardy-Weinberg equilibrium was detected at four loci associated with significant heterozygote deficiencies due to null alleles and presence of subpopulations that were mostly in the Tunisian sample. The 12 loci carried independent information. PMID- 21585956 TI - Development and characterization of 10 microsatellite markers for the semi evergreen tree species, Ligustrum ovalifolium (Oleaceae). AB - Ligustrum ovalifolium is a semi-evergreen tree distributed in the western part of Japan and southern Korea. This species contains an insular endemic variety, L. ovalifolium var. pacificum; this variety occurs only on the Izu Islands located south of the Japanese mainland Honshu. We isolated 10 polymorphic microsatellite loci from the species, and characterized them for 21 individuals from a population of L. ovalifolium. The primers developed in this study yielded an average 12.2 alleles per locus and an average expected heterozygosity of 0.78. These markers will be powerful tools for studying the genetic differentiation within the species. PMID- 21585957 TI - Application of universally amplifying plastid primers to environmental sampling of a stream periphyton community. AB - To demonstrate the utility of universal plastid primers for probing of environmental samples, we extracted DNA from a tropical stream periphyton community and created two environmental clone libraries. We demonstrate the recovery of DNA sequences corresponding to the major groups of algae observed microscopically in the sample, illustrating the utility of these primers for analysis of environmental samples. Using a touchdown polymerase chain reaction technique, almost 99% of recovered sequences correspond to plastid-containing or cyanobacterial taxa, which allows algae to be targeted to the almost complete exclusion of noncyanobacterial prokaryotes and nonplastid-containing eukaryotes. PMID- 21585958 TI - New microsatellite loci isolated from the field cricket Gryllus bimaculatus characterized in two cricket species, Gryllus bimaculatus and Gryllus campestris. AB - We have developed a new set of 27 polymorphic markers for each of two cricket species, Gryllus bimaculatus and Gryllus campestris. Initially, 14 published G. bimaculatus loci were tested in G. campestris; however, only five loci were polymorphic. Therefore, we isolated an additional 50 new microsatellite loci from G. bimaculatus and tested these in both species. In a minimum of 20 individuals, 27 of the new loci were polymorphic in G. bimaculatus and 25 in G. campestris. PMID- 21585959 TI - Microsatellite loci isolated from the tropical tree Hymenaea courbaril L. (Fabaceae). AB - We developed 11 microsatellite markers for Hymenaea courbaril for the purpose of studying spatial genetic structure and gene flow. The microsatellite loci were screened in 44 trees from two populations. All loci were polymorphic, exhibiting between two and 16 alleles, and levels of expected heterozygosity from 0.174 to 0.909. Departures from Hardy-Weinberg equilibrium were detected for all loci in one population. The estimated null allele frequency is low or moderate. No locus combinations exhibited linkage disequilibrium. PMID- 21585960 TI - Ten microsatellite loci from Solms-laubachia eurycarpa (Brassicaceae). AB - Solms-laubachia eurycarpa is a medicinal herb endemic to the Hengduan Mountains region of south-central China. We screened a partial genomic library enriched for microsatellites and characterized 10 polymorphic loci for S. eurycarpa. The number of alleles per locus ranged from five to 15, with an average of 9.6. The observed and expected heterozygosities ranged from 0.2 to 0.725 and from 0.585 to 0.871, respectively. Amplification in closely related taxa was successful for most loci. The results indicate significant potential for the utility of these markers in studying the population genetics of S. eurycarpa and related species. PMID- 21585961 TI - Microsatellite markers for the red band needle blight pathogen, Dothistroma septosporum. AB - Twelve microsatellite markers were developed for population analyses of the fungal pathogen, Dothistroma septosporum. Intersimple sequence repeat polymerase chain reaction (ISSR-PCR) and an enrichment protocol (fast isolation by amplified fragment length polymorphism of sequences containing repeats [FIASCO]) were both used to identify 28 unique microsatellite regions in the genome. From 22 primer pairs designed, 12 were polymorphic. These markers, screened on two populations representing 42 isolates, produced 40 alleles across all loci with an allelic diversity of 0.09-0.76 per locus. Cross-species amplification showed variable success with Dothistroma rhabdoclinis and Mycosphaerella dearnessi and some sequence variation within isolates of Dothistroma pini. These markers will be used to further study the population structure and diversity of D. septosporum. PMID- 21585962 TI - Isolation and characterization of 13 microsatellite markers for the viviparous surfperch Ditrema temmincki (Embiotocidae) and cross-species amplification. AB - Thirteen microsatellite loci were isolated from a size-selected genomic library of the surfperch (Ditrema temmincki Bleeker). All loci displayed a high degree of length polymorphism, as observed in the total number of alleles per locus (two to 23) and a high degree of estimated heterozygosity, ranging from 0.080 to 0.893. The primers developed for D. temmincki were also tested for their ability to amplify homologous sequences in D. viride and Neoditrema ransonetii. Distinct differences were observed among three species of surfperches, in both genetic variability and the frequency distribution of the alleles. PMID- 21585963 TI - A microsatellite DNA toolkit for studying population structure in Apis mellifera. AB - We present a set of 18 microsatellite DNA markers that can be run in two multiplex polymerase chain reactions as standard tool for assessing molecular ecological problems in honeybees (Apis mellifera). In addition to a set of six unlinked loci testing for classical population genetic parameters, we present three sets of four tightly linked loci, each located on three different chromosomes. These linked markers are useful for determining the number of colonies in a population as well as the parentage of drones and workers. Moreover, the tool kit can test for various modes of natural selection in honeybee populations. PMID- 21585964 TI - Characterization of 13 microsatellite loci for the deep-sea coral, Lophelia pertusa (Linnaeus 1758), from the western North Atlantic Ocean and Gulf of Mexico. AB - A suite of 13 polymorphic tri- and tetranucleotide microsatellite loci were isolated from the ahermatypic deep-sea coral, Lophelia pertusa. Among 51 individuals collected from three disjunct oceanic regions, allelic diversity ranged from six to 38 alleles and averaged 9.1 alleles per locus. Observed heterozygosity ranged from 9.1 to 96.8% and averaged 62.3% in the Gulf of Mexico population. For some loci, amplification success varied among collections, suggesting regional variation in priming site sequences. Four loci showed departures from Hardy-Weinberg equilibrium in certain collections which may reflect nonrandom mating. PMID- 21585965 TI - Microsatellite DNA markers in the giant freshwater prawn, Macrobrachium rosenbergii: a tool for genetic analysis. AB - Eight microsatellite loci were identified and characterized in the commercially important giant freshwater prawn, Macrobrachium rosenbergii. The microsatellite loci were detected by the random screening for dinucleotide repeat units within a partial genomic library developed for the species with biotinylated probes (CA)(15) , (AT)(15) and (GA)(15) . All the eight loci were found to be polymorphic. The number of alleles and observed heterozygosities per locus ranged between three to 16 and 0.22 to 0.71, respectively. These microsatellite markers will be useful for the conservation and management of wild and cultured stocks and population genetic studies of freshwater prawn. PMID- 21585966 TI - Isolation and characterization of microsatellite loci from the yellow-eyed penguin (Megadyptes antipodes). AB - Twelve microsatellite loci were isolated and characterized in the endangered yellow-eyed penguin (Megadyptes antipodes) using enriched genomic libraries. Polymorphic loci revealed two to eight alleles per locus and observed heterozygosity ranged from 0.21 to 0.77. These loci will be suitable for assessing current and historical patterns of genetic variability in yellow-eyed penguins. PMID- 21585967 TI - Ten polymorphic microsatellite loci for the trematode Curtuteria australis (Echinostomatidae). AB - Ten polymorphic loci were isolated and characterised from the intertidal New Zealand trematode Curtuteria australis. This common parasite manipulates the burrowing behaviour of its abundant bivalve host Austrovenus stutchburyi, with cascading impacts on the biodiversity of intertidal communities. Observed heterozygosities of the 10 loci ranged from 0.500 to 0.905, and three to 14 alleles were detected in 24 trematode metacercariae. These loci are currently being used to investigate the molecular ecology of this species within its intermediate hosts. PMID- 21585968 TI - Development of eight polymorphic microsatellites for a Zn/Cd hyperaccumulator Sedum alfredii Hance (Crassulaceae). AB - Sedum alfredii is a Zn/Cd hyperaccumulator distributed in East Asia. A total of eight polymorphic microsatellite markers were developed. These loci were screened in 25 individuals from one heavy metal-tolerant population and one nontolerant population, respectively. The average allele number of these markers was 5.25 per locus, ranging from two to nine. Population-specific alleles were found at each locus. The observed and expected heterozygosities ranged from 0.000 to 0.640 and from 0.451 to 0.819. Significant deviation from Hardy-Weinberg equilibrium was detected at both the species and the population level. No significant linkage disequilibrium was detected at population level. PMID- 21585969 TI - Development of microsatellite markers for the grapevine fungal pathogen Phaeomoniella chlamydospora. AB - Twenty polymorphic microsatellite markers from microsatellite-enriched genomic DNA of the grapevine fungal pathogen, Phaeomoniella chlamydospora, were developed and characterized. The markers were used to genotype isolates from Australia and from Europe/Eurasia. The number of alleles per locus ranged from two to 11. Gene diversity per locus ranged from 0.08 to 0.63 among Australian isolates, and from 0.2 to 0.77 among isolates from Europe/Eurasia, demonstrating the suitability of these markers for population genetic studies of P. chlamydospora. Eighteen of the 20 markers also amplified a product in the closely related Phaeoacremonium aleophilum. PMID- 21585970 TI - Eighteen new tetranucleotide microsatellite DNA markers for Coregonus lavaretus cloned from an alpine lake population. AB - We developed 18 polymorphic microsatellite markers for Coregonus lavaretus from genomic libraries enriched for (GACA)(n) and (GATA)(n) repeat sequences. Emphasis was placed on developing highly polymorphic, perfect repeats. These loci were screened in 69 individuals from two alpine populations in Austria. Allelic variation was high with nine to 37 alleles per locus and expected heterozygosities ranging from 0.37 to 0.95. The high level of polymorphism revealed by these loci will be relevant for population studies in context to the evolutionary history of this species. PMID- 21585971 TI - Isolation and characterization of polymorphic microsatellite markers from Asian malaria mosquito Anopheles sinensis (Diptera: Culicidae). AB - Microsatellite-containing region were isolated and characterized in Anopheles sinensis, a primary vector of malaria parasites in Asia. An enrichment protocol yielded 252 microsatellite sequences. We designed primers to amplify 20 unique microsatellites, 14 of which amplify cleanly and were polymorphic. A survey of 24 individuals showed that 12 loci are highly variable with the number of alleles ranging from two to 11, and expected heterozygosity ranging from 0.116 to 0.903. These markers will be useful for population genetic studies and genome mapping in A. sinensis. PMID- 21585972 TI - Characterization of 15 polymorphic microsatellite markers in the freshwater snail Aplexa marmorata (Mollusca, Gastropoda). AB - We describe 15 new variable microsatellites in the freshwater snail Aplexa (Physa) marmorata, as well as conditions for multiplexing and simultaneous genotyping sets of loci. Two to 11 alleles were detected per locus over the five populations studied, and up to eight alleles per locus and population. The observed heterozygosity was extremely low, most probably as the consequence of high selfing rates. The genetic differentiation among populations was large. These markers will constitute efficient tools for investigating the population structure in fragmented habitats. Cross-species amplification in three Physa species (P. acuta, P. fontinalis and P. gyrina) was rather unsuccessful. PMID- 21585973 TI - Isolation and characterization of polymorphic tetranucleotide microsatellite loci in the pelagic perciform fish Pomatomus saltatrix (Linnaeus, 1766) from South Africa. AB - Eight polymorphic microsatellite loci, containing simple tetranucleotide repeats, were isolated de novo from a Pomatomus saltatrix partial genomic library using the fast isolation by amplified fragment length polymorphism of sequences containing repeats protocol. These loci were further characterized in 100 individuals from two putative populations off the South African east coast. The loci are highly polymorphic with 18-37 alleles (on average 24 alleles/locus) and the observed heterozygosity in both populations was high (0.79). These loci will be used to assess population structuring in P. saltatrix along the southern African coast with consideration of implications for future management of this important linefish species. PMID- 21585974 TI - Characterization of microsatellite loci for the critically endangered cactus Ariocarpus bravoanus. AB - Ariocarpus bravoanus is common in trade but critically endangered in its natural habitat. With the ultimate aim of developing a certification scheme to aid in the conservation of this species, we have isolated A. bravoanus microsatellites from a nonenriched library. Fifty-four sequences contained a microsatellite array, of which eight were polymorphic among 23 individuals, 20 from one population and three plants from trade. PMID- 21585975 TI - Polymorphic tetranucleotide microsatellites for Cope's giant salamander (Dicamptodon copei) and Pacific giant salamander (Dicamptodon tenebrosus). AB - We present primers and amplification conditions for 15 microsatellite loci developed for the Cope's giant salamander (Dicamptodon copei), 14 of which are tetranucleotide repeats. Cross-species amplification revealed 10 of these loci to also be polymorphic in the Pacific giant salamander (Dicamptodon tenebrosus). Several loci produced nonoverlapping allelic ranges between the two species and may be useful in species identification. These polymorphic microsatellite loci are potentially useful for future studies of population genetics in dicamptodontid salamanders. PMID- 21585976 TI - Isolation and characterization of microsatellite loci for Hymenaea courbaril and transferability to Hymenaea stigonocarpa, two tropical timber species. AB - Hymenaea courbaril is a tropical timber species, intensely exploited and found in the Amazon, Atlantic Forest and Brazilian Cerrado biome. Nine highly polymorphic microsatellite loci were developed from a genomic library enriched for AG/TC repeats. In a total of 41 individuals, from two natural populations, seven to 13 alleles per locus were detected and expected heterozygosity ranged from 0.75 to 0.90. Seven loci were effectively transferred to Hymenaea stigonocarpa. High levels of polymorphism make the present primers useful for population genetic studies and are a powerful tool to investigate mating system, gene flow and spatial genetic structure. PMID- 21585977 TI - Isolation and characterization of microsatellite loci in Pimelodus maculatus (Siluriformes: Pimelodidae). AB - To evaluate genetic variability in Pimelodus maculatus, a small migratory catfish common in South America, we isolated and characterized several microsatellite markers from individuals collected from a population in the River Grande (Brazil). A total of 11 loci were obtained and analyzed. All the loci were polymorphic, with the number of alleles ranging from three to 27 per locus. Observed and expected heterozygosities ranged from 0.5 to 0.89 and from 0.53 to 0.95, respectively. These polymorphic markers can be used as effective tools to study the genetic structure in populations of this species. PMID- 21585978 TI - Characterization of microsatellite loci in the Hawaiian endemic shrub Schiedea adamantis (Caryophyllaceae) and amplification in related species and genera. AB - Schiedea adamantis is a rare, perennial shrub endemic to the Hawaiian island of Oahu where it consists of a single population. Using a nonradioactive protocol, 12 microsatellite primers were developed that consisted of di-, tri-, penta- and hexanucleotide repeats. Using multiplexed reactions, all but two primers exhibited polymorphism with an average of 3.67 alleles per primer. Most primers also amplified in 28 additional Schiedea species, revealing wide applicability across the genus; eight and nine primers also amplified in Honckenya peploides and Silene lanceolata, respectively, related genera in the Caryophyllaceae. This is the first known report of microsatellite primers developed in Schiedea. PMID- 21585979 TI - Isolation and characterization of nine microsatellite loci from the pike-perch, Sander lucioperca (Linnaeus, 1758). AB - In order to facilitate studies on the genetic structure of wild populations as well as to monitor genetic changes in cultured stocks, nine polymorphic microsatellite loci were isolated from pike-perch (Sander lucioperca). Single loci allele numbers varied between two (loci MSL-3 and MSL-7) and six (loci MSL-1 and MSL-2), and observed heterozygosities ranged from 0.36 (locus MSL-2) to 1.00 (locus MSL-9) in a test panel of 25 individuals. Only one pair of loci (MSL-5 and MSL-8) displayed significant linkage disequilibrium after sequential Bonferroni corrections. Hardy-Weinberg tests revealed significant excesses of heterozygotes at three loci (MSL-1, MSL-7, and MSL-9). PMID- 21585980 TI - Isolation and characterization of 11 polymerase chain reaction primers for microsatellite loci for the Chilean marine isopod Excirolana hirsuticauda. AB - The Chilean isopod Excirolana hirsuticauda is a marine benthic brooder with wide distributional range and low potential for long-distance dispersal. Eleven microsatellite markers were developed for E. hirsuticauda using enriched libraries. Characterization of those loci in 35 individuals from Playa Blanca beach showed high allelic diversity with a mean of 10.9 alleles per locus. The average expected and observed heterozygosities were 0.65 and 0.41. These microsatellite loci are the first published for any Excirolana species and should be useful to study the genetic structure of E. hirsuticauda. PMID- 21585981 TI - Characterization of eight microsatellite loci in the Galapagos endemic land snail Bulimulus reibischi, and their cross-species amplification. AB - Variation in and amplification conditions for eight polymorphic microsatellite loci initially identified from Bulimulus akamatus, a pulmonate land snail from Galapagos, are described. Intraspecific polymorphism and heterozygosity of the eight markers were studied in 19 populations of Bulimulus reibischi, a closely related species of B. akamatus. Furthermore, the eight loci were also cross amplified in six other closely related bulimulid species. The number of alleles across populations of B. reibischi at six loci is moderate (three to 10), but considerable for two other loci (19 and 20). There is no strong evidence for linkage among any of the loci examined. PMID- 21585982 TI - Isolation and characterization of microsatellite loci for the European tree frog (Hyla arborea). AB - We developed 11 new microsatellite markers for the European tree frog (Hyla arborea), and tested patterns of polymorphism in 54 adults (27 males and 27 females) from two ponds close to Lausanne (Western Switzerland). One marker was sex linked and two pairs displayed linkage disequilibrium. Comparisons of allele numbers with heterozygosity values support a stepwise-mutation model at neutral equilibrium, with mutation rates spanning nearly two orders of magnitude. These markers will prove useful for population genetic studies and fine-scale investigations requiring genetic assignment techniques. PMID- 21585983 TI - Isolation and characterization of novel microsatellites from the critically endangered hawksbill sea turtle (Eretmochelys imbricata). AB - We isolated and characterized 12 microsatellite loci from the hawksbill sea turtle (Eretmochelys imbricata). The loci exhibited a variable number of alleles that ranged from three to 14 with an average observed heterozygosity of 0.70 (SD 0.18) across 40 hawksbill turtles from the Caribbean. The polymorphism exhibited individually and in combination makes them suitable for fine-scale genetic studies. In particular, the low probability of identity and high paternity exclusion of these markers makes them highly useful for parentage and relatedness studies. These new markers greatly increase the power of genetic studies directed towards the conservation of this endangered species. PMID- 21585984 TI - Identification and characterization of 15 polymorphic microsatellite loci in the western drywood termite, Incisitermes minor (Hagen). AB - Despite recognition of the western drywood termite, Incisitermes minor (Hagen), as one of the most economically important and destructive termite species in the USA, both its population and colony breeding structure genetically remain unclear. Here, we present primer sequences and initial characterization for 15 polymorphic microsatellite loci. In a sample of 30 individuals, representing six geographically distinct locations collected in California, USA, three to 15 alleles were detected segregating per locus. Within a single population observed heterozygosity ranged from 0.050 to 0.866. PMID- 21585985 TI - Development of polymorphic microsatellite markers for the New Zealand black stilt (Himantopus novaezelandiae) and cross-amplification in the pied stilt (Himantopus himantopus leucocephalus). AB - Eight polymorphic microsatellite primer pairs were developed for the critically endangered New Zealand black stilt, Himantopus novaezelandiae, representing the first microsatellite markers available for birds in the family Recurvirostridae. The number of alleles ranged from two to four per locus. Observed and expected heterozygosities ranged from 0.30 to 0.80 and from 0.37 to 0.70, respectively. All eight loci were polymorphic in the related species Himantopus himantopus leucocephalus, indicating these primer pairs may be useful for additional taxa in the globally distributed genus Himantopus. PMID- 21585986 TI - Isolation of 10 tetranucleotide microsatellite loci in the blackcap (Sylvia atricapilla). AB - We isolated 10 polymorphic microsatellite DNA loci from the blackcap (Sylvia atricapilla) and optimized them for future studies of population differentiation in populations with different migration strategies in southwestern Germany. The loci were screened for polymorphism using 178 individuals from two populations in Germany and Spain. The primers amplified highly variable loci characterized by two to 19 alleles per locus and their observed and expected heterozygosities range from 0.47 to 0.81 and from 0.50 to 0.91, respectively. PMID- 21585987 TI - Isolation and characterization of polymorphic microsatellites for the bastard sole (Microchirus azevia). AB - The bastard sole (Microchirus azevia) is a species of commercial interest in Spain. Nevertheless, little information is currently available about the genetic characteristics of wild populations. In this survey, we have developed eight new microsatellites using an enriched genome library protocol. Primers were screened on a total of 54 individuals from two wild populations (Mediterranean and Atlantic) from the south coast of Spain, revealing six to 18 alleles per locus with expected heterozygosities ranging from 0.51 to 0.94. These markers can potentially be useful tools for use in population genetic studies. PMID- 21585988 TI - Isolation and characterization of microsatellite loci in Epidendrum puniceoluteum, an endemic orchid from the Atlantic Rainforest. AB - Epidendrum puniceoluteum is an endemic orchid of Atlantic Rainforest, restricted to few populations only due to the destruction and fragmentation of its native habitat. Here, we report on the development of 10 microsatellite markers isolated from this orchid species. Genetic variability was characterized in two distant populations from Brazil coast. The number of alleles observed for each locus ranged from two to 12 and with an average of 6.4 alleles per locus. These microsatellites should be valuable tools for studying both fine-scale genetic structure of scattered E. puniceoluteum population and patterns will be useful genetic markers for other closely related taxa. PMID- 21585989 TI - Isolation and characterization of new polymorphic microsatellite loci in the mixotrophic orchid Limodorum abortivum L. Swartz (Orchidaceae). AB - Here, we report the isolation and characterization of 11 polymorphic microsatellites in Limodorum abortivum. Allele variability has been characterized in three populations from Southern Italy and France. The number of alleles ranged from one to six per locus with an average of 3.8 alleles per locus. Observed and expected heterozygosity values ranged from 0.000 to 1.000 and from 0.492 to 0.806, respectively, with striking differences among populations. These microsatellites should be valuable tools for studying fine-scale genetic structure of scattered Limodorum abortivum populations, patterns of relationship with closely related taxa and the evolutionary ecology of its mycorrhizal interactions. PMID- 21585990 TI - Microsatellite markers for the fungal banana pathogens Mycosphaerella fijiensis, Mycosphaerella musicola and Mycosphaerella eumusae. AB - We developed a total of 50 microsatellite markers for the three fungal pathogens causing the most important leaf spot diseases of banana: 32 loci for Mycosphaerella fijiensis are presented, and nine loci each for Mycosphaerella musicola and Mycosphaerella eumusae. All these loci were polymorphic within each species on a sample of isolates collected from various locations around the world. Within M. fijiensis and M. musicola, most of the loci tested (> 80%) in a sample of isolates from a single location in Cameroon were also polymorphic. Multiplex polymerase chain reaction systems were developed with 15 loci for M. fijiensis. PMID- 21585991 TI - Microsatellite DNA markers for the Chinese wood frog (Rana chensinensis) and tests for their cross-utility in 15 ranid frog species. AB - We developed 22 microsatellite markers for the Chinese wood frog (Rana chensinensis) to study the impact of landscape features on its population structure. Thirty-four individuals from one breeding site were examined and 14 loci were polymorphic. The number of alleles, expected heterozygosity and observed heterozygosity varied from two to 14, from 0.0833 to 0.9118, and from 0.1376 to 0.8667, respectively. Cross-species amplification was tested for 15 ranid frog species. The Plateau brown frog, Rana kukunoris (n = 23), was successfully amplified at 18 loci, and 15 were polymorphic with number of alleles varying from two to 18. Ten other species were also amplified at a limited number of loci. PMID- 21585992 TI - Identification and characterization of nuclear microsatellite loci in the aquatic moss Platyhypnidium riparioides (Brachytheciaceae). AB - Eight microsatellite loci from the aquatic moss Platyhypnidium riparioides were identified using the method of microsatellite-enriched libraries. Polymorphism was assessed in a sample of four populations of 20 individuals each from four streams of the Meuse hydrographic basin in southern Belgium. The markers amplified three to seven alleles per locus. Comparison of observed and expected heterozygosities as well as F-statistics (F(ST) = 0.62) reveals a significant genetic differentiation among populations. These markers will be useful for further investigation of population genetic structure and diversity at different nested spatial scales. PMID- 21585993 TI - Ten polymorphic microsatellite DNA markers for the platypus, Ornithorhynchus anatinus. AB - We identified and optimized 10 microsatellite loci for the platypus, Ornithorhynchus anatinus (Monotremata: Ornithorhynchidae), and screened 21 individuals from the southern tablelands area of New South Wales, Australia. Each polymorphic locus possessed between two and 12 alleles with observed heterozygosities between 0.118 and 0.950. The intent of this effort was to provide informative loci for studies on the population genetics of this species. PMID- 21585994 TI - Development of polymorphic microsatellite markers for Cryptococcus neoformans. AB - Cryptococcus neoformans is a haploid basidiomycetous yeast that causes life threatening infections in patients with and without impaired immune function. Present typing systems for C. neoformans are limited by either poor standardization or high cost. We present eleven microsatellite loci that were developed from the published genomes of C. neoformans var. neoformans, and are applicable to the varieties and hybrids within C. neoformans. PMID- 21585995 TI - Development of primers to amplify mitochondrial DNA control region of Old World porcupines (subgenus Hystrix). AB - Eight primers were developed for the amplification of mitochondrial DNA control region of Old world porcupines (subgenus Hystrix). Successful amplifications of low-quality DNA extracted from old (12 years old) and recent quills were performed, thus facilitating field sampling. Successful cross-species amplifications were obtained for Hystrix africaeaustralis, H. cristata and H. indica. Length and structure of mitochondrial DNA control region were analysed and its usefulness as genetic marker for interspecific and population investigation was discussed. PMID- 21585996 TI - Development and characterization of microsatellite markers in Populus euphratica (Populaceae). AB - In this study, we developed 12 microsatellite loci for Populus euphratica and checked their variability in 27 individuals. The number of alleles for 12 loci ranged from five to nine, the observed and expected heterozygosities ranged from 0.32 to 0.48 and from 0.53 to 0.67. Frequencies of null alleles of all loci are not significantly greater than zero. None of the loci showed significant deviation from Hardy-Weinberg equilibrium. No significant linkage disequilibrium was observed between pairs of studied loci. These markers are useful in studies of population genetic structure of P. euphratica. PMID- 21585997 TI - Molecular markers to determine the ecological fate of Bacillus thuringiensis ssp. kurstaki. AB - A set of DNA markers was developed that successfully identifies Bacillus thuringiensis ssp. kurstaki (Btk) when screened against other Bacillus species and subspecies. These subspecies-specific primer sets allowed detection and characterization of Btk within an environmental background that contained many Bacillus species. Because Btk is used as an active ingredient in many commercial formulations, yet is not naturally widely distributed in North America or Europe, these markers will prove useful in investigations on the environmental persistence and ecological fate of Btk. PMID- 21585998 TI - Polymorphic microsatellite markers for the Mojave desert tortoise, Gopherus agassizii. AB - We describe primers and polymerase chain reaction (PCR) conditions to amplify 14 tri- and tetranucleotide microsatellite loci for the Mojave desert tortoise (Gopherus agassizii). Across three populations (87 individuals) located in the Mojave Desert, USA, the markers yielded a range of four to 33 alleles and an average observed heterozygosity of 0.733 (range 0.433 to 0.933). We neither detected linkage disequilibrium between any pair of loci nor did we find a consistent pattern of deviation from Hardy-Weinberg equilibrium. These microsatellites are designed for PCR multiplexing, and provide higher throughput capacity to aid in conservation genetics studies for this threatened species. PMID- 21585999 TI - Isolation and characterization of 17 polymorphic microsatellite loci for the three-toed woodpecker (Picoides tridactylus). AB - We describe primers and polymerase chain reaction conditions to amplify 17 di-, tri- and tetranucleotide microsatellite loci from the three-toed woodpecker (Picoides tridactylus). The primers were tested on 26 to 30 individuals from a single population breeding in southern Finland. The developed primer pairs yielded an average of 7.6 alleles per locus (range two to 15), an average observed heterozygosity of 0.69 (range 0.07 to 0.97), and an average polymorphic information content of 0.68 (range 0.06 to 0.90). PMID- 21586000 TI - New microsatellite markers isolated from mungbean (Vigna radiata (L.) Wilczek). AB - In this study, we reported the isolation and analysis of new polymorphic microsatellites in mungbean (Vigna radiata (L.) Wilczek). Twelve out of 210 primer pairs screened in 30 mungbean accessions gave polymorphism. The polymorphic markers detected two to three alleles per locus with an average of 2.08. Observed heterozygosity varied from 0 to 0.133, while expected heterozygosity ranged from 0.095 to 0.498. Tests for Hardy-Weinberg equilibrium (HWE) and pairwise linkage disequilibrium of the polymorphic loci revealed that all loci except MB-SSR14 significantly departed from HWE and four pairwise combinations, viz. MB-SSR14 vs. MB-SSR42, MB-SSR42 vs. MB-SSR87, MB-SSR114 vs. MB SSR121, and MB-SSR175 vs. MB-SSR231 significantly deviated from linkage disequilibrium. The markers are being used to study genetic diversity and genome mapping of mungbean. PMID- 21586001 TI - Polymorphic microsatellites in nene, the endangered Hawaiian goose (Branta sandvicensis). AB - The nene (Branta sandvicensis) is an endangered Hawaiian goose endemic to the Hawaiian Islands. The nene nearly went extinct in the mid-19.00s and the majority of the approximately 1300 individuals currently in Hawai'i are descendants from less than 30 birds. The low adult breeding success and juvenile survival is likely due, in part, to inbreeding depression in wild individuals. Thirty-eight microsatellite primer sets developed in nene, Canada goose, and waterfowl species provided 8 polymorphic loci. Four of these polymorphic loci exhibited only two alleles, which is likely a reflection of the high inbreeding in this species. PMID- 21586002 TI - Microsatellite loci for laticaudine sea kraits. AB - We report the development of 11 polymorphic microsatellite loci (three dinucleotides, one trinucleotide and seven tetranucleotides) that are useful for the detection of population subdivision and the study of philopatry, migration and mating biology in laticaudine sea kraits Laticauda saintgironsi and Laticauda laticaudata. Five loci are highly polymorphic and amplify reliably in both L. saintgironsi and L. laticaudata. An additional three are useful in L. saintgironsi and another three in L. laticaudata. PMID- 21586003 TI - A large panel of novel microsatellite markers for the bank vole (Myodes glareolus). AB - We describe a set of 66 highly polymorphic microsatellite loci isolated from the bank vole, Myodes (Clethrionomys) glareolus. These microsatellites were characterized for a long-term study on periodically fluctuating density of the bank vole population in Central Finland. We detected six to 38 alleles per locus in the population sampled at two different density phases, and the levels of observed and expected heterozygosities varied between 0.17 and 1.00, and between 0.72 and 0.95, respectively. This microsatellite panel serves as an informative tool for population and molecular genetic studies. PMID- 21586004 TI - Molecular taxonomy of Brazilian tyrant-flycatchers (Passeriformes: Tyrannidae). AB - The tyrannids are one of the most diverse groups of birds in the world, and the most numerous suboscine family in the Neotropics. Reflecting such diversity, many taxonomic issues arise in this group, mainly due to morphological similarities, even among phylogenetically distant species. Other issues appear at higher taxonomic levels, mostly brought up by genetic studies, making systematics a rather inconclusive issue. This study looks into the use of DNA barcodes method to discriminate and identify Tyrannidae species occurring in the Atlantic Forest and Cerrado biomes of Brazil. We analysed 266 individuals of 71 tyrant-flycatcher species from different geographical locations by sequencing 542 bp of the mtDNA COI gene. The great majority of the analysed species showed exclusive haplotypes, usually displaying low intraspecific diversity and high interspecific divergence. Only Casiornis fuscus and Casiornis rufus, suggested in some studies to belong to a single species, could not be phylogenetically separated. High intraspecific diversity was observed among Elaenia obscura individuals, which can suggest the existence of cryptic species in this taxon. The same was also observed for Suiriri suiriri, considered by some authors to comprise at least two species, and by others to be divided into three subspecies. Additionally, the use of sequences from voucher specimens allowed us to correct four misidentifications that had happened in the field. Our findings suggest a great power of the COI barcodes to discriminate species of the Tyrannidae family that are found in Brazil. PMID- 21586005 TI - Exploring the species diversity of Trichoderma in Norwegian drinking water systems by DNA barcoding. AB - A total of 123 Trichoderma strains were isolated from Norwegian surface-sourced drinking water. The water samples included raw water, treated water, and water from private homes and hospital installations. Trichoderma species are difficult to differentiate morphologically, but recent molecular identification tools, including DNA barcoding, successfully distinguish between closely related species. The diversity of Trichoderma spp. was explored by DNA sequencing of internal transcribed spacer (ITS) and translation elongation factor 1 alpha (TEF 1alpha). Sequence identification was performed in the TrichOKEY version 2.0 barcode program and in the multilocus similarity search database TrichoBLAST, combined with traditional blast searches in the EMBL/GenBank. A total of 11 known Trichoderma/Hypocrea species were identified. In addition, one group of unidentified Trichoderma strains was found to represent a separate, strongly supported subclade within the Pachybasium'A'/Hamatum clade, based on their TEF 1alpha haplotypes. Trichoderma viride comprised 49% of the identified strains, and was represented by four and eight slightly different ITS and TEF-1alpha haplotypes, respectively. Approximately 22% of the surface-derived water samples were positive for T. viride, and the species was frequently isolated throughout the surface-sourced drinking water distribution system. The results indicate that a broad range of Trichoderma species are present in Norwegian surface-sourced drinking. Water treatment has minor effect in removing Trichoderma from raw water, and active growth in the water distribution system is likely to occur. PMID- 21586006 TI - Species identification of aphids (Insecta: Hemiptera: Aphididae) through DNA barcodes. AB - A 658-bp fragment of mitochondrial DNA from the 5' region of the mitochondrial cytochrome c oxidase 1 (COI) gene has been adopted as the standard DNA barcode region for animal life. In this study, we test its effectiveness in the discrimination of over 300 species of aphids from more than 130 genera. Most (96%) species were well differentiated, and sequence variation within species was low, averaging just 0.2%. Despite the complex life cycles and parthenogenetic reproduction of aphids, DNA barcodes are an effective tool for identification. PMID- 21586007 TI - DNA barcoding discriminates echinoderm species. AB - DNA barcode sequences (a 657-bp segment of the mtDNA cytochrome oxidase I gene, COI) were collected from 191 species (503 specimens) of Echinodermata. All five classes were represented: Ophiuroidea, Asteroidea, Echinoidea, Holothuroidea and Crinoidea. About 30% of sequences were collected specifically for this study, the remainder came from GenBank. Fifty-one species were represented by multiple samples, with a mean intraspecific divergence of 0.62%. Several possible instances of cryptic speciation were noted. Thirty-two genera were represented by multiple species, with a mean congeneric divergence of 15.33%. One hundred and eighty-seven of the 191 species (97.9%) could be distinguished by their COI barcodes. Those that could not were from the echinoid genus Amblypneustes. Neighbour-joining trees of COI sequences generally showed low bootstrap support for anything other than shallow splits, although with very rare exceptions, members of the same class clustered together. Two ophiuran species, in both nucleotide and amino acid neighbour-joining trees, grouped loosely as sister taxa to Crinoidea rather than Ophiuroidea; sequences of these two species appear to have evolved very quickly. Results suggest that DNA barcoding is likely to be an effective, accurate and useful method of species diagnosis for all five classes of Echinodermata. PMID- 21586008 TI - DNA barcoding of eight North American coregonine species. AB - Coregonine fishes have a circumpolar distribution in the Arctic and sub-Arctic Northern Hemisphere. This subfamily of Salmonidae consists of three genera: Prosopium, Stenodus and Coregonus, including over 30 species. Many species overlap spatially and are difficult to distinguish based on morphological characteristics, especially as larvae or juveniles. Here we present a method for rapid and cost-effective species identification for representatives of the three genera based on sequence variation at the mitochondrial cytochrome c oxidase subunit I gene (COI). We examined eight species common to North America with distributional overlap in Alaska. Mean pairwise sequence divergence for all eight species was 7.04% and ranged from 0.46% to 14.23%. This sequence variation was used to develop a genetic assay based on restriction fragment length polymorphism. In a blind test, this assay provided correct species assignment for 48 of 49 individuals representing all eight species. The single incorrect assignment may reflect hybridization between two closely related species. This DNA barcode-based assay promises to aid fishery managers and researchers by providing a cost-effective alternative to large-scale sequence analysis for identification of North American coregonine fishes. PMID- 21586009 TI - The influence of family groups on inferences made with the program Structure. AB - Unsupervised clustering algorithms, like the program Structure, are increasingly used to infer the presence of population structure from a sample of genotyped individuals. We evaluate the extent to which the presence of related individuals can lead such algorithms to the false inference that there is population structure. First, we demonstrate this problem using a real data set from a rainbow trout (Oncorhynchus mykiss) population. Then we perform an extensive series of simulations involving the program Structure. Our simulations encompass both a simple scenario with fixed numbers of full- and half-siblings in the sample, and a more complicated scenario in which we investigate 360 combinations of population divergence, fraction of population sampled, variance in family size, mating system and number of loci. We find that the inclusion of family members in a sample may produce very strong evidence of population structure, even when population structure is absent. This problem becomes more pronounced when more loci are genotyped, and it is particularly likely in studies of monogamous species, especially if variance in family size is high and a large fraction of a small population has been sampled. Researchers working in such situations should test observed clusters for the presence of family members to distinguish family-induced structure from real population structure. Additionally, this work shows that Structure's ability to estimate the number of subpopulations may be influenced by a number of factors, and therefore should be interpreted guardedly. PMID- 21586010 TI - Multiplex SNP-SCALE: a cost-effective medium-throughput single nucleotide polymorphism genotyping method. AB - We describe a convenient, cost-effective and flexible medium-throughput single nucleotide polymorphism (SNP) genotyping method, Multiplex SNP-SCALE, which enables the simultaneous amplification by polymerase chain reaction (PCR) of up to 25 (or potentially more) loci followed by electrophoresis in an automated DNA sequencer. We extended the original SNP-SCALE method to include (i) use of a commercial multiplex PCR kit, (ii) a four-dye system, (iii) much-reduced (2-uL) reaction volumes, (iv) drying down of template DNA before PCR, (v) use of pig tailed primers, (vi) a PCR product weighting system, (vii) a standard optimized touchdown PCR thermocycling programme, and (viii) software (SNP-SCALE Primer Designer) that automatically designs suitable SNP-SCALE primers for a batch of loci. This new protocol was validated for different types of SNPs. The method is cost- and time-effective for medium-scale evolutionary and ecological projects involving 10s to 100s of loci. PMID- 21586011 TI - Computation vs. cloning: evaluation of two methods for haplotype determination. AB - Nuclear sequence data, often from multiple loci, are increasingly being employed in analyses of population structure and history, yet there has been relatively little evaluation of methods for accurately and efficiently separating the alleles or haplotypes in heterozygous individuals. We compared the performance of a computational method of haplotype reconstruction and standard cloning methods using a highly variable intron (ornithine decarboxylase, intron 6) in three closely related species of dabbling ducks (genus Anas). Cloned sequences from 32 individuals were compared to results obtained from phase 2.1.1 . phase correctly identified haplotypes in 28 of 30 heterozygous individuals when the underlying model assumed no recombination. Haplotypes of the remaining two individuals were also inferred correctly except for unique polymorphisms, the phase of which was appropriately indicated as uncertain (phase probability = 0.5). For a larger set of 232 individuals, results were essentially identical regardless of the recombination model used and haplotypes for all 30 of the tested heterozygotes were correctly inferred, with the exception of uncertain phase for unique polymorphisms in one individual. In contrast, initial sequences of one clone per sample yielded accurate haplotype determination in only 26 of 30 individuals; polymerase chain reaction (PCR)/cloning errors resulting from misincorporation of individual nucleotides could be recognized and avoided by comparison to direct sequences, but errors due to PCR recombination resulted in incorrect haplotype reconstruction in four individuals. The accuracy of haplotypes reconstructed by phase, even when dealing with a relatively small number of samples and numerous variable sites, suggests broad utility of computational approaches for reducing the cost and improving the efficiency of data collection from nuclear sequence loci. PMID- 21586012 TI - Improving the reliability of molecular sexing of birds using a W-specific marker. AB - Molecular techniques for identifying sex of birds utilize length differences between CHD-Z and CHD-W introns, but in some cases these methods can lead to sexing errors. Here we show that an additional W-specific primer can be used in conjunction with a pre-existing sexing primer pair to dramatically improve the reliability of molecular sexing methods. We illustrate the approach with American coots (Fulica americana), a species with CHD-Z polymorphism that could not be accurately sexed using traditional methods. We developed a reverse primer GWR2 designed to sit within the intron of the W chromosome and amplify a distinctively small DNA fragment that serves as a W-specific marker. Analysis of known-sex individuals indicates that this W-specific primer provides an efficient and reliable protocol to identify the sex of F. americana. The development of such sex-specific primers will likely increase the reliability of molecular sexing methods in other birds as well. Comparisons between CHD-Z alleles of coots and common moorhens (Gallinula chloropus) revealed that CHD-Z polymorphism evolved separately in these two closely related species. We discuss the implications of repeated evolution of CHD-Z polymorphisms among birds. PMID- 21586013 TI - concatenator: sequence data matrices handling made easy. AB - concatenator is a simple and user-friendly software that implements two very useful functions for phylogenetics data analysis. It concatenates NEXUS files of several fragments in a single NEXUS file ready to be used in phylogenetics software, such as paup and mrbayes and it converts FASTA sequence data files to NEXUS and vice-versa. Additionally, concatenated files can be prepared for partition tests in paup. It is freely available in http://cobig2.fc.ul.pt. PMID- 21586014 TI - caos software for use in character-based DNA barcoding. AB - The success of character-based DNA barcoding depends on the efficient identification of diagnostic character states from molecular sequences that have been organized hierarchically (e.g. according to phylogenetic methods). Similarly, the reliability of these identified diagnostic character states must be assessed according to their ability to diagnose new sequences. Here, a set of software tools is presented that implement the previously described Characteristic Attribute Organization System for both diagnostic identification and diagnostic-based classification. The software is publicly available from http://sarkarlab.mbl.edu/CAOS. PMID- 21586015 TI - Tetra: an improved program for population genetic analysis of allotetraploid microsatellite data. AB - Population genetic analysis of allotetraploid microsatellite data has lagged far behind that of diploid data, largely because of an inability to determine allele copy number for partial heterozygotes. tetrasat developed by Markwith et al. (2006) uses an iterative substitution process to account for all probable combinations of allele copy numbers in populations with partial heterozygote samples. However, tetrasat cannot deal with microsatellite data containing more than 15 partial heterozygotes, because of an exponential increase in genotype combinations. tetra can handle the microsatellite data containing infinite partial heterozygotes. In the program tetra, the frequencies of alleles are measured as the probability with which the known alleles occur in unknown allele locations. The Hardy-Weinberg expected heterozygosity and Nei's coefficient of gene differentiation are calculated based on allele frequencies. The mean and standard error of expected heterozygosity are estimated through bootstrap method. PMID- 21586016 TI - STORM: software for testing hypotheses of relatedness and mating patterns. AB - Storm is a software package that allows users to test a variety of hypotheses regarding patterns of relatedness and patterns of mate choice and/or mate compatibility within a population. These functions are based on four main calculations that can be conducted either independently or in the hypothesis testing framework: internal relatedness; homozygosity by loci; pairwise relatedness; and a new metric called allele inheritance, which calculates the proportion of loci at which an offspring inherits a paternal allele different from that inherited from its mother. STORM allows users to test four hypotheses based on these calculations and Monte Carlo simulations: (i) are individuals within observed associations or groupings more/less related than expected; (ii) do observed offspring have more/less genetic variability (based on internal relatedness or homozygosity by loci) than expected from the gene pool; (iii) are observed mating pairs more/less related than expected if mating is random with respect to relatedness; and (iv) do observed offspring inherit paternal alleles different from those inherited from the mother more/less often than expected based on Mendelian inheritance. PMID- 21586017 TI - Non-invasive genetic identification of small mammal species using real-time polymerase chain reaction. AB - DNA identification of non-invasive samples is a potentially useful tool for monitoring small mammal species. Here we describe a novel method for identifying five small mammal species: wood mouse, bank vole, common shrew, pygmy shrew and water shrew. Species-specific real-time polymerase chain reaction primers were designed to amplify fragments of the mitochondrial cytochrome b gene from hair and scat samples. We also amplified nuclear DNA from scats, demonstrating their potential as a source of DNA for population genetic studies. PMID- 21586018 TI - Polymerase chain reaction-based detection of Fusarium circinatum, the causal agent of pitch canker disease. AB - Pitch canker is a highly damaging disease of Pinus radiata and the New Zealand forest industry is concerned by the potential impact of the disease, should it arrive, in New Zealand. To provide a rapid identification technique for this pathogen, a polymerase chain reaction-based diagnostic method has been developed. The method is able to detect the presence of the pathogen within infected host tissue, as well as infested soil and the reliability of the test has been estimated using Bayesian statistics. PMID- 21586019 TI - Efficient molecular sexing in dioecious Silene latifolia and S. dioica and paternity analysis in F(1) hybrids. AB - Two polymerase chain reaction-based assays have been developed that work in combination with an efficient DNA extraction protocol to rapidly and reliably determine sex in the dioecious plant species Silene latifolia and S. dioica. In addition, one of the assays allows assessing paternity in the F(1) generation of intra- and interspecific matings involving the two species. PMID- 21586020 TI - Cross-species amplification of Eucalyptus microsatellite loci. AB - This study examined the interspecific amplification of nuclear microsatellite loci developed mainly for eucalypts in the subgenus Symphyomyrtus across five species within the second most speciose subgenus, subgenus Eucalyptus. A set of eight to 10 loci, depending on taxon, have been identified that are highly variable and easily scored. The successful transfer of microsatellite loci to these eucalypt species sidesteps the expensive and time-consuming development of species-specific microsatellite libraries. This primer set will enable the examination and cross-species comparison of the genetic resources of commercially and ecologically important members of the subgenus Eucalyptus. PMID- 21586021 TI - Characterization of 15 microsatellite loci in the pulmonate snail Pseudosuccinea columella (Mollusca, Gastropoda). AB - We characterized 15 new variable microsatellites in the freshwater snail Pseudosuccinea (Lymnaea) columella, as well as conditions for multiplexing and simultaneously genotyping sets of loci. Two to six alleles were detected per locus over the six populations studied. Gene diversity ranged from 0.000 to 0.498, but essentially no heterozygous individuals were observed. This resulted in extremely high F(IS) estimates, and therefore high selfing rates. The F(ST) estimates ranged from 0.18 to 1 among populations, but was generally high. These markers will constitute efficient tools for investigating the population structure of this invasive species. Cross-species amplification was on the whole unsuccessful. PMID- 21586022 TI - Isolation and characterization of 10 highly polymorphic di- and trinucleotide microsatellite markers in the mayfly Ameletus inopinatus (Ephemeroptera: Siphlonuridae). AB - We describe the isolation of ten polymorphic microsatellite loci from the mayfly Ameletus inopinatus. Loci had di- or trinucleotide repeat motifs and were highly variable with three to 17 alleles (mean = 7.15). Observed heterozygosity ranged from 0.143 to 0.905. One locus (Ami_202) showed significant deviation from Hardy Weinberg equilibrium in one population, but no evidence for null alleles. One locus (Ami_73) was significantly linked with three other loci. The remaining nine loci should prove highly informative for population genetic studies. PMID- 21586023 TI - Eight variable microsatellite loci for a Neotropical tree, Jacaranda copaia (Aubl.) D.Don (Bignoniaceae). AB - The Dendrogene Project (Genetic Conservation within Managed Forests in Amazonia) aims to understand the genetic and ecological processes that underpin tree species survival and in particular their response to forest management regimes. As part of the project, we developed eight microsatellite markers for Jacaranda copaia to be used for genetic structure, gene flow and reproductive biology studies. Polymorphism was evaluated using 96 adult trees from the Tapajos National Forest in the Eastern Brazilian Amazon. An average of 22 alleles per locus were detected, with expected heterozygosity ranging from 0.731 to 0.94. PMID- 21586024 TI - Characterization of eight microsatellite markers in the white sea bream, Diplodus sargus (Teleostei, Sparidae). AB - The white sea bream, Diplodus sargus (Teleostei, Sparidae), is a species with a high commercial importance in Mediterranean aquaculture. There is currently little information available about the genetic characteristics of cultured populations. In this survey, we have developed eight polymorphic microsatellites for the white sea bream using an enriched genome library protocol. All of them were polymorphic in the 67 individuals tested, 32 of which were wild specimens, and 35 were individuals from a captive F(1) broodstock. These markers can potentially be useful tools for use in population genetic studies. PMID- 21586025 TI - Sexing European rabbits (Oryctolagus cuniculus), European brown hares (Lepus europaeus) and mountain hares (Lepus timidus) with ZFX and ZFY loci. AB - We describe a new method for the sex determination of tissue originating from Oryctolagus cuniculus (European rabbit), Lepus europaeus (European brown hare) and Lepus timidus (mountain hare) based on PCR-RFLP analysis of point mutations that differentiate the ZFX and ZFY gene sequences. Among several applications, this PCR-RFLP method could be used to investigate gender ratio and evaluate the population dynamics of these species using samples collected when sex cannot be identified. PMID- 21586026 TI - Isolation and characterization of nine microsatellite markers for Brachypodium sylvaticum (Huds.) Beauv., a recently invasive grass species in Oregon. AB - The patterns of genetic diversity caused by rapid range expansions following recent colonizations are best observed using highly polymorphic genetic markers. We characterized nine microsatellite markers for Brachypodium sylvaticum, a bunchgrass invasive in the Northwestern United States and native to Eurasia. Loci exhibited from two to 10 alleles, and generally had high F(IS) values. These loci will help identify sources of new populations in the region, and they will be useful for studying patterns of genetic diversity during rapid range expansions. PMID- 21586027 TI - Sixteen EST-linked microsatellite markers in Gunther's walking catfish, Clarias macrocephalus. AB - Twenty-seven new microsatellite sequences were identified by screening 2029 expressed sequence tags from Gunther's walking catfish, Clarias macrocephalus. Sixteen loci were polymorphic with the number of alleles ranging from two to 16 per locus and the observed and expected heterozygosities ranging from 0.4667 to 0.9333 and from 0.427 to 0.8819 per locus, respectively. Cross-species amplifications of all 16 primer pairs were tested in four other species of catfish including Clarias gariepinus, Pangasius hypophthalmus, Pangasius larnaudii and Pangasianodon gigas. Eleven loci were found to amplify in other species, with the number of polymorphic loci ranging from one in P. larnaudii to nine in C. gariepinus. PMID- 21586028 TI - Isolation and characterization of 64 novel microsatellite markers from a fosmid library of female half-smooth tongue sole (Cynoglossus semilaevis). AB - Microsatellite markers were developed from a fosmid library of female half-smooth tongue sole, Cynoglossus semilaevis. Three hundred eighty-four clones were randomly selected to sequence (double strand reading), and 168 sequences in 143 clones were found to contain microsatellites. Of the 101 primer pairs designed, 64 gave polymorphic polymerase chain reaction products. Based on characterization with 36 individuals, the number of alleles ranged from two to nine. The values of observed and expected heterozygosities varied from 0.06 to 1.00 and from 0.05 to 0.94, respectively. These markers have the potential as tools for population structure evaluation, ecological analyses and linkage map construction. PMID- 21586029 TI - Microsatellite markers for the endangered fir Abies guatemalensis (Pinaceae). AB - Eight newly developed polymorphic microsatellite markers are presented for Abies guatemalensis Rehder, an endangered tree endemic to Mexico and Central America. These microsatellite markers are useful for evaluating the population genetics of the species which is threatened by greenery poaching in natural populations. Novel conservation plans are needed to secure a more sustainable use strategy and to preserve the genetic diversity of the species. PMID- 21586030 TI - Development of simple sequence repeat markers for the soybean rust fungus, Phakopsora pachyrhizi. AB - Twenty-four simple sequence repeat markers were developed for Phakopsora pachyrhizi, a fungal pathogen of soybean (Glycine max) and other legumes. All 24 of the loci were evaluated on 28 isolates of P. pachyrhizi. Twenty-one loci were polymorphic, with allelic diversity ranging from two to eight alleles, and null alleles were observed for eight of the 24 loci. A preliminary screen with the closely related species, P. meibomiae, indicated that these primer pairs are specific to P. pachyrhizi. PMID- 21586031 TI - Microsatellite loci for two East African tree species, Leptonychia usambarensis (Sterculiaceae) and Sorindeia madagascariensis (Anacardiaceae). AB - We isolated 20 trinucleotide microsatellites from two African tree species: Sorindeia madagascariensis (nine microsatellites) and Leptonychia usambarensis (11 microsatellites). Number of alleles ranged from three to seven in Sorindeia and two to 10 in Leptonychia. Observed heterozygosity ranged from 0.025 to 0.829 for Sorindeia and from 0.226 to 0.933 for Leptonychia. Two loci from each species departed from Hardy-Weinberg equilibrium. These microsatellite markers will be used to study how forest fragmentation affects pollination and seed dispersal processes of these tree species. PMID- 21586032 TI - Development and characterization of microsatellite markers for Hibiscus glaber Matsum. ex Nakai, an endemic tree species of the oceanic Bonin Islands, Japan. AB - Polymorphic microsatellite markers were developed for Hibiscus glaber, an endemic tree of the Bonin Islands. Eighty-seven of the 208 sequences from an enriched library were unique and containing microsatellites. Ten loci were proved to be highly polymorphic among 78 individuals from the Nishi-jima Island. Total exclusionary powers for the first and the second parents were 99.989% and 99.999%, respectively. Nine loci also amplified single fragment from genomic DNA of H. tiliaceus, a related and widespread congener. Our markers can be reliably used for the estimation of current gene flow within/among populations of the two woody Hibiscus species. PMID- 21586033 TI - Isolation and characterization of 12 polymorphic microsatellite markers in the tropical house gecko (Hemidactylus mabouia). AB - We present 12 variable microsatellite loci isolated from the invasive tropical house gecko, Hemidactylus mabouia. Polymerase chain reaction (PCR) primers were tested on 39 individuals from two locations in Miami, Florida. Heterozygote deficiency was detected for four loci, and we attribute this to possible null alleles or population substructure. Some loci successfully amplified PCR products in several congeners, indicating their potential for use in other geckos. PMID- 21586034 TI - Isolation and characterization of microsatellite markers for the tree-root endophytes Phialocephala subalpina and Phialocephala fortinii s.s. AB - Species of the Phialocephala fortinii s.l.-Acephala applanata complex are the dominant dark septate endophytes (DSE) in roots of species belonging to the Pinaceae. The two species Phialocephala subalpina and P. fortinii s.s. belong to the most widely distributed species within this complex. In the present study, 15 polymorphic microsatellite loci were developed for these two closely related species. Strains of a community which were analysed previously using single-copy restriction fragment length polymorphism were screened with the new markers. Microsatellites were suitable to classify the two species and to recognize individuals within species. PMID- 21586035 TI - Ten polymorphic microsatellite loci for Allobates femoralis, an Amazonian dendrobatoid frog. AB - Within the anuran amphibians, dendrobatoids (poison-arrow frogs) are renowned for their parental care, but the lack of highly variable DNA markers so far precluded precise and comprehensive measurements of their genetic mating system. Here we present 10 polymorphic microsatellites for Allobates femoralis, a widespread dendrobatoid from the Amazon basin. In 24 field-collected individuals, we found between seven and 15 alleles per locus, without deviations from Hardy-Weinberg equilibrium or linkage disequilibrium. The loci will be employed to quantify reproductive success in view of male territoriality and female mate choice, as well as to determine the fine-scale genetic structure of local populations. PMID- 21586036 TI - Development of microsatellite markers in Annona crassiflora Mart., a Brazilian Cerrado fruit tree species. AB - Annona crassiflora Mart. (Annonaceae) is a native fruit species of the region of Brazilian Cerrado with a high agronomic potential, although without any traces of domestication. A set of 10 microsatellite primer pairs was developed from an enriched genome library (TC13). An average of 19.3 alleles per locus was detected. Observed heterozygosity estimates were consistently lower than those obtained for gene diversity, evidencing a departure from Hardy-Weinberg expected proportions. The reported set of markers showed to be highly informative and constitutes a powerful tool for the development of genetic characterization studies in A. crassiflora. PMID- 21586037 TI - Development of nine microsatellite markers for Pomacentrus amboinensis. AB - The relatively long pelagic larval duration of Pomacentrus amboinensis, a tropical fish, suggests the potential for long-distance dispersal; however, several nongenetic studies have found substantial self-recruitment at one location. To analyse patterns of connectivity of this species, primers for nine independent microsatellite loci were developed for P. amboinensis using a magnetic bead enrichment protocol. Twenty individuals from one location were analysed and observed heterozygosities ranged from 0.7 to 0.95. Eight of nine loci were in Hardy-Weinberg equilibrium and no evidence of linkage or null alleles were found. PMID- 21586038 TI - Isolation and characterization of 15 microsatellite loci for the Japanese gudgeon Sarcocheilichthys variegatus. AB - A microsatellite-enriched genomic library was obtained for the Japanese gudgeon Sarcocheilichthys variegatus microoculus, and 15 dinucleotide markers were successfully isolated and characterized. These markers were also available for other Japanese congeners, Sarcocheilichthys variegatus variegatus and Sarcocheilichthys biwaensis. In three populations of Sarcocheilichthys from Lake Biwa and the Ashida River in western Japan, seven to 27 alleles were observed for each locus. Linkage equilibrium was observed among most loci, and only one locus showed significant deviation from Hardy-Weinberg equilibrium in a population. These microsatellite markers will be useful for studies of the genetic structure of the Japanese gudgeons. PMID- 21586039 TI - Development and characterization of microsatellite markers for lippia (Phyla canescens: Verbenaceae). AB - Lippia (Phyla canescens: Verbenaceae) is a serious weed of wetlands, riparian zones and floodplains, particularly in eastern Australia where many Ramsar wetlands are threatened by hydrological changes precipitated by soil-accreting lippia mats. Enriched genomic DNA libraries were used to develop nine informative microsatellite markers. These markers will be valuable tools to understand the genetic structure of the lippia populations in different regions throughout the world. PMID- 21586040 TI - Development of microsatellite markers for the wood cricket, Nemobius sylvestris (Orthoptera: Gryllidae). AB - Thirty-four novel microsatellite markers developed for wood cricket (Nemobius sylvestris) were tested and optimized. Twenty-five microsatellite loci were polymorphic, exhibiting between two and nine alleles. Observed heterozygosities ranged from 0.038 to 0.925. The microsatellites were also tested in a species belonging to another genus of the Gryllidae family (Gryllus bimaculatus). Two markers produced clear banding patterns with the expected product size. These markers will be used to study the effects of forest fragmentation on genetic connectivity using wood cricket as a model species. PMID- 21586041 TI - The D4 set: primers that target highly variable intron loops in plant chloroplast genomes. AB - Chloroplast group II introns offer high-quality, rapidly evolving single-copy loci for comparative sequence analysis. These introns feature diagnostic secondary structures with loops that are among the least evolutionarily constrained sequence in plastomes. We exploited these structures to develop universal primers that amplify and sequence the large Domain IV (D4) loop in several angiosperm introns. With a single sequence read, we recover 300-600 nucleotides of highly variable sequence across angiosperms, with rates of change that are equal to or higher than many of the best known intergenic spacers in plant chloroplast genomes. PMID- 21586042 TI - Development and cross-species testing of western bluebird (Sialia mexicana) microsatellite primers. AB - Western and eastern bluebirds (Sialia mexicana and S. sialis) are socially monogamous passerines that engage in extra-pair copulations. We obtained microsatellites from S. mexicana and optimized and characterized 15 microsatellite DNA loci in 60 individuals of this species. Primer pairs yielded an average of 13 alleles per locus in western bluebirds (range 3-35 alleles) with an average observed heterozygosity of 0.68 (range 0.27-0.88). All 15 loci also successfully amplified in S. sialis (n = 24), with an average of 11.5 alleles per locus (range 4-26) and an average observed heterozygosity of 0.59 (range 0.22 0.90). PMID- 21586043 TI - Isolation and characterization of polymorphic microsatellite markers in Iberolacerta monticola, and cross-species amplification in Iberolacerta galani and Zootoca vivipara. AB - Fourteen polymorphic microsatellite loci are described for the Iberian rock lizard, Iberolacerta monticola. Genetic variation in a sample of 20 individuals from Piornedo (northwestern Spain) was quantified both by the number of alleles per locus, which ranged from six to 13, and by the expected frequency of heterozygotes under random mating (heterozygosity), which ranged from 0.761 to 0.902. Single locus and global exclusion probabilities were also computed, and indicate a high power of these markers for paternity assignments and mating system studies of I. monticola. All the analysed loci were also polymorphic in Iberolacerta galani, but only seven in Zootoca vivipara. PMID- 21586044 TI - Microsatellite markers for eastern hemlock (Tsuga canadensis). AB - We describe polymerase chain reaction primer pairs and reaction conditions for amplification of 15 microsatellite loci from eastern hemlock (Tsuga canadensis). The primers were tested on 23 individuals from a natural population in southwestern North Carolina, USA. These primers yielded an average of 5.9 alleles per locus (range of 2-14), an average observed heterozygosity of 0.45 (range 0.14 0.73), and an average polymorphic information content of 0.54 (range 0.28-0.86). In addition, eight of the primer pairs were found to amplify microsatellite loci in one or more additional species of Tsuga. PMID- 21586045 TI - Development of 10 tri- and tetranucleotide microsatellite loci for population studies in the common carp (Cyprinus carpio L.). AB - Ten tri- and tetranucleotide microsatellite DNA markers were isolated and characterized from common carp (Cyprinus carpio L.) to estimate genetic potential. These markers were tested in the samples from two closely related carp populations (Cyprinus carpio var. xingguonensis and Cyprinus carpio var. wananensis). The number of the alleles ranged from three to nine, and observed and expected hererozygosities varied from 0.207 to 1.000 and from 0.499 to 0.900 in each population, respectively. No evidence for linkage disequilibrium was found, indicating that these markers will be useful for population studies. PMID- 21586046 TI - Development of polymorphic microsatellite markers in Hessian fly, Mayetiola destructor (Say). AB - A microsatellite library was prepared from size-selected genomic DNA of Hessian fly (Mayetiola destructor). Approximately 81% of recovered clones hybridized with microsatellite motif-specific probes. Subsequently, 2350 clones were sequenced. Sixty-two individual flies from laboratory strains were used to test for reliability and polymorphism in 50 of the microsatellites by gel electrophoresis; 18 were further tested with capillary electrophoresis. Of these, 17 behaved as a polymorphic single locus appropriate for population analysis. PMID- 21586047 TI - Eleven polymorphic microsatellite markers for Oedaleus decorus (Orthoptera, Acrididae), an endangered grasshopper in Central Europe. AB - We isolated and characterized 11 microsatellite loci in the grasshopper Oedaleus decorus (Orthoptera: Acrididae), an endangered species in Central Europe. Polymorphism was studied from two populations, one out of two populations known from Switzerland (n = 20 individuals) and one site from south of France (n = 20). The number of alleles and the expected heterozygosity ranged from five to 12 and from 0.559 to 0.898, respectively, in the Swiss population, and from 14 to 23 and from 0.895 to 0.974, respectively, in the French population. These microsatellite markers are suitable for further conservation genetic studies of O. decorus. PMID- 21586048 TI - Cross-species testing of 27 pre-existing microsatellites in Podarcis gaigeae and Podarcis hispanica (Squamata: Lacertidae). AB - We tested 27 microsatellite loci for cross-species amplification in the lacertids Podarcis gaigeae and Podarcis hispanica. We detected 11 and 15 polymorphic loci in the former and the latter species, respectively. In a larger sample of individuals from a single population of each species, the number of alleles ranged from five to 23 in 10 of the polymorphic loci in P. gaigeae, and between four and 13 in nine of polymorphic loci in P. hispanica. Two locus deviated from Hardy-Weinberg equilibrium in P. hispanica. Between 11 and 16 of the 27 loci also amplified successfully in three other Podarcis species. PMID- 21586049 TI - Isolation and characterization of microsatellite markers for Carolina hemlock (Tsuga caroliniana). AB - We describe the isolation and characterization of 31 polymorphic di- and trinucleotide microsatellite marker loci for Carolina hemlock (Tsuga caroliniana Englem.). In addition, primer pairs for 16 loci amplified scoreable alleles in six other Tsuga species. In eastern North America, both Carolina hemlock and eastern hemlock (Tsuga canadensis [L.] Carr.) populations are declining due to infestation by hemlock woolly adelgid, Adelges tsugae. The markers described here should enhance population genetic studies of hemlocks, providing valuable information for conserving and restoring these important forest tree species. PMID- 21586050 TI - Development and characterization of 11 microsatellite loci in a historically introduced carnivoran, the common genet (Genetta genetta). AB - Microsatellite markers were developed to assess population structure and patterns of translocation in the introduced European common genet (Genetta genetta). Primer pairs were designed for 60 microsatellite sequences enriched for CA, GA, CATC and TAGA repeat motifs. Eleven loci that proved to be polymorphic were genotyped in 33 individuals from southwestern France. The number of alleles per locus and observed heterozygosities varied from three to seven and from 0.2121 to 0.7576, respectively. One locus (B103) showed significant departure from Hardy Weinberg equilibrium, probably due to the presence of null alleles. Tests of linkage disequilibrium did not detect significant associations among loci. PMID- 21586051 TI - Cross-species tests of 45 microsatellite loci isolated from different species of ungulates in the Iberian red deer (Cervus elaphus hispanicus) to generate a multiplex panel. AB - The Iberian red deer (Cervus elaphus hispanicus) is an emblematic game species in Spain. To generate a battery of polymorphic markers for multiplex polymerase chain reactions for the Spanish red deer, 45 loci isolated in different species of ungulates were tested. Of the primers tested, 27 amplified but only 21 were polymorphic. Eleven of these markers were subsequently optimized for multiplex in four polymerase chain reactions. This allows analysing several molecular markers jointly to substantially reduce costs. Finally, we report descriptive summary statistics such as number of alleles for the former and also test of disequilibria and heterozygosity for the latter. PMID- 21586052 TI - Isolation and characterization of 12 dinucleotide microsatellites in the European eel, Anguilla anguilla L., and tests of amplification in other species of eels. AB - Twelve polymorphic dinucelotide microsatellites in the freshwater eel Anguilla anguilla L. were isolated and characterized. Genetic diversity was assessed in eels from Lake Constance, Germany. Allele numbers ranged from five to 26 per locus with observed heterozygosities between 0.125 and 0.875. A portion of locus AangCT77 aligns with a transcribed region of the zebrafish gene crystallin beta B2. Cross-species amplification of most markers was possible for nine other Anguilla eel species. The newly developed primer pairs will facilitate population and conservation genetic studies in order to refine the understanding of the subtle population genetic structure typical of eels, and to identify interspecies admixture due to global trade. PMID- 21586053 TI - Development and characterization of nine polymorphic microsatellite markers for Mexican spadefoot toads (Spea multiplicata) with cross-amplification in Plains spadefoot toads (S. bombifrons). AB - We developed nine polymorphic microsatellite markers for the Mexican spadefoot toad, Spea multiplicata. Allele numbers range from five to 12, with observed heterozygosities from 0.48 to 0.87. Because two loci are in linkage disequilibrium, these nine loci provide eight independent markers. Three loci exhibit departure from Hardy-Weinberg equilibrium, possibly resulting from null alleles or population admixture. These markers will be useful for assessing population structure and relatedness in S. multiplicata. Based on our success at cross-amplification in the Plains spadefoot toad (Spea bombifrons), these loci also may be useful in this species with additional optimization. PMID- 21586054 TI - Development of 11 polymorphic microsatellite loci in the small abalone (Haliotis diversicolor Reeve). AB - Eleven polymorphic microsatellite loci for Haliotis diversicolor were isolated and characterized from (CT)(n) - and (AC)(n) -enriched library. They were tested in 24 individuals from a natural population. All of them were polymorphic, with the number of alleles varying between three and 10. The observed heterozygosities and expected heterozygosities ranged from 0.083 to 0.913 and from 0.159 to 0.856, respectively. The 11 isolated microsatellite loci, except SA-JMU6 and SA-JMU12, followed Hardy-Weinberg expectations. Seven sets of primers also amplify in closely related species, H. ovina and H. asinine. These 11 polymorphic microsatellites will be useful for analysing the population structure and genetic diversity in H. diversicolor. PMID- 21586055 TI - Characterization of polymorphic microsatellite DNA markers in Banksia nivea, formerly Dryandra nivea. AB - A genomic library was constructed and 10 novel polymorphic microsatellite markers were developed for Banksia nivea subsp. uliginosa, a woody shrub endemic to the southwest of Western Australia. Polymorphism was investigated for these markers in 30 individuals from one population located in restricted habitat at the base of the Whicher Range east of Busselton. Expected heterozygosity ranged from 0.124 to 0.898 and averaged 0.570. Observed heterozygosity ranged from 0.133 to 0.933 and averaged 0.544. The number of alleles per locus ranged from 2.0 to 16.0 and averaged 7.3. These markers also produced amplification products in three other Banksia species and will be used to assay genetic diversity in these species. PMID- 21586056 TI - Development and characterization of novel, polymorphic microsatellite markers for oat crown rust, Puccinia coronata. AB - We report the development of 37 novel and polymorphic microsatellite markers for oat crown rust, Puccinia coronata f.sp. avenae. The allelic diversity ranged from two to 16 alleles per locus. Observed heterozygosity ranged from 0.000 to 0.971, and expected heterozygosity from 0.057 to 0.848. Thirteen of the loci were not in Hardy-Weinberg equilibrium, due to either the presence of null alleles, small sample size, or the effects of population subdivision (Wahlund's effect). All 37 primer pairs were tested with P. graminis and P. triticina showing that they are specific to P. coronata. PMID- 21586057 TI - Microsatellite primers for relatedness and population structure in great frigatebirds (Pelecaniformes: Fregatidae). AB - Eighteen moderately polymorphic microsatellite loci were isolated and characterized for great frigatebirds Fregata minor. Polymorphism for the 12 dinucleotide and six tetranucleotide markers was assessed in 23 birds from a Hawaii population. Allelic diversity ranged from two to 12 (mean 5.9), with observed heterozygosity from 0.304 to 0.956 (mean 0.637). Three loci showed homozygote excess, possibly due to null alleles. One additional pair of loci exhibited strong gametic disequilibrium. Thus, at least 14 loci will be useful for studies of relatedness and population structure. PMID- 21586058 TI - New polymorphic microsatellite loci for the Macedonian crested newt, Triturus macedonicus, and cross-priming testing in four other crested newt species. AB - Eleven microsatellites have been characterized for Triturus macedonicus. Nine loci showed different variation patterns in a sample of 40 individuals from a single breeding pond in Zagori province (Greece), with an average number of 4.2 alleles per locus and an expected heterozygosity ranging from 0.1199 to 0.8079. Distinct cross-priming amplification rates were recovered on four additional crested newt species. Two monomorphic T. macedonicus loci were polymorphic in other Triturus species. The microsatellites developed herein could be a useful intraspecific genetic tool to undertake fine-scale population genetic analyses as well as in the study of contact zones between crested newt species. PMID- 21586059 TI - Isolation of polymorphic microsatellite loci for the marine invader Microcosmus squamiger (Ascidiacea). AB - The ascidian Microcosmus squamiger is native to Australia and has recently spread worldwide. It has become a pest in some littoral communities within its introduced range. An enriched genomic library of M. squamiger resulted in a total of eight polymorphic loci that were genotyped in 20 individuals from a population within its introduced range, and 20 individuals more from a native population. The mean number of alleles per locus was 5.33 and mean observed heterozygosity was 0.432. No significant linkage disequilibrium was found among loci pairs. Significant genetic differentiation was observed between populations. PMID- 21586060 TI - Development of microsatellite markers in the St Lucia anole, Anolis luciae. AB - Anolis lizards are important models in studies of ecology and evolution. Here we describe 13 polymorphic microsatellites for use in population screening in the St Lucia anole, Anolis luciae, that can be used as a natural replicate to Anolis roquet on Martinique to study processes involved in population differentiation and speciation. Genotyping of 32 individuals using M13 tails and FAM-labelled universal M13 primers showed that all loci were polymorphic with high genetic diversity, averaging at 16.8 alleles per locus. Genotypic frequencies conformed to Hardy-Weinberg expectations, and there were no instances of linkage disequilibrium between loci. PMID- 21586061 TI - Isolation and characterization of microsatellite marker loci in the greylag goose (Anser anser). AB - Ten novel polymorphic microsatellite loci were isolated and characterized from the greylag goose, Anser anser, a long-term monogamous and biparental bird. Additionally, five new primers pairs were designed based on previously published microsatellite locus sequences from closely related species. Multiplex polymerase chain reactions conditions were optimized for all 15 primer pairs. The number of alleles ranged from two to 12 per locus with an observed heterozygosity ranging from 0.07 to 0.85. This marker set will be used to determine rates and origins of extra-pair and parasitic young in a population of individually banded greylag geese with known life histories. PMID- 21586062 TI - Eight polymorphic microsatellite loci for the Australian plague locust, Chortoicetes terminifera. AB - Few population genetics studies have been carried out on major locust species. In particular, an understanding of the population genetic structure of the Australian plague locust, Chortoicetes terminifera, is lacking. We isolated and characterized eight polymorphic microsatellite loci in C. terminifera, and described experimental conditions for polymerase chain reaction multiplexing and genotyping these loci. The number of alleles per locus ranged from 11 to 29 and the expected heterozygosity ranged from 0.797 to 0.977. One locus was found to be X-linked. Results of cross-taxon amplification tests are reported in four species of the Oedipodinae subfamily. PMID- 21586063 TI - Isolation and characterization of microsatellite markers in Acca sellowiana (Berg) Burret. AB - Acca sellowiana has commercial potential because of the quality and the unique flavor of its fruit. Conservation of natural populations and management of breeding programmes would benefit from the availability of molecular markers that could be used to characterize levels and distribution of genetic variability. Thus, 13 microsatellite markers were developed from an enriched genomic library of A. sellowiana. They were characterized using 40 samples. The expected and observed heterozygosities ranged from 0.513 to 0.913 and from 0.200 to 0.889, respectively. These are the first microsatellite loci characterized from A. sellowiana that will contribute to improve researches on the genetic conservation, characterization and breeding. PMID- 21586064 TI - Isolation and characterization of 14 polymorphic microsatellite markers for the blue and red shrimp, Aristeus antennatus (Crustacea, Decapoda). AB - Eighteen microsatellite loci were isolated and characterized from the blue and red shrimp, Aristeus antennatus Risso 1816, a commercially exploited marine crustacean widely distributed throughout the Mediterranean Sea and in the eastern Atlantic. Polymorphism was assessed in a population (n = 20) from the southwestern Sardinian seas; 14 loci resulted polymorphic and showed from three to 13 alleles. The observed heterozygosity ranged from 0.2 to 0.85. These microsatellites will be potentially useful for the study of A. antennatus population genetic structure. PMID- 21586065 TI - Isolation and characterization of 10 microsatellite loci in Callicarpa subpubescens (Verbenaceae), an endemic species of the Bonin Islands. AB - Ten microsatellite loci were isolated and characterized for Callicarpa subpubescens (Verbenaceae), an endemic tree species of the Bonin Islands. The observed number of alleles at each locus ranged from two to eight with an average of 4.9, and the expected heterozygosity ranged from 0.238 to 0.690 with an average of 0.483. All 10 loci were screened in cross-amplification tests for two other endemic Callicarpa species that also inhabit the Bonin Islands. All loci were successfully amplified in these species. PMID- 21586066 TI - Microsatellite markers isolated from a polyploid saltbush, Atriplex nummularia Lindl. (Chenopodiaceae). AB - Atriplex nummularia is a polyploid Australian saltbush which has been identified as a suitable species for use in the rehabilitation of agricultural land affected by salinity. We isolated 12 polymorphic loci for a preliminary assessment of genetic variability and structure within the species as a basis for a breeding programme. Preliminary screening of loci in 40 individuals from two populations revealed multibanded genotypes consisting of up to seven alleles in a single individual, with up to 29 alleles observed at a single locus. The multibanded patterns are consistent with the polyploid status of this species. PMID- 21586067 TI - Characterization of single nucleotide polymorphism markers for eelgrass (Zostera marina). AB - We characterized 37 single nucleotide polymorphism (SNP) makers for eelgrass Zostera marina. SNP markers were developed using existing EST (expressed sequence tag)-libraries to locate polymorphic loci and develop primers from the functional expressed genes that are deposited in The ZOSTERA database (V1.2.1). SNP loci were genotyped using a single-base-extension approach which facilitated high throughput genotyping with minimal optimization time. These markers show a wide range of variability among 25 eelgrass populations and will be useful for population genetic studies including evaluation of population structure, historical demography, and phylogeography. Potential applications include haplotype inference of physically linked SNPs and identification of genes under selection for temperature and desiccation stress. PMID- 21586068 TI - Isolation and characterization of microsatellite markers in an endemic Hawaiian planthopper (Nesosydne chambersi: Delphacidae). AB - We have isolated and characterized 17 microsatellite loci for the endemic Hawaiian planthopper Nesosydne chambersi (Delphacidae), a member of a large Hawaiian Nesosydne radiation. Thirty individuals from one population and 10 individuals from two populations across the species' range were tested to investigate polymorphism. The observed loci contained two to nine alleles per locus. Expected heterozygosity within this species ranged from 0.2 to 0.85. These markers will be used to assess intraspecific differentiation and population structure within N. chambersi. PMID- 21586069 TI - Development and characterization of microsatellite loci in the American white pelican (Pelecanus erythrorhynchos). AB - We isolated and characterized nine microsatellite loci from the American white pelican, Pelecanus erythrorhynchos. The loci were screened in 23 individuals from the eastern and western populations of North America and were polymorphic, with the number of alleles per locus ranging from two to eight. Polymorphic information content ranged from 0.185 to 0.820 and observed heterozygosity from 0.217 to 0.957. These new loci will provide tools for studies of population structure in this species, thereby aiding conservation planning. PMID- 21586070 TI - Characterization of new microsatellite markers derived from sequence databases for the emu (Dromaius novaehollandiae). AB - The emu (Dromaius novaehollandiae), a member of ratite family, is native to Australia and has been introduced to other countries worldwide. In this work, 10 polymorphic microsatellite loci were isolated and characterized for emu from public sequences. Polymorphism was surveyed in 22 individuals from two different populations kept in captivity. Between two and 11 alleles were found per locus, and the observed heterozygosity ranged from 0.05 to 0.85, in accordance with expectations. These markers will be useful as tools for detecting levels of genetic variation, reconstructing pedigrees (for quantitative genetic analysis) and identifying markers associated to fitness traits in emu populations. PMID- 21586071 TI - Isolation and characterization of microsatellite loci in the western long fingered bat, Miniopterus magnater. AB - We isolated and characterized 10 microsatellite loci in the western long-fingered bat, Miniopterus magnater. These loci were tested on 48 individuals from Anhui Province of China, and all loci were highly polymorphic. The mean number of observed alleles per locus was 13.6 (range from six to 27). Observed and expected heterozygosity values ranged from 0.364 to 0.957, and from 0.676 to 0.951, respectively. After Bonferroni correction, four loci deviated significantly from Hardy-Weinberg equilibrium. No pairs of loci were in linkage disequilibrium. These polymorphic markers will be used to examine population structure and genetic diversity in this species. PMID- 21586072 TI - Isolation and characteristics of 10 microsatellite markers from the endangered coconut crab (Birgus latro). AB - The coconut crab (Birgus latro), an endangered marine-dispersed crustacean, is facing severe and probably accelerating population extinction worldwide, but biological information on its conservation remains deficient. In order to reveal the genetic structure of B. latro, 10 microsatellite loci were developed. A high degree of polymorphism was observed with a mean number of alleles per locus of 16.9. The mean expected heterozygosities were also high, ranging from 0.742 to 0.965. The observed heterozygosities ranged from 0.210 to 0.925. Departures from Hardy-Weinberg equilibrium were observed at five loci after the Bonferroni correction. These hypervariable markers will be utilized to study the genetic diversity and conservation of B. latro throughout its distribution range in the Pacific and Indian Oceans. PMID- 21586073 TI - Isolation and characterization of microsatellite markers for the ornamental discus fish Symphysodon discus and cross-species amplification in other Heroini cichlid species. AB - The discus fishes (Symphysodon spp.) are economically important ornamental species. Thirteen microsatellite markers were developed from a CT(12) - and CA(12) -enriched whole genomic DNA library of Symphysodon discus. Allelic variability was tested on 44 individuals of two species (S. discus and S. aequifasciatus). Allelic richness ranged from two to 11 alleles per locus and observed heterozygosities from 0.083 to 0.998. All loci were at Hardy-Weinberg equilibrium, and no pair of loci showed linkage disequilibrium within a species. Cross-species amplification was also successfully performed in the Neotropical cichlids Uaru amphiacanthoides, Hoplarchus psittacus, Hypselecara coryphaenoides, Pterophyllum sp., Mesonauta sp. and Heros sp. PMID- 21586074 TI - Eight polymorphic microsatellite markers developed in the Chinese scorpion, Mesobuthus martensii (Scorpiones: Buthidae). AB - Eight polymorphic di- and trinucleotide microsatellite loci were developed in the Chinese scorpion, Mesobuthus martensii. The expected heterozygosity at these loci ranges from 0.019 to 0.860, with the observed allele numbers varying from two to 25. Overall, there were no deviations from Hardy-Weinberg equilibrium and no observed linkage disequilibrium after Bonferroni correction. Cross-species amplification of these loci in Mesobuthus eupeus revealed that five loci can amplify successfully in this species. The polymorphic microsatellite DNA markers reported here should provide helpful means to address questions concerning phylogeographical patterns and evolutionary history of M. martensii and closely related species. PMID- 21586075 TI - Eight new tetranucleotide microsatellite loci for the agile frog (Rana dalmatina). AB - We describe eight new polymorphic tetranucleotide microsatellite loci isolated from the agile frog (Rana dalmatina). In 25 individuals from the Nature Reserve Luneburger Heide (Lower Saxony, Germany), the number of alleles per locus ranged from four to nine and average observed heterozygosities from 69.1% to 80.7%. No evidence for linkage disequilibrium was found and none of the loci showed significant deviation from Hardy-Weinberg expectations. These microsatellite DNA markers are suitable tools for addressing population genetics issues in this endangered species. PMID- 21586076 TI - Isolation and characterization of microsatellite markers for Pinellia ternata and cross-species amplification. AB - In this study, we isolated and characterized 12 microsatellite loci for Pinellia ternata. Polymorphism of these 12 loci was assessed in 46 individuals collected from two wild populations. All the loci were polymorphic with four to 13 alleles per locus and the observed and expected heterozygosities ranged from 0.312 to 0.680 and from 0.506 to 0.734, respectively. None of the loci showed significant deviation from Hardy-Weinberg equilibrium (P < 0.05). No significant linkage disequilibrium was observed between pairs of studied loci. In addition, most markers amplified successfully in three closely related taxa that are Pinellia cordata, P. peltata and P. pedatisecta. These microsatellite markers could provide a useful tool for genetic structure studies of the Pinellia species. PMID- 21586077 TI - Characterization of microsatellite loci for the littorine snail Bembicium vittatum. AB - We describe the isolation and development of 17 polymorphic microsatellite loci for the intertidal snail Bembicium vittatum (Gastropoda: Littorinidae). The loci were tested in 46 individuals from a single population situated near the centre of the species distribution. No evidence of linkage disequilibrium was detected between any pair of loci. However, two loci showed significant departures from Hardy-Weinberg expectations. The number of alleles per locus ranged from two to 15. PMID- 21586078 TI - Isolation and characterization of microsatellite markers in Oligoryzomys longicaudatus (Muridae, Sigmodontinae, Oryzomini), the natural reservoir of genotype Andes hantavirus. AB - The rodent Oligoryzomys longicaudatus or long-tailed pygmy rice rat is the reservoir of the aetiological agent of the hantavirus pulmonary syndrome in southern Argentina and Chile. We characterize 11 polymorphic microsatellite loci which would be useful for studies on microgeographical population structure in the species. Amplification of these loci in 42 individuals from four natural populations revealed four to 21 alleles per locus, and values of observed heterozygosities ranging from 0.371 to 0.896. Cross-species amplifications showed that some of the primers designed may be useful for other species of the genus Oligoryzomys. PMID- 21586079 TI - Isolation and characterization of 100 polymorphic microsatellite loci for the Siberian jay (Perisoreus infaustus). AB - We describe primers and polymerase chain reaction conditions to amplify 100 microsatellite loci from the Siberian jay (Perisoreus infaustus). The primers were tested on two geographically separated Finnish populations. The developed primer pairs yielded an average of 4.72 alleles per locus (range one to 17) and an average observed heterozygosity of 0.55 (range 0.04 to 1). PMID- 21586080 TI - Polymorphic microsatellite DNA markers for Daviesia triflora (Papilionaceae). AB - We developed 11 polymorphic microsatellite DNA markers for an Australian native plant, Daviesia triflora. The number of alleles per locus in 40 individuals varied from four to 19, and observed and expected heterozygosities ranged from 0.450 to 0.925 and from 0.497 to 0.899, respectively. Nine loci showed no significant deviation from Hardy-Weinberg equilibrium (P > 0.05), and null alleles appear to exist at loci DT-A102 and DT-B103. All loci showed independent inheritance. PMID- 21586081 TI - Isolation and characterization of microsatellite loci in Palinurus elephas. AB - The European spiny lobster (Palinurus elephas) mean annual catches have decreased alarmingly during recent decades along its entire distribution area due to stock over-exploitation, which makes it a primary target for conservation plans. A total of 164 microsatellite loci were isolated from a genomic library of P. elephas enriched for CA, GA, CAA and GATA repeats. A total of 15 polymorphic loci have been screened in 48 individuals. High numbers of alleles per locus (averaging 20 +/- 10.5) and observed heterozygosity (averaging 0.789 +/- 0.197) have been detected. None of the pairs of loci showed significant linkage disequilibrium. Two of the loci (Pael1 and Pael2) showed significant departure from Hardy-Weinberg equilibrium in Sagres, while Pael38 showed significant departure in Tunis. These highly polymorphic markers will be useful in determining the spatial patterns of genetic diversity between and within populations of Palinurus elephas. PMID- 21586082 TI - Fourteen new di- and tetranucleotide microsatellite loci for the critically endangered Indian tiger (Panthera tigris tigris). AB - We describe 11 dinucleotide and three tetranucleotide microsatellite loci for the critically endangered Indian tiger, Panthera tigris tigris. All of them were polymorphic with four to nine alleles per locus and an observed heterozygosity between 0.13 and 1.0. All primers also amplify microsatellite loci in leopard, Panthera pardus, and 12 primer pairs yielded reproducible results in domestic cat, Felis catus. These new microsatellites specifically developed for Indian tiger - in combination with those already available - comprise a reasonable number of loci to genetically analyse wild and captive populations of this illustrative species and might allow for recognition of individual tigers. PMID- 21586083 TI - Twenty-three microsatellite DNA loci for population genetic studies and parentage assignment in orangethroat darter, Etheostoma spectabile. AB - The genus Etheostoma is a species-rich and ecologically important group of fishes in North America. The orangethroat darter (Etheostoma spectabile) is widely distributed and abundant in headwater streams throughout the central Midwest, and is an excellent model for ecological and mating system studies. We developed 23 novel, polymorphic, and independent microsatellite loci for E. spectabile. We found from two to 14 alleles per locus, and observed heterozygosities ranged from 0.39 to 1.0. These markers, in combination with others isolated from Etheostoma taxa, will be useful for ecological and evolutionary studies in the genus. PMID- 21586084 TI - Use of differential expression data for identification of novel immune relevant expressed sequence tag-linked microsatellite markers in Atlantic salmon (Salmo salar L.). AB - Despite the large number of genes contributing to the immune response, wildlife immunogenetic studies have tended to focus mostly on the major histocompatibility complex-related genes. Here, we utilized previously published microarray and competitive RNA hybridization information to identify 3750 immune relevant Atlantic salmon (Salmo salar) expressed sequence tags. We then identified those expressed sequence tags containing microsatellites and subsequently designed 48 primer pairs and tested them for polymorphism in Atlantic salmon. Altogether, 16 polymorphic markers were characterized, with allele numbers ranging from two to 18, and these 16 loci were further tested in five other salmonid species. PMID- 21586085 TI - Development of microsatellite markers for the bracken fern, Pteridium aquilinum. AB - We isolated eight novel polymorphic microsatellite loci from Pteridium aquilinum. These loci were characterized in 30 individuals, one from Bolivia, two from Peru, one from the USA, one from Japan, and 25 from Northeast China to Southwest China. The number of alleles per locus ranged from two to seven. The observed heterozygosity (H(O) ) ranged from 0.000 to 0.600 with an average of 0.3051, and the expected heterozygosity (H(E) ) ranged from 0.0966 to 0.7780 with an average of 0.4267. One locus deviated from Hardy-Weinberg equilibrium and four pairs of loci were found to be in linkage disequilibrium. These polymorphic loci will be useful in the study of the population genetic structure of Pteridium. PMID- 21586086 TI - Development of simple sequence repeat markers from expressed sequence tags of the black tiger shrimp (Penaeus monodon). AB - In this study, we describe the development of expressed sequence tag-simple sequence repeat markers from expressed sequence tags of the black tiger shrimp (Penaeus monodon) deposited in public sequence databases. A total of 46 primer pairs were designed and screened on 26 individuals of P. monodon from a natural population. Of these, 16 primer pairs showed polymorphic profiles with between two and five alleles per locus. The average unbiased and direct count heterozygosities were 0.4662 and 0.3516, respectively. Cross-amplification was tested with five individuals of Penaeus vannamei and polymorphic products were detected at five loci. PMID- 21586087 TI - Development of new microsatellite markers from a salt-marsh sedge Carex rugulosa by compound simple sequence repeat-polymerase chain reaction. AB - We developed 12 polymorphic microsatellite markers from a salt-marsh sedge Carex rugulosa. The number of alleles per locus ranged from two to four, with an average of 2.75. The observed and expected heterozygosities ranged from 0.067 to 0.600 and from 0.128 to 0.620, respectively. These simple sequence repeat markers will allow the identification of genets and evaluation of the genetic diversity of C. rugulosa. PMID- 21586088 TI - Isolation and characterization of microsatellite markers in the striped hamster (Cricetulus barabensis). AB - A total of 14 polymorphic microsatellite markers were isolated and characterized from the striped hamster, Cricetulus barabensis, a widespread rodent pest in northern China. Two to six alleles per locus were detected in 90 individuals from three locations in Shandong Province, China. The observed and expected heterozygosities ranged from 0.21 to 0.78 and from 0.30 to 0.80, respectively. These microsatellite markers provide new tools for investigating the population structure of this species. PMID- 21586089 TI - Characterization of 18 new microsatellite loci in Atlantic cod (Gadus morhua L.). AB - Eighteen new microsatellite loci consisting of 10 di-, 5 tri-, 2 tetra- and 1 heptanucleotide repeats are introduced for the Atlantic cod (Gadus morhua L.). All loci were co-amplified in two polymerase chain reactions (plus two previously published microsatellites) and all products were typed clearly. The number of alleles per locus ranged from six (PGmo130) to 45 (PGmo76) and the observed heterozygosity ranged from 0.356 (PGmo130) to 0.957 (PGmo95). All loci except one followed Hardy-Weinberg expectations. Genetic linkage disequilibrium analysis between all pairs of loci did not yield any significant values. PMID- 21586090 TI - Polymorphic microsatellite markers for the tsetse fly Glossina fuscipes fuscipes (Diptera: Glossinidae), a vector of human African trypanosomiasis. AB - Our understanding of Glossina fuscipes fuscipes, a major vector of sleeping sickness, has been severely constrained by a lack of genetic markers for mapping and population genetic studies. Here we present 10 newly developed microsatellite loci for this tsetse species. Heterozygosity levels in Moyo, an Ugandan population, averaged 0.57, with only two loci showing very low heterozygosity. Five loci carried more than six alleles. Together with five recently published microsatellite loci, this brings the number of available microsatellite loci for this species to 15. Their availability will greatly facilitate future studies on the genetics of this important human disease vector. PMID- 21586091 TI - Isolation and characterization of microsatellite markers in the newly discovered invasive fruit fly pest in Africa, Bactrocera invadens (Diptera: Tephritidae). AB - We describe the isolation and characterization of 11 polymorphic microsatellite loci from the recently discovered fruit fly pest, Bactrocera invadens. The polymorphism of these loci was tested in individual flies from two natural populations (Sri Lanka and Democratic Republic of Congo). Allele number per locus ranged from three to 15 and eight loci displayed a polymorphic information content greater than 0.5. These microsatellite loci provide useful markers for studies of population dynamics and invasion history of this pest species. PMID- 21586092 TI - Isolation and characterization of 12 microsatellites from the black surfperch, Embiotoca jacksoni, a reef fish that lacks a pelagic larval phase. AB - A set of 12 microsatellite markers was developed from Embiotoca jacksoni genomic DNA and tested for polymorphism using 64 individuals from two populations. All loci were polymorphic with a number of alleles ranging from two to 19 with expected heterozygosities ranging from 0.17 to 0.89. There was no evidence of linkage disequilibrium and all loci were in Hardy-Weinberg equilibrium, except for four loci in one population. High numbers of private alleles were consistent with strong population structure, and very limited dispersal. Six microsatellite markers successfully cross amplified and were polymorphic in closely related species, Embiotoca lateralis and Hyspurus caryi. PMID- 21586093 TI - Polymorphic microsatellite DNA markers for Banksia hookeriana (Proteaceae). AB - We developed 11 polymorphic microsatellite DNA markers for an Australian native shrub Banksia hookeriana (Proteaceae). The number of alleles per locus in 37 individuals varied from three to 17, observed and expected heterozygosities ranged from 0.297 to 0.838 and from 0.279 to 0.900, respectively. Two loci (BH-B5 and BH-B107) showed significant deviation from Hardy-Weinberg equilibrium (P < 0.05), and null alleles may be present at these two loci. All loci showed independent inheritance. PMID- 21586094 TI - Development of DNA microsatellite markers in the multiband butterflyfish (Chaetodon multicinctus). AB - Twelve polymorphic microsatellite loci were developed in the multiband (pebbled) butterflyfish Chaetodon multicinctus. The loci were scored in 45 individuals from Hawaii. There were five to 21 alleles per locus with observed heterozygosity ranging from 0.419 to 0.883. Four of the primer sets also reliably amplified polymorphic loci in Chaetodon quadrimaculatus. We expect these markers to be useful for studies of genetic population structure and kinship, for example to determine whether new recruits settling onto reefs are related. PMID- 21586095 TI - Amplification of rainbow trout microsatellites in Brachymystax lenok. AB - Brachymystax lenok is a cold freshwater fish accustomed to inhabit relatively high concentration of dissolved oxygen and clean upper streams. Here we present 13 polymorphic microsatellite primer pairs from rainbow trout to amplify in 32 B. lenok individuals from Ussuri River of China. The number of alleles ranged from two to seven with an average of 3.9 per locus. Observed heterozygosity ranged from 0.0625 to 0.9677. One locus showed significant deviation from Hardy-Weinberg equilibrium. These 13 loci will provide a good basis for investigation of B. lenok population structure and genetic diversity in different distribution region. PMID- 21586096 TI - Choroidal thickness following extrafoveal photodynamic treatment with verteporfin in patients with central serous chorioretinopathy. AB - PURPOSE: To evaluate the effect of verteporfin photodynamic treatment (PDT) on choroidal thickness in patients with central serous chorioretinopathy (CSC). METHODS: Choroidal thickness was measured with enhanced depth imaging- optical coherence tomography (EDI-OCT) before and after verteporfin PDT (full-dose verteporfin, half-light dose) in 16 eyes in 16 patients with serous detachment of the fovea secondary to extrafoveal angiographic fluorescein leakage. Treatment was confined to the area of leakage, whereas choroidal thickness before and after treatment was assessed over a larger area of the fundus using OCT. RESULTS: Complete resolution of the serous detachment was seen in all 16 eyes within 1 month of extrafoveal PDT, while choroidal thickness in the area where PDT was applied decreased from 407 MUm [mean; 95% confidence interval (CI(95) ) 356-458 MUm] to 349 MUm (mean; CI(95) 300-399 MUm; p < 0.0001), and subfoveal choroidal thickness was reduced from 421 MUm (mean; CI(95) 352-489 MUm) to 346 MUm (mean; CI(95) 278-414 MUm; p = 0.0001). Initially, subfoveal choroidal thickness was significantly increased in the treated eye compared with the healthy fellow eye (mean 324 MUm; CI(95) 273-376 MUm; p = 0.0003), but after treatment, the difference was not significant. DISCUSSION: Photodynamic therapy of active CSC was followed by choroidal thickness reduction, not only locally but also at considerable distance from the treated area. Thus, the process that causes choroidal thickening in CSC appears to spread laterally within the choroid. PMID- 21586097 TI - Elevated laser flare values correlate with complicated course of anterior uveitis in patients with juvenile idiopathic arthritis. AB - PURPOSE: To evaluate the prognostic value of anterior chamber (AC) laser flare (LF) in uveitis associated with juvenile idiopathic arthritis (JIA). METHODS: Monocentre, retrospective study of 150 JIA children (girls n = 107, 71.3%) with unilateral or bilateral chronic anterior uveitis (statistical analysis of one eye per patient). LF values (KOWA FM-500), visual acuity, intraocular pressure, glaucoma treatment and uveitis complications were investigated longitudinally. RESULTS: Patients were followed up for a mean of 8.7 months (range 1-36). High LF values correlated with poor visual acuity (p < 0.0001). Patients with low LF values (LF <= 20 photon units per millisecond) less often required glaucoma medication (p = 0.0005) or surgery (p = 0.01) and showed a lower prevalence of cataract, band keratopathy, posterior synechiae, epiretinal membrane, optic disc oedema and glaucoma/ocular hypertension (p < 0.05, each). Baseline LF > 20 photon units per millisecond was a better prognosticator for the development of subsequent complications than baseline AC cells (p = 0.04). CONCLUSIONS: High LF values in patients with JIA uveitis are associated with poor vision and a higher prevalence of uveitis complications. PMID- 21586098 TI - Recent avian influenza virus A/H5N1 evolution in vaccinated and unvaccinated poultry from farms in Southern Vietnam, January-March 2010. AB - We report 15 new avian influenza virus A/H5N1 haemagglutinin (HA) sequences sampled from visibly sick domestic poultry in southern Vietnam, between 1 January 2010 and 6 March 2010. These HA sequences form a new sub-clade of the clade 1 H5N1 viruses that have been circulating in Vietnam since 2003/2004. The viruses are characterized by a change from isoleucine to valine at position 514 (I514V) and are 1.8% divergent at the nucleotide level from HA sequences sampled in Vietnam in 2007. Five new amino acid changes were observed at previously identified antigenic sites, and three were located within structural elements of the receptor-binding domain. One new mutation removed a potential N-linked glycosylation site, and a methionine insertion was observed in one virus at the polybasic cleavage site. Five of these viruses were sampled from farms where poultry were vaccinated against H5N1, but there was no association between observed amino acid changes and flock vaccination status. Despite the current lack of evidence for antigenic drift or immune escape in Vietnamese H5N1 viruses, continued surveillance remains a high priority. PMID- 21586099 TI - Therapeutic targets for bone metastases in breast cancer. AB - Breast cancer is prone to metastasize to bone. Once metastatic cells are in the bone marrow, they do not, on their own, destroy bone. Instead, they alter the functions of bone-resorbing (osteoclasts) and bone-forming cells (osteoblasts), resulting in skeletal complications that cause pathological fractures and pain. In this review, we describe promising molecular bone-targeted therapies that have arisen from recent advances in our understanding of the pathogenesis of breast cancer bone metastases. These therapies target osteoclasts (receptor activator of nuclear factor kB ligand, integrin alphavbeta3, c-Src, cathepsin K), osteoblasts (dickkopf-1, activin A, endothelin A) and the bone marrow microenvironment (transforming growth factor beta, bone morphogenetic proteins, chemokine CXCL-12 and its receptor CXCR4). The clinical exploitation of these bone-targeted agents will provide oncologists with novel therapeutic strategies for the treatment of skeletal lesions in breast cancer. PMID- 21586100 TI - Effect of erythropoietin therapy on clinical outcome in patients after acute ischemic stroke: a debatable issue. PMID- 21586101 TI - Bench-to-bedside review: contrast enhanced ultrasonography--a promising technique to assess renal perfusion in the ICU. AB - Acute kidney injury (AKI) is common in critically ill patients and associated with important morbidity and mortality. Although alterations in renal perfusion are thought to play a causative role in the pathogenesis of AKI, there is, to date, no reliable technique that allows the assessment of renal perfusion that is applicable in the ICU. Contrast-enhanced ultrasound (CEUS) is an ultrasound imaging technique that makes use of microbubble-based contrast agents. These microbubbles, when injected into the bloodstream, allow visualization of vascular structures and, with contrast-specific imaging modes, detection of blood flow at the capillary level. Some recent CEUS-derived approaches allow quantification of blood flow in several organs, including the kidney. Current generation ultrasound contrast agents have strong stability and safety profiles. Along with post marketing surveillance, numerous studies report safe administration of these agents, including in critically ill patients. This review presents information on the physical principles underlying CEUS, the methods allowing blood flow quantification and the potential applications of CEUS in critical care nephrology, currently as a research tool but perhaps in the future as a way of monitoring renal perfusion. PMID- 21586102 TI - Glucocorticoids in sepsis: dissecting facts from fiction. AB - An intact hypothalamic-pituitary-adrenal (HPA) axis with effective intracellular glucocorticoid anti-inflammatory activity is essential for host survival following exposure to an infectious agent. Glucocorticoids play a major role in regulating the activity of nuclear factor-kappa- B, which has a crucial and generalized role in inducing cytokine gene transcription after exposure to an invading pathogen. Severe sepsis is, however, associated with complex alterations of the HPA axis, which may result in decreased production of cortisol as well as glucocorticoid tissue resistance. PMID- 21586103 TI - Distinction between induction and maintenance dosing in continuous renal replacement therapy. PMID- 21586105 TI - Delayed diagnosis of tooth aspiration in three multiple trauma patients with mechanical ventilation. PMID- 21586104 TI - Clinical review: adiponectin biology and its role in inflammation and critical illness. AB - Adiponectin is an adipokine first described just over a decade ago. Produced almost exclusively by adipocytes, adiponectin circulates in high concentrations in human plasma. Research into this hormone has revealed it to have insulin sensitizing, anti-inflammatory and cardioprotective roles. This review discusses the history, biology and physiological role of adiponectin and explores its role in disease, with specific focus on adiponectin in inflammation and sepsis. It appears that an inverse relationship exists between adiponectin and inflammatory cytokines. Low levels of adiponectin have been found in critically ill patients, although data are limited in human subjects at this stage. The role of adiponectin in systemic inflammation and critical illness is not well defined. Early data suggest that plasma levels of adiponectin are decreased in critical illness. Whether this is a result of the disease process itself or whether patients with lower levels of this hormone are more susceptible to developing a critical illness is not known. This observation of lower adiponectin levels then raises the possibility of therapeutic options to increase circulating adiponectin levels. The various options for modulation of serum adiponectin (recombinant adiponectin, thiazolidinediones) are discussed. PMID- 21586106 TI - Biosimilars: a regulatory perspective from America. AB - Biosimilars are protein products that are sufficiently similar to a biopharmaceutical already approved by a regulatory agency. Several biotechnology companies and generic drug manufacturers in Asia and Europe are developing biosimilars of tumor necrosis factor inhibitors and rituximab. A biosimilar etanercept is already being marketed in Colombia and China. In the US, several natural source products and recombinant proteins have been approved as generic drugs under Section 505(b)(2) of the Food, Drug, and Cosmetic Act. However, because the complexity of large biopharmaceuticals makes it difficult to demonstrate that a biosimilar is structurally identical to an already approved biopharmaceutical, this Act does not apply to biosimilars of large biopharmaceuticals. Section 7002 of the Patient Protection and Affordable Care Act of 2010, which is referred to as the Biologics Price Competition and Innovation Act of 2009, amends Section 351 of the Public Health Service Act to create an abbreviated pathway that permits a biosimilar to be evaluated by comparing it with only a single reference biological product. This paper reviews the processes for approval of biosimilars in the US and the European Union and highlights recent changes in federal regulations governing the approval of biosimilars in the US. PMID- 21586107 TI - Mesenchymal stem cells for the treatment of systemic lupus erythematosus: is the cure for connective tissue diseases within connective tissue? AB - Mesenchymal stem cells (MSCs) are now known to display not only adult stem cell multipotency but also robust anti-inflammatory and regenerative properties. After widespread in vitro and in vivo preclinical testing in several autoimmune disease models, allogenic MSCs have been successfully applied in patients with severe treatment-refractory systemic lupus erythematosus. The impressive results of these uncontrolled phase I and II trials - mostly in patients with non-responding renal disease - point to the need to perform controlled multicentric trials. In addition, they suggest that there is much to be learned from the basic and clinical science of MSCs in order to reap the full potential of these multifaceted progenitor cells in the treatment of autoimmune diseases. PMID- 21586108 TI - Antifungal susceptibility of invasive yeast isolates in Italy: the GISIA3 study in critically ill patients. AB - BACKGROUND: Yeasts are a common cause of invasive fungal infections in critically ill patients. Antifungal susceptibility testing results of clinically significant fungal strains are of interest to physicians, enabling them to adopt appropriate strategies for empiric and prophylactic therapies. We investigated the antifungal susceptibility of yeasts isolated over a 2-year period from hospitalised patients with invasive yeast infections. METHODS: 638 yeasts were isolated from the blood, central venous catheters and sterile fluids of 578 patients on general and surgical intensive care units and surgical wards. Etest strips and Sensititre panels were used to test the susceptibility of the isolates to amphotericin B, anidulafungin, caspofungin, fluconazole, itraconazole, posaconazole and voriconazole in 13 laboratories centres (LC) and two co-ordinating centres (CC). The Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method was used at the CCs for comparison. RESULTS: Etest and Sensititre (LC/CC) MIC90 values were, respectively: amphotericin B 0.5/0.38, 1/1 mg/L; anidulafungin 2/1.5 and 1/1 mg/L; caspofungin 1/0.75 and 0.5/0.5 mg/L; fluconazole 12/8 and 16/16 mg/L; itraconazole 1/1.5, 0.5/0.5 mg/L; posaconazole 0.5 mg/L and voriconazole 0.25 mg/L for all. The overall MIC90 values were influenced by the reduced susceptibility of Candida parapsilosis isolates to echinocandins and a reduced or lack of susceptibility of Candida glabrata and Candida krusei to azoles, in particular fluconazole and itraconazole. Comparison of the LC and CC results showed good Essential Agreement (90.3% for Etest and 92.9% for Sensititre), and even higher Categorical Agreement (93.9% for Etest and 96% for Sensititre); differences were observed according to the species, method, and antifungal drug. No cross-resistance between echinocandins and triazoles was detected. CONCLUSIONS: Our data confirm the different antifungal susceptibility patterns among species, and highlight the need to perform antifungal susceptibility testing of clinically relevant yeasts. With the exception of a few species (e.g. C. glabrata for azoles and C. parapsilosis for echinocandins), the findings of our study suggest that two of the most widely used commercial methods (Etest and Sensititre) provide valid and reproducible results. PMID- 21586109 TI - Complexities and subtleties in the measurement and reporting of breastfeeding practices. AB - BACKGROUND: Monitoring of breastfeeding is vital. However, infant feeding practices are difficult to assess at the population level. Although significant efforts have been made towards the consistent measurement and reporting of breastfeeding, few countries have successfully implemented a system to do so. Many inaccuracies, inconsistencies and issues remain. This paper highlights the main issues relating to the methods and indicators used to monitor breastfeeding, particularly exclusive breastfeeding, at the population level. In doing so, it aims to support progress in this area. DISCUSSION: Indicators are used primarily for comparative purposes and should be broadly consistent with recommended practice; regarding exclusive breastfeeding this is 'to six months'. There are limitations to both main methods used to measure and report on breastfeeding: current status (often 24-hour recall), and longer-term recall. Issues relate to how age is considered within the analysis and interpretation of data, including boundary points or cut offs, as well as how breastfeeding practices are reported against different ages, especially regarding whether to use the preposition 'to' or 'at'. Other issues include the conversion from weeks to months, as well as the 'regular' versus 'first' introduction of something other than breast milk, to signify the deviation from exclusive breastfeeding. Differences in how data are collected, and uncertainties around how data are interpreted, have led to the mixed and often inaccurate reporting of breastfeeding practices, particularly exclusive breastfeeding. Assuming a particular definition of exclusive breastfeeding, such as that of the World Health Organization, the period over which exclusive breastfeeding is measured and how it is determined in the survey are important in relation to indicator phrasing. Often compromises are made in data collected to report against exclusive breastfeeding, despite subsequent reporting of exclusivity. SUMMARY: Indicators to report on breastfeeding must be carefully phrased. The commonly reported indicator exclusive breastfeeding at six months is redundant and should never be reported, while the more appropriate indicator exclusive breastfeeding to six months may not be sufficiently sensitive to change, and cannot be measured by current status methods alone. Importantly, indicators must accurately reflect the data collected to ensure valid comparisons between surveys. PMID- 21586110 TI - Mapping of the minimal inorganic phosphate transporting unit of human PiT2 suggests a structure universal to PiT-related proteins from all kingdoms of life. AB - BACKGROUND: The inorganic (Pi) phosphate transporter (PiT) family comprises known and putative Na(+)- or H(+)-dependent Pi-transporting proteins with representatives from all kingdoms. The mammalian members are placed in the outer cell membranes and suggested to supply cells with Pi to maintain house-keeping functions. Alignment of protein sequences representing PiT family members from all kingdoms reveals the presence of conserved amino acids and that bacterial phosphate permeases and putative phosphate permeases from archaea lack substantial parts of the protein sequence when compared to the mammalian PiT family members. Besides being Na(+)-dependent P(i) (NaP(i)) transporters, the mammalian PiT paralogs, PiT1 and PiT2, also are receptors for gamma-retroviruses. We have here exploited the dual-function of PiT1 and PiT2 to study the structure function relationship of PiT proteins. RESULTS: We show that the human PiT2 histidine, H(502), and the human PiT1 glutamate, E(70),--both conserved in eukaryotic PiT family members--are critical for P(i) transport function. Noticeably, human PiT2 H(502) is located in the C-terminal PiT family signature sequence, and human PiT1 E(70) is located in ProDom domains characteristic for all PiT family members.A human PiT2 truncation mutant, which consists of the predicted 10 transmembrane (TM) domain backbone without a large intracellular domain (human PiT2DeltaR(254)-V(483)), was found to be a fully functional P(i) transporter. Further truncation of the human PiT2 protein by additional removal of two predicted TM domains together with the large intracellular domain created a mutant that resembles a bacterial phosphate permease and an archaeal putative phosphate permease. This human PiT2 truncation mutant (human PiT2DeltaL(183) V(483)) did also support P(i) transport albeit at very low levels. CONCLUSIONS: The results suggest that the overall structure of the P(i)-transporting unit of the PiT family proteins has remained unchanged during evolution. Moreover, in combination, our studies of the gene structure of the human PiT1 and PiT2 genes (SLC20A1 and SLC20A2, respectively) and alignment of protein sequences of PiT family members from all kingdoms, along with the studies of the dual functions of the human PiT paralogs show that these proteins are excellent as models for studying the evolution of a protein's structure-function relationship. PMID- 21586111 TI - Multidimensional evaluation of performance with experimental application of balanced scorecard: a two year experience. AB - BACKGROUND: In today's dynamic health-care system, organizations such as hospitals are required to improve their performance for multiple stakeholders and deliver an integrated care that means to work effectively, be innovative and organize efficiently. Achieved goals and levels of quality can be successfully measured by a multidimensional approach like Balanced Scorecard (BSC). The aim of the study was to verify the opportunity to introduce BSC framework to measure performance in St. Anna University Hospital of Ferrara, applying it to the Clinical Laboratory Operative Unit in order to compare over time performance results and achievements of assigned targets. METHODS: In the first experience with BSC we distinguished four perspectives, according to Kaplan and Norton, identified Key Performance Areas and Key Performance Indicators, set standards and weights for each objective, collected data for all indicators, recognized cause-and-effect relationships in a strategic map. One year later we proceeded with the next data collection and analysed the preservation of framework aptitude to measure Operative Unit performance. In addition, we verified the ability to underline links between strategic actions belonging to different perspectives in producing outcomes changes. RESULTS: The BSC was found to be effective for underlining existing problems and identifying opportunities for improvements. The BSC also revealed the specific perspective contribution to overall performance enhancement. After time results comparison was possible depending on the selection of feasible and appropriate key performance indicators, which was occasionally limited by data collection problems. CONCLUSIONS: The first use of BSC to compare performance at Operative Unit level, in course of time, suggested this framework can be successfully adopted for results measuring and revealing effective health factors, allowing health-care quality improvements. PMID- 21586112 TI - Local apoptosis promotes collagen production by monocyte-derived cells in transforming growth factor beta1-induced lung fibrosis. AB - BACKGROUND: Collagen-containing leukocytes (CD45+Col-I+) accumulate in diseased and fibrotic tissues. However, the precise identity of these cells and whether injury is required for their recruitment remain unknown. Using a murine model of pulmonary fibrosis in which an inducible, bioactive form of the human transforming growth factor (TGF)-beta1 gene is targeted to the lung, we characterized the cell surface phenotype of collagen-containing CD45+ cells in the lung and tested the hypothesis that apoptotic cell death responses are essential to the accumulation of CD45+Col-I+ cells. RESULTS: Our studies demonstrate that CD45+Col-I+ cells appearing in the TGF-beta1-exposed murine lung express markers of the monocyte lineage. Inhibition of apoptosis via pharmacological caspase blockade led to a significant reduction in CD45+Col-I+ cells, which appear to accumulate independently of alternatively activated macrophages. There are also increased levels of apoptosis and greater numbers of CD45+Col-I+ in the lung tissue of patients with two distinct forms of fibrotic lung disease, idiopathic pulmonary fibrosis and connective tissue disease-related interstitial lung disease, when compared to lung from healthy normal controls. These findings are accompanied by an increase in collagen production in cultured monocytes obtained from subjects with fibrotic lung disease. Treatment of these cultured cells with the caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O methyl]-fluoromethylketone (Z-VAD/fmk) reduces both apoptosis and collagen production in all subjects. CONCLUSIONS: Interventions that prevent collagen production by monocytes via modulation of caspase activation and of apoptosis may be ameliorative in monocyte-associated, TGF-beta1-driven processes such as pulmonary fibrosis. PMID- 21586113 TI - A fast and accurate method to detect allelic genomic imbalances underlying mosaic rearrangements using SNP array data. AB - BACKGROUND: Mosaicism for copy number and copy neutral chromosomal rearrangements has been recently identified as a relatively common source of genetic variation in the normal population. However its prevalence is poorly defined since it has been only studied systematically in one large-scale study and by using non optimal ad-hoc SNP array data analysis tools, uncovering rather large alterations (> 1 Mb) and affecting a high proportion of cells. Here we propose a novel methodology, Mosaic Alteration Detection-MAD, by providing a software tool that is effective for capturing previously described alterations as wells as new variants that are smaller in size and/or affecting a low percentage of cells. RESULTS: The developed method identified all previously known mosaic abnormalities reported in SNP array data obtained from controls, bladder cancer and HapMap individuals. In addition MAD tool was able to detect new mosaic variants not reported before that were smaller in size and with lower percentage of cells affected. The performance of the tool was analysed by studying simulated data for different scenarios. Our method showed high sensitivity and specificity for all assessed scenarios. CONCLUSIONS: The tool presented here has the ability to identify mosaic abnormalities with high sensitivity and specificity. Our results confirm the lack of sensitivity of former methods by identifying new mosaic variants not reported in previously utilised datasets. Our work suggests that the prevalence of mosaic alterations could be higher than initially thought. The use of appropriate SNP array data analysis methods would help in defining the human genome mosaic map. PMID- 21586114 TI - Four year experience of sarcoma of soft tissues and bones in a tertiary care hospital and review of literature. AB - BACKGROUND: Sarcoma encompasses an uncommon group of cancer and the data is insufficient from Pakistan. We report our four years experience of Sarcoma of soft tissues and bones. METHODS: This cross sectional study was carried out at Aga Khan University Hospital from 2004 to 2008. The patients were divided into two groups from the outset i.e. initially diagnosed and relapsed group and separate sub group analysis was conducted. RESULTS: Out of 93 newly diagnosed patients, 58 belonged to bone sarcoma and 35 to soft tissue sarcoma group. While for relapsed patients, 5 had soft tissue sarcoma and 9 had bone sarcoma. Mean age was 32.5 years. At presentation, approximately two third patients had localised disease while remaining one third had metastatic disease. The Kaplan Meier estimate of median recurrence free survival was 25 months, 35 months, and 44 months for Osteogenic sarcoma, Ewing's sarcoma and Chondrosarcoma respectively. For Leiomyosarcoma and Synovial sarcoma, it was 20 and 19 months respectively. The grade of the tumour (p = 0.02) and surgical margin status (p = 0.001) were statistically significant for determination of relapse of disease. CONCLUSION: The median recurrence free survival of patients in our study was comparable to the reported literature but with significant lost to follow rate. Further large scale, multi centre studies are needed to have a more comprehensive understanding of this heterogeneous disease in our population. PMID- 21586115 TI - Parental risk factors and anorectal malformations: systematic review and meta analysis. AB - BACKGROUND: Anorectal malformations (ARM) are rare forms of congenital uro-rectal anomalies with largely unknown causes. Besides genetic factors, prenatal exposures of the parents to nicotine, alcohol, caffeine, illicit drugs, occupational hazards, overweight/obesity and diabetes mellitus are suspected as environmental risk factors. METHODS: Relevant studies published until August 2010 were identified through systematic search in PubMed, EMBASE, ISI Web of Knowledge and the Cochrane Library databases. Furthermore, related and cross-referencing publications were reviewed. Pooled odds ratios (95% confidence intervals) were determined to quantify associations of maternal and paternal smoking, maternal alcohol consumption, underweight (body mass index [BMI] < 18.5), overweight (BMI 25-29.9), obesity (BMI >=30) and maternal diabetes mellitus with ARM using meta analyses. RESULTS: 22 studies that reported on the association between prenatal environmental risk factors and infants born with ARM were included in this review. These were conducted in the United States of America (n = 12), Spain (n = 2), Sweden (n = 2), the Netherlands (n = 2), Japan (n = 1), France (n = 1), Germany (n = 1) and Hungary (n = 1). However, only few of these studies reported on the same risk factors. Studies were heterogeneous with respect to case numbers, control types and adjustment for covariates. Consistently increased risks were observed for paternal smoking and maternal overweight, obesity and diabetes, but not for maternal smoking and alcohol consumption. In meta-analyses, pooled odds ratios (95% confidence intervals) for paternal smoking, maternal overweight, obesity, pre-gestational and gestational diabetes were 1.53 (1.04 2.26), 1.25 (1.07-1.47), 1.64 (1.35-2.00), 4.51 (2.55-7.97) and 1.81 (1.23-2.65), respectively. CONCLUSION: Evidence on risk factors for ARM from epidemiological studies is still very limited. Nevertheless, the few available studies indicate paternal smoking and maternal overweight, obesity and diabetes to be associated with increased risks. Further, ideally large-scale multicentre and register-based studies are needed to clarify the role of key risk factors for the development of ARM. PMID- 21586116 TI - Design and characterization of protein-quercetin bioactive nanoparticles. AB - BACKGROUND: The synthesis of bioactive nanoparticles with precise molecular level control is a major challenge in bionanotechnology. Understanding the nature of the interactions between the active components and transport biomaterials is thus essential for the rational formulation of bio-nanocarriers. The current study presents a single molecule of bovine serum albumin (BSA), lysozyme (Lys), or myoglobin (Mb) used to load hydrophobic drugs such as quercetin (Q) and other flavonoids. RESULTS: Induced by dimethyl sulfoxide (DMSO), BSA, Lys, and Mb formed spherical nanocarriers with sizes less than 70 nm. After loading Q, the size was further reduced by 30%. The adsorption of Q on protein is mainly hydrophobic, and is related to the synergy of Trp residues with the molecular environment of the proteins. Seven Q molecules could be entrapped by one Lys molecule, 9 by one Mb, and 11 by one BSA. The controlled releasing measurements indicate that these bioactive nanoparticles have long-term antioxidant protection effects on the activity of Q in both acidic and neutral conditions. The antioxidant activity evaluation indicates that the activity of Q is not hindered by the formation of protein nanoparticles. Other flavonoids, such as kaempferol and rutin, were also investigated. CONCLUSIONS: BSA exhibits the most remarkable abilities of loading, controlled release, and antioxidant protection of active drugs, indicating that such type of bionanoparticles is very promising in the field of bionanotechnology. PMID- 21586117 TI - Clustering patients on the basis of their individual course of low back pain over a six month period. AB - BACKGROUND: Several researchers have searched for subgroups in the heterogeneous population of patients with non-specific low back pain (LBP). To date, subgroups have been identified based on psychological profiles and the variation of pain. METHODS: This multicentre prospective observational study explored the 6- month clinical course with measurements of bothersomeness that were collected from weekly text messages that were sent by 176 patients with LBP. A hierarchical cluster analysis, Ward's method, was used to cluster patients according to the development of their pain. RESULTS: Four clusters with distinctly different clinical courses were described and further validated against clinical baseline variables and outcomes. Cluster 1, a "stable" cluster, where the course was relatively unchanged over time, contained young patients with good self- rated health. Cluster 2, a group of "fast improvers" who were very bothered initially but rapidly improved, consisted of patients who rated their health as relatively poor but experienced the fewest number of days with bothersome pain of all the clusters. Cluster 3 was the "typical patient" group, with medium bothersomeness at baseline and an average improvement over the first 4-5 weeks. Finally, cluster 4 contained the "slow improvers", a group of patients who improved over 12 weeks. This group contained older individuals who had more LBP the previous year and who also experienced most days with bothersome pain of all the clusters. CONCLUSIONS: It is possible to define clinically meaningful clusters of patients based on their individual course of LBP over time. Future research should aim to reproduce these clusters in different populations, add further clinical variables to distinguish the clusters and test different treatment strategies for them. PMID- 21586118 TI - The Roche Cancer Genome Database 2.0. AB - BACKGROUND: Cancer is a disease of genome alterations that arise through the acquisition of multiple somatic DNA sequence mutations. Some of these mutations can be critical for the development of a tumor and can be useful to characterize tumor types or predict outcome. DESCRIPTION: We have constructed an integrated biological information system termed the Roche Cancer Genome Database (RCGDB) combining different human mutation databases already publicly available. This data is further extended by hand-curated information from publications.The current version of the RCGDB provides a user-friendly graphical interface that gives access to the data in different ways: (1) Single interactive search by genes, samples, cell lines, diseases, as well as pathways, (2) batch searches for genes and cell lines, (3) customized searches for regularly occurring requests, and (4) an advanced query interface enabling the user to query for samples and mutations by various filter criteria. CONCLUSION: The interfaces of the presented database enable the user to search and view mutations in an intuitive and straight-forward manner. The database is freely accessible at http://rcgdb.bioinf.uni-sb.de/MutomeWeb/. PMID- 21586119 TI - Implementing a hypertension management programme in a rural area: local approaches and experiences from Ba-Vi district, Vietnam. AB - BACKGROUND: Costly efforts have been invested to control and prevent cardiovascular diseases (CVD) and their risk factors but the ideal solutions for low resource settings remain unclear. This paper aims at summarising our approaches to implementing a programme on hypertension management in a rural commune of Vietnam. METHODS: In a rural commune, a programme has been implemented since 2006 to manage hypertensive people at the commune health station and to deliver health education on CVD risk factors to the entire community. An initial cross-sectional survey was used to screen for hypertensives who might enter the management programme. During 17 months of implementation, other people with hypertension were also followed up and treated. Data were collected from all individual medical records, including demographic factors, behavioural CVD risk factors, blood pressure levels, and number of check-ups. These data were analysed to identify factors relating to adherence to the management programme. RESULTS: Both top-down and bottom-up approaches were applied to implement a hypertension management programme. The programme was able to run independently at the commune health station after 17 months. During the implementation phase, 497 people were followed up with an overall regular follow-up of 65.6% and a dropout of 14.3%. Severity of hypertension and effectiveness of treatment were the main factors influencing the decision of people to adhere to the management programme, while being female, having several behavioural CVD risk factors or a history of chronic disease were the predictors for deviating from the programme. CONCLUSION: Our model showed the feasibility, applicability and future potential of a community based model of comprehensive hypertension care in a low resource context using both top-down and bottom-up approaches to engage all involved partners. This success also highlighted the important roles of both local authorities and a cardiac care network, led by an outstanding cardiac referral centre. PMID- 21586120 TI - Relationships between lipid profiles and metabolic syndrome, insulin resistance and serum high molecular adiponectin in Japanese community-dwelling adults. AB - BACKGROUND: There are few studies to demonstrate the associations between newly addressed lipid profiles and metabolic syndrome (MetS)-associated variables. METHODS: Study participants without medications for hypertension, diabetes, or dyslipidemia {614 men aged 58 +/- 14 (mean +/- standard deviation; range, 20-89) years and 779 women aged 60 +/- 12 (range, 21-88) years} were randomly recruited from a single community at the time of their annual health examination. The association between lipid profiles (total cholesterol (T-C), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, T-C/HDL-C, TG/HDL-C, LDL-C/HDL-C ratio and MetS, Insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR), and serum HMW adiponectin were analyzed. RESULTS: In multiple linear regression analysis, TG/HDL-C and T-C/HDL-C ratios as well as TG showed significantly strong associations with all three MetS-associated variables in both men and women. In men, the ROC curve analyses showed that the best marker for these variables was TG/HDL-C ratio, with the AUC for presence of MetS (AUC, 0.82; 95% CI, 0.77-0.87), HOMA-IR (AUC, 0.75; 95% CI, 0.70-0.80), and serum HMW adiponectin (AUC, 0.67; 95% CI, 0.63-0.71), respectively. The T-C/HDL-C ratio, TG, HDL-C, LDL-C/HDL-C ratio, and non-HDL-C also discriminated these markers; however all their AUC estimates were lower than TG/HDL-C ratio. These results were similar in women. CONCLUSION: In Japanese community-dwelling adults, lipid ratios of TG/HDL-C, T-C/HDL-C, LDL C/HDL-C as well as TG and HDL-C were consistently associated with MetS, insulin resistance and serum HMW adiponectin. Lipid ratios may be used as reliable markers. PMID- 21586121 TI - Central and East European migrant men who have sex with men in London: a comparison of recruitment methods. AB - BACKGROUND: Following the expansion of the European Union, there has been a large influx of Central and East European (CEE) migrants to the UK. CEE men who have sex with men (MSM) represent a small minority within this population that are none-the-less important to capture in sexual health research among the CEE migrant community. This paper examines the feasibility of recruiting CEE MSM for a survey of sexual behaviour in London using respondent driven sampling (RDS), via gay websites and in GUM clinics. METHODS: We sought CEE MSM to start RDS chain referral among GUM clinic attendees, our personal contacts and at gay events and venues in central London. We recruited CEE MSM (n = 485) via two popular websites for gay men in Britain (March-May 2009) and at two central London GUM clinics (n = 51) (July 2008-March 2009). RESULTS: We found seventeen men who knew other CEE MSM in London and agreed to recruit contacts into the study. These men recruited only three men into the study, none of whom recruited any further respondents, and RDS was abandoned after 7 months (July 2008-January 2009). Half of the men that we approached to participate in RDS did not know any other CEE MSM in London. Men who agreed to recruit contacts for RDS were rather more likely to have been in the UK for more than one year (94.1% vs 70.0%, p = 0.052). Men recruited through gay websites and from GUM clinics were similar. CONCLUSIONS: The Internet was the most successful method for collecting data on sexual risk behaviour among CEE MSM in London. CEE MSM in London were not well networked. RDS may also have failed because they did not fully understand the procedure and/or the financial incentive was not sufficient motivation to take part. PMID- 21586123 TI - Suppressing glucose uptake and acetic acid production increases membrane protein overexpression in Escherichia coli. AB - BACKGROUND: The production of integral membrane spanning proteins (IMP's) constitutes a bottleneck in pharmaceutical development. It was long considered that the state-of-the-art was to produce the proteins as inclusion bodies using a powerful induction system. However, the quality of the protein was compromised and the production of a soluble protein that is incorporated into the membrane from which it is extracted is now considered to be a better method. Earlier research has indicated that a slower rate of protein synthesis might overcome the tendency to form inclusion bodies. We here suggest the use of a set of E. coli mutants characterized by a slower rate of growth and protein synthesis as a tool for increasing the amount of soluble protein in high- throughput protein production processes. RESULTS: A set of five IMP's was chosen which were expressed in three mutants and the corresponding WT cell (control). The mutations led to three different substrate uptake rates, two of which were considerably slower than that of the wild type. Using the mutants, we were able to express three out of the five membrane proteins. Most successful was the mutant growing at 50% of the wild type growth rate. A further effect of a low growth rate is a low acetic acid formation, and we believe that this is a possible reason for the better production. This hypothesis was further supported by expression from the BL21(DE3) strain, using the same plasmid. This strain grows at a high growth rate but nevertheless yields only small amounts of acetic acid. This strain was also able to express three out of the five IMP's, although at lower quantities. CONCLUSIONS: The use of mutants that reduce the specific substrate uptake rate seems to be a versatile tool for overcoming some of the difficulties in the production of integral membrane spanning proteins. A set of strains with mutations in the glucose uptake system and with a lower acetic acid formation were able to produce three out of five membrane proteins that it was not possible to produce with the corresponding wild type. PMID- 21586122 TI - The Enhancer of split transcription factor Her8a is a novel dimerisation partner for Her3 that controls anterior hindbrain neurogenesis in zebrafish. AB - BACKGROUND: Neurogenesis control and the prevention of premature differentiation in the vertebrate embryo are crucial processes, allowing the formation of late born cell types and ensuring the correct shape and cytoarchitecture of the brain. Members of the Hairy/Enhancer of Split (Hairy/E(spl)) family of bHLH-Orange transcription factors, such as zebrafish Her3, 5, 9 and 11, are implicated in the local inhibition of neurogenesis to maintain progenitor pools within the early neural plate. To better understand how these factors exert their inhibitory function, we aimed to isolate some of their functional interactors. RESULTS: We used a yeast two-hybrid screen with Her5 as bait and recovered a novel zebrafish Hairy/E(spl) factor--Her8a. Using phylogenetic and synteny analyses, we demonstrate that her8a evolved from an ancient duplicate of Hes6 that was recently lost in the mammalian lineage. We show that her8a is expressed across the mid- and anterior hindbrain from the start of segmentation. Through knockdown and misexpression experiments, we demonstrate that Her8a is a negative regulator of neurogenesis and plays an essential role in generating progenitor pools within rhombomeres 2 and 4--a role resembling that of Her3. Her8a co-purifies with Her3, suggesting that Her8a-Her3 heterodimers may be relevant in this domain of the neural plate, where both proteins are co-expressed. Finally, we demonstrate that her8a expression is independent of Notch signaling at the early neural plate stage but that SoxB factors play a role in its expression, linking patterning information to neurogenesis control. Overall, the regulation and function of Her8a differ strikingly from those of its closest relative in other vertebrates- the Hes6-like proteins. CONCLUSIONS: Our results characterize the phylogeny, expression and functional interactions involving a new Her factor, Her8a, and highlight the complex interplay of E(spl) proteins that generates the neurogenesis pattern of the zebrafish early neural plate. PMID- 21586124 TI - Concomitant detection of IFNalpha signature and activated monocyte/dendritic cell precursors in the peripheral blood of IFNalpha-treated subjects at early times after repeated local cytokine treatments. AB - BACKGROUND: Interferons alpha (IFNalpha) are the cytokines most widely used in clinical medicine for the treatment of cancer and viral infections. Among the immunomodulatory activities possibly involved in their therapeutic efficacy, the importance of IFNalpha effects on dendritic cells (DC) differentiation and activation has been considered. Despite several studies exploiting microarray technology to characterize IFNalpha mechanisms of action, there is currently no consensus on the core signature of these cytokines in the peripheral blood of IFNalpha-treated individuals, as well as on the existence of blood genomic and proteomic markers of low-dose IFNalpha administered as a vaccine adjuvant. METHODS: Gene profiling analysis with microarray was performed on PBMC isolated from melanoma patients and healthy individuals 24 hours after each repeated injection of low-dose IFNalpha, administered as vaccine adjuvant in two separate clinical trials. At the same time points, cytofluorimetric analysis was performed on CD14+ monocytes, to detect the phenotypic modifications exerted by IFNalpha on antigen presenting cells precursors. RESULTS: An IFNalpha signature was consistently observed in both clinical settings 24 hours after each repeated administration of the cytokine. The observed modulation was transient, and did not reach a steady state level refractory to further stimulations. The molecular signature observed ex vivo largely matched the one detected in CD14+ monocytes exposed in vitro to IFNalpha, including the induction of CXCL10 at the transcriptional and protein level. Interestingly, IFNalpha ex vivo signature was paralleled by an increase in the percentage and expression of costimulatory molecules by circulating CD14+/CD16+ monocytes, indicated as natural precursors of DC in response to danger signals. CONCLUSIONS: Our results provide new insights into the identification of a well defined molecular signature as biomarker of IFNalpha administered as immune adjuvants, and for the characterization of new molecular and cellular players, such as CXCL10 and CD14+/CD16+ cells, mediating and possibly predicting patient response to these cytokines. PMID- 21586125 TI - Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1beta and IL-6. AB - BACKGROUND: Chronic neurodegeneration comprises an inflammatory response but its contribution to the progression of disease remains unclear. We have previously shown that microglial cells are primed by chronic neurodegeneration, induced by the ME7 strain of prion disease, to synthesize limited pro-inflammatory cytokines but to produce exaggerated responses to subsequent systemic inflammatory insults. The consequences of this primed response include exaggerated hypothermic and sickness behavioural responses, acute neuronal death and accelerated progression of disease. Here we investigated whether inhibition of systemic cytokine synthesis using the anti-inflammatory steroid dexamethasone-21-phosphate was sufficient to block any or all of these responses. METHODS: ME7 animals, at 18-19 weeks post-inoculation, were challenged with LPS (500 MUg/kg) in the presence or absence of dexamethasone-21-phosphate (2 mg/kg) and effects on core-body temperature and systemic and CNS cytokine production and apoptosis were examined. RESULTS: LPS induced hypothermia and decreased exploratory activity. Dexamethasone-21-phosphate prevented this hypothermia, markedly suppressed systemic IL-1beta and IL-6 secretion but did not prevent decreased exploration. Furthermore, robust transcription of cytokine mRNA occurred in the hippocampus of both ME7 and NBH (normal brain homogenate) control animals despite the effective blocking of systemic cytokine synthesis. Microglia primed by neurodegeneration were not blocked from the robust synthesis of IL-1beta protein and endothelial COX-2 was also robustly synthesized. We injected biotinylated LPS at 100 MUg/kg and even at this lower dose this could be detected in blood plasma. Apoptosis was acutely induced by LPS, despite the inhibition of the systemic cytokine response. CONCLUSIONS: These data suggest that LPS can directly activate the brain endothelium even at relatively low doses, obviating the need for systemic cytokine stimulation to transduce systemic inflammatory signals into the brain or to exacerbate existing pathology. PMID- 21586126 TI - Converging seasonal prevalence dynamics in experimental epidemics. AB - BACKGROUND: Regular seasonal changes in prevalence of infectious diseases are often observed in nature, but the mechanisms are rarely understood. Empirical tests aiming at a better understanding of seasonal prevalence patterns are not feasible for most diseases and thus are widely lacking. Here, we set out to study experimentally the seasonal prevalence in an aquatic host-parasite system. The microsporidian parasite Hamiltosporidium tvarminnensis exhibits pronounced seasonality in natural rock pool populations of its host, Daphnia magna with a regular increase of prevalence during summer and a decrease during winter. An earlier study was, however, unable to test if different starting conditions (initial prevalence) influence the dynamics of the disease in the long term. Here, we aim at testing how the starting prevalence affects the regular prevalence changes over a 4-year period in experimental populations. RESULTS: In an outdoor experiment, populations were set up to include the extremes of the prevalence spectrum observed in natural populations: 5% initial prevalence mimicking a newly invading parasite, 100% mimicking a rock pool population founded by infected hosts only, and 50% prevalence which is commonly observed in natural populations in spring. The parasite exhibited similar prevalence changes in all treatments, but seasonal patterns in the 100% treatment differed significantly from those in the 5% and 50% treatments. Populations started with 5% and 50% prevalence exhibited strong and regular seasonality already in the first year. In contrast, the amplitude of changes in the 100% treatment was low throughout the experiment demonstrating the long-lasting effect of initial conditions on prevalence dynamics. CONCLUSIONS: Our study shows that the time needed to approach the seasonal changes in prevalence depends strongly on the initial prevalence. Because individual D. magna populations in this rock pool metapopulation are mostly short lived, only few populations might ever reach a point where the initial conditions are not visible anymore. PMID- 21586127 TI - Surgical trial in lobar intracerebral haemorrhage (STICH II) protocol. AB - BACKGROUND: Within the spectrum of spontaneous intracerebral haemorrhage there are some patients with large or space occupying haemorrhage who require surgery for neurological deterioration and others with small haematomas who should be managed conservatively. There is equipoise about the management of patients between these two extremes. In particular there is some evidence that patients with lobar haematomas and no intraventricular haemorrhage might benefit from haematoma evacuation. The STICH II study will establish whether a policy of earlier surgical evacuation of the haematoma in selected patients will improve outcome compared to a policy of initial conservative treatment. METHODS/DESIGN: An international multicentre randomised parallel group trial. Only patients for whom the treating neurosurgeon is in equipoise about the benefits of early craniotomy compared to initial conservative treatment are eligible. All patients must have a CT scan confirming spontaneous lobar intracerebral haemorrhage (<=1 cm from the cortex surface of the brain and 10-100 ml in volume). Any clotting or coagulation problems must be corrected and randomisation must take place within 48 hours of ictus. With 600 patients, the study will be able to demonstrate a 12% benefit from surgery (2p < 0.05) with 80% power.Stratified randomisation is undertaken using a central 24 hour randomisation service accessed by telephone or web. Patients randomised to early surgery should have the operation within 12 hours. Information about the status (Glasgow Coma Score and focal signs) of all patients through the first five days of their trial progress is also collected in addition to another CT scan at about five days (+/- 2 days). Outcome is measured at six months via a postal questionnaire to the patient. Primary outcome is death or severe disability defined using a prognosis based 8 point Glasgow Outcome Scale. Secondary outcomes include: Mortality, Rankin, Barthel, EuroQol, and Survival. TRIAL REGISTRATION: ISRCTN: ISRCTN22153967. PMID- 21586128 TI - Natriuretic peptide receptor a as a novel target for prostate cancer. AB - BACKGROUND: The receptor for the cardiac hormone atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPRA), is expressed in cancer cells, and natriuretic peptides have been implicated in cancers. However, the direct role of NPRA signaling in prostate cancer remains unclear. RESULTS: NPRA expression was examined by western blotting, RT-PCR and immunohistochemistry. NPRA was downregulated by transfection of siRNA, shRNA and NPRA inhibitor (iNPRA). Antitumor efficacy of iNPRA was tested in mice using a TRAMP-C1 xenograft. Here, we demonstrated that NPRA is abundantly expressed on tumorigenic mouse and human prostate cells, but not in nontumorigenic prostate epithelial cells. NPRA expression showed positive correlation with clinical staging in a human PCa tissue microarray. Down-regulation of NPRA by siNPRA or iNPRA induced apoptosis in PCa cells. The mechanism of iNPRA-induced anti-PCa effects was linked to NPRA induced expression of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine over-expressed in PCa and significantly reduced by siNPRA. Prostate tumor cells implanted in mice deficient in atrial natriuretic peptide receptor A (NPRA-KO) failed to grow, and treatment of TRAMP-C1 xenografts with iNPRA reduced tumor burden and MIF expression. Using the TRAMP spontaneous PCa model, we found that NPRA expression correlated with MIF expression during PCa progression. CONCLUSIONS: Collectively, these results suggest that NPRA promotes PCa development in part by regulating MIF. Our findings also suggest that NPRA is a potential prognostic marker and a target for PCa therapy. PMID- 21586129 TI - Dialectics of mindfulness: implications for western medicine. AB - Mindfulness as a clinical and nonclinical intervention for a variety of symptoms has recently received a substantial amount of interest. Although the application of mindfulness appears straightforward and its effectiveness is well supported, the concept may easily be misunderstood. This misunderstanding may severely limit the benefit of mindfulness-based interventions. It is therefore necessary to understand that the characteristics of mindfulness are based on a set of seemingly paradoxical structures. This article discusses the underlying paradox by disentangling it into five dialectical positions - activity vs. passivity, wanting vs. non-wanting, changing vs. non-changing, non-judging vs. non-reacting, and active acceptance vs. passive acceptance, respectively. Finally, the practical implications for the medical professional as well as potential caveats are discussed. PMID- 21586130 TI - Quantification of the energy gap in young overweight children. The PIAMA birth cohort study. AB - BACKGROUND: Overweight develops gradually as a result of a long term surplus on the balance between energy intake and energy expenditure. Aim of this study was to quantify the positive energy balance responsible for excess body weight gain (energy gap) in young overweight children. METHODS: Reported data on weight and height were used of 2190 Dutch children participating in the PIAMA birth cohort study. Accumulated body energy was estimated from the weight gain observed between age 2 and age 5-7. Energy gap was calculated as the difference in positive energy balance between children with and without overweight assuming an energy efficiency of 50%. RESULTS: Ten percent of the children were overweight at the age of 5-7 years. For these children, median weight gain during 4-years follow-up was 13.3 kg, as compared to 8.5 kg in the group of children who had a normal weight at the end of the study. A daily energy gap of 289-320 kJ (69-77 kcal) was responsible for the excess weight gain or weight maintenance in the majority of the children who were overweight at the age of 5-7 years. The increase in daily energy requirement to maintain the 4.8 kilograms excess weight gain among overweight children at the end of the study was approximately 1371 kJ. CONCLUSIONS: An energy gap of about 289-320 kJ per day over a number of years can make the difference between normal weight and overweight in young children. Closing the energy gap in overweight children can be achieved by relatively small behavior changes. However, much more effort is required to lose the excess weight gained. PMID- 21586131 TI - Impacts of both reference population size and inclusion of a residual polygenic effect on the accuracy of genomic prediction. AB - BACKGROUND: The purpose of this work was to study the impact of both the size of genomic reference populations and the inclusion of a residual polygenic effect on dairy cattle genetic evaluations enhanced with genomic information. METHODS: Direct genomic values were estimated for German Holstein cattle with a genomic BLUP model including a residual polygenic effect. A total of 17,429 genotyped Holstein bulls were evaluated using the phenotypes of 44 traits. The Interbull genomic validation test was implemented to investigate how the inclusion of a residual polygenic effect impacted genomic estimated breeding values. RESULTS: As the number of reference bulls increased, both the variance of the estimates of single nucleotide polymorphism effects and the reliability of the direct genomic values of selection candidates increased. Fitting a residual polygenic effect in the model resulted in less biased genome-enhanced breeding values and decreased the correlation between direct genomic values and estimated breeding values of sires in the reference population. CONCLUSIONS: Genetic evaluation of dairy cattle enhanced with genomic information is highly effective in increasing reliability, as well as using large genomic reference populations. We found that fitting a residual polygenic effect reduced the bias in genome-enhanced breeding values, decreased the correlation between direct genomic values and sire's estimated breeding values and made genome-enhanced breeding values more consistent in mean and variance as is the case for pedigree-based estimated breeding values. PMID- 21586132 TI - Monitoring resistance of Plasmdium vivax: point mutations in dihydrofolate reductase gene in isolates from Central China. AB - BACKGROUND: Malaria still represents a significant public health problem in China, and the cases dramatically increased in Central China after 2001. Antifolate resistance in Plasmodium vivax is caused by point mutations in genes encoding dihydrofolate reductase (pvdhfr) and dihydropteroate synthase (pvdhps). In this study, we used direct sequencing to investigate genetic variation in pvdhfr of malaria patients' samples from Central China. RESULTS: Among all the samples, 21.4% were wild-type, whereas mutations were detected at three codons (58, 61 and 117) including single mutant (34.6%) and double mutants (43.8%). The most prevalent mutant allele was the one with double mutation at codons 58 and 117 (24.6%). Three types of single mutation (S58R, T61M and S117N) were found in 2.1%, 11.8% and 20.9% of parasite isolates, respectively. The four P. vivax parasite populations in Central China also differed in pvdhfr allele frequencies. CONCLUSIONS: This study suggested that P. vivax in Central China may be relatively susceptible to pyrimethamine. And it also highlights genotyping in the pvdhfr genes remains a useful tool to monitor the emergence and spread of P. vivax pyrimethamine resistance. PMID- 21586133 TI - Oral P. gingivalis infection alters the vascular reactivity in healthy and spontaneously atherosclerotic mice. AB - BACKGROUND: Considering that recent studies have demonstrated endothelial dysfunction in subjects with periodontitis and that there is no information about vascular function in coexistence of periodontitis and atherosclerosis, we assessed the impact of oral inoculation with the periodontal pathogen Porphyromonas gingivalis on vascular reactivity in healthy and hypercholesterolemic apolipoprotein E-deficient (ApoE) mice. In vitro preparations of mesenteric arteriolar bed were used to determine the vascular responses to acetylcholine, sodium nitroprusside and phenylephrine (PE). RESULTS: Alveolar bone resorption, an evidence of periodontitis, was assessed and confirmed in all infected mice. Acetylcholine- and sodium nitroprusside-induced vasorelaxations were similar among all groups. Non-infected ApoE mice were hyperreactive to PE when compared to non-infected healthy mice. P gingivalis infection significantly enhanced the vasoconstriction to PE in both healthy and spontaneous atherosclerotic mice, when compared to their respective controls. CONCLUSIONS: This study demonstrates that oral P gingivalis affects the alpha adrenoceptor-mediated vascular responsiveness in both healthy and spontaneous atherosclerotic mice, reinforcing the association between periodontitis and cardiovascular diseases. PMID- 21586134 TI - A formal MIM specification and tools for the common exchange of MIM diagrams: an XML-Based format, an API, and a validation method. AB - BACKGROUND: The Molecular Interaction Map (MIM) notation offers a standard set of symbols and rules on their usage for the depiction of cellular signaling network diagrams. Such diagrams are essential for disseminating biological information in a concise manner. A lack of software tools for the notation restricts wider usage of the notation. Development of software is facilitated by a more detailed specification regarding software requirements than has previously existed for the MIM notation. RESULTS: A formal implementation of the MIM notation was developed based on a core set of previously defined glyphs. This implementation provides a detailed specification of the properties of the elements of the MIM notation. Building upon this specification, a machine-readable format is provided as a standardized mechanism for the storage and exchange of MIM diagrams. This new format is accompanied by a Java-based application programming interface to help software developers to integrate MIM support into software projects. A validation mechanism is also provided to determine whether MIM datasets are in accordance with syntax rules provided by the new specification. CONCLUSIONS: The work presented here provides key foundational components to promote software development for the MIM notation. These components will speed up the development of interoperable tools supporting the MIM notation and will aid in the translation of data stored in MIM diagrams to other standardized formats. Several projects utilizing this implementation of the notation are outlined herein. The MIM specification is available as an additional file to this publication. Source code, libraries, documentation, and examples are available at http://discover.nci.nih.gov/mim. PMID- 21586135 TI - Management outcomes in pubic diastasis: our experience with 19 patients. AB - BACKGROUND: Pubic diastasis, a result of high energy antero-posterior compression (APC) injury, has been managed based on the Young and Burguess classification system. The mode of fixation in APC II injury has, however, been a subject of controversy and some authors have proposed a need to address the issue of partial breach of the posterior pelvic ring elements in these injuries. METHODS: The study included a total of 19 patients with pubic diastasis managed by us from May 2006 to December 2007. There was a single patient with type I APC injury who treated conservatively. Type II APC injuries (13 patients) were treated surgically with symphyseal plating using single anterior/superior plates or double perpendicularly placed plates. Type III injuries (5 patients) in addition underwent posterior fixation using plates or percutaneous sacro-iliac screws. The outcome was assessed clinically (Majeed score) and radiologically. RESULTS: The mean follow-up was for 2.9 years (6 months to 4.5 years). Among the 13 patients with APC II injuries, the clinical scores were excellent in one (7.6%), good in 6 (46.15%), fair in 4 (30.76%) and poor in 2 (15.38%). Radiological scores were excellent in 2 (15.38%), good in 8 (61.53%), fair in 2 (15.38%) and poor in one patient (7.6%). Among the 5 patients with APC III injuries, there were 2 patients each with good (50%) and fair (50%) clinical scores while one patient was lost on long term follow up. The radiological outcomes were also similar in these. Complications included implant failure in 3 patients, postoperative infection in 2 patients, deep venous thrombosis in one patient and bladder herniation in one of the patients with implant failure. CONCLUSIONS: There is no observed dissimilarity in outcomes between isolated anterior and combined symphyseal (perpendicular) plating techniques in APC II injuries. Single anterior symphyseal plating along with posterior stabilisation provides a stable fixation in type III APC injuries. Limited dissection ensuring adequate intactness of rectus sheath is important to avoid long term post-operative complications. PMID- 21586136 TI - Human serum-derived hydroxy long-chain fatty acids exhibit anti-inflammatory and anti-proliferative activity. AB - BACKGROUND: Circulating levels of novel long-chain hydroxy fatty acids (called GTAs) were recently discovered in the serum of healthy subjects which were shown to be reduced in subjects with colorectal cancer (CRC), independent of tumor burden or disease stage. The levels of GTAs were subsequently observed to exhibit an inverse association with age in the general population. The current work investigates the biological activity of these fatty acids by evaluating the effects of enriched human serum extracts on cell growth and inflammation. METHODS: GTAs were extracted from commercially available bulk human serum and then chromatographically separated into enriched (GTA-positive) and depleted (GTA negative) fractions. SW620, MCF7 and LPS stimulated RAW264.7 cells were treated with various concentrations of the GTA-positive and GTA-negative extracts, and the effects on cell growth and inflammation determined. RESULTS: Enriched fractions resulted in poly-ADP ribose polymerase (PARP) cleavage, suppression of NFkappaB, induction of IkappaBalpha, and reduction in NOS2 mRNA transcript levels. In RAW264.7 mouse macrophage cells, incubation with enriched fractions prior to treatment with LPS blocked the induction of several pro-inflammatory markers including nitric oxide, TNFalpha, IL-1beta, NOS2 and COX2. CONCLUSIONS: Our results show that human serum extracts enriched with endogenous long-chain hydroxy fatty acids possess anti-inflammatory and anti-proliferative activity. These findings support a hypothesis that the reduction of these metabolites with age may result in a compromised ability to defend against uncontrolled cell growth and inflammation, and could therefore represent a significant risk for the development of CRC. PMID- 21586137 TI - Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR). AB - BACKGROUND: With infertility populations in the developed world rapidly aging, treatment of diminished ovarian reserve (DOR) assumes increasing clinical importance. Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances with DOR, and is now utilized by approximately one third of all IVF centers world-wide. Increasing DHEA utilization and publication of a first prospectively randomized trial now warrants a systematic review. METHODS: PubMed, Cochrane and Ovid Medline were searched between 1995 and 2010 under the following strategy: [ and ]. Bibliographies of relevant publications were further explored for additional relevant citations. Since only one randomized study has been published, publications, independent of evidence levels and quality assessment, were reviewed. RESULTS: Current best available evidence suggests that DHEA improves ovarian function, increases pregnancy chances and, by reducing aneuploidy, lowers miscarriage rates. DHEA over time also appears to objectively improve ovarian reserve. Recent animal data support androgens in promoting preantral follicle growth and reduction in follicle atresia. DISCUSSION: Improvement of oocyte/embryo quality with DHEA supplementation potentially suggests a new concept of ovarian aging, where ovarian environments, but not oocytes themselves, age. DHEA may, thus, represent a first agent beneficially affecting aging ovarian environments. Others can be expected to follow. PMID- 21586138 TI - Possible role of death receptor-mediated apoptosis by the E3 ubiquitin ligases Siah2 and POSH. AB - BACKGROUND: A functioning ubiquitin proteasome system (UPS) is essential for a number of diverse cellular processes and maintenance of overall cellular homeostasis. The ability of proteasome inhibitors, such as Velcade, to promote extrinsic apoptotic effects illustrates the importance of the ubiquitin proteasome system in the regulation of death receptor signaling. Here, we set out to define the UPS machinery, particularly the E3 ubiquitin ligases, that repress apoptosis through the extrinsic pathway. A cell-based genome-wide E3 ligase siRNA screen was established to monitor caspase-8 activity following the addition of TRAIL. RESULTS: Data from the high-throughput screen revealed that targeting the RING-finger containing E3 ligase Siah2 as well as the signaling platform molecule POSH (SH3RF1) conferred robust caspase-8 activation in response to TRAIL stimulus. Silencing Siah2 or POSH in prostate cancer cells led to increased caspase activity and apoptosis in response to both TRAIL and Fas ligand. The E3 activity of Siah2 was responsible for mediating apoptosis resistance; while POSH protein levels were critical for maintaining viability. Further characterization of Siah2 revealed it to function downstream of early death receptor events in the apoptotic pathway. The observed apoptosis resistance provides one biological explanation for the induction of Siah2 and POSH reported in lung and prostate cancer, respectively. Expanding on an initial yeast-two-hybrid screen we have confirmed a physical interaction between E3 ligases Siah2 and POSH. Utilizing a yeast-two-hybrid mapping approach we have defined the spacer region of POSH, more specifically the RPxAxVxP motif encompassing amino acids 601-607, to be the site of Siah2 binding. CONCLUSIONS: The data presented here define POSH and Siah2 as important mediators of death receptor mediated apoptosis and suggest targeting the interaction of these two E3 ligases is a promising novel cancer therapeutic strategy. PMID- 21586139 TI - Facilitating job retention for chronically ill employees: perspectives of line managers and human resource managers. AB - BACKGROUND: Chronic diseases are a leading contributor to work disability and job loss in Europe. Recent EU policies aim to improve job retention among chronically ill employees. Disability and occupational health researchers argue that this requires a coordinated and pro-active approach at the workplace by occupational health professionals, line managers (LMs) and human resource managers (HRM). Little is known about the perspectives of LMs an HRM on what is needed to facilitate job retention among chronically ill employees. The aim of this qualitative study was to explore and compare the perspectives of Dutch LMs and HRM on this issue. METHODS: Concept mapping methodology was used to elicit and map statements (ideas) from 10 LMs and 17 HRM about what is needed to ensure continued employment for chronically ill employees. Study participants were recruited through a higher education and an occupational health services organization. RESULTS: Participants generated 35 statements. Each group (LMs and HRM) sorted these statements into six thematic clusters. LMs and HRM identified four similar clusters: LMs and HRM must be knowledgeable about the impact of chronic disease on the employee; employees must accept responsibility for work retention; work adaptations must be implemented; and clear company policy. Thematic clusters identified only by LMs were: good manager/employee cooperation and knowledge transfer within the company. Unique clusters identified by HRM were: company culture and organizational support. CONCLUSIONS: There were both similarities and differences between the views of LMs and HRM on what may facilitate job retention for chronically ill employees. LMs perceived manager/employee cooperation as the most important mechanism for enabling continued employment for these employees. HRM perceived organizational policy and culture as the most important mechanism. The findings provide information about topics that occupational health researchers and planners should address in developing job retention programs for chronically ill workers. PMID- 21586141 TI - 18q deletion in a cystic fibrosis infant, increased morbidity and challenge for correct treatment choices: a case report. AB - Cystic Fibrosis (CF) is the most frequent recessive disease of Caucasian patients. Association with other diseases or syndromes has previously been reported. Co-morbidity may be a challenge for clinicians, who have to face more severe problems. We have described a CF infant, F508del homozygote, diagnosed by neonatal screening, who also had a chromosome 18q terminal deletion [del (18)(q22 qter)]. Some clinical features of the 18q deletion: e.g., cardiopathy, gastro oesophageal reflux and severe muscular hypotonia, worsened the CF clinical picture and his quality of life, with repeated pulmonary exacerbations and failure to thrive in the first six months of life. The treatment strategy was chosen following an accurate multi-disciplinary team study of overlapping chromosome syndrome and CF symptoms. The use of a gastrostomy device for enteral nutrition together with a new device (Ez-PAP) for chest physiotherapy led to normal growth, a notably reduced hospitalization rate and improved quality of life. This case shows how co-morbidities worsening the clinical course of a "complicated patient" can be faced thanks to unconventional therapies that represent a challenge for clinicians. PMID- 21586140 TI - Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma: a retrospective cohort study of the Eastern Cooperative Oncology Group. AB - BACKGROUND: Recent data in esophageal cancer suggests the variant allele of a single-nucleotide polymorphism (SNP) in XRCC1 may be associated with resistance to radiochemotherapy. However, this SNP has not been assessed in a histologically homogeneous clinical trial cohort that has been treated with a uniform approach. In addition, whether germline DNA may serve as a surrogate for tumor genotype at this locus is unknown in this disease. Our objective was to assess this SNP in relation to the pathologic complete response (pCR) rate in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy in a multicenter clinical trial (Eastern Cooperative Oncology Group 1201). As a secondary aim, we investigated the rate of allelic imbalance between germline and tumor DNA. METHODS: Eighty-one eligible treatment-naive subjects with newly diagnosed resectable esophageal adenocarcinoma received radiotherapy (45 Gy) concurrent with cisplatin-based chemotherapy, with planned subsequent surgical resection. The primary endpoint was pCR, defined as complete absence of tumor in the surgical specimen after radiochemotherapy. Using germline DNA from 60 subjects, we examined the base-excision repair SNP, XRCC1 Arg399Gln, and 4 other SNPs in nucleotide excision (XPD Lys751Gln and Asp312Asn, ERCC1 3' flank) and double-stranded break (XRCC2 5' flank) repair pathways, and correlated genotype with pCR rate. Paired tumor tissue was used to estimate the frequency of allelic imbalance at the XRCC1 SNP. RESULTS: The variant allele of the XRCC1 SNP (399Gln) was detected in 52% of subjects. Only 6% of subjects with the variant allele experienced a pCR, compared to 28% of subjects without the variant allele (odds ratio 5.37 for failing to achieve pCR, p = 0.062). Allelic imbalance at this locus was found in only 10% of informative subjects, suggesting that germline genotype may reflect tumor genotype at this locus. No significant association with pCR was noted for other SNPs. CONCLUSIONS: Assessed for the first time in a prospective, interventional trial cohort of esophageal adenocarcinoma, XRCC1 399Gln was associated with resistance to radiochemotherapy. Further investigation of this genetic variation is warranted in larger cohorts. In addition, these data indicate that germline genotype may serve as a surrogate for tumor genotype at this locus. PMID- 21586142 TI - Chronic diarrhea associated with persistent norovirus excretion in patients with chronic lymphocytic leukemia: report of two cases. AB - BACKGROUND: Chronic diarrhea in patients treated with immunosuppressive agents or suffering from immunosuppressive disease can represent a diagnostic and therapeutic challenge to the clinician. Norovirus infection, a major cause of acute epidemic diarrhea, has been described as a cause of chronic diarrhea in patients who are immunosuppressed, including transplant recipients and the very young. CASE PRESENTATIONS: We describe two patients, a 64 year-old man and a 59 year-old woman, both suffering from chronic lymphocytic leukemia and hypogammaglobulinemia, who developed chronic diarrhea resistant to therapy. In both cases, after months of symptoms, persistent norovirus infection--documented by repeatedly-positive high-sensitivity stool enzyme immunoassay--was found to be the cause. Both patients died with active diarrheal symptoms. CONCLUSIONS: We describe the first cases of advanced chronic lymphocytic leukemia to suffer from chronic symptomatic norovirus infection. Clinicians caring for such patients, particularly those with concomitant hypogammaglobulinema, who have chronic unexplained diarrhea, should consider norovirus infection in the differential diagnosis. PMID- 21586143 TI - Reporting of complex interventions in clinical trials: development of a taxonomy to classify and describe fall-prevention interventions. AB - BACKGROUND: Interventions for preventing falls in older people often involve several components, multidisciplinary teams, and implementation in a variety of settings. We have developed a classification system (taxonomy) to describe interventions used to prevent falls in older people, with the aim of improving the design and reporting of clinical trials of fall-prevention interventions, and synthesis of evidence from these trials. METHODS: Thirty three international experts in falls prevention and health services research participated in a series of meetings to develop consensus. Robust techniques were used including literature reviews, expert presentations, and structured consensus workshops moderated by experienced facilitators. The taxonomy was refined using an international test panel of five health care practitioners. We assessed the chance corrected agreement of the final version by comparing taxonomy completion for 10 randomly selected published papers describing a variety of fall-prevention interventions. RESULTS: The taxonomy consists of four domains, summarized as the "Approach", "Base", "Components" and "Descriptors" of an intervention. Sub domains include; where participants are identified; the theoretical approach of the intervention; clinical targeting criteria; details on assessments; descriptions of the nature and intensity of interventions. Chance corrected agreement of the final version of the taxonomy was good to excellent for all items. Further independent evaluation of the taxonomy is required. CONCLUSIONS: The taxonomy is a useful instrument for characterizing a broad range of interventions used in falls prevention. Investigators are encouraged to use the taxonomy to report their interventions. PMID- 21586144 TI - Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin. AB - BACKGROUND: The amyloid precursor protein (APP) is cleaved by beta- and gamma secretases to generate toxic amyloid beta (Abeta) peptides. Alternatively, alpha secretases cleave APP within the Abeta domain, precluding Abeta formation and releasing the soluble ectodomain, sAPPalpha. We previously showed that inhibition of the GTPase dynamin reduced APP internalization and increased release of sAPPalpha, apparently by prolonging the interaction between APP and alpha secretases at the plasma membrane. This was accompanied by a reduction in Abeta generation. In the present study, we investigated whether surface expression of the alpha-secretase ADAM (a disintegrin and metalloprotease)10 is also regulated by dynamin-dependent endocytosis. RESULTS: Transfection of human embryonic kidney (HEK) cells stably expressing M3 muscarinic receptors with a dominant negative dynamin I mutant (dyn I K44A), increased surface expression of both immature, and mature, catalytically active forms of co-expressed ADAM10. Surface levels of ADAM10 were unaffected by activation of protein kinase C (PKC) or M3 receptors, indicating that receptor-coupled shedding of the ADAM substrate APP is unlikely to be mediated by inhibition of ADAM10 endocytosis in this cell line. Dyn I K44A strongly increased the formation of a C-terminal fragment of ADAM10, consistent with earlier reports that the ADAM10 ectodomain is itself a target for sheddases. The abundance of this fragment was increased in the presence of a gamma-secretase inhibitor, but was not affected by M3 receptor activation. The dynamin mutant did not affect the distribution of ADAM10 and its C-terminal fragment between raft and non-raft membrane compartments. CONCLUSIONS: Surface expression and limited proteolysis of ADAM10 are regulated by dynamin-dependent endocytosis, but are unaffected by activation of signaling pathways that upregulate shedding of ADAM substrates such as APP. Modulation of ADAM10 internalization could affect cellular behavior in two ways: by altering the putative signaling activity of the ADAM10 C-terminal fragment, and by regulating the biological function of ADAM10 substrates such as APP and N-cadherin. PMID- 21586145 TI - Improvement of cardiac contractile function by peptide-based inhibition of NF kappaB in the utrophin/dystrophin-deficient murine model of muscular dystrophy. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is an inherited and progressive disease causing striated muscle deterioration. Patients in their twenties generally die from either respiratory or cardiac failure. In order to improve the lifespan and quality of life of DMD patients, it is important to prevent or reverse the progressive loss of contractile function of the heart. Recent studies by our labs have shown that the peptide NBD (Nemo Binding Domain), targeted at blunting Nuclear Factor kappaB (NF-kappaB) signaling, reduces inflammation, enhances myofiber regeneration, and improves contractile deficits in the diaphragm in dystrophin-deficient mdx mice. METHODS: To assess whether cardiac function in addition to diaphragm function can be improved, we investigated physiological and histological parameters of cardiac muscle in mice deficient for both dystrophin and its homolog utrophin (double knockout = dko) mice treated with NBD peptide. These dko mice show classic pathophysiological hallmarks of heart failure, including myocyte degeneration, an impaired force-frequency response and a severely blunted beta-adrenergic response. Cardiac contractile function at baseline and frequencies and pre-loads throughout the in vivo range as well as beta-adrenergic reserve was measured in isolated cardiac muscle preparations. In addition, we studied histopathological and inflammatory markers in these mice. RESULTS: At baseline conditions, active force development in cardiac muscles from NBD treated dko mice was more than double that of vehicle treated dko mice. NBD treatment also significantly improved frequency-dependent behavior of the muscles. The increase in force in NBD-treated dko muscles to beta adrenergic stimulation was robustly restored compared to vehicle-treated mice. However, histological features, including collagen content and inflammatory markers were not significantly different between NBD-treated and vehicle-treated dko mice. CONCLUSIONS: We conclude that NBD can significantly improve cardiac contractile dysfunction in the dko mouse model of DMD and may thus provide a novel therapeutic treatment for heart failure. PMID- 21586146 TI - Characterization of duck enteritis virus UL53 gene and glycoprotein K. AB - BACKGROUND: Most of the previous research work had focused on the epidemiology and prevention of duck enteritis virus (DEV). Whilst with the development of protocols in molecular biology, nowadays more and more information about the genes of DEV was reported. But little information about DEV UL53 gene and glycoprotein K(gK) was known except our reported data. RESULTS: In our paper, the fluorescent quantitative real-time PCR(FQ-RT-PCR) assay and nucleic acid inhibition test were used to study the transcription characteristic of the DEV UL53 gene. Except detecting the mRNA of DEV UL53 gene, the product gK encoded by UL53 gene was detected through the expression kinetics of UL53 gene by the purified rabbit anti-UL53 protein polyclonal antibodies. Western-blotting and indirect immunofluorescence assays were used to detect gK. From the results of these experiments, the UL53 gene and gK were respectively identified as a late gene and a really late protein. On the other hand, the indirect immunofluorescence assay provided another information that the intracellular localization of DEV gK was mainly distributed in cytoplasm. CONCLUSIONS: By way of conclusions, we conceded that DEV UL53 gene is a really late gene, which is coincident with properties of UL53 homologs from other herpesvirus, such as ILTV(Infectious Laryngotracheitis virus) and HSV-1(Herpes simplex virus type 1). The properties of intracellular localization about gK protein provided a foundation for further functional analysis and further studies will be focused on constructing of the UL53 gene DEV mutant. PMID- 21586147 TI - More accurate recombination prediction in HIV-1 using a robust decoding algorithm for HMMs. AB - BACKGROUND: Identifying recombinations in HIV is important for studying the epidemiology of the virus and aids in the design of potential vaccines and treatments. The previous widely-used tool for this task uses the Viterbi algorithm in a hidden Markov model to model recombinant sequences. RESULTS: We apply a new decoding algorithm for this HMM that improves prediction accuracy. Exactly locating breakpoints is usually impossible, since different subtypes are highly conserved in some sequence regions. Our algorithm identifies these sites up to a certain error tolerance. Our new algorithm is more accurate in predicting the location of recombination breakpoints. Our implementation of the algorithm is available at http://www.cs.uwaterloo.ca/~jmtruszk/jphmm_balls.tar.gz. CONCLUSIONS: By explicitly accounting for uncertainty in breakpoint positions, our algorithm offers more reliable predictions of recombination breakpoints in HIV-1. We also document a new domain of use for our new decoding approach in HMMs. PMID- 21586148 TI - The added value of ordinal analysis in clinical trials: an example in traumatic brain injury. AB - INTRODUCTION: In clinical trials, ordinal outcome measures are often dichotomized into two categories. In traumatic brain injury (TBI) the 5-point Glasgow outcome scale (GOS) is collapsed into unfavourable versus favourable outcome. Simulation studies have shown that exploiting the ordinal nature of the GOS increases chances of detecting treatment effects. The objective of this study is to quantify the benefits of ordinal analysis in the real-life situation of a large TBI trial. METHODS: We used data from the CRASH trial that investigated the efficacy of corticosteroids in TBI patients (n = 9,554). We applied two techniques for ordinal analysis: proportional odds analysis and the sliding dichotomy approach, where the GOS is dichotomized at different cut-offs according to baseline prognostic risk. These approaches were compared to dichotomous analysis. The information density in each analysis was indicated by a Wald statistic. All analyses were adjusted for baseline characteristics. RESULTS: Dichotomous analysis of the six-month GOS showed a non-significant treatment effect (OR = 1.09, 95% CI 0.98 to 1.21, P = 0.096). Ordinal analysis with proportional odds regression or sliding dichotomy showed highly statistically significant treatment effects (OR 1.15, 95% CI 1.06 to 1.25, P = 0.0007 and 1.19, 95% CI 1.08 to 1.30, P = 0.0002), with 2.05-fold and 2.56-fold higher information density compared to the dichotomous approach respectively. CONCLUSIONS: Analysis of the CRASH trial data confirmed that ordinal analysis of outcome substantially increases statistical power. We expect these results to hold for other fields of critical care medicine that use ordinal outcome measures and recommend that future trials adopt ordinal analyses. This will permit detection of smaller treatment effects. PMID- 21586149 TI - Aripiprazole augmentation in the treatment of military-related PTSD with major depression: a retrospective chart review. AB - BACKGROUND: In this chart review, we attempted to evaluate the benefits of adding aripiprazole in veterans with military-related PTSD and comorbid depression, who had been minimally or partially responsive to their existing medications. METHODS: A retrospective chart review of patients who received an open-label, flexible-dose, 12- week course of adjunctive aripiprazole was conducted in 27 military veterans meeting DSM-IV criteria for PTSD and comorbid major depression. Concomitant psychiatric medications continued unchanged, except for other antipsychotics which were discontinued prior to initiating aripiprazole. The primary outcome variable was a change from baseline in the PTSD checklist military version (PCL-M) and the Beck Depression Inventory (BDI-II). RESULTS: PTSD severity (Total PCL scores) decreased from 56.11 at baseline to 46.85 at 12 weeks (p < 0.0001 from Wilcoxon signed rank test) and the depression severity decreased from 30.44 at baseline to 20.67 at 12-weeks (p < 0.0001 from Wilcoxon signed rank test). Thirty seven percent (10/27) were considered responders, as defined by a decrease in total PCL scores of at least 20 percent and 19% (5/27) were considered as responders as defined by a decrease in total BDI score of at least 50%. CONCLUSIONS: The addition of aripiprazole contributed to a reduction in both PTSD and depression symptomatology in a population that has traditionally demonstrated poor pharmacological response. Further investigations, including double-blind, placebo-controlled studies, are essential to confirm and further demonstrate the benefit of aripiprazole augmentation in the treatment of military related PTSD. PMID- 21586150 TI - Understanding and predicting synthetic lethal genetic interactions in Saccharomyces cerevisiae using domain genetic interactions. AB - BACKGROUND: Synthetic lethal genetic interactions among proteins have been widely used to define functional relationships between proteins and pathways. However, the molecular mechanism of synthetic lethal genetic interactions is still unclear. RESULTS: In this study, we demonstrated that yeast synthetic lethal genetic interactions can be explained by the genetic interactions between domains of those proteins. The domain genetic interactions rarely overlap with the domain physical interactions from iPfam database and provide a complementary view about domain relationships. Moreover, we found that domains in multidomain yeast proteins contribute to their genetic interactions differently. The domain genetic interactions help more precisely define the function related to the synthetic lethal genetic interactions, and then help understand how domains contribute to different functionalities of multidomain proteins. Using the probabilities of domain genetic interactions, we were able to predict novel yeast synthetic lethal genetic interactions. Furthermore, we had also identified novel compensatory pathways from the predicted synthetic lethal genetic interactions. CONCLUSION: The identification of domain genetic interactions helps the understanding of originality of functional relationship in SLGIs at domain level. Our study significantly improved the understanding of yeast mulitdomain proteins, the synthetic lethal genetic interactions and the functional relationships between proteins and pathways. PMID- 21586151 TI - Seroprevalence of measles and natural rubella antibodies among children in Bangui, Central African Republic. AB - BACKGROUND: Passively acquired maternal antibodies are necessary to protect infants against circulating measles virus until they reach the eligible age of vaccination. Likewise, high levels of population immunity must be achieved and maintained to reduce measles virus transmission. This study was undertaken to (1) assess the presence of maternally acquired measles-specific IgG antibodies among infants less than 9 months of age in Bangui, Central African Republic and (2) determine the immune status of vaccination-age children and the concordance with reported vaccination status. A secondary objective was to describe the presence of rubella-specific IgG antibody in the study population. METHODS: Vaccination history and blood samples were collected from 395 children using blotting paper. Samples were analyzed for the presence of measles-specific IgG antibodies using commercial ELISA kits. RESULTS: Measles-specific IgG antibodies were detected in 51.3% of vaccinated children and 27.6% of non-vaccinated children. Maternally derived measles IgG antibodies were present in only 14.8% of infants aged 0-3 months and were absent in all infants aged 4-8 months. The presence of IgG specific measles antibodies varied among children of vaccination age, from 57.3% for children aged 9 months to 5 years, to 50.6% for children aged 6-9 years and 45.6% for chidren aged 10 years and above. The overall prevalence of rubella specific IgG was 55.4%, with a high prevalence (87.4%) among children over 10 years of age. CONCLUSION: The findings suggest that despite efforts to accelerate measles control by giving a second dose of measles vaccine, a large number of children remain susceptible to measles virus. Further research is required to determine the geographic extent of immunity gaps and the factors that influence immunity to measles virus in the Central African Republic. PMID- 21586152 TI - Recombination phenotypes of the NCI-60 collection of human cancer cells. AB - BACKGROUND: The NCI-60 is a collection of tumor cell lines derived from a variety of human adult cancer tissue types and is commonly used for genetic analysis and screening of potential chemotherapeutic agents. We wanted to understand the contributions of specific mechanisms of genomic instability to the etiology of cancers represented by the NCI-60. RESULTS: We screened the NCI-60 for dysregulated homologous recombination by using the gene cluster instability (GCI) assay we pioneered, and for defects in base excision repair by sensitivity to 5 hydroxymethyl-2'-deoxyuridine (hmdUrd). We identified subsets of the NCI-60 lines that either displayed the characteristic molecular signature of GCI or were sensitive to hmdUrd. With the exception of the NCI-H23 lung cancer line, these phenotypes were not found to overlap. None of the lines examined in either subset exhibited significant changes in the frequency of sister chromatid exchanges (SCE), neither did any of the lines in either subset exhibit microsatellite instability (MSI) indicative of defects in DNA mismatch repair. CONCLUSIONS: Gene cluster instability, sensitivity to hmdUrd and sister chromatid exchange are mechanistically distinct phenomena. Genomic instability in the NCI-60 appears to involve only one mechanism of instability for each individual cell line. PMID- 21586153 TI - Multiple-center evaluation of mortality associated with acute kidney injury in critically ill patients: a competing risks analysis. AB - INTRODUCTION: In this study, we aimed to assess the association between acute kidney injury (AKI) and mortality in critically ill patients using an original competing risks approach. METHODS: Unselected patients admitted between 1997 and 2009 to 13 French medical or surgical intensive care units were included in this observational cohort study. AKI was defined according to the RIFLE criteria. The following data were recorded: baseline characteristics, daily serum creatinine level, daily Sequential Organ Failure Assessment (SOFA) score, vital status at hospital discharge and length of hospital stay. Patients were classified according to the maximum RIFLE class reached during their ICU stay. The association of AKI with hospital mortality with "discharge alive" considered as a competing event was assessed according to the Fine and Gray model. RESULTS: Of the 8,639 study patients, 32.9% had AKI, of whom 19.1% received renal replacement therapy. Patients with AKI had higher crude mortality rates and longer lengths of hospital stay than patients without AKI. In the Fine and Gray model, independent risk factors for hospital mortality were the RIFLE classes Risk (sub-hazard ratio (SHR) 1.58 and 95% confidence interval (95% CI) 1.32 to 1.88; P < 0.0001), Injury (SHR 3.99 and 95% CI 3.43 to 4.65; P < 0.0001) and Failure (SHR 4.12 and 95% CI 3.55 to 4.79; P < 0.0001); nonrenal SOFA score (SHR 1.19 per point and 95% CI 1.18 to 1.21; P < 0.0001); McCabe class 3 (SHR 2.71 and 95% CI 2.34 to 3.15; P < 0.0001); and respiratory failure (SHR 3.08 and 95% CI 1.36 to 7.01; P < 0.01). CONCLUSIONS: By using a competing risks approach, we confirm in this study that AKI affecting critically ill patients is associated with increased in-hospital mortality. PMID- 21586154 TI - Travellers' malaria--'one shoe does not fit all'. AB - Travellers' malaria is an exciting topic. It is a field in flux with evolving options for chemoprophylaxis, self-diagnosis, self-treatment, risk/strategy analyses and surveillance. Ideologies vary and experts differ but debate is needed and can bring change. The launch of a new thematic series in the Malaria Journal--"Travellers' malaria"--creates an ideal forum to bring together research papers, reviews, opinion papers and commentaries, and will hopefully stimulate debate. PMID- 21586155 TI - Cost risk benefit analysis to support chemoprophylaxis policy for travellers to malaria endemic countries. AB - BACKGROUND: In a number of malaria endemic regions, tourists and travellers face a declining risk of travel associated malaria, in part due to successful malaria control. Many millions of visitors to these regions are recommended, via national and international policy, to use chemoprophylaxis which has a well recognized morbidity profile. To evaluate whether current malaria chemo-prophylactic policy for travellers is cost effective when adjusted for endemic transmission risk and duration of exposure. a framework, based on partial cost-benefit analysis was used. METHODS: Using a three component model combining a probability component, a cost component and a malaria risk component, the study estimated health costs avoided through use of chemoprophylaxis and costs of disease prevention (including adverse events and pre-travel advice for visits to five popular high and low malaria endemic regions) and malaria transmission risk using imported malaria cases and numbers of travellers to malarious countries. By calculating the minimal threshold malaria risk below which the economic costs of chemoprophylaxis are greater than the avoided health costs we were able to identify the point at which chemoprophylaxis would be economically rational. RESULTS: The threshold incidence at which malaria chemoprophylaxis policy becomes cost effective for UK travellers is an accumulated risk of 1.13% assuming a given set of cost parameters. The period a travellers need to remain exposed to achieve this accumulated risk varied from 30 to more than 365 days, depending on the regions intensity of malaria transmission. CONCLUSIONS: The cost-benefit analysis identified that chemoprophylaxis use was not a cost-effective policy for travellers to Thailand or the Amazon region of Brazil, but was cost-effective for travel to West Africa and for those staying longer than 45 days in India and Indonesia. PMID- 21586156 TI - Human resources for health and decentralization policy in the Brazilian health system. AB - BACKGROUND: The Brazilian health reform process, following the establishment of the Unified Health System (SUS), has had a strong emphasis on decentralization, with a special focus on financing, management and inter-managerial agreements. Brazil is a federal country and the Ministry of Health (MoH), through the Secretary of Labour Management and Health Education, is responsible for establishing national policy guidelines for health labour management, and also for implementing strategies for the decentralization of management of labour and education in the federal states. This paper assesses whether the process of decentralizing human resources for health (HRH) management and organization to the level of the state and municipal health departments has involved investments in technical, political and financial resources at the national level. METHODS: The research methods used comprise a survey of HRH managers of states and major municipalities (including capitals) and focus groups with these HRH managers - all by geographic region. The results were obtained by combining survey and focus group data, and also through triangulation with the results of previous research. RESULTS: The results of this evaluation showed the evolution policy, previously restricted to the field of 'personnel administration', now expanded to a conceptual model for health labour management and education-- identifying progress, setbacks, critical issues and challenges for the consolidation of the decentralized model for HRH management. The results showed that 76.3% of the health departments have an HRH unit. It was observed that 63.2% have an HRH information system. However, in most health departments, the HRH unit uses only the payroll and administrative records as data sources. Concerning education in health, 67.6% of the HRH managers mentioned existing cooperation with educational and teaching institutions for training and/or specialization of health workers. Among them, specialization courses account for 61.4% and short courses for 56.1%. CONCLUSIONS: Due to decentralization, the HRH area has been restructured and policies beyond traditional administrative activities have been developed. However, twenty years on from the establishment of the SUS, there remains a low level of institutionalization in the HRH area, despite recent efforts of the MoH. PMID- 21586157 TI - Nitric oxide/cGMP pathway signaling actively down-regulates alpha4beta1-integrin affinity: an unexpected mechanism for inducing cell de-adhesion. AB - BACKGROUND: Integrin activation in response to inside-out signaling serves as the basis for rapid leukocyte arrest on endothelium, migration, and mobilization of immune cells. Integrin-dependent adhesion is controlled by the conformational state of the molecule, which is regulated by seven-transmembrane Guanine nucleotide binding Protein-Coupled Receptors (GPCRs). alpha4beta1-integrin (CD49d/CD29, Very Late Antigen-4, VLA-4) is expressed on leukocytes, hematopoietic progenitors, stem cells, hematopoietic cancer cells, and others. VLA-4 conformation is rapidly up-regulated by inside-out signaling through Galphai-coupled GPCRs and down-regulated by Galphas-coupled GPCRs. However, other signaling pathways, which include nitric oxide-dependent signaling, have been implicated in the regulation of cell adhesion. The goal of the current report was to study the effect of nitric oxide/cGMP signaling pathway on VLA-4 conformational regulation. RESULTS: Using fluorescent ligand binding to evaluate the integrin activation state on live cells in real-time, we show that several small molecules, which specifically modulate nitric oxide/cGMP signaling pathway, as well as a cell permeable cGMP analog, can rapidly down-modulate binding of a VLA-4 specific ligand on cells pre-activated through three Galphai-coupled receptors: wild type CXCR4, CXCR2 (IL-8RB), and a non-desensitizing mutant of formyl peptide receptor (FPR DeltaST). Upon signaling, we detected rapid changes in the ligand dissociation rate. The dissociation rate after inside-out integrin de-activation was similar to the rate for resting cells. In a VLA-4/VCAM-1 specific myeloid cell adhesion system, inhibition of the VLA-4 affinity change by nitric oxide had a statistically significant effect on real-time cell aggregation. CONCLUSIONS: We conclude that nitric oxide/cGMP signaling pathway can rapidly down-modulate the affinity state of the VLA-4 binding pocket, especially under the condition of sustained Galphai-coupled GPCR signaling, generated by a non-desensitizing receptor mutant. This suggests a fundamental role of this pathway in de-activation of integrin-dependent cell adhesion. PMID- 21586159 TI - Power estimation of tests in log-linear non-uniform association models for ordinal agreement. AB - BACKGROUND: Log-linear association models have been extensively used to investigate the pattern of agreement between ordinal ratings. In 2007, log-linear non-uniform association models were introduced to estimate, from a cross classification of two independent raters using an ordinal scale, varying degrees of distinguishability between distant and adjacent categories of the scale. METHODS: In this paper, a simple method based on simulations was proposed to estimate the power of non-uniform association models to detect heterogeneities across distinguishabilities between adjacent categories of an ordinal scale, illustrating some possible scale defects. RESULTS: Different scenarios of distinguishability patterns were investigated, as well as different scenarios of marginal heterogeneity within rater. For sample size of N = 50, the probabilities of detecting heterogeneities within the tables are lower than .80, whatever the number of categories. In additition, even for large samples, marginal heterogeneities within raters led to a decrease in power estimates. CONCLUSION: This paper provided some issues about how many objects had to be classified by two independent observers (or by the same observer at two different times) to be able to detect a given scale structure defect. Our results also highlighted the importance of marginal homogeneity within raters, to ensure optimal power when using non-uniform association models. PMID- 21586160 TI - TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation. AB - BACKGROUND: The discovery of heat-sensitive Transient Receptor Potential Vanilloid (TRPV) ion channels provided a potential molecular explanation for the perception of innocuous and noxious heat stimuli. TRPV1 has a significant role in acute heat nociception and inflammatory heat hyperalgesia. Yet, substantial innocuous and noxious heat sensitivity remains in TRPV1 knockout animals. Here we investigated the role of two related channels, TRPV3 and TRPV4, in these capacities. We studied TRPV3 knockout animals on both C57BL6 and 129S6 backgrounds, as well as animals deficient in both TRPV3 and TRPV4 on a C57BL6 background. Additionally, we assessed the contributions of TRPV3 and TRPV4 to acute heat nociception and inflammatory heat hyperalgesia during inhibition of TRPV1. RESULTS: TRPV3 knockout mice on the C57BL6 background exhibited no obvious alterations in thermal preference behavior. On the 129S6 background, absence of TRPV3 resulted in a more restrictive range of occupancy centered around cooler floor temperatures. TRPV3 knockout mice showed no deficits in acute heat nociception on either background. Mice deficient in both TRPV3 and TRPV4 on a C57BL6 background showed thermal preference behavior similar to wild-type controls on the thermal gradient, and little or no change in acute heat nociception or inflammatory heat hyperalgesia. Masking of TRPV1 by the TRPV1 antagonist JNJ-17203212 did not reveal differences between C57BL6 animals deficient in TRPV3 and TRPV4, compared to their wild-type counterparts. CONCLUSIONS: Our results support the notion that TRPV3 and TRPV4 likely make limited and strain-dependent contributions to innocuous warm temperature perception or noxious heat sensation, even when TRPV1 is masked. These findings imply the existence of other significant mechanisms for heat perception. PMID- 21586161 TI - Multifocal ERG wavelet packet decomposition applied to glaucoma diagnosis. AB - BACKGROUND: Glaucoma is the second-leading cause of blindness worldwide and early diagnosis is essential to its treatment. Current clinical methods based on multifocal electroretinography (mfERG) essentially involve measurement of amplitudes and latencies and assume standard signal morphology. This paper presents a new method based on wavelet packet analysis of global-flash multifocal electroretinogram signals. METHODS: This study comprised twenty-five patients diagnosed with OAG and twenty-five control subjects. Their mfERG recordings data were used to develop the algorithm method based on wavelet packet analysis. By reconstructing the third wavelet packet contained in the fourth decomposition level (ADAA4) of the mfERG recording, it is possible to obtain a signal from which to extract a marker in the 60-80 ms time interval. RESULTS: The marker found comprises oscillatory potentials with a negative-slope basal line in the case of glaucomatous recordings and a positive-slope basal line in the case of normal signals. Application of the optimal threshold calculated in the validation cases showed that the technique proposed achieved a sensitivity of 0.81 and validation specificity of 0.73. CONCLUSIONS: This new method based on mfERG analysis may be reliable enough to detect functional deficits that are not apparent using current automated perimetry tests. As new stimulation and analysis protocols develop, mfERG has the potential to become a useful tool in early detection of glaucoma-related functional deficits. PMID- 21586162 TI - Willingness to pay for one-stop anesthesia in pediatric day surgery. AB - BACKGROUND: This study assesses the parents' Willingness To Pay (WTP) for One Stop Anesthesia (OSA). OSA is part of a free screening procedure that determines the timing of the anesthesiological assessment. In OSA-positive patients, the preoperative assessment is carried out on the same day as the surgery. The OSA allows patients who have to undergo surgery in a pediatric day surgery to avoid accessing the pre-admission clinic. METHOD: This is a descriptive cohort study. A sample of 106 parents were interviewed directly by means of a questionnaire. The questionnaire builds a hypothetical scenario where the interviewee has a chance to buy the OSA health service with the WTP. The WTP values are distributed in classes and are contingent to the market built in the questionnaire. The Chi Square and Cramer's V tests evaluate the WTP dependence on the parents' place of origin and occupation. RESULTS: The approximate average of the WTP classes is ?87.21 per family. The Chi Square test relative to the WTP classes and the places of origin is statistically significant (p < 0.05). The Cramer's V test is 0.347 and points to a positive association between the two demographics. The Cramer's V test of the WTP classes and the types of job is 0.339 and indicates a positive association. CONCLUSION: Nearly 90% of pediatric patients who were screened for timing the preoperative assessment are true positives to OSA. This allows doing away with the pre-hospitalization, with definite advantages for the families. This screening is a health service that families would be hypothetically willing to pay. PMID- 21586163 TI - Estimating background rates of Guillain-Barre Syndrome in Ontario in order to respond to safety concerns during pandemic H1N1/09 immunization campaign. AB - BACKGROUND: The province of Ontario, Canada initiated mass immunization clinics with adjuvanted pandemic H1N1 influenza vaccine in October 2009. Due to the scale of the campaign, temporal associations with Guillain-Barre syndrome (GBS) and vaccination were expected. The objectives of this analysis were to estimate the number of background GBS cases expected to occur in the projected vaccinated population and to estimate the number of additional GBS cases which would be expected if an association with vaccination existed. The number of influenza associated GBS cases was also determined. METHODS: Baseline incidence rates of GBS were determined from published Canadian studies and applied to projected vaccine coverage data to estimate the expected number of GBS cases in the vaccinated population. Assuming an association with vaccine existed, the number of additional cases of GBS expected was determined by applying the rates observed during the 1976 Swine Flu and 1992/1994 seasonal influenza campaigns in the United States. The number of influenza-associated GBS cases expected to occur during the vaccination campaign was determined based on risk estimates of GBS after influenza infection and provincial influenza infection rates using a combination of laboratory-confirmed cases and data from a seroprevalence study. RESULTS: The overall provincial vaccine coverage was estimated to be between 32% and 38%. Assuming 38% coverage, between 6 and 13 background cases of GBS were expected within this projected vaccinated cohort (assuming 32% coverage yielded between 5-11 background cases). An additional 6 or 42 cases would be expected if an association between GBS and influenza vaccine was observed (assuming 32% coverage yielded 5 or 35 additional cases); while up to 31 influenza-associated GBS cases could be expected to occur. In comparison, during the same period, only 7 cases of GBS were reported among vaccinated persons. CONCLUSIONS: Our analyses do not suggest an increased number of GBS cases due to the vaccine. Awareness of expected rates of GBS is crucial when assessing adverse events following influenza immunization. Furthermore, since individuals with influenza infection are also at risk of developing GBS, they must be considered in such analyses, particularly if the vaccine campaign and disease are occurring concurrently. PMID- 21586158 TI - Clustering patterns of physical activity, sedentary and dietary behavior among European adolescents: The HELENA study. AB - BACKGROUND: Evidence suggests possible synergetic effects of multiple lifestyle behaviors on health risks like obesity and other health outcomes. A better insight in the clustering of those behaviors, could help to identify groups who are at risk in developing chronic diseases. This study examines the prevalence and clustering of physical activity, sedentary and dietary patterns among European adolescents and investigates if the identified clusters could be characterized by socio-demographic factors. METHODS: The study comprised a total of 2084 adolescents (45.6% male), from eight European cities participating in the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) study. Physical activity and sedentary behavior were measured using self-reported questionnaires and diet quality was assessed based on dietary recall. Based on the results of those three indices, cluster analyses were performed. To identify gender differences and associations with socio-demographic variables, chi-square tests were executed. RESULTS: Five stable and meaningful clusters were found. Only 18% of the adolescents showed healthy and 21% unhealthy scores on all three included indices. Males were highly presented in the cluster with high levels of moderate to vigorous physical activity (MVPA) and low quality diets. The clusters with low levels of MVPA and high quality diets comprised more female adolescents. Adolescents with low educated parents had diets of lower quality and spent more time in sedentary activities. In addition, the clusters with high levels of MVPA comprised more adolescents of the younger age category. CONCLUSION: In order to develop effective primary prevention strategies, it would be important to consider multiple health indices when identifying high risk groups. PMID- 21586164 TI - Evolutionary plasticity determination by orthologous groups distribution. AB - BACKGROUND: Genetic plasticity may be understood as the ability of a functional gene network to tolerate alterations in its components or structure. Usually, the studies involving gene modifications in the course of the evolution are concerned to nucleotide sequence alterations in closely related species. However, the analysis of large scale data about the distribution of gene families in non exclusively closely related species can provide insights on how plastic or how conserved a given gene family is. Here, we analyze the abundance and diversity of all Eukaryotic Clusters of Orthologous Groups (KOG) present in STRING database, resulting in a total of 4,850 KOGs. This dataset comprises 481,421 proteins distributed among 55 eukaryotes. RESULTS: We propose an index to evaluate the evolutionary plasticity and conservation of an orthologous group based on its abundance and diversity across eukaryotes. To further KOG plasticity analysis, we estimate the evolutionary distance average among all proteins which take part in the same orthologous group. As a result, we found a strong correlation between the evolutionary distance average and the proposed evolutionary plasticity index. Additionally, we found low evolutionary plasticity in Saccharomyces cerevisiae genes associated with inviability and Mus musculus genes associated with early lethality. At last, we plot the evolutionary plasticity value in different gene networks from yeast and humans. As a result, it was possible to discriminate among higher and lower plastic areas of the gene networks analyzed. CONCLUSIONS: The distribution of gene families brings valuable information on evolutionary plasticity which might be related with genetic plasticity. Accordingly, it is possible to discriminate among conserved and plastic orthologous groups by evaluating their abundance and diversity across eukaryotes. PMID- 21586165 TI - Change in level of productivity in the treatment of schizophrenia with olanzapine or other antipsychotics. AB - BACKGROUND: When treating schizophrenia, improving patients' productivity level is a major goal considering schizophrenia is a leading cause of functional disability. Productivity level has been identified as the most preferred treatment outcome by patients with schizophrenia. However, little has been done to systematically investigate productivity levels in schizophrenia. We set out to better understand the change in productivity level among chronically ill patients with schizophrenia treated with olanzapine compared with other antipsychotic medications. We also assessed the links between productivity level and other clinical outcomes. METHODS: This post hoc analysis used data from 6 randomized, double-blind clinical trials of patients with schizophrenia or schizoaffective disorder, with each trial being of approximately 6 months duration. Change in productivity level was compared between olanzapine-treated patients (HGBG, n = 172; HGHJ, n = 277; HGJB, n = 171; HGLB, n = 281; HGGN, n = 159; HGDH, n = 131) and patients treated with other antipsychotic medications (separately vs. haloperidol [HGGN, n = 97; HGDH, n = 132], risperidone [HGBG, n = 167; HGGN, n = 158], quetiapine [HGJB, n = 175], ziprasidone [HGHJ, n = 271] and aripiprazole [HGLB, n = 285]). Productivity was defined as functional activities/work including working for pay, studying, housekeeping and volunteer work. Productivity level in the prior 3 months was assessed on a 5-point scale ranging from no useful functioning to functional activity/work 75% to 100% of the time. RESULTS: Chronically ill patients treated with olanzapine (OLZ) experienced significantly greater improvement in productivity when compared to patients treated with risperidone (RISP) (OLZ = 0.22 +/- 1.19, RISP = -0.03 +/- 1.17, p = 0.033) or ziprasidone (ZIP) (OLZ = 0.50 +/- 1.38, ZIP = 0.25 +/- 1.27, p = 0.026), but did not significantly differ from the quetiapine, aripiprazole or haloperidol treatment groups. Among first episode patients, OLZ therapy was associated with greater improvements in productivity levels compared to haloperidol (HAL), during the acute phase (OLZ = -0.31 +/- 1.59, HAL = -0.69 +/- 1.56, p = 0.011) and over the long-term (OLZ = 0.10 +/- 1.50, HAL = -0.32 +/- 1.91, p = 0.008). Significantly more chronically ill and first episode patients treated with olanzapine showed moderately high (>50%-75% of the time) and high levels of productivity (>75%-100% of the time) at endpoint, when compared to risperidone or haloperidol-treated patients (p < .05), respectively. Higher productivity level was associated with significantly higher study completion rates and better scores on the positive, negative, disorganized thoughts, hostility and depression subscales of the Positive and Negative Symptom Scale (PANSS). CONCLUSIONS: Some antipsychotic medications significantly differed in beneficial impact on productivity level in the long-term treatment of patients with schizophrenia. Findings further highlight the link between clinical and functional outcomes, showing significant associations between higher productivity, lower symptom severity and better persistence on therapy. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT00088049; NCT00036088. PMID- 21586166 TI - Validation of the Work Observation Method By Activity Timing (WOMBAT) method of conducting time-motion observations in critical care settings: an observational study. AB - BACKGROUND: Electronic documentation handling may facilitate information flows in health care settings to support better coordination of care among Health Care Providers (HCPs), but evidence is limited. Methods that accurately depict changes to the workflows of HCPs are needed to assess whether the introduction of a Critical Care clinical Information System (CCIS) to two Intensive Care Units (ICUs) represents a positive step for patient care. To evaluate a previously described method of quantifying amounts of time spent and interruptions encountered by HCPs working in two ICUs. METHODS: Observers used PDAs running the Work Observation Method By Activity Timing (WOMBAT) software to record the tasks performed by HCPs in advance of the introduction of a Critical Care clinical Information System (CCIS) to quantify amounts of time spent on tasks and interruptions encountered by HCPs in ICUs. RESULTS: We report the percentages of time spent on each task category, and the rates of interruptions observed for physicians, nurses, respiratory therapists, and unit clerks. Compared with previously published data from Australian hospital wards, interdisciplinary information sharing and communication in ICUs explain higher proportions of time spent on professional communication and documentation by nurses and physicians, as well as more frequent interruptions which are often followed by professional communication tasks. CONCLUSIONS: Critical care workloads include requirements for timely information sharing and communication and explain the differences we observed between the two datasets. The data presented here further validate the WOMBAT method, and support plans to compare workflows before and after the introduction of electronic documentation methods in ICUs. PMID- 21586167 TI - Molecular characterization of Chinese hamster cells mutants affected in adenosine kinase and showing novel genetic and biochemical characteristics. AB - BACKGROUND: Two isoforms of the enzyme adenosine kinase (AdK), which differ at their N-terminal ends, are found in mammalian cells. However, there is no information available regarding the unique functional aspects or regulation of these isoforms. RESULTS: We show that the two AdK isoforms differ only in their first exons and the promoter regions; hence they arise via differential splicing of their first exons with the other exons common to both isoforms. The expression of these isoforms also varied greatly in different rat tissues and cell lines with some tissues expressing both isoforms and others expressing only one of the isoforms. To gain insights into cellular functions of these isoforms, mutants resistant to toxic adenosine analogs formycin A and tubercidin were selected from Chinese hamster (CH) cell lines expressing either one or both isoforms. The AdK activity in most of these mutants was reduced to <5% of wild-type cells and they also showed large differences in the expression of the two isoforms. Thus, the genetic alterations in these mutants likely affected both regulatory and structural regions of AdK. We have characterized the molecular alterations in a number of these mutants. One of these mutants lacking AdK activity was affected in the conserved NxxE motif thereby providing evidence that this motif involved in the binding of Mg2+ and phosphate ions is essential for AdK function. Another mutant, FomR-4, exhibiting increased resistance to only C-adenosine analogs and whose resistance was expressed dominantly in cell-hybrids contained a single mutation leading to Ser191Phe alteration in AdK. We demonstrate that this mutation in AdK is sufficient to confer the novel genetic and biochemical characteristics of this mutant. The unusual genetic and biochemical characteristics of the FomR-4 mutant suggest that AdK in this mutant might be complexed with the enzyme AMP-kinase. Several other AdK mutants were altered in surface residues that likely affect its binding to the adenosine analogs and its interaction with other cellular proteins. CONCLUSIONS: These AdK mutants provide important insights as well as novel tools for understanding the cellular functions of the two isoforms and their regulation in mammalian cells. PMID- 21586168 TI - Structurally robust biological networks. AB - BACKGROUND: The molecular circuitry of living organisms performs remarkably robust regulatory tasks, despite the often intrinsic variability of its components. A large body of research has in fact highlighted that robustness is often a structural property of biological systems. However, there are few systematic methods to mathematically model and describe structural robustness. With a few exceptions, numerical studies are often the preferred approach to this type of investigation. RESULTS: In this paper, we propose a framework to analyze robust stability of equilibria in biological networks. We employ Lyapunov and invariant sets theory, focusing on the structure of ordinary differential equation models. Without resorting to extensive numerical simulations, often necessary to explore the behavior of a model in its parameter space, we provide rigorous proofs of robust stability of known bio-molecular networks. Our results are in line with existing literature. CONCLUSIONS: The impact of our results is twofold: on the one hand, we highlight that classical and simple control theory methods are extremely useful to characterize the behavior of biological networks analytically. On the other hand, we are able to demonstrate that some biological networks are robust thanks to their structure and some qualitative properties of the interactions, regardless of the specific values of their parameters. PMID- 21586169 TI - Predicting drug side-effect profiles: a chemical fragment-based approach. AB - BACKGROUND: Drug side-effects, or adverse drug reactions, have become a major public health concern. It is one of the main causes of failure in the process of drug development, and of drug withdrawal once they have reached the market. Therefore, in silico prediction of potential side-effects early in the drug discovery process, before reaching the clinical stages, is of great interest to improve this long and expensive process and to provide new efficient and safe therapies for patients. RESULTS: In the present work, we propose a new method to predict potential side-effects of drug candidate molecules based on their chemical structures, applicable on large molecular databanks. A unique feature of the proposed method is its ability to extract correlated sets of chemical substructures (or chemical fragments) and side-effects. This is made possible using sparse canonical correlation analysis (SCCA). In the results, we show the usefulness of the proposed method by predicting 1385 side-effects in the SIDER database from the chemical structures of 888 approved drugs. These predictions are performed with simultaneous extraction of correlated ensembles formed by a set of chemical substructures shared by drugs that are likely to have a set of side-effects. We also conduct a comprehensive side-effect prediction for many uncharacterized drug molecules stored in DrugBank, and were able to confirm interesting predictions using independent source of information. CONCLUSIONS: The proposed method is expected to be useful in various stages of the drug development process. PMID- 21586170 TI - Differential effects of natural palm oil, chemically- and enzymatically-modified palm oil on weight gain, blood lipid metabolites and fat deposition in a pediatric pig model. AB - BACKGROUND: Increasing prevalence of obesity and overweight in the Western world, continue to be a major health threat and is responsible for increased health care costs. Dietary intervention studies show a strong positive association between saturated fat intake and the development of obesity and cardiovascular disease. This study investigated the effect of positional distribution of palmitic acid (Sn-1, 2 & 3) of palm oil on cardiovascular health and development of obesity, using weaner pigs as a model for young children. METHODS: Male and female weaner piglets were randomly allocated to 4 dietary treatment groups: 1) pork lard (LRD); 2) natural palm olein (NPO); 3) chemically inter-esterified PO (CPO) and 4) enzymatically inter-esterified PO (EnPO) as the fat source. Diets were formulated with 11% lard or with palm olein in order to provide 31% of digestible energy from fat in the diet and were balanced for cholesterol, protein and energy across treatments. RESULTS: From 8 weeks onwards, pigs on EnPO diet gained (P<0.05) more weight than all other groups. Feed conversion efficiency (feed to gain) over the 12 week experimental period did not vary between treatment groups. Plasma LDL-C content and LDL-C/HDL-C ratio in pigs fed natural PO tended to be lower compared to all other diets. The natural PO lowered (P<0.02) the plasma triglyceride (TG) content relative to the lard or EnPO diets, but was not different from the CPO diet. The natural PO diet was associated with lower (P<0.05) saturated fat levels in subcutaneous adipose tissue than the CPO and EnPO diets that had lower saturated fat levels than the lard diet. Female pigs had lower lean and higher fat and fat:lean ratio in the body compared with male pigs. No difference in weight gain or blood lipid parameters was observed between sexes. CONCLUSIONS: The observations on plasma TG, muscle and adipose tissue saturated fatty acid contents and back fat (subcutaneous) thickness suggest that natural palm oil may reduce deposition of body fat. In addition, dietary supplementation with natural palm oil containing palmitic acid at different positions in meat producing animals may lead to the production of meat and meat products with lower saturated fats. An increase in fat content and a decrease in lean content in female pigs resulted in an increased body fat:lean ratio but gender had no effect on blood lipid parameters or insulin concentrations. PMID- 21586171 TI - Thymidine Phosphorylase/beta-tubulin III expressions predict the response in Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel. AB - BACKGROUND: To assess the role of Thymidine Phosphorylase and beta-tubulin III in clinical outcome of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel. METHODS: The clinical data and tumor biopsies prior treatment from 33 advanced gastric cancer patients receiving capecitabine plus paclitaxel (cohort 1, experimental group) and 18 patients receiving capecitabine plus cisplatin (cohort 2, control group) in Beijing Cancer Hospital from July 2003 to December 2008 were retrospectively collected and analyzed for Thymidine Phosphorylase and beta-tubulin III expressions by immunohistochemistry. The relationships between expressions of biomarkers and response or survival were determined by statistical analysis. RESULTS: The median age of 51 patients was 57 years (range, 27-75) with male 34 and female 17, and the response rate, median progression-free survival and overall survival were 43.1%, 120d and 265d. Among cohort 1, the response rate, median progression-free survival and overall survival in beta-tubulin III positive (n = 22) and negative patients (n = 11) were 36.4%/72.7% (positive vs negative, P = 0.049), 86d/237d (P = 0.046) and 201d/388d (P = 0.029), respectively; the response rate (87.5% vs 14.3%, P = 0.01) and median progression-free survival (251d vs 84d, P = 0.003) in Thymidine Phosphorylase positive & beta-tubulin III negative patients (n = 8) were also significantly higher than those in Thymidine Phosphorylase negative & beta tubulin III positive patients (n = 7). There was no correlation between beta tubulin III expression and response or survival among cohort 2 (n = 18). CONCLUSIONS: In Chinese advanced gastric cancer, Thymidine Phosphorylase positive & beta-tubulin III negative might predict response and prognosis to capecitabine plus paclitaxel chemotherapy. Further prospective evaluation in large samples should be performed to confirm these preliminary findings. PMID- 21586172 TI - A comparison of comorbidities obtained from hospital administrative data and medical charts in older patients with pneumonia. AB - BACKGROUND: The use of comorbidities in risk adjustment for health outcomes research is frequently necessary to explain some of the observed variations. Medical charts reviews to obtain information on comorbidities is laborious. Increasingly, electronic health care databases have provided an alternative for health services researchers to obtain comorbidity information. However, the rates obtained from databases may be either over- or under-reported. This study aims to (a) quantify the agreement between administrative data and medical charts review across a set of comorbidities; and (b) examine the factors associated with under- or over-reporting of comorbidities by administrative data. METHODS: This is a retrospective cross-sectional study of patients aged 55 years and above, hospitalized for pneumonia at 3 acute care hospitals. Information on comorbidities were obtained from an electronic administrative database and compared with information from medical charts review. Logistic regression was performed to identify factors that were associated with under- or over-reporting of comorbidities by administrative data. RESULTS: The prevalence of almost all comorbidities obtained from administrative data was lower than that obtained from medical charts review. Agreement between comorbidities obtained from medical charts and administrative data ranged from poor to very strong (kappa 0.01 to 0.78). Factors associated with over-reporting of comorbidities were increased length of hospital stay, disease severity, and death in hospital. In contrast, those associated with under-reporting were number of comorbidities, age, and hospital admission in the previous 90 days. CONCLUSIONS: The validity of using secondary diagnoses from administrative data as an alternative to medical charts for identification of comorbidities varies with the specific condition in question, and is influenced by factors such as age, number of comorbidities, hospital admission in the previous 90 days, severity of illness, length of hospitalization, and whether inhospital death occurred. These factors need to be taken into account when relying on administrative data for comorbidity information. PMID- 21586173 TI - An association between unrecognized gastroesophageal reflux disease and excessive daytime sleepiness in Taiwanese subjects suspected to have liver disease: a pilot study. AB - BACKGROUND: In traditional Chinese culture, liver disease is believed to underlie excessive daytime sleepiness (EDS). Consequently, Chinese patients with complaints of EDS and physicians who treat them suspect that a liver abnormality is present. If liver disease is ruled out, these patients are often discharged without treatment. Gastroesophageal reflux disease (GERD) is a common disorder also associated with EDS. This pilot study was undertaken to determine the prevalence of GERD among Taiwanese patients with complaints of EDS suspected to be related to liver disease but in whom no evidence for the latter was found. METHODS: From July 2009 to December 2009, 121 outpatients who presented to or were referred to the Department of Gastroenterology and Hepatology of the Chiayi Gung Memorial Hospital for evaluation of a complaint of EDS thought to be due to liver disease were examined. Demographic data were collected, and physical examinations and liver function tests were performed. Forty-eight patients had liver disease and were excluded. The Chinese Epworth Sleepiness Scale questionnaire (Chinese ESS) and the Chinese Gastroesophageal Reflux Disease Questionnaire (CGERDQ) were then administered to 73 included patients. RESULTS: More than half (56.2%) of the included patients were found to suffer from GERD. Patients with symptoms of GERD had higher mean CGERDQ scores than patients without symptoms of the disorder (18.88 +/- 5.49 and 5.56 +/- 3.57, respectively; P < 0.001). Patients with symptoms of GERD also had higher mean Chinese ESS scores than patients without symptoms (8.80 +/- 5.49 and 3.13 +/- 3.50, respectively; P < 0.001). Chinese ESS scores indicative of EDS were observed in 48.8% of patients with symptoms of GERD and in 3.1% of those without symptoms (P < 0.001). Differences between the two groups retained their significance after controlling for potential confounders. CONCLUSIONS: A significant percentage of Taiwanese patients who complained of EDS and were admitted to our Hepatology/Gastroenterology Department due to a suspicion of liver disease actually had symptoms of GERD. Further studies are needed to ascertain whether treatment of GERD will effectively resolve EDS in these patients. PMID- 21586174 TI - Trends in malaria research in 11 Asian Pacific countries: an analysis of peer reviewed publications over two decades. AB - BACKGROUND: Quantitative data are lacking on published malaria research. The purpose of the study is to characterize trends in malaria-related literature from 1990 to 2009 in 11 Asian-Pacific countries that are committed to malaria elimination as a national goal. METHODS: A systematic search was conducted for articles published from January 1990 to December 2009 in PubMed/MEDLINE using terms for malaria and 11 target countries (Bhutan, China, North Korea, Indonesia, Malaysia, Philippines, Solomon Islands, South Korea, Sri Lanka, Thailand and Vanuatu). The references were collated and categorized according to subject, Plasmodium species, and whether they contained original or derivative data. RESULTS: 2,700 articles published between 1990 and 2009 related to malaria in the target countries. The annual output of malaria-related papers increased linearly whereas the overall biomedical output from these countries grew exponentially. The percentage of malaria-related publications was nearly 3% (111/3741) of all biomedical publications in 1992 and decreased to less than 1% (118/12171; p < 0.001) in 2009. Thailand had the highest absolute output of malaria-related papers (n = 1211), followed by China (n = 609) and Indonesia (n = 346). Solomon Islands and Vanuatu had lower absolute numbers of publications, but both countries had the highest number of publications per capita (1.3 and 2.5 papers/1,000 population). The largest percentage of papers concerned the epidemiology and control of malaria (53%) followed by studies of drugs and drug resistance (47%). There was an increase in the proportion of articles relating to epidemiology, entomology, biology, molecular biology, pathophysiology and diagnostics from the first to the second decade, whereas the percentage of papers on drugs, clinical aspects of malaria, immunology, and social sciences decreased. CONCLUSIONS: The proportion of malaria-related publications out of the overall biomedical output from the 11 target Asian-Pacific countries is decreasing. The discovery and evaluation of new, safe and effective drugs and vaccines is paramount. In addition the elimination of malaria will require operational research to implement and scale up interventions. PMID- 21586175 TI - Suprasellar cysts: clinical presentation, surgical indications, and optimal surgical treatment. AB - BACKGROUND: To describe the clinical presentation of suprasellar cysts (SSCs) and surgical indications, and compare the treatment methods of endoscopic ventriculocystostomy (VC) and ventriculocystocisternotomy (VCC). METHODS: We retrospectively reviewed the records of 73 consecutive patients with SSC who were treated between June 2002 and September 2009. Twenty-two patients were treated with VC and 51 with VCC. Outcome was assessed by clinical examination and magnetic resonance imaging. RESULTS: The patients were divided into five groups based on age at presentation: age less than 1 year (n = 6), 1-5 years (n = 36), 6 10 years (n = 15), 11-20 years (n = 11), and 21-53 years (n = 5). The main clinical presentations were macrocrania (100%), motor deficits (50%), and gaze disturbance (33.3%) in the age less than 1 year group; macrocrania (75%), motor deficits (63.9%), and gaze disturbance (27.8%) in the 1-5 years group; macrocrania (46.7%), symptoms of raised intracranial pressure (ICP) (40.0%), endocrine dysfunction (40%), and seizures (33.3%) in the 6-10 years group; symptoms of raised ICP (54.5%), endocrine dysfunction (54.5%), and reduced visual field or acuity (36.4%) in the 11-20 years group; and symptoms of raised ICP (80.0%) and reduced visual field or acuity (40.0%) in the 21-53 years group. The overall success rate of endoscopic fenestration was 90.4%. A Kaplan-Meier curve for long-term efficacy of the two treatment modalities showed better results for VCC than for VC (p = 0.008). CONCLUSIONS: Different age groups with SSCs have different main clinical presentations. VCC appears to be more efficacious than VC. PMID- 21586176 TI - Societal costs and benefits of treatment with trastuzumab in patients with early HER2neu-overexpressing breast cancer in Singapore. AB - BACKGROUND: Trastuzumab has revolutionized the way we treat early Her2Neu positive breast cancer, as it significantly improves disease-free and overall survival. Little is known about the societal costs and benefits of treatment with trastuzumab in the adjuvant setting in Southeast Asia. METHODS: Societal costs (benefits) were estimated as the sum of direct and indirect costs minus benefits in the base case. Direct costs were derived from 4 treatment centers in Singapore (2 private and 2 public, comprising 60-70% of all patients with cancer seen in the island-nation); indirect costs were assessed as the loss of productivity caused by the disease or treatment. Benefits to society were based on extra years of productivity, as measured by GNI per capita, resulting from the quality adjusted life-years (QALYs) saved with the use of trastuzumab as determined in the models by Kurian, Liberato and Garrison. RESULTS: Incremental costs in Singapore, in 2005 US dollars, were $26,971.05. Average Cost per QALY was $19,174.59 (Median: $18,993.70). Costs (benefits) to society ranged from a cost of $79.42 to a benefit of $9,263.06, depending on the model used (Average benefit: $4,375.89, Median $3,944.03). Sensitivity analysis ranged from a cost of $10,685.00 to a Benefit of US$17,298.79 CONCLUSIONS: Treatment with adjuvant trastuzumab is likely to generate net societal economic benefits in Singapore. Nevertheless, the lower range of possible outcomes does not refute the possibility that treatment may actually generate costs. These costs however clearly fall within the usual range of acceptable cost-effectiveness. PMID- 21586179 TI - [A man with calcifications in his legs]. AB - A 70-year-old man had ulcers on his right lower leg for a year; he also had pitting oedema. On X-ray of his legs soft tissue calcifications were seen. These were caused by venous insufficiency. PMID- 21586177 TI - Supplementation of a western diet with golden kiwifruits (Actinidia chinensis var.'Hort 16A':) effects on biomarkers of oxidation damage and antioxidant protection. AB - BACKGROUND: The health positive effects of diets high in fruits and vegetables are generally not replicated in supplementation trials with isolated antioxidants and vitamins, and as a consequence the emphasis of chronic disease prevention has shifted to whole foods and whole food products. METHODS: We carried out a human intervention trial with the golden kiwifruit, Actinidia chinensis, measuring markers of antioxidant status, DNA stability, plasma lipids, and platelet aggregation. Our hypothesis was that supplementation of a normal diet with kiwifruits would have an effect on biomarkers of oxidative status. Healthy volunteers supplemented a normal diet with either one or two golden kiwifruits per day in a cross-over study lasting 2 * 4 weeks. Plasma levels of vitamin C, and carotenoids, and the ferric reducing activity of plasma (FRAP) were measured. Malondialdehyde was assessed as a biomarker of lipid oxidation. Effects on DNA damage in circulating lymphocytes were estimated using the comet assay with enzyme modification to measure specific lesions; another modification allowed estimation of DNA repair. RESULTS: Plasma vitamin C increased after supplementation as did resistance towards H2O2-induced DNA damage. Purine oxidation in lymphocyte DNA decreased significantly after one kiwifruit per day, pyrimidine oxidation decreased after two fruits per day. Neither DNA base excision nor nucleotide excision repair was influenced by kiwifruit consumption. Malondialdehyde was not affected, but plasma triglycerides decreased. Whole blood platelet aggregation was decreased by kiwifruit supplementation. CONCLUSION: Golden kiwifruit consumption strengthens resistance towards endogenous oxidative damage. PMID- 21586178 TI - The impact of distance and a shifting temperature gradient on genetic connectivity across a heterogeneous landscape. AB - BACKGROUND: Inter-population distance and differences in breeding times are barriers to reproduction that can contribute to genotypic differentiation between populations. Temporal changes in environmental conditions and local selective processes can further contribute to the establishment of reproductive barriers. Telopea speciosissima (Proteaceae) is an excellent subject for studying the effect of geographic, edaphic and phenological heterogeneity on genotypic differentiation because previous studies show that these factors are correlated with morphological variation. Molecular, morphological and environmental datasets were combined to characterise the relative influence of these factors on inter population differentiation, and Bayesian analyses were used to investigate current levels of admixture between differentiated genomes. RESULTS: A landscape genetic approach involving molecular and morphological analyses identified three endpoints of differentiated population groups: coastal, upland and southern. The southern populations, isolated from the other populations by an edaphic barrier, show low migration and no evidence of admixture with other populations. Amongst the northern populations, coastal and upland populations are connected along a skewed altitudinal gradient by genetically intermediate populations. The strong association between temperature and flowering time in Telopea speciosissima was shown to maintain a temporally unstable reproductive barrier between coastal and upland populations. CONCLUSIONS: Substrate-mediated allopatry appears to be responsible for long-term genetic isolation of the southern populations. However, the temperature-dependent reproductive barrier between upland and coastal populations bears the genetic signature of temporal adjustments. The extreme climatic events of the last glacial maximum are likely to have caused more complete allochronic isolation between upland and coastal populations, as well as exerting increased selective pressure upon local genomes. However, at intermediate altitudes, current climatic conditions allow for the incorporation of alleles from previously distinct genomes, generating new, intermediate genomic assemblages and possibly increasing overall adaptive potential. PMID- 21586180 TI - [A girl with rapidly progressive ataxia]. AB - A 4-year-old girl came to the emergency department with a headache since 4 weeks and ataxia since 1 day. Before she had had stomatitis. The girl tested positive for coxsackievirus. MRI showed multiple lesions in the white matter. The diagnosis was 'acute disseminated encephalomyelitis'. PMID- 21586181 TI - [Endovascular treatment of acute ischaemic stroke by means of a removable stent]. AB - In this article, we describe the use of a novel mechanical thrombectomy device aimed at removing a thrombus in patients with acute ischaemic stroke and proximal intracranial arterial occlusion. A self-expandable stent is deployed into the thrombus which results in the immediate restoration of blood flow. After a few minutes, the thrombus will anchor itself onto the mesh of the stent. The stent and the captured thrombus are subsequently retrieved during aspiration of the guiding catheter. PMID- 21586182 TI - [Amyloid-plaque imaging of the brain using PET]. AB - Alzheimer's disease (AD) is neuropathologically characterized by the presence of senile plaques. The formation of these plaques is caused by the accumulation of amyloid-beta protein (Abeta), a process that begins decades before the onset of the first clinical symptoms. Senile plaques can be visualized by using positron emission tomography (PET) and the tracer 11C-PIB. Such 'amyloid imaging' can contribute significantly to both early and differential diagnosis of Alzheimer's disease. In the future, amyloid imaging could also be useful for selecting patients for clinical trials and in evaluating the effects of disease modifying agents tailored at lowering Abeta burden. PMID- 21586183 TI - [Persistent polyclonal B-cell lymphocytosis]. AB - BACKGROUND: Persistent polyclonal B-cell lymphocytosis (PPBL) is a benign condition associated with smoking. CASE REPORT: A 42-year-old woman was referred to an internist because of an abnormal blood test outcome identified during routine sampling. She had no symptoms; she had smoked for thirty pack years. Physical examination revealed no abnormalities. Laboratory analysis showed absolute lymphocytosis. A blood smear identified binuclear ('buttock') cells. The diagnosis of persistent polyclonal B-cell lymphocytosis (PPBL) was made, with nicotine abuse as the probable cause. The patient was advised to quit smoking. CONCLUSION: Polyclonal B-cell lymphocytosis is a benign condition that is characterised by: (a) polyclonal increase of B-lymphocytes in peripheral blood; (b) the presence of binuclear lymphocytes (buttock cells) in microscopic differentiation; (c) polyclonal increase in IgM. Recognition is important for the prevention of unnecessary diagnostic testing. PMID- 21586184 TI - [Multimorbidity and comorbidity in the Dutch population--data from general practices]. AB - OBJECTIVE: To present an overview of the prevalence of multimorbidity and comorbidity of chronic diseases in the Dutch population. DESIGN: Data analysis. METHODS: Data from the Netherlands Information Network of General Practice (LINH), a large representative network of general practices over a period of 7 years (2002-2008) were analysed. Multimorbidity was defined as a patient having been diagnosed with two or more of 29 chronic diseases in the general practitioner's electronic medical records system. The prevalence of chronic diseases and multimorbidity was calculated for the total population and subsequently by sex and age groups. For the 10 most prevalent diseases in the elderly, clustering and comorbidity of chronic diseases in patients 55 years and older were analysed. RESULTS: Almost 13% of the total Dutch population and 37% of patients 55 years and older had 2 or more chronic diseases. More than 70% of the patients aged 55 years and older who had 1 of the 10 specific chronic diseases also had an additional chronic disease. Most disease pairs occurred more frequently than expected based on independency (clustering), particularly the combinations depression and anxiety disorder, coronary heart disease and heart failure, and COPD and heart failure. The five most common combinations of conditions associated with a certain disease concerned only a limited portion (30%) of all disease comorbidity. This means that 70% of patients with a chronic disease had 1 or more additional diseases not included in the 5 most frequently occurring diseases. CONCLUSION: Multimorbidity was identified in over two-thirds of the elderly with frequently occurring chronic diseases. Comorbidity encompassed many different combinations of chronic diseases. In light of an ageing population, multimorbidity should increasingly be taken into account when delivering healthcare, in medical research and in defining healthcare policies. PMID- 21586185 TI - [Rapid response system in derangement of vital signs: five years experience in a large general hospital]. AB - OBJECTIVE: Hospitalized patients are at risk for adverse events such as unexpected cardiac arrest or admission to an Intensive Care Unit (ICU). Prior to these adverse events these patients often have derangements in vital signs that are not recognized and treated adequately. To identify and treat those patients at risk, our hospital implemented a rapid response system in 2004. The purpose of this paper is to describe implementation and results of our rapid response system. DESIGN: Prospective cohort study. METHOD: The implementation of the rapid response system started by training all doctors and nurses to score vital signs using a dedicated score card. If a patient scores 3 or more points, the patients' treating physician has to see the patient and - if necessary - call the medical emergency team (MET), consisting of an ICU physician and an ICU nurse. We analyzed all consecutive MET calls in the period January 2005-December 2009. RESULTS: A total of 1058 MET calls for 981 patients were analyzed. In 606 patients (57.3%) it was decided to transfer the patient to a higher dependency unit, in most cases the ICU. In 353 patients (33.4%) treatment could be continued on the ward. In 88 patients (8.4%) it was decided that ICU treatment would not be beneficial and limits on treatment were put in place. Of the 981 patients, 255 (26.0%) died in hospital. CONCLUSION: In our hospital the rapid response system has developed into an important tool for the early identification and treatment of patients at risk. However, our data cannot prove the efficacy of the rapid response system in terms of reducing hospital mortality. PMID- 21586186 TI - [Index event bias: why causal factors appear not to apply to disease recurrence]. AB - In etiological epidemiological studies, bias is of constant concern. The peculiar phenomenon that causes of common disease do not predict the risk of recurrent disease may be explained by a specific form of bias that is not commonly recognised: index event bias. The principle of index event bias is that, in the presence of a specific cause of disease, the causal complement consisting of other disease causes is smaller than in the absence of this specific cause. Since the causal complement consists of both known and unknown disease causes, multivariable adjustment can only partially overcome this type of bias. Hence, in all forms of etiological studies addressing recurrent disease risk, index event bias is a source of potential underestimation of causal associations. PMID- 21586187 TI - [A higher place on the waiting list for kidney transplantation after earlier donation: a matter of give and take]. AB - In May 2011 the Dutch Health Council released an advice regarding living kidney donors who developed end-stage renal disease (ESRD) after donation. These donors with ESRD will have a high priority when they are on the waiting list for kidney transplantation. With this new rule the former donors will be transplanted within 6 weeks and transplantation can preferably be performed preemptively. It is expected that this measure shall prolong the waiting list for a donor kidney for the remaining patients with end stage renal disease by 6 days at most, on a total average waiting period of 4 years. PMID- 21586188 TI - [Priority for live kidney donors in transplantation]. AB - Patients in the Netherlands requiring a donor kidney spend 3 to 4 years on average on the transplant waiting list for a kidney from a deceased donor. Post mortem donor kidneys are in short supply. Consequently, over the past 15 years, an increasingly number of living persons have donated a kidney. This development raises the question as to whether these donors ought to be given priority on the donor kidney waiting list in the event of subsequently suffering from severe renal insufficiency. The Health Council of the Netherlands concludes that there are sound medical-ethical and legal arguments for awarding live kidney donors with end-stage renal failure 500 points in the points system that Eurotransplant uses to determine the position on the waiting list. Adopting this approach would mean that donors would qualify for pre-emptive transplant of a post-mortem donor kidney. The Council is of the opinion that the proposal is reconcilable with national and international legal rules and the principles on which they are based. PMID- 21586189 TI - Collaborative mental health care: where we have been, where we are now, and where we should be going. PMID- 21586190 TI - Toward understanding resilient outcomes. PMID- 21586191 TI - What is resilience? AB - OBJECTIVE: While everyone-including front-line clinicians-should strive to prevent the maltreatment and other severe stresses experienced by many children and adults in everyday life, psychiatrists and other health professionals also need to consider how best to support, throughout the lifespan, those people affected by severe adversity. The first step in achieving this is a clear understanding of the definitions and concepts in the rapidly growing study of resilience. Our paper reviews the definitions of resilience and the range of factors understood as contributing to it, and considers some of the implications for clinical care and public health. METHOD: This narrative review took a major Canadian report published in 2006 as its starting point. The databases, MEDLINE and PsycINFO, were searched for new relevant citations from 2006 up to July 2010 to identify key papers considering the definitions of resilience and related concepts. RESULTS: Definitions have evolved over time but fundamentally resilience is understood as referring to positive adaptation, or the ability to maintain or regain mental health, despite experiencing adversity. The personal, biological, and environmental or systemic sources of resilience and their interaction are considered. An interactive model of resilience illustrates the factors that enhance or reduce homeostasis or resilience. CONCLUSIONS: The 2 key concepts for clinical and public health work are: the dynamic nature of resilience throughout the lifespan; and the interaction of resilience in different ways with major domains of life function, including intimate relationships and attachments. PMID- 21586192 TI - Resilience following child maltreatment: a review of protective factors. AB - OBJECTIVE: Child maltreatment is linked with numerous adverse outcomes that can continue throughout the lifespan. However, variability of impairment has been noted following child maltreatment, making it seem that some people are more resilient. Our review includes a brief discussion of how resilience is measured in child maltreatment research; a summary of the evidence for protective factors associated with resilience based on those studies of highest quality; a discussion of how knowledge of protective factors can be applied to promote resilience among people exposed to child maltreatment; and finally, directions for future research. METHOD: The databases MEDLINE and PsycINFO were searched for relevant citations up to July 2010 to identify key studies and evidence syntheses. RESULTS: Although comparability across studies is limited, family level factors of stable family environment and supportive relationships appear to be consistently linked with resilience across studies. There was also evidence for some individual-level factors, such as personality traits, although proxies of intellect were not as strongly related to resilience following child maltreatment. CONCLUSIONS: Findings from resilience research needs to be applied to determine effective strategies and specific interventions to promote resilience and foster well-being among maltreated children. PMID- 21586193 TI - Prenatal care and adverse pregnancy outcomes among women with depression: a nationwide population-based study. AB - OBJECTIVE: To evaluate the quantity of prenatal care as a risk factor for giving birth to low birth weight (LBW), preterm, and small for gestational age (SGA) infants in a sample of women diagnosed with depressive disorder. METHOD: Our study used a population-based dataset, Taiwan's National Health Insurance Research Database, which we linked to Taiwan's birth certificate registry to identify a total of 5283 new mothers with depressive disorder. Multivariate logistic regression analyses were performed to measure the risk of giving birth to LBW, preterm, and SGA infants, relating to the number of prenatal care visits (10 or more, 8 to 9, and 7 or less) made by mothers with depressive disorder. RESULTS: After adjusting for a woman's age, monthly income, urbanization level of place of residence, geographic location, marital status, substance abuse, arterial hypertension, diabetes, anemia, coronary heart disease, malpresentation, insufficient or excessive fetal growth, placenta or previa abruption, and infant's sex and parity, regression analyses revealed that mothers with a history of depressive disorder who received prenatal care 7 times or less were 4.21 (95% CI 3.34 to 5.32, P < 0.001), 5.37 (95% CI 4.33 to 6.67, P < 0.001), and 2.41 (95% CI 2.03 to 2.86, P < 0.001) times as likely to have LBW, preterm, and SGA babies, respectively, compared with mothers with depressive disorder who received prenatal care visits 10 times or more. CONCLUSIONS: Mothers with a history of depressive disorder who make fewer prenatal care visits were at an increased risk of LBW, SGA, and preterm birth, compared with women with a history of depressive disorder who made an adequate number of prenatal visits. PMID- 21586194 TI - Psychiatric comorbidities in adolescents with attention-deficit hyperactivity disorder and their siblings. AB - OBJECTIVE: Despite high psychiatric comorbidities in adolescents with clinical diagnosis of attention-deficit hyperactivity disorder (ADHD), little is known about psychiatric comorbidities in their siblings. We investigated the psychiatric comorbid conditions in adolescents with ADHD, their siblings, and healthy control subjects from their school. METHOD: The sample included 136 adolescent probands with ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), diagnostic criteria; 136 siblings (47 affected and 89 unaffected) and 136 age- and sex-matched healthy school control subjects. All participants and their parents received the structured psychiatric interviews for current and lifetime DSM-IV psychiatric disorders of the participants. RESULTS: The rate of ADHD (34.6%) in the siblings of probands with ADHD was about 7 times higher than in the general population. Probands with ADHD were significantly more likely than unaffected siblings (OR 6.38; 95% CI 3.43 to 11.88) and healthy school control subjects (OR 9.60; 95% CI 5.31 to 17.34) to have a DSM-IV psychiatric disorder, including oppositional defiant disorder (ODD), conduct disorder (CD), tic disorders, major depressive disorder, specific phobia (more than control subjects only), nicotine use disorder, and sleep disorders. The affected siblings were significantly more likely than healthy school control subjects to have ODD, CD, specific phobia, and to have consumed alcohol (ORs ranging from 2.30 to 20.16). CONCLUSIONS: Our findings suggest that siblings of probands with ADHD have increased risks for ADHD and that the affected siblings have more psychiatric comorbidities than healthy school control subjects. It warrants early identification of ADHD symptoms and other psychiatric comorbid conditions as well in siblings of adolescents with ADHD. PMID- 21586195 TI - To detain or to release? Correlates of dispositions for individuals declared not criminally responsible on account of mental disorder. AB - OBJECTIVE: The extent to which risk assessment advances have influenced release decision-making by review boards (RBs) of individuals found not criminally responsible on account of mental disorder (NCRMD) remains unclear. Our objective is to identify the psychosocial, criminological, and risk measure correlates of RB decision-making. METHOD: Data were collected through structured interviews and file reviews conducted between October 2004 and August 2006 in the sole forensic psychiatric hospital in Quebec and in 2 civil psychiatric hospitals in a large metropolitan area designated to care for people found NCRMD. The final sample consisted of 96 men. RESULTS: Dynamic, clinical risk factors are associated with decisions to detain or release people found NCRMD, rather than traditional historical risk factors such as criminal history. CONCLUSION: Dynamic variables seem appropriate for the RBs to consider given the intention of the NCRMD legislation. Further, dynamic variables provide direction for titration of treatment and supervision. Results are discussed regarding enhancing evidence informed RB dispositions. PMID- 21586196 TI - [Counter-transference in eating disorder treatment:a systematic review]. AB - OBJECTIVE: To identify counter-transference occurrences and causes in therapists treating patients with eating disorders, and to present suggested solutions to overcome counter-transference's negative aspects and to enhance treatment quality. METHOD: Using the major health science and psychology databases, we have identified studies dealing with counter-transference in eating disorder treatment. RESULTS: Many counter-transference occurrences are identified. It seems that therapists often feel negative affects while treating patients with eating disorders. Counter transference seems to be affected by factors related to both the disorder and to the patient and therapist. Further, negative counter transference can lead to consequences interfering with proper conduct of treatment. The main solutions identified to deal with counter-transference are supervision, consulting with colleagues, and teamwork. CONCLUSIONS: Many factors involved in counter-transference seem hardly modifiable;hence it is important to implement efficient solutions allowing overcoming its negative aspects. Moreover, few empirical studies have focused on counter-transference in eating disorder treatment. That research field is highly pertinent but very rarely exploited, and it deserves the scientific community's attention. PMID- 21586197 TI - Treatment of large-vessel vasculitis: where do we stand? PMID- 21586199 TI - Infliximab or rituximab for refractory Wegener's granulomatosis: long-term follow up. A prospective randomised multicentre study on 17 patients. AB - OBJECTIVES: To compare efficacy and tolerance of infliximab versus rituximab to treat refractory Wegener's granulomatosis (WG), and clarify their respective indications. METHODS: Patients with systemic WG refractory to, or intolerant to steroids and consecutive immunosuppressant lines, including oral cyclophosphamide, were randomly assigned to receive infliximab or rituximab and their ongoing regimen. The primary endpoint was partial (PR) or complete remission (CR) at month 12. The secondary endpoint was the occurrence of adverse events. Long-term follow-up data were subjected to post-hoc analysis. RESULTS: Between 2004 and 2007, 9 infliximab and 8 rituximab patients were included. At M12, we observed 2 infliximab and 4 rituximab CR, 1 infliximab and 1 rituximab PR, 5 infliximab and 2 rituximab failures and 2 deaths (NS). Post-hoc analysis was conducted after 30.6+/-15.4 months of follow-up. Among the 15 survivors, 2 infliximab patients and 1 rituximab patient relapsed. Among 5 infliximab non responders, 4 were successfully switched to rituximab. During follow-up, one patient from each group died. Over the long term, 10/17 (59%) patients responded to rituximab, 1 to infliximab, 2 to other strategies and 2 died. Despite the 2 deaths, tolerance of both drugs was considered acceptable in terms of WG severity before treatment and previous treatment lines. CONCLUSIONS: Our observations demonstrate the usefulness of infliximab and/or rituximab to obtain remission of refractory WG with a trend at M12 favouring rituximab. During long-term follow up, rituximab was better able at obtaining and maintaining remission. PMID- 21586200 TI - IgG4-associated sclerosing mesenteritis. PMID- 21586201 TI - Assessment of disease activity and progression in Takayasu's arteritis. AB - Takayasu's arteritis (TA) is a rare, chronic panarteritis of the aorta and its major branches presenting commonly in young ages. Physical examination findings, presence of constitutional features, elevated acute-phase reactants, and new vessel involvement in imaging are major features of an active disease. However, assessment of disease activity and damage in TA is problematic given the chronic, indolent disease course and lack of specific laboratory and imaging findings. Although CT, MRI, and FDG-PET are commonly used imaging modalities, their lack of specificity to discriminate active disease from damage, limit their usefulness in routine practice. Two recently introduced multi-systemic clinical assessment tools, the DEI.Tak and the ITAS (both derived from BVAS), seem to be helpful in assessing disease activity and damage in TA. However, physician's global assessments of disease activity and decisions regarding treatments are still strongly influenced by changes in the acute-phase response and imaging. A comprehensive approach to both systemic and vascular features of TA to define a validated set of outcome measures for use in clinical trials and clinical practice is clearly needed. The OMERACT Vasculitis Working Group has taken on this task and has embarked on a research agenda to advance outcome measure development in TA. PMID- 21586202 TI - The pathology of large-vessel vasculitides. AB - Vasculitis affecting large elastic arteries, including the aorta and major proximal branches, encompasses various diseases including Takayasu arteritis, giant cell (or temporal) arteritis, and tertiary syphilis, but also may occur as a rare complication of Behcet's disease, rheumatoid arthritis, sarcoidosis, Cogan syndrome, Kawasaki disease, ankylosing spondylitis, systemic lupus erythematosus and Wegener's granulomatosis. Recent reports have also established a link between inflammatory abdominal aortic aneurysm as well as lymphoplasmacytic thoracic aortitis with an overabundance of IgG4-producing plasma cells and the burgeoning constellation of 'Hyper-IgG4' syndromes. This review focuses on morphologic aspects of large-vessel vasculitis pathology associated with giant cell arteritis, Takayasu arteritis, idiopathic or isolated aortitis, lymphoplasmacytic thoracic and ascending aortitis, and the inflammatory aneurysm/retroperitoneal fibrosis syndrome. PMID- 21586203 TI - Treatment of mixed cryoglobulinemia: a rheumatology perspective. AB - The treatment of the cryoglobulinemic syndrome or vasculitis (CV) must be targeted to the individual patient, and requires clinical expertise and knowledge of the disease biology. In general, the treatment is suggested by the clinical picture, but biologic issues should also be considered. Both immunosuppressive and antiviral approaches deserve equal attention based on the wide clinical spectrum and on disease biology, where the viral trigger and the downstream autoimmune response may play a different role in different disease stages. The severity of the disease, previous history and therapies administered, comorbidities and other individual factors should be analysed in the single case. Acute and life-threatening conditions usually require high dose steroids, plasmapheresis and/or cyclophosphamide. Rituximab often represents the best option for severe CV. Antiviral therapy is a cornerstone for the management of CV in hepatitis-related cases, and has the strongest biologic rationale, in general, in this disease and should be always considered in stabilised patients. A multispecialistic approach is needed to better define treatment strategies in different subsets of patients. PMID- 21586204 TI - Imaging findings in primary central nervous system vasculitis. AB - Primary central nervous system vasculitis (PCNSV) is a rare primary vasculitis limited to the brain and spinal cord. It can affect any age group, but has a predilection for subjects aged 40 to 60 years without clear gender predominance. Clinical manifestations are nonspecific, including headache, non-focal neurological features and, less frequently, focal neurological signs. Brain biopsy is the diagnostic gold standard, but may be falsely negative when unaffected tissue is sampled. In addition, brain biopsy carries a small but significant risk of serious complications. Imaging procedures are a key part of the workup of PCNSV patients. They can be used to document the extent and type of lesions, to gauge response to treatment, and sometimes as surrogates for brain biopsy. Magnetic resonance is extremely sensitive but non-specific. The most common findings are multiple bilateral ischaemic lesions often involving white and grey matter. Conventional or magnetic resonance angiography (MRA) typically shows segmental narrowing and dilation in multiple cerebral arteries. However, atypical findings have also been described both with magnetic resonance and angiography. This review discusses the state-of-the-art of current imaging techniques in the workup of PCNSV patients and highlights future prospects. PMID- 21586205 TI - Treating polyarteritis nodosa: current state of the art. AB - Defining treatment guidelines for polyarteritis nodosa (PAN) is complicated by the evolving definition and classification of this vasculitis, and because clinical trials have included patients with PAN, microscopic polyangiitis or, sometimes, Churg-Strauss syndrome. Nonetheless, clinical trial data support that the 'idiopathic generalised' form of PAN benefits from a severity-adapted treatment strategy, implying that cases with life-threatening manifestations require a regimen combining high-dose glucocorticoids and cyclophosphamide, whereas a non-severe disease may be treated with glucocorticoids alone. Results of uncontrolled studies indicate that hepatitis B virus-associated PAN management should include an antiviral agent, short-term glucocorticoids and plasma exchanges. No robust scientific evidence is available to guide the treatment of the limited variant 'cutaneous PAN'. Most experts recommend a less aggressive therapy with non-steroidal anti-inflammatory drugs or other agents, such as colchicine or dapsone. PAN has become an even more uncommon disease, probably due to classification changes and, perhaps also to a genuine modification of the epidemiology of this vasculitis. Although more data are needed to resolve outstanding questions, it is unclear whether all these matters can be studied in the future in large, sufficiently powered trials. PMID- 21586206 TI - Bilateral central retinal artery occlusion in a patient with Churg-Strauss vasculitis. PMID- 21586207 TI - Isolated vasculitis of the lower extremities in a patient with polymyalgia rheumatica and giant cell arteritis. PMID- 21586208 TI - Acute cardiac valvular involvement in Kawasaki Disease. PMID- 21586209 TI - IgA glomerulonephritis associated with Churg-Strauss syndrome. PMID- 21586211 TI - Association study of 3 rheumatoid arthritis risk loci in systemic sclerosis in European Caucasian population. AB - INTRODUCTION: Accumulating evidences show that shared autoimmunity is critical for the pathogenesis of many inflammatory rheumatic conditions. Specific phenotype could arise from specific genes, and/or combination of genetic factors and environment. Systemic sclerosis (SSc) belongs to connective tissue disorders and recent data have highlighted strong associations with some autoimmunity genes shared with other autoimmune diseases. OBJECTIVES: To determine whether novel risk loci associated with rheumatoid arthritis (RA) may confer susceptibility to SSc. Single nucleotide polymorphism from CCL21, CD244 and CDK6 were tested for association. METHODS: SNPs harbouring association with RA, CCL21-rs2812378, CDK6 rs42041 and CD244-rs6682654 were genotyped in a cohort of 1031 SSc patients and 1014 controls. All individuals were of European Caucasian origin. RESULTS: The three polymorphisms were in Hardy-Weinberg equilibrium in the control population and allelic frequencies were similar to those expected in European populations. Allelic and genotypic frequencies for these three polymorphisms were found to be similar in SSc patients and controls. Moreover, sub-phenotype analyses in particular for subgroups having diffuse subcutaneous subtype, specific auto antibodies or fibrosing alveolitis did not detect any difference between SSc patients and controls. CONCLUSIONS: These results obtained through a large cohort of European Caucasian SSc patients do not support the implication of CCL21, CD244 and CDK6 genes in the pathogenesis of SSc although these genes were recently identified as RA susceptibility genes. PMID- 21586212 TI - Epidemiology of systemic sclerosis in a district of northern Italy. AB - OBJECTIVES: To estimate, using both the American College of Rheumatology-ACR 1980 classification criteria and revised LeRoy and Medsger 2001 criteria, the incidence and prevalence of systemic sclerosis (SSc) in an area in north-eastern Italy with a referral base population of about 346,000 inhabitants. METHODS: Retrospective examination of all patients 16 years and older of native Italian origin and resident in the Ferrara district who had either been admitted to hospital or referred to our outpatient clinic with a diagnosis of SSc between 1st January 1999 and 31st December 2007. SSc subjects were identified both by a search of hospital discharge code 710.1, as per the international classification of disease-9 codes, and using a computerised search for this pathology code in the national health care system. The subjects referred to our outpatient clinic were identified from a dedicated data base. Incidence and prevalence rates were calculated as the number of cases per 100,000 inhabitants (population data based on the October 2001 national census). The medical records of each potential case were accurately examined and reviewed by the same physician who determined whether those patients identified as having a diagnosis of SSc did indeed meet the ACR 1980 classification criteria for SSc and/or the LeRoy and Medsger 2001 criteria. RESULTS: After reviewing all cases, of the 118 patients meeting the LeRoy-Medsger 2001 criteria, only 88 patients had a definitive diagnosis of SSc according to the ACR 1980 criteria. Considering the ACR criteria, the prevalence rate was 25.4 cases per 100,000 (95% CI: 22.2-28.6), and the annual incidence rate over the study period was 3.2 per 100,000 (95% CI: 2.0-4.4). Considering the LeRoy and Medsger criteria epidemiological data were respectively 34.1 cases per 100,000 (95% CI: 30.4-37.8) and 4.3 cases per 100,000 (95% CI: 3.0-5.6). According to the LeRoy and Medsger criteria, the SSc subsets were broken down as follows: 20 limited-SSc (19.2%), 76 limited cutaneous-SSc (62.1%), 22 diffuse cutaneous-SSc (18.7%). The female/male ratio was 9.7:1. CONCLUSIONS: Incidence and prevalence of SSc observed in an area in north-eastern Italy were found to be higher than reported in the various geographical area (UK, US, Australia, etc.) but similar to another Italian study adopting, as here, the LeRoy-Medsger criteria. The different diagnostic criteria adopted may explain some of the differences found in comparison to the studies based only on the ACR criteria, however, regional discrepancies in disease occurrence cannot easily be dismissed only on the basis of methodological approaches to case definition or ascertainment; genetic, ethnic and environmental factors should also be considered. Currently the main challenge remains to determine the scientific basis for the observed differences, distinguishing between changes deriving from geographic/ethnic features and from the analytic methods. PMID- 21586213 TI - Development and validation of French version of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument. AB - OBJECTIVES: The UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (UCLA-SCTCGIT) 2.0 was developed to assess systemic sclerosis (SSc) associated gastrointestinal tract (GIT) symptoms severity and its impact on patients' well-being. Our objective was to translate the UCLA-GIT 2.0 from English to French and to evaluate the reliability and validity of the French version. METHODS: UCLA-GIT 2.0 was adapted into French using a formal forward backward translation method and administered to 76 French speaking patients with SSc. The patients also completed the SF-36. We evaluated the internal consistency reliability and construct validity by exploring associations between the UCLA SCTC GIT 2.0 and SF-36 scales. Patients were also classified into two groups based on unintended weight loss within the past 6 months (>=5% vs. <5% of total body weight). RESULTS: Participants were mostly white (90%), female (81%) and had limited SSc (50%). Mean score of the UCLA-GIT 2.0 scales were: 0.35 for faecal soilage, 0.44 for diarrhoea, 0.45 for emotional well-being, 0.48 for both constipation and social functioning, 0.52 for reflux, and 0.95 for distension/bloating. The instrument had acceptable reliability (defined as Cronbach alpha>=0.69) except for the diarrhoea scale (alpha=0.56). The majority of hypothesized correlations were of moderate magnitude (coefficient>=0.30) and were in the appropriate direction. Patients with >=5% unintended weight loss had worse UCLA-GIT scores in all scales (p<0.05 for distention/bloating scale). CONCLUSIONS: The French version of the UCLA-GIT 2.0 has acceptable psychometric properties and can be used in French speaking SSc patients. PMID- 21586214 TI - Probiotics for the treatment of systemic sclerosis-associated gastrointestinal bloating/ distention. AB - OBJECTIVES: Treatment for gastrointestinal tract (GIT) disease in systemic sclerosis (SSc) is challenging as no immunosuppressive or anti-fibrotic therapy is available with clearly proven efficacy. Probiotics are viable, non-pathogenic microorganisms that are hypothesized to improve the composition of the intestinal microbiota from a potentially harmful composition to a composition that is beneficial to the host. Our hypothesis is that GIT symptoms in SSc patients with moderate bloating would improve with probiotic implementation. METHODS: Ten patients with a moderate-to-severe distention/bloating score (1.25-3.00) on the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0), but otherwise stable organ disease not requiring any medication adjustment were recruited from the University of Utah Scleroderma Center. We compared the GIT 2.0 scores at baseline and after 2 months of use of Align (bifidobacterium infantis; 109 CFU per capsule) or Culturelle (lactobacillus GG; 109 CFU per capsule) using paired t test and calculated effect size (ES). RESULTS: Significant improvement in total GIT 2.0 score (ES = 0.82), reflux (ES = 0.33), bloating/distention (ES = 1.76), and emotional scales (ES = 0.18) were reported after two months of daily probiotic use. CONCLUSIONS: This pilot study suggests probiotics significantly improve the reflux, distention/ bloating, and total GIT scales in SSc patients. As hypothesized, the largest effect was seen in distention/bloating scale. Probiotics may be useful for treatment of SSc-associated distention/ bloating. PMID- 21586215 TI - Effect of a multi-faceted intervention on gingival health among adults with systemic sclerosis. AB - OBJECTIVES: To evaluate the effect of adaptive oral hygiene devices and orofacial exercise to improve gingival health among adults with systemic sclerosis (SSc). METHODS: Forty-eight patients with SSc were assigned randomly to the multifaceted oral health intervention or usual dental care control group. Participants in the intervention group received a rechargeable, powered Oral-B(r) oscillating rotating-pulsating toothbrush and a Reach(r) AccessTM Flosser that has a toothbrush-like handle. For those with an oral aperture of less than 40 mm, orofacial exercises were taught. Participants in the control group were each given a manual toothbrush and dental floss. Participants in both groups received instructions and demonstration on the use of the devices, and were requested to perform the respective intervention twice a day for 6 months. Evaluations were at baseline, 3-, and 6-months. The main outcome was gingival index (GI), an indicator of gingival inflammation. RESULTS: Both groups showed significant reduction in GI scores at 6 months (ps<0.005). Reduction in GI scores of the intervention group at 6 months was 20.8% which is considered to be clinically significant. Compared to the control group, the intervention group showed a significant and larger reduction in GI score by 8% at 6 months (p=0.0007). CONCLUSIONS: Results support the use of adaptive devices and orofacial exercise to improve gingival health in adults with SSc when compared to use of manual toothbrushing and finger-held flossing. Recommending and educating patients with SSc to use adaptive devices to clean the tooth surfaces looks promising for long term oral health improvement. PMID- 21586216 TI - Quality indicator set for systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) is associated with a marked economic burden, high treatment costs and decreased productivity. Although treatment strategies for SSc can have a substantial effect on patients' outcomes, it is not known whether patients with SSc consistently receive such care. Evaluation of process of-care quality requires specification of quality indicators (QIs), clinically detailed statements of the eligible patients and the care they should receive to achieve a minimal level of quality of care. Our objective was to develop QIs for patients with SSc. METHODS: We performed a comprehensive literature review of diagnosis and treatment of SSc and proposed QIs that were evaluated by a national Expert Panel (n=9) who were asked to review the supporting literature and individually rank the validity of each QI. These rankings formed the basis of discussion at a face-to-face meeting following the RAND/UCLA method to integrate expert opinion with literature review to identify a set of final QIs. We then presented these QIs to members of the Scleroderma Clinical Trials Consortium (SCTC). RESULTS: Thirty-two QIs for SSc care were judged valid by the Expert Panel. The QI set includes 9 QIs for newly diagnosed with SSc, 12 follow-up QIs for management of SSc, and 11 treatment QIs. The SCTC experts agreed with the validity of each of the 32 QI and agreed that for all but one QI the specified tests, procedures and treatments recommended in the QI were generally available. CONCLUSIONS: We have developed 32 QIs for SSc using a rigorous methodology that can be employed to evaluate and improve care for patients with SSc, as well as inform policy decisions supporting appropriate care for SSc patients. PMID- 21586217 TI - Is there a role for TNFalpha antagonists in the treatment of SSc? EUSTAR expert consensus development using the Delphi technique. AB - OBJECTIVES: To obtain experiences and expert opinion on treatment of SSc patients with TNF-alpha antagonists. METHODS: An investigation was carried out among the EUSTAR centres into their expertise on use of TNF-alpha antagonists. Assessment forms on the frequency of TNF-alpha inhibitor use were distributed to EULAR Scleroderma Trials and Research Group (EUSTAR) centres. Afterwards, a three round Delphi exercise was performed to obtain expert consensus on the use of TNF-alpha inhibitors in SSc. RESULTS: Seventy-nine centres returned information on use of TNF-alpha antagonists in SSc patients. A total of 65 patients were treated with TNF-alpha inhibitors in 14 different centres. Forty-eight of the 65 patients treated with TNF-alpha inhibitors improved. Improvement was mainly seen in patients with arthritis, whereas the effects on fibrosis varied. In the first round of the subsequent Delphi approach, 71 out of 79 experts stated that they would use TNF-alpha antagonists in SSc. Arthritis was suggested as an indication for TNF-alpha antagonists by 75% of the experts. However, after the third stage of the Delphi exercise, the acceptance for the off-label use of TNF-alpha antagonists decreased and 59% recommended that TNF-alpha antagonists should not be used or only used in clinical trials in SSc patients, while 38% of the experts suggested the use of TNF-alpha antagonists for arthritis associated with SSc. CONCLUSIONS: Most of the experts do not recommend the routine use of TNF-alpha antagonists in systemic sclerosis. Arthritis might be a potential indication in SSc, although controlled clinical trials with TNF-alpha antagonists are needed before general recommendations can be given. PMID- 21586218 TI - Abnormal plasma levels of different angiogenic molecules are associated with different clinical manifestations in patients with systemic sclerosis. AB - OBJECTIVES: Systemic Sclerosis (SSc) is characterized by a microvascular damage due to an impairment of different angiogenic and angiostatic factors. Aim of this study was to measure plasma levels of nine molecules involved in these vascular processes in a group of SSc patients, respect to healthy controls (NC). METHODS: Sixty-five patients (M/F = 2/63; mean age = 57.29 yrs; mean disease duration = 9,63 yrs) with established SSc according to ARA criteria, and sixteen age- and sex-matched NC were enrolled. Plasma levels of vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), platelet derived growth factor- bb (PDGF-BB), platelet endothelial cellular adhesion molecule-1 (PECAM-1), leptin, hepathocyte growth factor (HGF), follistatin, granulocyte-colony stimulating factor (G-CSF) and interleukin 8 (IL-8) were measured using commercially available immunoassay kits (Human Angiogenesis 9-Plex Panel, Bio-Rad Laboratories). RESULTS: We detected a significant increase of Ang-2 (median value 1315.4 pg/ml vs 538.73 pg/ml; p=0.0292), HGF (median value 2886.16 pg/ml vs 1296.16 pg/ml; p=0.0001), IL 8 (median value 32.22 pg/ml vs 16.86 pg/ml; p=0.02), leptin (median value 32589,1 pg/mg vs 10679.61 pg/ml; p=0.0065), PDGF-BB (median value 7258.6 pg/ml vs 2913.44 pg/ml; p=0.0005), PECAM-1(median value 21681.81 pg/ml vs 10354.53 pg/ml; p=0.0003) and VEGF (median value 236.72 pg/ml vs 122.905 pg/ml; p=0.0073) in patients with SSc respect to NC. Higher levels of PDGF-BB (p=0.03) and PECAM-1 (p=0.05) were found in patients with digital ulcers while lower levels of PECAM-1 were found in patients with pulmonary hypertension (PH). Besides levels of IL-8 were higher in patients with PH (p=0.04) and lower in those with pulmonary fibrosis (p=0.5), while levels of Ang-2 were higher in those with a 'late' nailfold video-capillaroscopy (NVC) pattern respect to those with an 'early/active' one (p=0.05). Moreover, plasma levels of VEGF (p=0.02) and PDGF-BB (p= 0.04) were significantly higher in those patients positive for anti topoisomerase 1 antibodies. CONCLUSIONS: Our findings show significantly higher circulating levels of seven angiogenic parameters in SSc patients, thus reflecting the disregulation of endothelium in this disease. Abnormal levels of these molecules may be considered an attempt for compensatory although ineffective mechanisms of vascular function, leading to the development of the main clinical manifestations of SSc. PMID- 21586219 TI - Six-minute walk distance as a marker for disability and complaints in patients with systemic sclerosis. AB - OBJECTIVES: The role of the six-minute walk distance (6MWD), measured by a six minute walk test (6MWT), in the assessment of systemic sclerosis (SSc) patients remains to be evaluated. Here, we have analysed whether 6MWD is associated with clinical parameters obtained by an extended standardised assessment of SSc patients. METHODS: In 101 consecutive SSc patients, 6MWD was correlated with disease activity, Scleroderma Health Assessment Questionnaire (SHAQ) score, nutrition status, age, ESR, haemoglobin values, and several lung function parameters. RESULTS: Of the 101 SSc patients, 6 patients were excluded because of diseases that could influence the result of the 6MWT, such as asthma, COPD or peripheral vascular disease. In the remaining 95 patients the median 6MWD was 491.0 m (range 86.0-664.5 m). 6MWD weakly-to-moderately correlated with predicted FVC, FEV1, TLC, DLCO and nutrition status. Moderate negative correlations were found for the SHAQ score and disease activity, weaker correlations for age and BMI. Exclusion of patients with musculoskeletal limitations revealed similar results. Training status of the patients did not affect 6MWD. Multivariate analyses revealed SHAQ score and predicted DLCO values as the best parameters predicting 6MWD. Optimal 6MWD cut-off values for the presence of PAH, predicted FVC values <80%, and dyspnea NYHA III/IV were between 465 m and 480 m. CONCLUSIONS: 6MWD is a surrogate marker for disability and complaints in SSc patients. Therefore, 6MWT could provide a valuable outcome parameter although it lacks organ specificity. PMID- 21586220 TI - Addressing patient health care demands in systemic sclerosis: pre-post assessment of a psycho-educational group programme. AB - OBJECTIVES: Patients diagnosed with systemic sclerosis (SSc) report a high need for education and support. To address these needs, a short, group-based psycho educational programme for patients with SSc was developed and evaluated. METHODS: A pre-post test design was utilised. Participants completed questionnaires on physical and psychological functioning. Furthermore, patients were asked to evaluate the content of the programme by questionnaire. RESULTS: Data from 41 patients were available for analysis. Patients reported less helplessness after the intervention, and higher acceptance of their limitations. However, no difference in depressed mood and physical functioning was observed. Patients reported high satisfaction with the content of the programme. CONCLUSIONS: Despite the limited changes in psychological and physical functioning, this psycho-educational programme addresses patients' needs reported in previous study and therefore contributes to the improvement of care for patients with SSc. PMID- 21586221 TI - Recent advances in the diagnosis and treatment of interstitial lung disease in systemic sclerosis (scleroderma): a review. AB - Interstitial lung disease (ILD) in systemic sclerosis (scleroderma) is a rare and potentially lethal and devastating autoimmune disease, and yet the cause of it remains poorly understood. It is associated with tissue fibrosis not only in the lungs, but also other organs like the heart and kidneys. Although ILD can manifest itself in various disease presentations, ILD in systemic sclerosis is particularly and especially worrying because it has the highest case-specific mortality among all autoimmune rheumatic conditions. The unsatisfactory clinical outcome and prognosis for ILD in systemic sclerosis has, unsurprisingly, fuelled an intense search for early and accurate diagnosis, as well as new therapeutic strategies. Recent advances in diagnostic techniques and treatment interventions represent a significant step forward in our understanding and management of ILD in systemic sclerosis. Here, we review the current knowledge pertaining to the treatment of ILD in systemic sclerosis, and also address the various challenges involved as well as implications for the future. PMID- 21586222 TI - The genetics of systemic sclerosis: an update. AB - Systemic sclerosis (SSc) is a complex systemic disease characterised by fibrosis of the skin and internal organs, vasculopathy, and activation of the immune system. The complex pathophysiology of SSc implies the potential involvement of 'culprit' genes, either individually or, more likely, together, in driving the disease process. Most of the studies that have provided evidence for the contribution of various genes/loci in SSc pathogenesis are based on a candidate gene approach, on the basis of a shared autoimmune genetic background with other autoimmune diseases, such as systemic lupus erythematosus. In fact, autoimmune genes seem to play a pivotal role in SSc pathogenesis, while less is known about the genetic involvement in vasculopathy and fibrosis. Recently, the availability of genome-wide association studies, which make it possible to screen single nucleotide polymorphisms across the entire genome without previous knowledge of candidate regions or genes, has yielded a wealth of new genetic susceptibility loci leading to the identification of new pathogenetic mechanisms of complex genetic disorders. In this article, we aim to provide a comprehensive review of recent studies on the genetics of SSc, including genes associated with autoimmunity, fibrosis, and vascular disease. We also discuss the most relevant data obtained in genetic association studies of large populations that included a replication strategy, or studies for which independent replication was available. PMID- 21586223 TI - [Expression features of glypican-3 and its diagnostic and differential values in hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the expression features of glypican-3 (GPC-3) and its diagnostic and differential values in hepatocellular carcinoma (HCC). METHODS: Rat hepatoma models were made and the dynamic expression features of GPC-3 protein and its gene were investigated by Western blotting and RT-PCR respectively. Liver specimens from 36 HCC patients were collected by self-control method and the expression and clinicopathological features of GPC-3 were analyzed by immunohistochemistry. Serum GPC-3 levels were quantitatively detected by ELISA and its efficiency for HCC diagnosis was evaluated in patients with liver diseases. RESULTS: The incidence of GPC-3 was 0% in control, 83.3% in degeneration, 100% in precancerosis and 100% in canceration during dynamic formation of rat hepatoma, respectively. The positive GPC-3 was brown granule- like staining localized in membrane and cytoplasm in human HCC. CONCLUSIONS: The GPC-3 positive rates were 80.6% in HCC, 41.7% in surrounding tissues and none in distal tissues (P < 0.01), respectively. No positive relationship presented between GPC-3 and differentiation grade or the number of tumor except of tumor size (Z = 2.941, P < 0.01). The incidence of serum GPC-3 was 52.8% in HCC patients except of one patient with cirrhosis. No significant differences were found between GPC-3 and sex, age, AFP, tumor number, Child classification or extrahepatic metastasis except of tumor size (chi2 = 6.318, P < 0.05) and HBV infection (chi2 = 23.362, P < 0.01). Combined detection of GPC-3 and AFP could rise up diagnosis of HCC. GPC-3 expression closely associated with HCC and might be useful for early diagnosis of HCC. PMID- 21586224 TI - [High expression of thrombin receptor PAR1 in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma in early stage]. AB - OBJECTIVE: To evaluate the relationship between PAR1 (Protease-Activated Receptor 1) expression and the clinicopathologic features and to investigate the prognostic value of PAR1 expression in hepatocellular carcinoma (HCC) in early stage after curative resection. METHODS: Real-time PCR was used to detect PAR1 expression in 41 pairs of tumors and matched peritumoral samples of HCC in early stage. Prognostic value of PAR1 mRNA expression was evaluated. Meanwhile, another 49 tissue paraffin slices of HCC were tested using immunohistochemistry (Envision) and the prognostic value of PAR1 expression and other clinicopathologic factors were evaluated. RESULTS: Peritumoral PAR1 mRNA expression was significantly increased in HCCs from the patients with tumor recurrence as compared with those without recurrence (P < 0.05). Peritumoral PAR1 protein expression was related to tumor differentiation (P < 0.05). Kaplan-Meier analysis showed that Peritumoral PAR1 protein expression was associated with the overall survival (OS) (P < 0.05) of HCC patients and the time to recurrence (TTR) (P < 0.05). The 1, 3 and 5 -year overall survival time and the cumulative recurrence time in the high PAR1 protein expression group were significantly lower as compared to the low PAR1 expression group in the peritumoral liver tissue. CONCLUSIONS: Peritumoral PAR1 expression is closely associated with the prognosis of early stage HCC patients after curable surgery. PAR1 may be involved in thrombin-mediated invasion process and may be used as a prognostic marker for HCC. PMID- 21586225 TI - [The relationship between hepatocellular carcinoma recurrence and hepatitis B virus recurrence after liver transplantation]. AB - OBJECTIVE: To investigate the relationship between hepatocellular carcinoma (HCC) recurrence and hepatitis B virus (HBV) recurrence. METHODS: The clinical data of 340 patients underwent liver transplantation due to HBV related end-stage liver disease and received long-term follow up in our hospital from Jan 2004 to Dec 2008 were retrospectively analyzed. All patients received nucleoside analogues therapy formally before entering into the waiting list and nucleoside analogues combined low-dose HBIG therapy during and after transplantation. Patients were regularly followed up at the outpatient, monitoring the HBV recurrence and survival. Multivariate Cox regression analysis was used to evaluate the risk factors for hepatitis recurrence. RESULTS: 33 patients suffered from HBV recurrence post transplantation. The 1-, 3- and 5- year recurrence rates were 7.0%, 10% and 13% respectively. The median HBV recurrence time was 5 months (1-21 months). COX regression analysis revealed that risk factors for HBV recurrence were HCC (HR = 2.98; 95% CI 1.08-8.25; P < 0.05) and pre-transplantation HBV-DNA load over 5 log10 copies/ml (HR = 3.99; 95% CI 1.85-8.62; P < 0.01). Further stratified analysis showed that patients who suffered from carcinoma recurrence had a higher incidence of HBV recurrence than those who did not, which were 27.9% and 8.7% (HR = 4.58;95% CI 1.88-11.12; P < 0.01) respectively. 12 patients suffered from both HCC and HBV recurrence. Spearman correlation analysis demonstrated a strong correlation between HBV and HCC recurrence times (r = 0.583, P < 0.05). CONCLUSIONS: Post transplantation HCC recurrence is a risk factor for HBV recurrence. PMID- 21586226 TI - [Inhibitory effect of pyrrolidine dithiocarbamate combined with matrine on the growth of human hepatocellular carcinoma xenografts]. AB - OBJECTIVE: To investigate the relationship between activation of nuclear factor-K gene binding (NF-kappaB) and apoptosis induced by matrine(MT) in transplanted tumor of human hepatocellular carcinoma in nude mouse. METHODS: Tumors were established by injection of hepatocellular carcinoma cell line HepG2 into the back of nude mice. The mice were divided randomly into four groups: Control group, MT group (35 mg/kg), PDTC group (120 mg/kg) and Combination group: PDTC + MT group (120 mg/kg + 35 mg/kg), the reagents were injected peritoneally. The tumor growth curve of nude mice bearing transplanted tumor were observed and the inhibition ratios were evaluated. Apoptosis of carcinoma cells was analyzed by TUNEL. The DNA-binding activity of NF-kappaB was determined by electrophoretic mobility shift assay (EMSA). Expression of bcl-2 and bax in carcinoma tissue were detected by immunohistochemical method. NF-kappaB mRNA, bcl-2 mRNA and bax mRNA in carcinoma tissue were detected by RT-PCR. RESULTS: Pyrrolidine dithiocarbamate (PDTC) could enhance the inhibition of matrine on carcinoma proliferation (P < 0.05). The apoptosis and activation of NF-kappaB in carcinoma cells could be induced by matrine. PDTC significantly suppressed NF-kappaB activation induced by matrine in carcinoma cells from 93.64 +/- 2.95 to 65.78 +/- 5.65 (F = 124.754, P < 0.01). Meanwhile, PDTC increased the apoptosis induced by matrine from 55.9% +/ 2.8% to 74.3% +/- 4.8% (P < 0.05).A positive correlation observed between the expressions of NF-kappaB and of bcl-2 (Pearson correlation coefficient = 0.983, P < 0.01). CONCLUSIONS: Matrine could induce apoptosis and activation of NF-kappaB in transplanted tumor. PDTC could increase apoptosis in hepatocellular carcinoma cells might be due to the suppression of NF-kappaB activation and the enhancement of bcl-2 expression. PMID- 21586227 TI - [Inhibitory effect of miRNA silencing hypoxia-inducible factor alpha subunit gene on the proliferation of HepG2 cells]. AB - OBJECTIVE: To investigate the effect of miRNA silencing HIF-1alpha gene on the proliferation of HepG2 cells. METHODS: The eukaryotic expression plasmids of HIF 1alpha miRNA and report gene containing hypoxia-reponse element were constructed and transfected into HepG2 cells. The expressions of HIF-1alpha gene and protein were determined by real time-PCR and Western blotting. The expressions of HIF 1alpha, vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) were quantitatively detected by ELISA. The alterations of cell cycles and apoptosis rate were quantitatively measured by flow cytometry and Annexin V-FITC/PI double dyeing assay. RESULTS: 72 h after transfection the down regulations of HIF-1alpha mRNA and protein were 87% and 56% respectively, and the decrease of target gene was 46% in the report gene, 54% in VEGF and 36% in Ang-2, respectively. The apoptotic ratio of HepG2 cells was 22.46+/-0.61% (P < 0.01). The cell cycle changed greatly at the ratio of G1 (61.49+/-1.12%) and S (22.40+/-0.58%, P < 0.01). After being combined with doxorubicin, the apoptotic ratio increased to 36.99+/-0.88% and the ratios of G1 and S phases were upregulated to 65.68+/-0.91% and 19.47+/-1.34% respectively. CONCLUSIONS: HIF-1alpha miRNA or / and doxorubicin can regulate the growth cycles of HepG2 cells, promote the cell apoptosis and inhibit the cell proliferation. PMID- 21586228 TI - [Accuracy of FibroScan for the diagnosis of liver fibrosis influenced by serum alanine aminotransferase levels in patients with chronic hepatitis B]. AB - OBJECTIVE: To analyze whether or not the accuracy of liver stiffness measurement (LSM) with transient elastography (FibroScan) for the diagnosis of liver fibrosis influenced by serum alanine aminotransferase (ALT) levels in patients with chronic hepatitis B. METHODS: 213 consecutive CHB patients who underwent liver biopsy and LSM were enrolled and divided into three groups by the criteria of ALT < 1 x ULN, 1 x ULN <= ALT < 2 x ULN and ALT >= 2 x ULN. The areas under the receiver operating curve(AUC) were analyzed and the accuracy of FibroScan for the diagnosis of liver fibrosis were detected in the three groups. RESULTS: Significant correlation existed between the stages of liver fibrosis and LSM (rs = 0.773, 0.889 and 0.412, P < 0.05). AUCs of LSM in all patients for significant fibrosis (F >= 2, F0-1 vs F2-4) and cirrhosis (F = 4, F0-3 vs F4) were 0.916 and 0.971 respectively. The accuracy of diagnosis for significant fibrosis and cirrhosis were 84.0% and 93.4% respectively. AUCs of LSM in ALT < 1 x ULN, 1 x ULN <= ALT < 2 x ULN and ALT >= 2 x ULN groups for significant fibrosis were 0.939, 0.967 and 0.687 respectively. The sensitivity of the three groups was 90.0%, 89.7% and 47.8% respectively. The accuracies of the three groups was 90.5%, 93.9% and 68.4% respectively. The AUC, sensitivity and accuracy of ALT >= 2 x ULN group for significant fibrosis were significantly lower than the other two groups. AUCs of LSM in three groups for cirrhosis were 0.970, 0.985 and 0.952 respectively. The sensitivities of the three groups were 93.8%, 100% and 100% respectively. The accuracies of the three groups were 88.9%, 95.9% and 92.1% respectively. The AUCs, sensitivity and accuracy for cirrhosis of the three groups didn't change with elevated ALT. CONCLUSIONS: Transient elastography (FibroScan) is a reasonable noninvasive tool to diagnose significant fibrosis, especially liver cirrhosis in CHB patients. The accuracy of FibroScan for diagnosis of liver cirrhosis may not be influenced by elevated ALT. While in ALT >= 2 x ULN group, the accuracy of FibroScan for diagnosis of significant fibrosis was significantly lower as compared to the ALT <= 2 x ULN groups. PMID- 21586229 TI - [Construction and identification of siRNA eukaryotic expression vectors targeting on TGFbeta1, TIMP-1 and TIMP-2 genes in vitro]. AB - OBJECTIVE: To construct the siRNA eukaryotic expression vectors targeting on TGFbeta1, TIMP-1 and TIMP-2 and to investigate the inhibitory efficiency of target genes expression on rat hepatic stellate cell in vitro. METHODS: The siRNA cDNA sequences of TGFbeta1, TIMP-1 and TIMP-2 were designed, synthesized and inserted into plasmid pGenesil-1 respectively to generate eukaryotic expression plasmids. The plasmids were transfected into HSC T6 cells in vitro and the inhibitory efficiency of target genes expression was observed with real-time PCR and Western blot. RESULTS: The eukaryotic expression vectors were constructed successfully. The expressions of TGFbeta1 mRNA, TIMP-1 mRNA and TIMP-2mRNA in siRNA-transfected groups were decreased by 63.4% +/- 8.0%, 64.5% +/- 9.0% and 55.0% +/- 17.0% respectively and the expressions of TGFbeta1 protein, TIMP-1 protein and TIMP-2 protein were decreased by 57.8% +/- 3.0%, 55.1% +/- 5.0%, 49.3% +/- 1.0% respectively as compared to the control groups. CONCLUSIONS: The siRNA eukaryotic expression vectors constructed targeting on TGFbeta1, TIMP-1 and TIMP-2 could reduce the expressions of target genes and they might be able to used for the exploration of new anti-fibrosis drugs genetically. PMID- 21586230 TI - [Determination of ascitic bacterial 16S rRNA by quantitative PCR-microarray in the diagnosis of spontaneous bacterial peritonitis]. AB - OBJECTIVE: To evaluate the significance of determining ascitic bacterial 16S rRNA by quantitative PCR combined with microarray (PCR-microarray) in the diagnosis of spontaneous bacterial peritonitis (SBP). METHODS: Ascitic bacterial 16SrRNA was determined by real time fluorescent quantitative PCR-microarray in 76 cases of suspected SBP and 6 cases of non-infectious ascites with chronic liver diseases. The results were compared with ascitic bacterial culture simultaneously. RESULTS: Of 76 ascitic samples, 17 were detected bacteria positive by PCR-microarray, including 8 Grams positive(G+) and 9 Grams negative(G-), which was higher than that by bacterial culture which had only 6 ascitic samples detected positive (all G-); the positive rates were 22.4% vs 7.9%, respectively (P < 0.01). The bacterial strains detected by both methods in 6 cases had a consistency with each other. No bacteria were detected in another 6 cases of non-infectious ascites with chronic liver diseases. CONCLUSIONS: Determination of ascitic bacteria 16S rRNA by PCR-microarray has a higher specificity and sensitivity in the diagnosis of SBP as compared with the bacteria culture. Application of this novel method can not only accelerate SBP diagnosis but also stratify the different pathogens. PMID- 21586231 TI - [Protective effect and mechanism of hepcidin in rats with alcoholic liver damage]. AB - OBJECTIVE: To study the mechanism of how iron-regulatory protein (hepcidin) affect iron overload in alcoholic liver disease (ALD). METHODS: Thirty male wistar rats were randomly divided into 3 groups: Lieber-Decarli liquid without alcohol group (control group), Lieber-Decarli liquid with alcohol (alcohol group) and hepcidin intraperitoneally injected group (hepcidin group), each rat was fed for 6 weeks. The Serum concentration of Alanine Aminotransferase (ALT), Aspartate Amino Transferase (AST), Iron, Total Iron Binding capacity (TIBC), Ferritin, Malonyl Dialdehyde (MDA) and Hepcidin were determined. Hepatic tissue was examined by hematoxylin and eosin staining, prussian blue iron staining and immunohistochemistry staining. RESULTS: (1) Serum concentration of ALT in control group, alcohol group and hepcidin group were (25.2 +/- 4.6) U/L, (37.9 +/- 14.3) U/L and (40.9 +/- 14.1) U/L (F = 4.907, P < 0.05), respectively. Serum AST among three groups were (32.3 +/- 13.4) U/L, (55.0 +/- 18.6) U/L and (48.3 +/- 26.0) U/L (F = 3.742, P < 0.05), respectively. The secretions of ferritin were (224.72 +/- 85.49) ng/ml, (345.59 +/- 124.75) ng/ml and (339.47 +/- 138.47) ng/ml (F = 3.539, P < 0.05). The serum concentrations of TIBC were (147.30 +/- 31.98) MUmol/L, (148.04 +/- 58.74) MUmol/L and (143.28 +/- 37.38) MUmol/L (F = 1.209, P > 0.05), respectively. The serum concentrations of iron were (55.64 +/- 13.32) MUmol/L, (60.37 +/- 25.89) MUmol/L and (49.77 +/- 17.64) MUmol/L (F = 0.651, P > 0.05), respectively. The serum concentration of MDA were (5.84 +/- 2.17) nmol/ml, (6.51 +/- 2.23) nmol/ml and (4.27 +/- 2.68) nmol/ml (F = 2.782, P > 0.05), respectively. The serum concentration of Hepcidin were (155.96 +/- 44.91)ng/ml, (124.11 +/- 31.98) ng/ml and (114.96 +/- 25.81) ng/ml (F = 3.839, P < 0.05), respectively. (2) Significant fat change observed in the liver of alcohol group. The positive granulations of iron staining were (0.8 +/- 1.0), (1.2 +/- 1.6) and (1.1 +/- 1.1) (F = 0.254, P > 0.05), respectively. No differences found of liver iron express among the three groups. Intraperitoneal injection of hepcidin increased hepcidin expression in liver which was inhibited by alcohol (F = 4.139, P < 0.05). CONCLUSIONS: ALD rats with lower hepcidin expression in liver can result in iron metabolism disorder. Ectogenic hepcidin can protect liver against alcohol damage by inhibiting lipid peroxidation. PMID- 21586232 TI - [Polymorphism of ornithine decarboxylase antizyme inhibitor 1 gene is associated with liver cirrhosis in Chinese hepatitis B patients]. AB - A cirrhosis risk score (CRS) comprised of single nucleotide polymorphisms (SNPs) in seven genes that predicts the risk of cirrhosis in Caucasian hepatitis C has been reported. The present study was to evaluate the association of 11 separate but related SNPs and the CRS with cirrhosis risk in Chinese hepatitis B patients. A total of 563 Chinese subjects with persistent HBV infection (349 with evident liver cirrhosis and 214 without cirrhosis clinically or pathologically) were studied. The candidate SNPs were detected with a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) method. The allele frequency and genotype distribution of each polymorphism as well as the CRS value within the cirrhosis and non-cirrhosis subjects were compared. The rs2679757 polymorphism of the antizyme inhibitor 1 (AZIN1) gene was associated with the risk of cirrhosis (x2 = 6.79, P = 0.03, odds ratio for GG+AG versus AA = 1.63, 95% confidence interval = 1.13-2.35). A gene variant (rs886277) in the transient receptor potential cation channel subfamily M, member 5 gene (TRPM5) was associated with liver cirrhosis, but did not reach statistical significance (x2 = 5.77, P = 0.06). Two SNPs (rs4986791, rs62522600) are not polymorphic in Chinese. Genotype frequencies of other SNPs were not different between the cirrhosis and non-cirrhosis groups. The overall CRS values were not different between the cirrhotic and non-cirrhotic groups (median value 0.57 versus 0.62, Z = -1.05, P = 0.29). SNP rs2679757 in the AZIN1 gene is associated with the risk of HBV-related liver cirrhosis in Chinese. The CRS for Caucasian population has limited applicability for predicting liver cirrhosis in Chinese hepatitis B patients. SNPs associated with cirrhosis prognosis in hepatitis B patients and liver diseases with other etiologies warrant further clinical validation. PMID- 21586233 TI - [The role of HO-CO system in the hemodynamic disturbance of cirrhotic rats]. AB - To investigate the role of heme oxygenase(HO), a catalyzing enzyme of heme to produce CO, in modulation of systemic circulation in CCl4-induced cirrhotic rats. Saline(vehicle) and ZnPP were s.c. injected into the posterior necks of rats respectively and the rats were then anesthetized by pentobarbital sodium in four hours. Mean arterial pressure (MAP, kPa), heart rate (HR, b/min) and portal pressure (PP, cm/H2O) were measured by indwelling catheter. Plasma CO was determined by Chalmers method. Heme oxygenase acivity was determined by the rate of bilirubin formation. The cirrhotic rats showed significant hyperdynamic circulation indicated by decreased mean arterial pressure [MAP, (15.6+/-1.7) vs (18.9+/-0.9) kPa, t = 4.52, P less than 0.01] and increased portal pressure [PP, (16.7+/-0.8) vs (8.8+/-0.3) cm H2O, t = 23.10, P less than 0.01] as compared to normal control rats(NS). ZnPP could cause a significant increase in MAP [(17.3+/ 1.5) vs (15.6+/-1.7) kPa, t = 2.18, P less than 0.05] and significant decrease in PP [(13.2+/-0.7) vs (16.7+/-0.8) cm H2O, t = 8.53, P less than 0.01] in cirrhotic rats. The cirrhotic group presented a significant increase in plasma CO [(18.0+/ 1.9) vs (10.4+/-1.3)mumol/L, t = 8.42, P less than 0.01] and HO activity in the spleens [(11.1+/-0.9) vs (6.5+/-0.9) nmol bilirubin/mg protein/h, t = 9.28, P less than 0.01] and intestines [(2.5+/-0.1) vs. (1.3+/-0.2) nmol bilirubin/mg protein/h, t = 15.1, P less than 0.01]. ZnPP could cause significant decreases in plasma CO and HO activity in liver, spleen and intestine of both control and cirrhotic rats. HO-CO system activation may be an important reason for the hemodynamic disturbance of liver cirrhosis. PMID- 21586234 TI - [Study on the efficacy and HBeAg seroconversion related factors of telbivudine and entecavir therapy in HBeAg positive chronic hepatitis B patients]. AB - OBJECTIVE: To investigate the efficacy of Telbivudine and Entecavir for therapy of HBeAg positive chronic hepatitis B for 52 weeks. METHODS: In this random and control study, the efficacy of Telbivudine and Entecavir treatments were compared in 180 patients with HBeAg positive chronic hepatitis B.The patients were randomly assigned to a daily 600 mg Telbivudine treatment group or daily 0.5 mg Entecavir group for 52 weeks. RESULTS: At week 52, HBV DNA undetectable rate was better in the Entecavir-treated group than in the Telbivudine-treated group, but didn't reach statistical significance. The viral breakthrough rates were significantly lower in the Entecavir-treated group than in the Telbivudine treated group (x2 = 4.09, P <0.05). The clearance and seroconversion of HBeAg and the mean reductions of HBeAg from baseline at week 52 were significantly greater in the telbivudine-treated group than in the entecavir-treated group (x(2) clearance = 4.63, x(2) seroconversion = 4.80, (t-mean) reductions = 2.02; P < 0.05). The HBeAg seroconversion rates were not associated with both baseline ALT and baseline HBV DNA in both groups (P more than 0.05). In Telbivudine-treated group, the HBeAg decline is more than 2 log at week 24, HBeAg decline is more than 1 log at week 12 and the HBeAg baseline were independent factors correlated to HBeAg seroconversion rates at week 52 by Binary Logistic analysis, and also in entecavir-treated group the HBeAg decline is more than 2 log at week 24, HBeAg decline is more than 2 log at week 36 and the HBeAg decline is more than 2 log at week 12 were independent factors correlated to HBeAg seroconversion rates at week 52. CONCLUSION: Significant difference of HBeAg seroconversion rates at week 52 existed between Telbivudine-treated group and Entecavir-treated group. Entecavir is significantly superior to Telbivudine with less resistance to nucleosides. HBeAg decline is more than 2 log at week 24 is the best predicting factor for HBeAg seroconversion at week 52. PMID- 21586235 TI - [High rates of HBsAg loss and seroconversion result from prolonged course of pegasys treatment]. AB - OBJECTIVE: HBsAg loss and seroconversion in patients with chronic hepatitis B leads to long-lasting good clinical outcomes. The aim of this paper was to investigate to improve the rate of HBsAg loss and seroconversion in chronic hepatitis B patients by prolonged treatment of PEG-IFNa-2a. 217 cases of HBeAg positive or negative patients were collected from inpatient and outpatient in Beijing Ditan Hospital from May 2005 to October 2009 and subcutaneous injection of 135 ug or 180 ug PEGASYS were given once a week according to body weights. The drug doses were adjusted according to the neutrophilic granulocyte and platelet counts during treatment course. Quantitative HBV DNA test was conducted using a commercially available real-time fluorescence quantitative PCR kit. The serum HBsAg/anti-HBs and HBeAg/anti-HBe were quantitatively detected by Abbott i 2000 chemiluminescent kit before and during treatment every three months. Patients with HBsAg steadily decreased and reached serum HBsAg level below 200 IU/ml after 48 weeks of treatment would receive prolonged treatment. Patients with more than 12 weeks of treatment entered into analysis. Main efficacy of prolonged treatment was evaluated by the incidences of HBsAg loss and seroconversion. RESULTS: The treatment courses of the 217 patients ranged from 12.0 to 197.6 weeks with an average of 53.1+/-33.4 weeks, 118 cases took more than 48 weeks and another 89 cases less than 48 weeks. 13.4% (29/217) of patients achieved HBsAg loss or HBsAg seroconversion with treatment courses from 17.6 to 197.6 weeks (average 75.4+/ 42.8 weeks). Among these 29 patients 24 (82.8%) received more than 48 weeks of treatment, but the treatment courses of HBV DNA reached undetectable level were 20.8+/-8.9 weeks. In this study, 9.5% (14/148) of HBeAg-positive patients achieved HBsAg loss or seroconversion, all of them treated more than 48 weeks, from 48 to 194 weeks, average 81.32+/-39.36 weeks. 21.7% (15/69) of HBeAg negative patients achieved HBsAg loss or seroconversion, significantly higher than that of HBeAg-positive patients (9.5%) (x2 = 6.129, P = 0.013). The average treatment course for HBeAg-negative patients with HBsAg loss was 70.2+/-48.0 weeks, shorter than that of HBeAg-positive patients with HBsAg loss (81.3+/-39.4 weeks), but no significant difference (t = -0.522, P = 0.602) found between. CONCLUSION: Higher rate of HBsAg loss and seroconversion could be obtained by individual extended treatment courses in patients with rapid HBV DNA and HBsAg response to PEG-IFNa-2a treatment and the HBeAg-negative patients could got higher rate of HBsAg loss than HBeAg-positive patients. PMID- 21586236 TI - [Study on HBV antigens and IL-12 affecting T cell-mediated immunity in HBsAg carriers]. AB - OBJECTIVE: To investigate the effect of HBV antigens and pathological mechanism of chronic HBV infection by analyzing the cellular immune function of peripheral blood mononuclear cells (PBMCs) from HBsAg carriers. METHODS: PBMCs were prepared from individuals with chronic asymptomatic HBV infection and cultured in the presence of different antigens and/ or cytokines. The levels of cytokines in culture supernatants were detected by ELISA method. The phenotype of the cells was detected by FACS. RESULTS: The levels of IFN y secreted by PBMCs from HBsAg carriers were (48.3+/-19.8) pg/ml, significantly lower than that from healthy controls (t = 3.023, P less than 0.05); The IFN y produced by PBMCs from HBeAg positive patients due to HBsAg and HBcAg stimulation were (50.4+/-51.6) pg/ml and (63.2+/-36.9) pg/ml, significantly lower than that of HBeAg negative patients (t = 2.468 and 3.184, P less than 0.05, respectively). The IL-12p70 secreted by PBMCs from HBeAg positive patients was also significantly lower than that of HBeAg negative patients (P less than 0.05); Exogenous IL-12 promoted significantly PBMCs to secrete IFN y (P less than 0.01) and IL-12 combined with HBV antigens activated CD8+CD45RA+CCR7+ and CD8+CD45RA-CD62L+ cells. IL-12 secreted by PBMCs decreased in HBeAg positive patients, which may be the crucial reason of viral persistence in chronic HBV carriers. Exogenous IL-12 combined with specific HBV antigen could promote the central memory CD8+ T cells to produce IFN y. PMID- 21586237 TI - [The role of mir-221/222 in inhibiting endoplasmic reticulum stress-induced human hepatocarcinoma cell apoptosis]. AB - OBJECTIVE: To investigate the role of miR-221/222 in inhibiting endoplasmic reticulum stress-induced human hepatocarcinoma cells apoptosis. METHOD: miR 221/222 mimics and inhibitors were used to mimic or block the function of endogenous miR-221/222 respectively. Western blot and flow cytometry were used to test the effects of miR-221/222 on cell cycle and apoptosis under endoplasmic reticulum stress in human hepatocellular carcinoma cells. RESULTS: Endoplasmic reticulum stress resulted in miR-221/222 down-regulation in human hepatocellular carcinoma cells. miR-221/222 mimics and inhibitors inhibited and promoted respectively endoplasmic reticulum stress-mediated p27Kip1 induction. Moreover, p27Kip1 suppression not only resulted in reduction in the fraction of G1 phase cells, but also promoted the endoplasmic reticulum stress-mediated apoptosis in human hepatocellular carcinoma cells. CONCLUSION: miR-221/222 were downregulated by endoplasmic reticulum stress in human hepatocellular carcinoma cells, which subsequently protected human hepatocellular carcinoma cells against endoplasmic reticulum stress-induced apoptosis through p27Kip1 regulation. PMID- 21586238 TI - [Effects of non-bioartificial liver support system on Gc-globulin in patients with liver failure]. AB - OBJECTIVE: To investigate the effects of artificial liver support system(plasma exchange combined with continuous veno - venous hemodiafiltration, PE + CVVHDF) on Gc globulin in patients with liver failure. METHODS: 81 patients with liver failure were divided into 4 groups according to the treatment protocols and indicators such as liver function and clinical symptoms. Totally 29 effective cases and 14 ineffective cases in the ALSS group versus 15 effective cases and 23 ineffective cases in the medical group were included. Finally the changes of Gc globulin were observed in four subgroups before and after treatment. The correlation between Gc globulin and IL-10, IL-4, IL-18, TNFa, endotoxin, NO, sVCAM-1and sICAM-1were analyzed by Pearson correlation analysis. RESULTS: The effectiveness rate was 67.44% in ALSS group and 34.21% in the medical treatment (P less than 0.01). Gc globulin, one of liver cell protection proteins was notably increased following the artificial liver treatment as compared with the increase in the medical treatment (P less than 0.01). The time-response curve of Gc globulin level had a significant upward trend in the effective group as compared to no significant rise in the ineffective group. Moreover, the Gc globulin was negatively correlated with IL-4, IL-18, TNFa, SVCAM-1, SICAM-1 and NO. In contrast, no correlation existed between Gc globulin and IL-10. The treatment with artificial liver can improve the outcome of the patients with liver failure. The level of Gc globulin was correlated with the curative effect and thus may be used as a potential indicator for curative effect forcast in the patients with liver failure. PMID- 21586239 TI - [Relationship between the polymorphisms of UGT1A6 genes and anti-tuberculosis drug induced hepatic-injury]. AB - OBJECTIVE: To investigate the relationship between the polymorphisms of UGT1A6 genes and anti-tuberculosis drug induced hepatic-injury (ADIH). METHODS: 202 cases and 239 controls were collected and a case-control study was conducted. Information on related risk factors of tuberculosis was collected. The genotypes of UGT1A6-19T/G, UGT1A6-308C/A and UGT1A6-541A/G genetic polymorphisms were detected by polymerase chain reaction and restriction fragment length polymorphism technique (PCR-RFLP) in patients received anti-tuberculosis therapy. The Hha I, Dpn II and Nsi I enzyme were employed. Univariate and multivariate conditional logistic analyses were conducted using SPSS13.0 for windows software. RESULTS: RESULTS: The allele frequency of gene UGT1A6-19T/T, UGT1A6-19T/G, UGT1A6-19G/G, GT1A6-308C/C, UGT1A6-308C/A, UGT1A6-308A/A, UGT1A6-541AA, UGT1A6 541A/G and UGT1A6-541G/G in ADIH group were 51.5%, 39.6%, 8.9%, 52.0%, 40.6%, 7.4%, 57.9%, 33.7%, 8.4% and 71.1%, 25.5%, 3.3%, 79.1%, 19.2%, 1.7%, 79.5%, 19.2%, 1.3% in control group, respectively. Univariate analysis demonstrated that the frequency of UGT1A6-19T/G, UGT1A6-308C/A and UGT1A6-541A/G genotype in cases were significantly higher than that in controls (P less than 0.05). CONCLUSION: A positive association is found between UGT1A6 genotype and the occurrence of ADIH. The synergetic effect is proved on susceptibility to pulmonary tuberculosis between UGT1A6 mutant genotypes. PMID- 21586240 TI - [Randomized controlled trial of integrated traditional Chinese and western medicine treatment for posthepatitic cirrhotic ascites: a systematic review]. AB - OBJECTIVE: To research domestic general situation and quality of the clinical treatment of posthepatitic cirrhotic ascites in Integrated Traditional Chinese and Western Medicine. METHODS: Chose CNKI, VIP, Wang fang and CBM as data source and searched the literature of the clinical treatment of posthepatitic cirrhotic ascites in Integrated Traditional Chinese and Western Medicine which published officially from January 1980 to January 2010 and which received a Jaded score of 2 or greater to do a systematic evaluation, including the description of subjects, study design and methods, therapeutic efficacy and statistical methods. RESULTS: 136 articles in all met inclusion criteria and 58 articles which received a Jaded score of 2 or greater did this research. The main problems of domestic posthepatitic cirrhotic ascites in Integrated Traditional Chinese and Western Medicine in 30 years included: randomized controlled trial design was unreasonable, lack of blinding, lack of standardized criteria, the sample size was small and lack of specific estimation methods, lack of compliance, case off and withdraw, ignoring adverse reaction and the research of life quality. CONCLUSION: The clinical treatment of posthepatitic cirrhotic ascites in Integrated Traditional Chinese and Western Medicine have a "personalized" and "diversity" character and the methods and standards of clinical research need to be improved. PMID- 21586241 TI - [Pleomorphism of the myelin-like bodies in the hepatocytes of patients with Dubin Johnson syndrome complicated with chronic hepatitis B]. AB - OBJECTIVE: To explore characteristics of the myelin-like bodies in the hepatocytes of patients with Dubin-Johnson syndrome (DJS) complicated with chronic hepatitis B (CHB). METHODS: 11 cases of DJS complicated with CHB and 5 cases DJS without CHB were studied clinicopathologically. The hepatocyte ultrastructure was observed with transmission electron microscope and taken photos. The data were compared and analyzed using Fisher's Exact Test. RESULTS: Deposition of myelin-like bodies can be observed in the hepatocytes of DJS patients with CHB but can not in DJS patients without CHB. The morphology of pigment varys. The electron density and volume of pigment in DJS patients with CHB can be classified into five types: brights (2/11,18.2%), reticulation (1/11, 9.1%), punctiform (6/11, 54.5%), abnormity (1/11, 9.1%) and primary type (1/11, 9.1%). The myelin-like bodies in the hepatocytes of patients with DJS are high density and round with membrance (we named it as primary type) (5/5, 100%). CONCLUSIONS: The myelin-like bodies in the hepatocytes of DJS patients with CHB possess special pleomorphism and may have important diagnostic value. PMID- 21586242 TI - [The study on bacteria invading the intestinal mucosa barrier in mice with fulminant hepatic failure]. AB - OBJECTIVE: To explore the mechanism of fulminate hepatic failure (FHF) complicated with spontaneous peritonitis (SBP) through the research of bacteria invading the intestinal mucosa barrier. METHODS: 240 BalB/c male mice were divided into four groups as isotonic NS group (n = 40), lipopolysaccharide (LPS) group (n = 40), galactosamine (GalN) group (n = 40) and FHF model group (n = 120). Each mouse received same volume of NS, LPS (10 ug/kg), GalN (800 mg/kg) or LPS (10 ug/kg)/GalN (800 mg/kg) intraperitoneal injection according to its group. 8 mice were executed at 2, 6, 9, 12 and 24 hours after injection, respectively, and the liver and intestinal tissue samples were taken at the same time. ALT was measured by automatic biochemical analyzer and was compared between groups using Mann-Whitney U test. Liver and intestinal tissue received HE staining. The ultrastructure of intestinal mucosa and the method by which bacteria invaded the intestinal mucosa were observed by transmission electron microscopy. All data were analyzed by SPSS13.0 statistic software. RESULTS: ALT level, results of hepatic pathology, mortality and clinical manifestations of mice in the FHF model group met the diagnostic criteria of FHF. Intestinal tissue was found with slight edema and little inflammatory cells infiltration through HE staining in all the 4 groups of mice 9 hours after injection. Microvilli were found broken, shed and shorten in the intestinal epithelial cells with incomplete tight junction (TJs) and obviously changed organelles in the FHF model group of mice observed by transmission electron microscope. Mass hemorrhagic necrosis of liver cells with remnant liver cells swelling and many inflammatory cells infiltration by HE staining in the FHF model group. But the changes in hepatic pathology and intestinal mucosa ultrastructure were not so obvious in the mice of NS, LPS and GalN groups. Bacteria penetrated the intestinal wall by pinocytosis 6 to 9 hours after injection in the FHF model group, the microvilli were broken off and TJs turned rupture in the areas that the bacteria penetrated. The bacteria were found in the form of cyst 12 hours after injection. CONCLUSION: LPS (10 mg/kg)/GalN (800 mg/kg) combined injection was successful in establishing the FHF mice model. The rupture of TJs may provide conditions for intestinal bacteria to penetrate the intestinal mucosa in FHF. Rupture of TJs may be one of the reasons why FHF was complicated with SBP. PMID- 21586243 TI - [Improvement of patient handover]. PMID- 21586244 TI - [Patient handover involves numerous safety risks]. AB - Modern patient care requires collaboration among health-care workers belonging to various functional units, departments and hospitals. When the responsibility for patients is handed over, information is easily lost. This literature review identifies problems in patient handover situations and proposes solutions to these. We reviewed 417 papers and the analysis comprises 29 papers. The paper points out numerous problems in connection with the transfer of responsibility, showing the importance of focusing on patient handover as a vulnerable phase in patient care. PMID- 21586245 TI - [Indications for radioimmunotherapy for patients with non-Hodgkin's lymphoma]. AB - Radioimmunotherapy is a well-known treatment for non-Hodgkin's lymphoma. (90)yttrium (Y)-ibritumomab-tiuxetan consists of a radioisotope conjugated to a monoclonal anti-cluster of differentiation 20 antibody, which is targeted against B-lymphocytes. Initially the treatment indication was relapse of low-grade non Hodgkin's lymphoma. However, (90)Y-ibritumomab-tiuxetan has later been used in clinical trials in the treatment of other types of non-Hodgkin's lymphoma and prior to stem cell transplantation. Based on the literature this systematic review aims to throw light on the future possibilities of radioimmunotherapy. PMID- 21586246 TI - [Etomidate can not be recommended to patients with septic shock]. AB - Due to a low cardiovascular complication rate even in patients with shock, etomidate is often used for intubation. Etomidate inhibits the steroid synthesis. A single bolus injection of etomidate has so far been considered to be safe. However, new investigations have shown that even a single bolus dose of etomidate inhibits the steroid synthesis and is associated with increased mortality in patients with septic shock. PMID- 21586247 TI - [Anxiolytical, analgesic and sedative effects of melatonin in the perioperative phase]. AB - Melatonin is a hormone mainly produced in the pineal gland. The most well known effect is a modulation of the circadian rhythm. Patients undergoing surgery often get a disruption of this rhythm. Effects of melatonin have been examined in several randomised clinical studies. In this report we briefly review evidence regarding anxiolytical, analgesic and sedative effects of melatonin in relation to surgery. Studies show an effect in favour of medication with melatonin with regards to sedation and anxiety but the effect on analgesia has yet to be clarified with further clinical studies. PMID- 21586248 TI - [Successful training course in academic research in gynaecology and obstetrics]. AB - In 2003 The National Board of Health, Denmark, enforced a compulsory training course in academic research as part of the specialist training for doctors. The trainees must learn to search and evaluate relevant literature and be able to implement the results in clinical practice. The structure of the 20 days of academic training in gynaecology and obstetrics is described. In 2008, 17 doctors participated in these sessions. We performed a questionnaire survey to explore the implementation. The academic training was well rated by the participants with respect to content, form and outcome. PMID- 21586249 TI - [Glyceryl nitrates may cause hypertension]. AB - The patient was an 82-year-old woman with orthostatism, who was administrated one normal dose of glyceryl nitrate as a part of a tilt table test. The following ten minutes after administration, a paradoxical and significant blood pressure response was registered in the form of a rise to 205/111 mmHg. The conclusion was that her response was a paradoxical response to glyceryl nitrate, orthostatism and a pathological response to massage of the carotid artery. This is the third reported case on paradoxical hypertension induced by glyceryl nitrates. It is speculated that dysfunction of the cerebral bloodflow autoregulation may be one of the causes of this phenomenon. PMID- 21586250 TI - [Neonatal alloimmune neutropenia is a frequently overlooked diagnosis in neonates]. AB - Neonatal alloimmune neutropenia (NIN) results from the destruction of foetal neutrophils by maternal immunoglobulin G-class neutrophil-reactive antibodies crossing the foeto-placental barrier. We report two cases of neonatal patients presenting with unspecific symptoms and persisting neutropenia accompanied by thrombocytosis. Both were subsequently diagnosed with NIN. These two cases of persisting neutropenia highlight the diversity of symptoms and the diagnostic challenges remaining in NIN. Furthermore, the cases remind us that neutropenia in neonates may be rooted in several different pathophysiological mechanisms. PMID- 21586251 TI - [Precocious pseudopuberty in a seven year-old girl due to estrogen treatment of labial adhesion]. AB - Labial adhesions are well-known in prepubertal girls. We present a seven year-old girl treated with estrogen gel due to labial adhesion resulting in precocious pseudopuberty. Endocrine tests and bone age were normal. Symptoms regressed upon cessation of treatment. Labial adhesions often resolve spontaneously in early puberty. Precocious pseudopuberty is a well-known side effect to estrogen gel used in excess which should only be initiated in prepubertal girls with great caution and after careful consideration. PMID- 21586252 TI - [Mesenteric panniculitis is a rare inflammation of the mesenteric adipose tissue]. AB - Mesenteric panniculitis (MP) is a rare condition affecting the mesentery of the small bowel and/or colon. Obtaining a diagnosis is dependent on radiological and histological findings. With the increasing use of abdominal CT, more cases of MP will be discovered. We report a case of MP accidentally found at CT in a 64 year old woman who was evaluated for upper abdominal discomfort. Percutaneous ultrasonography guided biopsy secured the diagnosis. There is no consensus on the treatment and management of MP. An approach guided by the patient's symptoms seems suitable. PMID- 21586253 TI - An audiological communication disorder? PMID- 21586254 TI - Use of middle ear immittance testing in the evaluation of patulous eustachian tube. AB - BACKGROUND: Patulous Eustachian tube is the uncommon condition of a persistently open Eustachian tube, which causes the disturbing symptoms of autophony and respiratory-synchronous tinnitus. We review this condition and propose a specific evaluation protocol that can be performed quickly and easily using standard audiologic test equipment. We have used this protocol in the evaluation of a number of patients and will discuss our findings. PURPOSE: To establish a standardized protocol for the audiologic evaluation of patulous Eustachian tube using a standard clinical tympanometer and to establish norms with respect to tympanic membrane movement during breathing tasks. RESEARCH DESIGN: Quantitative analysis of test results obtained during clinical evaluation of patients referred for suspected patulous Eustachian tube during 2008 and 2009. STUDY SAMPLE: The cohort was 35 individuals including 25 patients referred for suspected patulous Eustachian tube and 10 control (normal) patients. Of the total group, 25 individuals were female, 10 were male, and the overall age range was 8 yr to 82 yr. DATA COLLECTION AND ANALYSIS: Patients underwent audiologic and otologic testing including quantitative measurement of middle ear compliance during breathing and nasal endoscopy. Two tympanometers were used to assess middle ear compliance: the Grason-Stadler Instruments Model 33 and Tympstar. Endoscopy was performed using either a Storz Endoskope Xenon Nova 175 or a Pentax EPM 1000. Results of middle ear immittance tests performed during breathing tasks were compared with results of endoscopy as well as the impressions of the examining physician. Magnitude of middle ear compliance was examined for mean and standard deviation, and the control/normal group results were compared with those of individuals complaining of symptoms suggestive of patulous Eustachian tube. RESULTS: We found that slightly greater than 75% of individual ears with patulous Eustachian tube exhibited middle ear compliance greater than 0.07 ml during breathing tasks. All ears with patulous Eustachian tube exhibited a respiratory synchronous compliance pattern during breathing tasks. Of individual ears without patulous Eustachian tube, 97% exhibited middle ear compliance during breathing of less than 0.07 ml with no respiratory-synchronous pattern. CONCLUSIONS: Measurement of middle ear compliance during breathing appears to be a sensitive and specific tool in the examination of patulous Eustachian tube, particularly when both the magnitude of compliance and the pattern of compliance are considered. PMID- 21586255 TI - Sudden bilateral sensorineural hearing loss following polysubstance narcotic overdose. AB - BACKGROUND: Auditory disorders associated with substance abuse are rare. Hearing loss secondary to heroin and hydrocodone abuse has been described variously as not always responsive to steroid management, as not always reversible, and in some cases, as nonresponsive profound sensorineural hearing loss requiring cochlear implantation. We present a case of a teenager with sudden-onset moderate to severe bilateral sensorineural hearing loss after documented polysubstance "binging." The hearing loss improved substantially after high-dose steroid and vasoactive therapy. PURPOSE: The purpose of this report is to describe the hearing disorder of a patient who had awakened with a bilateral severe hearing loss following a night of recreational drug abuse. RESEARCH DESIGN: Case report and review of the literature. DATA COLLECTION AND ANALYSIS: The subject of this report is an 18-yr-old patient with a history of substance abuse. Data collected were magnetic resonance /computed tomography brain imaging; metabolic, infectious disease, and autoimmune evaluation; and extensive audiologic evaluation, including pure-tone and speech audiometry, immittance measures, distortion product otoacoustic emissions, and auditory brainstem response testing. Serial audiograms were collected for 10 mo following the onset of symptoms. RESULTS: Two days of polysubstance abuse (heroin, benzodiazepine, alcohol, and crack [smoked cocaine]) resulted in moderately severe sensorineural hearing loss bilaterally. The loss responded to a 1 mo course of high-dose prednisone and a 10 mo course of pentoxifylline. Hearing sensitivity subsequently improved, leaving only residual high-frequency sensorineural hearing loss. CONCLUSIONS: This case report highlights the importance of "recreational" drug abuse in the evaluation of sudden hearing loss. Potential etiologies include altered pharmacokinetics, vascular spasm/ischemia, encephalopathy, acute intralabyrinthine hemorrhage, and genetic polymorphisms of drug-metabolizing enzymes. PMID- 21586256 TI - Effects of coarticulation, prosody, and noise freshness on the intelligibility of digit triplets in noise. AB - BACKGROUND: In a number of European countries, a functional self-test to screen for hearing impairment is available via telephone and the Internet. The tests estimate speech-reception thresholds using an adaptive procedure in which digit triplets are presented at varying signal-to-noise ratios. In different languages, the stimuli were created either with or without coarticulation; and some implementations use fresh noise samples, while others do not. PURPOSE: The present investigation concerns the influence of coarticulation, prosody, and noise freshness on measured thresholds. STUDY SAMPLE: We performed a laboratory study using 12 normal-hearing listeners. RESEARCH DESIGN: In a blocked design we compared speech-reception thresholds for conditions with and without fresh noise tokens. In each block we used three types of triplets: with coarticulation and prosody, with neither, and without coarticulation but with prosody. DATA COLLECTION AND ANALYSIS: Thirty-six thresholds were recorded per subject, and they were analyzed using analyses of variance. RESULTS: The results showed no significant differences among the three triplet conditions. The freshness of the noise did not affect thresholds when, at least, a fresh noise token was used per threshold estimate (23 presentations). Scores dropped significantly when a whole experimental block was performed with a single noise token. PMID- 21586257 TI - Normal characteristics of the ocular vestibular evoked myogenic potential. AB - BACKGROUND: Stimulus-evoked electromyographic changes can be recorded from the extraocular muscles. These short-latency negative-polarity evoked myogenic potentials are called ocular vestibular evoked myogenic potentials (oVEMPs). To date there has not yet been a large-scale study examining the effects of age on the amplitude, latency, threshold, and interaural differences of the oVEMP to air conducted stimuli. Further, before the oVEMP can become a useful clinical tool, the test-retest reliability of the response must be established. The oVEMP response, once more completely understood, may provide diagnostic information that is complementary to the cervical vestibular evoked myogenic potential (cVEMP; i.e., sternocleidomastoid muscle). PURPOSE: To describe the normal characteristics of oVEMP in a cohort of age-stratified subjects, to assess the test-retest reliability of the oVEMP, and to determine if reference contamination occurs using a common recommended infraorbital reference electrode derivation. RESEARCH DESIGN: A prospective, descriptive study design was used for an investigation with a threefold purpose in which oVEMP recordings were made from the extraocular muscles (e.g., inferior oblique muscle). STUDY SAMPLE: Fifty otologically and neurologically normal adults and children served as subjects. Subjects ranged in age from 8 to 88 yr. DATA COLLECTION AND ANALYSIS: In Investigation 1, oVEMPs were recorded from the ipsilateral and contralateral inferior oblique muscles for all subjects. The stimulus was a 95 dB nHL 500 Hz tone burst. Next, oVEMP thresholds were obtained. Amplitude, latency, and thresholds were tabulated, and descriptive statistics were used to calculate normative values. Age-related differences in oVEMP component latencies, amplitudes, interaural amplitude asymmetries (IAAs), and thresholds were determined using an analysis of variance. In Investigation 2, oVEMPs were recorded twice in 10 subjects, once (test) and once approximately 10 weeks later (retest). Test-retest reliability for the oVEMP peak-to-peak amplitude, n1 latency, p1 latency, n1 threshold, and IAA were assessed with intraclass correlation coefficients (ICCs) calculated using a two-way random-effects, absolute-agreement model. In Investigation 3, a four-channel oVEMP recording was conducted in 10 subjects. Both observational methods and paired-sample t-tests were used to evaluate the effect that reference electrode location had on the oVEMP. RESULTS: oVEMP responses were present bilaterally in 90% of our subjects. The upper limit of oVEMP amplitude asymmetry, defined as the mean plus two standard deviations, was 34% (mean = 14%, SD 10), and the mean n1 latency was 12.5 (SD 1.0) msec. The amplitude of the response significantly decreased and the threshold significantly increased with increasing age, with the greatest age effects occurring in subjects 50 yr and older. Test-retest reliability was acceptable (ICCs for the measurement variables ranged from .53 to .87). Using conventional recommended recording techniques, evidence of reference contamination occurred for all subjects, resulting in a mean amplitude reduction of 30% (range = 18%-43%). CONCLUSIONS: Age results in systematic changes in oVEMP measurement parameters. The test-retest reliability is acceptable, and reference contamination averaging 30% is guaranteed using a second infraorbital electrode as the inverting input (i.e., reference electrode) for bipolar recordings. The oVEMP can be used as a complementary diagnostic tool to the cVEMP in evaluating subjects with suspected peripheral vestibular disorders. PMID- 21586258 TI - Communication outcomes in audiologic reporting. AB - BACKGROUND: Audiologists often work collaboratively with other health professionals-particularly otolaryngology providers. Some form of written reporting of audiologic outcomes is typically the vehicle by which communication among providers occurs. Quality patient care is dependent on both accurate interpretation of outcomes and effectiveness of communication between providers. Audiologic reporting protocols tend to vary among clinics and providers, with most methods being based on preference rather than standardized definitions. PURPOSE: As part of an ongoing quality-improvement program, audiologic communication was reviewed by comparing written audiometric reports to descriptions of the audiometric results dictated by otolaryngology providers to evaluate the agreement of communication between provider groups. RESEARCH DESIGN: Retrospective chart review. STUDY SAMPLE: The study sample consisted of 6000 randomly selected charts from a total of 15,625 for the years 2004 and 2008 in the electronic medical record system of a large academic health-care system. DATA COLLECTION AND ANALYSIS: Audiogram reports and associated otolaryngology reports were reviewed by an audiologist and two audiology doctoral students. Communication occurred among 37 audiology providers and 39 otolaryngology providers. Data collected included rating of congruence or incongruence between reports, normal versus abnormal audiologic outcomes, and the nature of communication disparities. Data also included provider type (audiologist, audiology doctoral student, or trainee in clinical fellowship year [CFY]; otolaryngologist, otolaryngology resident, physician assistant, or nurse practitioner). RESULTS: Incongruent results were higher among the sample of audiologic evaluations with abnormal outcomes (29.2%) compared with normal outcomes (9.5%). Of those cases rated as incongruent, differences in reporting audiometric results stemmed largely from variance in reporting of numerical values from the audiogram (20%), apparent dictation errors (10.1%), and communication of the ear tested (8.6%). Of those cases in which the interpretations of audiology providers differed from those of otolaryngology providers, incongruent results occurred in the interpretation of degree (29.4%), tympanometric results (28.2%), type of hearing loss (12.8%), acoustic reflex results (4.0%), symmetry (3.3%), and other domains (4.2%). Rates of incongruent results were similar regardless of experience level of the audiology provider (audiologist or audiology doctoral student/CFY) but differed depending on the educational background and experience of the otolaryngology provider. The highest incongruent interpretations were found among residents (32.5%), followed by otolaryngologists (25.2%) and physician assistants and nurse practitioners (21%). CONCLUSIONS: This study highlights the need for audiologists to critically evaluate the effectiveness of their communication with other health-care providers and demonstrates the need for evidence-based approaches for interpreting audiologic information and reporting audiologic information to others. PMID- 21586259 TI - Regarding DiGiovanni and Pratt. PMID- 21586264 TI - Prioritisation of infectious diseases in public health: feedback on the prioritisation methodology, 15 July 2008 to 15 January 2009. AB - In 2004, the German public health institute, the Robert Koch Institute (RKI), prioritised pathogens by public health criteria and presented the methodology and findings. In order to further improve the methodology, the RKI invited experts to give feedback on this via a structured web-based questionnaire. The survey was completed by 72 participants during 15 July 2008 to 15 January 2009. Prioritisation of pathogens was considered as useful for public health purposes by 68 participants and for both surveillance and epidemiological research by 64 participants. Additional pathogens were suggested, including some that are resistant to antimicrobials. The criteria incidence, severity, outbreak potential, emerging potential and preventability were each considered as useful or very useful for the prioritisation (by more than 65 participants for each criterion). Weighting of the criteria was judged as relevant or very relevant by 67 of participants, but needs more explanation. It was also suggested that the group carrying out the prioritisation be composed of a median of 15 experts (range: 5-1,000). The feedback obtained in the survey has been taken into account in the modification of the methodology for the next round of prioritisation, which started in December 2010. PMID- 21586265 TI - Web query-based surveillance in Sweden during the influenza A(H1N1)2009 pandemic, April 2009 to February 2010. AB - At the Swedish Institute for Communicable Disease Control, statistical models based on queries submitted to a Swedish medical website are used as a complement to the regular influenza surveillance. The models have previously been shown to perform well for seasonal influenza. The purpose of the present study was to evaluate the performance of the statistical models in the context of the influenza A(H1N1)2009 pandemic, a period when many factors, for example the media, could have influenced people's search behaviour on the Internet and consequently the performance of the models. Our evaluation indicates consistent good reliability for the statistical models also during the pandemic. When compared to Google Flu Trends for Sweden, they were at least equivalent in terms of estimating the influenza activity, and even seemed to be more precise in estimating the peak incidence of the influenza pandemic. PMID- 21586266 TI - Molecular detection and phylogenetic analysis of West Nile virus lineage 2 in sedentary wild birds (Eurasian magpie), Greece, 2010. AB - A West Nile virus (WNV) lineage 2 strain was molecularly identified and characterised in a Eurasian magpie hunted in Greece in 2010, during a WNV outbreak in humans. Phylogenetic analysis revealed the highest sequence similarity (>99%) with other WNV lineage 2 strains derived from birds of prey in Austria and Hungary (2004-2009). This first molecular detection of WNV in sedentary wild birds in Greece, which are possible reservoirs of the virus, is a public health concern. PMID- 21586267 TI - Tularaemia in Berlin - two independent cases in travellers returning from central Anatolia, Turkey, February 2011. AB - Tularaemia, though rare, has recently been increasingly reported in Germany. Most cases are indigenous infections. This report describes two epidemiologically independent infections with Francisella tularensis subspecies holarctica detected in Berlin in February 2011 that were acquired in central Anatolia, Turkey. In Turkey, there have been repeated tularaemia outbreaks since 2000 and the disease should therefore be considered as a differential diagnosis in travellers returning from that country. PMID- 21586268 TI - From morbidity control to transmission control: time to change tactics against helminths on Unguja Island, Zanzibar. AB - In Zanzibar, the prevalence and intensity of helminth infections have markedly declined over the past 25 years, which is generally attributed to morbidity control programmes emphasising 'preventive chemotherapy'. Here we provide an update of the current situation of soil-transmitted helminthiasis and urinary schistosomiasis on Unguja Island, and highlight socioeconomic development, improvement in sanitation and health education as additional drivers against helminthiases. Our data were obtained from cross-sectional surveys carried out between 2006 and 2009 with stool and urine samples from 2858 and 879 individuals, respectively, examined for helminth eggs and larvae. Additionally, several hundred people were interviewed on sanitation and hygienic behaviour. Data on Unguja's economic growth and improvements in access to clean water and household latrines in the recent past were derived from the extant literature. Pooled prevalences of Trichuris trichiura, Schistosoma haematobium, Ascaris lumbricoides, hookworm and Strongyloides stercoralis were 35%, 29%, 12%, 10% and 6%, respectively. However, there were considerable differences in prevalences between different age-groups and at village and district level. Moreover, some hotspots for A. lumbricoides, T. trichiura and S. haematobium were identified with prevalences above 60% among school-aged children. Availability of a latrine and washing hands before eating did not significantly lower the risk of helminth infections in our study population. Nevertheless, a considerable increase in access to household latrines (from 49% to 72%) and piped water (from 45% to 71%) between 1991 and 2005 is likely to have contributed to reducing the force of transmission of helminthiases in Zanzibar. The next logical step in Unguja is to change the tactics from morbidity control to interruption of helminth transmission and ultimately local elimination. Hence, 'preventive chemotherapy' needs to be further consolidated, placing particular emphasis on health education and improved access to clean water and sanitation. PMID- 21586269 TI - Structural basis for the enhanced activity of cyclic antimicrobial peptides: the case of BPC194. AB - We report the molecular basis for the differences in activity of cyclic and linear antimicrobial peptides. We iteratively performed atomistic molecular dynamics simulations and biophysical measurements to probe the interaction of a cyclic antimicrobial peptide and its inactive linear analogue with model membranes. We establish that, relative to the linear peptide, the cyclic one binds stronger to negatively charged membranes. We show that only the cyclic peptide folds at the membrane interface and adopts a beta-sheet structure characterised by two turns. Subsequently, the cyclic peptide penetrates deeper into the bilayer while the linear peptide remains essentially at the surface. Finally, based on our comparative study, we propose a model characterising the mode of action of cyclic antimicrobial peptides. The results provide a chemical rationale for enhanced activity in certain cyclic antimicrobial peptides and can be used as a guideline for design of novel antimicrobial peptides. PMID- 21586270 TI - Characterization of the novel interaction between muskelin and TBX20, a critical cardiogenic transcription factor. AB - The genetic regulation necessary for the formation of a four-chambered heart is tightly regulated by transcription factors such as TBX20, a member of the T-box (TBX) transcription factor family. TBX20 is critical for proper cardiogenesis and is expressed in the heart throughout development. Missense mutations in TBX20 have been found in patients with congenital heart defects (CHD). Characterization of modifiers of TBX20 activity will help elucidate the genetic mechanisms of heart development and CHD. A yeast two-hybrid assay screening an embryonic mouse heart cDNA library with TBX20b as bait was used to identify potential modifiers of TBX20 activity and identified an interaction with muskelin (MKLN1), a primarily cytoplasmic protein with potential roles in signal transduction machinery scaffolding and nucleocytoplasmic protein shuttling. In cellular studies, MKLN1 directly binds to the T-box DNA-binding domain of only the TBX20b isoform by its kelch repeats domain. Immunostaining of mammalian cells transfected with tagged TBX20b and MKLN1 revealed colocalization primarily in the cytoplasm. Immunohistochemistry analysis of embryonic mouse hearts reveals coexpression in the developing endocardial valvular and myocardial interventricular cells. This novel interaction between TBX20b and MKLN1 may help elucidate new regulatory mechanisms within heart development. PMID- 21586271 TI - Dual effects of HTLV-1 bZIP factor in suppression of interferon regulatory factor 1. AB - Human T-cell leukemia virus type-1 (HTLV-1) causes ATL in 2.5% of carriers after a long period of latent infection. Moreover, half of adult T-cell leukemia (ATL) patients succumb to this disease within 1year of onset. HTLV-1 bZIP factor (HBZ) is constitutively expressed in all the ATL cells. Thus, suggesting that HBZ may play a key role in cellular leukemogenesis. Herein we present evidence that interferon regulatory factor IRF-1, which is a member of IRF transcription family, interacts with HBZ. The N-terminal of HBZ interacted with IRF-1. HBZ reduced both IRF-1 DNA-binding activity and stability via a proteasome-dependent pathway. In addition, IRF-1-mediated apoptosis is significantly reduced by ectopic production of the HBZ. These results suggested that HBZ has dual suppressive effects on IRF-1 function, which may contribute to HTLV-1 related pathogenesis. PMID- 21586272 TI - Siglec-15, a member of the sialic acid-binding lectin, is a novel regulator for osteoclast differentiation. AB - Osteoclasts are tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells derived from monocyte/macrophage-lineage precursors and are critically responsible for bone resorption. In giant cell tumor of bone (GCT), numerous TRAP-positive multinucleated giant cells emerge and severe osteolytic bone destruction occurs, implying that the emerged giant cells are biologically similar to osteoclasts. To identify novel genes involved in osteoclastogenesis, we searched genes whose expression pattern was significantly different in GCT from normal and other bone tumor tissues. By screening a human gene expression database, we identified sialic acid-binding immunoglobulin-like lectin 15 (Siglec 15) as one of the genes markedly overexpressed in GCT. The mRNA expression level of Siglec-15 increased in association with osteoclast differentiation in cultures of mouse primary unfractionated bone marrow cells (UBMC), RAW264.7 cells of the mouse macrophage cell line and human osteoclast precursors (OCP). Treatment with polyclonal antibody to mouse Siglec-15 markedly inhibited osteoclast differentiation in primary mouse bone marrow monocyte/macrophage (BMM) cells stimulated with receptor activator of nuclear factor kappaB ligand (RANKL) or tumor necrosis factor (TNF)-alpha. The antibody also inhibited osteoclast differentiation in cultures of mouse UBMC and RAW264.7 cells stimulated with active vitamin D(3) and RANKL, respectively. Finally, treatment with polyclonal antibody to human Siglec-15 inhibited RANKL-induced TRAP-positive multinuclear cell formation in a human OCP culture. These results suggest that Siglec-15 plays an important role in osteoclast differentiation. PMID- 21586273 TI - Identification of LY83583 as a specific inhibitor of Candida albicans MPS1 protein kinase. AB - Candida albicans is the most common and virulent fungus causing candidiasis in various parts of the body and can be lethal to immunocompromised patients. All currently known antifungal therapies are drugs which cause serious side effects in the host. An inhibitor specific for fungus survival is an ideal therapeutic. C. albicans MPS1 (monopolar spindle 1) has been reported as a kinase essential to its survival. Because CaMps1p shares limited sequence homology with the human ortholog (hMps1p), we screened for a chemical inhibitor in anticipation of finding one with Candida specific cytotoxicity. In vitro screening using a recombinant catalytic domain of CaMps1p identified LY83583 (6-anilino-5,8 quinolinedione), known as a guanylate cyclase inhibitor, to be blocking CaMps1p kinase activity. In addition to its in vitro kinase inhibition, LY83583 reduced the growth rate of C. albicans. Finally, we compared the inhibitory activity on CaMps1p and hMps1p among inhibitors against those kinases. LY83583 showed specific inhibition for CaMps1p with no effect on hMps1p activity. Conversely, the CaMps1p activity was not affected by known hMps1p inhibitors. These findings suggest that CaMps1p may well be an ideal target molecule for antifungal therapy. PMID- 21586274 TI - A fine balance between CCNL1 and TIMP1 contributes to the development of breast cancer cells. AB - Cyclin L1 (CCNL1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP1) are candidate genes involved in several types of cancer. However, the expression of CCNL1 and the relationship between CCNL1 and TIMP1 in breast cancer cells is unknown. Using patients' breast cancer tissues, the expression of CCNL1 and TIMP1 was measured by cDNA microarray and further confirmed by real-time RT-PCR and western blotting. Overexpression or repression of CCNL1 and TIMP1, individually or together, was performed in breast cancer MDA-MB-231 cells by transient transformation methods to investigate their role in breast cancer cell growth. Simultaneously, mRNA and protein expression levels of CCNL1 and TIMP1 were also measured. CCNL1 and TIMP1 expression was significantly elevated in breast cancer tissues compared with that in peri-breast cancer tissues of patients by cDNA microarray and these results were further confirmed by real-time RT-PCR and western blotting. Interestingly, in vitro experiments showed a stimulatory effect of TIMP1 and an inhibitory effect of CCNL1 on growth of MDA-MB-231 cells. Co expression or co-repression of these two genes did not affect cell growth. Overexpression of CCNL1 and TIMP1 individually induced overexpression of each other. These data demonstrate that there is a fine balance between CCNL1 and TIMP1, which may contribute to breast cancer development. PMID- 21586275 TI - Cardiac extracellular matrix tenascin-C deposition during fibronectin degradation. AB - Tenascin-C (TN-C) might aggravate left ventricular remodeling after myocardial infarction (MI). Our previous study demonstrated that ventricular remodeling after MI is linked with the degradation of fibronectin (FN). The aim of the present study was to determine whether cardiac extracellular matrix TN-C deposition after MI requires FN degradation. We found that treatment with angiotensin (ANG) II significantly down-regulated FN while remarkably up regulated TN-C in co-cultured cardiomyocytes and fibroblasts. Inhibitors of matrix metalloproteinase (MMP)-2, MMP-3 or MMP-9 significantly attenuated ANG II induced loss of FN and obviously blunted ANG II-induced re-expression of TN-C in co-cultured cells. Moreover, FN fragments dose-dependently induced the deposition of TN-C. In addition, MI induced a significant reduction of FN protein expression and a marked elevation of TN-C expression level at day 7 after MI compared with the sham group. The present findings suggest that cardiac TN-C matrix deposition after MI is induced by FN degradation, which is dependent on the activation of MMPs. These findings might contribute to gain mechanistic insights into the regulation of TN-C formation after MI. PMID- 21586276 TI - Exploring the common molecular basis for the universal DNA mutation bias: revival of Lowdin mutation model. AB - Recently, numerous genome analyses revealed the existence of a universal G:C->A:T mutation bias in bacteria, fungi, plants and animals. To explore the molecular basis for this mutation bias, we examined the three well-known DNA mutation models, i.e., oxidative damage model, UV-radiation damage model and CpG hypermutation model. It was revealed that these models cannot provide a sufficient explanation to the universal mutation bias. Therefore, we resorted to a DNA mutation model proposed by Lowdin 40 years ago, which was based on inter base double proton transfers (DPT). Since DPT is a fundamental and spontaneous chemical process and occurs much more frequently within GC pairs than AT pairs, Lowdin model offers a common explanation for the observed universal mutation bias and thus has broad biological implications. PMID- 21586277 TI - Connected cavity structure enables prenyl elongation across the dimer interface in mutated geranylfarnesyl diphosphate synthase from Methanosarcina mazei. AB - The mechanism for product chain-length determination of geranylfarnesyl diphosphate synthase from the methanogenic archaeon Methanosarcina mazei was investigated by constructing mutants based on structural information. Among the mutants, in which each of the bulky residues that constitute the bottom of the product-accommodating cavity was replaced with alanine, those having mutations on an alpha-helix existing at the subunit interface yielded longer products. In particular, replacement of isoleucine 112 on the alpha-helix greatly elongated the product chain-length, probably by connecting the reaction cavities of two subunits across the dimer interface. PMID- 21586279 TI - Ligustrazine inhibits lipopolysaccharide-induced proliferation by affecting P27, Bcl-2 expression in rat mesangial cells. AB - Ligustrazine has a renoprotective effect against nephritis. In the present study, we investigated the roles of ligustrazine on lipopolysaccharide-induced changes of proliferation, cell cycle in cultured rat mesangial cells. 3-(4,5 dimethyltiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay revealed that rat mesangial cells treated with lipopolysaccharide (10mg/l) underwent significant proliferation compared with control group. This effect was significantly inhibited by ligustrazine (400 to 2500 mg/l). Flow cytometric analysis revealed that cells treated with lipopolysaccharide showed significant reduction in the ratio of G0/G1 phase and significant elevation in the ratio of S+G2/M phase. The changes of cell cycle induced by lipopolysaccharide were reversed by ligustrazine. In addition, lipopolysaccharide suppressed P27 protein expression was significantly increased by ligustrazine (100, 500, 2500 mg/l). Moreover, rat mesangial cells treated with lipopolysaccharide showed scanty apoptosis with up regulation of Bcl-2expression, while Bax protein expression was not changed. Ligustrazine (100, 500, 2500 mg/l) significantly reversed lipopolysaccharide induced up-regulation of Bcl-2 protein and increased apoptotic cell death. In summary, ligustrazine displayed a significant inhibiting effect on lipopolysaccharide-induced proliferation through increasing P27 and decreasing Bcl-2 protein expression in rat mesangial cells. PMID- 21586278 TI - Stage-dependent regulation of mammary ductal branching by heparan sulfate and HGF cMet signaling. AB - Specific interactions of growth factors with heparan sulfate may function as "switches" to regulate stages of branching morphogenesis in developing mammalian organs, such as breast, lung, salivary gland and kidney, but the evidence derives mostly from studies of explanted tissues or cell culture (Shah et al., 2004). We recently provided in vivo evidence that inactivation of Ndst1, the predominant N deacetylase/N-sulfotransferase gene essential for the formation of mature heparan sulfate, results in a highly specific defect in murine lobuloalveolar development (Crawford et al., 2010). Here, we demonstrate a highly penetrant dramatic defect in primary branching by mammary epithelial-specific inactivation of Ext1, a subunit of the copolymerase complex that catalyzes the formation of the heparan sulfate chain. In contrast to Ext1 deletion, inactivation of Hs2st (which encodes an enzyme required for 2-O-sulfation of uronic acids in heparan sulfate) did not inhibit ductal formation but displayed markedly decreased secondary and ductal side-branches as well as fewer bifurcated terminal end buds. Targeted conditional deletion of c-Met, the receptor for HGF, in mammary epithelial cells showed similar defects in secondary and ductal side-branching, but did not result in any apparent defect in bifurcation of terminal end buds. Although there is published evidence indicating a role for 2-O sulfation in HGF binding, primary epithelial cells isolated from Hs2st conditional deletions were able to activate Erk in the presence of HGF and there appeared to be only a slight reduction in HGF-mediated c-Met phosphorylation in these cells compared to control. Thus, both c-Met and Hs2st play important, but partly independent, roles in secondary and ductal side branching. When considered together with previous studies of Ndst1-deficient glands, the data presented here raise the possibility of partially-independent regulation by heparan sulfate-dependent pathways of primary ductal branching, terminal end bud bifurcation, secondary branching, ductal side-branching and lobuloalveolar formation. PMID- 21586280 TI - Ginsenoside Rg(3) decelerates hERG K(+) channel deactivation through Ser631 residue interaction. AB - The human ether-a-go-go-related gene (hERG) cardiac K(+) channels are one of the representative pharmacological targets for development of drugs against cardiovascular diseases such as arrhythmia. Panax ginseng has been known to have cardio-protective effects. However, little is known about the molecular mechanisms of how ginsenosides, the active ingredients in Panax ginseng, interact with hERG K(+) channel proteins. In the present study, we first examined the effects of various ginsenosides on hERG K(+) channel activity by expressing human alpha subunits in Xenopus oocytes. Among them ginsenoside Rg(3) (Rg(3)) most potently enhanced outward I(hERG) and peak I(tail). Rg(3) induced a large persistent deactivating-tail current (I(deactivating-tail)) and profoundly decelerated deactivating current decay in both concentration- and voltage dependent manners. The EC(50) for steady-state I(hERG), peak I(tail), and persistent I(deactivating-tail) was 0.41+/-0.05, 0.61+/-0.11, and 0.36+/-0.04MUM, respectively. Rg(3) actions were blocked by bepridil, a hERG K(+) channel antagonist. Site-directed mutation of S631, which is located at the channel pore entryway, to S631C in hERG K(+) channel abolished Rg(3) actions on hERG K(+) channels. These results indicate that S631 residue of hERG K(+) channel plays an important role in Rg(3)-mediated induction of a persistent I(deactivating-tail) and in a deceleration of hERG K(+) channel deactivation. PMID- 21586281 TI - Effects of disodium cromoglycate on cationic exchange of deoxygenated sickle cells. AB - In the present work, we explored the way in which cromoglycate, a drug used to treat allergies acts on ion movements in sickle cells. Cells were either slowly deoxygenated by overnight exposure to nitrogen or acutely deoxygenated by exposure to metabisulfite, a strong reducing agent which induces sickling of red blood sickle cells. Flushing the cells with nitrogen increased the intracellular concentration of Na(+) and decreased the intracellular concentration of K(+) and the sum of the concentrations of the two cations. One hundred nM cromoglycate inhibited the decrease of intracellular K(+) and the increase of intracellular Na(+) induced by deoxygenation (n=17). Metabisulfite (100mM) increased the intracellular concentration of Ca(2+) (measured by Fura Red) (n=15) and the shape of the cells (measured by light scattering) (n=9). One MUM cromoglycate partially inhibited these two responses. In conclusion, cromoglycate partially inhibits abnormal K(+) loss, Ca(2+) entry pathways or Ca(2+) channels opened by cell deoxygenation and ensuing membrane modifications and prevents cell sickling. PMID- 21586282 TI - Chronic glucokinase activation reduces glycaemia and improves glucose tolerance in high-fat diet fed mice. AB - Glucokinase (GK) plays a key role in maintaining glucose homeostasis by promoting insulin secretion from pancreatic beta cells and increasing hepatic glucose uptake. Here we investigate the effects of acute and chronic GK activation on glucose tolerance and insulin secretion in mice with diet-induced insulin resistance. In the acute study, a small molecule GK activator (GKA71) was administered to mice fed a high-fat diet for 8 weeks. In the long-term study, GKA71 was provided in the diet for 4 weeks to high-fat diet-fed mice. Glucose tolerance was measured after intravenous glucose administration, and insulin secretion was measured both in vivo and in vitro. Acute GK activation efficiently improved glucose tolerance in association with increased insulin secretion after intravenous glucose both in control and high-fat fed mice. Chronic GK activation significantly reduced basal plasma glucose and insulin, and improved glucose tolerance despite reduced insulin secretion after intravenous glucose, suggesting improved insulin sensitivity. Isolated islets from chronically GKA71-treated mice displayed augmented insulin secretion at 8.3 mmol/l glucose, without affecting glucose oxidation. High-fat diet fed mice had reduced glycogen and increased triglyceride in liver compared to control mice, and these parameters were not altered by long-term GK activation. We conclude that GK activation in high-fat diet-fed mice potently reduces glycaemia and improves glucose tolerance, with combined effect both to stimulate insulin secretion from islets and improve insulin sensitivity. PMID- 21586283 TI - MicroRNA-126 inhibits ischemia-induced retinal neovascularization via regulating angiogenic growth factors. AB - To investigate the potential transcriptional regulation and signal pathway of a single microRNA in ischemia-induced retinal neovascularization (NV), we used oxygen-induced retinopathy (OIR) in establishing retinal NV model, and quantitative real-time reverse transcriptase PCR analyzing a microRNA (miR-126) alteration. The mice were treated with plasmid pCMV-MIR-126/liposome mixture intravitreal injection, using pCMV-MIR/liposome mixture as control. The expression levels of VEGF, IGF-2 and HIF-1alpha, and the level changes of total and phosphorylated p38, ERK in retina from OIR mice were determined by western blot analysis. The effects of miR-126 on retinal NV in OIR mice were identified with fluoresecin angiography and H & E staining. No effect of miR-126 intravitreal injection on retinal vessels was performed with CD31 stained retinal sections. Our results showed that miR-126 was significantly decreased in retina from OIR mice. We confirmed that restoration of miR-126 in retina overcame the high levels of VEGF, IGF-2 and HIF-1alpha through downregulating p38 and ERK signaling molecules in OIR model, and that miR-126 intravitreal injection reduced retinal NV in OIR model. These results suggest that miR-126 might play a potential transcriptional role in the pathogenesis in diabetic retinopathy. PMID- 21586284 TI - VAMP3 regulates podosome organisation in macrophages and together with Stx4/SNAP23 mediates adhesion, cell spreading and persistent migration. AB - The ability of cells to adhere, spread and migrate is essential to many physiological processes, particularly in the immune system where cells must traffic to sites of inflammation and injury. By altering the levels of individual components of the VAMP3/Stx4/SNAP23 complex we show here that this SNARE complex regulates efficient macrophage adhesion, spreading and migration on fibronectin. During cell spreading this complex mediates the polarised exocytosis of VAMP3 positive recycling endosome membrane into areas of membrane expansion, where VAMP3's surface partner Q-SNARE complex Stx4/SNAP23 was found to accumulate. Lowering the levels of VAMP3 in spreading cells resulted in a more rounded cell morphology and most cells were found to be devoid of the typical ring-like podosome superstructures seen normally in spreading cells. In migrating cells lowering VAMP3 levels disrupted the polarised localisation of podosome clusters. The reduced trafficking of recycling endosome membrane to sites of cell spreading and the disorganised podosome localisation in migrating macrophages greatly reduced their ability to persistently migrate on fibronectin. Thus, this important SNARE complex facilitates macrophage adhesion, spreading, and persistent macrophage migration on fibronectin through the delivery of VAMP3 positive membrane with its cargo to expand the plasma membrane and to participate in organising adhesive podosome structures. PMID- 21586285 TI - Loss of expression of miR-335 is implicated in hepatic stellate cell migration and activation. AB - Activation and migration of resident stellate cells (HSCs) within the hepatic space of Disse play an important role in hepatic fibrosis, which accounts for the increased numbers of activated HSCs in areas of inflammation during hepatic fibrosis. Currently, microRNAs have been found to play essential roles in HSC differentiation, proliferation, apoptosis, fat accumulation and collagen production. However, little is known about microRNA mediated HSC activation and migration. In this study, the miRNA expression profiles of quiescent HSCs, partially activated HSCs and fully activated HSCs were compared in pairs. Gene ontology (GO) and GO-Map network analysis indicated that the activation of HSCs was regulated by microRNAs. Among them miR-335 was confirmed to be significantly reduced during HSC activation by qRT-PCR, and restoring expression of miR-335 inhibited HSC migration and reduced alpha-SMA and collagen type I. Previous study revealed that tenascin-C (TNC), an extracellular matrix glycoprotein involved in cell migration, might be a target of miR-335. Therefore, we further studied the TNC expression in miR-335 over-expressed HSCs. Our data showed that exogenous TNC could enhance HSC migration in vitro and miR-335 restoration resulted in a significant inhibition of TNC expression. These results demonstrated that miR-335 restoration inhibited HSC migration, at least in part, via downregulating the TNC expression. PMID- 21586286 TI - Correlation of optical coherence tomography with clinical and histopathological findings in experimental autoimmune uveoretinitis. AB - Optical coherence tomography (OCT) is becoming the state-of-the-art method for the non-invasive imaging of a variety of ocular diseases. The aim of this study was to assess the application of OCT for the in vivo monitoring and follow-up of pathological changes during experimental autoimmune uveoretinitis (EAU) in rats. Initially we established OCT imaging in healthy brown Norway rats and correlated it with retinal histology. Subsequently, we induced EAU and imaged animals by OCT throughout the pre-peak, peak, and post-peak phases of the disease. The sensitivity of OCT imaging was determined by comparison with clinical EAU and histopathology scores obtained ex vivo at several time points throughout the disease course. Our data demonstrate that OCT imaging of the healthy rat retina closely correlates with histological observations and allows the clear visualization of all retinal layers. After induction of EAU, the first pathological changes could be detected by OCT at day (d) 8 post-immunization (p.i.) which corresponded to the time point of clinical disease onset. An increase in retinal thickness (RT) was detected from d10 p.i. onwards which peaked at d16 p.i. and decreased again to near control levels by d20 p.i. We introduce a novel semi-quantitative OCT scoring which correlates with histopathological findings and complements the clinical scores. Therefore, we conclude that OCT is an easily accessible, non-invasive tool for detection and follow-up of histopathological changes during EAU in rats. Indeed, significant differences in RT between different stages of EAU suggest that this OCT parameter is a sensitive marker for distinguishing disease phases in vivo. PMID- 21586287 TI - Blood-brain barrier disruption following subarchnoid hemorrhage may be faciliated through PUMA induction of endothelial cell apoptosis from the endoplasmic reticulum. AB - The blood-brain barrier (BBB) plays a vital role as both a physiologic and physical barrier in regulating the movement of water from the vasculature to the brain. During a subarachnoid hemorrhage (SAH), the BBB is disrupted by a variety of mediators, one of which can result in endothelial cell death. As a result, in the present study, we investigated the role of PUMA (p53 upregulated modulator of apoptosis) following SAH injury in rats. Specifically evaluating whether through the endoplasmic reticulum (ER), PUMA could orchestrate the induction of endothelial cell apoptosis and cause a disruption in the blood-brain barrier integrity. One hundred twelve male Sprague-Dawley rats were randomly divided into 4 groups: sham, SAH, SAH+control siRNA, SAH+PUMA siRNA. Outcomes measured include mortality rate, brain edema, BBB disruption, and neurobehavioral testing. We also used Western blotting techniques to measure the expression of key pro-apoptotic proteins such as BAX, BAK, and DRP1. PUMA siRNA treatment significantly reduced the mortality rate, cerebral edema, neurobehavioral deficits, and BBB disruption as measured by Evans blue assay following SAH injury. The T2WI images showed there was an increase in vasogenic edema in the brain following SAH, which could be alleviated by PUMA siRNA. Immunohistochemical staining and Western blot analysis demonstrated an increased expression of PUMA, BAX, BAK, GRP78 and DRP1 in the microvascular endothelial cells of the hippocampus, which was accompanied with endothelium apoptosis. This study showed that PUMA induced endothelial cell apoptosis may in fact play a significant role in BBB disruption following SAH and its mediation may be through the endoplasmic reticulum. By blocking the activity of PUMA using siRNA, we were able to prevent the accumulation of cerebral edema that occurs following BBB disruption. This translated into a preservation of functional integrity and an improvement in mortality. PMID- 21586289 TI - Development of an IgY-based rocket-immunoelectrophoresis for identity monitoring of Pertussis vaccines. AB - An important step in vaccine production and quality control is the analysis of identity of different lots. For that purpose chicken was immunized with acellular Pertussis components (Pertussis toxoid, Filamenteous haemagglutinin, Pertactin, Fimbriae 2/3 antigen). The resulting antibodies (IgY) were non-invasive extracted from egg yolk and used for rocket immunoelectrophoresis (RIE). We demonstrated that the Ab reacted with characteristic peaks ("rockets") with the corresponding antigen. The shape of the peaks varied depending on the manufacturer and the nature of antigen (adsorbed or non-adsorbed). The coefficients of variation was about 20% during a year period. In summary, our data illustrate that an IgY-based RIE is not only a cost-effective method but also proficient for monitoring Pertussis vaccines. PMID- 21586288 TI - High levels of folate from supplements and fortification are not associated with increased risk of colorectal cancer. AB - BACKGROUND & AIMS: Folate intake has been inversely associated with colorectal cancer risk in several prospective epidemiologic studies. However, no study fully assessed the influence of the high levels of folate that are frequently consumed in the United States as a result of mandatory folate fortification, which was fully implemented in 1998, and the recent increase in use of folate-containing supplements. There is evidence that consumption of high levels of folic acid, the form of folate used for fortification and in supplements, has different effects on biochemical pathways than natural folates and might promote carcinogenesis. METHODS: We investigated the association between folate intake and colorectal cancer among 43,512 men and 56,011 women in the Cancer Prevention Study II (CPS II) Nutrition Cohort; 1023 were diagnosed with colorectal cancer between 1999 and 2007, a period entirely after folate fortification began. Cox proportional hazards regression was used to calculate multivariate hazards ratios (RR) and 95% confidence interval (CI). RESULTS: Intake of high levels of natural folate (RRQ5vsQ1=0.86; 95% CI: 0.70-1.06; P trend=.12) or folic acid (RRQ5vsQ1=0.84; 95% CI: 0.68-1.03; P trend=.06) were not significantly associated with risk of colorectal cancer. Total folate intake was significantly associated with lower risk (RRQ5vsQ1=0.81; 95% CI: 0.66-0.99; P trend=.047). CONCLUSIONS: Intake of high levels of total folate reduces risk of colorectal cancer; there is no evidence that dietary fortification or supplementation with this vitamin increases colorectal cancer risk. PMID- 21586290 TI - New Spiroplasma in parasitic Leptus mites and their Agathemera walking stick hosts from Argentina. AB - Here we report the presence of Spiroplasma 16S rRNA in populations of two parasitic Leptus mites (Leptus sayi; Leptus lomani) and their Agathemera walking stick hosts. In walking sticks Spiroplasmas were detected in the gut, as well as muscle-tissues, but not in eggs. Throughout Argentina 15.4% of L. sayi populations and 14.3% of L. lomani populations surveyed screened positive for Spiroplasma. Phylogenetic analyses (ML, BCMC) place all sequences within the Ixodetis group. Most sequences form a well-supported sister subclade to the rest of Ixodetis. We briefly discuss the role of Leptus mites in the natural transmission of Spiroplasma. PMID- 21586292 TI - Local control in cardiac E-C coupling. AB - The development of local control theories in cardiac excitation-contraction coupling solved a major problem in the calcium-induced calcium release (CICR) hypothesis. Local control explained how regeneration, inherent in the CICR mechanism, might be limited spatially to enable graded Ca release (and force production). The key lies in the stochastic recruitment of individual calcium release units (couplons or CRUs) where adjacent CRUs are partially uncoupled by the distance between them. In the CRU, individual groups of sarcoplasmic reticulum calcium release channels (RyRs) are very close to the surface membrane where calcium influx, controlled by membrane depolarization, leads to high local Ca levels that enable a high speed response from RyRs that have a very low probability to opening at resting Ca levels. However, calcium diffusion from an activated CRU results in adjacent CRUs being exposed to much lower levels of Ca and probability of activation. This effectively uncouples the CRUs and limits overall regenerative gain to enable stability without compromising sensitivity. Nevertheless, it is still unclear how the CRU terminates its release of calcium on the physiological timescale, and possible mechanisms (and problems) are briefly reviewed. We suggest that modulation in RyR gating may serve to control average SR Ca levels to regulate other metabolic functions of the sarco(endo)plasmic reticulum beyond regulating contractility. This article is part of a special issue entitled "Local Signaling in Myocytes." PMID- 21586291 TI - Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts. AB - This study compared the effects of ATP-regulated potassium channel (K(ATP)) openers, diazoxide and pinacidil, on diseased and normal human atria and ventricles. We optically mapped the endocardium of coronary-perfused right (n=11) or left (n=2) posterior atrial-ventricular free wall preparations from human hearts with congestive heart failure (CHF, n=8) and non-failing human hearts without (NF, n=3) or with (INF, n=2) infarction. We also analyzed the mRNA expression of the K(ATP) targets K(ir)6.1, K(ir)6.2, SUR1, and SUR2 in the left atria and ventricles of NF (n=8) and CHF (n=4) hearts. In both CHF and INF hearts, diazoxide significantly decreased action potential durations (APDs) in atria (by -21+/-3% and -27+/-13%, p<0.01) and ventricles (by -28+/-7% and -28+/ 4%, p<0.01). Diazoxide did not change APD (0+/-5%) in NF atria. Pinacidil significantly decreased APDs in both atria (-46 to -80%, p<0.01) and ventricles ( 65 to -93%, p<0.01) in all hearts studied. The effect of pinacidil on APD was significantly higher than that of diazoxide in both atria and ventricles of all groups (p<0.05). During pinacidil perfusion, burst pacing induced flutter/fibrillation in all atrial and ventricular preparations with dominant frequencies of 14.4+/-6.1 Hz and 17.5+/-5.1 Hz, respectively. Glibenclamide (10 MUM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of K(ATP) targets were correlated to functional observations. Remodeling in response to CHF and/or previous infarct potentiated diazoxide-induced APD shortening. The activation of atrial and ventricular K(ATP) channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts. PMID- 21586293 TI - Tapping the brake on cardiac growth-endogenous repressors of hypertrophic signaling. AB - Cardiac hypertrophy is considered an early hallmark during the clinical course of heart failure and an important risk factor for cardiac morbidity and mortality. Although hypertrophy of individual cardiomyocytes in response to pathological stimuli has traditionally been considered as an adaptive response required to sustain cardiac output, accumulating evidence from studies in patients and animal models suggests that in most instances hypertrophy of the heart also harbors maladaptive aspects. Major strides have been made in our understanding of the pathways that convey pro-hypertrophic signals from the outside of the cell to the nucleus. In recent years it also has become increasingly evident that the heart possesses a variety of endogenous feedback mechanisms to counterbalance this growth response. These repressive mechanisms are of particular interest since they may provide valuable therapeutic options. In this review we summarize currently known endogenous repressors of pathological cardiac growth as they have been studied by gene targeting in mice. Many of the repressors that function in signal transduction appear to regulate calcineurin (e.g. PICOT, calsarcin, RCAN) and JNK signaling (e.g. CDC42, MKP-1) and some will be described in greater detail in this review. In addition, we will focus on factors such as Kruppel-like factors (KLF4, KLF15 and KLF10) and histone deacetylases (HDACs), which constitute a relevant group of nuclear proteins that repress transcription of the hypertrophic gene program in cardiomyocytes. PMID- 21586294 TI - Effects of calorie restriction on cardioprotection and cardiovascular health. AB - Multiple health benefits of calorie restriction (CR) and alternate day fasting (ADF) regimens are widely recognized. Experimental data concerning the effects of calorie restriction on cardiac health are more controversial, ranging from evidence that ADF protects heart from ischemic damage but results in developing of diastolic dysfunction, to reports that CR ameliorates the age-associated diastolic dysfunction. Here we investigated the effects of chronic CR on morphology and function of the cardiovascular system of aged rats and cardioprotective effect of CR against ischemic damage in the experimental rat model of MI. Cardiovascular fitness of 24-month old Fisher 344 rats maintained through life on ad libitum (AL) or CR diets was extensively evaluated via echocardiography, dobutamine stress test, pressure-volume loop analyses, pulse wave velocity measurements, and histology. Groups of 2-month old AL and 29-month old CR rats were studied for comparison. Myocardial infarction (MI) was induced by a permanent ligation of the anterior descending coronary artery in 5-month old rats maintained for 3 months on CR or AL. MI size was evaluated histologically 24 hrs following coronary ligation. Cardiac remodeling was followed-up via echocardiography. Age-associated changes in 24-month old rats consisted of 33% increase of fibrosis in the myocardium and more than 2 fold increase of the collagen in the tunica media of the aorta. There was a significant decrease in the density and total number of cardiomyocytes, while their size was increased. These morphological changes were manifested in a decline of systolic and diastolic cardiac function, increase of left ventricular and aortic stiffness, and arterio-ventricular uncoupling. Tachycardic response to dobutamine challenge was absent in the old rats. Compared to AL rats, 24-month old CR rats had reduced levels of cardiac and aortic fibrosis, increased density of cardiomyocytes that were smaller in size, attenuated diastolic dysfunction, normal systolic function and arterio-ventricular coupling. Tachycardic response to dobutamine was also intact in CR 24-month old rats and aortic stiffness was reduced. Adjustment for body weight differences through ratiometric or allometric scaling did not affect the overall pattern of differences between AL and CR rats. Attenuation of morphological and functional age-associated changes in 24-month old CR rats either was not observed at all or was smaller in 29-month old CR rats. Size of MI induced by a permanent coronary ligation as well as post-MI cardiac remodeling and function were similar in CR and AL rats. CR does not increase tolerance of myocardium to ischemic damage, but attenuates the age-associated changes in the heart and major vessels. The attenuation of age-associated changes by CR cannot be explained by the effect of lower body weight but are attributable to more intimate cellular mechanisms of CR itself. Attenuation of age-associated changes by CR waned with advancing age, and is consistent with the idea that CR postponed senescence. PMID- 21586295 TI - A model of the physiological basis of a multivariate phenotype that is mediated by Ca(2+) signaling and controlled by ryanodine receptor composition. AB - Calcium-signals occur in a wide variety of tissue types - from skeletal, smooth and cardiac muscle to pancreatic and brain tissues. Ca(2+) signals regulate diverse processes including muscle contraction, hormone secretion, neural communication and gene expression. Together these different tissues and processes form the basis of a multivariate trait. Calcium signals are characterized by Ca(2+) transients, which are sharp increases in Ca(2+) concentration over a short period of time. In this paper we derive and analyze a model of Ca(2+) transients for skeletal muscle, neurons and cardiac tissue based on underlying biophysical principles. Tissue differentiation in our model and in nature comes about by varying the ryanodine receptor (RyR) channel composition of tissues. In vertebrates, there are typically three types of RyR channels (labeled RyR1, RyR2 and RyR3 in mammals and alpha-RyR, cardiac-RyR and beta-RyR in birds, amphibians and fish). Different compositions of these three RyR channels generate different Ca(2+) transient properties. There are four Ca(2+) transient properties that we measure: maximum amplitude, duration, half duration (D(50)) and integrated concentration. In agreement with experimental work, our results find that the addition of RyR3 amplifies Ca(2+) transients in skeletal muscle. An important consequence of shared molecular components between tissue types in a multivariate setting is that the shared components cause individual traits of a multivariate trait to be correlated in function. Here we show how correlations in Ca(2+) transient properties between tissues can be predicted using an underlying biophysical model. PMID- 21586296 TI - Estrogen receptors and gonadal steroids in vulnerability and protection of dopamine neurons in a mouse model of Parkinson's disease. AB - 17beta-estradiol is well known to have neuroprotective effects in the 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We investigated the neuroprotective contribution of estrogen receptors (ERalpha and ERbeta) against MPTP toxicity by examining the membrane dopamine (DA) transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and tyrosine hydroxylase (TH) in ER knock out (ERKO) C57Bl/6 male mice compared to their plasma steroid levels. A dose-response to MPTP comparing wild-type (WT) to ERKO mice was studied. WT mice were also compared to ERKO mice pretreated with 17beta-estradiol alone and with MPTP. Specific radioligand binding autoradiography and in situ hybridization for DAT, VMAT2 and TH were assayed in the striatum and the substantia nigra (SN). Intact ERKObeta mice had both striatal transporters levels lower than WT and ERKOalpha mice. MPTP caused a dose-dependent loss of both striatal transporters that correlated with striatal DA concentrations. Compared to WT and ERKObeta mice, ERKOalpha mice DAT, VMAT2 and TH were affected at lower MPTP doses. In the striatum and SN, ERKOalpha mice were more vulnerable and 17beta-estradiol protected against MPTP toxicity only in WT mice. ERKOalpha mice blood plasma had higher levels of testosterone, dihydrotestosterone and 3beta-diol compared to the plasma of WT and ERKObeta mice. 17beta-estradiol treatment increased estradiol plasma levels in all genotypes. Striatal DA concentrations and SN TH mRNA correlated inversely with plasma testosterone and 3beta-diol levels. Hence, in male mice the lack of ERalpha or ERbeta altered their basal plasma steroid levels and both striatal DA transporters as well as their susceptibility to MPTP toxicity. PMID- 21586297 TI - Pain and post traumatic stress disorder - review of clinical and experimental evidence. AB - Pain and Post Traumatic Stress Disorder (PTSD) are highly comorbid conditions. Patients with chronic pain have higher rates of PTSD. Likewise, patients with PTSD are often diagnosed with numerous chronic pain conditions. Despite the high pain-PTSD comorbidity, the neurobehavioral mechanisms underlying this phenomenon are incompletely understood and only recently researchers have started investigating it using experimental models. In this article, we systematically review the substantial clinical evidence on the co-occurrence of pain and PTSD, and the limited experimental evidence of pain processing in this disorder. We provide a detailed overview of the psychophysical and brain imaging experiments that compared somatosensory and pain processing in PTSD and non-PTSD populations. Based on the presented evidence, an extensive body of literature substantiates the clinical coexistence of pain and PTSD in patients but the limited experimental data show inconsistent results highlighting the need for well controlled future studies. This article is part of a Special Issue entitled 'Post Traumatic Stress Disorder'. PMID- 21586299 TI - Lacosamide has protective disease modifying properties in experimental vincristine neuropathy. AB - Pain and paresthesias are the most common symptoms of chemotherapy induced painful neuropathy (CIPN). Current treatment and preventive strategies of CIPN are ineffective, and the neuropathy may lead to discontinuation of anti-tumor therapy. Here we used experimental vincristine-induced neuropathy in rats to evaluate the disease modifying potential of lacosamide using a sustained release formulation and the acute treatment effects of a rapid release formulation. Pain behavior was assessed by withdrawal responses to von Frey hairs, acetone drops, the Randall-Selitto device, and to radiant heat. Neuropathy was assessed using electrophysiological recordings. Preventive lacosamide treatment (30 mg/kg subcutaneously b.i.d. for 17 days) was well tolerated, and pharmacokinetic analysis revealed a peak plasma concentration 2 h post-injection with a plasma half-life of approximately 3 h. Rats treated with lacosamide, in contrast to vehicle treated rats, did not develop vincristine-induced cold allodynia. Neurophysiology showed a delayed F-wave latency in vehicle treated rats, which was not present in lacosamide treated animals. We could thus demonstrate a protective disease modifying potency of lacosamide in an animal model of CIPN. Lacosamide may be a promising candidate for preventive treatment of CIPN in patients receiving chemotherapy with vinca alkaloids or platinum drugs. PMID- 21586298 TI - Amantadine protects dopamine neurons by a dual action: reducing activation of microglia and inducing expression of GDNF in astroglia [corrected]. AB - Amantadine is commonly given to alleviate L-DOPA-induced dyskinesia of Parkinson's disease (PD) patients. Animal and human evidence showed that amantadine may also exert neuroprotection in several neurological disorders. Additionally, it is generally believed that this neuroprotection results from the ability of amantadine to inhibit glutamatergic NMDA receptor. However, several lines of evidence questioned the neuroprotective capacity of NMDA receptor antagonists in animal models of PD. Thus the cellular and molecular mechanism of neuroprotection of amantadine remains unclear. Using primary cultures with different composition of neurons, microglia, and astroglia we investigated the direct role of these glial cell types in the neuroprotective effect of amantadine. First, amantadine protected rat midbrain cultures from either MPP(+) or lipopolysaccharide (LPS), two toxins commonly used as PD models. Second, our studies revealed that amantadine reduced both LPS- and MPP(+)-induced toxicity of dopamine neurons through 1) the inhibition of the release of microglial pro inflammatory factors, 2) an increase in expression of neurotrophic factors such as GDNF from astroglia. Lastly, differently from the general view on amantadine's action, we provided evidence suggesting that NMDA receptor inhibition was not crucial for the neuroprotective effect of amantadine. In conclusion, we report that amantadine protected dopamine neurons in two PD models through a novel dual mechanism, namely reducing the release of pro-inflammatory factors from activated microglia and increasing the expression of GNDF in astroglia. PMID- 21586300 TI - Receptor tyrosine kinase inhibition causes simultaneous bone loss and excess bone formation within growing bone in rats. AB - During postnatal skeletal growth, adaptation to mechanical loading leads to cellular activities at the growth plate. It has recently become evident that bone forming and bone resorbing cells are affected by the receptor tyrosine kinase (RTK) inhibitor imatinib mesylate (STI571, Gleevec(r)). Imatinib targets PDGF, ABL-related gene, c-Abl, c-Kit and c-Fms receptors, many of which have multiple functions in the bone microenvironment. We therefore studied the effects of imatinib in growing bone. Young rats were exposed to imatinib (150mg/kg on postnatal days 5-7, or 100mg/kg on postnatal days 5-13), and the effects of RTK inhibition on bone physiology were studied after 8 and 70days (3-day treatment), or after 14days (9-day treatment). X-ray imaging, computer tomography, histomorphometry, RNA analysis and immunohistochemistry were used to evaluate bone modeling and remodeling in vivo. Imatinib treatment eliminated osteoclasts from the metaphyseal osteochondral junction at 8 and 14days. This led to a resorption arrest at the growth plate, but also increased bone apposition by osteoblasts, thus resulting in local osteopetrosis at the osteochondral junction. The impaired bone remodelation observed on day 8 remained significant until adulthood. Within the same bone, increased osteoclast activity, leading to bone loss, was observed at distal bone trabeculae on days 8 and 14. Peripheral quantitative computer tomography (pQCT) and micro-CT analysis confirmed that, at the osteochondral junction, imatinib shifted the balance from bone resorption towards bone formation, thereby altering bone modeling. At distal trabecular bone, in turn, the balance was turned towards bone resorption, leading to bone loss. PMID- 21586301 TI - Presynaptic action of Bothriopsis bilineata smargadina (forest viper) venom in vitro. AB - In this work, we examined the neuromuscular activity of Bothriopsis bilineata smargadina (forest viper) venom in vertebrate isolated nerve-muscle preparations. In chick biventer cervicis preparations the venom caused concentration-dependent (0.1-30 MUg/ml) neuromuscular blockade that was not reversed by washing, with 50% blockade occurring in 15-90 min. Muscle contractures to exogenous acetylcholine and KCl were unaffected by venom, but there was a slight increase in creatine kinase release after 120 min (from 80 +/- 15 to 206 +/- 25U/ml, n=6, p<0.05). In mouse phrenic nerve-diaphragm preparations, the venom (1, 10 and 30 MUg/ml) produced marked facilitation (~120% increase above basal) at the highest concentration followed by neuromuscular blockade; the effects at lower concentrations were considerably less marked. Venom increased the quantal content values after 15 and 30 min followed by significant inhibition at >= 90 min. However, venom did not alter the muscle membrane resting potential or the response to exogenous carbachol. In both preparations, incubation at 22 degrees C instead of 37 degrees C delayed the onset of blockade, as did inhibition of venom PLA(2) activity. In curarized mouse preparations, the venom produced only muscle facilitation. These results indicate that B. b. smargadina venom causes neuromuscular blockade in vitro by a presynaptic mechanism involving PLA(2). PMID- 21586303 TI - What can spike train distances tell us about the neural code? AB - Time scale parametric spike train distances like the Victor and the van Rossum distances are often applied to study the neural code based on neural stimuli discrimination. Different neural coding hypotheses, such as rate or coincidence coding, can be assessed by combining a time scale parametric spike train distance with a classifier in order to obtain the optimal discrimination performance. The time scale for which the responses to different stimuli are distinguished best is assumed to be the discriminative precision of the neural code. The relevance of temporal coding is evaluated by comparing the optimal discrimination performance with the one achieved when assuming a rate code. We here characterize the measures quantifying the discrimination performance, the discriminative precision, and the relevance of temporal coding. Furthermore, we evaluate the information these quantities provide about the neural code. We show that the discriminative precision is too unspecific to be interpreted in terms of the time scales relevant for encoding. Accordingly, the time scale parametric nature of the distances is mainly an advantage because it allows maximizing the discrimination performance across a whole set of measures with different sensitivities determined by the time scale parameter, but not due to the possibility to examine the temporal properties of the neural code. PMID- 21586302 TI - Anabolic-androgenic steroid effects on nociception and morphine antinociception in male rats. AB - The purpose of this study was to investigate the effects of acute and chronic administration of anabolic-androgenic steroids (AAS) on nociception and morphine antinociception in acute pain models, as well as on chronic inflammatory nociception. In Experiment 1, adult, gonadally intact male rats were injected s.c. for 28 days with either 5 mg/kg testosterone (T), dihydrotestosterone (DHT), stanozolol (STAN), or safflower oil vehicle (N=12-25/group). On day 28, rats in each group were tested on acute thermal and mechanical nociceptive assays, before and after morphine treatment. In Experiment 2, rats in each group (N=8-10/group) were injected with mineral oil or complete Freund's adjuvant (CFA) into one hindpaw after 28 days of AAS treatment, and then tested for thermal hyperalgesia, mechanical allodynia, inflammation and locomotor suppression intermittently for 28 days. Experiment 3 replicated nociceptive measurements in Experiments 1 and 2, but with a single AAS or vehicle injection occurring 3h prior to testing (N=10 12/group). While chronic AAS administration tended to decrease body weight gain and alter reproductive organ weights in the expected manner, it did not significantly alter acute nociception nor attenuate the development of various chronic pain indices after CFA administration. Morphine antinociceptive potency was significantly decreased by chronic DHT on the hot plate test only. Acute AAS administration also did not significantly alter acute or chronic nociception, or morphine antinociceptive potency. Comparisons between acute and chronic AAS administration suggest that steroid tolerance did not occur in rats treated with AAS chronically. Taken together, these data do not support the hypothesis that AAS exposure alters nociception or morphine antinociception in gonadally intact males. PMID- 21586304 TI - Biochemical markers and protein pattern analysis for canine coagulase-positive staphylococci and their distribution on dog skin. AB - Coagulase-positive staphylococci (CoPS) including S. pseudintermedius, S. schleiferi subsp. coagulans and S. aureus are etiological agents of dermatitis in companion animals and can be zoonotic pathogens. To date no consensual biochemical marker for routine microbiological identification of these species has been identified. The aim of this study was to evaluate biochemical markers and compare the results with the approved molecular method, multiplex-PCR (M PCR), and confirm their species-specific phenotypic characteristic by using SDS PAGE. The distribution and frequency of CoPS species were also determined. Three hundred and thirty-seven canine CoPS isolates were obtained from the nasal mucosa, perineum and groins of 66 healthy dogs and were identified by the M-PCR as S. aureus (n=5), S. pseudintermedius (n=263) and S. schleiferi subsp. coagulans (n=69). Selected biochemical tests including the Voges-Proskauer test, mannitol broth fermentation, the assimilation of maltose, galactose, trahalose and lactose using broth medium, were successfully used to distinguish the three species of canine CoPS from other CoPS species. Additionally, species-specific protein patterns were also found to be useful for phenotypic differentiation, with good agreement with the results of M-PCR and the use of biochemical markers. S. aureus occured infrequently on dog skin while co-colonization with S. pseudintermedius and S. schleiferi subsp. coagulans was observed. We propose the use of consensual biochemical markers of canine CoPS with the presence of the unique protein patterns as an alternative tool for conventional laboratory use. PMID- 21586305 TI - On the regularity of preparatory activity preceding movements with the dominant and non-dominant hand: a readiness potential study. AB - The readiness potential (RP), a slow negative electroencephalographic pre movement potential, was reported to commence earlier for movements with the non dominant left hand than with the dominant right hand. Latencies in these reports were always calculated from averaged RPs, whereas onset times of individual trials remained inaccessible. The aim was to use a new statistical approach to examine whether a few left hand trials with very early pre-movement activity disproportionally affect the onset of the average. We recorded RPs in 28 right handed subjects while they made self-paced repetitive unilateral movements with their dominant and non-dominant hand. Skewness, a measure of distribution asymmetry, was analysed in sets of single-trial RPs to discriminate between a symmetric distribution and an asymmetric distribution containing outlier trials with early onset. Results show that for right hand movements skewness has values around zero across electrodes and pre-movement intervals, whereas for left hand movements skewness has initially negative values which increase to neutral values closer to movement onset. This indicates a symmetric (e.g., Gaussian) distribution of onset times across trials for simple right hand movements, whereas cortical activation preceding movements with the non-dominant hand is characterised by outlier trials with early onset of negativity. These findings may explain differences in the averaged brain activation preceding dominant versus non-dominant hand movements described in previous electrophysiological/neuroimaging studies. The findings also constrain mental chronometry, a technique that makes conclusions upon the time and temporal order of brain processes by measuring and comparing onset times of averaged electroencephalographic potentials evoked by these processes. PMID- 21586306 TI - Clearance of Penaeus monodon densovirus in naturally pre-infected shrimp by combined ns1 and vp dsRNAs. AB - Penaeus monodon densovirus (PmDNV) is one of the major causes of stunted shrimp in Thailand and leads to considerable economic losses in overall shrimp production. Present study shows that the double-stranded RNA corresponding to the non-structural protein gene (ns1) and structural protein gene (vp) of PmDNV effectively inhibit viral propagation in naturally pre-infected shrimp. Multiple application of dsRNA was performed by injection into the haemolymph. The total amount of virus in the hepatopancreas of treated shrimp was measured by semi quantitative PCR and histological methods. Observations indicated that PmDNV was almost eradicated in comparison to the high viral propagation in the control groups (no dsRNA and non-related dsRNA-gfp). For heavily infected shrimp, simultaneously knock down of ns1 and vp genes exhibited greater potency for viral depletion than dsRNA-ns1 alone. Furthermore, typical hypertrophic nuclei were also reduced in treated shrimp. This study therefore demonstrates the first result of an effective anti-PmDNV therapy in naturally pre-infected shrimp. PMID- 21586307 TI - Local transdermal delivery of phenylephrine to the anal sphincter muscle using microneedles. AB - We propose pretreatment using microneedles to increase perianal skin permeability for locally targeted delivery of phenylephrine (PE), a drug that increases resting anal sphincter pressure to treat fecal incontinence. Microneedle patches were fabricated by micromolding poly-lactic-acid. Pre-treatment of human cadaver skin with microneedles increased PE delivery across the skin by up to 10-fold in vitro. In vivo delivery was assessed in rats receiving treatment with or without use of microneedles and with or without PE. Resting anal sphincter pressure was then measured over time using water-perfused anorectal manometry. For rats pretreated with microneedles, topical application of 30% PE gel rapidly increased the mean resting anal sphincter pressure from 7+/-2 cm H(2)O to a peak value of 43+/-17 cm H(2)O after 1 h, which was significantly greater than rats receiving PE gel without microneedle pretreatment. Additional safety studies showed that topically applied green fluorescent protein-expressing E. coli penetrated skin pierced with 23- and 26-gauge hypodermic needles, but E. coli was not detected in skin pretreated with microneedles, which suggests that microneedle-treated skin may not be especially susceptible to infection. In conclusion, this study demonstrates local transdermal delivery of PE to the anal sphincter muscle using microneedles, which may provide a novel treatment for fecal incontinence. PMID- 21586308 TI - Transgene regulation system responding to Rho associated coiled-coil kinase (ROCK) activation. AB - Recently, we have proposed a new system of gene regulation called 'drug or gene delivery system responding to cellular signals' (D-RECS). In this system, transgene expression is activated in response to intracellular target protein kinases or proteases for safe, cell-specific gene delivery by using peptide polymer conjugates. Here we applied this system to an intracellular Rho associated coiled-coil kinase (ROCK) signal, which is activated abnormally in cardiovascular diseases. A ROCK responsive polymer consisting of neutral polymers in main chain and cationic ROCK substrate peptides in side chains was prepared and could form the complex with plasmid DNA. The complex was transferred into NIH3T3 cells with or without L-alpha-lysophosphatidic acid (LPA) that increases ROCK activity. At an N/P ratio of 2.0, a significant increase of the gene expression was identified in LPA-treated NIH3T3 cells, but was disappeared in NIH3T3 cells treated with ROCK specific inhibitor, Y-27632. These results suggest that the ROCK responsive polymer can regulate gene expression in response to ROCK activity. PMID- 21586309 TI - Subchronic toxicity studies with ginsenoside compound K delivered to dogs via intravenous administration. AB - Compound K, i.e., 20-O-beta-d-glucopyranosyl-20(S)-protopanaxadiol, is the main metabolite of the protopanaxadiol type of ginseng saponin produced by intestinal bacteria after oral administration of ginseng extract. In the present study, the toxicity of compound K was evaluated in male and female dogs after 90 days continuous intravenous infusion. Beagle dogs were treated with compound K at doses of 6.7, 20 and 60 mg/kg/day, and observed for 90 days followed by recovery periods. Measurements included clinical observations, body weight, food consumption, temperature, electrocardiogram (ECG), hematology, blood chemistry, urinalysis, gross necropsy, organ weight and histopathology. Under the conditions, the clinical condition of the animals, body weights, body weight gains and food consumption were unaffected by compound K administration relative to the control group. Hematology, ECG data and urinalysis parameters were also unaffected. However, the hepatotoxicity was evident from the observation of multiple parameters, including histopathological evaluation of liver tissue upon necropsy as well as large increases in plasma levels of liver enzymes (alanine aminotransferase, ALT, Gamma-glutamyltranspeptidase, gamma-GT, alkaline phosphatase,ALP) in groups receiving compound K (20 or 60 mg/kg/day), and this hepatoxicity might be reversible. In addition, the NOAEL of compound K is 6.7 mg/kg/day in this 90 days toxicity study. PMID- 21586310 TI - Ruminococcin C, a new anti-Clostridium perfringens bacteriocin produced in the gut by the commensal bacterium Ruminococcus gnavus E1. AB - When colonizing the digestive tract of mono-associated rats, Ruminococcus gnavus E1 - a bacterium isolated from human faeces - produced a trypsin-dependent anti Clostridium perfringens substance collectively named Ruminococcin C (RumC). RumC was isolated from the caecal contents of E1-monocontaminated rats and found to consist of two antimicrobial fractions: a single peptide (RumCsp) of 4235 Da, and a mixture of two other peptides (RumCdp) with distinct molecular masses of 4324 Da and 4456 Da. Both RumCsp and RumCdp were as effective as metronidazole in combating C. perfringens and their activity spectra against different pathogens were established. Even if devoid of synergistic activity, the combination of RumCsp and RumCdp was observed to be much more resistant to acidic pH and high temperature than each fraction tested individually. N-terminal sequence analysis showed that the primary structures of these three peptides shared a high degree of homology, but were clearly distinct from previously reported amino acid sequences. Amino acid composition of the three RumC peptides did not highlight the presence of any Lanthionine residue. However, Edman degradation could not run beyond the 11th amino acid residue. Five genes encoding putative pre-RumC-like peptides were identified in the genome of strain E1, confirming that RumC was a bacteriocin. This is the first time that a bacteriocin produced in vivo by a human commensal bacterium was purified and characterized. PMID- 21586311 TI - Enzymatic characterization of isocitrate dehydrogenase from an emerging zoonotic pathogen Streptococcus suis. AB - Streptococcus suis, a Gram-positive coccus, is an emerging zoonotic pathogen for both humans and pigs, but little is known about the properties of its metabolic enzymes. Isocitrate dehydrogenase (IDH) is a key regulatory enzyme in the citric acid cycle that catalyzes the oxidative decarboxylation of isocitrate yielding alpha-ketoglutarate and NAD(P)H. Here, we report the overexpression and enzymatic characterization of IDH from S. suis Serotype 2 Chinese highly virulent strain 05ZYH33 (SsIDH). The molecular weight of SsIDH was estimated to be 74 kDa by gel filtration chromatography, suggesting a homodimeric structure. Additionally, SsIDH was divalent cation-dependent and Mg(2+) was found to be the most effective cation. The optimal pH of SsIDH was 7.0 (Mn(2+)) and 8.5 (Mg(2+)), and the maximum activity was around 30 degrees C (Mn(2+)) and 50 degrees C (Mg(2+)), respectively. Heat inactivation studies showed that SsIDH retained 50% activity after 20 min of incubation at 49 degrees C. Sequence comparison revealed that SsIDH had a significantly homologous identity to bacterial homodimeric IDHs. The recombinant SsIDH displayed a 117-fold (k(cat)/K(m)) preference for NAD(+) over NADP(+) with Mg(2+), and a 80-fold greater specificity for NAD(+) than NADP(+) with Mn(2+). Therefore, SsIDH has remarkably high coenzyme preference toward NAD(+). This current work is expected to shed light on the functions of metabolic enzymes in S. suis and provide useful information for SsIDH to be considered as a possible candidate for serological diagnostics and detection of S. suis infection. PMID- 21586312 TI - Activation of aldo-keto reductase family member 1B14 (AKR1B14) by bile acids: Activation mechanism and bile acid-binding site. AB - Aldo-keto reductase (AKR) 1B14, a rat ortholog of mouse androgen-dependent vas deferens protein (AKR1B7), is involved in the synthesis of prostaglandin F(2alpha) and detoxification of 4-oxononenal formed by lipid peroxidation. The NADPH-linked reductase activity of AKR1B14 was activated by various bile acids. Although the activation was increased by decreasing pH from 9.0 to 6.0, the concentrations giving maximum stimulation (2- to 18-fold) were 0.2-6.0 MUM for bile acids at pH 7.4. Kinetic analyses of the activation by glycochenodeoxycholic acid in the forward and reverse reactions, together with fluorescence changes and protection against 4-oxononenal-induced inactivation by bile acid, indicate that the bile acid binds to the enzyme and its coenzyme binary complex as a non essential activator. The bile acid binding to AKR1B14 mainly accelerates the NADP(+) dissociation, the rate-limited step of the enzyme reaction. AKR1B7 was also activated by bile acids, but the activation was low and independent of pH. The mutagenesis of His269 and Leu267 of AKR1B14 into the corresponding residues (Arg and Pro, respectively) of AKR1B7 resulted in low and pH-independent activation by bile acids. The results, together with the docking of the bile acid in the recently determined crystal structure of AKR1B14, identify the bile acid binding site of which His269 plays a key role in significant activation through its electrostatic interaction with the carboxyl group of bile acid, facilitating the release of NADP(+). PMID- 21586313 TI - Awareness is necessary for differential trace and delay eyeblink conditioning in humans. AB - Squire et al. have proposed that trace and delay eyeblink conditioning procedures engage separate learning systems: a declarative hippocampal/cortical system associated with conscious contingency awareness, and a reflexive sub-cortical system independent of awareness, respectively (Clark and Squire, 1998; Smith et al., 2005). The only difference between these two procedures is that the conditioned stimulus (CS) and the unconditioned stimulus (US) overlap in delay conditioning, whereas there is a brief interval (e.g., 1s) between them in trace conditioning. In two experiments using the same procedure as Clark and Squire's group, we observed differential conditioning only in participants who showed contingency awareness in a post-experimental questionnaire, with both trace and delay procedures. We interpret these results to suggest that, although there may be multiple brain regions involved in learning, these regions are organized as a coordinated system rather than as separate, independent systems. PMID- 21586314 TI - Chronic administration of phencyclidine produces decreased sensitivity to mechanical stimulation in the absence of altered affective behavior: Implications for pain processing in schizophrenia. AB - Patients with schizophrenia have been shown to display decreased sensitivity to pain, which can severely compound the impact of injuries and illnesses. Alterations in the sensory and affective systems of pain processing have been proposed as mechanisms, but the unique contribution of each of these systems has not been elucidated. The aim of this study was to investigate these two components of pain using the NMDA receptor antagonist, phencyclidine (PCP), an established animal model of schizophrenia. Animals underwent L5 spinal nerve ligation surgery in order to provoke a condition of ongoing pain responding, followed by treatment with 2.58 mg/kg of PCP, or saline, and 20 mg/kg of the atypical antipsychotic clozapine, or vehicle, in a block design. Responses to mechanical stimuli were assessed to determine changes in sensory processing, and affective pain processing was examined with the place escape avoidance paradigm. The results showed animals receiving PCP exhibited decreased sensitivity to mechanical stimulation and unaltered behavior in the avoidance paradigm. These findings corroborate and strengthen the human literature investigating schizophrenia and alterations in pain perception. More importantly, the differential findings between the tests of sensory and affective pain processing provide a novel means of understanding schizophrenia-related pain insensitivity. PMID- 21586316 TI - The pharmacokinetical study of plant alkaloid tetrandrine with a simple HPLC method in rabbits. AB - A simple HPLC method was developed to quantify rabbit plasma tetrandrine (Tet) with propranolol (Pro) as internal standard. Based on the established method Tet and Pro were eluted at 7.1 and 12.0 min, respectively. It was shown that the concentration-time data of Tet fit the classical two-compartment model, no matter the drug was administered intravenously or orally to rabbits. The values of AUC(0 -> infinity), clearance (Cl(0 -> infinity)), volume of distribution (Vd), and elimination half-life (t(1/2beta)) of Tet were 59861.149 +/- 26962.196 MUg/L*min, 0.503 +/- 0.173 L/min/kg, 179 +/- 76.185 L/kg, and 283.808 +/- 162.937 min for intravenous injection of 5mg/kg, or 18986.217 +/- 7462.308 MUg/L*min, 0.805 +/- 0.267 L/min/kg, 110.284 +/- 94.176 L/kg, and 732.919 +/- 847.32 min for gavage administration of 10mg/kg , respectively. The results indicate that Tet displays a limited absorption in intestinal tract, even though it has a favorable pharmacokinetic profile after oral or intravenous administration. PMID- 21586315 TI - SIRT3 and cancer: tumor promoter or suppressor? AB - Sirtuins (SIRT1-7), the mammalian homologues of the Sir2 gene in yeast, have emerging roles in age-related diseases, such as cardiac hypertrophy, diabetes, obesity, and cancer. However, the role of several sirtuin family members, including SIRT1 and SIRT3, in cancer has been controversial. The aim of this review is to explore and discuss the seemingly dichotomous role of SIRT3 in cancer biology with particular emphasis on its potential role as a tumor promoter and tumor suppressor. This review will also discuss the potential role of SIRT3 as a novel therapeutic target to treat cancer. PMID- 21586317 TI - Short-term plasticity and auditory processing in the ventral cochlear nucleus of normal and hearing-impaired animals. AB - The dynamics of synaptic transmission between neurons plays a major role in neural information processing. In the cochlear nucleus, auditory nerve synapses have a relatively high release probability and show pronounced synaptic depression that, in conjunction with the variability of interspike intervals, shapes the information transmitted to the postsynaptic cells. Cellular mechanisms have been best analyzed at the endbulb synapses, revealing that the recent history of presynaptic activity plays a complex, non-linear, role in regulating release. Emerging evidence suggests that the dynamics of synaptic function differs according to the target neuron within the cochlear nucleus. One consequence of hearing loss is changes in evoked release at surviving auditory nerve synapses, and in some situations spontaneous release is greatly enhanced. In contrast, even with cochlear ablation, postsynaptic excitability is less affected. The existing evidence suggests that different modes of hearing loss can result in different dynamic patterns of synaptic transmission between the auditory nerve and postsynaptic neurons. These changes in dynamics in turn will affect the efficacy with which different kinds of information about the acoustic environment can be processed by the parallel pathways in the cochlear nucleus. PMID- 21586319 TI - Antimicrobial, anti-inflammatory, antiparasitic, and cytotoxic activities of Galium mexicanum. AB - ETHNOPHARMACOLOGICAL RELEVANCE: To study the potential benefit of the traditional Mexican medicinal plant Galium mexicanum Kunth (Rubiaceae). Hexane, chloroform, and methanol extracts as well as various fractions from these extracts were tested to determine antibacterial, antifungal, antiparasitic or anti-inflammatory activities in vitro. MATERIALS AND METHODS: Aerial parts of the plant were extracted with various solvents and fractionated accordingly. Their antibacterial and antifungal activities were assessed on nine bacterial and four fungal strains. Leishmania donovani was used as a protozoan strain for antiparasitic activity. The anti-inflammatory activity of the compounds was investigated by measuring the secretion of interleukin-6 when macrophages were exposed to lipopolysaccharide. RESULTS: Various extracts and fractions obtained from this plant exhibit antibacterial, antifungal, antiparasitic, and anti-inflammatory activities. Of special interest was the hexane fraction HE 14 b, which show antibacterial (ranging between 67 and 666 MUg/ml) and antifungal (at concentrations of 333 MUg/ml) activities. Also the hexane fraction HE 5 exhibited antiparasitic activity (at concentrations of 260 MUg/ml), whereas the methanol fraction ME 13-15 showed a potent anti-inflammatory activity when compared to dexamethasone. Chemical analyses of the chloroform extract show the presence of triterpenes, saponins, flavonoids, sesquiterpene lactones, and glucosides, but no tannins were detected in the assayed extract. CONCLUSIONS: The benefit of Galium mexicanum as a traditional medicinal plant was confirmed using antibacterial and antifungal assays in vitro. We also report for the first time, and to the best of our knowledge, antiparasitic and anti-inflammatory activities of this plant. PMID- 21586318 TI - Synaptic short-term plasticity in auditory cortical circuits. AB - The auditory system must be able to adapt to changing acoustic environment and still maintain accurate representation of signals. Mechanistically, this is a difficult task because the responsiveness of a large heterogeneous population of interconnected neurons must be adjusted properly and precisely. Synaptic short term plasticity (STP) is widely regarded as a viable mechanism for adaptive processes. Although the cellular mechanism for STP is well characterized, the overall effect on information processing at the network level is poorly understood. The main challenge is that there are many cell types in auditory cortex, each of which exhibit different forms and degrees of STP. In this article, I will review the basic properties of STP in auditory cortical circuits and discuss the possible impact on signal processing. PMID- 21586320 TI - The relationship between age-related hearing loss and synaptic changes in the hippocampus of C57BL/6J mice. AB - To explore the relationship between age-related hearing loss (presbycusis) and synaptic degeneration in the hippocampal CA3 region of C57BL/6J mice, we investigated both cognitive performance and synaptic changes within the hippocampus of C57BL/6J mice from three age groups of 6-8, 24-26, and 42-44 weeks; CBA/CaJ mice served as controls. The auditory brainstem response was used as a measure of hearing threshold, and cognitive behavior was evaluated using the Morris water maze. The ultrastructure of synapses was observed with transmission electron microscopy, and the quantity and distribution of the synaptic markers synaptophysin and PSD-95 were observed with immunohistochemistry. The hearing threshold of C57BL/6J mice was significantly higher at 24-26 weeks than at 6-8 weeks, and hearing loss was profound at 42-44 weeks. This was accompanied by progressive degeneration of synapses within the auditory cortex. In contrast, the hearing threshold of CBA/CaJ mice was relatively unchanged at 24-26 weeks of age, and these mice developed only mild hearing loss at 42-44 weeks of age. Interestingly, C57BL/6J, but not CBA/CaJ mice clearly exhibited both decreased performance in the Morris water maze and degeneration of synapses within the hippocampus. We therefore conclude that age-related hearing loss is accompanied by the degeneration of synapses in the hippocampal CA3 region of C57BL/6J mice. PMID- 21586321 TI - Predicting human microRNA precursors based on an optimized feature subset generated by GA-SVM. AB - MicroRNAs (miRNAs) are non-coding RNAs that play important roles in post transcriptional regulation. Identification of miRNAs is crucial to understanding their biological mechanism. Recently, machine-learning approaches have been employed to predict miRNA precursors (pre-miRNAs). However, features used are divergent and consequently induce different performance. Thus, feature selection is critical for pre-miRNA prediction. We generated an optimized feature subset including 13 features using a hybrid of genetic algorithm and support vector machine (GA-SVM). Based on SVM, the classification performance of the optimized feature subset is much higher than that of the two feature sets used in microPred and miPred by five-fold cross-validation. Finally, we constructed the classifier miR-SF to predict the most recently identified human pre-miRNAs in miRBase (version 16). Compared with microPred and miPred, miR-SF achieved much higher classification performance. Accuracies were 93.97%, 86.21% and 64.66% for miR-SF, microPred and miPred, respectively. Thus, miR-SF is effective for identifying pre miRNAs. PMID- 21586322 TI - Segment-specific overexpression of redoxins after renal ischemia and reperfusion: protective roles of glutaredoxin 2, peroxiredoxin 3, and peroxiredoxin 6. AB - The disruption of redox control, i.e., oxidative stress, is one of the most destructive causes of ischemia-reperfusion (IR) injury. Thioredoxin (Trx) family proteins play a major role in the cellular response to oxidative stress. Here, we systematically investigated the levels and tissue distribution of 15 members of this family (Trx and TrxR 1 and 2, Nrx, Prx 1-6, and Grx 1-3 and 5) in mouse kidneys after induction of IR by comparing control, clamped, and contralateral organs. After IR, levels of various redoxins were quantified. Immunohistochemical analysis revealed segment-specific alterations induced by the ischemic insult. Grx2, Prx3, and Prx6 were highly expressed in proximal tubule cells. Overexpression of these proteins in HEK293 and HeLa cells subjected to hypoxia and reoxygenation revealed higher survival and proliferation rates and lower oxidative damage compared to controls. Furthermore, we report for the first time the accumulation of Grx1 at the apical side of distal convoluted cells and the specific secretion of Grx1 into the urine after IR. The differences in both the basal equipment and the segment-specific responses of the antioxidant proteins may contribute to the distinct susceptibilities and regeneration processes of the various segments of the nephron to the IR insult. PMID- 21586324 TI - Putative roles of cilia in polycystic kidney disease. AB - The last 10 years has witnessed an explosion in research into roles of cilia in cystic renal disease. Cilia are membrane-enclosed finger-like projections from the cell, usually on the apical surface or facing into a lumen, duct or airway. Ten years ago, the major recognised functions related to classical "9+2" cilia in the respiratory and reproductive tracts, where co-ordinated beating clears secretions and assists fertilisation respectively. Primary cilia, which have a "9+0" arrangement lacking the central microtubules, were anatomical curiosities but several lines of evidence have implicated them in both true polycystic kidney disease and other cystic renal conditions: ranging from the homology between Caenorhabditis elegans proteins expressed on sensory cilia to mammalian polycystic kidney disease (PKD) 1 and 2 proteins, through the discovery that orpk cystic mice have structurally abnormal cilia to numerous recent studies wherein expression of nearly all cyst-associated proteins has been reported in the cilia or its basal body. Functional studies implicate primary cilia in mechanosensation, photoreception and chemosensation but it is the first of these which appears most important in polycystic kidney disease: in the simplest model, fluid flow across the apical surface of renal cells bends the cilia and induces calcium influx, and this is perturbed in polycystic kidney disease. Downstream effects include changes in cell differentiation and polarity. Pathways such as hedgehog and Wnt signalling may also be regulated by cilia. These data support important roles for cilia in the pathogenesis of cystic kidney diseases but one must not forget that the classic polycystic kidney disease proteins are expressed in several other locations where they may have equally important roles, such as in cell-cell and cell-matrix interactions, whilst it is not just aberrant cilia signalling that can lead to de-differentiation, loss of polarity and other characteristic features of polycystic kidney disease. Understanding how cilia fit into the other aspects of polycystic kidney disease biology is the challenge for the next decade. This article is part of a Special Issue entitled: Polycystic Kidney Disease. PMID- 21586323 TI - Nox2 B-loop peptide, Nox2ds, specifically inhibits the NADPH oxidase Nox2. AB - In recent years, reactive oxygen species (ROS) derived from the vascular isoforms of NADPH oxidase, Nox1, Nox2, and Nox4, have been implicated in many cardiovascular pathologies. As a result, the selective inhibition of these isoforms is an area of intense current investigation. In this study, we postulated that Nox2ds, a peptidic inhibitor that mimics a sequence in the cytosolic B-loop of Nox2, would inhibit ROS production by the Nox2-, but not the Nox1- and Nox4-oxidase systems. To test our hypothesis, the inhibitory activity of Nox2ds was assessed in cell-free assays using reconstituted systems expressing the Nox2-, canonical or hybrid Nox1-, or Nox4-oxidase. Our findings demonstrate that Nox2ds, but not its scrambled control, potently inhibited superoxide (O(2)(* )) production in the Nox2 cell-free system, as assessed by the cytochrome c assay. Electron paramagnetic resonance confirmed that Nox2ds inhibits O(2)(*-) production by Nox2 oxidase. In contrast, Nox2ds did not inhibit ROS production by either Nox1- or Nox4-oxidase. These findings demonstrate that Nox2ds is a selective inhibitor of Nox2-oxidase and support its utility to elucidate the role of Nox2 in organ pathophysiology and its potential as a therapeutic agent. PMID- 21586325 TI - Donor or recipient TNF-A -308G/A polymorphism and acute rejection of renal allograft: A meta-analysis. AB - BACKGROUND: Results from published studies on the association of donor or recipient TNF-A -308G/A polymorphism with acute rejection (AR) of renal allograft are inconsistent. We performed a meta-analysis to summarize the possible association. METHODS: Studies were identified by searching PUBMED, EMBASE and Chinese National Knowledge Infrastructure (CNKI) databases until March 22, 2011. Meta-analysis was performed in a fixed/random-effect model using Revman 5.0.25 and STATA10.0. RESULTS: Eight studies evaluating the association between donor TNF-A -308G/A polymorphism and acute rejection of renal allograft were identified. Pooled OR based on 460 cases (whose recipient developed AR) and 623 controls (whose recipient did not develop AR) was 1.44 (95% CI=1.05-1.99, p=0.03). No association was detected in the subgroup analysis based on ethnicity. 28 studies evaluating the association between recipient TNF-A -308G/A polymorphism and acute rejection were identified. Pooled OR based on 1411 cases (patients did not develop AR) and 2088 controls was 1.39 (95% CI=1.06-1.82, p=0.02). Two studies evaluating the association between recipient TNF-A -308G/A polymorphism and recurrent acute rejection were identified. Pooled OR based on 225 cases (patients with <=1 AR) and 34 controls (patients with >=2 AR) was 0.28 (95% CI=0.13-0.62, p=0.002). CONCLUSIONS: Our meta-analysis provided evidence that TNF2 allele positive genotype of donor or recipient was associated with increased risk of incidence of acute rejection of renal allograft. Recipient TNF2 allele positive genotype is also associated with increased risk of recurrence of acute rejection of renal allograft. However, additional studies with large sample size and better study designs are warranted to verify our finding. PMID- 21586326 TI - Production of recombinant peptides as fusions with SUMO. AB - Recombinant production of non-native peptides requires using protein fusion technology to prevent peptide degradation by host-cell proteases. In this work, we have used SUMO protein as a fusion partner for the production of difficult-to express, antimicrobial, self-assembling and amyloidogenic peptides using Escherichia coli. SUMO-peptide fusions were expressed as intracellular products by utilizing pET based expression vectors constructed by Life Sensors Inc., USA. Histidine tagged SUMO-peptide fusions were purified using Ni-NTA affinity chromatography. Complete (100%) cleavage of the SUMO-peptide fusion was achieved using SUMO protease-1. Our findings demonstrate that SUMO fusion technology is a promising alternative for production of peptides in E. coli. The key advantage of this technology is that the enzymatic activity of SUMO protease-1 is specific and efficient leading to inexpensive costs for cleaving the peptide fusion when compared with other fusion systems. PMID- 21586327 TI - Orientation dependency of intrinsic optical signal dynamics in cat area 18. AB - Imaging studies based on intrinsic optical signals have been primarily performed by analyses of the signal amplitude as opposed to using the temporal information of the intrinsic optical signals. The present study focused on the dynamics of these signals in cat area 18, and quantitatively compared the waveforms after presentation of different stimuli across the same cortical regions. Optical imaging based on intrinsic signals was conducted on 18 hemispheres of 9 cats. For the visual stimuli, gratings with orientations that changed from horizontal (0 degrees ) to 157.5 degrees in 22.5 degrees steps were used. The signal time course was examined at each pixel, with the peak delay defined as the amount of time required after the stimulus onset for the intrinsic optical signal to reach its negative maximum. In the area that showed significant orientation preference to 0 degrees and 90 degrees but not to their 22.5 degrees separated nearby angles, the delays were 1.92 +/- 0.22s and 1.99 +/- 0.29s (mean +/- SE, n = 18), respectively. Delays of 2.31 +/- 0.20s and 2.28 +/- 0.25s were observed in the cortical areas that selectively responded to the orientation gratings of 45 degrees and 135 degrees but not their nearby angles. Statistically, the delays in areas exhibiting oblique orientation preferences were significantly longer than those showing cardinal orientation preferences. These results demonstrate anisotropy for the intrinsic optical signal dynamics in the cat area 18. The possible neural mechanisms underlying were discussed. PMID- 21586328 TI - Prospects for quantitative fMRI: investigating the effects of caffeine on baseline oxygen metabolism and the response to a visual stimulus in humans. AB - Functional magnetic resonance imaging (fMRI) provides an indirect reflection of neural activity change in the working brain through detection of blood oxygenation level dependent (BOLD) signal changes. Although widely used to map patterns of brain activation, fMRI has not yet met its potential for clinical and pharmacological studies due to difficulties in quantitatively interpreting the BOLD signal. This difficulty is due to the BOLD response being strongly modulated by two physiological factors in addition to the level of neural activity: the amount of deoxyhemoglobin present in the baseline state and the coupling ratio, n, of evoked changes in blood flow and oxygen metabolism. In this study, we used a quantitative fMRI approach with dual measurement of blood flow and BOLD responses to overcome these limitations and show that these two sources of modulation work in opposite directions following caffeine administration in healthy human subjects. A strong 27% reduction in baseline blood flow and a 22% increase in baseline oxygen metabolism after caffeine consumption led to a decrease in baseline blood oxygenation and were expected to increase the subsequent BOLD response to the visual stimulus. Opposing this, caffeine reduced n through a strong 61% increase in the evoked oxygen metabolism response to the visual stimulus. The combined effect was that BOLD responses pre- and post caffeine were similar despite large underlying physiological changes, indicating that the magnitude of the BOLD response alone should not be interpreted as a direct measure of underlying neurophysiological changes. Instead, a quantitative methodology based on dual-echo measurement of blood flow and BOLD responses is a promising tool for applying fMRI to disease and drug studies in which both baseline conditions and the coupling of blood flow and oxygen metabolism responses to a stimulus may be altered. PMID- 21586329 TI - Distinct anatomy for visual search and bisection: a neuroimaging study. AB - Individuals with spatial neglect following brain injury often show biased performance on landmark bisection tasks (judging if a single item is transected at its midpoint) and search tasks (where they seek target(s) from an array of items). Interestingly, it appears that bisection deficits dissociate from other measures of neglect (including search tasks), and neglect patients with bisection deficits typically have more posterior injury than those without these symptoms. While previous studies in healthy adults have examined each of these tasks independently, our aim was to directly contrast brain activity between these two tasks. Our design used displays that were interpreted as landmark bisection stimuli in some blocks of trials and as search arrays on other trials. Therefore, we used a design where low-level perceptual and motor responses were identical across tasks. Both tasks generated significant activity in bilateral midfusiform gyrus, largely right lateralized activity in the posterior parietal cortex, left lateralized activity in the left motor cortex (consistent with right handed response) and generally right lateralized insular activation. Several brain areas showed task-selective activations when the two tasks were directly compared. Specifically, the superior parietal cortex was selectively activated during the landmark task. On the other hand, the search task caused stronger bilateral activation in the anterior insula, along with midfusiform gyrus, medial superior frontal areas, thalamus and right putamen. This work demonstrates that healthy adults show an anatomical dissociation for visual search and bisection behavior similar to that reported in neurological patients, and provides coordinates for future brain stimulation studies. PMID- 21586330 TI - Neuronal correlates of altered empathy and social cognition in borderline personality disorder. AB - Borderline personality disorder (BPD) is a severe psychiatric condition of undetermined brain underpinnings, which involves profound emotion regulation deficits and interpersonal impairment. To elucidate biopsychological markers of the disorder, we performed two studies: i.) assessing empathy and social cognition and ii.) measuring the psychophysical properties and functional brain correlates of empathic functioning in a total of fifty-one affected patients and 50 age- and gender-matched controls. In the behavioral study we applied the Multifaceted Empathy Test (MET), a new, ecologically valid measure to assess cognitive (i.e., social cognition) and emotional (i.e., empathic concern) empathy to a subset of participants. In the second study, functional Magnetic Resonance Imaging and skin conductance measurements were performed while participants took a scanner-adapted version of the MET. Patients with BPD showed impairments in cognitive and emotional empathy. Brain responses during cognitive empathy were significantly reduced in patients compared to controls in the left superior temporal sulcus and gyrus (STS/STG), where this reduction was associated with levels of intrusive symptomatology in the BPD group. During emotional empathy, patients with BPD exhibited greater brain activity than controls in the right middle insular cortex, a response that was associated with skin conductance responses in the patients. Results indicate that altered functioning of the STS/STG and insula represents pathophysiological mediators for reduced empathy in BPD, with an important role for intrusive symptomatology and levels of arousal. The findings thus support a conceptualization of BPD as involving deficits in both inferring others' mental states and being emotionally attuned to another person. PMID- 21586331 TI - Functional community analysis of brain: a new approach for EEG-based investigation of the brain pathology. AB - Analysis of structure of the brain functional connectivity (SBFC) is a fundamental issue for understanding of the brain cognition as well as the pathology of brain disorders. Analysis of communities among sub-parts of a system is increasingly used for social, ecological, and other networks. This paper presents a new methodology for investigation of the SBFC and understanding of the brain based on graph theory and community pattern analysis of functional connectivity graph of the brain obtained from encephalograms (EEGs). The methodology consists of three main parts: fuzzy synchronization likelihood (FSL), community partitioning, and decisions based on partitions. As an example application, the methodology is applied to analysis of brain of patients with attention deficit/hyperactivity disorder (ADHD) and the problem of discrimination of ADHD EEGs from healthy (non-ADHD) EEGs. PMID- 21586332 TI - Stereotype-based modulation of person perception. AB - A core social-psychological question is how cultural stereotypes shape our encounters with other people. While there is considerable evidence to suggest that unexpected targets-such as female airline pilots and male nurses-impact the inferential and memorial aspects of person construal, it has yet to be established if early perceptual operations are similarly sensitive to the stereotype-related status of individuals. To explore this issue, the current investigation measured neural activity while participants made social (i.e., sex categorization) and non-social (i.e., dot detection) judgments about men and women portrayed in expected and unexpected occupations. When participants categorized the stimuli according to sex, stereotype-inconsistent targets elicited increased activity in cortical areas associated with person perception and conflict resolution. Comparable effects did not emerge during a non-social judgment task. These findings begin to elucidate how and when stereotypic beliefs modulate the formation of person percepts in the brain. PMID- 21586333 TI - Intelligence and cortical thickness in children with complex partial seizures. AB - Prior studies on healthy children have demonstrated regional variations and a complex and dynamic relationship between intelligence and cerebral tissue. Yet, there is little information regarding the neuroanatomical correlates of general intelligence in children with epilepsy compared to healthy controls. In vivo imaging techniques, combined with methods for advanced image processing and analysis, offer the potential to examine quantitative mapping of brain development and its abnormalities in childhood epilepsy. A surface-based, computational high resolution 3-D magnetic resonance image analytic technique was used to compare the relationship of cortical thickness with age and intelligence quotient (IQ) in 65 children and adolescents with complex partial seizures (CPS) and 58 healthy controls, aged 6-18 years. Children were grouped according to health status (epilepsy; controls) and IQ level (average and above; below average) and compared on age-related patterns of cortical thickness. Our cross sectional findings suggest that disruption in normal age-related cortical thickness expression is associated with intelligence in pediatric CPS patients both with average and below average IQ scores. PMID- 21586334 TI - Pretransplantation liver function impacts on the outcome of allogeneic hematopoietic stem cell transplantation: a study of 455 patients. AB - Liver dysfunction is frequent before allogeneic stem cell transplantation (allo SCT). However, its characteristics and impact on transplantation outcomes are uncertain, especially in the reduced-intensity conditioning (RIC) setting. We analyzed 455 patients receiving an allo-SCT in 3 Spanish centers. Pretransplantation aspartate aminotransferase (AST), alanine aminotransaminase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), total bilirubin, and international normalized ratio were analyzed. Pretransplantation liver function test abnormalities were found in 94 (22%) patients. The most frequent cause of pretransplantation liver dysfunction was isolated elevation of GGT/AP (n = 49, 53%). Patients with high bilirubin levels before allo-SCT showed higher 4-year nonrelapse mortality (4y-NRM) (hazard ratio [HR] 2 [95% confidence interval [CI] 1.1-3.8] P = .02) and patients with high GGT levels showed higher 100-day NRM and lower 4-year overall survival (OS) (HR 3.4 [95% CI 1.8-6.7] P < .001, and HR 2 [95% CI 1.4-3], P = .001), respectively. High levels of transaminases did not influence on survival or mortality. In conclusion, hepatic dysfunction before allo-SCT is frequent and has an impact on transplantation outcomes. The best indicator of liver dysfunction still has to be determined. PMID- 21586335 TI - The expression of REG 1A and REG 1B is increased during acute amebic colitis. AB - Entamoeba histolytica, a protozoan parasite, is an important cause of diarrhea and colitis in the developing world. Amebic colitis is characterized by ulceration of the intestinal mucosa. We performed microarray analysis of intestinal biopsies during acute and convalescent amebiasis in order to identify genes potentially involved in tissue injury or repair. Colonic biopsy samples were obtained from 8 patients during acute E. histolytica colitis and again 60 days after recovery. Gene expression in the biopsies was evaluated using microarray, and confirmed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). REG 1A and REG 1B were the most up-regulated of all genes in the human intestine in acute versus convalescent E. histolytica disease: as determined by microarray, the levels of induction were 7.4-fold and 10.7 fold for REG 1A and B; p=0.003 and p=0.006 respectively. Increased expression of REG 1A and REG 1B protein in the colonic crypt epithelial cells during acute amebiasis was similarly observed by immunohistochemistry. Because REG 1 protein is anti apoptotic and pro-proliferative, and since E. histolytica induces apoptosis of the intestinal epithelium as part of its disease process, we next tested if REG 1 might be protective during amebiasis by preventing parasite-induced apoptosis. Intestinal epithelial cells from REG 1-/- mice were found to be more susceptible to spontaneous, and parasite-induced, apoptosis in vitro (p=0.03). We concluded that REG 1A and REG 1B were upregulated during amebiasis and may function to protect the intestinal epithelium from parasite-induced apoptosis. PMID- 21586337 TI - Multi-linear regression models predict the effects of water chemistry on acute lead toxicity to Ceriodaphnia dubia and Pimephales promelas. AB - The current study examined the acute toxicity of lead (Pb) to Ceriodaphnia dubia and Pimephales promelas in a variety of natural waters. The natural waters were selected to range in pertinent water chemistry parameters such as calcium, pH, total CO(2) and dissolved organic carbon (DOC). Acute toxicity was determined for C. dubia and P. promelas using standard 48h and 96h protocols, respectively. For both organisms acute toxicity varied markedly according to water chemistry, with C. dubia LC50s ranging from 29 to 180MUg/L and P. promelas LC50s ranging from 41 to 3598MUg/L. Additionally, no Pb toxicity was observed for P. promelas in three alkaline natural waters. With respect to water chemistry parameters, DOC had the strongest protective impact for both organisms. A multi-linear regression (MLR) approach combining previous lab data and the current data was used to identify the relative importance of individual water chemistry components in predicting acute Pb toxicity for both species. As anticipated, the P. promelas best-fit MLR model combined DOC, calcium and pH. Unexpectedly, in the C. dubiaMLR model the importance of pH, TCO(2) and calcium was minimal while DOC and ionic strength were the controlling water quality variables. Adjusted R(2) values of 0.82 and 0.64 for the P. promelas and C. dubia models, respectively, are comparable to previously developed biotic ligand models for other metals. PMID- 21586338 TI - Chemoprotection of lipoic acid against microcystin-induced toxicosis in common carp (Cyprinus carpio, Cyprinidae). AB - This paper evaluated the chemoprotective effect of lipoic acid (LA) against microcystin (MC) toxicity in carp Cyprinus carpio. To determine the LA dose and the time necessary for the induction of three different classes (alpha, mu and pi) of glutathione S-transferase (GST) gene transcription, carp were i.p. injected with 40mg/kg lipoic acid solution. A group was killed 24h after the first i.p. injection (condition 1); another group received two i.p. injections with a 24h of interval between each one and was killed 48h after the first injection (condition 2) and a third group received one i.p. injection and was killed 48h latter (condition 3). Results showed that LA was effective in promoting an increase in GSTs gene transcription in liver only in the condition 2. A second experiment was done, where carp pre-treated with LA (condition 2) were gavaged twice with a 24h interval with 50MUg MC/kg. Ninety-six hours after experiment beginning, carp were killed, and organs were dissected. Results of GST activity in liver and brain suggest that LA can be a useful chemoprotection agent against MC induced toxicity, stimulating detoxification through the increment of GST activity (brain) or through reversion of GST inhibition (liver). PMID- 21586339 TI - Involvement of profilin-1 in angiotensin II-induced vascular smooth muscle cell proliferation. AB - Profilin-1, a regulator of actin polymerization, has recently been linked to vascular hypertrophy and remodeling. Whether profilin-1 is involved in angiotensin (Ang) II-induced proliferation of vascular smooth muscle cells leading to vascular remodeling in hypertension remains unclear. The present study was designed to analyze the correlation of profilin-1 and vascular remodeling during hypertension and to evaluate the role of profilin-1 in proliferation of vascular smooth muscle cells and the underlying mechanisms. The vascular morphology and the expression of profilin-1 in arterial tissues of spontaneously hypertensive rats and Wistar-Kyoto rats were assessed. The profilin-1 expression was significantly increased concomitantly with definite vascular remodeling by evaluating the media thickness, lumen diameter, media thickness-to-lumen diameter ratio and mean nuclear area in artery media in spontaneously hypertensive rats, which was inhibited by treatment with losartan. In cultured rat aortic smooth muscle cells (RASMCs), Ang II induced profilin-1 expression in a dose- and time dependent manner. Knockdown of profilin-1 using small hairpin RNA inhibited Ang II-induced proliferation of RASMCs. Moreover, blockade of JAK2/STAT3 signaling pathway also inhibited Ang II-induced proliferation of RASMCs and profilin-1 expression. These results suggest that profilin-1 mediates the proliferation of RASMCs induced by Ang II via activation of Ang II type 1 receptor/JAK2/STAT3 signaling pathway, which may contribute to vascular remodeling in hypertension. PMID- 21586336 TI - Retinyl ester hydrolases and their roles in vitamin A homeostasis. AB - In mammals, dietary vitamin A intake is essential for the maintenance of adequate retinoid (vitamin A and metabolites) supply of tissues and organs. Retinoids are taken up from animal or plant sources and subsequently stored in form of hydrophobic, biologically inactive retinyl esters (REs). Accessibility of these REs in the intestine, the circulation, and their mobilization from intracellular lipid droplets depends on the hydrolytic action of RE hydrolases (REHs). In particular, the mobilization of hepatic RE stores requires REHs to maintain steady plasma retinol levels thereby assuring constant vitamin A supply in times of food deprivation or inadequate vitamin A intake. In this review, we focus on the roles of extracellular and intracellular REHs in vitamin A metabolism. Furthermore, we will discuss the tissue-specific function of REHs and highlight major gaps in the understanding of RE catabolism. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. PMID- 21586340 TI - Myoferlin gene silencing decreases Tie-2 expression in vitro and angiogenesis in vivo. AB - Angiogenesis consists in the growth of new blood vessels from pre-existing ones. Although anti-angiogenesis interventions have been shown to have therapeutic properties in human diseases such as cancer, their effect is only partial and the identification of novel modulators of angiogenesis is warranted. Recently, we reported the unexpected proteomic identification in endothelial cells (EC) of Myoferlin, a member of the Ferlin family of transmembrane proteins. Ferlins are well known to regulate the fusion of lipid vesicles at the plasma membrane in muscle cells, and we showed that Myoferlin gene knockdown not only decreases lipid vesicle fusion in EC but also attenuates Vascular Endothelial Growth Factor (VEGF) Receptor-2 (VEGFR-2) expression. Herein, we show that Myoferlin gene silencing in cultured EC also results in attenuated expression of a second tyrosine kinase receptor, Tie-2, which is another well-described angiogenic receptor. Most importantly, we provide evidence that delivery of a low-volume Myoferlin siRNA preparation in mouse tissues results in attenuated angiogenesis and edema formation. This provides the first evidence that acute Myoferlin knockdown has anti-angiogenic effects and validates Myoferlin as an anti angiogenesis target. Furthermore, this supports the unexpected but increasingly accepted concept that proper tyrosine kinase receptors expression at the plasma membrane requires Myoferlin. PMID- 21586341 TI - A comparison of temporary self-expanding plastic and biodegradable stents for refractory benign esophageal strictures. AB - BACKGROUND & AIMS: It is a challenge to manage refractory benign esophageal strictures (RBES). We compared the efficacy and safety of self-expanding plastic stents (SEPSs) with placement of biodegradable stents for the treatment of RBES. METHODS: We studied 2 groups of consecutive patients with RBES who received temporary placement (6 weeks) of SEPSs (n = 20) or biodegradable stents (n = 18). Data were collected with respect to clinical outcome, complications, recurrent dysphagia, and reinterventions. RESULTS: SEPSs were removed in 16 (80%) patients. Stent placement was not successful in 1 patient, while stent removal was not performed in another 3 patients. Six (30%) patients with an SEPS were dysphagia free after a median follow-up of 385 days (range, 77-924 days). Ten (50%) developed recurrent dysphagia. Major complications occurred in 2 patients (10%; 1 with hemorrhage and 1 with perforation). Six patients (33%) with a biodegradable stent were dysphagia-free after a median follow-up of 166 days (range 21-559 days) (P = .83 compared with SEPS). Twelve patients (67%) had recurrent dysphagia. Major complications occurred in 4 patients (22%; 2 with hemorrhage, 2 with severe retrosternal pain) with a biodegradable stent (P = .30 compared with SEPS). Reinterventions were less frequently indicated after biodegradeble stent than after SEPS placement (15 [mean, 0.8 +/- 0.6 per stent placed] vs 21 [mean, 1.3 +/- 0.4 per stent placed], respectively; P = .03). CONCLUSIONS: Placement of SEPSs or biodegradable stents provides long-term relief of dysphagia in 30% and 33%, respectively, of patients with RBES. Biodegradable stents require fewer procedures than SEPSs, offering an advantage. Although stent placement is a viable strategy in patients with RBES, the ideal strategy still needs to be defined. PMID- 21586342 TI - Efficacy of Sevikar(r) compared to the combination of perindopril plus amlodipine on central arterial blood pressure in patients with moderate-to-severe hypertension: Rationale and design of the SEVITENSION study. AB - BACKGROUND AND RATIONALE: To date, few studies have investigated the effects of combined renin-angiotensin system blockade/calcium channel blockade on central aortic blood pressure. The Conduit Artery Function Evaluation (CAFE) sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) investigated the effects of amlodipine/perindopril and atenolol/bendroflumethiazide on central aortic blood pressure (CABP). Similar brachial blood pressure levels were achieved; however, there was a significant difference, in favor of the amlodipine/perindopril combination, on the effects of CABP. No study has investigated the effects of a combination of an angiotensin receptor blocker/calcium channel blocker compared to those of a calcium channel blocker/angiotensin-converting enzyme inhibitor combination. To confirm and support previous findings, the SEVITENSION study will assess the effects on CABP of treatment with the high dose combination of perindopril plus amlodipine as used in ASCOT-CAFE compared with the high dose combination of olmesartan/amlodipine in patients with moderate-to-severe hypertension uncontrolled on amlodipine monotherapy. OBJECTIVE: To demonstrate non-inferiority of fixed-dose olmesartan/amlodipine combination therapy compared with the combination of perindopril plus amlodipine on the mean change from baseline in central aortic systolic blood pressure. DESIGN: A multicenter, double blind, parallel-group, non-inferiority study comprising a 2-4-week open-label run in period with amlodipine and a 24-week active treatment period. CABP will be measured by the SphygmoCor(r) Vx Pulse Wave Velocity System. PATIENTS: 720 moderate-to-severe hypertensive patients aged >= 40 to <= 80 years and >= 3 additional risk factors will be enrolled. INTERVENTIONS: Study treatment will comprise orally-administered combination of olmesartan/amlodipine (40/10mg) or perindopril (8 mg) plus amlodipine (10mg), and matching placebos. (EudraCT number: 2009-012966-30; ClinicalTrials.gov identifier: NCT01101009). PMID- 21586343 TI - TLRs, macrophages, and NK cells: our understandings of their functions in uterus and ovary. AB - Inflammation involves multiple changes in many aspects of immune system. Interactions between immune system and female reproductive system strongly impact fertility and reproductive health in general. Many normal events of female reproduction system including ovulation, menstruation, implantation and labor onset are considered as inflammatory process. Emerging evidence reveals that three components of immune system that are critical to initiate and resolve inflammation, Toll-like receptors (TLRs), macrophages, and natural killer (NK) cells, play important roles not only to provide protection against infections by exogenous pathogens but also to regulate essential functions of uterus and ovary. This review will briefly summarize our understanding of the functions of TLRs, macrophages and NK cells in uterus and ovary. PMID- 21586344 TI - TLRs as pharmacological targets for plant-derived compounds in infectious and inflammatory diseases. AB - Toll-like receptors (TLRs) are generally involved in host immune responses against microbial invasions. Dysfunction of TLRs is closely related to infectious and inflammatory diseases, for which therapeutic manipulation with TLRs agonists and antagonists represent a promising drug strategy. Medicinal plants were used traditionally for the prevention and treatment of infectious and inflammatory diseases. Active compounds derived from these plants were also found with unique features as TLRs agonists and antagonists. These findings bring about new hopes for the application of these naturally existed TLRs modulators. They also provide evidences encouraging further research work of continued characterization for these compounds, which will become promising drug candidates in TLRs-based therapy in the future. PMID- 21586345 TI - Fluorofenidone inhibits Ang II-induced apoptosis of renal tubular cells through blockage of the Fas/FasL pathway. AB - OBJECTIVES: The present study was designed to investigate the inhibitory effects of fluorofenidone on Ang II-induced apoptosis in renal tubular cells and the related signaling pathway. METHODS: Rat proximal tubular epithelial cells (NRK 52E) were used to examine the anti-apoptosis effects of fluorofenidone. Cell proliferation was assessed by methyl thiazolyl tetrazolium assay. Apoptosis was examined by AO/EB staining and TUNEL assay. The expression of Fas/FasL pathway members, including Fas, FasL, Bax, Bcl-2, Caspase-8, and Caspase-3 was detected by real-time RT-PCR and/or Western blot, respectively. The activity of Caspase-8 and Caspase-3 was detected by spectrophotometry. RESULTS: Fluorofenidone didn't affect the proliferation of NRK-52E cells, but significantly inhibited the apoptosis of NRK-52E cells induced by Ang II. Fluorofenidone significantly reduced Ang II-induced increases in Fas, FasL, Bax, Caspase-8 and Caspase-3 at the mRNA level. Consistent with these observations, fluorofenidone also prevented Ang II-mediated up-regulation of FasL and Bax at the protein level. Additionally, Ang II-induced activation of Caspase-8 and Caspase-3 as well as Ang II-initiated downregulation of Bcl-2 at both mRNA and protein levels was all prevented by fluorofenidone. CONCLUSIONS: Fluorofenidone can inhibit Ang II-induced apoptosis of renal tubular cells through blockage of the Fas/FasL pathway. PMID- 21586346 TI - Modulation of the mitochondrial permeability transition by cyclophilin D: moving closer to F(0)-F(1) ATP synthase? AB - Cyclophilin D was recently shown to mask an inhibitory site of the mitochondrial permeability transition pore (PTP) for phosphate, and to constitutively bind F(0) F(1) ATP synthase resulting in the slowing of ATP synthesis and hydrolysis rates, thus regulating matrix adenine nucleotide levels. Here we review the striking similarities of the factors affecting the threshold for PTP induction, to those affecting binding of phosphate to formerly proposed sides on F(1)-ATPase affecting ATP hydrolytic activity, including critical arginine residues, matrix pH, [Mg(2+)], adenine nucleotides and proton motive force. Based on these similarities, we scrutinize the hypothesis that in depolarized mitochondria exhibiting reversal of F(0)-F(1) ATP synthase operation, the genetic ablation of cyclophilin D or its inhibition by cyclosporin A results in accelerated proton pumping by ATP hydrolysis, opposing a further decrease in membrane potential and promoting high matrix phosphate levels, both negatively affecting the probability of PTP opening. PMID- 21586347 TI - The roles of phosphate and the phosphate carrier in the mitochondrial permeability transition pore. AB - Phosphate activation of the mitochondrial permeability transition pore (MPTP) opening is well-documented and could involve the phosphate carrier (PiC) that we have proposed is the pore's cyclophilin-D binding component. However, others have reported that following CyP-D ablation Pi inhibits MPTP opening while cyclosporine-A (CsA) inhibits MPTP opening only when Pi is present. Here we demonstrate that Pi activates MPTP opening under all energised and de-energised conditions tested while CsA inhibits pore opening whether or not Pi is present. Using siRNA in HeLa cells we could reduce PiC expression by 65-80% but this inhibited neither mitochondrial calcium accumulation nor MPTP opening. PMID- 21586349 TI - Characterization of the single-stranded DNA binding protein pV(VGJPhi) of VGJPhi phage from Vibrio cholerae. AB - pV(VGJPhi), a single-stranded DNA binding protein of the vibriophage VGJPhi was subject to biochemical analysis. Here, we show that this protein has a general affinity for single-stranded DNA (ssDNA) as documented by Electrophoretic Mobility Shift Assay (EMSA). The apparent molecular weight of the monomer is about 12.7kDa as measured by HPLC-SEC. Moreover, isoelectrofocusing showed an isoelectric point for pV(VGJPhi) of 6.82 pH units. Size exclusion chromatography in 150mM NaCl, 50mM sodium phosphate buffer, pH 7.0 revealed a major protein species of 27.0kDa, suggesting homodimeric protein architecture. Furthermore, pV(VGJPhi) binds ssDNA at extreme temperatures and the complex was stable after extended incubation times. Upon frozen storage at -20 degrees C for a year the protein retained its integrity, biological activity and oligomericity. On the other hand, bioinformatics analysis predicted that pV(VGJPhi) protein has a disordered C-terminal, which might be involved in its functional activity. All the aforementioned features make pV(VGJPhi) interesting for biotechnological applications. PMID- 21586348 TI - Mitochondrial DNA variation in human metabolic rate and energy expenditure. AB - The role of climate in driving selection of mtDNA as Homo sapiens migrated out of Africa into Eurasia remains controversial. We evaluated the role of mtDNA variation in resting metabolic rate (RMR) and total energy expenditure (TEE) among 294 older, community-dwelling African and European American adults from the Health, Aging and Body Composition Study. Common African haplogroups L0, L2 and L3 had significantly lower RMRs than European haplogroups H, JT and UK with haplogroup L1 RMR being intermediate to these groups. This study links mitochondrial haplogroups with ancestry-associated differences in metabolic rate and energy expenditure. PMID- 21586350 TI - New proteomic developments to analyze protein isomerization and their biological significance in plants. AB - Spontaneous isoaspartyl formation from aspartyl dehydration or asparaginyl deamidation is a major source of modifications in protein structures. In cells, these conformational changes could be reverted by the protein L-isoaspartyl methyltransferase (PIMT) repair enzyme that converts the isoaspartyl residues into aspartyl. The physiological importance of this metabolism has been recently illustrated in plants. Recent developments allowing peptide isomer identification and quantification at the proteome scale are portrayed. The relevance of these new proteomic approaches based on 2-D electrophoresis or electron capture dissociation analysis methods was initially documented in mammals. Extended use to Arabidopsis model systems is promising for the discovery of controlling mechanisms induced by these particular post-translational modifications and their biological role in plants. PMID- 21586351 TI - Dr Bhatt is considered one of the experts on the role of antiplatelet and anticoagulant therapy in ACS. Foreword. PMID- 21586352 TI - Anticoagulant agents in acute coronary syndromes. AB - There has been substantial interest in novel antiplatelet therapies; yet, despite a growing number of studies with novel anticoagulants, there have been few comprehensive reviews summarizing the data for anticoagulants in acute coronary syndromes. Large-scale trials have demonstrated the efficacy of novel procedural anticoagulants, such as selective Factor-Xa inhibitors and direct thrombin inhibitors. Moreover, with as many as 10% of patients with non-ST-segment elevation acute coronary syndrome experiencing recurrent ischemia or death in the first 30 days, there is continued interest in oral anticoagulants. The purpose of this review is to synthesize the evidence for current anticoagulants, including heparins and more recent Factor Xa inhibitors and direct thrombin inhibitors, as well as oral anticoagulants and newer agents in later phases of clinical testing. PMID- 21586353 TI - Pharmacology of purine and pyrimidine receptors. Preface. PMID- 21586354 TI - The structure of the adenosine receptors: implications for drug discovery. AB - Extracellular adenosine mediates most of its physiological effects via an interaction with four G protein-coupled receptors (GPCRs), the adenosine receptors (ARs). These ARs are important pharmacological targets in the treatment of a wide variety of diseases from central nervous system disorders to ischemic injury. As for other GPCRs, drug development for the ARs has been hampered by the lack of structural data for this class of membrane proteins. However, in the past 3 years, this situation has changed with the elucidation of structures for the turkey beta(1)-adrenoceptor, the human beta(2)-adrenoceptor, squid rhodopsin, the activated form of bovine (rhod)opsin, the human adenosine A(2A) receptor, and most recently the CXCR4 chemokine receptor. In this review, the structural features of the human adenosine A(2A) receptor will be discussed with a particular focus on the ligand binding site. Further, the implications of this structural information for AR ligand selectivity, drug screening, homology modeling, and virtual ligand screening will be discussed. PMID- 21586355 TI - Adenosine receptors in health and disease. AB - The adenosine receptors A(1), A(2A), A(2B), and A(3) are important and ubiquitous mediators of cellular signaling, which play vital roles in protecting tissues and organs from damage. In particular, adenosine triggers tissue protection and repair by different receptor-mediated mechanisms, including an increase of oxygen supply/demand ratio, preconditioning, anti-inflammatory effects, and stimulation of angiogenesis. Considerable advances have been recently achieved in the pharmacological and molecular characterization of adenosine receptors, which have been proposed as targets for drug design and discovery. At the present time, it can be speculated that adenosine A(1), A(2A), A(2B), and A(3) receptor-selective ligands may show utility in the treatment of pain, ischemic conditions, glaucoma, asthma, arthritis, cancer, and other disorders in which inflammation is a feature. This chapter documents the present state of knowledge of adenosine receptors' role in health and disease. PMID- 21586356 TI - Adenosine and the regulation of metabolism and body temperature. AB - Adenosine levels are increased under conditions of energy deprivation, both because intracellular energy stores are reduced and because ATP is released. The adenosine thus formed can serve to influence energy homeostasis in a number of different ways, besides alterations in blood supply and cellular work (including contraction, maintenance of membrane potential, and biosynthesis), which will be covered in other chapters. Here, effects on energy homeostasis will be briefly reviewed. Adenosine acting at the A(1) receptor is a powerful and nonredundant inhibitor of lipolysis. It increases glucose uptake in fat and muscle, but its effects on insulin secretion may be even more important than the actions at insulin target tissues. Glucagon is also influenced. In addition to these peripheral actions, adenosine acts in the brain to regulate sleep-wakefulness, food intake, and body temperature. These effects are both direct at the relevant neurons and indirect by influences on regulatory transmitters and hormones. PMID- 21586357 TI - Regulation of leukocyte function by adenosine receptors. AB - The immune system responds to cues in the microenvironment to make acute and chronic adaptations in response to inflammation and injury. Locally produced purine nucleotides and adenosine provide receptor-mediated signaling to all bone marrow derived cells of the immune system to modulate their responses. This review summarizes recent advances in our understanding of the effects of adenosine signaling through G protein-coupled adenosine receptors on cells of the immune system. Adenosine A(2A) receptors (A(2A)Rs) have a generally suppressive effect on the activation of immune cells. Moreover, their transcription is strongly induced by signals that activate macrophages or dendritic cells through toll-like receptors, or T cells through T cell receptors. A(2A)R induction is responsible for producing a gradual dissipation of inflammatory responses. A(2A)R activation is particularly effective in limiting the activation of invariant NKT (iNKT) cells that play a central role in acute reperfusion injury. A(2A) agonists have clinical promise for the treatment of vaso-occlusive tissue injury. Blockade of A(2A) receptors may be useful to enhance immune-mediated killing of cancer cells. A(2B)R expression also is transcriptionally regulated by hypoxia, cytokines, and oxygen radicals. Acute A(2B)R activation attenuates the production of proinflammatory cytokines from macrophages, but sustained activation facilitates macrophage and dendritic cell remodeling and the production of acute phase proteins and angiogenic factors that may participate in evoking insulin resistance and tissue fibrosis. A(2B)R activation also influences macrophage and neutrophil function by influencing expression of the anti-inflammatory netrin receptor, UNC5B. The therapeutic significance of adenosine-mediated effects on the immune system is discussed. PMID- 21586359 TI - Interplay of hypoxia and A2B adenosine receptors in tissue protection. AB - That adenosine signaling can elicit adaptive tissue responses during conditions of limited oxygen availability (hypoxia) is a long-suspected notion that recently gained general acceptance from genetic and pharmacologic studies of the adenosine signaling pathway. As hypoxia and inflammation share an interdependent relationship, these studies have demonstrated that adenosine signaling events can be targeted to dampen hypoxia-induced inflammation. Here, we build on the hypothesis that particularly the A(2B) adenosine receptor (ADORA(2B)) plays a central role in tissue adaptation to hypoxia. In fact, the ADORA(2B) requires higher adenosine concentrations than any of the other adenosine receptors. However, during conditions of hypoxia or ischemia, the hypoxia-elicited rise in extracellular adenosine is sufficient to activate the ADORA(2B). Moreover, several studies have demonstrated very robust induction of the ADORA(2B) elicited by transcriptional mechanisms involving hypoxia-dependent signaling pathways and the transcription factor "hypoxia-induced factor" 1. In the present chapter, genetic and pharmacologic evidence is presented to support our hypothesis of a tissue protective role of ADORA(2B) signaling during hypoxic conditions, including hypoxia-elicited vascular leakage, organ ischemia, or acute lung injury. All these disease models are characterized by hypoxia-elicited tissue inflammation. As such, the ADORA(2B) has emerged as a therapeutic target for dampening hypoxia-induced inflammation and tissue adaptation to limited oxygen availability. PMID- 21586358 TI - Role of adenosine A(2B) receptors in inflammation. AB - Recent progress in our understanding of the unique role of A(2B) receptors in the regulation of inflammation, immunity, and tissue repair was considerably facilitated with the introduction of new pharmacological and genetic tools. However, it also led to seemingly conflicting conclusions on the role of A(2B) adenosine receptors in inflammation with some publications indicating proinflammatory effects and others suggesting the opposite. This chapter reviews the functions of A(2B) receptors in various cell types related to inflammation and integrated effects of A(2B) receptor modulation in several animal models of inflammation. It is argued that translation of current findings into novel therapies would require a better understanding of A(2B) receptor functions in diverse types of inflammatory responses in various tissues and at different points of their progression. PMID- 21586361 TI - Molecular mechanisms of purine and pyrimidine nucleotide release. AB - Given the widespread importance of purinergic receptor-evoked signaling, understanding how ATP and other nucleotides are released from cells in a regulated manner is an essential physiological question. Nonlytic release of ATP, UTP, UDP-glucose, and other nucleotides occurs in all cell types and tissues via both constitutive mechanisms, that is, in the absence of external stimuli, and to a greater extent in response to biochemical or mechanical/physical stimuli. However, a molecular understanding of the processes regulating nucleotide release has only recently begun to emerge. It is generally accepted that nucleotide release occurs in two different scenarios, exocytotic release from the secretory pathway or via conductive/transport mechanisms, and a critical review of our current understanding of these mechanisms is presented in this chapter. PMID- 21586362 TI - Impact of ectoenzymes on p2 and p1 receptor signaling. AB - P2 receptors that are activated by extracellular nucleotides (e.g., ATP, ADP, UTP, UDP, Ap(n)A) and P1 receptors activated by adenosine control a diversity of biological processes. The activation of these receptors is tightly regulated by ectoenzymes that metabolize their ligands. This review presents these enzymes as well as their roles in the regulation of P2 and P1 receptor activation. We focus specifically on the role of ectoenzymes in processes of our interest, that is, inflammation, vascular tone, and neurotransmission. An update on the development of ectonucleotidase inhibitors is also presented. PMID- 21586360 TI - Allosteric modulation of purine and pyrimidine receptors. AB - Among the purine and pyrimidine receptors, the discovery of small molecular allosteric modulators has been most highly advanced for the A(1) and A(3) adenosine receptors (ARs). These AR modulators have allosteric effects that are structurally separated from the orthosteric effects in SAR studies. The benzoylthiophene derivatives tend to act as allosteric agonists as well as selective positive allosteric modulators (PAMs) of the A(1) AR. A 2-amino-3 aroylthiophene derivative T-62 has been under development as a PAM of the A(1) AR for the treatment of chronic pain. Several structurally distinct classes of allosteric modulators of the human A(3) AR have been reported: 3-(2 pyridinyl)isoquinolines, 2,4-disubstituted quinolines, 1H-imidazo-[4,5-c]quinolin 4-amines, endocannabinoid 2-arachidonylglycerol, and the food dye Brilliant Black BN. Site-directed mutagenesis of A(1) and A(3) ARs has identified residues associated with the allosteric effect, distinct from those that affect orthosteric binding. A few small molecular allosteric modulators have been reported for several of the P2X ligand-gated ion channels and the G protein coupled P2Y receptor nucleotides. Metal ion modulation of the P2X receptors has been extensively explored. The allosteric approach to modulation of purine and pyrimidine receptors looks promising for development of drugs that are event and site specific in action. PMID- 21586364 TI - P2X receptors in health and disease. AB - Seven P2X receptor subunits have been cloned which form functional homo- and heterotrimers. These are cation-selective channels, equally permeable to Na(+) and K(+) and with significant Ca(2+) permeability. The three-dimensional structure of the P2X receptor is described. The channel pore is formed by the alpha-helical transmembrane spanning region 2 of each subunit. When ATP binds to a P2X receptor, the pore opens within milliseconds, allowing the cations to flow. P2X receptors are expressed on both central and peripheral neurons, where they are involved in neuromuscular and synaptic neurotransmission and neuromodulation. They are also expressed in most types of nonneuronal cells and mediate a wide range of actions, such as contraction of smooth muscle, secretion, and immunomodulation. Changes in the expression of P2X receptors have been characterized in many pathological conditions of the cardiovascular, gastrointestinal, respiratory, and urinogenital systems and in the brain and special senses. The therapeutic potential of P2X receptor agonists and antagonists is currently being investigated in a range of disorders, including chronic neuropathic and inflammatory pain, depression, cystic fibrosis, dry eye, irritable bowel syndrome, interstitial cystitis, dysfunctional urinary bladder, and cancer. PMID- 21586365 TI - Molecular pharmacology, physiology, and structure of the P2Y receptors. AB - The P2Y receptors are a widely expressed group of eight nucleotide-activated G protein-coupled receptors (GPCRs). The P2Y(1)(ADP), P2Y(2)(ATP/UTP), P2Y(4)(UTP), P2Y(6)(UDP), and P2Y(11)(ATP) receptors activate G(q) and therefore robustly promote inositol lipid signaling responses. The P2Y(12)(ADP), P2Y(13)(ADP), and P2Y(14)(UDP/UDP-glucose) receptors activate G(i) leading to inhibition of adenylyl cyclase and to Gbetagamma-mediated activation of a range of effector proteins including phosphoinositide 3-kinase-gamma, inward rectifying K(+) (GIRK) channels, phospholipase C-beta2 and -beta3, and G protein-receptor kinases 2 and 3. A broad range of physiological responses occur downstream of activation of these receptors ranging from Cl(-) secretion by epithelia to aggregation of platelets to neurotransmission. Useful structural models of the P2Y receptors have evolved from extensive genetic analyses coupled with molecular modeling based on three-dimensional structures obtained for rhodopsin and several other GPCRs. Selective ligands have been synthesized for most of the P2Y receptors with the most prominent successes attained with highly selective agonist and antagonist molecules for the ADP-activated P2Y(1) and P2Y(12) receptors. The widely prescribed drug, clopidogrel, which results in irreversible blockade of the platelet P2Y(12) receptor, is the most important therapeutic agent that targets a P2Y receptor. PMID- 21586363 TI - Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity. AB - Evolving studies in models of transplant rejection, inflammatory bowel disease, and cancer, among others, have implicated purinergic signaling in clinical manifestations of vascular injury and thrombophilia, inflammation, and immune disturbance. Within the vasculature, spatial and temporal expression of CD39 nucleoside triphosphate diphosphohydrolase (NTPDase) family members together with CD73 ecto-5'-nucleotidase control platelet activation, thrombus size, and stability. This is achieved by closely regulated phosphohydrolytic activities to scavenge extracellular nucleotides, maintain P2-receptor integrity, and coordinate adenosinergic signaling responses. The CD38/CD157 family of extracellular NADases degrades NAD(+) and generates Ca(2+)-active metabolites, including cyclic ADP ribose and ADP ribose. These mediators regulate leukocyte adhesion and chemotaxis. These mechanisms are crucial in vascular homeostasis, hemostasis, thrombogenesis, and during inflammation. There has been recent interest in ectonucleotidase expression by immune cells. CD39 expression identifies Langerhans-type dendritic cells and efficiently distinguishes T regulatory cells from other resting or activated T cells. CD39, together with CD73 in mice, serves as an integral component of the suppressive machinery of T cells. Purinergic responses also impact generation of T helper-type 17 cells. Further, CD38 and changes in NAD(+) availability modulate ADP ribosylation of the cytolytic P2X7 receptor that deletes T regulatory cells. Expression of CD39, CD73, and CD38 ectonucleotidases on either endothelial or immune cells allows for homeostatic integration and control of vascular inflammatory and immune cell reactions at sites of injury. Ongoing development of therapeutic strategies targeting these and other ectonucleotidases offers promise for the management of vascular thrombosis, disordered inflammation, and aberrant immune reactivity. PMID- 21586366 TI - P2Y receptors in health and disease. AB - The purine- and pyrimidine-sensitive P2Y receptors belong to the large group of G protein-coupled receptors that are the target of approximately one-third of the pharmaceutical drugs used in the clinic today. It is therefore not unexpected that the P2Y receptors could be useful targets for drug development. This chapter will discuss P2Y receptor-based therapies currently used, in development and possible future developments. The platelet inhibitors blocking the ADP-receptor P2Y(12) reduce myocardial infarction, stroke, and mortality in patients with cardiovascular disease. Clopidogrel (Plavix) was for many years the second most selling drug in the world. The improved P2Y(12) inhibitors prasugrel, ticagrelor, and elinogrel are now entering the clinic with even more pronounced protective effects. The UTP-activated P2Y(2) receptor stimulates ciliary movement and secretion from epithelial cells. Cystic fibrosis is a monogenetic disease where reduced chloride ion secretion results in a severe lung disease and early death. No specific treatment has been available, but the P2Y(2) agonist Denufosol has been shown to improve lung function and is expected to be introduced as treatment for cystic fibrosis soon. In preclinical studies, there are indications that P2Y receptors can be important for diabetes, osteoporosis, cardiovascular, and atherosclerotic disease. In conclusion, P2Y receptors are important for the health of humans for many diseases, and we can expect even more beneficial drugs targeting P2Y receptors in the future. PMID- 21586367 TI - P2 receptor signaling in neurons and glial cells of the central nervous system. AB - Purine and pyrimidine nucleotides are extracellular signaling molecules in the central nervous system (CNS) leaving the intracellular space of various CNS cell types via nonexocytotic mechanisms. In addition, ATP is a neuro-and gliotransmitter released by exocytosis from neurons and neuroglia. These nucleotides activate P2 receptors of the P2X (ligand-gated cationic channels) and P2Y (G protein-coupled receptors) types. In mammalians, seven P2X and eight P2Y receptor subunits occur; three P2X subtypes form homomeric or heteromeric P2X receptors. P2Y subtypes may also hetero-oligomerize with each other as well as with other G protein-coupled receptors. P2X receptors are able to physically associate with various types of ligand-gated ion channels and thereby to interact with them. The P2 receptor homomers or heteromers exhibit specific sensitivities against pharmacological ligands and have preferential functional roles. They may be situated at both presynaptic (nerve terminals) and postsynaptic (somatodendritic) sites of neurons, where they modulate either transmitter release or the postsynaptic sensitivity to neurotransmitters. P2 receptors exist at neuroglia (e.g., astrocytes, oligodendrocytes) and microglia in the CNS. The neuroglial P2 receptors subserve the neuron-glia cross talk especially via their end-feets projecting to neighboring synapses. In addition, glial networks are able to communicate through coordinated oscillations of their intracellular Ca(2+) over considerable distances. P2 receptors are involved in the physiological regulation of CNS functions as well as in its pathophysiological dysregulation. Normal (motivation, reward, embryonic and postnatal development, neuroregeneration) and abnormal regulatory mechanisms (pain, neuroinflammation, neurodegeneration, epilepsy) are important examples for the significance of P2 receptor-mediated/modulated processes. PMID- 21586368 TI - Role of purinergic receptors in CNS function and neuroprotection. AB - The purinergic receptor family contains some of the most abundant receptors in living organisms. A growing body of evidence indicates that extracellular nucleotides play important roles in the regulation of neuronal and glial functions in the nervous system through purinergic receptors. Nucleotides are released from or leaked through nonexcitable cells and neurons during normal physiological and pathophysiological conditions. Ionotropic P2X and metabotropic P2Y purinergic receptors are expressed in the central nervous system (CNS), participate in the synaptic processes, and mediate intercellular communications between neuron and gila and between glia and other glia. Glial cells in the CNS are classified into astrocytes, oligodendrocytes, and microglia. Astrocytes express many types of purinergic receptors, which are integral to their activation. Astrocytes release adenosine triphosphate (ATP) as a "gliotransmitter" that allows communication with neurons, the vascular walls of capillaries, oligodendrocytes, and microglia. Oligodendrocytes are myelin-forming cells that construct insulating layers of myelin sheets around axons, and using purinergic receptor signaling for their development and for myelination. Microglia also express many types of purinergic receptors and are known to function as immunocompetent cells in the CNS. ATP and other nucleotides work as "warning molecules" especially by activating microglia in pathophysiological conditions. Studies on purinergic signaling could facilitate the development of novel therapeutic strategies for disorder of the CNS. PMID- 21586370 TI - [Longevity: a chance for everybody]. PMID- 21586371 TI - [On frailty as a geriatric concept]. AB - Frailty as a geriatric concept has been considered as the beginning of a rapid downward spiral towards death. Nevertheless, the French word "fragilite" is different from frailty - and probably an erroneous translation. Furthermore, frailty can be considered as belonging to the human condition as such. PMID- 21586369 TI - Short-Term Effects of Nitrogen Dioxide on Mortality and Susceptibility Factors in 10 Italian Cities: The EpiAir Study. AB - BACKGROUND: Several studies have shown an association between nitrogen dioxide (NO2) and mortality. In Italy, the EpiAir multicentric study, "Air Pollution and Health: Epidemiological Surveillance and Primary Prevention," investigated short term health effects of air pollution, including NO2. OBJECTIVES: To study the individual susceptibility, we evaluated the association between NO2 and cause specific mortality, investigating individual sociodemographic features and chronic/acute medical conditions as potential effect modifiers. METHODS: We considered 276,205 natural deaths of persons > 35 years of age, resident in 10 Italian cities, and deceased between 2001 and 2005. We chose a time-stratified case-crossover analysis to evaluate the short-term effects of NO2 on natural, cardiac, cerebrovascular, and respiratory mortality. For each subject, we collected information on sociodemographic features and hospital admissions in the previous 2 years. Fixed monitors provided daily concentrations of NO2, particulate matter <= 10 MUm in aerodynamic diameter (PM10) and ozone (O3). RESULTS: We found statistically significant associations with a 10-MUg/m3 increase of NO2 for natural mortality [2.09% for lag 0-5; 95% confidence interval (CI), 0.96-3.24], for cardiac mortality (2.63% for lag 0-5; 95% CI, 1.53-3.75), and for respiratory mortality (3.48% for lag 1-5; 95% CI, 0.75-6.29). These associations were independent from those of PM10 and O3. Stronger associations were estimated for subjects with at least one hospital admission in the 2 previous years and for subjects with three or more specific chronic conditions. Some cardiovascular conditions (i.e., ischemic heart disease, pulmonary circulation impairment, heart conduction disorders, heart failure) and diabetes appeared to confer a strong susceptibility to air pollution. CONCLUSIONS: Our results suggest significant and likely independent effects of NO2 on natural, cardiac, and respiratory mortality, particularly among subjects with specific cardiovascular preexisting chronic conditions and diabetes. PMID- 21586372 TI - [Adverse effects of the herd immunity or when childhood vaccination becomes deleterious for the epidemiology of infectious diseases in adults]. AB - The irremediable ageing of the world population, the aged-related increasing in the prevalence of infectious diseases the fear of any influenza pandemic rife have recently led the European Union Geriatric Medicine Society (EUGMS) et the International Association of Geriatric and Gerontology European Regions (IAGG-ER) of establishing vaccine recommendations dedicated to individuals aged of 60 years or above and promoting a life-course vaccination programme. This approach is mainly motivated by the herd immunity-associated effect on the epidemiology of infectious diseases observed within the adult and old adult population. This review (1) after a presentation of the concept and its demonstrated beneficial effects; (2) will detail that herd immunity acts with adverse effects on the epidemiology of the infectious diseases in the adult and aged individual population; (3) in order to demonstrate that maintaining a vaccine pressure in every age groups is imperative. PMID- 21586374 TI - [Adherence and persistence in elderly subjects]. AB - Persistence and adherence describe complementary aspects of the medication. Persistence is defined as the duration of treatment intake, and compliance as the quality of drug intake in all its dimensions (dosage, frequency, regularity, duration). Their respect is to improve the benefit-risk medication. The prescription must be accompanied in the elderly of quality information and the development of assistive devices and human resources. PMID- 21586373 TI - [Oropharyngeal candidiasis in elderly patients]. AB - Oropharyngeal candidiasis is a common opportunistic infection of the oral cavity caused by an overgrowth of candida species, the commonest being Candida albicans. The prevalence in the hospital or institution varies from 13 to 47% of elderly persons. The main clinical types are denture stomatitis, acute atrophic glossitis, thrush and angular cheilitis. Diagnosis is usually made on clinical ground. Culture and sensitivity testing should be undertaken if initial therapy is unsuccessful. Predisposing factors of oral candidiasis could be local and/or systemic. Local factors include wearing dentures, impaired salivary gland function and poor oral health. Systemic factors include antibiotics and some other drugs, malnutrition, diabetes, immunosuppression and malignancies. Management involves an appropriate antifungal treatment and oral hygiene. Predisposing factors should be treated or eliminated where feasible. Oral hygiene involves cleaning the teeth and dentures. Dentures should be disinfected daily and left out overnight. PMID- 21586375 TI - [Adequacy between prescriptions and CHADS(2) score recommendations in geriatric patients]. AB - Atrial fibrillation (AF) is a major risk factor for stroke. Thromboprophylaxis with anticoagulant reduces the incidence of stroke and is warranted by the CHADS(2) recommendations when score >=2. But such therapy remains underused particularly among elderly patients. The aim of our study was to evaluate the adequacy between prescriptions and CHADS(2) recommendations in geriatric hospitalised patients with AF. METHOD: retrospective study set in the Geriatrics Department of the University hospital of Poitiers (France), of patients >75 y with AF, between July and December 2009. The description of the patients taken into the count: epidemiological data, functional daily activities (score GIR), cognitive assessment, antithrombotic treatment, and evaluation of the CHADS(2) and HEMORR(2)HAGES scores. RESULTS: in this study161 hospitalisations were analysed, mean age of the patients was 87.4 +/- 5.4 years. Antithrombotic treatment was prescribed in 84% of cases. The overall conformity to CHADS(2) recommendations was 44%. Most of hospitalisations (88.9%) included patients with CHADS(2) score >=2. Non-conformity rate was up to 60% in this group with 5 significant variables: MMSE score <26 (OR: 3.17 [95%IC: 1.23-8.17]), high risk of bleeding (2.88 [1.28-6.47]), dementia (2.46 [1.01-5.95]), functional impairment (GIR score <=4) (2.43 [1.23-4.84]) and history of fall (2.42 [1.13-5.17]). Still, the variables explained only 19% of the non-conform prescriptions and no variable was significantly relevant on multivariate analysis. DISCUSSION: our study show 56% of prescriptions that are non-conform to CHADS(2) recommendations, particularly in the elderly with a predictive embolic score >= 2. Antithrombotic treatment seems to be all the less conform as patients appear to be more vunerable. Due to the new score CHA(2)DS(2)-VASc, physicians really have to discuss the benefit-risk balance at an individual level. PMID- 21586376 TI - [Promoting factors of laryngeal penetrations in elderly]. AB - BACKGROUND: Swallowing disorders are common among elderly patients. Laryngeal penetration is among the most serious complications, resulting in airway obstruction, aspiration pneumonia or pneumonitis. Early diagnosis is therefore very important. OBJECTIVE: The main objective of this study is to identify factors associated with anamnestic and clinical onset of laryngeal penetration. METHODOLOGY: The study population is constituted of 127 consecutive patients hospitalized in our geriatric department. All following parameters were assessed: the patient's home, the reason for hospitalization, the medical history, treatment, anthropometric and biological parameters (nutritional status), a comprehensive geriatric assessment, a speech-language ability assessment and water swallow test according to DePippo method. All these parameters were correlated with the outcome of nasopharyngeal endoscopy. RESULTS: A total of 127 patients (mean age of 84 +/- 5 years) (average score of MMSE of 22) were evaluated. Most of them came from their home. The mean values of the Katz and Lawton scales were 9 +/- 5.5 and 27 +/- 8, respectively. About two third of patients had mood disorders (GDS > 1). A laryngeal penetration was present in 44% of cases. It occurred more frequently in patients taking neuroleptics, in those with a history of stroke, in case of extra-pyramidal syndrome or when the MMSE was pathological. The temporo-spatial disorientation, the presence of a salivary flow, the inability to perform adequately the different items of the speech language evaluation and the failure to achieve proper water swallowing test were also related to the presence of laryngeal penetrations. With multivariate analysis, after adjusting for all significant variables, abnormal water swallowing test (P = 0.0002, OR 13) emerged as the sole independent parameter associated with laryngeal penetrations. CONCLUSION: Laryngeal penetration is associated with hospital mortality and impaired geriatric status. It could thus represent a marker of the overall frailty. In a frail geriatric population, the water-swallowing test helps to identify patients at risk of laryngeal penetration. PMID- 21586377 TI - [Assessment of inappropriate prescribing in the elderly subject during acute care hospitalisation]. AB - OBJECTIVE: Inappropriate prescribing in elderly is considered as common (40% of subjects from community from the 3CStudy in France had a inappropriate prescription, using Beer's criteria), and can lead to severe issues. Few studies have assessed inappropriate prescribing for elderly inpatients in acute care, with multiple tools. Our study was designed to assess outcome prescriptions concordance of elderly inpatients, for potentially inappropriate medication use. METHODS: A retrospective study based on a random sample of 170 inpatients in 2009 was performed at Nantes University Hospital. We used standardized tools, especially general prescriptions rules of the "College professionnel des geriatres francais", Beers's criteria, the Anticholinergic Risk Scale, concordance for renal function, and search for medication with tight therapeutic edge. RESULTS: Mean age of inpatients was 85.2 +/- 4.1 years. Median numbers of prescribing drugs was eight. General prescriptions rules were followed up to 90% of inpatients: no forbidden drug-drug interaction was found. However, more than two psychotropic medications were prescribed for 3.9% of inpatients. At least one drug listed in Beers's criteria were found for 41 (27.0%) inpatients: amiodarone (18 inpatients) and long-term benzodiazepines (seven inpatients). A medication from the anticholinergic risk scale was found for 28 subjects (18.6%): however, for only seven of them, the score was higher than 3. Concordance for renal function was required for 126 inpatients (82.9%) for at least one prescription, 9 (7.1%) patients have a medication overdose according to their renal impairment. Medications with tight therapeutic edge were prescribed for 52 subjects (34.2%): mostly oral anticoagulants (27 subjects). In 15 cases, the dose was underneath the recommended level. CONCLUSION: Some potentially inappropriate medication uses were revealed by our study. It is essential to spread out results for clinicians, for a better knowledge of these risks. PMID- 21586378 TI - [Evaluation of circadian variation of blood pressure by ambulatory blood pressure monitoring in an elderly diabetic population with or without orthostatic hypotension]. AB - Orthostatic hypotension is frequently observed in the elderly population and has been previously identified as a significant risk factor for increased mortality. The link between this condition and increased mortality could be due to an abnormal circadian pattern of blood pressure. The absence of a physiological nocturnal decrease in blood pressure is termed the non-dipping pattern. This abnormality is relatively frequent in elderly people suffering from orthostatic hypotension, but its prevalence in the diabetic geriatric population is unknown. The purpose of this study is to compare blood pressure profiles on ambulatory blood pressure monitoring (ABPM) in a sample of elderly diabetic subjects suffering from orthostatic hypotension with those without postural hypotension. One hundred and ninety-eight patients were recruited by mail. The presence or absence of orthostatic hypotension was determined. They all subsequently underwent ABPM. One hundred and thirty-one of our subjects (68%) suffered from orthostatic hypotension; of these, 76% had a non-dipping pattern on ABPM, compared with 74% of the subjects not suffering from orthostatic hypotension (P = NS). This study thus demonstrates the high prevalence of orthostatic hypotension in an elderly diabetic population. On the other hand, we could not demonstrate a correlation between the non-dipping pattern and the presence of orthostatic hypotension. This is in contrast with previous work done in a non-diabetic elderly population. Further studies are needed to determine the effect of diabetes on blood pressure. PMID- 21586379 TI - [A thematic review on the topic of emotions and their disorders in the elderly]. PMID- 21586380 TI - [What is an emotion? An introduction to the study of emotions]. AB - Human emotions are hypothetic constructs based on psychological and physiological data. According to the psychoevolutionnist theories, all emotions derive from a set of discrete basic emotions, common to human and animals, genetically determined. Basic emotions are thus considered as physiological processes based on specific neuronal circuits. On the contrary, for appraisal and social theories, emotions are psychological processes resulting from the cognitive appraisal of the stimulus-event for the well-being and objectives of the subject, and are of social origin. They develop during life, especially in childhood, from interactions between the individual and his environement. According to the appraisal or constructivist theories, no sharp distinction is to be made between emotions and other manifestations of the affective life. Emotions require the global functioning of the brain, even if more specialized regions are involved. They play a fundamental role in the development of the child's psychological and social life. They mediate the subject's response to the stimulus-event, allowing more appropriate reactions than fixed instinctive ones. Nevertheless, the adaptative function of every emotion or their every component can be questioned. Emotional disturbances are major consequences of psychiatric or neurological disorders. The link between the results of neuropsychological studies of emotions based on the recognition of emotional facal expression according to the basic emotion theory, and the emotional disturbances experienced in daily life is highly questionable on account of the high complexity of human affective life. PMID- 21586381 TI - [Transient Epileptic Amnesia: a case report and a reappraisal]. AB - Transient Epileptic Amnesia is a late-onset form of temporal lobe epilepsy characterized by recurrent attacks of transient retrograde and anterograde amnesia usually lasting less than one hour and beginning in late-middle to old age. Attacks commonly occur on waking, a potentially helpful diagnostic clue. The amnesic attacks may be associated with persistent memory complaints. The diagnosis is made on the basis of the clinical history, wake or sleep - deprived EEG (often repeated) and/or a clear - cut response to anticonvulsivant therapy. The pathophysiology remains poorly understood. It is uncertain whether recurrent episodes of amnesia represent ictal or post-ictal phenomena. PMID- 21586382 TI - [Support for patients with Alzheimer's disease and their caregivers by gerontechnology]. AB - The increasing number of people suffering from Alzheimer's disease raises the question of their caring at home, especially when the disease causes disability and negative consequences in daily life such as isolation, falls, wandering, errors in drug taking. Furthermore, caregivers bear a substantial burden that can have adverse effects on their physical and mental health. New technologies of information could play an additional role as care providers without substituting family or professional caregivers help. A review of literature focused on the different technological solutions conceived for patients suffering from Alzheimer's disease and their carers shows that these appliances could help to provide reminders in daily life (drugs, tasks and appointments, meals cooking), to activate residual cognitive resources by computerized cognitive stimulation intervention, to reduce stress, anxiety and depressive symptoms in patients by visual contact with families and professionals (webconference), to contribute to patients safety by detecting falls and wandering, and to help families in the caring of patients with computerized information and counselling interventions. We also discuss the current limitations for a widespread use of these technologies and outline future research avenues. True needs of end-users are still poorly known and should be more clearly defined. Simplicity of the use of these appliances should be further improved. Demonstration of medical and social benefits for elderly people should be carried out in randomized, controlled studies. Ethical reflexion should be developed in conjunction with the use of these gerontechnologies. Finally, the economical model which would enable the providing of these appliances to the largest number of patients and caregivers should be implemented. Although these gerontechnologies are promising, research is still needed to tailor them properly to the needs of end-users, assess their benefit in ecological context of people with Alzheimer's disease in order to provide them with appropriate tools in daily life. PMID- 21586384 TI - [Autonomy and dementia]. AB - In the course of centuries, the value of autonomy has been greatly emphasized, though the content of the concept has varied. Between various meanings it has taken, which one does allow to retain it amongst the care objectives as long as possible during the dementia process? A critical examination of the philosophical and medico-social literature shows that the different meanings of autonomy can be organized according to two poles. The first one, the canonical one, is the most usual, and regards autonomy as a matter of internal competences of the subject (such as rationality, reflexivity, memory). Subjects with dementia are therefore more or less rapidly excluded from the access to autonomy. The second one is relational and refers to external conditions. Do the relationships, the institutions in which the demented person is included, and the policies on which he depends allow him the opportunity to act autonomously? In this meaning, others people are considered as a potential resource to identify the goals and means appropriate for the subject. Therefore, this relational pole recognises the possibility for the demented subject to be longer autonomous than according to the canonical pole because his autonomy does not depend only on himself but on all those who care for him directly or indirectly. In this meaning, he can exercise his autonomy in more domains. PMID- 21586383 TI - [Glioblastoma in the elderly]. AB - The incidence of malignant gliomas is growing in the elderly population. Unfortunately, increasing age is one of the most important negative prognostic factors for gliomas, and the optimal management of this population remains largely unsettled because older patients are often excluded from clinical trials. However, the former nihilistic approach is progressively changing towards more active strategies. Indeed prospective randomized studies have recently established the benefit of radiotherapy and the validity of an accelerated course of irradiation in older patients suffering from malignant gliomas. The interest of debulking surgery remains still unknown in this population, and the interest of chemotherapy, alone or concomitant with radiotherapy is still under evaluation. Symptomatic treatments such as corticosteroids and antiepileptic drugs may be less tolerated in the elderly compared to younger patients and should be used only if requered. Initial performance status, quality of life and concomitant pathologies are obviously important factors to consider before treatment onset. The willingness of the patient and his caregivers will also be a key for the therapeutic decision. In the future, specific schedules of treatment in the elderly should be developed, and prospective randomized clinical trials are needed to improve the pattern of care of malignant gliomas in this population. PMID- 21586385 TI - [Assessment of sociocognitive functions in neurological patients Presentation of a French adaptation of two tools and implementation in frontal dementia]. AB - This paper presents a French battery designed to assess emotional and sociocognitive abilities in neurological patients in clinical practice. The first part of this battery includes subtests assessing emotions: a recognition task of primary facial emotions, a discrimination task of facial emotions, a task of expressive intensity judgment, a task of gender identification, a recognition task of musical emotions. The second part intends to assess some sociocognitive abilities, that is mainly theory of mind (attribution tasks of mental states to others: false believe tasks of first and second order, faux-pas task) and social norms (moral/conventional distinction task, social situations task) but also abstract language and humour. We present a general description of the battery with special attention to specific methodological constraints for the assessment of neurological patients. After a brief introduction to moral and conventional judgments (definition and current theoretical basis), the French version of the social norm task from RJR Blair (Blair and Cipolotti, 2000) is developed. The relevance of these tasks in frontal variant of frontotemporal dementia (fvFTD is illustrated by the report of the results of a study conducted in 18 patients by the Cambridge group and by the personal study of a patient with early stage of vfFTD. The relevance of the diagnostic of sociocognitive impairment in neurological patients is discussed. PMID- 21586386 TI - Computer-assisted update of a consumer health vocabulary through mining of social network data. AB - BACKGROUND: Consumer health vocabularies (CHVs) have been developed to aid consumer health informatics applications. This purpose is best served if the vocabulary evolves with consumers' language. OBJECTIVE: Our objective was to create a computer assisted update (CAU) system that works with live corpora to identify new candidate terms for inclusion in the open access and collaborative (OAC) CHV. METHODS: The CAU system consisted of three main parts: a Web crawler and an HTML parser, a candidate term filter that utilizes natural language processing tools including term recognition methods, and a human review interface. In evaluation, the CAU system was applied to the health-related social network website PatientsLikeMe.com. The system's utility was assessed by comparing the candidate term list it generated to a list of valid terms hand extracted from the text of the crawled webpages. RESULTS: The CAU system identified 88,994 unique terms 1- to 7-grams ("n-grams" are n consecutive words within a sentence) in 300 crawled PatientsLikeMe.com webpages. The manual review of the crawled webpages identified 651 valid terms not yet included in the OAC CHV or the Unified Medical Language System (UMLS) Metathesaurus, a collection of vocabularies amalgamated to form an ontology of medical terms, (ie, 1 valid term per 136.7 candidate n-grams). The term filter selected 774 candidate terms, of which 237 were valid terms, that is, 1 valid term among every 3 or 4 candidates reviewed. CONCLUSION: The CAU system is effective for generating a list of candidate terms for human review during CHV development. PMID- 21586387 TI - [Effect of transgenic insect-resistant rice on biodiversity]. AB - Rice is the most important food crops in maintaining food security in China. The loss of China's annual rice production caused by pests is over ten million tons. Present studies showed that the transgenic insect-resistant rice can substantially reduce the application amount of chemical pesticides. In the case of no pesticide use, the pest density in transgenic rice field is significantly lower than that in non-transgenic field, and the neutral insects and natural enemies of pests increased significantly, indicating that the ecological environment and biodiversity toward the positive direction. The gene flow frequency from transgenic rice is dramatically reduced with the distance increases, reaching less than 0.01% at the distance of 6.2 m. Application of transgenic insect-resistant rice in China has an important significance for ensuring food security, maintaining sustainable agricultural development, and protecting the ecological environment and biodiversity. This review summarized the research progress in transgenic insect-resistant rice and its effect on biodiversity. The research directions and development trends of crop pest controlling in future are discussed. These help to promote better use of transgenic insect-resistant rice. PMID- 21586388 TI - [Description and evaluation of transformation approaches used in wheat]. AB - Genetic transformation is a valuable tool for direct crop improvement and functional genomics study. Unfortunately, wheat is considered as a recalcitrant plant to genetic transformation due to its low efficiency and genotype dependency. To overcome these problems, various transformation methods such as biolistic bombardment, Agrobacterium tumefaciens, pollen-tube pathway, ion implantation, laser microbeams puncture, treatment with polyethylene glycol and ultrasonic wave, and electroporation have been reported in wheat using various types of explants including immature embryos, mature embryos, anthers derived calluses, inflorescences, apical meristems, and other floral organs. In this review, several major transformation approaches and their applications in wheat are reviewed, and potential strategies for the development of safe transgenic wheat plants are discussed. The objective of this review is to provide an update on current status of wheat trans-formation, and to stimulate further research for improving transformation efficiency in wheat. PMID- 21586389 TI - [Transgenic technology and soybean quality improvement]. AB - Soybean is an important source of edible oil, protein and protein diet. The breeding process of high quality soybean can be accelerated via employment of transgenic technology, by which the key genes for soybean quality traits could be directly manipulated. Thus, various soybean varieties could be bred to fulfill different needs for specific consumers. Here, we reviewed the contribution of transgenic technology to improvement of soybean qualities in recent years. We also introduce some newly developed safe transgenic technologies and hope this information could relieve some concerns on the GM food. PMID- 21586390 TI - [Advances on transgene containment technologies]. AB - The biosecurity of transgenic organism has been widely concerned and extremely restricted its application. Recently, many technological strategies have been developed to ensure its biosecurity. Thus, transgene containment technologies have become one of the hotspots in current transgenic research. In this paper, several transgene containment technologies, such as marker-free transgenic technology, safety marker transgenic technology, chloroplast transgenic technologies, terminator technology, male sterility technology, and 'GM-gene deletor'technology were reviewed and evaluated. 'GM-gene-deletor' technology, as one of these technologies, demonstrated a prosperous future for safe application of transgenic organisms. Finally, the strategies for developing new transgene containment technologies have been suggested. PMID- 21586391 TI - [Advances in effects of insecticidal crystal proteins released from transgenic Bt crops on soil ecology]. AB - With the large scale cultivation of transgenic crops expressing Bacillus thuringiensis (Bt) insecticidal crystal proteins in the world, the problem of environmental safety caused by these Bt crops has received extensive attention. These insecticidal crystal proteins can be released into the soil continuously in the growing period of Bt plants. If their accumulation of the insecticidal crystal proteins exceeds consumption by insect larvae and degradation by the environmental factors, these insecticidal crystal proteins could constitute a hazard to non-target insects and soil microbiota. There are three main ways to release insecticidal crystal proteins into soil for Bt plants: root exudates, pollen falling, and crop reside returning. The Bt insecticidal crystal proteins released into soil can be adsorbed rapidly by active soil particles and the absorption equilibrium attained within 1-3 h. The adsorption protects Bt insecticidal crystal proteins against soil microbial degradation or enzyme degradation, which leads to remarkable prolong of the persistence of insecticidal activity. The change of soil microorganism species is an important index for evaluating the effect of Bt plants on soil ecology. The research showed that these insecticidal crystal proteins released by the Bt plant root exudates or Bt organism had no toxicity to the soil earthworms, nematodes, protozoa, bacteria and fungi; however, it could reduce the mycelium length of the arbuscular mycorrhizal fungi (AMF) and restrain AMF to form invasion unit. The influencing degree of Bt protein on soil enzyme activity varied with the releasing modes or growth period of Bt crops. Bt Cry1Ab protein can be taken up from soil by parts of following crops; however, different results were obtained with different commercial kits. To better understand the soil ecological evaluation about the insecticidal crystal proteins released from transgenic Bt crops, this review provides a comprehensive overview about the release, adsorption and residue of Bt insecticidal crystal proteins in soil, as well as their effects on soil protozoa, soil microorganism, soil enzyme activity and following crops. PMID- 21586392 TI - [An update on the development of transgenic animal technology]. AB - The animal transgenic technology has increasingly turned mature over several decades and promoted the research of transgenic technology to a new developmental phase. In this review, various kinds of transgenic technologies, including somatic cell nuclear transfer, gene transfer mediated by transposon, gene knockout mediated by RNA interference, and zinc-finger nucleases-gene targeting technology, are summarized. Recently, the success of induced pluripotent stem cells (iPS cells), which has provided an alternative way to derive pluripotent stem cells of large animals, will extend the field of transgenic animal studies. Here, we summarized the latest trends on the basis of previous studies. In addition, the characteristics of different kinds of transgenic methods in detail are discussed. PMID- 21586393 TI - [Advances of transgenic breeding in livestock]. AB - Transgenic technology represents a revolutionary way to produce elite livestock breeds, allowing introduction of alien gene into livestock genome. Currently, pronuclear microinjection of DNA and somatic cell nuclear transfer are two popular methods used to make transgenic farm animals. Transgenic technology can be used in livestock breeding for improving disease resistance, carcass composition, lactational performance, wool production, growth rate, and reproductive performance, as well as reducing negative environmental impact. In addition to introduction of animal transgenic technologies, this review described the status and the future perspective of transgenic breeding in livestock. PMID- 21586394 TI - [Issues and solutions of conditional gene targeting]. AB - Conditional gene targeting, based on the site-specific recombination system such as Cre-loxP, plays a vital role in the study of gene functions and the generation of disease mouse models. It was always under consideration that there were problems in the Cre-loxP recombination system, such as illegal expression pattern of Cre transgene, variation of Cre recombination efficiency and toxicity of Cre recombinase, as well as the potential influences of genetic background, breeding strategy, experimental control and gene compensation. Oversights of these issues may have a profound influence on the accuracy of gene functional dissection and conditional gene targeting mice phenotypic interpretation. Accordingly, solutions should be adopted including delicate regulative control of temporal-spatial specific Cre expression, detailed detection of Cre recombination efficiency, reduction of Cre toxicity, simplification of mouse genetic background, optimization of breeding, setting up of proper control and combined conditional gene targeting. PMID- 21586395 TI - [Applications of DNA transposons to the study of gene function in mice]. AB - In the past decade, transposon-mediated insertional mutagenesis has been widely used in mammalian molecular genetics. As a convenient and efficient tool for genetic manipulation, transposon has played an important role in making transgenic animal models, performing gene therapy, and annotating gene function at the cellular level and by animal studies in vivo. This review focuses on the structure, function and latest research progress of DNA transposons applied in mouse genetics. PMID- 21586396 TI - [Progress in transgenic fish techniques and application]. AB - Transgenic technique provides a new way for fish breeding. Stable lines of growth hormone gene transfer carps, salmon and tilapia, as well as fluorescence protein gene transfer zebra fish and white cloud mountain minnow have been produced. The fast growth characteristic of GH gene transgenic fish will be of great importance to promote aquaculture production and economic efficiency. This paper summarized the progress in transgenic fish research and ecological assessments. Microinjection is still the most common used method, but often resulted in multi site and multi-copies integration. Co-injection of transposon or meganuclease will greatly improve the efficiency of gene transfer and integration. "All fish" gene or "auto gene" should be considered to produce transgenic fish in order to eliminate misgiving on food safety and to benefit expression of the transferred gene. Environmental risk is the biggest obstacle for transgenic fish to be commercially applied. Data indicates that transgenic fish have inferior fitness compared with the traditional domestic fish. However, be-cause of the genotype-by environment effects, it is difficult to extrapolate simple phenotypes to the complex ecological interactions that occur in nature based on the ecological consequences of the transgenic fish determined in the laboratory. It is critical to establish highly naturalized environments for acquiring reliable data that can be used to evaluate the environ-mental risk. Efficacious physical and biological containment strategies remain to be crucial approaches to ensure the safe application of transgenic fish technology. PMID- 21586397 TI - [Inheritance and expression stability of transgene in transgenic animals]. AB - Transgenic technology is one of the most hotspots in biology. In the past decade, the progress in animal cloning has provided an alternative method to improve transgenic efficiency. Many kinds of transgenic animals have been successfully produced via the combination of transfection and nuclear transfer. However, the ultimate aim of transgenesis is not to produce several transgenic animals, but to service for the needs of human. In animal production, transgenic technology has been used to breed new livestock, which has received a lot of attention in China. It has been evidenced that inheritance and expression instability of transgene in transgenic animals is still the major limitation, which is attributed to position effect, epigenetic modification, and hereditary efficiency of transgene. In this review, we discussed the three points for promoting the industrialization of animal transgenic breeding. PMID- 21586398 TI - [Biological characteristics of defensin and its disease-resistance genetic engineering]. AB - Defensin is a kind of cysteine-rich small peptide, which has a broad spectrum of resistance to bacteria with a special resistance mechanism. So far, a large number of studies on defensins have been reported, and the different types of defensins have been isolated from various organisms. A broad prospect of application on defensins has been displayed both in genetic engineering and medicine field. This article reviewed the classification and the biological characteristics of defensins, including mammalian alpha-, beta-, theta-defensins, insect defensins, and plant defensins. The molecular structures, antibacterial activities, and antibacterial mechanisms of these definsins were summarized. The two mechanisms of de-fensin, including independent membrane mechanism and targeting of intracellular compounds by defensins, are ex-pounded. This paper also summarized the researches on isolation and expression of defensin genes and disease resistance genetic engineering of mammal and plant defensins. A prospect of the future applications of defensin both in biophar-maceutical sciences and plant disease resistance genetic engineering was discussed. PMID- 21586399 TI - [Study on the transgenic tobacco expressing truncated wheat cold shock protein gene TA3-13 and analysis of disease resistance]. AB - TA3-13 is a truncated gene coding for the fragment of wheat (Triticum aestivum L.) cold shock protein WCP1. It has been shown previously that the procaryotically expressed TA3-13 can induce resistance to Tobacco mosaic virus (TMV) when sprayed onto plant leaves. In this study, we constructed an expression vector pB-3-13 by cloning TA3-13 into the bionary vector pBI121 and transformed it into Agrobacterium tumefaciense strain EHA105 via freeze-thaw method. Tobacco (Nicotiana tobacum cv. Xanthi nc.) transformation was performed using the leaf disc infection method. After screening on MS medium containing kanamycin and PCR analysis, 33 T0 plantlets were identified as transgenic. Seeds from twenty T0 plants were collected and planted as T1 lines. Two T1 lines were selected for further characterization. PCR and GUS staining analysis showed that TA3-13 was integrated into the T1 tobacco genome and expressed. When inoculated on leaves, the transgenic tobacco showed significant resistance against TMV and rot pathogen Pectobactrium carotovorum subsp. carotovorum. These results suggest that the expression of TA3-13 in tobacco can induce defense responses to pathogen infection. PMID- 21586400 TI - [Production of porcine blastocysts expressed EGFP by handmade cloning]. AB - Production of transgenic animals via somatic cell nuclear transfer (SCNT) has been widely used worldwide. However, the application of SCNT is impeded by overall high costs and low efficiency. Here, we reported a modification of the existing technology in order to overcome some of the disadvantages associated with SCNT. Firstly, a marker gene, enhanced green fluorescent gene (EGFP), was transfected into pig fetal fibroblast cells, and was subsequently screened by fluorescent expression to ensure donor cells expressing EGFP. Porcine embryos expressing EGFP were then produced by a method called handmade cloning (HMC), a simplified method for micromanipulation. To demonstrate the concept, we collected a total of 378 fresh swine oocytes, from which 266 with the nucleus removed, obtained a total of 127 viable recombinant oocytes after fusion with EGFP expressing cells. In vitro incubation of the 127 recombinant oocytes for approximately 144 hours resulted in successful generation of 65 viable embryos, with an average success rate of 52.1+/-8.3%. Compared with the traditional SCNT, the method of HMC is not only easy to operate, but also increases the rate of recombinant embryo significantly. Furthermore, the modified method no longer relies on expensive instrument like micromanipulator, facilitating the industrialization of transgenic animal production. PMID- 21586401 TI - [The methylation status of PEG10 in placentas of cloned transgenic calves]. AB - The low efficiency of somatic cell nuclear transfer (SCNT) is a significant barrier to the production of highly valuable transgenic livestock. It is generally believed that the principal cause of the low SCNT efficiency is the aberrant nuclear epigenetic reprogramming of donor somatic cell. DNA methylation is a major epigenetic modification of the genome and plays a crucial role in nuclear reprogramming during SCNT. In order to assess whether the abnormal epigenetic modifications of the imprinted gene in placenta are correlated with the development abnormality and death of the cloned transgenic calves, the DNA methylation patterns of PEG10 were compared in the placentas from different kinds of cattle. This comparison included transgenic cloned calves died during perinatal stage and showed developmental defects (Death group), transgenic cloned calves survived and lived on healthily (Live group) and the normal reproduced calves (N group) used as the control group analyzed by Bisulfite Sequencing PCR (BSP) method and Combined Bisulfite Restriction Analy-sis (COBRA). Comparing to the control group, PEG10 gene in the Death group showed abnormal hypermethylation, but was not significant different in methylation level from the Live group. It can be postulated from the results that the incom-plete or abnormal DNA methylation epigenetic reprogramming of imprinting gene in placenta may be one of the main causes of the abnormal development and death of the transgenic cloned cattle. PMID- 21586402 TI - The psychological distress of the young driver: a brief report. AB - The objective of the research was to explore the role of psychological distress in the self-reported risky driving of young novice drivers. A cross-sectional online survey incorporating Kessler's Psychological Distress Scale and the Behaviour of Young Novice Drivers Scale was completed by 761 tertiary students aged 17-25 years with an intermediate (Provisional) driving licence in Queensland, Australia, between August and October 2009. Regression analyses revealed that psychological distress uniquely explained 8.5% of the variance in young novices' risky driving, with adolescents experiencing psychological distress also reporting higher levels of risky driving. Psychological distress uniquely explained a significant 6.7% and 9.5% of variance in risky driving for males and females respectively. Medical practitioners treating adolescents who have been injured through risky behaviour need to be aware of the potential contribution of psychological distress, while mental health professionals working with adolescents experiencing psychological distress need to be aware of this additional source of potential harm. The nature of the causal relationships linking psychological distress and risky driving behaviour are not yet fully understood, indicating a need for further research so that strategies such as screening can be investigated. PMID- 21586403 TI - Readiness for legally literate medical practice? Student perceptions of their undergraduate medico-legal education. AB - Medical councils increasingly require graduates to understand law and to practise medicine mindful of the legal rules. In the UK a revised curriculum for medical law and ethics has been published. However, coverage of law in medical education remains variable and doubts exist about how far students acquire legal knowledge and skills in its implementation. This survey of students in two UK medical schools measured their law learning and their confidence in using this knowledge. Concept maps and a self-audit questionnaire were used to capture students' understanding and perceptions of this knowledge domain and self-assessments of their legal knowledge and skills. A large sample was achieved across first, second and final year students. Students agree that a sound understanding of law is essential to being a good doctor. Their perceptions of law are generally positive but the interface between the legal rules and codes of medical ethics creates difficulty. In some areas students offer relatively confident self assessments of their legal knowledge and skills for practising law. However, levels of confidence in other areas of their law learning raise doubts about the degree to which they can advocate for and protect their patients. Conclusions are drawn about the effectiveness of students' law learning and recommendations made for further research. PMID- 21586404 TI - Retractions in the medical literature: how many patients are put at risk by flawed research? AB - BACKGROUND: Clinical papers so flawed that they are eventually retracted may put patients at risk. Patient risk could arise in a retracted primary study or in any secondary study that draws ideas or inspiration from a primary study. METHODS: To determine how many patients were put at risk, we evaluated 788 retracted English language papers published from 2000 to 2010, describing new research with humans or freshly derived human material. These primary papers-together with all secondary studies citing them-were evaluated using ISI Web of Knowledge. Excluded from study were 468 basic science papers not studying fresh human material; 88 reviews presenting older data; 22 case reports; 7 papers retracted for journal error and 23 papers unavailable on Web of Knowledge. Overall, 180 retracted primary papers (22.8%) met the inclusion criteria. Subjects enrolled and patients treated in 180 primary studies and 851 secondary studies were combined. RESULTS: Retracted papers were cited over 5000 times, with 93% of citations being research related, suggesting that ideas promulgated in retracted papers can influence subsequent research. Over 28 000 subjects were enrolled-and 9189 patients were treated-in 180 retracted primary studies. Over 400 000 subjects were enrolled-and 70 501 patients were treated-in 851 secondary studies which cited a retracted paper. Papers retracted for fraud (n=70) treated more patients per study (p<0.01) than papers retracted for error (n=110). CONCLUSIONS: Many patients are put at risk by retracted studies. These are conservative estimates, as only patients enrolled in published clinical studies were tallied. PMID- 21586405 TI - The social rationale of the gift relationship. AB - This paper argues that, for Richard Titmuss, the rationale of the gift relationship (TGR) as a national blood policy is to reconcile liberty with social justice in the provision of an essential health resource. Underpinned by a needs based distributive principle, TGR provides a social space for a plurality of values in which to engage with and motivate people to voluntarily give blood and other body materials as a common good. This understanding of TGR as a value pluralistic framework and its implications will be used to discuss the issue of using economic mechanisms to increase the supply of body materials or goods, including organs for transplantation. It is argued that, while TGR excludes a policy in which body goods are treated as private commodities and distributed primarily on the basis of achieving market efficiency, it is not in principle opposed to the use of material rewards, including financial ones, to motivate people to donate. PMID- 21586406 TI - Systematic reviews of t'ai chi: an overview. AB - Several systematic reviews (SRs) have assessed the effectiveness of t'ai chi for many conditions including hypertension, osteoarthritis and fall prevention; however, their conclusions have been contradictory. The aim of this overview was to critically evaluate the SRs of t'ai chi for any improvement of medical conditions or clinical symptoms. English, Chinese and Korean electronic databases were searched for relevant articles, and data were extracted according to predefined criteria; 35 SRs met our inclusion criteria. They were related to the following conditions: cancer, older people, Parkinson's disease, musculoskeletal pain, osteoarthritis, rheumatoid arthritis (RA), muscle strength and flexibility, improving aerobic capacity, cardiovascular disease and risk factors, lowering resting blood pressure, osteoporosis or bone mineral density, type 2 diabetes, psychological health, fall prevention and improving balance, and any chronic conditions. In several instances, the conclusions of these articles were contradictory. Relatively clear evidence emerged to suggest that t'ai chi is effective for fall prevention and improving psychological health and was associated with general health benefits for older people. However, t'ai chi seems to be ineffective for the symptomatic treatment of cancer and RA. In conclusion, many SRs of t'ai chi have recently been published; however, the evidence is convincingly positive only for fall prevention and for improvement of psychological health. PMID- 21586407 TI - Advances and challenges in enteral nutrition. PMID- 21586408 TI - Nutrition management for the patient requiring prolonged mechanical ventilation. AB - Patients requiring prolonged mechanical ventilation are often medically complex and present with a wide range of pulmonary conditions, including neuromuscular diseases, chronic pulmonary diseases, and chronic critical illness. These patients present the nutrition support professional with many challenges. However, accurate nutrition assessment, timely and effective nutrition interventions, and careful monitoring will help patients meet their medical and nutrition goals. PMID- 21586409 TI - Nutrition in the stroke patient. AB - Malnutrition is common both before and after stroke, with dysphagia adding to nutrition risk. Many patients require specialized nutrition support in the acute phase and beyond when swallowing function does not improve or return to allow for nutrition autonomy. When neurologic deficits improve, assessment of the swallowing function, introduction of dysphagia diets, and specialized swallowing techniques are used to transition away from enteral feeding tubes to oral diets. This article reviews the evaluation and treatment of dysphagia, use of specialized nutrition support, strategies for weaning enteral tube feedings, and the impact of nutrition on quality of life in the stroke patient population. PMID- 21586410 TI - Hypocaloric considerations in patients with potentially hypometabolic disease States. AB - The provision of nutrition has traditionally been driven by the desire to provide adequate calories. However, over the past decade it has become evident that provision of excess calories can be detrimental to patients' outcomes in both critical care and long-term care settings. This review examines patient populations for whom hypocaloric nutrition can be both appropriate and beneficial. In specific situations, critically ill patients, such as those with obesity, stroke, and spinal cord injury, may have decreased energy requirements. In patients with spinal cord injury, the level of injury significantly correlates with the extent of reduced caloric energy expenditure. Ventilator-dependent patients with amyotrophic lateral sclerosis (ALS) have decreased energy needs; energy expenditure for ALS patients is lower than the predictive equation value. Aging patients will have decreased energy needs relative to a reduction in lean body mass. Patients with cerebral palsy (CP) have significantly lower caloric requirements than anticipated using predictive equations. Patients with CP pose a particular challenge in nutrition assessment. Several studies demonstrate that patients with CP have significantly lower caloric requirements than anticipated using predictive equations; thus, patients with CP benefit from indirect calorimetry. Provision of nutrition for obese patients is briefly addressed, as this is an increasingly important consideration for nutrition support in both the critical care and long-term care settings. When indirect calorimetry is not available, clinicians should remember that most patients will have low resting energy expenditure regardless of functional status and require frequent evaluation during institution of nutrition recommendations to guard against overfeeding and obesity. PMID- 21586411 TI - Enteral nutrition for older adults in nursing facilities. AB - Older adults who reside in nursing facilities tend to be frail and to have multiple comorbidities, increased risk of unintended weight loss, and protein energy malnutrition. Approximately 5.8% of nursing facility residents in the United States receive enteral feedings. The prevalence is higher for residents with cognitive impairment, ranging from 18% to 34%. In cognitively impaired residents, the majority of tube feeding placements occur in the acute care setting and result in significant use of additional healthcare resources and high postinsertion mortality rates within 60 days of insertion. Nursing facilities must abide by state and federal regulations and undergo stringent survey evaluation while balancing complex decisions related to initial placement of feeding tubes. Informed choice, resident-centered care decisions, and the role of advance directives are essential in the decision-making process. In nursing facilities, it is often the registered dietitian who alerts the healthcare team to determine whether a feeding tube is appropriate. Once a tube is placed, healthcare practitioners must make careful decisions related to ordering, administering, and monitoring enteral nutrition (EN) delivery; adequacy of nutritional content; tolerance to feedings; monitoring for potential complications; and the possibility of return to oral feeding or, conversely, the decision to discontinue feedings. Further evidence-based research is needed to document effectiveness, along with research to support positive outcomes for residents in nursing facilities who receive EN. Optimal care requires careful coordination and an interdisciplinary approach across the continuum of care and between caregivers within the individual nursing facility. PMID- 21586412 TI - Optimizing the transition to home parenteral nutrition in pediatric patients. AB - Parenteral nutrition (PN) is commonly used in pediatric institutions in patients who either cannot be fed enterally or are unable to tolerate sufficient enteral calories to provide their nutrition requirements. Many pediatric patients, particularly those with short bowel syndrome or intestinal failure, will eventually require home PN (HPN) therapy. Although discharge to HPN is complex and can be associated with both immediate and long-term complications, it can be successfully achieved through collaboration between healthcare providers within the institution and the home care company and HPN education of the patient and caregivers. This review describes the processes that clinicians and institutions should consider when preparing for HPN discharge and serves as a guide for the effective transition to HPN in pediatric patients. PMID- 21586413 TI - Tubing misconnections: normalization of deviance. AB - BACKGROUND: Accidental connection of an enteral system to an intravenous (IV) system frequently results in the death of the patient. Misconnections are commonly attributed to the presence of universal connectors found in the majority of patient care tubing systems. Universal connectors allow for tubing misconnections between physiologically incompatible systems. METHODS: The purpose of this review of case studies of tubing misconnections and of current expert recommendations for safe tubing connections was to answer the following questions: In tubing connections that have the potential for misconnections between enteral and IV tubing, what are the threats to safety? What are patient outcomes following misconnections between enteral and IV tubing? What are the current recommendations for preventing misconnections between enteral and IV tubing? Following an extensive literature search and guided by 2 models of threats and errors, the authors analyzed case studies and expert opinions to identify technical, organizational, and human errors; patient-related threats; patient outcomes; and recommendations. RESULTS: A total of 116 case studies were found in 34 publications. Each involved misconnections of tubes carrying feedings, intended for enteral routes, to IV lines. Overwhelmingly, the recommendations were for redesign to eliminate universal connectors and prevent misconnections. Other recommendations were made, but the analysis indicates they would not prevent all misconnections. CONCLUSIONS: This review of the published case studies and current expert recommendations supports a redesign of connectors to ensure incompatibility between enteral and IV systems. Despite the cumulative evidence, little progress has been made to safeguard patients from tubing misconnections. PMID- 21586414 TI - Gluten-free diet in nonceliac disease. AB - A gluten-free diet (GFD) is commonly recognized as the treatment for celiac disease. It also has been investigated as a treatment option for other medical conditions, including dermatitis herpetiformis, irritable bowel syndrome, neurologic disorders, rheumatoid arthritis, diabetes mellitus, and HIV-associated enteropathy. The strength of the evidence for the use of a GFD in these nonceliac diseases varies, and future research may better define the benefits of a GFD for those conditions with weak existing evidence. PMID- 21586415 TI - Low-carbohydrate diet review: shifting the paradigm. AB - What does a clinician need to know about low-carbohydrate (LC) diets? This review examines and compares the safety and the effectiveness of a LC approach as an alternative to a low-fat (LF), high-carbohydrate diet, the current standard for weight loss and/or chronic disease prevention. In short-term and long-term comparison studies, ad libitum and isocaloric therapeutic diets with varying degrees of carbohydrate restriction perform as well as or better than comparable LF diets with regard to weight loss, lipid levels, glucose and insulin response, blood pressure, and other important cardiovascular risk markers in both normal subjects and those with metabolic and other health-related disorders. The metabolic, hormonal, and appetite signaling effects of carbohydrate reduction suggest an underlying scientific basis for considering it as an alternative approach to LF, high-carbohydrate recommendations in addressing overweight/obesity and chronic disease in America. It is time to embrace LC diets as a viable option to aid in reversing diabetes mellitus, risk factors for heart disease, and the epidemic of obesity. PMID- 21586416 TI - Dietary adherence to long-term controlled feeding in a calorie-restriction study in overweight men and women. AB - BACKGROUND: The success of clinical dietary interventions depends on the motivation and willingness of study participants to adhere to the prescribed or provided diet. The aim of this study was to assess participants' adherence to their provided diet over the 6-month duration of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE). METHODS: Investigators assessed the dietary adherence of 46 men and women who completed the first phase of the CALERIE trial. Volunteers were randomized to 1 of 4 dietary intervention groups: control, calorie restriction, calorie restriction with exercise, and low calorie diet. Participants were provided with foods during 2 weeks of baseline and during the first 12 weeks and the last 2 weeks of the intervention as outpatients, and they completed a daily self-report form to assess diet adherence. The data are expressed as mean +/- standard deviation or standard error of the mean. Pearson's correlation coefficient was determined to examine the relationship between assigned energy levels and total energy intake. RESULTS: Deviations reported were for eating nonstudy foods as well as not eating study foods. There were few deviations, and when converted to mean calories per day these did not affect total energy (weeks -3 to 2 = 10.25 +/- 4.82, weeks 1-4 = 9.93 +/- 12.52, weeks 5-11 = 8.38 +/- 7.42, weeks 22-23 = 0.53 +/- 3.97 kcal/d). The associations between assigned energy level and actual intake were high for all groups (P = .001), weeks -3 to -2 (r = 0.999), weeks 1-4 (r = 0.998), weeks 5 11 (r = 0.999), and weeks 22-23 (r = 0.998). CONCLUSIONS: The data provide evidence that dietary adherence is good when all foods are provided and when participants are highly motivated. PMID- 21586417 TI - Evaluation of a lifestyle modification program for treatment of overweight and nonmorbid obesity in primary healthcare and its influence on health-related quality of life. AB - BACKGROUND: The impact of overweight and nonmorbid obesity on health-related quality of life (HRQL) has not been widely researched. The aim of this study was to evaluate the effects of a lifestyle modification program (LMP) focused on diet, exercise, and psychological support on HRQL in overweight and nonmorbidly obese patients treated in a primary healthcare setting. METHODS: Sixty patients with grade II overweight and nonmorbid grade I-II obesity were included in this open pilot clinical trial; subjects' ages ranged from 18 to 50 years. They were provided with an LMP combining nutrition education, physical activity, and psychological support. Subjects attended group sessions every 2 weeks. The main outcome measures at baseline and 6 months were body composition parameters (body mass index, body fat percentage, and waist circumference) and HRQL using the 1.4 Spanish version of the SF-36 questionnaire. The questionnaire yields an 8-scale profile of physical functioning (PF), role--physical (RP), bodily pain (BP), vitality (VT), social functioning (SF), role--emotional (RE), mental health (MH), and general health (GH) factors. RESULTS: The LMP achieved improvements in SF-36 subscales at the end of the intervention: PF (80.37 +/- 18.90 vs 89.40 +/- 13.95, P < .001), RP (20.37 +/- 9.10 vs 23.14 +/- 6.67, P < .05), VT (58.71 +/- 21.98 vs 70.91 +/- 26.56, P < .01), SF (79.62 +/- 27.76 vs 86.57 +/- 25.45, P < .03), and GH (61.03 +/- 19.13 vs 69.42 +/- 18.80, P < .001). CONCLUSION: An LMP focused on balanced and moderate energy-restricted diets, increased physical activity, and psychological support may improve the anthropometric parameters and the quality of life in moderately obese patients treated in a primary healthcare center. PMID- 21586418 TI - Development of a tool to measure dietitians' involvement in the intensive care setting. AB - BACKGROUND: Intensive care is a relatively new work area for dietitians in Australasia, and the role of the dietitian appears to differ widely between facilities. This may create difficulties with multicenter research collaboration and workforce planning. The aim of this study was to develop a validated survey tool to assess dietitians' involvement in their intensive care teams. METHODS: A full list of all 182 adult intensive care units in Australia and New Zealand was obtained from the Australian and New Zealand Intensive Care Society, and all of these units were contacted. A survey tool was developed, piloted, and validated using correlation tests of construct validity; factor analysis was used to develop a 5-item short-form survey tool. RESULTS: At least 1 dietitian participated from each of the 182 hospitals that were contacted, and no dietitians declined to participate in the survey (100% response rate). The survey had strong validity and test-retest reliability in the population surveyed. CONCLUSIONS: The survey tools presented here can be used to assess dietitians' involvement in their intensive care team. The short-form tool developed in this study is conveniently brief and easy to administer, but it will need to be validated for use outside the Australian and New Zealand health systems prior to conduct of a large-scale survey. PMID- 21586419 TI - Nutrition for brain recovery after ischemic stroke: an added value to rehabilitation. AB - In patients who undergo rehabilitation after ischemic stroke, nutrition strategies are adopted to provide tube-fed individuals with adequate nutrition and/or to avoid the body wasting responsible for poor functional outcome and prolonged stay in the hospital. Investigations have documented that nutrition interventions can enhance the recovery of neurocognitive function in individuals with ischemic stroke. Experimental studies have shown that protein synthesis is suppressed in the ischemic penumbra. In clinical studies on rehabilitation patients designed to study the effects of counteracting or limiting this reduction of protein synthesis by providing protein supplementation, patients receiving such supplementation had enhanced recovery of neurocognitive function. Cellular damage in cerebral ischemia is also partly caused by oxidative damage secondary to free radical formation and lipid peroxidation. Increased oxidative stress negatively affects a patient's life and functional prognosis. Some studies have documented that nutrition supplementation with B-group vitamins may mitigate oxidative damage after acute ischemic stroke. Experimental investigations have also shown that cerebral ischemia changes synaptic zinc release and that acute ischemia increases zinc release, aggravating neuronal injury. In clinical practice, patients with ischemic stroke were found to have a lower than recommended dietary intake of zinc. Patients in whom daily zinc intake was normalized had better recovery of neurological deficits than subjects given a placebo. The aim of this review is to highlight those brain metabolic alterations susceptible to nutrition correction in clinical practice. The mechanisms underlying the relationship between cerebral ischemia and nutrition metabolic conditions are discussed. PMID- 21586420 TI - Are alternative supplements effective treatment for diabetes mellitus? PMID- 21586421 TI - Overestimation of the effects of adherence on outcomes: a case study in healthy user bias and hypertension. AB - BACKGROUND: The healthy user bias is usually overlooked as an explanation in studies in which a strong association is found between poor patient medication adherence and worse disease outcomes. Such studies are increasing in frequency across disease states and influence clinical practice. Adherence to antihypertensive medications was studied to illustrate confounding in such studies. METHODS: Using data from veterans with hypertension starting antihypertensive treatment, causal models were developed that predicted the risks of hospitalisation, myocardial infarction (MI) and death associated with poor adherence (<80%) while adjusting for patient demographics, baseline disease severity and disease comorbidity. In a second set of otherwise identical models, adjustment was made for time-varying blood pressure (BP), thus controlling for adherence effects that were mediated through the main pharmacological effects of the drugs. It was hypothesised that the second set of models would reveal a positive association between poor adherence and adverse disease outcomes that is largely explained by unmeasured confounders, including health-related behaviours. RESULTS: The models that did not adjust for time-varying BP levels showed that patients with poor adherence had statistically significantly increased risks of 3.7% for hospitalisation, 28.1% for MI and 23.3% for death. These estimates exceed the benefits of these drugs demonstrated by clinical trials. When controlling for time-varying BP, the increased risks were similar (3.4% for hospitalisation, 27.7% for MI and 23.4% for death). The findings were consistent across a range of adherence thresholds (50-90%) and when allowing disease status variables to vary. CONCLUSIONS: The associations between poor adherence and outcomes are largely independent of the pharmacological effects of the drugs on BP control as well as commonly measured patient covariates. This finding suggests that even carefully designed observational adherence studies using rich clinical data are impossibly confounded and probably overestimate the true magnitude of the effect. Clinical practice guidelines based on reported adherence effects should be reconsidered. PMID- 21586422 TI - Changes in left and right ventricular function of donor hearts during the first year after heart transplantation. AB - OBJECTIVE: Expected values of tissue Doppler imaging (TDI) velocities and myocardial performance index (MPI) after heart transplantation (HTx) have not been evaluated. This study assessed left and right ventricular (LV and RV) structure and function during the first year after HTx using these indexes. METHODS AND RESULTS: Echocardiography including MPI and TDI systolic (S'), early (E') and late (A') diastolic velocities of RV and LV were performed in 20 donors (mean age 35 +/- 13 years) and serially in 20 recipients (mean age 59 +/- 9 years) during the first year after HTx. Increase in LV mass occurred at 7 days, with normalisation at 3 months (p < 0.001). An increase in MPI (p<0.001) and a decrease in E', S' velocities on TDI occurred at week 1 with gradual improvement during the first year (p < 0.001). Normalisation of LV and RV MPI occurred at 6 months (p < 0.001) and LV TDI velocities at 1 year (p < 0.001). TDI velocities of both ventricles, however, at 1 year remained lower than at baseline. No patient had greater than grade IA rejection during the follow-up. No significant change was found in myocyte size within the first year. However, there was a 3.3-fold increase in fibrosis. CONCLUSIONS: This study is the first to identify the normal changes of TDI and MPI of both ventricles during the first year after HTx. An increase in LV mass and impairment of bi-ventricular systolic and diastolic function occur early after HTx with gradual improvement during the first year. No significant changes in myocyte size were observed, but there was a substantial increase in fibrosis. PMID- 21586423 TI - Myocardial gene expression of microRNA-133a and myosin heavy and light chains, in conjunction with clinical parameters, predict regression of left ventricular hypertrophy after valve replacement in patients with aortic stenosis. AB - BACKGROUND: Left ventricular (LV) reverse remodelling after valve replacement in aortic stenosis (AS) has been classically linked to the hydraulic performance of the replacement device, but myocardial status at the time of surgery has received little attention. OBJECTIVE: To establish predictors of LV mass (LVM) regression 1 year after valve replacement in a surgical cohort of patients with AS based on preoperative clinical and echocardiographic parameters and the myocardial gene expression profile at surgery. METHODS: Transcript levels of remodelling-related proteins and regulators were determined in LV intraoperative biopsies from 46 patients with AS by RT-PCR. Using multiple linear regression analysis, an equation was developed (adjusted R2=0.73; p<0.0001) that included positive [preoperative LVM, microRNA-133a, serum response factor (SRF, which is known to be a transactivator of miR-133) and age] and negative [body mass index (BMI), Wolf-Hirschhorn syndrome candidate-2 (WHSC2, which is a target for repression by miR-133a), beta-myosin heavy chain, myosin light chain-2, diabetes mellitus, and male gender] independent predictors of LVM reduction. RESULTS: Aortic valve area gain or the reduction in transvalvular gradient maintained no significant relationships with the dependent variable. Logistic regression analysis identified microRNA-133a as a significant positive predictor of LVM normalisation, whereas beta-myosin heavy chain and BMI constituted negative predictors. CONCLUSIONS: Hypertrophy regression 1 year after pressure overload release is related to the preoperative myocardial expression of remodelling related genes, in conjunction with the patient's clinical background. In this scenario, miR-133 emerges as a key element of the reverse remodelling process. Postoperative improvement of valve haemodynamics does not predict the degree of hypertrophy regression or LVM normalisation. These results led us to reconsider the current reverse remodelling paradigm and (1) to include criteria of hypertrophy reversibility in the decision algorithm used to decide timing for the operation; and (2) to modify other prevailing factors (overweight, diabetes, etc) known to maintain LV hypertrophy. PMID- 21586424 TI - How quickly should we titrate antihypertensive medication? Systematic review modelling blood pressure response from trial data. AB - CONTEXT: There are no evidence syntheses available to guide clinicians on when to titrate antihypertensive medication after initiation. OBJECTIVE: To model the blood pressure (BP) response after initiating antihypertensive medication. Data sources electronic databases including Medline, Embase, Cochrane Register and reference lists up to December 2009. STUDY SELECTION: Trials that initiated antihypertensive medication as single therapy in hypertensive patients who were either drug naive or had a placebo washout from previous drugs. DATA EXTRACTION: Office BP measurements at a minimum of two weekly intervals for a minimum of 4 weeks. An asymptotic approach model of BP response was assumed and non-linear mixed effects modelling used to calculate model parameters. RESULTS AND CONCLUSIONS: Eighteen trials that recruited 4168 patients met inclusion criteria. The time to reach 50% of the maximum estimated BP lowering effect was 1 week (systolic 0.91 weeks, 95% CI 0.74 to 1.10; diastolic 0.95, 0.75 to 1.15). Models incorporating drug class as a source of variability did not improve fit of the data. Incorporating the presence of a titration schedule improved model fit for both systolic and diastolic pressure. Titration increased both the predicted maximum effect and the time taken to reach 50% of the maximum (systolic 1.2 vs. 0.7 weeks; diastolic 1.4 vs. 0.7 weeks). CONCLUSIONS: Estimates of the maximum efficacy of antihypertensive agents can be made early after starting therapy. This knowledge will guide clinicians in deciding when a newly started antihypertensive agent is likely to be effective or not at controlling BP. PMID- 21586425 TI - Mental health service utilization in a community sample of rural adolescents: the role of father-offspring relations. AB - OBJECTIVE: Children and adolescents living in rural communities may be at particular risk for psychiatric problems, yet factors associated with mental health service use in these populations are not clear. This study examined the role of father warmth in offspring psychological treatment utilization in community sample of rural families (n = 298). METHODS: Observer ratings of paternal warmth were examined as a predictor of adolescent treatment seeking and as a moderator of the longitudinal association between adolescent depressive symptoms and treatment seeking. RESULTS: Paternal warmth was a marginally significant predictor of adolescent mental health service use. The association between adolescent depressive symptoms and treatment seeking varied as a function of paternal behavior; adolescents were more likely to seek needed help in the context of a warm, supportive father. CONCLUSIONS: These findings suggest that fathers can play an important role in the intrafamilial processes through which rural adolescents recognize and seek help for their psychological problems. PMID- 21586426 TI - Secondary mitral regurgitation: pathophysiology, diagnosis, and treatment. PMID- 21586427 TI - Controversies with On-TIME 2. PMID- 21586428 TI - My favourite flowering image: the role of cytokinin as a flowering signal. AB - My favourite flowering image shows a section in a shoot apical meristem of Sinapis alba undertaking the very first step of its transition to flowering. This step is the activation of the SaSOC1 gene, the Sinapis orthologue of Arabidopsis SUPPRESSOR OF OVEREXPRESSION OF CO1 (SOC1), in a few central cells of the meristem. Hidden behind this picture is my long quest of physiological signals controlling flowering. Milestones of this story are briefly recounted here and this gives me an opportunity to raise a number of questions about the nature and function of florigen. PMID- 21586429 TI - Fruit ripening in Vitis vinifera: spatiotemporal relationships among turgor, sugar accumulation, and anthocyanin biosynthesis. AB - This study reports the first observations indicating the spatiotemporal relationships among genetic and physiological aspects of ripening in the berry of Vitis vinifera. At the onset of ripening in the red flesh variety Alicante Bouschet, colour development began in the flesh at the stylar end of the fruit and progressed toward the pedicel end flesh and into the skin. Tissue solute potential and cell turgor also decreased first in the flesh. The decrease in flesh solute potential was due to accumulation of sugars, glucose and fructose, an accumulation that is integral to ripening. Expression of the anthocyanin biosynthesis-related genes VvMybA and VvUFGT was linearly related to the decrease in solute potential. Expression of VvMybA, and to a lesser extent VvUFGT, was correspondingly low in green tissue, higher in the red, stylar end flesh of berries beginning to ripen, and greatest in red berries. In contrast, expression of the abscisic acid biosynthesis-related genes VvNCED1 and VvNCED2 was not correlated with the other spatiotemporal aspects of the onset of ripening. These results, together with earlier work showing that sugar accumulation and acid loss also begin in the stylar flesh in other varieties, indicate that ripening in the grape berry originates in the stylar end flesh. PMID- 21586430 TI - Interactive effects of elevated CO2, warming, and drought on photosynthesis of Deschampsia flexuosa in a temperate heath ecosystem. AB - Global change factors affect plant carbon uptake in concert. In order to investigate the response directions and potential interactive effects, and to understand the underlying mechanisms, multifactor experiments are needed. The focus of this study was on the photosynthetic response to elevated CO(2) [CO2; free air CO(2) enrichment (FACE)], drought (D; water-excluding curtains), and night-time warming (T; infrared-reflective curtains) in a temperate heath. A/C(i) curves were measured, allowing analysis of light-saturated net photosynthesis (P(n)), light- and CO(2)-saturated net photosynthesis (P(max)), stomatal conductance (g(s)), the maximal rate of Rubisco carboxylation (V(cmax)), and the maximal rate of ribulose bisphosphate (RuBP) regeneration (J(max)) along with leaf delta(13)C, and carbon and nitrogen concentration on a monthly basis in the grass Deschampsia flexuosa. Seasonal drought reduced P(n) via g(s), but severe (experimental) drought decreased P(n) via a reduction in photosynthetic capacity (P(max), J(max), and V(cmax)). The effects were completely reversed by rewetting and stimulated P(n) via photosynthetic capacity stimulation. Warming increased early and late season P(n) via higher P(max) and J(max). Elevated CO(2) did not decrease g(s), but stimulated P(n) via increased C(i). The T*CO2 synergistically increased plant carbon uptake via photosynthetic capacity up-regulation in early season and by better access to water after rewetting. The effects of the combination of drought and elevated CO(2) depended on soil water availability, with additive effects when the soil water content was low and D*CO2 synergistic stimulation of P(n) after rewetting. The photosynthetic responses appeared to be highly influenced by growth pattern. The grass has opportunistic water consumption, and a biphasic growth pattern allowing for leaf dieback at low soil water availability followed by rapid re-growth of active leaves when rewetted and possibly a large resource allocation capability mediated by the rhizome. This growth characteristic allowed for the photosynthetic capacity up-regulations that mediated the T*CO2 and D*CO2 synergistic effects on photosynthesis. These are clearly advantageous characteristics when exposed to climate changes. In conclusion, after 1 year of experimentation, the limitations by low soil water availability and stimulation in early and late season by warming clearly structure and interact with the photosynthetic response to elevated CO(2) in this grassland species. PMID- 21586431 TI - The aromatic/arginine selectivity filter of NIP aquaporins plays a critical role in substrate selectivity for silicon, boron, and arsenic. AB - Nodulin-26-like intrinsic proteins (NIPs) of the aquaporin family are involved in the transport of diverse solutes, but the mechanisms controlling the selectivity of transport substrates are poorly understood. The purpose of this study was to investigate how the aromatic/arginine (ar/R) selectivity filter influences the substrate selectivity of two NIP aquaporins; the silicic acid (Si) transporter OsLsi1 (OsNIP2;1) from rice and the boric acid (B) transporter AtNIP5;1 from Arabidopsis; both proteins are also permeable to arsenite. Native and site directed mutagenized variants of the two genes were expressed in Xenopus oocytes and the transport activities for Si, B, arsenite, and water were assayed. Substitution of the amino acid at the ar/R second helix (H2) position of OsLsi1 did not affect the transport activities for Si, B, and arsenite, but that at the H5 position resulted in a total loss of Si and B transport activities and a partial loss of arsenite transport activity. Conversely, changes of the AtNIP5;1 ar/R selectivity filter and the NPA motifs to the OsLsi1 type did not result in a gain of Si transport activity. B transport activity was partially lost in the H5 mutant but unaffected in the H2 mutant of AtNIP5;1. In contrast, both the single and double mutations at the H2 and/or H5 positions of AtNIP5;1 did not affect arsenite transport activity. The results reveal that the residue at the H5 position of the ar/R filter of both OsLsi1 and AtNIP5;1 plays a key role in the permeability to Si and B, but there is a relatively low selectivity for arsenite. PMID- 21586432 TI - A pragmatic RCT of conventional versus increased concentration sucrose in freezing and thawing solutions for human embryos. AB - BACKGROUND: Intact frozen-thawed embryos have a greater potential than damaged embryos to establish successful pregnancies. This study aimed to determine whether elevated concentrations of sucrose during freezing would increase the proportion of patients with >= 50% of embryos intact after thawing (primary outcome), and improve clinical outcome. METHODS: In a two arm, parallel group, pragmatic trial, IVF/ICSI couples were randomized prospectively to have their supernumerary embryos frozen in a medium containing 0.1 M sucrose (control; n = 99) or 0.3 M sucrose (intervention; n = 102). RESULTS: More control (74/99) than intervention (63/102) couples had at least one embryo thawed (P = 0.07). Significantly more (P = 0.005) intervention (53/63) than control (45/74) couples had >= 50% of embryos intact. Freezing in a medium containing 0.3 M sucrose increased by 3.4-fold [95% confidence interval (CI) (1.45, 7.82)] the likelihood of a couple having >= 50% of their embryos intact. In the fresh cycle, live birth rate per transfer was similar in the control (35/95) and intervention (36/93) groups (P = 0.91). More control (19/63) than intervention (9/59) couples had a live birth after frozen embryo transfer (P = 0.08). When fresh and frozen cycles were combined, fewer intervention (n = 102) than control (n = 99) couples had at least one live birth (42 versus 53%). The difference in cumulative live birth rate was not significant [hazard ratio = 0.75, 95% CI (0.49, 1.13); P = 0.17]. CONCLUSIONS: Increasing the concentration of sucrose in the freezing medium improves embryo survival, but this is not reflected by increased cumulative birth rates. CLINICAL TRIALS REGISTRATION NUMBER: ISRCTN93314892. PMID- 21586433 TI - Promoting patient-centered care: a qualitative study of facilitators and barriers in healthcare organizations with a reputation for improving the patient experience. AB - OBJECTIVE: To investigate organizational facilitators and barriers to patient centered care in US health care institutions renowned for improving the patient care experience. DESIGN: A qualitative study involving interviews of senior staff and patient representatives. Semi-structured interviews focused on organizational processes, senior leadership, work environment, measurement and feedback mechanisms, patient engagement and information technology and access. SETTING: Eight health care organizations across the USA with a reputation for successfully promoting patient-centered care. PARTICIPANTS: Forty individuals, including chief executives, quality directors, chief medical officers, administrative directors and patient committee representatives. RESULTS: Interviewees reported that several organizational attributes and processes are key facilitators for making care more patient-centered: (i) strong, committed senior leadership, (ii) clear communication of strategic vision, (iii) active engagement of patient and families throughout the institution, (iv) sustained focus on staff satisfaction, (v) active measurement and feedback reporting of patient experiences, (vi) adequate resourcing of care delivery redesign, (vii) staff capacity building, (viii) accountability and incentives and (ix) a culture strongly supportive of change and learning. Interviewees reported that changing the organizational culture from a 'provider-focus' to a 'patient-focus' and the length of time it took to transition toward such a focus were the principal barriers against transforming delivery for patient-centered care. CONCLUSIONS: Organizations that have succeeded in fostering patient-centered care have gone beyond mainstream frameworks for quality improvement based on clinical measurement and audit and have adopted a strategic organizational approach to patient focus. PMID- 21586434 TI - The skin and freedom of speech. PMID- 21586435 TI - Low prevalence of DFNB1 (connexin 26) mutations in British Pakistani children with non-syndromic sensorineural hearing loss. AB - OBJECTIVE: To determine the clinical sensitivity of DFNB1 genetic testing (analysis of the connexin 26 gene GJB2) for non-syndromic sensorineural hearing loss (SNHL) in British Pakistani children and extend to a comparison with British White children and literature data. DESIGN: Retrospective cohort study. SETTING: City of Bradford, UK. PATIENTS: Overall, 177 children (152 families) were eligible; 147 children (123 families) were British Pakistani, and 30 children (29 families) were British White. INTERVENTIONS: DFNB1 testing was offered. MAIN OUTCOME MEASURES: Detection rate for pathogenic bi-allelic GJB2 mutations. RESULTS: DFNB1 testing yielded positive results in 6.9% British Pakistani families compared with 15.4% British White families. Of 65 British Pakistani children tested (from 58 families), five children (from four families) were found to be homozygous for the common South Asian GJB2 mutation p.Trp24X. Of 14 British White children tested (from 13 families), bi-allelic pathogenic GJB2 mutations were seen in two children (from two families). CONCLUSIONS: The contribution of DFNB1 to non-syndromic SNHL in the Bradford British Pakistani children appears to be low when compared with a White peer group and White populations in general. The high prevalence of genetic deafness in this community, attributed to family structure and immigration history, points to a dilution effect in favour of other recessive deafness genes/loci. PMID- 21586436 TI - Which symptoms and clinical features correctly identify serious respiratory infection in children attending a paediatric assessment unit? AB - OBJECTIVE: Parent-reported symptoms are frequently used to triage children, but little is known about which symptoms identify children with serious respiratory infections. The authors aimed to identify symptoms and triage findings predictive of serious respiratory infection, and to quantify agreement between parent and nurse assessment. DESIGN: Prospective diagnostic cohort study. SETTING: Paediatric Assessment Unit, University Hospitals Coventry and Warwickshire NHS Trust. PATIENTS: 535 children aged between 3 months and 12 years with suspected acute infection. METHODS: Parents completed a symptom questionnaire on arrival. Children were triaged by a nurse, who measured routine vital signs. The final diagnosis at discharge was used as the outcome. Symptoms and triage findings were analysed to identify features diagnostic of serious respiratory infection. Agreement between parent and triage nurse assessment was measured and kappa values calculated. RESULTS: Parent-reported symptoms were poor indicators of serious respiratory infection (positive likelihood ratio (LR+) 0.56-1.93) and agreed poorly with nurse assessment (kappa 0.22-0.56). The best predictor was clinical assessment of respiratory distress (LR+ 5.04). Oxygen saturations <94% were highly specific (specificity 95.1%) but had poor sensitivity (35.6%). Tachypnoea (defined by current Advanced Paediatric Life Support standards) offered little discriminatory value. CONCLUSION: Parent-reported symptoms were unreliable discriminators of serious respiratory infection in children with suspected acute infection, and did not correlate well with nurse assessment. Using symptoms to identify higher risk children in this setting is unreliable. Nurse triage assessment of respiratory distress and some vital signs are important predictors. PMID- 21586437 TI - Prevalence and risk factors for hypertension in Hong Kong Chinese adolescents: waist circumference predicts hypertension, exercise decreases risk. AB - PURPOSE: To determine the prevalence, risk factors for and patterns of hypertension in Chinese adolescents based on a territory-wide school based screening programme in Hong Kong. METHODS: Cross-sectional anthropometric and oscillometric blood pressure (BP) measurements and lifestyle information were obtained as part of a growth survey of students from randomly selected secondary schools in Hong Kong. Those with blood pressure >= 95th centile were screened a second or third time. Hypertension is defined as elevated blood pressure on three separate occasions. The independent effects of age, sex, body mass index, high waist circumference (>= 85th centile), sleep duration, family history of hypertension and frequency of exercise on hypertension were explored by multivariate analysis. RESULTS: Among the 6193 students screened, the prevalence of elevated blood pressure on the first, second and third screens was 9.54%, 2.77% and 1.44% respectively. Hypertension was more likely to be systolic. High waist circumference (>= 85th centile) was independently associated with a higher risk of hypertension (adjusted OR 2.4), while exercising twice or more per week was protective (adjusted OR 0.28). CONCLUSIONS: The prevalence of hypertension in Hong Kong Chinese adolescents is 1.44%. The current study shows high waist circumference is a predictor of hypertension in adolescents, while increased physical activity is a protective factor. Incorporating waist circumference into screening protocols may increase the sensitivity of cardiovascular risk stratification. Healthcare providers should be strong advocates helping to prevent obesity and promote physical activity in adolescents and children. PMID- 21586438 TI - How to diagnose spondyloarthritis early? Accuracy of peripheral enthesitis detection by power Doppler ultrasonography. AB - OBJECTIVE: Early diagnosis of spondyloarthritis (SpA) is sometimes difficult owing to the lack of reliable diagnostic criteria. The objective of this study was to determine the diagnostic accuracy of detecting enthesitis by power Doppler ultrasonography (PDUS) in patients with suspected SpA. METHODS: A prospective single-centre cohort study was performed in patients with symptoms suggestive of SpA (inflammatory back pain, arthritis, enthesitis or dactylitis, HLAB27+ uveitis) who underwent clinical examination, pelvic x-ray, MRI of lumbar spine/sacroiliac joints, HLA-B typing and other tests judged useful for diagnosis. Blinded PDUS examination of seven sites of enthesitis was performed at baseline. The gold standard was the diagnosis made by the referring rheumatologist according to the development of symptoms and findings, blinded to PDUS results, during routine follow-up for up to 2 years. RESULTS: Between November 2002 and October 2004, 118 patients were included in the study. After 2 years a definite diagnosis was retained for 99 patients (51 SpA and 48 non-SpA). PDUS detection of at least one vascularised enthesis provided good predictive value for diagnosing SpA (sensitivity 76.5%; specificity 81.3%; positive likelihood ratio 4.1; OR 14.1; p<0.0001). Vascularised enthesitis detected by PDUS and Amor's criteria were the only independent contributors to a diagnosis of SpA in multivariate logistic regression (c-index=0.87). Alternatively, CART analysis resulted in a highly sensitive and specific diagnostic tree by combining PDUS with Amor's criteria. CONCLUSIONS: PDUS appears to be a valuable first-line diagnostic tool to confirm a diagnosis of SpA. PMID- 21586439 TI - The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents. AB - BACKGROUND: It is unclear whether anti-tumour necrosis factor alpha and biological agents with different mechanisms of action have similar safety. This study evaluated the incidence of hospitalised infections among rheumatoid arthritis (RA) patients starting or switching various biological agents. METHODS: Using a database from a large US healthcare organisation from January 2005 to August 2009, the authors identified enrollees with RA and their treatment episodes entailing the new use of a biological agent, stratified by no biological use in the previous year ('biological-free') or switching from a different biological agent ('switchers'). Outcomes were hospitalised infections identified using previously validated algorithms. Proportional hazards models estimated the hazard ratio of hospitalised infections, comparing each biological agent with infliximab. RESULTS: Among 7847 biological treatment episodes, 63% were for biological-free patients and 37% for switchers. There were 364 hospitalised infections. Rates of hospitalised infection among biological-free patients and switchers were 4.6 and 7.0 per 100 person-years, respectively (p<0.0001). After multivariable adjustment controlling for biological-free/switcher status and other infection-related factors and compared with infliximab, users of abatacept (HR 0.68, 95% CI 0.48 to 0.96), adalimumab (HR 0.52, 0.39 to 0.71), etanercept (HR 0.64, 0.49 to 0.84) and rituximab (HR 0.81, 0.55 to 1.20) had lower rates of hospitalised infection. Patient risk factors contributed more to the risk of infection than did the risk associated with specific biological therapies. CONCLUSION: The rate of hospitalised infections among RA patients was highest for infliximab. Most of the variability in patients' risk of infection was driven by factors other than biological agent exposure. PMID- 21586440 TI - Validation of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis: slight improvement over the 1987 ACR criteria. AB - BACKGROUND: Recently, an American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) collaboration developed new classification criteria for rheumatoid arthritis (RA). OBJECTIVE: To evaluate the diagnostic and discriminative ability of these new criteria compared with the 1987 ACR criteria and the Visser decision rule. METHODS: 455 patients with early arthritis were studied. The diagnostic performance of the criteria was evaluated using methotrexate treatment within 1 year, expert opinion RA and erosive disease as 'gold standards'. Erosive disease was defined as a 0-3 year change in radiographic score of >=5. RESULTS: The discriminative ability of the three criteria sets (2010 ACR/EULAR, 1987 ACR criteria and Visser algorithm) was similar with areas under the curve of 0.71-0.78 ('gold standard' methotrexate), 0.74-0.80 (gold standard expert opinion RA) and 0.63-0.67 (gold standard erosive disease after 3 years). The sensitivity of the 2010 ACR/EULAR criteria was highest with 0.85 (gold standard methotrexate). 86% of patients with RA and 51% of 'non-RA' patients according to the new criteria used methotrexate. CONCLUSION: The 2010 ACR/EULAR criteria were slightly more sensitive, but otherwise performed similarly to the older criteria. A high percentage of 'non-RA' patients used methotrexate, the gold standard for RA. The ability of the new criteria to identify patients with erosive disease was low, possibly owing to the effect of intensive treatment. PMID- 21586441 TI - Arthritogenicity of annexin VII revealed by phosphoproteomics of rheumatoid synoviocytes. AB - OBJECTIVE: To identify novel proteins involved in the pathogenesis of rheumatoid arthritis (RA) and to characterise the identified proteins based on pathogenic and therapeutic aspects. METHODS: The authors applied differential phosphoproteomic analysis to articular synoviocytes between RA and osteoarthritis (OA) to identify proteins differently phosphorylated between RA and OA. Focusing on annexin VII (Anx7), one of the highly phosphorylated proteins in RA, the authors prepared Anx7-transgenic C57BL/6 (Anx7-Tg-B6) mice to evaluate their susceptibility to collagen-induced arthritis (CIA). In addition, the authors examined the effect of anti-Anx7 antibodies (Abs) on CIA and serum levels of cytokines in wild-type DBA/1J mice, which are known to be susceptible to CIA, and in Anx7-Tg-B6 mice. In vitro, the authors examined the effect of the Anx7 knockdown by small interfering RNA on the secretion of cytokines in rheumatoid synoviocytes and the human synovial sarcoma cell line SW982. RESULTS: The Anx7 transgene altered the CIA-resistant B6 mice to CIA-susceptible ones. The Abs treatment suppressed CIA even in the wild-type DBA/1J mice. The serum levels of cytokines including interleukin 6 (IL-6) and TNFalpha were not altered by the Abs treatment in vivo. On the other hand, the knockdown of Anx7 by small interfering RNA caused downregulation of IL-8 secretion in vitro. CONCLUSIONS: These results indicate that Anx7 participates in the pathogenesis of RA partly through the secretion of IL-8. The study data have demonstrated the pathogenic roles and therapeutic significance of Anx7 in RA for the first time. PMID- 21586443 TI - Reduction in mortality after epidural anaesthesia and analgesia in patients undergoing rectal but not colonic cancer surgery: a retrospective analysis of data from 655 patients in central Sweden. AB - BACKGROUND: There is some evidence that epidural analgesia (EDA) reduces tumour recurrence after breast and prostatic cancer surgery. We assessed whether EDA reduces long-term mortality after colorectal cancer surgery. METHODS: All patients having colorectal cancer surgery between January 2004 and January 2008 at Linkoping and Orebro were included. Exclusion criteria were: emergency operations, laparoscopic-assisted colorectal resection, and stage 4 cancer. Statistical information was obtained from the Swedish National Register for Deaths. Patients were analysed in two groups: EDA group or patient-controlled analgesia (PCA group) as the primary method of analgesia. RESULTS: A total of 655 patients could be included. All-cause mortality for colorectal cancer (stages 1 3) was 22.7% (colon: 20%, rectal: 26%) after 1-5 yr of surgery. Multivariate regression analysis identified the following statistically significant factors for death after colon cancer (P<0.05): age (>72 yr) and cancer stage 3 (compared with stage 1). A similar model for rectal cancer found that age (>72 yr) and the use of PCA rather than EDA and cancer stages 2 and 3 (compared with stage 1) were associated with a higher risk for death. No significant risk of death was found for colon cancer when comparing EDA with PCA (P=0.23), but a significantly increased risk of death was seen after rectal cancer when PCA was used compared with EDA (P=0.049) [hazards ratio: 0.52 (0.27-1.00)]. CONCLUSIONS: We found a reduction in all-cause mortality after rectal but not colon cancer in patients having EDA compared with PCA technique. PMID- 21586442 TI - Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus. AB - OBJECTIVES: Vitamin D deficiency is widespread and has been associated with many chronic diseases, including autoimmune disorders. A study was undertaken to explore the impact of low vitamin D levels on autoantibody production in healthy individuals, as well as B cell hyperactivity and interferon alpha (IFNalpha) activity in patients with systemic lupus erythematosus (SLE). METHODS: Serum samples from 32 European American female patients with SLE and 32 matched controls were tested for 25-hydroxyvitamin D (25(OH)D) levels, lupus-associated autoantibodies and serum IFNalpha activity. Isolated peripheral blood mononuclear cells were tested for intracellular phospho-ERK 1/2 as a measure of B cell activation status. RESULTS: Vitamin D deficiency (25(OH)D <20 ng/ml) was significantly more frequent among patients with SLE (n=32, 69%) and antinuclear antibody (ANA)-positive controls (n=14, 71%) compared with ANA-negative controls (n=18, 22%) (OR 7.7, 95% CI 2.0 to 29.4, p=0.003 and OR 8.8, 95% CI 1.8 to 43.6, p=0.011, respectively). Patients with high B cell activation had lower mean (SD) 25(OH)D levels than patients with low B cell activation (17.2 (5.1) vs 24.2 (3.9) ng/ml; p=0.009). Patients with vitamin D deficiency also had higher mean (SD) serum IFNalpha activity than patients without vitamin D deficiency (3.5 (6.6) vs 0.3 (0.3); p=0.02). CONCLUSIONS: The observation that ANA-positive healthy controls are significantly more likely to be deficient in vitamin D than ANA negative healthy controls, together with the finding that vitamin D deficiency is associated with certain immune abnormalities in SLE, suggests that vitamin D plays an important role in autoantibody production and SLE pathogenesis. PMID- 21586444 TI - Comparison of the C-MAC(r), Airtraq(r), and Macintosh laryngoscopes in patients undergoing tracheal intubation with cervical spine immobilization. AB - BACKGROUND: We aimed at comparing the performance of the C-MAC(r), Airtraq(r), and Macintosh laryngoscopes when performing tracheal intubation in patients undergoing neck immobilization using manual inline axial cervical spine stabilization. METHODS: Ninety consenting patients presenting for surgery requiring tracheal intubation were randomly assigned to undergo intubation using a C-MAC(r) (n=30), Airtraq(r) (n=29), or Macintosh (n=31) laryngoscope. All patients were intubated by one anaesthetist experienced in the use of each laryngoscope. RESULTS: The Airtraq(r) laryngoscope performed best in these patients, reducing the Intubation Difficulty Scale score, improving the Cormack and Lehane glottic view, and reducing the need for optimization manoeuvres, compared with both the Macintosh and the C-MAC(r). The C-MAC(r) and Macintosh laryngoscopes performed similarly. There were no differences in success rates or haemodynamic profiles post-intubation between any of the devices tested. CONCLUSIONS: The Airtraq(r) laryngoscope performed better than the C-MAC(r) and Macintosh laryngoscopes in patients undergoing cervical immobilization. PMID- 21586445 TI - Review focus on epigenetics and the histone code in vascular biology. PMID- 21586447 TI - Living donor exchange programs: theory and practice. AB - BACKGROUND: The crisis in organ availability has triggered innovative approaches to meet a rapidly expanding worldwide demand for donor kidneys. HLA and ABO incompatibility represents one of the most significant barriers to optimizing the utilization of living donors. Kidney paired donation (KPD) allows patients with incompatible live donors to receive compatible or better-matched organs by exchanging donors. SOURCES OF DATA: The data presented in this review have been published and represent the most up-to-date sources of the theory and practice of KPD. AREAS OF AGREEMENT: There is wide agreement that in most cases the best transplant solution for a patient with an incompatible donor is to receive a compatible organ in a KPD. AREAS OF CONTROVERSY: There has been disagreement about the capacity of KPD to solve the incompatibility problem. However, it is now clear that not all phenotypes will benefit from KPD. GROWING POINTS: Combining KPD with desensitization greatly expands the boundaries of each of these modalities. PMID- 21586446 TI - Will stem cell therapies be safe and effective for treating spinal cord injuries? AB - INTRODUCTION: A large number of different cells including embryonic and adult stem cells have been transplanted into animal models of spinal cord injury, and in many cases these procedures have resulted in modest sensorimotor benefits. In October 2010 the world's first clinical trial using human embryonic stem cells began, using stem cells converted into oligodendrocyte precursor cells. SOURCES OF DATA: In this review we examine some of the publically available preclinical evidence that some of these cell types improve outcome in animal models of spinal cord injury. Much evidence is not available for public scrutiny, however, being private commercial property of various stem cell companies. AREAS OF AGREEMENT: Transplantation of many different types of stem and progenitor cell enhances spontaneous recovery of function when transplanted acutely after spinal cord injury in animal models. AREAS OF DISAGREEMENT: The common mechanism(s) whereby the generic procedure of cellular transplantation enhances recovery of function are not well understood, although a range of possibilities are usually cited (including preservation of tissue, remyelination, axon sprouting, glial cell replacement). Only in exceptional cases has it been shown that functional recovery depends causally on the survival and differentiation of the transplanted cells. There is no agreement about the optimal cell type for transplantation: candidate stem cells have not yet been compared with each other or with other cell types (e.g. autologous Schwann cells) in a single study. AREAS TIMELY FOR DEVELOPING RESEARCH: Transplantation of cells into animals with a long lifespan is important to determine whether or not tumours will eventually form. It will also be important to determine whether long-term survival of cells is required for functional recovery, and if so, how many are optimal. PMID- 21586448 TI - Vascular disease and stem cell therapies. AB - INTRODUCTION AND BACKGROUND: Peripheral vascular disease is the leading cause of limb ischemia (LI). LI is manifested by claudication, ischemic rest pain, ulcers or gangrene. It is the result of peripheral arterial disease due to atherosclerosis. Over the last decade, several centers around the world have initiated clinical trials utilizing stem cells as a treatment for this disease. SOURCES OF DATA: Published medical literature, clinical trials announced in clinical trials.gov and TCA cellular therapy experience. AREAS OF AGREEMENT: There is general agreement that stem cells are useful for LI. AREAS OF CONTROVERSY: These arise from the type of cells, dose, route of administration and methods to evaluate efficacy. GROWING POINTS: Growing evidence suggests that bone marrow derived-mesenchymal stem cells are as good as or superior to mononuclear cells, and a combination of both cell types may be even better. AREAS TIMELY FOR DEVELOPING RESEARCH: Based on current trials and publications, several promising biological products could become part of the therapeutic arsenal for LI. This may include combinations of more than one type of adult/induced pluripotent stem cells/embryonic stem cells, use of stem cells with growth factors or extracellular matrix molecules. PMID- 21586449 TI - Vasculogenesis: a new piece of the endometriosis puzzle. AB - BACKGROUND; Endometriosis is a complex disease with a multifactorial pathogenesis, which is crucially dependent on the development of new blood vessels. Based on the current literature, the present review highlights the fact that the neovascularization of endometriotic lesions is not only driven by angiogenesis, but also involves de novo formation of microvessels from circulating endothelial progenitor cells (EPCs). This process, termed post-natal vasculogenesis, is a characteristic of various pathogenic conditions, such as tumour growth and atherosclerosis, and typically comprises the activation, mobilization and recruitment of bone marrow-derived EPCs to the sites of tissue hypoxia. METHODS ; Literature searches were performed in PubMed, MEDLINE and ISI Web of Knowledge for publications focusing on vasculogenesis in the endometrium and endometriotic lesions. RESULTS ; Recent studies indicate that up to 37% of the microvascular endothelium of ectopic endometrial tissue originates from EPCs, partly controlled by the stromal-cell-derived factor-1/chemokine receptor type 4 axis. Accordingly, blockade of EPC recruitment effectively inhibits the formation of microvascular networks in developing endometriotic lesions, indicating that vasculogenesis represents an integral part of the pathogenesis of endometriosis. CONCLUSIONS ; The involvement of vasculogenesis in endometriosis may offer the exciting opportunity for the future establishment of novel diagnostic and therapeutic strategies for this frequent gynaecological disease. PMID- 21586450 TI - Further privatisation is inevitable under the proposed NHS reforms. PMID- 21586451 TI - Let's talk about dying. PMID- 21586454 TI - Russia proposes strict limits on abortions to boost population. PMID- 21586458 TI - Safety through education. FY1 doctors still poor in prescribing intravenous fluids. PMID- 21586459 TI - "Fitness to practise" process. Competing GMC interests. PMID- 21586460 TI - NICE on ovarian cancer. Recommendations for detection in primary care are flawed. PMID- 21586461 TI - NICE on ovarian cancer. Please include GPs in developing guidelines. PMID- 21586462 TI - Safety through education. Human factors for all? PMID- 21586463 TI - Risk illiteracy rides again. Skill of interpreting imperfect investigations. PMID- 21586464 TI - Safety through education. Prevention is better than the law. PMID- 21586465 TI - Risk illiteracy rides again. Let's work together. PMID- 21586466 TI - Sharing raw data: another of Francis Galton's ideas. PMID- 21586467 TI - Qualitative methods. Competing philosophies? PMID- 21586468 TI - Qualitative methods. Measuring versus understanding. PMID- 21586469 TI - "Fitness to practise" process. Racial justice is long overdue. PMID- 21586470 TI - Risk illiteracy rides again. Come clean if you don't know. PMID- 21586471 TI - Risk illiteracy rides again. Role of cognitive bias. PMID- 21586472 TI - Risk illiteracy rides again. Balancing probabilities. PMID- 21586473 TI - People in richest countries live 23 years longer than those in poorest, finds WHO. PMID- 21586474 TI - Environmentalists seek to set research agenda on indoor air pollution. PMID- 21586475 TI - US government commits to new hepatitis plan but won't fund treatment. PMID- 21586476 TI - Is preoperative physiotherapy/pulmonary rehabilitation beneficial in lung resection patients? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether preoperative physiotherapy/pulmonary rehabilitation is beneficial for patients undergoing lung resection. Ten papers were identified using the reported search, of which five represented the best evidence to answer the clinical question. In 2007 a report showed in 13 subjects receiving a preoperative rehabilitation programme (PRP) an improvement of maximum oxygen uptake consumption (VO(2) max) of an average 2.4 ml/kg/min (95% confidence interval 1-3.8; P=0.002). A report in 2008 showed in 12 patients with chronic obstructive pulmonary disease (COPD) and VO(2) max <15 ml/kg/min that PRP could effect a mean improvement in VO(2) max of 2.8 ml/kg/min (P<0.001). An earlier report in 2005 demonstrated a reduced length of hospital stay (21+/-7 days vs. 29+/-9 days; P=0.0003) in 22 subjects who underwent PRP for two weeks compared with a historical control of 60 patients with COPD. It was shown in 2006 that by using a cross-sectional design with historical controls that one day of chest physiotherapy comprising inspiratory and peripheral muscle training compared with routine nursing care was associated with a lower atelectasis rate (2% vs. 7.7%) and a median length of stay that was 5.73 days vs. 8.33 days (P<0.0001). A prospective randomised controlled study in 1997, showed that two weeks of PRP followed by two months of postoperative rehabilitation produced a better predicted postoperative forced expiratory volume in one second in the study group than in the control group at three months (lobectomy + 570 ml vs. -70 ml; pneumonectomy + 680 ml vs. -110 ml). We conclude that preoperative physiotherapy improves exercise capacity and preserves pulmonary function following surgery. Whether these benefits translate into a reduction in postoperative pulmonary complication is uncertain. PMID- 21586477 TI - The impact of coronary artery disease on the quality of life of patients undergoing aortic valve replacement. AB - Of 415 patients, 200 undergoing aortic valve replacement (AVR) and 215 undergoing AVR in combination with myocardial revascularization [coronary artery bypass grafting (CABG)], had complete preoperative health-related quality of life (HRQOL) data. From this group, 224 patients had a follow-up of one year. To assess HRQOL, the EuroQol instrument was used. The EQ-5D index score was calculated, based on separate scores from five health domains, to express the global health status of the patient. The EQ visual analogue scale (VAS) was used to describe patients' subjective HRQOL. At baseline, the EQ-5D showed no significant differences between the two groups. The EQ-VAS score, however, was statistically significantly lower in the AVR+CABG patients (P=0.031). At one year postoperatively, both groups showed a statistically significant increase in the EQ-VAS (P=0.001 and P=0.001, respectively) and the EQ-5D (P=0.001 and P=0.001, respectively). This increase, however, could only be ascertained for the domain 'pain/discomfort' (P=0.001) in the AVR group, and for 'mobility' (P=0.018), 'usual activities' (P=0.001), 'pain/discomfort' (P=0.001) and 'anxiety/depression' (P=0.001) in the AVR+CABG group. At baseline, coronary artery disease had a negative influence on the patients' HRQOL, especially on the EQ-VAS. Postoperatively, all patients experienced significantly better HRQOL. However, the patients undergoing combined surgery experienced more benefit from their operation. PMID- 21586478 TI - Diagnosis and management of schistosomiasis. PMID- 21586479 TI - Lesson of the Week. When a cyst is not a cyst. PMID- 21586480 TI - Psychometric properties of the five facet mindfulness questionnaire in depressed adults and development of a short form. AB - In recent years, there has been a growing interest in therapies that include the learning of mindfulness skills. The 39-item Five Facet Mindfulness Questionnaire (FFMQ) has been developed as a reliable and valid comprehensive instrument for assessing different aspects of mindfulness in community and student samples. In this study, the psychometric properties of the Dutch FFMQ were assessed in a sample of 376 adults with clinically relevant symptoms of depression and anxiety. Construct validity was examined with confirmatory factor analyses and by relating the FFMQ to measures of psychological symptoms, well-being, experiential avoidance, and the personality factors neuroticism and openness to experience. In addition, a 24-item short form of the FFMQ (FFMQ-SF) was developed and assessed in the same sample and cross-validated in an independent sample of patients with fibromyalgia. Confirmatory factor analyses showed acceptable model fit for a correlated five-factor structure of the FFMQ and good model fit for the structure of the FFMQ-SF. The replicability of the five-factor structure of the FFMQ-SF was confirmed in the fibromyalgia sample. Both instruments proved highly sensitive to change. It is concluded that both the FFMQ and the FFMQ-SF are reliable and valid instruments for use in adults with clinically relevant symptoms of depression and anxiety. PMID- 21586481 TI - Fetal diagnosis of congenital heart disease by telemedicine. AB - OBJECTIVES: This study aimed to evaluate the feasibility, accuracy and user acceptability of performing remote fetal echocardiograms (FEs). SETTING: A regional fetal cardiology unit and a district general hospital (DGH). DESIGN: A prospective study over 20 months. An initial FE was performed by a radiographer in the DGH (D1) followed by a second FE transmitted to the regional centre, in real time, via a telemedicine link with live guidance by a fetal cardiologist (D2). A FE was performed later at the regional centre (D3, reference standard). Structured questionnaires were employed to evaluate the technical quality of each tele-link and the radiographers' confidence at performing FE. RESULTS: 69 remote FEs were performed and showed 58 normal hearts and 11 with congenital heart disease (CHD). D2 was accurate in 97% of cases compared with D3 (kappa score=0.89) indicating excellent agreement. All tele-links connected at first attempt with a mean study time = 13.9 min. Overall tele-link quality was rated highly (median=4/5). In 94% of tele-links, at least 11/12 components of the FE were confidently assessed. The mean composite radiographer's questionnaire score increased significantly during the study period (p<0.05). CONCLUSIONS: To date this is the largest study of its kind. CHD can be confidently diagnosed and excluded by remote FE. Radiographers report increased confidence and proficiency following involvement in real-time telemedicine. This application of telemedicine could improve access to fetal cardiology and support radiographers screening for CHD. PMID- 21586482 TI - Delayed cord clamping and blood flow in the superior vena cava in preterm infants: an observational study. AB - OBJECTIVE: To determine if timing of cord clamping affects blood flow in the upper body, as measured by flow in the superior vena cava (SVC). DESIGN: Observational study. SETTING: Neonatal Unit, Middlemore Hospital, Auckland, New Zealand. PATIENTS: 30 preterm infants <30 weeks' gestational age. INTERVENTION: Cord clamping was immediate in 17 infants and delayed by 30-45 s in 13. RESULTS: Infants in the two groups did not differ significantly in terms of gestational age, gender or use of antenatal steroids. Median flow in the SVC in the first 24 h was significantly higher in the group with delayed clamping (median 91 ml/kg/min; IQR 81-101) compared with 52 ml/kg/min (IQR 42-100) in the immediate clamping group (p=0.028). Fewer infants in the delayed group had low flow (1 compared with 9; p=0.017). All three infants with intraventricular haemorrhage (IVH) (of any grade) had low flow. CONCLUSIONS: Blood flow in the SVC was higher in infants where delayed cord clamping was performed. The relationship of IVH, low flow and timing of cord clamping requires further study. PMID- 21586483 TI - Effects of probiotic supplementation on liveweight gain and serum cortisol concentration in cattle. PMID- 21586484 TI - The association between perceived fatigue and actual level of physical activity in multiple sclerosis. AB - BACKGROUND: Both fatigue and reduced physical activity are important consequences of multiple sclerosis (MS). However, their mutual association is poorly understood. OBJECTIVE: The objective of the study was to determine the relation between perceived fatigue and home-based recording of motor activity in patients with MS. METHODS: Found associations were checked for confounding by age, Expanded Disability Status Scales (EDSS), disease duration, sub-type of MS, anxiety, and depression. Forty-three ambulatory patients with MS were recruited. Ambulatory physical activity was recorded for 24 hours. Fatigue was assessed with the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS) and the Checklist Individual Strength (CIS20R). Linear regression was applied after which potential confounding factors were introduced in a multivariate regression model. RESULTS: No significant associations between physical activity and fatigue scores were found, except for the MFIS sub-scale 'physical activity' (beta(physical_activity) [beta(pa)] = -0.044; SE = 0.020). The association between physical activity and the FSS score was distorted by age, MS-type, anxiety and depression and the association between physical activity and the MFIS score by age and depression. The inverse association between MFIS sub-scale 'physical activity' and physical activity was significantly strengthened by adjusting for age (beta(pa) = - 0.052; SE = 0.019), sub-type of MS (beta(pa) = - 0.048; SE = 0.020), anxiety (beta(pa) = - 0.070; SE = 0.023) and depression (beta(pa) = - 0.083; SE = 0.023). CONCLUSIONS: In MS, there is no, or at best a weak association between severity of perceived fatigue and physical activity. Depending on the fatigue questionnaire used, patient characteristics such as age, type of MS, depression and anxiety are factors that may affect this relationship. PMID- 21586485 TI - Sudden cardiac death in multiple sclerosis caused by active demyelination of the medulla oblongata. AB - Cardiovascular autonomic dysfunction is not uncommon in multiple sclerosis (MS) and is related to the involvement of the vegetative areas of cardiac innervations in the medulla oblongata. It has been suggested that this may contribute to the occurrence of sudden death in MS. In this case report, we present a patient with active relapsing-remitting MS who died unexpectedly due to the sudden onset of cardiac arrythmias. Post-mortem examination showed the presence of active demyelinating lesions in the medulla oblongata. As far as we know, this is the first case report clearly linking sudden cardiac death to active MS on the histopathological level. PMID- 21586486 TI - Examining the benefits of combining two learning strategies on recall of functional information in persons with multiple sclerosis. AB - BACKGROUND: Forgetfulness occurs commonly in people with multiple sclerosis (MS), but few treatments alleviate this problem. OBJECTIVE: This study examined the combined effect of two cognitive rehabilitation strategies to improve learning and memory in MS: self-generation and spaced learning. The hypothesis was that the combination of spaced learning and self-generation would yield better learning and memory recall performance than spaced learning alone. METHOD: Using a within groups design, 20 participants with MS and 18 healthy controls (HC) were presented with three tasks (learning names, appointment, and object location), each in three learning conditions (Massed, Spaced Learning, and combination of spaced and generated information). Participants were required to recall the information they learned in each of these conditions immediately and 30 min following the initial presentation. RESULTS: The combination of spaced learning and self-generation yielded better recall than did spaced learning alone. In turn, spaced learning resulted in better recall than the massed rehearsal condition. CONCLUSIONS: These findings reveal that the combination of these two learning strategies may possess utility as a cognitive rehabilitation strategy. PMID- 21586487 TI - Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability. AB - BACKGROUND: Although grey matter damage in multiple sclerosis is currently recognized, determinants of grey matter volume and its relationship with disability are not yet clear. OBJECTIVES: The objectives of the study were to measure grey and white matter volumes across different disease phenotypes; identify MRI parameters associated with grey matter volume; and study grey and white matter volume as explanatory variables for clinical impairment. METHODS: This is a cross-sectional study in which MRI data of 95 clinically isolated syndrome, 657 relapsing-remitting, 125 secondary-progressive and 50 primary progressive multiple sclerosis patients from three centres were acquired. Grey and white matter volumes were determined, together with T2 and T1 lesion volumes. Physical disability was assessed with the Expanded Disability Status Scale, cognitive impairment with the Paced Auditory Serial Addition Task. Data were analysed using multiple regression. RESULTS: Grey matter volume was lower in relapsing-remitting patients (mean [SD]: 0.80 [0.05] L) than in clinically isolated syndrome patients (0.82 [0.05] L), and even greater relative atrophy was found in secondary-progressive patients (0.77 [0.05] L). In contrast, white matter volume in secondary-progressive patients was comparable to that in relapsing-remitting patients. Grey matter volume was the strongest independent predictor of physical disability and cognitive impairment, and was associated with both T2 and T1 lesion volume. CONCLUSIONS: Our findings show that grey matter volume is lower in secondary-progressive than in relapsing-remitting disease. Grey matter volume explained physical and cognitive impairment better than white matter volume, and is itself associated with T2 and T1 lesion volume. PMID- 21586489 TI - Trends in annualized relapse rates in relapsing-remitting multiple sclerosis and consequences for clinical trial design. AB - BACKGROUND: Sample size calculation is a key aspect in the planning of any trial. Planning a randomized placebo-controlled trial in relapsing-remitting multiple sclerosis (RRMS) requires knowledge of the annualized relapse rate (ARR) in the placebo group. OBJECTIVES: This paper aims (i) to characterize the uncertainty in ARR by conducting a systematic review of placebo-controlled, randomized trials in RRMS and by modelling the ARR over time; and (ii) to assess the feasibility and utility of blinded sample size re-estimation (BSSR) procedures in RRMS. METHODS: A systematic literature review was carried out by searching PubMed, Ovid Medline and the Cochrane Register of Controlled Trials. The placebo ARRs were modelled by negative binomial regression. Computer simulations were conducted to assess the utility of BSSR in RRMS. RESULTS: Data from 26 placebo-controlled randomized trials were included in this analysis. The placebo ARR decreased by 6.2% per year (p < 0.0001; 95% CI (4.2%; 8.1%)) resulting in substantial uncertainty in the planning of future trials. BSSR was shown to be feasible and to maintain power at a prespecified level also if the ARR was misspecified in the planning phase. CONCLUSIONS: Our investigations confirmed previously reported trends in ARR. In this context adaptive strategies such as BSSR designs are recommended for consideration in the planning of future trials in RRMS. PMID- 21586490 TI - Risk of multiple sclerosis is not associated with exposure to crude oil, but increases with a low level of education. PMID- 21586492 TI - Freshwater clam extract decreased hemorrhagic shock-induced liver injury by attenuating TNF-alpha production. AB - Freshwater clam (Corbicula fluminea), a popular edible shellfish in Asia, is said to have beneficial effects on liver function. However, scientific evidence for such benefit is limited. In this study, the authors aimed to assess the treatment effects of freshwater clam extract (FCE) administration after hemorrhagic shock (HS) in rats. The authors randomly divided animals into three groups. After inducing HS in rats in the HS + FCE (n = 12) and HS groups, the authors fed 20 mg/kg FCE orally to rats in the HS group only. The authors neither induced HS in nor fed FCE to rats (n = 8) in the vehicle group. The authors measured the blood levels of white blood cells (WBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and tumor necrosis factor alpha (TNF-alpha) at several time points during the experiment. After 48 hr, the authors sacrificed the rats and harvested the livers for hematoxylin and eosin (HE) staining. The HS significantly decreased mean arterial pressure (MAP), increased blood AST, ALT, and LDH levels and induced liver injury in rats. Treatment with FCE increased MAP level and decreased AST, ALT, LDH, and TNF-alpha levels after hemorrhage. The HE staining showed diminished organ injury in the FCE-treated group. In conclusion, the administration of posttreatment FCE suppressed the release of pro-inflammatory TNF-alpha production after HS and decreased the levels of markers of liver injury associated with HS in rats. These beneficial effects suggest that FCE is a potential immunomodulator. PMID- 21586493 TI - Biomarkers for cognitive aging part II: oxidative stress, cognitive assessments, and medication adherence. AB - The purpose of this study was to further examine potential biomarkers of cognitive aging by looking at the associations among oxidative stress, cognitive abilities, and medication adherence in a community-based sample of middle-aged and older adults (n = 42; mean age = 69 years) prescribed at least one medication for hypertension. In addition to measures described in Part I, "Biomarkers for Cognitive Aging," a 12-hr urine collection for F(2)-isoprostanes served as an indicator of oxidative stress. Participants completed a battery of cognitive assessments and 8 weeks of electronic medication monitoring for adherence to one antihypertensive agent. Oxidative stress was significantly associated with logical memory, immediate (r = -.38, p < .01) and delayed recall (r = -.42, p < .01), and recognition memory (r = -.42, p < .01) from the Wechsler Memory Scale III, number of perseveration errors (r = .26, p < .05) and categories achieved (r = -.26, p < .01) on the Wisconsin Card Sorting Test (WSCT), and medication adherence (r = -.34, p <.05). Findings indicate that a biomarker of oxidative stress, F(2)-isoprostanes corrected for vitamin E, is significantly associated with cognitive measures and a functional outcome. PMID- 21586494 TI - Biomarkers for cognitive aging part I: telomere length, blood pressure and cognition among individuals with hypertension. AB - Chronological age is used as a marker for age-associated changes in cognitive function. However, there is great interindividual variability in cognitive ability among people of the same age. Physiological age rather than chronological age should be more closely associated with age-related cognitive changes because these changes are not universal and are likely dependent on several factors in addition to the number of years lived. Cognitive function is associated with successful self-management, and a biological marker that reflects physiological age and is associated with cognitive function could be used to identify risk for failure to self-manage. The purpose of this study was to investigate the association between telomere length, a known biomarker of age; blood pressure; cognitive assessments; and adherence to antihypertensive medication among community-dwelling middle-aged and older adults. The authors administered a battery of cognitive assessments to 42 participants (M = 69 years of age), collected blood samples, and isolated peripheral blood mononuclear leukocytes for genomic DNA. The authors determined relative telomere length using Cawthon's method for real-time quantitative polymerase chain reaction (RT-qPCR) and measured medication adherence using an electronic medication monitoring system (MEMS by Aardex) over 8 weeks. Findings indicate that telomere length was inversely associated with systolic blood pressure (r = -.38, p < .01) and diastolic blood pressure (r = -.42, p < .01) but not with cognitive assessments or adherence. The authors discuss the nonsignificant findings between telomere length and cognitive assessments including the potential modifying role of gender. PMID- 21586495 TI - The 6-min walk test: is it an effective method for evaluating heart failure therapies? AB - The 6-min walk (6MW) is a self-paced test for measuring functional capacity. Lower 6MW distances have been associated with adverse outcomes in patients with heart failure. The purpose of this article is to describe the history of the 6MW test and to evaluate its reliability, validity, and predictive value as well as the responsiveness of the test to therapies. In the literature we reviewed, reliability was affected by several factors including learning effects and protocol deviations. The 6MW distance was moderately correlated with peak oxygen consumption derived from cardiopulmonary exercise stress testing. In some studies the 6MW distance was predictive of hospitalization and mortality. In pharmacological and cardiac resynchronization trials the 6MW distance did not consistently detect clinical improvements. Despite limitations, the 6MW test is a viable alternative to stress testing for objectively evaluating functional capacity in some settings. We provide recommendations for using the 6MW test in future studies. PMID- 21586497 TI - Effect of obesity on cardiovascular disease risk factors in African American women. AB - Obesity is a growing health care concern with implications for cardiovascular disease (CVD). Obesity and CVD morbidity and mortality are highly prevalent among African American women. This pilot study examined the association between obesity and the traditional and emerging CVD risk factors in a sample of African American women. Participants comprised 48 women (27 obese, 21 normal weight) aged 18-45. with no known history of CVD. The women completed demographic and 7-day physical activity recall questionnaires. Height and weight were used to determine body mass index (BMI). Hypertension risk was assessed using the average of two resting blood pressure (BP) measurements. Lipid profile, blood glucose, fibrinogen, high sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1 (PAI 1), soluble intercellular adhesion molecule-1 (sICAM-1), and E-selectin (eSel) levels were assessed using fasting blood samples. Laboratory findings were interpreted using the American Diabetes Association (ADA) and Adult Treatment Panel (ATP) III reference guidelines as well as manufacturers' reference ranges for the novel CVD risk factors. The most common traditional risk factors were physical inactivity (72.9%), positive family history of CVD (58.3%), and obesity (56.3%). Obese individuals had elevated systolic BP (p = .0002), diastolic BP (p = .0007) and HDL-cholesterol (p = .01), triglyceride (p = .02), hs-CRP (p = .002), and fibrinogen (p = .01), when compared with normal-weight women. The findings suggest an association between obesity and higher prevalence of both traditional and emerging CVD risk factors in young African American women. PMID- 21586496 TI - Searching for the noninvasive biomarker holy grail: are urine proteomics the answer? AB - Recently, biobehavioral nursing scientists have focused their attention on the search for biomarkers or biological signatures to identify patients at risk for various health problems and poor disease outcomes. In response to the national impetus for biomarker discovery, the measurement of biological fluids and tissues has become increasingly sophisticated. Urine proteomics, in particular, may hold great promise for biobehavioral focused nursing scientists for examination of symptom-and syndrome-related research questions. Urine proteins are easily accessible secreted proteins that provide direct and indirect windows into bodily functions. Advances in proteomics and biomarker discovery provide new opportunities to conduct research studies with banked and fresh urine to benefit diagnosis, prognosis, and evaluation of outcomes in various disease populations. This article provides a review of proteomics and a rationale for utilizing urine proteomics in biobehavioral research. It addresses as well some of the challenges involved in data collection and sample preparation. PMID- 21586498 TI - The effect of music therapy on hospitalized psychiatric patients' anxiety, finger temperature, and electroencephalography: a randomized clinical trial. AB - PURPOSE: This study aimed to explore the effectiveness of music therapy in reducing anxiety in hospitalized psychiatric patients. METHODOLOGY: The authors used a randomized clinical trial design and randomly allocated the 24 enrolled participants to the experimental or the control group. Patients in the experimental group received music therapy in a therapy room at a set time for 30 min each morning for 11 days. The authors administered the Beck Anxiety Inventory (BAI) and measured skin temperature and brain waves to determine anxiety level before, during, and after music therapy. RESULTS: Experimental group participants had lower scores on the BAI than control participants, after the music therapy (z = -2.0, p < .05) and at 1-week follow-up (z = -2.2, p < .05), indicating that they were experiencing significantly less anxiety. The mean BAI anxiety score fell in the experimental group from 23.9 (SD = 9.9) at baseline to 13.9 (SD = 8.8), after music therapy, and 12.7. (SD = 10.5) at follow-up. The experimental group demonstrated a significant elevation in the average alpha electroencephalographic (EEG) percentage (from 38.1% to 46.7%) and a reduction in the average beta EEG percentage (from 61.9% to 53.4%) after the music therapy. After adjusting for change in patient finger temperature on the first day, mean change in finger temperature did not differ significantly between the experimental and control groups. CONCLUSIONS: Music therapy can relieve anxiety in hospitalized psychiatric patients and help them achieve a state of relaxation. PMID- 21586499 TI - Thermoregulation and thermography in neonatal physiology and disease. AB - INTRODUCTION: Infrared thermal imaging, or thermography, is a technique used to measure body surface temperature in the study of thermoregulation. Researchers are beginning to use this novel methodology to study cancer, peripheral vascular disease, and wound management. METHODS: The authors tested the feasibility of using an FLIR SC640 uncooled, infrared camera to measure body temperature in neonates housed in heated, humid incubators. The authors examined thermograms to analyze distributions between central and peripheral body temperature in extremely low birth weight infants. The authors have also used this technology to examine the relationship between body temperature and development of necrotizing enterocolitis in premature infants. RESULTS: Handheld, uncooled, infrared cameras are easy to use and produce high-quality thermograms that can be visualized in grayscale or color palettes to enhance qualitative and quantitative analyses. CONCLUSION: Future research will benefit from the use of this noninvasive, inexpensive measurement tool. Nurse researchers can use this methodology in adult and infant populations to study temperature differentials present in pathological conditions. PMID- 21586500 TI - Spit: saliva in nursing research, uses and methodological considerations in older adults. AB - Over the last 10 years, interest in the analysis of saliva as a biomarker for a variety of systemic diseases or for potential disease has soared. There are numerous advantages to using saliva as a biological fluid, particularly for nurse researchers working with vulnerable populations, such as frail older adults. Most notably, it is noninvasive and easier to collect than serum or urine. The authors describe their experiences with the use of saliva in research with older adults that examined (a) osmolality as an indicator of hydration status and (b) cortisol and behavioral symptoms of dementia. In particular, the authors discuss the timing of data collection along with data analysis and interpretation. For example, it is not enough to detect levels or rely solely on summary statistics; rather it is critical to characterize any rhythmicity inherent in the parameter of interest. Not accounting for rhythmicity in the analysis and interpretation of data can limit the interpretation of associations, thus impeding advances related to the contribution that an altered rhythm may make to individual vulnerability. PMID- 21586501 TI - Do pharmacological and behavioral interventions differentially affect treatment outcome for children with social phobia? AB - In a randomized trial for children with social phobia (SP), Social Effectiveness Therapy for Children (SET-C; a treatment consisting of exposure and social skills training) and fluoxetine were more effective than pill placebo in reducing social distress and behavioral avoidance, but only SET-C demonstrated significantly improved overall social skill and social competence. In the current study, the authors examined the specific social skills enhanced by SET-C using a recently developed coding schema. At posttreatment, children treated with SET-C displayed a more effective ability to manage the conversational topic (pragmatic social behaviors) and more appropriate motor movement, facial orientation, and posture (paralinguistic social behaviors) than children treated with fluoxetine or placebo. In contrast, children treated with fluoxetine displayed no more pragmatic or paralinguistic skill than children given a pill placebo. There were no group differences on ratings of voice volume and vocal inflection (speech and prosodic social behaviors). Furthermore, only children treated with SET-C improved from pre- to posttreatment on all three skill variables. Findings suggest that pharmacological interventions that only target reduction in anxious arousal may not have an impact on social skill deficits and may not be adequate to optimally treat SP. The relationship of social skill to social avoidance and the importance of social skills training to enhance social competence in the treatment of childhood SP are discussed. PMID- 21586502 TI - Two-year outcomes for children with autism after the cessation of early intensive behavioral intervention. AB - Evidence from recent meta-analytic and narrative review suggests that early intensive behavioral intervention (EIBI) may improve life chances of preschool children with autism. Unfortunately, there are few data indicating whether early gains are maintained after intervention ceases. The purpose of the present study was to establish the 2-year follow-up outcome for children with autism (N = 41) who had participated in an earlier 2-year controlled comparison of EIBI. Twenty three children in the intervention group (100% of original sample) and 18 in the treatment-as-usual comparison group (86% of original sample) were located and retested. Group differences favoring intervention substantially diluted in this period but varied significantly between subgroups who had received university supervised and parent-commissioned interventions, favoring the latter. These groups differed in terms of their baseline characteristics and intensity of intervention. Results strongly suggest a need for better characterization of those children who would benefit from more active maintenance programs. PMID- 21586503 TI - Bone age assessment by dual-energy X-ray absorptiometry in children: an alternative for X-ray? AB - OBJECTIVE: The aim of the study was to validate dual-energy X-ray absorptiometry (DXA) as a method to assess bone age in children. METHODS: Paired dual-energy X ray absorptiometry (DXA) scans and X-rays of the left hand were performed in 95 children who attended the paediatric endocrinology outpatient clinic of University Hospital Rotterdam, the Netherlands. We compared bone age assessments by DXA scan with those performed by X-ray. Bone age assessment was performed by two blinded observers according to the reference method of Greulich and Pyle. Intra-observer and interobserver reproducibility were investigated using the intraclass correlation coefficient (ICC), and agreement was tested using Bland and Altman plots. RESULTS: The intra-observer ICCs for both observers were 0.997 and 0.991 for X-ray and 0.993 and 0.987 for DXA assessments. The interobserver ICC was 0.993 and 0.991 for X-ray and DXA assessments, respectively. The mean difference between bone age assessed by X-ray and DXA was 0.11 years. The limits of agreement ranged from -0.82 to 1.05 years, which means that 95% of all differences between the methods were covered by this range. CONCLUSIONS: Results of bone age assessment by DXA scan are similar to those obtained by X-ray. The DXA method seems to be an alternative for assessing bone age in a paediatric hospital-based population. PMID- 21586504 TI - Malignant tumours of the small intestine: a review of histopathology, multidetector CT and MRI aspects. AB - Small bowel neoplasms, including adenocarcinoma, carcinoid tumour, lymphoma and gastrointestinal stromal tumours, represent a small percentage of gastrointestinal cancers, yet are among those with the poorest prognosis compared with other gastrointestinal malignancies. Unclear clinical scenarios and difficult radiological diagnosis often delay treatment with negative effects on patient survival. Recently, multidetector CT (MDCT) and MRI have been introduced as feasible and accurate diagnostic techniques for the identification and staging of small bowel neoplasms. These techniques are gradually replacing conventional barium radiography as the tool of choice. However, the inherent technical and physiological challenges of small bowel imaging require a familiarity with patient preparation and scan protocols. Adequate knowledge of the histopathology and natural evolution of small bowel neoplasms is also important for differential diagnosis. The aim of this article is to review MDCT and MRI protocols for the evaluation of small bowel tumours and to provide a concise yet comprehensive guide to the most relevant imaging features relative to histopathology. PMID- 21586505 TI - Reducing intratumour acute hypoxia through bevacizumab treatment, referring to the response of quiescent tumour cells and metastatic potential. AB - OBJECTIVES: The aim was to evaluate the influence of bevacizumab on intratumour oxygenation status and lung metastasis following radiotherapy, with specific reference to the response of quiescent (Q) cell populations within irradiated tumours. METHODS: B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2-deoxyuridine (BrdU) to label all proliferating (P) cells. They received gamma-ray irradiation following treatment with the acute hypoxia releasing agent nicotinamide or local mild temperature hyperthermia (MTH) with or without the administration of bevacizumab under aerobic conditions or totally hypoxic conditions, achieved by clamping the proximal end of the tumours. Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In the other tumour-bearing mice, macroscopic lung metastases were enumerated 17 days after irradiation. RESULTS: 3 days after bevacizumab administration, acute hypoxia-rich total cell population in the tumour showed a remarkably enhanced radiosensitivity to gamma-rays, and the hypoxic fraction (HF) was reduced, even after MTH treatment. However, the hypoxic fraction was not reduced after nicotinamide treatment. With or without gamma-ray irradiation, bevacizumab administration showed some potential to reduce the number of lung metastases as well as nicotinamide treatment. CONCLUSION: Bevacizumab has the potential to reduce perfusion-limited acute hypoxia and some potential to cause a decrease in the number of lung metastases as well as nicotinamide. PMID- 21586506 TI - Clinical dose performance of full field digital mammography in a breast screening programme. AB - OBJECTIVE: BreastCheck, the Irish Breast Screening Programme, has employed three different models of a full field digital mammography (FFDM) system since its transition to a digital service in 2007. The three models from GE Healthcare, Hologic and Sectra exhibit differences in their design and function, the most significant of which include anode target/filter choice, detector technology and the type of exposure automation. METHODS: The aim of this study was to use the results from a clinical breast dose survey to examine the differences between three different FFDM models in terms of exposure selection, breast mean glandular dose (MGD) and automatic exposure control (AEC) dose contribution. RESULTS: The accuracy of the dose estimation was improved by inclusion of the AEC pre-exposure dose contribution. The photon-counting system demonstrated the lowest average MGD. The GE Healthcare and Hologic flat-panel detector systems demonstrated a small but statistically significant dose difference. The pre-exposure dose contribution did not exceed 13% of the total exposure dose for any system in the survey. A comparison of the system calculated organ dose estimate from each machine with the corresponding MGD calculated from medical physics measurements indicated reasonably accurate organ dose estimates for most systems in the survey. CONCLUSION: The results of this study provide a comprehensive assessment of the breast dose performance of current digital mammography systems in a clinical screening setting. PMID- 21586508 TI - Is the patient's baseline inhaled steroid dose a factor for choosing the budesonide/formoterol maintenance and reliever therapy regimen? AB - OBJECTIVE: Baseline inhaled corticosteroid (ICS) dose may be a factor for prescribers to consider when they select a budesonide/formoterol maintenance and reliever therapy regimen for symptomatic asthmatics. METHODS: A 6-month randomized study compared two maintenance doses of budesonide/formoterol 160/4.5 ug, 1 * 2 and 2 * 2, plus as needed, in 8424 asthma patients with symptoms when treated with ICS +/- an inhaled long-acting beta(2)-agonist (LABA). In the total study population, 1339 (17%) were high-dose ICS (HD) users (>= 1600 ug/day budesonide). This HD stratum was compared with the rest of the study population, divided into low-dose (LD; 400 ug/day) and medium-dose strata (MD; 401-1599 ug/day) with regard to severe asthma exacerbations and mean changes in five-item Asthma Control Questionnaire (ACQ(5)) scores from baseline. RESULTS: In all three strata there were fewer exacerbations in the 2 * 2 treatment groups (yearly rates 0.268, 0.172 and 0.094) than in the 1 * 2 treatment groups (yearly rates 0.232, 0.138 and 0.764). In no stratum was the difference between the treatment groups statistically significant. There was no statistically significant difference in time to the first severe exacerbation between the treatments 2 * 2 and 1 * 2 in the HD group (hazard ratio 0.944, p = 0.75). The adjusted mean changes in ACQ(5) scores in the HD, MD and LD strata were -0.89, -0.61 and -0.65, respectively, with 1 * 2 treatment and -0.90, -0.74 and -0.76, respectively, with 2 * 2 treatment. In the MD and LD strata, the difference between doses was significant in favour of 2 * 2 (MD p < 0.0001; LD p = 0.004), but not in the HD stratum (p = 0.870). No difference in serious adverse events was seen. CONCLUSION: Compared with the LD and MD strata, the HD stratum patients had more exacerbations and a shorter time to first exacerbation. However, there were no differences in response between the 1 * 2 and 2 * 2 groups in any of the strata. This indicates that patients using budesonide/formoterol maintenance and reliever therapy, irrespective of baseline ICS dose, can be switched to 1 * 2 with its lower steroid load. ACQ(5) scores improved more in the HD stratum than in the MD and LD strata indicating, among other things, that HD patients were not overtreated at baseline. PMID- 21586507 TI - Cerebrospinal fluid flow imaging by using phase-contrast MR technique. AB - Cerebrospinal fluid (CSF) spaces include ventricles and cerebral and spinal subarachnoid spaces. CSF motion is a combined effect of CSF production rate and superimposed cardiac pulsations. Knowledge of CSF dynamics has benefited considerably from the development of phase-contrast (PC) MRI. There are several disorders such as communicating and non-communicating hydrocephalus, Chiari malformation, syringomyelic cyst and arachnoid cyst that can change the CSF dynamics. The aims of this pictorial review are to outline the PC MRI technique, CSF physiology and cerebrospinal space anatomy, to describe a group of congenital and acquired disorders that can alter the CSF dynamics, and to assess the use of PC MRI in the assessment of various central nervous system abnormalities. PMID- 21586509 TI - X-ray view box: on-site manufacture. AB - Radiographic films remain the norm in developing countries. Interpreting them is easier and more reliable, using a view box, than holding them up to a light. Commercial view boxes are expensive and difficult to repair. We designed and built an inexpensive radiographic view box using commonly available materials and local craftsmen. If they break, they can be easily repaired by hospital staff. This design can be replicated anywhere in the world. PMID- 21586510 TI - Childhood leprosy: lest we forget. AB - Leprosy remains an important public health and social issue in South Asia, particularly in India. Its presence in childhood is an immense social burden because of the associated disabilities and widely prevalent misconceptions regarding communicability and treatment potential. The prevalence of leprosy among children suggests a possible gap in the national programmes aimed at leprosy elimination. This article reports a 10-year retrospective study of childhood leprosy in a tertiary care hospital setting (2000-2009) along with an analysis of selected socio-epidemiologic correlates. We stress the importance of early detection and the application of appropriate prophylactic measures in susceptible children. PMID- 21586511 TI - Hepatitis B, hepatitis C and HIV co-infection at an antiretroviral centre in Delhi. AB - With an estimated 5.7 million people living with HIV/AIDS, India has the highest HIV/AIDS prevalence in the world, according to UNAIDS. Due to similar routes of transmission, co-infection of HIV with hepatitis B and hepatitis C viruses is a common event with significant clinical implications. The present study was undertaken to highlight the profile of patients of HIV with HBV/HCV co-infection, as literature from India on this topic is sparse. Out of 1953 patients suffering from HIV registered at our centre during the study period, 80 patients were co infected with HBV/HCV. HBV co-infection was detected in 2.61% of patients and HCV co-infection in 1.69% of subjects. Our study demonstrates low HIV /HCV/HBV co infection rates in Delhi as compared to most other studies from India, which is partly attributable to low incidence of intravenous drug use and infrequent transfusion-related infections in our study group. PMID- 21586512 TI - CHRNA5 as negative regulator of nicotine signaling in normal and cancer bronchial cells: effects on motility, migration and p63 expression. AB - Genome-wide association studies have linked lung cancer risk with a region of chromosome 15q25.1 containing CHRNA3, CHRNA5 and CHRNB4 encoding alpha3, alpha5 and beta4 subunits of nicotinic acetylcholine receptors (nAChR), respectively. One of the strongest associations was observed for a non-silent single-nucleotide polymorphism at codon 398 in CHRNA5. Here, we have used pharmacological (antagonists) or genetic (RNA interference) interventions to modulate the activity of CHRNA5 in non-transformed bronchial cells and in lung cancer cell lines. In both cell types, silencing CHRNA5 or inhibiting receptors containing nAChR alpha5 with alpha-conotoxin MII exerted a nicotine-like effect, with increased motility and invasiveness in vitro and increasing calcium influx. The effects on motility were enhanced by addition of nicotine but blocked by inhibiting CHRNA7, which encodes the homopentameric receptor alpha7 subunit. Silencing CHRNA5 also decreased the expression of cell adhesion molecules P120 and ZO-1 in lung cancer cells as well as the expression of DeltaNp63alpha in squamous cell carcinoma cell lines. These results demonstrate a role for CHRNA5 in modulating adhesion and motility in bronchial cells, as well as in regulating p63, a potential oncogene in squamous cell carcinoma. PMID- 21586514 TI - Development and validation of a timed urinary collection system for use in the cat. AB - The aim of the study was to develop and validate a feline urinary collection system for accurate 24 h urine output measurement and glomerular filtration rate (GFR) evaluation. We hypothesized that precise identification of urination time improves the accuracy of the collection system. In a group of nine cats, urinary volume and micturition times were repeatedly recorded for up to 48 h using purpose-built collection trays containing a temperature data logger. Collection time was determined both with and without using the data loggers on 22 occasions and agreement between estimated 24 h urine outputs obtained with the two calculation methods was evaluated. GFR was repeatedly measured by endogenous urinary creatinine clearance on three occasions. Twenty-four-hour urine output was measured in 98.5% of the attempted collections (300 cat-sampling days). Sensitivity and specificity of the detection system were 97.8% and 100%, respectively. Mean 24 h urine output was 12.4 +/- 4.94 mL/kg/day and mean intra cat between-days coefficient of variation (CV) was 16.6 +/- 5.6% when data loggers were used. The absolute relative volume error between the two calculation methods ranged from 0% to 131%. Median absolute relative [interquartile range] error was 9.1% [3.25-19.8]. Bias was -1.3% and lower and upper limits of agreement were -39.7% and 35.2%, respectively. Mean estimated GFR was lower than previously reported with comparable urinary clearance methods (1.92 +/- 0.37 mL/min/kg) and mean within-cat CV was 12 +/- 6.9%. The system was simple in design, readily affordable, allowed normal micturition behaviour and reduced intra-animal variability in 24 h feline urine collection. PMID- 21586513 TI - Prevention of carcinogenesis and inhibition of breast cancer tumor burden by dietary stearate. AB - Previous studies have shown that stearate (C18:0), a dietary long-chain saturated fatty acid, inhibits breast cancer cell neoplastic progression; however, little is known about the mechanism modulating these processes. We demonstrate that stearate, at physiological concentrations, inhibits cell cycle progression in human breast cancer cells at both the G(1) and G(2) phases. Stearate also increases cell cycle inhibitor p21(CIP1/WAF1) and p27(KIP1) levels and concomitantly decreases cyclin-dependent kinase 2 (Cdk2) phosphorylation. Our data also show that stearate induces Ras- guanosine triphosphate formation and causes increased phosphorylation of extracellular signal-regulated kinase (pERK). The MEK1 inhibitor, PD98059, reversed stearate-induced p21(CIP1/WAF1) upregulation, but only partially restored stearate-induced dephosphorylation of Cdk2. The Ras/mitogen-activated protein kinase/ERK pathway has been linked to cell cycle regulation but generally in a positive way. Interestingly, we found that stearate inhibits both Rho activation and expression in vitro. In addition, constitutively active RhoC reversed stearate-induced upregulation of p27(KIP1), providing further evidence of Rho involvement. To test the effect of stearate in vivo, we used the N-Nitroso-N-methylurea rat breast cancer carcinogen model. We found that dietary stearate reduces the incidence of carcinogen-induced mammary cancer and reduces tumor burden. Importantly, mammary tumor cells from rats on a stearate diet had reduced expression of RhoA and B as well as total Rho compared with a low-fat diet. Overall, these data indicate that stearate inhibits breast cancer cell proliferation by inhibiting key check points in the cell cycle as well as Rho expression in vitro and in vivo and inhibits tumor burden and carcinogen-induced mammary cancer in vivo. PMID- 21586515 TI - Occupational exposure to isoflurane during anaesthesia induction with standard and scavenging double masks in dogs, pigs and ponies. AB - Induction of anaesthesia using a face mask may cause workplace pollution with anaesthetics. The aim of this study was to compare the effect of the use of a standard versus a scavenging double face mask on isoflurane pollution during induction of anaesthesia in experimental animals: six dogs, 12 pigs and five ponies. Pigs were anaesthetized only once using either mask type randomly (n = 6). Dogs and ponies were anaesthetized twice, using different mask types for each occasion in a random order with at least 14 days between experiments. The masks were attached to a Bain breathing system (dogs and pigs) or to a circle system (ponies) using a fresh gas flow of 300 or 50 mL/kg/min, respectively, with 5% vaporizer dial setting. Isoflurane concentrations were measured in the anaesthetist's breathing zone using an infrared photoacoustic spectrometer. The peak isoflurane concentrations (pollution) during baseline and induction periods were compared with Wilcoxon test in all species, and values between the mask types were compared with either Wilcoxon (ponies and dogs) or Mann-Whitney tests (pigs) (P < 0.05). Pollution was higher during induction when compared with baseline regardless of the mask type used but it was only statistically significant in dogs and pigs. Pollution was lower during induction with double versus single masks but it was only significant in pigs. Despite the lack of statistical significance, large and consistent differences were noted in all species, hence using scavenging masks is recommended to reduce isoflurane workplace pollution. PMID- 21586516 TI - Sensitive and fast mapping of di-base encoded reads. AB - MOTIVATION: Discovering variation among high-throughput sequenced genomes relies on efficient and effective mapping of sequence reads. The speed, sensitivity and accuracy of read mapping are crucial to determining the full spectrum of single nucleotide variants (SNVs) as well as structural variants (SVs) in the donor genomes analyzed. RESULTS: We present drFAST, a read mapper designed for di-base encoded 'color-space' sequences generated with the AB SOLiD platform. drFAST is specially designed for better delineation of structural variants, including segmental duplications, and is able to return all possible map locations and underlying sequence variation of short reads within a user-specified distance threshold. We show that drFAST is more sensitive in comparison to all commonly used aligners such as Bowtie, BFAST and SHRiMP. drFAST is also faster than both BFAST and SHRiMP and achieves a mapping speed comparable to Bowtie. AVAILABILITY: The source code for drFAST is available at http://drfast.sourceforge.net PMID- 21586517 TI - Hidden conformations in protein structures. AB - MOTIVATION: Prediction of interactions between protein residues (contact map prediction) can facilitate various aspects of 3D structure modeling. However, the accuracy of ab initio contact prediction is still limited. As structural genomics initiatives move ahead, solved structures of homologous proteins can be used as multiple templates to improve contact prediction of the major conformation of an unsolved target protein. Furthermore, multiple templates may provide a wider view of the protein's conformational space. However, successful usage of multiple structural templates is not straightforward, due to their variable relevance to the target protein, and because of data redundancy issues. RESULTS: We present here an algorithm that addresses these two limitations in the use of multiple structure templates. First, the algorithm unites contact maps extracted from templates sharing high sequence similarity with each other in a fashion that acknowledges the possibility of multiple conformations. Next, it weights the resulting united maps in inverse proportion to their evolutionary distance from the target protein. Testing this algorithm against CASP8 targets resulted in high precision contact maps. Remarkably, based solely on structural data of remote homologues, our algorithm identified residue-residue interactions that account for all the known conformations of calmodulin, a multifaceted protein. Therefore, employing multiple templates, which improves prediction of contact maps, can also be used to reveal novel conformations. As multiple templates will soon be available for most proteins, our scheme suggests an effective procedure for their optimal consideration. AVAILABILITY: A Perl script implementing the WMC algorithm described in this article is freely available for academic use at http://tau.ac.il/~haimash/WMC. PMID- 21586519 TI - 3FunMap: full-sib family functional mapping of dynamic traits. AB - MOTIVATION: Functional mapping that embeds the developmental mechanisms of complex traits shows great power to study the dynamic pattern of genetic effects triggered by individual quantitative trait loci (QTLs). A full-sib family, produced by crossing two heterozygous parents, is characteristic of uncertainties about cross-type at a locus and linkage phase between different loci. Integrating functional mapping into a full-sib family requires a model selection procedure capable of addressing these uncertainties. 3FunMap, written in VC++ 6.0, provides a flexible and extensible platform to perform full-sib functional mapping of dynamic traits. Functions in the package encompass linkage phase determination, marker map construction and the pattern identification of QTL segregation, dynamic tests of QTL effects, permutation tests and numerical simulation. We demonstrate the features of 3FunMap through real data analysis and computer simulation. AVAILABILITY: http://statgen.psu.edu/software. PMID- 21586518 TI - Prediction of peptides binding to the PKA RIIalpha subunit using a hierarchical strategy. AB - MOTIVATION: Favorable interaction between the regulatory subunit of the cAMP dependent protein kinase (PKA) and a peptide in A-kinase anchoring proteins (AKAPs) is critical for translocating PKA to the subcellular sites where the enzyme phosphorylates its substrates. It is very hard to identify AKAPs peptides binding to PKA due to the high sequence diversity of AKAPs. RESULTS: We propose a hierarchical and efficient approach, which combines molecular dynamics (MD) simulations, free energy calculations, virtual mutagenesis (VM) and bioinformatics analyses, to predict peptides binding to the PKA RIIalpha regulatory subunit in the human proteome systematically. Our approach successfully retrieved 15 out of 18 documented RIIalpha-binding peptides. Literature curation supported that many newly predicted peptides might be true AKAPs. Here, we present the first systematic search for AKAP peptides in the human proteome, which is useful to further experimental identification of AKAPs and functional analysis of their biological roles. PMID- 21586520 TI - Genome-wide association studies pipeline (GWASpi): a desktop application for genome-wide SNP analysis and management. AB - MOTIVATION: Genome-wide association studies (GWAS) based on single nucleotide polymorphism (SNP) arrays are the most widely used approach to detect loci associated to human traits. Due to the complexity of the methods and software packages available, each with its particular format requiring intricate management workflows, the analysis of GWAS usually confronts scientists with steep learning curves. Indeed, the wide variety of tools makes the parsing and manipulation of data the most time consuming and error prone part of a study. To help resolve these issues, we present GWASpi, a user-friendly, multiplatform, desktop-able application for the management and analysis of GWAS data, with a novel approach on database technologies to leverage the most out of commonly available desktop hardware. GWASpi aims to be a start-to-finish GWAS management application, from raw data to results, containing the most common analysis tools. As a result, GWASpi is easy to use and reduces in up to two orders of magnitude the time needed to perform the fundamental steps of a GWAS. AVAILABILITY: Freely available on the web at http://www.gwaspi.org. Implemented in Java, Apache-Derby and NetCDF-3, with all major operating systems supported. CONTACT: gwaspi@upf.edu; arcadi.navarro@upf.edu. PMID- 21586521 TI - Comment on: Familial Mediterranean fever caused by homozygous E148Q mutation complicated by Budd-Chiari syndrome and polyarteritis nodosa. PMID- 21586522 TI - Knocking out of CD38 accelerates development of a lupus-like disease in lpr mice. AB - OBJECTIVES: CD38 participates in lymphocyte ontogeny and function and may be involved in autoimmunity. Absence of CD38 accelerates development of non-obese diabetic (NOD) mice diabetes and anti-CD38 antibodies are good markers of human disease. Little is known regarding systemic autoimmunity. Active SLE patients have higher numbers of CD38(+) T and B cells. CD38 is a candidate gene for the murine Lmb2 lupus locus. We aimed to investigate whether CD38 was involved in lupus development. METHODS: We developed Cd38(-/-)-Fas(lpr)/Fas(lpr) mice and monitored them for development of a lupus-like disease through measurement of protein excretion in urine, histological assessment of the kidneys, quantification of circulating immunoglobulins and autoantibodies. We have also immunophenotyped 2- and 6-month old Cd38(-/-)-Fas(lpr)/Fas(lpr) mice. RESULTS: We found that absence of CD38 accelerated disease development: female Cd38(-/-) Fas(lpr)/Fas(lpr) mice presented severe proteinuria, GN, deposition of ICs in the renal medulla and increased amounts of circulating immunoglobulin G (IgG), although anti-dsDNA autoantibodies and RF were not significantly increased at disease onset. We have found that Cd38(-/-)-Fas(lpr)/Fas(lpr) male mice, similarly to other murine models of lupus, were able to control disease. Absence of CD38 in lpr mice altered differentiation of T cells and dendritic cells (DC). CONCLUSION: Although the role of CD38 in tolerance is still to be elucidated, we provide evidence that it may play an active role in the control of a murine lupus like disease. PMID- 21586523 TI - Carpal tunnel syndrome and its relationship to occupation: a meta-analysis. AB - OBJECTIVE: To examine the association between work place exposure and CTS by meta analysis, including analyses with respect to exposure to hand force, repetition, vibration and wrist posture. METHODS: All relevant peer-reviewed articles published between January 1980 and December 2009 were identified by a systematic search using the MEDLINE, CINAHL and PubMed databases. Papers were critiqued independently by two researchers and the relevant exposure information was extracted. Using the raw data of exposed and unexposed cases, a cumulative effect of specific exposure risks were calculated for hand force, repetition, a combination of force and repetition, vibration and wrist posture using the statistical program, Stata version 11 (StataCorp, College Station, TX, USA). Heterogeneity, meta-regression, publication bias and subgroup sensitivity analyses were performed. RESULTS: Thirty-seven studies from English-language literature met the inclusion criteria. Using National Institute for Occupational Health and Safety criteria for case definition, a significant positive association between CTS and hand force, repetition, use of vibratory tools and wrist posture was observed with approximate doubling of risk for all exposures. Significant heterogeneity among studies was observed for most exposures and metaregression analyses identified CTS case definition, study design, country and risk of bias score to be the significant determinants. When a more conservative definition of CTS was employed to include nerve conduction abnormality with symptoms and/or signs, risk factors significantly associated with an increased risk of CTS among exposed workers were: vibration [odds ratio (OR) 5.40; 95% CI 3.14, 9.31], hand force (OR 4.23; 95% CI 1.53, 11.68) and repetition (OR 2.26; 95% CI 1.73, 2.94). There was a non-significant trend for the association between CTS and combined exposure to both force and repetition (OR 1.85; 95% CI 0.99, 3.45) and wrist posture (OR 4.73; 95% CI 0.42, 53.32). CONCLUSION: Occupational exposure to excess vibration, increased hand force and repetition increase the risk of developing CTS. Workplace strategies to avoid overexposure to these risk factors should be implemented. PMID- 21586525 TI - Qualitative research in RA. PMID- 21586524 TI - Lack of association between Toll-like receptor 4 gene polymorphisms and giant cell arteritis. AB - OBJECTIVE: Coding variants in Toll-like receptor 4 (TLR4) have been reported to be associated with inflammatory diseases. The aim of this study was to determine whether two of these polymorphisms (+896 A/G and +1196 C/T) are associated with susceptibility and clinical features of GCA. We also attempted to correlate the functional consequences of these polymorphisms. METHODS: A total of 72 patients with GCA and 126 age-matched controls were genotyped using allele-specific PCR and restriction fragment length polymorphism analysis. TLR4 expression was studied on peripheral blood mononuclear cells by flow cytometry and TLR4 function was assessed by stimulating monocytes in vitro with a specific ligand. RESULTS: There was no significant difference in allele frequency or genotype of TLR4 (+896 A/G and +1196 C/T) between GCA patients and controls. The clinical characteristics of these patients were unrelated to the presence of these polymorphisms. Furthermore, we did not observe an association with TLR4 expression or a distinct phenotype of TLR4 response with the +896 A/G and +1196 C/T genotypes. CONCLUSION: Our results do not support the association of these TLR4 variants with GCA. Studies including a larger number of patients and patient populations from different geographical origin are needed. PMID- 21586527 TI - Spontaneous resting-state BOLD fluctuations reveal persistent domain-specific neural networks. AB - Resting-state functional connectivity MRI (rs-fcMRI) analyses have identified intrinsic neural networks supporting domain-general cognitive functions including language, attention, executive control and memory. The brain, however, also has a domain-specific organization, including regions that contribute to perceiving and knowing about others (the 'social' system) or manipulable objects designed to perform specific functions (the 'tool' system). These 'social' and 'tool' systems, however, might not constitute intrinsic neural networks per se, but rather only come online as needed to support retrieval of domain-specific information during social- or tool-related cognitive tasks. To address this issue, we functionally localized two regions in lateral temporal cortex activated when subjects perform social- and tool conceptual tasks. We then compared the strength of the correlations with these seed regions during rs-fcMRI. Here, we show that the 'social' and 'tool' neural networks are maintained even when subjects are not engaged in social- and tool-related information processing, and so constitute intrinsic domain-specific neural networks. PMID- 21586528 TI - Relationships between tree size, crown shape, gender segregation and sex allocation in Pinus halepensis, a Mediterranean pine tree. AB - BACKGROUND AND AIMS: Sex allocation has been studied mainly in small herbaceous plants but much less in monoecious wind-pollinated trees. The aim of this study was to explore changes in gender segregation and sex allocation by Pinus halepensis, a Mediterranean lowland pine tree, within tree crowns and between trees differing in their size or crown shape. METHODS: The production of new male and female cones and sex allocation of biomass, nitrogen and phosphorus were studied. The relationship between branch location, its reproductive status and proxies of branch vigour was also studied. KEY RESULTS: Small trees produced only female cones, but, as trees grew, they produced both male and female cones. Female cones were produced mainly in the upper part of the crown, and male cones in its middle and lower parts. Lateral branch density was correlated with the number of male but not female cones; lateral branches were more dense in large than in small trees and even denser in hemispherical trees. Apical branches grew faster, were thicker and their phosphorus concentration was higher than in lateral shoots. Nitrogen concentration was higher in cone-bearing apical branches than in apical vegetative branches and in lateral branches with or without cones. Allocation to male relative to female function increased with tree size as predicted by sex allocation theory. CONCLUSIONS: The adaptive values of sex allocation and gender segregation patterns in P. halepensis, in relation to its unique life history, are demonstrated and discussed. Small trees produce only female cones that have a higher probability of being pollinated than the probability of male cones pollinating; the female-first strategy enhances population spread. Hemispherical old trees are loaded with serotinous cones that supply enough seeds for post-fire germination; thus, allocation to males is more beneficial than to females. PMID- 21586529 TI - Tetraploidization events by chromosome doubling of nucellar cells are frequent in apomictic citrus and are dependent on genotype and environment. AB - BACKGROUND AND AIMS: Polyploidy is a major component of plant evolution. The citrus gene pool is essentially diploid but tetraploid plants are frequently encountered in seedlings of diploid apomictic genotypes. The main objectives of the present study were to establish the origin of these tetraploid plants and to ascertain the importance of genotypic and environmental factors on tetraploid formation. METHODS: Tetraploid seedlings from 30 diploid apomictic genotypes were selected by flow cytometry and genotyped with 24 single sequence repeat (SSR) markers to analyse their genetic origin. Embryo rescue was used to grow all embryos contained in polyembryonic seeds of 'Tardivo di Ciaculli' mandarin, followed by characterization of the plantlets obtained by flow cytometry and SSR markers to accurately establish the rate of tetraploidization events and their potential tissue location. Inter-annual variations in tetraploid seedling rates were analysed for seven genotypes. Variation in tetraploid plantlet rates was analysed between different seedlings of the same genotype ('Carrizo' citrange; Citrus sinensis * Poncirus trifoliata) from seeds collected in different tropical, subtropical and Mediterranean countries. KEY RESULTS: Tetraploid plants were obtained for all the studied diploid genotypes, except for four mandarins. All tetraploid plants were identical to their diploid maternal line for SSR markers and were not cytochimeric. Significant genotypic and environmental effects were observed, as well as negative correlation between mean temperature during the flowering period and tetraploidy seedling rates. The higher frequencies (20 %) of tetraploids were observed for citranges cultivated in the Mediterranean area. CONCLUSIONS: Tetraploidization by chromosome doubling of nucellar cells are frequent events in apomictic citrus, and are affected by both genotypic and environmental factors. Colder conditions in marginal climatic areas appear to favour the expression of tetraploidization. Tetraploid genotypes arising from chromosome doubling of apomictic citrus are extensively being used as parents in breeding programmes to develop seedless triploid cultivars and have potential direct use as new rootstocks. PMID- 21586530 TI - Juvenility and flowering of Brunonia australis (Goodeniaceae) and Calandrinia sp. (Portulacaceae) in relation to vernalization and daylength. AB - BACKGROUND AND AIMS: The time at which plants are transferred to floral inductive conditions affects the onset of flowering and plant morphology, due to juvenility. Plants of Brunonia australis and Calandrinia sp. were used to investigate whether Australian native ephemeral species show a distinct juvenile phase that can be extended to increase vegetative growth and flowering. METHODS: The juvenile phase was quantified by transferring seedlings from less inductive (short day and 30/20 degrees C) to inductive (vernalization or long day) conditions at six different plant ages ranging from 4 to 35 d after seed germination. An increase in days to first visible floral bud and leaf number were used to signify the end of juvenility. KEY RESULTS: Brunonia australis was receptive to floral inductive long day conditions about 18-22 d after seed germination, whereas plants aged 4-35 d appeared vernalization sensitive. Overall, transferring plants of B. australis from short to long day conditions reduced the time to anthesis compared with vernalization or constant short day conditions. Calandrinia sp. showed a facultative requirement for vernalization and an insensitive phase was not detected. Floral bud and branch production increased favourably as plant age at time of transfer to inductive conditions increased. Younger plants showed the shortest crop production time. CONCLUSIONS: Both species can perceive the vernalization floral stimulus from a very young age, whereas the photoperiodic stimulus is perceived by B. australis after a period of vegetative growth. However, extending the juvenile phase can promote foliage development and enhance flower production of both species. PMID- 21586531 TI - The ERECTA gene controls spatial and temporal patterns of epidermal cell number and size in successive developing leaves of Arabidopsis thaliana. AB - BACKGROUND AND AIMS: ERECTA has been identified as a pleiotropic regulator of developmental and physiological processes in Arabidopsis thaliana. Previous work demonstrated a role for ERECTA in the control of compensation between epidermal cell expansion and division in leaves. METHODS: In this work, spatial and temporal analyses of epidermal cell division and expansion were performed on successive developing vegetative leaves of Arabidopsis thaliana in both ERECTA and erecta lines, LER and Ler, respectively, to understand how the ERECTA gene regulates compensation between these two processes. KEY RESULTS: The loss of ERECTA function leads to a low cell expansion rate in all zones of a leaf and in all successive leaves of a plant. This low cell expansion rate is counterbalanced by an increase in the duration of cell division. As a consequence, the ERECTA mutation eliminates the tip to base cellular gradient generally observed in the leaf epidermis and also flattens the heteroblastic changes in epidermal cell area and number within a rosette. Ablation of floral buds eliminates the heteroblastic changes in cellular patterns in an ERECTA-dependent manner. CONCLUSIONS: The results provide a detailed description of changes in leaf growth dynamics and cellular variables in both LER and Ler. Altogether they suggest that ERECTA influences leaf cellular development in relation to whole plant ontogeny. PMID- 21586532 TI - Exploration for functional nucleotide sequence candidates within coding regions of mammalian genes. AB - The primary role of a protein coding gene is to encode amino acids. Therefore, synonymous sites of codons, which do not change the encoded amino acid, are regarded as evolving neutrally. However, if a certain region of a protein coding gene contains a functional nucleotide element (e.g. splicing signals), synonymous sites in the region may have selective pressure. The existence of such elements would be detected by searching regions of low nucleotide substitution. We explored invariant nucleotide sequences in 10,790 orthologous genes of six mammalian species (Homo sapiens, Macaca mulatta, Mus musculus, Rattus norvegicus, Bos taurus, and Canis familiaris), and extracted 4150 sequences whose conservation is significantly stronger than other regions of the gene and named them significantly conserved coding sequences (SCCSs). SCCSs are observed in 2273 genes. The genes are mainly involved with development, transcriptional regulation, and the neurons, and are expressed in the nervous system and the head and neck organs. No strong influence of conventional factors that affect synonymous substitution was observed in SCCSs. These results imply that SCCSs may have double function as nucleotide element and protein coding sequence and retained in the course of mammalian evolution. PMID- 21586533 TI - In silico analysis of 3'-end-processing signals in Aspergillus oryzae using expressed sequence tags and genomic sequencing data. AB - To investigate 3'-end-processing signals in Aspergillus oryzae, we created a nucleotide sequence data set of the 3'-untranslated region (3' UTR) plus 100 nucleotides (nt) sequence downstream of the poly(A) site using A. oryzae expressed sequence tags and genomic sequencing data. This data set comprised 1065 sequences derived from 1042 unique genes. The average 3' UTR length in A. oryzae was 241 nt, which is greater than that in yeast but similar to that in plants. The 3' UTR and 100 nt sequence downstream of the poly(A) site is notably U-rich, while the region located 15-30 nt upstream of the poly(A) site is markedly A rich. The most frequently found hexanucleotide in this A-rich region is AAUGAA, although this sequence accounts for only 6% of all transcripts. These data suggested that A. oryzae has no highly conserved sequence element equivalent to AAUAAA, a mammalian polyadenylation signal. We identified that putative 3'-end processing signals in A. oryzae, while less well conserved than those in mammals, comprised four sequence elements: the furthest upstream U-rich element, A-rich sequence, cleavage site, and downstream U-rich element flanking the cleavage site. Although these putative 3'-end-processing signals are similar to those in yeast and plants, some notable differences exist between them. PMID- 21586534 TI - A cell-based assay to screen stimulators of the Hippo pathway reveals the inhibitory effect of dobutamine on the YAP-dependent gene transcription. AB - The mammalian Hippo pathway is composed of mammalian Ste20-like (MST) kinases and large tumour suppressor (LATS) kinases. Upon the activation of the pathway, MST kinases phosphorylate and activate LATS kinases, which in turn phosphorylate transcriptional co-activators, yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), recruit them to the cytosol from the nucleus and turn off cell cycle-promoting and anti-apoptotic gene transcriptions. Thus, the pathway restricts cell overgrowth and prevents tumourigenesis. Although a high cell density and stress signallings are known to activate the pathway, no specific stimulators are so far reported. As the dysfunction of the pathway is frequent in human cancers and correlates with poor prognosis, it is important to find out reagents that stimulate the pathway for not only basic research but also clinical medicine. We here developed a cell-based method of screening reagents that induce the recruitment of YAP to the cytosol. Using this method, we found that dobutamine inhibits the YAP-dependent gene transcription. Contrary to our expectations, the effect of dobutamine is independent of the Hippo pathway but our method opens the possibility to discover Hippo pathway stimulators or Hippo independent YAP inhibitors. PMID- 21586535 TI - Role of Asp187 and Gln190 in the Na+/proline symporter (PutP) of Escherichia coli. AB - Asp187 and Gln190 were predicted as conserved and closely located at the Na(+) binding site in a topology and homology model structure of Na(+)/proline symporter (PutP) of Escherichia coli. The replacement of Asp187 with Ala or Leu did not affect proline transport activity; whereas, change to Gln abolished the active transport. The binding affinity for Na(+) or proline of these mutants was similar to that of wild-type (WT) PutP. This result indicates Asp187 to be responsible for active transport of proline without affecting the binding. Replacement of Gln190 with Ala, Asn, Asp, Leu and Glu had no effect on transport or binding, suggesting that it may not have a role in the transport. However, in the negative D187Q mutant, a second mutation, of Gln190 to Glu or Leu, restored 46 or 7% of the transport activity of WT, respectively, while mutation to Ala, Asn or Asp had no effect. Thus, side chain at position 190 has a crucial role in suppressing the functional defect of the D187Q mutant. We conclude that Asp187 is responsible for transport activity instead of coupling-ion binding by constituting the translocation pathway of the ion and Gln190 provides a suppressing mutation site to regain PutP functional activity. PMID- 21586536 TI - Prognostic value of left atrial volume index in patents with first acute myocardial infarction. AB - AIMS: We evaluated the usefulness of left atrial volume index (LAVI) and the degree of changes in LAVI (delta LAVI) during hospitalization for the prediction of prognosis after acute myocardial infarction (AMI). METHODS AND RESULTS: We investigated 205 consecutive patients with first AMI. They underwent echocardiography on admission as well as at discharge. Delta LAVI was calculated by subtracting the value on admission from that at discharge. The primary endpoints were major cardiac events (MACE): cardiac death due to heart failure and heart failure hospitalization. During a mean follow-up of 26 months, MACE occurred in 29 patients. Patients were divided into two groups according to the optimal cut-off values of LAVI (32.0 mL/m(2)) at discharge and delta LAVI (2.5 mL/m(2)) derived from receiver operating characteristic curves, respectively; Group I: LAVI <= 32.0 mL/m(2), Group II: LAVI > 32.0 mL/m(2) and Group A: delta LAVI <= 2.5 mL/m(2), Group B: delta LAVI > 2.5 mL/m(2). In comparisons of two groups, respectively, the incidence of MACE between the groups showed significant differences [Group I (3.8%) vs. Group II (32.0%): P < 0.001, log-rank, Group A (7.4%) vs. Group B (20.0%): P = 0.0079, log-rank]. In multivariate analysis, LAVI at discharge [risk ratio (RR): 1.077, 95% CI: 1.035-1.124, P = 0.0002] and delta LAVI (RR: 1.056, 95% CI: 1.012-1.108, P = 0.0109) were significant. LAVI > 32.0 mL/m(2) at discharge (sensitivity: 93%, specificity: 69%) and delta LAVI > 2.5 mL/m(2) (sensitivity: 79%, specificity: 50%) were predictors of MACE. CONCLUSION: LAVI at discharge and delta LAVI would be useful predictors for MACE after first AMI. PMID- 21586537 TI - Utility of transthoracic echocardiography in characterizing proximal protrusion of a coronary stent. PMID- 21586538 TI - Additive neurocognitive deficits in adults with attention-deficit/hyperactivity disorder and depressive symptoms. AB - The purpose of this study was to examine the possible additive neurocognitive deficits in adults with both attention-deficit/hyperactivity disorder (ADHD) and serious depressive symptoms. Participants were 54 university students who completed a psycho-educational assessment. Three groups were examined: a group with comorbid ADHD and elevated depressive symptoms (ADHD + DEP; N = 18); a group with ADHD only (N = 18); and a group with elevated depressive symptoms only (DEP; N = 18). Group differences were examined on a battery of neurocognitive tests. The ADHD + DEP group performed significantly worse than the other groups on processing speed tasks and delayed recall of conceptual verbal information and significantly worse than the ADHD group on shifting tasks. Depressive symptom severity was significantly correlated with processing speed, verbal memory performance, and shifting in the ADHD and ADHD + DEP groups. Results suggest that the co-occurrence of ADHD and depressive symptoms in adults is associated with additional neurocognitive impairment. PMID- 21586539 TI - Comparison of different dosimetric methods for red marrow absorbed dose calculation in thyroid cancer therapy. AB - Several dosimetric methods have been proposed for estimating red marrow absorbed dose (RMAD) when radionuclide therapy is planned for differentiated thyroid cancer, although to date, there is no consensus as to whether dose calculation should be based on blood-activity concentration or not. Our purpose was to compare RMADs derived from methods that require collecting patients' blood samples versus those involving OLINDA/EXM software, thereby precluding this invasive procedure. This is a retrospective study that included 34 patients under treatment for metastatic thyroid disease. A deviation of <10 % between RMADs was found, when comparing the doses from the most usual invasive dosimetric methods and those from OLINDA/EXM. No statistical difference between the methods was discovered, whereby the need for invasive procedures when calculating the dose is questioned. The use of OLINDA/EXM in clinical routine could possibly diminish data collection, thus giving rise to a simultaneous reduction in time and clinical costs, besides avoiding any kind of discomfort on the part of the patients involved. PMID- 21586540 TI - A pilot study of the dependence of radon concentration on the tectonic structures, using simple geophysical methods. AB - It is well known that there are great variations in radon concentrations in the soil gas on building sites. The concentration may sometimes vary by more than two orders of magnitude. The tectonic structure of the bedrock is one of the factors that influence the intensity of the radon outflow. The simple ARES geophysical method [automatic resistivity system--main unit with standard accessories, multi electrode cable sections (MCS5)--eight electrodes per 5 m spacing] was used in various modes (Schlumberger, Dipole-Dipole and Pole-Dipole arrays) for in situ tectonic structure determination. The radon concentration in the soil gas was measured using the same network as for the resistivity measurements. The radon measurements were also followed up by in situ gamma spectrometry measurements. The behaviour of the radon concentration in the soil gas was correlated with the detected tectonic non-homogeneities. This pilot study opened up new questions for future analysis. PMID- 21586541 TI - Radon exchange dynamics in a karst system investigated by radon continuous measurements in water: first results. AB - In 2008 the underground Karst Laboratory of Bossea Cave started research on radon exchange dynamics between bedrock, cave waters (main collector and percolations) and indoor underground atmosphere. Radon air concentrations, normally high, increase more and more during the collector's floods. An explanation of this is a radon-water solubilisation process more effective in flood events, because of a greater rock-water contact surface. Radon is then carried by water into the cave and released into the air. To verify this, continuous measurements of radon concentration are needed not only in the air, but also in the waters of the cave. So a new device for continuous radon monitoring in water was tested, connected to the AlphaGuard radon monitor. For the first 6 months of 2010, for different sections of the cave, the correlations between radon in the air, radon in the waters and the collector's stream flow fluctuations were presented and discussed. PMID- 21586542 TI - Radon in workplaces: first results of an extensive survey and comparison with radon in homes. AB - Extensive radon surveys have been carried out in many countries only in dwellings, whereas surveys in workplaces are rather sparse and generally restricted to specific workplaces/activities, e.g. schools, spas and caves. Moreover, radon-prone areas are generally defined on the basis of radon surveys in dwellings, while radon regulations use this concept to introduce specific requirements in workplaces in such areas. This approach does not take into account that work activities and workplace characteristics can significantly affect radon concentration. Therefore, an extensive survey on radon in different workplaces have been carried out in a large region of Italy (Tuscany), in order to evaluate radon distribution in workplaces over the whole territory and to identify activities and workplace characteristics affecting radon concentration. The results of this extensive survey are compared with the results of the survey carried out in dwellings in the same period. The workplaces monitored were randomly selected among the main work activities in the region, including both public and industrial buildings. The survey monitored over 3500 rooms in more than 1200 buildings for two consecutive periods of ~6 months. Radon concentration was measured by means of passive nuclear track detectors. PMID- 21586543 TI - Radon lung dosimetry models. AB - Two different modelling approaches are currently used to calculate short-lived radon progeny doses to the lungs: the semi-empirical compartment model proposed by the International Commission on Radiological Protection and deterministic and stochastic airway generation models. The stochastic generation model IDEAL-DOSE simulates lung morphometry, transport, deposition and clearance of inhaled radionuclides, and cellular dosimetry by Monte Carlo methods. Specific dosimetric issues addressed in this paper are: (1) distributions of bronchial doses among and within bronchial airway generations; (2) relative contributions of radon progeny directly deposited in a given airway generation and those passing through from downstream generations to the bronchial dose in that generation; (3) distribution of bronchial doses among the five lobes of the human lung; (4) inhomogeneity of surface activities and resulting doses within bronchial airway bifurcations; (5) comparison of bronchial doses between non-smokers and smokers; (6) relative contributions of sensitive target cells in bronchial epithelium to lung cancer induction and (7) intra- and intersubject variations of bronchial doses. PMID- 21586544 TI - Statistical model of quality of radon measurements using electret ion chamber detectors. AB - This paper presents a statistical model for estimating probability, which states that a quality of radon measurements using the electret ion chamber system RM-1 will be accurate. The quality of the electret measurement was modelled as a ratio between the reference radon concentration and values measured under real conditions with varied levels of indoor radon concentration and microclimate indoor conditions. It was stated that the accuracy tolerance of measured values is 20 % of the given reference value. To estimate the uncertainty of the statistical model, the exact confidence limits for the estimated probabilities are computed. The statistical model was confirmed by an independent set of measurements. Moreover, the effect of absolute humidity on the quality estimation of electret detectors are also statistically analysed and discussed. The results of the statistical model confirm that the electret system is robust and suitable for estimation of radon concentration. PMID- 21586545 TI - Assessment of long-term radon concentration measurement precision in field conditions (Serbian Schools) for a survey carried out by an international collaboration. AB - In an international collaboration, a long-term radon concentration survey was carried out in schools of Southern Serbia with radon detectors prepared, etched and read-out in Italy. In such surveys it is necessary to evaluate measurement precision in field conditions, and to check whether quality assurance protocols were effective in keeping uncertainties under control, despite the complex organisation of measurements. In the first stage of the survey, which involves only some of the total number of municipalities, paired detectors were exposed in each monitored room in order to experimentally assess measurement precision. Paired passive devices (containing CR-39 detectors) were exposed for two consecutive 6-month periods. Two different measurement systems were used to read out CR-39s of the first and second period, respectively. The median of the coefficient of variation (CV) of the measured exposures was 8 % for 232 paired devices of the first 6-month period and 4 % for 242 paired devices of the second 6-month period, respectively. This difference was mainly due to a different track count repeatability of the two read-out systems, which was 4 and 1 %, respectively, as the median value of CV of repeated countings. The in-field measured precision results are very similar to the precision assessed in calibration conditions and are much lower than the room-to-room variation of radon concentration in the monitored schools. Moreover, a quality assurance protocol was followed to reduce extra-exposures during detector transport from Rome to schools measured and back. PMID- 21586546 TI - Evaluation and comparison of measurements of unattached and attached radon progeny in the radon chamber of PTB Braunschweig (Germany) with NRPI Praha (Czech Republic). AB - On the case of a parallel metrological measurement of unattached and attached concentrations of radon progeny, the evaluation by an inversion of the Jacobi Porstendorfer room model indicates a real overestimation of the concentration of RaA ((218)Po). PMID- 21586547 TI - Sperm flagella: comparative and phylogenetic perspectives of protein components. AB - Sperm motility is necessary for the transport of male DNA to eggs in species with both external and internal fertilization. Flagella comprise several proteins for generating and regulating motility. Central cytoskeletal structures called axonemes have been well conserved through evolution. In mammalian sperm flagella, two accessory structures (outer dense fiber and the fibrous sheath) surround the axoneme. The axonemal bend movement is based on the active sliding of axonemal doublet microtubules by the molecular motor dynein, which is divided into outer and inner arm dyneins according to positioning on the doublet microtubule. Outer and inner arm dyneins play different roles in the production and regulation of flagellar motility. Several regulatory mechanisms are known for both dyneins, which are important in motility activation and chemotaxis at fertilization. Although dynein itself has certain properties that contribute to the formation and propagation of flagellar bending, other axonemal structures-specifically, the radial spoke/central pair apparatus-have essential roles in the regulation of flagellar bending. Recent genetic and proteomic studies have explored several new components of axonemes and shed light on the generation and regulation of sperm motility during fertilization. PMID- 21586548 TI - hERGAPDbase: a database documenting hERG channel inhibitory potentials and APD prolongation activities of chemical compounds. AB - Drug-induced QT interval prolongation is one of the most common reasons for the withdrawal of drugs from the market. In the past decade, at least nine drugs, i.e. terfenadine, astemizole, grepafloxacin, terodiline, droperidol, lidoflazine, sertindole, levomethadyl and cisapride, have been removed from the market or their use has been severely restricted because of drug-induced QT interval prolongation. Therefore, this irregularity is a major safety concern in the case of drugs submitted for regulatory approval. The most common mechanism of drug induced QT interval prolongation may be drug-related inhibition of the human ether-a-go-go-related gene (hERG) channel, which subsequently results in prolongation of the cardiac action potential duration (APD). hERGAPDbase is a database of electrophysiological experimental data documenting potential hERG channel inhibitory actions and the APD-prolongation activities of chemical compounds. All data entries are manually collected from scientific papers and curated by a person. With hERGAPDbase, we aim to provide useful information for chemical and pharmacological scientists and enable easy access to electrophysiological experimental data on chemical compounds. Database URL: http://www.grt.kyushu-u.ac.jp/hergapdbase/. PMID- 21586549 TI - Development of a method for the determination of pulsatile growth hormone secretion in mice. AB - Measures of pulsatile GH secretion require frequent collection and analysis of blood samples at regular intervals. Due to blood volume constraints, repeat measures of circulating levels of GH in mice remain challenging. Consequently, few observations exist in which the pulsatile pattern of GH secretion in mice have been characterized. To address this, we developed a technique for the collection and analysis of circulating levels of GH at regular and frequent intervals in freely moving mice. This was achieved through the development of a sensitive assay for the detection of GH in small (2 MUl) quantities of whole blood. The specificity and accuracy of this assay was validated following guidelines established for single-laboratory validation as specified by the International Union of Pure and Applied Chemistry. We incorporated an established method for tail-clip blood sample collection to determine circulating levels of GH secretion in 36 whole blood samples collected consecutively over a period of 6 h. Resulting measures were characterized by peak secretion periods and interpulse stable baseline secretion periods. Periods characterized by elevated whole blood GH levels consisted of multicomponent peaks. Deconvolution analysis of resulting measures confirmed key parameters associated with pulsatile GH secretion. We show a striking decrease in pulsatile GH secretion in mice after 12-18 h of fasting. This model is necessary to characterize the pulsatile profile of GH secretion in mice and will significantly contribute to current attempts to clarify mechanisms that contribute to the regulation of GH secretion. PMID- 21586550 TI - Wild-type p53 attenuates cancer cell motility by inducing growth differentiation factor-15 expression. AB - A major function of the p53 tumor suppressor is the regulation of the cell cycle and apoptosis. In addition to its well-documented functions in malignant cancer cells, p53 can also regulate cell migration and invasion, which contribute to metastasis. Growth differentiation factor-15 (GDF-15), a member of the TGF-beta superfamily, has been shown to be a downstream target of p53 and is associated with diverse human diseases and cancer progression. In this study, we examined the potential role of GDF-15 in p53-regulated cancer cell motility. We show that overexpression of wild-type p53 in two highly invasive p53-null human cancer cell lines, SKOV3 and PC3, attenuated cell migration and the movement through Matrigel. Using wild-type p53 and DNA-binding-deficient p53 mutants, we found that the transcriptional activity of p53 is required in the induction of GDF-15 expression. Cell movement through uncoated and Matrigel-coated transwell decreased in response to treatment with recombinant GDF-15, whereas the cell proliferation was not affected by GDF-15 treatment. Moreover, the induction of GDF-15 expression and secretion by p53 and the reduction in cell movement through Matrigel were diminished by treatment with GDF-15 small interfering RNA. This study demonstrates a mechanism by which p53 attenuates cancer cell motility through GDF-15 expression. In addition, our results indicate that GDF-15 mediates the functions of p53 by autocrine/paracrine action. PMID- 21586551 TI - Perinatal exposure to bisphenol A at reference dose predisposes offspring to metabolic syndrome in adult rats on a high-fat diet. AB - Bisphenol A (BPA), a widely used environmental endocrine disruptor, has been reported to disrupt glucose homeostasis. BPA exposure may be a risk factor for type 2 diabetes. In this study, we investigated the effects of early-life BPA exposure on metabolic syndrome in rat offspring fed a normal diet and a high-fat diet. Pregnant Wistar rats were exposed to BPA (50, 250, or 1250 MUg/kg . d) or corn oil throughout gestation and lactation by oral gavage. Offspring were fed a normal diet or a high-fat diet after weaning. Body weight, parameters of glucose and lipid metabolism, morphology, and function of beta-cells were measured in offspring. On a normal diet, perinatal exposure to 50 MUg/kg . d BPA resulted in increased body weight, elevated serum insulin, and impaired glucose tolerance in adult offspring. On a high-fat diet, such detrimental effects were accelerated and exacerbated. Furthermore, severe metabolic syndrome, including obesity, dyslipidemia, hyperleptindemia, hyperglycemia, hyperinsulinemia, and glucose intolerance, was observed in high-fat-fed offspring perinatally exposed to 50 MUg/kg . d BPA. No adverse effect of perinatal BPA exposure at 250 and 1250 MUg/kg . d was observed no matter on a normal diet or a high-fat diet. These results suggest that perinatal exposure to BPA at reference dose, but not at high dose, impairs glucose tolerance in adult rat offspring on a normal diet and predisposes offspring to metabolic syndrome at adult on a high-fat diet. High-fat diet intake is a trigger that initiates adverse metabolic effects of BPA. PMID- 21586552 TI - Treatment with bazedoxifene, a selective estrogen receptor modulator, causes regression of endometriosis in a mouse model. AB - Endometriosis is a common estrogen-dependent disorder. Medical treatments currently consist of progestins or GnRH agonists; however, neither is fully effective and both entail significant side effects. Selective estrogen receptor (ER) modulators (SERM) have tissue-selective actions, acting as an ER agonist in some tissues and ER antagonist in others. The SERM bazedoxifene (BZA) effectively antagonizes estrogen-induced uterine endometrial stimulation without countering estrogenic effects in bone or central nervous system. These properties make it an attractive candidate for use in the treatment of endometriosis. Experimental endometriosis was created in reproductive-age CD-1 mice. After 8 wk, 10 animals received i.p. injections of BZA (3 mg/kg.d) for 8 wk, whereas 10 received vehicle control. Mice were killed, and implant size was assessed. The mean size of the implants after treatment was 60 mm(2) in the control group and 21 mm(2) in the BZA treatment group (P = 0.03). Quantitative PCR and immunohistochemical analysis were used to determine the effect on endometrial gene expression. PCNA, ERalpha, and LIF mRNA and protein expression were significantly decreased in endometrium of the treated group. Caspase 3 mRNA expression was increased. Expression of PR and Hoxa10 were not significantly altered by treatment. There was no evidence of ovarian enlargement or cyst formation. Decreased PCNA and ER expression demonstrated that the regression of endometriosis likely involved decreased estrogen-mediated cell proliferation. BZA may be an effective novel agent for the treatment of endometriosis due to greater endometrial-specific estrogen antagonism compared with other SERM. PMID- 21586553 TI - Pregnancy-associated plasma protein-A2 (PAPP-A2): tissue expression and biological consequences of gene knockout in mice. AB - Pregnancy-associated plasma protein-A2 (PAPP-A2) is a novel homolog of PAPP-A in the metzincin superfamily. However, compared with the accumulating data on PAPP A, very little is known about PAPP-A2. In this study, we determined the tissue expression pattern of PAPP-A2 mRNA in wild-type (WT) mice and characterized the phenotype of mice with global PAPP-A2 deficiency. Tissues expressing PAPP-A2 in WT mice were more limited than those expressing PAPP-A. The highest PAPP-A2 mRNA expression was found in the placenta, with abundant expression in fetal, skeletal, and reproductive tissues. Heterozygous breeding produced the expected Mendelian distribution for the pappa2 gene and viable homozygous PAPP-A2 knockout (KO) mice that were normal size at birth. The most striking phenotype of the PAPP A2 KO mouse was postnatal growth retardation. Male and female PAPP-A2 KO mice had 10 and 25-30% lower body weight, respectively, than WT littermates. Adult femur and body length were also reduced in PAPP-A2 KO mice, but without significant effects on bone mineral density. PAPP-A2 KO mice were fertile, but with compromised fecundity. PAPP-A expression was not altered to compensate for the loss of PAPP-A2 expression, and proteolysis of PAPP-A2's primary substrate, IGF binding protein-5, was not altered in fibroblasts from PAPP-A2 KO embryos. In conclusion, tissue expression patterns and biological consequences of gene KO indicate distinct physiological roles for PAPP-A2 and PAPP-A in mice. PMID- 21586554 TI - Steroidogenic factor-1 is required for TGF-beta3-mediated 17beta-estradiol synthesis in mouse ovarian granulosa cells. AB - The TGF-beta superfamily members are indicated to play key roles in ovarian follicular development, such as granulosa cell proliferation, estrogens, and progesterone production. However, little is known about the roles of TGF-beta3 in follicular development. In this study, we found that TGF-beta3 was predominantly expressed in granulosa cells of mouse ovarian follicles, and it significantly promoted 17beta-estradiol (E(2)) release in a dose-dependent manner. The orphan nuclear receptor steroidogenic factor-1 (SF-1) was required in TGF-beta3-induced Cyp19a1 (a key rate-limiting enzyme for estrogen biosynthesis) expression and E(2) release. Additionally, TGF-beta3 enhanced the binding of SF-1 to endogenous ovary-specific Cyp19a1 type II promoter, as evidenced by chromatin immunoprecipitation assays. The enhanced effect of SF-1 by TGF-beta3 may be mediated through functional interactions between SF-1 and mothers against decapentaplegic homolog (Smad)3 (a mediator of TGF-beta signaling pathway), because disruption of the interaction abolished the synergistic effects of SF-1, Smad3, and TGF-beta3 on Cyp19a1 mRNA expression. RNA interference and chromatin immunoprecipitation studies also demonstrated that Smad3 was required for SF-1 binding to Cyp19a1 type II promoter and activation of Cyp19a1. Smad3 thus acts as a point of convergence that involves integration of SF-1 and TGF-beta signaling in affecting E(2) production. Taken together, our data provide mechanistic insights into the roles of SF-1 in TGF-beta3-mediated E(2) synthesis. Understanding of potential cross-points between extracellular signals affecting estrogen production will help to discover new therapeutic targets in estrogen related diseases. PMID- 21586555 TI - Effects of farnesyl pyrophosphate accumulation on calvarial osteoblast differentiation. AB - Statins, drugs commonly used to lower serum cholesterol, have been shown to stimulate osteoblast differentiation and bone formation. Statins inhibit 3 hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase (HMGCR), the first step of the isoprenoid biosynthetic pathway, leading to the depletion of the isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). The effects of statins on bone have previously been attributed to the depletion of GGPP, because the addition of exogenous GGPP prevented statin-stimulated osteoblast differentiation in vitro. However, in a recent report, we demonstrated that the specific depletion of GGPP did not stimulate but, in fact, inhibited osteoblast differentiation. This led us to hypothesize that isoprenoids upstream of GGPP play a role in the regulation of osteoblast differentiation. We demonstrate here that the expression of HMGCR and FPP synthase decreased during primary calvarial osteoblast differentiation, correlating with decreased FPP and GGPP levels during differentiation. Zaragozic acid (ZGA) inhibits the isoprenoid biosynthetic pathway enzyme squalene synthase, leading to an accumulation of the squalene synthase substrate FPP. ZGA treatment of calvarial osteoblasts led to a significant increase in intracellular FPP and resulted in inhibition of osteoblast differentiation as measured by osteoblastic gene expression, alkaline phosphatase activity, and matrix mineralization. Simultaneous HMGCR inhibition prevented the accumulation of FPP and restored osteoblast differentiation. In contrast, specifically inhibiting GGPPS to lower the ZGA-induced increase in GGPP did not restore osteoblast differentiation. The specificity of HMGCR inhibition to restore osteoblast differentiation of ZGA-treated cultures through the reduction in isoprenoid accumulation was confirmed with the addition of exogenous mevalonate. Similar to ZGA treatment, exogenous FPP inhibited the mineralization of primary calvarial osteoblasts. Interestingly, the effects of FPP accumulation on osteoblasts were found to be independent of protein farnesylation. Our findings are the first to demonstrate that the accumulation of FPP impairs osteoblast differentiation and suggests that the depletion of this isoprenoid may be necessary for normal and statin-induced bone formation. PMID- 21586556 TI - The role of sonic hedgehog-Gli2 pathway in the masculinization of external genitalia. AB - During embryogenesis, sexually dimorphic organogenesis is achieved by hormones produced in the gonad. The external genitalia develop from a single primordium, the genital tubercle, and their masculinization processes depend on the androgen signaling. In addition to such hormonal signaling, the involvement of nongonadal and locally produced masculinization factors has been unclear. To elucidate the mechanisms of the sexually dimorphic development of the external genitalia, series of conditional mutant mouse analyses were performed using several mutant alleles, particularly focusing on the role of hedgehog signaling pathway in this manuscript. We demonstrate that hedgehog pathway is indispensable for the establishment of male external genitalia characteristics. Sonic hedgehog is expressed in the urethral plate epithelium, and its signal is mediated through glioblastoma 2 (Gli2) in the mesenchyme. The expression level of the sexually dimorphic genes is decreased in the glioblastoma 2 mutant embryos, suggesting that hedgehog signal is likely to facilitate the masculinization processes by affecting the androgen responsiveness. In addition, a conditional mutation of Sonic hedgehog at the sexual differentiation stage leads to abnormal male external genitalia development. The current study identified hedgehog signaling pathway as a key factor not only for initial development but also for sexually dimorphic development of the external genitalia in coordination with androgen signaling. PMID- 21586557 TI - Histone deacetylation during brain development is essential for permanent masculinization of sexual behavior. AB - Epigenetic histone modifications are emerging as important mechanisms for conveyance of and maintenance of effects of the hormonal milieu to the developing brain. We hypothesized that alteration of histone acetylation status early in development by sex steroid hormones is important for sexual differentiation of the brain. It was found that during the critical period for sexual differentiation, histones associated with promoters of essential genes in masculinization of the brain (estrogen receptor alpha and aromatase) in the medial preoptic area, an area necessary for male sexual behavior, were differentially acetylated between the sexes. Consistent with these findings, binding of histone deacetylase (HDAC) 2 and 4 to the promoters was higher in males than in females. To examine the involvement of histone deacetylation on masculinization of the brain at the behavioral level, we inhibited HDAC in vivo by intracerebroventricular infusion of the HDAC inhibitor trichostatin A or antisense oligodeoxynucleotide directed against the mRNA for HDAC2 and -4 in newborn male rats. Aspects of male sexual behavior in adulthood were significantly reduced by administration of either trichostatin A or antisense oligodeoxynucleotide. These results demonstrate that HDAC activity during the early postnatal period plays a crucial role in the masculinization of the brain via modifications of histone acetylation status. PMID- 21586559 TI - Effects of peripherally administered neuromedin U on energy and glucose homeostasis. AB - Neuromedin U (NMU) is a highly conserved peptide reported to modulate energy homeostasis. Pharmacological studies have shown that centrally administered NMU inhibits food intake, reduces body weight, and increases energy expenditure. NMU deficient mice develop obesity, whereas transgenic mice overexpressing NMU become lean and hypophagic. Two high-affinity NMU receptors, NMUR1 and NMUR2, have been identified. NMUR1 is found primarily in the periphery and NMUR2 primarily in the brain, where it mediates the anorectic effects of centrally administered NMU. Given the broad expression pattern of NMU, we evaluated whether peripheral administration of NMU has effects on energy homeostasis. We observed that acute and chronic peripheral administration of NMU in rodents dose-dependently reduced food intake and body weight and that these effects required NMUR1. The anorectic effects of NMU appeared to be partly mediated by vagal afferents. NMU treatment also increased core body temperature and metabolic rate in mice, suggesting that peripheral NMU modulates energy expenditure. Additionally, peripheral administration of NMU significantly improved glucose excursion. Collectively, these data suggest that NMU functions as a peripheral regulator of energy and glucose homeostasis and the development of NMUR1 agonists may be an effective treatment for diabetes and obesity. PMID- 21586558 TI - Voluntary exercise improves high-fat diet-induced leptin resistance independent of adiposity. AB - The efficacy of exercise as primary prevention of obesity is the subject of intense investigation. Here, we show that voluntary exercise in a mouse strain susceptible to diet-induced obesity (C57B6J) decreases fat mass and increases energy expenditure. In addition, exercise attenuates obesity in mice fed a high fat diet (HFD). Using FosB immunoreactivity as a marker of chronic neuronal activation, we found that exercise activates leptin receptor-positive neurons in the ventromedial hypothalamic nucleus, involved in homeostatic control of energy balance. FosB immunoreactivity in the ventromedial hypothalamic nucleus is decreased in sedentary mice exposed to HFD but is increased in exercised mice independent of adiposity. To determine whether the antiobesity effects of voluntary exercise improve central nervous system (CNS) leptin action, we measured the anorectic and weight reducing effects of intracerebroventricular (ICV) leptin in sedentary and exercised mice exposed to HFD (EH), as well as in sedentary mice that have been calorie restricted (SR) to match the fat mass of EH mice. ICV leptin was ineffective in lowering food intake and body weight (BW) in sedentary mice exposed to HFD mice. The anorectic potency of leptin was partially restored in EH and SR groups. However, ICV leptin significantly lowered BW in EH but not SR mice. Thus, exercise leads to the maintenance of a lower BW and leaner composition, as well as to improved CNS leptin action, independent of fat mass. These results support the notion that physical exercise directly influences the responsiveness of the CNS circuits involved in energy homeostasis by allowing the defense of a lowered BW. PMID- 21586560 TI - Axonal protection by 17beta-estradiol through thioredoxin-1 in tumor necrosis factor-induced optic neuropathy. AB - Axonal degeneration often leads to the death of neuronal cell bodies. Previous studies demonstrated the substantial protective role of 17beta-estradiol (E2) in several types of neuron. However, most studies examined cell body protection, and the role of 17beta-E2 in axonal degeneration of retinal ganglion cells (RGC) remains unclear. In this study, we showed the presence of thioredoxin-1 (Trx1) in the optic nerve axons and found that the levels of Trx1 protein were significantly decreased in isolated RGC and the optic nerve after intravitreal injection of TNF, which was shown previously to induce optic nerve degeneration and subsequent loss of RGC. These changes were concomitant with disorganization of the microtubules with neurofilament accumulation, which were blocked by 17beta E2 implantation. 17beta-E2 treatment also totally abolished TNF-induced decreases in Trx1 protein levels in isolated RGC and the optic nerve. The induction of Trx1 by 17beta-E2 in the optic nerve was significantly inhibited by simultaneous injection of Trx1 small interfering RNA (siRNA) with TNF. Up-regulation of Trx1 by 17beta-E2 in RGC-5 cells was prevented by Trx1 siRNA treatment. 17beta-E2 significantly prevented TNF-induced axonal loss, and this axonal-protective effect was inhibited by intravitreal injection of Trx1 siRNA. This finding was also supported by the quantification of microtubules and neurofilaments. These results suggest that a Trx1 decrease in RGC bodies and their axons may be associated with TNF-induced optic nerve axonal degeneration. Axonal protection by 17beta-E2 may be related to its regulatory effect on Trx1 induction. PMID- 21586561 TI - Phospholipase Cbeta3 mediates LH-induced granulosa cell differentiation. AB - Previous studies showed that under certain conditions LH can stimulate not only adenylate cyclase (AC) but also phospholipase Cbeta (PLCbeta) signaling in target cells; however, the physiological involvement of PLCbeta in LH-induced ovarian follicular cell differentiation has not been determined. To address this, ex vivo expression analyses and specific PLCbeta targeting were performed in primary bovine granulosa cells. Expression analyses in cells from small (2.0-5.9 mm), medium (6.0-9.9 mm), and ovulatory-size (10.0-13.9 mm) follicles revealed an increase in mRNA and protein levels of heterotrimeric G protein subunits-alphas, alphaq, -alpha11, and -alphai2 in ovulatory-size follicles, simultaneous with a substantial increase in LH receptor expression. Among the four known PLCbeta isoforms, PLCbeta3 (PLCB3) was specifically up-regulated in cells from ovulatory size follicles, in association with a predominantly cytoplasmic location of PLCB3 in these cells and a significant inositol phosphate response to LH stimulation. Furthermore, RNA interference-mediated PLCB3 down-regulation reduced the ability of LH to induce hallmark differentiation responses of granulosa cells, namely transcriptional up-regulation of prostaglandin-endoperoxide synthase 2 and down regulation of both aromatase expression and estradiol production. Responses to the AC agonist, forskolin, however, were not affected. In addition, PLCB3 down regulation did not alter cAMP responses to LH in granulosa cells, ruling out a primary involvement of AC in mediating the effects of PLCB3. In summary, we provide evidence of a physiological involvement of PLCbeta signaling in ovulatory size follicles and specifically identify PLCB3 as a mediator of LH-induced differentiation responses of granulosa cells. PMID- 21586562 TI - Angiopoietin-like 2, a circadian gene, improves type 2 diabetes through potentiation of insulin sensitivity in mice adipocytes. AB - Angiopoietin-like (Angptl)2, a member of the Angptl protein family, is predominantly secreted from adipose tissue and the heart. Here, we demonstrate that the expression of Angptl2 in epididymal adipose tissue of C57BL/6J mice shows pulsatility and circadian rhythmicity and that the rhythmicity was disrupted in high-fat-fed and leptin receptor-deficient diabetic db/db mice with insulin resistance. To investigate whether the reduction in Angptl2 expression was related to the progression of diabetes, we treated db/db mice with recombinant Angptl2 for 4 wk during the peak period of Angptl2 expression in C57BL/6J mice. Angptl2-treated mice showed decreases in plasma glucose, insulin, triglyceride, and fatty acid levels and an increase in plasma adiponectin, a therapeutic regulator of insulin resistance, leading to improvements in glucose tolerance. In cultured adipocytes, recombinant Angptl2 increased adiponectin expression and stimulated insulin sensitivity partially by reducing the levels of tribbles homolog 3, a specific Akt kinase inhibitory protein. Conversely, Angptl2 small interfering RNA reduced adiponectin expression, resulting in insulin resistance. In preadipocytes, treatment with Angptl2 small interfering RNA inhibited differentiation to adipocytes and reduced adiponectin expression. Taken together, our results suggest that replenishment of Angptl2 stimulates insulin sensitivity and improves the type 2 diabetic state. PMID- 21586563 TI - High-yield expression of a catalytically active membrane-bound protein: human P450 oxidoreductase. AB - P450 oxidoreductase (POR) is a two-flavin protein that reduces microsomal P450 enzymes and some other proteins. Preparation of active bacterially expressed human POR for biochemical studies has been difficult because membrane-bound proteins tend to interact with column matrices. To reduce column-protein interactions and permit more vigorous washing, human POR lacking 27 N-terminal residues (N-27 POR) was modified to carry a C-terminal Gly3His6-tag (N-27 POR G3H6). When expressed in Escherichia coli, N-27 POR-G3H6 could be purified to apparent homogeneity by a modified, single-step nickel-nitrilotriacetic acid affinity chromatography, yielding 31 mg POR per liter of culture, whereas standard purification of native N-27 POR required multiple steps, yielding 5 mg POR per liter. Both POR proteins had absorption maxima at 375 and 453 nm and both reduced cytochrome c with indistinguishable specific activities. Using progesterone as substrate for bacterially expressed purified human P450c17, the Michaelis constant for 17alpha-hydroxylase activity supported by N-27 POR or N-27 POR-G3H6 were 1.73 or 1.49 MUm, and the maximal velocity was 0.029 or 0.026 pmol steroids per picomole P450 per minute, respectively. Using 17-hydroxypregnenolone as the P450c17 substrate, the Michaelis constant for 17,20 lyase activity using N 27 POR or N-27 POR-G3H6 was 1.92 or 1.89 MUm and the maximal velocity was 0.041 or 0.042 pmol steroid per picomole P450 per minute, respectively. Thus, N-27 POR G3H6 is equally active as native N-27 POR. This expression and purification system permits the rapid preparation of large amounts of highly pure, biologically active POR and may be generally applicable for the preparation of membrane-bound proteins. PMID- 21586564 TI - Centrally administered resistin enhances sympathetic nerve activity to the hindlimb but attenuates the activity to brown adipose tissue. AB - Resistin, an adipokine, is believed to act in the brain to influence energy homeostasis. Plasma resistin levels are elevated in obesity and are associated with metabolic and cardiovascular disease. Increased muscle sympathetic nerve activity (SNA) is a characteristic of obesity, a risk factor for diabetes and cardiovascular disease. We hypothesized that resistin affects SNA, which contributes to metabolic and cardiovascular dysfunction. Here we investigated the effects of centrally administered resistin on SNA to muscle (lumbar) and brown adipose tissue (BAT), outputs that influence cardiovascular and energy homeostasis. Overnight-fasted rats were anesthetized, and resistin (7 MUg) was administered into the lateral cerebral ventricle (intracerebroventricular). The lumbar sympathetic nerve trunk or sympathetic nerves supplying BAT were dissected free, and nerve activity was recorded. Arterial blood pressure, heart rate, body core temperature, and BAT temperature were also recorded. Responses to resistin or vehicle were monitored for 4 h after intracerebroventricular administration. Acutely administered resistin increased lumbar SNA but decreased BAT SNA. Mean arterial pressure and heart rate, however, were not significantly affected by resistin. BAT temperature was significantly reduced by resistin, and there was a concomitant fall in body temperature. The findings indicate that resistin has differential effects on SNA to tissues involved in metabolic and cardiovascular regulation. The decreased BAT SNA and the increased lumbar SNA elicited by resistin suggest that it may contribute to the increased muscle SNA and reduced energy expenditure observed in obesity and diabetes. PMID- 21586565 TI - Enhanced lysosomal activity is involved in Bax inhibitor-1-induced regulation of the endoplasmic reticulum (ER) stress response and cell death against ER stress: involvement of vacuolar H+-ATPase (V-ATPase). AB - Bax inhibitor-1 (BI-1) is an evolutionarily conserved protein that protects cells against endoplasmic reticulum (ER) stress while also affecting the ER stress response. In this study, we examined BI-1-induced regulation of the ER stress response as well as the control of the protein over cell death under ER stress. In BI-1-overexpressing cells (BI-1 cells), proteasome activity was similar to that of control cells; however, the lysosomal fraction of BI-1 cells showed sensitivity to degradation of BSA. In addition, areas and polygonal lengths of lysosomes were greater in BI-1 cells than in control cells, as assessed by fluorescence and electron microscopy. In BI-1 cells, lysosomal pH was lower than in control cells and lysosomal vacuolar H(+)-ATPase(V-ATPase), a proton pump, was activated, suggesting high H(+) uptake into lysosomes. Even when exposed to ER stress, BI-1 cells maintained high levels of lysosomal activities, including V ATPase activity. Bafilomycin, a V-ATPase inhibitor, leads to the reversal of BI-1 induced regulation of ER stress response and cell death due to ER stress. In BI-1 knock-out mouse embryo fibroblasts, lysosomal activity and number per cell were relatively lower than in BI-1 wild-type cells. This study suggests that highly maintained lysosomal activity may be one of the mechanisms by which BI-1 exerts its regulatory effects on the ER stress response and cell death. PMID- 21586566 TI - High molecular weight kininogen activates B2 receptor signaling pathway in human vascular endothelial cells. AB - The nonenzymatic cofactor high molecular weight kininogen (HK) is a precursor of bradykinin (BK). The production of BK from HK by plasma kallikrein has been implicated in the pathogenesis of inflammation and vascular injury. However, the functional role of HK in the absence of prekallikrein (PK), the proenzyme of plasma kallikrein, on vascular endothelial cells is not fully defined. In addition, no clinical abnormality is seen in PK-deficient patients. Therefore, an investigation into the effect of HK, in the absence of PK, on human pulmonary artery endothelial cell (HPAEC) function was performed. HK caused a marked and dose-dependent increase in the intracellular calcium [Ca(2+)](i) level in HPAEC. Gd(3+) and verapamil potentiated the HK-induced increase in [Ca(2+)](i). HK induced Ca(2+) increase stimulated endothelial nitric oxide (NO) and prostacyclin (PGI(2)) production. The inhibitors of B(2) receptor-dependent signaling pathway impaired HK-mediated signal transduction in HPAEC. HK had no effect on endothelial permeability at physiological concentration. This study demonstrated that HK regulates endothelial cell function. HK could play an important role in maintaining normal endothelial function and blood flow and serve as a cardioprotective peptide. PMID- 21586567 TI - The extracellular regulated kinase-1 (ERK1) controls regulated alpha-secretase mediated processing, promoter transactivation, and mRNA levels of the cellular prion protein. AB - The alpha-secretases A disintegrin and metalloprotease 10 (ADAM10) and ADAM17 trigger constitutive and regulated processing of the cellular prion protein (PrP(c)) yielding N1 fragment. The latter depends on protein kinase C (PKC) coupled M1/M3 muscarinic receptor activation and subsequent phosphorylation of ADAM17 on its intracytoplasmic threonine 735. Here we show that regulated PrP(c) processing and ADAM17 phosphorylation and activation are controlled by the extracellular-regulated kinase-1/MAP-ERK kinase (ERK1/MEK) cascade. Thus, reductions of ERK1 or MEK activities by dominant-negative analogs, pharmacological inhibition, or genetic ablation all impair N1 secretion, whereas constitutively active proteins increase N1 recovery in the conditioned medium. Interestingly, we also observed an ERK1-mediated enhanced expression of PrP(c). We demonstrate that the ERK1-associated increase in PrP(c) promoter transactivation and mRNA levels involve transcription factor AP-1 as a downstream effector. Altogether, our data identify ERK1 as an important regulator of PrP(c) cellular homeostasis and indicate that this kinase exerts a dual control of PrP(c) levels through transcriptional and post-transcriptional mechanisms. PMID- 21586568 TI - Characterization of RIN3 as a guanine nucleotide exchange factor for the Rab5 subfamily GTPase Rab31. AB - The small GTPase Rab5, which cycles between GDP-bound inactive and GTP-bound active forms, plays essential roles in membrane budding and trafficking in the early endocytic pathway. Rab5 is activated by various vacuolar protein sorting 9 (VPS9) domain-containing guanine nucleotide exchange factors. Rab21, Rab22, and Rab31 (members of the Rab5 subfamily) are also involved in the trafficking of early endosomes. Mechanisms controlling the activation Rab5 subfamily members remain unclear. RIN (Ras and Rab interactor) represents a family of multifunctional proteins that have a VPS9 domain in addition to Src homology 2 (SH2) and Ras association domains. We investigated whether RIN family members act as guanine nucleotide exchange factors (GEFs) for the Rab5 subfamily on biochemical and cell morphological levels. RIN3 stimulated the formation of GTP bound Rab31 in cell-free and in cell GEF activity assays. RIN3 also formed enlarged vesicles and tubular structures, where it colocalized with Rab31 in HeLa cells. In contrast, RIN3 did not exhibit any apparent effects on Rab21. We also found that serine to alanine substitutions in the sequences between SH2 and RIN family homology domain of RIN3 specifically abolished its GEF action on Rab31 but not Rab5. We examined whether RIN3 affects localization of the cation-dependent mannose 6-phosphate receptor (CD-MPR), which is transported between trans-Golgi network and endocytic compartments. We found that RIN3 partially translocates CD MPR from the trans-Golgi network to peripheral vesicles and that this is dependent on its Rab31-GEF activity. These results indicate that RIN3 specifically acts as a GEF for Rab31. PMID- 21586569 TI - Atomic level characterization of the nonproton ligand-sensing domain of ASIC3 channels. AB - Acid-sensing ion channels (ASICs) are known to be primarily activated by extracellular protons. Recently, we characterized a novel nonproton ligand (2 guanidine-4-methylquinazoline, GMQ), which activates the ASIC3 channel subtype at neutral pH. Using an interactive computational-experimental approach, here we extend our investigation to delineate the architecture of the GMQ-sensing domain in the ASIC3 channels. We first established a GMQ binding mode and revealed that residues Glu-423, Glu-79, Leu-77, Arg-376, Gln-271, and Gln-269 play key roles in forming the GMQ-sensing domain. We then verified the GMQ binding mode using ab initio calculation and mutagenesis and demonstrated the critical role of the above GMQ-binding residues in the interplay among GMQ, proton, and Ca(2+) in regulating the function of ASIC3. Additionally, we showed that the same residues involved in coordinating GMQ responses are also critical for activation of the ASIC3(E79C) mutant by thiol-reactive compound DTNB. Thus, a range of complementary techniques provide independent evidence for the structural details of the GMQ-sensing domain at atomic level, laying the foundation for further investigations of endogenous nonproton ligands and gating mechanisms of the ASIC3 channels. PMID- 21586570 TI - NMR structures and interactions of temporin-1Tl and temporin-1Tb with lipopolysaccharide micelles: mechanistic insights into outer membrane permeabilization and synergistic activity. AB - Temporins are a group of closely related short antimicrobial peptides from frog skin. Lipopolysaccharide (LPS), the major constituent of the outer membrane of gram-negative bacteria, plays important roles in the activity of temporins. Earlier studies have found that LPS induces oligomerization of temporin-1Tb (TB) thus preventing its translocation across the outer membrane and, as a result, reduces its activity on gram-negative bacteria. On the other hand, temporin-1Tl (TL) exhibits higher activity, presumably because of lack of such oligomerization. A synergistic mechanism was proposed, involving TL and TB in overcoming the LPS-mediated barrier. Here, to gain insights into interactions of TL and TB within LPS, we investigated the structures and interactions of TL, TB, and TL+TB in LPS micelles, using NMR and fluorescence spectroscopy. In the context of LPS, TL assumes a novel antiparallel dimeric helical structure sustained by intimate packing between aromatic-aromatic and aromatic-aliphatic residues. By contrast, independent TB has populations of helical and aggregated conformations in LPS. The LPS-induced aggregated states of TB are largely destabilized in the presence of TL. Saturation transfer difference NMR studies have delineated residues of TL and TB in close contact with LPS and enhanced interactions of these two peptides with LPS, when combined together. Fluorescence resonance energy transfer and (31)P NMR have pointed out the proximity of TL and TB in LPS and conformational changes of LPS, respectively. Importantly, these results provide the first structural insights into the mode of action and synergism of antimicrobial peptides at the level of the LPS-outer membrane. PMID- 21586571 TI - Peptide-protein interactions suggest that acetylation of lysines 381 and 382 of p53 is important for positive coactivator 4-p53 interaction. AB - The human transcriptional positive coactivator 4 (PC4) activates several p53 dependent genes. It has been demonstrated that this is a consequence of direct interaction with p53. Previously, we have concluded that PC4 interacts mainly with the C-terminal negative regulatory domain of p53 through its DNA binding C terminal half. NMR chemical shift perturbation studies with peptide fragments indicated that amino acids 380-386 of p53 are crucial for interaction with PC4. This was verified by fluorescence anisotropy and sedimentation velocity studies. A peptide consisting of p53-(380-386) sequence, when attached to a cell penetration tag and nuclear localization signal, localizes to the nucleus and inhibits luciferase gene expression from a transfected plasmid carrying a Luc gene under a p53-dependent promoter. Acetylation of lysine 382/381 enhanced the binding of this peptide to PC4 by about an order of magnitude. NMR and mutagenesis studies indicated that serine 73 of PC4 is an important residue for recognition of p53. Intermolecular nuclear Overhauser effect placed aspartate 76 in the vicinity of lysine 381, indicating that the region around residues 73-76 of PC4 is important for p53 recognition. We conclude that the 380-386 region of p53 interacts with the region around residues 73-76 of PC4, and acetylation of lysine 382/381 of p53 may play an important role in modulating p53-PC4 interaction and as a consequence PC4 mediated activation of p53 target genes. PMID- 21586572 TI - Distinct functions of the mitogen-activated protein kinase-activated protein (MAPKAP) kinases MK2 and MK3: MK2 mediates lipopolysaccharide-induced signal transducers and activators of transcription 3 (STAT3) activation by preventing negative regulatory effects of MK3. AB - In LPS-treated macrophages, activation of STAT3 is considered to be crucial for terminating the production of inflammatory cytokines. By analyzing the role of MAPK-activated protein kinase (MK) 2 and MK3 for LPS-induced STAT3 activation in macrophages, the present study provides evidence that MK2 is crucial for STAT3 activation in response to LPS because it prevents MK3 from impeding IFNbeta gene expression. Accordingly, LPS-induced IFNbeta gene expression is down-regulated in MK2-deficient macrophages and can be reconstituted by additional ablation of the MK3 gene in MK2/3(-/-) macrophages. This is in contrast to LPS-induced IL-10 expression, which essentially requires the presence of MK2. Further analysis of downstream signaling events involved in the transcriptional regulation of IFNbeta gene expression suggests that, in the absence of MK2, MK3 impairs interferon regulatory factor 3 protein expression and activation and inhibits nuclear translocation of p65. This inhibition of p65 nuclear translocation coincides with enhanced expression and delayed degradation of IkappaBbeta, whereas expression of IkappaBalpha mRNA and protein is impaired in the absence of MK2. The observation that siRNA directed against IkappaBbeta is able to reconstitute IkappaBalpha expression in MK2(-/-) macrophages suggests that enhanced expression and delayed degradation of IkappaBbeta and impaired NFkappaB-dependent IkappaBalpha expression are functionally linked. In summary, evidence is provided that MK2 regulates LPS-induced IFNbeta expression and downstream STAT3 activation as it restrains MK3 from mediating negative regulatory effects on NFkappaB- and interferon regulatory factor 3-dependent LPS signaling. PMID- 21586573 TI - The Mycobacterium tuberculosis early secreted antigenic target of 6 kDa inhibits T cell interferon-gamma production through the p38 mitogen-activated protein kinase pathway. AB - We reported previously that the early secreted antigenic target of 6 kDa (ESAT-6) from Mycobacterium tuberculosis directly inhibits human T cell IFN-gamma production and proliferation in response to stimulation with anti-CD3 and anti CD28. To determine the mechanism of this effect, we treated T cells with kinase inhibitors before stimulation with ESAT-6. Only the p38 MAPK inhibitor, SB203580, abrogated ESAT-6-mediated inhibition of IFN-gamma production in a dose-dependent manner. SB203580 did not reverse ESAT-6-mediated inhibition of IL-17 and IL-10 production, suggesting a specific effect of SB203580 on IFN-gamma production. SB203580 did not act through inhibition of AKT (PKB) as an AKT inhibitor did not affect ESAT-6 inhibition of T cell IFN-gamma production and proliferation. ESAT-6 did not reduce IFN-gamma production by expanding FoxP3(+) T regulatory cells. Incubation of T cells with ESAT-6 induced phosphorylation and increased functional p38 MAPK activity, but not activation of ERK or JNK. Incubation of peripheral blood mononuclear cells with ESAT-6 induced activation of p38 MAPK, and inhibition of p38 MAPK with SB203580 reversed ESAT-6 inhibition of M. tuberculosis-stimulated IFN-gamma production by peripheral blood mononuclear cells from subjects with latent tuberculosis infection. Silencing of p38alpha MAPK with siRNA rendered T cells resistant to ESAT-6 inhibition of IFN-gamma production. Taken together, our results demonstrate that ESAT-6 inhibits T cell IFN-gamma production in a p38 MAPK-dependent manner. PMID- 21586574 TI - Characterization of O-acetylation of N-acetylglucosamine: a novel structural variation of bacterial peptidoglycan. AB - Peptidoglycan (PG) N-acetyl muramic acid (MurNAc) O-acetylation is widely spread in gram-positive bacteria and is generally associated with resistance against lysozyme and endogenous autolysins. We report here the presence of O-acetylation on N-acetylglucosamine (GlcNAc) in Lactobacillus plantarum PG. This modification of glycan strands was never described in bacteria. Fine structural characterization of acetylated muropeptides released from L. plantarum PG demonstrated that both MurNAc and GlcNAc are O-acetylated in this species. These two PG post-modifications rely on two dedicated O-acetyltransferase encoding genes, named oatA and oatB, respectively. By analyzing the resistance to cell wall hydrolysis of mutant strains, we showed that GlcNAc O-acetylation inhibits N acetylglucosaminidase Acm2, the major L. plantarum autolysin. In this bacterial species, inactivation of oatA, encoding MurNAc O-acetyltransferase, resulted in marked sensitivity to lysozyme. Moreover, MurNAc over-O-acetylation was shown to activate autolysis through the putative N-acetylmuramoyl-L-alanine amidase LytH enzyme. Our data indicate that in L. plantarum, two different O acetyltransferases play original and antagonistic roles in the modulation of the activity of endogenous autolysins. PMID- 21586575 TI - Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by CCAAT/enhancer-binding protein beta (C/EBPbeta). AB - The conversion of pyruvate to acetyl-CoA in mitochondria is catalyzed by the pyruvate dehydrogenase complex (PDC). Activity of PDC is inhibited by phosphorylation via the pyruvate dehydrogenase kinases (PDKs). Here, we examined the regulation of Pdk4 gene expression by the CCAAT/enhancer-binding protein beta (C/EBPbeta). C/EBPbeta modulates the expression of multiple hepatic genes including those involved in metabolism, development, and inflammation. We found that C/EBPbeta induced Pdk4 gene expression and decreased PDC activity. This transcriptional induction was mediated through two C/EBPbeta binding sites in the Pdk4 promoter. C/EBPbeta participates in the hormonal regulation of gluconeogenic genes. Previously, we reported that Pdk4 was induced by thyroid hormone (T(3)). Therefore, we investigated the role of C/EBPbeta in the T(3) regulation of Pdk4. T(3) increased C/EBPbeta abundance in primary rat hepatocytes. Knockdown of C/EBPbeta with siRNA diminished the T(3) induction of the Pdk4 and carnitine palmitoyltransferase (Cpt1a) genes. CPT1a is an initiating step in the mitochondrial oxidation of long chain fatty acids. Our results indicate that C/EBPbeta stimulates Pdk4 expression and participates in the T(3) induction of the Cpt1a and Pdk4 genes. PMID- 21586576 TI - From molecular details of the interplay between transmembrane helices of the thyrotropin receptor to general aspects of signal transduction in family a G protein-coupled receptors (GPCRs). AB - Transmembrane helices (TMHs) 5 and 6 are known to be important for signal transduction by G-protein-coupled receptors (GPCRs). Our aim was to characterize the interface between TMH5 and TMH6 of the thyrotropin receptor (TSHR) to gain molecular insights into aspects of signal transduction and regulation. A proline at TMH5 position 5.50 is highly conserved in family A GPCRs and causes a twist in the helix structure. Mutation of the TSHR-specific alanine (Ala-5935.50) at this position to proline resulted in a 20-fold reduction of cell surface expression. This indicates that TMH5 in the TSHR might have a conformation different from most other family A GPCRs by forming a regular alpha-helix. Furthermore, linking our own and previous data from directed mutagenesis with structural information led to suggestions of distinct pairs of interacting residues between TMH5 and TMH6 that are responsible for stabilizing either the basal or the active state. Our insights suggest that the inactive state conformation is constrained by a core set of polar interactions among TMHs 2, 3, 6, and 7 and in contrast that the active state conformation is stabilized mainly by non-polar interactions between TMHs 5 and 6. Our findings might be relevant for all family A GPCRs as supported by a statistical analysis of residue properties between the TMHs of a vast number of GPCR sequences. PMID- 21586577 TI - The assembly mode of the pseudopilus: a hallmark to distinguish a novel secretion system subtype. AB - In gram-negative bacteria, type II secretion systems assemble a piston-like structure, called pseudopilus, which expels exoproteins out of the cell. The pseudopilus is constituted by a major pseudopilin that when overproduced multimerizes into a long cell surface structure named hyper-pseudopilus. Pseudomonas aeruginosa possesses two type II secretion systems, Xcp and Hxc. Although major pseudopilins are exchangeable among type II secretion systems, we show that XcpT and HxcT are not. We demonstrate that HxcT does not form a hyper pseudopilus and is different in amino acid sequence and multimerization properties. Using structure-based mutagenesis, we observe that five mutations are sufficient to revert HxcT into a functional XcpT-like protein, which also becomes capable of forming a hyper-pseudopilus. Phylogenetic and experimental analysis showed that the whole Hxc system was acquired by P. aeruginosa PAO1 and other Pseudomonas species through horizontal gene transfer. We thus identified a new type II secretion subfamily, of which the P. aeruginosa Hxc system is the archetype. This finding demonstrates how similar bacterial machineries evolve toward distinct mechanisms that may contribute specific functions. PMID- 21586578 TI - Structural basis of outer membrane protein biogenesis in bacteria. AB - In Escherichia coli, a multicomponent BAM (beta-barrel assembly machinery) complex is responsible for recognition and assembly of outer membrane beta-barrel proteins. The functionality of BAM in protein biogenesis is mainly orchestrated through the presence of two essential components, BamA and BamD. Here, we present crystal structures of four lipoproteins (BamB-E). Monomeric BamB and BamD proteins display scaffold architectures typically implied in transient protein interactions. BamB is a beta-propeller protein comprising eight WD40 repeats. BamD shows an elongated fold on the basis of five tetratricopeptide repeats, three of which form the scaffold for protein recognition. The rod-shaped BamC protein has evolved through the gene duplication of two conserved domains known to mediate protein interactions in structurally related complexes. By contrast, the dimeric BamE is formed through a domain swap and indicates fold similarity to the beta-lactamase inhibitor protein family, possibly integrating cell wall stability in BAM function. Structural and biochemical data show evidence for the specific recognition of amphipathic sequences through the tetratricopeptide repeat architecture of BamD. Collectively, our data advance the understanding of the BAM complex and highlight the functional importance of BamD in amphipathic outer membrane beta-barrel protein motif recognition and protein delivery. PMID- 21586579 TI - IL-6-independent association of elevated serum neopterin levels with prevalent frailty in community-dwelling older adults. AB - BACKGROUND: neopterin is a monocyte/macrophage-derived immune activation marker and its levels increase with age. Frailty is an important clinical syndrome of old age. Previous studies have shown significant association between elevated interleukin-6 (IL-6) levels and frailty. The objective of this study was to evaluate IL-6-independent association of serum neopterin levels with prevalent frailty. METHODS: this is a cross-sectional study in community-dwelling older adults recruited from residential and retirement communities in Baltimore, MD, USA. Frailty was determined using validated screening criteria. Serum neopterin and IL-6 levels were measured using standard enzyme-linked immunosorbent assay. Pearson correlation and multivariate linear regression analysis was performed to assess the relationship between log(neopterin) and log(IL-6). Odds ratios (ORs) for frailty were calculated using log(neopterin) and log(IL-6) as continuous measures and across tertiles of neopterin and IL-6 levels, adjusting for age, race, sex, education and body mass index. RESULTS: one hundred and thirty-three individuals with a mean age of 84 years (range 72-97) completed the study. Neopterin levels were significantly higher in frail older adults than those in non-frail controls [median: 8.94 versus 8.35 nM, respectively, P < 0.001 t-test on log(neopterin)]. Log(neopterin) was significantly associated with prevalent frailty, adjusting for log(IL-6). Participants in the top tertile of neopterin had OR of 3.80 [95% confidence interval (CI) = 1.36-10.6, P < 0.01] for frailty. As expected, participants in the top tertile of IL-6 had OR of 3.29 (95% CI = 1.21-7.86, P < 0.05) for frailty. Log(neopterin) correlated with log(IL-6) (correlation coefficient = 0.19, P < 0.05). Moreover, OR for participants in the top neopterin tertile remained significant after adjusting for IL-6 (OR = 3.97, 95% CI = 1.15-13.72, P < 0.05). CONCLUSION: elevated neopterin levels had IL-6 independent association with prevalent frailty, suggesting potential monocyte/macrophage-mediated immune activation in the frail elderly. PMID- 21586580 TI - Genome-wide evidence for local DNA methylation spreading from small RNA-targeted sequences in Arabidopsis. AB - Transposable elements (TEs) and their relics play major roles in genome evolution. However, mobilization of TEs is usually deleterious and strongly repressed. In plants and mammals, this repression is typically associated with DNA methylation, but the relationship between this epigenetic mark and TE sequences has not been investigated systematically. Here, we present an improved annotation of TE sequences and use it to analyze genome-wide DNA methylation maps obtained at single-nucleotide resolution in Arabidopsis. We show that although the majority of TE sequences are methylated, ~26% are not. Moreover, a significant fraction of TE sequences densely methylated at CG, CHG and CHH sites (where H = A, T or C) have no or few matching small interfering RNA (siRNAs) and are therefore unlikely to be targeted by the RNA-directed DNA methylation (RdDM) machinery. We provide evidence that these TE sequences acquire DNA methylation through spreading from adjacent siRNA-targeted regions. Further, we show that although both methylated and unmethylated TE sequences located in euchromatin tend to be more abundant closer to genes, this trend is least pronounced for methylated, siRNA-targeted TE sequences located 5' to genes. Based on these and other findings, we propose that spreading of DNA methylation through promoter regions explains at least in part the negative impact of siRNA-targeted TE sequences on neighboring gene expression. PMID- 21586581 TI - G4 resolvase 1 tightly binds and unwinds unimolecular G4-DNA. AB - It has been previously shown that the DHX36 gene product, G4R1/RHAU, tightly binds tetramolecular G4-DNA with high affinity and resolves these structures into single strands. Here, we test the ability of G4R1/RHAU to bind and unwind unimolecular G4-DNA. Gel mobility shift assays were used to measure the binding affinity of G4R1/RHAU for unimolecular G4-DNA-formed sequences from the Zic1 gene and the c-Myc promoter. Extremely tight binding produced apparent K(d)'s of 6, 3 and 4 pM for two Zic1 G4-DNAs and a c-Myc G4-DNA, respectively. The low enzyme concentrations required for measuring these K(d)'s limit the precision of their determination to upper boundary estimates. Similar tight binding was not observed in control non-G4 forming DNA sequences or in single-stranded DNA having guanine rich runs capable of forming tetramolecular G4-DNA. Using a peptide nucleic acid (PNA) trap assay, we show that G4R1/RHAU catalyzes unwinding of unimolecular Zic1 G4-DNA into an unstructured state capable of hybridizing to a complementary PNA. Binding was independent of adenosine triphosphate (ATP), but the PNA trap assay showed that unwinding of G4-DNA was ATP dependent. Competition studies indicated that unimolecular Zic1 and c-Myc G4-DNA structures inhibit G4R1/RHAU-catalyzed resolution of tetramolecular G4-DNA. This report provides evidence that G4R1/RHAU tightly binds and unwinds unimolecular G4-DNA structures. PMID- 21586582 TI - iPBA: a tool for protein structure comparison using sequence alignment strategies. AB - With the immense growth in the number of available protein structures, fast and accurate structure comparison has been essential. We propose an efficient method for structure comparison, based on a structural alphabet. Protein Blocks (PBs) is a widely used structural alphabet with 16 pentapeptide conformations that can fairly approximate a complete protein chain. Thus a 3D structure can be translated into a 1D sequence of PBs. With a simple Needleman-Wunsch approach and a raw PB substitution matrix, PB-based structural alignments were better than many popular methods. iPBA web server presents an improved alignment approach using (i) specialized PB Substitution Matrices (SM) and (ii) anchor-based alignment methodology. With these developments, the quality of ~88% of alignments was improved. iPBA alignments were also better than DALI, MUSTANG and GANGSTA(+) in >80% of the cases. The webserver is designed to for both pairwise comparisons and database searches. Outputs are given as sequence alignment and superposed 3D structures displayed using PyMol and Jmol. A local alignment option for detecting subs-structural similarity is also embedded. As a fast and efficient 'sequence based' structure comparison tool, we believe that it will be quite useful to the scientific community. iPBA can be accessed at http://www.dsimb.inserm.fr/dsimb_tools/ipba/. PMID- 21586583 TI - Taxonomic classification of metagenomic shotgun sequences with CARMA3. AB - The vast majority of microbes are unculturable and thus cannot be sequenced by means of traditional methods. High-throughput sequencing techniques like 454 or Solexa-Illumina make it possible to explore those microbes by studying whole natural microbial communities and analysing their biological diversity as well as the underlying metabolic pathways. Over the past few years, different methods have been developed for the taxonomic and functional characterization of metagenomic shotgun sequences. However, the taxonomic classification of metagenomic sequences from novel species without close homologue in the biological sequence databases poses a challenge due to the high number of wrong taxonomic predictions on lower taxonomic ranks. Here we present CARMA3, a new method for the taxonomic classification of assembled and unassembled metagenomic sequences that has been adapted to work with both BLAST and HMMER3 homology searches. We show that our method makes fewer wrong taxonomic predictions (at the same sensitivity) than other BLAST-based methods. CARMA3 is freely accessible via the web application WebCARMA from http://webcarma.cebitec.uni-bielefeld.de. PMID- 21586584 TI - Re-engineering multicloning sites for function and convenience. AB - Multicloning sites (MCSs) in standard expression vectors are widely used and thought to be benign, non-interacting elements that exist for mere convenience. However, MCSs impose a necessary distance between promoter elements and genes of interest. As a result, the choice of cloning site defines the genetic context and may introduce significant mRNA secondary structure in the 5'-untranslated region leading to strong translation inhibition. Here, we demonstrate the first performance-based assessment of MCSs in yeast, showing that commonly used MCSs can induce dramatic reductions in protein expression, and that this inhibition is highly promoter and gene dependent. In response, we develop and apply a novel predictive model of structure-based translation inhibition to design improved MCSs for significantly higher and more consistent protein expression. In doing so, we were able to minimize the inhibitory effects of MCSs with the yeast TEF, CYC and GPD promoters. These results highlight the non-interchangeable nature of biological parts and represent the first complete, global redesign of a genetic circuit of such widespread importance as a multicloning site. The improved translational control offered by these designed MCSs is paramount to obtaining high titers of heterologous proteins in eukaryotes and to enabling precise control of genetic circuits. PMID- 21586585 TI - Identification of a DNA-binding site for the transcription factor Haa1, required for Saccharomyces cerevisiae response to acetic acid stress. AB - The transcription factor Haa1 is the main player in reprogramming yeast genomic expression in response to acetic acid stress. Mapping of the promoter region of one of the Haa1-activated genes, TPO3, allowed the identification of an acetic acid responsive element (ACRE) to which Haa1 binds in vivo. The in silico analysis of the promoter regions of the genes of the Haa1-regulon led to the identification of an Haa1-responsive element (HRE) 5'-GNN(G/C)(A/C)(A/G)G(A/G/C)G 3'. Using surface plasmon resonance experiments and electrophoretic mobility shift assays it is demonstrated that Haa1 interacts with high affinity (K(D) of 2 nM) with the HRE motif present in the ACRE region of TPO3 promoter. No significant interaction was found between Haa1 and HRE motifs having adenine nucleotides at positions 6 and 8 (K(D) of 396 and 6780 nM, respectively) suggesting that Haa1p does not recognize these motifs in vivo. A lower affinity of Haa1 toward HRE motifs having mutations in the guanine nucleotides at position 7 and 9 (K(D) of 21 and 119 nM, respectively) was also observed. Altogether, the results obtained indicate that the minimal functional binding site of Haa1 is 5' (G/C)(A/C)GG(G/C)G-3'. The Haa1-dependent transcriptional regulatory network active in yeast response to acetic acid stress is proposed. PMID- 21586586 TI - Identification and characterization of a novel ubiquitous nucleolar protein 'NARR' encoded by a gene overlapping the rab34 oncogene. AB - There are only few reports on protein products originating from overlapping mammalian genes even though computational predictions suggest that an appreciable fraction of mammalian genes could potentially overlap. Mass spectrometry-based proteomics has now acquired the tools to probe proteins in an unbiased manner, providing direct evidence of the output of the genomic and gene expression machinery. In particular, proteomics can refine gene predictions and discover novel gene-processing events and gene arrangements. Here, we report the mass spectrometric discovery and biochemical validation of the novel protein encoded by a gene overlapping rab34 oncogene. The novel protein is highly conserved in mammals. In humans, it contains 13 distinct Nine-Amino acid Residue-Repeats (NARR) with the consensus sequence PRVIV(S/T)PR in which the serine or threonine residues are phosphorylated during M-phase. NARR is ubiquitously expressed and resides in nucleoli where it colocalizes with ribosomal DNA (rDNA) gene clusters. Its distribution only partially overlaps with upstream binding factor, one of the main regulators of RNA Polymerase I activity, and is entirely uncoupled from it in mitotic cells and upon inhibition of transcription. NARR only partially colocalizes with fibrillarin, the pre-ribosomal RNA-processing protein, positioning NARR in a separate niche within the rDNA cluster. PMID- 21586587 TI - ChIP-Array: combinatory analysis of ChIP-seq/chip and microarray gene expression data to discover direct/indirect targets of a transcription factor. AB - Chromatin immunoprecipitation (ChIP) coupled with high-throughput techniques (ChIP-X), such as next generation sequencing (ChIP-Seq) and microarray (ChIP chip), has been successfully used to map active transcription factor binding sites (TFBS) of a transcription factor (TF). The targeted genes can be activated or suppressed by the TF, or are unresponsive to the TF. Microarray technology has been used to measure the actual expression changes of thousands of genes under the perturbation of a TF, but is unable to determine if the affected genes are direct or indirect targets of the TF. Furthermore, both ChIP-X and microarray methods produce a large number of false positives. Combining microarray expression profiling and ChIP-X data allows more effective TFBS analysis for studying the function of a TF. However, current web servers only provide tools to analyze either ChIP-X or expression data, but not both. Here, we present ChIP Array, a web server that integrates ChIP-X and expression data from human, mouse, yeast, fruit fly and Arabidopsis. This server will assist biologists to detect direct and indirect target genes regulated by a TF of interest and to aid in the functional characterization of the TF. ChIP-Array is available at http://jjwanglab.hku.hk/ChIP-Array, with free access to academic users. PMID- 21586588 TI - Cis-regulation of microRNA expression by scaffold/matrix-attachment regions. AB - microRNAs (miRNAs) spatio-temporally modulate gene expression; however, very little is known about the regulation of their expression. Here, we hypothesized that the well-known cis-regulatory elements of gene expression, scaffold/matrix attachment regions (MARs) could modulate miRNA expression. Accordingly, we found MARs to be enriched in the upstream regions of miRNA genes. To determine their role in cell type-specific expression of miRNAs, we examined four individual miRNAs (let-7b, miR-17, miR-93 and miR-221) and the miR-17-92 cluster, known to be overexpressed in neuroblastoma. Our results show that MARs indeed define the cell-specific expression of these miRNAs by tethering the chromatin to nuclear matrix. This is brought about by cell type-specific binding of HMG I/Y protein to MARs that then promotes the local acetylation of histones, serving as boundary elements for gene activation. The binding, chromatin tethering and gene activation by HMG I/Y was not observed in fibroblast control cells but were restricted to neuroblastoma cells. This study implies that the association of MAR binding proteins to MARs could dictate the tissue/context specific regulation of miRNA genes by serving as a boundary element signaling the transcriptional activation. PMID- 21586589 TI - Base pair opening kinetics study of the aegPNA:DNA hydrid duplex containing a site-specific GNA-like chiral PNA monomer. AB - Peptide nucleic acids (PNA) are one of the most widely used synthetic DNA mimics where the four bases are attached to a N-(2-aminoethyl)glycine (aeg) backbone instead of the negative-charged phosphate backbone in DNA. We have developed a chimeric PNA (chiPNA), in which a chiral GNA-like gamma(3)T monomer is incorporated into aegPNA backbone. The base pair opening kinetics of the aegPNA:DNA and chiPNA:DNA hybrid duplexes were studied by NMR hydrogen exchange experiments. This study revealed that the aegPNA:DNA hybrid is much more stable duplex and is less dynamic compared to DNA duplex, meaning that base pairs are opened and reclosed much more slowly. The site-specific incorporation of gamma(3)T monomer in the aegPNA:DNA hybrid can destabilize a specific base pair and its neighbors, maintaining the thermal stabilities and dynamic properties of other base pairs. Our hydrogen exchange study firstly revealed the unique kinetic features of base pairs in the aegPNA:DNA and chiPNA:DNA hybrids, which will provide an insight into the development of methodology for specific DNA recognition using PNA fragments. PMID- 21586590 TI - Comparing binding site information to binding affinity reveals that Crp/DNA complexes have several distinct binding conformers. AB - We show that the cAMP receptor protein (Crp) binds to DNA as several different conformers. This situation has precluded discovering a high correlation between any sequence property and binding affinity for proteins that bend DNA. Experimentally quantified affinities of Synechocystis sp. PCC 6803 cAMP receptor protein (SyCrp1), the Escherichia coli Crp (EcCrp, also CAP) and DNA were analyzed to mathematically describe, and make human-readable, the relationship of DNA sequence and binding affinity in a given system. Here, sequence logos and weight matrices were built to model SyCrp1 binding sequences. Comparing the weight matrix model to binding affinity revealed several distinct binding conformations. These Crp/DNA conformations were asymmetrical (non-palindromic). PMID- 21586592 TI - Impact of guideline-consistent therapy on outcome of patients with healthcare associated and community-acquired pneumonia. AB - BACKGROUND: A new category of healthcare-associated pneumonia (HCAP) has been added in the most recent American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines, since multidrug-resistant (MDR) pathogens are more common in patients with HCAP than in those with community-acquired pneumonia (CAP). The optimal empirical management of patients with HCAP remains controversial and adherence to guidelines is inconsistent. METHODS: A retrospective cohort study of 3295 adults admitted for pneumonia in an academic centre of Canada, between 1997 and 2008. RESULTS: MDR pathogens were more common among patients with HCAP than in those with CAP, but less so than in other studies. Compared with patients with CAP, those with HCAP had a higher all-cause 30 day mortality [68/563 (12%) versus 201/2732 (7%); P < 0.001] and more frequent need for mechanical ventilation [78/563 (14%) versus 276/2732 (10%); P = 0.01]. In patients with CAP, mortality was lower when treatment was concordant with guidelines [86/1557 (6%) versus 109/1097 (10%) if discordant; adjusted odds ratio 0.6 (0.4-0.8); P < 0.001]. In HCAP, mortality was similar whether or not empirical treatment was concordant with guidelines [6/35 (17%) versus 18/148 (12%) if discordant; P = 0.4]. However, 30 day mortality tended to be higher when the empirical treatment was microbiologically ineffective [4/22 (18%) versus 17/187 (9%) when effective; P = 0.3]. CONCLUSIONS: HCAP is associated with worse outcomes than CAP. MDR pathogens were implicated in only a small fraction of HCAP cases. In our study, unlike CAP, non-respect of current HCAP guidelines had no adverse effect on the ultimate outcome. Strategies for the empirical management of HCAP should be tailored to the local epidemiological context. PMID- 21586593 TI - Aminoglycoside resistance in multiply antibiotic-resistant Acinetobacter baumannii belonging to global clone 2 from Australian hospitals. AB - OBJECTIVES: To examine the distribution and context of aminoglycoside resistance genes in multiply antibiotic-resistant Acinetobacter baumannii isolates from Australia that are members of the global clone 2 and carry the bla(OXA-23) gene conferring resistance to carbapenems. METHODS: Sixty-one multiply antibiotic resistant A. baumannii strains isolated between 2000 and 2010 at six Australian hospitals that belonged to global clone 2 and carried the bla(OXA-23) gene were studied. Various molecular techniques were used to determine their relatedness and to detect antibiotic resistance genes and insertion sequences. Structures surrounding the aminoglycoside resistance genes were sequenced. RESULTS: The isolates all shared several antibiotic resistance genes, including the sul2 sulphonamide resistance gene, but varied in their pattern of resistance to aminoglycosides. The aminoglycoside resistance profiles of isolates were accounted for by four resistance genes-aadB, aacC1, aphA1b and aphA6-in various combinations. The aadB gene cassette was located at a secondary site on a 6 kb plasmid similar to pRAY. The aphA6 gene was in a transposon, TnaphA6, bounded by directly oriented copies of ISAba125. The aacC1 gene cassette in a class 1 integron and Tn6020 carrying aphA1b were always present together, but were not linked. CONCLUSIONS: Imipenem-resistant global clone 2 A. baumannii isolates containing bla(OXA-23) have been present in Australian hospitals for at least 10 years. Variation in this global clone 2 type has occurred with the introduction of various aminoglycoside resistance genes carried on a small plasmid or within transposons. PMID- 21586591 TI - Hepatic safety of antibiotics used in primary care. AB - Antibiotics used by general practitioners frequently appear in adverse-event reports of drug-induced hepatotoxicity. Most cases are idiosyncratic (the adverse reaction cannot be predicted from the drug's pharmacological profile or from pre clinical toxicology tests) and occur via an immunological reaction or in response to the presence of hepatotoxic metabolites. With the exception of trovafloxacin and telithromycin (now severely restricted), hepatotoxicity crude incidence remains globally low but variable. Thus, amoxicillin/clavulanate and co trimoxazole, as well as flucloxacillin, cause hepatotoxic reactions at rates that make them visible in general practice (cases are often isolated, may have a delayed onset, sometimes appear only after cessation of therapy and can produce an array of hepatic lesions that mirror hepatobiliary disease, making causality often difficult to establish). Conversely, hepatotoxic reactions related to macrolides, tetracyclines and fluoroquinolones (in that order, from high to low) are much rarer, and are identifiable only through large-scale studies or worldwide pharmacovigilance reporting. For antibiotics specifically used for tuberculosis, adverse effects range from asymptomatic increases in liver enzymes to acute hepatitis and fulminant hepatic failure. Yet, it is difficult to single out individual drugs, as treatment always entails associations. Patients at risk are mainly those with previous experience of hepatotoxic reaction to antibiotics, the aged or those with impaired hepatic function in the absence of close monitoring, making it important to carefully balance potential risks with expected benefits in primary care. Pharmacogenetic testing using the new genome wide association studies approach holds promise for better understanding the mechanism(s) underlying hepatotoxicity. PMID- 21586594 TI - Trend analysis of antimicrobial consumption and development of resistance in non fermenters in a tertiary care hospital in Delhi, India. AB - OBJECTIVES: Multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii are becoming increasingly important nosocomial pathogens worldwide. To study the evolution of non-fermenters in a tertiary care hospital, we undertook a retrospective 10 year (1999-2008) trend analysis of antimicrobial consumption and resistance in non-fermenters causing bacteraemia. METHODS: Antibiotic consumption and resistance were analysed by linear regression. The Pearson correlation coefficient was used for assessing correlation between them. RESULTS: A total of 69,010 blood cultures were performed, which grew 15,465 isolates (22% positivity rate), of which 1525 isolates (771 isolates of P. aeruginosa and 754 isolates of A. baumannii) were non-fermenters. Overall antibiotic consumption showed an increasing trend, from 158 to 319 defined daily doses (DDDs)/100 bed-days (r(2)= 0.62, P = 0.007). The largest relative increase in antibiotic consumption was seen for carbapenems (r(2)= 0.68, P = 0.022), followed by beta-lactam/inhibitor combinations (r(2 )= 0.45, P = 0.033), whereas third-generation cephalosporins, fluoroquinolones and aminoglycosides showed no significant changes. A significant increase in resistance in A. baumannii to fluoroquinolones (r(2 )= 0.63, P = 0.006), aminoglycosides (r(2 )= 0.63, P = 0.011) and carbapenems (r(2 )= 0.82, P = 0.013) and in P. aeruginosa to aminoglycosides (r(2 )= 0.59, P = 0.01) was observed. Carbapenem consumption was associated with the development of resistance in A. baumannii (r = 0.756, P = 0.049), whereas no such association was observed for other antimicrobials among non-fermenters. CONCLUSIONS: Our study highlights the growing problem of high antimicrobial consumption. The increasing prevalence of non-fermenters and the emergence of multidrug-resistant A. baumannii are associated with the consumption of carbapenems. The data cannot prove cause and effect. PMID- 21586595 TI - Antibiotic usage in south-western French hospitals: trends and association with antibiotic stewardship measures. AB - OBJECTIVES: French hospitals are urged by health authorities to develop antibiotic stewardship (ABS) programmes in order to improve antibiotic use and to decrease their consumption. We performed a longitudinal survey to describe ABS measures implementation and antibiotic use and to study relationships between ABS measures and trends in antibiotic use between 2005 and 2009. METHODS: Data on ABS, antibiotic use and activity were retrospectively collected by questionnaires sent to hospitals voluntarily participating in the south-western France network. ABS measures covered organization, resources, restrictive and persuasive actions. Antibiotic use was retrieved from pharmacy records and expressed as the number of defined daily doses/1000 patient-days according to national and WHO guidelines using 2009 defined daily dose values to monitor trends. Relationships between ABS measures and antibiotic use were studied by multivariate logistic regression. RESULTS: Between 2005 and 2009, the degree of implementation of ABS increased in the 74 participating hospitals. Antibiotic use remained stable, with variations according to hospital groups and antibiotic classes. In hospitals with more ABS measures, antibiotic use in general and fluoroquinolone use tended to remain stable or to decrease. Educational activities were associated with a decrease in fluoroquinolone use in the univariate analysis. In the multivariate analysis, practice audits and time dedicated by the antibiotic advisor were significantly associated with a decrease in total antibiotic use and fluoroquinolone use, respectively. CONCLUSIONS: This first longitudinal study, in 74 hospitals, showed that human resources and persuasive ABS measures, in the context of a multidisciplinary approach, are helpful in controlling total antibiotic and fluoroquinolone use. PMID- 21586596 TI - Disability, atrophy and cortical reorganization following spinal cord injury. AB - The impact of traumatic spinal cord injury on structural integrity, cortical reorganization and ensuing disability is variable and may depend on a dynamic interaction between the severity of local damage and the capacity of the brain for plastic reorganization. We investigated trauma-induced anatomical changes in the spinal cord and brain, and explored their relationship to functional changes in sensorimotor cortex. Structural changes were assessed using cross-sectional cord area, voxel-based morphometry and voxel-based cortical thickness of T1 weighted images in 10 subjects with cervical spinal cord injury and 16 controls. Cortical activation in response to right-sided (i) handgrip; and (ii) median and tibial nerve stimulation were assessed using functional magnetic resonance imaging. Regression analyses explored associations between cord area, grey and white matter volume, cortical activations and thickness, and disability. Subjects with spinal cord injury had impaired upper and lower limb function bilaterally, a 30% reduced cord area, smaller white matter volume in the pyramids and left cerebellar peduncle, and smaller grey matter volume and cortical thinning in the leg area of the primary motor and sensory cortex compared with controls. Functional magnetic resonance imaging revealed increased activation in the left primary motor cortex leg area during handgrip and the left primary sensory cortex face area during median nerve stimulation in subjects with spinal cord injury compared with controls, but no increased activation following tibial nerve stimulation. A smaller cervical cord area was associated with impaired upper limb function and increased activations with handgrip and median nerve stimulation, but reduced activations with tibial nerve stimulation. Increased sensory deficits were associated with increased activations in the left primary sensory cortex face area due to median nerve stimulation. In conclusion, spinal cord injury leads to cord atrophy, cortical atrophy of primary motor and sensory cortex, and cortical reorganization of the sensorimotor system. The degree of cortical reorganization is predicted by spinal atrophy and is associated with significant disability. PMID- 21586597 TI - Site-directed mutagenesis of the CC chemokine binding protein 35K-Fc reveals residues essential for activity and mutations that increase the potency of CC chemokine blockade. AB - Chemokines of the CC class are key mediators of monocyte recruitment and macrophage differentiation and have a well documented role in many inflammatory diseases. Blockade of chemokine activity is therefore an attractive target for anti-inflammatory therapy. 35K (vCCI) is a high-affinity chemokine binding protein expressed by poxviruses, which binds all human and murine CC chemokines, preventing their interaction with chemokine receptors. We developed an Fc-fusion protein of 35K with a modified human IgG1 Fc domain and expressed this construct in human embryonic kidney 293T cells. Purified 35K-Fc is capable of inhibiting CC chemokine-induced calcium flux, chemotaxis, and beta-arrestin recruitment in primary macrophages and transfected cells. To elucidate the residues involved in chemokine neutralization, we performed site-directed mutagenesis of six key amino acids in 35K and expressed the mutant Fc-fusion proteins in vitro. We screened the mutants for their ability to block chemokine-induced beta-arrestin recruitment in transfected cells and to inhibit primary macrophage signaling in an electric cell substrate impedance sensing assay. Using a sterile model of acute inflammation, zymosan-induced peritonitis, we confirmed that wild-type 35K Fc can reduce monocyte recruitment, whereas one mutant (R89A) showed a more pronounced blockade of monocyte influx and another mutant (E143K) showed total loss of function. We believe that 35K-Fc will be a useful tool for exploring the role of CC chemokines in chronic inflammatory pathologies, and we have identified a higher potency form of the molecule that may have potential therapeutic applications in chronic inflammatory disease. PMID- 21586598 TI - Effect of zein on biodegradable inserts for the delivery of tetracycline within periodontal pockets. AB - Treatment with antibiotics within the periodontal pocket against bacterial infections represents a useful and adjunctive tool to conventional therapy for healing and teeth preservation. With this function in view, an implantable, tetracycline delivery device for the treatment of periodontal disease was developed. The aim of this study was to develop biodegradable, tetracycline loaded microparticles made of two polymers: PLGA and zein which were compressed into monolithic devices. In this polymer delivery system, the encapsulation efficiency, release characteristics, drug-polymer interaction, and antibacterial activity of loaded drug were investigated. The interaction of tetracycline with the corn protein zein was studied by nuclear magnetic resonance (NMR), Fourier transform infrared, and X-ray diffraction. The hydrophobic interaction of tetracycline with zein in the formulations was deduced from the NMR studies, whereas X-ray diffraction studies showed a new crystalline state of the drug in the presence of the protein. Zein was not denatured by preparation of inserts. Sustained release of tetracycline was obtained, and the proportion of zein in the inserts had a great impact on the drug release. Finally, an effective tetracycline release from inserts against Staphylococcus aureus was achieved over 30 days. In conclusion, the PLGA:zein delivery system described in this study was found to be effective in controlled delivery of tetracycline, and hence may be suitable for intra-pocket delivery of antimicrobial agents in the treatment of periodontitis. PMID- 21586599 TI - Targeting neural stem cells with titanium dioxide nanoparticles coupled to specific monoclonal antibodies. AB - Aiming to characterize the use of biomaterials in cancer therapy, we took advantage of the n-type semiconductor properties, which upon irradiation excite their electrons into the conduction band to induce photoelectrochemical reactions generating oxygen reactive species (ROS). Indeed, photoactivated TiO(2) nanoparticles have been shown to kill in vitro either bacteria or tumor cells in culture following UV irradiation, as a consequence of the ROS levels generated; the killing was highly effective although devoid of specificity. In this report, we have directed the TiO(2) nanoparticles to particular targets by coupling them to the monoclonal antibody (mAb) Nilo1, recognizing a surface antigen in neural stem cells within a cell culture, to explore the possibility of making this process specific. TiO(2) nanoparticles generated with particular rutile/anatase ratios were coupled to Nilo1 antibody and the complexes formed were highly stable. The coupled antibody retained the ability to identify neural stem cells and upon UV irradiation, the TiO(2) nanoparticles were activated, inducing the selective photokilling of the antibody-targeted cells. Thus, these data indicate that antibody-TiO(2) complexes could be used to specifically remove target cell subpopulations, as demonstrated with neural stem cells. The possible applications in cancer therapy are discussed. PMID- 21586600 TI - Vitamin E (alpha-tocopherol) addition modifies P(D,L)LA sponge degradation and protein release. AB - Polylactic acid (PLA)-derived polymers are widely used in many biotechnological fields, thanks to their biocompatibility and resorbability through natural pathways. Moreover, PLA is one of the few polymers in which both the properties and the stereochemical structure can be easily modified, making possible a specific 'tailoring' of the final polymer according to the desired use. In this study, we obtained, by salt leaching technique, P(D,L)LA sponges in which various concentrations of alpha-tocopherol (Vit. E 10-40%, w/w) were incorporated. Vit.E is a natural biological antioxidant, also known to have anti-inflammatory activity, which has been extensively used to improve biostability and biocompatibility of different biomaterials. To assess whether Vit.E could modify the main physical-chemical properties of P(D,L)LA sponges, their morphology, water uptake and hydrolytic degradation kinetics, along with protein loading and releasing attitudes, were investigated. Our results highlighted that incorporation of Vit.E into P(D,L)LA sponges modified the sponge morphology, decreased P(D,L)LA water uptake and degradation, and modified protein releasing kinetics. These Vit.E-related effects could make P(D,L)LA more suitable as drug delivery system and tissue engineering scaffold. PMID- 21586601 TI - Structural and cellular characterization of electrospun recombinant human tropoelastin biomaterials. AB - An off-the-shelf vascular graft biomaterial for vascular bypass surgeries is an unmet clinical need. The vascular biomaterial must support cell growth, be non thrombogenic, minimize intimal hyperplasia, match the structural properties of native vessels, and allow for regeneration of arterial tissue. Electrospun recombinant human tropoelastin (rTE) as a medial component of a vascular graft scaffold was investigated in this study by evaluating its structural properties, as well as its ability to support primary smooth muscle cell adhesion and growth. rTE solutions of 9, 15, and 20 wt% were electrospun into sheets with average fiber diameters of 167 +/- 32, 522 +/- 67, and 735 +/- 270 nm, and average pore sizes of 0.4 +/- 0.1, 5.8 +/- 4.3, and 4.9 +/- 2.4 um, respectively. Electrospun rTE fibers were cross-linked with disuccinimidyl suberate to produce an insoluble fibrous polymeric recombinant tropoelastin (prTE) biomaterial. Smooth muscle cells attached via integrin binding to the rTE coatings and proliferated on prTE biomaterials at a comparable rate to growth on prTE coated glass, glass alone, and tissue culture plastic. Electrospun tropoelastin demonstrated the cell compatibility and design flexibility required of a graft biomaterial for vascular applications. PMID- 21586602 TI - In vitro 3D culture of human chondrocytes using modified epsilon-caprolactone scaffolds with varying hydrophilicity and porosity. AB - Two series of 3D scaffolds based on epsilon-caprolactone were synthesized. The pore size and architecture (spherical interconnected pores) was the same in all the scaffolds. In one of the series of scaffolds, made of pure epsilon polycaprolactone, the volume fraction of pores varied between 60% and 85% with the main consequence of varying the interconnectivity between pores since the pore size was kept constant. The other scaffolds were prepared with copolymers made of a epsilon-caprolactone-based hydrophobous monomer and hydroxyethyl acrylate, as the hydrophilic component. Thus, the hydrophilicity and, presumably, the adhesion properties varied monotonously in the copolymer series while porosity was kept constant. A suspension of human chondrocytes in culture medium was injected in the 3D scaffolds and cultured in static conditions up to 28 days. SEM and immunofluorescence assays allowed characterizing cells and extracellular matrix inside the scaffolds after different culture times. To do that, cross sections of the scaffolds were observed by SEM and confocal microscopy. The quantity of cells inside the scaffolds decreases with a decrease of the volume fraction of pores, due to the lack of interconnectivity between the cavities. The scaffolds up to a 30% of hydrophilicity behave in a similar way than the hydrophobous; a further increase of the hydrophilicity rapidly decreases cell viability. In all the experiments production of collagen type I, type II, and aggrecan was found, and some cells were Ki-67 positive, showing that some cells are adhered to the pore walls and maintain their dedifferentiated phenotype even when cultured in three-dimensional conditions. PMID- 21586603 TI - Exposure to an environmental neurotoxicant hastens the onset of amyotrophic lateral sclerosis-like phenotype in human Cu2+/Zn2+ superoxide dismutase 1 G93A mice: glutamate-mediated excitotoxicity. AB - Mice expressing the human Cu(2+)/Zn(2+) superoxide dismutase 1 (hSOD1) gene mutation (hSOD1(G93A); G93A) were exposed to methylmercury (MeHg) at concentrations that did not cause overt motor dysfunction. We hypothesized that low concentrations of MeHg could hasten development of the amyotrophic lateral sclerosis (ALS)-like phenotype in G93A mice. MeHg (1 or 3 ppm/day in drinking water) concentration-dependently accelerated the onset of rotarod failure in G93A, but not wild-type, mice. At the time of rotarod failure, MeHg increased Fluo-4 fluorescence (free intracellular calcium concentration [Ca(2+)](i)) in soma of brainstem-hypoglossal nucleus. These motor neurons control intrinsic and some extrinsic tongue function and exhibit vulnerability in bulbar-onset ALS. The alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione reduced [Ca(2+)](i) in all G93A mice, irrespective of MeHg treatment. N-acetyl spermine, which antagonizes Ca(2+)-permeable AMPA receptors, further reduced [Ca(2+)](i) more effectively in MeHg-treated than untreated G93A mice, suggesting that MeHg treated mice have a greater Ca(2+)-permeable AMPA receptor contribution. The non Ca(2+) divalent cation chelator N,N,N',N'-tetrakis(pyridylmethyl)ethylenediamine reduced Fluo-4 fluorescence in all G93A mice; FluoZin-(Zn(2+) indicator) fluorescence was increased in all MeHg-treated mice. Thus in G93A mice Zn(2+) apparently contributed measurably to the MeHg-induced effect. This is the initial demonstration of accelerated onset of ALS-like phenotype in a genetically susceptible organism by exposure to low concentrations of an environmental neurotoxicant. Increased [Ca(2+)](i) induced by the G93A-MeHg interaction apparently was associated with Ca(2+)-permeable AMPA receptors and may contribute to the hastened development of ALS-like phenotypes by subjecting motor neurons to excessive elevation of [Ca(2+)](i), leading to excitotoxic cell death. PMID- 21586604 TI - Identification of the factors that govern the ability of therapeutic antibodies to provide postchallenge protection against botulinum toxin: a model for assessing postchallenge efficacy of medical countermeasures against agents of bioterrorism and biological warfare. AB - Therapeutic antibodies are one of the major classes of medical countermeasures that can provide protection against potential bioweapons such as botulinum toxin. Although a broad array of antibodies are being evaluated for their ability to neutralize the toxin, there is little information that defines the circumstances under which these antibodies can be used. In the present study, an effort was made to quantify the temporal factors that govern therapeutic antibody use in a postchallenge scenario. Experiments were done involving inhalation administration of toxin to mice, intravenous administration to mice, and direct application to murine phrenic nerve-hemidiaphragm preparations. As part of this study, several pharmacokinetic characteristics of botulinum toxin and neutralizing antibodies were measured. The core observation that emerged from the work was that the window of opportunity within which postchallenge administration of antibodies exerted a beneficial effect increased as the challenge dose of toxin decreased. The critical factor in establishing the window of opportunity was the amount of time needed for fractional redistribution of a neuroparalytic quantum of toxin from the extraneuronal space to the intraneuronal space. This redistribution event was a dose-dependent phenomenon. It is likely that the approach used to identify the factors that govern postchallenge efficacy of antibodies against botulinum toxin can be used to assess the factors that govern postchallenge efficacy of medical countermeasures against any agent of bioterrorism or biological warfare. PMID- 21586605 TI - Navbeta subunits modulate the inhibition of Nav1.8 by the analgesic gating modifier MUO-conotoxin MrVIB. AB - Voltage-gated sodium channels (VGSCs) consist of a pore-forming alpha-subunit and regulatory beta-subunits. Several families of neuroactive peptides of Conus snails target VGSCs, including MUO-conotoxins and MU-conotoxins. Unlike MU conotoxins and the guanidinium alkaloid saxitoxin (STX), which are pore blockers, MUO-conotoxins MrVIA and MrVIB inhibit VGSCs by modifying channel gating. MUO MrVIA/B can block Na(v)1.8 (a tetrodotoxin-resistant isoform of VGSCs) and have analgesic properties. The effect of Na(v)beta-subunit coexpression on susceptibility to block by MUO-MrVIA/B and STX has, until now, not been reported. Here, we show that beta1-, beta2-, beta3-, and beta4-subunits, when individually coexpressed with Na(v)1.8 in Xenopus laevis oocytes, increased the k(on) of the block produced by MUO-MrVIB (by 3-, 32-, 2-, and 7-fold, respectively) and modestly decreased the apparent k(off). Strong depolarizing prepulses markedly accelerated MrVIB washout with rates dependent on beta-subunit coexpression. Thus, coexpression of beta-subunits with Na(v)1.8 can strongly influence the affinity of the conopeptide for the channel. This observation is of particular interest because beta-subunit expression can be dynamic, e.g., beta2-expression is up-regulated after nerve injury (J Neurosci, 25:10970-10980, 2005); therefore, the effectiveness of a MUO-conotoxin as a channel blocker could be enhanced by the conditions that may call for its use therapeutically. In contrast to MrVIB's action, the STX-induced block of Na(v)1.8 was only marginally, if at all, affected by coexpression of any of the beta-subunits. Our results raise the possibility that MUO-conotoxins and perhaps other gating modifiers may provide a means to functionally assess the beta-subunit composition of VGSC complexes in neurons. PMID- 21586606 TI - Risk factors associated with breast arterial calcifications. AB - BACKGROUND: A number of studies have linked the presence of breast arterial calcifications (BACs) with an increased risk of diabetes, hypertension, coronary artery disease (CAD), and cardiovascular mortality. Because there is a well established screening system for breast cancer, it has been proposed that the presence of BACs can be used as a warning sign indicating an increased risk of metabolic and vascular diseases. PURPOSE: To determine the relation between BAC and early renal dysfunction. MATERIAL AND METHODS: A retrospective review of 6118 mammograms identified 701 cases with BACs. Women with BACs were compared to a random selection of 362 women without BACs based on available laboratory data. Univariate analysis was conducted according to age groups. RESULTS: The prevalence of BACs was 11.5% in our study. Hyperglycemia increased the odds of BACs by 8.1 (95% CI 3.0-22.1, P < 0.001) in the 50-59-year age group. The presence of an elevated blood urea nitrogen (BUN) and serum creatinine increased the odds of BACs by 2.6 (95% CI 1.2-6.0, P = 0.016) and 2.3 (95% CI 1.0-5.2, P = 0.045) in women >=70 years of age. Hyperlipidemia was not a significant risk factor for BACs in any age group. CONCLUSION: Our results support the view that the presence of BACs on mammography may be indicative of diabetes in middle-aged women. On the other hand, BACs are not very useful for predicting early renal dysfunction in women <70 years of age. PMID- 21586607 TI - Feasibility of dual gradient-echo in-phase and opposed-phase magnetic resonance imaging for the evaluation of epicardial fat. AB - BACKGROUND: Dual gradient-echo in-phase (IP) and opposed-phase (OP) magnetic resonance imaging (MRI) can evaluate small amounts of fat, and is widely used for imaging abdominal organs. Epicardial fat has recently been revealed as having an important role in the development of heart disease, but IPOP-MRI has not been widely applied in this field, probably because of cardiac motion artifacts. PURPOSE: To demonstrate the feasibility of IPOP-MRI with electrocardiography (ECG)-gating for evaluation of epicardial fat in the normal human heart, compared to black-blood T1-weighted imaging (T1WI). MATERIAL AND METHODS: Ten healthy volunteers were studied. Epicardial fat volume was quantitatively evaluated on OP from-IP subtraction images and T1-weighted images. RESULTS: Epicardial fat was clearly visualized on the subtraction images as hyperintense areas that corresponded to regions identified as epicardial fat on the T1-weighted images. Epicardial fat volume correlated well between the two methods (r = 0.93, P <0.0001), and tended to be larger on the subtraction images than on the T1 weighted images (91.4 +/- 30.1 vs. 84.1 +/- 30.5 mL, P = 0.07). CONCLUSION: IPOP MRI with ECG-gating may be a useful alternative method to black-blood T1WI for evaluation of epicardial fat. PMID- 21586608 TI - Diffusion tensor imaging of prostate at 3.0 Tesla. AB - BACKGROUND: The feasibility of diffusion tensor imaging (DTI) of prostate has been confirmed by several studies. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of prostate with healthy or pathological changes remain controversial. PURPOSE: To investigate the efficacy of DTI at 3.0 T in diagnosing prostate cancer in the peripheral zone and to determine the normative ADC and FA values of the normal prostate. MATERIAL AND METHODS: T2 weighted imaging (T2WI) and DTI of the prostate was performed in 33 cases with diagnosis confirmed by biopsy at 3.0 T MR. ADC and FA values of cancerous and non cancerous sextants were compared. Receiver-operating characteristic (ROC) curves were used to compare the ability of ADC, FA and the two values combined in diagnosing prostate cancer in the peripheral zone. DTI data of 20 healthy young volunteers were also acquired. ADC and FA values of the normal central gland and the peripheral zone were compared. RESULTS: ADC value (1.10 +/- 0.09 * 10(-3) mm(2)/s) was lower while FA value (0.37 +/- 0.05) was higher in normal central gland, compared with that in normal peripheral zone (1.63 +/- 0.15 * 10(-3) mm(2)/s, 0.21 +/- 0.07, respectively) (P < 0.0001, P < 0.0001, respectively). Sixteen of 33 cases were confirmed to be malignant while 17 of 33 cases were benign. All the 198 sextants were confirmed by biopsy, including 136 non cancerous sextants and 62 cancerous sextants. There were significant differences between cancerous sextants (1.02 +/- 0.16 * 10(-3) mm(2)/s, 0.38 +/- 0.09) and non-cancerous sextants (1.22 +/- 0.14 * 10(-3) mm(2)/s, 0.31 +/- 0.06) for both ADC and FA values (P <0.0001, P <0.0001, respectively). Significant differences were noted between the AUC of DTI and FA alone (0.86 vs. 0.76, P = 0.0009), but no differences between the AUC of DTI and ADC alone (0.86 vs. 0.84, P = 0.1595). CONCLUSION: ADC and FA values of normal prostate may be compatible with the microstructural organization of prostate. Furthermore, DTI may be a potential tool in diagnosing prostate cancer in the peripheral zone. PMID- 21586609 TI - Identification of an animal sucrose transporter. AB - According to a classic tenet, sugar transport across animal membranes is restricted to monosaccharides. Here, we present the first report of an animal sucrose transporter, SCRT, which we detected in Drosophila melanogaster at each developmental stage. We localized the protein in apical membranes of the late embryonic hindgut as well as in vesicular membranes of ovarian follicle cells. The fact that knockdown of SCRT expression results in significantly increased lethality demonstrates an essential function for the protein. Experiments with Saccharomyces cerevisiae as a heterologous expression system revealed that sucrose is a transported substrate. Because the knockout of SLC45A2, a highly similar protein belonging to the mammalian solute carrier family 45 (SLC45) causes oculocutaneous albinism and because the vesicular structures in which SCRT is located appear to contain melanin, we propose that these organelles are melanosome-like structures and that the transporter is necessary for balancing the osmotic equilibrium during the polymerization process of melanin by the import of a compatible osmolyte. In the hindgut epithelial cells, sucrose might also serve as a compatible osmolyte, but we cannot exclude the possibility that transport of this disaccharide also serves nutritional adequacy. PMID- 21586610 TI - Management of antibiotic-resistant infection in the newborn. AB - We are inexorably entering an era where a wide range of multiply antibiotic resistant bacteria are commonplace. Until recently, multiresistance was mainly seen in Gram-positive bacteria. However, vancomycin remains adequate as a treatment of most infections with these bacteria. The potential threat from vancomycin-resistant bacteria has never fully materialised, and now there is a growing number of new anti-Gram-positive antibiotics. Of these, there is sufficient experience of using linezolid and daptomycin in neonates for these drugs to be recommended for some specific indications. The recent rapid international spread of multiresistant Gram-negative bacteria, including carbapenem-resistant strains, is much more ominous. Treatment options are extremely limited, which has prompted renewed interest in older and more toxic antibiotics such as colistin. However, the optimal management of serious neonatal infections with these bacteria remains to be determined. PMID- 21586611 TI - MicroRNA sequence and expression analysis in breast tumors by deep sequencing. AB - MicroRNAs (miRNA) regulate many genes critical for tumorigenesis. We profiled miRNAs from 11 normal breast tissues, 17 noninvasive, 151 invasive breast carcinomas, and 6 cell lines by in-house-developed barcoded Solexa sequencing. miRNAs were organized in genomic clusters representing promoter-controlled miRNA expression and sequence families representing seed sequence-dependent miRNA target regulation. Unsupervised clustering of samples by miRNA sequence families best reflected the clustering based on mRNA expression available for this sample set. Clustering and comparative analysis of miRNA read frequencies showed that normal breast samples were separated from most noninvasive ductal carcinoma in situ and invasive carcinomas by increased miR-21 (the most abundant miRNA in carcinomas) and multiple decreased miRNA families (including miR-98/let-7), with most miRNA changes apparent already in the noninvasive carcinomas. In addition, patients that went on to develop metastasis showed increased expression of mir 423, and triple-negative breast carcinomas were most distinct from other tumor subtypes due to upregulation of the mir~17-92 cluster. However, absolute miRNA levels between normal breast and carcinomas did not reveal any significant differences. We also discovered two polymorphic nucleotide variations among the more abundant miRNAs miR-181a (T19G) and miR-185 (T16G), but we did not identify nucleotide variations expected for classical tumor suppressor function associated with miRNAs. The differentiation of tumor subtypes and prediction of metastasis based on miRNA levels is statistically possible but is not driven by deregulation of abundant miRNAs, implicating far fewer miRNAs in tumorigenic processes than previously suggested. PMID- 21586612 TI - STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. AB - The STAT3 transcription factor is an important regulator of stem cell self renewal, cancer cell survival, and inflammation. In the pancreas, STAT3 is dispensable for normal development, whereas the majority of pancreatic ductal adenocarcinomas (PDAC) show constitutive activation of STAT3, suggesting its potential as a therapeutic target in this cancer. Here, we sought to define the mechanisms of STAT3 activation and its functional importance in PDAC pathogenesis. Large-scale screening of cancer cell lines with a JAK2 inhibitor that blocks STAT3 function revealed a more than 30-fold range in sensitivity in PDAC, and showed a close correlation of sensitivity with levels of tyrosine phosphorylated STAT3 and of the gp130 receptor, an upstream signaling component. Correspondingly, upregulation of the IL6/LIF-gp130 pathway accounted for the strong STAT3 activation in PDAC subsets. To define functions of STAT3 in vivo, we developed mouse models that test the impact of conditional inactivation of STAT3 in KRAS-driven PDAC. We showed that STAT3 is required for the development of the earliest premalignant pancreatic lesions, acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Moreover, acute STAT3 inactivation blocked PDAC initiation in a second in vivo model. Our results show that STAT3 has critical roles throughout the course of PDAC pathogenesis, supporting the development of therapeutic approaches targeting this pathway. Moreover, our work suggests that gp130 and phospho-STAT3 expression may be effective biomarkers for predicting response to JAK2 inhibitors. PMID- 21586613 TI - Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma. AB - The process of alternative splicing is widely misregulated in cancer, but the contribution of splicing regulators to cancer development is largely unknown. In this study, we found that the splicing factor hnRNP A2/B1 is overexpressed in glioblastomas and is correlated with poor prognosis. Conversely, patients who harbor deletions of the HNRNPA2B1 gene show better prognosis than average. Knockdown of hnRNP A2/B1 in glioblastoma cells inhibited tumor formation in mice. In contrast, overexpression of hnRNP A2/B1 in immortal cells led to malignant transformation, suggesting that HNRNPA2B1 is a putative proto-oncogene. We then identified several tumor suppressors and oncogenes that are regulated by HNRNPA2B1, among them are c-FLIP, BIN1, and WWOX, and the proto-oncogene RON. Knockdown of RON inhibited hnRNP A2/B1 mediated transformation, which implied that RON is one of the mediators of HNRNPA2B1 oncogenic activity. Together, our results indicate that HNRNPA2B1 is a novel oncogene in glioblastoma and a potential new target for glioblastoma therapy. PMID- 21586614 TI - Imaging DNA damage in vivo using gammaH2AX-targeted immunoconjugates. AB - DNA damage responses (DDR) occur during oncogenesis and therapeutic responses to DNA damaging cytotoxic drugs. Thus, a real-time method to image DNA damage in vivo would be useful to diagnose cancer and monitor its treatment. Toward this end, we have developed fluorophore- and radioisotope-labeled immunoconjugates to target a DDR signaling protein, phosphorylated histone H2A variant H2AX (gammaH2AX), which forms foci at sites of DNA double-strand breaks. Anti gammaH2AX antibodies were modified by the addition of diethylenetriaminepentaacetic acid (DTPA) to allow (111)In labeling or the fluorophore Cy3. The cell-penetrating peptide Tat (GRKKRRQRRRPPQGYG) was also added to the immunoconjugate to aid nuclear translocation. In irradiated breast cancer cells, confocal microscopy confirmed the expected colocalization of anti gammaH2AX-Tat with gammaH2AX foci. In comparison with nonspecific antibody conjugates, (111)In-anti-gammaH2AX-Tat was retained longer in cells. Anti gammaH2AX-Tat probes were also used to track in vivo DNA damage, using a mouse xenograft model of human breast cancer. After local X-ray irradiation or bleomycin treatment, the anti-gammaH2AX-Tat probes produced fluorescent and single photon emission computed tomography signals in the tumors that were proportionate to the delivered radiation dose and the amount of gammaH2AX present. Taken together, our findings establish the use of radioimmunoconjugates that target gammaH2AX as a noninvasive imaging method to monitor DNA damage, with many potential applications in preclinical and clinical settings. PMID- 21586615 TI - Erythropoietin induces lymph node lymphangiogenesis and lymph node tumor metastasis. AB - Cancer therapy often produces anemia, which is treated with erthropoietin (EPO) to stimulate erythrocyte production. However, concerns have recently arisen that EPO treatment may promote later tumor metastasis and mortality. The mechanisms underlying such effects are unknown, but it is clear that EPO has pleiotropic effects in cell types other than hematopoietic cells. In this study, we investigated how EPO affects lymphangiogenesis and lymph node tumor metastasis in mouse models of breast cancer and melanoma. In these models, EPO increased lymph node lymphangiogenesis and lymph node tumor metastasis in a manner associated with increased migration, capillary-like tube formation, and dose- and time dependent proliferation of human lymphatic endothelial cells. EPO increased sprouting of these cells in a thoracic duct lymphatic ring assay. These effects were abrogated by cotreatment with specific inhibitors of phosphoinositide 3 kinase or mitogen-activated protein kinase, under conditions in which EPO increased Akt and extracellular signal-regulated kinase 1/2 phosphorylation. Intraperitoneal administration of EPO stimulated peritoneal lymphangiogenesis, and systemic treatment of EPO increased infiltration of CD11b(+) macrophages in tumor-draining lymph nodes. Finally, EPO increased VEGF-C expression in lymph node-derived CD11b(+) macrophages as well as in bone marrow-derived macrophages in a dose- and time-dependent manner. Our results establish that EPO exerts a powerful lymphangiogenic function and can drive both lymph node lymphangiogenesis and nodal metastasis in tumor-bearing animals. PMID- 21586616 TI - A fortunate experiment? New Zealand's experience with a legislated code of patients' rights. PMID- 21586617 TI - Prelinguistic vocal development in young cochlear implant recipients and typically developing infants: year 1 of robust hearing experience. AB - This investigation examined the time course and sequence of prelinguistic vocal development during the first year of cochlear implant (CI) experience. Thirteen children who were implanted between 8 and 35 months and 11 typically developing (TD) infants participated in this longitudinal study. Adult-child play interactions were video- and audio-recorded at trimonthly intervals for each group, and child utterances were classified into categories representing progressively more mature productions: Precanonical Vocalizations, Basic Canonical Syllables, and Advanced Form vocalizations. Young CI recipients met the 20% criterion for establishment of the Basic Canonical Syllables and Advanced Forms levels with fewer months of robust hearing experience than the TD infants. Most CI recipients followed the sequence of development predicted by the Stark Assessment of Early Vocal Development-Revised. The relatively rapid progress of the CI children suggests that an earlier period of auditory deprivation did not have negative consequences for prelinguistic vocal development. It also supports the notion that young CI recipients comparatively advanced maturity facilitated expeditious auditory-guided speech development. PMID- 21586618 TI - Recognition by family members that relatives with neurodegenerative disease are likely to die within a year: a meta-ethnography. AB - OBJECTIVE: To synthesize evidence of family members recognizing that their relative is likely to die within the year, and identifying the need for palliative care. DESIGN: A meta-ethnography of studies of family members in multiple sclerosis (MS), Parkinson's disease (PD) and motor neuron disease (MND). REVIEW METHODS: Systematic search in electronic databases; thematic synthesis guided by the principles of meta-ethnography, which is a method for thematic synthesis of qualitative studies. RESULTS: Nine articles were included. The results of the synthesis identified two key themes. First, family members are intimately aware of changes in their relative's health and well-being. Sub-themes include family member awareness of different and progressive stages of the disease, noticing deterioration, noticing decline in functional abilities and recognizing that their relative will die. The second key theme is dilemmas of being involved in prognostication. Sub-themes include family member ambivalence toward hearing about prognostication, health professionals not being knowledgeable of the disease and family reluctance to receive palliative care. CONCLUSIONS: Family members monitor and recognize changes in their relative with PD, MND and MS and in themselves. Thus, drawing on the expertise of family members may be a useful tool for prognostication. PMID- 21586619 TI - Detection of bladder cancer using novel DNA methylation biomarkers in urine sediments. AB - BACKGROUND: Bladder cancer (BCa) remains a lethal malignancy that can be cured if detected early. DNA hypermethylation is a common epigenetic abnormality in cancer that may serve as a marker of disease activity. METHODS: We selected 10 novel candidate genes from the most frequently hypermethylated genes detected by DNA microarray and bisulfite pyrosequencing of bladder cancers and applied them to detect bladder cancer in urine sediments. We analyzed DNA methylation in the candidate genes by quantitative methylation-specific real-time PCR (qMSP) to detect bladder cancer in urine sediments from 128 bladder cancer patients and 110 age-matched control subjects. RESULTS: Based on a multigene predictive model, we discovered 6 methylation markers (MYO3A, CA10, SOX11, NKX6-2, PENK, and DBC1) as most promising for detecting bladder cancer. A panel of 4 genes (MYO3A, CA10, NKX6-2, and DBC1 or SOX11) had 81% sensitivity and 97% specificity, whereas a panel of 5 genes (MYO3A, CA10, NKX6-2, DBC1, and SOX11 or PENK) had 85% sensitivity and 95% specificity for detection of bladder cancer (area under curve = 0.939). By analyzing the data by cancer invasiveness, detection rate was 47 of 58 (81%) in non-muscle invasive tumors (pTa, Tis, and pT1) and 62 of 70 (90%) in muscle invasive tumors (T2, T3, and T4). CONCLUSIONS: This biomarker panel analyzed by qMSP may help the early detection of bladder tumors in urine sediments with high accuracy. IMPACT: The panel of biomarker deserves validation in a large well-controlled prospectively collected sample set. PMID- 21586620 TI - GSTM1, GSTT1 null variants, and GPX1 single nucleotide polymorphism are not associated with bladder cancer risk in Egypt. AB - BACKGROUND: Bladder cancer is the most common male malignancy in Egypt, consists predominantly of urothelial cell carcinoma (UCC) and squamous cell carcinoma (SCC), and disparities in incidence exist between men and women regardless of geographic region. Tobacco smoke exposure and Schistosoma haematobium (SH) infection and the presence of GSTM1, GSTT1, and GPX1 genotypes, as modulators of the carcinogenic effect of reactive oxidative species, were hypothesized to modify bladder cancer risk and possibly explain these gender differences. METHODS: We evaluated the association between bladder cancer risk and functional polymorphisms in the GSTM1, GSTT1, and GPX1 genes in 625 cases and 626 matched population-based controls in Egypt and assessed for potential interactions between these candidate genes and environmental exposures, such as smoking and SH infection. We analyzed the risk for developing UCC and SCC separately. RESULTS: None of these functional polymorphisms were significantly associated with bladder cancer risk. There were no significant interactions between genotypes and smoking or SH infection in this population, nor was any difference detected in genotypic risk between men and women. CONCLUSIONS: Our findings suggest that common genetic variations in GSTM1, GSTT1, and GPX1 are not associated with bladder cancer risk overall and that well-known environmental risk factors, such as smoking and SH infection, do not interact with these genes to modulate the risk. IMPACT: Our data indicate that common genetic variations in GSTM1, GSTT1, and GPX1 were not associated with bladder cancer risk. PMID- 21586621 TI - Polymorphisms in CYP1A1 and ethnic-specific susceptibility to acute lymphoblastic leukemia in children. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. The U.S. Surveillance Epidemiology and End Results (SEER) registry reports that Hispanic children have the highest incidence of ALL, however, it is unclear if this is due to genetic factors, unique environmental exposures, or both. Previous reports have shown an association between CYP1A1 variants and ALL. METHODS: To explore the contribution of CYP1A1 polymorphisms to ALL susceptibility in different ethnic groups, we conducted a case-control analysis in Caucasian, Hispanic, and African-American children. RESULTS: Increased risk of developing ALL was found in the whole sample group for homozygosity of variant alleles at CYP1A1*2C (OR 2.51, 95% CI 1.18-5.33, P = 0.016) and CYP1A1*2B (OR 3.24, 95% CI 1.43-7.34, P = 0.005). Stratified analyses showed increased risks in the Hispanic group (CYP1A1*2A, OR 2.70, 95% CI 1.27-5.74, P = 0.010; CYP1A1*2C, OR 2.47, 95% CI 1.13-5.38, P = 0.023; and CYP1A1*2B, OR 3.28, 95% CI 1.40-7.69, P = 0.006) but not for the other ethnic groups. Hispanic control subjects were significantly more likely to be carriers of variant alleles as compared to Caucasians (P < 0.0001) and African Americans (P = 0.005). CONCLUSIONS: Our study suggests that polymorphisms in CYP1A1 may contribute to the increased risk of ALL in Hispanic children due to both their impact on leukemia susceptibility and the increased prevalence of the at-risk alleles in the Hispanic population. IMPACT: Our study provides a novel and specific link between CYP1A1 polymorphisms and ethnic influence on ALL risk that may help explain varying susceptibilities across groups to environmental toxins. PMID- 21586622 TI - Plasma biomarker profiles differ depending on breast cancer subtype but RANTES is consistently increased. AB - BACKGROUND: Current biomarkers for breast cancer have little potential for detection. We determined whether breast cancer subtypes influence circulating protein biomarkers. METHODS: A sandwich ELISA microarray platform was used to evaluate 23 candidate biomarkers in plasma samples that were obtained from subjects with either benign breast disease or invasive breast cancer. All plasma samples were collected at the time of biopsy, after a referral due to a suspicious screen (e.g., mammography). Cancer samples were evaluated on the basis of breast cancer subtypes, as defined by the HER2 and estrogen receptor statuses. RESULTS: Ten proteins were statistically altered in at least one breast cancer subtype, including four epidermal growth factor receptor ligands, two matrix metalloproteases, two cytokines, and two angiogenic factors. Only one cytokine, RANTES, was significantly increased (P < 0.01 for each analysis) in all four subtypes, with areas under the curve (AUC) for receiver operating characteristic values that ranged from 0.76 to 0.82, depending on cancer subtype. The best AUC values were observed for analyses that combined data from multiple biomarkers, with values ranging from 0.70 to 0.99, depending on the cancer subtype. Although the results for RANTES are consistent with previous publications, the multi-assay results need to be validated in independent sample sets. CONCLUSIONS: Different breast cancer subtypes produce distinct biomarker profiles, and circulating protein biomarkers have potential to differentiate between true- and false positive screens for breast cancer. IMPACT: Subtype-specific biomarker panels may be useful for detecting breast cancer or as an adjunct assay to improve the accuracy of current screening methods. PMID- 21586623 TI - A large cohort study of long-term acetaminophen use and prostate cancer incidence. AB - BACKGROUND: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAID), particularly long-term use, has been associated with modestly reduced risk of prostate cancer in previous epidemiologic studies. Acetaminophen, a commonly used pain reliever, is not traditionally considered an NSAID but can have anti-inflammatory effects. Few studies have examined the association between long-term acetaminophen use and prostate cancer incidence. METHODS: We examined the association between acetaminophen use and prostate cancer incidence among 78,485 men in the Cancer Prevention Study II Nutrition Cohort. Information on acetaminophen use was obtained from a questionnaire completed at study enrollment in 1992 and updated by using follow-up questionnaires in 1997 and every two years thereafter. Relative risks (RR) were estimated by using proportional hazards regression models. All models were adjusted for age, race, education, body mass index, diabetes, NSAID use, and history of prostate-specific antigen testing. RESULTS: During follow-up from 1992 through 2007, 8,092 incident prostate cancer cases were identified. Current regular use of acetaminophen (30 or more pills per month) for 5 or more years was associated with lower risk of overall prostate cancer (RR = 0.62, 95% CI: 0.44-0.87) and aggressive prostate cancer (RR = 0.49, 95% CI: 0.27-0.88). Current regular use of less than 5 years duration was not associated with prostate cancer risk. CONCLUSION: These results suggest that long term regular acetaminophen use may be associated with lower prostate cancer risk. IMPACT: If the association between acetaminophen use and lower risk of prostate cancer is confirmed, it could provide clues about biological mechanisms that are important in prostate carcinogenesis. PMID- 21586624 TI - Genetic and viral etiology of glioblastoma--a unifying hypothesis. AB - Growing body of evidence implicates human cytomegalovirus (HCMV) in the etiology of glioblastoma (GBM). Although HCMV is a ubiquitous herpesvirus, only a minority of those infected develop GBM, suggesting the involvement of host genetic factors in susceptibility to HCMV-induced/spurred GBM. HCMV has evolved a large repertoire of strategies for decreasing the efficacy of the host immune response and interfering with viral clearance. One strategy involves the generation of proteins that have functional properties of the Fcgamma receptor (FcgammaR), which may enable the virus to evade host immunosurveillance by avoiding the effector consequences of antibody binding, such as antibody-dependent cellular cytotoxicity. Results of binding studies involving HCMV-encoded FcgammaR and genetically different immunoglobulin G proteins suggest that GM genes--genetic determinants of immunoglobulin gamma chains--could modulate this viral strategy and thus serve as functional risk factors for the development of GBM, potentially unifying its seemingly disparate infectious, immune, and genetic etiologies. PMID- 21586625 TI - Telomerase peptide vaccination combined with temozolomide: a clinical trial in stage IV melanoma patients. AB - PURPOSE: The study is a proof-of-principle trial evaluating toxicity, immune response, and clinical response in melanoma patients after combined therapy with temozolomide and the telomerase peptide vaccine GV1001. Our previous GV1001 trials showed immune responses in approximately 60% of lung or pancreatic cancer patients. EXPERIMENTAL DESIGN: Twenty-five subjects with advanced stage IV melanoma (M1B or M1C) received concomitant temozolomide and GV1001. Temozolomide was administered 200 mg/m2 orally for 5 days every fourth week, and GV1001 as eight injections over 11 weeks. Immune response was evaluated by delayed type hypersensitivity, T-cell proliferation, and cytokine assays. The immunologic responders continued monthly vaccination. RESULTS: The treatment was well tolerated. A GV1001-specific immune response was shown in 18 of 23 evaluated subjects (78%). Patients developing long-term T-cell memory survived more than those rapidly losing their responses. The immune response exhibited several characteristics of possible clinical significance including high IFNgamma/IL-10 ratios, polyfunctional cytokine profiles, and recognition of naturally processed antigens. Survival compared favorably with matched controls from a benchmark meta analysis (1 year: 44% vs. 24%, 2 years: 16% vs. 6.6%). The clinical responses developed gradually over years, contrary to what is expected from chemotherapy. Five patients developed partial tumor regression and six more recorded stable disease. One patient has no remaining disease on fluorodeoxyglucose positron emission tomography scans after 5 years. CONCLUSIONS: The immunologic response rate is considerable compared with previous GV1001 trials without concomitant chemotherapy, although low toxicity is retained. The results warrant further studies of GV1001/temozolomide treatment and support the general concept of combining cancer vaccination with chemotherapy. PMID- 21586626 TI - Epidermal growth factor receptor inhibition augments the expression of MHC class I and II genes. AB - PURPOSE: Diverse immune-related effects occur with the use of epidermal growth factor receptor inhibitors (EGFRI). In addition to the cutaneous inflammation induced by EGFRIs, these agents have been associated with the exacerbation of autoimmune skin disease and contact hypersensitivity, antiviral effects, and fatal alveolar damage in the setting of lung transplantation. Because EGFR ligands can modulate MHC class I (MHCI) and II (MHCII) molecule expression, we hypothesized that some of the immune-related effects of EGFRIs are due to direct effects on the expression of MHCI and/or MHCII molecules. EXPERIMENTAL DESIGN: Primary human keratinocytes and a malignant keratinocyte cell line (A431) were treated with EGFRIs alone or prior to IFN-gamma, a potent inducer of MHCI and MHCII molecule expression. CIITA, MHCI, and MHCII RNA expression was measured using quantitative real-time reverse transcriptase PCR, and cell surface MHCI and MHCII protein expression was measured using flow cytometry. Skin biopsies from patients were analyzed for MHCI and MHCII protein expression before and during therapy with an EGFRI using immunohistochemistry. RESULTS: Both EGFR tyrosine kinase inhibitors and ligand-blocking antibodies (cetuximab) augmented the induction of MHCI and MHCII molecules by IFN-gamma in primary and malignant human keratinocytes. Unexpectedly, the increase in MHCI protein expression did not require the presence of IFN-gamma. Consistent with these in vitro findings, skin biopsies from cancer patients exhibited increased epidermal MHCI protein expression during therapy with an EGFRI as well as increases in MHCI and MHCII molecule RNA. CONCLUSIONS: These studies suggest that EGFRIs may influence immune/inflammatory responses by directly modulating MHC expression. Clin Cancer Res; 17(13); 4400-13. (c)2011 AACR. PMID- 21586628 TI - Time-course imaging of therapeutic functional tumor vascular normalization by antiangiogenic agents. AB - We describe here new technology that enables noninvasive imaging of therapeutic functional normalization of tumor blood vessels by antiangiogenic agents. Noninvasive variable-magnification in vivo-fluorescence imaging as well as fluorescence tomography was used to visualize functional vessel normalization. Changes in the same vessel before and after drug treatment were imaged with high resolution in real time. Differences in vascular responses to the mTOR inhibitor rapamycin and to an anti-VEGF antibody were functionally imaged. Tumor vessel normalization was shown by significantly reduced leakiness and subsequent improved tumor delivery of Paclitaxel-BODPY as well as by normalized morphology. The tumor vascular pool agent, AngioSense(750), was retained only in tumors after either anti-VEGF antibody or rapamycin treatment, as visualized by noninvasive fluorescence tomography. The antiangiogenic therapy normalized vessels, which significantly enhanced the antitumor efficacy of paclitaxel because of increased drug penetration throughout the tumor. The optical imaging technology described here is thus a powerful, noninvasive, time-course imaging tool of functional tumor vessel normalization and its therapeutic consequences. PMID- 21586627 TI - Initial cognitive performance predicts longitudinal aviator performance. AB - OBJECTIVES: The goal of the study was to improve prediction of longitudinal flight simulator performance by studying cognitive factors that may moderate the influence of chronological age. METHOD: We examined age-related change in aviation performance in aircraft pilots in relation to baseline cognitive ability measures and aviation expertise. Participants were aircraft pilots (N = 276) aged 40-77.9. Flight simulator performance and cognition were tested yearly; there were an average of 4.3 (+/- 2.7; range 1-13) data points per participant. Each participant was classified into one of the three levels of aviation expertise based on Federal Aviation Administration pilot proficiency ratings: least, moderate, or high expertise. RESULTS: Addition of measures of cognitive processing speed and executive function to a model of age-related change in aviation performance significantly improved the model. Processing speed and executive function performance interacted such that the slowest rate of decline in flight simulator performance was found in aviators with the highest scores on tests of these abilities. Expertise was beneficial to pilots across the age range studied; however, expertise did not show evidence of reducing the effect of age. DISCUSSION: These data suggest that longitudinal performance on an important real world activity can be predicted by initial assessment of relevant cognitive abilities. PMID- 21586629 TI - Pharmacodynamic evaluation of the target efficacy of SB939, an oral HDAC inhibitor with selectivity for tumor tissue. AB - SB939 is an oral histone deacetylase (HDAC) inhibitor currently in phase II clinical trials potently inhibiting class I, II, and IV HDACs with favorable pharmacokinetic properties, resulting in tumor tissue accumulation. To show target efficacy, a Western blot assay measuring histone H3 acetylation (acH3) relative to a loading control was developed, validated on cancer cell lines, peripheral blood mononuclear cells (PBMC), and in animal tumor models. Exposure of cells to 60 nmol/L (22 ng/mL) SB939 for 24 hours was sufficient to detect an acH3 signal in 25 MUg of protein lysate. AcH3 levels of liver, spleen, PBMCs, bone marrow and tumor were measured in BALB/c mice, HCT-116 xenografted BALB/c nude mice, or in SCID mice orthotopically engrafted with AML (HL-60) after oral treatment with SB939. AcH3 could only be detected after treatment. In all tissues, the highest signal detected was at the 3-hour time point on day 1. On day 15, the signal decreased in normal tissues but increased in cancerous tissues and became detectable in the bone marrow of leukemic mice. In all tissues, acH3 correlated with SB939 dose levels (r(2)=0.76-0.94). When applied to PBMCs from 30 patients with advanced solid malignancies in a phase I clinical trial, a dose dependent (10-80 mg) increase in relative acH3 was observed 3-hour postdose on day 1, correlating with C(max) and AUC of SB939 concentrations in plasma (r=0.97, P=0.014). Our data show that the favorable pharmacokinetic and pharmacodynamic properties of SB939 are translated from preclinical models to patients. PMID- 21586631 TI - Recent decline in the incidence of human immunodeficiency virus infection among California men who have sex with men. AB - Monitoring the incidence of human immunodeficiency virus (HIV) infection among men who have sex with men (MSM) is imperative for developing targeted prevention programs and evaluating their effectiveness. The authors used California counseling and testing data to estimate the temporal trend in HIV incidence among MSM in California. HIV incidence rates were retrospectively calculated among MSM who had received at least 1 HIV test at a public California counseling and testing site between 1997 and 2007 and had a prior HIV-negative test from any HIV testing source. All study subjects were weighted on the basis of the interval between the last HIV-negative test and the current HIV test to account for the right-truncation bias introduced by more frequent testers. The authors observed that the HIV incidence rate among MSM in California increased from 2.0/100 person years (95% confidence interval (CI): 1.8, 2.2) in 1997 to 2.4/100 person-years (95% CI: 2.2, 2.6) in 2003 and then decreased to 1.9/100 person-years (95% CI: 1.7, 2.0) in 2006. Trend analyses showed that both the increase (P < 0.001) and the decrease (P < 0.01) were statistically significant. The study showed that HIV incidence among MSM in California had decreased since 2003. PMID- 21586630 TI - Development and characterization of a potent immunoconjugate targeting the Fn14 receptor on solid tumor cells. AB - TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor (FGF) inducible 14 (Fn14) are a TNF superfamily ligand-receptor pair involved in many cellular processes including proliferation, migration, differentiation, inflammation, and angiogenesis. The Fn14 receptor is expressed at relatively low levels in normal tissues, but it is known to be dramatically elevated in a number of tumor types, including brain and breast tumors. Thus, it seems to be an excellent candidate for therapeutic intervention. We first analyzed Fn14 expression in human tumor cell lines. Fn14 was expressed in a variety of lines including breast, brain, bladder, skin, lung, ovarian, pancreatic, colon, prostate, and cervical cancer cell lines. We then developed an immunoconjugate containing a high-affinity anti-Fn14 monoclonal antibody (ITEM-4) conjugated to recombinant gelonin (rGel), a highly cytotoxic ribosome-inactivating N glycosidase. Both ITEM-4 and the conjugate were found to bind to cells to an equivalent extent. Confocal microscopic analysis showed that ITEM4-rGel specifically and rapidly (within 2 hours) internalized into Fn14-positive T-24 bladder cancer cells but not into Fn14-deficient mouse embryonic fibroblasts. Cytotoxicity studies against 22 different tumor cell lines showed that ITEM4-rGel was highly cytotoxic to Fn14-expressing cells and was 8- to 8 * 10(4)-fold more potent than free rGel. ITEM4-rGel was found to kill cells by inducing apoptosis with high-mobility group box 1 protein release. Finally, ITEM4-rGel immunoconjugate administration promoted long-term tumor growth suppression in nude mice bearing T-24 human bladder cancer cell xenografts. Our data support the use of an antibody-drug conjugate approach to selectively target and inhibit the growth of Fn14-expressing tumors. PMID- 21586632 TI - A collaborative approach to diabetes management: the choice made for Colorado schools. AB - Students with diabetes deserve a school nurse who can effectively manage the disease. Tensions between the school and families sometimes emerge when a child with diabetes goes to school. To resolve these tensions in Colorado, stakeholders collaborated to implement a statewide program to meet the needs of students with diabetes. Colorado school nursing leadership partnered with the National Association of School Nurses to adapt components of the Managing and Preventing Diabetes and Weight Gain Program (MAP), funded by the Centers for Disease Control and Prevention. The Healthy Learner Model for Chronic Condition Management, integral to MAP, provided guidance for the Colorado Collaborative to design the Diabetes Resource Nurse Program. The program supports the practicing school nurse, and facilitates collaboration between the family, school, and health care provider. This article describes how stakeholders in Colorado chose to collaborate when faced with rising tensions over how to best manage students with diabetes. PMID- 21586633 TI - Virulence differences in Toxoplasma mediated by amplification of a family of polymorphic pseudokinases. AB - The population structure of Toxoplasma gondii includes three highly prevalent clonal lineages referred to as types I, II, and III, which differ greatly in virulence in the mouse model. Previous studies have implicated a family of serine/threonine protein kinases found in rhoptries (ROPs) as important in mediating virulence differences between strain types. Here, we explored the genetic basis of differences in virulence between the highly virulent type I lineage and moderately virulent type II based on successful genetic cross between these lineages. Genome-wide association revealed that a single quantitative trait locus controls the dramatic difference in lethality between these strain types. Neither ROP16 nor ROP18, previously implicated in virulence of T. gondii, was found to contribute to differences between types I and II. Instead, the major virulence locus contained a tandem cluster of polymorphic alleles of ROP5, which showed similar protein expression between strains. ROP5 contains a conserved serine/threonine protein kinase domain that includes only part of the catalytic triad, and hence, all members are considered to be pseudokinases. Genetic disruption of the entire ROP5 locus in the type I lineage led to complete attenuation of acute virulence, and complementation with ROP5 restored lethality to WT levels. These findings reveal that a locus of polymorphic pseudokinases plays an important role in pathogenesis of toxoplasmosis in the mouse model. PMID- 21586634 TI - Hydrogen-bonding networks and RNA bases revealed by cryo electron microscopy suggest a triggering mechanism for calcium switches. AB - Helical assemblies such as filamentous viruses, flagella, and F-actin represent an important category of structures in biology. As the first discovered virus, tobacco mosaic virus (TMV) was at the center of virus research. Previously, the structure of TMV was solved at atomic detail by X-ray fiber diffraction but only for its dormant or high-calcium-concentration state, not its low-calcium concentration state, which is relevant to viral assembly and disassembly inside host cells. Here we report a helical reconstruction of TMV in its calcium-free, metastable assembling state at 3.3 A resolution by cryo electron microscopy, revealing both protein side chains and RNA bases. An atomic model was built de novo showing marked differences from the high-calcium, dormant-state structure. Although it could be argued that there might be inaccuracies in the latter structure derived from X-ray fiber diffraction, these differences can be interpreted as conformational changes effected by calcium-driven switches, a common regulatory mechanism in plant viruses. Our comparisons of the structures of the low- and high-calcium states indicate that hydrogen bonds formed by Asp116 and Arg92 in the place of the calcium ion of the dormant (high-calcium) state might trigger allosteric changes in the RNA base-binding pockets of the coat protein. In turn, the coat protein-RNA interactions in our structure favor an adenine-X-guanine (A*G) motif over the G*A motif of the dormant state, thus offering an explanation underlying viral assembly initiation by an AAG motif. PMID- 21586635 TI - Neural correlates of illusory motion perception in Drosophila. AB - When the contrast of an image flickers as it moves, humans perceive an illusory reversal in the direction of motion. This classic illusion, called reverse-phi motion, has been well-characterized using psychophysics, and several models have been proposed to account for its effects. Here, we show that Drosophila melanogaster also respond behaviorally to the reverse-phi illusion and that the illusion is present in dendritic calcium signals of motion-sensitive neurons in the fly lobula plate. These results closely match the predictions of the predominant model of fly motion detection. However, high flicker rates cause an inversion of the reverse-phi behavioral response that is also present in calcium signals of lobula plate tangential cell dendrites but not predicted by the model. The fly's behavioral and neural responses to the reverse-phi illusion reveal unexpected interactions between motion and flicker signals in the fly visual system and suggest that a similar correlation-based mechanism underlies visual motion detection across the animal kingdom. PMID- 21586636 TI - Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers. AB - Respiratory syncytial virus (RSV), the main cause of infant bronchiolitis, remains a major unmet vaccine need despite more than 40 years of vaccine research. Vaccine candidates based on a chief RSV neutralization antigen, the fusion (F) glycoprotein, have foundered due to problems with stability, purity, reproducibility, and potency. Crystal structures of related parainfluenza F glycoproteins have revealed a large conformational change between the prefusion and postfusion states, suggesting that postfusion F antigens might not efficiently elicit neutralizing antibodies. We have generated a homogeneous, stable, and reproducible postfusion RSV F immunogen that elicits high titers of neutralizing antibodies in immunized animals. The 3.2-A X-ray crystal structure of this substantially complete RSV F reveals important differences from homology based structural models. Specifically, the RSV F crystal structure demonstrates the exposure of key neutralizing antibody binding sites on the surface of the postfusion RSV F trimer. This unanticipated structural feature explains the engineered RSV F antigen's efficiency as an immunogen. This work illustrates how structural-based antigen design can guide the rational optimization of candidate vaccine antigens. PMID- 21586638 TI - Low-dimensional topology and geometry. PMID- 21586637 TI - Detection and quantification of rare mutations with massively parallel sequencing. AB - The identification of mutations that are present in a small fraction of DNA templates is essential for progress in several areas of biomedical research. Although massively parallel sequencing instruments are in principle well suited to this task, the error rates in such instruments are generally too high to allow confident identification of rare variants. We here describe an approach that can substantially increase the sensitivity of massively parallel sequencing instruments for this purpose. The keys to this approach, called the Safe Sequencing System ("Safe-SeqS"), are (i) assignment of a unique identifier (UID) to each template molecule, (ii) amplification of each uniquely tagged template molecule to create UID families, and (iii) redundant sequencing of the amplification products. PCR fragments with the same UID are considered mutant ("supermutants") only if >=95% of them contain the identical mutation. We illustrate the utility of this approach for determining the fidelity of a polymerase, the accuracy of oligonucleotides synthesized in vitro, and the prevalence of mutations in the nuclear and mitochondrial genomes of normal cells. PMID- 21586639 TI - Longitudinal changes in Scores on the Autism Diagnostic Interview--Revised (ADI R) in pre-school children with autism: Implications for diagnostic classification and symptom stability. AB - We prospectively examined mean changes in Autism Diagnostic Interview-Revised (ADI-R) Total and Domains scores and stability of the ADI-R diagnostic classification in 28 children with autism initially assessed at age 2-4 years and reassessed 2 years later. Mean Total, Social Interaction, and Communication scores decreased significantly from Time 1 to Time 2 Restricted/repetitive Domain mean scores did not change over time. The ADI-R diagnostic classification was stable in 67% of children using the current published criteria. The stability increased to 78% when a modified criterion was used in the Restricted/repetitive Domain and to 88% when the broader ASD criteria were used. Among pre-schoolers with autism, parent-reported symptoms decreased significantly at two-year follow up in Social and Communication Domains but not in the Restricted/repetitive Domain. However, ADI-R diagnostic classification remained relatively stable over time. Revising ADI-R diagnostic criteria in the Restricted/repetitive Domain or including the broader ASD criteria may improve its sensitivity and diagnostic stability in younger children. PMID- 21586640 TI - Circulating cancer cells and their clinical applications. PMID- 21586641 TI - Detecting a bacterial protein to understand cancer risk. PMID- 21586642 TI - Attitudes and experiences: qualitative perspectives on erectile dysfunction from the female partner. AB - This study explored the woman's experience of her partner's erectile dysfunction (ED) focusing particularly on sexual experiences, relationship satisfaction, and communication. One hundred women completed a semi-structured interview, providing information about how ED impacted her relationship with her partner. For some women, there was a sense of hopelessness and frustration surrounding their sex lives, while for others, her partner's ED had led to efforts towards increasing non-physical intimacy and sexual communication. These findings demonstrate the importance of the relationship, including communication between the partners, in a women's experience of her partners' ED. PMID- 21586644 TI - Species-specific interactions of Src family tyrosine kinases regulate Chlamydia intracellular growth and trafficking. AB - Src family kinases (SFKs) regulate key cellular processes and are emerging as important targets for intracellular pathogens. In this commentary, we briefly review the role of SFKs in bacterial pathogenesis and highlight new work on the role of SFKs during the intracellular cycle of Chlamydia species. PMID- 21586645 TI - Requirement of replication checkpoint protein kinases Mec1/Rad53 for postreplication repair in yeast. AB - DNA lesions in the template strand block the replication fork. In Saccharomyces cerevisiae, replication through DNA lesions occurs via a Rad6/Rad18-dependent pathway where lesions can be bypassed by the action of translesion synthesis (TLS) DNA polymerases eta and zeta or by Rad5-mediated template switching. An alternative Rad6/Rad18-independent but Rad52-dependent template switching pathway can also restore the continuity of the replication fork. The Mec1/Rad53-dependent replication checkpoint plays a crucial role in the maintenance of stable and functional replication forks in yeast cells with DNA damage; however, it has remained unclear which of the lesion bypass processes requires the activation of replication checkpoint-mediated fork stabilization. Here we show that postreplication repair (PRR) of newly synthesized DNA in UV-damaged yeast cells is inhibited in the absence of Mec1 and Rad53 proteins. Since TLS remains functional in cells lacking these checkpoint kinases and since template switching by the Rad5 and Rad52 pathways provides the alternative means of lesion bypass and requires Mec1/Rad53, we infer that lesion bypass by the template switching pathways occurs in conjunction with the replication fork that has been stabilized at the lesion site by the action of Mec1/Rad53-mediated replication checkpoint. IMPORTANCE: Eukaryotic cells possess mechanisms called checkpoints that act to stop the cell cycle when DNA replication is halted by lesions in the template strand. Upon stalling of the ongoing replication at the lesion site, the recruitment of Mec1 and Rad53 kinases to the replication ensemble initiates the checkpoint wherein Mec1-mediated phosphorylation of Rad53 activates the pathway. A crucial role of replication checkpoint is to stabilize the replication fork by maintaining the association of DNA polymerases with the other replication components at the stall site. Our observations that Mec1 and Rad53 are required for lesion bypass by template switching have important implications for whether lesion bypass occurs in conjunction with the stalled replication ensemble or in gaps that could have been left behind the newly restarted forks. We discuss this important issue and suggest that lesion bypass in Saccharomyces cerevisiae cells occurs in conjunction with the stalled replication forks and not in gaps. PMID- 21586646 TI - From commensal to pathogen: translocation of Enterococcus faecalis from the midgut to the hemocoel of Manduca sexta. AB - A dynamic homeostasis is maintained between the host and native bacteria of the gastrointestinal tract in animals, but migration of bacteria from the gut to other organs can lead to disease or death. Enterococcus faecalis is a commensal of the gastrointestinal tract; however, Enterococcus spp. are increasingly frequent causes of nosocomial infections with a high mortality rate. We investigated the commensal-to-pathogen switch undergone by E. faecalis OG1RF in the lepidopteran model host Manduca sexta associated with its location in the host. E. faecalis persists in the harsh midgut environment of M. sexta larvae without causing apparent illness, but injection of E. faecalis directly into the larval hemocoel is followed by rapid death. Additionally, oral ingestion of E. faecalis in the presence of Bacillus thuringiensis insecticidal toxin, a pore forming toxin that targets the midgut epithelium, induces an elevated mortality rate. We show that the loss of gut integrity due to B. thuringiensis toxin correlates with the translocation of E. faecalis from the gastrointestinal tract into the hemolymph. Upon gaining access to the hemolymph, E. faecalis induces an innate immune response, illustrated by hemocyte aggregation, in larvae prior to death. The degree of hemocyte aggregation is dependent upon the route of E. faecalis entry. Our data demonstrate the efficacy of the M. sexta larval model system in investigating E. faecalis-induced sepsis and clarifies controversies in the field regarding the events leading to larval death following B. thuringiensis toxin exposure. IMPORTANCE: This study advances our knowledge of Enterococcus faecalis-induced sepsis following translocation from the gut and provides a model for mammalian diseases in which the spatial distribution of bacteria determines disease outcomes. We demonstrate that E. faecalis is a commensal in the gut of Manduca sexta and a pathogen in the hemocoel, resulting in a robust immune response and rapid death, a process we refer to as the "commensal-to-pathogen" switch. While controversy remains regarding Bacillus thuringiensis toxin-induced killing, our laboratory previously found that under some conditions, the midgut microbiota is essential for B. thuringiensis toxin killing of Lymantria dispar (N. A. Broderick, K. F. Raffa, and J. Handelsman, Proc. Natl. Acad. Sci. U. S. A. 103:15196-15199, 2006; B. Raymond, et al., Environ. Microbiol. 11:2556-2563, 2009; P. R. Johnston, and N. Crickmore, Appl. Environ. Microbiol. 75:5094-5099, 2009). We and others have demonstrated that the role of the midgut microbiota in B. thuringiensis toxin killing is dependent upon the lepidopteran species and formulation of B. thuringiensis toxin (N. A. Broderick, K. F. Raffa, and J. Handelsman, Proc. Natl. Acad. Sci. U. S. A. 103:15196-15199, 2006; N. A. Broderick, et al., BMC Biol. 7:11, 2009). This work reconciles much of the apparently contradictory previous data and reveals that the M. sexta-E. faecalis system provides a model for mammalian sepsis. PMID- 21586647 TI - The fungal pathogen Candida albicans autoinduces hyphal morphogenesis by raising extracellular pH. AB - pH homeostasis is critical for all organisms; in the fungal pathogen Candida albicans, pH adaptation is critical for virulence in distinct host niches. We demonstrate that beyond adaptation, C. albicans actively neutralizes the environment from either acidic or alkaline pHs. Under acidic conditions, this species can raise the pH from 4 to >7 in less than 12 h, resulting in autoinduction of the yeast-hyphal transition, a critical virulence trait. Extracellular alkalinization has been reported to occur in several fungal species, but under the specific conditions that we describe, the phenomenon is more rapid than previously observed. Alkalinization is linked to carbon deprivation, as it occurs in glucose-poor media and requires exogenous amino acids. These conditions are similar to those predicted to exist inside phagocytic cells, and we find a strong correlation between the use of amino acids as a cellular carbon source and the degree of alkalinization. Genetic and genomic approaches indicate an emphasis on amino acid uptake and catabolism in alkalinizing cells. Mutations in four genes, STP2, a transcription factor regulating amino acid permeases, ACH1 (acetyl-coenzyme A [acetyl-CoA] hydrolase), DUR1,2 (urea amidolyase), and ATO5, a putative ammonia transporter, abolish or delay neutralization. The pH changes are the result of the extrusion of ammonia, as observed in other fungi. We propose that nutrient-deprived C. albicans cells catabolize amino acids as a carbon source, excreting the amino nitrogen as ammonia to raise environmental pH and stimulate morphogenesis, thus directly contributing to pathogenesis. IMPORTANCE: Candida albicans is the most important fungal pathogen of humans, causing disease at multiple body sites. The ability to switch between multiple morphologies, including a rounded yeast cell and an elongated hyphal cell, is a key virulence trait in this species, as this reversible switch is thought to promote dissemination and tissue invasion in the host. We report here that C. albicans can actively alter the pH of its environment and induce its switch to the hyphal form. The change in pH is caused by the release of ammonia from the cells produced during the breakdown of amino acids. This phenomenon is unprecedented in a human pathogen and may substantially impact host physiology by linking morphogenesis, pH adaptation, carbon metabolism, and interactions with host cells, all of which are critical for the ability of C. albicans to cause disease. PMID- 21586648 TI - Streptococcus pneumoniae DNA initiates type I interferon signaling in the respiratory tract. AB - The mucosal epithelium is the initial target for respiratory pathogens of all types. While type I interferon (IFN) signaling is traditionally associated with antiviral immunity, we demonstrate that the extracellular bacterial pathogen Streptococcus pneumoniae activates the type I IFN cascade in airway epithelial and dendritic cells. This response is dependent upon the pore-forming toxin pneumolysin. Pneumococcal DNA activates IFN-beta expression through a DAI/STING/TBK1/IRF3 cascade. Tlr4(-/-), Myd88(-/-), Trif(-/-), and Nod2(-/-) mutant mice had no impairment of type I IFN signaling. Induction of type I IFN signaling contributes to the eradication of pneumococcal carriage, as IFN alpha/beta receptor null mice had significantly increased nasal colonization with S. pneumoniae compared with that of wild-type mice. These studies suggest that the type I IFN cascade is a central component of the mucosal response to airway bacterial pathogens and is responsive to bacterial pathogen-associated molecular patterns that are capable of accessing intracellular receptors. IMPORTANCE: The bacterium Streptococcus pneumoniae is a leading cause of bacterial pneumonia, leading to upwards of one million deaths a year worldwide and significant economic burden. Although it is known that antibody is critical for efficient phagocytosis, it is not known how this pathogen is sensed by the mucosal epithelium. We demonstrate that this extracellular pathogen activates mucosal signaling typically activated by viral pathogens via the pneumolysin pore to activate intracellular receptors and the type I interferon (IFN) cascade. Mice lacking the receptor to type I IFNs have a reduced ability to clear S. pneumoniae, suggesting that the type I IFN cascade is central to the mucosal clearance of this important pathogen. PMID- 21586650 TI - A randomized, double-blinded, placebo-controlled, crossover, add-on study of CoEnzyme Q10 in the prevention of pediatric and adolescent migraine. AB - OBJECTIVE: To evaluate the efficacy of Coenzyme Q10 (CoQ10) supplementation in the prevention of migraine in children using a placebo-controlled, double blinded, crossover, add-on trial. BACKGROUND: CoQ10 has been demonstrated to have efficacy in migraine prevention in adults but lacks pediatric research with more rigorous methodology. CoQ10 has been observed to be deficient in a significant number of children and adolescents presenting to tertiary headache centers. CoQ10 has the potential to modify both the inflammatory changes that occur during recurrent migraine and the alteration of mitochondrial function. A deficit of CoQ10 could thus affect the response to treatment and clinical characteristics of migraine in children and adults. METHODS: One-hundred-and-twenty children and adolescents with migraine headache were randomized in a crossover, double-blind, placebo-controlled, randomized, add-on study to receive a placebo or CoQ10 (100 mg) supplement for 224 days. Data for 76 patients were available at the crossover point and 50 were analysed at the endpoint. Response to treatment, overall headache improvement, and headache disability were assessed. RESULTS: Both the placebo and CoQ10 groups showed reduced migraine frequency [F(1, 60)=15.68, p<0.001], severity [F(1, 54)=8.09, p=0.006], and duration [F(1, 45)=6.27, p=0.016] over time. CoQ10 treated patients had a significantly greater improvement in frequency from subject reported baseline starting within 4 weeks of initiation. No group differences comparing the first 4 weeks of treatment with the last 4 weeks of treatment were found in migraine frequency [F(1, 60)=2.34, p>0.05], severity [F(1, 54)=0.06, p>0.05], or duration [F(1, 45)=0.14, p>0.05]. CONCLUSIONS: Overall, results of the study demonstrate that children and adolescents with migraine improved over time with multidisciplinary, standardized treatment regardless of supplementation with CoQ10 or placebo. There was no difference in headache outcomes between the CoQ10 and placebo groups at day 224. Due to the improvements seen in weeks 1-4, CoQ10 may lead to earlier improvement in headache severity, but given the sample size this conclusion warrants further investigation with a larger sample. PMID- 21586649 TI - The cytosolic/nuclear HSC70 and HSP90 molecular chaperones are important for stomatal closure and modulate abscisic acid-dependent physiological responses in Arabidopsis. AB - Cytosolic/nuclear molecular chaperones of the heat shock protein families HSP90 and HSC70 are conserved and essential proteins in eukaryotes. These proteins have essentially been implicated in the innate immunity and abiotic stress tolerance in higher plants. Here, we demonstrate that both chaperones are recruited in Arabidopsis (Arabidopsis thaliana) for stomatal closure induced by several environmental signals. Plants overexpressing HSC70-1 or with reduced HSP90.2 activity are compromised in the dark-, CO(2)-, flagellin 22 peptide-, and abscisic acid (ABA)-induced stomatal closure. HSC70-1 and HSP90 proteins are needed to establish basal expression levels of several ABA-responsive genes, suggesting that these chaperones might also be involved in ABA signaling events. Plants overexpressing HSC70-1 or with reduced HSP90.2 activity are hypersensitive to ABA in seed germination assays, suggesting that several chaperone complexes with distinct substrates might tune tissue-specific responses to ABA and the other biotic and abiotic stimuli studied. This study demonstrates that the HSC70/HSP90 machinery is important for stomatal closure and serves essential functions in plants to integrate signals from their biotic and abiotic environments. PMID- 21586651 TI - Cortical inhibition at rest and under a focused attention challenge in adults with migraine with and without aura. AB - OBJECTIVES: We aimed to further elucidate the functional and attentional regulation of cortical excitability in migraine patients. METHODS: We investigated the cortical silent period (CSP) after transcranial magnetic stimulation as a measure of cortical inhibition under three conditions: resting condition, cortical preactivation during reaction preparation, and during the post-processing of a motor response using a visual contingent negative variation paradigm in adults with migraine with aura, migraine without aura and healthy controls. RESULTS: CSP was reduced in individuals with migraine with aura and unaffected in those with migraine without aura under resting conditions. Along with the intensity of transcranial magnetic stimulation, CSP increased equally in all groups (equal slopes). Furthermore, the functional challenge by a contingent negative variation task requiring focused sustained attention led to a comparable reduction of CSP duration in all groups. DISCUSSION: Our data provide further hints towards the conclusion that a specific cortical inhibition deficit in migraine with aura but not migraine without aura is due to a tonic imbalance and not related to increased reactions to phasic stressors. Given that CSP at rest is related to GABA-ergic inhibition whereas the CSP reduction during late contingent negative variation is thought to be related to dopaminergic disinhibition in the basal ganglia, our results point towards reduced GABA-ergic cortical inhibition related to dysfunctional thalamo-cortical loops, especially in migraine with aura. PMID- 21586652 TI - Morphine-induced cardiogenic shock. AB - OBJECTIVE: Although animal and human models suggest that direct suppression of myocardial contractility may occur with morphine administration, to our knowledge, clinical observation of this potentially important effect has not been reported. This case report presents a unique case of morphine-induced transient reversible cardiogenic shock. CASE SUMMARY: A 44-year-old woman with a history of hypertension, diabetes, and asthma presented with a 3-day history of epigastric pain. Initial investigation results revealed elevated serum lipase level and computed tomography imaging that was consistent with a diagnosis of mild acute pancreatitis. Intravenous fluids and morphine, via patient-controlled analgesia, were started and the patient was admitted. The next day, she developed cardiogenic shock with a globally reduced left ventricular ejection fraction (LVEF) of 26% and was admitted to the intensive care unit. Morphine was discontinued and norepinephrine and naloxone were concurrently administered. Over the next 24 hours her clinical status improved, and an echocardiogram 29 hours after the initial echocardiogram showed normal LV function (LVEF 62%). DISCUSSION: To our knowledge, this represents the first reported case of clinically significant morphine-induced cardiogenic shock. An objective causality assessment using the Naranjo probability scale suggests that the cardiogenic shock was probably related to morphine. Other causes of shock were ruled out. Additionally, the fact that the transient nature of the observed LV dysfunction reversed with discontinuation of morphine and administration of naloxone provides further support, particularly with the evidence that opiates may depress cardiac myocytes and cardiac output in animal and human models. CONCLUSIONS: Opiates can cause severe LV dysfunction. Physicians should consider emergent evaluation for myocardial depression in patients who are receiving opioids and present with persistent hypotension or pulmonary edema without other known etiology. PMID- 21586653 TI - Evaluation of a simplified N-acetylcysteine dosing regimen for the treatment of acetaminophen toxicity. AB - BACKGROUND: Acetaminophen overdose is the most common pharmaceutical poisoning in the US. The labeled dosing regimen for Acetadote, the only intravenous N acetylcysteine (IV-NAC) product approved by the Food and Drug Administration (FDA) for treatment of acetaminophen toxicity, is a complex 3-step process that produces frequent medication errors. We have been using an off-label, uncomplicated dosing regimen consisting of a standard preparation of IV-NAC 30 g in 1 L of 5% dextrose in water, with a 150-mg/kg loading dose administered over 1 hour followed by an infusion of 14 mg/kg/h for 20 hours. OBJECTIVE: To evaluate the frequency of medication errors, resolution of hepatotoxicity, and tolerability of the protocol used in our institution for treatment of acetaminophen toxicity. METHODS: This single-center, retrospective chart review evaluated patients receiving IV-NAC for acetaminophen toxicity from August 2006 to August 2008. Charts were reviewed for prescribing practices, dosing errors, and clinical outcomes. RESULTS: Among 70 patients who met inclusion criteria, 35 medication errors occurred, including 22 administration errors and 13 protocol initiation errors. The frequency of administration errors was 13.5 errors per 100 administration interventions. Loading dose errors were most common with 11 rate related and 8 dose-related errors. Interruptions longer than 60 minutes occurred in only 3 patients. No adverse outcomes were associated with medication errors. The mean (SD) duration of therapy was 25.6 hours (n = 60 pts. [17.8], range 1 76.5), and mean length of stay was 2.99 days ([3.82], range 0.1-25.7). All patients with hepatotoxicity (aspartate aminotransferase >1000 units/L) due to acute acetaminophen toxicity had resolution of the toxicity and were successfully discharged. CONCLUSIONS: This single intravenous bag protocol is effective and well tolerated, and there is infrequent interruption of therapy. The overall rate of administration errors is similar to that in reports on the FDA regimen; thus, our protocol may be an acceptable alternative. PMID- 21586659 TI - Dramatic response to panitumumab and bevacizumab in metastatic gallbladder carcinoma. PMID- 21586654 TI - adPEO mutations in ANT1 impair ADP-ATP translocation in muscle mitochondria. AB - Mutations in the heart and muscle isoform of adenine nucleotide translocator 1 (ANT1) are associated with autosomal-dominant progressive external opthalmoplegia (adPEO) clinically characterized by exercise intolerance, ptosis and muscle weakness. The pathogenic mechanisms underlying the mitochondrial myopathy caused by ANT1 mutations remain largely unknown. In yeast, expression of ANT1 carrying mutations corresponding to the human adPEO ones causes a wide range of mitochondrial abnormalities. However, functional studies of ANT1 mutations in mammalian cells are lacking, because they have been hindered by the fact that ANT1 expression leads to apoptotic cell death in commonly utilized replicating cell lines. Here, we successfully express functional ANT1 in differentiated mouse myotubes, which naturally contain high levels of ANT1, without causing cell death. We demonstrate, for the first time in these disease-relevant mammalian cells, that mutant human ANT1 causes dominant mitochondrial defects characterized by decreased ADP-ATP exchange function and abnormal translocator reversal potential. These abnormalities are not due to ANT1 loss of function, because knocking down Ant1 in myotubes causes functional changes different from ANT1 mutants. Under certain physiological conditions, mitochondria consume ATP to maintain membrane potential by reversing the ADP-ATP transport. The modified properties of mutant ANT1 can be responsible for disease pathogenesis in adPEO, because exchange reversal occurring at higher than normal membrane potential can cause excessive energy depletion and nucleotide imbalance in ANT1 mutant muscle cells. PMID- 21586660 TI - The high tide of cancer research in Europe. PMID- 21586661 TI - Short-course versus standard chemoradiation in T3 rectal cancer. PMID- 21586662 TI - All nodes lead to chemo... PMID- 21586664 TI - Nanoleakage distribution at adhesive-dentin interfaces in 3D. AB - In spite of its role in the degradation of tooth-biomaterial interfaces, reports on nanoleakage are largely inconsistent. The aim of this work was to assess nanoleakage patterns qualitatively and quantitatively in 3D, to determine the influence of direction, position, and inclination of the field-of-view. Therefore, we applied a gold-standard 3-step etch-and-rinse adhesive to bur-cut dentin surfaces, after which interface samples were sectioned, infiltrated with an ammoniacal silver-nitrate solution, and embedded by common TEM procedures. High-resolution 3D models of interfaces were then generated by FIB and electron tomography, following strict conditions determined by Monte Carlo simulations. Inverted images in FIB tomography disclosed morphological characteristics analogous to those revealed by TEM. Quantitative analysis revealed large variations in silver-nitrate uptake between 2D image projections in different directions. Furthermore, silver-nitrate fractions in individual 2D image projections were seldom related to the total 3D volumetric fraction. Electron tomography showed that inclination also affected the morphology of silver-nitrate patterns. In conclusion, conventional nanoleakage evaluation is heavily influenced by direction, position, and inclination of the field-of-view, and thus may contain artifacts. PMID- 21586665 TI - Finn Brudevold: discovery of acidulated phosphate fluoride in caries prevention. AB - Finn Brudevold was a distinguished leader in dental research, recipient of many honors, and a Past President of IADR. This article traces his scientific career and focuses on his discovery and development of acidulated phosphate fluoride (APF) for practical use in caries prevention. Brudevold noticed that the low pH of stannous fluoride was very effective in getting fluoride into enamel in vitro. He hypothesized that an acidulated preparation that included phosphate to minimize enamel dissolution by a common ion effect would permit faster exchange of hydroxyls with fluoride. The clinical efficacy of APF is compared with other methods of professionally applied topical fluoride agents. PMID- 21586666 TI - Induced migration of dental pulp stem cells for in vivo pulp regeneration. AB - Dental pulp has intrinsic capacity for self-repair. However, it is not clear whether dental pulp cells can be recruited endogenously for regenerating pulp tissues, including mineralizing into dentin. This work is based on a hypothesis that dental pulp stem/progenitor cells can be induced to migrate by chemotactic cytokines and act as endogenous cell sources for regeneration and mineralization. Dental stem cells (DSCs) were isolated from adult human tooth pulp and seeded on the surfaces of 3D collagen gel cylinders that were incubated in chemically defined media with stromal-derived factor-1alpha (SDF1), basic fibroblast growth factor (bFGF), or bone morphogenetic protein-7 (BMP7). Significantly more cells were recruited into collagen gel by SDF1 or bFGF than without cytokines in 7 days, whereas BMP7 had little effect on cell recruitment. BMP7, however, was highly effective, equally to dexamethasone, in orchestrating mineralization of cultured DSCs. Cell membrane receptors for SDF1, bFGF, and BMP7 were up-regulated in treated DSCs. Upon in vivo delivery, bFGF induced re-cellularization and re vascularization in endodontically treated human teeth implanted into the dorsum of rats. Thus, endogenous dental pulp cells, including stem/progenitor cells, may be recruited and subsequently differentiated by chemotaxis of selective cytokines in the regeneration of dental pulp. PMID- 21586667 TI - The impact of school suspension on student tobacco use: a longitudinal study in Victoria, Australia, and Washington State, United States. AB - CONTEXT: School suspension may have unintended consequences in contributing to problem behaviors, including dropping out from school, substance use, and antisocial behavior. Tobacco use is an early-onset problem behavior, but prospective studies of the effects of suspension on tobacco use are lacking. METHOD: Longitudinal school-based survey of students drawn as a two-stage cluster sample, administered in 2002 and 2003, in Washington State, United States, and Victoria, Australia. The study uses statewide representative samples of students in Grades 7 and 9 (N = 3,599). RESULTS: Rates of tobacco use were higher for Victorian than Washington State students. School suspension remained a predictor of current tobacco use at 12-month follow-up, after controlling for established risk factors including prior tobacco and other drug use for Grade 7 but not Grade 9 students. CONCLUSIONS: School suspension is associated with early adolescent tobacco use, itself an established predictor of adverse outcomes in young people. Findings suggest the need to explore process mechanisms and alternatives to school suspensions as a response to challenging student behavior in early adolescence. PMID- 21586668 TI - Age and ethnic differences in cold weather and contagion theories of colds and flu. AB - Age and ethnic group differences in cold weather and contagion or germ theories of infectious disease were explored in two studies. A cold weather theory was frequently invoked to explain colds and to a lesser extent flu but became less prominent with age as children gained command of a germ theory of disease. Explanations of how contact with other people causes disease were more causally sophisticated than explanations of how cold weather causes it. Finally, Mexican American and other minority children were more likely than European American children to subscribe to cold weather theories, a difference partially but not wholly attributable to ethnic group differences in parent education. Findings support the value of an intuitive or naive theories perspective in understanding developmental and sociocultural differences in concepts of disease and in planning health education to help both children and their parents shed misconceptions so that they can focus on effective preventive actions. PMID- 21586669 TI - Involvement of Runx3 in the basal transcriptional activation of the mouse angiotensin II type 1 receptor-associated protein gene. AB - We previously cloned a molecule that interacts with angiotensin II type 1 (AT1) receptor to exert an inhibitory function on AT1 receptor signaling that we named ATRAP/Agtrap (for AT1 receptor-associated protein). In the present study we examined the regulation of basal ATRAP gene expression using renal distal convoluted tubule cells. We found that serum starvation upregulated basal expression of ATRAP gene, a response that required de novo mRNA and protein synthesis. Luciferase assay revealed that the proximal promoter region directs transcription and that a putative binding site of runt-related transcription factors (RBE) is important for transcriptional activation. The results of RBE decoy transfection and endogenous knockdown by small interference RNA showed that the runt-related transcription factor Runx3 is involved in ATRAP gene expression. Chromatin immunoprecipitation assay also supported the binding of Runx3 to the ATRAP promoter in renal distal convoluted tubule cells. Immunohistochemistry demonstrated the expression of Runx3 and ATRAP proteins in the distal convoluted and connecting tubules of the kidney in consecutive sections. Furthermore, the Runx3 immunostaining was decreased together with a concomitant suppression of ATRAP expression in the affected kidney after 7 days of unilateral ureteral obstruction. These findings indicate that Runx3 plays a role in ATRAP gene expression in renal distal tubular cells both in vitro and in vivo. PMID- 21586671 TI - Origins of interspecies variation in mammalian muscle metabolic enzymes. AB - Do the transcriptional mechanisms that control an individual's mitochondrial content, PGC1alpha (peroxisome proliferator-activated receptor gamma coactivator 1alpha) and NRF1 (nuclear respiratory factor-1), also cause differences between species? We explored the determinants of cytochrome c oxidase (COX) activities in muscles from 12 rodents differing 1,000-fold in mass. Hindlimb muscles differed in scaling patterns from isometric (soleus, gastrocnemius) to allometric (tibialis anterior, scaling coefficient = -0.16). Consideration of myonuclear domain reduced the differences within species, but interspecies differences remained. For tibialis anterior, there was no significant scaling relationship in mRNA/g for COX4-1, PGC1alpha, or NRF1, yet COX4-1 mRNA/g was a good predictor of COX activity (r(2) = 0.55), PGC1alpha and NRF1 mRNA correlated with each other (r(2) = 0.42), and both could predict COX4-1 mRNA (r(2) = 0.48 and 0.52) and COX activity (r(2) = 0.55 and 0.49). This paradox was resolved by multivariate analysis, which explained 90% of interspecies variation, about equally partitioned between mass effects and PGC1alpha (or NRF1) mRNA levels, independent of mass. To explore the determinants of PGC1alpha mRNA, we analyzed 52 mammalian PGC1alpha proximal promoters and found no size dependence in regulatory element distribution. Likewise, the activity of PGC1alpha promoter reporter genes from 30 mammals showed no significant relationship with body mass. Collectively, these studies suggest that not all muscles scale equivalently, but for those that show allometric scaling, transcriptional regulation of the master regulators, PGC1alpha and NRF1, does not account for scaling patterns, though it does contribute to interspecies differences in COX activities independent of mass. PMID- 21586672 TI - Controlling spike timing and synchrony in oscillatory neurons. AB - We describe an algorithm to control synchrony between two periodically firing neurons. The control scheme operates in real-time using a dynamic clamp platform. This algorithm is a low-impact stimulation method that brings the neurons toward the desired level of synchrony over the course of several neuron firing periods. As a proof of principle, we demonstrate the versatility of the algorithm using real-time conductance models and then show its performance with biological neurons of hippocampal region CA1 and entorhinal cortex. PMID- 21586670 TI - Deletion of a subgroup of ribosome-related genes minimizes hypoxia-induced changes and confers hypoxia tolerance. AB - Hypoxia is a widely occurring condition experienced by diverse organisms under numerous physiological and disease conditions. To probe the molecular mechanisms underlying hypoxia responses and tolerance, we performed a genome-wide screen to identify mutants with enhanced hypoxia tolerance in the model eukaryote, the yeast Saccharomyces cerevisiae. Yeast provides an excellent model for genomic and proteomic studies of hypoxia. We identified five genes whose deletion significantly enhanced hypoxia tolerance. They are RAI1, NSR1, BUD21, RPL20A, and RSM22, all of which encode functions involved in ribosome biogenesis. Further analysis of the deletion mutants showed that they minimized hypoxia-induced changes in polyribosome profiles and protein synthesis. Strikingly, proteomic analysis by using the iTRAQ profiling technology showed that a substantially fewer number of proteins were changed in response to hypoxia in the deletion mutants, compared with the parent strain. Computational analysis of the iTRAQ data indicated that the activities of a group of regulators were regulated by hypoxia in the wild-type parent cells, but such regulation appeared to be diminished in the deletion strains. These results show that the deletion of one of the genes involved in ribosome biogenesis leads to the reversal of hypoxia induced changes in gene expression and related regulators. They suggest that modifying ribosomal function is an effective mechanism to minimize hypoxia induced specific protein changes and to confer hypoxia tolerance. These results may have broad implications in understanding hypoxia responses and tolerance in diverse eukaryotes ranging from yeast to humans. PMID- 21586673 TI - Psychosocial determinants of socioeconomic inequalities in cancer screening participation: a conceptual framework. AB - Cancer screening participation shows a strong, graded association with socioeconomic status (SES) not only in countries such as the United States, where insurance status can be a barrier for lower income groups, but also in the United Kingdom, where the National Health Service provides all health care to residents, including screening, for free. Traditionally, the literature on socioeconomic inequalities has focused on upstream factors, but more proximal (downstream) influences on screening participation also need to be examined, particularly those that address the graded nature of the association rather than focusing specifically on underserved groups. This review offers a framework that links some of the components and corollaries of SES (life stress, educational opportunities, illness experience) to known psychosocial determinants of screening uptake (beliefs about the value of early detection, fatalistic beliefs about cancer, self-efficacy). The aim is to explain why individuals from lower SES backgrounds perceive cancer screening tests as more threatening, more difficult to accomplish, and less beneficial. A better understanding of the mechanisms through which lower SES causes negative attitudes toward screening could facilitate the development of intervention strategies to reduce screening inequalities. PMID- 21586674 TI - Arginine transport in human monocytic leukemia THP-1 cells during macrophage differentiation. AB - L-arginine metabolism in myeloid cells plays a central role in the processes of macrophage activation and in the regulation of immune responses. In this study, we investigated arginine transport activity and the expression of the related transporter genes during the differentiation of monocytes to macrophages. We show here that the induction of THP-1 monocyte differentiation by PMA markedly increases the expression of SLC7A7 mRNA and of y(+)LAT1 protein and consequently, the activity of system y(+)L-mediated arginine transport. Conversely, the activity of system y(+) decreases during macrophage differentiation as a result of a reduction in CAT1 protein expression. The PMA-induced, macrophage differentiated phenotype and the increased activity of system y(+)L through the induction of SLC7A7 gene are mediated by the specific activation of PKCbeta. SLC7A7 gene silencing causes a significant reduction of system y(+)L activity and a subsequent, marked increase of arginine and lysine cell content, thus suggesting that in macrophagic cells, system y(+)L activity is mainly directed outwardly. Differentiating agents other than PMA, i.e., VD3 and ATRA, are equally effective in the stimulation of system y(+)L transport activity through the increased expression of SLC7A7 mRNA and y(+)LAT1 protein. Moreover, we found that also during differentiation of human monocytes from peripheral blood SLC7A7 mRNA and system y(+)L activity are increased. These findings point to SLC7A7 gene as a marker of macrophage differentiation. PMID- 21586677 TI - Inhibitory effect of prostaglandin I2 on bone marrow kinetics of eosinophils in the guinea pig. AB - Enhanced eosinophil trafficking from bone marrow to the tissue is a hallmark of allergic diseases. We have shown previously that PGI(2) markedly attenuates the locomotion of human eosinophils in vitro. Here, we set out to determine the effect of PGI(2) on the trafficking of bone marrow eosinophils in the guinea pig. Shape change of bone marrow eosinophils was determined by flow cytometry, and chemotaxis assays were performed using a transwell migration system. Eosinophil release from bone marrow of guinea pigs was investigated in the isolated, perfused hind-limb preparation. We found that PGI(2) prevented the mobilization of eosinophils from bone marrow and attenuated the shape change and chemotactic responses of bone marrow eosinophils. These effects were mimicked by iloprost and were prevented by the IP antagonist CAY10441 and the adenylyl cyclase inhibitor SQ22536. Immunohistochemical staining of bone marrow confirmed the expression of IPs by bone marrow eosinophils. The rate-limiting enzyme of PGI(2) formation, PGIS, was found in large mononuclear cells. These data show that IP activation negatively modulates the mobilization and locomotion of bone marrow eosinophils and might therefore also protect against exaggerated recruitment of eosinophils to inflammatory sites. PMID- 21586676 TI - EBV LMP1, a viral mimic of CD40, activates dendritic cells and functions as a molecular adjuvant when incorporated into an HIV vaccine. AB - HIV-1 does not significantly activate cellular immunity, which has made it difficult to use attenuated forms of HIV-1 as a vaccine. In contrast, EBV induces robust T cell responses in most infected individuals, perhaps as this virus contains LMP1, a viral mimic of CD40, which is a key activating molecule for DCs and macrophages. Consequently, studies were conducted using LMP1 and LMP1-CD40, a related construct formed by replacing the intracellular signaling domain of LMP1 with that of CD40. Upon electroporation into DCs, LMP1 and LMP1-CD40 mRNAs were sufficient to up-regulate costimulatory molecules and proinflammatory cytokines, indicating that these molecules can function in isolation as adjuvant-like molecules. As a first step toward an improved HIV vaccine, LMP1 and LMP1-CD40 were introduced into a HIV-1 construct to produce virions encoding these proteins. Transduction of DCs and macrophages with these viruses induced morphological changes and up-regulated costimulatory molecules and cytokine production by these cells. HIV-LMP1 enhanced the antigen-presenting function of DCs, as measured in an in vitro immunization assay. Taken together, these data show that LMP1 and LMP1-CD40 are portable gene cassettes with strong adjuvant properties that can be introduced into viruses such as HIV, which by themselves, are insufficient to induce protective cellular immunity. PMID- 21586678 TI - Pulmonary functional imaging: qualitative comparison of Fourier decomposition MR imaging with SPECT/CT in porcine lung. AB - PURPOSE: To compare unenhanced lung ventilation-weighted (VW) and perfusion weighted (QW) imaging based on Fourier decomposition (FD) magnetic resonance (MR) imaging with the clinical reference standard single photon emission computed tomography (SPECT)/computed tomography (CT) in an animal experiment. MATERIALS AND METHODS: The study was approved by the local animal care committee. Lung ventilation and perfusion was assessed in seven anesthetized pigs by using a 1.5 T MR imager and SPECT/CT. For time-resolved FD MR imaging, sets of lung images were acquired by using an untriggered two-dimensional balanced steady-state free precession sequence (repetition time, 1.9 msec; echo time, 0.8 msec; acquisition time per image, 118 msec; acquisition rate, 3.33 images per second; flip angle, 75 degrees ; section thickness, 12 mm; matrix, 128 * 128). Breathing displacement was corrected with nonrigid image registration. Parenchymal signal intensity was analyzed pixelwise with FD to separate periodic changes of proton density induced by respiration and periodic changes of blood flow. Spectral lines representing respiratory and cardiac frequencies were integrated to calculate VW and QW images. Ventilation and perfusion SPECT was performed after inhalation of dispersed technetium 99m ((99m)Tc) and injection of (99m)Tc-labeled macroaggregated albumin. FD MR imaging and SPECT data were independently analyzed by two physicians in consensus. A regional statistical analysis of homogeneity and pathologic signal changes was performed. RESULTS: Images acquired in healthy animals by using FD MR imaging and SPECT showed a homogeneous distribution of VW and QW imaging and pulmonary ventilation and perfusion, respectively. The gravitation-dependent signal distribution of ventilation and perfusion in all animals was similarly observed at FD MR imaging and SPECT. Incidental ventilation and perfusion defects were identically visualized by using both modalities. CONCLUSION: This animal experiment demonstrated qualitative agreement in the assessment of regional lung ventilation and perfusion between contrast media-free and radiation-free FD MR imaging and conventional SPECT/CT. PMID- 21586679 TI - Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project. AB - Neuroblastoma is an enigmatic disease entity; some tumors disappear spontaneously without any therapy, while others progress with a fatal outcome despite the implementation of maximal modern therapy. However, strong prognostic factors can accurately predict whether children have "good" or "bad" disease at diagnosis, and the clinical stage is currently the most significant and clinically relevant prognostic factor. Therefore, for an individual patient, proper staging is of paramount importance for risk assessment and selection of optimal treatment. In 2009, the International Neuroblastoma Risk Group (INRG) Project proposed a new staging system designed for tumor staging before any treatment, including surgery. Compared with the focus of the International Neuroblastoma Staging System, which is currently the most used, the focus has now shifted from surgicopathologic findings to imaging findings. The new INRG Staging System includes two stages of localized disease, which are dependent on whether image defined risk factors (IDRFs) are or are not present. IDRFs are features detected with imaging at the time of diagnosis. The present consensus report was written by the INRG Imaging Committee to optimize imaging and staging and reduce interobserver variability. The rationales for using imaging methods (ultrasonography, magnetic resonance imaging, computed tomography, and scintigraphy), as well as technical guidelines, are described. Definitions of the terms recommended for assessing IDRFs are provided with examples. It is anticipated that the use of standardized nomenclature will contribute substantially to more uniform staging and thereby facilitate comparisons of clinical trials conducted in different parts of the world. PMID- 21586680 TI - Incidence of nephrogenic systemic fibrosis after adoption of restrictive gadolinium-based contrast agent guidelines. AB - PURPOSE: To retrospectively determine the incidence of nephrogenic systemic fibrosis (NSF) in a large academic medical center after the adoption of restrictive gadolinium-based contrast agent (GBCA) administration guidelines. MATERIALS AND METHODS: For this retrospective HIPAA-compliant study, institutional review board approval was obtained and the requirement for informed consent was waived. Restrictive GBCA guidelines were adopted in May 2007. The guidelines (a) require a recent serum creatinine level measurement in any patient who is aged 60 years or older and/or at risk for renal disease, (b) limit the maximal weight-based GBCA dose administered to any patient with an estimated glomerular filtration rate (eGFR) lower than 60 mL/min/m(2) to 20 mL, and (c) prohibit the administration of any GBCA in patients who have an eGFR lower than 30 mL/min/m(2) and/or are undergoing chronic dialysis treatment (except in emergency situations). The electronic medical records were searched for all contrast material-enhanced magnetic resonance (MR) imaging examinations performed during the post-guidelines adoption period between January 2008 and March 2010 and the pre-guidelines adoption and transitional period between January 2002 and December 2007. Separate pathology records were searched for biopsy-confirmed cases of NSF during the same study periods. The incidences of NSF during the pre guidelines adoption and transitional period and post-guidelines adoption period were compared by using the paired Z test. RESULTS: A total of 52,954 contrast enhanced MR examinations were performed during the post-guidelines adoption period. Of these 52,954 examinations, 46,464 (88%) were performed in adult patients with an eGFR of 60 mL/min/m(2) or higher or presumed normal renal function and 6454 (12%) were performed in patients with an eGFR of 30-59 mL/min/m(2). Thirty-six patients with an eGFR lower than 30 mL/min/m(2) underwent contrast-enhanced MR imaging for emergent indications. Review of the pathology records for January 2008 to September 2010 revealed no new cases of NSF resulting from GBCA exposure. CONCLUSION: After restrictive guidelines regarding GBCA administration were instituted, no new cases of NSF were identified among 52,954 contrast-enhanced MR examinations, including those performed in patients with an eGFR lower than 60 mL/min/m(2). PMID- 21586681 TI - Factors to consider in using [U-C]palmitate for analysis of sphingolipid biosynthesis by tandem mass spectrometry. AB - This study describes the use of a stable-isotope labeled precursor ([U 13C]palmitate) to analyze de novo sphingolipid biosynthesis by tandem mass spectrometry. It also describes factors to consider in interpreting the data, including the isotope's location (13C appears in three isotopomers and isotopologues: [M + 16] for the sphingoid base or N-acyl fatty acid, and [M + 32] for both); the isotopic enrichment of palmitoyl-CoA; and its elongation, desaturation, and incorporation into N-acyl-sphingolipids. For HEK293 cells incubated with 0.1 mM [U-13C]palmitic acid, ~60% of the total palmitoyl-CoA was 13C-labeled by 3 h (which was near isotopic equilibrium); with this correction, the rates of de novo biosynthesis of C16:0-ceramide, C16:0-monohexosylceramide, and C16:0-sphingomyelins were 62 +/- 3, 13 +/- 2, and 60 +/- 11 pmol/h per mg protein, respectively, which are consistent with an estimated rate of appearance of C16:0-ceramide using exponential growth modeling (119 +/- 11 pmol/h per mg protein). Including estimates for the very long-chain fatty acyl-CoAs, the overall rate of sphingolipid biosynthesis can be estimated to be at least ~1.6 fold higher. Thus, consideration of these factors gives a more accurate picture of de novo sphingolipid biosynthesis than has been possible to-date, while acknowledging that there are inherent limitations to such approximations. PMID- 21586682 TI - How can research on plants contribute to promoting human health? AB - One of the most pressing challenges for the next 50 years is to reduce the impact of chronic disease. Unhealthy eating is an increasing problem and underlies much of the increase in mortality from chronic diseases that is occurring worldwide. Diets rich in plant-based foods are strongly associated with reduced risks of major chronic diseases, but the constituents in plants that promote health have proved difficult to identify with certainty. This, in turn, has confounded the precision of dietary recommendations. Plant biochemistry can make significant contributions to human health through the identification and measurement of the many metabolites in plant-based foods, particularly those known to promote health (phytonutrients). Plant genetics and metabolic engineering can be used to make foods that differ only in their content of specific phytonutrients. Such foods offer research tools that can provide significant insight into which metabolites promote health and how they work. Plant science can reduce some of the complexity of the diet-health relationship, and through building multidisciplinary interactions with researchers in nutrition and the pathology of chronic diseases, plant scientists can contribute novel insight into which foods reduce the risk of chronic disease and how these foods work to impact human health. PMID- 21586683 TI - A small zinc finger thylakoid protein plays a role in maintenance of photosystem II in Arabidopsis thaliana. AB - This work identifies LOW QUANTUM YIELD OF PHOTOSYSTEM II1 (LQY1), a Zn finger protein that shows disulfide isomerase activity, interacts with the photosystem II (PSII) core complex, and may act in repair of photodamaged PSII complexes. Two mutants of an unannotated small Zn finger containing a thylakoid membrane protein of Arabidopsis thaliana (At1g75690; LQY1) were found to have a lower quantum yield of PSII photochemistry and reduced PSII electron transport rate following high-light treatment. The mutants dissipate more excess excitation energy via nonphotochemical pathways than wild type, and they also display elevated accumulation of reactive oxygen species under high light. After high-light treatment, the mutants have less PSII-light-harvesting complex II supercomplex than wild-type plants. Analysis of thylakoid membrane protein complexes showed that wild-type LQY1 protein comigrates with the PSII core monomer and the CP43 less PSII monomer (a marker for ongoing PSII repair and reassembly). PSII repair and reassembly involve the breakage and formation of disulfide bonds among PSII proteins. Interestingly, the recombinant LQY1 protein demonstrates a protein disulfide isomerase activity. LQY1 is more abundant in stroma-exposed thylakoids, where key steps of PSII repair and reassembly take place. The absence of the LQY1 protein accelerates turnover and synthesis of PSII reaction center protein D1. These results suggest that the LQY1 protein may be involved in maintaining PSII activity under high light by regulating repair and reassembly of PSII complexes. PMID- 21586686 TI - Death causes in breast cancer patients. AB - BACKGROUND: Due to improved outcomes in breast cancer (BCa), the proportion of affected women dying of other causes has increased. Thus, a better survival of BCa requires knowledge of other causes of death. MATERIALS AND METHODS: Data on the population, cancers, and causes of death were gathered from the nationwide Swedish Family-Cancer Database, enrolling ~3.68 million Swedish women. A Cox regression model, comparing BCa patients against all other women, was applied. Cause-of-death-specific hazard ratios (HRs) were calculated for both underlying and multiple causes of death. RESULTS: Among 641 000 deaths from 1987 to 2006, 48,000 were BCa patients. For underlying causes except BCa, the highest cause specific HRs were found for diseases of pulmonary circulation {1.51 [95% confidence interval (CI) 1.36-1.68]}, suicide [1.39 (1.19-1.63)], and heart failure [1.29 (1.22-1.37)]. For specific multiple causes, the highest ratios were found for external causes [1.86 (1.80-1.91)] and gastrointestinal disease [1.68 (1.62-1.74)]. CONCLUSIONS: Diagnosis of BCa is associated with increased risks of dying of various causes, including external causes, heart failure, diseases of pulmonary circulation, and gastrointestinal disease. The study fulfills the gap in knowledge of death causes in BCa patients and suggests to draw more attention to comorbidities. PMID- 21586684 TI - Interaction between the bHLH transcription factor FIT and ETHYLENE INSENSITIVE3/ETHYLENE INSENSITIVE3-LIKE1 reveals molecular linkage between the regulation of iron acquisition and ethylene signaling in Arabidopsis. AB - Understanding the regulation of key genes involved in plant iron acquisition is of crucial importance for breeding of micronutrient-enriched crops. The basic helix-loop-helix protein FER-LIKE FE DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT), a central regulator of Fe acquisition in roots, is regulated by environmental cues and internal requirements for iron at the transcriptional and posttranscriptional levels. The plant stress hormone ethylene promotes iron acquisition, but the molecular basis for this remained unknown. Here, we demonstrate a direct molecular link between ethylene signaling and FIT. We identified ETHYLENE INSENSITIVE3 (EIN3) and ETHYLENE INSENSITIVE3-LIKE1 (EIL1) in a screen for direct FIT interaction partners and validated their physical interaction in planta. We demonstrate that the ein3 eil1 transcriptome was affected to a greater extent upon iron deficiency than normal iron compared with the wild type. Ethylene signaling by way of EIN3/EIL1 was required for full-level FIT accumulation. FIT levels were reduced upon application of aminoethoxyvinylglycine and in the ein3 eil1 background. MG132 could restore FIT levels. We propose that upon ethylene signaling, FIT is less susceptible to proteasomal degradation, presumably due to a physical interaction between FIT and EIN3/EIL1. Increased FIT abundance then leads to the high level of expression of genes required for Fe acquisition. This way, ethylene is one of the signals that triggers Fe deficiency responses at the transcriptional and posttranscriptional levels. PMID- 21586687 TI - Small bowel adenocarcinoma copy number profiles are more closely related to colorectal than to gastric cancers. AB - BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare cancer and consequently, the options for clinical trials are limited. As they are treated according to either a colorectal or a gastric cancer regimen and the molecular biology of a tumor is a pivotal determinant for therapy response, chromosomal copy number aberrations were compared with the colorectal and gastric adenocarcinomas. MATERIALS AND METHODS: A total of 85 microsatellite stable (MSS) adenocarcinomas from the stomach, colorectum and small bowel were selected from existing array comparative genomic hybridization (aCGH) datasets. We compared the aCGH profiles of the three tumor sites by supervised analysis and hierarchical clustering. RESULTS: Hierarchical clustering revealed substantial overlap of 27 SBA copy number profiles with matched colorectal adenocarcinomas but less overlap with profiles of gastric adenocarcinomas. DNA copy number aberrations located at chromosomes 1p36.3-p34.3, 4p15.3-q35.2, 9p24.3-p11.1, 13q13.2-q31.3 and 17p13.3 p13.2 were the strongest features discriminating SBAs and colorectal adenocarcinomas from gastric adenocarcinomas. CONCLUSIONS: We show that MSS SBAs are more similar to colorectal than to gastric cancer, based on the 27 genome wide DNA copy number profiles that are currently available. These molecular similarities provide added support for treatment of MSS small bowel cancers according to colorectal cancer regimens. PMID- 21586688 TI - T-cell therapy for EBV-associated nasopharyngeal carcinoma: preparative lymphodepleting chemotherapy does not improve clinical results. AB - BACKGROUND: We and others have demonstrated that adoptive cell therapy with Epstein-Barr virus (EBV)-specific autologous cytotoxic T lymphocytes (CTLs) may control disease progression in patients with EBV-associated nasopharyngeal carcinoma (NPC). With the aim of favoring in vivo T-cell expansion, we optimized our cell therapy approach by administering higher doses of EBV-specific CTLs, following lymphodepleting chemotherapy. PATIENTS AND METHODS: Eleven patients with EBV-related NPC in whom conventional treatment failed have been enrolled. Patients received nonmyeloablative lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine. Two doses of autologous EBV-specific CTLs were subsequently infused, 2 weeks apart. Study end points were feasibility and clinical outcome. RESULTS: All patients enrolled completed the treatment and were assessable for analysis. The median dose of CTLs per infusion was 3.7 * 10(8). Therapy was well tolerated, with no severe adverse events ascribable to either chemotherapy or cell therapy. Disease control (defined as either tumor regression or disease stabilization lasting >4 months) was obtained in 6 of 11 patients, in keeping with previously published results. CONCLUSIONS: Our data confirm that EBV specific CTL therapy is safe and associated with antitumor activity in patients with advanced NPC. The use of lymphodepleting chemotherapy before high-dose CTL infusion did not enhance the clinical benefit observed in our previous series. PMID- 21586689 TI - Affirming the self to promote agreement with another: lowering a psychological barrier to conflict resolution. AB - Two studies investigated the capacity of a self-affirmation intervention to lower a psychological barrier to conflict resolution. Study 1 used a role-play scenario in which a student negotiated with a professor for greater rewards for work on a collaborative project. A self-affirmation manipulation, in which participants focused on an important personal value, significantly reduced their tendency to derogate a concession offered by the professor relative to one that had not been offered. Study 2 replicated this effect and showed that the phenomenon did not depend on the self-affirmed participant's experience of a heightened sense of deservingness or a tendency to make positive attributions about the professor. Distraction and explicit mood enhancement were also ruled out as mediators of the self-affirmation effect, which appears to stem from motivational rather than explicit cognitive processes. PMID- 21586690 TI - A pilot study to assess whether glucagon-like peptide-1 protects the heart from ischemic dysfunction and attenuates stunning after coronary balloon occlusion in humans. AB - BACKGROUND: The incretin hormone glucagon-like peptide-1 (GLP-1) has been shown to have cardioprotective properties in animal models of ischemia and infarction due to promotion of myocardial glucose uptake and suppression of apoptosis. We investigated whether GLP-1 protected the heart from dysfunction caused by supply ischemia during percutaneous coronary intervention (PCI). METHODS AND RESULTS: Twenty patients with normal left ventricular (LV) function and single-vessel coronary disease within the left anterior descending artery undergoing elective PCI were studied. A conductance catheter was placed into the LV through the femoral artery, and pressure-volume loops were recorded at baseline and during a 1-minute low-pressure balloon occlusion at the site of the stenosis. The patients were randomized to receive an infusion of either GLP-1(7-36) amide at 1.2 pmol/kg per minute or saline immediately after the first balloon occlusion. Coronary balloon occlusion caused LV stunning in the control group with cumulative LV dysfunction on subsequent occlusion that was not seen in the GLP-1 group. GLP-1 improved recovery of LV systolic and diastolic function at 30 minutes after balloon occlusion compared with control (delta dP/dt(max) from baseline, -1.6% versus -12.2%; P=0.02) and reduced the LV dysfunction after the second balloon occlusion (delta dP/dt(max), -13.1% versus -25.3%; P=0.01). CONCLUSIONS: In this pilot study, infusion of GLP-1 has been demonstrated to reduce ischemic LV dysfunction after supply ischemia during coronary balloon occlusion in humans and mitigates stunning. The findings require confirmation in a larger scale clinical trial. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.org. Unique identifier: ISRCTN 77442023. PMID- 21586691 TI - Impact of polymer formulations on neointimal proliferation after zotarolimus eluting stent with different polymers: insights from the RESOLUTE trial. AB - BACKGROUND: Polymer formulation may affect the efficacy of drug-eluting stents. Resolute, Endeavor, and ZoMaxx are zotarolimus-eluting stents with different stent platforms and different polymer coatings and have been tested in clinical trials. The aim of this analysis was to compare the efficacy of zotarolimus eluting stents with different polymers. METHODS AND RESULTS: Data were obtained from the first-in man trial or first randomized trials of each stent, The Clinical RESpOnse EvaLUation of the MedTronic Endeavor CR ABT-578 Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions (RESOLUTE), Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery Lesions (ENDEAVOR II), and ZoMaxx I trials. Follow-up intravascular ultrasound analyses (8 to 9 months of follow-up) were possible in 353 patients (Resolute: 88, Endeavor: 98, ZoMaxx: 82, Driver: 85). Volume index (volume/stent length) was obtained for vessel, stent, lumen, peristent plaque, and neointima. Cross sectional narrowing was defined as neointimal area divided by stent area (%). Neointima-free frame ratio was calculated as the number of frames without intravascular ultrasound-detectable neointima divided by the total number of frames within the stent. At baseline, vessel, lumen, and peristent plaque volume index were not significantly different among the 4 stent groups. At follow-up, percent neointimal obstruction was significantly lower in Resolute compared with Endeavor, ZoMaxx, and Driver (Resolute: 3.7+/-4.0, Endeavor: 17.5+/-10.1, ZoMaxx: 14.6+/-8.1, Driver: 29.4+/-17.2%; P<0.001). Greater maximum cross-sectional narrowing and higher neointima-free frame ratio, suggesting less neointimal coverage, were observed in Resolute compared with other stent groups. Multiple regression analysis confirmed that the biodurable polymer used in Resolute independently correlated with neointimal suppression among 3 zotarolimus-eluting stents. CONCLUSIONS: The different polymer formulations significantly affect the relative amount of neointima for zotarolimus-eluting stents. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00248079. PMID- 21586692 TI - Operator radiation exposure during percutaneous coronary procedures through the left or right radial approach: the TALENT dosimetric substudy. AB - BACKGROUND: Transradial percutaneous coronary procedures may be effectively performed through the right radial approach (RRA) or the left radial approach (LRA), but data on radiation dose absorbed by operators comparing the two approaches are lacking. The aim of the present study was to evaluate radiation dose absorbed by operators during coronary procedures through the RRA and LRA. METHODS AND RESULTS: Three operators were equipped with 5 different dosimeters (left wrist, shoulder, thorax outside the lead apron, thorax under the lead apron, and thyroid) during RRA or LRA for coronary procedures. Each month, the dosimeters were analyzed to determine the radiation dose absorbed. From February to December 2009, 390 patients were randomly assigned to the RRA (185 patients; age, 66+/-11 years) or the LRA (185 patients; age, 66+/-11 years). There were no significant differences in fluoroscopy time (for RRA, 369 seconds; interquartile range, 134 to 857 seconds; for LRA, 362 seconds; interquartile range, 142 to 885 seconds; P=0.58) between the 2 groups. There were no significant differences in monthly radiation dose at the thorax (0.85+/-0.46 mSv for RRA and 1.12+/-0.78 mSv for LRA, P=0.33), at the thyroid (0.36+/-0.2 mSv for RRA and 0.34+/-0.3 mSv for LRA, P=0.87), and at the shoulder (0.73+/-0.44 mSv for RRA and 0.94+/-0.42 mSv for LRA, P=0.27). The dose at the wrist was significantly higher for the RRA (2.44+/-1.12 mSv) compared with the LRA (1+/-0.8 mSv, P=0.002). In both radial approaches, the thoracic radiation dose under the lead apron was undetectable. CONCLUSIONS: Compared with RRA, LRA for coronary procedures is associated with similar radiation dose for operators at the body, shoulder, or thyroid level, with a possible significant advantage at the wrist. The cumulative radiation dose for both approaches is well under to the annual dose-equivalent limit. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00282646. PMID- 21586693 TI - Intravascular ultrasound findings of early stent thrombosis after primary percutaneous intervention in acute myocardial infarction: a Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) substudy. AB - BACKGROUND: Small stent area and residual inflow/outflow disease have been reported as the strongest intravascular ultrasound (IVUS) predictors of early stent thrombosis (ST) in patients with stable angina. IVUS predictors of early ST in patients with acute myocardial infarction have not been studied. METHODS AND RESULTS: In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) study, a formal substudy included poststent and 13-month follow-up IVUS at 36 centers. Twelve patients with baseline IVUS who had definite/probable early ST <=30 days after enrollment were compared with 389 patients without early ST. Significant residual stenosis was a lumen area <4.0 mm(2) with >=70% plaque burden <=10 mm from each stent edge. Significant edge dissection was more than medial dissection with lumen area <4 mm(2) or dissection angle >=60 degrees . Randomization to bivalirudin (P=0.29) or paclitaxel-eluting stent (P=0.74) was not related to early ST. Minimum lumen area was smaller in patients with versus without early ST (4.4 mm(2) [3.6, 6.9] versus 6.7 mm(2) [5.3, 8.0], respectively, P=0.014). Minimum lumen area <5 mm(2), significant residual stenosis, significant stent edge dissection, and significant tissue (plaque/thrombus) protrusion (more than the median that narrowed the lumen to <4 mm(2)) were more prevalent in patients with early ST, but significant acute malapposition (more than the median) was not. Overall, 100% of patients with early ST had at least 1 of these significant features: minimum lumen area <5 mm(2), edge dissection, residual stenosis, or tissue protrusion versus 23% in patients without early ST (P<0.01). CONCLUSIONS: Smaller final lumen area and inflow/outflow disease (residual stenosis or dissection) but not acute malapposition were related to early ST after acute myocardial infarction intervention. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966. PMID- 21586695 TI - Opposite effects of serum- and glucocorticoid-regulated kinase-1 and glucocorticoids on POMC transcription and ACTH release. AB - Serum- and glucocorticoid-regulated kinase-1 (SGK1) is a glucocorticoid early response gene; its function, however, has been elucidated mainly in the context of mineralocorticoid signaling. Here, we investigate the expression and function of SGK1 in the pituitary gland, one of the primary glucocorticoid targets. SGK1 is expressed in the human pituitary gland and colocalizes to ACTH. The AtT-20 murine corticotroph cell line was used for functional experiments. Glucocorticoids upregulated SGK1 mRNA and protein levels, parallel to decreasing proopiomelanocortin (POMC) transcription and ACTH release. Dexamethasone-induced changes in SGK1 protein were abolished by the steroid receptor antagonist RU-486 and reduced by the inhibition of PI 3-kinase with LY-294002. SGK1 overexpression increased CREB- and activator protein-1-dependent transcription, POMC transcription, and ACTH secretion but did not influence intracellular cAMP levels. SGK1 overexpression and corticotropin-releasing hormone had additive effects on POMC promoter activity but not on ACTH secretion. SGK1 knockdown by RNA interference decreased POMC promoter activity, demonstrating the importance of SGK1 for basal POMC signaling. In summary, SGK1 is strongly stimulated by glucocorticoids in pituitary corticotrophs; however, its effects on POMC transcription are antagonistic to the classical inhibitory glucocorticoid action, suggesting a cell-regulated counterregulatory mechanism to potentially detrimental glucocorticoid effects. PMID- 21586694 TI - Dietary fat impacts fetal growth and metabolism: uptake of chylomicron remnant core lipids by the placenta. AB - The fetus requires significant energy for growth and development. Although glucose is a major source of energy for the fetus, other maternal nutrients also appear to promote growth. Thus, the goal of these studies was to determine whether triglyceride-rich remnants are taken up by the placenta and whether maternal dietary lipids, independently of adiposity, can impact fetal growth. To accomplish our first goal, chylomicron particles were duallly labeled with cholesteryl ester and triglycerides. The placenta took up remnant particles/core lipids at rates greater than adipose tissue and skeletal muscle but less than the liver. Although the placenta expresses apoE receptors, uptake of chylomicron remnants and/or core lipids can occur independently of apoE. To determine the impact of dietary lipid on fetal growth, independent of maternal adiposity, females were fed high-fat diets (HFD) for 1 mo; there was no change in adiposity or leptin levels prior to or during pregnancy of dams fed HFD. Fetal masses were greater in dams fed HFD, and mRNA levels of proteins involved in fatty acid oxidation (CPT I, PPARalpha), but not glucose oxidation (pyruvate kinase) or other regulatory processes (HNF-4alpha, LXR), were increased with maternal dietary fat. There was also no change in mRNA levels of proteins involved in placental glucose and fatty acid transport, and GLUT1 protein levels in microvillous membranes were similar in placentas of dams fed either diet. Thus, the ability of the placenta to take up chylomicron remnant core lipids likely contributes to accelerated fetal growth in females fed high fat diets. PMID- 21586697 TI - Dynamic alteration of adiponectin/adiponectin receptor expression and its impact on myocardial ischemia/reperfusion in type 1 diabetic mice. AB - The present study determined the dynamic change of adiponectin (APN, a cardioprotective adipokine), its receptor expression, and their impact upon myocardial ischemia/reperfusion (MI/R) injury during type 1 diabetes mellitus (T1DM) progression, and involved underlying mechanisms. Diabetic state was induced in mice via multiple intraperitoneal injections of low-dose streptozotocin. The dynamic change of plasma APN concentration and cardiac APN receptor-1 and -2 (AdipoR1/2) expression were assessed immediately after diabetes onset (0 wk) and 1, 3, 5, and 7 wk thereafter. Indicators of MI/R injury (infarct size, apoptosis, and LDH release) were determined at 0, 1, and 7 wk of DM duration. The effect of APN on MI/R injury was determined in mice subjected to different diabetic durations. Plasma APN levels (total and HMW form) increased, whereas cardiac AdipoR1 expression decreased early after T1DM onset. With T1DM progression, APN levels were reduced and cardiac AdipoR1 expression increased. MI/R injury was exacerbated with T1DM progression in a time-dependent manner. Administration of globular APN (gAD) failed to attenuate MI/R injury in 1-wk T1DM mice, while an AMP-activated protein kinase (AMPK) activator (AICAR) reduced MI/R injury. However, administration of gAD (and AICAR) reduced infarct size and cardiomyocyte apoptosis in 7-wk T1DM mice. In conclusion, our results demonstrate a dynamic dysfunction of APN/AdipoR1 during T1DM progression. Reduced cardiac AdipoR1 expression and APN concentration may be responsible for increased I/R injury susceptibility at early and late T1DM stages, respectively. Interventions bolstering AdipoR1 expression during early T1DM stages and APN supplementation during advanced T1DM stages may potentially reduce the myocardial ischemic injury in diabetic patients. PMID- 21586696 TI - Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse. AB - The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative stress in liver and gastrocnemius. The STZ-induced insulin deficiency prevented the HFD- or insulin-induced increase in hepatic expression of long-chain acyl-CoA synthetases (ACSL), which are necessary for fatty acid activation. HFD increased mitochondrial contents of long-chain acyl CoAs, whereas it decreased mitochondrial ADP/ATP ratio, and these HFD-induced changes were prevented by the STZ-induced insulin deficiency. In cultured hepatocytes, we observed that expressions of ACSL1 and -5 were stimulated by insulin signaling. Results in cultured cells also showed that blunting insulin signaling by the PI3K inhibitor LY-294002 prevented fat accumulation, oxidative stress, and insulin resistance induced by the prolonged exposure to either insulin or oleate plus sera that normally contain insulin. Finally, knockdown of the insulin receptor prevented the oxidative stress and insulin resistance induced by the prolonged exposure to insulin or oleate plus sera. Together, our results show that insulin and insulin signaling are required for fat induction of insulin resistance in mice and cultured mouse hepatocytes. PMID- 21586698 TI - Aging is associated with hypoxia and oxidative stress in adipose tissue: implications for adipose function. AB - As a part of aging there are known to be numerous alterations which occur in multiple tissues of the body, and the focus of this study was to determine the extent to which oxidative stress and hypoxia occur during adipose tissue aging. In our studies we demonstrate for the first time that aging is associated with both hypoxia (38% reduction in oxygen levels, Po(2) 21.7 mmHg) and increases reactive oxygen species in visceral fat depots of aging male C57Bl/6 mice. Interestingly, aging visceral fat depots were observed to have significantly less change in the expression of genes involved in redox regulation compared with aging subcutaneous fat tissue. Exposure of 3T3-L1 adipocytes to the levels of hypoxia observed in aging adipose tissue was sufficient to alter multiple aspects of adipose biology inducing increased levels of in insulin-stimulated glucose uptake and decreased lipid content. Taken together, these data demonstrate that hypoxia and increased levels of reactive oxygen species occur in aging adipose tissue, highlighting the potential for these two stressors as potential modulators of adipose dysfunction during aging. PMID- 21586699 TI - Pharmacological inhibition of Kv1.3 fails to modulate insulin sensitivity in diabetic mice or human insulin-sensitive tissues. AB - Genetic ablation of the voltage-gated potassium channel Kv1.3 improves insulin sensitivity and increases metabolic rate in mice. Inhibition of Kv1.3 in mouse adipose and skeletal muscle is reported to increase glucose uptake through increased GLUT4 translocation. Since Kv1.3 represents a novel target for the treatment of diabetes, the present study investigated whether Kv1.3 is functionally expressed in human adipose and skeletal muscle and whether specific pharmacological inhibition of the channel is capable of modulating insulin sensitivity in diabetic mouse models. Voltage-gated K(+) channel currents in human skeletal muscle cells (SkMC) were insensitive to block by the specific Kv1.3 blockers 5-(4-phenoxybutoxy)psoralen (PAP-1) and margatoxin (MgTX). Glucose uptake into SkMC and mouse 3T3-L1 adipocytes was also unaffected by treatment with PAP-1 or MgTX. Kv1.3 protein expression was not observed in human adipose or skeletal muscle from normal and type 2 diabetic donors. To investigate the effect of specific Kv1.3 inhibition on insulin sensitivity in vivo, PAP-1 was administered to hyperglycemic mice either acutely or for 5 days prior to an insulin tolerance test. No effect on insulin sensitivity was observed at free plasma PAP-1 concentrations that are specific for inhibition of Kv1.3. Insulin sensitivity was increased only when plasma concentrations of PAP-1 were sufficient to inhibit other Kv1 channels. Surprisingly, acute inhibition of Kv1.3 in the brain was found to decrease insulin sensitivity in ob/ob mice. Overall, these findings are not supportive of a role for Kv1.3 in the modulation of peripheral insulin sensitivity. PMID- 21586700 TI - Metabolomic linkage reveals functional interaction between glucose-dependent insulinotropic polypeptide and ghrelin in humans. AB - The gastric peptide ghrelin promotes energy storage, appetite, and food intake. Nutrient intake strongly suppresses circulating ghrelin via molecular mechanisms possibly involving insulin and gastrointestinal hormones. On the basis of the growing evidence that glucose-dependent insulinotropic polypeptide (GIP) is involved in the control of fuel metabolism, we hypothesized that GIP and/or insulin, directly or via changes in plasma metabolites, might affect circulating ghrelin. Fourteen obese subjects were infused with GIP (2.0 pmol.kg(-1).min(-1)) or placebo in the fasting state during either euglycemic hyperinsulinemic (EC) or hyperglycemic hyperinsulinemic clamps (HC). Apart from analysis of plasma ghrelin and insulin levels, GC-TOF/MS analysis was applied to create a hormone-metabolite network for each experiment. The GIP and insulin effects on circulating ghrelin were analyzed within the framework of those networks. In the HC, ghrelin levels decreased in the absence (19.2% vs. baseline, P = 0.028) as well as in the presence of GIP (33.8%, P = 0.018). Ghrelin levels were significantly lower during HC with GIP than with placebo, despite insulin levels not differing significantly. In the GIP network combining data on GIP-infusion, EC+GIP and HC+GIP experiments, ghrelin was integrated into hormone-metabolite networks through a connection to a group of long-chain fatty acids. In contrast, ghrelin was excluded from the network of experiments without GIP. GIP decreased circulating ghrelin and might have affected the ghrelin system via modification of long-chain fatty acid pools. These observations were independent of insulin and offer potential mechanistic underpinnings for the involvement of GIP in systemic control of energy metabolism. PMID- 21586701 TI - Role of nonselective cation channels in spontaneous and protein kinase A stimulated calcium signaling in pituitary cells. AB - Several receptors linked to the adenylyl cyclase signaling pathway stimulate electrical activity and calcium influx in endocrine pituitary cells, and a role for an unidentified sodium-conducting channel in this process has been proposed. Here we show that forskolin dose-dependently increases cAMP production and facilitates calcium influx in about 30% of rat and mouse pituitary cells at its maximal concentration. The stimulatory effect of forskolin on calcium influx was lost in cells with inhibited PKA (cAMP-dependent protein kinase) and in cells that were haploinsufficient for the main PKA regulatory subunit but was preserved in cells that were also haploinsufficient for the main PKA catalytic subunit. Spontaneous and forskolin-stimulated calcium influx was present in cells with inhibited voltage-gated sodium and hyperpolarization-activated cation channels but not in cells bathed in medium, in which sodium was replaced with organic cations. Consistent with the role of sodium-conducting nonselective cation channels in PKA-stimulated Ca(2+) influx, cAMP induced a slowly developing current with a reversal potential of about 0 mV. Two TRP (transient receptor potential) channel blockers, SKF96365 and 2-APB, as well as flufenamic acid, an inhibitor of nonselective cation channels, also inhibited spontaneous and forskolin-stimulated electrical activity and calcium influx. Quantitative RT-PCR analysis indicated the expression of mRNA transcripts for TRPC1 >> TRPC6 > TRPC4 > TRPC5 > TRPC3 in rat pituitary cells. These experiments suggest that in pituitary cells constitutively active cation channels are stimulated further by PKA and contribute to calcium signaling indirectly by controlling the pacemaking depolarization in a sodium-dependent manner and directly by conducting calcium. PMID- 21586703 TI - The cover. Pilchard boats on St Ives Beach, Cornwall. PMID- 21586704 TI - A piece of my mind. Entering data. PMID- 21586702 TI - Coffee consumption and prostate cancer risk and progression in the Health Professionals Follow-up Study. AB - BACKGROUND: Coffee contains many biologically active compounds, including caffeine and phenolic acids, that have potent antioxidant activity and can affect glucose metabolism and sex hormone levels. Because of these biological activities, coffee may be associated with a reduced risk of prostate cancer. METHODS: We conducted a prospective analysis of 47,911 men in the Health Professionals Follow-up Study who reported intake of regular and decaffeinated coffee in 1986 and every 4 years thereafter. From 1986 to 2006, 5035 patients with prostate cancer were identified, including 642 patients with lethal prostate cancers, defined as fatal or metastatic. We used Cox proportional hazards models to assess the association between coffee and prostate cancer, adjusting for potential confounding by smoking, obesity, and other variables. All P values were from two-sided tests. RESULTS: The average intake of coffee in 1986 was 1.9 cups per day. Men who consumed six or more cups per day had a lower adjusted relative risk for overall prostate cancer compared with nondrinkers (RR = 0.82, 95% confidence interval [CI] = 0.68 to 0.98, P(trend) = .10). The association was stronger for lethal prostate cancer (consumers of more than six cups of coffee per day: RR = 0.40, 95% CI = 0.22 to 0.75, P(trend) = .03). Coffee consumption was not associated with the risk of nonadvanced or low-grade cancers and was only weakly inversely associated with high-grade cancer. The inverse association with lethal cancer was similar for regular and decaffeinated coffee (each one cup per day increment: RR = 0.94, 95% CI = 0.88 to 1.01, P = .08 for regular coffee and RR = 0.91, 95% CI = 0.83 to 1.00, P = .05 for decaffeinated coffee). The age adjusted incidence rates for men who had the highest (>=6 cups per day) and lowest (no coffee) coffee consumption were 425 and 519 total prostate cancers, respectively, per 100 000 person-years and 34 and 79 lethal prostate cancers, respectively, per 100 000 person-years. CONCLUSIONS: We observed a strong inverse association between coffee consumption and risk of lethal prostate cancer. The association appears to be related to non-caffeine components of coffee. PMID- 21586705 TI - CABG and medical therapy perform equally well in patients with heart failure. PMID- 21586706 TI - IOM: Data on health of lesbian, gay, bisexual, and transgender persons needed. PMID- 21586707 TI - Community a factor in suicide attempts by lesbian, gay, and bisexual teens. PMID- 21586708 TI - Study halted: no benefit seen from antiretroviral pill in preventing HIV in women. PMID- 21586709 TI - Maternal HIV infection and antibody responses in uninfected infants. PMID- 21586710 TI - Race, site of care, and hospital readmission rates. PMID- 21586711 TI - Diabetes quality measures. PMID- 21586712 TI - Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial. AB - CONTEXT: Gastroesophageal reflux disease (GERD) is a chronic, relapsing disease with symptoms that have negative effects on daily life. Two treatment options are long-term medication or surgery. OBJECTIVE: To evaluate optimized esomeprazole therapy vs standardized laparoscopic antireflux surgery (LARS) in patients with GERD. DESIGN, SETTING, AND PARTICIPANTS: The LOTUS trial, a 5-year exploratory randomized, open, parallel-group trial conducted in academic hospitals in 11 European countries between October 2001 and April 2009 among 554 patients with well-established chronic GERD who initially responded to acid suppression. A total of 372 patients (esomeprazole, n = 192; LARS, n = 180) completed 5-year follow-up. Interventions Two hundred sixty-six patients were randomly assigned to receive esomeprazole, 20 to 40 mg/d, allowing for dose adjustments; 288 were randomly assigned to undergo LARS, of whom 248 actually underwent the operation. MAIN OUTCOME MEASURE: Time to treatment failure (for LARS, defined as need for acid suppressive therapy; for esomeprazole, inadequate symptom control after dose adjustment), expressed as estimated remission rates and analyzed using the Kaplan Meier method. RESULTS: Estimated remission rates at 5 years were 92% (95% confidence interval [CI], 89%-96%) in the esomeprazole group and 85% (95% CI, 81% 90%) in the LARS group (log-rank P = .048). The difference between groups was no longer statistically significant following best-case scenario modeling of the effects of study dropout. The prevalence and severity of symptoms at 5 years in the esomeprazole and LARS groups, respectively, were 16% and 8% for heartburn (P = .14), 13% and 2% for acid regurgitation (P < .001), 5% and 11% for dysphagia (P < .001), 28% and 40% for bloating (P < .001), and 40% and 57% for flatulence (P < .001). Mortality during the study was low (4 deaths in the esomeprazole group and 1 death in the LARS group) and not attributed to treatment, and the percentages of patients reporting serious adverse events were similar in the esomeprazole group (24.1%) and in the LARS group (28.6%). CONCLUSION: This multicenter clinical trial demonstrated that with contemporary antireflux therapy for GERD, either by drug-induced acid suppression with esomeprazole or by LARS, most patients achieve and remain in remission at 5 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00251927. PMID- 21586713 TI - Factors associated with closures of emergency departments in the United States. AB - CONTEXT: Between 1998 and 2008, the number of hospital-based emergency departments (EDs) in the United States declined, while the number of ED visits increased, particularly visits by patients who were publicly insured and uninsured. Little is known about the hospital, community, and market factors associated with ED closures. Federal law requiring EDs to treat all in need regardless of a patient's ability to pay may make EDs more vulnerable to the market forces that govern US health care. OBJECTIVE: To determine hospital, community, and market factors associated with ED closures. DESIGN: Emergency department and hospital organizational information from 1990 through 2009 was acquired from the American Hospital Association (AHA) Annual Surveys (annual response rates ranging from 84%-92%) and merged with hospital financial and payer mix information available through 2007 from Medicare hospital cost reports. We evaluated 3 sets of risk factors: hospital characteristics (safety net [as defined by hospitals caring for more than double their Medicaid share of discharges compared with other hospitals within a 15-mile radius], ownership, teaching status, system membership, ED size, case mix), county population demographics (race, poverty, uninsurance, elderly), and market factors (ownership mix, profit margin, location in a competitive market, presence of other EDs). SETTING: All general, acute, nonrural, short-stay hospitals in the United States with an operating ED anytime from 1990-2009. MAIN OUTCOME MEASURE: Closure of an ED during the study period. RESULTS: From 1990 to 2009, the number of hospitals with EDs in nonrural areas declined from 2446 to 1779, with 1041 EDs closing and 374 hospitals opening EDs. Based on analysis of 2814 urban acute-care hospitals, constituting 36,335 hospital-year observations over an 18-year study interval (1990-2007), for-profit hospitals and those with low profit margins were more likely to close than their counterparts (cumulative hazard rate based on bivariate model, 26% vs 16%; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.5-2.1, and 36% vs 18%; HR, 1.9; 95% CI, 1.6-2.3, respectively). Hospitals in more competitive markets had a significantly higher risk of closing their EDs (34% vs 17%; HR, 1.3; 95% CI, 1.1-1.6), as did safety-net hospitals (10% vs 6%; HR, 1.4; 95% CI, 1.1-1.7) and those serving a higher share of populations in poverty (37% vs 31%; HR, 1.4; 95% CI, 1.1-1.7). CONCLUSION: From 1990 to 2009, the number of hospital EDs in nonrural areas declined by 27%, with for-profit ownership, location in a competitive market, safety-net status, and low profit margin associated with increased risk of ED closure. PMID- 21586714 TI - Effects of vitamin A or beta carotene supplementation on pregnancy-related mortality and infant mortality in rural Bangladesh: a cluster randomized trial. AB - CONTEXT: Maternal vitamin A deficiency is a public health concern in the developing world. Its prevention may improve maternal and infant survival. OBJECTIVE: To assess efficacy of maternal vitamin A or beta carotene supplementation in reducing pregnancy-related and infant mortality. DESIGN, SETTING, AND PARTICIPANTS: Cluster randomized, double-masked, placebo-controlled trial among pregnant women 13 to 45 years of age and their live-born infants to 12 weeks (84 days) postpartum in rural northern Bangladesh between 2001 and 2007. Interventions Five hundred ninety-six community clusters (study sectors) were randomized for pregnant women to receive weekly, from the first trimester through 12 weeks postpartum, 7000 MUg of retinol equivalents as retinyl palmitate, 42 mg of all-trans beta carotene, or placebo. Married women (n = 125,257) underwent 5 week surveillance for pregnancy, ascertained by a history of amenorrhea and confirmed by urine test. Blood samples were obtained from participants in 32 sectors (5%) for biochemical studies. MAIN OUTCOME MEASURES: All-cause mortality of women related to pregnancy, stillbirth, and infant mortality to 12 weeks (84 days) following pregnancy outcome. RESULTS: Groups were comparable across risk factors. For the mortality outcomes, neither of the supplement group outcomes was significantly different from the placebo group outcomes. The numbers of deaths and all-cause, pregnancy-related mortality rates (per 100,000 pregnancies) were 41 and 206 (95% confidence interval [CI], 140-273) in the placebo group, 47 and 237 (95% CI, 166-309) in the vitamin A group, and 50 and 250 (95% CI, 177-323) in the beta carotene group. Relative risks for mortality in the vitamin A and beta carotene groups were 1.15 (95% CI, 0.75-1.76) and 1.21 (95% CI, 0.81-1.81), respectively. In the placebo, vitamin A, and beta carotene groups the rates of stillbirth and infant mortality were 47.9 (95% CI, 44.3-51.5), 45.6 (95% CI, 42.1 49.2), and 51.8 (95% CI, 48.0-55.6) per 1000 births and 68.1 (95% CI, 63.7-72.5), 65.0 (95% CI, 60.7-69.4), and 69.8 (95% CI, 65.4-72.3) per 1000 live births, respectively. Vitamin A compared with either placebo or beta carotene supplementation increased plasma retinol concentrations by end of study (1.46 [95% CI, 1.42-1.50] MUmol/L vs 1.13 [95% CI, 1.09-1.17] MUmol/L and 1.18 [95% CI, 1.14-1.22] MUmol/L, respectively; P < .001) and reduced, but did not eliminate, gestational night blindness (7.1% for vitamin A vs 9.2% for placebo and 8.9% for beta carotene [P < .001 for both]). CONCLUSION: Use of weekly vitamin A or beta carotene in pregnant women in Bangladesh, compared with placebo, did not reduce all-cause maternal, fetal, or infant mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00198822. PMID- 21586715 TI - Newer-generation antiepileptic drugs and the risk of major birth defects. AB - CONTEXT: Epilepsy during pregnancy is a therapeutic challenge. Since the 1990s, the number of licensed antiepileptic drugs has substantially increased, but safety data on first-trimester use of newer-generation antiepileptic drugs and birth defects are limited. OBJECTIVE: To study the association between fetal exposure to newer-generation antiepileptic drugs during the first trimester of pregnancy and the risk of major birth defects. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study of 837,795 live-born infants in Denmark from January 1, 1996, through September 30, 2008. Individual-level information on dispensed antiepileptic drugs to mothers, birth defect diagnoses, and potential confounders were ascertained from nationwide health registries. MAIN OUTCOME MEASURES: Prevalence odds ratios (PORs) of any major birth defect diagnosed within the first year of life by fetal exposure to antiepileptic drugs. RESULTS: Of the 1532 infants exposed to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam during the first trimester, 49 were diagnosed with a major birth defect compared with 19,911 of the 836,263 who were not exposed to an antiepileptic drug (3.2% vs 2.4%, respectively; adjusted POR [APOR], 0.99; 95% confidence interval [CI], 0.72-1.36). A major birth defect was diagnosed in 38 of 1019 infants (3.7%) exposed to lamotrigine during the first trimester (APOR, 1.18; 95% CI, 0.83-1.68), in 11 of 393 infants (2.8%) exposed to oxcarbazepine (APOR, 0.86; 95% CI, 0.46-1.59), and in 5 of 108 infants (4.6%) exposed to topiramate (APOR, 1.44; 95% CI, 0.58-3.58). Gabapentin (n = 59) and levetiracetam (n = 58) exposure during the first trimester was uncommon, with only 1 (1.7%) and 0 infants diagnosed with birth defects, respectively. CONCLUSION: Among live-born infants in Denmark, first-trimester exposure to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam compared with no exposure was not associated with an increased risk of major birth defects. PMID- 21586716 TI - From efficacy to effectiveness in the face of uncertainty: indication creep and prevention creep. PMID- 21586717 TI - A unique researcher identifier for the Physician Payments Sunshine Act. PMID- 21586718 TI - Physician burnout: a potential threat to successful health care reform. PMID- 21586719 TI - When patients call, will physicians respond? PMID- 21586720 TI - JAMA patient page. Gastroesophageal reflux disease. PMID- 21586721 TI - Outcomes research and epidemiology: the synergy between public health and clinical practice. PMID- 21586722 TI - Personalizing evidence-based primary prevention with aspirin: individualized risks and patient preference. PMID- 21586723 TI - A brave new world? Measuring trends in percutaneous coronary intervention for stable angina after COURAGE. PMID- 21586724 TI - Clinical trial subgroups: challenges and opportunities in describing the benefits of therapy. PMID- 21586725 TI - Landmark analysis at the 25-year landmark point. AB - This statistical primer presents the landmark analysis method, exploring its appropriate use and interpretation while recognizing its limitations. This observational method is used for comparing time-to-event outcome between groups determined during study follow-up. The goal of the landmark method is to estimate in an unbiased way the time-to-event probabilities in each group conditional on the group membership of patients at a specific time point, the landmark time. The need that led to its development, the impact of the method, and its pros and cons, along with available alternative approaches, are presented. Simulations explore its performance, using realistic parameters from a recent cardiovascular study. As long as the limitations of the method are recognized and the interpretation of its results clearly reflect their "conditional" nature, landmark analysis, 25 years from its introduction, can still be of value. PMID- 21586726 TI - Calcium signaling in sperm: help from prostasomes. AB - Mammalian sperm cells are equipped with sophisticated Ca2+ signaling mechanisms that are fundamental to sperm's success in fertilization. Unlike most other cells, however, mature sperm generally do not have the luxury of synthesizing new proteins. New evidence indicates that human sperm have a very clever way to solve the conflict between the critical demand for Ca2+ signaling tools and the silence of protein translation. Just before encountering the female reproductive tract, sperm acquire some of the key molecules for Ca2+ signaling from the male reproductive tract itself: prostasomes secreted by the prostate gland. PMID- 21586727 TI - Network-based tools for the identification of novel drug targets. AB - In the past few years, network-based tools have become increasingly important in the identification of novel molecular targets for drug development. Systems-based approaches to predict signal transduction-related drug targets have developed into an especially promising field. Here, we summarize our studies, which indicate that modular bridges and overlaps of protein-protein interaction and signaling networks may be of key importance in future drug design. Intermodular nodes are very efficient in mediating the transmission of perturbations between signaling modules and are important in network cooperation. The analysis of stress-induced rearrangements of the yeast interactome by the ModuLand modularization algorithm indicated that components of modular overlap are key players in cellular adaptation to stress. Signaling crosstalk was much more pronounced in humans than in Caenorhabditis elegans or Drosophila melanogaster in the SignaLink (http://www.SignaLink.org) database, a uniformly curated database of eight major signaling pathways. We also showed that signaling proteins that participate in multiple pathways included multiple established drug targets and drug target candidates. Lastly, we caution that the pervasive overlap of cellular network modules implies that wider use of multitarget drugs to partially inhibit multiple individual proteins will be necessary to modify specific cellular functions, because targeting single proteins for complete disruption usually affects multiple cellular functions with little specificity for a particular process. Tools for analyzing network topology and especially network dynamics have great potential to identify alternative sets of targets for developing multitarget drugs. PMID- 21586728 TI - Ca2+ signaling tools acquired from prostasomes are required for progesterone induced sperm motility. AB - Progesterone-induced calcium ion (Ca2+) signals in the neck region of sperm play a pivotal role in promoting sperm motility. Here, we show that a long-lasting Ca2+ signal required for sperm motility in response to progesterone depends on their pH-dependent fusion with prostasomes, which are small vesicles secreted by the prostate. We found that prostasome fusion led to the transfer of progesterone receptors, cyclic adenosine diphosphoribose (cADPR)-synthesizing enzymes, ryanodine receptors (RyRs), and other Ca2+ signaling tools from prostasomes to the sperm neck. Progesterone-induced sperm motility relied on cADPR-mediated Ca2+ mobilization through RyR located on acidic Ca2+ stores, followed by Ca2+ entry through store-operated channels. Treatment of prostasome-fused sperm with a cADPR antagonist or fusion with prostasomes in which type 2 RyR was depleted resulted in low fertilization rates, reduced sperm motility, or both. Thus, we conclude that sperm motility depends on the acquisition of Ca2+ signaling tools from prostasomes. PMID- 21586729 TI - Stomatal closure by fast abscisic acid signaling is mediated by the guard cell anion channel SLAH3 and the receptor RCAR1. AB - S-type anion channels are direct targets of abscisic acid (ABA) signaling and contribute to chloride and nitrate release from guard cells, which in turn initiates stomatal closure. SLAC1 was the first component of the guard cell S type anion channel identified. However, we found that guard cells of Arabidopsis SLAC1 mutants exhibited nitrate conductance. SLAH3 (SLAC1 homolog 3) was also present in guard cells, and coexpression of SLAH3 with the calcium ion (Ca2+) dependent kinase CPK21 in Xenopus oocytes mediated nitrate-induced anion currents. Nitrate, calcium, and phosphorylation regulated SLAH3 activity. CPK21 dependent SLAH3 phosphorylation and activation were blocked by ABI1, a PP2C-type protein phosphatase that is inhibited by ABA and inhibits the ABA signaling pathway in guard cells. We reconstituted the ABA-stimulated phosphorylation of the SLAH3 amino-terminal domain by CPK21 in vitro by including the ABA receptor phosphatase complex RCAR1-ABI1 in the reactions. We propose that ABA perception by the complex consisting of ABA receptors of the RCAR/PYR/PYL family and ABI1 releases CPK21 from inhibition by ABI1, and then CPK21 is further activated by an increase in the cytosolic Ca2+ concentration, leading to its phosphorylation of SLAH3. Thus, the identification of SLAH3 as the nitrate-, calcium-, and ABA sensitive guard cell anion channel provides insights into the relationship among stomatal response to drought, signaling by nitrate, and nitrate metabolism. PMID- 21586730 TI - Severe dilated cardiomyopathy after propranolol treatment in an undiagnosed adrenal pheochromocytoma. PMID- 21586731 TI - Rare visualization of entrapped left ventricular thrombi in noncompacted myocardium. PMID- 21586732 TI - Discerning pulmonary venous from pulmonary arterial hypertension without the help of a catheter. PMID- 21586733 TI - Defining the phenotypes for pulmonary hypertension associated with diastolic heart failure. PMID- 21586734 TI - Heart failure patients in skilled nursing facilities: evidence needed. PMID- 21586735 TI - The socio-geography of heart failure: why it matters. PMID- 21586736 TI - Thromboembolism and antithrombotic therapy in patients with heart failure in sinus rhythm: current status and future directions. PMID- 21586737 TI - Equalization of right- and left-sided intracardiac pressures: is it constriction? PMID- 21586739 TI - Acute myocarditis demonstrated on CT coronary angiography with MRI correlation. PMID- 21586740 TI - Real-time 3-dimensional transesophageal echocardiography of the atrioventricular septal defect. PMID- 21586741 TI - High-sensitivity C-reactive protein, vascular imaging, and vulnerable plaque: more evidence to support trials of antiinflammatory therapy for cardiovascular risk reduction. PMID- 21586742 TI - T2-cardiac magnetic resonance: has Elvis left the building? PMID- 21586743 TI - Imaging biomarkers in atherosclerosis trials. PMID- 21586745 TI - First in vivo demonstration of coronary edema in culprit lesion of patient with acute coronary syndrome by cardiovascular magnetic resonance. PMID- 21586744 TI - Nonechocardiographic imaging in evaluation for cardiac resynchronization therapy. PMID- 21586746 TI - Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. AB - Cerebral adrenoleukodystrophy (cALD) remains a devastating neurodegenerative disease; only allogeneic hematopoietic cell transplantation (HCT) has been shown to provide long-term disease stabilization and survival. Sixty boys undergoing HCT for cALD from 2000 to 2009 were analyzed. The median age at HCT was 8.7 years; conditioning regimens and allograft sources varied. At HCT, 50% demonstrated a Loes radiographic severity score >= 10, and 62% showed clinical evidence of neurologic dysfunction. A total of 78% (n = 47) are alive at a median 3.7 years after HCT. The estimate of 5-year survival for boys with Loes score < 10 at HCT was 89%, whereas that for boys with Loes score >= 10 was 60% (P = .03). The 5-year survival estimate for boys absent of clinical cerebral disease at HCT was 91%, whereas that for boys with neurologic dysfunction was 66% (P = .08). The cumulative incidence of transplantation-related mortality at day 100 was 8%. Post transplantation progression of neurologic dysfunction depended significantly on the pre-HCT Loes score and clinical neurologic status. We describe the largest single-institution analysis of survival and neurologic function outcomes after HCT in cALD. These trials were registered at www.clinicaltrials.gov as #NCT00176904, #NCT00668564, and #NCT00383448. PMID- 21586747 TI - Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma permissive niche within murine secondary lymphoid organs. AB - Lymphoma cell survival and progression are putatively dependent on a specific microanatomic localization within secondary lymphoid organs. Despite compelling data correlating homeostatic chemokine receptor expression and human lymphoma pathogenesis, genetic models that either mimic lymphoma dissemination or dissect a crosstalk of lymphoma and stromal cells are missing. Applying the genetically tractable EMU-Myc transgenic mouse model, we show that the chemokine receptor CCR7 regulates EMU-Myc lymphoma homing to lymph nodes and distinctive microanatomic sites of the spleen. CCR7-controlled access of lymphoma cells to the splenic T-cell zone led to a significant survival advantage compared with CCR7-deficient lymphoma cells, which were excluded from this zone. Within the niche, lymphoma cells stimulated a reciprocal cross-talk with gp38(+) fibroblastic reticular cells. This reciprocal cooperation program was mediated by lymphoma B cell-presented lymphotoxin, which acted on lymphotoxin-beta-receptor bearing stromal cells followed by alteration of stromal cellular composition. Cross-talk inhibition by lymphotoxin-alpha deletion and using a lymphotoxin-beta receptor-immunoglobulin fusion protein impaired lymphoma growth. Thus, abrogation of CCR7-governed migration and of sustained lymphotoxin signaling could provide new targets in lymphoma therapy. PMID- 21586748 TI - Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output. AB - Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development by activating 3 receptor tyrosine kinases (RTKs), VEGFR-1, -2, and 3, and by binding to coreceptors such as neuropilin-1 (NRP-1). We investigated how different VEGF-A isoforms, in particular VEGF-A(165)a and VEGF-A(165)b, control the balance between VEGFR-2 recycling, degradation, and signaling. Stimulation of cells with the NRP-1-binding VEGF-A(165)a led to sequential NRP-1 mediated VEGFR-2 recycling through Rab5, Rab4, and Rab11 vesicles. Recycling was accompanied by dephosphorylation of VEGFR-2 between Rab4 and Rab11 vesicles and quantitatively and qualitatively altered signal output. In cells stimulated with VEGF-A(165)b, an isoform unable to bind NRP-1, VEGFR-2 bypassed Rab11 vesicles and was routed to the degradative pathway specified by Rab7 vesicles. Deletion of the GIPC (synectin) binding motif of NRP-1 prevented transition of VEGFR-2 through Rab11 vesicles and attenuated signaling. Coreceptor engagement was specific for VEGFR-2 because EGFR recycled through Rab11 vesicles in the absence of known coreceptors. Our data establish a distinct role of NRP-1 in VEGFR-2 signaling and reveal a general mechanism for the function of coreceptors in modulating RTK signal output. PMID- 21586749 TI - FLT3/ITD AML and the law of unintended consequences. AB - Acute myeloid leukemia with a FLT3 internal tandem duplication (FLT3/ITD) mutation is an aggressive hematologic malignancy with a generally poor prognosis. It can be successfully treated into remission with intensive chemotherapy, but it routinely relapses. At relapse, the blasts tend to have higher mutant allelic ratios and, in vitro, are more addicted to the aberrant signaling from the FLT3/ITD oncoprotein. They remain highly responsive to FLT3 ligand, the levels of which rise several-fold during the course of chemotherapy. The question now arises as to whether these high levels of FLT3 ligand are actually promoting relapse, and, if so, how we can use this information to adjust our therapeutic approach and improve the cure rate for acute myeloid leukemia with FLT3/ITD. PMID- 21586750 TI - The identification and characterization of zebrafish hematopoietic stem cells. AB - HSCs are defined by their ability to self-renew and maintain hematopoiesis throughout the lifespan of an organism. The optical clarity of their embryos and the ease of genetic manipulation make the zebrafish (Danio rerio) an excellent model for studying hematopoiesis. Using flow cytometry, we identified 2 populations of CD41-GFP(+) cells (GFP(hi) and GFP(lo)) in the whole kidney marrow of Tg(CD41:GFP) zebrafish. Past studies in humans and mice have shown that CD41 is transiently expressed in the earliest hematopoietic progenitors and is then silenced, reappearing in the platelet/thrombocyte lineage. We have transplanted flow-sorted GFP(hi) and GFP(lo) cells into irradiated adult zebrafish and assessed long-term hematopoietic engraftment. Transplantation of GFP(hi) cells did not reconstitute hematopoiesis. In contrast, we observed multilineage hematopoiesis up to 68 weeks after primary and secondary transplantation of GFP(lo) cells. We detected the CD41-GFP transgene in all major hematopoietic lineages and CD41-GFP(+) cells in histologic sections of kidneys from transplant recipients. These studies show that CD41-GFP(lo) cells fulfill generally accepted criteria for HSCs. The identification of fluorescent zebrafish HSCs, coupled with our ability to transplant them into irradiated adult recipients, provide a valuable new tool to track HSC homing, proliferation, and differentiation into hematopoietic cells. PMID- 21586751 TI - Paraproteins of familial MGUS/multiple myeloma target family-typical antigens: hyperphosphorylation of autoantigens is a consistent finding in familial and sporadic MGUS/MM. AB - Paratarg-7 (P-7) is a frequent paraprotein target in monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), and Waldenstrom macroglobulinemia. Patients with P-7-specific paraproteins carry a hyperphosphorylated paratarg-7 (pP-7). Because pP-7 carrier state is dominantly inherited, we determined the paraprotein targets in 4 families with familial MGUS/MM. No antigenic target was identified for the paraproteins from 2 members of one family. Paraproteins from affected members of 2 other families targeted P 7, and paraproteins from 4 affected members of a fourth family targeted P-8, which is encoded by the ATG13 gene. P-8 was hyperphosphorylated in the affected family members (pP-8) and pP-8 carrier state is inherited in a dominant fashion. Six additional autoantigenic nonfamilial paraprotein targets were also hyperphosphorylated in the respective patients compared with normal controls. We conclude that paraproteins of affected members with familial MGUS/MM share family typical hyperphosphorylated antigens and hyperphosphorylation of paraprotein targets might be a general mechanism underlying the pathogenesis of MGUS/MM. PMID- 21586752 TI - Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose and cell type-dependent manner. AB - Both monoallelic and biallelic oncogenic NRAS mutations are identified in human leukemias, suggesting a dose-dependent role of oncogenic NRAS in leukemogenesis. Here, we use a hypomorphic oncogenic Nras allele and a normal oncogenic Nras allele (Nras G12D(hypo) and Nras G12D, respectively) to create a gene dose gradient ranging from 25% to 200% of endogenous Nras G12D/+. Mice expressing Nras G12D(hypo)/G12D(hypo) develop normally and are tumor-free, whereas early embryonic expression of Nras G12D/+ is lethal. Somatic expression of Nras G12D/G12D but not Nras G12D/+ leads to hyperactivation of ERK, excessive proliferation of myeloid progenitors, and consequently an acute myeloproliferative disease. Using a bone marrow transplant model, we previously showed that ~ 95% of animals receiving Nras G12D/+ bone marrow cells develop chronic myelomonocytic leukemia (CMML), while ~ 8% of recipients develop acute T cell lymphoblastic leukemia/lymphoma [TALL] (TALL-het). Here we demonstrate that 100% of recipients transplanted with Nras G12D/G12D bone marrow cells develop TALL (TALL-homo). Although both TALL-het and -homo tumors acquire Notch1 mutations and are sensitive to a gamma-secretase inhibitor, endogenous Nras G12D/+ signaling promotes TALL through distinct genetic mechanism(s) from Nras G12D/G12D. Our data indicate that the tumor transformation potential of endogenous oncogenic Nras is both dose- and cell type-dependent. PMID- 21586753 TI - Shared molecular strategies of the malaria parasite P. falciparum and the human virus HIV-1. AB - We augmented existing computationally predicted and experimentally determined interactions with evolutionarily conserved interactions between proteins of the malaria parasite, P. falciparum, and the human host. In a validation step, we found that conserved interacting host-parasite protein pairs were specifically expressed in host tissues where both the parasite and host proteins are known to be active. We compared host-parasite interactions with experimentally verified interactions between human host proteins and a very different pathogen, HIV-1. Both pathogens were found to use their protein repertoire in a combinatorial manner, providing a broad connection to host cellular processes. Specifically, the two biologically distinct pathogens predominately target central proteins to take control of a human host cell, effectively reaching into diversified cellular host cellular functions. Interacting signaling pathways and a small set of regulatory and signaling proteins were prime targets of both pathogens, suggesting remarkably similar patterns of host-pathogen interactions despite the vast biological differences of both pathogens. Such an identification of shared molecular strategies by the virus HIV-1 and the eukaryotic intracellular pathogen P. falciparum may allow us to illuminate new avenues of disease intervention. PMID- 21586754 TI - Deep and highly sensitive proteome coverage by LC-MS/MS without prefractionation. AB - In-depth MS-based proteomics has necessitated fractionation of either proteins or peptides or both, often requiring considerable analysis time. Here we employ long liquid chromatography runs with high resolution coupled to an instrument with fast sequencing speed to investigate how much of the proteome is directly accessible to liquid chromatography-tandem MS characterization without any prefractionation steps. Triplicate single-run analyses identified 2990 yeast proteins, 68% of the total measured in a comprehensive yeast proteome. Among them, we covered the enzymes of the glycolysis and gluconeogenesis pathway targeted in a recent multiple reaction monitoring study. In a mammalian cell line, we identified 5376 proteins in a triplicate run, including representatives of 173 out of 200 KEGG metabolic and signaling pathways. Remarkably, the majority of proteins could be detected in the samples at sub-femtomole amounts and many in the low attomole range, in agreement with absolute abundance estimation done in previous works (Picotti et al. Cell, 138, 795-806, 2009). Our results imply an unexpectedly large dynamic range of the MS signal and sensitivity for liquid chromatography-tandem MS alone. With further development, single-run analysis has the potential to radically simplify many proteomic studies while maintaining a systems-wide view of the proteome. PMID- 21586755 TI - Retinoschisis: a predictive factor in vitrectomy for macular holes without retinal detachment in highly myopic eyes. AB - AIM: To explore the factors affecting surgical outcomes of highly myopic macular holes (HMMHs). METHODS: This is a retrospective cross-sectional study. Twenty-two eyes that underwent vitrectomy for HMMHs were included. The eyes were studied retrospectively and divided into two groups by preoperative optical coherence tomography (OCT): 10 eyes with retinoschisis around HMMH and 12 without. Preoperative status including age and posterior staphyloma height measured by OCT, and surgical outcome including postoperative final best-corrected visual acuity and reoperation rate, were evaluated and compared. RESULTS: The schisis group was significantly older (p<0.01) with a worse visual acuity (p<0.05) and greater posterior staphyloma height (p<0.05). The preoperative best-corrected visual acuity and the presence or absence of retinoschisis were significantly (p<0.01 and p=0.01, respectively) associated with the postoperative best corrected visual acuity; age was borderline (p=0.06). CONCLUSION: There are two types of macular holes (MHs) in highly myopic eyes with distinctly different prognoses. Preoperative OCT images must be interpreted carefully to determine the precise surgical results. Retinoschisis negatively impacts vitrectomy for HMMHs. PMID- 21586756 TI - Low-cost portable fluorescein angiography. AB - Fundus fluorescein angiography has great potential as a unique non-invasive tool to investigate in vivo the microvascular pathogenesis of a wide variety of diseases affecting the central nervous system. However, because it requires a bulky and expensive tabletop retinal camera, it is normally limited to cooperative and alert seated patients in well-resourced settings. Recently completed and ongoing studies of the pathogenesis of severe malaria are using fluorescein angiography to examine in detail the postulated central role of microvascular obstruction. We describe a novel method of fluorescein angiography with a portable retinal camera that can be adapted at very low cost for use in sick patients at the bedside. This method greatly expands the scope of potential studies utilising fluorescein angiography. PMID- 21586758 TI - Evaluation of triage methods used to select patients with suspected pandemic influenza for hospital admission. AB - OBJECTIVES: Prepandemic projections anticipated huge excess attendances and mortality in an influenza pandemic. A number of tools had been suggested for triaging patients with influenza for inpatient and critical care admission, but none had been validated in these patients. The authors aimed to evaluate three potential triage tools--CURB-65, PMEWS and the Department of Health community assessment tool (CAT)--in patients in the first waves of the 2009 H1N1 pandemic. SETTING: Prospective cohort study in three urban emergency departments (one adult, one paediatric, one mixed) in two cities. PARTICIPANTS: All patients presenting to the three emergency departments fulfilling the national definition of suspected pandemic influenza. OUTCOME MEASURES: 30-day follow-up identified patients who had died or had required advanced respiratory, cardiovascular or renal support. RESULTS: The pandemic was much less severe than expected. A total of 481 patients (347 children) were recruited, of which only five adults fulfilled the outcome criteria for severe illness. The c-statistics for CURB-65, PMEWS and CAT in adults in terms of discriminating between those admitted and discharged were 0.65 (95% CI 0.54 to 0.76), 0.76 (95% CI 0.66 to 0.86) and 0.62 (95% CI 0.51 to 0.72), respectively. In detecting adverse outcome, sensitivities were 20% (95% CI 4% to 62%), 80% (95% CI 38% to 96%) and 60% (95% CI 23% to 88%), and specificities were 94% (95% CI 88% to 97%), 40% (95% CI 32% to 49%) and 81% (95% CI 73% to 87%) for CURB-65, PMEWS and CAT, respectively. CONCLUSIONS: Although limited by a paucity of cases, this research shows that current triage methods for suspected pandemic influenza did not reliably discriminate between patients with good and poor outcomes. PMID- 21586757 TI - The Acute Asthma Severity Assessment Protocol (AASAP) study: objectives and methods of a study to develop an acute asthma clinical prediction rule. AB - Acute asthma exacerbations are one of the most common reasons for paediatric emergency department visits and hospitalisations, and a relapse frequently necessitates repeat urgent care. While care plans exist, there are no acute asthma prediction rules (APRs) to assess severity and predict outcome. The primary objective of the Acute Asthma Severity Assessment Protocol study is to develop a multivariable APR for acute asthma exacerbations in paediatric patients. A prospective, convenience sample of paediatric patients aged 5-17 years with acute asthma exacerbations who present to an urban, academic, tertiary paediatric emergency department was enrolled. The study protocol and data analysis plan conform to accepted biostatistical and clinical standards for clinical prediction rule development. Modelling of the APR will be performed once the entire sample size of 1500 has accrued. It is anticipated that the APR will improve resource utilisation in the emergency department, aid in standardisation of disease assessment and allow physician and non-physician providers to participate in earlier objective decision making. The objective of this report is to describe the study objectives and detailed methodology of the Acute Asthma Severity Assessment Protocol study. PMID- 21586759 TI - Physical and psychosocial ergonomic risk factors for low back pain in automobile manufacturing workers. AB - OBJECTIVES: To examine the association between ergonomic physical and psychosocial exposures and the risk of prevalent and incident low back pain (LBP) in a longitudinal cohort of automobile manufacturing workers. METHODS: Ergonomic exposure intensity and LBP presence were determined through questionnaires at baseline (n=1181) and to workers in the same job 1 year later (n=505). Models were constructed using log-binomial regression with special attention to interactions between ergonomic exposures. RESULTS: Awkward back posture (prevalence ratio (PR) 1.12, 95% CI 1.07 to 1.17), hand force (PR 1.06, 95% CI 1.02 to 1.10), physical effort (PR 1.10, 95% CI 1.04 to 1.16) and whole body vibration (PR 1.04, 95% CI 1.01 to 1.08) were each associated cross-sectionally with LBP. Awkward back posture (RR 1.13, 95% CI 0.98 to 1.31) and hand force (RR 1.07, 95% CI 0.93 to 1.22) also predicted incident LBP, although estimates were statistically less precise. Neither job control, psychological demands, nor job strain was independently related to risk of incident LBP. Among participants reporting high physical ergonomic exposures and moderate to high job control, increasing job demands was associated with a reduced LBP risk (RR 0.72, 95% CI 0.52 to 1.00). Among participants reporting high physical exposures and low job control, psychological demands was associated with an increased LBP risk (RR 1.30, 95% CI 1.02 to 1.66). CONCLUSIONS: Psychosocial workplace interventions for LBP should prioritise jobs in which there are high physical ergonomic exposures. Future studies of LBP should examine the interactions between physical ergonomic risk factors. PMID- 21586760 TI - The influence of newspaper coverage and a media campaign on smokers' support for smoke-free bars and restaurants and on secondhand smoke harm awareness: findings from the International Tobacco Control (ITC) Netherlands Survey. AB - OBJECTIVE: To assess the influence of newspaper coverage and a media campaign about Dutch smoke-free legislation on smokers' support for smoke-free bars and restaurants and on secondhand smoke (SHS) harm awareness. DESIGN AND MAIN OUTCOME MEASURES: A content analysis was conducted of 1041 newspaper articles on the smoke-free legislation published in six Dutch newspapers from March 2008 to April 2009. Smokers who were regular readers of at least one of these newspapers (n = 677) were selected from the pre-ban and post-ban waves of the International Tobacco Control Netherlands Survey. Exposure to newspaper coverage and the implementation campaign was correlated with changes in smokers' support for smoke free bars and restaurants and SHS harm awareness. RESULTS: Most newspaper coverage was found to be negative towards the smoking ban (57%) and focused on economic aspects (59%) rather than health aspects (22%). Exposure to this coverage had a small but significantly negative effect on support for smoke-free bars and restaurants (beta = -0.09, p = 0.013). Among higher educated smokers, exposure to positive newspaper coverage had a more positive effect on support for smoke-free bars and restaurants. In addition, exposure to the implementation campaign had a small but significantly positive effect on SHS harm awareness (beta = 0.11, p = 0.001). CONCLUSIONS: Media attention on smoke-free legislation can influence smokers' support for the legislation and SHS harm awareness. Tobacco control advocates should aim to establish positive media attention that puts forward the health arguments for the legislation. PMID- 21586761 TI - Typologies of smokers and non-smokers: encouraging changes over time. PMID- 21586762 TI - Superior identification of familiar visual patterns a year after learning. AB - Practice improves visual performance on simple tasks in which stimuli vary along one dimension. Such learning frequently is stimulus-specific and enduring, and has been associated with plasticity in striate cortex. It is unclear if similar lasting effects occur for naturalistic patterns that vary on multiple dimensions. We measured perceptual learning in identification tasks that used faces and textures, stimuli that engage multiple stages in visual processing. Performance improved significantly across 2 consecutive days of practice. More important, the effects of practice were remarkably stable across time: Improvements were maintained approximately 1 year later, and both the relative difficulty of identifying individual stimuli and individual differences in performance were essentially constant across sessions. Finally, the effects of practice were largely stimulus-specific. Our results suggest that the characteristics of perceptual learning are similar across a spectrum of stimulus complexities. PMID- 21586763 TI - Global social identity and global cooperation. AB - This research examined the question of whether the psychology of social identity can motivate cooperation in the context of a global collective. Our data came from a multinational study of choice behavior in a multilevel public-goods dilemma conducted among samples drawn from the general populations of the United States, Italy, Russia, Argentina, South Africa, and Iran. Results demonstrate that an inclusive social identification with the world community is a meaningful psychological construct that plays a role in motivating cooperation that transcends parochial interests. Self-reported identification with the world as a whole predicts behavioral contributions to a global public good beyond what is predicted from expectations about what other people are likely to contribute. Furthermore, global social identification is conceptually distinct from general attitudes about global issues, and has unique effects on cooperative behavior. PMID- 21586764 TI - Insensitivity of the human sentence-processing system to hierarchical structure. AB - Although it is generally accepted that hierarchical phrase structures are instrumental in describing human language, their role in cognitive processing is still debated. We investigated the role of hierarchical structure in sentence processing by implementing a range of probabilistic language models, some of which depended on hierarchical structure, and others of which relied on sequential structure only. All models estimated the occurrence probabilities of syntactic categories in sentences for which reading-time data were available. Relating the models' probability estimates to the data showed that the hierarchical-structure models did not account for variance in reading times over and above the amount of variance accounted for by all of the sequential-structure models. This suggests that a sentence's hierarchical structure, unlike many other sources of information, does not noticeably affect the generation of expectations about upcoming words. PMID- 21586765 TI - Assessment of the suspected fracture of the scaphoid. AB - A suspected fracture of the scaphoid remains difficult to manage despite advances in knowledge and imaging methods. Immobilisation and restriction of activities in a young and active patient must be balanced against the risks of nonunion associated with an undiagnosed and undertreated fracture of the scaphoid. The assessment of diagnostic tests for a suspected fracture of the scaphoid must take into account two important factors. First, the prevalence of true fractures among suspected fractures is low, which greatly reduces the probability that a positive test will correspond with a true fracture, as false positives are nearly as common as true positives. This situation is accounted for by Bayesian statistics. Secondly, there is no agreed reference standard for a true fracture, which necessitates the need for an alternative method of calculating diagnostic performance characteristics, based upon a statistical method which identifies clinical factors tending to associate (latent classes) in patients with a high probability of fracture. The most successful diagnostic test to date is MRI, but in low-prevalence situations the positive predictive value of MRI is only 88%, and new data have documented the potential for false positive scans. The best strategy for improving the diagnosis of true fractures among suspected fractures of the scaphoid may well be to develop a clinical prediction rule incorporating a set of demographic and clinical factors which together increase the pre-test probability of a fracture of the scaphoid, in addition to developing increasingly sophisticated radiological tests. PMID- 21586766 TI - Multicentre randomised clinical trials in trauma care. AB - Multicentre clinical trials in trauma care are gaining prominence as a means of generating good-quality evidence to inform and influence clinical practice. We believe multicentre trials have an important role to play in supporting evidence based practice, and further investment in such trials is justified. PMID- 21586767 TI - The Canadian Orthopaedic Trauma Society. AB - The Canadian Orthopaedic Trauma Society was started in an endeavour to answer the difficult problem of obtaining enough patients to perform top-quality research into fractures. By maintaining a high standard, including randomised study design, inclusivity, open discussion among surgeons and excellent long-term follow-up, this group has become a leader in the orthopaedic research community. This annotation describes the short history, important components and spirit necessary to build a research community or team which will function well despite the difficult research environment facing individual surgeons. PMID- 21586768 TI - The Chiari pelvic osteotomy for patients with dysplastic hips and poor joint congruency: long-term follow-up. AB - We report the mid- to long-term (mean 20.3 years, 10 to 32.5) results of the Chiari pelvic osteotomy in patients with pre- to advanced stage osteoarthritis in dysplastic hips. We followed 163 Japanese patients (173 hips) with a mean age at surgery of 20 years (9 to 54). Overall, 124 hips (72%) had satisfactory results, with Harris hip scores >= 80. Satisfactory results were seen in 105 of 134 hips with pre- or early osteoarthritis (78%) and 19 of 39 hips with advanced osteoarthritis (49%). A total of 15 hips (9%) underwent a total hip replacement (THR) with a mean interval between osteotomy and THR of 16.4 years. With conversion to THR as the endpoint, the 30-year survival rate was 85.9% (95% confidence interval 82.3 to 89.5). It was 91.8% for patients with pre- or early osteoarthritis and 43.6% for those with advanced osteoarthritis (p < 0.001). We now perform the Chiari osteotomy for patients with dysplastic hips showing poor joint congruency and who prefer a joint-conserving procedure to THR. PMID- 21586769 TI - Peri-acetabular rotational osteotomy with concomitant hip arthroscopy for treatment of hip dysplasia. AB - Reconstructive acetabular osteotomy is a well established and effective procedure in the treatment of acetabular dysplasia. However, the dysplasia is frequently accompanied by intra-articular pathology such as labral tears. We intended to determine whether a concomitant hip arthroscopy with peri-acetabular rotational osteotomy could identify and treat intra-articular pathology associated with dysplasia and thereby produce a favourable outcome. We prospectively evaluated 43 consecutive hips treated by combined arthroscopy and acetabular osteotomy. Intra operative arthroscopic examination revealed labral lesions in 38 hips. At a mean follow-up of 74 months (60 to 97) the mean Harris hip score improved from 72.4 to 94.0 (p < 0.001), as did all the radiological parameters (p < 0.001). Complications included penetration of the joint by the osteotome in one patient, a fracture of the posterior column in another and deep-vein thrombosis in one further patient. This combined surgical treatment gave good results in the medium term. We suggest that arthroscopy of the hip can be performed in conjunction with peri-acetabular osteotomy to provide good results in patients with symptomatic dysplasia of the hip, and the arthroscopic treatment of intra-articular pathology may alter the progression of osteoarthritis. PMID- 21586770 TI - An analysis of metal ion levels in the joint fluid of symptomatic patients with metal-on-metal hip replacements. AB - We retrospectively analysed concentrations of chromium and cobalt ions in samples of synovial fluid and whole blood taken from a group of 92 patients with failed current-generation metal-on-metal hip replacements. We applied acid oxidative digestion to our trace metal analysis protocol, which found significantly higher levels of metal ion concentrations in blood and synovial fluid than a non digestive method. Patients were subcategorised by mode of failure as either 'unexplained pain' or 'defined causes'. Using this classification, chromium and cobalt ion levels were present over a wider range in synovial fluid and not as strongly correlated with blood ion levels as previously reported. There was no significant difference between metal ion concentrations and manufacturer of the implant, nor femoral head size below or above 50 mm. There was a moderately positive correlation between metal ion levels and acetabular component inclination angle as measured on three-dimensional CT imaging. Our results suggest that acid digestion of samples of synovial fluid samples is necessary to determine metal ion concentrations accurately so that meaningful comparisons can be made between studies. PMID- 21586771 TI - First-time revision using impacted morsellised allograft bone with a cemented Exeter stem: radiostereometric analysis of stem migration over nine years. AB - Previously, radiostereometric analysis following hip revision performed using impacted morsellised allograft bone and a cemented Exeter stem has shown continuous subsidence of the stem for up to five years. It is not known whether the subsidence continues thereafter. In our study, 17 of 25 consecutive osteo arthritic patients with aseptically loose stems who underwent first-time revision using impacted morsellised allograft bone and a cemented Exeter stem were followed by yearly radiostereometric examinations for nine years. The mean subsidence at six weeks was 1.1 mm (0.1 to 2.3), from six weeks to one year 1.3 mm (0 to 2.6), from one to five years 0.7 mm (0 to 2.0), and from five to nine years 0.7 mm (0.1 to 3.1). That from six weeks to nine years was 2.7 mm (0 to 6.4) (95% confidence interval 2.0 to 3.5). The Charnley pain score significantly improved after revision, and was maintained at nine years, but walking ability deteriorated slightly as follow-up extended. Of the eight patients who were not followed for nine years, two had early subsidence exceeding 11 mm. Our findings show that in osteo-arthritic patients who undergo revision for aseptic loosening of the stem using impacted morsellised allograft bone and a cemented Exeter stem, migration of the stem continues over nine years at a slower rate after the first year, but without clinical deterioration or radiological loosening. PMID- 21586772 TI - Successful management of recalcitrant infection related to total hip replacement using pedicled rectus femoris or vastus lateralis muscle flaps. AB - Deep prosthetic joint infection remains an uncommon but serious complication of total hip replacement. We reviewed 24 patients with recalcitrant hip wounds following infected total hip replacement treated with either pedicled rectus femoris or vastus lateralis muscle flaps between 1998 and 2009. The mean age of the patients was 67.4 years (42 to 86) with ten men and 14 women. There had been a mean of four (1 to 8) previous attempts to close the wound. A total of 20 rectus femoris and five vastus lateralis flaps were used, with one of each type of flap failing and requiring further reconstruction. All patients had positive microbiology. At a mean follow-up of 47 months (9 to 128), 22 patients had a healed wound and two had a persistent sinus. The prosthesis had been retained in five patients. In the remainder it had been removed, and subsequently re implanted in nine patients. Six patients continued to take antibiotics at final follow-up. This series demonstrates the effectiveness of pedicled muscle flaps in healing these infected wounds. The high number of previous debridements suggests that these flaps could have been used earlier. PMID- 21586773 TI - Effect of vibration on the shear strength of impacted bone graft in revision hip surgery. AB - We developed a method of applying vibration to the impaction bone grafting process and assessed its effect on the mechanical properties of the impacted graft. Washed morsellised bovine femoral heads were impacted into shear test rings. A range of frequencies of vibration was tested, as measured using an accelerometer housed in a vibration chamber. Each shear test was repeated at four different normal loads to generate stress-strain curves. The Mohr-Coulomb failure envelope from which shear strength and interlocking values are derived was plotted for each test. The experiments were repeated with the addition of blood in order to replicate a saturated environment. Graft impacted with the addition of vibration at all frequencies showed improved shear strength when compared with impaction without vibration, with 60 Hz giving the largest effect. Under saturated conditions the addition of vibration was detrimental to the shear strength of the aggregate. The civil-engineering principles of particulate settlement and interlocking also apply to impaction bone grafting. Although previous studies have shown that vibration may be beneficial in impaction bone grafting on the femoral side, our study suggests that the same is not true in acetabular revision. PMID- 21586774 TI - Bone reaction to a biomimetic third-generation hydroxyapatite coating and new surface treatment for the Symax hip stem. AB - Four uncemented Symax hip stems were extracted at three weeks and nine, 13 and 32 months, respectively, for reasons other than loosening. The reasons for implant removal were infection in two cases, recurrent dislocation in one and acetabular fracture in one. They were analysed to assess the effect and behaviour of an electrochemically deposited, completely resorbable biomimetic BONIT hydroxyapatite (HA) coating (proximal part) and a DOTIZE surface treatment (distal part) using qualitative histology, quantitative histomorphometry and scanning electron microscopy (SEM). Early and direct bone-implant bonding with signs of active remodelling of bone and the HA coating were demonstrated by histology and SEM. No loose BONIT-HA particles or delamination of the coating were observed, and there was no inflammation or fibrous interposition at the interface. Histomorphometry showed bone-implant contact varying between 26.5% at three weeks and 83.5% at 13 months at the HA-coated implant surface. The bone density in the area of investigation was between 24.6% at three weeks and 41.1% at 32 months. The DOTIZE surface treatment of the distal part of the stem completely prevented tissue and bone apposition in all cases, thereby optimising proximal stress transfer. The overall features of this implant, in terms of geometry and surface texture, suggest a mechanically stable design with a highly active biomimetic coating, resulting in rapid and extensive osseo-integration, exclusively in the metaphyseal part of the stem. Early remodelling of the HA coating does not seem to have a detrimental effect on short-term bone-implant coupling. There were no adverse effects identified from either the BONIT-HA coating or the DOTIZE surface treatment. PMID- 21586775 TI - Human hip impingement morphology: an evolutionary explanation. AB - We examined the morphology of mammalian hips asking whether evolution can explain the morphology of impingement in human hips. We describe two stereotypical mammalian hips, coxa recta and coxa rotunda. Coxa recta is characterised by a straight or aspherical section on the femoral head or head-neck junction. It is a sturdy hip seen mostly in runners and jumpers. Coxa rotunda has a round femoral head with ample head-neck offset, and is seen mostly in climbers and swimmers. Hominid evolution offers an explanation for the variants in hip morphology associated with impingement. The evolutionary conflict between upright gait and the birth of a large-brained fetus is expressed in the female pelvis and hip, and can explain pincer impingement in a coxa profunda. In the male hip, evolution can explain cam impingement in coxa recta as an adaptation for running. PMID- 21586776 TI - Assessment of radiolucent lines around the Oxford unicompartmental knee replacement: sensitivity and specificity for loosening. AB - The Oxford unicompartmental knee replacement gives good results in patients with symptomatic osteoarthritis of the medial compartment. Previous studies have suggested that the presence of radiolucent lines (RLLs) does not reflect a poor outcome in such patients. However, the reliability and validity of this assessment have not been determined. Our aim was to assess the intra- and interobserver reliability and the sensitivity and specificity of the assessment of RLLs around both tibial and femoral components using standard radiographs. Two reviewers assessed the radiographs of 45 patients who had loosening of the tibial or femoral component confirmed at revision surgery and compared them with those of a series of 45 asymptomatic patients matched for age and gender. The results suggested that, using standard radiographs, tibial RLLs were 63.6% sensitive and 94.4% specific and femoral RLLs 63.9% sensitive and 72.7% specific for loosening. Overall intra- and interobserver reliability was highly variable, but zonal analysis showed that lucency at the tip of the femoral peg was significantly associated with loosening of the femoral component. Fluoroscopically guided radiographs may improve the zonal reliability of the assessment of RLLs, but further independent and comparative studies are required. In the meantime, the innocence of the physiological RLLs detected by standard radiographs should be viewed with caution. PMID- 21586777 TI - Complications and outcome of tibial lengthening using the Ilizarov method with or without a supplementary intramedullary nail: a case-matched comparative study. AB - We compared the complications and outcome of tibial lengthening using the Ilizarov method with and without the use of a supplementary intramedullary nail. In a retrospective case-matched series assembled from 176 patients with tibial lengthening, we matched 52 patients (26 pairs, group A with nail and group B without) according to the following criteria in order of importance: 1) difference in amount of lengthening (+/- 2 cm); 2) percentage difference in lengthening (+/- 5%); 3) difference in patient's age (+/- seven years); 4) aetiology of the shortening, and 5) level of difficulty in obtaining the correction. The outcome was evaluated using the external fixator index, the healing index and an outcome score according to the criteria of Paley. It was found that some complications were specific to group A or B respectively, but others were common to both groups. The outcome was generally better in lengthenings with a nail, although there was a higher incidence of rectifiable equinus deformity in these patients. PMID- 21586778 TI - Intramedullary limb lengthening with the Intramedullary Skeletal Kinetic Distractor in the lower limb. AB - We report the results of intramedullary leg lengthening conducted between 2002 and 2009 using the Intramedullary Skeletal Kinetic Distractor in 69 unilateral lengthenings involving 58 femora and 11 tibiae. We identified difficulties that occurred during the treatment and assessed whether they were specifically due to the implant or independent of it. Paley's classification for evaluating problems, obstacles and complications with external fixators was adopted, and implant specific difficulties were continuously noted. There were seven failures requiring premature removal of the device, in four due to nail breakage and three for other reasons, and five unsuccessful outcomes after completion of the lengthening. In all, 116 difficulties were noted in 45 patients, with only 24 having problem-free courses. In addition to the difficulties arising from the use of external fixators, there were almost the same number again of implant-specific difficulties. Nevertheless, successful femoral lengthening was achieved in 52 of the 58 patients (90%). However, successful tibial lengthening was only achieved in five of 11 patients (45%). PMID- 21586779 TI - The effects of zoledronic acid and hyperbaric oxygen on posterior lumbar fusion in a rabbit model. AB - We studied the effects of hyperbaric oxygen (HBO) and zoledronic acid (ZA) on posterior lumbar fusion using a validated animal model. A total of 40 New Zealand white rabbits underwent posterior lumbar fusion at L5-6 with autogenous iliac bone grafting. They were divided randomly into four groups as follows: group 1, control; group 2, HBO (2.4 atm for two hours daily); group 3, local ZA (20 MUg of ZA mixed with bone graft); and group 4, combined HBO and local ZA. All the animals were killed six weeks after surgery and the fusion segments were subjected to radiological analysis, manual palpation, biomechanical testing and histological examination. Five rabbits died within two weeks of operation. Thus, 35 rabbits (eight in group 1 and nine in groups 2, 3 and 4) completed the study. The rates of fusion in groups 3 and 4 (p = 0.015) were higher than in group 1 (p < 0.001) in terms of radiological analysis and in group 4 was higher than in group 1 with regard to manual palpation (p = 0.015). We found a statistically significant difference in the biomechanical analysis between groups 1 and 4 (p = 0.024). Histological examination also showed a statistically significant difference between groups 1 and 4 (p = 0.036). Our results suggest that local ZA combined with HBO may improve the success rate in posterior lumbar spinal fusion. PMID- 21586780 TI - The influence of socioeconomic status on the incidence, outcome and mortality of fractures of the hip. AB - This is the first study to use the English Indices of Multiple Deprivation 2007, the Government's official measure of multiple deprivation, to analyse the effect of socioeconomic status on the incidence of fractures of the hip and their outcome and mortality. Our sample consisted of all patients admitted to hospital with a fracture of the hip (n = 7511) in Nottingham between 1999 and 2009. The incidence was 1.3 times higher (p = 0.038) in the most deprived populations than in the least deprived; the most deprived suffered a fracture, on average, 1.1 years earlier (82.0 years versus 83.1 years, p < 0.001). The mortality rate proved to be significantly higher in the most deprived population (log-rank test, p = 0.033), who also had a higher number of comorbidities (p = 0.001). This study has shown an increase in the incidence of fracture of the hip in the most deprived population, but no association between socioeconomic status and mortality at 30 days. Preventative programmes aimed at reducing the risk of hip fracture should be targeted towards the more deprived if they are to make a substantial impact. PMID- 21586781 TI - The outcome of fractures in very elderly patients. AB - We compared case-mix and outcome variables in 1310 patients who sustained an acute fracture at the age of 80 years or over. A group of 318 very elderly patients (>= 90 years) was compared with a group of 992 elderly patients (80 to 89 years), all of whom presented to a single trauma unit between July 2007 and June 2008. The very elderly group represented only 0.6% of the overall population, but accounted for 4.1% of all fractures and 9.3% of all orthopaedic trauma admissions. Patients in this group were more likely to require hospital admission (odds ratio 1.4), less likely to return to independent living (odds ratio 3.1), and to have a significantly longer hospital stay (ten days, p = 0.01). The 30- and 120-day unadjusted mortality was greater in the very elderly group. The 120-day mortality associated with non-hip fractures of the lower limb was equal to that of proximal femoral fractures, and was significantly increased with a delay to surgery > 48 hours for both age groups (p = 0.04). This suggests that the principle of early surgery and mobilisation of elderly patients with hip fractures should be extended to include all those in this vulnerable age group. PMID- 21586782 TI - Fixation of intracapsular fractures of the femoral neck in young patients: risk factors for failure. AB - The aim of this study was to determine the comorbid risk factors for failure in young patients who undergo fixation of a displaced fracture of the femoral neck. We identified from a prospective database all such patients <= 60 years of age treated with reduction and internal fixation. The main outcome measures were union, failure of fixation, nonunion and the development of avascular necrosis. There were 122 patients in the study. Union occurred in 83 patients (68%) at a mean follow-up of 58 months (18 to 155). Complications occurred in 39 patients (32%) at a mean of 11 months (0.5 to 39). The rate of nonunion was 7.4% (n = 9) and of avascular necrosis was 11.5% (n = 14). Failures were more common in patients over 40 years of age (p = 0.03). Univariate analysis identified that delay in time to fixation (> 24 hours), alcohol excess and pre-existing renal, liver or respiratory disease were all predictive of failure (all p < 0.05). Of these, alcohol excess, renal disease and respiratory disease were most predictive of failure on multivariate analysis. Younger patients with fractures of the femoral neck should be carefully evaluated for comorbidities that increase the risk of failure after reduction and fixation. In patients with a history of alcohol abuse, renal or respiratory disease, arthroplasty should be considered as an alternative treatment. PMID- 21586783 TI - Weight-bearing-induced displacement and migration over time of fracture fragments following split depression fractures of the lateral tibial plateau: a case series with radiostereometric analysis. AB - We investigated the stability of seven Schatzker type II fractures of the lateral tibial plateau treated by subchondral screws and a buttress plate followed by immediate partial weight-bearing. In order to assess the stability of the fracture, weight-bearing inducible displacements of the fracture fragments and their migration over a one-year period were measured by differentially loaded radiostereometric analysis and standard radiostereometric analysis, respectively. The mean inducible craniocaudal fracture fragment displacements measured -0.30 mm (-0.73 to 0.02) at two weeks and 0.00 mm (-0.12 to 0.15) at 52 weeks. All inducible displacements were elastic in nature under all loads at each examination during follow-up. At one year, the mean craniocaudal migration of the fracture fragments was -0.34 mm (-1.64 to 1.51). Using radiostereometric methods, this case series has shown that in the Schatzker type II fractures investigated, internal fixation with subchondral screws and a buttress plate provided adequate stability to allow immediate post-operative partial weight-bearing, without harmful consequences. PMID- 21586784 TI - Low-energy shock waves enhance the susceptibility of staphylococcal biofilms to antimicrobial agents in vitro. AB - Biofilm-associated infections in wounds or on implants are difficult to treat. Eradication of the bacteria is nearly always impossible, despite the use of specific antibiotics. The bactericidal effects of high-energy extracorporeal shock waves on Staphylococcus aureus have been reported, but the effect of low energy shock waves on staphylococci and staphylococcal biofilms has not been investigated. In this study, biofilms grown on stainless steel washers were examined by electron microscopy. We tested ten experimental groups with Staph. aureus-coated washers and eight groups with Staph. epidermidis. The biofilm cultured washers were exposed to low-energy shock waves at 0.16 mJ/mm(2) for 500 impulses. The washers were then treated with cefuroxime, rifampicin and fosfomycin, both alone and in combination. All tests were carried out in triplicate. Viable cells were counted to determine the bactericidal effect. The control groups of Staph. aureus and Staph. epidermidis revealed a cell count of 6 * 10(8) colony-forming units/ml. Complete eradication was achieved using the combination of antibiotic therapy (single antibiotic in Staph. aureus, a combination in Staph. epidermidis) and shock wave application (p < 0.01). We conclude that shock waves combined with antibiotics could be tested in an in vitro model of infection. PMID- 21586785 TI - Adult presentation of congenital muscular torticollis: a series of 12 patients treated with a bipolar release of sternocleidomastoid and Z-lengthening. AB - Adult presentation of neglected congenital muscular torticollis is rare. We report 12 patients with this condition who underwent a modified Ferkel's release comprising a bipolar release of sternocleidomastoid with Z-lengthening. They had a mean age of 24 years (17 to 31) and were followed up for a minimum of two years. Post-operatively a cervical collar was applied for three weeks with intermittent supervised active assisted exercises for six weeks. Outcome was assessed using a modified Lee score and a Cheng and Tang score. The mean pre operative rotational deficit was 8.25 degrees (0 degrees to 15 degrees ) and mean lateral flexion deficit was 20.42 degrees (15 degrees to 30 degrees ), which improved after treatment to a mean of 1.67 degrees (0 degrees to 5 degrees ) and 7.0 degrees (4 degrees to 14 degrees ) after treatment, respectively. According to the modified Lee scoring system, six patients had excellent results, two had good results and four had fair results, and using the Cheng and Tang score, eight patients had excellent results and four had good results. Surgical management of adult patients with neglected congenital muscular torticollis using a modified Ferkel's bipolar release gives excellent results. The range of neck movement and head tilt improved in all 12 patients and cosmesis improved in 11, despite the long-standing nature of the deformity. PMID- 21586787 TI - Distal tibial physeal arrest after meningococcal septicaemia: management and outcome in seven ankles. AB - Survivors of infantile meningococcal septicaemia often develop progressive skeletal deformity as a result of physeal damage at many sites, particularly in the lower limb. Distal tibial physeal arrest typically occurs with sparing of the distal fibular physis leading to a rapidly progressive varus deformity. There have been reports of isolated cases of this deformity, but to our knowledge there have been no papers which specifically describe the development of the deformity and the options for treatment. Surgery to correct this deformity is complex because of the patient's age, previous scarring and the multiplanar nature of the deformity. The surgical goal is to restore leg-length equality and the mechanical axis at the end of growth. Surgery should be planned and staged throughout growth in order to achieve the best functional results. We report our experience in six patients (seven ankles) with this deformity, who were managed by corrective osteotomy using a programmable circular fixator. PMID- 21586786 TI - Adolescent slipped capital femoral epiphysis treated by a modified Dunn osteotomy with surgical hip dislocation. AB - Between June 2001 and November 2008 a modified Dunn osteotomy with a surgical hip dislocation was performed in 30 hips in 28 patients with slipped capital femoral epiphysis. Complications and clinical and radiological outcomes after a mean follow-up of 3.8 years (1.0 to 8.5) were documented. Subjective outcome was assessed using the Harris hip score and the Western Ontario and McMaster Universities osteoarthritis index questionnaire. Anatomical or near-anatomical reduction was achieved in all cases. The epiphysis in one hip showed no perfusion intra-operatively and developed avascular necrosis. There was an excellent outcome in 28 hips. Failure of the implants with a need for revision surgery occurred in four hips. Anatomical reduction can be achieved by this technique, with a low risk of avascular necrosis. Cautious follow-up is necessary in order to avoid implant failure. PMID- 21586788 TI - Transperitoneal removal of an intrapelvic acetabular component after total hip replacement and salvage of a destroyed acetabulum. AB - Intrapelvic migration of the acetabular component of a total hip replacement, with severe acetabular destruction making reconstruction impossible, is very rare. We present a patient in whom the component was removed using a laparotomy and a transperitoneal approach with subsequent salvage using a saddle prosthesis and a total femoral replacement. PMID- 21586789 TI - Avascular necrosis of the scaphoid in children treated by splint immobilisation: a report of two cases. AB - Avascular necrosis of the scaphoid following a fracture in children is rare and there is no established treatment protocol in the literature. We present two boys with nonunion and avascular necrosis of the scaphoid treated by simple immobilisation. Both cases healed with painless wrists and full movements. Our cases confirm that an ununited scaphoid fracture in children may heal with conservative treatment, even when an MRI scan suggests avascular necrosis. Unlike in adults, operative treatment need only be considered in children when conservative treatment fails. PMID- 21586790 TI - Acute haematogenous upper cervical osteomyelitis in neonates: a report of two cases. AB - Haematogenous osteomyelitis in newborns and infants usually occurs in the long bones and is rare in the short or flat bones. We present two neonates with osteomyelitis of the upper cervical spine affecting the second to fourth cervical vertebrae and the first and second cervical vertebrae, respectively. Despite some delay in diagnosis, both responded successfully to conservative treatment with antibiotics, a cervical collar and needle puncture. The latest follow-up at six and seven years, respectively, showed no persistent neurological deficit and a normal diameter of the cervical spinal canal on MRI. PMID- 21586792 TI - A simple and relatively painless technique for hysterosalpingography, using a thin catheter and closing the cervix with the vaginal speculum: a pilot study. AB - OBJECTIVE: To evaluate the use of a thin catheter for hysterosalpingography (HSG) for reducing the pain experienced during the procedure. METHODS: Infertile women undergoing tubal patency tests were randomised into two groups. In the study group (n=66) a thin catheter originally designed for intrauterine insemination was used to inject the dye. Leakage of the dye was prevented using a vaginal speculum to press on the portiovaginalis of the cervix. The control group (n=23) underwent HSG using the standard metal cannula. Visual analogue scale (VAS) was used to evaluate the level of pain immediately after the procedure. The main outcome measures were the level of pain experienced by the patient during the procedure and the efficacy of the new technique. RESULTS: The mean (+/-SD) VAS was 11.2+/-3.1 in the study group and 54.7+/-10.1 in the metal cannula group (p<0.0001). During the dye injection, the VAS was 10.3+/-5.2 in the study group compared to 64.1+/-17.3 in the metal cannula group (p<0.0001). The new technique was successful in filling the uterine cavity with the dye and studying the fallopian tubes. CONCLUSIONS: Using a thin catheter for HSG and pressing on the cervix with the vaginal speculum to prevent leakage of the dye is a successful method to study the uterine cavity and fallopian tubes, and it significantly reduces the pain as compared to a metal cannula. PMID- 21586793 TI - Epidermal growth factor receptor status in early stage breast cancer is associated with cellular proliferation but not cross-talk. AB - The epidermal growth factor receptor (EGFR) is a therapeutic target in a number of settings in solid malignancies, but its role in breast cancer has remained unclear and controversial. In 810 primary breast cancers derived from patients suitable for cytotoxic chemotherapy, EGFR was prospectively measured and interactions with tumour and clinical correlates were tested to observe whether postulated cross-talk mechanisms are likely to modulate breast cancer metastasis and proliferation. A minority (79 tumours, 9.8%) were EGFR positive; in a multivariate analysis the likelihood of being EGFR positive was significantly increased for patients with grade 3 disease, compared with grade 1 (OR 15.6; 95% CI 2 to 122, p=0.0001), and for oestrogen receptor-negative status compared with positive (OR 24.1; 95% CI 12.7 to 46.00, p=0.0001). EGFR expression may play a role in breast cancer proliferation, but appears unlikely to modify tumour pathology via postulated mechanisms of oestrogen receptor/EGFR-mediated cross talk. PMID- 21586794 TI - Outcomes of sulfur hexafluoride (SF6) versus perfluoroethane (C2F6) gas tamponade for non-posturing macular-hole surgery. AB - AIM: To compare the outcomes of non-posturing macular-hole surgery using sulfur hexafluoride (SF(6)) gas versus perfluoroethane (C(2)F(6)) for idiopathic macular hole repair. Design Interventional, comparative cohort study. METHODS: 39 eyes of 38 patients undergoing macular-hole surgery with SF(6) were compared with another consecutive group of 39 eyes (39 patients) in whom C(2)F(6) was used. All patients were operated on by a single surgeon and underwent 23G transconjunctival phakovitrectomy with no prone posturing in the postoperative period. The best corrected Snellen's visual acuity (VA) was converted to the logarithm of minimal angle of resolution (logmar) visual acuity for analysis. Optical coherence tomography documentation of anatomical closure and complications of surgery were recorded. RESULTS: Primary hole closure was achieved in 89.75% in the C(2)F(6) group and 87.2% in the SF(6) group. Secondary closure after non-posturing redo surgery with heavy oil (Oxane-HD) was 100% in both groups. The mean preoperative VA in the C(2)F(6) group and SF(6) group was 0.81 logMAR and 0.78 respectively. 2 weeks after surgey, SF(6) was completely absorbed in all cases, and the mean VA improved to 0.5 logMAR; however, it remained 1.9 logMAR in the C(2)F(6) group. The final mean VA at 6 months was 0.44 (range 0-0.78) and 0.38 (range 0-1) in the C(2)F(6) and SF(6) group respectively. There were no instances of pupillary capture in the SF(6) group, whereas there were four in the C(2)F(6) group. CONCLUSION: Macular-hole surgery with SF(6) gas achieves similar results to C(2)F(6) and is absorbed faster, allowing quicker visual rehabilitation for the patient. PMID- 21586795 TI - Serum parathyroid hormone and risk of adverse outcomes in patients with stable coronary heart disease. AB - BACKGROUND AND OBJECTIVE: Recent longitudinal studies have suggested an association of high serum parathyroid hormone levels (PTH) with elevated cardiovascular risk in the general population. This study presents analyses of the prognostic value of baseline PTH for subsequent cardiovascular events and all cause mortality in a high-risk population with stable coronary heart disease. METHODS: Based on measurements of PTH levels in 1133 patients recruited at two German rehabilitation clinics and followed over 8 years, multivariate Cox regression analysis was performed to estimate the risk of secondary cardiovascular events (including myocardial infarction, stroke and death due to cardiovascular diseases) and all-cause-mortality according to PTH quartiles (Q1 Q4) and continuous PTH concentrations. RESULTS: During follow-up, 153 cardiovascular events and 124 deaths occurred. Age and sex-adjusted Cox regression analysis yielded statistically significant positive associations of PTH with both cardiovascular event incidence and all-cause mortality (HR (95% CI) per SD increase of PTH: 1.35 (1.21-1.51) and 1.25 (1.11-1.42), respectively). Associations remained essentially unchanged after additional adjustment for multiple cardiovascular risk factors. More detailed dose-response analyses showed strong risk elevation for above-normal levels of PTH (> 95th percentile), with essentially no association at lower levels. CONCLUSION: The results of this first detailed study in a cohort of patients with stable coronary heart disease suggest an independent predictive value of above-normal PTH for the prognosis in patients with stable coronary heart disease. PMID- 21586796 TI - A novel conserved targeting motif found in ABCA transporters mediates trafficking to early post-Golgi compartments. AB - The ATP binding cassette, class A (ABCA) proteins are homologous polytopic transmembrane transporters that function as lipid pumps at distinct subcellular sites in a variety of cells. Located within the N terminus of these transporters, there exists a highly conserved xLxxKN motif of unknown function. To define its role, human ABCA3 was employed as a primary model representing ABCA transporters, while mouse ABCA1 was utilized to support major findings. Transfection studies showed colocalization of both transporters with surfactant protein C (SP-C), a marker peptide for successful protein targeting to lysosomal-like organelles. In contrast, alanine mutation of xLxxKN resulted in endoplasmic reticulum retention. As proof of principle, swapping xLxxKN for the known lysosomal targeting motif of SP-C resulted in post-Golgi targeting of the SP-C chimera. However, these products failed to reach their terminal processing compartments, suggesting that the xLxxKN motif only serves as a Golgi exit signal. We propose a model whereby an N-terminal signal sequence, xLxxKN, directs ABCA transporters to a post-Golgi vesicular sorting station where additional signals may be required for selective delivery of individual transporters to final subcellular destinations. PMID- 21586798 TI - [General practice in Iceland, the present situation]. PMID- 21586799 TI - [Treatment of type 1 diabetes in adults - problem solved?]. PMID- 21586797 TI - Kruppel-like factor 4 (KLF4) activates the transcription of the gene for the platelet isoform of phosphofructokinase (PFKP) in breast cancer. AB - Kruppel-like factor 4 (KLF4) is a transcription factor that plays an important role in cell differentiation, proliferation, and survival, especially in the context of cancers. This study revealed that KLF4 activates glycolytic metabolism in breast cancer cells by up-regulating the platelet isoform of phosphofructokinase (PFKP). KLF4 activated the transcription of the PFKP gene by directly binding to the PFKP promoter. Whereas glucose uptake and lactate production were inhibited by the knockdown of KLF4, they were activated by the overexpression of KLF4. Unlike PFKP, the expressions of the other isoforms of phosphofructokinase and glycolytic genes were unaffected by KLF4. The human breast cancer tissues showed a close correlation between KLF4 and PFKP expression. This study also showed that PFKP plays a critical role in cell proliferation in breast cancer cells. In conclusion, it is suggested that KLF4 plays a role in maintenance of high glycolytic metabolism by transcriptional activation of the PFKP gene in breast cancer cells. PMID- 21586800 TI - [Treatment of type 1 diabetes with continuous subcutaneous insulin infusion (CSII) in adults in Iceland]. AB - OBJECTIVE: The goal of the study was to evaluate the effect and safety of CSII treatment in individuals 18 years and older with type 1 diabetes mellitus in Iceland. METHODS: The research is retrospective. We gathered information from patient data of 40 individuals, age 19-57 years who had been treated with CSII in Iceland for 6 months or longer during the period January 2004 until December 2007 . We looked at the effect of the treatment on treatment complications, HbA1c, body mass index (BMI) and insulin requirements compared with multiple daily injections (MDI). RESULTS: HbA1c was lower on CSII but the difference was not significant. Mean initial HbA1c was 7.23 (95% confidence limits 6.29-8.18) for men and 6.93 (95% confidence limits 6.57-7.28) for women. The change in BMI was not significant. Mean initial BMI for men was 25.5 (95% confidence limits 23.6 27.3) and 25.9 (95% confidence limits 23.8-27.9) for women. Insulin requirements were significantly lower at the end of the study for both men and women. Insulin requirements decreased by mean 11.3 units for men (P=0.04) and 12.8 units for women (P=0.0009). There where six episodes of ketoacidosis, four of skin infections and two hypoglycemias that needed doctors attention while using CSII treatment. CONCLUSION: The experience of CSII treatment in Iceland is good. These results confirm that this treatment is safe and as effective as other treatment forms. Even though the difference in HbA1c was not significant the result showed that those who had the highest HbA1c at the beginning of CSII treatment did get the best result with the pump and the insulin dosage was lower with CSII than with MDI. PMID- 21586801 TI - [Elective splenectomy at landspitali university hospital 1993-2004 efficacy and long-term outcome]. AB - OBJECTIVE: To evaluate the long-term outcome of elective splenectomy, with emphasis on the incidence of complications, vaccine immunization and patient's knowledge about asplenia. MATERIAL AND METHODS: Medical reports of all patients, who underwent elective splenectomy during the time period of 1993-2004, were reviewed. Questionnaire was sent to 96% (44/46) patients alive. RESULTS: The average age was 50 (8-83) years. Thirty-five patients were male and 32 were female. Eighty percent responded to the questionnaire. Most of the patients (31) had idiopathic thrombocytopenic purpura (ITP). Complete response was obtained in 60% (18/30) and partial response in 23% (7/30). Five patients had spherocytosis and all of them had complete response. None of the three patients with autoimmune hemolytic anemia had any response to the splenectomy. Patients were vaccinated against pneumococci in 92% of the cases. In 44% of the cases revaccination was done. Only 41% of those who answered experienced that they had got a good education about the consequences of asplenia. Sixteen percent of the patients (10/64) had major postoperative complications. One patient with metastatic cancer and thrombocytopenia died within 30 days of surgery. Five patients had long-term complications. Two had pneumococcal sepsis, one of them was unvaccinated and the other had not been revaccinated. CONCLUSION: Splenectomy has a good long-term outcome for spherocytosis and ITP patients. The incidence of complications is high. It is possible that better guidelines and better patient's education can lower the complication rate and improve the outcome. PMID- 21586802 TI - [Sublobar resection for non-small cell lung cancer in Iceland]. AB - INTRODUCTION: A sublobar resection is performed on patients with non-small cell lung cancer (NSCLC) who are not candidates for a lobectomy due to reduced pulmonary function or comorbid disease. The aim of this study was to investigate the outcomes of these operations in Iceland. MATERIAL AND METHODS: A retrospective study of all patients with NSCLC who underwent wedge resection or segmentectomy with curative intent during 1994-2008. Data on indication, pathological TNM-stage, complications and overall survival was analyzed. All histological samples were re-evaluated. RESULTS: Forty four patients underwent 42 wedge and 5 segmental resections (age 69.1 yrs, 55.3% female), with 38.3% of cases detected incidentally. The majority of patients (55.3%) had a history of coronary artery disease and 40.4% had chronic obstructive pulmonary disease. Mean operative time was 83 minutes (range 30-131), mean intraoperative bleeding was 260 ml (range 100-650) and median hospital stay was 9 days (range 4-24). Pneumonia (14.9%) and prolonged air leakage (12.8%) were the most common complications. Two patients had major complications and 36.2% stayed in the intensive care unit overnight. No deaths occurred within 30 days of surgery. Adenocarcinoma was the most common histological type (66.7%). Most cases were stage IA/IB (78.7%), 17.0% were stage IIA/IIB and 4.3% were stage IIIA. One and 5 year survival was 85.1% and 40.9% respectively. CONCLUSION: In Iceland, both survival and complication rate after sublobar resection for NSCLC are comparable to results published for lobectomies, even though a higher percentage of patients have underlying cardiopulmonary disease. PMID- 21586803 TI - [Dissemination of medical knowledge to the public in Iceland by a country doctor 1782-1834]. AB - Jon Petursson (1733-1801) was an apprentice af the first Chief Medical Officer of Iceland. In 1765 Petursson enrolled in the Medical Faculty at the University of Copenhagen. In 1769 with the Faculties approval he published a monograph on the so called Icelandic Scurvy. In 1770-71 Petursson served as ship's surgeon in the Royal Danish Navy on an expedition to the Mediterranean. In 1772-1775 he served as an assistant to the Chief Medical Officer and the newly appointed apothecary, who shared premises at Nes, Reykjavik. In 1775 he was appointed surgeon (chirurgeon) to the Northern District. Petursson wrote two medical book while serving his district, both being prepared now for republication. A. The Laekningabok fyrir almuga (Leechbook for common people) published posthumously 1834, edited by Sveinn Palsson surgeon. It was undoubtedly inspired by the Swiss physician Tissot and his book Avis au peuple sur sa sante ou traite des maladies plus frequentes 1761. B. A treatise on rheumatism or dirorder of the joints (Stutt agrip um iktsyki edur lidaveiki, 1782). In Scand J Rheumatol 1996: 25; 134 7 the authors point out that Peturssons description of what he calls arthritis vaga encompasses these essential features: It is common, chronic, destructive, inflammatory polyarthritis, sometimes with systemic manifestations. It affects peope of all ages and has a female preponderance. They state that only rheumatoid arthritis fulfills these specifications. They conclude that medical history should give Petursson credit for the first definite description of rheumatoid arthritis. PMID- 21586805 TI - And now, Fukushima. PMID- 21586806 TI - Surface effects on the mechanical properties of nanoporous materials. AB - Using the theory of surface elasticity, we investigate the mechanical properties of nanoporous materials. The classical theory of porous materials is modified to account for surface effects, which become increasingly important as the characteristic sizes of microstructures shrink to nanometers. First, a refined Timoshenko beam model is presented to predict the effective elastic modulus of nanoporous materials. Then the surface effects on the elastic microstructural buckling behavior of nanoporous materials are examined. In particular, nanoporous gold is taken as an example to illustrate the application of the proposed model. The results reveal that both the elastic modulus and the critical buckling behavior of nanoporous materials exhibit a distinct dependence on the characteristic sizes of microstructures, e.g. the average ligament width. PMID- 21586807 TI - Growth of horizontally aligned dense carbon nanotubes from trench sidewalls. AB - Horizontally aligned, dense carbon nanotubes (HADCNTs) in the form of CNT cantilevers/bridges were grown from selected trench sidewalls in silicon substrate by chemical vapor deposition (CVD). The as-grown CNT cantilevers/bridges are packed with multiwalled carbon nanotubes (MWCNTs) with a linear density of about 10 CNTs um(-1). The excellent horizontal alignment of these CNTs is mainly ascribed to the van der Waals interactions within the dense CNT bundles. What is more, the Raman intensity ratio I(G)/I(D) shows a gradual increase from the CNT roots to tips, indicating a defect gradient along CNTs generated during their growth. These results will inspire further efforts to explore the fundamentals and applications of HADCNTs. PMID- 21586808 TI - Histological assessments for toxicity and functionalization-dependent biodistribution of carbon nanohorns. AB - Single-walled carbon nanohorns (SWNHs) intravenously administered to mice did not show severe toxicity during a 26-week test period, which was confirmed by normal gross appearance, normal weight gain and the lack of abnormality in the tissues on histological observations of the mice. SWNH biodistribution was influenced by chemical functionalization. Accumulation of SWNH in the lungs reduced as SWNH hydrophilicity increased; however, the most hydrophilic SWNHs modified with bovine serum albumin (BSA) were most likely to be trapped in the lungs, suggesting that the BSA moiety enhanced macrophage phagocytosis in the lungs. Clearance of some of the hydrophobic SWNHs from the lungs was observed, the mechanism of which is briefly discussed. PMID- 21586809 TI - Large-scale growth of Cu2ZnSnSe4 and Cu2ZnSnSe4/Cu2ZnSnS4 core/shell nanowires. AB - We present a fast and simple protocol for large-scale preparation of quaternary Cu(2)ZnSnSe(4) (CZTSe), as well as CZTSe/Cu(2)ZnSnS(4) (CZTS) core/shell nanowires using CuSe nanowire bundles as self-sacrificial templates. CuSe nanowire bundles were synthesized by reacting Cu(2 - x)Se nanowire bundles with sodium citrate solution. CZTSe nanowires were prepared by reacting CuSe nanowire bundles with Zn(CH(3)COO)(2) and SnCl(2) in triethylene glycol. X-ray diffraction (XRD) and selected area electron diffraction studies show that stannite CZTSe is formed. The formed CZTSe nanowire bundles have diameters of 200-400 nm and lengths of up to hundreds of micrometers. CZTSe/CZTS nanocable bundles with similar morphologies were grown by the addition of some elemental sulfur to the reaction system for growth of CZTSe bundles. The stannite CZTSe/kesterite CZTS core/shell structure of the grown nanocables was confirmed by XRD and high resolution transmission electron microscope investigation. The influence of S/Se molar ratio in the reaction system on the crystallographic structures and optical properties of CZTSe/CZTS nanocables was studied. The obtained CZTSe/CZTS core/shell nanocable bundles show broad and enhanced optical absorption over the visible and near-infrared region, which is promising for use in photovoltaic applications. PMID- 21586810 TI - Scanning transmission x-ray microscopy of polymer nanoparticles: probing morphology on sub-10 nm length scales. AB - Water-processable nanoparticle dispersions of semiconducting polymers offer an attractive approach to the fabrication of organic electronic devices since they offer: (1) control of nanoscale morphology and (2) environmentally friendly fabrication. Although the nature of phase segregation in these polymer nanoparticles is critical to device performance, to date there have been no techniques available to directly determine their intra-particle structure, which consequently has been poorly understood. Here, we present scanning transmission x ray microscopy (STXM) compositional maps for nanoparticles fabricated from poly(9,9-dioctyl-fluorene-2,7-diyl-co-bis-N, N'-(4-butylphenyl)-bis-N, N'-phenyl 1,4-phenylenedi-amine) (PFB) and poly(9,9-dioctylfluorene-2,7-diyl-co benzothiadiazole) (F8BT) 1:1 blend mixtures. The images show distinct phase segregation within the nanoparticles. The compositional data reveals that, within these nanoparticles, PFB and F8BT segregate into a core-shell morphology, with an F8BT-rich core and a PFB-rich shell. Structural modelling demonstrates that the STXM technique is capable of quantifying morphological features on a sub-10 nm length scale; below the spot size of the incident focused x-ray beam. These results have important implications for the development of water-based 'solar paints' fabricated from microemulsions of semiconducting polymers. PMID- 21586811 TI - Focused electron beam induced etching of titanium with XeF2. AB - Titanium is a relevant technological material due to its extraordinary mechanical and biocompatible properties, its nanopatterning being an increasingly important requirement in many applications. We report the successful nanopatterning of titanium by means of focused electron beam induced etching using XeF(2) as a precursor gas. Etch rates up to 1.25 * 10(-3) um(3) s(-1) and minimum pattern sizes of 80 nm were obtained. Different etching parameters such as beam current, beam energy, dwell time and pixel spacing are systematically investigated, the etching process being optimized by decreasing both the beam current and the beam energy. The etching mechanism is investigated by transmission electron microscopy. Potential applications in nanotechnology are discussed. PMID- 21586812 TI - Imaging conduction pathways in carbon nanotube network transistors by voltage contrast scanning electron microscopy. AB - The performance of field-effect transistors based on single-walled carbon nanotube (SWCNT) networks depends on the electrical percolation of semiconducting and metallic nanotube pathways within the network. We present voltage-contrast scanning electron microscopy (VC-SEM) as a new tool for imaging percolation in a SWCNT network with nano-scale resolution. Under external bias, the secondary electron contrast of SWCNTs depends on their conductivity, and therefore it is possible to image the preferred conduction pathways within a network by following the contrast evolution under bias in a scanning electron microscope. The experimental VC-SEM results are correlated to percolation models of SWCNT-bundle networks. PMID- 21586813 TI - Dramatically enhanced ultraviolet photosensing mechanism in a n-ZnO nanowires/i MgO/n-Si structure with highly dense nanowires and ultrathin MgO layers. AB - This study reports that the visible-blind ultraviolet (UV) photodetecting properties of ZnO nanowire based photodetectors were remarkably improved by introducing ultrathin insulating MgO layers between the ZnO nanowires and Si substrates. All layers were grown without pause by metal organic chemical vapor deposition and the density and vertical arrangement of the ZnO nanowires were strongly dependent on the thickness of the MgO layers. The sample in which an MgO layer with a thickness of 8 nm was inserted had high density nanowires with a vertical alignment and showed dramatically improved UV photosensing performance (photo-to-dark current ratio = 1344.5 and recovery time = 350 ms). The photoresponse spectrum revealed good visible-blind UV detectivity with a sharp cut off at 378 nm and a high UV/visible rejection ratio. A detailed discussion regarding the developed UV photosensing mechanism from the introduction of the i MgO layers and highly dense nanowires in the n-ZnO nanowires/i-MgO/n-Si substrates structure is presented in this work. PMID- 21586814 TI - A one-step approach for the fabrication of polymer and metal nanowires. AB - The fabrication of one-dimensional (1D) polymer and metal nanowires were obtained in a one-step mechanical approach. This approach is based on a controlled chattering process at the cutting edge of an oscillating diamond knife to conduct wavy cutting. Consecutive shallow wavy cuttings at different phases yield uniform ultra-long nanowire products with controlled lateral dimensions in the range of sub-100 nanometers to micrometers. The morphologies and lateral dimensions of the nanowires can be tuned through phase alignment, cutting depth and cutting speed, as demonstrated in this paper through examples of its application to polymethyl methacrylate, aluminum and copper. This facile one-step 'cutting-edge' method is robust, clean, involves no chemicals, and can be readily scaled up with precision machining for long-range and large-area fabrications. PMID- 21586815 TI - In situ observation of size-scale effects on the mechanical properties of ZnO nanowires. AB - In this investigation, the size-scale in mechanical properties of individual [0001] ZnO nanowires and the correlation with atomic-scale arrangements were explored via in situ high-resolution transmission electron microscopy (TEM) equipped with atomic force microscopy (AFM) and nanoindentation (NI) systems. The Young's modulus was determined to be size-scale-dependent for nanowires with diameter, d, in the range of 40 nm <= d <= 110 nm, and reached the maximum of ~ 249 GPa for d = 40 nm. However, this phenomenon was not observed for nanowires in the range of 200 nm <= d <= 400 nm, where an average constant Young's modulus of ~ 147.3 GPa was detected, close to the modulus value of bulk ZnO. A size-scale dependence in the failure of nanowires was also observed. The thick ZnO nanowires (d >= 200 nm) were brittle, while the thin nanowires (d <= 110 nm) were highly flexible. The diameter effect and enhanced Young's modulus observed in thin ZnO nanowires are due to the combined effects of surface relaxation and long-range interactions present in ionic crystals, which leads to much stiffer surfaces than bulk wires. The brittle failure in thicker ZnO wires was initiated from the outermost layer, where the maximum tensile stress operates and propagates along the (0001) planes. After a number of loading and unloading cycles, the highly compressed region of the thinner nanowires was transformed from a crystalline to an amorphous phase, and the region near the neutral zone was converted into a mixture of disordered atomic planes and bent lattice fringes as revealed by high resolution images. PMID- 21586816 TI - Dispersive hole transport in polymer:carbon nanotube composites. AB - The hole transport properties of poly(2-methoxy, 5-(2'-ethyl-hexoxy)-p-phenylene vinylene) (MEH-PPV) blended with acid oxidized multiwall carbon nanotubes (COOH MWCNTs) were investigated in a diode configuration using the time-of-flight (TOF) photocurrent method. While the room temperature hole mobility in pure MEH-PPV films was non-dispersive with positive field dependent mobility, MEH-PPV:COOH MWCNT blended devices exhibited dispersive transport and negative field dependent mobility. This indicates that the hole mobility in this composite is influenced by positional disorder caused by the presence of COOH-MWCNTs in the MEH-PPV matrix. These results strongly suggest that the distribution of COOH-MWCNTs optimising in the organic matrix is important for charge transport in the high mobility nanotube component to be activated, when used in hybrid material systems. PMID- 21586817 TI - A novel nanostructured iron oxide-gold bioelectrode for hydrogen peroxide sensing. AB - Fe(3)O(4) nanoparticles covalently linked to a gold electrode have been used for immobilizing catalase (CAT) enzyme to sense the presence of various concentrations of H(2)O(2). These nanoparticles ranging from 20 to 30 nm were synthesized by thermal co-precipitation of ferric and ferrous chlorides. SEM and XRD have been used for morphological and structural characterization of Fe(3)O(4) nanoparticles. CAT enzyme was linked covalently to the surface of iron oxide using carbodiimide in phosphate buffer (pH 7.4) at 4 degrees C. The enzyme-iron oxide link was confirmed by FT-IR spectroscopy. Sensing studies carried out using cyclic voltammetry showed a linear response of the CAT/nano Fe(3)O(4)/Au bioelectrode towards H(2)O(2) between 1.5 and 13.5 uM with a very sharp response time of 2 s. PMID- 21586818 TI - Accelerated reliability testing of highly aligned single-walled carbon nanotube networks subjected to DC electrical stressing. AB - We investigate the electrical reliability of nanoscale lines of highly aligned, networked, metallic/semiconducting single-walled carbon nanotubes (SWCNTs) fabricated through a template-based fluidic assembly process. We find that these SWCNT networks can withstand DC current densities larger than 10 MA cm(-2) for several hours and, in some cases, several days. We develop test methods that show that the degradation rate, failure predictability and total device lifetime can be linked to the initial resistance. Scanning electron and transmission electron microscopy suggest that fabrication variability plays a critical role in the rate of degradation, and we offer an empirical method of quickly determining the long term performance of a network. We find that well-fabricated lines subject to constant electrical stress show a linear accumulation of damage reminiscent of electromigration in metallic interconnects, and we explore the underlying physical mechanisms that could cause such behavior. PMID- 21586819 TI - A novel combination of TRAIL and doxorubicin enhances antitumor effect based on passive tumor-targeting of liposomes. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel anticancer agent for non-small cell lung cancer (NSCLC). However, approximately half of NSCLC cell lines are highly resistant to TRAIL. Doxorubicin (DOX) can sensitize NSCLC cells to TRAIL-induced apoptosis, indicating the possibility of combination therapy. Unfortunately, the therapeutic effect of a DOX and TRAIL combination is limited by multiple factors including the short serum half-life of TRAIL, poor compliance and application difficulty in the clinic, chronic DOX induced cardiac toxicity, and the multidrug resistance (MDR) property of NSCLC cells. To solve such problems, we developed the combination of TRAIL liposomes (TRAIL-LP) and DOX liposomes (DOX-LP). An in vitro cytotoxicity study indicated that DOX-LP sensitized the NSCLC cell line A-549 to TRAIL-LP-induced apoptosis. Furthermore, this combination therapy of TRAIL-LP and DOX-LP displayed a stronger antitumor effect on NSCLC in xenografted mice when compared with free drugs or liposomal drugs alone. Therefore, the TRAIL-LP and DOX-LP combination therapy has excellent potential to become a new therapeutic approach for patients with advanced NSCLC. PMID- 21586820 TI - Nanostructured gold microelectrodes for extracellular recording from electrogenic cells. AB - We present a new biocompatible nanostructured microelectrode array for extracellular signal recording from electrogenic cells. Microfabrication techniques were combined with a template-assisted approach using nanoporous aluminum oxide to develop gold nanopillar electrodes. The nanopillars were approximately 300-400 nm high and had a diameter of 60 nm. Thus, they yielded a higher surface area of the electrodes resulting in a decreased impedance compared to planar electrodes. The interaction between the large-scale gold nanopillar arrays and cardiac muscle cells (HL-1) was investigated via focused ion beam milling. In the resulting cross-sections we observed a tight coupling between the HL-1 cells and the gold nanostructures. However, the cell membranes did not bend into the cleft between adjacent nanopillars due to the high pillar density. We performed extracellular potential recordings from HL-1 cells with the nanostructured microelectrode arrays. The maximal amplitudes recorded with the nanopillar electrodes were up to 100% higher than those recorded with planar gold electrodes. Increasing the aspect ratio of the gold nanopillars and changing the geometrical layout can further enhance the signal quality in the future. PMID- 21586822 TI - Roles of exogenous and endogenous FGF-2 in animal models of depression. AB - PURPOSE: Several members of the fibroblast growth factor (FGF) family have been shown to be dysregulated in individuals with major depression, and treatment with antidepressants has been reported to increase FGF-2 mRNA levels in the forebrain. METHODS: We have used the tail suspension test (TST), and olfactory bulbectomy (OBX), and FGF-2 deficient mice to investigate putative roles of FGF-2 as an antidepressant and mediator of antidepressive drug actions. RESULTS: FGF-2 applied intraventricularly generated antidepressant-like effects in the TST. FGF 2, similar to the antidepressant amitriptyline, attenuated neuron demise in the piriform cortex and posterolateral cortical nucleus of the amygdala following OBX. Moreover, OBX induced reduction in hippocampal neurogenesis could be ameliorated by subsequent treatment with either amitriptyline or FGF-2. Furthermore, FGF-2 was effective in reversing depressive-like behavior induced by OBX, monitored in the locomotor activity and the passive avoidance test. In bulbectomized FGF-2 deficient mice, treatment with amitriptyline protected neurons, but failed to reverse behavioral alterations. CONCLUSIONS: Together, these results suggest that FGF-2 constitutes both a potential target for antidepressive treatments and an important growth factor in the cytokine network underlying the actions of antidepressive drugs. The results further suggest a requirement of endogenous FGF-2 for mediating behavioral, but not neuroprotective actions of amitriptyline. PMID- 21586823 TI - Transcranial alternating current stimulation in the low kHz range increases motor cortex excitability. AB - PURPOSE: External transcranial electric and magnetic stimulation techniques allow for the fast induction of sustained and measurable changes in cortical excitability. Here we aim to develop a paradigm using transcranial alternating current (tACS) in a frequency range higher than 1 kHz, which potentially interferes with membrane excitation, to shape neuroplastic processes in the human primary motor cortex (M1). METHODS: Transcranial alternating current stimulation was applied at 1, 2 and 5 kHz over the left primary motor cortex with a reference electrode over the contralateral orbit in 11 healthy volunteers for a duration of 10 min at an intensity of 1 mA. Monophasic single- pulse transcranial magnetic stimulation (TMS) was used to measure changes in corticospinal excitability, both during and after tACS in the low kHz range, in the right hand muscle. As a control inactive sham stimulation was performed. RESULTS: All frequencies of tACS increased the amplitudes of motor- evoked potentials (MEPs) up to 30-60 min post stimulation, compared to the baseline. Two and 5 kHz stimulations were more efficacious in inducing sustained changes in cortical excitability than 1 kHz stimulation, compared to sham stimulation. CONCLUSIONS: Since tACS in the low kHz range appears too fast to interfere with network oscillations, this technique opens a new possibility to directly interfere with cortical excitability, probably via neuronal membrane activation. It may also potentially replace more conventional repetitive transcranial magnetic stimulation (rTMS) techniques for some applications in a clinical setting. PMID- 21586821 TI - Improved picture naming in aphasia patients treated with cathodal tDCS to inhibit the right Broca's homologue area. AB - PURPOSE: Previous reports have suggested that noninvasive cortical stimulation could influence speech production in patients with chronic stroke. Here, we evaluated the hypothesis that cathodal transcranial DC stimulation (ctDCS), a technique that decreases excitability of stimulated cortical sites, applied over a healthy right Broca's homologue area could improve picture naming in patients with post-stroke aphasia. METHODS: Ten right-handed patients with post-stroke aphasia were enrolled in this double blind, counterbalanced sham-controlled, crossover study. Each patient received an intervention of ctDCS (2 mA for 20 min) and of sham tDCS (2 mA for 1 min) daily for 5 consecutive days in a randomized crossover manner with a minimum interval of one week between interventions, over a healthy right Broca's homologue area using a left supraorbital anode and simultaneous daily sessions of conventional word-retrieval training. The primary endpoint measure of this study was a standardized, validated Korean version of the Boston Naming Test, which is a measure of picture naming skills. RESULTS: ctDCS was not found to have any adverse effects. Furthermore, significantly improved picture naming (p = 0.02) was observed at 1 hour following the last (5th) ctDCS treatment session, but no changes were observed after sham tDCS. CONCLUSION: These results demonstrate that cathodal tDCS over the right healthy Broca's homologue area with a left supraorbital anodal location can improve picture naming task performance in post-stroke aphasia. PMID- 21586824 TI - Treatment of an autoimmune encephalomyelitis mouse model with nonmyeloablative conditioning and syngeneic bone marrow transplantation. AB - PURPOSE: Hematopoietic stem cell transplantation (HSCT) has been proposed as a novel therapy for multiple sclerosis (MS). CD4 + CD25 + regulatory T cells (Tregs) expressing Foxp3 play an important role in the maintenance of immune tolerance to self. Our study was conducted to confirm the efficiency of nonmyeloablative conditioning and syngeneic bone marrow transplantation (BMT) on experimental autoimmune encephalomyelitis (EAE) mice and to determine whether Tregs plays a role in the underlying mechanism. METHODS: EAE were induced in C57BL/6 mice and were randomly divided into 4 groups: the Conditioning group received the conditioning regimen, the Normal-EAE BMT group received conditioning and bone marrow (BM) grafts from normal mice, the EAE-EAE BMT group received conditioning and BM grafts from EAE mice and the EAE control group received no further therapy. The cumulative clinical score was used to assess the efficacy of the different treatments, and the proportion of Tregs in the spleen was measured by flow cytometry on day 40, 80 and 120 after BMT. Foxp3 mRNA expression was assessed by real-time PCR, and the expression of Foxp3 protein was tested by western blot on day 120 after BMT. RESULTS: Conditioning and conditioning with BMT led to a significant clinical improvement on day 80 after BMT compared with EAE without further treatment. On day 120 after BMT, the clinical score of the Conditioning group showed no significant difference from that of the EAE control group, whereas BMT led to a further amelioration of the disease score. On day 80 and day 120 after BMT, the proportions of Tregs of the two BMT groups were significantly higher than that in EAE control group, whereas no statistically significant difference was found between the Conditioning group and the EAE control group. On day 120 after BMT, the Foxp3 mRNA level and Foxp3 protein expression was higher in the two BMT groups than in EAE control group or Conditioning group. CONCLUSIONS: Nonmyeloablative conditioning could temporarily reverse already established EAE, but it was not sufficient for the induction of long-term EAE remission. Transplantation by BM cells from healthy or diseased donors was necessary and responsible for complete and long-time remission of EAE, and these beneficial effects may be the result of the induction of Tregs and the Treg-related factor Foxp3. PMID- 21586825 TI - Early passage bone marrow stromal cells express genes involved in nervous system development supporting their relevance for neural repair. AB - PURPOSE: The assessment of the capacity of bone marrow stromal cells (BMSC) to repair the nervous system using gene expression profiling. The evaluation of effects of long-term culturing on the gene expression profile of BMSC. METHODS: Fourty four k whole genome rat microarrays were used to study gene expression of cultured BMSC at passage (P)3 and to compare expression profiles between P3 and P14 BMSC. Quantitative PCR was employed to validate the microarray results. RESULTS: P3 BMSC expressed genes involved in neural developmental events such as glial differentiation, neuron proliferation, and neurite formation. They also express genes encoding for growth factors and for proteins involved in growth factor signaling. A total of 6687 genes were co-expressed in P3 and P14 BMSC. Of these co-expressed genes, 3% (202 genes) was differentially expressed with 159 genes higher in P3 BMSC and 43 genes higher in P14 BMSC. The gene expression patterns were independently validated using quantitative PCR. Functional data mining by Gene Ontology (GO)-analysis revealed that 85/159 and 22/43 genes were annotated in the GO database. In P3 BMSC, 53 GO-classes were overrepresented with several involved in organ development, cell proliferation, and neural repair. In P14 BMSC, three GO-classes were overrepresented with one involved in organ development. CONCLUSIONS: Our gene profiling results suggested a decreased plasticity and repair aptitude of long-term cultured BMSC. Our data indicated the use of early passage BMSC for neural repair approaches. PMID- 21586826 TI - Cortical reorganization in Bell's palsy. AB - PURPOSE: Bell's palsy, a unilateral, idiopathic facial nerve palsy, is a common disorder that is generally followed by a good recovery of function. The aim of this study was to investigate the impact of such a transiently decreased motor control (without deafferentation) on the functional reorganization of the brain. METHODS: To address this issue, functional MRI was applied to 10 patients in the acute state of Bell's palsy and after their complete clinical recovery. The functional paradigm consisted of unilateral facial movements with the affected as well as the non-affected side. RESULTS: We found an overactivity of several brain areas contralateral to the palsy that are related to error detection and sensory motor integration in the acute stage and motor integration and control in the follow-up. Functional connectivity was disrupted in the affected cortical motor system during the acute stage of Bell's palsy compared to the follow-up. This altered connectivity was found mostly between motor areas in the hemisphere contralateral to the paretic side, whereas the interhemispherical connectivity remained largely stable. CONCLUSION: Our results indicate that a transient peripheral deefferentation causes functional reorganization in the brain that partly persists even after an apparently complete clinical recovery. PMID- 21586827 TI - Determination of the local structure of a cage with an oxygen ion in Ca12Al14O33. AB - The crystal structure of mayenite (12CaO.7Al(2)O(3)) has been investigated by single-crystal synchrotron diffraction with high resolution and accuracy, using a four-circle diffractometer equipped with an avalanche photodiode detector (APD) detector installed at PF14A in Tsukuba, Japan. Analysis revealed random displacements of ions by the electrostatic force of the O(2-) ion (O3) clathrated in two out of 12 cages. O3 ions are located at general positions close to the ?bar 4 site at the centre of each cage. The difference-density map revealed two large peaks corresponding to displaced Ca ions. The positive ions close to O3 are displaced and one-to-one correspondence was found between one of the four equivalent O3 ions and the displaced ions. When an O3 ion is present in the cage the Al ion at the 16c position moves 0.946 (3) A toward the O3 ion. One of the Al O bonds is broken and a new Al-O3 bond is created. The result is an AlO(4) tetrahedron that is quite deformed. The three O1 ions and the O2 ion of the destroyed AlO(4) tetrahedron are forcibly displaced. O1 and O2 have two and one displaced ions, respectively. The local structure of the cage occupied by one of the four O3 ions was determined by calculating the electrostatic potential and electric field in the deformed cage, although the position of one of the displaced O1 ions was not clearly identified. PMID- 21586828 TI - Modulated anharmonic ADPs are intrinsic to aperiodic crystals: a case study on incommensurate Rb2ZnCl4. AB - A combination of structure refinements, analysis of the superspace MEM density and interpretation of difference-Fourier maps has been used to characterize the incommensurate modulation of rubidium tetrachlorozincate, Rb(2)ZnCl(4), at a temperature of T = 196 K, close to the lock-in transition at T(lock-in) = 192 K. The modulation is found to consist of a combination of displacement modulation functions, modulated atomic displacement parameters (ADPs) and modulated third order anharmonic ADPs. Up to fifth-order Fourier coefficients could be refined against diffraction data containing up to fifth-order satellite reflections. The center-of-charge of the atomic basins of the MEM density and the displacive modulation functions of the structure model provide equivalent descriptions of the displacive modulation. Modulations of the ADPs and anharmonic ADPs are visible in the MEM density, but extracting quantitative information about these modulations appears to be difficult. In the structure refinements the modulation parameters of the ADPs form a dependent set, and ad hoc restrictions had to be introduced in the refinements. It is suggested that modulated harmonic ADPs and modulated third-order anharmonic ADPs form an intrinsic part, however small, of incommensurately modulated structures in general. Refinements of alternate models with and without parameters for modulated ADPs lead to significant differences between the parameters of the displacement modulation in these two types of models, thus showing the modulation of ADPs to be important for a correct description of the displacive modulation. The resulting functions do not provide evidence for an interpretation of the modulation by a soliton model. PMID- 21586829 TI - Structure analysis of titanate nanorods by automated electron diffraction tomography. AB - A hitherto unknown phase of sodium titanate, NaTi(3)O(6)(OH).2H(2)O, was identified as the intermediate species in the synthesis of TiO(2) nanorods. This new phase, prepared as nanorods, was investigated by electron diffraction, X-ray powder diffraction, thermogravimetric analysis and high-resolution transmission electron microscopy. The structure was determined ab initio using electron diffraction data collected by the recently developed automated diffraction tomography technique. NaTi(3)O(6)(OH).2H(2)O crystallizes in the monoclinic space group C2/m. Corrugated layers of corner- and edge-sharing distorted TiO(6) octahedra are intercalated with Na(+) and water of crystallization. The nanorods are typically affected by pervasive defects, such as mutual layer shifts, that produce diffraction streaks along c*. In addition, edge dislocations were observed in HRTEM images. PMID- 21586830 TI - The effect of pressure on the crystal structure of bianthrone. AB - Bianthrone [10(10-oxoanthracen-9-ylidene)anthracen-9-one] consists of two tricyclic anthraceneone units connected by a carbon-carbon double bond. Crystals of the form obtained under ambient conditions are yellow and contain folded centrosymmetric conformers in which the central ring of the anthraceneone unit is non-planar. When hydrostatic pressure is applied the crystals assume a red colouration which gradually deepens as pressures increases. The colour change is limited in extent to the surface of the crystals, the bulk remaining yellow. Comparison of high-pressure, single-crystal UV-vis spectra and powder diffraction data demonstrate that the colour change is associated with the formation of a polymorph containing a conformer in which the tricyclic fragments are planar and the molecule is twisted about the central C-C bond. Single-crystal diffraction data collected as a function of pressure up to 6.5 GPa reveal the effect of compression on the yellow form, which consists of layers of molecules which stack along the [010] direction. The structure remains in a compressed form of the ambient-pressure phase when subjected to hydrostatic pressure up to 6.5 GPa, and the most prominent effect of pressure is to push the layers closer together. PIXEL calculations show that considerable strain builds up in the crystal as pressure is increased with a number of intermolecular contacts being pushed into destabilizing regions of their potentials. PMID- 21586831 TI - Solid-state and gas-phase structures of two conformers of N-(4-methylphenyl) N',N''-bis(morpholinyl) phosphoric triamide; insights from X-ray crystallography and DFT calculations. AB - A phosphoric triamide with the formula (4-CH(3)-C(6)H(4)NH)P(O)(NC(4)H(8)O)(2) has been synthesized and characterized. X-ray crystallography at 120 K reveals that the title compound is composed of two symmetrically independent molecules in the solid state. Density functional theory (DFT) calculations reveal that two conformers A and B are very close to each other from an energy point of view. Thus there is equal chance that the presence of two conformers in the lattice may lead to hydrogen-bonded chains with an ABABAB arrangement. Hydrogen bonds of the type O(P)...H-N (O(P) being the phosphoryl O atom) are established between the two conformers with binding energies of -18.8 and -20.3 kJ mol(-1) (at B3LYP/6 31+G*). The electronic delocalization LP(O(P)) -> sigma*(N-H), LP(O(P)) being the lone pair of O(P), leads to a decrease in the strength of the N-H bond during hydrogen bonding between the conformers. The charge density (rho) at the bond critical point (b.c.p.) of N-H decreases by ~0.012-0.014 e A(-3) when the molecule participates in hydrogen bonding. This may explain the red shift of the nu(N-H) stretching frequency from a single molecule in the gas phase to a hydrogen-bonded one in the solid state. PMID- 21586832 TI - Intermolecular interactions and charge transfer in the 2:1 tetrathiafulvalene bromanil complex, (TTF)2-BA. AB - The crystal structure of the 2:1 charge-transfer complex of tetrathiafulvalene [2,2'-bis(1,3-dithiolylidene)] and bromanil (tetrabromo-1,4-benzoquinone) [(TTF)(2)-BA, (C(6)H(4)S(4))(2)-C(6)Br(4)O(2)] has been determined by X-ray diffraction at room temperature, 100 and 25 K. No structural phase transition occurs in the temperature range studied. The crystal is made of TTF-BA-TTF sandwich trimers. A charge-transfer estimation between donor and acceptor (0.2 e) molecules is proposed in comparison to the molecular geometries of TTF-BA and TTF and BA isolated molecules. Displacement parameters of the molecules have been modeled with the TLS formalism. PMID- 21586833 TI - Charge-density analysis of 1-nitroindoline: refinement quality using free R factors and restraints. AB - Nitramines and related N-nitro compounds have attracted significant attention owing to their use in rocket fuel and as explosives. The charge density of 1 nitroindoline was determined experimentally and from theoretical calculations. Electron-density refinements were performed using the multipolar atom formalism. In order to design the ideal restraint strategy for the charge-density parameters, R-free analyses were performed involving a series of comprehensive refinements. Different weights were applied to the charge-density restraints, namely the similarity between chemically equivalent atoms and local symmetry. Additionally, isotropic thermal motion and an anisotropic model calculated by rigid-body analysis were tested on H atoms. The restraint weights which resulted in the lowest values of the averaged R-free factors and the anisotropic H-atom model were considered to yield the best charge density and were used in the final refinement. The derived experimental charge density along with intra- and intermolecular interactions was analysed and compared with theoretical calculations, notably with respect to the symmetry of multipole parameters. A comparison of different refinements suggests that the appropriate weighting scheme applied to charge-density restraints can reduce the observed artefacts. The topological bond orders of the molecule were calculated. PMID- 21586834 TI - A simplified empirical model for approximation of the 'bond valence-bond length' correlation for H-O bonds. AB - The 'bond valence (s)-bond length (r)' correlation reported earlier for H-O bonds [Brown (2009). Chem. Rev. 109, 6858-6919] has been closely approximated using the function s = (alpha - betar)(1/gamma), where alpha = 1.185 (10), beta = 0.321 (8) and gamma = 0.36. PMID- 21586836 TI - My strategic vision for the IJO of tomorrow. PMID- 21586837 TI - Ahmed glaucoma valve in post-penetrating-keratoplasty glaucoma: a critically evaluated prospective clinical study. AB - AIM: The aim was to evaluate the outcome of Ahmed glaucoma valve (AGV) in post penetrating-keratoplasty glaucoma (PKPG). MATERIALS AND METHODS: In this prospective study, 20 eyes of 20 adult patients with post-PKPG with intraocular pressure (IOP) >21 mmHg, on two or more antiglaucoma medications, underwent AG (model FP7) implantation and were followed up for a minimum of 6 months. Absolute success was defined as 5 < IOP < 21 mmHg and qualified success as 5 < IOP < 21 mmHg with medications or minor procedures. RESULTS: The mean IOP decreased from 42.95 +/- 10.24 to 17.69 +/- 3.64 mmHg (P < 0.001) and the use of medications dropped from 2.92 to 0.39 (P < 0.001) after AGV implantation. The absolute success was achieved in 11 eyes and qualified success in 9. There was no significant change in best corrected visual acuity, graft clarity, or graft thickness. Six device-related complications occurred after AGV implantations which were successfully managed with medical or minor surgical therapy. CONCLUSIONS: Postkeratoplasty refractory glaucoma managed by AGV implantation revealed a satisfactory outcome up to 6 months of follow-up. PMID- 21586838 TI - Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal neovascular membrane in age-related macular degeneration. AB - CONTEXT: Ranibizumab and bevacizumab are used widely for treating patients with choroidal neovascular membrane (CNVM) secondary to age-related macular degeneration (AMD). AIMS: To determine and compare the efficacy and safety of intravitreal ranibizumab and bevacizumab in treatment of CNVM due to AMD. SETTINGS AND DESIGN: Prospective comparative case series carried out in an eye institute and eye department of a hospital in Kolkata, India. MATERIALS AND METHODS: One hundred and four eyes with CNVM due to AMD were randomized into two groups. Group A (n=54; 24 occult) received monthly intravitreal ranibizumab injections (0.5 mg in 0.05 ml) and Group B (n=50; 22 occult) received monthly bevacizumab injections (1.25 mg in 0.05 ml) for 3 consecutive months and then as per study criteria. Data analysis done using SPSS software. P-value of <0.05 was considered statistically significant. RESULTS: The mean best corrected visual acuity (BCVA) in the ranibizumab group increased from 58.19 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline to 64 ETDRS letters at month 3 (P<0.001). In bevacizumab group mean BCVA increased from 56.80 to 61.72 ETDRS letters at month 3 (P<0.001). At the end of 18 months, there was no statistically significant difference between groups A and B with respect to change in BCVA (P=0.563) or central macular thickness (CMT; P=0.281), as measured by optical coherence tomography (Stratus OCT 3000). No significant sight threatening complications developed. CONCLUSIONS: Ranibizumab and bevacizumab are equally safe and efficacious in treating CNVM due to AMD. PMID- 21586839 TI - Intravitreal injection of methotrexate in an experimental rabbit model: determination of pharmacokinetics. AB - PURPOSE: To investigate the pharmacokinetics of intravitreally administered methotrexate. MATERIALS AND METHODS: Twenty-one New Zealand white rabbits were used in the study. The pharmacokinetics of intravitreally injected 800 MUg/0.1 ml of methotrexate was investigated. Intravitreal concentration of the drug was measured at seven different times, in six eyes at each occasion, on a total of 42 eyes of 21 rabbits from a period of 30 minutes to 72 hours. RESULTS: The volume of distribution was calculated as 1.33 ml following intravitreal injection of 800 MUg methotrexate. Vitreous concentrations of the drug were found to be decreasing related to the specific mathematical equation; drug concentration= 1426.73 e 0.1182(time) and remained over effective dose by 81 hours with a half life of 5.9 hours. CONCLUSIONS: These findings evidenced those vitreous levels of methotrexate at various time intervals after 800 MUg intravitreal injections which formulated a mathematical equation for calculation of vitreous level of the drug at each hour. PMID- 21586840 TI - Pupil cycle time and contrast sensitivity in type II diabetes mellitus patients: a pilot study. AB - CONTEXT: Pupil cycle time (PCT) has been widely used for examination of ocular diabetic autonomic neuropathy (DAN). AIMS: The primary aim of this study was to evaluate the difference of contrast sensitivity according to PCT results, and the secondary aim was to determine the factors associated with PCT difference for type II diabetes patients. SETTINGS AND DESIGN: A clinical pilot study that included a total of 60 eyes of 60 type II diabetes patients. MATERIALS AND METHODS: We divided all patients into three groups according to PCT results. Group A and Group C were composed of patients who had upper one third PCT and lower one third PCT, respectively. We analyzed difference of age, diabetes duration, hypertension duration, mean best corrected visual acuity (BCVA), mean spherical equivalent (SE), HbA1C, glomerular filtration rate (GFR), stage of diabetic retinopathy, and Cardiac Autonomic Function Score (CAFS). Contrast sensitivity and decrease of visual acuity by glare were also estimated and analyzed for 28 eyes of 28 non-proliferative diabetic retinopathy (NPDR) patients. Group [NPDR] A and Group [NPDR] C were defined as those who had lower one third PCT and upper one third PCT, respectively. STATISTICAL ANALYSIS: Statistical analysis was done using SPSS 17.0 software. RESULTS AND CONCLUSIONS: Each group contained 20 eyes. Significant differences between Group A and Group C were observed in duration of diabetes and CAFS (P <= 0.001 and P < 0.001, respectively). Contrast sensitivity in Group [NPDR] A was significantly more than in Group [NPDR] C at all cpds (all P <= 0.001). We found that PCT can influence contrast sensitivity or glare in diabetes patients and also confirmed a significant correlation of PCT with CAFS and duration of diabetes. PMID- 21586841 TI - Microalbuminuria and low hemoglobin as risk factors for the occurrence and increasing severity of diabetic retinopathy. AB - AIM: To assess the influence of urinary microalbuminuria and hemoglobin concentration on the occurrence and severity of diabetic retinopathy (DR), clinically significant macular edema (CSME) and hard exudate formation. MATERIALS AND METHODS: In this prospective cross-sectional study carried out over a period of 2 years, type 2 diabetic patients seeking ocular evaluation for DR were assessed for presence and severity of DR, presence of hard exudates and CSME. Retinal findings were correlated to severity of microalbuminuria, hemoglobin concentration and other systemic risk factors using linear regression analysis. RESULTS: Three hundred and six patients were included in the study. DR of any grade was seen in 132 (43%) patients, hard exudate formation in 93/306 (30.4%) patients, CSME in 50/306 (16.3%) patients and proliferative DR in 26/306 (8.5%) patients. Duration of diabetes (P < 0.001), microalbuminuria (P < 0.001) and low hemoglobin (P = 0.001) were found to be highly significant risk factors for the development and increasing severity of DR as well as for CSME and hard exudate formation. CONCLUSION: Microalbuminuria and low hemoglobin are strong predictors for DR, CSME and hard exudate formation in type 2 diabetics even after correcting for duration of diabetes and other systemic risk factors. Although not directly involved in the pathogenesis, microalbuminuria can help in identifying patients at risk for more severe diabetic eye disease. Microalbuminuria warrants intensive monitoring of both retinal and renal status. The hemoglobin levels should be monitored regularly in diabetic patients to detect and treat anemia, thereby reducing one risk factor for DR. PMID- 21586842 TI - Objective structured clinical examination for undergraduates: is it a feasible approach to standardized assessment in India? AB - BACKGROUND: There has been a growing concern among medical educators about the quality of medical graduates trained in various medical colleges in our country. Data based on the faculty and student perceptions of undergraduate curriculum indicate a need for laying more stress on practical skills during their training and assessment. The Objective Structured Clinical Examination (OSCE) is a reliable and an established and effective multistation test for the assessment of practical skills in an objective and a transparent manner. The aim of this article is to sensitize universities, examiners, organizers, faculty, and students across India to OSCE. MATERIALS AND METHODS: We designed an assessment based on 22-station OSCE and administered it to 67 students during their final year, integrating all the domains of learning, that is higher order cognitive domain, psychomotor domain, and affective domain. Data analysis was done using SPSS version 15. RESULTS: The OSCE was feasible to conduct and had high perceived construct validity. There was a significant correlation between the station score and total examination score for 19 stations. The reliability of this OSCE was 0.778. Both students and faculty members expressed a high degree of satisfaction with the format. CONCLUSION: Integrating a range of modalities into an OSCE in ophthalmology appears to represent a valid and reliable method of examination. The biggest limitation with this format was the direct expenditure of time and energy of those organizing an OSCE; therefore, sustaining the motivation of faculty might pose a challenge. PMID- 21586843 TI - Comparison of anisometropes with and without amblyopia. AB - BACKGROUND: To compare binocular functions in amblyopic and non-amblyopic anisometropes and to investigate the possible associated factors for amblyopia development such as type of refractive error and initial age of refractive error correction. MATERIALS AND METHODS: Prospectively anisometropic subjects with (n=42) and without amblyopia (n=33) were included in the study. Full ophthalmological examination including binocularity and motility was performed. RESULTS: There was no statistically significant difference between the ages at the time of initial refractive error correction (P =0.946). All of the anisometropes (100%) had fusion with Worth 4-dot test and Bagolini glasses. However 81% of amblyopic subjects had fusion with Worth 4 dot test and 88.1% had normal response with Bagolini glasses. Median stereopsis was 60 sec of arc in anisometropic subjects and 400 sec of arc in amblyopes. CONCLUSION: Our data support that, binocular functions are well developed in anisometropes without amblyopia and initial age at correction of refractive error has no primary effect on development of amblyopia. PMID- 21586844 TI - Visual recovery and predictors of visual prognosis after managing traumatic cataracts in 555 patients. AB - AIM: The aim was to evaluate the visual recovery after managing traumatic cataracts and determine the predictors of a better visual prognosis. MATERIALS AND METHODS: This was a prospective study. We enrolled patients with specific inclusion criteria, examined their eyes to review the comorbidities due to trauma, performed surgery for traumatic cataracts, and implanted lenses. The patients were reexamined 6 weeks postoperatively. We divided the cases of traumatic cataract into two groups, the "open globe" (Group 1) and "closed globe" (Group 2) groups, according to the ocular trauma based on the Birmingham Eye Trauma Terminology System (BETTS) and compared the determinants of visual acuity. RESULTS: Our cohort of 555 eyes with traumatic cataracts included 394 eyes in Group 1 and 161 in Group 2. Six weeks postoperatively, the visual acuity in the operated eye was >20/60 in 193 (48%) and 49 (29%) eyes in Groups 1 and 2, respectively (P = 0.002, ANOVA). At follow-up, >20/60 vision was significantly higher in Group 1 than in Group 2 (OR = 1.61; 95% CI, 0.85-3.02). Overall 242 (43.5%) eyes gained a final visual acuity of >20/60. CONCLUSIONS: Open globe injury has a favorable prognosis for satisfactory (>20/60) visual recovery after the management of traumatic cataracts. PMID- 21586845 TI - Ocular disorders in children with learning disabilities in special education schools of Pune, India. AB - AIM: The aim was to study and treat ocular disorders in children with learning disabilities (cLDs) and explore associations with their perinatal history. MATERIALS AND METHODS: cLDs attending 11 special schools were examined by a team consisting of an ophthalmologist, optometrist, and a social worker in 2007 and followed up in 2008. The students' intelligence quotient (IQ) and their medical histories were noted. Distant visual acuities were measured using Kay pictures or Snellen's tumbling E chart and complete ocular examination was performed. Students were assessed at the pediatric ophthalmology unit and low vision center, if needed. Statistical analysis was done with SPSS and the Chi-square test for ordinal data. RESULTS: A total of 664 students were examined, 526 of whom were <16 years of age; 323 (61.4%) were male. A total of 326 (60%) had moderate-to severe learning disabilities (IQs <50), and the mean IQ was 45.4. Two hundred and thirty-eight (45.3%) had ocular disorder; 143 (27.3%) had an uncorrected refractive error, followed by strabismus in 83 (15.8%), nystagmus in 36 (6.8%), optic atrophy in 34 (6.5%), and congenital anomalies in 13 (2.5%), 103 children had more than one abnormality. Only 12 of the 143 students with refractive errors were using spectacles. A total of 132 (48.7%) children with a history of perinatal insult had ocular problems. Ocular disorders were also common in those with a history of epilepsy, Down's syndrome, and cerebral palsy. CONCLUSION: Nearly half the cLDs in this study had ocular disorders and one-fourth had their vision improved. PMID- 21586846 TI - Eye-related visual hallucinations: consider 'Charles Bonnet syndrome'. AB - The Charles Bonnet Syndrome (CBS) is typically characterized by visual hallucinations in elderly people without cognitive defects. This article presents the case of an 80-year-old male patient with a one-year history of visual hallucinations, secondary to glaucoma, in both eyes. Neither a dopamine agonist nor cholinesterase inhibitor therapy improved his symptoms. In this case, the hallucinations were gradually improved after administration of a GABAergic drug, pregabalin, for diabetic polyneuropathy. Placebo-controlled clinical trials would be needed to support this effect of pregabalin, as suggested by this association. PMID- 21586847 TI - Mucous membrane grafting for the post-Steven-Johnson syndrome symblepharon: a case report. AB - An 18-year-old woman was referred with late sequelae of chloroquine-induced Steven-Johnson syndrome. At the time of presentation, the symblepharon was involving the upper lids to almost the whole of the cornea, and part of the lower bulbar conjunctiva with the lower lid bilaterally. Other ocular examinations were not possible due to the symblepharon. B-scan ultrasonography revealed acoustically clear vitreous, normal chorioretinal thickness, and normal optic nerve head, with an attached retina. Conjunctivo-corneal adhesion released by superficial lamellar dissection of the cornea. Ocular surface reconstruction was carried out with a buccal mucous membrane. A bandage contact lens was placed over the cornea followed by the symblepharon ring to prevent further adhesion. The mucosal graft was well taken up along with corneal re-epithelization. Best corrected visual acuity of 20/120 in both sides after 1 month and 20/80 after 3 months was achieved and maintained till the 2.5-year follow-up. PMID- 21586848 TI - Subretinal lipid exudation associated with untreated choroidal melanoma. AB - Subretinal lipid exudation in an untreated choroidal melanoma is very rare. It is seen following plaque radiotherapy in choroidal melanoma. There is only one case report of untreated choroidal melanoma with massive lipid exudation in a patient with metastatic hypernephroma. We report here a rare case of untreated choroidal melanoma with lipid exudation. Subretinal exudation that is rarely seen following plaque brachytherapy was noted at the borders of this untreated tumor. Lipid exudation partially resolved following brachytherapy. PMID- 21586849 TI - Preserved scleral patch graft for unexpected extreme scleral thinning found at the scleral buckling procedure: a case report. AB - Pre-existing scleral pathology is an important risk factor for globe rupture during scleral buckling procedures. We report here, the surgical management of an unexpected scleral pathology found at the scleral buckling procedure in a retinal detachment patient. A 77-year-old white female with retinal detachment underwent a scleral buckling procedure. The surgery was converted into a scleral graft procedure, as extreme scleral thinning was found intraoperatively. An alcohol preserved donor sclera graft was used. The second surgery for definitive retinal alignment was performed two weeks later. The presented case of an unexpected scleral pathology in a retinal detachment patient was managed with a combination of scleral grafting and pars plana vitrectomy, without any major complications. The anatomical outcome was excellent and the scleral rupture was prevented; the visual outcome was satisfactory. A conversion of the scleral buckling procedure into a scleral graft procedure has proved to be safe and effective for unexpected scleral pathology. PMID- 21586850 TI - Extrusion of hydrogel exoplant into upper eyelid 16 years after a scleral buckle procedure. AB - Sixteen years after scleral buckle surgery with a hydrogel episcleral exoplant, a 43-year-old woman presented with progressive binocular diplopia, ptosis, and an expanding mass in her upper eyelid. She underwent surgical removal of the hydrogel exoplant through an anterior approach. The exoplant proved to be friable, fragmented, and encapsulated in a fibrous tissue; the exoplant was removed in its entirety. Postoperatively, the eyelid mass resolved, while her diplopia and ptosis improved slightly. PMID- 21586851 TI - Frosted branch angiitis, neuroretinitis as initial ocular manifestation in Behcet disease. AB - Behcet disease is an idiopathic, multisystem disorder characterized by recurrent episodes of orogenital ulceration and vasculitis of the veins and arteries of all calibers. Ocular involvement may affect the conjunctiva, sclera, uveal tract, vitreous, blood vessels, and retina. Many theories have pointed toward an autoimmune response behind its pathogenesis, which may be triggered by exposure to an infectious agent. Frosted branch angiitis is characterized by vascular inflammation, sheathing, retinal edema, and retinal hemorrhages. The disease may be idiopathic in a majority of the cases or may be associated with ocular and systemic pathology. Association between Behetaet disease, Frosted branch angiitis, and neuroretinitis is not reported in literature. This uncommon combination reflects the varied systemic and ocular manifestations in Behcet disease, especially in patients who are not diagnosed and treated in time. We hereby report a case of bilateral frosted branch angiitis and neuroretinitis in a young male from Middle-east, suffering from Behcet disease. PMID- 21586852 TI - Photodynamic monotherapy or combination treatment with intravitreal triamcinolone acetonide, bevacizumab or ranibizumab for choroidal neovascularization associated with pathological myopia. AB - This retrospective, interventional case series analyses treatment outcomes in eyes with choroidal neovascularization (CNV) secondary to pathological myopia, managed with photodynamic therapy, (PDT), (Group 1, N = 11), PDT and intravitreal triamcinolone acetonide (4 mg/0.1ml) (Group 2, N = 3), PDT and intravitreal anti vascular endothelial growth factor (anti-VEGF) bevacizumab 1.25 mg/0.05 ml, ranibizumab 0.5 mg/0.05 ml and reduced-fluence PDT and intravitreal ranibizumab 0.5 mg/0.05 ml (Group 3, N=12). All the patients underwent PDT. Intravitreal injections were repeated as required. SPSS 14 software was used to evaluate the data. Wilcoxon signed ranks test was used to evaluate pre- and post-treatment vision. The Kruskal-Wallis test was used for comparison between the groups. All the groups were statistically comparable. All the eyes showed complete regression of CNV, with a minimum follow-up of six months. All groups had visual improvement; significantly in Group 3 ( p = 0.003). Combination PDT with anti VEGF agents appeared to be efficacious in eyes with myopic CNV. However, a larger study with a longer follow-up is required to validate these results. PMID- 21586853 TI - Massive retinal gliosis: an unusual case with immunohistochemical study. AB - Massive retinal gliosis (MRG) is a rare, benign intraocular condition that results from the proliferation of well-differentiated glial cells. Immunohistochemically, these cells show positivity for glial fibrillary acid protein (GFAP), neuron specific enolase (NSE), and S-100 protein. We encountered a case of a 45-year-old female with loss of vision in the left eye. She had a history of trauma to that eye two years ago. Enucleation was carried out, because malignancy was suspected due to retinal calcification. On the basis of light microscopy and immunohistochemistry (IHC) performed on the enucleated eye, it was diagnosed as massive retinal gliosis. PMID- 21586854 TI - Intravitreal bevacizumab (avastin) for circumscribed choroidal hemangioma. AB - Circumscribed choroidal hemangiomas are rare ophthalmic entities that cause diminution in vision due to accumulation of subretinal and/or intraretinal fluid in the macular area. Various treatment options ranging from conventional laser to photodynamic therapy have been employed to destroy the tumor and reduce the exudation; however, either the inability to penetrate through the exudative fluid or the collateral retinal damage induced by these treatment modalities make them unsuitable for lesions within the macula. We evaluated the role of intravitreal bevacizumab, a pan-vascular endothelial growth factor (VEGF) inhibitor, in reducing the sub- and intraretinal fluid in three patients with circumscribed choroidal hemangiomas. All the patients had complete resolution of the serous retinal detachment that was maintained till at least 12 months after the first injection. Intravitreal bevacizumab may be used in combination with thermal laser or photodynamic therapy in treating circumscribed choroidal hemangiomas with subretinal fluid. PMID- 21586855 TI - Tectonic corneal graft for conjunctival rhinosporidiosis with scleral melt. AB - A 16 year old girl presented with irritation and watering of the right eye for 3 months. On examination, the superior perilimbal sclera was ectatic with incarcerated uveal tissue covered by conjunctiva. The conjunctiva showed discreet, yellow white mucoid spots. Excision biopsy of the conjunctiva showed subepithelial spherules of sporangia containing numerous endospores, suggestive of rhinosporidiosis. Diathermy was applied to flatten the staphyloma. The ectatic area was covered with a corneal patch graft. The patient was started on prednisolone acetate eye drops and oral dapsone for 6 months. Corneal graft was well incorporated and conjunctivalized by 3 months. Since the graft was not seen within the palpebral aperture, there was good cosmetic result. The corneal graft had the added advantage of transparency which allowed visualization of the underlying tissue to diagnose early recurrence. There was no recurrence at 6 months. PMID- 21586856 TI - Predominant exudative retinopathy in incontinentia pigmenti and clinical course after peripheral laser photocoagulation. PMID- 21586857 TI - Anti-vascular endothelial growth factor drugs in polypoidal choroidal vasculopathy. PMID- 21586858 TI - Comment on rare complication of late posterior subluxation of a rollable intraocular lens after an uneventful microphacoemulsification cataract surgery. PMID- 21586859 TI - Excision of post small incision cataract surgery conjunctival inclusion cyst. PMID- 21586860 TI - Prognostic factors for final vision outcome in patients with open globe injuries. PMID- 21586861 TI - Comment on: is inclusion of Sabouraud dextrose agar essential for the laboratory diagnosis of fungal keratitis? PMID- 21586862 TI - Hemi-central retinal artery occlusion in young adults. PMID- 21586864 TI - Is inclusion of Sabouraud dextrose agar essential for the laboratory diagnosis of fungal keratitis? PMID- 21586863 TI - Intravitreal bevacizumab in choroidal neovascularization associated with Best's vitelliform dystrophy. PMID- 21586865 TI - Residual triamcinolone acetonide at macular hole after vitreous surgery. PMID- 21586866 TI - Factors influencing the final visual outcome in open globe injuries. PMID- 21586867 TI - Alkalinization in peribulbar anesthesia for surgery on inflamed eye. PMID- 21586868 TI - Real time observation of mouse fetal skeleton using a high resolution X-ray synchrotron. AB - The X-ray synchrotron is quite different from conventional radiation sources. This technique may expand the capabilities of conventional radiology and be applied in novel manners for special cases. To evaluate the usefulness of X-ray synchrotron radiation systems for real time observations, mouse fetal skeleton development was monitored with a high resolution X-ray synchrotron. A non monochromatized X-ray synchrotron (white beam, 5C1 beamline) was employed to observe the skeleton of mice under anesthesia at embryonic day (E)12, E14, E15, and E18. At the same time, conventional radiography and mammography were used to compare with X-ray synchrotron. After synchrotron radiation, each mouse was sacrificed and stained with Alizarin red S and Alcian blue to observe bony structures. Synchrotron radiation enabled us to view the mouse fetal skeleton beginning at gestation. Synchrotron radiation systems facilitate real time observations of the fetal skeleton with greater accuracy and magnification compared to mammography and conventional radiography. Our results show that X-ray synchrotron systems can be used to observe the fine structures of internal organs at high magnification. PMID- 21586869 TI - In vivo metabolism of Talosin A, new isoflavonol glycoside from Kitasatospora kifunensis, in rats. AB - The isoflavonol glycoside Talosin A, genistein (GT)-7-alpha-L-6-deoxy talopyranose (GT-Tal), was first isolated from the culture broth of Kitasatospora kifunensis MJM341. The aim of the present study was to evaluate the oral absorption and metabolism of the newly isolated isoflavonol glycoside, GT-Tal compared to genistin (GT-7-O-beta-D-glucopyranoside; GT-Glu). Free GT-Glu and GT Tal could not be detected prior to enzymatic hydrolysis of the corresponding conjugates in rat plasma. Following oral administration of GT-Tal (15 min), GT Tal was rapidly absorbed through the gastrointestinal tract and metabolized into GT-Tal conjugates with a mean C(max) of 2.74 ug/mL. GT-Tal was further metabolized to its aglycone, free GT and conjugated GT. After oral administration, GT-Glu was absorbed after being converted to its aglycone and then further metabolized into its conjugate metabolites (free GT with a mean C(max) of 0.24 mg/mL at 1.25 h; conjugated GT with a mean C(max) of 1.31 mg/mL at 2.00 h). Significant differences in absorption and metabolism of GT-Tal and GT Glu were observed. GT-Tal was metabolized into its corresponding conjugates or underwent deglycosylation to form GT, whereas GT-Glu was metabolized into its aglycone, GT. PMID- 21586870 TI - Evaluation of the estrogenic effects of dietary perinatal Trifolium pratense. AB - This study was designed to investigate the potential estrogenic effects of perinatal dietary phytoestrogens on the rat uterus. Pregnant rats were divided to three groups provided the following diets: (1) rat chow, (2) rat chow with 7.5% Trifolium (T.) pratense, or (3) rat chow supplemented with 17beta-estradiol (0.5 mg/kg). The dams in each group were kept on the same diet during pregnancy and lactation. Female offspring were euthanized on day 21 at which time body and organ weights were recorded and tissue samples were taken for histology. Immunohistochemistry was performed to detect estrogen receptor alpha (ERalpha) and progesterone receptor (PR) levels. Our results revealed estrogen-like biological effects of perinatal T. pratense exposure. Relative uterus and ovary weights in the experimental groups were increased compared to control. The number of uterine glands and luminal epithelium heights were also increased. However, there were no statistically significant changes detected in the immunostaining intensity of ERalpha and PR between the groups. PMID- 21586871 TI - Genetic variability of six indigenous goat breeds using major histocompatibility complex-associated microsatellite markers. AB - The present study aimed at analyzing the genetic variability of indigenous goat breeds (Capra hircus) using the MHC-associated microsatellite markers BF1, BM1818, BM1258, DYMS1, and SMHCC1. The following breeds were included: Chinese Xuhuai, Indian Changthangi and Pashmina, Kenyan Small East African (SEA) and Galla, and Albanian Vendi. To examine genetic variability, the levels of heterozigosity, degrees of inbreeding, and genetic differences among the breeds were analyzed. The mean number of alleles ranged from nine in the Galla to 14.5 in the Vendi breed. The mean observed heterozygosity and mean expected heterozygosity varied from 0.483 in the Vendi to 0.577 in the Galla breed, and from 0.767 in the SEA to 0.879 in the Vendi breed, respectively. Significant loss of heterozygosity (p < 0.01) indicated that these loci were not in Hardy-Weinberg equilibrium. The mean F(IS) values ranged from 0.3299 in the SEA to 0.4605 in the Vendi breed with a mean value of 0.3623 in all breeds (p < 0.001). Analysis of molecular variance indicated that 7.14% and 4.74% genetic variation existed among the different breeds and geographic groups, whereas 92.86% and 95.26% existed in the breeds and the geographic groups, respectively (p < 0.001). The microsatellite marker analysis disclosed a high degree of genetic polymorphism. Loss of heterozygosity could be due to genetic drift and endogamy. The genetic variation among populations and geographic groups does not indicate a correlation of genetic differences with geographic distance. PMID- 21586872 TI - Dynamic analysis of Ca2+ level during bovine oocytes maturation and early embryonic development. AB - Mammalian oocyte maturation and early embryo development processes are Ca(2+) dependent. In this study, we used confocal microscopy to investigate the distribution pattern of Ca(2+) and its dynamic changes in the processes of bovine oocytes maturation, in vitro fertilization (IVF), parthenogenetic activation (PA) and somatic cell nuclear transfer (SCNT) embryo development. During the germinal vesicle (GV) and GV breakdown stage, Ca(2+) was distributed in the cortical ooplasm and throughout the oocytes from the MI to MII stage. In IVF embryos, Ca(2+) was distributed in the cortical ooplasm before the formation of the pronucleus. In 4-8 cell embryos and morulas, Ca(2+) was present throughout the blastomere. In PA embryos, Ca(2+) was distributed throughout the blastomere at 48 h, similar to in the 4-cell and 8-cell phase and the morula. At 6 h after activation, there was almost no distribution of Ca(2+) in the SCNT embryos. However, Ca(2+) was distributed in the donor nucleus at 10 h and it was distributed throughout the blastomere in the 2-8 cell embryos. In this study, Ca(2+) showed significant fluctuations with regularity of IVF and SCNT groups, but PA did not. Systematic investigation of the Ca(2+) location and distribution changes during oocyte maturation and early embryo development processes should facilitate a better understanding of the mechanisms involved in oocyte maturation, reconstructed embryo activation and development, ultimately improving the reconstructed embryo development rate. PMID- 21586873 TI - Comparison of bare metal stent and paclitaxel-eluting stent using a novel rat aorta stent model. AB - The purpose of our study was to create a novel rat aorta stent implantation model. Stainless steel bare metal stents (BMS) or paclitaxel-eluting stents (PES) were implanted in male Sprague-Dawley rats (BW 400 +/- 20 g). Two and four weeks after stent implantation, the aorta were collected, fixed with 2% glutaraldehyde, and cut into two segments. One segment was used for scanning electron microscopy analysis to evaluate re-endothelialization, and the other segment was used to calculate the neointimal area. At 2 weeks after stenting, the appearance of neointimal hyperplasia was less in the PES group than in the BMS group. At 4 weeks after stenting, no significant difference in neointimal hyperplasia was observed between two groups. On the other hand, the PES group showed more thrombus formation and less re-endothelialization compared to the BMS group. This study demonstrated the ability of a novel rat model of aorta stenting via a common carotid artery to measure the efficacy and safety of commercially available drug-eluting stents. PMID- 21586874 TI - The stress of weaning influences serum levels of acute-phase proteins, iron binding proteins, inflammatory cytokines, cortisol, and leukocyte subsets in Holstein calves. AB - The purpose of our study was to investigate changes in immunological parameters induced by weaning stress (including milk restriction) in calves. Fifteen Holstein calves were subjected to weaning at 6 weeks of age. Blood samples were collected at -14, -7, -2, 1, 3, and 5 days post-weaning (DPW; 0 DPW = 42 days). Weaning caused significant (p < 0.01) increases in the neutrophil (NE):lymphocyte (LY) ratio at 5 DPW with a significant (p < 0.05) reduction of LYs. The concentration of acute-phase proteins (haptoglobin and serum amyloid A) also increased significantly (p < 0.05) at 3 and 5 DPW compared to -2 DPW. Levels of the iron-binding protein lactoferrin decreased significantly (p < 0.05) after weaning. Serum tumor necrosis factor-alpha and cortisol levels were elevated (p < 0.05) at 3 DPW, while those of serum interferon-gamma decreased (p < 0.05) at 1 and 3 DPW compared to levels observed before weaning. Weaning significantly (p < 0.05) decreased the percentage of CD25(+) T cells in the peripheral blood. In conclusion, weaning stress affected the NE:LY ratio along with the levels of acute phase proteins, lactoferrin, cortisol, and inflammatory cytokines in the peripheral blood of calves. Weaning stress may induce an acute phase response possibly through the elevation of cortisol production and modulation of inflammatory cytokines. PMID- 21586875 TI - Virulence factors in Escherichia coli isolated from calves with diarrhea in Vietnam. AB - This study was conducted to determine the prevalence and characteristics of pathogenic Escherichia (E.) coli strains from diarrheic calves in Vietnam. A total of 345 E. coli isolates obtained from 322 diarrheic calves were subjected to PCR and multiplex PCR for detection of the f5, f41, f17, eae, sta, lt, stx1, and stx2 genes. Of the 345 isolates, 108 (31.3%) carried at least one fimbrial gene. Of these 108 isolates, 50 carried genes for Shiga toxin and one possessed genes for both enterotoxin and Shiga toxin. The eae gene was found in 34 isolates (9.8%), 23 of which also carried stx genes. The Shiga toxin genes were detected in 177 isolates (51.3%) and the number of strains that carried stx1, stx2 and stx1/stx2 were 46, 73 and 58, respectively. Among 177 Shiga toxin-producing E. coli isolates, 89 carried the ehxA gene and 87 possessed the saa gene. Further characterization of the stx subtypes showed that among 104 stx1-positive isolates, 58 were the stx1c variant and 46 were the stx1 variant. Of the 131 stx2 positive strains, 48 were stx2, 48 were stx2c, 11 were stx2d, 17 were stx2g, and seven were stx2c/stx2g subtypes. The serogroups most prevalent among the 345 isolates were O15, O20, O103 and O157. PMID- 21586876 TI - White spots on the mucosal surface of the duodenum in dogs with lymphocytic plasmacytic enteritis. AB - Distended lacteals, described as expanded white villi in duodenum, are strongly indicative of primary intestinal lymphangiectasia. In the present study, we evaluated the significance of white spots present in the duodenal mucosa of dogs with lymphocytic plasmacytic enteritis (LPE). Fifty dogs with LPE were included in this study, and white spots were detected in the duodenal mucosa in 22 dogs during endoscopy. Hypoproteinemia was more frequent in dogs with white spots than in dogs without spots (p = 0.02). Serum protein and albumin concentration were significantly lower in LPE dogs with white spots (p = 0.038) compared to LPE dogs without white spots (p = 0.039). There was a significant correlation between white spots density and lymphatic dilatation histological scores (p = 0.023; rho = 0.481). These results suggest that the presence of white spots in the duodenal mucosa of dogs is not a finding exclusive for intestinal lymphangiectasia. Low serum protein and albumin concentrations together with lymphatic dilatation seem to be related to the presence of white spots in the duodenal mucosa of LPE dogs. PMID- 21586877 TI - Evaluation of the Perkins handheld applanation tonometer in horses and cattle. AB - The objective of this study was to evaluate and validate the accuracy of the Perkins handheld applanation tonometer for measuring intraocular pressure (IOP) in horses and cattle. Both eyes of 10 adult horses and cattle were evaluated in a postmortem study. The eyes from 10 clinically normal adult horses and cattle were also examined after bilateral auriculopalpebral nerve block and topical anesthesia for an in vivo study. IOP was measured postmortem using direct manometry (measured with an aneroid manometer) and tonometry (measured with a Perkins handheld applanation tonometer). The correlation coefficients (r(2)) for the data from the postmortem manometry and Perkins tonometer study were 0.866 for horses and 0.864 for cattle. In the in vivo study, IOP in horses was 25.1 +/- 2.9 mmHg (range 19.0~30.0 mmHg) as measured by manometry and 23.4 +/- 3.2 mmHg (range 18.6~28.4 mmHg) according to tonometry. In cattle, IOP was found to be 19.7 +/- 1.2 mmHg (range 18.0~22.0 mmHg) by manometry and 18.8 +/- 1.7 mmHg (range 15.9~20.8 mmHg) by tonometry. There was a strong correlation between the IOP values obtained by direct ocular manometry and the tonometer in both horses and cattle. Our results demonstrate that the Perkins handheld tonometer could be an additional tool for accurately measuring IOP in equine and bovine eyes. PMID- 21586878 TI - Establishment of a standard operating procedure for predicting the time of calving in cattle. AB - Precise calving monitoring is essential for minimizing the effects of dystocia in cows and calves. We conducted two studies in healthy cows that compared seven clinical signs (broad pelvic ligaments relaxation, vaginal secretion, udder hyperplasia, udder edema, teat filling, tail relaxation, and vulva edema) alone and in combination in order to predict the time of parturition. The relaxation of the broad pelvic ligaments combined with teat filling gave the best values for predicting either calving or no calving within 12 h. For the proposed parturition score (PS), a threshold of 4 PS points was identified below which calving within the next 12 h could be ruled out with a probability of 99.3% in cows (95.5% in heifers). Above this threshold, intermitted calving monitoring every 3 h and a progesterone rapid blood test (PRBT) would be recommended. By combining the PS and PRBT (if PS >= 4), the prediction of calving within the next 12 h improved from 14.9% to 53.1%, and the probability of ruling out calving was 96.8%. The PRBT was compared to the results of an enzyme immunoassay (sensitivity, 90.2%; specificity, 74.9%). The standard operating procedure developed in this study that combines the PS and PRBT will enable veterinarians to rule out or predict calving within a 12 h period in cows with high accuracy under field conditions. PMID- 21586879 TI - Maturation of bone marrow-derived dendritic cells by a novel beta-glucan purified from Paenibacillus polymyxa JB115. AB - We investigated the immunostimulatory effects of a novel beta-glucan purified from Paenibacillus (P.) polymyxa JB115 on bone marrow-derived dendritic cells (DCs), a type of potent antigen-presenting cells. beta-glucan isolated from P. polymyxa JB115 enhanced the viability and induced the maturation of DCs. beta glucan markedly increased the cytokine production of DCs and surface expression of DC markers. In addition, DCs treated with beta-glucan showed a higher capacity to stimulate allogeneic spleen cell proliferation compared to those treated with medium alone. These results demonstrate the effect of beta-glucan on DC maturation and may increase the use of beta-glucan. PMID- 21586880 TI - A simplified PCR assay for fast and easy mycoplasma mastitis screening in dairy cattle. AB - A simplified polymerase chain reaction (PCR) assay was developed for fast and easy screening of mycoplasma mastitis in dairy cattle. Species of major mycoplasma strains [Mycoplasma (M.) bovis, M. arginini, M. bovigenitalium, M. californicum, M. bovirhinis, M. alkalescens and M. canadense] in cultured milk samples were detected by this simplified PCR-based method as well as a standard PCR technique. The minimum concentration limit for detecting mycoplasma by the simplified PCR was estimated to be about 2.5 * 10(3) cfu/mL and was similar to that of the standard PCR. We compared the specificity and sensitivity of the simplified PCR to those of a culture method. Out of 1,685 milk samples cultured in mycoplasma broth, the simplified PCR detected Mycoplasma DNA in 152 that were also positive according to the culture assay. The sensitivity and specificity of the simplified PCR were 98.7% and 99.7%, respectively, for detecting mycoplasma in those cultures. The results obtained by the simplified PCR were consistent with ones from standard PCR. This newly developed simplified PCR, which does not require DNA purification, can analyze about 300 cultured samples within 3 h. The results from our study suggest that the simplified PCR can be used for mycoplasma mastitis screening in large-scale dairy farms. PMID- 21586881 TI - Etiologic and epidemiologic analysis of bacterial infectious upper respiratory disease in Thoroughbred horses at the Seoul Race Park. AB - Infectious upper respiratory disease (IURD) of Thoroughbred racehorses has been a frequent problem (29.6% of incidence) at the Seoul Race Park (Korea). Risk factors for IURD include the season with a high transfer rate (summer and fall), the stabling period (<= 3 months), and age (2 to 3 years old), suggesting that the movement and new environment may have depressed the immune system of the horses and decreased their ability to respond properly to pathogens. The bacterial strains (n = 98) isolated from IURD horses included Pseudomonas spp., Escherichia coli, Staphylococcus spp., Streptococcus equi subsp. equi and zooepidemicus. PMID- 21586882 TI - Catheter-guided percutaneous heartworm removal using a nitinol basket in dogs with caval syndrome. AB - Carval syndrome is a severe heartworm infection where the worms have migrated to the right atrium and vena cava; this condition is associated with a myriad of clinical signs. Several non-surgical and interventional methods are currently used for mechanical worm removal. However, the success rate and complications related to these methods are heavily dependent on methodology and retrieval devices used. In this study, we developed a catheter-guided heartworm removal method using a retrieval basket that can easily access pulmonary arteries and increase the number of worms removed per procedure. With this technique, we successfully treated four dogs with caval syndrome. PMID- 21586883 TI - [Two cases of urolithiasis induced by topiramate]. AB - Topiramate is an antiepileptic medicine that has been used adjunctively in the treatment of refractory seizures in Japan since 2007. Topiramate has been shown to inhibit specific carbonic anhydrase activity in the kidney and may induce a distal type of renal tubular acidosis. Case 1 : A 22-year-old male was referred to our hospital after complaining of left flank pain. He developed a seizure disorder and had been using topiramate for 4 months. Drip infusion pyelography showed a left ureteral stone. Case 2 : A 7-year-old boy presented with gross hematuria. He developed West syndrome and had been using topiramate for 6 months. A computed tomographic scan showed a right kidney stone. PMID- 21586884 TI - [A case of xp11.2 translocation renal cell carcinoma]. AB - Xp11.2/TFE3 translocation renal cell carcinoma (RCC), a recently classified distinct subtype, is a rare tumor that usually affects children and adolescents. The morphology and biological behavior are not widely recognized, Xp11.2 translocation RCC is suggestive of early metastases despite the small tumor size. The definitive diagnosis requires the evidence of several different reciprocal translocations involving the TFE3 gene located on chromosome Xp11.2. Here, we present a case of Xp11.2 translocation RCC in an 18-yearold male. He was referred to our hospital because of a right renal tumor with macroscopic hematuria and right flank colic. The radiographic evaluation including magnetic resonance imaging (MRI) suggested it to be a typical papillary renal cell carcinoma or benign renal tumor. He underwent laparoscopic nephrectomy against the repeat symptom in spite of small tumor (3.5 cm in diameter). The immunohistochemical study revealed nuclear staining for TFE3 protein in the cancer cells. The urologic and radiologic outcomes were satisfactory after more than 1 year of follow-up. PMID- 21586885 TI - [Successful resection of a gastrointestinal stromal tumor in the pelvis with imatinib mesylate as neoadjuvant therapy]. AB - We report a case of marginally resectable gastrointestinal stromal tumor (GIST) in the pelvis treated with neoadjuvant intent before subsequent successful surgical resection. A 46-year old man presented with urinary frequency and rectal discomfort with tenesmus. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a 12 cm diameter mass between the bladder and rectum and the margin of the tumor and prostate was unclear. No metastases were evident. Trans rectal needle core biopsy confirmed c-kit positive GIST. Because of the locally advanced nature of the tumor,immediate surgical resection would have required total pelvic exenteration with eternal colostomy and urinary diversion. Therefore,the patient was treated with imatinib mesylate 400 mg daily in anticipation of adequate tumor size reduction to enable a more simplified surgical approach. After 3 months of imatinib therapy,MRI demonstrated a reduction in tumor size of 60%. Consequently,a complete surgical resection including the bladder,prostate and part of the sigmoid colon with temporary ileostomy and ileal conduit was performed. Pathological findings of the resected specimen showed widespread degeneration with cystic changes,necrosis, and hypocellularlity,as well as nodules of residual viable c-kit positive tumor cells. The patient has been treated with imatinib mesylate for 39 months following the operation without tumor recurrence. PMID- 21586886 TI - [A case of inflammatory myofibroblastic tumor of the urinary bladder]. AB - A 61 year-old man complaining of asymptomatic gross hematuria was admitted to our hospital in May 2005. Transurethral resection of bladder tumor (TUR-BT) was performed for a bladder tumor (urothelial carcinoma (UC), pTa, G2). The TUR-BT was performed again because cystoscopy revealed a nonpapillary bladder tumor on the posterior bladder wall in September 2007. The pathological findings showed a UC, pTa, G2 and an inflammatory myofibroblastic tumor (IMT), pT1. The TUR-BT was performed two more times for tumor recurrences. We considered a total cystectomy because of the possibility of a pathologically low grade sarcoma and the considerable enlargement of the tumor size for a month after the TUR-BT. Ultimately, a malignant sarcoma was not diagnosed from the pathological findings. We practiced conservative therapy with a steroid and the tumor was reduced. PMID- 21586887 TI - [Organ-sparing surgery for contralateral testicular tumor following orchiectomy : a case report]. AB - A 30-year-old man underwent a left high orchiectomy because of stage I testicular tumor in December, 2006. A palpable nodule was noticed in the contralateral testicle in March, 2008. No tumor marker was elevated. Imaging studies including ultrasonography and magnetic resonance imaging showed a 13 mm tumor consisting of both a solid portion and a hemorrhagic cyst. A malignant tumor could not be ruled out completely based on examinations and his medical history. Tumor resection with partial orchiectomy was planned after informed consent. Preoperative serum concentration of free testosterone was 8.4 pg/ml, and motile sperm were found in the semen analysis. The tumor was resected while the spermatic cord was clamped transiently. The pathological diagnosis of frozen sections confirmed no malignancy, and the final pathological result was mature teratoma, no evidence of malignancy. No androgen substitution has been required. Furthermore, a few normal motile sperm were detected in the ejaculated semen after the surgery. Organ sparing surgery for the contralateral testicular tumor following orchiectomy, can be considered to avoid infertility and hormonal substitutions. PMID- 21586888 TI - [Chemotherapy for urological cancer : usefulness and feasibility of current protocols]. AB - In this symposium, we discussed the usefulness and feasibility of current chemotherapy protocols for urological cancers including renal cell carcinoma, urothelial cancer, prostate cancer and testicular cancer. (1) Renal cell carcinoma : Although molecular targeted therapy is now becoming a standard therapy for metastatic renal cell carcinoma, the current situation is somehow confusing due to unknown adverse effects and lack of guidelines for indication of each compound. (2) Urothelial cancer : gemcitabine and cisplatin (GC) therapy is taking over methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) therapy because of less toxicity. We focused on a novel biomarker, hENT1, to predict the anti tumor effect of GC therapy. (3)Prostate cancer : The survival benefit of docetaxel for castration resistant prostate cancer was proven by large clinical trials. We dealt with uracil and tegafur (UFT) therapy which has been widely used in Japan. (4)Testicular cancer : It is needles to say that BEP therapy was established as a standard induction therapy for metastatic testicular cancer. However, regarding salvage chemotherapy, it is still controversial whether vinblastine, ifosphamide and platinum (VIP), paclitaxel, ifosphamide and platinum (TIP) and high dose chemotherapy should be selected. PMID- 21586889 TI - [Current status in molecular-targeted therapy and IFNalpha for renal cell carcinoma in Japan]. AB - It has been two years since molecular-targeted therapy became available for advanced renal cell carcinoma (RCC) in Japan. It shall be validated whether molecular-targeted therapy really improved the prognosis of patients with advanced RCC in the near future. Here we review the two phase III clinical studies that demonstrated the superiority of sunitinib and temsirolimus over IFNalpha and discuss optimal therapy including IFNalpha for advanced RCC in the future biomarker era. PMID- 21586890 TI - [The prognostic significance of human equilibrative nucleoside transporter1 (hENT1) expression in metastatic bladder cancer patients treated with gemcitabine cisplatin based combination chemotherapy]. AB - Systemic combination chemotherapy, such as the methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) regimen, has shown certain activity in advanced bladder cancer, but is associated with a significant toxicity burden, with a treatment-related mortality of about 4%. Therefore, a great deal of interest has been focused on the gemcitabine-cisplatin (GC) combination chemotherapy which showed the same antitumor effect as MVAC chemotherapy with far less toxicity. Indeed, the GC regimen is now frequently administered as the first-line chemotherapy against metastatic bladder cancer. For the present, GC/MVAC regimens constitute alternative platform chemotherapy, until new evidence based strategy can be demonstrated. Accordingly it is important to be able to predict whether a regimen is effective in each patient with bladder cancer before the initiation of chemotherapy. Clinicopathological factors as the Karnofsky performance status and the presence of visceral metastases are well-established prognostic markers for poor survival. However, they are inadequate to predict the optimal therapeutic regimen for each individual patient. As for the predictive marker of cisplatin, ERCC1 may predict survival in bladder cancer treated by platinum-based therapy. The predictive potential of gemcitabine has not been previously considered in advanced bladder cancer treated by gemcitabine-combined systemic chemotherapy. In our retrospective study, the predictive value of a high expression level of hENT1 was assessed in bladder cancer treated by gemcitabine combined combination chemotherapy. PMID- 21586891 TI - [Combination chemotherapy of docetaxel and UFT against hormone refractory prostate cancer]. AB - Docetaxel-based chemotherapy has been shown to be effective and well tolerated by Japanese patients with metastatic hormone-refractory prostate cancer (HRPC). This study was undertaken to assess the feasibility of docetaxel in combination with UFT (a combination of tegafur and uracil) in Japanese patients with HRPC. Ten patients aged 60-86 years with HRPC, who were pre-treated with hormonal therapy and expected to have more than 3 month survival and without major organ dysfunction, were included in this study. Treatment consisted of docetaxel 70 mg/m2 every 3 weeks plus UFT 260 mg/m2 /day. The primary end point was prostate specific antigen (PSA) response, and the secondary end points included progression-free survival and toxicity. Nine patients were evaluable for efficacy and toxicity. The PSA response rate was 50% (1 CR and 4 PR). The most common non hematological adverse events (of any grade) possibly related to treatment were neutropenia and anorexia. Grade 3/4 neutropenia and anorexia occurred in 50 and 20% of patients, respectively. The combination of docetaxel and UFT was feasible and active in Japanese patients with HRPC, with a manageable adverse-event profile similar to that observed in lung cancer chemotherapy. PMID- 21586892 TI - [Salvage chemotherapy for patients with germ cell cancer]. AB - Bleomycin, etoposide and platinum (BEP) therapy is used on patients with metastatic germ cell cancer but approximately 20-30% of these patients fail to achieve a durable complete response following the administration of BEP therapy. For such patients, salvage chemotherapy is subsequently considered. Although either VIP of VeIP therapy had been tended to be selected as salvage chemotherapy, recent studies have suggested two novel strategies as an alternative to conventional regimen for salvage chemotherapy. One is high-dose chemotherapy, while the other is the use of a regimen containing newly developed chemotherapeutic agents. In this study, we summarize the current status of therapeutic strategy for patients with metastatic germ cell cancer refractory to BEP therapy, and then present the experience with salvage chemotherapy at our institution. PMID- 21586893 TI - Thrombophilic screening in Turner syndrome. AB - AIM: The aim of this study was to determine, in patients with Turner syndrome (TS), the prevalence of thrombophilic disorders correlating with a higher risk of venous thromboembolism (VTE), to evaluate if thrombophilia is associated with the genetic features of these patients and whether screening before hormone replacement therapy (HRT) is advisable. PATIENTS AND METHODS: We examined 82 TS patients. In all patients we analyzed activated factor VIII:C, fibrinogen, antithrombin (AT), protein C (PC), protein S (PS), activated PC resistance, and homocysteine. For every patient, an investigation for mutations in prothrombin G20210A, factor V R506Q, methylenetetrahydropholate reductase (MTHFR) C 677T and A1298C was conducted. RESULTS: Low values of PC in 3 patients (3.70%), low values of PS in 12 (14.81%), and hyperhomocysteinemia in 4 (4.87%) were found; 52 girls (64.2%) presented hyperfibrinogenemia. Three patients were heterozygous for the prothrombin G20210A allele mutation (3.66%) and the factor V mutation was present in 4 patients (4.88%). No TS patient had a homozygous mutation. Mutations in the MTHFR gene were present in 62 girls, in 17 patients (20.7%) they were homozygous and in 45 patients (54.88%) heterozygous. CONCLUSIONS: Considering the increased risks with the association between VTE and the higher prevalence of PC and PS deficiencies, TT genotype mutations and high level of fibrinogen, it is advisable to perform a complete thrombophilia screening in TS patients before starting HRT. PMID- 21586894 TI - Cardiovascular risk and all-cause mortality attributable to diabetes: Tehran lipid and glucose study. AB - AIM: To quantify the burden of cardiovascular diseases (CVD), and all-cause mortality attributable to diabetes. SUBJECTS AND METHODS: Data on an 8.6-yr follow-up of 6331 participants (2741 men), free of CVD at baseline, were analyzed to determine the burden of CVD and all-cause mortality attributable to self reported and screen-detected diabetes mellitus (SRDM and SDDM, respectively). Risks of events of interest were separately assessed for women and men using Cox proportional-hazard model. RESULTS: The mean age at baseline was 47 yr with 997 (15.7%) of participants having diabetes (men 14.8%, women 16.5%). SRDM and SDDM prevailed in 9.7% (men 9.2, women 10.2%) and 6.0% of participants (men 5.7, women 6.3%), respectively. During follow up (52,404 person-yr), we observed 447 incident cases of CVD [387 had coronary heart disease (CHD)] and 209 deaths. Among men, participants with SDDM had increased relative hazard for all-cause mortality translated to a population attributable risk fraction (PAF) of 10.1%. Among women, SDDM was associated with CVD and CHD but not with all-cause mortality; so that 9.3% and 8.8% of CVD and CHD events were respectively attributable to the SDDM. If SRDM had been eliminated from the population, the incidences of CVD, CHD, and death would have decreased by 10.5, 9.5, and 17.3% in men; and 22.0, 24.2, and 17.8% in women, respectively. CONCLUSION: SDDM and SRDM have high PAF for all-cause mortality and CVD. Besides diabetes treatment and prevention, screening to detect undiagnosed diabetes should warrant high priority among the public health strategies to lower the incidence of CVD and mortality. PMID- 21586895 TI - Hip circumference is associated with high density lipoprotein cholesterol response following statin therapy in hypertensive subjects. AB - AIM: This report investigated the relationship between anthropometric measurements of body fat distribution and lipid response to statins in hypercholesterolemic hypertensive patients. METHODS: We prospectively examined 129 subjects who used either simvastatin 20 mg/day (no.=83) or atorvastatin 10 mg/day (no.=46) for 3 months. Anthropometry included evaluation of body mass index, waist and hip circumferences, and waist-to-hip-ratio. RESULTS: Significant decreases in LDL (p<0.001), total cholesterol (p<0.001), and triglycerides (p=0.04) levels were detected after 3 months of therapy in the whole sample. At baseline, only an inverse correlation between waist circumference and HDLcholesterol levels was detected (r=-0.18; p=0.04). Conversely, a direct relationship between hip circumference and HDLcholesterol response to statins was found in the whole sample (r=0.24; p=0.006), while no other anthropometric measurement displayed significant correlation with lipid changes. The association between HDL-cholesterol response and hip circumference was further confirmed by stepwise regression analysis adjusted for baseline HDL-cholesterol levels, metabolic syndrome, body mass index, and waist circumference. CONCLUSIONS: Hip circumference, a surrogate marker of peripheral adiposity, is associated with HDL cholesterol changes following statin therapy in hypertensive patients. PMID- 21586898 TI - Barley stripe mosaic virus-induced gene silencing (BSMV-IGS) as a tool for functional analysis of barley genes potentially involved in nonhost resistance. AB - Barley is an alternative host for the rice blast fungus Magnaporthe oryzae but is resistant to Magnaporthe species associated with the grass genera Pennisetum and Digitaria. The latter cases are examples for nonhost resistance which confers effective and durable protection to plants against a broad spectrum of pathogens. Comparative transcript profiling of host and nonhost interaction revealed an early and pronounced change in gene expression in epidermal tissue of barley infected with a Magnaporthe nonhost isolate. Interestingly, this set of genes did not overlap considerably with the transcriptional response of barley against nonhost rust or powdery mildew isolates. For a functional testing of candidate genes a combined approach of virus-induced gene silencing (VIGS) and subsequent pathogen challenge was established. As anticipated, VIGS-mediated down-regulation of Mlo-transcripts led to higher resistance against Blumeria graminis f.sp. hordei and enhanced susceptibility against M. oryzae. PMID- 21586896 TI - Basal insulin-like factor 3 levels predict functional ovarian hyperandrogenism in the polycystic ovary syndrome. AB - AIM: The aims of the study were to understand the association between insulin like factor 3 (INSL3) and functional ovarian hyperandrogenism (FOH) in PCOS and the regulatory role played by LH. SUBJECTS AND METHODS: Fifteen PCOS women were classified as FOH (FOH-PCOS, no.=8) and non-FOH (NFOH-PCOS, no.=7) according to the response of 17OH-progesterone to buserelin (a GnRH analogue) with respect to 15 controls. FOH-PCOS and NFOH-PCOS were compared for basal INSL3 levels. In addition, the effect of buserelin on INSL3 concentrations and the relationship between basal and buserelin-stimulated LH and 17OH-progesterone and INSL3 were evaluated. RESULTS: Basal INSL3 levels were higher in FOH-PCOS than NFOH-PCOS (p=0.001) and controls (p=0.001), whereas they did not differ between NFOHPCOS and controls. In addition, FOH-PCOS had a higher response of LH to buserelin with respect to NFOH-PCOS. Within all PCOS women the levels of INSL3 positively correlated with free testosterone (p=0.022) and negatively with SHBG (r= p=0.031). Moreover, positive correlations with the absolute increase of 17OH progesterone (p<0.001) and with the LH area under the curve (p=0.001) after buserelin administration were found. In the multiple regression analysis INSL3 persisted significantly correlated only with 17OH-progesterone response to buserelin. Finally, INSL3 was not significantly modified after buserelin administration either in FOHPCOS or in NFOH-PCOS. CONCLUSIONS: These data suggest that INSL3 is related to FOH in PCOS women, but this association seems not to be mediated by LH, further reinforcing the concept that a pathophysiological heterogeneity for ovarian hyperandrogenism in PCOS exists. PMID- 21586899 TI - Diverging functions among calreticulin isoforms in higher plants. AB - The ER chaperone calreticulin plays vital roles in numerous cellular processes, including Ca2+-homeostasis, apoptosis, and cell adhesion, in animal cells. Although calreticulin has been systematically characterized in animal cells, the focus has been on one of the isoforms. However, recent advances in the plant calreticulin field have revealed functional divergence of calreticulin isoforms. While two of the plant isoforms appear to work within a general ER chaperone framework, the third isoform is associated with folding of receptors for brassinosteroids and bacterial peptides. Hence, the discovery of functional specialization of plant calreticulins opens up new vistas for calreticulins also in the animal field. PMID- 21586901 TI - Microarray coupled with methyl-CpG targeted transcriptional activation (MeTA array) identifies hypermethylated genes containing the stringent criteria of CpG islands at high frequency. AB - The identification of genes transcriptionally silenced by DNA hypermethylation is important in understanding the molecular basis of epigenetically regulated biological processes such as X chromosome inactivation, genomic imprinting and cancer development. Our previously developed methyl-CpG targeted transcriptional activation (MeTA) method reactivates epigenetically silenced genes by using a methyl-CpG binding domain from MBD2 with a transcriptional activation domain. We applied either MeTA or a conventional DNA demethylating agent, 5-aza-cytidine (Aza-CR), to human embryonic kidney cell line 293T and analyzed gene expression profiles by microarray: 138 and 202 genes that are upregulated 5-fold or more were identified by MeTA and Aza-CR, respectively. The top ten upregulated genes detected by MeTA were further analyzed. We found associations between expressional restorations by MeTA, methylation status and NFkappaB (AD)-MBD fusion protein bindings in CpG islands (CGIs) around the transcription start site of the genes. Importantly, MeTA can upregulate genes meeting the stringent criteria of CGIs defined by Takai and Jones at the promoter region at higher frequency: 109 of 138 (79.0%) genes in MeTA vs. 121 of 202 (59.9%) genes in Aza CR. Interestingly, only 27 genes were upregulated by both methods; MeTA may identify methylated genes that show low levels of induction by the DNA demethylating agents; demethylating agents may also induce factors that help re expression of genes that harbor less stringent or no CGIs. These results suggest that microarray coupled with MeTA (MeTA-array) is an efficient alternative way to identify transcriptionally silenced genes by DNA hypermethylation. PMID- 21586900 TI - Methylation, memory and addiction. AB - Dynamic chromatin remodeling is at the heart of most biological processes including gene transcription, DNA replication and repair, cell differentiation and apoptosis. Chromatin remodeling as a result of covalent histone modifications, including histone acetylation, methylation or SUMOylation, play important roles in these processes. Similarly, direct chemical modification of DNA, most notably DNA methylation, also plays a key role in controlling gene expression and basic aspects of cell biology. Memory, one of the most fundamental of all brain functions, is a complex process involving diverse cellular signaling cascades and coordinated regulation of entire networks of genes. Synaptic plasticity, which is defined as activity-dependent changes in synaptic strength between neurons, provides the cellular basis of memory. The role for covalent histone modifications in synaptic plasticity and in learning and memory has been now been firmly established. In contrast, much less had been known concerning DNA methylation in memory formation and storage. Emerging evidence now suggests that DNA methylation plays a central role in these processes, likely by directly influencing the expression of genes involved in synaptic plasticity. PMID- 21586902 TI - Cardiac genes show contextual SWI/SNF interactions with distinguishable gene activities. AB - Recent experimental evidence indicates that cardiac and chromatin remodeling are associated with changes in gene expression mediated by Brahma-related gene 1 (Brg1), a member of the large group of SWI/SNF subunits. The second catalytic member of this family is Brahma (Brm), which shares close sequence homology to Brg1. Despite the sequence similarities, these determinants are found in distinct regulatory complexes; however, the precise nature and role of these remodeling enzymes in the failing heart remains unknown. Here we have hypothesized that Brg1 and Brm form distinct complexes in regulating gene expression in an animal model of cardiac hypertrophy. We have identified that the hypertrophic myocardium is characterized by profound morphological changes associated with increased expression of ANP (Nppa), BNP (Nppb) and beta-MHC (Myh7) genes, correlating with reduced expression of the alpha-MHC (Myh6) and SERCA2A (Atp2a2) genes. Histone deacetylase inhibition prevented left ventricular hypertrophy indicating that the re-expression of gene activity can be associated with both contextual and distinct SWI/SNF interactions. We hypothesize that cardiac hypertrophy and the fetal gene expression program are associated with distinguishable binding of Brm and Brg1 on genes present in distinct complexes, suggesting possible independent regulatory roles. PMID- 21586903 TI - "ORCanization" on heterochromatin: linking DNA replication initiation to chromatin organization. AB - Specialized complexes in eukaryotic cells recognize defined epigenetic histone marks to mediate chromatin organization. DNA replication, cell cycle progression and chromatin organization are intimately linked to one another. In addition to having roles in DNA replication initiation, the human Origin Recognition Complex (ORC) binds along with ORC-associated proteins ORCA/ LRWD1 to prominent transcriptional repressive lysine methylation marks and localizes to HP1 containing heterochromatic structures. In humans, Drosophila and Xenopus, ORC associates with HP1, and this interaction is crucial for heterochromatin organization. Further, several subunits of human ORC are required for centromere and telomere function and participate in chromosome segregation. The conserved function of ORC in replication initiation as well as in organization and maintenance of chromosome structure suggests that these cellular events are well coordinated. PMID- 21586904 TI - Human diversity in wound care: a report from the field. PMID- 21586907 TI - Correct coding edits caused Medicare claims denials for revised debridement codes. PMID- 21586908 TI - Initial clinical assessment of a novel wound management system: a case series. AB - The importance of exudate management for maintaining local moisture balance and avoiding maceration in the chronic wound environment is well established. The authors performed the initial clinical testing of a novel wound management system, Sepaderm (Aalnex, Inc, Irvine, California), designed to vertically wick and sequester excess exudate away from wound/periwound tissues to promote a healthy wound environment. In this series of 14 patients with lower-extremity chronic venous leg and diabetic foot ulcers, the 3-component system was well tolerated and demonstrated the ability to prevent exudate leakage onto periwound tissue and reduce existing pain and itching. All ulcers lasting 1.2 to 360 months were previously treated with standard therapies, including human cell-derived skin substitutes in some of the patients. After treatment with the new system for 7 to 174 days, 8 patients had various degrees of wound closure, ranging from 44% to 100%. The 6 patients who failed to show wound closure were treated with the new system for an average of 5.7 days, but demonstrated other clinical benefits. Future studies in larger patient populations with quantitative wound closure assessments, as well as measurements of exudate, periwound maceration, and pain management, are needed. PMID- 21586909 TI - Knowledge and management of pressure ulcers: impact of lecture-based interactive workshops on training of nurses. AB - OBJECTIVE: The objective of this study was to determine if a structured workshop on knowledge and management of pressure ulcers (PrUs) for nurses led to an improvement of knowledge in the participants. METHODS: Nurses attended an interactive lecture-based workshop on knowledge and management of PrUs. After the participants were invited into the study, they were asked to take a test consisting of multiple-choice questions (MCQs) about the subjects covered in the presentation. The MCQ test was repeated after the teaching session to determine the participants' knowledge and practical skills. RESULTS: Twenty-eight nurses participated in the workshop. The MCQ test consisted of 21 questions. When the scores of the control test were compared with the scores after teaching, a substantial and statistically significant development was observed (mean, 11.1 [SD, 2.1], and mean, 14.6 [SD, 0.9] on 21 items, before and after teaching, respectively, P < .001). CONCLUSION: A lecture-based workshop on knowledge and management of PrUs helps improve nurses' knowledge and allows them to overcome training deficiencies. PMID- 21586910 TI - Cultured keratinocytes on urinary bladder matrix scaffolds increase angiogenesis and help in rapid healing of wounds. AB - INTRODUCTION: Urinary Bladder Matrix (UBM) is an extracellular matrix (ECM) scaffold. It is now used in wound care management of partial and full-thickness wounds where conventional methods for wound care usually fail to give satisfactory results. OBJECTIVE: In this study, the authors are comparing the healing of full-thickness excisional wounds in New Zealand rabbits using either UBM scaffolds alone or in combination with cultured keratinocytes. The wounds were compared grossly and histologically. MATERIALS AND METHODS: It is a comparative controlled study including 40 full-thickness wounds in 2 groups. Group (A) wounds: treated with UBM scaffolds, Group (B) wounds: treated with UBM scaffolds with cultured keratinocytes. The wounds were examined grossly after 1, 2, and 3 weeks, and were examined histologically at the end of the 3rd week using ordinary hematoxylin-eosin staining techniques. RESULTS: All the wounds healed completely by the end of the 3rd week. Early wound contraction was significantly less in group B. More angiogenic response was evident in all specimens of group B. CONCLUSION: This study shows that adding cultured keratinocytes to the rough surface of the UBM scaffold may be beneficial in reducing early wound contraction and improving wound vascularity in treatment of full-thickness wounds. PMID- 21586911 TI - Preventing pressure ulcers in people with spinal cord injury: targeting risky life circumstances through community-based interventions. AB - OBJECTIVE: The objectives of the study were to sensitize practitioners working with individuals with spinal cord injury (SCI) to the complex life circumstances that are implicated in the development of pressure ulcers (PrUs) and to document the ways that interventions can be adapted to target individual needs. METHODS: This study was a content analysis of weekly fidelity/quality control meetings that were undertaken as part of a lifestyle intervention for PrU prevention in community-dwelling adults with SCI. RESULTS: Four types of lifestyle-relevant challenges to ulcer prevention were identified: risk-elevating life circumstances, communication difficulties, equipment problems, and individual personality issues. Intervention flexibility was achieved by changing the order of treatment modules, altering the intervention content or delivery approach, or going beyond the stipulated content. CONCLUSION: Attention to recurrent types of individual needs, along with explicit strategies for tailoring interventions published in a manual, has the potential to enhance PrU prevention efforts for adults with SCI. PMID- 21586913 TI - Your electronic medical record training checklist. PMID- 21586914 TI - Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. AB - OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease related metabolic activity pattern. PMID- 21586915 TI - Piribedil-induced sleep attacks in patients without Parkinson disease: a case series. AB - BACKGROUND: Sleep attacks were initially described in 1999 in patients with Parkinson disease (PD) treated by dopamine agonists (DAs). Because the respective role of DAs or PD-induced excessive daytime sleepiness is still unclear, reports of sleep attacks in non-PD patients treated with DA would support the specific role of these drugs. Piribedil, a nonergot dopamine D2/D3 agonist with alpha(2) noradrenergic properties, is indicated in the treatment of PD as well as in patients with circulatory disorders. After a spontaneous report of sleep attack associated with piribedil use in a non-PD patient, we reviewed other cases from the French pharmacovigilance database. MATERIALS AND METHODS: Cases of piribedil associated with sleep attacks recorded between 1988 and December 2008 were identified in the French Pharmacovigilance database. Cases were retained for analysis only if patients were treated for conditions other than PD. RESULTS: Overall, a total of 35 cases of piribedil-induced sleep disorders were retrieved, and 7 cases suggestive of sleep attacks were retained for analysis. The mean time to onset after starting piribedil was 2.5 days. Piribedil was the only suspected drug in all but 1 patient. Complete recovery was noticed after piribedil discontinuation in all patients, and recurrence of symptoms was observed after piribedil reintroduction in 1 patient. CONCLUSIONS: Our series suggests that piribedil may be associated with sleep attack disorders independently of the treated disease and supports the prominent role of DAs in sleep disorders. PMID- 21586916 TI - Methylphenidate treatment in pediatric patients with attention deficit/hyperactivity disorder and comorbid trichotillomania: a preliminary report. AB - OBJECTIVES: Trichotillomania (TTM) is a heterogenic mental disorder with a high rate of comorbidity and stressful life events (SLEs). Serotonergic and dopaminergic dysfunction are implicated in the pathophysiology of TTM. As in other impulse control disorders, increased prevalence of attention deficit/hyperactivity disorder (ADHD) is reported in patients with TTM as well. This study aimed to assess the efficacy and tolerability of methylphenidate (MPH) treatment in children and adolescents who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for both ADHD and TTM. METHODS: Nine children and adolescents, aged 6 to 18 years, diagnosed with ADHD and TTM, were treated with MPH for a 12-week period. The severity of ADHD was assessed using the ADHD Rating Scale, and the hair pulling was rated using the Massachusetts General Hospital Hair-Pulling Scale. Additional scales were used for assessing depression and anxiety levels, and history of SLE was recorded. RESULTS: Significant improvement was detected in ADHD after MPH treatment (P < 0.003), but no significant change was observed in hair pulling, as measured by the Massachusetts General Hospital Hair-Pulling Scale (P = 0.096) or in depression and anxiety levels. Lack of response of TTM to MPH (improvement, <50%) was associated with higher rate of positive SLE history (P = 0.047). CONCLUSIONS: Some efficacy of MPH treatment was shown in TTM patients with low rate of SLE. A large-scale study is mandatory to evaluate the efficacy of MPH for TTM in ADHD/TTM patients. PMID- 21586917 TI - Neurobiological background for the development of new drugs in schizophrenia. AB - Psychopharmacology of schizophrenia has remained static for many years because the mechanisms explored have been basically monoaminergics, primarily focused toward the modification of dopaminergic function and, later on, serotonergic. In fact, most of the antipsychotics introduced in clinical practice in the last years have been antagonists or selective agonists of these receptors (D(2)/5 HT(2)). The exploration of other receptor pathways, and in particular those additionally involved in the action of the paradigmatic "atypical" antipsychotic clozapine (ie, cholinergic and noradrenergic), has not been very significant. Besides, research in the antipsychotics field has developed also by exploring pathways that are beyond the spectrum of clozapine. Among the most promising mechanisms are those based on the glutamatergic hypothesis of schizophrenia (agonists at the glycine-binding modulatory site of the N-methyl-D-aspartate receptor, glycine transporter inhibitors, modulators of the AMPA [alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid] receptor and selective agonists of the metabotropic receptor Glu(2)). Other less classic pathways are also under study and have led to some agents that are found in very early stages of development such as those acting on sigma receptors, cholecystokinin antagonists, neurotensin agonists, neurokinin receptor antagonists, GABAergic (+-aminobutyric acid [GABA]) enhancers, and cannabinoid(gamma-aminobutiric) receptor modulators. PMID- 21586918 TI - Serotonin syndrome due to duloxetine. AB - Serotonin syndrome is a toxic condition due to serotoninergic hyperstimulation, which is caused mostly by serotonergic agents either in overdose or in combination. The diagnosis is purely clinical and poorly validated. We described a patient with tremor, mydriatic pupils, clonus, and ataxia after a single dose of duloxetine; on the dosage of admission. Duloxetine belongs to a large class of antidepressants called reuptake inhibitors. The case is presented to emphasize this possible toxicity due to increasing availability of serotonergic agents. It is a complex but easily preventable and recognizable condition. We believe this to be one of the rare reports of serotonin syndrome associated with duloxetine. PMID- 21586919 TI - Adjunctive gabapentin for treatment-resistant insomnia of bipolar disorder: a case report. AB - We report a case with bipolar II disorder having mixed features, in which refractory insomnia persisted. We diagnosed his case as mixed depression with mood fluctuations because increased impulsivity and buying sprees became remarkable, with diminished ability to think or concentrate. Switching to carbamazepine and risperidone improved his mood fluctuations and impulsivity. Nevertheless, his intermittent awakening (fragmentation of the sleep-wake rhythm), related dysfunctional beliefs, anxiety about sleep, and mild impulsivity persisted. The addition of various benzodiazepine sleeping drugs, bromovalerylurea, and antipsychotics did not improve insomnia. His intractable insomnia was markedly responsive to gabapentin, engendering further improvement of mood symptoms. Eventually, its efficacy achieved his reinstatement at work. Results of this case suggest the clinical use of gabapentin for treating bipolar disorder, especially in cases with intractable insomnia, which is a very important point in the symptoms and therapeutics of bipolar disorder. PMID- 21586920 TI - Effective treatment with clozapine and valproate for refractory schizophrenia like psychosis after cerebellar hemorrhage. AB - BACKGROUND: The cerebellum has traditionally been regarded as an organ of motor coordination. However, the importance of the cerebellum in psychiatric disorders, behavior, and cognition is increasingly being recognized. There is no consensus concerning treatment of schizophrenia-like psychosis after cerebellar pathology. Reports describe the use of several antipsychotics, either alone or in combination with antidepressants or lithium. Clozapine is used for the treatment of refractory schizophrenia, but there are no reports of its use in the above mentioned situation. CASE PRESENTATION: We report the case of a 20-year-old woman who developed a schizophrenia-like psychosis after rupture of arteriovenous malformation at 13 years of age. The psychotic symptoms proved to be resistant to treatment, and several psychopharmacological schemas were tried. The clinical picture only showed consistent improvement with the combined use of clozapine and valproate. CONCLUSIONS: The relationship between chronic psychosis and cerebellar pathology remains poorly understood. Cases like the present one suggest that clozapine and valproate may be used safely and effectively in refractory schizophrenia-like psychosis associated with cerebellar pathology. PMID- 21586921 TI - Letter regarding "Treatment effects of gabapentin for primary insomnia". PMID- 21586922 TI - Intravenous mirtazapine. PMID- 21586923 TI - Diffusion-weighted imaging of the abdomen at 3 T: image quality comparison with 1.5-T magnet using 3 different imaging sequences. AB - OBJECTIVE: This study aimed to perform comparisons between diffusion-weighted imaging (DWI) sequences at 3 T with 1.5 T. METHODS: Thirteen healthy volunteers underwent abdominal DWI on both 3- and 1.5-T magnets using 3 sequences including breath hold without parallel imaging (PI), breath hold with PI, and free breathing with PI at b50 and b1000. Artifacts and subjective image quality scores, signal intensity, and apparent diffusion coefficient were compared. RESULTS: For breath hold without PI, higher artifact was noted at 3 T b50 compared with 1.5 T (P < 0.0001). For b50 and b1000 breath hold with PI, artifacts were not different between the magnets, but image quality was better at 3 T (P = 0.04 and P = 0.02, respectively). For b50 and b1000 free breathing sequences, artifact and image quality scores were significantly better at 1.5 T. For breath hold acquisitions, the signal-to-noise ratio of gallbladder, kidneys, and pancreas was generally higher and that of the liver was lower on 3 T. Imaging at 3 T showed significantly higher image quality and lower artifacts for breath hold with PI compared with free breathing. Most apparent diffusion coefficients were not significantly different between the 2 magnets (P > 0.05). CONCLUSIONS: Three-tesla magnets can provide good images using breath hold with PI sequence. PMID- 21586924 TI - Diffusion-weighted imaging in the characterization of focal liver lesions: efficacy of visual assessment. AB - OBJECTIVES: The objective of the study was to assess the value of visual assessment of signal intensities on b800 diffusion-weighted images and apparent diffusion coefficient (ADC) maps in differentiation of benign and malignant focal liver lesions (FLLs). METHODS: Approval for this retrospective study was obtained from the institutional review board. One hundred forty-three FLLs in 65 patients (38 women, 27 men; mean age, 50.8 years) underwent magnetic resonance (MR) imaging and diffusion-weighted imaging (DWI) with a respiratory-triggered single shot echo-planar imaging sequence. Focal liver lesions were evaluated visually according to the signal intensities on b800 and ADC map images, and ADC values were also calculated. The conventional MR imaging, follow-up imaging findings, and histopathologic data were regarded as gold standard. Normal distribution was assessed with Kolmogorov-Smirnov test. The accuracies of visual assessment and ADC values in differentiating benign and malignant FLLs were assessed with the Student t test, and threshold values were determined with receiver operating characteristic curve analysis. RESULTS: By using a cutoff value of 1.21 * 10-3 mm2/s, ADC had a sensitivity of 100%, a specificity of 89.3%, and an accuracy of 92.3% in the discrimination of malignant FLLs. With the visual assessment of the DWIs and ADC maps, malignant lesions were differentiated from benign ones, with 100% sensitivity, 92.2% specificity, and 94.4% accuracy. Although some benign lesions were interpreted as malignant, no malignant lesion was determined as benign in visual assessment. CONCLUSIONS: Most FLLs are benign ones such as hemangiomas and cysts, which can be readily and practically characterized only by using visual assessment of DWIs without requiring time-consuming conventional and dynamic contrast-enhanced imaging sequences. Some benign lesions that are falsely interpreted as malignant can be further characterized by using conventional and contrast-enhanced MR studies. PMID- 21586925 TI - Role of diffusion-weighted magnetic resonance imaging in characterization of renal tumors. AB - OBJECTIVE: To evaluate the role of diffusion-weighted magnetic resonance (MR) imaging in the characterization of renal tumors. MATERIALS AND METHODS: Prospective study was conducted on 52 consecutive patients (24 males and 28 females) with renal tumor. They underwent diffusion-weighted echo planar MR imaging of the abdomen with b-factor of 0 and 800 seconds/mm2. The apparent diffusion coefficient (ADC) value of the renal tumor was calculated and correlated with histopathological results. RESULTS: The mean ADC value of malignant renal tumors (1.56 +/- 0.26 * 10-3 mm2/s) was significantly different (P = 0.001) from that of benign tumors (1.87 +/- 0.50 * 10-3 mm2/s). Selection of 1.84 * 10-3 mm2/s as a cutoff point of ADC value to predict renal malignancy revealed accuracy of 89%, sensitivity of 89%, and specificity of 89%. The cutoff point of ADC value to differentiate renal cell carcinoma (RCC) from other malignancy (1.15 * 10-3 mm2/s) revealed 72% accuracy, 95% sensitivity, 50% specificity. The cutoff point of ADC value used to differentiate clear and papillary RCC from other subtypes of RCC was 1.84 * 10-3 mm2/s with an accuracy of 89%, sensitivity of 89%, and specificity of 89%. CONCLUSION: Apparent diffusion coefficient value can differentiate benign from malignant renal tumors and may be helpful for the differentiation of the histologic subtypes of RCC. PMID- 21586926 TI - Quantitative enhancement washout analysis of solid cortical renal masses using multidetector computed tomography. AB - PURPOSE: The aim of the study was to prospectively assess the utility of quantitative enhancement washout method in the differentiation of benign solid renal masses from various subtypes of malignant masses using multidetector computed tomography. METHODS: In a prospective investigation from January 2009 to May 2010, 97 patients with solid renal masses underwent CT scan examination with unenhanced, arterial, parenchymal, and delayed phases. The following features were analyzed: the maximum attenuation value in each phase, attenuation difference (enhancement) of the mass in each phase from the unenhanced phase (DeltaH), and parenchymal and delayed phases' washout. Of these patients, 82 (85%) underwent unilateral radical nephrectomy, 15 (15%) underwent partial nephrectomy. Group comparison was performed with the Kruskal-Wallis test and Mann Whitney U test. RESULTS: The masses included in our study were 45 clear cell renal cell carcinomas (CCRCCs); 18 chromophobe renal cell carcinomas, 16 papillary (PRCC), 14 oncocytomas, and 4 minimal fat containing angiomyolipomas. In the arterial phase, the CCRCC was the most enhancing type and could be differentiated from other renal masses (benign or malignant) with high sensitivity and specificity. In the parenchymal phase, the CCRCCs demonstrated the highest washout. Chromophobe renal cell carcinomas showed the second highest washout in this phase. Benign lesions and PRCCs did not exhibit significant washout in this phase. In the delayed phase, the malignant lesions (with the exception of PRCCs) showed the highest washout. Benign lesions showed significant washout but less than malignant lesions. CONCLUSIONS: Multiphasic multidetector CT utilizing arterial-phase attenuation and quantitative enhancement washout method could help in the preoperative differentiation of various types of solid renal masses. PMID- 21586927 TI - Magnetic resonance manifestations of hyperreactio luteinalis. AB - OBJECTIVE: Hyperreactio luteinalis (HL) is a rare benign physiological ovarian enlargement associated with gestational trophoblastic disease or pregnancy, and may mimic neoplasm. We evaluated magnetic resonance findings of HL to distinguish from neoplasm by using diffusion-weighted imaging with apparent diffusion coefficient (ADC) measurement. METHODS: Magnetic resonance manifestations of 15 cases of HL in 8 women (mean age, 32 years) were retrospectively evaluated. Diffusion-weighted imaging (b = 0 and 800 seconds/mm2) was obtained in 11 cases of HL, and ADC was compared with that in solid portions of 18 ovarian cancers. RESULTS: All cases of HL appeared as multilocular cystic masses with septations mimicking mucinous cystic tumors. Intervening ovarian stroma exhibited hyperintensity on diffusion-weighted imaging. The ADC in ovarian stroma in HL was significantly higher than that in solid portions of ovarian cancers. CONCLUSION: Ovarian stroma in HL may mimic solid tumorous components in mucinous tumors; however, high ADC reflecting edematous, luteinized stroma may be helpful for the diagnosis of HL. PMID- 21586928 TI - Automatic liver segmentation method featuring a novel filter for multiphase multidetector-row helical computed tomography. AB - PURPOSE: To introduce an automatic liver segmentation method that includes a novel filter for multiphase multidetector-row helical computed tomography. MATERIALS AND METHODS: We acquired 3-phase multidetector-row computed tomographic scans that included unenhanced, arterial, and portal phases. The liver was segmented using our novel adaptive linear prediction filter designed to reduce the difference between filter input and output values in the liver region and to increase these values outside the liver region. RESULTS: The segmentation algorithm produced a mean dice similarity coefficient (DSC) value of 91.4%. CONCLUSION: The application of our adaptive linear prediction filter was effective in automatically extracting liver regions. PMID- 21586929 TI - Effect of lapatinib on hepatic parenchymal enhancement on gadoxetate disodium (EOB)-enhanced MRI scans. AB - We present changes seen on hepatobiliary phase (HBP)-gadoxetate disodium (EOB) enhanced magnetic resonance image of a woman with liver metastases who was treated with lapatinib. After treatment, the HBP images appeared like portal venous phase images. This suggests that lapatinib, an inhibitor of organic anion transporting polypeptide 1B1, one of the substrates of EOB, inhibits EOB uptake by hepatocytes. In patients treated with lapatinib, the ability to diagnose liver tumors on HBP images may be compromised. PMID- 21586930 TI - Use of high-pitch dual-source computed tomography of the abdomen and pelvis to markedly reduce scan time: clinical feasibility study. AB - BACKGROUND: Increasing image pitch in computed tomographic (CT) imaging is a method through which scan time can be reduced, which can reduce motion artifacts. In this study, we assess the clinical feasibility of ultrahigh-pitch CT imaging made possible by dual-source CT. METHODS: Image pitch, total scan time, and image quality assessments were compared between 45 patients who underwent a high-pitch dual-source CT and 34 patients imaged by standard CT technique. Image noise and diagnostic image quality were assessed by 2 independent blinded readers on a 5 point scale. RESULTS: Mean pitch of high-pitch CT was 2.5 (mean scan time, 1.9 seconds) compared with the standard CT mean pitch of 0.6 (mean scan time, 9.8 seconds). There was no statistically significant difference in image noise between high-pitch CT (12.6) and standard CT (12.0); P > 0.3. Although reader 1 rated standard CT as superior to high-pitch CT (P 0.005), reader 2 rated no significant difference. No high-pitch CT studies were rated as limited diagnostically by either reader. CONCLUSION: High-pitch dual-source CT can reduce scan time while leading to minor losses of image quality, which may be useful in some patients. PMID- 21586931 TI - Feasibility of noninvasive temperature assessment during radiofrequency liver ablation on computed tomography. AB - PURPOSE: The purpose of this study was to assess the feasibility of noninvasive thermometry using high-resolution computer tomography (CT) for the monitoring of bovine liver during radiofrequency (RF) ablation. METHODS: Radiofrequency probes were used to ablate bovine livers from 20 degrees C to 98 degrees C. During the heating process, images were acquired using a multidetector CT scanner with simultaneous measurement of temperature using calibrated thermal sensors. The CT scanner's thermal sensitivity was derived from the correlation between the CT numbers and temperature. The CT scanner's thermal sensitivity was used to compute a temperature map, and this temperature map was overlaid on the original CT scan using a dedicated software application. RESULTS: The CT numbers of the bovine liver showed a linear decline with an increase in temperature and a CT thermal sensitivity of -0.60 +/- 0.026 Hounsfield unit/ degrees C (R2 = 0.87). Temperature maps were calculated using this correlation and were superimposed onto the CT scans presenting temperature distribution around the RF probe in the bovine liver. CONCLUSIONS: Noninvasive temperature determination is feasible during RF ablation of bovine liver using a high-resolution CT system. Therefore, the proposed method can be of potential use in clinical practice for noninvasive temperature mapping during ablation. PMID- 21586932 TI - Nonmass lesions in magnetic resonance imaging of the breast: additional T2 weighted images improve diagnostic accuracy. AB - OBJECTIVE: In magnetic resonance imaging (MRI) of the breast, contrast enhancements present as mass or nonmass (NM) lesions. This study aimed to test the usefulness of currently accepted T1-weighted Breast Imaging Reporting and Data System predictors and to determine the incremental value of new T2-weighted predictors for differentiation of benign from malignant NM lesions. METHODS: Consecutive patients undergoing surgery after MRI (1.5-T contrast-enhanced T1- and T2-weighted images) were investigated. Lesions were rated by 2 observers in consensus. Breast Imaging Reporting and Data System criteria for NM included spatial distribution, internal enhancement, and dynamic enhancement pattern. Additional criteria on T2-weighted images were signal intensity, presence of intraductal fluid, or cysts at the enhancements location. Independent differentiation criteria (benign vs malignant) were identified by logistic regression followed by receiver operating characteristics analysis. RESULTS: Of 316 patients, 65 demonstrated NM. The NM lesions were split almost equally into malignant (34) and benign (31) histology. Breast Imaging Reporting and Data System predictors did not differentiate benign from malignant lesions, whereas signal intensity and the presence of cysts on contrast-enhanced T2-weighted images did, with a sensitivity of 91.2% and a specificity of 64.5%. CONCLUSIONS: Differentiation of NM can be improved using additional T2-weighted images. PMID- 21586933 TI - Localization and evaluation of sentinel lymph node in breast cancer from computed tomographic lymphography. AB - OBJECTIVE: This study aimed to determine the accuracy of computed tomographic (CT) localization and CT-based diagnosis of sentinel lymph nodes (SLNs) metastasis. METHODS: Thirty-four patients with confirmed breast cancer underwent 40-row CT scanning, and the first one or several lymph node(s) in the lymphatic drainage pathway was/were defined as the SLN(s). Dye and gamma probe-guided SLN biopsy was performed on all patients. To accurately localize the SLN, 19 patients (55.9%) underwent the percutaneous lymph node puncture procedure. The morphologic features of all the SLNs on CT scans were analyzed and compared with the SLN biopsy pathologic diagnosis. RESULTS: Sentinel lymph nodes were successfully identified for all patients without any significant adverse effects. All localized SLNs corresponded well with SLNs identified on SLN biopsy, with an accuracy of 89.5%. Accuracy increased to 100% when the CT scan technique was combined with the blue dye method. The size criteria for metastatic diagnosis had a sensitivity of 85%, which increased to 94.7% when long-to-short-axis ratio and margin characteristics were also considered. CONCLUSIONS: The CT lymphography combined with the blue dye method accurately localized the SLNs. The CT-based diagnostic criteria improved the diagnostic accuracy of SLN metastases and were useful for evaluating the axillary status in early stage breast cancer patients. PMID- 21586934 TI - Comparison of the region-based and pixel-wise methods for cardiac T2* analysis in 50 transfusion-dependent Thai thalassemia patients. AB - PURPOSE: To compare the observer variability of the conventional region-based (RB) to the typical and proposed pixel-wise (PW) methods for cardiac T2* analysis in thalassemia patients. DESIGN AND METHODS: Fifty thalassemia major patients were enrolled for the study. Short-axis bright- and black-blood sequences were acquired and analyzed using the RB and PW methods. Regions were defined using the whole septum (WS) or partial septum (PS). From the same PS region, results were reported by mean (PS-PW) and median (MPS-PW). Intraobserver and interobserver variabilities were investigated on all data set by 2 independent observers blinded to the result. RESULTS: The T2* values from the PS-PW and MPS-PW methods were comparable to the conventional WS-RB method on both scanning techniques. When comparing the interobserver variability from the WS-RB to the PS-PW method, the coefficient of variation of the PS-PW method was equivalent (4.5% vs 4.7%, P = NS) for the bright-blood technique but 31% lower (4.0% vs 2.8%, P = 0.21) for the black-blood technique. The proposed MPS-PW method performed even better with respect to the conventional WS-RB method, decreasing interobserver coefficient of variation by 24% (4.5% vs 3.5%, P = 0.08) and 42% (4.0% vs 2.4%, P = 0.02), respectively. Intraobserver reproducibility followed the same trend. CONCLUSIONS: The proposed PW method using the median of T2* values calculated from partial interventricular septum region provided lower intraobserver and interobserver variabilities compared with the conventional RB or typical PW methods. PMID- 21586935 TI - Free-breathing single navigator gated cine cardiac magnetic resonance at 3 T: feasibility study in patients. AB - BACKGROUND: Cardiac magnetic resonance imaging (CMRI) is an important tool to assess cardiac function. However, one of the limitations of CMRI is the need for frequent breath-holding (BH) steps. This may be inconvenient to some patients and limit the use of this modality in patients unable to cooperate because of cognitive reasons or physically incapable of performing the required BH steps. The purpose of this study is to overcome the intrinsic timing and computation limitations of dual-navigator cine imaging and demonstrate the feasibility of free-breathing (FB) cine cardiac left ventricular function with a single respiratory-navigator gating at 3 T. RESULTS: Eight participants underwent cine CMRI with both the conventional 2-dimensional cine BH and FB navigator-gated techniques. Scan parameters were identical, except in the FB technique, in which a respiratory navigator and only 2 signal averages were used. Images were scored for quality. Left ventricular end-systolic volume and end-diastolic volume were calculated. The differences in the end-systolic volume and end-diastolic volume assessed by the BH and FB were not statistically significant with P = 0.9 and 0.2, respectively. There was a good agreement between LV volumes with the limits of agreement (+/- 2 SD = +/- 22.36 mL). Image quality score was not significantly different (P = 0.76). CONCLUSIONS: Free-breathing cine imaging utilizing a single respiratory-navigator gating technique is comparable to conventional BH technique in both qualitative and quantitative imaging measures. Therefore, the FB cine technique can be used as an alternative for children and patients who are unable to hold their breath. PMID- 21586936 TI - Is there a role for fluorine 18 fluorodeoxyglucose-positron emission tomography and positron emission tomography/computed tomography in evaluating patients with mycobacteriosis? A systematic review. AB - OBJECTIVE: This study was designed to review the emerging role of fluorine 18 fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) CT/computed tomography (PET/CT) in patients with mycobacteriosis. METHODS: A comprehensive literature search of published studies through October 2010 in PubMed/MEDLINE database regarding 18F-FDG-PET and PET/CT in patients with mycobacteriosis was performed. RESULTS: Ultimately, we identified 16 studies comprising a total of 220 patients with mycobacteriosis. Main findings of the included studies are presented. CONCLUSIONS: (1) Mycobacteriosis commonly causes increased 18F-FDG uptake; therefore, positive 18F-FDG-PET results should be interpreted with caution in differentiating benign from malignant abnormalities. (2) 18F-FDG-PET and PET/CT are potentially useful in detecting sites of Mycobacterium infection. (3) Dual-phase 18F-FDG-PET is not useful for the differential diagnosis between malignant lesions and sites of Mycobacterium infection. (4) 18F-FDG-PET and PET/CT are useful for the evaluation of disease activity and in monitoring response to therapy in patients with mycobacteriosis. (5) Dual-tracer PET and PET/CT are potentially useful for presumptive diagnosis of solitary pulmonary nodules. PMID- 21586937 TI - Radiological and clinical features of subcutaneous panniculitis-like T-cell lymphoma. AB - OBJECTIVE: To retrospectively analyze computed tomography (CT) and clinical findings of patients with subcutaneous panniculitis-like T-cell lymphoma (SPTCL). MATERIALS AND METHODS: The CT findings were retrospectively assessed in 8 patients (6 men, 2 women; age range, 23-60 years; mean age, 39.8 years) with pathologically proven SPTCL. The tumor location, number, distribution, size, and morphological characteristics on CT were evaluated, as were maximum standardized uptake values on positron emission tomography. We also evaluated patient symptoms, laboratory findings, immunophenotype, involvement of bone marrow, treatment, and outcomes. RESULTS: All 8 patients had multiple (range, 4 to numerous) soft tissue lesions involving subcutaneous fat tissue of the chest, abdominal wall, back, and buttock. Lesions varied in size (range, 0.5-10 cm) and showed reticular (n = 1), nodular (n = 4), and diffuse infiltrative (n = 3) patterns. Three patients had lesions involving the entire thickness of fat tissue, 3 had partial lesions, and 2 had variable lesions. Skin thickening was mild in 4 patients, moderate in 2, and severe in 2; fascia thickening was mild in 3 patients, moderate in one, severe in one, and variable in 2. In 7 patients, lesions were accompanied by engorged supplying vessels. At onset, maximum standardized uptake values varied from 1.2 to 4.7, decreasing to 0.0 to 4.2. Five patients had alphabeta type and one had gammadelta type. Clinical outcome varied: two remain alive with disease, two had no disease, and one died. CONCLUSIONS: The SPTCL is characterized by multiple, nodular, or diffuse soft tissue lesions involving subcutaneous fat tissue, accompanied by engorged vessels and skin and fascial thickening. Patients vary in presentation and in treatment outcomes. PMID- 21586938 TI - Role of whole-body staging computed tomographic scans for detecting distant metastases in patients with bladder cancer. AB - OBJECTIVE: This study aimed to establish the incidence of distant metastases on whole-body computed tomographic (CT) scans in patients with newly diagnosed bladder cancer and to determine whether there is a significant difference in the incidence of metastases in patients with superficial and muscle invasive cancers. MATERIALS AND METHODS: A total of 201 patients who had a proven histological diagnosis of transitional cell carcinoma of the bladder and a whole-body staging CT scan at diagnosis were identified from our MDT database during a 36-month period. Imaging was retrospectively reviewed with view to recording site, if any, of distant metastases. RESULTS: Of 201 patients, 11 (5.5%) were found to have distant metastases on CT. In univariable models, staging was not associated with either age (odds ratio, 0.98; 95% confidence interval, 0.92-1.04; P = 0.4) or sex (Fisher exact test, P = 0.07). Mean (SD) age was 74.1 (10.5) years. There was a significant association between staging and metastasis (odds ratio, 19.9; 95% confidence interval, 3.2-infinity; P = 0.0003). Of the patients, 7% of males had metastases versus 0% of the females. CONCLUSIONS: Staging CT scans for assessment of distant metastatic disease in patients with newly diagnosed bladder cancer can be restricted to patients with muscle invasive disease. PMID- 21586939 TI - Double inversion recovery magnetic resonance imaging (MRI) in the preoperative evaluation of hippocampal sclerosis: correlation with volumetric measurement and proton magnetic resonance spectroscopy (1H MRS). AB - OBJECTIVE: To determine whether the finding of hyperintense hippocampal signal intensity on double inversion recovery (DIR) magnetic resonance imaging is correlated with hippocampal volume loss and metabolic abnormalities in patients with mesial temporal lobe epilepsy (MTLE). METHODS: This retrospective study had institutional review board approval, and informed consent was obtained. Thirteen patients with unilateral hippocampal sclerosis and 13 age-matched healthy control subjects were included. Quantitative assessment for hippocampus of the patients and the control subjects was determined, including DIR, 3-dimensional T1-weighted imaging and proton magnetic resonance spectroscopy. Hippocampal relative signal intensity on DIR images (RSIDIR), volumes, and N-acetylaspartate-to-choline and creatine/phosphocreatine ratios were measured during one magnetic resonance imaging session, and asymmetry indexes (AI) of bilateral hippocampi were calculated. Hippocampal RSIDIR and AIDIR were compared between the patients and the control subjects. The RSIDIR and AIDIR were further correlated with the quantitative MR measures and with the age at onset and duration of MTLE. Statistical analyses were performed with Student t test, 1-way analysis of variance, and Pearson correlation. RESULTS: On DIR images, the hippocampi ipsilateral to the seizure focus demonstrated relatively extreme hyperintensity. The ipsilateral hippocampi showed significantly increased RSIDIR compared with contralateral hippocampi and the healthy subjects (F = 197.956, P < 0.001). The hippocampal AIDIR in the patients was also significantly higher than that in the control group (t = 24.896, P < 0.001). Significant Pearson correlations (2 tailed) were obtained between the RSIDIR and the volume of the ipsilateral hippocampi (r = -0.762, P < 0.01) and between the RSIDIR and duration of epilepsy (r = 0.557, P < 0.05). Moreover, there were significant correlations between the AIDIR and the AIvolume (r = 0.609, P < 0.05) and between the AIDIR and the duration of epilepsy (r = 0.610, P < 0.05). However, no significant correlations of hippocampal DIR measures with proton magnetic resonance spectroscopy were obtained. CONCLUSIONS: Double inversion recovery imaging of the brain can yield complementary information about hippocampal pathology and efficiently lateralize the hippocampal sclerosis in patients with MTLE. PMID- 21586940 TI - Microsurgery and craniofacial surgery are confluent systems in plastic surgery patient care. PMID- 21586941 TI - Heat adaptation of bioabsorbable plates: effects of the process on material properties. PMID- 21586942 TI - Highlights from the 11th International Congress on Cleft Palate and Related Craniofacial Anomalies. PMID- 21586943 TI - Vascular wall of head-facial hemangioma. AB - BACKGROUND: The aim of this work was to study some morphologic and histochemical characteristics of the wall of blood vessels in the hemangioma of the head and/or face. This disease represents a most frequent vascular pathology, consisting of an embryonic display involving the cranial-facial vascular network. METHODS: The clinical characteristics of head-facial hemangioma were studied in 28 individuals (9 males and 19 females) admitted in our hospital. Some of these patients (n = 16) were subjected to the surgical therapy for the removal of the hemangioma. During surgical therapy, all the removed tissues were transferred in our experimental laboratories for the staining of microanatomic details and for immune-chemical demonstration of some specific substances enclosed in the wall of the hemangioma vessels (proteoglycans, collagen type IV, and laminin). All results were submitted to the quantitative analysis of images and statistical evaluation of the data. PMID- 21586944 TI - Alveolar regions of the mandible for the installation of immediate-implant fixtures and bone screws of alveolar distractors. AB - The purposes of this study were to elucidate the anatomic relationship between the dental roots and surrounding tissues and to identify the optimal sites at which to install dental surgical devices including immediate-implant fixtures and alveolar distractors. We made 5 types of measurements on horizontal cross sections obtained at 1-mm intervals from 20 Korean mandibles. The following results were obtained: (1) the mandibular facial plate was thinnest at the canine (0.5-0.7 mm) and became thicker toward the molar region; (2) the thicknesses of the facial and lingual cortical bone in the interdental region increased from anterior to posterior and from coronal to apical aspects; (3) in each section, the buccolingual root was narrower than 4 mm at depths greater than 8 and 9 mm in the central and lateral incisors, respectively, and the maximum mesiodistal root widths were 3.0 and 3.3 mm; (4) the interroot distance increased from anterior to posterior and from coronal to apical aspects; and (5) on the sections of the first and second molars, the diameter of the septal bone ranged from 4.2 to 7.9 mm buccolingually and from 1.3 to 3.3 mm mesiodistally. Achieving successful placements of implant fixtures and bone screws requires an accurate understanding of the anatomic structure at the installation site. The reported anatomic data might facilitate successful treatments and provide crucial information for use when planning and performing placements of dental surgical devices. PMID- 21586945 TI - Width of the levator aponeurosis is broader than the tarsal plate. AB - The aim of this study was to compare the width of the levator aponeurosis and tarsal plate in different levels grossly and histologically. Twelve eyelids of 6 Korean adult cadavers were used. Ten eyelids were dissected, and 2 were prepared for histologic study. Widths of the tarsal plate at its lower border, midheight, and upper border were 21.8 +/- 1.8, 16.2 +/- 1.6, and 8.3 +/- 1.0 mm, respectively. The widths of the levator aponeurosis at the lower border, midheight, and upper border of the tarsal plate were 32.0 +/- 2.2, 29.2 +/- 3.5, and 27.2 +/- 3.9 mm, respectively. Its width was 19.9 +/- 4.3 mm at the anterior border of the superior transverse ligament. The width of the levator aponeurosis was broader than tarsal plate at all 3 levels. The medial brims of the levator aponeurosis at the lower border, midheight, and upper border of the tarsal plate were 3.6 +/- 1.1, 5.1 +/- 1.0, and 6.2 +/- 1.1 mm, respectively. The lateral brims of the levator aponeurosis at the lower border, midheight, and upper border of the tarsal plate were 6.6 +/- 0.9, 7.9 +/- 2.6, and 12.7 +/- 3.7 mm, respectively. The width of the levator aponeurosis is broader than the tarsal plate at all levels. This result might be useful in upper-eyelid surgery. PMID- 21586946 TI - Angular photogrammetric comparison of the soft-tissue facial profile of Kenyans and Chinese. AB - The purpose of this study was to determine the average angular dimensions that define the normal soft-tissue facial profiles of black Kenyans and Chinese and compare them with each other and with values proposed for whites. Standardized facial profile photographs, taken in natural head position, of 177 black Kenyans and 156 Chinese with normal occlusion and well-balanced faces were analyzed for 12 angular parameters. Two-sample t-tests were used to determine sex and racial differences. Kenyan and Chinese averages were compared with proposed white values using 1-sample t-tests. Eight parameters in Kenyans and 7 in Chinese showed sex differences. All angles, except for facial convexity, nasal dorsum, and inferior facial height, were different between Kenyans and Chinese. Kenyan and Chinese averages for all parameters were different from proposed white average, except for facial convexity. Nasolabial and mentolabial angles showed large individual variability and racial differences. The study demonstrated many differences in average angular measurements of the facial profiles of black Kenyans, Chinese, and white standards. Orthodontists, maxillofacial and plastic surgeons, and other clinicians working in the craniofacial region should bear these in mind when setting aesthetic treatment goals for patients of different races. Mean values from this study can be used for comparison with similar records of subjects with same ethnicity. PMID- 21586947 TI - Three-dimensional anatomic landmarks of the foramen magnum for the craniovertebral junction. AB - The foramen magnum (FM) has a vital importance to have a direct view of the vertebral artery, lower cranial nerves, and the brainstem. The morphologic analysis of the FM was studied in 352 occipital bones of adult human skulls by 3D Doctor V 3.5.050402 Demo version. The perimeter and area of the FM were calculated as 115.6 (SD, 9.9) mm and 829 (SD, 137.7) mm(2), respectively. The FM index was found as 84.02%, and the majority (38.4%) of holes were observed to have a narrow index.The FM was observed to 8 different types. The most frequently observed types were the tetragonal type in 25.66%, and the one formed by the combination of 2 semicircles in 23.28%. The large anterior margin of the FM type, such as types 1, 4, 5, and 6, can be easily performed partially. In the cases of types 2, 3, and 8, the anterior margin was determined as narrow, the resection procedure is completed with more difficulty. In Pearson correlation analysis, it is significant that a statistically strong relation was found between the area and perimeter, and the area and length of FM. This findings suggest that the resection should be started at the anterior margin, just lateral and then extended superolaterally. PMID- 21586948 TI - Optimum height from the roof of the choana for seeking the sphenoid ostium. AB - OBJECTIVE: The purpose of this study was to investigate the optimum height that the sphenoid sinus ostium can be probed safely from the roof of choana in a large group of patients. METHODS: The study was performed retrospectively. The 200 sphenoid ostia of the 100 patients whose thin-section computed tomography (CT) including the sphenoid sinus region, made for various reasons, were included in the study. The height of the sphenoid ostium and the skull base from the choana roof were measured on sagittal images of CT. Also, by calculating the ratio of first measurement to the second one, the location of the sphenoid ostium at the anterior wall of sphenoid sinus was determined proportionally. RESULTS: The mean height of the sphenoid ostium from the choana roof was 10.9 (SD, 2.3) mm (range, 5.7-21.5 mm), and the mean height of skull base along the anterior wall of sphenoid sinus from the choana roof was 21.3 (SD, 3.2) mm (range, 13.3-30.6 mm). The ratio of the first measurement to the second measurement was 0.5 (SD, 0.08) (range, 0.29-0.77). CONCLUSIONS: In conclusion, under endoscopic view, the sphenoid sinus ostium can be safely probed between 13.3 mm (the minimum skull base height) and 5.7 mm (the minimum sphenoid sinus ostium height) distance upward from the choana, but determining the height of the sphenoid sinus ostium preoperatively on CTs for each patient separately will increase the chance of success in probing the sphenoid sinus. PMID- 21586949 TI - Microsurgical anatomy for intraoperative preservation of the olfactory bulb and tract. AB - Damage to the olfactory bulb and tract is a frequently described complication of brain surgery in the frontal region, and it seems to be influenced by the surgical approaches. Eighty cerebral hemispheres and 5 formalin-fixed cadavers filled with colored latex were used. Parameters were directly measured, and after olfactory bulb and tract were mobilized with careful dissections, retraction of the frontal lobe was noted. The anterior border of the olfactory bulb is 22.21 (SD, 5.45) mm posterior to the frontomarginal sulcus, and arachnoidal dissection should be performed parallel to olfactory structures using sharp instruments to allow early visualization. Overall mobilization of the olfactory bulb and tract as 29.3 (SD, 6.4) mm in length is possible without disrupting the structures and enables a greater degree of the frontal-lobe elevation window up to 13.1 (SD, 3.2) mm. Using the morphometric data and anatomic knowledge may prevent unwanted anosmia complication during surgical approaches. PMID- 21586950 TI - A method for flap monitoring based on bioelectrical-resistance analysis. AB - Axial pattern flaps are characterized by a single vascular pedicle that supplies the whole flap and carry the danger of flap loss. For this reason, monitoring and early identification of vascular perfusion is important for flap prognosis. The most commonly used method for flap monitoring is clinical assessment, but it has certain limitations. The bioelectrical properties of tissues can be affected by ischemic conditions, and a preliminary study showed that the bioelectrical resistance of blood was decreased under thrombotic conditions. In this controlled study, the resistance values of the axial flaps were calculated during thrombosis. A total of 28 rats were randomly divided into a control group (n = 14) and an experimental group (n = 14). Axial flaps were elevated based on the inferior epigastric pedicle. For the ischemic group, microvascular clamps were placed in the ischemic group to produce artificial thrombosis from day 1 of the experiment. Bioelectrical resistance was measured every 30 minutes for the first 6 hours and then daily after that. The resistance values from the ischemic group decreased progressively, and 150 minutes after the clamping, the difference became statistically significant (P < 0.05). The results showed that the assessment of flap resistance is a valuable tool and may allow early recognition of a compromise in the vascular system before clinical signs become obvious. PMID- 21586951 TI - Stump rotation in a nerve autograft by 2 factors: cross-connection and difference in diameter. AB - The aim of this study was to determine the influence of stump rotation (fascicular cross-connection) on nerve autograft functional recovery. Thirty rat sciatic nerves were transected and repaired by autograft. The rats were divided into 3 groups according to the number of stump rotations of the autograft: (1) plain graft (PG-g, with no change in fascicular orientation, no difference in diameter), (2) graft rotation (GR-g, with no change in fascicular orientation, and diameter difference between fascicles), (3) stump rotation (SR-g, with cross connection and diameter difference between fascicles). Relative gastrocnemius muscle weight and nerve fiber count were examined as anatomic recovery indices, and autotomy score (ATS) and toe-out angle as functional recovery indices. The results showed that SR-g had a significantly low functional recovery compared with PG-g and GR-g. However, there was no difference found in the anatomic recovery. These findings suggest that the stump rotation in nerve autograft had no effect on neural regeneration and muscle reinnervation; however, it had a negative effect on functional recovery. Because GR-g was similar to PG-g rather than SR-g in functional recovery, the diameter difference between fascicles appears to have had little effect on the functional recovery. The results of this study suggest that a novel approach to ATS interpretation is needed. It is recommended that (1) ATS 2 be considered the onset of autotomy instead of ATS 1; and (2) the frequency of "ATS 2 and above" should be considered for the comparison of the autotomy rather than the mean ATS. PMID- 21586953 TI - Bilateral reconstruction of smile through muscular transplants neurotized to masseter nerves. AB - In recent years, microsurgical transplant of the gracilis muscle has been the most widely used technique in the dynamic rehabilitation of the smile. The most frequently used donor nerve is the seventh cranial nerve, as it allows for the most physiological rehabilitation, including the rehabilitation of spontaneous smile. An exception to this is the case of bilateral facial paralyses, in which there is no contralateral nerve to be used as a donor. In these cases, it is necessary to use other nerves such as the hypoglossal, the accessory nerve, or the masseter branch of the trigeminal nerve. In this article, we describe a case of dynamic bilateral facial rehabilitation with a bilateral transplant of the gracilis muscle neurotized to the masseter nerve to achieve a strong, symmetrical smile, which is properly controlled by the patient. PMID- 21586952 TI - Masseter myosin heavy chain composition varies with mandibular asymmetry. AB - Human jaw dysmorphologies are frequent and often affect young patients, resulting in malocclusion of teeth and inappropriate jaw relationships. Treatment is performed by means of orthodontics with orthognathic surgery as required. Mandibular asymmetry is one of the most frequent dysmorphologies, but in many cases, the specific cause is unknown.In healthy patients who were undergoing orthognathic surgery for correction of malocclusion, we tested the hypothesis that masseter muscle phenotype composition, which determines contractile properties, was different between sides in patients with mandibular asymmetry but not in those without mandibular asymmetry. After cephalometric analysis, 50 patients from whom we obtained samples of both right and left masseter muscles were separated into 2 groups: with or without mandibular lateral deviation. Samples were immunostained with myosin-isoform-specific antibodies to identify 4 skeletal muscle fiber types, and their fiber areas and proportions were measured. Two-tailed Wilcoxon test for paired samples was used to compare the 4 fiber-type compositions by means of percent occupancy and mean fiber area on both sides. Patients with mandibular asymmetry were associated with a significant increase of type II fiber occupancy (P = 0.0035) on the same side as the deviation. This finding that masseter muscle phenotype is significantly linked to mandibular asymmetry is of relevance to physiotherapeutic and surgical managements of jaw discrepancies and merits further investigation in the light of its possible role in the etiology of this condition. PMID- 21586954 TI - Osteofascial compartment syndrome. AB - The free fibula osteocutaneous flap has been widely used in the reconstruction of facial bone, especially the mandible. Donor-site morbidity for free fibula osteocutaneous flap is generally considered to be low and minor. However, a severe and rare complication, osteofascial compartment syndrome (OCS), should be paid more attention to after the harvesting of the fibula osteocutaneous flap. In this report, we described a case where the OCS occurred in 56-year-old man after fibula osteocutaneous flap was transplanted for mandible reconstruction, and its treatment is reported. We suggest that if free fibula osteocutaneous flap is used, the OCS of the leg should be considered seriously, and the drainage must be effective and adequate. PMID- 21586955 TI - Bimaxillary reconstruction with a single free fibular osteoseptocutaneous flap. AB - Flap combinations including free fibula have been commonly used to reconstruct composite maxillomandibular defects. On the other hand, a single free osteoseptocutaneous may be rarely used to reconstruct the bimaxilla. In this article, we report a bimaxillary reconstruction in a 63-year-old man with a single fibular osteoseptocutaneous free flap. PMID- 21586956 TI - Numerical survey of the different shapes of the human nose. AB - Experimental results are reported for the numerical quantities of the different shapes of human nose where, to the best of the author's knowledge, this approach has never been applied. The results are based on 1793 pictures of noses, of which 403 are artworks, 498 are photographs taken by the author in Europe-Holland, Belgium, and France-while visiting these places, 801 were photographed in Israel, and 91 are not clear where exactly photographed. One thousand eighty-one were photographs of men, and 712 were of women. The author has succeeded to classify all the noses into 14 groups, where for each nose shape it was possible to find also an artistic demonstration. Near each shape the percentage of the total number of noses of a certain nose shape is reported. The detailed results for the number of noses versus their shape and sources: artworks and photographing places Europe and Israel-are reported. The most widespread nose, 24.2%, is shape 1, the fleshy nose, where the least widespread nose, 0.45%, is shape 4. It should be emphasized also that shape 14, 0.05%, photographed in Israel is extremely unique and the only one existing among the 1793 noses that were considered. PMID- 21586957 TI - Tongue abscess with actinomycosis. AB - Actinomycosis of the tongue is uncommon, but without proper treatment, it causes extensive tissue destruction. A mass that may mimic both benign and malignant neoplasms can be seen at clinical presentation and may mislead the diagnosis. Early diagnosis is critical but usually difficult with cultures or imaging. We report a patient who presented with a tumor-like deeply localized primary actinomycosis of the tongue with its magnetic resonance imaging findings. PMID- 21586958 TI - Craniocervical necrotizing fasciitis of odontogenic origin with thoracic extension. AB - Craniocervical necrotizing fasciitis is an uncommon but aggressive infection with high morbidity and mortality. We present a case of craniocervical necrotizing fasciitis with thoracic extension caused by a dental infection in a 56-year-old man, with a successful outcome involving broad-spectrum intravenous antibiotics and an aggressive surgical debridement. PMID- 21586959 TI - Dental implants in patients with osteoporosis: a clinical reality? AB - Osteoporosis is a systemic disorder characterized by generalized decrease in bone mineral density. Dental implantology is a specialty with high predictability when both quantity and quality of the bone are respected. Therefore, the diagnosis and the implant treatment in patients with osteoporosis are important. In the current study, a literature review about osteoporosis and dental implant therapy was conducted. PubMed, Cochrane, ISI, Dentistry Oral Science, SciELO, and Bireme databases were consulted over the last 20 years. English- and Portuguese-language articles were included in this revision. Some authors stated that the osteoporotic bone is similar to the proposed model of bone type IV. Randomized clinical studies reported implant failure in patients with osteoporosis after menopause. Studies that contraindicate the use of implants in patients with osteoporosis infer that the impaired bone metabolism led to reduction of bone healing around the implants. Nevertheless, other authors believe that the presence of osteoporosis is not a definitive condition to contraindicate the therapy with dental implants. In these cases, the dentist should perform a proper treatment planning, modifying the implant geometry, and use larger implant diameter and with surface treatment. Thus, osteoporosis is not a contraindication for implant surgery because an accurate analysis of bone quality by means tomography is performed. PMID- 21586960 TI - Synchronous multicentric bilateral sinonasal inverted papilloma and frontal sinus osteoma. AB - Inverted papilloma is generally considered a benign unilateral sinonasal tumor. Its synchronous bilateral multicentric occurrence is extremely rare. A 22-year old male patient presented with stage III inverted papilloma involving both ethmoid sinuses, both frontal sinuses, and cribriform area. The patient also had a large osteoma emanating from the basal part of the frontal sinus septum, which completely obstructed both nasofrontal recesses, leaving no communication between the sinuses and the nasal cavity. The frontal sinus septum was intact, so there was no communication between the 2 sides either. Following the era of aggressive surgical approaches dominated by lateral rhinotomy and medial maxillectomy, the advent of endoscopic techniques has dramatically improved visualization of sinus chambers and nasal cavity, resulting in lower morbidity and similar results to those achieved with open surgical procedures. In our patient, the concomitant presence of a huge frontal sinus osteoma posed an unacceptable risk for endoscopic resection due to the possible residual disease in the nasofrontal recess regions. Surgical resection remains the mainstay treatment and should be tailored in accordance with the localization and spread of disease. The surgeon should be ready to use different surgical approaches and, if intraoperatively needed, to modify them accordingly. PMID- 21586961 TI - Bilateral antrochoanal polyps: possible pathogenesis. AB - Antrochoanal polyp is a rare, benign solitary mass that arises from maxillary sinus. It exits through sinus ostium, passes across the middle meatus, and reaches into the choana. In general, it represents up to 6% of all nasal polyps. Although it is usually unilateral, in extreme rare cases it could be bilateral.We herein report a case of an 11-year-old girl who presented with bilateral antrochoanal polyps and was managed successfully by endoscopic surgical approach. We also hypothesize a possible pathophysiologic explanation of this rare disease. PMID- 21586962 TI - Intraparotid facial nerve neurofibroma in neurofibromatosis type 1. AB - Benign tumors of the nerve sheath are of 2 types: schwannoma and neurofibroma. Neurofibromas are most commonly found with neurofibromatosis type 1 and characterized by incorporation of the nerve fibers within their matrix. Both benign and malignant tumors can affect the facial nerve. These tumors can be intrinsic or extrinsic; in other words, it can originate from the facial nerve itself or from a contiguous structure or a metastatic disease. Actually, extrinsic tumors are far more common than intrinsic tumors. Intraparotid location of benign tumors of the facial nerve sheath is considered a rare event compared with intratemporal location. PMID- 21586963 TI - Surgical management of recurrent malignant schwannoma of the scalp. AB - Localization of malignant schwannoma in the head and neck region is rare. Malignant schwannoma is a highly aggressive, slowly growing, encapsulated tumor of nerve sheath origin. The most common presentation of this tumor is a subcutaneous progressively enlarging mass with or without neurologic symptoms. These tumors arise from neurofibromas with or without von Recklinghausen disease, and most of the remains develop from peripheral nerve trunks. We report a case with recurrent malignant schwannoma of the scalp that is an uncommon presentation and discuss the clinicopathologic properties of this tumor. PMID- 21586964 TI - Giant atypical lipomatous tumor/well-differentiated liposarcoma of the neck. AB - Liposarcoma of the head and neck represents approximately 1% of head and neck sarcomas. Atypical lipomatous tumor/well-differentiated liposarcoma rarely occurs in the neck. The size of the neck liposarcomas rarely exceeds 10 cm during presentation. Surgical excision is the treatment of choice for liposarcomas. We report a very unusual size, which has not been reported to our knowledge, of an atypical lipomatous tumor of the neck, reaching a size of 25 * 22 cm. The patient underwent complete resection of the lesion without morbidity. Three months after the surgery, the patient is free of recurrence. PMID- 21586965 TI - Pleomorphic adenomas recurrences within the parapharyngeal space. AB - This study was undertaken to evaluate and concentrate on the recurrent pleomorphic adenomas (PAs) of the parapharyngeal space. The records of 9 patients treated for recurrent PAs occupying parapharyngeal space were retrospectively reviewed. The study population comprised 6 women and 3 men with a mean age of 51 (range, 35-79 years). Before the first revision surgery, imaging studies and clinical examinations showed 1 solitary mass in 4 patients, 2 solitary masses in 3 patients, and 3 or more masses in 2 patients. After first revision surgery, 4 patients had rerecurrences with multinodular disease. Two of 4 patients underwent radiation therapy (RT), and the other 2 patients underwent second revision surgery, among whom 1 patient underwent third revision surgery, and the other one was also submitted to RT. Overall, 12 reoperations were performed, and at the end of all operations, 4 patients had rerecurrences and residual disease. In conclusion, we recommend RT to patients with multinodular disease, known tumor spillage, and residual tumor in addition to revision surgery. Histopathologic features, surgical resection, relationship to surrounding vital tissues, and postoperative adjuvant radiotherapy are the most important determinants for recurrent PAs. PMID- 21586966 TI - Sialolithiasis of the submandibular gland. AB - Sialolithiasis of the salivary gland is a benign pathology that occurs most frequently in the submandibular gland because of its anatomic features. Depending on the sialolith size and calcification degree, it can be visible in radiographic examinations. Commonly, patients may experience pain and/or edema, when the ducts are obstructed. The authors report the case of sialolithiasis of the submandibular gland in a 42-year-old, female, white-skinned patient, noticed during routine dental examination. Following diagnosis confirmed by clinical and radiographic examinations, the treatment plan consisted of surgery for removal of the calcified mass. The prognosis is often good, and generally there is no recurrence. PMID- 21586967 TI - Pleomorphic adenoma of the palate. AB - Pleomorphic adenoma is the most common mixed benign tumor of major salivary glands. Approximately 80% of these tumors arise in the parotid gland, whereas 7% arise in the minor salivary glands. The most common sites for minor salivary gland where pleomorphic adenoma arises are the palates followed by lips and cheek. We report a palate mass in a 46-year-old male patient. The initial cytologic diagnosis by fine-needle aspiration biopsy was pleomorphic adenoma. This report describes a case of pleomorphic adenoma regarding all distinctive diagnoses with the review of the literature. PMID- 21586968 TI - Metastatic basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most common skin cancer with a high propensity for local recurrence. The incidence of metastases from BCC is rare. We report a 65-year-old man who had BCC of the medial canthus of the left eye. In the 10-year period, he had been operated on approximately 12 times because of local recurrences. Three years after the last operation, he had a suspicious lesion on the operated area and a lumbar pain. Radiologic examination showed multiple metastatic skeletal and liver lesions. He was referred to the oncology department for radiation therapy and chemotherapy. PMID- 21586969 TI - Giant cell-rich osteosarcoma or giant cell reparative granuloma of the mandible? AB - Giant cell-rich osteosarcoma (GCRO) is a rare subtype of osteosarcoma, and no literature has reported occurrence in the mandible region up to now. In this article, we report a case of GCRO originating from the mandible in a 67-year-old woman who presented a history of painless mass located in the left side of the mandible after teeth extraction. The curettage biopsy histologic diagnosis is giant cell reparative granuloma before mandibulectomy surgery, but panoramic radiograph revealed an osteolytic lesion. The tumor was completely resected with segmental mandibulectomy and soft tissue with postoperative histologic diagnosis of GCRO. The free fibula osteomyocutaneous flap was performed to reconstruct the defect of the mandible and gingival mucosa. The patient received postoperative radiotherapy and chemotherapy. The 1-year follow-up situation is fine. PMID- 21586970 TI - Primary orbital liposarcoma. AB - A 45-year-old-man presented a slightly painful proptosis and diplopia for 7 months. He had been kept elsewhere on oral steroids without evidence of any clinical response over an 8-week period with suspected diagnosis of an inflammatory pseudotumor upon referral to our clinic. An intraoperative biopsy positive for primary liposarcoma was followed by debulking surgery. Exenteration and radiotherapy were performed after pathologic confirmation of this diagnosis. No recurrence has been observed after 2 years of follow-up. We underline the importance of an accurate an early diagnosis in the management of this tumor, delayed in this case because of therapy with steroids. PMID- 21586971 TI - Mucopyocele of the concha bullosa presenting as a large nasal mass. AB - Concha bullosa that is a pneumatization of the middle turbinate is a common anatomic variant; the obstruction of its ostium may lead to mucocele and even pyocele after infection of retained secretion. Although the condition is rare, mucopyocele of concha bullosa may be presented as a large nasal mass. However, the diagnosis could be suspected from its characteristic radiologic signs. We present an adolescent boy with mucopyocele of the concha bullosa. PMID- 21586972 TI - Giant epidermoid cyst of the posterior neck. AB - A 49-year-old man was presented for evaluation of a painless mass on his right posterior neck. The mass had gradually enlarged for a 25-year period without inflammation or rupture. On physical examination, a round, nontender, soft-tissue mass, 8 cm in diameter, was noted on the right posterior neck. The neck is a common site of epidermoid cysts, but a mass more than 5 cm in diameter is rare. A contrast-enhanced neck computed tomographic (CT) scan revealed a 7.6 * 6.5 * 5.7 cm unilocular hypodense mass adjacent to the posterior neck muscles.The mass was completely excised under general anesthesia. A histopathologic examination of the excised specimen resulted in a diagnosis of an epidermoid cyst. The patient was discharged from the hospital on the third postoperative day. There were no recurrences in a 2-year follow-up period. PMID- 21586973 TI - Diffuse large B-cell lymphoma with oral manifestations. AB - Non-Hodgkin lymphomas (NHLs) are a heterogenic group of lymphoproliferative diseases with their different behavior pattern and response to treatments. As a Hodgkin disease, NHL occurs from lymphoid tissues and can spread to other organs. Prognosis depends on histologic type, grade, and treatment. In the World Health Organization classification, aggressive B-cell lymphomas are diffuse large B-cell lymphoma, Burkitt lymphoma/leukemia, and precursor lymphoblastic leukemia/lymphoma. They may present either nodal or extranodal disease, which may be either localized or disseminated. Diffuse large B-cell lymphoma is the most common type of lymphoma in adults and is clinically, morphologically, and genetically a heterogeneous group of malignant proliferations of mature B cells, too. Diffuse large B-cell lymphoma is the most common type of NHL and accounts for about 30% of the cases. In this clinical report, we evaluated clinically and histopathologically a 64-year-old male patient who had mild pain and edema in his mandibular premolar region, and the excisional biopsy showed diffuse large B-cell lymphoma. PMID- 21586974 TI - Giant mandibular condyle osteoma. AB - Osteomas are benign tumors composed of mature compact or cancellous bone. They represent an uncommon lesion that occurs mainly in craniofacial complex bones. In jaws, they can appear on the bone surface as a polypoid or sessile mass, characterizing a peripheral osteoma (PO), or can be a lesion in the medullar space, then it is called central osteoma. In view of the scarcely reported cases about POs, this article presents a case of PO of the maxillofacial area that was surgically resected using hemicoronal approach. PMID- 21586975 TI - Giant epidermal inclusion facial cyst. AB - Epidermal inclusion cyst is one of the most common subcutaneous tumors, and its size normally varies from 1 to 5 cm in diameter. Only few giant epidermal inclusion cysts have been reported in the literature, and giant epidermal cyst of the face has never been reported. An 83-year-old woman visited our hospital for a huge mass on the right side of her face extending to the temporal area, creating deformity of her right ear. The mass was 15 * 15 * 8 cm(3) with soft, cystic nature. It has developed since 20 years ago with no known etiology. Computed tomography scan was obtained for preoperative evaluation, which showed a 15 * 15 * 7-cm(3) huge, lobulated, and septated mass with no underlying bone or brain involvement. We performed complete excision sand biopsy. On histologic examination, the final diagnosis of epidermal inclusion cyst was made. Keratotic material was within the cyst, and the cystic wall was composed of lamellate keratin. Follow-up period was 10 months, and no signs of recurrence were seen. The patient was satisfied with the improvement of her facial appearance. We have observed a case of giant epidermal inclusion cyst of the face, which has never been reported, and present this case with a brief review of literature. PMID- 21586976 TI - Peri-implant squamous odontogenic tumor. AB - Squamous odontogenic tumor (SOT) is a benign, locally infiltrative intraosseous tumor composed of well-differentiated squamous epithelium in a fibrous stroma. It seems to derive from the epithelial rests of Malassez in the periodontal ligament space. It presents an odontogenic origin, involving both the upper and lower maxillary bone, mainly areas without teeth or connective tissue of the odontogenic cysts. Clinically, SOT could be asymptomatic (3 cases), notwithstanding it is mainly characterized by pain, swelling, and tooth/teeth mobility. The most typical presentation of SOT is a slowly growing endobony lesion arising within a single periodontal location. Frequent misdiagnosis concerns either ameloblastoma and squamous cell carcinoma and fibroma. Since its first description in 1975, less than 50 cases have been identified. In light of the few reported cases, there are no consistently recorded clinical and radiographic features of SOT, and there is no predictable sex or site predilection. Diagnosis is predicated on recognition of the histopathologic features of SOT to obviate possible misdiagnosis of malignancy or ameloblastoma.We report the first case of SOT that arose in the vicinity of an implant. Through a meticulous review of literature, we discuss current etiology, pathogenesis, and treatment. PMID- 21586977 TI - Nonossifying fibroma secondary to aneurysmal bone cyst in the mandibular condyle. AB - Nonossifying fibromas (NOFs) are benign lesions that unusually occur in the mandible. Nonossifying fibromas are asymptomatic and spontaneous resolution at skeletal maturity. Nonossifying fibromas associated with aneurysmal bone cyst (ABC) are very rare. In this clinical report, NOF secondary to ABC in the mandibular condyle was reported; however, it presents different clinical behavior than the usual NOF. In this case, severe destruction in the mandibular condyle as a characteristic of NOF was seen. In the follow-up period, no recurrence was seen subsequent to treatment of lesion with complete resection. Treatment of NOFs with secondary ABC would require aggressive intervention than the treatment of usual NOF. PMID- 21586978 TI - Tongue schwannoma: clinicopathological findings. AB - Schwannomas are peripheral nerve sheath tumors. Approximately 25% of extracranial schwannomas are located in the head and neck district, but only 1% shows an intraoral origin. We report a case of a 28-year-old patient with a tongue schwannoma. Morphologic analysis and immunohistochemical findings strongly support the diagnosis. Surgical treatment is discussed. PMID- 21586979 TI - Microvascular free flaps for mandibular reconstruction in Goldenhar syndrome. AB - Although Goldenhar syndrome is a relatively common craniofacial malformation, there is some debate regarding the ideal treatment of severe mandibular hypoplasia. Traditionally, patients with severe mandibular deficits have been treated with iliac or costochondral bone grafts followed by distraction osteogenesis, with mixed results. The authors present their experience with the use of the osteocutaneous fibula and scapula free flap for mandibular reconstruction in patients with severe mandibular hypoplasia. The cases of 4 patients who underwent free-flap reconstruction of a severely hypoplastic mandible due to Goldenhar syndrome are presented. Microvascular reconstruction of the severely hypoplastic mandible is possible with the osteocutaneous scapula and the fibula flap. Minimal donor-site morbidity is elicited. Furthermore, the vertical relationship can be restored adequately, and breathing is facilitated. The microvascular fibula and scapula flap are a viable option for reconstruction of the severely hypoplastic mandible in patients with Goldenhar syndrome. PMID- 21586980 TI - Treatment of recurrent mandibular ameloblastoma with segmental resection and revascularized fibula free flap. AB - The adamantinoma is characterized by a high rate of local recurrence. Because of this peculiarity, radical treatment is generally preferred than conservative surgery. Resection with free margins is associated with lower risk of recurrence but is not recurrence free; thus, the importance of long and scrupulous follow-up is evident. The aim of this study was to present a patient with recurrent mandibular adamantinoma after box resection with safety margins of 1 cm that has necessitated of a segmental resection with 1-step reconstruction with revascularized fibula free flap. PMID- 21586981 TI - Maxillary reconstruction for a huge odontogenic keratocyst. AB - A range of different entities may be responsible for cystic lesions in the maxillary region. However, sometimes an accurate diagnosis cannot be made based on clinical or radiologic presentation. In this case, the surgeon should evaluate the clinical situation so that a comprehensive surgical plan that addresses the patient's complaints can be made. We present a 25-year-old female patient with a huge maxillary cyst causing obvious cheek protrusion. For cosmetic concern, she received surgical excision of the cystic lesion and reconstruction of anterior maxillary defect. No recurrence was seen at 18 months' follow-up, and the patient was quite satisfied with the aesthetic result. We reported the case to provide an effective procedure for benign maxillary cysts that result in cosmetic concerns with simple excision and reconstruction. PMID- 21586983 TI - Follicular cysts, odontogenic keratocysts, and Gorlin-Goltz syndrome: some clinicopathologic aspects. PMID- 21586984 TI - A useful maneuver for facilitating anastomosis with fibrin glue. PMID- 21586985 TI - Drinking behaviors: the life narratives of indigenous Bunun women in Taiwan. AB - BACKGROUND: Alcohol intoxication is a serious health issue among Taiwan's indigenous Malayo-Polynesian groups. No published studies address the drinking perceptions and behaviors of Bunun women. PURPOSE: The purpose of this study was to describe the drinking perceptions and behaviors of Bunun women in Taiwan. METHODS: This study used an ethnographic approach to study the residents of one township located in eastern Taiwan. Researchers used semistructured, in-depth interviews to collect data from 10 Bunun women in 2006. RESULTS: Researchers identified six key culture themes from the data. These were (a) drinking to help make friends, (b) drinking to help solve emotional problems, (c) interpreting the meaning of drinking, (d) hurting the body due to alcohol abuse, (e) decreasing the bond of convention for drinking, and (f) establishing mechanisms to control drinking. CONCLUSIONS/IMPLICATION FOR PRACTICE: The results of this study may help one to understand the alcohol use behavior and attitudes of indigenous women in Taiwan and contribute to better cross-cultural nursing clinical practice. This study is expected to enhance the quality of nursing care provided to Taiwan's indigenous people. PMID- 21586986 TI - Factors related to milk supply perception in women who underwent cesarean section. AB - BACKGROUND: Perceived insufficient milk supply is common among postpartum women and is a major reason for early weaning. Studies indicate a significantly higher incidence of insufficient milk supply in women who undergo cesarean section as compared with women who undergo vaginal delivery. PURPOSE: This study was designed to determine perceived milk supply in postpartum women who underwent a planned cesarean section, as well as related factors. METHODS: Authors employed a descriptive correlational study design. Factors associated with milk supply perception in postpartum women (at 3 days postpartum) were collected from 141 postpartum women who planned to undergo cesarean section at a regional teaching hospital in northern Taiwan. A demographic data sheet, the Birth Practice Inventory, a visual pain analog scale, and the Hill and Humenick Lactation Scale were used to identify factors affecting the perceived milk supply of participants. RESULTS: The study used multiple linear regression to identify significant predictors of milk supply perception. Four factors, including parity, type of anesthesia, time to initial breastfeeding, and use of formula, explained 23.1% of total variance among participants. Women who experienced epidural patient-controlled analgesia, those with delayed initial breastfeeding or lower breastfeeding frequency, and those who used formula supplementation earned relatively lower perceived milk supply scores. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Study results indicate that medical staff should encourage postpartum women to commence breastfeeding, based on infant need, as early as possible and reduce formula use to increase breastfeeding frequency. Shifting to nonnarcotic analgesic medications from epidural patient-controlled analgesia as early as possible is also recommended to increase breastfeeding success. PMID- 21586987 TI - Effectiveness of interactive multimedia CD on self-care and powerlessness in hemodialysis patients. AB - BACKGROUND: Hemodialysis (HD) patients have low self-care knowledge, poor self care behavior, and powerlessness. PURPOSE: The authors designed this study to, first, understand the current state of first-year HD patients' self-care knowledge, self-care behavior, and powerlessness and, second, assess the effectiveness of an interactive multimedia CD educational intervention. METHOD: A quasi-experimental, repeated measures design, with intervention and comparison groups, was used. All subjects for this study were recruited from six dialysis centers in southern Taiwan. The three points for outcome testing included baseline, 4 weeks, and 8 weeks. Research tools included an HD self-care knowledge questionnaire, an HD self-care behavioral questionnaire, a powerlessness questionnaire, and an interactive multimedia CD. RESULTS: Results found that participants possessed insufficient knowledge, were incapable of completely achieving or comprehending routine self-care, and were affected by powerlessness. The interactive multimedia CD intervention effectively enhanced self-care knowledge (p < .000) and self-care behavior (p < .000) and improved powerlessness (p < .000). Positive results persisted well after the conclusion of the intervention. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Participants in the intervention group had better self-care knowledge and behaviors and feeling of control over their lives than those in the control group. This illustrates the positive effects of the interactive multimedia CD. Results demonstrate the potential benefits of using the interactive multimedia CD with elderly patients in HD and nursing practice education. PMID- 21586988 TI - Developing practical knowledge content of emergency nursing professionals. AB - BACKGROUND: There is a paucity of published research on clinical or practical nursing knowledge. The ways that nurses acquire, develop, and maintain emergency room (ER) nursing care skills is a research area, in particular, that deserves further investigation. PURPOSE: This study examined clinical setting learning processes to better understand the practical knowledge content of ER nurses. METHODS: This study used a phenomenological approach and in-depth interviews of 10 nurses. Each participant had at least 3 years of ER experience. Researchers used Moustakas' method to analyze interview data. Findings were checked for credibility, transferability, dependability, and confirmability. RESULTS: The authors identified four major practical knowledge themes for ER professionals. These were (a) basic emergency treatment procedure routines and symptom management; (b) disease mechanisms, pharmacodynamics, and treatment responses; (c) newly identified diseases, updated emergency treatments and techniques, and medical treatment discussions; and (d) identifying nursing values including nursing attitudes and continuing patient care. Participants in this study had experience with the first three themes and successfully combined various types of nursing knowledge in their nursing care duties. Only few participants indicated experience with the fourth theme. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Findings clarify that clinical or practical knowledge in ER nurses evolves first from declarative knowledge (e.g., basic emergency treatment routines and operating procedures) to procedural knowledge (e.g., instructions from supervisors, actual practice, and drills) to conditional knowledge (e.g., observation and treatment involving direct interactions with patients). Nurses should combine and apply the various knowledge types in their nursing practice to assess comprehensively each patient's condition and administer effective treatment and service. PMID- 21586989 TI - The effectiveness of exercise on improving cognitive function in older people: a systematic review. AB - BACKGROUND: The well-documented physical benefits of exercise and the value of exercise for improving mental health have raised the profile and role of exercise in healthcare. However, studies evaluating the effects of exercise on neurocognitive function have produced equivocal results. PURPOSE: This study was designed to examine the effectiveness of exercise on improving cognitive function in older people. METHODS: Researchers used a narrative synthesis approach in this review and conducted a computer-based search in MEDLINE, CINAHL, Cochrane Library, and Airiti Library (Chinese) from 2006 to 2009 using the search terms exercise, physical activity, and cognition. Research quality appraisal was rated using Consolidated Standards of Reporting Trials criteria. RESULT: This review included 12 medium- to high-quality randomized controlled trials. Most studies examined used a 60-minute exercise regimen scheduled three times per week that was continued for 24 weeks. Of the 12 studies, 8 revealed that exercise can improve cognitive function. Five studies focused on healthy older people and three studied older people who had impaired cognition at baseline. Analysis of the studies showed simple, one-component exercise as better for older people with cognitive impairment and multicomponent exercise as better for those without such impairment. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: This systematic review demonstrated that an exercise regimen of 6 weeks and at least 3 times per week for 60 minutes had a positive effect on cognition. Whether multicomponent exercise is significantly more effective in improving cognitive function, particularly in healthy older people, should be tested using larger trials with more rigorous methodology. PMID- 21586990 TI - Preceptors' experiences training new graduate nurses: a hermeneutic phenomenological approach. AB - BACKGROUND: Preceptors are a key to retaining new graduate nurses in a hospital setting. Thus, it is important to understand new staff teaching experiences from their own perspectives. Preceptor experience is an inadequately explored topic in Taiwan. PURPOSE: The purpose of this study was to explore preceptor experiences related to their training of new graduate nurses in a hospital setting in Taiwan. METHODS: For this interpretive phenomenological study, researchers purposively recruited 15 nurse preceptors from a medical center in central Taiwan. Study data were collected by means of semistructured, in-depth interviews. Tape recordings were transcribed verbatim, and transcripts were analyzed using a hermeneutic circle approach. RESULTS: Three general themes captured the new nurse training experiences of the preceptors: (a) applying a variety of teaching strategies, (b) feeling the burden of being a preceptor, and (c) developing a sense of achievement. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Being in the role of both a preceptor and nurse was perceived as a challenge by participants because of heavy workloads and fears of failure. Thus, reducing the preceptor's patient care responsibilities while educating new nurses should be a priority. This study also found cultivating a positive work climate as crucial to support preceptors and new nurses so that preceptors do not feel alienated or overly stressed. A workshop is a useful strategy to introduce preceptors and new nurses to standardized training procedures and documents; this, in turn, can provide a more holistic approach to teaching and learning and reduce pressures on preceptors caused by additional, unfamiliar paperwork. PMID- 21586991 TI - Using clinical caring journaling: nursing student and instructor experiences. AB - BACKGROUND: Journaling has been incorporated into many nursing courses as an active reflective teaching strategy that can facilitate the learning process, personal growth, and professional development of students. There is limited research support of journaling as an appropriate tool to promote reflection for the purpose of learning caring in nursing education. PURPOSE: The aim of this study was to explore the experiences and perceptions of student nurses and instructors who use clinical caring journaling (CCJ) in their clinical practicum. METHODS: Researchers used a descriptive qualitative research design. The study population was 880 senior student nurses and 90 clinical instructors from a nursing program at a university in Taiwan who used CCJ. After completion of 1 year of clinical practicum, 16 students and 7 instructors participated voluntarily in focus group interviews. Researchers used content analysis to sort interview data into themes. RESULTS: Six themes were categorized that encapsulated student and instructor experiences and perceptions regarding using CCJ in their clinical practicum. These themes were guiding caring behavior toward patients, enabling students' reflective caring abilities, building up students' self-confidence, increasing interaction between students and instructors, enhancing students' self-development, and overcoming writing difficulty. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Research findings may serve as a reference for nursing educators to use CCJ strategy in student nurses' clinical practicum. PMID- 21586993 TI - Fine-tuning our treatment strategies. PMID- 21586992 TI - A study of factors affecting acceptance of hospital information systems: a nursing perspective. AB - BACKGROUND: Hospital information systems (HISs) are widely used in Taiwan, and HIS performance must be carefully evaluated. Nursing personnel are the largest group of staff in a hospital and are the center of care delivery; thus, they play an important role in the adoption and evaluation of HISs. PURPOSE: The primary objective of this study was to explore the critical factors affecting the acceptance of HISs in Taiwan from a nursing perspective. On the basis of the technology acceptance model, we used six exogenous variables (system quality, information quality, user self-efficacy, compatibility, top management support, and project team competency) as investigation factors. METHODS: Survey research targeted nursing personnel in the selected case hospital as participants. A total of 545 questionnaires were sent out, and 501 were returned, indicating a valid response rate of 91.9%. Collected data were analyzed using multiple regression analysis. RESULTS: : Results indicate that user self-efficacy, top management support, compatibility, and information quality have significant impacts on perceived ease of use. In addition, top management support, compatibility, and information quality were identified as having significant impacts on perceived usefulness. Furthermore, nurses' perceived ease of use and perceived usefulness on HISs was found to impact significantly on system acceptance, with 45.1% of the total explained variance. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Results can help managers understand key considerations affecting HIS development and use and may be applied as a reference for system development and improvement. PMID- 21586994 TI - Behavioral activation therapy for remediating persistent social deficits in medication-responsive chronic depression. AB - The purpose of this article is to explore the use of behavioral activation therapy in patients with medication-responsive chronic depression who continue to experience social and occupational deficits. The classification of chronic depression includes a variety of disorders that are both common and debilitating and that frequently leave patients socially impaired even after remission of mood symptoms. Medication is often only partially effective in remedying these social impairments. As a result, other interventions, including forms of psychotherapy, may be justified as an adjunct to medication to improve residual social impairment. Behavioral activation therapy is one such treatment that may be especially appropriate for such individuals. The authors offer a brief description of behavioral activation therapy and examine how to adapt this therapy for use in patients with medication-responsive chronic depression. Preliminary evidence suggests that the therapy can be easily implemented with few modifications to improve social and occupational difficulties. PMID- 21586995 TI - Agitation in the inpatient psychiatric setting: a review of clinical presentation, burden, and treatment. AB - Agitation among psychiatric inpatients (particularly those diagnosed with schizophrenia or bipolar disorder) is common and, unless recognized early and managed effectively, can rapidly escalate to potentially dangerous behaviors, including physical violence. Inpatient aggression and violence have substantial adverse psychological and physical consequences for both patients and providers, and they are costly to the healthcare system. In contrast to the commonly held view that inpatient violence occurs without warning or can be predicted by "static" risk factors, such as patient demographics or clinical characteristics, research indicates that violence is usually preceded by observable behaviors, especially non-violent agitation. When agitation is recognized, staff should employ nonpharmacological de-escalation strategies and, if the behavior continues, offer pharmacological treatment to calm patients rapidly. Given the poor therapeutic efficacy and potential for adverse events associated with physical restraint and seclusion, and the potential adverse sequelae of involuntary drug treatment, these interventions should be considered last resorts. Pharmacological agents used to treat agitation include benzodiazepines and first- and second-generation antipsychotic drugs. Although no currently available agent is ideal, recommendations for selecting among them are provided. There remains an unmet need for a non-invasive and rapidly acting agent that effectively calms without excessively sedating patients, addresses the patient's underlying psychiatric symptoms, and is reasonably safe and tolerable. A treatment with these characteristics could substantially reduce the clinical and economic burden of agitation in the inpatient psychiatric setting. PMID- 21586996 TI - Guidelines for treatment-resistant mania in children with bipolar disorder. AB - OBJECTIVE: To implement a treatment algorithm to operationalize treatment resistance and improve patient outcomes in youth with pediatric bipolar disorder (PBD). The term "treatment resistance" was operationally defined as significant persistent symptoms following the application of a treatment algorithm. METHOD: Youth (6-17 years of age, n=120) with treatment-refractory bipolar I or II disorder, currently in a manic or mixed episode, were treated in accordance with the following 3 step algorithm: (1) removal of destabilizing agents (antidepressants, gamma aminobutyric acid [GABA]-agonists, and stimulants), (2) optimization of antimanic agents, and (3) use of a limited number (E 2) of mood stabilizers. The primary efficacy measure was change in scores on the Young Mania Rating Scale (YMRS) over the 6-month treatment course. Response was defined as repeated YMRS scores E 12. RESULTS: The sample was dichotomized into responders and non-responders. Both responders and non-responders improved significantly, with responders improving by a greater margin (d=3.2). At the end of 6 months, 75.8% of subjects demonstrated a significant and stable decrease in manic symptoms consistent with symptomatic remission (YMRS E 12). None of the subjects withdrew from the clinical process due to adverse events. CONCLUSION: The application of this proposed treatment algorithm allows for more accurate identification of true treatment resistance and can significantly reduce manic symptoms in patients previously described as having treatment-refractory bipolar disorder. PMID- 21586997 TI - Persistent cognitive dysfunction despite clinical improvement in schizophrenia: a 10-year follow-up study. AB - One negative outcome associated with schizophrenia is a deterioration of cognitive functioning. Little is known about what happens to cognitive abilities in the years following a diagnosis of first-episode schizophrenia. This study assessed the cognitive functioning of 61 individuals with first-episode schizophrenia who showed significant clinical improvement (Clinical Global Improvement rating of much or very much improved) after 10 years of treatment, comparing their cognitive functioning at the time of the initial diagnosis and at 10-year follow-up. Our results indicated deterioration in some cognitive abilities at baseline with further decline in this area found after 10 years. Visuomotor integration, working memory, and executive functioning deteriorated in the 10 years of treatment following diagnosis, and many individuals who were classified as much or very much improved still demonstrated abnormal cognitive functioning. These findings suggest the need for greater focus on cognitive functioning in treatment for schizophrenia. PMID- 21586998 TI - Phase I trials: from traditional to newer approaches. Part I. AB - Phase I clinical trials have traditionally been focused on populations of normal healthy volunteers with the goal of determining the safety, tolerability, and pharmacokinetic profile of new investigational agents. As CNS drug development shifts its focus to the development of novel molecular entities, this approach will undergo an evolution. In this first part of a two-part series, the authors describe the traditional Phase I approach as well as challenges facing CNS drug development. The second half of the series will propose modifications to the traditional phase I design, including the incorporation of different populations, bio-marker surrogates, and adaptive designs. PMID- 21586999 TI - Music, psychotherapy, and the soul: thoughts on singing Beethoven's Missa Solemnis. AB - The author draws upon the experience of singing Beethoven's Missa Solemnis to explore the feeling states aroused by religious choral music, especially the Mass. He relates them to working with patients in psychotherapy around issues of dying, death, the "oceanic feeling" of the religious experience, the human quest for knowledge, and yearning for an eternal, intelligent, and all-knowing entity in the ultimate reality. PMID- 21587000 TI - So they want you to be their medical director. AB - Clinicians, especially physicians, who become "medical directors" of facilities or agencies incur more responsibilities than they sometimes realize. Clinical administration, such as medical director roles and duties, creates personal, professional, management, and forensic issues. For some, their day-to-day work changes little; others experience a shift in duties and relationships, particularly duties to and relationships with the organization (as contrasted with its patients) that are unfamiliar to most clinical professionals. One who accepts such a position should understand the organization's needs and expectations and, within bounds of professional ethics, be prepared to meet them. Even medical directors of very small organizations, such as small private hospitals or clinics, routinely, and sometimes unknowingly, incur administrative and/or legal responsibilities for which they may later be held accountable. PMID- 21587001 TI - Use of aripiprazole in adolescents with a history of lupus-associated psychosis and refractory psychiatric manifestations. AB - Neurologic and psychiatric manifestations are prevalent in children and adults with lupus (labeled by convention neuropsychiatric systemic lupus erythematosus or NPSLE). However, there is a paucity of data on the evaluation and management of NPSLE in youth, with only a few publications describing the use of atypical antipsychotics in children and adolescents with lupus. In children, aripiprazole, a D2/5-HT1A partial agonist, appears to cause less prominent metabolic derangements than other second-generation antipsychotics. This agent may be an important tool in the treatment of pediatric patients with lupus who are at risk for weight gain and dyslipidemia due to disease and corticosteroid effects. The authors present two cases in which psychiatric symptoms associated with treatment refractory lupus responded to aripiprazole pharmacotherapy. PMID- 21587002 TI - Catatonia as the presenting symptom in systemic lupus erythematosus. AB - Catatonia is a syndrome of physical and behavioral abnormalities that can result from psychiatric, neurological, or medical illness. Although systemic lupus erythematosus (SLE) is commonly known to cause neurological and psychiatric manifestations, it has only rarely been reported to cause the catatonic syndrome. In nearly all previously reported cases, the diagnosis of catatonia was reported in patients with an established diagnosis of lupus. We report a case in which a woman with no known medical history presented with catatonia that did not respond to standard treatment with benzodiazepines, suffered a long and complicated hospital course, and was eventually diagnosed with lupus. With initiation of treatment for lupus, her symptoms of catatonia remitted. This case illustrates the importance of considering medical causes in the diagnosis and treatment of psychiatric disorders, especially the catatonic syndrome. PMID- 21587003 TI - Commentary on neuropsychiatric symptoms associated with lupus. AB - Treatments for neuropsychiatric complications of systemic lupus erythematosus are reviewed, including psychiatric medications, corticosteroids (which may also cause psychiatric complications), and emerging non-steroidal immune modulators. PMID- 21587004 TI - Development of an integrated psychosocial treatment to address the medical burden associated with bipolar disorder. AB - We developed an integrated psychosocial treatment for bipolar disorder to decrease the disproportionate medical burden associated with this illness. Three treatment modules, Nutrition/weight loss, Exercise, and Wellness Treatment (NEW Tx) were administered in twelve 60-minute group sessions over 14 weeks. After the first group (N=4) had completed the treatment, it was revised, and then a second group (N=6) completed the revised treatment. Participants completed all of the study assessments and attended 82% of the sessions. Both groups added over 100 minutes of weekly exercise to their baseline duration. Participants in the second group showed improvements in their quality of life, depressive symptoms, and weight. It appears that NEW Tx may be a feasible intervention with promising pilot data for reducing the medical burden in bipolar disorder, but future research is needed to further evaluate the efficacy of NEW Tx. PMID- 21587005 TI - Nurses pronouncing death. PMID- 21587010 TI - Learning from a U.K.-U.S. nursing student exchange. PMID- 21587011 TI - Engaging the patient and family as partners in practice. PMID- 21587015 TI - West Nile virus. PMID- 21587016 TI - Update your knowledge of the latest PALS guidelines. PMID- 21587017 TI - Tattooed poets and peanut butter. PMID- 21587018 TI - The secret life of lymphocytes. PMID- 21587020 TI - Caring for a snakebite victim. PMID- 21587019 TI - What does EMTALA mean for you? PMID- 21587022 TI - Should males be vaccinated against HPV? PMID- 21587023 TI - On alert for iatrogenic pneumothorax. PMID- 21587025 TI - Acute deep vein thrombosis. PMID- 21587027 TI - Antifungal azoles: old and new. PMID- 21587028 TI - Echinocandins in children. PMID- 21587029 TI - Mysterious foot lesions in a healthy eight year old. PMID- 21587030 TI - False-positive results of Campylobacter rapid antigen testing. PMID- 21587031 TI - Strategies for reducing cancer incidence and mortality in African American and Arab American and Chaldean communities in the Detroit metropolitan area. AB - OBJECTIVES: We studied the feasibility of implementing a community-based participatory process (CBPP) that addressed cancer education, prevention, and screening in 2 ethnic minority populations by evaluating the improvement in rates of cancer screening compared with historical benchmarks. METHODS: From 2003 to 2009, 2281 community members participated in CBPPs conducted by the Beaumont Cancer Institute in cooperation with the Arab American and Chaldean (AAC) Council, the National Cancer Institute, and the American Cancer Society. The study population consisted of 1067 individuals who completed a postcancer forum survey: 642 from the African American (AA) and 425 from the AAC forums. Data were collected on participants' screening history and participation in subsequent screening tests after the previous year's CBPP. RESULTS: Following attendance of at least one cancer forum the previous year, 329 (30.8%) of the 1067 participant respondents underwent some type of cancer screening, 32% in the AA forums and 28.9% in the AAC forums. Compared with published controls, the CBPPs led to a 38.6% increase in mammographic screening and a 28.7% increase in prostate specific antigen screening; the AA cohort had 39.7% and 28.4% increases whereas the AAC cohort had 36.3% and 28.9% increases in mammographic and prostate specific antigen screening, respectively. CONCLUSIONS: The results of this study suggest that implementing CBPPs are feasible in underscreened ethnic minority populations. Further studies need to be performed to determine the absolute benefit of CBPPs compared with baseline levels of screening within these ethnic minority populations. PMID- 21587032 TI - A case of congenital granular parakeratosis. PMID- 21587033 TI - The "intraepidermal epithelioma" revisited: immunohistochemical study of the borst-jadassohn phenomenon. AB - The true nature of the so-called intraepidermal epithelioma of Borst-Jadassohn is poorly understood; whether this represents a distinct tumor or a morphological phenomenon [Borst-Jadassohn phenomenon (BJP)] shared by different entities has been debated. So far, no detailed immunohistochemical studies have been performed to address this issue. The aim of our study was to get further insight into the pathogenesis of the intraepidermal epithelioma of Borst-Jadassohn/BJP. Tumors showing the BJP [mainly clonal seborrheic keratoses (cSK) and clonal Bowen disease (cBD)] were studied and compared with typical (nonclonal) counterparts. Cell nests in cSK, cBD, hidroacanthoma simplex (HS), and porocarcinoma (PC) showed strong expression of epidermal growth factor-receptors (EGF-R), Ki-67, p63, and p53. Cell nests of clonal SK and HS (but not of clonal BD or PC) expressed keratin 5/6. The expression of E-cadherin and the number of CD1a+ Langerhans cells were reduced within the nests of all lesions, whereas melanocytes were increased in all of them. Keratins 7 and 19 were not expressed in any of the lesions. Tumors showing the BJP exhibit some immunohistochemical differences, suggesting that they represent separate entities. However, they all show strong expression of EGF-R within intraepidermal keratinocyte nests, suggesting that the epithelial growth factor pathway plays a role in the development of the BJP. PMID- 21587034 TI - Pigmented paget disease of the breast nipple with underlying infiltrating carcinoma: a case report and review of the literature. AB - Paget disease of the breast represents a cutaneous manifestation of an underlying breast malignancy. The rare finding of a pigmented Paget disease mimicking melanoma represents a diagnostic problem. We report a case of a pigmented lesion involving the breast nipple with an underlying infiltrating breast carcinoma, and we describe the clinical presentation, histological findings, and immunohistochemical features with a review of reported cases. PMID- 21587035 TI - Prominent apoptosis in pautrier microabscesses: a distinctive finding in adult T cell leukemia/lymphoma? PMID- 21587036 TI - Perivascular migration: a clue to the histogenesis of PEComas? PMID- 21587037 TI - Cost analysis of implant-based breast reconstruction with acellular dermal matrix. AB - A comparative cost analysis of breast reconstruction using acellular dermal matrix (ADM) and traditional tissue expander-/implant-based techniques was carried out. Medicare reimbursement costs were calculated for tissue expander/implant alone (TE/I), TE/I with ADM (TE/I + ADM), and single-stage implant (SSI) with ADM (SSI + ADM). The most expensive procedure at baseline was TE/I + ADM ($11,255.78), followed by TE/I alone ($10,934.18), and SSI + ADM ($5,423.02). Incorporating the probability of complications as derived from the published literature into the cost analysis resulted in an increase in the excess cost of ADM-based procedures (TE/I + ADM, $11,829.02; TE/I, $11,238.60; SSI + ADM, $5,909.83). Although SSI + ADM have the lowest cost, not all patients are suitable candidates for this type of procedure. With increasing focus on healthcare expenditure, it is important that plastic surgeons are aware of the cost implications of using ADM products. PMID- 21587038 TI - Cancer recurrence involving a TRAM flap and abdominal donor site following mastectomy and immediate breast reconstruction: a case report. AB - Local tumor recurrence after mastectomy with immediate reconstruction is rare. Most reported recurrences involve invasive or in situ ductal carcinoma and occur at the skin or subcutaneous tissues near the mastectomy site. We report a case of a patient with malignant phyllodes tumor that recurred after mastectomy with immediate pedicle transverse rectus abdominis myocutaneous flap reconstruction. The recurrent disease involved the mastectomy bed, transverse rectus abdominis myocutaneous flap, abdominal donor site, and precostal tunnel. PMID- 21587039 TI - Innervation of the pectoralis major muscle: anatomical study. AB - BACKGROUND: Owing to the diverse application of the pectoralis major muscle (Pmaj) in reconstructive surgery, with special reference to its safe and functional transfer, a precise knowledge of its nerve supply becomes mandatory. The aim of the present study was to investigate its innervations. METHODS: A total of 30 specimens of pectoral regions pertaining to 15 embalmed adult human cadavers, aged between 30 and 67 years (10 males, 5 females), were dissected in pursuit of this aim. RESULTS: The proximal and the upper third of the distal segments of the muscle were constantly supplied by the ventral division, through medial and lateral branches, and the dorsal division of the lateral pectoral nerve, respectively. The ventral branches of either the pectoral loop (in 26/30 specimens) or the medial pectoral nerve (MPN) (4/30) penetrated the upper third of the pectoralis minor to supply the lower two-thirds of the distal segment of the Pmaj through 1 or 2 branches. Concomitantly, the dorsal branch of either the MPN (26/30) or the pectoral loop (4/30) supplied the posterior limb of its tendon. The fourth intercostal nerve participated in the inferolateral muscle supply (4/30). CONCLUSIONS: The muscle is mainly innervated by the lateral pectoral nerve supplemented by the branches of the MPN. The proximal segment, having a separate nerve, allows its functional transfer. Care should be practiced whenever the distal segment is to be harvested, because of having multiple nerves. PMID- 21587040 TI - The impact of reduction mammaplasty on breast sensation: an analysis of multiple surgical techniques. AB - Our prospective clinical trial collected sensory data using a computerized pressure-specified sensory device comparing 4 procedures for reduction mammaplasty. A total of 48 patients were assessed at baseline, 6 weeks (n = 42), 6 months (n = 15), and 1 year (n = 24) postoperatively. The findings of our study showed pressure sensitivity for women <43 years of age improved by pressure specified sensory device assessment; whereas, outcome data merely indicated return to baseline in pressure sensitivity for women >= 43 years of age. Improved sensitivities for moving and static pressures were found in patients receiving vertical or inferior pedicle reduction mammaplasties. Reductions based on superior pedicles exhibited sensory loss as compared with baseline measurements while those receiving free nipple grafts showed negligible change. Moving and static sensation showed differential return after breast reduction irrespective of the specific surgical approach but sensation was uniquely conserved for the nipple. In the total cohort, the type of breast reduction procedure did not produce significant differences in breast sensation. PMID- 21587041 TI - End-to-end versus end-to-side motor and sensory neurorrhaphy in the repair of the acute muscle denervation. AB - BACKGROUND: The aim of this study was to experimentally compare end-to-end and end-to-side neurorrhaphy in perineural window model after motor nerve lesion, evaluating which one was the most effective to preserve nerves. Also, differences in motor and sensorial nerve regeneration were tested to verify differences in nerve regeneration. METHODS: A total of 20 adult male Wistar rats were randomly assigned to 5 groups, and, in each one, a different treatment was performed: besides the control group, and end-to-end or end-to-side graft with motor or sensorial nerves was performed. Silastic sheet was used as a mechanical barrier to prevent innervation from adjacent nerves. After 16 weeks, the specimens were histologically assessed and wet weight was evaluated as a direct parameter of atrophy. RESULTS: The end-to-end neurorrhaphy group presented the best results in terms of mass preservation, but it did not differ significantly from the control group. Motor nerves presented similar results in muscular atrophy. The end-to side neurorrhaphy group with sensory nerve as donor showed the worst results. CONCLUSIONS: The use of sensory nerves to preserve skeletal muscle trophism is not justified, since, according to our model, it affects 50% to 80% of the muscle mass in a period of 16 weeks. End-to-side neurorrhaphy was demonstrated to be an option for re-enervation of a nerve-deprived motor muscle in selected cases. PMID- 21587042 TI - Endoscopy-assisted cubital tunnel release under carbon dioxide insufflation and anterior transposition. AB - PURPOSE: The optimal treatment for cubital tunnel syndrome is widely debated. The purpose of this study is to describe the technique of an endoscopic-assisted ulnar nerve decompression using carbon dioxide insufflation in association with subcutaneous anterior transposition and to assess the success or failure of the method of treatment. METHODS: In all, 8 male and 4 female patients with an average age of 42 years (range, 25-56) who presented signs, symptoms, and abnormal neurophysiological studies of cubital tunnel syndrome were recruited in the retrospective study. Between August 2008 and June 2009, they were operated on using a 0-degree lens endoscope. Preoperatively, they were classified according to the Dellon scale, and the Bishop rating system was used to evaluate the postoperative outcomes. RESULTS: Preoperatively, 5 patients were rated as mild, another 5 as moderate, and the remaining 2 as severe. The average length of the incision was 15 +/- 3 mm, the mean length of the ulnar nerve decompression was 18 +/- 2 cm, and the whole duration of surgery (skin to skin) lasted 30 +/- 5 minutes. The endoscopic-assisted cubital tunnel release under carbon dioxide insufflation and subcutaneous anterior transposition surgeries in all patients were performed with no difficulty. All the patients had improvement in symptoms of cubital tunnel syndrome and 10 of 12 patients scored excellent according to the modified Bishop Rating System at a minimum of 1 year after surgery. CONCLUSIONS: Endoscopy-assisted cubital tunnel release under carbon dioxide insufflation demonstrated similar results compared with conventional open surgeries, besides, it may avoid problems such as long incision, painful scarring, and have additional advantages of providing an extended endoscopic view, which is safe and mini-invasive with favorable results in a 12-month follow up. PMID- 21587043 TI - Approaching revisional surgery in augmentation and mastopexy/augmentation patients. AB - BACKGROUND: Breast augmentation and mastopexy augmentation procedures are becoming more common. The young plastic and reconstructive surgeon is often challenged revisional surgery operations in these patients. These cases are challenging, require significant operative time, and can be associated with a high revision rate. It is important for the young surgeon to have an approach to deal with these common and difficult scenarios. METHODS: A retrospective chart review was conducted on all patients who underwent a revision augmentation or revision mastopexy augmentation procedure between 2008 and 2010 by the authors. The most commonly encountered mitigating circumstances in the revision augmentation or revision mastopexy augmentation populations were identified and an algorithm was created on how to address these difficult problems. RESULTS: Between July 1, 2008 and July 1, 2010, 264 patients underwent revision augmentation or revision mastopexy augmentation procedures. The most commonly encountered patient scenarios were recurrence of ptosis, recurrent capsular contracture, implant malposition, rippling, and desiring a reduction in implant size. We encountered many mitigating circumstances that complicated the revisions. We devised a stepwise algorithmic approach to address these problems based on the following factors: (1) blood supply to the nipple-areola complex, (2) need to change implant plane, (3) patient desire to reduce or increase in breast implant volume, (4) need for total en bloc capsulectomy or capsulorrhaphy, (5) incision approach used to perform the capsulectomy, and (6) patient-related factors that need to be medically optimized or treated before, during, and after surgery. By adhering to these steps, outcomes can be accomplished more reliably and safely. CONCLUSION: Specialized preoperative planning is necessary to consistently deliver safe and aesthetic revision augmentation and revision mastopexy augmentation results. It is important for the operative surgeon to carefully consider the potential adverse effect of implants and prior mastopexy or reduction incisions and patterns on the blood supply to the nipple-areola complex. With educated planning, successful results can be achieved in most cases, and the risk of serious complications can be minimized. PMID- 21587044 TI - Reconstruction of large supra-eyebrow and forehead defects using the hatchet flap principle and sparing sensory nerve branches. AB - BACKGROUND: To reconstruct a forehead defect, a plastic surgeon must be knowledgeable about the neural, vascular, and muscular anatomy. The position of fixed structures such as eyebrows and hairline should be respected. For the past 5 years, we have used double hatchet flaps for reconstruction of relatively large supra-eyebrow and forehead defects. Because this flap does not appear to be among the techniques used by young plastic surgeons, we thought that it would be valuable to report our experience. METHODS: Supra-eyebrow and forehead defects ranging from 2.5 * 2.5 cm to 3.5 * 3.5 cm were reconstructed using double hatchet flaps in 10 patients. Pearls and pitfalls of the technique are discussed along with the presentation of 3 cases. RESULTS: The reconstructions were uneventful and the flaps were highly viable in all patients. There was no significant distortion in the eyebrow or hairline due to reconstruction in any of the patients. All the flaps were sensate. A mild anesthesia in the distribution of supraorbital/trochlear nerve proximal to the flaps was noted only in 3 patients. This was associated with inevitable nerve damage during excision of malignant skin lesions and/or flap dissection. No recurrence was noted during the follow-up period which ranged from 6 to 36 months (mean, 13.5 months). Overall patient satisfaction score based on scar appearance and perceived degree of forehead anesthesia was 3 (neither satisfied nor dissatisfied) in 1 patient, was 4 (somewhat satisfied) in 4 patients, and was 5 (very satisfied) in 5 patients. CONCLUSION: Hatchet flaps have similar color and texture to that of the adjacent supra-eyebrow and forehead defects. The scarring is acceptable with reliable and reproducible results. Oftentimes, sensory nerve branches can be preserved with careful planning and tedious dissection. This type of reconstruction should be considered in the armamentarium of supra-eyebrow and forehead defects. PMID- 21587045 TI - Is there a need for preoperative imaging of the internal mammary recipient site for autologous breast reconstruction? AB - Preoperative imaging of recipient-site vasculatur in autologous breast reconstruction may potentiate improved outcomes through the identification of individual variations in vascular architecture. There are a range of both normal and pathologic states which can substantially affect the internal mammary vessels in particular, and the identification of these preoperatively may significantly affect operative approach. There are a range of imaging modalities available, with ultrasound particularly useful, and computed tomography angiography (CTA) evolving as a useful option, albeit with radiation exposure. The benefits of CTA must be balanced against its risks, which include contrast nephrotoxicity and allergic reactions, and radiation exposure. The radiation risk with thoracic imaging is substantially higher than that for donor sites, such as the abdominal wall, with reasons including exposure of the contralateral breast to radiation (with a risk of contralateral breast cancer in this population 2 to 6 times higher than that of primary breast cancer, reaching a 20-year incidence of 15%), as well as proximity to the thyroid gland. Current evidence suggests that although many cases may not warrant such imaging because of risk, the benefits of preoperative CTA in selected patients may outweigh the risks of exposure, prompting an individualized approach. PMID- 21587046 TI - Accurate assessment of breast volume: a study comparing the volumetric gold standard (direct water displacement measurement of mastectomy specimen) with a 3D laser scanning technique. AB - Preoperative assessment of breast volume could contribute significantly to the planning of breast-related procedures. The availability of 3D scanning technology provides us with an innovative method for doing this. We performed this study to compare measurements by this technology with breast volume measurement by water displacement. A total of 30 patients undergoing 39 mastectomies were recruited from our center. The volume of each patient's breast(s) was determined with a preoperative 3D laser scan. The volume of the mastectomy specimen was then measured in the operating theater by water displacement. There was a strong linear association between breast volumes measured using the 2 different methods when using a Pearson correlation (r = 0.95, P < 0.001). The mastectomy mean volume was defined by the equation: mastectomy mean volume = (scan mean volume * 1.03) -70.6. This close correlation validates the Cyberware WBX Scanner as a tool for assessment of breast volume. PMID- 21587047 TI - Fleur-de-lis panniculectomy after bariatric surgery: our experience. AB - BACKGROUND: Plastic surgeons are faced with increasing numbers of patients presenting for insurance-covered skin excision procedures following bariatric surgery. Panniculectomy for symptomatic relief of rashes is commonly performed, but an isolated infraumbilical amputation-type panniculectomy is a highly unaesthetic procedure, leaving many patients deeply dissatisfied. It may be also fraught with complications due to large incisions and potential for dead-space. In these patients, many surgeons avoid the fleur-de-lis panniculectomy, despite the body contour aesthetic advantage, because of increased time, more scarring, and a perceived increase in complications. METHODS: This is a retrospective chart review of 130 consecutive postbariatric surgery patients who had panniculectomy over a 2-year period at our institution. RESULTS: A total of 30 patients underwent a traditional panniculectomy and 100 patients had a fleur-de-lis panniculectomy. Mean weight loss from bariatric surgery to panniculectomy was 58.2 kg, with an average body mass index (BMI) of 30. Fifty-seven patients had additional procedures performed at the time of panniculectomy. Twenty-two patients (17%) had complications, with 5 in the traditional group (17%) and 17 in the fleur-de-lis group (17%) (P = 1.0). Six males (40%) had more complications compared with 18 females (15.7%) (P = 0.034). Patients with BMI <30 had 10 complications compared with patients with BMI >=30 had 15 complications. CONCLUSIONS: There are many benefits of fleur-de-lis over traditional panniculectomy, even for medical necessity cases. There is limited undermining of tissue which minimizes/eliminates skin necrosis. Our experience with primarily fleur-de-lis panniculectomies shows a complication rate lower than most published data. Fleur-de-lis potentially creates a better symptom correction and cosmetic outcome by resecting maximal skin in both vertical and horizontal directions. These findings must be balanced against a potentially longer operation. PMID- 21587048 TI - The "sweet science" of reducing periorbital lacerations in mixed martial arts. AB - The popularity of mixed martial arts competitions and televised events has grown exponentially since its inception, and with the growth of the sport, unique facial injury patterns have surfaced. In particular, upper eyelid and brow lacerations are common and are especially troublesome given the effect of hemorrhage from these areas on the fighter's vision and thus ability to continue. We propose that the convexity of the underlying supraorbital rim is responsible for the high frequency of lacerations in this region after blunt trauma and offer a method of reducing subsequent injury by reducing its prominence. PMID- 21587049 TI - Isolated congenital partial absence of the left lower lateral nasal cartilage: case report. AB - Isolated congenital nasal anomalies are rare; the isolated absence of any specific nasal structure is even rarer. In this report, we present a patient with congenital isolated partial absence of the left lower lateral cartilage including only the lateral crura. PMID- 21587050 TI - Successful treatment of Parry-Romberg syndrome with autologous fat grafting: 14 year follow-up and review. AB - Parry first described the syndrome of progressive facial atrophy in 1825, followed by Romberg in 1846. The clinical hallmark of the syndrome is atrophy of the facial soft tissues, including fat and muscle as well as underlying bone. Clinicians have classically reserved treatment until the end of the disease process, after the "burn out" stage. Various treatment modalities have been attempted with differing results. In this study, we present a case of Parry Romberg syndrome treated with autologous fat grafting. This case report reviews the history of the disease, examines the safety and clinical outcomes of fat grafting as a treatment modality, and challenges the classic timing of that treatment. Additionally, long-term follow-up with photos and histological analysis of specimens are included. PMID- 21587051 TI - Mozart ear: diagnosis, treatment, and literature review. AB - Mozart ear is a congenital auricular deformity, which is mainly characterized by a bulging appearance of the anterosuperior portion of the auricle, a convexly protruded cavum conchae, and a slit-like narrowing of the orifice of the external auditory meatus. It is said to be uncommon, and because no one has yet fully described neither the disease nor the treatment, the concept of Mozart ear has not been unified. This report describes a case of a 13-year-old girl presented with an unusual congenital deformity which showed the features of Mozart ear. It is an extremely rare deformity that only about 4 clinical cases have been reported in medical literature thereby a treatment method has not been fully discussed. For surgical correction of our cases, we excised deformed conchal cartilage, turned it over, regrafted, and maintained a cosmetically positive result. We also reviewed and described the origin, current concept, and treatment method of Mozart ear. PMID- 21587052 TI - Free flap reconstruction of extensive defects following resection of large neurofibromatosis. AB - BACKGROUND: Neurofibromatosis type 1 (NF-1) is a locally invasive tumor that can grow extensively with diffuse infiltration into surrounding tissue. Resecting a large neurofibroma can result in an extensive defect that is difficult to reconstruct and can cause both aesthetic and functional deformities. METHODS: From 2000 to 2010, 5 patients with NF-1 underwent radical resection and immediate reconstruction with 6 free flaps at our institution. All patients presented with recurrent tumor, and involved head and neck region in 4 and foot in 1 patient. Ages ranged from 18 to 75 years. The follow-up ranged from 1 to 94 months. RESULTS: Defect sizes ranged from 84 to 252 cm. A single free flap was used in 4 cases and 2 free flaps were used in 1 case. All the flaps survived. Complications included loss of skin graft, necrosis of the distal tip of a flap, and wound dehiscence. All complications were successfully managed with minor surgical procedures. CONCLUSION: Immediate reconstruction using a free flap after resecting a large neurofibroma is a safe and reliable method that facilitates radical resection of the tumors that are difficult to resect and that may result in an extensive defect. PMID- 21587053 TI - Optimal timing of extracorporeal shock wave treatment to protect ischemic tissue. AB - Enhancement of flap survival through extracorporeal shock wave treatment (ESWT) is a promising new technique; however, no attempt has been made to define the optimal time point and frequency of ESWT to optimize treatment with ESWT for ischemic indications. Twenty-eight male Wistar rats were randomized into 4 groups and an oversized, random-pattern flap was raised and reattached in place in each animal. ESWT was applied 7 days before (group E7) or immediately after the surgical intervention (group E0). The third group was treated with ESWT 7 days before and additionally immediately after the operation (group E7/0). The fourth group served as a control group and did not receive any ESWT (group C). Seven days after flap harvest the results of flap survival, perfusion, microvessel density, and vascular endothelial growth factor concentrations were assessed. Flap survival was significantly increased in all ESWT groups as compared with the control group. The groups (E7 and E0) that received ESWT pre- or postoperatively showed a significant increase in flap perfusion and microvessel density. Combined pre- and postoperative ESWT application (group E0/E7) did not demonstrate a cumulative effect in any evaluation. In this study, we were be able to prove the effectiveness of ESWT in the protection of ischemic tissue flaps. This study suggests that single postoperative application is the most efficacious protocol for clinical applications of ESWT in the treatment of ischemic tissue. PMID- 21587054 TI - Angular artery cutaneous flap for reconstruction of difficult oronasal fistulas. AB - BACKGROUND: Oronasal fistulas after oromaxillary surgery may sometimes be encountered and remain a challenging problem. They can cause significant disabilities such as phonetic problems and food or liquid regurgitation while swallowing. A few methods are reported to solve this problem, including using a dental appliance, local tissue rotation, or even free-tissue transfer. MATERIALS AND METHODS: An angular artery cutaneous flap was designed to repair the defect. The flap that included the skin and superficial fascia fed by the flow of angular artery was rotated through the buccal mucosa into the oral cavity to cover the palate defect. CASE REPORTS: Two oronasal fistula cases were reported in this series. Case 1: A 71-year-old man had hard palate cancer and had received wide excision in our hospital 2 years previously. He had received adjuvant radiotherapy (28 times) and was transferred to the plastic surgery department for dealing with oronasal fistula. The palate defect was 2 * 2 cm. Case 2: A 72-year old woman was a patient with left palate mucoepidermoid carcinoma. She had received an operation and adjuvant radiotherapy 10 years previously. For her oronasal fistula and hypernasality, she had received reconstructive operations 3 times with local rotation flap for left-side palate defect at a previous hospital. However, the local flap failed and the fistula persisted. She then approached our plastic surgery department for help. The palate defect was about 1 * 1 cm. We successfully reconstructed the oronasal fistula by using the angular artery cutaneous flap. The flap successfully sealed the oral cavity during the follow-up period. CONCLUSION: Angular artery cutaneous flap is a good alternative for reconstruction of the oronasal fistula. Especially in elderly patients, donor site comorbidities are fewer due to the redundant aging skin and the missing tooth. PMID- 21587055 TI - Desmoid tumor: current multidisciplinary approaches. AB - Desmoid tumor, also known as aggressive or deep fibromatosis or musculoaponeurotic fibromatosis, is a rare tumor. Desmoids are characterized by their ability to locally infiltrate; while frequently locally recurrent, they lack metastatic potential. Desmoids typically arise within the abdomen or abdominal wall, but can be extra-abdominal, most commonly in the proximal extremities. The infiltrative and recurrent nature of desmoid tumors can render surgical resection challenging if acceptable function and cosmesis is to be maintained. Consequently, desmoid management frequently involves a multidisciplinary approach that combines the expertise of several surgical specialists, for example, surgical oncologists and plastic surgeons, and also medical and radiation oncologists. As will be reviewed in this article, working together before undertaking any definitive therapies, such expert teams may be optimally positioned to offer patients superior functional and aesthetic outcomes based on maximizing therapeutic efficacy while minimizing treatment-related morbidities. PMID- 21587056 TI - Contouring of the gluteal region in women: enhancement and augmentation. AB - Techniques for improving the appearance of the gluteal region are important elements in body contouring. In all cultures and communities, this aspect of the physique holds a special place among the elements comprising the ideals of physical beauty. Recent studies described the aesthetics of the gluteal region in terms of shape, volume, and projection. Accumulation of fat at the supragluteal, lower paralumbar, infragluteal, and/or trochanteric areas often disturbs the natural shape of the buttocks. The problem is accentuated by the lack of lateral projection. This study was designed to find a method for contouring of the gluteal region. This method is based on the enhancement of the shape by liposculpture of the areas around the buttocks, and lipoinjection to achieve the volume and projection. Between July 2008 and December 2009, the study included 40 female patients complaining of disfigurement of the gluteal region. With 1 year follow-up period, 36 patients showed high satisfaction with the results. Pre- and postoperative perimeters of the gluteal regions showed good improvement in proportion and projection. The study concluded that liposuction of the areas around the buttocks could enhance the shape of the gluteal region. Lipoinjection could add a balanced shape, size, and projection. A pleasing gluteal appearance could be achieved by the combination of enhancement and augmentation. PMID- 21587057 TI - Management of regional hidradenitis suppurativa with vacuum-assisted closure and split thickness skin grafts. AB - BACKGROUND: Hidradenitis suppurativa can be a debilitating chronic illness. The underlying cause of the disease is still not clear, but effective treatment of widespread regional disease relies on resection of all the involved skin and subcutaneous tissue. Closure of the resulting large wound is dependent on either flap or skin graft coverage. Many of the resulting wounds are too large for flap closure or result in unacceptable flap donor site deficits. METHODS: We present a series of 11 patients with 24 regional disease sites treated with a protocol of excision, followed by wound vacuum-assisted closure (VAC; KCI, San Antonio, TX) therapy to stimulate angiogenesis of exposed fat, and then skin grafting with the use of VAC to support the grafts on the recipient sites. RESULTS: Only 3 of the patients required regrafting. One patient had a VAC failure because of poor patient compliance, and 1 patient had 4 sites that each required regrafting as the epithelium would not fill in the residual open areas as it usually did in other patients. All patients were cured of their local disease. CONCLUSIONS: Massive regional hidradenitis suppurativa can be successfully managed with wide excision, VAC therapy, and skin grafting to allow these patients to live normal and productive lives. PMID- 21587058 TI - Chest wall reconstruction of severe mediastinitis with intercostal artery-based pedicled vertical rectus abdominis muscle flap with oblique-designed skin pedicle. AB - Recurrent poststernotomy mediastinitis has significant morbidity and mortality. Reconstructive treatment begins with pectoral muscle or omental flaps. When these options are unavailable or inadequate, surgeons resort to internal mammary artery based vertical rectus abdominis muscle flap. If the internal mammary artery is harvested for coronary artery bypass grafting, surgeons are reluctant to use the muscle for pedicled flap because of the elevated risks. However, recent reports suggest that if enough time passes for intercostal artery collaterals to develop, they would support the viability of the flap. Moreover, recent improvements in defining flap microvasculature and proposed surgical techniques have enabled us to further refine the procedure. Although it appears that the intercostal artery based pedicled vertical rectus abdominis muscle flap with oblique-designed skin pedicle is safe and effective for chest wall reconstruction, potential for failure remains elevated until sample size accumulates. PMID- 21587059 TI - Wound healing assessment: does the ideal methodology for a research setting exist? AB - INTRODUCTION: Studies on dressings frequently measure wound healing to demonstrate performance. Knowledge of existing methodologies available for wound healing assessment, including their advantages and limitations, is paramount when evaluating the literature on dressings. METHODOLOGY: Medline and Cochrane databases were searched for wound healing assessment methodologies used in research or in clinical practice. RESULTS: Twenty-nine methodologies were identified and classified into 8 categories: scales (n = 4), one-dimensional measurements (n = 2), area measurements (n = 4), volume measurements (n = 6), 3 dimensional wound reproduction systems (n = 5), methodologies based on wound physical characteristics (n = 3), rates and surrogates end point calculated from variation in wound dimensions (n = 4), and time to wound healing (n = 1). The main problems encountered during wound healing assessment include the following: boundary definition, assessor's contact with the wound, irregular wound shape, and difficulty in evaluating early healing. CONCLUSION: At this time, an ideal methodology does not exist. Research in this area is lacking and should be the focus in wound healing evaluation. PMID- 21587060 TI - Sleep and anesthesia: the histamine connection. PMID- 21587061 TI - Succinylcholine should be avoided in patients on statin therapy. PMID- 21587062 TI - Hypertonic saline hydroxyethylstarch restores right ventricular-arterial coupling after normovolemic hemodilution in piglets. AB - BACKGROUND: Normovolemic hemodilution is known to inhibit hypoxic pulmonary vasoconstriction. How the coupling between the pulmonary arterial (PA) circulation and the right ventricle (RV) is affected by normovolemic hemodilution and by the composition of replacement solutions remains unknown. Therefore, the effects of isotonic and hypertonic saline hydroxyethylstarch solutions on the pulmonary circulation and RV, in control and hypoxic conditions, were compared. METHODS: Anesthetized piglets (n = 14) were equipped with manometer-tipped catheters in the RV and main PA and an ultrasonic flow probe around the main PA. The pulmonary circulation was assessed by pressure-flow relations and vascular impedance, RV afterload by effective arterial elastance (Ea), RV contractility by end-systolic elastance (Ees), and RV-PA coupling by the Ees/Ea ratio. Measurements were done in control (Fio2 0.40) and hypoxic (Fio2 0.12) conditions before and after acute normovolemic hemodilution with either 20 ml/kg isotonic saline hydroxyethylstarch (hydroxyethylstarch 130/0.4 6% in NaCl 0.9%, Voluven, Fresenius-Kabi, Sevres, France) or 5 ml/kg hypertonic saline hydroxyethylstarch (hydroxyethylstarch 200/0.5 6% in NaCl 7.2%, HyperHES, Fresenius-Kabi) solutions. RESULTS: Hypoxic pulmonary vasoconstriction was associated with proportional increases in Ea and Ees and did not affect RV-PA coupling. Hemodilution attenuated the hypoxic response. Hemodilution with isotonic saline hydroxyethylstarch did not affect the RV-PA coupling, whereas hemodilution with hypertonic saline hydroxyethylstarch increased Ees and the Ees/Ea ratio. CONCLUSION: In experimental normovolemic hemodilution, both in control and in hypoxic conditions, RV-PA coupling is unaffected by isotonic saline hydroxyethylstarch but improved by hypertonic saline hydroxyethylstarch, mainly because of an increase in RV contractility. PMID- 21587063 TI - A review of current and emerging approaches to address failure-to-rescue. AB - Failure-to-Rescue, defined as hospital deaths after adverse events, is an established measure of patient safety and hospital quality. Until recently, approaches used to address failure-to-rescue have been focused primarily on improvement of response to a recognized patient crisis, with limited success in terms of patient outcomes. Less attention has been paid to improving the detection of the crisis. A wealth of retrospective data exist to support the observation that adverse events in general ward patients are preceded by a significant period (on the order of hours) of physiologic deterioration. Thus, the lack of early recognition of physiologic decline plays a major role in the failure-to-rescue problem. PMID- 21587064 TI - Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states. AB - PURPOSE OF REVIEW: Proinflammatory adipose tissue macrophages (ATMs) contribute to obesity-associated disease morbidity. We will provide an update of the current state of knowledge regarding the phenotypic and functional diversity of ATMs in lean and obese mice and humans. RECENT FINDINGS: The phenotypic diversity of ATMs is now known to include more than two types requiring an expansion of the simple concept of an M2 to M1 shift with obesity. Potential functions for ATMs now include the regulation of fibrosis and response to acute lipolysis in states of caloric restriction. Novel pathways that can potentiate ATM action have been identified, which include inflammasome activation and the response to lipodystrophic adipose tissue. Studies provide a new appreciation for the ability of ATMs to respond dynamically to the adipose tissue microenvironment. SUMMARY: ATMs play a key role in shaping the inflammatory milieu within adipose tissue, and it is now apparent that ATM heterogeneity is acutely shaped by the adipose tissue environment. To account for the new findings, we propose a new nomenclature for ATM subtypes that takes into account their diversity. PMID- 21587065 TI - Intestinal microbiota in inflammation and insulin resistance: relevance to humans. AB - PURPOSE OF REVIEW: The gut microbiota is a very complex ecosystem which interacts extensively with the host, influencing multiple metabolic and physiological functions. Several diseases have been shown to be associated with specific alterations in gut microbiota. It is more and more underscored as playing a major role in the development of insulin resistance and inflammation associated with excess weight gain. RECENT FINDINGS: Recent studies in obese patients have shown perturbations in gut microbiota with a weight gain-associated increase in the Firmicutes/Bacteroidetes ratio ameliorated by various attempts at inducing weight loss. SUMMARY: Intestinal microbiota may contribute to the development of inflammation and insulin resistance by two main mechanisms. First, gut microbiota might facilitate energy harvest from the gut leading via perturbation in energy homeostasis to fat deposition and increased adipokine production and plasma free fatty acid levels both contributing to insulin resistance and inflammation. Alternatively, it can initiate an inflammatory process either originating from the intestine or generated at the peripheral level via endotoxin leakage into the blood from the intestine, both leading secondarily to insulin resistance. PMID- 21587066 TI - The role of G-protein-coupled receptors in mediating the effect of fatty acids on inflammation and insulin sensitivity. AB - PURPOSE OF REVIEW: Chronic activation of inflammatory pathways mediates the pathogenesis of insulin resistance, and the macrophage/adipocyte nexus provides a key mechanism underlying decreased insulin sensitivity. Free fatty acids are important in the pathogenesis of insulin resistance, although their precise mechanisms of action have yet to be fully elucidated. Recently, a family of G protein-coupled receptors has been identified that exhibits high affinity for fatty acids. This review summarizes recent findings on six of these receptors, their ligands, and their potential physiological functions in vivo. RECENT FINDINGS: Upon activation, the free fatty acid receptors affect inflammation, glucose metabolism, and insulin sensitivity. Genetic deletion of GPR40 and GPR41, receptors for long-chain and short-chain fatty acids, respectively, results in resistance to diet-induced obesity. Deletion of GPR43 and GPR84 exacerbates inflammation, and deletion of the long-chain fatty acid receptors GPR119 and GPR120 reduces or is predicted to reduce glucose tolerance. SUMMARY: These studies provide a new understanding of the general biology of gastric motility and also shed valuable insight into some potentially beneficial therapeutic targets. Furthermore, highly selective agonists or antagonists for the free fatty acid receptors have been developed and look promising for treating various metabolic diseases. PMID- 21587068 TI - The 5-lipoxygenase/leukotriene pathway in obesity, insulin resistance, and fatty liver disease. AB - PURPOSE OF REVIEW: Obesity is a major risk factor for metabolic syndrome-related comorbidities such as insulin resistance, type-II diabetes, and nonalcoholic fatty liver disease (NAFLD). A wealth of evidence indicates that the associated pathologies of the metabolic syndrome are aggravated by the presence of a chronic state of 'low-grade' inflammation in the adipose tissue. This article discusses recent data implicating lipoxygenases and especially 5-lipoxygenase and its derived products, the leukotrienes, in mounting adipose tissue inflammation and related pathologies in obesity. RECENT FINDINGS: Overexpression of selected members of the 5-lipoxygenase pathway and increased leukotriene production are common findings in excessive visceral fat depots. In these conditions, 5 lipoxygenase products exert potent proinflammatory actions including induction of nuclear factor-kappaB and secretion of proinflammatory and insulin resistant adipokines (i.e., monocyte chemotactic protein-1, tumor necrosis factor-alpha, macrophage inflammatory protein-1gamma, and interleukin-6) by adipose tissue. The 5-lipoxygenase pathway also plays a major role in mounting inflammation in hepatic tissue and has emerged as a pathogenic factor in obesity-induced NAFLD. Similar role in NAFLD has been proposed for the 12/15-lipoxygenase pathway. SUMMARY: Modulation of lipoxygenases represents a novel target in the prevention of adipose tissue and hepatic dysfunction related to the metabolic syndrome. PMID- 21587067 TI - Role of intestinal inflammation as an early event in obesity and insulin resistance. AB - PURPOSE OF REVIEW: To highlight recent evidence supporting a concept that intestinal inflammation is a mediator or contributor to development of obesity and insulin resistance. RECENT FINDINGS: Current views suggest that obesity associated systemic and adipose tissue inflammation promote insulin resistance, which underlies many obesity-linked health risks. Diet-induced changes in gut microbiota also contribute to obesity. Recent findings support a concept that high-fat diet and bacteria interact to promote early inflammatory changes in the small intestine that contribute to development of or susceptibility to obesity and insulin resistance. This review summarizes the evidence supporting a role of intestinal inflammation in diet-induced obesity and insulin resistance and discusses mechanisms. SUMMARY: The role of diet-induced intestinal inflammation as an early biomarker and mediator of obesity, and insulin resistance warrants further study. PMID- 21587070 TI - Antibiotic stewardship: overcoming implementation barriers. AB - PURPOSE OF REVIEW: Antimicrobial stewardship is now recognized as a formal strategy for curbing the upward trend in antibiotic resistance. Literature on antimicrobial stewardship has focused on areas of strategic importance and operational delivery. A number of barriers have been recognized in the implementation of successful programs. These include lack of physician participation, lack of diagnostic facility, absence of formal mechanism of data collection, variation between countries, and lack of cooperative strategies. In this review, we suggest strategies to overcome these barriers. RECENT FINDINGS: In the last few years, it has been recognized that an executive program is necessary for successful implementation of strategies to control the growing antibiotic resistance. Efforts have been made at higher levels of government through organizations such as the European Centre for Disease Prevention and Control. The need for community healthcare involvement has also been recognized. At a local level, strategies to promote cooperation between various committees (e.g. infection control and antimicrobial management teams) have been proposed and adopting antibiotic care bundles as part of patient safety and healthcare is being explored. SUMMARY: We suggest that executive level planning, local cooperation, sustained education, emphasis on de-escalation, and use of care bundles could stem the tide of growing resistance. PMID- 21587071 TI - Prevention of catheter-related infection: toward zero risk? AB - PURPOSE OF REVIEW: This review identifies important findings in the recent literature related to the prevention of central line-associated bloodstream infection (CLABSI). RECENT FINDINGS: CLABSI rates obtained through surveillance programs have decreased in recent years. Reasons for this are multifactorial: bundle interventions for practice change; technology; and pressure from benchmarking and public reporting. Many studies on the successful use of bundle strategies have been published in the past 2 years, whereas technology has somewhat disappeared from the literature. Success stories made CLABSI prevention the example of healthcare-associated infection prevention. The overwhelming success of practice change together with emerging public awareness confronts hospitals with serious implementation challenges. Fortunately, a number of implementation guidance articles were published recently, which allow hospitals to detect and overcome implementation barriers. SUMMARY: The efforts made for CLABSI prevention exemplify not only the complexity of the problem but also the creativity and--most recently--success. Although 'zero' risk may not seem a realistic goal, the number of hospitals approaching this idealistic threshold is growing. The evidence is now clear that CLABSI can be reduced most effectively by 'state-of-the-art' insertion technique and catheter care. The question today is not 'what to do' but 'how to do it'. PMID- 21587069 TI - Nutrient-induced inflammation in the intestine. AB - PURPOSE OF REVIEW: To review our current understanding of the relationship between absorption of nutrients and intestinal inflammatory response. RECENT FINDINGS: There is increasing evidence linking gut local inflammatory events with the intake of nutrients. Our recent studies, using the conscious lymph fistula rat model, demonstrate that fat absorption activates the intestinal mucosal mast cells. This is accompanied by a dramatic increase in the lymphatic release of mast cell mediators including histamine, rat mucosal mast cell protease II (RMCPII), as well as the lipid mediator prostaglandin D2 (PGD2). Clinical studies suggest that increased consumption of animal fat may play a role in the pathogenesis of inflammatory bowel disease. This impact of dietary fat may not be restricted to the gut but may extend to the whole body. There is evidence linking a high-fat diet-induced metabolic syndrome, with a low-grade chronic inflammatory state. In this review, we hope to convince the readers that fat absorption can have far reaching physiological and pathophysiological consequences. SUMMARY: Understanding the relationship between nutrient absorption and intestinal inflammation is important. We need a better understanding of the interaction between enterocytes and the intestinal immune cells in nutrient absorption and the gut inflammatory responses. PMID- 21587072 TI - New approaches for influenza vaccination of healthcare workers. AB - PURPOSE OF REVIEW: Vaccination of healthcare workers (HCWs) against influenza is an important component of infection control in healthcare settings but HCW vaccination rates remain low. Here we review current and emerging strategies for influenza vaccination of HCWs. RECENT FINDINGS: Professional organizations have recommended annual influenza vaccination for HCWs since 1984, but HCW vaccination rates have improved minimally. Recent studies indicate that comprehensive influenza vaccination programs have failed to achieve adequate influenza vaccination rates for HCWs in spite of allocating substantial resources to HCW vaccination programs. Mandatory HCW influenza vaccination programs have been introduced and clearly outperform traditional comprehensive vaccination programs. Some argue that mandatory vaccination programs infringe on HCW autonomy, and introduction of mandatory vaccination programs can be controversial. Public reporting of institutional HCW influenza vaccination rates is another strategy to achieve high vaccination rates, as HCW influenza vaccination may be used in the future as a quality and safety metric. SUMMARY: HCW influenza vaccination in the setting of a comprehensive infection control program is a core patient-safety practice. Mandatory HCW influenza vaccination and public reporting of HCW vaccination rates will complement one another in achieving substantial gains for HCW influenza vaccination programs. PMID- 21587073 TI - Ventilator-associated pneumonia as a model for approaching cost-effectiveness and infection prevention in the ICU. AB - PURPOSE OF REVIEW: Nosocomial infection is a major cause of morbidity and mortality. In the ICU, ventilator-associated pneumonia (VAP) represents the most prevalent and visible hospital-acquired infection (HAI). Although some evidence based strategies reduce the incidence of VAP, despite a recent policy drive toward zero VAP rates, no evidence supports feasibility of VAP eradication. Furthermore, in the era of resource constraints, cost-effectiveness of various strategies is critical to consider. RECENT FINDINGS: Recent approaches to VAP prevention conglomerate single maneuvers into bundles. Although the cost effectiveness of some VAP-preventive interventions, such as continuous subglottic suctioning and silver-coated endotracheal tube, has been evaluated singly, less is known about the investments needed to implement the recommended bundled approaches in the context of their ability to prevent VAP and such important downstream implications as the use of antibiotics and other hospital resources. A well designed model from Australia examining the cost-effectiveness of a catheter related blood stream infection bundle can serve as robust scaffolding for building a credible value proposition for the VAP bundles. SUMMARY: Cost effectiveness of VAP prevention bundles is not known. This is a critical piece of information, particularly as it relates to such important downstream outcomes of VAP prevention as the use of antibiotics and hospital length of stay. Understanding the incremental cost-effectiveness of VAP bundles can help prioritize efforts to minimize the associated morbidity. PMID- 21587074 TI - Different effects of compounds decreasing cholesteryl ester transfer protein activity on lipoprotein metabolism. AB - PURPOSE OF REVIEW: Review literature on the effect of decreasing cholesteryl ester transfer protein (CETP) activity through pharmacological inhibition or modulation in preclinical and clinical settings compared to human CETP deficiency on lipoprotein characteristics, HDL remodelling and function. RECENT FINDINGS: Torcetrapib, anacetrapib and dalcetrapib inhibited the heterotypic transfer of cholesteryl ester from HDL to LDL and/or VLDL with similar potency, although the potency of dalcetrapib was time dependent. Homotypic transfer of cholesteryl ester from HDL3 to HDL2 via recombinant human CETP was inhibited by torcetrapib and anacetrapib (CETP inhibitors, CETPi) but not by dalcetrapib (CETP modulator, CETPm). In a hamster model of reverse cholesterol transport, only dalcetrapib increased efflux of fecal sterols from macrophages to feces. In clinical studies, dose-responses of CETPi and CETPm demonstrate qualitative and quantitative changes in HDL and LDL particle composition and distribution. SUMMARY: Recent studies of the CETPi torcetrapib and anacetrapib and the CETPm dalcetrapib have shown differences in the resulting increase in HDL-cholesterol and in the level of HDL remodelling and potential for effective reverse cholesterol transport. Results from ongoing clinical outcomes studies with anacetrapib and dalcetrapib will clarify the relevance of CETP inhibition versus modulation towards HDL remodelling in the treatment of cardiovascular diseases. PMID- 21587076 TI - People with intellectual disability who offend or are involved with the criminal justice system. AB - PURPOSE OF REVIEW: This review assesses the impact of recent research on the field of offenders with intellectual disabilities. Research includes work on prevalence, developments in appropriate assessments and investigations into the effectiveness of treatment procedures. RECENT FINDINGS: Methodological difficulties continued to beset studies on prevalence, with estimates ranging between 2 and 10% of the offender population having intellectual disabilities. Research on risk assessment has developed quickly in the last 7 years and current studies establish both the framework for assessment and new instruments that have been shown to predict offending incidents. There have been a number of promising studies on sex offender treatment and on the treatment of issues related to general offending. These studies continue to evaluate treatment progress in terms of improvements in behaviour, cognitive distortions and reductions of offending. One notable study had targeted reductions in sexual deviancy. With two exceptions, the main drawback in treatment studies continues to be the lack of control conditions. SUMMARY: These research studies will aid clinicians in the implementation of the assessment reviews and treatment programs for offenders with intellectual disabilities. PMID- 21587075 TI - Using yeast as a model to study membrane proteins. AB - PURPOSE OF REVIEW: Many cellular processes are controlled via either stable or transient protein-protein interactions (PPIs). Protein complexes are 'molecular machines' in which multiple interactive partners carry out various cellular functions. Given that almost a third of the proteome consists of membrane proteins and that more than 50% of currently available drugs are targeted toward them, investigation of membrane protein complexes has taken center stage over the past years. Thus, gaining an in-depth understanding of PPI networks will give us more insight into the functional relationship as well as downstream effectors of protein complexes, hence opening strategies for new drug target definitions. RECENT FINDINGS: Studying membrane proteins in yeast has recently been applied to many different classes of proteins with diverse functions and structures including membrane transporters. Techniques such as the split-ubiquitin membrane yeast two-hybrid or variants of the protein-fragment complementation assay have been successfully applied to both large-scale genome-wide screens and as smaller scale PPI studies in a reliable and robust fashion. SUMMARY: Yeast-based methods to study membrane PPI in vivo offer a powerful tool for the investigation of protein complexes from various organisms, including mammals. The investigation of global protein maps will serve as a foundation for mechanistic and quantitative studies of poorly characterized gene products and disease-associated proteins. Identification of PPIs is also of great interest for drug discovery as many human diseases result from abnormal PPIs. PMID- 21587077 TI - Sex differences in the disability associated with mental disorders. AB - PURPOSE OF REVIEW: It is well established that women have a higher prevalence of depression and anxiety disorders, but sex differences in the disability associated with depression and anxiety disorders have been less well researched. Earlier studies suggested that women were more disabled by their depression than were men. Studies of schizophrenia, in contrast, have always found that men were more disabled. Recent studies cast new light on this topic and suggest that sex differences in the disability associated with mental disorders may be more consistent than previously thought. RECENT FINDINGS: Two general population studies found that men (and boys) with depression or anxiety disorders (or symptoms) reported greater impairment in everyday functioning and social relationships than women with depression and anxiety. These findings are consistent with the research on psychotic disorders and with much of the research on sex differences in long-term sickness absence due to psychiatric disorder. SUMMARY: Men experience more functional and social impairment in association with episodes of depression, anxiety, and psychosis than their female counterparts. The greater social isolation among men with mental disorders may be attributable to male reticence about disclosing emotional distress, limiting their access to support. PMID- 21587078 TI - How do staff psychological factors influence outcomes for people with developmental and intellectual disability in residential services? AB - PURPOSE OF REVIEW: A broad range of organizational issues can have an impact on client outcomes in residential services for people with intellectual disabilities, and staff psychological factors are increasingly being recognized as important. This review explores some of the recent literature on staff attitudes, attributions, well being and other factors that may impact on outcomes for residents. RECENT FINDINGS: Staff beliefs are associated with the relationship between challenging behaviour and burnout experienced by staff; resident outcomes such as placement breakdown may also be influenced by staff attributions. There is also a body of evidence emerging that suggests staff psychological factors may influence the quality of physical healthcare received by people with intellectual disabilities. SUMMARY: Sufficient evidence exists to suggest that clinicians should routinely consider assessing and evaluating staff psychological factors in clinical interventions in order to assess their potential impact on client care. Further research is required, particularly, to evaluate the specific impact of staff psychological factors on resident outcome. PMID- 21587079 TI - Medical comorbidity of sleep disorders. AB - PURPOSE OF REVIEW: Recently published literature indicates that sleep disorders present with medical comorbidities quite frequently. The coexistence of a sleep disorder with a medical disorder has a substantial impact for both the patient and the health system. RECENT FINDINGS: Insomnia and hypersomnia are highly comorbid with medical conditions, such as chronic pain and diabetes, as well as with various cardiovascular, respiratory, gastrointestinal, urinary and neurological disorders. Restless legs syndrome and periodic leg movement syndrome have been associated with iron deficiency, kidney disease, diabetes, and neurological, autoimmune, cardiovascular and respiratory disorders. Rapid eye movement behaviour disorder has been described as an early manifestation of serious central nervous system diseases; thus, close neurological monitoring of patients referring with this complaint is indicated. SUMMARY: Identification and management of any sleep disorder in medical patients is important for optimizing the course and prognosis. Of equal importance is the search for undetected medical disorder in patients presenting with sleep disorders. PMID- 21587080 TI - Immunogenicity of hepatitis A vaccine in children with celiac disease. AB - OBJECTIVES: The response to hepatitis A vaccine has not been studied in children with celiac disease (CD). The aim of the present study was to evaluate the immunogenicity of an inactivated hepatitis A virus (HAV) vaccine and the effect of the human leukocyte antigen (HLA) type on immunogenicity in children with CD. PATIENTS AND METHODS: Thirty-three patients with CD and 62 healthy controls were enrolled in the study. Inactivated HAV vaccine (Havrix; GlaxoSmithKline Biologicals, Rixensart, Belgium) containing 720 enzyme-linked immunosorbent assay units of alum-adsorbed hepatitis A antigen was administered intramuscularly in a 2-dose schedule at 0 and 6 months. Seroconversion rates and antibody titers of HAV were measured at 1 and 7 months. RESULTS: At 1 month, seroconversion rates were 78.8% and 77.4% and geometric mean titers were 50.7 and 49.9 mIU/mL in the CD and control groups, respectively (P > 0.05). At 7 months, seroconversion rates were 97% and 98.4% and geometric mean titers were 138.5 and 133 mIU/mL in the CD and control groups, respectively (P > 0.05). The most frequent HLA types were HLA DQ2, -DR3, and -DR7 alleles in patients with CD and HLA-DQ3, -DQ6, -DR11, and DR14 in the controls. There was no association between HLA alleles and antibody titers of hepatitis A vaccine. CONCLUSION: Children with CD have a good immune response to hepatitis A vaccine, similar to healthy controls. PMID- 21587081 TI - "Extracaval shepherd's crook" sign: a characteristic radiographic sign of central venous catheter placement in the right internal thoracic vein. AB - Inaccurate positioning is a well-known and documented complication of central venous catheterization. Inadvertent placement of a central venous catheter into the right internal thoracic vein has been reported in the literature; however, the characteristic radiographic appearance for this complication has yet to be described. We report 3 cases that demonstrate central venous catheters improperly terminating in the right internal jugular vein. Characteristic radiographic findings of this altered catheter course are described. Recognition of these characteristic findings should prompt consideration for line repositioning or replacement. PMID- 21587082 TI - Positron emission tomography-computed tomography compared with invasive mediastinal staging in non-small cell lung cancer: results of mediastinal staging in the early lung positron emission tomography trial. AB - INTRODUCTION: Patients with non-small cell lung cancer (NSCLC) require careful preoperative staging to define resectability for potential cure. Fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET-CT) is widely used to stage NSCLC. If the mediastinum is positive on PET CT examination, some practitioners conclude that the patient is inoperable and refer the patient for nonsurgical treatment. METHODS: In this analysis of a previously reported trial comparing PET-CT with conventional imaging in the diagnostic work-up of patients with clinical stage I, II, or IIIA NSCLC, we determined the accuracy of PET-CT in mediastinal staging compared with invasive mediastinal staging either by mediastinoscopy alone or by mediastinoscopy combined with thoracotomy. RESULTS: All 149 patients had mediastinal nodal staging at mediastinoscopy alone (14), thoracotomy alone (64), or both (71). The sensitivity of PET-CT was 70% (95% confidence interval [CI], 48-85%), and specificity was 94% (95% CI, 88-97%). Of 22 patients with a PET-CT interpreted as positive for mediastinal nodes, 8 did not have tumor. The positive predictive value and negative predictive value were 64% (95% CI, 43-80%) and 95% (95% CI, 90 98%), respectively. Based on PET-CT alone, eight patients would have been denied potentially curative surgery if the mediastinal abnormalities detected by PET-CT had not been evaluated with an invasive mediastinal procedure. CONCLUSIONS: PET CT assessment of the mediastinum is associated with a clinically relevant false positive rate. Our study confirms the need for pathologic confirmation of mediastinal lymph node abnormalities detected by PET-CT. PMID- 21587083 TI - Mediastinal incidentalomas. AB - INTRODUCTION: Incidental mediastinal lymphadenopathy challenges pulmonologists to decide on eventual further diagnostic steps. The aim of this study was to characterize unexpected mediastinal findings by imaging and pathologic analysis. METHODS: Entry criterion for this prospective explorative study was mediastinal lymphadenopathy as an incidental finding on computed tomography (CT) scans made for indications other than the analysis and staging of neoplasms. Lymph node dimensions were measured on CT scan. Subsequent diagnostic investigations were positron emission tomography, endoscopic ultrasound- or endobronchial ultrasound guided punctures, and clinical follow-up. RESULTS: Eighty-three patients from eight hospitals met the entry criteria. The median number of Naruke stations with enlarged nodes was 7 (range 3-9). The median size of all nodes measured varied between 6 and 14 mm. The median number of lymph node stations with nodes of at least 10 mm was 3 (range 0-8). Hilar node enlargement was detected in 77% of patients. No definitive diagnosis was obtained in 7 of 83 (8%) patients. Lymphocytes were found in 55 of 83 (66%) and sarcoidosis in 18 of 83 (22%) of aspirates. Positron emission tomography showed metabolic activity in 87% of patients. Follow-up CT scans were available for 36 of 62 (58%) patients without a classifying diagnosis. Two patients developed lung cancer 2 years after initial analysis. CONCLUSIONS: Incidental mediastinal lymph nodes on CT are characterized by multiplicity, relative small sizes, and coexistence with hilar lymphadenopathy in the majority of patients. These nodes often display increased metabolic activity. The low predictive value for malignancy justifies a restrictive attitude toward invasive diagnostic testing. PMID- 21587084 TI - Higher dosage of the epidermal growth factor receptor mutant allele in lung adenocarcinoma correlates with younger age, stage IV at presentation, and poorer survival. AB - INTRODUCTION: The clinical significance of epidermal growth factor receptor (EGFR) mutant allele specific imbalance (MASI) in lung adenocarcinomas is unknown. METHODS: EGFR MASI was characterized by sequencing electropherograms (SEs) and EGFR fluorescence in situ hybridization (FISH) in 96 prospectively tested lung adenocarcinoma patients with a median follow-up of 20 months (all cases were EGFR mutation-positive). RESULTS: In 25 cases, the mutant allele (MA) peak was higher than the wild-type allele (WA) peak, indicating the presence of EGFR MASI (25/96, 26%). The adenocarcinomas with EGFR MASI had a 4.4-fold higher average EGFR/Chromosome Enumeration Probe 7 ratio than carcinomas without MASI (7.9 +/- 3.8 versus 1.8 +/- 0.6, p = 0.01). A high degree of correlation between the MA/WA ratio (SE) and the EGFR/CEP7 ratio (FISH) (rho = 0.757, p = 0.003) validated the quantitative nature of SE. Amplification was the most common mechanism of EGFR MASI (13/21, 62%). EGFR MASI was more commonly associated with exon 19 mutations than with exon 21 mutations (19/53, 36%, versus 6/43, 14%, p = 0.015, odds ratio [OR] = 3.4) and in patients younger than 65 years (17/46, 37%, versus 8/50, 16%, p = 0.019, OR = 3.1). Patients with EGFR MASI presented with stage IV disease more frequently (p = 0.01, OR = 3.5) and had a poorer disease specific survival rate (p = 0.021, 54% versus 83% at 31 months). CONCLUSIONS: EGFR MASI in lung adenocarcinomas can be assessed based on SE and can be used to identify younger patients with more aggressive disease. PMID- 21587086 TI - Primary mucoepidermoid carcinoma of the esophagus. AB - INTRODUCTION: Primary mucoepidermoid carcinoma (MEC) of the esophagus is an uncommon neoplasm characterized by a diffuse mixture of squamous and mucus secreting glandular carcinoma cells. Its biological behavior and response to therapies have not been well studied. Surgical resection is still the primary treatment, but the prognosis is poor. This retrospective study was designed to investigate the clinical characteristics, diagnosis, treatment, and prognosis of primary esophageal MEC. METHODS: Clinical data were retrospectively analyzed from 36 patients with pathologically confirmed primary esophageal MEC who underwent transthoracic esophagectomy with lymphadenectomy between January 1991 and June 2010 at the Cancer Hospital of Shantou University Medical College. There were 27 men and 9 women ranging in age from 40 to 78 years (median, 58 years). Twenty-six of the 36 patients were treated with surgery alone. The other 10 were treated with surgery plus postoperative radiotherapy. The Kaplan-Meier and log-rank methods were used to estimate and compare survival rates. Cox's hazard regression model was used to identify prognostic factors, with entry factors of gender, age (<=60 years versus >60 years), length of the primary lesion (<=5 cm versus >5 cm), location of the primary lesion, macroscopic tumor type, tumor cell differentiation, pT, pN, pTNM stage, operation type (radical/palliative), and radiotherapy (yes/no). RESULTS: The clinical symptoms, radiological and endoscopic features of primary esophageal MEC were similar to those of esophageal squamous cell carcinoma (ESCC). Of the 20 cases who underwent preoperative endoscopic biopsy, 18 cases were misdiagnosed as ESCC and 2 were misdiagnosed as esophageal adenosquamous carcinoma. The mean follow-up duration of this series was 38.8 months (range, 3-142 months). Twenty-two patients had died, 12 were still alive, and 2 were lost to follow-up. The median survival time of the 36 patients was 29.0 months (95% confidence interval = 20.0-38.0), and the 1-, 2-, 3 , and 5-year overall survival rates were 80.6%, 57.1%, 34.4%, and 25.8%, respectively. The 5-year survival rate of 25.8% was lower than 5-year absolute survival rate of 39.2% for ESCC patients who had undergone surgical resection during the same period at our center. For patients who underwent a radical operation, the 5-year survival rate of 32.0% for MEC patients was also lower than that of 41.7% (908/2175) for ESCC patients. In univariate analysis, pN (pN0/pN1 3) (p = 0.003) and operation type (radical/palliative) (p = 0.006) significantly influenced the median survival time of MEC patients. In multivariate analysis, pN (pN0/pN1-3) (p = 0.002) and operation type (radical/palliative) (p = 0.004) were independent prognostic factors. CONCLUSIONS: Primary esophageal MEC is a rare disease and prone to be misdiagnosed. Lymph node metastasis and operation are independent prognostic factors. Surgical resection is the primary treatment, but the prognosis is poor. PMID- 21587085 TI - Detection of ALK gene rearrangement in non-small cell lung cancer: a comparison of fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression. AB - INTRODUCTION: Accurate determination of ALK rearrangement is important in lung cancer patients, especially in determining their eligibility for crizotinib therapy. Fluorescence in situ hybridization (FISH) has been regarded as the gold standard method for detecting ALK rearrangement. However, FISH requires a fluorescence microscope, and the signals are labile and rapidly fade over time. This study evaluates the concordance between ALK gene rearrangement in non-small cell lung cancer assessed by ALK FISH and a newly developed ALK chromogenic in situ hybridization (CISH) and correlates the results with ALK protein expression assessed by immunohistochemistry. METHODS: A total of 465 formalin-fixed, paraffin-embedded non-small cell lung cancer samples were analyzed by ALK FISH (PathVysion, Vysis, Abbott) and ALK CISH. For comparison, all specimens were stained by immunohistochemistry (clone 5A4, Novocastra) and interobserver reproducibility was assessed. RESULTS: We found that agreement between the pathologists on the CISH-determined ALK status was achieved in 449 patients (96.6%), and ALK rearrangement was identified in 18 patients (4.0%) in CISH method. Among these cases, 443 cases (95.3%) had results matching the corresponding FISH results: 17 rearranged, 425 wild types, and 1 discordant case. There was high concordance in the assessment of ALK gene rearrangement between FISH and CISH techniques (kappa = 0.92) and between observers (kappa = 0.97). In addition, there was high concordance in the ALK gene status and ALK protein expression between CISH and IHC tests (kappa = 0.82). CONCLUSIONS: CISH is a highly reproducible and practical method to detect ALK gene rearrangement and correlated well with ALK protein expression. Here, we present a diagnostic algorithm (Chung's SNUBH ALK protocol) to detect lung cancer with ALK rearrangements using IHC, FISH and CISH. Because CISH allows a concurrent analysis of histological features of the tumors and gene rearrangement, it appears to be a useful method in determining ALK gene rearrangement. PMID- 21587087 TI - Building the bridge between lifestyle intervention, physical function, and cardiovascular risk in middle-aged women: lessons learned from the Women on the Move Through Activity and Nutrition study. PMID- 21587088 TI - Exercise as a treatment of gait dysfunction in postmenopausal women. PMID- 21587089 TI - Predicting age of menopause: what is the future of the antimullerian hormone biomarker? PMID- 21587090 TI - The complexity of breast cancer risk needs to be embraced, not oversimplified. PMID- 21587091 TI - Accuracy and efficacy of narrow-band imaging versus white light hysteroscopy for the diagnosis of endometrial cancer and hyperplasia: a multicenter controlled study. AB - OBJECTIVE: The aim of this study was to evaluate, in a multicenter study, whether the narrow-band imaging (NBI) technology may improve the diagnostic reliability of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia. METHODS: A total of 801 outpatient women undergoing diagnostic hysteroscopy were enrolled. All women underwent fluid minihysteroscopy with white light (WL) and NBI exploration with endometrial eye-directed biopsy. RESULTS: NBI hysteroscopy significantly improved the sensitivity for diagnosing endometrial cancer compared with WL (93% and 81%, P < 0.05). In detecting low-risk hyperplasia, the use of NBI significantly improved the sensitivity (82% vs 56%, P < 0.005) and positive predictive value (79% and 71%, P < 0.05) compared with WL hysteroscopy. In the diagnosis of high-risk hyperplasia, NBI significantly improved the sensitivity (60% vs 20%, P < 0.005) and positive predictive value (67% and 25%, P < 0.0001), whereas no difference was seen for specificity (99% and 99%, P > 0.005), negative predictive value (99% and 99%, P > 0.05), and accuracy (99% and 98%, P > 0.05). CONCLUSIONS: NBI showed significantly higher values in sensitivity for the detection of low-risk and high-risk hyperplasia, and this could be useful for reducing the risk of missing severe pathologies at hysteroscopy, and improving the diagnosis of preneoplastic and neoplastic pathologies. NBI hysteroscopy showed a very high diagnostic accuracy for the exploration of the uterine cavity, reducing the number of biopsies performed in wrong areas, although multicenter randomized trials are required to establish the true value of this interesting technological advancement. PMID- 21587092 TI - Chinese validation of the Pelvic Floor Impact Questionnaire Short Form. AB - OBJECTIVE: The Pelvic Floor Impact Questionnaire Short Form (PFIQ-7) is an International Continence Society-recommended disease-specific questionnaire evaluating the impact of pelvic floor disorders on women's quality of life. The PFIQ-7 has not been validated in China, which limits its use. The objective of this research was to validate the Chinese-translated version of the PFIQ-7. METHODS: The PFIQ-7 was translated into Chinese; 134 women with pelvic floor disorder completed the PFIQ-7 and the 12-item Short Form Health Survey (SF-12) questionnaires. Reliability and validity were analyzed. The reliability of the PFIQ-7 was assessed for internal consistency and test-retest reliability. The face/content validity was assessed subjectively by an expert panel and/or focus group participants. The criterion validity was evaluated using the Spearman correlation with the SF-12. The construct validity was determined by factor analysis. RESULTS: The PFIQ-7 has a high internal consistency (Cronbach alpha was 0.801) and high test-retest reliability (the intraclass correlation coefficients were 0.862, P < 0.01). PFIQ-7 scores were negatively correlated with those of the SF-12 (P < 0.01). A factor analysis showed good construct validity. CONCLUSIONS: The Chinese version of the PFIQ-7 has high reliability and validity for the Chinese population. It is highly recommended for clinical treatment and research. PMID- 21587093 TI - Rapid increase in use of antiviral therapy for hospitalized children with influenza during the 2009 H1N1 epidemic. AB - We used the Pediatric Health Information System to examine annual trends in antiviral prescribing for hospitalized children with influenza before and during the 2009 H1N1 epidemic. During the 2009 H1N1 epidemic, the Centers for Disease Control and Prevention issued recommendations advising antiviral therapy for all hospitalized patients with influenza infection. Before the 2009 H1N1 outbreak, antivirals were prescribed for only 28% of hospitalized children with influenza. This increased sharply to 84% during the 2009 H1N1 period, indicating a favorable response by physicians to clinical guidelines. PMID- 21587094 TI - Cyclosporin A treatment for Kawasaki disease refractory to initial and additional intravenous immunoglobulin. AB - BACKGROUND: There are still no definite treatments for refractory Kawasaki disease (KD). In this pilot study, we evaluated the use of cyclosporin A (CyA) treatment in patients with refractory KD. METHODS: We prospectively collected clinical data of CyA treatment (4-8 mg/kg/d, oral administration) for refractory KD patients using the same protocol among several hospitals. Refractory KD is defined as the persistence or recurrence of fever (37.5 degrees C or more of an axillary temperature) at the end of the second intravenous immunoglobulin (2 g/kg) following the initial one. RESULTS: Subjects were enrolled out of 329 KD patients who were admitted to our 8 hospitals between January 2008 and June 2010. Among a total of 28 patients of refractory KD treated with CyA, 18 (64.3%) responded promptly to be afebrile within 3 days and had decreased C-reactive protein levels, the other 4 became afebrile within 4 to 5 days. However, 6 patients (21.4%) failed to become afebrile within 5 days after the start of CyA and/or high fever returned after becoming afebrile within 5 days. Although hyperkalemia developed in 9 patients at 3 to 7 days after the start of CyA treatment, there were no serious adverse effects such as arrhythmias. Four patients (1.2%), 2 before and the other 2 after the start of CyA treatment, developed coronary arterial lesions. CONCLUSION: CyA treatment is considered safe and well tolerated, and a promising option for patients with refractory KD. Further investigations will be needed to clarify optimal dose, safety, and timing of CyA treatment. PMID- 21587095 TI - A community outbreak of rotavirus diarrhea associated with exposures in a hospital outpatient department in South China. AB - INTRODUCTION: Between October 1 and December 10, 2006, Bao'an, China had a 5-fold increase in acute rotavirus gastroenteritis (ARGE) cases compared with the same time in 2005. To identify the risk factors for ARGE during this outbreak, we conducted a case-control study among children <= 24 months old from the most heavily affected area. METHODS: We defined an ARGE case as diarrhea, with group A rotavirus antigen detected from fecal samples by the enzyme-linked immunosorbent assay test. In the case-control study, 86 confirmed ARGE cases were identified. We enrolled 98 healthy control children matched by age. We administered questionnaires about exposures through telephone interviews. RESULTS: Of 8 general exposure types, we identified the following as being associated with ARGE: visiting outpatient services of hospital X, odds ratio (OR) = 7.1 (95% confidence interval [CI], 2.2-26); contact with other children with diarrhea, OR = 2.1 (95% CI, 1.1-3.7); and hand-washing before eating, OR = 0.48 (95% CI, 0.27 0.82). After improvements in the outpatient department of hospital X, ARGE incidence in the community during the ARGE transmission season (October through December) decreased from 4.3/10000 in 2006 to 1.4/10000 in 2009. CONCLUSIONS: Outpatient services in hospital X may have contributed to the transmission of ARGE and improvements in infection control practices in this setting were associated a marked decrease incidence of ARGE in this community. PMID- 21587096 TI - Periconceptional events perturb postnatal growth regulation in sheep. AB - Periconceptional undernutrition and twin conception alter intrauterine growth and metabolism and are associated with later adverse metabolic outcomes. The contribution of postnatal growth to these outcomes is less well defined. We investigated whether maternal periconceptional undernutrition or twin conception altered postnatal growth regulation in ways that could lead to metabolic disease. Single and twin offspring of ewes undernourished (UN) from 61 d before until 30 d after mating, fed to achieve and maintain 10-15% weight loss (UN), were compared with offspring of maintenance-fed controls (N). At 2 h and 1, 6, and 12 wk after birth, lambs were weighed and plasma hormone and metabolite concentrations analyzed. Milk intake, measured by deuterium oxide dilution, was inversely related to birth weight only in N singles, although twins had the greatest postnatal growth velocity. Positive associations were seen between milk intake, growth velocity, and leptin concentrations in N, but not UN, offspring. We conclude that periconceptional undernutrition alters the relationships between regulators of postnatal growth, including nutrient intake and key hormonal axes, in both singles and twins without affecting size at birth or postnatal growth velocity. Dissociation of growth from its key regulators is one possible mechanism underlying adverse metabolic outcomes after periconceptional undernutrition. PMID- 21587097 TI - Effects of pasteurization on adiponectin and insulin concentrations in donor human milk. AB - Although pasteurization is recommended before distributing donor human milk in North America, limited data are available on its impact on metabolic hormones in milk. We aimed to investigate the effects of pasteurization on adiponectin and insulin concentrations in donor human milk. The study investigates concentrations of components in donor human milk before and after Holder pasteurization. After the guidelines of the Human Milk Bank Association of North America, human milk samples were pooled to produce 17 distinct batches (4 individuals per batch) and pasteurized at 62.5 degrees C for 30 min. Adiponectin, insulin, energy, fat, total protein, and glucose concentrations were measured pre- and postpasteurization. Pasteurization reduced milk adiponectin and insulin by 32.8 and 46.1%, respectively (both p < 0.0001). Adiponectin and insulin were significantly correlated with energy and fat milk composition (r = 0.36-0.47; all p < 0.05). Pasteurization effects on milk hormone concentrations remained significant after adjusting for fat and energy (beta +/- SEE: -4.11 +/- 1.27, p = 0.003 for adiponectin; -70.0 +/- 15.0, p < 0.0001 for insulin). Holder pasteurization reduced adiponectin and insulin concentrations in donor human milk. In view of emerging knowledge on the importance of milk components, continued work to find the optimal pasteurization process that mitigates risks but promotes retention of bioactive components is needed. PMID- 21587098 TI - Effects of antenatal uteroplacental hypoperfusion on neonatal microvascularisation and excitotoxin sensitivity in mice. AB - Vascular intrauterine growth restriction (IUGR) occurs in about 5% of pregnancies and may reduce the incidence of periventricular leukomalacia in preterm newborns. We evaluated neonatal excitotoxicity in a murine model of vascular IUGR involving unilateral uterine ligation on embryonic day (E)13.5. Birth weight was significantly decreased in the ligation group compared with the sham group (p < 0.001). VEGFs, VEGF receptors (VEGFRs), and NMDA receptor subunit mRNAs in brain extracts were assayed using quantitative RT-PCR. Ligation was associated with increased mRNAs for the vascular marker PECAM-1 on postnatal day (PD)2 and VEGFR 3 on PD2 and PD10, contrasting with decreased VEGFA and VEGFC on PD10. Microvessel density was increased on PD7. Ligated and sham pups received intracerebral ibotenate (NMDA agonist) on PD2 or PD10. Cortical and white matter (WM) lesions after 5 d were reduced in ligated versus sham pups injected on PD2 (p < 0.001 and p < 0.01, respectively); this effect persisted on PD42 (p < 0.01 and p < 0.05, respectively). With ibotenate on PD10, lesions were exacerbated after 5 d in the ligated group in the cortex (p < 0.05) and WM (p < 0.05) and on PD42 in the cortex (p < 0.05). In conclusion, vascular IUGR offered only transient protection against neonatal excitotoxic lesions, possibly via angiogenesis. PMID- 21587099 TI - Trends in the diagnosis of Rett syndrome in Australia. AB - Modifications to diagnostic criteria and introduction of genetic testing have likely affected the pattern and timing of Rett syndrome diagnosis. The trends in incidence and prevalence of Rett syndrome in Australia were examined; the cumulative risk of a female being diagnosed was determined; and the impact of changes to diagnostic criteria and availability of genetic testing on these frequencies was investigated. The population-based Australian Rett Syndrome Database was used to identify a total of 349 verified Rett syndrome females born 1976-2006 and diagnosed 1982-2008. The proportion of female cases born and diagnosed per year and the cumulative risk of a diagnosis were determined. The median age of Rett syndrome diagnosis decreased from 4.5 y if diagnosed before 2000 to 3.5 y if diagnosed after 1999. The cumulative risk of diagnosis had almost doubled by 32 y of age [1/8,905 or 11.23 per 100,000 person-years (95% CI, 10.03-12.45)] in comparison with 5 y of age [1/15,361 or 6.51 per 100,000 person years (95% CI, 5.65-7.39)]. Earlier age of diagnosis may result in families experiencing less stress and emotional strain compared with those with delayed diagnosis. PMID- 21587100 TI - Re: Ward K, Ogilvie JW, Singleton, et al. Validation of DNA-based prognostic testing to predict spinal curve progression in adolescent idiopathic scoliosis. Spine 2010;35:E1455-64. PMID- 21587101 TI - Autophagy is activated in injured neurons and inhibited by methylprednisolone after experimental spinal cord injury. AB - STUDY DESIGN: Experimental, controlled trial, animal study. OBJECTIVE: To assess autophagy expression after rat spinal cord injury (SCI) and investigate the effect of methylprednisolone treatment on autophagy. SUMMARY OF BACKGROUND DATA: Although it is evident that SCI induces necrosis and apoptosis, its relationship to autophagy is uncertain. Autophagy is implicated in various pathological states in the nervous system, such as neurodegenerative diseases, cerebral ischemia, and traumatic brain injury. Up to now, no autophagy expression was evidenced by transmission electronic microscope (TEM) and the autophagy marker, microtubule associated protein light chain 3 (LC3) in neural tissue after SCI. METHODS: Sixty six Sprague-Dawley rats were used for the experimental procedure. In the SCI group, laminectomy at T9 were performed, followed by impactor contusion of the spinal cord. In the sham group, only a laminectomy was performed without contusion. We used Western blot to analyze LC3 at 2 hours, 4 hours, 1 day, 3 days, and 7 days after SCI. We also investigated the effect of methylprednisolone on autophagy expression of contused spinal cord. Cellular localization and ultrastructural changes after spinal cord injury were compared with those sham operated rats using immunofluorescent double labeling and TEM, respectively. Data from the Western blot were analyzed using a nonparametric Kruskal-Wallis test with P < 0.05 being considered significant. RESULTS: We detected significantly elevated level of LC3 2 hours after SCI, and then the level declined until 1 week after SCI. Methylprednisolone decreased LC3 expression at 2 hours after SCI. LC3 positive cells were colocalized with neuronal nuclei, but not with glial fibrillary acidic protein. The existence of autophagy and progress of autophagic cell death after SCI were confirmed by TEM. CONCLUSION: Through observing the enhanced autophagy expression in neurons soon after contusion injury and the inhibitive effect of methylprednisolone treatment, this study demonstrates the characteristics of autophagy expression after SCI and suggests that autophagic cell death may play a role in neuronal death after spinal cord trauma. PMID- 21587102 TI - Back pain among farmers in a northern area of China. AB - STUDY DESIGN: This was a population-based survey conducted in 2008 in a northern area of China. OBJECTIVE: To investigate back pain prevalence and to examine the associations between potential risk factors and back pain among Chinese farmers. SUMMARY OF BACKGROUND DATA: Few studies have investigated back pain and its associated risk factors among farmers in low-income and developing nations. METHODS: Farmers ages 15 years and older were chosen from 800 families in Heilongjiang province of the People's Republic of China using cluster sampling methods. Complete survey data were obtained from 2045 farmers. The prevalence of self-reported back pain during the previous 3 months was reported. Associations between back pain and potential risk factors, which included age, gender, education levels, perceived stress, main farm activities, smoking, and drinking status, were examined in logistic regression models. RESULTS: A total of 786 (38.4%) farmers reported back pain. Two-thirds of those with back pain (66.0%) reported that back pain affected work quantity and quality. The adjusted odds ratios of reporting back pain increased with advancing age. Females and farmers who experienced stress regularly were also more likely to report back pain. CONCLUSION: Back pain is a common problem among Chinese farmers and is reported more frequently by females. Significant positive associations of gender, age, and perceived stress with back pain warrant additional study. PMID- 21587103 TI - The red wine polyphenol resveratrol shows promising potential for the treatment of nucleus pulposus-mediated pain in vitro and in vivo. AB - STUDY DESIGN: Descriptive and mechanistic investigation of the anti-inflammatory and anticatabolic effect of resveratrol in intervertebral discs (IVDs) in vitro and of the analgetic effect in vivo. OBJECTIVE: To determine whether resveratrol may be useful in treating nucleus pulposus (NP)-mediated pain. SUMMARY OF BACKGROUND DATA: Proinflammatory cytokines seem to be key mediators in the development of NP-mediated pain. Patients with discogenic or radiculopathic pain may substantially benefit from anti-inflammatory substances that could be used in a minimal-invasive treatment approach. Resveratrol, a polyphenolic phytoalexin found in red wine exhibits anti-inflammatory effects in various cell types and tissues, but no data exists so far with regards to the IVD in the context of low back and leg pain. METHODS: In part 1, the anti-inflammatory and anticatabolic effect of resveratrol was investigated in a cell culture model on interleukin 1beta (IL-1beta) prestimulated human IVD cells on the gene and protein expression level. In part 2, the molecular mechanisms underlying the effects observed upon resveratrol treatment were investigated (toll-like receptors, nuclear factor kappaB, sirtuin 1 (SIRT1), mitogen-activated protein (MAP) kinases p38/ERK/JNK). In part 3, the analgetic effects of resveratrol were investigated in vivo using a rodent model of radiculopathy and von Frey filament testing. All quantitative data were statistically evaluated either by Mann-Whitney U test or by one-way analysis of variance and Bonferroni post hoc testing (P < 0.05). RESULTS: In vitro, resveratrol exhibited an anti-inflammatory and anticatabolic effect on the messenger RNA and protein level for IL-6, IL-8, MMP1, MMP3 and MMP13. This effect does not seem to be mediated via the MAP kinase pathways (p38, ERK, JNK) or via the NF-kappaB/SIRT1 pathway, although toll-like receptor 2 was regulated to a minor extent. In vivo, resveratrol significantly reduced pain behavior triggered by application of NP tissue on the dorsal root ganglion for up to 14 days. CONCLUSION: Resveratrol was able to reduce levels of proinflammatory cytokines in vitro and showed analgetic potential in vivo. A decrease in proinflammatory cytokines may possibly be the underlying mechanism of pain reduction observed in vivo. Resveratrol seems to have considerable potential for the treatment of NP mediated pain and may thus be an alternative to other currently discussed (biological) treatment options. PMID- 21587104 TI - Reproducibility of radiographic measurements for subaxial cervical spine trauma. AB - STUDY DESIGN: Radiographic measurement study. OBJECTIVE: To assess the interobserver reliability of radiographic measurements for subaxial cervical spine trauma; to compare the reliability of measurements made on computed tomography (CT) versus those made using plain radiographs. SUMMARY OF BACKGROUND DATA: Despite the importance of imaging and classification of subaxial cervical injuries, the persistent lack of a uniform measurement protocol remains an obstacle. Recently, the Spine Trauma Study Group published a proposal for a standardized set of measurement techniques for the radiographic evaluation of subaxial cervical spine trauma. While a worthwhile venture, the observer error of these methods was not tested. METHODS: Lateral cervical plain radiographs and CT images of 30 patients who sustained a broad spectrum of subaxial cervical spine injuries were distributed to surgeons. Participants were asked to measure kyphosis, translation, vertebral body height loss, and facet joint apposition. Each rater was provided with a pictorial diagram illustrating the prescribed measurement technique. All measurements were made using plain radiographs and CT images with the exception of facet joint apposition, which was assessed using only CT. Reliability was examined by calculating the ICC and Pearson correlation coefficients. RESULTS.: Vertebral body translation was the most reproducible method on both CT images and plain radiographs. Kyphosis measurements were less reproducible, though the endplate method demonstrated superior reliability to the posterior tangent method. Plain radiographic measurement of anterior vertebral body height loss demonstrated moderate reliability while all other height loss measurements were found to show poor reliability. Facet joint apposition measurement demonstrated poor reproducibility. CONCLUSION: Despite a consensus regarding their importance in directing treatment, radiographic measurements for subaxial cervical spine trauma demonstrate inconsistent reliability. Even in the idealized setting used in this investigation, there was limited agreement between observers. Although translation and kyphosis showed satisfactory reproducibility, results for vertebral body height loss and facet joint apposition were unreliable. On the basis of these findings, it may be more appropriate to describe facet joint apposition binomially as "present" or "not present" instead of a numerical value; vertebral body height loss may be more appropriately characterized in quaternary terms, such as less than 25%, 25% to 50%, 50% to 75%, and more than 75%. Though simpler, such descriptions would need to be validated in future studies. PMID- 21587105 TI - Evaluation of treatment effectiveness for the herniated cervical disc: a systematic review. AB - STUDY DESIGN: Systematic review. OBJECTIVE: To assess the effectiveness of interventions for treating cervical disc herniation. SUMMARY OF BACKGROUND DATA: Cervical disc herniation is 1 of the 23 specific disorders included in the CANS (Complaints of the Arm, Neck, and/or Shoulder) model. Treatment options range from conservative to surgical, but evidence for the effectiveness of these interventions is not yet well documented. METHODS: The Cochrane Library, MEDLINE, EMBASE, PEDro, and CINAHL were searched for relevant systematic reviews and randomized clinical trials (RCTs) up to February 2009. Two reviewers independently selected relevant studies, assessed the methodological quality, and extracted data. RESULTS: Pooling of the data was not possible; thus, a best evidence synthesis was used to summarize the results. Of the 11 RCTs included, 1 compared conservative with surgical intervention, and 10 compared various surgical interventions. No evidence was found for the effectiveness of conservative treatment (nonsteroidal anti-inflammatory drugs, cortisonics, and physical therapy) compared with percutaneous nucleoplasty. Moderate evidence was found for the effectiveness of anterior cervical discectomy with fusion (ACDF) using a titanium cage compared with ACDF using polymethyl methacrylate, and for BRYAN cervical disc (Medtronic Sofamor Danek, Memphis, TN) prostheses compared with ACDF using allograft bone and plating. No outcomes regarding adjacent-level disease were reported. There is conflicting evidence for the effectiveness of ACD compared with ACDF. Only limited or no evidence was found for the other surgical interventions. CONCLUSION: No evidence for effectiveness of conservative treatment compared with surgery was found. Although there is moderate evidence for the effectiveness of some surgical interventions, no unequivocal evidence for the superiority of 1 particular surgical treatment was found. Worldwide, most patients receive supplementary implants; however, cervical discectomy without graft may be preferred because of similar outcomes, lower costs, and possibly a lower risk of adjacent-level disease. More high-quality RCTs using validated outcome measures (including adjacent level disease) are needed. PMID- 21587106 TI - Facet violation with the placement of percutaneous pedicle screws. AB - STUDY DESIGN: Independent review and classification of therapeutic procedures performed on cadavers by surgeons blinded to purpose of study. OBJECTIVE: The objective of this study is to determine the rate of facet violation with the placement of percutaneous pedicle screws. SUMMARY OF BACKGROUND DATA: Improvements in percutaneous instrumentation and fluoroscopic imaging have led to a resurgence of percutaneous pedicle screw insertion in lumbar spine surgery in an attempt to minimize many of the complications associated with open techniques of pedicle screw placement. Rates of pedicle breech and neurologic injury resulting from percutaneous insertion are reportedly similar to those of open techniques. Postoperative pain because of impingement and instability is believed to result from violation of the facet capsule or facet joint. To the authors' knowledge, however, the rate of facet injury associated with the placement of percutaneous pedicle screws is unreported in the literature. METHODS: Percutaneous pedicle screw placement was performed on 4 cadaveric specimens by 4 certified orthopedic surgeons who had clinical experience in the procedure and who were blinded to the study's purpose. The surgeons were instructed to place pedicle screws from L1-S1 using their preferred clinical techniques and a 5.5-mm screw system with which they were all familiar. All surgeons utilized 1 OEC C-arm for fluoroscopic imaging. After insertion, 2 independent spine surgeons each reviewed and classified the placement of all facet screws. RESULTS: A total of 48 screws were inserted and classified. The placement of 28 screws (58%) resulted in violation of facet articulation, with 8 of these screws being intra-articular. Interobserver reliability of the classification system was 100%. CONCLUSION: Percutaneous pedicle screw placement may result in a high rate of facet violation. Facet injury can be reliability classified and therefore, perhaps, easily prevented. PMID- 21587107 TI - Genetic predisposition in degenerative lumbar scoliosis due to the copy number variation. AB - STUDY DESIGN: Comparative genomic hybridization (CGH) microarrays. OBJECTIVE: To identify genomic copy number variations (CNVs) in degenerative lumbar scoliosis (DLS) patients, and investigate the possibility of genetic predisposition in DLS. SUMMARY OF BACKGROUND DATA: Genome scanning technology enables search for presence of CNVs. CGH microarray is a useful procedure in a genome-wide study. METHODS: Among 45 consecutive patients who were diagnosed as DLS, 15 patients who manifested greatest Cobb's angle were selected for the array-CGH based CNV analysis. Control group was blood samples from 58 individuals without DLS. Oligonucleotide CGH microarray was utilized to analyze the CNV. Gene searches were performed for CNV DNA with significant gene-dosage difference. Validation qualitative PCR(qPCR) was performed at 3 genetic loci: at chromosome 2--TMEM163 gene, at chromosome 16--ANKRD 11 gene, and at chromosome 18--NFATC1 gene. RESULTS: Genomic gains and losses were observed using the oligonucleotide CGH microarray. Identified CNVs were 446 +/- 129 per individual. Gain- and loss-CNVs were identified as 196 +/- 24 and 250 +/- 110, respectively. The length of total CNV per individual was 30,946,730 +/- 31,658,175 bp, and mean CNV-length was 61,017 +/- 40,620 (median length 6411 +/- 1994). Comparison with control group revealed 260 CNVs, which were significant (P < 10(-3)). Validation qPCR for gene dosage comparison of DLS group DNA versus control group DNA in TMEM163 (P < 0.001); ANKRD 11 (P = 0.000); and NFATC1 (P = 0.000) gene showed significant difference. CONCLUSION: Various whole-genome CNVs specific to DLS patients were observed. Validation qPCR confirmed significantly different gene-dosages for TMEM163, ANKRD 11, and NFATC1 genes. We consider that the expression of DLS is supported by various typical CNV-associated structural variants of the genome. PMID- 21587108 TI - The quantitative assessment of risk factors to overstress at adjacent segments after lumbar fusion: removal of posterior ligaments and pedicle screws. AB - STUDY DESIGN: Finite element method. OBJECTIVE: To investigate the changes in the disc stress and range of motion (ROM) at adjacent segments after lumbar fusion based on whether or not pedicle screws are removed and whether or not the continuity of the proximal posterior ligament complex (PLC) is preserved. SUMMARY OF BACKGROUND DATA: The ablation of proximal PLC continuity and the presence of pedicle screws have been reported to affect the biomechanics at adjacent segments after lumbar fusion. However, there have been few studies regarding the quantitative assessment of their contribution to overstress at adjacent segments after lumbar fusion. METHODS: In the validated intact lumbar finite element model (L2-L5), four types of L3-L4 fusion models were simulated. These models included the preservation of the PLC continuity with pedicle screws (Pp WiP), the preservation of PLC continuity without pedicle screws (Pp WoP), the sacrifice of PLC with pedicle screws (Sp WiP), and the sacrifice of PLC without pedicle screws (Sp WoP). In each scenario, the ROM, maximal von Mises stress of discs, and the facet joint contract force at adjacent segments were analyzed. RESULTS.: Among the four models, the Sp WiP yielded the greatest increase in the ROM and the maximal von Mises stress of the disc at adjacent segments under four moments. Following the SP WiP, the order of increase of the ROM and the disc stress was Pp WiP, Sp WoP, and Pp WoP. Furthermore, the increase of ROM and disc stress at the proximal adjacent segment was more than at the distal adjacent segment under all four moments in each model. The facet joint contact was also most increased in the Sp WiP under extension and torsion moment. CONCLUSION: The current study suggests that the preservation of the PLC continuity or the removal of pedicle screws after complete fusion could decrease the stress at adjacent segments, and their combination could act synergistically. PMID- 21587109 TI - Reliability and reproducibility of subaxial cervical injury description system: a standardized nomenclature schema. AB - STUDY DESIGN: Radiographic measurement study. OBJECTIVE: To develop a standardized cervical injury nomenclature system to facilitate description, communication, and classification among health care providers. The reliability and reproducibility of this system was then examined. SUMMARY OF BACKGROUND DATA: Description of subaxial cervical injuries is critical for treatment decision making and comparing scientific reports of outcomes. Despite a number of available classification systems, surgeons, and researchers continue to use descriptive nomenclature, such as "burst" and "teardrop" fractures, to describe injuries. However, there is considerable inconsistency with use of such terms in the literature. METHODS: Eleven distinct injury types and associated definitions were established for the subaxial cervical spine and subsequently refined by members of the Spine Trauma Study Group. A series of 18 cases of patients with a broad spectrum of subaxial cervical spine injuries was prepared and distributed to surgeon raters. Each rater was provided with the full nomenclature document and asked to select primary and secondary injury types for each case. After receipt of the raters' first round of classifications, the cases were resorted and returned to the raters for a second round of review. Interrater and intrarater reliabilities were calculated as percent agreement and Cohen kappa (kappa) values. Intrarater reliability was assessed by comparing a given rater's diagnosis from the first and second rounds. RESULTS: Nineteen surgeons completed the first and second rounds of the study. Overall, the system demonstrated 56.4% interrater agreement and 72.8% intrarater agreement. Overall, interrater kappa values demonstrated moderate agreement while intrarater kappa values showed substantial agreement. Analyzed by injury types, only four (burst fractures, lateral mass fractures, flexion teardrop fractures, and anterior distraction injuries) demonstrated greater than 50% interrater agreement. CONCLUSION: This study demonstrated that, even in ideal circumstances, there is only moderate agreement among raters regarding cervical injury nomenclature. It is hoped that more familiarity with the proposed system will increase reproducibility in the future. Additional research is required to establish the clinical utility of this novel nomenclature schema. PMID- 21587110 TI - Major complications in revision adult deformity surgery: risk factors and clinical outcomes with 2- to 7-year follow-up. AB - STUDY DESIGN: Retrospective cohort comparative study. OBJECTIVE: To determine the prevalence of major complications, identify risk factors, and assess long-term clinical benefit after revision adult spinal deformity surgery. SUMMARY OF BACKGROUND DATA: No study has analyzed risk factors for major complications in long revision fusion surgery and whether or not occurrence of a major complication affects ultimate clinical outcome. METHODS: Analysis of consecutive adult patients who underwent multilevel revision surgery for spinal deformity with a minimum 2-year follow-up was performed. All complications were classified as either major or minor. Outcome analysis was conducted with the Scoliosis Research Society and Oswestry Disability Index scores. RESULTS: A total of 166 patients (mean age = 53.8 years) were identified with a mean follow-up of 3.5 years (range: 2-7). Primary diagnoses included idiopathic/de novo scoliosis (107), degenerative (35), trauma (7), neuromuscular scoliosis (6), congenital deformity (5), ankylosing spondylitis (2), tumor (2), Scheuermann kyphosis (1), and rheumatoid arthritis (1). Most common secondary diagnoses that necessitated revision surgery were adjacent segment disease, fixed sagittal imbalance, and pseudarthrosis. Overall, 34.3% of patients developed major complications (19.3% perioperative; 18.7% follow-up). Associated risk factors for perioperative complications were patient- (age > 60 years, medical comorbidities, obesity) and surgery-related (pedicle subtraction osteotomy). Performance of a 3-column osteotomy and postoperative radiographic changes that suggested progressive loss of sagittal correction were recognized as risk factors for follow-up complications. Equivalent outcome scores were reported by patients preoperatively, but those experiencing follow-up complications reported lower scores at the final follow-up. CONCLUSION: Overall, 34.4% of patients experienced major complications after long revision fusion surgery. Different risk factors were identified for perioperative versus follow-up complications. The occurrence of a follow-up, not but perioperative, major complication seemed to have a negative impact on ultimate clinical outcome. PMID- 21587111 TI - Factors affecting the incidence of symptomatic adjacent-level disease in cervical spine after total disc arthroplasty: 2- to 4-year follow-up of 3 prospective randomized trials. AB - STUDY DESIGN: Prospective randomized clinical trials. OBJECTIVE: To compare the outcome data with respect to clinical success rates and incidence of adjacent level disease (ALD) in patients after total disc arthroplasty (TDA) or anterior cervical fusion (ACDF) for 1- and 2-level cervical disc disease. SUMMARY OF BACKGROUND DATA: Previously published studies have provided evidence that ACDF procedure for cervical degenerative disc disease (DDD) may increase the stress on the nonoperated adjacent cervical segments, thus possibly increasing the risk of degeneration at these levels. The theoretical assumption that TDA may reduce the incidence of future ALD by preserving motion at the affected segments has, however, never been validated by clinical evidence. METHODS: One hundred seventy patients with established symptomatic cervical disc disease at 1 or 2 levels participated in 3 prospective randomized clinical trials at 2 institutions. Participating subjects were randomized to receive TDA (treatment; n = 113) or ACDF (control; n = 57) by 6 independent investigating surgeons. Visual analogue pain scores (0-100), Neck Disability Index, neurological examination, and cervical spine radiographs were collected at enrollment and then 6 weeks and 3, 6, 12, 24, 36, and 48 months after surgery. Patients with persistent symptoms during the follow-up period were investigated for adjacent segment disease (ASD) with computed tomography/magnetic resonance imaging of the cervical spine, neurophysiology, and subsequent active interventions. RESULTS: At the median follow-up of 42 months (range: 28-54 months), 9 (14.3%) ACDF and 19 (16.8%) TDA patients developed and were actively treated for ASD. Osteopenia dust energy x ray absorptiometry T scores of -1.5 to -2.4) (P = 0.04; 95% confidence interval [CI]: 0.007-0.223) and concurrent lumbar degenerative disease (P = 0.02; 95% CI: 0.003-0.196) significantly increased the risk of ASD. CONCLUSION: The risk of developing adjacent segment degeneration was equivalent at median 38 months after both ACDF and TDA procedures in cervical DDD. Osteopenia and concurrent lumbar DDD significantly increase the risk of ALD. PMID- 21587112 TI - Excellence in robotic thyroid surgery: a comparative study of robot-assisted versus conventional endoscopic thyroidectomy in papillary thyroid microcarcinoma patients. AB - OBJECTIVE: To confirm the merits of robotic thyroid surgery by comparing the surgical outcomes of robotic-assisted and conventional endoscopic thyroidectomy in papillary thyroid microcarcinoma (PTMC) patients. BACKGROUND: Robot-assisted surgical techniques are widely utilized, and substantially, overcome the limitations of conventional endoscopic surgery. Furthermore, recently, robotic procedures were introduced to the thyroidectomy field. METHODS: From November 2001 to July 2009, 1150 patients with PTMC underwent endoscopic thyroidectomy using a gasless, trans-axillary approach. Of these patients, 580 underwent a robotic procedure (the robotic group; RG) and 570 a conventional endoscopic procedure (the conventional endoscopic group; EG). These 2 groups were retrospectively compared in terms of their clinicopathologic characteristics, early surgical outcomes, and surgical completeness. RESULTS: Total thyroidectomy was performed more frequently in the RG. Although mean operation times were not statistically different, the mean number of central nodes retrieved was greater in the RG than in the EG. Mean tumor size were not significantly different in the 2 groups, but the RG showed more frequent central node metastasis and capsular invasion. Tumor and nodal statuses in the RG were more advanced than in the EG. Regarding postoperative complications, transient hypocalcemia was more frequent in the RG, but other complication frequencies were not significantly different in the 2 groups. Postoperative serum thyroglobulin levels were similar in 2 groups, and short-term follow-up (1 year) revealed no recurrence by sonography and no abnormal uptake during radioactive iodine therapy in either group. CONCLUSIONS: The application of robotic technology to endoscopic thyroidectomy could overcome the limitations of conventional endoscopic surgery during the surgical management of PTMC. PMID- 21587113 TI - Updated recommendations for control of surgical site infections. AB - OBJECTIVE: The objective of this study is to provide updated guidelines for the prevention of surgical wound infections based upon review and interpretation of the current and past literature. BACKGROUND: The development and treatment of surgical wound infections has always been a limiting factor to the success of surgical treatment. Although continuous improvements have been made, surgical site infections continue to occur at an unacceptable rate, annually costing billions of dollars in economic loss caused by associated morbidity and mortality. METHODS: The Centers for Disease Control (CDC) provided extensive recommendations for the control of surgical infections in 1999. Review of the current literature with interpretation of the findings has been done to update the recommendations. RESULTS: New and sometimes conflicting studies indicate that coordination and application of techniques and procedures to decrease wound infections will be highly successful, even in patients with very high risks. CONCLUSIONS: This review suggests that uniform adherence to the proposed guidelines for the prevention of surgical infections could reduce wound infections significantly; namely to a target of less than 0.5% in clean wounds, less than 1% in clean contaminated wounds and less than 2% in highly contaminated wounds and decrease related costs to less than one-half of the current amount. PMID- 21587114 TI - Technical challenges of total esophageal reconstruction using a supercharged jejunal flap. AB - OBJECTIVE: To review our experience and technique of the supercharged jejunal flap for total esophageal reconstruction. BACKGROUND: A gastric pull-up is the first choice for total esophageal reconstruction. When this fails or when the stomach is unavailable, a supercharged jejunal flap may reestablish alimentary tract continuity. METHODS: We performed a retrospective review of 51 patients who underwent a supercharged jejunal flap for total esophageal reconstruction between March 2000 and September 2009 at a single institution. Patient characteristics, technical details, and outcomes were analyzed. RESULTS: Thirty-six men and 15 women patients were included with a mean age of 55 (28-74) years. An immediate reconstruction was performed in 34 (67%) patients and delayed in 17 patients. The jejunal conduit was passed through a substernal route in 31 (60%) patients and a retrocardiac route in 20 patients. Most common recipient arteries were the internal mammary and transverse cervical. Most common recipient veins were the internal mammary and internal jugular. The overall success rate was 94% with 3 flap failures. A total of 33 patients experienced 1 or more complications with abdominal wound infection and pulmonary complications being the 2 most frequent. Mean length of hospital stay was 21.5 +/- 14.0 days. Forty-four (90%) patients were able to achieve a regular diet and 39 (80%) patients discontinued their tube feeds. CONCLUSION: This technically challenging operation requires a multidisciplinary approach and careful planning, yet can be successfully performed with good long-term function and acceptable morbidity. An algorithm delineating the operative strategy is presented. PMID- 21587115 TI - Bilateral prophylactic mastectomy in Swedish women at high risk of breast cancer: a national survey. AB - BACKGROUND/OBJECTIVE: This study attempted a national inventory of all bilateral prophylactic mastectomies performed in Sweden between 1995 and 2005 in high-risk women without a previous breast malignancy. The primary aim was to investigate the breast cancer incidence after surgery. Secondary aims were to describe the preoperative risk assessment, operation techniques, complications, histopathological findings, and regional differences. METHODS: Geneticists, oncologists and surgeons performing prophylactic breast surgery were asked to identify all women eligible for inclusion in their region. The medical records were reviewed in each region and the data were analyzed centrally. The BOADICEA risk assessment model was used to calculate the number of expected/prevented breast cancers during the follow-up period. RESULTS: A total of 223 women operated on in 8 hospitals were identified. During a mean follow-up of 6.6 years, no primary breast cancer was observed compared with 12 expected cases. However, 1 woman succumbed 9 years post mastectomy to widespread adenocarcinoma of uncertain origin. Median age at operation was 40 years. A total of 58% were BRCA1/2 mutation carriers. All but 3 women underwent breast reconstruction, 208 with implants and 12 with autologous tissue. Four small, unifocal, invasive cancers and 4 ductal carcinoma in situ were found in the mastectomy specimens. The incidence of nonbreast related complications was low (3%). Implant loss due to infection/necrosis occurred in 21 women (10%) but a majority received a new implant later. In total, 64% of the women underwent at least 1unanticipated secondary operation. CONCLUSIONS: Bilateral prophylactic mastectomy is safe and efficacious in reducing future breast cancer in asymptomatic women at high risk. Unanticipated reoperations are common. Given the small number of patients centralization seems justified. PMID- 21587116 TI - Decompression of the portal bed and twice-baseline portal inflow are necessary for the functional recovery of a "small-for-size" graft. AB - BACKGROUND: In partial liver transplant, a reduction in the intrahepatic vascular bed produces a rise in the portal vein flow and the portal venous pressure gradient, leading to endothelial and, thereby, hepatocellular injury and death in a process known as "small-for-size" (SFS) syndrome. OBJECTIVE: To demonstrate that a calibrated portocaval shunt prevents superfluous inflow in a porcine model of SFS transplant. METHODS: Donor pigs (15-20 kg) underwent 70% hepatectomy. In 2 groups, a 6 mm (S6) (n = 6) or 12 mm (S12) (n = 6) Gore-Tex shunt was placed between the portal vein and infrahepatic inferior vena cava. In a third group, no portocaval shunt was placed (SFS) (n = 17). Grafts were stored for 5 hours at 4 degrees C and then transplanted into recipients (30-35 kg). RESULTS: Five-day survival was 29% in SFS, 100% in S6, and 0 in S12. Postreperfusion portal vein flow was 4-, 2-, and 1-times flow at baseline in SFS, S6, and S12, respectively. With respect to portal venous pressure gradient, both the 6- and 12-mm shunts effectively decompressed the portal bed. Aspartate aminotransferase and bilirubin rose and the Quick prothrombin time fell in all animals after reperfusion but improved significantly by day 5 in S6. Serum levels of endothelin-1 remained elevated in SFS and S12 but returned to baseline by 12 hours in S6: 2.76 (2.05 4.08) and 2.04 (1.97-2.12) versus 0.43 (0.26-0.50) pg/mL, respectively (P < 0.05 for both comparisons). CONCLUSIONS: A calibrated portocaval shunt that maintains portal vein flow about twice its baseline value produces a favorable outcome after SFS liver transplantation, avoiding endothelial injury due to portal hyperperfusion or to hypoperfusion because of excess shunting. PMID- 21587117 TI - Consensus building for development of outpatient adverse drug event triggers. AB - OBJECTIVES: Adverse drug event (ADE) detection is an important priority of patient safety research. Trigger tools have been developed to help identify ADEs. As part of a larger study, we developed complex and specific trigger algorithms intended for concurrent use with clinical care to detect outpatient ADEs. This article assesses the use of a modified Delphi process to obtain expert consensus on the value of these triggers. METHODS: We selected a panel of distinguished clinical and research experts to participate in the modified Delphi process. We created a set of outpatient ADE triggers based on literature review, clinical input, and methodological expertise. The importance of the targeted ADEs, associated drug classes, and trigger logic was used to rate each trigger. Specific criteria were developed to establish consensus. RESULTS: The modified Delphi process established consensus on 6 outpatient ADE triggers to test with patient-level data based on high ratings of utility for patient-level interventions. These triggers focused on detecting ADEs caused by the following drugs or drug classes: bone marrow toxins, potassium raisers, potassium reducers, creatinine, warfarin, and sedative hypnotics. Participants reported including all aspects of the trigger in their ratings, despite our efforts to separate evaluation of clinical need and trigger logic. Participants' expertise affected the evaluation of trigger rules, leading to contradictory feedback on how to improve trigger design. CONCLUSIONS: The efficiency of the modified Delphi method could be improved by allowing participants to produce an overall summary score that incorporates both the clinical value and the general logic of the trigger. Revising and improving trigger design should be conducted in a separate process limited only to trigger experts. PMID- 21587118 TI - Developing a high-performance team training framework for internal medicine residents: the ABC'S of teamwork. AB - OBJECTIVES: Effective teamwork and communication can prevent error and mitigate harm. High-performance team training was developed in the aviation industry for flight crews and is being incorporated in health care settings, such as emergency departments, operating rooms, and labor and delivery suites. We translated and adapted high-performance teamwork and communication principles from other industries and other disciplines to an inpatient internal medicine environment. METHODS: We selected key principles from aviation and anesthesia crew training programs in 2004 and organized them into the ABC'S of teamwork. These included appropriate Assertiveness, effective Briefings, Callback and verification, Situational awareness, and Shared mental models. Based on this content, we developed a training session for internal medicine residents and faculty, and evaluated learners' patient safety attitudes and knowledge before and after training with a written survey. RESULTS: More than 50 residents participated in the module. The percentage of correct answers on a question related to key teamwork principles increased from 35% before training to 67% after training (P = 0.03). Before training, 65% of the residents reported that they "would feel comfortable telling a senior clinician his/her plan was unsafe"; this increased to 94% after training (P = 0.005). After the training session, residents were able to provide examples from their clinical practice that emphasized all of the ABC'S of teamwork. CONCLUSIONS: Teamwork principles can be adapted from other disciplines and applied to internal medicine. After a single session, residents displayed greater knowledge of teamwork principles and reported changed attitudes toward key teamwork behaviors. PMID- 21587119 TI - Are sequential compression devices commonly associated with in-hospital falls? A myth-busters review using the patient safety net database. AB - OBJECTIVES: Sequential compression devices (SCDs) help prevent deep venous thrombosis and pulmonary embolism in hospitalized patients; however, clinicians often decline to use this therapy because of a perceived increased risk for patient falls. There is limited information regarding the association between the use of SCDs and patient falls. In this study, we analyze if SCD use is a common risk factor for in-hospital falls. METHODS: We used the Patient Safety Net event reporting system at our university-affiliated hospital to retrospectively quantify reports of SCD-related falls over a nearly 5-year period (July 1, 2004, through May 25, 2009). The primary outcome was to determine how often SCD-related falls occurred in relation to SCD patient days. Secondary aims of this study included an assessment of the severity of SCD-related falls, as well as potential risk factors for such falls. RESULTS: Three thousand five hundred sixty-two total falls were reported during our study period, 16 of which (0.45%) were SCD-related falls. There were 0.063 SCD-related falls per 1000 SCD patient days or 1 fall for every 15,774 SCD patient days. The mean age of patients was 57.8 +/- 14.4 years, 69% were male subjects, 81% were on a surgical ward, and 69% occurred while attempting to toilet. Only 2 of the SCD-related falls caused temporary harm that required intervention. CONCLUSIONS: Sequential compression device use is rarely associated with in-hospital patient falls, and SCD-related falls are not more harmful than other types of falls. PMID- 21587121 TI - Tracheobronchopulmonary carcinoid tumors: analysis of 40 patients. AB - INTRODUCTION: Carcinoid tumors are a type of neuroendocrine tumors which usually involve the upper airways and the patients most often complain of cough and hemoptysis. MATERIALS AND METHODS: This study was performed from 1990 through 2007 on 40 patients with carcinoid tumor who had been followed up for at least 3 years. The statistical analysis were based on tumor epidemiology, treatment and the 3-year survival. The factors influencing the survival were analyzed using SPSS and exact Fisher test. RESULTS: M/F was 16/24 with mean age 34 years. Their most common symptoms were coughing (90%) . The left main bronchus was the most common site of involvement (25%). 95% of all the cases underwent surgery and 5% of the patients underwent chemoradiotherapy due to distant metastasis . The most common surgical procedure was lobectomy or biloectomy (57.8%). Bronchial sleeve resection was performed on 10.4% of the patients. The most common pathology was the typical form (90%) and 5% of the madiastinal lymph nodes were involvd all of the atypical type. Carcinoid syndrome was seen in one patient (2.5%) and post operative adjuvant treatment was done in 5% of the patients after surgery because of mediastinal lymph node involvement. Post operative recurrence occurred in one patient (2.6%) of the atypical form with mediastinal lymph nodes involvement. The most common complication of surgery was a long- term air leakage (10.4%) and the surgical death rate was 0%. 3-year survival was 92.5%. The factors influencing the survival included the pathological type, distant metastasis and mediastinal lymph node involvement. CONCLUSION: Carcinoid tumors have mostly been responsive to surgical intervention, resulting in a long term survival. PMID- 21587120 TI - Thoracic endovascular aortic repair--indications and evidence. AB - PURPOSE: Since its introduction more than a decade ago, thoracic endovascular aortic repair (TEVAR) has shown promising results for patients with various thoracic aortic diseases. The aim of the current review is to assess the current literature to evaluate the safety and efficacy of TEVAR. METHODS: A thorough search of the existing literature on TEVAR was conducted on electronic databases, including Medline, Pubmed, EMBASE and Database of Abstracts of Review of Effectiveness. The most recent results were categorized according to the indications of performing TEVAR. RESULTS: A number of case-series studies and reviews have shown reduced early morbidity and mortality rates in a range of thoracic aortic diseases for TEVAR in comparison to open surgical repair. However, there is a lack of robust clinical data to suggest any improvement in long-term overall survival. CONCLUSION: Despite numerous encouraging results from a large number of publications in recent years, there remains a lack of level 1 evidence to support an improvement of long-term overall survival for patients who underwent TEVAR when compared with traditional treatment modalities. There appears to be an urgent need to conduct well-designed randomized-controlled trials in this rapidly expanding intervention. PMID- 21587122 TI - Lung metastasectomy for colorectal carcinoma in patients with a history of hepatic metastasis. AB - BACKGROUND: We reviewed resection of pulmonary metastases preformed by the Department of Thoracic Surgery at Kyoto University Hospital to confirm the clinical significance of this surgery in patients with colorectal carcinoma and a history of hepatic metastasis. METHODS: From 1992 to 2006, 19 patients with colorectal carcinoma and a history of hepatic metastasis underwent a pulmonary metastasectomy. Surgical outcomes of these patients were investigated in terms of various perioperative variables. RESULTS: Sixteen of 19 patients showed metachronous presentation of hepatic and pulmonary metastases, while 3 patients showed synchronous presentation. Overall survival rate after the pulmonary resection was 93%, at 1 year; 75%, at 3 years and 60% at 5 years. Three years after the pulmonary resection, none of the patients with synchronous hepatic and pulmonary metastases survived, while patients with metachronous metastases had an overall survival rate of more than 80%. Interestingly enough, the overall survival curve of the patients with colorectal carcinoma and a history of hepatic metastasis, who underwent a pulmonary metastasectomy was almost the same as that of patients who did not have the surgery, during the same period. CONCLUSION: Aggressive resection of pulmonary metastases in a select group of colorectal cancer patients with a history of liver metastases might result in prolonged survival. PMID- 21587123 TI - Risk of bronchioloalveolar carcinoma in patients with human T-cell lymphotropic virus type 1 (HTLV-I): case-control study results. AB - BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-I) causes not only adult T-cell leukemia (ATL) but also HTLV-I associated T-cell bronchioloalveolitis, which is often chronic and subclinical. We have experienced eight HTVL-I carriers with bronchioloalveolar carcinoma, which is known to arise from bronchioloalveolar pneumocytes. This case-control study clarified the risk of bronchioloalveolar carcinoma in HTLV-I carriers. MATERIALS AND METHODS: During the past four years, 212 lung cancer patients were examined for serum anti-HTLV-I antibody. They underwent surgical treatment for lung cancer at Kumamoto University Hospital. Of these, 8 (4%) were HTLV-I carriers. As controls for this case-control study, we selected 24 HTLV-I negative-lung cancer patients (1:3 case control ratio) matched for sex, age, and smoking status. The distributions of histological types of lung cancer were compared between the case (HTLV-I positive) and control (HTLV-I negative) groups. RESULTS: Histological types of the 8 HTLV-I carriers were bronchioloalveolar carcinoma in 6 patients and adenocarcinoma with bronchioloalveolar carcinoma component in 2. The prevalence of bronchioloalveolar carcinoma in HTLV-I carriers, 6 of 8 (75%), was significantly higher than the 6 of 24 (25%) in HTLV-I negative patients (p = 0.02). The prevalence of bronchioloalveolar carcinoma or adenocarcinoma with bronchioloalveolar carcinoma component in HTLV-I carriers, 8 of 8 (100%), was also significantly higher than the 13 of 24 (54%) in HTLV-I negative patients (p = 0.02). CONCLUSION: HTLV-I might be one risk of bronchioloalveolar carcinoma, probably because of inflammatory and/or immunologic responses involving bronchioloalveolar pneumocytes. PMID- 21587124 TI - Surgical results of completion pneumonectomy. AB - PURPOSE: We report our experience with completion pneumonectomy (CP). METHODS: We report on operative procedure and morbidity, mortality, and survival rates. RESULTS: CP was performed for malignancy in 12 patients and postoperative complications after the first operation in 4 patients. Intrapericardial dissection of vessels was performed in 14 patients (87.5%). Partial vertebrectomy from the second to the fifth vertebrae was performed in 1 patient. Carinal resection was performed in 2 patients. Morbidity including bronchopleural fistula, pulmonary insufficiency, pyothorax, and pulmonary infarction developed in 6 of the 16 patients (37.5%). Mortality rate was 18.8%. The actuarial 1-, 3-, and 5-year overall survival after CP for all malignancy was 80.8%, 49.0%, and 49.0% respectively. CONCLUSIONS: The morbidity and mortality rates are high in CP. Combined resection, especially carinal resection, appears to be contraindicated in CP. CP is one of the treatments of choice, even for malignancy, if complete resection is possible because of the good long-term survival. PMID- 21587125 TI - When is surgical tracheostomy indicated? Surgical "U-shaped" versus percutaneous tracheostomy. AB - OBJECTIVE: Tracheostomy is one of the most frequent interventions for ICU patients. The current trend in performing a tracheostomy is a percutaneous approach because of its popularity and significant advantages. In this study, certain indications of surgical tracheostomy (ST) are suggested and furthermore, ST is compared with percutaneous tracheostomy (PT). PATIENT AND METHODS: We performed a U-shaped ST in 121 patients and PT in 85 patients between March 2003 and December 2006. All of the STs were opened U-shaped in the operating room. In this technique; instead of removing the tracheal ring, it was used to create a flap. The tracheal flap was hung with a suture from middle of the 2nd or the 3rd cartilage rings, as a guide. Also, the PT procedure "Griggs dilatation technique" was performed in the ICU. RESULTS: PT and ST had similar complication rates: 4.1% for ST [bleeding in 2 patients, stenosis in 2, and stomal infection in 1] versus 3.6% for PT [bleeding in 2 patients, and pneomothorax in 1] (p = 0.08). No significant difference was found regarding mean operation time between ST [12 min (9-18)] and PT [8 min (6-16)] (p = 0.09) CONCLUSIONS: Staff utilization and cost seem like the major advantages of PT. However, our surgical technique has similar complication rates with PT and moreover, using ST still remains favorable for select patients with thyroid hyperplasia, short neck, tracheaomalacia, obesity, neck operation history and for children. PMID- 21587126 TI - Release of serum S-100beta protein and neuron-specific enolase after off-pump coronary artery bypass grafting with and without intracranial and cervical artery stenosis. AB - PURPOSE: The aim of this study was to quantify the amount of brain damage suffered by patients who underwent off-pump coronary artery bypass grafting (OPCAB) in which S-100beta protein and neuron-specific enolase were used. METHODS: Thirty-four patients undergoing scheduled OPCAB were enrolled in the study. The patients were divided into two groups according to the results of their magnetic resonance angiography (MRA) and cervical ultrasonography: 13 patients had cervical or intracranial arterial stenosis (Group A), and 21 patients did not (Group B). Blood samples were collected from the arterial catheters immediately before surgery, upon arrival to the intensive care unit, and 6 and 24 hours after surgery. RESULTS: In blood samples collected from patients upon arrival to the intensive care unit, the maximum concentration of serum s-100beta protein in Group A was significantly higher than that of Group B (p = 0.029). Though patients in Group A tended to have higher maximum neuron specific enolase (NSE) concentrations, there were no significant differences in NSE concentrations at any point between the two groups. CONCLUSIONS: Our findings show a correlation between the stenosis detected by MRA or cervical ultrasonography and brain damage after OPCAB. PMID- 21587127 TI - Factors influencing permanent neurologic dysfunction and mortality after total arch replacement with separate arch vessel grafting using selective cerebral perfusion. AB - OBJECTIVES: The present study was undertaken to identify risk factors for permanent neurological dysfunction (PND) and in-hospital mortality after total aortic arch replacement (TAR) with separate arch vessel grafting using selective cerebral perfusion (SCP) and hypothermic circulatory arrest. METHODS: Between 1998 and 2008, we preformed a TAR on 143 consecutive patients in two centers by identical methods. Of these, 19 (13.3%) were emergency operations, and 46 (32.2%) were open stent-graft placements. Statistical analysis was performed to determine risk factors for PND and mortality, and furthermore, the survival rate was analyzed. RESULTS: The in-hospital mortality rate was 4.9%, with chronic renal failure (p = 0.0013, odds ratio 10.0) as a significant risk factor. Nine patients (6.3%) had PND, with significant risk factors identified as (1) the presence of an old cerebral or silent lacunar infarction on preoperative imaging methods (p = 0.0458, odds ratio 8.0) and (2) duration of SCP (p = 0.0026, odds ratio 1.036). Long-term survival was the same in patients with or without PND. CONCLUSION: The enhanced vulnerability of the brain in patients with a pre-existing old cerebral infarction or silent lacunar infarction is reflected by a high incidence of PND. Chronic renal failure had an impact on in-hospital mortality. PMID- 21587128 TI - Percutaneous cardiopulmonary support of video-assisted metastasectomy for a patient with lung cancer following pneumonectomy. AB - We describe herein a case of a 68-year-old woman with primary lung cancer who had undergone induction chemoradiotherapy and then a right pneumonectomy for non small cell cancer (adenocarcinoma). Twenty-one months later, the cancer had metastasized to the brain, which was treated with 2-knife radiosurgery. She had been well for up to 32 months; however, the chest radiography and chest computed tomography (CT) demonstrated a nodule in the left upper lobe of the lung that was gradually growing. We preformed a partial resection of the left upper lobe by video-assisted thoracic surgery (VATS) under percutaneous cardiopulmonary support (PCPS), considering the oxygenation requirement of the patient. PCPS was applied via venoarterial (V-A) bypass, and the hemodynamic status of the patient was mostly stable. The postoperative course was uneventful, and the patient has no evidence of metastatic lung cancer, 10 months postoperatively, indicating that the minimally invasive VATS under PCPS was successful and safe. Although few reports have been described and some key questions remain unanswered, the method appears to be promising. PMID- 21587129 TI - Inflammatory pseudotumor suspected of lung cancer treated by thoracoscopic resection. AB - We report a relatively rare surgical treatment for two cases of inflammatory pseudotumors of the lung. In case 1, a 52-year-old male with a history of left chest pain was admitted to our hospital for an abnormal nodule with an irregular margin that was detected in the left upper lung field. The nodule, measuring 15 mm in diameter, was larger than the one observed six months earlier, which had been removed by a thoracoscopic resection. In case 2, a 64-year-old female with a history of chronic cough and hemoptysis was admitted to our hospital, and an abnormal nodule with pleural indentation was detected in the lower left lung field. The nodule, measuring 8 mm in diameter, was also removed by a thoracoscopic resection. In both cases, the histologic examination enabled us to diagnose the lesion as an inflammatory pseudotumor. In general, it is very difficult to differentiate inflammatory pseudotumors from malignant tumors of the lung. The best treatment for inflammatory pseudotumors is usually early and complete surgical resection, since it can lead to improved survival. Therefore, we consider thoracoscopy-aided surgery to be less invasive and more useful than other surgical methods in the diagnosis and treatment of inflammatory pseudotumor of the lung. PMID- 21587130 TI - Rigid bronchoscopy for malignant central airway obstruction from small cell lung cancer complicated by SVC syndrome. AB - Central airway obstruction (CAO) and superior vena cava (SVC) syndrome are potentially life-threatening complications in locally advanced lung cancer. Therapeutic rigid bronchoscopy has become an critical component in the treatment of the lung cancer patients with CAO who are not surgical candidates. However, the technique may pose significant risks in patients with coexisting SVC syndrome, especially, and even more so perhaps in patients over the age of eighty. In this case report, we address the potential risks and known benefits of therapeutic bronchoscopic intervention in an 85-year-old man with small cell lung cancer who presented with acute dyspnea secondary to advanced SVC syndrome and CAO involving the lower trachea and right main bronchus. Emergent therapeutic rigid bronchoscopy resulted in a marked improvement, in dyspnea, atelectasis, and postobstructive pneumonia, allowing rapid administration of systemic chemotherapy. PMID- 21587131 TI - Prognostic factors of pathologic stage IB non-small cell lung cancer. AB - PURPOSE: In pathologic IB (pIB) non-small cell lung cancer, especially in adenocarcinoma, adjuvant chemotherapy with uracil-tegafur is widely recognized as being effective. The aim of this study was to determine the prognostic factors of pIB disease. PATIENTS AND METHODS: Sixty patients who were diagnosed with pIB disease between 2004 and 2007 were retrospectively analyzed. RESULTS: Of 60 patients, 22 (36.7%) opted for surgery plus adjuvant chemotherapy with uracil tegafur, whereas 38 (63.3%) opted for surgery only. The oral administration dose of uracil-tegafur was 400 mg/body. Compliance of adjuvant chemotherapy with uracil-tegafur was 65.5% in 12 months, 57.3% in 24 months. Adjuvant chemotherapy was interrupted in 11 patients because of the recurrence of disease in 3 patients and adverse reaction in 8 patients. Anorexia was the most common adverse reaction. The larger tumor diameter (5 cm<) and p2 pleural invasion were the worse prognostic factors in disease free survival in a univariate analysis and a multivariate analysis (hazard ratio = 0.26 and 0.25; p = 0.028 and 0.032, respectively). CONCLUSION: The prognosis of the patients with pleural invasion and a tumor diameter >5 cm was poor, and these, partly support the forthcoming classification. PMID- 21587132 TI - Pleuroperitoneal shunt for chylothorax and chylopericardium in lung cancer: a case report. AB - A 70-year-old man with T1N3M1 stage IV squamous cell carcinoma in the right upper lobe of the lung developed chylothorax and chylopericardium as rare simultaneous complications. Intravenous hyperalimentation, repeated pleurodesis, and ligation of the thoracic duct were all ineffective. A pleuroperitoneal shunt was inserted into the right pleural cavity from the fifth intercostal space, and a peritoneal catheter was placed in the abdominal cavity. Chylothorax was markedly improved, and the quality of life of the patient increased. This case indicates that a pleuroperitoneal shunt can be used for lung cancer-related chylothorax, as well as for malignant pleural effusion. PMID- 21587133 TI - Complete left-sided pericardial defect in a lung cancer patient undergoing pneumonectomy without closure of the defect. AB - A 61-year-old asymptomatic man underwent a left pneumonectomy for Stage IIIA lung cancer. At thoracotomy, the pericardium was found to be completely absent; however, we did not close the defect. Although the heart was rotated toward the left pleural cavity in the postoperative chest computed tomography (CT), the postoperative course was uneventful, and the patient has remained asymptomatic for 7 months, since the resection. We reviewed the preoperative chest CT, which showed the heart extending unusually to the left, but the pericardial defect was not evident. Complete pericardial defects usually do not endanger the lives of patients, and if the patient is asymptomatic, surgical repair of the defect may be unnecessary even during a left pneumonectomy. PMID- 21587134 TI - Alveolar adenoma of the lung: a case report. AB - Alveolar adenoma is a rare pulmonary neoplasm. This report describes a case of alveolar adenoma of the lung in a 61-year-old woman. A chest X-ray demonstrated a solitary round pulmonary nodule. After six years of observation, this lesion had increased in size. Thoracoscopic left upper segmentectomy was performed on account of a possible low-grade malignant tumor. Histologically, the neoplastic epithelial cells, which had the appearance of proliferative type II pneumocytes, revealed no evidence of malignancy. These findings indicated that the tumor is alveolar adenoma of the lung. The course of disease remains uneventful, one year after the resection. PMID- 21587135 TI - A case of Good's syndrome: a rare acquired immunodeficiency associated with thymoma. AB - The patient was a 76-year-old man who had a prior history of recurrent pneumonia and severe, chronic sinusitis. Computed tomography showed a thymoma, and laboratory results revealed hypogammaglobulinemia. Therefore, Good's Syndrome (GS, rare adult-onset immunodeficiency with thymoma) was diagnosed. To treat his sinusitis, we started the patient on long-term clarithromycin therapy, preoperatively. A thymothymectomy was performed, but the immunological disorder was not resolved. Although standard gamma globulin replacement was not given, his sinusitis symptoms were ameliorated, and he has not had pneumonia since the operation. Long-term macrolide therapy probably plays some role in managing sino pulmonary infections associated with GS. PMID- 21587136 TI - Hernia of Morgagni and mediastinal lipoma: a case report. AB - A hernia of Morgagni (also called hernia of Morgagni-Larrey) is a congenital herniation of abdominal contents into the thoracic cavity through a retrosternal diaphragmatic defect. The Morgagni hernia can create uncertainty in its diagnosis and difficulty for subsequent treatment. If after clinical examination and x-ray we suspect the hernia, computed tomography imaging should be the desired imaging method to confirm the diagnosis. Surgery is the only definitive treatment. When a patient presents signs and symptoms of incarceration or strangulation, emergency surgery is required. We report the first life-threatening case of an association between a hernia of Morgagni and a mediastinal lipoma. We present an adult patient with mediastinal lipoma and a right incarcerated hernia of Morgagni with engagement of the stomach, the duodenum and the transverse colon, successfully treated without complications. To our knowledge, this is the first report of an association between those two rare entities in an acute setting. We discuss the differential diagnosis and physiopathology of the condition, referring to published reports. PMID- 21587137 TI - Acute mitral valve regurgitation due to complete rupture of anterior papillary muscle mimicking mitral valve vegetation. AB - We report the successful treatment of a 77-year-old man after a difficult diagnosis of mitral valve regurgitation resulting from complete rupture of the anterior papillary muscle. The patient with cardiogenic shock was an emergency admission. An electrocardiogram showed acute lateral wall myocardial infarction. He had complications of leukocytosis and a high-grade fever. Transesophageal echocardiography seemed to show the appearance of a large area of vegetation attached to the anterior mitral valve leaflet and aortic non-coronary cusp, resulting in severe mitral regurgitation. We performed coronary angiography, which showed complete obstruction of the circumflex coronary artery. We determined that the condition was caused by infective endocarditis. Emergency surgery showed the complete rupture of the anterior papillary muscle, but there was no vegetation. The mitral valve was replaced with a bioprosthetic valve and the circumflex coronary artery was bypassed with a saphenous vein graft. Pathological examination revealed mitral valve to be non-mycotic, and the postoperative course was uneventful. PMID- 21587138 TI - Aortic balloon used in a cardiac reoperation of a patient with patent coronary grafts. AB - Reoperation in patients with patent coronary artery bypass grafts behind the sternum is associated with a high risk of graft injury that may be life threatening. We recently performed mitral valve replacement in a patient with patent coronary artery bypass grafts and grade IV mitral regurgitation. Surgery was safely performed with minimal adhesion dissection and modified Port-Access Technique using an aortic balloon. PMID- 21587139 TI - A modified infarct exclusion repair of posterior postinfarction ventricular perforation: triple-patch technique for postinfarction ventricular septal perforation in 2 female patients. AB - We describe a new technique for the early surgical repair of a posterior postinfarction ventricular septal perforation (VSP) in two consecutive female patients. The occurrence of a posterior VSP is rare, and its repair is technically difficult because the posteromedial papillary muscle is located adjacent to the intraventricular septum. This modification appears to prevent leaks to the right ventricle through the VPS with a single direct patch and the use of two equine pericardial patches to form a single endocardial pouch. The women were 77 and 62 years old, and the time between the onset of acute MI and surgery was 3 and 6 days. On preoperative catheterization, Qp/Qs was 4.18 and 4.01. Neither operative death nor residual shunting was observed. PMID- 21587140 TI - A surgical case report of off-pump onlay patch grafting for pseudoaneurysm with diffusely calcified coronary artery. AB - Coronary pseudoaneurysm usually occurs after catheter-based intervention as a result of traumatic dissection or perforation of a coronary artery in 4%-5% of cases. Here, we report the successful case of pseudoaneurysm occurring after percutaneous coronary angioplasty (PTCA) against the severely calcified coronary artery treated with off-pump long onlay patch bypass technique using internal thoracic arteries. We report the case of a 59-year-old woman treated with off pump onlay patch grafting for pseudoaneurysm after coronary angioplasty against the diffusely calcified coronary lesion. The portion of the endoarterectomized left anterior descending coronary artery proximal to the resected aneurysm extending 5cm distally was successfully reconstructed with long onlay patch using the internal thoracic arterial graft. PMID- 21587141 TI - Adolf Kussmaul, the sword eater and modern challenges of digestive endoscopy. PMID- 21587142 TI - Endoscopic banding for esophageal variceal bleeding: technique and patient outcome. AB - AIM: Endoscopic variceal ligation (EVL) is recommended for the treatment of esophageal variceal bleeding. The aim of this study was to assess the most cost effective timing of endoscopic follow-up after variceal eradication. METHODS: Cirrhotics with esophageal varices treated between January 2008 and January 2009 until reached variceal obliteration were retrospectively analyzed for technical aspects and for outcomes. RESULTS: Out of 127 patients treated with EVL, 103 were included. Number of sessions to achieve variceal obliteration and number of bands for each session were 2.8+/-1.3 (range 1-7) and 4.6+/-1 (range 2-7), respectively. The placement of >5 bands per session was not associated with higher incidence of complications (19.6% vs. 17.8%, P=ns). Esophageal ulcers were observed in 42% of patients when the interbanding interval was <20 days (versus 15% for interval >20 days, P<0.05). Once obliteration was achieved, varices reappeared in 28% of patients; the early appearance of small varices was not associated with bleeding. CONCLUSION: A longer interbanding interval reduces the incidence of procedural-related complications. After variceal obliteration an early endoscopic control is not useful because it does not influence the approach and does not change the patient outcome. PMID- 21587143 TI - Use of probiotics for the treatment of constipation in Parkinson's disease patients. AB - AIM: The aim of this paper was to assess the effects of milk fermented with the probiotic strain Lactobacillus casei Shirota on constipation in Parkinson's disease patients. Constipation is a common secondary symptom in patients suffering from Parkinson's Disease (PD), generally treated with dietary therapy, soluble fiber supplements and macrogol laxatives without sodium sulfate. There are no studies on the use of probiotics in the treatment of constipation in these patients. The effects of the administration of Lactobacillus casei Shirota on gastrointestinal symptoms have been assessed in two randomized controlled trials on patients suffering from chronic constipation. METHODS: Forty PD patients suffering from constipation according to Rome III criteria were recruited. We compared the characteristic of intestinal function during two periods with different treatments: in the first week the patients treated constipation only with dietetic therapy; in the following 5 weeks the patients treated constipation not only with dietetic therapy, but also taking a 65 mL fermented milk drink containing 6.5*109 CFU of Lactobacilus casei Shirota daily.They completed a daily diary for 6 weeks, recording details related to their intestinal function. RESULTS: After probiotic intake we observed a statistically significant increase in the number of days per week in which stools were of normal consistency (P<0.01) and significant reductions in the number of days per week in which patients felt bloated (P<0.01), experienced abdominal pain (P<0.01) and sensation of incomplete emptying (P<0.01). CONCLUSION: This pilot study showed that a regular intake of probiotics can significantly improve stool consistency and bowel habits in Parkinson's disease patients. PMID- 21587144 TI - Echo-endoscopy: new therapeutic frontiers. AB - Endoscopic ultrasound (EUS) has been established as a valuable diagnostic modality as it offers high-resolution imaging and fine-needle biopsy, which is essential in detecting and staging malignancies. Since the introduction of EUS guided fine needle aspiration (EUS-FNA) in 1992, numerous novel EUS-based interventions and techniques have emerged. Currently, established interventional EUS techniques include celiac plexus block and neurolysis, drainage of pancreatic pseudocysts and pelvic fluid collections, and implantation of fiducial markers and radioactive seeds into the malignant tumors. Emerging EUS-guided experimental techniques include antitumor injection, ablation of tumors, and vascular access. Diagnostic and therapeutic access to the biliary tree and pancreatic duct is increasingly being used for failed ERCP procedures or inaccessible ducts. Interventional EUS is a very promising technique with many potential applications. The future holds promise for substantial progress in EUS-guided therapeutic interventions and their applications in clinical gastroenterology. PMID- 21587145 TI - Complications of endoscopic ultrasonography. AB - Since its development in the 1980s, endoscopic ultrasonography (EUS) has undergone a great deal of technological modifications. EUS has become an important tool in the evaluation of patients with various clinical disorders and is increasingly being utilized in many centers. EUS has been evolving over the years; EUS-guided fine needle aspiration (FNA) for cytological and/or histological diagnosis has become standard practice and a wide array of interventional and therapeutic procedures are performed under EUS guidance for diseases which otherwise would have needed surgery, with its associated morbidities. EUS shares the risks and complications of other endoscopic procedures. This article addresses the specific adverse effects and risks associated with EUS, EUS-FNA and interventional EUS, namely perforation, bleeding, pancreatitis and infection. Measures to help minimizing these risks will also be discussed. PMID- 21587146 TI - Management of small and diminutive colorectal polyps: a review of the literature. AB - Major advances in biomedical optics have increased our ability to detect more colorectal polyps. Increased small (6-9 mm) and diminutive (<6 mm) polyp detection has been reported however the impact of these increases in terms of colorectal cancer prevention is unknown. The same advances that have allowed increased detection have also made in vivo determination of polyp histology possible. As our in-vivo assessment accuracy improves, the need for resection of non neoplastic polyps and pathologic confirmation of low risk adenomas may eventually diminish. The clinical significance of small and diminutive polyps continues to be debated however both retrospective and prospective studies support a low prevalence of advanced pathology in colorectal polyps <10mm in size. Furthermore, natural history studies suggest these polyps exhibit little or slow growth and some may in fact regress over time. Though the overall risk of colonoscopy is low, polypectomy remains the single greatest risk factor, driving interest in methods to avoid polypectomy of non-neoplastic polyps thereby improving safety without reducing cancer prevention effectiveness. A "diagnose and discard" strategy for diminutive adenomas and a "diagnose and leave behind" strategy for diminutive hyperplastic polyps may offer risk and cost reduction without compromising effectiveness but will require the ability to make both accurate high confidence in-vivo polyp assessment and agreement in setting post polypectomy surveillance intervals. As both our technology and our knowledge increase, we will be better equipped to confidently provide a complete colorectal screening, to manage detected polyps according to their chance for neoplasia, and to provide an accurate assessment of lifetime colorectal cancer risk and need for future surveillance examinations. PMID- 21587147 TI - NOTES spin-off for the therapeutic gastroenterologist: natural orifice surgery. AB - Natural orifice transluminal endoscopic surgery (NOTES) has ushered in a new era in flexible endoscopy. Over the past decade, modest advances have been made in addressing the fundamental challenges of NOTES surgery including transluminal access and closure techniques, and advancement of NOTES-specific technology. Despite these encouraging initial efforts significant obstacles to widespread acceptance of NOTES as a surgical option persist. Moreover, due to the well documented safety and efficacy of laparoscopic techniques, the question remains as to the best candidate NOTES procedure. Presently, interest has shifted from true NOTES to hybrid procedures and single incision laparoscopic surgery, due to the lure of more immediate success. Additionally, there is also a growing awareness of the potential applications of natural orifice surgery techniques to the present field of therapeutic endoscopy. Research into transluminal access and closure has born several techniques and devices that are now being explored in endoscopic procedures such as full-thickness resection, endoscopic myotomy, direct endoscopic pancreatic necrosectomy and bariatric endoscopy. Such NOTES "spin-off" procedures are expanding the armamentarium of today's therapeutic endoscopists, and a growing body of literature suggests that they will play a significant role in the evolution of therapeutic endoscopy in the future. PMID- 21587148 TI - Colonic stenting in 2011. AB - Self expanding metal stents (SEMS) are an established treatment in the management of malignant obstructing lesions throughout the gastrointestinal tract. SEMS have been utilized both as palliation in and as a bridge to surgical resection for malignant colonic obstruction. Many studies have demonstrated that placement of SEMS for malignant colonic obstruction is both efficacious, with high technical and clinical success rates, and safe with a low complication rate. In contrast, there is a paucity of data on the role of SEMS in the management of benign colonic obstruction, an indication which remains controversial. This review outlines the most recent developments in colonic stenting, their current indications, and the evidence to support their use in these indications. PMID- 21587149 TI - Early diagnosis of pancreatic cancer, time to screen high-risk individuals? AB - Pancreatic cancer (PC) is considered as one of the malignant tumors with poorest survival rate (less than 5% 5-year survival). Despite new developments in imaging techniques, surgery and oncologic treatments, survival rate remains unchanged. In order to improve the outcome of this disease, it would be of interest the development of a screening program trying to detect small asymptomatic tumors or precursor lesions at the time when the disease is still at a curable stage. Although screening in general population is not feasible nowadays, screening programs in high risk individuals may be of help in this setting. A specific population has been defined to be screened, those with a >10-fold increased risk for developing the disease (inherited PC syndromes due to inherited gene mutations and individuals with a strong family history of PC with at least 2 first-degree relatives affected, but without a known genetic defect). Regarding the methods for screening, endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI) appears to be the most accurate, mainly based in their ability to detect those small pancreatic tumors and precursor lesions (like IPMN and PanIN lesions). In these patients screening should start at the age of 45, or 15 years earlier than the earliest occurrence of PC in the family, whichever is the earlier age. Explorations should be schedule every 1 to 3 years, depending on initial findings. PMID- 21587150 TI - An update on drug induced liver injury. AB - Drug induced liver injury (DILI) is an uncommon cause of acute and chronic liver injury of increasing importance to patients, clinicians, and regulators. The incidence of DILI due to an individual agent is not well defined but population based studies suggest that the overall incidence of DILI may be as high as 10 to 15 cases per 100000 patient years. Bona fide risk factors for DILI are also not well established, but ongoing multicenter registry studies such as the Drug Induced Liver Injury Network are attempting to identify the role of genetic, environmental, and immunological factors in DILI pathogenesis and outcomes. Acute hepatocellular injury (~50%) is more common than mixed or cholestatic liver injury but jaundiced DILI subjects with either type of liver injury have a ~10% risk of short-term mortality. Antibiotics are the most commonly implicated agents associated with DILI, but there are emerging reports of liver injury associated with the use of a multitude of herbal and dietary supplements. Despite their widespread use, the HMG-CoA reductase inhibitors or statins are an uncommon cause of idiosyncratic DILI. Furthermore, recent studies have shown that statins are actually safe and efficacious to use in hyperlipidemic patients with chronic liver disease. Acetaminophen hepatotoxicity remains a leading cause of severe acute liver injury. Limiting the amount of acetaminophen in prescription narcotic products may help reduce the incidence of future non-intentional overdoses but educating patients and providers of the multitude of over the counter products that contain acetaminophen is also recommended. PMID- 21587151 TI - Evaluation of flow and structure abnormalities of splanchnic system veins in cirrhotic patients without portal hypertension. AB - AIM: The aim of this study was to evaluate hemodynamic and anatomic alterations of the splanchnic venous system and the efficiency and safety of color Doppler radial endosonography in the assessment of cirrhotic patients by comparing Child A cirrhotic patients without portal hypertension findings versus a non-cirrhotic group. METHODS: The study was carried out between January 2009 and February 2010; the study population was 38 cirrhotic patients without portal hypertension and 140 control patients. RESULTS: Hepatopedal flow was monophasic in all the control patients; the flow pattern was chaotic and irregular in 8% of the cirrhotic patients; in the cirrhotic patients the portal vein diameter was increased and the flow velocity reduced; no differences in flow volume were observed between the two groups. Splenic vein diameter and flow velocity were normal. In the majority of the Child A cirrhotic patients without portal hypertension, no changes were seen in portal vein diameter or flow volume; in some patients no significant increase portal vein diameter was observed and showed the flow volumes were unchanged. CONCLUSION: Radial Doppler endosonography may be efficient and safe for assessing the splanchnic system. PMID- 21587152 TI - Role of endoscopy in the management of gastroenteropancreatic neuroendocrine tumours. AB - Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) represent in clinical practice a diagnostic dilemma because they are often very small, located deeply within the retroperitoneum or in an extramucosal site in the gastrointestinal (GI) tract and, lastly, because they may be multi-sited. Modern digestive endoscopy offers a myriad of techniques, useful for localization, diagnosis and treatment (therapeutic endoscopy). The available tools include upper digestive endoscopy (esophagogastroduodenoscopy, endoscopic retrograde cholangiopancreatography), lower digestive endoscopy (ileo-colonoscopy), enteroscopy (push-type, intra-operative, capsule, double or single balloon), for examining the small intestine, diagnostic and interventional echo-endoscopy (EUS), with radial, linear and miniprobe equipment. This narrative review offers scientific support to affirm that endoscopy and EUS give imaging and diagnostic possibilities that are unbeatable in the localization of GEP-NETs both of the GI tract and the pancreas. Endoscopy is useful for localization, bioptic diagnosis and curative resection of small neuroendocrine lesions of the stomach, duodenum, colon-rectum and more recently of the jejuno-ileum. EUS associated with dedicated instruments, particularly high frequency miniprobes, is a valuable procedure in locoregional staging of lesions of the GI wall and can supply information which has a clinical impact on therapeutic options and prognostic value. EUS is still today the sole technique in a certain number of cases which provides a definitive diagnosis of pancreatic insulinoma and to detect and follow subcentimetric lesions of the pancreas in patients with MEN-1 syndrome. It should be used in all those cases where results from radiographic imaging or nuclear medicine techniques show negative or dubious. PMID- 21587153 TI - Protocol for recombinant RBD-based SARS vaccines: protein preparation, animal vaccination and neutralization detection. AB - Based on their safety profile and ability to induce potent immune responses against infections, subunit vaccines have been used as candidates for a wide variety of pathogens. Since the mammalian cell system is capable of post translational modification, thus forming properly folded and glycosylated proteins, recombinant proteins expressed in mammalian cells have shown the greatest potential to maintain high antigenicity and immunogenicity. Although no new cases of SARS have been reported since 2004, future outbreaks are a constant threat; therefore, the development of vaccines against SARS-CoV is a prudent preventive step and should be carried out. The RBD of SARS-CoV S protein plays important roles in receptor binding and induction of specific neutralizing antibodies against virus infection. Therefore, in this protocol, we describe novel methods for developing a RBD-based subunit vaccine against SARS. Briefly, the recombinant RBD protein (rRBD) was expressed in culture supernatant of mammalian 293T cells to obtain a correctly folded protein with proper conformation and high immunogenicity. The transfection of the recombinant plasmid encoding RBD to the cells was then performed using a calcium phosphate transfection method with some modifications. Compared with the lipid transfection method, this modified calcium phosphate transfection method is cheaper, easier to handle, and has the potential to reach high efficacy once a transfection complex with suitable size and shape is formed. Finally, a SARS pseudovirus neutralization assay was introduced in the protocol and used to detect the neutralizing activity of sera of mice vaccinated with rRBD protein. This assay is relatively safe, does not involve an infectious SARS-CoV, and can be performed without the requirement of a biosafety-3 laboratory. The protocol described here can also be used to design and study recombinant subunit vaccines against other viruses with class I fusion proteins, for example, HIV, respiratory syncytial virus (RSV), Ebola virus, influenza virus, as well as Nipah and Handra viruses. In addition, the methods for generating a pseudovirus and subsequently establishing a pseudovirus neutralization assay can be applied to all these viruses. PMID- 21587154 TI - Non-surgical intratracheal instillation of mice with analysis of lungs and lung draining lymph nodes by flow cytometry. AB - Phagocytic cells such as alveolar macrophages and lung dendritic cells (LDCs) continuously sample antigens from the alveolar spaces in the lungs. LDCs, in particular, are known to migrate to the lung draining lymph nodes (LDLNs) where they present inhaled antigens to T cells initiating an appropriate immune response to a variety of immunogens. To model interactions between the lungs and airborne antigens in mice, antigens can be administered intranasally, intratracheally or as aerosols. Delivery by each route involves distinct technical skills and limitations that need to be considered before designing an experiment. For example, intranasal and aerosolized exposure delivers antigens to both the lungs and the upper respiratory tract. Hence antigens can access the nasal associated lymphoid tissue (NALT), potentially complicating interpretation of the results. In addition, swallowing, sneezing and the breathing rate of the mouse may also lead to inconsistencies in the doses delivered. Although the involvement of the upper respiratory tract may be preferred for some studies, it can complicate experiments focusing on events specifically initiated in the lungs. In this setting, the intratracheal (i.t) route is preferable as it delivers test materials directly into the lungs and bypasses the NALT. Many i.t injection protocols involve either blind intubation of the trachea through the oral cavity or surgical exposure of the trachea to access the lungs. Herein, we describe a simple, consistent, non-surgical method for i.t instillation. The opening of the trachea is visualized using a laryngoscope and a bent gavage needle is then inserted directly into the trachea to deliver the innoculum. We also describe procedures for harvesting and processing of LDLNs and lungs for analysis of antigen trafficking by flow cytometry. PMID- 21587155 TI - Biomolecular detection employing the Interferometric Reflectance Imaging Sensor (IRIS). AB - The sensitive measurement of biomolecular interactions has use in many fields and industries such as basic biology and microbiology, environmental/agricultural/biodefense monitoring, nanobiotechnology, and more. For diagnostic applications, monitoring (detecting) the presence, absence, or abnormal expression of targeted proteomic or genomic biomarkers found in patient samples can be used to determine treatment approaches or therapy efficacy. In the research arena, information on molecular affinities and specificities are useful for fully characterizing the systems under investigation. Many of the current systems employed to determine molecular concentrations or affinities rely on the use of labels. Examples of these systems include immunoassays such as the enzyme linked immunosorbent assay (ELISA), polymerase chain reaction (PCR) techniques, gel electrophoresis assays, and mass spectrometry (MS). Generally, these labels are fluorescent, radiological, or colorimetric in nature and are directly or indirectly attached to the molecular target of interest. Though the use of labels is widely accepted and has some benefits, there are drawbacks which are stimulating the development of new label-free methods for measuring these interactions. These drawbacks include practical facets such as increased assay cost, reagent lifespan and usability, storage and safety concerns, wasted time and effort in labelling, and variability among the different reagents due to the labelling processes or labels themselves. On a scientific research basis, the use of these labels can also introduce difficulties such as concerns with effects on protein functionality/structure due to the presence of the attached labels and the inability to directly measure the interactions in real time. Presented here is the use of a new label-free optical biosensor that is amenable to microarray studies, termed the Interferometric Reflectance Imaging Sensor (IRIS), for detecting proteins, DNA, antigenic material, whole pathogens (virions) and other biological material. The IRIS system has been demonstrated to have high sensitivity, precision, and reproducibility for different biomolecular interactions [1-3]. Benefits include multiplex imaging capacity, real time and endpoint measurement capabilities, and other high-throughput attributes such as reduced reagent consumption and a reduction in assay times. Additionally, the IRIS platform is simple to use, requires inexpensive equipment, and utilizes silicon-based solid phase assay components making it compatible with many contemporary surface chemistry approaches. Here, we present the use of the IRIS system from preparation of probe arrays to incubation and measurement of target binding to analysis of the results in an endpoint format. The model system will be the capture of target antibodies which are specific for human serum albumin (HSA) on HSA-spotted substrates. PMID- 21587156 TI - Three-dimensional optical-resolution photoacoustic microscopy. AB - Optical microscopy, providing valuable insights at the cellular and organelle levels, has been widely recognized as an enabling biomedical technology. As the mainstays of in vivo three-dimensional (3-D) optical microscopy, single-/multi photon fluorescence microscopy and optical coherence tomography (OCT) have demonstrated their extraordinary sensitivities to fluorescence and optical scattering contrasts, respectively. However, the optical absorption contrast of biological tissues, which encodes essential physiological/pathological information, has not yet been assessable. The emergence of biomedical photoacoustics has led to a new branch of optical microscopy optical-resolution photoacoustic microscopy (OR-PAM), where the optical irradiation is focused to the diffraction limit to achieve cellular or even subcellular level lateral resolution. As a valuable complement to existing optical microscopy technologies, OR-PAM brings in at least two novelties. First and most importantly, OR-PAM detects optical absorption contrasts with extraordinary sensitivity (i.e., 100%). Combining OR-PAM with fluorescence microscopy or with optical-scattering-based OCT (or with both) provides comprehensive optical properties of biological tissues. Second, OR-PAM encodes optical absorption into acoustic waves, in contrast to the pure optical processes in fluorescence microscopy and OCT, and provides background-free detection. The acoustic detection in OR-PAM mitigates the impacts of optical scattering on signal degradation and naturally eliminates possible interferences (i.e., crosstalks) between excitation and detection, which is a common problem in fluorescence microscopy due to the overlap between the excitation and fluorescence spectra. Unique for optical absorption imaging, OR PAM has demonstrated broad biomedical applications since its invention, including, but not limited to, neurology, ophthalmology, vascular biology, and dermatology. In this video, we teach the system configuration and alignment of OR PAM as well as the experimental procedures for in vivo functional microvascular imaging. PMID- 21587157 TI - Cerebral blood oxygenation measurement based on oxygen-dependent quenching of phosphorescence. AB - Monitoring of the spatiotemporal characteristics of cerebral blood and tissue oxygenation is crucial for better understanding of the neuro-metabolic-vascular relationship. Development of new pO2 measurement modalities with simultaneous monitoring of pO2 in larger fields of view with higher spatial and/or temporal resolution will enable greater insight into the functioning of the normal brain and will also have significant impact on diagnosis and treatment of neurovascular diseases such as stroke, Alzheimer's disease, and head injury. Optical imaging modalities have shown a great potential to provide high spatiotemporal resolution and quantitative imaging of pO2 based on hemoglobin absorption in visible and near infrared range of optical spectrum. However, multispectral measurement of cerebral blood oxygenation relies on photon migration through the highly scattering brain tissue. Estimation and modeling of tissue optical parameters, which may undergo dynamic changes during the experiment, is typically required for accurate estimation of blood oxygenation. On the other hand, estimation of the partial pressure of oxygen (pO2) based on oxygen-dependent quenching of phosphorescence should not be significantly affected by the changes in the optical parameters of the tissue and provides an absolute measure of pO2. Experimental systems that utilize oxygen-sensitive dyes have been demonstrated in in vivo studies of the perfused tissue as well as for monitoring the oxygen content in tissue cultures, showing that phosphorescence quenching is a potent technology capable of accurate oxygen imaging in the physiological pO2 range. Here we demonstrate with two different imaging modalities how to perform measurement of pO2 in cortical vasculature based on phosphorescence lifetime imaging. In first demonstration we present wide field of view imaging of pO2 at the cortical surface of a rat. This imaging modality has relatively simple experimental setup based on a CCD camera and a pulsed green laser. An example of monitoring the cortical spreading depression based on phosphorescence lifetime of Oxyphor R3 dye was presented. In second demonstration we present a high resolution two-photon pO2 imaging in cortical micro vasculature of a mouse. The experimental setup includes a custom built 2-photon microscope with femtosecond laser, electro-optic modulator, and photon-counting photo multiplier tube. We present an example of imaging the pO2 heterogeneity in the cortical microvasculature including capillaries, using a novel PtP-C343 dye with enhanced 2-photon excitation cross section. PMID- 21587158 TI - Brain imaging investigation of the memory-enhancing effect of emotion. AB - Emotional events tend to be better remembered than non-emotional events. One goal of cognitive and affective neuroscientists is to understand the neural mechanisms underlying this enhancing effect of emotion on memory. A method that has proven particularly influential in the investigation of the memory-enhancing effect of emotion is the so-called subsequent memory paradigm (SMP). This method was originally used to investigate the neural correlates of non-emotional memories, and more recently we and others also applied it successfully to studies of emotional memory (reviewed in). Here, we describe a protocol that allows investigation of the neural correlates of the memory-enhancing effect of emotion using the SMP in conjunction with event-related functional magnetic resonance imaging (fMRI). An important feature of the SMP is that it allows separation of brain activity specifically associated with memory from more general activity associated with perception. Moreover, in the context of investigating the impact of emotional stimuli, SMP allows identification of brain regions whose activity is susceptible to emotional modulation of both general/perceptual and memory specific processing. This protocol can be used in healthy subjects, as well as in clinical patients where there are alterations in the neural correlates of emotion perception and biases in remembering emotional events, such as those suffering from depression and post-traumatic stress disorder (PTSD). PMID- 21587160 TI - Quantitative visualization and detection of skin cancer using dynamic thermal imaging. AB - In 2010 approximately 68,720 melanomas will be diagnosed in the US alone, with around 8,650 resulting in death. To date, the only effective treatment for melanoma remains surgical excision, therefore, the key to extended survival is early detection. Considering the large numbers of patients diagnosed every year and the limitations in accessing specialized care quickly, the development of objective in vivo diagnostic instruments to aid the diagnosis is essential. New techniques to detect skin cancer, especially non-invasive diagnostic tools, are being explored in numerous laboratories. Along with the surgical methods, techniques such as digital photography, dermoscopy, multispectral imaging systems (MelaFind), laser-based systems (confocal scanning laser microscopy, laser doppler perfusion imaging, optical coherence tomography), ultrasound, magnetic resonance imaging, are being tested. Each technique offers unique advantages and disadvantages, many of which pose a compromise between effectiveness and accuracy versus ease of use and cost considerations. Details about these techniques and comparisons are available in the literature. Infrared (IR) imaging was shown to be a useful method to diagnose the signs of certain diseases by measuring the local skin temperature. There is a large body of evidence showing that disease or deviation from normal functioning are accompanied by changes of the temperature of the body, which again affect the temperature of the skin. Accurate data about the temperature of the human body and skin can provide a wealth of information on the processes responsible for heat generation and thermoregulation, in particular the deviation from normal conditions, often caused by disease. However, IR imaging has not been widely recognized in medicine due to the premature use of the technology several decades ago, when temperature measurement accuracy and the spatial resolution were inadequate and sophisticated image processing tools were unavailable. This situation changed dramatically in the late 1990s-2000s. Advances in IR instrumentation, implementation of digital image processing algorithms and dynamic IR imaging, which enables scientists to analyze not only the spatial, but also the temporal thermal behavior of the skin, allowed breakthroughs in the field. In our research, we explore the feasibility of IR imaging, combined with theoretical and experimental studies, as a cost effective, non-invasive, in vivo optical measurement technique for tumor detection, with emphasis on the screening and early detection of melanoma. In this study, we show data obtained in a patient study in which patients that possess a pigmented lesion with a clinical indication for biopsy are selected for imaging. We compared the difference in thermal responses between healthy and malignant tissue and compared our data with biopsy results. We concluded that the increased metabolic activity of the melanoma lesion can be detected by dynamic infrared imaging. PMID- 21587159 TI - Pressure controlled ventilation to induce acute lung injury in mice. AB - Murine models are extensively used to investigate acute injuries of different organs systems. Acute lung injury (ALI), which occurs with prolonged mechanical ventilation, contributes to morbidity and mortality of critical illness, and studies on novel genetic or pharmacological targets are areas of intense investigation. ALI is defined by the acute onset of the disease, which leads to non-cardiac pulmonary edema and subsequent impairment of pulmonary gas exchange. We have developed a murine model of ALI by using a pressure-controlled ventilation to induce ventilator-induced lung injury. For this purpose, C57BL/6 mice are anesthetized and a tracheotomy is performed followed by induction of ALI via mechanical ventilation. Mice are ventilated in a pressure-controlled setting with an inspiratory peak pressure of 45 mbar over 1-3 hours. As outcome parameters, pulmonary edema (wet-to-dry ratio), bronchoalveolar fluid albumin content, bronchoalveolar fluid and pulmonary tissue myeloperoxidase content and pulmonary gas exchange are assessed. Using this technique we could show that it sufficiently induces acute lung inflammation and can distinguish between different treatment groups or genotypes. Therefore this technique may be helpful for researchers who pursue molecular mechanisms involved in ALI using a genetic approach in mice with gene-targeted deletion. PMID- 21587161 TI - A beta-glucuronidase (GUS) based cell death assay. AB - We have developed a novel transient plant expression system that simultaneously expresses the reporter gene, beta-glucuronidase (GUS), with putative positive or negative regulators of cell death. In this system, N. benthamiana leaves are co infiltrated with a 35S driven expression cassette containing the gene to be analyzed, and the GUS vector pCAMBIA 2301 using Agrobacterium strain LBA4404 as a vehicle. Because live cells are required for GUS expression to occur, loss of GUS activity is expected when this marker gene is co-expressed with positive regulators of cell death. Equally, increased GUS activity is observed when anti apoptotic genes are used compared to the vector control. As shown below, we have successfully used this system in our lab to analyze both pro- and anti-death players. These include the plant anti-apoptotic Bcl-2 Associated athanoGene (BAG) family, as well as, known mammalian inducers of cell death, such as BAX. Additionally, we have used this system to analyze the death function of specific truncations within proteins, which could provide clues on the possible post translational modification/activation of these proteins. Here, we present a rapid and sensitive plant based method, as an initial step in investigating the death function of specific genes. PMID- 21587162 TI - A simple hanging drop cell culture protocol for generation of 3D spheroids. AB - Studies of cell-cell cohesion and cell-substratum adhesion have historically been performed on monolayer cultures adherent to rigid substrates. Cells within a tissue, however, are typically encased within a closely packed tissue mass in which cells establish intimate connections with many near-neighbors and with extracellular matrix components. Accordingly, the chemical milieu and physical forces experienced by cells within a 3D tissue are fundamentally different than those experienced by cells grown in monolayer culture. This has been shown to markedly impact cellular morphology and signaling. Several methods have been devised to generate 3D cell cultures including encapsulation of cells in collagen gels or in biomaterial scaffolds. Such methods, while useful, do not recapitulate the intimate direct cell-cell adhesion architecture found in normal tissues. Rather, they more closely approximate culture systems in which single cells are loosely dispersed within a 3D meshwork of ECM products. Here, we describe a simple method in which cells are placed in hanging drop culture and incubated under physiological conditions until they form true 3D spheroids in which cells are in direct contact with each other and with extracellular matrix components. The method requires no specialized equipment and can be adapted to include addition of any biological agent in very small quantities that may be of interest in elucidating effects on cell-cell or cell-ECM interaction. The method can also be used to co-culture two (or more) different cell populations so as to elucidate the role of cell-cell or cell-ECM interactions in specifying spatial relationships between cells. Cell-cell cohesion and cell-ECM adhesion are the cornerstones of studies of embryonic development, tumor-stromal cell interaction in malignant invasion, wound healing, and for applications to tissue engineering. This simple method will provide a means of generating tissue-like cellular aggregates for measurement of biomechanical properties or for molecular and biochemical analysis in a physiologically relevant model. PMID- 21587163 TI - Cecal ligation puncture procedure. AB - Human sepsis is characterized by a set of systemic reactions in response to intensive and massive infection that failed to be locally contained by the host. Currently, sepsis ranks among the top ten causes of mortality in the USA intensive care units. During sepsis there are two established haemodynamic phases that may overlap. The initial phase (hyperdynamic) is defined as a massive production of proinflammatory cytokines and reactive oxygen species by macrophages and neutrophils that affects vascular permeability (leading to hypotension), cardiac function and induces metabolic changes culminating in tissue necrosis and organ failure. Consequently, the most common cause of mortality is acute kidney injury. The second phase (hypodynamic) is an anti inflammatory process involving altered monocyte antigen presentation, decreased lymphocyte proliferation and function and increased apoptosis. This state known as immunosuppression or immune depression sharply increases the risk of nocosomial infections and ultimately, death. The mechanisms of these pathophysiological processes are not well characterized. Because both phases of sepsis may cause irreversible and irreparable damage, it is essential to determine the immunological and physiological status of the patient. This is the main reason why many therapeutic drugs have failed. The same drug given at different stages of sepsis may be therapeutic or otherwise harmful or have no effect. To understand sepsis at various levels it is crucial to have a suitable and comprehensive animal model that reproduces the clinical course of the disease. It is important to characterize the pathophysiological mechanisms occurring during sepsis and control the model conditions for testing potential therapeutic agents. To study the etiology of human sepsis researchers have developed different animal models. The most widely used clinical model is cecal ligation and puncture (CLP). The CLP model consists of the perforation of the cecum allowing the release of fecal material into the peritoneal cavity to generate an exacerbated immune response induced by polymicrobial infection. This model fulfills the human condition that is clinically relevant. As in humans, mice that undergo CLP with fluid resuscitation show the first (early) hyperdynamic phase that in time progresses to the second (late) hypodynamic phase. In addition, the cytokine profile is similar to that seen in human sepsis where there is increased lymphocyte apoptosis (reviewed in). Due to the multiple and overlapping mechanisms involved in sepsis, researchers need a suitable sepsis model of controlled severity in order to obtain consistent and reproducible results. PMID- 21587164 TI - Intraluminal middle cerebral artery occlusion (MCAO) model for ischemic stroke with laser doppler flowmetry guidance in mice. AB - Stroke is the third leading cause of death and the leading cause of disability in the world, with an estimated cost of near $70 billion in the United States in 2009. The intraluminal middle cerebral artery occlusion (MCAO) model was developed by Koizumi in 1986 to simulate this impactful human pathology in the rat. A modification of the MCAO method was later presented by Longa. Both techniques have been widely used to identify molecular mechanisms of brain injury resulting from ischemic stroke and potential therapeutic modalities. This relatively noninvasive method in rats has been extended to use in mice to take advantage of transgenic and knockout strains. To model focal cerebral ischemia, an intraluminal suture is advanced via the internal carotid artery to occlude the base of the MCA. Retracting the suture after a specified period of time mimics spontaneous reperfusion, but the suture can also be permanently retained. This video will be demonstrating the two major approaches for performing intraluminal MCAO procedure in mice in a stepwise fashion, as well as providing insights for potential drawbacks and pitfalls. The ischemic brain tissue will subsequently be stained by 2,3,5-triphenyltetrazolium chloride (TTC) to evaluate the extent of cerebral infarction. PMID- 21587165 TI - Evaluation of the dynamic conformal arc therapy in comparison to intensity modulated radiation therapy in prostate, brain, head-and-neck and spine tumors. AB - To evaluate dynamic conformal arc therapy (DAT) dose distribution and clinical applicability in comparison to intensity modulated radiotherapy (IMRT) in different types of tumors and locations, twelve patients with prostate cancer with no node involvement and three patients with single tumors in the pituitary, in the neck and in the thoracic spinal region treated with IMRT, were retrospectively planned with DAT using Eclipse (V8.1). The prostate cases were also planned with three-dimensional conformal radiation therapy (3DCRT). Dose distributions were evaluated through comparisons of dose-volumetric histograms and in-house IMRT protocol constraints, as well as validated via ion chamber array measurements. DAT plans for prostate showed a statistically comparable achievement of tumor conformity and dose sparing for bladder and rectum when compared to IMRT. Dose on femoral heads were similar to those achieved using 3DCRT. DAT could be planned with similar results to those obtained in IMRT for the dose constraints of the defined structures by using a 360 degrees arc for the brain lesion and several arcs including noncoplanar ones for the head-and neck and spinal tumors. Experimental validation of the calculated dose distributions via gamma analysis of composite distributions for DAT provided that more than 95% of the pixels satisfy the criteria 3 mm-3%, which was similar to that of IMRT. The average number of monitor units was approximately five times lower than IMRT. In conclusion, DAT is capable of providing conformal dose distributions to the targets accomplishing many of the IMRT dose constraints simultaneously. Experimental dose-validation accuracy, ease of planning and reduced treatment times make DAT both acceptable and attractive for clinical use. PMID- 21587166 TI - Accuracy of relocation, evaluation of geometric uncertainties and clinical target volume (CTV) to planning target volume (PTV) margin in fractionated stereotactic radiotherapy for intracranial tumors using relocatable Gill-Thomas-Cosman (GTC) frame. AB - The present study is aimed at determination of accuracy of relocation of Gill Thomas-Cosman frame during fractionated stereotactic radiotherapy. The study aims to quantitatively determine the magnitudes of error in anteroposterior, mediolateral and craniocaudal directions, and determine the margin between clinical target volume to planning target volume based on systematic and random errors. Daily relocation error was measured using depth helmet and measuring probe. Based on the measurements, translational displacements in anteroposterior (z), mediolateral (x), and craniocaudal (y) directions were calculated. Based on the displacements in x, y and z directions, systematic and random error were calculated and three-dimensional radial displacement vector was determined. Systematic and random errors were used to derive CTV to PTV margin. The errors were within +/- 2 mm in 99.2% cases in anteroposterior direction (AP), in 99.6% cases in mediolateral direction (ML), and in 97.6% cases in craniocaudal direction (CC). In AP, ML and CC directions, systematic errors were 0.56, 0.38, 0.42 mm and random errors were 1.86, 1.36 and 0.73 mm, respectively. Mean radial displacement was 1.03 mm +/- 0.34. CTV to PTV margins calculated by ICRU formula were 1.86, 1.45 and 0.93 mm; by Stroom's formula they were 2.42, 1.74 and 1.35 mm; by van Herk's formula they were 2.7, 1.93 and 1.56 mm (AP, ML and CC directions). Depth helmet with measuring probe provides a clinically viable way for assessing the relocation accuracy of GTC frame. The errors were within +/- 2 mm in all directions. Systematic and random errors were more along the anteroposterior axes. According to the ICRU formula, a margin of 2 mm around the tumor seems to be adequate. PMID- 21587167 TI - Advances in fiducial-free image-guidance for spinal radiosurgery with CyberKnife- a phantom study. AB - The image-guided CyberKnife radiosurgery system is apable of tracking spinal targets without fiducial implants. Recently, a new version of this fiducial-free image guidance modality ("enhanced Xsight spine tracking") has been introduced. We assessed the accuracy of this novel technique versus its precursor in a comparative phantom study. The CyberKnife consists of a 6 MV linac on a six-axis robot and a stereoscopic kV image guidance system. An anthropomorphic head-and neck phantom with a cervical spine section was mounted on the linac nozzle. The robotic manipulator was used to precisely move the phantom to defined positions in the CyberKnife workspace. Multiple stereoscopic images were acquired at different translational and rotational positions. The enhanced Xsight spine tracking readouts were recorded and compared to the nominal phantom position. These tests were repeated with the original Xsight spine tracking version to analyze potential differences. Enhanced Xsight spine tracking correctly reported translational offsets with an RMS error of less than 0.4 mm. Yaw and roll rotations were detected with an accuracy of 0.2 degrees , 0.25 degrees . Pitch offsets were slightly underestimated, with up to 0.3 degrees for an offset of +/ 2 degrees . Nominal X (left-right) translational offsets were partially misinterpreted as roll (0.2 degrees at a 10 mm offset). Apart from this, no correlation between rotational and translational directions was found. In comparison, the original Xsight spine tracking showed identical results for translations, but larger systematic and statistical errors for rotations. Enhanced Xsight spine tracking measurably improves precision in fiducial-free spinal radiosurgery with the CyberKnife. PMID- 21587168 TI - Interface dosimetry for electronic brachytherapy intracavitary breast balloon applicators. AB - In this study, we evaluate the attenuation of the dose due to barium-impregnation in the region between the surface of an electronic brachytherapy (EBT) balloon applicator for accelerated partial breast irradiation (APBI) and the prescription point at 1 cm depth in tissue. To perform the study, depth dose curves were calculated using a general purpose multi-particle transport code (FLUKA) for a range of balloon wall thicknesses with and without barium impregnation. Numerical data were verified with experimental readings using a parallel plate extrapolation ionization chamber for different wall thicknesses. Depth dose curves computed using both numerical and experimental methods show a 6.0% attenuation of the dose at the 1.0 cm prescription line due to the impregnation of barium in the balloon material, which agrees well with the manufacturer's specification. By applying this single attenuation factor, dose calculations throughout the entire planned volume are uniformly affected. However, at the balloon surface, attenuation on the order of 18.0% is observed. The AAPM TG-43 source data currently incorporated in commercially-available treatment planning systems do not account for the variable dose distributions attributable to balloon wall attenuation. Our results show that variable attenuation factors that may have clinical significance should be applied in order to determine near surface dose distributions when using barium impregnated balloons for intracavitary breast brachytherapy. Dose distributions at distances greater than 1 cm from the surface of the balloon appear to be accurately represented without further modification. PMID- 21587169 TI - RapidArc quality assurance through MapCHECK. AB - The purpose is to devise a patient-specific quality assurance procedure for RapidArc radiotherapy using the MapCHECK detector array. We use our existing MapCHECK system and a Solid Water phantom with an embedded ion chamber to develop a quality assurance procedure for RapidArc treatment after commissioning. The ion chamber used to measure the absolute dose is surrounded by 6 cm layers of solid water on the anterior and posterior sides. Partial arcs derived from the treatment planning system were used with MapCHECK to determine the actual shape of the dose and correct for the angular dependence. The ion chamber measurements were within 1% of the absolute doses predicted by the Eclipse treatment system. When using a partial arc from 60 degrees to 300 degrees on the MapCHECK array (gamma index <1: 3%, 3 mm, 10% threshold), we obtain a 97.52% average passing rate. A combination of ion chamber phantoms, partial arcs and the MapCHECK system can be used for quality assurance of RapidArc therapies. PMID- 21587170 TI - Dose perturbation in the radiotherapy of breast cancer patients implanted with the Magna-Site: a Monte Carlo study. AB - External beam radiation therapy (RT) is often offered to breast cancer patients after surgical mastectomy followed by breast reconstruction with silicone implants. In some cases, the RT is administered while the patient is still implanted with a temporary tissue expander including a high-density metallic port, which is expected to affect the planned dose distribution. This work uses Monte Carlo (MC) simulation in order to evaluate the aforementioned effect when the McGhan Style 133 Tissue Expander with the Magna-Site injection port is used. Simulations have been performed on a patient model built using the actual CT images of the patient for two irradiation schemes, involving two tangential photon beams of 6 MV and 18 MV respectively. MC results show that the presence of the Magna-Site within the two irradiation fields leads to an overall reduction of absorbed dose for points lying in the shadow of the metallic port (relative to each of the opposing beams). The relative reduction compared to dose results without the expander in place ranges from 7% to 13% for the 6 MV beam and is around 6% for the 18 MV photon beam. However, in the close vicinity of the metallic port, increased absorbed doses are observed, due to the increase of secondary electrons emerging from the metallic part of the insert. PMID- 21587171 TI - Target localization accuracy in a respiratory phantom using BrainLAB ExacTrac and 4DCT imaging. AB - This study evaluated the accuracy of measuring the motion of an internal target using four-dimensional computed tomography (4DCT) scanning and the BrainLAB ExacTrac X-ray imaging system. Displacements of a metal coil implanted in a commercial respiratory phantom were measured in each system and compared to the known motion. A commercial respiratory motion phantom containing a metal coil as a surrogate target was used. Phantom longitudinal motions were sinusoidal with a 4.0 second period and amplitudes ranging from 5-25 mm. We acquired 4DCT and ExacTrac images of the coil at specified respiratory phases and recorded the coordinates of the coil ends. Coil displacement relative to the 0% phase (full inhale) position were computed for the ExacTrac and 4DCT imaging systems. Coil displacements were compared to known displacements based on the phantom's sinusoidal motion. Coil length distortion due to 4DCT phase binning was compared to the known physical length of the coil (31 mm). The maximum localization error for both coil endpoints for all motion settings was 3.5 mm for the 4DCT and 0.8 mm for the ExacTrac gating system. Coil length errors measured on the 4DCT were less than 0.8 mm at end inhale/exhale phases, but up to 8.3 mm at mid-inhalation phases at the largest motion amplitude (25 mm). Due to the fast image acquisition time (100 ms), no coil distortion was observable in the ExacTrac system. 4DCT showed problems imaging the coil during mid-respiratory phases of higher velocity (phases 20%-30% and 70%-80%) due to distortion caused by residual motion within the 4DCT phase bin. The ExacTrac imaging system was able to accurately localize the coil in the respiratory phantom over all phases of respiration. For our clinic, where end-respiration phases from 4DCT may be used for treatment planning calculations, the ExacTrac system is used to measure internal target motion. With the ExacTrac system, planning target size and motion uncertainties are minimized, potentially reducing internal target volume margins in gated radiotherapy. PMID- 21587172 TI - Dosimetric characterization of whole brain radiotherapy of pediatric patients using modulated proton beams. AB - This study was designed to investigate dosimetric variations between proton plans with (PPW) and without (PPWO), a compensator for whole brain radiotherapy (WBRT). The retrospective study on PPW and PPWO in Eclipse and XiO systems and photon plans (XP) using controlled segments in Pinnacle system was performed on nine pediatric patients for craniospinal irradiations. DVHs and derived metrics, such as the homogeneity index (HI), the doses to 2% (D(2%)) and 5% (D(5%)) volumes, and mean dose (D(mean)) of the whole brain (i.e., PTV), and the organs at risk (OARs) such as lens and skull, were obtained. The PPW plans from both Eclipse and XiO systems uncovered the following advantages: (1) encompassing a cribriform plate area with the 100% isodose line was better than either PPWO or XP, according to calculated two-dimensional distributions of one patient; (2) the mean value of D(5%) for lens was reduced to 23.6% of D(P) from 54.1% for PPWO or 41.6% for XP; and (3) the mean value of D(mean) for skull was reduced to 94.8% of D(P) from either 98.4% for PPWO or 98.3% for XP. However, the PPW plans also exposed several disadvantages including: (1) the HI of PTV increased to 7.7 from 4.7 for PPWO or 3.7 for XP; (2) D(2%) to PTV increased to 108.8% of D(P) from 104.8% for PPWO or 105.1% for XP; and (3) D(5%) to the skull increased to 104.9% of D(P) from 101.6% for PPWO or 103.4% of for XP. One-half of the observed variations were caused by different penumbra on lateral profiles and distal fall off depth doses of protons in Eclipse and XiO. Because the utilization on the sharp proton distal fall-off was limited for WBRT, the difference between PPW and PPWO or XP indicated no distinguishable improvement by using a compensator in proton plans. PMID- 21587173 TI - An image-guided technique for planning and verification of supine craniospinal irradiation. AB - We present a technique for planning and verification of craniospinal treatment with the patient in the supine position. Treatment delivery and verification is streamlined through the use of modern imaging techniques. Treatments use two lateral brain fields abutted to a single or pair of posterior spine fields. Treatment delivery is simplified by aligning all isocenters in the anterior posterior and lateral directions. Patient positioning is accomplished via on board kV imaging. Verification of field shape and junctions is accomplished with BB placement and MV portal imaging. Daily treatment is simplified by using only longitundinal couch shifts, which are recorded in the patient chart and RV database. The technique is simple to implement in a clinic that is already using a similar beam arrangement with the patient prone. It requires no additional devices to be fabricated (for immobilization or QA), and it takes advantage of all the existing elements of a modern linac. PMID- 21587174 TI - A methodology for direct quantification of over-ranging length in helical computed tomography with real-time dosimetry. AB - In helical computed tomography (CT), reconstruction information from volumes adjacent to the clinical volume of interest (VOI) is required for proper reconstruction. Previous studies have relied upon either operator console readings or indirect extrapolation of measurements in order to determine the over ranging length of a scan. This paper presents a methodology for the direct quantification of over-ranging dose contributions using real-time dosimetry. A Siemens SOMATOM Sensation 16 multislice helical CT scanner is used with a novel real-time "point" fiber-optic dosimeter system with 10 ms temporal resolution to measure over-ranging length, which is also expressed in dose-length-product (DLP). Film was used to benchmark the exact length of over-ranging. Over-ranging length varied from 4.38 cm at pitch of 0.5 to 6.72 cm at a pitch of 1.5, which corresponds to DLP of 131 to 202 mGy-cm. The dose-extrapolation method of Van der Molen et al. yielded results within 3%, while the console reading method of Tzedakis et al. yielded consistently larger over-ranging lengths. From film measurements, it was determined that Tzedakis et al. overestimated over-ranging lengths by one-half of beam collimation width. Over-ranging length measured as a function of reconstruction slice thicknesses produced two linear regions similar to previous publications. Over-ranging is quantified with both absolute length and DLP, which contributes about 60 mGy-cm or about 10% of DLP for a routine abdominal scan. This paper presents a direct physical measurement of over-ranging length within 10% of previous methodologies. Current uncertainties are less than 1%, in comparison with 5% in other methodologies. Clinical implantation can be increased by using only one dosimeter if codependence with console readings is acceptable, with an uncertainty of 1.1% This methodology will be applied to different vendors, models, and postprocessing methods--which have been shown to produce over-ranging lengths differing by 125%. PMID- 21587175 TI - An analysis of the regulatory program of quality audits in radiotherapy in Brazil from 1995 to 2007. AB - The Brazilian Institute of Radiation Protection and Dosimetry (IRD/CNEN) carried out quality assurance regulatory audits in Brazilian radiotherapy facilities from 1995 to 2007. In this work, the set of data collected from 195 radiotherapy facilities that use high-energy photon beams are analyzed. They include results from audits in linear electron accelerators and/or Co-60 units. The inspectors of IRD/CNEN performed the dosimetry of high-energy radiotherapy photon beams according to the IAEA dosimetry protocols TRS 277 and TRS 398, and the values of measurements were compared to stated values. Other aspects of radiological protection were checked during on-site audits such as calibration certification of clinical dosimeters and portable monitors, existence and use of check source, use of barometer and thermometer, individual dose registry and training of staff. It was verified that no check source was available in 38% of the visited facilities; the training of personnel was not adequate in 9% of the facilities and the registry of accumulated individual doses was not being done in 6% of the facilities. Measurements of absorbed dose have indicated deviations in the range +/- 3% for 67.6% of the cobalt-60 units and 79.6% of medical linear accelerators; 18.5% of Co-60 irradiators and 9.6% of linear accelerators presented deviations in the range 3% < delta <= 5%. Finally, 13.9% of Co-60 facilities and 10.8% of linear accelerator facilities presented dosimetry deviations above 5%. The effort in dosimetric quality control performed by IRD/CNEN audits has yielded positive changes that make radiation treatment facilities more reliable. PMID- 21587176 TI - MRI-based polymer gel dosimetry for validating plans with multiple matrices in Gamma Knife stereotactic radiosurgery. AB - One of treatment planning techniques with Leksell GammaPlan (LGP) for Gamma Knife stereotactic radiosurgery (GKSRS) uses multiple matrices with multiple dose prescriptions. Computational complexity increases when shots are placed in multiple matrices with different grid sizes. Hence, the experimental validation of LGP calculated dose distributions is needed for those cases. For the current study, we used BANG3 polymer gel contained in a head-sized glass bottle to simulate the entire treatment process of GKSRS. A treatment plan with three 18 mm shots and one 8 mm shot in separate matrices was created with LGP. The prescribed maximum dose was 8 Gy to three shots and 16 Gy to one of the 18 mm shots. The 3D dose distribution recorded in the gel dosimeter was read using a Siemens 3T MRI scanner. The scanning parameters of a CPMG pulse sequence with 32 equidistant echoes were as follows: TR = 7 s, echo step = 13.6 ms, field-of-view = 256 mm * 256 mm, and pixel size = 1 mm * 1 mm. Interleaved acquisition mode was used to obtain 15 to 45 2-mm-thick slices. Using a calibration relationship between absorbed dose and the spin-spin relaxation rate (R2), we converted R2 images to dose images. MATLAB-based in-house programs were used for R2 estimation and dose comparison. Gamma-index analysis for the 3D data showed gamma values less than unity for 86% of the voxels. Through this study we accomplished the first application of polymer gel dosimetry for a true comparison between measured 3D dose distributions and LGP calculations for plans using multiple matrices for multiple targets. PMID- 21587177 TI - Applications of IMAT in cervical esophageal cancer radiotherapy: a comparison with fixed-field IMRT in dosimetry and implementation. AB - This study aimed to compare fixed-field, intensity-modulated radiotherapy (f IMRT) with intensity-modulated arc therapy (IMAT) treatment plans in dosimetry and practical application for cervical esophageal carcinoma. For ten cervical esophageal carcinoma cases, f-IMRT plan (seven fixed-fields) and two IMAT plans, namely RA (coplanar 360 degrees arcs) and RAx (coplanar 360 degrees arcs without sectors from 80 degrees to 110 degrees , and 250 degrees to 280 degrees ), were generated. DVHs were adopted for the statistics of above parameters, as well as conformal index (CI), homogeneity index (HI), dose-volumetric parameters of normal tissues, total accelerator output MUs and total treatment time. There were differences between RAx and f-IMRT, as well as RA in PTV parameters such as HI, V(95%) and V(110%), but not in CI. RAx reduced lung V5 from (50.9% +/- 9.8% in f-IMRT and (51.4% +/- 10.8% in RA to (49.3% +/- 10.4% in RAx (p < 0.05). However, lung V30, V40, V50 and MLD increased in RAx. There was no difference in the mean heart dose in three plans. Total MU was reduced from 1174.8 +/- 144.6 in f-IMRT to 803.8 +/- 122.2 in RA and 736.2 +/- 186.9 in RAx (p < 0.05). Compared with f-IMRT, IMAT reduced low dose volumes of lung and total MU on the basis of meeting clinical requirements. PMID- 21587178 TI - Evaluation of a new VMAT QA device, or the "X" and "O" array geometries. AB - We introduce a logical process of three distinct phases to begin the evaluation of a new 3D dosimetry array. The array under investigation is a hollow cylinder phantom with diode detectors fixed in a helical shell forming an "O" axial detector cross section (ArcCHECK), with comparisons drawn to a previously studied 3D array with diodes fixed in two crossing planes forming an "X" axial cross section (Delta4). Phase I testing of the ArcCHECK establishes: robust relative calibration (response equalization) of the individual detectors, minor field size dependency of response not present in a 2D predecessor, and uncorrected angular response dependence in the axial plane. Phase II testing reveals vast differences between the two devices when studying fixed-width full circle arcs. These differences are primarily due to arc discretization by the TPS that produces low passing rates for the peripheral detectors of the ArcCHECK, but high passing rates for the Delta4. Similar, although less pronounced, effects are seen for the test VMAT plans modeled after the AAPM TG119 report. The very different 3D detector locations of the two devices, along with the knock-on effect of different percent normalization strategies, prove that the analysis results from the devices are distinct and noninterchangeable; they are truly measuring different things. The value of what each device measures, namely their correlation with--or ability to predict--clinically relevant errors in calculation and/or delivery of dose is the subject of future Phase III work. PMID- 21587179 TI - A quality assurance phantom for electronic portal imaging devices. AB - Electronic portal imaging device (EPID) plays an important role in radiation therapy portal imaging, geometric and dosimetric verification. Consistent image quality and stable radiation response is necessary for proper utilization that requires routine quality assurance (QA). A commercial 'EPID QC' phantom weighing 3.8 kg with a dimension of 25 * 25 * 4.8 cm3 is used for EPID QA. This device has five essential tools to measure the geometric accuracy, signal-to-noise ratio (SNR), dose linearity, and the low- and the high-contrast resolutions. It is aligned with beam divergence to measure the imaging and geometric parameters in both X and Y directions, and can be used as a baseline check for routine QA. The low-contrast tool consists of a series of holes with various diameters and depths in an aluminum slab, very similar to the Las Vegas phantom. The high-resolution contrast tool provides the modulation transfer function (MTF) in both the x- and y-dimensions to measure the focal spot of linear accelerator that is important for imaging and small field dosimetry. The device is tested in different institutions with various amorphous silicon imagers including Elekta, Siemens and Varian units. Images of the QA phantom were acquired at 95.2 cm source-skin distance (SSD) in the range 1-15MU for a 26 * 26 cm2 field and phantom surface is set normal to the beam direction when gantry is at 0 degrees and 90 degrees . The epidSoft is a software program provided with the EPID QA phantom for analysis of the data. The preliminary results using the phantom on the tested EPID showed very good low-contrast resolution and high resolution, and an MTF (0.5) in the range of 0.3-0.4 lp/mm. All imagers also exhibit satisfactory geometric accuracy, dose linearity and SNR, and are independent of MU and spatial orientations. The epidSoft maintains an image analysis record and provides a graph of the temporal variations in imaging parameters. In conclusion, this device is simple to use and provides testing on basic and advanced imaging parameters for daily QA on any imager used in clinical practices. PMID- 21587180 TI - Can Hyperpolarized Helium MRI add to radiation planning and follow-up in lung cancer? AB - Locally advanced non-small-cell lung cancer (NSCLC) is a common disease with a low overall survival even with aggressive treatments. Standard imaging (CT and PET/CT) provide no information about normal lung function. We therefore, sought to pilot HeMRI in patients with non-small-cell lung cancer before and after definitive radiotherapy (RT). Five patients with NSCLC receiving RT were enrolled on a prospective IRB approved study. Patients underwent CT, FDG-PET and HeMRI before and (within 10 days) following RT. All images (CT, FDG-PET and HeMRI) were co-registered. The CT and PET GTVs were contoured, as well as the ventilation defects on HeMRI caused by the tumor. Patients also underwent pulmonary function tests (PFTs). Correlations between the images and PFTs were evaluated by linear regression. CT and FDG-PET tumor volumes were highly correlated (r2 = 0.91 before treatment and 0.99 following RT). There was less correlation between HeMRI and CT or PET (r2 = 0.67 (CT) and 0.38 (PET)) prior to treatment and 0.27 following RT). However, HeMRI volumes correlated very well with FEV1, both prior to and following RT. (r2 = 0.89 and 0.83, respectively). 3Helium MRI scanning is feasible in NSCLC before and after treatment. HeMRI provides important functional information in addition to CT and CT/PET scanning. PMID- 21587181 TI - Quality assurance using a photodiode array. AB - Improved treatment techniques in radiation therapy provide incentive to reduce treatment margins, thereby increasing the necessity for more accurate geometrical setup of the linear accelerator and accompanying components. In the present paper, we describe the development of a novel device that enables precise and automated measurement of geometric parameters for the purpose of improving initial setup accuracy, and for standardizing repeated quality control activities. The device consists of a silicon photodiode array, an evaluation board, a data acquisition card, and a laptop. Measurements that demonstrate the utility of the device are also presented. Using the device, we show that the radiation light field congruence for both 6 and 15 MV beams is within 1.3 mm. The maximum measured disagreement between radiation field edges and light field edges was 1.290 +/- 0.002 mm, while the smallest disagreement between the light field and radiation field edge was 0.016 +/- 0.003 mm. Because measurements are automated, ambiguities resulting from interobserver variability are removed, greatly improving the reproducibility of measurements across observers. We expect the device to find use in consistency measurements on linear accelerators used for stereotactic radiosurgery, during the commissioning of new linear accelerators, or as an alternative to film or other commercially available devices for performing monthly or annual quality control checks. PMID- 21587182 TI - Influence of reconstruction settings on the performance of adaptive thresholding algorithms for FDG-PET image segmentation in radiotherapy planning. AB - The purpose of this study was to analyze the behavior of a contouring algorithm for PET images based on adaptive thresholding depending on lesions size and target-to-background (TB) ratio under different conditions of image reconstruction parameters. Based on this analysis, the image reconstruction scheme able to maximize the goodness of fit of the thresholding algorithm has been selected. A phantom study employing spherical targets was designed to determine slice-specific threshold (TS) levels which produce accurate cross sectional areas. A wide range of TB ratio was investigated. Multiple regression methods were used to fit the data and to construct algorithms depending both on target cross-sectional area and TB ratio, using various reconstruction schemes employing a wide range of iteration number and amount of postfiltering Gaussian smoothing. Analysis of covariance was used to test the influence of iteration number and smoothing on threshold determination. The degree of convergence of ordered-subset expectation maximization (OSEM) algorithms does not influence TS determination. Among these approaches, the OSEM at two iterations and eight subsets with a 6-8 mm post-reconstruction Gaussian three-dimensional filter provided the best fit with a coefficient of determination R2 = 0.90 for cross sectional areas <= 133 mm2 and R2 = 0.95 for cross-sectional areas > 133 mm2. The amount of post-reconstruction smoothing has been directly incorporated in the adaptive thresholding algorithms. The feasibility of the method was tested in two patients with lymph node FDG accumulation and in five patients using the bladder to mimic an anatomical structure of large size and uniform uptake, with satisfactory results. Slice-specific adaptive thresholding algorithms look promising as a reproducible method for delineating PET target volumes with good accuracy. PMID- 21587183 TI - Quality assurance of electron and photon beam energy using the BQ-CHECK phantom. AB - The BQ-CHECK phantom (PTW Freiburg, Germany) has been designed to be used with a 2D ion chamber array to facilitate the quality assurance (QA) of electron and photon beam qualities (BQ). The BQ-CHECK phantom has three wedges covering the diagonal axes of the beam: two opposed aluminum wedges used to measure electron energy and a single copper wedge used to measure photon energy. The purpose of this work was to assess the suitability of the BQ-CHECK phantom for use in a routine QA program. A range of percentage depth dose (PDD) curves for two photon beams and four electron beams were measured using a MP3 plotting tank (PTW Freiburg). These beams were used to irradiate a STARCHECK array (PTW Freiburg) with and without the BQ-CHECK phantom on top of the array. For photons, the ratio of the signals from two chambers underneath the copper wedge was used as an effective TPR measurement (TPR(eff)) and, for electrons, the full width at half maximum of the profile (E(FWHM)) underneath the aluminum wedges was used as an electron energy constancy measurement. PDD measurements were compared with TPR(eff) and E(FWHM) to assess the sensitivity of the BQ-CHECK phantom. The clinical tolerances of TPReff were determined for 6 MV (0.634-0.649), and 10MV (0.683-0.692). For electrons, the clinical tolerances of EFWHM were determined for 6 MeV (94.8-103.4 mm), 8 MeV (105.5-114.0 mm), 10 MeV (125.4-133.9 mm) and 12 MeV (138.8-147.3 mm).Electron and photon energy metrics are presented which demonstrate that the BQ-CHECK phantom could be used to form part of an efficient routine monthly QA program. Acceptable beam quality limits for various nominal beam energies were established and at these limits, modified profiles were acquired using the STARCHECK array. From the modified profiles, E(FWHM) and TPR(eff) were determined for the electron and photon beams, respectively. It was demonstrated that both E(FWHM) and the TPR(eff) have a linear relationship with conventional beam quality metrics. PMID- 21587184 TI - Comparison of four commercial devices for RapidArc and sliding window IMRT QA. AB - For intensity-modulated radiation therapy, evaluation of the measured dose against the treatment planning calculated dose is essential in the context of patient-specific quality assurance. The complexity of volumetric arc radiotherapy delivery attributed to its dynamic and synchronization nature require new methods and potentially new tools for the quality assurance of such techniques. In the present study, we evaluated and compared the dosimetric performance of EDR2 film and three other commercially available quality assurance devices: IBA I'MatriXX array, PTW Seven29 array and the Delta4 array. The evaluation of these dosimetric systems was performed for RapidArc and IMRT deliveries using a Varian NovalisTX linear accelerator. The plans were generated using the Varian Eclipse treatment planning system. Our results showed that all four QA techniques yield equivalent results. All patient QAs passed our institutional clinical criteria of gamma index based on a 3% dose difference and 3 mm distance to agreement. In addition, the Bland-Altman analysis was performed which showed that all the calculated gamma values of all three QA devices were within 5% from those of the film. The results showed that the four QA systems used in this patient-specific IMRT QA analysis are equivalent. We concluded that the dosimetric systems under investigation can be used interchangeably for routine patient specific QA. PMID- 21587186 TI - Computed tomography dose index and dose length product for cone-beam CT: Monte Carlo simulations. AB - Dosimetry in kilovoltage cone beam computed tomography (CBCT) is a challenge due to the limitation of physical measurements. To address this, we used a Monte Carlo (MC) method to estimate the CT dose index (CTDI) and the dose length product (DLP) for a commercial CBCT system. As Dixon and Boone showed that CTDI concept can be applicable to both CBCT and conventional CT, we evaluated weighted CT dose index (CTDI(w)) and DLP for a commercial CBCT system. Two extended CT phantoms were created in our BEAMnrc/EGSnrc MC system. Before the simulations, the beam collimation of a Varian On-Board Imager (OBI) system was measured with radiochromic films (model: XR-QA). The MC model of the OBI X-ray tube, validated in a previous study, was used to acquire the phase space files of the full-fan and half-fan cone beams. Then, DOSXYZnrc user code simulated a total of 20 CBCT scans for the nominal beam widths from 1 cm to 10 cm. After the simulations, CBCT dose profiles at center and peripheral locations were extracted and integrated (dose profile integral, DPI) to calculate the CTDI per each beam width. The weighted cone-beam CTDI (CTDI(w,l)) was calculated from DPI values and mean CTDI(w,l) (CTDI(w,l)) and DLP were derived. We also evaluated the differences of CTDI(w) values between MC simulations and point dose measurements using standard CT phantoms. In results, it was found that CTDI(w,600) was 8.74 +/- 0.01 cGy for head and CTDI(w,900) was 4.26 +/- 0.01 cGy for body scan. The DLP was found to be proportional to the beam collimation. We also found that the point dose measurements with standard CT phantoms can estimate the CTDI within 3% difference compared to the full integrated CTDI from the MC method. This study showed the usability of CTDI as a dose index and DLP as a total dose descriptor in CBCT scans. PMID- 21587185 TI - Dose tolerance limits and dose volume histogram evaluation for stereotactic body radiotherapy. AB - Almost 20 years ago, Emami et al. presented a comprehensive set of dose tolerance limits for normal tissue organs to therapeutic radiation, which has proven essential to the field of radiation oncology. The paradigm of stereotactic body radiotherapy (SBRT) has dramatically different dosing schemes but, to date, there has still been no comprehensive set of SBRT normal organ dose tolerance limits. As an initial step toward that goal, we performed an extensive review of the literature to compare dose limits utilized and reported in existing publications. The impact on dose tolerance limits of some key aspects of the methods and materials of the various authors is discussed. We have organized a table of 500 dose tolerance limits of normal structures for SBRT. We still observed several dose limits that are unknown or not validated. Data for SBRT dose tolerance limits are still preliminary and further clinical trials and validation are required. This manuscript presents an extensive collection of normal organ dose tolerance limits to facilitate both clinical application and further research. PMID- 21587187 TI - Commissioning compensator-based IMRT on the Pinnacle treatment planning system. AB - We present a systematic approach to commissioning of the compensator-based IMRT in Pinnacle treatment planning system for commercially manufactured brass compensators. Some model parameters for the beams modulated by the variable thickness compensators can only be associated with a single compensator thickness. To intelligently choose that thickness for beam modeling, we empirically determined the most probable filter thickness occurring within the modulated portion of the compensators typically used in clinics. We demonstrated that a set of relative output factors measured with the brass slab of most probable thickness (2 cm) differs from the traditionally used open field set, and leads to improved agreement between measurements and calculations, particularly for the larger field sizes. By iteratively adjusting the modifier scatter factor and filter density, the calculated effective attenuation of the flat filters was brought to within 2% of the ion chamber measurement for the clinically-relevant range of filter thicknesses, depths and filed sizes. Beam hardening representation in Pinnacle provides for adequate depth dose modeling beyond the depth of about 5 cm. Disagreement at shallower depth for the large field sizes is likely due to the algorithm's inability to account for the low-energy scattered photons generated in the filter. The average ion chamber point dose error at isocenter for ten clinical compensator-based IMRT plans was under 1%. A biplanar 3D diode dosimeter was calibrated and validated for use with the compensators. The average gamma analysis (3%/3 mm) passing rate for ten IMRT plans was 98.9% +/ 1.0%. The device is particularly attractive because it easily generates dose comparisons at both the fraction and beam levels. Overlaying dose profiles for individual beams would easily uncover any errors in compensator orientation. PMID- 21587188 TI - Clinical usefulness of a newly developed body surface navigation and monitoring system in radiotherapy. AB - In radiotherapy, setup precision has great influence on the therapeutic effect. In addition, body movements during the irradiation and physical alternations during the treatment period might cause deviation from the planned irradiation dosage distribution. Both of these factors could undesirably influence the dose absorbed by the target. In order to solve these problems, we developed the "body surface navigation and monitoring system" (hereafter referred to as "Navi system"). The purpose of this study is to review the precision of the Navi-system as well as its usefulness in clinical radiotherapy. The Navi-system consists of a LED projector, a CCD camera, and a personal computer (PC). The LED projector projects 19 stripes on the patient's body and the CCD camera captures these stripes. The processed image of these stripes in color can be displayed on the PC monitor along with the patient's body surface image, and the digitalized results can be also displayed on the same monitor. The Navi-system calculates the height of the body contour and the transverse height centroid for the 19 levels and compares them with the reference data to display the results on the monitor on a real-time basis. These results are always replaced with new data after they are used for display; so, if the results need to be recorded, such recording commands should be given to the computer. 1) Evaluating the accuracy of the body surface height measurement: from the relationship between actual height changes and calculated height changes with torso surface by the Navi-system, for the height changes from 0.0 mm to +/- 10.0mm, the changes show the underestimation of 1.0 1.5 mm and for +/- 11.0mm to +/- 20.0 mm, the underestimation of 1.5-3.0 mm. 2) Evaluating the accuracy of the transverse height centroid measurement: displacement of the inclined flat panel to the right by 5.0 mm, 10.0 mm, 15.0 mm and 20.0 mm showed the transverse height centroid calculated by the Navi-system for 0.024 +/- 0.007 line/pair (mean +/- SD), 0.045 +/- 0.006 line/pair, 0.066 +/- 0.006 line/pair and 0.089 +/- 0.007 line/pair, respectively. Also, displacement of the inclined flat panel to the left by 5.0 mm, 10.0 mm, 15.0mm and 20.0 mm showed the transverse height centroid calculated by the Navi-system for 0.015 +/- 0.007 line/pair (mean +/- SD), 0.034 +/- 0.007 line/pair, 0.053 +/- 0.008 line/pair and 0.071 +/- 0.007 line/pair, respectively. 3) Clinical usefulness of the Navi-system: on using the Navi-system, the frequency of radiotherapy replanning increased from 5.2% to 21.8%, especially in pelvic or abdominal irradiation. We developed a new navigation system for the purpose of compensating for the weakness of MVCT, CBCT and other systems, as well as for having a screening function. This Navi-system can monitor the patient continuously and measure change in height of the patient's body surface from the basic plane, in real time. It can also show the results both qualitatively and quantitatively on the PC monitor. PMID- 21587189 TI - An algorithm to extract three-dimensional motion by marker tracking in the kV projections from an on-board imager: four-dimensional cone-beam CT and tumor tracking implications. AB - The purpose of this work is to extract three-dimensional (3D) motion trajectories of internal implanted and external skin-attached markers from kV cone-beam projections and reduce image artifact from patient motion in cone-beam computed tomography (CBCT) from on-board imager. Cone beam radiographic projections were acquired for a mobile phantom and liver patients with internal implanted and external skin-attached markers. An algorithm was developed to automatically find the positions of the markers in the projections. It uses normalized cross correlation between a template image of a metal seed marker and the projections to find the marker position. From these positions and time-tagged angular views, the marker 3D motion trajectory was obtained over a time interval of nearly one minute, which is the time required for scanning. This marker trajectory was used to remap the pixels of the projections to eliminate motion. Then, the motion corrected projections were used to reconstruct CBCT. An algorithm was developed to extract 3D motion trajectories of internal and external markers from cone-beam projections using a kV monoscopic on-board imager. This algorithm was tested and validated using a mobile phantom and patients with liver masses that had radio markers implanted in the tumor and attached to the skin. The extracted motion trajectories were used to investigate motion correlation between internal and external markers in liver patients. Image artifacts from respiratory motion were reduced in CBCT reconstructed from cone-beam projections that were preprocessed to remove motion shifts obtained from marker tracking. With this method, motion related image artifacts such as blurring and spatial distortion were reduced, and contrast and position resolutions were improved significantly in CBCT reconstructed from motion-corrected projections. Furthermore, correlated internal and external marker 3D-motion tracks obtained from the kV projections might be useful for 4DCBCT, beam gating and tumor motion monitoring or tracking. PMID- 21587190 TI - Role of adaptive radiation therapy for pediatric patients with diffuse pontine glioma. AB - We investigate the role of adaptive radiation therapy in pediatric patients with diffuse pontine glioma and the impact of steroid-related weight gain on treatment parameters utilizing cone-beam CT. Fifteen patients with diffuse pontine glioma were treated with three-dimensional conformal radiation therapy and enrolled on a daily localization protocol. The median age was 6 years (range: 2-13 years). Patient charts were examined to obtain the prescribed daily dose of dexamethasone and weight. The original treatment plan was recalculated based on the data obtained from the daily cone-beam CT. The changes in target and critical structure doses were calculated using gEUD. Correlations between prescribed dexamethasone, weight gain, source-to-skin distance (SSD) changes and dosimetric changes were investigated. Eleven of the 15 patients gained weight during radiation therapy, with an average gain of 2.2 kg (8.0%). The mean gEUD decreased was 0.57 Gy (range: 0.24-1.4 Gy) for the PTV, and the mean gEUD increase for critical structures was 1.14%. No strong correlations between prescribed dexamethasone doses, weight gain and dosimetric changes were found. Change in SSD vs. dose to PTV was correlated (R2 = 0.51). Weight gain and changes to the external surface are apparent in these patients; however, the dosimetric changes to the target and critical structures were small and in most cases did not warrant an adaptive plan. The potential exists for a decrease in target dose in these patients; therefore, they should be monitored to assess for replanning when necessary. PMID- 21587191 TI - Proton dose distribution measurements using a MOSFET detector with a simple dose weighted correction method for LET effects. AB - We experimentally evaluated the proton beam dose reproducibility, sensitivity, angular dependence and depth-dose relationships for a new Metal Oxide Semiconductor Field Effect Transistor (MOSFET) detector. The detector was fabricated with a thinner oxide layer and was operated at high-bias voltages. In order to accurately measure dose distributions, we developed a practical method for correcting the MOSFET response to proton beams. The detector was tested by examining lateral dose profiles formed by protons passing through an L-shaped bolus. The dose reproducibility, angular dependence and depth-dose response were evaluated using a 190 MeV proton beam. Depth-output curves produced using the MOSFET detectors were compared with results obtained using an ionization chamber (IC). Since accurate measurements of proton dose distribution require correction for LET effects, we developed a simple dose-weighted correction method. The correction factors were determined as a function of proton penetration depth, or residual range. The residual proton range at each measurement point was calculated using the pencil beam algorithm. Lateral measurements in a phantom were obtained for pristine and SOBP beams. The reproducibility of the MOSFET detector was within 2%, and the angular dependence was less than 9%. The detector exhibited a good response at the Bragg peak (0.74 relative to the IC detector). For dose distributions resulting from protons passing through an L-shaped bolus, the corrected MOSFET dose agreed well with the IC results. Absolute proton dosimetry can be performed using MOSFET detectors to a precision of about 3% (1 sigma). A thinner oxide layer thickness improved the LET in proton dosimetry. By employing correction methods for LET dependence, it is possible to measure absolute proton dose using MOSFET detectors. PMID- 21587193 TI - Evaluation of stereotactic radiosurgery conformity indices for 170 target volumes in patients with brain metastases. AB - A database of clinically approved stereotactic radiosurgery treatment plans was created. One hundred and seventy targets in the database were then retrospectively evaluated using conformity indices suggested by RTOG, SALT-Lomax and Paddick. Relationships between the three alternative conformity indices were determined. The Paddick index combines the information provided by the RTOG and SALT-Lomax indices into a single index. The variation in the geometric overlap ratio, which is related to the SALT-Lomax index, was found to be not clinically relevant for our cohort of patients, and thus the Paddick and RTOG indices can be directly related. It was found that access to a dose volume histogram or dose distribution for a treatment plan renders the RTOG conformity index sufficient for plan quality evaluation. PMID- 21587192 TI - An image quality comparison study between XVI and OBI CBCT systems. AB - The purpose of this study is to evaluate and compare image quality characteristics for two commonly used and commercially available CBCT systems: the X-ray Volumetric Imager and the On-Board Imager. A commonly used CATPHAN image quality phantom was used to measure various image quality parameters, namely, pixel value stability and accuracy, noise, contrast to noise ratio (CNR), high-contrast resolution, low contrast resolution and image uniformity. For the XVI unit, we evaluated the image quality for four manufacturer-supplied protocols as a function of mAs. For the OBI unit, we did the same for the full-fan and half fan scanning modes, which were respectively used with the full bow-tie and half bow-tie filters. For XVI, the mean pixel values of regions of interest were found to generally decrease with increasing mAs for all protocols, while they were relatively stable with mAs for OBI. Noise was slightly lower on XVI and was seen to decrease with increasing mAs, while CNR increased with mAs for both systems. For XVI and OBI, the high-contrast resolution was approximately limited by the pixel resolution of the reconstructed image. On OBI images, up to 6 and 5 discs of 1% and 0.5% contrast, respectively, were visible for a high mAs setting using the full-fan mode, while none of the discs were clearly visible on the XVI images for various mAs settings when the medium resolution reconstruction was used. In conclusion, image quality parameters for XVI and OBI have been quantified and compared for clinical protocols under various mAs settings. These results need to be viewed in the context of a recent study that reported the dose-mAs relationship for the two systems and found that OBI generally delivered higher imaging doses than XVI. PMID- 21587194 TI - Fast volumetric registration method for tumor follow-up in pulmonary CT exams. AB - An oncological patient may go through several tomographic acquisitions during a period of time, needing an appropriate registration. We propose an automatic volumetric intrapatient registration method for tumor follow-up in pulmonary CT exams. The performance of our method is evaluated and compared with other registration methods based on optimization techniques. We also compared the metrics behavior to inspect which metric is more sensitive to changes due to the presence of lung tumors. PMID- 21587195 TI - Forward planned intensity modulated radiotherapy (IMRT) for whole breast postoperative radiotherapy. Is it useful? When? AB - The purpose was to compare the dosimetric results observed in 201 breast cancer patients submitted to tangential forward intensity-modulated radiation therapy (IMRT) with those observed in 131 patients treated with a standard wedged 3D technique for postoperative treatment of whole breast, according to breast size and supraclavicular node irradiation. Following dosimetric parameters were used for the comparison: D(max), D(min), D(mean), V(95%) and V(107%) for the irradiated volume; D(max), D(mean), V(80%) and V(95%) for the ipsilateral lung; D(max), D(mean), V(80%) and V(95%) for the heart. Stratification was made according to breast size and supraclavicular (SCV) nodal irradiation. As respect to irradiated volume, a significant reduction of V(107%) (mean values: 7.0 +/- 6.6 versus 2.4 +/- 3.7, p < 0.001) and D(max) (mean % values: 111.2 +/- 2.7 versus 107.7 +/- 6.3, p < 0.001), and an increase of D(min) (mean % values: 65.0 +/- 17.4 versus 74.9 +/- 12.9, p < 0.001) were observed with forward IMRT. The homogeneity of dose distribution to target volume significantly improved with forward IMRT in all patient groups, irrespective of breast size or supraclavicular nodal irradiation. When patients treated with supraclavicular nodal irradiation were excluded from the analysis, forward IMRT slightly reduced V(80%) (mean values: 3.7 +/- 2.6 versus 3.0 +/- 2.4, p = 0.03) and V(95%) (mean values 1.9 +/- 1.8 versus 1.2%+/- 1.5; p = 0.001) of the ipsilateral lung. The dose to the heart tended to be lower with IMRT but this difference was not statistically significant. Tangential forward IMRT in postoperative treatment of whole breast improved dosimetric parameters in terms of homogeneity of dose distribution to the target in a large sample of patients, independent of breast size or supraclavicular nodal irradiation. Lung irradiation was slightly reduced in patients not undergoing to supraclavicular irradiation. PMID- 21587196 TI - Feasibility of using respiratory correlated mega voltage cone beam computed tomography to measure tumor motion. AB - The purpose of this study was to test the feasibility of using respiratory correlated mega voltage cone-beam computed tomography (MVCBCT), taken during patient localization, to quantify the size and motion of lung tumors. An imaging phantom was constructed of a basswood frame embedded with six different-sized spherical pieces of paraffin wax. The Quasar respiratory motion phantom was programmed to move the imaging phantom using typical respiratory motion. The moving imaging phantom was scanned using various MVCBCT imaging parameters, including two beam line types, two protocols with different ranges of rotation and different imaging doses. A static phantom was also imaged as a control. For all the 3D volumetric images, the contours of the six spherical inserts were measured manually. Compared with the nominal sphere diameter, the average relative error in the size of the respiratory correlated MVCBCT spheres ranged from 5.3% to 12.6% for the four largest spheres, ranging in size from 3.6 cc to 29 cc. Larger errors were recorded for the two smallest inserts. The average relative error in motion was 5.1% smaller than the programmed amplitude of 3.0 cm. We are able to conclude that it is feasible to use respiratory correlated MVCBCT to quantify tumor motion for lung cancer patients. PMID- 21587197 TI - Editorial: Patient safety revisited. PMID- 21587198 TI - Guest editorial: Can we really reduce error rates? PMID- 21587199 TI - Advances in physical activity monitoring and lifestyle interventions in obesity: a review. AB - Obesity represents a strong risk factor for developing chronic diseases. Strategies for disease prevention often promote lifestyle changes encouraging participation in physical activity. However, determining what amount of physical activity is necessary for achieving specific health benefits has been hampered by the lack of accurate instruments for monitoring physical activity and the related physiological outcomes. This review aims at presenting recent advances in activity-monitoring technology and their application to support interventions for health promotion. Activity monitors have evolved from step counters and measuring devices of physical activity duration and intensity to more advanced systems providing quantitative and qualitative information on the individuals' activity behavior. Correspondingly, methods to predict activity-related energy expenditure using bodily acceleration and subjects characteristics have advanced from linear regression to innovative algorithms capable of determining physical activity types and the related metabolic costs. These novel techniques can monitor modes of sedentary behavior as well as the engagement in specific activity types that helps to evaluate the effectiveness of lifestyle interventions. In conclusion, advances in activity monitoring have the potential to support the design of response-dependent physical activity recommendations that are needed to generate effective and personalized lifestyle interventions for health promotion. PMID- 21587200 TI - Maternal over-nutrition and offspring obesity predisposition: targets for preventative interventions. AB - Obesity now represents one of the major health care issues of the 21st century. Its prevalence has increased exponentially in both the developed and developing world during the last couple of decades. Such a rapid rise can therefore not be explained by a change in genotype, but must result from environmental factors and their interaction with our genes. There is clear evidence to show that current environmental factors such as current diet and level of physical activity can influence our risk of obesity. However, there is growing evidence to suggest that factors acting during very early life can influence long-term energy balance. One such factor that is emerging as an important player is maternal obesity and/or over-nutrition during pregnancy and lactation. Early life may therefore represent a critical period during which intervention strategies could be developed to reduce the prevalence of obesity. PMID- 21587201 TI - Body mass index classification misses subjects with increased cardiometabolic risk factors related to elevated adiposity. AB - CONTEXT: Body mass index (BMI) is widely used as a measure of overweight and obesity, but underestimates the prevalence of both conditions, defined as an excess of body fat. OBJECTIVE: We assessed the degree of misclassification on the diagnosis of obesity using BMI as compared with direct body fat percentage (BF%) determination and compared the cardiovascular and metabolic risk of non-obese and obese BMI-classified subjects with similar BF%. DESIGN: We performed a cross sectional study. SUBJECTS: A total of 6123 (924 lean, 1637 overweight and 3562 obese classified according to BMI) Caucasian subjects (69% females), aged 18-80 years. METHODS: BMI, BF% determined by air displacement plethysmography and well established blood markers of insulin sensitivity, lipid profile and cardiovascular risk were measured. RESULTS: We found that 29% of subjects classified as lean and 80% of individuals classified as overweight according to BMI had a BF% within the obesity range. Importantly, the levels of cardiometabolic risk factors, such as C-reactive protein, were higher in lean and overweight BMI-classified subjects with BF% within the obesity range (men 4.3 +/- 9.2, women 4.9 +/- 19.5 mg l(-1)) as well as in obese BMI-classified individuals (men 4.2 +/- 5.5, women 5.1 +/- 13.2 mg l(-1)) compared with lean volunteers with normal body fat amounts (men 0.9 +/- 0.5, women 2.1 +/- 2.6 mg l(-1); P<0.001 for both genders). CONCLUSION: Given the elevated concentrations of cardiometabolic risk factors reported herein in non-obese individuals according to BMI but obese based on body fat, the inclusion of body composition measurements together with morbidity evaluation in the routine medical practice both for the diagnosis and the decision-making for instauration of the most appropriate treatment of obesity is desirable. PMID- 21587202 TI - Insulin sensitivity at childhood predicts changes in total and central adiposity over a 6-year period. AB - OBJECTIVE: To examine the associations of insulin resistance at childhood with adiposity changes over a 6-year period (from 9 to 15 years) in a sample of 659 Swedish and Estonian children (52.7% girls) participating in the European Youth Heart Study. RESEARCH, DESIGN AND METHODS: We measured weight, height, waist circumference, biceps, triceps, subscapular, suprailiac, and medial calf skinfolds, and we calculated body mass index (BMI), sum of five skinfolds, and body fat percentage. Fasting plasma glucose and insulin were measured and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Changes in puberty stage, sex, centre and the corresponding baseline adiposity values were used as confounders in all analysis. RESULTS: HOMA-IR at childhood was significantly and positively associated with changes in BMI (beta=0.265; P=0.024), sum of five skinfolds (beta=0.3445; P=0.003), body fat percentage (beta=1.042; P=0.016) and waist circumference (beta=0.806; P=0.002) from childhood to adolescence. These relationships persisted when overweight children were excluded from the analysis. BMI, sum of five skinfolds, body fat percentage and waist circumference at childhood were not significantly associated with changes in HOMA-IR (P for all >0.1). CONCLUSIONS: These results give further support to the concept that lower insulin sensitivity at childhood may predict subsequent total and central adiposity gain at adolescence. These findings enhance the role of insulin sensitivity as a target of obesity prevention already from the first decades of life. PMID- 21587203 TI - Association of human adenovirus-36 in overweight Korean adults. AB - BACKGROUND: Although human adenovirus-36 (Ad-36) has been reported to be associated with obesity in US adults and children, Korean children and the Italian population, the association has not been found in Dutch or Belgian populations or in US military subjects. Therefore, we examined whether Ad-36 infection is associated with obesity in Korean adults. METHODS: A total of 540 age- and sex-matched individuals, who were normal weight, overweight or obese, were selected from participants in routine health examinations at the Ewha Womans University Medical Center. Overweight participants were defined as those with a body mass index (BMI) of 23 <= BMI<25 kg m(-2) and obese subjects were those with BMI >= 25 kg m(-2), according to the International Obesity Task Force definition. Ad-36 antibody was measured using a serum neutralization assay. RESULTS: Although more overweight participants than normal or obese subjects tested positive for the Ad-36 antibody (40%, 32.8% and 30%, respectively), the differences were not significant. The participants who tested positive for Ad-36 antibody had lower levels of triglycerides (TG) in each of the three groups, higher total cholesterol (TC) in the obese group and higher high-density lipoprotein cholesterol (HDL-C) in both the normal and obese groups. The odds ratio (OR) for Ad-36 antibody positivity was greater in overweight than in normal subjects (OR=2.03; 95% confidence interval (CI), 1.16-3.55) after adjusting for age, sex and waist circumference. However, this OR was non-significant in the obese group (OR=1.56; 95% CI, 0.67-3.67). CONCLUSION: Ad-36 seems to be strongly associated with overweight, but not obese, Korean adults. PMID- 21587206 TI - APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant. AB - An autosomal dominant mutation in the BRI2/ITM2B gene causes familial Danish dementia (FDD). Analysis of FDD(KI) mice, a mouse model of FDD genetically congruous to the human disease since they carry one mutant and one wild-type Bri2/Itm2b allele, has shown that the Danish mutation causes loss of Bri2 protein, synaptic plasticity and memory impairments. BRI2 is a physiological interactor of Abeta-precursor protein (APP), a gene associated with Alzheimer disease, which inhibits processing of APP. Here, we show that APP/Bri2 complexes are reduced in synaptic membranes of FDD(KI) mice. Consequently, APP metabolites derived from processing of APP by beta-, alpha- and gamma-secretases are increased in Danish dementia mice. APP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for APP metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that APP and BRI2 functionally interact, and that the neurological effects of the Danish form of BRI2 only occur when sufficient levels of APP are supplied by two alleles. This evidence establishes a pathogenic sameness between familial Danish and Alzheimer's dementias. PMID- 21587207 TI - Id2 expression delineates differential checkpoints in the genetic program of CD8alpha+ and CD103+ dendritic cell lineages. AB - Dendritic cells (DCs) have critical roles in the induction of the adaptive immune response. The transcription factors Id2, Batf3 and Irf-8 are required for many aspects of murine DC differentiation including development of CD8alpha(+) and CD103(+) DCs. How they regulate DC subset specification is not completely understood. Using an Id2-GFP reporter system, we show that Id2 is broadly expressed in all cDC subsets with the highest expression in CD103(+) and CD8alpha(+) lineages. Notably, CD103(+) DCs were the only DC able to constitutively cross-present cell-associated antigens in vitro. Irf-8 deficiency affected loss of development of virtually all conventional DCs (cDCs) while Batf3 deficiency resulted in the development of Sirp-alpha(-) DCs that had impaired survival. Exposure to GM-CSF during differentiation induced expression of CD103 in Id2-GFP(+) DCs. It did not restore cross-presenting capacity to Batf3(-/-) or CD103(-)Sirp-alpha(-)DCs in vitro. Thus, Irf-8 and Batf3 regulate distinct stages in DC differentiation during the development of cDCs. Genetic mapping DC subset differentiation using Id2-GFP may have broad implications in understanding the interplay of DC subsets during protective and pathological immune responses. PMID- 21587205 TI - Cellular stress response pathways and ageing: intricate molecular relationships. AB - Ageing is driven by the inexorable and stochastic accumulation of damage in biomolecules vital for proper cellular function. Although this process is fundamentally haphazard and uncontrollable, senescent decline and ageing is broadly influenced by genetic and extrinsic factors. Numerous gene mutations and treatments have been shown to extend the lifespan of diverse organisms ranging from the unicellular Saccharomyces cerevisiae to primates. It is becoming increasingly apparent that most such interventions ultimately interface with cellular stress response mechanisms, suggesting that longevity is intimately related to the ability of the organism to effectively cope with both intrinsic and extrinsic stress. Here, we survey the molecular mechanisms that link ageing to main stress response pathways, and mediate age-related changes in the effectiveness of the response to stress. We also discuss how each pathway contributes to modulate the ageing process. A better understanding of the dynamics and reciprocal interplay between stress responses and ageing is critical for the development of novel therapeutic strategies that exploit endogenous stress combat pathways against age-associated pathologies. PMID- 21587208 TI - Capsid-specific T-cell responses to natural infections with adeno-associated viruses in humans differ from those of nonhuman primates. AB - Hepatic adeno-associated virus serotype 2 (AAV2)-mediated gene transfer failed to achieve sustained transgene product expression in human subjects. We formulated the hypothesis that rejection of AAV-transduced hepatocytes is caused by AAV capsid-specific CD8(+) T cells that become reactivated upon gene transfer. Although this hypothesis was compatible with clinical data, which showed a rise in circulating AAV capsid-specific T cells following injection of AAV vectors, it did not explain that AAV vectors achieved long-term transgene expression in rhesus macaques, which are naturally infected with AAV serotypes closely related to those of humans. To address this apparent contradiction, we tested human and rhesus macaque samples for AAV capsid-specific T cells by intracellular cytokine staining combined with staining for T-cell subset and differentiation markers. This highly sensitive method, which could provide a tool to monitor adverse T cell responses in gene transfer trials, showed that AAV capsid-specific CD8(+) and CD4(+) T cells can be detected in blood of naturally infected humans and rhesus macaques. They are present at higher frequencies in rhesus macaques. Furthermore, T cells from humans and rhesus macaques exhibit striking differences in their differentiation status and in their functions, which may explain the disparate duration of AAV-mediated gene transfer in these two species. PMID- 21587209 TI - Feasibility of adenovirus-mediated hNIS gene transfer and 131I radioiodine therapy as a definitive treatment for localized prostate cancer. AB - We have developed a replication-competent adenovirus (Ad5-yCD/mutTK(SR39)rep hNIS) armed with two suicide genes and the human sodium iodide symporter (hNIS) gene. In this context, hNIS can be used as a reporter gene in conjunction with nuclear imaging and as a potentially therapeutic gene when combined with (131)I radioiodine therapy. Here, we quantified the volume and magnitude of hNIS gene expression in the human prostate following injection of a high Ad5 yCD/mutTK(SR39)rep-hNIS dose using a standardized injection algorithm, and estimated the radiation dose that would be delivered to the prostate had men been administered (131)I with curative intent. Six men with clinically localized prostate cancer received an intraprostatic injection of Ad5-yCD/mutTK(SR39)rep hNIS under transrectal ultrasound guidance. All men received 2 * 0.5 ml deposits (5 * 10(11) vp/deposit) in each of the four base and midgland sextants and 2 * 0.25 ml deposits (2.5 * 10(11) vp/deposit) in each of the two apex sextants for a total of 12 deposits (5 * 10(12) vp) in 5 ml. On multiple days after the adenovirus injection, men were administered sodium pertechnetate (Na(99m)TcO(4)) and hNIS gene expression in the prostate was quantified by single photon emission computed tomography (SPECT). hNIS gene expression was detected in the prostate of six of six (100%) men. On average, 45% (range 18-83%) of the prostate volume was covered with gene expression. Had men been administered 200 mCi (131)I, we estimate that the mean absorbed dose to the prostate would be 7.2 +/- 4.8 Gy (range 2.1-13.3 Gy), well below that needed to sterilize the prostate. We discuss the obstacles that must be overcome before adenovirus-mediated hNIS gene transfer and (131)I radioiodine therapy can be used as a definitive treatment for localized prostate cancer. PMID- 21587210 TI - Active immunotherapy combined with blockade of a coinhibitory pathway achieves regression of large tumor masses in cancer-prone mice. AB - Vaccines that aim to expand tumor-specific CD8(+) T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we here show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8(+) T-cell responses, which fail to affect the size of the tumors. In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B- and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8(+) T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression. PMID- 21587212 TI - Post-transcriptionally regulated expression system in human xenogeneic transplantation models. AB - Cells have developed a mechanism to discriminate between premature termination codons (PTCs) and normal stop codons during translation, sparking vigorous research to develop drugs promoting readthrough at PTCs to treat genetic disorders caused by PTCs. It was posed that this concept could also be applied to regulated gene therapy protocols by incorporating a PTC into a therapeutic gene, so active protein would only be made after administration of a readthrough agent. The strengths of the system are highlighted here by results demonstrating: (i) background expression levels were reduced to 0.01% to 0.0005% of wild type in unselected mass populations of cells depending upon the specific stop codon utilized and its position within the gene; (ii) expression levels responded well to multiple "On" and "Off" regulation cycles in vivo in human xenograft systems; (iii) the level of induction approached three logs using aminoglycoside activators including NB54, a newly synthesized aminoglycoside with significantly reduced toxicity; and (iv) expression levels could be appreciably altered when employing different promoters in a variety of cell types. These results strongly support the contention that this system should have important clinical applications when tight control of gene expression is required. PMID- 21587211 TI - Image-guided, tumor stroma-targeted 131I therapy of hepatocellular cancer after systemic mesenchymal stem cell-mediated NIS gene delivery. AB - Due to its dual role as reporter and therapy gene, the sodium iodide symporter (NIS) allows noninvasive imaging of functional NIS expression by (123)I scintigraphy or (124)I-PET imaging before the application of a therapeutic dose of (131)I. NIS expression provides a novel mechanism for the evaluation of mesenchymal stem cells (MSCs) as gene delivery vehicles for tumor therapy. In the current study, we stably transfected bone marrow-derived CD34(-) MSCs with NIS cDNA (NIS-MSC), which revealed high levels of functional NIS protein expression. In mixed populations of NIS-MSCs and hepatocellular cancer (HCC) cells, clonogenic assays showed a 55% reduction of HCC cell survival after (131)I application. We then investigated body distribution of NIS-MSCs by (123)I scintigraphy and (124)I-PET imaging following intravenous (i.v.) injection of NIS MSCs in a HCC xenograft mouse model demonstrating active MSC recruitment into the tumor stroma which was confirmed by immunohistochemistry and ex vivo gamma counter analysis. Three cycles of systemic MSC-mediated NIS gene delivery followed by (131)I application resulted in a significant delay in tumor growth. Our results demonstrate tumor-specific accumulation and therapeutic efficacy of radioiodine after MSC-mediated NIS gene delivery in HCC tumors, opening the prospect of NIS-mediated radionuclide therapy of metastatic cancer using MSCs as gene delivery vehicles. PMID- 21587213 TI - Safeguarding nonhuman primate iPS cells with suicide genes. AB - The development of technology to generate induced pluripotent stem (iPS) cells constitutes one of the most exciting scientific breakthroughs because of the enormous potential for regenerative medicine. However, the safety of iPS cell related products is a major concern for clinical translation. Insertional mutagenesis, possible oncogenic transformation of iPS cells or their derivatives, or the contamination of differentiated iPS cells with undifferentiated cells, resulting in the formation of teratomas, have remained considerable obstacles. Here, we demonstrate the utility of suicide genes to safeguard iPS cells and their derivatives. We found suicide genes can control the cell fate of iPS cells in vitro and in vivo without interfering with their pluripotency and self-renewal capacity. This study will be useful to evaluate the safety of iPS cell technology in a clinically highly relevant, large animal model and further benefit the clinical use of human iPS cells. PMID- 21587214 TI - Diagnostic and prognostic value of 3D NOGA mapping in ischemic heart disease. AB - The three-dimensional NOGA((r)) (Biologics Delivery Systems, a Johnson & Johnson company, Irwindale, CA, USA) electromechanical mapping system simultaneously registers the electrical and mechanical activities of the left ventricle, enabling online assessment of myocardial viability. The system distinguishes between viable, nonviable, stunned, and hibernating myocardium and can assess wall motion. The evaluation of the electrophysiological state of the tissue by NOGA((r)) mapping has been validated by comparing the electroanatomical voltage and local linear shortening maps obtained with this technique with several noninvasive diagnostic tests. Bipolar signal analysis and determination of the existence and degree of transmural infarctions are also possible with NOGA((r)). Immediately after percutaneous coronary intervention, an increased electromechanical discordance between voltage and local linear shortening maps indicates procedure-induced stunning that is caused by repetitive ischemia or microvascular compromise. Catheter-based direct intramyocardial injection of cells or gene constructs by NOGA((r)) reduces the likelihood of systemic toxicity of the injected substance, resulting in minimal washout, limited exposure of nontarget organs, and precise localization to ischemic and peri-ischemic myocardial regions in patients with chronic myocardial ischemia. In addition, direct intramyocardial injection enables the treatment of chronic myocardial infarction by provoking a chemotactic signal at the injection-injury site that contributes to cell engraftment. By measuring the electrical activation pattern in delayed-motion areas, NOGA((r)) might also be useful to predict response to cardiac resynchronization therapy. PMID- 21587216 TI - Stroke: blood pressure lowering in acute stroke--scant joy from SCAST. PMID- 21587217 TI - Medical oncology: Patients with brain metastases in early-phase trials. PMID- 21587215 TI - Diagnostic evaluation of left-sided prosthetic heart valve dysfunction. AB - Prosthetic heart valve (PHV) dysfunction is a rare, but potentially life threatening, complication. In clinical practice, PHV dysfunction poses a diagnostic dilemma. Echocardiography and fluoroscopy are the imaging techniques of choice and are routinely used in daily practice. However, these techniques sometimes fail to determine the specific cause of PHV dysfunction, which is crucial to the selection of the appropriate treatment strategy. Multidetector-row CT (MDCT) can be of additional value in diagnosing the specific cause of PHV dysfunction and provides valuable complimentary information for surgical planning in case of reoperation. Cardiac magnetic resonance imaging (CMR) has limited value in the evaluation of biological PHV dysfunction. In this Review, we discuss the use of established imaging modalities for the detection of left-sided mechanical and biological PHV dysfunction and discuss the complementary role of MDCT in this context. PMID- 21587220 TI - Too early to say, "no targeting of mitosis!". PMID- 21587221 TI - Screening: Bad breath ... scenting victory? PMID- 21587219 TI - Autophagy as a target for anticancer therapy. AB - Autophagy is an important homeostatic cellular recycling mechanism responsible for degrading unnecessary or dysfunctional cellular organelles and proteins in all living cells. Autophagy is particularly active during metabolic stress. In the cancer cell it fulfils a dual role, having tumor-promoting and tumor suppressing properties. Functional autophagy prevents necrosis and inflammation, which can lead to genetic instability. On the other hand, autophagy might be important for tumor progression by providing energy through its recycling mechanism during unfavorable metabolic circumstances. A central checkpoint that negatively regulates autophagy is mTOR, and anticancer drugs inhibiting the PI3K/Akt/mTOR axis putatively stimulate autophagy. However, whether autophagy contributes to the antitumor effect of these drugs or to drug resistance is largely unknown. The antimalarial drugs chloroquine and hydroxychloroquine inhibit autophagy, leading to increased cytotoxicity in combination with several anticancer drugs in preclinical models. The therapeutic clinical roles of autophagy induction and inhibition remain to be defined. To improve our understanding of autophagy in human cancers new methods for measuring autophagy in clinical samples need to be developed. This Review delineates the possible role of autophagy as a novel target for anticancer therapy. PMID- 21587222 TI - Basis for the use of localized hypothermia during radical pelvic surgery. AB - Controlled tissue cooling, or hypothermia, has been used therapeutically for decades to mitigate the negative effects of traumatic, ischemic, and surgical insults. When applied systemically, moderate hypothermia can attenuate or prevent the extent of neurologic sequelae. Localized hypothermia, on the other hand, has the capacity to reduce tissue edema, suppress inflammation, and minimize the severity of peripheral nerve injury. Therapeutic hypothermia has been used in critical care, neurosurgery, ophthalmology, otolaryngology, cardiothoracic surgery and most recently in urology. Nerve injury during radical pelvic surgery can result in urinary incontinence or retention, impotence and bowel dysfunction. Localized hypothermia during radical prostatectomy has demonstrated improved recovery of urinary continence and erectile function, and similar benefits might be observed in other types of radical pelvic surgery. PMID- 21587223 TI - A decade in prostate cancer: from NMR to metabolomics. AB - Over the past 30 years, continuous progress in the application of nuclear magnetic resonance (NMR) spectroscopy and magnetic resonance spectroscopic imaging (MRSI) to the detection, diagnosis and characterization of human prostate cancer has turned what began as scientific curiosity into a useful clinical option. In vivo MRSI technology has been integrated into the daily care of prostate cancer patients, and innovations in ex vivo methods have helped to establish NMR-based prostate cancer metabolomics. Metabolomic and multimodality imaging could be the future of the prostate cancer clinic--particularly given the rationale that more accurate interrogation of a disease as complex as human prostate cancer is most likely to be achieved through paradigms involving multiple, instead of single and isolated, parameters. The research and clinical results achieved through in vivo MRSI and ex vivo NMR investigations during the first 11 years of the 21st century illustrate areas where these technologies can be best translated into clinical practice. PMID- 21587224 TI - Misdiagnosis of clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (RCC) represents the most common histological subtype of malignant kidney tumors. Based on symptoms alone, clear cell RCC is indistinguishable from other histological classes of RCC unless the tumor is present in the context of an RCC syndrome. Histopathological examination is, therefore, important to accurately identify clear cell RCC. Clear cell RCCs have characteristic morphological criteria; these tumors can be easily identified upon typical presentation, but diagnosis can be challenging when tumor cell pattern is unusual or when availability of tissue samples is limited. In this Review, the clinical, radiological and pathological characteristics of clear cell RCCs are described, as well as the potential tumors that can be confused with clear cell RCC and need to be considered in the differential diagnoses. Finally, the importance of an accurate diagnosis is highlighted in the context of the increasing use of preoperative tissue sampling and the prevalence of clear cell tumors associated with hereditary syndromes, which could have different therapeutic and prognostic implications for patients and their families. PMID- 21587225 TI - Incontinence: the role of ambulatory urodynamics in spinal cord injury. PMID- 21587226 TI - Prostate cancer: targeted therapy for prostate cancer metastases to bone. PMID- 21587227 TI - Early fluid resuscitation in patients with rhabdomyolysis. AB - Extensive rhabdomyolysis is often lethal unless treated immediately. Early mortality arises from hypovolemic shock, hyperkalemia, acidosis and myoglobinuric acute kidney injury (AKI). Many individuals with rhabdomyolysis could be saved, and myoglobinuric AKI prevented, by early vigorous fluid resuscitation with >=12 l daily intravenous infusion of alkaline solution started at the scene of injury. This regimen stabilizes the circulation and mobilizes edema fluids sequestered in the injured muscles into the circulation, corrects hyperkalemia and acidosis, and protects against the nephrotoxic effects of myoglobinemia and hyperuricosuria. This regime results in a large positive fluid balance, which is well tolerated in young, carefully monitored individuals. In patients with rhabdomyolysis caused by muscle crush syndrome, mortality has been reduced from nearly 100% to <20% over the past 70 years through utilization of this intervention. This Perspectives discusses the lifesaving and limb-saving potential of early vigorous fluid resuscitation in patients with extensive traumatic and nontraumatic rhabdomyolysis. PMID- 21587228 TI - Phytoplankton growth after a century of dormancy illuminates past resilience to catastrophic darkness. AB - Photosynthesis evolved in the oceans more than 3 billion years ago and has persisted throughout all major extinction events in Earth's history. The most recent of such events is linked to an abrupt collapse of primary production due to darkness following the Chicxulub asteroid impact 65.5 million years ago. Coastal phytoplankton groups (particularly dinoflagellates and diatoms) appear to have been resilient to this biotic crisis, but the reason for their high survival rates is still unknown. Here we show that the growth performance of dinoflagellate cells germinated from resting stages is unaffected by up to a century of dormancy. Our results clearly indicate that phytoplankton resting stages can endure periods of darkness far exceeding those estimated for the Cretaceous-Paleogene extinction and may effectively aid the rapid resurgence of primary production in coastal areas after events of prolonged photosynthesis shut down. PMID- 21587229 TI - Active microrheology and simultaneous visualization of sheared phospholipid monolayers. AB - Two-dimensional films of surface-active agents-from phospholipids and proteins to nanoparticles and colloids-stabilize fluid interfaces, which are essential to the science, technology and engineering of everyday life. The 2D nature of interfaces present unique challenges and opportunities: coupling between the 2D films and the bulk fluids complicates the measurement of surface dynamic properties, but allows the interfacial microstructure to be directly visualized during deformation. Here we present a novel technique that combines active microrheology with fluorescence microscopy to visualize fluid interfaces as they deform under applied stress, allowing structure and rheology to be correlated on the micron scale in monolayer films. We show that even simple, single-component lipid monolayers can exhibit viscoelasticity, history dependence, a yield stress and hours-long time scales for elastic recoil and aging. Simultaneous visualization of the monolayer under stress shows that the rich dynamical response results from the cooperative dynamics and deformation of liquid-crystalline domains and their boundaries. PMID- 21587230 TI - Structure and Scm3-mediated assembly of budding yeast centromeric nucleosomes. AB - Much controversy exists regarding the structural organization of the yeast centromeric nucleosome and the role of the nonhistone protein, Scm3, in its assembly and architecture. Here we show that the substitution of H3 with its centromeric variant Cse4 results in octameric nucleosomes that organize DNA in a left-handed superhelix. We demonstrate by single-molecule approaches, micrococcal nuclease digestion and small-angle X-ray scattering that Cse4-nucleosomes exhibit an open conformation with weakly bound terminal DNA segments. The Cse4-octamer does not preferentially form nucleosomes on its cognate centromeric DNA. We show that Scm3 functions as a Cse4-specific nucleosome assembly factor, and that the resulting octameric nucleosomes do not contain Scm3 as a stably bound component. Taken together, our data provide insights into the assembly and structural features of the budding yeast centromeric nucleosome. PMID- 21587231 TI - Transcription factor IRF8 directs a silencing programme for TH17 cell differentiation. AB - T(H)17 cells are recognized as a unique subset of T helper cells that have critical roles in the pathogenesis of autoimmunity and tissue inflammation. Although RORgammat is necessary for the generation of T(H)17 cells, the molecular mechanisms underlying the functional diversity of T(H)17 cells are not fully understood. Here we show that a member of interferon regulatory factor (IRF) family of transcription factors, IRF8, has a critical role in silencing T(H)17 cell differentiation. Mice with a conventional knockout, as well as a T cell specific deletion, of the Irf8 gene exhibited more efficient T(H)17 cells. Indeed, studies of an experimental model of colitis showed that IRF8 deficiency resulted in more severe inflammation with an enhanced T(H)17 phenotype. IRF8 was induced steadily and inhibited T(H)17-cell differentiation during T(H)17 lineage commitment at least in part through its physical interaction with RORgammat. These findings define IRF8 as a novel intrinsic transcriptional inhibitor of T(H)17-cell differentiation. PMID- 21587232 TI - The neural circuits and sensory channels mediating harsh touch sensation in Caenorhabditis elegans. AB - Most animals can distinguish two distinct types of touch stimuli: gentle (innocuous) and harsh (noxious/painful) touch, however, the underlying mechanisms are not well understood. Caenorhabditis elegans is a useful model for the study of gentle touch sensation. However, little is known about harsh touch sensation in this organism. Here we characterize harsh touch sensation in C. elegans. We show that C. elegans exhibits differential behavioural responses to harsh touch and gentle touch. Laser ablations identify distinct sets of sensory neurons and interneurons required for harsh touch sensation at different body segments. Optogenetic stimulation of the circuitry can drive behaviour. Patch-clamp recordings reveal that TRP family and amiloride-sensitive Na(+) channels mediate touch-evoked currents in different sensory neurons. Our work identifies the neural circuits and characterizes the sensory channels mediating harsh touch sensation in C. elegans, establishing it as a genetic model for studying this sensory modality. PMID- 21587233 TI - Aurora B potentiates Mps1 activation to ensure rapid checkpoint establishment at the onset of mitosis. AB - The mitotic checkpoint prevents mitotic exit until all chromosomes are attached to spindle microtubules. Aurora B kinase indirectly invokes this checkpoint by destabilizing incorrect attachments; however, a more direct role remains controversial. In contrast, activity of the kinase Mps1 is indispensible for the mitotic checkpoint. Here we show that Aurora B and Hec1 are needed for efficient Mps1 recruitment to unattached kinetochores, allowing rapid Mps1 activation at the onset of mitosis. Live monitoring of cyclin B degradation reveals that this is essential to establish the mitotic checkpoint quickly at the start of mitosis. Delayed Mps1 activation and checkpoint establishment upon Aurora B inhibition or Hec1 depletion are rescued by tethering Mps1 to kinetochores, demonstrating that Mps1 recruitment is the primary role of Aurora B and Hec1 in mitotic checkpoint signalling. These data demonstrate a direct role for Aurora B in initiating the mitotic checkpoint rapidly at the onset of mitosis. PMID- 21587234 TI - Recovery from chronic monocular deprivation following reactivation of thalamocortical plasticity by dark exposure. AB - Chronic monocular deprivation induces severe amblyopia that is resistant to spontaneous reversal. However, dark exposure initiated in adulthood reactivates synaptic plasticity in the visual cortex and promotes recovery from chronic monocular deprivation in Long Evans rats. Here we show that chronic monocular deprivation induces a significant decrease in the density of dendritic spines on principal neurons throughout the deprived visual cortex. Nevertheless, dark exposure followed by reverse deprivation promotes the recovery of dendritic spine density of neurons in all laminae. Importantly, the ocular dominance of neurons in thalamo-recipient laminae of the cortex, and the amplitude of the thalamocortical visually evoked potential recover following dark exposure and reverse deprivation. Thus, dark exposure reactivates widespread synaptic plasticity in the adult visual cortex, including thalamocortical synapses, during the recovery from chronic monocular deprivation. PMID- 21587235 TI - IKKbeta regulates essential functions of the vascular endothelium through kinase dependent and -independent pathways. AB - Vascular endothelium provides a selective barrier between the blood and tissues, participates in wound healing and angiogenesis, and regulates tissue recruitment of inflammatory cells. Nuclear factor (NF)-kappaB transcription factors are pivotal regulators of survival and inflammation, and have been suggested as potential therapeutic targets in cancer and inflammatory diseases. Here we show that mice lacking IKKbeta, the primary kinase mediating NF-kappaB activation, are smaller than littermates and born at less than the expected Mendelian frequency in association with hypotrophic and hypovascular placentae. IKKbeta-deleted endothelium manifests increased vascular permeability and reduced migration. Surprisingly, we find that these defects result from loss of kinase-independent effects of IKKbeta on activation of the serine-threonine kinase, Akt. Together, these data demonstrate essential roles for IKKbeta in regulating endothelial permeability and migration, as well as an unanticipated connection between IKKbeta and Akt signalling. PMID- 21587236 TI - Predicting sites of ADAR editing in double-stranded RNA. AB - ADAR (adenosine deaminase that acts on RNA) editing enzymes target coding and noncoding double-stranded RNA (dsRNA) and are essential for neuronal function. Early studies showed that ADARs preferentially target adenosines with certain 5' and 3' neighbours. Here we use current Sanger sequencing protocols to perform a more accurate and quantitative analysis. We quantified editing sites in an ~800 bp dsRNA after reaction with human ADAR1 or ADAR2, or their catalytic domains alone. These large data sets revealed that neighbour preferences are mostly dictated by the catalytic domain, but ADAR2's dsRNA-binding motifs contribute to 3' neighbour preferences. For all proteins, the 5' nearest neighbour was most influential, but adjacent bases also affected editing site choice. We developed algorithms to predict editing sites in dsRNA of any sequence, and provide a web based application. The predictive power of the algorithm on fully base-paired dsRNA, compared with biological substrates containing mismatches, bulges and loops, elucidates structural contributions to editing specificity. PMID- 21587238 TI - Pediatric rheumatology: Strengths and challenges of a new guide for treating JIA. PMID- 21587237 TI - Food restriction enhances visual cortex plasticity in adulthood. AB - Neural circuits display a heightened sensitivity to external stimuli during well established windows in early postnatal life. After the end of these critical periods, brain plasticity dramatically wanes. The visual system is one of the paradigmatic models for studying experience-dependent plasticity. Here we show that food restriction can be used as a strategy to restore plasticity in the adult visual cortex of rats. A short period of food restriction in adulthood is able both to reinstate ocular dominance plasticity and promote recovery from amblyopia. These effects are accompanied by a reduction of intracortical inhibition without modulation of brain-derived neurotrophic factor expression or extracellular matrix structure. Our results suggest that food restriction could be investigated as a potential way of modulating plasticity. PMID- 21587239 TI - Neuropsychiatric disorders: What do neurologists think about conversion disorder? AB - A new survey of British neurologists shows that no commonly accepted model exists for the diagnosis of conversion disorder. Instead, the results indicate that the neurologist's diagnosis is influenced largely by their communication with the patients. PMID- 21587242 TI - Neurodevelopmental disorders: Clinical criteria for Rett syndrome. AB - Advances in the clinical and genetic understanding of Rett syndrome have meant that existing diagnostic guidelines for this neurodevelopmental disorder need to be revisited. New clinical criteria for the diagnosis of Rett syndrome by Neul and colleagues are welcome, but should more prominence be given to molecular diagnosis? PMID- 21587243 TI - Peripheral neuropathies: Molecular diagnosis of Charcot-Marie-Tooth disease. AB - Charcot-Marie-Tooth disease (CMT) is a hereditary neuropathy attributed to mutations in more than 30 different genes. A recent study identified the causative mutation in 67% of 787 screened patients with CMT, and the findings raise important issues concerning genetic testing for CMT. PMID- 21587244 TI - Subclinical hypercortisolism raises vertebral fracture risk. PMID- 21587246 TI - Biomarkers of paraganglioma metastatic potential identified. PMID- 21587245 TI - Puberty suppression in gender identity disorder: the Amsterdam experience. AB - The use of gonadotropin-releasing hormone analogs (GnRHa) to suppress puberty in adolescents with gender dysphoria is a fairly new intervention in the field of gender identity disorders or transsexualism. GnRHa are used to give adolescents time to make balanced decisions on any further treatment steps, and to obtain improved results in the physical appearance of those who opt to continue with sex reassignment. The effects of GnRHa are reversible. However, concerns have been raised about the risk of making the wrong treatment decisions, as gender identity could fluctuate during adolescence, adolescents in general might have poor decision-making abilities, and there are potential adverse effects on health and on psychological and psychosexual functioning. Proponents of puberty suppression emphasize the beneficial effects of GnRHa on the adolescents' mental health, quality of life and of having a physical appearance that makes it possible for the patients to live unobtrusively in their desired gender role. In this Review, we discuss the evidence pertaining to the debate on the effects of GnRHa treatment. From the studies that have been published thus far, it seems that the benefits outweigh the risks. However, more systematic research in this area is needed to determine the safety of this approach. PMID- 21587247 TI - Assembling the pieces. PMID- 21587248 TI - Social engineering for virtual 'big science' in systems biology. PMID- 21587249 TI - An active role for machine learning in drug development. PMID- 21587250 TI - A postreductionist framework for protein biochemistry. PMID- 21587251 TI - Getting pharmaceutical R&D back on target. PMID- 21587253 TI - RNA folding: a tale of two riboswitches. PMID- 21587254 TI - Signal transduction: STIM1 senses both Ca2+ and heat. PMID- 21587255 TI - Antitoxins: therapy for stressed bacteria. PMID- 21587256 TI - A multimarker QPCR-based platform for the detection of circulating tumour cells in patients with early-stage breast cancer. AB - BACKGROUND: The detection of circulating tumour cells (CTCs) has been linked with poor prognosis in advanced breast cancer. Relatively few studies have been undertaken to study the clinical relevance of CTCs in early-stage breast cancer. METHODS: In a prospective study, we evaluated CTCs in the peripheral blood of 82 early-stage breast cancer patients. Control groups consisted of 16 advanced breast cancer patients and 45 healthy volunteers. The CTC detection was performed using ErbB2/EpCAM immunomagnetic tumour cell enrichment followed by multimarker quantitative PCR (QPCR). The CTC status and common clinicopathological factors were correlated to relapse-free, breast cancer-related and overall survival. RESULTS: Circulating tumour cells were detected in 16 of 82 (20%) patients with early-stage breast cancer and in 13 out of 16 (81%) with advanced breast cancer. The specificity was 100%. The median follow-up time was 51 months (range: 17-60). The CTC positivity in early-stage breast cancer patients resulted in significantly poorer relapse-free survival (log rank test: P=0.003) and was an independent predictor of relapse-free survival (multivariate hazard ratio=5.13, P=0.006, 95% CI: 1.62-16.31). CONCLUSION: The detection of CTCs in peripheral blood of early-stage breast cancer patients provided prognostic information for relapse-free survival. PMID- 21587257 TI - Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer. AB - BACKGROUND: Combined therapy of metronomic cyclophosphamide, methotrexate and high-dose celecoxib targeting angiogenesis was used in a phase II trial. METHODS: Patients with advanced cancer received oral cyclophosphamide 50 mg o.d., celecoxib 400 mg b.d. and methotrexate 2.5 mg b.d. for two consecutive days each week. Response was determined every 8 weeks; toxicity was evaluated according to CTC version 2.0. Plasma markers of inflammation, coagulation and angiogenesis were measured. RESULTS: Sixty-seven of 69 patients were evaluable for response. Twenty-three patients had stable disease (SD) after 8 weeks, but there were no objective responses to therapy. Median time to progression was 57 days. There was a low incidence of toxicities. Among plasma markers, levels of tissue factor were higher in the SD group of patients at baseline, and levels of both angiopoietin-1 and matrix metalloproteinase-9 increased in the progressive disease group only. There were no changes in other plasma markers. CONCLUSION: This metronomic approach has negligible activity in advanced cancer albeit with minimal toxicity. Analysis of plasma markers indicates minimal effects on endothelium in this trial. These data for this particular regimen do not support basic tenets of metronomic chemotherapy, such as the ability to overcome resistant tumours by targeting the endothelium. PMID- 21587258 TI - Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients. AB - BACKGROUND: In colorectal cancer (CRC), tumour microsatellite instability (MSI) status and CpG island methylator phenotype (CIMP) status are indicators of patient outcome, but the molecular events that give rise to these outcomes remain largely unknown. Wnt5a is a critical regulator of non-canonical Wnt activity and promoter hypermethylation of this gene has emerging prognostic roles in CRC; however the frequency and prognostic significance of this epigenetic event have not been explored in the context of colorectal tumour subtype. Consequently, we investigated the frequency and prognostic significance of Wnt5a methylation in a large cohort of MSI-stratified CRCs. METHODS: Methylation was quantified in a large cohort of 1232 colorectal carcinomas from two clinically distinct populations from Canada. Associations were examined between methylation status and clinicopathlogical features, including tumour MSI status, BRAF V600E mutation, and patient survival. RESULTS: In Ontario, Wnt5a methylation was strongly associated with MSI tumours after adjustment for age, sex, and tumour location (odds ratio (OR)=4.2, 95% confidence interval (CI)=2.4-7.4, P<10(-6)) and with BRAF V600E mutation, a marker of CIMP (OR=12.3, 95% CI=6.9-21.7, P<10( 17)), but was not associated with patient survival. Concordant results were obtained in Newfoundland. CONCLUSION: Methylation of Wnt5a is associated with distinct tumour subtypes, strengthening the evidence of an epigenetic-mediated Wnt bias in CRC. PMID- 21587259 TI - Polypeptide N-acetylgalactosaminyltransferase 6 expression in pancreatic cancer is an independent prognostic factor indicating better overall survival. AB - BACKGROUND: The family of polypeptide N-acetylgalactosaminyltransferases (GalNAc Ts) is responsible for the altered glycosylation in cancer. The purpose of our study was to investigate the clinical significance of two isoforms, GalNAc-T6 and -T3, and their correlation with the prognosis of pancreatic cancer. METHODS: Immunohistochemistry was used to analyse GalNAc-T6 and -T3 expressions in 70 clinicopathologically characterised pancreatic cancer cases. RESULTS: Positive expressions of GalNAc-T6 and -T3 were immunohistochemically identified in 51% (36 of 70) and in 77% (54 of 70) of patients, respectively. A close relationship was noted between GalNAc-T6 positive expression and pathological well/moderate differentiated type (P=0.001), small tumour size (P=0.044), absence of vascular invasion (P=0.009), and low stage of the American Joint Committee on Cancer systems (P=0.043). The expression of GalNAc-T3 significantly correlated with good differentiation (P=0.001), but not with other clinicopathologic features. Furthermore, univariate and multivariate analyses revealed that GalNAc-T6 expression was an independent prognosis indicator for the disease, whereas GalNAc T3 expression had no impact on clinical outcome, even though 33 of 36 GalNAc-T6 positive cases also had a positive expression of GalNAc-T3 (P=0.001, r=0.356). CONCLUSION: Both GalNAc-T6 and -T3 expressions correlated significantly with tumour differentiation, whereas only GalNAc-T6 expression predicted prognosis in pancreatic cancer. PMID- 21587260 TI - Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas. AB - Local recurrence of glioblastomas is a major cause of patient mortality after definitive treatment. This review discusses the roles of the chemokine stromal cell-derived factor-1 and its receptor CXC chemokine receptor 4 (CXCR4) in affecting the sensitivity of glioblastomas to irradiation. Blocking these molecules prevents or delays tumour recurrence after irradiation by inhibiting the recruitment of CD11b+ monocytes/macrophages that participate in revascularising the tumour. We review the literature pertaining to the mechanism by which revascularisation occurs following tumour irradiation using experimental models. Areas of interest and debate in the literature include the process by which endothelial cells die after irradiation and the identity/origin of the cells that reconstitute the tumour blood vessels after injury. Understanding the processes that mediate tumour revascularisation will guide the improvement of clinical strategies for preventing recurrence of glioblastoma after irradiation. PMID- 21587261 TI - A-90289 A and B, new inhibitors of bacterial translocase I, produced by Streptomyces sp. SANK 60405. AB - During the course of screening for translocase I inhibitors, the new liposidomycin-related compounds, A-90289 A and B, were isolated from a culture broth of Streptomyces sp. SANK 60405. The structural elucidations were carried out by NMR and high-resolution mass spectral analyses, and they were classified as members of the liponucleoside antibiotics group with a sulfate group at the C 2' position. A-90289 A and B inhibited bacterial translocase I with IC(50) values of 36.5 ng ml(-1) and 33.8 ng ml(-1), respectively. PMID- 21587262 TI - Antibiotics in the clinical pipeline in 2011. AB - The emergence of multi-drug-resistant bacteria and the lack of new antibiotics in the antibiotic drug development pipeline, especially those with new modes of action, is a major health concern. This review lists the 20 new antibiotics launched since 2000 and records the 40 compounds currently in active clinical development. Compounds in the pipeline from new antibiotic classes are reviewed in detail with reference to their development status, mode of action, spectrum of activity and lead discovery. In addition, the NP or synthetic derivation is discussed, with activity against Gram-negative bacteria highlighted. PMID- 21587263 TI - Immunomodulatory effects of azithromycin on serum amyloid A production in lipopolysaccharide-induced endotoxemia in mice. PMID- 21587264 TI - Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphoma. AB - Romidepsin (Istodax), a selective inhibitor of histone deacetylases (HDACs), was approved for the treatment of cutaneous T-cell lymphoma in November 2009 by the US Food and Drug Administration. This unique natural product was discovered from cultures of Chromobacterium violaceum, a Gram-negative bacterium isolated from a Japanese soil sample. This bicyclic compound acts as a prodrug, its disulfide bridge being reduced by glutathione on uptake into the cell, allowing the free thiol groups to interact with Zn ions in the active site of class I and II HDAC enzymes. Due to the synthetic complexity of the compound, as well as the low yield from the producing organism, analogs are sought to create synthetically accessible alternatives. As a T-cell lymphoma drug, romidepsin offers a valuable new treatment for diseases with few effective therapies. PMID- 21587265 TI - Intrageneric diversity of type-I ketosynthase domain genes in the genus Nocardia. PMID- 21587266 TI - Comparison of drug sensitivity and genotypes of clinically isolated strains of levofloxacin-resistant Streptococcus pneumoniae obtained from Okinawa Island, the Japanese main island and Hong Kong. AB - The prevalence of fluoroquinolone-resistant Streptococcus pneumoniae is increasing worldwide. In the present study, a comparison of drug sensitivity and genotypes of clinically isolated strains of levofloxacin (LVFX)-resistant S. pneumoniae obtained from Hong Kong, Okinawa Island and the Japanese main island (Honshu) was performed. MICs of quinolones (LVFX, tosufloxacin, ciprofloxacin, gatifloxacin and sitafloxacin (STFX)) and other antibiotics (penicillin G, cefcapene, cefditoren, clarithromycin and azithromycin) were determined by a microdilution broth method according to the Clinical and Laboratory Standards Institute Standards. The quinolone-resistance determining regions (QRDRs) of gyrA, gyrB, parC and parE of these strains were analyzed by PCR-based sequencing. All 40 strains tested had more than one amino-acid substitution in the QRDRs of gyrA, gyrB, parC or parE. Although there seemed to be some clonality in strains obtained from Hong Kong, there was no clonality in strains obtained from Okinawa and Japan. Strains obtained from Hong Kong, Okinawa Island and the Japanese main island were genetically different by pulsed-field gel electrophoresis analysis. The range of MIC values of STFX against isolates resistant to LVFX (MIC 4-32 mg l(-1)) was 0.12-0.5 mg l(-1), and MIC(80) values of STFX against LVFX-resistant isolates were 0.25 mg l(-1). This study suggests that LVFX-resistant S. pneumoniae is similar in all three locations and STFX is potent against LVFX resistant S. pneumoniae with multiple mutations in QRDRs of gyrase A and topoisomerase IV. PMID- 21587267 TI - The applicability of SRTM in [(18)F]fallypride PET investigations: impact of scan durations. AB - The high-affinity radioligand [(18)F]fallypride (FP) is frequently used for quantification of striatal/extrastriatal D(2/3) receptors and the receptor occupancies of antipsychotics (APs). Its 110 minutes half-life allows long scan durations. However, the optimum scan duration is a matter of debate. This investigation focuses on scan-duration-related effects on simplified reference tissue model (SRTM) results and the time point of transient equilibrium in a large sample of dynamic FP positron emission tomography (PET) scans. Fifty drug free and 50 AP-treated subjects underwent FP-PET scans (180 minutes scan duration). The binding potential (BP(ND)) of the putamen, thalamus, and temporal cortex were calculated using the SRTM and the transient equilibrium model. Furthermore, receptor occupancies were calculated for AP-treated patients. Transient equilibrium in the unblocked putamen occurred after 121+/-29.6 minutes. The transient equilibrium occurred much earlier in the extrastriatal regions or under AP treatment. Stepwise scan shortening caused BP(ND) underestimations of 0.58% for the first 10-minute reduction (putamen, SRTM), finally reaching 5.76% after 1 hour scan-time reduction. We observed preferential extrastriatal AP binding irrespective of the analytical method. [(18)F]fallypride scan durations of 180 minutes reliably reach equilibrium even in D(2/3)-receptor-rich regions. Moderate reductions in FP scan durations only caused small changes to SRTM results even in receptor-rich regions. Apparently, the D(2/3) receptor occupancy results of APs, especially preferential extrastriatal binding observations, are not relevantly biased by inappropriate scan durations. PMID- 21587268 TI - Sex differences in neuroprotection provided by inhibition of TRPM2 channels following experimental stroke. AB - The calcium-permeable transient receptor potential M2 (TRPM2) ion channel is activated following oxidative stress and has been implicated in ischemic damage; however, little experimental evidence exists linking TRPM2 channel activation to damage following cerebral ischemia. We directly assessed the involvement of TRPM2 channels in ischemic brain injury using pharmacological inhibitors and short hairpin RNA (shRNA)-mediated knockdown of TRPM2 expression. Each of the four TRPM2 inhibitors tested provided significant protection to male neurons following in vitro ischemia (oxygen-glucose deprivation, OGD), while having no effect in female neurons. Similarly, TRPM2 knockdown by TRPM2 shRNA resulted in significantly reduced neuronal cell death following OGD only in male neurons. The TRPM2 inhibitor clotrimazole reduced infarct volume in male mice, while having no effect on female infarct volume. Finally, intrastriatal injection of lentivirus expressing shRNA against TRPM2 resulted in significantly smaller striatal infarcts only in male mice following middle cerebral artery occlusion, having no significant effect in female mice. Data presented in the current study demonstrate that TRPM2 inhibition and knockdown preferentially protects male neurons and brain against ischemia in vitro and in vivo, indicating that TRPM2 inhibitors may provide a new therapeutic approach to the treatment of stroke in men. PMID- 21587269 TI - Rotation of Editorial Board Members and new publication formats. PMID- 21587272 TI - Improving the interaction between the ophthalmology and histopathology departments. AB - PURPOSE: The purpose of this study was to improve communication between the ophthalmology and histopathology departments at Royal Hallamshire Hospital, Sheffield, by effectively changing the structure and completion of the histopathology request form through the process of a successful audit. This aimed to ensure that comprehensive information was made available to the histopathologist. METHODS: An audit was performed by review of 710 histopathology request forms, completed by the ophthalmology department, over a 1-year period, between July 2005 and June 2006 inclusive. Results were used to re-model the ophthalmic histopathology request form. New forms were circulated and all forms completed over a 3-month period, between January 2008 and March 2008, were reviewed, thus closing the audit loop. RESULTS: On the basis of audit results of 710 histopathology request forms, a new histopathology request form was created, which was easier to complete. Review of the 224 new histopathology request forms showed improved percentages of completion of important sections of the form. CONCLUSIONS: Through the audit process we have created a new ophthalmic histopathology request form that is more user-friendly for the ophthalmologist and more consistently provides the necessary information for the ophthalmic histopathologist. This has improved efficiency and effectiveness of communication between the specialities, which should contribute to minimise the chances of medical error and improved turnaround times for the planning and delivery of patient care. PMID- 21587271 TI - Five-year visual outcome following laser photocoagulation of diabetic macular oedema. AB - OBJECTIVE: To evaluate the 5-year visual outcome associated with laser photocoagulation treatment of diabetic macular oedema (DMO), and to investigate the relationship between systemic factors and visual outcomes in a real-life setting. METHODS: The mean annual visual outcomes and systemic parameters of 100 consecutive subjects with type 2 diabetes who underwent the first session of focal/grid macular laser photocoagulation for clinically significant macular oedema between 2003 and 2004 were collected retrospectively and compared with the outcomes of the laser arm of the Diabetic Retinopathy Clinical Research Network (DRCRN trial comparing intravitreal triamcinolone acetonide injection with laser photocoagulation treatment for DMO). The primary outcome measures included the mean change in visual acuity (VA) in 5 years and the influence of systemic factors on final visual outcome. RESULTS: The mean change in VA at 5 years was 5.23 in a real-life setting for an inner city population. The 3-year outcome was inferior to the clinical trial results with more people gaining vision (>=15 letter gain) in the DRCRN group compared with this cohort (26 vs 9%). Furthermore, three times more patients lost vision (>15 letter loss) in the real life setting of this cohort compared with the clinical trial results of the DRCRN group (27 vs 8%, respectively). CONCLUSIONS: The visual outcomes and the control of systemic factors of patients with DMO in this cohort were inferior to those recruited for the clinical trial involving the DRCRN group. PMID- 21587270 TI - Lithium-mediated long-term neuroprotection in neonatal rat hypoxia-ischemia is associated with antiinflammatory effects and enhanced proliferation and survival of neural stem/progenitor cells. AB - The aim of this study was to evaluate the long-term effects of lithium treatment on neonatal hypoxic-ischemic brain injury, inflammation, and neural stem/progenitor cell (NSPC) proliferation and survival. Nine-day-old male rats were subjected to unilateral hypoxia-ischemia (HI) and 2 mmol/kg lithium chloride was injected intraperitoneally immediately after the insult. Additional lithium injections, 1 mmol/kg, were administered at 24-hour intervals for 7 days. Animals were killed 6, 24, 72 hours, or 7 weeks after HI. Lithium reduced total tissue loss by 69%, from 89.4+/-14.6 mm(3) in controls (n=15) to 27.6+/-6.2 mm(3) in lithium-treated animals (n=14) 7 weeks after HI (P<0.001). Microglia activation was inhibited by lithium treatment, as judged by Iba-1 and galectin-3 immunostaining, and reduced interleukin-1beta and CCL2 levels. Lithium increased progenitor, rather than stem cell, proliferation in both nonischemic and ischemic brains, as judged by 5-bromo-2-deoxyuridine labeling 24 and 72 hours as well as by phospho-histone H3 and brain lipid-binding protein labeling 7 weeks after HI. Lithium treatment also promoted survival of newborn NSPCs, without altering the relative levels of neuronal and astroglial differentiation. In summary, lithium conferred impressive, morphological long-term protection against neonatal HI, at least partly by inhibiting inflammation and promoting NSPC proliferation and survival. PMID- 21587273 TI - Colour photographs for screening in neovascular age-related macular degeneration: are they necessary? AB - AIMS: To investigate whether optical coherence tomography (OCT) with associated infra-red images provide enough information to determine treatment decisions in the management of neovascular age-related macular degeneration (nAMD), or whether retinal colour photography is also necessary. METHODS: In all, 87 OCT scans of 82 eyes with nAMD undergoing monitoring post ranibizumab treatment were taken using the Zeiss Stratus (Carl Zeiss Meditec, Jena, Germany; n=87) together with their corresponding infra-red images. Fundus colour photographs were also taken. These images were reviewed by an experienced assessor, and a ranibizumab treatment decision was made during a multidisciplinary team retinal image review meeting. RESULTS: In all, 30 OCT scans (34.5%) showed intraretinal or subretinal oedema. A total of 24 colour photographs (19.5%) demonstrated retinal haemorrhage. Corresponding OCT infra-red images gave poor sensitivity in detecting haemorrhages (0.176). In 16.7% of decisions to treat, haemorrhage alone was the deciding factor. Signs of disease activity seen only on colour photography were the deciding factor in clinical decisions for 8% of scans assessed. CONCLUSIONS: The presence or increase of intra-retinal oedema is an important sign of activity triggering ranibizumab retreatment, but some eyes show signs of retinal haemorrhage without coexisting oedema. These haemorrhages are often only seen on either colour imaging or fundoscopy and are unclear or invisible on OCT scans and infra-red images. Therefore, although retinal colour photography creates additional expense, it is indispensable for making informed retreatment decisions, if patients are monitored using retinal imaging alone. PMID- 21587274 TI - Polypseudophakia for cataract surgery: 10-year follow-up on safety and stability of two poly-methyl-methacrylate (PMMA) intraocular lenses within the capsular bag. AB - PURPOSE: To report the long-term follow-up (more than 10 years) of three patients who have undergone polypseudophakia phacoemulsification cataract surgery. METHODS: A case series of three patients and four procedures. Two poly-methyl methacrylate (PMMA) intraocular lenses (IOLs) were placed within the capsular bag (P359UV, Storz, Tuttlingen, Germany). No complications occurred peri-operatively. A full ophthalmological examination was performed at 10-year follow-up, looking for decentration, tilt, and complications of interlenticular opacification (ILO) between the IOLs. RESULTS: Inferior ILO with Elschnig pearls was observed in only one case, and was likely to be visually insignificant. No ILO was observed in the other three eyes. In one patient, the piggyback IOL had been displaced 1-2 mm nasally, but there was no tilt of the IOLs, with the haptics remaining well aligned. There was no displacement or tilt of the piggyback IOL in the other three cases. Corneal endothelial cell count (SP-2000P, Topcon, Tokyo, Japan) was above 1000 cell/mm(2) in all cases. CONCLUSIONS: With the introduction of foldable IOLs, the piggyback IOL is usually placed in the sulcus, but we have shown good long-term stability and minimal complications of dual PMMA IOLs placed within the bag. PMID- 21587275 TI - Retinal tears after posterior vitreous detachment and vitreous hemorrhage in patients on systemic anticoagulants. AB - AIMS OR PURPOSE: To determine the rate of retinal tears (RTs) after posterior vitreous detachment (PVD) and vitreous hemorrhage (VH) in patients on systemic anticoagulants. METHODS: In all, 260 eyes of 260 patients with an acute PVD and VH were followed for evidence of an RT or detachment. Patients were divided into those taking systemic anticoagulants and those not taking anticoagulants. RESULTS: A total of 137 patients (53%) were taking anticoagulants, 123 (47%) were not. Overall, 72% of patients not taking any anticoagulant had evidence of an RT, whereas 46% of patients taking an anticoagulant had an RT (P-value 0.0002). Also, 37% of patients not taking an anticoagulant had a retinal detachment (RD), whereas 23% of patients taking any anticoagulant had an RD (P-value 0.01). CONCLUSIONS: In patients with an acute PVD and VH using anticoagulants, RTs and RDs were common. Anticoagulation status may be an important contributing factor in predicting the incidence of an RT or detachment. PMID- 21587276 TI - Performance in the Duke-Elder ophthalmology undergraduate prize examination and future careers in ophthalmology. AB - AIMS: Cognitive factors (eg, academic achievement) have had a significant role in selecting postgraduate surgical trainees in the past. This project sought to determine the role of a national undergraduate ophthalmology prize examination (Duke-Elder examination) in the selection of postgraduate ophthalmology trainees. This would also serve as a quality assurance exercise for the assessment, in which the ultimate aim is to encourage trainees into ophthalmology. METHODS: A retrospective analysis of the top 20 ranked candidates in the Duke-Elder examination from 1989 to 2005 (except 1995) was carried out to determine which of them subsequently entered the ophthalmic training and General Medical Council Specialist Registers. RESULTS: Out of the top 20 candidates in the exam, 29.5% went into specialist training in ophthalmology. Some appeared in the top 20 more than once, with 56% of them going into ophthalmic training, but they had a similar median time to enter training as those who appeared in the top 20 once. There was no significant evidence to suggest that the overall median ranking scores between the UK medical schools differed (P=0.23; Kruskal-Wallis test). However, there was a marked difference in frequency of top 20 candidates from each medical school, which could not be explained by the size of the medical school alone. CONCLUSION: It is difficult to conclude from these findings the importance that the Duke-Elder examination has in the selection of trainees into ophthalmology. The role of cognitive factors in selection into postgraduate medical/surgical training is discussed, along with the potential academic criteria, which may influence interview scores. PMID- 21587277 TI - Eccrine syringofibroadenoma of the eyelid in association with eye prosthesis. PMID- 21587278 TI - Regional factors interact with educational and income tax levels to influence food intake in France. AB - BACKGROUND/OBJECTIVES: The goal of the present study was to assess whether geographic factors affect the relationship between socioeconomic indicators and adherence to the French National Nutritional Health Programme (Programme National Nutrition Sante (PNNS)) guidelines. SUBJECTS/METHODS: The MONA LISA-NUT study (2005-2007) is a cross-sectional survey of a representative sample from northern, northeastern and southwestern France. Educational level and household income tax were recorded by trained interviewers. Food intake was assessed with a 3-day food diary in 3188 subjects aged from 35-64 years. Adherence to the PNNS guidelines was assessed with a validated score (the French score of indicators of the PNNS objective (FSIPO)). Multivariate analyses were adjusted for gender, age, marital status, body mass index, energy intake and medically prescribed diets. RESULTS: The FSIPO score was higher in southwestern France than in the two other regions (P<0.0001). The FSIPO score was correlated with the educational level in northern and northeastern France (P<0.0001) but not in southwestern France (region education interaction: P<0.001). This interaction was accounted for by fruit and vegetable (P<0.0001), calcium (P=0.03), saturated fatty acid (P<0.0001), and fibre (P=0.0001) components of the FSIPO score. In contrast, the income tax level and the FSIPO score were positively correlated (P<0.0001) to a similar extent in all three regions (region * income tax interaction: P=0.09). CONCLUSIONS: The relationship between educational level and adherence to the national nutritional health guidelines differs from one region of France to another, suggesting that nutrition education programmes should perhaps be adapted on a regional basis. In contrast, guideline adherence is correlated with income tax level independently of geographical factors, suggesting that financial constraints on food choices are uniform across France. PMID- 21587279 TI - Effects of essential fatty acids in iron deficient and sleep-disturbed attention deficit hyperactivity disorder (ADHD) children. AB - Inattention, hyperactivity and impulsivity constitute the core diagnostic criteria for attention deficit hyperactivity disorder (ADHD) children. Patients generally suffer from sleep disturbance and malnutrition that can account for tiredness during the day, poor concentration, poor eating and depressed mood, along with anemia and an n-3 polyunsaturated acid deficiency. The change of ADHD behavior in children (9-12) was studied, following 10 weeks of treatment with a polyunsaturated acid mixture on six variables: cooperation, mood, concentration, homework preparation, fatigue and sleep quality. Iron status was also examined. Polyunsaturated acid administration was associated with significant improvement in quality of life, ability to concentrate, sleep quality and hemoglobin levels. PMID- 21587280 TI - Fruit and vegetable intake influences the association between exposure to polycyclic aromatic hydrocarbons and a marker of oxidative stress in pregnant women. AB - BACKGROUND/OBJECTIVES: Exposure to polycyclic aromatic hydrocarbons (PAHs) during pregnancy is known to increase oxidative stress, which may influence pregnancy outcomes and health of the child. SUBJECTS/METHODS: This study investigated whether fruit and vegetable intake modifies the relationship between exposure to PAHs and oxidative stress status during pregnancy. Urinary levels of 2-naphthol and 1-hydroxypyrene (biomarkers of exposure to PAHs), and malondialdehyde (MDA; a biomarker of oxidative stress) were analyzed in 715 pregnant women at 12-28 weeks of gestation. The dietary antioxidant intake during pregnancy was estimated using the 24-h recall method. Urinary 2-naphthol, 1-hydroxypyrene and MDA levels were analyzed by high-performance liquid chromatography-fluorescence detection. RESULTS: The urinary MDA level was positively correlated with the 2-naphthol level (r=0.255, P<0.001) and 1-hydroxypyrene level (r=0.240, P<0.001). Multiple regression analysis after adjustment for covariates revealed that the urinary 1 hydroxypyrene level was positively associated with the MDA level; these positive associations only existed in pregnant women, with either the fruit and vegetable intake or the vitamin C intake in the first tertile (<390.1 g/day) or in the first and second tertiles (<141.5 mg/day), respectively. CONCLUSIONS: These results suggest that an adequate maternal intake of fruit, vegetables and vitamin C is beneficial to the defense against the oxidative stress associated with exposure to PAHs in pregnant women. PMID- 21587281 TI - The effect of parenteral nitrogen and energy intake on electrolyte balance in the preterm infant. AB - BACKGROUND/OBJECTIVES: Recent guidelines for preterm parenteral nutrition (PN) recommend an earlier and higher intake of amino acids (AA) and energy to avoid postnatal catabolism and approximate normal fetal growth. Few investigations explored how early PN may affect electrolyte and water homeostasis. We performed a prospective observational trial to assess the effect of nutrient intake on electrolyte homeostasis and balance. SUBJECTS/METHODS: During 16 months, all infants <=32 weeks were eligible. In the first week of life, we recorded the following daily: electrolytes (plasma and 8-h urine collection), nutritional intake, urine output, body weight, and we calculated sodium (Na) and potassium (K) balance. Infants were divided, for analysis, into three groups of AA intake: low <1.5 g/kg/day (LAA), medium 1.5-2 g/kg/day (MAA) and high >2 g/kg/day (HAA). RESULTS: A total of 154 infants were included. HAA group presented lower weight loss. Na balance was influenced by urine output and postnatal age, with little contribution of nutrition. Kalemia and K balance were mainly influenced by AA intake. K balance differed among groups: LAA, -2.3 mmol/kg/week; MAA, 1.1 mmol/kg/week; and HAA 2.6 mmol/kg/week (P<0.0001). In the HAA group, plasma and urine K were significantly lower and non-oliguric hyperkalemia was reduced. CONCLUSIONS: Na homeostasis was very slightly modified by early nutrition, suggesting that a negative Na balance is obligatory after birth. We showed that AA intake strongly affects K balance, minimize hyperkalemia and reduces weight loss. As K balance is strictly linked to cellular metabolism, we speculate that early nutrition may inhibit cellular catabolism and reduce the contraction of intracellular water compartment. PMID- 21587282 TI - Feasibility testing of an automated image-capture method to aid dietary recall. AB - BACKGROUND/OBJECTIVES: The accuracy of dietary recalls might be enhanced by providing participants with photo images of foods they consumed during the test period. SUBJECTS/METHODS: We examined the feasibility of a system (Image-Diet Day) that is a user-initiated camera-equipped mobile phone that is programmed to automatically capture and transmit images to a secure website in conjunction with computer-assisted, multipass, 24-h dietary recalls in 14 participants during 2007. Participants used the device during eating periods on each of the three independent days. Image processing filters successfully eliminated underexposed, overexposed and blurry images. The captured images were accessed by the participants using the ImageViewer software while completing the 24-h dietary recall on the following day. RESULTS: None of the participants reported difficulty using the ImageViewer. Images were deemed 'helpful' or 'sort of helpful' by 93% of participants. A majority (79%) of users reported having no technical problems, but 71% rated the burden of wearing the device as somewhat to very difficult, owing to issues such as limited battery life, self-consciousness about wearing the device in public and concerns about the field of view of the camera. CONCLUSION: Overall, these findings suggest that automated imaging is a promising technology to facilitate dietary recall. The challenge of managing the thousands of images generated can be met. Smaller devices with a broader field of view may aid in overcoming self-consciousness of the user with using or wearing the device. PMID- 21587283 TI - Predictors of lifestyle intervention outcome and dropout: the SLIM study. AB - BACKGROUND/OBJECTIVES: To evaluate the effect of a 4.1-year (range 3-6 years) lifestyle intervention according to general public health recommendations on glucose tolerance and dropout in a Dutch population with impaired glucose tolerance (IGT). SUBJECTS/METHODS: In the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht, 147 Caucasian IGT subjects were randomized to an intervention group (INT: n=74; 38 male, 36 female) and control group (CON: n=73; 37 male, 36 female). Annually, subjects underwent measurements of body weight, anthropometry, glucose tolerance (oral glucose tolerance test), insulin resistance (homeostasis model assessment-insulin resistance), maximal aerobic capacity (VO(2) max), blood lipids and blood pressure. INT received individual advice regarding a healthy diet and physical activity. RESULTS: INT decreased their saturated fat intake, increased their carbohydrate intake (P<0.05) and VO(2) max (P=0.04) compared with CON. Body weight did not change significantly (P=0.20) between the groups. After an initial decrease, 2-h glucose levels overall increased in INT (+0.11 mmol/l), but significantly less than CON (+1.18 mmol/l; P=0.04). Diabetes incidence was lower in INT versus CON (30 versus 56%, P=0.04). Change in body weight was associated with change in 2-h glucose levels (beta=0.399 mmol/l per kg, P=0.02). Dropouts had a lower aerobic fitness and socioeconomic status, and a higher body mass index (BMI) and 2-h glucose compared with non-dropouts. CONCLUSIONS: Prolonged feasible changes in diet and physical activity prevent deterioration of glucose tolerance and reduce diabetes risk. Low socioeconomic status, low aerobic fitness and high BMI and 2-h glucose are indicative of dropout to the program. PMID- 21587284 TI - Health economic consequences of reducing salt intake and replacing saturated fat with polyunsaturated fat in the adult Finnish population: estimates based on the FINRISK and FINDIET studies. AB - BACKGROUND/OBJECTIVES: To predict the health economic consequences of modest reductions in the daily intake of salt (-1.0 g per day) and replacement of saturated fat (SFA, -1.0 energy percent (E%)) with polyunsaturated fat (PUFA, +1.0 E%) in the Finnish population aged 30-74 years. SUBJECTS/METHODS: A Markov model with dynamic population structure was constructed to present the natural history of cardiovascular diseases (CVDs) based on the most current information about the age- and sex-specific cardiovascular risk factors, dietary habits and nutrient intake. To predict the undiscounted future health economic consequences of the reduction of dietary salt and SFA, the model results were extrapolated for the years 2010-2030 by replacing the baseline population in the year 2007 with the extrapolated populations from the official Finnish statistics. Finnish costs (?2009, societal perspective) and EQ-5D utilities were obtained from published references. RESULTS: During the next 20 years, a population-wide intervention directed at salt intake and dietary fat quality could potentially lead to 8000 13,000 prevented CVD cases among the Finnish adults compared the situation in year 2007. In addition, the reduced incidence of CVDs could gain 26,000-45,000 quality-adjusted life years and save ?150-225 million over the same time period. CONCLUSION: A modest reduction of salt and replacement of SFA with PUFA in food products can significantly reduce the burden of CVD in the adult Finnish population. This impact may be even larger in the near future due to the ageing of Finnish population. PMID- 21587285 TI - Does the Mediterranean dietary pattern or the Healthy Diet Index influence the risk of breast cancer in a large British cohort of women? AB - BACKGROUND/OBJECTIVE: To assess the risk of developing breast cancer associated with consumption of two common dietary patterns: a Mediterranean dietary pattern and a dietary pattern, which conforms to the World Health Organization Healthy Diet Index (WHO HDI). SUBJECTS/METHODS: Dietary data from a 217-item food frequency questionnaire were used to generate two dietary patterns according to pre-defined criteria in women from the UK Women's Cohort Study. Survival analysis using Cox regression was used to estimate hazards ratios for risk of breast cancer adjusted for known confounders. RESULTS: This analysis included 828 incident cases of breast cancer in 33,731 women with a mean follow-up of 9 years. There were no statistically significant associations between either the Mediterranean dietary pattern or the WHO HDI and risk of breast cancer. In premenopausal women, there was a nonsignificant trend suggesting that increasing compliance with the Mediterranean diet was associated with lower risk of breast cancer. Maximal adherence to the Mediterranean diet was associated with hazards ratio=0.65 (95% confidence interval: 0.42-1.02, P trend=0.09) compared with minimal adherence. In postmenopausal women, no clear trends were observed. CONCLUSIONS: In this study, no strong association between the risk of breast cancer and the consumption of either a Mediterranean-type diet or one characterized by adherence to the WHO HDI was observed. In premenopausal, but not postmenopausal women, there was a nonsignificant inverse association with increasing adherence to the Mediterranean diet pattern. PMID- 21587286 TI - Sleep: Neurons take a nap. PMID- 21587287 TI - Cortical development: Activity makes interneurons shape up. PMID- 21587288 TI - Using theoretical models to analyse neural development. AB - The development of the nervous system is an extremely complex and dynamic process. Through the continuous interplay of genetic information and changing intra- and extracellular environments, the nervous system constructs itself from precursor cells that divide and form neurons, which migrate, differentiate and establish synaptic connections. Our understanding of neural development can be greatly assisted by mathematical and computational modelling, because it allows us to bridge the gap between system-level dynamics and the lower level cellular and molecular processes. This Review shows the potential of theoretical models to examine many aspects of neural development. PMID- 21587289 TI - Microbes' roadmap to neurons. AB - The nervous system is protected by barriers that restrict the invasion of pathogens. Nevertheless, mechanisms have evolved by which microbes can pass these barriers, enter and exit neurons and target various regions of the nervous system. In the brain, immune responses to pathogens are generally not robust, so microbes can hide and survive or, conversely, cause severe uncontrolled infections. Depending on their sites of entry and the regions that they target, microbes can cause diverse nervous system dysfunctions and even influence host behaviour to their own advantage. This Review discusses routes by which microbes can reach the nervous system and cause persistent or life-threatening infections. PMID- 21587291 TI - The three SMC sisters. PMID- 21587293 TI - DNA damage: problems with too much packaging. PMID- 21587294 TI - Gene expression: personalized ribosomes. PMID- 21587290 TI - Ageing as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates. AB - Ageing is the greatest risk factor for the development of Parkinson's disease. However, the current dogma holds that cellular mechanisms that are associated with ageing of midbrain dopamine neurons and those that are related to dopamine neuron degeneration in Parkinson's disease are unrelated. We propose, based on evidence from studies of non-human primates, that normal ageing and the degeneration of dopamine neurons in Parkinson's disease are linked by the same cellular mechanisms and, therefore, that markers of cellular risk factors accumulate with age in a pattern that mimics the pattern of degeneration observed in Parkinson's disease. We contend that ageing induces a pre-parkinsonian state, and that the cellular mechanisms of dopamine neuron demise during normal ageing are accelerated or exaggerated in Parkinson's disease through a combination of genetic and environmental factors. PMID- 21587295 TI - Cell growth: RAC1 sizes up mTOR. PMID- 21587298 TI - Using electronic health records to drive discovery in disease genomics. AB - If genomic studies are to be a clinically relevant and timely reflection of the relationship between genetics and health status--whether for common or rare variants--cost-effective ways must be found to measure both the genetic variation and the phenotypic characteristics of large populations, including the comprehensive and up-to-date record of their medical treatment. The adoption of electronic health records, used by clinicians to document clinical care, is becoming widespread and recent studies demonstrate that they can be effectively employed for genetic studies using the informational and biological 'by-products' of health-care delivery while maintaining patient privacy. PMID- 21587297 TI - ARF family G proteins and their regulators: roles in membrane transport, development and disease. AB - Members of the ADP-ribosylation factor (ARF) family of guanine-nucleotide-binding (G) proteins, including the ARF-like (ARL) proteins and SAR1, regulate membrane traffic and organelle structure by recruiting cargo-sorting coat proteins, modulating membrane lipid composition, and interacting with regulators of other G proteins. New roles of ARF and ARL proteins are emerging, including novel functions at the Golgi complex and in cilia formation. Their function is under tight spatial control, which is mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that catalyse GTP exchange and hydrolysis, respectively. Important advances are being gained in our understanding of the functional networks that are formed not only by the GEFs and GAPs themselves but also by the inactive forms of the ARF proteins. PMID- 21587301 TI - Genetic analysis of post-mating reproductive barriers in hybridizing European Populus species. AB - Molecular genetic analyses of experimental crosses provide important information on the strength and nature of post-mating barriers to gene exchange between divergent populations, which are topics of great interest to evolutionary geneticists and breeders. Although not a trivial task in long-lived organisms such as trees, experimental interspecific recombinants can sometimes be created through controlled crosses involving natural F(1)'s. Here, we used this approach to understand the genetics of post-mating isolation and barriers to introgression in Populus alba and Populus tremula, two ecologically divergent, hybridizing forest trees. We studied 86 interspecific backcross (BC(1)) progeny and >350 individuals from natural populations of these species for up to 98 nuclear genetic markers, including microsatellites, indels and single nucleotide polymorphisms, and inferred the origin of the cytoplasm of the cross with plastid DNA. Genetic analysis of the BC(1) revealed extensive segregation distortions on six chromosomes, and >90% of these (12 out of 13) favored P. tremula donor alleles in the heterospecific genomic background. Since selection was documented during early diploid stages of the progeny, this surprising result was attributed to epistasis, cyto-nuclear coadaptation, heterozygote advantage at nuclear loci experiencing introgression or a combination of these. Our results indicate that gene flow across 'porous' species barriers affects these poplars and aspens beyond neutral, Mendelian expectations and suggests the mechanisms responsible. Contrary to expectations, the Populus sex determination region is not protected from introgression. Understanding the population dynamics of the Populus sex determination region will require tests based on natural interspecific hybrid zones. PMID- 21587300 TI - Genotype and SNP calling from next-generation sequencing data. AB - Meaningful analysis of next-generation sequencing (NGS) data, which are produced extensively by genetics and genomics studies, relies crucially on the accurate calling of SNPs and genotypes. Recently developed statistical methods both improve and quantify the considerable uncertainty associated with genotype calling, and will especially benefit the growing number of studies using low- to medium-coverage data. We review these methods and provide a guide for their use in NGS studies. PMID- 21587302 TI - Multilocus half-tetrad analysis and centromere mapping in citrus: evidence of SDR mechanism for 2n megagametophyte production and partial chiasma interference in mandarin cv 'Fortune'. AB - The genetic structure of 2n gametes and, particularly, the parental heterozygosity restitution at each locus depends on the meiotic process by which they originated, with first-division restitution and second-division restitution (SDR) being the two major mechanisms. The origin of 2n gametes in citrus is still controversial, although sexual polyploidisation is widely used for triploid seedless cultivar development. In this study, we report the analysis of 2n gametes of mandarin cv 'Fortune' by genotyping 171 triploid hybrids with 35 simple sequence repeat markers. The microsatellite DNA allele counting-peak ratios method for allele-dosage evaluation proved highly efficient in segregating triploid progenies and allowed half-tetrad analysis (HTA) by inferring the 2n gamete allelic configuration. All 2n gametes arose from the female genitor. The observed maternal heterozygosity restitution varied between 10 and 82%, depending on the locus, thus SDR appears to be the mechanism underlying 2n gamete production in mandarin cv 'Fortune'. A new method to locate the centromere, based on the best fit between observed heterozygosity restitution within a linkage group and theoretical functions under either partial or no chiasmata interference hypotheses was successfully applied to linkage group II. The maximum value of heterozygosity restitution and the pattern of restitution along this linkage group would suggest there is partial chiasma interference. The implications of such a restitution mechanism for citrus breeding are discussed. PMID- 21587299 TI - Regulation of X-chromosome inactivation by the X-inactivation centre. AB - X-chromosome inactivation (XCI) ensures dosage compensation in mammals and is a paradigm for allele-specific gene expression on a chromosome-wide scale. Important insights have been made into the developmental dynamics of this process. Recent studies have identified several cis- and trans-acting factors that regulate the initiation of XCI via the X-inactivation centre. Such studies have shed light on the relationship between XCI and pluripotency. They have also revealed the existence of dosage-dependent activators that trigger XCI when more than one X chromosome is present, as well as possible mechanisms underlying the monoallelic regulation of this process. The recent discovery of the plasticity of the inactive state during early development, or during cloning, and induced pluripotency have also contributed to the X chromosome becoming a gold standard in reprogramming studies. PMID- 21587303 TI - An autosomal locus controls sex reversal in interspecific XY hybrids of the medaka fishes. AB - Although the two medaka species Oryzias latipes and O. curvinotus share the sex determining gene Dmy, XY sex reversal occurs in interspecific hybridization between O. latipes females of the Hd-rR inbred strain and O. curvinotus males. In this Hd-rR-curvinotus mating, all XX and XY hybrids developed as females. In this study, we used another O. latipes inbred strain (HNI) for the mating, and found that 23% of XY hybrids developed as males, although all XX and the remaining XY hybrids developed as females. Linkage analysis using 236 XY hybrid males obtained from (Hd-rR * HNI) F(1) females showed that a single major locus, Hybrid maleless (Hml), on autosomal linkage group 17, contributed to the strain difference in the XY sex reversal. Furthermore, we found that crossing females of a different O. latipes inbred strain, HO4C, did not cause XY sex reversal in the interspecific hybrids, and that the XY hybrids from (Hd-rR * HO4C) F(1) females showed a 1:1 sex ratio. XY hybrid males had the HO4C allele at sequence-tagged site loci around the Hml locus whereas XY females had the Hd-rR allele, confirming the strong contribution of this locus to XY sex reversal. Reverse transcriptase PCR analysis showed a reduced expression of Dmy(curvinotus) in XY fry of the Hd-rR curvinotus hybrids at hatching. These results suggest that the Hd-rR allele at the Hml locus interfere with the function of Dmy(curvinotus) on a hybrid background, thus resulting in XY sex reversal. PMID- 21587304 TI - The influence of stochastic and selective forces in the population divergence of female colour polymorphism in damselflies of the genus Ischnura. AB - Disentangling the relative importance and potential interactions of selection and genetic drift in driving phenotypic divergence of species is a classical research topic in population genetics and evolutionary biology. Here, we evaluate the role of stochastic and selective forces on population divergence of a colour polymorphism in seven damselfly species of the genus Ischnura, with a particular focus on I. elegans and I. graellsii. Colour-morph frequencies in Spanish I. elegans populations varied greatly, even at a local scale, whereas more similar frequencies were found among populations in eastern Europe. In contrast, I. graellsii and the other five Ischnura species showed little variation in colour morph frequencies between populations. F(ST)-outlier analyses revealed that the colour locus deviated strongly from neutral expectations in Spanish populations of I. elegans, contrasting the pattern found in eastern European populations, and in I. graellsii, where no such discrepancy between morph divergence and neutral divergence could be detected. This suggests that divergent selection has been operating on the colour locus in Spanish populations of I. elegans, whereas processes such as genetic drift, possibly in combination with other forms of selection (such as negative frequency-dependent selection), appear to have been present in other regions, such as eastern Europe. Overall, the results indicate that both selective and stochastic processes operate on these colour polymorphisms, and suggest that the relative importance of factors varies between geographical regions. PMID- 21587305 TI - First-generation linkage map for the common frog Rana temporaria reveals sex linkage group. AB - The common frog (Rana temporaria) has become a model species in the fields of ecology and evolutionary biology. However, lack of genomic resources has been limiting utility of this species for detailed evolutionary genetic studies. Using a set of 107 informative microsatellite markers genotyped in a large full-sib family (800 F1 offspring), we created the first linkage map for this species. This partial map-distributed over 15 linkage groups-has a total length of 1698.8 cM. In line with the fact that males are the heterogametic sex in this species and a reduction of recombination is expected, we observed a lower recombination rate in the males (map length: 1371.5 cM) as compared with females (2089.8 cM). Furthermore, three loci previously documented to be sex-linked (that is, carrying male-specific alleles) in adults from the wild mapped to the same linkage group. The linkage map described in this study is one of the densest ones available for amphibians. The discovery of a sex linkage group in Rana temporaria, as well as other regions with strongly reduced male recombination rates, should help to uncover the genetic underpinnings of the sex-determination system in this species. As the number of linkage groups found (n=15) is quite close to the actual number of chromosomes (n=13), the map should provide a useful resource for further evolutionary, ecological and conservation genetic work in this and other closely related species. PMID- 21587307 TI - Remembering things past. PMID- 21587306 TI - Metal sources and exposures in the homes of young children living near a mining impacted Superfund site. AB - Children living near hazardous waste sites may be exposed to environmental contaminants, yet few studies have conducted multi-media exposure assessments, including residential environments where children spend most of their time. We sampled yard soil, house dust, and particulate matter with aerodynamic diameter <2.5 in 59 homes of young children near an abandoned mining area and analyzed samples for lead (Pb), zinc (Zn), cadmium (Cd), arsenic (As), and manganese (Mn). In over half of the homes, dust concentrations of Pb, Zn, Cd, and As were higher than those in soil. Proximity to mine waste (chat) piles and the presence of chat in the driveway significantly predicted dust metals levels. Homes with both chat sources had Pb, Zn, Cd, and As dust levels two to three times higher than homes with no known chat sources after controlling for other sources. In contrast, Mn concentrations in dust were consistently lower than in soil and were not associated with chat sources. Mn dust concentrations were predicted by soil concentrations and occupant density. These findings suggest that nearby outdoor sources of metal contaminants from mine waste may migrate indoors. Populations farther away from the mining site may also be exposed if secondary uses of chat are in close proximity to the home. PMID- 21587308 TI - Understand memory, design better vaccines. AB - Naive lymphocytes have a finite lifespan and are continually replaced by input from generative organs. In contrast, memory cells or their progeny can last a lifetime. The expanded populations of memory cells and their more widespread distribution provide protection against recurrent infection. PMID- 21587311 TI - GM-CSF: the secret weapon in the T(H)17 arsenal. AB - Identification of the pathogenic cytokines that underlie the IL-23-dependent disease progression of experimental autoimmune encephalomyelitis has proven elusive. Evidence now points to GM-CSF. PMID- 21587310 TI - A BATF-ling connection between B cells and follicular helper T cells. AB - The transcription factor BATF directly regulates key components of the formation and function of follicular helper T cells and antibody class switching in B cells. PMID- 21587312 TI - Fox factors fight over T cell quiescence. AB - The transcription factor Foxp1 helps maintain the quiescence of naive T cells by inhibiting IL-7Ralpha expression and diminishing signaling by the kinase Erk. PMID- 21587321 TI - The causality of de novo copy number variants is overestimated. PMID- 21587322 TI - Establishment of the first WHO international genetic reference panel for Prader Willi and Angelman syndromes. AB - Prader Willi and Angelman syndromes are clinically distinct genetic disorders both mapping to chromosome region 15q11-q13, which are caused by a loss of function of paternally or maternally inherited genes in the region, respectively. With clinical diagnosis often being difficult, particularly in infancy, confirmatory genetic diagnosis is essential to enable clinical intervention. However, the latter is challenged by the complex genetics behind both disorders and the unmet need for characterised reference materials to aid accurate molecular diagnosis. With this in mind, a panel of six genotyping reference materials for Prader Willi and Angelman syndromes was developed, which should be stable for many years and available to all diagnostic laboratories. The panel comprises three Prader Willi syndrome materials (two with different paternal deletions, and one with maternal uniparental disomy (UPD)) and three Angelman syndrome materials (one with a maternal deletion, one with paternal UPD or an epigenetic imprinting centre defect, and one with a UBE3A point mutation). Genomic DNA was bulk-extracted from Epstein-Barr virus-transformed lymphoblastoid cell lines established from consenting patients, and freeze-dried as aliquots in glass ampoules. In total, 37 laboratories from 26 countries participated in a collaborative study to assess the suitability of the panel. Participants evaluated the blinded, triplicate materials using their routine diagnostic methods against in-house controls or externally sourced uncertified reference materials. The panel was established by the Expert Committee on Biological Standardization of the World Health Organization as the first International Genetic Reference Panel for Prader Willi and Angelman syndromes. PMID- 21587323 TI - Fabry or not Fabry--a question of ascertainment. PMID- 21587324 TI - A comparative study of combined small-incision cataract surgery with sutureless trabeculectomy versus trabeculectomy using W-shaped incision. AB - INTRODUCTION: Manual small-incision cataract surgery with trabeculectomy is now an acceptable option in the surgical management of combined cataract and glaucoma uncontrolled with maximum tolerated medical therapy. OBJECTIVE: To compare the results and complications of combined manual small-incision cataract surgery (SICS) and posterior chamber intraocular lens (PCIOL) implantation with trabeculectomy by sutureless versus W-shaped incision technique. MATERIALS AND METHODS: The study included 30 eyes of 28 patients with senile cataract and primary open-angle glaucoma (POAG) who were randomly divided into two groups. The patients in Group A (n = 15) underwent SICS with sutureless trabeculectomy and those in Group B (n =15) underwent SICS with trabeculectomy using W-shaped incision with one suture. Post-operative evaluation was done at the first post operative day and thereafter on follow-ups at 1 week, 2 weeks, 4 weeks and 8 weeks. RESULTS: The mean preoperative and postoperative intraocular pressure (IOP) in Group A was 27.33 +/- 3.35 mmHg and 16.13 +/- 4.30 mmHg respectively and in Group B it was 29.46 +/- 6.06 mmHg and 14.66 +/- 2.69 mmHg respectively. The mean reduction in IOP after 8 weeks of follow-up in Group A was 12.52 +/- 3.59 mmHg and that in Group B was 16.47 +/- 3.79 mmHg (p less than 0.001). Besides this, the uncorrected visual acuity (UCVA) was better in Group B postoperatively with less surgically-induced against-the-rule (ATR) astigmatism. CONCLUSION: Combined SICS with trabeculectomy using W-shaped incision offers better prospective in terms of glaucoma control and visual performance than sutureless combined surgery. PMID- 21587325 TI - Ocular tuberculosis: an update. AB - Tuberculosis (TB) is an infectious disease responsible for significant morbidity and mortality worldwide. It is a resurgent disease in the developed world. The World Health Organization estimates that one third of the world's population is currently infected, with 9 million new cases occurring annually, leading to 3 million deaths per year (WHO Report, 2007). The disease affects the ocular anterior segment, the posterior segment, and adnexa. The purpose of this review is to describe the ocular manifestations, diagnosis and treatment of tuberculosis and to emphasize the fact that ocular tuberculosis may occur in the absence of systemic clinical activity and may mimic several clinical entities. Various studies have shown a clinical significance of purified protein derivative test results and computerized tomography of the chest while, molecular diagnostic procedures have provided a new approach to establishing the diagnosis of ocular tuberculosis. The current review focuses on the diagnostic modalities, various clinical features, and treatments for management of intraocular tuberculosis recommended in recent publications. It is an update on the manifestations and management of ocular tuberculosis. PMID- 21587326 TI - Pilomatrixoma of eyelid in a middle aged. AB - BACKGROUND: Pilomatrixoma , also known as Malherbes's calcifying epithelioma, known to occur in children, is not common especially in middle aged and those below 10 years of age . Pilomatrixoma presents as a firm skin nodule on eye lid or eye brow, so should be considered in the differential diagnosis of such lesions involving eyelids. CASE: A 45-year-old male presented with a swelling in the left upper lid for the last 4 months. There was firm to hard non tender nodule measuring 1.5 cm. x 1.5cm in size on the lateral aspect of the left upper eye lid , involving the lid margin with variegated appearance of overlying skin with a few ulcerated areas on the surface. A presumptive diagnosis of meibomian gland carcinoma was made and an excision biopsy with primary lid repair was carried out. Histopathological examination confirmed the diagnosis of pilomatrixoma. CONCLUSION: The present case is reported to sensitize the ophthalmologists to think beyond chalazion and meibomian gland carcinoma for a firm, nodular, non ulcerated, painless lid swelling. PMID- 21587327 TI - Intrathecal therapy for cancer and non-cancer pain. AB - BACKGROUND: Intrathecal drug infusion therapy is usually considered when spinal acting analgesics or antispasmodics administered via the oral or transdermal routes fail to control patients' pain or are associated with unacceptable side effects. The intrathecal administration of centrally acting agents bypasses the blood-brain-barrier resulting in much higher cerebrospinal fluid (CSF) concentrations while using reduced amounts of medication to achieve equipotent doses. The intrathecal approach is associated with higher rates of satisfactory pain relief and lower rates of treatment failures and technical complications compared to the epidural route. A paucity of randomized controlled trials (RCTs) has led to concern regarding proper use, selection criteria, and safety of these devices. Cost effectiveness and comparative therapies have now also become a focus of discussion. OBJECTIVE: The purpose of this systematic review is to evaluate and update the available evidence for the efficacy and safety of intrathecal infusions used in long-term management (> 6 months) of chronic pain. This paper will not focus on intrathecal administration for spasticity or movement disorders. STUDY DESIGN: A systematic review of intrathecal infusion through implanted drug delivery devices for chronic pain. METHODS: Literature search through EMBASE, Medline, Cochrane databases, and systematic reviews as well as peer-reviewed non-indexed journals from 1980 to December 2010. Studies are assessed using the Agency for Healthcare Research and Quality (AHRQ) criteria for observational studies and the Cochrane Musculoskeletal Review Group criteria for randomized trials. The level of evidence was determined using 5 levels of evidence, ranging from Level I to III with 3 subcategories in Level II, based on the quality of evidence developed by the U.S. Preventive Services Task Force (USPSTF). OUTCOME MEASURES: The primary outcome measure for chronic non-cancer is pain relief (short-term relief <= one-year and long-term > one-year), whereas it is 3 months for cancer. Secondary outcome measures of improvement in functional status, psychological status, return to work, and reduction in opioid intake. RESULTS: The level of evidence for this systematic review of non-cancer pain studies meeting the inclusion criteria of continuous use of an intrathecal drug delivery system (IDDS) for at least 12 months duration with at least 25 patients in the cohort, is Level II-3 based on USPSTF criteria. The level of evidence for this systemic review for cancer-related pain studies meeting the inclusion criteria of continuous use of IDDS for at least 3 months duration with at least 25 patients in the cohort is Level II-2 based on USPSTF criteria. CONCLUSION: Based on the available evidence, the recommendation for intrathecal infusion systems for cancer-related pain is moderate recommendation based on the high quality of evidence and the recommendation is limited to moderate based on the moderate quality of evidence from non-randomized studies for non-cancer related pain. PMID- 21587328 TI - Peripherally acting opioids and clinical implications for pain control. AB - Opioid receptors are widely expressed in the central and peripheral nervous system and in the non-neuronal tissues. Data from animal and human clinical studies support the involvement of peripheral opioid receptors in analgesia, especially in the presence of inflammation. Inflammation has been shown to increase the synthesis of opioid receptors in the dorsal root ganglion neurons and enhance transport and accumulation of opioid receptors in the peripheral terminals of sensory neurons. Under the influence of chemokines and adhesion molecules, opioid peptide-containing immune cells extravasate and accumulate in the injured tissues. Stress, chemokines, cytokines, and other releasing factors in inflamed tissues stimulate these granulocytes to release opioid peptides. Once secreted, opioid peptides bind to and activate peripheral opioid receptors on sensory nerve fibers and produce analgesia by decreasing the excitability of sensory nerves and/or inhibiting release of pro-inflammatory neuropeptides. Research has revealed that local application of exogenous opioid agonists produces a potent analgesic effect by activating peripheral opioid receptors in inflamed tissues. The analgesic activity occurs without activation of opioid receptors in the central nervous system (CNS), and therefore centrally mediated side effects, such as respiratory depression, mental clouding, altered consciousness, or addiction, are not associated with peripheral opioid activity. This discovery has stimulated research on developing peripherally restricted opioid agonists that lack CNS effects. In addition, it has been recognized that opioid receptors modulate inflammation, and that opioids have anti-inflammatory effects. The anti-inflammatory actions of opioids are not well known or understood. Conflicting reports on mu-opioids suggest both anti-inflammatory and pro-inflammatory effects. This article will present the basis for peripheral opioid analgesia and describe current research directed at developing novel treatments for pain with improved side effect profiles. PMID- 21587330 TI - Caudal normal saline injections for the treatment of post-dural puncture headache. AB - BACKGROUND: Post-dural puncture headache (PDPH) is the most common complication of procedures in which the dura mater is penetrated. OBJECTIVES: To evaluate the effectiveness of caudal saline injections as a therapeutic approach for handling post-dural puncture headache. STUDY DESIGN: Prospective observational study between 1995 and 2010. SETTING: Associated teaching hospital. METHODS: A 5-cm 20 gauge short-beveled needle, connected by extension tube to a 20-mL syringe filled with normal saline was used for injection. During injection in increments (limited by patient discomfort), the patients were asked continually to quantify their pain experience on a visual analog scale (VAS) and on a 0-3 verbal categorical rating scale (VRS) after 50, 80 and 100 mL of infusion over a 20 minute period. LIMITATIONS: This study is limited by its sample size, observational design, and lack of long-term outcomes. RESULTS: PDPH occurred in 60 of 1,716 patients undergoing dural puncture (3.5%). It was significantly more common in women and occurred more often in young adults. The rate was highest in the spinal catheter group (13%) and lowest in the Sprotte needle group (0.98%). Fifty-six patients underwent caudal saline injections which were repeated in sessions of 1-2 times a day for 1-2 days. Most patients (n = 48) needed 3 or 4 (n=18) sessions. Mean volumes during the 4 sessions were 120.0 mL, 114.9 mL, 106.5 mL, and 97.8 mL. Four patients were finally treated with a blood patch. CONCLUSIONS: The use of fine gauge pencil-point needles may reduce the incidence of PDPH. The technique of repeated caudal saline injections is easy, rapid, and effective in providing the patient with almost immediate headache relief. In cases where this treatment fails, a blood patch should be considered. Observations from this study suggest that randomized, controlled, double-blind studies may be warranted. PMID- 21587329 TI - Comparative evaluation of the accuracy of benzodiazepine testing in chronic pain patients utilizing immunoassay with liquid chromatography tandem mass spectrometry (LC/MS/MS) of urine drug testing. AB - BACKGROUND: Eradicating or appreciably limiting controlled prescription drug abuse, such as opioids and benzodiazepines, continues to be a challenge for clinicians, while providing needed, proper treatment. Detection of misuse and abuse is facilitated with urine drug testing (UDT). However, there are those who dispute UDT's diagnostic accuracy when done in the office (immunoassay) and claim that laboratory confirmation using liquid chromatography tandem mass spectrometry (LC/MS/MS) is required in each and every examination. STUDY DESIGN: A diagnostic accuracy study of UDT. STUDY SETTING: The study was conducted in a tertiary referral center and interventional pain management practice in the United States. OBJECTIVE: Comparing UDT results of in-office immunoassay testing (the index test) with LC/MS/MS (the reference test). METHODS: A total of 1,000 consecutive patients were recruited to be participants. Along with demographic information, a urine sample was obtained from them. A nurse conducted the immunoassay testing at the interventional pain management practice location; a laboratory conducted the LC/MS/MS. All index test results were compared with the reference test results. The index test's efficiency (agreement) was calculated as were calculations for sensitivity, specificity, false-positive, and false-negative rates. RESULTS: Approximately 36% of the specimens required confirmation. The index test's efficiency for prescribed benzodiazepines was 78.4%. Reference testing improved accuracy to 83.2%, a 19.6% increase, and 8.9% of participants were found to be taking non-prescribed benzodiazepines. The index test's false-positive rate for benzodiazepines use was 10.5% in patients receiving benzodiazepines. LIMITATIONS: This study was limited by its single-site location, its use of a single type of point of care (POC) kit, and reference testing being conducted by a single laboratory, as well as technical sponsorship. CONCLUSION: Clinicians should feel comfortable conducting in-office UDT immunoassay testing. The present study shows that it is reliable, expedient, and fiscally sound for all involved. In-office immunoassay testing compares favorably with laboratory testing for benzodiazepines, offering both high specificity and agreement. However, clinicians should be vigilant and wary when interpreting results, weighing all factors involved in their decision. PMID- 21587331 TI - Double needle technique: an alternative method for performing difficult sacroiliac joint injections. AB - The sacroiliac joint (SIJ) is a common source of low back pain. The most appropriate method of confirming SIJ pain is to inject local anesthesia into the joint to find out if the pain decreases. Unfortunately, although the SIJ is a large joint, it can be difficult to enter due to the complex nature of the joint and variations in anatomy. In my experience a double needle technique for sacroiliac joint injection can increase the chances of accurate injection into the SIJ in difficult cases. After obtaining appropriate fluoroscopic images, the tip of the needle is advanced into the SIJ. Once the tip of the needle is correctly placed, its position is checked under continuous fluoroscopy while moving the C-arm in the right and left oblique directions (dynamic fluoroscopy). On dynamic fluoroscopy the tip of the needle should remain within the joint line and not appear to be on the bone. If the tip of the needle appears to be on the bone a new joint line will need to be identified (the most translucent area through the joint) by dynamic fluoroscopy and another needle advanced into the newly identified joint line. Dynamic fluoroscopy is repeated again to confirm that the tip of the second needle remains within the joint line. Once both needles are in place contrast dye is injected through the needle that is most likely to be in the SIJ. If the contrast dye spread is not satisfactory then it is injected through the other needle. I have used this technique in 10 patients and found it very helpful in accurately performing SIJ injection which can at times be challenging. PMID- 21587333 TI - Peripheral nerve stimulation of the thoracic paravertebral plexus for chronic neuropathic pain. AB - Persistent post surgical pain is reported in 70% of patients following thoracotomy and mastectomy. This pain is often neuropathic in nature and occasionally it is refractory to traditional medical and interventional management. Neurostimulation of peripheral nerves can be a highly effective clinical modality for the management of neuropathic pain. The placement of a percutaneously sited electrode in the thoracic paravertebral plexus offers a new and novel mode of managing refractory thoracic neuropathic pain. We present 2 cases that demonstrate the effectiveness of this intervention in the long-term management of this clinical dilemma. The first case presented is that of a 61 year-old female, with unilateral neuropathic pain for 6 years following mastectomy refractory to traditional interventions. Targeted field stimulation of the thoracic paravertebral plexus resulted in significant improvement for 12 years. The second case is that of a 65-year-old male, with Type II diabetes with neuropathic thoracic pain for 6 years following multiple rib fractures (T4-T7) who responded positively to neurostimulation of the thoracic paravertebral plexus. Both of these cases demonstrate a relative reduction in pain intensity (> 80%), the elimination of oral analgesics, and improved functionality directly related to the novel use of this intervention. Effective and reproducible pain relief is achieved by specifically using a low frequency (10 Hz) and low amplitude (2 mA) stimulation technique. Equally important is that these cases highlight the increased risk of inadvertent pleural puncture with the development of a pneumothorax that can be associated with this intervention. Possible clinical, investigative and equipment modifications that need to be considered are discussed. The limitations include only 2 case reports, considered as the lowest level of evidence available in the era of evidence-based medicine, and lack of utilization of multiple other modalities of treatments utilized in managing neuropathic pain. In conclusion, these cases demonstrate the effectiveness of peripheral nerve stimulation of the thoracic paravertebral plexus in the long-term management of refractory neuropathic pain. They also serve to underline the importance of clinical awareness in order to improve patient safety. PMID- 21587332 TI - Improving the safety of transforaminal epidural steroid injections in the treatment of cervical radiculopathy. AB - BACKGROUND: Unplanned vascular trespass occurs in 20% of cervical transforaminal epidural steroid injections (CTFESI) and rarely results in devastating neurologic complications. The Trucath Spinal Injection System is a novel integrated catheter and needle device that is specifically designed to minimize vascular trespass risk. OBJECTIVE: To compare the vascular trespass incidence with the Trucath Spinal Injection System versus standard spinal needles during CTFESI treatment in patients with cervical radiculopathy. STUDY DESIGN: Prospective, multicenter, nonrandomized safety trial. SETTING: Six tertiary spinal pain management centers in the United States. METHODS: We treated 290 patients (411 levels) with recalcitrant cervical radiculopathy using CTFESI; 129 patients (180 levels) were treated with the Trucath Spinal Injection System (Test group) and 161 patients (231 levels) were treated with standard spinal needles (Control group). All injections were administered via a transforaminal approach. Each site attained IRB approval for this study before any research was performed. The primary study endpoint was vascular trespass per treated level. Secondary endpoints included nerve pain or paresthesia, injection accuracy, device performance measures, and procedural adverse events. RESULTS: Vascular trespass occurred more often (odds ratio (OR): 3.1, 95% Confidence Interval (CI): 1.8-5.4, P < 0.001) in Controls (26.8%, 62/231 levels) versus Test patients (10.6%, 19/180 levels). Radicular pain or paresthesia from device positioning was more frequent (OR: 21.1, 95% CI: 6.9-64.5, P < 0.001) in Controls (26.4%, 61/231) versus Test participants (1.7%, 3/179). Inadequate epiradicular flow was observed in 3.0% (7/231) of Controls and 5.6% (10/179) of Test participants (OR: 0.5, 95% CI: 0.2-1.4, P = 0.22). Based on subjective physician judgment (scale: 1-10), there were no differences between the Test and Control groups, respectively, for ease of use (mean 8.9 vs. 9.0), visualization under fluoroscopy (mean 9.2 vs. 9.0), and overall performance (mean 9.0 vs. 8.6). No additional adverse effects were reported in either treatment group in this clinical study. LIMITATIONS: The study did not randomly allocate the type of injection procedure to participants and no clinical outcomes beyond the initial treatment were collected. CONCLUSIONS: The Trucath Spinal Injection System demonstrated a statistically significant reduction in the rate of intravenous and intra-arterial trespass, procedural pain, and paresthesia, and has similar accuracy and performance versus standard spinal needles for CTFESI treatment of cervical radiculopathy. PMID- 21587334 TI - Pulsed radiofrequency of the sural nerve for the treatment of chronic ankle pain. AB - BACKGROUND: The application of radiofrequency (RF) has been successfully used in the treatment of chronic pain conditions, including facet arthropathy, sacroiliac joint pain, groin pain, radicular pain, cervicogenic headaches, and phantom limb pain. Due to the neurodestructive effect of continuous RF ablation and possible deafferentation sequelae, only pulsed radiofrequency (PRF) has been applied to peripheral sensory nerves. There are no previous reports of successful PRF application to the sural nerve. OBJECTIVES: To report on the successful use of PRF to the sural nerve for the treatment of ankle pain. To discuss current theories on the mechanism by which PRF produces pain relief. METHODS: The report presented here describes the case of a 39-year old patient who sustained injury to her ankle. The patient was complaining of pain in the distribution of the sural nerve, which was confirmed by electrodiagnostic studies. The pain did not respond to oral and topical analgesics. The patient had short-term relief with a sural block with bupivacaine and triamcinolone. The patient then underwent PRF application to the right sural nerve for 240 seconds at 45 volts. RESULTS: The patient reported complete relief. There was no pain recurrence 5 months after the procedure. LIMITATIONS: This report describes a single case report. CONCLUSIONS: It is conceivable that PRF may provide long-term pain relief in cases of sural nerve injury. The exact mechanism of the antinociceptive effect is still unknown. Possible mechanisms include changes in molecular structure by the electric field, early gene expression, stimulation of descending inhibitory pathways, and transient inhibition of excitatory transmission. PMID- 21587335 TI - The use of lumbar sympathetic blockade at L4 for management of malignancy-related bladder spasms. AB - BACKGROUND: Cancer-related bladder spasms may be a rare but severe symptom of bladder or metastatic cancer or its related treatments. Various treatments described in the literature include systemic medications, intravesical or epidural medications, or even sacral neurolectomies. OBJECTIVE: We present 3 patients who have suffered from bladder spasm either from invasion of the bladder wall by tumor (2 patients) or from intravesical chemotherapeutic treatment. DESIGN: Case Report. SETTING: Cancer pain management hospital. METHODS: For each patient, we describe the use of lumbar sympathetic block to successfully treat the bladder spasms. Sympathetic blockade was performed at the left anterolateral border of lumbar vertebra L4. We used 10 mL of local anesthetic (0.25% bupivacaine) delivered in 2 mL aliquots, each given after negative aspiration for heme. Each procedure was performed with fluoroscopic guidance (both AP and lateral views) with the use of iodine contrast (Omnipaque-180) to confirm the location of the medication and its resulting spread. RESULTS: All 3 patients had a reduction in the frequency and intensity of spasms, with 2 out of 3 patients not having a recurrence of the spasms for up to 2 months post procedure and follow up. LIMITATIONS: Case Report. CONCLUSION: Lumbar sympathetic blockade could be a useful treatment for recurrent bladder spasm in the oncologic population. Based on these findings, we feel that the branches of the sympathetic nerve set at L4 may be a good target for neurolytic procedures, such as radiofrequency ablation, for long term treatment of bladder spasms. Further research is necessary to determine the efficacy of this technique for the treatment of bladder spasms in the oncologic population. PMID- 21587336 TI - Intramuscular botulinum toxin A (BtxA) in complex regional pain syndrome. AB - BACKGROUND: Pain associated with complex regional pain syndrome (CRPS) is frequently excruciating and intractable. The use of botulinum toxin for relief of CRPS-associated pain has not been well described. OBJECTIVES: To assess whether intramuscular botulinum toxin injections cause relief of pain caused by CRPS, and to assess the risks of this treatment. STUDY DESIGN: Retrospective chart review. SETTING: Outpatient clinic. METHODS: PATIENTS: 37 patients with spasm/dystonia in the neck and/or upper limb girdle muscles. INTERVENTION: Electromyography guided injection of botulinum toxin A (BtxA), 10-20 U per muscle. Total dose used was 100 U in each patient. MEASUREMENT: Local pain score on an 11 point Likert scale, 4 weeks after BtxA injections. RESULTS: Mean pain score decreased by 43% (8.2 +/- 0.8 to 4.5 +/- 1.1, P < 0.001). Ninety-seven percent of the patients had significant pain relief. One patient had transient neck drop after the injections. LIMITATIONS: This is a retrospective study; it lacks a control group and therefore the placebo effect cannot be eliminated. This study does not provide information on the efficacy of this treatment after 4 weeks. CONCLUSION(S): Intramuscular injection of botulinum toxin A in the upper limb girdle muscles was beneficial for short term relief of pain caused by CRPS in this retrospective case series. The incidence of complications was low (2.7%). PMID- 21587337 TI - The impact of comparative effectiveness research on interventional pain management: evolution from Medicare Modernization Act to Patient Protection and Affordable Care Act and the Patient-Centered Outcomes Research Institute. AB - The Patient-Centered Outcomes Research Institute (PCORI) was established by the Affordable Care Act of 2010 to promote comparative effectiveness research (CER) to assist patients, clinicians, purchasers, and policy-makers in making informed health decisions by advancing the quality and relevance of evidence concerning the manner in which diseases, disorders, and other health conditions can effectively and appropriately be prevented, diagnosed, treated, monitored, and managed through research and evidence synthesis. The development of PCORI is vested in the Medicare Modernization Act (MMA) and the American Recovery and Reinvestment Act (ARRA). The framework of CER and PCORI describes multiple elements which are vested in all 3 regulations including stakeholder involvement, public participation, and open transparent decision-making process. Overall, PCORI is much more elaborate with significant involvement of stakeholders, transparency, public participation, and open decision-making. However, there are multiple issues concerning the operation of such agencies in the United States including the predecessor of Agency for Healthcare Research and Quality (AHRQ), the Agency for Healthcare Policy and Research (AHCPR), AHRQ Effectiveness Health Care programs, and others. The CER in the United States may be described at cross roads or at the beginnings of a scientific era of CER and evidence-based medicine (EBM). However the United States suffers as other countries, including the United Kingdom with its National Health Services (NHS) and National Institute for Health and Clinical Excellence (NICE), with major misunderstandings of methodology, an inordinate focus on methodological assessment, lack of understanding of the study design (placebo versus active control), lack of involvement of clinicians, and misinterpretation of the evidence which continues to be disseminated. Consequently, PCORI and CER have been described as government-driven solutions without following the principles of EBM with an extensive focus on costs rather than quality. It also has been stated that the central planning which has been described for PCORI and CER, a term devised to be acceptable, will be used by third party payors to override the physician's best medical judgement and patient's best interest. Further, stakeholders in PCORI are not scientists, are not balanced, and will set an agenda with an ultimate problem of comparative effectiveness and PCORI that it is not based on medical science, but rather on political science and not even under congressional authority, leading to unprecedented negative changes to health care. Thus, PCORI is operating in an ad hoc manner that is incompatible with the principles of evidence-based practice.This manuscript describes the framework of PCORI, and the role of CER and its impact on interventional pain management. PMID- 21587339 TI - The search for a cure for persistent HIV reservoirs. AB - The persistence of prolonged HIV reservoirs in patients on effective antiretroviral therapy is the main hurdle to HIV eradication. However, major advances have been made over the last few years, both in basic and clinical science of HIV reservoirs. Consequently, the scientific community no longer banishes the term "cure". Despite such renewed hope, there is little investment by both public and private groups in the field. It is therefore imperative to make this a priority and allocate sufficient resources, especially financial support, to aid in finding the cure since there is no effective preventive vaccine. This article discusses the main scientific aspects and strategies to address and build an international task force tackling issues associated with HIV reservoirs. PMID- 21587338 TI - Comprehensive consensus based guidelines on intrathecal drug delivery systems in the treatment of pain caused by cancer pain. AB - BACKGROUND: Chronic persistent pain as a result of terminal illness, either as a consequence of the disease or the necessary treatment, is common in patients with cancer. For these patients with moderate-to-severe intractable pain, intrathecal (IT) drug delivery systems may represent an effective option for pain management. Thus, IT drug delivery is a viable treatment strategy for both neuropathy and nociceptive pain in the cancer population. However, there is a scarcity of comprehensive guidelines in implanting IT drug delivery systems in the treatment of pain caused by cancer. OBJECTIVE: This article outlines consensus guidelines for the implementation of intrathecal therapy in patients with cancer-related pain and other end of life states causing pain. We highlight the multidisciplinary criteria that warrant careful consideration to ensure meaningful analgesia. METHODS: Evidence was compiled, ranked, and strength considered by an invited panel of well-published and innovative clinician research leaders in pain medicine. Based on that analysis, an accumulation of evidence from observational and randomized prospective trials supports the use of intrathecal (IT) drug delivery to provide effective analgesia for patients with cancer-related pain, including individuals at the end of life. Although not all patients are candidates for this invasive treatment modality, clinicians can determine the appropriateness of proceeding with device implantation by carefully evaluating the individual's overall medical status, psychological stability, social support system, and prognosis of disease. Further, consumption of health care resources and cost-effective treatment is becoming more of a priority; not only is this therapy appropriate medically, but also economically. This multifaceted approach to patient selection assists in maximizing treatment effect and avoiding unintended consequences of therapy. LIMITATIONS: The limitations of these guidelines include that these are of expert panel guidelines. The literature describes appropriate preparation of guidelines based on evidence derived from randomized trials and systematic reviews. However, there is also value for consensus-based guidelines due to non-availability of evidence from either systematic reviews of randomized trials or randomized trials alone. In addition, the evidence is not available on many aspects of intrathecal infusion systems even with observational studies and case reports. Thus, the present approach with expert consensus guidelines is acceptable. CONCLUSIONS: These consensus guidelines are intended to assist clinicians in identifying the candidacy of patients with cancer-related pain and end of life diseases causing pain that may benefit from intrathecal drug delivery. With careful consideration of the patient's medical comorbidities and prior therapies, communication with the oncologist, proper psychological evaluation, and appropriate trialing technique, clinicians can effectively optimize the use of IT therapy for cancer pain. The panel advocates for a much wider application of IT therapy to provide meaningful analgesia for patients with cancer pain, including those at the end of life from a variety of causes. PMID- 21587340 TI - Natural killer cells in HIV-1 infection: a double-edged sword. AB - In order to propagate and persist within the host, HIV-1 subverts a variety of checkpoints of innate and adaptive viral immunosurveillance. Many of these are related to natural killer cells, which bridge innate and adaptive immunity and play a major role in defeating virus infections. HIV-1 affects cytotoxicity of natural killer cells towards infected cells and natural killer cell-mediated priming of effector cells of the adaptive immune system. Moreover, a subpopulation of natural killer cells was found sensitive to infection by HIV-1. Consequently, an efficient immune response against HIV-1 cannot be mounted in most patients. The current review highlights the molecular interplay between HIV 1 and effector cells of the host immune system with a focus on natural killer cells, and summarizes strategies of HIV-1 to escape from natural killer cell immunosurveillance. A detailed knowledge of these immune escape strategies might lead to the identification of access points for intervention in order to block infection and progression to AIDS. PMID- 21587341 TI - European recommendations for the clinical use of HIV drug resistance testing: 2011 update. AB - The European HIV Drug Resistance Guidelines Panel, established to make recommendations to clinicians and virologists, felt that sufficient new information has become available to warrant an update of its recommendations, explained in both pocket guidelines and this full paper. The Panel makes the following recommendations concerning the indications for resistance testing: for HIV-1 (i) test earliest sample for protease and reverse transcriptase drug resistance in drug-naive patients with acute or chronic infection; (ii) test protease and reverse transcriptase drug resistance at virologic failure, and other drug targets (integrase and envelope) if such drugs were part of the failing regimen; (iii) consider testing for CCR5 tropism at virologic failure or when a change of therapy has to be made in absence of detectable viral load, and in the latter case test DNA or last detectable plasma RNA; (iv) consider testing earliest detectable plasma RNA when a successful nonnucleoside reverse transcriptase inhibitor-containing therapy was inappropriately interrupted; (v) genotype source patient when postexposure prophylaxis is considered; for HIV-2, (vi) consider resistance testing where treatment change is needed after treatment failure. The Panel recommends genotyping in most situations, using updated and clinically evaluated interpretation systems. It is mandatory that laboratories performing HIV resistance tests take part regularly in external quality assurance programs, and that they consider storing samples in situations where resistance testing cannot be performed as recommended. Similarly, it is necessary that HIV clinicians and virologists take part in continuous education and discuss problematic clinical cases. Indeed, resistance test results should be used in the context of all other clinically relevant information for predicting therapy response. PMID- 21587342 TI - The role of HIV and antiretroviral therapy in bone disease. AB - Current knowledge suggests that both HIV and antiretroviral drugs are likely to contribute to bone disorders in patients with HIV infection. This article includes a review and update on the part played by the virus and the drugs in the low bone mineral density of HIV-infected patients, and a discussion about their implications in clinical practice. HIV viral proteins may affect osteoblast and osteoclast function, and many clinical studies have shown that during antiretroviral therapy, especially at the beginning, there is an accelerated bone mineral loss associated with bone resorption markers, which may be of differing intensity depending on the HIV drugs used. Vitamin D insufficiency/deficiency is highly prevalent and in some investigations it has been associated with antiretroviral therapy, more often with regimens based on efavirenz. Recent data suggest that immune reconstitution may play a major role in early antiretroviral therapy-related bone loss. Given the complex interaction between HIV and drugs in causing low bone mineral density, optimization of antiretroviral therapy and preemptive strategies aimed to prevent bone loss during therapy may be of paramount importance. PMID- 21587344 TI - Paradoxical Patellar Reflex As A Presenting Sign Of Acute Inflammatory Demyelinating Polyradiculoneuropathy. AB - We report a case of paradoxical patellar reflex as a presenting sign of acute inflammatory demyelinating polyradiculoneuropathy. PMID- 21587343 TI - Cardiovascular risk factors and HIV disease. AB - An increased rate of coronary heart diseases is becoming an important cause of morbidity and mortality among HIV-infected patients. This emerging problem is due to the antiretroviral therapy success that allows HIV-positive patients to live longer. Increased coronary heart disease rates in the HIV population, as in the noninfected population, may be related to traditional risk factors, including advancing age, higher smoking rates, dyslipidemia, insulin resistance, and impaired glucose tolerance. Some nontraditional factors have to be considered too: these are due to the direct effects of the virus on the vasculature, as well as to direct effects of specific antiretroviral drugs, including inflammation, endothelial dysfunction, metabolic disorders, prothrombotic state, and changes in body composition with loss of subcutaneous fat and/or accumulation of visceral fat. The aim of this paper is to review traditional and emerging cardiovascular risk factors and consider their possible interactions in HIV-infected patients. PMID- 21587345 TI - NaAg(2)Mo(3)O(9)AsO(4). AB - The title compound, sodium disilver arsenatotrimolybdate, Na(0.93 (1))Ag(2.07 (1))Mo(3)AsO(13), was prepared by a solid-state reaction. In the crystal structure, isolated AsO(4) tetra-hedra share corners with groups of three edge sharing MoO(6) octa-hedra. This arrangement leads to the formation of anionic (1) (infinity)[Mo(3)AsO(13)](n) ribbons extending parallel to [100]. The three metal sites show occupational disorder by Ag(I) and Na(I) cations, each with a different Ag:Na ratio. The metal cations are situated in the space between the ribbons and are surrounded by terminal O atoms of the ribbons in the form of distorted MO(7) polyhedra (M = Ag, Na) for distances < 3.0 A. The title compound shows weak ionic conductivity. Structural relationships between different compounds in the quaternary systems M-Sb-P-O, M-Nb-P-O and M-Mo-As-O (M is Ag or an alkali metal) are also discussed. PMID- 21587346 TI - Poly[diaqua-tetra-MU-seleno-cyanato-cadmium(II)dipotassium(I)]. AB - In the title compound, [CdK(2)(NCSe)(4)(H(2)O)(2)](n), the cadmium(II) cation is situated on a twofold rotation axis and is coordinated in a slightly distorted tetra-hedral geometry by two symmetry-related MU-1,1,1,3 and two-symmetry related MU-1,1,3,3 bridging seleno-cyanate anions, all of which are Se bonded. These bridging seleno-cyanate anions are further coordinated to two symmetry-related potassium ions. Each of the potassium ions is coordinated by one terminally bonded water mol-ecule and six seleno-cyanate anions, two of which are crystallographically independent. The asymmetric unit consists of one cadmium and one potassium cation, two bridging seleno-cyanate anions and one water mol-ecule. The polymeric subunits are further connected via the seleno-cyanate anions into a three-dimensional coordination network. In this coordination network, intramolecular hydrogen bonds between neighbouring water molecules can be found. PMID- 21587347 TI - A ramsayite-type oxide, Ca(2)Sn(2)Al(2)O(9). AB - The title compound, dicalcium nonaoxidodistannate(IV)dialuminate, is the second example which crystallizes in the isotypic structure of a pyroxene silicate, Na(2)Ti(2)Si(2)O(9) (ramsayite). (infinity) (1)[Sn(2)O(8)] chains and pyroxene type (infinity) (1)[Al(2)O(6)] chains are formed along the b axis by sharing O atoms. The Ca atoms are situated in the resulting channels and exhibit a coordination number of 7. PMID- 21587348 TI - V(1.42)in(1.83)mo(15)se(19). AB - The structure of the title compound, vanadium indium penta-deca-molybdenum nona deca-selenide, V(1.42)In(1.83)Mo(15)Se(19), is isotypic with In(2.9)Mo(15)Se(19) [Gruttner et al. (1979 ?). Acta Cryst. B35, 285-292]. It is characterized by two cluster units Mo(6)Se(i) (8)Se(a) (6) and Mo(9)Se(i) (11)Se(a) (6) (where i represents inner and a apical atoms) that are present in a 1:1 ratio. The cluster units are centered at Wyckoff positions 2b and 2c and have point-group symmetry and , respectively. The clusters are inter-connected through additional Mo-Se bonds. In the title compound, the V(3+) cations replace the trivalent indium atoms present in In(2.9)Mo(15)Se(19), and a deficiency is observed on the monovalent indium site. One Mo, one Se and the V atom are situated on mirror planes, and two other Se atoms and the In atom are situated on threefold rotation axes. PMID- 21587349 TI - catena-Poly[[diaqua-strontium(II)]-bis-[MU-2-(3-benzoyl-phen-yl)propano-ato]]. AB - In the title coordination polymer, [Sr(C(16)H(13)O(3))(2)(H(2)O)(2)](n), the Sr(II) cation is eight-coordinated by six O atoms from four different 2-(3 benzoyl-phen-yl)propano-ate ligands and two O atoms of two water mol-ecules in a distorted dodeca-hedral geometry. Adjacent Sr(II) cations are bridged by two 2-(3 benzoyl-phen-yl)propano-ate ligands, forming an infinite chain along the b axis; the chains are further linked by inter-molecular O-H-O hydrogen bonds into a three-dimensional supra-molecular network. PMID- 21587350 TI - Acetato-(N-[(E)-1-(6-methyl-2-pyrid-yl)methyl-idene]-2-{2-[(E)-1-(6-methyl-2 pyrid-yl)methyl-idene-amino]-pheneth-yl}aniline)nickel(II) perchlorate. AB - In the title complex, [Ni(CH(3)COO)(C(28)H(26)N(4))]ClO(4), the Ni(II) atom is coordinated by two imine N atoms and two pyridine N atoms of the N-[(E)-1-(6 methyl-2-pyrid-yl)methyl-idene]-2-(2-[(E)-1-(6-methyl-2-pyrid-yl)methyl-idene amino]-pheneth-yl)aniline donor ligand and two O atoms of the acetate ion in a distorted octa-hedral coordination. The average Ni-N and Ni-O bond lengths are 2.131 (13) and 2.098 (11) A, respectively. An intramolecular N-H?O inter-action occurs. Relatively weak inter-molecular C-H?O inter-actions between the ligands and the ClO(4) (-) ions result in a chain extending along the b axis. PMID- 21587351 TI - A tetra-silver(I)ditungsten(VI) cluster with sulfide and bis-(diphenyl phosphino)methane ligands. AB - The asymmetric unit of the title complex, [Ag(4)W(2)S(8)(C(25)H(22)P(2))(3)].2C(3)H(7)NO, tris-[MU(2)-bis-(diphenyl phosphino)meth-ane]-3:6kappa(2)P:P';4:5kappa(2)P:P';5:6kappa(2)P:P'-MU(5)-sulfido 2:3:4:5:6kappa(5)S-MU(3)-sulfido-1:3:4kappa(3)S-tetra-MU(2)-sulfido 1:3kappa(2)S;1:4kappa(2)S;2:5kappa(2)S;2:6kappa(2)S-disulfido-1kappaS,2kappaS tetra-silver(I)ditungsten(VI) N,N-dimethyl-formamide disolvate, contains two [WS(4)](2-) anions, four silver cations, three bidentate-bridging bis-(diphenyl phosphino)methane (dppm) ligands and two N,N-dimethyl-formamide (DMF) solvent mol ecules. The coordination geometry of each Ag atom is distorted tetra-hedral. Two Ag ions are coordinated by MU(2)-S and MU(5)-S atoms, and by two P atoms from two dppm ligands, while the other two Ag atoms are coordinated by MU(2)-S, MU(3)-S and MU(5)-S atoms, and by one P atom from a dppm ligand. PMID- 21587352 TI - A two-dimensional manganese(II) complex: poly[bis-(MU(2)-4,4'-bipyrid-yl)tetra kis-(MU(2)-3,5-dinitro-benzoato)dimanganese(II)]. AB - The Mn atom in the title compound, [Mn(2)(C(7)H(3)N(2)O(6))(4)(C(10)H(8)N(2))(2)](n), is six-coordinated by two N atoms and four O atoms, forming a distorted octa-hedral geometry. The Mn-O bond lengths are in the range 2.1281 (13)-2.2011 (12) A and the Mn-N bond lengths are 2.269 (2) and 2.278 (2) A. Mn(II) atoms are double-bridged along the a axis by two pairs of bi-monodentate carboxyl groups, forming a double-stranded chain, while the bidentate 4,4'-bipyridine ligand bridges the Mn atom along the b axis. This results in a two-dimensional structure constructed of oblong grids with the sides of length 11.634 and 5.075 A PMID- 21587353 TI - Aqua-(9,10-dioxoanthracene-1,5-disul-fonato-kappaO)bis-(1,10-phenanthroline kappaN,N')nickel(II). AB - In the mononuclear title complex, [Ni(C(14)H(6)O(8)S(2))(C(12)H(8)N(2))(2)(H(2)O)], the Ni(II) atom is in a distorted octa-hedral coordination formed by four N atoms from two chelating 1,10 phenanthroline ligands and by two O atoms, one from a 9,10-dioxoanthracene-1,5 disulfonate ligand and the other from a water mol-ecule. An intra-molecular O-H?O hydrogen bond occurs. In the crystal, inter-molecular O-H?O hydrogen bonds link the mononuclear complexes into chains extending parallel to [010]. Furthermore, pi-pi stacking inter-actions [centroid-centroid distance = 3.5696 (6) A] stabilize the crystal structuure. PMID- 21587354 TI - Bis(carbonyl-kappaC)(N,N-dimethyl-thio-carbamoyl-kappaC,S)(pyridine-2-thiol-ato kappaN,S)(triphenyl-phosphine-kappaP)molybdenum(II). AB - There are two independent mol-ecules with similar configurations in the title complex, [Mo(C(3)H(6)NS)(C(5)H(4)NS)(C(18)H(15)P)(CO)(2)]. The geometry around the metal atom is that of a capped octa-hedron. The thio-cabamoyl and pyridine-2 thiol-ate ligands coordinate to the molybdenum metal center through the C and S atoms, and N and S atoms, respectively. NMR, IR and MS analyses are in agreement with the structure of the title compound. PMID- 21587356 TI - catena-Poly[[tetra-kis-(hexa-methyl-phospho-ramide-kappaO)bis-(nitrato kappaO,O')dysprosium(III)] [silver(I)-di-MU-sulfido-tungstate(VI)-di-MU sulfido]]. AB - Hexa-methyl-phospho-ramide (hmp), tetra-thio-tungstate, silver sulfide and dysprosium nitrate were self-assembled, forming an anionic [AgWS(4)](n) (n) (-) chain in the title compound, {[Dy(NO(3))(2)(C(6)H(18)N(3)OP)(4)][AgWS(4)]}(n). The central Dy atom in the cation is coordinated by eight O atoms from two didentate nitrate and four hmp ligands, giving rise to a distorted square anti prismatic structure. Together with the two nitrate ligands, the cation is univalent, which leads to the anionic chain having a [WS(4)Ag] repeat unit. The polymeric anionic chain, with W-Ag-W and Ag-W-Ag angles 161.16 (2) and 153.606 (11) degrees , respectively, presents a distorted linear configuration. The title compound is isotypic with other rare earth complexes. PMID- 21587355 TI - Undeca-carbonyl-1kappaC,2kappaC,3kappaC-[tris-(2-chloro-eth-yl) phosphite 1kappaP]-triangulo-triruthenium(0). AB - In the title triangulo-triruthenium compound, [Ru(3)(C(6)H(12)Cl(3)O(3)P)(CO)(11)], one equatorial carbonyl ligand is substituted by a monodentate phosphite ligand, leaving one equatorial and two axial carbonyl ligands on one Ru atom. The remaining two Ru atoms each carry two equatorial and two axial terminal carbonyl ligands. In the crystal structure, the mol-ecules are linked into a one-dimensional column along [100] by inter molecular C-H?O hydrogen bonds. PMID- 21587357 TI - [MU-N,N,N',N'-Tetra-kis(2-pyridyl-meth-yl)butane-1,4-diamine]-bis-[diacetato cadmium(II)] nona-hydrate. AB - The title dinuclear complex, [Cd(2)(CH(3)CO(2))(4)(C(28)H(32)N(6))].9H(2)O, is located on a crystallographic inversion center. The unique Cd(II) ion displays a 5 + 2 coordination. A distorted square-pyramidal geometry is formed by the dipicolyl-amine unit of the ligand via the N atoms in a meridional fashion and two O atoms of the acetate ligands with short Cd-O distances. The coordination is completed by two loosely bound O atoms of the acetate ligands. The Cd-N distances involving the pyridine N atoms differ slightly from each other and the Cd-N distance involving the tertiary N atom is the longest. In the crystal structure, complex mol-ecules and solvent water mol-ecules are connected into a three dimensional network via inter-molecular O-H?O hydrogen bonds. One of the water mol-ecules lies on a twofold rotation axis. PMID- 21587358 TI - [MU-N,N,N',N'-Tetra-kis(2-pyridyl-meth-yl)butane-1,4-diamine]-bis [dinitratocadmium(II)]. AB - The title dinuclear cadmium complex, [Cd(2)(NO(3))(4)(C(28)H(32)N(6))], is located on an inversion center. The unique Cd(II) ion displays a 5 + 2 coordination. A distorted square-pyramidal geometry is formed by the dipicolyl amine group of the ligand via the N atoms in a meridional fashion and two O atoms of the nitrate ligands with short Cd-O distances. The coordination is completed by two loosely bound O atoms of the nitrate ligands. PMID- 21587359 TI - [MU-N,N,N',N'-Tetra-kis(2-pyridyl-meth-yl)butane-1,4-diamine]-bis [dibromidocopper(II)]. AB - The title dinuclear copper complex, [Cu(2)Br(4)(C(28)H(32)N(6))], is located on an inversion center. The unique Cu(II) ion is in a slightly distorted square pyramidal environment in which the N atoms of a dipicolyl-amine group and a bromide ligand form the basal plane. The apical site is occupied by a second Br atom. While the Cu-N distances involving the pyridine N atoms are the same within experimental error, the Cu-N distance involving the tertiary N atom is slightly elongated. Due to the typical Jahn-Teller distortion of copper(II) complexes, the apical Cu-Br distance is elongated. PMID- 21587360 TI - [MU-N,N,N',N'-Tetra-kis(2-pyridyl-meth-yl)butane-1,4-diamine]-bis-[dichlorido copper(II)] trihydrate. AB - The title dinuclear copper complex, [Cu(2)Cl(4)(C(28)H(32)N(6))].3H(2)O, is located on a crystallographic inversion center. The unique Cu(II) ion is coordinated in a slightly distorted square-pyramidal environment in which the N atoms of the dipicolyl-amine group and a chloride ligand form the basal plane. The apical position is occupied by a second chloride atom. While the Cu-N distances of the pyridine N atoms are the same within expermental error, the Cu-N distance to the tertiary N atom is slightly elongated. The apical Cu-Cl distance is elongated due to typical Jahn-Teller distortion. One of the water O atoms was refined as disordered over two sites with occupancies 0.734 (17):0.266 (17) and another with half occupancy. H atoms for the disordered solvent atoms were not included in the refinement. PMID- 21587361 TI - [MU-N,N,N',N'-Tetra-kis-(2-pyridyl-meth-yl)pentane-1,5-diamine]-bis-[dichlorido copper(II)] sesquihydrate. AB - In the title dinuclear copper complex, [Cu(2)Cl(4)(C(29)H(34)N(6))].1.5H(2)O, both Cu(II) ions are coordinated in a slightly distorted square-pyramidal environment in which the N atoms of the dipicolyl-amine group and a chloride ligand form the basal plane. The apical position is occupied by a second chloride atom. The Cu-N distances involving the pyridine N atoms differ slightly from each other and the Cu-N distance involving the tertiary N atom is the longest. The apical Cu-Cl distance is elongated compared to its basal counterpart due to typical Jahn-Teller distortion. In the crystal structure, complex and water mol ecules are linked via inter-molecular O-H?O and O-H?Cl hydrogen bonds into chains along [001]. One of the water mol-ecules was refined with half occupancy. PMID- 21587363 TI - Tetra-aqua-bis-(MU(2)-4,4'-bipyridine)-dodeca-kis-(MU(2)-2-methyl-prop-2 enoato)octa-kis-(2-methyl-prop-2-enoato)tetra-ytterbium(III)tetra-zinc(II). AB - The asymmetric unit of the title compound, [Yb(4)Zn(4)(C(4)H(5)O(2))(20)(C(10)H(8)N(2))(2)(H(2)O)(4)], contains half of a centrosymmetric octa-nuclear mol-ecule in which each Zn(II) ion is four coordinated by three O atoms from three 2-methyl-prop-2-enoate (L) ligands and one N atom from a 4,4'-bipyridine (bipy) ligand in a distorted pyramidal geometry. The two independent Yb(III) ions, each coordinated by eight O atoms in an irregular geometry, exhibit different coordination environments, viz. one water mol-ecule, five bridging bidentate and one chelating bidentate carboxyl-ate groups for one Yb(III) ion, and one water mol-ecule, three bridging bidentate and two chelating bidentate carboxyl-ate groups for the other Yb(III) ion. In the crystal structure, inter-molecular O-H?O and C-H?O hydrogen bonds help to establish the packing. PMID- 21587362 TI - [(2-Pyrid-yl)methanol-kappaN,O]bis-(thio-cyanato-kappaN)manganese(II). AB - In the title complex, [Mn(NCS)(2)(C(6)H(7)NO)(2)], the Mn(II) atom shows site symmetry 2. The distorted octa-hedral environment of Mn(II) is defined by two N atoms [Mn-N = 2.217 (4) and 2.132 (5) A] and one O atom [Mn-O 2.305 (4) A]. There are inter-molecular O-H?S hydrogen bonds and inter-molecular pi-pi stacking inter actions between adjacent (2-pyrid-yl)methano-late ligands [centroid-centroid distance = 3.5569 (7) A], leading to a chain structure running along [100]. PMID- 21587364 TI - Bis[2-(1H-pyrazol-3-yl-kappaN)pyridine-kappaN]dithio-cyanato-kappaN,kappaS cadmium(II). AB - The mol-ecular structure of the mononuclear complex, [Cd(SCN)(2)(C(8)H(7)N(3))(2)], contains a Cd(II) atom in a distorted octa-hedral coordination defined by five N atoms from two bidentate chelate 2-(1H-pyrazol-3 yl)pyridine ligands and by one SCN(-) anion. The second SCN(-) anion provides its S atom for completion of the coordination sphere. The complex is linked to four others by N-H?N and N-H?S hydrogen-bonding inter-actions between the pyrazol N-H group and the terminal S and N atoms of neighbouring SCN(-) anions. This arrangement leads to the formation of sheets parallel to (100). Face-to-face pi pi stacking inter-actions with shortest inter-planar distances of 3.805 (2) and 3.696 (2) A help to consolidate the crystal packing. PMID- 21587365 TI - Aqua-(benzene-1,2-dicarboxyl-ato-kappaO)bis-[2-(1H-pyrazol-3-yl-kappaN)pyridine kappaN]cadmium(II). AB - In the mononuclear title complex, [Cd(C(8)H(4)O(4))(C(8)H(7)N(3))(2)(H(2)O)], the Cd(II) atom is six-coordinated in a distorted octa-hedral geometry by four N atoms from two bidentate chelating 2-(1H-pyrazol-3-yl)pyridine ligands, one O atom from a benzene-1,2-dicarboxyl-ate ligand and one water mol-ecule. The mol ecular structure features intra-molecular O-H?O and N-H?O hydrogen bonds. In the crystal structure, the complex mol-ecules are assembled into a two-dimensional supra-molecular layer parallel to (011) via O-H?O and N-H?O hydrogen bonds and pi pi stacking inter-actions between the pyridyl and pyrazole rings [centroid centroid distances = 3.544 (2) and 3.722 (3) A]. PMID- 21587367 TI - A dimeric zinc(II) complex: bis-[MU-1,2-bis-(1,2,4-triazol-4-yl)ethane kappaN:N]bis-[dinitritozinc(II)]. AB - The coordination geometry of the Zn(II) atom in the title complex, [Zn(2)(NO(2))(4)(C(6)H(8)N(6))(2)], is distorted octa-hedral, in which the Zn(II) atom is coordinated by two N atoms from the triazole rings of two symmetry related 1,2-bis-(1,2,4-triazol-4-yl)ethane ligands and four O atoms from two nitrite ligands. Two Zn(II) atoms are bridged by two organic ligands, forming a centrosymmetric dimer. Weak C-H?N and C-H?O hydrogen bonds play an important role in the inter-molecular packing. PMID- 21587368 TI - Poly[(MU(2)-2,2'-bipyridine-kappaN:N')bis-(MU(3)-2,2,2-trifluoro-acetato kappaO:O:O')disilver(I)]. AB - In the title salt, [Ag(2)(CF(3)CO(2))(2)(C(10)H(8)N(2))](n), which may also be regarded as a coordination polymer if long Ag?O inter-actions are considered, each of the N atoms of the somewhat twisted 2,2'-bipyridine mol-ecule [N-C-C-N = 27.5 (4) degrees ] binds to an Ag atom, and each of the carboxyl-ate ligands is tridentate, linking to three Ag atoms. The bidentate carboxyl-ate O atoms bridge the same two Ag atoms, resulting in the formation of Ag(2)O(2) rings. These rings are bridged by the 2,2'-bipyridine ligands, forming a chain along the b axis. The chains are linked into double chains via the remaining Ag-O bonds and Ag?Ag contacts. As a consequence of the Ag?Ag contacts, the NO(4) donor set about each Ag atom is heavily distorted. Finally, the chains are linked into a three dimensional network by a combination of C-H?O and C-H?F inter-actions. PMID- 21587369 TI - Aqua-(trifluoro-methane-sulfonato)-bis-(1,3,7-trimethyl-purine-2,6 dione)silver(I). AB - In the title compound, [Ag(CF(3)SO(3))(C(8)H(10)N(4)O(2))(2)(H(2)O)], the Ag(I) atom is coordinated by two caffeine N atoms and, at longer distances, two O atoms of a coordinated water mol-ecule and the trifluoro-methane-sulfonate anion, resulting in an AgN(2)O(2) seesaw geometry. The caffeine mol-ecules are roughly coplanar [dihedral angle = 5.81 (5) degrees ]. In the crystal, mol-ecules self assemble into a linear supra-molecular chain along the c axis via O-H?O hydrogen bonds involving the coordinated water moledcule and carbonyl O atoms. The packing is consolidated by weak C-H?O inter-actions. PMID- 21587366 TI - Dichloridobis[2-(2-fur-yl)-1-(2-furylmeth-yl)-1H-benzimidazole kappaN]cadmium(II). AB - In the title complex, [CdCl(2)(C(16)H(12)N(2)O(2))(2)], the Cd(II) ion exhibits site symmetry 2. It shows a distorted tetra-hedral coordination defined by two N atoms from symmetry-related 2-(2-fur-yl)-1-(2-furylmeth-yl)-1H-benzimidazole ligands and by two symmetry-related Cl atoms. Intra-molecular C-H?O hydrogen bonds stabilize the mol-ecular configuration. Adjacent mol-ecules are linked through C-H?Cl hydrogen bonds into a network structure. PMID- 21587370 TI - catena-Poly[[[(2-pyridone-kappaO)silver(I)]-MU-2-pyridone-kappaO:O] hexa-fluorido phosphate]. AB - The asymmetric unit of the polymeric title salt, {[Ag(C(5)H(5)NO)(2)]PF(6)}(n), comprises an Ag(I) cation (located on a twofold axis), two 2-pyridone ligands (with distinct coordination modes), and half a PF(6) (-) anion (situated on a centre of inversion). The Ag(I) atom is in an approximately octa-hedral AgO(6) coordination geometry, which is stabilized by intra-molecular N-H?O hydrogen bonds. The result of the bridging mode of the 2-pyridone ligand is the formation of a supra-molecular chain along the c axis; these are consolidated in the crystal by C-H?F inter-actions. PMID- 21587371 TI - (2,2'-Bipyridine-kappaN,N')tetra-bromidoplatinum(IV). AB - In the title complex, [PtBr(4)(C(10)H(8)N(2))], the Pt(IV) ion has a slightly distorted octa-hedral coordination defined by two N atoms of the chelating 2,2' bipyridine ligand and four bromide ions. As a result of the different trans effects of the N and Br atoms, the Pt-Br bonds trans to the N atom are slightly shorter than those to mutually trans Br atoms. In the crystal structure, the mol ecules are arranged in a V-shaped packing pattern along the b axis and stacked in columns along the a axis. In the columns, several inter-molecular pi-pi inter actions between the pyridine rings are present. The shortest ring centroid centroid distance is 3.921 (6) A, with a dihedral angle of 1.6 (5) degrees between the ring planes. The complexes are connected by C-H?Br hydrogen bonds, forming chains along the b axis. PMID- 21587372 TI - Poly[(MU(4)-biphenyl-3,3'-dicarboxyl-ato)bis[MU(2)-1,1'-(butane-1,4-di yl)diimidazole](MU(2)-oxalato)dimanganese(II)]. AB - In the title coordination compound, [Mn(2)(C(14)H(8)O(4))(C(2)O(4))(C(10)H(14)N(4))(2)](n), the biphenyl-3,3' dicarboxyl-ate and oxalate anions, both situated on inversion centres, function in a bridging mode, linking the dinuclear Mn(II) atoms into wave-like layers. Each 1,1'-(1,4-butane-1,4-di-yl)diimidazole ligand coordinates to two Mn(II) atoms located in adjacent layers via Mn-N coordination bonds, giving a three dimensional network. As the methyl-ene groups can bend freely relative to each other due to the C atoms connected via single bonds, the 1,1'-(butane-1,4-di yl)diimidazole ligand forms an S-shaped conformation, which makes the void in the three-dimensional network distorted. PMID- 21587373 TI - {2,6-Bis[(4-bromo-phen-yl)imino-meth-yl]pyridine-kappaN,N',N''}trichlorido chromium(III). AB - In the title compound, [CrCl(3)(C(19)H(13)Br(2)N(3))], the Cr(3+ )ion is coordinated by the tridentate 2,6-bis-[(4-bromo-phen-yl)imino-meth-yl]pyridine Schiff base ligand in a fac-octa-hedral geometry. The dihedral angles between the pyridine and benzene rings are 23.9 (6) and 70.7 (1) degrees . PMID- 21587374 TI - catena-Poly[[(1,10-phenanthroline-kappaN,N')copper(I)]-MU-thio-cyanato-kappaN:S]. AB - In the title complex, [Cu(NCS)(C(12)H(8)N(2))](n), the Cu(I) ion is in a distorted tetra-hedral CuN(3)S coordination geometry. The thio-cyanate ligand acts as bridging ligand, forming chains along [100]. A crystallographic mirror plane runs through the Cu(I) ion, the thio-cyanate ligand and the middle of the phenanthroline ligand. PMID- 21587375 TI - Chlorido[tris-(3-fluoro-phen-yl)phosphine]gold(I). AB - In the title gold complex, [AuCl(C(18)H(12)F(3)P)], the P-Au-Cl unit is nearly linear, with an angle of 178.13 (5) degrees . The three phosphine-substituted benzene rings make dihedral angles of 77.7 (3), 84.4 (3) and 77.4 (3) degrees with each other. Two of the three F atoms are disordered over two positions, with refined site occupancies of 0.591 (11):0.409 (11) and 0.730 (12):0.270 (12). In the crystal structure, mol-ecules are linked into a three-dimensional network by inter-molecular C-H?Cl and C-H?F hydrogen bonds. PMID- 21587376 TI - Aqua-bis-[4-(methyl-sulfan-yl)benzoato-kappaO]bis-(pyridine-kappaN)copper(II). AB - In the title mol-ecule, [Cu(C(8)H(7)O(2)S)(2)(C(5)H(5)N)(2)(H(2)O)], the Cu(II) ion is penta-coordinated in a distorted square-pyramidal geometry by two O atoms of two 4-(methyl-sulfan-yl)benzoate anions and two N atoms of two pyridine ligands and a water O atom situated at the apical site. In the crystal structure, O-H?O hydrogen bonds link mol-ecules into chains along the b axis. PMID- 21587377 TI - Poly[[tris-(N,N-dimethyl-formamide)(MU(4)-5-nitro-isophthalato)(MU(3)-5-nitro isophthalato)dicobalt(II)] N,N-dimethyl-formamide monosolvate]. AB - In the polymeric title compound, [Co(2)(C(3)H(7)NO)(3)(C(8)H(3)NO(6))(2)].C(3)H(7)NO, one 5-nitro-isophthalate dianion has its two carboxyl-ate groups chelating to one Co(II) atom while simultaneously coordinating to another metal atom in a MU(4)-bridging mode. The other 5-nitro-isophthalte dianion has one carboxyl-ate group chelating to a metal atom whereas the other bridges two metal atoms in a MU(3)-bridging mode. Both metal atoms show an octa-hedral coordination. The polymer adopts a layer motif, with the lattice dimethyl-formamide mol-ecules occupying the space between adjacent layers. PMID- 21587378 TI - catena-Poly[[tribenzyl-tin(IV)]-MU-2-(piperidin-1-ylcarbothio-ylsulfan-yl)acetato kappaO:O']. AB - The Sn atom in the title polymeric compound, [Sn(C(7)H(7))(3)(C(8)H(12)NO(2)S(2))](n), exists in a trans-C(3)O(2) trigonal bipyramidal coordination environment in the two independent formula units. The carboxyl-ate moiety functions in a bridging mode, linking adjacent triorganotin cations into a linear chain running along the shortest axis of the triclinic unit cell; the repeat distance of the polymer is half the a-axial length. In one formula unit, the Sn atom is displaced out of the equatorial plane in the direction of the Sn-O(covalent) bond by 0.093 (4) A and in the second mol-ecule, the Sn atom is displaced by 0.105 (4) A in the same direction. PMID- 21587379 TI - Bis(3-amino-pyrazine-2-carboxyl-ato-kappaN,O)diaqua-manganese(II) mono-hydrate. AB - In the title compound, [Mn(C(5)H(4)N(3)O(2))(2)(H(2)O)(2)].H(2)O, the Mn(II) cation, located on a twofold rotation axis, is N,O-chelated by two 3-amino pyrazine-2-carboxyl-ate anions and coordin-ated by two water mol-ecules in a distorted octa-hedral geometry. The uncoordinated water mol-ecules lies on a twofold rotation axis. Adjacent mol-ecules are linked by O-H?O and N-H?O hydrogen bonds into a three-dimensional network motif. PMID- 21587380 TI - (R)-2-Methyl-piperazine-1,4-diium diaqua-tetra-chloridoferrate(II). AB - In the title salt, (C(5)H(14)N(2))[FeCl(4)(H(2)O)(2)], the Fe(II) cation is coordinated by four Cl(-) anions and two water mol-ecules in a distorted octa hedral geometry. The piperazine ring adopts a normal chair conformation. Inter molecular N-H?Cl, N-H?(Cl,Cl) and O-H?Cl hydrogen bonding is present in the crystal structure. PMID- 21587381 TI - Bis[2-amino-6-methyl-pyrimidin-4(1H)-one-kappaN,O]dichloridocadmium(II). AB - In the title compound, [CdCl(2)(C(5)H(7)N(3)O)(2)], the Cd(II) atom is six coordinated by two heterocyclic N atoms [Cd-N = 2.261 (2) and 2.286 (2) A] and two O atoms [Cd-O = 2.624 (2) and 2.692 (2) A] from two bidentate chelate 2-amino 6-methyl-pyrimidin-4(1H)-one ligands and two chloride ions [Cd-Cl = 2.4674 (6) and 2.4893 (7) A]. The crystal packing is characterized by an open-framework architecture with the crystal packing stabilized by inter-molecular N-H?Cl and N H?O hydrogen bonds. PMID- 21587382 TI - Incorporation of MU(3)-CO(3) into an Mn/Mn Mn(12) cluster: {[(cyclam)Mn(MU O)(2)Mn(H(2)O)(MU-OH)](6)(MU(3)-CO(3))(2)}Cl(8).24H(2)O. AB - The centrosymmetric title cluster, hexa-aquadi-MU(3)-carbonato-hexa-cyclamhexa MU(2)-hydroxido-dodeca-MU(2)-oxido-hexa-mang-an-ese(IV)hexa-manganese(III) octa chloride tetra-cosa-hydrate, [Mn(12)(CO(3))(2)O(12)(OH)(6)(C(10)H(24)N(4))(6)(H(2)O)(6)]Cl(8).24H(2)O, has two MU(3)-CO(3) groups that not only bridge octahedrally coordinated Mn(III) ions but also act as acceptors to two different kinds of hydrogen bonds. The carbonate anion is planar within experimental error and has an average C-O distance of 1.294 (4) A. The crystal packing is stabilized by O-H?Cl, O-H?O, N-H?Cl and N-H?O hydrogen bonds. Two of the four independent chloride ions are disordered over five positions, and eight of the 12 independent water mol-ecules are disordered over 21 positions. PMID- 21587383 TI - Bis(3-amino-pyrazine-2-carboxyl-ato-kappaN,O)diaqua-manganese(II). AB - The Mn(II) atom in the title compound, [Mn(C(5)H(4)N(3)O(2))(2)(H(2)O)(2)], exhibits an octa-hedral geometry comprising the two O atoms and two N atoms from two 3-amino-pyrazine-2-carboxyl-ate ligands, which act as chelating ligands, and two water mol-ecules. An intra-molecular N-H?O hydrogen bond occurs. In the crystal, N-H?O, O-H?N and O-H?O hydrogen bonds link adjacent mol-ecules into a three-dimensional network. The mol-ecule lies on a twofold rotation axis. PMID- 21587384 TI - catena-Poly[[(1,10-phenanthroline)copper(II)]-MU-oxalato]. AB - In the title coordination polymer, [Cu(C(2)O(4))(C(12)H(8)N(2))](n), the Cu(II) atom is six-coordinated by four O atoms from two oxalate ligands and two N atoms from one 1,10-phenanthroline (phen) ligand in a distorted octa-hedral coordination geometry. The oxalate anions act as bis-bidentate ligands, bridging the Cu-phen units in zigzag chains extending parallel to [100]. Inter-chain C-H?O hydrogen bonding and pi-pi stacking inter-actions [centroid-centroid distance = 3.7439 (17) A] assemble neighboring chains, forming a three-dimensional supra molecular network. PMID- 21587385 TI - catena-Poly[(MU(2)-3-carb-oxy-5-nitro-benzoato)(MU(3)-5-nitro-benzene-1,3 dicarboxyl-ato)(1,10-phenanthroline)gadolinium(III)]. AB - The crystal structure of the title complex, [Gd(C(8)H(3)NO(6))(C(8)H(4)NO(6))(C(12)H(8)N(2))](n), contains polymeric chains made up of Gd(III) atoms, 1,10-phenanthroline and fully or half-deproton-ated 5 nitro-benzene-1,3-dicarb-oxy-lic acid (H(2)L) ligands. The Gd(III) atom is coordinated in a distorted bicapped trigonal-prismatic fashion by six O atoms from two HL(-) and three L(2-) ligands, and by two N atoms from the 1,10 phenanthroline ligand. The L(2-) ligands bridge the Gd-phenanthroline units, forming chains running parallel to [100]. O-H?O hydrogen bonding as well as pi-pi stacking inter-actions with an inter-planar distance of 3.599 (2) A assemble neighboring polymeric chains. PMID- 21587386 TI - Bis[5-(2-pyrid-yl)pyrazine-2-carbonitrile]-silver(I) tetra-fluorido-borate. AB - In the title mononuclear complex, [Ag(C(10)H(6)N(4))(2)]BF(4), the Ag(I) atom adopts a square-planar N(4 )coordination geometry and is surrounded by two 5-(2 pyrid-yl)pyrazine-2-carbonitrile ligands. The tetra-fluorido-borate anions link the mononuclear cations through inter-molecular C-H?F hydrogen-bonding inter actions, forming an infinite tape structure along [110]. Other weak inter-actions occur: pi-pi stacking with centroid-centroid distances of 3.820 (2) and 3.898 (1) A between pyridyl rings and 3.610 (2) and 3.926 (2) A between pyrazinyl rings as well as F?pi contacts involving the tetra-fluorido-borate anions and pyrazine rings [F?centroid = 2.999 (3) A]; these combine with the hydrogen-bonding inter actions to link the mononuclear cations into a three-dimensional supra-molecular architecture. PMID- 21587387 TI - Poly[[diaqua-bis-(MU(3)-isonicotinato-kappaN:O:O')bis-(MU(2)-isonicotinato kappaN:O)gadolinium(III)disiliver(I)] nitrate monohydrate]. AB - In the title compound, {[Ag(2)Gd(C(6)H(4)NO(2))(4)(H(2)O)(2)]NO(3).H(2)O}(n), the Gd(III) ion is coordinated by eight O atoms from six isonicotinate ligands and two water mol-ecules in a distorted square anti-prismatic geometry. Two Ag(I) ions are each bonded to two N atoms from two isonicotinate ligands in a linear or bow-like fashion [N-Ag-N angles = 178.6 (2) and 147.1 (2) degrees ]. These metal ions are connected by the isonicotin-ate ligands into a layer parallel to (010). O-H?O hydrogen bonds donated by the coordinated and uncoordinated water mol ecules and intra-layer pi-pi stacking inter-actions between the pyridine rings [centroid-centroid distances = 3.551 (4) and 3.555 (4) A] are observed. The layers inter-act with each other by inter-layer Ag?O(aqua) contacts [2.731 (4) A] and pi-pi stacking inter-actions between the pyridine rings [centroid-centroid distances = 3.466 (3) and 3.516 (3) A], resulting in the formation of a three dimensional supra-molecular structure. PMID- 21587388 TI - Dichlorido(2,9-dimethyl-1,10-phenanthroline-kappaN,N')cobalt(II). AB - In the title compound, [CoCl(2)(C(14)H(12)N(2))], the Co(II) atom is four coordinated in a distorted tetra-hedral geometry by two N atoms from a 2,9 dimethyl-1,10-phenanthroline ligand and two Cl atoms. The Co atom and the phenanthroline unit are located on a mirror plane. The methyl H atoms are disordered about the mirror plane and areeach half-occupied. In the crystal structure, pi-pi inter-actions between the pyridine and benzene rings and between the pyridine rings [centroid-centroid distances = 3.8821 (9) and 3.9502 (10) A, respectively] stabilize the structure. PMID- 21587389 TI - catena-Poly[silver(I)-bis-[MU-bis-(diphenyl-phosphino)methane-kappaP:P']-MU-thio cyanato-kappaS:S-silver(I)-MU-thio-cyanato-kappaS:N]. AB - The title compound, [Ag(NCS)(C(25)H(22)P(2))](n), contains two Ag(+) ions, two thio-cyanate ions and two bis-(diphenyl-phosphino)methane (dppm) ligands in the asymmetric unit. One of the thiocyanate ions bridges the two Ag(+) ions in a MU(2)-mode from its S atom and the two dppm ligands bridge the silver ions in a MU(1),MU(1) mode. The remaining SCN(-) ion bridges the binuclear units via its N and S atoms, generating a one-dimensional polymer propagating in [01]: the resulting AgP(2)SN and AgP(2)S(2) coordination geometries could be described as distorted tetra-hedral. PMID- 21587390 TI - Bis(3-methyl-phenolato-kappaO)(nitros-yl-kappaN)[tris-(3,5-dimethyl-pyrazol-1-yl kappaN)hydridoborato]molybdenum(II). AB - The title complex, [Mo(C(15)H(22)BN(6))(C(7)H(7)O)(2)(NO)], contains an {MoNO}(4) core stabilized by kappa(3)--hydrotris-(3,5-dimethyl-pyrazol-1-yl)borate, [Tp(Me2)](-), and two anionic m-cresolate ligands, leading to a distorted octa hedral geometry for the Mo atom. The short Mo-O bond lengths [1.935 (2) and 1.971 (2) A], as well as large Mo-O-Csp(2) angles [134.2 (2) and 143.54 (19) degrees ], indicate dpi(Mo)-ppi(O) inter-actions, which are clearly weaker when compared with {Mo(NO)(Tp(Me2))} alkoxides. The nitrosyl system is virtually linear [179.3 (3) degrees ] with Mo-N and N-O bond lengths of 1.760 (2) and 1.205 (3) A, respectively. Intra- and inter-molecular C-H((Ph or CH(3)))?pi((Ph)) inter actions between adjacent phenyl rings are found in the crystal structure (d(H?Ph) in the range 2.743-2.886 A). One of the Ph rings shows disorder, i.e. swinging in the ring plane. PMID- 21587391 TI - Dibromido(6-methyl-2,2'-bipyridine-kappaN,N')zinc(II). AB - In the title compound, [ZnBr(2)(C(11)H(10)N(2))], the Zn(II) atom is four coordinated in a distorted tetra-hedral configuration by two N atoms from a 6 methyl-2,2'-bipyridine ligand and two terminal Br atoms. Weak inter-molecular C H?Br hydrogen bonds and pi-pi stacking inter-actions between the pyridine rings [centroid-centroid distances = 3.763 (5) and 3.835 (6) A] contribute to crystal packing effects. PMID- 21587392 TI - catena-Poly[[(tetra-hydro-furan-kappaO)lithium(I)]-bis-(MU-trimethyl-silanolato kappaO:O)-gallium(III)-bis-(MU-trimethyl-silanolato-kappaO:O)-[(tetra-hydro-furan kappaO)lithium(I)]-MU-bromido]. AB - The title chain polymer compound, [GaLi(2)Br(C(3)H(9)OSi)(4)(C(4)H(8)O)(2)](n), was obtained in the reaction of GaBr(3) with Me(3)SiOLi in toluene/tetra-hydro furan. The Ga(III) atom, located on a twofold rotation axis, is coordinated by four trimethyl-silanolate ligands and has a distorted tetra-hedral geometry. The Li(I) atom is four coordinated by one bridging Br atom located on an inversion centre, two trimethyl-silanolate ligands and one tetra-hydro-furane mol-ecule in a distorted tetra-hedral geometry. The polymeric chains extend along [001]. The tetra-hydro-furane mol-ecule is disordered over two positions with site-occupancy factors of 0.57 (2) and 0.43 (2). PMID- 21587393 TI - {Bis[2-(3,5-dimethyl-pyrazol-1-yl-kappaN)eth-yl]amine kappaN}chloridopalladium(II) chloride 0.25-hydrate. AB - The title compound, [PdCl(C(14)H(23)N(5))]Cl.0.25H(2)O, is a pseudopolymorph of the previously reported compound [PdCl(C(14)H(23)N(5))]Cl.2H(2)O [de Mendoza et al. (2006 ?). Acta Cryst. E62, m2934-m2936]. The cationic complex and chloride anion are disordered over two positions each in a 0.584 (4):0.416 (4) ratio. The geometry about the Pd atom is distorted square-planar. The pyrazole rings are almost perpendicular, forming a dihedral angle of 86.6 (6) degrees to each other, to mitigate steric conflict between their methyl groups. PMID- 21587394 TI - Poly[bis-(MU(4)-acetato-kappaO:O:O':O')bis-(MU(3)-acetato-kappaO:O:O)(MU(2) acetato-kappaO:O')(MU(2)-acetic acid-kappaO:O')di-MU-aqua-copper(II)tris-odium]. AB - In the title compound, [CuNa(3)(CH(3)CO(2))(5)(CH(3)COOH)(H(2)O)(2)](n), the Cu(II) atom lies on an inversion center and is coordinated by four O atoms from four acetate ligands, leading to a square-planar geometry. One Na(I) atom, lying on an inversion center, is coordinated by four O atoms from four acetate ligands and two bridging water mol-ecules in a distorted octa-hedral geometry. The other Na(I) atom is coordinated by five O atoms from five acetate ligands and a bridging water mol-ecule. A hy-droxy H atom lies on a twofold rotation axis and is shared by two acetate ligands. The crystal packing exhibits a polymeric layer parallel to (100), which is further stablized by intra-layer O-H?O hydrogen bonds. The layers are linked by inter-layer O-H?O hydrogen bonds. PMID- 21587395 TI - Bis(2,2'-bipyridine)(2-hy-droxy-2,2-diphenyl-acetato)-copper(II) nitrate dihydrate. AB - In the title complex, [Cu(C(14)H(11)O(3))(C(10)H(8)N(2))(2)]NO(3).2H(2)O, the Cu(II) atom is coordinated by four N atoms from two 2,2'-bipyridine ligands and two O atoms from one benzilate ligand in a distorted octa-hedral geometry. A supra-molecular network is formed via inter-molecular O-H?O and C-H?O hydrogen bonding inter-actions. pi-pi stacking inter-actions between neighboring pyridine rings are also present, the centroid-centroid distance being 3.808 (2) A. PMID- 21587396 TI - {6,6'-Dimeth-oxy-2,2'-[4,5-dimethyl-o-phenyl-enebis(nitrilo-methyl idyne)]diphenolato}nickel(II). AB - In the title Schiff base complex, [Ni(C(24)H(22)N(2)O(4))], the Ni(II) atom has a slightly distorted square-planar coordination environment. The dihedral angles between the central benzene ring and the two outer rings are 7.62 (16) and 9.78 (17) degrees . The crystal structure is stabilized by inter-molecular C-H?O hydrogen bonds and pi-pi inter-actions with a centroid-centroid distance of 3.8218 (19) A. PMID- 21587397 TI - 7-(1,3-Dioxolan-2-ylmethyl)-1,3-di-methyl-2,6-dioxo-2,3,6,7-tetra-hydro-1H-purin 9-ium tetra-chloridoferrate(III). AB - The asymmetric unit of the title compound, (C(11)H(15)N(4)O(4))[FeCl(4)], contains two independent protonated 7-(1,3-dioxolan-2-ylmeth-yl)-3,7-dihydro-1,3 dimethyl-1H-purine-2,6-dione (doxofyllinium) and two tetrahedral tetra-chlorido ferrate(III) anions. In the doxofyllinium, two disordered methyl-ene C atoms are observed in each dioxolane ring with an occupancy ratio of 0.54 (4):0.46 (4). In the crystal, mol-ecules are connected by N-H?O hydrogen bonds and weak C-H?O and C-H?Cl inter-actions. PMID- 21587398 TI - Tribenzoatobismuth(III): a new -polymorph. AB - A new polymorph (beta) was obtained for an active pharmaceutical ingredient, bis muth tribenzoate, [Bi(C(6)H(5)CO(2))(3)]. The new beta-polymorph is 1.05 times denser than the previously known polymorph [Rae et al. (1998 ?). Acta Cryst. B54, 438-442]. In the beta-polymorph, the Bi atom is linked with three benzoate anions, each of them acting as a bidentate ligand, and these assemblies with C(3) point symmetry can be considered as 'mol-ecules'. The structure of the beta polymorph has no polymeric chains, in contrast to the previously known polymorph. The 'mol-ecules' in the beta-polymorph are stacked along [001], so that the phenyl rings of the neighbouring mol-ecules are parallel to each other. Based on the pronounced difference in the crystal structures, one can suppose that two polymorphs should differ in the dissolution kinetics and bioavailability. PMID- 21587399 TI - Aqua-{MU-N-[3-(dimethyl-amino)-prop-yl]-N'-(2-oxidophen-yl)oxamidato(3-)}(1,10 phenanthroline)dicopper(II) nitrate. AB - The title complex, [Cu(2)(C(13)H(16)N(3)O(3))(C(12)H(8)N(2))(H(2)O)]NO(3), consists of a nitrate ion and a binuclear Cu(II) unit in which the oxamide ligand has a cis geometry, is fully deprotonated and acts in a bidentate fashion to one Cu(II) atom and in a tetradentate fashion to the other Cu(II) atom. The Cu(II) atom coordination geometries are distorted square-planar and distorted square pyramidal. In the crystal structure, binuclear complexes and nitrate ions are connected by classical O-H?O and non-classical C-H?O hydrogen bonds into a three dimensional framework. The alkyl chains of the anion are equally disorded over two positions. PMID- 21587400 TI - [Benz-yl(2-pyridyl-methyl-idene)amine]-dichloridomercury(II). AB - The Hg(II) ion in the title complex, [HgCl(2)(C(13)H(12)N(2))], adopts a distorted tetra-hedral geometry being coordinated by two Cl anions and by two N atoms of the benz-yl(2-pyridyl-methyl-ene)amine ligand. The Cl-Hg-Cl plane is twisted at 70.1 (1) degrees from the mean plane of the chelate ring. In the crystal structure, inter-molecular pi-pi inter-actions [centroid-centroid distance = 3.793 (3) A] between the aromatic rings link the mol-ecules into zigzag chains extending along [010]. PMID- 21587401 TI - (Dimethyl-formamide-kappaO)(2-hy-droxy-benzoato-kappaO,O)[tris-(1-methyl-1H benzimidazol-2-ylmethyl-kappaN)amine-kappaN]manganese(II) perchlorate dimethyl formamide monosolvate. AB - In the title complex, [Mn(C(7)H(5)O(3))(C(27)H(27)N(7))(C(3)H(7)NO)]ClO(4).C(3)H(7)NO, the Mn(II) ion is coordinated in a slightly distorted monocapped trigonal-prismatic geometry. The tris-(1-methyl-1H-benzimidazol-2-ylmeth-yl)amine (Mentb) ligand coordinates in a tetra-dentate mode and the coordination is completed by a bis-chelating salicylate ligand and a dimethyl-formamide ligand. The hy-droxy group and the ortho H atoms of the salicylate ligand were refined as disordered over two sites with occupancies of 0.581 (8) and 0.419 (8). Both disorder components of the hy droxy group form intra-molecular O-H?O hydrogen bonds. PMID- 21587402 TI - catena-Poly[[[diaqua-cadmium(II)]-bis-[MU-3,5-bis-(isonicotinamido)benzoato]] tetra-hydrate]. AB - The title compound, {[Cd(C(19)H(13)N(4)O(4))(2)(H(2)O)(2)].4H(2)O}(n) or {[Cd(BBA)(2)(H(2)O)(2)].4H(2)O}(n), where BBA is 3,5-bis-(iso-nicotin-amido) benzoate, is isotypic with its Mn isologue [Chen et al. (2009 ?). J. Coord. Chem.62, 2421-2428]. The cation sits on a twofold axis and is six-coordinated in a slightly distorted octa-hedral geometry; the polyhedra are linked into zigzag chains, which are further connected by N-H?O, O-H?O and O-H?N hydrogen bonds as well as pi-pi inter-actions [centroid-centroid distance of 3.639 (2) A], giving a three-dimensional supra-molecular framework. PMID- 21587403 TI - Aqua-{N-[(4-methyl-phen-yl)sulfon-yl]glycinato(2-)-kappaN,O}(1,10-phenan throline)copper(II). AB - In the title complex, [Cu(C(9)H(9)NO(4)S)(C(12)H(8)N(2))(H(2)O)], the Cu(II) ion is coordinated in a distorted square-pyramidal geometry by the two N atoms from a 1,10-phenanthroline ligand, one N atom from the deprotonated amino group of an N tosyl-glycinate ligand, one O atom from the carboxyl-ate part of the N-tosyl glycinate ligand and a water O atom. Inter-molecular O-H?O hydrogen bonds involving the water H atoms link neighboring mol-ecules into supra-molecular chains along [010]. Weak pi-pi stacking inter-actions [centroid-centroid distances of 3.456 (1) and 3.691 (1) A] between the benzene rings of 1,10 phenanthroline ligands of adjacent mol-ecules extend the chains into a layer structure parallel to (001). PMID- 21587404 TI - catena-Poly[(E)-4,4'-(ethene-1,2-di-yl)dipyridinium [[bis-(thio-cyanato kappaN)ferrate(II)]-di-MU-thio-cyanato-kappaN:S;kappaS:N]]. AB - In the title compound, {(C(12)H(12)N(2))[Fe(NCS)(4)]}(n), each Fe(II) cation is coordinated by four N-bonded and two S-bonded thio-cyanate anions in an octa hedral coordination mode. The asymmetric unit consists of one Fe(II) cation, located on a center of inversion, as well as one protonated (E)-4,4'-(ethene-1,2 di-yl)dipyridinium dication and two thio-cyanate anions in general positions. The crystal structure consists of Fe-(NCS)(2)-Fe chains extending along the a axis, in which two further thio-cyanate anions are only terminally bonded via nitro gen. Non-coordinating (E)-4,4'-(ethene-1,2-di-yl)dipyrid-inium cations are found between the chains. PMID- 21587405 TI - Poly[dichloridobis[MU-1-(4-pyridyl-meth-yl)-1,2,4-triazole]cadmium(II)]. AB - In the title coordination polymer, [CdCl(2)(C(8)H(8)N(4))(2)](n), the Cd(II) atom, lying on an inversion center, is coordinated by two Cl atoms and two triazole N atoms and two pyridyl N atoms from four 1-(4-pyridyl-meth-yl)-1,2,4 triazole (pmta) ligands in a distorted trans-CdCl(2)N(4) octa-hedral arrangement. The bridg-ing pmta ligands, with a dihedral angle between the triazole and pyridyl rings of 71.86 (8) degrees , link the Cd atoms into a 4(4) sheet parallel to (02). pi-pi inter-actions between the triazole rings [centroid-centroid distance = 3.428 (2) A] connect the sheets. PMID- 21587406 TI - catena-Poly[bis-(MU(4)-adipato-1:2:1':2'kappaO:O:O:O)bis-(N,N-dimethyl-formamide) 1kappaO,2kappaO-dicopper(II)]. AB - In the title polymeric complex, [Cu(2)(C(6)H(8)O(4))(2)(C(3)H(7)NO)(2)](n), the carboxyl-ate groups of the approximately U-shaped adipate dianion each bridge a pair of inversion-related, DMF-coordinated copper(II) atoms, generating a ribbon motif that runs along the b axis. The geometry of the copper(II) atom is distorted square-pyramidal; the apical site is occupied by the O atom of the DMF mol-ecule whereas the four basal sites are occupied by carboxyl-ate O atoms. PMID- 21587407 TI - 1-Amino-pyridinium triiodidoplumbate(II). AB - The title complex, (C(5)H(7)N(2))[PbI(3)], consists of a 1-amino-pyridinium cation, disordered about a mirror plane, and a [PbI(3)](-) anion. The Pb(2+) ion (site symmetry ) is surrounded by six I atoms in a slightly distorted octa-hedral coordination. The PbI(6) octa-hedra share faces, building up (infinity) (1)[PbI(6/2)] chains running along [010]. The cations are situated between the chains. Coulombic attractions and van der Waals inter-actions between the inorganic and organic components are mainly responsible for the cohesion of the structure. PMID- 21587408 TI - Tri-MU-sulfato-kappaO:O'-bis-[aqua-(1,10-phenanthroline-kappaN,N')indium(III)] dihydrate. AB - In the title dinuclear In(III) compound, [In(2)(SO(4))(3)(C(12)H(8)N(2))(2)(H(2)O)(2)].2H(2)O, each In(III) cation is coordinated by a 1,10-phenanthroline (phen) ligand, a water mol-ecule and three sulfate O atoms in a distorted InN(2)O(4) octa-hedral geometry. Three sulfate anions bridge two In(III) cations, forming the dinuclear entities. O-H?O and weak C-H?O hydrogen bonding is observed in the crystal structure. The crystal structure is further consolidated by pi-pi stacking between nearly parallel phen ring systems [dihedral angle = 4.2 (4) degrees ], the centroid-centroid distance between benzene rings of adjacent phen ligands being 3.528 (9) A. PMID- 21587409 TI - catena-Poly[[[tetra-aqua-cadmium(II)]-MU-3,3'-[p-phenyl-enebis(oxymethyl-ene)]bis (1-pyridinioacetate)] dinitrate hemihydrate]. AB - In the title polymeric coordination complex, {[Cd(C(22)H(20)N(2)O(6))(H(2)O)(4)](NO(3))(2).0.5H(2)O}(n), obtained from the self-assembly of the flexible double betaine 3,3'-[p-phenyl-enebis(oxymethyl ene)]bis-(1-pyridinioacetate) with cadmium nitrate, both the octa-hedrally coordinated Cd(II) cation and the substituted betaine ligand lie on inversion centres. The chains constructed through the trans-related acetate groups of the ligand are inter-connected via O-H?O hydrogen bonds involving coordinated aqua ligands, the nitrate anions and the partial-occupancy (0.25) water mol-ecule of solvation, forming a three-dimensional structure. PMID- 21587410 TI - Poly[MU(6)-adipato-diaquadi-MU(2)-oxalato-digadolinium(III)]. AB - In the centrosymmetric title compound, [Gd(2)(C(6)H(8)O(4))(C(2)O(4))(2)(H(2)O)(2)](n), the Gd(3+) cations are each coordinated by nine O atoms, three from adipate anions, two from oxalate anions and one from an aqua ligand, completing a distorted tricapped trigonal-prismatic geometry. These tricapped trigonal prisms are bridged by the adipate ligands, generating layers lying parallel to (010). The coordination polymer layers are linked into a three-dimensional framework by the rigid oxalate ligands. The adipate and oxalate ions are all located on centers of inversion. A part of the adipate anion is disordered over two positions in a 0.75:0.25 ratio. PMID- 21587411 TI - (eta-Penta-methyl-cyclo-penta-dien-yl)(eta-toluene)-ruthenium(II) hexa-fluorido phosphate. AB - In the title complex, [Ru(C(7)H(8))(C(10)H(15))]PF(6), the cation lies on a mirror plane and the anion lies on an inversion center. The distance between the Ru atom and the centroid of the benzene ring is 1.706 (5) A and the distance between the Ru atom and the cyclo-penta-dienyl ring is 1.811 (5) A. The crystal structure is stabilized by weak C-H?F hydrogen bonds. The H atoms of the methyl groups which lie on the mirror plane are disordered over two sites with equal occupancies. PMID- 21587413 TI - catena-Poly[[triphenyl-tin(IV)]-MU(2)-[3-(cyclo-hexyl-carbamo-yl)propanoato kappaO:O]]. AB - The Sn atom in the polymeric title compound, [Sn(C(6)H(5))(3)(C(10)H(16)NO(3))](n), is five-coordinated within a trans C(3)O(2) donor set that defines an approximate trigonal-bipyramidal geometry. The carboxyl-ate ligand is monodentate and the amide O atom bridges a symmetry related Sn atom, generating a chain along [010] with a linear topology. An intra molecular carboxyl-ate-carbonyl N-H?O hydrogen bond is responsible for the curved conformation within the carboxyl-ate ligand. PMID- 21587412 TI - Disodium 4,5,6-trihy-droxy-benzene-1,3-disulfonate dihydrate. AB - In the title compound, 2Na(+).C(6)H(4)O(9)S(2) (2-).2H(2)O, the benzene rings of the 4,5,6-trihy-droxy-benzene-1,3-disulfonate ions, which are stacked parallel to each other forming rods parallel to the a axis, are slightly deformed (planarity, symmetry) mainly because of the high degree of substitution. The two sodium ions, located within pockets of the anion rods, are coordinated by six and seven O atoms, resulting in octa-hedral and penta-gonal-bipyramidal coordinations, respectively. In addition to these coordinative bonds towards sodium, an extended network of intra- and inter-molecular hydrogen bonds occurs. PMID- 21587414 TI - Octa-methyl-bis-(MU(2)-2-methyl-benzoato-kappaO:O')bis-(2-methyl-benzoato kappaO)di-MU(3)-oxido-tetra-tin(IV). AB - The title compound, [Sn(4)(CH(3))(8)(C(8)H(7)O(2))(4)O(2)], is a distann-oxane derivative of 2-methyl-benzoic acid. The crystal structure is composed of centrosymmetric dimers lying about inversion centres. Both independent Sn atoms adopt distorted trigonal-bipyramidal SnC(2)O(3) coordination geometries with the basal planes consisting of two C-atoms from the methyl groups and a bridging O atom. The Sn-C and Sn-O bond lengths lie in the ranges 2.090 (2)-2.104 (3) and 2.0241 (14)-2.2561 (15) A, respectively. The central four-membered planar Sn(2)O(2) ring [Sn?Sn distance = 3.2993 (2) A] makes dihedral angles of 5.43 (11) and 59.50 (7) degrees with the methyl-phenyl groups, which are themselves oriented at a dihedral angle of 61.38 (8) degrees . Besides weak C-H?O and C-H?pi inter-actions, the packing mainly features van der Waals forces between the mol ecules. PMID- 21587415 TI - (Dimethyl-formamide)(2-methyl-propen-oato)[tris-(1-methyl-1H-benzimidazol-2 ylmeth-yl)amine]-manganese(II) perchlorate dimethyl-formamide solvate. AB - In the title complex, [Mn(C(4)H(5)O(2))(C(27)H(27)N(7))(C(3)H(7)NO)]ClO(4).C(3)H(7)NO, the Mn(II) ion is seven-coordinated in a distorted monocapped trigonal-prismatic geometry formed by a tetra-dentate tris-(1-methyl-1H-benzimidazol-2-ylmeth-yl)amine mol-ecule, a bidentate 2-methacrylate anion and a dimethyl-formamide mol-ecule. The methyl groups of the coordinated dimethyl-formamide mol-ecule and the perchlorate anions are disordered over two positions with occupancy factors of 0.640 (8) and 0.360 (8). PMID- 21587416 TI - Di-MU-azido-bis-({N'-[1-(2-pyrid-yl-kappaN)ethyl-idene]acetohydrazidato kappaN',O}dicopper(II)). AB - The dimeric title compound, [Cu(2)(C(9)H(10)N(3)O)(2)(N(3))(2)], is located on a crystallographic inversion center. The Cu atom is coordinated by a tridentate anionic hydrazone ligand and two bridging azide ligands in a distorted square pyramidal coordination geometry. The non-bonding Cu?Cu distance is 3.238 (1) A. Non-classical inter-molecular C-H?N hydrogen bonds link the dimers into chains along the c axis. PMID- 21587417 TI - Tetra-kis(MU-3,4-dimeth-oxy-phenyl-acetato)-bis-[(3,4-dimeth-oxy-phenyl acetato)(1,10-phenanthroline)holmium(III)]. AB - In the centrosymmetric title compound, [Ho(2)(C(10)H(11)O(4))(6)(C(12)H(8)N(2))(2)], the Ho(III) atom is nine coordinated by seven O atoms from the 3,4-dimeth-oxy-phenyl-acetate (L) anions and two N atoms from a 1,10-phenanthroline (phen) mol-ecule. The L ligands are coordinated to the Ho(III) ions in three modes: chelating, bridging and bridging tridentate. Intra-molecular C-H?O inter-actions occur. The crystal packing is stabilized by inter-molecular C-H?O inter-actions and weak aromatic pi-pi inter actions between phen mol-ecules and the aromatic rings of the L ligands [centroid centroid distance = 3.821 (2) A]. PMID- 21587418 TI - {N,N-Dimethyl-N'-[1-(2-pyrid-yl)ethyl-idene]propane-1,3-diamine}bis(thio-cyanato kappaN)-copper(II). AB - In the title complex, [Cu(NCS)(2)(C(12)H(19)N(3))], the Cu(II) atom is five coordinated in a square-pyramidal geometry defined by one pyridine N, one imine N, and one amine N atom of the tridentate Schiff base ligand and two N-bonded thio-cyanate ions (one of the latter occupying the apical site). The three bridging C atoms and the two terminal C atoms of the Schiff base are disordered over two sets of sites, with occupancies of 0.465 (2) and 0.535 (2). PMID- 21587419 TI - 2-[5-(1,3-Benzodioxol-5-yl)-3-ferrocenyl-4,5-dihydro-1H-pyrazol-1-yl]-4-phenyl 1,3-thia-zole. AB - In the title compound, [Fe(C(5)H(5))(C(24)H(18)N(3)O(2)S)], the pyrazoline ring adopts a twist conformation. The thia-zole ring forms dihedral angles of 83.7 (2) and 34.4 (2) degrees with the benzene ring of the benzodioxole ring and the fused phenyl ring, respectively. The mol-ecular conformation is stabilized by an intra-molecular C-H?pi inter-action. The crystal packing features inter-molecular C-H?N, C-H?O hydrogen bonds and weak C-H?pi inter-actions. PMID- 21587420 TI - 8-Hy-droxy-2-methyl-quinolinium dibromido(2-methyl-quinolin-8-olato kappaN,O)zincate(II) methanol monosolvate. AB - The anion of the title salt, (C(10)H(10)NO)[ZnBr(2)(C(10)H(8)NO)].CH(3)OH, has its metal atom N,O-chelated by the deprotonated 2-methyl-8-hy-droxy-quinoline ligand. The hy-droxy unit of the cation is a hydrogen-bond donor to the alkoxide O atom of the tetra-hedrally coordinated anion, whereas the ammonium cation is a hydrogen-bond donor to the methano-lic O atom. In the crystal, adjacent ion pairs and solvent mol-ecules are linked by a methanol-halogen O-H?Br hydrogen bond, generating a chain running along the a axis. PMID- 21587421 TI - 8-Hy-droxy-2-methyl-quinolinium diiodido(2-methyl-quinolin-8-olato kappaN,O)zincate(II) methanol monosolvate. AB - The anion of the title salt, (C(10)H(10)NO)[Zn(C(10)H(8)NO)I(2)].CH(3)OH, has its metal atom N,O-chelated by the deprotonated 2-methyl-8-hy-droxy-quinoline ligand. The hy-droxy unit of the cation is a hydrogen-bond donor to the alkoxide O atom of the tetra-hedrally coordinated anion, whereas the ammonium cation acts as a hydrogen-bond donor to the methano-lic O atom. In the crystal, adjacent ion pairs and solvent mol-ecules are linked by a methanol-halogen O-H?I hydrogen bond, generating a chain running along the a axis. PMID- 21587422 TI - Bromido(quinolin-8-ol-kappaN,O)(quinolin-8-olato-kappaN,O)zinc(II) methanol monosolvate. AB - The title compound, [ZnBr(C(9)H(6)NO)(C(9)H(7)NO)].CH(3)OH, has its metal atom N,O-chelated by a neutral and a deproton-ated 8-hy-droxy-quinoline ligand. The hy droxy unit of the neutral ligand is a hydrogen-bond donor to the methanol O atom and the alk-oxy O atom of the monoanionic ligand is a hydrogen-bond acceptor to the methanol O atom. In the crystal, adjacent mol-ecules are linked by these two hydrogen bonds, generating a chain running along the a axis. PMID- 21587423 TI - Bis(2-amino-pyrimidine-kappaN)aqua-(nitrato-kappaO)(nitrato-kappaO,O')zinc(II). AB - The water-coordinated Zn atom in the title monoaqua zinc nitrate adduct of 2 amino-pyrimidine, [Zn(NO(3))(2)(C(4)H(5)N(3))(2)(H(2)O)], is bonded to a monodentate nitrate ion and is chelated by the other nitrate ion. The heterocyclic ligands coordinate through ring N-donor sites. The coordination geometry about the Zn(II) atom is a distorted octa-hedron. Intra-molecular N-H?O hydrogen bonds occur. In the crystal, adjacent adduct mol-ecules are linked by O H?O, O-H?N and N-H?O hydrogen bonds into a layer motif parallel to (001). PMID- 21587424 TI - 6,7-Dihydro-5H-1,4-diazepino[1,2,3,4-lmn][1,10]phenanthroline-4,8-diium tris (thio-cyanato-kappaN)cuprate(I). AB - The title copper(I) salt, (C(15)H(14)N(2))[Cu(NCS)(3)], exists as non-inter acting cations and trigonal-planar anions. The cation is buckled, the r.m.s. deviation of the atoms passing through the phenanthroline portion being 0.16 A. The Cu(I) atom is displaced by 0.019 (2) A out of the N(3) triangle. The crystal studied was a non-merohedral twin with twin domains in an approximate ratio of 55:45. PMID- 21587426 TI - catena-Poly[[aqua-bis-(pyridine-kappaN)copper(II)]-MU-2,2'-(p-phenyl-enedi oxy)diacetato-kappaO:O']. AB - In the title compound, [Cu(C(10)H(8)O(6))(C(5)H(5)N)(2)(H(2)O)](n), the Cu atom is five-coordinated by two O atoms from two carboxyl-ate groups of two different 2,2'-(p-phenyl-enedi-oxy)diacetate ligands, two N atoms from two pyridine mol ecules and one water O atom. The geometry is square-pyramidal with the water O atom occupying the apical position. The carboxyl-ate group bridges adjacent Cu atoms, forming an infinite zigzag chain extending parallel to [001]. The chains are linked into layers by O-H?O hydrogen bonds. The Cu and water O atoms lie on special positions of site symmetry 2. PMID- 21587425 TI - Bis(di-2-pyridyl-methane-diol-kappaN,O,N')nickel(II) dibenzoate. AB - The title compound, [Ni(C(11)H(10)N(2)O(2))(2)](C(7)H(5)O(2))(2), consists of an Ni(II) ion coordinated by two tridentate chelating (2-py)(2)C(OH)(2) ligands (py is pyrid-yl) and two benzoate anions. The Ni(II) ion is located on a twofold rotation axis, and its geometry is distorted octa-hedral. The gem-diol ligand (2 py)(2)C(OH)(2) adopts an eta(1):eta(1):eta(1) coordination mode. There are O-H?O hydrogen bonds between the gem-diol ligands and benzoate anions. PMID- 21587427 TI - Dichlorido(6,6'-dimethyl-2,2'-bipyridine-kappaN,N')cobalt(II). AB - In the title compound, [CoCl(2)(C(12)H(12)N(2))], the Co(II) atom is four coordinated in a distorted tetra-hedral geometry by two N atoms from a 6,6' dimethyl-2,2'-bipyridine ligand and two terminal Cl atoms. Inter-molecular C-H?Cl hydrogen bonds and pi-pi stacking inter-actions between the pyridine rings [centroid-centroid distances = 3.788 (1) and 3.957 (1) A] are present in the crystal structure. PMID- 21587428 TI - Diaqua-bis-(1,10-phenanthroline)nickel(II) tetra-kis-(cyanido kappaC)nickelate(II) tetra-hydro-furan solvate monohydrate. AB - The title complex, [Ni(C(12)H(8)N(2))(2)(H(2)O)(2)][Ni(CN)(4)].C(4)H(8)O.H(2)O, consists of a cationic [Ni(C(12)H(8)N(2))(2)(H(2)O)(2)](2+) unit, an anionic [Ni(CN)(4)](2-) unit, one uncoordinated water and one tetra-hydro-furan mol ecule. In the cationic unit, the Ni(2+) atom is coordinated by four N atoms and two O atoms from two 1,10-phenanthroline ligands and two water mol-ecules in a distorted octa-hedral coordination environment. In the anionic unit, the Ni(2+) atom is in a square-planar coordination by four C atoms from four monodentate terminal cyanide ligands. O-H?N and O-H?O hydrogen bonds link neighboring cationic and anionic units, forming a three-dimensional supra-molecular network. The inter-stitial tetra-hydro-furan mol-ecule is independently disordered over two sites in a 1:1 ratio. PMID- 21587429 TI - Bis{1,4-bis-[(3-butyl-imidazolium-1-yl)meth-yl]benzene}-silver(I) bis-(hexa fluoridophosphate). AB - The asymmetric unit of the title complex, [Ag(2)(C(22)H(30)N(4))(2)](PF(6))(2), consists of one Ag(I) ion, one 1,4-bis-[(3-butyl-imidazolium-1-yl)meth-yl]benzene ligand and one discrete hexa-fluoridophosphate anion. The formula unit is generated by an inversion center. The unique Ag(I) ion is coordinated by two C atoms of two heterocyclic carbene ligands in an essentially linear geometry. In the crystal structure, cations and anions are linked through weak C-H?F hydrogen bonds, forming a three-dimensional network. PMID- 21587430 TI - 4-(4-Pyrid-yl)pyridinium penta-aqua(pyridazine-4,5-dicarboxyl ato)praseodymate(III). AB - In the title complex, (C(10)H(9)N(2))[Pr(C(6)H(2)N(2)O(4))(2)(H(2)O)(5)], the Pr atom is nine-coordinated by nine O atoms from two pyridazine-4,5-dicarboxyl-ate anions and five water mol-ecules. It is noteworthy that there is a protonated bipyridine mol-ecule in the structure. Inter-molecular O-H?O, O-H?N and N-H?N hydrogen bonds are present, resulting in a three-dimensional network. PMID- 21587431 TI - Poly[(MU(6)-benzene-1,3,5-tricarboxyl-ato-kappaO:O:O:O:O:O)tris-(N,N-dimethyl formamide-kappaO)tris-(MU(3)-formato-kappaO:O')trimagnesium(II)]. AB - The title complex, [Mg(3)(CHO(2))(3)(C(9)H(3)O(6))(C(3)H(7)NO)(3)](n), exhib-its a two-dimensional structure parallel to (001), which is built up from the Mg(II) atoms and bridging carboxyl-ate ligands (3 symmetry). The Mg(II) atom is six coordinated by one O atom from a dimethyl-formamide mol-ecule, two O atoms from two MU(6)-benzene-1,3,5-tricarboxyl-ate ligands and three O atoms from three MU(3)-formate ligands in a distorted octa-hedral geometry. PMID- 21587432 TI - Bis[2-(4-benzo-yloxy-2-hy-droxy-benzo-yl)-1-phenyl-ethenolato]diethano-lzinc(II). AB - The mononuclear title complex, [Zn(C(22)H(15)O(5))(2)(C(2)H(5)OH)(2)], contains a Zn(II) atom (site symmetry ) surrounded by six O atoms of the keto groups of two substituted 1,3-diketonate ligands and of two ethanol mol-ecules, resulting in a distorted octa-hedral coordination environment. The mol-ecular configuration is stabilized by an intra-molecular hydrogen bond between the phenolic hy-droxy group and the adjacent keto group. The hy-droxy group acts likewise as an acceptor of an inter-molecular O-H?O hydrogen bond with the hy-droxy group of the ethanol mol-ecule as the donor. The hydrogen-bonding scheme leads to the formation of supra-molecular layers parallel to (010). PMID- 21587433 TI - Triimidazolium tris-(pyridine-2,6-di-carboxyl-ato)dysprosate(III) trihydrate. AB - The structure of the title compound, (C(3)N(2)H(5))(3)[Dy(C(7)H(3)NO(4))(3)].3H(2)O, contains a mononuclear Dy(III) complex with the rare earth metal cation in a distorted tricapped trigonal prismatic environment. The Dy(III) ion is in each case O,N,O'-chelated by three tridentate pyridine-2,6-dicarboxyl-ate anions. Three protonated imidazole mol ecules act as counter-cations and three lattice water mol-ecules are also present. Numerous N-H?O and O-H?O hydrogen bonding inter-actions, some of which are bifurcated, help to stabilize the packing of the structure. PMID- 21587434 TI - Bis(2-amino-3-methyl-pyridine)-dichlorido-cobalt(II). AB - In the title compound, [CoCl(2)(C(6)H(8)N(2))(2)], the Co(II) ion is four coordinated by two pyridine N atoms from the 2-amino-3-methyl-pyridine ligands and two chloride ions in a distorted tetra-hedral geometry. A weak intra molecular N-H?Cl inter-action occurs. The crystal packing is stabilized by inter molecular N-H?Cl and C-H?Cl hydrogen-bond inter-actions. PMID- 21587435 TI - (2-Amino-benzoato-kappaO,O')(rac-5,5,7,12,12,14-hexa-methyl-1,4,8,11-tetra-aza cyclo-tetra-decane-kappaN,N',N'',N''')nickel(II) perchlorate monohydrate. AB - In the title salt, [Ni(C(7)H(6)NO(2))(C(16)H(36)N(4))]ClO(4).H(2)O, the Ni(II) cation is O,O'-chelated by the benzoate anion and N,N',N'',N'''-chelated by the macrocycle ligand, confering a distorted octa-hedral geometry on the metal atom. The complex cations, perchlorate anions and uncoordinated water mol-ecules are linked by N-H?O and O-H?O hydrogen bonds into a three-dimensional network. The perchlorate ion is disordered over two positions in a 0.554 (8):0.446 (8) ratio. PMID- 21587436 TI - [2,6-Bis(p-tol-ylimino-meth-yl)pyridine-kappaN,N',N'']dichloridocopper(II). AB - The title compound, [CuCl(2)(C(21)H(19)N(3))], lies on a twofold rotation axis that passes through the N(pyrid-yl)-Cu bond; this symmetry element relates one half of the organic ligand to the other as well as one Cl ligand to the other. The three N atoms span the axial-equatorial-axial sites of the trigonal bipyramidal coordination polyhedron; the geometry of the Cu(II) atom is 31% distorted from trigonal-bipyramidal (towards square-pyramidal along the Berry pseudorotation pathway). PMID- 21587437 TI - [2,6-Bis(6-methyl-quinolin-2-yl)pyridine-kappaN,N',N'']dichloridomanganese(II). AB - In the mol-ecule of the title compound, [MnCl(2)(C(25)H(19)N(3))], the three N atoms span the axial-equatorial-axial sites of the trigonal-bipyramidal coordination polyhedron; the geometry of the Mn(II) atom is 34% distorted from trigonal-bipyramidal (towards square-pyramidal along the Berry pseudorotation pathway). One of the Cl atoms is disordered over two positions in a 0.82 (3):0.18 (3) ratio. Weak inter-molecular C-H?Cl hydrogen bonding occurs in the crystal structure. PMID- 21587438 TI - [2,6-Bis(6-methyl-quinolin-2-yl)pyridine-kappaN,N',N'']dichloridoiron(II). AB - In the mol-ecule of the title compound, [FeCl(2)(C(25)H(19)N(3))], the three N atoms span the axial-equatorial-axial sites of the trigonal-bipyramidal coordination polyhedron; the geometry of the Fe(II) atom is 32% distorted from trigonal-bipyramidal (towards square-pyramidal along the Berry pseudorotation pathway). One of the Cl atoms is disordered over two positions in a 0.938 (11):0.062 (11) ratio. Inter-molecular C-H?Cl hydrogen bonding occurs in the crystal structure. PMID- 21587439 TI - Poly[[hexa-aqua-tris-[MU(2)-2,5-dihy-droxy-1,4-benzoquinona-to(2 )]diholmium(III)] octa-deca-hydrate]. AB - In the polymeric title compound, {[Ho(2)(C(6)H(2)O(4))(3)(H(2)O)(6)].18H(2)O}(n), the Ho(III) ion is nine-coordinated by six O atoms derived from three bidentate 2,5-dihy-droxy-1,4-benzoquinonate (DHBQ(2-)) ligands and three O atoms from three water mol-ecules. The Ho(III) ions are connected via three ligands, resulting in the formation of a two-dimensional honeycomb layer parallel to the ab plane. The layer is racemic in which Delta- and Lambda-coordination geometries around Ho(III) ions are alternately arranged. The asymmetric unit comprises a third of a Ho(III) ion, located on a threefold axis, one-half of a DHBQ(2-) ion, located on a centre of inversion, one coordinated water mol-ecule and three uncoordinated water mol-ecules. PMID- 21587440 TI - catena-Poly[[[dipyridine-copper(II)]-MU-2,3,5,6-tetra-methyl-benzene-1,4-di carboxyl-ato] monohydrate]. AB - In the title complex, {[Cu(C(12)H(12)O(4))(C(5)H(5)N)(2)].H(2)O}(n), the Cu(II) ion lies on an inversion center and is coordinated by two O atoms from two 2,3,5,6-tetra-methyl-benzene-1,4-dicarboxyl-ate (TBDC) ligands and two N atoms from two pyridine ligands in a slightly distorted square-planar environment. The TBDC ligands act as bridging ligands, forming chains along [110]. These chains are further linked into a two-dimensional network via inter-molecular O-H?O hydrogen bonds. The solvent water mol-ecule lies on a twofold rotation axis. PMID- 21587441 TI - Poly[(acetato-kappaO,O')aqua-(MU(4)-1H-benzimidazole-5,6-dicarboxyl-ato kappaN:O,O:O,O:O)praseodymium(III)]. AB - In the title complex, [Pr(C(9)H(4)N(2)O(4))(C(2)H(3)O(2))(H(2)O)](n), the Pr(III) ion is coordinated by five O atoms and one N atom from four benzimidazole-5,6 dicarboxyl-ate ligands, two O atoms from an acetate ligand and one water mol ecule, giving a tricapped trigonal-prismatic geometry. The benzimidazole-5,6 dicarboxyl-ate and acetate ligands connect the Pr(III) ions, forming a layer in the ac plane; the layers are further linked by N-H?O and O-H?O hydrogen bonding and pi-pi stacking inter-actions between neighboring pyridine rings [the centroid centroid distance is 3.467 (1) A], assembling a three-dimensional supra-molecular network. The acetate methyl group is disordered over two positions with site occupancy factors of 0.75 and 0.25. PMID- 21587442 TI - A binuclear vanadium oxyfluoride: di-MU-oxido-bis-[fluoridooxido(1,10-phenanthro line)vanadium(V)]. AB - The title compound, [V(2)F(2)O(4)(C(12)H(8)N(2))(2)], is a centrosymmetric binuclear vanadium(V) species with the metal ions in a distorted octa-hedral environment. The symmetry-equivalent V(V) atoms exhibit coordination geometries defined by cis-terminal fluoride and oxide groups, unsymmetrically bridging oxide groups and the N-atom donors of the phenanthroline ligands. The crystal packing is stabilized by weak inter-molecular C-H?O and C-H?F hydrogen bonds. PMID- 21587443 TI - A one-dimensional copper(II) phenyl-ene-diphospho-nate: catena-poly[[(1,10 phenanthroline-kappaN,N')copper(II)]-MU(3)-[m-phenyl-enediphospho-nato kappaO:O':O'']]. AB - The title compound, [Cu(1,3-HO(3)PC(6)H(4)PO(3)H)(C(12)H(8)N(2))](n), is a coordination polymer of the metal-diphospho-nate family. The chain structure is constructed from '4+1' square-py-rami-dally coordinated copper(II) atoms bonded to chelating phenanthroline (phen) ligands and linked through 1,3 phenyldihydrogendiphospho-nate ligands. The basal plane of the Cu(II) site is defined by the phen nitro-gen donors and phospho-nate oxygen atoms from two diphospho-nate ligands, while the apical position is occupied by an oxygen donor from a third diphospho-nate ligand. The chains propagate along the a-axis direction. Inversion-related phen groups engage in pi-pi stacking with a mean distance of 3.376 (2) A between the ring planes. O-H?O hydrogen-bonding inter actions between the protonated {P-OH} groups of one chain and the {P=O} groups of adjacent chains stabilize the crystal packing. PMID- 21587444 TI - Bis[2-(1H-benzimidazol-2-yl)benzoato]copper(II) dihydrate. AB - In the title compound, [Cu(C(14)H(9)N(2)O(2))(2)].2H(2)O, the Cu(II) ion lies on a centre of symmetry and is four-coordinated by two N atoms and two O atoms from two 2-(1H-benzimidazol-2-yl)benzoate ligands in a square-planar environment. The benzimidazol and benzyl rings form a dihedral angle of 42.8 (5) degrees . The mol ecule contains two H-bonded carboxyl O acceptors and two H-bonded N-H donors in the benzimidazol groups, which inter-act with two symmetry-related uncoordinated water mol-ecules so that neighboring mol-ecular units are linked by (O H)(water)?O(carbox-yl) hydrogen bonds with an R(2) (4)(8) graph-set motif, generating a helical chain in the a-axis direction. These chains are, in turn, inter-connected by (N-H)(benzimidazol)?O(water) hydrogen bonds, forming a three dimensional supra-molecular network. PMID- 21587445 TI - Tetra-imidazolium hexa-MU(4)-oxido-dodeca-MU(2)-oxido-dodeca-oxidohexa arsenate(III)hexa-molybdenum(VI)cuprate(II). AB - The title compound, (C(3)H(5)N(2))(4)[As(6)CuMo(6)O(30)], is made up of a centrosymmetric anionic cluster and four imidazolium cations. In the cluster, the central Cu(II) atom is six-coordinated and lies on an inversion center. Adjacent clusters are linked via N-H?O hydrogen bonds between the imidazole cations and polyoxidoanions into a three-dimensional supra-molecular architecture. PMID- 21587446 TI - catena-Poly[hexaaqua-1kappaO,2kappaO,3kappaO-(MU(4)-3,5-dicarboxylatopyrazol-1 ido-3':1:2:3kappaO:N,O:N,O:O)(MU(2)-3,5-dicarboxylatopyrazol-1-ido 1:2kappaN,O:N,O)-1,2-dicopper(II)-3-manganese(II)]. AB - In the title compound, [Cu(2)Mn(C(5)HN(2)O(4))(2)(H(2)O)(6)](n), the Cu(II) ion is coordinated by two N atoms, two O atoms and one water O atom in a distorted square-pyramidal geometry. The Mn(II) ion is coordinated by two O atoms and four water O atoms in a distorted octa-hedral geometry. Two pyrazolyl-3,5-dicarboxyl ate anions chelate to two copper ions, forming a dinuclear unit, which further connects the Mn(II )ions into chains extending along [100]. Both independent coordinated water mol-ecules on the Mn(II) ion are disordered in a 50:50 fashion. PMID- 21587447 TI - Potassium (2,2'-bipyridine-kappaN,N')bis-(carbonato-kappaO,O')cobaltate(III) dihydrate. AB - In the title compound, K[Co(CO(3))(2)(C(10)H(8)N(2))].2H(2)O, the Co(III) atom is coordinated by two bipyridine N atoms and four O atoms from two bidentate chelating carbonate anions, and thus adopts a distorted octa-hedral N(2)O(4) environment. The [Co(bipy)(CO(3))(2)](-) (bipy is 2,2'-bipyridine) -units are stacked along [100] via pi-pi stacking inter-actions, with inter-planar distances between the bipyridine rings of 3.36 (4) and 3.44 (6) A, forming chains. Classical O-H?O hydrogen-bonding inter-actions link the chains, forming channels along (100) in which the K(+) ions reside and leading to a three-dimensional supra-molecular architecture. PMID- 21587448 TI - 4-Cyano-1-(4-nitro-benz-yl)pyridinium bis-(2-thioxo-1,3-dithiole-4,5-dithiol-ato kappaS,S)nickelate(III). AB - In the title salt, (C(13)H(10)N(3)O(2))[Ni(C(3)S(5))(2)], the Ni(III) cation is S,S'-chelated by two 2-thioxo-1,3-dithiole-4,5-dithiol-ate anions in a distorted square-planar geometry. The complex anion is approximately planar with a maximum deviation of 0.097 (1) A. In the 1-(4-nitro-benz-yl)-4-cyano-pyridinium cation, the pyridine ring is twisted at a dihedral angle of 73.84 (16) degrees with respect to the benzene ring. pi-pi stacking is observed between nearly parallel [dihedral angle = 4.71 (7) degrees ] dithiole and benzene rings, the centroid centroid distance being 3.791 (2) A. PMID- 21587449 TI - (2,2'-Bipyridine-kappaN,N')hydroxido[N-(4-tolyl-sulfonyl)-alaninato kappaN,O]copper(II) hemihydrate. AB - In the title complex, [Cu(C(10)H(12)NO(4)S)(OH)(C(10)H(8)N(2))].0.5H(2)O, the Cu(II) ion shows a distorted square-pyramidal coordination geometry with two N atoms from the 2,2'-bipyridine ligand and one N and one O atom from the N-tosyl alpha-alaninato ligand forming the basis of the coordination polyhedron and another O atom of the hydroxo group acting as the apex of the pyramid. The solvent water mol-ecule is statistically disordered over two positions. PMID- 21587450 TI - Poly[bis(MU(3)-thio-cyanato-kappaN:S:S')(MU(2)-thio-cyanato-kappaN:S)(4'-p-tolyl 2,2':6',2''-terpyridine-kappaN,N',N'')cadmium(II)silver(I)]. AB - The title compound, [AgCd(NCS)(3)(C(22)H(17)N(3))](n), is a hetero-atom ribbon coordination polymer. The central Cd atom is chelated by the 4'-p-tolyl 2,2':6',2''-terpyridine ligand and is coordinated by the N atoms of three thio cyanate ions in an octa-hedral geometry whereas the Ag atom is coordinated by the four S atoms of four thio-cyanate ions in a distorted tetra-hedral geometry. Of the three thio-cyanate ions, one functions in a MU(2)-bridging mode and two in a MU(3)-bridging mode. The ribbon coordination polymer propagates along the a-axis. PMID- 21587451 TI - Bis{1-[(E)-o-tolyl-diazen-yl]-2-naphtho-l-ato}copper(II). AB - In the title complex, [Cu(C(17)H(13)N(2)O)(2)], the Cu(II) atom is tetra coordinated by two N atoms and two O atoms from two bidentate 1-[(E)-o-tolyl diazen-yl]-2-naphtho-late ligands, forming a slightly distorted square-planar environment. The two N atoms and two O atoms around the Cu(II) atom are trans to each other, with an O-Cu-O bond angle of 177.00 (9) degrees and an N-Cu-N bond angle of 165.63 (10) degrees . The average distances between the Cu(II) atom and the coordinated O and N atoms are 1.905 (2) and 1.995 (2)A, respectively. PMID- 21587452 TI - Bis(9-amino-acridinium) bis-(pyridine-2,6-dicarboxyl-ato)cuprate(II) trihydrate. AB - The asymmetric unit of the title compound, (C(13)H(11)N(2))(2)[Cu(C(7)H(3)NO(4))(2)].3H(2)O, consists of one [Cu(pydc)(2)](2 ) dianion (pydc is pyridine-2,6-dicarboxyl-ate), two 9-amino-acridinum monocations and three uncoordinated water mol-ecules. The Cu(II) atom is coordinated by two pydc dianions acting as tridentate ligands, and forming five membered chelate rings with copper(II) as the central atom. The Cu(II) atom is surrounded by four O atoms in the equatorial plane and two pyridine N atoms in axial positions, resulting in a distorted octa-hedral coordination geometry. In the crystal, there are two types of O-H?O and N-H?O hydrogen-bonding synthons linking the anionic and cationic fragments and the water mol-ecules, namely R(4) (4)(16), and R(4) (2)(8). There are also weak C-H?O hydrogen bonds, pi-pi stacking inter-actions [the shortest centroid-centroid distance is 3.350 (2) A], and a C-O?pi inter-action [O?centroid distance = 3.564 (2) A], which connect the various components into a three-dimensional network. PMID- 21587453 TI - Bis(9-amino-acridinium) bis-(pyridine-2,6-dicarboxyl-ato)cuprate(II) trihydrate. AB - The asymmetric unit of the title compound, (C(13)H(11)N(2))(2)[Cu(C(7)H(3)NO(4))(2)].3H(2)O or (9 aminoAcr)[Cu(pydc)(2)].3H(2)O, contains a Cu(pydc)(2) (pydc = pyridine-2,6 dicarboxyl-ate) anion, two protonated 9-amino-acridine (9-aminoAcr)(+) counter ions and three uncoordinated water mol-ecules. The anion contains a six coordinated Cu(II) atom within a distorted octa-hedral geometry. Non-covalent inter-actions i.e. N-H?O and O-H?O hydrogen bonds and inter-molecular pi-pi contacts between the pyridine rings [centroid-centroid distance = 3.7773 (13) A] and acridine rings [centroid-centroid distance = 3.4897 (13), 3.7784 (14) and 3.8627 (15) A] result in the formation of a three-dimensional network. PMID- 21587454 TI - Bis(2-amino-4-methyl-pyrimidin-3-ium) trans-diaqua-bis-(pyrazine-2,3-di-car boxylato)cobaltate(II) hexa-hydrate. AB - In the crystal structure of the mononuclear title compound, (C(5)H(8)N(3))(2)[Co(C(6)H(2)N(2)O(4))(2)(H(2)O)(2)].6H(2)O or (ampymH)(2)[Co(pyzdc)(2)(H(2)O)(2)].6H(2)O (ampym = 2-amino-4-methyl pyrimidine, pyzdcH(2) = pyrazine-2,3-dicarb-oxy-lic acid), the Co(II) ion is hexa-coordinated by two (pyzdc)(2-) groups in the equatorial plane and two water mol-ecules in axial positions, giving an N(2)CoO(4) bound set. The (pyzdc)(2-) anion acts as a bidentate ligand through one carboxyl-ate group O atom and pyrazine ring N atom. There are diverse N-H? O and O-H?O and O-H?N hydrogen-bonding inter-actions, which lead to the formation of a three-dimensional supra-molecular architecture. Off-set or slipped pi-pi stacking inter-actions are also observed between adjacent pyrimidine rings with face-to-face distances of 3.6337 (9) A. PMID- 21587455 TI - Hexaaqua-cobalt(II) 4,4'-(1,2-dihy-droxy-ethane-1,2-di-yl)dibenzoate monohydrate. AB - The title compound, [Co(H(2)O)(6)](C(16)H(12)O(6)).H(2)O, is composed of one 4,4' (1,2-dihy-droxy-ethane-1,2-di-yl)dibenzoate anion lying on an inversion center, one [Co(H(2)O)(6)](2+) dicationic complex and a solvent water mol-ecule located on mirror planes. In the crystal, a chain is constructed via O-H?O hydrogen bonds involving the carboxyl-ate and hydroxyl groups of the organic anion; the chains are further connected into a three-dimensional framework by additional O-H?O hydrogen bonds between the [Co(H(2)O)(6)](2+) cations, solvent water mol-ecules and the anions. PMID- 21587456 TI - Tetra-aqua-bis-[4-(pyrazin-2-ylsulfanylmethyl-kappaN)benzoato]cobalt(II). AB - In the title compound, [Co(C(12)H(9)N(2)O(2)S)(2)(H(2)O)(4)], the Co(II) ion, lying on an inversion center, has an octa-hedral coordination involving two N atoms of two 4-(pyrazin-2-ylsulf-anylmeth-yl)benzoate ligands and four water mol ecules. In the crystal, O-H?O hydrogen bonds between the coordinated water mol ecules and uncoordinated carboxyl-ate O atoms, and weak pi-pi inter-actions [centroid-centroid distance = 4.105 (2) A] between the benzene and pyrazine rings lead to a three-dimensional supra-molecular network. PMID- 21587457 TI - catena-Poly[[silver(I)-MU-4-aminopyridine] perchlorate]: a 1-D staircase coordination polymer. AB - Reaction of 4-amino-pyridine with silver(I) perchlorate leads to a one dimensional coordination polymer, {[Ag(C(5)H(6)N(2))]ClO(4)}(n), in which the amino-pyridine binds through both N atoms. The perchlorate anion is hydrogen bonded to the amino H atoms and inter-acts weakly with the silver(I) atoms (Ag-O > 2.70 A), both located on inversion centres, and some aromatic H atoms (O-H > 2.55 AA), thereby extending the dimensionality of the assembly. This is the first silver complex in which this ligand acts in a bridging mode. PMID- 21587458 TI - Bromidobis(1,10-phenanthroline-kappaN,N')copper(II) dicyanamidate. AB - The title compound, [CuBr(C(12)H(8)N(2))(2)][N(CN)(2)], is formed of discrete [CuBr(phen)(2)](+) complex cations and uncoordinated [N(CN)(2)](-) anions (phen is 1,10-phenanthroline). The Cu atom is five-coordinated in a distorted trigonal bipyramidal geometry by two phen mol-ecules and one bromide ligand, which coordinates in the equatorial plane at a distance of 2.5228 (4) A and lying along with the Cu and the amide N atoms on a twofold rotation axis. The two axial Cu-N distances [1.9926 (15) A] are slightly shorter than the two equatorial Cu-N bonds [2.0979 (15) A]. The structure is stabilized by a weak C-H?N hydrogen bond, with a cyanide N atom of the dicyanamide ligand as an acceptor, and pi-pi inter actions between nearly parallel phenyl and pyridine rings of two adjacent phen mol-ecules [centroid-centroid distance = 3.589 (1) A], and between pi electrons of the dicyanamide anion and the pyridine ring [N?Cg(pyridine) = 3.511 (3) A; C N?Cg(pyridine) = 80.2 (2) degrees ]. PMID- 21587459 TI - catena-Poly[[(2,9-dimethyl-1,10-phenanthroline-kappaN,N')cobalt(II)]-MU-malonato kappaO,O:O,O]. AB - In the title compound, [Co(C(3)H(2)O(4))(C(14)H(12)N(2))](n), the Co(II) ion is in a distorted octa-hedral coordination being chelated by a 2,9-dimethyl-1,10 phenanthroline mol-ecule (dmphen) and two carboxyl-ate groups of two malonate ligands The malonate ligand acts in a bridging mode, forming coordination chains along [100]. pi-pi stacking inter-actions between dmphen ligands [inter-planar distances = 3.414 (4) and 3.447 (4) A] organize the coordination polymers into supra-molecular double chains. PMID- 21587460 TI - Tetra-MU-acetato-kappaO:O'-bis{[(E)-2-styrylpyrazine-kappaN]copper(II)}. AB - In the binuclear title compound, [Cu(2)(CH(3)COO)(4)(C(12)H(10)N(2))(2)], the copper(II) ions are coordinated by four O atoms from two pairs of bridging acetate ligands and one N atom from a (E)-2-styryl-pyrazine ligand in a distorted tetra-hedral geometry. The structure displays no hydrogen bonding or pi-pi stacking inter-actions between the discrete binuclear entities. PMID- 21587461 TI - (MU-2',6'-Dicarboxy-biphenyl-2,6-dicar-boxylato)bis[(1,10 phenanthroline)silver(I)]. AB - In the dimeric title complex, [Ag(2)(C(16)H(8)O(8))(C(12)H(8)N(2))(2)] or [Ag(2)(H(2)bta)(phen)(2)] (H(4)bta = biphenyl-2,2',6,6'-tetra-carb-ox-y-lic acid, phen = 1,10-phenanthroline), each Ag(I) ion displays an approximatively planar trigonal geometry, being surrounded by one chelating phen ligand and one carboxyl ate O atom from an H(2)bta ligand. Owing to the the presence of crystallographic twofold rotation axes, the four C atoms bisecting the H~2~bta ligand are located on a special position. Each H(2)bta ligand acts as a bis-monodentate ligand, ligating two Ag(I) ions into a dimeric compound. Inter-molecular O-H?O inter actions are observed in the crystal structure. PMID- 21587462 TI - The cobalt(II) salt of the azo dye Orange G. AB - Crystallizing the cobalt(II) salt of the azo dye Orange G from water was found to give the solvent-separated ion-pair species hexa-aqua-cobalt(II) 7-oxo-8-(2 phenyl-hydrazin-1-ylidene)-7,8-dihydro-naphthalene-1,3-disulfonate tetra-hydrate, [Co(H(2)O)(6)](C(16)H(10)N(2)O(7)S(2)).4H(2)O. The asymmetric unit of the cobalt(II) salt contains three independent octa-hedral [Co(OH(2))(6)](2+) cations, three azo anions, all with similar configurations, and 12 uncoordinated water mol-ecules. The structure is closely related to that of one of the known magnesium analogues. Both structures have Z' = 3, feature nearly planar azo anions [maximum displacement of azo-N atoms from the plane of the phenyl ring = 0.058 (7) A] in their hydrazone tautomeric form, form layer structures with hydro philic and hydro-phobic layers alternating along the b-axis direction, and are stabilized by an extensive network of hydrogen bonds.. PMID- 21587463 TI - (Methanol-kappaO)bis-{2-meth-oxy-6-[(4-methyl-phen-yl)iminiometh-yl]phenolato kappaO,O'}tris-(nitrato-kappaO,O')lanthanum(III). AB - The asymmetric unit of title compound, [La(NO(3))(3)(C(15)H(15)NO(2))(2)(CH(3)OH)], consists of two Schiff base 2-meth oxy-6-[(4-methyl-phen-yl)iminiometh-yl]phenolato (HL) ligands, three independent nitrate anions and one methanol mol-ecule coordinated to La(III). The coordination environment of the La(III) ion is formed by eleven O atoms. Three bidentate nitrate anions coordinate to the La(III) ion, while two HL ligands chelate the metal center with O atoms from the phenolate and meth-oxy groups. The HL ligands are zwitterionic, with protonated imine N atoms. The coordination sphere is completed by one methanol mol-ecule. The protonated imine N atoms are involved in intra-molecular N-H?O hydrogen bonds with the phen-oxy groups and nitrate ligands. One O atom of one nitrate group is disordered over two sites of equal occupancy. PMID- 21587464 TI - Bis(benzyl-triethyl-ammonium) hexa-chloridostannate(IV). AB - The reaction between benzyl-triethyl-ammonium chloride and dimethyl-tin dichloride yields the title salt, [(C(6)H(5)CH(2))(C(2)H(5))(3)N](2)[SnCl(6)]. The Sn(IV) atom, located on a center of inversion, exists in an octa-hedral coordination environment. The cation links with the anion via weak C-H?Cl hydrogen bonding. PMID- 21587465 TI - Bromidotricarbon-yl[4-iodo-N-(pyridin-2-yl-methyl-idene)aniline kappaN,N']rhenium(I). AB - In the title compound, [ReBr(C(12)H(9)IN(2))(CO)(3)], the coordination geometry of the Re(I) ion is a distorted fac-ReC(3)BrN(2) octa-hedron, arising from the N,N'-bidentate ligand, a bromide ion and a facial arrangement of three carbonyl ligands. The dihedral angle between the aromatic rings in the 4-iodo-N-(pyridin-2 yl-methyl-idene)aniline ligand is 46.2 (3) degrees . The bromide ion and its corresponding trans CO mol-ecule are disordered over two sets of sites in a 0.966 (3):0.034 (3) ratio. PMID- 21587466 TI - catena-Poly[[(5-carb-oxy-2H-1,2,3-triazole-4-carboxyl-ato-kappaN,O)sodium]-di-MU aqua-kappaO:O]. AB - In the title coordination polymer, [Na(C(4)H(2)N(3)O(4))(H(2)O)(2)](n), the Na(I) atom is six-coordinated by one O atom and one N atom from a 2H-1,2,3-triazole-4 carb-oxy-5-carboxyl-ate ligand and four O atoms from four water mol-ecules, forming a distorted octa-hedal geometry. The Na(I) atoms are bridged by water mol ecules into a chain structure along [100]. Inter-molecular N-H?O, O-H?N and O-H?O hydrogen bonds connect the chains. An intra-molecular O-H?O hydrogen bond between the carboxyl-ate groups is observed. PMID- 21587467 TI - MU-Actetato-1:2kappaO:O'-tribromido-2kappaBr-(5,5,7,12,12,14-hexa-methyl-1,4,8,11 tetra-aza-cyclo-tetra-deca-1,7-diene-1kappaN)dizinc(II). AB - In the title compound, [Zn(2)Br(3)(CH(3)COO)(C(16)H(32)N(4))], one Zn(II) atom has a distorted square-planar coordination formed by the four macrocyclic N atoms with an acetate O atom in the apical position and the other Zn(II) atom has a tetra-hedral coordination environment formed by three Br atoms and one O acetate atom. The two Zn(II) atoms are linked by an acetate bridge. In the crystal, mol ecules are linked into centrosymmetric dimers with graph-set motifs R(2) (2)(16) by an N-H?Br inter-action. The mol-ecular configuration is stabilized by an intra molecular N-H?Br hydrogen bond. PMID- 21587468 TI - (meso-5,7,7,12,14,14-Hexamethyl-1,4,8,11-tetra-aza-cyclo-tetra-deca-4,11 diene)nickel(II) dibromide dihydrate. AB - The asymmetric unit of the title compound, [Ni(C(16)H(32)N(4))]Br(2).2H(2)O, consists of one half [Ni(C(16)H(32)N(4))](2+) cation, one Br(-) anion and one water mol-ecule of crystallization. The Ni(II) ion lies on an inversion centre in a square-planar environment formed by the four macrocyclic ligand N atoms. In the crystal structure, the cations, anions and water mol-ecules are linked via inter molecular N-H?Br and O-H?Br hydrogen bonds, forming discrete chains with set graph motif D(2)D(2) (2)(7)D(2) (1)(3)D(3) (2)(8). The water mol-ecules and Br(-) ions are linked with set-graph motif R(4) (2)(8). PMID- 21587469 TI - Bis(pyridine-2-carbaldehyde thio-semi-carbazone)zinc(II) dinitrate dihydrate. AB - The asymmetric unit of the title compound, [Zn(C(7)H(8)N(4)S)(2)](NO(3))(2).2H(2)O, contains two Zn(pht)(2) cations (pht is pyridine-2-carbaldehyde thio-semicarbazone), four nitrate anions and four water mol-ecules. In the cations, each Zn(II) ion adopts a distorted octa-hedral coordination geometry, being chelated by two tridentate pht ligands. In the crystal, the cations, anions and water mol-ecules are connected via O-H?O and N H?O hydrogen bonds into a three-dimensional network. PMID- 21587470 TI - Chlorido{N,N-dibenzyl-N,N-bis-[(diphenyl-phosphan-yl)meth-yl]pyridine-2,6 diamine}-methyl-platinum(II). AB - In the title mononuclear complex, [Pt(CH(3))Cl(C(45)H(41)N(3)P(2))], the pyridine 2,6-diamine ligand can be viewed as a centrosymmetric motif having two pendant N benzyl-N-[(diphenyl-phosphan-yl)meth-yl] arms, the two P atoms of which chelate to the Pt(II) ion, forming a ten-membered metallocycle. A distorted square-planar coordination geometry around the Pt(II) atom is completed by a methyl ligand and a chloride ion. The packing between the mononuclear units is achieved through C H?pi inter-actions, which link the mol-ecules into chains along the c axis. PMID- 21587471 TI - catena-Poly[cobalt(II)-bis-(MU-2-amino-ethane-sulfonato) kappaN,O:O';kappaO:N,O']. AB - The hydro-thermally prepared title compound, [Co(C(2)H(6)NO(3)S)(2)](n), is isotypic with its Ni(II) analogue. The Co(II) cation is in a distorted octa hedral environment, coordinated by four sulfonate O atoms and two N atoms from the taurine ligands. In comparison with the Ni(II) analogue, the Co-N and Co-O bonds are longer than the Ni-N and Ni-O bonds, whereas all other bond lengths and angles as well as the hydrogen-bonding motifs are very similar in the two structures. The sulfonate groups doubly bridge symmetry-related Co(II) atoms, forming polymeric chains along the a axis. N-H?O hydrogen bonding interactions consolidate the crystal packing. PMID- 21587472 TI - Flutolanil [N-(3-isopropoxyphen-yl)-2-(trifluoro-meth-yl)benzamide]. AB - The title compound, C(17)H(16)F(3)NO(2), crystallizes with two independent mol ecules in the asymmetric unit. The dihedral angles between the isopropoxyphenyl and trifluoro-methyl-phenyl rings are 85.78 (5) and 63.15 (6) degrees in the two mol-ecules. In the crystal structure, inter-molecular N-H?O and C-H?pi inter actions are observed. PMID- 21587473 TI - 3-[2-(1,3-Benzothia-zol-2-ylsulfan-yl)eth-yl]-1,3-oxazolidin-2-one. AB - The title compound, C(12)H(12)N(2)S(2)O(2), consists of a benzothia-zole group and a oxazolidin-1-one linked via a flexible ethane-1,2-diyl spacer. The benzothiazole group and the oxazolidine ring are each almost planar [with maximum deviations of 0.007 (2) and 0.044 (3) A, respectively] and make a dihedral angle of 9.35 (10) degrees . In the crystal structure, adjacent mol-ecules were connected through C-H?O and C-H?N hydrogen bonds, and further extended into a three-dimensional network structure through inter-molecular aromatic pi-pi stacking inter-actions in which the centroid-centroid distance is 3.590 (1) A. PMID- 21587474 TI - 1-(4-{[(E)-4-Methyl-benzyl-idene]amino}-phen-yl)ethanone oxime. AB - In the title compound, C(16)H(16)N(2)O, the dihedral angle formed by the two benzene rings is 50.3 (1) degrees . In the crystal structure, mol-ecules are linked into an infinite one-dimensional supra-molecular structure by inter molecular O-H?N hydrogen-bond inter-actions. PMID- 21587475 TI - 1-(4-{[(E)-5-Chloro-2-hy-droxy-benzyl-idene]amino}-phen-yl)ethanone oxime. AB - The title compound, C(15)H(13)ClN(2)O(2), is an aromatic Schiff base having an aldoxime substituent; the two rings on the azomethine linkage are twisted by 44.4 (1) degrees . The phenolic H atom is intra-molecularly hydrogen bonded to the azomethine N atom, generating an S(6) ring. In the crystal, inversion dimers linked by pairs of O-H?N hydrogen bonds occur. The crystal studied was a non merohedral twin with a 35% minor component. PMID- 21587476 TI - 9-(1,1-Dimethyl-3-oxobut-yl)adenine. AB - The title compound, C(11)H(15)N(5)O, crystallizes with two independent mol-ecules in the asymmetric unit, both of which contain essentially planar imidazole and pyrimidine rings [maximum deviations = 0.002 (2) and 0.026 (2) A, respectively, for the first mol-ecule, and 0.001 (2) and 0.025 (2) A for the second]; the dihedral angles between the rings are 2.1 (2) and 1.7 (2) degrees in the two mol ecules. The crystal structure is stabilized by inter-molecular N-H?N hydrogen bonds, defining chains along a, which are further linked by weak inter-molecular pi-pi contacts [centroid centroid distance = 3.7989 (16) A] into planes parallel to (01). PMID- 21587477 TI - 2-(2,4-Dichloro-phen-oxy)-1-(1H-pyrazol-1-yl)ethanone. AB - In the title compound, C(11)H(8)Cl(2)N(2)O(2), the 2,4-dichloro-phen-oxy and 1H pyrazole groups are almost planar [r.m.s. deviations of 0.0157 and 0.0008 A, respectively] and are oriented at a dihedral angle of 64.17 (5) degrees with respect to one another. In the crystal, the mol-ecules are stabilized in the form of dimers due to inversion-related C-H?O hydrogen bonds, with R(2) (2)(10) ring motifs. PMID- 21587478 TI - (2E)-3-(1,3-Benzodioxol-5-yl)-1-(3-bromo-2-thien-yl)prop-2-en-1-one. AB - In the title mol-ecule, C(14)H(9)BrO(3)S, the the prop-2-en-1-one (enone) fragment is close to planar [C-C-C-O = 2.5 (7) degrees ] and it subtends dihedral angles of 12.5 (3) and 5.3 (4) degrees with respect to the thio-phene and benzene rings, respectively. The dihedral angle between the aromatic ring systems is 12.60 (18) degrees . Two C-H?O inter-actions help to consolidate the non centrosymmetic crystal packing, which features undulating (100) sheets incorporating C(11) and C(12) chain motifs. PMID- 21587479 TI - Ethyl 4-(2,4-dichloro-phen-yl)-6-(6-meth-oxy-2-naphth-yl)-2-oxocyclo-hex-3-ene-1 carboxyl-ate. AB - In the title compound, C(26)H(22)Cl(2)O(4), the cyclo-hexenone ring adopts an approximate half-chair conformation, with two C atoms displaced by -0.485 (6) and 0.218 (6) A from the plane of the other four ring atoms. The dihedral angles between its four almost coplanar [maximum deviation = 0.006 (2) A] atoms and the benzene and naphthalene ring systems are 59.26 (13) and 79.94 (9) degrees , respectively. The dihedral angle between the aromatic rings systems is 77.14 (7) degrees . A short intra-molecular C-H?Cl contact generates an S(6) ring. In the crystal, mol-ecules are linked by C-H?O and C-H?Cl inter-actions to generate a three-dimensional network. PMID- 21587480 TI - (E)-1-(2,5-Dichloro-3-thien-yl)-3-(3,4-dimeth-oxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C(15)H(12)Cl(2)O(3)S, the prop-2-en-1-one (enone) fragment is almost planar [C-C-C-O = 2.2 (4) degrees ] and it subtends dihedral angles of 11.9 (2) and 11.0 (2) degrees with the thio-phene and benzene rings, respectively. The dihedral angle between the aromatic rings is 3.47 (16) degrees . In the crystal, weak C-H?O and C-H?Cl inter-actions link the mol-ecules, leading to R(2) (2)(14), R(2) (2)(24) and C(11) supra-molecular motifs occurring within the three-dimensional network. Weak aromatic pi-pi stacking [centroid centroid separations = 3.6823 (15) and 3.8722 (15) A] may also help to consolidate the packing. PMID- 21587481 TI - 1-(2,5-Dichloro-3-thien-yl)ethanone: infinite sheets mediated by O?Cl halogen bonds. AB - In the title compound, C(6)H(4)Cl(2)OS, the acetyl group is almost coplanar with the thio-phene ring [dihedral angle = 4.01 (2) degrees ]. In the crystal, short inter-molecular O?Cl contacts [2.9494 (14) and 3.1191 (14) A] link the mol-ecules into infinite (100) sheets and aromatic pi-pi stacking [centroid-centroid separation = 3.5422 (10) A] consolidates the packing. PMID- 21587482 TI - N-Ethyl-6-ethyl-amino-4-oxo-1,3,5-triazin-2-aminium chloride (Oxysimazine.HCl). AB - In the title molecular salt, C(7)H(14)N(5)O(+).Cl(-) (the HCl salt of the oxo derivative of the triazine herbicide simazine), the cation and anion are linked by N-H?Cl hydrogen bonds. The chloride ion is also involved in a close electrostatic inter-action with an inversion-related triazine ring [Cl?centroid distance = 3.201 (1) A]. A pi-pi inter-action having a centroid?centroid distance of 3.456 (2) A exists between pairs of rings via another inversion relation. The triazine ring and adjacent non-H atoms are essentially planar (r.m.s. deviation = 0.042 A), while both methyl groups are approximately perpendicular and on the same side of the plane [torsion angles = 79.3 (3) and -84.6 (3) degrees ]. Upon exposure to X-rays for about two days, the color of the title compound changed from colorless to a pale yellow-orange with no apparent affect on the structure as evidenced by no significant change in the intensities of the standard reflections. PMID- 21587483 TI - N'-(4-Hy-droxy-benzyl-idene)-2-methyl-benzohydrazide. AB - The title hydrazone compound, C(15)H(14)N(2)O(2), was prepared by the condensation of 4-hy-droxy-benzaldehyde with 2-methyl-benzohydrazide in methanol. The dihedral angle between the two benzene rings is 42.3 (2) degrees . In the crystal structure, mol-ecules are linked by inter-molecular O-H?O, O-H?N and N H?O hydrogen bonds, forming a three-dimensional framework. PMID- 21587484 TI - 5-(4-Chloro-phen-yl)-6-isopropyl-5,6-dihydro-4H-pyrrolo-[3,4-c]isoxazole. AB - The title compound, C(14)H(15)ClN(2)O, contains an eight-membered 5,5-fused bicycle with two substituents. The dihedral angle between the nearly planar eight membered ring [maximum deviation = 0.033 (2) A] and the benzene ring is 25.0 (1) degrees . In the crystal structure, mol-ecules are stacked in columns along the b axis and C-H?pi inter-actions are observed between the columns. PMID- 21587485 TI - 6-Amino-5-(1-amino-2,2-dicyano-vin-yl)-3,3a,4,5-tetra-hydro-2H-indene-4-spiro-1' cyclo-pentane-3a,7-dicarbonitrile-thio-phene-2-carbaldehyde (1/0.5). AB - In each of the two independent indene-4-spiro-pentane mol-ecules in the asymmetric unit of the title 2:1 adduct, C(19)H(18)N(6).0.5C(5)H(4)OS, the cyclo hexene ring adopts a half-chair conformation and the cyclo-pentene and cyclo pentane rings adopt envelope conformations. The mean plane through the cyclo hexene/cyclo-pentene fused system is aligned at a dihedral angle of 77.9 (1) degrees with respect to the mean plane through the cyclo-pentane ring in one mol ecule and 87.0 (1) degrees in the other. In the crystal, adjacent indene-4-spiro pentane mol-ecules are linked by N-H?N hydrogen bonds into a three-dimensional network. The spaces within the network are occupied by the thio-phene-2 carbaldehyde mol-ecules. The thio-phene-2-carbaldehyde unit is disordered over two positions of equal occupancy. The crystal studied was found to be a non morohedral twin with two minor twin components of 18.4 and 9.7%. PMID- 21587486 TI - 1,3,5-Trinitro-2,4-bis-(2-phenyl-ethen-yl)benzene. AB - In the title compound, C(22)H(15)N(3)O(6), the central benzene ring and one of the phenyl rings are essentially parallel to each other, making a dihedral angle of 1.35 (16) degrees . The dihedral angle between the two phenyl rings is 83.56 (19) degrees . Intra-molecular C-H?N and C-H?O hydrogen bonds occur. In the crystal, mol-ecules are linked through C-H?O hydrogen bonds. Furthermore, offset face-to-face pi-pi inter-actions with centroid-centroid distances of 3.644 (2) A help to stabilize the crystal structure. PMID- 21587488 TI - Dimethyl 3,3'-diphenyl-2,2'-[(S)-thio-phene-2,5-diylbis(carbonyl-aza-nedi yl)]dipropano-ate tetra-hydro-furan monosolvate. AB - The title compound, C(26)H(26)N(2)O(6)S.C(4)H(8)O, a solvated bis-amide derivative, is also a chiral amino acid ester with l-phenyl-alanine methyl ester groups as amine substituents. The thio-phene-2,5-dicarboxamide core approximates C(2) point symmetry. The tetra-hydro-furan solvent mol-ecule is linked to the main mol-ecule through an inter-molecular N-H?O hydrogen bond. The central ring makes dihedral angles of 90.0 (2) and 76.5 (2) degrees with the pendant rings. PMID- 21587487 TI - 1-(2-Hy-droxy-eth-yl)-3-(3-meth-oxy-phen-yl)thio-urea. AB - In the title compound, C(10)H(14)N(2)O(3)S, the 3-meth-oxy-phenyl unit is almost planar, with an r.m.s. deviation of 0.013 A. The dihedral angle between the benzene ring and the plane of the thio-urea unit is 62.57 (4) degrees . In the crystal, N-H?O and O-H?S hydrogen bonds link the mol-ecules into a three dimensional network. PMID- 21587489 TI - 4-Isopropyl-N-phenyl-cyclo-hexa-1,3-diene-1-carboxamide. AB - In the crystal structure of the title compound, C(16)H(19)NO, mol-ecules are linked through a pair of N-H?O hydrogen bonds, forming chains along the a axis. PMID- 21587490 TI - 4-[(E)-(4-Hy-droxy-2-oxo-2H-chromen-3-yl)methyl-idene-amino]-1,5-dimethyl-2 phenyl-1H-pyrazol-3(2H)-one monohydrate. AB - In the title compound, C(21)H(17)N(3)O(4).H(2)O, the coumarin ring system is almost planar (r.m.s. deviation = 0.002 A) and makes dihedral angles of 1.50 (7) and 57.75 (7) degrees with the pyrazole and phenyl rings, respectively. The dihedral angle between the pyrazole and phenyl rings is 56.60 (9) degrees . The pyrazole ring adopts a twisted comformation. The mol-ecular conformation is stabilized by intra-molecular N-H?O and C-H?O hydrogen bonds, both of which form S(6) ring motifs. In the crystal, each water mol-ecule is linked to its adjacent organic mol-ecule via pairs of O-H?O hydrogen bonds. The packing is further consolidated by pairs of inter-molecular C-H?O hydrogen bonds, which link the mol ecules into dimers; the dimers are stacked along the b axis. PMID- 21587491 TI - 3-Chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine. AB - In the title compound, C(9)H(9)ClN(4), the dihedral angle between the aromatic rings is 6.25 (9) degrees . The whole mol-ecule is approximately planar (r.m.s. deviation = 0.070 A). In the crystal, pi-pi inter-actions between the centroids of the pyridazine rings [separation = 3.5904 (10) A] occur. PMID- 21587492 TI - 4-(3-Fluoro-phen-yl)-1-(2-oxoindolin-3-yl-idene)thio-semicarbazide. AB - In the title compound, C(15)H(11)FN(4)OS, there are three independent mol-ecules, each with a disordered 3-fluoro-phenyl group [occupancy ratios = 0.547 (17):0.453 (17), 0.645 (5):0.355 (5) and 0.626 (15):0.374 (15)] and displaying dihedral angles of 4.2 (3), 25.2 (6) and 32.4 (5) degrees between the 2-oxoindoline and fluoro-substituted phenyl rings. Strong intra-molecular N-H?N and N-H?O and weak intra-molecular C-H?S hydrogen bonds complete S(5) and S(6) ring motifs, while strong inter-molecular N-H?O hydrogen bonds inter-connect the three independent mol-ecules through R(3) (3)(12) ring motifs. The three-mol-ecule units are in turn linked into polymeric sheets via C-H?F and C-H?S hydrogen bonds and pi-pi inter-actions [centroid-centroid distances in the range 3.520 (2)-3.820 (9) A]. PMID- 21587493 TI - 2-Amino-4,6-dimethyl-pyridinium benzoate. AB - In the title compound, C(7)H(11)N(2) (+).C(7)H(5)O(2) (-), the 2-amino-4,6 dimethyl-pyridinium cation and the benzoate anion are linked by two N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The H atoms in both the methyl groups are rotationally disordered, with fixed site occupancies of 0.50. In the crystal structure, the mol-ecules are stabilized by inter-molecular N-H?O hydrogen bonds. A pi-pi inter-action, with a centroid-centroid distance of 3.661 (2) A, is also observed. PMID- 21587494 TI - (E)-Ethyl 2-cyano-3-[5-nitro-2-(pyrrolidin-1-yl)phen-yl]acrylate. AB - The title compound, C(16)H(17)N(3)O(4), was prepared by the reaction of 5-nitro-2 (pyrrolidin-1-yl)benzaldehyde and ethyl cyano-acetate. The mol-ecular structure adopts an E conformation with respect to the C=C double bond. The five-membered ring has a half-chair conformation, with puckering parameters Q(2)= 0.399 (2) A and phi = 93.1 (3) degrees . In the crystal, inversion dimers , linked by pairs of C-H?O inter-actions, are further connected through C-H?N hydrogen bonds. Weak slipped pi-pi inter-actions occur between symmetry-related benzene rings [centroid-centroid distance = 3.785 (1)A]. PMID- 21587495 TI - 1-[(4-Chloro-phen-yl)(phenyl-imino)-meth-yl]-7-meth-oxy-2-naphthol-1,4-diaza bicyclo-[2.2.2]octane (2/1). AB - In the crystal structure of the title cocrystal, 2C(24)H(18)ClNO(2).C(6)H(12)N(2), the 1,4-diaza-bicyclo-[2.2.2]octane mol-ecule is located on a twofold rotation axis and linked to the two triaryl-imine mol ecules by O-H?N hydrogen bonds, forming a 2:1 aggregate. C-H?Cl inter-actions are also observed. In the triaryl-imine mol-ecule, the naphthalene ring system makes dihedral angles of 80.39 (6) and 82.35 (6) degrees , respectively, with the phenyl and benzene rings. The dihedral angle between these two latter rings is 87.09 (7) degrees . PMID- 21587496 TI - 3-[(2E)-2-(Butan-2-yl-idene)hydrazin-yl]-6-chloro-pyridazine. AB - The asymmetric unit of the title compound, C(8)H(11)ClN(4), contains two independent mol-ecules (A and B) with slightly different conformations: the dihedral angles between the 3-chloro-6-hydrazinylpyridazine units and butyl side chains are 4.5 (2) and 11.98 (16) degrees . In the crystal, the A and B mol ecules are linked by a pair of N-H?N hydogen bonds, generating an R(2) (2)(8) loop. PMID- 21587497 TI - N-(6-Bromo-meth-yl-2-pyrid-yl)acetamide. AB - The title acetamide compound, C(8)H(9)BrN(2)O, crystallizes with three crystallographically independent mol-ecules (A, B and C) in the asymmetric unit. In mol-ecule A, the mean plane through the acetamide unit is inclined at a dihedral angle of 4.40 (11) degrees with respect to the pyridine ring [10.31 (12) and 2.27 (11) degrees , respectively, for mol-ecules B and C]. In the crystal structure, mol-ecules are inter-connected into sheets parallel to the ac plane by N-H?O, C-H?Br, C-H?O and C-H?N hydrogen bonds. The structure is further stabilized by weak inter-molecular C-H?pi inter-actions. PMID- 21587498 TI - N-[(4-Amino-5-sulfanyl-idene-4,5-dihydro-1H-1,2,4-triazol-3-yl)meth-yl]-4-methyl benzamide. AB - In the title compound, C(11)H(13)N(5)OS, the dihedral angle between the triazole ring and the benzene ring is 84.21 (7) degrees . The amino group adopts a pyramidal configuration. An intra-molecular N-H?O hydrogen bond stabilizes the mol-ecular structure and generates an S(8) ring. In the crystal, mol-ecules are linked by inter-molecular N-H?O, N-H?S, N-H?N and C-H?S hydrogen bonds into layers lying parallel to the bc plane. The crystal structure is further stabilized by aromatic pi-pi stacking inter-actions [centroid-centroid distance = 3.3330 (7) A]. PMID- 21587499 TI - Ranunculin. AB - In the title mol-ecule {systematic name: (5S)-5-[(beta-d-gluco-pyranos-yloxy)meth yl]furan-2(5H)-one}, C(11)H(16)O(8), the five-membered ring is essentially planar, the maximum deviation being 0.0151 (13) A for the O atom. The six membered ring adopts a chair conformation with puckering parameters Q = 0.581 (2) A, theta = 9.0 (2) degrees and phi = 39.7 (13) degrees , and with all of the substituents of the glucoside unit having normal equatorial orientations. The crystal structure is stabilized by extensive O-H?O and C-H?O hydrogen bonding, resulting in a three-dimensional network. PMID- 21587500 TI - (1E)-6-Meth-oxy-3,4-dihydro-naphthalen-1(2H)-one oxime. AB - In the crystal structure of the title compound, C(11)H(13)NO(2), the mol-ecules are paired into centrosymmetric dimers via inter-molecular O-H?N hydrogen bonds. PMID- 21587501 TI - 1-{5-[4-(Hex-yloxy)phen-yl]-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl}ethanone. AB - The crystal structure of the title compound, C(23)H(28)N(2)O(2), is composed of discrete mol-ecules with bond lengths and angles quite typical for pyrazoline derivatives of this class. The plane containing the pyrazoline unit is nearly planar with the mean plane of the phenyl ring at the 3-position, making a dihedral angle of 1.96 (3) degrees . The crystal packing is stabilized by weak C H?pi inter-actions involving both of the aromatic rings. PMID- 21587502 TI - 1-Benzyl-3-(1,2-diphenyl-ethen-yl)-1H-indole. AB - In the title compound, C(29)H(23)N, the planar [maximum deviation from the least squares plane = 0.056 (1) A] indole ring makes dihedral angles of 83.4 (4), 69.9 (1) and 59.9 (1) degrees , with the least-squares planes of three benzene rings. The mol-ecular packing is stabilized by weak inter-molecular C-H?pi inter actions. PMID- 21587503 TI - N-Benzyl-N-ethyl-4-methyl-benzene-sulfonamide. AB - In the title compound, C(16)H(19)NO(2)S, the dihedral angle between the two aromatic rings is 84.78 (7) degrees . Weak inter-molecular C-H?O inter-actions stabilize the crystal structure by the formation of a 16-membered R(2) (2)(16) ring motif. PMID- 21587504 TI - Methyl 3-[(1H-benzimidazol-1-yl)meth-yl]-1-methyl-4-(4-methyl-phen-yl)-2' oxopyrrolidine-2-spiro-3'-1-benzimidazole-3-carboxyl-ate. AB - In the title compound, C(29)H(28)N(4)O(3), the pyrrolidine ring adopts a twist conformation whereas the oxindole and benzimidazole residues are approximately planar with maximum deviations of 0.159 (1) and 0.011 (1) A, respectively. The oxindole residue is almost perpendicular to the benzimidazole residue, making a dihedral angle of 89.2 (1) degrees . The methyl-substituted benzene ring is oriented at angles of 47.7 (1) and 71.0 (1) degrees , respectively, with respect to the oxindole and benzimidazole residues. An intra-molecular C-H?O hydrogen bond is observed. In the crystal, mol-ecules associate via N-H?N hydrogen bonds, forming R(2) (2)(9) dimers. PMID- 21587505 TI - 2-Meth-oxy-quinoline-3-carbaldehyde. AB - In the title compound, C(11)H(9)NO(2), the quinoline ring system is essentially planar (r.m.s. deviation = 0.005 A) and the meth-oxy and aldehyde groups are almost coplanar with it [N-C-O-C = 6.24 (19) and O-C-C-C = 0.3 (2) degrees ]. In the crystal, mol-ecules are linked by pairs of C-H?O hydrogen bonds, forming centrosymmetric R(2) (2)(10) dimers. The dimers are linked via pi-pi inter actions involving the pyridine and benzene rings [centroid-centroid distance = 3.639 (1) A]. PMID- 21587506 TI - Trihexyphenidyl hydro-chloride: a powder diffraction study. AB - IN THE CATION OF THE TITLE COMPOUND [SYSTEMATIC NAME: 1-(3-cyclo-hexyl-3-hy-droxy 3-phenyl-prop-yl)piperidinium chloride], C(20)H(32)NO(+).Cl(-), the cyclo-hexyl and piperidine rings are in chair conformations. In the crystal structure, cations and anions are linked into chains along the c-axis direction via O-H?Cl and N-H?Cl hydrogen bonds. Weak inter-molecular C-H?Cl inter-actions link further these chains into layers parallel to the bc plane. The salt, obtained from a racemic solution, was found to crystallize in the chiral P2(1)2(1)2 space group, indicating that, in the absence of any evident chirality-inducing process, the polycrystalline powders consist of an equivalent mixture of R and S enanti-omers, forming a racemic conglomerate. PMID- 21587507 TI - 1-{1-[2,8-Bis(trifluoro-meth-yl)-4-quin-olyl]-5-methyl-1H-1,2,3-triazol-4 yl}ethanone. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(16)H(10)F(6)N(4)O. The triazole ring is not coplanar with the quinoline ring system; the dihedral angle between the two planes being 74.47 (12) and 63.97 (13) degrees in the two mol-ecules. The crystal structure is characterized by inter-molecular C-H?F, C-H?N and C-H?O hydrogen bonding. Weak intra-molecular C-H?F inter-actions are observed. Disorder is observed in two F atoms of one of the trifluoro-methyl groups of one independent mol-ecule [occupancy ratios 0.77 (3):0.23 (3) and 0.77 (4):0.23 (4)] and in all three F atoms of one of the trifluoro-methyl groups of the second independent mol-ecule [occupancy ratios 0.520 (14):0.480 (14), 0.615 (17):0.385 (17) and 0.783 (11):0.217 (11)]. The O atom is also disordered over two positions with occupancies of 0.60 (13) and 0.40 (13) in the first mol-ecule. PMID- 21587508 TI - 5-Chloro-3-[(E)-1,2-diphenyl-ethen-yl]-1H-indole. AB - In the title compound, C(22)H(16)ClN, the pyrrole system makes a dihedral angle of 68.9 (1) degrees with the plane of phenyl ring at the ethenyl 1-position. An intra-molecular C-H?pi inter-action is observed. In the crystal, inter-molecular C-H?pi inter-actions link the mol-ecules into infinite chains running along the b axis. PMID- 21587509 TI - 1,8-Diiodo-anthracene. AB - The mol-ecule of the title compound, C(14)H(8)I(2), an inter-mediate in the synthesis of organic materials, is nearly planar, the maximum deviation from the mean plane being 0.032 (1) A for the C atoms and 0.082 (2) A for the I atoms. In the crystal structure, a sandwich-herringbone arrangement of mol-ecules is observed, whereas a columnar pi-stacking arrangement has been reported for the chlorinated congener 1,8-dichloro-anthracene. Similar effects of halogen substituents on the modulation of packing arrangements are reported for halogenated aromatic compounds such as tetra-cenes and chrycenes. PMID- 21587510 TI - 2-Sulfanyl-idene-1,2-dihydro-pyridine-3-carbohydrazide. AB - All non-H atoms of the title compound, C(6)H(7)N(3)OS, which exists in the thione form, lie in a common plane (r.m.s. of non-H atoms = 0.08 A). The amino group of the -NH-NH(2) substituent forms an intra-molecular hydrogen bond to the S atom. The terminal -NH(2) group is pyramidally coordinated; it forms a weak N-H?O and a weak N-H?S hydrogen bond. Furthermore, the N atom is an acceptor for a C-H?N contact. The amino group of the ring is a hydrogen-bond donor to the carbonyl O atom of an adjacent mol-ecule, this inter-action giving rise to a linear chain motif running along the b axis. PMID- 21587511 TI - Bis[2-((4,6-dimethyl-pyrimidin-2-yl){2-[(4,6-dimethyl-pyrimidin-2-yl)sulfan yl]eth-yl}amino)-eth-yl] disulfide. AB - Bis[2-(4,6-dimethyl-pyrimidin-2-ylsulfan-yl)eth-yl]amine under hydro-thermal conditions has unexpectedly been transformed into the title compound, C(32)H(44)N(10)S(4). In the title mol-ecule, the zigzag 3,10-diaza-6,7 disulfanyldodecyl skeleton has two dimethyl-pyrimidinylsulfanyl groups at both ends, and the aza atoms each carry a dimethyl-pyrimidinyl unit. The N atoms in the skeleton show a planar coordination. PMID- 21587512 TI - (E)-1-(3,5-Difluoro-phen-yl)-3-(2,4-dimeth-oxy-phen-yl)prop-2-en-1-one. AB - The title compound, C(17)H(14)F(2)O(3), is approximately planar, the dihedral angle between the rings being 5.46 (2) degrees . The H atoms of the central propenone group are trans. The crystal structure is stabilized by inter-molecular C-H?F hydrogen bonds. PMID- 21587513 TI - 2-(4-Fluoro-phen-yl)-1,4,5-triphenyl-1H-imidazole. AB - In the title mol-ecule, C(27)H(19)FN(2), the imidazole ring is essentially planar [maximum deviation = 0.004 (1) A] and makes dihedral angles of 62.80 (6), 36.98 (6), 33.16 (6) and 46.24 (6) degrees , respectively, with the substituent rings in the 1-, 2-, 4- and 5-positions. No classical hydrogen bonds are observed in the crystal structure. PMID- 21587514 TI - 2,2'-(Propane-2,2-di-yl)dibenzothia-zole. AB - The two symmetry-independent mol-ecules in the asymmetric unit of the title compound, C(17)H(14)N(2)S(2), have similar geometry; the dihedral angles between the least-squares planes of the benzothia-zole groups in the two mol-ecules are 83.93 (3) and 81.26 (3) degrees . PMID- 21587515 TI - N-Benzyl-2-(3-chloro-4-hy-droxy-phen-yl)acetamide. AB - The title compound, C(15)H(14)ClNO(2), was synthesized as part of a project to generate a combinatorial library based on the fungal natural product 2-(3-chloro 4-hy-droxy-phen-yl)acetamide. It crystallizes as non-planar discrete mol-ecules [the peripheral 3-chloro-4-hy-droxy-phenyl and benzyl groups are twisted out of the plane of the central acetamide group, with N-C-C-C and C-C-C-C torsion angles of -58.8 (3) and 65.0 (2) degrees , respectively] linked by inter-molecular N-H?O and O-H?O hydrogen bonds. PMID- 21587516 TI - 2-Anilino-3-(2-hy-droxy-phen-yl)quinazolin-4(3H)-one-triphenyl-phosphine oxide (1/1). AB - In the title compound, C(20)H(15)N(3)O(2).C(18)H(15)OP, the pyrimidinone heterocycle and the fused phenyl ring are inclined at 1.92 (7) degrees . Only the hy-droxy group is involved in hydrogen bonding, whereas the amino group is shielded from potential acceptors. PMID- 21587517 TI - 4-Chloro-N-[(E)-2,4-dichloro-benzyl-idene]aniline. AB - In the mol-ecule of the title compound, C(13)H(8)Cl(3)N, the 4-chloro-aniline and 2,4-dichloro-benzaldehyde moieties are planar with r.m.s. deviation of 0.0115 and 0.0116 A, respectively, and are oriented at a dihedral angle of 13.94 (8) degrees . PMID- 21587518 TI - N,N'-Dibenzyl-N''-(2,6-difluoro-benzo-yl)-N,N'-dimethyl-phospho-ric triamide. AB - The phosphoryl and carbonyl groups in the title compound, C(23)H(24)F(2)N(3)O(2)P, are anti to each other. The P atom is in a tetra-hedral coordination environment and the environment of each N atom is essentially planar, the average bond angles at the two N atoms being 119.9 and 119.1 degrees . The H atom of the C(=O)NHP(=O) group is involved in an inter-molecular -P=O?H-N hydrogen bond, forming centrosymmetric dimers. PMID- 21587519 TI - (E)-1-(2,4,6-Trimeth-oxy-phen-yl)pent-1-en-3-one. AB - The title compound, C(14)H(18)O(4), was obtained unintentionally as the major product of an attempted synthesis of (E,E)-2,5-bis-[2-(2,4,6-trimeth-oxy-phen yl)ethen-yl]pyrazine. The crystal packing features layers based on two weak C-H?O hydrogen bonds involving the O atom of the carbonyl group and two O(meth oxy)?C(meth-oxy) inter-actions [3.109 (2) A]. The sheets are inter-connected via meth-oxy-meth-oxy dimers and C-H?pi inter-actions. PMID- 21587520 TI - 4,5-Bis(4-meth-oxy-phen-oxy)phthalonitrile. AB - The title compound, C(22)H(16)N(2)O(4), was obtained unintentionally as the product of an attempted synthesis of a new phthalocyanine. The dihedral angles formed by the central benzene ring with the aromatic rings of the meth-oxy-phen oxy groups are 85.39 (5) and 64.19 (5) degrees . PMID- 21587521 TI - 2-Chloro-5-nitro-benzaldehyde thio-semicarbazone. AB - The title Schiff base compound, C(8)H(7)ClN(4)O(2)S, was prepared by the reaction of equimolar quanti-ties of 2-chloro-5-nitro-benzaldehyde with thio-semicarbazide in methanol. The mol-ecule adopts a trans configuration with respect to the azomethine group and the dihedral angle between the benzene ring and the thio semicarbazide group is 6.8 (3) degrees . In the crystal, mol-ecules are linked through inter-molecular N-H?S hydrogen bonds, forming chains propagating in [010]. PMID- 21587522 TI - 7-[2-(3-Fur-yl)eth-yl]-7,8-dimethyl-3,5,6,6a,7,8,9,10-octa-hydro-1H-naphtho-[1,8a c]furan-3-one. AB - In the title mol-ecule, C(20)H(26)O(3), a clerodane diterpenoid isolated from Dodonaea viscosa-, the trans-fused six-membered rings of the deca-line system display chair conformations. The five-membered lactone ring adopts an envelope conformation and the five-membered furan ring is essentially planar with a maximum deviation of 0.0052 (12) A. PMID- 21587523 TI - {3-[(2-Chloro-1,3-thia-zol-4-yl)meth-yl]-1,3-thia-zolidin-2-yl-idene-amino} formonitrile. AB - In the title compound, C(8)H(7)ClN(4)S(2), the dihedral angle between the thia zolidine ring (r.m.s. deviation = 0.028 A) and the thia-zole ring (r.m.s. deviation = 0.004 A) is 74.74 (6) degrees . The formonitrile group is almost coplanar with the attached ring [C-N-C-N torsion angle = 167 (2) degrees . PMID- 21587524 TI - (2E)-2-Benzyl-idene-5,6-dimethoxy-indan-1-one. AB - The mol-ecular structure of the title compound, C(18)H(16)O(3), is roughly planar; the maximum deviation of the indanone ring system is 0.027 (1) A and it makes a dihedral angle of 2.69 (3) degrees with the phenyl ring. The torsion angles between the two meth-oxy groups and the -indanone ring are -14.67 (11) and -1.11 (12) degrees . In the crystal, mol-ecules are connected into a ribbon along the a axis via weak inter-molecular C-H?O hydrogen bonds. Weak inter-molecular C H?pi and pi-pi [centroid-centroid distance = 3.7086 (6) A] inter-actions are also observed. PMID- 21587525 TI - 5,6-Dimeth-oxy-4',5'-diphenyl-indane-2-spiro-3'-pyrrolidine-2'-spiro-3''-indoline 1,2''-dione. AB - In the title compound, C(33)H(28)N(2)O(4), the central pyrrolidine ring adopts a half-chair conformation. Both the indolinone and indanone groups are twisted, with their five-membered rings adopting a half-chair and an envelope conformation, respectively. The two benzene rings and the mean plane of the indolinone and indanone groups make dihedral angles of 71.98 (10), 84.32 (10), 86.26 (9) and 78.50 (9) degrees , respectively, with the central pyrrolidine ring. Intra-molecular C-H?O hydrogen bonds stabilize the mol-ecular conformation. In the crystal, pairs of inter-molecular N-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers. The dimers are inter-connected into ribbons propagating along [110] via weak inter-molecular C-H?O hydrogen bonds. Weak inter molecular C-H?pi and pi-pi [centroid-centroid distance = 3.6509 (11) A] inter actions are also observed. PMID- 21587526 TI - 2-Amino-5-chloro-pyridinium 2-carb-oxy-benzoate-benzene-1,2-dicarb-oxy-lic acid (3/1). AB - The asymmetric unit of the title compound, 3C(5)H(6)ClN(2) (+).3C(8)H(5)O(4) ( ).C(8)H(6)O(4), contains three independent 2-amino-5-chloro-pyridinium cations, three independent hydrogen phthal-ate anions and one phthalic acid mol-ecule. In the crystal structure, there are two kinds of supra-molecular tapes. One is formed by two independent cations with two anions through N-H?O and C-H?O hydrogen bonds. Another one is formed by the other cation and anion, and the phthalic acid mol-ecule via N-H?O, O-H?O and C-H?O hydrogen bonds. These two tapes are connected by an O-H?O hydrogen bond, forming a double-tape structure. PMID- 21587527 TI - Ethyl 6-amino-5-cyano-2,4-bis-(4-methyl-phen-yl)-4H-pyran-3-carboxyl-ate. AB - In the title compound, C(23)H(22)N(2)O(3), the pyran ring adopts a twisted boat conformation. The tolyl rings and carboxyl-ate group are attached to the pyran ring with torsion angles of -77.1 (2), 59.5 (3) and 17.8 (3) degrees , respectively. The ethyl group is disordered over two orientations with a site occupancy ratio of 0.508 (5):0.492 (5). In the crystal, mol-ecules are linked by N-H?N and N-H?O hydrogen bonds, generating a chain running the a axis. Weak C H?O, C-H?N and C-H?pi inter-actions are also observed. PMID- 21587528 TI - N,N'-[(8-endo,11-endo-Dihy-droxy-penta-cyclo-[5.4.0.0.0.0]undecane-8,11-di-yl)bis (methyl-enecarbon-yl)]di-l-phenyl-alanine. AB - The title compound, C(33)H(36)N(2)O(8), is the first example of a disubstituted peptidic pentacycloundecane (PCU) diol. The structure displays an array of inter- and intra-molecular hydrogen bonding by both amide and alcohol functional groups. This hydrogen-bonding system connects the mol-ecules into a three-dimensional network. PMID- 21587529 TI - 3,4-Dimethyl-N-[(E)-3-nitro-benzyl-idene]-1,2-oxazol-5-amine. AB - In the title compound, C(12)H(11)N(3)O(3), the dihedral angle between the 3-nitro benzaldehyde and 5-amino-3,4-dimethyl-1,2-oxazole moieties is 2.46 (12) degrees . The mol-ecule is close to planar, the r.m.s. deviation for the non-H atoms being 0.028 A. The packing only features van der Waals inter-actions between the mol ecules. PMID- 21587530 TI - 1-(3-Bromo-2-thien-yl)ethanone. AB - In the title compound, C(6)H(5)BrOS, the non-H and aromatic H atoms lie on a crystallographic mirror plane. In the crystal, mol-ecules are linked into chains propagating along the c axis by inter-molecular C-H?O hydrogen bonds. PMID- 21587531 TI - Cabraleahy-droxy-lactone from the leaves of Aglaia exima. AB - Cabraleahy-droxy-lactone, C(27)H(44)O(3), isolated from the leaves of Aglaia exima, has three six-membered rings fused together that adopt chair conformations. Its two five-membered rings are enveloped shaped. The hy-droxy group is in an axial position. It is a hydrogen-bond donor to the carbonyl O atom of an adjacent mol-ecule; the O-H?O inter-actions lead to the formation of a helical chain that runs along the b axis. There are two independent mol-ecules in the asymmetric unit. PMID- 21587532 TI - 2,4-Dichloro-N-(2-methyl-phen-yl)benzene-sulfonamide. AB - In the title compound, C(13)H(11)Cl(2)NO(2)S, the methyl-substituted aromatic ring is disordered over two positions [occupancy ratio 0.705 (5):0.295 (5)]. The dihedral angles between the two aromatic rings are 74.9 (1) and 71.0 (3) degrees in the two disorder components. The crystal structure features centrosymmetric dimers linked by pairs of N-H?O hydrogen bonds. PMID- 21587533 TI - 2-(2-Nitro-anilino)-4,5,6,7-tetra-hydro-benzo[b]thio-phene-3-carbonitrile. AB - The title compound, C(15)H(13)N(3)O(2)S, was synthesized by the reaction of 2 amino-5,6,7,8-tetra-hydro-4H-cyclo-hepta-[b]thio-phene-3-carbonitrile and o fluoro-nitro-benzene. The dihedral angle between the thio-phene and nitro-phenyl rings is 75.15 (2) degrees . In the crystal, inter-molecular N-H?N and C-H?O inter-actions lead to the formation of a supra-molecular chain extending along the c-axis direction. PMID- 21587534 TI - 2-Amino-4-nitro-phenol monohydrate. AB - The title compound, C(6)H(6)N(2)O(3).H(2)O, crystallizes with two formula units in the asymmetric unit. The mol-ecules are essentially planar with the nitro groups twisted slightly out of the ring planes [maximum deviations from the ring plane of 0.13 (2) and 0.22 (2) A in the two mol-ecules]. The respective O-N-C-C torsion angles are 6.0 (4) and 12.5 (4) degrees . In the crystal structure, mol ecules are linked by inter-molecular N-H?O, C-H?O, O-H?O and O-H?N inter-actions into a three-dimensional network. PMID- 21587535 TI - Eth-oxy-carbonyl-methyl 3-(4-chloro-benzyl-idene)dithio-carbazate. AB - Mol-ecules of the title compound, C(12)H(13)ClN(2)O(2)S(2), are linked into centrosymmetric dimers by pairs of inter-molecular N-H?S hydrogen bonds. In the crystal structure, there are pi-pi stacking inter-actions between symmetry related benzene rings with a centroid-centroid distance of 3.7305 (13) A, a perpendicular distance between the planes of 3.2851 (9) A and a slippage of 1.768 A. The structure is further stabilized by weak inter-molecular C-H?O hydrogen bonds. PMID- 21587536 TI - 2-(4-Chloro-phen-yl)-6-meth-oxy-chroman-4-one. AB - In the title mol-ecule, C(16)H(13)Cl O(3), the two aromatic rings form a dihedral angle of 65.3 (1) degrees . In the crystal structure, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers, which are further packed into columns propagating in [100] by weak C-H?pi inter-actions. PMID- 21587537 TI - N-[(2-Chloro-3-quinol-yl)meth-yl]-4-fluoro-aniline. AB - In the title compound, C(16)H(12)ClFN(2), the dihedral angle between the quinoline ring system and the flourophenyl ring is 86.70 (4) degrees . In the crystal, mol-ecules are linked into chains along the a axis by N-H?N hydrogen bonds. In addition, C-H?pi inter-actions involving the two benzene rings are observed. PMID- 21587538 TI - 1-(2,4-Dichloro-benzyl-idene)-4-ethyl-thio-semicarbazide. AB - The title compound, C(10)H(11)Cl(2)N(3)S, was prepared by the reaction of 4-ethyl thio-semicarbazide and 2,4-dichloro-benzaldehyde. It is approximately planar, the dihedral angle between the benzene ring and the thio-urea unit being 8.43 (18) degrees . In the crystal, inversion dimers linked by pairs of N-H?S hydrogen bonds generate R(2) (2)(8) loops. PMID- 21587539 TI - 3-(4-Chloro-phenyl-sulfin-yl)-2,5-dimethyl-1-benzofuran. AB - In the crystal structure of the title compound, C(16)H(13)ClO(2)S, the 4-chloro phenyl ring is oriented approximately perpendicular to the benzofuran ring plane [dihedral angle = 82.45 (5) degrees ]. In the crystal, mol-ecules are linked by weak inter-molecular C-H?O and C-H?pi inter-actions. PMID- 21587540 TI - (2E)-1-(3-Bromo-phen-yl)-3-(6-meth-oxy-2-naphth-yl)prop-2-en-1-one. AB - In the title compound, C(20)H(15)BrO(2), the prop-2-en-1-one fragment is substanti-ally twisted [C-C-C-O = 23.0 (11) degrees ]. The dihedral angle between the benzene and naphthalene rings is 44.28 (13) degrees . The only possible directional inter-actions in the crystal are weak C-H?pi contacts, which generate (001) sheets. PMID- 21587541 TI - 2-Hy-droxy-5-{[(E)-4-meth-oxy-benzyl-idene]aza-nium-yl}benzoate. AB - In the title zwitterion, C(15)H(13)NO(4), obtained from the condensation of 5 amino-salicylic acid and 4-meth-oxy-benz-alde-hyde, the 4-hydoxyanilinic group of the 5-amino-salicylic acid moiety and the 4-meth-oxy-benzaldehyde moiety are twisted with respect to one another, making a dihedral angle of 10.37 (7) degrees . The carboxyl-ate group makes a dihedral angle of 5.7 (2) degrees with the parent 4-hydoxyanilinic group. An intra-molecular O-H?O hydrogen bond forms an S(6) ring motif. In the crystal, inter-molecular C-H?O and N-H?O hydrogen bonds with R(2) (1)(7) ring motifs link the mol-ecules into infinite chains extending along the c axis. The occurence of slipped pi-pi stacking between symmetry related aromatic rings reinforces the packing. PMID- 21587542 TI - 1-Phenyl-1H-naphtho-[1,2-e][1,3]oxazin-3(2H)-one. AB - In the title compound, C(18)H(13)NO(2), the naphthalene (r.m.s. deviation = 0.025 A) and benzaldehyde (r.m.s. deviation = 0.006 A) groups are oriented at a dihedral angle of 89.48 (4) degrees . The oxazine group is oriented at dihedral angles of 13.36 (4) and 85.08 (5) degrees , respectively, with respect to the naphthalene and benzaldehyde fragments. In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds generate R(2) (2)(8) loops. The dimers are linked into [010] chains via N-H?O hydrogen bonds. Weak C-H?pi links and aromatic pi-pi stacking between the centroids of the naphthalene phenyl rings [centroid centroid separation = 3.5977 (8) A] help to consolidate the packing. PMID- 21587543 TI - 2-Phenyl-anilinium dihydrogen phosphate. AB - In the crystal structure of the title compound, C(12)H(12)N(+).H(2)PO(4) (-), the dihydrogen phosphate anions and the 2-phenyl-anilinium cations are associated via O-H?O and N-H?O hydrogen bonds so as to build inorganic layers around the x = 1/2 plane. The organic entities are anchored between these layers through C-H?O hydrogen bonds, forming a three-dimensional infinite network. The dihedral angle between the aromatic rings is 44.7 (4) degrees . PMID- 21587544 TI - (1E,2E)-1,2-Bis(2,3,4-trimeth-oxy-benzyl-idene)hydrazine. AB - The title compound, C(20)H(24)N(2)O(6), was obtained as an unexpected product by the reaction of hydrazinium dithio-carbazate with 2,3,4-trimeth-oxy-benzaldehyde in refluxing ethanol. The mol-ecule lies on a center of inversion. The crystal packing is stabilized by weak inter-molecular C-H?O inter-actions. PMID- 21587545 TI - Lamotriginium dihydrogen phosphate-4-(dimethyl-amino)-benzaldehyde (1/1). AB - In the title compound, C(9)H(8)Cl(2)N(5) (+).H(2)PO(4) (-).C(9)H(11)NO [systematic name: 3,5-diamino-6-(2,3-dichloro-phen-yl)-1,2,4-triazin-2-ium dihydrogen phosphate-4-(dimethyl-amino)-benz-alde-hyde (1/1)], inter-molecular N H?O and O-H?O hydrogen bonds produce R(2) (2)(8) and R(3) (2)(8) rings, generating a layer. Inter-molecular N-H?N inter-actions also occur. The dihedral angle between the rings in the cation is 71.73 (12) degrees . PMID- 21587546 TI - (E)-1-(2-Fur-yl)-3-(2,4,6-trimeth-oxy-phen-yl)prop-2-en-1-one. AB - In the title heteroaryl chalcone derivative, C(16)H(16)O(5), the dihedral angle between the furan and benzene rings is 14.45 (6) degrees . The three meth-oxy groups are almost coplanar with their attached benzene ring [C-C-O-C torsion angles = 2.07 (17), -5.04 (17) and 2.85 (16) degrees ]. An intra-molecular C-H?O hydrogen bond occurs. In the crystal, adjacent mol-ecules are linked into X shaped chains along the c axis by weak C-H?O(enone) inter-actions. These chains are stacked along the b axis. C?O [3.3308 (13)-3.4123 (14) A] short contacts are also observed. PMID- 21587547 TI - 6-Methyl-2-pyridyl N-acetyl-1-thio-beta-d-glucosa-minide methanol monosolvate. AB - In the title compound, C(14)H(20)N(2)O(5)S.CH(4)O, the pyran-ose and pyridine rings are linked through an S atom. The pyran-ose ring has a normal chair conformation. An intra-molecular O-H?N hydrogen bond occurs. Inter-molecular O H?O, N-H?O, O-H?N and weak C-H?O hydrogen bonding is present in the crystal structure. PMID- 21587548 TI - N'-(3,5-Dichloro-2-hy-droxy-benzyl-idene)-4-nitro-benzohydrazide methanol solvate. AB - In the title compound, C(14)H(9)Cl(2)N(3)O(4).CH(4)O, the dihedral angle between the two benzene rings in the hydrazone mol-ecule is 6.3 (3) degrees . An intra molecular N-H?O hydrogen bond stabilizes the mol-ecular conformation. In the crystal, centrosymmetrically related mol-ecules are linked through inter molecular O-H?O and N-H?O hydrogen bonds. PMID- 21587549 TI - 4-{[5-(4-Chloro-phen-yl)-1-(4-fluoro-phen-yl)-1H-pyrazol-3-yl]carbon-yl}-N-(4 cyano-phen-yl)piperazine-1-carboxamide. AB - In the title compound, C(28)H(22)ClFN(6)O(2), the piperazine ring adopts a chair conformation and the least-squares plane through the four coplanar atoms forms dihedral angles of 69.37 (13) and 56.56 (12) degrees , respectively, with the pyrazole and cyano-phenyl rings. The dihedral angles formed between the pyrazole and the attached fluoro- and chloro-phenyl rings are 34.16 (10) and 73.27 (12) degrees , respectively. In the crystal, inter-molecular N-H?O, C-H?N and C-H?O hydrogen bonds link the mol-ecules into sheets parallel to the ac plane. PMID- 21587550 TI - 1,4,5,8-Tetra-n-butyl-anthracene. AB - The mol-ecule of the title compound, C(30)H(42), occupies a special position on an inversion center. The four butyl side chains have all-trans planar conformations, and the alkyl planes are nearly orthogonal to the anthracene plane [C-C-C-C torsion angles of 79.6 (2) and 78.2 (2) degrees ]. The overall mol-ecule has a stair-like shape with the n-butyl groups at the 1 and 8 positions extending towards the same side of the anthracene plane. In the crystal structure, mol ecules adopt a slipped-parallel arrangement without pi-pi stacking. PMID- 21587551 TI - 1,4-Bis(carb-oxy-meth-yl)piperazine-1,4-diium bis-(dihydrogen phosphate) dihydrate. AB - In the title salt, C(8)H(16)N(2)O(4) (2+).2H(2)PO(4) (-).2H(2)O, the piperazine ring is located around an inversion center and adopts a chair conformation. The dihydrogen phosphate anions and free water mol-ecules are linked via O-H?O hydrogen bonds into two-dimensional hydrogen-bonding layers, which are further connected through O-H?O and N-H?O hydrogen bonds involving the protonated piperazine into a three-dimensional supra-molecular network. PMID- 21587552 TI - 2-(3-Oxo-3,4-dihydro-2H-1,4-benzothia-zin-4-yl)acetamide. AB - In the title compound, C(10)H(10)N(2)O(2)S, the thia-zine ring approximates to an envelope form with the S atom in the flap position. The amide group attached to the acetate group is almost perpendicular to the mean plane of the thia-zine ring [dihedral angle = 88.83 (8) degrees ]. In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds occur. Further N-H?O and C-H?O hydrogen bonds link the dimers into a three-dimensional network. PMID- 21587553 TI - Fluconazolium picrate. AB - The title compound, C(13)H(13)F(2)N(6)O(+).C(6)H(2)N(3)O(7) (-), is the first structurally characterized salt of the cation of fluconazole [systematic name 2 (2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol], a synthetic anti fungal agent. In the crystal, the components are linked by O-H?O hydrogen bonding between the hy-droxy group of the fluconazolium cation and the C=O(-) group of the picrate anion. This complex is additionally stabilized by secondary, but relatively short, C-H?O inter-actions. The dimers thus formed are connected by N H?N cation-cation hydrogen bonds into helices running along [010]. Neighboring helices of opposite handedness are joined by weak anion-anion C-H?O(nitro) inter actions. In the cation, the mean planes of the three rings are approximately, within ca 25 degrees , parallel to the central C-O bond. In the picrate anion two nitro groups, in turn, are almost coplanar with the ring plane [forming dihedral angles of 6.5 (2) and 3.8 (2) degrees ] while the third nitro group is significantly twisted [by 46.79 (13) degrees ]. PMID- 21587554 TI - 2-(4-Chloro-phen-yl)-4-[1-(4-chloro-phen-yl)-3-methyl-1H-pyrazol-5-yl]-5-methyl 1H-pyrazol-3(2H)-one. AB - The title compound, C(20)H(16)Cl(2)N(4)O, has two mol-ecules in the asymmetric unit. The two five-membered rings form a dihedral angle of 54.2 (3) degrees in one mol-ecule and 56.8 (3) degrees in the other independent mol-ecule. The amino group of the dihydro-pyrazolone unit of one mol-ecule acts as a hydrogen-bond donor to the carbonyl group of the dihydro-pyrazolone system of the other mol ecule. The resulting N-H?O hydrogen bonds generate a chain running along the c axis. The crystal selected was a pseudo-merohedral twin with a 44.9 (3)% twin component. PMID- 21587555 TI - 2,9-Di-3-pentyl-anthra[1,9-def:6,5,10-d'e'f']diisoquinoline-1,3,8,10-tetrone. AB - The asymmetric unit of the title compound, C(34)H(30)N(2)O(4), contains four independent half-mol-ecules, the complete mol-ecules being generated by inversion symmetry. The mol-ecules each have planar (within 4sigma) perylene-tetra-carb-oxy lic diimide fragments with bent side chains. In one of the independent mol ecules, each 3-pentyl fragment is disordered over two conformations in a 7:3 ratio. In the crystal, pi-pi inter-actions link mol-ecules into stacks propagated in [010]. The crystal packing also exhibits weak inter-molecular C-H?O hydrogen bonds. PMID- 21587556 TI - 3-Benzoyl-1,1-dibenzyl-thio-urea. AB - Two independent thio-urea mol-ecules comprise the asymmetric unit of the title compound, C(22)H(20)N(2)OS. The central N-C(=S)N(H)C(=O) atoms in each mol-ecule are virtually superimposable and each is twisted [C-N-C-S torsion angles = 121.3 (3) and -62.3 (4) degrees ]. The mol-ecules differ only in terms of the relative orientations of the benzyl benzene rings [major difference between the C-N-C-C torsion angles of -146.6 (3) and -132.9 (3) degrees ]. The presence of N-H?S hydrogen bonding leads to the formation of supra-molecular chains along the a axis. These are consolidated in the crystal packing by C-H?O inter-actions. The crystal was found to be a combined non-merohedral and racemic twin (twin law 00/00/001), with the fractional contribution of the minor components being approximately 9 and 28%. PMID- 21587557 TI - 4-[(2-Hy-droxy-benzyl-idene)amino]-N-(5-methyl-isoxazol-3-yl)benzene-sulfonamide: a monoclinic polymorph. AB - The title compound, C(17)H(15)N(3)O(4)S, is a monoclinic polymorph with space group P2(1)/c of the previously reported triclinic form in P [Subashini et al. (2009 ?). J. Chem. Crystallogr.39, 112-116]. In both polymorphs, intra-molecular O-H?N hydrogen bonds and dimer formation via a pair of inter-molecular N-H?N hydrogen bonds with an R(2) (2)(8) motif are observed. The two polymorphs differ in the next level of supra-molecular organization involving C-H?O hydrogen bonds with varied packing and different conformations. PMID- 21587558 TI - 5-Ethyl-3-(4-Fluoro-phenyl-sulfon-yl)-2-methyl-1-benzofuran. AB - In the title mol-ecule, C(17)H(15)FO(3)S, the 4-fluoro-phenyl ring makes a dihedral angle of 74.06 (4) degrees with the mean plane of the benzofuran fragment. In the crystal structure, mol-ecules are linked by weak inter-molecular C-H?O and C-H?pi inter-actions. The crystal structure also exhibits aromatic pi pi inter-actions between the benzene rings of adjacent mol-ecules [centroid centroid distance = 3.629 (2) A]. PMID- 21587559 TI - 4-Oxocyclo-hexa-neacetic acid: catemeric hydrogen bonding and spontaneous resolution of a single conformational enanti-omer in an achiral ?-keto acid. AB - The asymmetric unit of the title compound, C(8)H(12)O(3), consists of a single conformational enanti-omer, which aggregates in the catemeric acid-to-ketone hydrogen-bonding mode [O?O = 2.682 (4) A and O-H?O = 172 (6) degrees ]. Four hydrogen-bonding chains of translationally related mol-ecules pass through the cell orthogonal to the 4(3) screw axis along c, alternating in the 110 and the 10 direction, with alignment with respect to this axis of + + - -. Successive chains are rotated by 90 degrees around the c axis. One C-H?O=C close contact, involving the carboxyl group, exists. PMID- 21587560 TI - Piperazine-1,4-diium bis-(2-carb-oxy-1H-pyrazole-4-carboxyl-ate) tetra-hydrate. AB - The asymmetric unit of the title compound, C(4)H(12)N(2) (2+).2C(5)H(3)N(2)O(4) ( ).4H(2)O, comprises one-half of a piperazine-1,4-diium cation, which lies on an inversion centre, a 2-carb-oxy-1H-pyrazole-4-carboxyl-ate anion and two water mol ecules. An extensive network of inter-molecular O-H?O, N-H?O, N-H?N and C-H?O hydrogen bonds between the cations, anions and water mol-ecules leads to a three dimensional supra-molecular framework. PMID- 21587561 TI - 1,2-Bis(2-bromo-benz-yl)diselane. AB - In the title compound, C(14)H(12)Br(2)Se(2), the Se-Se bond length [2.3034 (9) A] is similar to those in diphenyl diselenide [2.3066 (7) and 2.3073 (10) A] and shorter than that in 1,8-diselenona-phthalene [2.0879 (8)A]. The mol-ecule adopts a classical gauche conformation. PMID- 21587562 TI - 2,2-Dimethyl-1,3-benzodioxol-4-yl N-methyl-carbamate. AB - In the title compound, C(11)H(13)NO(4), the two fused rings are almost coplanar, making a dihedral angle of 3.02 (8) degrees . In the crystal, chains are formed parallel to [010] through N-H?O hydrogen bonds between the amine and carbonyl groups. PMID- 21587563 TI - rac-1-(Furan-2-ylmeth-yl)-N-nitro-5-(oxolan-2-ylmeth-yl)-1,3,5-triazinan-2-imine. AB - In the title compound C(13)H(19)N(5)O(4), which belongs to the insecticidally active neonicotinoid group of compounds, the triazane ring exhibits a half-chair conformation. The large discrepancy between the two nitro O-N-N bond angles [116.1 (2) and 123.98 (19) degrees ] may be attributed to intra-molecular N-H?O hydrogen bonding involving one of the nitro O atoms as the acceptor. The delocalization of the electrons extends as far as the nitro group, forming coplanar pi-electron networks. In the crystal, inversion dimers lined by pairs of N-H?O hydrogen bonds occur. PMID- 21587564 TI - 2-Ethyl-5-triphenyl-methyl-1,3-dioxane. AB - In the title compound, C(25)H(26)O(2), the dioxane ring adopts a chair conformation with the two substituent groups occupying equatorial positions. PMID- 21587565 TI - N-[(E)-2,4-Dichloro-benzyl-idene]-4-methyl-aniline. AB - In the title compound, C(14)H(11)Cl(2)N, the dihedral angle between the 4-methyl anilinic and 2,4-dichloro-benzaldehyde moieties is 7.37 (8) degrees . In the crystal, C-H?pi inter-actions between the terminal methyl group and a symmetry related ring of the anilinic group help to establish the packing. PMID- 21587566 TI - (1S,2S,6S,9S)-6-Methyl-5-oxobicyclo-[4.4.0]decane-2,9-diyl diacetate. AB - The chiral title compound, C(15)H(22)O(5), is an inter-mediate in the total synthesis of biologically active 9,11-secosterols. In the crystal, the cyclo hexane rings are trans-fused and both adopt chair conformations. In the crystal, mol-ecules are loosely held together in a layer parallel to (100) by weak inter molcular C-H?O hydrogen bonds accepted by carbonyl O atoms of the acetyl groups. PMID- 21587567 TI - 9-O-Ethyl-berberrubinium iodide monohydrate. AB - IN THE TITLE COMPOUND (SYSTEMATIC NAME: 9-eth-oxy-10-meth-oxy-5,6-dihydro-1,3 dioxolo[4,5-g]isoquinolino-[3,2-a]isoquin-olin-7-ium iodide monohydrate), 2C(21)H(20)NO(4) (+).2I(-).H(2)O, two independent mol-ecules pack in the unit cell, where interactions between the molecules are stabilized by weak inter molecular pi-pi stacking inter-actions [centroid-centroid distances in the range 3.571 (4) to 3.815 (4)A]. Inter-molecular C-H?O inter-actions are also observed. The iodide anions are disordered with occupancy ratios of 0.94 (1):0.06 (1) and 0.91 (1):0.09 (1). The cationic molecule is planar in structure with a small torsion resulting from the dihydropyridine ring. PMID- 21587568 TI - 7-[(3,5-Di-tert-butyl-2-hy-droxy-benzyl-idene)amino]-4-methyl-2H-chromen-2-one. AB - The title compound, C(25)H(29)NO(3), is a Schiff base derivative of coumarin 120. There are two structurally similar but crystallographically independent mol ecules in the asymmetric unit. Both mol-ecules exist in E configurations with respect to the C=N double bonds. The dihedral angles between the coumarin and 3,5 di-tert-butyl-2-hy-droxy-benzyl-idene ring planes are 4.62 (7) and 14.62 (7) degrees for the two mol-ecules. Intra-molecular O-H?N hydrogen bonding involving the O-H groups and the azomethine N atoms generate S(6) rings. In the crystal structure, independent mol-ecules are linked by C-H?pi inter-actions, with groups of four mol-ecules stacked along the c axis. PMID- 21587569 TI - N-(Diethyl-carbamothio-yl)-4-nitro-benzamide. AB - In the title compound, C(12)H(15)N(3)O(3)S, the 4-nitro and carbonyl groups are nearly coplanar with the benzene ring [C-C-N-O = -175.72 (14) and C-C-C-O = 172.75 (14) degrees ]. The diethyl-carbamothioyl group is twisted significantly from the plane of the benzene ring [C-N-C-N = -89.79 (15) degrees ] with the S atom pointing away from each of these groups [C-N-C-S = 91.12 (14) degrees ]. In the crystal, an inter-molecular N-H?O hydrogen bond, which forms an infinite polymeric chain along the c axis, and weak C-H?O and C-H?S hydrogen bonds are observed. PMID- 21587570 TI - 2,2'-(Disulfanediyl)dibenzoic acid-N,N'-bis-(3-pyridyl-meth-yl)ethane-diamide (1/1). AB - The asymmetric unit of the title cocrystal, C(14)H(14)N(4)O(2).C(14)H(10)O(4)S(2), comprises a twisted 2,2' (disulfanediyl)dibenzoic acid mol-ecule [dihedral angle between the benzene rings = 76.35 (10) degrees ] and a U-shaped N,N'-bis-(3-pyridyl-meth-yl)ethane-diamide mol-ecule with the pyridyl groups lying to the same side of the central diamide moiety [C-C-C-N = 113.8 (2) and -117.6 (2) degrees ]. The latter aggregate into supra-molecular tapes propagating along the a axis via centrosymmetric eight membered amide {?OCNH}(2) synthons. Intra-molecular N-H?O hydrogen bonds are observed. The 2,2'-(disulfanediyl)dibenzoic acid mol-ecules form carbox-yl pyridine O-H?N hydrogen bonds, bridging a pyridine residue below the plane of the tape and one above the plane with two inter-vening N,N'-bis-(3-pyridyl-meth yl)ethane-diamide mol-ecules. The supra-molecular chains are consolidated in the crystal packing by C-H?O contacts. An inter-molecular C-H?S inter-action also occurs. PMID- 21587571 TI - 2,2'-(Disulfanedi-yl)dibenzoic acid-N,N'-bis-(4-pyridyl-meth-yl)ethane-dithio amide (1/1). AB - The asymmetric unit of the title co-crystal, C(14)H(14)N(4)S(2).C(14)H(10)O(4)S(2), comprises a twisted 2,2'-(disulfanedi yl)dibenzoic acid mol-ecule [dihedral angle between the benzene rings = 83.53 (14) degrees ] and a U-shaped mol-ecule of N,N'-bis-(4-pyridyl-meth-yl)ethane dithio-amide in which intra-molecular N-H?S hydrogen bonds are observed. Two mol ecules of each form a centrosymmetric ring, with an extended chair conformation, mediated by carbox-yl-pyridine O-H?N hydrogen bonds between the carboxylic acid groups of two 2,2'-(disulfanediyl)dibenzoic acid molecules and pyridine-N atoms of two N,N'-bis(4-pyridylmethyl)ethanedithioamide molecules. The tetra-meric aggregates are linked into a supra-molecular chain along the b axis via amide carbonyl N-H?O hydrogen bonds. PMID- 21587572 TI - 2-Amino-6-(2,4-dichloro-phen-yl)-4-oxo-3,5-diphenyl-cyclo-hex-2-enecarbonitrile. AB - In the title compound, C(25)H(18)Cl(2)N(2)O, the cyclo-hexene ring has a sofa conformation. All the substituents in the cyclo-hexene ring, except the cyano group (which is axial) occupy equatorial positions. The crystal structure is stabilized through N-H?O hydrogen bonds, forming a chain extending along the b axis and through C-H?N and C-H?Cl inter-actions. It is remarkable that only one of the amino H atoms is involved in hydrogen bonding. PMID- 21587573 TI - (E)-3-(4-Chloro-phen-yl)-3-[3-(4-chloro-phen-yl)-1H-pyrazol-1-yl]prop-2-enal. AB - In the title compound, C(18)H(12)Cl(2)N(2)O, the pyrazole ring is almost planar [r.m.s. deviation = 0.002 A] while the two chloro-phenyl rings are twisted out from the plane of the pyrazole ring, making dihedral angles of 5.3 (1) and 65.34 (4) degrees . In the crystal, centrosymmetric R(2) (2)(24) dimers are formed about crystallographic inversion centres through a pair of C-H?Cl inter-actions. These dimers are further linked through a C-H?O hydrogen bond, forming a C(8) chain extending along the a axis. C-H?pi inter-actions are also observed. PMID- 21587574 TI - (2S)-3-Carbamoyl-2-(4-meth-oxy-benzene-sulfonamido)-propanoic acid. AB - In the title compound, C(11)H(14)N(2)O(6)S, an amino acid-derived sulfonamide, the acetamido group and the carb-oxy-lic group are oriented at dihedral angles of 45.84 (5) degrees and 47.97 (5) degrees respectively, with respect to the aromatic ring. In the crystal, the mol-ecules are connected by N-H?O and O-H?O hydrogen bonds and weak C-H?O inter-actions, forming a three-dimensional network. PMID- 21587575 TI - (+)-Methyl 3beta-acet-oxy-13-carb-oxy-19-hy-droxy-11-oxo-C-norolean-18-en-30-oate gamma-lactone. AB - The title compound, C(33)H(46)O(7), is an unusual oxydation product of the therapeutic agent glycyrrhetinic acid that has, in comparison to the latter, a distinctly altered triterpene structure with one five- and four six-membered carbocycles complemented by a gamma-lactone ring with a spiro-junction and a ring double bond. The junction between the five-membered ring C, a cyclo-penta-none ring, and the six-membered ring D, previously in question, was found to be cis, confirming earlier structure assignments based solely on chemical transformations. In the solid state, the compound exhibits five intra- and four inter-molecular C-H?O inter-actions with H?O distances less than or equal to 2.70 A and C-H?O greater than 100 degrees . PMID- 21587576 TI - 1-(3-Chloro-pyridin-2-yl)hydrazine. AB - The title compound, C(5)H(6)ClN(3), was synthesized by the reaction of 2,3 dichloro-pyridine and hydrazine hydrate. An intra-molecular N-H?Cl hydrogen bond results in the formation of a planar (mean deviation 0.038 A) five-membered ring. In the crystal, inter-molecular N-H?N hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21587577 TI - tert-Butyl 6-acetamido-3,4-dihydro-2H-1,4-benzoxazine-4-carboxyl-ate. AB - The title mol-ecule, C(15)H(20)N(2)O(4), contains a benzene ring fused to an oxazine ring and one tert-but-oxy-carbonyl group bound to the N atom. An intra molecular C-H?O inter-action occurs. In the crystal, mol-ecules are linked through inter-molecular N-H?O and C-H?O hydrogen bonds. PMID- 21587578 TI - 1-Benzoyl-3,3-dibutyl-thio-urea. AB - The title mol-ecule, C(16)H(24)N(2)OS, is twisted about the central N(H)-C bond with a C-N(H)-C-N torsion angle of -62.67 (15) degrees . The carbonyl group is twisted out of the plane of the benzene ring, forming a C-C-C=O torsion angle of 25.06 (17) degrees . In the crystal, mol-ecules related by centres of symmetry are linked by pairs of inter-molecular N-H?S hydrogen bonds, forming eight membered {?HNCS}(2) synthons. These are further connected by weak via C-H?O contacts, forming a two-dimensional array in the bc plane. PMID- 21587579 TI - 2,2'-(Disulfanedi-yl)dibenzoic acid-2,9-dimethyl-phenanthroline-tetra-hydro-furan (1/2/1). AB - The asymmetric unit of the title co-crystal solvate, C(14)H(10)O(4)S(2).2C(14)H(12)N(2).C(4)H(8)O, comprises a 2,2'-(disulfanedi yl)dibenzoic acid mol-ecule, two mol-ecules of 2,9-dimethyl-phenanthroline and a tetra-hydro-furan (THF) solvent mol-ecule. Each end of the twisted diacid [dihedral angle between the benzene rings = 74.33 (17) degrees ] forms a strong O H?N hydrogen bond with a 2,9-dimethyl-phenanthroline mol-ecule, forming a trimeric aggregate. The crystal structure comprises layers of acid and THF mol ecules, and layers of 2,9-dimethyl-phenanthroline mol-ecules that alternate along the a axis, the main connections between them being of the type C-H?O. PMID- 21587580 TI - N'-(2,6-Dichloro-benzyl-idene)-2-hy-droxy-benzohydrazide. AB - In the title compound, C(14)H(10)Cl(2)N(2)O(2), the dihedral angle between the two aromatic rings is 17.39 (4) degrees . An intra-molecular O-H?O hydrogen bond forms a six-membered R(6)(1) (1 )ring motif. In the crystal structure, inter molecular N-H?O and O-H?O hydrogen-bonding inter-actions occur. PMID- 21587581 TI - Methyl 7-oxo-12-propyl-amino-13-nitro-deisopropyl-dehydro-abietate. AB - In the title compound, C(21)H(28)N(2)O(5) (systematic name: methyl 1,4a-dimethyl 7-nitro-9-oxo-6-propyl-amino-1,2,3,4,4a,9,10,10a-octa-hydro-phenanthrene-1 carboxyl-ate) the cyclo-hexane ring (A) and the central cyclo-hexene ring (B) exist at a trans ring junction, with the two methyl groups in the axial positions of the six-membered rings. Ring A has a chair conformation and ring B a half chair conformation. An intra-molecular N-H?O hydrogen bond occurs. The crystal structure is stabilized by inter-molecular C-H?O and N-H?O inter-actions. PMID- 21587582 TI - N-[2-(2-Chloro-phen-yl)-2-hy-droxy-eth-yl]propan-2-aminium 4-methyl-benzoate. AB - The title compound, C(11)H(17)ClNO(+).C(8)H(7)O(2) (-), was obtained by the reaction of chlorprenaline {or 1-(2-chloro-phen-yl)-2-[(1-methyl-eth-yl)amino] ethanol} and p-toluic acid. The chlorpren-aline is twisted moderately with a C-C C-C torsion angle of 109.6 (2) degrees . The two mol-ecules are linked by classical O-H?O and N-H?O hydrogen bonds. Further N-H?O hydrogen bonds link two of these units into dimers. PMID- 21587583 TI - Ethyl 2-(2-methyl-4-nitro-1H-imidazol-1-yl)acetate. AB - In the title compound, C(8)H(11)N(3)O(4), the dihedral angle between the imidazole ring and the ethyl acetate plane is 103.1 (8) degrees . The crystal packing is stabilized by weak inter-molecular C-H?O and C-H?N hydrogen bonds. PMID- 21587584 TI - tert-Butyl N-[(11-exo-benzyl-oxy-carbonyl-8-oxopenta-cyclo-[5.4.0.0.0.0]undecane 11-endo-yloxy)carbon-yl-methyl]carbamate. AB - The structure of the title compound, C(26)H(29)NO(7), at 173 K has an inter molecular N-H?O hydrogen bond. This is one of the few examples where a mono ketone penta-cyclo-undecane (PCU) mol-ecule exibits hydrogen bonding in the solid state. The dihedral angles of the amide and ester groups are normal and unaffected by the cage structure. A longer than normal C-C bond [1.571 (4) A] was found within the cage structure. PMID- 21587585 TI - 2-(Biphenyl-4-yl)acetic acid (felbinac). AB - The structure of the title compound, C(14)H(12)O(2), displays the expected inter molecular hydrogen bonding of the carb-oxy-lic acid groups, forming dimers. The dihedral angle between the two aromatic rings is 27.01 (7) degrees . PMID- 21587586 TI - 4-[(2-Hy-droxy-5-nitro-benzyl-idene)amino]-benzene-sulfonamide. AB - The title Schiff base compound, C(13)H(11)N(3)O(5)S, exists in an E configuration with respect to the C=N double bond. The benzene rings are almost coplanar, making a dihedral angle of 2.82 (6). The sulfonamide group is twisted away from the attached phenyl ring with an N-S-C-C torsion angle of 64.84 (11) degrees . An intra-molecular O-H?N hydrogen bond stabilizes the mol-ecule, generating an S(6) ring motif. In the crystal, inter-molecular N-H?O and C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21587587 TI - 2,3-Dihydro-1H-pyrrolizin-1-one. AB - There are two nearly identical mol-ecules in the asymmetric unit of the title compound, C(7)H(7)NO. The mol-ecules are nearly planar (r.m.s. deviations of 0.025 and 0.017 A) and oriented at a dihedral angle of 28.98 (3) degrees . The two mol-ecules are linked by a C-H?O hydrogen bond. In the crystal, weak inter molecular C-H?O hydrogen bonds link the mol-ecules into zigzag chains along the c axis. PMID- 21587588 TI - 1-Phenyl-piperazine-1,4-diium bis-(hydrogen sulfate). AB - In the title compound, C(10)H(16)N(2) (2+).2HSO(4) (-), the S atoms adopt slightly distorted tetra-hedral geometry and the diprotonated piperazine ring adopts a chair conformation. In the crystal, the 1-phenyl-piperazine-1,4-diium cations are anchored between chains formed by the sulfate entities via inter molecular bifurcated N-H?(O,O) and weak C-H?O hydrogen bonds. These hydrogen bonds contribute to the cohesion and stability of the network of the crystal structure. PMID- 21587589 TI - 2-(Phenyl-carbonothio-ylsulfan-yl)acetic acid. AB - The title compound, C(9)H(8)O(2)S(2), can be used as a chain transfer agent and may be used to control the behavior of polymerization reactions. O-H?O hydrogen bonds of moderate character link the mol-ecules into dimers. In the crystal, the dimers are linked into sheets by C-H?O inter-actions, forming R(4) (2)(12) and R(2) (2)(8) edge-fused rings running parallel to [101]. There are no inter molecular inter-actions involving the S atoms. PMID- 21587590 TI - 3,3'-Dimethyl-4,4'-(hexane-1,6-di-yl)bis-[1H-1,2,4-triazol-5(4H)-one]. AB - The title compound, C(12)H(20)N(6)O(2), has a centre of symmetry. The mol-ecule consists of two triazole rings joined by an aliphatic -(CH(2))(6)- chain. The crystal structure is stabilized by inter-molecular N-H?O hydrogen bonds and by pi pi stacking inter-actions between the triazole rings of inversion-related mol ecules [centroid-centroid distance = 3.277 (8) A]. PMID- 21587591 TI - 2-Amino-7-oxo-4,5,6,7-tetra-hydro-1-benzothio-phene-3-carbonitrile. AB - In the title compound, C(9)H(8)N(2)OS, the benzothio-phene ring is substituted with amino, oxo and carbonitrile groups. The thio-phene ring is essentially planar (r.m.s. deviation = 0.0003 A), while the cyclo-hexene ring is in a half chair conformation. In the crystal, N-H?O hydrogen bonds generate chains of mol ecules in a zigzag pattern along the b axis. Pairs of N-H?N hydrogen bonds form centrosymmetric head-to-head dimers about inversion centres, corresponding to an R(2) (2)(12) graph-set motif. In addition, rather weak N-H?S inter-actions are also present in the structure and the supra-molecular assembly is further consolidated by pi-pi stacking inter-actions between the benzothio-phene rings, disposed at a distance of 3.742 (3) A. PMID- 21587592 TI - 3,9-Diisopropyl-2,4,8,10-tetra-thia-spiro-[5.5]undeca-ne. AB - The mol-ecule of the title compound, C(13)H(24)S(4), has C2 symmetry and it crystallizes as a racemate. The structure displays two six-membered rings exhibiting chair conformations, with the isopropyl substituents in equatorial positions. In the crystal structure, weak inter-molecular C-H?S inter-actions are observed, leading to a channel-like arrangement along the c axis. PMID- 21587593 TI - 2alpha,8alpha-Diacet-oxy-cis-himachalane. AB - The title compound, C(19)H(32)O(4), was synthesized from gamma-himachalene, wich was isolated from essential oils of Cedrus atlantica. The mol-ecule is built up from two fused six- and seven-membered rings. The six-membered ring has a screw boat conformation, whereas the seven-membered ring displays a half-chair conformation; the dihedral angle between the mean planes of the rings is 61.99 (6) degrees . PMID- 21587594 TI - N'-[(1E)-1-(3,5-Dichloro-2-hy-droxy-phen-yl)propyl-idene]-4-meth-oxy benzohydrazide monohydrate. AB - The title compound, C(17)H(16)Cl(2)N(2)O(3).H(2)O, displays a trans conformation with respect to the C=N double bond. The dihedral angle between the two benzene rings is 30.77 (5) degrees and there is one intra-molecular N-H?O hydrogen bond. In the crystal, mol-ecules are linked by hydrogen bonding to the water molecules of crystallization, which acts as both an acceptor and a donor, into a three dimensional network. PMID- 21587595 TI - 2,5-Bis(4-methyl-phen-yl)-4-oxopenta-noic acid. AB - The title compound, C(19)H(20)O(3), was obtained from 1,4-bis-(4-methyl-phen yl)but-3-yn-2-one in the presence of carbon monoxide by Ni(CN)(2) catalysis in a basic aqueous medium. Inter-molecular O-H?O hydrogen bonds lead to the formation of hydrogen-bonded carb-oxy-lic acid dimers [graph-set motif R(2) (2)(8)]. Weak C H?O hydrogen bonds between neighbouring dimers further extend the structure to give rise to a three-dimensional supra-molecular network. PMID- 21587596 TI - Naphthalene-1,8-dicarb-oxy-lic anhydride: a monoclinic polymorph. AB - A new type of naphthalene-1,8-dicarb-oxy-lic anhydride, C(12)H(6)O(3), was synthesized hydro-thermally. Unlike the two previously reported polymorphs, which crystallize in the ortho-rhom-bic space groups P2(1)2(1)2(1) [Shok et al. (1971). Kristallografiya, 16, 500-502; Grigor'eva & Chetkina (1975). Kristallografiya, 20, 1289-1290] and Pbca [Shok & Gol'der (1970). Zh. Strukt. Khim.11, 939-940], this present structure crystallizes in the monoclinic space group P2(1)/c. In this structure, the planar [total puckering amplitude Q = 0.0362 (15)] mol-ecules lie parallel to each other along the a axis. PMID- 21587597 TI - beta-Polymorph of phenazepam: a powder study. AB - THE TITLE COMPOUND [SYSTEMATIC NAME: 7-bromo-5-(2-chloro-phen-yl)-1H-1,4 benzodiazepin-2(3H)-one] (beta-polymorph), C(15)H(10)BrClN(2)O, has been obtained via cryomodification of the known alpha-polymorph of phenazepam [Karapetyan et al. (1979 ?). Bioorg. Khim.5, 1684-1690]. In both polymorphs, the mol-ecules, which differ only in the dihedral angles between the aromatic rings [75.4 (2) degrees and 86.2 (3) degrees in the alpha- and beta-polymorphs, respectively], are linked into centrosymmetric dimers via N-H?O hydrogen bonds. In the crystal structure of the beta-polymorph, weak inter-molecular C-H?O hydrogen bonds further link these dimers into layers parallel to bc plane. PMID- 21587598 TI - 2-Dibutyl-amino-1-(2,7-dichloro-9H-fluoren-4-yl)ethanol. AB - In the title compound, C(23)H(29)Cl(2)NO, the fluorene ring is essentially planar, with a maximum deviation from the mean plane of 0.041 (1) A. The amine group adopts a pyramidal configuration, the sum of the bond angles being 336.2 (3) degrees . In the crystal, the mol-ecules are linked into dimers by inter molecular O-H?N and C-H?O hydrogen bonds. Weak C-H?pi and pi-pi [centroid centroid distance = 3.7544 (7) A] inter-actions are also observed. PMID- 21587599 TI - Biphenyl-2,2',4,4'-tetra-carb-oxy-lic acid monohydrate. AB - In the title compound, C(16)H(10)O(8).H(2)O, the dihedral angle between the two benzene rings is 71.63 (5) degrees . In the crystal structure, pairs of inversion related mol-ecules are stacked [mean inter-planar spacing = 3.5195 (18) A], and O H?O and C-H?O hydrogen bonds create a three-dimensional network. PMID- 21587600 TI - Dihydro-myricetin hexa-acetate. AB - In the title compound, C(27)H(24)O(14), also known as 2,3-di-acetoxy-5-[(2RS,3RS) 3,5,7-triacetoxy-4-oxochromen-2-yl]phenyl acetate, the heterocyclic ring adopts a distorted half-chair conformation, with two C atoms displaced by 0.1775 (16) and 0.5950 (16) A from the mean plane of the other four atoms. The dihedral angle between the aromatic rings is 57.81 (8) degrees . In the crystal, the mol-ecules inter-act by C-H?O bonds, aromatic pi-pi stacking [centroid-centroid separation = 3.6206 (9) A] and C-H?pi inter-actions. PMID- 21587601 TI - 3-(3-Cyano-phen-yl)-N-phenyl-oxirane-2-carboxamide. AB - In the title compound, C(16)H(12)N(2)O(2), both terminal benzene rings are located at the same side of the central epoxide ring, showing a cis conformation. The epoxide ring makes dihedral angles of 76.59 (10) and 62.40 (11) degrees with the phenyl and cyano-phenyl rings, respectively. Inter-molecular N-H?O and weak C H?O hydrogen bonding is present in the crystal structure. PMID- 21587602 TI - 2-Phenyl-acetic acid-(E,E)-4,4'-(hydra-zinediylidene)dipyridine (2/1). AB - The asymmetric unit of the title co-crystal, C(12)H(10)N(4).2C(8)H(8)O(2), comprises a single mol-ecule of 2-phenyl-acetic acid and half a mol-ecule of 4 pyridine-aldazine as this is situated about a centre of inversion. Mol-ecules are connected into a three component aggregate via O-H?N hydrogen bonds. As the carb oxy-lic acid group is almost normal to the plane through the benzene ring to which it is attached [C-C-C-C = 93.7 (3) degrees ], and the 4-pyridine-aldazine mol-ecule is planar (r.m.s. deviation of the 16 non-H atoms = 0.010 A), the overall shape of the aggregate is that of an extended chair. In the crystal packing, layers of three component aggregates stack along the c axis. PMID- 21587603 TI - Isoprop-yl (3,4-dimethyl-5,5-dioxo-4H-pyrazolo-[4,3-c][1,2]benzothia-zin-2 yl)acetate. AB - In the title mol-ecule, C(16)H(19)N(3)O(4)S, the heterocyclic thia-zine ring adopts a half-chair conformation, with the S and N atoms displaced by 0.547 (2) and -0.254 (3) A, respectively, from the plane formed by the remaining atoms. In the crystal, weak C-H?N and C-H?O hydrogen bonds link the mol-ecules. PMID- 21587604 TI - 2-(1,3-Dioxoisoindolin-2-yl)acetonitrile. AB - The asymmetric unit of the title compound, C(10)H(6)N(2)O(2), contains two independent mol-ecules. The dihedral angles between the acetonitrile and the 1H isoindole-1,3(2H)-dione units are 69.0 (7) degrees and 77.0 (5) degrees in the two mol-ecules. One of the two terminal N atoms is disordered over two positions in a 0.66 (8):0,34 (8) ratio. In the crystal structure, the mol-ecules are linked by inter-molecular C-H?O hydrogen bonds. PMID- 21587605 TI - (2-Pyrid-yl)[5-(2-pyridyl-carbon-yl)-2-pyrid-yl]methanone. AB - In the centrosymmetric title compound, C(17)H(11)N(3)O(2), the dihedral angle between the central and pendant pyridyl rings is 50.29 (9) degrees . In the crystal, mol-ecules stack along the a axis by pi-pi inter-actions between the pyridine rings with centroid-centroid distances of 3.845 (2) A. The N atom and one of the C atoms of the central ring are disordered by symmetry. PMID- 21587606 TI - 3-(tert-But-oxy-carbon-yl)-2-(4-chloro-phen-yl)-1,3-thia-zolidine-4-carb-oxy-lic acid. AB - In the title compound, C(15)H(18)ClNO(4)S, the thia-zolidine ring adopts a twisted conformation about the S-C(methyl-ene) bond. The dihedral angle between the five- and six-membered rings is 77.2 (3) degrees . In the crystal, the mol ecules are linked by O-H?O hydrogen bonds, generating C(7) chains propagating in [100]. PMID- 21587607 TI - 4,6-Dimeth-oxy-pyrimidin-2-amine-2-(1H-indol-3-yl)acetic acid (1/1). AB - In the title co-crystal C(6)H(9)N(3)O(2).C(10)H(9)NO(2), the 4,6-dimeth-oxy pyrimidin-2-amine mol-ecule inter-acts with the carboxyl group of the 2-(1H-indol 3-yl)acetic acid mol-ecule through N-H?O and O-H?N hydrogen bonds, forming a cyclic hydrogen-bonded R(2) (2)(8) motif, which is further linked by an N-H?N hydrogen bond, forming a supra-molecular chain along the c axis. Neighboring chains are inter-linked via C-H?O hydrogen bonds, forming a supra-molecular ladder. PMID- 21587608 TI - 4-Dimethyl-amino-N'-(3-pyridyl-methyl-idene)benzohydrazide. AB - The title compound, C(15)H(16)N(4)O, was prepared by the reaction of pyridine-3 carbaldehyde with 4-dimethyl-amino-benzo-hydrazide in methanol. The dihedral angle between the pyridine and the benzene rings is 5.1 (3) degrees . In the crystal structure, the hydrazone mol-ecules are linked through inter-molecular N H?O hydrogen bonds, forming chains along the b axis. PMID- 21587609 TI - 1,3,5-Triaza-adamantan-7-amine. AB - The title compound, C(7)H(14)N(4), represents the first structurally characterized, isolated triaza-adamantane. In the crystal structure, weak inter molecular N-H?N hydrogen bonds link the mol-ecules into columns about the crystallographic fourfold axis. PMID- 21587610 TI - 2,6-Dichloro-pyridine-3,5-dicarbonitrile. AB - In the crystal, essentially planar (r.m.s. deviation = 0.003 A) mol-ecules of the title compound, C(7)HCl(2)N(3), form chains along the b axis by means of C-H?N inter-actions. These chains are further linked into layers parallel to the ab plane by C-Cl?N inter-actions. PMID- 21587611 TI - 2-[(E)-4-(Diethyl-amino)-styr-yl]-1-methyl-pyridinium iodide. AB - In the title compound, C(18)H(23)N(2) (+).I(-), the cation exists in the E configuration with respect to the ethenyl C=C bond. The pyridinium and benzene rings are nearly coplanar, making a dihedral angle of 4.63 (7) degrees . The two ethyl groups of the diethyl-amino substituent point in opposite directions with respect to the benzene plane. In the crystal, the cation and the iodide anion are linked by a weak C-H?I inter-action. The cations are stacked in an anti-parallel manner along the a axis by a pi-pi inter-action with a centroid-centroid distance of 3.5262 (9) A. The crystal structure is further stabilized by C-H?pi inter actions. PMID- 21587612 TI - 2,5-Dichloro-N-cyclo-hexyl-benzene-sulfonamide. AB - The structure of the title sulfonamide, C(12)H(15)Cl(2)NO(2)S, features a distorted tetra-hedral geometry for the S atom [maximum deviation: O-S-O = 120.23 (14) degrees ]. One of the sulfonamide O atoms is coplanar with the benzene ring [C-C-S-O torsion angle = -174.5 (2) degrees ], whereas the other lies well above the plane [C-C-S-O = 57.0 (3) degrees ]. A chair conformation is found for the cyclo-hexyl ring. In the crystal, supra-molecular chains aligned along the c axis are formed via N-H?O hydrogen bonds; these are consolidated in the three dimensional packing by C-H?O contacts involving the second sulfonamide O atom. PMID- 21587613 TI - Ethyl 7-(2-chloro-phen-yl)-5-trifluoro-meth-yl-4,7-dihydro-1,2,4-triazolo[1,5 a]pyrimidine-6-carboxyl-ate. AB - In the title compound, C(15)H(12)ClF(3)N(4)O(2), the dihydro-pyrimidine ring exhibits an envelope conformation. The dihedral angle between the mean planes of the dihydro-pyrimidine and phenyl rings is 83.94 (6) degrees . The OCH(2)CH(3) group is disordered over two sites with occupancies of 0.155 (3) and 0.845 (3). The crystal packing is stabilized by inter-molecular N-H?N hydrogen bonds. PMID- 21587614 TI - 4,4'-Dichloro-2,2'-[(3aR,7aR/3aS,7aS)-2,3,3a,4,5,6,7,7a-octa-hydro-1H-1,3 benzimidazole-1,3-di-yl)bis-(methyl-ene)]diphenol. AB - Mol-ecules of the the title compound, C(21)H(24)Cl(2)N(2)O(2), are located on a twofold rotation axis, which passes through the C atom linking the two N atoms. Two intra-molecular O-H?N hydrogen bonds were observed. In the crystal, non classical inter-molecular C-H?O hydrogen bonds link the mol-ecules into chains along the a axis. The crystal studied was a racemic twin. PMID- 21587615 TI - Bis[4-hy-droxy-3,5-dimeth-oxy-benzalde-hyde (2,4-dinitro-phen-yl)hydrazone] N,N dimethyl-formamide disolvate monohydrate. AB - In the title compound, 2C(15)H(14)N(4)O(7).2C(3)H(7)NO.H(2)O, the hydrazone mol ecules are roughly planar, with the two benzene rings twisted slightly relative to each other by dihedral angle of 6.04 (11) and 7.75 (11) degrees in the two mol-ecules. The water mol-ecule is linked to the Schiff base mol-ecule by an O H?O hydrogen bond. Intra-molecular N-H?O hydrogen bonds occur. In the crystal, mol-ecules are linked by inter-molecular N-H?O and O-H?O hydrogen bonds. PMID- 21587616 TI - 1,5-Bis-[1-(2-hy-droxy-phen-yl)ethyl-idene]carbonohydrazide dimethyl-formamide monosolvate. AB - In the title compound, C(17)H(18)N(4)O(3).C(3)H(7)NO, the main disubstituted urea and solvate mol-ecules are linked by pairs of N-H?O hydrogen bonds. In the main mol-ecules, the benzene rings form a dihedral angle of 15.59 (13) degrees a;nd two intra-molecular O-H?N hydrogen bonds influence the mol-ecular conformation. In the crystal structure, weak inter-molecular C-H?O inter-actions link the hydrogen-bonded pairs into chains along the b axis. The chains associate via C H?pi inter-actions. PMID- 21587617 TI - [2,2'-Imino-diethano-lato(2-)-kappaO,N,O'][4-(meth-oxy-carbonyl-meth-yl)phen yl]boron. AB - The title compound, C(13)H(18)BNO(4), was readily obtained from the reaction of methyl 4-boronobenzene acetate with ethano-lamine. A combination of inter molecular N-H?O hydrogen bonds and C-H?pi inter-actions leads to the pairwise association of mol-ecules. PMID- 21587618 TI - Metronidazolium perchlorate. AB - IN THE CRYSTAL STRUCTURE OF THE TITLE COMPOUND [SYSTEMATIC NAME: 1-(2-hy-droxy eth-yl)-2-methyl-5-nitro-1H-imidazol-3-ium perchlorate], C(6)H(10)N(3)O(3) (+).ClO(4) (-), the cations are linked by inter-molecular N-H?O hydrogen bonds into zigzag chains along the c axis. The cations and anions are connected by O H?O and C-H?O hydrogen bonds. A weak intra-molecular C-H?O hydrogen bond is also observed. PMID- 21587619 TI - 1-(4-Fluoro-phen-yl)biguanid-1-ium chloride. AB - The title compound, C(8)H(11)FN(5) (+).Cl(-), crystallized with a monoprotonated 1-(4-fluoro-phen-yl)biguanidinium cation and a chloride anion in the asymmetric unit. The biguanidium group is not planar [dihedral angle between the two CN(3) groups = 52.0 (1) degrees ] and is rotated with respect to the phenyl group [tau = 54.3 (3) degrees ]. In the crystal, N-H?N hydrogen-bonded centrosymmetric dimers are connected into ribbons, which are further stabilized by N-H?Cl interactions, forming a three-dimensional hydrogen-bonded network. PMID- 21587620 TI - 1-[(Biphenyl-4-yl)(phen-yl)meth-yl]-1H-imidazole (bifonazole). AB - In the title compound, C(22)H(18)N(2), the dihedral angles formed by the imidazole ring with the phenyl ring and the benzene ring of the biphenyl group are 87.02 (5) and 78.20 (4) degrees , respectively. In the crystal, mol-ecules inter-act through inter-molecular C-H?N hydrogen bonds, forming chains parallel to the b axis. These chains are further linked into a three-dimensional network by C-H?pi stacking inter-actions. PMID- 21587621 TI - 3-(4-Meth-oxy-phen-yl)pyrido[2,3-b]pyrazine. AB - In the title mol-ecule, C(14)H(11)N(3)O, the benzene ring is twisted by 14.0 (2) degrees from the plane through the fused ring system. In the crystal, pi-pi inter-actions [centroid-centroid distances = 3.609 (1), 3.639 (1) and 3.735 (1) A] form stacks of mol-ecules propagating along the b axis. The crystal packing is further stabilized by weak inter-molecular C-H?O and C-H?N hydrogen bonds. PMID- 21587622 TI - 1-[3-(4-Chloro-phen-yl)-6-methyl-1,6-di-hydro-1,2,4,5-tetra-zin-1-yl]ethanone. AB - In the title compound, C(11)H(11)ClN(4)O, the tetra-zine ring adopts a non symmetrical boat conformation. The crystal packing exhibits relatively short inter-molecular C?N contacts of 3.118 (3) A. PMID- 21587623 TI - Ethyl 2-benzamido-4,5,6,7-tetra-hydro-1-benzothio-phene-3-carboxyl-ate. AB - The mol-ecule of the title compound, C(18)H(19)NO(3)S, adopts an approximately planar conformation: the thio-phene and phenyl rings form a dihedral angle of 8.13 (11) degrees while the ethyl ester group (r.m.s. deviation = 0.0217 A) is inclined at 1.25 (14) and 8.61 (13) degrees , respectively, to the thio-phene and phenyl rings. An intra-molecular N-H?O hydrogen bond with an S(6) ring motif occurs as well as an intra-molecular S?O hypervalent inter-action [S?O = 2.7369 (18) A]. The cyclo-hexene ring adopts a half-chair conformation and is disordered over two positions with site occupation factors of 0.641 (6) and 0.359 (6). In the crystal, inversion dimers linked by pairs of O-H?O hydrogen bonds generate R(2) (2)(10) loops. PMID- 21587624 TI - 1,1'-(p-Phenyl-enedimethyl-ene)dipyridinium bis-(hexa-fluoridophosphate). AB - The title salt, C(18)H(18)N(2) (2+).2PF(6) (-), exists as non-inter-acting cations and anions. In the cation, the pyridine and phenyl-ene rings are aligned at 62.9 (1) degrees ; the pyridine ring lies on a special position of m site symmetry and the phenyl-ene ring on a special position of 2/m site symmetry. The angle at the methyl-ene C atom is 112.8 (1) degrees . The anion lies on a special position of m site symmetry; four F atoms lie on this mirror plane. PMID- 21587625 TI - 2-Methyl-4,4-dioxo-N-phenyl-5,6-di-hydro-1,4-oxathiine-3-carboxamide (Oxycarboxin). AB - In the title compound, C(12)H(13)NO(4)S, a systemic fungicide, the heterocycle adopts a lounge chair conformation and the dihedral angle between the ring planes is 25.8 (2) degrees . Inter-molecular C-H?O hydrogen bonds are noted in the crystal structure. Also observed is a short inter-action of a methyl-ene hydrogen atom with the pi-electron system of a phenyl ring in an adjacent mol-ecule. PMID- 21587626 TI - 1-Acetyl-5-isobutyl-2-sulfanylidene-imidazolidin-4-one. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(9)H(14)N(2)O(2)S. In the crystal, the mol-ecules are linked by N-H?O hydrogen bonds, forming a chain along the a axis. PMID- 21587627 TI - 1-Carboxymethyl-1'-carboxylatomethyl-3,3'-[p phenylenebis(oxymethylene)]dipyridinium bromide dihydrate. AB - In the crystal structure of the title salt, C(22)H(21)N(2)O(6) (+).Br(-).2H(2)O, pairs of betaine mol-ecules are bridged by protons (the bridging proton is disordered), forming strong and symmetrical O-H?O hydrogen bonds, leading to an infinite chain along the b axis. The water mol-ecules are linked to the betaine mol-ecule and the bromide ion through O-H?O and O-H?Br inter-actions. The central ring, located on an inversion centre, makes dihedral angles of 1.2 (2) degrees with the outer rings. One of the carboxylic acid groups is deprotonated. PMID- 21587628 TI - N'-(Butan-2-yl-idene)furan-2-carbohydrazide. AB - The title Schiff base compound, C(9)H(12)N(2)O(2), was obtained from a condensation reaction of butan-2-one and furan-2-carbohydrazide. The furan ring and the hydrazide fragment are roughly planar, the largest deviation from the mean plane being 0.069 (2)A, but the butanyl-idene group is twisted slightly with respect to this plane by a dihedral angle of 5.2 (3) degrees . In the crystal, inter-molecular N-H?O hydrogen bonds link pairs of inversion-related mol-ecules, forming dimers of R(2) (2)(8) graph-set motif. PMID- 21587629 TI - Ethyl 3-oxo-3H-benzo[f]chromene-2-carboxyl-ate. AB - In the title compound, C(16)H(12)O(4), the chromene ring system is almost planar [maximum deviation = 0.026 (1) A] and makes dihedral angles of 1.24 (9) and 26.5 (2) degrees with the fused benzene ring and the plane of the ethyl carboxyl-ate group, respectively. PMID- 21587631 TI - [(3R,4S)-4-(4-Fluoro-phen-yl)-1-methyl-piperidin-3-yl]methyl 4-methyl-benzene sulfonate. AB - In the title compound, C(20)H(24)FNO(3)S, the piperidine ring adopts a chair conformation. The dihedral angle between the aromatic rings is 47.01 (17) degrees . PMID- 21587630 TI - (2,7-Dimeth-oxy-naphthalen-1-yl)(phen-yl)methanone. AB - The asymmetric unit of the title compound, C(19)H(16)O(3), contains three independent conformers. Each of the three conformers has essentially the same feature of non-coplanar aromatic rings whereby the aroyl group at the 1-position of the naphthalene ring is twisted in a perpendicular manner to the naphthalene ring. The dihedral angles between the benzene ring planes and the naphthalene ring systems are 75.34 (7), 86.47 (7) and 76.55 (6) degrees in the three conformers. The crystal structure is stabilized by inter-molecular C-H?O hydrogen bonds. PMID- 21587632 TI - Methyl 2-meth-oxy-4-{[2-(4-nitro-phen-yl)hydrazinyl-idene]meth-yl}benzoate. AB - The mol-ecule of the title Schiff base compound, C(16)H(15)N(3)O(5), obtained from a condensation reaction of 4-acet-oxy-3-meth-oxy-benzaldehyde and 4-nitro phenyl-hydrazine, adopts an E geometry with respect to the C=N double bond. The mol-ecule is roughly planar, with the two benzene rings twisted slightly with respect to each other by a dihedral angle of 6.90 (9) degrees . In the crystal, inter-molecular N-H?O hydrogen bonds link centrosymmetrically related pairs of mol-ecules, forming dimers of R(2) (2)(22) graph-set motif. The dimers are further connected through slipped pi-pi inter-actions between symmetry-related benzene rings [centroid-centroid distance of 3.646 (1) A, offset angle of 15.4 degrees ]. PMID- 21587633 TI - 3-(2-Formyl-phen-oxy)propanoic acid. AB - In the structure of the title compound, C(10)H(10)O(4), the carboxyl group forms a catemer motif in the [100] direction instead of the expected dimeric structures. The carboxylic acid group is found in the syn conformation and the three-dimensional organization in the crystal is based on C-H?O and O-H?O interactions. PMID- 21587634 TI - 4-Amino-N-(3-meth-oxy-pyrazin-2-yl)benzene-sulfonamide. AB - The overall mol-ecular geometry of the title compound, C(11)H(12)N(4)O(3)S, is bent, with a dihedral angle of 89.24 (5) degrees between the best planes through the two aromatic rings. Each mol-ecule behaves as a hydrogen-bond donor toward three different mol-ecules, through its amidic and the two aminic H atoms, and it behaves as a hydrogen-bond acceptor from two other mol-ecules via one of its sulfonamidic O atoms. In the crystal, mol-ecules linked by N-H?N and N-H?O hydrogen bonds form kinked layers parallel to (001), adjacent layers being connected by van der Waals inter-actions. PMID- 21587635 TI - 1-Benzoyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetra-zine. AB - In the title compound, C(21)H(16)N(4)O, the central tetra-zine ring adopts an unsymmetrical boat conformation with the two N atoms as the bow and stern. The crystal packing is stabilized by inter-molecular N-H-O hydrogen bonds. PMID- 21587636 TI - 4-Methyl-9-[(4-methyl-phen-yl)sulfon-yl]thio-pyrano[3,4-b]indole-3(9H)-thione. AB - The title compound, C(19)H(15)NO(2)S(3), is the first example of a dithia analogue of pyrano[3,4-b]indolone. The almost planar thio-pyrano-indole-thione ring system (r.m.s. deviation for all non-H atoms = 0.030 A) makes a dihedral angle of 80.70 (8) degrees with the p-tolyl ring. In the crystal, mol-ecules are connected via C-H?O hydrogen bonds into two chains along the b axis. These chains are connected via pi-pi inter-actions between symmetry-related thio-pyrano-indole thione ring systems [centroid-centroid distance = 3.588 (1) A]. PMID- 21587637 TI - N'-(2-Meth-oxy-benzyl-idene)aceto-hydrazide. AB - In the title mol-ecule, C(10)H(12)N(2)O(2), the acetohydrazide group is almost planar [within 0.0306 (12) A] and forms a dihedral angle of 12.15 (14) degrees with the benzene ring. The meth-oxy group deviates from the attached benzene ring with a C-O-C-C torsion angle of 4.2 (4) degrees .The mol-ecule adopts a trans configuration with respect to the C=N bond. In the crystal, mol-ecules are linked into centrosymmetric dimers by pairs of N-H?O hydrogen bonds and intermolecular C H?O interactions further stabilize the structure. PMID- 21587638 TI - N'-[(E)-1-(3,5-Dichloro-2-hy-droxy-phen-yl)ethyl-idene]-4-meth-oxy-benzo hydrazide monohydrate. AB - The title compound, C(16)H(14)Cl(2)N(2)O(3).H(2)O, displays a trans conformation with respect to the C=N double bond. The dihedral angle between the two benzene rings is 4.98 (12) degrees . Intra-molecular O-H?N and O-H?O hydrogen bonds occur. The crystal structure is stabilized by inter-molecular O-H?O and N-H?O hydrogen bonds. In addition, there are pi-pi inter-actions between the chemically distinct benzene rings of inversion-related mol-ecules [centroid-centroid separation = 3.715 (1) A]. PMID- 21587639 TI - 1,1',2,2'-Tetra-methyl-3,3'-(p-phenyl-ene-dimethyl-ene)diimidazol-1-ium bis-[bis (trifluoro-methyl-sulfon-yl)imide]. AB - The cation of the imidazolium-based ionic-liquid title salt, C(16)H(24)N(4) (2+).2C(2)F(6)NO(4)S(2) (-), lies on a center of inversion; in the cation, the five-membered imidazolium ring is aligned at 84.4 (1) degrees with respect to the phenyl-ene ring; the angle at the methyl-ene C atom is 113.0 (2) degrees . In the anion, the negative charge formally resides on the two-coordinate N atom; the S-N-S angle at this atom is 125.2 (1) degrees . PMID- 21587641 TI - [(Methyl-carbamothio-yl)disulfan-yl]methyl N-methyl-carbamodithio-ate. AB - The title compound, C(5)H(10)N(2)S(5), was unintentionally obtained as the product of an attempted synthesis of a methyl-carbamodithioic acid using methyl amine and carbon disulfide. In the mol-ecule, two dithio-carbamate groups are bridged by a -CH(2)S- unit. The C-S-S-C torsion angle is -90.13 (11) degrees . The crystal structure is stabilized by N-H?S inter-actions between neighbouring mol-ecules. An intra-molecular N-H?S hydrogen bond also occurs. PMID- 21587640 TI - (Z)-3-(Anthracen-9-yl)-1-(2-eth-oxy-phen-yl)prop-2-en-1-one. AB - The mol-ecule of the title chalcone, C(25)H(20)O(2), consisting of 2-eth-oxy phenyl and anthracene rings bridged by a prop-2-en-1-one unit, is twisted and exists in the Z configuration with respect to the central C=C bond. The dihedral angle between the benzene and anthracene rings is 78.17 (9) degrees . The propene unit makes dihedral angles of 44.5 (2) and 81.1 (2) degrees with the benzene and anthracene rings, respectively. The eth-oxy substituent is almost coplanar with the attached benzene ring [C-O-C-C torsion angle = 178.57 (19) degrees ]. In the crystal, mol-ecules are linked into chains along the a axis by weak C-H?O inter actions. The crystal structure is further stabilized by C-H?pi inter-actions. PMID- 21587642 TI - 2-{[(E)-1,3-Benzodioxol-5-yl]methyl-idene-amino}-benzoic acid. AB - In the title compound, C(15)H(11)NO(4), the dihedral angle between the aromatic rings is 23.8 (2) degrees and an intra-molecular O-H?N hydrogen bond generates an S(6) ring. In the crystal, C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21587643 TI - 5H-Thio-chromeno[2,3-b]pyridine-5,10,10-trione. AB - The asymmetric unit of the title compound, C(12)H(7)NO(3)S, contains two independent mol-ecules with different geometric-al configurations. The dihedral angles between the benzene and pyridine rings in the two mol-ecules are 3.7 (2) and 5.40 (19) degrees . The central heterocyclic fused rings have different puckering parameters [Q = 0.122 (3) A, theta = 100.4 (13), phi = 185.3 (19) degrees in one mol-ecule, 0.101 (3) A, 101.4 (3) and 2 (2) degrees in the other]. The SO(2) group is oriented at dihedral angles of 81.06 (14) and 82.58 (15) degrees with the benzene and pyridine rings, respectively, in one mol-ecule [87.21 (14) and 87.66 (14) degrees in the second]. In the crystal, the mol ecules are linked into zigzag polymeric chains along the b axis by inter molecular C-H?O hydrogen bonding. pi-pi inter-actions with centroid-centroid distances in the range 3.825 (3)-4.153 (3) A stabilize the structure. S-O?pi and C-O?pi inter-actions are also observed. PMID- 21587644 TI - Triphen-yl[(4-phenyl-benzo-yl)meth-yl]phospho-nium trifluoro-methane-sulfonate. AB - In the cation of the title compound, C(32)H(26)OP(+).CF(3)O(3)S(-), the dihedral angle between the benzene rings of the biphenyl group is 42.37 (8) degrees . In the crystal, the cations and anions inter-act through inter-molecular C-H?O hydrogen bonds, forming chains parallel to the b axis. These chains are further linked by C-H?pi stacking inter-actions into layers parallel to the bc plane. PMID- 21587645 TI - (2-Hy-droxy-7-meth-oxy-naphthalen-1-yl)(phen-yl)methanone. AB - In the mol-ecule of the title compound, C(18)H(14)O(3), there is an intra molecular O-H?O=C hydrogen bond between the carbonyl and hy-droxy groups on the naphthalene ring system. The angles between the C=O bond vector and the least squares planes of the naphthalene ring system and the phenyl ring are 30.58 (6) and 42.82 (7) degrees , respectively, while the dihedral angle between the naphthalene ring system and the phenyl ring is 58.65 (5) degrees . In the crystal, mol-ecules are connected by pairs of inter-molecular O-H?O=C hydrogen bonds, forming centrosymmetric dimers. PMID- 21587646 TI - (1E,3E)-1,4-Bis(4-meth-oxy-phen-yl)buta-1,3-diene. AB - The title compound, C(18)H(18)O(2), which exhibits blue emission in the solid state, is an inter-mediate in the preparation of liquid crystals and polymers. The mol-ecule is located on an inversion centre. In the crystal, mol-ecules are arranged in a herringbone motif. PMID- 21587647 TI - Guanidinium l-glutamate. AB - In the title compound, CH(6)N(3) (+).C(5)H(8)NO(4) (-), there are two independent cations and two independent anions in the asymmetric unit. In the crystal structure, cations and anions are linked by inter-molecular N-H?O hydrogen bonds into a three-dimensional network. PMID- 21587648 TI - 3-Amino-pyridinium picrate. AB - During the formation of the title compound, C(5)H(7)N(2) (+).C(6)H(2)N(3)O(7) ( ), a phenolic proton is transferred to the pyridine N atom. In the crystal structure, the ions are linked by inter-molecular N-H?O and N-H?(O,O) hydrogen bonds into layers running parallel to (100). These layers are connected by weak pi-pi stacking inter-actions between symmetry-related pyridine and picric benzene rings with a centroid-centroid distance of 3.758 (2) A, forming a three dimensional network. PMID- 21587649 TI - tert-Butyl 4-cyano-phenyl carbonate. AB - The title compound, C(12)H(13)NO(3), was prepared by reacting one equivalent of di-tert-butyl dicarbonate with 4-cyano-phenol. Herringbone crystal packing is observed and there are no significant inter-molecular inter-actions. PMID- 21587650 TI - tert-Butyl 4-{[5-(4-chloro-phen-yl)-1-(4-fluoro-phen-yl)-1H-pyrazol-3-yl]carbon yl}piperazine-1-carboxyl-ate. AB - In the title pyrazole derivative, C(25)H(26)ClFN(4)O(3), both benzene rings are twisted out of the plane through the pyrazole ring, with dihedral angles of 67.62 (10) and 27.63 (10) degrees for the fluoro- and chloro-substituted rings, respectively. The dihedral angle between the two benzene rings is 64.54 (9) degrees . The piperazine ring (with a chair conformation) is linked to the pyrazole ring via a carbonyl spacer and is orientated to lie to one side of the pyrazole plane. In addition to an intra-molecular C-H?N contact, there are inter molecular C-H?O inter-actions, which generate a supra-molecular chain with an undulating topology along the c axis that is sustained by alternating centrosymmetric ten-membered {?HCNCO}(2) and {?HC3O}(2) synthons. PMID- 21587651 TI - 1,2,4,5-Tetra-fluoro-3,6-diiodo-benzene-4-(pyridin-4-ylsulfan-yl)pyridine (1/1). AB - The asymmetric unit of the title 1:1 adduct, C(10)H(8)N(2)S.C(6)F(4)I(2), comprises a half-mol-ecule of 1,2,4,5-tetra-fluoro-3,6-diiodo-benzene, and half a 4-(pyridin-4-ylsulfan-yl)pyridine mol-ecule. The former is completed by crystallographic inversion symmetry, the latter by twofold symmetry, with the S atom lying on the rotation axis. The almost planar 1,2,4,5-tetra-fluoro-3,6 diiodo-benzene mol-ecule (r.m.s. deviation of all 12 atoms = 0.016 A) and twisted 4-(pyridin-4-ylsulfan-yl)pyridine mol-ecule [dihedral angle between pyridyl rings = 54.88 (13) degrees ] are connected by N?I inter-actions [2.838 (4) A], generating a supra-molecular chain with a step-ladder topology. These chains are connected in the crystal by C-H?F and C-H?pi(pyrid-yl) inter-actions. PMID- 21587652 TI - 2-Phenyl-acetic acid-3-{(E)-2-[(E)-pyridin-3-yl-methyl-idene]hydrazin-1 ylidenemeth-yl}pyridine (2/1). AB - The asymmetric unit of the title 1:2 adduct, C(12)H(10)N(4).2C(8)H(8)O(2), comprises a single mol-ecule of 2-phenyl-acetic acid and half a mol-ecule of 3 pyridine-aldazine; the latter is completed by crystallographic inversion symmetry. In the crystal, mol-ecules are connected into a three-component aggregate via O-H?N hydrogen bonds. As the carboxyl group lies above the plane through the benzene ring to which it is attached [C-C-C-C = 62.24 (17) degrees ] and the 4-pyridine-aldazine mol-ecule is almost planar (r.m.s. deviation of the 16 non-H atoms = 0.027 A), the overall shape of the aggregate is that of a flattened extended chair. Layers of these aggregates are connected by C-H?O and C H?pi inter-actions and stack parallel to (220). PMID- 21587653 TI - 1-(3,4-Dimethyl-benzyl-idene)-4-ethyl-thio-semicarbazide. AB - The title compound, C(12)H(17)N(3)S, was prepared by the reaction of 4-ethyl-thio semicarbazide and 3,4-dimethyl-benzaldehyde. The dihedral angle between the thiourea unit and the benzene ring is 7.09 (8) degrees . In the crystal, inversion dimers linked by pairs of N-H?S hydrogen bonds occur. PMID- 21587654 TI - 1-Benzyl-idene-4-ethyl-thio-semicarbazide. AB - The title compound, C(10)H(13)N(3)S, was prepared by the reaction of 4-ethyl-thio semicarbazide and benzaldehyde. The dihedral angle between the benzene ring and the thio-urea unit is 8.96 (7) degrees and an intra-molecular N-H?N hydrogen bond generates an S(5) ring. In the crystal, inversion dimers linked by pairs of N-H?S hydrogen bonds generate R(2) (2)(8) loops. PMID- 21587655 TI - 3,5,5,6,8,8-Hexamethyl-5,6,7,8-tetra-hydro-2-naphthoic acid (AHTN-COOH). AB - The title compound, C(17)H(24)O(2), is the product of a haloform reaction of 6 acetyl-1,1,2,4,4,7-hexa-methyl-tetra-line (AHTN). The compound is a racemic mixture with a disorder in its aliphatic ring [occupany ratio 0.683 (4):0.317 (4)] due to two possible half-chair forms. The carb-oxy-lic acid unit is slightly twisted out of coplanarity with the aromatic system [dihedral angle = 29.26 (6) degrees ]. In the crystal, pairs of short classical inter-molecular O-H?O hydrogen bonds link pairs of mol-ecules around a center of symmetry. PMID- 21587656 TI - Butallyl-onal 1,4-dioxane hemisolvate. AB - THE ASYMMETRIC UNIT OF THE TITLE COMPOUND [SYSTEMATIC NAME: 5-(1-bromo-prop-2-en 1-yl)-5-sec-butyl-pyrimidine-2,4,6-trione 1,4-dioxane hemisolvate], C(11)H(15)BrN(2)O(3).0.5C(4)H(8)O(2), contains one half-mol-ecule of 1,4-dioxane and one mol-ecule of butallyl-onal, with an almost planar barbiturate ring [largest deviation from the mean plane = 0.049 (5) A]. The centrosymmetric dioxane mol-ecule adopts a nearly ideal chair conformation. The barbiturate mol ecules are linked together by an N-H?O hydrogen bond, giving a single-stranded chain. Additionally, each dioxane mol-ecule acts as a bridge between two anti parallel strands of hydrogen-bonded barbiturate mol-ecules via two hydrogen bonds, N-H?O(dioxane)O?H-N. Thus, a ladder structure is obtained, with the connected barbiturate mol-ecules forming the 'stiles' and the bridging dioxane mol-ecules the 'rungs'. PMID- 21587657 TI - 2-Bromo-4-chloro-6-[(E)-o-tolyl-imino-meth-yl]phenol. AB - The title compound, C(14)H(11)BrClNO, is a Schiff base compound derived from the condensation of 3-bromo-5-chloro-salicyl-aldehyde and o-toluidine in methanol. The aromatic rings make a dihedral angle of 38.3 (1) degrees . The mol-ecular conformation is stabilized by an intra-molecular O-H?N hydrogen bond, generating an S(6) ring. PMID- 21587658 TI - 3-Phenyl-2-(1H-tetra-zol-1-yl)propanoic acid monohydrate. AB - In the title compound, C(10)H(10)N(4)O(2).H(2)O, the dihedral angle between the tetra-zole and benzene rings is 63.24 (11) degrees . The crystal structure is stabilized by intra-molecular O-H?N and O-H?O hydrogen bonds. PMID- 21587659 TI - 1-(1-Phenyl-ethyl-idene)carbonohydrazide. AB - The title compound, C(9)H(12)N(4)O, crystallizes with two independent mol-ecules in the asymmetric unit. In the crystal, inter-molecular N-H?O and N-H?N hydrogen bonds link the mol-ecules into paired ribbons propagated in [100]. The crystal studied was a twin (twin law 00/00/001) with a minor component of 25%. PMID- 21587660 TI - N'-(2-Hy-droxy-1,2-diphenyl-ethyl-idene)benzohydrazide. AB - In the title compound, C(21)H(18)N(2)O(2), the amino group is involved in an intra-molecular N-H?O hydrogen bond. The rings make dihedral angles of 37.9 (2), 64.4 (2) and 83.6 (2) degrees . In the crystal, inter-molecular O-H?N and O-H?O hydrogen bonds link the mol-ecules into chains running along [100]. PMID- 21587661 TI - 11-{[2-(3-Fluoro-phen-yl)eth-yl](meth-yl)amino}-penta-cyclo-[5.4.0.0.0.0]undecan 8-one. AB - In the title compound, C(20)H(22)FNO, the distances close to the carbonyl and amine are: N-O = 3.232 (4) A and N-C = 2.666 (5) A. The crystal packing is unremarkable. PMID- 21587662 TI - 4-[(E)-2-(2,4,6-Trinitro-phenyl)ethyl-idene]benzonitrile. AB - In the crystal of the title compound, C(15)H(8)N(4)O(6), the mol-ecules are organized in layers due to their linkage by weak C-H?N hydrogen bonds. The layers are themselves inter-connected by weak C-H?O hydrogen bonds and pi-pi inter actions [centroid-centroid distances = 3.8690 (15) and 3.9017 (16) A]. The dihedral angle between the rings is 31.9 (1) degrees . PMID- 21587663 TI - 4-Benzyl-4-methyl-morpholinium hexa-fluoro-phosphate. AB - In the title compound, C(12)H(18)NO(+).PF(6) (-), the asymmetric unit consists of two cation-anion pairs. The six F atoms of one anion are disordered over two sets of sites in a 0.592 (6):0.408 (6) ratio. The morpholinium rings adopt chair conformations. PMID- 21587664 TI - N'-[4-(Dimethyl-amino)-benzyl-idene]furan-2-carbohydrazide. AB - The title compound, C(14)H(15)N(3)O(2), was prepared by the reaction of 4 (dimethyl-amino)-benzaldehyde and furan-2-carbohydrazide. The dihedral angle between the benzene ring and the furan ring is 25.59 (19) degrees . In the crystal, mol-ecules are linked by inter-molecular N-H?O hydrogen bonds, forming chains along [010]. PMID- 21587665 TI - N-{2-[4-(2-Meth-oxy-phen-yl)piperazin-1-yl]eth-yl}-4-nitro-N-(2-pyrid yl)benzamide. AB - In the title compound, C(25)H(27)N(5)O(4), the piperizine ring adopts a chair conformation. The dihedral angles between the pyridine ring and the two benzene rings are 65.5 (4) and 70.7 (4) degrees , while the dihedral angle between the two benzene rings is 17.3 (3) degrees . An intra-molecular C-H?O hydrogen bond occurs. PMID- 21587666 TI - Dipotassium dialuminium cyclo-octa-phosphate. AB - Single crystals of the title compound, K(2)Al(2)P(8)O(24), were obtained by solid state reaction. The monoclinic structure is isotypic with that of the Ga(III) analogue and is built of eight-membered phosphate ring anions P(8)O(24) (8-) (2/m symmetry) isolated from each other and further linked by isolated AlO(6) octa hedra ( symmetry) by sharing corners. Each AlO(6) octa-hedron is linked to four P(8)O(24) (8-) rings in such a way that two rings are linked through bidentate diphosphate groups attached in the cis positions on two opposite parallel edges of the octa-hedron. The two other rings are linked via corner-sharing to the two remaining corners in the trans positions of the AlO(6) octa-hedron. Each P(8)O(24) (8-) ring anion is linked to eight AlO(6) octa-hedra. More accurately, each ring anion is linked to four AlO(6) octa-hedra through bidentate diphosphate groups attached in the cis positions to the AlO(6) octa-hedron and to the four remaining octa-hedra by sharing corners. This three-dimensional linkage delimits channels running parallel to [001] in which the ten-coordinated K(+) cations (2 symmetry) are distributed over two columns. These columns alternate with empty octa-gonally-shaped channels expanding through the P(8)O(24) (8-) ring anions. PMID- 21587667 TI - The quinter-nary thio-phosphate Cs(0.5)Ag(0.5)Nb(2)PS(10). AB - The quinter-nary thio-phosphate Cs(0.5)Ag(0.5)Nb(2)PS(10), cesium silver tris (disulfido)[tetra-thio-phosphato(V)]diniobate(IV), has been prepared from the elements using a CsCl flux. The crystal structure is made up of (infinity) (1)[Nb(2)PS(10)] chains expanding along [010]. These chains are built up from bicapped trigonal-prismatic [Nb(2)S(12)] units and tetra-hedral [PS(4)] groups and are linked through a linear S-Ag-S bridge, forming a two-dimensional layer. These layers then stack on top of each other, completing the three-dimensional structure with an undulating van der Waals gap. The disordered Cs(+) ions reside on sites with half-occupation in the voids of this arrangement. Short [2.8843 (5) A] and long [3.7316 (4) A] Nb-Nb distances alternate along the chains, and anionic S(2) (2-) and S(2-) species are observed. The charge balance of the com pound can be represented by the formula [Cs(+)](0.5)[Ag(+)](0.5)[Nb(4+)](2)[PS(4) (3-)][S(2) (2-)](3). PMID- 21587668 TI - Sodium samarium tetra-kis-(poly-phosphate), NaSm(PO(3))(4). AB - NaSm(PO(3))(4) has been prepared by solid state reactions. It belongs to type II of the structural family of M(I)Ln(III)(PO(3))(4) compounds (M(I) = alkali metal and Ln(III) = rare earth metal) and is composed of (infinity)(PO(3))(n)](n-) polyphosphate chains with a repeating unit of four PO(4) tetra-hedra. The chains extend parallel to [100] and share O atoms with irregular SmO(8) polyhedra, forming a three-dimensional framework which delimits tunnels occupied by Na(+) cations in a distorted octa-hedral environment. PMID- 21587669 TI - [5,10,15,20-Tetra-kis(4-tol-yl)porphyrin]zinc(II) dichloro-methane solvate. AB - In the title complex, [Zn(C(48)H(36)N(4))].CH(2)Cl(2), the Zn(II) atom lies on an inversion center and the dichloro-methane solvent mol-ecule is disordered around an inversion center. The tolyl substituents are twisted compared to the central aromatic ring system of the porphyrin, similar to what is seen in previously published structures of this molecule [Dastidar & Goldberg (1996 ?). Acta Cryst. C52, 1976-1980]. The dihedral angles between the mean planes of the tolyl rings and the central ring are 66.98 (6) and 60.40 (6) degrees . PMID- 21587670 TI - MU(3)-Oxido-tris-{dichlorido[1,3-bis-(1,3,5-trimethyl-phen-yl)imidazol-2-yl idene]gold(III)} bis-(trifluoro-methane-sulfon-yl)imide-[bis-(trifluoro-methane sulfon-yl)imide]-silver(I) (1/2). AB - The unusual trinuclear Au(III) oxide title complex, [Au(3)Cl(6)O(C(21)H(24)N(2))(3)](C(2)F(6)NO(4)S(2)).2[Ag(C(2)F(6)NO(4)S(2))], is the side product of the reaction of [1,3-bis-(1,3,5-trimethyl-phen-yl)imidazol-2 yl-idene]dichloridophenyl-gold(III) with silver bis-(trifluoro-methane-sulfon yl)imide in the presence of traces of water. In contrast to corresponding Au(I) complexes, the core structure of the title compound is planar. Two silver(I) bis (trifluoro-methane-sulfon-yl)imide units are loosely bound to the complex cation. Here the silver atoms, disordered over two positions in a 0.870 (2):0.130 (2) ratio, inter-act either with the lone pairs of three chlorine ligands or two chlorine ligands and one edge of the mesityl pi-system. The crystal under investigation was a partial racemic twin. PMID- 21587671 TI - Bis[MU-(E)-N'-(4-oxido-4-phenyl-but-3-en-2-yl-idene)benzohydrazidato]bis [pyridine-copper(II)]. AB - In the crystal structure of the title centrosymmetric dimer, [Cu(2)(C(17)H(14)N(2)O(2))(2)(C(5)H(5)N)(2)], the Cu(II) atom has an almost perfect square-pyramidal geometry. The Cu(II) ion is coordin-ated by the NO(2) donor atoms of the hydrazide Schiff base ligand, the N atom of the pyridine group and an O atom of the symmetry-related unit. The dihedral angles between the pyridine ring and the two phenyl rings of the ligand are 21.4 (3) and 24.0 (2) degrees . The mol-ecular structure is stabilized by intra-molecular C-H?O inter actions. PMID- 21587672 TI - Dimethyl-ammonium tetra-chloridoferrate(III) 18-crown-6 clathrate. AB - The reaction of dimethyl-amine hydro-chloride, 18-crown-6 and ferric chloride in ethanol yields the title compound, (C(2)H(8)N)[FeCl(4)].C(12)H(24)O(6), which exhibits an unusual supramolecular structure. The protonated dimethyl-amine contains one NH(2) (+) group, resulting in a 1:1 supra-molecular rotator-stator structure (CH(3)-NH(2) (+)-CH(3))(18-crown-6), through N-H?O hydrogen-bonding inter-actions between the ammonium group of the cation and the O atoms of the crown ether. In the crystal, all three components lie on a common crystallographic mirror plane normal to [010]. PMID- 21587673 TI - Bis{2-[(diisopropyl-phosphan-yl)amino]-pyridine-kappaN,P}copper(I) hexa-fluorido phosphate. AB - The crystal structure of the title compound, [Cu(C(11)H(19)N(2)P)(2)]PF(6), is composed of discrete [Cu(PN-iPr)(2)](+) cations [PN-iPr is 2-(diisopropyl phosphanyl-amino)-pyridine] and PF(6) (-) anions. The Cu(I) atom is bis-chelated by two independent PN-iPr ligands. It has a distorted tetra-hedral coordination by two P atoms [Cu-P = 2.2277 (4) and 2.2257 (4) A] and two pyridine N atoms [Cu N = 2.0763 (11) and 2.0845 (12) A]. Bond angles about Cu vary from 85.11 (3) (P Cu-N) to 130.37 (2) degrees (P-Cu-P). In the crystal, N-H?F hydrogen bonds link the Cu complexes and the PF(6) (-) anions into continuous chains, which show a cross-bedded spatial arrangement. In addition, several weaker C-H?F inter-actions contribute to the coherence of the structure. PMID- 21587674 TI - trans-Dichlorido(2,2-dimethyl-propane-1,3-diamine)-bis-(triphenyl phosphane)ruthenium(II). AB - In the title compound, [RuCl(2)(C(5)H(14)N(2))(C(18)H(15)P)(2)], the Ru(II) atom is six-coordinated, forming a slightly distorted octa-hedral geometry, with two chloride ions in an axial arrangement, and two P atoms of two triphenyl-phosphane and two chelating N atoms of the bidentate 2,2-dimethyl-propane-1,3-diamine ligand located in the equatorial plane. The average Ru-P, Ru-N and Ru-Cl bond lengths are 2.325 (18), 2.1845 (7) and 2.4123 (12) A, respectively. PMID- 21587675 TI - Chlorido(2,3,7,8,12,13,17,18-octa-ethyl-porphyrinato)iron(III) dichloro-methane sesquisolvate. AB - The title mol-ecule, [Fe(C(36)H(44)N(4))Cl].1.5CH(2)Cl(2), is a high-spin square pyramidal iron(III) porphyrinate with an average value for the equatorial Fe-N bond lengths of 2.065 (3) A and an axial Fe-Cl distance of 2.2430 (13) A. The iron cation is displaced by 0.518 (1) A from the 24-atom mean plane of the porphyrin ring. These values are typical for high-spin iron(III) porphyrinates. PMID- 21587676 TI - catena-Poly[[(4-methyl-benzoato-kappaO)manganese(II)]-MU-aqua-bis-(MU-4-methyl benzoato-kappaO:O')[(4-methyl-benzoato-kappaO)manganese(II)]-bis-(MU-N,N-diethyl nicotinamide)-kappaN:O;O:N]. AB - The asymmetric unit of the title complex, [Mn(2)(C(8)H(7)O(2))(4)(C(10)H(14)N(2)O)(2)(H(2)O)](n), contains two crystallographically independent units. In each one, the Mn(II) ions are bridged by two 4-methyl-benzoate (PMB) ligands and one water mol-ecule. In the crystal structure, each Mn(II) ion is coordinated by three PMB ligands, one water mol ecule and two symmetry-related N,N-diethyl-nicotinamide (DENA) ligands. Symmetry related Mn(II) ions are bridged by the N and O atoms of symmetry-related DENA ligands, forming polymeric chains parallel to [100]. The coord-ination environmnts for the Mn(II) ions are slightly distorted octa-hedral. Intra molecular O-H?O hydrogen bonds link bridging water mol-ecules to the carboxyl-ate O atoms of a neigh-boring polymeric chain. In the crystal structure, pi-pi contacts between benzene rings [centroid-centroid distance = 3.562 (1) A] and weak C-H?pi inter-actions are also observed. PMID- 21587677 TI - Hexa-kis-(4-acetyl-pyridinium) octa-deca-chloridotetra-anti-monate(III). AB - The title compound, (C(7)H(8)NO)(6)[Sb(4)Cl(18)], contains centrosymmetric hexa anions built up from four vertex-sharing alternating SbCl(5) square-based pyramids and highly distorted SbCl(6) octa-hedra when long (<3.2 A) 'secondary' Sb-Cl inter-actions are taken into account. The inter-polyhedral Sb-Cl bonds define a square-shape. In the crystal, the components are linked by N-H?Cl, C H?Cl and C-H?O hydrogen bonds, generating a three-dimensional network. PMID- 21587678 TI - Diaqua-(1,4,8,11-tetra-aza-cyclo-tetra-deca-ne)nickel(II) fumarate tetra-hydrate. AB - The asymmetric unit of the title complex salt, [Ni(C(10)H(24)N(4))(H(2)O)(2)](C(4)H(2)O(4)).4H(2)O, comprises half of a nickel(II) complex dication, half of a fumarate dianion and two water mol-ecules. Both the Ni(II) cation and fumarate anion lie on a crystallographic inversion center. The Ni(II) ion in the cyclam complex is six-coordinated within a distorted N(4)O(2) octa-hedral geometry, with the four cyclam N atoms in the equatorial plane and the two water mol-ecules in apical positions. The six membered metalla ring adopts a chair conformation, whereas the five-membered ring exists in a twisted form. In the crystal packing, inter-molecular O-H?O hydrogen bonds between the water molecules and the carboxyl groups of the fumarate anions lead to the formation of layers with R(4) (2)(8) ring motifs. Ni(II) complex cations are sandwiched between two such layers, being held in place by O-H?O, N H?O and C-H?O hydrogen bonds, consolidating a three-dimensional network. PMID- 21587679 TI - 4-Fluoro-anilinium tetra-chloridoferrate(III) 18-crown-6 clathrate. AB - The reaction of 4-fluoro-aniline hydro-chloride, 18-crown-6 and ferric chloride in methano-lic solution yields the title compound, (C(6)H(7)FN)[FeCl(4)].C(12)H(24)O(6), which has an unusual supramolecular structure. N-H?O hydrogen-bonding inter-actions between the NH(3) (+) substituents of the 4-fluoro-anilinium cations and the O atoms of the crown ether mol-ecules result in a rotator-stator-like structure. PMID- 21587680 TI - (4-Amino-benzene-sulfonato)-hepta-aqua-gadolinium(III) 4-amino-benzene-sulfonate nitrate 4,4'-bipyridyl tetra-solvate dihydrate. AB - In the title compound, [Gd(C(6)H(6)O(3)S)(H(2)O)(7)](C(6)H(6)O(3)S)(NO(3)).4C(10)H(8)N(2).2H(2)O, the Gd(III) ion is octa-coordinated by seven water mol-ecules and one O-bonded 4 amino-benzene-sulfonate anion in a square-anti-prismatic arrangement. In the crystal, the components are linked by N-H?O, O-H?N and O-H?O hydrogen bonds. PMID- 21587681 TI - Poly[tetra-kis-(seleno-cyanato-kappaN)bis-(methanol-kappaO)tris-(MU-pyrimidine kappaN:N')dicobalt(II)]. AB - In the title compound, [Co(2)(NCSe)(4)(C(4)H(4)N(2))(3)(CH(3)OH)(2)](n), the Co(II) ion is coordinated by three N-bonded pyrimidine ligands, two N-bonded seleno-cyanate anions and one O-bonded methanol mol-ecule in an octa-hedral coordination mode. The asymmetric unit consists of one Co(II) ion, one pyrimidine ligand, two seleno-cyanate anions and one methanol mol-ecule in general positions as well as one pyrimidine ligand located around a twofold rotation axis. In the crystal structure, the pyrimidine ligands bridge [Co(CNSe)(2)(CH(3)OH)] units into zigzag-like chains, which are further connected by pyrimidine ligands into layers parallel to (010). PMID- 21587682 TI - Bis{4,4'-[oxalylbis(aza-nedi-yl)]dipyridinium} octa-molybdate. AB - In the crystal structure of the title compound, (C(12)H(12)N(4)O(2))(2)[Mo(8)O(26)], the amino and pyridinium groups of the N(1),N(2)-di(pyridinium-4-yl)oxalamide cations are hydrogen bonded to the O atoms of the centrosymmetric isopolyoxometalate beta-[Mo(8)O(26)](4-) anions, forming a three-dimensional supra-molecular architecture. PMID- 21587683 TI - catena-Poly[[bis-(MU-3-amino-pyrazine-2-carboxyl-ato) kappaN,O:O;kappaO:N,O)dilithium]-di-MU-aqua]. AB - The title compound, [Li(C(5)H(4)N(3)O(2))(H(2)O)](n), is composed of centrosymmetric dinuclear units, in which the Li(I) ions are bridged by two carboxyl-ate O atoms donated by two ligands. The dinuclear unit is nearly planar [r.m.s. deviation = 0.0125 (2) A]. The Li(I) ion is coordinated by an N,O chelating ligand, a bridging carboxyl-ate O atom from another ligand and two bridging water O atoms in a distorted trigonal-bipyra-midal geometry. The water O atoms bridge the dinuclear units into a polymeric mol-ecular column along [010]. The columns are held together by O-H?O and N-H?N hydrogen bonds. An intra molecular N-H?O inter-action also occurs. PMID- 21587684 TI - Bis(1,10-phenanthroline-kappaN,N')(sulfato-kappaO,O')nickel(II) propane-1,3-diol solvate. AB - In the structure of the title compound, [Ni(SO(4))(C(12)H(8)N(2))(2)].C(3)H(8)O(2), the Ni(II) ion (site symmetry 2) is six-coordinated in a distorted octa-hedral manner by four N atoms from two chelating 1,10-phenanthroline (phen) ligands and two O atoms from a bidentate sulfate ligand (2 symmetry). The dihedral angle between the two chelating NCCN groups is 80.9 (1) degrees . The central C atom of the propane-1,3-diol solvent mol-ecule is likewise located on a twofold rotation axis. In the crystal structure, the [Ni(SO(4))(C(12)H(8)N(2))(2)] and C(3)H(8)O(2) entities are connected through inter-molecular O-H?O hydrogen bonding. PMID- 21587685 TI - catena-Poly[nickel(II)-bis-(MU-2-amino-ethane-sulfonato kappaN,O:O';kappaO:N,O')]. AB - In the title polymeric complex, [Ni(C(2)H(6)NO(3)S)(2)](n), the Ni(II) ion occupies a special position on an inversion centre and displays a slightly distorted octa-hedral coordination geometry, being linked to four sulfonate O atoms and to two N atoms of the taurine ligands. The sulfonate groups doubly bridge symmetry-related Ni(II) centers, forming polymeric chains along the a axis. PMID- 21587686 TI - Poly[bis-(MU(3)-dodecyl sulfato)-calcium]. AB - In the title compound [Ca(C(12)H(25)O(4)S)(2)](n), the unique Ca(II) ion lies on an inversion center and is coordinated in a slightly distorted octa-hedral environment by six O atoms from dodecyl sulfate anions. The crystal structure is based on hydro-carbon (dodecyl sulfate) layers which sandwich the Ca(II) ions. Within the layers, the hydro-carbon zigzag chains are parallel to one another and inter-act via van der Waals forces. PMID- 21587687 TI - catena-Poly[[dichloridozinc(II)]-MU-1,1'-(butane-1,4-di-yl)diimidazole-kappaN:N]. AB - The title compound, [ZnCl(2)(C(10)H(14)N(4))](n), is a coordination polymer consisting of zigzag chains propagating in [001], in which the metal cation exhibits a distorted tetrahedral ZnCl(2)N(2) coordination. Adjacent chains are linked by inter-molecular C-H?Cl hydrogen bonds, forming a three-dimensional supra-molecular network. PMID- 21587688 TI - Bis(MU-3,5-dinitro-2-oxidobenzoato)-kappaO,O:O;kappaO:O,O-bis[aqua-(2-phenyl 1,3,7,8-tetra-azacyclo-penta-[l]phenanthrene-kappaN,N)cobalt(II)]. AB - In the title compound, [Co(2)(C(7)H(2)N(2)O(7))(2)(C(19)H(12)N(4))(2)(H(2)O)(2)], the Co(II) atom is six-coordinated by two N atoms from a 2-phenyl-1H-1,3,7,8, tetraaza-cyclo-penta-[l]phenanthrene (L) ligand, three O atoms from two 3,5 dinitro-2-oxidobenzoate (3,5-dinitro-salicylate or DNSA) ligands and one O atom from a water mol-ecule in a distorted octa-hedral geometry. The Co(II) atoms are bridged by two carboxyl-ate O atoms from two DNSA ligands, forming a centrosymmetric dinuclear structure. Neighbouring dinuclear units inter-act with each other through two types of pi-pi inter-actions between the L ligands [shortest centroid-centroid distance = 3.646 (3) A] and between the L and DNSA ligands [shortest atom-to-centroid distance = 3.794 (3) A]. N-H?O, O-H?N and O H?O hydrogen bonds are observed, which lead to a three-dimensional structure. PMID- 21587689 TI - Bis(ferrocene-carboxyl-ato-kappaO)bis-(2-pyridyl-methanol-kappaN,O)cobalt(II). AB - The title complex mol-ecule, [Fe(2)Co(C(5)H(5))(2)(C(6)H(4)O(2))(2)(C(6)H(7)NO)(2)], has a crystallographic imposed centre of symmetry. The Co(II) atom displays a distorted octa-hedral coordination geometry, provided by the O atoms of two monodentate ferrocene carboxyl-ate anions and by the N and O atoms of two 2-pyridyl-methanol mol-ecule. The mol-ecular conformation is stabilized by intra-molecular C-H?O hydrogen bonds. PMID- 21587690 TI - Bis[4-(4-pyridyl-meth-oxy)phenol-kappaN]silver nitrate monohydrate. AB - In the title compound, [Ag(C(12)H(11)NO(2))(2)]NO(3).H(2)O, the Ag(I) ion is coordinated by two N atoms from two different 4-(4-pyridyl-meth-oxy)phenol ligands, generating a nearly linear coordination geometry with an N-Ag-N angle of 167.1 (1) degrees . A three-dimensional supra-molecular network is built from the uncoordinated nitrate anion, the water mol-ecule and the cation through O-H?O hydrogen bonds. PMID- 21587691 TI - Diiodido[4'-(4-pyrid-yl)-2,2':6',2''-terpyridine-kappaN,N',N'']copper(II). AB - The Cu(II) atom in the title compound, [CuI(2)(C(20)H(14)N(4))], has a distorted square-pyramidal coordination formed by the N atoms of the tridentate 4'-(4-pyrid yl)-2,2':6'2''-terpyridine (pyterpy) ligand and two I atoms; one of the I atoms is in the apical position. In contrast to other known square-pyramidal diiodido- and dibromidocopper complexes of the pyterpy ligand in which metal-halogen distances are significantly different, in the title compound the apical and equatorial Cu-I bonds are almost identical [2.6141 (8) and 2.6025 (8) A, respectively]. PMID- 21587692 TI - Tris(2,2'-bipyridine)-cobalt(II) MU(6)-oxido-dodeca-MU(2)-oxido-hexa-oxidohexa molydate(VI). AB - In the title compound, [Co(C(10)H(8)N(2))(3)][Mo(6)O(19)], the Co(2+) cation is surrounded in a distorted octa-hedral coordination by six N atoms from three 2,2' bipyridine ligands. The distribution of Mo-O bond lengths in the Lindqvist isopolyanion is consistent with other structures containing the same unit. In the crystal, the cations and anions are linked by C-H?O inter-actions. PMID- 21587693 TI - catena-Poly[di-MU(1,1)-azido-(1,10-phenanthroline)cadmium(II)]. AB - The asymmetric unit of the title Cd(II) compound, [Cd(N(3))(2)(C(12)H(8)N(2))](n), contains a Cd(II) atom, located on a twofold axis passing through the middle of the phenanthroline mol-ecule, one azide ion and half of a 1,10-phenanthroline mol-ecule. The Cd(II) atom exhibits a distorted octa-hedral coordin-ation including one chelating 1,10-phenanthroline ligand and four azide ligands. The crystal structure features chains along the c direction in which azide groups doubly bridge two adjacent Cd(II) atoms in an end-on (EO) mode. Inter-chain pi-pi stacking inter-actions, with centroid-centroid separations of 3.408 (2) A between the central aromatic rings of 1,10 phenanthroline mol-ecules, lead to a supra-molecular sheet parallel to the bc plane. PMID- 21587694 TI - Penta-aqua-[2-(5-carboxyl-ato-2-oxido-1-pyridinio)acetato]zinc(II) monohydrate. AB - In the title compound, [Zn(C(8)H(5)NO(5))(H(2)O)(5)].H(2)O, the Zn(II) atom is coordinated by one O atom from the 2-(5-carboxyl-ato-2-oxidopyridinium-1 yl)acetate ligand and by five water mol-ecules, forming a distorted octa-hedral geometry. Coordinated and uncoordinated water mol-ecules form O-H?O hydrogen bonds, leading to a three-dimensional framework. PMID- 21587695 TI - Bis(MU-2,4-dihy-droxy-benzoato-kappaO:O')bis-[aqua-(2,4-dihy-droxy-benzoato kappaO)(1,10-phenanthroline-kappaN,N')cadmium(II)]. AB - In the title centrosymmetric dimeric Cd(II) complex, [Cd(2)(C(7)H(5)O(4))(4)(C(12)H(8)N(2))(2)(H(2)O)(2)], the Cd(II) cation is coord inated by a bidentate phenanthroline (phen) ligand, three dihy-droxy-benzoate (dhba) anions and one water mol-ecule in a distorted CdN(2)O(4) octa-hedral geometry. Among the dhba anions, two anions bridge two Cd(II) cations to form the dimeric complex with significant different Cd-O bond distances of 2.2215 (19) and 2.406 (2) A. The centroid-centroid distance of 3.4615 (19) A between two nearly parallel benzene rings of the dhba and phen ligands coordinating to the same Cd(II) cation indicates the existence of intra-molecular pi-pi stacking in the complex. Extensive O-H?O hydrogen bonding and inter-molecular weak C-H?O hydrogen bonding help to stabilize the crystal structure. One hy-droxy group of the monodentate dhba ligand is disordered over two sites with a site-occupancy ratio of 0.9:0.1. PMID- 21587696 TI - Bis(2-amino-3H-benzothia-zolium) bis-(7-oxabicyclo-[2.2.1]heptane-2,3-di-carbox yl-ato)manganate(II) hexa-hydrate. AB - In the crystal structure of the title salt, (C(7)H(7)N(2)S)(2)[Mn(C(8)H(8)O(5))(2)].6H(2)O, the heterocyclic N atom of the 2 amino-benzothia-zole mol-ecule is protonated. The Mn(II) atom (site symmetry ) has a slightly distorted octa-hedral MnO(6) coordination defined by the bridging O atoms of the bicyclo-heptane unit and four carboxyl-ate O atoms of two symmetry related and fully deprotonated ligands. The crystal packing is stabilized by N H?O hydrogen bonds between the cations and anions and by O-H?O hydrogen bonds including the crystal water mol-ecules. PMID- 21587697 TI - Bis(2-amino-3H-benzothia-zolium) bis-(7-oxabicyclo-[2.2.1]heptane-2,3-dicarboxyl ato)cobaltate(II) hexa-hydrate. AB - In the crystal structure of the title salt, (C(7)H(7)N(2)S)(2)[Co(C(8)H(8)O(5))(2)].6H(2)O, the heterocyclic N atom of the 2 amino-benzothia-zole mol-ecule is protonated. The Co(II) atom is situated on an inversion centre and exhibits a slightly distorted octa-hedral CoO(6) coordination defined by the bridging O atoms of the bicyclo-heptane unit and four carboxyl-ate O atoms of two symmetry-related and fully deprotonated ligands. The crystal packing is stabilized by N-H?O hydrogen bonds between the cations and anions and by O-H?O hydrogen bonds including the crystal water mol-ecules. PMID- 21587698 TI - {Ba[Au(SCN)(2)](2)}(n): a three-dimensional net comprised of monomeric and trimeric gold(I) units. AB - The noteworthy structural feature of the title complex, poly[acetonitrile-tetra MU(2)-thio-cyanato-barium(II)digold(I)], {[Au(2)Ba(SCN)(4)(CH(3)CN)]}(n), is that the bis-(thio-cyanato)-aurate(I) anion adopts both monomeric and trimeric motifs. The trimer unit has an Au?Au distance of 3.1687 (3) A. In both the monomeric and trimeric units, the Au(I) atoms are also bonded to two S atoms. Within the trimeric unit, the Au(I) atoms exist in differing environments; one Au atom has a T-shaped three-coordinate geometry while the other has a square-planar four coordinate geometry. The Au(I) atom of the monomer adopts a linear two-coordinate geometry. The extended structure can be described as a three-dimensional coordination polymer consisting of chains of Ba atoms bridged by thio-cyanate N atoms. These chains are cross-linked via the gold monomeric and trimeric units. PMID- 21587699 TI - Dibromido[1,1'-dibutyl-2,2'-(pentane-1,1-di-yl)di-1H-benzimidazole]-copper(II). AB - In the title compound, [CuBr(2)(C(27)H(36)N(4))], the Cu(II) ion exhibits a distorted tetra-hedral coordination geometry provided by two bromide ions and by chelation of two imine N-atom donors from a bis-(benzimidazole) ligand. Chelation results in a six-membered boat-shaped ring which links the benzimidazole groups. Each bis-(benzimidazole) fragment contains three n-butyl substituents, two of which have the expected trans conformation; the third exhibits the higher-energy cis conformation, an orientation consistent with several short intra-molecular C H?Br inter-actions. Essentially planar (r.m.s. deviations of 0.0101 and 0.0183 A) benzimidazole groups are oriented so as to give the bis-(benzimidazole) fragment a V-shaped appearance in profile with the cis and trans n-butyl groups directed to opposite sides of the planes. In the crystal, columns of mol-ecules along the b-axis direction form layers parallel to the (202) planes. Within a given column, the mol-ecules are linked by C-H?Br hydrogen bonds. The mol-ecules in adjacent columns are also linked by inter-molecular C-H?pi interactions, forming a three dimensional network. PMID- 21587700 TI - Dicylopenta-dien-yl[4-(4-vinyl-benz-yloxy)pyridine-2,6-dicarboxyl ato]titanium(IV) monohydrate. AB - The title compound, [Ti(C(5)H(5))(2)(C(16)H(11)NO(5))].H(2)O, exhibits a titanocene unit coordinated to a styrene-substituted pyridine-2,6-dicarboxyl-ate ligand synthesized for use as a monomer for polymerization or copolymerization yielding metallocene-containing polymers. The compound crystallized as a monohydrate and the solvent water mol-ecule forms strong O-H?O hydrogen bonds with the carboxyl-ate O atoms of the Ti complex, which play an important role in the connection of adjacent mol-ecules. In addition, weak inter-molecular C-H?O hydrogen bonds also contribute to the crystal packing arrangement. PMID- 21587701 TI - Acetato-aqua-{4,4',6,6'-tetra-tert-butyl-2,2'-[(2-pyridyl-meth-yl)imino-dimethyl ene]diphenolato}manganese(III) ethanol solvate. AB - In the title complex, [Mn(C(36)H(50)N(2)O(2))(CH(3)COO)(H(2)O)].CH(3)CH(2)OH, the Mn(III) atom is in an octa-hedral environment and is coordinated by the tetra dentate amine-bis-(phenolate) ligand, a monodentate acetate anion and a water mol ecule. An ethanol solvent mol-ecule is also found in the asymmetric unit. The structure displays O-H?O and C-H?O hydrogen bonding. PMID- 21587702 TI - Bis[N,N-dimethyl-1-(10H-pyrido[3,2-b][1,4]benzothia-zin-10-yl)propan-2-aminium] tetrakis-(thio-cyanato-kappaN)cobaltate(II). AB - The asymmetric unit of the title salt, (C(16)H(20)N(3)S)(2)[Co(NCS)(4)], comprises one monovalent isothio-pendylium cation and one-half of a divalent thio cyanatocobaltate(II) anion (2 symmetry). The central thia-zine ring of the cation is slightly twisted in a boat-like fashion, with r.m.s. deviations from the mean plane of 0.272 (1) and 0.2852 (8) A for the N and S atoms. The mol-ecular structure of the cation is stabilized by an intra-molecular N-H?N hydrogen bond. Within the complex anion, the Co(II) atom is tetra-hedrally surrounded by four N atoms of the thio-cyanate ligands. pi-pi stacking, with a distance of 3.7615 (10) A between the centroids of benzene and pyridine rings, helps to consolidate the packing. PMID- 21587703 TI - Diaqua-bis-(hydrogen tartrato)copper(II) dihydrate. AB - The title complex, [Cu(C(4)H(5)O(6))(2)(H(2)O)(2)].2H(2)O, contains a Cu(II) ion lying on an inversion centre. The coordination geometry of the Cu(II) ion is a distorted octa-hedron with four O atoms from two hydrogen tartrate ions occupying the equatorial positions and two O atoms from two coordinated water mol-ecules occupying the axial positions. In the crystal structure, inter-molecular O-H?O and C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21587704 TI - {N,N'-Bis[1-(2-pyrid-yl)ethyl-idene]ethane-1,2-diamine-kappaN,N',N'',N'''}bis (thio-cyanato-kappaN)manganese(II). AB - The mol-ecule of the title compound, [Mn(NCS)(2)(C(16)H(18)N(4))], has crystallographic twofold rotation symmetry, with the Mn(II) atom lying on the rotation axis. The Mn(II) atom is six-coordinated by four N atoms of the Schiff base ligand and by two N atoms of two thio-cyanate ligands, forming a distorted octa-hedral geometry. PMID- 21587705 TI - {N,N'-Bis[1-(2-pyrid-yl)ethyl-idene]propane-1,2-diamine-kappaN,N',N'',N'''}bis (thio-cyanato-kappaN)manganese(II). AB - In the title compound, [Mn(NCS)(2)(C(17)H(20)N(4))], the Mn(II) atom is six coordinated by the N,N',N'',N'''-tetra-dentate Schiff base ligand and by two trans-N atoms from two thio-cyanate anions, forming a distorted octa-hedral geometry. The dihedral angle between the aromatic rings of the Schiff base is 9.5 (3) degrees . PMID- 21587706 TI - {N,N'-Bis[1-(2-pyrid-yl)ethyl-idene]ethane-1,2-diamine-kappaN,N',N'',N'''}(thio cyanato-kappaN)zinc(II) perchlorate. AB - In the title compound, [Zn(NCS)(C(16)H(18)N(4))]ClO(4), the Zn(II) atom is five coordinated by four N atoms of the Schiff base ligand N,N'-bis-[1-(2-pyrid yl)ethyl-idene]ethane-1,2-diamine in the basal plane, and by the N atom of a thio cyanate ligand at the apical position, forming a distorted square-pyramidal geometry. The r.m.s. deviation from a plane through the four N atoms of the Schiff base is 0.015 (3) A, and the deviation of the Ni atom from that plane is 0.591 (2) A. Bond lengths are comparable with those observed in similar zinc(II) complexes with Schiff bases. The two methyl-ene C atoms of the ethane-1,2-diamine bridge of the Schiff base ligand are disordered over two sites with occupancies of 0.587 (3) and 0.413 (3). PMID- 21587707 TI - Tetra-aqua-bis-(pyridine-kappaN)nickel(II) dinitrate. AB - In the title compound, [Ni(C(5)H(5)N)(2)(H(2)O)(4)](NO(3))(2), the Ni(II) ion is coordinated by two N-bonded pyridine ligands and four water mol-ecules in an octa hedral coordination mode. The asymmetric unit consists of one Ni(II) ion located on an inversion center, as well as one pyridine ligand, one nitrate anion and two water mol-ecules in general positions. In the crystal structure, the discrete complex cations and nitrate anions are connected by O-H?O and C-H?O hydrogen bonds. PMID- 21587708 TI - Poly[[bis-(MU-4,4'-bipyridyl-kappaN:N')bis-(thio-cyanato-kappaN)manganese(II)] diethyl ether disolvate]. AB - In the title compound, {[Mn(NCS)(2)(C(10)H(8)N(2))(2)].2C(4)H(10)O}(n), the Mn(II) ion is coordinated by four N-bonded 4,4'-bipyridine (bipy) ligands and two N-bonded thio-cyanate anions in a distorted octa-hedral coordination geometry. The asymmetric unit consists of one Mn(II) ion and two bipy ligands each located on a twofold rotation axis, as well as one thio-cyanate anion and one diethyl ether mol-ecule in general positions. In the crystal structure, the metal centers with terminally bonded thicyanate anions are bridged by the bipy ligands into layers parallel to (001). The diethyl ether solvent mol-ecules occupy the voids of the structure. PMID- 21587709 TI - Bis[MU-4-(dimethyl-amino)-benzoato]-kappaO,O':O;kappaO:O,O'-bis-{aqua-[4 (dimethyl-amino)-benzoato-kappaO,O'](nicotinamide-kappaN)cadmium(II)}. AB - In the centrosymmetric dimeric Cd(II) title compound, [Cd(2)(C(9)H(10)NO(2))(4)(C(6)H(6)N(2)O)(2)(H(2)O)(2)], each seven-coordin-ated Cd(II) atom is chelated by the carboxyl-ate groups of the two 4-(dimethyl-amino) benzoate (DMAB) anions; the two monomeric units are bridged through the two O atoms of the two carboxyl groups. In the crystal structure, inter-molecular O H?O, N-H?O and C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. pi-pi contacts between the pyridine rings [centroid-centroid distance = 3.974 (1) A] may further stabilize the structure. Weak C-H?pi inter-actions are also observed. PMID- 21587710 TI - Diaqua-(isonicotinamide-kappaN)(4-meth-oxy-benzoato-kappaO,O')(4-meth-oxy benzoato-kappaO)cobalt(II). AB - In the title complex, [Co(C(8)H(7)O(3))(2)(C(6)H(6)N(2)O)(H(2)O)(2)], the Co(II) atom is coordinated by three O atoms from two 4-meth-oxy-benzoate ligands, which act in different modes, viz. monodentate and bidentate, two water mol-ecules and one N atom of the isonicotinamide ligand in a distorted octa-hedral geometry. The monodentate-coordinated carboxyl-ate group is involved in an intra-molecular O H?O hydrogen bond with the coordinated water mol-ecule. In the crystal structure, inter-molecular O-H?O and N-H?O hydrogen bonds link the mol-ecules into layers parallel to the ab plane. The crystal packing is further stabilized by weak C-H?O hydrogen bonds and pi-pi inter-actions indicated by the short distance of 3.6181 (8) A between the centroids of the benzene and pyridine rings of neighbouring mol ecules. PMID- 21587711 TI - Trichloridobis(ethyl-diphenyl-phosphine)(tetra-hydro-furan)-molybdenum(III). AB - In the mononuclear title compound, [MoCl(3)(C(4)H(8)O)(C(14)H(15)P)(2)], obtained by the reaction of trichloro-tris-(tetra-hydro-furan)-molybdenum(III) and ethyl diphenyl-phosphine in tetra-hydro-furan (THF) solution, the Mo(III) atom is six coordinated by one O atom of a THF mol-ecule, two P atoms from two ethyl-diphenyl phosphine ligands and three Cl atoms in a distorted octa-hedral geometry. The C atoms of the THF molecule are disordered over two positions in a 0.55 (2):0.45 (2) ratio. PMID- 21587712 TI - Bis(acetato-kappaO)[1,2-bis-(2-pyridyl-meth-oxy)benzene-kappaN,O,O',N']copper(II) tetra-hydrate. AB - In the title compound, [Cu(CH(3)COO)(2)(C(18)H(16)N(2)O(2))].4H(2)O, the Cu(II) ion is six-coordinated in a Jahn-Teller-distorted octa-hedral geometry environment defined by four O atoms and two N atoms. A chain structure along [100] is built up by inter-molecular O-H?O hydrogen bonds involving the uncoordinated water mol-ecules. PMID- 21587713 TI - catena-Poly[[[(2-phenyl-acetato-kappaO)zinc(II)]bis-[MU-4,4'-(disulfanedi yl)dipyridine-kappaN:N']] monohydrate]. AB - In the title compound, {[Zn(C(8)H(7)O(2))(2)(C(10)H(8)N(2)S(2))(2)].H(2)O}(n), the Zn(II) atom is coordinated by four N atoms from four 4,4'-(disulfanedi yl)dipyridine (bpds) ligands and two O atoms from two 2-phenyl-acetate anions in a distorted octa-hedral coordination geometry. The two bpds ligands of the same axial chirality bridge Zn(II) atoms, generating repeated rhomboidal chains, which are linked by O-H?O hydrogen bonds into a ladder structure. PMID- 21587714 TI - (5,15-Dianthracen-9-yl-10,20-dihexyl-porphyrinato)nickel(II): a planar nickel(II) porphyrin. AB - The title compound, [Ni(C(60)H(52)N(4))], is an example of a meso tetra substituted nickel(II) porphyrin with both meso aryl and alkyl residues. The mol ecule exhibits a planar macrocycle with an average deviation of the 24 macrocycle atoms from their least-squares plane (Delta24) of 0.01 A and an average Ni-N bond length of 1.960 (2) A. The Ni(II) atom lies on a center of inversion. The structure presents a rare example for a planar nickel(II) porphyrin, as meso substituted nickel(II) porphyrins with either only meso-aryl or with meso-alkyl residues typically exhibit a ruffled conformation. PMID- 21587715 TI - (2-Meth-oxy-benz-yl)(2-meth-oxy-benzyl-idene)aza-nium (2-meth-oxy-phen yl)methanaminium tetra-chloridozincate(II) monohydrate. AB - The title compound, (C(8)H(12)NO)(C(16)H(18)NO(2))[ZnCl(4)].H(2)O, was obtained as a by-product of the Zn(2+) and HCl catalyzed condensation of (2-meth-oxy-phen yl)methanamine in water. Both cations feature an intra-molecular N-H?O hydrogen bond. In the crystal, the components are linked by an extensive three-dimensional network of N-H?O, O-H?Cl and N-H?Cl hydrogen bonds (three of them bifurcated). Weak C-H?O intera-ctions also occur. PMID- 21587716 TI - Tricyclo-hex-yl{2-[(3,5-di-tert-butyl-4-hy-droxy-benz-yl)sulfan-yl]acetato kappaO}tin(IV). AB - The title compound, [Sn(C(6)H(11))(3)(C(17)H(25)O(3)S)], exists as a monomeric mol-ecule with the Sn(IV) atom in a distorted tetra-hedral C(3)O coordination geometry. The presence of two bulky tert-butyl groups on the carboxyl-ate prevents any hydrogen-bonding inter-actions involving the hy-droxy group. PMID- 21587717 TI - (2-{[1,1-Bis(hy-droxy-meth-yl)-2-oxidoeth-yl]imino-meth-yl}-4-chloro-phenolato kappaO,N,O')dibutyl-tin(IV). AB - In the title compound, [Sn(C(4)H(9))(2)(C(11)H(12)BrNO(4))], the Schiff base ligand chelates to the Sn(IV) atom through the two deprotonated hy-droxy groups, as well as through the N atom, to confer an overall cis-C(2)SnNO(2) trigonal bipyramidal geometry at the Sn(IV) atom [C-Sn-C = 129.92 (9) degrees ]. The remaining methyl-enehy-droxy groups engage in O-H?O hydrogen bonding with the O atoms of adjacent mol-ecules, leading to infinite supra-molecular chains propagating in [001]. PMID- 21587718 TI - catena-Poly[[aqua-(imidazole)-cadmium(II)]-MU(3)-benzene-1,3-dicarboxyl-ato]. AB - In the title compound, [Cd(C(8)H(4)O(4))(C(3)H(4)N(2))(H(2)O)](n), the Cd(II) ion is seven-coordinated by five O atoms from three crystallographically independent benzene-1,3-carboxylate ligands, one N atom from the imidazole ligand and one coordinated water mol-ecule. Neighboring Cd(II) ions are bridged by the benzene 1,3-dicarboxyl-ate ligands, forming a zigzag polymeric chain structure. These chains are further extended into a three-dimensional supra-molecular structure through O-H?O and N-H?O hydrogen bonds. PMID- 21587719 TI - Chlorido[hydridotris(pyrazol-1-yl-kappaN)borato](1H-pyrazole-kappaN)(triphenyl phosphine-kappaP)ruthenium(II). AB - In the title compound, [Ru(C(9)H(10)BN(6))Cl(C(3)H(4)N(2))(C(18)H(15)P)], the Ru(II) atom is coordinated by an N,N',N''-tridentate hydrido-trispyrazolylborate (Tp) ligand, a pyrazole (HPz) mol-ecule, a chloride ion and a triphenyl-phosphine ligand, resulting in a distorted RuClPN(4) octa-hedral coordination for the metal ion: the tridentate N atoms occupy one octa-hedral face and the Cl and P atoms are cis. One of the phenyl rings is disordered over two orientations in a 0.547 (10):0.453 (10) ratio, and a weak intra-molecular N-H?Cl hydrogen bond generates an S(5) ring. PMID- 21587720 TI - Penta-kis(ethyl-enediammonium) tri-MU-sulfato-bis-[tris-ulfatocerate(IV)] trihydrate. AB - In the cerate(IV) anion of the title salt, (C(2)H(10)N(2))(5)[Ce(2)(SO(4))(9)].3H(2)O, the two metal atoms are bridged by three sulfate units; each metal atom is itself chelated by other three sulfate units so that the metal atoms exist in nine-coordinate tricapped trigonal prismatic geometries. The anions, cations and uncoordinated water mol-ecules are linked by O-H?O and N-H?O hydrogen bonds, forming a three-dimensional network. One of the five cations is disordered with respect to the ethyl-ene portion in a 1:1 ratio. PMID- 21587721 TI - Potassium bis-(1,1,1,5,5,5-hexa-fluoro-pentane-2,4-dionato)bis-(4,4,4-trifluoro-1 phenyl-butane-1,3-dionato)europate(III). AB - In the crystal structure of the title complex, K[Eu(C(5)HF(6)O(2))(2)(C(10)H(6)F(3)O(2))(2)], the Eu(III) ion is in a slightly distorted square-anti-prismatic coordination geometry which is defined by eight O atoms of the anionic beta-diketone ligands. The two K(+) ions lie on crystallographic inversion centers. The Eu-O bond distances are in the range 2.294 (5)-2.413 (5) A. The crystal used was a non-merohedral twin, the ratio of the twin domains being 0.5236 (5):0.4764 (5). PMID- 21587722 TI - (Acetyl-acetonato-kappaO,O')chlorido-trimethano-latoniobium(V). AB - In the title compound, [Nb(CH(3)O)(3)(C(5)H(7)O(2))Cl], the Nb(V) atom is coordinated by two O atoms from the chelating acetyl-acetonate ligand, three O atoms from the methano-late groups and one chloride ligand. The octa-hedral environment around niobium is slightly distorted with Nb-O distances in the range 1.8603 (15)-2.1083 (15) A and an Nb-Cl distance of 2.4693 (9) A. The O-Nb-O angles vary between 80.74 (6) and 100.82 (7) degrees , while the trans Cl-Nb-O angle is 167.60 (5) degrees . There are no hydrogen bonds observed, only an inter molecular C-H?O inter-action. PMID- 21587723 TI - Dibut-yl{N'-[1-(5-chloro-2-oxidophenyl-kappaO)ethyl-idene]-3-hy-droxy-2-naphtho hydrazidato-kappaN',O}tin(IV). AB - The five-coordinate Sn(IV) atoms in the two crystallographically independent mol ecules of the title compound, [Sn(C(4)H(9))(2)(C(19)H(13)ClN(2)O(3))], are in distorted cis-C(2)NO(2)Sn trigonal-bipyramidal coordination environments. The tridentate dianion of the Schiff base, N'-[1-(5-chloro-2-oxidophen-yl)ethyl idene]-3-hy-droxy-2-naphtho-hydrazide, displays inter-molecular O-H?N hydrogen bonding, which stabilizes the overall compound. PMID- 21587724 TI - Hexaaqua-zinc(II) bis-(2,4,5-tricarboxybenzoate) 4,5-diaza-fluoren-9-one disolvate dihydrate. AB - The asymmetric unit of the title complex, [Zn(H(2)O)(6)](C(10)H(5)O(8))(2).2C(11)H(6)N(2)O.2H(2)O, contains one half of the complex cation with the Zn(II) ion located on an inversion center, a monovalent 2,4,5-tricarboxybenzoate (1,2,4,5-BTC) counter-anion, a 4,5-diaza-fluoren-9-one (DAFO) mol-ecule and an uncoordinated water mol-ecule. In the crystal structure, O-H?O and O-H?N hydrogen bonds link the cations, anions and water mol-ecules into a three-dimensional network. PMID- 21587725 TI - Bis(2,9-dimethyl-1,10-phenanthroline-kappaN,N')bis-(nitrato-kappaO,O')lead(II). AB - In the title complex, [Pb(NO(3))(2)(C(14)H(12)N(2))(2)], the lead ion is chelated by two 2,9-dimethyl-1,10-phenanthroline (dmphen) ligands and two nitrate anions in a slightly distorted square-anti-prismatic geometry. Intra- and inter molecular pi-pi stacking is present in the crystal structure, and the centroid centroid distances between the benzene and pyridine rings of adjacent dmphen ligands are 3.492 (3) and 3.592 (3) A, respectively. Inter-molecular C-H?O hydrogen bonds and C-H?pi inter-actions help to stabilize the crystal structure. PMID- 21587726 TI - Di-MU-nicotinamide-kappaO:N;kappaN:O-bis-[aqua-bis-(4-meth-oxy-benzoato kappaO)copper(II)]. AB - The asymmetric unit of the centrosymmetric dinuclear title compound, [Cu(2)(C(8)H(7)O(3))(4)(C(6)H(6)N(2)O)(2)(H(2)O)(2)], contains one half of the complex mol-ecule. Each Cu(II) atom is five-coordinated by one N atom from one bridging nicotinamide ligand and one O atom from another symmetry-related bridging nicotinamide ligand, two O atoms from two 4-meth-oxy-benzoate ligands, and one water mol-ecule, forming a distorted square-pyramidal geometry. Inter molecular O-H?O and N-H?O hydrogen bonds link the mol-ecules into layers parallel to (01). pi-pi inter-actions, indicated by short inter-molecular distances of 3.801 (1) A between the centroids of the benzene rings and 3.653 (1) A between the centroids of the pyridine rings, further stabilize the structure. PMID- 21587727 TI - Hexaaqua-manganese(II) 4,4'-(1,2-dihy-droxy-ethane-1,2-di-yl)dibenzoate monohydrate. AB - In the title compound, [Mn(H(2)O)(6)](C(16)H(12)O(6)).H(2)O, the [Mn(H(2)O)(6)](2+) complex cation lies on a mirror plane, the 4,4'-(1,2-dihy droxy-ethane-1,2-di-yl)dibenzoate anion is located on an inversion center and the solvent water mol-ecule also lies on a mirror plane. Extensive O-H?O hydrogen bonding inter-actions between the cations, anions and water mol-ecules stabilize the three-dimensional network. PMID- 21587728 TI - Diaqua-bis-(4-carb-oxy-2-propyl-1H-imidazole-5-carboxyl-ato-kappaN,O)zinc(II) N,N dimethyl-formamide disolvate. AB - In the crystal structure of the title compound, [Zn(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)].2C(3)H(7)NO, the Zn(II) atom is coordinated by two N,O-bidentate 2-propyl-1H-imidazole-4,5-dicarboxyl-ate anions and two water mol-ecules in a distorted octa-hedral environment. The asymmetric unit consists of one Zn(II) atom located on a center of inversion as well as one anion, one water mol-ecule and one additional dimethyl-formamide mol-ecule that occupy general positions. Between the carboxyl and the carboxyl-ate group an intra-molecular hydrogen bond is found in which the hydroxy H atom is disordered. Disorder is also found for the H atoms of one of the three methyl groups. In the crystal structure, additional inter-molecular N-H?O and O-H?O hydrogen bonding is found. PMID- 21587729 TI - Tetra-carbonyl-1kappaC,3kappaC-bis[1,3(eta)-cyclo-penta-dien-yl]dihydroxido 2kappaO-diirontin(2 Fe-Sn) monohydrate. AB - In the title hydrate, [Fe(2)Sn(C(5)H(5))(2)(OH)(2)(CO)(4)].H(2)O, the central Sn atom is tetra-hedrally coordinated by two {Cp(CO)(2)Fe} fragments and two hydroxide groups. The [{Cp(CO)(2)Fe}(2)Sn(OH)(2)] and water mol-ecules are linked by O-H?O hydrogen bridges, giving two-dimensional arrays with 4.8(2) topology that stack along the c axis. PMID- 21587730 TI - Hexa-kis-(dimethyl sulfoxide-kappaO)thallium(III) trinitrate. AB - The title compound, [Tl(C(2)H(6)OS)(6)](NO(3))(3), consists of six dimethyl sulfoxide (DMSO) mol-ecules coordinated to a Tl(III) atom, which lies on a axis, and three nitrate anions (3. symmetry) to neutralize the charge. The coordination polyhedron around the Tl(III) atom is octa-hedral, defined by six O atoms of the DMSO mol-ecules. In the crystal structure, C-H?O hydrogen bonds are observed. One of the nitrate groups exhibits half-occupation. PMID- 21587731 TI - [(1S,2S)-2-(1-{[2-(2-Oxidobenzyl-idene-amino)-cyclo-hex-yl]imino}-eth yl)phenolato-kappaO,N,N',O']copper(II). AB - In the title compound, [Cu(C(21)H(22)N(2)O(2))], the cyclo-hexyl ring adopts a chair conformation with the two imine groups linked at equatorial positions. The Cu(II) ion is coordinated by two N atoms and two O atoms from the bis-Schiff base ligand in a slightly distorted square-planar geometry. The dihedral angle between the two benzene rings is 45.89 (9) degrees . The crystal structure is devoid of any classical hydrogen bonds. However, inter-molecular C-H?O inter-actions are present and stabilize the structure. PMID- 21587732 TI - Chloridotris[MU(2)-2-(dimethyl-amino)-ethano-lato]-MU(3)-hydroxido-tri-MU(2) trifluoro-acetato-tetra-copper(II) tetra-hydro-furan solvate. AB - The title compound, [Cu(4)(C(2)F(3)O(2))(3)(C(4)H(10)NO)(3)Cl(OH)].C(4)H(8)O or [Cu(4)(TFA)(3)(dmae)(3)Cl(OH)].THF (dmae is dimeth-yl-amino-ethano-late, TFA is trifluoro-acetate and THF is tetra-hydro-furan), has an approximate mol-ecular threefold symmetry with three equivalent {Cu(dmae)(TFA)} units bridging between a Cu-Cl and a hydroxide unit, with the latter two lying on the mol-ecular threefold axis. However, in the solid state, the tetranuclear complex has C(i) symmetry. The Cu atom bonded to the Cl atom has a distorted tetra-hedral geometry. The other three Cu atoms have distorted square-pyramidal geometries with an NO(4) coordination environment. The bonds within the CuNO(3) base of the pyramid range from 1.953 (2) to 2.033 (3) A, while the apical Cu-O bonds are significantly longer, ranging from 2.286 (2) to 2.377 (2) A. The square-pyramidal geometries are augmented by weak inter-actions towards a sixth O atom, forming a highly distorted octa-hedral coordination environment [long Cu-O distances = 2.712 (2) 2.824 (2) A]. The hydroxide group is hydrogen bonded to the tetra-hydro-furan solvent mol-ecule. One of the -CF(3) groups shows minor disorder over two positions, with a refined occupancy ratio of 0.894 (4):0.106 (5). PMID- 21587733 TI - Tris(1,10-phenanthroline)cobalt(II) bis-(perrhenate) monohydrate. AB - In the title compound, [Co(C(12)H(8)N(2))(3)][ReO(4)](2).H(2)O, the Co(II) atom is coordinated by three 1,10-phenanthroline ligands in a distorted octa-hedral arrangement. In the crystal, the components are linked by O-H?O, C-H?O and aromatic pi-pi stacking [shortest centroid-centroid separation = 3.659 (5) A] inter-actions. PMID- 21587734 TI - Bis(1,10-phenanthroline-kappaN,N')(sulfato-kappaO,O')cadmium(II) propane-1,3-diol solvate. AB - In the title compound, [Cd(SO(4))(C(12)H(8)N(2))(2)].C(3)H(8)O(2), the Cd(II) atom has a distorted octa-hedral coordination composed of four N atoms from two chelating 1,10-phenanthroline ligands and two O atoms from an O,O'-bidentate sulfate group. The two chelating NCCN groups subtend a dihedral angle of 82.21 (9) degrees . The Cd(II) ion, the S atom and the middle C atom of the propane-1,3 diol solvent mol-ecule are located on special positions, site symmetry 2. The solvate features a pair of O-H?O hydrogen bonds with the uncoordinated O atoms of the sulfate ion. The OH group of the propane-1,3-diol solvent is disordered over two positions of equal occupancy. PMID- 21587735 TI - (Ferrocene-carboxyl-ato-kappaO)triphenyl-tin(IV). AB - In the title compound, [FeSn(C(5)H(5))(C(6)H(5))(3)(C(6)H(4)O(2))], the Sn(IV) atom displays a distorted tetra-hedral coordination geometry, provided by one O atom of the monodentate ferrocene-carboxyl-ate ligand [Sn-O = 2.079 (2) A] and by three C atoms of the three phenyl groups [average Sn-C = 2.130 (4) A]. No classic hydrogen bonds or inter-molecular inter-actions are observed in the crystal. PMID- 21587736 TI - MU(4)-Sulfido-bis-{(MU-2-furyl-methane-thiol-ato)bis-[tricarbonyl-iron](Fe-Fe)}. AB - The title compound, [Fe(4)(C(5)H(5)OS)(2)S(CO)(12)], was prepared by the direct reaction of Fe(3)(CO)(12) and 2-furyl-methane-thiol in tetra-hydro-furan. Desulfurization took place readily to form an Fe(4)S(3) cluster. The mol-ecule consists of two similar [(MU-2-C(4)H(3)O-CH(2)S)Fe(2)(CO)(6)] moieties joined to a spiro-type four-coordinate MU(4)-S atom such that this bridging sulfur is tetra hedrally coordinated to the four Fe atoms. In each diiron subcluster core, the 2 furyl-methane-thiol-ate ligand bridges the two Fe atoms. PMID- 21587737 TI - catena-Poly[[(1,10-phenanthroline-kappaN,N')lead(II)]-MU-azido-kappaN:N-MU nitrito-kappaO,O':O'-[(1,10-phenanthroline-kappaN,N')lead(II)]-di-MU-azido kappaN:N]. AB - The title coordination polymer, [Pb(2)(N(3))(3)(NO(2))(C(12)H(8)N(2))(2)](n), has as the repeat unit a centrosymmetric dinuclear mol-ecule having azide and nitrite groups that bridge adjacent heterocycle-coordinated metal centers. One of the azide group uses its terminal ends to bridge whereas the nitrite group chelates to one metal atom and uses one of its O atoms to bridge. The azide and nitrite groups are disordered with respect to each other in a 1:1 ratio. Adjacent dinuclear mol-ecules are further bridged by the other two azide groups, generating a linear chain motif parallel to [010]. Half of the Pb atoms show a Psi-dodeca-hedral coordination and the other half show a Psi-penta-gonal bipyramidal coordination. PMID- 21587738 TI - (MU-Oxalato-kappaO,O:O,O)bis-[bis-(2,2'-bipyridine-kappaN,N')cobalt(II)] MU(6) oxido-dodeca-MU(2)-oxido-hexa-oxido-hexa-tungstate(VI). AB - The asymmetric unit of the title compound, [Co(2)(C(2)O(4))(C(10)H(8)N(2))(4)][W(6)O(19)], consists of one half of the complex [Co(2)(C(2)O(4))(C(10)H(8)N(2))(4)](2+) cation and one half of the Lindqvist-type [W(6)O(19)](2-) isopolyanion. Both constituents are completed by crystallographic inversion symmetry. In the dimeric cation, the Co(II) atom is surrounded in a distorted octa-hedral coordination by four N atoms from two chelating 2,2'-bipyridine ligands and by two O atoms from the chelating oxalate anion. The Lindqvist-type anion exhibits the characteristic W-O bond-length distribution, with the shortest bonds being the W-O(terminal) bonds and the longest being those to the central O atom. PMID- 21587739 TI - Bis(MU-4-phenyl-pyridine N-oxide-kappaO:O)bis-[bis-(1,1,1,5,5,5-hexa-fluoro pentane-2,4-dionato)copper(II)]. AB - The asymmetric unit of the title compound, [Cu(2)(C(5)HF(6)O(2))(4)(C(11)H(9)NO)(2)], contains one half of the centrosymmetric dinuclear complex. The coordination geometry of the Cu(II) atom is octa-hedral, exhibiting a typical Jahn-Teller distortion. One trifluoro-methyl group is rotationally disordered between two orientations in a 1:1 ratio. PMID- 21587740 TI - Bis(2-amino-4-methyl-pyridinium) trans-diaqua-bis-(pyrazine-2,3-dicarboxyl ato)cuprate(II) hexa-hydrate. AB - The title compound, (C(6)H(9)N(2))(2)[Cu(C(6)H(2)N(2)O(4))(2)(H(2)O)(2)].6H(2)O, consists of a mononuclear trans-[Cu(pzdc)(2)(H(2)O)(2)](2-) dianion (pzdc is pyrazine-2,3-dicarboxyl-ate) and two [ampyH](+) cations (ampy is 2-amino-4-methyl pyridine) with six water mol-ecules of solvation. The Cu(II) atom is hexa coordinated by two pzdc groups and two water mol-ecules. The coordinated water mol-ecules are in trans-diaxial positions and the pzdc dianion acts as a bidentate ligand through an O atom of the carboxyl-ate group and the N atom of the pyrazine ring. There are diverse hydrogen-bonding inter-actions, such as N H?O and O-H?O contacts, which lead to the formation of a three-dimensional supra molecular architecture. PMID- 21587741 TI - Bis{2-[(2-benzoyl-hydrazin-1-yl-idene)meth-yl]-6-meth-oxy-phenolato}iron(III) chloride monohydrate. AB - In the title mononuclear iron(III) complex, [Fe(C(15)H(13)N(2)O(3))(2)]Cl.H(2)O, the Fe(III) atom has a distorted octa-hedral geometry and is six-coordinated by four O atoms and two N atoms from two ligands. In the crystal structure, the complex cations, Cl(-) anions and water mol-ecules are connected into a chain along [100] through N-H?O, O-H?Cl and N-H?Cl hydrogen bonds. Two adjacent chains are linked by O-H?O hydrogen bonds. PMID- 21587742 TI - catena-Poly[[bis-(pyridine-kappaN)zinc(II)]-MU-benzene-1,4-dicarboxyl-ato kappaO:O]. AB - In the title coordination polymer, [Zn(C(8)H(4)O(4))(C(5)H(5)N)(2)](n), the Zn(II) atom, located on a twofold rotation axis, is tetra-coordinated by two monodentate O atoms from two different carboxyl-ate groups and two pyridyl N atoms, forming a distorted tetra-hedral geometry. The Zn(II) atoms are bridged by terephthalate ligands, generating an infinite zigzag chain along [101]. PMID- 21587743 TI - 1-Cyano-meth-yl-1,4-diazo-niabicyclo-[2.2.2]octane tetra-bromidocuprate(II). AB - In the crystal structure of the title complex, (C(8)H(15)N(3))[CuBr(4)], the Cu atom is coordinated by four bromido ligands within a strongly distorted tetra hedron. The anions and cations are connected by weak N-H?Br and C-H?Br hydrogen bonding inter-actions. PMID- 21587744 TI - N-(4-Ferrocenylphenyl)benzamide. AB - In the title compound, [Fe(C(5)H(5))(C(18)H(14)NO)], the unsubstituted cyclo penta-dienyl ring is disordered over two sets of sites with occupancy ratio of 0.55 (1):0.45 (1). One conformation has the rings eclipsed and the other staggered. An intra-molecular C-H?O hydrogen bond forms an S(6) ring motif. In the crystal, inter-molecular C-H?O and N-H?O hydrogen bonds lead to R(2) (1)(7) ring motifs. The mol-ecules are linked into polymeric chains extending along the b axis. PMID- 21587745 TI - Poly[MU(6)-pyridine-2,4-dicarboxyl-ato-barium]. AB - In the title complex, [Ba(C(7)H(3)NO(4))](n), the coordination geometry around the Ba(II) ion can be described as a distorted bicapped trigonal-prismatic BaNO(7) arrangement. The pyridine-2,4-dicarb-oxy-lic acid ligands exhibit a new coordination mode. Adjacent metal centers are linked by the O atoms of the pyridine-2,4-dicarb-oxy-lic acid ligands, and then form a three-dimensional supra molecular polymeric framework. PMID- 21587746 TI - Bis(4-aminobenzenesulfonato)tri-aqua-bis(1,10-phenanthroline)neodymium(III) nitrate tetrahydrate. AB - The title complex, [Nd(C(6)H(6)NO(3)S)(2)(C(12)H(8)N(2))(2)(H(2)O)(3)]NO(3).4H(2)O, comprises a mononuclear cation, an NO(3) (-) anion and two uncoordinated water mol-ecules; the Nd(III) cation, one coordinated water mol-ecule, and the NO(3) (-) anion each lie on a twofold axis of symmetry. The Nd(III) ion exhibits an NdN(4)O(5) coordination environment comprising two O atoms of two monodentate 4-amino benzene-sulfonato ligands, four N atoms of the bidentate 1,10-phenanthroline ligands, and three water-O atoms. The coordination geometry is based on a tricapped triangular-prismatic arrangement. The components are consolidated into a three-dimensional network via O-H?O, O-H?N and N-H?O hydrogen-bonding inter actions. PMID- 21587747 TI - catena-Poly[[[aqua(7-hydroxy-2H-1-benzopyran-2-one)sodium]-di-MU-aqua] 2-oxo-2H-1 benzopyran-7-olate monohydrate]. AB - The asymmetric unit of the title compound, {[Na(C(9)H(6)O(3))(H(2)O)(3)](C(9)H(5)O(3)).H(2)O}(n), contains two crystallographically independent Na atoms, two 7-hy-droxy-coumarin ligands, six coordinated water mol-ecules, two 7-hy-droxy-coumarin anions and two uncoordinated water mol-ecules. Both Na atoms exhibit a distorted octa-hedral coordination geometry and are coordinated by five water O atoms and the terminal O atom from a 7-hy-droxy-coumarin ligand. Four of the water mol-ecules are bridging, whereas the fifth is terminal. Na-O bond distances are in the range 2.288 (2)-2.539 (2) A. In the chains, extending parallel to [100], adjacent Na atoms are separated by 3.60613 (7) A. The uncoordinated water mol-ecules and 7-hy droxy-coumarin phenolate anions are located between the chains and are hydrogen bonded to the chains. PMID- 21587748 TI - Diaqua-bromido-copper(II)-18-crown-6-water (1/1/2). AB - In the title compound, [CuBr(2)(H(2)O)(2)].C(12)H(24)O(6).2H(2)O, the Cu(II) atom, which is situated on an inversion centre and has a slightly distorted square-planar geometry, and the two coordinated water mol-ecules are linked to the 18-crown-6 macrocycles by O-H?O hydrogen bonds. The water mol-ecule of crystallization further links the metal complex and the crown ether macrocycles into a chain along the c axis. PMID- 21587749 TI - Bis(nitrato-kappaO)(5,7,12,14-tetra-methyl-1,4,8,11-tetra-aza-cyclo-tetra-decane 6,13-diaminium-kappaN,N,N,N)copper(II) dinitrate tetra-hydrate. AB - In the title compound, [Cu(NO(3))(2)(C(14)H(36)N(6))](NO(3))(2).4H(2)O, the Cu(II) atom, lying on an inversion center, is six-coordinated in a distorted octa hedral environment by four N atoms from a centrosymmetric 14-membered tetra-aza cyclo-tetra-decane macrocyclic ligand and two O atoms from two nitrate anions. The supra-molecular network is consolidated by extensive O-H?O and N-H?O hydrogen bonding inter-actions. PMID- 21587750 TI - (E)-3-Ferrocenyl-1-(2-hy-droxy-phen-yl)-prop-2-en-1-one. AB - The mol-ecular structure of the title compound, [Fe(C(5)H(5))(C(14)H(11)O(2))] consists of a ferrocenyl and 2-hy-droxy-phenyl group linked through the prop-2-en 1-one spacer and is stabilized by an intra-molecular O-H?O hydrogen bond between the hydroxyl and the carbonyl groups. PMID- 21587751 TI - 12-Tungstophospho-ric acid-1,1'-methyl-enebis(imidazolidine-2,4-dione) imidazolidine-2,4-dione-water (2/1/4/21.5). AB - In the asymmetric unit of the title organic-inorganic hybrid material, 2{H(3)[PW(12)O(40)]}.4C(3)H(4)N(2)O(2).C(7)H(8)N(4)O(4).21.5H(2)O, there are four crystallographically independent hydantoin mol-ecules, one dimerized hydantoin mol-ecule, viz. 1,1'-methyl-enebis(imidazolidine-2,4-dione, two independent H(3)PW(12)O(40) mol-ecules and 21.5 solvent water mol-ecules. Nine of the solvent water mol-ecules were refined as 0.5 occupancy. The tungstophosphoric acid moieties show characteristic features with respect to the bond lengths and angles. PMID- 21587752 TI - catena-Poly[[diaqua-bis-(isoquinoline-kappaN)cobalt(II)]-MU-succinato-kappaO:O]. AB - In the title compound, [Co(C(4)H(4)O(4))(C(9)H(7)N)(2)(H(2)O)(2)](n), the Co(II) cation, located on an inversion center, is coordinated by two succinate anions, two isoquinoline ligands and two water mol-ecules in a distorted octa-hedral geometry. The succinate anion, located across another inversion center, bridges the Co cations, forming polymeric chains running along the b axis. The partially overlapped arrangement of parallel isoquinoline ring systems of adjacent polymeric chains and the shorter face-to-face distance of 3.402 (6) A indicates the existence of weak pi-pi stacking in the crystal structure. Classical intra- and inter-molecular O-H?O hydrogen bonding and weak non-classical inter-molecular C-H?O hydrogen bonding help to stabilize the crystal structure. PMID- 21587753 TI - Bis(MU-4-methyl-benzoato-kappaO:O')bis-[aqua-(4-methyl-benzoato kappaO,O')zinc(II)]-bis-(MU-4-methyl-benzoato-kappaO:O')bis-[(4-methyl-benzoato kappaO)(nicotinamide-kappaN)zinc(II)]-water (1/1/2). AB - The crystal structure of the title compound, [Zn(2)(C(8)H(7)O(2))(4)(H(2)O)(2)].[Zn(2)(C(8)H(7)O(2))(4)(C(6)H(6)N(2)O)(2)].2H( )O, consists of two kinds of dinuclear Zn(II) complexes (complex A and complex B) and uncoordinated water mol-ecules. In complex A, [Zn(2)(C(8)H(7)O(2))(4)(H(2)O)(2)], each Zn cation is chelated by a 4-methyl benzoate (PMB) anion and coordinated by a water mol-ecule, and is further bridged by two PMB anions in a trigonal-bipyramidal geometry. In complex B, [Zn(2)(C(8)H(7)O(2))(4)(C(6)H(6)N(2)O)(2)], each Zn(II) cation is coordinated by a monodentate PMB anion and one nicotinamide (NA) ligand, and is further bridged by two PMB anions in a tetra-hedral geometry. Weak intra-mol-ecular pi-pi stacking between adjacent benzene rings is observed in complex B, the centroid centroid distance being 3.710 (2) A. Extensive O-H?O and N-H?O hydrogen bonding and weak C-H?O hydrogen bonding is present in the crystal structure. The crystal studied was a racemic twin; the minor twin component refined to 38%. PMID- 21587754 TI - Hexaaqua-chromium(III) pyridine-2,4,6-tricarboxyl-ate dihydrate. AB - The chromium(III) atom in the title salt, [Cr(H(2)O)(6)](C(8)H(2)NO(6)).2H(2)O, has an octa-hedral coordination geometry. In the crystal, the cation, anion and uncoordinated water mol-ecules, both of which are disordered over two positions in a 1:1 ratio, are linked by O-H?O hydrogen bonds. PMID- 21587755 TI - Tetra-butyl-ammonium bis-[4,4'-dimethyl-2,2'-(3,7-dimethyl-1H-4,2,1-benzothiaza siline-1,1-di-yl)dibenzene-thiol-ato]vanadium(III) acetonitrile tetra-solvate. AB - In the title compound, [N(C(4)H(9))(4)][V(C(23)H(21)NS(3)Si)(2)].4CH(3)CN, the V(III) atom (site symmetry ) is coordinated by two N,S,S'-tridentate 4,4' dimethyl-2,2'-(3,7-dimethyl-1H-4,2,1-benzothiaza-siline-1,1-di-yl)dibenzene-thiol ate ligands in a distorted trans-VN(2)S(4) octa-hedral geometry. The complete cation is generated by crystallographic twofold symmetry, with the V atom lying on the rotation axis. The unusual ligand arose from nucleophilic attack on the coordinated nitrile by the thiol-ate precursor and reduction of nitrile to the imidate. PMID- 21587756 TI - Poly[3,3'-diethyl-1,1'-(ethane-1,2-di-yl)diimidazolium [tetra-MU-bromido- diargentate(I)]]. AB - The asymmetric unit of the title salt, {(C(12)H(20)N(4))[Ag(2)Br(4)]}(n), contains one-half of a substituted imidazolium cation, one Ag(+) and two Br(-) ions. The cation is completed by crystallographic inversion symmetry. The crystal structure is made up from polymeric sheets of {[AgBr(2)](-)}(n) anions extending parallel to (100). The basic building unit of the anion is a slightly distorted AgBr(4) tetra-hedron. A four- and 12-membered ring system is formed by corner sharing of the AgBr(4) tetra-hedra. The imidazolium cations are located between the anionic sheets and partly protrude into the voids defined by the 12-membered rings. PMID- 21587757 TI - Bis(1,3-dibenzyl-imidazolium) MU-oxido-bis-[trichloridoferrate(III)]. AB - In the title compound (C(17)H(17)N(2))(2)[Fe(2)Cl(6)O], obtained from the solid state reaction of FeCl(2) and N,N'-dibenzyl-imidazolium chloride, the complex anion has approximate D(3d) symmetry with crystallographically imposed inversion symmetry coincident with the bridging MU-O atom. The stereochemistry about each FeCl(3)O centre is distorted tetra-hedral [Fe-Cl = 2.2176 (5)-2.2427 (5) A and Fe O = 1.7545 (2) A]. The Cl atoms are involved in weak anion-cation C-H?Cl inter actions, giving a network structure. PMID- 21587758 TI - Poly[aqua-(MU(1,1)-azido)(MU-3H-1,2,3-tri-azolo[4,5-b]pyridin-3 olato)cobalt(II)]. AB - In the title compound, [Co(C(5)H(3)N(4)O)(N(3))(H(2)O)](n), the cobalt ion is coordinated by three N atoms of two organic ligands, two N atoms of two azide anions and one water mol-ecule in a distorted octa-hedral geometry. The metal atoms are connected via the ligands into layers, which are further connected by O H?N and O-H?O hydrogen bonding. PMID- 21587759 TI - Bis[N,N-bis-(2-hy-droxy-eth-yl)glycinato]cobalt(II). AB - The asymmetric unit of the title compound, [Co(C(6)H(12)NO(4))(2)], contains one half-mol-ecule with the Co(II) ion situated on an inversion center. Inter molecular O-H?O hydrogen bonds generate a three-dimensional hydrogen-bonding network, which consolidates the crystal packing. PMID- 21587760 TI - (4-Carb-oxy-2-sulfonato-benzoato-kappaO,O)bis-(1,10-phenanthroline kappaN,N')manganese(II). AB - In the title complex, [Mn(C(8)H(4)O(7)S)(C(12)H(8)N(2))(2)], the Mn(II) atom is chelated by one 4-carb-oxy-2-sulfonato-benzoate anion and two phenathroline (phen) ligands in a distorted octa-hedral MnN(4)O(2) geometry. The benzene ring of the 4-carb-oxy-2-sulfonato-benzoate anion is twisted with respect to the two phen ring systems at dihedral angles of 66.38 (9) and 53.56 (9) degrees . In the crystal, inter-molecular O-H?O and C-H?O hydrogen bonding links the mol-ecules into chains running parallel to [100]. Inter-molecular pi-pi stacking is also observed between parallel phen ring systems, the face-to-face distance being 3.432 (6) A. PMID- 21587761 TI - Aqua-{6,6'-dimeth-oxy-2,2'-[ethane-1,2-diylbis(nitrilo-methyl idyne)]diphenolato}methano-lmanganese(III)) perchlorate hemihydrate. AB - The asymmetric unit of the title compound, [Mn(C(18)H(18)N(2)O(4))(CH(3)OH)(H(2)O)]ClO(4).0.5H(2)O, contains two complex cations and two perchlorate anions, one of which is disordered over two positions in a 0.767 (8):0.233 (8) ratio. The Mn(III) atoms are in distorted octa-hedral environments. In addition to the equatorial tetra-dentate salicylaldimine ligand, each Mn is axially coordinated by both a methanol and a water mol-ecule. The complex is a dimer held together by multiple strong and weak hydrogen-bonding inter-actions between the coordinated water mol-ecule on one monomer with all the phenolic and meth-oxy O atoms on the other monomer. In addition, the two perchlorate anions are linked by hydrogen bonds to the two methanol mol-ecules coordinated to each Mn center. The Mn-O phenolic bond distances range from 1.868 (2) to 1.882 (2) A while the Mn-N distances range from 1.978 (2) to 1.981 (2) A. Mn-O distances for the axial water and methanol ligands are longer at 2.226 (2)/2.257 (2) and 2.313 (2)/2.324 (2) A, reflecting the usual Jahn-Teller distortion as found in Mn(III) complexes. PMID- 21587762 TI - fac-Tris(4-amino-benzohydroxamato)iron(III) ethanol solvate. AB - In the structure of the title compound, [Fe(C(7)H(7)N(2)O(2))(3)].CH(3)CH(2)OH, the Fe(III) atom is in a distorted octa-hedral O(6) environment with the three hydroxamate O atoms (and the three carbonyl O atoms) arranged in a fac configuration and one of the hydroxamate ligands being puckered. The methyl C atom of the ethanol solvent mol-ecule is disordered over two positions with occupancies of 0.626 (13) and 0.374 (13), respectively. The cocrystallized ethanol mol-ecule is hydrogen bonded to one of the hydroxamate O atoms. O-H?O and N-H?O inter-actions generate infinite three-dimensional networks along [100], [010] and [001]. PMID- 21587763 TI - Poly[(MU(3)-4-amino-benzene-sulfonato-kappaN:O:O)(triphenyl-phosphine kappaP)silver(I)]. AB - In the title 1:1 silver 4-amino-benzene-sulfonate adduct with triphenyl phosphine, [Ag(C(6)H(6)NO(3)S)(C(18)H(15)P)](n), the sulfon-ate -SO(3) unit bridges, through only one O atom, two phosphine-coordinated Ag atoms, forming a centrosymmetric Ag(2)O(2) rhombus. The Ag(+) cation adopts a considerably distorted a tetra-hedral coordination. In the crystal, adjacent binuclear mol ecules are connected into a layer motif through the amino group of the anion; the layers are perpendicular to the a axis. PMID- 21587764 TI - trans-Tetra-kis(4-methyl-pyridine-kappaN)dioxidorhenium(V) hexa-fluorido phosphate. AB - The title compound, [ReO(2)(C(6)H(7)N)(4)]PF(6), contains octa-hedral [ReO(2)(4 Mepy)(4)](+) cations (4-Mepy is 4-methyl-pyridine) and PF(6) (-) anions. Both the cation and the anion reside on special positions, the Re atom on a crystallographic center of inversion and the P atom on a C(2) axis parallel to the b axis. The Re(V) atom in the cation exhibits an octa-hedral coordination geometry with two O atoms in the apical positions and four N atoms of the 4-Mepy ligands in the equatorial plane. The Re=O and Re-N bond lengths fall in the typical ranges of trans-dioxidorhenium(V) complexes. PMID- 21587765 TI - Tetra-ethyl-ammonium bromidotricarbon-yl(tropolonato)rhenate(I). AB - In the title salt, (C(8)H(20)N)[ReBr(C(7)H(5)O(2))(CO)(3)], the Re(I) atom is octa-hedrally surrounded by three facially orientated carbonyl ligands, one bidendate tropolonate ligand and a bromide ligand. The small O-Re-O bite angle of 74.88 (12) degrees leads to a distortion of the octa-hedral coordination sphere. The bromide ligand and the axial carbonyl ligand are substitutionally disordered over two positions in a 0.922 (3):0.078 (3) ratio. An array of C-H?O and C-H?Br hydrogen-bonding inter-actions between the cations and neighbouring rhenate anions stabilizes the crystal packing. PMID- 21587766 TI - Tetra-kis{MU(3)-2-[(2-hy-droxy-eth-yl)amino]-ethano-lato}tetra-kis [chloridonickel(II)] methanol solvate. AB - The complex mol-ecule of the title compound, [Ni(4)(C(4)H(10)NO(2))(4)Cl(4)].CH(3)OH, consists of a cubane-like {Ni(4)O(4)} core in which each nickel(II) atom is six-coordinated in a distorted octa-hedral geometry by one N and four O atoms of three mono-deprotonated diethano-lamine ligands and by a chloride anion. The mol-ecular conformation is stabilized by intra-molecular O-H?Cl bonds. In the crystal structure, complex mol-ecules and methanol solvent mol-ecules are linked into a three-dimensional network by N H?Cl, N-H?O and O-H?Cl hydrogen-bonding inter-actions. PMID- 21587767 TI - Tripyridinium cis-tetra-chlorido-dioxido-molybdate(VI) chloride. AB - In the title compound, (C(5)H(6)N)(3)[MoCl(4)O(2)]Cl, the pyridinium cations are N-H?Cl hydrogen bonded to the anionic [MoCl(4)O(2)](2-) complexes and to the two crystallographically independent chloride anions (located on C2 axes). The Mo(6+) centre adopts a highly distorted octa-hedral geometry, being surrounded by four chloride and two terminal oxide groups. The oxide ligands are mutually cis. PMID- 21587768 TI - Azido-(benzonitrile-kappaN)[hydrido-tris(pyrazol-1-yl-kappaN)borato](triphenyl phosphine-kappaP)ruthenium(II). AB - Facile ligand substitution is observed when the ruthenium-azide complex, [RuN(3)(Tp)(PPh(3))(2)] [Tp,HB(pz)(3), pz = pyrazol-yl, PPh(3) = triphenyl phosphine] is treated with benzo-nitrile, yielding the title compound, [Ru(C(9)H(10)BN(6))(N(3))(C(7)H(5)N)(C(18)H(15)P)]. The asymmetric unit contains two crystallographically independent mol-ecules. In each one, the Ru(II) atom is six-coordinated in a distorted octa-hedral geometry by five N atoms from an htpb ligand, an azide ligand and a benzonitrile ligand and one P atom from a triphenyl phosphine (tpp) ligand. The azide group is almost linear and is coordinated to Ru with an average Ru-N-N angle of 124.9 (3) degrees . PMID- 21587769 TI - (Acetato-kappaO,O')bis-(1,10-phenanthroline-kappaN,N')copper(II) trifluoro acetate tetra-hydrate. AB - In the title compound, [Cu(CH(3)CO(2))(C(12)H(8)N(2))(2)](CF(3)CO(2)).4H(2)O, the Cu(II) atom shows a distorted octa-hedral coordination with four N atoms [Cu-N = 2.015 (3)-2.244 (3) A] from the two phenanthroline ligands and two O atoms from the acetate [Cu-O = 1.953 (3) and 2.764 (3) A]. Strong inter-molecular O-H?O hydrogen-bonding inter-actions consolidate the crystal packing. The F atoms of the anion are disordered over two positions in a 0.5233 (3):0.4767 (3) ratio. PMID- 21587770 TI - 2,4-Dichloro-N-(3-methyl-phen-yl)benzene-sulfonamide. AB - In the title compound, C(13)H(11)Cl(2)NO(2)S, the conformations of the N-C bonds in the C-SO(2)-NH-C segments have gauche torsions with respect to the S=O bonds. The dihedral angle between the two benzene rings is 68.6 (1) degrees . The crystal structure features inversion dimers linked by pairs of N-H?O hydrogen bonds. PMID- 21587771 TI - 4,4'-[2,5-Bis(dodec-yloxy)-p-phenyl-ene]bis-(2-methyl-but-3-yn-2-ol). AB - In the title compound, C(40)H(66)O(4), the C and O atoms of the propinyl and dodecoxyl substituents are nearly coplanar with the benzene ring, 1.735 (6), 8.804 (1), 8.786 (1) and 9.577 (3) degrees , respectively. In the crystal, mol ecules are connected by inter-molecular O-H?O hydrogen bonds. PMID- 21587772 TI - (E)-N'-(4-Nitro-benzyl-idene)-4-(8-quinol-yloxy)butano-hydrazide. AB - In the title compound, C(20)H(18)N(4)O(4), conformation along the bond sequence linking the benzene and quinoline rings, which have a mean inter-planar dihedral angle of 2.7 (5) degrees , is trans-(+)gauche-trans-trans-(-)gauche-trans-trans. In the crystal structure, a pair of inter-molecular N-H?O hydrogen bonds links the mol-ecules into centrosymmetric cyclic R(2) (2)(8) dimers, which are aggregated via pi-pi inter-actions into parallel sheets [quinoline-benzene ring centroid separation = 3.6173 (16)-3.6511 (16) A]. The sheets are further connected through weak C-H?O inter-actions, giving a supra-molecular two dimensional network. PMID- 21587773 TI - 2,2',6,6'-Tetra-ethyl-4,4'-methyl-enedibenzonitrile. AB - The asymmetric unit of the title compound, C(23)H(26)N(2), contains one half-mol ecule, which is completed by the operation of a crystallographic twofold axis. In the mol-ecule, the two benzene rings form a dihedral angle of 77.09 (7) degrees . PMID- 21587774 TI - 8b,8c-Diphenyl-2,6-bis(4-pyridyl-meth-yl)-perhydro-2,3a,4a,6,7a,8a-hexa-aza-cyclo penta-[def]fluorene-4,8-dithione chloro-form solvate. AB - In the thio-glycoluril system of the title compound, C(32)H(30)N(8)S(2).CHCl(3), the two pyridine rings are roughly parallel, forming a dihedral angle of 7.2 (1) degrees , and the distance between the centroids of the two phenyl rings is 3.951 (5) A. The chloro-form solvent mol-ecule is linked to the main mol-ecule via a weak C-H?N hydrogen bond. PMID- 21587775 TI - Phenyl 2,3,4-tri-O-benzyl-1-thio-alpha-d-mannopyran-oside monohydrate. AB - In the title compound, C(33)H(34)O(5)S.H(2)O, the mannopyran-oside ring adopts a chair conformation with the 2-alpha-thio-phenyl group occupying an axial position. One of the pendant benzyl groups is disordered over two sets of sites in a 0.5:0.5 ratio. In the crystal, the water mol-ecule makes two O-H?O hydrogen bonds to an adjacent sugar mol-ecule with the O atoms of the primary alcohol and ether groups acting as acceptors. At the same time, the OH group of the sugar makes a hydrogen bond to a water mol-ecule. PMID- 21587776 TI - 2-Eth-oxy-6-[(methyl-imino)-meth-yl]phenol. AB - In the title compound, C(10)H(13)NO(2), synthesized by the reaction of 2-hy-droxy 3-eth-oxy-benzaldehyde with methyl-amine, there is an an intra-molecular O-H?N hydrogen bond involving the hy-droxy substituent and the amino N atom. In the crystal, mol-ecules form inversion dimers connected by pairs of C-H?O hydrogen bonds. PMID- 21587777 TI - 1-Cyano-methyl-4-aza-1-azonia-bicyclo-[2.2.2]octane bromide dihydrate. AB - In the crystal structure of the title compound, C(8)H(14)N(3) (+).Br(-).2H(2)O, inter-molecular O-H?O and O-H?Br hydrogen bonding occurs. The water mol-ecules are connected into chains extending in the a-axis direction. The bromide anions are connected to the water mol-ecules, forming 10-membered rings. The cations are connected to the anions via weak C-H?Br inter-actions. Two carbon atoms of the cation are disordered and were refined using a split model (occupancy ratio 0.70:0.3). PMID- 21587778 TI - 2-Amino-4,6-dimethyl-pyrimidin-1-ium 1-oxo-2,6,7-trioxa-1lambda-phosphabicyclo [2.2.2]octane-4-carboxyl-ate. AB - In the title compound, C(6)H(10)N(3) (+).C(5)H(6)O(6)P(-), the cation and anion are linked by pairs of N-H?O hydrogen bonds. There are additional inter-molecular N-H?N hydrogen bonds, which generate centrosymmetric tetramers of two cations and two anions. PMID- 21587779 TI - N-(4-Meth-oxy-phen-yl)maleamic acid. AB - In the title compound, C(11)H(11)NO(4), the asymmetric unit contains two unique mol-ecules, both of which are almost planar, with r.m.s. deviations of 0.047 and 0.059 A. The dihedral angles between the benzene ring and the plane of maleamic acid unit are 3.43 (5) and 5.79 (3) degrees in the two mol-ecules. The mol ecular structures are stabilized by a short intra-molecular O-H?O hydrogen bond within each maleamic acid unit. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into zigzag chains extending along [10]. Weak intermolecular C-H?O hydrogen bonds also exist. PMID- 21587780 TI - Acanthoic Acid. AB - THE TITLE COMPOUND [SYSTEMATIC NAME: (1R,4aR,7S,8aS,10aS)-1,4a,7-trimethyl-7 vinyl-1,2,3,4,4a,6,7,8,8a,9,10,10a-dodeca-hydro-phenanthrene-1-carb-oxy-lic acid], C(20)H(30)O(2), is a pimarane-type diterpene extracted from Croton oblongifolius. There are two independent mol-ecules in the asymmetric unit. In both of these, the six-membered rings A, B and C adopt chair, boat and half-chair conformations, respectively. Rings A and B are trans-fused. The two mol-ecules in the asymmetric unit form O-H?O hydrogen-bonded R(2) (2)(8) dimers. The absolute configuration was assigned on the basis of the published literature on analogous structures. PMID- 21587781 TI - 1-[(E)-4-(5-Bromo-1H-indol-3-yl)-1-methyl-2,5,6,7-tetra-hydro-1H-azepin-2-yl idene]propan-2-one. AB - In the title compound, C(18)H(19)BrN(2)O, the seven-membered azepine ring adopts a twist-boat conformation: the bond angles about the azepine N atom are indicative of sp(2) hybridization. The dihedral angle between the plane of the carbon-carbon double bond of the enone unit and the mean plane of the indole ring is 27.8 (1) degrees . In the crystal, an N-H?O hydrogen bond links the mol-ecules into chains along the b axis. PMID- 21587782 TI - N-[4-Cyano-3-(trifluoro-meth-yl)phen-yl]-2-eth-oxy-benzamide. AB - In the title compound, C(17)H(13)F(3)N(2)O(2), the two aromatic rings are essentially coplanar, forming a dihedral angle of 2.78 (12) degrees . The non-H atoms of the eth-oxy group are coplanar with the attached ring [maximum deviation = 0.271 (3) A]. An intra-molecular N-H?O hydrogen bond occurs. In the crystal structure, mol-ecules are linked by inter-molecular C-H?N and C-H?F hydrogen bonds. PMID- 21587783 TI - (E,E)-3,3'-Dimethyl-1,1'-diphenyl-4,4'-{(ethane-1,2-diyldiimino)-bis-[(2-fur yl)methyl-idyne]}di-1H-pyrazol-5(4H)-one. AB - The complete molecule of the title compound of the title compound, C(32)H(28)N(6)O(4), is generated by crystallographic inversion symmetry. The dihedral angles between the pyrazalone ring and the pendant phenyl and furan rings are 15.65 (8) and 65.06 (8) degrees , respectively. In the crystal, the molecules are linked by N-H?O, C-H?O and weak C-H?pi interactions. PMID- 21587784 TI - 2,4-Dichloro-7,8-dimethyl-quinoline. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(11)H(9)Cl(2)N, both of which are essentially planar [maximum deviations of 0.072 (5) and 0.072 (7) A]. In the crystal structure, weak pi-pi stacking inter-actions [centroid-centroid distances = 3.791 (3) A and 3.855 (3) A] link pairs of mol-ecules. PMID- 21587785 TI - (E)-4-Hy-droxy-2-[(2-hy-droxy-phen-yl)iminiometh-yl]phenolate. AB - The title compound, C(13)H(11)NO(3), crystallizes in a zwitterionic form and has a trans configuration about the C=N bond. The mol-ecule is almost planar, the dihedral angle between the two benzene rings being 4.32 (8) degrees . The two hy droxy substit-uents are coplanar with each of their attached benzene rings [r.m.s. deviations of 0.0053 (2) and 0.0052 (2) A]. An intra-molecular N-H?O hydrogen bond formed between the iminium N and the phenolate O atom generates an S(6) ring motif. In the crystal, the mol-ecules are linked through O-H?O hydrogen bonds into chains along [110]. Two neighbouring chains are further connected through O-H?O hydrogen bonds in an anti-parallel manner. pi-pi inter-actions are also observed, with centroid-centroid distances of 3.7115 (19) and 3.743 (2) A. PMID- 21587786 TI - 9-(4-Hy-droxy-3-meth-oxy-phen-yl)-3,3,6,6-tetra-methyl-3,4,5,6-tetra-hydro-9H xanthene-1,8(2H,7H)-dione. AB - In the title compound, C(24)H(28)O(5), the two cyclo-hexene rings adopt envelope conformations, and the planes through the coplanar atoms makes dihedral angles of 82.86 (6) and 77.90 (6) degrees with the benzene ring. The two cyclo-hexene rings make a dihedral angle of 5.33 (6) degrees between their least-squares planes. The pyran ring adopts a flattened boat conformation. In the crystal packing, mol-ecules are linked into two-dimensional networks parallel to the ab plane via O-H?O and C-H?O inter-actions. PMID- 21587787 TI - 16-[(E)-Benzyl-idene]-13-hy-droxy-4-methyl-2-phenyl-4,14-diaza-penta-cyclo [12.3.1.0.0.0]octa-deca-7(12),8,10-triene-6,17-dione. AB - In the title compound, C(30)H(26)N(2)O(3), the two pyrrolidine rings adopt twisted and envelope conformations, whereas the cyclo-pentane ring adopts an envelope conformation. The least-squares planes through the pyrrolidine rings form a dihedral angle of 41.72 (10) degrees . The mol-ecular structure is stabilized by an intra-molecular O-H?N hydrogen bond, which generates an S(5) ring motif. Centrosymmetrically related mol-ecules are linked via two pairs of inter-molecular C-H?O inter-actions, forming R(2) (2)(16) ring motifs. In the crystal packing, the mol-ecules are linked into two-dimensional networks parallel to the ab plane via C-H?O inter-actions. PMID- 21587788 TI - (2-Chloro-8-meth-oxy-quinolin-3-yl)methanol monohydrate. AB - In the title compound, C(11)H(10)ClNO(2).H(2)O, the organic mol-ecule is roughly planar (r.m.s. deviation = 0.074 A). In the crystal structure, molecues are linked by O-H?O and O-H?N hydrogen bonds and weak C-H?pi and pi-pi inter-actions [centroid-centroid distance = 3.578 (3) A] consolidate the packing. A short Cl?O contact [3.147 (3) A] is also observed. PMID- 21587789 TI - (2-Chloro-8-methyl-quinolin-3-yl)methanol. AB - The mol-ecule of title compound, C(11)H(10)ClNO, is close to being planar (r.m.s deviation for the non-H atoms = 0.017 A). In the crystal, mol-ecules inter-act by way of O-H?O hydrogen bonds, generating C(2) chains propagating in [010]. The crystal structure is consolidated by C-H?pi inter-actions and aromatic pi-pi stacking inter-actions [centroid-centroid distance = 3.661 (2) A]. PMID- 21587790 TI - (2-Chloro-6-methyl-quinolin-3-yl)methanol. AB - The title compound, C(11)H(10)ClNO, is close to being planar (r.m.s deviation for the non-H atoms = 0.026 A). In the crystal, mol-ecules are linked by O-H?O hydrogen bonds, generating C(2) chains, and weak C-H?pi inter-actions and aromatic pi-pi stacking inter-actions [centroid-centroid distance = 3.713 (3) A] help to consolidate the structure. PMID- 21587791 TI - 3-[(2-Chloro-6-methyl-quinolin-3-yl)meth-yl]quinazolin-4(3H)-one. AB - In the title mol-ecule, C(19)H(14)ClN(3)O, the quinoline and quinazoline ring systems form a dihedral angle of 80.75 (4) degrees . In the crystal, the mol ecules are linked by pairs of C-H?N hydrogen bonds into centrosymmetric dimers, generating R(2) (2)(6) ring motifs. The structure is further stabilized by C-H?pi inter-actions and pi-pi stacking inter-actions [centroid-centroid distances = 3.7869 (8) and 3.8490 (8) A]. PMID- 21587792 TI - 2,5-Dihexyl-3,6-diphenyl-pyrrolo-[3,4-c]pyrrole-1,4(2H,5H)-dione. AB - The asymmetric unit of the title compound, C(30)H(36)N(2)O(2), contains one half mol-ecule, the other half being generated by a crystallographic inversion centre. The crystal structure is devoid of any classical hydrogen bonds however, non classical C-H?O inter-actions link the mol-ecules into chains propagating in [001] and a C-H?pi inter-action leads to the formation of a two-dimensional network in (011). PMID- 21587793 TI - 1,3-Dibenzyl-1,2,3,4-tetra-hydro-quinazoline-2,4-dione. AB - The asymmetric unit of the title compound, C(22)H(18)N(2)O(2), contains two independent mol-ecules, which differ in the orientations of the benzyl groups with respect to the planar (r.m.s. deviations of 0.031 and 0.020 A) quinazoline 2,4-dione skeletons [dihedral angles of 73.97 (4) and 70.07 (4) degrees in the first mol-ecule and 75.63 (4) and 63.52 (3) degrees in the second]. The crystal structure is stabilized by weak inter-molecular C-H?O and C-H?pi interactions and aromatic pi-pi stacking inter-actions [centroid-centroid distance = 3.735 (2) A]. PMID- 21587794 TI - 9-Benzyl-10-methyl-acridinium trifluoro-methane-sulfonate. AB - In the crystal structure of the title compound, C(21)H(18)N(+).CF(3)OS(3) (-), the cations form inversion dimers through pi-pi inter-actions between the acridine ring systems. These dimers are further linked by C-H?pi inter-actions. The cations and anions are connected by C-H?O, C-F?pi and S-O?pi inter-actions. The acridine and benzene ring systems are oriented at a dihedral angle of 76.8 (1) degrees with respect to each other. The acridine moieties are either parallel or inclined at an angle of 62.4 (1) degrees in the crystal structure. PMID- 21587795 TI - N'-[1-(2-Hy-droxy-phen-yl)ethyl-idene]-2-meth-oxy-benzohydrazide. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(16)H(16)N(2)O(3), in which the dihedral angles between the two aromatic rings are 13.0 (3) and 6.4 (3) degrees . Intra-molecular O-H?N and N-H?O hydrogen bonds are observed in both mol-ecules, forming S(6) rings in all cases. PMID- 21587796 TI - 4-Amino-benzoic acid-1,2-bis-(4-pyrid-yl)ethane (2/1). AB - In the title compound, C(12)H(12)N(2).2C(7)H(7)NO(2), the 4-amino-benzoic acid mol-ecules are linked by O-H?N hydrogen bonds to 1,2-bis-(4-pyrid-yl)ethane, forming linear hydrogen bonded chains parallel to [21]. The structure exhibits a hydrogen-bonding network involving COOH?N(pyrid-yl) and amine and carb-oxy-lic N H? O inter-actions. In addition, pi-pi stacking inter-actions [centroid-centroid distance = 3.8622 (14) A] are also present. PMID- 21587797 TI - 2,4-Dichloro-N-(3-chloro-phen-yl)benzene-sulfonamide. AB - In the title compound, C(12)H(8)Cl(3)NO(2)S, the conformation of the N-H bond in the C-SO(2)-NH-C segment is anti to the meta-Cl in the aniline ring. The mol ecule is twisted at the S atom, the C-SO(2)-NH-C torsion angle being 62.3 (2) degrees . The dihedral angle between the two benzene rings is 69.3 (1) degrees . The crystal structure features inversion dimers linked by pairs of N-H?O hydrogen bonds. PMID- 21587798 TI - 4-Carb-oxy-pyridinium bromide. AB - In the title compound, C(6)H(6)NO(2) (+).Br(-), the hy-droxy and carbonyl groups make torsion angles of 164.8 (4) and -17.6 (6) degrees , respectively, with the pyridinium ring. Inter-molecular N-H?Br, O-H?Br and C-H?O hydrogen bonds contribute to the stability of the structure and link the mol-ecules into chains along the b axis. PMID- 21587799 TI - N-(2-Methyl-phen-yl)maleamic acid. AB - In the title compound, C(11)H(11)NO(3), the conformation of the N-H bond is anti to the C=O bond in the amide segment, while it is syn to the ortho-methyl group in the phenyl ring. In the maleamic acid unit, the amide C=O bond is anti to the adjacent C-H bond, while the carboxyl C=O bond is syn to the adjacent C-H bond. The C=O and O-H bonds of the acid group are in the relatively rare anti position to each other. This is an obvious consequence of the intra-molecular O-H?O hydrogen bond donated to the amide carbonyl group. The ortho-substituted phenyl ring makes a dihedral angle of 12.7 (1) degrees with the mean plane of the maleamic acid unit. In the crystal structure, inter-molecular N-H?O hydrogen bonds link the mol-ecules into zigzag chains parallel to [001]. These chains are further linked into sheet by weak pi-pi inter-actions [centroid-centroid distance = 3.425 (2) A]. PMID- 21587800 TI - 2-(3-Bromo-4-meth-oxy-phen-yl)acetic acid. AB - The title compound C(9)H(9)BrO(3), was synthesized by the regioselective bromination of 4-meth-oxy-phenyl-acetic acid using bromine in acetic acid in a 84% yield. In the mol-ecular structure, the meth-oxy group is almost coplanar with the phenyl ring within 0.06 A; the acetic acid substituent is tilted by 78.15 (7) degrees relative to the ring. The C-C-C angles at the OMe, acetyl and Br substituents are 118.2 (2), 118.4 (2) and 121.5 (2) degrees , respectively, indicating that the Br atom is electron-withdrawing, whereas the other substituents possess electron-donating properties. In the crystal, the mol-ecules form centrosymmetric strongly O-H?O hydrogen-bonded dimers of the type R(2) (2)(8). PMID- 21587801 TI - 4-(Cyano-meth-yl)anilinium 4-methyl-benzene-sulfonate monohydrate. AB - In the title salt, C(8)H(9)N(2) (+).C(7)H(7)O(3)S(-).H(2)O, the dihedral angle between the cation and anion benzene rings is 50.1 (4) degrees . In the cation, the cyano-methyl group is twisted from the plane of the benzene ring [C-C-C-N = 86 (12) degrees ]. In the crystal, the cations, anions and water mol-ecules are linked by N-H?O and O-H?O hydrogen bonds, forming a chain along the c axis. PMID- 21587802 TI - 1-(4-Fluoro-phen-yl)thio-urea. AB - In the title compound, C(7)H(7)FN(2)S, the aromatic ring plane and the thio-urea unit are twisted with a torsion angle C-C-N-C7 of 44.6 (2) degrees . In the crystal, N-H?S and N-H?F inter-molecular hydrogen bonds link the mol-ecules into infinite sheets that are stacked along the c axis. PMID- 21587803 TI - 3-Chloro-N-(4-sulfamoylphen-yl)propanamide. AB - In the title compound, C(9)H(11)ClN(2)O(3)S, the dihedral angle between the benzene ring and the amido -NHCO- plane is 15.0 (2) degrees . An intra-molecular C-H?O hydrogen bond generates an S(6) ring motif. In the crystal structure, the amino NH(2) group is involved in inter-molecular N-H?O hydrogen bonds, which connect the mol-ecules into a double layer structure expanding parallel to the bc plane. The layers are further linked by an amido N-H?O hydrogen bond. Between the layers, a weak pi-pi inter-action with a centroid-centroid distance of 3.7447 (12) A is also observed. PMID- 21587804 TI - 2,3-Dimethyl-N-[(E)-4-nitro-benzyl-idene]aniline. AB - In the title compound, C(15)H(14)N(2)O(2), the aromatic rings are oriented at a dihedral angle of 24.52 (5) degrees . The dihedral angle between the nitro group and its parent benzene ring is 9.22 (16) degrees . In the crystal, mol-ecules inter-act through aromatic pi-pi stacking inter-actions [centroid-centroid separations = 3.8158 (14) and 3.9139 (14) A]. PMID- 21587805 TI - N-[(E)-4-Chloro-benzyl-idene]-2,3-dimethyl-aniline. AB - In the title compound, C(15)H(14)ClN, the conformation about the C=N bond is trans and the dihedral angle between the aromatic rings is 51.48 (4) degrees . In the crystal, some very weak C-H?pi inter-actions may help to establish the packing. PMID- 21587806 TI - 2,4-Dimethyl-anilinium chloride. AB - In the crystal structure of the title compound, C(8)H(12)N(+).Cl(-), all H atoms bonded to the ammonium N atom are hydrogen bonded to the chloride ions, with N?Cl distances in the range 3.080 (2)-3.136 (2) A, resulting in 16-membered macrocyclic rings involving four formula units of the title compound. PMID- 21587807 TI - 3-Methyl-4H-chromen-4-one. AB - In the title chromenone derivative, C(10)H(8)O(2), the two fused six-membered rings are coplanar, with a mean deviation of 0.0261 (1) A from the plane through the non-H atoms of the rings. The carbonyl and methyl substituents of the pyran ring also lie close to that plane, with the O and C atoms deviating by 0.0557 (1) and 0.1405 (1) A, respectively. In the crystal, weak C-H?O contacts form chains along the a axis. PMID- 21587808 TI - Ethyl 3-(4-methyl-benzyl-idene)carbazate. AB - There are two mol-ecules in the asymmetric unit of the title compound, C(11)H(14)N(2)O(2), which have similar conformations. In the crystal, the mol ecules are linked by N-H?O hydrogen bonds, generating C(4) chains propagating in [001]. PMID- 21587809 TI - Redetermination and absolute configuration of 7alpha-hy-droxy-royleanone. AB - THE TITLE COMPOUND [SYSTEMATIC NAME: 7alpha,12-dihy-droxy-8,12-abietadiene,11,14 dione or (4bS,8aS,10R)-3,10-dihy-droxy-2-isopropyl-4b,8,8-trimethyl 1,4,4b,5,6,7,8,8a,9,10-deca-hydro-phenanthrene-1,4-dione], C(20)H(28)O(4), is an abietane diterpen-oid, which was isolated from the roots of Premna obtusifolia (Verbenaceae). Its crystal structure has been reported previously [Chen et al. (2000 ?). Jiegou Huaxue, 19, 122-125], but the absolute configuration could not be determined using data collected with Mo radiation. This redetermination using Cu radiation shows the the absolute configurations of the stereogenic centres at positions 4b, 8a and 10 to be S, S and R, respectively. Two intra-molecular O-H?O hydrogen bonds [one generating an S(5) ring and one generating an S(6) ring] and a number of short C-H?O contacts occur. In the crystal, mol-ecules are linked into infinite chains propagating in [100] by O-H?O hydrogen bonds and weak C-H?O inter-actions. PMID- 21587810 TI - (E)-2-[(4-Iodo-phen-yl)imino-meth-yl]-6-methyl-phenol. AB - The title compound, C(14)H(12)INO, adopts the phenol-imine tautomeric form. The dihedral angle between the aromatic rings is 20.6 (3) degrees . The mol-ecular conformation is stabilized by an intra-molecular O-H?N hydrogen bond while in the crystal, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into a zigzag chain parallel to the b axis. PMID- 21587811 TI - 1,1'-(Ethane-1,2-di-yl)bis-(indoline-2,3-dione). AB - The mol-ecule of the title compound, C(18)H(12)N(2)O(4), is situated on a crystallographic centre of symmetry. The mol-ecule has a zigzag structure, with two parallel symmetry-related indoline-2,3-dione fragments linked by an ethyl-ene group at each N atom. In the crystal, the mol-ecules stack in columns along the b axis. There are two such columns in the structure. The mol-ecules within each column are parallel; however, the mol-ecules in the two columns differ in the respective orientation of the indoline-2,3-dione fragments. In one column, they are approximately parallel to (112), while in the other they are approximately parallel to (12). The inter-planar angle between the indoline-2,3-dione fragments in the two columns is 80.83 (3) degrees . The mol-ecules within each column are related by mutual displacement of their centres of symmetry, that is (0, +/-1/2, +/-1/2). The packing between the mol-ecules is provided by weak inter-actions only, viz. C-H?O hydrogen bonds and pi-pi [centroid-centroid distance = 3.8745 (8) A] and C=O?pi inter-actions. PMID- 21587812 TI - (1R*,2R*)-1-(4-Chloro-phen-yl)-4-dimethyl-amino-1-(3-meth-oxy-2-naphth-yl)-2-(1 naphth-yl)butan-2-ol. AB - In the title compound, C(33)H(32)ClNO(2), the benzene ring is oriented at dihedral angles of 6.23 (5) and 66.44 (5) degrees with respect to the two naphthalene ring systems. An intra-molecular O-H?N hydrogen bond between the hydr oxy H atom and the amine N atom generates an S(6) ring. PMID- 21587813 TI - (5S*,6R*,7R*)-6-Formyl-5-phenyl-7-propyl-perhydro-pyrazolo[1,2-a]pyrazol-1-one. AB - The title compound, C(16)H(20)N(2)O(2), was obtained by catalytic asymmetric cyclo-addition of trans-3-propyl-acrolein with 1-benzyl-idenepyrazolid-3-one betaine. There are two symmetry-independent mol-ecules in the asymmetric unit. In both mol-ecules, the two five-membered heterocyclic rings adopt envelope conformations. PMID- 21587814 TI - 4-(Carboxy-meth-oxy)anilinium bromide. AB - In the title hydro-bromide salt, C(8)H(10)NO(3) (+).Br(-), the positive charge resides on the N atom and the carboxyl -CO(2) end of the cation carries an H atom. In the crystal, N-H?Br, O-H?Br and N-H?O hydrogen bonds link the cations and anions, forming a ladder propagating along the a axis. PMID- 21587815 TI - 4-Methyl-anilinium 3,5-dinitro-benzoate. AB - The crystal structure of the title compound, C(7)H(10)N(+).C(7)H(3)N(2)O(6) (-), displays N-H?O hydrogen bonding between the ammonium groups and the O atoms of the 3,5-dinitro-benzoate anions. Inter-molecular C-H?O inter-actions further stabilize the packing. An O atom of each of the nitro groups is disordered over two sites with site occupancy factors of 0.59 (5) and 0.41 (6). PMID- 21587816 TI - 2,4-Dimethyl-anilinium perchlorate. AB - The crystal packing of the title compound, C(8)H(12)N(+).ClO(4) (-), is stabilized by N-H?O hydrogen bonds, the protonated amine group acting as a hydrogen-bond donor with the perchlorate O atoms as acceptors. These connect neighbouring cations and anions, forming a two-dimensional network. Variable temperature dielectric constant measurements on the salt indicated that no distinct phase transition occurred within the measured temperature range of 80 293 K. PMID- 21587817 TI - (S)-tert-Butyl 3-(3-phenyl-1,2,4-oxa-diazol-5-yl)piperidine-1-carboxyl-ate. AB - The title compound, C(18)H(23)N(3)O(3), crystallized with two independent mol ecules (A and B) in the asymmetric unit. The phenyl ring and the 1,2,4-oxadiazole ring are inclined to one another by 19.9 (3) degrees in mol-ecule A and 7.3 (3) degrees in mol-ecule B. The absolute structure of the title compound was referred to the transfered chiral center (S) of one of the starting reacta-nts. In the crystal, A mol-ecules are linked by C-H?N inter-actions involving the two oxadiazole N atoms. PMID- 21587818 TI - 1,8-Bis(benz-yloxy)-3,6-diiodo-naphthalene. AB - In the crystal structure of the title compound, C(24)H(18)I(2)O(2), one benzene ring is almost coplanar with the naphthyl system [dihedral angle = 6.6 (4) degrees ], whereas the other is almost orthogonal [73.1 (2) degrees ]. The crystal structure is consolidated by C-H?O and C-H?pi inter-actions. PMID- 21587819 TI - (E)-2-(2-Furylmethyl-idene)-2,3-dihydro-1H-pyrrolizin-1-one. AB - The title compound, C(12)H(9)NO(2), was prepared by an Aldol reaction of furfuraldehyde with 2,3-dihydro-1H-pyrrolizin-1-one. The mol-ecule is almost planar, with an r.m.s. deviation of 0.045 A, excluding the methyl-ene H atoms. In the crystal structure, mol-ecules are linked via weak inter-molecular C-H?O hydrogen bonding and aromatic pi-pi stacking [centroid-centroid distance = 3.6151 (9) A]. PMID- 21587820 TI - 2,2-Bis(hy-droxy-meth-yl)-2,3-dihydro-1H-pyrrolizin-1-one. AB - The title compound, C(9)H(11)NO(3), was prepared by an Aldol reaction of 2,3 dihydro-1H-pyrrolizin-1-one with formaldehyde. The asymmetric unit contains six mol-ecules. The pyrrolizine ring system in each mol-ecule is planar, the maximum atomic deviation being 0.066 (2) A. In the crystal structure, mol-ecules are liked together by an extensive O-H?O hydrogen-bonding network. PMID- 21587821 TI - 8-Meth-oxy-3,3,5-trimethyl-3,11-dihydro-pyrano[3,2-a]carbazole. AB - In the title compound, C(19)H(19)NO(2), commonly called koenimbine, the pyran ring adopts a sofa conformation. The carbazole ring system is planar [r.m.s. deviation = 0.063 (1) A]. A C(10) zigzag chain running along the b axis is formed through inter-molecular C-H?O hydrogen bonds. The chains are linked via weak C H?pi and N-H?pi inter-actions. PMID- 21587822 TI - (E)-N'-[4-(Dimethyl-amino)-benzyl-idene]-4-hy-droxy-benzohydrazide hemihydrate. AB - In the title compound, C(16)H(17)N(3)O(2).0.5H(2)O, the two hydrazide mol-ecules are approximately planar: the dihedral angles between the two substituted benzene rings are 7.7 (2) and 4.2 (2) degrees . Both hydrazone mol-ecules exist in a trans geometry with respect to their methyl-idene units. In the crystal, the water mol-ecule lies between the two organic mol-ecules and makes bifurcated O H?(N,O) hydrogen bonds to both of them. The hydrazide mol-ecules form N-H?O and O H?O hydrogen bonds, resulting in a three-dimensional network. PMID- 21587823 TI - 1,5-Dimethyl-4-{[1-(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl-idene)eth yl]amino}-2-phenyl-1H-pyrazol-3(2H)-one. AB - In the title compound, C(23)H(23)N(5)O(2), an intra-molecular N-H?O hydrogen bond generates an S(6) ring, and the dihedral angle between the pyrazole rings is 48.42 (8) degrees . The dihedral angles between the pyrazole rings and their attached phenyl rings are 10.06 (8) and 47.53 (8) degrees . PMID- 21587824 TI - 1,4-Diazo-niabicyclo-[2.2.2]octane bis-(2,4,6-trinitro-phenolate). AB - In the title compound, C(6)H(14)N(2) (2+).2C(6)H(2)N(3)O(7) (-), the cation possesses crystallographically imposed twofold rotation symmetry. In the crystal structure, the cation and anions are linked into a trimeric aggregate by inter molecular N-H?O hydrogen bonds. The trimeric units are further connected by pi-pi inter-actions [centroid-centroid distances = 3.507 (2)-3.660 (3) A], forming layers parallel to the bc plane. PMID- 21587825 TI - (3,4-Dimeth-oxy-phen-yl)(4-fluoro-phen-yl)methanone. AB - In the title compound, C(15)H(13)FO(3), the dihedral angle between the two aromatic rings is 52.78 (8) degrees . In the crystal, inter-molecular C-H?O hydrogen bonds link mol-ecules into chains running parallel to the c axis. PMID- 21587826 TI - (E)-1-Diphenyl-methyl-idene-2-[(1H-indol-3-yl)methyl-idene]hydrazine. AB - In the title compound, C(22)H(17)N(3), the 1H-indole unit is essentially planar, with a dihedral angle of 0.95 (10) degrees between the pyrrole ring and the fused benzene ring. The dihedral angle between the two phenyl rings is 65.09 (10) degrees . In the crystal, an inter-molecular N-H?N hydrogen bond forms an infinite chain in the b-axis direction. PMID- 21587827 TI - 1-[3-(2-Nitro-phen-yl)-5-phenyl-2-pyrazolin-1-yl]ethanone. AB - The title compound, C(17)H(15)N(3)O(3), was prepared from 1-(2-nitro-phen-yl)-3 phenyl-prop-2-en-1-one and hydrazine. The dihedral angle between the benzene and phenyl rings is 74.55 (2) degrees . The pyrazoline ring is in a slight envelope conformation with the C atom bonded to the phenyl ring forming the flap. In the crystal structure, weak inter-molecular C-H?O hydrogen bonds connect mol-ecules into chains along [100]. PMID- 21587828 TI - 4-{(E)-[2-(4-Iodo-but-oxy)benzyl-idene]amino}-1,5-dimethyl-2-phenyl-1H-pyrazol 3(2H)-one. AB - The title Schiff base compound, C(22)H(24)IN(3)O(2), adopts an E configuration about the central C=N bond. The pyrazolone ring makes a dihedral angle of 49.68 (10) degrees with its attached phenyl ring. The phenolate plane makes dihedral angles of 16.78 (9) and 50.54 (9) degrees , respectively, with the pyrazolone ring and the terminal phenyl ring. An intra-molecular C-H?O hydrogen bond generates an S(6) ring motif. In the crystal structure, an inter-molecular C-H?O hydrogen bond is also observed. PMID- 21587829 TI - Ethyl 1-(2-hy-droxy-eth-yl)-2-p-tolyl-1H-benzimidazole-5-carboxyl-ate. AB - The asymmetric unit of the title compound, C(19)H(20)N(2)O(3), contains two mol ecules (A and B) with slightly different orientations of the ethyl groups with respect to the attached carboxyl-ate groups. Intra-molecular C-H?O hydrogen bonds generate S(8) ring motifs in both mol-ecules A and B. In each mol-ecule, the benzimidazole ring system is essentially planar, with maximum deviations of 0.023 (1) and 0.020 (1) A, respectively, for mol-ecules A and B. The dihedral angle between the benzimidazole ring system and the phenyl ring is 37.34 (5) degrees for mol-ecule A and 42.42 (5) degrees for mol-ecule B. In the crystal, O-H?N and C-H?O hydrogen bonds link the mol-ecules into [100] columns with a cross-section of two-mol-ecule by two-mol-ecule wide, and further stabilization is provided by weak C-H?pi and pi-pi inter-actions [centroid separations = 3.5207 (7) and 3.6314 (8) A]. PMID- 21587830 TI - (E)-3-[4-(Dimethyl-amino)-benzyl-idene]-2,3-di-hydro-1H,9H-pyrrolo-[2,1 b]quinazolin-9-one. AB - The title compound, C(20)H(19)N(3)O, was obtained by condensation of 2,3-dihydro 1H,9H-pyrrolo-[2,1-b]quinazolin-9-one (alkaloid de-oxy-vasicinone, isolated from Peganum Harmala) with 4-(dimethyl-amino)-benzaldehyde in the presence of sodium methoxide. The 2,3-dihydro-1H,9H-pyrrolo-[2,1-b]quinazolin-9-one part of the mol ecule is roughly planar (r.m.s. deviation = 0.0178 A) and is essentially coplanar with the benzil-idene ring (r.m.s. deviation = 0.0080 A), forming a dihedral angle of 5.0 (1) degrees . The crystal structure is stabilized by two aromatic pi pi stacking inter-actions observed between the benzene rings of neighboring mol ecules [centroid-centroid distance = 3.7555 (19) A. PMID- 21587831 TI - 4-(2-Methyl-anilino)pent-3-en-2-one. AB - The title enamino ketone, C(12)H(15)NO, a derivative of 4-(phenyl-amino)-pent-3 en-2-one, presents a roughly planar [greatest displacement of an atom from the pentenone plane is 0.033 (2) A] pentenone backbone, enhanced by an intra molecular N-H?O hydrogen bond; the asymmetry in C-C distances in the group suggests the presence of unsaturated bonds. The overall geometry in the free ligand differs significantly from that in other reported compounds, in which it is coordinated to rhodium; this is reflected in the bond distances [the N?O distance is significantly increased (0.2 A) upon coordination to the metal] and the dihedral angle between the benzene ring and the pentenone backbone [49.53 (5) degrees ]. All of the methyl goups are rotationally disordered over two orientations of equal occupancy. PMID- 21587832 TI - 3-Acetyl-benzoic acid. AB - In the crystal structure of the title compound, C(9)H(8)O(3), essentially planar mol-ecules [the carboxyl group makes a dihedral angle of 4.53 (7) degrees with the plane of the ring, while the acid group forms a dihedral angle of 3.45 (8) degrees to the ring] aggregate by centrosymmetric hydrogen-bond pairing of ordered carboxyl groups. This yields dimers which have two orientations in a unit cell, creating a herringbone pattern. In addition, two close C-H?O inter molecular contacts exist: one is between a methyl H atom and the ketone of a symmetry-related mol-ecule and the other involves a benzene H atom and the carboxyl group O atom of another mol-ecule. The crystal studied was a non merohedral twin with twin law [100, 00, 0] and a domain ratio of 0.8104(14): 0.1896(14). PMID- 21587833 TI - 2-Chloro-N-(4-sulfamoylphen-yl)acetamide. AB - In the title compound, C(8)H(9)ClN(2)O(3)S, the benzene ring makes a dihedral angle of 4.1 (9) degrees with the amido -NHCO- plane including the major occupancy component of the carbonyl O atom [19 (4) degrees for the minor component]. An intra-molecular C-H?O inter-action occurs. The O atom of the carbonyl group is disordered over two positions with site-occupancy factors of 0.67 (11) and 0.33 (11). Inter-molecular N-H?O hydrogen bonds help to stabilize the crystal structure. PMID- 21587834 TI - Bis(N,N'-diphenyl-benzamidinium) fumarate. AB - The crystal structure of the title compound, 2C(19)H(17)N(2) (+).C(4)H(2)O(4) (2 ), consists of centrosymmetric trimers built up of two crystallographically independent N,N'-diphenyl-benzamid-in-ium cations and one fumarate dianion, which is located on a centre of inversion. The components of the trimers are linked by N-H?O hydrogen bonding. In the cation, the outer rings make dihedral angles of 53.66 (5) and 78.38 (5) degrees with the central ring. The two outer rings make a dihdral angle of 81.49 (5) degrees . PMID- 21587835 TI - p-Tolyl 2-O-benzoyl-3-O-benzyl-4,6-O-benzyl-idene-1-thio-alpha-l-idopyran-oside. AB - The title compound, C(34)H(32)O(6)S, is an ido-configured thio-glycoside building block for heparan sulfate fragments. It contains disordered tolyl and O-benzyl groups with occupancy ratios of 0.539 (13):0.461 (13) and 0.613 (13):0.387 (13), respectively, as determined from a weakly diffracting crystal. The fused rings adopt chair conformations with the mol-ecules packing into a three-dimensional network via C-H?O and three C-H?pi inter-actions. The former inter-actions, occuring between mol-ecules related by a twofold axis, define an R(2) (2)(26) motif. PMID- 21587836 TI - (2E)-Methyl 2-(7-benz-yloxy-1-naphth-yl)-3-meth-oxy-acrylate. AB - In the title compound, C(22)H(20)O(4), the dihedral angle between the phenyl and naphthalene ring systems is 86.10 (10) degrees . The methoxyacrylate group is disordered over two orientations in a 0.905 (3):0.095 (3) ratio. PMID- 21587837 TI - (E)-1-[(2-Hy-droxy-1-naphth-yl)methyl-idene-amino]-imidazolidine-2,4-dione. AB - The title compound, C(14)H(11)N(3)O(3), adopts an E or trans configuration with respect to the C=N bond. In the mol-ecule there is an intra-molecular O-H?N hydrogen bond involving the hy-droxy substituent at the 2-positon of the naphthalene ring and the adjacent methyl-ene-amino N atom. The mol-ecule is roughly planar, the dihedral angle between the naphthalene and imidazolidine-2,4 dione mean planes being 8.4 (1) degrees . In the crystal, pairs of N-H?O hydrogen bonds link mol-ecules into inversion dimers. These dimers are futher linked via C H?O inter-actions, forming a three-dimensional network. PMID- 21587838 TI - 4-{[(E)-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl-idene]amino}-1,5-dimethyl-2 phenyl-1H-pyrazol-3(2H)-one. AB - The title Schiff base compound, C(23)H(23)N(5)O, was synthesized by the reaction of 4-amino-phenazone and 3,5-dimethyl-1-phenyl-pyrazole-4-carbaxaldehyde. The mol ecule adopts an E configuration about the central C=N double bond. A weak intra molecular C-H?O hydrogen bond generates an S(6) ring motif. The dihedral angle between the pyrazole rings is 24.72 (10) degrees and the dihedral angles between the pyrazole rings and the adjacent phenyl rings are 58.67 (10) and 46.58 (11) degrees . The crystal structure is stabilized by weak C-H?pi inter-actions involving the pyrazolone and phenyl rings. PMID- 21587839 TI - Absolute configuration of methyl isoeichlerialactone. AB - The title compound, C(28)H(44)O(4).0.56H(2)O, is a co-crystal of methyl isoeichlerialactone monohydrate as the major component and methyl isoeichlerialactone as the minor component in a 0.55778 (3):0.44222 (3) ratio. The conformations of both components are identical except for that of the COOCH(3) group of the methyl propanoate side chain on the cyclo-hexane ring which is positionally disordered over two orientations. The mol-ecule of methyl isoeichlerialactone has three fused rings and all rings are trans-fused. The two cyclo-hexane rings are in standard chair conformations and the cyclo-pentane ring adopts an envelope conformation. In the crystal, weak C-H?O inter-actions link methyl isoeichlerialactone mol-ecules into screw chains along [010]. The crystal structure is further stabilized by O-H?O hydrogen bonds and weak C-H?O inter actions. PMID- 21587840 TI - 2-Oxo-4-trifluoro-meth-yl-2H-chromen-7-yl 2-bromo-2-methyl-propano-ate. AB - In the title compound, C(14)H(10)BrF(3)O(4), the coumarin ring system is almost plannar (r.m.s. deviation = 0.025 A) and a short C-H?F contact occurs. The propano-ate fragment is orientated almost perpendicular to the ring [dihedral angle = 71.80 (12) degrees ]. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, generating [100] chains. PMID- 21587841 TI - 1-{6-Chloro-2-[(2-chloro-3-quinol-yl)meth-oxy]-4-phenyl-3-quinol-yl}ethan-1-one. AB - In the title compound, C(27)H(18)Cl(2)N(2)O(2), the 2-chloro-quinoline and 6 chloro-quinoline rings are almost planar, with maximum deviations from their mean planes of 0.072 (1) and 0.044 (1) A, respectively, for the Cl atoms. The inter planar angle between these rings is 14.36 (5) degrees . The inter-planar angle between the 6-chloro-quinoline and phenyl rings is 66.00 (8) degrees . In the crystal, mol-ecules are inter-linked by weak C-H?O, C-H?pi and pi-pi stacking [centroid-centroid distances = 3.7453 (10) and 3.7557 (9) A] inter-actions. PMID- 21587842 TI - 4-(2-Ethyl-phen-yl)-1-(2-oxoindolin-3-yl-idene)thio-semicarbazide. AB - The title compound, C(17)H(16)N(4)OS, is stabilized in the form of a two dimensional polymeric network due to inter-molecular N-H?S and N-H?O hydrogen bonds. An intra-molecular N-H?N hydrogen bond forms an S(5) ring, whereas inter actions of the N-H?O and C-H?S types complete S(6) ring motifs. pi-pi inter actions with a centroid-centroid distance of 3.6514 (10) A are found between the ethyl-substituted benzene ring and the heterocyclic ring of the isatin derivative. PMID- 21587843 TI - 2,7-Bis(prop-2-yn-1-yl-oxy)naphthalene. AB - The title compound, C(16)H(12)O(2), was synthesized from naphthalene-2,7-diol and prop-2-ynyl 4-methyl-benzene-sulfonate in the presence of sodium hydride. The crystal packing exhibits inter-molecular non-classical C-H?O hydrogen bonds and C H?pi inter-actions. PMID- 21587844 TI - (4S)-4-Benzyl-N-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]sulfon-yl}-2-oxo-1,3 oxazolidine-3-carboxamide. AB - The title compound, C(21)H(21)N(3)O(7)S, contains an oxazolidinone ring and a sulfonamide group, both characteristic for biologically and pharrmaceutically active compounds. Both stereogenic centres reveal an S absolute configuration. The two oxazolidinone rings are in an envelope conformation with the methyl-ene carbon flap atoms deviating by 0.428 (1) and 0.364 (2) A from the best least square planes formed by the four other ring atoms. An intra-molecular N-H?O hydrogen bond contributes to the folded conformation of the mol-ecule. In the crystal, weak inter-molecular C-H?O inter-actions connect the mol-ecules into helices along the the twofold screw axes. PMID- 21587845 TI - 3-(6-Meth-oxy-2-naphth-yl)-1-(2-pyrid-yl)prop-2-en-1-one. AB - There are two mol-ecules in the asymmetric unit of the title compound, C(19)H(15)NO(2), in which the dihedral angles between the naphthalene ring system and the pyridine ring are 40.5 (3) and 41.2 (4) degrees . In the crystal, C-H?O hydrogen bonds link the mol-ecules. PMID- 21587846 TI - (Z)-2-(2-Isopropyl-5-methyl-phen-oxy)-N'-(2-oxoindolin-3-yl-idene)acetohydrazide. AB - In the title Mannich base, C(20)H(21)N(3)O(3), an isatin derivative of thymol, the O-CH(2)-C(=O)-N(H)-N fragment connect-ing the aromatic and fused-ring systems is approximately planar, with the N-N single bond in a Z configuration. The amino H atom of this N-N fragment is intra-molecularly hydrogen bonded to the carbonyl O atom of the indolinone fused ring as well as to the phen-oxy O atom of the aromatic ring. The amino H atom of the indoline fused ring forms a hydrogen bond with the double-bond O atom of an adjacent mol-ecule, this hydrogen bond giving rise to a linear chain motif. PMID- 21587847 TI - 3',4'-Dichloro-biphenyl-4-yl 2,2,2-trichloro-ethyl sulfate. AB - The four independent mol-ecules in the asymmetric unit of the title compound, C(14)H(9)Cl(5)O(4)S, are related by pseudo-inversion centres. The mol-ecules have C(aromatic)-O bond lengths ranging from 1.426 (10) to 1.449 (9) A and biphenyl-4 yl sulfate ester bond lengths ranging from 1.563 (6) to 1.586 (6) A, which is comparable to structurally related sulfuric acid diesters. The dihedral angles between the benzene rings range from 22.5 (4) to 29.1 (4) degrees and are significantly smaller than the calculated dihedral angle of 41.2 degrees . PMID- 21587848 TI - (RS)-1-(1-Acetyl-indolin-5-yl)-2-chloro-propan-1-one. AB - The mol-ecule of the title compound, C(13)H(14)ClNO(2), is roughly planar [maximum deviation = 0.060 (2) A] with the disordered Cl/CH(3) group asymetrically distributed on both sides of the mean plane. Indeed, the Cl and CH(3) located on the stereogenic carbon exchange each other with occupancy factors in the ratio 0.60:0.40. The whole crystal is a racemate. Non-classical C H?O hydrogen bonds and pi-pi inter-actions [centroid-centroid distance = 3.6959 (9) A] between symmetry-related phenyl rings stabilize the crystal structure. PMID- 21587849 TI - Benzyl-ammonium tetra-fluoro-borate 18-crown-6 clathrate. AB - The reaction of benzyl-ammonium tetra-fluoro-borate and 18-crown-6 in a methano lic solution yields the title compound, C(7)H(10)N(+).BF(4) (-).C(12)H(24)O(6)O6, which displays a supra-molecular structure. The -NH(3) (+) substituent of the benzyl-ammonium cation forms a 1:1 supra-molecular rotator-stator structure by N H?O hydrogen-bonding inter-actions. PMID- 21587850 TI - Polymorphic form II of 4,4'-methyl-enebis(benzene-sulfonamide). AB - In the title compound, C(13)H(14)N(2)O(4)S(2) (alternative names: diphenyl methane-4,4'-disulfonamide, nirexon, CRN: 535-66-0), the two benzene rings form a dihedral angle of 70.8 (1) degrees . There are two sets of shorter (H?O < 2.1 A) and longer (H?O > 2.4 A) N-H?O hydrogen bonds per sulfonamide NH(2) group, which together result in hydrogen-bonded sheets parallel (102). Adjacent sheets are connected to one another by an additional N-H?N inter-action so that a three dimensional network of hydrogen-bonded mol-ecules is formed. The investigated polymorph is identical with the form II previously described by Kuhnert Brandstatter & Moser [(1981). Mikrochim. Acta, 75, 421-440]. PMID- 21587851 TI - 4,4'-(Propane-1,3-diyldi-oxy)dibenz-aldehyde. AB - The title compound, C(17)H(16)O(4), is a dialdehyde in which two formyl-phen-oxy units are linked by a -CH(2)CH(2)CH(2)- chain; the mol-ecule is V-shaped with the middle methyl-ene C atom as the apex. The two benzene rings are aligned at 77.4 (1) degrees . In the crystal, mol-ecules are linked into centrosymmetric dimers by pairs of non-classical C-H?O hydrogen bonds. PMID- 21587852 TI - 14-Hy-droxy-8,14-secogammacera-7-ene-3,21-dione from the bark of Lansium domesticum Corr. AB - In the title compound (kokosanolide B), C(30)H(48)O(3), the hexa-hydro- and octa hydro-naphthalen-2-one ring systems are connected through an ethyl-ene fragment, with a C-CH(2)-CH(2)-C torsion angle of 176.2 (2) degrees . The cyclo-hexene ring adopts a half-chair conformation, while the other six-membered rings adopt distorted chair conformations. In the crystal, adjacent mol-ecules are linked into a zigzag chain along the b axis by O-H?O hydrogen bonds involving the hy droxy and carbonyl groups. PMID- 21587853 TI - 5-Phenyl-3,4,4a,5,6,12c-hexa-hydro-2H-benzo[f]pyrano[3,2-c]quinoline. AB - In the title compound, C(22)H(21)N, the pyridine ring adopts a distorted boat conformation, while the adjacent pyran ring adopts a chair conformation; the heterocyclic rings make a dihedral angle of 40.1 (2) degrees with each other. PMID- 21587854 TI - (2R*,6S*)-tert-Butyl 2,6-bis-(hydroxy-meth-yl)morpholine-4-carboxyl-ate. AB - In the title compound, C(11)H(21)NO(5), the H atoms of the hydr-oxy groups are disordered over two positions, each in a 1:1 ratio. In the crystal, inter molecular O-H?O hydrogen bonds link pairs of mol-ecules into centrosymmetric dimers. Weak inter-molecular O-H?O inter-actions further link these dimers into chains extended in the [100] direction. PMID- 21587855 TI - 3-Mesityl-2-oxo-1-oxaspiro-[4.4]non-3-en-4-yl benzoate. AB - In the title compound, C(24)H(24)O(4), a derivative of the potent insecticide and miticide spiro-mesifen, one cyclo-pentane C atom is disordered over two positions with occupancies of 0.574 (12) and 0.426 (12), resulting in respective envelope and twisted conformations for the cyclo-pentane ring. The atom at the flap position is 0.620 (5) A out of the mean plane formed by the other four atoms of the envelope form. The furan ring makes dihedral angles of 68.26 (3) and 69.38 (2) degrees , respectively, with the 2,4,6-trimethyl-phenyl and benzene rings. The dihedral angle between the two benzene rings is 62.27 (3) degrees . PMID- 21587856 TI - Triethyl-ammonium 1,1'-binaphthyl-2,2'-diyl phosphate. AB - In the crystal structure of the title compound, C(6)H(16)N(+).C(20)H(12)O(4)P(-), an N-H?O inter-action links the cation to the anion. The N atom in the triethyl ammonium cation exhibits a trigonal-bipyramidal coordination geometry and forms an N-H?O inter-action with one phosphate O atom of the 1,1'-binaphthyl-2,2'-diyl phosphate ligand. A bifurcated C-H?O inter-action with the other phosphate O atom links molecules along the a axis. The dihedral angle between the two naphthyl ring systems is 58.92 (3) degrees . The refined Flack parameter value of 0.50 (10) indicates inversion twinning. PMID- 21587857 TI - (1-Adamant-yl)diphenyl-methano-l. AB - In the title compound, C(23)H(26)O, the adamantane cage consists of three fused cyclo-hexane rings in classical chair conformations with absolute values of the C C-C angles in the range 106.57 (11)-111.56 (12) degrees . The dihedral angle between the two phenyl rings is 81.38 (4) degrees . Although a hy-droxy group is present as a conceivable donor, no hydrogen bonds are observed in the crystal structure. PMID- 21587858 TI - (4-Chloro-phen-yl)methanaminium chloride hemihydrate. AB - In the title hydrated salt, C(7)H(9)ClN(+).Cl(-).0.5H(2)O, the water O atom lies on a crystallographic twofold axis. In the crystal, the monoprotonated 4-chloro benzyl-ammonium cation forms N-H?Cl and N-H?O hydrogen bonds and the water mol ecule forms O-H?Cl hydrogen bonds, generating layers lying parallel to the bc plane. PMID- 21587859 TI - 4-Acetyl-pyridinium iodide. AB - In the title compound, C(7)H(8)NO(+).I(-), N-H?I hydrogen bonding and pi-pi stacking inter-actions [centroid-centroid distance = 5.578 (4) A] stabilize the structure. PMID- 21587860 TI - 4-(3-Iodo-phen-yl)-1-(2-oxoindolin-3-yl-idene)thio-semicarbazide. AB - In the title compound, C(15)H(11)IN(4)OS, intra-molecular N-H?N, N-H?O and C-H?S inter-actions generate one S(5) and two S(6) ring motifs. In the crystal, mol ecules form centrosymmetric dimers via pairs of N-H?O inter-actions, generating R(2) (2)(8) ring motifs. In addition a short inter-molecular I?S contact of 3.352 (3) A is observed. PMID- 21587861 TI - Methyl 4-(piperidin-1-ylcarbon-yl)benzoate. AB - In the title compound, C(14)H(17)NO(3), the piperidine ring has a chair conformation and an intra-molecular C-H?O inter-action stabilizes the mol-ecular conformation. In the crystal, weak inter-molecular C-H?O inter-actions occur. PMID- 21587862 TI - N'-(5-Chloro-2-hy-droxy-benzyl-idene)-2-meth-oxy-benzohydrazide. AB - The title Schiff base compound, C(15)H(13)ClN(2)O(3), was prepared by the reaction of equimolar quanti-ties of 5-chloro-2-hy-droxy-benzaldehyde with 2-meth oxy-benzohydrazide in a methanol solution. The dihedral angle between the two benzene rings is 20.6 (3) degrees . An intra-molecular O-H?N hydrogen bond may influence the mol-ecular conformation. In the crystal structure, mol-ecules form chains along the b direction via inter-molecular N-H?O hydrogen bonds which are bifurcated involving an intra-molecular N-H?O hydrogen bond. PMID- 21587863 TI - (Z)-3-(2-{2-[1-(4-Hy-droxy-phen-yl)ethyl-idene]hydrazin-1-yl}-1,3-thia-zol-4-yl) 2H-chromen-2-one. AB - In the title compound, C(20)H(15)N(3)O(3)S, an intra-molecular C-H?O hydrogen bond generates an S(6) ring motif. The chromene ring system is inclined at dihedral angles of 14.21 (9) and 9.91 (10) degrees , respectively, with respect to the thia-zole and benzene rings. The thia-zole ring makes a dihedral angle of 24.06 (11) degrees with the benzene ring. In the crystal structure, O-H?O hydrogen bonds link the mol-ecules into a zigzag chain along [20]. Weak N-H?O and C-H?O inter-actions connect the chains into a three-dimensional network. pi-pi stacking inter-actions with a centroid-centroid distance of 3.4209 (14) A are also observed between the chains. PMID- 21587864 TI - 11-Butyl-3-meth-oxy-11H-benzo[a]carbazole. AB - The title compound, C(21)H(21)NO, consists of a carbazole skeleton with a meth oxy-benzene ring fused to the carbazole, and a butyl group attached to the carbazole N atom. The carbazole skeleton is nearly planar [maximum deviation = 0.078 (2) A], and it is oriented at a dihedral angle of 4.22 (4) degrees with respect to the adjacent meth-oxy-benzene ring. PMID- 21587865 TI - 1,3,5,7-Tetra-kis(4-iodo-phen-yl)adamantane benzene tetra-solvate. AB - The title mol-ecule, C(34)H(28)I(4).4C(6)H(6), has crystallographic symmetry and crystallizes with four symmetry-related benzene solvent mol-ecules. The phenyl group is eclipsed with one of the adamantane C-C bonds. The tetra-phenyl adamantane units and the benzene solvent mol-ecules are connected by weak inter molecular phen-yl-benzene C-H?pi and benzene-benzene C-H?pi inter-actions. In the crystal, mol-ecules are linked along the c-axis direction via the iodo-phenyl groups by a combination of weak inter-molecular I?I [3.944 (1) A] and I?pi(phen yl) [3.608 (6) and 3.692 (5) A] inter-actions. PMID- 21587866 TI - 5-Fluoro-3-(4-fluoro-phenyl-sulfin-yl)-2-methyl-1-benzofuran. AB - In the title compound, C(15)H(10)F(2)O(2)S, the S=O and the 4-fluoro-phenyl groups are located on opposite sides of the plane of benzofuran ring system, and the 4-fluoro-phenyl ring is nearly perpendicular to the benzofuran plane with a dihedral angle of 89.93 (4) degrees . In the crystal structure, mol-ecules are linked by weak inter-molecular C-H?O hydrogen bonding and C-H?pi inter-actions. PMID- 21587867 TI - (2E)-1-(2-Bromo-phen-yl)-3-(4-chloro-phen-yl)prop-2-en-1-one. AB - In the title compound, C(15)H(10)BrClO, the dihedral angle between the mean planes of the benzene rings in the ortho-bromo- and para-chloro-substituted rings is 70.5 (6) degrees . The dihedral angles between the mean plane of the prop-2-en 1-one group and the mean planes of the benzene rings in the 4-chloro-phenyl and 2 bromo-phenyl rings are 14.9 (3) and 63.3 (8) degrees , respectively. In the crystal, inversion dimers linked by pairs of weak C-H?O interactions are observed as well as aromatic pi-pi stacking inter-actions. PMID- 21587868 TI - 4-(2-Carb-oxy-vin-yl)pyridinium iodide. AB - In the crystal structure of the title salt, C(8)H(8)NO(2) (+).I(-), the cations and anions are linked by bifurcated N-H?(O,I) hydrogen bonds. A near-linear O-H?I hydrogen bond also exists between the cation and anion, resulting in a two dimensional network. In the cation, the carboxyl group is twisted with respect to the pyridine ring at a dihedral angle of 15.34 (17) degrees . PMID- 21587869 TI - rac-N-[Hy-droxy(4-pyrid-yl)meth-yl]picolinamide: a hemiamidal. AB - The title compound, C(12)H(11)N(3)O(2), a hemiamidal, was synthesized by solvent free aldol condensation at room temperature by grinding picolinamide with isonicotinaldehyde in a 1:1 molar ratio. In the mol-ecule, the two pyridine rings are inclined to one another by 58.75 (6) degrees . They are linked, at positions 2 and 4, by the hemiamidal bridge (-CO-NH-CHOH-). The NH-group H atom forms an intra-molecular hydrogen bond with the N atom of the picolinamide pyridine ring. In the crystal, symmetry-related mol-ecules are linked via N-H?O hydrogen bonds, involving the NH group H atom of the hemiamidal bridge and the hy-droxy O atom, forming inversion-related dimers, with graph-set R(2) (2)(8). Adjacent mol-ecules are also linked via O-H?N hydrogen bonds, involving the hy-droxy substituent and the 4-pyridine N atom. Together these inter-actions lead to the formation of double-stranded ribbon-like hydrogen-bonded polymers propagating in [010]. The latter are further connected via C-H?O hydrogen bonds involving the carbonyl O atom, so forming a two-dimensional network in (011). PMID- 21587870 TI - 2,4-Dichloro-N-(2-chloro-phen-yl)benzene-sulfonamide. AB - In the title compound, C(12)H(8)Cl(3)NO(2)S, the conformation of the N-H bond in the C-SO(2)-NH-C segment is syn to the ortho-Cl in the aniline ring. The dihedral angle between the two benzene rings is 74.3 (1) degrees . An intra-molecular N H?Cl hydrogen bond occurs. In the crystal, pairs of N-H?O hydrogen bonds link the mol-ecules into dimers. PMID- 21587871 TI - N-(3,4-Dichloro-phen-yl)maleamic acid. AB - The asymmetric unit of the title compound, C(10)H(7)Cl(2)NO(3), contains two unique mol-ecules, both being stabilized by an intra-molecular O-H?O hydrogen bond within their maleamic units. In the crystal structure, inter-molecular N-H?O hydrogen bonds link the mol-ecules into chains extending along [1] which are further assembled into sheets via short inter-molecular C-Cl?O=C contacts [3.102 (2) and 3.044 (2) A]. PMID- 21587872 TI - N-(3-Chloro-phen-yl)maleamic acid. AB - In the title compound, C(10)H(8)ClNO(3), the molecular conformation is stabilized by two intra-molecular hydrogen bonds. The first is a short O-H?O hydrogen bond within the maleamic acid unit and the second is a C-H?O hydrogen bond which connects the amide group with the phenyl ring. The maleamic acid unit is essentially planar, with an r.m.s. deviation of 0.044 A, and makes a dihedral angle of 15.2 (1) degrees with the phenyl ring. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into C(7) chains running [010]. PMID- 21587873 TI - 3,5-Diamino-1-phenyl-1,2,4-triazolium bromide. AB - The title salt, C(8)H(10)N(5) (+).Br(-), crystallizes with two independent structural units in the asymmetric unit. The two independent cations have different conformations, the triazole and phenyl rings forming dihedral angles of 32.57 (6) and 52.27 (7) degrees . In both cations, the amino groups are planar (the sum of the angles at the N atom of each amino group is 360 degrees ) and conjugated with the triazole ring. Inter-molecular N-H?N and N-H?Br hydrogen bonds consolidate the crystal packing. PMID- 21587874 TI - 4-[(E)-({4-[Bis-(2-hy-droxy-eth-yl)amino]-phen-yl}imino)-meth-yl]phenol. AB - In the title compound, C(17)H(20)N(2)O(3), the amino N atom is in a planar environment (sum of angles = 360.0 degrees ). All hy-droxy H atoms are involved in hydrogen bonding. In the crystal structure, two O-H?O and an O-H?N(imino) hydrogen bond result in the formation of a three-dimensional network. The latter hydrogen bonding causes distortion of the planarity of the 4-HO-C(6)H(4)-CH=N C(6)H(4)- fragment by rotation around the =N-C(Ph) bond. The crystal studied was a non-merohedral twin [refined BASF parameter for the major component = 0.5293 (7)]. PMID- 21587875 TI - Triethyl-ammonium 4-nitro-benzene-sulfonate. AB - In the anion of the title molecular salt, C(6)H(16)N(+).C(6)H(4)O(5)S(-), the nitro group is twisted slightly from the benzene ring, making a dihedral angle of 3.16 (10) degrees . In the crystal structure, the cations and anions are linked into a two-dimensional network parallel to the ab plane by C-H?O and N-H?O hydrogen bonds. PMID- 21587876 TI - Dispiro-[cyclo-propane-1,5'-endo-tricyclo-[5.2.1.0]deca-3,8-diene-10',1''-cyclo propane]. AB - The title compound, C(14)H(16), is built up from three five-membered rings. Two of the five-membered rings display an envelope conformation and the third one is almost planar (r.m.s. deviation = 0.014 A). PMID- 21587877 TI - (3-Pyrid-yl)methanaminium 4-nitro-phenolate 4-nitro-phenol solvate. AB - In the crystal structure of the title compound, C(6)H(9)N(2) (+).C(6)H(4)NO(3) ( ).C(6)H(5)NO(3), ions and mol-ecules are connected via inter-molecular N-H?O, N H?N, O-H?O and C-H?O hydrogen bonds into a three-dimensional network. PMID- 21587878 TI - N'-(2-Hy-droxy-1-naphth-yl-methylidene)-3-meth-oxy-benzohydrazide. AB - In the title compound, C(19)H(16)N(2)O(3), the dihedral angle between the naphthalene ring system and the benzene ring is 19.8 (3) degrees . An intra molecular O-H?N hydrogen bond stabilizes the mol-ecular conformation. In the crystal, mol-ecules are linked via inter-molecular N-H?O hydrogen bonds, forming chains along the a axis. PMID- 21587879 TI - rac-Ethyl 4-hy-droxy-6-(2-hy-droxy-phen-yl)-2-oxo-4-(trifluoro-methyl)per-hydro pyrimidine-5-carboxyl-ate. AB - In the title compound, C(14)H(15)F(3)N(2)O(5), prepared by reaction of 2-hy-droxy benzaldehyde, ethyl 4,4,4-trifluoro-3-oxobutano-ate and urea, the tetra pyrimidine ring adopts a half-chair conformation. The crystal structure is stabilized by five inter-molecular hydrogen bonds, three O-H?O and two N-H?O, giving cyclic dimers (through three hydrogen bonds) which are further extended into a two-dimensional network. PMID- 21587880 TI - (E)-N'-(4-Hy-droxy-benzyl-idene)-2-nitro-benzohydrazide. AB - In the title compound, C(14)H(11)N(3)O(4), the two benzene rings form a dihedral angle of 45.3 (3) degrees . The nitro group is twisted out of the attached ring by a dihedral angle of 37.5 (3) degrees . In the crystal structure, mol-ecules are linked into a two-dimensional network parallel to (100) by O-H?O and N-H?O hydrogen bonds. PMID- 21587881 TI - Pyrrolo-[2,1-c][1,4]benzodiazepine-5,11-dithione. AB - The seven-membered fused-ring in the title compound, C(12)H(12)N(2)S(2), adopts a boat conformation (with the two phenyl-ene C atoms representing the stern and the methine C atom the prow). This methine C atom and the tertiary N atom also belong to a five-membered ring, which has an envelope conformation. In the crystal structure, mol-ecules are linked about a center of inversion by pairs of N-H?S hydrogen bonds. PMID- 21587882 TI - (2E)-2-[2-(4-Chloro-phen-yl)hydrazin-1-yl-idene]-4,4,4-trifluoro-3-oxobutanal. AB - The title compound, C(10)H(6)ClF(3)N(2)O(2), was synthesized by coupling 4 dimethyl-amino-1,1,1-trifluoro-but-3-en-2-one with 4-chloro-benzene-diazo-nium chloride. It crystallizes with two mol-ecules in the asymmetric unit, which form two similar centrosymmetric dimers via hydrogen bonds. Extensive electron delocalization and intra-molecular N-H?O hydrogen bonds are responsible for a planar conformation of the mol-ecules (maximum deviations = 0.010 and -0.015 A for the two molecules). In addition to hydrogen bonds, pi-pi stacking inter actions with centroid-centroid distances of 3.604 (2) and 3.583 (2) A contribute to the stability of the crystal structure. PMID- 21587883 TI - Ethyl 3,4-dimethyl-5-[(E)-(phenyl-imino)-meth-yl]-1H-pyrrole-2-carboxyl-ate. AB - In the title compound, C(16)H(18)N(2)O(2), the mol-ecule adopts an E conformation about the C=N double bond. The dihedral angle between the pyrrole and phenyl rings is 41.55 (8) degrees . In the crystal structure, pairs of inter-molecular N H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers. In the dimer, the two pyrrole rings are almost coplanar and the two phenyl rings are parallel to each other. PMID- 21587884 TI - 4-[(E)-(2,4,5-Trimeth-oxy-benzyl-idene)amino]-1,5-dimethyl-2-phenyl-1H-pyrazol 3(2H)-one. AB - The title compound, C(21)H(23)N(3)O(4), adopts an E configuration about the central C=N double bond and the pyrazolone ring is almost planar, with a maximum deviation of 0.042 (1) A. The central pyrazolone ring makes dihedral angles of 51.96 (5) and 3.82 (5) degrees with the attached phenyl and the trimeth-oxy substituted benzene rings, respectively. The dihedral angle between the phenyl ring and the trimeth-oxy-substituted benzene ring is 50.19 (5) degrees and an intra-molecular C-H?O hydrogen bond generates an S(6) ring motif. The crystal structure is stabilized by inter-molecular C-H?O and C-H?N hydrogen bonds. PMID- 21587885 TI - (E)-N'-(5-Bromo-2-hy-droxy-benzyl-idene)-2-meth-oxy-benzohydrazide. AB - In the title compound, C(15)H(13)BrN(2)O(3), the mol-ecule adopts an E configuration about the C=N bond and the two benzene rings form a dihedral angle of 20.3 (3) degrees . In the mol-ecule, there are two intra-molecular hydrogen bonds, viz. O-H?N and N-H?O, involving the hy-droxy substituent, the meth-oxy O atom and the hydrazide NH group and N atom. In the crystal structure, mol-ecules are linked through N-H?O hydrogen bonds, forming chains propagating along [010]. PMID- 21587886 TI - (E)-N'-(3-Nitro-benzyl-idene)-4-(8-quinol-yloxy)butano-hydrazide. AB - In the title Schiff base compound, C(20)H(18)N(4)O(4), the conformation along the bond sequence linking the benzene and quinoline rings is trans-(+)gauche-trans trans-(+)gauche-trans-trans. The dihedral angle between the aromatic ring systems is 80.3 (6) degrees . In the crystal, a pair of inter-molecular N-H?N hydrogen bonds link the mol-ecules into centrosymmetric R(2) (2)(20) dimers, which are aggregated via pi-pi inter-actions into sheets [quinoline-benzene ring centroid centroid separation = 3.572 (2)-3.773 (3) A]. PMID- 21587887 TI - 4-(8-Eth-oxy-2,3-dihydro-1H-cyclo-penta-[c]quinolin-4-yl)butane-1-peroxol. AB - In the title mol-ecule, C(18)H(23)NO(3), the hydro-per-oxy-butyl substituent is nearly fully extended, with the four torsion angles in the range 170.23 (10) 178.71 (9) degrees . The O-O distance in the hydro-peroxide group is 1.4690 (13) A. This group acts as an inter-molecular hydrogen-bond donor to a quinoline N atom. This results in dimeric units about the respective inversion centers, with graph-set notation R(2) (2)(18). PMID- 21587888 TI - (2E)-1-(2-Bromo-phen-yl)-3-(4-meth-oxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C(16)H(13)BrO(2), two benzene rings form a dihedral angle of 44.3 (9) degrees . In the crystal, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into chains propagating in [010]. The crystal packing also exhibits short Br?Br contacts of 3.4787 (8) A. A comparison of the DFT-optimized gas-phase mol-ecular geometry with that in the crystal structure revealed only small differences. PMID- 21587889 TI - (E)-N'-(5-Bromo-2-hy-droxy-benzyl-idene)-4-hy-droxy-3-meth-oxy-benzohydrazide methanol solvate. AB - In the title compound, C(15)H(13)BrN(2)O(4).CH(4)O, the two benzene rings form a dihedral angle of 3.2 (2) degrees . An intra-molecular O-H?N hydrogen bond is observed. In the crystal structure, mol-ecules are linked through O-H?O and N-H?O hydrogen bonds, forming a two-dimensional network parallel to (10). PMID- 21587890 TI - Polythia-zide. AB - The crystal structure of the title compound, C(11)H(13)ClF(3)N(3)O(4)S(3) (systematic name: 6-chloro-2-methyl-3-{[(2,2,2-trifluoro-eth-yl)sulfan-yl]meth yl}-3,4-dihydro-2H-1,2,4-benzothia-diazine-7-sul-f-on-amide 1,1-diox-ide; CRN: 346-18-9), exhibits a two-dimensional network of hydrogen-bonded mol-ecules parallel to (01). The NH and NH(2) groups act as donor sites and the sulfonyl O atoms as acceptor sites in N-H?O hydrogen bonds, and a C-H?O interaction also occurs. The thiadiazine ring adopts an envelope conformation with the N atom bonded to sulfur at the tip of the flap, and the methyl substituent is in an axial position. PMID- 21587891 TI - (R)-2-Benzyl-4-methyl-pentyl (R)-2-meth-oxy-2-(1-naphth-yl)propionate. AB - The relative configuration of the alcohol component in the title ester, C(27)H(32)O(3), has been assigned as (R) from the known configuration of (R)-(-) 2-meth-oxy-2-(1-naphth-yl)propionic acid [(R)-MalphaNP acid]. In the crystal structure, the C atom of the methyl group of the MalphaNP acid lies in the extended plane of the naphthyl ring system [methyl C atom deviates from plane by 0.211 (2) A; r.m.s. deviation of fitted atoms = 0.0187 A] and a weak intra molecular C-H?O hydrogen bond links the naphthyl ring system and the meth-oxy group. These structural properties are similar to those of most MalphaNP acid esters. PMID- 21587892 TI - (6S,7S,8R,8aS)-6-Ethyl-perhydro-indolizine-7,8-diol. AB - In the title compound, C(10)H(19)NO(2), the piperidine and pyrrolidine rings of the perhydro-indolizine ring system adopt chair and envelope conformations, respectively. In the crystal structure, inter-molecular O-H?N and O-H?O hydrogen bonds link the mol-ecules into a chain running along the a axis. PMID- 21587893 TI - 1-Chloro-methyl-4-nitro-benzene. AB - In the title compound, C(7)H(6)ClNO(2), the nitro group is almost coplanar with the aromatic ring [dihedral angle = 2.9 (2) degrees ], but the Cl atom deviates from the ring plane by 1.129 (1) A. In the crystal, mol-ecules are linked by weak C-H?O inter-actions to generate chains. PMID- 21587894 TI - Cholest-5-en-7-one. AB - In the deca-hydro-phenanthrenone ring system of the title compound, C(27)H(44)O, the two cyclo-hexane rings adopt chair conformations, whereas the cyclo-hexene ring adopts an envelope conformation. The cyclo-pentane ring is twisted. In the crystal structure, mol-ecules are stacked along the a axis, but no significant inter-molecular inter-actions are observed. PMID- 21587895 TI - Methyl 4-methyl-sulfonyl-2-nitro-benzoate. AB - The title compound, C(9)H(9)NO(6)S, was prepared by the reaction of methanol and thionyl chloride with 4-methyl-sulfonyl-2-nitro-benzoic acid under mild conditions. The dihedral angle between the nitro group and benzene ring is 21.33 (19) degrees and that between the carboxyl-ate group and the benzene ring is 72.09 (17) degrees . The crystal structure is stabilized by weak inter-molecular bifurcated C-H?O inter-actions occurring in the (100) plane. PMID- 21587896 TI - N'-(4-Cyano-benzyl-idene)furan-2-carbohydrazide monohydrate. AB - In the title compound, C(13)H(9)N(3)O(2).H(2)O, the dihedral angle between the aromatic rings is 10.7 (4) degrees and an intra-molecular N-H?O hydrogen bond occurs. In the crystal, the components are linked by N-H?O, O-H?N and O-H?O hydrogen bonds. PMID- 21587897 TI - N-(3-Nitro-phen-yl)maleamic acid. AB - In the title compound, C(10)H(8)N(2)O(5), the mol-ecule is slightly distorted from planarity. The mol-ecular structure is stabilized by two intra-molecular hydrogen bonds. The first is a short O-H?O hydrogen bond (H?O distance = 1.57 A) within the maleamic acid unit and the second is a C-H?O hydrogen bond (H?O distance = 2.24 A) which connects the amide group with the benzene ring. The nitro group is twisted by 6.2 (2) degrees out of the plane of the benzene ring. The crystal structure manifests a variety of hydrogen bonding. The packing is dominated by a strong inter-molecular N-H?O inter-action which links the mol ecules into chains running along the b axis. The chains within a plane are further assembled by three additional types of inter-molecular C-H?O hydrogen bonds to form a sheet parallel to the (01) plane. PMID- 21587898 TI - 3,6,14,17-Tetramethoxy-22,23-diphenyl-1,10,12,21 tetraazahexacyclo[19.2.1.0.0.0.0]tetracosa-2(7),3,5,13(18),14,16-hexaene-11,24-di thione. AB - The title compound, C(36)H(34)N(4)O(4)S(2), is a thio-glycoluril derivative, which bears two phenyl substituents on its convex face and two meth-oxy substituted o-xylylenes as sidewalls of the molecular clip. There is one half-mol ecule in the asymmetric unit: a crystallographic twofold axis generates the complete molecule. The non-planar seven-membered rings adopt chair conformations, while the two five-membered rings exhibit envelope conformations and make a dihedral angle of 68.46 (12) degrees . The O atoms of the meth-oxy groups are coplanar with the six-membered o-xylylene sidewalls. PMID- 21587899 TI - (1-Phenyl-1H-1,2,3-triazol-4-yl)methyl pyridine-3-carboxyl-ate. AB - In the title compound, C(15)H(12)N(4)O(2), the dihedral angle between the planes of the nicotino-yloxy fragment and triazole ring is 88.61 (5) degrees . The dihedral angle between the planes of triazole and benzene rings is 16.54 (11) degrees . The crystal structure is stabilized by inter-molecular C-H?N, C-H?O and C-H?pi(triazole) hydrogen bonds and aromatic pi-pi stacking inter-actions between the benzene and triazole rings [centroid-centroid distance = 3.895 (1) A]. PMID- 21587900 TI - Dimethyl 2,2'-[ethane-1,2-diylbis(sulfanedi-yl)]dibenzoate. AB - The title compound, C(18)H(18)O(4)S(2), was synthesized by the reaction of 1,2 dibromo-ethane with methyl thio-salicylate. The complete molecule is generated by crystallographic twofold symmetry: two methyl benzoate units are linked by an -S (CH(2))(2)-S- bridging chain with a gauche S-CH(2)-CH(2)-S torsion angle [72.88 (16) degrees ]. The two aromatic rings form a dihedral angle of 79.99 (6) degrees . In the crystal, adjacent mol-ecules are linked into a three-dimensional network by non-classical C-H?O hydrogen bonds. PMID- 21587901 TI - (2E)-1-(2-Bromo-phen-yl)-3-(3,4,5-trimeth-oxy-phen-yl)prop-2-en-1-one. AB - In the chalcone title compound, C(18)H(17)BrO(4), the dihedral angle between the mean planes of the 2-bromo- and 3,4,5-trimethoxy-substituted benzene rings is 89.3 (1) degrees . The angles between the mean plane of the prop-2-en-1-one group and the 2-bromo-phenyl and 3,4,5-trimeth-oxy-phenyl ring planes are 59.7 (1) and 40.5 (8) degrees , respectively. While no classical hydrogen bonds are present, three weak inter-molecular C-H?O inter-actions and weak C-H?Br and C-H?Cg pi-ring stacking inter-actions [C-H?Cg distance = 3.377 (2) A] are observed, which contribute to the stability of crystal packing. PMID- 21587902 TI - Conformation and absolute configuration of (1S,2S)-2-(phenyl-selan-yl)cyclo-hexyl (R)-2-meth-oxy-2-(1-naphth-yl)propionate. AB - The relative and absolute configurations of the title compound, C(26)H(28)O(3)Se, were assigned from the known configuration of (R)-(-)-2-meth-oxy-2-(1-naphth yl)propionic acid used as starting material, and by examination of the Bijvoet (Friedel) pairs, using the anomalous dispersion data collected with Mo Kalpha radiation at low temperature. The geometry around the carbonyl group exists in the syn conformation, as reflected in torsion angles involving this group, and the stability of the structure is affected by weak bifurcated intra-molecular C H?O hydrogen bonds. PMID- 21587903 TI - 5-Meth-oxy-1-(3,4,5-trimethoxy-phen-yl)-1H-indole. AB - The title compound, C(18)H(19)NO(4), was prepared as an indole derivative with possible anti-mitotic properties. The planes of the indole and trimethoxy-phenyl rings make a dihedral angle of 45.35 (5) degrees with one another. In the crystal, mol-ecules related by a twofold screw axis exhibit arene C-H?arene-pi inter-actions which are 3.035 (1) A in length. PMID- 21587904 TI - N-Methyl-N-(2-methyl-phen-yl)acetamide. AB - In the title compound, C(10)H(13)NO, the N atom and the methyl group are almost coplanar with the benzene ring to which they are bonded [deviations of 0.131 (1) and 0.038 (1) A, respectively, from the ring plane]. In the crystal structure, inter-molecular C-H?O hydrogen bonds form a three-dimensional network. Mol-ecules are stacked parallel to the b-axis direction. PMID- 21587905 TI - 2-(4-Fluoro-phen-yl)-5-iodo-7-methyl-3-methyl-sulfinyl-1-benzofuran. AB - In the title compound, C(16)H(12)FIO(2)S, the O atom and the methyl group of the methyl-sulfinyl substituent lie on opposite sides of the plane through the benzofuran fragment. The 4-fluoro-phenyl ring is rotated slightly out of the benzofuran plane, as indicated by the dihedral angle of 7.43 (6) degrees . In the crystal structure, pairs of short I?O [3.074 (2) A] contacts link the mol-ecules into centrosymmetric dimers. These dimers are further linked via aromatic pi-pi inter-actions between the benzene and the 4-fluoro-phenyl rings of neighbouring mol-ecules [centroid-centroid distance = 3.617 (3) A]. PMID- 21587906 TI - Diethyl 7,8,18,19-tetra-methyl-2,13-dioxo-hexa-cyclo-[10.10.2.0.0.0.0]tetra-cosa 5,7,9,16,18,20-hexa-ene-23,24-dicarboxyl-ate. AB - The asymmetric unit of the title compound, C(30)H(34)N(4)O(6), contains two independent mol-ecules. In one independent mol-ecule, the two eth-oxy-carbonyl groups are each disordered over two conformations with occupancy ratios of 0.586 (2):0.414 (2) and 0.508 (2):0.492 (2). The crystal packing exhibits weak inter molecular C-H?O hydrogen bonds. PMID- 21587907 TI - N-(3-Eth-oxy-phen-yl)-4-methyl-benzene-sulfonamide. AB - In the title compound, C(15)H(17)NO(3)S, the two aromatic rings make a dihedral angle of 69.42 (9) degrees with each other and the bridging C-N-S-C torsion angle is 65.76 (16) degrees . Weak intra-molecular C-H?O inter-actions may affect the mol-ecular conformation. Two neighbouring mol-ecules generate a hydrogen bonded dimer about a center of inversion through a pair of inter-molecular N-H?O inter-actions, forming an R(2) (2)(8) ring motif. Furthermore, two inter molecular C-H?pi inter-actions contribute to the stability of the crystal packing. PMID- 21587908 TI - 10-Hy-droxy-10-(1,3-thia-zol-2-ylmeth-yl)phenanthren-9(10H)-one. AB - In the title phenanthrenone compound, C(18)H(13)NO(2)S, the dihydro-phenanthrene ring system is not planar, with its central ring distorted to a screw-boat conformation. The essentially planar thia-zole ring [maximum deviation = 0.005 (1) A] is inclined at an inter-planar angle of 23.36 (5) degrees with respect to the mean plane through the dihydro-phenanthrene ring system. In the crystal packing, inter-molecular O-H?N hydrogen bonds link the mol-ecules into infinite chains along the a axis. Weak inter-molecular C-H?pi inter-actions further stabilize the crystal packing. PMID- 21587909 TI - 3-Methyl-anilinium nitrate. AB - In the title compound, C(7)H(10)N(+).NO(3) (-), the 3-methyl-anilinium cations inter-act with the nitrate anions through strong bifurcated N(+)-H?(O,O) hydrogen bonds, forming a two-dimensional hydrogen-bonded network. PMID- 21587910 TI - 1-Acetyl-3-[2-(2,3,5,6-tetra-fluoro-phen-yl)hydrazin-1-yl-idene]indolin-2-one. AB - In the title compound, C(16)H(9)F(4)N(3)O(2), the dihedral angle between the aromatic ring systems is 4.10 (14) degrees and a bifurcated intra-molecular N H?(O,F) hydrogen bond generates an S(6) ring for the O-atom acceptor and an S(5) ring for the F-atom acceptor. A short C-H?O conact also occurs. In the crystal, mol-ecules are linked by C-H?O inter-actions. PMID- 21587911 TI - N-Cyclo-hexyl-benzamide. AB - The structure of the title compound, C(13)H(17)NO, features an anti disposition of the N-H and carbonyl groups. The amide group is twisted with respect to the benzene ring [N-C(=O)-C-C torsion angle = -30.8 (4) degrees ]. In the crystal, C(4) chains propagating in [100] are formed by inter-molecular N-H?O hydrogen bonds. Weak C-H?pi inter-actions link the chains into sheets. PMID- 21587912 TI - 7-(5-Methyl-sulfanyl-beta-d-erythrofuran-osyl)-7H-pyrrolo-[2,3-d]pyrimidin-4 amine monohydrate (MT-tubercidin.H(2)O). AB - The title compound, C(12)H(16)N(4)O(3)S.H(2)O, which has potential as a possible anti-malarial drug, was studied when small deviations in melting points, for two differently aged preparations, were observed. The unexpected existence of a water mol-ecule of crystallization is considered to be the cause of this variation. The 7H-pyrrolo-[2,3-d]pyrimidine unit is very slightly puckered with a total puckering amplitude of 0.035 (2) A; its mean plane makes an angle of 88.40 (12) degrees with the mean plane through the ribofuranosyl unit. In the crystal, the mol-ecules are bound by strong O-H?N and N-H?O hydrogen bonds, utilizing all available protons and linking mainly through the water of crystallization. PMID- 21587913 TI - Methyl 1-benzyl-1H-1,2,3-triazole-4-carboxyl-ate. AB - In the title compound, C(11)H(11)N(3)O(2), prepared by the [3+2] cycloaddition reaction of benzyl azide with methyl propiolate, the dihedral angle between the ring planes is 67.87 (11) degrees . PMID- 21587914 TI - N-[(2S)-2-(4-Bromo-phen-yl)-4-oxo-1,3-thia-zolidin-3-yl]pyridine-3-carboxamide. AB - In the title compound, C(15)H(12)BrN(3)O(2)S, the dihedral angle between the pyridine and benzene rings is 73.17 (19) degrees . The five-membered 1,3-thia zolidine ring has an envelope conformation, with the S atom displaced by 0.196 (1) A from the mean plane of the four other ring atoms. An intra-molecular C-H?N inter-action occurs. The crystal structure is stabil-ized by inter-molecular N H?O and C-H?O hydrogen bonds and C-H?pi inter-actions. In addition, a weak pi-pi stacking inter-action is also observed between the 1,3-thia-zolidine and pyridine rings [centroid-centroid distance = 3.805 (2) A]. PMID- 21587915 TI - 1-{6-Chloro-2-[(2-chloro-6-methyl-quinolin-3-yl)meth-oxy]-4-phenyl-quinolin-3 yl}ethanone. AB - In the title compound, C(28)H(20)Cl(2)N(2)O(2), the 2-chloro-quinoline and 6 chloro-quinoline ring systems are twisted slightly, making a dihedral angle of 4.05 (3) degrees . The dihedral angle between the 2-quinoline ring system and the phenyl ring attached to it is 74.43 (5) degrees . In the crystal structure, a pair of inter-molecular C-H?O hydrogen bonds connect the mol-ecules, forming centrosymmetric dimers with R(2) (2)(16) motifs. The dimers are further consolidated by a C-H?pi inter-action and a pi-pi stacking inter-action with a centroid-centroid distance of 3.6562 (10) A. PMID- 21587916 TI - 2'-Eth-oxy-1,3,3-trimethyl-spiro-[indoline-2,3'-3H-naphtho-[2,1-b][1,4]oxazine]. AB - In the title compound, C(24)H(24)N(2)O(2), the five-membered ring of the indoline ring system adopts an envelope conformation with the spiro C atom at the flap. The dihedral angle between the benzene ring of the indoline ring system and the naphthalene ring system is 71.70 (7) degrees . In the crystal structure, pair of weak C-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers. PMID- 21587917 TI - 1-[1-(4-Bromo-phen-yl)ethyl-idene]-4-(2,4-dimeth-oxy-phen-yl)thio-semicarbazide. AB - In the title compound, C(17)H(18)BrN(3)O(2)S, the dihedral angle between the aromatic rings is 9.15 (17) degrees . A bifurcated intra-molecular N-H?(N,O) hydrogen bond generates two S(5) rings and a weak intra-molecular C-H?S inter action completes an S(6) ring motif. In the crystal, inversion dimers linked by pairs of N-H?S hydrogen bonds generate R(2) (2)(8) loops and weak C-H?S and C H?pi inter-actions are also present. PMID- 21587918 TI - 4-Methyl-5-phenyl-1H-pyrazol-3-ol. AB - The title compound, C(10)H(10)N(2)O, crystallizes with two independent mol-ecules in the asymmetric unit, having closely comparable geometries. The dihedral angles between the 1H-pyrazole and benzene rings in the two mol-ecules are 39.57 (14) and 41.95 (13) degrees . The two mol-ecules are each connected to neighbouring mol-ecules by pairs of inter-molecular O-H?N hydrogen bonds, forming dimers with R(2) (2)(8) ring motifs. These dimers are further linked into R(4) (4)(10) ring motifs by inter-molecular N-H?O hydrogen bonds, forming chains along [101]. The crystal structure is further stabilized by a C-H?pi inter-action. PMID- 21587919 TI - 6-(Trifluoro-meth-yl)pyrimidine-2,4(1H,3H)-dione monohydrate. AB - The title compound, C(5)H(3)F(3)N(2)O(2).H(2)O, was prepared by the reaction of ethyl 4,4,4-trifluoro-3-oxobutano-ate with urea. In the crystal, the 6-(trifluoro meth-yl)pyrimidine-2,4(1H,3H)-dione and water mol-ecules are linked by N-H?O and O-H?O hydrogen bonds. A ring dimer structure is formed by additional inter molecular N-H?O hydrogen bonds. PMID- 21587920 TI - (E)-3-(3-Chloro-phen-yl)-N-(4-hy-droxy-3-meth-oxy-benz-yl)acryl-amide. AB - In the title compound, C(17)H(16)ClNO(3), the 4-hy-droxy-3-meth-oxy-benzyl group is planar [maximum atomic deviation = 0.0138 (16) A] and is nearly perpendicular to the chloro-benzene ring, making a dihedral angle of 84.67 (4) degrees . The chloro-benzene and amide groups are located on the opposite sides of the C=C bond, showing an E configuration. The relatively long C=O bond distance of 1.2364 (19) A and the short C-N bond distance of 1.341 (2) A suggest electron delocalization in the amide fragment. Inter-molecular O-H?O, N-H?O and weak C-H?O hydrogen bonding is present in the crystal structure. PMID- 21587921 TI - (2E)-1-(2-Bromo-phen-yl)-3-(4-bromo-phen-yl)prop-2-en-1-one. AB - The title compound, C(15)H(10)Br(2)O, is a chalcone with 2-bromo-phenyl and 4 bromo-phenyl rings bonded to opposite sides of a propenone group. The dihedral angle between mean planes of the benzene rings is 71.3 (1) degrees . The angle between the mean plane of the prop-2-ene-1-one group and the mean planes of the 2 bromo-phenyl and 4-bromo-phenyl rings are 64.2 (9) and 71.3 (1) degrees , respectively. A weak inter-molecular C-H?O inter-action and two weak C-Br?pi inter-actions are observed, which contribute to the stability of the crystal packing. PMID- 21587922 TI - 4-Chloro-N-(3-chloro-phen-yl)-2-methyl-benzene-sulfonamide. AB - In the title compound, C(13)H(11)Cl(2)NO(2)S, the conformation of the N-H bond in the C-SO(2)-NH-C segment is anti to the meta-Cl atom on the aniline ring and syn to the ortho-methyl group on the sulfonyl-benzene ring. Furthermore, the torsion angle of the C-SO(2)-NH-C segment in the mol-ecule is 80.1 (3) degrees . The two benzene rings are tilted relative to each other by 70.9 (1) degrees . In the crystal, pairs of inter-molecular N-H?O hydrogen bonds link the mol-ecules via inversion-related dimers into infinite column-like chains. PMID- 21587923 TI - 2-(4-Fluoro-phen-yl)-4,5-dimethyl-1-(4-methyl-phen-yl)-1H-imidazole. AB - In the title mol-ecule, C(18)H(17)FN(2), the imidazole ring is essentially planar [maximum deviation of 0.005 (1) A and makes dihedral angles of 72.33 (8) and 18.71 (8) degrees with the methyl-phenyl and fluoro-phenyl rings, respectively. The dihedral angle between the two benzene rings is 75.05 (7) degrees . The crystal packing is stabilized by inter-molecular C-H?N hydrogen bonds. PMID- 21587924 TI - (3R,3aS,6R,6aR)-3-(1-Nitro-eth-yl)perhydro-furo[3,2-b]furan-3,6-diol. AB - The mol-ecule of the title compound, C(8)H(13)NO(6), a sucrose derivative, consists of two fused tetra-hydro-furan rings having the cis arrangement at the ring junctions, giving a V-shaped mol-ecule. An intra-molecular O-H?O inter action occurs. Inter-molecular O-H?O hydrogen bonds help to stabilize the crystal structure. PMID- 21587925 TI - Di-tert-butyl 2,2'-[9H-fluorene-9,9-diylbis(p-phenyl-ene-oxy)]diacetate. AB - In the title mol-ecule, C(37)H(38)O(6), the non-fused C atom belonging to the five-membered ring of the fluorene system is connected to two p-phenyl-ene rings, the rings opening up the C(ar-yl)-C-C(ar-yl) angle to 113.1 (1) degrees . The four-atom -O-CH(2)-C(=O)-O- chain between the p-phenyl-ene ring and the tert butyl group assumes a more regular W-shaped conformation for one substituent [O-C C-C torsion angle = 171.9 (2) degrees ] but a less regular W-shaped conformation for the other [torsion angle = 147.4 (2) degrees ]. PMID- 21587926 TI - 2-Methyl-propan-2-aminium 4-hy-droxy-benzoate. AB - In the crystal of the title mol-ecular salt, C(4)H(12)N(+).C(7)H(5)O(3) (-), the cation is linked to three nearby anions by N-H?O hydrogen bonds. An O-H?O hydrogen bond between anions further consolidates the packing. PMID- 21587927 TI - Ammonium [(1S)-(endo,anti)]-(-)-3-bromo-camphor-8-sulfonate. AB - In the title mol-ecular salt, NH(4) (+).C(10)H(14)BrO(4)S(-), the norbornane skeleton of the anion is composed of two five-membered rings in envelope conformations and a six-membered ring with one Br atom, one carbonyl O atom and a methyl group held in a boat conformation by a bridging methyl-ene group. Short intra-molecular C-H?O and C-H?Br inter-actions occur. In the crystal, the component ions are linked by inter-molecular N-H?O and C-H?O hydrogen bonds. PMID- 21587928 TI - 9-Ethynyl-1,2-dimethyl-1,2-dicarba-closo-dodeca-borane (1,2-Me(2)-9-HC C-closo 1,2-C(2)B(10)H(9)). AB - The asymmetric unit of the title compound, C(6)H(16)B(10), contains one mol-ecule that is close to possessing a non-crystallographic plane of mirror symmetry in the space group Pna2(1). The orientation of the mol-ecules in the ortho-rhom-bic cell shows that the structure can not be described in the space group Pnma, which has the same systematic absence conditions. The long inner-cluster C-C distance of 1.510 (5) A is typical for {1,2-Me(2)-closo-1,2-C(2)B(10)} derivatives. PMID- 21587929 TI - Mesit-yl(2,4,6-trimeth-oxy-phen-yl)borinic acid. AB - In the title mol-ecule, C(18)H(23)BO(4), the dihedral angle between the least squares planes of the aromatic rings is 84.88 (3) degrees . The B atom deviates by 0.202 (1) A from the least-squares plane of the mesityl ring. All of the meth oxy groups are approximately coplanar with the 2,4,6-trimeth-oxy-phenyl ring, whereas the BOH group is twisted with respect to it by 19.5 degrees . The borinic OH group is engaged in an intra-molecular O-H?O hydrogen bond with one of ortho meth-oxy groups. The mol-ecular structure is stabilized by weak C-H?O contacts. In the crystal, mol-ecules are linked by weak C-H?O and C-H?pi inter-actions, generating a three-dimensional network. PMID- 21587930 TI - 2-(2,3,4,9-Tetra-hydro-1H-carbazol-1-ylidene)propane-dinitrile. AB - In the title mol-ecule, C(15)H(11)N(3), the dihedral angle between the benzene ring and the fused pyrrole ring is 1.07 (5) degrees . The cyclo-hexene ring adopts an envelope conformation: the dicyano-methyl-ene group at position 1 has a coplanar orientation. An intra-molecular N-H?N hydrogen bond generates an S(7) ring motif. Inter-molecular N-H?N hydrogen bonds form an R(2) (2)(14) ring in the crystal. A C-H?pi inter-action involving the benzene ring is also found in the structure. PMID- 21587931 TI - 4-Ethyl-1-(4-meth-oxy-benzyl-idene)thio-semicarbazide. AB - In the title compound, C(11)H(15)N(3)OS, the dihedral angle between the aromatic ring and the thio-urea unit is 4.28 (7) degrees and an intra-molecular N-H?N hydrogen bond generates an S(5) ring. In the crystal, mol-ecules are linked into (001) sheets by N-H?S hydrogen bonds. PMID- 21587932 TI - 4-Ethyl-1-[4-(methyl-sulfan-yl)benzyl-idene]thio-semicarbazide. AB - There are four independent mol-ecules in the asymmetric unit of the title compound, C(11)H(15)N(3)S(2), with different conformations: the dihedral angles between the benzene rings and thio-urea units are 16.85 (9), 0.56 (10), 8.05 (12) and 4.56 (8) degrees . Each mol-ecule contains an intra-molecular N-H?N hydrogen bond, generating an S(5) ring. The crystal structure is stabilized by inter molecular N-H?S hydrogen bonds. PMID- 21587933 TI - 2-(4-Fluoro-benzyl-idene)-N-(4-meth-oxy-benzylidene)-1,3,4-thia-diazol-2-amine. AB - The title compound, C(16)H(12)FN(3)OS, was synthesized by the reaction of 5-(4 meth-oxy-phen-yl)-1,3,4-thia-diazol-2-amine and 4-fluoro-benzaldehyde. An intra molecular C-H?S hydrogen bond results in the formation of two five-membered rings. In the crystal structure, inter-molecular C-H?N hydrogen bonding links the mol-ecules, forming a two-dimensional network. PMID- 21587934 TI - (2E)-1-(2,5-Dichloro-3-thien-yl)-3-(6-meth-oxy-2-naphth-yl)prop-2-en-1-one. AB - In the title compound, C(18)H(12)Cl(2)O(2)S, the dihedral angle between the thio phene ring and the naphthalene ring system is 2.13 (4) degrees . In the crystal, pairs of weak inter-molecular C-H?O hydrogen bonds form centrosymmetric dimers. PMID- 21587935 TI - 4,4'-[(2,7-Dibromo-fluorene-9,9-di-yl)dimethyl-ene]dipyridinium bis (perchlorate). AB - In the crystal of the title compound, C(25)H(20)Br(2)N(2) (2+).2ClO(4) (-), inter molecular N-H?O and C-H?O hydrogen bonds, along with C-H?pi inter-actions, stabilize the crystal structure. PMID- 21587936 TI - N'-(4-Hy-droxy-benzyl-idene)thio-phene-2-carbohydrazide. AB - In the title compound, C(12)H(10)N(2)O(2)S, the dihedral angle between the benzene and thio-phene rings is 23.34 (16) degrees . In the crystal structure, mol-ecules are linked by N-H?O and O-H?O hydrogen bonds, forming (100) sheets. PMID- 21587937 TI - N'-Benzyl-idene-furan-2-carbohydrazide. AB - In the title compound, C(12)H(10)N(2)O(2), the dihedral angle between the benzene ring and the furan ring is 24.6 (2) degrees . In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, generating C(4) chains propagating in [010]. PMID- 21587938 TI - N-(4-Nitro-pheneth-yl)formamide. AB - The title compound, C(9)H(10)N(2)O(3), was synthesized by direct N-formyl-ation of 4-nitro-phenethyl-amine hydro-chloride with formic acid and sodium formate in the absence of catalyst and solvent. In the crystal structure, mol-ecules are linked by inter-molecular N-H?O hydrogen-bond inter-actions into chains parallel to the a axis. PMID- 21587939 TI - 1-Benzyl-piperazine-1,4-diium bis-(perchlorate) monohydrate. AB - In the title compound, C(11)H(18)N(2) (2+).2ClO(4) (-).H(2)O, one perchlor-ate anion is disordered over two orientations in a 0.66 (3):0.34 (3) ratio. Inter molecular O-H?O, N-H?O and C-H?O hydrogen bonds link the cations, anions and water mol-ecules into ribbons extending along [100]. PMID- 21587940 TI - 2-(6-Bromo-3-pyrid-yl)-8-methyl-imidazo[1,2-a]pyrazine. AB - The structure of the title compound, C(12)H(9)BrN(4), prepared by the reaction of 2-bromo-1-(6-bromo-3-pyrid-yl)ethanone with 2-amino-3-methyl-pyrazine indicates that the compound with the bromo-pyridyl substituent at position 2 of the imidazopyrazine fused-ring system represents the major product of this reaction. The plane of the pyridine ring forms a dihedral angle of 16.2 (2) degrees with the essentially planar (r.m.s. deviation = 0.006 A) imidazopyrazine system. In the crystal, mol-ecules are linked by weak C-H?N inter-actions. PMID- 21587941 TI - Methyl 6-de-oxy-6-iodo-alpha-d-galactoside. AB - In the crystal of the title compound, C(7)H(13)IO(5), the molecules are linked by O-H?O hydrogen bonds, which build linkages around one screw axis of the cell. These C(5) and C(6) packing motifs expand to R(2) (2)(10) and C(2) (2)(11) motifs and are similar to those found for closely related compounds. The galactoside ring has a (1)C(4) chair conformation. PMID- 21587942 TI - 1-(3,4-Dihy-droxy-phen-yl)hexan-1-one. AB - In the title compound, C(12)H(16)O(3), a fully extened hexyl carbon chain is attached to a benzene ring; the mean planes formed by the atoms in the benzene ring and the hexa-none are inclined at an angle 8.5 (2) degrees with respect to each other. In the crystal, inter-molecular O-H?O hydrogen bonds join the mol ecules into an infinite sheet. PMID- 21587943 TI - 4-Meth-oxy-anilinium hexa-fluoro-phosphate monohydrate. AB - In the structure of the title compound, C(7)H(10)NO(+).PF(6) (-).H(2)O, the protonated 4-meth-oxy-anilinium cations and hexa-fluoro-phosphate anions are bridged by the water mol-ecule via N-H?O and O-H?F hydrogen bonds. The resulting zigzag chains extend along the c axis. In addition, C-H?pi inter-actions are observed in the crystal packing. PMID- 21587944 TI - N-{2-[4-(2-Meth-oxy-phen-yl)piperazin-1-yl]eth-yl}pyridin-2-amine monohydrate. AB - In the title compound, C(18)H(24)N(4)O.H(2)O, the piperizine ring adopts a chair conformation and the dihedral angle between the phenyl and pyridine rings is 39.9 (3) degrees . The comformations of the attachment of the anisole and N-ethyl pyridin-2-amine groups to the piperazine ring are +anti-periplanar. An intra molecular C-H?O inter-action occurs. In the crystal, the water mol-ecule links the mol-ecules into chains through O-H?N hydrogen bonds. Weak N-H?O, C-H?N and C H?O inter-actions further stabilize the crystal structure. PMID- 21587945 TI - N-Ethyl-N-(2-meth-oxy-phen-yl)benzene-sulfonamide. AB - In the title mol-ecule, C(15)H(17)NO(3)S, the C-S-N-C(benzene) torsion angle is 81.45 (16) degrees , and the two aromatic rings form a dihedral angle of 45.83 (12) degrees . In the crystal structure, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into chains parallel to the b axis. PMID- 21587946 TI - N-{2-[N-(4-Methyl-phen-yl)oxamo-yl]phen-yl}propanamide. AB - The title compound, C(18)H(18)N(2)O(3), is the product of the heterocyclic ring cleavage at position 2 of 1-propionylisatin. Two centrosymmetric cyclic motifs, viz. R(2) (2)(14) and R(2) (2)(18), are formed by N-H?O hydrogen bonds with the propanamide and amino-phenyl units, respectively, as the N-H donors. These motifs combine into two C(2) (2)(8) chain motifs parallel to the b axis. The chain structure is stabilized by C-H?pi inter-actions between the benzene rings, where C-H is from the phenyl ring of the cleaved part of 1-pro-pionylisatin. PMID- 21587947 TI - Dibutyl 5-[(4-ethoxycarbonylphenyl)diazenyl]benzene-1,3-dicarboxylate. AB - In the title compound, C(25)H(30)N(2)O(6), the dihedral angle between the aromatic rings is 3.79 (1) A and the N=N bond shows a trans conformation. Both butyl side chains show evidence of disorder. PMID- 21587948 TI - (2-Decan-amido-eth-yl)dimethyl-amine N-oxide. AB - In the title compound, C(14)H(30)N(2)O(2), the almost planar nonyl chains are fully extended: the N-C-C-N torsion angle of -161.95 (8) degrees indicates an anti conformation. The crystal structure features N-H?O hydrogen bonds and C-H?O inter-actions. PMID- 21587949 TI - 4-[(3,4-Dimeth-oxy-benzyl-idene)amino]-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H) one. AB - The imino-carbon double-bond in the title Schiff base, C(20)H(21)N(3)O(3), has an E configuration; the six-membered aromatic substituent (r.m.s. deviation = 0.012 A) is nearly coplanar with five-membered pyrazole substituent (r.m.s. deviation = 0.031 A), the dihedral angle between the two systems being 11.4 (1) degrees ]. The phenyl ring connected to the pyrazole ring is aligned at 45.5 (1) degrees with respect to this five-membered ring. The N atoms in the ring show pyramidal coordinations. PMID- 21587950 TI - trans-3-(3,4-Dimeth-oxy-phen-yl)-2-(4-nitro-phen-yl)prop-2-ene-nitrile. AB - The asymmetric unit of the title compound, C(17)H(14)N(2)O(4), contains two independent mol-ecules in which the benzene rings are in a trans arrangement with respect to the C=C double bond and the rings are inclined by 4.3 (1) and 22.1 (1) degrees with respect to each other. PMID- 21587951 TI - (7E)-5-Benzyl-7-(2-chloro-benzyl-idene)-3-(2-chloro-phen-yl)-2-phenyl 3,3a,4,5,6,7-hexa-hydro-2H-pyrazolo-[4,3-c]pyridine. AB - In the title 2H-pyrazolo-[4,3-c]pyridine derivative, C(32)H(27)Cl(2)N(3), the dihydro-pyrazole ring adopts an envelope conformation and the piperidine fused ring a twisted-chair conformation. Two short intra-molecular C-H?Cl contacts are observed. The crystal packing is characterized by dimeric C-Cl?pi inter-actions involving the 5-benzyl ring, with Cl?centroid and closest atomic Cl?pi distances of 3.778 (2) and 3.366 (4) A, respectively. PMID- 21587952 TI - Ethyl 5-cyano-8-nitro-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline-5 carboxylate. AB - In the title compound, C(17)H(19)N(3)O(4), the piperidine ring adopts a chair conformation. The crystal structure features inversion dimers linked by pairs of weak C-H?N hydrogen bonds. PMID- 21587953 TI - 1-(2-Phenyl-eth-yl)adamantane. AB - In the title compound, C(18)H(24), the adamantane cage consists of three fused cyclo-hexane rings in almost ideal chair conformations, with C-C-C angles in the range 108.0 (14)-111.1 (15) degrees . The phenyl and 1-adamantyl substituents adopt anti orientations with a C-C-C-C torsion angle of 177.10 (16) degrees . In the crystal packing, the mol-ecules are linked by weak C-H?pi inter-actions into chains along the a axis. PMID- 21587954 TI - 2-(4-Fluoro-phen-yl)-3-[5-(4-nitro-phen-yl)-1,3,4-thia-diazol-2-yl]-1,3-thia zolidin-4-one. AB - In the title compound, C(17)H(11)FN(4)O(3)S(2), the five-membered thia-zolidinone and thia-diazole rings are almost planar, with r.m.s. deviations of 0.017 and 0.0019 A, respectively. The 4-fluoro-phenyl ring is almost perpendicular to the thia-diazole ring, making a dihedral angle of 89.5 (3) degrees . The 4-nitro phenyl ring is nearly coplanar with the thia-diazole ring, the dihedral angle being 7.9 (3) degrees . The crystal structure is stabilized by two inter molecular C-H?O hydrogen bonds. PMID- 21587955 TI - Benzimidazolium 3,5-dicarb-oxy-benzoate trihydrate. AB - Cocrystallization of benzimidazole with benzene 1,3,5-tricarb-oxy-lic acid in slightly basic medium afforded the title compound, C(7)H(7)N(2) (+).C(9)H(5)O(6) (-).3H(2)O, in which one of the imidazole N atom is protonated and one carb-oxy lic group of aromatic acid is deprotonated. In the crystal structure, inter molecular N-H?O hydrogen-bonding connects the two organic components into dimers, which are further linked into a three-dimensional network by O-H?O and N-H?O inter-actions between the water mol-ecules and the dimers. PMID- 21587956 TI - Di-tert-butyl 2,2'-[(biphenyl-4,4'-diyl)-dioxy]diacetate. AB - The complete molecule of the title compound, C(24)H(30)O(6), is generated by a crystallographic inversion centre. In the unique part of the mol-ecule, the four atom -O-CH(2)-C(= O)-O- chain between the benzene ring and the tert-butyl group assumes a zigzag conformation [O-C-C-O torsion angle = -162.3 (1) degrees ]. PMID- 21587957 TI - Dimethyl-ammonium perchlorate 18-crown-6 monohydrate clathrate. AB - The reaction of dimethyl-amine, 18-crown-6, and perchloric acid in methanol yields the title compound, C(2)H(8)N(+).ClO(4) (-).C(12)H(24)O(6).H(2)O. The dimethyl-ammonium cation and the water mol-ecule inter-act with the 18-crown-6 unit: N-H?O hydrogen bonds are formed between the ammonium NH(2) (+) group and four O atoms of the crown ether, while the water mol-ecule on the other side of 18-crown-6 ring forms O-H?O hydrogen bonds with two other O atoms of the crown ether. All conventional donors and acceptors in the cations are thus engaged in hydrogen bonding. The ClO(4) (-) anion is disordered over two sites, and occupancies for the disordered O atoms were fixed at 0.5. In the crystal, the cations and anions are arranged in alternating layers. PMID- 21587958 TI - 2-O-tert-Butyl-dimethyl-silyl-4,6-O-ethyl-idene-myo-insitol 1,3,5-orthoformate. AB - In the title compound, C(15)H(26)O(6)Si, the dioxa six-membered ring bonded to the myo-inositol skeleton is in a boat conformation while the rest of the six membered rings adopt chair conformations. PMID- 21587959 TI - 3,4-Dimeth-oxy-benzaldehyde [2,8-bis-(trifluoro-meth-yl)quinolin-4-yl]hydrazone. AB - In the title compound, C(20)H(15)F(6)N(3)O(2), the quinoline ring system is almost coplanar with the benzene ring; the dihedral angle between the two planes is 2.31 (8) degrees . The crystal structure displays an inter-molecular C-H?F hydrogen bond. In addition, a weak pi-pi inter-action is observed between the unfused benzene ring and the benzene ring of quinoline, with a centroid-centroid distance of 3.586 (1) A. PMID- 21587960 TI - 4,5,6,7-Tetra-chloro-2-(2,2,2-trifluoro-eth-yl)isoindoline-1,3-dione. AB - In the title compound, C(10)H(2)Cl(4)F(3)NO(2), the isoindoline ring system is almostplanar, the maximum atomic deviation being 0.064 (2) A. The C-C bond of the ethyl-ene group is twisted with respect to the isoindoline plane by a dihedral angle of 59.58 (12) degrees . In the crystal, weak inter-molecular C-H?F hydrogen bonding links the mol-ecules into supra-molecular chains running along the a axis. A short inter-molecular Cl?O contact of 2.950 (3) A is also observed. PMID- 21587961 TI - 4,5,6,7-Tetra-chloro-2-(4-fluoro-phen-yl)isoindoline-1,3-dione. AB - The title compound, C(14)H(4)Cl(4)FNO(2), has crystallographic twofold symmetry with the N and F atoms and two C atoms of the benzene ring located on a twofold rotation axis. The isoindole-dione ring system is almost planar [maximum atomic deviation = 0.036 (3) A], and is twisted with respect to the florobenzene ring, making a dihedral angle of 58.56 (16) degrees . Weak inter-molecular C-H?Cl hydrogen bonding is present in the crystal structure. PMID- 21587962 TI - 2-(2,2,2-Trifluoro-eth-yl)isoindoline-1,3-dione. AB - In the title compound, C(10)H(6)F(3)NO(2), the isoindole ring system is planar, the maximum atomic deviation being 0.012 (2) A. The C-C bond of the trifluoro ethyl group is twisted with respect to the isoindole ring by a dihedral angle of 62.58 (17) degrees . Weak inter-molecular C-H?O and C-H?F hydrogen bonding is present in the crystal structure. PMID- 21587963 TI - (Z)-Ethyl 2-oxo-3-(1,2-dihydroquinolin-2-yl-idene)propano-ate. AB - Both independent mol-ecules in the asymmetric unit of the tautomeric title compound, C(14)H(13)NO(3), a synthetic product obtained from 2-lithio-methyl quinoline and diethyl oxalate, crystallize in the enaminone form with a Z configuration around the double bond. Intra-molecular N-H?O hydrogen bonds occur, generating an S(6) graph-set motif. In the crystal, weak inter-molecular C-H?O and pi-pi stacking inter-actions [centroid-centroid distances = 3.7020 (14) 3.7429 (13)A] define a three-dimensional supra-molecular network. PMID- 21587964 TI - 1-(Morpholino-meth-yl)indoline-2,3-dione. AB - In the title compound, C(13)H(14)N(2)O(3), the morpholine ring displays a chair conformation, with the (2,3-dioxoindolin-1-yl)methyl group in an equatorial position. The crystal structure is stabilized by inter-molecular C-H?O hydrogen bonds. PMID- 21587965 TI - 1-[2-Oxo-5-(trifluoro-meth-oxy)indolin-3-yl-idene]-4-[4-(trifluoro-methyl)-phen yl]thio-semicarbazide. AB - In the title compound, C(17)H(10)F(6)N(4)O(2)S, an intra-molecular N-H?N hydrogen bonds forms an S(5) ring whereas N-H?O and C-H?S inter-actions complete S(6) ring motifs. The dihedral angle between the fused ring system and the phenyl ring is 6.68 (8) degrees . In the crystal, the mol-ecules are dimerized due to N-H?O inter-actions. pi-pi inter-actions are present between the benzene rings [centroid-centroid distance = 3.6913 (15) A] and between the five membered ring and the trifluoro-meth-yl)phenyl ring [centroids-centroid distance = 3.7827 (16) A]. One of the trifluoro-meth-oxy F atoms is disordered over two sites with occupancy ratio of 0.76 (3):0.24 (3). The F atoms of the p-trifluoro-methyl substituent are disordered over three sets of sites with an occupancy ratio of 0.70 (2):0.152 (11):0.147 (13). PMID- 21587966 TI - tert-Butyl 2-[4-(2-{4-[(tert-butoxycar-bonyl)methoxy]-3-methylphenyl}-2-propyl)-2 methylphenoxy]acetate. AB - In the mol-ecule of the title compound, C(29)H(40)O(6), the carbon atom belonging to the propyl chain is connected to two aromatic rings that open up the C(ar-yl) C-C(ar-yl) angle to 111.5 (1) degrees . The four-atom -O-CH(2)-C(=O)-O- linkage between the aromatic ring and the tert-butyl group assumes a (-)anti-periplanar conformation for one substituent and a (-)syn-periplanar conformation for the other substituent; the O-C-C-O torsion angles are -173.7 (2) and -10.2 (3) degrees . PMID- 21587967 TI - 4-{[4-(Dimethylamino)benzylidene]-amino}-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H) one. AB - The azomethine double-bond in the title Schiff base, C(20)H(22)N(4)O, has an E configuration. The aromatic ring of the benzyl-idene portion (r.m.s. deviation 0.011 A) and the five-membered pyrazolyl ring (r.m.s. deviation 0.033 A) form a dihedral angle of 19.0 (1) degrees . The phenyl substituent is twisted by 55.0 (1) degrees with respect to the five-membered ring. PMID- 21587968 TI - 1-[(Phenyl-iminio)amino]-2-naphtho-late. AB - In the zwitterionic title compound, C(16)H(12)N(2)O, the dihedral angle between the benzene ring and naphthalene ring system is 2.0 (1) degrees . The azo group adopts a trans configuration and an intra-molecular N-H?O hydrogen bond is found. In the crystal, the mol-ecules are packed by strong pi-pi inter-actions [centroid centroid distance between aromatic rings = 3.375 (3) A]. PMID- 21587969 TI - 3-(7,8,13,14-Tetra-hydrodi-benzo-[a,i]phen-an-thridin-5-yl)benzene-1,2-diol. AB - In the title compound, C(27)H(21)NO(2), the half-chair conformation of the alicyclic rings gives rise to a slightly folded structure of the central tricyclic tetra-hydrophenanthridine unit. Tandem intra-molecular O-H?N and O-H?O hydrogen bonds give rise to adjacent S(6) and S(5) rings, respectively, which dictate the conformation of the 5-aryl substituent. In the crystal structure, an inter-molecular C-H?O contact generates chains parallel to [101]. Short O-H?pi and C-H?pi contacts are also observed. PMID- 21587970 TI - N,N'-Dicyclo-hexyl-N,N'-dimethyl-N''-(4-nitro-benzo-yl)phospho-ric triamide. AB - The P atom in the title compound, C(21)H(33)N(4)O(4)P, is in a slightly distorted tetra-hedral coordination environment and the phosphoryl and carbonyl groups are anti to each other. The environment of each N atom is essentially planar (average angles of 119.9 and 118.4 degrees ). In the crystal structure, the H atom of the C(=O)NHP(=O) group is involved in an inter-molecular -P=O?H-N- hydrogen bond, forming centrosymmetric dimers. PMID- 21587971 TI - p-Tolyl bis-(o-tolyl-amido)-phosphinate. AB - In the title compound, C(21)H(23)N(2)O(2)P, the P atom has a distorted tetra hedral configuration. The O atom of the OC(6)H(4)-4-CH(3) group and the N atoms show sp(2) character. In the crystal, adjacent mol-ecules are linked by N-H?O hydrogen bonds into helical chains parallel to the b axis. PMID- 21587972 TI - 3-(1-Adamant-yl)-1-{[4-(2-meth-oxy-phen-yl)piperazin-1-yl]meth-yl}-4-methyl-1H 1,2,4-triazole-5(4H)-thione. AB - The title compound, C(25)H(35)N(5)OS, is a functionalized triazoline-3-thione with substituted piperazine and adamantyl substituents attached at the 2- and 5 positions, respectively, of a triazole spacer with an approximately C-shaped conformation of the mol-ecule. The piperazine ring adopts a chair conformation. PMID- 21587973 TI - 6-Nitro-benzimidazolium dihydrogen phosphate 6-nitro-benzimidazole solvate dihydrate. AB - In the crystal structure of the title compound, C(7)H(6)N(3)O(2) (+).H(2)PO(4) ( ).C(7)H(5)N(3)O(2).2H(2)O, the components are connected through O-H?O, N-H?O and O-H?N hydrogen-bonding inter-actions, forming a sheet-like structure parallel to (101). Adjacent sheets are further linked together by strong O-H?O hydrogen-bonds involving the dihydrogenphosphate groups. pi-pi stacking inter-actions between neighbouring aromatic constituents [centroid-centroid distance 3.653 (3) A] help to consolidate the crystal packing. PMID- 21587974 TI - N-Cyclo-hexyl-nicotinamide. AB - In the title compound, C(12)H(16)N(2)O, the dihedral angle between the pyridine ring and C/O/N plane is 22.93 (7) degrees . In the crystal structure, inter molecular N-H?O hydrogen bonds link the mol-ecules, forming extended chains along [001]. pi-pi inter-actions between inversion-related pyridine rings [centroid centroid distance = 3.825 (2)A] are also observed. PMID- 21587975 TI - 1,3-Bis(4-chloro-phen-yl)-1-methyl-1H-benzo[f]chromene. AB - The title compound, C(26)H(18)Cl(2)O, is a heterocyclic structure consisting of a benzo[f]chromene ring and two aromatic rings. The non-H atoms of the benzo[f]chromene ring are almost coplanar (rms deviation = 0.107 A), and the methyl C atom lies 1.340 (4) A from the mean plane of the benzo[f]chromene ring. The chromene ring forms dihedral angles of 88.45 (2) degrees with the benzene ring linked to the quaternary C atom and 50.74 (3) degrees with the benzene ring linked to the 3-position, while the dihedral angle between the two benzene rings is 67.58 (3) degrees . PMID- 21587976 TI - (4-Chloro-phen-yl)(3,6-dibromo-2-hy-droxy-7-meth-oxy-1-naphth-yl)methanone. AB - The asymmetric unit of the title compound, C(18)H(11)Br(2)ClO(3), contains two crystallographically independent mol-ecules in which the dihedral angles between the naphthalene ring systems and the benzene rings are 55.64 (11) and 60.50 (11) degrees . In each mol-ecule, an intra-molecular O-H?O=C hydrogen bond generates a six-membered ring. In the crystal structure, inter-molecular C-H?O and C-H?Cl hydrogen bonds and two different Br?O halogen bonds [2.9850 (19) and 3.2169 (19) A] are observed. PMID- 21587977 TI - Ethyl 1,6-dimethyl-2-oxo-4-(quinolin-4-yl)-1,2,3,4-tetra-hydro-pyrimidine-5 carboxyl-ate. AB - In the title compound, C(18)H(19)N(3)O(3), the tetra-hydro-pyrimidone ring adopts a distorted boat conformation. In the crystal structure, inter-molecular N-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers, which are further linked via inter-molecular C-H?pi inter-actions. In addition, an intra-molecular C-H?O hydrogen bond occurs. PMID- 21587978 TI - 1-Hydroxy-4-aza-1-azoniabicyclo[2.2.2]octane picrate. AB - In the crystal structure of the title compound, C(6)H(13)N(2)O(+).C(6)H(2)N(3)O(7) (-), the anions and cations are linked by O H?O, C-H?O and C-H?N hydrogen bonds into a three-dimensional network. The O atoms of a nitro group of the picrate anion are disordered over two positions of equal occupancy. PMID- 21587979 TI - 4-Nitroaniline-2,4,6-trimethoxybenz-aldehyde (1/1). AB - In the title co-crystal, C(6)H(6)N(2)O(2.)C(10)H(12)O(4), the two components are held together by an N-H?O(aldehyde) hydrogen bond. Adjacent co-crystals are linked by weaker N-H?O(nitro) hydrogen bonds, forming a linear chain. The two aromatic rings of the components are aligned at 75.2 (1) degrees . The crystal studied was a non-merohedral twin with a 24% minor component. PMID- 21587980 TI - 2-Hydroxy-N,N'-diisopropylpropane-1,3-diaminium dichloride. AB - In the crystal structure of the title amino alcohol derivative, C(9)H(24)N(2)O(2+).2Cl(-), the cations and anions are linked by inter-molecular O H?Cl and N-H?Cl hydrogen bonds into a three-dimensional network. PMID- 21587981 TI - 3-Methyl-1-(prop-2-en-1-yl)quinoxalin-2(1H)-one. AB - In the mol-ecule of the title compound, C(12)H(12)N(2)O, the quinoxaline ring is planar with an r.m.s. deviation of 0.007 (15) A. The dihedral angle between the quinoxaline and propenyl planes is 82.1 (2) degrees . The crystal packing is stabilized by offset pi-pi stacking between the quinoxaline rings [centroid centroid distance = 3.8832 (9) A]. PMID- 21587982 TI - N-{[4-(4-Meth-oxy-benzene-sulfonamido)-phen-yl]sulfon-yl}acetamide. AB - In the title compound, C(15)H(16)N(2)O(6)S(2), the dihedral angle between the benzene rings is 83.2 (3) degrees . The mol-ecular conformation is stabilized by an intra-molecular C-H?O inter-action. In the crystal structure, mol-ecules are linked by N-H?O and C-H?O hydrogen bonds and additional stabilization is provided by weak C-H?pi inter-actions. PMID- 21587983 TI - N-(2-Meth-oxy-phen-yl)benzene-sulfonamide. AB - The asymmetric unit of the title compound, C(13)H(13)NO(3)S, contains two crystallographically independent mol-ecules in which the dihedral angles between the phenyl and benzene rings are 88.16 (12) and 44.50 (12) degrees . One of the mol-ecules features an intra-molecular N-H?O hydrogen bond. In the crystal, the mol-ecules are linked into dimers by pairs of N-H?O hydrogen bonds. The dimers are further connected by C-H?O and C-H?pi inter-actions, forming a three dimensional network. PMID- 21587984 TI - 1-Benzyl-3-[(trimethyl-sil-yl)meth-yl]benzimidazolium chloride monohydrate. AB - The title compound, C(18)H(23)N(2)Si(+).Cl(-).H(2)O, was synthesized from 1 [(trimethyl-sil-yl)meth-yl]benzimidazole and benzyl chloride in dimethyl formamide. The benzimidazole ring system is approximately planar, with a maximum deviation of 0.022 (2) A, and makes an angle of 74.80 (12) degrees with the phenyl ring. The crystal packing is stabilized by O-H?Cl, C-H?Cl, C-H?O and C H?pi inter-actions between symmetry-related mol-ecules together with pi-pi stacking inter-actions between the imidazolium and benzene rings [centroid centroid distance = 3.5690 (15) A] and between the benzene rings [centroid centroid distance = 3.7223 (14) A]. PMID- 21587985 TI - N-(4-Methyl-benzo-yl)benzene-sulfonamide. AB - In the title compound, C(14)H(13)NO(3)S, the conformation of the N-H bond in the C-SO(2)-NH-C(O) segment is anti to the C=O bond. The dihedral angle between the sulfonyl benzene ring and the S-N-C-O segment (r.m.s. deviation = 0.039 A) is 77.1 (1) degrees and that between the sulfonyl and benzoyl benzene rings is 71.9 (1) degrees . PMID- 21587986 TI - 4-Chloro-N-(3-chloro-benzo-yl)benzene-sulfonamide monohydrate. AB - In the title compound, C(13)H(9)Cl(2)NO(3)S.H(2)O, the conformation of the C=O bond is syn to the meta-Cl group in the benzoyl ring. The mol-ecules are twisted at the S-N bond with a C-S-N-C torsion angle of 72.9 (2) degrees . The dihedral angle between the sulfonyl benzene ring and the S-NH-C-O segment is 77.8 (1) degrees and that between the sulfonyl and benzoyl benzene rings is 80.5 (1) degrees . In the crystal, mol-ecules are linked into a two-dimensional network parallel to (100) by N-H?O and O-H?O hydrogen bonds. PMID- 21587987 TI - N-Benzyl-carbamothioyl-2-chloro-benzamide. AB - In the title compound, C(15)H(13)ClN(2)OS, the dihedral angles between the sulfourea group and the benzene ring and the chloro-benzene ring are 35.8 (6) and 81.6 (6) degrees respectively. An intra-molecular N-H?O inter-action occurs. In the crystal, a combination of inter-molecular pi-pi stacking inter-actions [centroid-centroid distance = 4.0616 (16) A] and N-H?S hydrogen bonds stabilizes the structure. PMID- 21587988 TI - (E)-N'-[4-(Dimethyl-amino)-benzyl-idene]-2-meth-oxy-benzohydrazide. AB - In the title compound, C(17)H(19)N(3)O(2), the two benzene rings form a dihedral angle of 89.2 (2) degrees . In the crystal structure, mol-ecules are linked through N-H?O hydrogen bonds, forming C(4) chains running along the c axis. PMID- 21587989 TI - 2-[(2-Hy-droxy-4-meth-oxy-benzyl-idene)aza-nium-yl]benzoate monohydrate. AB - In the title compound, C(15)H(13)NO(4).H(2)O, the Schiff base exists in a zwitterionic form and a bifurcated intra-molecular N-H?(O,O) hydrogen bond generates two S(6) rings. The dihedral angle between the two benzene rings is 25.8 (2) degrees . The crystal structure is stabilized by inter-molecular O-H?O hydrogen bonds. PMID- 21587990 TI - 2,4,6-Triphenyl-aniline. AB - Individual mol-ecules of the title compound, C(24)H(19)N, do not participate in hydrogen-bonding inter-actions due to the steric bulk of the phenyl rings ortho to the amine. The dihedral angles between the central ring and the pendant rings are 68.26 (10), 55.28 (10) and 30.61 (11) degrees . PMID- 21587991 TI - (1R,6R,13R,18R)-(Z,Z)-1,18-Bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3,16-dimethyl ene-8,20-diaza-dispiro-[5.6.5.6]tetra-cosa-7,19-diene. AB - The crystal structure of the title compound, C(34)H(54)N(2)O(4), has been solved in order to prove the relative and absolute chirality of the newly-formed stereocentres which were established using an asymmetric Diels-Alder reaction at an earlier stage in the synthesis. This unprecedented stable dialdimine contains a 14-membered ring and was obtained as the minor diastereoisomer in the Diels Alder reaction. The absolute stereochemistry of the stereocentres of the acetal functionality was known to be R based on the use of a chiral (R)-tris-ubstituted dienophile derived from enanti-opure (S)-glyceraldehyde. The assignment of the configuration in the dienophile and the title di-aldimine differs from (S) glyceraldehyde due to a change in the priority order of the substituents. The crystal structure establishes the presence of six stereocentres all attributed to be R. The 14-membered ring contains two aldimine bonds [C-N = 1.258 (2) and 1.259 (2) A]. It adopts a similar conformation to that proposed for trans-trans-cyclo tetra-deca-1,8-dienes. PMID- 21587992 TI - (2E)-1-(6-Chloro-2-methyl-4-phenyl-quinolin-3-yl)-3-phenyl-prop-2-en-1-one. AB - In the title compound, C(25)H(18)ClNO, the conformation about the C=C double bond is E. Significant twists are evident in the mol-ecule, with the benzene ring forming a dihedral angle of 53.92 (11) degrees with the quinolinyl residue. Further, the chalcone residue is approximately perpendicular to the quinolinyl residue [C(q)-C(q)-C(c)-O(c) torsion angle = -104.5 (3) degrees , where q = quinolinyl and c = chalcone]. In the crystal, the presence of C-H?O and C-H?pi inter-actions leads to supra-molecular layers lying parallel to (02). PMID- 21587993 TI - 1-Nitro-4-(2-nitro-prop-1-en-yl)benzene. AB - The asymmetric unit of the title compound, C(9)H(8)N(2)O(4), contains two crystallographically independent mol-ecules, both of which adopt an E configuration about the C=C bond. In the crystal, the mol-ecules stack into columns along the c axis through pi-pi inter-actions, with centroid-centroid distances of 3.695 (3) and 3.804 (3) A. The columns are further connected into a three-dimensional network by C-H?O hydrogen bonds. PMID- 21587994 TI - 4-[(9-Ethyl-9H-carbazol-3-yl)methyl-idene-amino]-1,5-dimethyl-2-phenyl-1H-pyrazol 3(2H)-one. AB - The imino-carbon double bond in the title Schiff base, C(26)H(24)N(4)O, has an E configuration. The 13-membered carbazolyl fused-ring (r.m.s. deviation = 0.056 A) is nearly coplanar with five-membered pyrazole ring (r.m.s. deviation = 0.036 A) [dihedral angle between the two systems = 10.4 (1) degrees ]; the phenyl substituent is twisted by 51.1 (1) degrees with respect to the five-membered ring. PMID- 21587995 TI - N-[4-(Dimethyl-amino)-benzyl-idene]-3,4-dimethyl-isoxazol-5-amine. AB - The aromatic rings attached to the azomethine double bond in the title compound, C(14)H(17)N(3)O, are trans to each other [C-C=N-C torsion angle = 179.5 (1) degrees ], and they are approximately coplanar [dihedral angle between the five- and six-membered rings = 13.7 (1) degrees ]. PMID- 21587996 TI - 4-[2-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl-idene)hydrazin-1-yl]benzo-nitrile. AB - In the title compound, C(13)H(11)N(3)O(4), the dioxane ring adopts an envelope conformation with the C atom bonded to the dimethyl group in the flap position [deviation = 0.613 (1) A]. The nitrile group and the attached benzene ring are roughly coplanar [maximum deviation = 0.087 (1) A]. An intra-molecular N-H?O hydrogen bond involving the hydrazinyl group generates an S(6) ring. The N-N and C-N bond lengths indicate that the compound may be a mixture of the azo and hydrazone tautomeric forms but the presence of the N-bound H atom supports the hydrazone form. The crystal structure is stabilized by weak inter-molecular C H?O, C-H?N and C-H?pi inter-actions. PMID- 21587997 TI - Benz-yl(meth-yl)phosphinic acid. AB - The title compound, C(8)H(11)O(2)P, is a phosphinic compound with a tetra coordinate penta-valent P atom. The phosphinic function plays a predominant role in the cohesion of the crystal structure, both by forming chains along the b axis via strong inter-molecular O-H?O hydrogen bonds and by cross-linking these chains perpendicularly via weak inter-molecular C-H?O hydrogen bonds, generating a two dimensional network parallel to (001). PMID- 21587998 TI - 2-[(3,5-Di-tert-butyl-4-hy-droxy-benz-yl)sulfan-yl]benzoic acid. AB - In the title compound, C(22)H(28)O(3)S, the dihedral angle between the two aromatic rings is 80.56 (6) degrees . The hy-droxy group is shielded by the two sterically hindered tert-butyl groups and therefore is not involved in any hydrogen bonding. The C-O-H fragment is coplanar with the aromatic ring, the dihedral angle between them being 7(5) degrees . In the crystal structure, pairs of mol-ecules are hydrogen bonded across crystallographic centers of symmetry. PMID- 21587999 TI - 3-{2-[2-(Diphenyl-methyl-ene)hydrazin-yl]thia-zol-4-yl}-2H-chromen-2-one. AB - In the title compound, C(25)H(17)N(3)O(2)S, the coumarin ring system is essentially planar with a maximum deviation of 0.019 (2) A. A weak intra molecular C-H?O hydrogen bond stabilizes the mol-ecular structure, so that the coumarin plane is approximately coplanar with the thia-zole ring, making a dihedral angle of 2.5 (10) degrees . The two phenyl rings are nearly perpendicular to each other, with a dihedral angle of 81.44 (12) degrees . In the crystal structure, the mol-ecules are linked into an infinite chain along the b axis by inter-molecular C-H?O hydrogen bonds. Weak C-H?pi inter-actions are observed between the chains. PMID- 21588000 TI - 1,8-Bis(4-chloro-benzo-yl)-7-meth-oxy-naphthalen-2-ol ethanol monosolvate. AB - In the title compound, C(25)H(16)Cl(2)O(4).C(2)H(6)O, the two 4-chloro-benzoyl groups are in syn orientations with respect to the naphthalene ring system and are approximately parallel to each other: the dihedral angle between the benzene rings is 11.43 (16) degrees . The conformation around each of the carbonyl C (C=O)-C groups forms a larger angle to the plane of the naphthalene ring system than that to the benzene ring; the angles of the C=O bond vector with the naphthalene ring system and the benzene ring are 55.4 (3) versus 13.5 (3) degrees and 52.2 (3) versus 17.9 (3) degrees . An intra-molecular O-H?O=C hydrogen bond generates a six-membered ring. In the crystal structure, inter-molecular O-H?O hydrogen bonds including the ethanol solvent mol-ecule are observed. A C-H?O inter-action also occurs. The ethyl group of the ethanol mol-ecule is disordered over two positions with site occupancies of 0.63 and 0.37. The crystal studied was an inversion twin. PMID- 21588001 TI - 2-(4-Fluoro-phen-yl)-1-(4-meth-oxy-phen-yl)-4,5-dimethyl-1H-imidazole. AB - In the title compound, C(18)H(17)FN(2)O, the imidazole ring makes dihedral angles of 76.46 (7) and 40.68 (7) degrees with the meth-oxy-phenyl and fluoro-phenyl rings, respectively. The dihedral angle between the two benzene rings is 71.25 (6) degrees . PMID- 21588002 TI - (Z)-2-Amino-5-[2,4-dimeth-oxy-6-(4-methoxy-styr-yl)benzyl-idene]-1,3-thia-zol 4(5H)-one methanol solvate. AB - In the crystal structure of the title compound, C(21)H(20)N(2)O(4)S.CH(3)OH, mol ecules are linked into chains by a series of inter-molecular N-H?O, N-H?N and O H?O hydrogen bonds. The mol-ecular structure shows a double bond with Z geometry, connecting the thia-zolone and resveratrol units. The dihedral angle between the thiazolone ring and the nearest dimethoxy-benzene ring is 53.02 (7) degrees . PMID- 21588003 TI - (E,E)-1-Methyl-2,6-distyrylpyridinium iodide. AB - In the title compound, C(22)H(20)N(+).I(-), the dihedral angles between the central pyridine ring and two outer benzene rings are 15.30 (10) and 11.82 (11) degrees . There are inter-molecular pi-pi stacking inter-actions between the nearest phenyl ring over an inversion-related pyridyl ring, the shortest centroid centroid distance being 3.672 (3) A. The crystal structure of the compound indicates the 2,6-distyryl substituents have an E configuration. PMID- 21588004 TI - 4-Methyl-anilinium p-toluene-sulfonate. AB - The crystal structure of the title compound, C(7)H(10)N(+).C(7)H(7)O(3)S(-), displays strong N-H?O and N-H?S hydrogen bonding between the ammonium group and the p-toluene-sulfonate anion, linking the cations and anions into chains along the b axis. PMID- 21588005 TI - Neoirietriol. AB - The title compound {systematic name: (1R,4S,4aS,7R,8aR)-4-bromo-7-[(1S,3R)-3 bromo-1,2,2-trimethyl-cyclo-pent-yl]-1,4a-dimethyl-deca-hydro-naphthalene-1,7,8a triol}, C(20)H(34)Br(2)O(3), is a neoirieane-type bromo-diterpenoid isolated from Laurencia yonaguniensis Masuda et Abe, species inedita. The absolute stereochemistry was established as (1S,4R,5R,7R,10S,11S,14R). The structure displays inter- and intra-molecular O-H?O hydrogen bonding. PMID- 21588006 TI - 8-[(1E)-1-(2-Aminophenyl-iminio)eth-yl]-2-oxo-2H-chromen-7-olate. AB - The title Schiff base, C(17)H(14)N(2)O(3), exists as an NH tautomer with the H atom of the phenol group transferred to the imine N atom. The iminium H atom is involved in a strong intra-molecular N(+)-H?O(-) hydrogen bond to the phenolate O atom, forming an S(6) motif. In the crystal structure, N-H?O hydrogen bonds form a C(9) chain parallel to [100] and a C(11) chain parallel to [010], while C-H?O hydrogen bonds form a C(11) chain parallel to [010]. The combination of N-H?O and C-H?O hydrogen bonds generates R(4) (3)(30) rings parallel to the ab plane. PMID- 21588007 TI - 1,5-Dimethyl-3-propargyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione. AB - The asymmetric unit of the title compound, C(14)H(14)N(2)O(2), comprises two independent mol-ecules, which slightly differ in the orientation of the propargyl chain. In both molecules, the diazepine ring adopts a boat conformation with the propargyl-bearing C atom as the prow and the C atoms at the ring junction as the stern. The carbonyl O atom of one independent mol-ecule is hydrogen bonded to the acetyl-enic H atom of the other independent mol-ecule. In the crystal, symmetry related mol-ecules are linked together by C-H?O hydrogen bonds, forming a ribbon like structure along the c axis. PMID- 21588008 TI - 2',3,4,4'-Tetra-meth-oxy-chalcone. AB - IN THE TITLE COMPOUND [SYSTEMATIC NAME: 1-(2,4-dimethoxyphenyl)-3-(3,4 dimethoxyphenyl)prop-2-en-1-one], C(19)H(20)O(5), the dihedral angle between the benzene rings is 26.88 (5) degrees . One of the meth-oxy groups is twisted slightly away from the plane [C-O-C-C torsion angle = -12.8 (3) degrees ] while the others are almost co-planer [C-O-C-C torsion angles = -3.2 (3), 2.6 (3) and 3.6 (3) degrees ]. The crystal packing is stabilized by inter-molecular C-H?O inter-actions. A weak intra-molecular C-H?O inter-action occurs. PMID- 21588009 TI - 2-(Bicyclo-[2.2.1]hept-5-en-2-yl)-1H-pyrrolo-[2,3-b]pyridine. AB - The crystal structure of the title compound, C(14)H(14)N(2), displays inter molecular N-H?N hydrogen bonds, forming dimers of enanti-omeric mol-ecules via a crystallographic centre of inversion. PMID- 21588010 TI - 3-Methyl-quinoxaline-2-carb-oxy-lic acid 4-oxide monohydrate. AB - In the crystal structure of the title compound, C(10)H(8)N(2)O(3).H(2)O, mol ecules are linked via inter-molecular O-H?O and O-H?N hydrogen bonds into a two dimensional network. PMID- 21588011 TI - 4,5-Diaza-9H-fluoren-9-imine. AB - In the title compound, C(11)H(7)N(3), the diaza-fluorene rings are almost coplanar with an r.m.s. deviation of 0.0160 A. In the crystal structure, C-H?N hydrogen bonds link mol-ecules into sheets parallel to the ab plane. Mol-ecules are also stacked regularly along the c axis by a variety of pi-pi inter-actions with centroid-centroid distances in the range 3.527 (2)-3.908 (2) A. PMID- 21588012 TI - N-(3-Butyl-4-oxo-1,3-thia-zolidin-2-yl-idene)benzamide. AB - In the title compound, C(14)H(16)N(2)O(2)S, the thia-zolidine ring is planar [maximum atomic deviation = 0.0080 (14) A] and twisted slightly with respect to the phenyl ring, making a dihedral angle of 4.46 (14) degrees . The butyl group displays an extended conformation, with a torsion angle of 169.4 (4) degrees . In the crystal structure, weak inter-molecular C-H?O hydrogen bonds link the mol ecules, forming supra-molecular chains. PMID- 21588013 TI - N-(4,5-Diaza-9H-fluoren-9-yl-idene)-4-meth-oxy-aniline. AB - In the title compound, C(18)H(13)N(3)O, the diaza-fluorene ring system is almost coplanar (r.m.s. deviation = 0.0640 A) and subtends an angle of 61.5 (4) degrees with the plane of the meth-oxy-substituted benzene ring. In the crystal structure, pairs of C-H?O hydrogen bonds link mol-ecules into centrosymmetric dimers parallel to the ab plane. Mol-ecules are also stacked in an obverse fashion along the c axis by a variety of pi-pi inter-actions with centroid centroid distances in the range 3.557 (2)-3.921 (2) A. PMID- 21588014 TI - (E)-N'-(5-Bromo-2-hy-droxy-benzyl-idene)-3-meth-oxy-benzohydrazide. AB - In the title compound, C(15)H(13)BrN(2)O(3), the two benzene rings form a dihedral angle of 16.9 (2) degrees . An intra-molecular O-H?N hydrogen bond affects the mol-ecular conformation. In the crystal structure, mol-ecules are linked through N-H?O hydrogen bonds into chains running along the a axis. PMID- 21588015 TI - 1,4-Dibromo-2,5-dimeth-oxy-benzene. AB - The asymmetric unit of the title compound, C(8)H(8)Br(2)O(2), contains one half mol-ecule, the complete mol-ecule being generated by inversion symmetry. PMID- 21588016 TI - 2,3-Diphenyl-quinoxalin-1-ium chloride. AB - The title compound, C(20)H(15)N(2) (+).Cl(-), was prepared by the reaction of benzil with o-phenyl-enediamine in refluxing ethanol and then crystallized in 5% hydro-chloric acid. The two phenyl rings are oriented at dihedral angles of 50.93 (8) and 50.28 (8) degrees with respect to the quinoxalin-1-ium ring system. The dihedral angle between the two phenyl rings is 56.71 (10) degrees . In the crystal, the cations and anions are linked by N-H?Cl and C-H?Cl inter-actions, forming chains along the b axis. PMID- 21588017 TI - (3E)-3-[4-(Dimethyl-amino)-phen-yl]-1-(4-hy-droxy-phen-yl)prop-2-en-1-one. AB - The asymmetric unit of the title compound, C(17)H(17)NO(2), contains two crystallographically independent mol-ecules. Both mol-ecules adopt a trans configuration about the C=C bond, with the C-C=C-C fragments in the two mol ecules twisted in opposite directions [torsion angles of 174.2 (2) and -175.8 (2) degrees ]. The two benzene rings in each of the mol-ecules make dihedral angles of 20.21 (6) and 48.64 (4) degrees . In the crystal, adjacent mol-ecules are linked by O-H?O hydrogen bonds into infinite polymeric chains. PMID- 21588018 TI - N-(3,4-Difluoro-phen-yl)phthalimide. AB - In the title compound, C(14)H(7)F(2)NO(2), the phthalimide ring system is nearly planar [maximum atomic deviation = 0.028 (1) A] and it is twisted with respect to the attached benzene ring, making a dihedral angle of 55.70 (6) degrees . Weak inter-molecular C-H?F hydrogen bonds are present in the crystal structure. PMID- 21588019 TI - N-[3-Chloro-4-(3-fluoro-benz-yloxy)phen-yl]-6-iodo-quinazolin-4-amine. AB - In the title mol-ecule, C(21)H(14)ClFIN(3)O, the bicyclic ring system has a twisted conformation; the two fused rings form a dihedral angle of 4.5 (1) degrees . The dihedral angles between the fused ring system and the benzene rings are 27.3 (6) and 5.3 (5) degrees while the dihedral angle between the benzene rings is 22.0 (5) degrees . In the crystal structure, weak inter-molecular N-H?N hydrogen bonds link the mol-ecules into chains propagating in [100]. A short inter-molecular distance of 3.806 (3) A between the centroids of the fluorobenzene and iodobenzene rings suggests the existence of pi-pi stacking inter-actions. PMID- 21588020 TI - 6-(4-Amino-phen-yl)-2-eth-oxy-4-(2-thien-yl)nicotinonitrile. AB - In the title nicotinonitrile derivative, C(18)H(15)N(3)OS, the central pyridyl ring makes dihedral angles of 25.22 (10) and 24.80 (16) degrees with the 4-amino phenyl and thio-phene rings, respectively. The thio-phene ring is disordered over two orientations by rotation around the C(thio-phene)-C(pyridine) bond; the occupancies are 0.858 (2) and 0.142 (2). The eth-oxy group is slightly twisted from the attached pyridyl ring [C-O-C-C torsion angle = 171.13 (16) degrees ]. In the crystal structure, mol-ecules are linked by N-H?N hydrogen bonds into chains along [010]. These chains are stacked along the a axis. C-H?pi weak inter-actions involving the thio-phene ring are observed. PMID- 21588021 TI - 3-(4-Fluoro-phenyl-sulfon-yl)-2,5,7-trimethyl-1-benzofuran. AB - In the title compound, C(17)H(15)FO(3)S, the 4-fluoro-phenyl ring makes a dihedral angle of 72.67 (5) degrees with the benzofuran plane. In the crystal, mol-ecules are linked by weak inter-molecular C-H?O hydrogen bonds. PMID- 21588022 TI - 3-Ethyl-sulfinyl-5-iodo-2-phenyl-1-benzofuran. AB - In the title compound, C(16)H(13)IO(2)S, the phenyl ring is rotated out of the benzofuran plane, as indicated by the dihedral angle of 32.56 (6) degrees . The crystal structure is stabilized by an I?O halogen inter-action [3.200 (2) A]. PMID- 21588023 TI - 2,6-Di(pyrrolidin-1-yl)pyridinium chloride monohydrate. AB - In the organic cation of the title compound, C(13)H(20)N(3) (+).Cl(-).H(2)O, the two pyrrolidine rings adopt twisted conformations. The pyridine ring makes dihedral angles of 14.57 (6) and 23.96 (6) degrees with the mean planes of the pyrrolidine rings. In the crystal structure, pairs of bifurcated inter-molecular O-H?Cl hydrogen bonds link the water mol-ecules and chloride anions into an R(4) (4)(8) ring motif. Inter-molecular N-H?Cl, C-H?Cl and C-H?O hydrogen bonds further inter-connect these rings with the organic cations into a two-dimensional network parallel to the bc plane. PMID- 21588024 TI - (E)-2,3-Dimethyl-N-(2-nitro-benzyl-idene)aniline. AB - In the title compound, C(15)H(14)N(2)O(2), the 2,3-dimethyl-anilinic and benzaldehyde groups are planar, with r.m.s. deviations of 0.0101 and 0.0241 A, respectively, and are oriented at a dihedral angle of 11.69 (3) degrees . The nitro group is inclined to the benzaldehyde group by 34.02 (9) degrees . The mol ecule adopts an E configuration about the C=N bond. In the crystal, mol-ecules are linked via C-H?O inter-actions, giving rise to the formation of zigzag polymeric chains extending along [010]. They are also linked by C-H?pi, and pi-pi inter-actions [centroid-centroid distance of 3.7185 (11) A] involving symmetry related aniline and benzene rings. The H atoms of the ortho-methyl group are disordered over two sites with a refined occupancy ratio of 0.69 (2):0.31 (2). PMID- 21588025 TI - (R)-4-Phenyl-2-[(S)-1,2,3,4-tetra-hydro-isoquinolin-3-yl]-4,5-dihydro-1,3 oxazole. AB - The asymmetric unit cell of the title compound, C(18)H(18)N(2)O, contains four molecules. In the crystal structure, an inter-molecular N-H?N hydrogen bond helps to establish the packing. PMID- 21588026 TI - Methyl 5-chloro-2-[N-(3-eth-oxy-carbonyl-prop-yl)-4-methyl-benzene-sulfonamido] benzoate. AB - In the title compound, C(21)H(24)ClNO(6)S, the benzene rings are oriented at a dihedral angles of 41.6 (2) degrees . In the crystal structure, weak inter molecular C-H?O inter-actions link the mol-ecules. PMID- 21588027 TI - Benzamide-picric acid (1/1). AB - In the title compound, C(7)H(7)NO.C(6)H(3)N(3)O(7), one of the nitro groups of the picric acid mol-ecule lies in the plane of the attached benzene ring [dihedral angle = 1.4 (1) degrees ] while the other two are twisted away by 9.9 (1) and 30.3 (1) degrees . In the benzamide mol-ecule, the amide group is almost coplanar with the benzene ring [dihedral angle = 4.4 (1) degrees ]. An intra molecular O-H?O hydrogen bond generates an S6 ring motif. In the crystal, mol ecules are linked into a ribbon-like structure along the b axis by O-H?O and N H?O inter-molecular hydrogen bonds. In addition, C-H?O hydrogen bonds and short O?O contacts [2.828 (2) A] are observed. PMID- 21588029 TI - 3-[(3S)-3-Ethyl-1-methyl-azepan-3-yl]phenyl N-(4-fluoro-phen-yl)carbamate. AB - The asymmetric unit of the title compound, C(22)H(27)FN(2)O(2), a (-)-S meptazinol derivative, contains two mol-ecules. The azepane ring adopts a similar twist chair form in both mol-ecules, while the dihedral angles between the two benzene rings are 88.17 (14) and 89.93 (14) degrees in the two mol-ecules. The absolute configuration of the mol-ecule was determined from the synthetic starting material. The crystal structure is stabilized by classical inter molecular N-H?O hydrogen bonds. PMID- 21588028 TI - 2-Amino-pyridinium picrate. AB - In the title compound, C(5)H(7)N(2) (+).C(6)H(2)N(3)O(7) (-), there are two crystallographically independent cations and anions (A and B) in the asymmetric unit. In both picrate anions, one of the nitro groups lies in the plane of the benzene ring [r.m.s. deviations = 0.014 (2) and 0.014 (2) A for anions A and B, respectively] and the other two are twisted away by 39.0 (2) and 18.8 (2) degrees in A, and 18.2 (1) and 2.5 (2) degrees in B. In the crystal, the cations and anions are linked by inter-molecular N-H?O and C-H?O hydrogen bonds, forming a two-dimensional network. PMID- 21588030 TI - 2-Chloro-7-methyl-12-phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-one. AB - In the title compound, C(23)H(15)ClN(2)O, the fused ring system is planar: the deviation of all the non-H atoms from the plane through all four fused rings is less than 0.31 A. The plane of the phenyl ring is inclined at 71.78 (5) degrees to the mean plane of the 1,8-naphthrydine ring system. The crystal structure is devoid of any classical hydrogen bonds but pi-pi inter-actions are present. PMID- 21588031 TI - Ethyl 1-(2-hy-droxy-eth-yl)-2-phenyl-1H-benzimidazole-5-carboxyl-ate. AB - There are two mol-ecules in the asymmetric unit of the title compound, C(18)H(18)N(2)O(3). In each one, the benzimidazole ring system is essentially planar, with maximum deviations of 0.027 (1) and 0.032 (1)A, and makes dihedral angles of 38.64 (6) and 41.48 (6) degrees , respectively, with the attached benzene rings. An intra-molecular C-H?O hydrogen bond is observed in each mol ecule. The two independent mol-ecules are connected into a dimer by two inter molecular O-H?N hydrogen bonds. In the crystal, mol-ecules form a two-dimensional layers parallel to (012) via weak inter-molecular C-H?O hydrogen bonds. In addition, weak pi-pi stacking inter-actions are observed with centroid-centroid distances of 3.5244 (12) and 3.6189 (12) A. PMID- 21588032 TI - A monoclinic modification of 2-[(1,3-benzothia-zol-2-yl)imino-meth-yl]phenol. AB - In the title Schiff base, C(14)H(10)N(2)OS, the azomethine double bond is in an E configuration; the benzothiazolyl ring (r.m.s. deviation = 0.007 A) is coplanar with the phenyl-ene ring (r.m.s. deviation = 0.007 A), the two rings being slightly bent at 2.6 (1) degrees . The hy-droxy H atom forms an intra-molecular hydrogen bond to the imino group. The bond dimensions of the monoclinic modification are similar to those of the ortho-rhom-bic modification [Liu et al. (2009 ?). Acta Cryst. E65, o738]. PMID- 21588034 TI - 2-Chloro-4-nitro-1H-imidazole. AB - The mol-ecule of the title compound, C(3)H(2)ClN(3)O(2), is almost planar; the dihedral angle between the imidazole ring and the nitro group is 1.7 (2) degrees . In the crystal structure, pairs of inter-molecular C-H?O hydrogen bonds link inversion-related mol-ecules into dimers, generating R(2) (2)(10) ring motifs. The dimers are inter-connected into two-dimensional networks parallel to (102) via inter-molecular N-H?N hydrogen bonds. Further stabilization is provided by short inter-molecular Cl?O inter-actions [3.142 (2) and 3.1475 (19) A]. PMID- 21588033 TI - 2-{3-[1-(3,4-Dichloro-phen-yl)eth-yl]-1,3-thia-zolidin-2-yl-idene}malononitrile. AB - In the title compound, C(14)H(11)Cl(2)N(3)S, the thia-zole ring is in an envelope conformation with the -CH(2)- group bonded to the S atom forming the flap. The crystal structure is stabilized by weak inter-molecular C-H?Cl and C-H?N hydrogen bonds. PMID- 21588036 TI - 1,3,3-Trimethyl-1,2,3,4-tetra-hydro-pyrido[1,2-a]benzimidazol-1-ol. AB - In the title compound, C(14)H(18)N(2)O, the benzimidazole grouping is close to planar, with a maximum deviation of 0.042 A; the six-membered non-aromatic ring adopts an envelope conformation. In the crystal structure, mol-ecules are linked into infinite sheets lying parallel to the bc plane by O-H?N and C-H?O hydrogen bonds. PMID- 21588035 TI - 2,3-Dimethyl-6-nitro-quinoxaline. AB - The asymmetric unit of the title quinoxaline compound, C(10)H(9)N(3)O(2), contains two crystallographically independent mol-ecules (A and B). The quinoxaline ring systems are essentially planar, with maximum deviations of 0.006 (1) and 0.017 (1) A, respectively, for mol-ecules A and B. In mol-ecule A, the dihedral angle formed between the quinoxaline ring system and nitro group is 10.94 (3) degrees [6.31 (13) degrees for mol-ecule B]. In the crystal, mol ecules are linked into chains propagating along [001]: one forms zigzag chains linked by C-H?O hydrogen bonds, whilst the other forms ladder-like chains by way of C-H?N and C-H?O hydrogen bonds. The packing is further consolidated by weak pi pi inter-actions [range of centroid-centroid distances = 3.5895 (7)-3.6324 (7) A]. PMID- 21588037 TI - Tris(2-benzamido-eth-yl)ammonium tetra-fluoro-borate. AB - In the title compound, C(27)H(31)N(4)O(3) (+).BF(4) (-), the central N atom is protonated. The three arms form a pocket and one amidic O atom accepts an inter molecular hydrogen bond with the protonated amine. The tetra-fluoro-borate anion is outside the cavity and is hydrogen bonded to one amide N atom. Adjacent organic cations are connected by a pair of N-H?O hydrogen bonds, forming a chain. PMID- 21588038 TI - 8-Methyl-2-[4-(trifluoro-meth-yl)phen-yl]-8H-pyrazolo-[4,3-e][1,2,4]triazolo[1,5 c]pyrimidin-5-amine methanol disolvate. AB - In the title compound, C(14)H(10)F(3)N(7).2CH(4)O, the heterocyclic ring system is essentially planar (r.m.s. deviation = 0.009 A) and makes a dihedral angle of 6.91 (8) degrees with the attached benzene ring. In the crystal, the main mol ecules form centrosymmetric R(2) (2)(8) dimers via pairs of N-H?N hydrogen bonds between the amino groups and pyrimidine N atoms. One of the independent methanol mol-ecules and its inversion equivalent are linked to the dimers via O-H?N and N H?O hydrogen bonds, forming R(4) (4)(16) graph-set motifs. The dimers along with the hydrogen-bonded methanol mol-ecules are stacked along the a axis, with pi-pi inter-actions between the pyrazole and triazole rings [centroid-centroid distance = 3.4953 (10) A]. PMID- 21588039 TI - (E)-7-(Pyren-1-yl)hept-6-enoic acid. AB - The title compound, C(23)H(20)O(2), is a precursor of a pyrene-based supra molecular element for non-covalent attachment to a carbon nanotube. The asymmetric unit contains three independent mol-ecules. The carb-oxy-lic acid group in each of these mol-ecules serves as an inter-molecular hydrogen-bond donor and acceptor, generating the commonly observed double O-H?O hydrogen-bond motif in an eight-membered ring. Weaker C-H?O, pi-pi [centroid-centroid distance = 3.968 (4) A] and C-H?pi inter-actions are also found in the crystal structure. PMID- 21588040 TI - (1R,3S,4R,4aS,7R,7aS,10R,12aR)-3-Azido-4,7,10-trimethyl-1,10-epidioxy-per hydropyrano[4,3-j][1,2]benzodiox-epine. AB - In the title compound, C(15)H(23)N(3)O(4), the six-membered pyran, cyclo-hexane and trioxane rings adopt chair, chair and boat conformations, respectively, while the seven-membered rings adopt distorted boat and very distorted chair conformations. In the crystal, adjacent mol-ecules are connected by weak C-H?N and C-H?O inter-actions. PMID- 21588041 TI - 1,3-Bis(3,5-dimethyl-phen-yl)-5-methyl-benzene. AB - In the title compound, C(23)H(24), the dihedral angles formed by the central benzene ring with the peripheral benzene rings are 29.90 (5) and 34.95 (5) degrees . The crystal packing is stabilized by pi-pi stacking inter-actions with centroid-centroid distances of 3.815 (4) A. PMID- 21588042 TI - 2-Amino-5-methyl-pyridinium 4-carb-oxy-butano-ate. AB - In the title salt, C(6)H(9)N(2) (+).C(5)H(7)O(4) (-), the 2-amino-5-methyl pyridinium cation is essentially planar, with a maximum deviation of 0.008 (1) A. In the crystal, the protonated N atom and the 2-amino group are hydrogen bonded to the carboxyl-ate O atoms via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The 4-carb-oxy-butano-ate anions are linked via O-H?O hydrogen bonds. The crystal structure is further stabilized by weak C-H?O inter-actions. PMID- 21588043 TI - 2-Amino-4-methyl-pyridinium 3-chloro-benzoate. AB - In the title salt, C(6)H(9)N(2) (+).C(7)H(4)ClO(2) (-), the 2-amino-4-methyl pyridinium cation is almost planar, with a maximum deviation of 0.010 (1) A. In the crystal, the protonated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The ion pairs are further connected via N-H?O and C-H?O hydrogen bonds, forming a two-dimensional network parallel to the bc plane. PMID- 21588044 TI - 2,2,4-Trimethyl-7-nitro-2,3-dihydro-1H-1,5-benzodiazepin-5-ium perchlorate. AB - In the title mol-ecular salt, C(12)H(16)N(3)O(2) (+).ClO(4) (-), the nitro group is close to being coplanar with the benzene ring [dihedral angle = 8.1 (3) degrees ]. The seven-membered ring has a maximum deviation of 0.502 (3) A at the C atom between the dimethyl- and methyl-substituted C atoms. In the crystal, the components are linked into infinite sheets lying parallel to the bc plane by N H?O and C-H?O hydrogen bonds. A short O?N contact of 2.896 (4) A occurs within the sheets and a short O?O contact of 2.608 (4) A occurs between the sheets. PMID- 21588045 TI - 2,3,6,7-Tetra-kis(bromo-meth-yl)naphthalene. AB - The title compound, C(14)H(12)Br(4), crystallizes with imposed inversion symmetry. In the crystal, the mol-ecules pack in layers parallel to (10). The layers involve two Br?Br and one H?Br contact. Between the layers, one contact each of types Br?Br, H?Br and Br?pi is observed. PMID- 21588046 TI - rac-5-Acetyl-6-hy-droxy-3,6-dimethyl-4-phenyl-2H-4,5,6,7-tetra-hydro-indazol-1 ium chloride. AB - The structure of the title compound, C(17)H(21)N(2)O(2) (+).Cl(-), is of inter est with respect to its biological activity. The title compound comprises an organic cation and a chloride anion in the asymmetric unit. The positive charge is localized in a pyrazole moiety forming a pyrazolium cation. The structure displays inter-molecular O-H?Cl and N-H?Cl hydrogen bonding. PMID- 21588047 TI - 3-Methyl-N-(2-methyl-phen-yl)benzamide. AB - The mol-ecular structure of the title compound, C(15)H(15)NO, involves an intra molecular C-H?O hydrogen bond. The central amide group -NH-C(=O)- is twisted by 37.95 (12) degrees out of the meta-substituted benzoyl ring and by 37.88 (12) degrees out of the ortho-substituted aniline ring. The two benzene rings are inclined to one another at only 4.2 (1) degrees having an inter-planar spacing of ca 0.90 A. The crystal structure is stabilized by inter-molecular N-H?O hydrogen bonds, which link the mol-ecules into chains running along the b axis. A weak inter-molecular C-H?pi inter-action is also present. PMID- 21588048 TI - N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide-naphthalene 2,3-diol (1/1). AB - In the reaction of naphthalene-2,3-diol and 4-amino-anti-pyrine in the presence of acetic acid, the amine function is acetyl-ated and the resulting acetamide co crystallizes with the diol in the title compound, C(13)H(15)N(3)O(2).C(10)H(8)O(2), with 1:1 molar stoichiometry. The two components are linked by two O-H?O=C hydrogen bonds. One of the hy-droxy groups inter-acts with the pyrazolone carbonyl O atom and the other hy-droxy group inter acts with the amide O atom of another component, generating a chain motif. Adjacent chains are linked into a layer motif via N-H?O inter-actions involving only the heterocyclic acetamide component. PMID- 21588049 TI - 1,3-Diallyl-1H-anthra[1,2-d]imidazole-2,6,11(3H)-trione. AB - In the title compound, C(21)H(16)N(2)O(3), the fused-ring system (r.m.s. deviation = 0.067 A) is slightly buckled at the carbonyl C atom of the anthracenyl ring system [deviation = 0.177 (1) A] that is closer to an allyl substituent. The two allyl units lie on the same side of the fused-ring plane but are oriented in opposite directions, with N-C-C-C torsion angles of 126.9 (2) and 116.7 (2) degrees . In the crystal, the mol-ecules are linked into chains propagating along the b axis by C-H?O hydrogen bonds. PMID- 21588050 TI - 2-Hy-droxy-5-nitro-N-phenyl-benzamide. AB - The mol-ecule of the title compound, C(13)H(10)N(2)O(4), is almost planar with a dihedral angle between the benzene rings of 1.99 (13) degrees . The nitro group and its parent benzene ring are oriented at a dihedral angle of 7.6 (3) degrees . Intra-molecular C-H?O and N-H?O hydrogen bonds form two planar S(6) motifs. Inter molecular O-H?O=C hydrogen bonds join mol-ecules into chains extending along the c axis. PMID- 21588051 TI - 6,7-Dihydro-3H-1,4-diazepino[1,2,3,4-lmn][1,10]phenanthroline-3,9(5H)-dione. AB - In the title compound, C(15)H(12)N(2)O(2), the seven-membered ring bearing the three methyl-ene C atoms displays a puckered conformation, with the methyl-ene C atoms deviating from the plane of the benzene ring by 0.05 (1), 0.98 (1) and 1.04 (1) A. The phenanthroline unit is not planar; the dihedral angles between this benzene ring and the other pyridyl rings are 9.62 (4) and 9.31 (4) degrees . The crystal packing is stabilized by pi-pi inter-actions between two phenanthroline ring systems, forming a centrosymmetric dimer with a centroid-centroid distance of 3.656 (1) A. PMID- 21588052 TI - 3-(2-Amino-eth-yl)-2-[4-(trifluoro-meth-oxy)anilino]quinazolin-4(3H)-one. AB - In the title compound, C(17)H(15)F(3)N(4)O(2), the dihedral angle between the trifluoro-meth-oxy-substituted benzene ring and the pyrimidinone ring is 45.1 (5) degrees , while that between the fused benzene ring and the pyrimidinone ring is 0.67 (1) degrees . Part of one of the benzene rings and its trifluoro-meth-oxy substituent are disordered over two positions of approximately equal occupancy (0.51:0.49). Inter-molecular N-H?O and N-H?N hydrogen bonds contribute to the stability of the crystal structure. A weak intra-molecular C-H?F contact is also found. In addition, pi-pi stacking inter-actions, with centroid-centroid distances in the range 3.673 (6)-3.780 (8) A, and weak C-H?pi inter-actions are also observed. PMID- 21588053 TI - 3-Fluoro-4-(4-hy-droxy-phen-oxy)benzonitrile. AB - The title compound, C(13)H(8)FNO(2), was synthesized from 3,4-difluoro benzonitrile and hydro-quinone. The dihedral angle between the two aromatic rings is 70.9 (2) degrees . In the crystal structure, mol-ecules are linked by O-H?N hydrogen bonds, forming zigzag chains. PMID- 21588054 TI - Methyl 2-[(4-chloro-2-meth-oxy-5-oxo-2,5-dihydro-furan-3-yl)amino]-acetate. AB - The title compound, C(8)H(10)ClNO(5), was obtained via a tandem Michael addition elimination reaction of 3,4-dichloro-5-meth-oxy-furan-2(5H)-one and glycine methyl ester in the presence of triethyl-amine. The mol-ecular structure contains an approximately planar [maximum atomic deviation = 0.010 (2) A] five-membered furan-one ring. The crystal packing is stabilized by inter-molecular N-H?O and weak C-H?O hydrogen bonding. PMID- 21588055 TI - 1,3-Bis(4-meth-oxy-benz-yl)-6-methyl-pyrimidine-2,4(1H,3H)-dione. AB - The title compound, C(21)H(22)N(2)O(4), was prepared by reaction of 6-methyl pyrimidine-2,4(1H,3H)-dione and 1-chloro-methyl-4-meth-oxy-benzene. In the title mol-ecule, the central pyrimidine ring forms dihedral angles of 62.16 (4) and 69.77 (3) degrees with the two benzene rings. In the crystal, weak inter molecular C-H?O hydrogen bonds link the mol-ecules into chains. PMID- 21588056 TI - N-(2,3,4-Trifluoro-phen-yl)phthalimide. AB - In the title compound, C(14)H(6)F(3)NO(2), the benzene ring and the phthalimide ring system make a dihedral angle of 60.12 (7) degrees . Weak inter-molecular C H?O and C-H?F hydrogen bonds are present in the crystal structure. PMID- 21588057 TI - 2,6-Bis(3-fluoro-phen-yl)-3-isopropyl-piperidin-4-one. AB - In the title compound, C(20)H(21)F(2)NO, the piperidine ring in each of the two independent mol-ecules in the asymmetric unit adopts a normal chair conformation with an equatorial orientation of the 3-fluoro-phenyl groups. The dihedral angles between the two 3-fluoro-phenyl rings are 49.89 (7) and 50.35 (7) degrees in the two mol-ecules. PMID- 21588058 TI - 1-Diphenyl-methyl-4-ethyl-piperazine-1,4-diium dichloride. AB - In the title compound, C(19)H(26)N(2) (2+).2Cl(-), the piperazinediium ring exhibits a chair conformation. The dihedral angle between the two benzene ring planes is 76.45 (13) degrees . Both amine-group H atoms participate in hydrogen bonding with the two Cl atoms. PMID- 21588059 TI - 3-Ethyl-sulfinyl-5-fluoro-2-(4-iodo-phen-yl)-1-benzofuran. AB - In the title compound, C(16)H(12)FIO(2)S, the 4-iodo-phenyl ring is rotated slightly out of the benzofuran plane, as indicated by the dihedral angle of 11.41 (7) degrees . The crystal structure is stabilized by an inter-molecular pi-pi inter-action between the benzene and 4-iodo-phenyl rings [centroid-centroid distance = 3.757 (3) A]. The crystal structure also exhibits a weak inter molecular C-H?O hydrogen bond and a short I?O [3.2575 (16) A] contact. PMID- 21588060 TI - 3,3-Bis[(4-chloro-phen-yl)sulfan-yl]-1-methyl-piperidin-2-one. AB - The piperidone ring in the title compound, C(18)H(17)Cl(2)NOS(2), has a distorted half-chair conformation. The S-bound benzene rings are approximately perpendicular to and splayed out of the mean plane through the piperidone ring [dihedral angles = 71.86 (13) and 46.94 (11) degrees ]. In the crystal, C-H?O inter-actions link the mol-ecules into [010] supra-molecular chains with a helical topology. C-H?Cl and C-H?pi inter-actions are also present. PMID- 21588061 TI - 3,9-Bis(2,4-dichloro-phen-yl)-2,4,8,10-tetra-oxaspiro-[5.5]undeca-ne. AB - In the title compound, C(19)H(16)Cl(4)O(4), the two halves of the mol-ecule are related by a crystallographic twofold rotation axis passing through the central spiro-C atom. The two non-planar six-membered heterocycles both adopt chair conformations, and the dihedral angle between the two benzene rings is 76.6 (1) degrees . In the crystal structure, inter-molecular C-H?O hydrogen bonds link the mol-ecules into chains along the c axis. PMID- 21588062 TI - p-Phenyl-enedimethanaminium dibromide. AB - In the title salt, C(8)H(14)N(2) (2+).2Br(-), the cation has a crystallographically imposed centre of symmetry. The compound is isostructural with the chloride analogue. In the crystal structure, the cations and anions are connected via N-H?Br hydrogen bonds, forming layers parallel to the bc plane. PMID- 21588063 TI - 4-(4-Meth-oxy-phen-yl)-2-methyl-but-3-yn-2-ol. AB - The mol-ecular structure of the title compound, C(12)H(14)O(2), features a nearly coplanar arrangement including the aromatic ring, the C C-C group and the ether O atom. The maximum deviation from the least-squares plane of these ten atoms is 0.0787 (8) A for the ether O atom. In the crystal, mol-ecules are connected via O H?O hydrogen bonds (involving the hy-droxy O atom both as hydrogen-bond donor and acceptor) and weaker (ar-yl)C-H?pi(ar-yl) contacts, leading to the formation of strands running parallel to the b axis. Further stabilization results from weaker (meth-yl)C-H?pi(acetyl-ene) inter-actions between different strands. PMID- 21588064 TI - N-{2-Methyl-5-[(5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-2-yl)amino]-phen yl}benzamide. AB - In the title compound, C(29)H(24)N(2)O(2), the two aromatic rings of the tricyclic unit are oriented at a dihedral angle of 32.27 (8) degrees . In the crystal N-H?O hydrogen bonds link the mol-ecules into chains along the a axis. Further N-H?.O inter-actions link the chains. PMID- 21588065 TI - 2-(7-Meth-oxy-1-naphth-yl)acetonitrile. AB - The mol-ecule of the title compound, C(13)H(11)NO, is almost planar (r.m.s. deviation = 0.013 A), apart from the cyanide group, for which the C and N atoms deviate from the mean plane of the other atoms by 0.341 (3) and 0.571 (4) A, respectively. In the crystal, weak aromatic pi-pi stacking [centroid-centroid distance = 3.758 (3) A] may help to stabilize the structure. PMID- 21588066 TI - Methyl 2,6-bis-[(5-chloro-4,6-dimeth-oxy-pyrimidin-2-yl)-oxy]benzoate. AB - In the title compound, C(20)H(18)Cl(2)N(4)O(8), the two pyrimidine rings are inclined at dihedral angles of 66.68 (5) and 71.91 (6) degrees with respect to the central benzene ring. In the crystal structure, inter-molecular C-H?N hydrogen bonds link neighbouring mol-ecules into a ribbon-like structure along the b axis. The ribbons are inter-connected into a two-dimensional network parallel to the bc plane by short inter-molecular Cl?Cl [3.4427 (6) A] and Cl?O [3.1420 (9) and 3.1750 (11) A] inter-actions. The crystal structure is further stabilized by inter-molecular pi-pi inter-actions [centroid-centroid distance 3.4552 (8) A] involving the pyrimidine rings. PMID- 21588067 TI - Methyl 2,6-bis-[(5-bromo-4,6-dimeth-oxy-pyrimidin-2-yl)-oxy]benzoate. AB - In the title compound, C(20)H(18)Br(2)N(4)O(8), the inter-planar angle of the pyrimidine rings is 75.1 (2) degrees . The central benzene ring is inclined at inter-planar angles of 66.5 (2) and 71.9 (2) degrees with respect to the two pyrimidine rings. In the crystal structure, adjacent mol-ecules are connected into two-mol-ecule-thick arrays parallel to the bc plane via short Br?Br [3.5328 (12) A] and Br?O [3.206 (3) and 3.301 (4) A] inter-actions. A weak inter molecular pi-pi aromatic stacking inter-action [centroid-centroid distance = 3.526 (3) A] is also observed. PMID- 21588068 TI - Hydrogen bis-[2-(4-ammonio-phen-oxy)acetate] triiodide. AB - In the title compound, C(16)H(19)N(2)O(6) (+).I(3) (-), the carboxyl-ate groups of a pair of (4-amino-phen-oxy) acetate ligands are bridged by an H atom in a rather classical configuration. The H atom is located on an inversion center and the pair of carboxyl-ate groups are centrosymmetrically related with an O?O distance of 2.494 (5) A. The I(3) (-) anion is also located on an inversion center. In the crystal, N-H?O and N-H?I hydrogen-bond inter-actions build up a three-dimensionnal network. PMID- 21588069 TI - 3-Benzyl-6-bromo-2-(2-fur-yl)-3H-imidazo[4,5-b]pyridine. AB - In the title mol-ecule, C(17)H(12)BrN(3)O, the imidazopyridine ring system is almost coplanar with the furan ring [dihedral angle = 2.0 (3) degrees ]. The benzyl phenyl ring is oriented at dihedral angles of 85.2 (2) and 85.5 (1) degrees , respectively, with respect to the furan ring and the imidazopyridine ring system. In the crystal, mol-ecules are linked into chains propagating along the b axis by C-H?N hydrogen bonds. Adjacent chains are linked via short Br?Br contacts [3.493 (1) A]. PMID- 21588070 TI - 3-Hy-droxy-8-oxo-3-nor-methyl-chamigrane-2,7-peroxide. AB - In the title compound, C(14)H(22)O(4) (systematic name: 9-hy-droxy-1,5,5 trimethyl-1,8-epidi-oxy-spiro-[5.5]decan-2-one), which was isolated from the fermentation broth of Steccherinum ochraceum, the two six-membered rings adopt chair conformations and are bridged by a peroxide group. The hy-droxy H atom forms a three-centre cyclic inter-molecular O-H?(O,O') hydrogen-bonding inter action with a peroxide and a carbonyl O-atom acceptor, forming [100] chains. PMID- 21588071 TI - 3-(4-Fluoro-phenyl-sulfin-yl)-5-iodo-2-methyl-1-benzofuran. AB - In the title compound, C(15)H(10)FIO(2)S, the O atom and the 4-fluoro-phenyl group of the 4-fluoro-phenyl-sulfinyl substituent are located on opposite sides of the plane through the benzofuran fragment; the 4-fluoro-phenyl ring is nearly perpendicular to this plane, making a dihedral angle of 83.37 (7) degrees . The crystal structure is stabilized by weak inter-molecular C-H?O hydrogen bonds and an I?O inter-action [I?O = 3.255 (2) A]. The crystal structure also exhibits inter-molecular C-F?pi inter-actions [3.068 (2) A], and aromatic pi-pi inter actions between the furan and benzene rings of neighbouring benzofuran fragments [centroid-centroid distance = 3.636 (2) A]. PMID- 21588072 TI - 2,2'-[(1E,1'E)-2,2'-(2,5-Dibut-oxy-1,4-phenyl-ene)bis-(ethene-2,1-di yl)]dipyridine. AB - The centrosymmetric title mol-ecule, C(28)H(32)N(2)O(2), has a central benzene ring subsituted in the 1- and 4-positions by (ethene-2,1-di-yl)pyridine groups, and in the 2- and 5-positions by but-oxy groups. The whole mol-ecule is X-shaped and relatively flat, the dihedral angle between the pyridine and the central benzene ring being 11.29 (10) degrees . In the crystal, neighboring mol-ecules are linked by weak C-H?N inter-actions, forming a two-dimensional undulating network. PMID- 21588073 TI - 3beta-Hy-droxy-lup-20(29)-en-28-yl 1H-imidazole-1-carboxyl-ate. AB - The title triterpene, C(34)H(52)N(2)O(3), is a C-28 carbamate derivative of betulin prepared in a one-step reaction from the commercially available 1,1' carbonyl-diimidazole (CDI). All rings are fused trans. The X-ray study shows the retention of the configuration of C-28 with respect to the known chiral centres of the molecule. In the crystal, the mol-ecules are O-H?O hydrogen bonded via the hy-droxy group and the carbonyl group of the carbamate function into chains running along the c axis. A quantum-mechanical ab initio Roothaan Hartree-Fock calculation of the equilibrium geometry of the isolated mol-ecule gives values for bond-lengths and valency angles close to the experimental values. The calculations also reproduce the mol-ecular conformation well, with calculated puckering parameters that agree well with the observed values. PMID- 21588074 TI - N'-[(E)-1-(5-Chloro-2-hy-droxy-phen-yl)ethyl-idene]pyridine-3-carbohydrazide monohydrate. AB - In the title compound, C(14)H(12)ClN(3)O(2).H(2)O, the benzene ring and the pyridine rings are oriented at a dihedral angle of 57.73 (12) degrees and an intra-molecular O-H?N hydrogen bond generates an S(6) ring. In the crystal, the water mol-ecule forms O-H?O and O-H?N hydrogen bonds to the organic mol-ecule, leading to chains containing R(4) (4)(16) loops. In addition, weak aromatic pi-pi stacking inter-actions between the centroids of pyridine rings [at distance of 3.864 (2) and 4.013 (2) A] and C-H?pi inter-actions occur. PMID- 21588075 TI - N'-[(E)-(1-Methyl-1H-pyrrol-2-yl)methyl-idene]pyridine-4-carbohydrazide. AB - In the title compound, C(12)H(12)N(4)O, the pyridine and pyrrole rings are inclined at an angle of 29.22 (8) degrees and an intra-molecular C-H?N inter action geneates an S(6) ring. In the crystal, mol-ecules are linked by N-H?N hydrogen bonds, forming (010) C(7) chains. The chains are cross-linked by weak C H?O inter-actions, which generate R(2) (2)(18) ring motifs within an infinite sheet. Finally, two C-H?pi inter-actions are present, where the C-H groups are from the pyridine ring and pi is the pyrrole ring. PMID- 21588076 TI - Erratum: Tetra-kis-MU-l-alanine-kappaO:O'-bis-[tetra-aqua-terbium(III)] hexa perchlorate. Corrigendum. AB - The surname of one of the authors and the affiliation of that author in the paper by Mohamed et al. [Acta Cryst. (2009), E66, m193-m194] are corrected.[This corrects the article DOI: 10.1107/S1600536809028955.]. PMID- 21588077 TI - Calcium disodium hexa-thio-diphosphate(IV) octa-hydrate. AB - Single crystals of the title compound, CaNa(2)(P(2)S(6)).8H(2)O, were obtained by adding calcium hydroxide to an aqueous solution of Na(4)(P(2)S(6)).6H(2)O. The structure is isotypic with that of its strontium analogue and consists of one Ca(2+) cation, two Na(+) cations, one-half of a centrosymmetric (P(2)S(6))(4-) anion with staggered confirmation and four water mol-ecules in the asymmetric unit. The crystal structure can be described as being built up from layers of cations and anions extending parallel to (101). Within a layer, each CaO(8) polyhedron is connected via edge-sharing to two NaO(4)S(2) octa-hedra and to one NaO(2)S(4) octa-edron. The NaO(4)S(2) octa-hedra are, in turn, linked with two (P(2)S(6))(4-) anions through common corners. Various O-H?S hydrogen-bonding inter-actions lead to cohesion of adjacent layers. The Ca(2+) and one Na(+) cation are situated on a twofold rotation axis and the second Na(+) cation is situated on an inversion centre. PMID- 21588078 TI - Strontium disodium hexa-thio-diphosphate(IV) octa-hydrate. AB - The crystal structure of SrNa(2)(P(2)S(6)).8H(2)O is isotypic with that of its calcium analogue. The asymmetric unit consists of one Sr(2+) cation (2 symmetry), two Na(+) cations (2 and symmetry, respectively), one-half of a centrosymmetric (P(2)S(6))(4-) anion with a staggered confirmation and four water mol-ecules. The crystal structure is built up from layers of cations and anions extending parallel to (101). Each SrO(8) polyhedron is connected via edge-sharing to two NaO(4)S(2) octa-hedra and to one NaO(2)S(4) octa-hedron. The NaO(4)S(2) octa-edra are, in turn, connected with two (P(2)S(6))(4-) anions through common corners. Adjacent layers are held together by several O-H?S hydrogen-bonding inter actions. PMID- 21588079 TI - Tl(2)Mo(9)Se(11). AB - The structure of Tl(2)Mo(9)Se(11), dithallium nona-molybdenum undeca-selenide, is isotypic with Tl(2)Mo(9)S(11) [Potel et al. (1980 ?). Acta Cryst. B36, 1319 1322]. The structural set-up is characterized by a mixture of Mo(6)Se(i) (8)Se(a) (6) and Mo(12)Se(i) (14)Se(a) (6) cluster units in a 1:1 ratio. Both components are inter-connected through inter-unit Mo-Se bonds. The cluster units are centered at Wyckoff positions 3a and 3b (point-group symmetry .). The two Tl(I) atoms are situated in the voids of the three-dimensional arrangement. Two of the five independent Se atoms and the Tl atoms lie on sites with 3. symmetry (Wyckoff site 6c). PMID- 21588080 TI - Hexa-kis-(thio-urea-kappaS)nickel(II) nitrate: a redetermination. AB - A preliminary X-ray study of the title mol-ecular salt, [Ni(CH(4)N(2)S)(6)](NO(3))(2), has been reported twice previously, by Madar [Acta Cryst. (1961), 14, 894] and Rodriguez, Cubero, Vega, Morente & Vazquez [Acta Cryst. (1961), 14, 1101], using film methods. We confirm the previous studies, but to modern standards of precision and with all H atoms located. The central Ni atom (site symmetry ) of the dication is octa-hedrally coordinated by six S-bound thio-urea mol-ecules. The crystal structure is stabilized by intra- and inter molecular N-H?S and N-H?O hydrogen bonds. PMID- 21588081 TI - KPr(PO(3))(4). AB - Single crystals of the title compound, potassium praseodymium(III) polyphosphate, were obtained by solid-state reaction. The monoclinic non-centrosymmetric structure is isotypic with all other KLn(PO(3))(4) analogues from Ln = La to Er, inclusive. The crystal structure of these long-chain polyphosphates is built up from infinite crenelated polyphosphate chains of corner-sharing PO(4) tetra-hedra with a repeating unit of four tetra-hedra. These chains, running along [100], are arranged in a pseudo-tetra-gonal rod packing and are further linked by isolated PrO(8) square anti-prisms [Pr-O = 2.3787 (9)-2.5091 (8) A], forming a three dimensional framework. The K(+) ions reside in channels parallel to [010] and exhibit a highly distorted coordination sphere by eight O atoms at distances ranging from 2.7908 (9) to 3.1924 (11) A. PMID- 21588082 TI - trans-K(3)[TcO(2)(CN)(4)]. AB - The structure of the title compound, tripotassium trans-tetra cyanidodioxidotechnetate(V), is isotypic with its Re analogue. The [TcO(2)(CN)(4)](3-)trans-tetra-cyanido-dioxido-technetate anion has a slightly distorted octa-hedral configuration. The Tc atom is located on a center of inversion and is bound to two O atoms in axial and to four cyanide ligands in equatorial positions. The Tc-O distance is consistent with a double-bond character. The two potassium cations, one located on a center of inversion and one in a general position, reside in octa-hedral or tetra-hedral environments, respectively. K?O and K?N inter-actions occur in the 2.7877 (19)-2.8598 (15) A range. PMID- 21588083 TI - Tris(2-meth-oxy-ethanaminium) dodeca-molybdophosphate trihydrate. AB - The asymmetric unit of the polyoxidometalate-based organic-inorganic hybrid title compound, (C(3)H(10)NO)(3)[PMo(12)O(40)].3H(2)O, consists of one alpha-Keggin type [PMo(12)O(40)](3-) polyoxido-anion, three independent [CH(3)-O-CH(2)-CH(2) NH(3)](+) cations and three solvent water mol-ecules. The polyoxidoanion shows characteristic features with respect to bond lengths and angles. In the crystal structure, extensive inter-molecular N-H?O and O-H?O hydrogen bonding between the organic cations, inorganic anions and solvent water mol-ecules leads to a three dimensional supra-molecular network. PMID- 21588084 TI - Dichloridobis(N,N'-diethyl-thio-urea-kappaS)mercury(II). AB - There are two mol-ecules in the asymmetric unit of the title compound, [HgCl(2)(C(5)H(12)N(2)S)(2)]. In both mol-ecules, the N,N'-diethyl-thio-urea ligands exhibit a cis,trans geometry around their C-N amide bonds. The shapes of the mol-ecules are, to a large extent, determined by intra-molecular N-H?Cl hydrogen bonds formed by the N-H groups from the cis amide groups. In one mol ecule, these groups are involved in three-center hydrogen bonds involving both chloride ligands, whereas in the other mol-ecule only one Cl ligand takes part in intra-molecular hydrogen bonding. The coordination around the Hg atom is distorted tetra-hedral with an S(2)Cl(2) donor set. Inter-molecular hydrogen bonds between N-H groups from the trans amide units of the thio-amide ligands and the chloride ligands connect the mol-ecules into a polymeric chain extending along the c axis. One of the ethyl groups of the N,N'-diethyl-thio-urea ligands is disordered over two positions in one of the mol-ecules, with an occupancy of 0.654 (17) for the major component. PMID- 21588085 TI - Bis(MU-naphthalene-1,8-dicarboxyl-ato-kappaO:O)bis-[aqua-bis-(N,N'-dimethyl formamide-kappaO)copper(II)]. AB - In the centrosymmetric dinuclear title complex, [Cu(2)(C(12)H(6)O(4))(2)(C(3)H(7)NO)(4)(H(2)O)(2)], the coordination environment of each Cu(II) atom displays a distorted CuO(5) square-pyramidal geometry, which is formed by two carboxyl-ate O atoms of two MU-1,8-nap ligands (1,8-nap is naphthalene-1,8-dicarboxyl-ate), two O atoms of two DMF (DMF is N,N'-dimethyl formamide) and one coordinated water mol-ecule. The Cu-O distances involving the four O atoms in the square plane are in the range 1.9501 (11)-1.9677 (11) A, with the Cu atom lying nearly in the plane [deviation = 0.0726 (2) A]. The axial O atom occupies the peak position with a Cu-O distance of 2.885 (12) A, which is significantly longer than the rest of the Cu-O distances. Each 1,8-nap ligand acts as bridge, linking two Cu(II) atoms into a dinuclear structure. Inter molecular O-H?O and C-H?O hydrogen-bonding inter-actions consolidate the structure. PMID- 21588086 TI - Tetra-pyridinium MU-oxido-di-MU-sulfato-bis-[chloridodioxidomolybdate(VI)]. AB - The title salt, (C(5)H(6)N)(4)[Mo(2)Cl(2)O(5)(SO(4))(2)], comprises four pyridinium cations for each [(MoClO(2))(2)(MU-O)(MU-SO(4))(2)](4-) anionic unit. The asymmetric unit consists of three aggregates of the empirical formula. The tetra-anionic bimetallic molybdenum(VI) cluster is unprecedented and contains two sulfate and one oxide bridges. This structure constitutes the first example of a non-polymeric compound with terminal oxide, sulfate and halide ligands bonded to the same metal. The hydrogen bonds connecting the pyridinium cations to the molybdenum clusters are diverse, varying from strong and directional interactions to bifurcated bonds with a subsequent loss of directionality. PMID- 21588087 TI - Hexaaqua-cobalt(II) 3,3'-dicarb-oxy-biphenyl-4,4'-dicarboxyl-ate. AB - In the crystal structure of the title compound, [Co(H(2)O)(6)](C(16)H(8)O(8)), both the cation and anion are centrosymmetric. The Co cation displays a CoO(6) octa-hedral geometry formed by six water mol-ecules. In the anion, the two carboxyl groups are oriented at dihedral angles of 4.8 (5) and 10.4 (7) degrees with respect to the benzene ring. Very strong O-H?O hydrogen bonds between the protonated and deprotonated carboxylate groups occur. Neighbouring cations and anions are connected through O-H?O hydrogen bonds into a three-dimensional supra molecular structure. PMID- 21588088 TI - Di-MU-nicotinato-kappaN:O;kappaO:N-bis-[aqua-bis-(4-bromo-benz-yl)(nicotinato kappaO,O')tin(IV)]. AB - Two nicotinate binding modes are observed in the dinuclear title compound, [Sn(2)(C(7)H(6)Br)(4)(C(6)H(4)NO(2))(4)(H(2)O)(2)]: in the first, a terminal O,O' chelating molecule binds to a water-coordinated diorganotin cation, while the second mode corresponds to an O:N-bridging molecule which binds to two cations. The two Sn atoms exist in trans-C(2)SnNO(4) penta-gonal-bipyramidal geometries. Adjacent dinuclear units are linked by O-H?N hydrogen bonds, generating a linear chain, which propagates in the b-axis direction. O-H?O inter-actions are also observed. PMID- 21588089 TI - Poly[[bis-{MU(3)-2-[(3,5-dimethyl-1H-pyrazol-1-yl)(phen-yl)meth-yl]propane dioato}tetra-sodium(I)] 7.5-hydrate]. AB - The asymmetric unit of the title polymer, {[Na(4)(C(15)H(14)N(2)O(4))(2)].7.5H(2)O}(n), contains two 2-[(3,5-dimethyl-1H pyrazol-1-yl)(phen-yl)meth-yl]propane-dioate (ppmp) anions, eight water mol ecules (one located on a twofold rotation axis) and five sodium cations (one located on an inversion center and the other one located on a twofold rotation axis). The carboxyl-ate groups of the ppmp anions and the water mol-ecules bridge the Na cations, forming a two-dimensional polymeric structure. In the structure there are two types of coordination environment around the metal cations: one Na cation is coordinated by five O atoms in a distorted square-pyramidal geometry while the other four Na cations are coordinated by six O atoms in a distorted octa-hedral geometry. Extensive O-H?O and O-H?N hydrogen bonding is present in the crystal structure. The H atoms of one methyl group of the ppmp anion are disordered equally over two positions. PMID- 21588090 TI - Pyridinium diaqua-bis-(methyl-enediphospho-nato-kappaO,O')chromate(III) tetra hydrate. AB - In the title complex, (C(5)H(6)N)[Cr(CH(4)O(6)P(2))(2)(H(2)O)(2)].4H(2)O, the Cr(III) atom, lying on an inversion centre, is coordinated by two bidentate methyl-ene diphospho-nate ligands and two water molecules in a distorted octa hedral coordination geometry. The pyridinium cation is located on an inversion centre, with an N atom and a C atom sharing a position each at a half occupancy. A three-dimensional network is constructed by O-H?O, N-H?O and C-H?O hydrogen bonds between the pyridin-ium cation, complex anion and uncoordinated water mol ecules. PMID- 21588091 TI - (S)-1,2,4-Trimethyl-piperazine-1,4-diium tetra-chloridozincate(II). AB - In the title compound, (C(7)H(18)N(2))[ZnCl(4)], the Zn atom adopts a slightly distorted tetra-hedral geometry. The diprotonated piperazine ring adopts a chair conformation. In the crystal structure, the cations and anions are linked by inter-molecular N-H?Cl hydrogen bonds into a chain along [001]. PMID- 21588092 TI - Diaqua-bis-(seleno-cyanato-kappaN)bis-(pyrimidine-kappaN)manganese(II). AB - In the crystal structure of the title compound, [Mn(NCSe)(2)(C(4)H(4)N(2))(2)(H(2)O)(2)], the manganese(II) cation is coordinated by two N-bonded pyrimidine ligands, two N-bonded seleno-cyanate anions and two O bonded water mol-ecules in a distorted octa-hedral coordination mode. The asymmetric unit consists of one manganese(II) cation, located on a centre of inversion, as well as one seleno-cyanate anion, one water mol-ecule and one pyrimidine ligand in general positions. The crystal structure consists of discrete building blocks of composition [Mn(NCSe)(2)(pyrimidine)(2)(H(2)O)(2)], which are connected into layers parallel to (101) by strong water-pyrimidine O H?N hydrogen bonds. PMID- 21588093 TI - Hexaaqua-nickel(II) tetra-aqua-bis-(MU-pyridine-2,6-dicarboxyl-ato)bis-(pyridine 2,6-dicarboxyl-ato)trinickelate(II) octa-hydrate. AB - The title compound, [Ni(H(2)O)(6)][Ni(3)(C(7)H(3)NO(4))(4)(H(2)O)(4)].8H(2)O, was obtained by the reaction of nickel(II) nitrate hexa-hydrate with pyridine-2,6 dicarb-oxy-lic acid (pydcH(2)) and 1,10-phenanothroline (phen) in an aqueous solution. The latter ligand is not involved in formation of the title complex. There are three different Ni(II) atoms in the asymmetric unit, two of which are located on inversion centers, and thus the [Ni(H(2)O)(6)](2+) cation and the trinuclear {[Ni(pydc)(2)](2)-MU-Ni(H(2)O)(4)}(2-) anion are centrosymmetric. All Ni(II) atoms exhibit an octa-hedral coordination geometry. Various inter-actions, including numerous O-H?O and C-H?O hydrogen bonds and C-O?pi stacking of the pyridine and carboxyl-ate groups [3.570 (1), 3.758 (1) and 3.609 (1) A], are observed in the crystal structure. PMID- 21588094 TI - catena-Poly[[MU(3)-hydroxido-tetra-MU(2)-pyrid-azine 1:2kappaN:N';1:3kappaN:N';2:3kappaN:N'-tetrakis(selenocyanato) 1kappaN,2kappaN,3kappaN-trizinc(II)]-MU-cyanido-1:2'kappaC:N]. AB - In the crystal structure of the title compound, [Zn(3)(NCSe)(4)(OH)(CN)(C(4)H(4)N(2))(4)](n) one of the two crystallograph-ically independent zinc(II) cations is coordinated by two terminal N-bonded seleno cyanato anions and two N atoms of two symmetry-related pyridazine ligands in a trigonal-bipyramidal geometry, while the other zinc(II) cation is coordinated by one terminal N-bonded seleno-cyanato anion, one MU-1,2-cyanido anion and three N atoms of three crystallographically independent pyridazine ligands in a slightly distorted octa-hedral coordination geometry. The zinc(II) atoms are further connected via a MU(3)-hydroxido anion into trinuclear building blocks. The formula unit consists of three zinc cations, four seleno-cyanato anions, one MU(3)-hydroxido anion, four pyridazine mol-ecules as well as one cyanido anion. The asymmetric unit contains half of a formula unit. One of the zinc atoms, two seleno-cyanato anions, two pyridazine ligands and the MU(3)-hydroxido anion are located on a crystallographic mirror plane, whereas the cyanido anion is located on a twofold rotation axis. Therefore, this anion is disordered due to symmetry. The cyanido anions connect the metal centres into polymeric zigzag chains propagating along the a axis. PMID- 21588095 TI - (Acetyl-acetone isonicotinoylhydrazonato-kappaO,N',O')dioxidovanadate(V) monohydrate. AB - The hydrazone anion in the title compound, [V(C(11)H(12)N(3)O(2))O(2)].H(2)O, is zwitterionic as its pyridyl N atom is protonated; the O, N and O' atoms span the axial-equatorial-axial positions of the trigonal-bipyramidal coord-in-ation polyhedron of the metal atom. All non-H atoms lie on a crystallographic mirror plane apart from the oxide ligands, which are related by mirror symmetry. The pyridinium N atom acts as a hydrogen-bond donor to the solvent water mol-ecule, which is in turn a hydrogen-bond donor to the both oxide ligands. These hydrogen bonding inter-actions give rise to a three-dimensional network motif. PMID- 21588096 TI - (Acetyl-acetone 3-hy-droxy-2-naphtho-yl-hydrazonato-kappaO,N',O')(methoxo kappaO)oxidovanadate(V). AB - The tridentate Schiff base ligand in the title compound, [V(C(16)H(14)N(2)O(3))(CH(3)O)O], has its O, N and O' atoms spanning three basal positions of the square-based-pyrimidally V(V) atom. The fourth basal site is occupied by a methoxo ligand, which results from a deprotonated methanol solvent molecule, and the oxido ligand occupies the apical position. The hy-droxy H atom forms an intra-molecular O-H?N hydrogen bond with an N-atom acceptor site. PMID- 21588097 TI - Bis{1-[(E)-(2-methyl-phen-yl)diazen-yl]-2-naphtho-lato}palladium(II). AB - In the title compound, [Pd(C(17)H(13)N(2)O)(2)], the Pd(II) atom is tetra coordinated by two N atoms and two O atoms from two bidentate methylphenyl diazenylnaphtolate ligands, forming a square-planar complex. The two N atoms and two O atoms around the Pd(II) atom are trans to each other (as the Pd(II) atom lies on a crystallographic inversion centre) with O-Pd-N bond angles of 89.60 (11) and 90.40 (11) degrees . The distances between the Pd(II) atom and the coordinated O and N atoms are 1.966 (3) and 2.009 (3) A, respectively. PMID- 21588098 TI - (2,2'-Dimethyl-4,4'-bi-1,3-thia-zole-kappaN,N')diiodidomercury(II). AB - In the title compound, [HgI(2)(C(8)H(8)N(2)S(2))], the Hg(II) atom is four coordinated in a distorted tetra-hedral geometry by two N atoms from a 2,2' dimethyl-4,4'-bithia-zole ligand and two I atoms. In the crystal structure, adjacent mol-ecules are connected by pi-pi contacts between the thia-zole rings [centroid-centroid distance = 3.591 (3) A]. PMID- 21588099 TI - Dichlorido(6,6'-dimethyl-2,2'-bipyridine-kappaN,N')cadmium(II). AB - In the title compound, [CdCl(2)(C(12)H(12)N(2))], the Cd(II) atom is four coordinated in a distorted tetra-hedral geometry by two N atoms from a 6,6' dimethyl-2,2'-bipyridine ligand and two terminal Cl atoms. Inter-molecular C-H?Cl hydrogen bonds and pi-pi stacking inter-actions between the pyridyl rings [centroid-centroid distance = 3.7337 (18) A] are present in the crystal structure. PMID- 21588100 TI - Aqua(dimethylformamide){tris[(1-methyl-1H-benzimidazol-2 yl)methyl]amine}nickel(II) dipicrate. AB - In the title complex, [Ni(C(27)H(27)N(7))(C(3)H(7)NO)(H(2)O)](C(6)H(2)N(3)O(7))(2), the Ni(II) ion is coordinated in a slightly distorted octa-hedral coordination evironment by an NiN(4)O(2) ligand set. The tris-(N-methyl-benzimidazol-2-ylmeth-yl)amine ligand is in a tetra-dentate mode while a coordinated water molecule and a dimethyl formamide ligand complete the coordination. In the crystal structure, inter molecular O-H?O hydrogen bonds link the cation and one of the pictrate anions into four-component centrosymmetric clusters. PMID- 21588101 TI - Bis(1,1,2,2-tetramethyldiphosphane-1,2-dithione-kappaS,S')gold(I) trifluoro methane-sulfonate. AB - In the title compound, [Au(C(4)H(12)P(2)S(2))(2)](CF(3)SO(3)), the gold(I) atom is tightly bonded to two S atoms belonging to different ligand mol-ecules and forms two weaker contacts to the remaining S atoms. The coordination geometry around gold is inter-mediate between linear-dicoordinate and tetra-hedral with an S-Au-S angle of 161.49 (3) degrees . PMID- 21588102 TI - Dichlorido[(S)-N-(1-phenyl-ethyl-idene)-1-(pyridin-2-yl)ethanamine kappaN,N']zinc(II) dichloro-methane solvate. AB - In the title compound, [ZnCl(2)(C(15)H(16)N(2))].CH(2)Cl(2), the Zn(II) atom has a distorted tetra-hedral coordination by two Cl atoms and two N atoms from the organic ligand [the average Zn-N and Zn-Cl bond lengths are 2.060 (4) A and Zn-Cl = 2.179 (16) A, respectively]. The dihedral angle between the N-Zn-N and Cl-Zn-Cl planes is 89.9 (1) degrees . The phenyl ring forms a dihedral angle of 40.6 (5) degrees with the imine plane. PMID- 21588103 TI - (N-Benzoyl-N'-phenyl-thio-urea-kappaS)chlorido(eta-1,5-cyclo-octa diene)rhodium(I). AB - The title compound, [RhCl(C(8)H(12))(C(14)H(12)N(2)OS)], is a rhodium(I) derivative with a functionalized thio-urea ligand. Despite the presence of several heteroatoms, the thio-urea ligand coordinates only in a monodentate fashion via the S atom. The geometry of the coordination sphere is approximately square planar about the Rh(I) atom, with two bonds to the pi-electrons of the 1,5 cyclo-octa-diene ligand, one bond to the Cl(-) ligand and one bond to the S atom of the thio-urea ligand. The mol-ecular structure is stabilized by intra molecular N-H?O and N-H?Cl hydrogen bonding. Inter-molecular N-H?O hydrogen bonding inter-actions lead to the formation of layers extending parallel to (011). PMID- 21588104 TI - Diacetonitrile-(3-{2-[8-(2-bromo-eth-oxy)-9,10-dioxoanthracen-1-yl-oxy]eth-yl}-1 (2-pyridyl-meth-yl)imidazolium)silver(I) bis-(hexa-fluorido-phosphate). AB - The title compound, [Ag(C(27)H(23)BrN(3)O(4))(CH(3)CN)(2)](PF(6))(2), is a mononuclear salt species in which the silver(I) atom is coordinated by one ligand and two acetonitrile mol-ecules and exhibits a distorted T-shaped coordination. The asymmetric unit contains one independent cation and two independent hexa fluorido-phosphate anions, one of which is disordered over two positions in a 0.756 (11):0.244 (11) ratio. Weak pi-pi inter-actions between the anthraquinone ring systems [centroid-centroid distance = 3.676 (3) A], inter-molecular Ag-pi inter-actions [Cg?Ag = 3.405 A] and C-H?pi inter-actions between pairs of adjacent mol-ecules are observed. PMID- 21588105 TI - Bis(dimethyl sulfoxide)-hydridobis(triphenyl-phosphane)cobalt(I). AB - The title compound, [CoH(C(18)H(15)P)(2)(C(2)H(6)OS)(2)], was synthesized by the reaction of chloridotris(triphenyl-phosphane)cobalt(I), [ClCo(PPh(3))(3)], in the presence of one equivalent potassium hydridotris(pyrazol-yl)borate in dimethyl sulfoxide. The structure displays a distorted trigonal-pyramidally coordinated cobalt(I) atom, with two phosphane ligands and one DMSO ligand in the equatorial plane. The coordination is completed by one further DMSO ligand and the anionic hydride in the axial positions. PMID- 21588106 TI - [MU-1,2-Bis(diphenyl-phosphino)ethane-kappaP:P']bis-{[1,2-bis-(diphenyl phosphino)ethane-kappaP,P']cyanidocopper(I)} methanol disolvate. AB - The title centrosymmetric complex, [Cu(2)(CN)(2)(C(26)H(24)P(2))(3)].2CH(3)OH, consists of two five-membered [Cu(dppe)CN] rings [dppe is 1,2-bis-(diphenyl phosphino)ethane] bridged by one MU(2)-dppe ligand, and two methanol solvent mol ecules. The angles around the central metal atom indicate that each Cu(I) atom is located in the center of a distorted tetra-hedron. The coordination sphere of each Cu(I) atom is formed by three P atoms from two dppe ligands, and one C atom from the cyanide ligand. The crystal structure is stabilized by O-H?N hydrogen bonds, which are formed by the O-H donor group from methanol and the N-atom acceptor from a cyanide ligand. PMID- 21588107 TI - {N,N'-Bis[1-(2-pyrid-yl)ethyl-idene]propane-1,2-diamine}-bis(thio-cyanato-kappaN) nickel(II). AB - In the title complex, [Ni(NCS)(2)(C(17)H(20)N(4))], the Ni(2+) ion (site symmetry 2) is coordinated by the N,N,N,N-tetra-dentate Schiff base ligand and two thio cyanate ligands, forming a distorted NiN(6) octa-hedral geometry, with the thio cyanate N atoms in a trans orientation. The pendant methyl group of the central propane-1,2-diamine fragment of the ligand is statistically disordered over two sets of positions. In the crystal, weak aromatic pi-pi stacking between pyridine rings [centroid-centroid separation = 3.7081 (17) A] may help to establish the packing. PMID- 21588108 TI - catena-poly[[[(2,2'-bipyridine-2kappaN,N')-MU-cyanido-1:2kappaN:C-cyanido-2kappaC tris-(methanol-1kappaO)(nitrato-1kappaO,O')iron(II)yttrium(III)]-di-MU-cyanido 1:2'kappaN:C;2:1'kappaC:N] methanol solvate hemihydrate]. AB - The title complex, {[Fe(II)Y(III)(CN)(4)(NO(3))(C(10)H(8)N(2))(CH(3)OH)(3)].CH(3)OH.0.5H(2)O}(n), is built up of ladder-like chains oriented along the c axis. Each ladder consists of two strands based on alternating Fe(II) and Y(III) ions connected by cyanide bridges. Two such parallel chains are connected by additional cyanide anions (the 'rungs' of the ladder), which likewise connect Fe(II) and Y(III) ions, such that each [Fe(bipy)(CN)(4)](2-) (bipy is 2,2'-bipyridine) unit coordinates with three Y(III) ions and each Y(III) ion connects with three different [Fe(bipy)(CN)(4)](2 ) units. The Fe(II) atom is six-coordinated in a distorted octa-hedral geometry and the Y(III) atom cation is eight-coordinated in a distorted dodeca-hedral environment. The uncoordinated methanol solvent mol-ecules are involved in hydrogen-bonding inter-actions with the one terminal cyanide group and a coordinated methanol mol-ecule from another [Y(III)(NO(3))(CH(3)OH)(3)](2+) unit. Adjacent ladder-like chains are also held together by hydrogen bonds between the terminal cyanide ligands of the [Fe(CN)(4)(bipy)](2-) units in one chain and the OH donors of CH(3)OH ligands from [Y(III)(NO(3))(CH(3)OH)(3)] units in neighboring chains. The water molecule exhibits half-occupation. PMID- 21588109 TI - Sodium quercetin-8-sulfonate trihydrate. AB - The organic anion of the title compound, {[Na(C(15)H(9)O(10)S)(H(2)O)(2)].H(2)O}(n) {systematic name: poly[[diaqua-[MU-2 (3,4-dihy-droxy-phen-yl)-3,5,7-trihy-droxy-4-oxo-4H-chromene-8-sulfon-ato] sodium] monohydrate]}, has a nearly planar structure. The Na atom is six coordinated by O atoms, two from water mol-ecules and four from the anion. The dihedral angle between the ring systems in the anion is 10.1 (1) degrees . Intra molecular O-H?S and O-H?O inter-actions occur. In the crystal structure, an extensive network of classical inter-molecular O-H?S and O-H?O hydrogen bonds forms layers along the c axis. PMID- 21588110 TI - Bis[4-(2-benzoyl-1-oxidoethen-yl)-3-hy-droxy-phenyl benzoato]diethano-l cobalt(II). AB - In the title complex, [Co(C(22)H(15)O(5))(2)(C(2)H(5)OH)(2)], the Co(II) atom (site symmetry ) is coordinated by two O,O'-bidentate 4-(2-benzoyl-1-oxidoethen yl)-3-hy-droxy-phenyl benzoate anions and two ethanol O atoms, resulting in a slightly distorted CoO(6) octa-hedral coordination. An intra-molecular O-H?O hydrogen bond in the ligand generates an S(6) ring. The dihedral angle between the aromatic rings joined to the acetyl-acetonate unit is 6.4 (2) degrees . The ethanol mol-ecule is disordered over two orientations in a 0.65 (3):0.35 (3) ratio. In the crystal, mol-ecules are linked by O-H?O bonds. PMID- 21588111 TI - Dichlorido[tris-(benzimidazol-2-ylmeth-yl)amine]-indium(III) chloride ethanol solvate dihydrate. AB - In the title complex, [InCl(2)(C(24)H(21)N(7))]Cl.C(2)H(5)OH.2H(2)O, the In(III) ion is coordinated by four N atoms from the tris-(benz-imidazol-2-ylmeth-yl)amine (NTB) ligand and two Cl atoms in a distorted octa-hedral environment. In the crystal structure, inter-molecular N-H?O, O-H?O, O-H?Cl and weak C-H?Cl hydrogen bonds connect the cations, anions and solvent mol-ecules into a three-dimensional network. The ethanol solvent mol-ecule is disordered over two sites with refined occupancies of 0.54 (2) and 0.46 (2). PMID- 21588112 TI - Tetra-ethyl-ammonium tricarbonyl-chlorido(quinoxaline-2-carboxyl-ato kappaN,O)rhenate(I). AB - In the title compound, (C(8)H(20)N)[Re(C(9)H(5)N(2)O(2))Cl(CO)(3)], the Re(I) atom is coordinated facially by three carbonyl groups, the bidentate quinoxaline 2-carbaldehyde ligand and a chloride atom, forming a distorted octahedral geometry.. The crystal packing is controlled by C-H?O hydrogen bonding and pi-pi stacking inter-actions involving the benzene rings, with a centroid-centroid distance of 3.4220 (1) A. PMID- 21588113 TI - Bis(2,2'-bi-1H-imidazole)-copper(II) bis-(1,1,3,3-tetra-cyano-2-eth-oxy propenide). AB - In the title compound, [Cu(C(6)H(6)N(4))(2)](C(9)H(5)N(4)O)(2), the Cu(2+) ion (site symmetry ) is coordinated by two N,N'-bidentate 2,2'-biimidazole (H(2)biim) ligands, generating a square-planar CuN(4) geometry. The dihedral angle between the aromatic rings in the ligand is 0.70 (9) degrees . In the polynitrile 1,1,3,3 tetra-cyano-2-eth-oxy-propenide (tcnoet) anion, the C-N, C-C and C-O bond lengths indicate extensive electronic delocalization. An alternative description for the metal-ion geometry is an extremely distorted CuN(6) octa-hedron, with two N bonded tcnoet anions completing the coordination. In the crystal, the components are linked by N-H?N and C-H?N inter-actions. PMID- 21588114 TI - Furfuryl-ammonium chloridozincophosphate. AB - In the title compound, [ZnCl(HPO(4))](C(5)H(8)NO), polymeric inorganic layers constructed from ZnO(3)Cl and PO(4) tetra-hedra are linked by O atoms: O-H?O hydrogen bonds occur within the layers. The organic cations occupy the interlayer regions and interact with the layers by way of N-H?O, N-H?Cl, and C-H?Cl hydrogen bonds. PMID- 21588115 TI - Chloridobis{N-[(dimethyl-amino)-dimethyl-sil-yl]-2,6-dimethyl-anilido kappaN,N'}titanium(III). AB - In the monomeric title titanium(III) compound, [Ti(C(12)H(21)N(2)Si)(2)Cl], the metal atom is surrounded by two N-silylated anilide ligands in an N,N''-chelating mode. The two ends of the N-Si-N chelating unit exhibit different affinity to the metal center. The Ti-N(amine) bond is longer than the Ti-N(anilide) bond by about 0.29 A. The two ligands are arranged trans to each other and the mol-ecule demonstrates a pseudo-twofold rotation along the axis of the Ti-Cl bond. The five coordinate Ti atom demonstrates a highly distorted trigonal-bipyramidal geometry. PMID- 21588116 TI - {2-[2-(Carb-oxy-meth-oxy)-phen-oxy]acetato}[2,2'-(o-phenyl-enedi-oxy)diacetic acid]sodium 4,4'-bipyridine hemisolvate monohydrate. AB - In the title compound, [Na(C(10)H(9)O(6))(C(10)H(10)O(6))].0.5C(10)H(8)N(2).H(2)O, the Na atom is eight coordinated in an distorted dicapped-octa-hedral geometry by eight O atoms from a 2-(2-carb-oxy-meth-oxy-phen-oxy)acetate (o-BDOAH) anion and a 2,2'-(o-phenyl enedi-oxy)diacetic acid (o-BDOAH(2)) mol-ecule. The uncoordinated 4,4'-bipyridine mol-ecule is arranged around an inversion center and exhibits rotational disorder. A three-dimensional supra-molecular network is built up in the crystal through O-H?O and O-H?N hydrogen bonds between the uncoordinated water mol-ecule, the uncoordinated 4,4'-bipyridine mol-ecule and the sodium complex mol-ecule. PMID- 21588117 TI - Poly[[1-(2-pyrid-yl)ethanone-kappaN,O]di-MU(2)-thio-cyanato-kappaN:S;kappaS:N cadmium(II)]. AB - In the title compound, [Cd(NCS)(2)(C(7)H(7)NO)](n), the Cd(2+) ion is six coordinated by one N,O-bidentate 1-(2-pyridyletahanone ligand, two N-bonded thio cyanate ions and two S-bonded thio-cyanate ions. In the resulting distorted CdOS(2)N(3) octa-hedron, the N atoms adopt a fac arrangement. The bridging thio cyanate ions lead to infinite sheets oriented parallel to (101) in the crystal structure. PMID- 21588118 TI - 1,4,8,11-Tetra-azoniacyclo-tetra-decane tetra-chloridocobaltate(II) dichloride. AB - The asymmetric unit of the title compound, (C(10)H(28)N(4))[CoCl(4)]Cl(2), contains two half-mol-ecules of the macrocycle, which are both completed by crystallographic inversion symmetry. In the dianion, the Co(2+) cation is tetra hedrally coordinated by four Cl atoms; the Co-Cl bond lengths correlate with the number of hydrogen bonds that the chloride ions accept. The crystal cohesion is supported by electrostatic inter-actions which, together with numerous N-H?Cl, N H?(Cl,Cl) and C-H?Cl hydrogen bonds, lead to a three-dimensional network. PMID- 21588119 TI - (Perchlorato-kappaO)tris-(triphenyl-phosphine-kappaP)silver(I). AB - In the title complex, [Ag(C(18)H(15)P)(3)(ClO(4))], the silver coord-ination environment is dominated by the distorted P(3)AgO tetra-hedron in which Ag-O = 2.608 (12) A and the Ag-P bond lengths are 2.5663 (17), 2.5076(16) and 2.5450 (17) A. The perchlorate O-atoms are disordered over two positions in a 0.584 (14):0.416 (14) ratio. PMID- 21588120 TI - [1,2-Bis(2-pyridyl-meth-oxy)benzene-kappaN,O,O',N']bis-(nitrato kappaO)copper(II). AB - In the title compound, [Cu(NO(3))(2)(C(18)H(16)N(2)O(2))], the Cu(II) ion is six coordinated in a Jahn-Teller-distorted octa-hedral environment defined by two O and two N atoms from the ligand and two O atoms from two monodentate nitrate anions. PMID- 21588121 TI - Poly[{MU(10)-[(phosphono-meth-yl)imino-dimethyl-ene]diphospho nato}dithallium(I)]. AB - The title compound, [Tl(2)(C(3)H(10)NO(9)P(3))](n), a Tl(I) organic-inorganic hybrid complex, was synthesized by the reaction of nitrilo-tris(methyl-enephospho nic acid) with thallium(I) nitrate. There are two types of Tl(+) ions in the complex, with coordination numbers of eight and seven and with stereochemically active and inactive lone-pair electrons, respectively. In the crystal, the doubly deprotonated ligands form two-dimensional hydrogen-bonded layers through O-H?O hydrogen bonds. The NH group is involved in a trifurcated intra-molecular hydrogen bond. Coordination of the phospho-nate ligands to the Tl(+) ions creates a three-dimensional structure. PMID- 21588122 TI - catena-Poly[[[tetra-aqua-erbium(III)]-MU-oxalato-kappaO,O:O,O] [bromidobis(pyrazine-2-carboxyl-ato-kappaN,O)cuprate(II)] tetra-hydrate]. AB - In the title heterometallic complex, {[Er(C(2)O(4))(H(2)O)(4)][CuBr(C(5)H(3)N(2)O(2))(2)].4H(2)O}(n), the Er(III) atom is eight-coordin-ated by four O atoms from two centrosymmetric oxalate ligands and four water mol-ecules, displaying a bicapped trigonal-prismatic geometry. The oxalate ligands bridge the Er atoms into a polymeric cationic chain along [110]. The Cu(II) atom is five-coordinated in a square-pyramidal geometry by two pyrazine-2-carboxyl-ate ligands and a Br atom, forming a discrete anion. The polymeric cations, complex anions and uncoordinated water mol-ecules are self assembled into a three-dimensional supra-molecular network through O-H?N, O-H?O and O-H?Br hydrogen bonds. PMID- 21588123 TI - Dichloridobis(isoquinoline-kappaN)zinc(II). AB - In the title compound, [ZnCl(2)(C(9)H(7)N)(2)], the Zn(II) cation is coordinated by two Cl(-) anions and two isoquinoline ligands in a distorted ZnCl(2)N(2) tetra hedral geometry; the two isoquinoline ring systems are twisted with respect to each other at a dihedral angle of 45.72 (8) degrees . The parallel isoqiunoline ring systems of adjacent mol-ecules are partially overlapped, with the shorter face-to-face distance of 3.438 (19) A indicating the existence of weak pi-pi stacking in the crystal structure. PMID- 21588124 TI - Bis[N-(4-chloro-phen-yl)pyridine-3-carboxamide]-silver(I) nitrate. AB - In the title compound, [Ag(C(12)H(9)ClN(2)O)(2)]NO(3), two N atoms from two pyridine rings of two N-(4-chloro-phen-yl)pyridine-3-carboxamide ligands coordinate to the Ag(I) atom, forming a nearly linear geometry with an N-Ag-N angle of 173.41 (7) degrees . The crystal structure is stabilized by N-H?O, C-H?O and C-H?Cl hydrogen bonds and pi-pi stacking inter-actions [centroid-centroid distance = 3.5469 (16) A] between the pyridyl and benzene rings. The shortest Ag?Ag distance is 3.2574 (5) A. PMID- 21588125 TI - [2-(3,5-Dimethyl-1H-pyrazol-1-yl-kappaN)-1,10-phenanthroline-kappaN,N']bis (nitrito-kappaO,O')cadmium(II). AB - In the title complex, [Cd(NO(2))(2)(C(17)H(14)N(4))], the Cd(II) ion assumes a distorted monocapped octa-hedral coordination geometry defined by an N(3)O(4) donor set. The crystal structure is stabilized by pi-pi stacking inter-actions [shortest centroid-centroid distance = 3.5537 (18) A]. PMID- 21588126 TI - Poly[(MU-beta-hexa-cosa-oxidoocta-molybdato)tetra-kis-[3-(2-pyrid-yl)pyrazole] dizinc(II)]. AB - In the hydro-thermally prepared title compound, [Mo(8)Zn(2)O(26)(C(8)H(7)N(3))(4)](n) or {[Zn(C(8)H(7)N(3))(2)](2)(Mo(8)O(26))}(n), the Zn(II) atom is coordinated by two N,N'-bidentate 3-(2-pyrid-yl)pyrazole ligands and two O atoms from adjacent octa molybdate polyanions, generating a distorted cis-ZnO(2)N(4) octa-hedral geometry for the divalent metal ion. The complete octa-molbydate unit is generated by crystallographic inversion symmetry. The polyhedral connectivity leads to [100] chains in the crystal and N-H?O and N-H?(O,O) hydrogen bonds help to consolidate the packing. PMID- 21588127 TI - Dibromido{2-[1-(cyclo-propyl-imino)-eth-yl]pyridine}-zinc(II). AB - In the title compound, [ZnBr(2)(C(10)H(12)N(2))], the Zn(2+) ion is coordinated by the N,N'-bidentate Schiff base ligand and two bromode ions in a distorted tetra-hedral arrangement. The dihedral angle between the pyridine and the cyclo propyl rings is 95.4 (8) degrees . PMID- 21588128 TI - Bis[2-(cyclo-pentyl-imino-meth-yl)-5-meth-oxy-phenolato]copper(II). AB - The title compound, [Cu(C(13)H(16)NO(2))(2)], is a mononuclear copper(II) complex derived from the Schiff base ligand 2-(cyclo-pentyl-imino-meth-yl)-5-meth-oxy phenol and copper acetate. The Cu(II) atom is four-coordinated by the phenolate O atoms and imine N atoms from two Schiff base ligands, in a highly distorted square-planar geometry. The O- and N-donor atoms are mutually trans and the dihedral angle between the two benzene rings is 55.8 (3) degrees . PMID- 21588129 TI - catena-Poly[diacridinium [zinc(II)-di-MU-pyrazine-2,3-dicarboxyl-ato kappaN,O:O;O:N,O]]. AB - The crystal structure of the title compound, {(C(13)H(10)N)(2)[Zn(C(6)H(2)N(2)O(4))(2)]}(n), consists of polymeric Zn complex anions and discrete acridinium cations. The Zn cation, located on an inversion center, is N,O-chelated by two pyrazine-2,3-dicarboxyl-ate (pyzdc) anions in the basal plane, and is further coordinated by two carboxyl-ate O atoms from adjacent pyzdc anions in the axial directions with a longer Zn-O bond distance, forming a distorted ZnN(2)O(4) coordination geometry. The pyzdc anions bridge the Zn cations, forming polymeric chains running along the crystallographic b axis. The acridinium cations are linked to the complex chains via N-H?O and C-H?O hydrogen bonding. Significant pi-pi stacking between parallel acridinium ring systems is observed in the crystal structure, face-to-face distances being 3.311 (3) and 3.267 (4) A. PMID- 21588130 TI - Bis{1-[3-(diethyl-ammonio)-propyl-imino-meth-yl]naphthalen-2-olato}nickel(II) dinitrate. AB - The asymmetric unit of the title compound, [Ni(C(18)H(24)N(2)O)(2)](NO(3))(2), consists of one half of the centrosymmetric nickel(II) complex cation and a nitrate anion. The Ni(II) atom, lying on an inversion center, is four-coordinated by the phenolate O atoms and imine N atoms of two Schiff base ligands, forming a square-planar geometry. The O- and N-donor atoms are mutually trans. In the crystal structure, the nitrate anions are linked to the complex cations by inter molecular N-H?O hydrogen bonds. PMID- 21588131 TI - 1,5-Bis[2,6-bis-(2,4,6-triisopropyl-phen-yl)phen-yl]-2,3,4,6,7-penta-tellura-1,5 di-stannabicyclo-[3.1.1]hepta-ne. AB - The title compound, [Sn(2)(C(72)H(98))Te(2)(Te(3))], has a cage-like structure with bulky aryl substituents on the Sn atoms. The mol-ecule sits over a crystallographic twofold axis, and hence the asymmetric unit consists of one half mol-ecule. Due to the twofold axis, the tritelluride part has a 1:1 disorder. One of the six-membered rings has a boat conformation, whereas the other has a chair conformation. The ditelluradistannane ring has a bent structure, with a dihedral angle of 32.89 (2) degrees between the two Te-Sn-Te planes. PMID- 21588132 TI - Diaqua-(1,4,8,11-tetra-aza-cyclo-tetra-decane-kappaN,N,N,N)copper(II) dihepta noate dihydrate. AB - The Cu(II) atom in the title salt, [Cu(C(10)H(24)N(4))(H(2)O)(2)][CH(3)(CH(2))(5)CO(2)](2).2H(2)O, is chelated by the four N atoms of the 1,4,8,11-tetra-aza-cyclo-tetra-decane (cyclam) ligand and is coordinated by two water mol-ecules in a tetra-gonally Jahn-Teller-distorted octa-hedral geometry. The Cu(II) atom lies on a center of inversion. The cations, anions and uncoordinated water mol-ecules are linked by N-H?O and O-H?O hydrogen bonds, forming a layer structure parallel to (100). The alkyl chain of the anion is disordered over two positions in a 0.82 (1):0.18 (1) ratio. PMID- 21588133 TI - Diaqua-(1,4,8,11-tetra-aza-cyclo-tetra-decane-kappaN,N,N,N)copper(II) dideca noate dihydrate. AB - The Cu(II) atom in the title salt, [Cu(C(10)H(24)N(4))(H(2)O)(2)][CH(3)(CH(2))(8)CO(2)](2).2H(2)O, is chelated by the four N atoms of the 1,4,8,11-tetra-aza-cyclo-tetra-decane (cyclam) ligand and is coordinated by two water mol-ecules in a Jahn-Teller-type tetra-gonally distorted octa-hedral geometry. The Cu(II) atom lies on a center of inversion. The cations, anions and uncoordinated water mol-ecules are linked by N-H?O and O H?O hydrogen bonds, forming a layer structure parallel to (001). PMID- 21588134 TI - Diaqua-(1,4,8,11-tetra-aza-cyclo-tetra-decane-kappaN,N,N,N)copper(II) bis (2,3,4,5,6-penta-fluoro-benzoate) dihydrate. AB - The Cu(II) atom in the title salt, [Cu(C(10)H(24)N(4))(H(2)O)(2)](C(6)F(5)CO(2))(2).2H(2)O, is chelated by the four N atoms of the 1,4,8,11-tetra-aza-cyclo-tetra-decane (cyclam) ligand and is coordinated by two water mol-ecules in a Jahn-Teller-type tetra-gonally distorted octa-hedral geometry. The Cu(II) atom lies on a center of inversion. The cations, anions and uncoordinated water mol-ecules are linked by N-H?O and O-H?O hydrogen bonds, forming a layer structure parallel to (001). PMID- 21588135 TI - Diaqua-(1,4,8,11-tetra-aza-cyclo-tetra-decane-kappaN,N,N,N)copper(II) bis-(4 methyl-benzoate) monohydrate. AB - The Cu(II) atom in the title salt, [Cu(C(10)H(24)N(4))(H(2)O)(2)](C(8)H(7)O(2))(2).H(2)O, is chelated by the four N atoms of the 1,4,8,11-tetra-aza-cyclo-tetra-decane (cyclam) ligand and is coordinated by two water mol-ecules in a Jahn-Teller-type of tetra-gonally distorted octa-hedral geometry. The cations, anions and lattice water mol-ecules are linked by N-H?O and O-H?O hydrogen bonds to form a layer structure parallel to (001). PMID- 21588136 TI - Diaqua-bis-(4-meth-oxy-benzoato-kappaO)bis-(nicotinamide-kappaN)nickel(II) dihydrate. AB - In the mononuclear title compound, [Ni(C(8)H(7)O(3))(2)(C(6)H(6)N(2)O)(2)(H(2)O)(2)].2H(2)O, the Ni(II) ion is located on a crystallographic inversion center. The asymmetric unit further contains one 4-meth-oxy-benzoate anion, one nicotinamide (NA) ligand and one coordinated and one uncoordinated water mol-ecule; all ligands are monodentate. The four O atoms in the equatorial plane around the Ni(II) ion form a slightly distorted square-planar arrangement, while the slightly distorted octa-hedral coordination is completed by the two pyridine N atoms of the NA ligands in the axial positions. The dihedral angle between the carboxyl-ate group and the attached benzene ring is 7.2 (1) degrees , while the pyridine and benzene rings are oriented at a dihedral angle of 72.80 (4) degrees . An intra-molecular O-H?O hydrogen bond links the uncoordinated water mol-ecule to one of the carboxyl-ate groups. In the crystal structure, inter-molecular O-H?O, N-H?O and C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21588137 TI - (18-Crown-6)(trifluoro-methane-sulfonato)-sodium. AB - The title compound, [Na(CF(3)O(3)S)(C(12)H(24)O(6))], features a sodium cation that is coordinated by eight O atoms in an irregular hexa-gonal bipyramidal environment. The equatorial positions are occupied by the six O atoms of an 18 crown-6 ether ring. In the axial positions, there is one O atom of a trifluoro methane-sulfonate anion and an ether O atom of a symmetry-equivalent crown ether ring. In this way, centrosymmetric dimers are formed. PMID- 21588138 TI - (1,4,7,10-Tetra-aza-cyclo-dodecane-kappaN,N,N,N)(tetra-oxidomolybdato kappaO)copper(II) monohydrate. AB - In the title compound, [CuMoO(4)(C(8)H(20)N(4))].H(2)O, the Cu(II) atom is coordinated by four N atoms of the 1,4,7,10-tetra-aza-cyclo-dodecane (cyclen) ligand and one O atom of the molybdate unit in a distorted square-pyramidal environment. The water mol-ecules are linked to the complex unit to form centrosymmetric dimers [R(4) (4)(12) and R(4) (4)(16)] and discrete D(3) (2)(9), D(3) (3)(11) and D(3) (3)(13) chains by O-H?O and N-H?O inter-actions. Additionally, the complex mol-ecules are linked into C(4) (4)(18) chain motifs by N-H?O inter-actions. As a result [(cyclen)CuMoO(4)] units and water molecules are linked to layers that are oriented parallel to the ac plane. The stacking of the layers in the b-axis direction is supported by weak C-H?O hydrogen bridges. PMID- 21588139 TI - Bis(1-benzyl-piperazine-1,4-diium) hexa-chloridocadmate(II) dihydrate. AB - The asymmetric unit of the title compound, (C(11)H(18)N(2))(2)[CdCl(6)].2H(2)O, consists of one 1-benzyl-piperazine-1,4-diium dication, one water mol-ecule and one-half of a [CdCl(6)](4-) anion, located on an inversion centre. The crystal packing is governed by an extensive three-dimensional network of inter-molecular O-H?Cl, C-H?Cl, N-H?O and N-H?Cl hydrogen bonds, two of them bifurcated. PMID- 21588140 TI - Diaqua-bis-(4-carb-oxy-2-propyl-1H-imidazole-5-carboxyl-ato-kappaN,O)copper(II) N,N-dimethyl-formamide disolvate. AB - In the title complex, [Cu(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)].2C(3)H(7)NO, the Cu(II) ion, lying on an inversion center, is six-coordinated in a slightly distorted octa-hedral geometry. Two N atoms and two O atoms from two H(2)pimda (H(3)pimda is 2-propyl-1H-4,5-dicarb-oxy-lic acid) ligands are in the equatorial plane. The axial positions are occupied by two O atoms from two water mol-ecules. A two dimensional supra-molecular network parallel to (001) is constructed by N-H?O and O-H?O hydrogen bonds. An intra-molecular O-H?O hydrogen bond is also observed. PMID- 21588141 TI - Diaqua-bis-(5-carb-oxy-2-propyl-1H-imidazole-4-carboxyl-ato-kappaN,O)nickel(II) tetra-hydrate. AB - In the title complex, [Ni(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)].4H(2)O, the Ni(II) ion is coordinated in a slightly distorted octa-hedral environment formed by two bis chelating H(2)pimda (H(3)pimda is 2-propyl-1H-4,5-dicarb-oxy-lic acid) ligands and two coordinated water mol-ecules. In the crystal structure, a three dimensional framework is formed by inter-molecular O-H?O and N-H?O hydrogen bonds involving the solvent water mol-ecules, coordinated water mol-ecules, carboxyl ate O atoms and the protonated N atoms of the H(2)pimda ligands. The propyl groups of each H(2)pimda ligand are disordered over two sets of sites with refined occupancies of 0.50 (2):0.50 (2) and 0.762 (11):0.238 (11). In one water solvent mol-ecule, one of the H atoms was refined as disordered over two sites of equal occupancy. PMID- 21588142 TI - Di-MU-chlorido-bis-{chlorido[(R)/(S)-1,5-di-phenyl-3-(2-pyridyl-kappaN)-2 pyrazoline-kappaN]zinc(II)}. AB - In the centrosymmetric binuclear title compound, [Zn(2)Cl(4)(C(20)H(17)N(3))(2)], the coordination geometry of the Zn(II) ion can be described as a distorted ZnN(2)Cl(3) trigonal bipyramid (tau = 0.89), arising from the N,N'-bidentate ligand, a terminal chloride ion and two bridging chloride ions. The N atoms occupy one axial and one equatorial site and the terminal chloride ion occupies an equatorial site. The dihedral angle between the pyridine and pyrazole rings is 12.8 (2) degrees . In the crystal, aromatic pi-pi stacking [centroid-centroid separations = 3.812 (3) and 3.848 (3) A] and C-H?Cl and C-H?pi inter-actions help to establish the packing. PMID- 21588143 TI - Poly[dimethyl-ammonium [aquadi-MU(2)-oxalato-dysprosate(III)] trihydrate]. AB - The title compound, {(C(2)H(8)N)[Dy(C(2)O(4))(2)(H(2)O)].3H(2)O}(n), was obtained as an unexpected product under hydro-thermal conditions. The Dy(III) atom is chelated by four oxalate anions, two of which are situated on two different centres of inversion. The distorted tricapped trigonal-prismatic coordination sphere of the Dy(III) atom is completed by a water mol-ecule. The bridging mode of the anions results in the formation of a three-dimensional network with cavities where the ammonium cations and the uncoordinated water mol-ecules reside. The structure is stabilized by numerous N-H?O and O-H?O hydrogen-bonding inter-actions. PMID- 21588144 TI - catena-Poly[[(nitrato-kappaO,O')silver(I)]-MU-N,N'-bis-(3-pyridyl-methyl idene)benzene-1,4-diamine]. AB - In the title compound, [Ag(NO(3))(C(18)H(14)N(4))](n), the Ag(I) atom is coordinated by two N atoms from two N,N'-bis-(3-pyridyl-methyl-idene)benzene-1,4 diamine (bpbd) mol-ecules and two O atoms from a bidentate nitrate anion. The bpbd mol-ecules bridge the Ag atoms into a chain. Two adjacent chains are further connected by Ag?Ag inter-actions [3.1631 (8) A], forming a double-chain structure. A pi-pi inter-action [centroid-centroid distance = 3.758 (3) A] occurs between the double chains. Inter-chain C-H?O hydrogen bonds are observed. PMID- 21588145 TI - Bis(4-acetyl-3-methyl-1-phenyl-1H-pyrazol-5-olato-kappaO,O')bis-(N,N-dimethyl formamide-kappaO)nickel(II). AB - The title complex, [Ni(C(12)H(11)N(2)O(2))(2)(C(3)H(7)NO)(2)], lies on on an inversion center. The Ni(II) ion is coordinated in a slightly distorted octa hedral coordination enviroment by four O atoms from two bis-chelating 4-acety-3 methyl-1-phenyl-1H-pyrazol-5-olate ligands in the equatorial plane and two O atoms from two N,N-dimethyl-formamide ligands in the axial sites. In the crystal structure, weak inter-molecular pi-pi stacking inter-actions with centroid centroid distances of 3.7467 (13) A link mol-ecules into chains extending alongthe b axis. PMID- 21588146 TI - catena-Poly[[aqua-(5,5'-dimethyl-2,2'-bipyridine-kappaN,N')copper(II)]-MU-2,2' oxydibenzoato-kappaO:O']. AB - In the title compound, [Cu(C(14)H(8)O(5))(C(12)H(12)N(2))(H(2)O)](n), the Cu(II) ion is penta-coordinated in a square-pyramidal geometry. Two N atoms of the chelating 5,5'-dimethyl-2,2'-bipyridine (dbp) ligand and two O atoms of two different 2,2'-oxydibenzoic (odb) ligands occupy the basal plane while the water O atom completes the square-pyramidal geometry at the apical site. The non-water N(2)O(2) donor atoms are nearly coplanar, with a mean deviation from the least squares plane of 0.0518 (11) A and the Cu atom is displaced by 0.1507 (11) A from this plane towards the apical water O atom. Further coordination via the 2,2' oxydibenzoate anions forms a one-dimensional coordination polymer extending parallel to [010]. In the crystal structure, O-H?O hydrogen bonds link the mol ecules into a two-dimensional supra-molecular structure. PMID- 21588147 TI - Racemic tricarbon-yl(eta-7-meth-oxy-flavan)chromium(0). AB - IN THE TITLE COMPOUND [SYSTEMATIC NAME: tricarbonyl(eta(6)-7-methoxy-2-phenyl-3,4 dihydro-2H-1-benzopyran)chromium(0)], [Cr(C(16)H(16)O(2))(CO)(3)], the Cr(CO)(3) unit is coordinated by the phenyl-ene ring of the flavan ligand, exhibiting a three-legged piano-stool conformation, with a point to plane distance of 1.750 (1) A. The phenyl ring is twisted away from the fused ring system by 36.49 (5) degrees (r.m.s. deviation = 0.027 A; fitted atoms are the C(6) ring and the attached fused-ring C and O atoms). The dihydro-pyran ring displays a distorted envelope configuration by displacement of the phenyl-bearing and the adjacent ring C atoms from the fused-ring system plane by 0.356 (2) and 0.402 (2) A, respectively. PMID- 21588148 TI - A binuclear molybdenum oxyfluoride: MU-oxido-bis-[(2,2'-bipyrid yl)fluoridodioxidomolybdenum(VI)]. AB - The title compound, [Mo(2)F(2)O(5)(C(10)H(8)N(2))(2)], is a centrosymmetric binuclear molybdenum(VI) species with the metal atoms in a distorted octa-hedral environment. The coordination geometries of the symmetry-equivalent molybdenum sites are defined by the cis-terminal oxide groups and the N-atom donors of the bipyridyl ligand in the equatorial plane with axial F and bridging O atoms. The bridging O atom occupies a center of symmetry. The mol-ecules stack in the a-axis direction, and the crystal packing is stabilized by weak intra- and inter molecular C-H?O and C-H?F hydrogen bonds. PMID- 21588149 TI - Diaqua-bis-(4-meth-oxy-benzoato-kappaO)bis-(nicotinamide-kappaN)cobalt(II) dihydrate. AB - In the mononuclear title compound, [Co(C(8)H(7)O(3))(2)(C(6)H(6)N(2)O)(2)(H(2)O)(2)].2H(2)O, the Co(II) ion is located on a crystallographic inversion center. The asymmetric unit is completed by one 4-meth-oxy-benzoate anion, one nicotinamide (NA) ligand and one coordinated and one uncoordinated water mol-ecule. All ligands act in a monodentate mode. The four O atoms in the equatorial plane around the Co(II) ion form a slightly distorted square-planar arrangement, while the slightly distorted octa-hedral coordination is completed by the two pyridine N atoms of the NA ligands in the axial positions. The dihedral angle between the carboxyl-ate group and the attached benzene ring is 6.47 (7) degrees , while the pyridine and benzene rings are oriented at a dihedral angle of 72.80 (4) degrees . An O-H?O hydrogen bond links the uncoordinated water mol-ecule to one of the carboxyl-ate groups. In the crystal structure, inter-molecular O-H?O, N-H?O and C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21588150 TI - Bromido(2-{1-[2-(morpholin-4-yl)ethyl-imino]-eth-yl}phenolato)copper(II). AB - In the title complex, [CuBr(C(14)H(19)N(2)O(2))], the Cu(II) atom is coordinated by one phenolate O, one imine N and one amine N atom of the tridentate Schiff base ligand and by one bromide ion, resulting in a distorted CuBrN(2)O square planar geometry, with the N atoms in a cis arrangement. The morpholine ring adopts a chair conformation. PMID- 21588151 TI - Bromido(2-{1-[2-(piperidin-1-yl)ethyl-imino]-eth-yl}phenolato)copper(II). AB - In the title complex, [CuBr(C(15)H(21)N(2)O)], the Cu(II) atom is coordinated by one phenolate O, one imine N and one amine N atom of the tridentate Schiff base ligand and by one bromide ion, resulting in a distorted CuBrN(2)O square-planar geometry for the metal ion, with the N atoms in a cis conformation. PMID- 21588152 TI - 1-[(2,3,4,5,6-Penta-fluoro-phen-yl)ethyn-yl]ferrocene. AB - The mol-ecular structure of the title compound, [Fe(C(5)H(5))(C(13)H(4)F(5))], consists of a ferrocenyl group and a 2,3,4,5,6-penta-fluoro-benzene group linked through an ethyne spacer. The crystal packing is dominated by inter-molecular C H?F hydrogen bonds, C-F?pi inter-actions between the penta-fluoro-benzene groups [F?centroid distances = 3.882 (2) and 3.884 (2) A] and pi-pi inter-actions between the penta-fluoro-benzene and cyclo-penta-dienyl rings [centroid-centroid distance = 3.741 (1) A]. PMID- 21588153 TI - [(1R,4S)-(+)-3-Benzoyl-1,7,7-trimethyl-bicyclo-[2.2.1]heptan-2-olato kappaO,O](eta-norbornadiene)rhodium(I). AB - In the title complex mol-ecule, [Rh(C(17)H(19)O(2))(C(7)H(8))], the rhodium(I) metal centre is coordinated by the O atoms of a benzoyl-camphorate anion and the C=C bonds of the norbornadiene mol-ecule into a slightly distorted square-planar coordination geometry. The six-membered chelate ring is essentially planar (r.m.s. deviation = 0.0378 A) and forms a dihedral angle of 31.67 (11) degrees with the phenyl ring. PMID- 21588154 TI - Bis(2,6-diamino-pyridin-1-ium) hexa-aqua-cobalt(II) disulfate dihydrate. AB - In the title compound, (C(5)H(8)N(3))(2)[Co(H(2)O)(6)](SO(4))(2).2H(2)O, the complete complex cation is generated by crystallographic inversion symmetry, such that the Co(II) cation is octa-hedrally coordinated by six water mol-ecules. The organic cation is essentially planar, with a maximum deviation of 0.013 (1) A. In the crystal structure, the ions and mol-ecules are linked into a pseudo-layered three-dimensional supra-molecular network via O-H?O and N-H?O hydrogen bonds. Weak inter-molecular pi-pi inter-actions further stabilize the crystal structure [centroid-centroid distance = 3.5231 (4) A]. PMID- 21588155 TI - trans-{1,8-Bis[(S)-1-phenyl-eth-yl]-1,3,6,8,10,13-hexa-aza-cyclo-tetra-deca ne}bis(thio-cyanato--kappaN)copper(II). AB - In the title thio-cyanate-coordinated aza-macrocyclic copper(II) complex, [Cu(NCS)(2)(C(24)H(38)N(6))], the Cu(II) atom is coordinated by the four secondary N atoms of the aza-macrocyclic ligand and by the two N atoms of the thio-cyanate ions in a tetra-gonally distorted octa-hedral geometry. The average equatorial Cu-N bond length is shorter than the average axial Cu-N bond length [2.010 (2) and 2.528 (4) A, respectively]. An N-H?N hydrogen-bonding inter-action between the secondary amine N atom and the adjacent thio-cyanate ion leads to a polymeric chain along the a axis. PMID- 21588156 TI - [1,2-Bis(diphenyl-phosphino)ethane]-chlorido(eta-penta-methyl-cyclo-penta-dien yl)iron(II) dichloro-methane solvate. AB - In the title compound, [Fe(C(10)H(15))Cl(C(26)H(24)P(2))].CH(2)Cl(2), the Fe(II) atom is coordinated by two P atoms from a 1,2-bis-(diphenyl-phosphino)ethane ligand [Fe-P = 2.2130 (7) and 2.2231 (7) A], a chloride anion [Fe-Cl = 2.3329 (7) A] and a penta-methyl-cyclo-penta-dienyl (Cp*) ligand [Fe-centroid(Cp*) = 1.732 (3) A] in a typical piano-stool geometry. In the crystal structure, the complex and solvent mol-ecules are paired via weak C-H?Cl inter-actions. PMID- 21588157 TI - Bis[N,N-bis-(diphenyl-phosphan-yl)pentyl-amine-kappaP,P']platinum(II) bis-(hexa fluoridophosphate) dichloro-methane disolvate. AB - The Pt(II) atom in the title compound, [Pt(C(29)H(31)NP(2))(2)](PF(6))(2).2CH(2)Cl(2), is coordinated by four P atoms from two bis-(di-phenyl-phosphan-yl)pentyl-amine ligands with an average Pt-P distance of 2.300 (1) A. The coordination around the Pt(II) atom shows a highly distorted square-planar geometry, as evidenced by the P-Pt-P bite angles of 70.45 (3) and 70.64 (3) degrees . The asymmetric unit contains two hexa fluoridophosphate ions, the metal complex and two dichloro-methane solvent mol ecules. One of the chloride atoms of one of the dichloro-methane mol-ecules is disordered over two sites in a 0.515 (3):0.485 (3) ratio. C-H?F hydrogen bonds stabilize the crystal packing. PMID- 21588158 TI - {4-Hy-droxy-N'-[(2-oxido-1-naphthyl-kappaO)methyl-idene]benzohydrazidato kappaN',O}dimethyl-tin(IV). AB - Two independent but very similar mol-ecules comprise the asymmetric unit of the title compound, [Sn(CH(3))(2)(C(18)H(12)N(2)O(3))]. Each Sn atom is coordinated by two methyl groups and two O atoms and an N atom from the dinegative tridentate ligand. The resultant C(2)NO(2) donor set defines a coordination geometry inter mediate between square-pyramidal and trigonal-pyramidal, with a small tendency towards the former. Zigzag chains running along the a axis mediated by O-H?N hydrogen bonding characterize the crystal packing. These are connected into layers in the ab plane by a combination of C-H?N and pi-pi [centroid-centroid distances = 3.658 (2) and 3.6740 (18) A] inter-actions. The layers are connected along the c axis via C-H?O inter-actions. PMID- 21588159 TI - Tris(ethyl-enediamine)-nickel(II) 1H-pyrazole-3,5-dicarboxyl-ate 1.67-hydrate. AB - The asymmetric unit of the title compound, [Ni(C(2)H(8)N(2))(3)](C(5)H(2)N(2)O(4)).1.67H(2)O, consists of three [Ni(en)(3)](2+) dications (en is ethyl-enediamine), three [(pzdc)(3)](2-) dianions (pzdc is pyrazole-3,5-dicarboxyl-ate) and five water mol-ecules. In each complex dication, the Ni(II) atom is coordinated by six N atoms from three en ligands forming a distorted octa-hedral coordination geometry. In the crystal, the ions and water mol-ecules are linked into a three-dimensional framework by a large number of N-H?O and O-H?O hydrogen bonds. PMID- 21588160 TI - {4-[(3-Formyl-4-hy-droxy-phen-yl)diazen-yl]benzoato}triphenyl-tin. AB - In the title compound, [Sn(C(6)H(5))(3)(C(14)H(9)N(2)O(4))], the Sn atom has a distorted tetra-hedral geometry with one of the carboxyl-ate O atoms and the C atoms from three phenyl groups. The other carboxyl-ate O atom of the benzoate ligand inter-acts weakly with the Sn atom, with an Sn?O distance of 2.790 (2) A, which causes a distortion of the tetra-hedral coordination geometry. PMID- 21588161 TI - Poly[diaqua-[3,5-bis-(trifluoro-meth-yl)pyrazolido]potassium]. AB - The asymmetric unit of the title compound, [K(C(5)HF(6)N(2))(H(2)O)(2)](n), is composed of two 3,5-bis-(trifluoro-meth-yl)pyrazol-ide anions, two potassium cations and four water mol-ecules. The water mol-ecules and 3,5-bis-(trifluoro meth-yl)pyrazolide anions act as bridges between the potassium cations. Each potassium cation is surrounded by four O atoms [K-O = 2.705 (3)-2.767 (3) A] and four F atoms [K-F = 2.870 (7)-3.215 (13) A]. The water mol-ecules and the 3,5-bis (trifluoro-meth-yl)pyrazolide anions are connected by O-H?N hydrogen bonds, forming layers in the ab plane. All -CF(3) groups show rotational disorder between two orientations each. PMID- 21588162 TI - Nonacarbonyl-1kappaC,2kappaC,3kappaC-MU-bis-(diphenyl-arsino)methane 1:2kappaAs:As'-[tris-(2-chloro-eth-yl) phosphite-3kappaP]-triangulo triruthenium(0). AB - In the title triangulo-triruthenium(0) compound, [Ru(3)(C(25)H(22)As(2))(C(6)H(12)Cl(3)O(3)P)(CO)(9)], the bis-(diphenyl arsino)methane ligand bridges an Ru-Ru bond and the monodentate phosphine ligand bonds to the third Ru atom. Both the arsine and phosphine ligands are equatorial with respect to the Ru(3) triangle. In addition, each Ru atom carries one equatorial and two axial terminal carbonyl ligands. In the crystal packing, the mol-ecules are linked by inter-molecular C-H?O hydrogen bonds into a three dimensional framework. Weak inter-molecular C-H?pi inter-actions further stabilize the crystal structure. PMID- 21588163 TI - catena-Poly[[triphenyl-tin(IV)]-MU-2-(cyclo-hexyl-amino-carbon-yl)benzoato kappaO:O]. AB - In the title polymeric complex, [Sn(C(6)H(5))(3)(C(14)H(16)NO(3))](n), adjacent triphenyl-tin cations are bridged by the N-cyclo-hexyl-phthalamate anion through the carboxyl-ate and carbonyl O atoms, forming a helical chain running along the b axis. The amide N atom is a hydrogen-bond donor to the uncoordinated carboxyl ate O atom. The geometry at the five-coordinate Sn atom is trans-C(3)SnO(2) trigonal-bipyramidal. PMID- 21588164 TI - Poly[bis-[MU-1,4-bis-(1,2,4-triazol-1-ylmeth-yl)benzene kappaN:N]dichloridomanganese(II)]. AB - The Mn(II) atom in the title coordination polymer, [MnCl(2)(C(12)H(12)N(6))(2)](n), lies on a center of inversion in a six coordinate octa-hedral environment comprising four N-atom donors from four N heterocyclic ligands and two chloride atoms. Bridging by the ligands results in a layer structure of a 14.79 (5) * 14.79 (5) A (4,4) rhombic net topology, with the Mn(II) atoms all lying on a plane. The parallel layers stack in an ABCABC... manner through inter-layer C-H?N and C-H?Cl hydrogen bonds. PMID- 21588165 TI - catena-Poly[[dibromidozinc(II)]-MU-4-(3-pyrid-yl)-4H-1,2,4-triazole]. AB - The title complex, [ZnBr(2)(C(7)H(6)N(4))](n), was formed under hydro-thermal conditions using the ligand 4-(3-pyrid-yl)-4H-1,2,4-triazole (L). The unique Zn(II) ion is coordinated by one triazole N atom, one pyridine N atom and two Br atoms in a slightly distorted tetra-hedral coordination environment. Symmetry related Zn(II) ions are connected by bridging L ligands into chains parallel to [001] in which the Zn?Zn separation is 8.643 (7) A. In the crystal structure, weak inter-molecular C-H?Br hydrogen bonds link the chains into a three dimensional network. PMID- 21588166 TI - MU-Adipato-bis-[chlorido(2,2':6',2''-terpyridine)-copper(II)] tetra-hydrate. AB - In the title compound, [Cu(2)(C(6)H(8)O(4))Cl(2)(C(15)H(11)N(3))(2)].4H(2)O, the dinuclear copper complex is located on a crystallographic inversion centre. Each Cu atom is in a distorted square-pyramidal coordination environment, with one O atom of an adipate dianion and three N atoms from the 2,2':6',2''-terpyridine ligand occupying the basal plane, and one chlorine in the apical site. In addition, there is weak Cu-O inter-action opposite of the chlorine with a distance of 2.768 (1) A. The adipate ligand adopts a gauche-anti-gauche conformation. The inter-stitial water mol-ecules form hydrogen-bonded tertramers that are connected to the complexes via O-H?O and O-H?Cl hydrogen bonds, thus leading to the formation of tightly hydrogen-bonded layers extending perpendicular to the b-axis direction. PMID- 21588167 TI - {2-[2-(Isopropyl-amino)-ethyl-imino-meth-yl]-5-meth-oxy-phenolato}(thio-cyanato- kappaN)nickel(II). AB - In the title mononuclear complex, [Ni(C(13)H(19)N(2)O(2))(NCS)], the Ni(II) ion is coordinated by one phenolate O atom, one imine N atom, and one amine N atom of a 2-[2-(isopropyl-amino)-ethyl-imino-meth-yl]-5-meth-oxy-phenolate Schiff base ligand, and by one N atom of a thio-cyanate ligand, forming a slightly distorted square-planar geometry. PMID- 21588168 TI - (Methanol-kappaO)bis-{2-meth-oxy-6-[(4-methyl-phen-yl)iminiometh-yl]phenolato kappaO,O'}tris-(nitrato-kappaO,O')cerium(III). AB - The asymmetric unit of title compound, [Ce(NO(3))(3)(C(15)H(15)NO(2))(2)(CH(3)OH)], consists of two Schiff base 2-meth oxy-6-[(4-methyl-phen-yl)iminiometh-yl]phenolate (HL) ligands, three nitrate anions and a methanol ligand. The Ce(III) ion is 11-coordinated: three nitrate radical anions coordinate to the Ce(III) ion through O atoms, two HL ligands chelate the Ce(III) ion through the O atoms of the phenolate and meth-oxy groups, and one methanol mol-ecule coordinates to Ce(III) ion through its O atom. The O atom of one nitrate anion is disordered over two sites of equal occupancy. The protonated imine N atoms are involved in intra-molecular hydrogen bonds with the phenoxide groups. C-H?O inter-actions are also observed. PMID- 21588169 TI - Bis{MU-4,4',6,6'-tetra-tert-butyl-2,2'-[N-(2-oxidoeth-yl)imino-dimethyl ene]diphenolato}dialuminium(III). AB - The title compound, [Al(2)(C(32)H(48)NO(3))(2)], exists as a dimer with bridging ethoxide groups. It was isolated from a reaction mixture of the parent ligand and trimethyl-aluminium in tetra-hydro-furan. The geometry around the Al(III) atom is a slightly distorted trigonal-bipyramid, typical of atrane derivatives. PMID- 21588170 TI - Di-n-butyl-bis-(N-cyclo-hexyl-N-ethyl-dithio-carbamato-kappaS,S')tin(IV). AB - The Sn(IV) atom in the title compound, [Sn(C(4)H(9))(2)(C(9)H(16)NS(2))(2)], is chelated by the two dithio-carbamate ions in a six-coordinate skew-trapezoidal bipyramidal geometry. The two butyl groups are disordered over two positions in a 1:1 ratio. PMID- 21588171 TI - Bromido{N-methyl-N'-[1-(2-pyrid-yl)ethyl-idene]ethane-1,2-diamine-kappaN,N',N''} (thio-cyanato-kappaN)-copper(II). AB - In the title mononuclear copper(II) compound, [CuBr(NCS)(C(10)H(15)N(3))], the Cu(II) atom is five-coordinated by three N atoms of the Schiff base ligand, the N atom of a thio-cyanate ligand and by one bromide ion forming a distorted square pyramidal geometry. In the crystal structure, mol-ecules are linked through inter molecular N-H?Br hydrogen bonds into chains propagating along [101]. PMID- 21588172 TI - Diacetato-(N,N-diethyl-ethylenediamine)-zinc(II). AB - In the title compound, [Zn(CH(3)COO)(2)(C(6)H(16)N(2))], the Zn(II) atom is coordinated by two N atoms of one bidentate diethyl-ethylenediamine ligand and two O atoms of two acetate anions in a distorted tetra-hedral geometry. The acetate ligands are asymmetrically coordinated to the Zn atom with two different C-O distances of 1.234 (4) and 1.275 (4) A. The dihedral angle between the N/Zn/N and O/Zn/O planes is 83.11 (8) degrees . There are two independent mol-ecules in the asymmetric unit. N-H?O hydrogen bonding links mol-ecules into a three dimensional network. PMID- 21588173 TI - (OC-6-33)-(2,2'-Bipyridine-kappaN,N')trimeth-yl(2-methyl-sulfanyl-2-thia-zoline kappaN)platinum(IV) tetra-fluoridoborate. AB - The asymmetric unit of the title complex, [Pt(CH(3))(3)(C(10)H(8)N(2))(C(4)H(7)NS(2))]BF(4), contains two crystallographically independent mol-ecules. The Pt(IV) atom in each complex cation exhibits a distorted octa-hedral coordination geometry, built up by three methyl ligands in a facial binding fashion, a bipyridine ligand and a monodentately N-bound 2-methyl-sulfanyl-2-thia-zoline ligand (configuration index: OC-6-33). In the crystal structure, weak inter-molecular C-H?F hydrogen bonds are found between the complex cations and BF(4) (-) anions. PMID- 21588174 TI - catena-Poly[[[bis-(thio-cyanato-kappaN)zinc(II)]-MU-1,2-bis-{[2-(2-pyrid-yl)-1H imidazol-1-yl]meth-yl}benzene] 0.28-hydrate]. AB - The title one-dimensional coordination polymer, {[Zn(NCS)(2)(C(24)H(20)N(6))(2)].0.28H(2)O}(n), was obtained by the reaction of Zn(OAc)(2).2H(2)O, KSCN and 1,2-bis-{[2-(2-pyrid-yl)-1H-imid-azol-1-yl]meth yl}benzene (hereafter L). The Zn(II) ion shows a distorted octa-hedral coordination geometry and is coordin-ated by two N atoms from two SCN(-) anions and four N atoms from two organic ligands. The L ligands act as bridging bis chelating ligands with cis coordination modes at the Zn(II) ion. One-dimensional coordination polymers are arranged into layers by pi-pi stacking inter-actions between the imidazole rings of adjacent chains, with an inter-planar distance of 3.46 (1) A and centroid-centroid distances of 3.8775 (16) A. One of the thio cyanate ligands is disordered over two positions with an occupancy factor of 0.564 (3) for the major component. The partially occupied water mol-ecule forms an O-H?S hydrogen bond with the disordered thio-cyanate group. PMID- 21588175 TI - Poly[aqua-hemi(MU(4)-oxalato)[MU(3)-5-(pyrazin-2-yl)tetra-zolato]cadmium(II)]. AB - In the title polymeric complex, [Cd(C(5)H(3)N(6))(C(2)O(4))(0.5)(H(2)O)](n), the Cd(II) ion is coordinated by four O atoms and three N atoms from two 5-(pyrazin-2 yl)tetra-zolate ligands, two oxalate ligands and one water mol-ecule, displaying a distorted monocapped octa-hedral geometry. The bridging ligands link metal centres, forming a three-dimensional network which is stabilized by inter molecular O-H?N hydrogen-bonding inter-actions. PMID- 21588176 TI - Bis(quinoline-2-carboxyl-ato-kappaN,O)lead(II). AB - The Pb(II) atom in the title compound, [Pb(C(10)H(6)NO(2))(2)], is N,O-chelated by two quinoline-2-carboxyl-ate anions in a distorted Psi-trigonal-bipyramidal environment; four atoms are connected to the Pb(II) atom by regular coordination bonds. The structure also features two somewhat long Pb?O inter-actions [2.952 (3) and 3.014 (3) A]. These long inter-actions give rise to a layer coordination polymer having the lead atom in a distorted Psi-monocapped octa-hedral geometry. PMID- 21588177 TI - Chloridomethyl-phen-yl(quinoline-2-carboxyl-ato-kappaN,O)tin(IV). AB - The Sn atom in the title compound, [Sn(CH(3))(C(6)H(5))(C(10)H(6)NO(2))Cl], shows a distorted C(2)SnNOCl trigonal-bipyramidal coordination; the apical sites are occupied by the N and Cl atoms. PMID- 21588178 TI - (Quinoline-2-carboxyl-ato-kappaO)(quinoline-2-carb-oxy-lic acid-kappaO)bis (quinoline-2-carb-oxy-lic acid-kappaN,O)potassium. AB - The K atom in the title complex, [K(C(10)H(6)NO(2))(C(10)H(7)NO(2))(3)], lies on a twofold rotation axis that relates one N,O-chelating quinoline-2-carb-oxy-lic acid to the other; their N and O atoms are cis to each other in the distorted octa-hedral coordination geometry. The K atom is also coordinated by another monodentate quinoline-2-carb-oxy-lic acid; the acid is disordered with respect to a monodentate quinoline-2-carboxyl-ate anion; the acid and anion are linked by an O-H?O hydrogen bond. An O-H?N hydrogen bond links adjacent mol-ecules into a linear chain structure along the a axis. PMID- 21588179 TI - Bis(acetyl-acetonato-kappaO,O')[copper(II)nickel(II)(0.31/0.69)]: a mixed-metal complex. AB - The title complex, [Cu(0.31)Ni(0.69)(C(5)H(7)O(2))(2)], was isolated from the reaction of bis-(N,N-dimethyamino-ethanol)copper(II) with bis-(acetyl acetonato)nickel(II), which yielded crystals with mixed sites at the central metal position; the refined copper-nickel occupancy ratio is 0.31 (4):0.69 (4). Two acetyl-acetonate ligands, related by a centre of symmetry, are coordinated to the central metal atom in a square-planar configuration while the methyne C atoms of the acetyl-acetonate ligands, ca 3.02 A away, are orthogonal to this plane at the metal site. PMID- 21588180 TI - Dibromidobis(N,N,N',N'-tetra-methyl-thio-urea-kappaS)cadmium(II). AB - In the title compound, [CdBr(2)(C(5)H(12)N(2)S)(2)], the Cd(II) atom lies on a twofold rotation axis. It exhibits a distorted tetra-hedral coordination environment defined by two S atoms of two tetra-methyl-thio-urea (tmtu) ligands and two bromide ions. The crystal structure is consolidated by C-H?N and C-H?S hydrogen bonds. PMID- 21588181 TI - Diiodidobis(N,N,N',N'-tetra-methyl-thio-urea-kappaS)cadmium(II). AB - In the title compound, [CdI(2)(C(5)H(12)N(2)S)(2)], the Cd(II) ion is located on a twofold rotation axis and is coordinated in a distorted tetra-hedral mode by two iodide ions and by two tetra-methyl-thio-urea (tmtu) ligands through their S atoms. The crystal structure is stabilized by C-H?N and C-H?S hydrogen bonds. PMID- 21588182 TI - Dichloridobis(N,N,N',N'-tetra-methyl-thio-urea-kappaS)mercury(II). AB - In the title compound, [HgCl(2)(C(5)H(12)N(2)S)(2)], the Hg(II) atom is located on a twofold rotation axis and is bonded in a distorted tetra-hedral coordination mode to two chloride ions and to two tetra-methyl-thio-urea (tmtu) mol-ecules through their S atoms. The crystal structure is stabilized by C-H?N and C-H?S hydrogen bonds. PMID- 21588184 TI - Bis(isonicotinamide-kappaN)bis-(4-methyl-benzoato-kappaO)copper(II) dihydrate. AB - In the centrosymmetric title compound, [Cu(C(8)H(7)O(2))(2)(C(6)H(6)N(2)O)(2)].2H(2)O, the Cu(II) ion is located on a crystallographic inversion center. The asymmetric unit is completed by one 4 methyl-benzoate anion, one isonicotinamide (INA) ligand and one uncoordinated water mol-ecule; all the ligands are monodentate. The two O and the two N atoms around the Cu(II) ion form a slightly distorted square-planar arrangement. The dihedral angle between the carboxyl-ate group and the attached benzene ring is 13.86 (9) degrees , while the pyridine and benzene rings are oriented at a dihedral angle of 86.08 (5) degrees . The uncoordinated water mol-ecules are linked to the INA ligands by O-H?O hydrogen bonds. In the crystal structure, inter-molecular O-H?O, N-H?O and C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21588183 TI - catena-Poly[[bis-(4-methyl-benzoato-kappaO:O')lead(II)]-MU-nicotinamide kappaN:O]. AB - In the title compound, [Pb(C(8)H(7)O(2))(2)(C(6)H(6)N(2)O)](n), the Pb(II) ion is coordinated by two 4-methyl-benzoate (PMB) and one nicotinamide (NA) ligands while symmetry-related NA ligands bridge adjacent Pb(II) ions, forming polymeric chains along the c axis. The carboxyl-ate groups in the two PMB ions are twisted away from the attached benzene ring by 22.9 (2) and 4.6 (2) degrees . The two benzene rings of the PMB ions are oriented at a dihedral angle of 83.7 (1) degrees . In a polymeric chain, the NA ligands are linked to PMB ions through intra-molecular N-H?O hydrogen bonds. In the crystal structure, adjacent polymeric chains inter-act via N-H?O and C-H?O hydrogen bonds, forming a two dimensional network parallel to the bc plane. PMID- 21588185 TI - Tetra-kis(4-cyano-pyridine)-palladium(II) bis-(trifluoro-methane-sulfonate). AB - The title salt, [Pd(C(6)H(4)N(2))(4)](CF(3)SO(3))(2), comprises Pd(4-cyano pyridine)(4) dications balanced by two trifluoro-methane-sulfonate anions. The Pd(II) atom lies in a square-planar geometry defined by four N atoms which form equivalent Pd-N inter-actions. The 4-cyano-pyridine ligands are twisted out of the N(4) plane, forming dihedral angles ranging from 66.5 (2) to 89.9 (2) degrees . In the crystal packing, columns of edge-to-edge dications define channels in which reside the anions. A range of C-H?N and C-H?O hydrogen-bonding interactions stabilizes the crystal packing. PMID- 21588186 TI - Dibromido(2,3,5,6-tetra-2-pyridyl-pyrazine-kappaN,N,N)zinc(II). AB - In the title compound, [ZnBr(2)(C(24)H(16)N(6))], the Zn(II) ion is coordinated by the N,N',N''-tridentate 2,3,5,6-tetra-2-pyridyl-pyrazine ligand and two bromide ions, generating a distorted ZnN(3)Br(2) trigonal-bipyramidal geometry for the metal ion, with both bromide ions in equatorial sites. The dihedral angles between the pyrazine ring and the coordinated pyridine rings are 13.3 (2) and 24.8 (2) degrees ; those between the pyrazine ring and the uncoordinated pyradine rings are 31.3 (2) and 44.2 (2) degrees . In the crystal, inversion dimers linked by pairs of weak C-H?Br hydrogen bonds occur. PMID- 21588187 TI - Tris(2-amino-1,3-thia-zole-kappaN)(7-oxa-bicyclo-[2.2.1]heptane-2,3-dicarboxyl ato-kappaO,O,O)cadmium(II) dihydrate. AB - In the crystal structure of the title complex, [Cd(C(8)H(8)O(5))(C(3)H(4)N(2)S)(3)].2H(2)O, the Cd(II) atom exhibits a slightly distorted octa-hedral CdO(3)N(3) coordination, defined by the bridging O atom of the bicyclo-heptane unit, two O atoms from the carboxyl-ate groups and by three N atoms from three 2-amino-thia-zole ligands. Uncoordinated lattice water mol ecules are also present in the crystal structure. N-H?O and O-H?O hydrogen bonding inter-actions link the components into a three-dimensional structure. PMID- 21588188 TI - Bis(MU-quinoline-2-carboxyl-ato)-kappaN,O:O;kappaO:N,O-bis-[(acetato kappaO,O')(methanol-kappaO)lead(II)]. AB - The dinuclear title compound, [Pb(2)(C(10)H(6)NO(2))(2)(CH(3)COO)(2)(CH(3)OH)(2)], lies across an inversion center. The methanol-coordinated Pb(II) atom is chelated by the acetate anion as well as by the quinoline-2-carboxyl-ate anion. One O atom of the quinoline-2 carboxyl-ate anion bridges two symmetry-related Pb(II) atoms, forming the dinuclear compound. Aside from the six atoms connected to the Pb(II) atom by regular coordination bonds, the structure features a long Pb?O inter-action [3.145 (3) A] that gives rise to a distorted Psi-square-anti-prismatic geometry at the metal center. The H atom of the methanol is hydrogen bonded to an O atom of the acetate. PMID- 21588189 TI - Bis(MU-quinolin-8-olato)-kappaN,O:O;kappaO:N,O-bis-[chloridomethyl-phenyl tin(IV)]. AB - The Sn(IV) atom in the centrosymmetric dinculear title compound, [Sn(2)(CH(3))(2)(C(6)H(5))(2)(C(9)H(6)NO)(2)Cl(2)], shows a trans-C(2)SnNO(2)Cl distorted octa-hedral coordination [C-Sn-C = 157.83 (8) degrees ]. The quinolin-8 olate anion chelates to the Sn atom; its O atom also binds to the inversion related Sn atom, forming the dinuclear compound. In the crystal structure, weak inter-molecular C-H?Cl hydrogen bonding links the mol-ecules, forming supra molecular chains running along [100]. PMID- 21588190 TI - Chloridometh-yl(2-methyl-quinolin-8-olato-kappaN,O)phenyl-tin(IV). AB - The asymmetric unit of the title complex, [Sn(CH(3))(C(6)H(5))(C(10)H(8)NO)Cl], consists of two independent mol-ecules, both of which have the N,O-chelated Sn(IV) atom in a cis-C(2)SnNOCl trigonal-bipyramidal geometry [C-Sn-C = 124.82 (8) and 137.69 (8) degrees ]. The Cl atom of the mol-ecule with the smaller C-Sn C angle inter-acts weakly with the Sn(IV) atom of the mol-ecule with the wider C Sn-C angle at an Sn?Cl distance of 3.595 (1) A. Weak inter-molecular C-H?O and C H?Cl hydrogen bonding is present in the crystal structure. PMID- 21588191 TI - Dichloridobis(2-chloro-benz-yl)tin(IV). AB - Mol-ecules of the title compound, [Sn(C(7)H(6)Cl)(2)Cl(2)], lie on a twofold rotation axis which passes through the Sn atom. The Sn(IV) atom exists in a distorted tetra-hedral geometry. Adjacent mol-ecules are linked by weak Sn?Cl contacts [3.703 (1) A], forming a linear chain motif extending along the b axis. PMID- 21588192 TI - Bis[2,6-bis-(1H-benzimidazol-2-yl)pyridine]-nickel(II) dipicrate dimethyl formamide disolvate. AB - In the title compound, [Ni(C(19)H(13)N(5))(2)](C(6)H(2)N(3)O(7))(2).2C(3)H(7)NO, the Ni(II) ion is coordinated by two tridentate 2,6-bis-(1H-benzimidazol-2 yl)pyridine ligands in a distorted octa-hedral geometry. In the crystal structure, the picrate anions and solvent dimethyl-formamide (DMF) mol-ecules are connected to the cation via inter-molecular N-H?O hydrogen bonds. Further stabilization is provided by weak inter-molecular C-H?O hydrogen bonds. One of the DMF moleclues is disordered over two sites with refined occupancies of 0.737 (3) and 0.263 (3). PMID- 21588193 TI - Hexaaqua-zinc(II) 4,4'-(1,2-dihy-droxy-ethane-1,2-di-yl)dibenzoate monohydrate. AB - The title compound, [Zn(H(2)O)(6)](C(16)H(12)O(6)).H(2)O, consists of one 4,4' (1,2-dihy-droxy-ethane-1,2-di-yl)dibenzoate anion lying on an inversion centre, one [Zn(H(2)O)(6)](2+) dication lying on a mirror plane and one solvent water mol ecule located on a mirror plane. The octahedral [Zn(H(2)O)(6)](2+) cations, solvent water mol-ecules and anions inter-act via O-H?O hydrogen bonds, forming a three-dimensional network. PMID- 21588194 TI - (Methanol-kappaO)(perchlorato-kappaO)bis-(triphenyl-phosphine-kappaP)silver(I). AB - In the title complex, [Ag(ClO(4))(CH(3)OH)(C(18)H(15)P)(2)], the angles around the central Ag(+) ion indicate that it is in a distorted tetrahedral coordination. The coordination sphere of silver is formed by two P atoms of two triphenyl-phosphine ligands, one O atom of a perchlorate anion and one O atom of a methanol mol-ecule. The crystal structure is stablized by a bifurcated inter molecular O-H?O hydrogen bond, involving the O-H donor from methanol and two acceptor O atoms from the perchlorate anion, so forming a zigzag chain propagating in [010]. PMID- 21588195 TI - Tetra-aqua-(1,10-phenanthroline-kappaN,N')cadmium(II) sulfate dihydrate. AB - In the title mononuclear complex, [Cd(C(12)H(8)N(2))(H(2)O)(4)]SO(4).2H(2)O, the coordination geometry around the Cd(II) atom is a distorted octa-hedron, with two aqua ligands occupying the axial positions. Inter-molecular O-H?O hydrogen bonds lead to the formation of a two-dimensional layer structure parallel to (001). The layers are connected by pi-pi inter-actions between the pyridyl and benzene rings of the phenanthroline ligands [centroid-centroid distances = 3.591 (1) and 3.610 (1) A]. PMID- 21588196 TI - Bis(tetra-phenyl-phospho-nium) bis-[N-(phenyl-sulfon-yl)dithio-carbimato kappaS,S']platinate(II) monohydrate. AB - The asymmetric unit of the title compound, (C(24)H(20)P)(2)[Pt(C(7)H(5)NO(2)S(3))(2)].H(2)O, consists of two tetra-phenyl phospho-nium cations, two half bis-[N-(phenyl-sulfon-yl)dithio-carbim ato]platinate(II) dianions and one water mol-ecule. The anions are completed by crystallographic inversion symmetry associated with the central Pt(II) ion. The Pt(II) ion is doubly S,S'-chelated by two symmetry-related phenyl-sulfonyl-dithio carbimate ligands, forming a slightly distorted square-planar configuration. Besides the electrostatic attraction between oppositely charged ions in the crystal packing, intra-molecular C-H?O and several inter-molecular C-H?O, C-H?N and O-H?O hydrogen-bonding inter-actions between the cations, anions and water mol-ecules are observed. PMID- 21588197 TI - Poly[tetra-MU(1,1)-azido-bis-(MU(2)-pyrimidine-2-carboxyl-ato)tricopper(II)]. AB - In the title compound, [Cu(3)(C(5)H(3)N(2)O(2))(2)(N(3))(4)](n), one of the Cu(II) atoms lies on an inversion centre and is octa-hedrally coordinated by two bidentate chelating pyrimidine-2-carboxyl-ate ligands and two azide anions, each of which gives an N:N-bridge to the second inversion-related Cu(II) centre in the formula unit. The second Cu(II) atom is five-coordinated with a distorted square pyramidal coordination sphere comprising a single bidentate chelating pyrimidine 2-carboxyl-ate anion and three azide N anions, two of which doubly bridge centrosymmetric Cu(II) centres, giving a two-dimensional network structure extending parallel to (010). PMID- 21588198 TI - Poly[(MU(4)-1,2,3-benzothia-diazole-7-carboxyl-ato)silver(I)]. AB - In the crystal structure of the title compound, [Ag(C(7)H(3)N(2)O(2)S)](n), the Ag(I) atom is coordinated by two N atoms and three O atoms of four organic ligands forming a distorted square pyramid. The carboxyl-ate group acts as a bidentate ligand on one Ag(I) atom and as a bridging group for a symmetry-related Ag(I) atom, forming a dimer. Futhermore, the two N atoms of two thia-diazole rings bridge a third symmetry-related Ag(I) atom, forming a six-membered ring. These two frameworks, AgO(2)Ag and AgN(4)Ag, extend in three directions, forming a three-dimensionnal polymer. The whole polymer is organized around inversion centers. PMID- 21588199 TI - Chlorido[1-(2-eth-oxy-phen-yl)3-(4-nitro-phen-yl)triazenido]mercury(II). AB - In the title compound, [Hg(C(14)H(13)N(4)O(3))Cl], the Hg(II) atom is four coordinated by one O atom and two N atoms from a tridentate 1-(2-eth-oxy-phen-yl) 3-(4-nitro-phen-yl)triazenide ligand and one terminal chloride ion in a distorted square-planar geometry. In the crystal structure, the mononuclear complexes are linked into pairs through C-H?O and C-H?Cl hydrogen bonds as well as pi-pi and C H?pi stacking inter-actions. In addition, weak Hg-MU(6)-arene pi-inter-actions [mean distance of 3.667 (2) A] are present between these dimers. The pi-pi stacking inter-actions are between aromatic rings with a centroid-centroid distance of 3.884 (2) A. Moreover, edge-to-face inter-actions are present between eth-oxy CH groups and aromatic rings with H?pi distances of 2.81 A. PMID- 21588200 TI - [rac-2-(1-Amino-eth-yl)phenyl-kappaC,N](ethyl-endiamine-kappaN,N')palladium(II) 3 methyl-benzoate monohydrate. AB - In the title compound, [Pd(C(8)H(10)N)(C(2)H(8)N(2))](C(8)H(7)O(2)).H(2)O, the palladium ion is coordinated in a distorted square-planar fashion by the two N atoms from the chelating ethyl-enediamine group and by the N and a C atom of the deprotonated chiral amine. The resulting cationic complex, the 3-methyl-benzoate anion and the hydrate water mol-ecule are inter-connected by N-H?O and O-H?O hydrogen bonds. PMID- 21588201 TI - [rac-2-(1-Amino-eth-yl)phenyl-kappaC,N](ethyl-endiamine-kappaN,N')palladium(II) 3,5-dimethyl-benzoate. AB - In the title compound, [Pd(C(8)H(10)N)(C(2)H(8)N(2))](C(9)H(9)O(2)), the palladium ion is coordinated in a distorted square-planar fashion by the two N atoms from the chelating ethyl-enediamine group and by the N and a C atom of the deprotonated chiral amine. The resulting cationic complex and the 3,5-dimethyl benzoate anion are inter-connected by N-H?O hydrogen bonds. PMID- 21588202 TI - catena-Poly[[tris-(4-fluoro-benz-yl)tin(IV)]-MU-2-[(piperidin-1-yl)carbothio ylsulfan-yl]acetato-kappaO:O']. AB - Adjacent units of the title polymeric complex, [Sn(C(7)H(6)F)(3)(C(8)H(12)NO(2)S(2))], are bridged by the carboxyl-ate ion into a helical chain running along the b axis. The Sn(IV) atom shows a distorted trans C(3)SnO(2) trigonal-bipyramidal coordination and is displaced by 0.113 (2) A out of the C(3)Sn girdle in the direction of the covalently bonded O atom. The ring is disordered of two positions with an occupancy of 0.631 (4) for the major occupied site. PMID- 21588203 TI - Tetra-aqua-bis-(tetra-zolido-kappaN)magnesium. AB - In the crystal structure of the title compound, [Mg(CHN(4))(2)(H(2)O)(4)], the Mg(II) atom is six-coordinated by two N atoms from two tetra-zolide anions and four O atoms from four coordinated water mol-ecules in a slightly distorted octa hedral geometry. The Mg atom is located on centres of inversion whereas the tetra zolide anion and the water mol-ecules occupy general positions. The crystal packing is stabilized by intermolecular O-H?N hydrogen bonding between the tetra zolide anions and the coordinated water mol-ecules. PMID- 21588204 TI - Dibenzoatobis[3-(pyrrol-1-ylmeth-yl)pyridine]-zinc(II). AB - In the title compound, [Zn(C(7)H(5)O(2))(2)(C(10)H(10)N(2))(2)], the Zn(II) ion, located on a twofold axis, is coordinated by two N atoms from two 3-(pyrrol-1 ylmeth-yl)pyridine ligands and two O atoms from two benzoate ligands in a distorted tetra-hedral geometry. The pyridine and the pyrrole rings are nearly perpendicular to each other, making a dihedral angle of 84.83 (7) degrees . PMID- 21588205 TI - Bis(MU-5-carboxyl-atotetra-zolido)bis-[aqua-(2,2'-bipyrid-yl)cadmium(II)]. AB - In the title dinuclear Cd(II) complex, [Cd(2)(C(2)N(4)O(2))(2)(C(10)H(8)N(2))(2)(H(2)O)(2)], each Cd atom is in a slightly distorted octa-hedral coordination by two N atoms and one O atom of two 1H-tetra-zole-5-carboxyl-ate (TZC) ligands, two N atoms of a 2,2'-bipyridyl ligand and one water O atom. The TZC ligand acts in a tridentate N,O-chelating N bridging mode to two symmetry-equivalent Cd(II) atoms. The complex reveals mol ecular C(i) symmetry. Extensive O-H?O hydrogen bonding plays an important role in the crystal packing. PMID- 21588206 TI - Poly[[[aqua(2,2'-bipyridine-kappaN,N')zinc(II)]-MU-2-nitroterephthalato-kappaO:O] monohydrate]. AB - In the title compound, {[Zn(C(8)H(3)NO(6))(C(10)H(8)N(2))(H(2)O)].H(2)O}(n), the Zn(II) ion is square-pyramidally coordinated, and bridged by 2-nitro terephthalate ligands, forming a chain running along [10]. Intra-molecular hydrogen bonds are formed between the coordinated water mol-ecules and the nitro O atoms. Adjacent chains are linked by hydrogen bonds between the coordinated water mol-ecules and the O atoms of the monodentate carboxyl groups. PMID- 21588207 TI - Potassium clavulanate. AB - The title salt, K(+).C(8)H(8)NO(5) (-) [systematic name: potassium (2R,5R,Z)-3-(2 hy-droxy-ethyl-idene)-7-oxo-4-oxa-1-aza-bicyclo-[3.2.0]heptane-2-carb-oxyl-ate], a widely used beta-lactam anti-biotic, is usually chemically unstable even in the solid state owing to its tendency to be hydrolysed. In the crystal structure, the potassium cations are arranged along the a axis, forming inter-actions to the carboxyl-ate and hy-droxy groups, resulting in one-dimensional ionic columns. These columns are arranged along the b axis, connected by O-H?O hydrogen bonds, forming a layer in the ab plane. PMID- 21588208 TI - catena-Poly[[(1,10-phenanthroline)lead(II)]bis-(MU-5-chloro-2-hy-droxy benzoato)]. AB - In the title polymer, [Pb(C(7)H(4)ClO(3))(2)(C(12)H(8)N(2))](n), the Pb(II) ion displays a distorted pseudo-octa-hedral coordination geometry. The metal center is coordinated by six O atoms from four 5-chloro-salicylate ligands and two N atoms from a chelating phenanthroline ligand. The polymeric structure is built up from bridging carboxyl-ate O atoms, forming chains along [100]. The crystal structure is stabilized by pi-pi inter-actions between the 1,10-phenanthroline and 5-chloro-salicylate ligands, the shortest centroid-centroid separation between neighbouring aromatic rings being 3.652 (1) A. PMID- 21588209 TI - cis-Bis(1,10-phenanthroline-kappaN,N')bis-(thio-cyanato-kappaN)magnesium(II). AB - The title compound, [Mg(NCS)(2)(C(12)H(8)N(2))(2)], has been synthesized from the hydro-thermal reaction of MgCl(2), KSCN, 1,10-phenanthroline and H(2)O. Its structure is isotypic with the Mn(II), Fe(II), Co(II), Ni(II), Cu(II) and Zn(II) analogues. The Mg(II) cation has a slightly distorted octa-hedral geometry containing four N atoms from two 1,10-phenanthroline mol-ecules and two N atoms from two thio-cyanate anions. The asymmetric unit contains one-half mol-ecule, and the complete complex has 2 symmetry. PMID- 21588210 TI - (1R,2R)-N,N'-Bis(ferrocenylmeth-yl)-1,2-diphenyl-ethane-1,2-diamine. AB - The title compound, [Fe(2)(C(5)H(5))(2)(C(26)H(26)N(2))], was synthesized from a chiral diamine and ferrocenecarboxaldehyde and subsequent reduction with NaBH(4). It has two chiral centers which both exhibit an R configuration. Two ferrocene groups are present in the mol-ecular structure, with their cyclo-penta-dienyl ring planes showing an almost perpen-dicular arrangement [dihedral angle 88.6 (1) degrees ]. PMID- 21588211 TI - {[Na1(MU-H(2)O)Na2](2)[(C(2)O(4))(2)Cr(MU-OH)(2)Cr(C(2)O(4))(2)].H(2)O}(n), a novel hydrated form. AB - The unit cell of the title compound, poly[[MU-aqua-MU-hydroxido-di-MU-oxalato chromium(III)disodium] monohydrate], {[CrNa(2)(C(2)O(4))(2)(OH)(H(2)O)].H(2)O}(n), contains four [Na1(MU H(2)O)Na2][(C(2)O(4))(2)Cr(MU-OH).H(2)O] formula units, each of which consists of two crystallographically independent Na(+) sites (bridged by one aqua ligand), one half of a centrosymmetric di-MU-hydroxido-bis-[cis-bis (oxalato)chromate(III)] dimer, [(C(2)O(4))(2)Cr(MU-OH)(2)Cr(C(2)O(4))(2)](4-), and one uncoordin-ated water mol-ecule. The structure is best described as a coordination polymer in which the three-dimensional lattice framework is realized by the inter-connection of the metallic atoms via the O atoms of the aqua, hydroxide and oxalate ligands. One Na atom is hepta-coordinated by one water, one hydroxide and five oxalate O atoms, whilst the other is penta-coordinated by one water and four oxalate O atoms. The coordination around the Cr(3+) sites is pseudo-octa-hedral, involving four aqua and two hydroxide O atoms. Adjacent Na atoms are separated by 3.593 (2) A, whereas the intra-dimer Cr?Cr spacing is 2.978 (1) A. The crystal structure is consolidated by extended relatively weak O H?O hydrogen bonding with O?O distances ranging from 2.808 (4) to 3.276 (5) A. PMID- 21588212 TI - Dichloridobis(1,3-phenyl-propane-1,3-dionato-kappaO,O')tin(IV) toluene hemisolvate. AB - The two Sn-O-C-C-C-O chelate rings in the title compound, [Sn(C(15)H(11)O(2))(2)Cl(2)].0.5C(7)H(8), adopt envelope conformations, with the Sn atom deviating from the least-squares plane passing through the C and O atoms by 0.626 (1) A in one ring and by 0.690 (1) A for the other. The two planes are aligned at an angle of 59.6 (1) degrees . The Cl atoms occupy cis positions in the octa-hedral SnCl(2)O(4) coordination environment. The solvent mol-ecule is disordered about a center of inversion. PMID- 21588213 TI - Dibromido[1,1'-dibenzyl-2,2'-(sulfane-diyl-dimethyl-ene)di-1H-benzimidazole] cadmium(II) dimethyl-formamide solvate. AB - In the title compound, [CdBr(2)(C(30)H(26)N(4)S)].C(3)H(7)NO, both the complex and solvent mol-ecule lie on a crystallographic mirror plane. The Cd(II) ion is coordinated in a disorted square-pyramidal CdBr(2)N(2)S environment with one of the Br atoms in the apical site. In the crystal structure, the benzimidazole ring systems are involved in weak inter-molecular pi-pi stacking inter-actions [centroid-centroid distances = 3.606 (2) and 3.753 (2) A]. Further stabilization is provided by weak inter-molecular C-H?O hydrogen bonds. The methyl H atoms of the dimethyl-formamide solvent mol-ecule are disordered about a mirror plane. PMID- 21588214 TI - Bis[N,N-bis-(diphenyl-phosphan-yl)cyclo-hexyl-amine-kappaP,P']platinum(II) bis (hexa-fluorido-phosphate) dichloro-methane disolvate. AB - In the title compound, [Pt(C(30)H(31)NP(2))(2)](PF(6))(2).2CH(2)Cl(2), the four coordinated Pt(II) atom, situated on an inversion centre, exhibits a highly distorted square-planar geometry illustrated by the P-Pt-P bite angle of 70.76 (3) degrees . The cyclo-hexyl ring and one of the phenyl rings display 0.630 (7):0.37 (7) and 0.60 (2):0.40 (2) positional disorder, respectively. The dichloro-methane solvent mol-ecule displays 0.526 (4):0.474 (4) positional disorder. C-H?F hydrogen bonds stabilize the crystal packing. PMID- 21588215 TI - Dibromido(4,4'-dimethyl-2,2'-bipyridine-kappaN,N')zinc(II). AB - The asymmetric unit of the title compound, [ZnBr(2)(C(12)H(12)N(2))], contains two half-mol-ecules; both are completed by crystallographic twofold axes running through the Zn(II) atoms which are coordinated by an N,N'-bidentate 4,4'-dimethyl 2,2'-bipyridine ligand and two Br(-) ions, resulting in distorted ZnN(2)Br(2) tetra-hedral coordination geometries. In the crystal, C-H?Br inter-actions link the mol-ecules. PMID- 21588216 TI - Dicyanidobis(thio-urea-kappaS)cadmium(II) monohydrate. AB - In the title compound, [Cd(CN)(2)(CH(4)N(2)S)(2)].H(2)O, the Cd atom lies on a twofold rotation axis and is bonded to two S atoms of thio-urea and two C atoms of the cyanide anions in a distorted tetra-hedral environment. The crystal structure is stabilized by N-H?N(CN), N-H?O, O-H?N and N-H?S hydrogen bonds. PMID- 21588217 TI - [2,3,7,8,13,14,17,18-Octa-kis(ethyl-sulfan-yl)-5,10,15,20 porphyrazinato]zinc(II). AB - In the title compound, [Zn(C(32)H(40)N(8)S(8))], the Zn(II) ion is coordinated by four N atoms in a slightly distorted square-planar environment. In addition, there is a Zn?S contact involving a symmetry-related S atom which, when considered, forms a pseudo-square-pyramidal coordination with respect to the Zn(II) ion. Three of the ethyl groups are disordered over two sites with occupancy ratios of 0.841 (10):0.159 (10), 0.802 (10):0.198 (10) and 0.457 (13):0.543 (13). Weak intra-molecular C-H?N and C-H?S inter-actions contribute to the stability of the mol-ecular conformation. Inter-molecular C-H?S contacts, weak C-H?pi inter-actions and pi-pi stacking inter-actions [centroid-centriod distances = 3.832 (4) and 3.850 (5) A] contribute to the stabilization of the crystal structure. PMID- 21588218 TI - anti-1',6',7',8',9',14',15',16'-Octa-chloro-dispiro-[1,3-dioxolane-2,17'-penta cyclo-[12.2.1.1.0.0]octa-decane-18',2''-1,3-dioxolane]-7',15'-diene. AB - The title compound, C(22)H(20)Cl(8)O(4), was prepared as part of the synthesis of precursors for the preparation of fluorinated mol-ecular tweezers. The mol-ecule sits on an inversion center, thus requiring that the cyclo-octane ring adopt a chair conformation. PMID- 21588219 TI - 5-Hy-droxy-7-meth-oxy-2-methyl-4H-chromen-4-one from Dysoxylum macrocarpum (Meliaceae). AB - Both independent mol-ecules in the asymmetric unit of the title compound, C(11)H(10)O(4), are almost planar (r.m.s. deviations = 0.011 and 0.033 A). In both mol-ecules, the hy-droxy group is intra-molecularly hydrogen bonded to the ketonic O atom. The independent mol-ecules are stacked alternately along the a axis, with the centroids of their chromene ring separated by distances of 4.490 (1) and 3.621 (1) A. PMID- 21588220 TI - 4'-(Morpholino-meth-yl)biphenyl-2-carbonitrile. AB - In the title compound, C(18)H(18)N(2)O, the morpholine ring adopts a chair conformation and the dihedral angle between the aromatic rings is 49.16 (7) degrees . In the crystal, weak C-H?pi inter-actions may help to establish the packing. PMID- 21588221 TI - 9-Ethyl-9H-carbazole-3-carbaldehyde. AB - The title mol-ecule, C(15)H(13)NO, approximates a planar conformation except for the alkyl chain (ethyl group) bonded to the N atom with a maximum deviation from the least-squares plane through the 15 planar atoms of 0.120 (2) A for the O atom. The distance of the formyl O atom from the plane of the carbazole ring is 0.227 (2) A. The N-C bond lengths in the central ring are significantly different, reflecting the electron-withdrawing properties of the aldehyde group. As a consequence, charge transfer may occur from the carbazole N atom to the substituted benzene ring. PMID- 21588222 TI - 6,7,8,9-Tetra-hydro-4b,9b-dihy-droxy-indano[1,2-b]indoline-9,10-dione monohydrate. AB - In the title compound, C(15)H(13)NO(4).H(2)O, the organic mol-ecule adopts a V shaped conformation in which the dihedral angle between the five-membered rings is 68.33 (5) degrees . The cyclo-hexenone ring adopts an envelope conformation, with one of the methyl-ene C atoms displaced by 0.607 (4) A from the plane through the other atoms. In the crystal, inter-molecular N-H?(O,O) and O-H?O hydrogen bonds link the components into (001) sheeets and C-H?O inter-actions and aromatic pi-pi stacking [centroid-centroid separation = 3.6176 (19) A] help to consolidate the packing. PMID- 21588223 TI - (E)-1-(4-Meth-oxy-benzyl-idene)-2-phenyl-hydrazine. AB - In the title compound, C(14)H(14)N(2)O, the dihedral angle between the aromatic rings is 9.30 (6) degrees . In the crystal, mol-ecules are linked by C-H?pi and N H?pi inter-actions. PMID- 21588224 TI - N'-[(E)-(1-Methyl-1H-pyrrol-2-yl)methyl-idene]benzohydrazide. AB - In the title compound, C(13)H(13)N(3)O, the phenyl and pyrrole rings are inclined at 47.45 (8) degrees . In the crystal, inter-molecular N-H?O and C-H?O hydrogen bonds form R(2) (1)(6) ring motifs. Mol-ecules connected through these hydrogen bonds are arranged into polymeric chains extending along the c axis. PMID- 21588225 TI - 2-(4-Methyl-cyclo-hex-3-en-yl)propan-2-yl N-phenyl-carbamate. AB - In the title carbamate compound, C(17)H(23)NO(2), one of the Csp(3) atoms of the cyclo-hexene ring is disordered over two sites with refined occupancies of 0.55 (2) and 0.45 (2), both disorder components resulting in half-boat conformations. The mean plane through the carbamate unit is inclined at inter-planar angles of 14.80 (13), 18.30 (17) and 24.0 (2) degrees , respectively, with respect to the phenyl ring, and the major and minor disorder component cyclo-hexene rings. In the crystal structure, adjacent mol-ecules are linked into chains along [001] via inter-molecular N-H?O hydrogen bonds. The crystal structure is further stabilized by weak inter-molecular C-H?pi inter-actions. PMID- 21588226 TI - 4-Methyl-N-[(E)-4-methyl-1-(4-methyl-phenyl-sulfon-yl)-1,2-dihydropyridin-2-yl idene]benzene-sulfonamide. AB - The reaction of 2-(amino-meth-yl)pyridine and 4-toluene-sulfonyl chloride in CH(2)Cl(2) at pH 8 led to the title compound, C(20)H(20)N(2)O(4)S(2). The aromatic rings are almost perpendicular to each other and the dihedral angles between the aromatic ring planes are 74.33 (9) (central pyridine versus benzene ring of the tosyl group bonded to the imine functionality), 73.77 (6) (pyridine versus benzene ring of the tosyl group bonded to pyridinic N atom) and 79.83 (9) degrees (benzene rings of tosyl groups). In the crystal structure, inter molecular aromatic pi-pi stacking inter-actions [centroid-centroid separation = 3.6274 (14) A] help to consolidate the packing. PMID- 21588227 TI - 4-Nitro-6-[(8-quinolyl-amino)-methyl-idene]cyclo-hexa-2,4-dien-1-one. AB - The mol-ecule of the title compound, C(16)H(11)N(3)O(3), exists in the keto form and the C=O and N-H bonds are mutually cis in the crystal structure. There are two crystallographically independent mol-ecules per asymmetric unit with broadly similar structural data. The only noticeable difference between the two is the dihedral angles between the benzene and the quinoline rings: 1.04 (4) and 3.07 (4) degrees . In the structure, intra-molecular N-H?O(carbon-yl) and N H?N(pyridine) hydrogen bonds exist but there is no evidence of formal inter molecular hydrogen-bonding associations. PMID- 21588228 TI - Guanidinium phenyl-arsonate-guanidine-water (1/1/2). AB - In the structure of the title compound, CH(6)N(3) (+).C(6)H(6)AsO(3) ( ).CH(5)N(3).2H(2)O, the phenyl-arsonate anion participates in two R(2) (2)(8) cyclic hydrogen-bonding inter-actions, one with a guanidinium cation, the other with a guanidine mol-ecule. The anions are also bridged by the water mol-ecules, one of which completes a cyclic R(5) (3)(9) hydrogen-bonding association with the guanidinum cation, conjoint with one of the three R(2) (2)(8) associations about that ion, as well as forming an R(2) (1)(6) cyclic association with the guanidine mol-ecule. The result is a three-dimensional framework structure. PMID- 21588229 TI - 2-(2,4-Dinitro-benz-yl)pyridinium 2-hy-droxy-3,5-dinitro-benzoate. AB - In the structure of the title salt, C(12)H(10)N(3)O(4) (+).C(7)H(3)N(2)O(7) (-), the cations and the anions are linked by a single N(+)-H?O(carbox-yl) hydrogen bond, the discrete cation-anion unit having no inter-molecular associations other than weak cation-anion aromatic ring pi-pi inter-actions [ring centroid separation = 3.7320 (14) A] and a number of weak inter-unit aromatic C-H?O contacts. An intramolecular C-H?O hydrox-yl-carboxyl hydrogen bond occurs in the anion. PMID- 21588230 TI - Ethyl 4-(4-bromo-phen-yl)-6-r-phenyl-2-oxocyclo-hex-3-ene-1-t-carboxyl-ate. AB - In the title compound, C(21)H(19)BrO(3), the cyclo-hexene ring adopts an envelope conformation, with all substituents equatorial. The plane through its five coplanar atoms makes dihedral angles of 28.88 (10) and 71.94 (10) degrees with the bromo-benzene and phenyl rings, respectively. The dihedral angle between the latter two rings is 51.49 (15) degrees . Inter-molecular C-H?O hydrogen bonds are found in the crystal structure; a C-H?pi inter-action is also present. PMID- 21588231 TI - 2-Chloro-N-(2,3-dimethyl-phen-yl)benzamide. AB - In the title compound, C(15)H(14)ClNO, the N-H and C=O bonds in the amide group are anti to each other. The amide group is inclined at 60.3 (1) degrees to the chloro-substituted benzoyl ring and at 59.2 (1) degrees to the dimethyl substituted aniline ring. The mean planes through the two benzene rings make a dihedral angle of 7.7 (1) degrees . In the crystal structure, mol-ecules are linked by inter-molecular N-H?O hydrogen bonds, forming chains along [010]. PMID- 21588232 TI - Methyl 4-isonicotinamido-benzoate monohydrate. AB - The title compound, C(14)H(12)N(2)O(3).H(2)O, synthesized by the reaction of methyl 4-amino-benzoate with isonicotinoyl chloride hydro-chloride, is relatively planar, with the pyridine ring being inclined by 7.46 (7) degrees to the benzene ring. In the crystal, the methyl 4-isonicotinamido-benzoate mol-ecules are inter linked by water mol-ecules via N-H?O, O-H?N and O-H?O hydrogen bonds, leading to the formation of a double-chain ribbon-like structure. PMID- 21588233 TI - N'-[Bis(benzyl-sulfan-yl)methyl-idene]-4-meth-oxy-benzohydrazide. AB - In the title compound, C(23)H(22)N(2)O(2)S(2), the dihedral angles between the 4 meth-oxy-substituted phenyl ring and the other two phenyl rings are 84.4 (4) and 77.7 (1) degrees , respectively, while the dihedral angle between the two phenyl rings is 57.5 (2) degrees . The amino group is not involved in an N-H hydrogen bond. The crystal packing is established by inter-molecular C-H?O packing inter actions involving a relatively rare weak three-center hydrogen bond between the keto O atom and H atoms of the two nearby phenyl rings, which link the mol-ecules into chains running along the a axis. Additional weak inter-molecular hydrogen bond inter-actions between the 4-meth-oxy O atom and one of the phenyl rings and provide added stability to the crystal packing. PMID- 21588234 TI - N-(4-Methyl-phen-yl)-6-(pyrazol-1-yl)pyridazin-3-amine. AB - In the title compound, C(14)H(13)N(5), the pyrazole ring is disordered over two orientations in a 0.571 (10):0.429 (10) ratio and the dihedral angle between the pyridazine ring and the benzene ring is 28.07 (10) degrees . In the crystal, pairs of N-H?N and C-H?N hydrogen bonds link the mol-ecules into dimers, with the aid of a crystallographic twofold axis. The packing is consolidated by further C H?N bonds and weak C-H?pi inter-actions. PMID- 21588235 TI - 1,7-Dimethyl-penta-cyclo-[5.4.0.0.0.0]undecane-8,11-dione. AB - The structure of the title compound, C(13)H(14)O(2), a penta-cyclo-undecane cage derivative, exhibits unusual Csp(3)-Csp(3) single-bond lengths ranging from 1.505 (3) to 1.607 (2) A and strained bond angles as small as 88.7 (1) degrees and as large as 121.0 (2) degrees . In this meso compound, an inter-nal non crystallographic mirror plane exists, bis-ecting the mol-ecule. In the crystal, weak C-H?O hydrogen bonds link the mol-ecules into an infinite spiral about a twofold screw axis along the [100] direction. PMID- 21588236 TI - 4-Allyl-6-bromo-2-phenyl-4H-imidazo[4,5-b]pyridine monohydrate. AB - In the mol-ecule of the title compound, C(15)H(12)BrN(3).H(2)O, the phenyl ring is coplanar with the imidazopyridine ring system [dihedral angle = 0.4 (1) degrees ]. The water mol-ecule is disordered over two positions with occupancies of 0.58 (1) and 0.42 (1), and it is linked to the main mol-ecule via an O-H?N hydrogen bond. PMID- 21588237 TI - 6-Bromo-1,3-dimethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one. AB - The non-H atoms of the two independent mol-ecules in the asymmetric unit of the title compound, C(8)H(8)BrN(3)O, are planar (r.m.s. deviations = 0.015 and 0.019 A). In the crystal, the mol-ecules are linked into a zigzag chain along the c axis by C-H?O hydrogen bonds. PMID- 21588238 TI - N'-(1-Allyl-2-oxoindolin-3-yl-idene)benzohydrazide. AB - In the title compound, C(18)H(15)N(3)O(2), the dihedral angle between the ring systems is 15.1 (1) degrees . The amino H atom is hydrogen bonded to the exocyclic O atom of the five-membered ring, forming an S(6) motif. PMID- 21588239 TI - 2-Isopropyl-3-methyl-quinoxaline 1,4-dioxide. AB - In the title compound, C(12)H(14)N(2)O(2), the quinoxaline ring system and the C atoms of the methylene and methyl substituents lie on a mirror plane. The crystal packing is stabilized by weak pi-pi inter-actions [centroid-centroid distance = 3.680 (7) A]. PMID- 21588240 TI - (2S)-2-(4-Ethyl-2,3-dioxopiperazine-1-carboxamido)-2-(4-hy-droxy-phen-yl)acetic acid. AB - There are two mol-ecules in the asymmetric unit of the title compound, C(15)H(17)N(3)O(6). The 2,3-dioxopiperazine ring adopts a half-chair conformation with torsion angles of -7.6 (4) and 35.1 (4) degrees in one mol-ecule, and 5.3 (4) and 45.4 (4) degrees in the other mol-ecule. In the crystal structure, the carb-oxy groups are involved in classical inversion-related O-H?O hydrogen bonds, which link the mol-ecules into centrosymmetric dimers. These dimers are further linked by inter-molecular O-H?O and C-H?O hydrogen bonds. Each independent mol ecule also exhibits an intra-molecular N-H?O hydrogen bond. The H atoms of the carb-oxy groups are disordered over two positions, with refined site-occupancy factors of 0.5. PMID- 21588241 TI - 5-Fluoro-3-(4-fluoro-phenyl-sulfon-yl)-2-methyl-1-benzofuran. AB - In the title compound, C(15)H(10)F(2)O(3)S, the 4-fluoro-phenyl ring makes a dihedral angle of 73.20 (4) degrees with the plane of the benzofuran fragment. The crystal structure is stabilized by aromatic pi-pi inter-actions between the furan and benzene rings of neighbouring mol-ecules [centroid-centroid distance = 3.805 (3) A]. The crystal structure also exhibits weak inter-molecular C-H?O and C-H?F inter-actions. PMID- 21588242 TI - Diethyl 4-hy-droxy-4-methyl-6-oxo-2-phenyl-cyclo-hexane-1,3-dicarboxyl-ate. AB - In the title mol-ecule, C(19)H(24)O(6), the cyclo-hexa-none ring adopts a chair conformation. The dihedral angle between the phenyl ring and the best plane through the six atoms of the cyclo-hexa-none ring is 89.68 (7) degrees . In the crystal structure, mol-ecules are linked via pairs of inter-molecular O-H?O hydrogen bonds into centrosymmetric dimers and these dimers are connected by C H?O inter-actions into columns down the a axis. PMID- 21588243 TI - 5-(3,4,5-Trimeth-oxy-phen-yl)-1,3,4-oxadiazole-2(3H)-thione. AB - The two rings in the title compound, C(11)H(12)N(2)O(4)S, are roughly coplanar [dihedral angle = 6.77 (8) degrees ]. Whereas the two outer methyl groups of the three meth-oxy groups are almost coplanar with the aromatic ring to which they are attached [C-C-O-C torsion angles = 8.5 (3) and -8.3 (3) degrees ], the methyl group of the central meth-oxy substituent is not [C-C-C-C = -78.4 (3) degrees ]. The crystal packing is stabilized by N-H?O hydrogen bonding. PMID- 21588244 TI - 2-Hy-droxy-3-nitro-benzaldehyde. AB - The title compound, C(7)H(5)NO(4), isolated from the leaves of Actephila merrilliana, is essentially planar (r.m.s. deviation = 0.026 A). The conformation is supported by an intra-molecular O-H?O hydrogen bond, which generates an S(6) ring. In the crystal, C-H?O inter-actions and aromatic pi-pi stacking [centroid centroid distance = 3.754 (4) A] help to establish the packing. PMID- 21588245 TI - 4,6-Dimeth-oxy-2-(methyl-sulfon-yl)pyrimidine. AB - The asymmetric unit of the title compound, C(7)H(10)N(2)O(4)S, comprises of two independent mol-ecules (A and B) which differ in the orientation of the methyl sulfonyl group [C-S-C-N = 157.98 (13) degrees in mol-ecule A and 6.09 (18) degrees in mol-ecule B]. In the crystal structure, mol-ecules of type A are linked into chains along the a axis by inter-molecular C-H?O hydrogen bonds. The B mol-ecules are linked to these chains by C-H?O hydrogen bonds. PMID- 21588246 TI - A triclinic polymorph of (E)-2-(2-nitro-ethen-yl)furan. AB - The title compound, C(6)H(5)NO(3), crystallizes in the triclinic system with six independent mol-ecules in the asymmetric unit. In a previous study, the structure of the title compound was determined in the monoclinic P2(1)/n space group at 100 K [Valerga et al. (2009 ?). Acta Cryst. E65, o1979]. All six independent mol ecules display an E configuration about the C=C double bond, with the dihedral angles between the planes of the furan rings and the nitro-alkenyl groups ranging from 0.61 (7) to 5.03 (7) degrees . The crystal structure is stabilized by inter molecular C-H?O hydrogen-bonding inter-actions. PMID- 21588247 TI - 1-Methyl-3,5-bis-(3-methyl-phen-yl)benzene. AB - In the title compound, C(21)H(20), the dihedral angles formed by the central benzene ring with the outer benzene rings are 21.43 (6) and 31.70 (4) degrees . The crystal packing is stabilized by a weak pi-pi stacking inter-action, with a centroid-centroid distance of 3.843 (3) A. PMID- 21588248 TI - Amino-(5-{2-[amino-(iminio)meth-yl]hydrazin-1-yl}-3,5-dimethyl-4,5-dihydro-1H pyrazol-1-yl)methaniminium dinitrate. AB - The reaction of aqueous solutions of amino-guanidine hydrogennitrate and acetyl acetone produces the title pyrazole salt, C(7)H(18)N(8) (2+).2NO(3) (-). The crystal structure is stabilized by a complex N-H?O hydrogen-bonding network. The difference in the engagement of the two nitrate anions in hydrogen bonding is reflected in the variation of the corresponding N-O bond lengths. PMID- 21588249 TI - Bis{(E)-N'-[2,4-bis(trifluoro-meth-yl)benzyl-idene]isonicotinohydrazide} monohydrate. AB - The asymmetric unit of the title compound, 2C(15)H(9)F(6)N(3)O.H(2)O, contains two independent Schiff base mol-ecules and one water mol-ecule. Both Schiff base mol-ecules exist in an E configuration with respect to the C=N double bonds and the dihedral angles between the benzene and the pyridine rings in the two mol ecules are 17.53 (12) and 20.62 (12) degrees . In the crystal structure, mol ecules are linked by inter-molecular N-H?O and C-H?O hydrogen bonds into infinite one-dimensional chains along the a axis. In addition, inter-molecular O-H?N, O H?F, C-H?F and C-H?O hydrogen bonds further link these chains into a three dimensional network. Weak pi-pi inter-actions with centroid-centroid distances in the range 3.6495 (17)-3.7092 (16) A are also observed. PMID- 21588250 TI - 4-Hy-droxy-anilinium perchlorate dihydrate. AB - In the crystal structure of the title compound, C(6)H(8)NO(+).ClO(4) (-).2H(2)O, inter-molecular N-H?O and O-H?O hydrogen bonds occur. The protonated amine cations and the perchlorate anions are linked through the water mol-ecules, and the hy-droxy groups of the cations and the anions are linked through the water mol-ecules. The cations are connected to the perchlorate anions via inter molecular N-H?O hydrogen bonds. In addition, the crystal structure exhibits weak inter-molecular C-H?pi inter-actions. PMID- 21588251 TI - 2-[4-(2,6-Dimeth-oxy-phen-yl)but-yl]-1,3-dimeth-oxy-benzene. AB - The title compound, C(20)H(26)O(4), crystallizes such that the alkyl chain adopts an all-anti conformation. The crystal packing displays edge-to-face arene-arene inter-actions with a dihedral angle of 87 degrees . The complete molecule is generated by inversion symmetry. PMID- 21588252 TI - 1-Benzyl-3-methyl-quinoxalin-2(1H)-one. AB - The asymmetric unit of the title compound, C(16)H(14)N(2)O, contains three independent mol-ecules. The dihedral angles between the quinoxaline and phenyl planes in the three mol-ecules are 82.58 (8), 85.66 (9) and 85.36 (9) degrees . The crystal packing is stabilized by C-H?O and C-H?N hydrogen bonds. PMID- 21588253 TI - N,N-Dimethyl-4-[(2-pyrid-yl)diazen-yl]aniline. AB - The title compound, C(13)H(14)N(4), adopts a trans configuration about the azo bond. There is a dihedral angle of 12.18 (7) degrees between the pyridine and benzene rings and the mean plane of the dimethyl-amino substituent is twisted by 6.1 (2) degrees relative to the benzene ring. In the crystal, weak inter molecular C-H?N hydrogen bonds result in a zigzag arrangement along [010]. PMID- 21588254 TI - 2-[(2Z,3E)-2-Hy-droxy-imino-5-phenyl-2,3-dihydro-3-thienyl-idene]-2-phenyl acetonitrile. AB - In the crystal structure of the title compound, C(18)H(12)N(2)OS, centrosymmetric dimers are stabilized both by van der Waals inter-actions and by two types of inter-molecular O-H?N hydrogen bonds. In addition, an intra-molecular C-H?S hydrogen bond is observed. The dihedral angles between the central ring and the two pendant phenyl rings are 7.4 (1) and 45.06 (9) degrees . PMID- 21588255 TI - Bis(2-amino-4-methyl-pyridinium) terephthalate tetra-hydrate. AB - In the crystal structure of the title salt, 2C(6)H(9)N(2) (+).C(8)H(4)O(4) (2 ).4H(2)O, the terephthalate carboxyl-ate groups inter-acts with the 2-amino-4 methyl-pyridinium cations via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The water mol-ecules form an R(6) (6)(12) ring motif through O H?O hydrogen bonds and these motifs are fused, forming a supra-molecular chain along the c axis. The R(2) (2)(8) and R(6) (6)(12) ring motifs are connected via O-H?O hydrogen bonds. In addition, pi-pi stacking inter-actions are observed between the pyridinium rings [centroid-centroid distance = 3.522 (12) A]. PMID- 21588256 TI - 14-De-oxyxyloccensin K from Chisocheton ceramicus (Meliaceae). AB - The title limonoid 14-de-oxyxyloccensin K, C(27)H(34)O(7), isolated from Chisocheton ceramicus (Meliaceae), features an oxygen linkage between carbon-3 and carbon-8 along with a tetra-hydro-furyl sub-unit. The six-membered rings adopt chair configurations and the tetra-hydro-furyl sub-unit has an envelope shape. PMID- 21588257 TI - 2,5-Dihy-droxy-terephthalic acid dihydrate. AB - The title compound, C(8)H(6)O(6).2H(2)O, was obtained by accident within a project on the synthesis of metal-organic coordination polymers by the reaction of LiOH with 2,5-dihy-droxy-terephthalic acid under solvothermal conditions. The asymmetric unit consists of half a 2,5-dihy-droxy-terephthalic acid mol-ecule located on a centre of inversion and one solvent water mol-ecule that occupies a general position. The 2,5-dihy-droxy-terephthalic acid mol-ecules are connected to the water mol-ecules via O-H?O hydrogen bonding to form a layer in the ab plane. PMID- 21588258 TI - 2-Amino-1,3-benzothia-zol-3-ium dihydrogen phosphate. AB - The cation of the title compound, C(7)H(7)N(2)S(+).H(2)PO(4) (-), is almost planar (r.m.s deviation = 0.017 A for all non-H atoms). In the crystal structure, the cations and anions are connected by N-H?O and O-H?O hydrogen bonds, with pi pi stacking inter-actions between neighbouring 1,3-thia-zole and benzene rings [centroid-centroid distance = 3.5711 (11) A], forming a three-dimensional network. PMID- 21588259 TI - 1-{6-Chloro-2-[(2-chloro-8-methyl-3-quinol-yl)meth-oxy]-4-phenyl-quinolin-3 yl}ethanone. AB - In the title mol-ecule, C(28)H(20)Cl(2)N(2)O(2), the dihedral angle between the 2 chloro-quinoline and 6-chloro-quinoline rings is 7.55 (6) degrees . The dihedral angle between the phenyl ring and its attached quinoline ring is 62.59 (4) degrees . In the crystal, aromatic pi-pi stacking inter-actions [centroid centroid distances = 3.771 (3) and 3.612 (3) A] help to establish the packing. PMID- 21588260 TI - (E)-1,3-Bis(2,3,4,5,6-penta-fluoro-phen-yl)prop-2-en-1-one. AB - In the title compound, C(15)H(2)F(10)O, the two perfluorinated arene rings are tilted at an angle of 66.08 (5) degrees with respect to each other. The olefinic double bond adopts an E configuration and the single bond between the olefinic and carbonyl double bonds has an s-trans conformation. The carbonyl group is not in a coplanar alignment with respect to the neighbouring arene ring (0.963 A from aryl plane) while being coplanar with regard to the olefinic double bond (0.0805 A from olefinic bond). The crystal packing does not feature significant hydrogen bond-type or stacking inter-actions. PMID- 21588261 TI - 2-Amino-4-methyl-pyridinium 2-carb-oxy-benzoate. AB - In the title mol-ecular salt, C(6)H(9)N(2) (+).C(8)H(5)O(4) (-), the anion is stabilized by an intra-molecular O-H?O hydrogen bond, which generates an S(7) ring motif. In the crystal, the cations and anions are linked to form extended chains along [001] by O-H?O and N-H?O hydrogen bonds. Adjacent chains are crosslinked via C-H?O inter-actions into sheets lying parallel to (100). PMID- 21588262 TI - 2-Amino-4-methylpyridinium 2-hy-droxy-3,5-dinitro-benzoate. AB - In the anion of the title mol-ecular salt, C(6)H(9)N(2) (+).C(7)H(3)N(2)O(7) (-), the two nitro groups are twisted from the attached benzene ring with dihedral angles of 27.36 (10) and 4.86 (11) degrees . The anion is stabilized by an intra molecular O-H?O hydrogen bond, which generates an S(6) ring motif. In the crystal, the cations and anions are linked by N-H?O and C-H?O inter-actions and are further consolidated by C-H?pi inter-actions, to generate a three-dimensional network. A short O?N contact of 2.876 (2) A also occurs. PMID- 21588263 TI - 2-Amino-5-bromo-pyridine-4-hy-droxy-benzoic acid (1/1). AB - The title 1:1 adduct, C(5)H(5)BrN(2).C(7)H(6)O(3), contains two mol-ecules of each species in the asymmetric unit, with similar geometries. In the crystal, mol ecules are linked to form extended chains along [100] by N-H?O, O-H?O, O-H?N and C-H?O hydrogen bonds. Adjacent chains are crosslinked via further N-H?O inter actions into sheets lying parallel to (001). The crystal studied was an inversion twin with a 0.54 (2):0.46 (2) domain ratio. PMID- 21588264 TI - 3-Ethyl-4-phen-oxy-1-(2,2,2-trifluoro-eth-yl)-1H-pyrazol-5-ol. AB - The title compound, C(13)H(13)F(3)N(2)O(2), crystallizes with two independent mol ecules in the asymmetric unit, with different conformations of their ethyl side chains. The dihedral angles formed between the 1H-pyrazole and benzene rings in the two mol-ecules are 79.44 (6) and 77.81 (6) degrees . In the crystal, mol ecules are linked by O?H-N hydrogen bonds into chains propagating along [001] and the packing is further stabilized by pi-pi inter-actions [centroid-centroid separations = 3.5409 (10) and 3.6335 (10) A]. PMID- 21588265 TI - 9,9-Bis[4-(prop-2-yn-yloxy)phen-yl]-9H-fluorene. AB - In the title compound, C(31)H(22)O(2), the bond angle at the C atom belonging to the five-membered ring of the fluorene system is opened to 112.64 (12) degrees . The two benzene rings are twisted with respect to the fluorene ring system at dihedral angles of 72.81 (6) and 81.83 (6) degrees . One C(ar-yl)-O-C-C fragment is extended, with a C-O-C-C torsion angle of -178.77 (13) degrees , but the other C(ar-yl)-O-C-C fragment is bent, with a C-O-C-C torsion angle of 64.78 (19) degrees . Inter-molecular weak C-H?O hydrogen bonding is present in the crystal structure. PMID- 21588266 TI - Propane-1,3-diyl bis-(4-amino-benzoate). AB - Mol-ecules of the title compound, C(17)H(18)N(2)O(4), lie on a twofold rotation axis that passes through the central methyl-ene C atom. The mol-ecules adopt a 'V' shape and the trimethyl-ene unit assumes a gauche-gauche conformation. The amino N atom shows a nonplanar coordination. Adjacent mol-ecules are connected by N-H?O hydrogen bonds into chains running along [001]. Furthermore, N-H?N hydrogen bonds connect these chains into a three-dimensional network. PMID- 21588267 TI - Cyanomethanaminium tetra-fluoro-borate. AB - In the title compound, C(2)H(5)N(2) (+).BF(4) (-), the cations and anions are connected via inter-molecular N-H?F and C-H?F hydrogen bonds, forming a three dimensional network. PMID- 21588268 TI - N-Methyl-2-thio-cytisine. AB - The rings of the three-ring cytisine system in the title compound [systematic name: (1R,5S)-1,2,3,4,5,6-hexa-hydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazo-cine 8-thione], C(12)H(16)N(2)S, have planar [maximum deviation 0.0170 (7) A], half chair and chair conformations. In the crystal structure, relatively short and directional C-H?pi inter-actions and weaker secondary C-H?S contacts join the mol ecules into helical chains along the [001] direction. PMID- 21588269 TI - 1-Benzyl-sulfanyl-2-[(2-chloro-phen-yl)diazen-yl]benzene. AB - The title compound, C(19)H(15)ClN(2)S, a divalent organosulfur compound belonging to the class of ortho-mercaptoazo compounds, is non-ionic in nature. The azo group in the mol-ecule is moved away from the S atom to attain the stable trans azo configuration. Here the S atom is not electron deficient, so no intra molecular N?S inter-action exists. Due to steric reasons, the mol-ecule is non planar: the chlorophenyl and benzyl rings are oriented at dihedral angles of 3.21 (8) and 78.18 (5) degrees , respectively, with respect to the thiophenyl ring. There are no hydrogen bonds and the crystal structure is stabilized by van der Waals inter-actions. PMID- 21588270 TI - 4-Eth-oxy-anilinium chloride. AB - The title compound, C(8)H(12)NO(+).Cl(-), consists of an almost planar protonated 4-eth-oxy-anilinium cation with the N atom showing the biggest deviation from the plane formed by all non-H atoms of the cation [0.066 (1) A]. In the crystal, N H?Cl hydrogen bonds link cations and anions into chains along the a axis. Additional C-H?pi and pi-pi inter-actions [centroid-centroid distance = 4.873 (2) A] stabilize the crystal structure. PMID- 21588271 TI - 2-Amino-anilinium 2-chloro-acetate. AB - In the crystal structure of the title compound, C(6)H(9)N(2) (+).ClCH(2)COO(-), prepared by the reaction of OPDA (orthophenelynediamine) with chloro-acetic acid, N-H?O hydrogen bonds generate ladder-like chains and very weak inter molecular C-H?Cl hydrogen-bonding inter-actions between the anions and cations lead to a supra-molecular network. C-H?O inter-actions also occur. PMID- 21588272 TI - Guanidinium 3-nitro-benzoate. AB - The title compound, CH(6)N(3) (+).C(7)H(4)NO(4) (-), an anhydrous guanidinium salt, shows a N-H?O hydrogen-bond network in which the guanidinium cation is involved in three cyclic R(2) (1)(6) hydrogen-bonding associations with separate carboxyl-ate O-atom acceptors. Further peripheral associations include a cyclic R(1) (2)(4) cation-anion inter-action, forming inter-linked undulating sheets in the three-dimensional structure. PMID- 21588273 TI - Guanidinium 2-phenyl-acetate. AB - In the structure of the title salt, CH(6)N(3) (+).C(8)H(7)O(2) (-), the guanidinium cation gives three cyclic hydrogen-bonding inter-actions with O-atom acceptors of three independent phenyl-acetate anions, one R(2) (2)(8) and two R(2) (1)(6), giving one-dimensional columnar structures which extend down the 4(2) axis in the tetra-gonal cell. Within these structures, there are solvent accessible voids of volume 86.5 A(3). PMID- 21588274 TI - 3,5-Bis(4-fluoro-phen-yl)-1-phenyl-4,5-dihydro-1H-pyrazole. AB - In the title compound, C(21)H(16)F(2)N(2), the dihedral angle between the fluoro phenyl groups is 66.34 (8) degrees , and the dihedral angle between the envelope configured pyrazole group (N/N/C/C/C) and the benzene ring is 11.50 (9) degrees . The dihedral angles between the benzene and the two fluoro-substituted phenyl groups are 77.7 (6) and 16.7 (5) degrees . Weak C-H?pi interactions contribute to the stability of the crystal structure. PMID- 21588276 TI - (E)-1-(2-Bromo-phen-yl)-3-(2,5-dimeth-oxy-phen-yl)prop-2-en-1-one. AB - The title compound, C(17)H(15)BrO(3), is a chalcone with the 2-bromo-phenyl and 2,5-dimeth-oxy-phenyl rings bonded at opposite ends of a propene group. The dihedral angle between the mean planes of the ortho-bromo and ortho,meta-dimeth oxy-substituted benzene rings is 77.3 (1) degrees . The dihedral angles between the mean plane of the prop-2-ene-1-one group and the mean planes of the 2-bromo phenyl and 2,5-dimeth-oxy-phenyl rings are 58.6 (1) and 30.7 (4) degrees , respectively. Weak C-H?O, C-H?Br and pi-pi stacking inter-molecular inter-actions [centroid-centroid distance = 3.650 (2) A] are present in the structure. PMID- 21588275 TI - 1-[3,5-Bis(4-chloro-phen-yl)-4,5-dihydro-1H-pyrazol-1-yl]ethanone. AB - In the title compound, C(17)H(14)Cl(2)N(2)O, the dihedral angles between the pyrazole ring and the mean planes of the benzene and chloro-substituted benzene rings are 75.97 (1) and 16.63 (1) degrees respectively. In the crystal, two weak C-H?O inter-molecular hydrogen bonds and pi-pi stacking inter-actions [centroid centroid distances = 3.774 (4) and 3.716 (7) A] are observed. PMID- 21588277 TI - 2,3-Dimethyl-N-[(E)-2,4,5-trimeth-oxy-benzyl-idene]aniline. AB - In the title compound, C(18)H(21)NO(3), the C=N bond has a trans conformation and the benzene rings are oriented at a dihedral angle of 61.32 (6) degrees . The C atoms of the three meth-oxy groups are all roughly coplanar with their attached ring [deviations = 0.219 (2), -0.097 (2) and -0.137 (2) A]. In the crystal, a weak C-H?pi inter-action may help to establish the packing. PMID- 21588278 TI - 2-[1-(tert-But-oxy-carbonyl)-pyrrolidin-2-yl]-4,4,5,5-tetra-methyl-4,5-dihydro-1H imidazole-1-oxyl 3-oxide. AB - In the title compound, C(16)H(28)N(3)O(4), the plane of the pyrrolidine ring system is twisted with respect to the plane of the nitronyl nitroxide unit, making a dihedral angle of 79.80 (6) degrees . The crystal structure is stabilized by C-H?O hydrogen bonds. PMID- 21588279 TI - (E)-1-(2-Nitro-benzyl-idene)-2-phenyl-hydrazine. AB - The asymmetric unit of the title compound, C(13)H(11)N(3)O(2), contains two mol ecules with slightly different conformations: the dihedral angle between the aromatic rings is 13.01 (10) degrees in one mol-ecule and 14.05 (10) degrees in the other. Both mol-ecules feature short intra-molecular C-H?O contacts, which generate S(6) rings. In the crystal, both mol-ecules form inversion dimers linked by pairs of N-H?O hydrogen bonds, thereby generating R(2) (2)(16) rings. PMID- 21588280 TI - Methyl 2-benzene-sulfonamido-benzoate. AB - In the title compound, C(14)H(13)NO(4)S, the conformation of the C-S-N-C segment is gauche and the two benzene rings are tilted relative to each other by 85.62 (8) degrees . An intra-molecular N-H?O hydrogen bond generates an S(6) ring and an C-H?O inter-action also occurs. In the crystal, inter-molecular C-H?O hydrogen bonds are observed, which link the mol-ecules into [100] C(7) chains. PMID- 21588282 TI - 5,11-Diisopropyl-2,8-dimethyl-1H,7H-diimidazo[c,h][1,6]diazecine dihydrate. AB - Crystals of the title compound, C(18)H(30)N(6).2H(2)O, are composed of units of diimidazo[c,h][1,6]diazecine and two water mol-ecules. The asymmetric unit contains one half-molecule of diazecine and one uncoordinated water molecule in a general position. The complete ten-membered heterocycle is generated by an inversion center.The organic residue and water mol-ecules form a two-dimensional hydrogen-bonded network. The 1,6-diazecine ring shows a chair conformation, with angles and distances in normal ranges. PMID- 21588281 TI - N-[2-(3-Methyl-1-oxo-1,2-dihydro-pyrrolo-[1,2-a]pyrazin-2-yl)eth-yl]methane sulfonamide. AB - In the title compound, C(11)H(15)N(3)O(3)S, the dihedral angle between the five- and six-membered rings is 1.13 (18) degrees . The ethyl-methane-sulfonamide group is in a (+)synclinal conformation. In the crystal, inter-molecular N-H?O and C H?O hydrogen-bond inter-actions link mol-ecules into zigzag ribbons parallel to the b axis. The ribbons are further connected by C-H?pi inter-actions. PMID- 21588283 TI - N-(6-{2-[6-(2,2-Dimethyl-propanamido)-2-pyrid-yl]eth-yl}-2-pyrid-yl)-2,2-dimethyl propanamide. AB - The title compound, C(22)H(30)N(4)O(2), lies about a crystallographic inversion center. The whole mol-ecule is disordered over two positions with a refined occupancy ratio of 0.636 (10):0.364 (10). The pyridine rings are approximately planar, with maximum deviations of 0.033 (10) and 0.063 (17) A for the major and minor components, respectively. The mean planes of the pyridine rings form dihedral angles of 17 (2) degrees in the major component and 18 (2) degrees in the minor component with the respective formamide groups attached to them. In the crystal packing, inter-molecular N-H?O and C-H?O hydrogen bonds link the mol ecules into two-dimensional networks parallel to the ab plane. PMID- 21588284 TI - 2-Amino-4-methyl-pyridinium (E)-3-carb-oxy-prop-2-enoate. AB - In the title salt, C(6)H(9)N(2) (+).C(4)H(3)O(4) (-), the dihedral angle between the pyridine ring and the plane formed by the hydrogen fumarate anion is 85.67 (6) degrees . Excluding the amino and methyl groups, the atoms of the cation are coplanar, with a maximum deviation of 0.005 (1) A. In the crystal structure, the protonated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. These motifs are further connected through N-H?O and C H?O hydrogen bonds, leading to a supra-molecular chain along the c axis. These chains are further cross-linked via a pair of O-H?O hydrogen bonds involving centrosymmetrically related hydrogen fumarate anions, forming a two-dimensional network parallel to (101). These planes are further interconnected by O-H?O interactions into a three-dimensional network. PMID- 21588285 TI - 2-Amino-5-bromo-pyridinium 4-carb-oxy-butano-ate. AB - In the title salt, C(5)H(6)BrN(2) (+).C(5)H(7)O(4) (-), the 2-amino-5-bromo pyridinium cation is essentially planar, with a maximum deviation of 0.005 (3) A. In the crystal structure, the proton-ated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The ion pairs are further connected via O-H?O, N-H?O and C-H?O hydrogen bonds, forming a two dimensional network parallel to the bc plane. In the network, the hydrogen glutarate (4-carb-oxy-butano-ate) anions self-assemble through O-H?O hydrogen bonds, forming a supra-molecular chain along the c axis. PMID- 21588286 TI - Diethyl 2-[(3,5-dimethyl-1H-pyrazol-1-yl)(4-meth-oxy-phen-yl)meth-yl]propane dioate. AB - The title compound, C(20)H(26)N(2)O(5), was prepared in good yield (76%) through condensation of diethyl (4-meth-oxy-benz-yl)propane-dioate with 3,5-dimethyl-1H pyrazole. The dihedral between the benzene and pyrazole rings is 83.96 (10) degrees . The crystal packing is stabilized by a C-H?O inter-action, which links the mol-ecules into centrosymmetric dimers. PMID- 21588287 TI - 3,4,6-Trimethyl-1-phenyl-1H-pyrazolo-[3,4-b]pyridine. AB - In the title compound, C(15)H(15)N(3), the 1H-pyrazolo-[3,4-b]pyridine system and the phenyl ring are each individually planar, with r.m.s. deviations of 0.017 (2) and 0.011 (2) A, respectively; the dihedral angle between the two aromatic systems is 9.33 (10) degrees . The crystal packing is stabilized by offset pi-pi stacking between parallel pyrazolo-[3,4-b]pyridine ring systems [face-to-face distance = 3.449 (6) A]. PMID- 21588288 TI - Bis(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carb-oxy-lic acid) monohydrate. AB - The crystal structure of the title compound, 2C(10)H(9)N(3)O(2).H(2)O, synthesized from azido-benzene and ethyl acetyl-acetate, is stabilized by O-H?O and O-H?N hydrogen bonds. PMID- 21588289 TI - 4-[(1-Hy-droxy-2-naphth-yl)methyl-ene-amino]-1,5-dimethyl-2-phenyl-1H-pyrazol 3(2H)-one. AB - The title anti-pyrine derivative, C(22)H(19)N(3)O(2), was synthesized by the reaction of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one and 1-hy droxy-naphthalene-2-carbaldehyde in methanol solution. As expected, the compound adopts a trans configuration about the central C=N bond. The N atom is involved in an intra-molecular O-H?N bond which stabilizes the mol-ecular configuration. In the crystal structure, adjacent mol-ecules stack with no short contacts. PMID- 21588290 TI - Tetra-butyl-ammonium N-benzoyl-6-nitro-1,3-benzothia-zol-2-aminide. AB - In the title salt, C(16)H(36)N(+).C(14)H(8)N(3)O(3)S(-), the torsion angles within the cation reveal that one butyl group displays an anti conformation and the other three butyl groups show gauche conformations. The anion is almost planar, with a largest deviation of 0.166 (6) A from the least-squares plane (r.m.s. deviation of fitted atoms = 0.052 A). In the crystal structure, the component ions inter-act by means of weak inter-molecular C-H?O hydrogen bonds. PMID- 21588291 TI - tert-Butyl 6-bromo-1,4-dimethyl-9H-carbazole-9-carboxyl-ate. AB - The title compound, C(19)H(20)BrNO(2), consists of a carbazole skeleton with methyl groups at positions 1 and 4, a protecting group located at the N atom and a Br atom at position 6. The pyrrole ring is oriented at dihedral angles of 1.27 (7) and 4.86 (7) degrees with respect to the adjacent benzene rings. The dihedral angle between the benzene rings is 5.11 (7). The crystal structure is determined mainly by intra-molecular C-H?O and inter-molecular pi-pi inter actions. pi-stacking between adjacent molecules forms columns with a parallel arrangement of the carbazole ring systems. The presence of the tert-but-oxy carbonyl group on the carbazole N atom and the intra-molecular hydrogen bond induce a particular conformation of the exocyclic N-C bond within the mol-ecule. PMID- 21588292 TI - (E)-1-(4-Amino-phen-yl)-3-(2,4,5-trimeth-oxy-phen-yl)prop-2-en-1-one. AB - Mol-ecules of the title amino-chalcone, C(18)H(19)NO(4), are twisted, with a dihedral angle of 11.26 (6) degrees between the 4-amino-phenyl and 2,4,5-trimeth oxy-phenyl rings. The conformations of the three meth-oxy groups with respect to the benzene ring are slightly different. Two meth-oxy groups are almost coplanar with the attached benzene ring [C-O-C-C torsion angles of -1.45 (19) and 1.5 (2) degrees ], while the third is (-)-synclinal with the attached benzene ring [C-O-C C = -81.36 (17) degrees ]. In the crystal structure, mol-ecules are stacked into columns along the b axis and mol-ecules in adjacent columns are linked by N-H?O hydrogen bonds into V-shaped double columns. Weak pi-pi inter-actions are also observed, with a centroid-centroid distance of 3.7532 (8) A. PMID- 21588293 TI - (E)-2-[4-(Dimethyl-amino)-styr-yl]-1-methyl-pyridinium 4-methyl-benzene-sulfonate monohydrate. AB - The cation of the title compound, C(16)H(19)N(2) (+).C(7)H(7)O(3)S(-).H(2)O, exists in the E configuration with respect to the C=C double bond and is essentially planar, the dihedral angle between the pyridinium and benzene rings being 3.55 (13) degrees . In the crystal, pi-conjugated planes of cations and anions are inclined to each other at 84.30 (11) degrees . The crystal structure is stabilized by O-H?O hydrogen bonds and weak C-H?O inter-actions, which link the cations, anions and water mol-ecules into chains along the b axis. These chains are stacked along the a axis by pi-pi inter-actions with centroid-centroid distances of 3.6032 (16) and 3.6462 (16) A. PMID- 21588294 TI - N-(4-Chloro-phen-yl)-2-(8-quinol-yloxy)acetamide monohydrate. AB - In the title compound, C(17)H(13)ClN(2)O(2).H(2)O, the dihedral angle between the quinoline ring system and the benzene ring is 13.0 (1) degrees . An intra molecular N-H?O hydrogen bond may influence the mol-ecular conformation. In the crystal structure, acetamide mol-ecules are linked to water mol-ecules via inter molecular O-H? N and N-H?O hydrogen bonds and in turn linked into chains along [010] via O-H?O hydrogen bonds. PMID- 21588295 TI - 1-(4-Meth-oxy-phen-yl)-2-(1H-1,2,4-triazol-1-yl)ethanone. AB - In the title compound, C(11)H(11)N(3)O(2), the dihedral angle between the central ethanone fragment and the 4-meth-oxy-phenyl group is 2.9 (2) degrees , while that between the ethanone fragment and the triazole ring is 83.4 (2) degrees . The dihedral angle between the planes of the triazole and benzene rings is 81.7 (1) degrees . The 4-meth-oxy-phenyl group is cis with respect to the ethanone fragment O atom across the exocyclic C-C bond. In the crystal, mol-ecules are linked by C-H?N inter-actions into C(9) chains along [001]. PMID- 21588296 TI - Opipramol dipicrate. AB - In the crystal structure of the title compound, C(23)H(31)N(3)O(2+).2C(6)H(2)N(3)O(7) (-), {systematic name: 1-[3-(5H dibenz[b,f]azepin-5-yl)prop-yl]-4-(2-hy-droxy-eth-yl)piperazine-1,4-diium bis (2,4,6-trinitro-phrenolate)} the piperazine group in the opipramol dication is protonated at both N atoms. Each picrate anion inter-acts with the protonated N atom in the cation through a bifurcated N-H?O hydrogen bond, forming an R(2) (1)(6) ring motif. In the cation, the dihedral angle between the mean planes of the two benzene rings is 50.81 (8) A. Inter-molecular O-H?O and weak C-H?O hydrogen bonds, and weak pi-ring and pi-pi stacking inter-actions dominate the crystal packing. PMID- 21588297 TI - (E)-3-[1-(2,4-Difluoro-phen-yl)eth-yl]-5-methyl-N-nitro-1,3,5-oxadiazinan-4 imine. AB - The 1,3,5-oxadiazinane ring in the title compound, C(12)H(14)F(2)N(4)O(3), has a conformation inter-mediate between half-chair and screw-boat. The crystal structure is stabilized by weak inter-molecular C-H?O hydrogen bonds. Weak pi-pi inter-actions are indicated by the relatively long centroid-centroid distance of 3.9199 (12) A and inter-planar distance of 3.803 A between symmetry-related benzene rings from neighbouring mol-ecules. PMID- 21588298 TI - Ethyl 4-hy-droxy-2,6-diphenyl-1-(2-thio-morpholino-acet-yl)-1,2,5,6-tetra-hydro pyridine-3-carboxyl-ate. AB - In the title compound, C(26)H(30)N(2)O(4)S, the thio-morpholine ring adopts a chair conformation whereas the tetra-hydro-pyridine ring is in a half-chair conformation. The dihedral angle between the two phenyl rings is 33.3 (2) degrees . A strong intra-molecular O-H?O hydrogen bond generates an S(6) motif. In the crystal, mol-ecules are linked by inter-molecular C-H?O hydrogen bonds, generating a ribbon-like structure propagating along the a axis. PMID- 21588299 TI - N-(3,4-Dimethyl-phen-yl)benzene-sulfonamide. AB - The structure of the title compound, C(14)H(15)NO(2)S, shows the sulfonamide N atom to be approximately perpendicular to the plane through the S-bound benzene ring [the N-S-C-C torsion angle is -87.4 (3) degrees ] and to lie to the opposide side of this ring to the two sulfonamide O atoms. The N-bound benzene ring is splayed out with respect to the rest of the mol-ecule so that overall, the mol ecule adopts a twisted conformation. The dihedral angle between the two benzene rings is 64.5 (3) degrees . In the crystal, supra-molecular chains aligned along the b axis are formed via N-H?O hydrogen bonds. PMID- 21588300 TI - Diethyl 2,2'-(biphenyl-2,2'-diyldi-oxy)diacetate. AB - In the title compound, C(20)H(22)O(6), the mean planes through the benzene rings make a dihedral angle of 59.82 (7) degrees with each other. Weak inter-molecular C-H?O inter-actions together with pi-pi stacking inter-actions [centroid-centroid distance = 3.830 (1) A] between benzene rings are observed in the crystal packing. PMID- 21588301 TI - 3-Ethyl-sulfinyl-2-(4-iodo-phen-yl)-5-methyl-1-benzofuran. AB - In the title compound, C(17)H(15)IO(2)S, the 4-iodo-phenyl ring makes a dihedral angle of 35.39 (8) degrees with the plane of the benzofuran fragment. In the crystal, mol-ecules are linked by inter-molecular C-H?O and C-H?pi inter-actions, and an I?O contact [3.378 (2) A]. The crystal structure also exhibits aromatic pi pi inter-actions between the benzene rings of neighbouring mol-ecules [centroid centroid distance = 3.495 (3) A]. PMID- 21588302 TI - 3-Benzyl-3-hy-droxy-2-phenyl-3H-indole 1-oxide. AB - The asymmetric unit of the title compound, C(21)H(17)NO(2), contains two crystallographically independent mol-ecules of similar geometry. The indole ring systems form dihedral angles of 8.30 (5) and 9.58 (5) degrees with the attached phenyl rings, and 56.96 (5) and 57.68 (5) degrees with the aromatic rings of the respective benzyl groups. The mol-ecular conformations are stabilized by intra molecular C-H?O hydrogen bonds. In the crystal structure, centrosymmetrically related pairs of mol-ecules are linked into dimers through pairs of inter molecular O-H?O hydrogen bonds, generating 12-membered rings with R(2) (2)(12) motifs. The dimers are further linked into a three-dimensional network by C-H?O inter-actions. PMID- 21588303 TI - 1-{3-[(4-Oxopiperidin-1-yl)carbon-yl]benzoyl}piperidin-4-one. AB - Two independent mol-ecules comprise the asymmetric unit in the title compound, C(18)H(20)N(2)O(4). One of the mol-ecules exhibits disorder in one of its 4 piperidone rings, which is disposed over two orientations [site occupancy of the major component = 0.651 (5)]. The first independent mol-ecule and the minor component of the second disordered mol-ecule are virtually superimposable. The central four C atoms in the major component of the disordered mol-ecule have an opposite orientation. All the 4-piperidone rings have a chair conformation. The carbonyl groups in each mol-ecule have approximate anti conformations [O=C?C=O = 146.2 (2) and -159.9 (2) degrees ]. The 4-piperidone rings lie to opposite sides of the central benzene ring in both mol-ecules. In the crystal, mol-ecules are linked by C-H?O inter-actions. The crystal studied was found to be a non merohedral twin (twin law -1 0 0, 0 1 0, 0 - 1/2 - 1), the fractional contribution of the minor component being approximately 11%. PMID- 21588304 TI - 4-Bromo-N-cyclo-hexyl-benzene-sulfonamide. AB - The title compound, C(12)H(16)BrNO(2)S, adopts an L-shaped conformation with the central C-S-N-C torsion angle being -77.8 (3) degrees . The crystal packing features N-H?O hydrogen bonds, which lead to C(4) chains propagating in [010]; the second O atom is involved in short intra-molecular C-H?O contacts. PMID- 21588305 TI - A monoclinic polymorph of N-eth-oxy-carbonyl-N'-(3-phenyl-1H-1,2,4-triazol-5 yl)thio-urea. AB - The title compound, C(12)H(13)N(5)O(2)S {systematic name: ethyl N-[N-(3-phenyl-1H 1,2,4-triazol-5-yl)carbamothio-yl]carbamate}, is a monoclinic polymorph (space group P2(1)/c) which crystallizes with three similar independent mol-ecules in the asymmetric unit. The triazole ring makes dihedral angles of 6.6 (2), 8.4 (2) and 10.6 (2) degrees with the phenyl ring in the three independent molecules. The structure was previously reported [Dolzhenko et al. (2010a ?). Acta Cryst., E46, o425] as a triclinic polymorph crystallizing in space group P. Mol-ecules in both polymorphs possess two S(6) rings generated by intra-molecular N-H?S and N H?O hydrogen bonds, resulting in similar mol-ecular geometries. However, the two polymorphs differ in the crystal packing. In contrast to the dimers of the triclinic polymorph, mol-ecules of the monoclinic polymorph are connected by inter-molecular N-H?S and N-H?N hydrogen bonds, forming pseudosymmetric trimers arranged in sheets parallel to (302). PMID- 21588306 TI - 2-Methyl-N-(2-methyl-benzo-yl)benzene-sulfonamide. AB - In the title compound, C(15)H(15)NO(3)S, the 2-methyl-phenyl ring bonded to the sulfonyl group is disordered with site-occupation factors of 0.75:0.25. The dihedral angles between the two aromatic rings are 67.6 (1) and 69.2 (1) degrees for the major and the minor occupied sites, respectively. In the crystal, mol ecules are linked into centrosymmetric dimers by pairs of N-H?O hydrogen bonds. PMID- 21588307 TI - 5,8-Dibromo-14,15,17,18-tetra-methyl-2,11-dithia-[3.3]paracyclo-phane. AB - In the title mol-ecule [systematic name: 1(2),1(5)-dibromo-5(2),5(3),5(5),5(6) tetramethyl-3,7-dithia-1,5(1,4)-dibenzenacyclooctaphane], C(20)H(22)Br(2)S(2), the distance between the centroids of the two benzene rings is 3.326 (4) A, and their mean planes are almost parallel, forming a dihedral angle of 1.05 (7) degrees . The crystal packing exhibits no inter-molecular contacts shorter than the sum of van der Waals radii. PMID- 21588308 TI - Ethyl 2-(2,3,4,5,6-Penta-bromo-phen-yl)acetate. AB - The title compound PBPEA, C(10)H(7)Br(5)O(2), has its ethyl acetate portion nearly orthogonal to the benzene ring, with a C-C-C-C torsion angle of 88.3 (5) degrees . The packing involves an inter-molecular contact with a Br?Br distance of 3.491 (1) A, having C-Br?Br angles of 173.4 (2) and 106.0 (2) degrees . The crystal studied was an inversion twin. PMID- 21588309 TI - (E)-1-(4-Bromo-phen-yl)-3-(2-meth-oxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C(16)H(13)BrO(2), the dihedral angle between the mean planes of the meth-oxy- and bromo-substituted benzene rings is 24.6 (1) degrees . The angles between the mean plane of the prop-2-en-1-one group and the 4-bromo phenyl and 2-meth-oxy-phenyl ring planes are 18.8 (1) and 6.0 (1) degrees , respectively. PMID- 21588310 TI - (E)-3-(4-Meth-oxy-phen-yl)-1-[4-(piperidin-1-yl)phen-yl]prop-2-en-1-one. AB - The piperidine ring in the title compound, C(21)H(23)NO(2), is in a slightly distorted chair conformation. The dihedral angle between the two benzene rings is 5.6 (4) degrees . The dihedral angles between the propenone unit and the benzene and meth-oxy-substituted benzene rings are 5.6 (7) and 10.7 (8) degrees , respectively. Weak inter-molecular C-H?O hydrogen bonds and weak C-H?pi inter actions contribute to the stability of the crystal structure. PMID- 21588311 TI - N-(4-Chloro-benzo-yl)-2-methyl-benzene-sulfonamide. AB - The asymmetric unit of the title compound, C(14)H(12)ClNO(3)S, contains two independent mol-ecules. The conformations of the N-C bonds in the C-SO(2)-NH-C(O) segments have gauche torsions with respect to the S=O bonds. The mol-ecules are twisted at the S atoms with torsion angles of -54.2 (2) and 63.8 (2) degrees in the two mol-ecules. The dihedral angles between the sulfonyl benzene rings and the -SO(2)-NH-C-O segments are 85.0 (1) and 87.0 (1) degrees . Furthermore, the dihedral angles between the sulfonyl and benzoyl benzene rings are 89.4 (1) and 82.4 (1) degrees in the two mol-ecules. In the crystal, mol-ecules are linked by N-H?O(S) hydrogen bonds. PMID- 21588312 TI - Pirimicarb: 2-dimethylamino-5,6-dimethylpyrimidin-4-yl dimethyl-carbamate. AB - In the title compound, C(11)H(18)N(4)O(2) (systematic name: 2-dimethyl-amino-5,6 dimethyl-pyrimidin-4-yl N,N-dimethyl-carb-amate), the pyrimidine ring and dimethyl-amino group are almost in the same plane, making a dihedral angle of 1.6 (1) degrees . The dihedral angle between the mean plane of the pyrimidine ring and that of the dimethyl-carbamate group is 83.42 (5) degrees . In the crystal structure, inter-molecular C-H?O hydrogen bonds contribute to the stabilization of the packing. PMID- 21588313 TI - Ethyl 5-methyl-imidazo[1,2-a]pyridine-2-carboxyl-ate. AB - The title compound, C(11)H(12)N(2)O(2), was synthesized from the reaction of 6 methyl-pyridin-2-amine and ethyl 3-bromo-2-oxopropionate. In the mol-ecular structure, the six- and five-membered rings are individually almost planar with r.m.s. deviations of 0.003 and 0.002 A, respectively. The two rings are almost coplanar, the dihedral angle between their planes being 1.4 (3) degrees . Inter molecular C-H?O and C-H?N hydrogen bonds are present in the crystal structure. PMID- 21588314 TI - 4-Chloro-N-(4-chloro-phen-yl)-2-methyl-benzene-sulfonamide. AB - In the title compound, C(13)H(11)Cl(2)NO(2)S, the conformations of the N-C bonds in the C-SO(2)-NH-C segment have gauche torsions with respect to the S=O bonds. Further, the conformation of the N-H bond is syn to the ortho-methyl group in the sulfonyl benzene ring. The torsion angle of the C-SO(2)-NH-C segment in the mol ecule is 55.0 (2) degrees . The two benzene rings are tilted relative to each other by 67.0 (1) degrees . In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into infinite column-like chains. PMID- 21588315 TI - 3-Acetyl-2-methyl-4-phenyl-quinolin-1-ium chloride. AB - An N-H?Cl hydrogen bond connects the ions in the title salt, C(18)H(16)NO(+).Cl( ). The quinolin-1-ium residue is almost planar (r.m.s. deviation = 0.020 A) but both the acetyl group [O-C-C-C torsion angle = 62.73 (17) degrees ] and adjacent benzene ring [C-C-C-C torsion angle = -104.06 (14) degrees ] are twisted out of this plane; the acetyl and benzene substituents are non-parallel [dihedral angle = 66.16 (7) degrees ]. The crystal packing is consolidated by C-H?O and C-H?Cl contacts. PMID- 21588316 TI - 1-[6-Chloro-4-(2-chloro-phen-yl)-2-methyl-3-quinol-yl]ethanone. AB - The title compound, C(18)H(13)Cl(2)NO, features an essentially planar quinoline ring system (r.m.s. deviation = 0.023 A) with the acetyl [C-C-C-O torsion angle = -78.27 (17) degrees ] and benzene [C-C-C-C torsion angle = 110.11 (14) degrees ] substituents being twisted out of the plane; the dihedral angle formed between the mean planes of these two substituents is 58.01 (8) degrees . The acetyl O and benzene-bound Cl atoms lie to opposite sides of the mol-ecule. Centrosymmetric aggregates mediated by pairs of C-H?O contacts are found in the crystal structure, and these are connected into a two-dimensional array in the (01) plane via Cl?O [3.0508 (11) A] inter-actions. PMID- 21588317 TI - 3beta,11alpha-Dihy-droxy-17a-oxa-d-homoandrost-5-en-17-one. AB - The title compound, C(19)H(28)O(4), was prepared from DHEA (dehydro epiandrosterone) by its biotransformation using whole cells of the filamentous fungus Beauveria bassiana. The asymmetric unit contains two mol-ecules. The lactone ring is trans-positioned to the neighboring six-membered ring. In the crystal structure, O-H?O hydrogen bonds form layers, which are linked to each other by O-H?O and C-H?O hydrogen bonds. PMID- 21588318 TI - Methyl 4-(cyclopropylmethoxy)-3-hydroxybenzoate [corrected]. AB - In the title compound, C(12)H(14)O(4), the dihedral angle between the benzene ring and the cyclo-propyl ring is 60.3 (4) degrees . In the crystal structure, mol-ecules are linked by inter-molecular O-H?O hydrogen bonds into chains running parallel to [101]. PMID- 21588319 TI - Ethyl 4-hy-droxy-2,6-diphenyl-1-[2-(piperidin-1-yl)acet-yl]-1,2,5,6-tetra-hydro pyridine-3-carboxyl-ate. AB - In the title compound, C(27)H(32)N(2)O(4), the piperidine and tetra-hydro pyridine rings adopt chair and half-chair conformations, respectively. The dihedral angle between the two phenyl rings is 32.9 (1) degrees . The mol-ecular structure is stabilized by a strong intra-molecular O-H?O hydrogen bond, generating an S(6) motif. In the crystal, inter-molecular C-H?O inter-actions form a ribbon-like structure along the a axis. PMID- 21588320 TI - 3-[(2-Hy-droxy-1-naphth-yl)(pyrrolidin-1-yl)meth-yl]benzonitrile. AB - The title compound, C(22)H(20)N(2)O, was obtained from the condensation reaction of 3-formyl-benzonitrile, 2-naphthol and pyrrolidine. There are two mol-ecules in the asymmetric unit, having similar conformations. Intra-molecular O-H?N and C H?O hydrogen bonds occur, with only van der Waals forces between mol-ecules. The dihedral angles between the naphthalene ring system and the phenyl ring in the two molecules are 75.28 (10) and 76.07 (11) degrees . The five-membered rings adopt half-chair conformations. PMID- 21588321 TI - 2-Bromo-2-methyl-N-(4-methyl-2-oxo-2H-chromen-7-yl)propanamide. AB - In the title compound C(14)H(14)BrNO(3), the coumarin ring system is almost planar (r.m.s. deviation = 0.008 A) and an intra-molecular C-H?O inter-action generates an S(6) ring. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, with the C=O unit of the coumarin ring system acting as the acceptor group, generating [010] C(8) chains. The chain connectivity is reinforced by two C-H?O inter-actions. PMID- 21588322 TI - 2-Amino-5-chloro-pyridinium 4-carb-oxy-butano-ate. AB - In the title salt, C(5)H(6)ClN(2) (+).C(5)H(7)O(4) (-), the 2-amino-5-chloro pyridinium cation is essentially planar, with a maximum deviation of 0.010 (3) A. In the crystal structure, the protonated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The ion pairs are further connected via O-H?O, N-H?O and C-H?O hydrogen bonds, forming a layer parallel to the bc plane. In the layer, the hydrogen glutarate anions self assemble via O-H?O hydrogen bonds, forming a supra-molecular chain along the c axis. Furthermore, the cations and anions are stacked down along the a axis, forming a three-dimensional network. PMID- 21588323 TI - 4-Amino-pyridinium 2-hy-droxy-benzoate. AB - In the salicylate anion of the title salt, C(5)H(7)N(2) (+).C(7)H(5)O(3) (-), an intra-molecular O-H?O hydrogen bond generating an S(6) ring motif is observed. In the crystal structure, the cations and anions are linked into a two-dimensional network parallel to the ab plane by N-H?O and C-H?O hydrogen bonds. The network contains R(2) (2)(7) and R(1) (2)(4) ring motifs. Weak pi-pi inter-actions between the benzene and pyridinium rings [centroid-centroid distance = 3.688 (1) A] are also observed. PMID- 21588324 TI - 4-(4-Chloro-phen-yl)-4-hy-droxy-piperidinium maleate maleic acid solvate. AB - In the cation of the title compound, C(11)H(15)ClNO(+).C(4)H(3)O(4) ( ).C(4)H(4)O(4), the dihedral angle between the mean planes of the chlorine substituted aromatic ring and the 4-hy-droxy-piperidinium ring (C-C-C-C-C-N) is 61.9 (8) degrees . Intra-molecular O-H?O and inter-molecular O-H?O and N-H?O hydrogen bonding, as well as weak pi-stacking inter-actions [centroid-centroid distance = 3.646 (5) A] help to establish the packing. PMID- 21588325 TI - 4-Bromo-2-({4-[(hy-droxy-imino)-meth-yl]phen-yl}imino-meth-yl)phenol. AB - In the title compound, C(14)H(11)BrN(2)O(2), the mean planes of the two benzene rings are almost parallel to each other, making a dihedral angle of 4.09 (1) degrees . An intra-molecular O-H?N hydrogen bond occurs. In the crystal, inter molecular O-H?N and C-H?O hydrogen bonds link the mol-ecules into a chain-like supra-molecular structure. PMID- 21588326 TI - (E)-N'-(2-Hy-droxy-benzyl-idene)furan-2-carbohydrazide. AB - In the title compound, C(12)H(10)N(2)O(3), the dihedral angle between the benzene ring and the furan ring is 16.12 (13) degrees . The conformation is stabilized by an intra-molecular O-H?N hydrogen bond. Inter-molecular N-H?O hydrogen bonds with the keto group as acceptor lead to strands along [001]. The mol-ecule displays a trans configuration with respect to the C=N and N-N bonds. PMID- 21588327 TI - 3-Chloro-6-(1H-pyrazol-1-yl)pyridazine. AB - The title compound, C(7)H(5)ClN(4), is almost planar (r.m.s. deviation = 0.022 A). The dihedral angle between the aromatic rings is 2.82 (5) degrees . The packing results in polymeric chains extending along the a axis. In the crystal, mol-ecules are connected to each other through inter-molecular C-H?N hydrogen bonds, resulting in R(2) (2)(10) ring motifs. PMID- 21588328 TI - 2-Chloro-N-isopropyl-N-phenyl-acetamide. AB - In the title compound, C(11)H(14)ClNO, the herbicide propachlor, there are significant differences between the three N-C bond lengths [N-C(carbon-yl) = 1.354 (3) A, N-C(phen-yl) = 1.444 (2) A and N-C(isoprop-yl) = 1.496 (3) A], indicating the presence of pi delocalization involving the carbonyl group. The N atom lies 0.074 (2) A from the plane defined by the the three bonded C atoms. PMID- 21588329 TI - 2,3-Dibromo-1,3-bis-(4-fluoro-phen-yl)propan-1-one. AB - In the title compound, C(15)H(10)Br(2)F(2)O, the dihedral angle between the two 3 fluoro-substituted benzene rings is 5.7 (5) degrees . The two bromine substituents on the chalcone moiety are close to anti as the Br-C-C-Br torsion angle is 176.9 (7) degrees . Weak C-Br?pi inter-actions may contribute to the crystal stability. PMID- 21588330 TI - 3,4-Dimethyl-N-(2,4,5-trimeth-oxy-benzyl-idene)-1,2-isoxazol-5-amine. AB - In the title compound, C(15)H(18)N(2)O(4), the aromatic rings on the azomethine double bond are trans to each other [C-C=N-C torsion angle = -178.29 (12) degrees ] and they are approximately coplanar, the dihedral angle between them being 5.0 (1) degrees . PMID- 21588331 TI - 4-Chloro-2,5-dimethyl-quinoline. AB - Mol-ecules of the title compound, C(11)H(10)ClN, are essentially planar (r.m.s. deviation for all non-H atoms = 0.009 A) and are stacked along the a axis with the centroids of the benzene and pyridine rings alternately separated by 3.649 (1) and 3.778 (1) A. PMID- 21588332 TI - 5-Bromo-1H-thieno[2,3-d]imidazole. AB - The crystal structure of the title compound, C(5)H(3)BrN(2)S, shows that bromination of 1H-thieno[2,3-d]imidazole with N-bromo-succinimide in acetonitrile occurs at position 5 of the bicyclic system. The mol-ecule is almost planar, with a mean deviation of 0.015 A from the least-squares plane through all the non-H atoms. In the crystal, N-H?N hydrogen bonds link the mol-ecules into infinite C(4) chains running along [101]. PMID- 21588333 TI - (S)-3-Chloro-4-(4-ethyl-piperazin-1-yl)-5-[(1R,2S,5R)-2-isopropyl-5-methyl-cyclo hex-yloxy]furan-2(5H)-one. AB - The title compound, C(20)H(33)ClN(2)O(3), was obtained via a tandem asymmetric Michael addition-elimination reaction of 3,4-dichloro-5-(S)-(l-menth-yloxy)furan 2(5H)-one and 1-ethyl-piperazine in the presence of potassium fluoride. The mol ecular structure contains an approximately planar five-membered furan-one ring [maximum atomic deviation = 0.024 (2) A] and two six-membered rings adopting chair conformations. Weak inter-molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 21588334 TI - Benzyl N-{(1S)-2-hy-droxy-1-[N'-(2-nitro-benzyl-idene)hydrazinylcarbon-yl]eth yl}carbamate. AB - The carbamate and hydrazone groups in the title compound, C(18)H(18)N(4)O(6), are approximately orthogonal [dihedral angle = 83.3 (4) degrees ], and the carbonyl groups are effectively anti [O=C?C=O torsion angle = -116.2 (7) degrees ]. The conformation about the imine bond [1.295 (11) A] is E. The crystal packing is dominated by O-H?O and N-H?O hydrogen bonding, which leads to two-dimensional arrays in the ab plane. PMID- 21588335 TI - 2-(Eth-oxy-carbon-yl)pyridinium nitrate. AB - In the title compound, C(8)H(10)NO(2) (+).NO(3) (-), the cation is essentially planar with C-O-C-C and C-O-C-O torsion angles of -178.1 (2) and 2.1 (4) degrees , respectively. In the crystal, N-H?O and C-H?O hydrogen-bond inter-actions stabilize the structure. PMID- 21588336 TI - N'-[(E)-2-Chloro-5-nitro-benzyl-idene]-2-nitro-benzohydrazide. AB - In the title compound, C(14)H(9)ClN(4)O(5), the mol-ecule exists in a trans geometry with respect to the methyl-idene unit. The dihedral angle between the two substituted benzene rings is 62.7 (2) degrees . In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(8) loops. PMID- 21588338 TI - (Butane-1,3-diyne-1,4-diyl)bis-(tri-isopropyl-silane). AB - The mol-ecule of the title compound, C(22)H(42)Si(2), lies on a center of inversion, and the triisopropyl-silyl groups are staggered. PMID- 21588337 TI - 3-Hy-droxy-methyl-1-(4-meth-oxy-phen-yl)imidazolidine-2,4-dione. AB - In the title mol-ecule, C(11)H(12)N(2)O(4), the dihedral angle between the benzene ring and imidazolidine ring is 7.1 (5) degrees . In the crystal structure, the hy-droxy groups are involved in the formation of inter-molecular O H?O hydrogen bonds, which link the mol-ecules related by translation into C(2) chains along the b axis. PMID- 21588339 TI - [Hydrogen bis-(1,2,4-triazole)] 1,2,4-triazolium bis-(3-carb-oxy-4-hy-droxy benzene-sulfonate) 1,2,4-triazole disolvate. AB - The title compound, C(2)H(4)N(3) (+).[H(C(2)H(3)N(3))(2)](+).2C(7)H(5)O(6)S( ).2C(2)H(3)N(3), consists of two types of 1,2,4-triazole monocation, one protonated at the 2-site lying across a twofold axis and the other protonated at the 4-site with the H atom disordered over a center of symmetry, a 5 sulfosalicylate anion and a neutral 1,2,4-triazole mol-ecule. The component ions are linked into a three-dimensional network by a combination of N-H?O, N-H?N, O H?O, O-H?N, C-H?O and C-H?N hydrogen bonds. In addition, benzene-benzene pi-pi inter-actions of 3.942 (2) A [inter-planar spacing = 3.390 (2) A] and C-O?pi (3.331 A) inter-actions are observed. PMID- 21588340 TI - 4,4'-Diphenyl-2,2'-bi-1,3-thia-zole. AB - In the centrosymmetric title compound, C(18)H(12)N(2)S(24), the five- (r.m.s. deviation = 0.002 A) and six-membered (r.m.s. deviation = 0.002 A) rings are essentially coplanar [dihedral angle between rings = 1.9 (1) degrees ]. PMID- 21588341 TI - N-{4-[(4-Methyl-phen-yl)sulfamo-yl]phen-yl}acetamide. AB - The title mol-ecule, C(15)H(16)N(2)O(3)S, has a twisted U-shaped conformation. The twist occurs in the central C-S(=O)(2)N(H)-C unit with the C-S-N-C torsion angle being -58.38 (14) degrees . The benzene rings lie to the same side of the mol-ecule and form a dihedral angle of 67.03 (10) degrees . The crystal packing features N-H?O hydrogen bonding, which leads to supra-molecular chains with a tubular topology along the b axis. Intra-molecular C-H?O inter-actions are also observed. PMID- 21588342 TI - A new monoclinic polymorph of 3-diethyl-amino-4-(4-meth-oxy-phen-yl)-1,1-dioxo-4H 1lambda,2-thia-zete-4-carbonitrile. AB - A new monoclinic form of the title compound, C(14)H(17)N(3)O(3)S, has been found upon slow crystallization from water. Another monoclinic form of the compound was obtained previously from a mixture of dichloro-methane and diethyl ether [Clerici et al. (2002 ?). Tetra-hedron, 58, 5173-5178]. Both phases crystallize in space group P2(1)/n with one mol-ecule in the asymmetric unit. The formally single exocyclic C-N bond that connects the -NEt(2) unit with the thia-zete ring is considerably shorter than the adjacent, formally double, endocyclic C=N bond. This is likely to be due to the extended conjugated system between the electron donor diethyl-ammine fragment and the electron-withdrawing sulfonyl group. In the newly discovered polymorph, the meth-oxy group is rotated by almost 180 degrees around the phen-yl-OCH(3) bond, resulting in a different mol-ecular conformation. PMID- 21588343 TI - 2-[1-(3-Oxo-1,3-dihydro-2-benzofuran-1-yl)-1H-benzimidazol-2-yl]benzoic acid methanol solvate. AB - The condensation of 2-carb-oxy-benzaldehyde with 1,2-phenyl-enediamine unexpectedly yielded the title compound, C(22)H(14)N(2)O(4).CH(4)O. The benzimidazole ring system is almost perpendicular to the phthalazine ring system, making a dihedral angle of 88.4 (5) degrees . Inter-molecular O-H?N and O-H?O hydrogen-bonding inter-actions stabilize the crystal structure. PMID- 21588344 TI - tert-Butyl 3-(8-bromo-4H,10H-1,2-oxazolo[4,3-c][1]benzoxepin-10-yl)-2-methyl-1H indole-1-carboxyl-ate. AB - In the title compound, C(25)H(23)BrN(2)O(4), the seven-membered ring adopts a twisted-boat conformation. The indole ring system is planar within 0.021 (2) A and the ester group [-C(=O)-O-C-] is almost coplanar with it [dihedral angle = 3.0 (2) degrees ]. The conformation of the ester group is influenced by intra molecular C-H?O inter-actions. In the crystal structure, mol-ecules are linked into chains along the b axis by C-H?N hydrogen bonds. PMID- 21588345 TI - 1-Ethyl-3-(2,4,6-trimethyl-phen-yl)imidazolium tetra-fluoro-borate. AB - The title compound, C(14)H(19)N(2) (+).BF(4) (-), was obtained by reaction of 1 ethyl-3-(2,4,6-trimethyl-phen-yl)imidazolium tetra-fluoro-borate with sodium tetra-fluoro-borate. The imidazole ring makes a dihedral angle of 78.92 (13) degrees with the benzene ring. PMID- 21588346 TI - 1-(3-tert-Butyl-4-hy-droxy-phen-yl)ethanone. AB - The title compound, C(12)H(16)O(2), is approximately planar (r.m.s. deviation = 0.030 A), apart from two methyl groups of the tert-butyl unit [deviations of the C atoms = 1.140 (2) and -1.367 (1) A]. In the crystal, inter-molecular O-H?O hydrogen bonds link the mol-ecules into hexa-meric rings with R(6) (6)(48) graph set motifs. PMID- 21588347 TI - (5-Bromo-2-methyl-phen-yl)(4-eth-oxy-phen-yl)methanone. AB - In the title compound, C(16)H(15)BrO(2), the dihedral angle between the benzene rings is 68.5 (2) degrees . In the crystal structure, mol-ecules are linked by weak C-H?O hydrogen bonds into chains parallel to the b axis. PMID- 21588348 TI - N-[(E)-4-Chloro-benzyl-idene]-N'-phenyl-benzene-1,4-diamine. AB - The title compound, C(19)H(15)ClN(2), adopts an E configuration with respect to the position of the chloro-benzene and diphenyl-amine groups on the C=N azomethine bond. The mol-ecule is not planar, the central six-membered ring making angles of 12.26 (10) and 44.18 (11) degrees with the 4-chloro-phenyl and phenyl rings, respectively. In the crystal structure, weak C-H?pi inter-actions contribute to the stabilization of the packing. PMID- 21588349 TI - Pregna-1,4,20-trien-3-one, a cytotoxic marine steroid from the marine soft coral Nephthea sp. AB - The title compound, C(21)H(28)O, was isolated from the cytotoxic lipid extract of the Fidjian soft coral Nephthea sp. The steroid showed inhibitory activity to human colon adenocarcinoma SW480 cells (IC(50) = 2.5 ug ml(-1)). The mol-ecular structure indicates that the A ring is almost planar (r.m.s. deviation = 0.032 A), the B and C rings adopt chair conformations and the five-membered D ring is a half-chair. The B/C and C/D ring junctions are trans-fused. PMID- 21588350 TI - 4-[(2'-Cyano-biphenyl-4-yl)methyl]-morpholin-4-ium nitrate. AB - The title ion pair, C(18)H(19)N(2)O(+).NO(3) (-), features an N-H?O hydrogen bond linking the cation to the anion. The morpholine portion adopts a chair conformation; the aromatic rings of the biphenyl-ene portion are twisted [torsion angles for the four atoms involving the ar-yl-aryl bond = 35.1 (2)-40.4 (2) degrees ]. PMID- 21588351 TI - N-[2-(4-Methyl-2-quinol-yl)phen-yl]acetamide: a P1 structure with Z = 4. AB - The title compound, C(18)H(16)N(2)O, crystallizes in the triclinic space group P1, with four independent mol-ecules in the asymmetric unit wherein two mol ecules have an irregular -ac, -ac, +ap conformation (ap, antiperiplanar; ac, anticlinal), while the other mol-ecules exhibit a different, +ac, +ac, +ap conformation. The planar (r.m.s. deviation = 0.006 A in each of the four molecules) quinoline ring systems of the four mol-ecules are oriented at dihedral angles of 32.8 (2), 33.4 (2), 31.7 (2) and 32.3 (2) degrees with respect to the benzene rings. Intra-molecular N-H?N inter-actions occur in all four independent mol-ecules. The crystal packing is stabilized by inter-molecular N-H?O and C-H?O hydrogen bonds, and are further consolidated by C-H?pi and pi-pi stacking inter actions [centroid-centroid distances = 3.728 (3), 3.722 (3), 3.758 (3) and 3.705 (3) A]. PMID- 21588352 TI - (E)-N'-(5-Bromo-2-hy-droxy-benzyl-idene)-3,5-dihy-droxy-benzohydrazide monohydrate. AB - The Schiff base mol-ecule in the title compound, C(14)H(11)BrN(2)O(4).H(2)O, is almost planar with an r.m.s. deviation for the non-H atoms of 0.16 A. In the crystal structure, the Schiff base mol-ecules and the water mol-ecules are linked together by inter-molecular N-H?O and O-H?O hydrogen bonds, leading to layers parallel to the bc plane. An intra-molecular O-H?N hydrogen bond involving the imine N atom and a hy-droxy substituent is also observed. PMID- 21588353 TI - N-[(9-Ethyl-9H-carbazol-3-yl)methyl-idene]-3,4-dimethyl-isoxazol-5-amine. AB - The azomethine double bond in the title Schiff base, C(20)H(19)N(3)O, has an E configuration. The 13-membered carbazolyl fused ring system [r.m.s. deviation = 0.023 (9) A] is nearly coplanar with the five-membered pyrazole ring [r.m.s. deviation = 0.003 (4) A]; the dihedral angle between the two systems is 10.8 (2) degrees . The crystal studied was a non-merohedral twin having a 35% minor component. PMID- 21588354 TI - 2-(1H-Benzimidazol-2-yl)-4,6-dichloro-phenol. AB - The title compound, C(13)H(8)Cl(2)N(2)O, was prepared by the reaction of 3,5 dichloro-2-hy-droxy-benzaldehyde with 1,2-diamino-benzene in methanol at ambient temperature. The title mol-ecule is essentially planar, the mean deviation from the plane of the non-H atoms being 0.037 (2) A. There is an intra-molecular O-H?N hydrogen bond in the mol-ecule. In the crystal, symmetry-related mol-ecules are linked through N-H?O hydrogen bonds, forming polymeric chains propagating in [001]. The chains are linked by pi-pi inter-actions involving the dichloro-phenol ring and the benzoimidazole ring system [centroid-centroid distances = 3.535 (2) and 3.724 (2) A]. PMID- 21588355 TI - N-[4-(Benzyl-sulfamo-yl)phen-yl]acetamide. AB - A folded conformation is found for the title compound, C(15)H(16)N(2)O(3)S, whereby the benzene rings come into close proximity [centroid-centroid distance = 4.0357 (12) A and the dihedral angle between them = 24.37 (10) degrees ]. The amide group is coplanar with the benzene ring to which it is bound [C-C-N-C torsion angle = 11.1 (3) degrees ]. In the crystal packing, two-dimensional arrays in the (101) plane are formed via N-H?O hydrogen bonding. PMID- 21588356 TI - 5-Bromo-3-(4-fluoro-phenyl-sulfon-yl)-2-methyl-1-benzofuran. AB - In the title compound, C(15)H(10)BrFO(3)S, the 4-fluoro-phenyl ring makes a dihedral angle of 76.51 (6) degrees with the plane of the benzofuran fragment. In the crystal, mol-ecules are linked by weak non-classical inter-molecular C-H?O hydrogen bonds and an aromatic pi-pi inter-action between the benzene rings of neighbouring mol-ecules [centroid-centroid distance = 3.540 (3) A]. PMID- 21588357 TI - 4-Amino-2,8-dimethyl-6H-pyrimido[1,2-a][1,3,5]triazin-6-one. AB - In the title compound, C(8)H(9)N(5)O, the mean planes through the pyrimidine and triazine rings form a dihedral angle of 2.83 (16) degrees . The amino group adopts a trigonal-planar configuration and forms an intra-molecular resonance assisted N-H?O=C hydrogen bond with the carbonyl group. In the crystal, mol ecules are linked via inter-molecular N-H?N hydrogen bonds into chains of C(2) (2)(6)[R(2) (2)(6)] motif. The molecules form two types of sheet parallel to (201) and (01), respectively. PMID- 21588358 TI - 1-Benzyl-N-methyl-1H-pyrrole-2-carboxamide. AB - The asymmetric unit of the title compound, C(13)H(14)N(2)O, contains two independent mol-ecules, which differ in the twist of the phenyl ring: the N(pyrrole)-C(H(2))-C-C torsion angles are -73.0 (3) and 17.1 (3) degrees . In the crystal structure, mol-ecules are linked through N-H?O hydrogen bonds into chains extending along the a axis. PMID- 21588359 TI - 4-(1H-Benzimidazol-2-ylmeth-oxy)-3-eth-oxy-benzaldehyde trihydrate. AB - In the title compound, C(17)H(16)N(2)O(3).3H(2)O, the dihedral angle between the mean planes of the benzene and benzimidazole systems is 26.2 (3) degrees . These groups are slightly twisted around the eth-oxy-methane unit [C-C-O-C torsion angle = 177.64 (15) degrees ]. The crystal packing is stabilized by N-H?O, O-H?N and O-H?O hydrogen-bond inter-actions involving the water mol-ecules. Weak pi-pi stacking inter-actions [centroid-centroid distances = 3.7943 (7), 3.6919 (13) and 3.7533 (14) A] contribute to the mol-ecular stability. PMID- 21588360 TI - 8-Bromo-1,3-diphenyl-2,3-dihydro-1H-naphtho-[1,2-e][1,3]oxazine. AB - The title compound, C(24)H(18)BrNO, consists of an envelope-configured oxazine ring with a fused 8-bromo-1,3-diphenyl group and two bonded phenyl rings. The dihedral angles between the mean planes of the 8-bromo-1,3-diphenyl and the phenyl rings are 54.5 (6) and 87.4 (8) degrees , respectively. The oxazine is essentially coplanar with the 8-bromo-1,3-diphenyl [dihedral angle = 9.4 (1) degrees ]. Weak C-H?pi inter-actions contribute to the crystal packing. PMID- 21588361 TI - N-{(E)-[4-(Dimethyl-amino)-phen-yl]methyl-idene}-2,3-dimethyl-aniline. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(17)H(20)N(2), in which the dihedral angles between the aromatic rings are 30.34 (11) and 41.44 (8) degrees . In the crystal, weak C-H?pi inter-actions may help to establish the packing. PMID- 21588362 TI - 4,4'-Ethyl-enedipyridinium bis-(3,4,5-trihy-droxy-benzoate) sesquihydrate. AB - The asymmetric unit of the title compound, C(12)H(14)N(2) (2+).2C(7)H(5)O(5) ( ).1.5H(2)O, contains two 4,4'-ethyl-enedipyridinium cations, four gallate anions and three water mol-ecules. In the 4,4'-ethyl-enedipyridinium cations, the dihedral angles between the pyridinium rings are 4.3 (3) and 18.6 (3) degrees . Extensive classical N-H?O and O-H?O hydrogen bonding and weak C-H?O hydrogen bonding and C-H?pi inter-actions are present in the crystal structure. pi-pi stacking is also observed, the centroid-centroid separations between the benzene and pyridine rings being 3.611 (3), 3.448 (3) and 3.536 (3) A. PMID- 21588363 TI - N'-[5-(4-Nitro-phen-yl)furan-2-yl-methyl-idene]-N,N-diphenyl-hydrazine. AB - The title compound, C(23)H(17)N(3)O(3), has an E configuration with respect to the C=N bond. The dihedral angle between the two phenyl rings bonded to the hydrazine group is 86.45 (13) degrees . The furan ring makes dihedral angles of 3.4 (2) and 7.06 (13) degrees , respectively, with the methyl-idenehydrazine C=N N plane and the benzene ring. PMID- 21588364 TI - Absolute configuration of isovouacapenol C. AB - The title compound, C(27)H(34)O(5) {systematic name: (4aR,5R,6R,6aS,7R,11aS,11bR) 4a,6-dihy-droxy-4,4,7,11b-tetra-methyl-1,2,3,4,4a,5,6,6a,7,11,11a,11b-dodeca hydro-phenanthro[3,2-b]furan-5-yl benzoate}, is a cassane furan-oditerpene, which was isolated from the roots of Caesalpinia pulcherrima. The three cyclo-hexane rings are trans fused: two of these are in chair conformations with the third in a twisted half-chair conformation, whereas the furan ring is almost planar (r.m.s. deviation = 0.003 A). An intra-molecular C-H?O inter-action generates an S(6) ring. The absolute configurations of the stereogenic centres at positions 4a, 5, 6, 6a, 7, 11a and 11b are R, R, R, S, R, S and R, respectively. In the crystal, mol-ecules are linked into infinite chains along [010] by O-H?O hydrogen bonds. C?O [3.306 (2)-3.347 (2) A] short contacts and C-H?pi inter-actions also occur. PMID- 21588365 TI - N'-(3,4-Dimethyl-benzyl-idene)furan-2-carbohydrazide. AB - The title compound, C(14)H(14)N(2)O(2), was prepared by the reaction of 3,4 dimethyl-benzaldehyde and furan-2-carbohydrazide. The dihedral angle between the aromatic rings is 35.48 (14) degrees . In the crystal, mol-ecules are linked by N H?O hydrogen bonds, generating C(4) chains propagating in [010]. PMID- 21588366 TI - (E)-4-Bromo-N-(2,3,4-trimeth-oxy-benzyl-idene)aniline. AB - The title Schiff base compound, C(16)H(16)BrNO(3), adopts an E configuration with respect to the C=N bond. The dihedral angle between the two aromatic rings is 64.02 (6) degrees . PMID- 21588367 TI - 1-(3,5-Diethyl-1H-pyrazol-1-yl)-3-phenyl-isoquinoline. AB - In the title mol-ecule, C(22)H(21)N(3), the isoquinoline ring is almost planar [maximum deviation = 0.046 (1) A] and makes dihedral angles of 52.01 (4) and 14.61 (4) degrees with the pyrazole and phenyl rings, respectively. The phenyl ring and the pyrazole ring are twisted by 44.20 (6) degrees with respect to each other. The terminal C atoms of both of the ethyl groups attached to the pyrazole ring are disordered over two sites with occupancy ratios of 0.164 (7):0.836 (7) and 0.447 (16):0.553 (16). A weak intra-molecular C-H?N contact may influence the mol-ecular conformation. The crystal structure is stabilized by C-H?pi contacts involving the phenyl and pyrazole rings, and by pi-pi stacking inter-actions involving the pyridine and benzene rings [centroid-centroid distance = 3.5972 (10) A]. PMID- 21588368 TI - 4-Ethyl-anilinium 4-methyl-benzene-sulfonate. AB - In the crystal structure of the title molecular salt, C(8)H(12)N(+).C(7)H(7)O(3)S(-), the 4-ethyl-anilinium cations and 4-methyl benzene-sulfonate anions are linked into chains parallel to the b axis by inter molecular N-H?O hydrogen bonds. PMID- 21588369 TI - Brasilixanthone. AB - THE TITLE XANTHONE [SYSTEMATIC NAME: 5,13-dihy-droxy-3,3,10,10-tetra-methyl-3H dipyrano[3,2-a:2',3'-i]xanthen-14(10H)-one], C(23)H(20)O(6), was isolated from the roots of Cratoxylum formosum ssp. pruniflorum. There are two mol-ecules (A and B) in the asymmetric unit, which show chemical but not crystallographic inversion symmetry. The xanthone skeleton in both mol-ecules is approximately planar, with an r.m.s. deviation of 0.0326 (9) A for mol-ecule A and 0.0355 (9) A for mol-ecule B from the plane through the 14 non-H atoms. The pyran rings in both mol-ecules adopt sofa conformations. Intra-molecular O-H?O hydrogen bonds generate S(5) and S(6) ring motifs. Viewed onto the bc plane, the crystal structure resembles a herringbone pattern. Stacks of mol-ecules are stabilized by pi-pi inter-actions with centroid-centroid distances of 3.600 (5) A. The crystal structure is further stabilized by weak C-H?O and C-H?pi inter-actions. PMID- 21588370 TI - 9,9'-(Biphenyl-2,2'-di-yl)difluoren-9-ol 4-methyl-pyridine solvate. AB - The title compound, C(38)H(26)O(2).C(6)H(7)N, crystallized as a host-guest complex from a solvent mixture of 4-methyl-pyridine and acetone. The dihedral angle between the rings in the biphenyl unit is 87.06 (3) degrees . The methyl pyridine guest mol-ecules are linked to the host mol-ecules via O-H? N hydrogen bonds, forming discrete pairs. The other OH group of the host forms an intra molecular O-H?O hydrogen bond. PMID- 21588371 TI - Ethyl 2-(2-oxo-4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-1-yl)acetate. AB - The seven-membered ring in the title compound, C(19)H(18)N(2)O(3), adopts a boat conformation with the two phenyl-ene C atoms representing the stern and the methyl-ene C atom the prow. The dihedral angle between the best plane through the seven-membered ring (r.m.s deviation = 0.343 A) and the phenyl substituent is 31.9 (1) degrees . The dihedral angle between this best plane and the best plane through the eth-oxy-carbonyl-methyl substituent (r.m.s. deviation = 0.058 A) is 72.2 (1) degrees . PMID- 21588372 TI - Methyl 1-{4-[(S)-2-(meth-oxy-carbon-yl)pyrrolidin-1-yl]-3,6-dioxocyclo-hexa-1,4 dien-1-yl}pyrrolidine-2-carboxyl-ate. AB - The complete mol-ecule of the title diproline ester quinone, C(18)H(22)N(2)O(6), is generated by a crystallographic twofold axis, which passes through the centre of the benzene ring. Both -CO(2)Me groups are orientated to the same side of the benzene ring, with the carbonyl groups pointing roughly towards each other. The conformation of the proline residue is an envelope. In the crystal, a three dimensional network is sustained by C-H?O inter-actions involving both the quinone and carbonyl O atoms. PMID- 21588373 TI - Ethyl 2-{[7-fluoro-4-oxo-3-(1H-1,2,4-triazol-1-yl)-4H-thio-chromen-2-yl]sulfan yl}acetate. AB - In the title compound, C(15)H(12)FN(3)O(3)S(2), the two six-membered rings are essentially coplanar, their mean plnes making a dihedral angle of 1.1 (2) degrees . The carbonyl C, the two attached non-fused C atoms and the S atom deviate from the plane of the benzene ring by -0.046 (5), -0.017 (5), 0.000 (6), 0.026 (4) A, respectively. The angle between the mean planes of the triazole ring and the sulfur heterocycle is 53.3 (1) degrees . In the crystal, inter-molecular C-H?O hydrogen bonds link the mol-ecules in a stacked arrangement along the a axis. PMID- 21588374 TI - (2Z,N'E)-N'-[(2-Hy-droxy-1-naphth-yl)methyl-idene]furan-2-carbohydrazonic acid. AB - In the title compound, C(16)H(12)N(2)O(3), the dihedral angle between the mean planes of the naphthalene ring system and the furan ring is 21.3 (6) degrees . The mol-ecular structure is stabilized by an intra-molecular O-H?N hydrogen bond, which generates an S(6) graph-set motif. PMID- 21588375 TI - Bis[dieth-yl(hy-droxy)ammonium] benzene-1,4-dicarboxyl-ate. AB - In the centrosymmetric title compound, 2C(4)H(12)NO(+).C(8)H(4)O(4) (2-), two N,N dieth-yl(hy-droxy)ammonium cations are linked to a benzene-1,4-dicarboxyl-ate dianion by a combination of O-H?O and N-H?O hydrogen bonds, which can be described in graph-set terminology as R(2) (2)(7). The crystal structure is further stabilized by C-H?O hydrogen bonds, leading to the fomation of a ribbon like network. PMID- 21588376 TI - 2-[2-(2-Anilino-4-oxo-3,4-dihydro-quinazolin-3-yl)phen-oxy]-3-phenyl-quinazolin 4(3H)-one methanol hemisolvate. AB - In the title compound, C(34)H(23)N(5)O(3).0.5CH(3)OH, each pyrimid-in-one heterocycle and its adjacent benzene ring are almost coplanar, making dihedral angles of 0.69 (13) and 1.87 (13) degrees . The lower pyrimidinone ring makes a dihedral angle of 40.41 (15) degrees with the -NH- bonded phenyl ring. O-H?O hydrogen bonds and weak C-H?pi inter-actions are observed in the crystal structure. The methanol solvent molecule is disordered over two positions of equal occupancy. PMID- 21588377 TI - N-(4-Bromo-benzyl-idene)-3,4-dimethyl-isoxazol-5-amine. AB - In the title compound, C(12)H(11)BrN(2)O, the 4-bromo-benzaldehyde and 5-amino 3,4-dimethyl-isoxazole units are oriented at a dihedral angle of 4.89 (8) degrees . In the crystal, weak pi-pi inter-actions are present between the benzene rings at a centroid-centroid distance of 3.7862 (14) A. PMID- 21588378 TI - (2Z)-2-[(2,3-Dimethyl-phen-yl)imino]-1,2-diphenyl-ethanone. AB - In the title compound, C(22)H(19)NO, the 2,3-dimethyl-anilinic group is planar with an r.m.s. deviation of 0.0226 A. The phenyl rings with the carbonyl and imine substituents are also planar with r.m.s. deviations of 0.0019 and 0.0048 A, respectively. These phenyl rings are oriented at dihedral angles of 74.70 (5) and 79.43 (5) degrees , respectively, with the 2,3-dimethyl-anilinic group, whereas the dihedral angle between them is 88.28 (4) degrees . Weak intra-molecular C-H?N hydrogen bonding occurs and completes an S(5) ring motif in the mol-ecule. In the crystal, weak pi-pi inter-actions are present between the carbonyl-containing phenyl rings at a centroid-centroid distance of 3.5958 (12) A. C-H?pi inter actions between the 2,3-dimethyl-anilinic and the carbonyl-containing phenyl rings are also present, where the C-H group is from the former. PMID- 21588379 TI - 2,3-Bis[(2-cyano-eth-yl)sulfan-yl]-1,4,5,8-tetra-thia-fulvalene-6,7 dicarbonitrile. AB - In the title compound, C(14)H(8)N(4)S(6), the two five-membered rings lie in the same plane with an r.m.s. deviation of 0.0334 (5) A. The crystal structure features inter-molecular S?N inter-actions of 3.295 (4) A. PMID- 21588380 TI - 1-[2-(2-Oxo-1,3-oxazolidin-3-yl)eth-yl]-4-phenyl-1H-1,5-benzodiazepin-2(3H)-one. AB - The seven-membered ring in the title compound, C(20)H(19)N(3)O(3), adopts a boat conformation with the two phenyl-ene C atoms representing the stern and the methyl-ene C atom the prow. The dihedral angle between the best plane through the seven-membered ring (r.m.s deviation = 0.358 A) and the phenyl substituent is 55.8 (1) degrees . The two rings at either ends of the ethyl chain are staggered [N-CH(2)-CH(2)-N torsion angle = 57.5 (4) degrees ]. PMID- 21588381 TI - 3-Ethyl-sulfanyl-2,5-diphenyl-1-benzofuran. AB - In the title compound, C(22)H(18)OS, the 2-phenyl ring is rotated out of the benzofuran plane, making a dihedral angle of 29.18 (6) degrees . The dihedral angle between the 5-phenyl ring and the benzofuran plane is 20.42 (5) degrees . In the crystal structure, mol-ecules are linked by weak inter-molecular C-H?pi inter-actions. PMID- 21588382 TI - Vadimezan: 2-(5,6-dimethyl-9-oxo-9H-xanthen-4-yl)acetic acid. AB - In the title mol-ecule, C(17)H(14)O(4), the C atom of the carboxyl group deviates by 1.221 (3) A from the plane [maximum deviation = 0.0122(2) A] of the tricycic ring system. In the crystal structure, inter-molecular O-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers, and pi-pi inter-actions [centroid centroid distances = 3.491 (3), 3.591 (3), 3.639 (3) and 3.735 (3) A] link these dimers into layers parallel to the ac plane. Weak inter-molecular C-H?O inter actions further consolidate the crystal packing. PMID- 21588383 TI - 16-[(E)-Benzyl-idene]-2-hy-droxy-12,13-diphenyl-1,11-diaza-penta-cyclo [12.3.1.0.0.0]octa-deca-3(8),4,6-triene-9,15-dione. AB - In the title compound, C(35)H(28)N(2)O(3), an intra-molecular O-H?N hydrogen bonds generates a five-membered ring, producing an S(5) ring motif. The piperidone ring adopts a half-chair conformation and the two pyrrolidine rings adopt an envelope conformation. The dihedral angles formed between adjacent benzene rings are 74.39 (5) and 37.70 (6) degrees . In the crystal crystal, inter molecular C-H?O hydrogen bonds link mol-ecules into dimers, which are further inter-connected into two-dimensional networks parallel to the ac plane by inter molecular C-H?O hydrogen bonds. The crystal structure is consolidated by weak C H?pi inter-actions. PMID- 21588384 TI - 2-Hy-droxy-16-[(E)-4-methyl-benzyl-idene]-13-(4-methyl-phen-yl)-12-phenyl-1,11 diaza-penta-cyclo-[12.3.1.0.0.0]octa-deca-3(8),4,6-triene-9,15-dione. AB - In the title compound, C(37)H(32)N(2)O(3), an intra-molecular O-H?N hydrogen bond generates a five-membered ring, producing an S(5) motif. The piperidone ring adopts a half-chair conformation. The two fused pyrrolidine rings have similar envelope conformations. The interplanar angles between the benzene rings A/B and C/D are 75.68 (7) and 30.22 (6) degrees , respectively. In the crystal structure, adjacent mol-ecules are inter-connected into chains propagating along the [010] direction via inter-molecular C-H?O hydrogen bonds. Further stabilization is provided by weak C-H?pi inter-actions. PMID- 21588385 TI - 1-(2,5-Dimeth-oxy-phen-yl)-3-(2-hy-droxy-eth-yl)urea. AB - In the title compound, C(11)H(16)N(2)O(4), the 2,5-dimeth-oxy-phenyl moiety is almost planar, with an r.m.s. deviation of 0.026 A. The dihedral angle between the benzene ring and the plane of the urea moiety is 13.86 (5) degrees . The mol ecular structure is stabilized by a short intra-molecular N-H?O hydrogen bond. In the crystal, inter-molecular N-H?O and O-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21588386 TI - 1,3-Bis(2,6-diisopropyl-phen-yl)imidazolidinium tetra-phenyl-borate dichloro methane disolvate. AB - The title compound, C(27)H(39)N(2) (+).C(24)H(20)B(-).2CH(2)Cl(2), is the first reported imidazolidinium cation with the sterically demanding 2,6-diisopropyl phenyl groups in the 1,3-positions. The crystal structure is stabilized by weak inter-molecular C-H?pi(arene) inter-actions. Due to the bulky nature of both the flanking 2,6-diisopropyl-phenyl substituents and the tetra-phenyl-borate counter ion, anion inter-actions with the imidazolidinium H atom in the 2-position are not observed, also a first for this class of ortho-alkyl-substituted Arduengo type carbene precursors. PMID- 21588387 TI - 10,13-Dimethyl-16-oxo-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetra-deca-hydro-1H cyclo-penta-[a]phenanthren-17-yl acetate. AB - In the title compound, C(21)H(30)O(3), the five-membered ring adopts an envelope conformation, the cyclo-hexene ring displays a half-chair conformation and the two cyclo-hexane rings have normal chair conformations. In the crystal structure, weak inter-molecular C-H?O hydrogen bonding links the mol-ecules into supra molecular chains running along [100]. PMID- 21588388 TI - Bis-(2-amino-5-methyl-pyridinium) fumarate-fumaric acid (1/1). AB - In the crystal structure of the title compound, C(6)H(9)N(2) (+).0.5C(4)H(2)O(4) (2-).0.5C(4)H(6)O(4), the fumarate dianion and fumaric acid mol-ecule are located on inversion centres. The 2-amino-5-methyl-pyrimidinium cation inter-acts with the carboxyl-ate group of the fumarate anion through a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. These motifs are centrosymmetrically paired via N-H?O hydrogen bonds, forming a complementary DDAA array. The carboxyl groups of the fumaric acid mol-ecules and the carboxyl-ate groups of the fumarate anions are hydrogen bonded through O-H?O hydrogen bonds, leading to a supra molecular chain along [101]. The crystal structure is further stabilized by weak C-H?O hydrogen bonds. PMID- 21588389 TI - 2-Amino-4-methyl-pyridinium 3-carb-oxy-4-hy-droxy-benzene-sulfonate monohydrate. AB - In the crystal structure of the title salt, C(6)H(9)N(2) (+).C(7)H(5)O(6)S( ).H(2)O, the water mol-ecule acts as an acceptor of bifurcated N-H?O hydrogen bonds from the pyridinium H atom and one H atom of the 2-amino group, forming an R(2) (1)(6) ring. The 3-carb-oxy-4-hy-droxy-benzene-sulfonate anions self assemble via O-H?O hydrogen bonds, leading to supra-molecular chains along the a axis. These chains and R(2) (1)(6) motifs are linked via O-H?O, N-H?O and C-H?O hydrogen bonds, forming a layer parallel to the ac plane. There is also an intra molecular O-H?O hydrogen bond in the 3-carb-oxy-4-hy-droxy-benzene-sulfonate anion, generating an S(6) ring motif. PMID- 21588390 TI - Trichodermin (12,13-ep-oxy-trichethec-9-en-4beta-yl 4-fluoro-benzoate). AB - IN THE TITLE TRICHODERMIN COMPOUND (SYSTEMATIC NAME: 12,13-ep-oxy-trichothec-9-en 4beta-yl 4-fluoro-benzoate), C(22)H(25)FO(4), the five-membered ring displays an envelope conformation, whereas the two six-membered rings show the different conformations, viz. chair and half-chair. As for the seven-membered ring, the dihedral angle between the mean planes formed by the four C atoms of the envelope unit and the three C and one O atoms of the six-membered chair is 68.67 (2) degrees ; these two mean planes are nearly perpendicular to the ep-oxy ring with angles of 87.97 (2)and 88.14 (2) degrees , respectively. PMID- 21588391 TI - Methyl 4-(4-chloro-phen-yl)-3,3a,4,4a,5,12c-hexa-hydro-2-thia-naphtho [1',2':3,2]furo[5,4-b]pyrrolizine-4a-carboxyl-ate. AB - In the title compound, C(25)H(22)ClNO(3)S, both the pyrrolidinyl and thia-zolyl rings adopt envelope conformations whereas the dihydro-pyran ring adopts a half chair conformation. The chloro-phenyl and naphthalenyl ring systems are oriented at a dihedral angle of 59.7 (1) degrees . The crystal packing is stabilized by an intra-molecular C-H?N hydrogen bond and weak inter-molecular C-H?pi inter actions. PMID- 21588392 TI - (E)-1-(2,5-Dimethyl-3-thien-yl)-3-(2,4,5-trimeth-oxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C(18)H(20)O(4)S, the thio-phene and benzene rings are oriented at a dihedral angle of 10.83 (11) degrees . The central chain makes dihedral angles of 1.86 (13) and 9.25 (12) degrees with the benzene and thio phene rings, respectively. In the crystal, mol-ecules are linked through weak inter-molecular C-H?O inter-actions. pi-pi inter-actions are also observed between the benzene rings with a centroid-centroid distance of 3.6832 (12) A. The slippage between the benzene rings is 0.956 A. PMID- 21588393 TI - 1-(2,4-Dinitro-phen-yl)-2-(1,2,3,4-tetra-hydro-naphthalen-1-yl-idene)hydrazine. AB - In the title compound, C(14)H(14)N(4)O(4), the dihedral angle between the benzene rings is 10.42 (8) degrees . The nitro groups make dihedral angles of 5.3 (2) and 6.47 (15) degrees with their parent ring and are oriented at 11.2 (3) degrees with respect to each other. An intra-molecular N-H?O hydrogen bond completes an S(6) ring motif. In the crystal, mol-ecules are linked by C-H?O inter-actions, thus forming (010) chains in which R(2) (2)(13) ring motifs are present. There also exist aromatic pi-pi stacking inter-actions [centroid-centroid separation = 3.7046 (9) A]. PMID- 21588394 TI - Monoclinic form I of clopidogrel hydrogen sulfate from powder diffraction data. AB - The asymmetric unit of the title compound, C(16)H(17)ClNO(2)S(+).HSO(4) (-), (I) [systematic name: (+)-(S)-5-[(2-chloro-phen-yl)(meth-oxy-carbon-yl)meth-yl] 4,5,6,7-tetra-hydro-thieno[3,2-c]pyridin-5-ium hydrogen sulfate], contains two independent cations of clopidogrel and two independent hydrogensulfate anions. The two independent cations are of similar conformation; however, this differs from that observed in ortho-rhom-bic form (II) [Bousquet et al. (2003 ?). US Patent No. 6 504 030]. The H-N-C(chiral)-H fragment shows a trans conformation in both independent cations in (I) and a gauche conformation in (II). In (I), classical inter-molecular N-H?O and O-H?O hydrogen bonds link two independent cations and two independent anions into an isolated cluster, in which two cations inter-act with one anion only via N-H?O hydrogen bonds. Weak inter-molecular C H?O hydrogen bonds further consolidate the crystal packing. PMID- 21588395 TI - 1-(3-Chloro-4-fluoro-phen-yl)-5-(2-diazo-acet-yl)-4-phenyl-pyrrolidin-2-one. AB - In the title compound, C(18)H(13)ClFN(3)O(2), the pyrrolidine ring adopts an envelope conformation and the planar part is rotated by 4.3 (6) degrees from the plane of the benzene ring and is almost perperdicular both to the diazo-acetyl unit [dihedral angle = 78.93 (7) degrees ] and the phenyl ring [dihedral angle = 86.07 (7) degrees ]. In the crystal, mol-ecules are linked into a three dimensional framework by C-H?O inter-actions. The mol-ecular conformation is stabilized by an intra-molecular C-H?O hydrogen bond. PMID- 21588396 TI - Diethyl 1-(4-methyl-phen-yl)-3-phenyl-5-oxopyrrolidine-2,2-dicarboxyl-ate. AB - In the title compound, C(23)H(25)NO(5), the lactam ring adopts an envelope conformation and both eth-oxy-carbonyl side chains show an s-cis conformation: one is nearly planar, the dihedral angle between CO(2) and OCH(2)CH(3) groups being 7.95 (14) degrees and the other is almost orthogonal, the C-O-C-C torsion angle being 85.33 (9) degrees . Dimers related by inversion symmetry are stabilized by C-H?O hydrogen bonds. The crystal structure is consolidated by weak intermolecular C-H?O inter-actions. Weak intra-molecular inter-actions of the same kind also occur. PMID- 21588397 TI - 3-Nitro-5-(4-pyridinio)benzoate. AB - The title compound, C(12)H(8)N(2)O(4), crystallizes as a zwitterion in which the pyridyl N atom is protonated. The dihedral angle between the benzene and pyridinium rings is 27.9 (2) degrees . In the crystal, N-H?O hydrogen bonds link adjacent zwitterions into a three-dimensional structure. PMID- 21588398 TI - 3-Chloro-6-[(E)-2-(1-phenyl-ethyl-idene)hydrazin-yl]pyridazine. AB - Two independent mol-ecules are present in the asymmetric unit of the title compound, C(12)H(11)ClN(4), (Z' = 2): the dihedral angles between the phenyl and pyridizine rings are 8.35 (10) and 37.64 (6) degrees . In the crystal, the two mol-ecules form inversion dimers with R(2) (2)(8) ring motifs through inter molecular N-H?N hydrogen bonds. The crystal structure is stabilized by pi-pi inter-actions between the pyridazine rings of symmetry-related molecules. In one of the independent mol-ecules, the centroid-centroid separations are 3.6927 (13) and 3.7961 (13) A, whereas in the other, the separations are 3.6909 (13) and 3.9059 (13) A. PMID- 21588399 TI - 4-Amino-pyridinium 4-carb-oxy-butano-ate. AB - The asymmetric unit of the title salt, C(5)H(7)N(2) (+).C(5)H(7)O(4) (-), contains two 4-amino-pyridinium cations and two 4-carb-oxy-butano-ate anions. Each 4-amino-pyridinium cation is planar, with a maximum deviation of 0.005 (2) A. Both 4-carb-oxy-butano-ate anions adopt an extended conformation. In the crystal structure, the cations and anions are linked via N-H?O, O-H?O and C-H?O hydrogen bonds, forming a two-dimensional network parallel to the bc plane. PMID- 21588400 TI - 2,6-Difluoro-benzoic acid. AB - In the title compound, C(7)H(4)F(2)O(2), the dihedral angle between the benzene ring and the carboxyl-ate group is 33.70 (14) degrees . In the crystal structure, inversion dimers linked by pairs of O-H?O hydro-gren bonds occur, generating R(2) (2)(8) loops. The dimers are linked into sheets lying parallel to (102) by C-H?F hydrogen bonds. PMID- 21588401 TI - 4-(Benz-yloxy)benzaldehyde. AB - The title compound, C(14)H(12)O(2), has an essentially planar conformation with the two aromatic rings forming a dihedral angle of 5.23 (9) degrees and the aldehyde group lying in the plane of its aromatic group [maximum deviation = 0.204 (3) A]. Weak inter-molecular C-H?O contacts are found to be shortest between the aldehyde O-atom acceptor and the H atoms of the methyl-ene group. PMID- 21588402 TI - Xyloccensin L. AB - The title compound, C(32)H(40)O(10), also known as xyloccensin L [systematic name: (1R,4aR,4bS,5aR,6aR,9R,10S,10aS,10bR,2aR,13R)-1-(furan-3-yl)-6a-hy-droxy-10 (2-meth-oxy-2-oxoeth-yl)-9,10a,12a-trimethyl-3-oxododeca-hydro-1H,3H,5aH-6,9 methano-isochromeno[6,5-f]oxireno[g]chromen-13-yl (2E)-2-methyl-but-2-enoate], is a limonoid with a C1-C29 oxygen bridge: this is the first report of the X-ray crystal structure of such a limonoid. Two fused pyran rings and two cyclo-hexane rings adopt boat conformations, while another cyclo-hexane ring and the d-lactone ring are in half-chair conformations. The mol-ecular structure is stabilized by intra-molecular O-H?O hydrogen bonding. PMID- 21588403 TI - 1-Benzoyl-3,3-bis-(propan-2-yl)thio-urea. AB - Two independent thio-urea derivatives comprise the asymmetric unit of the title compound, C(14)H(20)N(2)OS. The major difference between the mol-ecules relates to a twist in the relative orientation of the benzene rings [torsion angles = 4.5 (2) and -19.9 (2) degrees for the two independent mol-ecules]. The thio-carbonyl and carbonyl groups lie to opposite sides of the mol-ecule as there are twists about the central N-S bond [torsion angles = 83.90 (15) and 81.77 (15) degrees ]. Supra-molecular chains extending parallel to [101] with a stepped topology and mediated by N-H?O hydrogen bonding feature in the crystal structure. C-H?O and C H?pi inter-actions are also present. PMID- 21588404 TI - (+/-)-2-Methyl-piperazin-1-ium perchlorate. AB - In the title compound, C(5)H(13)N(2) (+).ClO(4) (-), the monoprotonated piperazine ring adopts a chair conformation. In the crystal structure, cations and anions are linked by inter-molecular N-H?O and N-H?N hydrogen bonds into layers parallel to (01). PMID- 21588405 TI - Glycine ethyl ester hydro-chloride. AB - In the crystal structure of the title compound, C(4)H(10)NO(2) (+).Cl(-) (systematic name: 3-eth-oxy-3-oxopropan-1-aminium chlor-ide), there are strong inter-molecular N-H?Cl, C-H?Cl and C-H?O hydrogen-bonding inter-actions between the free chloride anion and the organic cation, resulting in a two-dimensional supra-molecular network in the ab plane. PMID- 21588406 TI - Tris[4-(methyl-sulfan-yl)phen-yl]arsine. AB - In the title compound, C(21)H(21)AsS(3), the three benzene rings make dihedral angles of 88.41 (10), 87.75 (9) and 74.74 (10) degrees with each other. The methyl-sulfanyl groups are roughly coplanar with their attached benzene rings [C S-C-C torsion angles = -7.6 (2), 11.2 (2) and 4.1 (2) degrees ]. In the crystal, weak C-H?pi inter-actions link the mol-ecules. PMID- 21588407 TI - Benzoic acid-2,9-dimethyl-phenanthroline (1/1). AB - The constituents of the title 1:1 co-crystal, C(7)H(6)O(2).C(14)H(12)N(2), are connected into dimeric aggregates by a bifurcated O-H?N hydrogen bond; the hydroxyl-H atom is hydrogen bonded to the two N atoms of the 2,9-dimethyl phenanthroline. The hydrogen-bonded residues are almost orthogonal to each other [dihedral angle = 78.56 (7) degrees ]. In the crystal packing, the aggregates are assembled into layers in the bc plane by pi?pi inter-actions [ring centroid?ring centroid distance = 3.5577 (16) A] involving the pyridyl rings, and C-H?pi contacts involving the phenanthroline-H atom and the phenyl ring of the acid. PMID- 21588408 TI - 1,1'-(9-Octyl-9H-carbazole-3,6-di-yl)diethanone. AB - The central structural element of the title compound, C(24)H(29)NO(2), is a carbazole unit substituted with two acetyl residues and an octyl chain. The acetyl residues are nearly coplanar [dihedral angles = 5.37 (14) and 1.0 (3) degrees ] with the carbazole unit which is essentially planar (r.m.s. deviation for all non-H atoms = 0.025 A). The octyl chain adopts an all-trans conformation. The crystal packing is stabilized by C-H?O hydrogen bonds. PMID- 21588409 TI - 5,8-Dibromo-14,17-difluoro-2,11-dithia-[3.3]paracyclo-phane. AB - The title compound, C(16)H(12)Br(2)F(2)S(2) [systematic name: 1(2),1(5)-dibromo 5(2),5(5)-difluoro-2,7-dithia-1,5(1,4)-dibenzenaocta-phane], has two approximately parallel benzene rings with a dihedral angle of 1.53 (15) degrees between them and with a centroid-centroid distance of 3.3066 (18) A. In the crystal structure, mol-ecules are stacked along the a axis through an inter molecular pi-pi inter-action with a centroid-centroid distance of 3.7803 (18) A. Mol-ecules are also connected by a C-H?S inter-action, forming a chain along the b axis. PMID- 21588410 TI - 2,10-Bis(3-bromo-phen-yl)-3,7,11,15-tetra-oxa-8,16-diaza-tricyclo-[12.2.1.1]octa deca-1(16),6(18),8,14(17)-tetra-ene. AB - The title compound, C(24)H(20)Br(2)N(2)O(4), is an 18-membered tricycle including two isoxazole rings. The asymmetric unit contains one half of the formula unit; a centre of inversion is located at the centroid of the compound. The dihedral angle between adjacent isoxazole and benzene rings is 84.0 (2) degrees . The compound displays intra- and inter-molecular pi-pi stacking inter-actions between the isoxazole rings, the shortest centroid-centroid distances being 3.837 (3) and 3.634 (3) A, respectively. The mol-ecules are stacked in columns along the a axis with short Br?Br contacts [3.508 (1) A]. PMID- 21588411 TI - Hydrogen-bonding patterns in pyrimethaminium pyridine-3-sulfonate. AB - IN THE ASYMMETRIC UNIT OF THE TITLE SALT [SYSTEMATIC NAME: 2,4-diamino-5-(4 chloro-phen-yl)-6-ethyl-pyrimidin-1-ium pyri-dine-3-sulfonate], C(12)H(14)N(4)Cl(+).C(5)H(4)NSO(3) (-), there are two independent pyrimethaminium cations and two 3-pyridine sulfonate anions. Each sulfonate group inter-acts with the corresponding protonated pyrimidine ring through two N-H?O hydrogen bonds, forming a cyclic hydrogen-bonded bimolecular R(2) (2)(8) motif. Even though the primary mode of association is the same, the next higher level of supra-molecular architectures are different due to different hydrogen-bonded networks. In one of the independent molecules in the asymmetric unit, the pyrimethamine cation is paired centrosymmetrically through N-H?N hydrogen bonds, generating an R(2) (2)(8) ring motif. In the other molecule, the pyrimethamine cation does not form any base pairs; instead it forms hydrogen bonds with the 3-pyridine sulfonate anion. The structure is further stabilized by C-H?O, C-H?N and pi-pi stacking [centroid-centroid distance = 3.9465 (13) A] inter-actions. PMID- 21588412 TI - 6,14-Dibromo-2,11-dithia-[3.3]paracyclo-phane. AB - In the title compound, C(16)H(14)Br(2)S(2) [systematic name: 1(2),5(2)-dibromo 2,7-dithia-1,5(1,4)-dibenzenaocta-phane], the cen-troids of the two benzene rings are separated by 3.313 (5) A. The crystal packing exhibits weak inter-molecular S?S contacts of 3.538 (2) A. PMID- 21588413 TI - 4-Bromo-N,N,N,N-tetra-ethyl-pyridine-2,6-dicarboxamide. AB - The title compound, C(15)H(22)BrN(3)O(2), consists of a pyridine ring with a bromine atom in the para position and two diethyl-amide groups in the ortho positions of the ring. Despite the positions of the three substituents on the pyridine ring, the mol-ecule does not exhibit either local or crystallographic twofold symmetry as the two diethyl-amido units exhibit significantly different N(py)-C-C-N(am) torsion angles of 46.3 (4) and 62.7 (4) degrees (py is pyridine and am is amine). Inter-molecular C-H?O inter-actions support the packing. PMID- 21588414 TI - 5,8-Dibromo-2,11-dithia-[3,3](2,6)pyridino-paracyclo-phane. AB - The title compound, C(15)H(13)Br(2)NS(2) [systematic name: 1(2),1(5)-dibromo-2,7 dithia-1(1,4)-benzena-5(2,6)-pyridinaocta-phane], contains a dibromo-substituted benzene ring and a pyridine ring that are linked by a pair of bridging CH(2)SCH(2)- groups. There is a weak pi-pi inter-action between the rings, the distance between the ring centroids being 3.572 (4) A. The rings are not parallel, but form a dihedral angle of 18.29 (4) degrees . PMID- 21588415 TI - 4-Decyl-phenyl 4-benz-yloxy-3-methyl-benzoate. AB - In the title compound, C(31)H(38)O(3), the central benzene ring makes dihedral angles of 66.06 (9) and 65.21 (8) degrees , respectively, with the benzyl and 4 decyl-phenyl rings. PMID- 21588416 TI - N-(4-Chloro-benzyl-idene)-3,4-dimethyl-isoxazol-5-amine. AB - The mol-ecule of the title compound, C(12)H(11)ClN(2)O, has E configuration at the azomethine double bond and is virtually planar with a dihedral angle of 1.25 (13) degrees between the benzene and isoxazole rings. C-H?pi inter-actions stabilize the crystal structure. PMID- 21588417 TI - 1-Ethyl-sulfinyl-2-(4-iodo-phen-yl)naphtho-[2,1-b]furan. AB - In the title compound, C(20)H(15)IO(2)S, the 4-iodo-phenyl ring makes a dihedral angle of 44.21 (7) degrees with the plane of the naphtho-furan fragment. In the crystal, mol-ecules are linked by weak inter-molecular C-H?O and C-H?pi inter actions. PMID- 21588418 TI - 3,3,6,6-Tetra-methyl-9-(2-nitro-phen-yl)-3,4,6,7-tetra-hydro-2H-xanthene 1,8(5H,9H)-dione. AB - In the title compound, C(23)H(25)NO(5), the pyran ring adopts a flattened boat conformation, while the two cyclo-hexenone rings are in envelope conformations. The 3-nitro-phenyl ring is almost perpendicular to the pyran ring, making a dihedral angle of 87.1 (3) degrees . PMID- 21588419 TI - 1,5-Dichloro-4,8-dinitro-anthraquinone. AB - The ring skeleton of the title compound, C(14)H(4)Cl(2)N(2)O(6), is close to planar (r.m.s. deviation of the carbon atoms 0.091 A); the nitro goups are twisted with respect to the mean plane of the ring system by 70.8 (1) and 86.7 (2) degrees . The crystal studied was found to be a merohedral twin, with a domain ratio of 0.61 (8):0.39 (8). PMID- 21588420 TI - N'-[(2-n-Butyl-4-chloro-1H-imidazol-5-yl)-methyl-idene]adamantane-1-carbo hydrazide sesquihydrate ethanol hemi-solvate. AB - In the asymmetric unit of the title compound, C(19)H(27)ClN(4)O.0.5C(2)H(6)O.1.5H(2)O, there are two mol-ecules of the Schiff base, which has a rigid adamantyl cage at one end of the C(= O)NH-N=CH- chain and an almost planar [torsion angles = 1.3 (1) and 7.9 (2) degrees imidazolyl ring at the other end, three mol-ecules of water and one mol-ecule of ethanol. In both independent mol-ecules of the Schiff base, this chain displays an extended zigzag configuration. All their amino groups function as hydrogen-bond donors to water mol-ecules; these are linked to other acceptor atoms, generating a layer structure. O-H?O and O-H?N inter-actions involving the water mol-ecules also occur. PMID- 21588421 TI - Ammonium hexa-fluorido-phosphate-18-crown-6 (1/1). AB - In the crystal structure of the title compound, NH(4) (+).PF(6) ( ).C(12)H(24)O(6), the cation is situated in the 18-crown-6 ring, forming a supra molecular rotator-stator-like structure held by N-H?O hydrogen bonds. The six O atoms of the crown ether lie approximately in a plane [mean deviation 0.2129 (3) A]; the N atom is displaced by 0.864 (3)A from the centroid of the 18-crown-6 ring. The slightly distorted tetra-hedral cations further inter-act with the slightly distorted octa-hedral anions via inter-molecular N-H?F hydrogen bonds. PMID- 21588422 TI - (2E)-3-(3,4-Dimeth-oxy-phen-yl)-1-(2,5-dimethyl-thio-phen-3-yl)prop-2-en-1-one. AB - The mol-ecule of the title compound, C(17)H(18)O(3)S, is essentially planar: the phenyl and thio-phene rings form a dihedral angle of 2.79 (10) degrees and they are inclined to the central propenone unit by 6.20 (15) and 4.78 (15) degrees , respectively. In the crystal, mol-ecules are connected into dimers via pairs of C H?O inter-actions, generating R(2) (2)(14) motifs. pi-pi stacking inter-actions between the thio-phene rings also occur, with a centroid-centroid distance of 3.8062 (12) A. PMID- 21588423 TI - N-{4-[(3,4-Dimethyl-phen-yl)sulfamo-yl]phen-yl}acetamide. AB - Two independent mol-ecules comprise the asymmetric unit of the title compound, C(16)H(18)N(2)O(3)S. Small but significant twists about the (S)N-C and S-C bonds differentiate the mol-ecules but the most obvious difference is found in the relative orientation of the meta-methyl groups, which lie on opposite sides of the mol-ecules. Overall, both mol-ecules adopt a U shape but with significant twisting evident, particularly in the second independent mol-ecule [dihedral angles between benzene rings = 63.90 (13) and 35.78 (11) degrees ]. In the crystal, N-H?O hydrogen bonds lead to supra-molecular chains with a tubular topology propagating in [100] and C-H?O contacts cross-link the chains. PMID- 21588424 TI - (2-Methyl-phen-yl)(phen-yl)methanol. AB - In the title compound, C(14)H(14)O, the two benzene rings are almost orthogonal [dihedral angle = 87.78 (8) degrees ]. The hy-droxy group lies approximately in the plane of its attached benzene ring [O-C-C-C torsion angle = -17.47 (17) degrees ], and the hydroxyl and methyl groups lie to the same side of the mol ecule and are gauche to each other. In the crystal, a hexa-meric aggregate mediated by a ring of six O-H?O hydrogen bonds occurs, generating an R(6) (6)(12) loop. PMID- 21588425 TI - Phosmet: O,O-dimethyl S-phthalimidomethyl phospho-rodithio-ate. AB - In the title compound, C(11)H(12)NO(4)PS(2), the dihedral angle between the phthalimidyl ring plane and the PS(2) plane of the phospho-rodithio-ate group is 60.41 (3) degrees . In the crystal structure, weak inter-molecular C-H?O hydrogen bonds and S?S inter-actions [3.3825 (9) A] contribute to the stabilization of the packing. PMID- 21588426 TI - 7-Hy-droxy-6-meth-oxy-2H-chromen-2-one. AB - The title compound, C(10)H(8)O(4), is one of the coumarins existing in Morinda citrifolia L (Noni). The chromenone ring system is approximately planar with a maximum deviation of 0.0208 (14) A. The meth-oxy group does not deviate from this plane [C-O-C-C torsion angle = -1.5 (3) degrees ], indicating that the whole mol ecule is almost planar. In the crystal packing, inter-molecular O-H?O hydrogen bonds link the mol-ecules into chains. These are further connected by C-H?O hydrogen bonds. PMID- 21588427 TI - 3-Oxo-18alpha-olean-28,13beta-olide. AB - The title terpene, C(30)H(46)O(3), is a 28,13beta-lactone of oleanolic acid prepared with bis-muth trifluoro-methane-sulfonate (OTf), Bi(OTf)(3).xH(2)O. All rings are trans-fused. The X-ray study shows the inversion of the orientation of 18-H in the lactonization reaction. A quantum chemical ab-initio Roothaan Hartree Fock calculation of the equilibrium geometry of the isolated mol-ecule gives values for bond lengths and valency angles in close agreement with experimental values. The calculation also reproduces the observed mol-ecular conformation, with puckering parameters that agree well with those determined from the crystallographic study. PMID- 21588428 TI - Ethyl 3-amino-4-[(2-hy-droxy-ethyl)-amino]benzoate. AB - In the crystal structure of the title compound, C(11)H(16)N(2)O(3), mol-ecules are linked by one O-H?N and two N-H?O inter-molecular hydrogen bonds into a three dimensional network, which incorporates R(2) (2)(14) and R(2) (2)(16) graph-set motifs. PMID- 21588429 TI - Cyclo-art-24-ene-3beta,26-diol from the leaves of Aglaia exima. AB - Cyclo-art-24-ene-3beta,26-diol, C(30)H(50)O(2), isolated from the leaves of Aglaia exima, has three six-membered rings fused together that adopt chair conformations. There are two independent mol-ecules in the asymmetric unit. O-H?O hydrogen bond inter-actions between the hydroxyl groups in the 3beta and 26 positions lead to the formation of a layer structure parallel to (10). PMID- 21588430 TI - Ethyl 2-[4-(1,3-benzothiazol-2-yl)-anilino]acetate. AB - In the title compound, C(17)H(16)N(2)O(2)S, the dihedral angle between the benzothia-zole ring system and the benzene ring is 1.20 (2) degrees . The substituted amino substituent is in an extended conformation with an N-C-C-O torsion angle of 179.4 (3) degrees . In the crystal structure, pairs of mol ecules are connected by inter-molecular N-H?O and weak C-H?O hydrogen bonds, forming centrosymmetric dimers. PMID- 21588431 TI - 5,8-Dibromo-15,18-dimeth-oxy-2,11-dithia-[3.3]paracyclo-phane. AB - IN THE TITLE COMPOUND [SYSTEMATIC NAME: 1(2),1(5)-dibromo-5(2),5(5)-dimethoxy-2,7 dithia-1,5(1,4)-dibenzenaoctaphane], C(18)H(18)Br(2)O(2)S(2), the dihedral angle between the aromatic rings is 0.6 (2) degrees and their centroid separation is 3.251 (2) A, indicating that a trans-annular pi-pi interaction occurs. The dimeth oxy and dibromo substituents are located at crossed positions because of the electronic and the steric nature of the substituents. PMID- 21588432 TI - 2-Benzoyl-2H-1,4-benzothia-zin-3(4H)-one. AB - In the title compound, C(15)H(11)NO(2)S, the dihedral angle between the aromatic rings is 80.35 (7) degrees . The heterocyclic six-membered ring is not planar: the puckering parameters of this ring are Q = 0.5308 (15) A, theta = 63.11 (18) and phi = 23.5 (2) degrees . The mol-ecules are linked into inversion dimers with R(2) (2)(8) ring motifs by pairs of N-H?O hydrogen bonds. The dimers are inter linked into polymeric sheets extending parallel to the bc plane by C-H?O hydrogen bonds, generating R(2) (1)(7) ring motifs. pi-pi inter-actions occur between the benzoyl phenyl rings with centroid-centroid separations of 3.9187 (15) A. PMID- 21588433 TI - Triethyl-ammonium O-3beta-cholest-5-en-3-yl (4-meth-oxy-phen-yl)dithio-phospho nate. AB - In the crystal structure of the title compound, C(6)H(16)N(+).C(34)H(52)O(2)PS(2) (-) or [(CH(3)CH(2))(3)NH](+).[C(34)H(52)O(2)PS(2)](-), the cation and anion are paired via weak, inter-molecular, bifurcated N-H?(S,S) hydrogen bonds. The cholesteryl units form an alternating (herringbone) motif as well as an infinitely stacked layered structure along the b axis. The P-S bond lengths [1.975 (2) and 1.981 (2) A compared with ca 1.92 A for a formal P=S double bond and with ca 2.01 A for a P-S single bond] suggest delocalization of the negative charge between the P-S bonds. A distorted tetra-hedral geometry around the P atom is revealed by non-ideal O-P-C and S-P-S bond angles of 96.7 (2) and 115.52 (11) degrees , respectively. PMID- 21588434 TI - (Z)-2-(1,3-Thia-zolidin-2-yl-idene)cyan-amide. AB - In the title compound, C(4)H(5)N(3)S, the tdihydrothiazole ring is almost planar, the maximum and minimum deviations being 0.188 (2) A and 0.042 (3) A, respectively. The crystal structure involves intermolecular N-H?N hydrogen bonds. PMID- 21588435 TI - 1,5-Dimethyl-2-phenyl-4-{[(E)-3,4,5-trimethoxybenzylidene]amino}-1H-pyrazol-3(2H) one. AB - In the title compound, C(21)H(23)N(3)O(4), the pyrazole ring forms dihedral angles of 21.58 (8) and 66.64 (7) degrees with the benzene and phenyl rings, respectively. The crystal structure is stabilized by weak inter-molecular C-H?O hydrogen bonds. PMID- 21588436 TI - 2-Amino-6-(2,6-difluoro-benzamido)-pyridinium chloride. AB - In the cation of the title compound, C(12)H(10)F(2)N(3)O(+).Cl(-), the dihedral angle between the pyridine and benzene rings is 16.1 (1) degrees . In the crystal structure, mol-ecules linked into two-dimensional sheets parallel to the bc plane by inter-molecular N-H?Cl, C-H?Cl and C-H?F hydrogen bonds. PMID- 21588437 TI - 2-Amino-4-methyl-pyridinium 2-hy-droxy-benzoate. AB - The asymmetric unit of the title mol-ecular salt, C(6)H(9)N(2) (+).C(7)H(5)O(3) ( ), contains two cations and two anions. Both the salicylate anions contain an intra-molecular O-H?O hydrogen bond, which generates an S(6) ring. Both the 2 amino-4-methyl-pyridine mol-ecules are protonated at their pyridine N atoms. In the crystal, both cations form two N-H?O hydrogen bonds to their adjacent anions, forming ion pairs. Further N-H?O links generate sheets lying parallel to the ab plane. In addition, weak C-H?O bonds and aromatic pi-pi stacking inter-actions [centroid-centroid distances = 3.5691 (9) and 3.6215 (9) A] are observed between the cations and anions. PMID- 21588438 TI - 2-Amino-5-methyl-pyridinium 3-carb-oxy-4-hy-droxy-benzene-sulfonate. AB - The asymmetric unit of the title salt, C(6)H(9)N(2) (+).C(7)H(5)O(6)S(-), contains two crystallographically independent 2-amino-5-methylpyridinium cations and two sulfosalicylate anions. In the crystal structure, the sulfonate group of each 3-carb-oxy-4-hy-droxy-benzene-sulfonate anion inter-acts with the corresponding 2-amino-5-methyl-pyridinium cation via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The ionic units are linked by N-H?O, O H?O and C-H?O hydrogen bonds. Furthermore, the crystal structure is stabilized by pi-pi inter-actions between the benzene and pyridine rings [centroid-centroid distances = 3.5579 (8) and 3.8309 (8) A]. There are also intra-molecular O-H?O hydrogen bonds in the anions, which generate S(6) ring motifs. PMID- 21588439 TI - Ethyl 5,8-dibromo-2-dibromo-methyl-6,7-dimeth-oxyquinoline-3-carb-oxy-late. AB - The title compound, C(15)H(13)Br(4)NO(4), was obtained via radical bromination reaction of ethyl 6,7-dimeth-oxy-2-methyl-quinoline-3-carboxyl-ate and N-bromo succinimide (NBS) in the presence of benzoyl peroxide (BPO) under photocatalytic conditions. The quinoline ring system is approximately planar with a maximum deviation from the mean plane of 0.035 (1) A. The dihedral angle between the six membered rings is 2.33 (2) degrees . The meth-oxy O atoms of the two neighboring meth-oxy groups are in-plane while their methyl C atoms are located on either side of the quinolyl ring plane at distances of -1.207 (1) and 1.223 (1) A. PMID- 21588440 TI - N-[3,5-Dichloro-4-(1,1,2,2-tetra-fluoro-eth-oxy)phen-yl]-2,6-difluoro-benzamide. AB - In the title compound, C(15)H(7)Cl(2)F(6)NO(2), the conformation of the N-H bond in the amide segment is anti to the C=O bond and the dihedral angle between the two benzene rings is 78.6 (3) degrees . The terminal -CHF(2) group is disordered over two orientations in a 0.67:0.33 ratio. In the crystal, the mol-ecules are linked by N-H?O hydrogen bonds, generating C(4) chains propagating in [100]. PMID- 21588441 TI - (E)-N'-[4-(Methyl-sulfan-yl)benzyl-idene]furan-2-carbohydrazide monohydrate. AB - In the title compound, C(13)H(12)N(2)O(2)S.H(2)O, the dihedral angle between the aromatic rings is 35.34 (19) degrees and an intra-molecular N-H?O hydrogen bond generates an S(5) ring. In the crystal, mol-ecules are linked by N-H?O and O-H?O hydrogen bonds, generating (001) sheets. PMID- 21588442 TI - 4-(4-Meth-oxy-pheneth-yl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. AB - The dihedral angle between the two rings in the title compound, C(12)H(15)N(3)O(2), is 49.03 (1) degrees . The crystal structure is stabilized by inter-molecular N-H?O and C-H?O hydrogen bonds and pi-pi stacking inter-actions between the triazole rings with a centroid-centroid distance of 3.394 A. PMID- 21588443 TI - 3-(4-Methyl-phen-yl)-2-thioxo-1,3-thia-zolidin-4-one. AB - In the title compound, C(10)H(9)NOS(2), the toluene group and the 2-thioxo-1,3 thia-zolidin-4-one unit are planar with r.m.s. deviations of 0.0082 and 0.0136 A, respectively. The dihedral angle between them is 71.20 (9) degrees . In the crystal, the mol-ecules are stabilized through inter-molecular C-H?O contacts, forming polymeric sheets extending parallel to the (01) plane. C-H?pi contacts also occur. PMID- 21588444 TI - 4-Ethyl-anilinium 2-carb-oxy-acetate. AB - In the crystal structure of the title compound, C(8)H(12)N(+).C(3)H(3)O(4) (-), the hydrogen malonate anions are linked into infinite chains parallel to the b axis by inter-molecular O-H?O hydrogen bonds of the type COO(-)?HO(2)C in a head to-tail fashion. The 4-ethyl-anilinium cations link adjacent anion chains by inter-molecular N-H?O hydrogen bonds into a two-dimensional network parallel to the b and c axes. PMID- 21588445 TI - 3beta-Acet-oxy-8beta,10beta-dihy-droxy-6beta-meth-oxy-eremophil-7(11)-en-8,12 olide. AB - The title compound, C(18)H(26)O(7), is an eremophilenolide which has been isolated from the plant Ligularia duciformis for the first time. The present study confirms the atomic connectivity assigned on the basis of (1)H and (13)C NMR spectroscopy. The mol-ecule contains three fused rings, two six-membered rings in chair confomations and a five-membered ring in a flattened envelope conformation. Two hy-droxy groups are involved in formation of intra- and inter molecular O-H?O hydrogen bonds. The latter ones link mol-ecules into chains propagating in [010]. PMID- 21588446 TI - 3-Phenyl-4-{3-[(p-tol-yloxy)meth-yl]-7H-1,2,4-triazolo[3,4-b][1,3,4]thia-diazin-6 yl}sydnone. AB - IN THE TITLE COMPOUND (SYSTEMATIC NAME: 3-phenyl-4-{3-[(p-tol-yloxy)meth-yl]-7H 1,2,4-triazolo[3,4-b][1,3,4]thia-diazin-6-yl}-1,2,3-oxadiazol-3-ium-5-olate), C(20)H(16)N(6)O(3)S, an intra-molecular C-H?O hydrogen bond generates an S(6) ring motif. The 3,6-dihydro-1,3,4-thia-diazine ring adopts a twist-boat conformation. The 1,2,3-oxadiazole and 1,2,4-triazole rings are inclined to each other at an inter-planar angle of 44.13 (13) degrees . The phenyl ring makes an inter-planar angle of 67.40 (13) degrees with the attached 1,2,3-oxadiazole ring. In the crystal structure, adjacent mol-ecules are inter-connected into two mol-ecule-thick arrays parallel to (100) via C-H?O and C-H?N hydrogen bonds. A short S?O contact [2.9512 (18) A] is observed. PMID- 21588447 TI - 2-Amino-5-bromo-pyridinium 2-hy-droxy-benzoate. AB - In the title compound, C(5)H(6)BrN(2) (+).C(7)H(5)O(3) (-), the 2-amino-5-bromo pyridinium cation and 2-hy-droxy-benzoate anion are essentially planar with maximum deviations of 0.020 (1) and 0.018 (2) A, respectively. The anion is stabilized by an intra-molecular O-H?O hydrogen bond, which generates an S(6) ring motif. In the crystal, the cations and anions are linked by N-H?O hydrogen bonds into chains propagating along [010]. The chains contain R(2) (2)(8) ring motifs. The structure is further stabilized by pi-pi stacking inter-actions [centroid-centroid distances = 3.4908 (10) and 3.5927 (10) A] and also features short Br?O contacts [2.9671 (13) A]. PMID- 21588448 TI - Absolute configuration of vouaca-pen-5alpha-ol. AB - The title compound, C(20)H(30)O(2), {systematic name: (4aR,6aS,7R,11aS,11bR) 4,4,7,11b-tetra-methyl-1,2,3,4,4a,5,6,6a,7,11,11a,11b-dodeca-hydro-phenanthro[3,2 b]furan-4a-ol}, is a cas-sane furan-oditerpene which was isolated from the roots of Caesalpinia pulcherrima. The absolute configurations at positions 4a, 6a, 7, 11a and 11b are R, S, R, S and R, respectively. The mol-ecule has four-fused rings consisting of three cyclo-hexane rings and one furan ring. The three cyclo hexane rings are trans-fused. Two cyclo-hexane rings are in chair conformations, while the third is in an envelope conformation. In the crystal structure, the mol ecules are linked by inter-molecular O-H?O hydrogen bonds into a zigzag chain along the a axis. A short O?O contact [3.0398 (14) A] is also present. PMID- 21588449 TI - Bis[(3-chloro-benz-yl)ammonium] 2-phenyl-propane-dioate dihydrate. AB - In the asymmetric unit of the title compound, 2C(7)H(9)ClN(+).C(9)H(6)O(4) (2 ).2H(2)O, there are two crystallographically independent cations, one dianion and two water mol-ecules. The dihedral angle between the two carboxyl-ate groups of the dianion is 78.1 (2) degrees . In the crystal, the components are held together by N-H?O, O-H?O and C-H?O hydrogen bonds, forming a layer parallel to the bc plane, with the hydro-philic and hydro-phobic groups located in the inner and outer regions of the layers, respectively. PMID- 21588450 TI - 3-Chloro-benzohydrazide. AB - In the title compound, C(7)H(7)ClN(2)O, the hydrazide group is inclined at a dihedral angle of 32.30 (11) degrees with respect to the benzene ring. The amino H atoms form inter-molecular N-H?O hydrogen bonds with the O atoms of two adjacent mol-ecules, resulting in 10-membered rings of graph-set motif R(2) (2)(10). The imino H atom is also involved in an inter-molecular hydrogen bond with an amino N atom of a symmetry-related mol-ecule, resulting in a zigzag chain along the b axis. The structure is further consolidated by an intra-molecular N H?O inter-action, which results in a five-membered ring. PMID- 21588452 TI - (Z)-N-{3-[1-(4-Chloro-phen-yl)eth-yl]thia-zolidin-2-yl-idene}cyanamide. AB - The title compound, C(12)H(12)ClN(3)S, features a thia-zolyl ring having an envelope conformation with the -CH(2)- group bonded to the S atom forming the flap. The C=N double bond has a Z configuration. The crystal structure shows inter-molecular C-H?S hydrogen bonds. PMID- 21588451 TI - (E,E)-1,2-Bis[1-(2-bromo-phen-yl)ethyl-idene]hydrazine. AB - In the title compound, C(16)H(14)Br(2)N(2), the complete molecule is generated by a crystallographic twofold axis. The dihedral angle between the two benzene rings is 35.28 (8) degrees and that between the best planes of two ethyl idinehydrazine N-N=C-Me units is 87.67 (11) degrees . Each of these N/N/C/C planes makes a dihedral angle of 63.81 (10) degrees with the adjacent benzene ring. In the crystal, the mol-ecules are arranged into a layer parallel to the ac plane through C-H?pi inter-actions. C?Br short contacts [3.4032 (18)-3.5969 (19) A] are also observed. PMID- 21588453 TI - 2-(4-Bromo-phen-yl)-5-fluoro-3-phenyl-sulfinyl-1-benzofuran. AB - In the title compound, C(20)H(12)BrFO(2)S, the O atom and the phenyl group of the phenyl-sulfinyl substituent lie on opposite sides of the plane through the benzofuran fragment; the phenyl ring is nearly perpendicular to this plane [dihedral angle = 86.98 (6) degrees ]. The 4-bromo-phenyl ring is rotated slightly out of the benzofuran plane, making a dihedral angle of 1.56 (8) degrees . The crystal structure features aromatic pi-pi inter-actions between the furan and phenyl rings of neighbouring mol-ecules [centroid-centroid distance = 3.506 (3) A], and an inter-molecular C-H?pi inter-action. The crystal structure also exhibits a short inter-molecular S?S contact [3.2635 (8) A]. PMID- 21588454 TI - Ethyl (2,5-dioxo-1-phenyl-2,3-dihydro-1H,5H-1-benzofuro[3,2-d]imidazo[1,2 a]pyrimidin-3-yl)acetate. AB - In the title compound, C(22)H(17)N(3)O(5), synthesized via the aza-Wittig reaction of ethyl 3-(phenyl-imino-methyl-ene-amino)-benzofuran-2-carboxyl-ate, benzene isocyanate and diethyl 2-amino-succinate, the imidazo[1,2 a]benzo[4,5]furo[2,3-d]pyrim-idine ring system is essentially planar (r.m.s. deviation for all 16 non-H atoms = 0.020 A). The phenyl ring is twisted with respect to this ring system, making a dihedral angle of 54.23 (4) degrees . The crystal packing is stabilized by weak inter-molecular C-H?O inter-actions. PMID- 21588455 TI - 2-(1-Adamant-yl)-1,3-diphenyl-propan-2-ol. AB - In the title compound, C(25)H(30)O, the adamantane cage consists of three fused cyclo-hexane rings in classical chair conformations, with C-C-C angles in the range 107.15 (9)-111.55 (9) degrees . The dihedral angle between the benzene rings is 46.91 (4) degrees and the conformation is stabilized by a weak intra molecular C-H?pi inter-action. PMID- 21588456 TI - Ep-oxy-cytochalasin H methanol solvate. AB - In the title solvate, C(30)H(39)NO(5).CH(4)O {systematic name: 21-acet-oxy-18,21 dihy-droxy-5,6,16,18-tetra-methyl-10-phenyl-6,7-ep-oxy-[11]cytochalasa-13,19-dien 1-one methanol solvate}, the organic mol-ecule exhibits the tetra-cyclic terpenoid skeleton of cytochalasin, consisting of fused five-, six-, three- and 11-membered rings. The five-membered ring adopts an envelope conformation, while the six-membered ring is in a boat conformation. The ep-oxy O atom on the six membered ring is pointing away from the five-membered ring. An inter-stitial methanol solvent mol-ecule is hydrogen bonded to the cytochalasin mol-ecules and inter-molecular O-H?O and N-H?O hydrogen bonds connect the mol-ecules into infinite chains along the (10) direction. PMID- 21588457 TI - 4-[3-(Phen-oxy-meth-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thia-diazin-6-yl]-3-(p-tol yl)sydnone. AB - In the title triazolothia-diazine derivative, C(20)H(16)N(6)O(3)S {systematic name: 3-(4-methyl-phen-yl)-4-[3-(phen-oxy-meth-yl)-7H-1,2,4-triazolo[3,4 b][1,3,4]thia-diazin-6-yl]-1,2,3-oxadiazol-3-ium-5-olate}, an S(6) ring motif is generated by an intra-molecular C-H?O hydrogen bond. The 3,6-dihydro-1,3,4-thia diazine ring adopts a twist-boat conformation. The dihedral angle between the 1,2,3-oxadiazole and 1,2,4-triazole rings is 46.45 (14) degrees . The 1,2,3 oxadiazole ring is inclined at dihedral angle of 59.49 (13) degrees with respect to the benzene ring attached to it. In the crystal structure, inter-molecular C H?O and C-H?N hydrogen bonds link neighbouring mol-ecules into two-mol-ecule thick arrays parallel to the bc plane. A short S?O inter-action [2.9565 (19) A] also occurs. PMID- 21588458 TI - 8-Quinolyl 5-(dimethyl-amino)-naphthalene-1-sulfonate. AB - In the title compound, C(21)H(18)N(2)O(3)S, the dihedral angle between the naphthalene and quinoline ring systems is 55.53 (2) degrees , and the torsion angle involving the connecting C-S-O-C atoms is 87.60 (3) degrees . In the crystal structure, weak inter-molecular C-H?O hydrogen bonds connect mol-ecules into chains along [100] and there are pi-pi stacking inter-actions between pairs of chains with a centroid-centroid distance of 3.5485 (15) A. PMID- 21588459 TI - 1-[5-(Dimethyl-amino)-1-naphthylsulfon-yl]imidazolidine-2-thione. AB - In the title mol-ecule, C(15)H(17)N(3)O(2)S(2), the dihedral angle between the naphthalene ring system and the imidazole ring is 89.63 (2) degrees . The crystal structure is stablized by weak inter-molecuar C-H?pi and N-H?pi inter-actions. PMID- 21588460 TI - 1-Bromo-2-(10beta-dihydro-artemisin-oxy)ethane. AB - The title compound, C(17)H(27)BrO(5), DEB, is a derivative of artemisinin which is used in malara therapy. The OR-group at C12 is cis to the CH(3)-group at C11 and axially oriented on ring D which has a chair conformation. The crystal packing is stabilized by several weak inter-molecular C-H?O inter-actions, which combine to form a C-H-O bonded network parallel to (001). PMID- 21588461 TI - 2-(2-Chloro-phen-yl)-3-(3,4-dimeth-oxy-phen-yl)quinoxaline. AB - The title compound, C(22)H(17)ClN(2)O(2), was synthesized by the condensation reaction between 1,2-phenyl-enediamine and 2-chloro-3',4'-dimeth-oxy-benzil in boiling acetic acid. The chloro-phenyl and dimeth-oxy-phenyl rings make dihedral angles of 78.45 (5) and 35.60 (4) degrees , respectively, with the quinoxaline unit. PMID- 21588462 TI - tert-Butyl 4-formyl-1H-imidazole-1-carboxyl-ate. AB - In the crystal structure of the title compound, C(9)H(12)N(2)O(3), weak inter molecular C-H?O hydrogen bonds link the mol-ecules into chains. Further weak C H?O hydrogen bonds together with pi-pi inter-actions [centroid-centroid distance = 3.672 (4) A] between neighbouring chains lead to a double-chain structure propagating in [100]. PMID- 21588463 TI - N-(4-Chloro-phen-yl)-4-methyl-pyridin-2-amine. AB - In the title compound, C(12)H(11)ClN(2), the dihedral angle between the benzene and pyridyl rings is 48.03 (8) degrees . Twists are also evident in the mol ecule, in particular about the N(a)-C(b) (a = amine and b = benzene) bond [C-N-C C = -144.79 (18) degrees ]. In the crystal, inversion dimers linked by pairs of N H?N hydrogen bonds result in the formation of eight-membered {?NCNH}(2) synthons [or R(2) (2)(8) loops]. PMID- 21588464 TI - 2-(3-Meth-oxy-phen-oxy)pyrimidine. AB - In the title compound, C(11)H(10)N(2)O(2), the benzene ring faces towards one of the pyrimidine N atoms, and is almost orthogonal to the plane through the pyrimidine ring [dihedral angle = 84.40 (14) degrees ]. In the crystal, the presence of C-H?pi and pi-pi [centroid-centroid separation = 3.7658 (18) A] inter actions leads to a supra-molecular array in the ac plane. The layers thus formed inter-digitate along the b axis. PMID- 21588465 TI - Benzene-1,3-diol-1,4-diaza-bicyclo-[2.2.2]octane (1/1). AB - There are two independent but virtually identical mol-ecules of each component in the asymmetric unit of the title 1:1 adduct, C(6)H(12)N(2).C(6)H(6)O(2). In the crystal, the constituents are connected into a supra-molecular chain along the b axis by O-H?N hydrogen bonds. Weak C-H?O bonds cross-link the chains. PMID- 21588466 TI - 2,2'-(4-{[(E)-4-Meth-oxy-benzyl-idene]amino}-phenyl-imino)-diethanol. AB - In the title compound, C(18)H(22)N(2)O(3), the dihedral angle between the aromatic rings is 3.9 (2) degrees . Both H atoms of the hy-droxy groups are involved in inter-molecular O-H?O hydrogen bonding. In the crystal structure, this hydrogen bonding assembles mol-ecules into chains of 2(1) symmetry extending parallel to the b axis. The almost planar (within 0.09 and 0.06 A) 4-CH(3)O C(6)H(4)-CH=N-C(6)H(4)- groups are oriented outwards the twofold screw axis. PMID- 21588467 TI - 6-Benzyl-oxycoumarin. AB - In the title compound, 6-benz-yloxy-2H-1-benzopyran-2-one, C(16)H(12)O(3), the coumarin unit and benzyl plane in the mol-ecule are perpendicular to each other [86.92 (7) degrees ]. The crystal packing is stabilized by pi-pi stacking inter actions, with an inter-planar separation between inversion-related coumarin units of 3.618 (3) A. The crystal structure shows inter-molecular C-H?O hydrogen bonding between neighboring mol-ecules. PMID- 21588468 TI - Piperazine-1,4-diium 2-(carb-oxy-meth-yl)-2-hy-droxy-butane-dioate monohydrate. AB - In the crystal structure of the title compound, C(4)H(12)N(2) (2+).C(6)H(6)O(7) (2-).H(2)O, the cations, anions and water mol-ecules are linked by inter molecular N-H?O, O-H?O and weak C-H?O hydrogen bonds into a three-dimensional network. An intra-molecular O-H?O inter-action occurs in the dianion. PMID- 21588469 TI - Erratum: N'-[(E)-(1-Methyl-1H-pyrrol-2-yl)methyl-idene]pyridine-4-carbohydrazide. Corrigendum. AB - The name of one of the authors in the paper by Hussain et al. [Acta Cryst. (2010), E66, o1881] is corrected.[This corrects the article DOI: 10.1107/S1600536810025341.]. PMID- 21588470 TI - Redetermination of Fe(2)[BP(3)O(12)]. AB - Explorations of phases in the quaternary Fe(III)-B(III)-P(V)-O system prepared by the high temperature solution growth (HTSG) method led to single-crystal growth of anhydrous diiron(III) borotriphosphate, Fe(2)[BP(3)O(12)]. This phase has been synthesized previously as a microcrystalline material and its structure refined in space group P3 from powder X-ray diffraction data using the Rietveld method [Chen et al. (2004 ?). J. Inorg. Mater.19, 429-432]. In the current single crystal study, it was shown that the correct space group is P6(3)/m. The three dimensional structure of the title compound is built up from FeO(6) octa-hedra (3.. symmetry), trigonal-planar BO(3) groups ( symmetry) and PO(4) tetra-hedra (m.. symmetry). Two FeO(6) octa-hedra form Fe(2)O(9) dimers via face-sharing, while the anionic BO(3) and PO(4) groups are connected via corner-sharing to build up the [BP(3)O(12)](6-) anion. Both units are inter-connected via corner sharing. PMID- 21588471 TI - K(3)Gd(PO(4))(2). AB - The title compound, tripotassium gadolinium(III) bis-[ortho-phosphate(V)], was synthesized by a high-temperature solution reaction. Of the 12 atoms of the asymmetric unit (1 * Gd, 2 * P, 3 * K, 6 * O), all but two O atoms (which are in general positions) lie on mirror planes. The crystal structure features sheets of composition [Gd(PO(4))(2)](3-) which extend parallel to (100) and are built up from isolated PO(4) tetra-hedra and GdO(7) monocapped prisms through corner- and edge-sharing. The K(+) ions, which have coordination numbers of 10, 9 and 11, help to stack the anionic sheets along [100] into a three-dimensional structure. PMID- 21588472 TI - The two-dimensional thio-phosphate CsCrP(2)S(7). AB - The quaternary title compound, caesium chromium(III) hepta-thio-diphosphate(V), CsCrP(2)S(7), has been synthesized using the reactive halide flux method. It is isotypic with other AMP(2)S(7) (A = alkali metal; M = Cr, V or In) structures and consists of two-dimensional (infinity) (2)[CrP(2)S(7)](-) layers extending parallel to (001) which are separated from each other by Cs(+) ions (symmetry 2). The layer is built up from slightly distorted octa-hedral [CrS(6)] units (symmetry 2) and bent [P(2)S(7)] units consisting of two corner-sharing [PS(4)] tetra-hedra. The [CrS(6)] octa-hedra share two edges and two corners with the [PS(4)] tetra-hedra. There are only van der Waals inter-actions present between the layers. The Cs(+) ions are located in this van der Waals gap and stabilize the structure through weak ionic inter-actions. The classical charge balance of the title compound can be expressed as [Cs(+)][Cr(3+)][P(5+)](2)[S(2-)](7.). PMID- 21588473 TI - Sesquicaesium hemisodium tetra-cyanidoplatinate(II) sesquihydrate. AB - The title compound, Cs(1.5)Na(0.5)[Pt(CN)(4)].1.5H(2)O, was isolated from solution as a salt. The tetra-cyanidoplatinate (TCP) anions are stacked in a linear quasi-one-dimensional arrangement along the b axis, with Pt?Pt inter actions of 3.6321 (5) A. The mixed alkali metal TCP contains three distinct alkali metal positions in the structure that do not show any mixed occupancy: Cs1 (site symmetry 2), Cs2 (general position) and Na1 (site symmetry ). The Na(+) ion contains an octa-hedral coordination environment composed of two water mol-ecules and four N-terminal cyanides, which serve to bridge TCP anions. The Cs(+) cations contain mono- and bicapped square-prismatic environments, where the square prisms are formed from cyanide N atoms with water mol-ecules capping the faces. The 1.5 water mol-ecules per formula unit are a result of two fully occupied sites, one on a general position and one on a twofold rotation axis. Weak hydrogen-bonding inter-actions are observed between one water mol-ecule and terminal N-atom acceptors from TCP, while the second water mol-ecule is not involved in hydrogen bonding. PMID- 21588474 TI - Redetermination of tantalum penta-bromide, (TaBr(5))(2). AB - Crystals of di-MU-bromido-bis-[tetra-bromidotantalum(V)], (TaBr(5))(2), were obtained by recrystallization at 773 K. A first crystal structure study of (TaBr(5))(2) was reported by Rolsten [J. Am. Chem. Soc. (1958) ?, 80, 2952-2953], who analysed the powder diffraction pattern and came to the conclusion that it crystallizes isotypically with (NbBr(5))(2) in a primitive ortho-rhom-bic cell. These findings are not in agreement with our current results of a monoclinic C centred structure. (TaBr(5))(2) is isotypic with alpha-(NbCl(5))(2). The crystal structure contains [TaBr(6)] octa-hedra sharing common edges forming [TaBr(5)](2) dimers. Two crystallographically independent dimers with symmetries m and 2/m and Ta?Ta distances of 4.1574 (11) and 4.1551 (15) A, respectively, are present in the structure. PMID- 21588475 TI - Apatite-type SrPr(4)(SiO(4))(3)O. AB - Single crystals of the title compound, strontium tetra-praseo-dymium tris (silicate) oxide, SrPr(4)(SiO(4))(3)O, have been grown by the self-flux method using SrCl(2). The structure is isotypic with the apatite supergroup family having the generic formula (IX)M1(2) (VII)M2(3)((IV)TO(4))(3)X, where M = alkaline earth and rare earth metals, T = Si and X = O. The M1 site (3.. symmetry) is occupied by Pr and Sr atoms with almost even proportions and is surrounded by nine O atoms forming a tricapped trigonal prism. The M2 site (m.. symmetry) is almost exclusively occupied by Pr and surrounded by seven O atoms, forming a distorted penta-gonal bipyramid. The Si atom (m.. symmetry) is surrounded by two O (m.. symmetry) and two O atoms in general positions, forming an isolated SiO(4) tetra-hedron. Another O atom at the inversion centre (.. symmetry) is surrounded by three M2 sites, forming an equilateral triangle perpendicular to the c axis. PMID- 21588476 TI - Undeca-carbonyl-1kappaC,2kappaC,3kappaC-{tris-[4-(methyl-sulfanyl)-phen-yl]arsine 1kappaAs}-triangulo-triruthenium(0). AB - The crystal structure of the title triangulo-triruthenium compound, [Ru(3)(C(21)H(21)AsS(3))(CO)(11)], confirms that during the synthesis one equatorial carbonyl ligand is substituted by a monodentate arsine ligand, leaving one equatorial and two axial carbonyl substituents on an Ru atom. The other two Ru atoms each carry two equatorial and two axial carbonyl ligands. The three arsine-substituted benzene rings make dihedral angles of 77.94 (13), 86.37 (13) and 73.22 (12) degrees with each other. Two of the methylsulfanyl groups are disordered over two positions with refined site occupancies of 0.720 (7):0.280 (7) and 0.644 (8):0.356 (8). In the crystal structure, mol-ecules are linked into infinite chains along the a axis by weak inter-molecular C-H?O hydrogen bonds. PMID- 21588477 TI - Tetra-MU-acetato-kappaO:O'-bis-{[N-(4-chloro-phen-yl)-4-methyl-pyridin-2-amine kappaN]copper(II)}. AB - In the crystal structure of the title complex, [Cu(2)(CH(3)COO)(4)(C(12)H(11)ClN(2))(2)], the complete binuclear mol-ecule is generated by a crystallographic centre of inversion; the four acetate groups each bridge a pair of Cu(II) atoms. The coordination of the metal atom is distorted octa-hedral within a donor set defined by four O atoms, the heterocyclic N atom and the second Cu atom. The pyridine ring is twisted with respect to the benzene ring, forming a dihedral angle of 33.9 (2) degrees . An intra-molecular N-H?O hydrogen bond is present between the amino group and a carboxyl O atom. Inter molecular inter-actions of the C-H?pi type link mol-ecules in the crystal structure. PMID- 21588478 TI - Oxido{N-[(2-oxido-1-naphthyl-kappaO)methyl-idene]asparaginato-kappaO,N}(1,10 phenanthroline-kappaN,N')vanadium(IV) N,N-dimethyl-formamide monosolvate. AB - The tridentate Schiff base ligand of the title complex, [V(C(15)H(12)N(2)O(4))O(C(12)H(8)N(2))].C(3)H(7)NO, was derived from the condensation of 2-hy-droxy-1-naphthaldehyde and l-asparagine. The central V(IV) atom is six-coordinated by one oxide O atom, two N atoms from 1,10-phenanthroline and one N atom and two O atoms from the Schiff base ligand in a distorted octa hedral geometry. In the crystal structure, inter-molecular N-H?O hydrogen bonds connect mol-ecules into centrosymmetric dimers. The C atoms of the dimethyl formamide solvent mol-ecule are disordered over two sites with site-occupancy factors of 0.732 (13) and 0.268 (13). PMID- 21588479 TI - Bis[(2-amino-phen-yl)methanol-kappaO,N]bis-(nitrato-kappaO)manganese(II). AB - In the title compound, [Mn(NO(3))(2)(C(7)H(9)NO)(2)], the Mn(II) atom (site symmetry 2) is coordinated by two N,O-bidentate (2-amino-phen-yl)methanol ligands and two monodentate nitrate anions in a distorted cis-MnN(2)O(4) octa-hedral coordination geometry. In the crystal, N-H?O, O-H?O and C-H?O hydrogen bonds help to establish the packing. PMID- 21588480 TI - Tetra-kis(1,3-diphenyl-propane-1,3-dionato)hafnium(IV). AB - In the title compound, [Hf(C(15)H(11)O(2))(4)], the Hf(IV) atom is coordinated by four 1,3-diphenyl-propane-1,3-dionato ligands with an average Hf-O distance of 2.17 (3) A and O-Hf-O bite angles varying from 74.5 (1) to 75.02 (9) degrees . The coordination polyhedron shows a slightly distorted Archimedean square-anti prismatic geometry. The crystal packing is stabilized by weak C-H?O inter actions. PMID- 21588481 TI - Aqua-(2,2'-bipyridine-kappaN,N')(3,5-dinitro-benzoato-kappaO)copper(II) tetra hydro-furan monosolvate. AB - The title complex, [Cu(C(7)H(3)N(2)O(6))(2)(C(10)H(8)N(2))(H(2)O)].C(4)H(8)O, features a penta-coordinate Cu(II) atom bound by two monodentate carboxyl-ate ligands, a bidentate 2,2'-bipyridine mol-ecule [dihedral angle between pyridine rings = 5.0 (2) degrees ] and a water mol-ecule. The resulting N(2)O(3) donor set defines a distorted square-pyramidal geometry with the coordinated water mol ecule in the apical position. In the crystal, the presence of O-H(w)?O(c) (w = water and c = carbon-yl) hydrogen bonding leads to the formation of a supra molecular chain propagating along the c axis, which associates into a double chain via C-H? O and pi-pi contacts between pyridyl rings [centroid-centroid distance = 3.527 (3) A]. The solvent mol-ecules, which are disordered over two orientations in a 0.678 (11):0.322 (11) ratio, occupy voids defined by the complex mol-ecules and are held in place via C-H?O inter-actions. PMID- 21588482 TI - Bis[(2-amino-phen-yl)methanol-kappaN,O]bis-(nitrato-kappaO)zinc(II). AB - In the title compound, [Zn(NO(3))(2)(C(7)H(9)NO)(2)], the Zn(II) atom, lying on a twofold rotation axis, is six-coordinated in a distorted octa-hedral geometry by two N atoms and two O atoms from two (2-amino-phen-yl)methanol ligands and two O atoms from two monodentate nitrate anions. Inter-molecular N-H?O, O-H?O and C-H?O hydrogen bonds stabilize the crystal structure. PMID- 21588483 TI - Aqua-[1,3-bis-(benzimidazol-2-yl)-2-oxapropane]-diethano-lmanganese(II) dipicrate ethanol disolvate. AB - In the title complex, [Mn(C(16)H(14)N(4)O)(C(2)H(5)OH)(2)(H(2)O)](C(6)H(2)N(3)O(7))(2).2C(2)H(5)OH, the Mn(II) ion is in a distorted octa-hedral coordination environment, defined by an MnN(2)O(4) donor set. The 1,3-bis-(benz-imid-azol-2-yl)-2-oxapropane ligand is tridentate. In the crystal structure, inter-molecular N-H?O and O-H?O hydrogen bonds link the components into a three-dimensional network. The O atoms of one of the nitro groups are disordered over two sets of sites with refined occupancies of 0.577 (11) and 0.423 (11). PMID- 21588484 TI - catena-Poly[[(pyrimidine-2-carb-oxy-lic acid)iron(II)]-MU-oxalato]. AB - In the title complex, [Fe(C(2)O(4))(C(5)H(4)N(2)O(4))](n), the Fe(II) ion is coordinated by two oxalate anions and a pyrimidine-2-carb-oxy-lic acid ligand in a slightly distorted octa-hedral geometry. Each oxalate anion chelates to two Fe(II) ions, forming chains along the a axis. The chains are further connected by O-H?O and C-H?O hydrogen bonds, stabilizing the structure. An intra-molecular O H?N inter-action results in a five-membered ring. PMID- 21588485 TI - Dicyanidobis(N,N'-dimethythio-urea-kappaS)mercury(II). AB - In the title complex, [Hg(CN)(2)(C(3)H(8)N(2)S)(2)], the Hg(II) atom is located on a twofold rotation axis. It is four-coordinate having an irregular tetra hedral geometry composed of two cyanide C atoms [Hg-C = 2.090 (6) A] and two thione S atoms of N,N'-dimethyl-thio-urea (dmtu) [Hg-S = 2.7114 (9) A]. The NC-Hg CN bond angle of 148.83 (13) degrees has the greatest deviation from the ideal tetra-hedral geometry. The mol-ecular structure is stabilized by intra-molecular N-H?S inter-actions involving dmtu units related by the twofold symmetry. In the crystal, inter-molecular N-H?N(CN) hydrogen-bonding inter-actions link symmetry related mol-ecules into a two-dimensional network in (110). PMID- 21588486 TI - (Acetyl-acetonato)(dicyanamido)(1,10-phenanthroline)copper(II) dihydrate. AB - In the title compound, [Cu(C(5)H(7)O(2))(C(2)N(3))(C(12)H(8)N(2))].2H(2)O, the Cu(II) atom is five-coordinated in a square-pyramidal geometry with two acetyl acetonate O and two phenanthroline N atoms forming the base. The apical position is occupied by the central N atom of the dicyanamide ligand. The dicyanamide N atoms are each involved in hydrogen bonds to water mol-ecules. There are also hydrogen bonds between both the water mol-ecules and their centrosymmetric pairs, creating a hydrogen-bonded chain along the b-axis direction. PMID- 21588487 TI - Tris(2-chloro-benz-yl)(1H-1,2,4-triazole-5-thiol-ato-kappaS)tin(IV)-tris-(2 chloro-benz-yl)(4H-1,2,4-triazole-3-thiol-ato-kappaS)tin(IV) (1/1). AB - Tris(2-chloro-benz-yl)tin hydroxide condenses with 3-mercapto-1,2,4-triazole to form the 1:1 cocrystal of the title compound, [Sn(C(7)H(6)Cl)(3)(C(2)H(2)N(3)S)]. The asymmetric unit contains two mol-ecules which differ only in the position of the nitro-gen-bound H atom of the triazole ring; one mol-ecule is linked to the other mol-ecule by an N-H?N hydrogen bond. In the second mol-ecule, two of the chloro-benzyl units are disordered over two positions in a 0.73 (1):0.27 (1) ratio. The Sn atom in both mol-ecules shows a distorted tetra-hedral SnSC(3) coordination. PMID- 21588488 TI - A one-dimensional inorganic-organic hybrid compound: catena-poly[ethyl enediammonium [indate(III)-di-MU-hydrogenphosphato(V)-MU-hydroxido] monohydrate]. AB - The title compound, (C(2)H(10)N(2))[In(HPO(4))(2)(OH)].H(2)O, was synthesized under hydro-thermal conditions. The structure of this hybrid compound consists of isolated inorganic chains with composition (infinity)[In(HPO(4))(4/2)(OH)(2/2)] running along [010]. The coordination of the In(III) atom is distorted octa hedral. The ethyl-enediammonium cation and the disordered water mol-ecule (site occupation factors = 0.7:0.3) ensure the cohesion of the structure via N-H?O and O-H?O hydrogen bonds. PMID- 21588489 TI - Bis(MU-pyridine-2,4-dicarboxyl-ato)-kappaN,O:O;kappaO:N,O-bis-[triaqua magnesium(II)]. AB - In the title centrosymmetric Mg(II) complex, [Mg(2)(C(7)H(3)NO(4))(2)(H(2)O)(6)], each Mg cation is N,O-chelated by a pyridine-2,4-dicarboxyl-ate dianion and is coordinated by three water mol-ecules. A carboxyl-ate O atom from the neighboring pyridine-2,4-dicarboxyl-ate dianion bridges the Mg cation to complete the MgNO(5) distorted octa-hedral coordination geometry. The dinuclear complex mol-ecules are linked by inter-molecular O-H?O hydrogen bonding, forming a three-dimensional supra-molecular structure. PMID- 21588490 TI - trans-Diaqua-bis-[2-(2-pyrid-yl)acetato-kappaN,O]nickel(II). AB - In the centrosymmetric title complex, [Ni(C(7)H(6)NO(2))(2)(H(2)O)(2)], the Ni(II )atom, located on an inversion center, is six-coordinated in a distorted octa hedral geometry defined by two N and four O atoms from the two chelating 2-(2 pyrid-yl)acetate ligands and two aqua ligands. The mol-ecules form a three dimensional framework by O-H?O hydrogen bonds and aromatic pi-pi stacking inter actions, with a centroid-centroid distance of 3.506 (3) A. PMID- 21588491 TI - Poly[(MU(3)-5-amino-isophthalato-kappaO,O':O'':O''')[MU(2)-1,2-bis-(4-pyrid yl)ethane-kappaN:N']cobalt(II)]. AB - In the title compound, [Co(C(8)H(5)NO(4))(C(12)H(12)N(2))](n), the Co(II) ion presents a distorted CoO(4)N(2) octa-hedral coordination geometry, formed by three 5-amino-isophthalate dianions and two 1,2-bis-(4-pyrid-yl)ethane ligands. One carboxyl-ate group of the 5-amino-isophthalate dianion chelates a Co cation and the other carboxyl-ate group bridges the other two Co cations, while the terminal N atoms of the 1,2-bis-(4-pyrid-yl)ethane ligand coordinate the neighboring Co cations, forming a two-dimensional polymeric architecture. Two pyridine rings of the 1,2-bis-(4-pyrid-yl)ethane ligand are twisted to each other with a dihedral angle of 50.94 (16) degrees . Weak C-H?O hydrogen bonding and N H?pi inter-actions are observed in the crystal structure. A void of 69 (5) A(3) is present in the crystal structure, but no solvent mol-ecule can be located reasonably. PMID- 21588492 TI - Poly[[MU(2)-1,2-bis-(4-pyrid-yl)ethene-kappaN:N']-di-MU(3)-bromido-dicopper(I)]. AB - In the title polymeric Cu(I) compound, [Cu(2)Br(2)(C(12)H(10)N(2))](n), the Cu cation is coordinated by an N atom from the 1,2-bis-(4-pyrid-yl)ethene ligand and three Br(-) anions in a distorted tetra-hedral CuBr(3)N coordination geometry. Each Br(-) anion bridges three Cu cations related by inversion centers, forming a stair-like polymeric chain along the a axis, and the terminal N atoms of the 1,2 bis-(4-pyrid-yl)ethene ligand, located across an inversion center, coordinate the Cu cations from neighboring chains, forming polymeric sheets. PMID- 21588493 TI - Poly[[MU(3)-chlorido-bis(MU(2)-thio-urea-kappaS)disilver(I)] nitrate]. AB - The mol-ecular structure of the title polymeric complex, {[Ag(2)Cl(CH(4)N(2)S)(2)]NO(3)}(n), consists of a binuclear cationic complex and a nitrate counter-ion. The cationic complex contains two bridging thio-urea (Tu) ligands and a triply bridging MU(3)-Cl anion. The latter is probably released from 2-amino-ethane-thiol hydro-chloride during the synthesis. The coordination environment around the two Ag(I) atoms is different; one is trigonal planar, being coordinated by two thio-urea ligands through the S atoms and to one Cl(-) ion, while in the other the Ag(I) atom is tetra-hedrally coordinated by two thio urea ligands through the S atoms and to two Cl(-) ions. These units aggregate through the Cl(-) anion and the Tu S atoms, forming a chain propagating in [100]. In the crystal structure, the polymeric chains are linked via N-H?O and N-H?Cl hydrogen bonds, forming a double layer two-dimensional network propagating in (011). PMID- 21588494 TI - {2-[(2-Carbamothiol-ylhydrazin-1-yl-idene-kappaN,S)meth-yl]-6-hy-droxy-phenolato kappaO}(triphenyl-phosphine-kappaP)nickel(II) chloride. AB - The deprotonated Schiff base ligand in the title compound, [Ni(C(8)H(8)N(3)O(2)S)(C(18)H(15)P)]Cl, functions as an N,O,S-chelating anion to the phosphine-coordinated Ni atom, which exists in a distorted square-planar geometry. The hy-droxy group forms an intra-molecular O-H?O hydrogen bond. The two amino groups of the cation are hydrogen-bond donors to the chloride anion; the hydrogen bonds generate a chain structure running along the b axis. PMID- 21588495 TI - Bis(2,2'-bipyridine)-1kappaN,N';3kappaN,N'-hexa-MU-methacrylato 1:2kappaO:O';2:3kappaO:O'-(nitrato-2kappaO,O')-1,3-dicobalt(II)-2-terbium(III). AB - In the title trinuclear cobalt-terbium complex, [Co(2)Tb(C(4)H(5)O(2))(6)(NO(3))(C(10)H(8)N(2))(2)], the central Tb(III) and each of the Co(II) ions are bridged by three carboxyl-ate groups of the methacrylate anions. The Tb(III) cation is coordinated by six O atoms from six methacrylate anions and two O atoms from a chelating nitrate anion in a distorted square-anti prismatic geometry. Each Co(II) ion is coordinated by three O atoms from three methyl-acrylate anions and two N atoms of a 2,2'-bypiridine ligand in a distorted square-pyramidal geometry. In the crystal structure, pi-pi stacking between the pyridine rings [centroid-centroid distances = 3.682 (8) and 3.760 (8) A] is observed and weak inter-molecular C-H?O hydrogen bonding is also present. PMID- 21588496 TI - Bis{1-[(4-methyl-phen-yl)imino-meth-yl]-2-naphtho-lato-kappaN,O}copper(II). AB - In the title complex, [Cu(C(18)H(14)NO)(2)], the Cu(II) ion lies on an inversion center and is coordinated in a slightly distorted square-planar environment. The 1-[(4-methyl-phen-yl)imino-meth-yl]-2-naphtho-late ligands are coordinated in a trans arrangement with respect to the N and O atoms. PMID- 21588497 TI - Tetra-MU-acetato-kappaO:O'-bis-{[4-methyl-N-(4-methyl-phen-yl)pyridin-2-amine kappaN]copper(II)}. AB - The title complex, [Cu(2)(CH(3)COO)(4)(C(13)H(14)N(2))(2)], features a binuclear mol-ecule, which lies about a crystallographic centre of inversion; the four acetate ions each bridge a pair of Cu(II) atoms. The coordination of the metal atom is distorted octa-hedral within a donor set defined by four O atoms, the heterocyclic N atom and the second Cu atom. The pyridine ring is twisted with respect to the tolyl ring and forms a dihedral angle of 35.34 (9) degrees . A bifurcated N-H?(O,O) hydrogen bond is present, linking the amine group to two carboxyl-ate O atoms derived from different acetate ions. In the crystal, C-H?pi inter-actions link mol-ecules into a supra-molecular array in the bc plane. PMID- 21588498 TI - catena-Poly[(S)-2-methyl-piperazine-1,4-diium [[trichloridobismuthate(III)]-di-MU chlorido]]. AB - In the crystal structure of the title compound, {(C(5)H(14)N(2))[BiCl(5)]}(n), the Bi(III) cation is coordinated by six Cl(-) anions in a distorted octa-hedral geometry. Two Cl(-) anions bridge neighboring Bi(III) cations, forming a zigzag polymeric chain along the a axis. The discrete methylpiperazinediium cation adopts a normal chair conformation and is linked to the polymeric chains by N H?Cl hydrogen bonding. PMID- 21588499 TI - 3,3-Dimethyl-1,1-(propane-1,3-di-yl)diimidazol-1-ium tetra-bromido-cadmate(II). AB - The title compound, (C(11)H(18)N(4))[CdBr(4)], was prepared by an anion exchange. The dihedral angle between the two planar imidazolium rings in the cation is 74.4 (4) degrees . The crystal packing is stabilized by weak inter-molecular C-H?Br hydrogen bonds between the cation and the tetrahedral anion, building up a three dimensionnal network. PMID- 21588501 TI - (Acridine-kappaN)(dimethyl sulfoxide-kappaS)diiodidoplatinum(II). AB - In the title complex, [PtI(2)(C(13)H(9)N)(C(2)H(6)OS)], the Pt(II) atom is four coordinated in an essentially square-planar environment defined by the N atom of the acridine ligand, the S atom of dimethyl sulfoxide, and two iodide ions. The dihedral angle between the nearly planar PtI(2)NS unit [maximum deviation = 0.083 (2) A] and the acridine ligand [maximum deviation = 0.038 (6) A] is 89.29 (7) degrees . In the crystal structure, the complex mol-ecules are arranged in a V shaped packing pattern along the c axis and linked by inter-molecular C-H?O contacts into supra-molecular chains. There are also several inter-molecular pi pi inter-actions between the six-membered rings, with a shortest ring centroid centroid distance of 3.804 (5) A. PMID- 21588500 TI - Bis[1-(2-eth-oxy-phen-yl)-3-(4-nitro-phen-yl)triazenido]mercury(II). AB - In the title compound, [Hg(C(14)H(13)N(4)O(3))(2)], the central Hg atom (site symmetry 2) is six-coordinated by two tridentate 1-(2-eth-oxy-phen-yl)-3-(4-nitro phen-yl)triazenide ligands through two N and one O atoms. The mononuclear complex mol-ecules are connected into two parallel chains by inter-molecular C-H?O hydrogen-bonding inter-actions. These chains are connected to each other by face to-edge C-H?pi inter-actions between the CH of the ethoxy groups and the aromatic rings, resulting in a two-dimensional architecture in the ac plane. PMID- 21588502 TI - 2,9-Dimethyl-1,10-phenanthrolin-1-ium (6-carb-oxy-4-hy-droxy-pyridine-2-carboxyl ato-kappaO,N,O)(4-hy-droxy-pyridine-2,6-dicarboxyl-ato-kappaO,N,O)nickelate(II) 2.35-hydrate: a proton-transfer compound. AB - The title proton-transfer compound, (C(14)H(13)N(2))[Ni(C(7)H(3)NO(5))(C(7)H(4)NO(5))].2.35H(2)O, consists of an [Ni(hypydc)(hypydcH)](-) anion, a dmpH(+) cation and 2.35 uncoordinated water mol ecules (where hypydcH(2) = 4-hy-droxy-pyridine-2,6-dicarb-oxy-lic acid and dmp = 2,9-dimethyl-1,10-phenanthroline). The Ni(II) atom is coordinated by two N atoms and four O atoms from the carboxyl-ate groups of the (hypydc)(2-) and (hypydcH)( ) ligands, forming a distorted octa-hedral environment. In the anion, the two pyridine rings are inclined to one another by 89.24 (10) degrees . In the crystal, cations are linked via O-H?O hydrogen bonds forming dimers, graph-set [R(2) (2)(16)], centered about inversion centers. These dimers are further linked by other cation O-H?O hydrogen bonds, graph-set [R(6) (6)(42)], forming a two dimensional network in (011). Additional inter-molecular O-H?O, N-H?O, N-H?N, and weak C-H?O hydrogen bonds, and pi-pi inter-actions [shortest centroid-centroid distance = 3.5442 (14) A], connect the two dimensional networks, forming a three dimensional arrangement. The H atoms of one of the methyl groups are disordered over two sites with equal occupancy. PMID- 21588503 TI - Racemic tricarbonyl[(4a,5,6,7,8,8a-eta)-2-phenyl-3,4-dihydro-2H-1 benzopyran]chromium(0). AB - The title compound, [Cr(C(15)H(14)O)(CO)(3)], displays a distorted envelope configuration of the dihydro-pyrane ring. The dihedral angle between the phenyl and phenyl-ene rings is 50.63 (4) degrees . The Cr(0) atom is coordinated by three CO groups and the phenyl-ene ring of the flavan ligand in an eta(6) mode, with a common arene-to-metal distance. PMID- 21588504 TI - (N-Benzyl-N-isopropyl-dithio-carbamato)chloridodiphenyl-tin(IV). AB - The Sn(IV) atom in the title organotin dithio-carbamate, [Sn(C(6)H(5))(2)(C(11)H(14)NS(2))Cl], is penta-coordinated by an asymmetrically coordinating dithio-carbamate ligand, a Cl and two ispo-C atoms of the Sn-bound phenyl groups. The resulting C(2)ClS(2) donor set defines a coordination geometry inter-mediate between square-pyramidal and trigonal-bipyramidal with a slight tendency towards the latter. The formation of close intra-molecular C-H?Cl and C H?S contacts precludes the Cl and S atoms from forming significant inter molecular contacts. The presence of C-H?pi contacts leads to the formation of supra-molecular arrays that stack along the b axis. PMID- 21588505 TI - mer-Bis[2-(1,3-benzothiazol-2-yl)phenyl-kappaC,N][3-phenyl-5-(2-pyridyl)-1,2,4 triazol-1-ido-kappaN,N]iridium(III) deuterochloro-form 3.5-solvate. AB - In the title compound, [Ir(C(13)H(9)N(4))(C(13)H(8)NS)(2)].3.5CDCl(3), the coordination at iridium is octa-hedral, but with narrow ligand bite angles. The bond lengths at iridium show the expected trans influence, with the Ir-N bonds trans to C being appreciably longer than those trans to N. The chelate rings are mutually perpendicular, the inter-planar angles between them all lying within 6 degrees of 90 degrees . All ligands are approximately planar; the maximum inter planar angles within ligands are ca 10 degrees . The three ordered deuterochloro form mol-ecules are all involved in C?D-A contacts that can be inter-preted as hydrogen bonds of various types. The fourth deuterochloroform is disordered over an inversion centre. PMID- 21588506 TI - MU-Oxido-bis-({2,2'-[o-phenylenebis(nitrilo-methylidyne)]diphenolato}iron(III)) methanol monosolvate dihydrate. AB - The title complex, [Fe(2)(C(20)H(14)N(2)O(2))(2)O].CH(4)O.2H(2)O, is composed of MU-oxido-bridged ferric 2,2'-[o-phenylene-bis(nitrilo-methylidyne)]diphenolate (salphen) dimers, one methanol mol-ecule and two H(2)O mol-ecules. Each iron(III) ion, surrounded by two coordinating N and O atoms from the salphen ligand and one bridging O atom, shows a five-coordinate square-pyramidal geometry. One of the two solvent water mol-ecules is disordered over three positions with occupancies of 0.44 (1), 0.37 (1) and 0.19 (1). PMID- 21588507 TI - A binuclear vanadium oxyfluoride: di-MU-oxido-bis-[(2,2'-bipyrid-yl)fluorido oxidovanadium(V)]. AB - The title compound, [V(2)F(2)O(4)(C(10)H(8)N)(2)], is a centrosymmetric binuclear vanadium(V) species with the metal ions in a distorted octa-hedral environment. The coordination geometries of the symmetry-equivalent V(V) atoms are defined by cis-terminal fluoride and oxide groups, unsymmetrically bridging oxide groups and the N-atom donors of the bipyridyl ligand. The crystal packing is stabilized by weak inter-molecular C-H?O and C-H?F hydrogen bonds. PMID- 21588508 TI - catena-Poly[sodium [[tris(3-methyl-pyridine-2-carboxylato)europate(III)]-MU-3 methylpyridine-2-carboxylato] trihydrate]. AB - In the title structure, {Na[Eu(C(7)H(6)NO(2))(4)].3H(2)O}(n), the Eu(III) atom is nine-coordin-ated within a slightly distorted tricapped trigonal-prismatic coordination geometry defined by five carboxyl-ate-O atoms and four pyridine-N atoms. One of the carboxyl-ate ligands bridges the Eu cations, forming a one dimensional coordination polymer along the b axis. The Eu-O bond distances lie within the range 2.362 (4)-2.461 (4) A. In the crystal structure, inter-molecular O-H?O hydrogen bonds link the polymers into a three-dimensional network. PMID- 21588509 TI - Diaqua-bis-(5-carb-oxy-2-propyl-1H-imidazole-4-carboxyl-ato-kappaN,O)zinc(II) 3.5 hydrate. AB - In the title complex, [Zn(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)].3.5H(2)O, the Zn(II) ion is coordinated by two N,O-bidentate H(2)pimda ligands (H(3)pimda = 2-propyl 1H-imidazole-4,5-dicarb-oxy-lic acid) and two water mol-ecules in a distorted octa-hedral environment. In the crystal structure, extensive inter-molecular O H?O and N-H?O hydrogen bonds stabilize the three-dimensional supra-molecular network. Intra-molecular O-H?O hydrogen bonds between the carboxyl groups are also observed. The propyl groups of the two H(2)pimda ligands are disordered each over two sites, with occupancy factors of 0.752 (5):0.248 (5) and 0.519 (7):0.481 (7). One of the water mol-ecules is half-occupied. PMID- 21588510 TI - Diaqua-bis-(5-carb-oxy-2-propyl-1H-imidazole-4-carboxyl-ato kappaN,O)manganese(II) 3.5-hydrate. AB - In the title complex, [Mn(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)].3.5H(2)O, the Mn(II) cation is six-coordinated by two N,O-bidentate H(2)pimda(-) ligands (H(2)pimda(-) = 5-carb-oxy-2-propyl-1H-imidazole-4-carboxyl-ate) and two water mol-ecules in a distorted octa-hedral environment. The complete solid-state structure can be described as a three-dimensional supra-molecular framework stabilized by a wide range of O-H?O and N-H?O hydrogen bonds. The propyl groups of H(2)pimda(-) are disordered over two sets of sites with refined occupancies of 0.759 (5):0.241 (5) and 0.545 (7):0.455 (7). PMID- 21588511 TI - {4-[(7-Chloro-4-quinol-yl)amino]-N,N-di-ethyl-penta-naminium}(triphenyl-phos phine)gold(I) dinitrate. AB - The title compound, [Au(C(18)H(27)ClN(3))(C(18)H(15)P)](NO(3))(2), is a coordination complex of gold(I) triphenyl-phosphine with the N atom in the quinoline ring of the common anti-malarial compound chloro-quine (CQ). The pendant diethyl-amino group of the CQ ligand was found to be protonated. The complex exhibits a nearly linear coordination geometry around the Au(I) atom [N Au-P = 176.94 (6) degrees ], with Au-N and Au-P bond lengths of 2.070 (2) and 2.2338 (7) A, respectively. The diethylammonium group and one of the two nitrate counter-ions are disordered with occupancy ratios of 0.519 (4):0.481 (4). The nitrate anions are hydrogen bound to both the amino and ammonium groups of the N,N-diethylpentanaminium fragment of the CQ. PMID- 21588512 TI - Bis{2-[1-(benzyl-imino)-eth-yl]phenolato}palladium(II). AB - In the title compound, [Pd(C(15)H(14)NO)(2)], the Pd atom lies on an inversion center and is coordinated by two ligand mol-ecules through the O and N atoms in a bidentate manner, forming a slightly distorted square-planar geometry. The dihedral angle between the two benzene rings in the ligand is 76.53 (19) degrees . The mol-ecular packing is stablized by C-H?O and C-H?pi inter-actions. PMID- 21588513 TI - MU-Oxalato-bis-[(2,2'-bipyridyl)-copper(II)] bis(perchlorate) dimethyl-formamide disolvate monohydrate. AB - The title compound, [Cu(2)(C(2)O(4))(C(10)H(8)N(2))(4)](ClO(4))(2).2C(3)H(7)NO.H(2)O, contains doubly charged centrosymmetric dinuclear oxalato-bridged copper(II) complex cations, perchlorate anions, and DMF and water solvate mol-ecules. In the complex cation, the oxalate ligand is coordinated in a bis-bidentate bridging mode to the Cu atoms. Each Cu atom has a distorted tetra-gonal-bipyramidal environment, being coordinated by two N atoms of the two chelating bipy ligands and two O atoms of the doubly deprotonated oxalate anion. Pairs of perchlorate anions and water mol ecules are linked into recta-ngles by O-H?O bonds in which the perchlorate O atoms act as acceptors and the water mol-ecules as donors. Methyl groups of the DMF solvent molecule are disordered over two sites with occupancies of 0.453 (7):0.547 (7), and the water molecule is half-occupied. PMID- 21588514 TI - 1,4,8,11-Tetra-azoniacyclo-tetradecane diaqua-tetra-chloridomanganese(II) dichloride dihydrate. AB - The title compound, (C(10)H(28)N(4))[MnCl(4)(H(2)O)(2)]Cl(2).2H(2)O, consists of isolated octa-hedral [MnCl(4)(H(2)O)(2)](2-) anions, tetra-protonated 1,4,8,11 tetra-azoniacyclo-tetradecane cations, chloride anions and water mol-ecules connected by a network of hydrogen bonds. The Mn(II) atom is situated on an inversion centre, and the 1,4,8,11-tetra-azoniacyclo-tetradecane cation is located on a mirror plane. PMID- 21588515 TI - Poly[[tetra-kis-(MU(2)-pyrazine N,N'-dioxide-kappaO:O')neodymium(III)] tris (perchlorate)]. AB - The title three-dimensional coordination network, {[Nd(C(4)H(4)N(2)O(2))(4)](ClO(4))(3)}(n), is isostructural to that of other lanthanides. The Nd(+3 )cation lies on a fourfold roto-inversion axis. It is coordinated in a distorted square-anti-prismatic fashion by eight O atoms from bridging pyrazine N,N'-dioxide ligands. There are two unique pyrazine N,N' dioxide ligands. One ring is located around an inversion center, and there is a twofold rotation axis at the center of the other ring. There are also two unique perchlorate anions. One is centered on a twofold rotation axis and the other on a fourfold roto-inversion axis. The perchlorate anions are located in channels that run perpendicular to (001) and (110) and inter-act with the coordination network through C-H?O hydrogen bonds. PMID- 21588516 TI - Poly[[tetra-kis-(MU(2)-pyrazine N,N'-dioxide-kappaO:O')dysprosium(III)] tris (perchlorate)]. AB - The title three-dimensional coordination network, {[Dy(C(4)H(4)N(2)O(2))(4)](ClO(4))(3)}(n), is isostructural of other lanthanides. The Dy(+3 )cation lies on a fourfold roto-inversion axis. It is coordinated in a distorted square-anti-prismatic fashion by eight O atoms from bridging pyrazine N,N'-dioxide ligands. There are two unique pyrazine N,N'-dioxide ligands. One ring is located around an inversion center, and there is a a twofold rotation axis at the center of the other ring. There are also two unique perchlorate anions. One is centered on a twofold rotation axis and the other on a fourfold roto-inversion axis. The perchlorate anions are located in channels that run perpendicular to (001) and (110) and inter-act with the coordination network through C-H?O hydrogen bonds. PMID- 21588517 TI - Poly[[tetra-kis-(MU(2)-pyrazine N,N'-dioxide-kappaO:O')holmium(III)] tris (perchlorate)]. AB - The title three-dimensional coordination network, {[Ho(C(4)H(4)N(2)O(2))(4)](ClO(4))(3)}(n), is isostructural to that of other lanthanides. The Ho(+3 )cation lies on a fourfold roto-inversion axis. It is coordinated in a distorted square anti-prismatic fashion by eight O atoms from bridging pyrazine N,N'-dioxide ligands. There are two unique pyrazine N,N' dioxide ligands. One ring is located around an inversion center, and there is a a twofold rotation axis at the center of the other ring. There are also two unique perchlorate anions. One is centered on a twofold rotation axis and the other on a fourfold roto-inversion axis. The perchlorate anions are located in channels that run perpendicular to (001) (110) and inter-act with the coordination network through C-H?O hydrogen bonds. PMID- 21588518 TI - Poly[[tetra-kis-(MU(2)-pyrazine N,N'-dioxide-kappaO:O')erbium(III)] tris (perchlorate)]. AB - The title three-dimensional coordination network, {[Er(C(4)H(4)N(2)O(2))(4)](ClO(4))(3)}(n), is isostructural to that of other lanthanides. The Er(+3 )cation lies on a fourfold roto-inversion axis. It is coordinated in a distorted square-anti-prismatic fashion by eight O atoms from bridging pyrazine N,N'-dioxide ligands. There are two unique pyrazine N,N' dioxide ligands. One ring is located around an inversion center, and there is a a twofold rotation axis at the center of the other ring. There are also two unique perchlorate anions. One is centered on a twofold rotation axis and the other on a fourfold roto-inversion axis. The perchlorate anions are located in channels that run perpendicular to (001) and (110) and inter-act with the coordination network through C-H?O hydrogen bonds. PMID- 21588519 TI - Aqua-chlorido{2-[2-(cyclo-hexyl-carbamo-thioyl-kappaS)hydrazinyl-idene kappaN]propano-ato(2-)}phenyl-tin(IV). AB - In the title organotin compound, [Sn(C(6)H(5))(C(10)H(15)N(3)O(2)S)Cl(H(2)O)], the Sn atom is coordinated by the S, O, and imine N atoms of the dinegative tridentate ligand, a chloride ligand, the ipso-C atom of a phenyl ligand and by a water mol-ecule in a distorted octa-hedral coordination environment. Coordin-ated water mol-ecules link the organotin mol-ecules by forming O-H?O hydrogen bonds with both carbonyl and carboxyl-ate O atoms, leading to 12-membered {?OCO?HOH?}(2) synthons. This results in the formation of supra-molecular chains along the c axis. The chains pack in the ac plane and stack along the b axis with links between layers afforded by N-H?Cl hydrogen bonds. PMID- 21588520 TI - [(1,2,5,6-eta)-1,5-Cyclo-octa-diene](1-isopropyl-3-methyl-imidazolin-2-yl idene)(triphenyl-phosphine)iridium(I) tetra-fluorido-borate dichloro-methane solvate. AB - In the title compound, [Ir(C(8)H(12))(C(7)H(12)N(2))(C(18)H(15)P)]BF(4).CH(2)Cl(2), the Ir(I) atom has a square-planar conformation with normal bond lengths. One of the phenyl rings, and the solvent dichloro-methane mol-ecule, were refined using separate two part disorder models, each in an approximately 1:1 ratio. PMID- 21588521 TI - Di-MU-sulfato-kappaO:O'-bis-[diaqua-(1H-imidazo[4,5 f][1,10]phenanthroline)manganese(II)] dihydrate. AB - In the title centrosymmetric dinuclear compound, [Mn(2)(SO(4))(2)(C(13)H(8)N(4))(2)(H(2)O)(4)].2H(2)O, the Mn(II) atom is octa hedrally coordinated by two N atoms from a 1H-imidazo[4,5-f][1,10]phenanthroline (ip) ligand, two O atoms belonging to two bridging sulfate anions and two water O atoms. In the crystal structure, the complex mol-ecules and the uncoodinated water mol-ecules are connected by O-H?O, O-H?N and N-H?O hydrogen bonds into a three-dimensional network. A pi-pi stacking inter-action between the pyridyl ring of the ip ligand and the benzene ring of the neighboring ligand [centroid centroid distance = 3.579 (2) A] is also observed. PMID- 21588522 TI - [MU-1,2-Bis(4-pyrid-yl)ethane-kappaN:N']bis-[(4'-phenyl-2,2':6',2''-terpyridine kappaN,N',N'')silver(I)] bis-(trifluoro-methane-sulfonate). AB - In the title compound, [Ag(2)(C(12)H(12)N(2))(C(21)H(15)N(3))(2)](CF(3)SO(3))(2), the Ag(I) atom is coordinated by three N atoms of one 4'-phenyl-2,2':6',2'' terpyridine (phtpy) ligand and one pyridyl N atom of the 1,2-bis-(4-pyrid yl)ethane (bpe) ligand, displaying a distorted square-planar geometry. Two Ag(I) atoms are bridged by one trans-bpe ligand, generating a dinuclear cation. The dinuclear cation is located on a centre of inversion, which is in the middle of the ethyl-ene fragment of the bpe ligand. In the crystal, the pyridyl rings of neighboring dinuclear units are stacked by pi-pi inter-actions with centroid centroid distances of 3.667 (2) and 3.835 (2) A. The F and O atoms of the CF(3)SO(3) (-) anions are involved in inter-molecular C-H?F and C-H?O hydrogen bonding inter-actions, respectively, with -CH groups from the phtpy ligands. PMID- 21588523 TI - Tris(2,2'-bipyridine)-nickel(II) hexa-molybdate. AB - The asymmetric unit of the title compound, [Ni(C(10)H(8)N(2))(3)][Mo(6)O(19)], consists of one complex [(Ni(C(10)H(8)N(2))(3)](2+) cation and one Lindqvist-type [Mo(6)O(19)](2-) polyanion. The Ni(2+) ion is in a distorted octa-hedral coordination by six N atoms from three chelating 2,2'-bipyridine ligands. The Lindqvist-type anion exhibits the characteristic Mo-O bond-length distribution, with the shortest bonds being the Mo-O(terminal) bonds [mean = 1.679 (2) A] and the longest being those to the central O atom [mean = 2.318 (7) A]. A number of C H?O inter-actions contribute to the crystal packing. PMID- 21588524 TI - Di-MU-azido-kappaN:N-bis-[(1,10-phen-anthroline-kappaN,N')(thio-cyanato kappaN)lead(II)]. AB - In the centrosymmetric binuclear title compound, [Pb(2)(N(3))(2)(NCS)(2)(C(12)H(8)N(2))(4)], the N-donor atoms of one N heterocycle and the N-donor atom of a thio-cyanate anion along with the sterically active lone-pair electrons comprise an approximate square; a plane through three atoms of this square is twisted slightly with respect to the square made up of the other four atoms (two from the other N-heterocycle and one each from the bridging azide anions) at a dihedral angle of 18.7 (1) degrees . The Pb(II) atom is in a Psi-square-anti-prismaic coordination. PMID- 21588525 TI - Bis{4-chloro-N'-[phen-yl(2-pyrid-yl)methyl-idene]benzohydrazidato kappaN',O}cobalt(III) nitrate methanol disolvate. AB - In the title compound, [Co(C(19)H(13)ClN(3)O)(2)]NO(3).2CH(3)OH, the central Co(III) atom in the cation is surrounded by two tridentate ligands in a distorted octa-hedral fashion by four N and two O atoms. Classical O-H?O hydrogen bonds link both methanol solvent mol-ecules with the nitrate anion. PMID- 21588526 TI - Bis[2,4-dibromo-6-(ethyl-imino-methyl)phenolato-kappaN,O]cobalt(II). AB - In the title compound, [Co(C(9)H(8)Br(2)NO)(2)], the Co(II) atom, located on a twofold axis, is in a pseudo-tetra-hedral environment, with two bidentate 2,4 dibromo-6-(ethyl-imino-meth-yl)phenolate Schiff base ligands acting as chelates through their phenolate O and azomethine N atoms. C-H?O hydrogen bonds link the complex mol-ecules to form a chain parallel to the b axis. PMID- 21588527 TI - Bis[2,4-dibromo-6-(n-propyl-imino-methyl)phenolato-kappaN,O]cobalt(II). AB - In the title complex, [Co(C(10)H(10)Br(2)NO)(2)], the Co(II) atom lies on a twofold rotation axis, the N(2)O(2) units having distorted tetra-hedral coordination environments comprising two bidentate chelate 2,4-dibromo-6-(n propyl-imino-meth-yl)phenolate Schiff base ligands [Co-N = 1.989 (3) A, Co-O = 1.924 (2) A and O/N-Co-O/N = 94.53 (10)-125.40 (15) degrees ]. In the crystal structure, the mol-ecules are linked via weak inter-molecular C-H?O hydrogen bonds [3.334 (5) A] and there are also short inversion-related intermolecular Br?Br contacts [3.4263 (6) A]. PMID- 21588528 TI - Bis(2,2'-bi-1H-imidazole-kappaN,N)bis-(dimethyl sulfoxide-kappaO)copper(II) bis (tetra-fluoridoborate). AB - In the title copper(II) salt, [Cu(C(6)H(6)N(4))(2)(C(2)H(6)OS)(2)](BF(4))(2), the Jahn-Teller distorted octa-hedral coordination sphere of copper is formed from four 2,2'-bi-1H-imidazole N atoms and two dimethyl sulfoxide O atoms. The Cu atom lies on a center of inversion. N-H?O and N-H?F hydrogen bonds give rise to a one dimensional structure. The BF(4) (-) anion is disordered over two sites in a 0.671 (10):0.329 (10) ratio. PMID- 21588529 TI - Bis[(2-amino-phen-yl)methanol-kappaN,O]bis-(nitrato-kappaO)cobalt(II). AB - The asymmetric unit of the title compound, [Co(NO(3))(2)(C(7)H(9)NO)(2)], contains one-half of the mol-ecule. The Co(II) atom (site symmetry 2) is six coordinate in a distorted octahedral configuration bonded by two N and two O atoms from two (2-amino-phen-yl)methanol ligands and two O atoms from the two nitrate anions. Crystal packing is stabilized by inter-molecular N-H?O, O-H?O and C-H?O hydrogen-bonding inter-actions. PMID- 21588530 TI - {3-Methyl-2-[(1-oxido-2-naphth-yl)methyl-idene-amino-kappaO,N]butano-ato kappaO}(1H-pyrazole-kappaN)nickel(II). AB - In either of the two independent mol-ecules within the asymmetric unit of the title compound, [Ni(C(16)H(15)NO(3))(C(3)H(4)N(2))], the Ni(II) atom is coordinated by the two N atoms and two O atoms in a distorted square-planar geometry. The crystal packing is stabilized by strong and weak inter-molecular C H?O hydrogen bonds, as well as weak centroid-centroid pi-stacking inter-actions [centroid-centroid separation = 3.526 (3) A]. PMID- 21588531 TI - Di-MU-sulfato-bis-[diaqua-(1H-imidazo[4,5-f][1,10]phenanthroline)iron(II)] dihydrate. AB - The title dinuclear Fe(II) complex, [Fe(2)(SO(4))(2)(C(13)H(8)N(4))(2)(H(2)O)(4)].2H(2)O, is centrosymmetric. Two sulfate anions bridge two Fe(II) cations to form the binuclear complex. Each Fe(II) cation is coordinated by two N atoms from a 1H-imidazo[4,5 f][1,10]phenanthroline (IP) ligand, two O atoms from two sulfate anions and two water mol-ecules in a distorted octa-hedral geometry. Extensive O-H?O, N-H?O and O-H?N hydrogen bonding is present in the crystal structure. Weak pi-pi stacking is observed between parallel IP ring systems, the face-to-face separation being 3.428 (14) A. PMID- 21588532 TI - Dichlorido(2-{[2-(piperazin-4-ium-1-yl)eth-yl]imino-meth yl}phenolate)cadmium(II). AB - In the title compound, [CdCl(2)(C(13)H(19)N(3)O)], the Cd(II) ion is penta coordinated with the N,N,O-tridentate Schiff base 2-{[2-(piperazin-4-ium-1-yl)eth yl]imino-meth-yl}phenolate ligand and two Cl atoms in a highly distorted square pyramidal geometry; the piperazine ring adopts a chair conformation. In the crystal structure, adjacent mol-ecules are linked together via N-H?O and N-H?Cl hydrogen bonds, forming infinite layers parallel to the ab plane. The layers are further connected through C-H?Cl inter-actions into a three-dimensional network. PMID- 21588533 TI - Diaqua-bis-(2-bromo-benzoato-kappaO)bis-(N,N-diethyl-nicotinamide kappaN)cobalt(II). AB - In the mononuclear title compound, [Co(C(7)H(4)BrO(2))(2)(C(10)H(14)N(2)O)(2)(H(2)O)(2)], the Co(II) ion is located on a crystallographic inversion center. The asymmetric unit is completed by one 2 bromo-benzoate anion, one diethyl-nicotinamide (DENA) ligand and one coordinated water mol-ecule; all ligands are monodentate. The four O atoms in the equatorial plane around Co(II) form a slightly distorted square-planar arrangement, while the slightly distorted octa-hedral coordination is completed by the two pyridine N atoms of the DENA ligands in axial positions. The dihedral angle between the carboxyl-ate group and the attached benzene ring is 84.7 (1) degrees ; the pyridine and benzene rings are oriented at a dihedral angle of 43.64 (6) degrees . In the crystal structure, inter-molecular O-H?O and C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21588534 TI - Dichloridobis(3,4,5-trimethyl-1H-pyrazole-kappaN)cobalt(II). AB - In the title compound, [Co(II)Cl(2)(C(6)H(10)N(2))(2)], a pair of 3,4,5-trimethyl pyrazoles act as monodentate ligands. Two Cl(-) anions are also bonded directly to the Co(II) atom, which has a CoN(2)Cl(2) chromophore in a slightly distorted tetra-hedral geometry. The two mol-ecules in the asymmetric unit are related by an approximate twofold rotation roughly parallel to the a axis. The amino H atom in the pyrazole ring participates in weak N-H?Cl hydrogen bonds to form chains that propagate roughly parallel to the c axis. PMID- 21588535 TI - Bis(4-meth-oxy-benzoato)-kappaO,O';kappaO-bis-(nicotinamide-kappaN)zinc(II). AB - The asymmetric unit of the title complex, [Zn(C(8)H(7)O(3))(2)(C(6)H(6)N(2)O)(2)], contains three crystallographically independent mol-ecules with similar configurations. The Zn(II) cation is coordinated by two N atoms of two nicotinamide ligands and three O atoms from two 4-meth-oxy-benzoate anions in a distorted trigonal-bipyramidal geometry. In each independent mol-ecule, one Zn-O bond distance [2.5181 (12), 2.5931 (12) and 2.4085 (12) A for the three mol-ecules] is significantly longer than the other two. In the crystal structure, extensive N-H?O and C-H?O hydrogen bonding links the mol-ecules into a three-dimensional network. pi-pi contacts between the pyridine rings and between the pyridine and benzene rings [centroid-centroid distances = 3.7655 (9) and 3.8453 (10) A, respectively] further stabilize the crystal structure. PMID- 21588536 TI - Dioxidobis{2-[(E)-p-tolyl-imino-meth-yl]phenolato}molybdenum(VI). AB - The asymmetric unit of the title compound, [Mo(C(14)H(12)NO)(2)O(2)], comprises half of the complex with the full mol-ecule generated by the application of twofold symmetry. The Mo(VI) atom is surrounded by two oxide O atoms and the two sets of N,O-donor atoms of the bidentate Schiff base ligands. The resulting N(2)O(4) donor set defines a distorted octa-hedral coordination geometry. Inter molecular C-H?O contacts link mol-ecules into chains along the b axis. The crystal structure is further stabilized by inter-molecular pi-pi inter-actions [ring centroid-centroid distance = 3.724 (6) A]. PMID- 21588537 TI - [(4-Bromo-phen-yl)(2-pyridyl-methyl-idene)amine-kappaN,N']bis-(1,1,1,5,5,5-hexa fluoro-pentane-2,4-dionato-kappaO,O')cobalt(II). AB - In the title complex, [Co(C(5)HF(6)O(2))(2)(C(12)H(9)BrN(2))], the Co(II) atom exhibits a pseudo-octa-hedral coordination geometry, comprising two N-donor atoms from a bidentate chelate (4-bromo-phen-yl)(2-pyridyl-methyl-idene)amine (ppa(Br)) ligand [Co-N = 2.098 (2) and 2.209 (2) A] and four O-donor atoms from two bidentate chelate 1,1,1,5,5,5-hexa-fluoro-pentane-2,4-dionate (hfac) ligands [Co O range = 2.0452 (19)-2.0796 (19) A]. The packing of the structure involves weak pi-pi inter-actions between the pyridyl and benzene rings of neighbouring ppa(Br) ligands [centroid-centroid distance = 3.928 (2) A] and inter-actions between the Br atom on the ppa(Br) ligand and the hfac ligand [Br?C = 3.531 (2) A]. PMID- 21588538 TI - trans-Bis(ethyl-enediamine)-bis-{2-[N-(2-hy-droxy-eth-yl)oxamoyl-amino] benzoato}nickel(II). AB - The title mononuclear Ni(II) complex, [Ni(C(11)H(11)N(2)O(5))(2)(C(2)H(8)N(2))(2)], is built up by inversion symmetry associated with the central Ni atom. The ethyl-enediamine ligands are non-planar. The r.m.s. deviation from the mean plane of the five-membered Ni-ethyl-amine chelate ring plane is 0.1945 A. In the crystal structure, complex mol-ecules are linked to each other via N-H?O and O--H?O hydrogen bonding through translation symmetry along the b and c axes, resulting in an extended supra-molecular network. PMID- 21588539 TI - Monoclinic modification of aquadi-n-butyl-bis-(pyrazine-2-carboxyl-ato kappaN,O)tin(IV). AB - The asymmetric unit of the title organotin(IV) compound, [Sn(C(4)H(9))(2)(C(5)H(3)N(2)O(2))(2)(H(2)O)], contains one-and-a-half mol ecules. The half-mol-ecule is completed by crystallographic twofold symmetry, with its Sn and water O atoms lying on the rotation axis. Both mol-ecules feature seven-coordinate Sn atoms in trans-C(2)SnN(2)O(3) penta-gonal-bipyramidal coordination environments. The carboxyl-ate anions N,O-chelate to the Sn atom. In the crystal, the carboxyl-ate O atoms not involved in coordination serve as acceptors for O-H?O hydrogen bonds from adjacent water mol-ecules, generating a three-dimensional network. PMID- 21588540 TI - Bis(acridine-kappaN)dibromidoplatinum(II). AB - In the title complex, [PtBr(2)(C(13)H(9)N)(2)], the Pt(II) ion is four coordinated in a slightly distorted square-planar environment by two N atoms from two acridine ligands and two Br atoms. The Pt atom is located on an inversion centre, and thus the asymmetric unit contains one half of the complex and the PtN(2)Br(2) unit is exactly planar. The dihedral angle between the PtN(2)Br(2) unit and acridine ligand is 78.98 (9) degrees . In the crystal structure, the complex mol-ecules are arranged in two distinct chains along [110] and [10]. In the chains, inter-molecular pi-pi inter-actions between the pyridyl and benzene rings connect the complex mol-ecules, with a centroid-centroid distance of 3.631 (4) A. PMID- 21588541 TI - {4-Chloro-2-[(2-hy-droxy-eth-yl)imino-meth-yl]phenolato}{4-chloro-2-[(2-oxido-eth yl)imino-meth-yl]phenolato}cobalt(III). AB - In the title mononuclear cobalt(III) compound, [Co(C(9)H(8)ClNO(2))(C(9)H(9)ClNO(2))], the Co(II) atom is six-coordinated by two imine N atoms, two phenolate O atoms, and one hy-droxy and one oxide O atom from two Schiff base ligands, forming an octa-hedral geometry. In the crystal structure, adjacent mol-ecules are linked through inter-molecular O-H?O hydrogen bonds. The 2-oxidoethyl group is disordered over two positions in a 0.638 (3):0.362 (3) ratio. PMID- 21588542 TI - (N-sec-Butyl-N-n-propyl-dithio-carbamato-kappaS,S')triphenyl-tin(IV). AB - The Sn atom in the title compound, [Sn(C(6)H(5))(3)(C(8)H(16)NS(2))], is penta coordinated by two S atoms, derived from an asymmetrically coordinating dithio carbamate ligand, and three ipso-C atoms. The coordination geometry is inter mediate between square-pyramidal and trigonal-bipyramidal, with a leaning towards the latter. The presence of close intra-molecular C-H?S contacts preclude the S atoms from forming significant inter-molecular inter-actions. Rather, mol-ecules are consolid-ated in the crystal structure by C-H?pi inter-actions. PMID- 21588543 TI - Diaqua-bis-(perchlorato)(1,10-phenanthroline)copper(II). AB - In the title compound, [Cu(ClO(4))(2)(C(12)H(8)N(2))(H(2)O)(2)], the Cu(II) atom is coordinated in a square-planar fashion by the two N atoms of a chelating 1,10 phenanthroline ligand and by two water mol-ecules trans to the N atoms. The coordination sphere of the metal atom is augmented by O atoms of two weakly bonded perchlorate anions, thus yielding a strongly distorted CuN(2)O(4) octa hedral environment. The crystal packing is stabilized by O-H?O hydrogen bonds between the water mol-ecules and the perchlorate anions. In addition, the organic mol-ecules are associated by pi-pi stacking inter-actions between symmetry equivalent anti-parallel non-nitro-gen aromatic rings, with inter-planar distances of 3.543 (2) A. PMID- 21588544 TI - [2-(sec-Butyl-imino-meth-yl)quinoline]-chlorido(eta-1-isopropyl-4-methyl-benzene) ruthenium(II) hexa-fluorido-phosphate. AB - In the title compound, [RuCl(C(10)H(14))(C(14)H(16)N(2))]PF(6), the aromatic ring of the isopropyl-methyl-benzene fragment shows an eta(6)-arene coordination to the ruthenium atom. Its coordination sphere is completed by a chloride ligand and 2-(sec-butyl-imino-meth-yl)quinoline. The dihedral angle between the eta(6)-arene ring and the quinoline Schiff base is 45.64 (9) degrees . The sec-butyl substituent and the PF(6) (-) anion are disordered over two positions with ratios of 0.595 (11):0.405 (11) and 0.752 (8):0.248 (8), respectively. PMID- 21588545 TI - Tris(ethane-1,2-diamine-kappaN,N')cobalt(III) carbonate iodide tetra-hydrate. AB - The title compound, [Co(C(2)H(8)N(2))(3)](CO(3))I.4H(2)O, crystallizes with a [Co(en)(3)](3+) cation (en is ethane-1,2-diamine), CO(3) (2-) and I(-) anions and four water mol-ecules in the asymmetric unit. In the cation, the three rings formed by the ethyl-enediamine units and the Co(III) metal ion are in slightly distorted twist conformations. Numerous O-H?O, N-H?O, N-H?I and O-H?I inter molecular hydrogen bonds between the cation and two anions in concert with the four water mol-ecules dominate the crystal packing and create a supra-molecular infinite three-dimensional framework. PMID- 21588546 TI - Bis([MU-bis-(diphenyl-phosphino)methane-1:2kappaP:P']nona-carbonyl 1kappaC,2kappaC,3kappaC-{tris-[4-(methyl-sulfan-yl)phen-yl]arsine-3kappaAs} triangulo-triruthenium(0)) dichloro-methane monosolvate. AB - The asymmetric unit of the title triangulo-triruthenium compound, 2[Ru(3)(C(21)H(21)AsS(3))(C(25)H(22)P(2))(CO)(9)].CH(2)Cl(2), consists of one triangulo-triruthenium complex mol-ecule and one half of a dichloro-methane mol ecule which lies across a crystallographic inversion center, leading to the disorder of this mol-ecule over two positions of equal occupancy. The bis (diphenyl-phosphino)methane ligand bridges an Ru-Ru bond and the monodentate arsine ligand bonds to the third Ru atom. Both the arsine and phosphine ligands are equatorial with respect to the Ru(3) triangle. Each Ru atom carries one equatorial and two axial terminal carbonyl ligands. The three arsine-substituted benzene rings make dihedral angles of 82.69 (9), 70.43 (9) and 89.45 (9) degrees with each other. The dihedral angles between the two benzene rings are 85.14 (11) and 77.61 (10) degrees for the two diphenyl-phosphino groups. In the crystal packing, mol-ecules are linked together into dimers via inter-molecular C-H?O hydrogen bonds and these dimers are stacked along the a axis. Weak inter molecular C-H?pi inter-actions are also present. PMID- 21588548 TI - (eta-Cyclo-penta-dien-yl)[(1,2,3,4,4a,12a-eta)-naphtho-[2,3 b][1,4]benzodioxine]iron(II) hexa-fluoridophosphate. AB - At 296 (2) K, both complexed rings in the iron(II) complex cation of the title salt, [Fe(C(5)H(5))(C(16)H(10)O(2))]PF(6), are almost parallel [dihedral angle between planes = 2.4 (3) degrees ]. The quaternary C atoms of the complexed arene ring are located at the longest distance from the Fe atom, with Fe-C distances of 2.112 (4) and 2.105 (3) A, which are slightly longer than the average Fe-C distance for this ring (2.083 A). The Fe ion is located 1.660 (1) and 1.543 (1) A, respectively, from the cyclo-penta-dienyl and the complexed arene ring. PMID- 21588547 TI - Bis([MU-bis-(diphenyl-arsino)methane-1:2kappaAs:As']nona-carbonyl 1kappaC,2kappaC,3kappaC-{tris-[4-(methyl-sulfan-yl)phen-yl]arsine-3kappaAs} triangulo-triruthenium(0)) dichloro-methane monosolvate. AB - The asymmetric unit of the title triangulo-triruthenium compound, 2[Ru(3)(C(25)H(22)As(2))(C(21)H(21)AsS(3))(CO)(9)].CH(2)Cl(2), consists of one triangulo-triruthenium complex mol-ecule and one half of a dichloro-methane mol ecule which lies across a crystallographic inversion center, leading to the disorder of this mol-ecule over two positions of equal occupancy. The bis (diphenyl-arsino)methane ligand bridges an Ru-Ru bond and the monodentate arsine ligand bonds to the third Ru atom. All arsine ligands are equatorial with respect to the Ru(3) triangle. Each Ru atom carries one equatorial and two axial terminal carbonyl ligands. The three methyl-sulfanyl-substituted benzene rings make dihedral angles of 70.02 (8), 82.85 (9) and 89.49 (8) degrees with each other. The dihedral angles between the two phenyl rings are 78.25 (9) and 86.59 (9) degrees for the two diphenyl-arsino groups. In the crystal, weak inter-molecular C-H?pi inter-actions are observed. PMID- 21588549 TI - Acetato-chlorido[2,2'-(ethane-1,2-di-yl)di-1H-benzimidazole]-copper(II) monohydrate. AB - In the title complex, [Cu(CH(3)COO)Cl(C(16)H(14)N(4))].H(2)O, the Cu(II) ion is five-coordinated by two N atoms from a 2,2'-(ethane-1,2-di-yl)di-1H-benzimidazole ligand, two O atoms from a chelating acetate ligand and one terminal monodentate Cl atom in a distorted square-pyramidal geometry. In the crystal, adjacent mol ecules are linked through O-H?Cl, N-H?Cl, N-H?O and O-H?O hydrogen bonds into a three-dimensional network. PMID- 21588550 TI - Poly[[tris-(MU(2)-4,4'-bipyridine N,N'-di-oxide)hexa-nitratodieuropium(III)] dichloro-methane disolvate]. AB - The title one-dimensional coordination network, {[Eu(2)(NO(3))(6)(C(10)H(8)N(2)O(2))(3)].2CH(2)Cl(2)}(n), is isostructural with the previously reported Tb and Tl coordination networks and to its Gd analog. The Eu(III) cation is coordinated in a distorted tricapped trigonal-prismatic fashion by nine O atoms from three bridging 4,4'-bipyridine N,N'-dioxide ligands and three chelating nitrate anions. None of the atoms lie on a special position, but there is an inversion center located between the rings of one of the ligands. The network topology is ladder-like, and each ladder inter-acts with six neighboring ladders through C-H?O hydrogen bonds. The packing motif of the ladders allows for the formation of channels that run parallel to the a axis; these channels are filled with CH(2)Cl(2) solvent mol-ecules that inter-act with the ladders through C-H?O hydrogen bonds. PMID- 21588551 TI - Poly[[tris-(MU(2)-4,4'-bipyridine N,N'-di-oxide)hexa-nitratodigadolinium(III)] dichloro-methane disolvate]. AB - The title one-dimensional coordination network, {[Gd(2)(NO(3))(6)(C(10)H(8)N(2)O(2))(3)].2CH(2)Cl(2)}(n), is isostructural with the previously reported Tb and Tl coordination networks and to its Eu analog. The Gd(III) cation is coordinated in a distorted tricapped trigonal-prismatic fashion by nine O atoms from three bridging 4,4'-bipyridine N,N'-dioxide ligands and three chelating nitrate anions. None of the atoms lie on a special position, but there is an inversion center located between the rings of one of the ligands. The network topology is ladder-like, and each ladder inter-acts with six neighboring ladders through C-H?O hydrogen bonds. The packing motif of the ladders allows for the formation of channels that run parallel to the a axis; these channels are filled with CH(2)Cl(2) solvent mol-ecules that inter-act with the ladders through C-H?O hydrogen bonds. PMID- 21588552 TI - Benzoyl-dicarbon-yl(eta-inden-yl)ruthenium(II). AB - In the title mol-ecule, [Ru(C(9)H(7))(C(7)H(5)O)(CO)(2)], the dihedral angle between the mean plane of the indene ring system and the phenyl ring is 86.28 (8) degrees . The crystal structure is stabilized by weak inter-molecular C-H?O and C H?pi(arene) inter-actions. The Ru-eta(5)-cyclopentadienyl centroid bond length is 1.946 (11) A PMID- 21588553 TI - Poly[diaqua-MU(2)-oxalato-di-MU(4)-terephthalato-diytterbium(III)]. AB - The crystal structure of the title complex, [Yb(2)(C(8)H(4)O(4))(2)(C(2)O(4))(H(2)O)(2)](n), features an extended three dimensional framework made up of Yb(3+) ions coordinated by terephthalate ligands, oxalate ligands and water mol-ecules. The Yb(3+) ion has a distorted square-anti-prismatic coordination formed by one aqua ligand, two O atoms from an oxalate ligand and five O atoms belonging to four terephthalate anions. Two symmetry-independent terephthalate anions, as well as the oxalate anion, occupy special positions on inversion centers. The water molecule participates in O-H?O hydrogen bonding with both terephthalate anions. PMID- 21588554 TI - Poly[(MU(3)-4-carb-oxy-pyridine-3-carboxyl-ato-kappaN:O:O)(triphenyl-phosphine kappaP)silver(I)]. AB - In the title 1:1 silver(I) 4-carb-oxy-pyridine-3-carboxyl-ate adduct with triphenyl-phosphine, [Ag(C(7)H(4)NO(4))(C(18)H(15)P)](n), the carboxyl-ate anion bridges the phosphine-coordinated Ag atoms through its N and O atoms, generating a coordination polymer forming layers in the bc plane. The Ag atom exists in a distorted tetra-hedral geometry. The H atom of the carboxyl-ate is midway between two O atoms of the two carboxyl groups, thus forming a strong intra-molecular hydrogen bond. PMID- 21588555 TI - catena-Poly[[[aqua-pyridine-zinc(II)]-MU(2)-3,3'-(p-phenyl-ene)diacrylato] pyridine solvate]. AB - The title compound, {[Zn(C(12)H(8)O(4))(C(5)H(5)N)(H(2)O)].C(5)H(5)N}(n), has been prepared by hydro-thermal reaction. The Zn(II) atom is six-coordinated by four carboxyl-ate O atoms of two p-phenylenediacrylate (ppda(2-)) ligands, one N atom of a pyridine mol-ecule and one O atom of a water mol-ecule in a distorted octa-hedral environment. The carboxyl-ate groups of the ppda(2-) anions are in a bridging-chelating mode, in which two O atoms chelate one Zn(2+) ion. These connections result in an extended chain structure. Parallel packing of the chains forms a two-dimensional network with inter-molecular edge-to-face inter-actions. Further linkages between the layers through O-H?O hydrogen-bonding inter-actions result in a three-dimensional supra-molecular architecture with one-dimensional recta-nglar channels. PMID- 21588556 TI - (Methanol-kappaO)(2-methyl-3-nitro-benzoato-kappaO)triphenyl-tin(IV). AB - The five-coordinate Sn atom in the title compound, [Sn(C(6)H(5))(3)(C(8)H(6)NO(4))(CH(3)OH)], exists in a trans-C(3)SnO(2) trigonal bipyramidal coordination polyhedron of which the O atoms of the methanol mol ecule and carboxyl-ate group occupy the apical sites. In the crystal, adjacent mol-ecules are linked by inter-molecular O-H?O inter-actions, generating a helical hydrogen-bonded chain running along the b axis. PMID- 21588557 TI - Bis(N-sec-butyl-N-n-propyl-dithio-carbamato-kappaS,S')(1,10-phenanthroline kappaN,N')zinc(II). AB - Two independent but very similar mol-ecules comprise the asymmetric unit of the title compound, [Zn(C(8)H(16)NS(2))(2)(C(12)H(8)N(2))]. The N(2)S(4) donor set about Zn is defined by two symmetrically chelating dithio-carbamate ligands and a 1,10-phenanthroline ligand. Distortions from the ideal octa-hedral coordination geometry arise from the restricted bite angles of the ligands. The main feature of the crystal packing is the formation of tetra-meric supra-molecular aggregates mediated by C-H?S inter-actions. Disorder was found in each of the sec-butyl groups. This was resolved over two positions in each case with the major components of the disorder having site occupancies in the range 0.551 (6)-0.725 (5). PMID- 21588558 TI - Poly[[bis-[MU(2)-N,N'-bis-(2-pyridyl-meth-yl)oxalamide-kappaN,O:N',O'][MU(2)-N,N' bis-(2-pyridyl-meth-yl)oxalamide-kappaN:N']disilver(I)] bis-(trifluoro-methane sulfonate)]. AB - The asymmetric unit of the title salt, [Ag(C(14)H(14)N(4)O(2))(1.5)](CF(3)SO(3)), comprises a Ag(+) cation, three half-mol-ecules of N,N'-bis-(2-pyridyl-meth yl)oxalamide (each of which is dis-posed about a centre of inversion) and a trifluoro-methane-sulfonate anion. Distinct coordination modes are found for the bridging ligands, i.e., a MU(2),kappa(2)-bridging mode involving pyridine N atoms for one ligand, and a MU(2),kappa(4)-bridging mode, employing both pyridine N and amide O atoms for the remaining ligands. The Ag(+) cations, which are in a distorted square-pyramidal coordination, and the ligands combine to form a two dimensional array parallel to (101); these arrays are connected into a three dimensional structure by trifluoro-methane-sulfonate anions via N-H?O, C-H?O, and C-F?O inter-actions. PMID- 21588559 TI - Aqua-chlorido(2,2':6',2''-terpyrid-yl)copper(II) chloride monohydrate. AB - The title complex, [CuCl(C(15)H(11)N(3))(H(2)O)]Cl.H(2)O, is composed of a monocation that possesses mirror symmetry. The Cu(II) atom has a distorted square pyramidal geometry, being coordinated by the three N atoms of the terpyridine ligand and a Cl atom in the equatorial plane, and by a water mol-ecule O atom in the axial position. The charges are balanced by a chloride anion positionally disorded over two positions related by the mirror symmetry. The compound crystallizes as a monohydrate, with the water mol-ecule also being positionally disordered over two positions related by the mirror symmetry. In the crystal, the various components of the complex are linked via O-H?O and O-H?Cl hydrogen bonds, forming a two-dimensional network in the ab plane. There are also a number of C H?Cl and C-H?O inter-actions which stabilize the crystal structure. PMID- 21588560 TI - [2-(Diphenyl-phosphan-yl)benzene-thiol-ato-kappaP,S](pyridine-2-thiol-ato kappaS)(triphenyl-phosphine-kappaP)palladium(II). AB - In the title compound, [Pd(C(5)H(4)NS)(C(18)H(14)PS)(C(18)H(15)P)], the Pd(II) atom has a slightly distorted square-planar environment. Two coordination sites are occupied by a P,S-chelating 2-(diphenyl-phosphan-yl)benzene-thiol-ate ligand and the other two by a P atom from a triphenyl-phosphine ligand and an S atom from a pyridine-2-thiol-ate ligand, exhibiting a trans arrangement of the two P donor atoms. In the crystal structure, weak intra- and inter-molecular C-H?pi and pi-pi inter-actions are observed. The pyridyl ring is equally disordered over two positions. PMID- 21588561 TI - catena-Poly[[{2-[(2-hy-droxy-eth-yl)imino-meth-yl]-6-meth-oxy phenolato}copper(II)]-MU-thio-cyanato]. AB - In the title thio-cyanate-bridged polynuclear copper(II) complex, [Cu(C(10)H(12)NO(3))(NCS)](n), the Cu atom is five-coordinated in a square pyramidal geometry, with one phenolato O, one imino N and one hy-droxy O atom of a Schiff base ligand and one thio-cyanato N atom defining the basal plane, and with one thio-cyanato S atom occupying the apical position. In the crystal structure, pairs of adjacent complex mol-ecules are linked through inter molecular O-H?O hydrogen bonds into dimers. The dimers are further linked via Cu?S inter-actions, forming two-dimensional layers parallel to the bc plane. PMID- 21588562 TI - Bis(4,6-dimethyl-pyrimidine-2-thiol-ato)dimethyl-tin(IV). AB - The asymmetric unit of the title complex, [Sn(CH(3))(2)(C(6)H(7)N(2)S)(2)], contains two independent mol-ecules with similar configurations. In each, the Sn(IV) cation is coordinated by two methyl and two 4,6-dimethyl-pyrimidine-2 thiol-ate anions in a distorted SnS(2)C(2) tetra-hedral geometry. In the two mol ecules, the S-Sn-S bond angles are 87.70 (5) and 88.93 (4) degrees , while the C Sn-C bond angles are 125.7 (3) and 125.9 (2) degrees . Weak C-H?N hydrogen bonding is present in the crystal structure. PMID- 21588563 TI - Diaqua-bis-(5-carb-oxy-2-propyl-1H-imidazole-4-carboxyl-ato-kappaN,O)cadmium(II) 3.5-hydrate. AB - In the title complex, [Cd(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)].3.5H(2)O, the Cd(II) is coordinated by two water mol-ecules and N,O-chelated by two 5-carb-oxy-2-propyl 1H-imidazole-4-carboxyl-ate anions in a distorted octa-hedral geometry. The two imidazole rings are oriented to each other with a dihedral angle of 75.1 (2) degrees . Strong O-H?O hydrogen bonds between protonated and deprotonated carboxyl-ate groups occur in the mol-ecular structure. In the crystal structure extensive O-H?O and N-H?O hydrogen bonds help to stabilize the three-dimensional supra-molecular framework. The propyl groups of anions are disordered over two sites with refined occupancies of 0.768 (6):0.232 (6) and 0.642 (8):0.358 (8). PMID- 21588564 TI - {6,6'-Dimeth-oxy-2,2'-[(cyclo-hexane-1,2-di-yl)bis-(nitriliomethyl idyne)]diphenolato}trinitratolanthanum(III) methanol monosolvate. AB - In the title mononuclear complex, [La(NO(3))(3)(C(22)H(26)N(2)O(4))].CH(3)OH, the La(III) ion is coordinated by three bidentate nitrate counter-ions and one zwitterionic 6,6'-dimeth-oxy-2,2'-[(cyclo-hexane-1,2- di-yl)bis-(nitriliomethyl idyne)]diphenolate ligand through two phenolate and two meth-oxy O atoms, while the protonated N atoms remain uncoordinated. H atoms located on the two N atoms are involved in intra-molecular hydrogen bonds with the deprotonated phenol O atoms, indicating that proton migration occurs during the lanthanum complexation. PMID- 21588565 TI - trans-Diaqua-bis-[5-carb-oxy-4-carboxyl-ato-2-(4-pyridinio)-1H-imidazol-1-ido kappaN,O]zinc(II). AB - In the title complex, [Zn(C(10)H(6)N(3)O(4))(2)(H(2)O)(2)], the Zn(II) atom is located on a twofold rotation axis and is coordinated by two trans-positioned N,O bidentate and zwitterionic 5-carb-oxy-4-carboxyl-ato-2-(4-pyridinio)-1H-imidazol 1-ide (H(2)PIDC(-)) ligands and two water mol-ecules, defining a distorted octa hedral environment. The complete solid-state structure can be described as a three-dimensional supra-molecular framework, stabilized by extensive hydrogen bonding inter-actions involving the coordinated water mol-ecules, uncoordin-ated imidazole N atom, protonated pyridine N and carboxyl-ate O atoms of the H(2)PIDC( ) ligands. PMID- 21588566 TI - (tert-Butyl-imido)bis-(eta-cyclo-penta-dien-yl)pyridine-zirconium(IV). AB - The title compound, [Zr(C(5)H(5))(2)(C(4)H(9)N)(C(5)H(5)N)], was obtained from the reaction of (C(5)H(5))(2)Zr(py)(eta(2)-Me(3)SiC(2)SiMe(3)) (py is pyridine) and (t)BuN=C=N(t)Bu alongside the formation of (C(5)H(5))(2)Zr(CN(t)Bu)(eta(2) Me(3)SiC(2)SiMe(3)). The zirconium atom is coordinated in a distorted tetra hedral geometry by two cyclo-penta-dienyl ligands, a pyridine ligand, and a tert butyl-imido ligand via a Zr=N double bond. The tert-butyl group is disordered over two positions in a 0.634 (5):0.366 (5) ratio. PMID- 21588567 TI - Tetra-MU-acetato-kappaO:O'-bis-[(N-ethyl-pyrimidin-2-amine)-copper(II)](Cu-Cu). AB - In the centrosymmetric title mol-ecule, [Cu(2)(CH(3)COO)(4)(C(6)H(9)N(3))(2)], each of the four acetate groups bridges a pair of Cu(II) atoms [Cu-Cu = 2.6540 (4) A]. The distorted octa-hedral geometry of the metal atom is completed by an N donor atom of the N-ethyl-pyrimidin-2-amine ligand: an intra-molecular N-H?O hydrogen links its N-H group to an acetate carboxyl-ate O atom. In the crystal, C H?O inter-actions link the mol-ecules into a supra-molecular chain along the b axis. PMID- 21588568 TI - Bis{1-[(o-tol-yl)imino-meth-yl]-2-naphthol-ato}copper(II). AB - In the title complex, [Cu(C(18)H(14)NO)(2)], the Cu(II) ion lies on a crystallographic inversion centre and is bonded to the O- and N-donor atoms of the two bidentate chelate 1-[(o-tol-yl)imino-meth-yl]-2-naphtho-late ligands in a trans arrangement. The distorted square-planar geometry about Cu(II) has normal dimensions, with Cu-O = 1.8881 (15) A and Cu-N = 1.9804 (17) A. PMID- 21588569 TI - 2-Amino-5-methyl-pyridinium 2-carb-oxy-benzoate. AB - In the title salt, C(6)H(9)N(2) (+).C(8)H(5)O(4) (-), the hydrogen phthalate anion is essentially planar, with a maximum deviation of 0.011 (2) A. In the crystal structure, the protonated N atom of the pyridine ring and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. In the hydrogen phthalate anion, there is a very strong, almost symmetric, intra molecular O-H?O hydrogen bond, generating an S(7) motif [O?O = 2.382 (3) A]. Furthermore, these two molecular motif rings are connected by a bifurcated N H?(O,O) hydrogen-bonded motif R(1) (2)(4), forming a supra-molecular ribbon along the b axis. The crystal structure is further stabilized by pi-pi inter-actions between the cations and anions [centroid-centroid distance = 3.6999 (10) A]. PMID- 21588570 TI - 1,3-Bis(2,6-diisopropyl-phen-yl)imidazolidin-2-yl-idene. AB - The title compound, C(27)H(38)N(2), is the first reported free imidazolidin-2-yl idene carbene with 2,6-diisopropyl-phenyl groups in the 1,3-positions. The five membered ring adopts a twisted conformation and the dihedral angle between the aromatic rings is 48.81 (6) degrees . Both isopropyl groups attached to one of the benzene rings are disordered over two sets of sites in 0.74 (2):0.26 (2) and 0.599 (8):0.401 (8) ratios. PMID- 21588571 TI - 2,2'-Bi-1,3,4-thia-diazole-5,5'-diamine tetra-hydrate. AB - In the title compound, C(4)H(4)N(6)S(2).4H(2)O, the complete organic mol-ecule is generated by crystallographic twofold symmetry and the dihedral angle between the aromatic rings is 10.24 (3) degrees . In the crystal, inter-molecular N-H?N, N H?O, O-H?N and O-H?O hydrogen bonds and aromatic pi-pi stacking inter-actions [centroid-centroid separations = 3.530 (3) and 3.600 (3) A] are observed. PMID- 21588572 TI - 3,10-C-meso-3,5,7,7,10,12,14,14-Octa-methyl-4,11-diaza-1,8-diazo-niacyclo-tetra decane bis-(perchlorate). AB - The structure determination of the title salt, C(18)H(42)N(4) (2+).2ClO(4) (-), reveals that protonation has occurred at diagonally opposite amine N atoms. Intra molecular N-H?N hydrogen bonds stabilize the conformation of the dication. In the crystal, the dications are bridged by perchlorate ions via N-H?O hydrogen bonds into supra-molecular chains propagating along the c axis and weak C-H?O inter actions cross-link the chains. PMID- 21588573 TI - 4-{3-[(2-Isopropyl-5-methyl-phen-oxy)meth-yl]-7H-1,2,4-triazolo[3,4-b][1,3,4]thia diazin-6-yl}-3-(p-tol-yl)sydnone. AB - In the title triazolothia-diazin compound, C(24)H(24)N(6)O(3)S (systematic name: 4-{3-[(2-isopropyl-5-methyl-phen-oxy)meth-yl]-7H-1,2,4-triazolo[3,4-b][1,3,4]thia diazin-6-yl}-3-(4-methyl-phen-yl)-1,2,3-oxadiazol-3-ium-5-olate), an intra molecular C-H?O hydrogen bond generates an S(6) ring motif. The two terminal methyl groups of the isopropyl unit are disordered over two sets of positions in a 0.715 (4):0.285 (4) ratio. The mean planes formed through the major and minor disordered isopropyl units are inclined at inter-planar angles of 73.1 (4) and 86.6 (8) degrees , respectively, with the attached phenyl ring. The 3,6-dihydro 1,3,4-thia-diazine ring adopts a twist-boat conformation. The inter-planar angle formed between 1,2,3-oxadiazole and 1,2,4-triazole rings is 18.80 (11) degrees . In the crystal, neighbouring mol-ecules are linked into sheets lying parallel to the bc plane by C-H?N hydrogen bonds. Weak inter-molecular pi-pi inter-actions [centroid-centroid distances = 3.2935 (11) and 3.5590 (12) A] further stabilize the crystal structure. PMID- 21588574 TI - 2-Amino-5-bromo-pyridinium 3-carb-oxy-prop-2-enoate. AB - In the title salt, C(5)H(6)BrN(2) (+).C(4)H(3)O(4) (-), the 2-amino-5-bromo pyridinium cation and hydrogen maleate anion are planar, with maximum deviations from their mean planes of 0.016 (1) and 0.039 (1) A, respectively. An intra molecular O-H?O hydrogen bond generates an S(7) ring motif in the anion. In the crystal, the protonated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The motifs are linked into a two dimensional network parallel to (011) by N-H?O and C-H?O hydrogen bonds. PMID- 21588575 TI - 3,3'-Dimethyl-1,1'-(methyl-enedi-p-phenyl-ene)diimidazolium bis-(hexa-fluoro phosphate). AB - The title N-heterocyclic carbene compound, C(21)H(22)N(4) (2+).2PF(6) (-), crystallizes as an inversion twin. There are two independent N-heterocyclic carbene dications (A and B) and four independent hexa-fluoro-phosphate anions in the asymmetric unit. The cations are L-shaped with the benzene rings being inclined to one another by 88.82 (16) degrees in cation A and 87.03 (16) degrees in cation B. The imidazole rings make dihedral angles of 35.7 (2) and 32.83 (18) degrees with the attached benzene rings in cation A, and 30.14 (19) and 31.96 (18) degrees in cation B. In the crystal, the cations are linked via C-H?F hydrogen bonds, forming a three-dimensional network. pi-pi inter-actions involving the benzene and imidazole rings [centroid-centroid distances = 3.602 (2) and 3.723 (2) A] and C-H?pi inter-actions are also present. PMID- 21588576 TI - 2-Hydroxy-3-methoxybenzaldehyde 2,4-dinitrophenylhydrazone pyridine monosolvate. AB - The Schiff base molecule of the title compound, C(14)H(12)N(4)O(6).C(5)H(5)N, was obtained from the condensation reaction of 2-hy-droxy-3-meth-oxy-benzaldehyde and 2,4-dinitro-phenyl-hydrazine. The C=N bond of the Schiff base has a trans arrangement and the dihedral angle between the two benzene rings is 3.49 (10) degrees . An intra-molecular N-H?O hydrogen bond generates an S(6) ring. In the crystal, O-H?O hydrogen bonds link the Schiff base mol-ecules. PMID- 21588577 TI - 3-Eth-oxy-2-hy-droxy-benzaldehyde 2,4-di-nitro-phenylhydrazone N,N-di-methyl formamide monosolvate. AB - The Schiff base of the title compound, C(15)H(14)N(4)O(6).C(3)H(7)NO, was obtained from the condensation reaction of 3-eth-oxy-2-hy-droxy-benzaldehyde and 2,4-dinitro-phenyl-hydrazine. The dihedral angle between the benzene rings is 3.05 (10) degrees and intra-molecular N-H?O and O-H?O hydrogen bonds generate S(6) and S(5) ring motifs, respectively. In the crystal, the Schiff base and dimethyl-formamide solvent mol-ecules are linked by an O-H?O hydrogen bond. PMID- 21588578 TI - Diisopropyl pyrazine-2,5-dicarboxyl-ate. AB - The mol-ecule of the title compound, C(12)H(16)N(2)O(4), is located on an inversion center. The carboxyl-ate groups are twisted slightly with respect to the pyrazine ring, making a dihedral angle of 6.4 (3) degrees . PMID- 21588579 TI - Tris(2,4-di-tert-butyl-phen-yl) phosphate. AB - The title compound, C(42)H(63)O(4)P, was isolated from the leaves of Vitex negundo. Two of the tert-butyl groups are disordered over two orientations with occupancy ratios of 0.57 (1):0.43 (1) and 0.67 (1):0.33 (1). Several intra molecular C-H?O inter-actions are observed in the mol-ecular structure. PMID- 21588580 TI - Biphenyl-4,4'-dicarb-oxy-lic acid N,N-dimethyl-formamide monosolvate. AB - Biphenyl-4,4'-dicarb-oxy-lic acid was recrystallized from N,N-dimethyl-formamide (DMF) yielding the title compound, C(14)H(10)O(4).2C(3)H(7)NO. The acid mol ecules are located on crystallographic centres of inversion and are hydrogen bonded to DMF mol-ecules. These hydrogen-bonded units form infinite chains although there is no inter-action between the methyl groups of neighboring DMF mol-ecules. PMID- 21588581 TI - 2-Amino-pyrimidinium 4-hy-droxy-pyridinium-2,6-dicarboxyl-ate monohydrate. AB - In the crystal structure of the title compound, C(4)H(6)N(3) (+).C(7)H(4)NO(5) ( ).H(2)O, inter-molecular N-H?N, N-H?O and O-H?O hydrogen bonds link the cations and anions into almost planar sheets parallel to (102). These hydrogen-bonded sheets are packed into the crystal with the formation of centrosymmetric voids of 68 A(3), which are filled by the water mol-ecules, each of which is disordered over four positions. PMID- 21588582 TI - 2-Hy-droxy-4-meth-oxy-benzaldehyde thio-semicarbazone. AB - The title Schiff base compound, C(9)H(11)N(3)O(2)S, was prepared by the reaction of equimolar quanti-ties of 2-hy-droxy-4-meth-oxy-benzaldehyde with thio semicarbazide in methanol. The mol-ecule adopts a trans configuration with respect to the azo-methine group and an intra-molecular O-H?N hydrogen bond generates an S(6) ring. In the crystal structure, mol-ecules are linked through inter-molecular N-H?O and N-H?S hydrogen bonds, forming a three-dimensional network. PMID- 21588583 TI - 2-(Pyrimidin-2-yl-oxy)phenol. AB - The pyrimidine and benzene rings in the title compound, C(10)H(8)N(2)O(2), form a dihedral angle of 71.03 (7) degrees , with the roughly orthogonal benzene ring being folded towards one of the pyrimidine N atoms. In the crystal, pairs of O H?N hydrogen bonds connect mol-ecules related by twofold symmetry into dimeric aggregates. These associate into a supra-molecular chain propagating along the b axis by way of C-H?pi contacts. The chains are cross-linked by pi-pi inter actions that occur between pyrimidine rings [ring centroid-centroid distances = 3.5393 (9) and 3.5697 (9) A]. PMID- 21588584 TI - 2-Ethyl-sulfanyl-7-fluoro-3-(1H-1,2,4-triazol-1-yl)-4H-thio-chromen-4-one. AB - The asymmetric unit of the title compound, C(13)H(10)FN(3)OS(2), contains two independent mol-ecules, which differ slightly in the relative orientations of the triazole and ethyl-sulfanyl groups with respect to the planar thio-chromen-4-one frameworks. The dihedral angles between the mean planes of the triazole groups and the corresponding six-membered C(5)OS rings are 56.8 (1) and 52.9 (1) degrees , while the S-C-S-C dihedral angles are -11.7 (2) and -16.3 (2) degrees . In the crystal structure, inter-molecular C-H?O and C-H?N hydrogen bonds link the mol ecules in a stacked arrangement along the a axis. A weak intramolecular C-H?.O interaction results in the formation of a non-planar five-membered ring. PMID- 21588585 TI - Piperazine-1,4-diium bis-(perchlorate) dihydrate. AB - The asymmetric unit of the title compound, C(4)H(12)N(2) (2+).2ClO(4) (-).2H(2)O, contains half of a piperazinediium cation, one perchlorate anion and one water mol-ecule. The diprotonated piperazine ring, which is completed by crystallographic inversion symmetry, adopts a chair conformation. In the crystal structure, the cations and anions are linked by inter-molecular N-H?O and O-H?O hydrogen bonds into a three-dimensional network. PMID- 21588586 TI - 2-(5-Bromo-pent-yl)-4-chloro-5-[2-(4-meth-oxy-phen-yl)ethyl-amino]-pyridazin 3(2H)-one. AB - The asymmetric unit of the title compound, C(18)H(23)BrClN(3)O(2), consists of two mol-ecules which exhibit different conformations of the pentyl chains [C-C-C C torsion angles of -60.4 (4) and 175.8 (3) degrees ]. The crysal packing exhibits a chain structure, generated through the O atom of the pyridazinone forming a hydrogen bond with the N-H group of an adjacent mol-ecule. PMID- 21588587 TI - (E)-1-(2,2-Dimeth-oxy-eth-yl)-2-(nitro-methyl-idene)imidazolidine. AB - In the title compound, C(8)H(15)N(3)O(4), the 2-(nitro-methyl-ene)imidazolidine fragment is close to being planar (r.m.s. deviation = 0.027 A), which may be correlated with delocalization of the electrons and the effect of the strongly electron-withdrawing NO(2) group. An intra-molecular N-H?O link generates an S(6) ring. The same H atom also forms a weak inter-molecular N-H?O hydrogen bond, which results in C(7) chains propagating in [010]. PMID- 21588588 TI - (E)-4-Bromo-N-(2,3-dimeth-oxy-benzyl-idene)aniline. AB - The title Schiff base compound, C(15)H(14)BrNO(2), was prepared by the condensation of 2,3-dimeth-oxy-benzaldehyde with 4-bromo-aniline. It adopts an E configuration with respect to the C=N bond. The dihedral angle between the two aromatic rings is 56.79 (8) degrees . Weak C-H?O and C--H?pi bonds can be found in the crystal structure. PMID- 21588589 TI - 5-tert-Butyl-2-hy-droxy-3-(2-thien-yl)benzaldehyde. AB - In the crystal structure of the title compound, C(15)H(16)O(2)S, the thio-phene ring is essentially planar (r.m.s. deviation = 0.006 A for all non-H atoms) and roughly coplanar with the benzene ring, the dihedral angle between the mean planes of the rings being 4.35 (8) degrees . An intra-molecular O-H?O hydrogen bond is observed between the OH group and the aldehyde O atom. PMID- 21588590 TI - 4,5-Dimethyl-1,2-diphenyl-1H-imidazole monohydrate. AB - In the title compound, C(17)H(16)N(2).H(2)O, the imidazole ring is essentially planar [maximum deviation = 0.0037 (7) A]. The imidazole ring makes dihedral angles of 80.74 (7) and 41.62 (7) degrees with the phenyl rings attached to the N and C atoms, respectively. The dihedral angle between the two phenyl rings is 75.83 (8) degrees . Inter-molecular O-H?N and O-H?O hydrogen bonds are found in the crystal structure. PMID- 21588591 TI - N-(4-Chloro-benzyl-idene)-4-nitro-benzene-1,2-diamine. AB - In the title compound, C(13)H(10)ClN(3)O(2), the dihedral angle between the two benzene rings is 3.61 (6) degrees . In the crystal structure, mol-ecules are linked by weak inter-molecular C-H?O hydrogen bonds, forming layers parallel to the bc plane. Short inter-molecular Cl?Cl contacts [3.491 (1) A] are also observed. PMID- 21588592 TI - 1-(4-Bromo-3-chloro-phen-yl)-3-meth-oxy-3-methyl-urea (chlorbromuron). AB - In the title urea-based herbicide, C(9)H(10)BrClN(2)O(2), there exist multiple inter- and intra-molecular inter-actions. Most notably, the intra-molecular hydrogen bond between the urea carbonyl O atom and an aromatic H atom affects the planarity and torsion angles of the mol-ecule by restricting rotations about the Ar-secondary amine N and the secondary amine N and the carbonyl C. The two N atoms in the urea fragment are in different environments. One is planar; the other, pseudo-C(3v). It is likely that the different nitro-gen-atom geometries and the restricted rotations within the mol-ecule impact the bioactivity of chlorbromuron. PMID- 21588593 TI - 1,4,5,8-Tetra-isopropyl-anthracene. AB - The mol-ecules of the title compound, C(26)H(34), possess crystallographically imposed inversion symmetry. The anthracene ring system is planar within 0.038 (1) A. The two methyl groups in each independent isopropyl group are oriented on either side of the anthracene plane. In the crystal structure, the mol-ecules adopt a herringbone-like arrangement without pi-pi stacking. PMID- 21588594 TI - Redetermination of 4-(dimethyl-amino)-pyridinium tribromide. AB - In the title salt, C(7)H(11)N(2) (+).Br(3) (-), the essentially planar cation (r.m.s. deviation = 0.006 A) forms an N-H?Br hydrogen bond to one of the Br atoms of the almost linear anion [Br-Br-Br = 179.31 (2) degrees ]. The crystal studied was found to be a racemic twin. The whole-mol-ecule disorder of the cation and anion about a twofold rotation axis described earlier [Ng (2009). Acta Cryst. E65, o1276] is an artifact of halving one of the axes of the ortho-rhom-bic unit cell. PMID- 21588595 TI - 5-Ethyl-5-methyl-4-phenyl-5H-1,2,4-triazol-3(4H)-thione. AB - The five-membered ring of the title compound Delta(1)-1,2,4-triazoline-5-thione, C(11)H(13)N(3)S, is almost planar (r.m.s. deviation = 0.009 A); the phenyl ring is aligned at 84.6 (2) degrees with respect to the five-membered ring. The crystal studied was a racemic twin with an approximate 20% minor twin component. Weak inter-molecular C-H?N hydrogen bonding is present in the crystal structure. PMID- 21588596 TI - 2-Anilino-3-(2-hy-droxy-phen-yl)quinazolin-4(3H)-one methanol monosolvate. AB - In the title compound, C(20)H(15)N(3)O(2).CH(3)OH, the quinazolin-one ring system is approximately planar, the dihedral angle between the pyrimidinone ring and the adjacent benzene ring being 1.73 (6) degrees . The pyrimidinone ring makes dihedral angles of 77.58 (6) and 29.62 (6) degrees , respectively, with the hy droxy-phenyl and phenyl rings. In the crystal, the components are connected by O H?O and C-H?O hydrogen bonds, forming a zigzag chain along the b axis. PMID- 21588597 TI - Paraherquamide e. AB - In the title compound, C(28)H(35)N(3)O(4), also known as 14-de-oxy-paraherquamide A,the two pyrrolidine rings adopt envelope conformations. The piperazine ring of the diaza-bicyclo-[2.2.2]octan-3-one unit adopts a boat conformation whereas the two piperidine rings are in distorted boat conformations. Intra-molecular C-H?O hydrogen bonds are observed. In the crystal, the mol-ecules are linked into chains along the b axis by inter-molecular N-H?O hydrogen bonds. PMID- 21588598 TI - Ethyl 1-tert-butyl-5-phenyl-1H-pyrazole-4-carboxyl-ate. AB - In the title compound, C(16)H(20)N(2)O(2), the pyrazole ring is essentially planar [maximum deviation = 0.008 (2) A] and is inclined at an angle of 82.82 (10) degrees with respect to the phenyl ring. The crystal packing is consolidated by pairs of inter-molecular C-H?O hydrogen bonds, which link the mol ecules into centrosymmetric dimers stacked along the a axis. PMID- 21588599 TI - 1,2-Bis{2-[(1,3-benzothia-zol-2-yl)sulfanylmeth-yl]phen-oxy}ethane. AB - The mol-ecule of the title compound, C(30)H(24)N(2)O(2)S(4), adopts a Z-shaped conformation. The terminal benzothia-zole ring systems are oriented at a dihedral angle of 60.81 (8) degrees , while the central benzene rings are twisted to each other by a dihedral angle of 13.56 (14) degrees . Weak inter-molecular C-H?pi inter-actions are present in the crystal structure. PMID- 21588600 TI - (E)-1-(2,4,6-Trihy-droxy-benzyl-idene)-4-ethyl-thio-semicarbazide dihydrate. AB - In the title mol-ecule, C(10)H(13)N(3)O(3)S.2H(2)O, the thio-semi-carbazide =N-NH C(=S)-NH- fragment [torsion angle = 0.2 (1) degrees ] is nearly coplanar with the benzene ring [dihedral angle = 2.4 (1) degrees ]. The benzene ring and semicarbazide moiety are located on opposite sites of the C=N bond, showing an E configuration. The hy-droxy, imino and water H atoms are engaged in extensive hydrogen bonding, forming a three-dimensional network. PMID- 21588601 TI - Acridinium 3-carb-oxy-pyrazine-2-carboxyl-ate. AB - The title ion pair, C(13)H(10)N(+).C(6)H(3)N(2)O(4) (-), contains a protonated acridine cation and a 3-carb-oxy-pyrazine-2-carboxyl-ate monoanion, which are linked together through O-H?O, N-H?O and weak C-H?O hydrogen bonds. These hydrogen bonds generate a C(10) chain graph-set motif. The crystal structure is further stabilized by extensive pi-pi stacking inter-actions between nearly parallel [dihedral angle = 1.21(2) degrees ] acridine systems. The shortest distance between the centroids of the six-membered rings within the cations is 3.6315 (8) A. In addition, C-H?pi edge-to-face inter-actions are present. PMID- 21588602 TI - (Z)-1-Acetyl-3-[2-oxo-1-phenyl-2-(3-pyrid-yl)ethyl-idene]indolin-2-one. AB - The title compound, C(23)H(16)N(2)O(3), exists in a Z configuration with respect to the acyclic C=C bond. The pyridine and phenyl rings are oriented at dihedral angles of 72.97 (4) and 45.05 (4) degrees , respectively, with respect to the almost planar indoline ring system [maximum deviation 0.080 (1) A]. The pyridine and phenyl rings are oriented almost perpendicular to each other [dihedral angle 88.93 (5) degrees ]. In the crystal, mol-ecules are inter-connected into a three dimensional framework via inter-molecular C-H?O and C-H?N hydrogen bonds and weak pi-pi inter-actions [centroid-centroid distance = 3.681 (1) A]. PMID- 21588603 TI - 10-(2-Eth-oxy-1,3-thia-zol-5-yl)-10-hy-droxy-phenanthren-9(10H)-one. AB - In the title compound, C(19)H(15)NO(3)S, the dihydro-phenanthrene unit is not planar, its central ring being distorted towards a sofa conformation. The essentially planar thia-zole ring [maximum deviation = 0.005 (1) A] is inclined at a dihedral angle of 85.29 (5) degrees with respect to the mean plane formed through the dihydro-phenanthrene unit. In the crystal structure, pairs of inter molecular C-H?O hydrogen bonds link adjacent mol-ecules into inversion dimers. Inter-molecular O-H?N hydrogen bonds further inter-connect these dimers into chains along the a axis. The crystal structure is further stabilized by weak inter-molecular C-H?pi inter-actions involving the thia-zole ring. PMID- 21588604 TI - 3,5-Bis(4-meth-oxy-phen-yl)-4H-1,2,4-triazol-4-amine. AB - The title compound, C(16)H(16)N(4)O(2), crystallizes with two mol-ecules in the asymmetric unit, which are related by a non-crystallographic centre of inversion. The phenyl-ene rings are twisted out of the mean plane of the triazole ring by 19.3 (1) and 21.4 (1) degrees for one independent mol-ecule and by 16.3 (1) and 18.1 (1) degrees for the other mol-ecule. In the crystal, adjacent mol-ecules are linked by amine-triazole N-H?N hydrogen bonds, forming chains running along the a axis. PMID- 21588605 TI - Nicotinaldehyde [2,8-bis-(trifluoro-meth-yl)quinolin-4-yl]hydrazone monohydrate. AB - In the title compound, C(17)H(10)F(6)N(4).H(2)O, the pyridine ring is not coplanar with the quinoline ring system; the dihedral angle between the two planes is 21.3 (1) degrees . One of the trifluoro-methyl group is disordered over two orientations with occupancies of 0.70 (1) and 0.30 (1). The water mol-ecule is disordered over two positions with occupancies of 0.76 (1) and 0.24 (1). In the crystal, the water mol-ecule is linked to the main mol-ecule via N-H?O and C H?O hydrogen bonds, and inversion-related pairs are linked via O-H?N hydrogen bonds. In addition, a weak pi-pi inter-action is observed between the pyridine ring and the pyridine ring of the quinoline unit, with a centroid-centroid distance of 3.650 (2) A. PMID- 21588606 TI - l-Asparagine-l-tartaric acid (1/1). AB - In the title compound, C(4)H(8)N(2)O(3).C(4)H(6)O(6), the amino acid mol-ecule exists as a zwitterion and the carb-oxy-lic acid in an un-ionized state. The tartaric acid mol-ecules are linked into layers parallel to the ab plane by O-H?O hydrogen bonds. The amino acid mol-ecules are also linked into layers parallel to the ab plane by N-H?O and C-H?O hydrogen bonds. The alternating tartaric acid and amino acid layers are linked into a three-dimensional framework by N-H?O and O H?O hydrogen bonds. PMID- 21588607 TI - Ethyl 2-methyl-5-oxo-4-(3,4,5-trimeth-oxy-phen-yl)-1,4,5,6,7,8-hexa-hydro quinoline-3-carboxyl-ate. AB - In the mol-ecular structure of the title compound, C(22)H(27)NO(6), the dihydro pyridine ring adopts a flattened boat conformation while the cyclo-hexenone ring is in an envelope conformation. In the crystal, mol-ecules stack parallel to the crystallographic a axis linked by inter-molecular N-H?O and C-H?O hydrogen bonds. PMID- 21588608 TI - N-(4-Chloro-benzo-yl)-N'-(3-fluoro-phen-yl)thio-urea. AB - In the title compound, C(14)H(10)ClFN(2)OS, the mol-ecule adopts a trans-cis geometry of the thio-urea unit. The dihedral angles between the benzene rings is 34.47 (7) degrees . The crystal packing features inter-molecular N-H?S and C-H?O hydrogen bonds, forming a chain along the b axis. A short C-H?S intramolecular contact is also observed. PMID- 21588609 TI - (E)-Methyl 2-(3-cinnamoyl-thio-ureido)acetate. AB - In the title compound, C(13)H(14)N(2)O(3)S, the methyl 2-(3-formyl-thio ureido)acetate fragment and the phenyl ring adopt an E configuration. The mol ecule exhibits an intra-molecular N-H?O hydrogen bond, which completes a six membered ring. The crystal packing is stabilized by inter-molecular N-H?S contacts, generating a two-dimensional hydrogen-bonding network. PMID- 21588610 TI - 2-(2,3-Dioxoindolin-1-yl)ethyl 4-(4-nitro-phen-yl)piperazine-1-carbodithio-ate. AB - In the title compound, C(21)H(20)N(4)O(4)S(2, )the piperazine ring adopts a chair conformation. The 1-ethyl-indoline-2,3-dione system links to one N atom of the piperazine ring via a carbodithio-ate group. The indoline-2,3-dione ring and the nitro-benzene ring subtend adihedral angle of 37.27 (7) degrees . In the crystal structure, weak C-H?O and pi-pi stacking inter-actions [centroid-centroid distances = 3.534 (5) and 3.797 (5) A] may help to establish the packing. PMID- 21588611 TI - 4-Phenyl-piperazin-1-ium dihydrogen phosphate. AB - The title compound, C(10)H(15)N(2) (+).H(2)PO(4) (-), is built up from 4-phenyl piperazin-1-ium cations and dihydrogen phosphate anions. The inter-connection between two adjacent anions is assured by two strong O-H?O hydrogen bonds, which lead to the formation of infinite wave-like chains which spread along the a axis. The organic cations connect these chains via N-H?O hydrogen bonds. The crystal cohesion and stability are ensured by electrostatic and van der Waals inter actions which, together with N-H?O and O-H?O hydrogen bonds, build up a two dimensional network. PMID- 21588612 TI - 2-Amino-5-bromo-pyridinium 6-oxo-1,6-dihydro-pyridine-2-carboxyl-ate monohydrate. AB - In the crystal structure of the title salt, C(5)H(6)BrN(2) (+).C(6)H(4)NO(3) ( ).H(2)O, the protonated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The ion pairs are further connected via O-H?O, N-H?O, N-H?Br and C-H?O hydrogen bonds, forming a two-dimensional network parallel to the bc plane. The water mol-ecules self-assemble through O-H?O hydrogen bonds, forming one-dimensional supra-molecular chains along the a axis, with graph-set notation C(2) (2)(4). PMID- 21588613 TI - 1-sec-Butyl-3-[hy-droxy(1-methyl-1H-indol-3-yl)methyl-idene]pyrrolidine-2,4 dione. AB - In the title compound, C(18)H(20)N(2)O(3), the dihedral angle between the indole ring system (r.m.s. deviation = 0.018 A) and the hy-droxy-methyl-enepyrrolidine 2,4-dione plane (r.m.s. deviation = 0.036 A) is 9.87 (7) degrees . The keto and enol groups are involved in an intra-molecular O-H?O hydrogen bond. An intra molecular C-H?O inter-action also occurs. The sec-butyl group is disordered over two orientations corresponding to an approximate 180 degrees rotation about the N-C bond, with occupancies of 0.670 (6) and 0.330 (6). In the crystal, mol-ecules are linked into chains along the c axis by C-H?O hydrogen bonds. PMID- 21588614 TI - 1,2-Dimeth-oxy-3-[(E)-2-nitro-ethen-yl]benzene. AB - The title compound, C(10)H(11)NO(4), was synthesized via condensation of 2,3 dimeth-oxy-benzaldehyde with nitro-methane using microwave irradiation without solvent. The H atoms of the -CH=CH- group are in a trans configuration. The dihedral angle between the mean planes of the benzene ring and the nitro-alkenyl group is 23.90 (6) degrees . PMID- 21588615 TI - Bis(4-amino-pyridinium) sulfate monohydrate. AB - The asymmetric unit of the title compound, 2C(5)H(7)N(2) (+).SO(4) (2-).H(2)O, contains two 4-amino-pyridinium cations (A and B), a sulfate dianion and a water mol-ecule. One of the 4-amino-pyridinium cations (B) is disordered over two orientations with refined site occupancies of 0.568 (4) and 0.432 (4). The non-H atoms of the 4-amino-pyridinium cations are essentially coplanar, with a maximum deviation of 0.055 (1) A (in cation A), 0.022 (3) A (for the major component in cation B) and 0.009 (3) A (for the minor component in cation B). In the crystal, the sulfate O atoms link the 4-amino-pyridinium cations and water mol-ecules into a three-dimensional network via inter-molecular O-H?O, N-H?O and C-H?O hydrogen bonds. The crystal structure is further consolidated by N-H?O(water) and C H?O(water) hydrogen bonds. PMID- 21588616 TI - Bis(2-amino-5-bromo-pyridinium) fumarate dihydrate. AB - In the title compound, 2C(5)H(6)BrN(2) (+).C(4)H(2)O(4) (2-).2H(2)O, the complete fumarate dianion is generated by crystallographic inversion symmetry. The cation is approximately planar, with a maximum deviation of 0.036 (1) A. In the anion, the carboxyl-ate group is twisted slightly away from the attached plane; the dihedral angle between carboxyl-ate and (E)-but-2-ene planes is 6.11 (14) degrees . In the crystal, the carboxyl-ate O atoms form bifurcated (N-H?O and C-H?O) and N-H?O hydrogen bonds with the cations. The crystal packing is stabilized by R(2) (2)(8) ring motifs which are generated by pairs of N-H?O hydrogen bonds. The crystal structure is further consolidated by water mol-ecules via O(water)-H?O and N-H?O(water) hydrogen bonds. The components are linked by these inter-actions into three-dimensional network. PMID- 21588617 TI - 8-Hy-droxy-quinolinium 2-carb-oxy-acetate. AB - In the title compound, C(9)H(8)NO(+).C(3)H(3)O(4) (-), the cation and anion are each essentially planar, with maximum deviations of 0.043 (1) and 0.060 (1) A, respectively. The dihedral angle between these two planes is 2.20 (4) degrees . The conformation of the anion is stabilized by an intra-molecular O-H?O hydrogen bond, which forms an S(6) ring motif. The hy-droxy group of the oxine unit makes a hydrogen bond with the one of the O atoms of the carboxyl-ate group of the 2 carb-oxy-acetate anion. Two other carboxyl-ate O atoms form R(2) (2)(7) ring motifs via inter-molecular C-H?O and N-H?O hydrogen bonds. The crystal structure is consolidated by weak inter-molecular C-H?O inter-actions, which link the cations and anions into a three-dimensional network. PMID- 21588618 TI - 2-Amino-5-methyl-pyridinium 2-hy-droxy-benzoate. AB - In the title compound, C(6)H(9)N(2) (+).C(7)H(5)O(3) (-), the protonated 2-amino 5-methyl-pyridinium cation and the 2-hy-droxy-benzoate anion are both essentially planar, with maximum deviations of 0.026 (2) and 0.034 (1) A, respectively. The anion is stabilized by an intra-molecular O-H?O hydrogen bond, which forms an S(6) ring motif. In the solid state, the anions are linked to the cations via pairs of inter-molecular N-H?O hydrogen bonds forming R(2) (2)(8) ring motifs. The crystal structure is further stabilized by N-H?O and C-H?O inter-actions which link the mol-ecules into chains along [010]. A pi-pi stacking inter-action [centroid-centroid-distance = 3.740 (2) A] is also observed. PMID- 21588619 TI - 1'-Acetyl-3-phenyl-6-oxa-4-thia-2-aza-spiro-[bicyclo-[3.2.0]hept-2-ene-7,3' indolin]-2'-one. AB - In the title indoline compound, C(19)H(14)N(2)O(3)S, the pyrrolidine ring adopts an envelope conformation with the four-connected (spiro) C atom as the flap [displacement = 0.148 (3) A]. The mean plane formed through the indoline unit is inclined at dihedral angles of 89.92 (16) and 59.54 (12) degrees with the thia zole and phenyl rings, respectively; the dihedral angle between the latter rings is 9.55 (14) degrees . In the crystal, pairs of inter-molecular C-H?O hydrogen bonds link neighbouring mol-ecules into inversion dimers, producing R(2) (2)(6) hydrogen-bond ring motifs. Weak inter-molecular C-H?pi as well as pi-pi inter actions [centroid-centroid distance = 3.4041 (15) A] further consolidate the crystal structure. PMID- 21588620 TI - (E)-1-(2,5-Dimethyl-3-thien-yl)-3-(2-hy-droxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C(15)H(14)O(2)S, the dihedral angle between the aromatic rings is 8.46 -(8) degrees . The central enone group is planar (r.m.s. deviation = 0.0267 A) and is oriented at a dihedral angle of 1.20 (9) degrees with respect to the benzene ring and at 8.27 (9) degrees with respect to the thio-phene group. In the crystal, the mol-ecules are linked into polymeric chains extending along the b axis due to inter-molecular O-H?O hydrogen bonding. An S(6) ring motif is formed due to a short intra-molecular C-H?O contact. C-H?pi inter actions involving a methyl group of the 2,5-dimethyl-thienyl group and the benzene ring are present. pi-pi inter-actions between the centroids of the benzene and heterocyclic rings [3.7691 (9) A] also occur. PMID- 21588621 TI - (E)-1-[4-(Prop-2-yn-1-yl-oxy)phen-yl]-3-(3,4,5-trimeth-oxy-phen-yl)prop-2-en-1 one. AB - The mol-ecule of the title chalcone derivative, C(21)H(20)O(5), consists of two substituted aromatic rings bridged by a prop-2-en-1-one group. The dihedral angle between the two benzene rings is 28.7 (7) degrees . In the crystal, mol-ecules are linked into C(10) chains running along the a axis by inter-molecular C-H?O hydrogen bonds, and the chains are cross-linked via C-H?pi inter-actions. PMID- 21588622 TI - (4S,5S,6S)-4-Hy-droxy-3-meth-oxy-5-methyl-5,6-ep-oxy-cyclo-hex-2-en-1-one. AB - The title compound, C(8)H(10)O(4), was isolated from culture extracts of the endophytic fungus Xylaria sp. (PB-30). The cyclo-hexenone ring exhibits a flattened boat conformation. In the crystal structure, mol-ecules related by translation along the b axis are linked into chains through O-H?O hydrogen bonds. Weak non-classical C-H?O contacts are also observed in the structure. PMID- 21588623 TI - N-{4-[(5-Methyl-isoxazol-3-yl)sulfamo-yl]phen-yl}benzamide. AB - In the title compound, C(17)H(15)N(3)O(4)S, the five-membered isoxazole ring makes dihedral angles of 80.5 (2) and 81.3 (2) degrees with the two benzene rings, which form a dihedral angle of 39.81 (18) degrees with each other. A short intra-molecular C-H?O contact occurs. The crystal structure is stabilized by inter-molecular N-H?O hydrogen bonds, which generate [001] chains, and further consolidated by weak C-H?O inter-actions. PMID- 21588624 TI - 3-Methyl-5alpha-cholest-2-ene. AB - In the title cholestane derivative, C(28)H(48) [systematic name: (1S,2S,7R,10R,11R,14R,15R)-2,5,10,15-tetra-methyl-14-[(2R)-6-methyl-heptan-2 yl]tetra-cyclo-[8.7.0.0(2,7).0(11,15)]hepta-dec-4-ene], the cyclo-hexene ring adopts a half-chair conformation. The parent 5alpha-cholest-2-ene and the equivalent fragment of the title compound are almost superimposable (r.m.s. deviation = 0.033 A). PMID- 21588625 TI - 5-(Hy-droxy-meth-yl)furan-2-carbaldehyde. AB - The title compound (HMF), C(6)H(6)O(3), is one of the products of acid-catalyzed dehydration of high-fructose corn syrup, and has been shown to be toxic to honey bees. The compound was crystallized at 276 K, and it was found that the two independent mol-ecules in the asymmetric unit form an infinite O-H?O hydrogen bonding chain that is linked into a three-dimensional network structure by weak inter-molecular C-H?O contacts. PMID- 21588626 TI - 1-[4-(Difluoro-meth-oxy)phen-yl]-N-(3,4-dimeth-oxy-phen-yl)-1H-1,2,4-triazole-3 carboxamide. AB - Two crystallographically independent mol-ecules, A and B, with similar conformations are present in the asymmetric unit of the title compound, C(18)H(16)F(2)N(4)O(4). In mol-ecule A, the plane of the 1,2,4-triazole ring is tilted relative of the 4-difluoro-meth-oxy-substituted and the 3,4-dimeth-oxy substituted benzene rings by 6.5 (2) and 16.4 (1) degrees , respectively. The CHF(2) group is twisted away from the plane of the benzene ring, with a dihedral angle between the O-C bond of the OCHF(2) group and the plane of the adjacent phenyl ring of 38.6 (3) degrees . The corresponding parameters for mol-ecule B are 7.7 (1), 9.5 (2) and 25.2 (2) degrees . In both mol-ecules, the conformations are stabilized by intra-molecular N-H?N and C-H?O hydrogen bonds. There are also C-H?pi contacts between the methyl groups and the benzene rings, and pi-pi stacking inter-actions between the benzene rings of adjacent parallel A mol ecules [centroid-centroid distance = 3.8942 (17) A]. pi-pi inter-actions are also observed between the triazole ring and one of the benzene rings of parallel B mol ecules [centroid-centroid distance = 3.7055 (16) A]. PMID- 21588627 TI - 2-Amino-5-bromo-pyridinium 2-carb-oxy-benzoate. AB - The asymmetric unit of the title compound, C(5)H(6)BrN(2) (+).C(8)H(5)O(4) (-), consists of two crystallographically independent 2-amino-5-bromo-pyridinium cations (A and B) and two 2-carb-oxy-benzoate anions (A and B). Each 2-amino-5 bromo-pyridinium cation is approximately planar, with a maximum deviation of 0.047 (1) A in cation A and 0.027 (1) A in cation B. The 2-amino-5-bromo pyridinium unit in cation A is inclined at dihedral angles of 4.9 (3) and 2.2 (3) degrees with the phenyl rings of the A and B 2-carb-oxy-benzoate anions, respectively. The corresponding angles for cation B are 3.0 (3) and 5.6 (3) degrees . The mol-ecular structure is stabilized by an intra-molecular O-H?O hydrogen bond,which generates an S(7) ring motif. The cations and anions are linked via inter-molecular N-H?O and C-H?O hydrogen bonds, generating R(2) (2)(8) ring motifs. In the crystal packing, mol-ecules are linked into wave-like chains along [001] via adjacent ring motifs. Short inter-molecular distances between the phenyl and pyridine rings [3.613 (4) and 3.641 (4) A] indicate the existence of pi-pi inter-actions. The crystal structure is a non-merohedral twin with a contribution of 0.271 (3) of the minor component. PMID- 21588628 TI - (R)-(1-Ammonio-eth-yl)phospho-nate. AB - The title compound, C(2)H(8)NO(3)P, crystallizes in its zwitterionic form H(3)N(+)CH(CH(3))PO(O(-))(OH). In the crystal, the molecules are linked by N-H?O and O-H?O hydrogen bonds. PMID- 21588629 TI - Arborinol methyl ether from Areca catechu L. AB - The title compound isolated from Areca catechu L. (common name: arborinol methyl ether; a member of the arborane family) was established as 3alpha-methoxyarbor 9(11)-ene, C(31)H(52)O. Rings A/B/C/D assume a chair conformation, while ring E has an envelope conformation. The absolute configuration was determined to be (3R,5R,8S,10S,13R,14S,17S,18S, 21S) by analysis of Bijvoet pairs based on resonant scattering of light atoms, yielding a Hooft parameter y of -0.03 (3). PMID- 21588630 TI - Ergometrinine. AB - The absolute configuration of ergometrinine, C(19)H(23)N(3)O(2) {systematic name: (6aR,9S)-N-[(S)-1-hy-droxy-propan-2-yl]-7-methyl-4,6,6a,7,8,9-hexa-hydro indolo[4,3-fg]quinoline-9-carb-ox-amide}, was established based on epimerization reaction of ergometrine, which was followed by preparative HPLC. The non-aromatic ring (ring C of the ergoline skeleton) directly fused to the aromatic rings is nearly planar [maximum deviation = 0.271 (3) A] and shows an envelope conformation, whereas ring D, involved in an intra-molecular N-H?N hydrogen bond, exibits a slightly distorted chair conformation. The structure displays undulating layers in the ac plane formed by O-H?O and N-H?O hydrogen bonds. PMID- 21588631 TI - N-(3-Methyl-phen-yl)quinoxalin-2-amine monohydrate. AB - The quinoxaline system in the title hydrate, C(15)H(13)N(3).H(2)O, is roughly planar, the r.m.s. deviation for the 18 non-H atoms being 0.188 A; this conformation features a short intra-molecular C-H?N(pyrazine) inter-action. In the crystal, the amine H atom forms an N-H?O hydrogen bond to the water mol ecule, which in turn forms two O-H?N hydrogen bonds to the pyrazine N atoms of different organic mol-ecules. These inter-actions lead to supra-molecular arrays in the bc plane that are two mol-ecules thick; additional pi-pi inter-actions stabilize the layers [ring centroid-centroid distance = 3.5923 (7) A]. The layers stack along the a-axis direction via C-H?pi contacts. PMID- 21588632 TI - 5-Chloro-3-ethyl-sulfinyl-2-(4-iodo-phen-yl)-7-methyl-1-benzofuran. AB - In the title compound, C(17)H(14)ClIO(2)S, the 4-iodo-phenyl ring makes a dihedral angle of 1.61 (9) degrees with the benzofuran ring system. In the crystal, mol-ecules are linked through a weak inter-molecular C-H?O hydrogen bond and an I?O contact [3.416 (2) A]. The ethyl group is disordered over two orientations with site-occupancy factors of 0.402 (7) and 0.598 (7). PMID- 21588633 TI - 4-Ethyl-anilinium perchlorate-18-crown-6 (1/1). AB - The asymmetric unit of the title compound, C(8)H(12)N(+).ClO(4) ( .)C(12)H(24)O(6), contains one half of the cationic [(C(2)H(5)-C(6)H(4)-NH(3))(18 crown-6)](+) moiety and one half of the ClO(4) (-) anion. Two O atoms of the crown ether, four C atoms and the N atom of the ethylanilinium unit and the Cl and two O atoms of the anion lie on a mirror plane. In the crystal structure, the -NH(3) (+) group lies in the 18-crown-6 ring, forming a supra-molecular rotator stator-like structure linked by intra-molecular N-H?O hydrogen bonds. The six O atoms of the crown ether lie approximately in a plane, the mean deviation being 0.1771 (3) A; the N atom lies approximately 0.855 (3) A from the centroid of the crown ether ring. PMID- 21588634 TI - 2-(2-Meth-oxy-5-methyl-phen-yl)-2H-benzotriazole. AB - In the title mol-ecule, C(14)H(13)N(3)O, the dihedral angle between the mean planes of the benzotriazole ring system and the benzene ring is 57.8 (2) degrees . PMID- 21588635 TI - 1-(6-Methyl-4-phenyl-2-sulfanyl-idene-1,2,3,4-tetrahydro-pyrimidin-5-yl)ethanone. AB - In the title compound, C(13)H(14)N(2)OS, the heterocyclic ring adopts a flattened boat conformation with the plane through the four coplanar atoms making a dihedral angle of 86.90 (13) degrees with the phenyl ring, which adopts an axial orientation. The thionyl, acetyl and methyl groups all have equatorial orientations. Inter-molecular N-H?O, N-H?S and C-H?O hydrogen bonds are found in the crystal structure. PMID- 21588636 TI - [4-(Di-tert-butyl-fluoro-silan-yl)phenyl]methanol. AB - The asymmetric unit of the title compound, C(15)H(25)FOSi, contains two independent mol-ecules. Each of the Si atoms approximates the expected tetra hedral geometry with Si-F bond lengths of 1.6128 (11) and 1.6068 (11) A in the two independent mol-ecules. In the crystal, supra-molecular chains along a are found mediated by O-H?O hydrogen bonds. PMID- 21588637 TI - Ethyl 1,5-diphenyl-1H-pyrazole-4-carboxyl-ate. AB - The asymmetric unit of the title compound, C(18)H(16)N(2)O(2), contains two independent mol-ecules (A and B). In mol-ecule A, the pyrazole ring is inclined at angles of 48.86 (6) and 60.80 (6) degrees with respect to the two phenyl rings; the corresponding angles for mol-ecule B are 46.86 (6) and 58.63 (6) degrees . In the crystal, mol-ecules of type A are linked into sheets parallel to (001) via weak C-H?O hydrogen bonds, whereas the mol-ecules of type B are linked into chains along [010] via weak C-H?O hydrogen bonds. PMID- 21588638 TI - 1-Chloro-acetyl-2,6-bis-(2-chloro-phen-yl)-3,5-dimethyl-piperidin-4-one. AB - In the title compound, C(21)H(20)Cl(3)NO(2), the piperidin-4-one ring adopts a boat conformation. The two 2-chloro-phenyl groups are approximately perpendicular to each other, making a dihedral angle of 74.07 (8) degrees . PMID- 21588639 TI - 2,2',5,5'-Tetra-chloro-benzidine. AB - In the crystal structure of the title compound, C(12)H(8)Cl(4)N(2), mol-ecules lie on crystallographic twofold axes at the centre of the C-C bonds linking the benzene rings, such that the asymmetric unit consists of a half-mol-ecule. The individual mol-ecules participate in inter-molecular N-H?N, N-H?Cl, C-H?Cl and Cl?Cl [3.4503 (3) A] inter-actions. PMID- 21588640 TI - 4-{2-[5-(4-Chloro-phen-yl)-1-(4-fluoro-phen-yl)-1H-pyrazol-3-yl]thia-zol-4 yl}benzonitrile. AB - The asymmetric unit of the title compound, C(25)H(14)ClFN(4)S, contains two independent mol-ecules (A and B). Each mol-ecule consists of five rings, namely chloro-phenyl, fluoro-phenyl, 1H-pyrazole, thia-zole and benzonitrile. In mol ecule A, the 1H-pyrazole ring makes dihedral angles of 52.54 (8), 35.96 (8) and 15.43 (8) degrees with respect to the attached chloro-phenyl, fluoro-phenyl and thia-zole rings. The corresponding values in mol-ecule B are 51.65 (8), 37.26 (8) and 8.32 (8) degrees . In the crystal, mol-ecules are linked into dimers by C-H?N hydrogen bonds, generating R(2) (2)(10) ring motifs. These dimers are further linked into two-dimensional arrays parallel to the ab plane via inter-molecular weak C-H?N and C-H?F hydrogen bonds. The crystal structure is further stabilized by weak pi-pi inter-actions [with centroid-centroid distances of 3.4303 (9) and 3.6826 (9) A] and weak C-H?pi inter-actions. PMID- 21588641 TI - 10,12-Dimethyl-pteridino[6,7-f][1,10]phenanthroline-11,13(10H,12H)-dione-chloro form (1/1). AB - In the title co-crystal, C(18)H(12)N(6)O(2).CHCl(3), intra-molecular Cl(3)C-H?N hydrogen-bonding inter-actions occur between a single CHCl(3) and both N atoms at the 1,10-positions on the phenanthroline portion of the mol-ecule. The inter planar distance between inversion-related mol-ecules is 3.241 (2) A. PMID- 21588642 TI - 2-(3-Oxo-3,4-dihydro-2H-1,4-benzothia-zin-4-yl)acetohydrazide. AB - In the title compound, C(10)H(11)N(3)O(2)S, the thia-zine ring exists in a conformation inter-mediate between twist-boat and half-chair. The dihedral angle between the mean plane of the thia-zine ring and the hydrazide group is 89.45 (13) degrees . In the crystal, N-H?O hydrogen bonds link the mol-ecules into (100) sheets and weak C-H?O inter-actions further consolidate the packing. PMID- 21588643 TI - 2-Methyl-benzimidazolium thio-cyanate-2-methyl-benzimidazole (1/1). AB - In the crystal structure of the title compound, C(8)H(9)N(2) (+).SCN( ).C(8)H(8)N(2), the three components are linked by inter-molecular N-H?N and N H?S hydrogen bonds into infinite chains along the c axis. PMID- 21588644 TI - (11-Methyl-pyrido[2,3-b][1,4]benzo-diazepin-6-yl)(phen-yl)methanone. AB - In the title compound, C(20)H(15)N(3)O, the diazepine ring adopts a boat conformation. The dihedral angle between pyridine and benzene rings is 55.2 (1) degrees . The benzoyl phenyl ring forms dihedral angles of 49.4 (1) and 75.9 (1) degrees , respectively, with the pyridine and benzene rings. In the crystal, mol ecules are linked into centrosymmetric dimers by pairs of C-H?N hydrogen bonds. PMID- 21588645 TI - 1-[2-(3,5-Difluoro-benz-yloxy)phen-yl]ethanone. AB - In the title compound, C(15)H(12)F(2)O(2), the dihedral angle between the aromatic rings is 70.43 (4) degrees . The crystal packing exhibits no significantly short inter-molecular contacts. PMID- 21588646 TI - 2,6-Diamino-4-oxo-3,4-dihydropyrim-idin-1-ium chloride dihydrate. AB - In the crystal structure of the title compound, C(4)H(7)N(4)O(+).Cl(-).2H(2)O, adjacent cations are connected to one another through N-H?O hydrogen bonds, forming infinite chains along the b axis. These chains are further hydrogen bonded to the chloride anions and water mol-ecules, resulting in a three dimensional network. The pyrimidine rings of adjacent mol-ecules are arranged in an anti-parallel manner above each other with centroid-centroid distances of 3.435 (1) A, indicative of pi-pi inter-actions. PMID- 21588647 TI - 2,3-Dimethyl-N-[(E)-(1H-pyrrol-2-yl)methyl-idene]aniline. AB - In the title compound, C(13)H(14)N(2), the dihedral angle between the aromatic rings is 69.73 (14) degrees . In the crystal, inversion dimers linked by pairs of N-H?N hydrogen bonds generate R(2) (2)(10) loops. A weak C-H?pi inter-action also occurs. PMID- 21588648 TI - 5,5'-Bis(diethyl-amino)-2,2'-[2,2-di-methyl-propane-1,3-diylbis-(nitrilo methylidyne)]diphenol. AB - The asymmetric unit of the title compound, C(27)H(40)N(4)O(2), comprises one mol ecule of a potentially tetra-dentate Schiff base ligand. The dihedral angle between the two phenyl rings is 67.13 (10) degrees . Strong intra-molecular O-H?N hydrogen bonds generate S(6) ring motifs. One terminal methyl among the four diethyl-amino groups is disordered over two positions with the refined site occupancy ratio of 0.660 (7)/0.340 (7). PMID- 21588649 TI - Nifedipine-pyrazine (2/1). AB - In the title compound, 2C(17)H(18)N(2)O(6).C(4)H(4)N(2) [systematic name: 3,5 dimethyl 2,6-dimethyl-4-(2-nitro-phen-yl)-1,4-di-hydro-pyridine-3,5-dicarboxyl ate-pyrazine (2/1)], the complete pyrazine molecule is generated by crystallographic inversion symmetry. The center of the pyrazine ring lies on an inversion center. The nifedipine mol-ecules are linked into chains along the c axis through N-H?O hydrogen bonds, while the pyrazine mol-ecules are organized in the structure through van der Waals inter-actions. PMID- 21588650 TI - 8-Methyl-2,3,4,9-tetra-hydro-1H-carbazol-1-one. AB - In the title compound, C(13)H(13)NO, the dihedral angle between the benzene ring and the fused pyrrole ring is 0.96 (7) degrees . The cyclohexenone ring adopts an envelope conformation. Inter-molecular N-H?O hydrogen bonds form R(2) (2)(10) ring motifs in the crystal structure. Weak C-H?pi inter-actions involving the benzene ring also occur. PMID- 21588651 TI - Spiro-[cyclo-pentane-1,2'(1'H)-pyrido[2,3-d]pyrimidin]-4'(3'H)-one. AB - The title compound, C(11)H(13)N(2)O, was obtained by cyclo-condensation of 2 amino-pyridine-3-carbonitrile with cyclo-penta-none. The mol-ecule is built up from two fused six-membered rings and one five-membered ring linked through a spiro C atom. Both the pyrimidine and the cyclo-pentane rings adopt envelope conformations. In the crystal structure, mol-ecules are linked by inter-molecular N-H?O hydrogen bonds. PMID- 21588652 TI - 1-(4-Chloro-phen-yl)-3-(3,4-dimethyl-phen-yl)prop-2-en-1-one. AB - The title compound, C(17)H(15)ClO, was prepared from 3,4-dimethyl-benzaldehyde and 4-chloro-hypnone by Aldol condensation. The dihedral angle formed by the two benzene rings is 48.91 (8) degrees . Only van der Waals forces affect the packing. PMID- 21588653 TI - 2-(4-Meth-oxy-phen-oxy)pyrazine. AB - In the title compound, C(11)H(10)N(2)O(2), the aromatic rings are almost orthogonal to each other [dihedral angle = 86.97 (8) degrees ], with the benzene ring orientated to face one of the pyrazine N atoms. In the crystal, centrosymmetrically related pairs are connected via pairs of C-H?pi inter-actions and the dimeric units thus formed pack into undulating layers that stack along the a axis. PMID- 21588654 TI - N-Isopropyl-6-methyl-2-phenyl-quinoline-3-carboxamide. AB - In the title compound, C(20)H(20)N(2)O, the dihedral angle between the quinoline ring system and the phenyl ring is 49.40 (5) degrees . In the crystal structure, zigzag layers of mol-ecules, in which the quinoline units are parallel to the (10) plane, are arranged perpendicular to the b axis. Inter-molecular N-H?O hydrogen bonds connect the mol-ecules into chains along [010], reinforcing the cohesion between the layers of the structure. PMID- 21588655 TI - 4'-Chloro-biphenyl-3-yl 2,2,2-trichloro-ethyl sulfate. AB - The title compound, C(14)H(10)Cl(4)O(4)S, is a 2,2,2-trichloro-ethyl-protected precursor of 4'-chloro-biphenyl-3-yl sulfate, a sulfuric acid ester of 4'-chloro biphenyl-3-ol. The C(aromatic)-O and O-S bond lengths of the C(aromatic)-O-S unit are comparable to those in structurally analogous biphenyl-4-yl 2,2,2-trichloro ethyl sulfates with no electro-negative chlorine substituent in the benzene ring with the sulfate ester group. The dihedral angle between the aromatic rings is 27.47 (6) degrees . PMID- 21588656 TI - 4-(4-Chloro-5-methyl-3-trifluoro-meth-yl-1H-pyrazol-1-yl)-6-(prop-2-ynyl oxy)pyrimidine. AB - The molecule of the title compound, C(12)H(8)ClF(3)N(4)O, is twisted as indicated by the C-O-C-C torsion angle of 76.9 (3) degrees . Moreover, the trifluoro-methyl group shows rotational disorder of the F atoms, with site-occupancy factors of 0.653 (6) and 0.347 (6). The dihedral angle between the rings is 1.88 (12) A. PMID- 21588657 TI - 3,3'-Dibenzyl-1,1'-ethyl-enediimidazolium dibromide. AB - In the title compound, C(22)H(24)N(4) (2+).2Br(-), the imidazolium dication is located on a crystallographic inversion center. The imidazole and benzene rings make a dihedral angle of 73.1 (9) degrees . In the crystal, non-classical inter molecular C-H?Br hydrogen bonds link the ion pairs into a two-dimensional network. PMID- 21588658 TI - Ethyl 3,4-dimethyl-1H-pyrrole-2-carboxyl-ate. AB - The non-H atoms of the title compound, C(9)H(13)NO(2), are almost coplanar (r.m.s. deviation = 0.0358 A). Weak inter-molecular N-H?O hydrogen bonds link the mol-ecules into zigzag chains along the b axis with graph-set motif C(5). The chains are further linked into a three-dimensional network by C-H?O hydrogen bonds and C-H?pi inter-actions. PMID- 21588659 TI - 2-[(4-Chlorobenzyl)iminomethyl]phenol. AB - The title Schiff base compound, C(14)H(12)ClNO, was prepared from 4-chloro-benzyl amine and salicyl-aldehyde. The mol-ecule is V-shaped: the dihedral angle between the aromatic rings is 67.51 (5) degrees . The rings are located on the opposite side of the C=N bond, giving an E configuration. An intra-molecular N-H?O hydrogen bond generates a S(6) ring. In the crystal structure, only weak non classical C-H?O contacts are observed. PMID- 21588660 TI - 3-Phenyl-diazen-yl-1,2-dimethyl-1H-indole. AB - In the title mol-ecule, C(16)H(15)N(3), the indole ring system is planar within 0.021 (3) A and the phenyl ring is inclined to this plane by 17.32 (14) degrees . pi-pi contacts involving the pyrrole rings of inversion-related indole units [centroid-centroid distance = 3.5187 (17) A] stabilize the crystal structure. PMID- 21588661 TI - 5,8-Dimeth-oxy-2-phenyl-1,4-dihydro-quinoline-3-carbonitrile. AB - The crystal structure of the title mol-ecule, C(18)H(16)N(2)O(2), can be described as two types of crossed layers parallel to the (110) and (10) planes. An intra-molecular N-H?O hydrogen bond occurs. PMID- 21588662 TI - 4-Hy-droxy-3-(3-meth-oxybenzoyl)-2-[(3-meth-oxybenzoyl)methyl]-2H-1,2-benzothia zine 1,1-dioxide. AB - In the title compound, C(25)H(21)NO(7)S, the heterocyclic thia-zine ring adopts a half-chair conformation, with the S and N atoms displaced by -0.284 (3) and 0.411 (3) A, respectively, from the plane formed by the remaining ring atoms; the puckering parameters are: Q = 0.4576 (13) A, theta = 58.6 (2) and phi = 34.3 (3) degrees . The structure is devoid of any classical hydrogen bonds. However, intra molecular C-H?N and O-H?O hydrogen bonds result in six-membered rings and inter molecular C-H?O inter-actions stabilize the crystal structure. PMID- 21588663 TI - Ortho-rhom-bic modification of bis-[4-(3-pyridyl-methyl-idene-amino)-phen yl]methane. AB - The title compound, C(25)H(20)N(4), is a disubstituted methane derivative having two pyridyl-methyl-ene-amino-phenyl arms, one of which is essentially rigid as all atoms lie on a plane (r.m.s. deviation = 0.074 A), whereas the other is twisted [dihedral angle between the phenyl-ene and pyridyl rings = 51.1 (4) degrees ]. The angle at the methyl-ene C atom is 113.2 (2) degrees . PMID- 21588664 TI - 9,9-Bis[4-(2-chloro-eth-oxy)phen-yl]-9H-fluorene. AB - The title compound, C(29)H(24)Cl(2)O(2), a fluorene derivative, features a C atom that is connected to four phenyl-ene rings, two of which are almost coplanar (r.m.s. deviation = 0.035 A) as they belong to the fluorene system. The other two rings are aligned at angles of 67.5 (5) and 85.5 (5) degrees with respect to the pair. The O and Cl atoms of the -OCH(2)CH(2)Cl- units adopt a gauche conformation [torsion angles = 61.6 (6) and 66.6 (5) degrees ]. PMID- 21588665 TI - 2-(4H-1,2,4-Triazol-4-yl)phenol. AB - In the title compound, C(8)H(7)N(3)O, the dihedral angle between the benzene and triazole rings is 41.74 (12) degrees . PMID- 21588666 TI - 5-(4-Hy-droxy-benzyl-idene)-2,2-dimethyl-1,3-dioxane-4,6-dione. AB - The title compound, C(13)H(12)O(5), was prepared by the reaction of 2,2-dimethyl 1,3-dioxane-4,6-dione and 4-hy-droxy-benz-alde-hyde in ethanol. The 1,3-dioxane ring is in a distorted boat conformation. In the crystal, inversion dimers linked by pairs of O-H?O hydrogen bonds generate R(2) (2)(20) rings. PMID- 21588667 TI - N-(3,4-Difluoro-phen-yl)-N'-(2,5-di-methoxy-phen-yl)urea. AB - In the title compound, C(15)H(14)F(2)N(2)O(3), the dihedral angle between the benzene rings is 64.5 (1) degrees . One F atom is disordered over two meta positions, with occupancy factors of 0.72 and 0.28. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds involving two N-H and one C=O groups of the urea central fragment, leading to a supra-molecular chain along [011]. PMID- 21588668 TI - 2-(1,2,3,4-Tetra-hydro-1-naphth-yl)imidazolium chloride monohydrate. AB - In the title compound, C(13)H(15)N(2) (+).Cl(-).H(2)O, the ions and water mol ecules are -connected by N-H?Cl, O-H?Cl, NH?Cl?HO, NH?Cl?HN and OH?Cl?HO inter actions, forming discrete D(2) and D(2) (1)(3) chains, C(2) (1)(6) chains and R(4) (2)(8) rings, leading to a neutral two-dimensional network. The crystal structure is further stabilized by pi-pi stacking inter-actions [centroid centroid distance = 3.652 (11) A]. PMID- 21588669 TI - 4-Phenyl-2,6-bis-(4-tol-yl)pyridine. AB - The title mol-ecule, C(25)H(21)N, situated on the crystallographic twofold axis has a symmetry point group 2. The inter-planar angles between the central pyridyl ring and the phenyl and the methyl-phenyl rings are 32.8 (2) and 23.7 (2) degrees , respectively. In the crystal packing, the central pyridyl rings of adjacent mol ecules are involved in pi-pi inter-actions, forming one-dimensional arrays along the c axis with centroid-centroid distances of 3.714 (1) A. PMID- 21588670 TI - 2-Amino-5-chloro-pyridinium 3-carb-oxy-4-hy-droxy-benzene-sulfonate. AB - The asymmetric unit of the title salt, C(5)H(6)ClN(2) (+).C(7)H(5)O(6)S(-), contains two independent 2-amino-5-chloro-pyridinium cations and two independent 3-carb-oxy-4-hy-droxy-benzene-sulfonate anions. In both anions, the O atoms of the sulfonate group are disordered over two sets of positions, with occupancy ratios of 0.47 (5):0.53 (5) and 0.50 (8):0.50 (8). In each anion, an intra molecular O-H?O hydrogen bond generating an S(6) motif is observed. In the crystal structure, the cations and anions are linked via N-H?O, O-H?O and C-H?O hydrogen bonds, forming a two-dimensional network parallel to (110). The structure is further stabilized by pi-pi inter-actions between cations and anions [centroid-centroid distance = 3.5454 (12) A]. The crystal studied was a non merohedral twin, with a ratio of the twin components of 0.715 (3):0.285 (3). PMID- 21588671 TI - 3-(4-Chloro-phenyl-sulfin-yl)-2,5,7-tri-methyl-1-benzofuran. AB - In the title compound, C(17)H(15)ClO(2)S, the O atom and the 4-chloro-phenyl group of the 4-chloro-phenyl-sulfinyl substituent are located on opposite sides of the plane through the benzofuran fragment; the 4-chloro-phenyl ring is approximately perpendicular to this plane [dihedral angle = 87.12 (3) degrees ]. In the crystal structure, mol-ecules are linked through a weak inter-molecular C H?O hydrogen bond, and by weak C-S?pi [3.394 (2) A] and C-Cl?pi [3.800 (2) A] inter-actions. PMID- 21588672 TI - [Amino-(iminio)meth-yl]phospho-nate. AB - The title compound, CH(5)N(2)O(3)P, exists as a zwitterion. The N atom of the imino group is protonated and the phospho-nic acid group is deprotonated. The mol ecular geometry about the central C atom of this zwitterionic species was found to be strictly planar with the sum of the three angles about C being precisely 360 degrees . In the crystal, the mol-ecules are inter-linked by O-H?O and N-H?O hydrogen-bonding inter-actions, forming a three-dimensional supra-molecular network structure. PMID- 21588673 TI - 4-Hy-droxy-2-[(4-iodo-benzo-yl)meth-yl]-3-(3-meth-oxy-benzo-yl)-2H-1,2-benzothia zine 1,1-dioxide. AB - In the title mol-ecule, C(24)H(18)INO(6)S, the heterocyclic thia-zine ring adopts a half-chair conformation, with the S and N atoms displaced by 0.381 (5) and 0.449 (5) A, respectively, from the plane formed by the remaining atoms in the ring; the puckering parameters are Q = 0.550 (2) A, theta = 61.7 (2) degrees and phi = 31.4 (3) degrees . The conformation is stabilized by an intra-molecular O H?O hydrogen bond. The two nonfused benzene rings lie almost parallel to each other [dihedral angle = 9.18 (4) degrees ], with a separation of 3.754 (2) A between the centres of gravity of the two rings, indicating strong pi-pi inter actions. PMID- 21588674 TI - Dieth-yl(hy-droxy)ammonium 3-carb-oxy-benzoate. AB - In the title molecular compound, C(4)H(12)NO(+).C(8)H(5)O(4) (-), the N,N-dieth yl(hy-droxy)ammonium cation (DTHA) is linked to the 3-carb-oxy-benzoate anion (HBDL) by O-H?O and N-H?O hydrogen bonds with a graph-set motif R(2) (2)(7). In the crystal, helical chains are formed by O-H?O hydrogen bonds, propagating along [010]. The crystal structure is further stabilized by pi-pi inter-actions between inversion-related HBDL benzene rings [centroid-centroid distance = 3.900 (4) A] and C-H?O inter-actions. PMID- 21588675 TI - 4-Chloro-2-methyl-N-(4-methyl-phen-yl)benzene-sulfonamide. AB - The asymmetric unit of the title compound, C(14)H(14)ClNO(2)S, contains two independent mol-ecules. The torsion angles of the C-SO(2)-NH-C segments in the two mol-ecules are -76.5 (5) and -48.3 (4) degrees . The two aromatic rings are tilted relative to each other by 76.6 (2) degrees in one mol-ecule and 70.7 (2) degrees in the other. In the crystal structure, inter-molecular N-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers. PMID- 21588676 TI - 1-[(1,3-Dithio-lan-2-yl)meth-yl]-6-methyl-8-nitro-1,2,3,5,6,7-hexa-hydro imidazo[1,2-c]pyrimidine. AB - In the title compound, C(11)H(18)N(4)O(2)S(2), the dithiol-ane ring displays an envelope conformation, the tetra-hydro-pyrimidine ring has a conformation that is between half-chair and screw-boat, and the imidazole ring is essentially planar (r.m.s. deviation = 0.0017 A). No significant directional inter-molecular inter actions are present in the structure. PMID- 21588677 TI - (Diphenyl-phosphor-yl)(2-nitro-phen-yl)methanol. AB - In the title compound, C(19)H(16)NO(4)P, the dihedral angle between the mean planes of the phenyl rings bonded to the P atom is 75.4 (1) degrees . In the crystal, mol-ecules are linked into chains running along the a axis by inter molecular O-H?O hydrogen bonds. Mol-ecules are further connected into a three dimensional array by weak C-H?O hydrogen bonds. PMID- 21588678 TI - N-[(Z)-4-Meth-oxy-benzyl-idene](meth-oxy-carbon-yl)methanamine oxide. AB - The title compound, C(11)H(13)NO(4), contains a nitrone group, C=N-O-R, the geometry of which shows a Z configuration with near planarity (r.m.s. deviation = 0.0787 A) around the C=N double bond. An intra-molecular C-H?O hydrogen bond generates an S(6) ring motif. In the crystal packing, mol-ecules are linked into R(2) (2)(12) dimers and R(2) (2)(14) rings via C-H?O inter-molecular hydrogen bonds. PMID- 21588679 TI - Ethyl 2-[(Z)-2-benzyl-hydrazin-1-yl-idene]-2-bromo-acetate. AB - In the title compound, C(11)H(13)BrN(2)O(2), the dihedral angle between the phenyl ring and the almost planar (r.m.s. deviation = 0.011 A) C-C(Br)=N-N(H)- fragment is 74.94 (16) degrees . In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, which generate C(6) chains propagating in [010]. Weak aromatic pi pi stacking [centroid-centroid separation = 3.784 (3) A] may also help to consolidate the packing. PMID- 21588680 TI - Bis[2-(2-pyridyl-sulfan-yl)eth-yl]ammonium perchlorate. AB - The cation and anion of the title salt, C(14)H(18)N(3)S(2) (+).ClO(4) (-), lie on a twofold rotation axis. The cation is a W-shaped entity with the aromatic rings at the ends; the ammonium NH(2) (+) group is a hydrogen-bond donor to the pyridyl N atoms. The perchlorate ion has one O atom disordered over two sites in a 0.50:0.50 ratio. PMID- 21588681 TI - 4-(4-Chloro-phen-yl)-1-methyl-3-trifluoro-methyl-1H-pyrazol-5-amine. AB - The five-membered ring of the title compound, C(11)H(9)ClF(3)N(3), is almost planar (r.m.s. deviation = 0.002 A) and the phenyl-ene ring is aligned at 44.8 (1) degrees . The N atom of the amino substituent shows a pyramidal geometry and is a hydrogen-bond donor to a Cl atom and to a ring N atom, which together generate a layer motif. PMID- 21588682 TI - N-(4-Chloro-benzyl-idene)-1-naphthyl-amine. AB - The title compound, C(17)H(12)ClN, represents a trans isomer with respect to the C=N bond; the dihedral angle between the planes of the naphthyl and benzene groups is 66.53 (5) degrees . PMID- 21588683 TI - 2-Amino-5-chloro-pyridinium 6-oxo-1,6-dihydro-pyridine-2-carboxyl-ate 0.85 hydrate. AB - In the title salt, C(5)H(6)ClN(2) (+).C(6)H(4)NO(3) (-).0.85H(2)O, the pyridin ium ring is planar, with a maximum deviation of 0.010 (2) A. In the crystal structure, the cations, anions and water mol-ecules are linked via N-H?O, O-H?O and C-H?O hydrogen bonds, forming a three-dimensional network. PMID- 21588684 TI - N-(4-Meth-oxy-phen-yl)-N'-(5-nitro-1,3-thia-zol-2-yl)urea. AB - The title compound, C(11)H(10)N(4)O(4)S, is a derivative of N-(4-meth-oxy-benz yl)-N'-(5-nitro-1,3-thia-zol-2-yl)urea (AR-A014418), a known glycogen synthase kinase 3beta (GSK-3beta) inhibitor. All non-H atoms in the mol-ecule are essentially coplanar, with an r.m.s. deviation of 0.045 A and a maximum deviation of 0.115 (2) A for the carbonyl O atom. In the crystal structure, mol-ecules are linked via N-H?O hydrogen bonds into one-dimensional chains along [101]. PMID- 21588685 TI - 2-Fluoro-4-(meth-oxy-carbon-yl)benzoic acid. AB - In the crystal of the title compound, C(9)H(7)FO(4), classical carboxylate inversion dimers are linked by pairs of O-H?O hydrogen bonds. The packing is consolidated by C-H?F and C-H?O interactions. The benzene ring and the methoxycarbonyl group are nearly coplanar, with a dihedral angle of 1.5 (3) degrees between them, whereas the carboxyl group has a dihedral angle of 20.2 (4) degrees with respect to the benzene ring. PMID- 21588686 TI - 2,3;5,6-Di-O-isopropyl-idene-1-O-(2-phenyl-acet-yl)-alpha-d-mannofuran-ose. AB - The title compound, C(20)H(26)O(7), was prepared by esterification of 2,3;5,6-di O-isopropyl-idene-alpha-d-mannofuran-ose with phenyl-acetic acid under standard DCC/DMAP (DCC = dicyclohexylcarbodiimide and DMAP = 4-dimethylaminopyridine) con ditions. The solid-state structure confirms the retention of the alpha configuration at the anomeric C atom. The compound is characterized by a relatively rigid framework with only a few degrees of freedom. Comparison with other di-O-isopropyl-idenemannofuran-ose derivatives shows the main differences to be associated with the flexible dimethyl-dioxolane ring, and that there are only small differences for the 2,3-O-isopropyl-idene-alpha-d-manno-furan-ose backbone. The packing is marked by a large number of weak C-H?O inter-actions. PMID- 21588687 TI - 2-Hy-droxy-ethanaminium 2,4-dinitro-phenolate hemihydrate. AB - In the title salt, C(2)H(8)NO(+).C(6)H(3)N(2)O(5) (-).0.5H(2)O, the anions, cations and water mol-ecules are linked via N-H?O and O-H?O hydrogen bonds, forming a three-dimensionl network. PMID- 21588688 TI - Methyl 2-(tert-but-oxy-carbonyl-amino)-1,3-thia-zole-5-carboxyl-ate. AB - The title compound, C(10)H(14)N(2)O(4)S, was synthesized by the reaction of methyl 2-amino-thia-zole-5-carboxyl-ate and di-tert-butyl carbonate. In this structure, the thia-zole ring is planar (mean deviation = 0.0011 A). Two weak intra-molecular C-H?O hydrogen bonds are formed between two of the methyl groups and one carbonyl O atom, resulting in the formation of two twisted six-membered rings. Inter-molecular N-H?N hydrogen bonds link the mol-ecules to form centrosymmetric dimeric units, and the hydrogen-bond scheme is completed by inter molecular C-H?O contacts. PMID- 21588689 TI - Methyl (Z)-3-({5-[(E)-(tert-butyl-amino)-methyl-idene]-4-oxo-4,5-dihydro-1,3-thia zol-2-yl}sulfan-yl)prop-2-enoate. AB - In the title compound, C(12)H(16)N(2)O(3)S(2), the S-vinyl, and tert-butyl enamine fragments make dihedral angles of 14.19 (2) and 0.85 (2) degrees , respectively, with the thia-zole ring. In the crystal, mol-ecules are linked into chains with graph-set motifs C(5) along [100] by C-H?O inter-actions. The mol ecular conformation is stabilized by an intra-molecular N-H?O hydrogen bond. PMID- 21588690 TI - (E)-3-(4-Eth-oxy-phen-yl)-1-(2-hy-droxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C(17)H(16)O(3), the carbonyl group is in an s-cis configuration with respect to the olefinic double bond. The dihedral angle between the two benzene rings is 2.85 (3) degrees . The prop-2-en-1-one bridge makes dihedral angles of 4.77 (4) and 4.15 (4) degrees , respectively, with the 2 hy-droxy-phenyl and 4-eth-oxy-phenyl rings. The eth-oxy group is coplanar with the attached phenyl ring [C(ar)-O-C-C = 179.72 (5) degrees ]. An intra-molecular O-H?O hydrogen bond generates an S(6) ring motif. In the crystal structure, mol ecules are stacked in an anti-parallel manner to form columns along the b axis. The columnar structure is stabilized by C-H?pi inter-actions involving the 2-hy droxy-phenyl ring. PMID- 21588691 TI - 1-(2-Oxo-3,4-dihydro-2H-1,3-benzoxazin-4-yl)urea monohydrate. AB - The organic molecule in the title hydrate, C(9)H(9)N(3)O(3).H(2)O, was obtained by the condenstation of salicylic aldehyde with urea in acetonitrile. The oxazine ring adopts a slightly distorted sofa conformation, with the N atom deviating from the plane passing through the other atoms of the ring by 0.267 (2) A. The crystal structure displays inter-molecular N-H?O and O-H?O hydrogen bonding. PMID- 21588692 TI - (1E,2E)-1,2-Bis(2,2-diphenyl-hydrazin-1-yl-idene)ethane. AB - In the crystal structure of the title compound, C(26)H(22)N(4), the mol-ecule is located on an inversion centre and shows an E configuration with respect to each C=N bond. The dihedral angle between the phenyl rings in the diphenyl-hydrazone group is 83.69 (11) degrees . These two rings make dihedral angles of 30.53 (15) and 84.53 (16) degrees with the central N-N=C-C=N-N dihydrazonoethane plane. Inter-molecular C-H?pi inter-actions are observed. PMID- 21588693 TI - 5-Chloro-3-(4-fluoro-phenyl-sulfon-yl)-2-methyl-1-benzofuran. AB - In the title compound, C(15)H(10)ClFO(3)S, the 4-fluoro-phenyl ring makes a dihedral angle of 75.83 (5) degrees with the plane of the benzofuran fragment. In the crystal, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers, which are further linked via an aromatic pi-pi inter action between the benzene rings of adjacent mol-ecules [centroid-centroid distance = 3.510 (2) A]. PMID- 21588694 TI - 5-(2-Hy-droxy-phen-yl)-3-methyl-4,5-di-hydro-1H-pyrazole-1-carbaldehyde. AB - In the title compound, C(11)H(12)N(2)O(2), the dihydro-pyrazole and benzene rings are oriented at a dihedral angle of 68.35 (5) degrees . The dihydro-pyrazole ring is planar, with a mean deviation from the mean plane of 0.0409 A. The crystal structure is stabilized by O-H?O and C-H?O hydrogen bonds. PMID- 21588695 TI - 2-Isopropyl-5-methyl-cyclo-hexyl N-cyclo-hexyl-P-phenyl-phospho-namidate. AB - The title compound, C(22)H(36)NO(2)P, features a P atom bonded to a phenyl ring, a cyclo-hexyl-amine unit and the O atom of a menthyl group. In the crystal structure, inter-molecular N-H?O hydrogen bonds connect mol-ecules into a one dimensional chain in the b direction. PMID- 21588696 TI - Redetermination of {5-[(7-chloro-quinolinium-4-yl)amino]-2-hy-droxy-benz yl}diethyl-ammonium dichloride dihydrate. AB - THE STRUCTURE OF THE TITLE COMPOUND (COMMON NAME: amodiaquinium dichloride dihydrate), C(20)H(24)ClN(3)O(2) (+).2Cl(-).2H(2)O, was previously determined from powder diffraction data [Llinas et al. (2006 ?). Acta Cryst. E62, o4196 o4199]. It has now been refined from diffractometer data to a significantly higher precision. The dihedral angle between the quinoline and benzene rings is 54.57 (6) degrees . The central amino N atom inter-acts more strongly with the quinoline ring than with the benzene ring, as indicated by the shorter C-N bond length [1.341 (2) A compared to 1.431 (2) A]. In the crystal, mol-ecules are packed into a three-dimensional network/supra-molecular structure through hydrogen bonds between the amodiaquinium cations, chloride anions and water mol ecules. PMID- 21588697 TI - 4-Chloro-N-[(E)-(3,4-dimeth-oxy-phen-yl)methyl-idene]aniline. AB - The asymmetric unit of the title compound, C(15)H(14)ClNO(2), contains two mol ecules with significantly different conformations: the dihedral angles between the 4-chloro-aniline and 3,4-dimeth-oxy-phenyl (excluding C atoms) moieties are 19.68 (7) and 45.54 (4) degrees . In the crystal, the mol-ecules are linked by C H?O hydrogen bonds and weak C-H?pi inter-actions. PMID- 21588698 TI - 2-(4-Chloro-phen-yl)acetic acid-2-{(E)-[(E)-2-(2-pyridyl-methyl-idene)hydrazin-1 yl-idene]meth-yl}pyridine (1/1). AB - In the crystal of the title 1:1 adduct, C(8)H(7)ClO(2).C(12)H(10)N(4), the components are linked by an O-H?N hydrogen bond between the carb-oxy-lic acid and one of the pyridine N atoms. In the acid, the carb-oxy-lic acid group is approximately normal to [dihedral angle = 72.9 (2) degrees ] but twisted with respect to the plane through the benzene ring [C-C-C-O torsion angle = 25.4 (5) degrees ]. The base is roughly planar [dihedral angle between rings = 12.66 (15) degrees ; r.m.s. deviation of the 16 non-H atoms = 0.107 A] and the conformations about both imine bonds are E. The dimeric aggregates are linked into a supra molecular layer in the ab plane by C-H?O inter-actions. PMID- 21588699 TI - Quinoline-2-carbonitrile-fumaric acid (1/0.5). AB - The asymmetric unit of the title compound, C(10)H(6)N(2).0.5C(4)H(4)O(4), consists of one quinoline-2-carbonitrile mol-ecule and a half-mol-ecule of fumaric acid, which lies on an inversion center. The quinoline-2-carbonitrile mol ecule is almost planar, with an r.m.s. deviation of 0.008 (1) A. The acid and base are linked together via pairs of inter-molecular C-H?O and O-H?N hydrogen bonds, forming R(2) (2)(8) ring motifs. In the crystal, the carbonitrile mol ecules are further linked by inter-molecular C-H?N hydrogen bonds, generating R(2) (2)(10) ring motifs, resulting in zigzag chains running along the c axis. PMID- 21588700 TI - (2E)-1-(2,5-Dimethyl-3-thien-yl)-3-(2-meth-oxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C(16)H(16)O(2)S, the central propenone group is almost planar (r.m.s. deviation = 0.009 A) and subtends dihedral angles of 8.55 (8) and 16.22 (8) degrees to the 2-meth-oxy-phenyl and 2,5-dimethyl-thio-phene residues, respectively. The dihedral angle between the ring systems is 23.47 (5) degrees . In the crystal, mol-ecules are linked by weak C-H?pi inter-actions and aromatic pi-pi stacking [phenyl ring centroid-centroid separation = 3.6418 (11) A; thio phene-thio-phene ring separation = 3.8727 (9) A]. PMID- 21588701 TI - (E)-1-[(1,3-Dioxan-4-yl)meth-yl]-2-(nitro-methyl-idene)imidazolidine. AB - In the title compound, C(9)H(15)N(3)O(4), the 1,3-dioxane ring displays a chair conformation and the five-membered ring is close to planar (r.m.s. deviation = 0.054 A). An intra-molecular N-H?O hydrogen bond to one of the nitro-group O atoms generates an S(6) ring. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into C(6) chains propagating in [010] and a C-H?O link also occurs. PMID- 21588702 TI - (E)-N'-(2-Thienyl-methyl-idene)-p-toluene-sulfono-hydrazide. AB - The S-N(H)-N=C linkage in the title mol-ecule, C(12)H(12)N(2)O(2)S(2), is non planar [torsion angle = 15.5 (1) degrees ] as the amino N atom is pyramidally coordinated. The amino group acts as a hydrogen-bond donor to an O atom of an adjacent mol-ecule, generating chains running parallel to the c axis. PMID- 21588703 TI - (E)-N'-(9-Anthryl-methyl-idene)-p-toluene-sulfono-hydrazide. AB - The S-N(H)-N=C linkage in the title mol-ecule, C(22)H(18)N(2)O(2)S, is non-planar [torsion angle = 30.6 (1) degrees ] as the amino N atom is pyramidally coordinated. In the crystal, the amino group acts as a hydrogen-bond donor to an O atom of an adjacent mol-ecule, generating chains running parallel to the b axis. PMID- 21588704 TI - 2,4,6-Trimethyl-pyridinium nitrate. AB - In the title compound, C(8)H(12)N(+).NO(3) (-), the cation lies on a mirror plane and the N and one C atom lie on a twofold axis. In the crystal, the anions and cations are linked by N-H?O inter-actions along the b axis and a short N-O?pi contact [3.2899 (5) A] also occurs. PMID- 21588705 TI - 4-Methyl-N-[(S)-1-phenyl-eth-yl]benzene-sulfonamide. AB - In the title compound, C(15)H(17)NO(2)S, the dihedral angle between the aromatic rings is 14.47 (8) degrees . The mol-ecule is bent at the N atom, with a C-SO2-NH C torsion angle of 79.06 (13) degrees . In the crystal structure, the sulfonamide groups are hydrogen bonded via N-H?O links, forming chains of mol-ecules along the crystallographic b axis. pi-pi inter-actions [centroid-centroid distance = 3.81 (3) A] also occur. PMID- 21588706 TI - 2-(4-Bromo-phen-yl)-5-dodec-yloxy-1,3-thia-zole. AB - In the structure of the title compound, C(21)H(30)BrNOS, an important inter mediate for the preparation of liquid crystal compounds, the saturated C(12) chain shows a linear conformation while the benzene and thia-zole rings are essentially coplanar [dihedral angle = 4.5 (4) degrees ]. The crystal packing shows no significant inter-molecular inter-actions. PMID- 21588707 TI - 5-(4-Fluoro-benzyl-idene)-2,2-dimethyl-1,3-dioxane-4,6-dione. AB - The title compound, C(13)H(11)FO(4), was prepared by the reaction of 2,2-dimethyl 1,3-dioxane-4,6-dione and 4-fluoro-benz-alde-hyde in ethanol. The 1,3-dioxane ring adopts an envelope conformation. The crystal structure is stabilized by weak inter-molecular C-H?O hydrogen bonds. PMID- 21588708 TI - 4-[4-Eth-oxy-carbonyl-5-(3,4-methyl-ene-dioxy-phen-yl)-3-oxocyclo-hex-1-en-1-yl] 3-phenyl-sydnone. AB - In the title compound {systematic name: 4-[4-eth-oxy-carbonyl-5-(3,4-methyl-ene dioxy-phen-yl)-3-oxocyclo-hex-1-en-1-yl]-3-phenyl-1,2,3-oxadiazol-3-ium-5-olate}, C(24)H(20)N(2)O(7), the cyclo-hexene and dioxole rings adopt envelope conformations. The sydnone ring and the attached phenyl ring form a dihedral angle of 79.0 (1) degrees . In the mol-ecular structure, a C-H?O hydrogen bond generates an S(6) ring and a C-H?pi inter-action involving the phenyl ring is observed. In the crystal structure, mol-ecules are linked into a ribbon-like structure along the a axis by C-H?O hydrogen bonds. PMID- 21588709 TI - 2,3-Diamino-pyridinium (2E,4E)-hexa-2,4-dienoate. AB - In the title salt, C(5)H(8)N(3) (+).C(6)H(7)O(2) (-), the pyridine N atom of the 2,3-diamino-pyridine mol-ecule is protonated. The 2,3-diamino-pyridinium cation is essentially planar, with a maximum deviation of 0.068 (2) A for one of the amino N atoms. The sorbate anion adopts an extended conformation. In the crystal structure, the protonated N atom and one of the two amino-group H atoms are hydrogen bonded to the sorbate anion through a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The ion pairs are further connected via inter molecular N-H?O and C-H?O hydrogen bonds, forming two-dimensional networks parallel to (100). PMID- 21588710 TI - 2-Hy-droxy-11-methyl-16-[(E)-4-methyl-benzyl-idene]-13-(4-methyl-phen-yl)-1,11 diaza-penta-cyclo-[12.3.1.0.0.0]octa-deca-3(8),4,6-triene-9,15-dione. AB - In the title compound, C(32)H(30)N(2)O(3), the piperidin-4-one and the two fused pyrrolidine rings adopt envelope conformations. The two methyl-phenyl rings are oriented at dihedral angle of 20.36 (7) and 56.24 (7) degrees , respectively, with respect to the indanone ring system. In the crystal structure, inter molecular O-H?N and C-H?O hydrogen bonds link the mol-ecules into chains propagating along [001]. Weak C-H?pi inter-actions are also observed. PMID- 21588711 TI - 5-Carb-oxy-2,4-dihy-droxy-anilinium chloride. AB - In the title salt, C(7)H(8)NO(4) (+).Cl(-), the organic group is planar with an r.m.s. deviation of 0.0265 A. An S(6) ring motif is formed due to an intra molecular O-H?O hydrogen bond. The compound consists of dimers due to inter molecular O-H?O hydrogen bonds with an R(2) (2)(8) ring motif. The dimers are inter-linked through strong N-H?Cl and O-H?Cl hydrogen bonds, resulting in a three-dimensional polymeric network. PMID- 21588712 TI - [2-(2,3-Dimethyl-anilino)phen-yl]methanol. AB - In the title compound, C(15)H(17)NO, the 2,3-dimethyl-phenyl group is disordered over two sites with an occupancy ratio of 0.869 (3):0.131 (3). The major and minor components of the 2,3-dimethyl-anilino group are planar, with r.m.s. deviations of 0.0214 and 0.0303 A, respectively, and are oriented at a dihedral angle of 2.6 (6) degrees . The phenyl-methanol-benzene ring is oriented at dihedral angles of 83.16 (6) and 81.0 (3) degrees with respect to the major and minor components of the 2,3-dimethyl-anilino group, respectively. An S(6) ring motif is present due to intra-molecular N-H?O hydrogen bonding. In the crystal, mol-ecules are connected into supra-molecular chains via O-H?O hydrogen bonding along the b axis. C-H?pi inter-actions help to stabilize the crystal structure. PMID- 21588713 TI - Ethyl (Z)-2-chloro-2-(2-phenyl-hydrazin-1-yl-idene)acetate. AB - The title compound, C(10)H(11)ClN(2)O(2), features an almost planar C(ar)-N(H) N=C(Cl) unit [torsion angle = 0.8 (1) degrees whose phenyl substituent is almost coplanar with it [dihedral angle = 2.8 (2) degrees ]; this unit is slightly twisted with respect to the carboxyl -CO(2) fragment [dihedral angle = 10.3 (2) degrees ]. In the crystal, the amino group acts as a hydrogen-bond donor to the carbonyl O atom of an adjacent mol-ecule; the hydrogen bond generates a helical chain that runs along the b axis of the monoclinic unit cell. PMID- 21588714 TI - Ethyl 2-chloro-[2-(4-chloro-phen-yl)hydrazin-1-yl-idene]acetate. AB - The title compound, C(10)H(10)Cl(2)N(2)O(2), features a planar C(ar)-N(H)-N=C(Cl) unit [torsion angle = 5.5 (4) degrees ] whose benzene substituent is coplanar with it [dihedral angle = 4.7 (4) degrees ]; this unit is slightly twisted with respect to the carboxyl -CO(2) fragment [dihedral angle = 2.2 (52) degrees ]. The amino group acts as a hydrogen-bond donor to the carbonyl O atom of an adjacent mol-ecule; the hydrogen bond generates a helical polymer that runs along the b axis of the monoclinic unit cell. PMID- 21588715 TI - 5-[(E)-2-Bromo-benzyl-idene]-8-(2-bromo-phen-yl)-2-hy-droxy-10-methyl-3,10-di-aza hexa-cyclo-[10.7.1.1.0.0.0]henicosa-1(20),12,14,16,18-pentaen-6-one. AB - In the title compound, C(33)H(26)Br(2)N(2)O(2), the piperidine group adopts an envelope conformation while the two pyrrolidine groups adopt half-chair and envelope conformations. The dihydro-acenaphthyl-ene group is almost planar, with a maximum deviation of 0.105 (1) A. The dihedral angle between the two bromo phenyl rings is 60.19 (8) degrees . An intra-molecular O-H?N inter-action is observed, generating an S(5) ring motif. The crystal structure is stabilized by inter-molecular C-H?O inter-actions. Short Br?Br [3.461 (1) A] and Br?C [3.322 (2) A] inter-molecular contacts are observed, as well as pi-pi inter-actions [centroid-centroid distance = 3.793 (1) A]. PMID- 21588716 TI - 1,1,2,2-Tetra-kis(1,3-benzothia-zol-2-yl)ethene chloro-form disolvate. AB - The asymmetric unit of the title solvate, C(30)H(16)N(4)S(4).2CHCl(3), contains one half-molecule of tetrakis(2-benzothiazolyl)ethene, the complete molecule being generated by inversion symmetry, and one molecule of chloroform. Pairs of the benzothia-zole rings attached to the same carbon atom are almost perpendicular to each other, with an angle between planes of 85.74 (4) degrees . In the crystal, weak C-H?N and C-H?Cl interactions generate a three-dimensional network. PMID- 21588717 TI - 5-(4-Fluoro-phen-yl)-2-[2-(5-phenyl-1,3-oxazol-2-yl)phen-yl]-1,3-oxazole. AB - In the title compound, C(24)H(15)FN(2)O(2), the dihedral angles between the central benzene ring and the oxazole rings are 10.7 (6) and 64.1 (5) degrees . The dihedral angles between the oxazole rings and their pendant rings are 2.0 (3) and 24.3 (2) degrees . The F atoms are disordered over two sites with occupancies of 0.627 (3) and 0.373 (3) in the phenyl-ene-oxazol-yl-phenyl and in oxazol-yl phenyl fragments, respectively. In the crystal structure, mol-ecules are linked through a network of C-H?F and weak pi-pi stacking inter-actions. PMID- 21588718 TI - rac-(3aR,6aR)-(E)-Methyl 2-(3a-methyl-perhydro-furo[3,2-b]furan-2-yl idene)acetate. AB - The constitution and relative configuration at the stereogenic centres and stereochemistry of the C-C double bond formed during Pd(II)-catalysed domino reaction was established by X-ray analysis of the title compound, C(10)H(14)O(4). The asymmetric unit contains two mol-ecules. PMID- 21588719 TI - Trithia-cyanuric acid: a second triclinic polymorph. AB - The title compound, C(3)H(3)N(3)S(3), is a triclinic modification. The other reported modification crystallizes with just one mol-ecule in the asymmetric unit, [Guo et al. (2006 ?). Cryst. Growth Des.6, 846-848] and was solved by power X-ray diffraction data. The present modification has Z' = 2. In the crystal, mol ecules are linked by strong intra-molecular N-H?S hydrogen bonds with set graph motif R(2) (2)(8). In both mol-ecules, all of the N atoms and two of the S atoms are involved in hydrogen bonding, with an average H?S distance of 2.58 A and N H?S angles in the range 163-167 degrees . pi-pi stacking inter-actions are not observed. In the solid state, the mol-ecules exist in the thione form. The mol ecular and supra-molecular properties are similar in both polymorphs. PMID- 21588720 TI - Ethyl 2-isopropyl-amino-6-methyl-8-oxo-3-phenyl-3H,8H-furo[2,3 d][1,2,4]triazolo[1,5-a]pyrimidine-7-carboxyl-ate. AB - In the title compound, C(20)H(21)N(5)O(4), the ring system containing the three fused rings is essentially planar (r.m.s. deviation for all 12 non-H atoms = 0.041 A). The phenyl ring makes a dihedral angle of 54.41 (6) degrees with this ring system. The isopropyl group is disordered over two positions, with site occupancy factors of 0.753 (9) and 0.247 (9). The structure is mainly stabilized by weak inter-molecular N-H?O and intra-molecular C-H?O hydrogen-bonding inter actions and pi-pi inter-actions, with inter-planar distances of 3.415 (1) A between adjacent furan ring centroids and 3.420 (1) A between the benzene and pyrimidinone rings. PMID- 21588721 TI - Dimethyl 3,3'-diphenyl-2,2'-[(S)-thio-phene-2,5-diylbis(carbonyl-aza-nedi yl)]dipropano-ate. AB - The asymmetric unit of the title compound, C(26)H(26)N(2)O(6)S, contains two independent mol-ecules; each has twofold symmetry with the S atom and the mid point of the C-C bond of the thio-phene ring located on a twofold rotation axis. In the two mol-ecules, the terminal benzene rings are oriented at dihedral angles of 65.8 (3) and 63.5 (3) degrees with respect to the central thio-phene rings. The meth-oxy-carbonyl group of one mol-ecule is disordered over two positions with site-occupancy factors of 0.277 (12) and 0.723 (12). Inter-molecular N-H?O hydrogen bonding is present in the crystal structure. PMID- 21588722 TI - 6,6'-Dimethyl-2,2'-[oxalylbis(aza-nedi-yl)]dipyridinium dichloride acetonitrile solvate. AB - In the crystal structure of the title compound, C(14)H(16)N(4)O(2) (2+).2Cl( ).CH(3)CN, weak inter-molecular N-H?Cl hydrogen bonds are found between the H atoms bound to the pyridine and amine N atoms and the chloride anions. The asymmetric unit consits of one half cationic mol-ecule which is located on a centre of inversion, one chloride anion in a general position and one half acetonitrile mol-ecule which is located on a twofold axis. Because of symmetry, the C-H hydrogens of the acetonitrile solvent mol-ecule are disordered over two orientations. PMID- 21588723 TI - 1-(2-Oxoindolin-3-yl-idene)-4-[2-(tri-fluoro-meth-yl)phen-yl]thio-semicarbazide. AB - In the title compound, C(16)H(11)F(3)N(4)OS, the dihedral angle between the aromatic ring systems is 69.15 (10) degrees . Intra-molecular N-H?N and N-H?O hydrogen bonds generate S(5) and S(6) rings, respectively. A short N-H?F contact also occurs. In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(8) loops. The dimers are linked by N-H?F hydrogen bonds, forming polymeric chains propagating in [100]. pi-pi inter-actions also exist between the centroids of the benzene rings of the 2-oxoindoline group at a distance of 3.543 (3) A and a short C=O?pi contact occurs. Two F atoms of the trifluoro-methyl group are disordered over two sets of sites in a 0.517 (8):0.483 (8) ratio. PMID- 21588724 TI - N-(2,5-Dimeth-oxy-phen-yl)-N'-[4-(2-hy-droxy-eth-yl)phen-yl]urea. AB - In the title compound, C(17)H(20)N(2)O(4), the 2,5-dimeth-oxy-phenyl unit is essentially planar, with an r.m.s. deviation of 0.015 A. The dihedral angle between the benzene rings is 43.66 (4) degrees . The mol-ecular structure is stabilized by a short intra-molecular N-H?O hydrogen bond. In the crystal, inter molecular N-H?O and O-H?O hydrogen bonds link the mol-ecules into a three dimensional network. PMID- 21588725 TI - 4-(1H-Tetra-zol-5-yl)-1H-indole. AB - There are two mol-ecules with similar configurations in the asymmetric unit of the title compound, C(9)H(7)N(5), which are linked by inter-molecular N-H?N hydrogen bonds into chains with graph-set motif C(2) (2)(8) along the b axis. The indole core has the expected planar geometry in the two mol-ecules, with a maximum deviation of 0.008 (8) A from the least-squares plane defined by the nine constituent atoms, and the dihedral angles between the indole and tetra-zole rings are similar [42.4 (2) and 42.7 (2) degrees ]. PMID- 21588726 TI - 2,2'-Dimethyl-5,5'-dipropan-2-yl-4,4'-(phenyl-methyl-ene)diphenol. AB - In the title mol-ecule, C(27)H(32)O(2), the aromatic rings are in a propeller configuration. In the crystal, mol-ecules are linked through O-H?O hydrogen bonds forming a two-dimensional network which develops parallel to (010). Futhermore, weak C-H?pi inter-actions involving the two substituted rings build up a three dimensional network. PMID- 21588727 TI - 1-(Prop-2-en-1-yl)-3-[(trimethyl-sil-yl)meth-yl]benzimidazolium bromide monohydrate. AB - In the title compound, C(14)H(21)N(2)Si(+).Br(-).H(2)O, the benzimidazole ring system is almost planar [maximum deviation = 0.021 (2) A]. In the crystal, O-H?Br and C-H?O hydrogen bonds link the ions via the O atoms of the water mol-ecules. In addition, there are pi-pi stacking inter-actions between the centroids of the benzene and imidazole rings of the benzimidazole ring system [centroid-centroid distances = 3.521 (3) and 3.575 (2) A]. PMID- 21588728 TI - 9beta-Hy-droxy-1beta,10alpha-ep-oxy-parthenolide. AB - The title compound, C(15)H(20)O(5) (systematic name: 5-hydroxy-1a,4a-dimethyl-7 methyleneperhydrodioxireno[5,6:9,10]cyclo-deca[1,2-b]furan-8-one), was obtained by the reaction of 3-chloro-perbenzoic acid with 9beta-hy-droxy-parthenolide. The five-membered ring adopts a twist conformation, whereas the ten-membered ring displays an approximate chair-chair conformation. In the crystal structure, mol ecules are linked into chains propagating along the b axis by inter-molecular O H?O hydrogen bonds. PMID- 21588729 TI - Quinoline-2-carbonitrile. AB - In the title compound, C(10)H(6)N(2), the mol-ecule is almost planar, with an r.m.s. deviation of 0.014 A. The dihedral angle between the aromatic rings is 1.28 (16) degrees . In the crystal, mol-ecules are stacked along the a axis by way of weak aromatic pi-pi stacking inter-actions between the benzene and pyridine rings of adjacent mol-ecules [centroid-centroid separation = 3.7943 (19) A]. PMID- 21588730 TI - 2-Amino-4-methyl-pyridinium hexa-2,4-dienoate dihydrate. AB - In the title salt, C(6)H(9)N(2) (+).C(6)H(7)O(2) (-).2H(2)O, the non-H atoms of the 2-amino-4-methyl-pyridinium cation are coplanar, with a maximum deviation of 0.010 (1) A. In the crystal structure, the pyridinium N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The sorbate anions and water mol-ecules are linked through O-H?O hydrogen bonds, forming R(10) (10)(28) and R(6) (4)(12) ring motifs. The motifs form part of a three-dimensional framework. PMID- 21588731 TI - Bis(imidazolium) galacta-rate dihydrate. AB - In the structure of the title salt, 2C(3)H(5)N(2) (+).C(6)H(8)O(8) (2-).2H(2)O, the galacta-rate dianions have crystallographic inversion symmetry and together with the water mol-ecules of solvation form hydrogen-bonded sheet substructures which extend along (110). The imidazolium cations link these sheets peripherally down c through carboxyl-ate O-H-N and N'-H?O(hy-droxy) bridges, giving a three dimensional framework structure. PMID- 21588732 TI - N-(4-Methyl-phen-yl)-3-nitro-pyridin-2-amine. AB - Two independent mol-ecules comprise the asymmetric unit of the title compound, C(12)H(11)N(3)O(2). These differ in terms of the relative orientations of the benzene rings as seen in the respective dihedral angles formed between the pyridine and benzene rings [17.42 (16) and 34.64 (16) degrees ]. Both mol-ecules are twisted about the amine-tolyl N-C bonds [respective torsion angles = 22.3 (5) and 35.9 (5) degrees ] but only about the amine-pyridine N-C bond in the first independent mol-ecule [respective torsion angles = -11.7 (5) and 0.8 (5) degrees ]. Intra-molecular N-H?O hydrogen bonds preclude the amine H atoms from forming significant inter-molecular inter-actions. The crystal packing features inter molecular C-H?O and C-H?pi and pi-pi [centroid-centroid distance: pyridine benzene = 3.6442 (19) A and pyridine-pyridine = 3.722 (2) A] contacts. PMID- 21588733 TI - (E,E)-1,2-Bis(2,4,6-trimeth-oxy-benzyl-idene)hydrazine. AB - The title mol-ecule, C(20)H(24)N(2)O(6), lies on an inversion centre. All non-H atoms are essentially coplanar, with an r.m.s. deviation of 0.0415 (1) A and a maximum deviation of 0.1476 (1) A for the meth-oxy C atom at the 4-position of the benzene ring. The crystal structure is stabilized by weak C-H?N and C-H?pi inter-actions. PMID- 21588734 TI - 3-Phenyl-2-(pyrrolidin-1-yl)-5,6-dihydro-8H-thio-pyrano[4',3':4,5]thieno[2,3 d]pyrimidin-4(3H)-one. AB - In the title compound, C(19)H(19)N(3)OS(2), the thio-pyran ring adopts a twist chair conformation and the pyrimidinone unit is essentially planar, with a mean deviation of 0.0497 A. The thio-phene ring is essentially planar with a maximum deviation of 0.024 (2) A, while the pyrrolidine ring exhibits an envelope conformation. The pyrimidinone and thio-phene rings are almost coplanar, forming a dihedral angle of 6.31 (15) degrees , while the dihedral angle between the mean planes of the phenyl ring and the pyrimidinone ring is 68.13 (10) degrees . In the crystal structure, adjacent mol-ecules are linked by C-H?O hydrogen bonds, forming a two-dimensional network in the ac plane. PMID- 21588735 TI - (2E)-3-[4-(Dimethyl-amino)-phen-yl]-1-(2,5-dimethyl-3-thien-yl)prop-2-en-1-one. AB - The asymmetric unit of the title compound, C(17)H(19)NOS, contains two independent mol-ecules which differ in the dihedral angles between the five- and six-membered rings [12.52 (10) and 4.63 (11) degrees ]. Weak inter-molecular C H?O hydrogen bonds link the two independent mol-ecules into pseudocentrosymmetric dimers. In one mol-ecule, the O atom of the carbonyl group is disordered over two positions in a 0.699 (4):0.301 (4) ratio. PMID- 21588736 TI - (E)-Methyl 3-(3,5-dibromo-2-hy-droxy-benzyl-idene)carbazate. AB - The title compound, C(9)H(8)Br(2)N(2)O(3), crystallizes with two very similar independent mol-ecules in the asymmetric unit, each of which adopts a trans configuration with respect to the C=N bond. Intra-molecular O-H?N hydrogen bonds are observed in each independent mol-ecule. In the crystal structure, mol-ecules are linked into chains propagating along [010] by N-H?O and C-H?O hydrogen bonds. In addition, C-H?pi inter-actions stabilize the structure. PMID- 21588737 TI - Cyclo-hexane-1,3-diyl bis-(N-phenyl-carbamate). AB - The asymmetric unit of the title compound, C(20)H(22)N(2)O(4), comprises two crystallographically independent mol-ecules (A and B) with slightly different geometries. The dihedral angle between the two terminal phenyl rings is 61.7 (1) degrees in mol-ecule A and 29.6 (1) degrees in B. The cyclo-hexane rings adopt chair conformations. In the crystal packing, inter-molecular N-H?O hydrogen bonds inter-connect adjacent mol-ecules into a ladder-like structure along the c axis incorporating R(2) (2)(20) ring motifs. The crystal packing is further stabilized by weak inter-molecular C-H?pi inter-actions. PMID- 21588738 TI - 2-Amino-5-bromo-pyridinium 3-carb-oxy-4-hy-droxy-benzene-sulfonate. AB - The asymmetric unit of the title salt, C(5)H(6)BrN(2) (+).C(7)H(5)O(6)S(-), contains two independent 2-amino-5-bromo-pyridinium cations and two independent 3 carb-oxy-4-hy-droxy-benzene-sulfonate anions. The hy-droxy and carboxyl groups of the anions are involved in intra-molecular O-H?O hydrogen bonds, which generate S(6) ring motifs. In the crystal structure, the ions are linked by N-H?O and O H?O hydrogen bonds into a two-dimensional network parallel to (110). Adjacent networks are linked via C-H?O hydrogen bonds. PMID- 21588739 TI - (2E)-N'-[(E)-4-Chloro-benzyl-idene]-3-phenyl-prop-2-enohydrazide monohydrate. AB - The conformation about each of the imine and ethene bonds in the title hydrazide hydrate, C(16)H(13)ClN(2)O.H(2)O, is E. The hydrazide mol-ecule is approximately planar (r.m.s. deviation of the 20 non-H atoms = 0.172 A). The most significant twist occurs about the ethene bond [C-C=C-C = 164.1 (5) degrees ] and the dihedral angle formed between the benzene rings is 5.3 (2) degrees ]. In the crystal, the presence of N-H?O(w) and O-H?O(c) (* 2; w = water and c = carbon-yl) hydrogen bonds leads to a supra-molecular array in the bc plane. PMID- 21588740 TI - Ethyl 1-sec-butyl-2-(4-chloro-phen-yl)-1H-benzimidazole-5-carboxyl-ate. AB - In the title compound, C(20)H(21)ClN(2)O(2), the ethyl 1H-benzimidazole-5 carboxyl-ate ring system, excluding the methyl-ene and methyl H atoms, is almost planar, with a maximum deviation of 0.055 (1) A, and makes a dihedral angle of 40.63 (4) degrees with the benzene ring. The sec-butyl group is disordered over two positions, with refined site occupancies of 0.855 (4) and 0.145 (4). In the crystal, mol-ecules are linked into chains along [010] via inter-molecular C-H?O hydrogen bonds and are further inter-connected by C-H?Cl inter-actions into two dimensional networks parallel to (001). The crystal structure is further consolidated by C-H?pi inter-actions. PMID- 21588741 TI - 3-(2-Amino-5-nitro-anilino)-5,5-dimethyl-cyclo-hex-2-en-1-one 0.25-hydrate. AB - The asymmetric unit of the title compound, C(14)H(17)N(3)O(3).0.25H(2)O, comprises two independent organic mol-ecules and a water mol-ecule lying on a crystallographic twofold rotation axis with 50% site occupancy. In both independent mol-ecules, the cyclo-hexene rings adopt envelope conformations but superposition of the two molecules shows that the flap atoms point in opposite directions. In the crystal, N-H?O and C-H?O hydrogen bonds inter-connect adjacent mol-ecules into a three-dimensional network. Weak inter-molecular pi-pi aromatic stacking inter-actions [centroid-centroid distances = 3.4985 (9) and 3.6630 (9) A] are also observed. PMID- 21588742 TI - 1-[(1,3-Dithio-lan-2-yl)meth-yl]-8-nitro-6-propyl-1,2,3,5,6,7-hexa-hydro imidazo[1,2-c]pyrimidine. AB - In the title compound, C(13)H(22)N(4)O(2)S(2), the six-membered ring displays a half-chair conformation. The olefin amine unit is close to being coplanar with the imidazolidine ring (r.m.s. deviation = 0.059 A). The dithiol-ane ring adopts a twisted conformation. In the crystal, mol-ecules are linked by weak C-H?O inter actions. PMID- 21588743 TI - 4-Bromo-N-[4-(diethyl-amino)-benzyl-idene]aniline. AB - The asymmetric unit of the title compound, C(17)H(19)BrN(2), contains two independent mol-ecules. The dihedral angles between the two benzene rings in are 60.4 (2) and 61.0 (2) degrees . PMID- 21588744 TI - 2-Hy-droxy-7-meth-oxy-9H-carbazole-3-carbaldehyde. AB - The title compound, C(14)H(11)NO(3), was isolated from the roots of Clausena wallichii. The carbazole ring system is approx-imately planar (r.m.s. deviation = 0.039 A) and the dihedral angle between the two benzene rings is 4.63 (7) degrees . An intra-molecular O-H?O hydrogen bond generates an S(6) ring motif. In the crystal, mol-ecules are linked into a zigzag network extending parallel to the ac plane by O-H?N and N-H?O hydrogen bonds. PMID- 21588745 TI - 4-Methyl-3-nitro-benzaldehyde. AB - In the crystal structure of the title compound, C(8)H(7)NO(3), mol-ecules are linked through weak inter-molecular C-H?O hydrogen bonding. PMID- 21588746 TI - Ethyl 7-(4-bromo-phen-yl)-5-trifluoro-methyl-4,7-dihydro-tetra-zolo[1,5 a]pyrimidine-6-carboxyl-ate. AB - In the title compound, C(14)H(11)BrF(3)N(5)O(2), the pyrimidine ring adopts a flattened envelope conformation with sp(3)-hybridized carbon as the flap [deviation = 0.177 (3) A]. The dihedral angle between tetra-zole and bromo-phenyl rings is 84.3 (1) degrees . In the crystal, mol-ecules are linked into centrosymmetric dimers by pairs of N-H?N hydrogen bonds. PMID- 21588747 TI - 2-Bromo-4-chloro-6-{(E)-[4-(diethyl-amino)-phen-yl]imino-meth-yl}phenol. AB - In the title compound, C(17)H(18)BrClN(2)O, the dihedral angle between the aromatic rings is 3.0 (1) degrees . The methyl-ethanamine group assumes an extended conformation. An intra-molecular O-H?N hydrogen bond generates an S(6) ring motif. The crystal packing is stabilized by C-H?pi and pi-pi [centroid centroid distances = 3.691 (1) and 3.632 (1) A] inter-actions. PMID- 21588748 TI - Salicyl-aldehyde-4-(dimethyl-amino)-pyridine (1/1). AB - In the title compound, C(7)H(10)N(2).C(7)H(6)O(2), the components are linked by an O-H?N hydrogen bond. The mean planes of two mol-ecules form a dihedral angle of 78.68 (5) degrees . The crystal packing exhibits weak non-classical C-H?O contacts. PMID- 21588749 TI - 3-[(4-Fluoro-phen-yl)sulfon-yl]-5-iodo-2-methyl-1-benzofuran. AB - In the title compound, C(15)H(10)FIO(3)S, the 4-fluoro-phenyl ring makes a dihedral angle of 72.27 (6) degrees with the mean plane of the benzofuran fragment [mean deviation of 0.014 (2) A from the plane defined by the nine constituent atoms]. In the crystal, pairs of weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers, which are further linked via an aromatic pi-pi inter-actions between the iodo-benzene rings of neighbouring mol-ecules [centroid-centroid distance = 3.569 (3) A]. PMID- 21588750 TI - 1,2,3,4-Tetra-hydro-phenazine 5,10-dioxide. AB - The complete mol-ecule of the title compound, C(12)H(12)N(2)O(2), lies on two crystallographic symmetry elements: a twofold axis and a mirror plane. In the mol ecular structure, the quinoxaline ring and two methyl-ene substituents lie on the mirror plane while the other two methyl-ene groups are disordered about the plane. The crystal packing is stabilized by weak inter-molecular pi-pi stacking inter-actions with centroid-centroid distances of 3.6803 (7) A. PMID- 21588751 TI - 7-(2-Chloro-phen-yl)-2,6,9-trimethyl-dibenzo[b,h][1,6]naphthyridine. AB - In the title compound, C(25)H(19)ClN(2), the dibenzo[b,h][1,6]naphthyridine system is planar to within 0.16 (2) A, and the chloro-phenyl ring is inclined to it by 82.53 (7) degrees . In the crystal, mol-ecules are linked by C-H?N hydrogen bonds, forming chains propagating in [100]. There are also a number of weak pi-pi stacking inter-actions present [centroid-centroid distances = 3.8531 (1) and 3.7631 (1) A]. PMID- 21588752 TI - 2-(4-Meth-oxy-phen-oxy)-3-nitro-pyridine. AB - In the title mol-ecule, C(12)H(10)N(2)O(4), the pyridine and benzene rings are almost orthogonal [dihedral angle = 86.69 (11) degrees ], with the pyridine N atom directed towards the centre of the benzene ring. The -NO(2) [O-N-C-C = -26.1 (3) degrees ] and -OMe [C-O-C-C = 166.5 (2) degrees ] substituents are not coplanar with their respective aromatic rings. In the crystal, supra-molecular layers in the ab plane are formed via C-H?pi inter-actions involving methyl H atoms and the pyridine and benzene rings. Short N-O?pi contacts (where the pi system is derived from the pyridine ring) occur between layers in the c-axis direction. PMID- 21588753 TI - 2-(3-Nitro-phen-oxy)quinoxaline. AB - In the title mol-ecule, C(14)H(9)N(3)O(3), the dihedral angle between the quinoxaline and benzene rings is 77.13 (9) degrees . The mol-ecule is twisted about the ether-benzene O-C bond, with a C-O-C-C torsion angle of -102.8 (2) degrees . In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming layers in the ab plane, with one nitro O atom accepting two such inter-actions. The layers stack along the c-axis direction via weak C-H?pi inter-actions. PMID- 21588754 TI - 4-Amino-N-(4,6-dimethyl-pyrimidin-2-yl)benzene-sulfonamide-benzoic acid (1/1). AB - The constituents of the title co-crystal, C(12)H(14)N(4)O(2)S.C(7)H(6)O(2), are connected by an eight-membered hetero-synthon {?NCNH?OCOH}, whereby the carb-oxy lic acid forms donor and acceptor hydrogen bonds with a pyrimidine N atom and the adjacent amine, respectively. The dimeric aggregates thus formed are arranged in rows with their terminal NH(2) groups forming N-H?O hydrogen bonds with neighbouring aggregates to form a two-dimensional array in the ac plane with an overall T-shaped topology. Layers inter-digitate along the b axis being connected by C-H?O, C-H?pi and pi-pi [centroid-centroid distance = 3.6316 (19) A] inter actions. PMID- 21588755 TI - 7'-Methyl-5'-oxo-2',3'-dihydro-spiro-[1,3-dioxolane-2,1'(5'H)-indolizine]-6' carbonitrile. AB - In the title compound, C(12)H(12)N(2)O(3), the five-membered ring attached to the aromatic ring adopts an envelope conformation with a C atom in the flap position. The spiro-linked five-membered ring adopts a twisted conformation. In the crystal, C-H?O hydrogen bonds link the mol-ecules into C(5) chains propagating in [001]. PMID- 21588756 TI - 4,5,6,7-Tetra-chloro-N-(2-fluoro-phen-yl)phthalimide. AB - In the title compound, C(14)H(4)Cl(4)FNO(2), the benzene ring and the phthalimide plane are nearly planar, the maximum deviations being 0.005 (2) and 0.010 (2) A, respectively, but the mol-ecule as a whole is not planar: the dihedral angle between the two planar ring systems is 68.06 (10) degrees . A short Cl?O contact of 2.914 (2) A exists in the crystal structure. PMID- 21588757 TI - 2,6-Diamino-pyridinium 2-carb-oxy-benzoate. AB - In the crystal of the title mol-ecular salt, C(5)H(8)N(3) (+).C(8)H(5)O(4) (-), the diamino-pyridine cation and the phthalate anion are linked by a pair of N-H?O hydrogen bonds. Within the phthalate anion, an almost symmetrical O-H?O hydrogen bond is observed. The ion pairs are linked by further N-H?O hydrogen bonds, generating a two-dimensional network lying parallel to (10). PMID- 21588758 TI - 2-Hy-droxy-N-(3-nitro-phen-yl)benzamide. AB - In the crystal structure of title compound, C(13)H(10)N(2)O(4), as expected, the nitro- and hy-droxy-substituted benzene rings are planar with r. m. s. deviations of 0.0037 and 0.0014 A, respectively, but are twisted slightly relative to each other, making a dihedral angle of 12.23 (7) degrees . The nitro group is only slightly twisted [by 2.71 (16) degrees ] with respect to its parent ring. An intra-molecular N-H?O hydrogen bond forms an S(6) ring motif. Inter-molecular N H?O and O-H?O hydrogen bonds build up sheets parallel to the ab plane. Futhermore, weak pi-pi inter-actions [centroid-centroid distances = 3.7150 (8) 3.7342 (6) and 3.9421 (8) A] between the rings yield a three-dimensional network. PMID- 21588759 TI - 4-{2-[(Z)-(5-Methyl-2-fur-yl)methyl-idene-amino]-eth-yl}benzene-sulfonamide. AB - In the title compound, C(14)H(16)N(2)O(3)S, the dihedral angle between the phenyl and 5-methyl-furan groups is 54.89 (14) degrees and the C=N bond assumes a trans conformation. In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(8) ring motifs. The dimers are inter-linked by N-H?N hydrogen bonds, resulting in the formation of infinite chains extending along the b axis. The packing is consolidated by weak C-H?pi inter-actions. PMID- 21588760 TI - Absolute configuration of odorine. AB - The title compound, known as odorine or roxburghiline {systematic name: (S)-N [(R)-1-cinnamoylpyrrolidin-2-yl]-2-methyl-butanamide}, C(18)H(24)N(2)O(2), is a nitro-genous compound isolated from the leaves of Aglaia odorata. The absolute configuration was determined by refinement of the Flack parameter with data collected using Cu Kalpha radiation showing positions 2 and 2' to be S and R, respectively. The pyrrolidine ring adopts an envelope conformation. In the crystal, mol-ecules are linked into chains along [010] by inter-molecular N-H?O hydrogen bonds. PMID- 21588761 TI - 2-[(E)-(2,3-Dimethyl-phen-yl)imino-meth-yl]phenol. AB - In the title compound, C(15)H(15)NO, the almost planar 2,3-dimethyl-aniline unit and the salicyl-aldehyde group (r.m.s. deviations of 0.0156 and 0.0109 A, respectively) are oriented at a dihedral angle of 43.69 (9) degrees with respect to each other. An S(6) ring motif is formed due to intra-molecular O-H?N hydrogen bonding. In the crystal, C-H?pi inter-actions occur between the 2,3-dimethyl aniline unit and the salicyl-aldehyde group, where the CH is from the o-methyl group. PMID- 21588762 TI - 2-(2,3-Dimethyl-phen-yl)-1H-isoindole-1,3(2H)-dione. AB - In the title compound, C(16)H(13)NO(2), the 2,3-dimethyl-phenyl group and the 1H isoindole-1,3(2H)-dione group are essentially planar, with r.m.s. deviations of 0.006 and 0.013 A, respectively, and are oriented at an angle of 78.19 (3) degrees with respect to each other. In the crystal, weak C-H?O inter-actions link the mol-ecules, forming a zigzag chain parallel to the b axis. Futhermore, C H?pi inter-actions are present between the C-H group of isoindole and the 2,3 dimethyl-phenyl benzene ring. The H atoms of the ortho-methyl group are statistically disordered over two positions. Such disorder might be related to the antagonism between intra-molecular steric repulsions and inter-molecular C H?O inter-actions. PMID- 21588763 TI - 3-Chloro-6-[2-(propan-2-yl-idene)hydrazin-yl]pyridazine. AB - In the title compound, C(7)H(9)ClN(4), the 3-chloro-6-hydrazinylpyridazine unit is planar (r.m.s. deviation = 0.0219 A) and is oriented at a dihedral angle 4.66 (27) degrees with respect to the propan-2-yl-idene group. In the crystal, the mol-ecules are linked into non-planar dimers due to a crystallographic twofold rotation via N-H?N hydrogen bonds with R(2) (2)(8) graph-set ring motifs. PMID- 21588764 TI - Tetra-kis(4-tert-butyl-benz-yl)silane. AB - The title compound, C(44)H(60)Si, was prepared as an inter-nal standard for diffusion-ordered NMR spectroscopy. The Si atom lies on a special position with site symmetry. PMID- 21588765 TI - Redetermination of bis-{(1S,2S,4S,5R)-2-[(R)-hy-droxy(6-meth-oxy-4-quinol-yl)meth yl]-5-vinyl-quinuclidinium} sulfate dihydrate. AB - The structure of the title compound, known as quinine sulfate dihydrate, 2C(20)H(25)N(2)O(2) (+).SO(4) (2-).2H(2)O, was previously reported by Mendel [Proc. K. Ned. Akad. Wet. (1955), 58, 132-134], but only the [010] projection was determined. Hence, we have redetermined its crystal structure at 100 K using three-dimensional data. The asymmetric unit consists of a quininium cation, viz. (R)-(6-meth-oxy-quinolinium-4-yl)[(1S,2S,4S,5R)-5-vinyl-quinuclid-in-ium-2 yl]methanol, one half of a sulfate anion and a water mol-ecule. The S atom occupies a special position on a twofold axis. The packing is characterized by infinite columns, consisting of sulfate anions and water mol-ecules, linked through hydrogen bonds along the b axis, and further stabilized by hydrogen bonds to quininium cations. The quininium cations inter-act further through C-H?O and C H?pi inter-actions. PMID- 21588766 TI - Ethyl 5-amino-1-(6-chloro-pyridazin-3-yl)-1H-pyrazole-4-carboxyl-ate. AB - In the title compound, C(10)H(10)ClN(5)O(2), the dihedral angle between the aromatic rings is 0.16 (9) degrees . Two S(6) ring motifs are formed due to intra molecular N-H?N and N-H?O hydrogen bonds. In the crystal, inversion dimers linked by pairs of N-H?N hydrogen bonds generate R(2) (2)(14) [or R(4) (4)(10) via the intra-molecular hydrogen bonds] ring motifs. Polymeric chains propagating in [210] are formed as a result of inter-linking the dimers by pairs of C-H?N inter actions, completing R(2) (2)(6) ring motifs. PMID- 21588767 TI - N-(3-Methyl-phen-yl)pyrimidin-2-amine. AB - Two independent mol-ecules comprise the asymmetric unit in the title compound, C(11)H(11)N(3). These differ in terms of the relative orientations of the aromatic rings: the first is somewhat twisted, while the second is approximately planar [dihedral angles between the pyrimidine and phenyl rings = 39.00 (8) and 4.59 (11) degrees ]. The mol-ecules also form distinct patterns in their hydrogen bonding. The first independent mol-ecule forms centrosymmetric dimers featuring an eight-membered {HNCN}(2) synthon. The second independent mol-ecule forms an N H?N hydrogen bond with the other pyrimidine N atom of the first mol-ecule. Thereby, tetra-meric aggregates are formed. These associate via C-H?N and C-H?pi inter-actions, consolidating the crystal packing. PMID- 21588768 TI - 1-(2-Oxoindolin-3-yl-idene)-4-[2-(trifluoro-meth-oxy)phen-yl]thio-semi-carbazide. AB - The crystal structure of the title compound, C(16)H(11)F(3)N(4)O(2)S, is stabilized in the form of polymeric chains by N-H?O inter-actions. In the mol ecular structure, two S(5) ring motifs are formed by intra-molecular N-H?N and N H?O hydrogen bonding and two S(6) rings are present due to N-H?O and C-H?S inter actions. pi-pi inter-actions are present with distances of 3.2735 (17), 3.563 (2) and 3.664 (4)/3.688 (3) A between the centroids of the heterocyclic rings, between the centroids of the heterocyclic ring and trifluoro-meth-oxy-substituted phenyl ring, and between the centroids of the trifluoro-meth-oxy-substituted phenyl rings, respectively. The trifluoro-meth-oxy-phenyl group is disordered over two sites with an occupancy ratio of 0.642 (10):0.358 (10). PMID- 21588769 TI - 5'-Amino-2-oxo-2',3'-dihydro-spiro-[indoline-3,7'-thieno[3,2-b]pyran]-6' carbonitrile 1',1'-dioxide. AB - In the title compound, C(15)H(11)N(3)O(4)S, the dihedral angle between the mean planes of the dihydro-indol-2-one (r.m.s. deviation = 0.015 A) and dihydro thieno[3,2-b]pyran (r.m.s. deviation = 0.011 A) ring systems is 89.53 (3) degrees . The crytal packing is consolidated by inter-molecular N-H?O and N-H?N hydrogen bonds, which link the mol-ecules into a two-dimensional network into sheets lying parallel to (100). PMID- 21588770 TI - 5-Chloro-3-ethyl-sulfinyl-2-(4-iodo-phen-yl)-1-benzofuran. AB - In the title compound, C(16)H(12)ClIO(2)S, the 4-iodo-phenyl ring is rotated out of the benzofuran plane by 9.4 (1) degrees . In the crystal structure, inter molecular C-H?pi inter-actions and short inter-molecular I?O contacts [3.142 (2) A] are observed. PMID- 21588771 TI - 6,6'-Dimeth-oxy-2,2'-[(cyclo-hexane-1,2-di-yl)bis-(nitrilo-methyl idyne)]diphenol. AB - The mol-ecule of the title compound, C(22)H(26)N(2)O(4), has two azomethine linkages, both of which are in an E configuration. The cyclo-hexyl ring adopts a chair conformation. The dihedral angle between the benzene rings is 66.57 (9) degrees . The mol-ecular structure is stabilized by two intra-molecular O-H?N hydrogen bonds. PMID- 21588772 TI - 1-(2,2-Dimeth-oxy-eth-yl)-8-nitro-1,2,3,5,6,7-hexa-hydro-imidazo[1,2-a]pyridin-5 ol. AB - In the title compound, C(11)H(19)N(3)O(5), the six-membered ring displays a half chair conformation and the imidazolidine ring is essentially planar (r.m.s. deviation = 0.088 A). An inter-molecular hydrogen bond between the hy-droxy O atom and a nitro O atom stabilizes the crystal packing. PMID- 21588773 TI - 17-Acet-oxy-mulinic acid. AB - THE TITLE COMPOUND, [SYSTEMATIC NAME: 5a-acet-oxy-methyl-3-isopropyl-8-methyl 1,2,3,3a,4,5,5a,6,7,10,10a,10b-dodeca-hydro-7,10-endo-epidi-oxy-cyclo-hepta [e]indene-3a-carb-oxy-lic acid], C(22)H(32)O(6) (I), is closely related to methyl 5a-acet-oxy-methyl-3-isopropyl-8-methyl-1,2,3,3a,4,5,5a,6,7,10,10a,10b-dodeca hydro-7,10-endo-epidi-oxy-cyclo-hepta-[e]indene-3a-carboxyl-ate, (II) [Brito et al., (2008 ?). Acta Cryst. E64, o1209]. There are two mol-ecules in the asymmetric unit, which are linked by two strong intra-molecular O-H?O hydrogen bonds with graph-set motif R(2) (2)(8). In both (I) and (II), the conformation of the three fused rings are almost identical. The five-membered ring has an envelope conformation, the six-membered ring has a chair conformation and the seven-membered ring has a boat conformation. The most obvious differences between the two compounds is the observed disorder of the acet-oxy-methyl fragments in both mol-ecules of the asymmetric unit of (I). This disorder is not observed in (II). The crystal structure and the molecular conformation is stabilized by intermolecular C-H?O hydrogen bonds. The ability to form hydrogen bonds is different in the two compounds. The crystal studied was a non-merohedral twin, the ratio of the twin components being 0.28 (1):0.72 (1). PMID- 21588774 TI - Di-n-butyl-ammonium 2-[(3,5-di-tert-butyl-4-hy-droxy-benz-yl)sulfan-yl]benzoate. AB - The title salt, C(8)H(20)N(+).C(22)H(27)O(3)S(-), is a proton-transfer compound derived from the recently reported parent carb-oxy-lic acid [Alhadi et al. (2010). Acta Cryst. E66, o1787] by the addition of a second equivalent of di-n butyl-amine, yielding the di-n-butyl-ammonium carboxyl-ate salt. The structure of the carboxyl-ate anion resembles that of the parent carb-oxy-lic acid. The main difference lies in the position of the H atom in the 4-hy-droxy group. In the anion the O-H bond is perpendicular, rather than parallel, to the benzyl ring. This position appears to facilitate hydrogen bonding to an O atom of the carboxyl ate group of a symmetry-related anion. In addition, there are three N-H?O hydrogen bonds. In contrast, the neutral species hydrogen bonds via a carboxylic acid dimer. The dihedral angle between the benzene rings in the anion is 79.19 (7) degrees . PMID- 21588775 TI - 1,1',2,2'-Tetra-methyl-3,3'-(p-phenyl-enedimethyl-ene)diimidazol-1-ium bis (trifluoro-methane-sulfonate). AB - In the solid form of the title imidazolium-based ionic liquid salt, C(18)H(24)N(4) (2+).2CF(3)SO(3) (-), the complete cation is generated by a crystallographic inversion centre. The five-membered imidazole ring is approximately perpendicular to the six-membered phenyl-ene ring [dihedral angle = 85.11 (11) degrees ]. In the crystal, the components are linked by C-H?O interactions. PMID- 21588776 TI - rac-(E)-3-[1-(2-Chloro-phen-yl)eth-yl]-5-methyl-N-nitro-1,3,5-oxadiazinan-4 imine. AB - In the title compound, C(12)H(15)ClN(4)O(3), which has potential insecticidal activity, the oxadiazine ring and the benzene ring make a dihedral angle of 84.63 (2) degrees to one another. The crystal packing involves weak inter-molecular C H?O hydrogen bonds. PMID- 21588777 TI - 2-Amino-5-chloro-pyridinium (Z)-3-carb-oxy-prop-2-enoate 0.25-hydrate. AB - In the title hydrated salt, C(5)H(6)ClN(2) (+).C(4)H(3)O(4) (-).0.25H(2)O, the water O atom lies on a twofold axis with 0.25 occupancy. The 2-amino-5-chloro pyridinium cation is almost planar, with a maximum deviation of 0.015 (3) A. In the hydrogen malate anion, an intra-molecular O-H?O hydrogen bond generates an S(7) ring and results in a folded conformation. In the crystal, the protonated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The ion pairs are further connected via O-H?O, N-H?O and C-H?O hydrogen bonds, forming layers parallel to the ab plane which stack down the c axis. PMID- 21588778 TI - 2-Isopropyl-6-methyl-pyrimidin-4(3H)-one. AB - The mol-ecular structure of the title compound, C(8)H(12)N(2)O, indicates that 2 isopropyl-6-methyl-pyrimidin-4-ol (the enol-form) undergoes an enol-to-keto tautomerism during the crystallization process. The pyrimidin-4(3H)-one group is essentially planar, with a maximum deviation of 0.081 (1) A for the O atom. In the crystal structure, symmetry-related mol-ecules are linked into centrosymmetic dimers via pairs of inter-molecular N-H?O hydrogen bonds, generating R(2) (2)(8) rings. These dimers are stacked along the a axis. PMID- 21588779 TI - 2-[(E)-(2-Chloro-phen-yl)imino-meth-yl]-6-methyl-phenol. AB - The title compound, C(14)H(12)ClNO, a Schiff base derived from 3-methyl-salicyl aldehyde, crystallizes in the phenol-imine tautomeric form with an E conformation for the imine functionality. The mol-ecule is not planar, the dihedral angle between the aromatic rings being 36.38 (5) degrees . The hy-droxy H atom is involved in a strong intra-molecular O-H?N hydrogen bond, generating an S(6) ring. PMID- 21588780 TI - 3-[2-(5H-Indolo[2,3-b]quinoxalin-5-yl)eth-yl]-1,3-oxazolidin-2-one. AB - The title compound, C(19)H(16)N(4)O(2), has an almost planar fused N-heterocyclic system (r.m.s. deviation = 0.031 A) and an almost planar five-membered 1,3 oxazolidine ring (r.m.s. deviation = 0.015 A) at the ends of an ethyl-ene chain [N-C-C-N torsion angle = -65.6 (2) degrees ]. The ring systems are inclined at 38.1 (1) degrees to one another. PMID- 21588781 TI - 10-(2-Pyrid-yloxy)phenanthren-9-ol. AB - In the title compound, C(19)H(13)NO(2), the pyridyl ring makes a dihedral angle of 87.04 (6) degrees with the plane of the phenanthrene ring system. In the crystal, mol-ecules are linked through weak inter-molecular C-H?O hydrogen bonds and C-H?pi inter-actions. PMID- 21588782 TI - (1S,2S,4R)-3,3-Dichloro-4,8,12,12-tetra-methyl-tricyclo-[5.5.0.0]dodeca-6,8 diene. AB - The title compound, C(16)H(22)Cl(2), a derivative of beta-himachalene, was semi synthesized from natural essential oils of Cedrus atlantica. The mol-ecule is built up from two fused six- and seven-membered rings. The six-membered ring has a perfect chair conformation, whereas the seven-membered ring displays a screw boat conformation; the dihedral angle between the rings is 46.48 (9) degrees . PMID- 21588783 TI - 6-Butyryl-5-hy-droxy-4-phenyl-seselin. AB - IN THE TITLE COUMARIN COMPOUND (SYSTEMATIC NAME: 6-butyryl-5-hy-droxy-8,8 dimethyl-4-phenyl-2H,8H-benzo[1,2-b;3,4-b']dipyran-2-one), C(24)H(22)O(5), also known as mammea A/AC cyclo D, the chromene and pyran rings are almost coplanar with a maximum deviation from the mean plane of 0.295 (2) A. The attached phenyl group is inclined at 53.49 (8) degrees with respect to the chromene ring. The mol-ecular structure is stabilized by an intra-molecular O-H?O hydrogen bond. In the crystal, mol-ecules are linked into sheets parallel to (101) by inter molecular C-H?O hydrogen bonds. Adjacent sheets are sustained by inter-molecular C-H?pi and pi-pi [centroid-centroid distance = 4.471 (2) A] inter-actions. PMID- 21588784 TI - 2-[(E)-(3-Carb-oxy-4-hy-droxy-phen-yl)iminiometh-yl]-4-chloro-phenolate. AB - The title Schiff base compound, C(14)H(10)ClNO(4), has been synthesized by the reaction of 5-amino-2-hy-droxy-benzoic acid and 5-chloro-2-hy-droxy-benzaldehyde. The mol-ecule is a zwitterion in the crystal, with the phenolic hy-droxy group deprotonated and the imine N atom protonated. It adopts an E configuration about the central C=N double bond. The dihedral angle between the two benzene rings is 3.83 (7) degrees . Intra-molecular N-H?O and O-H?O hydrogen bonding generates S(6) ring motifs. In the crystal, mol-ecules are connected by inter-molecular O H?O and C-H?Cl hydrogen bonds, forming a supra-molecular chain. PMID- 21588785 TI - 4-Meth-oxy-benzaldehyde (5-bromo-pyrimidin-2-yl)hydrazone monohydrate. AB - In the title Schiff base compound, C(12)H(11)BrN(4)O.H(2)O, the organic mol-ecule exists in an E configuration with respect to the C=N double bond. The pyrimidine ring is approximately planar, with a maximum deviation of 0.011 (2) A, and forms a dihedral angle of 10.68 (8) degrees with the benzene ring. In the crystal, inter-molecular O-H?N, N-H?O and C-H?O hydrogen bonds link the mol-ecules into a two-dimensional network parallel to the ac plane. PMID- 21588786 TI - 1-[4-(3,5-Difluoro-benz-yloxy)-2-hy-droxy-phen-yl]ethanone. AB - The title compound, C(15)H(12)F(2)O(3), has been obtained by the reaction of 2,4 dihy-droxy-lacetonephenone, potassium carbonate and 3,5-difluoro-benzyl bromide. The hy-droxy group is involved in an intra-molecular O-H?O hydrogen bond in each of the two independent mol-ecules in the asymmetric unit. The dihedral angle between the aromatic rings is 0.5 (2) degrees in one molecule and 1.9 (2) degrees in the other. In the crystal, weak C-H?O inter-actions link the mol ecules into tetra-meric units aligned perpendicular to b. PMID- 21588787 TI - 3,5-Bis(4-hy-droxy-phen-yl)-4H-1,2,4-triazol-4-amine monohydrate. AB - The triazole ring in the title compound, C(14)H(12)N(4)O(2).H(2)O, makes dihedral angles of 36.9 (1) and 37.3 (1) degrees with the two benzene rings. Each hy droxy group is a hydrogen-bond donor to a two-coordinate N atom of an adjacent mol-ecule; these O-H?N hydrogen bonds generate a layer parallel to the ab plane. Adjacent layers are linked by N--H?O and O(water)-H?O hydrogen bonds into a three dimensional network. PMID- 21588788 TI - Ethane-1,2-diammonium dibromide: a redetermination at 100 K. AB - In the redetermined [for the previous study, see Sotofte (1976 ?). Acta Chem. Scand. Ser. A, 30, 309-311] crystal structure of the title compound, C(2)H(10)N(2) (2+).2Br(-), the H atoms have been located and the hydrogen-bonding scheme is described. The ethane-1,2-diammonium cation lies over a crystallographic inversion centre and straddles a crystallographic mirror plane with the C and N atoms in special positions. In the crystal, the cations and anions are linked by N-H?Br and N-H?(Br,Br) hydrogen bonds, which generate various ring and chain motifs including an R(10) (5)(32) loop. PMID- 21588789 TI - The gamma-polymorph of AgZnPO(4) with an ABW zeolite-type framework topology. AB - The gamma-polymorph of the title compound, silver zinc orthophos-phate, was synthesized under hydro-thermal conditions. The structure consists of ZnO(4), PO(4) and AgO(4) units. The coord-ination spheres of Zn(II) and P(V) are tetra hedral, whereas the Ag(I) atom is considerably distorted from a tetra-hedral coordination. Each O atom is linked to each of the three cations. An elliptic eight-membered ring system is formed by corner-sharing of alternating PO(4) and ZnO(4) tetra-hedra, leading to a framework with an ABW-type zeolite structure. The framework encloses channels running parallel to [100] in which the Ag cations are located, with Ag?Ag contacts of 3.099 (3) A. This short distance results from d(10)?d(10) inter-actions, which play a substantial role in the crystal packing. The structure of gamma-AgZnPO(4) is distinct from the two other polymorphs alpha AgZnPO(4) and beta-AgZnPO(4), but is isotypic with NaZnPO(4)-ABW, NaCoPO(4)-ABW and NH(4)CoPO(4)-ABW. PMID- 21588790 TI - The cyclo-tetra-phosphate Cd(2)P(4)O(12), a member of the isotypic series M(2)P(4)O(12) (M = Mg, Mn, Fe, Co, Ni, Cu). AB - The title compound, Cd(2)P(4)O(12), dicadmium cyclo-tetra-phosphate, crystallizes isotypically with the members of the series M(II) (2)P(4)O(12), where M = Mg, Mn, Fe, Co, Ni or Cu. Two CdO(6) octa-hedra, one with 2 and one with symmetry, share corners with the centrosymmetric P(4)O(12) (4-) ring anion that is built up from four corner-sharing PO(4) tetra-hedra. The isolated ring anions are arranged in layers parallel to (10) with the CdO(6) octa-hedra situated between these layers. The main difference between the individual M(II) (2)P(4)O(12) structures pertains to the different sizes of the MO(6) octa-hedra whereas the geometric parameters of all cyclo-P(4)O(12) (4-) anions are very similar. PMID- 21588791 TI - alpha-Ba(2)P(2)O(7). AB - Single crystals of alpha-Ba(2)P(2)O(7), dibarium diphosphate, were obtained by solid-state reaction. The ortho-rhom-bic structure is isotypic with alpha Sr(2)P(2)O(7) and is the second polymorph obtained for this composition. The structure is built from two different BaO(9) polyhedra (both with m symmetry), with Ba-O distances in the ranges 2.7585 (10)-3.0850 (6) and 2.5794 (13)-2.9313 (4) A. These polyhedra are further linked by sharing corners along [010] and either edges or triangular faces perpendicularly to [010] to form the three dimensional framework. This polyhedral linkage delimits large channels parallel to [010] where the P(2)O(7) diphosphate anions are located. These groups (symmetry m) are characterized by a P-O-P angle of 131.52 (9) degrees and an eclipsed conformation. They are connected to the BaO(9) polyhedra through edges and corners. PMID- 21588792 TI - trans-Bromido(pyrimidinyl-kappaC)bis-(triphenyl-phosphane-kappaP)palladium(II). AB - In the title complex, [PdBr(C(4)H(3)N(2))(C(18)H(15)P)(2)], the geometry around the Pd(II) atom is distorted square-planar with the Pd(II) atom displaced by 0.0150 (5) A from the least-squares BrP(2)C plane. Two PPh(3) ligands are in trans positions [P-Pd-P = 176.743 (17) degrees ], while the pyrimidinyl ligand and Br atom are trans to one another [C-Pd-Br = 176.56 (5) degrees ]. Structural parameters from NMR, IR and mass spectra are in agreement with the crystal structure of the title compound. PMID- 21588793 TI - Aqua-dipyridine-bis-(N-p-tolysulfonyl-l-leucinato)nickel(II). AB - In each of the two mol-ecules in the asymmetric unit of the title compound, [Ni(C(13)H(18)NO(4)S)(2)(C(5)H(5)N)(2)(H(2)O)], the geometry of the Ni(2+) ion is an extremely distorted trans-NiN(2)O(4) octa-hedron, arising from its coordination by one water mol-ecule, two pyridine mol-ecules, and one O monodentate and one O,O'-bidentate deprotonated N-p-tolysulfonyl-l-leucine ligand. In the crystal, mol-ecules are linked by N-H?O and O-H?O hydrogen bonds, forming chains along the c axis. An intra-molecular O-H?O hydrogen bond occurs in one of the mol-ecules. PMID- 21588794 TI - Poly[[diaqua-tris-(MU(2)-3-methyl-pyridine-2-carboxyl-ato)(3-methyl-pyridine-2 car-boxyl-ato)sodiumterbium(III)] ethanol monosolvate monohydrate]. AB - In the title compound, {[NaTb(C(7)H(6)NO(2))(4)(H(2)O)(2)].C(2)H(5)OH.H(2)O}(n), the Tb(III) atom is eight-coordinated in a slightly distorted square-anti prismatic geometry defined by four carboxyl-ate O atoms and four pyridine N atoms. The bond lengths lie within the range 2.3000 (2)-2.326 (2) A for the Tb-O bonds and 2.543 (3)-2.553 (3) A for the Tb-N bonds. The Na(I) atom is five coordinated by two water O atoms and three carboxyl-ate O atoms in a distorted square-pyramidal geometry. In the crystal, inter-molecular O-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21588795 TI - Diazido-(2,2'-bipyrid-yl)dimethanol-nickel(II). AB - The title complex, [Ni(N(3))(2)(C(10)H(8)N(2))(CH(3)OH)(2)], lies on a twofold roation axis which runs through the Ni(II) ion and the mid-point of the bipyridine ligand. The Ni(II) ion is coordinated in a distorted octa-hedral environment by two azide ligands in a trans configuration. The methanol ligands are in a cis configuration and their hy-droxy groups form intra-molecular O H?(N,N) hydrogen bonds with the azide ligands. PMID- 21588796 TI - (Di-2-pyridyl-amine)-(methanol)sulfato-copper(II). AB - The title complex, [Cu(SO(4))(C(10)H(9)N(3))(CH(3)OH)], is a mononuclear species with the Cu(II) ion in a Jahn-Teller-distorted '4 + 1' square-pyramidal geometry. The basal plane is defined by the pyridyl N-atom donors of the bipyridyl-amine (bpa) ligand and two O-atom donors of the sulfate ligand. The coordination geometry is completed by the axial coordination of a methanol O-atom donor. The axial bond length displays the usual elongation: Cu-O(axial) = 2.168 (2), Cu O(basal) = 2.016 (2) (average) and Cu-N(basal) = 1.951 (3) A (average). In the crystal structure, the complex mol-ecules are linked through N-H?O and O-H?O hydrogen bonds into chains along [100]. PMID- 21588797 TI - Bis{2-[3-(dimethyl-ammonio)-propyl-imino-methyl-kappaN]-6-meth-oxy-phenolato kappaO}bis-(thio-cyanato-kappaN)nickel(II). AB - The asymmetric unit of the title complex, [Ni(NCS)(2)(C(13)H(20)N(2)O(2))(2)], consists of two half-mol-ecules, both of which are completed by crystallographic inversion symmetry (Ni(2+) site symmetry = in both cases). Both metal ions are six-coordinated in distorted trans-NiO(2)N(4) geometries arising from two N,O bidentate Schiff base ligands and two N-bonded thio-cyanate ions. The mol-ecular conformations are reinforced by two intra-molecular N-H?O hydrogen bonds. PMID- 21588798 TI - Chloridodimeth-yl(thio-semi-carbazide)tin(IV) chloride. AB - In the title salt, [Sn(CH(3))(2)Cl(CH(4)N(3)S)]Cl, the Sn(IV) atom is five coordinated in a distorted trigonal-bipyramidal geometry with two methyl groups and one S atom in the equatorial plane, and one N atom and one Cl atom occupying the apical positions. In the crystal, mol-ecules are linked by inter-molecular N H?S hydrogen bonds with set graph-motif C(4) along [010]. N-H? Cl hydrogen bonds with graph-set motif D(2) and D(3) (3)(10) link cations and anions. PMID- 21588799 TI - Poly[ethyl-enediammonium [tris-[MU(3)-hydrogenphosphato(2-)]dicadmium] monohydrate]. AB - The title compound, {(C(2)H(10)N(2))[Cd(2)(HPO(4))(3)].H(2)O}(n), was synthesized under hydro-thermal conditions. The structure of this hybrid compound consists of CdO(6), CdO(5) and PO(4) polyhedra arranged so as to build an anionic inorganic layer, namely [Cd(2)(HPO(4))(3)](2-), parallel to the ab plane. The edge-sharing CdO(6) octa-hedra form infinite chains running along the a axis and are linked by CdO(5) and PO(4) polyhedra. The ethyl-ene-diammonium cation and the water mol ecule are located between two adjacent inorganic layers and ensure the cohesion of the structure via N-H?O and O-H?O hydrogen bonds. PMID- 21588800 TI - (MU-Ethane-1,2-diamine-kappaN:N')bis-[bis-(ethane-1,2-diamine-kappaN,N')zinc(II)] tetra-kis-(perchlorate). AB - In the title salt, [Zn(2)(C(2)H(8)N(2))(5)](ClO(4))(4), an ethyl-enediamine mol ecule bridges two bis-(ethyl-enediamine)-zinc units; the five-coordinate Zn atoms show a trigonal-bipyramidal coordination geometry that is distorted towards square-pyramidal (that of one Zn atom is distorted by 12% and that of the other by 34%). The perchlorate ions are all disordered over two positions in a 1:1 ratio. The cation inter-acts weakly with the anion by N-H?O hydrogen bonds, generating a three-dimensional network. PMID- 21588801 TI - Aqua-(4-bromo-benzoato-kappaO)bis-(1,10-phenanthroline-kappaN,N')zinc(II) 4-bromo benzoate 1.5-hydrate. AB - In the title compound, [Zn(C(7)H(4)BrO(2))(C(12)H(8)N(2))(2)(H(2)O)](C(7)H(4)BrO(2)).1.5H(2)O, the Zn(II) atom is coordinated by four N atoms from two chelating 1,10-phenanthroline (phen) ligands, one O atom from a 4-bromo-benzoate ligand and one water mol ecule, completing a distorted ZnN(4)O(2) octa-hedral geometry. The two phen ligands exhibit nearly perfect coplanarity (r.m.s. deviations = 0.027 and 0.031 A), making a dihedral angle of 85.7 (1) degrees . The mean inter-planar distances of 3.36 (2) and 3.41 (3) A between adjacent phen ligands indicate pi-pi stacking inter-actions. The uncoordinated water mol-ecules are partly occupied. One carboxyl-ate O atom and two Br atoms are each disordered over two sites, with occupancy factors of 0.60 and 0.40. In the crystal structure, O-H?O and C-H?O hydrogen bonds and pi-pi stacking inter-actions link the complex cations, uncoordinated 4-bromo-benzoate anions and water mol-ecules into a three dimensional supra-molecular network. An intra-molecular O-H?.O hydrogen bond is observed in the cation. PMID- 21588802 TI - Acetonitrile-bis-(2-methyl-1,10-phenanthroline)copper(II) tetra-fluoridoborate. AB - In the title compound, [Cu(CH(3)CN)(C(13)H(10)N(2))(2)](BF(4))(2), the fivefold coordinate Cu(II) atom is located on a twofold rotation axis, imposing twofold symmetry to the complete cation. The structure exhibits disorder of the anion, which was successfully refined using a two-site model with 0.810 (3):0.190 (3) occupancy. The methyl group of the acetonitrile ligand is likewise disordered, here about the twofold rotation axis in a 1:1 ratio. PMID- 21588803 TI - Bis(N'-benzoyl-pyridine-4-carbohydrazide)(1,10-phenanthroline)copper(II) dinitrate. AB - In the title complex, [Cu(C(13)H(11)N(3)O(2))(2)(C(12)H(8)N(2))](NO(3))(2), the Cu(II )atom (site symmetry 2) is coordinated by four N atoms from one 1,10 phenanthroline and two hydrazine ligands, respectively. The hydrazine ligands coordinate to the Cu(II)atom by a pyridine N atom. These four atoms form a slightly distorted square-planar N(4) donor set. In the packing, two additional Cu?O inter-actions occur [Cu?O = 2.462 (2) A], resulting in a typical Jahn-Teller distorted octahedral environment around the Cu atom. N-H?O hydrogen bonds result in a three-dimensional network. The O atoms of the anion are disordered over two positions in a 0.68 (2):0.32 (2) ratio. PMID- 21588804 TI - Bis[4-(4-chloro-benzo-yl)-3-methyl-1-phenyl-1H-pyrazol-5-olato-kappaO,O']bis (methanol-kappaO)nickel(II). AB - The mol-ecular structure of the neutral mononuclear title complex, [Ni(C(17)H(12)ClN(2)O(2))(2)(CH(3)OH)(2)], is centrosymmetric. The Ni(II) atom, which is located on an inversion center, is in a distorted octahedral coordination, defined by four O atoms from two ligands as well as two O atoms from two methanol mol-ecules. Inter-molecular O-H?N hydrogen bonds between the hy droxy group of methanol and a pyrazole N atom link the mol-ecules, forming a two dimensional network parallel to (100). PMID- 21588805 TI - Bis[[(6-carb-oxy-pyridazine-3-carboxyl-ato-kappaN,O)lithium]-MU-penta-hydrogen dioxy-gen(1+)]. AB - The structure of the title compound, [Li(C(6)H(3)N(2)O(4))(2)(H(5)O(2))], is composed of centrosymmetric monomers in which an Li(I) ion is chelated by two N,O bonding groups donated by two ligands. The Li(I) ion and both ligand mol-ecules are coplanar [r.m.s. deviation 0.0047 (2) A] and water O atoms are in the axial positions. The second carboxyl group of each ligand remains protonated. An additional H atom, located between adjacent coordinated water mol-ecules and observed on Fourier maps, maintains the charge balance within the monomers and bridges them by short symmetric hydrogen bonds of 2.518 (3) A to form catenated ribbons. The monomers also inter-act via hydrogen bonds in which water and carboxyl O atoms act as donors. PMID- 21588806 TI - (Ferrocenyl-thio-phospho-nato-kappaS)(triphenyl-phosphane-kappaP)gold(I) dichloro methane monosolvate. AB - In the title compound, [AuFe(C(5)H(5))(C(5)H(5)O(2)PS)(C(18)H(15)P)].CH(2)Cl(2), the two-coordinate gold(I) atom shows a slightly distorted linear arrangement, with a P-Au-S bond angle of 176.81 (6) degrees . The difference in P=O and P-O(H) bond lengths, which are 1.503 (6) and 1.541 (5) A, respectively, implies there is apparently no delocalization between the P-O bonds, and the proton appears to be localized on one O atom only. In the crystal structure, inter-molecular O-H?O hydrogen bonds link dinuclear mol-ecules into chains propagated in the [010] direction. The dichloro-methane solvent mol-ecule was disordered between two positions in a 0.63 (3):0.37 (3) ratio. PMID- 21588807 TI - (6-Hydroxy-2-{[2-(N-methyl-carbamo-thiol-yl)hydrazin-1-yl-idene-kappaN,S]meth-yl} phenolato-kappaO)(triphenyl-phosphane-kappaP)nickel(II) chloride. AB - The deprotonated Schiff base ligand in the title salt, [Ni(C(9)H(10)N(3)O(2)S)(C(18)H(15)P)]Cl, functions as an N,O,S-chelating anion to the phosphine-coordinated nickel(II) atom, which exists in a distorted square planar geometry. The hy-droxy group forms an intra-molecular O-H?O hydrogen bond. The two amino groups of the cation are hydrogen-bond donors to the chloride anion; the hydrogen bonds generate a chain structure running along the b axis. PMID- 21588808 TI - 1-(4-Bromo-2-fluoro-benz-yl)pyridinium bis-(2-thioxo-1,3-dithiole-4,5-dithiol ato)nickelate(III). AB - The title compound, (C(12)H(10)BrFN)[Ni(C(3)S(5))(2)], is an ion-pair complex consisting of N-(2-fluoro-4-bromo-benz-yl)pyridinium cations and [Ni(dmit)(2)](-) anions (dmit = 2-thioxo-1,3-dithiole-4,5-dithiol-ate). In the anion, the Ni(III) ion exhibits a square-planar coordination involving four S atoms from two dmit ligands. In the crystal structure, weak S?S [3.474 (3), 3.478 (3) and 3.547 (3) A] and S?pi [S?centroid distances = 3.360 (3), 3.378 (2), 3.537 (2) and 3.681 (3) A] inter-actions and C-H?F hydrogen bonds lead to a three-dimensional supra molecular network. PMID- 21588809 TI - Chlorido(eta-cyclo-octa-1,5-diene)(N,N'-diethyl-thio-urea-kappaS)rhodium(I). AB - In the title rhodium(I) complex, [RhCl(C(8)H(12))(C(5)H(12)N(2)S)], N,N'-diethyl thio-urea acts as a monodenate S-donor ligand. The rhodium(I) coordination sphere is completed by the Cl atom and the COD [= 1,5-cyclo-octa-diene] ligand inter acting through the pi-electrons of the double bonds. If the midpoints of these two bonds are taken into account, the Rh atom exhibits a distorted square-planar coordination. The syn conformation of the N,N'-diethyl-thio-urea ligand with respect to the Cl atom is stabilized by an intra-molecular N-H?Cl hydrogen bond. A weak inter-molecular N-H?Cl inter-action links mol-ecules along the a axis. PMID- 21588810 TI - Redetermination of (eta-s-cis-1,3-butadiene)tricarbonyl-iron(0). AB - The crystal structure of the title compound, [Fe(C(4)H(6))(CO)(3)], was previously reported by Mills & Robinson [Acta Cryst. (1963) ?, 16, 758-761]. The compound crystallizes in the centrosymmetric space goup Pnma with the complex located on a mirror plane. The redetermination of this structure at 100 K yielded almost equilibrated C-C bond lengths within the butadiene ligand according to a metal-to-ligand bonding-back-bonding mechanism. The C-C bond lengths presented herein are significantly shorter than those reported earlier. The H-atom positions that have not been reported so far were located by difference Fourier maps. The positional parameters of all H atoms and individual U(iso) values were refined freely. PMID- 21588811 TI - (+)-{1,2-Bis[(2R,5R)-2,5-diethyl-phospho-lan-1-yl]ethane-kappaP,P'}(eta-cyclo octa-1,5-diene)rhodium(I) tetra-fluoridoborate. AB - The title compound, [Rh(C(8)H(12))(C(18)H(36)P(2))]BF(4), exhibits a rhodium(I) complex cation with a bidentate bis-phosphine ligand and a bidentate eta(2),eta(2)-coordinated cyclo-octa-1,5-diene ligand. The ligands form a slightly distorted square-planar coordination environment for the Rh(I) atom. An intra-molecular P-Rh-P bite angle of 83.91 (2) degrees is observed. The dihedral angle between the P-Rh-P and the X-Rh-X planes (X is the centroid of a double bond) is 14.0 (1) degrees . The BF(4) anion is disordered over two positions in a 0.515 (7):0.485 (7) ratio. PMID- 21588812 TI - catena-Poly[[dipyridine-cadmium(II)]-MU-5-amino-2,4,6-triiodo-isophthalato]. AB - The hydro-thermal reaction of cadmium(II) nitrate with 5-amino-2,4,6-triiodo isophthalic acid and pyridine in DMF solution leads to the formation of the title compound, [Cd(C(8)H(2)I(3)NO(4))(C(5)H(5)N)(2)](n). The structure contains a four coordinate Cd(2+ )ion in a distorted tetra-hedral geometry, which lies on a crystallographic twofold rotation axis. The Cd(2+ )ion is bonded to two N atoms from two pyridine ligands and two carboxyl-ate O atoms from two 5-amino-2,4,6 triiodo-isophthalate anions. The Cd-O distances are 2.429 (5) and 2.305 (5) A and the Cd-N distance is 2.236 (8) A. The two carboxyl-ate groups of individual 5 amino-2,4,6-triiodo-isophthalate anions act as a bridge to the Cd(2+) atoms. leading to a chain structure along the c axis. PMID- 21588813 TI - Tribenzylbis(triphenyl-arsine oxide-kappaO)tin(IV) tetra-phenyl-borate. AB - The crystal structure of the title salt, [Sn(C(7)H(7))(3)(C(18)H(15)AsO)(2)][B(C(6)H(5))(4)], consists of discrete cations and anions; the tin atom of the cation is five-coordinated in a distorted trans C(3)SnO(2) trigonal-bipyramidal geometry [summation of C-Sn-C angles 360.0 (3) degrees and O-Sn-O angle 173.1 (1) degrees ]. The structure contains voids of 113 (19) A(3), but no solvent mol-ecule could reasonably be located there. PMID- 21588814 TI - (3-Hydroxy-2-{[1-(2-oxidophenyl)ethyl-idene]amino-kappaO,N}propanoato kappaO)diphenyltin(IV). AB - In the title compound, [Sn(C(6)H(5))(2)(C(11)H(11)NO(4))], the tin(IV) atom is penta-coordinated in a distorted trigonal-bipyramidal SnC(2)NO(2) geometry. In the crystal structure, inter-molecular O-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers. Weak C-H?O inter-actions further link the dimers into chains extending in [010]. PMID- 21588815 TI - catena-Poly[[[tetra-aqua-iron(II)]-MU-5,5'-diazenediylditetra-zolido] dihydrate]. AB - In the title compound, {[Fe(C(2)N(10))(H(2)O)(4)].2H(2)O}(n), the coordin-ation geometry around the Fe(II) atom, which lies on a center of inversion, is distorted octa-hedral, with bonds to four O atoms and two N atoms. The azotetra zolate ligand displays a bridging coordination mode, forming an infinite zigzag chain. Inter-molecular O-H?O and O-H?N hydrogen bonding and offset face-to-face pi-pi stacking inter-actions [centroid-centroid distance = 3.4738 (13) A] lead to a three-dimensional network. PMID- 21588816 TI - Tetra-aqua-bis-(1,10-phenanthroline-kappaN,N')strontium 5,5'-diazene-diyl-ditetra zolide. AB - The title complex, [Sr(C(12)H(8)N(2))(2)(H(2)O)(4)](C(2)N(10)), contains an [Sr(phen)(2)(H(2)O)(4)](2+) cation (phen is 1,10-phenanthroline) and a 5,5' diazenediylditetra-zolide anion (site symmetry 2). The Sr(2+) cation (site symmetry 2) is coordinated by four N atoms from two chelating phen and four water mol-ecules. In the crystal structure, the water mol-ecules and the N atoms in the tetra-zolide rings form an extensive range of O-H?N hydrogen bonds which link the complex into a two-dimensional structure. An adjacent layer further yields a three-dimensional supramolecular network by offset face-to-face pi-pi stacking inter-actions of the phen ligands [with centroid-centroid distances of 3.915 (2) and 4.012 (2) A]. The two bridging N atoms of the anion are equally disordered about the twofold rotation axis. PMID- 21588817 TI - Tetra-kis[MU-2-(3,4-dimeth-oxy-phen-yl)acetato]-kappaO:O';kappaO,O':O;kappaO:O,O' bis-{[2-(3,4-dimeth-oxy-phen-yl)acetato-kappaO,O'](1,10-phenanthroline kappaN,N')samarium(III)}. AB - In the centrosymmetric dinuclear title complex, [Sm(2)(C(10)H(11)O(4))(6)(C(12)H(8)N(2))(2)], the Sm(III) ion is nine-coordinated by seven O atoms of five 2-(3,4-dimeth-oxy-phen-yl)acetate (DMPA) ligands and two N atoms of one bis-chelating 1,10-phenanthroline (phen) ligand, forming a distorted tricapped trigonal-prismatic environment. The DMPA ligands coordinate in bis-chelate, bridging and bridging tridentate modes. An intra-molecular C-H?O hydrogen bond occurs. Inter-molecular C-H?O inter-actions are also present in the crystal. PMID- 21588818 TI - {MU-6,6'-Dimeth-oxy-2,2'-[cyclo-hexane-1,2-diylbis(nitrilo-methyl idyne)]diphenolato}methanol-MU-nitrato-dinitratocopper(II)europium(III). AB - In the title dinuclear salen-type complex, [CuEu(C(22)H(24)N(2)O(4))(NO(3))(3)(CH(3)OH)], the Cu(II) ion is five-coordinated to two imine N atoms and two phenolate O atoms and one O from the bridging nitrate group. The Eu(III) ion is ligated to three nitrate groups, four O atoms from the salen-type ligand and one methanol mol-ecule, leading to a distorted tenfold coordination for the rare earth cation. One of the three nitrate anions is disordered over two positions in a 0.66 (5):0.34 (5) ratio. PMID- 21588819 TI - trans-Carbonyl-chloridobis[tris-(4-chloro-phen-yl)phosphane]rhodium(I) acetone monosolvate. AB - The title compound, trans-[RhCl(C(18)H(12)Cl(3)P)(2)(CO)].C(3)H(6)O, contains an Rh(I) atom in a distorted square-planar coordination with a P-Rh-P angle of 175.27 (2) degrees and Rh-P bond lengths of 2.3127 (4) and 2.3219 (4) A. The rhodium complexes link each other through weak inter-molecular contacts between the acetone methyl groups and the carbonyl O atom. Inter-actions between the acetone solvent mol-ecule and the Cl-Rh unit results in a reduced P-Rh-Cl angle of 86.675 (15) degrees . PMID- 21588820 TI - Poly[[aqua-calcium(II)]-MU(4)-1H-imidazole-4,5-dicarboxyl-ato]. AB - In the title compound, [Ca(C(5)H(2)N(2)O(4))(H(2)O)](n), the Ca(2+) cations are eigthtfold coordinated by six O atoms and one N atom of four symmetry-related anions and one water mol-ecule within an irregular polyhedron. These CaO(7)N polyhedra are connected via the anions into a three-dimensional network. The anions are additionally linked by N-H?O and O-H?O hydrogen bonding. PMID- 21588821 TI - Hexaaqua-nickel(II) 4,4'-(1,2-dihy-droxy-ethane-1,2-di-yl)dibenzoate monohydrate. AB - In the title compound, [Ni(H(2)O)(6)](C(16)H(12)O(6)).H(2)O, the Ni(II) cation is located on a mirror plane and is coordinated by six water mol-ecules, two of which are also located on the mirror plane, in a distorted octa-hedral geometry. The 4,4'-(1,2-dihy-droxy-ethane-1,2-di-yl)dibenzoate anion is centrosymmetric with the mid-point of the central ethane C-C bond located on an inversion center. The uncoordinated water mol-ecule is located on a mirror plane. Extensive O-H?O hydrogen bonding is present in the crystal structure. PMID- 21588822 TI - catena-Poly[[[{5,5'-dimeth-oxy-2,2'-[ethane-1,2-diylbis(nitrilo-methyl idyne)]diphenolato}manganese(III)]-MU-acetato] methanol monosolvate]. AB - The title Mn(III) compound, {[Mn(C(18)H(18)N(2)O(4))(CH(3)COO)].CH(3)OH}(n), was synthesized by a reaction between mangan-ese(II) acetate and ethyl-enebis(4-meth oxy-salicylaldimine). The structure is made up of bis-(4-meth-oxy salicyldene)ethyl-enediaminatomanganese(III) units bridged by acetate groups, with Mn-N = 1.9786 (9), Mn-O = 1.8784 (10) and Mn-O(acetate) = 2.056 (9) and 2.2571 (9) A, forming a one dimensional polymer (-Mn-acetate-Mn-acetate-) along [100]. The Mn(III) atom is in a Jahn-Teller-distorted octa-hedral environment with cis angles ranging from 81.87 (4) to 96.53 (4) degrees and trans angles ranging from 166.11 (3) to 173.93 (3) degrees . The methanol solvent mol-ecule is hydrogen bonded to the phenolate O atom. In addition to this classical hydrogen bond, there are weak C-H?O inter-actions. The structure was determined from a crystal twinned by pseudo-merohedry. PMID- 21588823 TI - Bis({tris[2-(3,5-di-tert-butyl-2-oxido-benzylideneamino)ethyl]amine}cerium(III)) diethyl ether solvate. AB - The title compound, 2[Ce(C(51)H(75)N(4)O(3))].C(4)H(10)O, was obtained in high yield (92%) by reduction of (TRENDSAL)Ce(IV)Cl [TRENDSAL is N,N',N''-tris-(3,5-di tert-butyl-salicyl-ide-natoamino)-triethyl-amine] with potassium in THF. The bulky tripodal TRENDSAL ligand effectively encapsulates the central Ce(III) cation with a Ce-N(imine) distance of 2.860 (2) A and an average C-N(amine) distance of 2.619 A within a distorted monocapped octahedral coordination. PMID- 21588824 TI - Bis(1H-pyrazole-kappaN)bis-(2,4,6-tri-isopropyl-benzoato-kappaO)cobalt(II). AB - The title compound, [Co(C(16)H(23)O(2))(2)(C(3)H(4)N(2))(2)] or (C(3)H(4)N(2))(2)Co(O(2)CC(6)H(2) (i)Pr(3)-2,4,6), is a rare example of a tetra coordinate cobalt(II) carboxyl-ate stabilized by ancillary N-heterocyclic ligands. The Co(II) ion resides on a crystallographic twofold axis so that the asymmetric unit comprises one half-mol-ecule. Due to the steric bulk of the 2,4,6 triisopropyl-phenyl substituents, the carboxyl-ate ligands are both coordinated in a monodentate fashion despite the low coordination number. The coordination geometry around the central Co(II) ion is distorted tetra-hedral with angles at Co ranging from 92.27 (18) degrees to 121.08 (14) degrees . PMID- 21588825 TI - Diaqua-bis-[1-ethyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3 carboxyl-ato]magnesium(II) hexa-hydrate. AB - In the title compound, [Mg(C(16)H(17)FN(3)O(3))(2)(H(2)O)(2)].6H(2)O, the Mg(2+) ion (site symmetry ) exhibits a distorted MgO(6) octa-hedral geometry defined by two O,O-bidentate 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazin-yl)-3 quinoline-carb-oxyl-ate (norf) anions and two water mol-ecules. In the crystal, O H?O and O-H?N hydrogen bonds help to establish the packing. PMID- 21588826 TI - Tris(2,4-dimethyl-benzene-thiol-ato)phenyl-tin(IV). AB - In the title compound, [Sn(C(6)H(5))(C(8)H(9)S)(3)], the Sn atom has an approximately tetra-hedral SNCS(3) geometry, with angles at this atom ranging from 105.13 (3) to 113.54 (9) degrees . The crystal packing does not involve any significant inter-molecular inter-actions, although the benzene rings are involved in a number of weak intra- and inter-molecular C-H?pi inter-actions. PMID- 21588827 TI - Tricarbon-yl[eta-2-(methyl-diphenyl-phosphanium-yl)-1,3,4-triphenylcyclo-penta dienyl]molybdenum(0). AB - The title compound, [Mo(C(36)H(29)P)(CO)(3)], contains an Mo(0) atom with a typical piano-stool coordination defined by the phospho-nium cyclo-penta dienylide ligand eta(5)-1-(methyl-diphenyl-phosphanium-yl)-2,3,5-triphenyl-2,4 cyclo-penta-dien-1-yl and by three carbonyl groups. The distance between the Mo(0) atom and the cyclo-penta-dienyl ring is 2.0616 (13) A. PMID- 21588828 TI - Diaqua-(nitrato-kappaO,O')[2-(1H-1,2,4-triazol-1-yl-kappaN)-1,10-phenanthroline kappaN,N']cadmium(II) nitrate. AB - In the title complex, [Cd(C(14)H(9)N(5))(NO(3))(H(2)O)(2)]NO(3), the Cd(II) ion is coordinated in a distorted penta-gonal-bipyramidal geometry. The equatorial sites are occupied by a 2-(1H-1,2,4-triazol-1-yl)-1,10-phenanthroline ligand in a tridentate coordination mode and a bis-chelating nitrate ligand. Two aqua ligands are coordinated at the axial sites. All non-H atoms in the equatorial plane are co-planar within 0.0673 A. In the crystal, inter-molecular O-H?O and O-H?N hydrogen bonds connect the components into a two-dimensional network parallel to (001). In addition, there is a pi-pi stacking inter-action between symmetry related benzene rings, with a centroid-centroid distance of 3.598 (3) A. PMID- 21588829 TI - Hexa-kis-(N,N'-dimethyl-thio-urea-kappaS)nickel(II) nitrate. AB - The title complex salt, [Ni(C(3)H(8)N(2)S)(6)](NO(3))(2), consists of an [Ni(Dmtu)(6)](2+) (Dmtu is N,N'-dimethyl-thio-urea) dication and two nitrate counter-anions. The Ni(II) atom (site symmetry ) is coordinated by the S atoms of six Dmtu ligands within a slightly distorted octa-hedral environment. The crystal structure is characterized by weak intra-molecular N-H?S inter-actions and by inter-molecular N-H?O hydrogen bonds involving the nitrate anion (site symmetry 3.). These inter-molecular inter-actions lead to the formation of two-dimensional networks lying parallel to the ab plane. The networks are linked via non classical inter-molecular C-H?O hydrogen bonds, forming a three-dimensional arrangement. PMID- 21588830 TI - catena-Poly[(MU(3)-2-hy-droxy-4-isopropyl-cyclo-hepta-2,4,6-trien-1-onato)(MU(2) 2-hy-droxy-4-isopropyl-cyclo-hepta-2,4,6-trien-1-onato)lead(II)]. AB - In the title compound, [Pb(C(10)H(11)O(2))(2)](n) or [Pb(hino)(2)](n), the lead(II) ion is chelated by two hinokitiolate ligands in a distorted square pyramidal configuration, with Pb-O bond lengths in the range 2.327 (6)-2.479 (9) A. The 6s(2) lone electron pair of the lead(II) ion becomes stereochemically active and is directed towards the apex of this pyramid. The crystal structure of the title compound consists of chains formed by the bis-(hinokitiolato)lead(II) mol-ecules situated along the twofold screw axis. The coordination sphere around the lead(II) ion is completed by three additional O atoms, at 2.625 (7), 3.016 (8) and 3.064 (8) A, from the two neighbouring Pb(hino)(2) units. Both isopropyl groups are rotationally disordered. PMID- 21588831 TI - Aqua-{4,4',6,6'-tetra-fluoro-2,2'-[(piperazine-1,4-di-yl)dimethyl ene]diphenolato}copper(II). AB - In the title compound, [Cu(C(18)H(16)F(4)N(2)O(2))(H(2)O)], the Cu(II) atom shows a distorted square-pyramidal coordination geometry with the N,N',O,O'-tetra dentate piperazine-diphenolate ligand forming the basal plane. The apical site is occupied by the O atom of a coordinated water mol-ecule. Neighbouring complexes are associated through inter-molecular O-H?O and O-H?F hydrogen bonds between the water mol-ecule and a phenolate O atom or an F atom from an adjacent ligand, respectively, forming a centrosymmetric dimer. Dimers are linked by additional inter-molecular C-H?O and C-H?F hydrogen bonds, giving infinite chains propagating along the a axis. PMID- 21588832 TI - Tris[2-eth-oxy-6-(methyl-imino-meth-yl)phenolato-kappaN,O]cobalt(III) monohydrate. AB - In the title compound, [Co(C(10)H(12)NO(2))(3)].H(2)O, the Co(III) ion is coordinated by three O atoms and three N atoms from three bidentate 2-eth-oxy-6 (methyl-imino-meth-yl)phenolate ligands in a slightly distorted octa-hedral environment. The water mol-ecule connects two ligands by O-H?O hydrogen bonds. One terminal methyl group is disordered over two positions, with site-occupancy factors of 0.412 (15) and 0.588 (15). PMID- 21588833 TI - Iodidobis(eta-penta-methyl-cyclo-penta-dien-yl)titanium(III). AB - In the title complex mol-ecule, [Ti(C(10)H(15))(2)I], the paramagnetic Ti(III) atom is coordinated by two penta-methyl-cyclo-penta-dienyl (Cp*) ligands and one iodide ligand. The two Cp* ligands are in a staggered orientation. The coordination geometry at the titanium atom can be described as distorted trigonal planar. PMID- 21588834 TI - Bis(tetra-phenyl-arsonium) di-MU-hy-droxido-bis-[(nitrilo-triacetato) cobalt(III)] octa-hydrate. AB - In the title compound, (C(24)H(20)As)(2)[Co(2)(C(6)H(6)NO(6))(2)(OH)(2)].8H(2)O, the Co(III) atom in the binuclear centrosymmetric anion is octa-hedrally surrounded by one N atom and three O atoms of the tetra-dentate nitrilo triacetate ligand and two MU-hydroxide ligands. The crystal packing is controlled by C-H?O and O-H?O hydrogen-bonding inter-actions. The crystal employed in this study proved to be a two-component twin around (01). PMID- 21588835 TI - catena-Poly[{MU-eta:eta-1-[2-(dimethyl-amino)-ethyl-kappaN]cyclo-penta-dien-yl} lithium(I)-(MU-1,1,3,3-tetra-tert-butyl-triphosphane-kappaP:P,P)lithium(I)]. AB - The title compound, [Li(2)(C(9)H(14)N)(C(16)H(36)P(3))](n), is a by-product of the reaction of [Cp(C(5)H(4)CH(2)CH(2)NMe(2))ZrCl(2)](n) with (t)Bu(2)P P(SiMe(3))Li in toluene. It is a coordination polymer composed of infinite chains running along [010]. One Li(I) atom is chelated by the cyclo-penta-dienyl ring and and the N atom of the scorpionate ligand and a P atom, whereas the other Li(I) atom is coordinated by the backside of the cyclo-penta-dienyl ring and two P atoms. Both Li(I) atoms adopt a distorted trigonal coordination. The structure was determined from a twinned crystal, but only the data from the main twin component was used. The fraction of components in the crystal was 0.555:0.445 and the twin matrix corresponds to twofold rotation about the c axis (00/00/001). PMID- 21588836 TI - catena-Poly[[[tetra-aqua-zinc(II)]-MU-1,4-bis-(1,2,4-triazol-1-yl)butane kappaN:N] biphenyl-4,4'-dicarboxyl-ate]. AB - The asymmetric unit of the polymeric title compound, {[Zn(C(8)H(12)N(6))(H(2)O)(4)](C(14)H(8)O(4))}(n) or {[Zn(BTB)(H(2)O)(4)](BPDC)}(n) [BTB is 1,4-bis-(1,2,4-triazol-1-yl)butane and H(2)BPDC is biphenyl-4,4'-dicarb-oxy-lic acid], contains half a [Zn(BTB)(H(2)O)(4)](2+) cation and half a BPDC anion, both ions lying about a crystallographic inversion centre. The crystal structure consists of zigzag polymeric cationic chains parallel to the c axis and uncoordinated anions linked into a three-dimensional supra-molecular architecture by O-H?O, C-H?O hydrogen bonds and C-H?pi inter-actions. PMID- 21588837 TI - catena-Poly[[diaqua-cadmium(II)]-MU-4,4'-sulfonyl-dibenzoato-kappaO:O]. AB - The title compound, [Cd(C(14)H(8)O(6)S)(H(2)O)(2)](n), comprises zigzag chains parallel to [111] of alternating [Cd(H(2)O)(2)](2+) and sulfonyl-dibenzoate units, with the Cd and S atoms lying on crystallographic twofold axes. The central Cd(II) ion is in a slightly distorted octa-hedral geometry, coordinated by six O atoms from two carboxyl-ate groups and two water O atoms. An intra molecular C-H?O hydrogen bond occurs. In the crystal, inter-molecular hydrogen bonds between carboxyl-ate O atoms and coordinated water mol-ecules in adjacent chains lead to the formation of a three-dimensional network structure. The compound is isotypic with the Zn analog. PMID- 21588838 TI - Bis(MU(2)-4-amino-3-nitro-benzoato)bis-(4-amino-3-nitro-benzoato)octa-butyldi MU(3)-oxido-tetra-tin(IV). AB - The tetranuclear molecules of the title compound, [Sn(4)(C(4)H(9))(8)(C(7)H(5)N(2)O(4))(4)O(2)], reside on a crystallographic inversion center. Both the two independent Sn atoms are five-coordinate, with distorted trigonal-bipyramidal geometries. One Sn atom is coordinated by two O atoms of the carboxyl-ate anions, one bridging O atom and two butyl groups and the other Sn atom is coordinated by an O atom of the carboxyl-ate anion, two bridging O atoms and two butyl groups. All the butyl groups are equatorial with respect to the SnO(3) trigonal plane. The mol-ecular structure is stabilized by intra-molecular N-H?O hydrogen bonds. In the crystal, pairs of inter-molecular bifurcated acceptor N-H?O and C-H?O hydrogen bonds link the mol-ecules into chains along [10]. Weak inter-molecular C-H?pi and pi-pi inter-actions [centroid centroid distance = 3.713 (2) A] are also observed. PMID- 21588839 TI - mer-[3-Phenyl-5-(2-pyridyl-kappaN)-1,2,4-triazol-1-ido-kappaN]bis-(2 quinolylphenyl-kappaC,N)iridium(III) deuterochloro-form disolvate. AB - In the title compound, [Ir(C(13)H(9)N(4))(C(15)H(10)N)(2)].2CDCl(3), the coordination at iridium is octa-hedral, but with narrow ligand bite angles ranging from 74.85 (8) to 83.99 (8) degrees . The bond lengths at iridium show the expected trans influence, with Ir-N trans to C being appreciably longer than trans to N. The chelate rings are mutually perpendicular to a reasonable approximation [interplanar angles ranging from 77.79 (6) to 83.93 (7) degrees ]. All ligands are approximately planar; the maximum inter-planar angles within ligands are ca 12 degrees . One CDCl(3) solvent molecule is severly disordered and was excluded from the refinement. PMID- 21588840 TI - 4-(Dimethyl-amino)-pyridinium trans-diaqua-bis-[oxalato(2-) kappaO,O]chromate(III). AB - In the title salt, (C(7)H(11)N(2))[Cr(C(2)O(4))(2)(H(2)O)(2)], the asymmetric unit contains one half-cation and one half-anion. The Cr atom, the C and N atoms involved in C- N(exocyclic) bonding and the N and H atoms of N-H groups lie on twofold rotation axis. The Cr(III) atom of the complex anion is six-coordinated in a distorted (4 + 2) octa-hedral geometry with four equatorial O atoms of two nearly coplanar oxalate and two quasi-axial aqua O atoms. In the crystal, the protonated N atoms of the pyridine rings are hydrogen bonded to the carbonyl O atoms of the anions, forming chains along [010]. These chains are connected by lateral O-H?O hydrogen bonds, stabilizing the structure. PMID- 21588841 TI - Tetra-kis[MU-2-(3,4-dimeth-oxy-phen-yl)acetato]-kappaO,O:O;kappaO:O,O;kappaO:O bis-{[2-(3,4-dimeth-oxy-phen-yl)acetato-kappaO,O](1,10-phenanthroline kappaN,N')erbium(III)}. AB - In the dimeric centrosymmetric title complex, [Er(2)(C(10)H(11)O(4))(6)(C(12)H(8)N(2))(2)], the Er(III) ion is nine-coordinated by five 2-(3,4-dimeth-oxy-lphen-yl)acetic acid (DMPA) ligands via seven O atoms and two N atoms from a bis-chelating 1,10-phenanthroline (phen) ligand in a distorted tricapped trigonal-prismatic geometry. The DMPA ligands are coordinated to the Er(III) ion in bis-chelate, bridging and bridging tridentate modes. Relatively weak intra-molecular C-H?O inter-actions reinforce the stability of the mol-ecular structure. Inter-molecular C-H?O inter-actions are also observed. PMID- 21588842 TI - n-Butyl-dichlorido(2-{(1E)-1-[2-(pyridin-2-yl)hydrazin-1-yl-idene]eth yl}phenolato)tin(IV). AB - Two independent mol-ecules comprise the asymmetric unit of the title compound, [Sn(C(4)H(9))(C(13)H(12)N(3)O)Cl(2)]. The Sn atom in each is coordinated by the tridentate ligand via the phenoxide O, hydrazine N and pyridyl N atoms, forming five- and six-membered chelate rings. The approximately octa-hedral coordination geometry is completed by the alpha-C atom of the n-butyl group (which is trans to the hydrazine N atom) and two mutually trans Cl atoms. Differences between the mol-ecules are evident in the relative planarity of the chelate rings and in the conformations of the n-butyl groups [C-C-C-C = 177.2 (5) and -64.4 (11) degrees ]. Significant differences in the Sn-Cl bond lengths are related to the formation of N-H?Cl hydrogen bonds, which link the mol-ecules comprising the asymmetric unit into dimeric aggregates. These are consolidated in the crystal packing by C H?Cl contacts. The structure was refined as an inversion twin; the minor twin component is 37 (3)%. PMID- 21588843 TI - 1-Cyano-methyl-1,4-diazo-niabicyclo-[2.2.2]octane tetra-chloridomanganate(II). AB - In the crystal structure of the title compound, (C(8)H(15)N(3))[MnCl(4)], the Mn atom is coordinated by four chloride ligands in a slightly distorted tetra-hedral geometry. Each [MnCl(4)](2-) anion is connected to the 1-cyano-methyl-1,4-diazo niabicyclo-[2.2.2]octane dications by N-H?Cl hydrogen bonds, forming chains parallel to [001]. PMID- 21588844 TI - Aqua-(hippurato)bis-(1,10-phenanthroline)cobalt(II) nitrate monohydrate. AB - In the title compound, [Co(C(9)H(8)NO(3))(C(12)H(8)N(2))(2)(H(2)O)]NO(3).H(2)O, the Co(II) atom is six-coordinated by a carboxylate O atom of the hippurate (Hc) anion, a water O atom and four N atoms from two 1,10-phenanthroline ligands in a distorted octa-hedral geometry. The uncoordinated O atom of the hippuric acid anion is involved in an intra-molecular hydrogen bond to the coordinated water mol-ecule. The crystal packing is stabilized by inter-molecular O-H?O hydrogen bonds involving the Hc anions, the coordinated water mol-ecule, the nitrate anion and the uncoordinated water mol-ecule. PMID- 21588845 TI - 1-(Diphenyl-phosphinothio-yl)-2-[(4-methyl-phen-yl)meth-oxy-meth-yl]ferrocene. AB - Following our continuing inter-est in developing new chiral phosphine-containing ferrocenyl ligands, we synthesized the title compound, [Fe(C(5)H(5))(C(26)H(24)OPS)], in which there are two nearly identical mol-ecules in the asymmetric unit. The conformation of the cyclo-penta-dienyl (Cp) rings in each ferrocenyl group are inter-mediate between eclipsed and staggered, with twist angles of 16.6 (2) and 8.9 (2) degrees . The protecting S atom is located endo with respect to the substituted Cp ring. In the crystal, mol-ecules are connected through inter-molecular C-H?pi inter-actions. PMID- 21588846 TI - Poly[[MU(10)-2,3-bis(carboxymethyl)butanedioato]disodium]. AB - The asymmetric unit of the title compound, [Na(2)(C(8)H(8)O(8))](n), contains one Na(+) ion and half of a 2,3-bis(carboxymethyl)butanedioate (H(2)BTC(2-)) dianion, which lies on a center of symmetry. The dianion exhibits a MU(10)-bridging mode. Each Na atom lies in a NaO(6) octa-hedron defined by six O atoms from five dianions. Adjacent NaO(6) octa-hedra share a common O-O edge, generating a biocta hedron; adjacent biocta-hedra are O-O edge-connected to one another, building up a chain along [001]. The chains are connected by adjacent H(2)BTC(2-) anions into a three-dimensional framework. The structure is further stabilized by O-H?O hydrogen bonds. PMID- 21588847 TI - trans-Dichlorido-bis-[tris(4-meth-oxy-phenyl)-phosphane]palladium(II) toluene solvate. AB - In the title compound, trans-[PdCl(2){P(4-MeOC(6)H(4))(3)}(2)].C(7)H(8), the Pd(II) atom lies on a center of symmetry, resulting in a distorted trans-square planar geometry. The Pd-P and Pd-Cl bond lengths are 2.3409 (4) and 2.2981 (4) A, respectively. An intra-molecular C-H?Cl hydrogen bond occurs. In the crystal, weak C-H?O inter-actions are observed between the aromatic rings of adjacent mol ecules. The toluene solvate molecule is equally disordered over two sets of sites. PMID- 21588848 TI - (5-Amino-isophthalato-kappaN)triaqua-(1,10-phenanthroline-kappaN,N')cobalt(II) trihydrate. AB - The Co(II) atom in the title compound, [Co(C(8)H(5)NO(4))(C(12)H(8)N(2))(H(2)O)(3)].3H(2)O, is six-coordinated in a CoN(3)O(3) octa-hedral geometry; the water-coordinated Co(II) atom is chelated by the N-heterocycle. An inter-molecular N-H?O hydrogen bond occurs. The carboxyl ate entity coordinates through the amino group. The carboxyl-ate donor unit, coordinated and uncoordinated water mol-ecules inter-act through O-H?O and N-H?O hydrogen bonds, generating a tightly-held three-dimensional cage-like network. PMID- 21588849 TI - [2,2'-Dihy-droxy-N,N-(3-hy-droxy-imino-pentane-2,4-di-yl)dibenzo-hydra-zid ato]copper(II). AB - The Cu(II) atom in the title complex, [Cu(C(19)H(17)N(5)O(5))], is coordinated by two N atoms and two O atoms of one 2,2'-dihy-droxy-N(2),N(2)'-(3-hy-droxy-imino pentane-2,4-di-yl)dibenzo-hydrazidate ligand, exhibiting a distorted square planar geometry. The dihedral angle between the two benzene rings in the oxime hydrazone is 7.62 (15) degrees . The molecular configuration is stabilized by intramolecular O-H?N hydrogen bonds. Pairs of centrosymmetrically related molecules are linked into dimers by two inter-molecular C-H?O hydrogen bonds. Each dimer is further connected to four neighboring dimers via four O-H?O hydrogen bonds, forming an extended two-dimensional structure. The oxime O atom is disordered over two orientations in a 2:1 ratio. PMID- 21588850 TI - {MU(2)-6,6'-Dimeth-oxy-2,2'-[butane-1,4-diylbis(nitrilo-methyl idyne)]diphenolato}trinitratocopper(II)neodymium(III). AB - In the title complex, [CuNd(C(20)H(22)N(2)O(4))(NO(3))(3)], the Cu(II) ion is coordinated in a distorted square-planar environment by two O atoms and two N atoms of a tetra-dentate Schiff base ligand. The Nd(III) ion is ten-coordinated by three bis-chelating nitrate groups and four O atoms of the Schiff base ligand. The atoms of one of the nitrato ligands are disordered over two sets of sites, with refined occupancies of 0.567 (13) and 0.433 (17). PMID- 21588851 TI - [MU-2,3,5,6-Tetra-kis(2-pyrid-yl)pyrazine-kappaN,N,N:N,N,N]bis-[diaqua(dihydrogen m-phenylene-diphospho-nato-kappaO)nickel(II)] dihydrate. AB - The title compound [Ni(2)(C(6)H(6)O(6)P(2))(2)(C(24)H(16)N(6))(H(2)O)(4)].2H(2)O or [Ni(2)(tpyprz)(1,3-HO(3)PC(6)H(4)PO(3)H)(2)(H(2)O)(4)].2H(2)O [tpyprz = tetra kis-(2-pyrid-yl)pyrazine, C(24)H(16)N(6)] is a binuclear complex with a crystallographic inversion center located at the center of the pyrazine ring. The equivalent nickel(II) sites exhibit a distorted {NiO(3)N(3)} octa-hedral coordination, with the three nitro-gen donors of each terminus of the tpyprz ligand in a meridional orientation. An aqua ligand occupies the position trans to the pyrazine nitro-gen donor, while the second aqua ligand is trans to the oxygen donor of the dihydrogen-1,3-phenyl-diphospho-nate ligand. The Ni-O and Ni-N bond lengths fall in the range 2.011 (3) to 2.089 (3) A. The protonation sites on the organo-phospho-nate ligand are evident in the significantly longer P-O bonds compared to the unprotonated sites. In the crystal structure, the complex mol ecules and the solvent water mol-ecules are linked into a three-dimensional hydrogen-bonded framework through O-H?O inter-actions between the aqua ligands, the protonated organo-phospho-nate oxygen atoms and the water mol-ecules of crystallization. Intra-molecular pi-stacking between the phenyl group of the phospho-nate ligand and a pyridyl group of the tpyprz ligand, at a distance of 3.244 (5) A between ring centroids, is also observed. PMID- 21588852 TI - Tetra-aqua(2,2'-bipyridine-kappaN,N')magnesium(II) bis-(4-bromo-benzoate). AB - In the complex cation of the title compound, [Mg(C(10)H(8)N(2))(H(2)O)(4)](C(7)H(4)BrO(2))(2), the Mg(II) atom is coordinated by two N atoms from a 2,2'-bipyridine ligand and four water O atoms in a distorted MgN(2)O(4) octa-hedral geometry. The cation is located on a special position on a twofold rotation axis which passes through the Mg(II) atom and the centroid of the 2,2'-bipyridine ligand. The 2,2'-bipyridine ligands exhibit nearly perfect coplanarity (r.m.s. deviation = 0.0035 A) . In the crystal, O-H?O and C-H?O, C-H?Br hydrogen bonds and pi-pi stacking inter-actions [mean inter planar distance of 3.475 (6) A between adjacent 2,2'-bipyridine ligands] link the cations and anions into a three-dimensional supra-molecular network. One Br atom is disordered over two sites with occupancy factors of 0.55 and 0.45. PMID- 21588853 TI - catena-Poly[bis(MU(3)-3-aminobenzoato-kappaN:O:O,O')bis(MU(2)-3-aminobenzoato kappaO,O':O)dilead(II)]. AB - The Pb(II )atom in the title compound, {[Pb(2)(C(7)H(6)NO(2))(4)]}(n), is chelated by two 3-aminobenzoato ligands in a distorted pentagonal-bipyramidal coordination geometry with five oxygen donors in the equatorial positions, one nitro-gen donor and one oxygen donor in the axial positions. Two mol-ecules are linked through a centre of inversion, forming a dinuclear entity. These entities are linked in a MU(3)-bridging mode through the amino N atom and two carboxyl-ate O atoms into a chain along the b axis. Classical inter-molecular N-H?O hydrogen bonding is observed in the structure. The supra-molecular structure is consolidated by pi-pi stacking inter-actions with centroid-centroid distances between benzene rings of 3.837 (8) A. PMID- 21588854 TI - Bis[MU-2-(4-hydroxyphenyl)acetato]-kappaO,O':O;kappaO:O,O'-bis{aqua(4,4'-bi-pyri dine-kappaN)bis[2-(4-hydroxyphenyl)acetato-kappaO,O']gadolinium(III)} monohydrate. AB - In the dinuclear title complex, [Gd(2)(C(8)H(7)O(3))(6)(C(10)H(8)N(2))(2)(H(2)O)(2)].H(2)O, the two Gd(III) ions are nine-coordinated by seven O atoms from four deprotonated p-hy-droxy-phenyl acetic acid (PAA) ligands, one water O atom and an N atom from a 4,4'-bypyridine (bipy) ligand in a distorted tricapped trigonal-prismatic geometry. The deprotonated PAA ligands are coordinated to the Gd(III) atom either as chelating on the same metal or in a tridentate bridging mode. Numerous O-H?O and O-H?N hydrogen bonds involving hydroxyl, coordinated and uncoordinated water mol-ecules build up an intricate three-dimensional network. PMID- 21588855 TI - Tetra-kis(1H-imidazole-kappaN)(2-phenyl-propanedioato-kappaO,O)nickel(II). AB - In the title complex, [Ni(C(9)H(6)O(4))(C(3)H(4)N(2))(4)], the Ni(II) ion is O,O' chelated by the phenyl-malonato ligand and coordinated by four imidazole ligands in a slightly distorted octa-hedral geometry. In the crystal structure, symmetry related mol-ecules are linked by N-H?O hydrogen bonds, generating a three dimensional network. PMID- 21588856 TI - catena-Poly[[[tetraaqua(3,5-dinitro-4-oxidopyridine N-oxide kappaO)neodymium(III)]-MU-oxalato-kappaO,O:O,O] tetrahydrate]. AB - In the title coordination polymer, {[Nd(C(5)H(2)N(3)O(6))(C(2)O(4))(H(2)O)(4)].4H(2)O}(n), the oxalate dianions link adjacent nine-coordinate, tricapped trigonal-prismatic Nd(III) atoms into a chain running along the b axis. The 3,5-dinitropyridin-4-oxido N-oxide ligand is formally a zwitterionic anion; the anion binds to the metal atom through the N oxide O atom. The chains are connected into a three-dimensional network by O-H?O hydrogen bonds involving the coordinated and uncoordinated water mol-ecules. PMID- 21588857 TI - catena-Poly[[[pentaaquaeuropium(III)]-MU-5-sulfonatoisophthalato-kappaO,O:O,O] 4,4'-bipyridine N,N'-dioxide hemisolvate trihydrate]. AB - In the crystal structure of the title compound, {[Eu(C(8)H(3)O(7)S)(H(2)O)(5)].0.5C(10)H(8)N(2)O(2).3H(2)O}(n), the Eu(III) coordination polymer displays a ribbon motif as the 5-sulfoisopthalate anion uses one of carboxyl -CO(2) units to chelate to a Eu atom and the other to bind to other two Eu atoms; the sulfonyl -SO(3) unit is not involved in coordination. Adjacent ribbons are linked by O-H?O hydrogen bonds, generating a three dimensional network. The 4,4'-bipyridine-N,N'-dioxide mol-ecule lies on an inversion centre and is hydrogen-bonded to the complex network. The coordination geometry of the Eu atom is a monocapped square anti-prism. PMID- 21588858 TI - Di-MU-iodido-bis{[hydroxy(methoxy)bis(2-pyridyl)methane kappaN,O,N']iodidocadmium(II)}. AB - In the centrosymmetric dinuclear title compound, [Cd(2)I(4)(C(12)H(12)N(2)O(2))(2)], two MU-I atoms bridge two Cd(II) atoms and each Cd(II) atom is also bonded to a terminal I atom and a hy-droxy-meth-oxy-bis (2-pyrid-yl)methane ligand, which functions in an N,O,N'-tridentate mode, resulting in a distorted octa-hedral coordination environment. Inter-molecular O H?I hydrogen bonds and pi-pi stacking inter-actions between the pyridine rings [centroid-centroid distance = 3.790 (2) A] are present in the crystal structure. PMID- 21588859 TI - Poly[[[MU(3)-N'-(carboxymethyl)ethylene-di-amine-N,N,N' triacetato]dysprosium(III)] trihydrate]. AB - In the title coordination polymer, {[Dy(C(10)H(13)N(2)O(8))].3H(2)O}(n), the dysprosium(III) ion is coordinated by two N atoms and six O atoms from three different (carb-oxy-meth-yl)ethyl-ene-diamine-triacetate ligands in a distorted square-anti-prismatic geometry. The ligands connect the metal atoms, forming layers parallel to the ab plane. O-H?O hydrogen bonds further assemble adjacent layers into a three-dimensional supra-molecular network. PMID- 21588860 TI - catena-Poly[[diaqua-magnesium(II)]-bis-(MU-5-ammonio-isophthalato-kappaO:O)]. AB - In the title compound, [Mg(C(8)H(6)NO(4))(2)(H(2)O)(2)](n), the Mg(II) ion lies on a twofold roatation axis and is coordinated in a slightly distorted octa hedral environment. Pairs of bridging ammonium-isophthalate ligands connect symmetry-related Mg(II) ions, forming chains along [010]. In the crystal, inter molecular O-H?O and N-H?O hydrogen bonds link these chains into a three dimensional network. The centroids of pairs of symmetry-related benzene rings within a chain are separated by 3.5707 (12) A. PMID- 21588861 TI - Bis[N'-(2-oxo-1H-indol-3-ylidene)thiophene-2-carbohydrazidato kappaO,N',O']zinc(II) N,N-dimethyl-formide mono-solvate monohydrate. AB - The metal atom of the title compound, [Zn(C(13)H(8)N(3)O(2)S)(2)].C(3)H(7)NO.H(2)O, is O,N,O'-chelated by two deprotonated Schiff bases and it exists in a distorted octa-hedral geometry. The N-H groups of the ligands, the carbonyl group of the DMF mol-ecule and uncoordinated water mol-ecule engage in N-H?O and O-H?O inter-actions, generating a hydrogen-bonded ribbon that propagates along [110]. One thienyl ring is disordered over two positions in a 1:1 ratio. PMID- 21588862 TI - Bis[N'-(2-oxo-1H-indol-3-ylidene)furan-2-carbohydrazidato kappaO,N',O']manganese(II) N,N-dimethyl-formide monosolvate monohydrate. AB - In the title compound, [Mn(C(13)H(8)N(3)O(3))(2)].C(3)H(7)NO.H(2)O, the metal atom is O,N,O'-chelated by two deprotonated Schiff bases and exists in a distorted octa-hedral geometry. The N-H groups, the carbonyl group of the DMF mol ecule and the uncoord-inated water mol-ecule engage in N-H?O and O-H?O hydrogen bonding inter-actions, generating a hydrogen-bonded ribbon that propagates along [110]. PMID- 21588863 TI - catena-Poly[[(1,10-phenanthroline-kappaN,N')cadmium(II)]-MU-oxalato kappaO,O:O,O]. AB - In the title complex, [Cd(C(2)O(4))(C(12)H(8)N(2))](n), the Cd(II) atom has a distorted octa-hedral coordination, defined by four O atoms from two symmetry related oxalate ligands and by two N atoms from a bidentate 1,10-phenanthroline ligand. Each oxalate ligand bridges two Cd(II) atoms, generating a zigzag chain structure propagating along [100]. The packing of the structure is consolidated by non-classical C-H?O hydrogen-bonding inter-actions. PMID- 21588864 TI - catena-Poly[[diaqua-calcium(II)]-bis-(MU-quinoline-3-carboxyl-ato)]. AB - In the title complex, [Ca(C(10)H(6)NO(2))(2)(H(2)O)(2)](n), the Ca(II) ion is eight-coordinated by six carboxyl-ate O atoms from four separate quinoline-3 carboxyl-ate ligands, two of which are bidentate chelate and two bridging, and two water mol-ecules in a distorted square-anti-prismatic geometry. The bridging groups form a polymeric chain substructure extending along the c axis, the chains being connected by coordinated-water O-H?N and O-H?O(carboxyl-ate) hydrogen bonds into a three-dimensional framework structure. PMID- 21588865 TI - Diaqua-bis-(4-carb-oxy-2-propyl-1H-imidazole-5-carboxyl-ato-kappaN,O)cobalt(II) N,N-dimethyl-formamide disolvate. AB - In the title complex, [Co(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)].2C(3)H(7)NO, the Co(II) cation (site symmetry ) is six-coordinated by two 5-carb-oxy-2-propyl-1H imidazole-4-carboxyl-ate ligands and two water mol-ecules in a distorted octa hedral environment. In the crystal structure, the complex mol-ecules and dimethyl formamide solvent mol-ecules are linked by extensive O-H?O and N-H?O hydrogen bonding into sheets lying parallel to (21). PMID- 21588866 TI - Bis{[6-meth-oxy-2-(4-methyl-phen-yl)iminiometh-yl]phenolate-kappaO,O'}tris (nitrato-kappaO,O')europium(III). AB - The crystal structure of title compound, [Eu(NO(3))(3)(C(15)H(15)NO(2))(2)], contains two Schiff base 6-meth-oxy-2-[(4-methyl-phen-yl)imino-meth-yl]phenolate (L) ligands and three independent nitrate ions that chelate to the europium(III) ion via the O atoms. The coordination number of the Eu(III) ion is ten. The L ligands chelate with a strong Eu-O(deprotonated phenolate) bond and a weak Eu O(meth-oxy) contact, the latter can be inter-preted as the apices of the bicapped square-anti-prismatic Eu(III) polyhedron. Intra-molecular N-H?O hydrogen bonds occur. PMID- 21588867 TI - Diaqua-bis-(1,10-phenanthroline-kappaN,N')manganese(II) sulfate hexa-hydrate. AB - In the title compound, [Mn(C(12)H(8)N(2))(2)(H(2)O)(2)]SO(4).6H(2)O, the complex cations assemble into positively charged sheets parallel to (010) via inter molecular pi-pi stacking inter-actions with a mean interplanar distance of 3.410 (6) along [100] and 3.465 (5) A along [001]. The sulfate anions and uncoordinated water mol-ecules are inter-connected between these layers by hydrogen bonds, forming negatively charged layers which are linked to the positive layers through O-H?O hydrogen bonds, forming a three-dimensional architecture. Both the positive and negative sheets are stacked along [010] in an ?ABAB? sequence, the A layers being shifted by 1/2a along [100] with respect to the B layers. One of the uncoordinated water molecules is equally disordered over two positions. PMID- 21588868 TI - Dichloridobis(1-ethyl-2,6-dimethyl-pyridinium-4-olate-kappaO)zinc(II). AB - In the title compound, [ZnCl(2)(C(9)H(13)NO)(2)], the Zn(II) ion is coordinated by two Cl(-) anions and two O atoms of two zwitterionic organic ligands in a distorted tetra-hedral arrangement. In the crystal, mol-ecules are linked into sheets parallel to the bc plane by C-H?Cl and C-H?O hydrogen bonds and weak pi-pi inter-actions [centroid-centroid distance = 3.669 (1) A]. PMID- 21588869 TI - Acetonitrile-bis-(2,9-dimethyl-1,10-phen-an-throline)copper(II) bis-(tetra fluorido-borate). AB - The title compound, [Cu(CH(3)CN)(C(12)H(12)N(2))(2)](BF(4))(2), crystallizes with two copper-containing cations and four tetra-fluoro-borate anions in the asymmetric unit. The structure represents a second crystal form of the salt, the first being an acetonitrile solvate [Watton (2009 ?). Acta Cryst. E65, m585 m586]. The complex cation has a distorted trigonal-bipyramidal geometry, whereas the previous structure exhibits a distorted square-pyramidal geometry. One of the four BF(4) (-) counter-ions is disordered, with a refined site occupancy of 0.8615 (17):0.1385 (17). PMID- 21588870 TI - Di-MU-hydroxido-bis-[aqua-(pyridine-2,6-dicarboxyl-ato)iron(III)] monohydrate. AB - In the dinuclear title complex, [Fe(2)(OH)(2)(C(7)H(3)NO(4))(2)(H(2)O)(2)].H(2)O, the two Fe atoms are separated by 3.063 (1) A. Inter-molecular O-H?O hydrogen bonds form an extensive three-dimensional hydrogen-bonding network, which consolidates the crystal packing. PMID- 21588871 TI - Tris(1,2-diamino-ethane)-nickel(II) hexa-fluoridosilicate. AB - The ionic title complex, [Ni(C(2)H(8)N(2))(3)](SiF(6)), is built up of [Ni(en)(3)](2+) complex cations (en = 1,2-diamino-ethane) and hexa fluoridosilicate anions. Single crystals of the title complex were isolated from an aqueous-ethano-lic Ni(2+)-en-SiF(6) (2-) system. The Ni(II) and Si atoms are each located on a special position with site symmetry 3.2. The Ni(II) atom coordination sphere is octa-hedrally deformed, being coordinated by three chelating diamine ligands with an Ni-N distance of 2.1233 (18) A. The crystal packing of the respective ions corresponds to the structure type of the hexa gonal form of BN. Beside ionic forces, the packing is governed by N-H?F hydrogen bonds, which lead to the formation of hydro-phobic channels running along the 6(3) screw axis. The structure was refined as an inversion twin [0.49 (3): 0.51 (3)]. PMID- 21588872 TI - Bis[bis-(3,5-diamino-1H-1,2,4-triazol-4-ium)copper(I)] tris-(hexa fluoridosilicate). AB - In the title compound, [Cu(C(2)H(6)N(5))(2)](2)(SiF(6))(3), the asymmetric unit is composed of one [Cu(HL)(2)](3+) cation (where L is 3,5-diamino-1,2,4-triazole) and one and a half SiF(6) (2-) anions. The rather large positively charged guanazole ligand moiety promotes the low metal coordination number of 2 for the Cu(I) atom. The compound was obtained using the electrochemical alternating current technique starting from an ethanol-methanol solution of CuSiF(6).4H(2)O and guanazole. In the crystal, N-H?F hydrogen bonds play an important role in the formation of a three-dimensional network. As a result of these hydrogen bonds, there are also pi-pi inter-actions [centroid-centroid distance = 3.3024 (14) A] involving one of the triazole groups in mol-ecules related by an inversion center, and short Cu?N inter-actions [2.909 (3) A] involving an -NH(2) group, leading to the formation of a dimer-like arrangement. PMID- 21588873 TI - [meso-Tetra-kis(4-heptyl-oxyphen-yl)porphyrinato]nickel(II). AB - In the title compound, [Ni(C(72)H(84)N(4)O(4))], the four-coordinate Ni(II) ion in the middle of the planar 24-membered porphyrin ring is located on a crystallograpic inversion center, with Ni-N distances of 1.946 (2)-1.951 (2) A. The 4-heptyl-oxyphenyl groups are twisted with respect to the porphyrin mean plane, the dihedral angles being 88.5 (3) and 79.1 (2) degrees . PMID- 21588874 TI - Poly[[MU(2)-1,2-bis-(1H-imidazol-1-ylmeth-yl)benzene-kappaN:N](MU(2)-tereph thalato-kappaO:O)zinc(II)]. AB - In the title coordination polymer, [Zn(C(8)H(4)O(4))(C(14)H(14)N(4))](n), the Zn(II) atom is coordinated by two N atoms from two 1,2-bis-(imidazol-1-ylmeth yl)benzene ligands as well as by the two O atoms from two terephthalate ligands, confering a tetra-hedral coordination geometry. The bridging ligands generate a three-dimensional structure. PMID- 21588875 TI - catena-Poly[[bis[quinazolin-4(3H)-one-kappaN]cadmium(II)]-di-MU-chlorido]. AB - The asymmetric unit of the title compound, [CdCl(2)(C(8)H(6)N(2)O)(2)](n), consists of one mol-ecule of the 3H-quinazolin-4-one ligand, one Cd(2+) cation, which is located on a twofold axis, and one chlorido ligand in a general position. The latter bridges metal cations, forming a one-dimensional polymer along the b axis. The Cd?Cd distance along the chain is 3.7309 (7) A. The octa hedral coordination around the metal is completed by two ligands in a trans axial geometry which coordinate through the N atom in 1 position. Moderately strong classical N-H?O hydrogen bonds around crystallographic inversion centers cross link adjacent polymeric chains. PMID- 21588876 TI - (Ethanolato)[2,3,7,8,12,13,17,18-octa-ethylporphyrinato(2-)]iron(III). AB - The title compound, [Fe(C(2)H(5)O)(C(36)H(44)N(4))], contains a five-coordinate iron-porphyrin complex with an axial eth-oxy ligand. The iron(III) atom is displaced by 0.504 (2) A towards the eth-oxy ligand from the 24-atom mean plane of the porphyrin. The average Fe-N(p) distance is 2.078 (2) A and the Fe-O distance is 1.8232 (18) A. The eth-oxy C atoms are disordered in a 0.581 (12):0.419 (12) ratio. The bond angles of the Fe-O-C linkage are 128.6 (3) and 130.4 (3) degrees , respectively, for the major and minor occupancy C atoms. PMID- 21588877 TI - catena-Poly[[bis-(MU-5-bromo-pyridine-3-carboxyl-ato-kappaO:O')dicopper(II)]-bis (MU-5-bromo-pyridine-3-carboxyl-ato)-kappaO,O':N;kappaN:O,O']. AB - The title compound [Cu(2)(C(6)H(3)BrNO(2))(4)](n), forms sheets in the bc plane. The structure features the dinuclear paddle-wheel cage motif common to copper(II) carboxyl-ates. The polymeric structure is achieved through bridging between binuclear units by the pyridyl donors of two of the four carboxyl-ates of the cage. Each cage engages in axial bonding at each copper atom to a pyridyl nitro gen donor and extends two 5-bromo-pyridine-3-carboxyl-ate groups to bridge to adjacent binuclear sites in the bc plane. Each cage is linked to four adjacent cages in the plane. The intra-dimer Cu?Cu distance is 2.6465 (5) A. The remaining 5-bromo-pyridine-3-carboxyl-ate groups project into the inter-lamellar domain and inter-digitate in pairs from each neighboring layer. PMID- 21588878 TI - A novel inorganic-organic hybrid borate, poly{[Na(2)(C(4)H(2)O(4))(H(3)BO(3))(H(2)O)(4)].H(3)BO(3)}. AB - The structure of the title compound, catena-poly[[[di-MU-aqua-MU-fumarato-MU (boric acid)-disodium]-di-MU-aqua] boric acid monosolvate], contains two crystallographically independent Na(+) cations, each being six-coordinated by one fumarate O atom, one boric acid O atom and four water O atoms in a distorted octa hedral geometry. Adjacent [NaO(2)(OH(2))(4)] units share edges and are linked into chains propagating parallel to [100]. The free boric acid mol-ecules are connected to the chains through strong inter-molecular O-H?O hydrogen bonds. Additional O-H?O hydrogen bonds between the water mol-ecules, the free and coordinated boric acid mol-ecules and the fumarate anion lead to the formation of a three-dimensional supra-molecular structure. With the exception of the two water mol-ecules, all other atoms lie on mirror planes. PMID- 21588879 TI - catena-Poly[[[diaquacadmium(II)]bis[MU-2-(pyridinium-1-yl)butanedioato] kappaO:O;kappaO:O] tetrahydrate], a polymeric chain structure. AB - In the title complex, {[Cd(C(9)H(8)NO(4))(2)(H(2)O)(2)].4H(2)O}(n), the Cd(II) atom (site symmetry 2) is coordinated by six O atoms from four crystallographically related 1-(1,2-dicarboxyl-ate)pyridin-1-ium ligands (L) and from two water molecules in a distorted octahedral geometry. Paired L ligands connect Cd(II) atoms into a chain motif parallel to [001], which is further inter linked by O-H?O hydrogen bonds into a three-dimensional supra-molecular net. PMID- 21588880 TI - trans-Dichloridobis{[4-(dimethyl-amino)-phen-yl]diphenyl-phosphane}palladium(II). AB - The title compound, trans-[PdCl(2){PPh(2)(4-Me(2)NC(6)H(4))}(2)], crystallizes with the Pd atom on a center of symmetry, resulting in a distorted trans PdCl(2)P(2) square-planar geometry. The Pd-P and Pd-Cl bond lengths are 2.3550 (7) and 2.2906 (7) A, respectively. Some weak inter-actions are observed between the aromatic rings of adjacent mol-ecules, with an inter-planar distance between two pi-stacked rings of 3.505 (3) A. Intra- and intermolecular C-H?Cl hydrogen bonds also occur. PMID- 21588881 TI - Di-MU-thio-cyanato-kappaN:S;kappaS:N-bis-[bis-(2-methyl-1H-benzimidazole kappaN)(thio-cyanato-kappaN)cadmium(II)]. AB - The title compound, [Cd(2)(NCS)(4)(C(8)H(8)N(2))(4)], is a centrosymmetric dinuclear cadmium(II) complex in which each two metal ions are linked by a pair of thio-cyanate N:S-bridges. Two 2-methyl-benzimidazole N-atom donors and one terminal thio-cyanate N atom complete a highly distorted square-pyramidal geometry around the Cd atom. In the crystal structure, two N-H?S hydrogen-bonding inter-actions occur, resulting in a three-dimensional polymeric structure. The apical 2-methyl-benzimidazole ring and its symmetry-related counterpart are arranged in an anti-parallel manner with a centroid-centroid separation of 3.6050 (14) A, indicative of a pi-pi inter-action. PMID- 21588882 TI - (MU-4,4'-Bipyridine-kappaN:N')bis-[bis-(N,N-dimethyl-dithio-carbamato kappaS,S')zinc(II)]. AB - The title dinuclear Zn(II) complex, [Zn(2)(C(3)H(6)NS(2))(4)(C(10)H(8)N(2))], is centrosymmetric; the mid-point of the C-C bond linking the two pyridine rings is located on an inversion center. The pyridine N atom coordinates to the Zn(II) cation, which is also chelated by two dimethyl-dithio-carbamate anions, giving a trigonal-bipyramidal ZnNS(4) geometry. Weak inter-molecular C-H?S hydrogen bonding is present in the crystal structure. PMID- 21588883 TI - (3-Amino-pyrazin-4-ium-2-carboxyl-ate-kappaN,O)diaqua-zinc(II) dinitrate. AB - The water-coordinated Zn(II) atom in the title salt, [Zn(C(5)H(5)N(3)O(2))(2)(H(2)O)(2)](NO(3))(2), is N,O-chelated by a zwitterionic amino-pyraziniocarboxyl-ate unit; the metal atom, which lies on a center of inversion, shows an octa-hedral coordination. The nitrate ion inter-acts indirectly, through N-H?O hydrogen bonds. In the crystal, adjacent cations and anions are connected by O-H?O hydrogen bonds into a three-dimensional network motif. The crystal studied was a non-merohedral twin with two minor components of 15.1 (1) and 8.0 (1)%. PMID- 21588884 TI - MU-Cyanido-1:2kappaN:C-tricyanido-2kappaC-(rac-5,5,7,12,12,14-hexa-methyl 1,4,8,11-tetra-aza-cyclo-tetra-decane-1kappaN,N',N'',N''')dinickel(II) N,N-di methyl-formamide monosolvate hemi-hydrate. AB - The two Ni(II) atoms in the title complex, [Ni(2)(CN)(4)(C(16)H(36)N(4))].C(3)H(7)NO.0.5H(2)O, are bridged by a cyanide ion. The macrocycle folds around one Ni(II) atom, which is five-coordinated in an NiN(5) square-pyramidal geometry. The other Ni(II) atom is surrounded by the cyanide ions in an NiN(4) square-planar geometry. The dimethyl-formamide solvent mol-ecule is disordered over two positions in a 0.62 (1):0.38 (1) ratio and the water mol-ecule is disordered about a center of inversion. The dinuclear mol ecule and solvent mol-ecules are linked by N-H?O, N-H?N and O-H?O hydrogen bonds, forming a three-dimensional network. PMID- 21588885 TI - (2-Carb-oxy-acetato-kappaO,O)(rac-5,5,7,12,12,14-hexa-methyl-1,4,8,11-tetra-aza cyclo-tetra-decane-kappaN,N',N'',N''')nickel(II) perchlorate acetonitrile solvate. AB - In the crystal structure of the title salt, [Ni(C(3)H(3)O(4))(C(16)H(36)N(4))]ClO(4).CH(3)CN, the macrocycle folds around the Ni(II) atom, which is also chelated by the carboxyl-ate monoanion. The geometry is a distorted NiN(4)O(2) octa-hedron. The formula units are connected by N-H?O hydrogen bonds into centrosymmetric dimers. Further N-H?O and O-H?O hydrogen bonds link the complex mol-ecules and the perchlorate ions. PMID- 21588886 TI - Bis(2,6-dihy-droxy-benzoato-kappaO,O)(nitrato-kappaO,O')bis-(1,10-phenanthroline kappaN,N')neodymium(III). AB - In the mononuclear title complex, [Nd(C(7)H(5)O(4))(2)(NO(3))(C(12)H(8)N(2))(2)], the Nd(III) atom is in a distorted bicapped square-anti-prismatic geometry formed by four N atoms from two chelating 1,10-phenanthroline (phen) ligands, four O atoms from two 2,6-dihy-droxy-benzoate (DHB) ligands and two O atoms from a nitrate anion. pi-pi stacking inter-actions between the phen and DHB ligands of adjacent complexes [centroid-centroid distances = 3.520 (6) and 3.798 (6) A] stabilize the crystal structure. Intra-molecular O-H?O hydrogen bonds are observed in the DHB ligands. PMID- 21588887 TI - Dichlorido{2-morpholino-N-[1-(2-pyri-dyl)ethyl-idene]ethanamine kappaN,N',N''}cadmium. AB - In the title compound, [CdCl(2)(C(13)H(19)N(3)O)], the Cd(II) ion is five coordinate, with the N,N',N''-tridentate Schiff base ligand 2-morpholino-N-[1-(2 pyrid-yl)ethyl-idene]ethanamine and two Cl atoms in a distorted square-pyramidal geometry. In the crystal structure, C-H?Cl hydrogen-bonding inter-actions connect the mol-ecules into a three-dimensional network. PMID- 21588888 TI - Bis{MU-N-[(dimethyl-amino)-dimethyl-sil-yl]-2,6-dimethyl-anilido} kappaN:N';kappaN':N-dicopper(I). AB - The title compound, [Cu(2)(C(12)H(21)N(2)Si)(2)], is a binuclear Cu(I) complex. The dimeric mol-ecule has an inversion center located at the mid-point of the Cu Cu bond [Cu-Cu = 2.7209 (7) A]. The bidentate ligand behaves in an N:N'-bridging mode, coordinating the metal atoms. The N-Cu-N unit is close to being linear [176.60 (8) degrees ]. The two N atoms exhibit different affinities for the metal atom. The Cu-N(amino) bond is longer than the Cu-N(anilido) bond by 0.079 A. The core of the mol-ecule, the [Cu-N-Si-N](2) eight-membered ring, adopts a chair configuration. PMID- 21588889 TI - {6,6'-Dieth-oxy-2,2'-[4,5-dimethyl-o-phenyl-enebis(nitrilo-methyl idyne)]diphenolato}copper(II). AB - In the title complex, [Cu(C(26)H(26)N(2)O(4))], the Cu(II) ion lies on a crystallographic twofold rotation axis and is coordinated in a slightly distorted square-planar environment. The dihedral angle between the central benzene ring and each of the two symmetry-related outer benzene rings is 5.1 (2) degrees . The crystal structure is stabilized by inter-molecular pi-pi inter-actions with centroid-centroid distances in the range 3.466 (2)-3.6431 (16) A. PMID- 21588890 TI - Tris(N,N'-diisopropyl-benzamidinato)cerium(III). AB - The title compound, [Ce(C(13)H(19)N(2))(3)], was obtained in moderate yield (67%) by treatment of anhydrous cerium trichloride with three equivalents of Li[PhC(N(i)Pr)(2)] in tetra-hydro-furan. It is the first homoleptic lanthanide complex of this amidinate ligand. The central Ce(III) ion is coordinated by three chelating benzamidinate anions in a distorted octa-hedral fashion, with Ce-N distances in the narrow range 2.482 (2)-2.492 (2) A. The dihedral angles between the phenyl rings and the chelating N-C-N units are in the range 73.3-87.9 degrees , thus preventing conjugation between the two pi-systems. The mol-ecule is located on a twofold rotation axis, and one of the phenyl rings is equally disordered over two alternative symmetry-equivalent positions around this axis. PMID- 21588891 TI - [2-({3-[(3-Amino-prop-yl)amino]-prop-yl}imino-meth-yl)phenolato kappaO,N,N'',N''']bromidocopper(II). AB - In the title compound, [Cu(C(13)H(20)N(3)O)Br], the Cu(II) atom is coordinated by three N atoms and one O atom from the deprotonated ligand derived from the Schiff base condensation of 3,3-imino-bis-(propyl-amine) and salicyl-aldehyde. The three N and the O atoms occupy equatorial positions, while the Br atom occupies an axial position. The amine H atoms form inter-molecular hydrogen bonds with the Br and O atoms of adjoining mol-ecules. PMID- 21588892 TI - Tetra-kis[MU-2-(4-hy-droxy-phenyl)-acetato]-kappaO,O':O;kappaO:O,O'-bis-{aqua (4,4'-bi-pyridine-kappaN)bis-[2-(4-hy-droxy-phenyl)-acetato kappaO,O]neodymium(III)} monohydrate. AB - The title complex, [Nd(2)(C(8)H(7)O(3))(6)(C(10)H(8)N(2))(2)(H(2)O)(2)].H(2)O, contains two Nd atoms, six 4-hy-droxy-phenyl-acetate (hpaa) anions, two 4,4' bipyridine mol-ecules (bipy) and two water mol-ecules; an additional water mol ecule of solvation is also present in the crystal structure. Each of the Nd(III) ions is nine-coordinated by seven O atoms from four hpaa ligands, an N atom from a bipy ligand and an O atom from a water mol-ecule in a distorted tricapped trigonal-prismatic geometry. The hpaa ligands are coordinated to the Nd(III) ions in the bridging and bridging tridentate modes. Extensive O-H?O, O-H?N and C-H?O hydrogen bonding stabilizes the crystal structure. PMID- 21588893 TI - Poly[hexa-MU-acetato-bis-(dimethyl sulfoxide)-trimanganese(II)]. AB - In the title complex, [Mn(3)(CH(3)CO(2))(6)(C(2)H(6)SO)(2)](n), the Mn(II) ions exhibit similar MnO(6) octa-hedral coordination geometries but with different coordination environments. One type of Mn(II) ion is surrounded by five acetate groups and a terminal dimethyl sulfoxide group, while the other lies on a twofold axis and is coordinated by six O atoms from three symmetry-related acetate ions. The acetate anions exhibit three independent bridging modes, which flexibly bridge the Mn(II) ions along the c-axis direction, forming an infinite chain structure; the chains are further inter-connected through weak C-H?O and C-H?S hydrogen-bonding inter-actions. PMID- 21588894 TI - catena-Poly[[tetra-kis-(hexa-methyl-phospho-ramide-kappaO)bis-(nitrato kappaO,O')dysprosium(III)] [molybdenum(VI)-di-MU-sulfido-silver(I)-di-MU sulfido]]. AB - Hexamethyl-phospho-ramide (hmp), tetra-thio-molybdate, silver sulfide and dysprosium nitrate were self-assembled to form an anionic [AgMoS(4)](n) (n-) chain in the title complex, {[Dy(NO(3))(2)(C(6)H(18)N(3)OP)(4)][AgMoS(4)]}(n). The central Dy atom in the cation is coordinated by eight O atoms from two nitrate and four hmp ligands, resulting in a distorted square-anti-prismatic environment. Together with the two nitrate ligands, the cation is monovalent, which leads to the anionic chain having an [AgMoS(4)] repeat unit. The polymeric anionic chain, with Mo-Ag-Mo and Ag-Mo-Ag angles of 161.911 (13) and 154.014 (13) degrees , respectively, presents a distorted linear configuration. The title complex is isostructural with the W analogue. PMID- 21588895 TI - catena-Poly[[[(triphenyl-phosphane)copper(I)]-di-MU-iodido-[(triphenyl phosphane)copper(I)]-MU-[3,6-bis-(4-pyrid-yl)-1,2,4,5-tetra-zine]] acetonitrile disolvate]. AB - The title compound, {[Cu(2)I(2)(C(12)H(8)N(6))(C(18)H(15)P)(2)].2CH(3)CN}(n), contains centrosymmetric dinuclear Cu(2)I(2)(PPh(3))(2) units bridged by 3,6-bis (4-pyrid-yl)-1,2,4,5-tetra-zine ligands lying also across crystallographic inversion centers, giving a chain structure in the ab plane. The distorted tetra hedral Cu(I) atoms in the dinuclear unit are coordinated by two bridging iodide anions, one pyridine N atom from the substituted tetra-zine ligand and one terminal triphenyl-phosphine P-atom donor. The Cu?Cu distance is 2.8293 (12) A, implying a weak Cu?Cu inter-action. PMID- 21588896 TI - Diazido-bis-[4,4,5,5-tetra-methyl-2-(1,3-thia-zol-2-yl)-2-imidazoline-1-oxyl 3 oxide-kappaN,O]nickel(II). AB - In the title compound, [Ni(N(3))(2)(C(10)H(14)N(3)O(2)S)(2)], the Ni(II) atom lies on an inversion center and adopts a distorted trans-NiO(2)N(4) octa-hedral geometry, coordinated by two N,O-bidentate 4,4,5,5-tetra-methyl-2-(5-methyl imidazol-4-yl)-2-imidazoline-1-oxyl 3-oxide nitronyl nitroxide radical ligands and two monodentate azide anions. PMID- 21588897 TI - catena-Poly[silver(I)-MU-acridine-9-carboxyl-ato-kappaN:O,O']. AB - In the title coordination polymer, [Ag(C(14)H(8)NO(2))](n), the Ag(I) cation is coordinated by two O atoms and one N atom from two symmetry-related acridine-9 carboxyl-ate ligands in a distorted trigonal-planar geometry. The metal atoms are connected by the ligands to form chains running parallel to the b axis. pi-pi stacking inter-actions [centroid-to-centroid distances 3.757 (2)-3.820 (2) A] and weak Ag?O inter-actions further link the chains to form a layer network parallel to the ab plane. The Ag(I) cation is disordered over two positions, with refined site-occupancy factors of 0.73 (3):0.27 (3). PMID- 21588898 TI - Tetra-aqua-{1-[(1H-1,2,3-benzotriazol-1-yl)meth-yl]-1H-1,2,4-triazole}sulfato zinc(II) dihydrate. AB - In the title complex, [Zn(SO(4))(C(9)H(8)N(6))(H(2)O)(4)].2H(2)O, the Zn(II) ion is six-coordinated by one N atom from a 1-[(1H-1,2,3-benzotriazol-1-yl)meth-yl] 1H-1,2,4-triazole ligand and five O atoms from one monodentate sulfate anion and four water mol-ecules in a distorted octa-hedral geometry. The sulfate tetra hedron is rotationally disordered over two positions in a 0.618 (19):0.382 (19) ratio. In the crystal, adjacent mol-ecules are linked through O-H?O and O-H?N hydrogen bonds involving the cation, the anion, and the coordinated and uncoordinated water mol-ecules into a three-dimensional network. PMID- 21588899 TI - Bis(MU-3-nitro-phthalato-kappaO:O)bis-[aqua-(2,2'-bipyridine kappaN,N')copper(II)] dihydrate. AB - Two 3-nitro-phthalate dianions bridge two water-coordinated 2,2'-bipyridine chelated Cu(II) atoms about a center of inversion to generate the title dinuclear compound, [Cu(2)(C(8)H(3)NO(6))(2)(C(10)H(8)N(2))(2)(H(2)O)(2)].2H(2)O. The geometry of the Cu(II) atom is a distorted square pyramid. Adjacent mol-ecules are linked through the coordinated and solvent water mol-ecules to form a linear ribbon running along the a axis of the monoclinic unit cell. PMID- 21588900 TI - Bis{2-[bis-(2-hy-droxy-eth-yl)amino]-acetato-kappaO,N,O'}zinc(II). AB - In the crystal structure of the zinc(II) complex of bicine, [Zn(C(6)H(12)NO(4))(2)], the deprotonated amino acid O,N,O'-chelates to the metal atom through a carboxyl-ate O atom, a hy-droxy O atom and the N atom, the three atoms occupying fac positions of the distorted octa-hedron surrounding the metal atom. The metal atom lies on a center of inversion. The uncoordinated carboxyl ate O atom is hydrogen bonded to the hy-droxy groups of adjacent mol-ecules, these two hydrogen bonds leading to the formation of a three-dimensional network. PMID- 21588901 TI - catena-Poly[[(1,10-phenanthroline-kappaN,N')copper(I)]-MU(2)-iodido]. AB - The solvothermal reaction of copper(I) iodide and 1,10-phenanthroline (phen) in ethanol yielded the title polymeric compound, [CuI(C(12)H(8)N(2))](n). The asymmmetric unit comprises one Cu(+) cation, one I(-) anion and one phen ligand. Each Cu(+) cation is in a distorted tetrahedral coordination by two iodide anions and two N atoms from a bidentate chelating phen ligand. The Cu(+) cations are bridged through the iodide anions, leading to a zigzag chain structure extending parallel to [100]. There are pi-pi inter-actions among adjacent phen ligands of one chain [centroid-centroid distance = 3.693 (3) A]. PMID- 21588902 TI - Tetra-MU(3)-methano-lato-tetra-kis-[(2-formyl-6-meth-oxy-phenolato)methano lnickel(II)]. AB - The molecule of the title compound, [Ni(4)(CH(3)O)(4)(C(8)H(7)O(3))(4)(CH(3)OH)(4)], has S(4) symmetry. Each of the four Ni(II) atoms occupies every other corner of a cube, with the alternate corners occupied by MU(3)-methano-late bridging groups linking to three Ni(II) atoms. Each Ni(II) atom is in an O(6) octa-hedral coordination environment formed by three O atoms from three MU(3)-methano-late groups, one from methanol, and two others from a bidentate 2-formyl-6-meth-oxy-phenolate ligand. The Ni-O bond distances range from 2.0020 (14) to 2.0938 (14) A, the cis bond angles range from 81.74 (6) to 97.63 degrees , and the trans bond angles range from 168.76 (5) to 175.22 (6) degrees . There are bifurcated hydrogen-bonding inter-actions between the coordinated methanol OH groups and both the phenolic and meth-oxy O atoms of an adjoining 2-formyl-6-meth-oxy-phenolate moiety. In addition, there are weak inter-molecular C-H?O inter-actions involving the meth-oxy O atoms. PMID- 21588903 TI - Bis[MU-2-(4-hy-droxy-phen-yl)acetato]-kappaO,O':O;kappaO:O,O'-bis-{aqua-(4,4' bipyridine-kappaN)bis-[2-(4-hy-droxy-phen-yl)acetato-kappaO,O']ytterbium(III)} monohydrate. AB - In the title dinuclear complex, [Yb(2)(C(8)H(7)O(3))(6)(C(10)H(8)N(2))(2)(H(2)O)(2)].H(2)O, the Yb(III) atoms are coordinated by eight O atoms from four 2-(4-hy-droxy-phen-yl)acetate (HPAA) ligands and a water mol-ecule, and one N atom from a 4,4'-bipyridine (bipy) ligand in a distorted tricapped trigonal-prismatic geometry. Whereas four HPAA ligands coordinate to just two Yb(III) atoms, the remaining two ligands bridge the two Yb(III) atoms. In the crystal structure, O-H?O and O-H?N hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21588904 TI - Poly[[[[1-ethyl-6,8-difluoro-7-(3-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro quinoline-3-carboxyl-ato]cadmium]-MU-benzene-1,4-dicarboxyl-ato] trihydrate]. AB - In the title layered coordination polymer, {[Cd(C(17)H(18)F(2)N(3)O(3))(C(8)H(4)O(4))].3H(2)O}(n), the Cd(II) atom exhibits a very distorted CdO(6) octa-hedral geometry defined by one O(3),O(4)-bidentate 1 ethyl-6,8-difluoro-7-(3-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-3 carboxyl-ate (lome) ligand, one O,O'-bidentate benzene-1,4-dicarboxyl-ate (bdc) dianion and two O-monodentate bdc dianions. Both the bdc species in the asymmetric unit are completed by crystallographic inversion symmetry. The bridging bdc dianions link the cadmium nodes into a recta-ngular grid lying parallel to (01). A network of N-H?O and O-H?O hydrogen bonds helps to establish the packing. PMID- 21588905 TI - Poly[bis-[8-ethyl-5-oxo-2-(piperazin-1-yl)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6 carboxyl-ato]cadmium]. AB - The title layered coordination polymer, [Cd(C(14)H(16)N(5)O(3))(2)](n) or [Cd(ppa)(2)](n), where ppa is 8-ethyl-5-oxo-2-(piperazin-1-yl)-5,8-dihydro pyrido[2,3-d]pyrimidine-6-carboxyl-ate, was syn-thesized under hydro-thermal conditions. The Cd(II) atom (site symmetry 2) exhibits a distorted cis-CdN(2)O(4) octa-hedral geometry defined by two N-monodentate and two O,O'-bidentate ppa monoanions. The extended two-dimensional structure resulting from the bridging ppa species is a grid lying parallel to (001). An N-H?O hydrogen bond helps to establish the crystal packing. PMID- 21588906 TI - 1,3-Bis(1-adamant-yl)imidazolium tetra-chloridoferrate(III). AB - The crystal structure of the title compound, (C(23)H(33)N(2))[FeCl(4)], consists of 1,3-bis-(1-adamant-yl)imidazolium (BAIM) cations and tetra-hedral tetra chloridoferrate(III) (TCF) anions. The BAIM cation possesses m symmetry, with the central imidazole ring and four C atoms of each terminal adamantyl group located on a mirror plane. The Fe and two Cl atoms of the TCF anion are also located on the mirror plane. The cyclo-hexane rings of the adamantyl groups adopt normal chair conformations. PMID- 21588907 TI - [Bis(diphenyl-phosphan-yl)dimethyl-silane-kappaP,P']tetra-carbonyl-chromium(0). AB - The title compound, [Cr(C(26)H(26)P(2)Si)(CO)(4)], was obtained by the reaction of Ph(2)PSiMe(2)PPh(2) with Cr(CO)(6) in refluxing toluene by ligand exchange. The CrC(4)P(2) coordination geometry at the Cr atom is distorted octa-hedral, with a P-Cr-P bite angle of 80.27 (1) degrees . PMID- 21588908 TI - [2,2-Bis(diphenyl-phosphan-yl)propane-kappaP,P']tetra-carbonyl-chromium(0) dichloro-methane monosolvate. AB - The title compound, [Cr(C(27)H(26)P(2))(CO)(4)].CH(2)Cl(2), was obtained by the reaction of Ph(2)PCMe(2)PPh(2) with Cr(CO)(6) in refluxing toluene by substitution of two carbonyl ligands. The CrC(4)P(2) coordination geometry at the Cr atom is distorted octa-hedral, with a P-Cr-P bite angle of 70.27 (2) degrees . PMID- 21588909 TI - Bis[MU-4-methyl-2-(2-pyridyl-methyl-sulfan-yl)pyrimidine-kappaN]bis-[(trifluoro methanesulfonato-kappaO)silver(I)]. AB - In the centrosymmetric dinuclear title complex, [Ag(2)(CF(3)SO(3))(2)(C(11)H(11)N(3)S)(2)], the Ag(I) atom is coordinated by two N atoms from two 4-methyl-2-(2-pyridyl-methyl-sulfan-yl)pyrimidine ligands and one O atom from a trifluoro-methane-sulfonate anion in a distorted T-type coordination geometry. The ligand adopts a bidentate bridging coordination mode through one pyridyl N atom and one pyrimidine N atom. In the crystal structure, pi-pi inter-actions are present between adjacent pyrimidine rings, with a centroid-to-centroid distance of 3.875 (7) A. PMID- 21588910 TI - Bis[MU-2-(4-hy-droxy-phen-yl)acetato]-kappaO,O':O;kappaO:O,O'-bis-{aqua-(4,4' bipyridine-kappaN)bis-[2-(4-hy-droxy-phen-yl)acetato-kappaO,O']thulium(III)} mono hydrate. AB - In the title dinuclear complex, [Tm(2)(C(8)H(7)O(3))(6)(C(10)H(8)N(2))(2)(H(2)O)(2)].H(2)O, the Tm(III) atoms are coordinated by eight O atoms from four 2-(4-hy-droxy-phen-yl)acetate (HPAA) ligands and a water mol-ecule, and one N atom from a 4,4'-bipyridine ligand in a distorted tricapped trigonal-prismatic geometry. While four of the HPAA ligands coordinate to just one Tm atom, the remaining two HPAA ligands bridge the two Tm atoms. In the crystal, O-H?O and O-H?N hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21588911 TI - catena-Poly[[cobalt(II)-MU-aqua-MU-propano-ato-kappaO:O'-MU-propano-ato-kappaO:O] monohydrate]. AB - The title compound, {[Co(C(2)H(5)COO)(2)(H(2)O)].H(2)O}(n), was synthesized by the reaction of cobalt(II) carbonate hydrate with aqueous propionic acid. The structure consists of polymeric infinite linear chains with composition [Co(C(2)H(5)COO)(4/2)(H(2)O)(2/2)](infinity) running along [010]. The chains are formed by Co(2+) ions linked with bridging propionate groups and water mol ecules, with a Co?Co distance along the chains of 3.2587 (9) A. The Co(2+) ion is six-coordinated in a strongly distorted octa-hedral geometry. The chains are connected to each other by a network of O-H?O hydrogen bonds involving solvent water mol-ecules. PMID- 21588912 TI - cis-Dichloridobis(2-phenyl-pyridine-kappaN)platinum(II). AB - In the title complex, cis-[PtCl(2)(C(11)H(9)N)(2)], the Pt(II) ion is situated in a slightly distorted square-planar environment coordinated by two N atoms from two 2-phenyl-pyridine ligands and two Cl atoms. The two pyridyl planes are inclined with dihedral angles of 59.1 (2) and 61.84 (19) degrees with respect to the PtCl(2)N(2) plane. In the crystal, the complex mol-ecules display inter- and intra-molecular pi-pi stacking inter-actions, with centroid-centroid distances of 3.806 (5)-3.845 (5) A, which form a one-dimensional column structure along the a axis. PMID- 21588913 TI - catena-Poly[cadmium-bis-(MU-N,N-dimethyl-dithio-carbamato-kappaS,S':S)]. AB - In the title compound, [Cd(C(3)H(6)NS(2))(2)](n), the Cd(II) atom, lying on a twofold rotation axis, is coordinated by six S atoms from four different N,N dimethyl-dithio-carbamate ligands in a distorted octa-hedral geometry. The bridging of S atoms of the ligands leads to the formation of a one-dimensional structure along [001]. PMID- 21588914 TI - Morpholinium styphnate. AB - In the title mol-ecular salt (systematic name: morpholinium 3-hy-droxy-2,4,6 trinitro-phenolate), C(4)H(10)NO(+).C(6)H(2)N(3)O(8) (-), two of the nitro groups of the anion are close to parallel with the plane of the benzene ring [dihedral angles = 3.46 (9) and 11.60 (10) degrees ] and one is almost perpendicular [dihedral angle = 82.23 (8) degrees ]. An intra-molecular O-H?O hydrogen bond occurs in the anion. The morpholinium cation has a slightly distorted chair conformation. In the crystal, the components are linked by simple N-H?O and trifurcated N-H?(O,O,O) hydrogen bonds. PMID- 21588915 TI - Penta-fluoro-phenyl (3R,4R,5S)-5-{[(3R,4R,5S)-5-azido-methyl-3,4-dimeth-oxy 2,3,4,5-tetra-hydro-furan-3-carboxamido]-meth-yl}-3,4-dimeth-oxy-2,3,4,5-tetra hydro-furan-3-carboxyl-ate. AB - The title compound, C(22)H(25)F(5)N(4)O(9), is a stable penta-fluoro-phenyl ester inter-mediate in the synthesis of novel homo-oligomeric structures containing branched carbon chains. The structure is epimeric to the previously characterized dimeric penta-fluoro-phenyl ester with stereochemistry (3R,4R,5R), which was synthesized using d-ribose as starting material. The crystal structure of the title mol-ecule removes any ambiguities arising from the relative stereochemistries of the six chiral centres. Two hydrogen bonds, bifurcating from the NH group, stabilize the crystal: one intra-molecular and one inter-molecular, both involving O atoms of the meth-oxy groups. The asymmetric unit contains two independent mol-ecules not related by any pseudo-symmetry operators. The major conformational differences are localized, leading to one mol-ecule being extended compared to the other. The collected crystal was twinned (twin ratio is 0.939:0.061), and the azide group is positionally disordered over two positions in one mol-ecule [occupancy ratio 0.511 (18):0.489 (18)]. PMID- 21588916 TI - 4,4'-(Ethane-1,2-diyl)dipyridinium bis-(2-hy-droxy-benzoate). AB - In the crystal structure of the title compound, C(12)H(14)N(2) (2+).2C(7)H(5)O(3) (-), the cations and anions are linked via N-H?O hydrogen bonds and weak inter molecular C-H?O inter-actions also occur. pi-pi stacking is observed between the nearly parallel benzene and pyridine rings [dihedral angle = 6.03 (8) degrees ], the centroid-centroid separation being 3.7546 (16) A. The 4,4'-(ethane-1,2 diyl)dipyridinium cation is centrosymmetric and the mid-point of the ethyl-ene C C bond is located on an inversion center. An intra-molecular O-H?O hydrogen bond occurs in the anion. PMID- 21588917 TI - 3-(4-Chloro-phenyl-sulfin-yl)-2,4,6-trimethyl-1-benzofuran. AB - In the title mol-ecule, C(17)H(15)ClO(2)S, the 4-chloro-phenyl ring is oriented approximately perpendicular to the mean plane of the benzofuran ring [dihedral angle = 88.98 (4) degrees ]. In the crystal, mol-ecules are linked through weak inter-molecular C-H?O and C-H?pi inter-actions, forming right-hand pseudo-helices along the a axis. PMID- 21588918 TI - 2-{[(E)-2-Hy-droxy-benzyl-idene]amino}-1H-isoindole-1,3(2H)-dione. AB - In the title compound, C(15)H(10)N(2)O(3), the isoindoline ring system is almost planar [maximum deviation = 0.020 (2) A] and makes a dihedral angle of 1.57 (7) degrees with the benzene ring. Intra-molecular O-H?N and C-H?O hydrogen bonds are observed. PMID- 21588919 TI - 12beta,14-Dihy-droxy-3-oxo-5beta,20(22)-cardenolide monohydrate. AB - The title compound, digoxigenone, C(23)H(30)O(5).H(2)O, was biotransformed from digoxigenin. In the crystal, inter-molecular O-H?O hydrogen bonds contribute to the formation of a three-dimensional supra-molecular structure. The title compound has three fused six-membered rings (A,B,C) and two non-fused five membered rings (D,E). As in other structures, compound nucleus has a cis-trans cis conformation for the A-B,B-C,C-D ring junctions with rings A, B and C exhibiting chair conformations. PMID- 21588921 TI - 3-(6-Fluoro-4-oxo-4H-chromen-3-yl)-3,4-dihydro-2H-1,2,4-benzothia-diazine-1,1 dione. AB - In the title compound, C(16)H(11)FN(2)O(4)S, the mean planes of the bicyclic chromone system and of the benzene ring of the benzothia-diazine derivative make a dihedral angle of 54.28 (5) degrees . An intra-molecular N-H?O hydrogen bond occurs. In the crystal, mol-ecules are linked into layers by N-H?O and C-H?O hydrogen bonds, generating an infinite two-dimensional network. PMID- 21588920 TI - N-(2,5-Dimeth-oxy-phen-yl)-N'-(4-hy-droxy-pheneth-yl)urea. AB - In the title compound, C(17)H(20)N(2)O(4), the 2,5-dimeth-oxy-phenyl unit is almost planar, with an r.m.s. deviation of 0.015 A. The dihedral angle between the 2,5-dimeth-oxy-phenyl ring and the urea plane is 20.95 (8) degrees . The H atoms of the urea NH groups are positioned syn to each other. The mol-ecular structure is stabilized by a short intra-molecular N-H?O hydrogen bond. In the crystal, inter-molecular N-H?O and O-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21588922 TI - 2-Chloro-ethyl 4-nitro-benzoate. AB - The title compound, C(9)H(8)ClNO(4), crystallizes with two mol-ecules in the asymmetric unit. In each mol-ecule, the carboxyl-ate group is nearly coplanar with the benzene ring, forming dihedral angles of 2.4 (1) and 4.9 (1) degrees . In the crystal, mol-ecules are linked through weak C-H?O and C-H?Cl hydrogen bonds. A short O?N contact of 2.7660 (19) A occurs between the nitro groups of adjacent mol-ecules. PMID- 21588923 TI - 2-Cyano-quinolin-1-ium hydrogen sulfate. AB - The title salt, C(10)H(7)N(2) (+).HSO(4) (-), is formed by the transfer of a proton from H(2)SO(4) to the N atom of 2-cyano-quinoline during crystallization. The quinoline ring system is approximately planar with a maximum deviation of 0.013 (3) A. In the crystal, the cations are linked to the anions via inter molecular N-H?O, O-H?O and C-H?O hydrogen bonds, forming a layered network. PMID- 21588924 TI - (2E)-3-(4-Methyl-phen-yl)-1-(2-methyl-4-phenyl-quinolin-3-yl)prop-2-en-1-one monohydrate. AB - The title hydrate, C(26)H(21)NO.H(2)O, exhibits significant twists of the benzene ring [dihedral angle = 87.24 (6) degrees ] and chalcone residue [C-C-C-C torsion angle = -94.46 (17) degrees ] out of the plane through the quinoline ring system. The conformation about the C=C bond [1.341 (2) A] is E. The solvent water mol ecule forms hydrogen bonds to carbonyl O and quinoline N atoms derived from two mol-ecules and through the application of a centre of inversion, a 16-membered {?HOH?OC(3)N}(2) synthon is formed to stabilize the resulting tetra-meric (two organic mol-ecules plus two water mol-ecules) aggregate. These are connected into a two-dimensional array via two C-H?O contacts, also involving the water mol ecule. The layers stack along the c axis, being linked by C-H?pi inter-actions. PMID- 21588925 TI - Bis(homopiperazine-1,4-diium) cyclo-tetra-phosphate-telluric acid (1/2). AB - The title compound, 2C(5)H(14)N(2) (2+).P(4)O(12) (4-).2Te(OH)(6), involves doubly protonated homopiperazinium cations, cyclo-tetra-phosphate anions and telluric acid mol-ecules. The framework possesses very large channels wherein the organic cations reside. A network of O-H?O, N-H?O and C-H?O hydrogen bonds consolidates the crystal packing. PMID- 21588926 TI - 2-Fluoro-l-histidine. AB - The title compound, C(6)H(8)FN(3)O(2), an analog of histidine, shows a reduced side-chain pK(a) (ca 1). The title structure exhibits a shortening of the bond between the proximal ring N atom and the F-substituted ring C atom, indicating an increase in pi-bond character due to an inductive effect of fluorine. PMID- 21588927 TI - 2-Amino-1-methyl-1H-imidazol-4(5H)-one dimethyl sulfoxide monosolvate. AB - In the title compound, C(4)H(7)N(3)O.C(2)H(6)OS, creatinine [2-amino-1-methyl-1H imidazol-4(5H)one] exists in the amine form. The ring is planar (r.m.s. deviation for all non-H atoms = 0.017 A). In the crystal, two creatinine mol-ecules form centrosymmetric hydrogen-bonded dimers linked by pairs of N-H?N hydrogen bonds. In addition, creatinine is linked to a dimethyl sulfoxide mol-ecule by an N-H?O inter-action. The packing shows layers parallel to (120). PMID- 21588928 TI - 2-Methyl-N'-(4-nitro-benzyl-idene)benzohydrazide. AB - The title hydrazone compound, C(15)H(13)N(3)O(3), was prepared by the condensation of 4-nitro-benzaldehyde with 2-methyl-benzohydrazide in methanol. The dihedral angle between the two benzene rings is 14.8 (2) degrees . In the crystal, mol-ecules are linked through inter-molecular N-H?O hydrogen bonds, forming chains along the a axis. PMID- 21588930 TI - N,N-Bis[4-(dimethyl-amino)-benzyl-idene]pyridine-2,6-dicarbohydrazide monohydrate. AB - In the title compound, C(25)H(27)N(7)O(2).H(2)O, the bis-[4-(dimethyl-amino) benzyl-idene]pyridine-2,6-dicarbohydrazide mol-ecule and the water mol-ecule are located on a twofold rotation axis. The benzene and pyridine rings form a dihedral angle of 17.13 (7) degrees . In the crystal, inter-molecular N-H?O and O H?O hydrogen bonds link the mol-ecules into a two-dimensional supermolecular structure parallel to the ab plane. PMID- 21588929 TI - 5,7-Dihy-droxy-3,6-dimeth-oxy-2-(4-meth-oxy-phen-yl)-4H-chromen-4-one monohydrate. AB - The title compound, C(18)H(16)O(7).H(2)O, is a flavonoid isolated from Dodonaea viscosa-. The benzopyran ring system of the flavonoid is essentially planar [maximum deviation = 0.025 (2) A] and inclined at 5.83 (2) degrees to the attached benzene ring. The water of hydration is involved in extensive hydrogen bonding, assembling the mol-ecules into a supra-molecular network via classical inter-molecular O-H?O hydrogen bonding. The crystal structure is further stabilized by pi-pi stacking inter-actions [centroid-centroid distance between benzene rings = 3.564 (3) A]. PMID- 21588931 TI - (E)-3,5-Dimeth-oxy-benzaldehyde oxime. AB - In the title compound, C(9)H(11)NO(3), the oxime grouping is twisted by 12.68 (6) degrees with respect to the dimethoxyl-benzene ring. In the crystal, mol-ecules are linked into an infinite [100] chain via O-H?N hydrogen bonds, instead of the more common oxime packing motif of dimers with an R(2) (2)(6) graph-set motif. PMID- 21588932 TI - 5-(4-Methyl-phen-yl)-2,3-diphenyl-5,6-dihydro-imidazo[1,2-c]quinazoline. AB - In the title compound, C(29)H(23)N(3), the pyrimidine ring adopts an envelope conformation. The dihedral angle between the phenyl rings attached to the pyrimidine-ring double bond is 62.09 (7) degrees . In the crystal, mol-ecules are linked by N-H?N hydrogen bonds, forming extended chains in the c-axis direction. PMID- 21588933 TI - 5-Bromo-3-(4-chloro-phenyl-sulfin-yl)-2-methyl-1-benzofuran. AB - In the title compound, C(15)H(10)BrClO(2)S, the 4-chloro-phenyl ring is oriented approximately perpendicular to the mean plane of the benzofuran ring [dihedral angle = 89.55 (9) degrees ]. In the crystal, mol-ecules are linked through weak inter-molecular C-H?O hydrogen bonds and and a Br?Br contact [3.783 (3) A]. PMID- 21588934 TI - N-(4-Bromo-phen-yl)pyrazine-2-carbox-amide. AB - The mol-ecule of the title compound, C(11)H(8)BrN(3)O, is close to planar (r.m.s. deviation of all 16 non-H atoms = 0.103 A), a conformation stabilized by an intra molecular N-H?N hydrogen bond, which generates an S(5) ring. In the crystal structure, supra-molecular chains mediated by C-H?O contacts (along a) are linked into a double layer via N?Br halogen bonds [3.207 (5) A] and C-Br?pi inter actions [Br?ring centroid(pyrazine) = 3.446 (3) A]. The layers stack along the b axis via weak pi-pi inter-actions [ring centroid(pyrazine)?ring centroid(benzene) distance = 3.803 (4) A]. PMID- 21588935 TI - 4-[(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl-idene-amino]-1,5-dimethyl-2 phenyl-1H-pyrazol-3(2H)-one. AB - In the mol-ecule of the title compound, C(22)H(20)ClN(5)O, the atoms of the two pyrazole rings and the -C=N- group which joins them are essentially coplanar, with an r.m.s. deviation of 0.054 (2) A. The phenyl rings form dihedral angles of 41.24 (5) and 55.53 (5) degrees with this plane. The crystal structure is stabilized by weak inter-molecular pi-pi inter-actions, with centroid-to-centroid distances of 3.6179 (13) A between the imidazole rings. PMID- 21588936 TI - N-Morpholino-Delta-dihydro-abietamide. AB - The title compound, C(24)H(39)NO(2) (systematic name: 4-{[1,4a-dimethyl-7-(propan 2-yl)-1,2,3,4,4a,5,6,7,8,9,10,10a-dodeca-hydro-phenanthren-1-yl]carbon yl}morpholine), has been synthesized from Delta(8)-dihydro-abietic acid. Two cyclo-hexene rings adopt half-chair conformations, whereas the cyclo-hexane and morpholine rings are each in the chair conformation. Two methyl groups are in an axial position with respect to the tricyclic hydro-phenanthrene nuclei. PMID- 21588937 TI - 2-Cyano-quinolin-1-ium nitrate. AB - A proton is transferred from the nitric acid to the N atom of 2-cyano-quinoline during crystallization, resulting in the formation of the title salt, C(10)H(7)N(2) (+).NO(3) (-). The quinolinium ring system is approximately planar, with a maximum deviation of 0.013 (3) A. In the crystal, a very asymmetric bifurcated N-H?(O,O) hydrogen bond to two O atoms of an adjacent nitrate anion occurs, generating an R(2) (1)(4) ring motif. C-H?O hydrogen bonds link the ions into sheets stacking along the a axis. PMID- 21588938 TI - 1-(4-Meth-oxy-benzyl-idene)-4-methyl-thiosemicarbazide. AB - The title compound, C(10)H(13)N(3)OS, was prepared by the reaction of 4-meth-oxy benzaldehyde and 4-methyl-thio-semicarbazide. The dihedral angle between the benzene ring and the thio-urea unit is 8.64 (7) degrees and an intra-molecular N H?N hydrogen bond generates an S(5) ring. In the crystal, inversion dimers linked by pairs of N-H?S hydrogen bonds generate R(2) (2)(8) loops. The dimers are linked into (001) sheets by further N-H?S links. PMID- 21588939 TI - 4-Chloro-N'-(4-meth-oxy-benzyl-idene)benzohydrazide methanol monosolvate. AB - The title compound, C(15)H(13)ClN(2)O(2).CH(4)O, consists of a 4-chloro-N'-(4 meth-oxy-benzyl-idene)benzohydrazide (CMB) mol-ecule and a methanol mol-ecule of crystallization. It was obtained by the condensation of 4-meth-oxy-benzaldehyde with 4-chloro-benzohydrazide. In the CMB mol-ecule, the dihedral angle between the two benzene rings is 50.1 (3) degrees . The methanol mol-ecule is linked to the CMB mol-ecule through O-H?O and O-H?N hydrogen bonds. In the crystal, CMB mol ecules are linked through inter-molecular N-H?O hydrogen bonds, involving the methanol mol-ecule, forming chains propagating along [010]. PMID- 21588940 TI - 2-[3-(1H-Benzimidazol-2-yl)prop-yl]-1H-benzimidazol-3-ium 3,5-dicarb-oxy-benzoate benzene-1,3,5-tricarb-oxy-lic acid-water (1/1/1). AB - The title compound, C(17)H(17)N(4) (+).C(9)H(5)O(6) (-).C(9)H(6)O(6).H(2)O, contains a protonated 2,2'-(1,3-propanedi-yl)bis-(1H-benzimidazole) cation, a deprotonated benzene-1,3,5-tricarb-oxy-lic acid anion, a neutral benzene-1,3,5 tricarb-oxy-lic acid mol-ecule and a water mol-ecule, which are linked together through N-H?O, O-H?O and weak C-H?O hydrogen bonds into almost double sheets parallel to (4). These hydrogen-bonded sheets are packed in the crystal with the formation of centrosymmetric voids of 25.5 A(3), which are filled by the water mol-ecules. PMID- 21588941 TI - 2-(4-Methyl-phen-yl)-2H-indazole. AB - The title compound, C(14)H(12)N(2), was synthesized by the reaction of 4-methyl-N (2-nitro-benz-yl)aniline with tin(II) chloride dihydrate in ethanol at 313 K. The indazole ring system is almost planar with a dihedral angle of 1.58 (10) degrees between the rings, whereas the plane of the attached p-tolyl substituent shows a dihedral angle of 46.26 (5) degrees with respect to the indazole core. PMID- 21588942 TI - 1-(2-Azido-acet-yl)-3-methyl-2,6-diphenyl-piperidin-4-one. AB - In the title compound, C(20)H(20)N(4)O(2), the piperidine ring adopts a distorted boat conformation. The two phenyl rings form dihedral angles of 82.87 (1) and 84.40 (1) degrees with respect to the piperidine ring. The crystal packing is stabilized by inter-molecular C-H?O and C-H?N inter-actions. PMID- 21588943 TI - 1,5-Diphenyl-carbonohydrazide N,N-di-methyl-formamide. AB - In the title compound, C(13)H(14)N(4)O.C(3)H(7)NO, a 1,5-phenyl-carbonohydrazide mol-ecule cocrystallizes with an N,N-dimethyl-formamide mol-ecule. In the 1,5 phenyl-carbonohydrazide mol-ecule, the two phenyl rings are twisted by an angle of 45.8 (5) degrees . Inter-molecular N-H?O hydrogen bonds and weak inter molecular C-H?O inter-actions contribute to a supra-molecular two-dimensional network in the (101) plane. PMID- 21588944 TI - 5-[(E)-Benzyl-idene]-2-hy-droxy-10-methyl-8-phenyl-3,10-diazahexa-cyclo [10.7.1.1.0.0.0]henicosa-1(19),12(20),13,15,17-pentaen-6-one ethanol 0.25-solvate 0.6-hydrate. AB - In the title compound, C(33)H(28)N(2)O(2).0.25C(2)H(6)O.0.6H(2)O, the piperidone ring adopts a chair conformation and the pyrrolidine ring adopts an envelope conformation. The dihedral angle between the two phenyl rings is 70.83 (16) degrees . One of the N atoms of the organic mol-ecule is disordered over two positions in a 0.52 (4):0.48 (4) ratio and the two solvent mol-ecules are partially occupied and show high displacement parameters. In the crystal, mol ecules are connected by inter-molecular O-H?O and C-H?O hydrogen bonds, forming a three-dimensional network. PMID- 21588945 TI - 7-Methoxy-1-{[(Z)-3-nitrophenylimino](phenyl)methyl}-2-naphthol. AB - In the title compound, C(24)H(18)N(2)O(4), the phenyl and benzene rings are both oriented almost perpendicular to the naphthalene ring system at dihedral angles of 70.97 (5) and 84.64 (5) degrees . The former rings make a dihedral angle of 87.15 (6) degrees . The mol-ecule has a Z configuration about the C=N bond. In the crystal, mol-ecules are connected by a pair of inter-molecular O-H?O hydrogen bonds between the hy-droxy and the nitro group, forming centrosymmetric dimers. Inter-molecular C-H?O inter-actions also occur. PMID- 21588946 TI - Tris{2-[(3-thien-yl)methyl-idene-amino]-eth-yl}amine. AB - The title compound, C(21)H(24)N(4)S(3), is a tripodal Schiff base that was obtained from the reaction of tris-(2-amino-eth-yl)amine (tren) and thio-phene-3 carbaldehyde. The compound forms a cavity with approximate C3 symmetry. One of the thio-phene units is disordered in a 0.764 (2):0.236 (2) ratio. In the crystal, the three thio-phene ligands are involved in intra-molecular C-H?pi inter-actions and the mol-ecules are connected by C-H?N inter-actions, forming hydrogen-bonded chains. PMID- 21588947 TI - 4,4'-Bipyridine-cyclo-hexane-1,2,4,5-tetra-carb-oxy-lic acid (1/1). AB - In the title 1:1 adduct, C(10)H(8)N(2).C(10)H(12)O(8), the dihedral angle between the pyridine rings in the 4,4-bipyridine molecule is 8.33 (13) degrees . In the crystal, the cyclo-hexane-1,2,4,5-tetra-carb-oxy-lic acid mol-ecules inter-act with each other through inter-molecular O-H?O hydrogen bonds, forming an infinite chain along the a axis, which is further linked perpendicularly by O-H?N hydrogen bonds involving bipyridine, resulting in a supra-molecular corrugated sheet parallel to the (110) plane. PMID- 21588948 TI - 6-(2-Chloro-benz-yl)-1-(4-chloro-phen-yl)-7-hy-droxy-2,3-dihydro-1H-imidazo[1,2 a]pyrimidin-5-one. AB - The title compound, C(19)H(15)Cl(2)N(3)O(2), was obtained by a one-step cyclo condensation of 2-amino-1-(4-chloro-phen-yl)imidazoline with diethyl (2-chloro benz-yl)malonate under basic conditions. In the crystalline state, the mol-ecule exists as the 7-hy-droxy-5-oxo tautomer. The dihedral angles between the fused imidazopyrimidine and aromatic chloro-phenyl and chloro-benzyl rings are 14.2 (1) and 70.7 (1) degrees , respectively. The conformation of the mol-ecule is influenced by the intra-molecular C-H?O and C-H?N hydrogen bonds, giving a nearly planar five-ring fused system [maximum deviation from the mean plane = 0.296 (2) A]. In the crystal structure, strong inter-molecular O-H?O hydrogen bonds link the mol-ecules into chains along the c axis. These chains are further stabilized by weak C-H?Cl and pi-pi inter-actions [centroid-centroid distance = 3.6707 (12) A]. PMID- 21588949 TI - Ethyl 2-{(2Z)-2-[(1-naphthyl-sulfon-yl)imino]-2,3-dihydro-1,3-thia-zol-4 yl}acetate monohydrate. AB - The title compound, C(17)H(16)N(2)O(4)S(2).H(2)O, is of inter-est with respect to its anti-diabetic and anti-obesity activity. In the crystal, the packing is stabilized by three cooperative inter-actions: offset pi-pi inter-actions [centroid-centroid distance = 3.604 (2) A], as well as C-H?O and O-H?O hydrogen bonds. N-H?O inter-actions also occur. PMID- 21588950 TI - 3-(1,2-Diphenyl-ethen-yl)-2-phenyl-1H-indole. AB - In the title compound, C(28)H(21)N, the planar pyrrole ring makes dihedral angles of 1.5 (2), 42.4 (2), 65.4 (2) and 79.7 (1) degrees , with the least squares planes of the four phenyl rings. The mol-ecular structure and crystal packing are stabilized by weak inter- and intra-molecular C-H?pi inter-actions. PMID- 21588951 TI - 2-Amino-4-(4-hy-droxy-3,5-dimeth-oxy-phen-yl)-6-phenyl-nicotinonitrile. AB - In the title compound, C(20)H(17)N(3)O(3), the dihedral angles between the central pyridine ring and the two terminal rings are 15.07 (3) and 43.24 (3) degrees . The dihedral angle between the two terminal rings is 37.49 (4) degrees In the crystal, inter-molecular amine N-H?N(nitrile) hydrogen-bonding inter actions form inversion dimers, which are linked into chains through amine N H?O(meth-oxy) hydrogen bonds. PMID- 21588952 TI - 3,4-Diaminopyridinium 2-carboxy-4,6-dinitrophenolate. AB - In the title salt, C(5)H(8)N(3) (+).C(7)H(3)N(2)O(7) (-), the pyridine N atom of the 3,4-diamino-pyridine mol-ecule is protonated. The 3,5-dinitro-salicylate anion shows whole-mol-ecule disorder over two orientations with a refined occupancy ratio of 0.875 (4): 0.125 (4). In the crystal, the cations and anions are connected by inter-molecular N-H?O and C-H?O hydrogen bonds, forming a three dimensional network. PMID- 21588953 TI - 4-Amino-benzoic acid-4,4'-(propane-1,3-diyl)dipyridine (1/1). AB - In the crystal structure of the title compound, C(13)H(14)N(2).C(7)H(7)NO(2), the 4,4'-trimethyl-ene-dipyridine (TMDP) mol-ecule displays an approximately planar structure, the maximum atomic deviation excluding H atoms being 0.118 (2) A and the dihedral angle between the pyridine rings 4.59 (10) degrees . The TMDP and 4 amino-benzoic acid (ABA) mol-ecules are linked by O-H?N and N-H?N hydrogen bonding, while ABA mol-ecules are linked by O-H?O hydrogen bonding. C-H?pi interactions are also observed between the methyl-ene groups of TMDP mol-ecules and the benzene rings of ABA mol-ecules. PMID- 21588954 TI - 2-({4-[(1H-Imidazol-2-ylsulfanyl)methyl]-2,5-dimethylbenzyl}sulfanyl)-1H imidazole. AB - The title compound, C(16)H(18)N(4)S(2), was prepared by the substitution reaction of two equivalents of 2-mercaptoimidazole for every bromine substituent of 1,4 bis-(bromo-meth-yl)-2,5-dimethyl-benzene. The mol-ecule is located on a crystallographic centre of inversion and therefore adopts a trans configuration with regards to the orientation of the two sulfur atoms. An inter-molecular N-H?N hydrogen bond forms layers of mol-ecules parallel to (03). The dihedral angle between the central and terminal rings is 174.8 (2) degrees . PMID- 21588955 TI - (3R,4R,5R)-5-(Acetamido-meth-yl)-N-benzyl-3,4-dihy-droxy-tetra-hydro-furan-3 carboxamide. AB - X-ray crystallographic analysis with Cu Kalpha radiation established the relative configurations of the stereogenic centers in the title compound, C(15)H(20)N(2)O(5), and clarified mechanistic ambiguities in the synthesis. The conformation of the five-membered ring approximates twisted, about a C-O bond. The absolute configuration of this carbon-branched dipeptide isostere was known based on the use of d-ribose as the starting material. Refinement of the Flack parameter gave an ambiguous result but the refined Hooft parameter is in agreement with the assumed (d-ribose) absolute structure. The crystal structure consists of N-H?O and O-H?O hydrogen-bonded bi-layers, with the terminal methyl and phenyl groups forming a hydro-phobic inter-layer inter-face. Some weak C-H?O inter-actions are also present. PMID- 21588956 TI - [2,7-Dimethoxy-8-(4-methylbenzoyl)-1-naphthyl](4-methylphenyl)methanone. AB - In the title compound, C(28)H(24)O(4), the two 4-methyl-benzoyl groups at the 1- and 8-positions of the naphthalene ring system are aligned almost anti-parallel, the dihedral angle between the two phenyl rings being 9.64 (7) degrees . The dihedral angles between the two phenyl rings and the naphthalene ring system are 71.82 (6) and 71.58 (6) degrees . In the crystal, inter-molecular C-H?O inter actions between the carbonyl oxygen and aromatic hydrogen are observed. PMID- 21588957 TI - (E)-5,6-Dimeth-oxy-2-(pyridin-4-yl-methyl-idene)-2,3-dihydro-1H-inden-1-one. AB - The mol-ecule of the title compound, C(17)H(15)NO(3), is slightly twisted, with a dihedral angle of 12.12 (3) degrees between the dihydro-indenone group and the pyridine ring. In the crystal, mol-ecules are connected into layers parallel to the ab plane via inter-molecular C-H?O hydrogen bonds. Weak pi-pi [centroid centroid distance = 3.5680 (6) A] inter-actions are also observed. PMID- 21588958 TI - Methyl 4-(1H-benzimidazol-2-yl)benzoate trihydrate. AB - The title compound, C(15)H(12)N(2)O(2).3H(2)O, has been prepared from the reaction of a Schiff base of benzene-1,2-diamine and iron perchlorate at room temperature. The dihedral angle between the benzimidazole ring and the 4 substituted benzene ring is 0.47 (3) degrees . Hydrogen bonding involving water mol-ecules, imidazole N, imidazole imine H and ester O atoms stabilizes the crystal structure. PMID- 21588959 TI - Tris[2-(2-thienyl-methyl-amino)-eth-yl]ammonium triiodide. AB - In the title compound, C(21)H(33)N(4)S(3) (3+).3I(-), three secondary amines are protonated, while the central amine remains unprotonated. One thio-phene is disordered with an occupancy ratio of 0.868 (6)/0.132 (6). Each protonated amine is involved in N-H?I hydrogen-bonding inter-actions with the iodide anions. PMID- 21588960 TI - 4'-[4-(Pyridin-2-yl)phen-yl]-2,2':6',2''-terpyridine. AB - In the title compound, C(26)H(18)N(4), each ring is almost planar with maximum deviation of 0.012 (5) A. In the crystal, mol-ecules are stacked by weak C-H?pi inter-actions, forming a three-dimensional framework. PMID- 21588961 TI - 4-Phenyl-sulfon-yl-2-(p-tolyl-sulfon-yl)-1H,8H-pyrrolo-[2,3-b]indole. AB - The title compound, C(23)H(18)N(2)O(4)S(2), contains a pyrrolo group fused onto the plane of an indole ring with phenyl-sulfonyl and p-toluene-sulfonyl groups bonded to the indole and pyrrolo rings. The angles between the mean planes of the pyrrolo-indole ring and the phenyl-sulfonyl and p-toluene-sulfonyl rings are 73.7 (6) and 80.6 (0) degrees , respectively. The dihedral angle between the mean planes of the two benzene rings is 78.7 (4) degrees . In the crystal, both classical N-H?O and non-classical C-H?O inter-molecular hydrogen-bonding inter actions are observed, as well as weak pi-pi inter-actions [centroid-centroid distances = 3.6258 (8) and 3.9298 (8) A], which contribute to the stability of the packing. PMID- 21588962 TI - 2-[(E)-2-(Nitro-methyl-idene)imidazolidin-1-yl]ethanol. AB - In the title compound, C(6)H(11)N(3)O(3), the imidazolidine NH group is involved in a three-center N-H?O hydrogen bond, with intra-molecular and inter-molecular branches, to the nitro group O atoms. The centrosymmetric dimers that are formed are further connected by O-H?O hydrogen bonds between the hy-droxy and nitro groups into a two-dimensional polymeric structure extending parallel to (101). PMID- 21588963 TI - 5-Cyclo-hexyl-4-methyl-1H-pyrazol-3(2H)-one monohydrate. AB - In the title compound, C(10)H(16)N(2)O.H(2)O, the cyclo-hexane ring is in a chair conformation and its least-squares plane makes a dihedral angle of 53.68 (5) degrees with the approximately planar pyrazole ring [maximum deviation = 0.034 (1) A]. Pairs of inter-molecular N-H?O hydrogen bonds form inversion dimers between neighbouring pyrazolone mol-ecules, generating R(2) (2)(8) ring motifs. The pyrazolone and water mol-ecules are further linked by inter-molecular N-H?O, C-H?O and O-H?O hydrogen bonds into two-dimensional sheets parallel to the bc plane. PMID- 21588964 TI - 1-[4-(4-Nitro-phen-yl)piperazin-1-yl]-2-(4,5,6,7-tetra-hydro-thieno[3,2-c]pyridin 5-yl)ethanone. AB - The title compound, C(19)H(22)N(4)O(3)S, comprises a thienopyridine moiety which is characteristic for anti-platelet agents of the clopidogrel class of compounds. In the crystal, inversion dimers are formed through pairs of C-H?O inter-actions. The benzene ring plane and the nitro plane are almost coplanar, with a dihedral angle of 0.83 (2) degrees . The piperazine ring adopts a chair conformation. PMID- 21588965 TI - N-Phenyl-cyclo-hexa-necarboxamide. AB - In the title compound, C(13)H(17)NO, the cyclo-hexane ring adopts a chair conformation and the amide C(=O)-N moiety is almost coplanar with the phenyl ring [C-N-C-O = 4.1 (2) degrees ]. In the crystal, mol-ecules are linked to form a C(4) infinite [001] chain via N-H?O hydrogen bonds, unlike the cyclic motif seen in related structures. PMID- 21588966 TI - o-Benzoquinone dioxime. AB - The title compound, C(6)H(6)N(2)O(2), was obtained as a product of an in vitro study of the metabolism of benzofuroxan. The molecule exhibits a amphi configuration of the oxime groups C=N-OH. One oxime group is involved in the formation of a strong intra-molecular O-H?N hydrogen bond, while another links mol-ecules into zigzag chains along the c axis via inter-molecular O-H?N hydrogen bonds. PMID- 21588967 TI - 5-(2,3,4,5,6-Penta-fluoro-phen-yl)-1,3,4-thia-diazol-2-amine. AB - The title compound, C(8)H(2)F(5)N(3)S, was synthesized by the reaction of perfluoro-benzoic acid and thio-semicarbazide. The dihedral angle between the thia-diazole and perfluoro-phenyl ring is 35.41 (6) degrees . In the crystal, inter-molecular N-H?N hydrogen bonds link the mol-ecules, forming a three dimensional network. PMID- 21588968 TI - N,N-Bis(pyridin-2-yl-methyl-idene)pyridine-2,6-dicarbohydrazide dimethyl formamide monosolvate. AB - In the crystal of the title compound, C(22)H(22)N(8)O(3), the dicarbohydrazide mol-ecules are linked into a chain along [010] by C-H?N inter-actions involving the pyridyl N atoms and aromatic C-H groups. The DMF mol-ecule is hydrogen bonded with the amide N-H via N-H?O inter-actions. C-H?O inter-actions also occur. PMID- 21588969 TI - Methyl 4-(4-meth-oxy-phen-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3 carboxyl-ate. AB - In the title compound, C(19)H(21)NO(4), the dihydro-pyridine ring adopts a distorted screw-boat conformation. The fused cyclo-hexenone ring forms a slightly distorted envelope conformation. The dihedral angle between the mean planes of the benzene and heterocyclic rings is 86.1 (7) degrees . An intra-molecular C-H?O inter-action occurs. In the crystal, mol-ecules are linked by inter-molecular N H?O hydrogen bonds, forming an infinite chain along the c axis. PMID- 21588970 TI - Redetermination of 3-methyl-isoquinoline at 150 K. AB - The structure of the title compound, C(19)H(9)O, has been redetermined at 150 K. The redetermination is of significantly higher precision than a previous room temperature structure [Ribar et al. (1974 ?). Cryst. Struct. Commun.3, 323-325]. The C-N bond lengths for this redetermination are much closer to those observed in comparable structures, and the orientation of the methyl group with respect to the isoquinoline plane is clarified. Inter-molecular weak C-H?N contacts are present in the crystal. PMID- 21588971 TI - 9-(4-Fluoro-phen-oxy-carbon-yl)-10-methyl-acridinium trifluoro-methane-sulfonate. AB - In the crystal structure of the title compound, C(21)H(15)FNO(2) (+).CF(3)SO(3) ( ), the cations form inversion dimers through C-H?O, C-F?pi and pi-pi inter actions. These dimers are further linked by pi-pi inter-actions. The cations and anions are connected through C-H?O, C-F?pi and S-O?pi inter-actions. The acridine and benzene ring systems are oriented at a dihedral angle of 74.1 (1) degrees . The carboxyl-ate group is twisted at an angle of 4.4 (1) degrees relative to the acridine skeleton. The mean planes of the adjacent acridine moieties are parallel or inclined at an angle of 55.4 (1) degrees in the crystal structure. PMID- 21588972 TI - 9-(4-Chloro-phen-oxy-carbon-yl)-10-methyl-acridinium trifluoro-methane-sulfonate. AB - In the crystal of the title compound, C(21)H(15)ClNO(2) (+).CF(3)SO(3) (-), adjacent cations are linked through C-H?pi and pi-pi inter-actions [centroid centroid distance = 3.987 (2) A], and neighboring cations and anions via C-H?O and C-F?pi inter-actions. The acridine ring system and benzene ring are oriented at a dihedral angle of 1.0 (1) degrees while the carboxyl group is twisted at an angle of 85.0 (1) degrees relative to the acridine skeleton. The mean planes of adjacent acridine units are either parallel or inclined at an angle of 78.2 (1) degrees in the crystal structure. PMID- 21588973 TI - 10-Methyl-9-[2-(propan-2-yl)phenoxy-carbonyl]-acridinium trifluoro-methane sulfonate. AB - In the crystal of the title compound, C(24)H(22)NO(2) (+).CF(3)SO(3) (-), adjacent cations and anions are connected through C-H?O, C-H?F and S-O?pi inter actions, while neighboring cations via pi-pi inter-actions [centroid-centroid distance = 3.962 (2) A]. The acridine and benzene ring systems are oriented at a dihedral angle of 14.6 (1) degrees . The carboxyl group is twisted at an angle of 87.6 (1) degrees relative to the acridine skeleton. The mean planes of adjacent acridine units are parallel or inclined at an angle of 13.4 (1) degrees in the crystal structure. PMID- 21588974 TI - (1E)-6-Meth-oxy-3,4-dihydro-naphthalen-1(2H)-one O-(p-tolyl-sulfon-yl)oxime. AB - In the title compound, C(18)H(19)NO(4)S, the two benzene rings form a dihedral angle of 68.37 (11) degrees . One of the C atoms of the fused ring bonded to the N atom displays positional disorder with site-occupation factors of 0.763 (7) and 0.237 (7) and the ring has an envelope conformation with the disordered C atoms located on opposite sides of the plane formed by the other atoms. In the crystal, inter-molecular C-H?O hydrogen bonds link the mol-ecules to form a two dimensional supra-molecular network. The crystal structure is further stablized by weak inter-molecular C-H?pi inter-actions. PMID- 21588975 TI - 1-(3,5-Dimethyl-phen-yl)-4,5-dimethyl-2-phenyl-1H-imidazole hemihydrate. AB - In the title compound, C(19)H(20)N(2).0.5H(2)O, the imidazole ring is essentially planar [maximum deviation = 0.005 (1) A]. The imidazole ring makes dihedral angles of 67.46 (10) and 23.10 (11) degrees with the attached benzene and phenyl rings, respectively. The dihedral angle between the benzene and phenyl rings is 68.22 (10) degrees . Inter-molecular O-H?N and C-H?N hydrogen bonds are found in the crystal structure. PMID- 21588976 TI - 3-Ethyl-4-[3-(1H-imidazol-1-yl)prop-yl]-5-phenyl-4H-1,2,4-triazole dihydrate. AB - In the title compound, C(16)H(19)N(5).2H(2)O, the triazole ring makes dihedral angles of 70.61 (6) and 41.89 (8) degrees , respectively, with the imidazole and benzene rings. The water mol-ecules are involved in inter-molecular O-H?N and O H?O hydrogen bonds, which stabilize the crystal packing. PMID- 21588977 TI - 2,2,2-Trifluoro-ethyl 4-methyl-benzene-sulfonate. AB - In the crystal structure of the title compound, C(9)H(9)F(3)O(3)S, inter molecular C-H?O hydrogen bonds link the mol-ecules along the c-axis direction. Also present are slipped pi-pi stacking inter-actions between phenyl-ene rings, with perpendicular inter-planar distances of 3.55 (2) A and centroid-centroid distances of 3.851 (2) A. PMID- 21588978 TI - 4-Azido-methyl-7-methyl-2-oxo-2H-chromene-6-sulfonyl azide. AB - In the title compound, C(11)H(8)N(6)O(4)S, the plane of the coumarin aromatic ring is twisted by 17.2 (2) degrees with respect to the plane of the azide group bound to the methyl-ene substituent, whereas it is twisted by 83.2 (2) degrees to the plane of the azide attached to the sulfonyl group. The crystal structure is stabilized by weak C-H?O inter-actions, leading to the formation of dimers with R(2) (2)(12) graph-set motifs. These dimers are further linked by weak S O?pi and pi-pi contacts [centroid-centroid distance = 3.765 (2) A], leading to the formation of a layered structure. PMID- 21588979 TI - N-[4-(Phenyl-imino-meth-yl)phen-yl]acetamide 0.67-hydrate. AB - The title compound, C(15)H(14)N(2)O.0.67H(2)O, was prepared by the reaction of 4 acetoamine-benzaldehyde and aniline. The asymmetric unit contains six organic mol ecules and four water mol-ecules. The dihedral angles between the aromatic ring planes in each organic mol-ecule vary from 42.4 (2) to 53.8 (2) degrees . In the crystal, an extensive network of inter-molecular N-H?O, O-H?N and O-H?O hydrogen bonds link the mol-ecules into [010] chains. PMID- 21588980 TI - 5-(3-Chloro-phen-yl)-2-phenyl-3,4-dihydro-2H-pyrrole. AB - In the title compound, C(16)H(14)ClN, the conformation of the five-membered ring approximates to an envelope with a C atom as the flap. The dihedral angle between the aromatic rings is 78.71 (9) degrees . PMID- 21588981 TI - 4-[(E)-3-Meth-oxy-5-nitro-4-(4-nitro-benz-yloxy)benzyl-idene-amino]-1,5-dimethyl 2-phenyl-1H-pyrazol-3(2H)-one. AB - In the title compound, C(26)H(23)N(5)O(7), the central benzene ring makes dihedral angles of 35.08 (6), 48.75 (7) and 69.55 (8) degrees with the pyrazolone ring, the nitro-benzene ring and the terminal phenyl ring, respectively. An intra-molecular C-H?O inter-action generates an S(6) ring. The packing is stabilized by weak nonclassical inter-molecular C-H?O=C hydrogen bonds that link adjacent mol-ecules into chains. PMID- 21588982 TI - (E)-Ethyl 2-(3-cinnamoyl-thio-ureido)acetate. AB - In the title compound, C(14)H(16)N(2)O(3)S, the phenyl ring and the ethyl 2-(3 formyl-thio-ureido)acetate fragment adopt an E configuration with respect to the C=C bond. An intra-molecular N-H?O hydrogen bond generating an S(6) ring motif is observed. In the crystal, mol-ecules are linked by N-H?S, C-H?S and C-H?O hydrogen bonds, forming sheets lying parallel to the ab plane. PMID- 21588983 TI - (S)-(+)-4-(Oxiran-2-ylmeth-oxy)-9H-carbazole. AB - In the title compound, C(15)H(13)NO(2), all atoms of the carbazole group are coplanar (r.m.s. deviation = 0.005 A), and the dihedral angle between this plane and C-O-C plane of oxane group is 57.1 (4) degrees . The crystal packing is stabilized by an N-H?O hydrogen bond, resulting in infinite supra-molecular chains along [001]. PMID- 21588984 TI - 5-(Anthracen-9-yl)-3-(4-nitro-phen-yl)-1-phenyl-4,5-dihydro-1H-pyrazole. AB - In the title compound, C(29)H(21)N(3)O(2), the five-membered pyrazoline ring is nearly planar, the maximum deviation being 0.037 (3) A. The anthracene ring system is approximately perpendicular to the central pyrazoline ring, making a dihedral angle of 86.55 (16) degrees , whereas the two attached benzene rings are oriented at smaller dihedral angles of 12.9 (2) and 14.7 (2) degrees with respect to the pyrazoline ring. An intra-molecular C-H?N hydrogen bond is observed. PMID- 21588985 TI - 8beta-Acet-oxy-14alpha-benzo-yloxy-N-methyl-13beta,15alpha-dihy-droxy 1alpha,6alpha,16beta-trimeth-oxy-4beta-(meth-oxy-meth-yl)aconitane: hypaconitine isolated from 'fuzi'. AB - The title compound, C(33)H(45)NO(10), has an aconitine carbon skeleton with four six-membered rings and two five-membered rings. The five-membered rings adopt envelope configurations and the six-membered N-containing heterocyclic ring displays a chair conformation. Two intra-molecular O-H?O hydrogen bonds occur. PMID- 21588986 TI - Quinoxaline: Z' = 1 form. AB - A new Z' = 1 crystal structure of quinoxaline (or 1,4-diaza-naphthalene), C(8)H(6)N(2), with one-fifth the volume of the earlier known Z' = 5 structure was obtained by means of an in situ cryocrystallization technique. PMID- 21588987 TI - Oleanolic acid ethanol monosolvate. AB - CRYSTALS OF THE TITLE COMPOUND (SYSTEMATIC NAME: 3beta-hy-droxy-olean-12-en-28 oic acid ethanol monosolvate), C(30)H(48)O(3).C(2)H(5)OH, were obtained from unsuccessful co-crystallization trials. The asymmetric unit contains two symmetry independent oleanolic acid mol-ecules, as well as two ethanol solvent mol-ecules. Inter-molecular O-H?O hydrogen bonds stabilize the crystal packing. In the oleanolic acid mol-ecules, ring C has a slightly distorted envelope conformation, while rings A, B, D and E adopt chair conformations and rings D and E are cis fused. Both independent ethanol mol-ecules are orientationally disordered [occupancy ratios of 0.742 (8):0.258 (8) and 0.632 (12):0.368 (12). PMID- 21588988 TI - Tetra-methyl 1,1,2-triphenyl-2H-1lambda-phosphole-2,3,4,5-tetra-carboxyl-ate. AB - The title compound, C(30)H(27)O(8)P (1), was formed as one of two products {(1) and (2) [Krawczyk et al. (2010 ?). Acta Cryst. E66 (cv2753)]} in the reaction of dimethyl acetyl-enedicarboxyl-ate with triphenyl-phosphine. The mol-ecule of (1) consists of a five-membered ring, in which the P atom is incorporated. One of the phenyl groups of the triphenyl-phosphine migrated to a vicinal C atom during the reaction. The five-membered ring of (1) is corrugated [r.m.s. deviation = 0.0719 (8) A], whereas that in compound (2) is planar, the r.m.s. deviation being only 0.009 (2) A. PMID- 21588989 TI - Trimethyl-3-meth-oxy-4-oxo-5-triphenyl-phospho-ranyl-idene-cyclo-pent-1-ene-1,2,3 tricarboxyl-ate. AB - The title compound, C(30)H(27)O(8)P (2), was formed as one of two products {(1) [Krawczyk et al. (2010 ?). Acta Cryst. E66 (cv2752)] and (2)} in the reaction of dimethyl acetyl-enedicarboxyl-ate with triphenyl-phosphine. The mol-ecule of (2) consists of a five-membered carbocyclic ring. The P atom is a part of a triphenylphosphoranylidene substituent. In contrast to (1), the five-membered ring of (2) is planar, the r.m.s. deviation being only 0.009 (2) A. PMID- 21588990 TI - Tripropyl-ammonium trithio-cyanurate. AB - IN THE TITLE COMPOUND (SYSTEMATIC NAME: tripropyl-azanium 2,4,6-tris-ulfanyl idene-cyclo-hexan-1-ide), (C(3)H(7))(3)HN(+).C(3)H(2)N(3)S(3) (-), one H atom of trithio-cyanuric acid is accepted by tripropyl-amine to form the ammonium ion. Coplanar trithio-cyanurate and tripropyl-ammonium ions [dihedral angle = 82.33 (8) degrees ] form the salt, which is stabilised by various N-H?S and N-H?N contacts. PMID- 21588991 TI - 3-(2,4,6-Trimethyl-benzo-yl)-2-naphthoic acid. AB - The asymmetric unit of the title compound, C(21)H(18)O(3), contains two crystallographically independent mol-ecules. The two mol-ecules are linked into cyclic centrosymmetric dimers R(2) (2)(8) by O-H?O hydrogen bonds. The dihedral angles between the naphthalene ring system and the benzene ring are 87.0 (8) and 84.4 (2) degrees in the two mol-ecules. The crystal packing is stabilized by O H?O, C-H?pi and pi-pi inter-actions [centroid-centroid distance = 3.664 (11) A]. In one mol-ecule, the mesityl ring is disordered over two positions [occupancy ratio 0.690 (3):0.690 (3)]. PMID- 21588992 TI - (4-Bromo-phen-yl)(3,6-dimeth-oxy-2-naphth-yl)methanone. AB - In the title compound, C(19)H(15)BrO(3), the dihedral angle between the naphthalene ring system and the benzene ring is 62.51 (8) degrees . The bridging carbonyl C-C(=O)-C plane makes dihedral angles of 47.07 (6) degrees with the naphthalene ring system and 24.20 (10) degrees with the benzene ring. A weak inter-molecular C-H?O hydrogen bond exists between the H atom of one meth-oxy group and the O atom of the other meth-oxy group in an adjacent mol-ecule. The crystal packing is additionally stabilized by two types of weak inter-molecular inter-actions involving the Br atom, C-H?Br and Br?O [3.2802 (14) A]. PMID- 21588993 TI - Cinnamoyl-thio-urea. AB - IN THE TITLE COMPOUND [SYSTEMATIC NAME: 1-(3-phenyl-prop-2-eno-yl)thio-urea], C(10)H(10)N(2)OS, the acetyl-thio-urea fragment and the phenyl ring adopt an E configuration. The roughly planar but-2-enoyl-thio-urea fragment [maximum deviation = 0.053 (3) A] forms a dihedral of 10.54 (11) degrees with the phenyl ring. An intra-molecular N-H?O hydrogen bond generates an S(6) ring. In the crystal, mol-ecules are linked into sheets parallel to (100) by N-H?S hydrogen bonds. PMID- 21588994 TI - 3,5-Bis(3-butylimidazolium-1-ylmethyl)toluene bis(hexafluorophosphate). AB - IN THE TITLE COMPOUND [SYSTEMATIC NAME: 3,3'-Dibutyl-1,1'-(5-methyl-m-phenyl enedimethyl-ene)diimidazol-1-ium bis-(hexa-fluoridophosphate)], C(23)H(34)N(4) (2+).2PF(6) (-), the imidazole rings are inclined at angles of 68.06 (7) and 75.05 (8) degrees with respect to the central benzene ring. In the crystal, mol ecules are linked into one-dimensional columns along [010] via weak inter molecular C-H?F hydrogen bonds. The crystal structure is further consolidated by weak C-H?pi(arene) inter-actions. One of the n-butyl groups is disordered over two sites with refined occupancies of 0.694 (5) and 0.306 (5). In addition, four of the F atoms of one of the PF(6) (-) cations are disordered over two sites with occupancies of 0.64 (3) and 0.36 (3). PMID- 21588995 TI - 3-Ethyl-6-[3-(4-fluoro-phen-yl)-1H-pyrazol-4-yl]-1,2,4-triazolo[3,4-b][1,3,4]thia diazole. AB - In the title compound, C(14)H(11)FN(6)S, the 1,2,4-triazolo[3,4-b][1,3,4]thia diazole ring system is essentially planar [maximum deviation = 0.022 (3) A] and is inclined at dihedral angles of 15.00 (18) and 52.82 (16) degrees with respect to the pyrazole and phenyl rings. In the crystal, mol-ecules are linked into two dimensional networks parallel to (100) via inter-molecular N-H?N and weak C-H?N hydrogen bonds. The crystal packing is further consolidated by weak pi-pi stacking inter-actions, with a centroid-centroid distance of 3.590 (2) A. The crystal studied was an inversion twin with a 0.37 (13):0.63 (13) domain ratio. PMID- 21588996 TI - 1'-(4-Bromo-phen-yl)-4'-{4-[(2-oxo-1,2,3,4-tetra-hydro-naphthalen-2-yl-idene)meth yl]phen-yl}-3'',4''-dihydro-acenaphthylene-1-spiro-2'-pyrrolidine-3'-spiro-2'' naphthalene-2,1''(1H,2''H)-dione. AB - In the title compound, C(47)H(34)BrNO(3), the central benzene ring makes a dihedral angle of 42.71 (7) degrees with the bromo-phenyl ring. The pyrrolidine ring adopts an envelope conformation. The mol-ecular structure is stabilized by weak intra-molecular C-H?O inter-actions and the crystal packing is stabilized by weak inter-molecular C-H?pi inter-actions. PMID- 21588997 TI - (alphaR,4R,4aR,6aS,7R,8S,10R,11S)-Methyl alpha-acet-oxy-4-(3-furan-yl)-10-hy droxy-4a,7,9,9-tetra-methyl-2,13-dioxo-1,4,4a,5,6,6a,7,8,9,10,11,12-dodeca-hydro 7,11-methano-2H-cyclo-octa-[f][2]benzopyran-8-acetate (6-O-acetyl-swietenolide) from the seeds of Swietenia macrophylla. AB - The mol-ecule of O-acetyl-swietenolide, C(29)H(36)O(9), isolated from the seeds of Swietenia macrophylla, features four six-membered rings connected together in the shape of a bowl; one of the inner rings adopts a twisted chair conformation owing to the C=C double bond. The furyl substitutent is connected to an outer ring, and it points away from the bowl cavity. The hy-droxy group is connected to a carbonyl O atom of an adjacent mol-ecule by an O-H?O hydrogen bond, generating a chain running along the b axis. PMID- 21588998 TI - 3-(6-Bromo-hex-yl)-1,5-dimethyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione. AB - The seven-membered ring in the title compound, C(17)H(23)BrN(2)O(2), adopts a boat-shaped conformation (with the C atoms of the fused-ring as the stern and the methine C atom as the prow). The bromo-hexyl substituent occupies an equatorial position, with the hexyl chain exhibiting an extended conformation. Weak inter molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 21588999 TI - 3-(12-Bromo-dodec-yl)-1,5-dimethyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione. AB - The seven-membered ring in the title compound, C(23)H(35)BrN(2)O(2), adopts a boat-shaped conformation (with the C atoms of the fused-ring as the stern and the methine C atom as the prow). The bromo-dodecyl substituent occupies an equatorial position, with the dodecyl chain exhibiting an extended conformation. Weak inter molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 21589000 TI - 3-Hy-droxy-2-[(2-hy-droxy-4,4-dimethyl-6-oxocyclo-hex-1-en-1-yl)(3-nitro-phen yl)meth-yl]-5,5-dimethyl-cyclo-hex-2-en-1-one. AB - Each of the cyclohexenone rings in the title compound, C(23)H(27)NO(6), adopts a half-chair (envelope) conformation with the C atom carrying the methyl groups lying out of the plane defined by the five remaining C atoms; the O atoms lie to the same side of the mol-ecule as the respective >C(CH(3))(2) atoms. The hy-droxy and carbonyl O atoms face each other and are orientated to allow for the formation of two intra-molecular O-H?O hydrogen bonds. In the crystal, the presence of C-H?O contacts leads to the formation of supra-molecular chains along the b axis. These aggregate into layers that stack along c. PMID- 21589001 TI - A monoclinic polymorph of N-(3-chloro-phen-yl)benzamide. AB - The title compound, C(13)H(10)ClNO, (I), is a polymorph of the structure, (II), first reported by Gowda et al. [Acta Cryst. (2008), E64, o462]. In the original report, the compound crystallized in the ortho-rhom-bic space group Pbca (Z = 8), whereas the structure reported here is monoclinic P21/c (Z = 4). The principal difference between the two forms lies in the relative orientations of the phenyl and benzene rings [dihedral angle = 8.90 (13) degrees for (I) and 61.0 (1) degrees for (II)]. The inclination of the amide -CONH- units to the benzoyl ring is more similar [15.8 (7) degrees for (I) and 18.2 (2) degrees for (II)]. In both forms, the N-H bonds are anti to the 3-chloro substituents of the aniline rings. In the crystal, inter-molecular N-H?O hydrogen bonds form C(4) chains along c. These chains are bolstered by weak C-H?O inter-actions that generate R(2) (1)(6) and R(2) (1)(7) ring motifs. PMID- 21589002 TI - 1,4-Diazo-niacyclo-hexane bis-(3-carb-oxy-pyrazine-2-carboxyl-ate) dihydrate. AB - In the title compound, C(4)H(12)N(2) (2+).2C(6)H(3)N(2)O(4) (-).2H(2)O or (1,4 dacH(2))(pyzdcH)(2).2H(2)O, the complete dication is generated by crystallographic inversion symmetry. An intra-molecular O-H?O hydrogen bond occurs in the anion. In the crystal, O-H?O, O-H?N, N-H?O and N-H?N hydrogen bonds result in the formation of a three-dimensional network. Additionally, pi-pi stacking inter-actions between the pyrazine rings with centroid-centroid distances of 3.7065 (2) A are observed. PMID- 21589003 TI - 1-(3-Chloro-phen-yl)-3-(4-nitro-phen-yl)urea. AB - In the title compound, C(13)H(10)ClN(3)O(3), prepared by the reaction of 1-chloro 3-isocyanato-benzene with 4-nitro-benzenamine, the two substituent benzene rings are roughly coplanar [inter-ring dihedral angle = 8.70 (7) degrees ]. In the crystal, mol-ecules make cyclic inter-molecular associations through two urea nitro N-H?O hydrogen bonds, forming a chain structure [give chain direction] in which there are also weak inter-molecular C-H?Cl inter-actions. The urea O atom has only intra-molecular aromatic ring C-H?O associations. PMID- 21589004 TI - Benzoic acid-2-{(E)-[(E)-2-(2-pyridyl-methyl-idene)hydrazin-1-yl-idene]meth yl}pyridine (2/1). AB - The asymmetric unit of the title cocrystal, C(12)H(10)N(4).2C(7)H(6)O(2), comprises a single mol-ecule of benzoic acid and one half-mol-ecule of 2-pyridine aldazine situated about a centre of inversion. The carboxyl group is coplanar with the benzene ring to which it is connected [O-C-C-C = -172.47 (12) degrees ] and similarly, the 2-pyridine-aldazine mol-ecule is planar (r.m.s. deviation of the 16 non-H atoms = 0.017 A). In the crystal, mol-ecules are connected into a non-planar three-mol-ecule aggregate [dihedral angle between the benzene and pyridyl ring connected by the hydrogen bond = 61.30 (7) degrees ] with a twisted Z-shape. Layers of 2-pyridine-aldazine mol-ecules in the ab plane are sandwiched by benzoic acid mol-ecules being connected by O-H?N and C-H?O inter-actions, the latter involving the carbonyl O atom so that each benzoic acid mol-ecule links three different 2-pyridine-aldazine mol-ecules. Inter-digitated layers stack along the c axis. PMID- 21589005 TI - 4,4',5,5'-Tetra-phenyl-3,3'-[methyl-idene-bis(sulfanedi-yl)]bis-(4H-1,2,4 triazole). AB - The asymmetric unit of the title compound, C(29)H(22)N(6)S(2), contains one half mol-ecule situated on a twofold rotational axis. The two triazole rings form a dihedral angle of 27.6 (2) degrees . In the crystal, weak inter-molecular C-H?N hydrogen bonds link the mol-ecules into ribbons extending along [001]. PMID- 21589006 TI - 1-(4-Fluoro-phen-yl)-3-methyl-4-phenyl-sulfanyl-1H-pyrazol-5(4H)-one. AB - The title compound, C(16)H(13)FN(2)OS, has undergone enol-to-keto tautomerism during the crystallization process. The 1H-pyrazole-5-one ring [maximum deviation = 0.0198 (11) A] is inclined at angles of 33.10 (5) and 79.57 (5) degrees with respect to the fluoro-phenyl [maximum deviation = 0.0090 (12) A] and phenyl-thiol [maximum deviation = 0.0229 (3) A] rings attached to it. In the crystal, neighbouring mol-ecules are linked into inversion dimers, generating R(2) (2)(8) ring motifs. These dimers are further linked into two-dimensional arrays parallel to the bc plane via inter-molecular N-H?O, C-H?F and C-H?O hydrogen bonds. The crystal is further stabilized by weak pi-pi [centroid-centroid distance = 3.6921 (7) A] and C-H?pi inter-actions. PMID- 21589007 TI - (9S,13R,14S)-7,8-Didehydro-4-(4-iodo-benz-yloxy)-3,7-dimeth-oxy-17-methyl morphinan-6-one monohydrate. AB - In the title compound, C(26)H(28)INO(4).H(2)O, benzene rings are inclined at a dihedral angle of 69.9 (1) degrees . The N-containing ring exhibits a chair conformation, while the other rings approximate to envelope conformations. In the crystal, the uncoordinated water mol-ecule forms inter-molecular O-H?O and O-H?N hydrogen bonds. PMID- 21589008 TI - 4-[2,3-Dibromo-3-(4-bromo-phen-yl)propano-yl]-2-phenyl-1,2,3-oxadiazol-2-ium-5 olate. AB - In the title compound, C(17)H(11)Br(3)N(2)O(3), the whole mol-ecule is disordered over two positions with a refined occupancy ratio of 0.770 (5):0.230 (5). In the major component, the 1,2,3-oxadiazo-lidine ring is essentially planar [maximum deviation = 0.017 (6) A] and makes dihedral angles of 22.5 (3) and 70.2 (3) degrees with the 4-bromo-phenyl and phenyl rings, respectively. In the minor component, the corresponding values are 18.9 (11) and 84.9 (12) degrees . In the crystal, inter-molecular C-H?Br hydrogen bonds link the mol-ecules into ribbons along [010]. There is a short O?N contact [2.83 (3) A] in the minor component. In the major component, the mol-ecular structure is stabilized by an intra-molecular C-H?O hydrogen bond, which forms an S(6) ring motif. PMID- 21589009 TI - (2-Hy-droxy-7-meth-oxy-naphthalen-1-yl)(4-methyl-phen-yl)methanone. AB - In the title compound, C(19)H(16)O(3), an intra-molecular O-H?O=C hydrogen bond is formed between the hy-droxy and carbonyl groups on the naphthalene ring system, resulting in an S(6) ring. The angles between the C=O bond vector and the least-squares planes of the naphthalene ring system and the benzene ring are 27.63 (6) and 47.99 (7) degrees , respectively. The dihedral angle between the latter planes is 61.39 (5) degrees . In the crystal, two mol-ecules are connected by pairs of inter-molecular O-H?O=C hydrogen bonds, forming centrosymmetric dimers with an R(2) (2)(4) graph-set motif. The mol-ecular packing features C H?pi interactions. PMID- 21589010 TI - Ethyl 4-(furan-2-yl)-6-methyl-2-oxo-1,2,3,4-tetra-hydro-pyrimidine-5-carboxyl ate. AB - The asymmetric unit of the title compound, C(12)H(14)N(2)O(4), contains two independent mol-ecules. In one independent mol-ecule, the furanyl fragment is rotationally disordered between two orientations in a 0.625 (6):0.375 (6) ratio. In the crystal, inter-molecular pyrimidine-pyrimidinone N-H?O hydrogen bonds link the mol-ecules into centrosymmetric tetra-mers, which are further associated into ribbons extending in [010] via weak inter-molecular pyrimidine-carboxyl N-H?O hydrogen bonds. PMID- 21589011 TI - (R)-(1-Ammonio-prop-yl)phospho-nate. AB - The title compound, C(3)H(10)NO(3)P, crystallizes in its zwitterionic form, H(3)N(+)CH(C(2)H(5))PO(O(-))(OH), with the asymmetric unit being composed by two of such entities (Z' = 2). The crystal packing leads to a sequence of hydro phobic and hydro-philic layers. While the hydro-phobic layer comprises the aliphatic substituent groups, the hydro-philic one is held together by a series of strong and rather directional N(+)-H?O and O-H?O hydrogen bonds. PMID- 21589012 TI - (E)-2-(2H-Benzotriazol-2-yl)-4-methyl-6-(phenyl-imino-meth-yl)phenol. AB - In the title compound, C(20)H(16)N(4)O, the non-H atoms of the benzotriazole ring system and those of the methyl-phenol group are essentially coplanar, with an r.m.s. deviation of 0.004 (2) A. The mean plane of these atoms forms a dihedral angle of 60.9 (2) degrees with the phenyl ring. There is an intra-molecular O H?N hydrogen bond between the phenol and benzotriazole groups. PMID- 21589014 TI - 4-(o-Tolyl-amino)-benzaldehyde. AB - In the title compound, C(14)H(13)NO, the dihedral angle between the aromatic rings is 49.64 (18) degrees . The crystal structure is stabilized by N-H?O, C-H?O and C-H?pi hydrogen bonds. PMID- 21589013 TI - 4,5-Dimethyl-2-phenyl-1-(p-tol-yl)-1H-imidazole. AB - In the title compound, C(18)H(18)N(2), the imidazole ring is essentially planar [maximum deviation = 0.004 (1) A] and makes dihedral angles of 68.91 (8) and 20.43 (9) degrees with the tolyl and phenyl rings, respectively. The dihedral angle between the latter rings is 73.62 (8) degrees . The crystal packing is stabilized by inter-molecular C-H?N hydrogen bonds. PMID- 21589015 TI - 4-(p-Tolyl-amino)-benzaldehyde. AB - In the title compound, C(14)H(13)NO, the dihedral angle between the aromatic rings is 66.08 (9) degrees . Chains are formed along the b axis through inter molecular N-H?O hydrogen bonds. The crystal structure is further stabilized by C H?pi inter-actions. PMID- 21589016 TI - 2-(4-Chloro-phen-oxy)-N'-[2-(4-chloro-phen-oxy)acet-yl]acetohydrazide monohydrate. AB - In the title compound, C(16)H(14)Cl(2)N(2)O(4).H(2)O, the hydrazine and water mol ecules are both located on twofold axes. The C-N-N-C torsion angle is -72.66 (1) degrees and the dihedral angle between the two benzene rings is 67.33 (1) degrees . In the crystal, mol-ecules are linked into a layer structure by a combination of O-H?O, N-H?O and C-H?O hydrogen bonds. Adjacent layers are linked into a three-dimensional network by Cl?Cl inter-actions [3.400 (2) A]. C-H?pi inter-actions are also observed. PMID- 21589017 TI - 10-(Prop-2-yn-yl)-10H-phenothia-zine. AB - In the mol-ecule of the title compound, C(15)H(11)NS, the butterfly angle between the two planes defined by the two wings of the phenothia-zine unit is 33.5 (8) degrees . The dihedral angles between the two benzene rings and the propynyl group are 85 (4) and 63 (4) degrees . PMID- 21589018 TI - 4,4'-Dimeth-oxy-2,2'-[(butane-1,4-diyldi-oxy)bis-(nitrilo-methyl-idyne)]diphenol. AB - The title Schiff base bis-oxime compound, C(20)H(24)N(2)O(6), lies across an inversion centre and adopts an E configuration with respect to the C=N bond. In the mol-ecule, the oxime group is roughly coplanar with the benzene ring, forming a dihedral angle of 1.77 (2) degrees . An intra-molecular O-H?N hydrogen bond forms a six-membered ring with an S(6) motif. Weak inter-molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 21589019 TI - (1E)-1-(3-Bromo-phen-yl)ethanone 2,4-di-nitro-phenyl-hydrazone. AB - The title compound, C(14)H(11)BrN(4)O(4), contains 3-bromo-phenyl and 2,4-dinitro phenyl groups on opposite sides of a hydrazone unit and crystallizes with two mol ecules in the asymmetric unit. The dihedral angles between the two ring systems in each mol-ecule are 2.0 (1) and 2.5 (4) degrees . Weak C-H?O hydrogen bonds and weak pi-pi stacking inter-actions [centroid-centroid distance = 3.7269 (14) A] help to establish the packing. Intra-molecular N-H?O hydrogen bonds are also observed. On one of the rings, the Br atom is disordered over two equivalent positions of the phenyl ring [occupancy ratio 0.8734 (10):0.1266 (10). PMID- 21589020 TI - 5-Hy-droxy-7-phenyl-5-(prop-2-yn-1-yl)-5,6-dihydro-1-benzofuran-2(4H)-one monohydrate. AB - In the title compound, C(17)H(14)O(3).H(2)O, the six-membered ring, which adopts a half-chair conformation, makes a dihedral angle of 24.3 (2) degrees with the phenyl ring. In the crystal, the components are linked by O-H?O hydrogen bonds involving the water mol-ecule, and the hy-droxy and carbonyl groups of the organic compound. These inter-actions form a square-like supra-molecular synthon unit which propagates as chains parallel to the crystallographic b axis. A C-H?O interaction also occurs. PMID- 21589021 TI - 5,5',5''-Triphenyl-2,2',2''-[2,4,6-tri-methyl-benzene-1,3,5-triyltris(methyl idene-sulfanedi-yl)]tris-(1,3,4-oxadiazole). AB - In the title compound, C(36)H(30)N(6)O(3)S(3), the phenyl rings are twisted from the attached oxadiazole rings in the three arms by 1.5(2), 2.4 (2) and 25.7 (2) degrees . The crystal packing exhibits weak inter-molecular C-H?N inter-actions. PMID- 21589022 TI - 4-Bromo-anilinium perchlorate 18-crown-6 clathrate. AB - The reaction of 4-bromo-aniline, 18-crown-6, and perchloric acid in methanol yields the title compound, C(6)H(7)BrN(+).ClO(4) (-).C(12)H(24)O(6), in which the protonated -NH(3) (+) group forms three bifurcated N-H?O hydrogen bonds to the O atoms of the crown ether. PMID- 21589023 TI - 3-(4-Meth-oxy-benzyl-idene)-1,5-dioxa-spiro-[5.5]undecane-2,4-dione. AB - In the title mol-ecule, C(17)H(18)O(5), which was prepared by the reaction of (R) 1,5-dioxaspiro-[5.5]undecane-2,4-dione and 4-meth-oxy-benzaldehyde with ethanol, the 1,3-dioxane ring is in a distorted envelope conformation with the spiro C atom forming the flap. The crystal structure is stabilized by weak inter molecular C-H?O hydrogen bonds. PMID- 21589024 TI - 4-Amino-3,5-dichloro-benzene-sulfonamide. AB - In the title compound, C(6)H(6)Cl(2)N(2)O(2)S, the O atoms of the sulfonamide group lie on one side of the benzene ring and the amino group lies on the opposite side. An inter-molecular N-H?Cl inter-action occurs. In the crystal, adjacent mol-ecules are linked by N-H?O hydrogen bonds, forming a three dimensional structure with supporting pi-pi stacking inter-actions [centroid centroid distance = 3.7903 (12) A]. A short Cl?Cl contact [3.3177 (10) A] also occurs. PMID- 21589025 TI - 1-Propyl-1H-2,1-benzothia-zin-4(3H)-one 2,2-dioxide. AB - In the title compound, C(11)H(13)NO(3)S, a benzothia-zine derivative, the heterocycle adopts a sofa conformation. In the crystal, weak C-H?O hydrogen bonds connect the mol-ecules into a three-dimensional network. PMID- 21589026 TI - 1-Methane-sulfonyl-1H-1,2,3-benzotriazole. AB - The mol-ecular geometry of the title compound, C(7)H(7)N(3)O(2)S, does not differ much from that of the previously reported 4-toluene-sulfonyl analogue. Unlike the latter compound, however, mol-ecules of the title compound associate primarily via pi-pi stacking inter-actions of their benzene rings [centroid-centroid distance = 3.5865 (8) A], forming columnar stacks along the crystallographic 2(1) axes. These stacks are inter-connected via weak C-H?O and C-H?N hydrogen bonds. PMID- 21589027 TI - (E)-N'-(3,3-Dimethyl-2,6-diphenyl-piperidin-4-yl-idene)isonicotinohydrazide. AB - In the title mol-ecule, C(25)H(26)N(4)O, the piperidine ring adopts a chair conformation, with the plane through the four coplanar atoms making dihedral angles of 84.76 (6), 82.28 (5) and 81.91 (6) degrees with the pyridine-ring and the phenyl rings at the 2 and 6 positions, respectively. The pyridine ring makes dihedral angles of 64.13 (8) and 10.75 (8) degrees with the phenyl rings at the 2 and 6 positions, respectively. The dihedral angle between the two phenyl rings is 53.57 (8) degrees . The phenyl rings and one of the methyl groups at position 3 have an equatorial orientation. In the crystal, mol-ecules are linked by N-H?O and C-H?O hydrogen bonds. PMID- 21589028 TI - 1-Allyl-4-(1,3-benzothia-zol-2-yl)-5-methyl-2-phenyl-1H-pyrazol-3(2H)-one. AB - The title compound, C(20)H(17)N(3)OS, is a 1H-pyrazol-3(2H)-one having aromatic 4 (1,3-benzothia-zol-2-yl)- and 2-phenyl substituents. The five-membered ring and fused ring system are planar, the r.m.s. deviations being 0.021 and 0.005 A, respectively. The five-membered ring is aligned at 7.9 (2) degrees with respect to the fused-ring system. The allyl and phenyl parts of the mol-ecule are both disordered over two positions in a 1:1 ratio. Weak inter-molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 21589029 TI - 4-(1,3-Benzothia-zol-2-yl)-5-methyl-2-phenyl-1-propynyl-1H-pyrazol-3(2H)-one. AB - The title compound, C(20)H(15)N(3)OS, is a 1H-pyrazol-3(2H)-one having aromatic 4 (1,3-benzothia-zol-2-yl) and 2-phenyl substit-uents. The five-membered ring and the fused-ring system are close to planar, the r.m.s. deviations being 0.025 and 0.005 A, respectively. The five-membered ring is aligned at 67.5 (1) degrees with respect to the phenyl ring and at 4.7 (1) degrees with respect to the fused ring system. In the crystal, adjacent mol-ecules are linked through the acetyl enic H atom by a C-H?O hydrogen bond into C(8) chains propagating in [010]. PMID- 21589030 TI - Curcumenol from Curcuma zedoaria: a second monoclinic modification. AB - The title compound, systematic name 9-isopropyl-idene-2,6-dimethyl-11-oxatricyclo [6.2.1.0(1,5)]undec-6-en-8-ol, C(15)H(22)O(2), which crystallizes with two mol ecules of similar conformation in the asymmetric unit, features three fused rings, two of which are five-membered and the third six-membered. Of the two five membered rings, the one with an O atom has a distinct envelope shape (with the O atom representing the flap). The six-membered ring is also envelope-shaped as it shares a common O atom with the five-membered ring. In the crystal, the two independent mol-ecules are linked by a pair of O-H?O hydrogen bonds, generating a dimer. PMID- 21589031 TI - 9-Phenyl-10H-acridinium trifluoro-methane-sulfonate. AB - In the crystal structure of the title compound, C(19)H(14)N(+).CF(3)SO(3) (-), the cations are linked to each other by very weak C-H?pi inter-actions, while the cations and anions are connected by N-H?O, C-H?O and S-O?pi inter-actions. The acridine ring system and the phenyl ring are oriented at an angle of 80.1 (1) degrees with respect to each other. The mean planes of adjacent acridine units are either parallel or inclined at an angle of 35.6 (1) degrees . The trifluoro methane-sulfonate anions are disordered over two positions; the site occupancy factors are 0.591 (8) and 0.409 (8). PMID- 21589032 TI - 8-(Diphenyl-phosphan-yl)quinoline. AB - The title compound, C(21)H(16)NP, is a known P-N chelator and various crystal structures of its metal complexes have been reported. However, no crystallographic evidence of the free ligand has been given to date. The phenyl rings are almost orthogonal to one another [dihedral angle = 88.9 (1) degrees ], and they are twisted from the mean plane of the quinoline by 80.5 (1) and 76.3 (1) degrees . PMID- 21589033 TI - 3-Acet-oxy-2-naphthoic acid. AB - In the title compound, C(13)H(10)O(4), an analog of acetyl-salicylic acid, the naphthalene unit is twisted slightly due to ortho disubstitution [dihedral angle between conjugated rings system in the naphthalene unit = 2.0 (2) degrees ]. The mean planes of the carb-oxy-lic and ester groups are almost coplanar and perpendicular, respectively, to the mean plane of the conjugated aromatic system, making dihedral angles of 8.9 (3) and 89.3 (1) degrees . In the crystal, mol ecules are paired through their carb-oxy-lic groups by the typical centrosymmetric O-H?O inter-actions with R(2) (2)(8) hydrogen-bond motifs. In addition, several weak C-H?O inter-molecular contacts are also observed. Finally, the mol-ecules are stacked along crystallographic [100] and [010] directions. PMID- 21589034 TI - 1,4-Bis(pyrimidin-2-yl-sulfanyl)-butane. AB - The -SCH(2)CH(2)CH(2)CH(2)S- portion of the title compound, C(12)H(14)N(2)S(2), adopts an extended zigzag conformation. The angles at the tetra-hedral carbon atoms are marginally increased [113.63 (12) degrees and 111.38 (17) degrees for S-C-C and C-C-C respectively] from the idealized tetra-hedral angle. The mol ecule lies on an inversion center located at the mid-point of the butyl chain. In the crystal, there is a pi-pi stacking inter-action between inversion-related pyrimidine rings with mean inter-planar spacing of 3.494 (2) A. PMID- 21589035 TI - (4S)-(-)-4-Benzyl-2,2-dimethyl-3-o-toluoyl-1,3-oxazolidine. AB - The absolute configuration of the title compound, C(20)H(23)NO(2), has been confirmed as 4S. The benzyl residue and H atom at the asymmetric C-atom centre occupy pseudo-axial and bis-ectional positions, respectively. The oxazolidine ring adopts an envelope conformation. In the crystal structure, the mol-ecular packing is stabilized by non-classical C-H?O hydrogen bonds. PMID- 21589036 TI - Methyl 3-[(E,E)-3-phenyl-prop-2-enyl-idene]dithio-carbazate. AB - In the title compound, C(11)H(12)N(2)S(2), the dithio-carbazate group adopts an EE configuration with respect to the C=C and C=N bonds of the propenyl-idene group. The atoms of the propenyl-idene and dithio-carbazate unit are essentially co-planar, with a maximum deviation of 0.058 (1) A; the phenyl ring forms a dihedral angle of 18.3 (1) degrees with this fragment. In the crystal, mol ecules form inversion dimers via pairs of N-H?S hydrogen bonds involving the terminal S atom. PMID- 21589037 TI - 6-Hy-droxy-4-(pyridin-3-yl)-5-(2-thienyl-carbon-yl)-6-trifluoro-meth-yl-3,4,5,6 tetra-hydro-pyrimidin-2(1H)-one. AB - In the title compound, C(15)H(12)F(3)N(3)O(3)S, the pyrimidine ring adopts a half chair conformation with the mean plane formed by the ring atoms excluding the C atom bonded to thio-phene-2-carbonyl group lying nearly perpendicular to the pyridine and thio-phene rings, making dihedral angles of 84.91 (4) and 87.40 (5) degrees , respectively. The dihedral angle between the pyridine and thio-phene rings is 54.44 (5) degrees . The crystal structure is stabilized by inter molecular O-H?O and N-H?N hydrogen bonds and weak C-H?O inter-actions further consolidate the structure. PMID- 21589038 TI - 4-Methyl-1-(4-methylbenzylidene)thio-semicarbazide. AB - The title compound, C(10)H(13)N(3)S, prepared by the reaction of 4-methyl benzaldehyde and 4-methyl-thio-semicarbazide, is approximately planar (r.m.s. deviation for the non-H atoms = 0.032 A). Its conformation is stabilized by an intra-molecular N-H?N hydrogen bond, generating an S(5) ring. In the crystal, inversion dimers linked by pairs of N-H?S hydrogen bonds occur. Further weak N H?S links connect the dimers into (100) sheets. PMID- 21589039 TI - (Z)-1-Phenyl-3-(3-pyridyl-meth-ylamino)-but-2-en-1-one. AB - The reaction of 3-C(5)H(4)NCH(2)NH(2) and C(6)H(5)COCH(2)COCH(3) affords the title compound, C(16)H(16)N(2)O. The O=C-C=C-N portion is essentially planar [maximum deviation = 0.046 (2) A] and is aligned at dihedral angles of 22.6 (1) and 78.9 (1) degrees to the phenyl and pyridyl rings, respectively. The N-H and O=C groups are linked by an intra-molecular hydrogen bond. In the crystal, C-H?O hydrogen bonds and C-H?pi inter-actions occur. PMID- 21589040 TI - N-(5-Chloro-2-meth-oxy-phen-yl)benzene-sulfonamide. AB - In the title compound, C(13)H(12)ClNO(3)S, the dihedral angle between the two aromatic rings is 73.94 (9) degrees . An intra-molecular C-H?O hydrogen bond occurs. In the crystal, inter-molecular N-H?O hydrogen bonds connect the mol ecules to centrosymmetric dimers, forming an R(2) (2)(8) ring motif. The packing is consolidated by C-H?O hydrogen bonds and weak pi-pi inter-actions [centroid centroid distances = 3.81 (3) and 3.81 (3) A]. PMID- 21589041 TI - N-[(2-Chloro-8-methyl-quinolin-3-yl)meth-yl]-4-meth-oxy-aniline. AB - In the title compound, C(18)H(17)ClN(2)O, the quinoline ring system is essentially planar; the r.m.s. deviation for the non-H atoms is 0.04 A with a maximum deviation from the mean plane of 0.026 (4) A for the C atom bonded to the -CH(2)- group. The meth-oxy-substituted benzene ring forms a dihedral angle of 70.22 (4) degrees with this ring system. The crystal structure can be described as zigzag layers in which the quinoline ring systems are parallel to (011) and molecules are connected via inter-molecular N-H?N hydrogen bonds, forming chains along [100]. The crystal studied was an inversion twin with a 0.86 (5):0.14 (5) domain ratio. PMID- 21589042 TI - 3,3-Dichloro-1-(chloro-meth-yl)indolin-2-one. AB - In the title compound, C(9)H(6)Cl(3)NO, the pyrrole ring is almost coplanar with the benzene ring [dihedral angle = 1.90 (9) degrees ], while the Cl-C-N-C torsion angle is 98.78 (17) degrees . In the crystal, pairs of mol-ecules are inter connected by pairs of Cl?Cl inter-actions [3.564 (5) A], forming dimers, which are further peripherally connected through inter-molecular C-H?O=C and pi-pi inter-actions [centroid-centroid distances = 4.134 (7), 4.134 (6) and 4.238 (7) A], forming a two-dimensional network. PMID- 21589043 TI - 4-Hy-droxy-3-[(4-hy-droxy-6,7-dimethyl-2-oxo-2H-chromen-3-yl)(4-oxo-4H-chromen-3 yl)meth-yl]-6,7-dimethyl-2H-chromen-2-one. AB - In the title compound, C(32)H(24)O(8), the mol-ecular structure is disordered over two positions with refined site occupancies of 0.8746 (10) and 0.1254 (10). The mean plane of the three chromeno rings make dihedral angles with each other of 65.12 (4), 62.91 (4) and 59.70 (4) degrees in the major occupancy component and 59.1 (3), 66.1 (3) and 58.8 (3) degrees in the minor component. Intra molecular O-H?O hydrogen bonds stabil-ize the mol-ecular structure and the crystal structure is stabilized by weak C-H?pi and pi-pi inter-actions [centroid centroid distances 3.496 (6)-3.672 (7) A]. PMID- 21589044 TI - 3-Methyl-4-[(E)-3-thien-ylmethyl-idene-amino]-1H-1,2,4-triazole-5(4H)-thione. AB - The asymmetric unit of the title compound, C(8)H(8)N(4)S(2), contains two crystallographically independent mol-ecules. The thio-phene ring of one mol-ecule is disordered over two positions with refined site occupancies of 0.6375 (19) and 0.3625 (19). One mol-ecule is almost planar and the other one is twisted, the dihedral angles between the thio-phene and triazole rings being 7.28 (7) and 48.9 (2) degrees [48.5 (4) degrees for the minor component], respectively. An intra molecular C-H?S hydrogen bond stabilizes the mol-ecular conformation of the planar molecule. In the crystal, the two mol-ecules are inter-connected by N-H?S hydrogen bonds into dimers, which are further consolidated into chains along the b axis by C-H?N hydrogen bonds. Weak C-H?pi and pi-pi inter-actions [centroid centroid distance = 3.5149 (7) A] are also observed. PMID- 21589045 TI - 4-Chloro-2-(6-nitro-1H-benzimidazol-2-yl)phenol N,N-dimethyl-form-amide solvate. AB - In the title compound, C(13)H(8)ClN(3)O(3).C(3)H(7)NO, the benzimidazole and benzene rings make a dihedral angle of 0.63 (11) degrees . An intra-molecular O H?N hydrogen bond generates an S(6) ring motif. The solvent mol-ecule is hydrogen bonded to the benzimidazole mol-ecule by inter-molecular N-H?O and C-H?O hydrogen bonds, generating an R(1) (2)(7) ring motif. In the crystal, the mol-ecules are arranged into parallel layers perpendicular to the c axis and stabilized by weak pi-pi inter-actions [centroid-centroid distances in the range 3.4036 (18)-3.5878 (16) A]. PMID- 21589046 TI - (E)-2-(3-Chloro-benzyl-idene)-5,6-dimeth-oxy-2,3-dihydro-1H-inden-1-one. AB - In the title compound, C(18)H(15)ClO(3), the dihydro-indenone group makes a dihedral angle of 8.56 (6) degrees with the bezene ring. In the crystal, the mol ecules are inter-connected into a three-dimensional network via inter-molecular C H?O hydrogen bonds. Weak C-H?pi and pi?pi [centroid-centroid distances 3.6598 (9) 3.6913 (9) A] inter-actions are also observed. PMID- 21589047 TI - 2-Hy-droxy-3-oct-yloxy-N,N,N-trimethyl-propan-1-aminium bromide. AB - In the title compound, C(14)H(32)NO(2) (+).Br(-), organic cationsstacked parallel to the a axis andbromide anions placed between the head groups of the cations form ionic pairs via weak inter-molecular O-H?Br hydrogen bonds. The octyl chain in the cation adopts an all-trans conformation. The O-CH(2)-CH(-OH)-CH(2) portion of the molecule is disordered over two sets of sites with occupancy factors of 0.57 (3) and 0.47 (3). PMID- 21589048 TI - Flavokavain B from the rhizome of Alpinia mutica Roxb. AB - THE TITLE COMPOUND [SYSTEMATIC NAME: (E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3 phenylprop-2-en-1-one], C(17)H(16)O(4), has an aromatic ring at both ends of the CH= CH-C(=O)- fragment with the -CH=CH- bond in a trans configuration. The phenyl ring is nearly coplanar with this fragment [dihedral angle 4.8 (3) degrees ] as is the hy-droxy-ldimeth-oxy-lphenyl unit [dihedral angle 6.3 (3) degrees ]. The hy-droxy group is the donor in an intra-molecular hydrogen bond to the double bonded O atom. PMID- 21589049 TI - 4-(4-Hydroxybenzoyl)phenol mono-hydrate. AB - The aromatic rings of the title compound, C(13)H(10)O(3).H(2)O, are aligned at dihedral angles of 20.6 (1) and 40.8 (1) degrees with respect to the triangular C(ar-yl)-C(=O)-C(ar-yl) fragment. The hy-droxy groups are each hydrogen-bond donors to separate water mol-ecules, the water mol-ecule itself being hydrogen bonded to one hy-droxy group and one carbonyl group. The water mol-ecule exists in an unusual four-coordinate environment in the resulting layer structure. PMID- 21589050 TI - (3S,4R,4aS,7aR,12bS)-3-Cyclo-propyl-meth-yl-4a,9-dihy-droxy-3-methyl-7-oxo 2,3,4,4a,5,6,7,7a-octa-hydro-1H-4,12-methano-1-benzofuro[3,2-e]isoquinolin-3-ium 2,2,2-trifluoro-acetate methanol solvate. AB - In the title compound, C(21)H(26)F(3)NO(6) (+).CF(3)COO(-).CH(3)OH or S MNTX.CF(3)COO(-).CH(3)OH (MNTX = methyl-naltrexone), the conformation of the polycyclic backbone of the noroxy-morphone skeleton can be simplified in terms of the angles between the least-squares planes of these rings. The dihedral angle between the cyclohexene and piperidine rings is 84.5 (6) degrees , while the dihedral angles between the planes of cyclohexane ring and the benzene, cyclohexene and piperidine rings, respectively, are 85.8 (6),80.0 (7) and 10.3 (7) degrees . In the crystal, mol-ecules are linked by O-H?O hydrogen bonds. The trifluoro-acetate F atoms are disordered in a 0.710 (14):0.710 (14) ratio. The absolute stereochemistry was inferred from the use of (4R,4aS,7aR,12bS)-3-(cyclo propyl-meth-yl)-4a,9-dihy-droxy-2,3,4,4a,5,6-hexa-hydro-1H-4,12-meth-ano benzofuro[3,2-e]isoquinolin-7(7aH)-one as one of the starting materials. PMID- 21589051 TI - N,N-Bis[(2-chloro-6-methyl-quinolin-3-yl)methyl-idene]ethane-1,2-diamine. AB - The title mol-ecule, C(24)H(20)Cl(2)N(4), lies on an inversion center in an extended trans conformation. In the crystal, weak C-H?Cl inter-actions connect the mol-ecules into chains along [010]. PMID- 21589052 TI - 4-[(4-Methyl-benz-yl)amino]-3-[(4-methyl-benz-yl)imino-meth-yl]-2H-chromen-2-one. AB - The title compound, C(26)H(24)N(2)O(2), was prepared from the reaction of 4 chloro-3-formyl-coumarin with p-methyl-benzyl-amine. Even though there are no strong and specific inter-actions in the crystal structure, the translationally related mol-ecules form chains along the b axis. The coumarin moieties are stacked through pi-pi inter-actions [centroid-centroid distance = 3.5275 (7) A], forming layers perpendicular to the stacking direction. PMID- 21589053 TI - (Z)-N-[3-(Phenyl-sulfon-yl)thia-zolidin-2-yl-idene]cyanamide. AB - In the title compound, C(10)H(9)N(3)O(2)S(2), the dihedral angle between the benzene and thia-zolidine rings is 79.8 (2) degrees . Inter-molecular C-H?N and C H?O inter-actions help to stabilize the crystal structure. PMID- 21589054 TI - 3-(Pyridin-2-yl)coumarin. AB - In the title compound, C(14)H(9)NO(2), the dihedral angle between the pyridine ring and the lactone ring is 10.40 (3) degrees . The coumarin ring system is nearly planar, with a dihedral angle of 1.40 (2) degrees between the lactone and benzene rings. An intra-molecular C-H?O hydrogen bond occurs. In the crystal, inversion dimers linked by pairs of C-H?O inter-actions occur, generating R(2) (2)(14) loops. PMID- 21589055 TI - 4,4'-[Oxalylbis(azanediyl)]dipyridinium bis(perchlorate). AB - In the title molecular salt, C(12)H(12)N(4)O(2) (2+).2ClO(4) (-), the complete cation is generated by crystallographic inversion symmetry. In the crystal, the cations and anions are linked via N-H?O and N-H?(O,O) hydrogen bonds, forming a three-dimensional framework. PMID- 21589056 TI - (E)-N-(2,4-Dimeth-oxy-benzyl-idene)-4-ethoxyaniline. AB - In the title compound, C(17)H(19)NO(3), the mol-ecule has an E configuration with respect to the C=N bond and the dihedral angle between the aromatic rings is 56.07 (5) degrees . In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds occur. The dimers are linked by weak C-H?pi inter-actions, forming a three-dimensional network. PMID- 21589057 TI - (E)-2-(3,4-Dimeth-oxy-benzyl-idene)-5,6-dimeth-oxy-2,3-dihydro-1H-inden-1-one. AB - In the title compound, C(20)H(20)O(5), the 2,3-dihydro-1H-indene ring system is essentially planar [maximum deviation = 0.010 (1) A] and is inclined at an angle of 4.09 (4) degrees with respect to the phenyl ring. The C=C bond has an E configuration. In the crystal, the mol-ecules are linked into chains propagating in [102] via inter-molecular C-H?O hydrogen bonds. The crystal structure is further consolidated by C-H?pi inter-actions. PMID- 21589058 TI - 2-Amino-5-methyl-pyridinium 1H-pyrazole-3,5-dicarboxyl-ate trihydrate. AB - In the title compound, 2C(6)H(9)N(2) (+).C(5)H(2)N(2)O(4) (2-).3H(2)O, the 1H pyrazole-3,5-dicarboxyl-ate anion is close to planar [maximum deviation = 0.208 (1) A]. The two distinct 2-amino-5-methyl-pyridinium cations are also almost planar, with maximum deviations of 0.018 (2) and 0.014 (2) A. In the crystal, pairs of inter-molecular N-H?O and O-H?O hydrogen bonds connect neighbouring mol ecules into dimers, generating R(2) (2)(8) and R(2) (4)(8) ring motifs, respectively. Further inter-molecular N-H?O, O-H?O and C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21589059 TI - (E)-2-[4-(Piperidin-1-yl)benzyl-idene]-2,3-dihydro-1H-inden-1-one. AB - In the title compound, C(21)H(21)NO, the indene ring system is essentially planar with a maximum deviation of 0.066 (1) A and makes dihedral angles of 7.93 (6) and 2.43 (6) degrees , respectively, with the benzene plane and the mean plane of the piperidine ring. These latter two planes make a dihedral angle of 7.61 (7) degrees . In the crystal, mol-ecules are linked by C-H?O inter-actions, forming infinite chains along the b axis. PMID- 21589060 TI - N-(4-Bromo-phen-yl)urea. AB - In the title compound, C(7)H(7)BrN(2)O, both the urea moiety [maximum deviation 0.003 (2) A] and the benzene ring are essentially planar [maximum deviation 0.003 (2) A] but are rotated with respect to each other by a dihedral angle of 47.8 (1) degrees . The crystal assembly is stabilized by N-H?O hydrogen bonds between all NH protons as conventional hydrogen bond donors and the C=O oxygen as a trifurcated hydrogen-bond acceptor. Both the overall mol-ecular geometry and the crystal packing of the title compound are very similar to those of N-phenyl-urea, which is underscored by a practically isostructural relationship between these two urea derivatives. PMID- 21589061 TI - syn-Dispiro-[1,3-dioxolane-2,17'-penta-cyclo-[12.2.1.1.0.0]octa-decane-18',2'' [1,3]dioxolane]-7',15'-diene. AB - The title compound, C(22)H(28)O(4), is composed of a central octa-decane ring and two spiro-[bicyclo-[2.2.1]hept[2]ene-7,2'-[1,3]dioxolane] units. This polycycle has pseudo twofold symmetry and the central cyclo-octane ring has a distorted boat configuration. PMID- 21589062 TI - N,N-Bis(diphenyl-phosphanyl)cyclo-propyl-amine. AB - In the title compound, C(27)H(25)NP(2), the diphenyl-phosphino groups are staggered relative to the PNP backbone. The dihedral angles between the phenyl rings bonded to each P atom are 51.74 (5) and 68.23 (4) degrees . The coordination around the N atom deviates from trigonal-pyrimidal geometry towards an almost planar arrangement between the N atom and the adjacent P and C atoms; the distance between the N atom and the plane formed by the adjacent C/P/P atoms is 0.098 (2) A. PMID- 21589063 TI - 2,5-Dimethyl-7,8,9,10-tetra-hydro-cyclo-hepta-[b]indol-6(5H)-one. AB - In the title mol-ecule, C(15)H(17)NO, the dihedral angle between the benzene and pyrrole rings is 1.45 (13) degrees . The cyclo-heptene ring adopts a slightly distorted boat conformation. In the crystal structure, inter-molecular C-H?O hydrogen bonds are found. PMID- 21589064 TI - N,N'-Bis[(E)-(5-chloro-2-thienyl)methyl-idene]ethane-1,2-diamine. AB - The full mol-ecule of the title compound, C(12)H(10)Cl(2)N(2)S(2), is generated by the application of a centre of inversion. The thio-phene and imine residues are co-planar [the N-C-C-S torsion angle is -2.5 (4) degrees ] and the conformation about the imine bond [1.268 (4) A] is E. Supra-molecular arrays are formed in the bc plane via C-Cl?pi inter-actions and these stack along the a axis. PMID- 21589065 TI - N,N'-Bis[(E)-(3-methyl-2-thienyl)methyl-idene]ethane-1,2-diamine. AB - Two independent half-mol-ecules, each being completed by inversion symmetry, comprise the asymmetric unit of the title compound, C(14)H(16)N(2)S(2). The major difference between the mol-ecules is found in the central C-C bond [the C-N-C-C torsion angles are 114.66 (18) and 128.94 (18) degrees in the two mol-ecules]. The thio-phene and imine groups are almost co-planar in each case [S-C-C-N torsion angles = -6.9 (2) and -3.6 (2) degrees ]. In the crystal, the mol-ecules aggregate into supra-molecular chains via C-H?pi inter-actions. PMID- 21589066 TI - 1,2,4,5-Tetra-fluoro-3,6-diiodo-benzene-2,3-bis-(pyridin-2-yl)pyrazine (1/1). AB - The components of the title 1:1 co-crystal, C(14)H(10)N(4).C(6)F(4)I(2), are connected via an N?I [2.959 (4) A] halogen bond, in which the N atom is part of the relatively electron-rich pyrazine ring. The C(6)F(4)I(2) mol-ecule is almost planar [r.m.s. deviation = 0.038 A] but there are significant twists in the pyrazine derivative, as seen in the dihedral angles [31.3 (2) and 54.6 (2) degrees ] formed between the pendant pyridyl rings and the central pyrazine ring. The bimolecular aggregates are sustained in the crystal by C-H?F and pi-pi inter actions [ring centroid(pyrid-yl)-ring centroid(benzene) = 3.678 (3) A]. PMID- 21589067 TI - N-(2-Chloro-eth-yl)pyrazine-2-carboxamide. AB - In the title mol-ecule, C(7)H(8)ClN(3)O, the pyrazine and amide groups are almost co-planar [N-C-C-N torsion angle = -2.4 (2) degrees ], a conformation stabilized by an intra-molecular N-H?N hydrogen bond. The chloro-ethyl group lies out of the plane [N-C-C-Cl = -65.06 (17) degrees ]. In the crystal, the presence of N-H?N hydrogen bonds leads to the formation of a C(6) supra-molecular chain along the b axis. The carbonyl-O atom accepts two C-H?O inter-actions. These, plus Cl?Cl short contacts [3.3653 (6) A], consolidate the packing of the chains in the crystal. PMID- 21589068 TI - 2-(2,5-Dichloro-benzene-sulfonamido)-3-methyl-butanoic acid. AB - The structure of the title compound, C(11)H(13)Cl(2)NO(4)S, shows one sulfonamide O atom to lie almost in the plane of the benzene ring [C-C-S-O = -178.7 (2) degrees ] and the other to one side [C-C-S-O = -49.4 (3) degrees ]. Lying to the other side is the amine residue, which occupies a position almost perpendicular to the plane [C-S-N-C = 70.2 (2) degrees ]; the carb-oxy-lic acid group is orientated to lie over the benzene ring. In the crystal, the appearance of an 11 membered {?OH?OCOH?OC(2)NH} synthon, which features the hy-droxy group forming both donor (to a carbonyl-O) and acceptor (from the amine-H) inter-actions, leads to the formation of a supra-molecular chain along the a axis. Chains are connected in the crystal structure by C-H?O contacts. PMID- 21589069 TI - 2',3,4,4',5-Penta-meth-oxy-chalcone. AB - In the title chalcone [systemetic name 1-(2,4-dimeth-oxy-phen-yl)-3-(3,4,5 trimeth-oxy-phen-yl)prop-2-en-1-one], C(20)H(22)O(6), the dihedral angle between the plane of the two benzene rings is 7.03 (4) degrees with all but one of the meth-oxy groups essentially co-planar with these rings [C-C-O-C torsion angles = 76.1 (2), -0.7 (3), 1.8 (3), -6.2 (3), 2.0 (3) degrees ]. An intra-molecular C H?O inter-action occurs. The crystal packing is stabilized by weak inter molecular C-H?O hydrogen bonds. PMID- 21589070 TI - Dimethyl 2,6,8-trimethyl-1,2-dihydroquinoline-2,4-dicarboxylate. AB - The title compound, C(16)H(19)NO(4), the hydrogenated ring adopts a twisted conformation. In the crystal, inter-molecular C-H?O hydrogen bonds link the mol ecules into centrosymmetric R(2) (2)(10) dimers. These dimers are further connected via inter-molecular N-H?O hydrogen bonds, forming infinite double chains along [001]. PMID- 21589071 TI - Ethyl-enediammonium bis-(3,4-dihy-droxy-benzoate) monohydrate. AB - In the title compound, C(2)H(10)N(2) (2+).2C(7)H(5)O(4) (-).H(2)O, the cation lies on a centre of symmetry. The crystal structure is stabilized by various inter-molecular O-H?O and N-H?O hydrogen bonds, and by weak pi-pi stacking inter actions with centroid-centroid distances between symmetry-related benzene rings ranging from 3.5249 (13) to 3.7566 (14) A. PMID- 21589072 TI - 17beta-Hy-droxy-17alpha-(hy-droxy-meth-yl)estr-4-en-3-one. AB - The title compound, C(19)H(28)O(3), the fungal-transformed metabolite of the steroid methyl-oestrenol contains four fused rings A, B, C and D. Ring A adopts a half-chair and the trans-fused rings B and C adopt chair confirmations; the five membered D ring is folded like an envelope. In the crystal, adjacent mol-ecules are linked by O-H?O(carbon-yl) and O-H?O(hy-droxy) hydrogen bonds into a layer structure. PMID- 21589073 TI - (Phen-yl)(1-phenyl-sulfonyl-1H-indol-3-yl)methanone. AB - In the title compound, C(21)H(15)NO(3)S, the sulfonyl-bound phenyl ring forms a dihedral angle of 86.28 (5) degrees with the indole ring system. The mol-ecular structure is stabilized by intra-molecular C-H?O hydrogen bonds. The crystal packing is stabilized by weak inter-molecular C-H?O and C-H?pi inter-actions. PMID- 21589074 TI - N-[(Piperidin-1-yl)carbothioyl]benz-amide. AB - In the title compound, C(13)H(16)N(2)OS, the piperidine ring exhibit a classical chair conformation. In the crystal, the mol-ecules are linked by N-H?O hydrogen bonds, forming zigzag chains running parallel to the c axis. PMID- 21589075 TI - ent-5alpha,3,15-Dioxodolabr-4(18)-ene-16,18-diol. AB - The title compound, C(20)H(30)O(4), is a dolabrane diterpenoid isolated from Ceriops tagal, in which one of the three fused cyclo-hexane rings adopts a half chair conformation and the other two are in the standard chair conformations. The hy-droxy-methyl-idene substituent is attached to the half-chair cyclo-hexane. An intra-molecular O-H?O hydrogen bond generate an S(6) ring motif. In the crystal, mol-ecules are arranged into screw chains along the [001] direction. The crystal is stabilized by O-H?O hydrogen bonds and weaker C-H?O inter-actions. PMID- 21589076 TI - 6alpha-Hy-droxy-5,6-dihydro-salviasperanol. AB - In the title compound, C(20)H(28)O(4), a diterpenoid isolated from the roots of Premna obtusifolia (Verbenaceae), the five-membered ring is in a half-chair conformation. One six-membered ring exists in a twisted-boat conformation while the other is in half-boat conformation. The crystal packing is stabilized by inter-molecular O-H?O and weak C-H?O inter-actions, generating (001) sheets. PMID- 21589077 TI - Tetra-imidazolium piperazinediium bis-(benzene-1,3,5-tricarboxyl-ate) dihydrate. AB - During the crystallization of the title compound, 4C(3)H(5)N(2) (+).C(4)H(12)N(2) (+).2C(9)H(3)O(6) (3-).2H(2)O, the acidic protons were transferred to the imidazole and piperazine N atoms, forming the final 4:1:2:2 hydrated mixed salt. The mean planes of the three carboxyl-ate groups in the anion are twisted with respect to the the central benzene ring, making dihedral angles of 13.5 (1), 14.5 (1) and 16.9 (1) degrees . In the crystal, the component ions are linked into a three-dimensional network by a combination of inter-molecular N-H?O, O-H?O and weak C-H?O hydrogen bonds. Further stabilization is provided by pi-pi stacking inter-actions with centroid-centroid distances of 3.393 (2) A and weak C=O?pi inter-actions [O-centroid = 3.363 (2) A]. PMID- 21589078 TI - 1,5-Bis(1-phenyl-ethyl-idene)carbonohydrazide. AB - In the title mol-ecule, C(17)H(18)N(4)O, the two phenyl rings form a dihedral angle of 18.15 (17) degrees . In the crystal, pairs of inter-molecular N-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers. Weak inter molecular C-H?O inter-actions further link the dimers into chains running along [010]. PMID- 21589079 TI - 2,7-Dimeth-oxy-1,8-bis-(4-phen-oxy-benzo-yl)naphthalene. AB - In the title mol-ecule {systematic name: [2,7-dimethoxy-8-(4 phenoxybenzoyl)naphthalen-1-yl](4-phenoxyphenyl)methan-one}, C(38)H(28)O(6), the 4-phen-oxy-benzoyl units adopt a syn orientation with respect to the naphthalene ring system. The inter-nal benzene rings, A and B, make dihedral angles of 86.72 (5) and 79.22 (5) degrees with the naphthalene ring system. The two terminal benzene rings, C and D, of the 4-phen-oxy-benzoyl groups are twisted with respect to benzene rings A and B, with dihedral angles of A/C = 62.72 (8) and B/D = 87.61 (6) degrees . In the crystal, H atoms in the naphthalene system make two types of inter-molecular C-H?O inter-actions with the carbonyl O atom and the phenyl etheral O atom of neighbouring mol-ecules. Mol-ecules are further linked by C H?pi inter-actions involving a H atom of terminal benzene ring D and the pi system of the inter-nal benzene ring A, forming dimers centered about an inversion center. PMID- 21589080 TI - 1,8-Bis(4-amino-benzo-yl)-2,7-dimeth-oxy-naphthalene. AB - The title compound {systematic name: [8-(4-aminobenzoyl)-2,7-dimethoxynaphthalen 1-yl](4-aminophenyl)methanone}, C(26)H(22)O(4)N(2), possesses crystallographically imposed twofold symmetry, with two C atoms lying on the rotation axis. In the crystal, the mol-ecules inter-act through inter-molecular N H?O hydrogen bonds between the amino and meth-oxy groups on the naphthalene ring systems and N-H?pi inter-actions between the amino groups and the naphthalene rings. Furthermore, weak C-H?O hydrogen bonds and pi-pi stacking inter-actions between the benzene rings are observed. The centroid-centroid and inter-planar distances between the benzene rings of the aroyl group and the naphthalene ring systems of adjacent mol-ecules are 3.6954 (8) and 3.2375 (5) A, respectively. The dihedral angle between the mean planes of the benzene ring and the naphthalene ring system is 83.59 (5) degrees . The benzene ring and the carbonyl group in the benzoyl unit are almost coplanar [C-C-C-O torsion angle = 175.91 (10) degrees ]. PMID- 21589081 TI - 4-Bromo-methyl-6-meth-oxy-2H-chromen-2-one. AB - The structure of the title coumarin derivative, C(11)H(9)BrO(3), is stabilized by weak inter-molecular C-H?O hydrogen bonds. PMID- 21589082 TI - 8-Hy-droxy-quinolin-1-ium nitrate. AB - In the title salt, C(9)H(8)NO(+).NO(3) (-), the quinoline ring system is essentially planar with a maximum deviation of 0.043 (1) A. In the crystal, an R(2) (2)(7) ring motif is formed by inter-molecular N-H?O and C-H?O hydrogen bonds between the cation and the anion. In addition, inter-molecular O-H?O and C H?O hydrogen bonds link the two ions, generating an R(2) (2)(8) ring motif. These sets of ring motifs are further linked into a ribbon along the a axis via inter molecular C-H?O hydrogen bonds. PMID- 21589083 TI - 4-(4-Fluoro-anilino)-N-(4-fluoro-phen-yl)-3-nitro-benzamide. AB - In the title compound, C(19)H(13)F(2)N(3)O(3), the anilinobenzamide unit is essentially planar, with a maximum deviation of 0.036 (3) A. The nitro group and the benzene ring form dihedral angles of 9.6 (5)and 62.20 (8) degrees , respectively, with the anilinobenzamide unit. An intra-molecular N-H?O inter action occurs. In the crystal, mol-ecules are linked by weak inter-molecular C H?O, N-H?O and C-H?F hydrogen bonds, which stabilize the structure. PMID- 21589084 TI - N-[2-(2-Chloro-phen-yl)-2-hy-droxy-eth-yl]propan-2-aminium benzoate. AB - In the title compound, C(11)H(17)ClNO(+).C(7)H(5)O(2) (-), obtained by the reaction of chlorprenaline {or 1-(2-chlorophenyl)-2-[(1 methylethyl)amino]ethanol} and benzoic acid, the chlorprenaline is twisted moderately [C-C-C-C torsion angle = -76.00 (17) degrees ] compared with related compounds. The mol-ecules as usual form dimers. In the crystal structure, the two components are connected by classical O-H?O and N-H?O hydrogen bonds. PMID- 21589085 TI - (1S,2R,8R)-2,2-Dichloro-3,7,7,10-tetra-methyltricyclo-[6.4.0.0]dodec-10-en-9-one. AB - The title compound, C(16)H(22)Cl(2)O, was synthesized from beta-himachalene, which was isolated from essential oil of the Atlas cedar (cedrus atlantica). The asymmetric unit contains two independent mol-ecules, in each of which the six membered ring shows a half-chair conformation, whereas the seven-membered ring displays a boat conformation. The dihedral angle between the two rings is slightly different in the two mol-ecules [63.22 (13) and 61.81 (14) degrees ]. PMID- 21589086 TI - 2-(Benzothia-zol-2-yl-sulfanyl)-acetic acid. AB - In the title compound, C(9)H(7)NO(2)S(2), the benzine ring is essentially co planar with the thia-zole ring, making a dihedral angle of 0.36 (7) degrees . In the crystal structure, mol-ecules are linked by inter-molecular O-H?N hydrogen bonds between the carb-oxy group and the thia-zole N atom into chains along [10]. The chains are assembled into a supermolecular layer structure by thia-zole ring S?S contacts [3.5679 (7) A]. PMID- 21589087 TI - 2-Methyl-benzimidazolium thio-cyanate. AB - In the crystal structure of the title compound, C(8)H(9)N(2) (+).SCN(-), the nearly planar 2-methyl-benzimidazolium cation [r.m.s. deviation = 0.0123 (4) A] is perpendicular to a mirror plane and the methyl H atoms are disordered about the mirror plane with equal occupancies. The thio-cyanate anion also lies on a mirror plane. N-H?N hydrogen bonds link the components into an infinite chain along the b axis. PMID- 21589088 TI - N'-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazin-3-yl]propanohydrazide. AB - In the title compound, C(10)H(14)N(8)O, the tetra-zine and pyrazole rings form a dihedral angle of 48.81 (2) degrees . In the crystal, inter-molecular N-H?N and N H?O hydrogen bonds link the mol-ecules into layers parallel to (101). PMID- 21589089 TI - Ethyl 4-[(3,5-di-tert-butyl-2-hy-droxy-benzyl-idene)-amino]-benzoate. AB - The title compound, a Schiff base, C(24)H(31)NO(3), has a substituted aromatic ring at both ends of the azomethine linkage and these make a dihedral angle of 24.9 (1) degrees . There is an intra-molecular hydrogen bond between the hy-droxy group (donor) and the N atom of themazomethine linkage. PMID- 21589090 TI - Ethyl 4-[(3,5-di-tert-butyl-2-hy-droxy-benz-yl)amino]-benzoate. AB - The title amine, C(24)H(33)NO(3), has two substituted aromatic rings at either end of the -CH(2)NH- linkage [C(ar-yl)-CH(2)-NH-C(ar-yl) torsion angle = 77.4 (3) degrees ]. The amino and hy-droxy groups are hydrogen-bond donors to the carbonyl O atom of an adjacent mol-ecule. These hydrogen bonds give rise to a chain that runs along the b axis. One of the tert-butyl groups is disordered over two positions with a site-occupation factor of 0.834 (6) for the major occupied site. PMID- 21589091 TI - (5-n-Hexyl-2-hydroxymethyl-1,3-dioxan-2-yl)methanol. AB - In the title compound, C(12)H(24)O(4), the dioxane ring adopts a chair conformation; the n-hexyl chain, which occupies an equatorial position, has an extended zigzag conformation. In the crystal, mol-ecules are connected by O-H?O hydrogen-bonds into a zigzag chain running along the b axis, giving rise to a herringbone pattern. PMID- 21589092 TI - (5-n-Heptyl-2-hydroxymethyl-1,3-dioxan-2-yl)methanol. AB - In the title compound, C(13)H(26)O(4), the dioxane rings adopts a chair conformation; the n-heptyl chain occupies an equatorial position. In the crystal, mol-ecules are connected by O-H?O hydrogen bonds into a zigzag chain running along the a axis, giving rise to a herringbone pattern. There are two independent mol-ecules in the asymmetric unit. PMID- 21589093 TI - 2,2'-Biimidazolium 5-amino-2,4,6-tri-bromo-isophthalate. AB - In the cation of the title salt, C(6)H(8)N(4) (2+).C(8)H(2)Br(3)NO(4) (2-), the dihedral angle between the two five-membered rings is 2.1 (3) degrees . In the anion, the mean planes of the carboxyl units are twisted from the benzene ring by 84.3 (4) and 86.2 (3) degrees . In the crystal, the components are linked by imidazolium-carboxyl-ate N-H?O hydrogen bonds, generating a chain running along [10]. PMID- 21589094 TI - Diethyl-ammonium 4-hy-droxy-benzoate. AB - In the crystal structure of the title compound, C(4)H(12)N(+).C(7)H(5)O(3) (-), the cations and anions are linked by N-H?O and O-H?O hydrogen bonds, leading to the formation of a three-dimensional network. PMID- 21589095 TI - 5-Chloro-2-hy-droxy-benzoic acid. AB - The asymmetric unit of the title compound, C(7)H(5)ClO(3), contains two mol ecules; both feature an intra-molecular O-H?O hydrogen bond, which generates an S(6) ring. In the crystal, both mol-ecules form inversion dimers linked by pairs of O-H?O hydrogen bonds with R(2) (2)(8) ring motifs. The dimers are inter-linked by C-H?O inter-actions. PMID- 21589096 TI - N-(4-Chloro-phen-yl)-2-hy-droxy-benzamide. AB - In the title compound, C(13)H(10)ClNO(2), the dihedral angle between the aromatic rings is 20.02 (6) degrees and intra-molecular N-H?O and C-H?O hydrogen bonds both generate S(6) rings. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds into C(6) chains propagating in [010]. PMID- 21589097 TI - 5-[(E)-(2,6-Dichloro-benzyl-idene)amino]-2-hy-droxy-benzoic acid. AB - There are two geometrically different mol-ecules in the asymmetric unit of the title compound, C(14)H(9)Cl(2)NO(3). The 5-amino-2-hy-droxy-benzoic acid units [r.m.s. deviations of 0.0323 and 0.0414 A] and 2,6-dichloro-benzaldehyde groups [r.m.s. deviations of 0.0285 and 0.0226 A] are roughly planar and oriented at dihedral angles of 11.69 (13) and 83.12 (6) degrees in the two mol-ecules. An intra-molecular O-H?O hydrogen bond completes an S(6) ring motif in each mol ecule. The two mol-ecules form dimers with each other through inter-molecular O H?N and C-H?O hydrogen bonds, completing an R(2) (2)(8) ring motif. The dimers are inter-linked via inter-molecular O-H?N and C-H?O hydrogen bonds, forming polymeric sheets. PMID- 21589098 TI - Benzoic acid-4-{(1E)-[(E)-2-(pyridin-4-yl-methyl-idene)hydrazin-1-yl-idene]meth yl}pyridine (2/1). AB - In the title co-crystal, C(12)H(10)N(4).2C(7)H(6)O(2), the complete 4-pyridine aldazine mol-ecule is generated by a crystallographic centre of inversion. In the crystal, mol-ecules are connected into a three component aggregate via O-H?N hydrogen bonds. As both the benzoic acid [O-C-C-C torsion angle = 174.8 (2) degrees ] and 4-pyridine-aldazine (r.m.s. deviation of the 16 non-H atoms = 0.041 A) mol-ecules are almost planar, the resulting three-component aggregate is essentially planar. The crystal packing comprises layers of the three-component aggregates of alternating orientation stacked along the b axis; the connections between the mol-ecules are of the types C-H?pi and pi-pi [pyridine-benzene centroid-centroid distance = 3.787 (4) A]. PMID- 21589099 TI - Ethyl 2-[5-(4-chloro-phen-yl)-1-(4-fluoro-phen-yl)-1H-pyrazol-3-yl]-4-methyl-thia zole-5-carboxyl-ate. AB - In the title compound, C(22)H(17)ClFN(3)O(2)S, the pyrazole ring is approximately planar with a maximum deviation of 0.001 (4) A and makes dihedral angles of 4.95 (19), 35.78 (18) and 54.73 (18) degrees with the thia-zole, fluoro-benzene and chloro-benzene rings, respectively. In the crystal, inter-molecular C-H?O hydrogen bonds link the mol-ecules into chains along the a axis. PMID- 21589100 TI - 11-[(E)-4-Bromo-benzyl-idene]-8-(4-bromo-phen-yl)-14-hy-droxy-3,13-diaza-hepta cyclo-[13.7.1.1.0.0.0.0]tetra-cosa-1(22),15,17,19(23),20-pentaen-10-one. AB - In the title compound, C(35)H(28)Br(2)N(2)O(2), the piperidone ring adopts a chair conformation and the five-membered ring of the pyrrolidine ring adopts an envelope conformation. The naphthalene ring system makes dihedral angles of 37.12 (8) and 50.62 (9) degrees with the terminal bromo-substituted benzene rings. The dihedral angle between the two bromo-substituted benzene rings is 72.54 (10) degrees . In the crystal, adjacent mol-ecules are connected by a pair of inter molecular C-H?O hydrogen bonds, forming an inversion dimer. An intra-molecular O H?N hydrogen bond is also present. PMID- 21589101 TI - 5-(Pyridin-4-yl)isophthalic acid. AB - In the title compound, C(13)H(9)NO(4), the two carb-oxy-lic groups and the benzene ring are approximately co-planar with a maximum atomic deviation 0.175 (4) A, while the pyridine ring is oriented at a dihedral angle of 31.07 (18) degrees with respect to the benzene ring. In the crystal, mol-ecules are linked by O-H?O, O-H?N and weak C-H?O hydrogen bonds, forming a three-dimensional supra molecular framework. PMID- 21589102 TI - 9-(2,6-Dimethyl-phen-oxy-carbon-yl)-10-methyl-acridinium trifluoro-methane sulfonate. AB - In the crystal structure of the title compound, C(23)H(20)NO(2) (+).CF(3)SO(3) ( ), adjacent cations are linked through a network of C-H?pi and pi-pi inter actions, and neighboring cations and anions via C-H?O inter-actions. The acridine and benzene ring systems are oriented at a dihedral angle of 31.4 (1) degrees . The carboxyl group is twisted at an angle of 66.3 (1) degrees relative to the acridine skeleton. The mean planes of the adjacent acridine moieties are parallel in the crystal structure. PMID- 21589103 TI - 5,5'-Diphenyl-2,2'-[butane-1,4-diylbis(sulfanedi-yl)]bis-(1,3,4-oxadiazole). AB - The complete mol-ecule of the title compound, C(20)H(18)N(4)O(2)S(2), is generated by crystallographic inversion symmetry. The benzene ring is almost coplanar with the oxadiazole ring [dihedral angle = 7.2 (2) degrees ]. PMID- 21589104 TI - rac-6-Hy-droxy-4-(4-nitro-phen-yl)-5-(2-thienyl-carbon-yl)-6-(trifluoro-meth-yl) 3,4,5,6-tetra-hydro-pyrimidin-2(1H)-one monohydrate. AB - The title compound, C(16)H(12)F(3)N(3)O(5)S.H(2)O, was prepared by reaction of 4 nitro-benzaldehyde, 4,4,4-trifluoro-1-(thio-phen-2-yl)butane-1,3-dione and urea. The asymmetric unit contains two independent mol-ecules, with essentially identical geom-etries and conformations. The dihydro-pyrimidine rings adopt a half-chair conformation. The dihedral angles between the benzene ring and the thio-phene ring are 54.82 (8) and 58.72 (8) degrees in the two mol-ecules. The mol-ecular conformation of one of the mol-ecules is stabilized by two intra molecular O-H?O hydrogen bonds, generating an S(6) ring. The crystal structure is stabilized by inter-molecular O-H?O and N-H?O hydrogen bonds. PMID- 21589105 TI - (2R,4R)-3-(tert-But-oxy-carbon-yl)-2-(3-chloro-phen-yl)-1,3-thia-zolidine-4-carb oxy-lic acid monohydrate. AB - In the title compound, C(15)H(18)ClNO(4)S.H(2)O, the thia-zolidine ring displays a half-chair conformation. In the crystal, the water mol-ecules are linked to the organic acid mol-ecules via inter-molecular O-H?O hydrogen bonds. PMID- 21589106 TI - 3'-Hy-droxy-methyl-1'-methyl-3'-nitro-4'-(o-tol-yl)spiro-[indoline-3,2' pyrrolidin]-2-one. AB - The title compound, C(20)H(21)N(3)O(4), crystallizes with two mol-ecules in the asymmetric unit. In both mol-ecules, the pyrrolidine ring adopts an envelope conformation. The crystal structure is stabilized by inter-molecular C-H?O, N-H?O and O-H?O hydrogen bonds. PMID- 21589107 TI - (2E)-1-(3-Bromo-phen-yl)-3-(4,5-dimeth-oxy-2-nitro-phen-yl)prop-2-en-1-one. AB - In the title compound, C(17)H(14)BrNO(5), the dihedral angle between the 3-bromo substituted benzene ring and the 4,5-dimeth-oxy-2-nitro-phenyl ring is 15.2 (1) degrees . The dihedral angles between the mean plane of the propenone group and the mean planes of the 3-bromo-substituted benzene and 4,5-dimeth-oxy-2-nitro phenyl rings are 6.9 (6) and 20.5 (5) degrees , respectively. Weak inter molecular C-H?O inter-actions contribute to crystal stability and pi-pi inter actions [centroid-centroid distances = 3.7072 (18) and 3.6326 (18) A] are also observed. PMID- 21589108 TI - 1-[Phen-yl(pyridin-2-yl-amino)-meth-yl]-2-naphthol. AB - The title compound, C(22)H(18)N(2)O, was synthesized from naphthalen-2-ol, benzaldehyde and pyridin-2-amine. In the crystal, mol-ecules are linked into centrosymmetric R(2) (2)(16) dimers by pairs of O-H?N hydrogen bonds. The mol ecular conformation is stabilized by an N-H?O hydrogen bond. The dihedral angle between the naphthylene ring system and the phenyl ring is 72.86 (12) degrees . PMID- 21589109 TI - (4-Bromo-phen-yl)(2,7-dimeth-oxy-1-naphth-yl)methanone. AB - In the title compound, C(19)H(15)BrO(3), the dihedral angle between the naphthalene ring system and the benzene ring is 72.02 (9) degrees . The bridging carbonyl C-C(=O)-C plane makes dihedral angles of 70.88 (10) and 1.87 (12) degrees , respectively, with the naphthalene ring system and the benzene ring. In the crystal, two types of weak inter-molecular C-H?O inter-actions and a short Br?C contact [3.345 (2) A] are observed. PMID- 21589110 TI - 2-[4-tert-Butyl-5-(2-chloro-benz-yl)-1,3-thia-zol-2-yl]isoindoline-1,3-dione. AB - In the title compound, C(22)H(19)ClN(2)O(2)S, the dihedral angle between the phenyl-ene ring and the phthalimide ring system is 4.4 (1) degrees . There is no hydrogen bonding or pi-pi stacking in the crystal structure. PMID- 21589111 TI - N'-[1-(4-Chloro-phen-yl)ethyl-idene]acetohydrazide. AB - In the title compound, C(10)H(11)ClN(2)O, the dihedral angle between the acetohydrazide group and the aromatic ring is 33.76 (9) degrees . In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(8) loops. PMID- 21589112 TI - N'-(4-Hy-droxy-benzyl-idene)-4-nitro-benzohydrazide. AB - The title compound, C(14)H(11)N(3)O(4), was prepared by the reaction of 4-nitro benzohydrazide with 4-hy-droxy-benz-alde-hyde. The whole mol-ecule of the compound is approximately planar, with a mean deviation from the least-squares plane through all the non-H atoms of 0.050 (2) A; the dihedral angle between the two benzene rings is 2.0 (2) degrees . In the crystal, the benzohydrazide mol ecules are linked through inter-molecular O-H?O and N-H?O hydrogen bonds, forming layers in the bc plane. PMID- 21589113 TI - (E)-2,2-Dimethyl-5-(3-phenyl-allyl-idene)-1,3-dioxane-4,6-dione. AB - The title compound, C(15)H(14)O(4), was prepared by the reaction of 2,2-dimethyl 1,3-dioxane-4,6-dione and (Z)-3-phenyl-acryl-aldehyde in ethanol. The dioxane ring is in a sofa conformation with the C atom bonded to the two methyl groups forming the flap. With the exception of the flap atom and the methyl group C atoms, all other non-H atoms are essentially planar, with an r.m.s. deviation of 0.067 (1) A. The crystal structure is stabilized by weak inter-molecular C-H?O hydrogen bonds. PMID- 21589114 TI - (E)-1-(2-Hy-droxy-4,6-dimeth-oxy-phen-yl)-3-(4-meth-oxy-phen-yl)prop-2-en-1-one from Kaempferia rotunda Val. AB - The planar -CH=CHC(=O)- fragment (r.m.s. deviation = 0.074 A) in the title compound, C(18)H(18)O(5), connects the planar hy-droxy-dimeth-oxy-phenyl (r.m.s. deviation = 0.039 A) and meth-oxy-lphenyl (r.m.s. deviation = 0.021 A) parts. The central fragment forms a dihedral angle of 13.7 (1) degrees with the hy-droxy dimeth-oxy-phenyl part and 32.0 (1) degrees with the meth-oxy-phenyl part. The hy-droxy group forms an intra-molecular hydrogen bond to the carbonyl O atom. PMID- 21589115 TI - [1R-(1alpha,2alpha,4alpha,5beta,6alpha,7alpha)]-4-Benzoyl-oxymethyl-5,6-dihy droxy-3,8-dioxa-tricyclo-[5.1.0.0]octan-5-yl acetate (3-deacetyl-crotepoxide) from Kaempferia rotunda Val. AB - The title compound, C(16)H(16)O(7), isolated from Kaempferia rotunda rhizomes, features a six-membered cyclo-hexane ring that adopts a twisted-boat conformation owing to the presence of two adjacent epoxide attachments that lock in four of the six axial positions. The CH(3)CO(2)- and HO- substituents occupy equatorial positions. However, the bond angles at the ring carbon connected to the C(6)H(5)CO(2)CH(2)- substituent deviate signifcantly from the idealized tetra hedral angles as the carbon atom is part of an epoxide ring. In the crystal, the molecules are linked into chains by O-H?O hydrogen bonds. PMID- 21589116 TI - 2,4-Dichloro-6-[2-meth-oxy-4-(prop-2-en-1-yl)phen-oxy]-1,3,5-triazine. AB - The title compound, C(13)H(11)Cl(2)N(3)O(2), was obtained by the reaction of eugenol and cyanuric chloride. The dihedral angle between the benzene and triazine rings is 87.56 (4) degrees . Two C atoms of the allyl group are disordered over two sites in a 0.72 (2):0.28 (2) ratio. PMID- 21589117 TI - 6-Isopropyl-5-meth-oxy-3-phenyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7(6H)-one. AB - In the title compound, C(14)H(15)N(5)O(2), the whole mol-ecule apart from the terminal C atoms of the isopropyl group is located on a crystallographic mirror plane. An intra-molecular C-H?N hydrogen-bonding inter-action may stabilize the mol-ecular conformation. The crystal packing features weak slipped pi-pi inter actions between the pyrimidine and the phenyl rings of symmetry-related mol ecules [centroid-centroid distance = 3.746 (1)A, slippage of 1.574 A]. PMID- 21589118 TI - 7-Chloro-1,2-dihydro-furo[2,3-c]isoquinolin-5-amine. AB - In the title compound, C(11)H(9)ClN(2)O, the fused-ring system is essentially planar, with a maximum deviation of 0.0323 (16) A. In the crystal, mol-ecules are connected by N-H?O hydrogen bonds forming a zigzag chain along the c axis. Mol ecules are further stacked along the a axis through weak pi-pi inter-actions, the shortest distance between ring centroids being 3.6476 (8) A. PMID- 21589119 TI - 2-Isopropyl-6-methyl-4-oxo-3,4-dihydro-pyrimidin-1-ium 2-carb-oxy-4,6-dinitro phenolate monohydrate. AB - In the title mol-ecular salt, C(8)H(13)N(2)O(+).C(7)H(3)N(2)O(7) (-).H(2)O, the pyrimidinium cation is essentially planar, with a maximum deviation of 0.009 (1) A. The cation undergoes an enol-keto tautomerism during the crystallization. In the crystal, the ion pairs and water mol-ecules are connected via O-H?O, N-H?O and C-H?O hydrogen bonds, forming two-dimensional networks parallel to the bc plane. There is an intra-molecular O-H?O hydrogen bond in the 3,5-dinitro salicylate anion, which generates an S(6) ring motif. PMID- 21589120 TI - N'-(4-Fluoro-benzyl-idene)acetohydrazide. AB - The title compound, C(9)H(9)FN(2)O, was prepared by the reaction of 4-fluoro benzophenone and acethydrazide. In the mol-ecule, all non-H atoms are essentially coplanar [r.m.s. deviation = 0.065 (2) A]. In the crystal, mol-ecules are linked into centrosymmetric dimers by pairs of inter-molecular N-H?O hydrogen bonds. PMID- 21589121 TI - Ammonium (E)-3-(4-hy-droxy-3-meth-oxy-phen-yl)prop-2-enoate monohydrate. AB - In structure of the title compound ammonium ferulate monohydrate, NH(4) (+).C(10)H(9)O(4) (-).H(2)O, O-H?O and N-H?O hydrogen bonds link the ammonium cations, ferulate anions and water mol-ecules into a three-dimensional array. The ferulate anion is approximately planar, with a maximum deviation of 0.307 (2) A. PMID- 21589122 TI - Triflumizole. AB - In the title compound {systematic name: 4-chloro-N-[1-(1H-imidazol-1-yl)-2 propoxyethyl-idene]-2-(trifluoro-meth-yl)aniline}, C(15)H(15)ClF(3)N(3)O, the dihedral angle between the aniline and imidazole ring planes is 81.80 (4) degrees . In the crystal structure, weak inter-molecular C-H?X (X = N, O or F) hydrogen bonds and C-H?pi inter-actions help to consolidate the packing. PMID- 21589123 TI - N-(2-Chloro-pyrimidin-4-yl)-N,2-di-methyl-2H-indazol-6-amine. AB - In the title compound, C(13)H(12)ClN(5), which is a derivative of the anti-tumor agent pazopanib {systematic name: 5-[[4-[(2,3-di-methyl-2H-indazol-6 yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide}, the indazole and pyrim-idine fragments form a dihedral angle of 62.63 (5) degrees . In the crystal, pairs of mol-ecules related by twofold rotational symmetry are linked into dimers through pi-pi inter-actions between the indazole ring systems [centroid-centroid distance = 3.720 (2) A]. Weak inter-molecular C-H?N hydrogen bonds further assemble these dimers into columns propagated in [001]. PMID- 21589124 TI - 2-(5-Bromo-2-methyl-phen-yl)propan-2-ol. AB - The title compound, C(10)H(13)BrO, crystallizes with four independent mol-ecules of similar geometry in the asymmetric unit. The crystal packing is stabilized by inter-molecular O-H?O hydrogen bonds, which link the mol-ecules into tetra-mers. PMID- 21589125 TI - (4-Bromo-phen-yl)(1-phenyl-sulfonyl-1H-indol-2-yl)methanone. AB - In the title compound, C(21)H(14)BrNO(3)S, the indole ring system forms dihedral angles of 65.64 (8) and 59.30 (8) degrees , respectively, with the phenyl and bromo-phenyl rings. In the crystal, mol-ecules are connected by a C-H?O hydrogen bond, forming a chain along [101]. The chains are further connected by weak inter molecular C-H?pi inter-actions, forming a layer parallel to the ac plane. PMID- 21589126 TI - 7-(4-Methyl-phen-yl)cyclo-penta-[a]quinolizine-10-carbaldehyde. AB - In the title compound, C(20)H(15)NO, the heterotricycle is essential planar [maximum deviation = 0.0790 (5) A] and makes a dihedral angle of 50.70 (2) degrees with the benzene ring. The formyl group is almost coplanar with the tricyclic ring, the C-C-C-O torsion angle being -0.78 (13) degrees . PMID- 21589127 TI - 3-(4-Cyano-phen-yl)-N-phenyl-oxirane-2-carboxamide. AB - The asymmetric unit of the crystal structure of the title compound, C(16)H(12)N(2)O(2), contains two independent mol-ecules. In each mol-ecule, the two aromatic rings adopt a cis configuration about the central epoxide ring, and are oriented at dihedral angles of 61.5 (5) and 74.4 (5) degrees with respect to the epoxide ring in one mol-ecule, and 60.1 (5) and 72.1 (5) degrees in the other one. Inter-molecular classical N-H?O and weak C-H?O hydrogen bonds are present in the crystal structure. PMID- 21589128 TI - 5-Bromo-2-(4-chloro-phen-yl)-3-ethyl-sulfinyl-7-methyl-1-benzofuran. AB - In the title compound, C(17)H(14)BrClO(2)S, the 4-chloro-phenyl ring makes a dihedral angle of 13.42 (4) degrees with the mean plane of the benzofuran ring. In the crystal, pairs of inter-molecular Br?O contacts [3.125 (1) A] link the mol ecules into centrosymmetric dimers, which are further linked via inter-molecular C-H?O hydrogen bonds. PMID- 21589129 TI - 3-Bromo-1-(3-chloro-pyridin-2-yl)-N-(4-eth-oxy-phen-yl)-1H-pyrazole-5-carbox amide. AB - In the title compound, C(17)H(14)BrClN(4)O(2), the pyrazole ring is almost coplanar with the benzene ring [dihedral angle = 0.5 (2) degrees ], whereas the pyrazole ring is close to perpendicular to the 3-chloro-pyridine ring [dihedral angle = 73.7 (2) degrees ]. An intra-molecular C-H?O hydrogen bond occurs. The dominant inter-action in the crystal packing is an N-H?N hydrogen bond, which generates a chain along the c axis. Weak inter-molecular C-H?O and C-H?N contacts are also observed. PMID- 21589130 TI - (Dimeth-oxy-phosphor-yl)(furan-2-yl)methyl 2-(2,4-dichloro-phen-oxy)acetate. AB - In the title compound, C(15)H(15)Cl(2)O(7)P, the benzene and furan rings form a dihedral angle of 73.54 (1) degrees . In the crystal, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into layers parallel to (100). PMID- 21589131 TI - 2-Chloro-N-(4-meth-oxy-phen-yl)benzamide. AB - In the title compound, C(14)H(12)ClNO(2), the chloro- and meth-oxy-substituted benzene rings are close to orthogonal [dihedral angle = 79.20 (3) degrees ]. These rings also make angles of 45.9 (3) and 33.5 (3) degrees with the amide CONH- unit. The meth-oxy substituent lies close to the meth-oxy-benzene ring plane, with a maximum deviation of 0.142 (3) A for the methyl C atom. The N-H bond is anti to the 2-chloro substituent of the aniline ring. In the crystal structure, inter-molecular N-H?O hydrogen bonds form C(4) chains augmented by a weak C-H?O inter-action involving an ortho H atom of the meth-oxy benzene ring that generates an R(2) (1)(6) motif. The chains stack the mol-ecules into columns down the b axis. Adjacent columns are linked by additional C-H?O and C-H?pi contacts, generating a three-dimensional network. PMID- 21589132 TI - 2-(1,2,3,4-Tetra-hydro-9H-carbazol-1-yl-idene)propane-dinitrile. AB - In the title compound, C(15)H(11)N(3), the cyclo-hexene ring adopts a sofa conformation. An intra-molecular N-H?N hydrogen bond generates an S(7) ring motif. In the crystal, mol-ecules are linked by inter-molecular N-H?N, C-H?N and C-H?pi inter-actions into a three-dimensional network. PMID- 21589133 TI - Ethyl 3-{[(3-methyl-anilino)(1H-1,2,4-triazol-1-yl)methyl-idene]amino}-1 benzofuran-2-carboxyl-ate. AB - The crystal structure of the title compound, C(21)H(19)N(5)O(3), is stabilized by inter-molecular N-H?N and C-H?O hydrogen bonds. The mol-ecule contains a planar [maximum deviations = -0.026 (1) and 0.027 (2) A] benzofuran ring system, which forms dihedral angles of 78.75 (8) and 39.78 (7) degrees with the benzene and triazole rings, respectively. PMID- 21589134 TI - rac-2-Hy-droxy-2-(2-oxocyclo-pent-yl)-1H-indene-1,3(2H)-dione. AB - In the title compound, C(14)H(12)O(4), the indene unit is essentially planar [r.m.s. deviation = 0.0309 (1) A] and the cyclo-penta-none ring adopts a twist form. In the crystal, mol-ecules are joined via pairs of O-H?O hydrogen bonds into centrosymmetric dimers. PMID- 21589135 TI - 1,5-Bis[1-(2,4-dihy-droxy-phen-yl)ethyl-idene]carbonohydrazide dimethyl-formamide disolvate. AB - In the title compound, C(17)H(18)N(4)O(5).2C(3)H(7)NO, two solvent mol-ecules are linked to the main mol-ecule via N-H?O and O-H?O hydrogen bonds, forming a hydrogen-bonded trimer. Intra-molecular O-H?N hydrogen bonds influence the mol ecular conformation of the main mol-ecule, and the two benzene rings form a dihedral angle of 10.55 (18) degrees . In the crystal, inter-molecular O-H?O hydrogen bonds link hydrogen-bonded trimers into ribbons extending along the b axis. PMID- 21589136 TI - 2-[2-(1,3-Dioxoisoindolin-2-yl)acetamido]-acetic acid. AB - The title mol-ecule, C(12)H(10)N(2)O(5), is non-planar with dihedral angles of 89.08 (7) and 83.21 (7) degrees between the phthalimide and acetamide mean planes, and the acetamide and acetic acid mean planes, respectively. In the crystal, symmetry-related mol-ecules are linked via N-H?O and O-H?O hydrogen bonds, forming an undulating two-dimensional network. There are also a number of weak C-H?O inter-actions, leading to the formation of a three-dimensional arrangement. PMID- 21589137 TI - 4-(Phenyl-sulfan-yl)benzene-1,2-dicarbonitrile. AB - In the title compound, C(14)H(8)N(2)S, the dicyano-substituted aromatic ring and the phenyl ring attached to the central S atom adopt an angular V-shaped configuration. The dihedral angle between the rings is 103.6 degrees . PMID- 21589138 TI - Ethyl 3-[2-(p-tolyl-carbamothio-yl)hydrazinyl-idene]butano-ate. AB - The title compound, C(14)H(19)N(3)O(2)S, was obtained from a condensation reaction of N-(p-tol-yl)hydrazinecarbothio-amide and ethyl acetoacetate. The mol ecule assumes an E configuration; the thio-semicarbazide and ester groups are located on the opposite sides of the C=N bond. The almost planar thio semicarbazide unit (r.m.s. deviation = 0.0130 A) is tilted at a dihedral angle of 49.54 (12) degrees with respect to the benzene ring. Inter-molecular N-H?N and N H?S hydrogen bonding stabilizes the crystal structure. The eth-oxy group of the ester unit is disordered over two positions, with a site-occupancy ratio of 0.680 (10):0.320 (10). PMID- 21589139 TI - (2,7-Dimeth-oxy-naphthalen-1-yl)(3-nitro-phen-yl)methanone. AB - The title compound, C(19)H(15)NO(5), has an intra-molecular C-H?O=C hydrogen bond between a naphthalene H atom and the O atom of the carbonyl group. The inter planar angle between the naphthalene ring system and the benzene ring is 69.59 (5) degrees . The dihedral angle between the bridging carbonyl C-C(=O)-C plane and the naphthalene ring system is 61.02 (6) degrees , which is far larger than that between the bridging carbonyl plane and the benzene ring [12.68 (7) degrees ]. The nitro group is slightly out of the plane of the benzene ring [O-N-C-C torsion angle = 4.97 (17) degrees ]. In the crystal, the packing is mainly stabilized by C-H?O inter-actions between an H atom of the benzene ring and an O atom of the nitro group. PMID- 21589140 TI - N-[11-(4-Chloro-phen-yl)-11,12-dihydro-benzo[c]phenanthridin-6-yl]benzamide. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(30)H(21)ClN(2)O, which differ slightly in the orientation of the unsubstituted phenyl ring. Inter-molecular C-H?pi inter-actions stabilize the crystal structure. The crystal studied was found to be a racemic twin. The dihedral angles between the substituted phenyl ring and the benzo[c]phenanthridine system are 87.13 (5) and 79.25 (5) degrees in the two molecules. PMID- 21589141 TI - Dimethyl 4,4'-(pyridine-2,6-diyl)dibenzoate. AB - The title mol-ecule, C(21)H(17)NO(4), reveals axial symmetry, with the pyridine N atom located on a crystallographic twofold axis. The mol-ecule is dish-shaped, with dihedral angles between the benzene and pyridine rings of 24.643 (1) and 24.797 (1) degrees , respectively. The -COO plane and the benzene ring are almost coplanar [dihedral angle = 5.286 (1) degrees ]. PMID- 21589142 TI - N-(2-Meth-oxy-phen-yl)-4-methyl-benzene-sulfonamide. AB - In the title compound, C(14)H(15)NO(3)S, the geometry around the S atom of the SO(2) group is distorted tetra-hedral. The meth-oxy- and methyl-substituted aromatic rings are oriented at a dihedral angle of 71.39 (9) degrees . Inter molecular N-H?O hydrogen bonds form inversion dimers, which stabilize the crystal structure. PMID- 21589143 TI - 2-[(2-Bromo-phen-yl)imino-meth-yl]-6-methyl-phenol. AB - In the title compound, C(14)H(12)BrNO, is a Schiff base which adopts the phenol imine tautomeric form in the solid state. The dihedral angle between the two aromatic rings is 34.26 (9) degrees and an intra-molecular O-H?N hydrogen bond generates an S(6) ring. PMID- 21589144 TI - 2,4-Bis(2-methyl-phen-yl)-3-aza-bicyclo[3.3.1]nonan-9-one O-methyl-oxime. AB - The mol-ecule of the title compound, C(23)H(28)N(2)O, exists in a twin-chair conformation, with equatorial orientation of the ortho-tolyl groups on both sides of the secondary amino group. The title oxime compound and its ketone precursor 2,4-bis-(2-methyl-phen-yl)-3-aza-bicyclo-[3.3.1]nonan-9-one exhibit similar stereochemistries, with the orientation of the o-tolyl rings almost identical in both compounds. In the title compound, the tolyl rings are at an angle of 23.77 (3) degrees with respect to one another; the angle in the precursor is 29.4 (1) degrees [Vijayalakshmi, Parthasarathi, Venkatraj & Jeyaraman (2000 ?), Acta Cryst. C56, 1240-1241]. The cyclo-hexane ring and the oxime ether are disordered over two alternative orientations, with a refined site-occupancy ratio of 0.813 (2):0.186 (4). The crystal structure of the title compound is stabilized by inter molecular N-H?pi inter-actions. PMID- 21589145 TI - 2-(2-Oxothio-lan-3-yl)isoindoline-1,3-dione. AB - In the title compound, C(12)H(9)NO(3)S, the isoindoline-1,3-dione group is almost planar, with an r.m.s. deviation of 0.020 A, whereas the heterocyclic ring approximates to an envelope with the methyl-ene group not adjacent to the S atom in the flap position. A short intra-molecular C-H?O contact generates an S(6) ring motif. In the crystal structure, weak aromatic pi-pi stacking inter-actions occur between the centroids of the benzene rings at a distance of 3.558 (2) A. PMID- 21589146 TI - N-Benzyl-N-(2-meth-oxy-phen-yl)benzene-sulfonamide. AB - In the title mol-ecule, C(20)H(19)NO(3)S, the dihedral angle between the phenyl rings is 48.93 (18) degrees , and they make dihedral angles of 38.37 (17) and 86.50 (19) degrees with the benzene ring. A weak intra-molecular C-H?O inter action might stabilize the mol-ecular conformation. In the crystal, weak pi-pi stacking inter-actions between the benzene rings [centroid-centroid distance = 3.774 (2) A] may help to establish the packing. PMID- 21589147 TI - 5-Chloro-2-hy-droxy-benzaldehyde thio-semicarbazone. AB - In the title compound, C(8)H(8)ClN(3)OS, the whole mol-ecule assumes a planar structure, with an r.m.s. deviation of 0.108 (2) A, and an intra-molecular O-H?N hydrogen bond generates and S(6) and ring motif. In the crystal structure, each of two pairs of inter-molecular N-H?S hydrogen bonds connects two mol-ecules, forming inversion dimers with R(2) (2)(8) motifs. PMID- 21589148 TI - N'-[(E)-2-Hy-droxy-5-meth-oxy-benzyl-idene]pyridine-4-carbohydrazide. AB - In the title compound, C(14)H(13)N(3)O(3), the dihedral angle between the pyridine and benzene rings is 15.17 (18) degrees . The torsion angle of the -C=N N-C- system between two aromatic rings is -167.1 (3) degrees . Intra-molecular O H?N hydrogen bonding generates S(6) rings. In the crystal structure, neighbouring mol-ecules are linked together along the c axis by weak inter-molecular C-H?O and N-H?O hydrogen bonds, generating R(1) (2)(6) ring motifs. PMID- 21589149 TI - 1,5-Dimethyl-3-[(3-phenyl-4,5-dihydro-1,2-oxazol-5-yl)meth-yl]-1H-1,5 benzodiazepine-2,4(3H,5H)-dione. AB - The reaction of 3-allyl-1,5-dimethyl-1,5-benzodiazepine-2,4-dione and benzaldoxime leads to the title compound, C(21)H(21)N(3)O(3). The mol-ecular structure is built up from two fused six- and seven-membered rings linked to a chain including a five- and six-membered ring (isoxazoline and phen-yl) via a methyl-ene group. The seven-membered ring displays a boat conformation. The dihedral angle between the two six-membered rings is 74.3 (1) degrees . PMID- 21589150 TI - 1-Benz-yloxy-4-(2-nitro-ethen-yl)benzene. AB - The title compound, C(15)H(13)NO(3), crystallizes with three independent mol ecules per asymmetric unit (Z' = 3). One of these mol-ecules is found to have a configuration with a greater twist between its two aromatic rings than the other two [compare 70.26 (13) and 72.31 (12) degrees with 84.22 (12) degrees ]. There are also differences in the number and nature of the weak inter-molecular C-H?O contacts formed by each of the three mol-ecules. PMID- 21589151 TI - Isopropyl 4-chloro-3,5-dinitro-benzoate. AB - In the title compound, C(10)H(9)ClN(2)O(6), the two nitro groups and the ester group are oriented with respect to the benzene ring at dihedral angles of 49.42 (13)/87.61 (13) and 9.10 (10) degrees , respectively. In the crystal structure, a weak C-H?O inter-action is present. A short Cl?O contact of 2.972 (2) A is also observed in the crystal structure. PMID- 21589152 TI - [2-Cyclo-propyl-4-(4-fluoro-phenyl)quinolin-3-yl]methanol. AB - The title compound, C(19)H(16)FNO, crystallizes with two independent mol-ecules in the asymmetric unit. In the two mol-ecules, the dihedral angles between the benzene and quinoline rings are 72.6 (5) and 76.2 (5) degrees , between the cyclo propane and quinoline rings they are 65.2 (5) and 66.0 (5) degrees , and between the benzene and cyclo-propane rings they are 25.9 (5) and 33.9 (5) degrees . There are inter-molecular O-H?O, O-H?N and C-H?O hydrogen bonds, as well as intra molecular C-H?O hydrogen bonds, which may be effective in stabilizing the crystal structure. PMID- 21589153 TI - (-)-(S)-N,N'-Bis[1-(1-naphth-yl)eth-yl]-oxalamide. AB - The title mol-ecule, C(26)H(24)N(2)O(2), displays C(2) symmetry, with the mol ecule located on a twofold axis perpendicular to the plane of the oxalamide unit NH-CO-CO-NH-. The oxalamide core deviates from planarity, as reflected by the O=C C=O and N-C-C-N torsion angles of 164.3 (5) and 163.2 (5) degrees , respectively. The naphthyl groups are oriented toward the same face of the oxalamide mean plane and make a dihedral angle of 43.76 (8) degrees . This conformation is suitable for the formation of inter-molecular N-H?O hydrogen bonds, giving noncentrosymmetric dimers incorporating R(2) (2)(10) ring motifs. These nonbonding inter-actions propagate along the 6(1) screw axis normal to the mol ecular twofold axis, resulting in a single-stranded right-handed helix parallel to [001]. In the crystal, Delta helices are arranged side-by-side and inter-act through pi-pi contacts between naphthyl groups. The shortest centroid-centroid separation between inter-acting benzene rings is 3.623 (4) A. PMID- 21589154 TI - 5-(4-Nitro-benz-yl)-1H-1,2,3,4-tetra-zole. AB - In the title compound, C(8)H(7)N(5)O(2), the dihedral angle between the benzene and tetra-zole rings is 63.13 (8) degrees . The crystal structure exhibits inter molecular N-H?N hydrogen bonds which lead to the formation of one-dimensional chains along the [010] direction. PMID- 21589155 TI - 6-Butyl-5-(4-methyl-phen-oxy)-3-phenyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7(6H) one. AB - In the title compound, C(21)H(21)N(5)O(2), the triazolopyrimidine ring system is essentially planar [maximum displacement = 0.021 (4) A] and forms dihedral angles of 41.17 (9) and 67.99 (8) degrees with the phenyl and benzene rings, respectively. The n-butyl side chains is disordered over two positions with an ccupancy ratio of 0.77:0.23. An intra-molecular C-H?O hydrogen-bonding inter action stabilizes the mol-ecular conformation. In the crystal, mol-ecules are linked by inter-molecular C-H?O and C-H?N hydrogen bonds into a three-dimensional network. In addition, pi-pi stacking inter-actions involving the triazole and pyrimidine rings of adjacent mol-ecules are observed, with centroid-centroid distances of 3.545 (1) A. PMID- 21589156 TI - 2-[(E)-4-(Dimethyl-amino)-styr-yl]-1-methyl-pyridinium 4-chloro-benzene-sulfonate monohydrate. AB - In the title hydrated mol-ecular salt, C(16)H(19)N(2) (+).C(6)H(4)ClO(3)S( ).H(2)O, the 2-[4-(dimethyl-amino)-styr-yl]-1-methyl-pyridinium cation exists in an E configuration with respect to the C=C bond and is slightly twisted, with the dihedral angle between the pyridinium and benzene rings being 9.33 (10) degrees . In the crystal structure, the packing is stabilized by O-H?O hydrogen bonds and weak C-H?O inter-actions, which link the cations, anions and water mol-ecules into chains propagating in [010]. These chains are stacked along the a axis by pi pi inter-actions, with centroid-to-centroid distances of 3.6429 (12) and 3.6879 (12) A; weak C-H?pi inter-actions are also observed. PMID- 21589157 TI - (1E,2E)-1,2-Bis[1-(2-methoxy-phen-yl)ethyl-idene]hydrazine. AB - There are two crystallographically independent mol-ecules in the asymmetric unit of the title compound, C(18)H(20)N(2)O(2). The two mol-ecules exist in an E,E configuration with respect to the two C=N double bonds. The dihedral angles between the two benzene rings in each mol-ecule are 16.89 (6) and 18.84 (6) degrees . In each mol-ecule, the two meth-oxy groups are coplanar with their attached benzene rings, with r.m.s. deviations of 0.0078 and 0.0336 A in one mol ecule, and 0.0163 and 0.0207 A in the other. An intra-molecular C-H?O hydrogen bond is present in one mol-ecule. In the crystal structure, mol-ecules are arranged into ribbons along the c axis. These ribbons are further stacked along the a axis. The mol-ecules are consolidated by C?N [3.306 (2)-3.427 (2) A] and C?O [3.3284 (16)-3.3863 (15) A] short contacts. C-H?pi inter-actions are also observed. PMID- 21589158 TI - Acridinium 2-hy-droxy-benzoate. AB - In the title compound, C(13)H(10)N(+).C(7)H(5)O(3) (-) or (acrH)(+)(Hsal)(-), the asymmetric unit contains one acridinium cation and one salicylate anion. The acridinium N atom is protonated and the carb-oxy-lic acid group of salicylic acid is deprotonated. Both moieties are planar, with an r.m.s. deviation of 0.0127 A for the acr cation and 0.0235 degrees for the sal anion. They are aligned with a dihedral angle of 71.68 (3) degrees between them. The crystal structure is stabilized by a network of inter-molecular N-H?O, O-H?O and C-H?O hydrogen bonds. C-H?pi inter-actions are also present. PMID- 21589159 TI - 6,8-Dibromo-quinoline. AB - The title mol-ecule, C(9)H(5)Br(2)N, is almost planar, with an r.m.s. deviation of 0.027 A. The dihedral angle between the aromatic rings is 1.5 (3) degrees . In the crystal, pi-pi stacking inter-actions are present between the pyridine and benzene rings of adjacent mol-ecules [centroid-centroid distances = 3.634 (4) A], and short Br?Br contacts [3.4443 (13) A] occur. PMID- 21589160 TI - 5-Bromo-2-hy-droxy-benzaldehyde thio-semicarbazone. AB - The mol-ecule of the title compound, C(8)H(8)BrN(3)OS, is close to being planar, with maximum deviations of -0.127 (3) and 0.135 (5) A for the N atoms of the -NH- and NH(2)- groups, respectively. Intra-molecular N-H?N and O-H?N hydrogen bonds to the same acceptor N atom generate S(5) and S(6) ring motifs. In the crystal structure, mol-ecules are connected into [010] chains by pairs of N-H?S hydrogen bonds with R(2) (2)(8) graph-set motifs. The crystal used for data collection was found to be an inversion twin. PMID- 21589161 TI - 1,2-Bis(4-methyl-phen-oxy)ethane. AB - In the title compound, C(16)H(18)O(2), the two aromatic rings are almost orthogonal, making a dihedral angle of 89.41 (2) degrees . There is a C-H?pi contact between the methyl-ene group and the 4-methyl-phenyl ring. The molecule exhibits twofold symmetry.. PMID- 21589162 TI - 2-(4-Eth-oxy-carbon-yl-5-methyl-1H-1,2,3-triazol-1-yl)acetic acid mono-hydrate. AB - The title compound, C(8)H(11)N(3)O(4).H(2)O, was synthesized by reaction of 2 azido-acetic acid and ethyl acetyl-acetate. In the crystal packing, mol-ecules are linked by strong inter-molecular O-H?N and O-H?O hydrogen bonds into double layers parallel to the ab plane. PMID- 21589163 TI - 3'-Benzoyl-1'-methyl-4'-phenyl-spiro[acenaphthyl-ene-1(2H),2'-pyrrolidin]-2-one. AB - In the title compound, C(29)H(23)NO(2), the pyrrolidine ring adopts a twisted conformation about one of the C-N bonds. The acenaphthone ring (r.m.s. deviation = 0.025 A) lies almost perpendicular to the pyrrolidine ring [dihedral angle = 88.08 (8) degrees ]. The dihedral angle between the phenyl rings is 88.12 (11) degrees . In the crystal structure, weak C-H?pi inter-actions connect the mol ecules. PMID- 21589164 TI - 2-(4-Formyl-2,6-dimeth-oxy-phenoxy)-acetic acid. AB - In the title compound, C(11)H(12)O(6), the aldehyde group is disordered over two sites in a 0.79:0.21 ratio. The carb-oxy-lic acid chain is found in the [ap,ap] conformation due to two intramolecular O-H?O hydrogen bonds. PMID- 21589165 TI - N'-(3-Hy-droxy-benzyl-idene)-4-nitro-benzohydrazide. AB - The title mol-ecule, C(14)H(11)N(3)O(4), is approximately planar, with an inter planar angle between the two benzene rings of 5.8 (2) degrees . In the crystal, four mol-ecules are linked by an R(4) (4)(12) motif with pairs of strong O-H?O and N-H?O hydrogen bonds. The motif is situated about the crystallographic centres of symmetry and it is composed of two pairs of parallel mol-ecules. This quadruplet of mol-ecules is further extended by symmetry-equivalent hydrogen bonds to form layers parallel to the (10) plane. In addition to the hydrogen bonds, there is also a weak pi-pi inter-action between the benzene rings. PMID- 21589166 TI - 5-Chloro-methyl-1,3-dimethyl-1H-pyrazole. AB - The pyazole ring in the title compound, C(6)H(9)ClN(2), is almost planar (r.m.s. deviation = 0.003 A). In the crystal, mol-ecules are linked by C-H?N inter actions, forming [100] chains. PMID- 21589167 TI - N-Benzyl-2,3,4,5,6-penta-fluoro-benz-amide. AB - In the title compound, C(14)H(8)F(5)NO, the dihedral angle between the planes of the penta-fluoro-phenyl and phenyl rings is 18.34 (5) degrees . An inter molecular N-H?O hydrogen bond between the amide groups connects these mol-ecules to form an infinite chain through the crystal structure. One weak intermolecular C-H?O contact and one pi-pi interaction [centroid-centroid distance = 3.772 (3) A] are also involved in crystal structure stabilization between the phenyl rings. PMID- 21589168 TI - Anilinium 3-(4-hy-droxy-3-meth-oxy-phenyl)prop-2-enoate. AB - The structure of the title salt, C(6)H(8)N(+).C(10)H(9)O(4) (-), is stabilized by N-H?O and O-H?O hydrogen bonding between 3-(4-hy-droxy-3-meth-oxy-phen-yl)prop-2 enoate anions and anilinium cations, which links the components into a two dimensional array. PMID- 21589169 TI - 3-Methyl-1,4-diphenyl-1H-pyrazolo-[3,4-b]quinoline. AB - In the title mol-ecule, C(23)H(17)N(3), the phenyl substituents at positions 1 and 4 are twisted relative to the central core by 27.09 (5) and 66.62 (4) degrees , respectively. In the crystal, mol-ecules are assembled into centrosymmetric dimers via pi-pi stacking inter-actions between the 1H-pyrazolo-[3,4-b]quinoline units, with an inter-planar distance of 3.601 (2) A and by weak inter-molecular C H?N inter-actions. PMID- 21589170 TI - 3-Acetyl-5-methyl-1-(4-methyl-phen-yl)-1H-pyrazole-4-carboxamide. AB - In the title compound, C(14)H(15)N(3)O(2), the phenyl-ene ring is disordered over two orientations. As a result, the almost planar pyrazole ring (r.m.s. deviation = 0.004 A) forms dihedral angles of 59.8 (1) and -61.9 (1) degrees with the two orientations of the phenyl-ene ring. The dihedral angle between the two orientations is 59.2 (1) degrees . In the crystal, inversion dimers lined by pairs of N-H?O hydrogen bonds occur; there is also an intramolecular N-H?O bond. PMID- 21589171 TI - 4-[(4-Methyl-phen-yl)amino]-pent-3-en-2-one. AB - The title enamino-ketone, C(12)H(15)NO, is a derivative of 4-(phenyl-amino)-pent 3-en-2-one with an approximately planar pentenone backbone, the greatest displacement from the plane being 0.042 (1) A; the asymmetry in C-C distances in the group suggests the presence of unsaturated bonds. The dihedral angle between the benzene ring and the pentenone plane is 29.90 (4) degrees . In the crystal, an intra-molecular N-H?O inter-action and an inter-molecular C-H?O hydrogen bond are observed. PMID- 21589172 TI - Yuzurimine from of Daphniphyllum macropodum Miq. AB - The title compound, C(27)H(37)NO(7), is a Daphniphyllum alkaloid isolated from a branch of Daphniphyllum macropodum Miq. All of the five-membered rings adopt envelope conformations while the six- and seven-membered ring adopt chair conformations. Classical inter-molecular O-H?O and weak C-H?N hydrogen bonds are present in the crystal structure. PMID- 21589173 TI - (Z)-3-Hydrazinyl-idene-1-phenyl-indolin-2-one. AB - The indoline fused-ring system of the title Schiff base, C(14)H(11)N(3)O, is planar (r.m.s. deviation = 0.005 A); the phenyl substituent is aligned at 66.5 (1) degrees with respect to the ring system. The amino -NH(2) unit forms an intra-molecular hydrogen bond with the carbonyl O atom. Mol-ecules are connected by an inter-molecular N-H?N hydrogen bond, generating a zigzag chain that runs along the short c axis of the unit cell. PMID- 21589174 TI - (E)-3-(2,4-Dimeth-oxy-phen-yl)-1-(3,4-dimeth-oxy-phen-yl)prop-2-en-1-one. AB - The title compound, C(19)H(20)O(5), is approximately planar; the dihedral angle between the benzene rings is 3.82 (8) degrees , and the central propenone C(=O) C=C plane makes dihedral angles of 1.95 (10) and 3.17 (11) degrees with the two benzene rings. In the crystal structure, intra- and inter-molecular C-H?O hydrogen bonds are observed. PMID- 21589175 TI - (Z)-Ethyl 2-(4-chloro-phen-yl)-3-[(2,4-difluoro-phen-yl)amino]-prop-2-enoate. AB - In the title compound, C(17)H(14)ClF(2)NO(2), the amino-acrylo-yloxy group makes dihedral angles of 47.55 (11) degrees with the 4-chloro-phenyl group and 8.74 (12) degrees with the difluoro-phenyl group; the dihedral angle between the rings is 52.32 (11) degrees . The structure of the title compound reveals a Z configuration with respect to the C=C double bond in the amino-acrylate fragment. A bifurcated intramolecular N-H?(O,F) hydrogen bond occurs. In the crystal, molecules are linked into chains by C-H?O hydrogen bonds. PMID- 21589176 TI - (E)-N'-(2,3,4-Trihy-droxy-benzyl-idene)-isonicotinohydrazide dihydrate. AB - In the title isoniazid derivative, C(13)H(11)N(3)O(4).2H(2)O, the Schiff base mol ecule exists in an E configuration with respect to the acyclic C=N bond. An intra molecular O-H?N hydrogen bond forms a six-membered ring, producing an S(6) ring motif. The essentially planar pyridine ring [maximum deviation = 0.0119 (8) A] is inclined at a dihedral angle of 7.30 (4) degrees with respect to the benzene ring. In the crystal, inter-molecular O-H?N, O-H?O, N-H?O and C-H?O hydrogen bonds link the mol-ecules into two-dimensional arrays lying parallel to the (10) plane. These arrays are further inter-connected into a three-dimensional extended network via O-H?O and C-H?O hydrogen bonds. A weak inter-molecular pi-pi inter action [centroid-to-centroid distance = 3.5627 (5) A] is also observed. PMID- 21589177 TI - 4,5,6,7,8,9-Hexahydro-2H-cyclo-octa[c]pyrazol-1-ium-3-olate. AB - The title compound, C(9)H(14)N(2)O, exists in the zwitterionic form in the crystal. The cyclo-octane ring adopts a twisted boat-chair conformation. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into sheets lying parallel to bc. The structure is also stabilized by pi-pi inter-actions, with a centroid-to-centroid distance of 3.5684 (8) A. PMID- 21589178 TI - 3-(2,5-Dimethyl-furan-3-yl)-1H-pyrazol-5-ol-ethyl 3-(propan-2-yl-idene)carbazate (1/1). AB - In the title 1:1 adduct, C(6)H(12)N(2)O(2).C(9)H(10)N(2)O(2), the maximum deviations from the 1H-pyrazole-5-ol and furan rings are 0.014 (1) and 0.003 (1) A, respectively. The dihedral angle formed between the 1H-pyrazol-5-ol and 2,5 dimethyl-furan rings is 21.07 (5) degrees . In the crystal, pairs of inter molecular O-H?N hydrogen bonds form inversion dimers of the 3-(2,5-dimethyl-furan 3-yl)-1H-pyrazol-5-ol species, generating R(2) (2)(8) ring motifs. Mol-ecules are further linked by inter-molecular N-H?O, N-H?N and C-H?O hydrogen bonds to form ribbons along the [010] direction containing bifurcated R(1) (2)(5) and R(2) (1)(7) ring motifs. Further stablization of the packing is provided by weak pi-pi [centroid-centroid distance = 3.5686 (15) A] and C-H?pi inter-actions. PMID- 21589179 TI - 3-[(E)-3-(2,4-Dichloro-phen-yl)prop-2-en-oyl]-4-hy-droxy-2H-chromen-2-one. AB - In the title compound, C(18)H(10)Cl(2)O(4), the chromen-2-one ring system is almost planar [maximum deviation = 0.028 (1) A] and is inclined at an angle of 16.35 (4) degrees with respect to the benzene ring. The C=C bond has an E configuration. The mol-ecular conformation is stabilized by an almost symmetric intra-molecular O?H?O hydrogen bond and a C-H?O inter-action, both of which form S(6) ring motifs. In the crystal structure, mol-ecules are linked into sheets lying parallel to (100) via inter-molecular C-H?O hydrogen bonds. The crystal packing is further consolidated by pi-pi stacking inter-actions [centroid-to centroid separation = 3.6615 (6) A]. PMID- 21589180 TI - 5-Chloro-indoline-2,3-dione. AB - The title compound, C(8)H(4)ClNO(2), is almost planar (r.m.s. deviation for the non-H atoms = 0.023 A). In the crystal, N-H?O hydrogen bonds link the mol-ecules into C(4) chains propagating in [001] and C-H?O inter-actions cross-link the chains. PMID- 21589181 TI - Methyl 2-amino-5-chloro-benzoate. AB - The title compound, C(8)H(8)ClNO(2), is almost planar, with an r.m.s. deviation of 0.0410 A from the plane through the non-hydrogen atoms. In the crystal structure, inter-molecular N-H?O hydrogen bonds link the mol-ecules into chains along the b axis. An intra-molecular N-H?O hydrogen bond results in the formation of a six-membered ring. PMID- 21589182 TI - 3,9-Dichloro-2,4,8,10-tetra-oxa-3,9-di-phosphaspiro-[5.5]undecane-3,9-dione. AB - In the title compound, C(5)H(8)Cl(2)O(6)P(2), the two six-membered rings display chair conformations. The P=O bond distances are 1.444 (2) and 1.446 (2) A. Weak inter-molecular C-H?O hydrogen bonds are present in the crystal structure. PMID- 21589183 TI - Diethyl 2-amino-5-[(E)-(furan-2-yl-methyl-idene)amino]-thio-phene-3,4-di-carboxyl ate. AB - In the crystal structure of the title compound, C(15)H(16)N(2)O(5)S, the azomethine adopts the E configuration. The two heterocyclic rings adopt an anti periplanar orientation. The mean planes of the thio-phene and furan rings are twisted by 2.51 (4) degrees . The crystal structure exhibits inter-molecular N H?O hydrogen bonding. pi-pi stacking is also observed, the centroid-to-centroid distance being 3.770 (4) A. PMID- 21589184 TI - N-(2-Hy-droxy-1,1-dimethyl-eth-yl)-benzene-sulfonamide. AB - In the title mol-ecule, C(10)H(15)NO(3)S, the S atom is bonded in a distorted tetra-hedral geometry. In the crystal structure, inter-molecular N-H?O, O-H?O and weak C-H?O hydrogen bonds connect the mol-ecules to form a two-dimensional network parallel to (100). The 2-methyl-propan-1-ol group is disordered over two orientations with occupancies of 0.570 (3) and 0.430 (3). PMID- 21589185 TI - 2,3-Dibromo-1-[4-(2,3-dibromo-4,5-di-meth-oxy-benz-yl)-2,5-dimeth-oxy-benz-yl] 4,5-dimeth-oxy-benzene. AB - The mol-ecule of the title compound, C(26)H(26)Br(4)O(6), is located around a crystallographic inversion center. The dihedral angle between the central benzene ring and the outer benzene ring is 89.26 (1) degrees . PMID- 21589186 TI - rac-1-(6-Hy-droxy-3,6-dimethyl-4-phenyl-4,5,6,7-tetra-hydro-2,1-benzoxazol-5 yl)ethanone. AB - The structure of the title compound, C(17)H(19)NO(3), is of inter-est with respect to anti-bacterial properties, anti-biotic properties and biological activity. The structure displays inter-molecular O-H?N hydrogen bonding. PMID- 21589187 TI - 3-(5-Nitro-2-fur-yl)-1-phenyl-prop-2-yn-1-one. AB - In the title compound, C(13)H(7)NO(4), the 2-furyl ring is essentially planar, with a maximum deviation of 0.004 (1) A. It is inclined at an angle of 11.69 (4) degrees to the benzene ring. The nitro group is slightly twisted out of the plane of the 2-furyl ring, with a dihedral angle of 5.72 (8) degrees . There is a short O?C contact of 2.8562 (8) A (symmetry code: -x, -y, 2 - z). In the crystal packing, mol-ecules are linked via a pair of inter-molecular C-H?O hydrogen bonds, giving rise to an R(2) (2)(10) ring motif. Mol-ecules are further linked into two-dimensional networks parallel to [100] via other inter-molecular C-H?O hydrogen bonds. The crystal structure is consolidated by C-H?pi inter-actions. PMID- 21589188 TI - Melaminium nitrate-melamine-water (1/1/1). AB - In the crystal structure of the title salt, C(3)H(7)N(6) (+).NO(3) ( ).C(3)H(6)N(6).H(2)O, the asymmetric unit consists of two neutral melamine (1,3,5 triazine-2,4,6-triamine) mol-ecules, two melaminium cations, two nitrate anions and two solvent water mol-ecules. One of the nitrate anions is disordered over two sets of positions, with a refined occupancy ratio of 0.909 (3):0.091 (3). The cations and neutral mol-ecules are approximately planar, with maximum deviations of 0.018 (2), 0.024 (2), 0.019 (2) and 0.007 (2) A for each, respectively. In the crystal structure, melaminium cations and netural melamine mol-ecules self assemble via N-H?N hydrogen bonds to form a supra-molecular hexa-gonal-shaped motif. In addition, the nitrate anions and water mol-ecules are connected by N H?O hydrogen bonds to form a three-dimensional network. PMID- 21589189 TI - 3,3,9,9-Tetra-phenyl-2,4,8,10-tetra-oxa-spiro-[5.5]undeca-ne. AB - In the title compound, C(31)H(28)O(4), the asymmetric unit contains two crystallographically independent mol-ecules. In these two mol-ecules, the four dihedral angles between each pair of phenyl rings on the same C atoms are 75.4 (1), 83.0 (1), 85.0 (1) and 80.4 (2) degrees . All of the nonplanar six-membered heterocycles adopt chair conformations. Inter-molecular C-H?pi and weak C-H?O inter-actions link the mol-ecules and are effective in the stabilization of the crystal structure. PMID- 21589190 TI - 3,3-Dinitro-azetidinium 2-hy-droxy-benzoate. AB - In the title gem-dinitro-azetidinium 2-hy-droxy-benzoate salt, C(3)H(6)N(3)O(4) (+).C(7)H(5)O(3) (-), the azetidine ring is virtually planar, with a mean deviation from the plane of 0.0242 A. The dihedral angle between the two nitro groups is 87.5 (1) degrees . PMID- 21589191 TI - N,N'-Bis(3-methyl-phen-yl)propane-diamide. AB - The mol-ecular structure of the title compound, C(17)H(18)N(2)O(2), is symmetrical around the central C atom. The two halves of the mol-ecule are related by a twofold rotation axis. In each half of the mol-ecule, the structure is stabilized by intra-molecular C-H?O hydrogen bonds. Furthermore, each amide group is almost coplanar with the adjacent benzene ring [dihedral angle is 9.2 (2) degrees ]. The planes of the amide groups are inclined at an angle of 68.5 (1) degrees , while the two benzene rings make a dihedral angle of 70.40 (3) degrees . In the crystal, mol-ecules are linked by inter-molecular N-H?O hydrogen bonds into chains running along the c axis. Neighbouring chains are weakly coupled by pi-pi stacking inter-actions [centroid-centroid distance = 3.7952 (8) A]. PMID- 21589193 TI - Ethyl {4-[(1,5-dimethyl-2,4-dioxo-2,3,4,5-tetra-hydro-1H-1,5-benzo-diazepin-3 yl)meth-yl]-1,2,3-triazol-1-yl}acetate. AB - In the title compound, C(18)H(21)N(5)O(4), the diazepine ring adopts a boat conformation with the triazolylmethyl-bearing C atom as the prow and the C atoms at the ring junction as the stern. PMID- 21589192 TI - N,N'-Bis(2-chloro-phen-yl)propane-diamide. AB - The crystal structure of the title compound, C(15)H(12)Cl(2)N(2)O(2), contains three intramolecular hydrogen bonds; two C-H?O and a nonclassical N-H?Cl. The structure is further stabilized by intermolecular N-H?O hydrogen bonds and C-H?pi interactions, resulting in a three-dimensional network. The two benzene rings make an interplanar angle of 58.0 (1) degrees . PMID- 21589194 TI - 4-tert-Butyl-4'-(4-meth-oxy-phen-yl)-3'-(4-methyl-phen-yl)-1,2,3,4-tetra-hydro spiro-[naphthalene-2,5'(4'H)-1,2-oxazol]-1-one. AB - In the title compound, C(30)H(31)NO(3), the tolyl ring is almost coplanar with the isoxazole ring [dihedral angle = 12.51 (7) degrees ], whereas the meth-oxy phenyl ring is almost perpendicular to the isoxazole ring [dihedral angle = 89.77 (5) degrees ]. In the crystal, mol-ecules are connected through C-H?O hydrogen bonds, forming chains running along the a axis. PMID- 21589195 TI - 3beta-Acet-oxy-lup-20(29)-en-28-yl 1H-1,2,4-tri-azole-1-carboxyl-ate. AB - The title triterpene, C(35)H(53)N(3)O(4), is a C-28 carbamate derivative of 3beta acet-oxy-betulin prepared in a one-step reaction from the commercially available 1,1'-carbonyl-di(1,2,4-triazole) (CDT), crystallized from acetone/n-hexane. All rings are trans fused. The carbamate and acetate substituents are in axial and equatorial positions, respectively. A quantum chemical ab initio Roothaan Hartree Fock calculation of the equilibrium geometry of the isolated mol-ecule gives values for bond lengths and valency angles in close agreement with experimental values. The calculation also reproduces the observed mol-ecular conformation, with puckering parameters that agree well with those determined from the crystallographic study. PMID- 21589196 TI - (1R,4S)-7,8-Dichloro-1,2,3,4-tetra-hydro-1,11,11-trimethyl-1,4-methano-phenazine. AB - The title compound, C(16)H(16)Cl(2)N(2), was synthesized by the condensation reaction between 4,5-dichloro-o-phenyl-ene-diamine and (1R)-(-)-camphorquinone in boiling acetic acid. The two crystallographically independent mol-ecules in the unit cell are related by a pseudo-inversion center. PMID- 21589197 TI - Erratum: 2-C-Hydro-xymethyl-2,3-O-iso-propyl-idene-d-ribono-1,5-lactam. Corrigendum. AB - The name of one of the authors in the paper by Newton et al. [Acta Cryst. (2004), E60, o909-o910] is corrected.[This corrects the article on p. o909 in vol. 60.]. PMID- 21589198 TI - Erratum: Reinvestigation of bis-(2,2'-bipyridine)(nitrato-kappaO,O')cobalt(III) hydroxide nitrate tetra-hydrate. Corrigendum. AB - The chemical formula in the paper by Wojciechowska & Daszkiewicz [Acta Cryst. (2007), E63, m2975-m2976] is corrected.[This corrects the article on p. m2975 in vol. 63.]. PMID- 21589199 TI - Erratum: Melaminium nitrate-melamine-water (1/1/1). Corrigendum. AB - The name of one of the authors in the paper by Adam et al. [Acta Cryst. (2010), E66, o3033-o3034] is corrected.[This corrects the article DOI: 10.1107/S1600536810043941.]. PMID- 21589200 TI - Erratum: 3-(2,5-Dimethyl-furan-3-yl)-1H-pyrazol-5-ol-ethyl 3-(propan-2-yl idene)carbazate (1/1). Corrigendum. AB - The address of three of the authors in the paper by Shahani et al. [Acta Cryst. (2010), E66, o3020-o3021] is corrected.[This corrects the article DOI: 10.1107/S1600536810043886.]. PMID- 21589201 TI - K(2)LaCl(5). AB - The ternary title compound, dipotassium lanthanum penta-chloride, K(2)LaCl(5), is isotypic with Y(2)HfS(5) and various ternary rare-earth metal(III) halides with the general formula A(2)MX(5) (A = NH(4), In(I), Na-Cs; M = La-Dy; X = Cl-I). The La(3+) cations and three of the four symmetry-independent chloride anions are located on a crystallographic mirror plane. The La(3+) cations are surrounded by seven chloride anions, each in the shape of a monocapped trigonal prism, whereas the coordination spheres of the K(+) cations exhibit one more cap. Three of the four independent chloride anions reside in a fivefold cationic coordination, leading to distorted square pyramids. The fourth chloride anion has only four cationic neighbours, forming no specific polyhedron. PMID- 21589202 TI - Zn(1.86)Cd(0.14)(OH)VO(4). AB - The title compound, dizinc cadmium hydroxide tetraoxido-vanadate, Zn(1.86)Cd(0.14)(OH)VO(4), was prepared under low-temperature hydro-thermal conditions. It is isostructural with Zn(2)(OH)VO(4) and Cu(2)(OH)VO(4). In the crystal structure, chains of edge-sharing [ZnO(6)] octahedra are inter-connected by VO(4) tetra-hedra (site symmetries of both V atoms and their coordination polyhedra are .m.) to form a three-dimensional [Zn(OH)VO(4)](2-) framework with channels occupied by Zn and Zn/Cd cations adopting trigonal-bipyramidal and distorted octa-hedral coordinations, respectively. Zn(1.86)Cd(0.14)(OH)VO(4) is topologically related to adamite-type phases, and descloizite- and tsumcorite type structures. PMID- 21589203 TI - (Ca(x)Nd(11-x))Ru(4)O(24) (x = 4.175). AB - Single crystals of the title compound, calcium neodymium ruthenate, (Ca(x)Nd(11 x))Ru(4)O(24) (x = 4.175), have been grown by the flux method. The structure consists of two crystallographically independent RuO(6) octa-hedra, which are isolated from each other and embedded in a matrix composed of the Ca and Nd atoms. There are seven M sites which accommodate the Ca and Nd atoms with different populations. Four M sites at general positions are enriched with Nd, whereas the remaining three M sites on twofold rotation axes are enriched with Ca. The coordination numbers of O atoms to the M sites range from 6 to 9. The mean oxidation state of Ru was estimated at +4.79 from the composition analysis. The title compound is non-centrosymmetric and potentially multiferroic. PMID- 21589204 TI - Dibarium tricadmium bis-muthide(-I,-III) oxide, Ba(2)Cd(3-delta)Bi(3)O. AB - Ba(2)Cd(2.13)Bi(3)O, a new bis-muthide(-I,-III) oxide, crystallizes with a novel body-centered tetra-gonal structure (Pearson code tI36). The crystal structure contains eight crystallographically unique sites in the asymmetric unit, all on special positions. Two Ba, one Cd and two Bi atoms have site symmetry 4mm, the third Bi atom has mmm. and the O atom has m2 symmetry; the second Cd site (2mm. symmetry) is not fully occupied. The layered structure is complex and can be considered as an inter-growth of two types of slabs, viz. BaCdBiO with the ZrCuSiAs type and BaCd(2)Bi(2) with the CeMg(2)Si(2) type. PMID- 21589205 TI - TbNb(6)Sn(6): the first ternary compound from the rare earth-niobium-tin system. AB - The title compound, terbium hexa-niobium hexastannide, TbNb(6)Sn(6), is the first ternary compound from the rare earth-niobium-tin system. It has the HfFe(6)Ge(6) structure type, which can be analysed as an inter-growth of the Zr(4)Al(3) and CaCu(5) structures. All the atoms lie on special positions; their coordination geometries and site symmetries are: Tb (dodeca-hedron) 6/mmm; Nb (distorted icosa hedron) 2mm; Sn (Frank-Caspar polyhedron, CN = 14-15) 6mm and m2; Sn (distorted icosa-hedron) m2. The structure contains a graphite-type Sn network, Kagome nets of Nb atoms, and Tb atoms alternating with Sn2 dumbbells in the channels. PMID- 21589206 TI - Kozulite, an Mn-rich alkali amphibole. AB - The crystal structure of kozulite, an Mn-rich alkali amphibole with the ideal formula NaNa(2)[Mn(4) (2+)(Fe(3+),Al)]Si(8)O(22)(OH)(2), tris-odium tetra manganese iron/aluminium octa-silicate dihydroxide, was refined from a natural specimen with composition (K(0.20)Na(0.80))(Na(1.60)Ca(0.18)Mn(2+) (0.22))(Mn(2+) (2.14)Mn(3+) (0.25)Mg(2.20)Fe(3+) (0.27)Al(0.14))(Si(7.92)Al(0.06)Ti(0.02))O(22)[(OH)(1.86)F(0.14)]. The site occupancies determined from the refinements are M1 = 0.453 (1) Mn + 0.547 (1) Mg, M2 = 0.766 (1) Mn + 0.234 (1) Mg, and M3 = 0.257 (1) Mn + 0.743 (1) Mg, where Mn and Mg represent (Mn+Fe) and (Mg+Al), respectively. The average M-O bond lengths are 2.064 (1), 2.139 (1), and 2.060 (1) A for the M1, M2, and M3 sites, respectively, indicating the preference of large Mn(2+) for the M2 site. Four partially occupied amphibole A sites were revealed from the refinement, with A(m) = 0.101 (4) K, A(m)' = 0.187 (14) Na, A(2) = 0.073 (6) Na, and A(1) = 0.056 (18) Na, in accord with the result derived from microprobe analysis (0.20 K + 0.80 Na), considering experimental uncertainties. PMID- 21589207 TI - Hydro-thermally synthesized alpha-Ba(2)P(2)O(7). AB - Single crystals of alpha-Ba(2)P(2)O(7), dibarium diphosphate, were obtained under hydro-thermal conditions. The structure belongs to the diphosphate A(2)P(2)O(7) series with A being an alkaline earth cation. alpha-Ba(2)P(2)O(7) crystallizes isotypically with alpha-Sr(2)P(2)O(7). All atomic sites have site symmetry m with the exception of two O atoms which reside on general positions. Both Ba(2+) cations are coordinated by nine terminal O atoms from eclipsed diphosphate P(2)O(7) anions to form a three-dimensional network throughout the structure. PMID- 21589208 TI - beta-Nd(2)Mo(4)O(15). AB - The title compound, dineodymium(III) tetra-molybdate(VI), has been prepared by a flux technique and is the second polymorph of composition Nd(2)Mo(4)O(15). The crystal structure is isotypic with those of Ce(2)Mo(4)O(15) and Pr(2)Mo(4)O(15). It features a three-dimensional network composed of distorted edge- and corner sharing NdO(7) polyhedra, NdO(8) polyhedra, MoO(4) tetra-hedra and MoO(6) octa hedra. PMID- 21589209 TI - Ni(2)Sr(PO(4))(2).2H(2)O. AB - The title compound, dinickel(II) strontium bis-[ortho-phosphate(V)] dihydrate, was obtained under hydro-thermal conditions. The crystal structure consists of linear chains (infinity) (1)[NiO(2/2)(OH(2))(2/2)O(2/1)] of edge-sharing NiO(6) octa-hedra ( symmetry) running parallel to [010]. Adjacent chains are linked to each other through PO(4) tetra-hedra (m symmetry) and arranged in such a way to build layers parallel to (001). The three-dimensional framework is accomplished by stacking of adjacent layers that are held together by SrO(8) polyhedra (2/m symmetry). Two types of O-H?O hydrogen bonds involving the water mol-ecule are present, viz. one very strong hydrogen bond perpendicular to the layers and weak trifurcated hydrogen bonds parallel to the layers. PMID- 21589210 TI - Poly[bis-[MU-1,4-bis-(1H-imidazol-5-yl)benzene-kappaN:N]diformatomanganese(II)]. AB - In the title compound, [Mn(CHO(2))(2)(C(12)H(10)N(4))(2)](n), the Mn(II) atom and the benzene ring of the ligand lie on an inversion centers. The Mn(II) atom has an octa-hedral coordination environment composed of four N atoms from two different symmetry-related N-heterocyclic ligands forming the basal plane, and two O atoms from symmetry-related formate anions occupying the apical positions. The title compound forms a two-dimensional (4,4) net parallel to (100) with all the Mn(II) atoms lying on a plane. The crystal structure is consolidated by inter molecular N-H?O hydrogen bonds.. PMID- 21589211 TI - Dichlorido{4-cyclo-hexyl-1-[1-(2-pyridyl-kappaN)ethyl-idene]thio-semicarbazidato kappaN,S}phenyl-tin(IV). AB - The Sn(IV) atom in the title compound, [Sn(C(6)H(5))(C(14)H(19)N(4)S)Cl(2)], exists within a distorted octa-hedral geometry defined by the N,N',S-tridentate monodeprotonated Schiff base ligand, two mutually trans Cl atoms, and the ipso-C atom of the Sn-bound phenyl group; the latter is trans to the azo-N atom. The greatest distortion from the ideal geometry is found in the nominally trans angle formed by the S and pyridyl-N atoms at Sn [151.03 (4) degrees ]. With the exception of the cyclo-hexyl group (chair form), the Schiff base ligand is almost planar (r.m.s. deviation of non-H and Sn atoms = 0.053 A). The nearly orthogonal orientation of the Sn-bound phenyl group [N-Sn-C-C torsion angle = 70.8 (5) degrees ] to the planar portion of the Schiff base allows for the formation of significant intra-molecular C-H?Cl inter-actions which preclude the Cl atoms from participating in N-H?Cl hydrogen bonds. Instead, C-H?pi contacts, involving methyl-ene H and the Sn-bound phenyl group, lead to the formation of supra molecular chains that pack in the bc plane. Connections between these layers are of the type C-H?Cl. PMID- 21589212 TI - Bis[MU-2-(4-hy-droxy-phen-yl)acetato]-kappaO,O':O;kappaO:O,O'-bis-{aqua-(4,4' bipyridine-kappaN)bis-[2-(4-hy-droxy-phen-yl)acetato-kappaO,O']dysprosium(III)} monohydrate. AB - In the title dinuclear complex, [Dy(2)(C(8)H(7)O(3))(6)(C(10)H(8)N(2))(2)(H(2)O)(2)].H(2)O, the Dy(III) atoms are coordinated by eight O atoms from four 2-(4-hy-droxy-phen-yl)acetate (HPAA) ligands and a water mol-ecule, and one N atom from a 4,4'-bipyridine (bipy) ligand in a distorted tricapped trigonal prismatic geometry. Whereas four HPAA ligands coordinate to just two Dy(III) atoms, the remaining two ligands bridge the two Dy(III) atoms. In the crystal, O-H?O and O-H?N hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21589213 TI - Piperidinium N-(ferrocenylcarbon-yl)glycinate. AB - The title compound, (C(5)H(12)N)[Fe(C(5)H(5))(C(8)H(7)NO(3))], resulting from neutralization of N-(ferrocenylcarbon-yl)glycine with piperidine, is built up from discrete ions that assemble into sheets via the combination of conventional and weak hydrogen bonds. The key repeating unit is constituted by two piperidium cations and two carboxylate anions that assemble into a centrosymmetric array via conventional and bifurcated N-H?O hydrogen bonds. The aggregates thus formed are further interlinked by N-H?O interactions and supportive C-H?O contacts into layers oriented parallel to the bc plane. PMID- 21589214 TI - Bis[2-(methyl-amino)-troponato]copper(II). AB - In the title compound, [Cu(C(8)H(8)NO)(2)], a strictly square-planar geometry about the Cu(II) metal atom is observed. Substitution of an O atom with a methyl functionalized N atom does not significantly alter the bond distances and angles in the copper(II) complex when compared with a similar bis-(troponato)copper(II) complex. pi-pi stacking is observed between the tropolone rings, with inter planar distances of 3.5039 (16) and 3.2933 (15) A, respectively. Additional stabilisation of the structure is accomplished through C-H?O hydrogen-bonding interactions. PMID- 21589215 TI - Poly[MU(2)-aqua-diaqua-(MU(8)-3-nitro-benzene-1,2-dicarboxylato)(MU(6)-3-nitro benzene-1,2-dicarboxylato)tetra-sodium]. AB - In the title layered coordination polymer, [Na(4)(C(8)H(3)NO(6))(2)(H(2)O)(3)](n), the doubly deprotonated 3-nitro-benzene 1,2-dicarboxyl-ate ligands exhibit MU(8)- and MU(6)-coordination modes to the sodium ions, generating sheets lying parallel to (001). The coordination environments of the sodium ions are distorted octa-hedral, distorted trigonal bipyramidal and moncapped trigonal-prismatic. One of the nitro groups is disordered over two sets of sites with site-occupancy factors 0.580 (8):0.419 (2). A network of O-H?O and O-H?N hydrogen bonds helps to establish the packing. PMID- 21589216 TI - Bis[MU-2-(4-hy-droxy-phen-yl)acetato]-kappaO,O':O;kappaO:O,O'-bis-{aqua-(4,4' bipyridine-kappaN)[2-(4-hy-droxy-phen-yl)acetato-kappaO,O']samarium(III)} monohydrate. AB - The dinuclear title complex, [Sm(2)(C(8)H(7)O(3))(6)(C(10)H(8)N(2))(2)(H(2)O)(2)].H(2)O, contains two Sm(III) atoms, six deprotonated p-hy-droxy-phenyl-acetic acid (PAA) mol-ecules, two 4,4' bipyridine (bipy) mol-ecules, two coordinated water mol-ecules and one solvent water molecule. Each Sm(III)ion is nine-coordinated by seven O atoms from four PAA ligands, one water O atom and one N atom from a bipy ligand in a distorted geometry. The PAA ligands are coordinated to the Sm(III) ion in bridging and bridging tridentate modes. The asymmetric unit also contains one uncoordinated water mol-ecule. The occurrence of numerous O-H?O and O-H?N hydrogen bonds involving coordinated and non-coordinated water mol-ecules builds up an intricate three-dimensional network. PMID- 21589217 TI - Bis[MU-2-(4-hy-droxy-phen-yl)acetato]-kappaO,O':O;kappaO:O,O'-bis-{aqua-(4,4'-bi pyridine-kappaN)[2-(4-hy-droxy-phen-yl)acetato-kappaO,O']erbium(III)} monohydrate. AB - The title dinuclear complex, [Er(2)(C(8)H(7)O(3))(6)(C(10)H(8)N(2))(2)(H(2)O)(2)].H(2)O, contains two Er(III) atoms in the asymmetric unit, six 2-(4-hy-droxy-phen-yl)acetate (PAA) anions, two 4,4'-bipyridine (bipy) mol-ecules, two coordinated water mol-ecules and one solvent water mol-ecule. The central Er(III) atoms are nine-coordinated. The coordination environment includes six O atoms from three PAA anions, one bridging O atom from a PAA anion, one O atom from a water mol-ecule and an N atom from a bipy ligand in a distorted tricapped trigonal-prismatic geometry. The occurrence of numerous O-H?O and O-H?N hydrogen bonds involving coordinated and noncoordinated water as well as bipy groups builds up an intricate three dimensional network. PMID- 21589218 TI - catena-Poly[[triaqua-chlorido-MU(3)-malonato-cerium(III)] hemihydrate]. AB - The asymmetric unit of the title compound, {[Ce(C(3)H(2)O(4))Cl(H(2)O)(3)].0.5H(2)O}(n), contains a Ce(3+) atom coordinated by a chloride anion, three water mol-ecules and a malonate ligand, and one water mol-ecule of crystallization with a factor of occupancy of 50%. The malonate ligand is bonded to three different symmetry-related metal atoms yielding a one dimensional coordination polymer running parallel to the a axis. A supra molecular network composed of strong and highly directional O-H?O and O-H?Cl hydrogen bonds ensures a close and effective packing of adjacent polymeric chains. PMID- 21589219 TI - Poly[hexa-aqua-hexa-kis-(MU-pyridine-2,4-dicarboxyl ato)tricopper(II)dieuropium(III)]. AB - The asymmetric unit of the title heterometallic coordination polymer, [Cu(3)Eu(2)(C(7)H(3)NO(4))(6)(H(2)O)(6)](n), contains one Eu(III) and two Cu(II) atoms, three pyridine-2,4-dicarboxylate (pdc)(2-) anions and three water molecules. One Cu(II) atom is located on an inversion center and is N,O-chelated by two pdc(2-) anions in the equatorial plane and further coordinated by two carboxyl-ate O atoms from another two pdc anions in the axial positions, with an elongated octa-hedral geometry [Cu-O = 2.409 (3) A in the axial direction]; the other Cu atom is N,O-chelated by two pdc anions in the coordination basal plane and coordinated by a carboxyl O atom at the apical position with a distorted square-pyramidal geometry [Cu-O = 2.359 (3) A in the apical direction]. The Eu atom is eight-coordinated with a distorted square-anti-prismatic geometry formed by five carboxyl-ate O atoms from five pdc anions and three water mol-ecules. The carboxyl-ate anions bridge adjacent Eu and Cu atoms, forming the coordination polymer. Inter- and intra-molecular O-H?O hydrogen bonding occurs in the structure. pi-pi stacking further consolidates the crystal structure, the centroid-centroid distance between parallel pyridine rings being 3.367 (2) A. PMID- 21589220 TI - catena-Poly[[dichloridozinc(II)]-MU-1,4-bis-(1H-imidazol-1-yl)benzene]. AB - In the title one-dimensional coordination polymer, [ZnCl(2)(C(12)H(10)N(4))](n), the Zn(II) atom (site symmetry 2) is coordinated by two chloride ions and two 1,4 bis-(imidazol-1-yl)benzene ligands, generating a distorted tetra-hedral ZnCl(2)N(2) geometry for the metal ion. The bridging ligand, which is completed by crystallographic inversion symmetry, links the Zn(II) atoms into zigzag chains propagating in [101]. Within the ligand, the dihedral angle between the central benzene ring and terminal imidazole ring is 27.82 (13) degrees . PMID- 21589221 TI - Bis[MU-3-(2-hy-droxy-phen-yl)propenoato]bis-{aqua-(4,4'-bipyridine)-bis-[3-(2 hydroxy-phen-yl)propenoato]yttrium(III)} 4,4'-bipyridine disolvate. AB - The title compound, [Y(2)(C(9)H(7)O(3))(6)(C(10)H(8)N(2))(2)(H(2)O)(2)].2C(10)H(8)N(2), contains two eight-coordinated Y(III) ions, which are linked by two carboxyl-ate groups from two 2-hy-droxy-cinnamate anions, leading to a centrosymmetric dinuclear structure surrounded by solvent 4,4'-bipyridine mol-ecules. It forms a three-dimensional framework connected by extensive O-H?O and O-H?N hydrogen-bonding inter-actions. PMID- 21589222 TI - [MU-1,3-Bis(3,5-dimethyl-1H-pyrazol-1-yl-kappaN)propan-2-olato-kappaO:O]bis [(ethanol-kappaO)zinc(II)] bis-(perchlorate). AB - In the centrosymmetric dinuclear title complex, [Zn(2)(C(13)H(19)N(4)O)(2)(C(2)H(5)OH)(2)](ClO(4))(2), the Zn(II) atom is in a distorted trigonal-bipyramidal coordination geometry. The equatorial plane is constructed by one N atom and one O atom from two 1,3-bis-(3,5-dimethyl-pyrazol-1 yl)propan-2-olate (bppo) ligands and one O atom from an ethanol mol-ecule. One N atom and one O atom from the two bppo ligands occupy the axial positions. Inter molecular O-H?O hydrogen bonds between the ethanol mol-ecules and perchlorate anions, and O?pi inter-actions between the perchlorate anions and pyrazole rings [O?centroid distances = 3.494 (3) and 3.413 (3) A], lead to a chain structure along [010]. PMID- 21589223 TI - Bis(nitrato-kappaO,O')bis-[N-(triphenyl-meth-yl)pyridin-2-amine kappaN]nickel(II). AB - In the title compound, [Ni(NO(3))(2)(C(24)H(20)N(2))(2)], the Ni(II) atom has a distorted pseudo-octa-hedral coordination geometry defined by two chelating nitrate groups and two pyridine N atoms of the monodentate N-(triphenyl-meth yl)pyridin-2-amine ligands. Intra-molecular N-H?O hydrogen bonds help to establish the configuration. PMID- 21589224 TI - catena-Poly[[[aqua-(pyrazino-[2,3-f][1,10]phenanthroline-kappaN,N)zinc(II)]-MU penta-nedioato] monohydrate]. AB - In the title compound, {[Zn(C(5)H(6)O(4))(C(14)H(8)N(4))(H(2)O)].H(2)O}(n), the Zn(2+) ion is coordinated by an N,N'-bidentate pyrazino-[2,3 f][1,10]phenanthroline (pyphen) ligand, a water molecule and a monodentate glutarate (glu) dianion. A symmetry-generated O:O'-bidentate glu dianion completes a distorted cis-ZnN(2)O(4) octa-hedral coordination geometry for the metal ion. The bridging glu species generates [110] polymeric chains in the crystal. O-H?O hydrogen bonds involving both the coordinated and uncoordinated water mol-ecules help to consolidate the structure and neighbouring pyphen units inter-act through numerous aromatic pi-pi inter-actions [minimum centroid centroid separation = 3.654 (3) A], resulting in a two-dimensional network. PMID- 21589225 TI - Diaqua-bis-{2-hy-droxy-5-[(pyridin-2-yl)methyl-idene-amino]-benzoato kappaN,N'}zinc(II) dihydrate. AB - The complex mol-ecule of the title compound, [Zn(C(13)H(9)N(2)O(3))(2)(H(2)O)(2)].2H(2)O, has 2 symmetry with the Zn(II) cation located on a twofold rotation axis. The Zn cation is N,N'-chelated by two 5-[(pyridin-2-yl)methyl-idene-amino]-2-hy-droxy-benzoate anions and coordinated by two water mol-ecules in a distorted octa-hedral geometry. Within the anionic ligand, the pyridine ring is oriented at a dihedral angle of 49.54 (10) degrees with respect to the benzene ring. The carboxyl-ate group of the anionic ligand is not involved in coordination but is O-H?O hydrogen bonded to the coordinated and uncoordinated water mol-ecules. Weak inter-molecular C-H?O hydrogen bonding is also present in the crystal structure. PMID- 21589226 TI - Tetra-aqua-bis-[4-(pyrazin-2-ylsulfanylmeth-yl)benzoato]manganese(II) dihydrate. AB - The title compound, [Mn(C(12)H(9)N(2)O(2)S)(2)(H(2)O)(4)].2H(2)O, has been synthesized with a flexible asymmetrical bridging ligand, 4-(pyrazin-2 ylsulfanylmeth-yl)benzoic acid (Hpztmb). The Mn(II) ion exhibits a centrosymmetric octa-hedral geometry involving two carboxyl-ate O atoms of two different pztmb ligands and four O atoms of four coordinated water mol-ecules. The packing shows a three-dimensional supra-molecular network via O-H?O and O-H?N hydrogen bonds and pi-pi stacking inter-actions [centroid-centroid distances = 3.884 (8) and 4.034 (8) A] between the benzene ring of one pztmb anion and the pyrazine ring of an adjacent anion. PMID- 21589227 TI - MU(2)-Acetone-diacetone[MU(3)-tris-(trifluoro-meth-yl)methano-lato]bis-[MU(2) tris-(trifluoro-meth-yl)methano-lato]trilithium. AB - The title compound, [Li(3)(C(4)F(9)O)(3)(C(3)H(6)O)(3)], features an open Li/O cube with an Li ion missing at one corner. Three of the four bridging O atoms of the cube carry a fluorinated tert-butyl residue, whereas the fourth is part of an acetone mol-ecule. Two of the Li atoms are further bonded to a non-bridging acetone mol-ecule. Two of the lithium ion coordination geometries are very distorted LiO(4) tetra-hedra; the third could be described as a very distorted LiO(3) T-shape with two distant F-atom neighbours. The Li?Li contact distances for the three-coordinate Li(+) ion [2.608 (14) and 2.631 (12) A] are much shorter that the contact distance [2.940 (13) A] between the tetra-hedrally coordinated species. PMID- 21589228 TI - 6-(4-Methyl-phen-yl)-2,10-dioxo-3,9-dioxa-6-aza-1(1,1')-ferrocenacyclo-deca phane. AB - In the title compound, [Fe(C(23)H(23)NO(4))], the two cyclo-penta-dienyl (Cp) rings are nearly parallel, with a dihedral angle of 2.1 (1) degrees . The distance between the centroids of the Cp rings is 3.277 (8) A. The relative orientation of the two Cp rings is characterized by a torsion angle of -64.3 (3) degrees defined by the two centroids and two substituted atoms. PMID- 21589229 TI - catena-Poly[[tetra-aqua-[MU(2)-1,4-bis-(1,2,4-triazol-1-yl)butane kappaN:N]cadmium(II)] sulfate]. AB - In the polymeric title compound, {[Cd(C(8)H(12)N(6))(H(2)O)(4)]SO(4)}(n), the Cd(II) atom is located on an inversion center and coordinated by four water mol ecules and two 1,4-bis-(1,2,4-triazol-yl)butane ligands in a distorted CdO(4)N(2) octa-hedral geometry. The 1,4-bis-(1,2,4-triazol-yl)butane ligand is centrosymmetric, the mid-point of the central C-C bond being located on an inversion center. It links adjacent water-coordinated metal atoms into polymeric chains running along the c axis. Adjacent chains are linked by O-H?N hydrogen bonds. The S atom of the sulfate anion is located on a twofold rotation axis, thus the sulfate anion is equally disordered over two sites. The sulfate anion links with the polymeric chains via O-H?O hydrogen bonds, generating a three dimensional supra-molecular network. PMID- 21589230 TI - Aqua-(2,2'-bipyridine-kappaN,N')bis-(4-iodo-benzoato-kappaO)copper(II). AB - The Cu(II) atom in the title compound, [Cu(C(7)H(4)IO(2))(2)(C(10)H(8)N(2))(H(2)O)], is N,N'-chelated by a 2,2' bipyridine ligand and is coordinated by two monodentate carboxyl-ate ions and a water mol-ecule in a distorted square-pyramidal geometry. The apical site is occupied by one of the carboxyl-ate O atoms. The water mol-ecule forms intra molecular hydrogen bonds to the uncoordinated carboxyl O atoms. The crystal studied was a nonmerohedral twin with minor components in 0.381 (3) and 0.108 (2) proportions. PMID- 21589231 TI - Dichlorido[MU-10,21-dimethyl-2,7,13,18-tetra-phenyl-3,6,14,17-tetra-aza-tricyclo [17.3.1.1]tetra-cosa-1(23),2,6,8,10,12(24),13,17,19,21-deca-ene-23,24 diolato]dicopper(II) ethanol hemisolvate dihydrate. AB - The dinuclear title complex, [Cu(2)(C(46)H(38)N(4)O(2))Cl(2)].0.5C(2)H(5)OH.2H(2)O, is located on crystallographic inversion centres with two half-mol-ecules in the asymmetric unit. The two Cu(II) atoms are coordinated by a hexa-dentate dianionic ligand formed in situ from the condensation of two tridentate ligands by four imine N atoms and two bridging phenolate O atoms along with two Cl atoms at axial positions. The coordination geometry around the metal atoms is distorted square pyramidal (tau = 0.185 and 0.199). The non-bonding Cu?Cu distances are 2.9556 (12) and 2.9506 (12) A in the two dimers. The packing is stabilized through solvent-mediated inter-molecular O-H?O and O-H?Cl hydrogen bonds. The diamine chain of one of the dimers is disordered over two positions in a 0.680 (5):0.320 (5) ratio. PMID- 21589232 TI - trans-Bis[(1-ammonio-pentane-1,1-di-yl)diphospho-nato-kappaO,O']diaqua copper(II). AB - In the title compound, [Cu(C(5)H(14)NO(6)P(2))(2)(H(2)O)(2)], the Cu(II) atom occupies a special position on an inversion centre. It exhibits a distorted octa hedral coordination environment consisting of two O,O'-bidentate (1-ammonio pentane-1,1-di-yl)diphospho-nate anions in the equatorial plane and two trans water mol-ecules located in axial positions. The ligand mol-ecules are coordinated to the Cu(II) atom in their zwitterionic form via two O atoms from different phospho-nate groups, creating two six-membered chelate rings with a screw-boat conformation. The CuO(6) coordination polyhedron is strongly elongated in the axial direction with 0.6 A longer bonds than those in the equatorial plane. Intra-molecular N-H?O hydrogen bonding helps to stabilize the mol-ecular configuration. The presence of supra-molecular -PO(OH)?O(OH)P- units parallel to (100) and other O-H?O and N-H?O hydrogen bonds establish the three-dimensional set-up. PMID- 21589233 TI - (Benzyl-diphenyl-phosphane)chlorido-gold(I). AB - In the title compound, [AuCl(C(19)H(17)P)], the Au(I) atom exists within a P and Cl donor set that constitutes an almost linear geometry. The three phenyl rings make dihedral angles of 38.33 (14), 81.26 (15) and 81.28 (14) degrees with each other. In the crystal, mol-ecules are linked into chains along the b axis by inter-molecular C-H?Cl hydrogen bonds. PMID- 21589234 TI - (MU-Butane-1,2,3,4-tetra-carboxyl-ato)bis-[triaqua-(1,10 phenanthroline)nickel(II)] hexa-hydrate. AB - The asymmetric unit of the title compound, [Ni(2)(C(8)H(6)O(8))(C(12)H(8)N(2))(2)(H(2)O)(6)].6H(2)O, contains a half of the centrosymmetric dinuclear complex mol-ecule and three uncoordinated water mol ecules. In the dinuclear mol-ecule, two Ni(II) cations are bridged by the butane 1,2,3,4-tetra-carboxyl-ate (BTC(4-)) anion. Each Ni(II) atom is coordinated by two N atoms from the 1,10-phenanthroline ligand, one O atom from the BTC(4-) anion and three aqua ligands in a distorted octa-hedral geometry. Inter-molecuar O-H?O hydrogen bonds and pi-pi stacking inter-ations [centroid-centroid distances = 3.646 (2), 3.781 (2) and 3.642 (2) A] consolidate the crystal packing. PMID- 21589235 TI - catena-Poly[[[(1,10-phenanthroline)copper(I)]-MU-cyanido] ethanol hemisolvate]. AB - In the title coordination polymer, {[Cu(CN)(C(12)H(10)N(2))].0.5C(2)H(5)OH}(n), there are two Cu(I) ions, two 1,10-phenanthroline (phen) ligands and two cyanide ions in the asymmetric unit along with a highly disordered ethanol solvent mol ecule, which was modelled as being disordered over two sets of sites in a 0.829 (7):0.171 (7) ratio. The orientation/ordering of the C and N atoms of the cyanide ions could not be determined in the present refinement and they were modelled as being statistically disordered. Both copper ions are coordinated by an N,N' bidentate phen ligand and two cyanide ligands, generating distorted tetra-hedral CuN(2)Q(2) (Q = C or N) tetra-hedra. The MU-cyanide ligands link the metal ions, forming a zigzag chain propagating in [001]. The chains are cross-linked by numerous aromatic pi-pi stacking contacts between adjacent phen rings [minimum centroid-centroid separation = 3.620 (3) A]. PMID- 21589236 TI - Poly[[hexa-aqua-(MU(2)-fumarato-kappaO,O:O,O)bis-(MU(3)-maleato kappaO,O:O:O)disamarium(III)] hexa-hydrate]. AB - In the title coordination polymer, {[Sm(2)(C(4)H(2)O(4))(3)(H(2)O)(6)].6H(2)O}(n), the Sm(III) ion is nine coordinated by four O atoms from three different maleate ligands, two O atoms from one fumarate ligand and three O atoms from three water mol-ecules. The fumarate ligand lies on an inversion center. Adjacent Sm(III) ions are bridged by the maleate and fumarate ligands, forming a layer parallel to (011). The layers are further linked by inter-molecular O-H?O hydrogen bonds into a three dimensional supra-molecular network. PMID- 21589237 TI - Bis(4-cyano-phenolato)[hydro-tris-(3,5-dimethyl-pyrazol-yl)borato]nitro-syl molybdenum(II)-4-hydroxy-benzonitrile-dichloro-methane (1/1/1). AB - In the title compound, [Mo(C(15)H(22)BN(6))(C(7)H(4)NO)(2)(NO)].C(7)H(5)NO.CH(2)Cl(2), the central Mo(II) atom adopts a distorted cis-MoO(2)N(4) octa-hedral geometry with the hydro tris-(3,5-dimethyl-pyrazolylborate) anion attached to the metal in an N,N',N'' tridentate tripodal coordination mode. Two O-bonded 4-cyano-phenolate anions and a nitrosyl cation complete the coodination of the Mo(II) atom. Two intra molecular C-H?O and one C-H?N hydrogen bonds help to establish the configuration of the complex mol-ecule. The crystal structure is stabilized by inter-molecular C-H?N and C-H?O hydrogen bonds. PMID- 21589238 TI - 19-Ferrocenyl-18-oxa-8,16-diaza-penta-cyclo-[8.6.3.0.0.0]nona-deca-2(7),3,5 triene-9,17-dione. AB - In the title compound, [Fe(C(5)H(5))(C(21)H(19)N(2)O(3))], both pyrrol-idine rings of the pyrrolizine substructure show an envelope conformation. In the ferrocenyl moiety, the unsubstituted cyclo-penta-dienyl ring is disordered over two orientations with site occupancies of 0.64 (2) and 0.36 (2). In the pyrrolizine ring, one C atom is disordered over two positions, with site occupancies of 0.71 (1) and 0.29 (1). Intra-molecular C-H?O inter-actions occur. The crystal packing is established through weak inter-molecular C-H?O and N-H?O inter-actions. PMID- 21589239 TI - Diaqua-bis-[2-(5-isopropyl-5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2 yl)nicotinato]cobalt(II). AB - In the title complex, [Co(C(13)H(14)N(3)O(3))(2)(H(2)O)(2)], the Co(II) atom has a distorted octa-hedral coordination, formed by four N atoms from two (+/-)-2-(5 isopropyl-5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)nicotinate ligands and two O atoms from two water mol-ecules. Intra-molecular N-H?O and O-H?O hydrogen bonds are present. In the crystal, inter-molecular O-H?O hydrogen bonds link the complex mol-ecules into a chain along [010]. PMID- 21589240 TI - Poly[di-MU(2)-aqua-MU(4)-chlorido-MU(4)-(2-mercaptopyrimidine-4,6-diolato kappaO:O:O':O')-disodium(I)]. AB - In the title coordination polymer, [Na(2)(C(4)H(3)N(2)O(2)S)Cl(H(2)O)(2)](n), the Na(I) ion lies on a twofold rotation axis and the chloride anion on an inversion center. The Na(I) ion is six-coordinated by two O atoms from two zwitterionic 2 mercaptopyrimidine-4,6-diolate ligands (mm2 symmetry), two water O atoms (m symmetry) and two Cl atoms in a distorted octa-hedral geometry. Adjacent Na(I) ions are bridged by an olate group, a water mol-ecule and a chloride anion into a three-dimensional network. The crystal structure is further stabil-ized by N H?Cl, O-H?O and O-H?S hydrogen bonds. PMID- 21589241 TI - (N,N-Dimethyl-formamide-kappaO)bis-(3-hy-droxy-picolinato-kappaN,O)phenyl-bis muth(III). AB - The title organometallic complex, [Bi(C(6)H(5))(C(6)H(4)NO(3))(2)(C(3)H(7)NO)], features a Bi(III) atom in a distorted pentagonal-pyramidal coordination by two N,O-donating bidentate 3-hy-droxy-picolinate (3-hpic) ligands, one monodentate dimethyl-formamide (dmf) mol-ecule and one phenyl ring. The C atom of the aryl ligand occupies the apical position of the BiCN(2)O(3) coordination polyhedron, while the equatorial plane is formed by one O atom of the dmf ligand and two sets of N and O atoms from the chelating 3-hpic ligands. Inter-molecular secondary Bi?O [3.485 (3) A] and O-H?O hydrogen-bonding inter-actions connect the complexes into a three-dimensional network. Intramolecular O-H?O hydrogen bonds are also observed. PMID- 21589242 TI - Bis[MU-2,2'-dimethyl-1,1'-(3-oxapentane-1,5-di-yl)di-1H-benzimidazole kappaN:N]bis-[bis-(4-meth-oxy-benzoato)-kappaO;kappaO,O'-cobalt(II)]. AB - The complete mol-ecule of the title complex, [Co(2)(C(8)H(7)O(3))(4)(C(20)H(22)N(4)O)(2)], is a dimer of the paddle-wheel-type generated by crystallographic inversion symmetry. The Co(II) ion is penta coordinated by three O atoms from two 4-meth-oxy-benzoate anions (one bidentate and one monodentate) and two N atoms from two 2,2'-bis-(2-methyl-1H benzimidazole)-ether ligands. This results in a very distorted trigonal bipyramidal geometry for the metal ion, with both N atoms in equatorial sites. The dihedral angle between the benzimidazole ring systems in the ligand is 60.04 (8) degrees . The configuration of the mol-ecule is supported by intra-molecular C-H?O hydrogen bonds. PMID- 21589243 TI - Aqua-(4-nitro-phthalato-kappaO)bis-[2-(1H-pyrazol-3-yl-kappaN)pyridine-kappaN] mangan-ese(II) hemihydrate. AB - In the title compound, [Mn(C(8)H(3)NO(6))(C(8)H(7)N(3))(2)(H(2)O)].0.5H(2)O, the Mn(2+) ion is octa-hedrally coordinated by two 2-(1H-pyrazol-3-yl)pyridine ligands, one 4-nitro-phthalate ligand and one coordinated water mol-ecule leading to an overall MnN(4)O(2) coordination environment. The two 2-(1H-pyrazol-3 yl)pyridine ligands, which deviate from planarity by 0.0187 (2) and 0.0601 (2) A, make a dihedral angle of 81.90 (6) degrees . An intra-molecular N-H?O hydrogen bond occurs. Inter-molecular pi-pi stacking inter-actions with a face-to-face separation of 3.61 (1) A between the 2-(1H-pyrazol-3-yl)pyridine ligands is observed. Additionally, O-H?O hydrogen bonding involving the uncoordinated water (which is situated on an inversion center), coordinated water mol-ecules and 2 (1H-pyrazol-3-yl)pyridine ligands leads to a three-dimensional network in the crystal structure. PMID- 21589244 TI - Bis(2-hy-droxy-ethanaminium) tetra-chloridopalladate(II). AB - In the title compound, (C(2)H(8)NO)(2)[PdCl(4)], 2-hy-droxy-ethanaminium cations and tetra-chloridopalladate(II) dianions crystallize in a 2:1 ratio with the anion residing on a crystallographic inversion center. The cations and anions are linked in a complex three-dimensional framework by three types of strong hydrogen bonds (N-H?O, N-H?Cl, and O-H?Cl), which form various ring and chain patterns of up to the ternary graph-set level. PMID- 21589245 TI - [N-(3-Meth-oxy-2-oxidobenzyl-idene-kappaO)leucinato-kappaN,O](1,10-phenanthroline kappaN,N')copper(II) monohydrate. AB - The asymmetric unit of the title complex, [Cu(C(14)H(17)NO(4))(C(12)H(8)N(2))].H(2)O, contains two independent Cu(II) complex mol-ecules and two uncoordinated water mol-ecules. In each complex mol ecule, the Cu atom is O,N,O'-chelated by the tridentate Schiff base ligand and N,N'-chelated by the 1,10-phenanthroline ligand in a distorted square-pyramidal geometry. The Cu-N bond distances in the apical directions are 2.298 (4) and 2.268 (4) A. In the crystal, inter-molecular O-H?O and C-H?O hydrogen bonds together with C-H?pi inter-actions result in a three-dimensional supra-molecular structure. PMID- 21589246 TI - Poly[[diaqua-(MU(2)-5,5-dioxodibenzo[b,d]thio-phene-3,7-dicarboxyl-ato)(MU(2) ethyl-ene glycol)manganese(II)] dimethyl-acetamide solvate]. AB - In the title complex, {[Mn(C(14)H(6)O(6)S)(C(2)H(6)O(2))(H(2)O)(2)].C(4)H(9)NO}(n), the Mn(II) ion is six-coordinated in a trans-octa-hedral geometry by two carboxyl-ate O atoms from two 5,5-dioxodibenzo[b,d]thio-phene-3,7-dicarboxyl-ate (L) ligands in a monodentate mode, two O atoms from two ethyl-ene glycol (EG) mol-ecules and two aqua O atoms. The metal ions are linked by the EG and L ligands, forming two dimensional coordination networks, which are associated into the three dimensional structure through O-H?O hydrogen bonds. PMID- 21589247 TI - Poly[MU-bromido-MU-(2,2-dimethyl-propane-1,3-diyl diisocyanide)-silver(I)]: a powder diffraction study. AB - In the title compound, [AgBr(C(7)H(10)N(2))](n), adjacent Ag(I) atoms are bridged by bidentate CNCH(2)C(CH(3))(2)CH(2)NC ligands via the NC groups, forming [Ag{CNCH(2)C(CH(3))(2)CH(2)NC}](n) chains with the metal atom in a distorted tetrahedral coordination. The bromide counter-anions cross-link the Ag(I) atoms of the chains, forming a two-dimensional polymeric network {[Ag(I)(CNCH(2)C(CH(3))(2)CH(2)NC)]Br}(n) extend-ing parallel to (010). The polymeric structure is similar to that of the very recently reported Cl(-), I(-) and NO(3) (-) analogues. This gives a strong indication that 2,2-dimethyl-propane 1,3-diyl diisocyanide is a potential ligand for giving polymeric structures on treatment with AgX (X = Cl(-), Br(-), I(-) or NO(3) (-)) regardless of the counter-anion used. PMID- 21589248 TI - Chlorido(pyridine-2-carboximidamide-kappaN,N)zinc(II) chloride dihydrate. AB - In the title salt, [ZnCl(C(6)H(7)N(3))(2)]Cl.2H(2)O, the pyridine-2 carboximidamide ligands chelate to the Zn(II) atom, which is also coordinated by a Cl atom. The Zn(II) atom shows a trigonal-bipyramidal coordination, with the pyridyl N atoms occupying the axial positions. The cation, anion and water mol ecules are linked by N-H?Cl, N-H?O, O-H?Cl and O-H?O hydrogen bonds into a three dimensional structure. PMID- 21589249 TI - (4-Chloro-benzohydrazidato-kappaN',O)[2-(4-chloro-benzoyl-hydrazinyl-idene kappaN,O)-3-phenyl-propionato(2-)-kappaO]oxidovanadium(V) methanol monosolvate. AB - The V(V) atom in the title compound, [V(C(7)H(6)ClN(2)O)(C(16)H(11)ClN(2)O(3))O].CH(3)OH, is N,O-chelated by the benzoyl-hydrazidate anion and O,N,O'-chelated by the (benzoyl-hydrazinyl idene)propionate dianion. The distorted octa-hedral trans-N(2)O(4) coordination geometry is completed by the vanadyl O atom. The mononuclear and solvent mol ecules are linked by N-H?O and O-H?O hydrogen bonds about a center of inversion, generating a dimer. PMID- 21589250 TI - Bis[MU-4-(methyl-amino)-benzoato]-kappaO,O':O;kappaO:O,O'-bis-{aqua-[4-(methyl amino)-benzoato-kappaO,O'](nicotinamide-kappaN)cadmium(II)}. AB - In the dinuclear centrosymmetric Cd(II) compound, [Cd(2)(C(8)H(8)NO(2))(4)(C(6)H(6)N(2)O)(2)(H(2)O)(2)], the metal atom is chelated by two carboxyl-ate groups from 4-(methyl-amino)-benzoate (PMAB) anions, and coordinated by one nicotinamide and one water mol-ecule; a carboxyl-ate O atom from the adjacent PMAB anion bridges to the Cd atom, completing the irregular seven-coordination geometry. In the crystal, inter-molecular O-H?O, N-H?O and C H?O hydrogen bonds link the mol-ecules into a three-dimensional network. pi-pi contacts between the pyridine rings [centroid-centroid distance = 3.965 (1) A] may further stabilize the structure. A weak C-H?pi inter-action also occurs. PMID- 21589251 TI - catena-Poly[[(3,5-dicarb-oxy-pyrazine-2,6-dicarboxyl-ato-kappaO,N,O)lithium(I)] MU-aqua-[triaqua-lithium(I)]-MU-aqua]. AB - The title coordination polymer, [Li(2)(C(8)H(2)N(2)O(8))(H(2)O)(5)](n) contains two symmetry-independent Li(+) ions; one is coordin-ated by five water O atoms, the other by an O,N,O'-tridentate doubly deprotonated pyrazine-2,3,5,6-tetra carboxyl-ate ligand and two water O atoms. Water mol-ecules bridge adjacent Li(+) ions into ribbons propagating in [100]; an alternative analysis of the structure considers it to contain alternating [Li(C(8)H(2)N(2)O(8))(H(2)O)(2)](-) anions and [Li(H(2)O)(3)](+) cations. In the polymeric model, both lithium ions show distorted trigonal-bipyramidal coordination geometries. Within the ligand, the carboxyl H atoms participate in short, almost symmetric O?H?O hydrogen bonds in which the non-coordinated carboxyl-ate O atoms are donors and acceptors. In the crystal, the ribbons inter-act via a network of O-H?O hydrogen bonds in which the coordinated water mol-ecules act as donors and ligand carboxyl-ate O atoms as acceptors. PMID- 21589252 TI - Bis(MU-2,2'-disulfanediyldibenzoato)bis-[aqua-(2,2'-bipyridine)-nickel(II)]. AB - In the centrosymmetric title complex, [Ni(2)(C(14)H(8)O(4)S(2))(2)(C(10)H(8)N(2))(2)(H(2)O)(2)], the Ni(II) atom is coordinated by two N atoms from one 2,2'-bipyridine ligand, three carboxyl-ate O atoms (one bidentate and one monodentate) from two different disulfanediyldibenzoate ligands and one O atom from a coordinated water mol-ecule in an octa-hedral coordination geometry. The disulfanediyldibenzo-ate dianion bridges two Ni(II )atoms. Adjacent mol-ecules are linked through the coordinated water mol-ecules, forming a O-H?O hydrogen-bonded chain running along the a axis. PMID- 21589253 TI - (eta-Penta-methyl-cyclo-penta-dien-yl)(eta-4-phenyl-butan-2-one)ruthenium(II) tetra-phenyl-borate. AB - The title compound, [Ru(C(10)H(15))(C(10)H(12)O)][B(C(6)H(5))(4)], crystallizes as discrete (eta(5)-penta-methyl-cyclo-penta-dien-yl)Ru(eta(6)-4-phenyl-butan-2 one)](+) cations and [BPh(4)](-) anions. In the cation, the non-H atoms of the butan-2-one group are approximately planar (r.m.s. deviation = 0.056 A) and lie nearly perpendicular to the plane of the phenyl ring with a dihedral angle between the two planes of 69.3 (1) degrees . No significant C-H?O inter-actions are observed between the methyl and phenyl H atoms and the carbonyl O atom. PMID- 21589254 TI - Tetra-MU-acetato-kappaO:O';kappaO,O':O;kappaO:O,O'-bis-[(acetato-kappaO,O')(1,10 phenanthroline-kappaN,N')europium(III)]. AB - In the title centrosymmetric dinuclear complex, [Eu(2)(CH(3)CO(2))(6)(C(12)H(8)N(2))(2)], the Eu(III) atom is nine-coordinated by two N atoms from a 1,10-phenanthroline ligand and seven O atoms from five acetate ligands (two bidentate, three monodentate). The crystal structure is stabilized by pi-pi stacking inter-actions between the pyridine and benzene rings of adjacent mol-ecules, with a centroid-centroid distance of 3.829 (2) A. PMID- 21589255 TI - Tetra-aqua-diazido-cobalt(II) 3,3'-dicarb-oxy-l-ato-1,1'-ethyl-enedipyridinium. AB - The asymmetric unit of the title compound, [Co(N(3))(2)(H(2)O)(4)].C(14)H(12)N(2)O(4), comprises half of the cobalt(II) complex mol-ecule and a half of the 3,3'-dicarboxyl-ato-1,1'-ethyl enedipyridinium mol-ecule. The Co(II) atom is located on an inversion centre and hence the complex mol-ecule adopts a centrosymmetric trans-octa-hedral geometry. The zwitterionic organic mol-ecule is also centrosymmetric with the centre of the C-C bond of the ethyl-ene moiety coinciding with an inversion centre. The adduct of metal complex and organic mol-ecule is associated into a three-dimenional network through O-H?O hydrogen bonds. PMID- 21589256 TI - Bis[4-chloro-N'-(2-pyridyl-methyl-idene)benzohydrazidato]cobalt(III) nitrate sesquihydrate. AB - In the title compound, [Co(C(13)H(9)ClN(3)O)(2)]NO(3).1.5H(2)O, the central Co(3+) atom in the cation is coordinated by four N and two O atoms from the two tridentate ligands in a distorted octa-hedral fashion. In the crystal, the cobalt complex cations are linked to the half-occupied and the fully occupied water mol ecules, and the nitrate anion via classical inter-molecular O-H?O and O-H?N hydrogen bonds and weak C-H?O contacts. PMID- 21589257 TI - Diaqua-bis-{2-hy-droxy-5-[(pyridin-2-yl)methyl-idene-amino]-benzoato kappaN,N'}nickel(II) dihydrate. AB - In the title complex, [Ni(C(13)H(9)N(2)O(3))(2)(H(2)O)(2)].2H(2)O, the Ni(II) atom, located on a twofold rotation axis, is in a distorted octa-hedral geometry, defined by four N atoms from two 2-hy-droxy-5-[(pyridin-2-yl)methyl-idene-amino] benzoate ligands and two O atoms from two water mol-ecules. In the crystal, inter molecular O-H?O hydrogen bonds link the complex mol-ecules and uncoordinated water mol-ecules into a three-dimensional network. Intra-molecular O-H?O hydrogen bonds are present between the hy-droxy and carboxyl-ate groups. PMID- 21589258 TI - {2,2'-[4-Chloro-5-methyl-o-phenyl-enebis(nitrilo-methyl idyne)]diphenolato}nickel(II). AB - In the title complex, [Ni(C(21)H(15)ClN(2)O(2))], the Ni(II) ion is coordinated by two N and two O atoms from the tetra-dentate Schiff base ligand in a distorted square geometry. The crystal packing exhibits short inter-molecular Ni?Ni distances of 3.273 (3) A. PMID- 21589259 TI - Triaqua-(benzene-1,3-dicarboxyl-ato)(4,5-diaza-fluoren-9-one)cadmium(II) penta hydrate. AB - In the title compound, [Cd(C(8)H(4)O(4))(C(11)H(6)N(2)O)(H(2)O)(3)].5H(2)O, the Cd(II) atom is seven-coordinated by two N atoms from one bidentate phenanthroline derived ligand and by five O atoms, two from one bidentate benzene-1,3-dicarboxyl ate (1,3-BDC) ligand and three from water mol-ecules, in a distorted penta-gonal bipyramidal geometry. Neighbouring units inter-act through pi-pi inter-actions [centroid-centroid distances = 3.380 (3) and 3.283 (4) A]. Finally, three types of O-H?O hydrogen bonds exist between coordinated dissociative water mol-ecules and hybridization water mol-ecules and carboxyl-ate O atoms, resulting in a two dimensional network parallel to (010). PMID- 21589260 TI - catena-Poly[[(2,2'-bipyridine)-nickel(II)]-MU-2,4'-oxydibenzoato]. AB - In the title compound, [Ni(C(14)H(8)O(5))(C(10)H(8)N(2))](n), the Ni(II) atom is six-coordinated in a slightly distorted octa-hedral geometry by four O atoms from two chelating carboxyl-ate groups of symmetry-related 2,4'-oxydibenzoate anions and by two N atoms from a 2,2'-bipyridine ligand. The Ni(II) atoms are bridged by the 2,4'-oxydibenzoate anions, resulting in the formation of helical chains parallel to [010] with a repeating unit of 15.039 (2) A. PMID- 21589261 TI - (2,2'-Bipyridine-kappaN,N')chlorido(1,4,7-trithia-cyclo-nonane kappaS,S',S'')ruthenium(II) nitrate monohydrate. AB - In the title compound, [RuCl(C(10)H(8)N(2))(C(6)H(12)S(3))]NO(3).H(2)O or [RuCl(bpy)([9]aneS(3))]NO(3).H(2)O, ([9]aneS(3) is 1,4,7-tri-thia-cyclo-nonane and bpy is 2,2'-bipyridine), the Ru(II) cation has a slightly distorted octa hedral environment composed of three facially coordinated S atoms from ([9]aneS(3)), two N atoms from bpy and a chloride anion. The nitrate counter-ion and the water mol-ecule of crystallization are engaged in O-H?O hydrogen-bonding inter-actions, leading to a supra-molecular chain running parallel to the c axis. PMID- 21589262 TI - Poly[diaqua-bis-[MU-1-hy-droxy-2-(imidazol-3-ium-1-yl)ethane-1,1-diyldiphospho nato]tricopper(II)]. AB - In the title coordination polymer, [Cu(3)(C(5)H(7)N(2)O(7)P(2))(2)(H(2)O)(2)](n), one Cu(II) atom is five-coordinated by five O atoms from three 1-hy-droxy-2 (imidazol-3-ium-1-yl)ethane-1,1-diyldiphospho-nate (L) ligands in a distorted square-pyramidal geometry. The other Cu(II) atom, lying on an inversion center, is six-coordinated in a distorted octa-hedral geometry by four O atoms from two L ligands and two O atoms from two water mol-ecules. The five-coordinated Cu(II) atoms are linked by phospho-nate O atoms of the L ligands, forming a polymeric chain. These chains are further linked by the six-coordinated Cu atoms into a layer parallel to (01). N-H?O and O-H?O hydrogen bonds connect the layers into a three-dimensional supra-molecular structure. PMID- 21589263 TI - Bis[tetra-aqua-(1,10-phenanthroline-kappaN,N')cobalt(II)] hexa-aqua-cobalt(II) bis-[3,5-bis-(carboxyl-atometh-oxy)benzoate] tetra-hydrate. AB - The title compound, [Co(C(12)H(8)N(2))(H(2)O)(4)](2)[Co(H(2)O)(6)](C(11)H(7)O(8))(2).4H(2)O, was obtanied by the reaction of cobalt acetate with 3,5-bis-(carb-oxy-meth oxy)benzoic acid and 1,10-phenanthroline. The asymmetric unit contains one tetra aqua-(1,10-phenanthroline)cobalt(II) cation, one half of a hexa-aqua-cobalt(II) cation that is completed by inversion symmetry, one 3,5-bis-(carboxyl-atometh oxy)benzoate trianion and two lattice water mol-ecules. The two Co(II) atoms each show a slightly distorted octa-hedral coordination (CoO(6) and CoO(4)N(2)). The cations, anions and lattice water mol-ecules are linked by an intricate network of O-H?O hydrogen bonds into a three-dimensional structure. PMID- 21589264 TI - Bis[MU(2)-1,1-(butane-1,4-di-yl)-2,3-dicyclo-hexyl-guanidinato]bis-[(tetra-hydro furan)-lithium](Li-Li). AB - In the dinuclear centrosymmetric title complex, [Li(2)(C(17)H(30)N(3))(2)(C(4)H(8)O)(2)], the Li(+) cation is coordinated by three N atoms from two guanidinate ligands and an O atom from tetra-hydro-furan (THF) in a strongly distorted tetrahedral environment. In the guanidinate-bridged THF-stabilized dimer the Li?Li separation is short at 2.479 (8) A. PMID- 21589265 TI - catena-Poly[[dichloridozinc(II)]-MU-[1,1'-(butane-1,4-di-yl)diimidazole kappaN:N]]. AB - The title one-dimensional coordination polymer, [ZnCl(2)(C(10)H(14)N(4))](n), was synthesized by hydro-thermal methods from ZnCl(2) and 1,1'-(butane-1,4-di yl)diimidazole. The Zn atom is coordinated by two chloride ions and two N atoms from two symmetry-independent organic ligands and shows a distorted tetra-hedral coordination geometry. The 1,1'-(butane-1,4-di-yl)diimidazole ligands are located around two sets of inversion centers and bridge Zn(II) ions, forming a zigzag polymeric chain. C-H?Cl hydrogen bonding results in the formation of a three dimensional supra-molecular network. PMID- 21589266 TI - Hexaaqua-magnesium(II) bis-(pyridinium-2,6-dicarboxyl-ate). AB - In the title compound, [Mg(H(2)O)(6)](C(7)H(4)NO(4))(2), a single six-coordinate Mg(2+) cation (site symmetry 2/m) is bonded to six water mol-ecules in a distorted octa-hedral geometry. The crystal packing between the complex cation and the zwitterionic organic cation (m symmetry) is stabilized by inter-molecular O-H?O hydrogen bonds and weak inter-molecular C-H?O inter-actions. PMID- 21589267 TI - Bis[MU-3-(1H-benzimidazol-2-yl)benzoato]dicopper(I). AB - The dimeric title complex, [Cu(2)(C(14)H(9)N(2)O(2))(2)], resides on a center of symmetry. In the crystal, the mol-ecules are packed via pi-pi stacking inter actions alternating between imidazole and benzene rings [mean inter-planar distances = 3.754 (3) and 3.624 (3) A]. An inter-molecular N-H?O hydrogen bond links the dimers together. The two-coordinate Cu(I) atom displays an O-Cu-N bond angle of 176.3 (2) degrees . The Cu?Cu distance within the dimer is 5.100 (2) A. PMID- 21589268 TI - Bis(benzoato-kappaO,O')(2,2'-bipyridine-kappaN,N')lead(II) benzoic acid monosolvate. AB - The reaction of lead acetate, benzoic acid and 2,2'-bipyridine (bipy) in aqueous solution yielded the title complex, [Pb(C(7)H(5)O(2))(2)(C(10)H(8)N(2))].C(7)H(6)O(2). The asymmetric unit contains two independent complex mol-ecules as well as two independent benzoic acid solvent mol-ecules, one of which is disordered over two positions with almost equal occupancies [0.504 (5) and 0.496 (5)]. The two complex mol-ecules have similar configurations with the hexa-coordinated environment of the Pb(II) atom formed by four carboxyl-ate O atoms of two chelate benzoate ligands and two N atoms of the bipy ligand. The Pb-O bonds involving one of the benzoate ligands are almost coplanar with Pb-N bonds to the bipy ligand [dihedral angles of 12.67 (11) and 14.73 (11) degrees ] ; if the second benzoate ligand is treated as one coordination site, the overall coordination may be represented as a distorted pseudo-square pyramid. Weak inter-molecular Pb?O inter-actions [3.046 (3) and 3.359 (3) A] link each of the complex mol-ecules into two symmetry-independent centrosymmetric dimers. Hydrogen bonds involving the carboxyl H atoms of solvent benzoic acid mol-ecules and metal-coordinated carboxyl-ate O atoms link complex mol-ecules and benzoic acid solvent mol-ecules into insular aggregates. PMID- 21589269 TI - Dichlorido{1-[(2-hy-droxy-eth-yl)imino-meth-yl]-2-naphtho-lato}pyridine-iron(III) pyridine monosolvate. AB - In the title complex, [Fe(C(13)H(12)NO(2))Cl(2)(C(5)H(5)N)].C(5)H(5)N, the iron(III) atom is six-coordinated by the N and O atoms from the Schiff base ligand, the N atom from a pyridine mol-ecule and two chloride anions in a distorted octa-hedral geometry. The crystal packing is stabilized by inter molecular O-H?N hydrogen bonds and C-H?pi inter-actions. PMID- 21589270 TI - [1,1'-Bis(diphenyl-phosphan-yl)ferrocene-kappaP,P']dichloridocadmium(II) dichloro methane disolvate. AB - In the title complex, [CdFe(C(17)H(14)P)(2)Cl(2)].2CH(2)Cl(2), the Cd(II) atom has a distorted tetra-hedral coordination geometry by two chloride anions and two P atoms of 1,1'-bis-(diphenyl-phosphan-yl)ferrocene. In the crystal, complex mol ecules are linked into a three-dimensional network by C-H?Cl hydrogen bonds involving the dichloro-methane solvent mol-ecules. PMID- 21589271 TI - Bis[2-(pyridin-2-yl)ethanol-kappaN,O]bis-(thio-cyanato-kappaN)nickel(II). AB - In the title complex, [Ni(NCS)(2)(C(7)H(9)NO)(2)], the Ni(II) atom is in a distorted octa-hedral coordination environment defined by two N atoms of the two thio-cyanate ions and by the N and O atoms of the two chelating 2-(pyridin-2 yl)ethanol ligands. The complex mol-ecule is located around a crystallographic inversion center. In the crystal, mol-ecules are connected into a two-dimensional polymeric structure parallel to (100) by O-H?S hydrogen bonds. PMID- 21589272 TI - Diaqua-bis-(3-nitro-benzoato-kappaO)bis-[1H-5-(3-pyrid-yl)-3-(4-pyrid-yl)-1H 1,2,4-triazole-kappaN]cobalt(II) dihydrate. AB - In the centrosymmetric title compound, [Co(C(7)H(4)NO(4))(2)(C(12)H(9)N(5))(2)(H(2)O)(2)].2H(2)O, the Co(II) atom, located on an inversion center, is coordinated by two N atoms [Co-N = 2.155 (3) A] and four O atoms [Co-O = 2.099 (2)-2.117 (3) A] in a distorted octa-hedral geometry. Inter-molecular N-H?O, O-H?N and O-H?O hydrogen bonds link the components into a three-dimensional supramolecular framework. PMID- 21589273 TI - trans-Chlorido{3-chloro-2-[(1-naphth-yl)imino-meth-yl]phenyl-kappaC,N}bis (trimethyl-phosphane)nickel(II). AB - The title compound, [Ni(C(17)H(11)ClN)Cl(C(3)H(9)P)(2)], was obtained as a product of the reaction of [Ni(PMe(3))(4)] with a molar equivalent of 2,6 dichloro-N-naphthyl-benzaldehyde-amine in diethyl ether. The tau parameter is 0.3, indicating that the coordination geometry is square-pyramidal. The Ni(II) atom lies in the center of a square pyramidal in which one C, one Cl and two P atoms form the basal plane, with the imine N atom in an apical position. Two P atom donors are located in trans positions. PMID- 21589274 TI - {2,2'-[1,1'-(Ethane-1,2-diyldinitrilo)-diethyl-idyne]diphenolato}bis (pyrrolidine)cobalt(III) perchlorate p-xylene hemisolvate. AB - In the mononuclear title complex, [Co(C(18)H(18)N(2)O(2))(C(4)H(9)N)(2)]ClO(4).0.5C(8)H(10), the Co(III) ion has a slightly distorted octa-hedral coordination geometry. In the Me-salen ligand, the benzene rings are almost parallel, making a dihedral angle of 0.48 (13) degrees , but the torsion angle along the central C-C bond is 41.1 (2) degrees .The pyrrolidine rings are in slightly distorted chair conformations. The N atoms of the pyrrolidine axial ligands are involved in N-H?O hydrogen bonds with the perchlorate anions, and these hydrogen bonds connect the ionic species into infinite chains along the b axis. Some relatively short C-H?pi inter-actions are also present in the crystal structure and C-H?O inter-actions occur. The guest solvent p-xylene mol-ecule lies on a special position at the inversion centre. PMID- 21589275 TI - (C-meso-N-meso-5,12-Dimethyl-7,14-diphenyl-1,4,8,11-tetra-aza-cyclo-tetra-deca 4,11-diene)copper(II) bis-[O,O'-bis-(4-methyl-phen-yl)dithio-phosphate]. AB - In the title compound, [Cu(C(24)H(32)N(4))](C(14)H(14)O(2)PS(2))(2), the Cu(II) atom lies on an inversion center and is chelated by the macrocyclic ligand in a distorted CuN(4) square-planar geometry. Two O,O'-bis-(4-methyl-phen-yl)dithio phosphate anions occupy the axial positions with long Cu?S distances of 3.0090 (8) A. Inter-molecular N-H?S and C-H?S hydrogen bonding is present between the anions and the cation. PMID- 21589276 TI - (meso-5,5,7,12,12,14-Hexamethyl-1,4,8,11-tetra-aza-cyclo-tetra-deca-ne)copper(II) bis-[O,O'-(o-phenyl-ene)dithio-phosphate]. AB - In the title compound, [Cu(C(16)H(36)N(4))](C(6)H(4)O(2)PS(2))(2), the Cu(II) cation lies on an inversion center and is chelated by the macrocyclic tetra-amine ligand in a slightly distorted CuN(4) square-planar geometry. The axial positions are occupied by two O,O'-(o-phenyl-ene)dithio-phosphate anions with long Cu?S distances of 3.0940 (7) A. Inter-molecular N-H?S and C-H?O hydrogen bonding is present between the anions and the cation and helps to stabilize the crystal structure. PMID- 21589277 TI - (4,4'-Dimethyl-2,2'-bipyridine-kappaN,N')(dimethyl sulfoxide kappaO)diiodidozinc(II). AB - In the title compound, [ZnI(2)(C(12)H(12)N(2))(C(2)H(6)OS)], the Zn(II) ion is coordinated by two N atoms from a 4,4'-dimethyl-2,2'-bipyridine ligand, one O atom from a dimethyl sulfoxide mol-ecule and two I atoms in a distorted trigonal bipyramidal geometry. Intra-molecular C-H?O hydrogen bonds and inter-molecular pi pi stacking inter-actions between the pyridine rings [centroid-centroid distances = 3.637 (4) and 3.818 (4) A] are present in the crystal structure. PMID- 21589278 TI - Bis(2-aminopyridinium) tetra-chloridozincate(II). AB - In the title compound, (C(5)H(7)N(2))(2)[ZnCl(4)], the pyridine N atoms are protonated and the [ZnCl(4)](2-) anions adopt a slightly distorted tetra-hedral configuration. In the crystal, weak N-H?Cl hydrogen bonds link the mol-ecules into layers, while weak pi-pi inter-actions [centroid-centroid distance = 4.2758 (18) A] also help to stabilize the packing. PMID- 21589279 TI - Triazidotris[MU-2-(2-pyridyl)ethanolato]dicobalt(II) acetonitrile monosolvate. AB - In the title compound, [Co(2)(C(7)H(8)NO)(3)(N(3))(3)].CH(3)CN, the two Co(II) ions in the dinuclear complex have different coordination environments, both in a distorted octa-hedral geometry. One Co(II) atom is coordinated by three O atoms from the three 2-hy-droxy-ethyl-pyridine (HEP) bridging ligands, two N atoms from two HEP ligands and one azido ligand, while the other Co(II) atom is coordinated by the same three O atoms, one N atom from an HEP ligand and two azido ligands. Weak inter-molecular C-H?N hydrogen bonds link the dinuclear complexes into corrugated layers parallel to the bc plane. These layers are further packed with the formation of channels propagating in [010] and filled with the disordered [in a ratio 0.691 (13):0.309 (13)] acetonitrile solvate mol-ecules. PMID- 21589280 TI - [1,1-(Butane-1,4-diyl)-2,3-dicyclohexylguanidinato]dimethylaluminum(III). AB - In the crystal structure of the title complex, [Al(CH(3))(2)(C(17)H(30)N(3))], the Al(III) cation is coordinated by two methyl ligands and two N atoms from the guanidinato ligand in a distorted tetra-hedral geometry. The dihedral angle between the CN(2) and AlC(2) planes is 85.37 (2) degrees . The two N atoms of the guanidinato ligand exhibit an almost uniform affinity to the metal atom. PMID- 21589281 TI - Poly[dimethyl-ammonium [tris-(MU(2)-formato-kappaO:O')cadmate(II)]]. AB - In the coordination polymer, {(C(2)H(8)N)[Cd(CHO(2))(3)]}(n), the Cd(II) atom lies on a special position of site symmetry in an octa-hedron of O atoms. The formate unit bridges the metal atoms, generating a three-dimensional polyanionic framework. The disordered cations occupy the cavities within the framework, and are N-H?O hydrogen-bonded to the framework. PMID- 21589282 TI - Diiodido(2,3,5,6-tetrapyridin-2-yl-pyrazine-kappaN,N,N)zinc(II). AB - In the title compound, [ZnI(2)(C(24)H(16)N(6))], the Zn(II) ion is five coordinated in a distorted trigonal-bipyramidal geometry by an N,N,N-tridentate 2,3,5,6-tetra-2-pyridinylpyrazine ligand and two iodide ions. The I(-) ions both occupy equatorial sites. Within the ligand, the dihedral angles between the central pyrazine ring and the two chelating pyridine (py) rings are 14.74 (17) and 26.72 (18) degrees . The equivalent angles for the non-coordinating py rings are 28.63 (16) and 42.19 (17) degrees . There is no aromatic pi-pi stacking in the crystal. PMID- 21589283 TI - catena-Poly[[[diaqua-(nitrato-kappaO,O')cerium(III)]-bis-[MU-2-(4-hy-droxy-phen yl)acetato]-kappaO,O':O;kappaO:O,O'] mono-hydrate]. AB - In the title compound, {[Ce(C(8)H(7)O(3))(2)(NO(3))(H(2)O)(2)].H(2)O}(n), the Ce(III) ion is coordinated by eight O atoms from four 2-(4-hy-droxy-phen yl)acetate (HPAA) ligands, two O atoms from the chelating nitrate anion and two water mol-ecules in a distorted bis-capped quadrangular prismatic geometry. The HPAA ligands coordinate in a bridging tridentate mode. In the crystal, inter molecular O-H?O hydrogen bonds form a three-dimensional network which consolidates the packing. PMID- 21589284 TI - Bis{6-meth-oxy-2-[(4-methyl-phen-yl)iminiometh-yl]phenolate-kappaO,O'}tris (nitrato-kappaO,O')holmium(III) mono-hydrate. AB - The crystal structure of the title compound, [Ho(NO(3))(3)(C(15)H(15)NO(2))(2)].H(2)O, contains two Schiff base 6-meth-oxy-2 [(4-methyl-phen-yl)iminiometh-yl]phenolate (L) ligands, three independent nitrate ions that chelate to the Ho(III) ion with O atoms and a hydrate water mol-ecule. The coordination environment of the Ho(III) ion is ten-coordinate. The L ligands chelate with a strong Ho-O(phenolate) bond and weaker Ho-O(meth-oxy) contacts. The latter can be inter-preted as the apices of the bicapped square-anti prismatic [HoO(10)] polyhedron. Inter-molecular N-H?O hydrogen bonds occur. Intra molecular O-H?O inter-actions link the complex mol-ecules and uncoordinated water mol-ecules. PMID- 21589285 TI - Tetra-kis[1-phenyl-3-(1H-1,2,4-triazol-1-yl-kappaN)propan-1-one]bis-(thio-cyanato kappaN)manganese(II). AB - In the mononuclear title complex, [Mn(NCS)(2)(C(11)H(11)N(3)O)(4)], the Mn(II) atom, lying on an inversion center, is coordinated by two monodentate thio cyanate anions and four monodentate 1-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-1 one ligands in a distorted octa-hedral geometry. Each complex mol-ecule is linked to four neighboring ones by weak C-H?N and C-H?S hydrogen bonds, forming a two dimensional sheet parallel to (001). PMID- 21589286 TI - Hexaaqua-zinc(II) bis-[tris-(3-carb-oxy-pyridine-2-carboxyl-ato)zincate(II)]. AB - The title compound, [Zn(H(2)O)(6)][Zn(C(7)H(4)NO(4))(3)](2), consists of two [Zn(py-2,3-dcH)(3)](-) anions (py-2,3-dcH is 3-carboxy-pyridine-2-carboxylate) and one [Zn(H(2)O)(6)](2+) cation. The anion is a six-coordinate complex located on a threefold rotation axis with a slightly distorted octa-hedral geometry around Zn(2+) ion. The cation is also six-coordinate with an octa-hedral geometry around the Zn atom, located at a axis. Non-covalent inter-actions such as pi-pi stacking [centroid-centroid distance = 3.828 (4)A] and O-H?O hydrogen bonds play important roles in stabilizing the supra-molecular structure. PMID- 21589287 TI - trans-Bis(4,7-diphenyl-1,10-phenanthroline-kappaN,N')bis-(nitrato kappaO,O')zinc(II). AB - The title compound, [Zn(NO(3))(2)(C(24)H(16)N(2))(2)], is a twofold axially symmetric coordination compound. Given that the Zn-O interactions [2.4926 (15) and 2.6673 (15) A] can be considered as weakly bonding and the nitrate ions share the same C(2) axis of the Zn(dpp)(2) fragment (dpp is 4,7-diphenyl-1,10 phenanthroline), these anions belong to the coordination sphere of Zn(2+), leading to a complex with an overall coordination number of 8 for the metal ion. PMID- 21589288 TI - Diaqua-(2,6-dihy-droxy-benzoato-kappaO,O)bis-(2,6-dihy-droxy-benzoato-kappaO)bis (1,10-phenanthroline-kappaN,N')lanthanum(III)-1,10-phenanthroline (1/1). AB - In the title compound, [La(C(7)H(5)O(4))(3)(C(12)H(8)N(2))(3)(H(2)O)(2)].C(12)H(8)N(2), the La(III) atom is coordinated by four N atoms from two chelating 1,10-phenanthroline (phen) ligands, four O atoms from three 2,6-dihy-droxy-benzoate (DHB) anions (one monodentate, the other bidentate) and two water O atoms, completing a distorted LaN(4)O(6) bicapped square-anti-prismatic geometry. Within the mononuclear complex mol-ecule, intra-molecular pi-pi stacking inter-actions are observed, the first between a coordinated phen mol-ecule and a DHB ligand [centroid-centroid distance = 3.7291 (16) A], and the second between a coordinated phen mol-ecule and an uncoordinated phen ligand [centroid-centroid distance = 3.933 (2) A]. Inter-molecular pi-pi stacking is observed between adjacent complexes [inter planar distance = 3.461 (3) A]. Intra- and inter-molecular O-H?O hydrogen bonds are observed in the DHB ligands and between a water mol-ecule and DHB ligands, respectively. O-H?N hydrogen bonds are also observed in the DHB ligands and between uncoordinated phen mol-ecules and aqua ligands. PMID- 21589289 TI - Bis(2,6-dihy-droxy-benzoato-kappaO,O)(nitrato-kappaO,O')bis-(1,10-phenanthroline kappaN,N')europium(III). AB - The title mononuclear complex, [Eu(C(7)H(5)O(3))(2)(NO(3))(C(12)H(8)N(2))(2)], is isostructural with those of other lanthanides. The Eu atom is in a pseudo bicapped square-anti-prismatic geometry, formed by four N atoms from two chelating 1,10-phenanthroline (phen) ligands and by six O atoms, four from two 2,6-dihy-droxy-benzoate (DHB) ligands and the other two from a nitrate anion. pi pi stacking inter-actions between phen and DHB ligands [centroid-centroid distances = 3.5312 (19) and 3.8347 (16) A], and between phen and phen ligands [face-to-face separation = 3.433 (4) A] of adjacent complexes stabilize the crystal structure. Intra-molecular O-H?O hydrogen bonds are observed in the DHB ligands. PMID- 21589290 TI - Bis(2,6-dihy-droxy-benzoato-kappaO,O)(nitrato-kappaO,O')bis-(1,10-phenanthroline kappaN,N')samarium(III). AB - The title mononuclear complex, [Sm(C(7)H(5)O(3))(2)(NO(3))(C(12)H(8)N(2))(2)], is isostructural with that of other lanthanides. The Sm atom is in a pseudo-bicapped square-anti-prismatic geometry, formed by four N atoms from two chelating 1,10 phenanthroline (phen) ligands and by six O atoms, four from two 2,6-dihy-droxy benzoate (DHB) ligands and the other two from a nitrate anion. pi-pi stacking inter-actions between phen and DHB ligands [centroid-centroid distance = 3.528 (4) and 3.812 (3) A], and phen and phen ligands [face-to-face separation = 3.420 (10) A] of adjacent complexes stabilize the crystal structure. Intra-molecular O H?O hydrogen bonds are observed in the DHB ligands. PMID- 21589291 TI - Bis(2,6-dihy-droxy-benzoato-kappaO,O)(nitrato-kappaO,O')bis-(1,10-phenanthroline kappaN,N')gadolinium(III). AB - In the mononuclear title complex, [Gd(C(7)H(5)O(3))(2)(NO(3))(C(12)H(8)N(2))(2)], the Gd atom is in a pseudo-bicapped square-anti-prismatic geometry formed by four N atoms from two chelating 1,10-phenanthroline (phen) ligands and by six O atoms, four from two 2,6-dihy-droxy-benzoate (DHB) ligands and the other two from a nitrate anion. pi-pi stacking inter-actions between phen-DHB [centroid-centroid distances = 3.5334 (18) and 3.8414 (16) A] and phen-phen [face-to-face separation = 3.4307 (17) A] ligands of adjacent complex molecules stabilize the crystal structure. Intra-molecular O-H?O hydrogen bonds are observed in the DHB ligands. PMID- 21589292 TI - Poly[[tetra-aqua-(MU(4)-imidazole-4,5-dicarboxyl-ato)(MU(3)-imidazole-4,5 dicarboxyl-ato)-MU(3)-sulfato-MU(2)-sulfato-cobalt(II)dierbium(III)] monohydrate]. AB - The asymmetric unit of the title compound, {[CoEr(2)(C(5)H(2)N(2)O(4))(2)(SO(4))(2)(H(2)O)(4)].H(2)O}(n), contains a Co(II) ion, two Er(III) ions, two imidazole-4,5-dicarboxyl-ate (imdc) ligands, two SO(4) (2-) anions, four coordinated water mol-ecules and one uncoordinated water mol ecule. The Co(II) ion is six-coordinated by two O atoms from two coordinated water mol-ecules and two O atoms and two N atoms from two imdc ligands in a slightly distorted octa-hedral geometry. Both Er(III) ions are eight-coordinated in a bicapped trigonal-prismatic coordination geometry. One Er(III) ion is coordinated by four O atoms from two imidazole-4,5-dicarboxyl-ate ligands, three O atoms from three SO(4) (2-) anions and one water O atom; the other Er(III) ion is bonded to five O atoms from three imdc ligands, two O atoms from two SO(4) (2 ) anions as well as one coordinated water mol-ecule. The coordinated metal units are connected by bridging imdc ligands and sulfate ions, generating a two dimensional heterometallic layer. The two-dimensional layers are stacked along the b axis via N-H?O, O-H?O and C-H?O hydrogen-bonding inter-actions between water mol-ecules, SO(4) (2-) anions, and imdc ligands, generating a three dimensional framework. PMID- 21589293 TI - Azido-{2-[bis-(2-hy-droxy-eth-yl)amino]-ethano-lato-kappaN,O,O',O''}cobalt(II). AB - In the title complex, [Co(C(6)H(14)NO(3))(N(3))] or [Co(teaH(2))N(3)], the Co(II) atom resides in a trigonal-bipymidal O(3)N(2) environment formed by three O atoms and one N atom from a simply deprotonated tetra-dentate triethano-lamine ligand, and one N atom from an azide ligand. The O atoms define the equatorial plane whereas both N atoms are in axial positions. The mononuclear units are linked through O-H?O hydrogen-bonding inter-actions between the ethanol OH groups and the ethano-late O atom of a neighbouring complex into chains running parallel to [010]. PMID- 21589294 TI - catena-Poly[[[aqua-tris-(pyridine-kappaN)nickel(II)]-MU-2,3,5,6-tetra-chloro benzene-1,4-dicarboxyl-ato-kappaO:O] pyridine monosolvate]. AB - The asymmetric unit of the title compound, {[Ni(C(8)Cl(4)O(4))(C(5)H(5)N)(3)(H(2)O)].C(5)H(5)N}(n), contains two independent nickel(II) cations displaying a distorted octa-hedral coordination geometry provided by the N atoms of three pyridine mol-ecules, the O atom of a water mol ecule, and O atoms of two monodentate MU(2)-bridging tetra-chloro-terephthalate dianions. The metal atoms are linked by the dianions into zigzag chains running parallel to [11]. The crystal packing is stabilized by O-H?N and O-H?O hydrogen bonds. PMID- 21589295 TI - catena-Poly[[[diaqua-(nitrato-kappaO,O')(2,2':6',2''-terpyridine kappaN,N',N'')ytterbium(III)]-MU-cyanido-kappaN:C-[dicyanido-platinum(II)]-MU cyanido-kappaC:N] acetonitrile monosolvate]. AB - The title compound, {[PtYb(CN)(4)(NO(3))(C(15)H(11)N(3))(H(2)O)(2)].CH(3)CN}(n), was isolated from solution as a one-dimensional coordination polymer. The Yb(3+) site has ninefold coordination with a distorted tricapped trigonal-prismatic geometry, while the Pt(II) ion is coordinated by four cyanide groups in an almost regular square-planar geometry. cis-Bridging by the tetra-cyanidoplatinate(II) anions links the Yb(3+) cations, forming chains. Additionally, each Yb(3+) is coordinated by two water mol-ecules, one bidentate nitrate anion, and one tridentate 2,2':6',2''-terpyridine mol-ecule. O-H?N hydrogen-bonding inter actions are found between adjacent chains and help to consolidate the crystal packing. In addition, pi-pi stacking inter-actions exist between the terpyridine ligand and the two corresponding terpyridine ligands along the adjacent chain (average inter-planar distance = 3.667 A). Moderate Pt?Pt inter-actions [3.5033 (4) A] are observed in the structure. PMID- 21589296 TI - Tetra-MU(3)-tert-butano-lato-tetra-thallium(I). AB - The title compound, [Tl(4)(C(4)H(9)O)(4)], featuring a (Tl-O)(4) cube, crystallizes with a quarter-mol-ecule (located on a special position of site symmetry ..) and a half-mol-ecule (located on a special position of site symmetry 23.) in the asymmetric unit. The Tl-O bond distances range from 2.463 (12) to 2.506 (12) A. All O-Tl-O bond angles are smaller than 90 degrees whereas the Tl O-Tl angles are wider than a recta-ngular angle. PMID- 21589297 TI - (2,2'-Biquinoline-kappaN,N')dibromido-zinc(II). AB - In the title compound, [ZnBr(2)(C(18)H(12)N(2))], the Zn(II) atom is four coordinated in a distorted tetra-hedral configuration by two N atoms from the 2,2'-biquinoline ligand and two terminal Br atoms. The crystal packing is stabilized by weak inter-molecular C-H?Br hydrogen bonds and extensive inter molecular pi-pi contacts between the pyridine and benzene rings [centroid centroid distances = 3.775 (4), 3.748 (4), 3.735 (4), 3.538 (4), 3.678 (4) and 3.513 (4) A]. PMID- 21589298 TI - Tetra-aqua-(2,2'-bipyridine-kappaN,N')magnesium(II) bis-(4-fluoro-benzoate). AB - The title compound, [Mg(C(10)H(8)N(2))(H(2)O)(4)](C(7)H(4)FO(2))(2), consists of a bivalent [Mg(C(10)H(8)N(2))(H(2)O)(4)](2+) cation and two 4-fluorbenzoate anions. In the complex cation, the Mg(II) atom is coordinated by two N atoms from a 2,2'-bipyridine ligand and four water O atoms in a distorted MgN(2)O(4) octa hedral geometry. The Mg(II) atom is located on a twofold rotation axis and thus a cation exhibits C(2) mol-ecular symmetry. The 2,2'-bipyridine ligands exhibit nearly perfect planarity (r.m.s. deviations = 0.0061 A). In the crystal, O-H?O and C-H?O hydrogen bonds link the cations and anions into a three-dimensional supra-molecular network. PMID- 21589299 TI - 1-Cyano-methyl-1,4-diazo-niabicyclo-[2.2.2]octane tetra-chloridocuprate(II). AB - In the crystal structure of the title compound, (C(8)H(15)N(3))[CuCl(4)], the cations and anions, in which the Cu(II) atom is tetra-hedrally coordinated, are linked via N-H?Cl hydrogen bonds into chains that are elongated in the c-axis direction. PMID- 21589300 TI - Bis{(E)-2-[1-(eth-oxy-imino)-eth-yl]-1-naphtho-lato-kappaN,O}copper(II). AB - In the title complex, [Cu(C(14)H(14)NO(2))(2)], the discrete complex mol-ecules have crystallographic inversion symmetry. The slightly distorted square-planar coordination sphere of the Cu(II) atom comprises two phenolate O atoms and two oxime N atoms from two bidentate-chelate 2-[1-(eth-oxy-imino)-eth-yl]-1-naphtho late O-ethyl oxime (L(-)) ligands [Cu-O = 1.8919 (17) A and Cu-N = 1.988 (2) A]. The two naphthalene ring systems in the mol-ecule are parallel, with a perpendicular inter-planar spacing of 1.473 (2) A, while each complex unit forms links to four other mol-ecules via inter-molecular methyl C-H?pi inter-actions, giving an infinite cross-linked layered supra-molecular structure. PMID- 21589301 TI - catena-Poly[[trimethyl-tin(IV)]-MU-2-phenyl-butano-ato]. AB - In the title polymeric coordination compound, [Sn(CH(3))(3)(C(10)H(11)O(2))](n), the Sn atom has a distorted trigonal-bipyramidal coordination geometry, with two O atoms of two symmetry-related carboxyl-ate ligands in axial positions and three methyl groups in equatorial positions. In the crystal structure, carboxyl-ate bridges link the metal atoms, forming zigzag chains parallel to the b axis. PMID- 21589302 TI - Aqua-bis-(1-methyl-1H-imidazole-kappaN)bis-(nitrato-kappaO)copper(II). AB - The title complex mol-ecule, [Cu(NO(3))(2)(C(4)H(6)N(2))(2)(H(2)O)], has crystallographically imposed twofold symmetry. The Cu(II) atom displays a distorted square-pyramidal CuN(2)O(3) coordination geometry. In the crystal, inter-molecular O-H?O hydrogen bonds between the coordinated water mol-ecule and the nitrate anions form chains parallel to the c axis. PMID- 21589303 TI - (R)-2-Methyl-piperazine-1,4-diium tetra-chloridoanti-monate(III) chloride. AB - In the complex anion of the title compound, (C(5)H(14)N(2))[SbCl(4)]Cl, the Sb atom is tetra-coordinate within a saw-horse configuration. The cation adopts a chair conformation. The crystal structure is stabilized by inter-molecular N-H?Cl hydrogen bonds. PMID- 21589304 TI - Bis(2-acetylpyridine-kappaN,O)silver(I) tetra-fluoridoborate: a complex with silver in a seesaw coordination geometry. AB - The reaction of 2-acetylpyridine with silver(I) tetra-fluorido-borate leads to the discrete title complex, [Ag(C(7)H(7)NO)(2)]BF(4), in the cation of which the Ag atom is coordinated by two 2-acetylpyridine ligands, each of which is N,O bidentate, albeit with stronger bonding to the N atoms [Ag-N = 2.2018 (15) and 2.2088 (14) A; Ag-O = 2.5380 (13) and 2.5454 (13) A]. The four-coordinate Ag atom has a seesaw coordination geometry with a tau(4) index of 0.51. The tetra fluoridoborate anion is disordered over two orientations with 0.568 (10):0.432 (10) occupancies. PMID- 21589305 TI - MU-Peroxido-bis-[acetonitrile-bis-(ethyl-enediamine)-cobalt(III)] tetrakis(per chlorate). AB - The title compound, [Co(2)(O(2))(CH(3)CN)(2)(C(2)H(8)N(2))(4)](ClO(4))(4), consists of centrosymmetric binuclear cations and perchlorate anions. Two Co(III) atoms, which have a slightly distorted octa-hedral coordination, are connected through a peroxido bridge; the O-O distance is 1.476 (3) A. Both acetonitrile ligands are situated in a trans position with respect to the O-O bridge. In the crystal, the complex cations are connected by N-H?O hydrogen bonds between ethyl endiamine NH groups and O atoms from the perchlorate anions and peroxide O atoms. PMID- 21589306 TI - Bis(4-chloro-pyridine){2,2'-[ethane-1,2-diylbis(nitrilo-methyl idyne)]diphenolato}cobalt(III) perchlorate methanol monosolvate. AB - In the title complex, [Co(C(16)H(14)N(2)O(2))(C(5)H(4)ClN)(2)]ClO(4).CH(3)OH, the Co(III) ion is in a slightly distorted octa-hedral CoN(4)O(2) coordination environment with the two 4-chloro-pyridine ligands in a trans arrangement. PMID- 21589307 TI - Bis(4-amino-benzoic acid-kappaN)dichloridozinc(II). AB - Mol-ecules of the title compound [ZnCl(2)(C(7)H(7)NO(2))(2)], are located on a twofold rotation axis. Two 4-amino-benzoic acid moieties, and two chloride ligands are coordinated to a Zn atom in a tetra-hedral fashion, forming an isolated mol-ecule. Neighbouring mol-ecules are linked through hydrogen-bonded carboxyl groups, as well as N-H?Cl hydrogen-bonding inter-actions between amine groups and the chloride ligands of neighbouring mol-ecules, forming a three dimensional network. PMID- 21589308 TI - [2-Hydroxy-N'-(4-oxo-4-phenyl-butan-2-yl-idene)benzohydrazidato(2-)]pyridine copper(II). AB - The mononuclear title complex, [Cu(C(17)H(14)N(2)O(3))(C(5)H(5)N)], was synthesized by the reaction of CuCl(2).2H(2)O with N-(4-oxo-4-phenyl-butan-2-yl idene)benzohydrazide (H(2)L). The central Cu(II) atom exhibits a distorted square planar coordination geometry, defined by two O atoms, one N atom from the ligand and one pyridine N atom with Cu-N distances of 1.874 (4) and 1.963 (4) A, while the Cu-O distances are 1.857 (3) and 1.890 (3) A. An intra-molecular O-H?N inter action occurs. PMID- 21589309 TI - Diaqua-bis-[4-(dimethyl-amino)-benzoato-kappaO]bis-(nicotinamide-kappaN)zinc(II) dihydrate. AB - In the centrosymmetric title structure, [Zn(C(9)H(10)NO(2))(2)(C(6)H(6)N(2)O)(2)(H(2)O)(2)].2H(2)O, the Zn(II) cation, located on an inversion center, is coordinated by two 4-(methyl-amino)-benzoate anions, two nicotinamide ligands and two water mol-ecules in a slightly distorted octa-hedral geometry. The dihedral angle between the carboxyl-ate group and the attached benzene ring is 3.09 (9) degrees , while the pyridine and benzene rings are oriented at a dihedral angle of 77.10 (4) degrees . The uncoordinated water mol-ecule is linked to nicotinamide ligands by O-H?O hydrogen bonds. In the crystal, inter-molecular N-H?O, O-H?O and C-H?O hydrogen bonds link the mol ecules into a three-dimensional network. A weak N-H?pi inter-action also occurs. PMID- 21589310 TI - catena-Poly[[bis-(acetato-kappaO,O')cobalt(II)]-MU-4,4'-bis-(benzimidazol-1 yl)biphenyl-kappaN:N]. AB - In the title one-dimensional coordination polymer, [Co(C(2)H(3)O(2))(2)(C(26)H(18)N(4))](n), the Co(II) atom (site symmetry 2) is coordinated by two O,O'-bidentate acetate ions and two 4,4'-bis-(benzimidazol-1 yl)biphenyl ligands in a distorted cis-CoN(2)O(4) octa-hedral geometry. The bridging ligand, which is completed by crystallographic twofold symmetry, links the Co(II) atoms into [10] chains. Within the ligand, the dihedral angle between the benzene and benzimidazole rings is 48.31 (8) degrees . PMID- 21589311 TI - Chlorido{2-[(dimethyl-amino)-methyl]phenyl-kappaC,N}(1-methyl-1H-imidazole kappaN)palladium(II). AB - In the title compound, [Pd(C(9)H(12)N)Cl(C(4)H(6)N(2))], which was synthesized from the reaction of 1-methyl-imidazole with dimeric dichloridobis[2-(dimethyl amino)-benz-yl]palla-dium(II), the ring-deprotonated N,N-dimethyl-benzyl-amine ligand acts in a C,N-bidentate fashion. The dihedral angle between the ring of the 1-methyl-imidazole ligand and the palladacycle plane is 57.88 (16) degrees . The two N atoms from the N,N-dimethyl-benzyl-amine and 1-methyl-imidazole ligands are trans coordinated to the Pd(II) atom. PMID- 21589312 TI - Aqua-[2-(3-carb-oxy-5-carboxyl-atophen-oxy)acetato-kappaO]bis-(1,10 phenanthroline-kappaN,N')manganese(II) dihydrate. AB - In the title complex, [Mn(C(10)H(6)O(7))(C(12)H(8)N(2))(2)(H(2)O)].2H(2)O, the Mn(II) atom is coordinated by two O atoms from one 2-(3-carb-oxy-5-carboxyl atophen-oxy)acetate (HOABDC(2-)) dianion and one water mol-ecule and by four N atoms from two 1,10-phenanthroline (phen) ligands within a distorted octa-hedral geometry. O-H?O hydrogen bonding between -COOH and -COO(-) groups of adjacent mol ecules and between carboxyl-ate groups and coordinated and uncoordin-ated water mol-ecules leads to a three-dimensional structure which is further stabilized by weak pi-pi inter-actions of adjacent phen ligands with centroid-centroid separations of 4.2932 (1) A. PMID- 21589313 TI - Phenyl-hydrazinium (6-carb-oxy-pyridine-2-carboxyl-ato)(pyridine-2,6-dicarboxyl ato)cobaltate(II)-pyridine-2,6-dicarb-oxy-lic acid-water (1/1/3). AB - The asymmetric unit of the title compound, (C(6)H(9)N(2))[Co(C(7)H(3)NO(4))(C(7)H(4)NO(4))].C(7)H(5)NO(4).3H(2)O, contains one (6-carb-oxy-pyridine-2-carboxyl-ato)(pyridine-2,6-dicarboxyl ato)cobaltate(II) anion, one phenyl-hydrazinium cation, one pyridine-2,6-dicarb oxy-lic acid mol-ecule and three uncoordin-ated water mol-ecules, part of which are disordered. The Co(II) ion is coordinated by a pyridine-2,6-dicarboxyl-ate ion and a 6-carb-oxy-pyridine-2-carboxyl-ate ligand almost perpendicular to each other [the angle between the least-squares planes is 87.38 (4) degrees ] and is surrounded by two O atoms and two N atoms in the equatorial plane and two O atoms in axial positions, resulting in a distorted octa-hedral coordination geometry. There is an extensive three-dimensional network of O-H?O and N-H?O hydrogen bonds, which link the components. PMID- 21589314 TI - Bis(dicyclo-hexyl-ammonium) MU-oxalato-kappaO,O:O,O-bis-[aqua-(oxalato kappaO,O)diphenyl-stannate(IV)]. AB - The structure of the title compound, (C(12)H(24)N)(2)[Sn(2)(C(6)H(5))(4)(C(2)O(4))(3)(H(2)O)(2)], consists of a bischelating oxalate ion, located on an inversion center, which is linked to two SnPh(2) groups. The coordination sphere of the Sn(IV) ion is completed by a monochelating oxalate anion and a water mol-ecule. The Sn(IV) atoms are thus seven-coordinated. The discrete binuclear units are further connected by hydrogen bonds, leading to a supra-molecular crystal structure. The asymmetric unit contains one half dianion and one (Cy(2)NH(2))(+) cation. PMID- 21589315 TI - Bromidotricarbon-yl[4-chloro-N-(2-pyridyl-methyl-idene)aniline kappaN,N']rhenium(I). AB - In the title compound, [ReBr(C(12)H(9)ClN(2))(CO)(3)], the Re(I) atom has a distorted octa-hedral configuration with the three carbonyl ligands showing a facial arrangement. The main distortion of the octa-hedron is due to a small bite angle of the chelating bidentate diimine ligand [N-Re-N = 75.3 (3) degrees ]. PMID- 21589316 TI - MU-Oxido-bis{[2,2-bis-(3,5-dimethyl-1H-pyrazol-1-yl)acetato kappaN,O,N]chloridooxidomolybdenum(V)} mono-hydrate. AB - In the binuclear title compound, [Mo(2)(C(12)H(15)N(4)O(2))(2)Cl(2)O(3)].H(2)O, the complex mol-ecules have approximate C(2) symmetry. Both Mo(V) atoms have a distorted octa-hedral coordination environment with cis-positioned terminal chloride and oxide groups. The heteroscorpionate organic ligand binds to the Mo(V) atom via an N(2)O donor set. The water mol-ecule bridges two complex mol ecules, forming O-H?O and O-H?Cl hydrogen bonds to the acetate group and to the chloride ligands. PMID- 21589317 TI - [N,N'-Bis(3-meth-oxy-2-oxidobenzyl-idene)cyclo-hexane-1,2-diaminium kappaO,O',O'',O''']tris-(nitrato-kappaO,O')europium(III) methanol monosolvate. AB - In the title mononuclear salen-type complex, [Eu(NO(3))(3)(C(22)H(26)N(2)O(4))].CH(3)OH, the Eu(III) ion is ten-coordinated by three bidentate nitrate counter-ions and one organic salen-type ligand, which acts in a bis-bidentate chelating mode through its phenolate and meth-oxy O atoms. The protonated imine groups are involved in intra-molecular N-H?O hydrogen bonds to the phenolate O atomss, emphasizing the zwitterionic nature of the ligand. An O-H?O hydrogen bond links the complex and solvent mol-ecules. PMID- 21589318 TI - Bis(MU-5-carb-oxy-benzene-1,3-dicarboxyl-ato)-kappaO,O:O;kappaO:O,O-bis-[(2 phenyl-1,3,7,8-tetra-aza-cyclo-penta-[l]phenanthrene-kappaN,N)lead(II)]. AB - In the title compound, [Pb(2)(C(9)H(4)O(6))(2)(C(19)H(12)N(4))(2)], the Pb(II) atom is five-coordinated by two N atoms from a chelating 2-phenyl-1H-1,3,7,8 tetra-aza-cyclo-penta-[l]phenanthrene (L) ligand and three O atoms from two Hbtc ligands (H(3)btc is benzene-1,3,5-tricarb-oxy-lic acid), resulting in a distorted PbN(2)O(3) coordination. Two Pb(II) atoms are bridged by the Hbtc ligands, forming a discrete centrosymmetric dinuclear complex. Inter-molecular N-H?O and O H?O hydrogen bonds and pi-pi inter-actions between the pyridine and imidazole rings, and between the pyridyl rings of the L ligands [centroid-centroid distances = 3.600 (6) and 3.732 (6) A] lead to a three-dimensional supra molecular structure. PMID- 21589319 TI - Bis(2,6-dihy-droxy-benzoato-kappaO,O)(nitrato-kappaO,O')bis-(1,10-phenanthroline kappaN,N')dysprosium(III). AB - In the mononuclear title complex, [Dy(C(7)H(5)O(4))(2)(NO(3))(C(12)H(8)N(2))(2)], the Dy(III) atom is in a distorted bicapped square-anti-prismatic geometry formed by four N atoms from two chelating 1,10-phenanthroline (phen) ligands, four O atoms from two 2,6-dihy-droxy-benzoate (DHB) ligands and two O atoms from a nitrate anion. Inter-molecular pi-pi stacking inter-actions between the phen and DHB ligands [centroid-centroid distances = 3.542 (4) and 3.879 (4) A] and between the pyridine and benzene rings of adjacent phen ligands [centroid-centroid distance = 3.751 (4) A] stabilize the crystal structure. Intra-molecular O-H?O hydrogen bonds are observed in the DHB ligands. PMID- 21589320 TI - (Z)-3-(4-Bromo-anilino)-1-ferrocenylbut-2-en-1-one. AB - In the title compound, [Fe(C(5)H(5))(C(15)H(13)BrNO)], formed from the reaction of ferrocenoylacetone and 4-bromo-aniline, the mol-ecular structure is stabilized by an intra-molecular N-H?O hydrogen bond between the amine and carbonyl groups. PMID- 21589321 TI - Monoclinic form of (cyanato-kappaN){2,2'-[ethane-1,2-diylbis(nitrilo-methyl idyne)]diphenolato-kappaO,N,N',O'}manganese(III). AB - The title compound, [Mn(C(16)H(14)N(2)O(2))(NCO)], is a monoclinic polymorph of the previously published ortho-rhom-bic form [Lu et al. (2006 ?). Inorg. Chem.45, 3538-3548]. The Mn(III) ion is chelated by a tetra-dentate Schiff base ligand and coordinated by the N atom of a cyanate ligand in a distorted square-pyramidal arrangement. In the crystal, there are short inter-molecular Mn?O(phenolate) distances of 2.752 (3) A between pairs of inversion-related mol-ecules. PMID- 21589322 TI - catena-Poly[[tetra-kis-(hexa-methyl-phospho-ramide-kappaO)bis-(nitrato kappaO,O')cerium(III)] [silver(I)-di-MU-sulfido-tungstate(VI)-di-MU-sulfido]]. AB - Hexa-methyl-phospho-ramide (hmp), tetra-thio-tungstate, silver sulfide and cerium nitrate were self-assembled to form a one-dimensional anionic [Ag(4)W(4)S(16)](n) (4n-) chain in the title compound, {[Ce(NO(3))(2)(C(6)H(18)N(3)OP)(4)][AgWS(4)]}(n). The asymmetric unit contains four crystallographically independent [Ce(hmp)(4)(NO(3))(2)](+) cations, which leads to a one-dimensional polymeric anionic chain having a tetra-valent [W(4)S(16)Ag(4)] repeat unit. Each central Ce atom is coordinated by eight O atoms from two chelating nitrate and four hmp ligands, which gives rise to a distorted square-anti-prismatic structure. The polymeric chain with average W-Ag W and Ag-W-Ag bond angles of 163.75 and 151.84 degrees , respectively, presents a distorted linear configuration. The title complex with a non-centrosymmetric structure, is analogous to the Yb, Y, Eu, Nd, La and Dy isomorphs, which exhibit centrosymmetric structures. PMID- 21589323 TI - (2,2'-Bipyridine-kappaN,N')[2-tert-butyl-anilinato(2-)]dichloridooxido molybdenum(VI) dichloro-methane hemisolvate. AB - The Mo(VI) atom in the title structure, [Mo(C(10)H(13)N)Cl(2)O(C(10)H(8)N(2))].0.5CH(2)Cl(2), has a distorted octa-hedral coord-ination sphere with cis-orientated oxide and imide ligands, trans-chloride ligands and the 2,2'-bipyridine (bipy) ligand N atoms lying trans to the oxide and imide ligands. An imide-ligand tert-butyl-methyl-group H atom makes a close approach with the oxide ligand (distance = 2.53 A) and the imide-ligand N atom (distance = 2.41 A). Another imide-ligand tert-butyl-methyl-group H atom makes a close approach to a chloride ligand (distance = 2.82 A). One bipy-ligand alpha-H atom makes a close approach to the oxide ligand (distance = 2.4 A) and the other alpha-H atom makes a close approach to the imide-ligand phenyl-ring ortho-H atom (distance = 2.52 A). These close approaches suggest the presence of weak intra molecular hydrogen bonds. The solvent molecule has been modelled under consideration of half-occupancy. PMID- 21589324 TI - Bis(benzoato-kappaO,O')(1,10-phenanthroline-kappaN,N')lead(II) benzoic acid mono solvate. AB - The reaction of lead acetate, benzoic acid and 1,10-phenanthroline (phen) in aqueous solution yielded the title complex, [Pb(C(7)H(5)O(2))(2)(C(12)H(8)N(2))].C(7)H(6)O(2). In the crystal, the Pb(II) ion is hexa-coordinated by two N atoms from one 1,10-phenanthroline ligand and four O atoms from two chelate benzoate anions. If the second benzoate ligand is treated as one coordination site, the overall coordination may be represented as a distorted pseudo-square pyramid. An inter-molecular O-H?O hydrogen bond links the solvent benzoic acid mol-ecule with a metal-coordinated benzoate ligand. The shortest Pb?Pb distance is 3.864 (4) A, indicating a weak metal-metal inter action. Two complex mol-ecules related by an inversion centre form dimeric units via Pb?O inter-actions of 3.206 (4) A. PMID- 21589325 TI - (C-meso-N-meso-5,12-Dimethyl-7,14-diphenyl-1,4,8,11-tetra-aza-cyclo-tetra-deca 4,11-diene)nickel(II) bis-[O,O'-bis-(4-methyl-phen-yl) dithio-phosphate]. AB - The title complex, [Ni(C(24)H(32)N(4))](C(14)H(14)O(2)PS(2))(2), comprises a centrosymmetric [Ni(meso-diphen-yl[14]dien)](2+) dication (meso-diphen-yl[14]dien is C-meso-N-meso-5,12-dimethyl-7,14-diphenyl-1,4,8,11-tetra-aza-cyclo-tetra-deca 4,11-diene) and two O,O'-bis-(4-methyl-phen-yl) dithio-phosphate anions. The Ni(II) ion lies on an inversion center and is chelated by a tetra-amine macrocycle ligand in a slightly distorted NiN(4) square-planar geometry. Two S atoms from symmetry-related anions are located in pseudo-axial positions with respect to the Ni(II) ion, with Ni?S distances of 3.1869 (8) A. In the crystal, bifurcated inter-molecular N-H?S(S) hydrogen bonds connect cations and pairs of anions into three-component clusters. Weak inter-molecular C-H?S hydrogen bonds link these clusters into chains along [100]. PMID- 21589326 TI - Poly[[aqua-tris-(MU(3)-hexa-methyl-ene-tetra-mine-kappaN,N',N'')tris-(p-toluene sulfonato-kappaO)tris-ilver(I)] trihydrate]. AB - There are three Ag(I) cations, three p-toluene-sulfonate (pts) anions, three hexa methyl-ene-tetra-mine (hmt) mol-ecules and four water mol-ecules in the asymmetric unit of the title coordination polymer, {[Ag(3)(C(7)H(7)O(3)S)(3)(C(6)H(12)N(4))(3)(H(2)O)].3H(2)O}(n). Two of the pts anions show positional disorder of their O atoms in 0.60:0.40 and 0.50:0.50 ratios. The Ag(I) ion is coordinated by three hmt mol-ecules in an approximate trigonal-planar AgN(3) arrangement. In each case, longer Ag-O bonds to a water mol-ecule and a pts anion complete a distorted trigonal-bipyramidal AgN(3)O(2) geometry for the metal ion. In the crystal, the bridging hmt mol-ecules and pts ions generate a wave-like layer parallel to (001) and O-H?O hydrogen-bonding inter-actions consolidate the packing. PMID- 21589327 TI - Tetra-aqua-bis-[5-(3-pyrid-yl)tetra-zolido-kappaN]zinc(II) tetra-hydrate. AB - The title compound, [Zn(C(6)H(4)N(5))(2)(H(2)O)(4)].4H(2)O, was synthesized by the hydro-thermal reaction of Zn(CH(3)COO)(2).2H(2)O with 3-(2H-tetra-zol-5 yl)pyridine. The Zn(II) ion is located on an inversion center and is coordinated by two pyridine N atoms from two 5-(3-pyrid-yl)tetra-zolide ligands and four coordinated water mol-ecules in a slightly distorted octa-hedral geometry. The dihedral angle between the pyridine and tetra-zole rings is 9.920 (7) degrees . In the crystal, mol-ecules are linked into a three-dimensional network by inter molecular O-H?O and O-H?N hydrogen bonds involving the tetra-zole group N atoms, the aqua ligands and solvent water mol-ecules. PMID- 21589328 TI - Diaqua-bis-[2-(5-isopropyl-5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl kappaN)nicotinato-kappaN]manganese(II). AB - In the title compound, [Mn(C(13)H(14)N(3)O(3))(2)(H(2)O)(2)], the Mn(II) ion is coordinated by four N atoms from two (+/-)-2-(5-isopropyl-5-methyl-4-oxo-4,5 dihydro-1H-imidazol-2-yl)nicotinate ligands and two water mol-ecules in a distorted octa-hedral environment. Inter-molecular O-H?O hydrogen bonds lead to a chain along [010]. Intra-molecular N-H?O and O-H?O hydrogen bonds are observed. PMID- 21589329 TI - Monoclinic modification of di-n-butyl-dichlorido(1,10-phenanthroline kappaN,N')tin(IV). AB - The Sn(IV) atom in the title compound, [Sn(C(4)H(9))(2)Cl(2)(C(12)H(8)N(2))], is chelated by the N-heterocycle; the n-butyl groups are trans to each other whereas the Cl atoms are cis to each other. The crystal studied was a non-merohedral twin with the minor domain being in a 15.8 (1)% proportion. PMID- 21589330 TI - Bis(MU-2,2'-{[4-(carb-oxy-meth-oxy)phen-yl]aza-nedi-yl}diacetato)-bis-[(1,10 phenanthroline)copper(II)]. AB - The crystal structure of the binuclear title compound, [Cu(2)(C(12)H(11)NO(7))(2)(C(12)H(8)N(2))(2)], consists of a complex mol-ecule, which lies about a crystallographic inversion centre with one half-mol-ecule in the asymmetric unit. The Cu(II) cation is bonded to three N atoms and three O atoms, in a Jahn-Teller-distorted octa-hedral geometry. The basal plane is defined by the two N atoms from the 1,10-phenathroline and two deprotonated O atoms of the polycarboxyl-ate ligand. The axial positions are occupied by the azane N atom and a bridging carboxyl-ate O atom from the second polycarboxyl-ate ligand. The complex mol-ecules are linked through O-H?O hydrogen bonds into extended chains running parallel to [010]. PMID- 21589331 TI - 1-Cyano-methyl-1,4-diazo-niabicyclo-[2.2.2]octane tetra-bromidocadmate(II). AB - In the title salt, (C(8)H(15)N(3))[CdBr(4)], four Br atoms coordinate the Cd(II) atom in a distorted tetra-hedral geometry. In the crystal, weak N-H?Br inter actions connect the anion to three symmetry-related cations. The crystal structure also displays very weak C-H?Br inter-actions. PMID- 21589332 TI - Dipotassium tetra-aqua-bis-[3,5-bis-(dicyano-methyl-ene)cyclo-pentane-1,2,4 trionato(1-)-kappaN]cobaltate(II). AB - The title structure, K(2)[Co(C(11)N(4)O(3))(2)(H(2)O)(4)], is isotypic with K(2)[Fe(C(11)N(4)O(3))(2)(H(2)O)(4)]. The Co(II) atom is in a distorted octa hedral CoN(2)O(4) geometry, forming a dianionic mononuclear entity. Each dianionic unit is associated with two potassium cations and inter-acts with adjacent units through O-H?N and O-H?O hydrogen bonds. PMID- 21589333 TI - [N,N'-Bis(2,6-diisopropyl-phen-yl)methanimidamidato][eta-1,4-bis-(tri-methyl-sil yl)cyclo-octa-tetra-enyl](tetra-hydro-furan)-samarium(III) toluene monosolvate. AB - The title compound, [Sm(C(25)H(35)N(2))(C(14)H(24)Si(2))(C(4)H(8)O)].C(7)H(8), was prepared by treatment of anhydrous samarium trichloride with a 1:1 mixture of in situ-prepared Li(DippForm) [DippFormH = N,N'-bis-(2,6-diisopropyl-phen yl)methanimidamide] and Li(2)(COT'') [COT'' = 1,4-bis-(trimethyl-sil-yl)cyclo octa-tetra-enyl] in tetra-hydro-furan (THF). Despite the presence of two very bulky ligands (COT'' and DippForm), the mol-ecule still contains one coordinated THF ligand. The overall coordination geometry around the Sm(III) atom resembles a three-legged piano-stool with the COT'' ligand being eta(8)-coordinated and the DippForm(-) anion acting as an N,N'-chelating ligand [Sm-N = 2.5555 (15) and 2.4699 (15) A]. The asymmetric unit also contains a disordered mol-ecule of toluene, the refined ratio of the two components being 0.80 (4):0.20 (4). PMID- 21589334 TI - Poly[(MU(3)-biphenyl-3,4'-dicarboxyl-ato-kappaO:O:O,O)(1H-imidazo[4,5 f][1,10]phenanthroline-kappaN,N)manganese(II)]. AB - In the title compound, [Mn(C(14)H(8)O(4))(C(13)H(8)N(4))](n), the Mn(II) atom is six-coordinated in a distorted octa-hedral geometry by four O atoms from three different carboxyl-ate groups and two N atoms from one imidazo[4,5 f][1,10]phenanthroline mol-ecule. The organic ligands link inorganic Mn(II) nodes, forming a zigzag chain along the c axis. PMID- 21589335 TI - catena-Poly[[{diaqua-[2-(4-hy-droxy-phen-yl)acetato-kappaO,O']cerium(III)}-bis [MU-2-(4-hy-droxy-phen-yl)acetato]-kappaO,O':O;kappaO:O,O'] 4,4'-bipyridine disolvate monohydrate]. AB - In the polymeric title complex, {[Ce(C(8)H(7)O(3))(3)(H(2)O)(2)].2C(10)H(8)N(2).H(2)O}(n), the Ce(III) ion is coordinated by ten O atoms from four 2-(4-hy-droxy-phen-yl)acetate (HPAA) ligands and two water mol-ecules. One HPAA ligand coordinates just to one Ce(III) ion, whereas the remaining two bridge two Ce(III) ions. The 4,4'-bipyridine mol-ecule and one water mol-ecule are not coordinated to Ce. In the crystal, O-H?O and O H?N hydrogen bonds link mol-ecules into a three-dimensional network. PMID- 21589336 TI - cis-Dichlorido[2-methyl-8-(pyridin-2-ylmeth-oxy)quinoline kappaN,O,N'](triphenylphosphane-kappaP)ruthenium(II) methanol monosolvate. AB - In the structure of the title compound, [RuCl(2)(C(16)H(14)N(2)O)(C(18)H(15)P)].CH(3)OH, he Ru(II) ion shows a slightly distorted octahedral coordination by two N atoms and one O atom from the 2-methyl 8-(pyridin-2-ylmeth-oxy)quinoline acting as an N,O,N'-tridentate ligand, two Cl atoms, and one P atom from a PPh(3) ligand. The two Cl atoms adopt a cis arrangement with the PPh(3) ligand trans to one Cl atom. The N,O,N'-tridentate ligand occupies a mer position in the coordination sphere. PMID- 21589337 TI - Diaqua-dichloridobis[quinazolin-4(1H)-one-kappaN]copper(II). AB - In the title complex, [CuCl(2)(C(8)H(6)N(2)O)(2)(H(2)O)(2)], the Cu(II) ion is located on an inversion center and is octahedrally coordinated by two N atoms of the 1H-quinazolin-4-one ligand, two chloride ligands and two aqua ligands. The axial Cu-O distances are significantly longer [2.512 (2) A], than the Cu-N [2.022 (2) A] and Cu-Cl [2.3232 (4) A] distances as a result of Jahn-Teller distortion. Aqua ligands are involved in intra- and inter-molecular hydrogen bonding, and N H?O inter-molecular hydrogen bonds are formed between the organic ligands. In addition, weak pi-pi inter-actions are observed between the benzene rings of the ligand [centroid-centroid distance = 3.678 (1) A]. PMID- 21589338 TI - [N,N-Bis(2,6-diisopropyl-phen-yl)pent-2-ene-2,4-diiminato(1-)]bis-(1,2,4-diaza phosphol-1-yl)aluminium(III). AB - In the title compound, [Al(C(29)H(41)N(2))(C(2)H(2)N(2)P)(2)], the Al(III) atom is coordinated by four N atoms from beta-diketiminate and 1,2,4-diaza-phospho lide ligands in a slightly distorted tetra-hedral fashion. PMID- 21589339 TI - Poly[di-MU(2)-chlorido-MU(2)-(1,4-dioxane-kappaO:O')-cadmium(II)]. AB - In the title complex, [CdCl(2)(C(4)H(8)O(2))](n), two different Cd(II) ions are present, one in a general position and one with site symmetry 2. The Cd(II) ions are coordinated by two O atoms from two 1,4-dioxane ligands and four chloride anions in a slightly distorted octa-hedral geometry and is connected to neighboring Cd(II) ions by two bridging chloride anions, generating infinite linear chains along the a axis. These chains are further inter-connected by bridging 1,4-dioxane ligands, affording a three-dimensional network. PMID- 21589340 TI - {MU-6,6'-Dimeth-oxy-2,2'-[cyclo-hexane-1,2-diylbis(nitrilo-methyl idyne)]diphenolato}trinitratocopper(II)lutetium(III). AB - In the title dinuclear Cu(II)-Lu(III) salen-type complex, [CuLu(C(22)H(24)N(2)O(4))(NO(3))(3)], with the ligand 6,6'-dimeth-oxy-2,2'-[cyclo hexane-1,2-diylbis(nitrilo-methyl-idyne)]diphenolate, the irregular nine coordinate Lu(III) coordination sphere comprises four O atoms from the ligand and five O atoms from three nitrate groups, two bidentate and one monodentate [Lu-O = 2.230 (3)-2.621 (4) A]. The slightly distorted square-planar four-coordinate Cu(II) atom comprises two imine N atoms [Cu-N = 1.903 (4) and 1.912 (4) A] and two phenolate O atoms from the ligand mol-ecule [Cu-O = 1.897 (3) and 1.906 (3) A]. All atoms of the cyclo-hexane ring of the ligand mol-ecule are disordered over two sets of sites with equal occupancy. PMID- 21589341 TI - Chlorido[4-(pyridin-2-yl-kappaN)pyrimidine-2-sulfonato-kappaN,O]palladium(II). AB - In the title compound, [Pd(C(9)H(6)N(3)O(3)S)Cl], the Pd(II) ion is coordinated by one O and two N atoms from a 4-(pyridin-2-yl)pyrimidine-2-sulfonate ligand and one chloride anion in a distorted square-planar geometry. In the crystal, all mol ecules are situated on mirror planes and inter-act through weak inter-molecular C H?O hydrogen bonds. PMID- 21589342 TI - catena-Poly[[(benzoato-kappaO,O')(2,2'-bipyridine-kappaN,N')lead(II)]-MU(3) nitrato-kappaO:O,O':O'']. AB - In the title coordination polymer, [Pb(C(7)H(5)O(2))(NO(3))(C(10)H(8)N(2))](n), the Pb(II) ion is eight-coordinated by two N atoms from one 2,2'-bipyridine ligand, two O atoms from one benzoate anion and four O atoms from three nitrate groups (one chelating, two bridging) in a distorted dodecahedral geometry. Adjacent Pb(II) ions are linked by bridging nitrate O atoms through the central Pb(2)O(2) and Pb(2)O(4)N(2) cores, resulting in an infinite chain structure along the b axis. The crystal structure is stabilized by pi-pi stacking inter-actions between 2,2'-bipyridine and benzoate ligands belonging to neighboring chains, with shortest centroid-centroid distances of 3.685 (8) and 3.564 (8) A. PMID- 21589343 TI - Tetra-kis[1-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-1-one-kappaN]bis-(thio-cyanato kappaN)nickel(II). AB - In the centrosymmetric mononuclear title complex, [Ni(NCS)(2)(C(11)H(11)N(3)O)(4)], the Ni(II) atom, located on an inversion centre, is hexa-coordinated in a distorted octa-hedral geometry comprising four N atoms of four monodentate 1-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-1-one ligands and two N atoms from thio-cyanate anions. PMID- 21589344 TI - {2,2-Bis[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]propane}-bis-(N,N-dimethyl formamide)-copper(II) bis-[hexa-fluoridoanti-monate(V)]. AB - In the title compound, [Cu(C(15)H(26)N(2)O(2))(C(3)H(7)NO)(2)][SbF(6)](2), which is a potential catalyst in the catalytic asymmetric Gosteli-Claisen rearrangement, the central Cu(II) atom is in a nearly square-planar cis-N(2)O(2) environment in the cation arising from its coordination by an N,N-bidentate 2,2 bis-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]propane ligand and two O-bonded N,N-dimethyl-formamide mol-ecules. Two SbF(6) (-) anions are positioned on opposite sides of the plane through the CuN(2)O(2) unit, generating an axially distorted CuN(2)O(2)F(2) octa-hedral geometry for the metal ion. PMID- 21589345 TI - A 2:1 cocrystal of the cis and trans isomers of bis-[1,1,1,5,5,5-hexa-fluoro pentane-2,4-dionato(1-)-kappaO,O']bis-(4-phenyl-pyridine N-oxide kappaO)copper(II). AB - The title compound is a co-crystal of the cis and trans isomers, namely cis-bis [1,1,1,5,5,5-hexa-fluoro-pentane-2,4-dionato(1-)-kappa(2)O,O']bis-(4-phenyl pyridine N-oxide-kappaO)copper(II)-trans-bis-[1,1,1,5,5,5-hexa-fluoro-pentane-2,4 dionato(1-)-kappa(2)O,O']bis(4-phenyl-pyridine N-oxide-kappaO)copper(II) (2/1), [Cu(C(5)HF(6)O(2))(2)(C(11)H(9)NO)(2)]. In both isomers, the coordination geometry of the Cu(2+) atom is octa-hedral, exhibiting typical Jahn-Teller distortion. The metal atom of the trans isomer is located on an inversion centre. In the cis isomer, the phenyl ring in one 4-phenyl-pyridine N-oxide ligand is disordered over two orientations in a 1:1 ratio. In the crystal, weak inter molecular C-H?F and C-H?O contacts establish connections between the cis and trans isomers. PMID- 21589346 TI - Bis(MU-bis-{[4-(2-pyrid-yl)pyrimidin-2-yl]sulfan-yl}methane)-disilver(I) bis (perchlorate). AB - In the macrocyclic centrosymmetric dinuclear complex, [Ag(2)(C(19)H(14)N(6)S(2))(2)](ClO(4))(2), the Ag(I) atom, bis-{[4-(2-pyrid yl)pyrimidin-2-yl]sulfan-yl}methane (2-bppt) ligand and perchlorate anion each lie on a twofold rotation axis. The 2-bppt ligand chelates two four-coordinated Ag(I) atoms through its two bipyridine-like arms. The O atoms of the perchlorate anion are disordered each over two positions of equal occupancy. Adjacent complex mol-ecules are linked by pi-pi inter-actions between the pyridine and pyrimidine rings [centroid-centroid distance = 3.663 (8) A]. PMID- 21589347 TI - Bis(2,2'-bipyridine-kappaN,N')dichloridocadmium(II). AB - The Cd(II) atom in the title compound, [CdCl(2)(C(10)H(8)N(2))(2)] exists in a distorted octa-hedral geometry [N-Cd-N = 148.29 (17) degrees ]; the Cl atoms are cis with respect to each other. PMID- 21589348 TI - Metal-nucleobase inter-action: bis[4-amino-pyrimidin-2(1H)-one kappaN]dibromidozinc(II). AB - In the title complex, [ZnBr(2)(C(4)H(5)N(3)O)(2)], the central metal ion is coordinated to two bromide ions and endocyclic N atoms of the two cytosine mol ecules leading to a distorted tetra-hedral geometry. The structure is isotypic with [CdBr(2)(C(4)H(5)N(3)O)(2)] [Muthiah et al. (2001). Acta Cryst. E57, m558 m560]. There are two inter-ligand N-H?Br hydrogen bonds, generating two hydrogen bonded rings stabilizing the coordination sphere. The complex aggregates, forming supra-molecular chains, sheets and staircases through N-H?O and N-H?Br hydrogen bonding and pi-pi stacking inter-actions [centroid-centroid distance = 3.616 (2) A]. PMID- 21589349 TI - Poly[[triaqua-(MU(3)-4-oxidopyridine-2,6-dicarboxyl-ato)europium(III)] monohydrate]. AB - In the title coordination polymer, {[Eu(C(7)H(2)NO(5))(H(2)O)(3)].H(2)O}(n), the Eu(III) atom is eight-coordinated by a tridentate 4-oxidopyridine-2,6-dicarboxyl ate (hpc) trianion, two monodentate hpc anions and three water mol-ecules, forming a distorted bicapped trigonal-prismatic coordination geometry. The hpc ligands bridge adjacent Eu(III) ions, forming infinite double chains. Adjacent chains are further connected by hpc ligands into sheets. O-H?O hydrogen bonds then generate a three-dimensional supra-molecular framework. PMID- 21589350 TI - (4-tert-Butyl-pyridine)-chlorido[hydro-tris-(3,5-dimethyl-pyrazol-1 yl)borato]nitro-sylmolybdenum(I) dichloro-methane monosolvate. AB - In the title compound, [Mo(C(15)H(22)BN(6))Cl(NO)(C(9)H(13)N)].CH(2)Cl(2), the Mo(I) atom adopts a distorted MoClN(5) octa-hedral geometry with the hydro-tris (3,5-dimethyl-pyrazol-yl)borate anion in an N,N',N''-tridentate tripodal (facial) coordination mode. A 4-tert-butyl-pyrine ligand, chloride anion and a nitrosyl cation complement the coodination of the Mo(I) atom and an intra-molecular C-H?Cl hydrogen bond helps to stabilize the configuration of the complex mol-ecule. The packing is stabilized by an inter-molecular C-H?Cl hydrogen bond involving the complex mol-ecule and the CH(2)Cl(2) solvent mol-ecule. PMID- 21589351 TI - Octa-butyl-bis-(MU(2)-2-chloro-5-nitro-benzoato)bis-(2-chloro-5-nitro-benzoato)di MU(3)-oxido-tetra-tin(IV). AB - The title complex, [Sn(4)(C(4)H(9))(8)(C(7)H(3)ClNO(4))(4)O(2)], is a cluster formed by a crystallographic inversion center around the central Sn(2)O(2) ring. Both of the two independent Sn atoms are five-coordinated, with distorted trigonal-bipyramidal SnC(2)O(3) geometries. One Sn atom is coordinated by two butyl groups, one O atom of the benzoate anion and two bridging O atoms, whereas the other Sn atom is coordinated by two butyl groups, two O atoms of the benzoate anions and a bridging O atom. The O atoms of the bridging benzoate anion are disordered over two sites with an occupancy ratio of 0.862 (12):0.138 (12). One of the butyl groups coordinated to the Sn(2)O(2) ring is disordered over two sites with an occupancy ratio of 0.780 (8):0.220 (8), whereas both of the two butyl groups coordinated to the other Sn atom are disordered over two sites with occupancy ratios of 0.788 (5):0.212 (5) and 0.827 (10):0.173 (10). All the butyl groups are equatorial with respect to the SnO(3) trigonal plane. In the crystal, complex mol-ecules are stacked down [010] with weak inter-molecular C-H?pi inter actions stabilizing the crystal structure. PMID- 21589352 TI - catena-Poly[lead(II)-bis-(MU-2-amino-1,3-benzothia-zole-6-carboxyl-ato)]. AB - The title complex, [Pb(C(8)H(5)N(2)O(2)S)(2)](n), consists of one Pb(II) ion located on a crystallographic twofold axis and two symmetry-related 2-amino-1,3 benzothia-zole-6-carboxyl-ate (ABTC) ligands. The central Pb(II) ion has a (4 + 2) coordination by four O atoms of the two ABTC ligands and two weaker Pb-S bonding inter-actions (Pb-S secondary bonds) from S atoms of other two neighbouring ABTC ligands. These bonds link the metal ions into zigzag chains along the c axis, which, in turn, aggregate through pi-pi inter-actions [centroid centroid distance = 3.7436 A] between ABTC rings and N-H?O and N-H?N hydrogen bonds. PMID- 21589353 TI - Chlorido(4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridine)-platinum(II) tetra fluorido-borate. AB - In the title compound, [PtCl(C(27)H(35)N(3))]BF(4), the Pt(II) atom is in a pseudo-square-planar coordination, which is typical of Pt-terpyridine complexes. The Pt-Cl bond distance is 2.2998 (7) A. The Pt-N distance of the N atom on the central pyridine is 1.931 (2) A, while the peripheral N atoms have Pt-N distances of 2.018 (2) and 2.022 (2) A. The cations pack as dimers in a head-to-tail orientation with an inter-molecular Pt?Pt distance of 3.5214 (2) A and Pt?N distances of 3.527 (2), 3.873 (2) and 4.532 (2) A. In the crystal, cations and anions are linked by weak C-H?F hydrogen-bonding inter-actions. PMID- 21589354 TI - Chlorido(4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridine)-platinum(II) chloride toluene monosolvate. AB - In the title compound, [PtCl(C(27)H(35)N(3))]Cl.C(7)H(8), the Pt(II) atom is coordinated in a pseudo-square-planar fashion by the N atoms of a 4,4',4''-tri tert-butyl-2,2':6',2''-terpyridine (tbtrpy) ligand and a Cl atom. The Pt-N distance of the N atom on the central pyridine is 1.941 (4) A, while the peripheral N atoms have Pt-N distances of 2.015 (4) and 2.013 (4) A. The Pt-Cl bond distance is 2.3070 (10) A. The cations pack as dimers in a head-to-tail orientation with an inter-molecular Pt?Pt distance of 3.2774 (3) A and Pt?N distances of 3.599 (4), 3.791 (4) and 4.115 (4) A. The solvent mol-ecule is disordered and occupies two positions with a ratio of 0.553 (6):0.447 (6). PMID- 21589355 TI - cyclo-Tetra-kis(MU-naphthalene-1,8-dicarboxyl-ato)tetra-kis-[diaqua-(2,2' bipyridine)-manganese(II)] tetra-hydrate. AB - In the title centrosymmetric tetra-nuclear complex, [Mn(4)(C(12)H(6)O(4))(4)(C(10)H(8)N(2))(4)(H(2)O)(8)].4H(2)O, two independent Mn(II) ions are coordinated in a slightly disorted octa-hedral environment by two aqua ligands, two naphthalene-1,8-dicarboxyl-ate (1,8-nap) ligands and one bis chelating 2,2'-bipyridine (2,2'-bipy) ligand. In the crystal, mol-ecules are linked by inter-molecular O-H?O hydrogen bonds into chains along [100]. These chains are further linked by weak pi-pi inter-actions with centroid-centroid distances in the range of 3.609 (2)-3.758 (1) A, forming a three-dimensional supra-molecular network. PMID- 21589356 TI - Bis(propane-1,2-diammonium) benzene-1,2,4,5-tetra-carboxyl-ate dihydrate. AB - In the crystal of the title hydrated molecular salt, 2C(3)H(12)N(2) (2+).C(10)H(2)O(8) (4-).2H(2)O, the packing is stabilized by extensive N-H?O and O-H?O hydrogen-bonding inter-actions involving all three species, forming a supra molecular three-dimensional structure. The tetraanion is generated by inversion. PMID- 21589357 TI - 1-Benzyl-2,5-dioxopyrrolidine-3,4-diyl diacetate. AB - The pyrrolidine-2,5-dione ring in the title compound, C(15)H(15)NO(6), is in a twisted conformation with the acetyl C atoms projecting to opposite sides of the ring. The acetyl groups lie to opposite sides of the five-membered ring. The benzene ring is roughly perpendicular to the heterocyclic ring, forming a dihedral angle of 76.57 (14) degrees with it. In the crystal, mol-ecules are connected through a network of C-H?O and C-H?pi inter-actions. PMID- 21589358 TI - 11-[(E)-Benzyl-idene]-14-hy-droxy-8-phenyl-3,13-diaza-hepta-cyclo [13.7.1.1.0.0.0.0]tetra-cosa-1(22),15,17,19(23),20-pentaen-10-one. AB - In the title compound, C(35)H(30)N(2)O(2), the piperidine ring adopts a chair conformation and the pyrrolidine ring adopts an envelope conformation. The naphthalene ring makes dihedral angles of 24.56 (3) and 36.13 (4) degrees with the terminal phenyl rings. The dihedral angle between the two terminal phenyl rings is 55.27 (5) degrees . One of the C atoms in the pyrrolidine ring is disordered over two sites, with a refined occupany ratio of 0.670 (3):0.330 (3). An intra-molecular O-H?N hydrogen bond generates an S(6) ring. In the crystal structure, inversion dimers linked by pairs of C-H?O hydrogen bonds generate R(2) (2)(18) loops within sheets of mol-ecules lying parallel to the bc plane. PMID- 21589359 TI - Methyl 3-[(E)-(2-hy-droxy-1-naphth-yl)methyl-idene]carbazate. AB - The title compound, C(13)H(12)N(2)O(3), has an E configuration with respect to the C=N bond: the conformation is stabilized by an intramolecular O-H?N hydrogen bond. In the crystal, an N-H?O interaction links the molecules into a C(4) chain along [100]. PMID- 21589360 TI - Tetra-ethyl 1,1'-(ethane-1,2-di-yl)bis-(2,5-dimethyl-1H-pyrrole-3,4-dicarboxyl ate). AB - The asymmetric unit of the title compound, C(26)H(36)N(2)O(8), comprises two independent mol-ecules. In each mol-ecule, the two pyrrole rings are linked by a CH(2)CH(2)- bridge, with dihedral angles between the two pyrrole rings of 14.5 (3) and 16.4 (3) degrees in the two mol-ecules. Each pyrrole ring carries 2- and 5-methyl substituents and eth-oxy-carbonyl groups at the 3- and 5-positions. PMID- 21589361 TI - 1-(2-Hy-droxy-benzo-yl)thio-semicarbazide hemihydrate. AB - The asymmetric unit of the title compound, C(8)H(9)N(3)O(2)S.0.5H(2)O, contains two thiosemicarbazide mol-ecules with the short distance of 3.521 (3) A between the centroids of the benzene rings, and one water mol-ecule. In the two independent mol-ecules, the benzene rings and the thio-semicarbazone fragments are twisted at 9.2 (3) and 18.5 (3) degrees . An extensive three-dimensional hydrogen-bonding network, formed by inter-molecular N-H?O, N-H?S and O-H?O hydrogen bonds, consolidates the crystal packing. PMID- 21589362 TI - p-Tolyl-methanaminium cyclo-hexane-1,2-diyl phosphate. AB - In the title mol-ecular salt, C(8)H(12)N(+).C(6)H(10)O(4)P(-), the cation and anion are connected by N-H?O hydrogen bonds. The C atoms of the cyclo-hexane ring are disordered over two sets of sites in a 0.51 (4):0.49 (4) occupancy ratio to generate two superimposed chair conformations. One of the terminal phosphate O atoms is also disordered in a 0.62 (2):0.38 (2) ratio. PMID- 21589363 TI - 5-Isobutyl-4-phenyl-sulfonyl-1H-pyrazol-3(2H)-one. AB - The title compound, C(13)H(16)N(2)O(3)S, consists of two crystallographically independent mol-ecules with similar geometries and exists in a keto form, the C=O bond lengths being 1.267 (2) and 1.254 (2) A. In both mol-ecules, the pyrazole rings are approximately planar, with maximum deviations of 0.017 (2) and 0.010 (2) A, and the dihedral angles between the pyrazole and phenyl rings are 83.63 (11) and 70.07 (12) degrees . In one mol-ecule, an intra-molecular C-H?O hydrogen bond with an S(6) ring motif is observed. In the crystal, inter-molecular N-H?O and C-H?O hydrogen bonds link the mol-ecules into two-dimensional networks parallel to the ab plane. PMID- 21589364 TI - 1-[(E)-(2-Methyl-3-nitro-phen-yl)imino-meth-yl]-2-naphthol. AB - The title Schiff base compound, C(18)H(14)N(2)O(3), has an inter-mediate state between NH and OH tautomers. The mol-ecular structure is stabilized by an O-H?N hydrogen bond. The dihedral angle between the naphthalene ring system and the benzene ring is 37.44 (5) degrees . PMID- 21589365 TI - N-Benzyl-N,4-dimethyl-benzene-sulfonamide. AB - The mol-ecule of the title compound, C(15)H(17)NO(2)S, has a C-S-N-C torsion angle of 71.4 (2) degrees , and the dihedral angle between the benzene rings is 82.83 (16) degrees . In the crystal, mol-ecules are linked into chains along the b axis via C-H?O hydrogen bonds. A C-H?pi inter-action is also present in the crystal structure. PMID- 21589366 TI - Tris{2-[(2-amino-benzyl-idene)amino]-ethyl}amine. AB - The title Schiff base, C(27)H(33)N(7), is a tripodal amine displaying C(3) symmetry, with the central tertiary N atom lying on the threefold crystallographic axis. The N-CH(2)-CH(2)-N conformation of the pendant arms is gauche [torsion angle = 76.1 (3) degrees ], which results in a claw-like mol ecule, with the terminal aniline groups wrapped around the symmetry axis. The lone pair of the apical N atom is clearly oriented inwards towards the cavity, and should thus be chemically inactive. The amine NH(2) substituents lie in the plane of the benzene ring to which they are bonded. With such an arrangement, one amine H atom forms an S(6) motif through a weak N-H?N hydrogen bond with the imine N atom, while the other is engaged in an inter-molecular N-H?pi contact involving the benzene ring of a neighbouring mol-ecule related by inversion. The benzene rings also participate in an intra-molecular C-H?pi contact of similar strength. In the crystal structure, mol-ecules are separated by empty voids (ca 5% of the crystal volume), although the crystal seems to be unsolvated. PMID- 21589367 TI - 2-Oxo-2-(2-thien-yl)acetic acid. AB - The structure of the title compound, C(6)H(4)O(3)S, displays inter-molecular hydrogen-bonding dimers. The structure exhibits a thienyl-ring flip disorder of the main mol-ecule [occupancy ratio = 91.3 (2):8.7 (2)]. PMID- 21589368 TI - Bromido(dodecafluorosubphthalo-cyaninato)boron(III). AB - The title compound, C(24)BBrF(12)N(6) or Br-F(12)BsubPc (BsubPc is boronsubphtalocyanine), has a bowl-shaped structure with an approximate mol ecular C(3v) symmetry characteristic of boronsubphthalocyanine compounds. In the crystal, mol-ecules are arranged in one-dimensional columns and the boron subphthalocyanine units within each column are offset and angled in a bowl-to ligand packing arrangement such that the axial Br atom rests in the aromatic concaved bowl of the neighboring subphthalocyanine with an inter-molecular Br?B distance of 3.721 (3) A. PMID- 21589369 TI - (Dodecafluorosubphthalocyaninato)(4-methylphenolato)boron(III). AB - In the title compound, C(31)H(7)BF(12)N(6)O, mol-ecules are arranged into one dimensional columns with an inter-molecular B?B distance of 5.3176 (8) A. Bowl shaped mol-ecules are arranged within the columns in a concave bowl-to-ligand arrangement separated by a ring centroid distance of 3.532 (2) A between the benzene ring of the 4-methyl-phen-oxy ligand and one of the three five-membered rings of a symmetry-related mol-ecule. PMID- 21589370 TI - N-(2,3-Dichloro-phen-yl)-2,4-dimethyl-benzene-sulfonamide. AB - In the title compound, C(14)H(13)Cl(2)NO(2)S, the dihedral angle between the two aromatic rings is 70.4 (1) degrees . The mol-ecular conformation is stabilized by an intra-molecular N-H?Cl hydrogen bond. PMID- 21589371 TI - N-(2,6-Dichloro-phen-yl)benzene-sulfonamide. AB - In the title compound, C(12)H(9)Cl(2)NO(2)S, the mol-ecule is bent at the S atom with a C-SO(2)-NH-C torsion angle of 82.5 (2) degrees . The benzene rings are tilted relative to each other by 43.5 (1) degrees . The crystal structure features chains linked by N-H?O hydrogen bonds. PMID- 21589372 TI - N-(2,3-Dichloro-phen-yl)-4-methyl-benzene-sulfonamide. AB - The title compound, C(13)H(11)Cl(2)NO(2)S, contains two molecules in the asymmetric unit in which the dihedral angles between the benzene rings are 76.0 (1) and 79.9 (1) degrees . The conformations of the N-H bonds with respect to their adjacent ortho-chlorine atoms are syn. In the crystal, N-H?O hydrogen bonds link the molecules into dimers. PMID- 21589373 TI - N'-(2,4-Dichloro-benzyl-idene)-2-methyl-benzohydrazide. AB - In the title hydrazone compound, C(15)H(12)Cl(2)N(2)O, the dihedral angle between the two benzene rings is 12.2 (2) degrees . In the crystal, mol-ecules are linked through inter-molecular N-H?O hydrogen bonds, forming forming C(4) chains propagating in [001]. PMID- 21589374 TI - 1,3-Bis[4-(meth-oxy-carbon-yl)benz-yl]benzimidazolium bromide monohydrate. AB - In the title compound, C(25)H(23)N(2)O(4) (+).Br(-).H(2)O, the dihedral angles between the benzimidazole ring system and the two benzene rings are 87.77 (11) and 63.05 (11) degrees ; the dihedral angle between the two benzene rings is 66.25 (13) degrees . The crystal structure exhibits C-H?O and O-H?Br inter actions; it is also stabilized by pi-pi stacking inter-actions, with a face-to face separation of 3.456 A between parallel benzimidazole ring systems. PMID- 21589375 TI - 3-(4-Chloro-phenyl-sulfon-yl)-2,5-dimethyl-1-benzofuran. AB - In the title compound, C(16)H(13)ClO(3)S, the 4-chloro-phenyl ring makes a dihedral angle of 79.96 (5) degrees with the mean plane of the benzofuran fragment. In the crystal, mol-ecules are linked through weak inter-molecular C H?O and C-H?pi inter-actions. PMID- 21589376 TI - 1,2,4-Trimeth-oxy-dibenzo[b,d]furan-3-ol. AB - The title compound, C(15)H(14)O(5), is a natural product, isolated from Sorbus lanata Syn. Pyrus lanata (D. Don) found in Pakistan. The compound is composed of three spiro-fused rings. The dihedral angle between the mean planes of the benzene rings is 4.81 (13) degrees . The meth-oxy groups are oriented at dihedral angles of 74.44 (14), 83.0 (2) and 66.3 (2) degrees with respect to the planes of the benzene rings to which they are attached. The mol-ecule is consolidated by three intra-molecular O-H?O and C-H?O hydrogen bonds. In the crystal, mol-ecules are linked by inter-molecular O-H?O hydrogen bonds, forming infinite chains along the b axis. PMID- 21589377 TI - 2-(4-Meth-oxy-benzyl-idene)-4,4-dimethyl-3,4-dihydro-naphthalen-1(2H)-one. AB - The title compound C(20)H(20)O(2), has the exocyclic C=C double bond in an E configuration. The two benzene rings form a dihedral angle of 72.92 (6) degrees . PMID- 21589378 TI - 3-(2-Bromo-eth-oxy)-4-(4-bromo-phen-yl)furan-5(2H)-one. AB - In the title compound, C(12)H(10)Br(2)O(3), the dihedral angle between the furan 5(2H)-one ring and the benzene ring is 1.2 (3) degrees . Two intra-molecular C H?O inter-actions occur in the mol-ecule, both of which generate S(6) rings. The bromo-ethyl fragment is disordered over two sets of sites in a 0.773 (8):0.227 (8) ratio. In the crystal, inversion dimers linked by pairs of C-H?pi inter actions occur. PMID- 21589379 TI - Ethyl 2-(3-amino-4-hy-droxy-phen-yl)acetate. AB - The asymmetric unit of the title compound, C(10)H(13)NO(3), contains two crystallographically independent mol-ecules with different conformations of the eth-oxy-carbonyl groups; the terminal C-C-O-C torsion angles in the two mol ecules are 83.6 (6) and -171.1 (3) degrees , resulting in twisted and straight chain conformations, respectively. The crystal structure is stabilized by inter molecular N-H?O, O-H?N and C-H?O hydrogen bonds. Intra-molecular hydrogen bonds occur between the amino N and phenolic O atoms. PMID- 21589380 TI - (E)-1-(2-Fur-yl)-3-(3,4,5-trimeth-oxy-phen-yl)prop-2-en-1-one. AB - The title mol-ecule, C(16)H(16)O(5), is twisted; the dihedral angle between the furan and 3,4,5-trimeth-oxy-phenyl rings is 12.14 (13) degrees . The two meth-oxy groups at the meta positions of the benzene ring are close to being coplanar with the ring [C-O-C-C = -0.6 (3) and 1.4 (3) degrees ], whereas the third meth-oxy group, at the para position, is (+)-anti-clinal with respect to the benzene ring [C-O-C-C = 104.9 (2) degrees ]. In the crystal, mol-ecules are linked by weak C H?O bonds to stack along the b axis and further C-H?O inter-actions consolidate the structure. PMID- 21589381 TI - 2,5-Bis(4-meth-oxy-phen-yl)-1,3,4-oxadiazole. AB - In the title compound, C(16)H(14)N(2)O(3), the essentially planar 1,3,4 oxadiazole ring [maximum deviation = 0.0021 (11) A] is inclined at dihedral angles of 8.06 (6) and 11.21 (6) degrees with respect to the two benzene rings; the dihedral angle between the latter rings is 11.66 (5) degrees . In the crystal, short inter-molecular C?O inter-actions [2.9968 (15) A] connect adjacent mol-ecules into chains propagating in [203]. The crystal structure is further stabilized by weak inter-molecular C-H?pi inter-actions. PMID- 21589382 TI - 14-(1,3-Benzodioxol-5-yl)-7,14-dihydro-dibenzo[a,j]acridine. AB - The title compound, C(28)H(19)NO(2), was synthesized by the reaction of 1,3 benzodioxole-5-carbaldehyde with naphthalen-2-amine catalyzed by thio-salicylic acid in acetic acid. The central dihydropyridine ring adopts a boat conformation. The two planar (r.m.s. deviations = 0.0158 and 0.0552 A) bicyclic parts make a dihedral angle of 16.16 (5) degrees with respect to each other. The crystal packing is stabilized by inter-molecular N-H?O hydrogen bonds and C-H?pi inter actions. PMID- 21589383 TI - 4-Eth-oxy-phenyl 4-[(meth-oxy-carbon-yl)-oxy]benzoate. AB - In the title compound, C(17)H(16)O(6), the two benzene rings form a dihedral angle of 54.95 (10) degrees . Only weak inter-molecular inter-actions are present in the crystal structure, viz. C-H?O hydrogen bonds and C-H?pi inter-actions involving one of the benzene rings. PMID- 21589384 TI - 3-Ethyl 2-methyl 8-bromo-2-phenyl-1,2,3,3a,4,9b-hexa-hydro-chromeno[4,3-b]pyrrole 2,3-dicarboxyl-ate. AB - The title compound, C(22)H(22)BrNO(5), was synthesized by the intra-molecular cyclo-addition reaction of (E)-ethyl 4-(4-bromo-2-formyl-phen-oxy)but-2-enoate and methyl 2-amino-2-phenyl-acetate. The pyrrolidine and 3,4-dihydro-2H-pyran rings exhibit envelope conformations. The two benzene rings are twisted to each other at a dihedral angle of 59.36 (18) degrees . The eth-oxy group of the ester unit is disordered over two sites with an occupancy ratio of 0.503 (11):0.497 (11). Weak inter-molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 21589385 TI - N-Benzyl-pyridin-2-amine. AB - In the crystal of the title compound, C(12)H(12)N(2), inter-molecular N-H?N hydrogen bonds form rings of graph-set motif R(2) (2)(8) and C-H?pi inter-actions further consolidate the dimers. Neighbouring dimers are further connected into a three-dimensional network by C-H?pi inter-actions. The benzyl and pyridyl rings form a dihedral angle of 67.2 (1) degrees PMID- 21589386 TI - N-Benzyl-pyridin-2-amine. AB - In the title compound, C(12)H(12)N(2), the dihedral angle between the benzene and pyridine rings is 67.63 (8) degrees . Mol-ecules are linked into centrosymmetric dimers by a simple inter-molecular N-H?N hydrogen bond with graph-set motif R(2) (2)(8). PMID- 21589387 TI - 2,4-Dichloro-N-(1,3-thia-zol-2-yl)benzamide. AB - In the mol-ecular structure of the title compound, C(10)H(6)Cl(2)N(2)OS, the dihedral angle between the benzene plane and the plane defined by the amide functionality is 8.6 (1) degrees , while the thia-zole ring plane is twisted with respect to the amide plane by 68.71 (5) degrees . In the crystal, pairs of inter molecular N-H?N hydrogen-bond inter-actions connect the mol-ecules into inversion dimers. pi-pi inter-actions are also observed between neighbouring thia-zole and phen-yl rings [centroid-centroid distance = 3.5905 (13) A] and a weak C-H?pi interaction also occurs. PMID- 21589388 TI - (1R,4aS,10aR)-1,4a-Dimethyl-N-[(morpholin-4-yl)carbothio-yl]-7-(propan-2-yl) 1,2,3,4,4a,9,10,10a-octa-hydro-phenanthrene-1-carboxamide. AB - In the title compound, C(25)H(36)N(2)O(2)S, the cyclo-hexane and morpholine rings adopt chair conformations. The cyclo-hexene and cyclo-hexane rings form a trans ring junction with the two methyl groups in axial positions. The N-H and C=O bonds in the urea group are anti to each other. The crystal structure is stabilized by inter-molecular N-H?O hydrogen bonds. PMID- 21589389 TI - 3-(6-Bromo-4-oxo-4H-chromen-3-yl)-3,4-dihydro-2H-1,2,4-benzothia-diazine-1,1 dione. AB - The mol-ecular structure of the title compound, C(16)H(11)BrN(2)O(4)S, is very similar to that of the previously reported fluoro analogue [al-Rashida et al. (2010 ?). Acta Cryst. E66, o2707]. The mean planes of the bicyclic chromone system and the benzene ring of the benzothia-diazine derivative make a dihedral angle of 58.23 (8) degrees . An intra-molecular N-H?O hydrogen bond occurs. In the crystal, mol-ecules are linked into layers by N-H?O and C-H?O hydrogen bonds, generating an infinite two-dimensional network. PMID- 21589390 TI - Benzene-1,3,5-tricarb-oxy-lic acid-1,10-bis-(1,2,4-triazol-1-yl)deca-ne-water (1/1/2). AB - In the title 1:1:2 association, C(14)H(24)N(6).C(9)H(6)O(6).2H(2)O, the alkyl chain in the 1,10-bis-(1,2,4-triazol-1-yl)decane mol-ecule adopts an extended conformation and the dihedral angle between the aromatic rings is 10.28 (13) degrees . The benzene-1,3,5-tricarb-oxy-lic acid mol-ecule is close to being planar (r.m.s. deviation = 0.052 A). In the crystal, the components are linked by O-H?O and O-H?N hydrogen bonds, generating a layered network. PMID- 21589391 TI - 4-(3-Fluoro-4-meth-oxy-phen-yl)-1-(4-meth-oxy-phen-yl)-5-(3,4,5-trimeth-oxy-phen yl)-1H-imidazole. AB - In the title mol-ecule, C(26)H(25)FN(2)O(5), the fluoro-meth-oxy-, meth-oxy- and trimeth-oxy-substituted benzene rings form dihedral angles of 12.65 (2), 84.15 (2) and 55.67 (2) degrees , respectively, with the imidazole ring. The crystal structure is stabilized weak inter-molecular C-H?F and C-H?O hydrogen bonds. PMID- 21589392 TI - Bis[(5-phenyl-1,3,4-thia-diazol-2-yl)sulfan-yl]methane. AB - The asymmetric unit of the title compound, C(17)H(12)N(4)S(4), contains one half mol-ecule situated on a twofold rotational axis. In the mol-ecule, the thia diazole and attached phenyl rings are twisted by 5.8 (3) degrees . PMID- 21589393 TI - 4-Amino-pyridinium azide 4-amino-pyridine solvate. AB - In the title compound, C(5)H(7)N(2) (+).N(3) (-).C(5)H(6)N(2), all N atoms of the azide anion are situated on a twofold rotational axis, so the 4-amino-pyridinium cation and 4-amino-pyridine mol-ecule, being related by symmetry, occupy one position in the asymmetric unit. Inter-molecular N-H?N hydrogen bonds generate a three-dimensional hydrogen-bonding network which consolidates the crystal packing. PMID- 21589394 TI - 3-[(4-Chloro-phen-yl)sulfin-yl]-2,4,6,7-tetra-methyl-1-benzofuran. AB - In the title compound, C(18)H(17)ClO(2)S, the 4-chloro-phenyl ring is oriented approximately perpendicular to the mean plane of the benzofuran ring [dihedral angle = 87.49 (5) degrees ]. In the crystal, mol-ecules are linked through weak inter-molecular C-H?pi inter-actions, forming left- and right-handed pseudo helices along the a axis. PMID- 21589395 TI - (3,4-Dihy-droxy-oxolan-2-yl)methyl 4-methyl-benzene-sulfonate. AB - The racemic title compound, C(12)H(16)O(6)S, possesses a five-membered ring that adopts an envelope-shaped conformation; the two hy-droxy groups occupy quasi axial positions. Adjacent mol-ecules are linked by O-H?O hydrogen bonds to generate a ribbon that runs along the a axis of the ortho-rhom-bic unit cell. The crystal studied was an inversion twin. PMID- 21589396 TI - 2-{[4-(Diethyl-amino)-phen-yl]imino-methyl}-4,6-diiodo-phenol. AB - In the title compound, C(17)H(18)I(2)N(2)O, the dihedral angle between the aromatic rings is 5.4 (1) degrees . An intra-molecular O-H?N hydrogen bond generates an S(6) ring motif. The crystal packing is stabilized by C-H?pi and pi pi inter-actions [centroid-centroid distance = 3.697 (1) A]. PMID- 21589397 TI - 4-Allyl-3-(2-methyl-4-quinol-yl)-1H-1,2,4-triazole-5(4H)-thione. AB - In the title compound, C(15)H(14)N(4)S, the quinoline and triazole rings form a dihedral angle of 41.48 (7) degrees . In the crystal, adjacent mol-ecules are linked by N-H?N hydrogen bonds, forming chains along [100]. PMID- 21589398 TI - 2-(Dimethyl-amino)-anthraquinone. AB - The mol-ecule of the title compound, C(16)H(13)NO(2), is almost planar, with a maximum deviation of 0.013 (2) A from the best plane; the dihedral angle between the two aromatic rings is 1.06 (1) degrees . In the crystal, mol-ecules are linked through weak intra-molecular C-H?O inter-actions, forming chains running parallel to [10]. PMID- 21589399 TI - Triethyl-ammonium 3,4-dihy-droxy-benzoate. AB - In the title compound, C(6)H(16)N(+).C(7)H(5)O(4) (-), the hy-droxy groups of the 3,4-dihy-droxy-benzoate anion form O-H?O hydrogen bonds to the carboxyl-ate groups of two adjacent anions, generating layers propagating in the ac plane. The triethyl-ammonium cations lie between these layers, forming N-H?O hydrogen bonds to the carboxyl-ate groups of the anions. The structure is consolidated by weak inter-molecular C-H?O inter-actions. PMID- 21589400 TI - 2-Benzyl-sulfanyl-3-(2,2,2-trifluoro-ethoxy)pyridine. AB - The title compound, C(14)H(12)F(3)NOS, was synthesized by the reaction of 2 chloro-3-(2,2,2-trifluoro-eth-oxy)pyridine and phenyl-methane-thiol. The dihedral angle between the aromatic rings is 76.7 (2) degrees . In the crystal structure, weak aromatic pi-pi stacking between inversion-related pairs of pyridine rings [centroid-to-centroid separation = 3.776 (2) A] may help to establish the packing. PMID- 21589401 TI - 2,3-Dibromo-3-(2-bromo-phen-yl)-1-(3-phenyl-sydnon-4-yl)propan-1-one. AB - IN THE TITLE COMPOUND [SYSTEMATIC NAME: 2,3-dibromo-3-(2-bromo-phen-yl)-1-(5 oxido-3-phenyl-1,2,3-oxadiazol-3-ium-4-yl)propan-1-one], C(17)H(11)Br(3)N(2)O(3), the oxadiazole ring is essentially planar, with a maximum deviation of 0.003 (1) A. The -CHBr-CHBr- chain and bromo-phenyl ring are disordered over two sets of sites with a refined occupany ratio of 0.756 (5):0.244 (5). The central oxadiazole ring makes dihedral angles of 54.07 (11) and 13.76 (18) degrees with the attached phenyl and the major component of the bromo-substituted benzene rings, respectively. The dihedral angle between the major and minor components of the bromo-phenyl rings is 13.4 (5) degrees . In the crystal structure, mol-ecules are connected by C-H?O hydrogen bonds, forming [010] ribbons. PMID- 21589402 TI - (2R,3R,4aS,6S,7S,8aS)-4a-Fluoro-8a-hy-droxy-perhydro-naphthalene-2,3,6,7-tetrayl tetraacetate. AB - The title compound, C(18)H(25)FO(9), exhibits a similar unit cell and packing to the alpha polymorph of axial 4a,8a-dihy-droxy-per-hydro-naph-tha-lene-2,3,6,7 tetrayl tetraacetate. The carbonyl O atoms of two of the four acetate groups in the molecule are disordered over two sites with occupancy ratios of 0.59 (4):0.41 (4) and 0.57 (6):0.43 (6). Crystal packing is effected via inter-molecular O-H?O hydrogen bonds, which link the tetra-acetate mol-ecules into tapes along the c axis. PMID- 21589403 TI - Dicyclo-hexyl-ammonium 3-[(hy-droxy-meth-yl)carbamo-yl]propano-ate. AB - The title compound, C(12)H(24)N(+).C(5)H(8)NO(4) (-), contains one dicyclo-hexyl ammonium cation and one 3-[(hy-droxy-meth-yl)carbamo-yl]propano-ate anion in the asymmetric unit. In the crystal, the ions are linked by inter-molecular N-H?O and O-H?O hydrogen bonds, forming chains propagating along [100]. PMID- 21589404 TI - 2,3:4,5-Di-O-isopropyl-idenefructos-1-yl p-toluene-sulfonate. AB - The title compound, C(19)H(26)O(8)S, has been synthesized from 2,3:4,5-di-O isopropyl-idene-beta-d-fructopyran-ose. The absolute configuration of the fused ring is confirmed by anomalous dispersion effects in the diffraction measurement. The six-membered beta-fructopyran-ose ring has a twist-boat conformation with the two five-membered rings trans to each other. In the crystal, inter-molecular non classical C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21589405 TI - 1-Methyl-2-[(E)-2,4,5-trimeth-oxy-styr-yl]-pyridinium iodide. AB - In the title compound, C(17)H(20)NO(3) (+).I(-), the cation exists in the E configuration. The pyridinium and benzene rings are close to coplanar, with a dihedral angle of 7.43 (12) degrees between them. The three meth-oxy groups of 2,4,5-trimeth-oxy-phenyl are essentially coplanar with the benzene plane, with C O-C-C torsion angles of 1.0 (3), -1.9 (3) and 3.6 (3) degrees . A weak intra molecular C-H?O inter-action generates an S(6) ring motif. In the crystal, the cations are stacked in columns in an anti-parallel manner along the a axis through pi-pi inter-actions, with a centroid-centroid distance of 3.7714 (16) A. The iodide anion is situated between the columns and linked to the cation by a weak C-H?I inter-action. PMID- 21589406 TI - N-(3-Chloro-phen-yl)-2-hy-droxy-benzamide. AB - In the title compound, C(13)H(10)ClNO(2), the dihedral angle between the aromatic rings is 5.57 (9) degrees and intra-molecular N-H?O and C-H?O hydrogen bonds both generate S(6) rings. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds into C(6) chains propagating along [010]. Mol-ecules from neighbouring chains along the z axis are involved in C-H?pi and pi-pi stacking inter-actions [centroid-centroid distance = 3.9340 (10) A]. PMID- 21589407 TI - 2,4-Dinitro-1-naphthol. AB - In the title compound, C(10)H(6)N(2)O(5), the two fused rings are almost co planar, with an r.m.s. deviation of 0.0163 A. The nitro groups are oriented at dihedral angles of 2.62 (11) and 44.69 (11) degrees with respect to the plane of the parent fused rings. Intra-molecular O-H?O and C-H?O hydrogen bonds complete S(6) ring motifs. In the crystal, mol-ecules are linked into chains along [101] by inter-molecular O-H?O hydrogen bonds. pi-pi inter-actions [centroid-centroid distances = 3.6296 (15), 3.8104 (15) and 3.6513 (14) A] might play a role in stabilizing the structure. PMID- 21589408 TI - (2SR,3SR)-Isopropyl 3-{[dimeth-yl(phenyl)-sil-yl]meth-yl}-2-hy-droxy-2-vinyl-pent 4-enoate. AB - The relative configuration of the title compound, C(19)H(28)O(3)Si, which was synthesized using a dienolate-[2,3]-Wittig rearrangement, was corroborated by single-crystal X-ray diffraction analysis. The Si-C bond distances are in the range 1.858 (2)-1.880 (2) A and an intra-molecular O-H?O hydrogen bond helps to stabilize the mol-ecular conformation. PMID- 21589409 TI - 2-[(Isopropoxycarbonothio-yl)sulfanyl]-acetic acid. AB - The title compound, C(6)H(10)O(3)S(2), features a planar C atom connected to one O and two S atoms, the C-S single bond being distinctly longer than the C-S double bond. Two mol-ecules are linked by an O-H?O hydrogen bond about a center of inversion, generating a dimer. PMID- 21589410 TI - 6-Chloro-4-(2-phenyl-ethen-yl)chroman-2-one. AB - The title compound, C(17)H(13)ClO(2), was obtained from the oxidation of 6-chloro 4-(2-phenyl-ethen-yl)chroman-2-ol, which was synthesized by the reaction of of (E)-3-(5-chloro-2-hy-droxy-phen-yl)acryl-aldehyde with styrylboronic acid using diethyl-amine as a catalyst. The six-membered pyran-one ring of the chromane system has a screw-boat conformation. The dihedral angle between the least squares planes of the chromane ring system and the styryl group is 85.28 (9) degrees . PMID- 21589411 TI - (1R,3S)-Methyl 6,7-dimeth-oxy-1-(4-meth-oxy-phen-yl)-1,2,3,4-tetra-hydro isoquinoline-3-carboxyl-ate. AB - The title compound, C(20)H(23)NO(5), is the third in a series of tetra hydoisoquinoline (TIQ) compounds that are precursors to novel chiral catalysts. The N-containing six-membered ring assumes a half-boat conformation. No hydrogen bonding is observed in the crystal structure. PMID- 21589412 TI - (E)-2,4-Dichloro-6-{1-[(2-chloro-eth-yl)imino]-eth-yl}phenol. AB - The title Schiff base compound, C(10)H(10)Cl(3)NO, was prepared by the condensation of 1-(3,5-dichloro-2-hy-droxy-phen-yl)ethanone with chloro-ethyl amine. The imine adopts an E configuration with respect to the C=N bond. The H atom of the phenolic OH group is disordered over two positions with site occupation factors of 0.52 (7) and 0.48 (7), respectively, and the major occupancy component is involved in an intramolecular N-H?O hydrogen bond. The compound therefore exists in an iminium-phenolate as well as in the imino-phenol form. In the crystal, mol-ecules are connected by C-H?O and C-H?Cl hydrogen bonds and Cl?Cl inter-actions [3.7864 (9) A] into a three-dimensional network. In addition, inter-molecular pi-pi stacking inter-actions [centroid-centroid distance = 4.4312 (9) A] are observed. PMID- 21589413 TI - 1,2,3-Tri-O-acetyl-5-de-oxy-d-ribofuran-ose. AB - The title compound, C(11)H(16)O(7), was obtained from the breakage reaction of the glycosidic bond of 5'-de-oxy-2',3'-diacetyl-inosine. The ribofuran-ose ring has a C2-exo, C3-endo twist configuration. No alteration of the relative configuration compared with d-(-)-ribose is observed. PMID- 21589414 TI - 5-Diethyl-amino-2-{[2-(2,4-dinitro-phen-yl)hydrazin-1-yl-idene]meth-yl}phenol. AB - In the title compound, C(17)H(19)N(5)O(5), obtained from the condensation reaction of 4-diethyl-amino-2-hy-droxy-benzalde-hyde and 2,4-dinitro-phenyl hydrazine, the two benzene rings are twisted by a dihedral angle of 1.75 (12) degrees . The nitro groups are slightly twisted with the respect to the benzene ring to which they are attached, making dihedral angles of 8.20 (15) and 5.78 (15) degrees . An intra-molecular O-H?N hydrogen bond occurs. In the crystal, mol ecules are linked by pairs of inter-molecular N-H?O hydrogen bonds, forming dimers through R(2) (2)(12) rings. These dimers are further linked by C-H?O and C H?pi and weak slipped pi-pi inter-actions [centroid-centroid distance = 3.743 (2)A]. One of the ethyl groups is disordered over two positions, with occupancy factors in the ratio 0.72:0.28. PMID- 21589415 TI - 3,3,6-Tribromo-1-methyl-1H-2,1-benzo-thia-zin-4(3H)-one 2,2-dioxide. AB - In the title compound, C(9)H(6)Br(3)NO(3)S, a halogenated benzothia-zine derivative, the thia-zine ring adopts a sofa conformation. The crystal studied was a racemic twin with a contribution of 72 (1)% of the major domain. PMID- 21589416 TI - (Z)-3-Diethyl-amino-6-({2-[(E)-4-(diethyl-amino)-2-hy-droxy-benzyl-idene-amino] 4,5-dimethyl-phen-yl}amino-methyl-idene)cyclo-hexa-2,4-dienone-5,5'-bis-(diethyl amino)-2,2'-[4,5-dimethyl-o-phenyl-enebis(nitrilo-methyl-idyne)]diphenol. AB - The asymmetric unit of the title Schiff base compound, C(30)H(38)N(4)O(2), comprises two crystallographically independent mol-ecules, A and B. The structure is non-merohedrally twinned with a refined BASF ratio of 0.219 (6):0.701 (6). Mol ecule B shows both phenol-imine and keto-amine tautomeric forms in a single structure. The dihedral angles between the central ring and the two outer rings are 5.9 (3) and 48.4 (3) degrees in mol-ecule A, and 48.3 (3) and 6.9 (3) degrees in mol-ecule B. Strong intra-molecular O-H?N and N-H?O hydrogen bonds generate S(6) ring motifs. The crystal structure is further stabilized by inter molecular C-H?O, C-H?pi and pi-pi inter-actions [centroid-centroid distances = 3.870 (4)-3.871 (4) A]. PMID- 21589417 TI - (6S,7S,8S,8aS)-6-Ethyl-7,8-dihy-droxy-1,5,6,7,8,8a-hexa-hydro-indolizin-3(2H)-one monohydrate. AB - The absolute configuration of the title compound, C(10)H(17)NO(3).H(2)O, was assigned from the synthesis. In the mol-ecular structure, the central six membered ring of the indolizine moiety adopts a chair conformation, with two atoms displaced by -0.578 (2) and 0.651 (1) A from the plane of the other four atoms [maximum deviation 0.019 (2) A] The conformation of the fused oxopyrrolidine ring is close to that of a flat envelope, with the flap atom displaced by 0.294 (1) A from the plane through the remaining four atoms. In the crystal, one of the hy-droxy groups is hydrogen-bonded to two water mol-ecules, while the other hy-droxy group exhibits an inter-molecular hydrogen bond to the carbonyl O atom, resulting in a chain parallel to the b axis. PMID- 21589418 TI - Dimethyl 3-phenyl-penta-nedioate. AB - In the title compound, C(13)H(16)O(4), the terminal carboxyl-ate groups are twisted to each other at a dihedral angle of 23.80 (9) degrees . Weak inter molecular C-H?O hydrogen bonds link the mol-ecules into supra-molecular chains along the a axis. PMID- 21589419 TI - 3',7',7'-Trimethyl-1'-phenyl-5',6',7',8'-tetra-hydro-spiro-[indoline-3,4'-(1H,4H pyrazolo-[3,4-b]chromene)]-2,5'-dione. AB - The title spiro-oxindole compound, C(26)H(23)N(3)O(3), was prepared by the reaction of isatin, 3-methyl-1-phenyl-2-pyrazolin-5-one and 5,5-dimethyl-cyclo hexane-1,3-dione in an ethanol solution. The fused cyclo-hexene ring adopts an envelope conformation. The dihedral angle between the aromatic and pyrazoline rings is 23.70 (8) degrees . An intra-molecular C-H?O inter-action occurs. The crystal structure is stabilized by N-H?N hydrogen-bonding inter-actions, leading to a zigzag chain along the b axis. PMID- 21589420 TI - Diethyl 2,5-diphenyl-furan-3,4-dicarboxyl-ate. AB - In the title compound, C(22)H(20)O(5), the substituted benzene rings are twisted away from the furan ring, making dihedral angles of 54.91 (14) and 20.96 (15) degrees with the furan ring. The dihedral angle between the two benzene rings is 46.89 (13) degrees . One ethyl group of one eth-oxy-carbonyl unit is disordered over two sets of sites with occupancies of 0.56 (12) and 0.44 (12). In the crystal, weak intra-molecular C-H?O hydrogen bonds link the mol-ecules into chains along the c axis. PMID- 21589421 TI - (R)-[1-(2-Chloro-phen-yl)-2-meth-oxy-2-oxoeth-yl][2-(thio-phen-2-yl)eth yl]ammonium (+)-camphor-10-sulfonate acetone monosolvate. AB - The title compound, C(15)H(17)ClNO(2)S(+).C(10)H(15)O(4)S(-).C(3)H(6)O, was synthesized by N-alkyl-ation of alpha-amino-(2-chloro-phen-yl)acetate with 2 thienylethyl p-toluene-sulfonate, followed by reaction with (+)-camphor-10 sulfonic acid. In the crystal, the cations and anions are linked through N-H?O hydrogen bonds. The thio-phene ring of the cation was found to be disordered over two sites, with refined occupancies of 0.798 (4) and 0.202 (4). PMID- 21589422 TI - 1-[(3-Methyl-piperidin-1-yl)(3-nitro-phen-yl)meth-yl]naphthalen-2-ol. AB - The title compound, C(23)H(24)N(2)O(3), was synthesized from naphthalen-2-ol, 3 nitro-benzaldehyde and 3-methyl-piperidine. The dihedral angles between the naphthalene system and the nitro-benzene and methyl-piperidine rings are 78.53 (13) and 64.14 (15) degrees , respectively. The mol-ecular conformation is stabilized by a strong intra-molecular O-H?N hydrogen bond. PMID- 21589423 TI - Diethyl 2-[(4-bromo-anilino)methyl-idene]malonate. AB - In the title compound, C(14)H(16)BrNO(4), inter-molecular C-H?O hydrogen bonds link the mol-ecules, forming a stable structure. An intra-molecular N-H?O hydrogen bond results in the formation of a six-membered ring and helps to establish the mol-ecular conformation which is almost planar, with an r.m.s deviation of 0.0842 A. PMID- 21589424 TI - 3-Phenyl-sulfanyl-4-phenyl-sulfonyl-1,2,5-oxadiazole 2-oxide. AB - In the title compound, C(14)H(10)N(2)O(4)S(2),the furoxan heterocyclic ring and the two S atoms are almost co-planar, with a mean deviation of 0.036 A. The bond lengths in the penta-gonal ring show electron delocalization and the furoxan N-O bond length is quite short [1.211 (3) A]. The dihedral angles between the central ring and pendant phenyl rings are 78.05 (14) and 84.28 (2) degrees . PMID- 21589425 TI - 1,3-Bis(2,6-diisopropyl-phen-yl)-4,5-dihydro-1H-imidazol-3-ium triiodide. AB - In the crystal structure of the title compound, C(27)H(39)N(2) (+).I(3) (-), the imidazolidinium ring is perpendicular to a mirror plane which bis-ects the cation. The dihedral angle between the imidazolidinium ring and the benzene ring is 89.0 (2) degrees . The triiodide anion also lies on a mirror plane and is almost linear with an I-I-I bond angle of 178.309 (18) degrees . PMID- 21589426 TI - 2-(4-Fluoro-phen-yl)-3-hy-droxy-4H-chromen-4-one. AB - In the crystal structure of the title compound, C(15)H(9)FO(3), inversely oriented mol-ecules form inversion dimers through pairs of O-H?O hydrogen bonds. The benzene ring is twisted at an angle of 12.0 (1) degrees relative to the 4H chromene skeleton of the mol-ecule. Adjacent 4H-chromene units are parallel in a given column or oriented at an angle of 50.0 (1) degrees in neighboring, inversely oriented, columns, forming a herringbone pattern. PMID- 21589428 TI - Benzoic acid-2,2'-biimidazole (2/1). AB - In the title compound, C(6)H(6)N(4).2C(7)H(6)O(2), the asymmetric unit contains a half-mol-ecule of biimidazole and one benzoic acid mol-ecule. The unit cell contains two biimidazole mol-ecules and four benzoic acid mol-ecules, giving the reported 2:1 ratio of benzoic acid to biimidazole. The biimidazole mol-ecule is located on an inversion center (passing through the central C-C bond). Strong N H?O and O-H?N hydrogen bonds link the benzoic acid mol-ecules with the neutral biimidazole mol-ecules, which lie in planar sheets. In the crystal packing, the parallel sheets are related by a twofold rotation axis and an inversion centre, respectively, forming an inter-woven three-dimensional network via weak C=O?pi inter-molecular inter-actions between neighboring mol-ecules. PMID- 21589427 TI - N,N'-Bis[(E)-(2-chloro-8-methyl-quinolin-3-yl)methyl-idene]ethane-1,2-diamine. AB - The complete mol-ecule of the title compound, C(24)H(20)Cl(2)N(4), is generated by a crystallographic inversion centre. A kink in the mol-ecule is evident [C-N-C C torsion angle = -147.0 (3) degrees ] owing to the twist in the central ethyl ene bridge. Further, there is a small twist between the imine [N=C = 1.267 (3) A] and quinoline residues [N-C-C-C = -12.4 (4) degrees ]. In the crystal, a combination of pi-pi [pyridine-benzene centroid-centroid distance = 3.5670 (14) A] and C-H?N contacts leads to supra-molecular chains propagating in [010]. PMID- 21589429 TI - (1S,3R,8S,9R,10S)-2,2-Dichloro-3,7,7,10-tetra-methyl-9,10-ep-oxy-tricyclo [6.4.0.0]dodeca-ne. AB - The title compound, C(16)H(24)Cl(2)O, was synthesized from beta-himachalene (3,5,5,9-tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzocyclo-heptene), which was isolated from the essential oil of the Atlas cedar (cedrus atlantica). The mol ecule forms an extended sheet of two fused rings which exhibit different conformations. The six-membered ring has a half-chair conformation, while the seven-membered ring displays a chair conformation; the dihedral angle between the two rings is 38.2 (1) degrees . PMID- 21589430 TI - (E)-4-Hy-droxy-N'-(4-hy-droxy-3-meth-oxy-benzyl-idene)benzohydrazide. AB - In the title compound, C(15)H(14)N(2)O(4), the N=C double bond has an E configuration. The two benzene rings make a dihedral angle of 28.59 (6) degrees . In the crystal, mol-ecules are linked into a three-dimensional network by inter molecular N-H?O, O-H?O and C-H?O hydrogen bonds and stabilized by weak C-H?pi inter-actions. PMID- 21589431 TI - 2,3-Dibromo-3-(5-nitro-2-fur-yl)-1-(4-nitro-phen-yl)propan-1-one. AB - In the title compound, C(13)H(8)Br(2)N(2)O(6), the 2-furyl ring is essentially planar, with a maximum deviation of 0.002 (2) A. It is inclined at an angle of 33.94 (9) degrees to the benzene ring. Both nitro groups are slightly twisted away from their attached rings; the dihedral angles are 4.6 (2) degrees between the nitro group and the 2-furyl ring, and 13.72 (19) degrees between the nitro group and the benzene ring. In the crystal, mol-ecules are linked into chains along [110] and [10] via two pairs of inter-molecular C-H?O hydrogen bonds, displaying R(2) (2)(10) ring motifs. PMID- 21589432 TI - 3-Acetyl-4-hy-droxy-6,7-dimethyl-2H-chromen-2-one. AB - In the title coumarin derivative, C(13)H(12)O(4), the 2H-chromene ring system is essentially planar [maximum deviation = 0.047 (1) A]. An intra-molecular hydrogen bond is observed between the hy-droxy and the ketonic O atoms. In the crystal, pairs of inter-molecular C-H?O hydrogen bonds link inversion-related mol-ecules into dimers. Additional inter-molecular C-H?O hydrogen bonds further inter connect these dimers into two-dimensional arrays incorporating R(2) (2)(9) ring motifs. PMID- 21589433 TI - 2,3-Dibromo-1,3-bis-(4-chloro-phen-yl)propan-1-one. AB - In the title compound, C(15)H(10)Br(2)Cl(2)O, the terminal benzene rings make a dihedral angle of 31.1 (2) degrees with each other. In the crystal, mol-ecules are stacked along the a axis and consolidated by C-H?pi inter-actions. Short Cl?Cl [3.1140 (17) A] and Br?Cl [3.4565 (13) A] contacts are observed. PMID- 21589434 TI - 2-(5,6-Dibromo-7-methyl-3H-imidazo[4,5-b]pyridin-2-yl)phenol. AB - In the title compound, C(13)H(9)Br(2)N(3)O, the mol-ecular skeleton, influenced by an intra-molecular O-H?N hydrogen bond, is roughly planar, with a mean deviation of 0.033 A. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into chains propagating in [100]. Weak inter-molecular pi-pi inter actions [centroid-centroid distances = 3.760 (3) and 3.723 (3) A] further consolidate the packing. PMID- 21589435 TI - 3,6,8-Tribromo-quinoline. AB - The title mol-ecule, C(9)H(4)Br(3)N, is almost planar, the maximum deviation being 0.110 (1) A. The crystal structure is stabilized by weak aromatic pi-pi inter-actions [centroid-centroid distance = 3.802 (4) A] between the pyridine and benzene rings of the quinoline ring systems of adjacent mol-ecules. PMID- 21589436 TI - 2-[(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-1-methyl-2 oxoethyl pyrrolidine-1-carbodithio-ate. AB - In the title compound, C(19)H(24)N(4)O(2)S(2), inversion-related mol-ecules are linked together to form a dimer by N-H?O and C-H?O hydrogen bonds, generating two R(2) (1)(6) rings and one R(2) (2)(10) ring motif. An inter-molecular C-H?O hydrogen bond connects the dimers to each other. An intra-molecular C-H?O inter action occurs. In the pyrrolidine ring, the two C atoms of the ring not bonded to the N atom displays positional disorder with site-occupation factors of 0.630 (18) and 0.370 (18). PMID- 21589437 TI - trans-2-(2-Nitro-1-phenyl-eth-yl)cyclo-hexa-none. AB - In the title compound, C(14)H(17)NO(3), the plane of the phenyl ring and the least-squares plane of the cyclo-hexyl moiety enclose an angle of 89.14 (6) degrees . The cyclohexyl ring adopts a chair conformation. In the crystal, the molecules are linked by weak C-H?O bonds, with each of the nitro-O atoms accepting two such interactions. PMID- 21589438 TI - 3-[2-(1H-Benzimidazol-2-ylsulfan-yl)eth-yl]-1,3-oxazolidin-2-one. AB - In the title compound, C(12)H(13)N(3)O(2)S, the oxazolidin ring displays an envelope conformation. The dihedral angle between the benzimidazole ring and the 1,3-oxazolidin-2-one mean plane is 69.85 (13) degrees . In the crystal, mol ecules are linked by inter-molecular N-H?N hydrogen bonds, forming a chain parallel to the b axis. PMID- 21589439 TI - 3-Diethyl-amino-6-[(Z)-(4-hy-droxy-anilino)methyl-idene]cyclo-hexa-2,4-dienone. AB - In the mol-ecule of the title compound, C(17)H(20)N(2)O(2), the aromatic rings are oriented at a dihedral angle of 6.23 (22) degrees . Intra-molecular N-H?O hydrogen bonding involving the amine H atom and the carbonyl O atom affects the conformation of the mol-ecule. One of the ethyl arms is disordered over two conformations, with occupancies of 0.59 (2) and 0.41 (2). The crystal packing is stabilized by inter-molecular C-H?O and O-H?O hydrogen bonds, and weak C-H?pi inter-actions. PMID- 21589440 TI - 3-Benzyl-6-butyl-5-propyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7(6H)-one. AB - In the title compound, C(18)H(23)N(5)O(2), the triazolopyrimidine ring system is essentially planar, with a maximum displacement of 0.032 (2) A, and forms a dihedral angle of 87.59 (15) degrees with the phenyl ring. In the crystal, mol ecules are linked by inter-molecular C-H?O hydrogen bonds and C-H?pi inter actions into chains parallel to the c axis. PMID- 21589441 TI - 4-{[2-(2,4-Dinitro-phen-yl)hydrazinyl-idene]meth-yl}phenol ethanol hemisolvate. AB - In the title compound, C(13)H(10)N(4)O(5).0.5C(2)H(5)OH, the two benzene rings form a dihedral angle of 4.29 (9) degrees . The ethanol solvent mol-ecule was treated as disordered between two orientations related by symmetry (center of inversion), with occupancies fixed at 0.5. The crystal packing, stabilized by inter-molecular O-H?O and N-H?O hydrogen bonds and pi-pi inter-actions [indicated by the short distance of 3.7299 (7) A between the centroids of benzene rings from neighbouring mol-ecules], exhibits short inter-molecular O?O contacts of 2.8226 (3) A. PMID- 21589442 TI - N'-(2,4-Dichloro-benzyl-idene)-4-hy-droxy-benzohydrazide. AB - The title hydrazone compound, C(14)H(10)Cl(2)N(2)O(2), was synthesized by the reaction of 2,4-dichloro-benzaldehyde and 4-hy-droxy-benzohydrazide. The mol ecule adopts an E geometry with respect to the azomethine group and the dihedral angle between the aromatic rings is 7.0 (2) degrees . In the crystal, mol-ecules are linked through inter-molecular N-H?Cl and O-H?O hydrogen bonds, forming a three-dimensional network. PMID- 21589443 TI - N-(2,4-Dichloro-phen-yl)-2,4-dimethyl-benzene-sulfonamide. AB - In the title compound, C(14)H(13)Cl(2)NO(2)S, the mol-ecule is bent at the S atom with an C-SO(2)-NH-C torsion angle of -69.9 (2) degrees . The dihedral angle between the sulfonyl and aniline benzene rings is 44.0 (1) degrees . The crystal structure features inversion dimers linked by pairs of N-H?O hydrogen bonds. An intra-molecular N-H?Cl hydrogen bond is also observed. PMID- 21589444 TI - (E)-2-(Furan-2-yl-methyl-idene)-8-methyl-2,3,4,9-tetra-hydro-1H-carbazol-1-one. AB - In the title mol-ecule, C(18)H(15)NO(2), the carbazole unit is not planar [maximum deviation from mean plane = 0.236 (2) A]. The pyrrole ring makes dihedral angles of 1.21 (10) and 16.74 (12) degrees with the benzene and the furan rings, respectively. The cyclo-hexene ring adopts a half-chair conformation. In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(10) loops. PMID- 21589445 TI - 1-(1-Hy-droxy-8-methyl-9H-carbazol-2-yl)ethanone. AB - The title compound, C(15)H(13)NO(2), crystallizes with four independent mol ecules (A, B, C and D) in the asymmetric unit. The carbazole units are almost planar [maximum deviations = 0.015 (3) for A, 0.024 (3) for B, 0.026 (3) for C and 0.046 (3) A for D]. In all four mol-ecules, there is an O-H?O hydrogen bond involving the hy-droxy substituent and the carbonyl O atom of the adjacent acetyl group, which forms a six-membered ring. In the crystal, the four independent mol ecules are linked via N-H?O and C-H?O inter-actions. PMID- 21589446 TI - 3-(Pyridin-4-ylmeth-oxy)phenol. AB - In the title compound, C(12)H(11)NO(2), the phenolic ring is inclined at an angle of 32.70 (1) degrees with respect to the pyridine ring. In the crystal, inter molecular O-H?N hydrogen bonds link the mol-ecules into C(11) chains along [001]. PMID- 21589447 TI - 2-[(E)-1-(4-Meth-oxy-phen-yl)pent-1-en-3-yl-idene]malononitrile. AB - In the title compound, C(15)H(14)N(2)O, the mol-ecule skeleton displays an approximately planar structure except for the ethyl group [maximum deviation = 0.042 (1) A]. The meth-oxy-phenyl ring and butanylidenemalononitrile groups are located on opposite sides of the C=C bond, showing an E configuration. Weak inter molecular C-H?N hydrogen bonding is present in the crystal structure. PMID- 21589448 TI - 2-Phenyl-2-(pyridin-2-yl)hexahydro-pyrimidine. AB - The title compound, C(15)H(17)N(3), was prepared by reaction of benzoyl-pyridine and hexahydropyrimidine. The 1,3-diazinane ring adopts a chair conformation with one N-H group axial and the other equatorial. The axial N-H group participates in very weak hydrogen bonding to the lone pair of electrons of the N atom with the equatorial H atom producing a very weakly hydrogen-bonded dimer. The pyridine N atom accepts an inter-nal hydrogen bond from the equatorial H atom. The phenyl ring adopts an equatorial position while the pyridine ring is axial. The phenyl ring exhibits a slight twist (ca 25 degrees ) relative to the hexahydropyrimidine ring. The pyridine ring stacks with symmetry-related pyridine rings. PMID- 21589449 TI - 4-[3-(1H-Imidazol-1-yl)prop-yl]-3-methyl-5-(thio-phen-2-ylmeth-yl)-4H-1,2,4 triazole monohydrate. AB - In the title compound, C(14)H(17)N(5)S.H(2)O, the triazole ring makes dihedral angles of 48.15 (8) and 84.92 (8) degrees with the imidazole and thio-phenyl rings, respectively. The water mol-ecule is involved in inter-molecular O-H?N hydrogen bonding. PMID- 21589450 TI - N-{4-[(3,4-Dimethyl-phen-yl)(eth-yl)sulfamo-yl]phen-yl}-N-ethyl-acetamide. AB - When viewed down the central S?N axis of the title compound, C(20)H(26)N(2)O(3)S, it is apparent that the mol-ecule adopts a gauche conformation with all O atoms lying to one side of the central benzene ring; the carbonyl O atom is directed away from the central ring and the N-bound ethyl groups lie to one side of the mol-ecule. Supra-molecular helical chains aligned along the b axis and sustained by C-H?O contacts feature in the crystal packing. These are consolidated in the three-dimensional structure by C-H?pi inter-actions. PMID- 21589451 TI - Mefenacet [2-(1,3-benzothia-zol-2-yl-oxy)-N-methyl-N-phenyl-acetamide]. AB - The title compound, C(16)H(14)N(2)O(2)S, crystallizes with two independent mol ecules in the asymmetric unit. The dihedral angles between the plane of the benzothia-zole ring system and the phenyl ring plane are 51.63 (7) and 60.46 (5) degrees . In the crystal structure, weak inter-molecular C-H?O hydrogen bonds and C-H?pi inter-actions contribute to the stabilization of the packing. PMID- 21589452 TI - 2-(2-Chloro-pyridin-3-yl)-N-ethyl-4-methyl-1,3-oxazole-5-carboxamide. AB - In the title compound, C(12)H(12)ClN(3)O(2), the dihedral angle between the aromatic rings is 8.42 (10) degrees . In the crystal, mol-ecules are linked by N H?O hydrogen bonds, generating C(4) chains propagating in [001]. PMID- 21589453 TI - Ethyl 1,3,10,12-tetra-phenyl-19,20-dioxa-hexa-cyclo-[10.6.1.1.0.0.0]icosa 4(9),5,7,13(18),14,16-hexa-ene-2-carboxyl-ate. AB - The title compound, C(45)H(34)O(4), is the product of a tandem 'pincer' Diels Alder reaction consisting of two consecutive [4 + 2] cyclo-additions between two 2-benzofuran units and ethyl propiolate. The mol-ecule comprises a fused hexa cyclic system containing four five-membered rings, which are in the usual envelope conformation, and two six-membered rings. In addition, four phenyl rings are attached to the hexa-cyclic system. The packing is stabilized by C-H?pi inter actions. PMID- 21589454 TI - 2-Amino-1-(2-carboxyl-atoeth-yl)pyrimidin-1-ium monohydrate. AB - In the title structure, C(7)H(9)N(3)O(2).H(2)O, there are two formula units in the asymmetric unit. The mol-ecule is a zwitterion, containing a quaternary N atom and a deprotonated carboxyl group, with C-O distances in the range 1.256 (2) 1.266 (3) A. The two independent mol-ecules form a hydrogen-bonded R(2) (2)(16) dimer about an approximate inversion center via N-H?O hydrogen bonds, with N?O distances of 2.766 (2) and 2.888 (2) A. O-H?O hydro-gen bonds involving the water mol-ecules and additional N-H?O hydrogen bonds link these dimers, forming double chains. PMID- 21589455 TI - 3,5-Dinitro-N-(4-nitro-phen-yl)benzamide. AB - In the title mol-ecule, C(13)H(8)N(4)O(7), the amide fragment has an anti configuration. The mean planes of the two benzene rings form a dihedral angle of 7.78 (4) degrees . The mean planes of the three nitro groups are twisted by 6.82 (3), 5.01 (4) and 18.94 (7) degrees with respect to the benzene rings to which they are attached. In the crystal, mol-ecules are linked by weak inter-molecular N-H?O hydrogen bonds into chains along [100]. PMID- 21589456 TI - N,N'-Di-tert-butyl-N''-(2,6-difluoro-benzo-yl)phospho-ric triamide. AB - In the title compound, C(15)H(24)F(2)N(3)O(2)P, the phosphoryl and carbonyl groups adopt anti positions relative to each other. The P atom is in a tetra hedral coordination environment and the environment of each N atom is essentially planar. In the crystal, adjacent mol-ecules are linked via N-H?O=P and N-H?O=C hydrogen bonds into an extended chain parallel to the a axis. The crystal studied was a non-merohedral twin with a minor twin component of 36.4 (1)%. PMID- 21589457 TI - Bis(4-carbamoylpiperidinium) biphenyl-4,4'-disulfonate. AB - In the title isonipecotamide salt 2C(6)H(13)N(2)O(+).C(12)H(8)O(6)S(2) (2-), the asymmetric unit comprises one biphenyl-4,4'-disulfonate dianion which lies across a crystallographic inversion centre and another in a general position [dihedral angle between the two phenyl rings is 37.1 (1) degrees ], together with three isonipecotamide cations. Two of these cations give a cyclic homomeric amide-amide dimer inter-action [graph set R(2) (2)(8)], the other giving a similar dimeric inter-action but across an inversion centre, both dimers then forming lateral cyclic R(4) (2)(8) pyrimidinium-amide N-H?O inter-actions. These units are linked both laterally and longitudinally to the sulfonate groups of the dianions through piperidinium N-H?O hydrogen bonds, giving a three-dimensional framework structure. PMID- 21589458 TI - 4-Carbamoylpiperidinium acetate monohydrate. AB - In the structure of the title compound, C(6)H(13)N(2)O(+).C(2)H(3)O(2) (-).H(2)O, the amide H atoms of the cations form centrosymmetric cyclic hydrogen-bonding associations incorporating two water mol-ecules [graph set R(4) (2)(8)], which are conjoint with cyclic water-bridged amide-amide associations [R(4) (4)(12)] and larger R(4) (4)(20) associations involving the water mol-ecule and the acetate anions, which bridge through the piperidinium H-bond donors, giving an overall three-dimensional framework structure. PMID- 21589459 TI - meso-Dimethyl 2,5-dibromo-hexa-ne-dioate. AB - The title compound, C(8)H(12)Br(2)O(4), lies about a crystallographic center of inversion at the midpoint of the central C-C bond. The latter is also repsonsible for the observation of the meso form. There are no intra-molecular hydrogen bonds, but mol-ecules are connected by inter-molecular C-H?O inter-actions, forming a three-dimensional network. PMID- 21589460 TI - 2-Benzoyl-1H-benzimidazole. AB - In the title compound, C(14)H(10)N(2)O, the benzoyl ring and benzimidazole ring system are aligned at a dihedral angle of 50.2 (2) degrees . In the crystal, inter-molecular N-H?N hydrogen bonds between adjacent imidazole groups generate supra-molecular C(4) chains running along the b axis. PMID- 21589461 TI - 4-(4-Pyrid-yl)pyridinium 3-amino-5-carb-oxy-2,4,6-triiodo-benzoate-5-amino-2,4,6 triiodo-isophthalic acid (1/1). AB - In the title ammonium carboxyl-ate-carb-oxy-lic acid co-cystal, C(10)H(9)N(2) (+).C(8)H(3)I(3)NO(4) (-.)C(8)H(4)I(3)NO(4), the carboxyl-ate anion and carb-oxy lic acid mol-ecule are linked by O-H?O and N-H?O hydrogen bonds to form a chain running along the c axis of the monoclinic unit cell. The chains are linked by pyridinum and pyridine N-H?O hydrogen bonds, generating a layer motif. O-H?N and O-H?O hydrogen bonds are also observed. PMID- 21589462 TI - 1,2:3,5-Bis[(4-tert-butyl-phen-yl)boranedi-yl]-alpha-d-glucofuran-ose. AB - The crystal structure of the title compound, C(26)H(34)B(2)O(6), comprises two crystallographically independent mol-ecules. In the crystal, the mol-ecules are linked by multiple inter-molecular O-H?O and C-H?O hydrogen bonds into a two dimensional array. PMID- 21589463 TI - Levocetirizinium dipicrate. AB - There are two cation-dianion pairs in the asymmetric unit of the title compound, C(21)H(27)ClN(2)O(3) (2+).2C(6)H(2)N(3)O(7) (-) {systematic name: 1-[2-(carb-oxy meth-oxy)eth-yl]-4-[(R)-(4-chloro-phen-yl)phenyl-meth-yl]piperazine-1,4-diium bis (2,4,6-trinitro-phenol-ate)}. The piperazine group in the levocetirizinium cation is protonated at both N atoms. The acetyl end groups form R(2) (2)(8) hydrogen bonded motifs with adjacent cations. Each picrate anion inter-acts with the proponated N atom in the cation through a bifurcated N-H?O hydrogen bond, forming R(1) (2)(6) ring motifs. Strong and weak inter-molecular N-H?O and strong O-H?O hydrogen bonds, and weak pi-ring and pi-pi stacking inter-actions [centroid centroid distance = 3.7419 (14) A] dominate the crystal packing, creating a three dimensional supra-molecular structure. PMID- 21589464 TI - rac-2-[2-(4-Fluoro-phen-yl)-2-oxo-1-phenyl-eth-yl]-4-methyl-3-oxo-N-phenyl-penta namide. AB - The title compound, C(26)H(24)FNO(3), is a critical inter-mediate of a selective and competitive inhibitor of the enzyme 3-hy-droxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Inter-molecular N-H?O hydrogen bonding generates a chain along [give direction] that is the dominant inter-action in the crystal packing. Inter-molecular C-H?O inter-actions are also observed. PMID- 21589465 TI - Pyridine-2-carboximidamidate chloride monohydrate. AB - The title compound, C(6)H(8)N(3) (+).Cl(-).H(2)O, crystallizes with three formula units in the asymmetric unit. The cations are non-planar with the -C(NH(2))(2) groups twisted out of the ring planes. Each pyridine carboximidamidate cation is linked to another cation through N-H?N hydrogen bonds, to chloride ions by N-H?Cl hydrogen bonds, and to water mol-ecules by N-H?O hydrogen bonds. Water mol-ecules and chloride ions are also linked together via O-H?Cl hydrogen bonds. In the crystal, all these inter-molecular inter-actions result in a three-dimensional network. PMID- 21589466 TI - 1,3-Diphenyl-1H-pyrazole-4-carbaldehyde. AB - There are four mol-ecules in the asymmetric unit of the title compound, C(16)H(12)N(2)O. The dihedral angle between the phenyl rings in the mol-ecules are 22.2 (2), 22.4 (2), 25.1 (3) and 41.9 (2) degrees . In the crystal, mol ecules form dimers due to inter-molecular C-H?O hydrogen bonds, which result in one R(2) (2)(10) and two R(2) (1)(7) ring motifs. Weak aromatic pi-pi stacking [centroid-centroid separation = 3.788 (3) A] and C-H?pi inter-actions may also consolidate the packing. PMID- 21589467 TI - Diethyl 5-acetamido-3-methyl-thio-phene-2,4-dicarboxyl-ate. AB - The title compound, C(13)H(17)NO(5)S, is approximately planar (r.m.s. deviation for the non-H atoms = 0.055 A). Its conformation is stabilized by N-H?O and C-H?O hydrogen bonds, which both generate S(6) rings. The crystal packing only features van der Waals contacts. PMID- 21589468 TI - (2Z)-4-[(2-Hy-droxy-phen-yl)carbamo-yl]prop-2-enoic acid. AB - In the title compound, C(10)H(9)NO(4), the 2-hy-droxy-anilinic and the 4-oxobut-2 enoic acid groups are almost planar, with r.m.s. deviations of 0.0086 and 0.0262 A, respectively. The dihedral angle between the two groups is 6.65 (1) degrees . Intra-molecular N-H?O, C-H?O and O-H?O hydrogen bonds form S(5), S(6) and S(7) ring motifs. In the crystal, the mol-ecules are dimerized due to C-H?O and O-H?O inter-molecular hydrogen bonds, with R(2) (2)(8) ring motifs. The dimers are inter-linked into polymeric chains along [010] with R(4) (3)(13) ring motifs by C H?O, N-H?O and O-H?O hydrogen bonds. PMID- 21589469 TI - 1-Chloro-methyl-1H-1,2,3-benzotriazole. AB - In the title compound, C(7)H(6)ClN(3), the benzotriazole ring is essentially planar with a maximum deviation of 0.0110 (15)A, and makes a dihedral angle of 0.46 (8) degrees with the benzene ring. In the crystal, mol-ecules are linked through inter-molecular C-H?N hydrogen bonds, forming chains along the c axis. PMID- 21589470 TI - 1-[5-(4-Meth-oxy-phen-yl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl]ethanone. AB - The title mol-ecule, C(18)H(18)N(2)O(2), is V-shaped with the pyrazoline moiety being inclined to the adjacent phenyl ring by an angle of 6.49 (9) degrees , while the 4-meth-oxy-substituted ring is inclined to the pyrazoline ring by 82.99 (9) degrees . In the crystal, adjacent mol-ecules are linked by C-H?O inter actions, forming chains propagating in [100]. There are also C-H?pi inter-actions involving adjacent mol-ecules and those related by an inversion center. PMID- 21589471 TI - The dicyclo-hexyl-amine salt of RG108 (N-phthalyl-l-tryptophan), a potential epigenetic modulator. AB - The dicyclo-hexyl-amine salt of RG108 (N-phthalyl-l-tryptophan) co-crystallizes with a water mol-ecule and a disordered mol-ecule of dimethyl-formamide (DMF), viz. dicyclo-hexyl-aminium (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(1H-indol-3 yl)propanoate dimethyl-formamide solvate monohydrate, C(12)H(24)N(+).C(19)H(13)N(2)O(4) (-).C(3)H(7)NO.H(2)O. The conformation of the deprotonated compound is constrained by charge-assisted strong hydrogen bonds with the dicyclo-hexyl-aminium ion and a dense hydrogen-bond network involving co crystallized solvent mol-ecules. The dihedral angle between the fused ring systems in the anion is 58.35 (4) degrees . PMID- 21589472 TI - Low-temperature redetermination of 1,3-bis-(penta-fluoro-phen-yl)triazene. AB - The crystal structure of the title compound, (C(6)F(5))(2)N(3)H, is stabilized by N-H?N hydrogen bonding, forming centrosymmetric dimers organized in a herringbone motif. Important geometrical parameters are N-N = 1.272 (2) and 1.330 (2) A and N N-N = 112.56 (15) degrees . The dihedral angle between C(6)F(5) groups is 21.22 (9) degrees . The room temperature structure was reported by Leman et al. (1993). Inorg. Chem.32, 4324-4336]. In the current determination, the data were collected to a higher theta angle, resulting in higher precision for the C-C bond lengths(0.001-0.005 versus 0.003 A). PMID- 21589473 TI - 4-({[4-Amino-5-(4-chloro-anilinometh-yl)-4H-1,2,4-triazol-3-yl]sulfan-yl}acet-yl) 3-(4-meth-oxy-phen-yl)-1,2,3-oxadiazol-3-ium-5-olate. AB - In the title sydnone compound, C(20)H(18)ClN(7)O(4)S, the oxadiazole, triazole, chloro-substituted and meth-oxy-substituted phenyl rings are essentially planar, with maximum deviations of 0.007 (3), 0.009 (2), 0.017 (2) and 0.002 (3) A, respectively. The dihedral angles between the chloro-substituted phenyl ring and the triazole ring, the triazole ring and the oxadiazole ring, and the oxadiazole ring and the methoxy-substituted phenyl ring are 80.02 (13), 85.68 (14) and 51.62 (14) degrees , respectively. In the crystal, mol-ecules are connected via inter molecular N-H?N, N-H?O and C-H?O hydrogen bonds, forming sheets lying parallel to the ac plane. PMID- 21589474 TI - Triethyl-ammonium 3,4-dihy-droxy-benzoate monohydrate. AB - In the structure of the title compound, C(6)H(16)N(+).C(7)H(5)O(4) (-).H(2)O, O H?O and N-H?O hydrogen bonds link the components into a three-dimensional array. The 3,4-dihy-droxy-benzoate anion is approximately planar, with a maximum deviation of 0.083 (2) A. PMID- 21589475 TI - 2-(3-Morpholino-prop-yl)-2,3-dihydro-1H-pyrrolo-[3,4-b]quinolin-1-one monohydrate. AB - In the title compound, C(18)H(21)N(3)O(2).H(2)O, the fused-ring system is approximately planar [maximum atomic deviation = 0.028 (3) A]; the morpholine ring displays a chair conformation. The crystal packing is stabilized by classical inter-molecular O-H?O and O-H?N hydrogen bonds and weak C-H?O hydrogen bonds between the organic mol-ecules and the water mol-ecules. PMID- 21589476 TI - 1-Benzoyl-3-(4-hy-droxy-phen-yl)thio-urea. AB - In the title compound, C(14)H(12)N(2)O(2)S, the amino-phenol and the benzoyl groups adopt a syn-anti configuration with respect to the thiono C=S group across the thio-urea C-N. The dihedral angle between the mean planes of the benzoyl and hy-droxy-phenyl rings is 36.77 (8) degrees . The mol-ecules are stabilized by intra-molecular N-H?O hydrogen bonds. In the crystal, weak inter-molecular C-H?O, O-H?S and N-H?O hydrogen bonds link the mol-ecules into a chain along the c axis. PMID- 21589477 TI - 1-Benzoyl-3-[4-(3-benzoyl-thio-ureido)phen-yl]thio-urea. AB - The mol-ecule of the title compound, C(22)H(18)N(4)O(2)S(2), lies across a crystallographic inversion centre. The mol-ecule adopts a syn-anti configuration with respect to the positions of the carbonyl groups and terminal phenyl rings relative to the thione S atom across the C-N bond. There are two intra-molecular N-H?O and C-H?S hydrogen bonds within each molecule, resulting in the formation of four six-membered S(6) rings. The central and terminal rings make a dihedral angle of 13.55 (15) degrees . In the crystal, mol-ecules are linked by inter molecular C-H?S hydrogen bonds, forming R(2) (2)(14) rings and resulting in zigzag chains. PMID- 21589478 TI - 8-Benzoyl-7-hy-droxy-4-methyl-2H-1-benzopyran-2-one monohydrate. AB - In the title compound, C(17)H(12)O(4).H(2)O, the coumarin ring system is approximately planar with a maximum atomic deviation of 0.011 (2) A, and is nearly perpendicular to the phenyl ring at a dihedral angle of 86.63 (9) degrees . In the crystal, mol-ecules are linked by classical O-H?O and weak C-H?O hydrogen bonds. pi-pi stacking is also present [centroid-centroid distance = 3.6898 (12) A]. PMID- 21589479 TI - 5,6-Diamino-1,3-benzodithiole-2-thione. AB - The mol-ecule of the title compound, C(7)H(6)N(2)S(3), is almost planar, the dihedral angle between the benzene plane and the 1,3-dithiole-2-thione plane being 2.21 (6) degrees . In the crystal, mol-ecules are linked by inter-molecular N-H?S and N-H?N hydrogen bonds into a three-dimensional network. The crystal packing also exhibits weak inter-molecular S?S inter-actions [3.5681 (9) A]. PMID- 21589480 TI - Solvate-free bis-(triphenylphosphine)iminium chloride. AB - The title compound, C(36)H(30)NP(2) (+).Cl(-), crystallized in the solvate-free form from a CH(3)CN/OEt(2) solution. The chloride anion and the N atom of the [(Ph(3)P)(2)N](+) cation are located on a twofold axis, yielding overall symmetry 2 for the cation. The central P-N-P angle [133.0 (3) degrees ] is at the low end of the range of observed P-N-P angles. PMID- 21589481 TI - Bis(triphenylphosphine)iminium bromide acetonitrile monosolvate. AB - The title compound, C(36)H(30)NP(2) (+).Br(-).C(2)H(3)N, crystallized from a CH(3)CN/OEt(2) solution as an acetonitrile solvate. The central P-N-P angle [142.88 (10) degrees ] is significantly larger than in the corresponding chloride and iodide structures. PMID- 21589482 TI - 2-Phenyl-biguanidinium hydrogen succinate methanol monosolvate. AB - In the crystal of the title compound, C(8)H(12)N(5) (+).C(4)H(5)O(4) (-).CH(3)OH, the hydrogen succinate anions form infinite [010] chains via short, almost symmetrical, O?H?O hydrogen bonds. The 2-phenyl-biguanidium cations inter-connect these chains into layers lying parallel to the bc plane by way of N-H?O links. These planes only weakly inter-act in the direction of the a axis via C-H?pi contacts between offset phenyl rings, leaving as much as 17% of the unit-cell volume accessible for the solvent. However, the methanol solvent mol-ecules could not be resolved due to extensive disorder and their assumed presence was removed from the overall scattering by the PLATON SQUEEZE procedure. PMID- 21589483 TI - 2-But-oxy-N-[2-(diethyl-amino)-eth-yl]quinoline-4-carboxamide (dibucaine). AB - The mol-ecular conformation of the title compound, C(20)H(29)N(3)O(2), is stabilized by an intra-molecular C-H?O hydrogen bond. The orientation of the amide group to the ring system is characterized by a C-C-C-O dihedral angle of 137.5 (3) degrees . In the crystal, inter-molecular N-H?O hydrogen bonds between the amide groups form C(4) chains running parallel to the a axis. PMID- 21589484 TI - 4-Chloro-benzoic acid-quinoline (1/1). AB - In the title compound, C(7)H(5)ClO(2).C(9)H(7)N, the 4-chloro-benzoic acid mol ecule is almost planar, with a dihedral angle of 2.9 (14) degrees between the carb-oxy group and the benzene ring. In the crystal, the two components are connected by an O-H?N hydrogen bond. In the hydrogen-bonded unit, the dihedral angle between the quinoline ring system and the benzene ring of the benzoic acid is 44.75 (4) degrees . The two components are further linked by inter-molecular C H?O hydrogen bonds, forming a layer parallel to the ab plane. PMID- 21589485 TI - 4,4'-Dibromo-7,7'-dimeth-oxy-1,1'-spiro-biindane. AB - In the title compound, C(19)H(18)Br(2)O(2), the dihedral angle between the two benzene rings of the spiro-biindane molecule is 70.44 (8) degrees . In the crystal, mol-ecules are inter-connected along the c axis by C-H?O hydrogen bonds and pi-pi stacking [centroid-centroid distance = 3.893 (2) A] inter-actions, forming an infinite chain structure. The chains are further inter-connected through another set of C-H?O hydrogen bonds, forming layers approximately parallel to the bc plane. PMID- 21589486 TI - N-(4-Cyano-phen-yl)-2,6-difluoro-benzamide. AB - In the title compound, C(14)H(8)F(2)N(2)O, the amide plane is inclined at dihedral angles of 28.12 (12) and 32.89 (12) degrees with respect to the two benzene rings; the dihedral angle between the two rings is 5.58 (5) degrees . In the crystal, inter-molecular N-H?O and C-H?F hydrogen bonds link adjacent mol ecules into a double-chain structure along the b axis. PMID- 21589487 TI - [(Pyrrolidin-1-yl)carbothio-ylsulfan-yl]methyl pyrrolidine-1-carbodithio-ate. AB - The title compound, C(11)H(18)N(2)S(4), was unexpectedly obtained during studies on the reactivity of the complex tris-(acac-kappa(2)O,O')gallium(III) (acac is acetyl-acetonate) with C(4)H(8)NCS(2)H in dichloro-methane. The title compound shows disordered two pyrrolidine rings with major and minor occupancies of 0.546 (4) and 0.454 (4). Two (pyrrolidin-1-yl)carbothio-ylsulfanyl units are linked together through a methyl-ene C atom and weak C-H?S inter-actions are found. PMID- 21589488 TI - 4-[(9-Ethyl-9H-carbazol-3-yl)imino-meth-yl]phenol. AB - In the title compound, C(21)H(18)N(2)O, the dihedral angle between the phenol ring and the carbazole system is 39.34 (2) degrees . Inter-molecular O-H?N hydrogen bonds and C-H?pi and pi-pi inter-actions [centroid-centroid distances = 3.426 (2) and 3.768 (2) A] stabilize the crystal structure. PMID- 21589489 TI - Methyl 2-(4-hy-droxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl)acetate. AB - In the title compound, C(13)H(13)NO(4), the bicyclic quinolone fragment and the ester group are approximately orthogonal, making a dihedral angle of 83.3 (2) degrees and an intramolecular C-H?O interaction occurs. In the crystal, inter molecular O-H?O hydrogen bonding generates a zigzag chain along the c axis. PMID- 21589490 TI - 1-Butyl-4-hy-droxy-3-methyl-quinoline-2(1H)-one. AB - In the crystal of the title compound, C(14)H(17)NO(2), mol-ecules are arranged into chains along the b axis linked via O-H?O hydrogen bonds. While the benzene ring is essentially planar, with a maximum deviation from the best plane of 0.003 (1) A, the pyridine ring is slightly V-shaped: the distance of the carbonyl C atom from the benzene best plane is 0.120 (1) A. The hy-droxy group is inclined markedly towards the benzene ring reducing the C-C-O bond angle to 113.21 (10) degrees . PMID- 21589491 TI - Dimeth-yl(2-oxo-2-phenyl-eth-yl)sulfanium bromide. AB - Single crystals of the title compound, C(10)H(13)OS(+).Br(-), were obtained from ethyl acetate/ethyl ether after reaction of acetophenone with hydro-bromic acid and dimethyl-sulfoxide. The carbonyl group is almost coplanar with the neighbouring phenyl ring [O-C-C-C = 178.9 (2) degrees ]. The sulfanium group shows a trigonal-pyramidal geometry at the S atom. The crystal structure is stabil-ized by C-H?Br hydrogen-bonding inter-actions. Weak pi-pi inter-actions link adjacent phenyl rings [centroid-centroid distance = 3.946 (2) A]. PMID- 21589492 TI - (E)-6-Chloro-2-(furan-2-yl-methyl-idene)-2,3,4,9-tetra-hydro-1H-carbazol-1-one. AB - In the title compound, C(17)H(12)ClNO(2), the carbazole unit is nearly planar [maximum deviation = 0.052 (1) A]. The pyrrole ring makes dihedral angles of 1.92 (8) and 4.71 (11) degrees with the benzene and furan rings, respectively. Inter molecular N-H?O hydrogen bonds form R(2) (2)(10) rings in the crystal structure. PMID- 21589493 TI - 4-Chloro-N-methyl-2-(1,2,3,4-tetra-hydro-isoquinolin-1-yl)aniline. AB - The racemic title compound, C(16)H(17)ClN(2), shows a tetra-hydro-isoquinoline skeleton with a 4-chloro-N-methyl-aniline group linked to the C atom at position 1. The dihedral angle between the benzene rings is 85.82 (4) degrees . An intra molecular N-H?N hydrogen bond occurs. In the crystal, mol-ecules are linked through inter-molecular C-H?pi inter-actions. PMID- 21589494 TI - 9-(2,4-Dichloro-phen-yl)-3,3,6,6-tetra-methyl-3,4,5,6-tetra-hydro-9H-xanthene 1,8(2H,7H)-dione. AB - The title compound, C(23)H(24)Cl(2)O(3), was synthesized by reaction of 2,4 dichloro-benzaldehyde and 5,5-dimethyl-cyclo-hexane-1,3-dione in ethyl-ene glycol. The central ring of the xanthene moiety is almost planar (with an r.m.s. deviation of 0.0268 A from the least-squares plane) while the two outer rings, in a cis arrangement, display envelope conformations. The ring of the 2,4-dichloro phenyl substituent is nearly perpendicular [85.89 (4) degrees ] to the xanthene ring system. PMID- 21589495 TI - (E)-1-[1-(4-Chloro-phen-yl)eth-yl]-3,5-dimethyl-N-nitro-1,3,5-triazinan-2-imine. AB - In the title compound, C(13)H(18)ClN(5)O(2), the 1,3,5-triazinane ring exhibits an envelope conformation with an E form. The chloro-phenyl ring and the nitro group are each twisted with respect to the mean plane of the triazinane ring, making dihedral angles of 67.30 (9) and 83.54 (8) degrees , respectively. In the crystal, weak inter-molecular C-H?O hydrogen bonds build up a corrugated layer parallel to the (101) plane. PMID- 21589496 TI - (Z)-3-[(4-Eth-oxy-phen-yl)(hy-droxy)methyl-idene]-1-isopropyl-pyrrolidine-2,4 dione. AB - In the title compound, C(16)H(19)NO(4), a potent new herbicide, the dihedral angle between the benzene and pyrrolidine rings is 11.09 (8) degrees . Intra molecular O-H?O and C-H?O hydrogen bonds are observed. PMID- 21589497 TI - 3-Benzyl-6-(2-chloro-benzo-yl)-1,3-benzoxazol-2(3H)-one. AB - In the title compound, C(21)H(14)ClNO(3), the benzoxazolone ring system is planar (r.m.s. deviation = 0.022 A) and forms dihedral angles of 75.38 (10) and 65.92 (13) degrees with the mean planes of the chloro-benzoyl (r.m.s. deviation = 0.045 A, excluding O atom) and benzyl (r.m.s. deviation = 0.023 A) groups. The observed structure is stabilized by weak C-H?O hydrogen bonds and weak inter molecular C-H?pi inter-actions. PMID- 21589498 TI - 4-Chloro-2,6-dinitro-phenol. AB - The aromatic ring of the title compound, C(6)H(3)ClN(2)O(5), is almost planar (r.m.s. deviation = 0.007 A); one nitro substituent is nearly coplanar with the ring [dihedral angle = 3(1) degrees ], whereas the other is twisted [dihedral angle = 36 (1) degrees ]. The phenol OH group is intra-molecularly hydrogen bonded to the nitro group that is coplanar with the ring, generating an S(6) graph-set motif. PMID- 21589499 TI - Diethyl 4-acetyl-5-(2-nitro-phen-yl)pyrrolidine-2,2-dicarboxyl-ate. AB - The title compound, C(18)H(22)N(2)O(7), was synthesized by the 1,3-dipolar cyclo addition reaction of but-3-en-2-one, diethyl 2-amino-malonate and 2-nitro benzaldehyde. In the mol-ecule, the pyrrolidine ring possesses an envelope conformation. Inter-molecular N-H?O and C-H?O hydrogen bonds are present in the crystal structure. PMID- 21589500 TI - (Z)-N-[3-(4-Bromo-benzo-yl)-1,3-thia-zolidin-2-yl-idene]cyanamide. AB - In the title compound, C(11)H(8)BrN(3)OS, the dihedral angle between the benzene and thia-zolidine rings is 63.4 (2) degrees . Inter-molecular C-H?N inter-actions help to stabilize the crystal structure. PMID- 21589502 TI - N-crotylphthalimide. AB - In the title compound {systematic name: 2-[(E)-but-2-en-1-yl]isoindoline-1,3 dione}, C(12)H(11)NO(2), the phthalimide ring system is essentially planar, with a maximum deviation of 0.008 (1) A, while the plane of the N-crotyl substituent is orthogonal to the phthalimide ring system, making a dihedral angle of 87.5 (1) degrees . PMID- 21589501 TI - Ethyl 1-benzyl-5-{[(isopropyl-amino)(3-nitro-phen-oxy)methyl-idene]amino}-1H 1,2,3-triazole-4-carboxyl-ate. AB - In the title compound, C(22)H(24)N(6)O(5), the triazole ring is essentially planar with a maximum deviation of 0.005 (2) A and forms dihedral angles of 79.78 (11) and 86.22 (11) degrees with the phenyl and benzene rings, respectively. In the crystal, mol-ecules are linked by inter-molecular N-H?N, C-H?O and C-H?pi inter-actions into a three-dimensional network. PMID- 21589503 TI - (3R,6R,12R,20S,24S)-20,24-Ep-oxy-dammarane-3,6,12,25-tetraol dihydrate. AB - The title compound, C(30)H(52)O(5).2H(2)O, was degraded from pseudoginsenoside F11 which was extracted and seperated from Panax quinquefolium saponin. The three six-membered rings are in chair conformations. The five-membered ring is in an envelope conformation and the tetra-hydro-furan ring has a conformation inter mediate between half-chair and envelope. In the crystal, inter-molecular O-H?O hydrogen bonds link mol-ecules into a three-dimensional network. Intra-molecular O-H?O hydrogen bonds also occur. PMID- 21589504 TI - (1H-Pyrrol-2-ylmethylidene)(3-{[(1H-pyrrol-2 ylmethylidene)amino]methyl}benzyl)amine. AB - In the title compound, C(18)H(18)N(4), the dihedral angles between the pyrrole rings and the phenyl ring are 85.07 (8) degrees and 77.13 (9) degrees . Inter molecular N-H?N hydrogen bonds contribute to the stabilization of the crystal packing. PMID- 21589505 TI - 4,4'-(1,3,4-Oxadiazole-2,5-diyl)di-pyri-dinium dibromide monohydrate. AB - In the title compound, C(12)H(10)N(4)O(+).2Br(-).H(2)O, the cation is approximately planar: the terminal rings make a dihedral angle of 7.91 (6) degrees with each other and dihedral angles of 6.02 (1) and 6.50 (8) degrees with the central ring. It is linked to the bromide anions and water mol-ecules by N-H?Br hydrogen bonds. In addition, O-H?Br and N-H?Br hydrogen bonds link these units into a three-dimensional network. C-H?N, C-H?Br and N-H?O inter-actions are also observed. PMID- 21589506 TI - 2-Chloro-ethyl 2-(2-chloro-phen-yl)-2-(4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5 yl)acetate. AB - The mol-ecular packing of the title compound, C(17)H(17)Cl(2)NO(2)S, is stabilized by weak C-H?O and C-H?Cl inter-actions. The ester chain is almost planar with a mean deviation of 0.0605 A and makes dihedral angles of 71.60 (4) and 74.70 (8) degrees with the benzene ring and the thio-phene ring, respectively. The benzene and thio-phene rings make a dihedral angle of 84.22 (7) degrees . PMID- 21589507 TI - 2-Chloro-1-(4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)ethanone. AB - In the title compound, C(9)H(10)ClNOS, the dihedral angle between the planar thio phene ring and 2-chloro-ethane moiety (r.m.s deviations of 0.003 and 0.015 A, respectively) is 45.79 (6) degrees . The tetra-hydro-pyridine ring adopts a half chair conformation. The crystal packing reveals inter-molecular C-H?O inter actions. PMID- 21589508 TI - 6-(Adamantan-1-yl)-3-(3-fluoro-phen-yl)-1,2,4-triazolo[3,4-b][1,3,4]thia-diazole. AB - The title mol-ecule, C(19)H(19)FN(4)S, displays C(s) mol-ecular symmetry, in which the crystallographic mirror plane bis-ects the adamantan-1-yl unit while the 3-fluoro-phenyl triazole ring is located on the mirror plane. The F atom of the 3-fluoro-phenyl ring is positionally disordered [occupancy ratio 0.9:0.1]. In the crystal, pi-pi inter-actions between the triazole and phenyl rings occur [centroid-centroid distance = 3.5849 (7) A] and weak C-H?F inter-actions form a ribbon propagating in [010]. PMID- 21589509 TI - 6-[Bis(ethoxycarbonyl)methyl]-6-deoxy-1,2;3,4-di-O-isopropyl-idene-d-galacto pyran-ose. AB - The title compound, C(19)H(30)O(9), was prepared by substitution at the C6 position in 1,2;3,4-di-O-isopropyl-idene-6-O-trifluoro-methane-sulfonyl-d galactose using sodium eth-oxy-malonate in dimethyl-formamide. The conformation is skew-boat (0)S(2), slightly distorted towards boat B(2,5). The inflexible pyran-ose structure makes the title compound a suitable inter-mediate for further synthetic work by keeping stereogenic carbon atoms safe from inversion. Several short intra-molecular C-H? O contacts may stabilize the conformation of the mol ecule. Inter-molecular C-H?O inter-actions also occur. PMID- 21589510 TI - 8-Chloro-5,5-dimethyl-5,6-dihydro-tetra-zolo[1,5-c]quinazoline. AB - In the title compound, C(10)H(10)ClN(5), the tetra-zole ring and the phenyl ring make a dihedral angle of 7.7 (2) degrees . The hexa-hydro-pyrimidine ring adopts a screw-boat conformation. In the crystal, inter-molecular bifurcated N-H?(N,N) hydrogen bonds link the mol-ecules into [001] chains. PMID- 21589511 TI - 2,3-Dibromo-1-(4-chloro-phen-yl)-3-(5-nitro-2-fur-yl)propan-1-one. AB - In the title compound, C(13)H(8)Br(2)ClNO(4), the linking -CHBr-CHBr- fragment is disordered over two orientations with refined site occupancies of 0.512 (11) and 0.488 (11). The dihedral angle between the furan ring and the phenyl ring is 21.86 (16) degrees . In the crystal, the mol-ecules are linked into [011] chains by inter-molecular C-H?O hydrogen bonds. PMID- 21589512 TI - Diethyl 2-amino-5-[(E)-(1-methyl-1H-pyrrol-2-yl)methylideneamino]thiophene-3,4 dicarboxylate. AB - The structure of the title compound, C(16)H(19)N(3)O(4)S, shows the planes described by the thio-phene and the pyrroles are twisted by 17.06 (4) degrees . Additionally, the structure shows the azomethine bond adopts the E configuration, while the pyrrole is disordered as a heterocycle flip [occupancy ratio 0.729 (5):0.271 (5)]. The three-dimensional network is well packed and involves N-H?O hydrogen bonding and pi-pi stacking [centroid-centroid distance = 4.294 (8) A]. PMID- 21589513 TI - 2-[(2-{Bis[2-(2-hy-droxy-5-nitro-benzyl-idene-amino)-eth-yl]amino}-eth-yl)imino meth-yl]-4-nitro-phenol acetonitrile monosolvate. AB - In the title compound, C(27)H(27)N(7)O(9).CH(3)CN, the three nitro groups of the polydentate tripodal Schiff base are located approximately parallel to their respective carrier benzene rings, making dihedral angles of 3.9 (4), 5.0 (4) and 6.3 (4) degrees . Intra-molecular O-H?N hydrogen bonds between the hy-droxy O atoms and the imine N atoms, with O?N distances in the range 2.607 (3)-2.665 (3) A, form nearly planar six-membered rings. In the crystal, weak inter-molecular C H?O and C-H?N hydrogen bonds occur and several intra- and inter-molecular pi-pi inter-actions are present between adjacent benzene rings, with a shortest centroid-centroid distance of 3.507 (2) A. PMID- 21589514 TI - Ethyl 3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)propano-ate. AB - In the title compound, C(13)H(14)N(2)O(3), the fused ring system is almost planar (r.m.s. deviation = 0.015 A). The r.m.s. deviation for all the non-H atoms of the mol-ecule is 0.065A. In the crystal, N-H?O and C-H?O hydrogen bonds generate polymeric chains along the b axis containing alternating centrsymmetric R(2) (2)(8) and R(2) (2)(20) loops. PMID- 21589515 TI - 3,4-Dihy-droxy-benzoic acid pyridine monosolvate. AB - The asymmetric unit of the title compound, C(7)H(6)O(4).C(5)H(5)N, consists of one 3,4-dihy-droxy-benzoic acid and one pyridine mol-ecule, both located on general positions. The 3,4-dihy-droxy-benzoic acid mol-ecules are arranged in layers and are connected by inter-molecular O-H?O hydrogen bonding, forming channels along the a axis in which the pyridine mol-ecules are located. The pyridine and the acid mol-ecules are additionally linked by strong O-H?N hydrogen bonding and by weak pi-pi stacking inter-actions with centroid-centroid distances between the pyridine rings of 3.727 (2) A. PMID- 21589516 TI - 1,3-Dimethyl-5-methyl-sulfonyl-1H-pyrazolo-[4,3-e][1,2,4]triazine. AB - In the title compound, C(7)H(9)N(5)O(2)S, the pyrazolo-[4,3-e][1,2,4]triazine fused-ring system is essentially planar [maximum deviation = 0.0420 (3) A]. In the crystal, mol-ecules related by twofold axes are linked into a mol-ecular net via inter-molecular C-H?O and C-H?N hydrogen bonds. pi-pi inter-actions are observed between the triazine and pyrazole rings of mol-ecules related by the the twofold axis and inversion symmetry with centroid-centroid distances of 3.778 (3) and 3.416 (3) A, respectively. PMID- 21589517 TI - 1-Allyl-3-methyl-3',5'-diphenyl-spiro-[quinoxaline-2(1H),2'(3'H)-[1,3,4]thia diazole]. AB - In the title spiro compound, C(25)H(22)N(4)S, the planar quinoxaline (r.m.s. deviation = 0.070 A) and planar thia-diazole (r.m.s. deviation = 0.060 A) ring systems share a common C atom; their mean planes are aligned at 89.7 (1) degrees . The thia-zole ring possesses two aromatic ring substituents and is nearly coplanar with these rings [the dihedral angles between the thia-diazole and phenyl rings are 5.7 (1) and 10.7 (1) degrees ]. The allyl unit is disordered over two positions in a 0.65 (1):0.35 (1) ratio. PMID- 21589518 TI - 7-Chloro-1,5-dipropargyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione. AB - The seven-membered ring of the title compound, C(15)H(11)ClN(2)O(2), adopts a boat-shaped conformation (with the C atoms of the fused-ring as the stern and the methyl-ene C atom as the prow). The N atoms exists in a trigonal-planar coordination; one of the acetyl-enic H atoms forms a C-H?O hydrogen bond to the O atom of an adjacent mol-ecule, generating a linear chain along a body diagonal. PMID- 21589519 TI - tert-Butyl 6-methyl-2-oxo-4-[4-(trifluoro-meth-oxy)anilino]cyclo-hex-3-ene-1 carboxyl-ate. AB - In the title compound, C(19)H(22)F(3)NO(4), the dihedral angle between the benzene ring and the conjugated part of the enaminone ring is 42.5 (1) degrees . The ester substituent makes a dihedral angle of 81.3 (2) degrees with this latter moiety. The crystal structure is held together by strong N-H?O and weak C H?O inter-molecular inter-actions. The enaminone ring is disordered over two orientations with relative occupancies of 0.794 (4) and 0.206 (4). PMID- 21589520 TI - 1,1'-(p-Phenyl-enedimethyl-idene)diimidazol-3-ium bis-{2-[(2-carb-oxy-phen yl)disulfan-yl]benzoate} dihydrate. AB - The title salt, C(14)H(16)N(4) (2+).2C(14)H(9)O(4)S(2) (-).2H(2)O, was obtained by the co-crystalization of 2,2'-dithio-dibenzoic acid with 1,4-bis-(imidazol-1 ylmeth-yl)benzene. It consists of 2-[(2-carb-oxy-phen-yl)disulfan-yl]benzoate anions, centrosymmetric 1,1'-(p-phenyl-enedimethyl-idene)diimidazol-3-ium cations and water mol-ecules. O-H?O, O-H?S and N-H?O hydrogen-bonding inter-actions among the components lead to the formation of a three-dimensional network. PMID- 21589521 TI - 1,3-Dimethyl-5,6,7,8-tetra-hydro-4H-cyclo-hepta-[c]thio-phene-4,8-dione. AB - In the title compound, C(11)H(12)O(2)S, the C and S atoms of the central thio phene and the methyl groups, and the two carbonyl groups of the cyclo-hepta nedione are almost coplanar [maximum deviation from the mean plane = 0.221 (2) A]. The packing is stabilized by pi-pi inter-actions between the conjugated thio phenes, the shortest centroid-centroid distance between thio-phene rings being 3.9759 (10) A. PMID- 21589522 TI - 2-Amino-4-methyl-pyridinium 6-carb-oxy-pyridine-2-carboxyl-ate sesquihydrate. AB - In the title compound, C(6)H(9)N(2) (+).C(7)H(4)NO(4) (-).1.5H(2)O, extensive O H?O, O-H?N, N-H?O and C-H?O hydrogen bonds, as well as ion pairing, pi-pi stacking inter-actions [centroid-centroid distances = 3.4690 (8) and 3.6932 (8) A between aromatic rings] occur in the crystal. There are hydrogen-bonding inter actions between water mol-ecules, which result in cyclic tetra-meric water clusters. One of the water O molecules has half occupancy. In the anion molecules, the -CO(2) and -CO(2)H groups make torsion angles of 1.73 (18) and 12.14 (18) degrees with respect to the ring. PMID- 21589523 TI - 1-{[5-(4-Chloro-phen-yl)-1-(4-fluoro-phen-yl)-1H-pyrazol-3-yl]carbon yl]}piperidin-4-one. AB - In the title compound, C(21)H(17)ClFN(3)O(2), the 1H-pyrazole ring makes dihedral angles of 36.73 (7), 18.73 (7) and 60.88 (8) degrees , respectively, with the mean planes of the chloro-phenyl, 4-oxo-piperidine and fluoro-phenyl rings. The mol-ecular structure is stabilized by an intra-molecular C-H?N hydrogen bond, which forms an S(6) ring motif. In the crystal, inter-molecular C-H?O hydrogen bonds link mol-ecules into chains along [101]. In addition, inter-molecular C-H?F hydrogen bonds with an R(2) (1)(7) ring motif connect neighbouring chains into layers parallel to the ac plane. PMID- 21589524 TI - 2-Amino-anilinium picrate. AB - In the title compound, C(6)H(9)N(2) (+).C(6)H(2)N(3)O(7) (-), the three nitro groups of the anion are twisted from the central benzene ring at dihedral angles of 5.4 (1), 27.1 (1) and 32.9 (1) degrees . In the crystal, inter-molecular N H?O, N-H?(O,O) and N-H?N hydrogen bonds link the cations and anions into layers parallel to the bc plane. PMID- 21589525 TI - Diethyl [4-(1,3-benzothia-zol-2-yl)benz-yl]phospho-nate. AB - In the title mol-ecule, C(18)H(20)NO(3)PS, the benzene ring and the benzothia zole mean plane are almost coplanar, forming a dihedral angle of 2.29 (2) degrees . The two ethyl groups are each disordered over two conformations in ratios that refined to 0.59 (1):0.41 (1) and 0.56 (1):0.44 (1). In the crystal, weak inter molecular C-H?O hydrogen bonds link the mol-ecules into layers parallel to the bc plane. PMID- 21589526 TI - 4-(9,10-Dioxo-9,10-dihydro-anthracen-1-yl)-4-oxobutanoic acid. AB - In the title compound, C(18)H(12)O(5), the anthracene moiety is almost planar (r.m.s. deviation = 0.0399 A). In the crystal, mol-ecules are linked to each other by inter-molecular O-H?O and weak C-H?O hydrogen bonds. PMID- 21589527 TI - N-(4-Chloro-phen-yl)-7-oxabicyclo-[2.2.1]hept-5-ene-2,3-dicarboximide. AB - In the title racemic compound, C(14)H(10)ClNO(3), which contains four stereogenic centres, the cyclo-hexane ring tends towards a boat conformation, while the tetra hydro-furan and dihydro-furan rings adopt envelope conformations. The dihedral angle between the mean planes of the pyrrolidine-2,5-dione unit and the 4-chloro phenyl ring is 49.0 (2) degrees . PMID- 21589528 TI - 9alpha-Acet-oxy-1beta,10alpha-ep-oxy-parthenolide. AB - The title compound, C(17)H(22)O(6), was semi-synthesized from 9-hy-droxy arthenolide, which was isolated from the chloro-form extract of the aerial parts of Anvillea radiata. The mol-ecule contains fused five- and ten-membered rings: the five-membered lactone ring has a twisted conformation, whereas the ten membered ring displays an approximate chair-chair conformation. The dihedral angle between the rings is 24.76 (9) degrees . PMID- 21589529 TI - (E)-4-Meth-oxy-N'-(4-nitro-benzyl-idene)benzohydrazide methanol monosolvate. AB - The hydrazone mol-ecule of the title compound, C(15)H(13)N(3)O(4).CH(4)O, is nearly planar, with a dihedral angle between the two benzene rings of 1.2 (4) degrees . The mol-ecule exists in a trans configuration with respect to the central methyl-idene unit. In the crystal, the benzohydrazide and methanol mol ecules are linked through inter-molecular O-H?O, O-H?N and N-H?O hydrogen bonds, forming chains along the a axis. PMID- 21589530 TI - 1,4-Bis(2,2':6',2''-terpyridin-4'-yl)benzene. AB - The asymmetric unit of the title compound, C(36)H(24)N(6), comprises a whole mol ecule. Supra-molecular inter-actions between neighbouring mol-ecules are essentially pi-pi stacking inter-actions with small inter-planar distances [3.5140 (15) and 3.6041 (15) A]. The central phenyl-ene ring is tilted with respect to the two pyridine substituents, subtending angles of 36.17 (11) and 34.95 (11) degrees . Three of the peripheral pyridine substituents are almost coplanar with the central pyridines [dihedral angles = 5.10 (12)-8.21 (12) degrees ], but one subtends an angle of 24.86 (12) degrees . PMID- 21589531 TI - Trimethyl 2,2',2''-[1,3,5-triazine-2,4,6-tri-yltris-(aza-nedi-yl)]triacetate. AB - The title compound, C(12)H(18)N(6)O(6), was synthesized via nucleophilic substitution by reacting 2,4,6-trichloro-1,3,5-triazine with glycine methyl ester hydro-chloride in reflux (dried toluene) under anhydrous atmosphere. Individual mol-ecules self-assemble via strong N-H?O hydrogen bonds into supra-molecular double tapes running parallel to the [010] crystallographic direction. The close packing of supra-molecular tapes is mediated by geometrical reasons in tandem with a number of weaker N-H?O and C-H?N hydrogen-bonding inter-actions. PMID- 21589532 TI - (9H-Carbazol-9-ylmeth-yl)diethyl-amine. AB - The asymmetric unit of the title compound, C(17)H(20)N(2), contains two mol ecules, whose bond lengths and angles differ only slightly. In the crystal, neighbouring mol-ecules form pillar structures via edge-to-face pi-pi stacking inter-actions [edge-to-face distances = 3.538 (3) and 3.496 (3)A]. PMID- 21589533 TI - (4-Acetyl-phenolato)(subphthalo-cyaninato)boron(III). AB - In the title compound, C(32)H(19)BN(6)O(2), the B atom adopts a BON(3) tetra hedral coordination geometry. In the crystal, pairs of mol-ecules are associated through aromatic pi-pi stacking inter-actions between the concave faces of the boronsubphthalocyanine fragments at a centroid-centroid distance of 3.4951 (19) A and a weaker inter-action of the same type between the convex faces of the same group [centroid-centroid separation = 3.5669 (18) A] also occurs. PMID- 21589534 TI - N-[(E)-Morpholin-4-yl-methyl-idene]-1-phenyl-1H-1,2,4-triazole-3,5-diamine monohydrate. AB - In the title compound, C(13)H(16)N(6)O.H(2)O, the mean planes of the benzene and 1,2,4-triazole rings form a dihedral angle of 54.80 (5) degrees . The N atom of the amino group adopts a trigonal-pyramidal configuration. Conjugation in the amidine N=C-N fragment results in sufficient shortening of the formal single bond. In the crystal, inter-molecular N-H?O and O-H?N hydrogen bonds link mol ecules into double layers parallel to the bc plane. PMID- 21589535 TI - Ethyl 4,6-O-benzyl-idene-2-de-oxy-N-phthalimido-1-thio-beta-d-glucopyran-oside. AB - In the title compound, C(23)H(23)NO(6)S, the plane of the N-phthalimido group makes a dihedral angle of 67.4 (1) degrees with the least square plane of the sugar ring defined by the C2, C3, C5 and O5 atoms using standard glucose nomenclature. The thio-ethyl group has the exo-anomeric conformation. In the crystal, inter-molecular hydrogen bonds involving the hy-droxy groups and the carbonyl O atoms of adjacent N-phthalimido groups form chains parallel to the b axis. The chains are further stabilized by C-H?pi inter-actions. PMID- 21589536 TI - Ethyl 3,6-di-O-benzyl-2-de-oxy-N-phthalimido-1-thio-beta-d-glucopyran-oside. AB - In the title compound, C(30)H(31)NO(6)S, the plane of the N-phthalimido group is nearly orthogonal to the least-squares plane of the sugar ring (defined by atoms C2, C3, C5 and O5 using standard glucose nomenclature), making a dihedral angle of 72.8 (1) degrees . The thio-ethyl group has the exo-anomeric conformation. The hy-droxy group forms an inter-molecular hydrogen bond to the O atom in the sugar ring, generating [100] chains. There are four close pi-pi contacts with centroid centroid distances less than 4.0 A, all with dihedral angles between the inter acting pi systems of only ? 8 degrees , supporting energetically favourable stacking inter-actions. PMID- 21589537 TI - 3-(p-Anis-yl)sydnone. AB - IN THE TITLE SYDNONE COMPOUND [SYSTEMATIC NAME: 3-(4-meth-oxy-phen-yl)-1,2,3 oxadiazol-3-ium-5-olate], C(9)H(8)N(2)O(3), the essentially planar oxadiazole ring [maximum deviation = 0.005 (1) A] is inclined at a dihedral angle of 30.32 (8) degrees with respect to the benzene ring. In the crystal, adjacent mol ecules are inter-connected by inter-molecular C-H?O hydrogen bonds into sheets lying parallel to (100). Weak inter-molecular pi-pi inter-actions [centroid centroid distance = 3.5812 (8) A] further stabilize the crystal packing. PMID- 21589538 TI - Benzyl N-[(S)-2-hy-droxy-1-({[(E)-2-hy-droxy-4-meth-oxy-benzyl-idene]hydrazin yl}carbon-yl)eth-yl]carbamate. AB - The shape of the title compound, C(19)H(21)N(3)O(6), is curved with the conformation about the imine bond [1.291 (3) A] being E. While the hy-droxy substituted benzene ring is almost coplanar with the hydrazinyl residue [N-N-C-C = 177.31 (18) degrees ], an observation correlated with an intra-molecular O-H?N hydrogen bond leading to an S(6) ring, the remaining residues exhibit significant twists. The carbonyl residues are directed away from each other as are the amines. This allows for the formation of O-H?O and N-H?O hydrogen bonds in the crystal, which lead to two-dimensional supra-molecular arrays in the ac plane. Additional stabilization to the layers is afforded by C-H?pi inter-actions. PMID- 21589539 TI - Triethyl-ammonium hydrogen chloranilate. AB - IN THE CRYSTAL STRUCTURE OF THE TITLE COMPOUND (SYSTEMATIC NAME: triethyl ammonium 2,5-dichloro-4-hy-droxy-3,6-dioxo-cyclo-hexa-1,4-dien-1-olate), C(6)H(16)N(+).C(6)HCl(2)O(4) (-), two hydrogen chloranilate anions are connected by a pair of bifurcated O-H?O hydrogen bonds into a dimeric unit. The triethyl ammonium cations are linked on both sides of the dimer via bifurcated N-H?O hydrogen bonds into a centrosymmetric 2:2 aggregate. The 2:2 aggregates are further linked by inter-molecular C-H?O hydrogen bonds. PMID- 21589540 TI - 1-(4-Chloro-benzyl-idene)-4-ethyl-thio-semicarbazide. AB - In the title compound, C(10)H(12)ClN(3)S, the dihedral angle between the benzene ring and the thio-urea unit is 2.35 (19) degrees . In the crystal, inversion dimers linked by pairs of N-H?S hydrogen bonds generate R(2) (2)(8) loops. PMID- 21589541 TI - Diclomezine: 6-(3,5-dichloro-4-methyl-phen-yl)pyridazin-3(2H)-one. AB - In the title compound, C(11)H(8)Cl(2)N(2)O, the benzene and pyridazine rings are tilted by 8.6 (1) degrees relative to each other. In the crystal, pairs of inter molecular N-H?O hydrogen bonds form centrosymmetric dimers. pi-pi contacts with centroid-centroid distances of 3.698 (2) and 3.751 (1) A and halogen-halogen inter-actions [3.379 (1) A] also stabilize the structure. PMID- 21589542 TI - (2R,4R)-1-(tert-But-oxy-carbon-yl)-4-meth-oxy-pyrrolidine-2-carb-oxy-lic acid. AB - In the title compound, C(11)H(19)NO(5), the five-membered pyrrolidine ring adopts an envelope conformation. The dihedral angles between the carboxyl group plane, the pyrrolidine ring and the meth-oxy group are 59.50 (3) and 62.02 (1) degrees , respectively. In the crystal, inter-molecular O-H?O hydrogen bonds link the mol ecules into chains along [100]. The absolute configuration is assigned in accord with that of (2R,4R)-1-(tert-but-oxy-carbon-yl)-4-hy-droxy-pyrrolidine-2-carb-oxy lic acid, which was the starting material in the synthesis. PMID- 21589543 TI - 1-Acetyl-2-r,6-c-bis-(4-chloro-phen-yl)-3-methyl-1,2,5,6-tetra-hydro-pyridin-4-yl acetate. AB - In the title compound, C(22)H(21)Cl(2)NO(3), the pyridine ring adopts a half chair conformation and the 4-chloro-phenyl groups occupy axial positions. The 4 chloro-phenyl groups are almost perpendicular to the plane of the tetra-hydro pyridine ring forming dihedral angles 84.62 (6) and 85.55 (5) degrees ; the dihedral angle between the two 4-chloro-phenyl rings is 12.16 (4) degrees . The crystal structure is stabilized by inter-molecular C-H?O inter-actions. PMID- 21589544 TI - 4-Carbamoylpiperidinium phenyl-acetate hemihydrate. AB - The asymmetric unit of the title compound, C(6)H(13)N(2)O(+).C(8)H(7)O(2) ( ).0.5H(2)O, comprises two isonipecotamide cations, two phenyl-acetate anions and a water mol-ecule of solvation. The hydrogen-bonding environments for both sets of ion pairs are essentially identical with the piperidinium and amide 'ends' of each cation involved in lateral heteromolecular hydrogen-bonded cyclic N-H?O associations [graph set R(2) (2)(11)] which incorporate a single carboxyl O-atom acceptor. These cyclic motifs enclose larger R(5) (5)(21) cyclic systems, forming sheet substructures which lie parallel to (101) and are linked across b by the single water mol-ecule via water O-H?O(c) (c = carboxylate) associations, giving a duplex-sheet structure. PMID- 21589545 TI - 2-(4-Fluoro-phen-yl)-5-iodo-3-isopropyl-sulfinyl-1-benzofuran. AB - In the title compound, C(17)H(14)FIO(2)S, the 4-fluoro-phenyl ring makes a dihedral angle of 18.88 (9) degrees with the mean plane of the benzofuran ring. In the crystal, pairs of inter-molecular I?O contacts [3.153 (2) A] link the mol ecules into inversion dimers. PMID- 21589546 TI - 1-Adamantylmethyl 2-amino-benzoate. AB - The asymmetric unit of the title compound, C(18)H(23)NO(2), consists of two crystallographically independent mol-ecules bearing an adamantane cage consisting of three fused cyclo-hexane rings in almost ideal chair conformations, with C-C-C angles in the range 108.47 (16)-110.59 (15) degrees . Both aryl rings are essentially planar, the maximum deviation from the best plane being 0.0125 (19) A. One conformer forms chains parallel to the b axis via N-H?O hydrogen bonds, whereas the second exhibits only an intra-molecular N-H?O hydrogen bond. The crystal structure is stabilized by further weak N-H?O and N-H?N inter-actions. PMID- 21589547 TI - 1beta,10alpha:4beta,5alpha-Diep-oxy-7alphaH-germacran-6beta-ol monohydrate. AB - In the title compound, C(15)H(26)O(3).H(2)O, a sesquiterpenoid mol-ecule with a germacrene backbone that contains two epoxide groups and one hydroxyl group. Inter-molecular O-H?O hydrogen bonds between the ep-oxy groups and solvent water mol-ecules give rise to an infinite three-dimensional supra-molecular structure. PMID- 21589548 TI - 7-Phenyl-sulfonyl-2,3-dihydro-7H-1,4-benzodioxino[6,7-b]carbazole. AB - In the title compound, C(24)H(17)NO(4)S, the phenyl ring makes a dihedral angle of 88.12 (5) degrees with the carbazole unit. The mol-ecular structure is stabilized by weak intra-molecular C-H?O inter-actions and the crystal packing exhibits weak inter-molecular C-H?O and C-H?pi inter-actions. Two C atoms of the 2,3-dihydro-1,4-dioxine fragment are disordered over two positions with site occupancy factors of 0.718 (11) and 0.282 (11). PMID- 21589549 TI - 2,6-Dibromo-4-butyl-anilinium chloride. AB - In the crystal structure of the title salt, C(10)H(14)Br(2)N(+).Cl(-), the organic cations and chloride anions are linked into one-dimensional chains parallel to the a axis by N-H?Cl and N-H?Br hydrogen bonds. PMID- 21589550 TI - 10H-Phenothia-zine 5-oxide. AB - In the title compound, C(12)H(9)NOS, the sulfoxide O atom is disordered over two sites with occupancies of 0.907 (4) and 0.093 (4). The dihedral angle betweeen the two aromatic rings is 18.40 (14) degrees . Different types of supramolecular interactions including inter-molecular N-H?O hydrogen bonds and pi-pi contacts [centroid-centroid distances = 3.9096 (16) and 4.1423 (16) A] between the aromatic rings of symmetry-related mol-ecules are observed in the crystal structure. PMID- 21589551 TI - 2,6-Dibromo-4-butyl-aniline. AB - In the title compound, C(10)H(13)Br(2)N, the amino N atom is essentially coplanar with the benzene ring, with an r.m.s. deviation of 0.004 A. Weak intra-molecular N-H?Br hydrogen bonds occur. In the crystal, mol-ecules are linked into a zigzag chain parallel to the b axis by weak N-H?N hydrogen bonds. PMID- 21589552 TI - tert-Butyl 6-amino-3,4-dihydro-2H-1,4-benzoxazine-4-carboxyl-ate. AB - The title mol-ecule, C(13)H(18)N(2)O(3), contains a benzene ring fused to an oxazine ring and one tert-but-oxy-carbonyl group bound to the N atom of the oxazine ring. A weak intra-molecular C-H?O inter-action occurs. In the crystal, inter-molecular N-H?O and C-H?O hydrogen bonds stack the mol-ecules down the b axis. Weak C-H?N contacts connect the stacks, generating a three-dimensional network. PMID- 21589553 TI - 2,4,5-Trimeth-oxy-benzaldehyde monohydrate. AB - In the title compound, C(10)H(12)O(4).H(2)O, the 2,4,5-trimeth-oxy-benzaldehyde mol-ecule is almost planar (rms deviation = 0.0183 A). There is an R(1) (2)(5) ring motif due to O-H?O hydrogen bonding. In the crystal, the mol-ecules are stabilized in the form of one-dimensional polymeric chains extending along [010] due to O-H?O hydrogen bonding with adjacent water mol-ecules. The H atoms involved in inter-molecular hydrogen bonding are disordered over two sets of sites of equal occupancy. PMID- 21589554 TI - (E)-2-(4-tert-Butyl-phen-yl)-1-(4-chloro-1-ethyl-3-methyl-1H-pyrazol-5-yl)-2 cyano-ethenyl 2,2-dimethyl-propano-ate. AB - In the title compound, C(24)H(30)ClN(3)O(2), the dihedral angle between the aromatic rings is 30.78 (10) degrees . PMID- 21589555 TI - Ethyl 8-(4-nitro-phen-yl)imidazo[1,2-a]pyridine-7-carboxyl-ate. AB - In the title compound, C(16)H(13)N(3)O(4), the imidazo[1,2-a]pyridine and benzene rings make a dihedral angle of 56.21 (2) degrees . The crystal packing is stabilized by weak pi-pi stacking inter-actions [centroid-centroid distances = 3.787 (2) A] and C-H?O inter-molecular hydrogen-bonding inter-actions. PMID- 21589556 TI - Tetra-phenyl piperazine-1,4-diyldiphos-pho-nate. AB - The mol-ecule of the title compound, C(28)H(28)N(2)O(6)P(2), is organized around an inversion center located at the centre of the piperazine ring. Both piperazine N atoms are substituted by P(O)(OC(6)H(5))(2) phospho-ester groups. The P atoms display a slightly distorted tetra-hedral environment; the N atoms show some deviation from planarity. The O atoms of the P=O groups are involved in inter molecular C-H?O hydrogen bonds, building R(2) (2)(22) rings, in extended chains parallel to the a axis. C-H?pi inter-actions involving the phenyl rings further stabilize the packing. PMID- 21589557 TI - (E)-1-[4-(Hex-yloxy)phen-yl]-3-(3-hy-droxy-phen-yl)prop-2-en-1-one. AB - There are two mol-ecules in the asymmetric unit of the title compound, C(21)H(24)O(3), in which the dihedral angles between the aromatic rings are 6.4 (1) and 7.0 (1) degrees . The enone moiety of both mol-ecules adopts an s-cis configuration. In the crystal, inter-molecular O-H?O and C-H?O inter-actions to the same acceptor O atom generate R(2) (1)(6) ring motifs and further C-H?O inter actions generate R(2) (2)(8) ring motifs. Topologically, the R(2) (1)(6) and R(2) (2)(8) ring motifs are arranged alternately, forming [001] chains of mol-ecules. The crystal structure is further stabilized by C-H?pi inter-actions. PMID- 21589558 TI - (S)-3-Bromo-4-diallyl-amino-5-[(1R,2S,5R)-2-isopropyl-5-methyl-cyclo-hex yloxy]furan-2(5H)-one. AB - The title compound, C(20)H(30)BrNO(3), was obtained via a tandem asymmetric Michael addition-elimination reaction of 3,4-dibromo-5-(S)-(l-menth-yloxy)-2(5H) furan-one and diallyl-amine in the presence of potassium fluoride. In the mol ecule, the five-membered furan-one ring is approximately planar [maximum atomic deviation = 0.030 (3) A], and the six-membered cyclo-hexane ring adopts a chair conformation. PMID- 21589559 TI - Diniconazole. AB - THE ASYMMETRIC UNIT OF THE TITLE COMPOUND [SYSTEMATIC NAME: (E)-1-(2,4-dichloro phen-yl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pent-1-en-3-ol], C(15)H(17)Cl(2)N(3)O, contains two mol-ecules in which the dihedral angles between the triazole and benzene rings are 9.4 (2) and 35.0 (2) degrees . In the crystal, the mol-ecules are linked by O-H?N hydrogen bonds, forming C(7) chains propagating in [010]. PMID- 21589560 TI - (2R,3S)-Methyl 2-hy-droxy-3-(4-methyl-benzene-sulfonamido)-3-phenyl-propano-ate. AB - In the title mol-ecule, C(17)H(19)NO(5)S, the p-tolyl ring is oriented approximately parallel to the phenyl ring [dihedral angle = 17.2 (1) degrees ], resulting in an intra-molecular pi-pi inter-ation [centroid-centroid distance = 3.184 (10) A]. In the crystal, mol-ecules are linked through O-H?O and C-H?O hydrogen bonds, forming hydrogen-bonded sheets lying diagonally across the ac face. PMID- 21589561 TI - 4-Amino-3-ammonio-benzene-sulfonate. AB - The title compound, C(6)H(8)N(2)O(3)S, crystallized as a sulfonate-aminium zwitterion. In the crystal, inter-molecular N-H?O hydrogen bonds generate an extensive three-dimensional network, which consolidates the packing. PMID- 21589562 TI - 3,3'-Dimethyl-1,1'-[(1,3-dihy-droxy-propane-2,2-di-yl)dimethyl idene]diimidazolium bis-(hexa-fluoro-phosphate). AB - The title compound, C(13)H(22)N(4)O(2) (2+).2PF(6) (-), was prepared by the anion exchange of the dibromide ionic liquid with potassium hexa-fluoro-phosphate. The two imidazole rings are each planar (r.m.s. deviations = 0.0016 and 0.0060 A) and make a dihedral angle of 45.3 (18) degrees . Intra-molecular O-H?F hydrogen bonds occur. Inter-molecular C-H?F, O-H?O and C-H?O hydrogen bonds stabilize the crystal structure. PMID- 21589563 TI - 7-Meth-oxy-1-{[(Z)-2-nitro-phenyl-imino](phen-yl)meth-yl}-2-naphthol chloro-form monosolvate. AB - In the title compound, C(24)H(18)N(2)O(4).CHCl(3), the phenyl and benzene rings make a dihedral angle of 38.60 (9) degrees and connect in an orientation almost perpendicular to the naphthalene ring system at dihedral angles of 78.73 (8) and 81.20 (7) degrees . The mol-ecule has a Z configuration about the C=N bond. In the crystal, mol-ecules are linked by inter-molecular O-H?N=C hydrogen bonds between the imino moiety and hy-droxy groups. Inter-molecular C-Cl?C inter actions between Cl atoms of the CHCl(3) mol-ecule and C atoms of the naphthalene rings are also present [Cl?C = 3.353 (2) and 3.326 (19) A]. The nitro group and the chloro-form solvent mol-ecule are disordered over two positions with site occupancies of 0.884 (4) and 0.116 (4). PMID- 21589564 TI - (2E)-3-(4-Eth-oxy-phen-yl)-1-(2-methyl-4-phenyl-quinolin-3-yl)prop-2-en-1-one monohydrate. AB - The title hydrate, C(27)H(23)NO(2).H(2)O, features an almost planar quinoline residue (r.m.s. deviation = 0.015 A) with the benzene [dihedral angle = 63.80 (7) degrees ] and chalcone [C-C-C-O torsion angle = -103.38 (18) degrees ] substituents twisted significantly out of its plane. The configuration about the C=C bond [1.340 (2) A] is E. In the crystal, mol-ecules related by the 2(1) symmetry operation are linked along the b axis via water mol-ecules that form O H?O(c) and O-H?N(q) hydrogen bonds (c = carbonyl and q = quinoline). A C-H?O inter-action also occurs. PMID- 21589565 TI - N-(3-Octyl-4-oxo-1,3-thia-zolidin-2-yl-idene)benzamide. AB - In the title compound, C(18)H(24)N(2)O(2)S, the thia-zolidinone ring is almost coplanar [maximum atomic deviation = 0.017 (3) A], and is coplanar with the phenyl ring [dihedral angle = 0.62 (13) degrees ]. The octyl group displays an extended conformation. In the crystal, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into supra-molecular chains along [210]. PMID- 21589566 TI - 4-Anilino-3-nitro-N-phenyl-benzamide. AB - In the title compound, C(19)H(15)N(3)O(3), the anilino and benzamide rings make dihedral angles of 10.66 (16) and 50.39 (16) degrees , respectively, with the nitro-substituted benzene ring. The nitro group is slightly twisted by 11.49 (17) degrees with respect to the attached benzene ring. There is an intra-molecular N H?O hydrogen bond forming an S(6) ring. In the crystal, weak inter-molecular N H?O and C-H?O hydrogen bonds link the mol-ecules into a chain parallel to the b axis. Futhermore, weak slipped pi-pi inter-actions [centroid-centroid distance = 3.819 (2) A, inter-planar distance = 3.567 A and offset angle [how is the offset angle defined?] = 21 degrees ] between the anilino ring and its symmetry-related counterpart may help to stabilize the packing. PMID- 21589567 TI - 4-Anilino-3-nitro-benzonitrile. AB - In the title compound, C(13)H(9)N(3)O(2), the aromatic rings are twisted with respect to each other, making a dihedral angle of 49.41 (9) degrees . The nitro group and the nitrile group are nearly in the plane of the benzonitrile ring, the largest deviation from the plane being 0.123 (1) A. There is an intra-molecular N H?O hydrogen bond forming an S(6) ring. Weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into a chain parallel to the c axis. Futhermore, slipped pi pi inter-actions between symmetry-related phenyl rings [centroid-centroid distance 3.808 (1) A, inter-planar distance 3.544 (8) A with an offset of 21.5 degrees ] stabilize the structure. PMID- 21589568 TI - 4-(1-Naphth-yl)benzonitrile. AB - The title compound, C(17)H(11)N, crystallizes with two mol-ecules in the asymmetric unit which are linked by a weak C-H?N hydrogen bond. The dihedral angles between the benzene ring and the naphthalene ring system in the two mol ecules are 60.28 (3) and 60.79 (3) degrees . In the crystal, mol-ecules are linked into a three-dimensional network by weak C-H?pi inter-actions. PMID- 21589569 TI - Phenyl 3,5-di-tert-butyl-2-hy-droxy-benzoate. AB - The title mol-ecule, C(21)H(26)O(3), has a six-membered planar carbon ring as the central core, substituted at position 1 with phen-oxy-carbonyl, at position 2 with hy-droxy and at positions 3 and 5 with tert-butyl groups. The structure shows two independent but very similar mol-ecules within the asymmetric unit. For both independent mol-ecules, the ester carboxyl-ate group is coplanar with the central core, as reflected by the small C-C-O-C torsion angles [179.95 (17) and 173.70 (17) degrees ]. In contrast, the phenyl substituent is almost perpendicular to the carboxyl-ate -CO(2) fragment, as reflected by C-O-C-C torsion angles, ranging from 74 to 80 degrees . The coplanarity between the central aromatic ring and the ester carboxyl-ate -CO(2)- group allows the formation of an intra-molecular hydrogen bond, with O?O distances of 2.563 (2) and 2.604 (2) A. PMID- 21589570 TI - 2-Amino-4-(3-fluoro-phen-yl)-6-(naphthalen-1-yl)pyridine-3-carbonitrile. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(22)H(14)FN(3), which differ slightly in the relative orientations of the naphthyl and phenyl groups with respect to the pyridyl ring framework. In one mol-ecule, the naphthyl ring system and the phenyl ring form dihedral of angles 56.50 (2) and 48.23 (3) degrees , respectively, with the pyridyl ring plane. In the other mol-ecule, the corresponding dihedral angles are 50.01 (2) and 51.1 (3) degrees , respectively. In the crystal, inter-molecular N-H?N hydrogen bonds connect the independent mol-ecules into dimers. PMID- 21589571 TI - (1-Adamant-yl)(2-methyl-phen-yl)methanone. AB - In the title compound, C(18)H(22)O, the dihedral angle between the carbonyl and benzene planes is 69.11 (6) degrees . In the adamantyl group, the three fused cyclo-hexane rings have almost ideal chair conformations, with C-C-C angles in the range 108.14 (11)-110.50 (11) degrees . No specific inter-molecular inter actions (other than van der Waals inter-actions) are present in the crystal. PMID- 21589572 TI - N-[(E)-1,3-Benzodioxol-5-yl-methyl-idene]-4-methyl-aniline. AB - The two symmetry-independent mol-ecules in the asymmetric unit of the title compound, C(15)H(13)NO(2), differ in conformation, with the virtually planar 4 methyl-aniline (r.m.s. deviations of 0.0511 and 0.0082 A) and piperonal groups (r.m.s. deviations of 0.0241 and 0.0486 A) forming dihedral angles of 19.40 (5) and 42.90 (6) degrees . In the crystal, mol-ecules are linked by C-H?O and C-H?pi inter-actions. The H atoms of the two methyl groups are disordered over two sets of sites of equal occupancy. PMID- 21589573 TI - 2-[(5,7-Dibromo-quinolin-8-yl)-oxy]-N-(2-meth-oxy-phen-yl)acetamide. AB - In the title compound, C(18)H(14)Br(2)N(2)O(3), an intra-molecular N-H?N hydrogen bond forms an eight-membered ring. The dihedral angle between the planes of the quinoline system and the benzene ring is 41.69 (1) degrees . The crystal packing is stabilized by inter-molecular C-H?O hydrogen bonds and short Br?O inter actions [3.0079 (19) A]. PMID- 21589574 TI - 3-Cyano-anilinium iodide monohydrate. AB - In the crystal structure of the title compound, C(7)H(7)N(2) (+).I(-).H(2)O, [C(7)H(7)N(2) (+)](n) chains extending along the a-axis direction are linked via N-H?N hydrogen bonds. The cations are further connected to the anions by N-H?I, N H?O and O-H?I hydrogen bonds, leading to the formation of a sheet parallel to the ac plane. pi-pi inter-actions [centroid-centroid distance = 3.8378 (7) A] link the sheets into a three-dimensional network. PMID- 21589575 TI - 2-Amino-anilinium benzoate. AB - In the crystal of the title molecular salt, C(6)H(9)N(2) (+).C(7)H(5)O(2) (-), the cations and anions are linked by N-H?O hydrogen bonds, buiding an R(2) (2)(9) ring. Futher N-H?O hydrogen bonds generate chains, which develop parallel to the a axis through the formation of R(4) (3)(10) rings.. PMID- 21589576 TI - 4-(1H-Tetra-zol-5-yl)pyridinium chloride. AB - In the cation of the title compound, C(6)H(6)N(5) (+).Cl(-), the tetra-zole and pyridine rings are nearly coplanar, making a dihedral angle of 5.58 (11) degrees . The organic cations are linked to the chloride anions via N-H?Cl hydrogen bonds, forming chains along [110]. PMID- 21589577 TI - 2-[(4-Meth-oxy-benz-yl)imino-meth-yl]phenol. AB - In the title Schiff base compound, C(15)H(15)NO(2), prepared from 4-meth-oxy benzyl-amine and salicyl-aldehyde, an intra-molecular O-H?N hydrogen bonds influences the mol-ecular conformation; the two aromatic rings form a dihedral angle of 73.5 (1) degrees . In the crystal, weak inter-molecular C-H?O inter actions link the mol-ecules into chains propagating in [010]. PMID- 21589578 TI - 2,3,4,6-Tetra-O-acetyl-2-phthalimido-beta-d-glucopyran-oside. AB - In the crystal structure of the title compound, C(24)H(27)NO(11), a substituted tetra-acetyl glucopyran-oside derivative, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into ribbons propagated in [010]. The d configuration has been attributed on the basis of the synthesis and the beta anomer has been determined from the structure. PMID- 21589579 TI - 2,2'-[p-Phenyl-enebis(methyl-idene-aza-ne-di-yl)]dipyridinium bis (hydrogensulfate) dihydrate. AB - The cation of the title salt, C(18)H(20)N(4) (2+).2HSO(4) (-).2H(2)O, lies on a center of inversion with the mid-point directly in the middle of the p-phenyl-ene ring. Within the hydrogensulfate ion, the S-O(H) bond is the longest of the S-O bonds. The dihedral angle between the central and terminal ring of the cation is 78.6 (2) degrees . In the crystal, the cation, anion and water mol-ecule inter act by O-H?O and N-H?O hydrogen bonds, generating a three-dimensional network. PMID- 21589580 TI - (20S)-20-Acet-oxy-4-pregnene-3,16-dione from Commiphora wightii. AB - The title triterpene compound, C(23)H(32)O(4), isolated from Commiphora wightii features four trans-fused rings, among which the five-membered ring adopts an envelope conformation, the cyclo-hexene ring adopts a half-chair conformation and the two cyclo-hexane rings exist in chair conformations. The asymmetric unit contains two independent mol-ecules. Weak inter-molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 21589581 TI - 3-(4-Fluoro-phenyl-sulfon-yl)-2-methyl-naphtho-[1,2-b]furan. AB - In the title compound, C(19)H(13)FO(3)S, the 4-fluoro-phenyl ring makes a dihedral angle of 68.59 (5) degrees with the mean plane of the naphtho-furan fragment. In the crystal, mol-ecules are linked by weak inter-molecular C-H?O, C H?F and C-H?pi inter-actions. The crystal structure also exhibits aromatic pi-pi inter-actions between the central benzene and the outer benzene rings of neighbouring mol-ecules [centroid-centroid distance = 3.650 (3) A]. PMID- 21589582 TI - 1-(4-Hy-droxy-phen-yl)-3-(3,4,5-tri-methoxy-phen-yl)thio-urea. AB - In the title compound, C(16)H(18)N(2)O(4)S, the dihedral angle between the hy droxy-phenyl ring and the plane of the thio-urea moiety is 54.53 (8) degrees . The H atoms of the NH groups of thio-urea are positioned anti to each other. In the crystal, inter-molecular N-H?S, N-H?O, and O-H?S hydrogen bonds link the mol ecules into a three-dimensional network. PMID- 21589583 TI - 12-(4-Chloro-phen-yl)-7-methyl-10-phenyl-3,4,5,6,8,10-hexa-aza-tricyclo [7.3.0.0]dodeca-1(9),2,4,7,11-penta-ene. AB - The 12 non-H atoms defining the triple-fused-ring system in the title compound, C(19)H(13)ClN(6), are almost coplanar (r.m.s. deviation = 0.023 A). The chloro substituted ring is almost effectively coplanar with the central atoms [dihedral angle = 6.74 (13) degrees ], but the N-bound benzene ring is not [dihedral angle = 54.38 (13) degrees ]. In the crystal, supra-molecular chains along the a axis sustained by C-H?pi and pi-pi [centroid-centroid distance between N(4)C and C(4)N five-membered rings = 3.484 (2) A] stacking occur. A very long C-Cl?pi contact is also seen. PMID- 21589584 TI - 2,3-Bis(methyl-sulfan-yl)-1,4,5,8-tetra-thia-fulvalene. AB - In the title compound, C(8)H(8)S(6), the five-membered rings form a dihedral angle of 25.06 (9) degrees . In the absence of short inter-molecular contacts, the mol-ecules are packed by van der Waals forces in the crystal. PMID- 21589585 TI - N,N'-Bis(3-phenyl-prop-2-en-1-yl-idene)-2,2'-disulfanediyldianiline. AB - In the title compound, C(30)H(24)N(2)S(2), the two phenyl rings attached to the S atoms are oriented nearly perpendicularly, making a dihedral angle of 86.14 (8) degrees . Each of the two ArCH=CHCH=N units is almost planar, having maximum deviations from the least-squares planes of 0.125 and 0.149 A, and rotated around the C-N bonds relative to the adjacent phenyl ring by 110.26 and 30.30 degrees . PMID- 21589586 TI - 4,4'-Bipyridine-2-(carb-oxy-methyl-sulfan-yl)pyridine-3-carb-oxy-lic acid (1/1). AB - In the title co-crystal, C(10)H(8)N(2).C(8)H(7)NO(4)S, the formate group is coplanar with the pyridyl ring of the acid [dihedral angle = 6.2 (7) degrees ], while the carb-oxy-methyl-sulfanyl group makes a C-S-C-C torsion angle of 70.2 (1) degrees with the pyridine ring. The dihedral angle between the pyridyl rings of the 4,4'-bipyridine mol-ecule is 27.4 (1) degrees . The acid and the 4,4' bipyridine mol-ecules are involved in hydrogen bonding via carb-oxy-lic O and pyridyl N atoms. The structure is further consolidated by inter-molecular C-H?O hydrogen bonds, generating a three-dimensional network. PMID- 21589587 TI - (2E,6E)-2,6-Bis(2-fluoro-5-meth-oxy-benzyl-idene)cyclo-hexan-1-one. AB - The title compound, C(22)H(20)F(2)O(3), a derivative of curcumin, crystallized with two independent mol-ecules in the asymmetric unit. The mean planes of the two 2-fluoro-5-meth-oxy-phenyl groups are aligned at 24.88 (11) degrees in one mol-ecule and 24.19 (15) degrees in the other. The dihedral angles between the mean plane of the penta-1,4-dien-3-one group and those of the two 2-fluoro-5-meth oxy-phenyl rings are 51.16 (11) and 49.16 (10) degrees in the first mol-ecule, and 45.69 (15) and 54.00 (14) degrees in the second. The mol-ecules adopt E configurations about the central olefinic bonds. PMID- 21589589 TI - 2-(Methyl-sulfin-yl)benzamide. AB - In the crystal of the title compound, C(8)H(9)NO(2)S, synthesized by the oxidation of 2-(methyl-sulfan-yl)benzamide using NaOCl with 2,2,6,6-tetra-methyl piperidyl-1-oxy (TEMPO) as the catalyst, mol-ecules are linked via inter molecular N-H?O(amide) hydrogen bonds, forming centrosymmetric amide-amide dimers which are extended into a two-dimensional lamellar framework parallel to (100) through amide-sulfinyl N-H?O hydrogen bonds. The benzene ring forms a dihedral angle of 25.6 (2) degrees with the amide group. PMID- 21589588 TI - 5-[1-(Carb-oxy-meth-yl)pyridinium-4-yl]-1,2,3,4-tetra-zol-1-ide. AB - In the title compound, C(8)H(7)N(5)O(2), the tetra-zole and pyridine rings are twisted from each other by a dihedral angle of 17.97 (1) degrees . The zwitterionic mol-ecules are connected by O-H?N hydrogen bonds into a chain parallel to [20]. Further C-H?O and C-H?N hydrogen bonds link the chains, building up a three-dimensional network. PMID- 21589590 TI - (E)-3-(Anthracen-9-yl)-1-(2-bromo-phen-yl)prop-2-en-1-one. AB - The mol-ecule of the title chalcone, C(23)H(15)BrO, is not planar and exists in the E configuration with respect to the central C=C bond. The dihedral angle between the benzene and anthracene rings is 83.58 (6) degrees . The prop-2-en-1 one bridge makes dihedral angles of 63.00 (7) and 42.62 (16) degrees with the benzene and anthracene rings, respectively. In the crystal, mol-ecules are linked into dimers by weak C-H?O inter-actions. These dimers are arranged parallel to the bc plane and are further stacked along the a axis by pi-pi inter-actions with a centroid-centroid distance of 3.7561 (9) A. The crystal structure is further stabilized by C-H?pi inter-actions. PMID- 21589591 TI - 2-Hy-droxy-5-[(E)-(1H-indol-3-yl-methyl-idene)aza-nium-yl]benzoate. AB - The zwitterionic title compound, C(16)H(12)N(2)O(3), was obtained as a result of the condensation of 5-amino-salicylic acid and 1H-indole-3-carbaldehyde. The whole mol-ecule is roughly planar: the 4-hy-droxy-anilinic group and the 1H indole-3-carbaldehyde moieties are only slightly twisted, making a dihedral angle of 7.77 (11) degrees , whereas, the carboxyl-ate group makes a dihedral angle of 3.34 (45) degrees with the parent 4-hy-droxy-anilinic group. S(6) ring motifs are formed due to intra-molecular O-H?O hydrogen bonding. In the crystal, inter molecular N-H?O and C-H?O hydrogen bonds build up pseudo-rings with R(1) (2)(4), R(2) (1)(7) and R(2) (2)(14) ring motifs. These pseudo-dimers are further linked by N-H?O hydrogen bonds into a chain extending along [101]. C-H?pi inter-actions also occur, along with offset pi-pi inter-actions between the anilinic phenyl and the heterocyclic five-membered rings with a centroid-centroid distance of 3.5716 (19) A. PMID- 21589592 TI - Piperazine-2,3,5,6-tetra-one. AB - The mol-ecule of the title compound, C(4)H(2)N(2)O(4), is located around an inversion center and the four O atoms are in the 2,3,5,6-positions of the piperazine ring. In the crystal, bifurcated N-H?O hydrogen bonds link the mol ecules into a corrugated layer parallel to (101). PMID- 21589593 TI - 4-Meth-oxy-anilinium iodide. AB - The crystal structure of the title compound, C(7)H(10)NO(+).I(-), displays N-H?I hydrogen bonds between the 4-meth-oxy-anilinium cations and the iodide anion together with weaker C-H?pi contacts. PMID- 21589594 TI - 4-(2-Sulfanyl-idene-1,3-benzothia-zol-3-yl)butan-2-one. AB - In the title compound, C(11)H(11)NOS(2), the benzine ring is coplanar with the thia-zole ring, making a dihedral angle of 0.81 (1) degrees . In the crystal, adjacent mol-ecules are connected into a helical chain along the b axis by S?S contacts [3.4345 (18) A]. These helical chains are further assembled into a three dimensional supermolecular network by inter-molecular C-H?O hydrogen bond between aromatic ring H atoms and carbonyl groups. PMID- 21589595 TI - rac-(1R,2R,4S)-1,2-Dibromo-4-[(1R)-1,2-dibromo-eth-yl]cyclo-hexa-ne. AB - In the title compound, C(8)H(12)Br(4), the cyclo-hexane ring exhibits a chair conformation. The C-Br distances range from 1.964 (6) to 1.985 (5) A and the C-C distances range from 1.496 (6) to 1.543 (7) A. Short inter-molecular Br?Br contacts [3.467 (4) A] occur in the crystal. PMID- 21589596 TI - Bonvalotidine A acetone solvate from Delphinium bonvalotii Franch. AB - THE TITLE COMPOUND (SYSTEMATIC NAME: 5,6beta-dihy-droxy-1alpha,14alpha,16beta trimeth-oxy-4-methyl-7beta,8-methyl-enedi-oxy-20-ethyl-aconitan-6-yl acetate acetone monosolvate), C(27)H(41)NO(8).C(3)H(6)O, was isolated from Delphinium bonvalotii Franch, and is a typical C(19)-diterpenoid alkaloid. The mol-ecule has a lycoctonine carbon skeleton with four six-membered rings and three five membered rings. Three six-membered rings adopt the chair conformations while the fourth adopts a boat conformation, while the five-membered rings have the envelope conformations. The solvent mol-ecule links with the organic mol-ecule via a classical O-H?O hydrogen bond. Weak C-H?O hydrogen bonding is present in the structure. An intra-molecular O-H?O hydrogen bond also occurs. PMID- 21589597 TI - N-(4-Chloro-pyridin-2-yl)-N-(4-methyl-phenyl-sulfon-yl)acetamide. AB - The crystal structure of the title compound, C(14)H(13)ClN(2)O(3)S, features a three-dimensional network stabilized by inter-molecular C-H?O hydrogen bonds between the mol-ecules. The 4-methyl-phenyl-sulfonyl ring forms a dihedral angle of 30.6 (1) degrees with the 4-chloro-pyridine ring. PMID- 21589598 TI - N-(4-Chloro-pyridin-2-yl)-N-meth-oxy-methyl-4-methyl-benzene-sulfonamide. AB - In the crystal structure of the title compound, C(14)H(15)ClN(2)O(3)S, each mol ecule is connected via inter-molecular C-H?O hydrogen bonds to three further mol ecules, generating a three-dimensional network. The 4-methyl-phenyl-sulfonyl ring forms a dihedral angle of 40.7 (2) degrees with the 4-chloro-pyridine ring. PMID- 21589599 TI - N,N-Bis(diphenyl-phosphan-yl)cyclo--penta-namine. AB - The coordination around the N atom in the title compound, C(29)H(29)NP(2), shows an almost planar geometry, defined by the attached P and C atoms, in order to accomodate the steric bulk of the phenyl rings. The distortion of the trigonal pyramidal geometry of the N atom is illustrated by the bond angles ranging between 115.22 (12) and 121.76 (9) degrees . The P atoms present a pyramidal environment with bond angles ranging from 100.62 (9) to 104.71 (8) degrees . One of the C atoms in the cyclo-pentyl ring displays a 0.822 (4):0.178 (4) positional disorder. Within the crystal structure, intra-molecular C-H?P hydrogen bonds together with inter- and intra-molecular C-H?pi inter-actions link the mol-ecules into a supra-molecular two-dimensional network. PMID- 21589600 TI - 4-Methyl-1-(3-pyridyl-methyl-idene)thio-semicarbazide. AB - All the non-H atoms of the title compound, C(8)H(10)N(4)S, lie on a crystallographic mirror plane and an intra-molecular N-H?N hydrogen bond helps to stabilize the mol-ecular conformation. In the crystal, mol-ecules are linked through inter-molecular N-H?N hydrogen bonds, forming zigzag C(7) chains along the a axis. PMID- 21589601 TI - Ethyl 4-(3-bromo-phen-yl)-6-methyl-2-oxo-1,2,3,4-tetra-hydro-pyrimidine-5 carboxyl-ate. AB - In the title compound, C(14)H(15)BrN(2)O(3), the dihydro-pyrimidin-one ring adopts a boat conformation. In the crystal, adjacent mol-ecules are linked through N-H?O hydrogen bonds forming an R(2) (2)(8) ring motif and generating a zigzag chain extending in [010]. PMID- 21589602 TI - (E,E)-3,3'-Dimethyl-1,1'-diphenyl-4,4'-{[3-aza-pentane-1,5-diylbis(aza-nedi yl)]bis-(phenyl-methyl-idyne)}di-1H-pyrazol-5(4H)-one. AB - The asymmetric unit of the title compound, C(38)H(37)N(7)O(2), contains one half mol-ecule, situated on a twofold rotational axis, in which one amino group is involved in intra-molecular N-H?O hydrogen bond and the two phenyl rings are twisted from the plane of pyrazolone ring by 26.69 (10) and 79.64 (8) degrees . The crystal packing exhibits no classical inter-molecular contacts. PMID- 21589603 TI - N-Carbamothioyl-amino-7-oxabicyclo-[2.2.1]hept-5-ene-2,3-dicarboximide. AB - The title compound, C(9)H(9)N(3)O(3)S, comprises a racemic mixture of chiral mol ecules containing four stereogenic centres. The cyclo-hexane ring tends towards a boat conformation, while the tetra-hydro-furan ring and the dihydro-furan ring adopt envelope conformations. The dihedral angle between the thio-semicarbazide fragment and the fused-ring system is 77.20 (10) degrees . The crystal structure is stabilized by two inter-molecular N-H?O hydrogen bonds. PMID- 21589604 TI - 5,5'-(Butane-1,4-di-yl)bis-(1H-tetra-zole) dihydrate. AB - The title compound, C(6)H(10)N(8).2H(2)O, was prepared by the reaction of hexanedinitrile and sodium azide. The di-1H-tetra-zole mol-ecule lies on a crystallographic centre of inversion and is linked to the water mol-ecules by N H?O and O-H?N hydrogen bonds, forming a two-dimensional supra-molecular structure in the crystal. PMID- 21589605 TI - (5S)-4-(2,2-Dimethyl-prop-yl)-5-isopropyl-1,3,4-oxadiazinan-2-one. AB - The title compound, C(11)H(22)N(2)O(2), has one chiral center and packs in the monoclinic space group P2(1). The asymmetric unit has five crystallographically independent mol-ecules, four of which engage in inter-molecular N-H?O hydrogen bonding. PMID- 21589606 TI - 12-Acetyl-6-hy-droxy-3,3,9,9-tetra-methyl-furo[3,4-b]pyrano[3,2-h]xanthene 7,11(3H,9H)-dione. AB - The title compound, Artonol B, C(24)H(20)O(7), isolated from the stem bark of Artocarpus kemando, consists of four six-membered rings and one five-membered ring. The tricyclic xanthone ring system is almost planar [maximum deviation 0.115 (5) A], whereas the pyran-oid ring is in a distorted boat conformation.The furan ring is almost coplanar with the fused aromatic ring, making a dihedral angle of 3.76 (9) degrees . The phenol ring serves as a intra-molecular hydrogen bond donor to the adjacent carbonyl group and also acts as an inter-molecular hydrogen-bond acceptor for the methyl groups of adjacent mol-ecules, forming a three-dimensional network in the crystal. PMID- 21589607 TI - 2,6-Dimethyl-4-(1,3,4-oxadiazol-2-yl)quinoline. AB - The title compound, C(13)H(11)N(3)O, a potential chemotherapeutic agent, contains a essential planar [maximum deviation = 0.0144 (14) A] quinoline moiety. The quinoline ring system and the five-membered heterocycle form a dihedral angle of 7.81 (6) degrees . In the crystal, inter-molecular non-classical C-H?N hydrogen bonding is present. PMID- 21589608 TI - (3E,5E)-3,5-Bis(4-hy-droxy-3,5-di-methoxy-benzyl-idene)oxan-4-one monohydrate. AB - In the title compound, C(23)H(24)O(8).H(2)O, the six-membered ring of the oxan-4 one (tetra-hydro-pyran-4-one) ring displays an envelope conformation with the heterocyclic O atom at the flap position. The dihedral angles between the terminal benzene rings is 37.23 (10) degrees . Classical intermolecular O-H?O and weak C-H?O hydrogen bonds are present in the crystal structure. PMID- 21589609 TI - (2S)-2-[(2S*,5R*,6R*)-5,6-Dimeth-oxy-5,6-dimethyl-1,4-dioxan-2-yl]-1-[(S)-1,1 dimethyl-ethylsulfon-yl]aziridine. AB - The reaction of a sulfur ylide with a chiral non-racemic sulfinyl imine afforded the desired aziridine in excellent yield and subsequent oxidation of the sulfinyl moiety dissolved in anhydrous dichloro-methane using a 75% aqueous solution of 3 chloro-per-oxy-benzoic acid afforded the title compound, C(14)H(27)NO(6)S. The configuration of the newly formed stereogenic center at the point of attachment of the 1,4-dioxane ring to the aziridine ring is S. The configurations of the pre existing sites 2-, 5-, and 6-positions of the 1,4-dioxane ring prior to reaction of sulfinyl imine with the sulfur ylide are S, R, and R, respectively. The C-N bond lengths of the aziridine are 1.478 (2) and 1.486 (2) A. PMID- 21589610 TI - 1,4-Dibenzyl-piperazine. AB - In the title compound, C(18)H(22)N(2), which possesses non-crystallographic inversion symmetry, the central piperazine ring adopts a chair conformation. The phenyl rings are not exactly parallel and make a dihedral angle of 1.3 (1) degrees . No significant inter-molecular contacts are observed in the crystal. PMID- 21589611 TI - Ethyl 3-benzyl-idenecarbazate. AB - In the title compound, C(10)H(12)N(2)O(2), the dihedral angle between the mean planes of the aromatic ring and the side chain (r.m.s. deviation = 0.035 A) is 18.23 (13) degrees . In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, generating C(4) amide chains propagating in [010]. PMID- 21589612 TI - Methyl 2-(4-chloro-benzamido)-benzoate. AB - In the title compound, C(15)H(12)ClNO(3), the central C-C(O)-N-C amide unit makes dihedral angles of 6.60 (2) and 3.42 (2) degrees , respectively, with the 4 chloro-benzene and anilino rings. The dihedral angle between the two benzene rings is 3.32 (3) degrees . Intra-molecular N-H?O and C-H?O hydrogen bonds form S(6) rings and contribute to the planarity of this portion of the mol-ecule. In the crystal, inter-molecular C-H?O hydrogen bonds are observed, which link the mol-ecules into [010] C(7) chains. PMID- 21589613 TI - 2-Amino-pyridinium 1-phenyl-cyclo-propane-1-carboxyl-ate. AB - In the title salt, C(5)H(7)N(2) (+).C(10)H(9)O(2) (-), 2-amino-pyridine and 1 phenyl-cyclo-propane-1-carb-oxy-lic acid crystallize together, forming a 2-amino pyridinium-carboxyl-ate supra-molecular heterosynthon involving two N-H?O hydrogen bonds, which in turn dimerizes to form a four-component supra-molecular unit also sustained by N-H?O hydrogen bonding. A C-H?pi inter-action between a pyridine C-H group and the centroid of the phenyl ring of the anion further stabilizes the four-component supra-molecular unit. The overall crystal packing also features C-H?O inter-actions. PMID- 21589614 TI - Hydro-nium perchlorate-dibenzo-18-crown-6 (1/1): monoclinic polymorph. AB - The asymmetric unit of the title compound, H(3)O(+).ClO(4) (-).C(20)H(24)O(6), contains two mol-ecules/ions of each species. Both dibenzo-18-crown-6 mol-ecules have a complexed hydro-nium ion inside their cavity with O-H?O and O-H?(O,O) links between the two species. The associated perchlorate anions also accept O H?O hydrogen bonds from the hydro-nium ion. Both crown ether mol-ecules are present in a butterfly conformation with approximate C(2v) symmetry and their cavities are closed by the benzene ring of a neighbouring mol-ecule. The packing is consolidated by C-H?O and C-H?pi inter-actions. PMID- 21589615 TI - N-[(1S,2S)-2-Amino-1,2-diphenyl-eth-yl]-4-methyl-benzene-sulfonamide [(S,S) TsDPEN]. AB - The crystal structure of the title compound, C(21)H(22)N(2)O(2)S, shows a network of N-H?N and N-H?O hydrogen bonds. The tolyl and 1-phenyl rings are almost mutually coplanar [7.89 (9) degrees ], while the 2-phenyl ring makes a dihedral angle of 50.8 (1) degrees with the 1-phenyl ring. An intra-molecular N-H?N hydrogen bond stabilizes the mol-ecular conformation. PMID- 21589616 TI - 3,4,7-Trimethyl-2-(4-methyl-phen-yl)-2H-pyrazolo-[3,4-d]pyridazin-5-ium thio cyanate. AB - 1,1'-[5-Methyl-1-(4-methyl-phen-yl)-1H-pyrazole-3,4-di-yl)di-ethan-one condenses with thio-semicarbazide in the presence of acetic acid to form the title salt, C(15)H(17)N(4) (+).NCS(-). The fused-ring system of the cation is almost planar (r.m.s. deviation = 0.020 A) and the aromatic substituent is aligned at an angle of 48.2 (1) degrees with respect to the mean plane of the fused-ring system. The N atom at the 5-position is protonated and forms a N-H?N hydrogen bond to the thio-cyanate cointer-ion. PMID- 21589617 TI - Ammonium 4-(4-carb-oxy-phen-oxy)benzoate. AB - The anions of the title salt, NH(4) (+).HO(2)CC(6)H(4)-O-C(6)H(4)CO(2) (-), are linked by inter-molecular -CO(2)H?O(2)C- hydrogen bonds, forming a polyanionic chain in the crystal; adjacent chains are connected through the ammonium cation into a layer structure, with the ammonium cation serving as hydrogen-bond donor to four carboxyl-ate O atoms. The cation and anion both lie on special positions of 2 site symmetry. In the anion, the rings make a dihedral angle of 65.3 (1) degrees . The acid H atom is disordered about the special position. PMID- 21589618 TI - Diacetamidinium sulfate. AB - In the crystal structure of the title compound, 2C(2)H(7)N(2) (+).SO(4) (2-), which contains four cations and two anions in the asymmetric unit, the ions are inter-connected by an extensive hydrogen-bonding system whereby two of the O atoms of sulfate ion are hydrogen-bonded to the amidinium H atoms of two cations, leading to the formation of two eight-membered rings. The two remaining O atoms inter-connect two H atoms of acetamidinium cations, forming an infinite chain. The C?N separations within the H(2)N?C?NH(2) moieties are similar, with an average value of 1.305 (2) A, which is in good agreement with a delocalization model. PMID- 21589619 TI - 4-Eth-oxy-anilinium bromide. AB - The title compound, C(8)H(12)NO(+).Br(-), is built up from roughly planar (r.m.s. deviation for the non-H atoms = 0.062 A) protonated 4-eth-oxy-anilimium cations and Br(-) anions. In the crystal, the cations and anions are linked by N-H?Br and N-H?(Br,Br) hydrogen bonds, generating (100) sheets. Very weak C-H?pi inter actions may also help to stabilize the crystal structure. PMID- 21589620 TI - N-(2,3-Dimethyl-phen-yl)-4-methyl-benzene-sulfonamide. AB - In the title compound, C(15)H(17)NO(2)S, the dihedral angle between the aromatic rings is 38.3 (1) degrees . The conformation of the N-H bond is anti to the methyl groups in the adjacent aromatic ring. In the crystal, N-H?O hydrogen bonds link the molecules into infinite chains. PMID- 21589621 TI - 10-Methyl-isoalloxazine 5-oxide from synchrotron powder diffraction data. AB - THE TITLE COMPOUND [SYSTEMATIC NAME: 10-methyl-benzo[g]pteridine-2,4(3H,10H) dione 5-oxide], C(11)H(8)N(4)O(3), consists of a large rigid isoalloxazine group which is approximately planar (r.m.s. deviation = 0.037 A). In the crystal, inter molecular N-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers. Dimers related by translation along the c axis form stacks through pi-pi inter actions [centroid-centroid distances = 3.560 (5) and 3.542 (5) A]. Weak inter molecular C-H?O inter-actions further consolidate the crystal packing. PMID- 21589622 TI - 4-Bromo-methyl-7,8-dimethyl-coumarin. AB - In the title mol-ecule, C(12)H(11)BrO(2), all non-H atoms with the exception of the Br atom are essentially coplanar (r.m.s. deviation = 0.018 A). The C-Br bond is inclined by 80.17 (12) degrees to this plane. The crystal structure is stabilized by weak C-H?O hydrogen bonds. PMID- 21589623 TI - 2-[4,5-Bis(butyl-sulfan-yl)-1,3-dithiol-2-yl-idene]-5-methyl-5H-1,3-dithiolo[4,5 c]pyrrole-4-carbaldehyde. AB - In the title compound, C(18)H(23)NOS(6), the dithiol-opyrrole ring is almost planar [r.m.s. deviation = 0.044 (3) A] and makes a dihedral angle of 25.11 (7) degrees with the dithiole ring. In the crystal, pairs of neighboring mol-ecules are connected by weak inter-molecular C-H?O inter-actions. These dimers are further linked into a chain along [110] by C-H?O inter-actions. PMID- 21589624 TI - 2,2-Difluoro-4-phenyl-1,3,2-dioxaborolo[4,5-c]chromen-5-ium-2-ide. AB - In the crystal, the inversely oriented mol-ecules of the title compound, C(15)H(9)BF(2)O(3), form stacks along the a axis via pi-pi inter-actions between parallel phenyl-chromenium fragments. Linked by a network of C-H?F inter-actions, the stacks form layers in the ac plane that are dispersively stabilized in the crystal structure. Two F atoms bonded to the B atom are located in the plane perpendicular to the planar skeleton of the mol-ecule made rigid by two intra molecular C-H?O inter-actions. PMID- 21589625 TI - A functionalized enol lactone containing a protected alpha-amino acid. AB - The crystal structure of N-(3,9-dimethyl-4-phenyl-2,5-dioxo-3,4-dihydro-2H,5H pyrano[3,2-c]chromen-3-yl)-N-methylbenzamide methanol monosolvate, C(28)H(23)NO(5).CH(3)OH, has been determined at room temperature by X-ray diffraction. Structural parameters are discussed with reference to ab initio calculations. PMID- 21589626 TI - Diphenyl (p-tolyl-amido)-phosphate. AB - The P atom in the title compound, C(19)H(18)NO(3)P, exhibits a distorted tetra hedral configuration while the N atom shows a planar coordination. In the crystal, inter-molecular N-H?O hydrogen bonds form centrosymmetric dimers. PMID- 21589627 TI - 1-[2-(2-Bromo-phen-yl)eth-yl]-4-chloro-2-nitro-benzene. AB - In the title mol-ecule, C(14)H(11)BrClNO(2), the dihedral angle between the mean planes of the bromo-substitued benzene and the chloro-substituted benzene rings is 1.8 (4) degrees . The nitro group is twisted by 15.8 (6) degrees from the mean plane of the benzene ring to which it is attached. The crystal packing is influenced by weak inter-molecular C-H?O inter-actions and weak pi-pi stacking inter-actions [centroid-centroid distances = 3.903 (2), 3.596 (2) and 3.903 (2) A]. PMID- 21589628 TI - (2-Amino-phen-yl)(p-tol-yl)methanone. AB - In the title compound, C(14)H(13)NO, the two six-membered rings make a dihedral angle of 52.8 (3) degrees . An intra-molecular N-H?O hydrogen bond involving an amine H atom and the adjacent carbonyl O atom occurs. In the crystal, N-H?O and C H?N inter-molecular hydrogen bonds are observed, which may be effective in stabilizing the structure. PMID- 21589629 TI - (E)-N'-(2,4-Dichloro-benzyl-idene)-3-nitro-benzohydrazide. AB - The title compound, C(14)H(9)Cl(2)N(3)O(3), was prepared by the reaction of 3 nitro-benzohydrazide with 2,4-dichloro-benzalde-hyde. The mol-ecule adopts an E configuration about the C=N bond. The dihedral angle between the two benzene rings is 4.6 (2) degrees . In the crystal, the hydrazone mol-ecules are linked through inter-molecular N-H?O hydrogen bonds, forming chains along the c axis. PMID- 21589630 TI - N'-(3,5-Dibromo-2-hy-droxy-benzyl-idene)-2-methyl-benzohydrazide. AB - The asymmetric unit of the title compound, C(15)H(12)Br(2)N(2)O(2), contains two independent mol-ecules in which the dihedral angles between the benzene rings are 49.5 (7) and 66.4 (7) degrees . Intra-molecular O-H?N hydrogen bonds generate S(6) ring motifs in each mol-ecule. In the crystal, mol-ecules are linked through inter-molecular N-H?O hydrogen bonds, forming chains along the b axis. PMID- 21589631 TI - 1,3,6-Trihy-droxy-7-meth-oxy-2,8-bis-(3-methyl-but-2-en-yl)-9H-xanthen-9-one. AB - The title compound (trivial name alpha-mangostin), C(24)H(26)O(6), isolated from Cratoxylum glaucum, is characterized by a xanthone skeleton of three fused six membered rings and two 3-methyl-but-2-enyl side chains. The three rings in the structure are nearly coplanar, with an r.m.s. deviation for the tricyclic ring system of 0.0014 A. The two 3-methyl-but-2-enyl side chains are in (+)-synclinal and (-)-anti-clinal conformations. Intra-molecular O-H?O and C-H?O inter-actions occur. The crystal structure is stabilized by inter-molecular O-H?O, C-H?O and C H?pi inter-actions. PMID- 21589632 TI - 4-[(3-Oxo-1,3-dihydro-2-benzofuran-1-yl)amino]-benzoic acid. AB - In the title compound, C(15)H(11)NO(4), the dihedral angle formed by the benzene ring and the essentially planar 2-benzofuran ring system is 55.93 (3) degrees . In the crystal, inter-molecular O-H?O hydrogen bonds link pairs of mol-ecules, generating centrosymmetric R(2) (2)(8) ring motifs. These dimeric units are connected via N-H?O hydrogen bonds, forming C(6) chains along [100]. PMID- 21589633 TI - 2-[(E)-4-(2-Bromo-phen-yl)but-3-en-2-yl-idene]malononitrile. AB - The title compound, C(13)H(19)BrN(2), is planar structure except for the methyl H atoms, the maximum atomic deviation for the non-H atoms being 0.100 (1) A. The bromo-phenyl and isopropanylidenemalononitrile units are located on opposite sides of the C=C bond, showing an E configuration. PMID- 21589634 TI - 2-(4-Hy-droxy-phen-oxy)propanoic acid. AB - In the title compound, C(9)H(10)O(4), the carboxyl group is oriented at a dihedral angle of 84.6 (3) degrees with respect to the benzene ring. In the crystal, mol-ecules are linked via O-H?O hydrogen bonds. PMID- 21589635 TI - 1,2-Bis(dimethyl-amino)-1,2-bis-(2,4,6-triisopropyl-phen-yl)diborane(4). AB - In the mol-ecular structure of the title compound, C(34)H(58)B(2)N(2), each B atom of the diborane(4) is connected to one dimethyl-amino group and one Tip ligand (Tip = 2,4,6-triisopropyl-phen-yl). These findings indicate that the increased steric demand of the Tip groups exerts influence solely on the B-B separation but not on the overall geometry of the title compound. PMID- 21589636 TI - 3,9-Di-tert-butyl-2,4,8,10-tetra-oxaspiro-[5.5]undeca-ne. AB - The title compound, C(15)H(28)O(4), was prepared by the condensation of pivalaldehyde with penta-erythritol. In the crystal, the two halves of the mol ecule are related by a crystallographic twofold rotation axis passing through the central spiro-C atom. The two non-planar six-membered heterocycles both adopt chair conformations with the two tert-butyl groups both located in the equatorial positions. PMID- 21589637 TI - N'-(2,3-Dihy-droxy-benzyl-idene)isonicotinohydrazide. AB - The title compound, C(13)H(11)N(3)O(3), crystallized with two independent mol ecules in the asymmetric unit. One of the mol-ecules is twisted while the other is almost planar, with dihedral angles of 28.02 (6) and 2.42 (9) degrees , respectively, between the benzene and pyridine rings. Intra-molecular O-H?O and O H?N hydrogen bonds are present in both mol-ecules. The two independent mol-ecules are linked by pairs of O-H?O hydrogen bonds. The crystal structure is further stabilized by inter-molecular N-H?N hydrogen bonds and C-H?N and C-H?O inter actions. PMID- 21589638 TI - Large scale library generation for high throughput sequencing. AB - BACKGROUND: Large efforts have recently been made to automate the sample preparation protocols for massively parallel sequencing in order to match the increasing instrument throughput. Still, the size selection through agarose gel electrophoresis separation is a labor-intensive bottleneck of these protocols. METHODOLOGY/PRINCIPAL FINDINGS: In this study a method for automatic library preparation and size selection on a liquid handling robot is presented. The method utilizes selective precipitation of certain sizes of DNA molecules on to paramagnetic beads for cleanup and selection after standard enzymatic reactions. CONCLUSIONS/SIGNIFICANCE: The method is used to generate libraries for de novo and re-sequencing on the Illumina HiSeq 2000 instrument with a throughput of 12 samples per instrument in approximately 4 hours. The resulting output data show quality scores and pass filter rates comparable to manually prepared samples. The sample size distribution can be adjusted for each application, and are suitable for all high throughput DNA processing protocols seeking to control size intervals. PMID- 21589639 TI - Long-term climate forcing in loggerhead sea turtle nesting. AB - The long-term variability of marine turtle populations remains poorly understood, limiting science and management. Here we use basin-scale climate indices and regional surface temperatures to estimate loggerhead sea turtle (Caretta caretta) nesting at a variety of spatial and temporal scales. Borrowing from fisheries research, our models investigate how oceanographic processes influence juvenile recruitment and regulate population dynamics. This novel approach finds local populations in the North Pacific and Northwest Atlantic are regionally synchronized and strongly correlated to ocean conditions--such that climate models alone explain up to 88% of the observed changes over the past several decades. In addition to its performance, climate-based modeling also provides mechanistic forecasts of historical and future population changes. Hindcasts in both regions indicate climatic conditions may have been a factor in recent declines, but future forecasts are mixed. Available climatic data suggests the Pacific population will be significantly reduced by 2040, but indicates the Atlantic population may increase substantially. These results do not exonerate anthropogenic impacts, but highlight the significance of bottom-up oceanographic processes to marine organisms. Future studies should consider environmental baselines in assessments of marine turtle population variability and persistence. PMID- 21589643 TI - Gd(3+)-DTPA-DG: novel nanosized dual anticancer and molecular imaging agent. AB - BACKGROUND: Difficulties in the use, preparation, and cost of radioactively labeled glycosylated compounds led to this research and development study of a new gadolinium-labeled glucose compound that does not have a radioactive half life or difficulties in its synthesis and utilization. METHODS: Based on the structure of the 2-fluoro-2-deoxy-D-glucose molecule ((18)FDG), a new compound consisting of D-glucose (1.1 nm) conjugated to a well-known chelator, diethylenetriamine penta-acetic acid (DTPA), was synthesized, labeled with Gd(3+), and examined in vitro and in vivo. RESULTS: This novel compound not only demonstrated excellent and less costly imaging capability, but also showed anticancer effects on treated cells. Our results demonstrated that the new Gd(3+) DTPA-DG compound (GDD, with GDD conjugate aggregation of about 8 nm at 0.02 mg/mL concentration) significantly decreased HT1080 and HT29 tumor cell numbers. Application of GDD to cancer cells also increased levels of tumor necrosis factor alpha, but did not alter blood glucose levels. Interestingly, no toxicological findings were seen in normal human kidney cells. CONCLUSION: Dual application of GDD for both imaging and treatment of tumor cells could be remarkably advantageous in both the diagnosis and treatment of cancer. PMID- 21589640 TI - Transcriptome analysis of Neisseria meningitidis in human whole blood and mutagenesis studies identify virulence factors involved in blood survival. AB - During infection Neisseria meningitidis (Nm) encounters multiple environments within the host, which makes rapid adaptation a crucial factor for meningococcal survival. Despite the importance of invasion into the bloodstream in the meningococcal disease process, little is known about how Nm adapts to permit survival and growth in blood. To address this, we performed a time-course transcriptome analysis using an ex vivo model of human whole blood infection. We observed that Nm alters the expression of ~30% of ORFs of the genome and major dynamic changes were observed in the expression of transcriptional regulators, transport and binding proteins, energy metabolism, and surface-exposed virulence factors. In particular, we found that the gene encoding the regulator Fur, as well as all genes encoding iron uptake systems, were significantly up-regulated. Analysis of regulated genes encoding for surface-exposed proteins involved in Nm pathogenesis allowed us to better understand mechanisms used to circumvent host defenses. During blood infection, Nm activates genes encoding for the factor H binding proteins, fHbp and NspA, genes encoding for detoxifying enzymes such as SodC, Kat and AniA, as well as several less characterized surface-exposed proteins that might have a role in blood survival. Through mutagenesis studies of a subset of up-regulated genes we were able to identify new proteins important for survival in human blood and also to identify additional roles of previously known virulence factors in aiding survival in blood. Nm mutant strains lacking the genes encoding the hypothetical protein NMB1483 and the surface-exposed proteins NalP, Mip and NspA, the Fur regulator, the transferrin binding protein TbpB, and the L-lactate permease LctP were sensitive to killing by human blood. This increased knowledge of how Nm responds to adaptation in blood could also be helpful to develop diagnostic and therapeutic strategies to control the devastating disease cause by this microorganism. PMID- 21589644 TI - Recent advances of chitosan nanoparticles as drug carriers. AB - Chitosan nanoparticles are good drug carriers because of their good biocompatibility and biodegradability, and can be readily modified. As a new drug delivery system, they have attracted increasing attention for their wide applications in, for example, loading protein drugs, gene drugs, and anticancer chemical drugs, and via various routes of administration including oral, nasal, intravenous, and ocular. This paper reviews published research on chitosan nanoparticles, including its preparation methods, characteristics, modification, in vivo metabolic processes, and applications. PMID- 21589645 TI - Cardiovascular application of polyhedral oligomeric silsesquioxane nanomaterials: a glimpse into prospective horizons. AB - Revolutionary advances in nanotechnology propose novel materials with superior properties for biomedical application. One of the most promising nanomaterials for biomedical application is polyhedral oligomeric silsesquioxane (POSS), an amazing nanocage consisting of an inner inorganic framework of silicon and oxygen atoms and an outer shell of organic groups. The unique properties of this nanoparticle has led to the development of a wide range of nanostructured copolymers with significantly enhanced properties including improved mechanical, chemical, and physical characteristics. Since POSS nanomaterials are highly biocompatible, biomedical application of POSS nanostructures has been intensely explored. One of the most promising areas of application of POSS nanomaterials is the development of cardiovascular implants. The incorporation of POSS into biocompatible polymers has resulted in advanced nanocomposite materials with improved hemocompatibility, antithrombogenicity, enhanced mechanical and surface properties, calcification resistance, and reduced inflammatory response, which make these materials the material of choice for cardiovascular implants. These highly versatile POSS derivatives have opened new horizons to the field of cardiovascular implant. Currently, application of POSS containing polymers in the development of new generation cardiovascular implants including heart valve prostheses, bypass grafts, and coronary stents is under intensive investigation, with encouraging outcomes. PMID- 21589646 TI - Evaluation of iron oxide nanoparticle biocompatibility. AB - Nanotechnology is an exciting field of investigation for the development of new treatments for many human diseases. However, it is necessary to assess the biocompatibility of nanoparticles in vitro and in vivo before considering clinical applications. Our characterization of polyol-produced maghemite gamma Fe(2)O(3) nanoparticles showed high structural quality. The particles showed a homogeneous spherical size around 10 nm and could form aggregates depending on the dispersion conditions. Such nanoparticles were efficiently taken up in vitro by human endothelial cells, which represent the first biological barrier to nanoparticles in vivo. However, gamma-Fe(2)O(3) can cause cell death within 24 hours of exposure, most likely through oxidative stress. Further in vivo exploration suggests that although gamma-Fe(2)O(3) nanoparticles are rapidly cleared through the urine, they can lead to toxicity in the liver, kidneys and lungs, while the brain and heart remain unaffected. In conclusion, gamma Fe(2)O(3) could exhibit harmful properties and therefore surface coating, cellular targeting, and local exposure should be considered before developing clinical applications. PMID- 21589647 TI - Solid self-nanoemulsifying cyclosporin A pellets prepared by fluid-bed coating: preparation, characterization and in vitro redispersibility. AB - BACKGROUND: The objective of this study was to evaluate fluid-bed coating as a new technique to prepare a pellet-based solid self-nanoemulsifying drug delivery system (SNEDDS) using cyclosporin A as a model of a poorly water-soluble drug. METHODS: The rationale of this technique was to entrap a Liquid SNEDDS in the matrix of the coating material, polyvinylpyrrolidone K30, by fluid-bed coating. Pseudoternary phase diagrams were used to screen the liquid SNEDDS formulations. The optimal formulation was composed of Labrafil M((r)) 1944 CS, Transcutol P((r)), and Cremophor((r)) EL in a ratio of 9:14:7. To prepare solid SNEDDS pellets, liquid SNEDDS was first dispersed in an aqueous solution of polyvinylpyrrolidone and then sprayed onto the surface of non-pareil pellets. Upon evaporation of water, polyvinylpyrrolidone precipitated and formed tight films to entrap the liquid SNEDDS. Visual observation and scanning electron microscopic analysis confirmed good appearance of the solid SNEDDS pellets. RESULTS: Our results indicated that up to 40% of the liquid SNEDDS could be entrapped in the coating layer. Powder x-ray diffraction analysis confirmed nonexistence of crystalline cyclosporin A in the formulation. Solid SNEDDS pellets showed a slower redispersion rate than the liquid SNEDDS. An increase in the total liquid SNEDDS loading led to faster redispersion, whereas increased coating weight (up to 400%) significantly decreased the redispersion rate. Both cyclosporin A loading and protective coating with 5% polyvinylpyrrolidone K30 did not significantly affect the redispersion rate. CONCLUSION: It is concluded that fluid-bed coating is a new technique with considerable potential for preparation of pellet-based solid SNEDDS formulations. PMID- 21589648 TI - A gold nanoshell with a silica inner shell synthesized using liposome templates for doxorubicin loading and near-infrared photothermal therapy. AB - Gold (Au) nanoshells with solid silica cores have great potential for cancer photothermal therapy. However, this nanostructure cannot carry enough drugs. Here, we report a Au nanoshell with a hollow silica core for drug loading and cancer therapy. The silica shells were synthesized using nanoliposome templates, and then Au nanoshells were grown on the outer surface of the silica shells. Transmission-electron and scanning-electron microscopy showed that the Au nanoshells were successfully fabricated, and that the liposome/SiO(2)/Au core shell nanocomposites were spherical with a narrow size distribution. Images of several broken spheres, and the fact that hollow templates (liposomes) were used, suggest that the fabricated Au nanoshells were hollow. After doxorubicin (DOX) was incorporated into liposome/SiO(2)/Au, the DOX-loaded Au nanoshells killed cancer cells with high therapeutic efficacy when irradiated with near-infrared light, suggesting that the Au nanoshells delivered both DOX chemotherapy and photothermal therapy with a synergistic effect. PMID- 21589649 TI - Dual-modal tracking of transplanted mesenchymal stem cells after myocardial infarction. AB - PURPOSE: Results for implantation efficiency and effective improvement of cardiac function in the field of mesenchymal stem cells (MSCs) are controversial. To attempt to clarify this debate, we utilized magnetic resonance imaging (MRI) and near-infrared optical imaging (OI) to explore the effects of different delivery modes of mesenchymal stem cells on cell retention time and cardiac function after myocardial infarction (MI). METHODS: Rat MSCs were labeled with superparamagnetic iron oxide nanoparticles and 1, 1'-dioctadecyl-3,3,3',3' tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt (DiD) for noninvasive cell tracking in a rat MI model. Rats underwent coronary artery ligation and were randomized into three experimental groups: intravenous (IV), intramyocardial (IM), and a control group. The first two groups referred to the route of delivery of the transplanted dual-labeled MSCs; whereas the control group was given an IV injection of serum-free medium one day post-MI. Cellular engraftment was determined 1 day and 7 days post cell delivery by measuring the iron and optical signals in explanted organs. Prussian blue staining and fluorescent microscopy were performed on histological sections for iron and DiD, respectively. Cardiac function was measured by echocardiography on day 7. RESULTS: The cardiac function of the IM group increased significantly compared to the IV and control groups at day 7. In the IM group, labeled cells were visualized in the infracted heart by serial MRI, and the intensity by OI was significantly higher on day 1. In the IV group, the heart signals were significantly attenuated by dual-modal tracking at two time points, but the lung signals in OI were significantly stronger than the IM group at both time points. CONCLUSION: IM injection of MSCs increased cell engraftment within infarcted hearts and improved cardiac function after MI. However, IV infusion has a low efficacy due to the cell trapping in the lung. Therefore, direct injection may provide an advantage over IV, with regard to retention of stem cells and protection of cardiac function. PMID- 21589650 TI - Application of hydroxyapatite nanoparticles in development of an enhanced formulation for delivering sustained release of triamcinolone acetonide. AB - We report an analysis of in vitro and in vivo drug release from an in situ formulation consisting of triamcinolone acetonide (TR) and poly(D,L-lactide-co glycolide) (PLGA) and the additives glycofurol (GL) and hydroxyapatite nanoparticles (HA). We found that these additives enhanced drug release rate. We used the Taguchi method to predict optimum formulation variables to minimize the initial burst. This method decreased the burst rate from 8% to 1.3%. PLGA-HA acted as a strong buffer, thereby preventing tissue inflammation at the injection site caused by the acidic degradation products of PLGA. Characterization of the optimized formulation by a variety of techniques, including scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Fourier transform near infrared spectroscopy, revealed that the crystalline structure of TR was converted to an amorphous form. Therefore, this hydrophobic agent can serve as an additive to modify drug release rates. Data generated by in vitro and in vivo experiments were in good agreement. PMID- 21589651 TI - Nanovaccine for leishmaniasis: preparation of chitosan nanoparticles containing Leishmania superoxide dismutase and evaluation of its immunogenicity in BALB/c mice. AB - BACKGROUND: Leishmaniasis is a protozoan disease, affecting 12 million people in different regions of the world with a wide spectrum of diseases. Although several chemotherapeutic agents have been used for treating the disease, long-term therapy, limited efficacy and the development of drug-resistant parasites remain the major limitations. METHODS: To develop a new nanovaccine for leishmaniasis, recombinant Leishmania superoxide dismutase (SODB1) was loaded onto chitosan nanoparticles by the ionotropic gelation method. Size and loading efficiency of the nanoparticles were evaluated and optimized, and an immunization study was undertaken on BALB/c mice. The mice received phosphate buffer saline (PBS), superoxide dismutase B1 (SODB1) in PBS and nanoparticles via subcutaneous injection. Soluble Leishmania Antigens (SLA) and complete Freund's adjuvant (CFA) were also injected subcutaneously three times every three weeks (some groups received only a single dose). Three weeks after the last injection, blood samples were collected and assessed with ELISA to detect IgG2a and IgG1. RESULTS: Immunological analysis showed that in single and triple doses of SODB1 nanoparticles, IgG2a and IgG2a/IgG1 were significantly higher than the other groups (P<0.05). CONCLUSION: The results revealed that formulations of SODB1 in biodegradable and stable chitosan nanoparticles can increase the immunogenicity toward cell-mediated immunity (T(H)1 cells producing IgG2a in mice) that is effective in Leishmania eradication and could be presented as a single dose nanovaccine for leishmaniasis. PMID- 21589652 TI - Plasmid-encapsulated polyethylene glycol-grafted polyethylenimine nanoparticles for gene delivery into rat mesenchymal stem cells. AB - BACKGROUND: Mesenchymal stem cell transplantation is a promising method in regenerative medicine. Gene-modified mesenchymal stem cells possess superior characteristics of specific tissue differentiation, resistance to apoptosis, and directional migration. Viral vectors have the disadvantages of potential immunogenicity, carcinogenicity, and complicated synthetic procedures. Polyethylene glycol-grafted polyethylenimine (PEG-PEI) holds promise in gene delivery because of easy preparation and potentially targeting modification. METHODS: A PEG8k-PEI25k graft copolymer was synthesized. Agarose gel retardation assay and dynamic light scattering were used to determine the properties of the nanoparticles. MTT reduction, wound and healing, and differentiation assays were used to test the cytobiological characteristics of rat mesenchymal stem cells, fluorescence microscopy and flow cytometry were used to determine transfection efficiency, and atomic force microscopy was used to evaluate the interaction between PEG-PEI/plasmid nanoparticles and mesenchymal stem cells. RESULTS: After incubation with the copolymer, the bionomics of mesenchymal stem cells showed no significant change. The mesenchymal stem cells still maintained high viability, resettled the wound area, and differentiated into adipocytes and osteoblasts. The PEG-PEI completely packed plasmid and condensed plasmid into stable nanoparticles of 100-150 nm diameter. After optimizing the N/P ratio, the PEG-PEI/plasmid microcapsules delivered plasmid into mesenchymal stem cells and obtained an optimum transfection efficiency of 15%-21%, which was higher than for cationic liposomes. CONCLUSION: These data indicate that PEG-PEI is a valid gene delivery agent and has better transfection efficiency than cationic liposomes in mesenchymal stem cells. PMID- 21589653 TI - Musical experience and the aging auditory system: implications for cognitive abilities and hearing speech in noise. AB - Much of our daily communication occurs in the presence of background noise, compromising our ability to hear. While understanding speech in noise is a challenge for everyone, it becomes increasingly difficult as we age. Although aging is generally accompanied by hearing loss, this perceptual decline cannot fully account for the difficulties experienced by older adults for hearing in noise. Decreased cognitive skills concurrent with reduced perceptual acuity are thought to contribute to the difficulty older adults experience understanding speech in noise. Given that musical experience positively impacts speech perception in noise in young adults (ages 18-30), we asked whether musical experience benefits an older cohort of musicians (ages 45-65), potentially offsetting the age-related decline in speech-in-noise perceptual abilities and associated cognitive function (i.e., working memory). Consistent with performance in young adults, older musicians demonstrated enhanced speech-in-noise perception relative to nonmusicians along with greater auditory, but not visual, working memory capacity. By demonstrating that speech-in-noise perception and related cognitive function are enhanced in older musicians, our results imply that musical training may reduce the impact of age-related auditory decline. PMID- 21589654 TI - Red fluorescent protein-aequorin fusions as improved bioluminescent Ca2+ reporters in single cells and mice. AB - Bioluminescence recording of Ca(2+) signals with the photoprotein aequorin does not require radiative energy input and can be measured with a low background and good temporal resolution. Shifting aequorin emission to longer wavelengths occurs naturally in the jellyfish Aequorea victoria by bioluminescence resonance energy transfer (BRET) to the green fluorescent protein (GFP). This process has been reproduced in the molecular fusions GFP-aequorin and monomeric red fluorescent protein (mRFP)-aequorin, but the latter showed limited transfer efficiency. Fusions with strong red emission would facilitate the simultaneous imaging of Ca(2+) in various cell compartments. In addition, they would also serve to monitor Ca(2+) in living organisms since red light is able to cross animal tissues with less scattering. In this study, aequorin was fused to orange and various red fluorescent proteins to identify the best acceptor in red emission bands. Tandem-dimer Tomato-aequorin (tdTA) showed the highest BRET efficiency (largest energy transfer critical distance R(0)) and percentage of counts in the red band of all the fusions studied. In addition, red fluorophore maturation of tdTA within cells was faster than that of other fusions. Light output was sufficient to image ATP-induced Ca(2+) oscillations in single HeLa cells expressing tdTA. Ca(2+) rises caused by depolarization of mouse neuronal cells in primary culture were also recorded, and changes in fine neuronal projections were spatially resolved. Finally, it was also possible to visualize the Ca(2+) activity of HeLa cells injected subcutaneously into mice, and Ca(2+) signals after depositing recombinant tdTA in muscle or the peritoneal cavity. Here we report that tdTA is the brightest red bioluminescent Ca(2+) sensor reported to date and is, therefore, a promising probe to study Ca(2+) dynamics in whole organisms or tissues expressing the transgene. PMID- 21589655 TI - Cancer screening by systemic administration of a gene delivery vector encoding tumor-selective secretable biomarker expression. AB - Cancer biomarkers facilitate screening and early detection but are known for only a few cancer types. We demonstrated the principle of inducing tumors to secrete a serum biomarker using a systemically administered gene delivery vector that targets tumors for selective expression of an engineered cassette. We exploited tumor-selective replication of a conditionally replicative Herpes simplex virus (HSV) combined with a replication-dependent late viral promoter to achieve tumor selective biomarker expression as an example gene delivery vector. Virus replication, cytotoxicity and biomarker production were low in quiescent normal human foreskin keratinocytes and high in cancer cells in vitro. Following intravenous injection of virus >90% of tumor-bearing mice exhibited higher levels of biomarker than non-tumor-bearing mice and upon necropsy, we detected virus exclusively in tumors. Our strategy of forcing tumors to secrete a serum biomarker could be useful for cancer screening in high-risk patients, and possibly for monitoring response to therapy. In addition, because oncolytic vectors for tumor specific gene delivery are cytotoxic, they may supplement our screening strategy as a "theragnostic" agent. The cancer screening approach presented in this work introduces a paradigm shift in the utility of gene delivery which we foresee being improved by alternative vectors targeting gene delivery and expression to tumors. Refining this approach will usher a new era for clinical cancer screening that may be implemented in the developed and undeveloped world. PMID- 21589656 TI - Archipelago-wide island restoration in the Galapagos Islands: reducing costs of invasive mammal eradication programs and reinvasion risk. AB - Invasive alien mammals are the major driver of biodiversity loss and ecosystem degradation on islands. Over the past three decades, invasive mammal eradication from islands has become one of society's most powerful tools for preventing extinction of insular endemics and restoring insular ecosystems. As practitioners tackle larger islands for restoration, three factors will heavily influence success and outcomes: the degree of local support, the ability to mitigate for non-target impacts, and the ability to eradicate non-native species more cost effectively. Investments in removing invasive species, however, must be weighed against the risk of reintroduction. One way to reduce reintroduction risks is to eradicate the target invasive species from an entire archipelago, and thus eliminate readily available sources. We illustrate the costs and benefits of this approach with the efforts to remove invasive goats from the Galapagos Islands. Project Isabela, the world's largest island restoration effort to date, removed >140,000 goats from >500,000 ha for a cost of US$10.5 million. Leveraging the capacity built during Project Isabela, and given that goat reintroductions have been common over the past decade, we implemented an archipelago-wide goat eradication strategy. Feral goats remain on three islands in the archipelago, and removal efforts are underway. Efforts on the Galapagos Islands demonstrate that for some species, island size is no longer the limiting factor with respect to eradication. Rather, bureaucratic processes, financing, political will, and stakeholder approval appear to be the new challenges. Eradication efforts have delivered a suite of biodiversity benefits that are in the process of revealing themselves. The costs of rectifying intentional reintroductions are high in terms of financial and human resources. Reducing the archipelago-wide goat density to low levels is a technical approach to reducing reintroduction risk in the short term, and is being complemented with a longer-term social approach focused on education and governance. PMID- 21589657 TI - Differential evolvability along lines of least resistance of upper and lower molars in island house mice. AB - Variation within a population is a key feature in evolution, because it can increase or impede response to selection, depending on whether or not the intrapopulational variance is correlated to the change under selection. Hence, main directions of genetic variance have been proposed to constitute "lines of least resistance to evolution" along which evolution would be facilitated. Yet, the screening of selection occurs at the phenotypic level, and the phenotypic variance is not only the product of the underlying genetic variance, but also of developmental processes. It is thus a key issue for interpreting short and long term evolutionary patterns to identify whether main directions of phenotypic variance indeed constitute direction of facilitated evolution, and whether this is favored by developmental processes preferably generating certain phenotypes. We tackled these questions by a morphometric quantification of the directions of variance, compared to the direction of evolution of the first upper and lower molars of wild continental and insular house mice. The main phenotypic variance indeed appeared as channeling evolution between populations. The upper molar emerged as highly evolvable, because a strong allometric component contributed to its variance. This allometric relationship drove a repeated but independent evolution of a peculiar upper molar shape whenever size increased. This repeated evolution, together with knowledge about the molar development, suggest that the main direction of phenotypic variance correspond here to a "line of least developmental resistance" along which evolution between population is channeled. PMID- 21589659 TI - Experimental demonstration of the fitness consequences of an introduced parasite of Darwin's finches. AB - BACKGROUND: Introduced parasites are a particular threat to small populations of hosts living on islands because extinction can occur before hosts have a chance to evolve effective defenses. An experimental approach in which parasite abundance is manipulated in the field can be the most informative means of assessing a parasite's impact on the host. The parasitic fly Philornis downsi, recently introduced to the Galapagos Islands, feeds on nestling Darwin's finches and other land birds. Several correlational studies, and one experimental study of mixed species over several years, reported that the flies reduce host fitness. Here we report the results of a larger scale experimental study of a single species at a single site over a single breeding season. METHODOLOGY/PRINCIPAL FINDINGS: We manipulated the abundance of flies in the nests of medium ground finches (Geospiza fortis) and quantified the impact of the parasites on nestling growth and fledging success. We used nylon nest liners to reduce the number of parasites in 24 nests, leaving another 24 nests as controls. A significant reduction in mean parasite abundance led to a significant increase in the number of nests that successfully fledged young. Nestlings in parasite-reduced nests also tended to be larger prior to fledging. CONCLUSIONS/SIGNIFICANCE: Our results confirm that P. downsi has significant negative effects on the fitness of medium ground finches, and they may pose a serious threat to other species of Darwin's finches. These data can help in the design of management plans for controlling P. downsi in Darwin's finch breeding populations. PMID- 21589658 TI - Association of adiponectin SNP+45 and SNP+276 with type 2 diabetes in Han Chinese populations: a meta-analysis of 26 case-control studies. AB - Recently, many studies have reported that the SNP+45(T>G) and SNP+276(G>T) polymorphisms in the adiponectin gene are associated with type 2 diabetes (T2DM) in the Chinese Han population. However, the previous studies yielded many conflicting results. Thus, a meta-analysis of the association of the adiponectin gene with T2DM in the Chinese Han population is required. In the current study, we first determined the distribution of the adiponectin SNP+276 polymorphism in T2DM and nondiabetes (NDM) control groups. Our results suggested that the genotype and allele frequencies for SNP+276 did not differ significantly between the T2DM and NDM groups. Then, a meta-analysis of 23 case-control studies of SNP+45, with a total of 4161 T2DM patients and 3709 controls, and 11 case-control studies of SNP+276, with 2533 T2DM patients and 2212 controls, was performed. All subjects were Han Chinese. The fixed-effects model and random-effects model were applied for dichotomous outcomes to combine the results of the included studies. The results revealed a trend towards an increased risk of T2DM for the SNP+45G allele as compared with the SNP+45T allele (OR = 1.34; 95% CI, 1.11-1.62; P<0.01) in the Chinese Han population. However, there was no association between SNP+276 and T2DM (OR = 0.90; 95% CI, 0.73-1.10; P = 0.31). The results of our association study showed there was no association between the adiponectin SNP+276 polymorphism and T2DM in the Yunnan Han population. The meta-analysis results suggested that the SNP+45G allele might be a susceptibility allele for T2DM in the Chinese Han population. However, we did not observe an association between SNP+276 and T2DM. PMID- 21589660 TI - Comparison of a double poling ergometer and field test for elite cross country sit skiers. AB - BACKGROUND: Sport specific ergometers are important for laboratory testing (i.e. peak oxygen consumption (VO(2))) and out of season training. OBJECTIVES: The purpose of this study was to compare cardiorespiratory variables during exercise on a double poling ergometer to a field test in elite sit skiers. METHODS: Three male and four female athletes from the Canadian National / Developmental team (17 54 years of age, six with complete paraplegia and one with cerebral palsy) completed a field test and a double poling ergometer protocol separated by at least 24 hours. Both protocols consisted of three maximal trials of skiing of three minutes duration separated by 1.5 minutes of rest. A wireless metabolic system and heart rate monitor were used to measure cardiorespiratory responses [peak heart rate, peak VO(2), and peak respiratory exchange ratio (RER)] during each test. Arterialized blood lactate was measured before the beginning of exercise, after each trial and at 5, 10 and 15 minutes post exercise. RESULTS: No significant differences existed between the field and ergometer tests for peak oxygen consumption (VO(2)) (field=34.7+/-5.5 mL.kg-1.min-1 vs. ergometer=33.4+/ 6.9 mL.kg-1.min-1). Significantly higher peak heart rate and RER were found during the ergometer test. Significantly higher lactates were found during the ergometer test after trial 2 and trial 3. CONCLUSION: The double poling ergometer is similar to a field test for evaluating peak VO(2) in elite cross country sit skiers; however, the ergometer test elicits a higher heart rate and anaerobic response. PMID- 21589661 TI - Use of a functional movement screening tool to determine injury risk in female collegiate athletes. AB - BACKGROUND: Athletes often utilize compensatory movement strategies to achieve high performance. However, these inefficient movement strategies may reinforce poor biomechanical movement patterns during typical activities, resulting in injury. OBJECTIVES: This study sought to determine if compensatory movement patterns predispose female collegiate athletes to injury, and if a functional movement screening (FMSTM) tool can be used to predict injuries in this population. METHODS: Scores on the FMSTM, comprised of seven movement tests, were calculated for 38 NCAA Division II female collegiate athletes before the start of their respective fall and winter sport seasons (soccer, volleyball, and basketball). Seven athletes reported a previous history of anterior cruciate ligament reconstruction (ACLR). Injuries sustained while participating in sport activities were recorded throughout the seasons. RESULTS: The mean FMSTM score and standard deviation for all subjects was 14.3+/-1.77 (maximum score of 21). Eighteen injuries (17 lower extremity, 1 lower back) were recorded during this study. A score of 14/21 or less was significantly associated with injury (P=0.0496). Sixty-nine percent of athletes scoring 14 or less sustained an injury. Odds ratios were 3.85 with inclusion of all subjects, and 4.58 with exclusion of ACLR subjects. Sensitivity and specificity were 0.58 and 0.74 for all subjects, respectively. A significant correlation was found between low scoring athletes and injury (P=0.0214, r=0.76). DISCUSSION: A score of 14 or less on the FMSTM tool resulted in a 4-fold increase in risk of lower extremity injury in female collegiate athletes participating in fall and winter sports. The screening tool was able to predict injury in female athletes without a history of major musculoskeletal injury such as ACLR. CONCLUSION: Compensatory fundamental movement patterns can increase the risk of injury in female collegiate athletes, and can be identified by using a functional movement screening tool. PMID- 21589662 TI - Weight-bearing hip rotation range of motion in female golfers. AB - BACKGROUND: Many sports involve movements during which the lower extremity functions as a closed kinetic chain, requiring weight-bearing (WB) range of motion (ROM). Assessment of the capacity for internal and external rotation motion at the hip is typically performed with the individual in a prone, supine, or seated position. Such measurements represent ROM in a non-weight bearing (NWB) position, and, as a result, may not appropriately assess the capacity of the joint to meet the demands of the athlete's sport. To date, no research exists which documents WB hip ROM in golfers relative to the ROM demands of the golf swing or the symmetry of weight-bearing hip rotation ROM in female golfers. OBJECTIVES: Weight-bearing hip rotation ROM was measured in female golfers and compared to the actual hip rotation ROM that occurred during a full golf swing. METHODS: Fifteen right-handed, female collegiate golfers participated in the study. The WB hip rotation ROM was measured during three different stance conditions and during full golf swings using a custom-built testing device. These actions were captured using a 3-D motion analysis system. RESULTS: The golfers WB ROM was symmetrical for external rotation and internal rotation, p = 0.648 and p = 0.078, respectively. During the backswing, the golfers used approximately 20 25% of their available WB right internal rotation, and 50-75% of their available WB left external rotation. For the downswing, the golfers used approximately 34 37% of their available WB right external rotation and 84-131% of their available WB left internal rotation. The golfers used significantly more external and internal hip rotation ROM on the left (lead) hip during both phases of the full golf swing (p < 0.001), demonstrating an asymmetrical movement pattern. DISCUSSION: In general, golfers did not exceed the measured WB ROM limits during the golf swing but did demonstrate decreased WB internal rotation on the lead hip. CONCLUSION: Clinicians need to pay special attention to functional (WB) hip rotation ROM in female golfers in order to assess injury risk related to the rotational hip asymmetry present during the golf swing. PMID- 21589664 TI - The Effects of Open versus Closed Kinetic Chain Exercises on Patients with ACL Deficient or Reconstructed Knees: A Systematic Review. AB - BACKGROUND: There is no consensus among the existing published evidence as to whether closed kinetic chain (CKC) or open kinetic chain (OKC) exercises should be the intervention of choice following an anterior cruciate ligament (ACL) injury or reconstruction. The commonly held belief has been that OKC exercises cause increased strain on the ACL as well as increased joint laxity and anterior tibial translation. OBJECTIVE: To investigate the effects of OKC and CKC exercises on the knees of patients with ACL deficiency or reconstruction. DATA SOURCES: MEDLINE, ProQuest Medical Library, and CINAHL STUDY SELECTION: Six articles were chosen for inclusion in the systematic review. The authors narrowed 50 articles down to 6 by review of titles and abstracts. Included articles were randomized controlled trials written in English, published during 2000-2008, that evaluated the effects of OKC and CKC exercises on ACL deficient or reconstructed knees. DATA EXTRACTION: Quality of the included studies was defined by the PEDro scale(1), which has been found to be reliable.(2) DATA SYNTHESIS: Scores on the PEDro scale(1) ranged from 4-6/10. One article found positive significant effects with inclusion of OKC exercises in the rehabilitation program and another found significant benefits with combining OKC and CKC exercises. CKC exercises alone were not found by any studies to be superior to OKC exercises. CONCLUSION: These studies reveal favorable results for utilization of both open and closed kinetic chain exercises for intervention with ACL deficient or reconstructed knees. However, further research needs to be completed. PMID- 21589663 TI - Differences in transverse abdominis activation with stable and unstable bridging exercises in individuals with low back pain. AB - BACKGROUND: The transversus abdominis (TrA) is a spine stabilizer frequently targeted during rehabilitation exercises for individuals with low back pain (LBP). Performance of exercises on unstable surfaces is thought to increase muscle activation, however no research has investigated differences in TrA activation when stable or unstable surfaces are used. OBJECTIVE: The purpose of this study was to investigate whether TrA activation in individuals with LBP is greater when performing bridging exercises on an unstable surface versus a stable surface. METHODS: Fifty one adults (mean +/- SD, age 23.1 +/- 6.0 years, height 173.60 +/- 10.5 cm, mass 74.7 +/- 14.5 kg) with stabilization classification of LBP were randomly assigned to either exercise progression utilizing a sling bridge device or a traditional bridging exercise progression, each with 4 levels of increasing difficulty. TrA activation ratio (TrA contracted thickness/TrA resting thickness) was measured during each exercise using ultrasound imaging. The dependent variable was the TrA activation ratio. RESULTS: The first 3 levels of the sling-based and traditional bridging exercise progression were not significantly different. There was a significant increase in the TrA activation ratio in the sling-based exercise group when bridging was performed with abduction of the hip (1.48 +/- .38) compared to the traditional bridge with abduction of the hip (1.22 +/- .38; p<.05). CONCLUSION: Both types of exercise result in activation of the TrA, however, the sling based exercise when combined with dynamic movement resulted in a significantly higher activation of the local stabilizers of the spine compared to traditional bridging exercise. This may have implications for rehabilitation of individuals with LBP. PMID- 21589665 TI - Rehabilitation of a female dancer with patellofemoral pain syndrome: applying concepts of regional interdependence in practice. AB - Due to complex movements and high physical demands, dance is often associated with a multitude of impairments including pain of the low back, pelvis, leg, knee, and foot. This case report provides an exercise progression, emphasizing enhancement of strength and neuromuscular performance using the concept of regional interdependence in a 17 year old female dancer with patellofemoral pain syndrome. PMID- 21589666 TI - Evaluating change in clinical status: reliability and measures of agreement for the assessment of glenohumeral range of motion. AB - OBJECTIVES: To evaluate intra-rater and inter-rater reliability and measurement error in glenohumeral range of motion (ROM) measurements using a standard goniometer. STUDY DESIGN: 17 adult subjects with and without shoulder pathology were evaluated for active and passive range of motion. Fifteen shoulder motions were assessed by two raters to determine reliability. The intra-class correlation coefficients (ICC) were calculated and examined to determine if reliability of ICC >= 0.70 existed. The standard error of measurement (SEM) and the minimal clinical difference (MCD) were also calculated. RESULTS: Thxe criterion reliability was achieved in both groups for intra-rater reliability of standing AROM abduction; supine AROM and PROM abduction, flexion, external rotation at 0 degrees abduction; and for inter-rater reliability of supine AROM and PROM abduction, external rotation at 0 degrees abduction. The SEM ranged from 4 degrees -7 degrees for intra-rater and 6 degrees -9 degrees for inter-rater agreement on movements that achieved the criterion reliability. The MCD ranged from 11 degrees -16 degrees for a single evaluator and 14 degrees -24 degrees for two evaluators. CONCLUSIONS: Assessment of AROM and PROM in supine achieves superior reliability. The use of either a single or multiple raters affects the number of movements that achieved clinically meaningful reliability. Some movements consistently did not achieve the criterion and may not be the best movements to monitor treatment outcome. PMID- 21589667 TI - Contralateral effects of disinhibitory tens on quadriceps function in people with knee osteoarthritis following unilateral treatment. AB - BACKGROUND: Quadriceps activation failure is common in patients with tibiofemoral osteoarthritis (TFOA) and has been reported to occur bilaterally following acute and chronic knee injuries. Sensory transcutaneous electrical stimulation (TENS) applied to the knee has increased ipsilateral quadriceps activation, yet it remains unknown if repeated sensory TENS treatments affect activation in the contralateral quadriceps. OBJECTIVE: To determine the effects of unilateral TENS treatment to the involved leg, in conjunction with 4-weeks of therapeutic exercise, on volitional quadriceps activation in the contralateral leg. METHODS: Thirty-three patients with radiographically diagnosed TFOA were randomly assigned to the TENS, placebo, and the control groups. The involved leg was defined as the knee with highest degree of radiographically assessed TFOA. All participants completed a supervised 4-week lower extremity exercise program for the involved leg only. TENS and placebo TENS were worn throughout the rehabilitation sessions as well as during daily activities for those groups on the involved leg. Quadriceps central activation ratio (CAR), a measure of volitional muscular activation, was assessed in the uninvolved leg at baseline, 2-weeks and 4-weeks following the initiation of the intervention. RESULTS: There were no differences between groups for quadriceps CAR (P=0.3). DISCUSSION: Although significant differences were not found, strong to moderate within group effect sizes were calculated for the TENS group at 2 (d = .87) and 4 weeks (d = .54), suggesting that significant differences may be found in a larger population. CONCLUSIONS: Contralateral quadriceps CAR was not affected following a 4-week unilateral disinhibitory intervention in this sample. PMID- 21589668 TI - Associations between three clinical assessment tools for postural stability. AB - STUDY DESIGN: Clinical Measurement, Correlation, Reliability OBJECTIVES: To assess the relationship between the Single Leg Balance (SLB), modified Balance Error Scoring System (mBESS), and modified Star Excursion Balance (mSEBT) tests and secondarily to assess inter-rater and test-retest reliability of these tests. BACKGROUND: Ankle sprains often result in chronic instability and dysfunction. Several clinical tests assess postural deficits as a potential cause of this dysfunction; however, limited information exists pertaining to the relationship that these tests have with one another. METHODS: Two independent examiners measured the performance of 34 healthy participants completing the SLB Test, mBESS test, and mSEBT at two different time periods. The relationship between tests was assessed using the Pearson Correlation and Fisher's Exact Tests. Inter rater and test-retest reliability were assessed using the intraclass correlation coefficient (ICC) and Kappa statistics. RESULTS: A significant correlation (r = 0.35) was observed between the mSEBT and the mBESS. Fisher's Exact Test showed a significant association between the SLB Test and mBESS (P = .048), but no association between the SLB and mSEBT (P = 1.000). Inter-rater reliability was excellent for the mSEBT and fair for the mBESS (ICCs of .91 and .61 respectively). Excellent agreement was observed between raters for the SLB test (k = 1.00). Test-retest reliability was excellent for the mSEBT (ICC = 0.98) and fair for the mBESS (ICC = 0.74). There was poor test-retest agreement for the SLB test (k = .211). CONCLUSION: THERE WAS A SIGNIFICANT RELATIONSHIP OBSERVED BETWEEN THE SLB TEST, MBESS TEST, AND MSEBT: however; strength of association measures showed limited overlap between these tests. This suggests that these tests are interrelated but may not assess equal components of postural stability. PMID- 21589669 TI - Return to division ia football following a 1 metatarsophalangeal joint dorsal dislocation. AB - BACKGROUND.: Although rare in occurrence, a dorsal dislocation of the 1st metatarsophalangeal (MTP) joint has been successfully treated using surgical and/or non-operative treatment. No descriptions of conservative intervention following a dorsal dislocation of the MTP joint in an athlete participating in a high contact sport are present in the literature. OBJECTIVES.: The purpose of this case report is to describe the intervention and clinical reasoning during the rehabilitative process of a collegiate football player diagnosed with a 1st MTP joint dorsal dislocation. The plan of care and return to play criteria used for this athlete are presented. CASE DESCRIPTION.: The case involved a 19-year old male Division IA football player, who suffered a traumatic dorsal dislocation of the 1st MTP joint during practice. The dislocation was initially treated on site by closed reduction. Non-operative management included immobilization, therapeutic exercises, non-steroidal anti-inflammatories, manual treatment, modalities, prophylactic athletic taping, gait training, and a sport specific progression program for full return to Division IA football. OUTCOMES.: Discharge from physical therapy occurred after six weeks of treatment. At discharge, no significant deviations existed during running, burst, and agility related drills. At a six-month follow-up, the patient reported full return to all football activities including contact drills without restrictions. DISCUSSION.: This case describes an effective six-week rehabilitation intervention for a collegiate football player who sustained a traumatic great toe dorsal dislocation. Further study is suggested to evaluate the intervention strategies and timeframe for return to contact sports. PMID- 21589670 TI - Conservative rehabilitation of sciatic nerve injury following hamstring tear. AB - STUDY DESIGN: Resident's case report BACKGROUND: There have been only a few case reports in the literature mentioning sciatic nerve injury following a hamstring tear. In previous cases surgical intervention was performed to debride scar tissue around the sciatic nerve with the goal of full return to function for the patient. OBJECTIVES: The purpose of this case report is to describe the conservative interventions that allowed for recovery from a hamstring tear with sciatic nerve involvement. CASE DESCRIPTION: The subject was a 53 year old female who developed foot drop and weakness in the common fibular nerve distribution following a grade 3 hamstring injury sustained during Nordic skiing. Nerve function and strength gradually returned over the course of several months of conservative rehabilitation which included on neural gliding and strengthening exercises. OUTCOMES: At 18 months post injury, the subject had returned to 95% of full sport function and 98% of full function with activities of daily living, as rated by the Hip Outcome Scale, and had full strength with manual muscle testing. Isokinetic testing revealed strength deficits of 11-23% in knee flexion peak torque at 60 degrees/second and 180 degrees/second respectively. DISCUSSION: Sciatic nerve injury is a rare, but important potential consequence of severe hamstring strains. Clinicians should be cognizant of the potential injury to the nerve tissue following hamstring strains, so they may be dealt with in a prompt and appropriate manner. The use of neural gliding may be worth considering for a prophylactic effect following hamstring strains. PMID- 21589671 TI - Rehabilitation following knee dislocation with lateral side injury: implementation of the knee symmetry model. AB - Rehabilitation following lateral side knee ligament repair or reconstruction has traditionally utilized a conservative approach. An article outlining a new concept in rehabilitation following ACL reconstruction called the Knee Symmetry Model was recently published(13). The Knee Symmetry Model can also be applied to rehabilitation of other knee pathologies including a knee dislocation with a lateral side injury.This Clinical Commentary describes the rehabilitation procedures used with patients who underwent surgery to repair lateral side ligaments, based upon the Knee Symmetry Model. These procedures were used previously to rehabilitate a group of patients with lateral side ligament repair as reported by Shelbourne et al(10). Outcome data and subjective knee scores for these patients were recorded via the International Knee Documentation Committee (IKDC) guidelines and modified Noyes survey scores and are summarized in this paper, as previously published. Rehabilitation following lateral side knee ligament repair using guidelines based upon the Knee Symmetry Model appears to provide patients with excellent long-term stability, normal ROM and strength, and a high level of function. PMID- 21589672 TI - Evidence-supported rehabilitation of patellar tendinopathy. AB - Chronic tendinopathy is a common musculoskeletal disorder that frequently affects athletes who train and compete at all levels. This Clinical Commentary presents a review of the etiology, incidence, and contributory factors related specifically to patellar tendinopathy. Examination and differential diagnosis considerations are provided, and an evidence-based, staged rehabilitation program is described. PMID- 21589673 TI - The value of blowing up a balloon. AB - Suboptimal breathing patterns and impairments of posture and trunk stability are often associated with musculoskeletal complaints such as low back pain. A therapeutic exercise that promotes optimal posture (diaphragm and lumbar spine position), and neuromuscular control of the deep abdominals, diaphragm, and pelvic floor (lumbar-pelvic stabilization) is desirable for utilization with patients who demonstrate suboptimal respiration and posture. This clinical suggestion presents a therapeutic exercise called the 90/90 bridge with ball and balloon. This exercise was designed to optimize breathing and enhance both posture and stability in order to improve function and/or decrease pain. Research and theory related to the technique are also discussed. PMID- 21589674 TI - A new exercise for tennis elbow that works! AB - Eccentric exercise has been effectively used in the management of tendinopathies in multiple regions of the body. Lateral epicondylosis ("tennis elbow") is a common tendinopathy that has shown improvement following treatment utilizing isokinetic eccentric exercise. A novel exercise was developed for home-based eccentric exercise that has shown promise for use with patients with lateral epicondylosis. Clinicians should be aware of this exercise and consider it as an evidence-based intervention. PMID- 21589675 TI - Bipolar versus fixed-head hip arthroplasty for femoral neck fractures in elderly patients. AB - Between 2002 and 2007, fifty elderly patients with displaced femoral neck fractures were treated with hip replacement at Emergency Hospital, Mansoura University. Patients were randomly selected, 25 patients had either cemented or cementless bipolar prosthesis, and another 25 patients had either cemented or cementless fixed-head prosthesis. There were 34 women and 16 men with an average age of 63.5 years (range between 55 and 72 years). All patients were followed up both clinically and radiologically for an average 4.4 years (range between 2 and 6 years). At the final follow-up, the average Harris hip score among the bipolar group was 92 points (range between 72 and 97 points), while the fixed-head group was 84 points (range between 65 and 95 points). Radiologically, joint space narrowing more than 2 mm was found in only 8% (2 patients) among the bipolar group, and in 28% (7 patients) of the fixed-head group. Through the follow-up period, total hip replacement was needed in two cases of the bipolar group and seven cases of the fixed-head group. Bipolar hemiarthroplasty offered a better range of movement with less pain and more stability than the fixed-head hemiarthroplasty in elderly patients with displaced femoral neck fractures. PMID- 21589677 TI - Pelvic support osteotomy by Ilizarov's concept: Is it a valuable option in managing neglected hip problems in adolescents and young adults? AB - For evaluating pelvic support osteotomy as a salvage procedure in managing neglected hip problems in adolescents and young adults, PSO was performed for 20 hips in 20 patients (5 men and 15 women). The mean age was 21.5 years. The etiology was neglected developmental dysplasia of the hip in 9 patients, post septic hip sequelae in 9 patients, and paralytic dislocation due to poliomyelitis in 2 patients. All patients were treated by two osteotomies: a proximal femoral osteotomy to support the pelvis and correct the flexion and rotational deformities of the hip and a distal varization and lengthening osteotomy. Final clinical evaluation was done 6 months after frame removal. The mean external fixation time was 6.4. Lengthening and mechanical axis parallelism was achieved in all patients. At the final follow-up and according to a predesigned scoring system, there were 7(35%) excellent results, 6(30%) good results, 7(35%) fair results, and no poor results. Hip reconstruction by Ilizarov's concept can be technically demanding and involving lengthy period wearing the frame but found to be a valuable salvage procedure for numerous neglected hip problems particularly in young patients. PMID- 21589676 TI - Arthroplasty versus internal fixation for femoral neck fractures in the elderly. AB - We studied 140 patients with femoral neck fractures treated from January 1999 to December 2006. There were 68 men and 72 women with a mean age of 72 years (range 60-80 years). Seventy patients were treated with closed reduction and internal fixation (group A), and 70 patients with hip arthroplasty (group B). The duration of surgery, length of hospitalization, complications, postoperative Harris hip score, and need for reoperation were recorded. Group B had significantly higher blood loss, increased surgical time and length of hospitalization compared to group A patients. The Harris hip score was significantly higher in group B at the 3, 6, and 12-month follow-up evaluations; however, the differences were no longer significant at the 24-month evaluation. The overall complications rate was 18.6% (13 patients) in group A compared to 25.7% (18 patients) in group B; this was not statistically significant (P = 0.309). A statistically significant difference was found regarding reoperation rate in group A (11.4%, eight patients) compared to group B (1.4%, one patient) (P = 0.016). Arthroplasty compared to internal fixation for displaced femoral neck fractures is associated with a significantly higher functional score and lower risk of reoperation at the cost of greater infection rates, blood loss, and operative time. PMID- 21589678 TI - Modified hybrid fixator for high-energy Schatzker V and VI tibial plateau fractures. AB - High-energy tibial plateau fractures associated with severe soft tissue injury are difficult to manage. The risk of wound complications following open reduction and internal fixation is notably high owing to extensive soft tissue dissection. Alternatively, application of hybrid external fixator minimizes soft tissue dissection and provides adequate fracture stabilization to allow early range of motion and correction of any mal-alignment. With this technique, soft tissue complications particularly surgical site infections are expected to be significantly reduced. This prospective study aims to determine the effectiveness of a modified hybrid external fixator in the management of high-energy tibial plateau fractures. Thirty-three patients with high-energy Schatzker V and VI tibial plateau fracture with severe soft tissue injury precluding formal open reduction were enrolled into the study. The fixator was a construct combining the Ilizarov ring with a monolateral external fixator. The results-bony union, range of motion, and associated complications of the treatment-were assessed. All fractures united within an average time of 14 weeks. Neither loss of reduction nor surgical site wound breakdown/osteomyelitis was noted. Eight patients developed superficial pin track infection and one septic arthritis of the knee joint. Hybrid external fixation is a safe option for complex high-energy tibial plateau fractures by simultaneously providing adequate fracture stabilization and protection of soft tissue healing to achieve bony union. The complication is mainly related to pin tract infection. PMID- 21589679 TI - Direct and indirect loading of the Ilizarov external fixator: the effect on the interfragmentary movements and compressive loads. AB - The amount of weight bearing and the force transmission to the frame have an important influence on the results of treatment with an Ilizarov external fixator. The frame provides beneficial interfragmentary movements and compressive loads at the fracture site through elastic wires. Mobilisation can be achieved by applying a weight-bearing platform at the distal end of the fixator. The effect on the interfragmentary movements and the compressive loads in indirect and direct loading were analysed in this study using a composite tibia bone model. Displacement transducers were attached to measure the interfragmentary movements and to detect relative movements of the bone fragments and movements between the rings. The compressive loads in the osteotomy were measured with loading cells in the defect zone. The weight-bearing platform had a substantial effect on the biomechanical behaviour of the frame. It led to an indirect force transmission through the fixator with respect to the osteotomy, resulting in lower compressive loads, lower interfragmentary movements and higher mechanical stress on the frame. PMID- 21589680 TI - Repeated floating elbow injury after high-energy trauma. AB - The floating elbow is an uncommon injury occurring both in children and in adults. Two reports of rare variants of floating elbow injury have been published, but to the best of our knowledge, no recurrence of this injury has been described. We present a complex pattern of floating injury, occurring in the same limb 3 years after a floating elbow lesion, which included supracondylar fracture of the humerus and associated ipsilateral midshaft fracture of forearm bones. Satisfactory outcomes were finally obtained. This clinical case illustrates the importance of carefully assessing floating elbow injuries when they occur to optimize the surgical strategies and the adequate timing of the treatment. A comprehensive literature review of the floating elbow injuries is here reported. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11751-011-0102-7) contains supplementary material, which is available to authorized users. PMID- 21589681 TI - Patellar tendon reconstruction using LARS ligament: surgical technique and case report. AB - Neglected patella tendon ruptures require reconstruction using tendon grafts. The LARS ligament has been successfully used in cruciate and collateral knee ligament reconstruction. We present a technique using LARS ligament for the reconstruction of a chronic patella tendon rupture in a low-demand patient. The result after 1 year follow-up was deemed successful. PMID- 21589682 TI - Fascia research 2012: third international fascia research congress. PMID- 21589683 TI - Massage therapy techniques as pain management for erythromelalgia: a case report. AB - BACKGROUND: Erythromelalgia is characterized by temperature-dependent redness, pain, and warmth in one or more extremities. It may be a primary disease, or it may occur secondarily because of underlying illness. It is a chronic, debilitating condition often resistant to medical treatment. PURPOSE: The present report evaluates massage as a complementary therapy to reduce pain and other symptoms associated with erythromelalgia. PARTICIPANT: A 31-year-old female with a long-standing history of erythromelalgia bilaterally in the lower extremities presented with complaints of acute pain exacerbation, anxiety, decreased quality of sleep, and difficulty with activities of daily living for prolonged periods of time. She had no previous experience with massage therapy or any other complementary therapies. INTERVENTION: Massage therapy was introduced over the course of 9 treatments, each 1 hour in duration, using various massage therapy techniques, remedial exercise, and recommended home care. RESULTS: In this patient with erythromelalgia, effleurage and petrissage as massage therapy techniques provided temporary pain relief in the lower extremities and long-term benefits that relieved anxiety, which improved restorative sleep and increased the patient's participation in activities of daily living. CONCLUSIONS: For this treatment protocol, therapist observation and patient feedback suggest that massage therapy may lead to a state of increased relaxation, decreased stress, decreased muscle tension, and improved sleep. These positive effects may have an indirect role in the ability of the patient to cope with erythromelalgia day to day. PMID- 21589684 TI - Survey of the use of massage for children with cerebral palsy. AB - BACKGROUND: Conventional medicine and complementary and alternative medicine (CAM) are merging into the broader field of "integrative medicine." Massage is no longer considered complementary or alternative in some conventional medical circles today. PURPOSE: We aimed to determine the prevalence of massage use among children with cerebral palsy (CP) in the Pacific Northwest in the United States, the reasons that massage is being used, and the limits of recruitment for a future randomized controlled trial. METHODS: This study, the first step in a three-stage research plan, was conducted at the Neurodevelopmental and Neurology clinics at Seattle Children's Hospital, a tertiary pediatric hospital that provides service to patients primarily from Washington, Alaska, Montana, and Idaho. As a feasibility study (stage one), it precedes a planned pilot study (stage two), and subsequently, a full-scale randomized controlled trial (stage three) of whether massage can improve the health of children with CP. The study subjects-104 families with a child with CP ranging in age from 17 months to 21 years-were surveyed by the principal investigator and a research assistant in exam rooms at the hospital. RESULTS: In the families surveyed, 80% of the children had received massage at some point. Massage was currently being used in 51%, and trained professionals were providing the massage in 23%. Most families use massage for musculoskeletal relaxation, to improve quality of life, and to help their children sleep. Lower maternal income was associated with relatives as compared with professional massage therapists providing the massage. Massage therapy use by the mother and more severe CP were significantly associated with current use of massage for the child. CONCLUSIONS: Most children with CP in the Pacific Northwest have used massage. Most parents surveyed believe that massage is helpful to their child. Additional research is needed to determine whether massage should be routinely recommended for children with CP. PMID- 21589685 TI - Clinical, biomechanical, and physiological translational interpretations of human resting myofascial tone or tension. AB - BACKGROUND: Myofascial tissues generate integrated webs and networks of passive and active tensional forces that provide stabilizing support and that control movement in the body. Passive [central nervous system (CNS)-independent] resting myofascial tension is present in the body and provides a low-level stabilizing component to help maintain balanced postures. This property was recently called "human resting myofascial tone" (HRMT). The HRMT model evolved from electromyography (EMG) research in the 1950s that showed lumbar muscles usually to be EMG-silent in relaxed gravity-neutral upright postures. METHODS: Biomechanical, clinical, and physiological studies were reviewed to interpret the passive stiffness properties of HRMT that help to stabilize various relaxed functions such as quiet balanced standing. Biomechanical analyses and experimental studies of the lumbar multifidus were reviewed to interpret its passive stiffness properties. The lumbar multifidus was illustrated as the major core stabilizing muscle of the spine, serving an important passive biomechanical role in the body. RESULTS: Research into muscle physiology suggests that passive resting tension (CNS-independent) is generated in sarcomeres by the molecular elasticity of low-level cycling cross-bridges between the actomyosin filaments. In turn, tension is complexly transmitted to intimately enveloping fascial matrix fibrils and other molecular elements in connective tissue, which, collectively, constitute the myofascial unit. Postural myofascial tonus varies with age and sex. Also, individuals in the population are proposed to vary in a polymorphism of postural HRMT. A few people are expected to have outlier degrees of innate postural hypotonicity or hypertonicity. Such biomechanical variations likely predispose to greater risk of related musculoskeletal disorders, a situation that deserves greater attention in clinical practice and research. Axial myofascial hypertonicity was hypothesized to predispose to ankylosing spondylitis. This often-progressive deforming condition of vertebrae and sacroiliac joints is characterized by stiffness features and particular localization of bony lesions at entheseal sites. Such unique features imply concentrations and transmissions of excessive force, leading to tissue micro-injury and maladaptive repair reactions. CONCLUSIONS: The HRMT model is now expanded and translated for clinical relevance to therapists. Its passive role in helping to maintain balanced postures is supported by biomechanical principles of myofascial elasticity, tension, stress, stiffness, and tensegrity. Further research is needed to determine the molecular basis of HRMT in sarcomeres, the transmission of tension by the enveloping fascial elements, and the means by which the myofascia helps to maintain efficient passive postural balance in the body. Significant deficiencies or excesses of postural HRMT may predispose to symptomatic or pathologic musculoskeletal disorders whose mechanisms are currently unexplained. PMID- 21589686 TI - Integrating the international classification of functioning, disability, and health model into massage therapy research, education, and practice. AB - Without an increase in clearly defined and clinically significant outcomes research in massage therapy (MT), the practice is in jeopardy of remaining on the fringes of accepted and utilized therapeutic care. This reality will slow the integration of MT into routine preventive, rehabilitative, curative, and supportive care. The International Classification of Functioning, Disability, and Health (ICF) developed by the World Health Organization is a comprehensive model of functioning and disability that provides a universal taxonomy of human functioning that is recognized globally. Integration of the ICF model into MT research, education, and practice would provide a foundation for a common language, particularly in regard to examining outcomes of MT.Here, we review the dynamic and respected ICF model as it applies to massage research, outcomes dissemination, education, and practice, with these specific objectives:To describe the specific domains of the ICF modelTo apply the described ICF domains to current massage practice and researchTo discuss how integration of the ICF model enhances communication and translation among those within and to those outside the MT fieldThe ICF model is ideal for application to MT interests because it works outside the typical focus on pathology or a specific organ system. Instead, the ICF focuses on impairment or limitations in functioning associated with health conditions. The ICF also highlights and incorporates the complex interactions of environment and personal factors and the impact that those factors exert on the domains of body structure, activity, and participation. This interaction has unique implications for MT practitioners, researchers, and clients/patients. Furthermore, the ICF model provides a framework for classifying outcomes, which is a critical aspect of clinical research. PMID- 21589688 TI - PubMed Central Inclusion, Quertle Indexing, Outbound Reference Linking, and Editorial Board Successions: Encouraging Developments in the IJTMB's Evolution. PMID- 21589689 TI - Practitioner-generated massage therapy research. PMID- 21589690 TI - Effects of patterns of pressure application on resting electromyography during massage. AB - BACKGROUND: To increase the understanding of the physiological mechanisms by which massage therapy produces health benefits such as pain relief and anxiety reduction, the relationship between specific elements of massage and physiological outcomes must be addressed. PURPOSE: The effects on resting muscular activity of applying varying levels of pressure during massage were investigated. METHODS: In this clinical crossover study, conducted in a simulated clinical setting, human subjects (n = 25; mean age: 34.1 years) received 3 different levels of massage pressure to the legs. A licensed therapist applied pressure to the rectus femoris in a distal-to-proximal direction. Each volunteer received the 3 levels of pressure in 2 different orders-increasing (IP) and decreasing pressures (DP)-separated by at least 4 weeks. Surface electromyography (EMG) was used to measure muscle activity levels at baseline and after each pressure level. RESULTS: During the trials of IP, EMG did not vary significantly [Greenhouse-Geisser corrected analysis of variance F(1.71 df) = 0.30, p = 0.71]. During the trials of DP, EMG varied significantly [Greenhouse-Geisser corrected analysis of variance F(1.58 df) = 4.49, p = 0.03], with the largest variation, an increase of 235%, noted between baseline activity and activity after deep pressure. After application of light pressure, activity returned to baseline levels. Interestingly, the overall levels of force required to achieve subjective pressure levels as reported by the client were higher in the DP protocol than in the IP protocol (p < 0.02). CONCLUSIONS: These results suggest that the physiological response of the muscle depends on the pattern of applied pressure during massage. That finding is consistent with a mechanism by which light- or moderate-pressure massage (or a combination) may reduce the gain of spinal nociceptive reflexes. As those reflexes are elevated in chronic pain syndromes, pressure variation provides a possible mechanism for the relief of chronic pain by massage therapy. PMID- 21589691 TI - The effects of massage on pain, stiffness, and fatigue levels associated with ankylosing spondylitis: a case study. AB - OBJECTIVES: To study the effects of massage on pain, stiffness, and fatigue in a patient recently diagnosed with ankylosing spondylitis (AS). METHODS: A 47-year old woman with AS diagnosed 11 months earlier received 7 massages across a 28-day period. Her pain, stiffness, and fatigue were recorded using visual analogue scales daily during the study period. Spinal mobility was measured at each massage session with finger-to-floor measurements for both forward and lateral flexion. The client also used a daily journal to supply pertinent information on quality of life. RESULTS: Improvement was recorded in all dependent variables, with stiffness intensity showing the greatest improvement, to a final value of 0.75 from an initial value of 5. Duration of stiffness also showed improvement, to a final value of 1.2 from an initial value of 3.5. Improvement was also found in general pain (final value: 1; initial value: 4), fatigue (final value: 1.5; initial value 5), and forward and lateral flexion (forward flexion distance final: 4 inches; initial: 6 inches; lateral flexion, left distance: final, 16.5 inches; initial, 21 inches; right distance: final, 16.5 inches; initial, 20.5 inches). CONCLUSIONS: Massage shows promise as a treatment for symptoms associated with AS. Further study is needed to validate these effects and to determine the feasibility of massage as an adjunct to standard care for AS patients with mild-to-moderate symptoms of AS. PMID- 21589692 TI - A descriptive study of the practice patterns of massage new zealand massage therapists. AB - BACKGROUND: Massage therapy has grown in popularity, yet little is known globally or in New Zealand about massage therapists and their practices. PURPOSE AND SETTING: The aims of this study were to describe the practice patterns of trained Massage New Zealand massage therapists in New Zealand private practice, with regard to therapist characteristics; practice modes and settings, and therapy characteristics; referral patterns; and massage therapy as an occupation. RESEARCH DESIGN AND PARTICIPANTS: A survey questionnaire was mailed to 66 trained massage therapist members of Massage New Zealand who were recruiting massage clients for a concurrent study of massage therapy culture. RESULTS: Most massage therapists were women (83%), NZ European (76%), and holders of a massage diploma qualification (89%). Massage therapy was both a full- (58%) and part-time (42%) occupation, with the practice of massage therapy being the only source of employment for 70% of therapists. Nearly all therapists (94%) practiced massage for more than 40 weeks in the year, providing a median of 16 - 20 hours of direct client care per week. Most massage therapists worked in a "solo practice" (58%) and used a wide and active referral network. Almost all therapists treated musculoskeletal symptoms: the most common client issues or conditions treated were back pain/problem (99%), neck/shoulder pain/problem (99%), headache or migraine (99%), relaxation and stress reduction (96%), and regular recovery or maintenance massage (89%). The most frequent client fee per treatment was NZ$60 per hour in a clinic and NZ$1 per minute at a sports event or in the workplace. Therapeutic massage, relaxation massage, sports massage, and trigger-point therapy were the most common styles of massage therapy offered. Nearly all massage therapists (99%) undertook client assessment; 95% typically provided self care recommendations; and 32% combined other complementary and alternative medicine therapies with their massage consultations. CONCLUSIONS: This study provides new information about the practice of massage therapy by trained massage therapists. It will help to inform the massage industry and other health care providers, potential funders, and policymakers about the provision of massage therapy in the NZ health care system. PMID- 21589695 TI - Translational research queries, fascia research congress sequels, and beyond.... PMID- 21589693 TI - Gait characteristics, range of motion, and spasticity changes in response to massage in a person with incomplete spinal cord injury: case report. AB - PURPOSE: Our study set out to measure the effect of a specific routine of massage on gait characteristics, range of motion, and spasticity in a person with incomplete spinal cord injury. METHODS: This descriptive, pre-post case study, conducted at the outpatient program of a rehabilitation facility, used neuromuscular techniques in massage for a 42-year-old man with incomplete chronic C5 spinal cord injury. The massage was applied to the iliopsoas, triceps surae, and hamstring muscle groups for 3 consecutive days. MAIN OUTCOME MEASURES: Pre- and post-intervention testing included standard goniometric measurement of joint range of motion in the lower extremities, spasticity evaluation using the modified Ashworth scale, and evaluation of gait characteristics using GAITRite Walkway (CIR Systems, Havertown, PA, USA) pressure mapping for ambulation time, cadence, velocity, stride length, base of support, and single- and double-limb support. RESULTS: AFTER THE THERAPEUTIC INTERVENTION, THE FOLLOWING GAIT CHANGES WERE DEMONSTRATED: increase in velocity and cadence of gait, decrease in ambulation time, increase in stride length, and improvements in the percentages of the swing and stance phases of the gait cycle. CONCLUSIONS: Specific application of massage therapy influenced gait speed, stride length, and swing and stance phase percentages in one person with incomplete spinal cord injury. Further study is warranted to determine the extent to which massage may affect musculoskeletal and neural impairments that limit gait in people with incomplete spinal cord injury, and the method or routine whose application will yield the most benefit. PMID- 21589697 TI - Sustained manual loading of the fascial system can evoke tonic reactions: preliminary results. PMID- 21589696 TI - The effects of massage therapy on pain management in the acute care setting. AB - BACKGROUND: Pain management remains a critical issue for hospitals and is receiving the attention of hospital accreditation organizations. The acute care setting of the hospital provides an excellent opportunity for the integration of massage therapy for pain management into the team-centered approach of patient care. PURPOSE AND SETTING: This preliminary study evaluated the effect of the use of massage therapy on inpatient pain levels in the acute care setting. The study was conducted at Flagstaff Medical Center in Flagstaff, Arizona-a nonprofit community hospital serving a large rural area of northern Arizona. METHOD: A convenience sample was used to identify research participants. Pain levels before and after massage therapy were recorded using a 0 - 10 visual analog scale. Quantitative and qualitative methods were used for analysis of this descriptive study. PARTICIPANTS: Hospital inpatients (n = 53) from medical, surgical, and obstetrics units participated in the current research by each receiving one or more massage therapy sessions averaging 30 minutes each. The number of sessions received depended on the length of the hospital stay. RESULT: Before massage, the mean pain level recorded by the patients was 5.18 [standard deviation (SD): 2.01]. After massage, the mean pain level was 2.33 (SD: 2.10). The observed reduction in pain was statistically significant: paired samples t(52) = 12.43, r = .67, d = 1.38, p < .001. Qualitative data illustrated improvement in all areas, with the most significant areas of impact reported being overall pain level, emotional well-being, relaxation, and ability to sleep. CONCLUSIONS: This study shows that integration of massage therapy into the acute care setting creates overall positive results in the patient's ability to deal with the challenging physical and psychological aspects of their health condition. The study demonstrated not only significant reduction in pain levels, but also the interrelatedness of pain, relaxation, sleep, emotions, recovery, and finally, the healing process. PMID- 21589700 TI - Release of myofascial pain with deep cross-friction named "roptrotherapy". PMID- 21589698 TI - The use of mixed methods for therapeutic massage research. AB - Mixed methods research is the integration of quantitative and qualitative components in a research project. Whether you are reading or designing a mixed methods research project, it is important to be familiar with both qualitative and quantitative research methods and the specific purposes for which they are brought together in a study: triangulation, complementarity, expansion, initiation, or development. In addition, decisions need to be made about the sequencing and the priority or importance of each qualitative and quantitative component relative to the other components, and the point or points at which the various qualitative and quantitative components will be integrated.Mixed methods research is increasingly being recognized for its ability to bring multiple points of view to a research project, taking advantage of the strengths of each of the quantitative and qualitative components to explain or resolve complex phenomena or results. This ability becomes critical when complex healing systems such as therapeutic massage are being studied. Complex healing systems may have multiple physiologic effects, often reflected in changes throughout the patient's body. Additionally, the patient's experience of the treatment may be an important outcome. PMID- 21589699 TI - Muscle repositioning: combining subjective and objective feedbacks in the teaching and practice of a reflex-based myofascial release technique. AB - Muscle Repositioning (MR) is a new style of myofascial release that elicits involuntary motor reactions detectable by electromyography. This article describes the principal theoretical and practical concepts of MR, and summarizes a workshop presented October 31, 2009, after the Second International Fascia Research Congress, held at Vrije Universitiet, Amsterdam.The manual mechanical input of MR integrates the client's body segments into a block, which is evident as a result of the diagnostic manual oscillations the practitioner imparts to the client's body. Segmental integration is achieved when the client's body responds as a unit to the oscillatory assessment. It appears that manually sustaining the condition of segmental integration evokes involuntary muscle reactions, which reactions might correspond to mechanisms that maintain homeostasis, such as pandiculation. It might be that these reactions are part of the MR mechanism of action and underlie its clinically observed efficacy in the treatment of musculoskeletal disorders.For the practitioner and the client alike, segmental integration provides unique sensations. In teaching MR, these paired sensations can be used as kinesthetic feedback resources, because quality of touch can be guided by the client's reported sensations, which should match the practitioner's sensations. Another form of feedback with respect to quality of touch is the visually discernable degree of segmental integration. Finally, because the involuntary motor activity elicited by the MR touch can be objectively monitored through electromyography and possibly other instrumented measurements, the MR approach might yield objectivity, precision, and reproducibility-features seldom found in manual therapies. PMID- 21589701 TI - The fascial manipulation technique and its biomechanical model: a guide to the human fascial system. PMID- 21589702 TI - Resolving dilemmas through bodywork. AB - Pamela Ellen Ferguson and Debra Persinger, co-authors and co-editors of Sand to Sky-Conversations with Teachers of Asian Medicine (Bloomington, IN: iUniverse; 2008), interview Marianne Steele in Germany on her shiatsu and massage therapy work in various forms of trauma and posttraumatic stress disorder. The interview was conducted in a series of e-mail exchanges and telephone calls during late 2009 and early 2010 and is intended for a future German edition of Sand to Sky. PMID- 21589704 TI - The massage therapy foundation: focus on education. PMID- 21589705 TI - Massage therapy education online: student satisfaction and achievement, part I. AB - In recent years, providers of massage therapy education have, in growing numbers, started to use online technologies to support the learning processes of their students. Using a narrative review of the existing online learning literature, this paper aims to provide a solid pedagogical foundation for these early explorations. It identifies five key factors-instructional pedagogy, quality of instruction, interaction and communication, individual learner qualities, and the online interface-that contribute to student satisfaction and achievement in the online context. The relationships between those factors and the experience of the online learner are discussed with reference to maximization of student satisfaction and achievement. PMID- 21589706 TI - Treatment of knee arthrofibrosis and quadriceps insufficiency after patellar tendon repair: a case report including use of the graston technique. AB - Arthrofibrosis of the knee is a surgical complication that can limit range of motion, inhibit muscle activity, and decrease patient function. Optimal conservative treatment has not been well established in the literature, leaving a clinician with limited evidence for treatment planning. Described here is part of the rehabilitative course of care for a patient with arthrofibrotic limitations after a mid-substance patellar tendon repair with augmentation. Marked limitations in knee flexion range of motion and quadriceps activity were addressed using the Graston Technique to deal with soft-tissue adhesions; traditional physical therapy care was also provided. Clear improvement in range of motion and quadriceps activity and function was noted over the course of 5 treatments during 1 month. Treatment process and clinical reasoning are offered to promote understanding and to facilitate future inquiry. PMID- 21589709 TI - The influence of practice standards on massage therapists' work experience: a phenomenological pilot study. AB - This original research is framed in phenomenological methodology, based on interviews conducted and interpreted using qualitative research methods. The findings suggest that, because of both direct and indirect factors (such as the nebulous nature of the work, general isolation in work conditions, and physical concerns), massage therapists perform their work with multiple sources of ambiguity that are potentially anxiety-causing. Licensing offers potential relief for this anxiety, but also generates a new set of frustrations and work concerns. The new concerns include the potential that practice will change to adapt to non relevant standards and the difficulty of defining a body of work that frequently defies a "one size fits all" categorization. This pilot study suggests several areas for further exploration and also demonstrates the generativity of phenomenological methodology for research related to massage therapy. PMID- 21589710 TI - Measuring the effects of massage on exercise performance and cardiopulmonary response in children with and without heart disease: a pilot study. AB - BACKGROUND: Congenital heart disease, a common and serious birth defect, affects 8 per 1000 live-born infants. Decreased exercise capacity and development of obesity is common in this population. These children may benefit from therapies, such as massage therapy, that could enhance cardiovascular and skeletal muscle function when they exercise. PURPOSE: A pilot study conducted at the pediatric cardiology clinic of the Mattel Children's Hospital of the University of California-Los Angeles examined the safety and feasibility of measuring the effects of pre-exercise massage on exercise performance and cardiopulmonary response in children with and without heart disease. PARTICIPANTS AND METHODS: SIXTEEN CHILDREN (MEAN AGE: 9.2 +/- 2.2 years) participated in the study. Ten participants had various forms of heart disease, and six children were healthy. A female certified massage therapist with specialized training in pediatric massage provided a 30-minute massage to the participants. Using a standard protocol, each participant underwent two exercise tests: one test with and one without pre exercise massage. Heart rate, blood pressure, and oxygen uptake (VO(2)) were measured in the participants. RESULTS: All recruited participants completed the study. No adverse events occurred during any of the exercise tests or massage sessions. Measurements during exercise with or without a preceding massage were compared, and the pre-exercise massage condition yielded a significantly higher heart rate and higher minute ventilation. Measurements during exercise in children with heart disease and in healthy participants showed no significant differences in peak heart rate, blood pressure, peak VO(2), peak work rate, minute ventilation, or respiratory quotient. CONCLUSIONS: In this study, peak heart rate, peak VO(2), and peak minute ventilation were higher when children received a massage before exercise testing. Larger studies will be needed to investigate the strength of this finding. Future studies should include measurements of anxiety and psychological factors in addition to cardiopulmonary measures. PMID- 21589711 TI - The ethical implications of research and education in the massage therapy profession. AB - As a therapist operating my own practice, I am constantly reminded of the ethical aspects of my work in dealing with situations involving clients and the everyday running of my business. Professional boundaries and ethical practices are recognized within our profession as an important aspect of our work, as evidenced by mandatory classes on ethics in most U.S. states and also by the clearly stated ethical codes and practices set out by our professional organizations. The reasoning behind these measures is clear. Ethical declarations and a thorough understanding of them and their application are needed. They set standards of integrity. They help to define massage therapy as a profession and have significant repercussions on how massage therapists are perceived by the public. PMID- 21589712 TI - Faculty perception of and resistance to online education in the fields of acupuncture, chiropractic, and massage therapy. AB - This paper reports findings of a research study undertaken to determine the attitudes and perceptions of acupuncture, chiropractic, and massage therapy faculty with regard to online learning within their respective disciplines, and to determine how they might be persuaded to teach online. The study surveyed faculty teaching at schools in these three fields and followed up with additional interviews. The study results indicate that, in general, acupuncture, chiropractic, and massage therapy faculty lack awareness of the capabilities of online education and the elements of good online learning. There is also a perception that what they teach cannot be taught online because of its kinesthetic requirements. The faculty hold this perception in spite of the success of medical science and related health care fields in the online environment, and they do not seem to separate the kinesthetic from the didactic. The present study indicates that faculty opinions about online instruction in this alternative type of education range from being willing to look at the potential of online education to outright dismissing it. PMID- 21589713 TI - International Journal of Therapeutic Massage and Bodywork (IJTMB): A Second-Year Retrospective Reflecting Google Analytics and Open Journal Systems Sources. PMID- 21589714 TI - On Refining Certain IJTMB Features. PMID- 21589715 TI - Affective massage therapy. PMID- 21589716 TI - Value of qualitative research in the study of massage therapy. AB - Qualitative inquiry is increasingly used in health research because it is particularly suited to the study of complex topics or issues about which little is known and concerning which quantification cannot easily create or effectively convey understanding. By exploring the lived experience of people providing and receiving massage therapy and the meaning that those people ascribe to those experiences, in-depth understanding of the nature of massage therapy and of how it affects people's lives is possible. Qualitative research may also provide insights into the outcomes, process and context of massage therapy that cannot be fully achieved through quantification alone.The purpose of the present article is to describe qualitative research and to discuss its value to the massage therapy profession. The target audience is massage therapists who want to be able to better understand the research literature, novice massage therapy researchers who are unfamiliar with qualitative research, and teachers of research methods courses in massage therapy training programs who want to include qualitative research methods in their curriculum. PMID- 21589717 TI - Massage therapy protocol for post-anterior cruciate ligament reconstruction patellofemoral pain syndrome: a case report. AB - BACKGROUND: The intent of the present study was to determine the effectiveness of massage therapy in the rehabilitation of post-anterior cruciate ligament reconstruction patellofemoral pain syndrome. The primary complications following surgical repair of the anterior cruciate ligament-classified as patellofemoral pain syndrome-are hamstring flexion contracture and quadriceps weakness, leading to patellofemoral dysfunction and retropatellar pain. METHODS: Treatment included lymphatic drainage, myofascial release, neuromuscular techniques including trigger point release, muscle energy techniques and cross-fiber friction. Orthopedic physical assessment tests were used to chart changes in patellofemoral function and changes in range of motion in the knee during the course of the massage interventions. Subjective reporting on pain level and function were also documented. RESULTS: A decrease in pain level, hamstring flexion contracture and lateral tracking of the patella were documented. CONCLUSION: Massage therapy was determined to be an effective complementary therapy in the treatment of patellofemoral pain syndrome. PMID- 21589719 TI - On qualitative research, outcome measures, and the fostering of professional dialogue. PMID- 21589720 TI - A Qualitative Investigation into Why the Motivation of Massage Therapy Students Changes over the Course of Their Professional Education. AB - PURPOSE: In previous research, the motivation of massage therapy students was observed to change between commencement of their professional studies and entry into practice. The change involved a decrease in intrinsic motivation (associated with altruism) and an increase in extrinsic motivation (associated with the prospect of external rewards). This paper reports on the influences underlying those changes. METHODS: The research used a qualitative design in which data were collected during a series of individual in-depth semi-structured interviews with massage therapy graduates, just after completion of a 2-year (2200-hour) full time program. After informed consent was obtained, interviews were taped, transcribed, and analyzed, resulting in identification of a number of themes and subthemes. RESULTS: Previously noted changes in student motivation involved an increase in the influence of extrinsic rewards and a decrease in motivation related to helping and working with people. The findings of the present study suggest that these changes are explained by two main themes, each with a number of subthemes. The first theme, The Reality of Life in Practice, is associated with two subthemes: Debt Load, and Effectiveness in Achieving Positive Health Outcomes. The second theme, An Evolving Self-Image As a Health Care Professional, is associated with three sub-themes: Rigor/Intensity of the Educational Program, Developing Perspective of Massage Therapy As a Career, and Interaction with Faculty. CONCLUSIONS: The data suggest that the change in motivation noted in previous work (increased extrinsic motivation and decreased intrinsic motivation) is influenced in different ways by each identified theme. Although schools must be vigilant in ensuring that their programs support the humanistic mission of health care, the present study indicates that the change in motivation noted in earlier work is not sinister. Rather, it appears to be related to the development of a realistic perspective of life as a health care practitioner, which departs from the more naive expectations of students when they commence their professional studies. PMID- 21589722 TI - Letter to the editor. PMID- 21589721 TI - IN-CAM Outcomes Database: Its Relevance and Application in Massage Therapy Research and Practice. AB - One of the most commonly used complementary and alternative medicine (CAM) modalities in North America is massage therapy (MT). Research to date indicates many potential health benefits of MT, suggesting that ongoing research efforts to further elucidate and substantiate preliminary findings within the massage profession should be given high priority. Central to the development of a sound evidence base for MT are the use of valid, reliable, and relevant outcome measures in research, and practice in assessing the effectiveness of MT. The purpose of the present article is to introduce MT researchers and massage therapists interested in using outcome measures in research and clinical practice to the IN-CAM Outcomes Database website by describing the Outcomes Database and identifying its utility in MT research and practice. The IN-CAM Outcomes Database is a centralized location where information on outcome measures is collected and made accessible to users. Outcome measures are organized in the database within the Framework of Outcome Domains. The Framework includes health domains relevant to conventional medicine and CAM alike, and health domains that have been identified as important to CAM interventions. Users of the website may search for information on a specific outcome measure, plan research projects, and engage in discussions related to outcomes assessment in the CAM field with other users and with members of the CAM research community. As the MT profession continues to evolve and move toward evidence-informed practice, the IN-CAM Outcomes Database website can be a valuable resource for MT researchers and massage therapists. PMID- 21589723 TI - Response to dylan Thomas lott. PMID- 21589724 TI - Letter to the editor. PMID- 21589725 TI - Response to pamela fitch. PMID- 21589727 TI - Second international fascia research congress. AB - Findings from papers published by key speakers at the 2007 Fascia Research Congress are presented in preparation for the second congress, October 2009, in Amsterdam.The role of fascia is demonstrated in new scientific findings in mechanotransduction between the cytoskeletal structure and the extracellular matrix, and its implications for health and disease.the presence of contractile cells (myofibroblasts) within the fascial fabric. Clinicians are interested in their role in creating contractile tonus in the fascial fabric-how myofibroblasts form, how they are activated, and their influence on passive muscle tonus.the biomechanical properties of fascial tissues: creep, relaxation, hysteresis, effect of sustained spinal flexion on lumbar tissues, strain-induced hydration changes, myofascial manipulation, and fascial viscoelastic deformation. These properties underlie the response of these tissues to therapy.how fascia is innervated, and how proprioception and pain are created, detected, and modulated by the spinal cord and the rest of the nervous system.forms of mechanical signaling within the fascial matrix, such as the tugging in the collagen matrix created by twisting acupuncture needles.new techniques for measurement of fascial motion in living tissue. PMID- 21589730 TI - Letter to the editor. PMID- 21589728 TI - Children with cancer and blood diseases experience positive physical and psychological effects from massage therapy. AB - BACKGROUND: Previous research has shown positive effects from massage therapy (MT) for premature infants and for children with asthma, arthritis, and other illnesses. Although these effects have been demonstrated, MT research on children with cancer and blood disease is needed. PURPOSE AND SETTING: The present study, conducted at the Cancer Center, Shands Hospital, at the University of Florida, Gainesville, measured the physical and psychological effects of MT on pediatric oncology and hematology patients. The participants were 30 children with cancer or blood disease, ages 6 months to 17 years. RESEARCH DESIGN: This randomized, non-blinded prospective study used measures of physical health and mental wellbeing that were completed before, during, and after four MT sessions were implemented. Descriptive statistics, one-way between-subjects analysis of variance, and an independent-samples t-test were used to analyze the data. INTERVENTION: The treatment group received 20-minute sessions of Swedish MT once daily for approximately 4 days (inpatients), or once weekly for approximately 4 weeks (outpatients); the control group received no MT. RESULTS: Between-groups analyses indicated significant psychological improvements for the MT group on state anxiety (F(1,58) = 16.79, p < 0.000), trait anxiety (F(1,58) = 3.95, p < 0.000), and emotional state (F(1,238) = 42.39, p < 0.001)]. Between-groups analyses indicated significant physical improvements for the MT group on muscle soreness (F(1,238) = 38.96, p < 0.001), discomfort (F(1,238) = 50.16, p < 0.001), respiratory rate (F(1,237) = 22.47, p < 0.000)], and overall progress (t(28) = 25.55, p < 0.000). No significant differences were found between groups on parent completed ratings of their child's physical or psychological health, pulse rate, or blood pressure. CONCLUSIONS: In children with cancer and blood diseases, MT can reduce psychological and physical distress and can have a positive effect on quality of life. PMID- 21589732 TI - International journal of therapeutic massage and bodywork: a first-year retrospective view reflecting google analytics and open journal systems sources. PMID- 21589729 TI - Directions and dilemmas in massage therapy research: a workshop report from the 2009 north american research conference on complementary and integrative medicine. AB - BACKGROUND: Massage therapy (MT) is widely used and expanding rapidly, but systematic research on its mechanisms and effects has, in contrast with many other therapeutic fields, a short history. PURPOSE: To take stock of the current state of MT research and to explore approaches, directions, and strategies with the potential to make the next two decades of MT research optimally productive. SETTING: The 2009 North American Research Conference on Complementary and Integrative Medicine held in Minneapolis, Minnesota. METHOD: Using a modified Delphi method, the study authors led an interactive workshop that aimed to identify established MT research findings, needed MT research, weaknesses and limitations in currently available MT research, and directions to pursue in the next two decades of MT research. PARTICIPANTS: The thirty-seven conference attendees-including MT researchers, educators, and practitioners, and other health care practitioners who already work interprofessionally with MT-actively participated in the workshop and ensured that a diversity of perspectives were represented. RESULTS: The MT field has made rapid and laudable progress in its short history, but at the same time this short history is probably the main reason for most of the current shortcomings in MT research. Drawing on a diversity of backgrounds, workshop participants identified many opportunities and strategies for future research. CONCLUSION: Though lost time can never be recovered, the field's late start in research should not be allowed to be a demoralizing handicap to progress. Modern scientific methods and technologies, applied to the range of directions and dilemmas highlighted in this report, can lead to impressive progress in the next twenty years of MT research. PMID- 21589733 TI - Fascia Research II: Second International Fascia Research Congress. PMID- 21589734 TI - Understanding the process of fascial unwinding. AB - BACKGROUND: Fascial or myofascial unwinding is a process in which a client undergoes a spontaneous reaction in response to the therapist's touch. It can be induced by using specific techniques that encourage a client's body to move into areas of ease. Unwinding is a popular technique in massage therapy, but its mechanism is not well understood. In the absence of a scientific explanation or hypothesis of the mechanism of action, it can be interpreted as "mystical." PURPOSE: This paper proposes a model that builds on the neurobiologic, ideomotor action, and consciousness theories to explain the process and mechanism of fascial unwinding. HYPOTHETICAL MODEL: During fascial unwinding, the therapist stimulates mechanoreceptors in the fascia by applying gentle touch and stretching. Touch and stretching induce relaxation and activate the parasympathetic nervous system. They also activate the central nervous system, which is involved in the modulation of muscle tone as well as movement. As a result, the central nervous system is aroused and thereby responds by encouraging muscles to find an easier, or more relaxed, position and by introducing the ideomotor action. Although the ideomotor action is generated via normal voluntary motor control systems, it is altered and experienced as an involuntary response. CONCLUSIONS: Fascial unwinding occurs when a physically induced suggestion by a therapist prompts ideomotor action that the client experiences as involuntary. This action is guided by the central nervous system, which produces continuous action until a state of ease is reached. Consequently, fascial unwinding can be thought of as a neurobiologic process employing the self-regulation dynamic system theory. PMID- 21589735 TI - The integrated taxonomy of health care: classifying both complementary and biomedical practices using a uniform classification protocol. AB - BACKGROUND: Since the late 1980s, several taxonomies have been developed to help map and describe the interrelationships of complementary and alternative medicine (CAM) modalities. In these taxonomies, several issues are often incompletely addressed: A simple categorization process that clearly isolates a modality to a single conceptual categoryClear delineation of verticality-that is, a differentiation of scale being observed from individually applied techniques, through modalities (therapies), to whole medical systemsRecognition of CAM as part of the general field of health care METHODS: DEVELOPMENT OF THE INTEGRATED TAXONOMY OF HEALTH CARE (ITHC) INVOLVED THREE STAGES: Development of a precise, uniform health glossaryAnalysis of the extant taxonomiesUse of an iterative process of classifying modalities and medical systems into categories until a failure to singularly classify a modality occurred, requiring a return to the glossary and adjustment of the classifying protocol RESULTS: A full vertical taxonomy was developed that includes and clearly differentiates between techniques, modalities, domains (clusters of similar modalities), systems of health care (coordinated care system involving multiple modalities), and integrative health care. Domains are the classical primary focus of taxonomies. The ITHC has eleven domains: chemical/substance-based work, device-based work, soft tissue-focused manipulation, skeletal manipulation, fitness/movement instruction, mind-body integration/classical somatics work, mental/emotional based work, bio-energy work based on physical manipulation, bio-energy modulation, spiritual-based work, unique assessments. Modalities are assigned to the domains based on the primary mode of interaction with the client, according the literature of the practitioners. CONCLUSIONS: THE ITHC HAS SEVERAL STRENGTHS: little interpretation is used while successfully assigning modalities to single domains; the issue of taxonomic verticality is fully resolved; and the design fully integrates the complementary health care fields of biomedicine and CAM. PMID- 21589736 TI - Letter to the editor. PMID- 21589738 TI - The 2010 highlighting massage therapy in complementary and integrative medicine research conference. PMID- 21589739 TI - Communicating about fascia: history, pitfalls, and recommendations. AB - The modern reader and author need to be aware of possible ambiguities and misunderstandings stemming from different meanings of the word "fascia" because the general meaning of the term can be so vague as to imply little more than some form of connective tissue. "Fascia" encompasses both loose and dense, superficial and deep, and multiple- and single-layered connective tissues. To foster communication, we here suggest twelve specific terms to describe specified aspects of fascial tissue:Dense connective tissueAreolar connective tissueSuperficial fasciaDeep fasciaIntermuscular septaInterosseal membranePeriostNeurovascular tractEpimysiumIntra- and extramuscular aponeurosisPerimysiumEndomysium. PMID- 21589740 TI - The architecture of the connective tissue in the musculoskeletal system-an often overlooked functional parameter as to proprioception in the locomotor apparatus. AB - The architecture of the connective tissue, including structures such as fasciae, sheaths, and membranes, is more important for understanding functional meaning than is more traditional anatomy, whose anatomical dissection method neglects and denies the continuity of the connective tissue as integrating matrix of the body.The connective tissue anatomy and architecture exhibits two functional tendencies that are present in all areas of the body in different ways and relationships. In body cavities, the "disconnecting" quality of shaping space enables mobility; between organs and body parts, the "connecting" dimension enables functional mechanical interactions. In the musculoskeletal system, those two features of the connective tissue are also present. They cannot be found by the usual analytic dissection procedures. An architectural description is necessary.This article uses such a methodologic approach and gives such a description for the lateral elbow region. The result is an alternative architectural view of the anatomic substrate involved in the transmission and conveyance of forces over synovial joints. An architectural description of the muscular and connective tissue organized in series with each other to enable the transmission of forces over these dynamic entities is more appropriate than is the classical concept of "passive" force-guiding structures such as ligaments organized in parallel to actively force-transmitting structures such as muscles with tendons.The discrimination between so-called joint receptors and muscle receptors is an artificial distinction when function is considered. Mechanoreceptors, also the so-called muscle receptors, are arranged in the context of force circumstances-that is, of the architecture of muscle and connective tissue rather than of the classical anatomic structures such as muscle, capsules, and ligaments. In the lateral cubital region of the rat, a spectrum of mechanosensitive substrate occurs at the transitional areas between regular dense connective tissue layers and the muscle fascicles organized in series with them. This substrate exhibits features of type and location of the mechanosensitive nerve terminals that usually are considered characteristic for "joint receptors" as well as for "muscle receptors."The receptors for proprioception are concentrated in those areas where tensile stresses are conveyed over the elbow joint. Structures cannot be divided into either joint receptors or muscle receptors when muscular and collagenous connective tissue structures function in series to maintain joint integrity and stability. In vivo, those connective tissue structures are strained during movements of the skeletal parts, those movements in turn being induced and led by tension in muscular tissue. In principle, because of the architecture, receptors can also be stimulated by changes in muscle tension without skeletal movement, or by skeletal movement without change in muscle tension. A mutual relationship exists between structure (and function) of the mechanoreceptors and the architecture of the muscular and regular dense connective tissue. Both are instrumental in the coding of proprioceptive information to the central nervous system. PMID- 21589742 TI - Investigating the relation of social support functions and the demographic features of diabetic patients. AB - BACKGROUND: Social support is a form of social capital which can be related to the health of patients. Chronic diseases, such as diabetes, are incurable but they can be controlled. However, the patient is always facing stressful physical, mental and social factors. Therefore, he needs to receive different kinds of supports. The present research aimed to determine the factors of social support in diabetic patients and its relation with the demographic features of the patients. METHODS: This descriptive, cross-sectional study was conducted in 2008. The population of the study was all of the dia-betic patients of Khorramabad who went to the clinics for treatment. Among this population, 150 cases were selected and a questionnaire including a demographic section and a social support section was used for data collection. Social support was assessed by integrating and balancing four standard questionnaires of social support for diabetic patients. RESULTS: The results revealed that factors of social support have not been optimal in 59% of the cases. Among all factors, emotional support scored the highest (36.8%). In addition, age, sex, job, education, and the duration of disease had statistically significant relationship with some of the factors of social support. CONCLUSIONS: Due to non-optimality of some factors and effects of some demographic variables in receiving social support, it can be recommended that authorities should plan programs with consulting, educational and instrumental contents in order to promote patient's reception of social support from different support sources. PMID- 21589743 TI - Effects of two educational method of lecturing and role playing on knowledge and performance of high school students in first aid at emergency scene. AB - BACKGROUND: This study aimed to investigate the effects of two educational methods on students' knowledge and performance regarding first aid at emergency scenes. METHODS: In this semi-experimental study, the sample was selected randomly among male and female public high school students of Isfahan. Each group included 60 students. At first the knowledge and performance of students in first aid at emergency scene was assessed using a researcher-made questionnaire. Then necessary education was provided to the students within 10 sessions of two hours by lecturing and role playing. The students' knowledge and performance was as sessed again and the results were compared. RESULTS: It was no significant relationship between the frequency distribution of students' age, major and knowledge and performance before the educational course in the two groups. The score of knowledge in performing CPR, using proper way to bandage, immobilizing the injured area, and proper ways of carrying injured person after the education was significantly increased in both groups. Moreover, the performance in proper way to bandage, immobilizing injured area and proper ways of carrying injured person after educational course was significantly higher in playing role group compared to lecturing group after education. CONCLUSIONS: Iran is a developing country with a young generation and it is a country with high risk of natural disasters; so, providing necessary education with more effective methods can be effective in reducing mortality and morbidity due to lack of first aid care in crucial moments. Training with playing role is suggested for this purpose. PMID- 21589744 TI - Respecting to patients' autonomy in viewpoint of nurses and patients in medical surgical wards. AB - BACKGROUND: Respect to patients' autonomy is a cornerstone of medical ethics and nurses have a key role in respecting patients' autonomy. In review of Iranian literature, there is no study investigating the respect to patients' autonomy during nursing cares. The aim of the present study was to compare nurses and patients' perceptions regarding respecting to patients' autonomy during nursing care. METHODS: This study had a comparative descriptive design and conducted in 2008. The study population was consisted of all nursing staff (n = 79) working in three related hospitals of Tabriz University of Medical Science using census sampling. Also, 187 hospitalized patients in these hospitals participated with convenience sampling. To assess the respecting to patients' autonomy, two parallel questionnaires were prepared. Data analysis was done in SPSS using Mann Whitney and Kruskal-Wallis tests and Spearman correlation coefficient. RESULTS: Nurses reported that they respected to patients' autonomy, but patients believed that their autonomy was not respected. Also, there was a significant statistical relation between perception of health status, need for nursing care, and age of patient and their report of respect to their autonomy. CONCLUSIONS: There is an exiting difference in viewpoint of nurses and patients regarding respecting to patient autonomy. But, because of insufficient evidence more studies are recommended. PMID- 21589745 TI - The effect of physical exercise on physical and psychological problems. AB - BACKGROUND: Despite therapeutic effect of hemodialysis in end stage renal disease (ESRD) patients, these patients encounter different physical and psychological tensional factors. Physical exercises have beneficial physical and psychological effects on patients under hemodialysis as one of the accessory therapeutic methods. As few studies have been done about the effects of physical exercise on physical and psychological problems in Iran than other countries, we assessed the effect in patients under hemodialysis. METHODS: For this purpose, 43 qualified hemodialysis patients receiving hemodialysis in hospitals of Tabriz University of Medical Sciences were included, but only 35 patients did the exercises for 8 weeks completely. Exercise program was done for 1 hour every session and was composed of ergometer, treadmill and ball playing. Before and after intervention data were collected by interview through a synthetic and adjusted questionnaire. At the end of the intervention, two special questions were added about the improvement of physical and psychological problems. Paired t-test was used to compare the scores of before and after intervention. RESULTS: There were significant differences between scores of before and after intervention considering physical problems including sleep, pain and discomfort, daily activities, and physical function; but about sexual activity, there was not a significant difference between scores of before and after intervention. Psychological problems improved after doing exercises too. About first special question, 85.6% of patients expressed an improvement in physical conditions and about second special question, 91.4% of patients expressed an improvement in psychological conditions. CONCLUSIONS: Since physical exercise improves the physical (physical function, daily activities, pain and discomfort, sleep), and psychological problems, it is suggested that responsible people prepare equipment for these patients, until they do exercise forever. Nurses would present them the ways of a correct exercise, and doing it in days after hemodialysis, in order to improve physical, and psychological problems in hemodialysis patients, and finally to enhance their quality of life. PMID- 21589746 TI - Type of body fat distribution in postmenopausal women and its related factors. AB - BACKGROUND: The type of body fat distribution has an important role for identifying risk of diseases. One of the simple anthropometric indexes for estimating type of body fat distribution is waist circumference index. This study is aimed to determine the type of body fat distribution in postmenopausal women and its related factors. METHODS: This is a cross sectional descriptive analytical study. Samples were 278 postmenopausal women in Isfahan who were selected by stratified sampling and then were invited to 64 health centers of Isfahan. Data was gathered using a questionnaire and standard meter. Data was analyzed using SPSS software and descriptive and inferential statistics. RESULTS: Results showed that in postmenopausal women the mean of waist circumference index was 93.63 (10.66) and its range was 54 to 119 cm. There was a meaningful relation between job, educational status, total pregnancies, total deliveries, age of first pregnancy, lactation history and menopausal age with waist circumference index. CONCLUSIONS: Results showed that the type of body fat distribution of postmenopausal women is of android type. Considering side effects of this kind of distribution, necessary teachings about healthy eating, movement and exercises must be given to women of these ages. PMID- 21589747 TI - Study on effect of massage therapy on pain severity in orthopedic patients. AB - BACKGROUND: Pain as a main social problem has involved millions of people. Usually pharmaceutical methods use for treating pain but they have side effects which make them less effective. Massage is one of the effective ways for reducing pain after surgery. The aim of this study was to evaluate the effect of massage therapy on pain severity in orthopedic patients. METHODS: This is a clinical trial study on 60 arthroscopic knee surgery patients who were hospitalized in men's orthopedic ward of Al-Zahra and Kashani hospitals. A two part questionnaire was used for collecting data. Samples were selected using easy continuity method and then they were randomly divided into two groups. In intervention group, besides routine treatments, patients were massaged by the researcher for 20 minutes each day and pain severity was evaluated before and after the massage. Data was analyzed using descriptive and inferential statistics and SPSS software. RESULTS: Results showed that there was a meaningful different between mean score of pain severity before and after the massage in intervention group (p < 0.001) but this difference wasn't meaningful in control group (p = 0.32). Also comparing the mean score of pain severity in both groups before any interventions showed that there were no meaningful differences (p = 0.34) but this difference was meaningful after interventions (p = 0.001). CONCLUSIONS: Considering massage as a safe and effective intervention, it could be used as an easy, cheap and executable method for treating pain in all medical health care centers and even at patient's home. PMID- 21589748 TI - Effects of therapeutic touch on the vital signs of patients before coronary artery bypass graft surgery. AB - BACKGROUND: Currently healthy heart word considered to be the objective of community health applications in many countries of the world because cardiovascular diseases are the most important factor in mortality of humans, worldwide. Coronary artery bypass graft surgery is one of the most common surgery procedures for these patients. The purpose of this study is to assess the impact of therapeutic touch on medical vital signs of patients before coronary artery bypass graft surgery. METHODS: The present study is a clinical trial with 44 samples that were selected by easy sampling method and based on two separate lists of random numbers for both men and women; they were divided into two groups. In the therapeutic touch group, intervention therapy was applied on patents for 20 minutes. Data was analyzed using descriptive and inferential statistics. RESULTS: Test results showed that there was a significant difference between the mean pulse rate before and after intervention in both groups (p < 0.001). Results also showed that there was a significant difference between the average number of breathing before and after intervention in both groups (p < 0.001). CONCLUSIONS: Considering the effects of therapeutic touch therapy as a safe and effective intervention on the patients which were revealed in this study, this technique can be used as a simple, cheap and applicable technique in all health care centers to help these patients. PMID- 21589749 TI - Effect of aquatic exercise on the multiple sclerosis patients' quality of life. AB - BACKGROUND: The appearance of a new innovation in medical science named aquatic exercise has faded the effects of other preventive exercises in patients with multiple sclerosis to a large extent. Since exercise is one of the beneficial factors in enhancement of quality of life, researchers decided to investigate the role of aquatic exercise on the patients' quality of life. METHODS: This study is a semi experimental research that was performed on 22 patients chosen by simple random sampling. The standard SF-36 questionnaire was used and data was gathered by interview before and after aquatic exercise. Data was analyzed by paired t test via SPSS software version 10. RESULTS: The mean age of participants was 32.86 years. 68.2% of participants were married and 45.5% of them were high school graduates. The paired t test showed the significant differences between different aspects of quality of life before and after aquatic exercise. CONCLUSIONS: The findings of this research revealed that aquatic exercise has enhanced the aspects of multiple sclerosis patients' quality of life; therefore the program of this exercise is suggested to be used for the patients with multiple sclerosis along with other methods of treatment for improvement in quality of their lives. PMID- 21589750 TI - Biochemical and histologic changes in rats after prolonged administration of the crude aqueous extract of the leaves of Vitex grandifolia. AB - BACKGROUND: In recent times, many herbal remedies are used to treat variety of ailments. The leaves of Vitex grandifolia is claimed to be effective in the treatment of diabetes mellitus and as a diuretic in the treatment of high blood pressure. However, there are no scientific reports on the therapeutic benefits or toxicity of this plant. This study therefore investigated the effect of prolonged administration of the aqueous extract of the leaves of this plant in Sprague Dawley rats. METHODS: The plant leaves (No. FHI 107055) were dried at 40 degrees C, powdered and extracted at room temperature in water (pH 5.72) by percolation. Extract was dried in vacuo to give a yield of 27.32 %w/v. The extract, 0.5-2 g/kg b. wt. was administered by gastric probe to rats for 14 days. The liver and kidney functions, blood chemistry, histopathologic alterations of vital organs and extract effect on rats b. wt. were investigated. RESULTS: V. grandifolia caused significant increase in the serum electrolytes, creatinine, and liver function enzyme dose dependently compared with the control (P<= 0.001). The extract had no effect on the heart; however, the architecture of the liver, kidney, and lungs were significantly altered in the treated groups compared with the control. The treated rats had significantly reduced body weight compared with the control (P<= 0.001). Major clinical signs observed in the treated groups were polydipsia, polyuria, puffiness of hair, and calmness, which were consistent with increase in dose of the extract. CONCLUSION: It could be clearly concluded that prolonged administration of the aqueous leaf extract of V. grandifolia at the dose used in this study tends to be toxic to the rats. Its use in folkloric medicine should be with utmost care. PMID- 21589751 TI - 1,1-Diphenyl-2-picrylhydrazyl radical and superoxide anion scavenging activity of Rhizophora mangle (L.) bark. AB - BACKGROUND: Rhizophora mangle (L.) produce a variety of substances that possesses pharmacological actions. Although it shown antioxidant properties in some assays, there is no available information about its effect on some free radical species. So the objective of the present research is to evaluate the DPPH radical and superoxide anion scavenging properties of R. mangle extract and its polyphenol fraction. METHODS: Rhizophora mangle (L.) bark aqueous extract and its major constituent, polyphenols fraction, were investigated for their antioxidant activities employing 2 in vitro assay systems: 1,1-diphenyl-2-picrylhydrazyl (DPPH) and superoxide anion radicals scavenging. RESULTS: IC(50) for DPPH radical scavenging activity was 6.7 ug tannins/mL for extract and 7.6 ug tannins/mL for polyphenolic fraction. The extract showed better activity than its fraction (P < 0.05) in the DPPH radicals reducing power. Polyphenolic fraction exhibited better superoxide anion scavenging ability (IC(50) = 21.6 ug tannins/mL) than the extract (IC(50) = 31.9 ug tannins/mL). Antioxidant activities of both samples increased with the rise of tannins concentration. The comparison of regression lines showed significant differences (P < 0.05) between extract and its polyphenolic fraction in both assays, indicating that extract was more effective in DPPH radical scavenging than its fraction at tannin concentrations below the crossing point of both lines, while that fraction was more effective than extract inhibiting the superoxide anions generation. CONCLUSIONS: R. mangle aqueous extract showed a potent antioxidant activity, achieved by the scavenging ability observed against DPPH radicals and superoxide anions. Regarding its polyphenolic composition, the antioxidant effects observed in this study are due, most probably, to the presence of polyphenolic compounds. PMID- 21589752 TI - Standardization of Alpinia calcarata Roscoe rhizomes. AB - BACKGROUND: Rhizomes of Alpinia calcarata Roscoe (Family: Zingiberaceae) possess several bioactivities and are used in the traditional medicinal systems of Sri Lanka. METHODS: The present investigation was carried out to standardize the rhizomes of A. calcarata by (a) screening for phytochemicals (b) determination of physico-chemical parameters and (c) development of a Densitogram. RESULTS: Phytochemical screening revealed the presence of polyphenols, tannins, flavonoids, steroid glycosides and alkaloids in A. calcarata rhizomes. The percentages of moisture, total ash, acid insoluble ash, water soluble ash, ethanol extractable matter and water extractable matter were of 5.5 - 6.8, 8.3 - 8.8, 0.036 - 0.040, 7.2 - 7.8, 22.6 - 24.8 and 18.6 - 20.5 respectively. CONCLUSION: The results obtained from this study can be used to standardize rhizomes of A. calcarata grown in Sri Lanka. PMID- 21589753 TI - Evaluation of binding property of mucilage from Litsea glutinosa wall. AB - BACKGROUND: Litsea glitinosa is an evergreen tree of medium size which grows to a height of about 20 to 30 feet. It belongs to family Lauraceae. In India it is found mainly in North Eastern region. The leaves and the mucilage from the bark of plant is utilized in the gum for poultices. METHODS: Mucilage of Litsea glutinosa was isolated from powdered bark by continuous hot extraction technique using water and precipitation by absolute alcohol (38% w/w yield). The mucilage was evaluated for binding properties in tablets and granules, using paracetamol as a model drug. The granules were prepared using 4 different concentrations of mucilage (4%, 6%, 8%, and 10%) and evaluated for percentage of fines, average particle size, total porosity, compressibility index, and flow properties. The prepared tablets were evaluated for content uniformity, hardness, friability, disintegration time, and in vitro dissolution profiles. RESULTS: The results obtained with the lower concentrations of mucilage, that is, less than 6% were not so encouraging. The tablets prepared by using 10% mucilage of L. glutinosa as binder exhibited more hardness as compared with the starch. CONCLUSION: It may be concluded that the concentration ranging from 6% to 8% of L. glutinosa mucilage may be considered as better option as a binding agent for the preparation of tablets as compared to the starch (10%). PMID- 21589754 TI - A comparison of traditional anti-inflammation and anti-infection medicinal plants with current evidence from biomedical research: Results from a regional study. AB - BACKGROUND: In relation to pharmacognosy, an objective of many ethnobotanical studies is to identify plant species to be further investigated, for example, tested in disease models related to the ethnomedicinal application. To further warrant such testing, research evidence for medicinal applications of these plants (or of their major phytochemical constituents and metabolic derivatives) is typically analyzed in biomedical databases. METHODS: As a model of this process, the current report presents novel information regarding traditional anti inflammation and anti-infection medicinal plant use. This information was obtained from an interview-based ethnobotanical study; and was compared with current biomedical evidence using the Medline((r)) database. RESULTS: Of the 8 anti-infection plant species identified in the ethnobotanical study, 7 have related activities reported in the database; and of the 6 anti-inflammation plants, 4 have related activities in the database. CONCLUSION: Based on novel and complimentary results from the ethnobotanical and biomedical database analyses, it is suggested that some of these plants warrant additional investigation of potential anti-inflammatory or anti-infection activities in related disease models, and also additional studies in other population groups. PMID- 21589755 TI - Production of camptothecin in cultures of Chonemorpha grandiflora. AB - BACKGROUND: Chonemorpha grandiflora (Syn. Chonemorpha fragrans (Apocynaceae) is an endangered medicinal plant. It is used in different preparations, such as sudarsanasavam and kumaryasavam used in Kerala Ayurvedic system. C. grandiflora is used for the treatment of fever and stomach disorders. Phytochemical investigations have revealed the presence of steroidal alkaloids, such as chonemorphine and funtumafrine in C. grandiflora. Camptothecin, a well-known anticancer alkaloid has been detected in ethanolic extracts of stem with bark and callus cultures derived from C. grandiflora. METHODS: Callus cultures of C. grandiflora were raised on Murashige and Skoog's medium supplemented with 2, 4-D. Stem with bark and callus were used for phytochemical analysis mainly the alkaloids. Detection and identification of camptothecin was carried out using thin-layer chromatography (TLC), high-performance thin-layer chromatography, (HPTLC) and high-performance liquid chromatography (HPLC). RESULTS: An important anticancer alkaloid, camptothecin was detected in ethanolic extracts of stem with bark and callus cultures of C. grandiflora. camptothecin content was 0.013 mg/g in stem with bark and 0.003 mg/g in callus. CONCLUSION: This is the first report on in vivo and in vitro production of camptothecin in C. grandiflora. Camptothecin is known to occur only in six plant sources so, alternative sources for camptothecin are needed. Thus of C. grandiflora could be a new promising alternative source of camptothecin. PMID- 21589756 TI - Development and evaluation of formulations of microbial biotransformed extract of tobacco leaves for hair growth potential. AB - BACKGROUND: Extensive researches are going on to explore the effective and safe drug for their hair growth. Tobacco leaves are traditionally known to potentiate hair growth promotion. Therefore, the aim of present study was to formulate and evaluate the microbial biotransformed extract of tobacco leaves for hair growth potential in male albino wister rats. MATERIALS AND METHODS: The extract of was prepared by microbial biotransformation of tobacco leaves in cow urine for 28 days. The herbal formulations (lotion) were formulated by general method using o/w type base in various rations or concentrations such as 10%, 20% and 30% of extract. These lotions were applied on shaved skin area of rats for 30 days once in a day and hair length, serum total protein, and total testosterone were measured. RESULTS: Our formulations show increase in hair growth and serum total protein at concentration dependent manner with effect to standard and control groups. Serum total testosterone decreases according to a concentration dependent manner. CONCLUSION: Further, series of investigations are, however, necessary to remain exploration, which includes their structural elucidation, characterization, clinical safety, reliability and molecular mechanism involved in this pharmacological activity. PMID- 21589757 TI - Formulation and evaluation of floating tablets of liquorice extract. AB - BACKGROUND: Floating tablets prolong the gastric residence time of drugs, improve bioavailability, and facilitate local drug delivery to the stomach. With this objective, floating tablets containing aqueous extract of liquorice as drug was prepared for the treatment of Helicobacter pylori and gastric ulcers. METHODS: The aqueous extract of liquorice was standardized by HPTLC. Tablets containing HPMC K100M (hydrophilic polymer), liquorice extract, sodium bicarbonate (gas generating agent), talc, and magnesium stearate were prepared using direct compression method. The formulations were evaluated for physical parameters like diameter, thickness, hardness, friability, uniformity of weight, drug content, buoyancy time, dissolution, and drug release mechanism. The formulations were optimized on the basis of buoyancy time and in vitro drug release. RESULTS: The diameter of all formulations was in the range 11.166-11.933 mm; thickness was in the range 4.02-4.086 mm. The hardness ranged from 3.1 to 3.5 kg/cm(2). All formulations passed the USP requirements for friability and uniformity of weight. The buoyancy time of all tablet formulations was less than 5 min and tablet remained in floating condition throughout the study. All the tablet formulations followed zero-order kinetics and Korsemeyer-Peppas model in drug release. CONCLUSION: The optimized formulation was found to be F6 which released 98.3% of drug in 8 h in vitro, while the buoyancy time was 3.5 min. Formulations containing psyllium husk, sodium bicarbonate and HPMC K100M in combination can be a promising for gastroretentive drug delivery systems. PMID- 21589758 TI - Variation in gymnemic acid content and non-destructive harvesting of Gymnema sylvestre (Gudmar). AB - BACKGROUND: Madhunashini (Gymnema sylvestre R. Br.) commonly known as 'Gudmar' in Hindi is an important medicinal climber and extensively used in almost all Indian System of Medicine as a remedy for diabetes, rheumatism, cough, ulcer, jaundice, dyspepsia, constipation, eyes pain and also in snakebite. In India, it is found growing in Andhra Pradesh, Bihar, Chhattisgarh, Karnataka, Kerala, Madhya Pradesh, Maharastra, Orissa, Tamil Nadu, Uttar Pradesh and West Bengal. The major phytoconstituents are gymnemic acids, gudmarin and saponins. METHODS: In the present study, Gymnema germplasm collected from various regions of Madhya Pradesh was evaluated on the basis of their morphological characteristics and gymnemic acid content. Gymnemic acid content in the leaves was estimated by HPLC. We have also standardized the non-destructive harvesting practices of Gudmar. Selective harvesting was done without harming the main plant. Only mature leaves (60%) were hand plucked in the month of October. Second harvest was done in the month of June. RESULTS: Data revealed that gymnemic acid content varied between 0.96% +/- 0.03 (Seoni) to 1.58% +/-0.03 (Amarkantak). It was also observed that the leaves left at the time of 1(st) harvest during October matured in June at the time of 2(nd) harvest. CONCLUSION: Non destructive harvesting practice did not have any negative impact on overall development of the plant. It is evident that there is wide variation in the morphological characteristics and gymnemic acid content in G. sylvestre collected from various locations, which can be exploited for further crop improvement programmes. PMID- 21589759 TI - A study of the anti-inflammatory effect of the leaves of Psidium guajava Linn. on experimental animal models. AB - INTRODUCTION: The aim is to study the anti-inflammatory effect of the ethanolic extract of the leaves of Psidium guajava(PGE) on experimental animal models. MATERIALS AND METHODS: Fresh leaves were collected, air-dried, powdered, and percolated in 95% ethanol. Acute toxicity test was done according to OECD guidelines. Four groups of animals of either sex, weighing 150-200g of the species Rattus norvegicus were taken for the study (n = 6). Group A was taken as control (3% gum acacia in 10 mL/kg body weight), Group B as test group (PGE 250 mg/kg body weight), Group C as test group (PGE 500 mg/kg body weight), and Group D as standard (Aspirin 100 mg/kg body weight). The animals were studied for acute inflammation by Carrageenan-induced rat paw edema, subacute inflammation by Granuloma pouch method, and chronic inflammation by Freund's adjuvant-induced arthritis method. Statistical analysis was done by one-way analysis of variance followed by multiple comparison tests. RESULTS: In acute inflammation, there was significant inhibition of paw edema in Groups B, C, and D in comparison with Group A (P < 0.05). In subacute inflammation, there was significant inhibition of exudate formation in Groups B, C, and D in comparison to Group A (P < 0.05). In chronic inflammation, there was significant inhibition of paw edema and inhibition of weight reduction in Groups B, C, and D compared with Group A. Downregulation of arthritis index was also significant in Groups B, C, and D in comparison with Group A (P < 0.05). CONCLUSION: The ethanolic extract of PGE has significant anti-inflammatory activity. PMID- 21589760 TI - Evaluation of physicochemical and phytochemical properties of Safoof-E-Sana, a Unani polyherbal formulation. AB - BACKGROUND: Although the formulations of the Unani system of medicine are popular, not much scientific work has been reported so far. The present article is an attempt to establish the scientific basis of one of the popular Unani formulations Safoof-ESana, a polyherbal formulation widely used as a laxative. METHODS: Investigations were carried out to study the physicochemical and phytochemical properties of Safoof-E-Sana and its active ingredients. RESULTS AND CONCLUSION: The values of percentage loss on drying, angle of repose, Hausner ratio, and Carr's index of the formulation were calculated as 8.25 +/- 0.582, 27.68, 1.23, and 19 respectively, which indicate that the moisture content of the formulation is within the range and depict good flow characteristics. The total ash, acid- nsoluble ash, and water-soluble ash were found to be 19.146 +/- 0.237, 2.351 +/- 0.223, and 49.216 +/- 0.634, respectively; the value of total ash indicates that the inorganic contents of the formulation are below the limits. Alcoholic and aqueous extracts of the formulation and ingredients were prepared and evaluated for phytochemical analysis and extractive values, and the results show that alkaloids of the formulation are more soluble in water than in alcohol and the higher aqueous extractive value (45.784 +/- 0.876) of Unani formulation depicts that water is a better solvent of extraction for the formulation than ethanol. PMID- 21589761 TI - Is the term substitution relevant to Pharmacognosy and/ or vegetable crude drug industry? AB - Since each and every drug plant has its own characteristic features, in terms of its botanical characters, chemical composition and therapeutic properties, considering the highly potential drug plants as genuine plant and less potential (allied or non-allied) drug plants as substitutes is unjustifiable. Moreover, the term Substitution is being used for a couple of centuries in a wrong sense in pharmacognostic studies or in the vegetable crude drug industry. Therefore, the term 'Substitution' has to be replaced by the relevant and appropriate term, 'Alternative' or 'Alternative source'. PMID- 21589763 TI - Synthesis and cytotoxic activity of some 2-amino-4-aryl-3-cyano-7-(dimethylamino) 4H-chromenes. AB - A series of 2-amino-4-aryl-3-cyano-7- (dimethylamino)-4H-chromenes was synthesized by condensation of 3- (dimethylamino) phenol, an aromatic aldehyde and malonitrile in ethanol containing piperidine. The assignments of the structure of all synthesized compounds were based on spectral data (IR, Mass and(1)H NMR). The cytotoxic activities of the synthesized compounds against six human tumor cell lines were determined by MTT assay. Several compounds showed significant cytotoxic activity. PMID- 21589762 TI - Are antioxidants helpful for disease prevention? AB - Free radicals are produced continuously in the cells as part of normal cellular function, however excess production might play a role in pathophysiology of many disease conditions, including cancer, Alzheimer's disease, atherosclerosis and some of the drug-induced toxicity. Many basic research studies and observational epidemiologic studies in human suggest that antioxidants can prevent oxidative damage. However, this is still a controversial issue because the results of clinical trials have been inconsistent. This article provides a brief overview of some of the diseases which are associated with free radicals, then discusses the roles of some of dietary antioxidant supplements in disease prevention, with particular reference to the findings of latest clinical trials. PMID- 21589764 TI - Mutating Asn-666 to Glu in the O-helix region of the taq DNA polymerase gene. AB - Taq DNA polymerase is widely used in laboratories and for this reason many investigators have focused their attention on understanding the role of various regions and amino acids in this enzyme. O-helix is a part of taq polymerase suggested to play an important role in the enzyme fidelity. The influence of Asn666 in this helix on the enzyme function has never been investigated, and therefore by using nested PCR, a portion of taq DNA polymerase gene containing Asn666Glu mutation was amplified. This DNA was digested with Eco RI restriction enzyme to confirm the presence of Asn666Glu mutation. After digesting this product and the wild type taq-pET-15b plasmid with NheI and BamHI restriction enzymes, they were ligated and used for the transformation of E. coli DH5alpha competent cells. The obtained colonies were screened for the presence of the mutated taq polymerase gene using EcoRI, NdeI and BamHI restriction enzymes. In conclusion, with the use of the obtained recombinant plasmid it is possible to study the role of this amino acid on taq DNA polymerase function. PMID- 21589765 TI - Evaluation of the effects of galbanic acid from Ferula szowitsiana and conferol from F. badrakema, as modulators of multi-drug resistance in clinical isolates of Escherichia coli and Staphylococcus aureus. AB - Galbanic acid, a sesquiterpene coumarin from Ferula szowitsiana, and conferol, another sesquiterpene coumarin from F. badrakema, were evaluated for their effects on the reversal of multi-drug resistance in clinical isolates of Staphylococcus aureus and Escherichia coli, respectively. Neither galbanic acid (up to 1000 MUg/ml) nor conferol (up to 400 MUg/ml) by itself shows any antibacterial activities against tested strains. The minimum inhibitory concentrations (MICs) of ciprofloxacin and tetracycline were determined using macrodilution technique in the presence and absence of sub-inhibitory concentrations of galbanic acid (31.25-1000 MUg/ml) or conferol (50-400 MUg/ml), however they caused no change in MICs of the antibiotics. Galbanic acid did not show any inhibitory effect on efflux phenomenon of E. coli. This can be related to the outer membrane of gram-negative bacteria which is impermeable to lipophilic compounds or another mechanism rather than efflux responsible for resistance in tested E. coli strains. An inhibitory effect of conferol on the efflux was compared with verapamil as a positive control. Because efflux is the only known mechanism of resistance to ethidium bromide (model efflux substrate) and verapamil reduced MIC of ethidium bromide, efflux mechanism can be considered as one of the resistance mechanisms in tested S. aureus strains. Conferol, however, did not enhance the antibiotic efficacy mediated by inhibiting efflux pumps in bacteria. PMID- 21589766 TI - Development of theophylline floating microballoons using cellulose acetate butyrate and/or Eudragit RL 100 polymers with different permeability characteristics. AB - The objective of the present investigation was to design a sustained release floating microcapsules of theophylline using two polymers of different permeability characteristics; Eudragit RL 100 (Eu RL) and cellulose acetate butyrate (CAB) using the oil-in-oil emulsion solvent evaporation method. Polymers were used separately and in combination to prepare different microcapsules. The effect of drug-polymer interaction was studied for each of the polymers and for their combination. Encapsulation efficiency, the yield, particle size, floating capability, morphology of microspheres, powder X-ray diffraction analysis (XRD), and differential scanning calorimetry (DSC) were evaluated. The in vitro release studies were performed in PH 1.2 and 7.4. The optimized drug to polymer ratios was found to be 4:1 (F(2)) and 0.75:1 (F'(2)) with Eu RL and CAB, respectively. The best drug to polymer ratio in mix formulation was 4:1:1 (theophylline: Eu RL: CAB ratio). Production yield, loading efficiencies, and particle size of F(2) and F'(2) were found to be 59.14% and 45.39%, 73.93% and 95.87%, 372 and 273 micron, respectively. Microsphere prepared with CAB showed the best floating ability (80.3 +/- 4.02% buoyancy) in 0.1 M HCl for over 12 h. The XRD and DSC showed that theophylline in the drug loaded microspheres was stable and in crystaline form. Microparticles prepared using blend of Eu RL and CAB polymers indicated more sustained pattern than the commercial tablet (P<0.05). Drug loaded floating microballoons prepared of combination of Eu RL and CAB with 1:1 ratio were found to be a suitable delivery system for sustained release delivery of theophylline which contained lower amount of polymer contents in the microspheres. PMID- 21589767 TI - Influence of Murraya koenigii on experimental model of diabetes and progression of neuropathic pain. AB - The aim of the present study was to evaluate the effect of ethanolic extract of Murraya koenigii leaves (MKL) on blood glucose level and in prevention or management of diabetic neuropathy. In the present study the diabetic neuropathy was developed 9 weeks after single injection of streptozotocin (STZ, 70 mg/kg i.v.) in rat. The treatment with MKL (300 and 500 mg/kg p.o.) was started after stabilization of blood glucose level (13 days after STZ) and evaluated for determination of glycemic level, glycated haemoglobin, grip strength, pain sensitivity and threshold. The result showed that the treatment with MKL possessed hypoglycemic effect in diabetic treated animals. The results also indicated that the decreases in the grip strength in diabetic animals represented the induction of neuropathy 9 weeks after STZ treatment. Prior treatments with MKL increased the grip strength of diabetic rats. The results of pain sensitivity indicated the loss of pain perception in diabetic animals because of nerve damage. While prior treatment with MKL upto 9 week in diabetic animals resulted in the increase in the licking time and withdrawal latency in hot plate and tail flick tests, respectively, which indicates the presence of pain perception and prevention of nerve damage due to protective effect of MKL in progression of diabetic neuropathic pain. Therefore, the present study concludes that the chronic treatment with MKL significantly decreased the glycemic level as well as it protected the animals against development of diabetic neuropathy. PMID- 21589768 TI - Preparation and characterization of solid dispersions of carvedilol with PVP K30. AB - Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. The poor solubility of carvedilol leads to poor dissolution and hence variation in bioavailability. The purpose of the present investigation was to increase the solubility and dissolution rate of carvedilol for enhancement of oral bioavailability. In the present investigation solid dispersions with PVP K30 were prepared by solvent evaporation method. The physical mixture and solid dispersion (s) were characterized for drug-carrier interaction, drug content, solubility and dissolution rate. The solubility of drug increased with increasing polymer concentration. The dissolution rate was substantially improved for carvedilol from its solid dispersion compared with pure drug and physical mixture. As indicated from X-ray diffraction pattern and DSC thermograms carvedilol was in the amorphous form, which confirmed the better dissolution rate of solid dispersions. The solid dispersion was stable under accelerated storage conditions. The solid dispersion technique with PVP K30 as a carrier provides a promising way to enhance the solubility and dissolution rate of carvedilol. PMID- 21589769 TI - Polarographic determination of certain cephalosporins in pharmaceutical preparations. AB - Polarographic methods have been developed for the determination of two cephalosporins namely cefotaxime (CTX) and ceftriaxone (CTR) in pharmaceutical formulations. Well defined peaks at potentials -1.432 V vs. SCE for CTX and 1.627 V vs. SCE for CTR were obtained in the presence of tungsten (VI). The method has been successfully applied for the determination of above mentioned cephalosporins in commercial dosage forms. The salient features of this investigation are presented in this communication. PMID- 21589770 TI - Comparison of healing time of the 2 degree burn wounds with two dressing methods of fundermol herbal ointment and 1% silver sulfadiazine cream. AB - BACKGROUND: Burn wounds are one of the health problems in modern societies that are associated with irreparable harms and many side problems for patients and their families. Infection due to burn wounds is the main cause of death in such patients. One of the methods to prevent infection of burn wounds is topical antibiotic ointments. This study aimed to investigate and identify effective ointments to treat burn wounds. For this purpose, the effects of two types of ointment, fundermol and 1% silver sulfadiazine cream on second degree burn wounds were compared. METHODS: This was a clinical trial study conducted in 2008. Using convenient and continuous sampling method, 50 patients referred to Imam Mousa Kazem Burn Injury Clinic in Isfahan, Iran with 2(nd) degree burn wounds in 1% to 10% surface area were enrolled. The patients were randomly divided into two groups of treatment with fundermol and sulfadiazine and the dressing was changed once a day. The healing time for burn wounds in each patient was recorded in a checklist and data were analyzed by independent t-test via SPSS software. RESULTS: The healing time of burn wounds in the group treated with fundermol was shorter than that in the group treated with sulfadiazine (p < 0.001). CONCLUSIONS: The present study showed that fundermol ointment accelerates burn wound healing. Therefore, fundermol can be introduced as a good replacement for current treatments of burn wounds. PMID- 21589771 TI - The effects of family education program on the caregiver burden of families of elderly with dementia disorders. AB - BACKGROUND: Family caregivers are an essential part of health care services for elderly with dementia disorders, because of providing care for such patients is a big burden for their families. This study aimed to assess the effects of family education program in reducing the burden of families of elderly with dementia. METHODS: This was a clinical trial, in which 50 family caregivers of the elderly patients with dementia who had referred to two referral centers for dementia in the city of Isfahan were selected with convenient sampling method and were randomized to experimental and control groups. The experimental group participated in a family education program but the control group did not. Data were collected by Zarit's caregiver burden scale completed by caregivers of both groups before, right after, and one month after family education program. Also, Mini-Mental Status Examination was conducted for elderly before the program. Finally, data were analyzed in SPSS software. RESULTS: Caregivers' burden was gradually increased in the controls, but decreased in the experimental group during the study. The means of caregivers' burden before, right after, and one month after family education program were 42, 35.44, and 33.56 in the experimental group, respectively, while they were 43.28, 46.8 and 50.64 in the control group, respectively. Also, there was a significant difference between caregivers' burden of the two groups immediately after intervention, but one month after intervention no significant difference was seen between the two groups. CONCLUSIONS: Since conducting this program could reduce caregivers' burden of families of elderly with dementia, developing such programs and evaluating them within research projects are recommended. PMID- 21589772 TI - Four hour ambulation after angioplasty is a safe practice method. AB - BACKGROUND: During the last 3 decades, there were increasing tendency towards angioplasty because of its benefits. But, this procedure has its acute problems like bleeding and formation of hematoma in the removal place of the sheet. Based on researchers' clinical experiences, patients need a time of 8-12 hours for bed rest after coronary angioplasty. Recognizing desirable time for bed rest after angioplasty and remove the arterial sheet forms the foundation of related researches in the world. Getting out of bed soon after angioplasty, causes more comfortable feelings, less hospitalization period, fewer side effects of prolonged bed rest and less hospitalization expenses. Regarding less time for bed rest after angioplasty, the aim of this study was to assess the effect of the time of getting out of bed after angioplasty on the complications after removing the sheet in coronary angioplasty patients. METHODS: This was an experimental clinical study conducted in one step and two groups. Samples were included 124 angioplasty patients (62 in each group) who were chosen randomly from the CCU of Shahid Chamran hospital of the Isfahan University of Medical Sciences in 2007. Data were gathered by observing and evaluating the patients, using a questionnaire and a checklist. After angioplasty, patients from the intervention group were taken out of bed in 4 hours and patients from the control group were taken out of bed in 8 hours. After taking out of bed, patients were examined for bleeding and formation of hematoma in the place of taking out the arterial sheet. Data were analyzed using descriptive and inferential statistics via SPSS software. RESULTS: Results showed no meaningful difference between the two groups after getting out of bed (p > 0.05) regarding relative frequency of bleeding (p = 0.50), formation of hematoma (p = 0.34) and average diameter of hematoma (p = 0.39). CONCLUSIONS: Results of this study showed that reducing the bed rest time to 4 hours after removing the arterial sheet of size 7 do not increase bleeding and formation of hematoma in the removal place of the sheet. So, those angioplasty patients who do not have critical clinical condition and their vital symptoms are stabilized will be able to get out of bed 4 hours after removing the sheet. PMID- 21589773 TI - A study on the relationship of sexual satisfaction and common contraceptive methods employed by the couples. AB - BACKGROUND: Sexual relationship is a basis for mental health and continuity of the healthy generation. Enjoying the healthy body and mind will cause the sexual relationships to run their normal course in life. One of the problems that couples are faced within their sexual relationships is the issue of employing family planning methods. Studies have revealed that contraceptive methods are in connection with the sexual function and health in different ways. This study was aimed to determine the mean and the relation of scores of sexual satisfaction of men and women with the common contraceptive methods. METHODS: This was a descriptive-correlative study. Samples included 280 individuals (140 couples) to use the common contraceptive methods including withdrawal method, tubal ligation in women, oral contraceptive method, condom, vasectomy, IUD and injection contraceptive method. Tools for gathering the data were Female Sexual Function Index (FSFI) and the questionnaire provided by Dr. Abdo on sexual satisfaction in men in 2004. The validity and reliability of these questionnaires were approved by researches conducted in worldwide and Iran. Descriptive and inferential statistic methods were applied in analyzing the data. RESULTS: The results suggested a significant statistic relation between scores of men's sexual satisfaction and separate contraceptive methods (p = 0.001) whereas this relation was not observed between the women's scores of sexual satisfaction and the contraceptive methods. CONCLUSIONS: According to the results of the present study, training family planning counselors in relation to choose suitable contraceptive method, in view of its probable effects on the couple's sexual satisfaction, seems essential. PMID- 21589774 TI - The relationship between serum zinc level and preeclampsia. AB - BACKGROUND: Preeclampsia is one of the commonest causes of prenatal and maternity related death in the world. Preeclampsia is caused by multiple factors and finding any factor related to this disorder can help on time prevention of this disease, which reduces the mortality of mothers and infants. Zinc deficiency is a possible risk factor for risky pregnancies and the results of studies on this subject are controversial. This study investigated the relationship between mothers' serum zinc and risky pregnancies. METHODS: This was a case-control study on 48 normal pregnancies as controls and 48 preeclamptic pregnancies as case group. The women were studied in their third month of pregnancy. Simple random sampling was done based on inclusion and exclusion criteria. The two groups were matched in mothers' age, pregnancy age, number of childbirth, and socioeconomic status. Data were collected by blood sampling and a questionnaire. Serum zinc level was assessed by atomic absorption spectrometry method. Data were analyzed using SPSS Software. RESULTS: The level of serum zinc in most women in both groups was under 50 mg/dl (62.5% in normal pregnancy group and 79.2% in preeclamptic group). There was no significant difference between the mean (SD) serum zinc concentration of the two groups (47.83 (12.72) for normal pregnancy and 43.66 (11.98) for preeclampsia). There was an association between serum zinc concentration and the severity of preeclampsia (p = 0.04, r = -0.12). We did not find any significant relation between serum zinc level and the following variables: mothers' age (p = 0.15, r = -0.11), pregnancy age (p = 0.07, r = 0.24), and parity (p = 0.02, r = -0.39). CONCLUSIONS: The findings of this study showed that the assessment of serum zinc level does not have any clinical values for managing preeclampsia. However, based on the relationship between serum zinc concentration and the severity of preeclampsia in this study, we recommend assessment of serum zinc concentration as an index for predicting the severity of preeclampsia. PMID- 21589775 TI - Effect of black tea on enteral feeding tolerance in ICU patients. AB - BACKGROUND: Tea consumption has been known mostly as a well-drink after water in the world. Tea drink can affect balance of fluids and renal function. In addition, it can cause loss of many viruses in the stomach and can increase or decrease gastrointestinal movements. This research was done to determine the effect of tea on increasing enteral feeding tolerance in ICU patients in Alzahra Hospital. METHODS: In this clinical trial study, 45 patients were enrolled in two groups, tea consumption group and the standard method of nutrition as control group. Tea gavage was performed two times in the morning; 100 cc tea used for the study group and the same volume of water was used for the control group. Residual volume was measured before gavage. Data collected for one week. Information sheet had two pages; the first page described how to complete the form and the method of tea gavage and the second page was for data collection. Data were analyzed by t-student test, chi-square, and analysis of variance. RESULTS: In two groups, 92% of patients tolerated liquid gavage. Their difference by chi-square test was not significant. Average urine volume after black tea gavage was 783.3 L in the study group and 802.2 L in the control group. ANOVA test showed no significant difference. CONCLUSIONS: Although the difference was not statistically significant between the two groups, but in study group consumption of tea was acceptable by patients. PMID- 21589776 TI - Effects of massage therapy of asthmatic children on the anxiety level of mothers. AB - BACKGROUND: Asthma is the most common chronic disease of childhood and its prevalence is increasing all over the world. Asthma influences on many aspects of family daily life. Health care of children with chronic asthma can have deep impact on health and welfare of the family members. Studies showed a relation between the life quality of children suffering from asthma and the anxiety level of parents. These parents are looking for ways to confront with their stress, to reduce their anxiety in encountering with their asthmatic children, and to improve their performance. This research was accomplished with the aim of determining the influence of massage therapy on anxiety level of mothers with asthmatic children. METHODS: This was a quasi-experimental study with two groups and a pretest and posttest design. The samples of research were 60 mothers of 5 14 year-old asthmatic children who were under treatment in medical centers of Isfahan. They were randomly divided into two groups of control and massage therapy by convenience sampling method. The data were collected by standard Spielberger questionnaire. Mothers of massage group were trained to massage head, neck, face, shoulder, hand, leg, and back of their children every night before bedtime for one month while there was no intervention for the control group during this month except the standard treatment. In both groups, the Spielberger standard questionnaire was filled by mothers. The data were analyzed by descriptive analysis, independent t-test, paired-t test, and chi-square test. RESULTS: The results showed no significant difference in mean anxiety level between the two groups before the intervention but there was a significant difference between them after intervention (p < 0.03). Also, there was a significant difference in mean level of anxiety score of mothers before and after the intervention in massage group (p < 0.001). CONCLUSIONS: The anxiety level of mothers can be reduced by effective utilization of daily child massage therapy and giving an active role to the mothers in caring and treating the child. Daily massage helped mothers to have more sense of participation in caring their children and as a non-pharmacological method can be accompanied with pharmacological methods. PMID- 21589777 TI - The intelligence quotient of school aged children delivered by cesarean section and vaginal delivery. AB - BACKGROUND: There has always been an asking question with physicians and health staff whether delivery mode can effect on child intelligence. This study was conducted to compare the intelligence quotient (IQ) of school aged children delivered by cesarean section and vaginal delivery in Mashhad, Iran. METHODS: This study conducted in two stages; a cross-sectional section in which 5000 randomly selected children, who were 6-7 years old, attended at 10 Cognitive Examination Posts in Mashhad. The examination was performed by the Exceptional Education and Training Institute affiliated to Ministry of Education for all 6-7 years old children at the entry to the primary school. At the second stage, we selected two matched groups of 189 children who delivered by cesarean section or spontaneous vaginal delivery and then compared their IQ scores. RESULTS: The cesarean delivery group had significantly higher IQ test scores. Maternal and paternal educational levels were related to children's IQ scores. After adjusting of maternal and paternal education, maternal age and parity, there was not any significant difference between IQ scores of cesarean delivery and natural vaginal delivery groups 101(3.67) vs. 100.7(4.28). CONCLUSIONS: Based on our findings, the association between cesarean deliveries with better cognitive development in children cannot be supported. PMID- 21589778 TI - Nurses' knowledge of blood transfusion in medical training centers of Shahrekord University of Medical Science in 2004. AB - BACKGROUND: Using blood and blood components is a common therapeutic procedure in hospitals. Nurses have an important role in a safe blood transfusion. Therefore, it is crucial for nurses to have sufficient knowledge of situations, amount and methods of using blood components, possible side effects and necessary cares. This study investigated nurses' knowledge of blood transfusion. METHODS: This was a cross-sectional descriptive study on 117 nurses in medical training hospitals of Shahrekord University of Medical Sciences in 2004, aiming to evaluate their knowledge of blood transfusion. Data were collected using a questionnaire including 4 sections and 29 questions. Sections included demographic data, nurses' knowledge of blood components, nurses' knowledge of blood components infusion techniques, and nurses' knowledge of indication and side effects of blood components infusion. Knowledge scores were first coded and then categorized in three levels of good, average, and poor. Data were analyzed using SPSS software. RESULTS: The nurses' knowledge of blood and blood component, techniques of blood components infusion, and its indication and side effects was average (66.7%, 65.8% and 59%, respectively). CONCLUSIONS: The findings showed that the nurses' knowledge of blood and blood component was average and insufficient. Therefore, it is recommended to activate the blood transfusion committees in hospitals to increase the quality of this common procedure and prevent side effects by in-service trainings of nurses. PMID- 21589779 TI - Relationship between communication manners of head nurses with job satisfaction of nurses under their supervision in educational hospitals of Isfahan University of Medical Sciences in 2006. AB - BACKGROUND: Interpersonal communication is considered as an important and effective factor of job satisfaction and efficiency and has special significance in nursing career because of the face to face relationship with patients. This study aimed to determine the association between head nurses' interpersonal communication and job satisfaction of nurses under their supervision. The study was conducted in educational hospitals of Isfahan University of Medical Sciences in 2006. METHODS: This was a descriptive and analytical study on 203 nursing personnel working in educational hospitals of Isfahan University of Medical Sciences in 2006. Data were collected using Job Descriptive Index (JDI) developed by Smith and Kendall and interpersonal communication was measured using a researcher-made questionnaire. Data were analyzed using SPSS software and Pearson's test and presented in tables and diagrams. RESULTS: The majority of the participants (148 subjects, 73%) believed that head nurses' interpersonal communication was excellent and in general Pearson's test showed a significant association between head nurses' interpersonal communication and their personnel's job satisfaction (p < 0.011). CONCLUSIONS: Based on the results of this study on the relationship between interpersonal communication of the head nurses and job satisfaction of their personnel, we can improve the job satisfaction of nursing personnel as well as patients' satisfactory and level of services by developing educational courses and workshops on importance and effectiveness of interpersonal communication for head nurses. PMID- 21589780 TI - Creating national care standards for neonatal intensive care units in 2007. AB - BACKGROUND: Infant mortality rate was reported 3.18 in 1000 births in Iran. International organizations such as World Health Organization (WHO) and United Nations Children's Fund (UNICEF) consider applicable standards essential for providing effective health services in hospitals and health centers. Therefore, it is essential to create national care standards for neonatal intensive care units (NICU) in Iran. METHODS: This was a multiple triangulation study conducted in 2007. In the first step, international standards were extracted from appropriate sites. Then, using Delphi method, as well as the viewpoints of 15 experts in clinical medical sciences, a set of suggested standards for intensive care unit was prepared. In the third step, 42 clinical science experts of Iran were selected, and their viewpoints on applicability of the suggested standards were investigated through a descriptive survey method. Data obtained in this step were analyzed using descriptive statistics. RESULTS: First, intensive care standards were extracted; then clinical science experts reviewed the suitability and applicability of suggested set of standards for Iran and finalized them. Finally, 386 standards for intensive care were drafted and approved by 77.5% to 100% desirability rate for NICUs of Iran. CONCLUSIONS: The findings of the study showed that most standards were either appropriate or fairly appropriate. So, necessary changes in final standards were made based on subjects, viewpoints and suggestions as well as the results of consulting with supervisors. PMID- 21589781 TI - Elderly self-management: a qualitative study. AB - BACKGROUND: The population of elderly in Iran and in the world is increasing. It is predicted that the population of elderly reaches to 10 millions in Iran by the year 2019. Elders more than other age groups are at risk of chronic diseases and health problems; and elderly affects their self-management and makes them feel disabled. Since the knowledge of self-management for Iranian elderly is not well developed, this paper aimed to determine the concept of self-management for Iranian elders. METHODS: This was a qualitative study with grounded theory approach on Iranian elderly self-management. Data were collected through deep interviews with 26 participants in a period of one year and were analyzed using a Strauss Corbin analysis method. RESULTS: Self-management in the context of power means using different managing methods in dealing with daily life needs, especially in interactions with others in a way that accelerates affairs with efficiency and satisfaction. The main categories emerged from this qualitative study included: managing plans, managing life goals and policies, persuading the desired goals, managing self-care, directing others, coordinating and consulting with others. CONCLUSIONS: The findings of this study provided a deep understanding of elderly perceptions of self-management in their lives. These findings can be a baseline for future researches on developing effective health interventions such as developing a nursing model for increasing the elderly self management abilities in Iran. Such a model can provide a strong basis for nursing care. PMID- 21589782 TI - The effects of a designed program on oxygen saturation and heart rate of premature infants hospitalized in neonatal intensive care unit of Al-Zahra Hospital in Isfahan in 2008-2009. AB - BACKGROUND: Prematurity is the main cause of death in infants under one year of age and is the main reason for neonatal intensive care unit (NICU) hospitalization. The stressful environment of NICU exposes preterm infants to inappropriate stimuli. This study aimed to determine and compare the mean heart rate and oxygen saturation of premature infants before and during a designed program in NICU. METHODS: In a clinical trial study (before-after intervention) on a single group, 31 hospitalized premature newborns in NICU of Al-Zahra Hospital in Isfahan were selected by simple continuous sampling method. Data were collected through interview, observation and checklist records. The data were analyzed using SPSS and descriptive and inferential statistics. RESULTS: Out of 31 premature infants in the study, 60% were boys and 35% were girls. The mean (standard deviation) of oxygen saturation before and during the designed program were 92.80 (2.54) and 94.22 (2.59) percent, respectively. The results of paired t test showed a significant difference between the means of oxygen saturation of the infants before and during the program (p = 0.048), but there was no significant difference between the mean of the infants' heart beat before and during the intervention. CONCLUSIONS: The findings showed that applying daily silence periods can greatly help to increase oxygen saturation and can improve the growth of premature infants. Therefore, by providing more facilities in clinical environments of NICU, conducting programs to reduce light and noise in these wards would be possible. PMID- 21589783 TI - Relationship between quality of life and self-care ability in patients receiving hemodialysis. AB - BACKGROUND: Although hemodialysis has a therapeutic effect on end stage renal disease (ESRD), these patients encounter many physical, psychological, and social stressful factors that lead to a decrease in their quality of life (QOL). One of the factors that are effective on increasing the QOL is the self-care ability. Review of literature demonstrated a few studies done on different aspects of QOL in ESRD patients under hemodialysis and their relationships with self-care ability in Iran. So, in this research besides determining the quality of life and its dimensions and self-care ability of hemodialysis patients, we evaluated their relationships with each other. METHODS: For this purpose, all hemodialysis patients who had inclusion criteria and were hospitalized in hemodialysis wards of Bonab, Maragheh, and Miandoab hospitals were selected and data were collected by interview using a questionnaire that included three parts, demographic factors, quality of life, and self-care ability. RESULTS: The results indicated that quality of life in 34%, and self-care ability in 78.3% of hemodialysis patients were desirable, and there was a direct and significant relationship between these two variables (p < 0.001, r = 0.4), as self-care ability explained 29% of variance of QOL. In quality of life subsectors, social dimension in 98.3% of patients was desirable, while physical dimension (80%) and psychological dimension (63.5%) in most patients were undesirable. Physical dimension was the most impressible dimension of quality of life in self-care ability whereas self care ability explained 27% of total variance of physical dimension of QOL. CONCLUSIONS: Nearly two thirds of mentioned patients had no desirable QOL and regarding the positive relationship between QOL and self-care ability, it is suggested that health care planner and managers prepare the condition that through educating and reinforcing self-care ability in these patients improve the QOL in hemodialysis patients. PMID- 21589784 TI - Women's experience of pain during childbirth. AB - BACKGROUND: Labor pain is one of the most severe pains which has ever evaluated and its fear is one of the reasons women wouldn't go for natural delivery. Considering different factors which affect experiencing pain, this study aimed to explain women's experiences of pain during childbirth. METHODS: This was a qualitative phenomenological study. The study population was composed of 14 women in 6 weeks post-partum period of natural delivery. The data were collected by interview. The data were analyzed by Colaizzi's seven-stage method. RESULTS: AFTER ANALYZING THE INTERVIEWS, FOUR MAIN CATEGORIES WERE EXTRACTED: the nature of delivery pain, the related factors in labor pain, the results of labor pain, and the perception of caseworkers. CONCLUSIONS: Assessing the women's experiences can be useful in giving better care. It helps understand the delivery pain phenomenon. Positive aspects of delivery pain must be strengthened and its negative aspects must be reduced as much as possible to create a suitable vision towards it. PMID- 21589785 TI - The relationship between learning organization and organizational commitment among nursing managers in educational hospitals of Isfahan University of Medical Sciences in 2008-9. AB - BACKGROUND: Old methods of administrating can't cover the rapid changes of today. These changes redounded new organizations like learning organizations to be formed. The purpose of this research was to study the relationship between learning organization and organizational commitment among nursing managers. METHODS: This was a descriptive analytic survey. The population of study included 90 nursing managers of 9 educational hospitals. Data gathering was done via learning organizational (LO) and organizational commitment (OC) questionnaires. Data analysis was done using SPSS software. RESULTS: The mean score of LO was 56.9 +/- 18.1 among nursing mangers, and the mean score of OC was 62.3 +/- 10.1. In general, there was a significant relationship between LO and OC and there was a significant relationship between LO and job experience based on ANOVA test. CONCLUSIONS: In today's changing environment of very rapid changes which have been seen in different areas of science and technology and the increasing complexity and dynamics of environmental factors, only organizations with active adaptation (dynamic equilibrium) can survive and remain capable of growth. This aim can be fulfilled just in learning organizations. PMID- 21589786 TI - Compatibility of personality and major among freshman undergraduate nursing students of the Kerman University of Medical Sciences. AB - BACKGROUND: Personality traits are major effective factors on student's learning, educational achievements and employer's job satisfaction. Metacognitive characteristics such as personality are only changeable up to 30% in the best educational condition. Therefore, students should be evaluated for such characteristics including their personality compatibility with their major. The present study investigated the personality compatibility of freshman undergraduate nursing students of the Kerman University of Medical Sciences in 2008 with nursing profession. METHODS: This was a descriptive study using a standard questionnaire based on Holland's career and personality theory on 82 freshman nursing students of Kerman University of Medical Sciences in 2008. Data were analyzed using SPSS software. RESULTS: More than 50% of the participants evaluated their information of nursing profession average. The personality of 41.3% was not compatible with nursing profession and the personality of 26.2% was relatively compatible. Only 32.5% of the participants had completely compatible personalities with this profession. CONCLUSIONS: Considering the limitations of the present study and previous studies, further studies are recommended. It seems that students' knowledge of majors and careers are increasing, but it is necessary to plan and make more effort to recognize personal characteristics and personality compatibility with professions. Knowledge of professions and personalities along with each other are valuable and neglecting one would be an obstacle to achieve goals including decreasing job resignation, increasing job efficiency and satisfaction. PMID- 21589787 TI - The effect of exercise on the severity of the fatigue in colorectal cancer patients who received chemotherapy in Ahwaz. AB - BACKGROUND: One of the common side effects of cancer is fatigue that affects patients' life quality and leads to disability. Exercise has an important role in improving these patients' life quality and can be used as a complementary treatment. Moreover, there are few studies on the impact of exercise on fatigue among patients with colon cancer. Therefore, the present study investigated the effects of exercise on the severity of fatigue in patients with colorectal cancer who underwent chemotherapy in Ahwaz. METHODS: In a quasi-experimental study, the adults with colorectal cancer were enrolled. The sample included 36 people. The study environment included adult hematology and chemotherapy wards of Shefa Hospital in Ahwaz. Data were collected using a demographic form and a questionnaire in order to measure the severity of fatigue. Then, the patients had 40 minutes of exercise, 3 times a week for 4 weeks. The effect of exercise versus fatigue intensity was measured at the end of every week. Data were analyzed using SPSS software. RESULTS: The mean of the fatigue severity in the weeks after exercise was significantly different from the week before it. Friedman test showed significant differences between all the weeks before and after the exercise. The mean of the fatigue severity was 3.69 on the week 0 (before the exercise), and decreased to 3.57 on the first week after exercise, 3.46 on the second week, 2.58 on the third week, and 1.69 on the forth week. CONCLUSIONS: Considering the results of this study, exercise and work-out can be an effective factor in reducing fatigue in patients. PMID- 21589788 TI - The study of optimal nursing position in health care delivery system in Iran. AB - BACKGROUND: In the recent decade, due to the overwhelming importance of health and prevention of diseases, nurses, the greatest part of the health care system, are acting in any position of the health care delivery system; because nursing have a key role in promotion of health and health care everywhere. The objective of this research was to study the desired positions of nursing in the health care delivery system in Iran. METHODS: This was a triangulation study done on three steps during 2005-2007. At the first step, the positions of nurses were elicited out of library and internet sources. At the second step, the comments of 15 participants were collected using an open questionnaire. Thereafter, at the third step, using the collected data, a questionnaire was made for a poll (all over the country) on the optimal positions of nursing in Iran, and 64 participants answered it. The results were analyzed using descriptive statistics. RESULTS: DERIVED POSITIONS WERE CATEGORIZED IN TWO GROUPS: hospital, and community positions. The results showed that all positions were accepted more than 70%. CONCLUSIONS: Considering positions of nursing and in order to promote the nursing itself and community health, it is suggested that proper planning should be implemented for nurses' activities in these positions by health planners. PMID- 21589789 TI - Ambiguity in knowledge transfer: The role of theory-practice gap. AB - BACKGROUND: In spite of much literature written about the theory-practice gap in the international nursing journals, there is evidence that indicates this subject has not been probed comprehensively since nursing education was transferred to universities in Iran. In the recent years, the public and the government have criticized Iranian nurses because of poor quality of patient care. Although this subject has been lamented by some researchers, there is no comprehensive work on how this gap resulted. In the process of a larger study on "nursing knowledge translation to practice", of one PhD thesis, this process was explored. METHODS: Using grounded theory analysis, indepth interviews were undertaken with a purposive sample of 29 nurses, with different levels of experience, from the school of nursing in Tehran University of Medical Sciences in 2006 from January to August. Data were analyzed using the constant comparative method. RESULTS: Three main themes emerging from this study included clinical behavior structure, paradoxical knowledge and practice, and divergent nursing organization. CONCLUSIONS: It seems that nursing education with some praxis and paradoxes in the realm of nursing knowledge and practice, along with divergent organizational structure have decreased nurses' ability in applying their professional knowledge and skills in order to bridge the gap between theory and practice. Moreover, in spite of increased academic input into nursing education, clinical behaviors of both education and practice settings was perceived as "traditional routine based". PMID- 21589790 TI - The effects of massage therapy on dysmenorrhea caused by endometriosis. AB - BACKGROUND: Studying women's quality of life, we come across some harmful effects that factor such as dysmenorrhea caused by endometriosis leaves on their lives, their ability to work, their familial relations, and their self-confidence. Due to the repeated medical follow-ups and the side effects of medical therapies and endometriosis surgeries, many patients tend to use less expensive, nonmedical, and nonaggressive methods. The present study aimed to assess the effects of massage therapy, one of the aforementioned methods on endometriosis caused dysmenorrhea. METHODS: This was a semi-empirical clinical trial. Considering inclusion criteria, 23 patients suffering from endometriosis visited the Infertility Center of Isfahan, who were later confirmed by laparoscopy or laparotomy were picked as the sample through a simple method. The visual analog scale and McGill questionnaires were used once before and twice after the end of intervention for each patient. The data were analyzed using SPSS software. RESULTS: There was a statistically significant difference between the intensity of pain before the intervention started, immediately after, and also six weeks after it (p < 0.001). CONCLUSIONS: According to the results of this study and confirmations of other ones, it seems that massage therapy can be a fitting method to reduce the menstrual pain caused by endometriosis. PMID- 21589791 TI - Evaluation of needle stick injuries among nurses of Khanevadeh Hospital in Tehran. AB - BACKGROUND: Accidental needle-stick injuries (NSIs) are a hazard for health-care workers and general public health. Nursing workers are at high risk for occupational exposure to blood-borne pathogens (such as HBV, HCV and HIV) via sharp injuries of needle stick. METHODS: This descriptive analytical cross sectional study was done on 158 nursing workers of Khanevadeh Hospital in Tehran to assess needle stick injuries prevalence and related factors via a questionnaire in 2008. Data were processed through SPSS (16.0)software using Pearson's correlation coefficient, chi-square, independent t, and Fisher exact tests. RESULTS: About 40.5% of all participants were men and 59.5% were women. Mean age was 33.26 (8.03) years; 56.96% of participants had history of at least one needle stick injury and 22.15% of them had needle stick injury during last year. Injections were the most common action resulted to exposure (24.44%) and recapping of needles was at the second order (21.11%). Operation room had the highest prevalence (18.9%) of needle stick injuries among all wards of hospital. Emergency ward and ICU were next orders (15.6%). Exposed people believed that the most important and basic reason for needle stick injuries was patients crowdedness and hospital chaos (37.8%). There was no relation between ages, gender, years of professional life, education level and needle stick injuries but men used latex gloves less than women and did recapping needles more than them. CONCLUSIONS: The needle-stick injuries in nursing workers of Khanevadeh hospital (Tehran) were significantly less than other similar studies in Iran. PMID- 21589792 TI - Nursing students' immediate responses to distressed clients based on Orlando's theory. AB - BACKGROUND: Nowadays, problem solving skills, clinical decision making ability and making a proper relationship to clients are essential necessities for nursing graduates; however there are few studies which investigated nursing students' responses to clients with problematic situations based on nursing theories addressing interactions. The purpose of this study was to analyze the nursing students' immediate responses to distressed clients' behaviors focusing on collaborative Orlando's theory. METHODS: This exploratory study was assessed 60 nursing students' responses to a simulated clients' questionnaire based on Orlando's theory in 2008. All of the students were enrolled in bachelor degree of nursing. The data were analyzed by dimensional content analysis to specify the key categories, according to concepts of Orlando's theory. RESULTS: According to Orlando's theory, students' immediate responses to physical and mental problems of distressed clients were classified into 6 main categories: physical caring, uncertainty, assuring, recommending, asking information and explaining. The most frequent responses to clients' behaviors were physical caring, assuring and recommending and most of the students were unable to respond to mental problems. CONCLUSIONS: Nursing students responded to clients' needs automatically and they did not consider clients' ability in decision making. Medical diagnosis, physical caring and assuring were their main concerns and they were confused in responding to mental problems. Orlando's theory emphasizes on nurse-client interactions and considers nurses' perceptions, thoughts, and feelings. It views clients as a participant in care giving, so teaching this theory can enhance students' communication skills and improve quality of nursing care. PMID- 21589793 TI - The relationship between knowledge of ergonomic science and the occupational health among nursing staff affiliated to Golestan University of Medical Sciences. AB - BACKGROUND: Occupational hazards are much higher for nurses than many other jobs and neglecting this fact may reduce the quality of nursing services. The aim of this study was to investigate the relationship between knowledge of ergonomics and occupational health among the nursing staff affiliated to Golestan University of Medical Sciences. METHODS: It was a cross-sectional analytical study on 423 nursing staff working in various medical centers affiliated to Golestan University of Medical Sciences in 2008, selected by quota randomized sampling. Data collection instrument was Ergonomics Questionnaire, which consisted of 72 questions. Cronbach's alpha for main sections of the questionnaire was 0.8, 0.8 and 0.9. Descriptive and analytical tests were used for data analysis and an alpha error of 5% was considered. RESULTS: Of all the subjects, 36.1% had 5-10 years of work experience, 61.9% had a good knowledge of ergonomic principles, and 83% were exposed to a mild level of occupational hazards. There was no significant relationship between knowledge of ergonomics and occupational health (p = 0.08). The relationships between knowledge of ergonomics and age, gender, marital status, work experience, the type, and the location of service were significant (p < 0.05). The relationship between occupational health and age, work experience, employment type, and location of service were also statistically significant (p < 0.05). CONCLUSIONS: Training staff to do their job in the best way, taking breaks between long working hours, using appropriate tools and facilities and paying attention to ergonomics can provide a healthier work environment for nurses and optimize human resource efficiency. PMID- 21589794 TI - The relationship between work-family conflict and the level of self-efficacy in female nurses in Alzahra Hospital. AB - BACKGROUND: Work-family conflict has many negative outcomes for organization and career and family life of each person. The aim of present study was to determine the relationship between work-family conflict and the level of self-efficacy in female nurses. METHODS: In this cross-sectional descriptive research, the relationship between work-family conflict and the level of self-efficacy in female nurses of Alzahra Hospital was assessed. Questionnaire, demographic data form, work-family conflict scale and self-efficacy scale were the data collection tools. Content analysis and Cronbach's alpha were used for evaluating the validity and reliability of questionnaire. The study sample included 160 nurses (80 permanent nurses and 80 contract-based nurses) selected through simple random sampling from nurses working in different wards of Alzahra Hospital. Data analysis was done using SPSS software. RESULTS: There was significant difference in work-family conflict between the two groups of permanent and contract-based nurses (p = 0.02). Also, a significant difference in the level of self-efficacy was observed between the two groups of nurses (p = 0.03). CONCLUSIONS: The level of self-efficacy and work-family conflict in contract-based nurses was not acceptable. Therefore, it is suggested to arrange courses to train effective skills in the field of management of work-family conflicts in order to increase the level of self-efficacy for contract-based nurses. PMID- 21589795 TI - Microencapsulation: A promising technique for controlled drug delivery. AB - MICROPARTICLES OFFER VARIOUS SIGNIFICANT ADVANTAGES AS DRUG DELIVERY SYSTEMS, INCLUDING: (i) an effective protection of the encapsulated active agent against (e.g. enzymatic) degradation, (ii) the possibility to accurately control the release rate of the incorporated drug over periods of hours to months, (iii) an easy administration (compared to alternative parenteral controlled release dosage forms, such as macro-sized implants), and (iv) Desired, pre-programmed drug release profiles can be provided which match the therapeutic needs of the patient. This article gives an overview on the general aspects and recent advances in drug-loaded microparticles to improve the efficiency of various medical treatments. An appropriately designed controlled release drug delivery system can be a foot ahead towards solving problems concerning to the targeting of drug to a specific organ or tissue, and controlling the rate of drug delivery to the target site. The development of oral controlled release systems has been a challenge to formulation scientist due to their inability to restrain and localize the system at targeted areas of gastrointestinal tract. Microparticulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. The objective of this paper is to take a closer look at microparticles as drug delivery devices for increasing efficiency of drug delivery, improving the release profile and drug targeting. In order to appreciate the application possibilities of microcapsules in drug delivery, some fundamental aspects are briefly reviewed. PMID- 21589796 TI - Investigations on interpolymer complexes of cationic guar gum and xanthan gum for formulation of bioadhesive films. AB - The present study was aimed at evaluating the possible use of inter polymer complexed (IPC) films of xanthan gum (XG) and cationic guar gum (CGG) for formulating domperidone bioadhesive films. Formation of bonds between -COO- groups of XG and -N(+)(CH(3))(3) groups of CGG was evident in the FTIR spectra of IPC films. Bioadhesive strength of the films was evaluated employing texture analyser. Water uptake studies indicated swelling to be a function of XG concentration in the interpolymer complexes. The bioadhesive films were found to possess neutral pH. In vitro drug release studies and residence time studies indicated that the film comprising CGG:XG (80:20) released 98% of domperidone in 8 h and exhibited a residence time of approximately 8 h. Enhanced bioavailability of domperidone was observed from bioadhesive films as compared to orally administered conventional tablets. Overall, the findings suggest that IPC films of XG and CGG, exhibiting desired bioadhesive strength and enhanced bioavailability of domperidone, can be prepared. PMID- 21589797 TI - Preparation and characterization of microparticles of piroxicam by spray drying and spray chilling methods. AB - Piroxicam, an anti-inflammatory drug, exhibits poor water solubility and flow properties, poor dissolution and poor wetting. Consequently, the aim of this study was to improve the dissolution of piroxicam. Microparticles containing piroxicam were produced by spray drying, using isopropyl alcohol and water in the ratio of 40:60 v/v as solvent system, and spray chilling technology by melting the drug and chilling it with a pneumatic nozzle to enhance dissolution rate. The prepared formulations were evaluated for in vitro dissolution and solubility. The prepared drug particles were characterized by scanning electron microscopy (SEM), differential scanning calorimeter, X-ray diffraction and Fourier transform infrared spectroscopy. Dissolution profile of the spray dried microparticles was compared with spray-chilled microparticles, pure and recrystallized samples. Spray dried microparticles and spray chilled microparticles exhibited decreased crystallinity and improved micromeritic properties. The dissolution of the spray dried microparticle and spray chilled particles were improved compared with recrystallized and pure sample of piroxicam. Consequently, it was believed that spray drying of piroxicam is a useful tool to improve dissolution but not in case of spray chilling. This may be due to the degradation of drug or variations in the resonance structure or could be due to minor distortion of bond angles. Hence, this spray drying technique can be used for formulation of tablets of piroxicam by direct compression with directly compressible tablet excipients. PMID- 21589798 TI - Evidence of active transport involvement in morphine transport via MDCKII and MDCK-PGP cell lines. AB - Several transporters appear to be important in transporting various drugs. Many patients, who receive morphine as analgesic medication, also receive other medications with potency of changing morphine transport by affecting P glycoprotein (P-GP) and oatp2 transport system. This could influence morphine pharmacokinetics and pharmacodynamics. The aim of present study was to elucidate the transport mechanisms involved in transporting morphine via MDCKII and MDCK PGP cells. Morphine permeability was examined in the presence of various compounds with ability in inhibiting different transport systems including: digoxin, probenecid and d- glucose. The effect of morphine concentration changes on its transport was also examined. Morphine concentration was measured using HPLC with electrochemical detector. Morphine permeability via a MDCK II cells was greater than sucrose permeability, and reduced when a P-GP expressed cell line was used. Its permeability was increased significantly in the presence of a strong P-GP inhibitor. Morphine permeability decreased significantly in the presence of digoxin but not in the presence of d-glucose or probenecid. These results showed that morphine was a P-GP substrate, and digoxin related transporters such as oatp2 were involved in its transport. Morphine was not substrate for glucose or probenecid-sensitive transporters. PMID- 21589799 TI - Niosome as a drug carrier for topical delivery of N-acetyl glucosamine. AB - Niosomes are non-ionic surfactant vesicles that have potential applications in the delivery of hydrophilic and hydrophobic drugs. The topical form of N-acetyl glucosamine (NAG) recently has been considered in the treatment of hyperpigmentation disorders due to its inhibitory effect on thyrosinase enzymes in melanocytes. To improve NAG penetration into the skin we formulated the drug in niosomes and investigated its flux across excised rat skin using Franz diffusion cells. The drug assay was performed by a novel and specific high performance liquid chromatography method. Niosomal vesicles were further characterized by optical and scanning electron microscopy and particle size analysis. Niosomes prepared with Span 40 produced a drug encapsulation of about 50%. The vesicle size was markedly dependent on the composition of the niosome formulations and was in range of 500-4500 nm (Span 80 < Span 60 < Span 40 niosomes). Span 40-niosomes provided a higher NAG flux across the skin than Span 60- and Span 80-nisomes. All formulations significantly improved the extent of drug assessed to be localized in the skin (P< 0.05), as compared to NAG hydroalcoholic (HA) solution. Our study demonstrated the potential of niosomes for improved NAG localization in the skin, as needed in hyperpigmentation disorders. PMID- 21589800 TI - Effect of cerium lanthanide on Hela and MCF-7 cancer cell growth in the presence of transferring. AB - The anti-cancer activity of metal ions in the lanthanide group is being considered recently. It has been reported that cerium salts might stimulate the metabolism and therefore, produce anti-cancer effects. However, little is known about the effects of protein-cerium complex in controlling cancer cell growth. The aim of the present study was to elucidate the possible pathways for the cytotoxic effect of cerium in the presence of apo-transferrin on two cancer cell lines (Hela and MCF-7), that express transferrin receptors 3-4 fold higher than normal cells. The effect of different concentrations of cerium (0.1, 1, 10, 100 MUM) in the presence and absence of transferrin for 48 h and 72 h incubation periods (37 degrees C, 5% CO2 and 95% humidity) was studied using the MTT assay. The results showed that cerium has a cell-proliferation inhibitory activity which is significantly increased by transferrin protein. Compared with the direct treatment of cancer cells with cerium, the presence of transferrin assisted inhibition of cell proliferation by 20% and 40% in Hela and MCF-7 cells, respectively. Though apo-transferrin could lightly induce cell growth particularly in MCF-7 cells by itself, this phenomenon could not overcome the cerium-protein cell-proliferation inhibition activity. In conclusion, our results indicate that at a certain concentration, the cerium compounds could be possibly involved in the control of cell proliferation and inhibiting the growth of cancer cells. PMID- 21589801 TI - In vitro controlled release of colon targeted mesalamine from compritol ATO 888 based matrix tablets using factorial design. AB - A controlled release matrix formulation for mesalamine was designed and developed to achieve a 24 h release profile. Using compritol 888 ATO (glyceryl behenate) as an inert matrix-forming agent to control the release of mesalamine, formulation granules containing the solid dispersions were investigated. Pectin, a polysaccharide, was used as bacterial dependent polymer for colon targeting. The matrix tablets for these formulations were prepared by direct compression and their in vitro release tests were carried out. A 3(2) full factorial design was used for optimization by taking the amounts of glyceryl behenate (X(1)) and pectin (X(2)) as independent variables and percentage drug released at 2 (Q(2)), 16 (Q(16)) and 24 (Q(24)) h as dependent variables. Drug release from the matrix tablets formulations lasted for over 24 h. Images of the tablet surface and cross section were characterized by scanning electron microscopy to show the formed pores and channels in the matrices. These may provide the release pathway for the inner embedded drugs. The co-mixing of polysaccharide pectin, into the waxy matrices played a meaningful role in targeting the tablets to colon. The drug release from the novel formulation may be attributed to the diffusion-controlled mechanism. The results of the full factorial design indicated that an optimum amount of compritol ATO 888 and a high amount of pectin favors the colon targeting and controlled release of mesalamine from dosage form. PMID- 21589802 TI - Enhanced dissolution rate of felodipine using spherical agglomeration with Inutec SP1 by quasi emulsion solvent diffusion method. AB - Felodipine is a second generation calcium channel blocker widely used as antihypertensive and antianginal drug which belongs to BCS class II category. Hence, its low water solubility limits the pharmacological effect. The aim of this study was to improve the dissolution rate of felodipine using spherical agglomeration technique with acetone, water and dichloromethane as good solvent, poor solvent and bridging liquid, respectively. The quasi emulsion solvent diffusion technique was used as a method for spherical agglomeration. Inutec SP1 was used as an emulsion stabilizer and as hydrophilic polymer in agglomeration process. The FTIR and DSC results showed no change in the drug after crystallization process. PXRD studies showed sharp peaks in the diffractograms of spherical agglomerates with minor reduction in height of the peaks. The particle size of spherical agglomerates (FI-2) was about 134.33 +/- 13.57 um, n=3 and the dissolution efficiency of felodipine up to 120 min increased to about 4-fold in phosphate buffer containing 1.8% Tween 80 (pH 6.8). Spherical agglomerates showed enhanced solubility compared to untreated powder possibly due to the partial conversion to amorphous form. PMID- 21589803 TI - Assessment of potassium current in Royan B(1) stem cell derived cardiomyocytes by patch-clamp technique. AB - Embryonic stem cells are capable of differentiating to variety of cell tissues including cardiomyocytes. This developmental change is accompanied with a great deal of ion channel expression and functions. Mouse stem cell derived cardiomyocytes were prepared and separated to yield isolated single cell suspension for cell current recording. In the present study some properties of the K(+)-current in Royan B(1) stem cell derived cardiomyocytes were investigated using whole cell patch-clamp technique. When the holding potential was - 60 mV, in some cells a major outward current was elicited by square depolarizing pulses from -60 mV to +50 mV. This outward current was sustained for the duration of 300 ms test pulse. The sustained outward K(+) current was inhibited by tetraethylammonium (10 mM) indicating the activity of Ca(2+) activated K(+) channel in these cells. In some of the cells with 0.2 mM 3,ethylene glycol-bis (beta-aminoethyl ether) N,N,N('),N(')-tetraacetic acid in the pipette, only a very small outward current was recorded which suggests that in these cells the voltage activated K(+) channels is either absent or if existed it is not fully functional. Other cells were in far between, indicating that voltage activated K(+) channels are developing in these cells but it is not yet fully functional. In conclusion, we have identified functional large conductance Ca(2+) activated K(+) channel in Royan B(1) stem cell derived cardiomyocytes. PMID- 21589804 TI - Financial performance of the teaching pharmacies in Isfahan: an economic evaluation. AB - Teaching pharmacies are amongst the important cornerstones of a healthcare system for drug supplying, pharmacy education and pharmacy practice research. Assessment of the Iranian healthcare system costs shows that after personnel charges, drug outlay is the second expensive factor. This great financial mass requires integral audit and management in order to provide costumers satisfaction in addition to financial viability. Teaching pharmacies are required to realize financial viability as well as providing several educational and drug servicing goals, which makes microeconomic analysis important. The aim of this study was to evaluate the financial performance of the teaching pharmacies affiliated with the Isfahan University of Medical Sciences (with the abrreviated names as: SHM, ISJ, AZH for the confidentialiy of the financial data). This is a descriptive and cross-sectional study done in 2008. The target pharmacies of this study were all the 3 teaching pharmacies affiliated with the Isfahan University of Medical Sciences. The data collecting template was prepared using the standard scientific methods according to the goals of this research The goals also nominated necessary items needed in economic profit evaluation. The data collection template was completed by reference to the teaching pharmacies financial documents and reports, used as a base for calculating the total income and the total costs in 2007-2008 financial year. The difference between these two balances showed the value of profits or loss. The profit/cost ratio was also calculated, using the proportion of the total income to the total costs. The collected data was statistically analyzed using the Excel software (Microsoft 2007). For the financial year 2007-2008, the difference between the total income and the total costs was -831.6 million Rials (excess costs to income) for the SHM pharmacy, + 25.4 billion Rials for the ISJ pharmacy and -429.5 million Rials for the AZH pharmacy. According to our findings there is a strong requirement to improve the financial performance of all the three teaching pharmacies while maintaining a high standardard of teaching and educational affairs. PMID- 21589805 TI - Screening the methanol extracts of some Iranian plants for acetylcholinesterase inhibitory activity. AB - Acetylcholinesterase (AChE) is the main enzyme for the breakdown of acetylcholine. Nowadays, usage of the inhibitors of this enzyme is one of the most important types of treatment of mild to moderate neurodegenerative diseases such as Alzheimer's disease. Herbal medicines can be a new source of inhibitors of this enzyme. In this study we examined around 100 different plants to evaluate their inhibitory properties for AChE enzyme. Plants were scientifically identified and their extracts were prepared by methanol percolation. Acetylcholinesterase activity was measured using a colorimetric method in the presence or absence of the extracts. Eserine was used as a positive control. Methanol extracts of the Levisticum officinale, Bergeris integrima and Rheum ribes showed more than 50% AChE inhibitory activity. The inhibition kinetics were studied in the presence of the most effective extracts. L. officinale and B. integrima inhibited AChE activity in a non-competitive manner, while R. ribes competitively inhibitied the enzyme as revealed by double-reciprocal Linweaver Burk plot analysis. Under controlled condition, K(m) and V(max) values of the enzyme were found to be 9.4 mM and 0.238 mM/min, respectively. However, in the presence of L. officinale, B. integrima, and R. ribes extracts, V(max) values were 0.192, 0.074 and 0.238 mM/min, respectively. Due to the competitive inhibition of the enzyme by R. ribes extract, the K(m) value of 21.2 mM was obtained. The concentration required for 50% enzyme inhibition (IC50 value) was 0.5, 0.9, and 0.95 mg/ml for the L. officinale, B. integrima and R. ribes extracts, respectively. The IC50 of the eserine was determined to be 0.8 mg/ml. PMID- 21589806 TI - Oral bioavailability and pharmacokinetic study of cetrizine HCl in Iranian healthy volunteers. AB - The objective of the present study was to evaluate the pharmacokinetic parameters and bioavailability of a selective histamine (H1)-receptor antagonist, cetirizine hydrochloride (CTZ), following administration of a single oral dose of the drug. The properties of a test compound were compared with those of a reference product in a randomized cross-over study in 12 volunteers. Blood samples were collected at selected time intervals up to 24 h and plasma concentrations of CTZ were determined using a validated HPLC method. Pharmacokinetic parameters including T(1/2), T(1/2)(abs), K, K(a), T(max), C(max), V(d)/F, Cl/F, AUC(0-24), AUC (0 infinity) and MRT were determined from plasma concentration-time profiles for tested products and found to be in good agreement with previous reports. The analysis of variance did not show any significant differences between the test and reference products. The confidence intervals for the ratio of C(max) (95 110%), AUC(0-24) (91-112%) and AUC(0-infinity) (92-109%) for the test and reference products were within the acceptable interval of 80-125%. ANOVA assessment of logarithmically transformed data did not reveal any significant subject, period or sequence effects. It was, therefore, concluded that the two products were bioequivalent and could be used interchangeably. PMID- 21589807 TI - QSAR study of some 5-methyl/trifluoromethoxy- 1H-indole-2,3-dione-3 thiosemicarbazone derivatives as anti-tubercular agents. AB - In the present study, quantitative relationships between molecular structure and anti-tubercular activity of some 5-methyl/trifluoromethoxy-1H-indole-2,3-dione-3 thiosemicarbazone derivatives were discovered. The detailed application of an efficient linear method and principal component regression (PCR) for the evaluation of quantitative structure activity relationships of the studied compounds is demonstrated. Components produced by principal component analysis were used as the input for a linear model development. Results indicate a linear relationship between the principal components obtained from molecular descriptors and the inhibitory activity of this set of molecules. The maximum variance in the activity of the molecules in PCR method was 73%. The performance of the developed model was tested by several validation methods. PMID- 21589808 TI - Cytotoxic activities of selected medicinal plants from Iran and phytochemical evaluation of the most potent extract. AB - Methanolic extract of 15 Iranian medicinal plants were prepared and tested for their cytotoxic activities against three cancer cell lines (MCF7, HepG2, WEHI164) and one normal cell line (MDBK). Some plants showed cytotoxic activities. The extract of Ferula szowitsiana root, which proved to be the most active, was chosen for further phytochemical studies. The major compounds of the most potent acetone extract were isolated. They were identified as chimgin and chimganin, two known monoterpenoids, by spectroscopic means. Their cytotoxic activity was evaluated in three cell lines. The results show that these compounds are responsible, at least in part, for the cytotoxic activity of this plant. PMID- 21589809 TI - From the Executive Editor's Perspective ... PMID- 21589810 TI - From the Editor-in-Chief's Perspective ... PMID- 21589811 TI - From the Research Editor's Perspective... PMID- 21589812 TI - From the Education Editor's Perspective ... PMID- 21589813 TI - From the Practice Editor's Perspective ... PMID- 21589814 TI - Clinical reasoning in massage therapy. AB - BACKGROUND: Clinical reasoning has long been a valuable tool for health care practitioners, but it has been under-researched in the field of massage therapy. Case reports have been a useful method for exploring the clinical reasoning process in various fields of manual therapy and can provide a model for similar research in the field of massage therapy. A diagnostically challenging case concerning a client with low back pain serves as a guideline for examining the clinical reasoning process of a massage therapist. METHODS: A two-part methodology was employed: Client profileReflective inquiry The inquiry included questions pertaining to beliefs about health problems; beliefs about the mechanisms of pain; medical conditions that could explain the client's symptoms; knowledge of the client's anatomy, assessment, and treatment choices; observations made during treatment; extent of experience in treating similar problems; and ability to recognize clinical patterns. RESULTS: The clinical reasoning process of a massage therapist contributed to a differential diagnosis, which provided an explanation for the client's symptoms and led to a satisfactory treatment resolution. CONCLUSION: The present report serves as an example of the value of clinical reasoning in the field of massage therapy, and the need for expanded research into its methods and applications. The results of such research could be beneficial in teaching the clinical reasoning process at both the introductory and the advanced levels of massage therapy education. PMID- 21589815 TI - Steps toward massage therapy guidelines: a first report to the profession. AB - The massage profession has grown rapidly since the late 1980s. As with business startups that begin informally and successfully mature into larger enterprises, growth brings new organizational challenges, together with greater visibility and opportunity. The maturation of massage as a health care profession increases the need for a process to formalize the synthesis of massage therapy knowledge from clinical experience and research-to collect what we know and to make such baseline knowledge widely available to practitioners, consumers, and other health care stakeholders. In short, we need to create a process for setting guidelines.The present paper lays out the motivations and framework for creating massage therapy guidelines that are informed both by research and by clinical experience. It also acts as a report to the massage therapy profession and to other stakeholders about the work of the Best Practices Committee of the Massage Therapy Foundation since 2006. And it has the additional goal of providing a health care literature basis for future academic discussions of massage.The discussion here is based on a definition from the Institute of Medicine and on research into the nature of expertise. Guidelines are targeted for submission to the National Guideline Clearinghouse. Challenges in creating guidelines for massage therapy are discussed. Various stakeholders are considered. Current literature from the wider scope of health care is extensively reviewed. Topics addressed include guideline creation, credentialing of complementary and alternative medicine practitioners, definition of competence, and the increasing role of technology (that is, informatics) in managing training and task-necessary competencies. Finally, a process for creation of massage therapy guidelines is proposed. A central feature of the proposal is the use of a "World Cafe" symposium to elicit knowledge and solutions from diverse experts. The role of transparency and broad and open peer review is emphasized as essential to the usability and credibility of guidelines. PMID- 21589818 TI - Does Helicobacter pylori play a role in the pathogenesis of childhood chronic idiopathic thrombocytopenic purpura? AB - Idiopathic thrombocytopenic purpura (ITP) is an acute self-limited bleeding disorder that can progress to chronic form in 10-15% of the cases. Helicobacter pylori (H. pylori) infection is a possible cause of chronic ITP. We studied 30 children with resistant chronic ITP for H. pylori infection based on the detection of H. pylori fecal antigen. This retrospective study was based on data obtained from medical records of 30 children aged between five and 17 years (median age at ITP diagnosis was ten years). A specially-designed data sheet was used to record information on age, sex, duration of disease, family history of bleeding disorders, previous treatments and median platelet count. In patients with H. pylori infection, antimicrobial treatment consisted of amoxicillin, metronidazol and omeprazol. Response was assessed every month for one year and defined as complete (platelet count >150*10(9)/L) or partial (platelet count between 50 and 150*10(9)/L). We detected H. pylori infection in 5 patients. In 4 of them increased platelet count was seen during one year of follow-up and in one patient the platelet count was acceptable during six months. Although the pathological mechanism of H. pylori-induced thrombocytopenia was unclear in our patient sample, the assessment of H. pylori infection and use of eradication therapy should be attempted in chronic and resistant ITP patients. PMID- 21589819 TI - A thirteen year old female with primary T-cell rich B-cell lymphoma of bone masquerading as chronic recurrent multifocal osteomyelitis. AB - Primary lymphoma of the bone (PLB) accounts for 2% of all non-Hodgkin's lymphomas, and until recently it had not been well characterized in literature. Most cases present in adulthood (average age 50), with localized painful lesions in the long bones, cranium, or axial skeleton.We describe a case of multifocal PLB in an adolescent female. In this case, the initial presentation, with migratory large joint polyarthralgias and bone pain, mimicked chronic recurrent multifocal osteomyelitis (CRMO). Had a biopsy not been performed the diagnosis would have been missed. PMID- 21589817 TI - Metabolic syndrome in the pediatric population: a short overview. AB - The metabolic syndrome (MS) in adults is defined as a concurrence of obesity, disturbed glucose and insulin metabolism, hypertension and dyslipidemia, and is associated with increased morbidity and mortality from cardiovascular diseases and type 2 diabetes. Studies now indicate that many of its components are also present in children and adolescents. Moreover, the clustering of these risk factors has been documented in some children, who are at increased cardiovascular risk in adulthood. The MS is highly prevalent among overweight children and adolescents. Identifying these children is important for early prevention and treatment of different components of the syndrome. The first-line treatment comprises lifestyle modification consisting of diet and exercise. The most effective tool for prevention of the MS is to stop the development of childhood obesity. The first attempt at consensus-based pediatric diagnostic criteria was published in 2007 by the International Diabetes Federation. Nevertheless, national prevalence data, based on uniform pediatric definition, protocols for prevention, early recognition and effective treatment of pediatric MS are still needed.The aim of this article is to provide a short overview of the diagnosis and treatment options of childhood MS, as well as to present the relationships between MS and its individual components. PMID- 21589820 TI - Methylenetetrahydrofolate reductase homozygous mutation in a young boy with cerebellar infarction. AB - Posterior circulation vascular occlusive disease in children is a rare and uncommonly reported event. Among the numerous risk factors, the methylenetetrahydrofolate reductase (MTHFR) mutation is considered to be a common genetic cause of thrombosis in adults and children. Recently, a link between the MTHFR mutation and cerebrovascular disorders was reported in children. Diffusion tensor imaging (DTI) is a great improvement on magnetic resonance imaging (MRI), making the in vivo anatomical and pathological study of the brain and its fibers possible. In our patient cerebellar infarction was associated with MTHFR mutation and, in a standard neurological examination, DTI revealed normal white matter tracts. PMID- 21589821 TI - Henoch-Schonlein purpura presenting with symptoms mimicking balanoposthitis. AB - Henoch-Schonlein purpura is a leukocytoclastic vasculitis, characterized with palpable purpuric rush and collection of immunglobuline A (Ig A) around small vessels. Onset of purpuric rush at gluteus and lower extremities is the main symptom of the disease, however it presents with a wide variety of signs and symptoms. Here, we present a two-year-old boy who had presented with penile swelling and color change. Then, purpuric rush was occurred and it was seen spontenous resolution on second day without treatment. PMID- 21589822 TI - Amyand's hernia in a child with permanent neonatal diabetes due to pancreatic agenesis. AB - Acute or perforated appendicitis within inguinal hernia is rarely encountered and it is known as Amyand's hernia. We report on the first case occurring in a 4-year old boy affected by permanent neonatal diabetes mellitus due to pancreatic agenesis, an extremely rare condition. The initial suspicion of inguinal hernia was confirmed by ultrasound examination of the right inguinal region which revealed omental layers inside a swollen inguinal canal; this finding and the clinical presentation allowed a prompt and appropriate surgical management. The careful evaluation of this patient and early recognition of this unique presentation of appendicitis allowed trans-hernial appendectomy and immediate herniorrhaphy. Ultrasonography played a pivotal role to reach the correct diagnosis and to start a prompt treatment. PMID- 21589823 TI - Autologous adipocyte graft in endoscopic treatment of vesico-renal reflux in children: a preliminary study. AB - No bulking agent is ideal for endoscopically treating vesico-renal reflux in children. Many teams have tried to find a safe and efficient material, ideally an autologous material. We describe here a protocol for the use of autologous viable fat in the treatment of primary vesico-renal reflux in children aged from 3 to 15 years. Fat harvesting was done from the medial side of the thigh by manual aspiration. Samples were centrifuged to purify the graft from blood and lipid. Lastly fat was injected beneath the pathologic ureter by a conventional endoscopic technique. A voiding cystourethrography (VCUG) closed the procedure. Follow-up included renal ultrasonography the day after surgery, and one and three months later. A VCUG was performed systematically at three months and, in cases of acute pyelonephritis, during the survey.Sixty-four children with 94 refluxing units were treated by autologous fat injection with a follow-up from 6 to 40 months. At the end of the procedure, we systematically obtained a very good increase in height of the pathologic meatus and VCUG was normal in all cases. None presented with an obstruction during the follow-up period. Two children presented with an acute pyelonephritis before the third month. At three months, VCUG was not realized in 14 cases (22%) because the parents refused the procedure. One of those children presented with an acute pyelonephritis five months after endoscopic treatment. VCUG was normal for 17 of 50 children (34%), and showed a real improvement for 19 other children (38%). Three children had a surgical reimplantation because of the persistence of an unchanged high-grade vesico-renal reflux; histological examination found viable adipocytes on sections of the distal pathologic ureter. Clinically, 11 children (17%) presented with an acute pyelonephritis after treatment at a mean follow-up time of 10 months.These preliminary findings led us to modify the technique in order to improve our results. Our first concern is feasibility and safety of this technique, regardless of the use of other synthetic bulking agents the innocuousness of which is uncertain. PMID- 21589824 TI - An unusual cause of intestinal obstruction in an adolescent: a case report and management review. AB - A 15-year-old boy presented with intestinal obstruction two weeks following a blunt abdominal trauma. He had progressive bilious vomiting without abdominal distension or peritonitis. The contrast computed tomography (CT) scan of the abdomen provided the definitive diagnosis: there was an obstructing duodenal hematoma, which might have been slowly progressing or have arisen from secondary hemorrhage after the initial injury. The boy remained stable over a ten-day period of conservative treatment, and his obstructive symptoms and signs were resolved completely. A follow-up CT scan of the abdomen (16 days after admission) showed an almost complete resolution of the hematoma. Delayed duodenal hematoma causing intestinal obstruction has been reported rarely in previous literature. Occasionally a significant secondary hemorrhage resulting in intestinal obstruction can become life threatening. Clinical follow-up is paramount after initial recovery. Although conservative treatment suffices in most cases, the surgeon should be wary of the need for definitive surgical intervention if there is evidence of ongoing acute hemorrhage or of the obstructing hematoma failing to resolve. Laparoscopic drainage of the hematoma provides optimistic results for patients failing conservative management. PMID- 21589825 TI - Pediatric thioridazine poisoning as a result of a pharmacy compounding error. AB - The adverse effects or overdose of thioridazine including sudden death, fatal arrhythmia, or retinopathy, in addition to the neurological signs have been reported. A three-year-old boy with bronchitis was prescribed erythromycin by a local clinic, but he started to complain of severe drowsiness and became unconscious. It was decided that this was a result of a compounding error of thioridazine instead of erythromycin owing to their similar commercial names. The thioridazine concentration in the child's serum on admission was two to three times higher than the Cmax for adults with the same dosage. The concentration of the lavage saline on admission was only 0.3% of the ingested amount, indicating that the lavage was not effective in our case. Pharmacokinetic analysis revealed the parameters as Tmax, 1.5 hr; Cmax, 1700 ng/mL; Ka, 2.01 L/hr; Vd, 3.6 L/kg; and T1/2, 6.8 hr. Further investigations on clinical cases with a pharmacokinetic analysis should be done to confirm the pharmacokinetic evidence obtained here and to give specific therapeutic guidelines for overdose management especially in children. PMID- 21589826 TI - Evans syndrome and antibody deficiency: an atypical presentation of chromosome 22q11.2 deletion syndrome. AB - We report a case of an 8-year-old male patient with Evans syndrome and severe hypogammaglobulinemia, subsequently in whom the 22q11.2 deletion syndrome (22q11.2 DS) was diagnosed. No other clinical sign of 22q11.2 DS was present with the exception of slight facial dysmorphism. The case is of particular interest because it suggests the need to research chromosome 22q11.2 deletion in patients who present with autoimmune cytopenia and peculiar facial abnormalities, which could be an atypical presentation of an incomplete form of 22q11.2 DS. PMID- 21589827 TI - Liver transplantation in Greek children: 15 years experience. AB - Liver transplantation (LT) is the only available live-saving procedure for children with irreversible liver failure. This paper reports our experience from the follow-up of 16 Greek children with end-stage liver failure who underwent a LT. Over a period of 15 years, 16 pediatric liver recipients received follow up after being subjected to OLT (orthotopic liver transplantation) due to end-stage liver failure. Nine children initially presented with extrahepatic biliary atresia, 2 with acute liver failure after toxic mushroom ingestion, 2 with intrahepatic cholestasis, 2 with metabolic diseases and one with hepatoblastoma. Ten children received a liver transplant in the Organ Transplantation Unit of Aristotle University of Thessaloniki and the rest in other transplant centers. Three transplants came from a living-related donor and 13 from a deceased donor. Six children underwent immunosuppressive treatment with cyclosporine, mycophenolate mofetil and corticosteroids, and 7 with tacrolimus, mycophenolate mofetil and corticosteroids. Three out of 16 children died within the first month after the transplantation due to post-transplant complications. Three children presented with acute rejection and one with chronic organ rejection which was successfully managed. Five children presented with cytomegalovirus infection, 5 with Epstein-Barr virus, 2 with HSV(1,2), 2 with ParvoB19 virus, 2 with varicella zoster virus and one with C. Albicans infection. One child presented with upper gastrointestinal hemorrhage and one with small biliary paucity. A satisfying outcome was achieved in most cases, with good graft function, except for the patient with small biliary paucity who required re-transplantation.The long-term clinical course of liver transplanted children is good under the condition that they are attended in specialized centers. PMID- 21589828 TI - Predictive value of developmental testing in the second year for cognitive development at five years of age. AB - There is mixed evidence about the predictive validity of the Griffiths mental developmental scales. This study aimed to assess the predictive value of developmental assessments of children in their second year using the Griffiths mental development scales for neuro-developmental status at five years using the Wechsler preschool and primary scale of intelligence, revised (WPPSI-R). In a longitudinal study 253 children were assessed in their second year of life using the Griffiths scales and again at five years using the WPPSI-R. The scores were compared and the predictability of the WPPSI-R outcome on the basis of Griffiths scores was assessed. The WPPSI-R full scale IQ and the performance IQ at age five could be predicted moderately by the Griffiths general quotient (GQ) and by the personal/social scale. The Griffiths GQ was not a significant predictor of verbal IQ at age 5. The Griffiths performance scale predicted subsequent WPPSI-R performance IQ, and marginally the Full Scale IQ. For the early identification of children at risk for language delay, the Griffiths scales may not be suitable. However, a shortened form would be useful to predict overall cognitive development from the second year to school entry, focussing on the personal social and performance scales. PMID- 21589829 TI - Weight status and depressive symptoms in 18 year-old Greek adolescents. AB - Depressive symptoms in adolescence have been a subject of considerable controversy in terms of their nature, severity and identification. The aim of the study was to investigate the possible association between weight status and depressive symptoms among 18 year-old Greek adolescents. A cross-sectional study design was used. The study population consisted of 200 students of the University of Athens who fulfilled the following criteria: age 18 years, absence of clinical depression, no history of hospitalization in a mental institution, no history of alcohol abuse. Weight status was assessed by Body Mass Index (BMI) (kg/m(2)) and calculated from weight and height measurements. Severity of depressive symptoms was assessed by Centre for Epidemiologic Studies-Depression Scale (CES-D). In univariate analysis, CES-D score was significantly associated with adolescents' gender and BMI. The multivariate analysis showed that CES-D score was negatively related to BMI even after controlling the confounding effect of gender (P=0.018, B=-0.378). Depressive symptoms are related to weight status of adolescents. PMID- 21589830 TI - Efficacy of intravenous ondansetron to prevent vomiting episodes in acute gastroenteritis: a randomized, double blind, and controlled trial. AB - Acute gastroenteritis is one of the most common infectious diseases of childhood. Its symptoms are vomiting, diarrhea, and dehydration. In the emergency ward, intravenous rather than oral rehydration is usually preferred because of the high likelihood of emesis. Treatments to reduce emesis are of value in improving the rehydration procedure. Our study is a double-blind randomized trial and proposes the use of ondansetron as an antiemetic drug to treat children with acute gas troenteritis. Seventy-four in-patients, aged 3 months to 15 years, were enrolled and randomly assigned to an ondansetron or placebo group. Inclusion criteria were the diagnosis of acute gastroenteritis and the absence of other diseases or allergies to drugs. A single bolus (0.15 mg/kg) of ondansetron was injected intravenously; normal 0.9% saline solution was used as a placebo. This treatment induced vomiting cessation in the ondansetron group significantly in comparison to the placebo group. The length of the hospital stay and the oral rehydration fluid volume were similar in the two groups and no adverse effects were noticed. Thus, safety, low cost, and overall benefit of ondansetron treatment suggests that this drug can be administered successfully to children with acute gastroenteritis. PMID- 21589831 TI - Colonic phasic motor activity is stronger in patients with repaired anorectal malformations than patients with severe colonic dismotility. AB - In this study, colonic manometry studies of the patients with repaired anorectal malformations (ARM) were compared with those of patients with severe colonic dismotility due to chronic constipation (CC) and acute pseudo-obstruction (PSO). The patients with repaired ARM were accepted as group #1 (n=10). The patients with CC and acute PSO composed group #2 (n=10). Eight-channel water perfused catheter was inserted into the colon under sedation. Colonic activity was recorded in three phases including fasting, after meal and after bisacodyl installation. The results were assessed by Pearson chi(2) test, P<.05 was considered statistically significant. Mean age was 9.6 and 12.1 in groups #1 and #2, respectively. Ninety-five per cent of all patients had propagated contractions (PCs) and 20% and 40% of the patients in group #1 had PCs during fasting and after meal, respectively. These contractions were seen 30% and 70% of the patients in group #2, but no statistical difference was found between the groups. PCs after bisacodyl were observed 90% and 40% of the patients in groups #1 and #2, respectively, and this difference was statistically significant (P=.019). In this study, the prominent difference between the groups was found in response to intraluminal stimulation. This finding may indicate that the colon of the patients with ARM has more capacity to develop PCs by peripheral stimuli and more regular enteric nervous integrity. PMID- 21589832 TI - Impact of child obesity on adipose tissue physiology: assessment of adipocytokines and inflammatory cytokines as biomarkers of obesity. AB - Obesity could be interpreted as a low grade inflammatory state. The role of cytokines for innate and acquired immune response and adipocytokines in pathogenesis of obesity is not completely understood. The aim of the study was to evaluate anthropometric parameters, adipocytokines and inflammatory cytokine levels as biomarkers of childhood obesity. This investigation was designed as a longitudinal observational study. Forty-seven obese children (19 males and 28 females) were enrolled by Pediatric Clinic of the Foundation IRCCS Policlinico San Matteo, Pavia, Italy. For each patients a blood sample, used for other biochemical evaluations, was collected. Cytokines and adipocytokines plasmatic levels were determined using an ELISA method. Plasma leptin levels are in correlation with age (r=0.5; P<0.001) and BMI-z score (r=0.36; P<0.001), particularly in girls; plasma resistin levels are in inverse correlation with age, particularly in boys (r=-0.67; P<0.001) and in correlation with BMI-z score (r=0.52; P=0.002). Plasma leptin and resistin levels show a good correlation with antrophometric parameters of child obesity (sex and BMI z score). This study suggests that leptin and resistin can be considered as biomarker of childhood obesity and its comorbility. We observed a statistically significant correlation between plasma leptin and resistin levels and antrophometric parameters of child obesity (sex and BMI z score). This study suggests that adipocytokines, such as leptin and resistin, can be considered as biomarkers of childhood obesity. PMID- 21589833 TI - Protein-losing enteropathy associated with Henoch-Schonlein purpura. AB - The gastrointestinal manifestations of Henoch-Schonlein purpura include abdominal pain, gastrointestinal bleeding, intussusception, and perforation. Protein-losing enteropathy is rarely associated with Henoch-Schonlein purpura. Two pediatric patients with Henoch-Schonlein purpura who developed protein-losing enteropathy are reported. Tc-99m human serum albumin scintigraphy is useful in the detection of protein-losing enteropathy. PMID- 21589834 TI - Inclusion of non-viable neonates in the birth record and its impact on infant mortality rates in Shelby County, Tennessee, USA. AB - Rates of infant death are one of the most common indicators of a population's overall health status. Infant mortality rates (IMRs) are used to make broad inferences about the quality of health care, effects of health policies and even environmental quality. The purpose of our study was threefold: i) to examine the characteristics of births in the area in relation to gestational age and birthweight; ii) to estimate infant mortality using variable gestational age and/or birthweight criteria for live birth, and iii) to calculate proportional mortality ratios for each cause of death using variable gestational age and/or birthweight criteria for live birth. We conducted a retrospective analysis of all Shelby County resident-linked birth and infant death certificates during the years 1999 to 2004. Descriptive test statistics were used to examine infant mortality rates in relation to specific maternal and infant risk factors. Through careful examination of 1999-2004 resident-linked birth and infant death data sets, we observed a disproportionate number of non-viable live births (<=20 weeks gestation or <=350 grams) in Shelby County. Issuance of birth certificates to these non-viable neonates is a factor that contributes to an inflated IMR. Our study demonstrates the complexity and the appropriateness of comparing infant mortality rates in smaller geographic units, given the unique characteristics of live births in Shelby County. The disproportionate number of pre-viable infants born in Shelby County greatly obfuscates neonatal mortality and de-emphasizes the importance of post-neonatal mortality. PMID- 21589835 TI - Similar erythrocyte sedimentation rate and C-reactive protein sensitivities at the onset of septic arthritis, osteomyelitis, acute rheumatic fever. AB - The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are employed in the evaluation of patients with suspected septic arthritis, osteomyelitis, and acute rheumatic fever. The purpose of this study is to determine if one test has greater sensitivity (rises earlier) than the other. Laboratory data were retrieved for pediatric patients hospitalized with one of the above three conditions, who had both ESR and CRP tests done on or shortly prior to admission. Sensitivity calculations were performed for mild, moderate, and severe degrees of ESR and CRP elevation. Microcytic erythrocytes, as defined by mean corpuscular volume (MCV) <80 uL, were identified to see if this affects the ESR. ESR or CRP sensitivities depend on the cutoff value (threshold) chosen as a positive test. The sensitivities were similar for similar degrees of elevation. ESR and CRP discordance was not significantly related to MCV. We concluded that the CRP does not rise earlier than the ESR (their sensitivities are similar). Previously published conclusions are dependent on arbitrary thresholds. We could not find any evidence that MCV affects the ESR. PMID- 21589836 TI - A seventeen-year-old female with hepatosplenic T-cell lymphoma associated with parvoviral infection. AB - Hepatosplenic T-cell lymphoma (HSTL) is rare, being derived from cytotoxic T cells, and manifests as an extranodal systemic lymphoma. We present an unusual case of a seventeen-year-old female, with no significant prior medical history, presenting with a hepatosplenic T-cell lymphoma. The diagnosis was confirmed by histological examination, immunohistochemisty, and flow cytometry. A staging work up demonstrated bone marrow involvement by HSTL with concomitant intranuclear parvoviral inclusions. PMID- 21589837 TI - Hyperuricemia in obese children and adolescents: the relationship with metabolic syndrome. AB - The prevalence of hyperuricemia in obese children and adolescents and its association with metabolic syndrome are largely unknown. The objective of our study was to characterize hyperuricemia in relation to metabolic syndrome in Japanese children and adolescents with obesity. Between 2005 and 2008, we performed a cross-sectional study of 1,027 obese children and adolescents aged 6 14 years. Based on the reference value of serum uric acid we had established previously, hyperuricemia was defined as one standard deviation over the mean value at each age. The diagnosis of metabolic syndrome was made based on the Japanese criteria for children. A total of 213 children and adolescents (20.7%) was found to have hyperuricemia. The prevalence of hyperuricemia was significantly higher in the male gender and older age group. Sixty-five out of 213 subjects with hyperuricemia (30.5%) had metabolic syndrome, whereas 111 out of 814 subjects without hyperuricemia (13.6%) had metabolic syndrome. The most common abnormal component of metabolic syndrome was triglyceride, followed by diastolic blood pressure, systolic blood pressure, fasting blood glucose, and HDL cholesterol. Such a tendency was almost identical between the two groups. We concluded that considering the association between hyperuricemia and metabolic syndrome in obese Japanese children and adolescents, the role of hyperuricemia in metabolic syndrome should receive more attention, beginning in early childhood. PMID- 21589838 TI - Acute osteomyelitis of the acetabulum induced by Staphylococcus capitis in a young athlete. AB - Acute hematogenous osteomyelitis (AHOM) of the acetabulum is a rare condition in children and usually caused by Staphylococcus aureus. We present an 11-year-old soccer athlete who suffered from acute osteomyelitis involving the acetabulum caused by S. capitis, a normal flora of the human skin but never reported in this condition. The disease was associated with repetitive skin injuries of the knee and potential osseous microtrauma of the hip joint by frequent rigorous exercise. This unusual case suggests that osseous microtrauma of the acetabulum, in addition to repetitive skin injuries, allowed normal skin flora to colonize to the ipsilateral acetabulum, which served as a favorable niche and subsequently led to AHOM. PMID- 21589839 TI - Prevalence and determinants of pre-term deliveries in the University of Ilorin Teaching Hospital, Ilorin, Nigeria. AB - In Nigeria, over 900,000 children under the age of five years die every year. Early neonatal death is responsible for a little over 20% of these deaths. Prematurity remains a significant cause of these early neonatal deaths. In some series, it is reported to be responsible for 60-70% of these deaths. This study aimed to determine the prevalence and determinants of pre-term deliveries at the University of Ilorin Teaching Hospital, Ilorin. This was a prospective cohort study conducted over a 9-month period at the University of Ilorin Teaching Hospital. Records of deliveries and data on maternal socio-biological and antenatal variables were collected during this period in order to determine the prevalence and determinants of pre-term deliveries. Out of the 2,489 deliveries that took place over a 9-month period, there were 293 pre-terms, giving a pre term delivery rate of 120 per 1,000 deliveries. Of the total deliveries, 1,522 singleton deliveries that satisfied inclusion criteria were recruited; 185 of them were pre-term deliveries giving a case:control ratio of 1:7. Significant determinants of pre-term delivery identified were previous pre-term delivery (P=0.001; OR=3.55; 95% CI=1.71-7.30), antepartum hemorrhage (P=0.000; OR=8.95; 95%CI=4.06-19.78), premature rupture of the membranes (P=0.000; OR=6.48; 95%CI=4.33-9.67), maternal urinary tract infection (P=0.006; OR=5.89; 95%CI=1.16 27.57), pregnancy induced hypertension (P=0.007; OR=3.23; 95%CI=2.09-4.99), type of labor (P=0.000; OR=6.44; 95%CI=4.42-9.38) and booking status (P=0.000; OR=4.67; 95%CI=3.33-6.56). The prevalence of pre-term delivery was 120 per 1,000 live births. Factors significantly associated with pre-term delivery were low socio-economic class, previous pre-term delivery, antepartum hemorrhage, premature rupture of fetal membranes, urinary tract infection, pregnancy induced hypertension, induced labor, and booking elsewhere outside the teaching hospital. PMID- 21589840 TI - Isolated short stature as a presentation of celiac disease in Saudi children. AB - The aim of this study is to assess the prevalence of isolated short stature as a clinical presentation of celiac disease in Saudi Arab children and whether some of the routine laboratory tests performed to determine the cause of short stature could suggest the diagnosis of celiac disease. A total of 91 children with short stature were included in the study. Extensive endocrine and biochemical assessments, including total protein, serum albumin, calcium phosphate and alkaline phosphatase assays; renal function tests; coagulation profile; anti endomysial antibodies and anti-tissue transglutaminase antibody, growth hormone, thyroid stimulating hormone, free-thyroxin (FT4) assays; stool tests for giardiasis; bone age; and endoscopic intestinal biopsies, were done for all children. Ten of the 91 children had positive intestinal biopsies in the form of total villous atrophy, an increase in crypt height, and an increase in intra epithelial lymphocyte (IEL) numbers up to >40 IEL/100 EC (Type 3C) according to the Oberhuber classification, confirming the diagnosis of celiac disease. Five children had mild villous atrophy according to this classification (Type 3A), and they were considered to have potential celiac disease. Seventy-six children had normal intestinal biopsies. Therefore, the prevalence of celiac disease among Saudi children with short stature was 10.9%, and 4.3% of the children were diagnosed as having potential celiac disease. After confirming the diagnosis of celiac disease, all children were kept on a gluten-free diet and all of them showed improvement in their growth rate. We concluded that celiac disease is a very important cause of short stature in children without gastrointestinal complaints in Saudi Arabia. We highly recommend anti-tissue transglutaminase and anti-endomysial antibody screening tests, and a small bowel biopsy to confirm the diagnosis of celiac disease irrespective of the results of the antibody assays, in children with short stature in Saudi Arabia. Once the diagnosis is confirmed, children should be kept on a gluten-free diet so they can catch up their growth early before they develop permanent short stature. PMID- 21589841 TI - Intraosseous fluid resuscitation in meningococcal disease and lower limb injury. AB - We set out to review the recent incidence of extravasation and compartment syndrome in children with meningococcal disease admitted to our Paediatric Intensive Care Unit (PICU) who had been resuscitated with intraosseous (IO) needles. Over a 12-month period, 18 children were admitted to PICU with meningococcal sepsis. Four of these children were resuscitated with IO needles and 2 developed serious complications as a result of extravasation and compartment syndrome. Clinical practice guidelines for children with severe sepsis advocate aggressive early fluid resuscitation therapy. We have identified extravasation and lower limb injury as a potential issue of increasing concern with appropriate aggressive IO fluid resuscitation in severe septic shock in children. Powered IO access systems such as the EZ-IO system offer advantages in terms of placement speed, accuracy and bone entry site profile at minimal extra financial cost. PMID- 21589842 TI - A 5-year old male with "leukemic form" of disseminated post-transplant lymphoproliferative disorder. PMID- 21589843 TI - Health outcomes of children born to mothers with chronic kidney disease: a pilot study. AB - This study aimed to study the health of children born to mothers with chronic kidney disease. Twenty-four children born to mothers with chronic kidney disease were compared with 39 matched control children born to healthy mothers without kidney disease. The well-being of each child was individually assessed in terms of physical health, neurodevelopment and psychological health. Families participating with renal disease were more likely to be from lower socio-economic backgrounds. Significantly fewer vaginal deliveries were reported for mothers with renal disease and their infants were more likely to experience neonatal morbidity. Study and control children were comparable for growth parameters and neurodevelopment as assessed by the Griffiths scales. There was no evidence of more stress amongst mothers with renal disease or of impaired bonding between mother and child when compared to controls. However, there was evidence of greater externalizing behavioral problems in the group of children born to mothers with renal disease. Engaging families in such studies is challenging. Nonetheless, families who participated appreciated being asked. The children were apparently healthy but there was evidence in this small study of significant antenatal and perinatal morbidity compared to controls. Future larger multi center studies are required to confirm these early findings. PMID- 21589844 TI - Chiari type I malformation, syncope, headache, hypoglycemia and hepatic steatosis in an 8-year old girl: a causal association? AB - Chiari type I malformation (CMI) is a congenital hindbrain anomaly characterized by downward displacement of the cerebellar tonsils through the foramen magnum. Chiari type I malformation often presents with a complex clinical picture and can be sporadic or linked to a variety of genetic conditions. We report on a girl in whom Chiari type I malformation was associated with hypoglycemia, headache, vertigo, syncope and hepatic steatosis. We hypothesize that these symptoms are primarily a consequence of Chiari type I malformation. PMID- 21589845 TI - Neonatal mortality: a scenario in a tertiary level hospital of a developing country. AB - This study was designed to observe the overall neonatal mortality and pattern of neonatal death in a developing country. The factors related to neonatal mortality are also analyzed. This retrospective study was carried out in all pediatric patients in a tertiary level hospital of a developing country in the year 2008. Total neonatal (0-28 days) and non-neonatal (after 28 days-12 years) admissions and death records were analyzed. There were a total of 3,194 admissions in the year 2008. Neonatal and non-neonatal admissions numbered 942 and 2,252, respectively. There were a total of 146 (15.5%) neonatal deaths among neonatal admissions and 114 (5.06%) non-neonatal deaths among non-neonatal admissions. There were 87 (59.59%) preterm related deaths and 98 (67.12%) deaths due to Low Birth Weight (LBW). There were 102 (70%) deaths among neonates who had no antenatal follow-up. Mother's age was under 20 years in 80 (55%) cases of neonatal death. The number of neonatal deaths is high in developing countries. Preterm with Low Birth Weight (LBW) is the major cause of mortality. Regular antenatal care and social discouragement of early marriage can greatly reduce neonatal death. Skilled and trained nursing care is necessary for the survival of the preterm and Low Birth Weight (LBW) baby in the hospitals of developing countries. PMID- 21589846 TI - Cerebral hemodynamic failure presenting as limb-shaking transient ischemic attacks. AB - Limb-shaking transient ischemic attacks (TIA) may occur in patients with insufficient brain perfusion due to an underlying occlusive disease. We present the case of a 64-year-old patient who suffered from repetitive TIA presenting with shaking movements of the right-sided extremities and accompanying speech arrest. Symptoms are documented in the online supplementary video (www.karger.com/doi/10.1159/000327683). These episodes were frequently triggered in orthostatic situations. The diagnosis of limb-shaking TIA was established. The diagnostic workup revealed pseudo-occlusion of the left internal carotid artery, a poor intracranial collateral status and, as a consequence, an exhausted vasomotor reserve capacity. At ultrasound examination, symptoms were provoked by a change of the patient's position from supine to sitting. During evolvement of symptoms, a dramatic decrease of flow velocities in the left middle cerebral artery was observed. This case thus documents the magnitude and dynamics of perfusion failure in a rare manifestation of cerebral ischemic disease. PMID- 21589847 TI - Peripapillary Neovascular Membrane in a Young Pregnant Woman and Prompt Response to Ranibizumab Injections following Uneventful Delivery. AB - PURPOSE: Occurrence of choroidal neovascularization (CNV) during pregnancy has been reported as a complication of presumed ocular histoplasmosis syndrome or punctuate inner chorioretinopathy. To our knowledge, idiopathic CNV (ICNV) during pregnancy has only been reported once in the relevant literature. Bevacizumab has been used for the treatment of ICNV in small case series. However, there is limited experience regarding the use of ranibizumab for the management of ICNV. CASE REPORT: A 31-year-old woman in the eighth month of her second pregnancy was diagnosed with mild macular and papillary edema. She was followed up using biomicroscopy, fluorescein angiography (FA), and optical coherence tomography (OCT). After 3 months, visual acuity further deteriorated and funduscopy, FA and OCT findings revealed a juxtapapillary choroidal neovascular membrane (CNVM). After two ranibizumab injections, best-corrected visual acuity increased significantly, physiological macular anatomy was restored and no subretinal fluid was observed. DISCUSSION: In this case report, we present a young pregnant patient with peripapillary ICNV and neurosensory detachment involving the macula, and treatment of the eye with intravitreal ranibizumab following uneventful delivery. Increased angiogenic factor levels associated with pregnancy may contribute to the onset of CNV although this relationship has to be investigated experimentally. The rapid response to ranibizumab suggests that this anti-VEGF agent may be an alternative treatment option in the management of peripapillary ICNV. PMID- 21589848 TI - Subretinal hemorrhage after photodynamic therapy for juxtapapillary retinal capillary hemangioma. AB - A 75-year-old Japanese woman presented with a juxtapapillary retinal capillary hemangioma (RCH) in her left eye. Twelve months after the initial examination, the size of the hemangioma had increased and the exudation from the RCH involved the macula. Her best-corrected visual acuity (BCVA) had decreased from 0.8 to 0.3. A total of five intravitreal injections of bevacizumab (IVB; 1.25 mg) was given but the RCH did not respond. A photodynamic therapy (PDT) was done using multiple laser spots to avoid damaging the optic nerve head. After the first PDT, the subfoveal fluid was reduced but not completely gone. One week after the second PDT, a massive subretinal hemorrhage developed. The subretinal hemorrhage was successfully displaced by injecting intraocular sulfur hexafluoride (SF(6)) gas. At the 3-year follow-up examination, no subretinal hemorrhage or fluid was observed at the macula and the BCVA remained at 0.05. Our case was resistant to the combination of anti-vascular endothelial growth factor (VEGF) and PDT and had a rare massive subretinal hemorrhage. A further collection of RCH cases treated with anti-VEGF and PDT that would justify this treatment is necessary. PMID- 21589849 TI - Penalized Composite Quasi-Likelihood for Ultrahigh-Dimensional Variable Selection. AB - In high-dimensional model selection problems, penalized least-square approaches have been extensively used. This paper addresses the question of both robustness and efficiency of penalized model selection methods, and proposes a data-driven weighted linear combination of convex loss functions, together with weighted L(1) penalty. It is completely data-adaptive and does not require prior knowledge of the error distribution. The weighted L(1)-penalty is used both to ensure the convexity of the penalty term and to ameliorate the bias caused by the L(1) penalty. In the setting with dimensionality much larger than the sample size, we establish a strong oracle property of the proposed method that possesses both the model selection consistency and estimation efficiency for the true non-zero coefficients. As specific examples, we introduce a robust method of composite L1 L2, and optimal composite quantile method and evaluate their performance in both simulated and real data examples. PMID- 21589850 TI - Metastatic serous carcinoma of the testis: a case report and review of the literature. AB - Serous tumours of the testis and paratestis are rare, with fewer than 50 cases reported in the literature. The majority of the reported cases have been borderline serous tumours, and these tend not to recur or metastasize. Conversely, serous carcinomas can metastasize but this is often a late event. The presence of invasion in an otherwise borderline tumour has also been associated with the development of metastatic disease several years later, thus highlighting the importance of extensive sampling of all cases of borderline serous tumours. We report a case of a young man diagnosed with serous carcinoma of the testis, occurring 18 years after first diagnosis of a testicular germ cell tumour in the contralateral testis. This pattern has not previously been reported. PMID- 21589851 TI - A Hyper-Solution Framework for SVM Classification: Application for Predicting Destabilizations in Chronic Heart Failure Patients. AB - Support Vector Machines (SVMs) represent a powerful learning paradigm able to provide accurate and reliable decision functions in several application fields. In particular, they are really attractive for application in medical domain, where often a lack of knowledge exists. Kernel trick, on which SVMs are based, allows to map non-linearly separable data into potentially linearly separable one, according to the kernel function and its internal parameters value. During recent years non-parametric approaches have also been proposed for learning the most appropriate kernel, such as linear combination of basic kernels. Thus, SVMs classifiers may have several parameters to be tuned and their optimal values are usually difficult to be identified a-priori. Furthermore, combining different classifiers may reduce risk to perform errors on new unseen data. For such reasons, we present an hyper-solution framework for SVM classification, based on meta-heuristics, that searches for the most reliable hyper-classifier (SVM with a basic kernel, SVM with a combination of kernel, and ensemble of SVMs), and for its optimal configuration. We have applied the proposed framework on a critical and quite complex issue for the management of Chronic Heart Failure patient: the early detection of decompensation conditions. In fact, predicting new destabilizations in advance may reduce the burden of heart failure on the healthcare systems while improving quality of life of affected patients. Promising reliability has been obtained on 10-fold cross validation, proving our approach to be efficient and effective for an high-level analysis of clinical data. PMID- 21589852 TI - Broadening the socio-technical horizons of health informatics. PMID- 21589853 TI - caGrid-Enabled caBIG Silver Level Compatible Head and Neck Cancer Tissue Database System. AB - There are huge amounts of biomedical data generated by research labs in each cancer institution. The data are stored in various formats and accessed through numerous interfaces. It is very difficult to exchange and integrate the data among different cancer institutions, even among different research labs within the same institution, in order to discover useful biomedical knowledge for the healthcare community. In this paper, we present the design and implementation of a caGrid-enabled caBIG(TM) silver level compatible head and neck cancer tissue database system. The system is implemented using a set of open source software and tools developed by the NCI, such as the caCORE SDK and caGrid. The head and neck cancer tissue database system has four interfaces: Web-based, Java API, XML utility, and Web service. The system has been shown to provide robust and programmatically accessible biomedical information services that syntactically and semantically interoperate with other resources. PMID- 21589854 TI - Quantification of Epicardial Fat by Cardiac CT Imaging. AB - The aim of this work is to introduce and design image processing methods for the quantitative analysis of epicardial fat by using cardiac CT imaging.Indeed, epicardial fat has recently been shown to correlate with cardiovascular disease, cardiovascular risk factors and metabolic syndrome. However, many concerns still remain about the methods for measuring epicardial fat, its regional distribution on the myocardium and the accuracy and reproducibility of the measurements.In this paper, a method is proposed for the analysis of single-frame 3D images obtained by the standard acquisition protocol used for coronary calcium scoring. In the design of the method, much attention has been payed to the minimization of user intervention and to reproducibility issues.In particular, the proposed method features a two step segmentation algorithm suitable for the analysis of epicardial fat. In the first step of the algorithm, an analysis of epicardial fat intensity distribution is carried out in order to define suitable thresholds for a first rough segmentation. In the second step, a variational formulation of level set methods - including a specially-designed region homogeneity energy based on Gaussian mixture models- is used to recover spatial coherence and smoothness of fat depots.Experimental results show that the introduced method may be efficiently used for the quantification of epicardial fat. PMID- 21589855 TI - Datamining approach for automation of diagnosis of breast cancer in immunohistochemically stained tissue microarray images. AB - Cancer of the breast is the second most common human neoplasm, accounting for approximately one quarter of all cancers in females after cervical carcinoma. Estrogen receptor (ER), Progesteron receptor and human epidermal growth factor receptor (HER-2/neu) expressions play an important role in diagnosis and prognosis of breast carcinoma. Tissue microarray (TMA) technique is a high throughput technique which provides a standardized set of images which are uniformly stained, facilitating effective automation of the evaluation of the specimen images. TMA technique is widely used to evaluate hormone expression for diagnosis of breast cancer. If one considers the time taken for each of the steps in the tissue microarray process workflow, it can be observed that the maximum amount of time is taken by the analysis step. Hence, automated analysis will significantly reduce the overall time required to complete the study. Many tools are available for automated digital acquisition of images of the spots from the microarray slide. Each of these images needs to be evaluated by a pathologist to assign a score based on the staining intensity to represent the hormone expression, to classify them into negative or positive cases. Our work aims to develop a system for automated evaluation of sets of images generated through tissue microarray technique, representing the ER expression images and HER-2/neu expression images. Our study is based on the Tissue Microarray Database portal of Stanford university at http://tma.stanford.edu/cgi-bin/cx?n=her1, which has made huge number of images available to researchers. We used 171 images corresponding to ER expression and 214 images corresponding to HER-2/neu expression of breast carcinoma. Out of the 171 images corresponding to ER expression, 104 were negative and 67 were representing positive cases. Out of the 214 images corresponding to HER-2/neu expression, 112 were negative and 102 were representing positive cases. Our method has 92.31% sensitivity and 93.18% specificity for ER expression image classification and 96.67% sensitivity and 88.24% specificity for HER-2/neu expression image classification. PMID- 21589856 TI - Genetic classification of populations using supervised learning. AB - There are many instances in genetics in which we wish to determine whether two candidate populations are distinguishable on the basis of their genetic structure. Examples include populations which are geographically separated, case control studies and quality control (when participants in a study have been genotyped at different laboratories). This latter application is of particular importance in the era of large scale genome wide association studies, when collections of individuals genotyped at different locations are being merged to provide increased power. The traditional method for detecting structure within a population is some form of exploratory technique such as principal components analysis. Such methods, which do not utilise our prior knowledge of the membership of the candidate populations. are termed unsupervised. Supervised methods, on the other hand are able to utilise this prior knowledge when it is available.In this paper we demonstrate that in such cases modern supervised approaches are a more appropriate tool for detecting genetic differences between populations. We apply two such methods, (neural networks and support vector machines) to the classification of three populations (two from Scotland and one from Bulgaria). The sensitivity exhibited by both these methods is considerably higher than that attained by principal components analysis and in fact comfortably exceeds a recently conjectured theoretical limit on the sensitivity of unsupervised methods. In particular, our methods can distinguish between the two Scottish populations, where principal components analysis cannot. We suggest, on the basis of our results that a supervised learning approach should be the method of choice when classifying individuals into pre-defined populations, particularly in quality control for large scale genome wide association studies. PMID- 21589857 TI - Hypoxia and prostaglandin E receptor 4 signalling pathways synergise to promote endometrial adenocarcinoma cell proliferation and tumour growth. AB - The prostaglandin endoperoxide synthase (PTGS) pathway is a potent driver of tumour development in humans by enhancing the biosynthesis and signalling of prostaglandin (PG) E(2). PTGS2 expression and PGE(2) biosynthesis is elevated in endometrial adenocarcinoma, however the mechanism whereby PTGS and PGE(2) regulate endometrial tumour growth is unknown. Here we investigated (a) the expression profile of the PGE synthase enzymes (PTGES, PTGES-2, PTGES-3) and PGE receptors (PTGER1-4) in endometrial adenocarcinomas compared with normal endometrium and (b) the role of PTGER4 in endometrial tumorigenesis in vivo. We found elevated expression of PTGES2 and PTGER4 and suppression of PTGER1 and PTGER3 in endometrial adenocarcinomas compared with normal endometrium. Using WT Ishikawa endometrial adenocarcinoma cells and Ishikawa cells stably transfected with the full length PTGER4 cDNA (PTGER4 cells) xenografted in the dorsal flanks of nude mice, we show that PTGER4 rapidly and significantly enhances tumour growth rate. Coincident with enhanced PTGER4-mediated tumour growth we found elevated expression of PTGS2 in PTGER4 xenografts compared with WT xenografts. Furthermore we found that the augmented growth rate of the PTGER4 xenografts was not due to enhanced angiogenesis, but regulated by an increased proliferation index and hypoxia. In vitro, we found that PGE(2) and hypoxia independently induce expression of PTGER4 indicating two independent pathways regulating prostanoid receptor expression. Finally we have shown that PGE(2) and hypoxia synergise to promote cellular proliferation of endometrial adenocarcinoma cells. PMID- 21589858 TI - Distinct and shared roles of beta-arrestin-1 and beta-arrestin-2 on the regulation of C3a receptor signaling in human mast cells. AB - BACKGROUND: The complement component C3a induces degranulation in human mast cells via the activation of cell surface G protein coupled receptors (GPCR; C3aR). For most GPCRs, agonist-induced receptor phosphorylation leads to the recruitment of beta-arrestin-1/beta-arrestin-2; resulting in receptor desensitization and internalization. Activation of GPCRs also leads to ERK1/2 phosphorylation via two temporally distinct pathways; an early response that reflects G protein activation and a delayed response that is G protein independent but requires beta-arrestins. The role of beta-arrestins on C3aR activation/regulation in human mast cells, however, remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: We utilized lentivirus short hairpin (sh)RNA to stably knockdown the expression of beta-arrestin-1 and beta-arrrestin-2 in human mast cell lines, HMC-1 and LAD2 that endogenously expresses C3aR. Silencing beta arrestin-2 attenuated C3aR desensitization, blocked agonist-induced receptor internalization and rendered the cells responsive to C3a for enhanced NF-kappaB activity as well as chemokine generation. By contrast, silencing beta-arrestin-1 had no effect on these responses but resulted in a significant decrease in C3a induced mast cell degranulation. In shRNA control cells, C3a caused a transient ERK1/2 phosphorylation, which peaked at 5 min but disappeared by 10 min. Knockdown of beta-arrestin-1, beta-arrestin-2 or both enhanced the early response to C3a and rendered the cells responsive for ERK1/2 phosphorylation at later time points (10-30 min). Treatment of cells with pertussis toxin almost completely blocked both early and delayed C3a-induced ERK1/2 phosphorylation in beta arrestin1/2 knockdown cells. CONCLUSION/SIGNIFICANCE: This study demonstrates distinct roles for beta-arrestins-1 and beta-arrestins-2 on C3aR desensitization, internalization, degranulation, NF-kappaB activation and chemokine generation in human mast cells. It also shows that both beta-arrestin-1 and beta-arrestin-2 play a novel and shared role in inhibiting G protein-dependent ERK1/2 phosphorylation. These findings reveal a new level of complexity for C3aR regulation by beta-arrestins in human mast cells. PMID- 21589859 TI - Deficiency of the mitochondrial electron transport chain in muscle does not cause insulin resistance. AB - BACKGROUND: It has been proposed that muscle insulin resistance in type 2 diabetes is due to a selective decrease in the components of the mitochondrial electron transport chain and results from accumulation of toxic products of incomplete fat oxidation. The purpose of the present study was to test this hypothesis. METHODOLOGY/PRINCIPAL FINDINGS: Rats were made severely iron deficient, by means of an iron-deficient diet. Iron deficiency results in decreases of the iron containing mitochondrial respiratory chain proteins without affecting the enzymes of the fatty acid oxidation pathway. Insulin resistance was induced by feeding iron-deficient and control rats a high fat diet. Skeletal muscle insulin resistance was evaluated by measuring glucose transport activity in soleus muscle strips. Mitochondrial proteins were measured by Western blot. Iron deficiency resulted in a decrease in expression of iron containing proteins of the mitochondrial respiratory chain in muscle. Citrate synthase, a non-iron containing citrate cycle enzyme, and long chain acyl-CoA dehydrogenase (LCAD), used as a marker for the fatty acid oxidation pathway, were unaffected by the iron deficiency. Oleate oxidation by muscle homogenates was increased by high fat feeding and decreased by iron deficiency despite high fat feeding. The high fat diet caused severe insulin resistance of muscle glucose transport. Iron deficiency completely protected against the high fat diet-induced muscle insulin resistance. CONCLUSIONS/SIGNIFICANCE: The results of the study argue against the hypothesis that a deficiency of the electron transport chain (ETC), and imbalance between the ETC and beta-oxidation pathways, causes muscle insulin resistance. PMID- 21589860 TI - PAX6 haplotypes are associated with high myopia in Han chinese. AB - BACKGROUND: The paired box 6 (PAX6) gene is considered as a master gene for eye development. Linkage of myopia to the PAX6 region on chromosome 11p13 was shown in several studies, but the results for association between myopia and PAX6 were inconsistent so far. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped 16 single nucleotide polymorphisms (SNPs) in the PAX6 gene and its regulatory regions in an initial study for 300 high myopia cases and 300 controls (Group 1), and successfully replicated the positive results with another independent group of 299 high myopia cases and 299 controls (Group 2). Five SNPs were genotyped in the replication study. The spherical equivalent of subjects with high myopia was <= 8.0 dioptres. The PLINK package was used for genetic data analysis. No association was found between each of the SNPs and high myopia. However, exhaustive sliding-window haplotype analysis highlighted an important role for rs12421026 because haplotypes containing this SNP were found to be associated with high myopia. The most significant results were given by the 4-SNP haplotype window consisting of rs2071754, rs3026393, rs1506 and rs12421026 (P = 3.54*10( 10), 4.06*10(-11) and 1.56*10(-18) for Group 1, Group 2 and Combined Group, respectively) and the 3-SNP haplotype window composed of rs3026393, rs1506 and rs12421026 (P = 5.48*10(-10), 7.93*10(-12) and 6.28*10(-23) for the three respective groups). The results remained significant after correction for multiple comparisons by permutations. The associated haplotyes found in a previous study were also successfully replicated in this study. CONCLUSIONS/SIGNIFICANCE: PAX6 haplotypes are associated with susceptibility to the development of high myopia in Chinese. The PAX6 locus plays a role in high myopia. PMID- 21589861 TI - Honeybees' speed depends on dorsal as well as lateral, ventral and frontal optic flows. AB - Flying insects use the optic flow to navigate safely in unfamiliar environments, especially by adjusting their speed and their clearance from surrounding objects. It has not yet been established, however, which specific parts of the optical flow field insects use to control their speed. With a view to answering this question, freely flying honeybees were trained to fly along a specially designed tunnel including two successive tapering parts: the first part was tapered in the vertical plane and the second one, in the horizontal plane. The honeybees were found to adjust their speed on the basis of the optic flow they perceived not only in the lateral and ventral parts of their visual field, but also in the dorsal part. More specifically, the honeybees' speed varied monotonically, depending on the minimum cross-section of the tunnel, regardless of whether the narrowing occurred in the horizontal or vertical plane. The honeybees' speed decreased or increased whenever the minimum cross-section decreased or increased. In other words, the larger sum of the two opposite optic flows in the horizontal and vertical planes was kept practically constant thanks to the speed control performed by the honeybees upon encountering a narrowing of the tunnel. The previously described ALIS ("AutopiLot using an Insect-based vision System") model nicely matches the present behavioral findings. The ALIS model is based on a feedback control scheme that explains how honeybees may keep their speed proportional to the minimum local cross-section of a tunnel, based solely on optic flow processing, without any need for speedometers or rangefinders. The present behavioral findings suggest how flying insects may succeed in adjusting their speed in their complex foraging environments, while at the same time adjusting their distance not only from lateral and ventral objects but also from those located in their dorsal visual field. PMID- 21589862 TI - Plasma proteome profiles associated with inflammation, angiogenesis, and cancer. AB - Tumor development is accompanied by a complex host systemic response, which includes inflammatory and angiogenic reactions. Both tumor-derived and systemic response proteins are detected in plasma from cancer patients. However, given their non-specific nature, systemic response proteins can confound the detection or diagnosis of neoplasia. Here, we have applied an in-depth quantitative proteomic approach to analyze plasma protein changes in mouse models of subacute irritant-driven inflammation, autoreactive inflammation, and matrix associated angiogenesis and compared results to previously described findings from mouse models of polyoma middle T-driven breast cancer and Pdx1-Cre Kras(G12D) Ink4a/Arf (lox/lox)-induced pancreatic cancer. Among the confounding models, approximately 1/3 of all quantified plasma proteins exhibited a significant change in abundance compared to control mice. Of the proteins that changed in abundance, the majority were unique to each model. Altered proteins included those involved in acute phase response, inflammation, extracellular matrix remodeling, angiogenesis, and TGFbeta signaling. Comparison of changes in plasma proteins between the confounder models and the two cancer models revealed proteins that were restricted to the cancer-bearing mice, reflecting the known biology of these tumors. This approach provides a basis for distinguishing between protein changes in plasma that are cancer-related and those that are part of a non-specific host response. PMID- 21589863 TI - Transmission pattern of drug-resistant tuberculosis and its implication for tuberculosis control in eastern rural China. AB - OBJECTIVE: Transmission patterns of drug-resistant Mycobacterium tuberculosis (MTB) may be influenced by differences in socio-demographics, local tuberculosis (TB) endemicity and efficaciousness of TB control programs. This study aimed to investigate the impact of DOTS on the transmission of drug-resistant TB in eastern rural China. METHODS: We conducted a cross-sectional study of all patients diagnosed with drug-resistant TB over a one-year period in two rural Chinese counties with varying lengths of DOTS implementation. Counties included Deqing, with over 11 years' DOTS implementation and Guanyun, where DOTS was introduced 1 year prior to start of this study. We combined demographic, clinical and epidemiologic information with IS6110-based restricted fragment length polymorphism (RFLP) and Spoligotyping analysis of MTB isolates. In addition, we conducted DNA sequencing of resistance determining regions to first-line anti tuberculosis agents. RESULTS: Of the 223 drug-resistant isolates, 73(32.7%) isolates were identified with clustered IS6110RFLP patterns. The clustering proportion among total drug-resistant TB was higher in Guanyun than Deqing (26/101.vs.47/122; p,0.04), but not significantly different among the 53 multidrug-resistant isolates (10/18.vs.24/35; p,0.35). Patients with cavitary had increased risk of clustering in both counties. In Guanyun, patients with positive smear test or previous treatment history had a higher clustering proportion. Beijing genotype and isolates resistant to isoniazid and/or rifampicin were more likely to be clustered. Of the 73 patients with clustered drug-resistant isolates, 71.2% lived in the same or neighboring villages. Epidemiological link (household and social contact) was confirmed in 12.3% of the clustered isolates. CONCLUSION: Transmission of drug-resistant TB in eastern rural China is characterized by small clusters and limited geographic spread. Our observations highlight the need for supplementing DOTS with additional strategies, including active case finding at the village level, effective treatment for patients with cavities and drug susceptibility testing for patients at increased risk for drug resistance. PMID- 21589864 TI - Detection and localisation of PrP(Sc) in the liver of sheep infected with scrapie and bovine spongiform encephalopathy. AB - Prions are largely contained within the nervous and lymphoid tissue of transmissible spongiform encephalopathy (TSE) infected animals. However, following advances in diagnostic sensitivity, PrP(Sc), a marker for prion disease, can now be located in a wide range of viscera and body fluids including muscle, saliva, blood, urine and milk, raising concerns that exposure to these materials could contribute to the spread of disease in humans and animals. Previously we demonstrated low levels of infectivity in the liver of sheep experimentally challenged with bovine spongiform encephalopathy. In this study we show that PrP(Sc) accumulated in the liver of 89% of sheep naturally infected with scrapie and 100% of sheep challenged with BSE, at both clinical and preclinical stages of the disease. PrP(Sc) was demonstrated in the absence of obvious inflammatory foci and was restricted to isolated resident cells, most likely Kupffer cells. PMID- 21589865 TI - Transient gastric irritation in the neonatal rats leads to changes in hypothalamic CRF expression, depression- and anxiety-like behavior as adults. AB - AIMS: A disturbance of the brain-gut axis is a prominent feature in functional bowel disorders (such as irritable bowel syndrome and functional dyspepsia) and psychological abnormalities are often implicated in their pathogenesis. We hypothesized that psychological morbidity in these conditions may result from gastrointestinal problems, rather than causing them. METHODS: Functional dyspepsia was induced by neonatal gastric irritation in male rats. 10-day old male Sprague-Dawley rats received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days. At 8-10 weeks of age, rats were tested with sucrose preference and forced-swimming tests to examine depression-like behavior. Elevated plus maze, open field and light-dark box tests were used to test anxiety-like behaviors. ACTH and corticosterone responses to a minor stressor, saline injection, and hypothalamic CRF expression were also measured. RESULTS: Behavioral tests revealed changes of anxiety- and depression-like behaviors in IA treated, but not control rats. As compared with controls, hypothalamic and amygdaloid CRF immunoreactivity, basal levels of plasma corticosterone and stress induced ACTH were significantly higher in IA-treated rats. Gastric sensory ablation with resiniferatoxin had no effect on behaviors but treatment with CRF type 1 receptor antagonist, antalarmin, reversed the depression-like behavior in IA-treated rats CONCLUSIONS: The present results suggest that transient gastric irritation in the neonatal period can induce a long lasting increase in depression- and anxiety-like behaviors, increased expression of CRF in the hypothalamus, and an increased sensitivity of HPA axis to stress. The depression like behavior may be mediated by the CRF1 receptor. These findings have significant implications for the pathogenesis of psychological co-morbidity in patients with functional bowel disorders. PMID- 21589867 TI - Bayesian inference underlies the contraction bias in delayed comparison tasks. AB - Delayed comparison tasks are widely used in the study of working memory and perception in psychology and neuroscience. It has long been known, however, that decisions in these tasks are biased. When the two stimuli in a delayed comparison trial are small in magnitude, subjects tend to report that the first stimulus is larger than the second stimulus. In contrast, subjects tend to report that the second stimulus is larger than the first when the stimuli are relatively large. Here we study the computational principles underlying this bias, also known as the contraction bias. We propose that the contraction bias results from a Bayesian computation in which a noisy representation of a magnitude is combined with a-priori information about the distribution of magnitudes to optimize performance. We test our hypothesis on choice behavior in a visual delayed comparison experiment by studying the effect of (i) changing the prior distribution and (ii) changing the uncertainty in the memorized stimulus. We show that choice behavior in both manipulations is consistent with the performance of an observer who uses a Bayesian inference in order to improve performance. Moreover, our results suggest that the contraction bias arises during memory retrieval/decision making and not during memory encoding. These results support the notion that the contraction bias illusion can be understood as resulting from optimality considerations. PMID- 21589866 TI - Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response. AB - Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4(th) Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)-methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements. PMID- 21589868 TI - Barriers to initiation of antiretrovirals during antituberculosis therapy in Africa. AB - BACKGROUND: In the developing world, the principal cause of death among HIV infected patients is tuberculosis (TB). The initiation of antiretroviral therapy (ART) during TB therapy significantly improves survival, however it is not known which barriers prevent eligible TB patients from initiating life-saving ART. METHOD: Setting. A South African township clinic with integrated tuberculosis and HIV services. Design. Logistic regression analyses of a prospective cohort of HIV 1 infected adults (>=18 years) who commenced TB therapy, were eligible for ART, and were followed for 6 months. FINDINGS: Of 100 HIV-1 infected adults eligible for ART during TB therapy, 90 TB patients presented to an ART clinic for assessment, 66 TB patients initiated ART, and 15 TB patients died. 34% of eligible TB patients (95%CI: 25-43%) did not initiate ART. Male gender and younger age (<36 years) were associated with failure to initiate ART (adjusted odds ratios of 3.7 [95%CI: 1.25-10.95] and 3.3 [95%CI: 1.12-9.69], respectively). Death during TB therapy was associated with a CD4+ count <100 cells/uL. CONCLUSION: In a clinic with integrated services for tuberculosis and HIV, one third of eligible TB patients--particularly young men--did not initiate ART. Strategies are needed to promote ART initiation during TB therapy, especially among young men. PMID- 21589869 TI - RAD21 cooperates with pluripotency transcription factors in the maintenance of embryonic stem cell identity. AB - For self-renewal, embryonic stem cells (ESCs) require the expression of specific transcription factors accompanied by a particular chromosome organization to maintain a balance between pluripotency and the capacity for rapid differentiation. However, how transcriptional regulation is linked to chromosome organization in ESCs is not well understood. Here we show that the cohesin component RAD21 exhibits a functional role in maintaining ESC identity through association with the pluripotency transcriptional network. ChIP-seq analyses of RAD21 reveal an ESC specific cohesin binding pattern that is characterized by CTCF independent co-localization of cohesin with pluripotency related transcription factors Oct4, Nanog, Sox2, Esrrb and Klf4. Upon ESC differentiation, most of these binding sites disappear and instead new CTCF independent RAD21 binding sites emerge, which are enriched for binding sites of transcription factors implicated in early differentiation. Furthermore, knock down of RAD21 causes expression changes that are similar to expression changes after Nanog depletion, demonstrating the functional relevance of the RAD21- pluripotency transcriptional network association. Finally, we show that Nanog physically interacts with the cohesin or cohesin interacting proteins STAG1 and WAPL further substantiating this association. Based on these findings we propose that a dynamic placement of cohesin by pluripotency transcription factors contributes to a chromosome organization supporting the ESC expression program. PMID- 21589870 TI - Ambient oxygen promotes tumorigenesis. AB - Oxygen serves as an essential factor for oxidative stress, and it has been shown to be a mutagen in bacteria. While it is well established that ambient oxygen can also cause genomic instability in cultured mammalian cells, its effect on de novo tumorigenesis at the organismal level is unclear. Herein, by decreasing ambient oxygen exposure, we report a ~50% increase in the median tumor-free survival time of p53-/- mice. In the thymus, reducing oxygen exposure decreased the levels of oxidative DNA damage and RAG recombinase, both of which are known to promote lymphomagenesis in p53-/- mice. Oxygen is further shown to be associated with genomic instability in two additional cancer models involving the APC tumor suppressor gene and chemical carcinogenesis. Together, these observations represent the first report directly testing the effect of ambient oxygen on de novo tumorigenesis and provide important physiologic evidence demonstrating its critical role in increasing genomic instability in vivo. PMID- 21589871 TI - Unc-51/ATG1 controls axonal and dendritic development via kinesin-mediated vesicle transport in the Drosophila brain. AB - BACKGROUND: Members of the evolutionary conserved Ser/Thr kinase Unc-51 family are key regulatory proteins that control neural development in both vertebrates and invertebrates. Previous studies have suggested diverse functions for the Unc 51 protein, including axonal elongation, growth cone guidance, and synaptic vesicle transport. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we have investigated the functional significance of Unc-51-mediated vesicle transport in the development of complex brain structures in Drosophila. We show that Unc-51 preferentially accumulates in newly elongating axons of the mushroom body, a center of olfactory learning in flies. Mutations in unc-51 cause disintegration of the core of the developing mushroom body, with mislocalization of Fasciclin II (Fas II), an IgG-family cell adhesion molecule important for axonal guidance and fasciculation. In unc-51 mutants, Fas II accumulates in the cell bodies, calyx, and the proximal peduncle. Furthermore, we show that mutations in unc-51 cause aberrant overshooting of dendrites in the mushroom body and the antennal lobe. Loss of unc-51 function leads to marked accumulation of Rab5 and Golgi components, whereas the localization of dendrite-specific proteins, such as Down syndrome cell adhesion molecule (DSCAM) and No distributive disjunction (Nod), remains unaltered. Genetic analyses of kinesin light chain (Klc) and unc-51 double heterozygotes suggest the importance of kinesin-mediated membrane transport for axonal and dendritic development. Moreover, our data demonstrate that loss of Klc activity causes similar axonal and dendritic defects in mushroom body neurons, recapitulating the salient feature of the developmental abnormalities caused by unc-51 mutations. CONCLUSIONS/SIGNIFICANCE: Unc-51 plays pivotal roles in the axonal and dendritic development of the Drosophila brain. Unc-51-mediated membrane vesicle transport is important in targeted localization of guidance molecules and organelles that regulate elongation and compartmentalization of developing neurons. PMID- 21589872 TI - PRL-3, a metastasis associated tyrosine phosphatase, is involved in FLT3-ITD signaling and implicated in anti-AML therapy. AB - Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of FLT3 inhibitors in the clinic. We demonstrated that combining ABT-869, a FLT3 inhibitor, with SAHA, a HDAC inhibitor, led to synergistic killing of the AML cells with FLT3 mutations and suppression of colony formation. We identified a core gene signature that is uniquely induced by the combination treatment in 2 different leukemia cell lines. Among these, we showed that downregulation of PTP4A3 (PRL-3) played a role in this synergism. PRL 3 is downstream of FLT3 signaling and ectopic expression of PRL-3 conferred therapeutic resistance through upregulation of STAT (signal transducers and activators of transcription) pathway activity and anti-apoptotic Mcl-1 protein. PRL-3 interacts with HDAC4 and SAHA downregulates PRL-3 via a proteasome dependent pathway. In addition, PRL-3 protein was identified in 47% of AML cases, but was absent in myeloid cells in normal bone marrows. Our results suggest such combination therapies may significantly improve the therapeutic efficacy of FLT3 inhibitors. PRL-3 plays a potential pathological role in AML and it might be a useful therapeutic target in AML, and warrant clinical investigation. PMID- 21589873 TI - Visible light responsive photocatalyst induces progressive and apical-terminus preferential damages on Escherichia coli surfaces. AB - BACKGROUND: Recent research shows that visible-light responsive photocatalysts have potential usage in antimicrobial applications. However, the dynamic changes in the damage to photocatalyzed bacteria remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: Facilitated by atomic force microscopy, this study analyzes the visible light driven photocatalyst-mediated damage of Escherichia coli. Results show that antibacterial properties are associated with the appearance of hole-like structures on the bacteria surfaces. Unexpectedly, these hole-like structures were preferentially induced at the apical terminus of rod shaped E. coli cells. Differentiating the damages into various levels and analyzing the percentage of damage to the cells showed that photocatalysis was likely to elicit sequential damages in E. coli cells. The process began with changing the surface properties on bacterial cells, as indicated in surface roughness measurements using atomic force microscopy, and holes then formed at the apical terminus of the cells. The holes were then subsequently enlarged until the cells were totally transformed into a flattened shape. Parallel experiments indicated that photocatalysis induced bacterial protein leakage is associated with the progression of hole-like damages, further suggesting pore formation. Control experiments using ultraviolet light responsive titanium-dioxide substrates also obtained similar observations, suggesting that this is a general phenomenon of E. coli in response to photocatalysis. CONCLUSION/SIGNIFICANCE: The photocatalysis-mediated localization preferential damage to E. coli cells reveals the weak points of the bacteria. This might facilitate the investigation of antibacterial mechanism of the photocatalysis. PMID- 21589874 TI - Structural similarity and classification of protein interaction interfaces. AB - Interactions between proteins play a key role in many cellular processes. Studying protein-protein interactions that share similar interaction interfaces may shed light on their evolution and could be helpful in elucidating the mechanisms behind stability and dynamics of the protein complexes. When two complexes share structurally similar subunits, the similarity of the interaction interfaces can be found through a structural superposition of the subunits. However, an accurate detection of similarity between the protein complexes containing subunits of unrelated structure remains an open problem. Here, we present an alignment-free machine learning approach to measure interface similarity. The approach relies on the feature-based representation of protein interfaces and does not depend on the superposition of the interacting subunit pairs. Specifically, we develop an SVM classifier of similar and dissimilar interfaces and derive a feature-based interface similarity measure. Next, the similarity measure is applied to a set of 2,806*2,806 binary complex pairs to build a hierarchical classification of protein-protein interactions. Finally, we explore case studies of similar interfaces from each level of the hierarchy, considering cases when the subunits forming interactions are either homologous or structurally unrelated. The analysis has suggested that the positions of charged residues in the homologous interfaces are not necessarily conserved and may exhibit more complex conservation patterns. PMID- 21589875 TI - Risk factors for neck and upper extremity disorders among computers users and the effect of interventions: an overview of systematic reviews. AB - BACKGROUND: To summarize systematic reviews that 1) assessed the evidence for causal relationships between computer work and the occurrence of carpal tunnel syndrome (CTS) or upper extremity musculoskeletal disorders (UEMSDs), or 2) reported on intervention studies among computer users/or office workers. METHODOLOGY/PRINCIPAL FINDINGS: PubMed, Embase, CINAHL and Web of Science were searched for reviews published between 1999 and 2010. Additional publications were provided by content area experts. The primary author extracted all data using a purpose-built form, while two of the authors evaluated the quality of the reviews using recommended standard criteria from AMSTAR; disagreements were resolved by discussion. The quality of evidence syntheses in the included reviews was assessed qualitatively for each outcome and for the interventions. Altogether, 1,349 review titles were identified, 47 reviews were retrieved for full text relevance assessment, and 17 reviews were finally included as being relevant and of sufficient quality. The degrees of focus and rigorousness of these 17 reviews were highly variable. Three reviews on risk factors for carpal tunnel syndrome were rated moderate to high quality, 8 reviews on risk factors for UEMSDs ranged from low to moderate/high quality, and 6 reviews on intervention studies were of moderate to high quality. The quality of the evidence for computer use as a risk factor for CTS was insufficient, while the evidence for computer use and UEMSDs was moderate regarding pain complaints and limited for specific musculoskeletal disorders. From the reviews on intervention studies no strong evidence based recommendations could be given. CONCLUSIONS/SIGNIFICANCE: Computer use is associated with pain complaints, but it is still not very clear if this association is causal. The evidence for specific disorders or diseases is limited. No effective interventions have yet been documented. PMID- 21589876 TI - Contrasting diversity patterns of crenarchaeal, bacterial and fungal soil communities in an alpine landscape. AB - BACKGROUND: The advent of molecular techniques in microbial ecology has aroused interest in gaining an understanding about the spatial distribution of regional pools of soil microbes and the main drivers responsible of these spatial patterns. Here, we assessed the distribution of crenarcheal, bacterial and fungal communities in an alpine landscape displaying high turnover in plant species over short distances. Our aim is to determine the relative contribution of plant species composition, environmental conditions, and geographic isolation on microbial community distribution. METHODOLOGY/PRINCIPAL FINDINGS: Eleven types of habitats that best represent the landscape heterogeneity were investigated. Crenarchaeal, bacterial and fungal communities were described by means of Single Strand Conformation Polymorphism. Relationships between microbial beta diversity patterns were examined by using Bray-Curtis dissimilarities and Principal Coordinate Analyses. Distance-based redundancy analyses and variation partitioning were used to estimate the relative contributions of different drivers on microbial beta diversity. Microbial communities tended to be habitat specific and did not display significant spatial autocorrelation. Microbial beta diversity correlated with soil pH. Fungal beta-diversity was mainly related to soil organic matter. Though the effect of plant species composition was significant for all microbial groups, it was much stronger for Fungi. In contrast, geographic distances did not have any effect on microbial beta diversity. CONCLUSIONS/SIGNIFICANCE: Microbial communities exhibit non-random spatial patterns of diversity in alpine landscapes. Crenarcheal, bacterial and fungal community turnover is high and associated with plant species composition through different set of soil variables, but is not caused by geographical isolation. PMID- 21589877 TI - Distinct roles of Bcl-2 and Bcl-Xl in the apoptosis of human bone marrow mesenchymal stem cells during differentiation. AB - BACKGROUND: Adult mesenchymal stem cells (MSCs) can be maintained over extended periods of time before activation and differentiation. Little is known about the programs that sustain the survival of these cells. PRINCIPAL FINDINGS: Undifferentiated adult human MSCs (hMSCs) did not undergo apoptosis in response to different cell death inducers. Conversely, the same inducers can readily induce apoptosis when hMSCs are engaged in the early stages of differentiation. The survival of undifferentiated cells is linked to the expression of Bcl-Xl and Bcl-2 in completely opposite ways. Bcl-Xl is expressed at similar levels in undifferentiated and differentiated hMSCs while Bcl-2 is expressed only in differentiated cells. In undifferentiated hMSCs, the down-regulation of Bcl-Xl is associated with an increased sensitivity to apoptosis while the ectopic expression of Bcl-2 induced apoptosis. This apoptosis is linked to the presence of cytoplasmic Nur 77 in undifferentiated hMSCs. SIGNIFICANCE: In hMSCs, the expression of Bcl-2 depends on cellular differentiation and can be either pro- or anti-apoptotic. Bcl-Xl, on the other hand, exhibits an anti-apoptotic activity under all conditions. PMID- 21589878 TI - Effect of soluble ICAM-1 on a Sjogren's syndrome-like phenotype in NOD mice is disease stage dependent. AB - INTRODUCTION: Intercellular adhesion molecule-1 (ICAM-1) is involved in migration and co-stimulation of T and B cells. Membrane bound ICAM-1 is over expressed in the salivary glands (SG) of Sjogren's syndrome (SS) patients and has therefore been proposed as a potential therapeutic target. To test the utility of ICAM-1 as a therapeutic target, we used local gene therapy in Non Obese Diabetic (NOD) mice to express soluble (s)ICAM-1 to compete with membrane bound ICAM-1 for binding with its receptor. Therapy was given prior to and just after the influx of immune cells into the SG. METHODS: A recombinant serotype 2 adeno associated virus (rAAV2) encoding ICAM-1/Fc was constructed and its efficacy tested in the female NOD mice after retrograde instillation in SG at eight (early treatment) and ten (late treatment) weeks of age. SG inflammation was evaluated by focus score and immunohistochemical quantification of infiltrating cell types. Serum and SG tissue were analyzed for immunoglobulins (Ig). RESULTS: Early treatment with ICAM 1/Fc resulted in decreased average number of inflammatory foci without changes in T and B cell composition. In contrast, late treated mice did not show any change in focus scores, but immunohistochemical staining showed an increase in the overall number of CD4+ and CD8+ T cells. Moreover, early treated mice showed decreased IgM within the SGs, whereas late treated mice had increased IgM levels, and on average higher IgG and IgA. CONCLUSIONS: Blocking the ICAM-1/LFA-1 interaction with sICAM-1/Fc may result in worsening of a SS like phenotype when infiltrates have already formed within the SG. As a treatment for human SS, caution should be taken targeting the ICAM-1 axis since most patients are diagnosed when inflammation is clearly present within the SG. PMID- 21589879 TI - A motif unique to the human DEAD-box protein DDX3 is important for nucleic acid binding, ATP hydrolysis, RNA/DNA unwinding and HIV-1 replication. AB - DEAD-box proteins are enzymes endowed with nucleic acid-dependent ATPase, RNA translocase and unwinding activities. The human DEAD-box protein DDX3 has been shown to play important roles in tumor proliferation and viral infections. In particular, DDX3 has been identified as an essential cofactor for HIV-1 replication. Here we characterized a set of DDX3 mutants biochemically with respect to nucleic acid binding, ATPase and helicase activity. In particular, we addressed the functional role of a unique insertion between motifs I and Ia of DDX3 and provide evidence for its implication in nucleic acid binding and HIV-1 replication. We show that human DDX3 lacking this domain binds HIV-1 RNA with lower affinity. Furthermore, a specific peptide ligand for this insertion selected by phage display interferes with HIV-1 replication after transduction into HelaP4 cells. Besides broadening our understanding of the structure-function relationships of this important protein, our results identify a specific domain of DDX3 which may be suited as target for antiviral drugs designed to inhibit cellular cofactors for HIV-1 replication. PMID- 21589880 TI - Oligodendrocytes as regulators of neuronal networks during early postnatal development. AB - Oligodendrocytes are the glial cells responsible for myelin formation. Myelination occurs during the first postnatal weeks and, in rodents, is completed during the third week after birth. Myelin ensures the fast conduction of the nerve impulse; in the adult, myelin proteins have an inhibitory role on axon growth and regeneration after injury. During brain development, oligodendrocytes precursors originating in multiple locations along the antero-posterior axis actively proliferate and migrate to colonize the whole brain. Whether the initial interactions between oligodendrocytes and neurons might play a functional role before the onset of myelination is still not completely elucidated. In this article, we addressed this question by transgenically targeted ablation of proliferating oligodendrocytes during cerebellum development. Interestingly, we show that depletion of oligodendrocytes at postnatal day 1 (P1) profoundly affects the establishment of cerebellar circuitries. We observed an impressive deregulation in the expression of molecules involved in axon growth, guidance and synaptic plasticity. These effects were accompanied by an outstanding increase of neurofilament staining observed 4 hours after the beginning of the ablation protocol, likely dependent from sprouting of cerebellar fibers. Oligodendrocyte ablation modifies localization and function of ionotropic glutamate receptors in Purkinje neurons. These results show a novel oligodendrocyte function expressed during early postnatal brain development, where these cells participate in the formation of cerebellar circuitries, and influence its development. PMID- 21589881 TI - Multiple aggregates and aggresomes of C-terminal truncated human alphaA crystallins in mammalian cells and protection by alphaB-crystallin. AB - BACKGROUND: Cleavage of 11 (alphaA162), 5 (alphaA168) and 1 (alphaA172) residues from the C-terminus of alphaA-crystallin creates structurally and functionally different proteins. The formation of these post-translationally modified alphaA crystallins is enhanced in diabetes. In the present study, the fate of the truncated alphaA-crystallins expressed in living mammalian cells in the presence and absence of native alphaA- or alphaB-crystallin has been studied by laser scanning confocal microscopy (LSM). METHODOLOGY/PRINCIPAL FINDINGS: YFP tagged alphaAwt, alphaA162, alphaA168 and alphaA172, were individually transfected or co transfected with CFP tagged alphaAwt or alphaBwt, expressed in HeLa cells and studied by LSM. Difference in protein aggregation was not caused by different level of alpha-crystallin expression because Western blotting results showed nearly same level of expression of the various alpha-crystallins. The FRET acceptor photo-bleaching protocol was followed to study in situ protein-protein interaction. alphaA172 interacted with alphaAwt and alphaBwt better than alphaA168 and alphaA162, interaction of alphaBwt being two-fold stronger than that of alphaAwt. Furthermore, aggresomes were detected in cells individually expressing alphaA162 and alphaA168 constructs and co-expression with alphaBwt significantly sequestered the aggresomes. There was no sequestration of aggresomes with alphaAwt co-expression with the truncated constructs, alphaA162 and alphaA168. Double immunocytochemistry technique was used for co-localization of gamma-tubulin with alphaA-crystallin to demonstrate the perinuclear aggregates were aggresomes. CONCLUSIONS/SIGNIFICANCE: alphaA172 showed the strongest interaction with both alphaAwt and alphaBwt. Native alphaB-crystallin provided protection to partially unfolded truncated alphaA-crystallins whereas native alphaA-crystallin did not. Aggresomes were detected in cells expressing alphaA162 and alphaA168 and alphaBwt co-expression with these constructs diminished the aggresome formation. Co-localization of gamma-tubulin in perinuclear aggregates validates for aggresomes. PMID- 21589882 TI - The first sequenced carnivore genome shows complex host-endogenous retrovirus relationships. AB - Host-retrovirus interactions influence the genomic landscape and have contributed substantially to mammalian genome evolution. To gain further insights, we analyzed a female boxer (Canis familiaris) genome for complexity and integration pattern of canine endogenous retroviruses (CfERV). Intriguingly, the first such in-depth analysis of a carnivore species identified 407 CfERV proviruses that represent only 0.15% of the dog genome. In comparison, the same detection criteria identified about six times more HERV proviruses in the human genome that has been estimated to contain a total of 8% retroviral DNA including solitary LTRs. These observed differences in man and dog are likely due to different mechanisms to purge, restrict and protect their genomes against retroviruses. A novel group of gammaretrovirus-like CfERV with high similarity to HERV-Fc1 was found to have potential for active retrotransposition and possibly lateral transmissions between dog and human as a result of close interactions during at least 10.000 years. The CfERV integration landscape showed a non-uniform intra- and inter-chromosomal distribution. Like in other species, different densities of ERVs were observed. Some chromosomal regions were essentially devoid of CfERVs whereas other regions had large numbers of integrations in agreement with distinct selective pressures at different loci. Most CfERVs were integrated in antisense orientation within 100 kb from annotated protein-coding genes. This integration pattern provides evidence for selection against CfERVs in sense orientation relative to chromosomal genes. In conclusion, this ERV analysis of the first carnivorous species supports the notion that different mammals interact distinctively with endogenous retroviruses and suggests that retroviral lateral transmissions between dog and human may have occurred. PMID- 21589884 TI - Increased resting-state perfusion after repeated encoding is related to later retrieval of declarative associative memories. AB - Electrophysiological studies in animals have shown coordinated reactivation of neuronal ensembles during a restricted time period of behavioral inactivity that immediately followed active encoding. In the present study we directly investigated off-line processing of associative memory formation in the human brain. Subjects' regional cerebral blood flow (rCBF) as a surrogate marker of neural activity during rest was measured by MR-based perfusion imaging in a sample of 14 healthy male subjects prior to (Pre2) and after (Post) extensive learning of 24 face-name associations within a selective reminding task (SR). Results demonstrated significant Post-Pre2 rCBF increases in hippocampal and temporal lobe regions, while in a control comparison of two perfusion scans with no learning task in-between (Pre2-Pre1) no differences in rCBF emerged. Post perfusion scanning was followed by a surprise cued associative recall task from which two types of correctly retrieved names were obtained: older names already correctly retrieved at least once during one of the SR blocks, and recent names acquired during the last SR block immediately prior to the Post scan. In the anterior hippocampus individual perfusion increases were correlated with both correct retrievals of older and recent names. By contrast, older but not recently learned names showed a significant correlation with perfusion increases in the left lateral temporal cortex known to be associated with long-term memory. Recent, but not older names were correlated with dopaminergic midbrain structures reported to contribute to the persistence of memory traces for novel information. Although the direct investigation of off-line memory processing did not permit concomitant experimental control, neither intentional rehearsal, nor substantial variations in subjects' states of alertness appear to contribute to present results. We suggest that the observed rCBF increases might reflect processes that possibly contribute to the long-term persistence of memory traces. PMID- 21589883 TI - T cells from Programmed Death-1 deficient mice respond poorly to Mycobacterium tuberculosis infection. AB - BACKGROUND: Programmed Death-1 (PD-1; CD279) receptor molecule is widely believed to be a negative regulator predominantly expressed by exhausted/activated mouse T cells. Upon interaction with its ligands, PD-L1 and PD-L2, PD-1 inhibits activation of T cells and cytokine production, which has been documented in various viral and fungal infections as well as in vitro studies. Therefore, inhibition of T cell responses by PD-1 resulted in disease resistance in a variety of mouse infection models studied heretofore. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that PD-1 deficient (PD-1(-/-)) mice infected with Mycobacterium tuberculosis (M. tb) H37Rv by the aerosol route have increased susceptibility as compared with their wild type littermates. Surprisingly, M. tb antigen-specific T cell proliferation was dramatically reduced in PD-1 deficient animals compared with wild-type littermates, and this was due to increased numbers of regulatory T cells (Tregs) and recruitment of mesenchymal stem cells. Furthermore, PD-1(-/-) mice exhibited decreases in the autophagy-induced LC3-B marker protein in macrophages. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that PD-1 does not play an inhibitory role during M. tb infection and instead promotes mycobacterial clearance in mice. PMID- 21589885 TI - Vaginal recurrence more than 17 years after hysterectomy and adjuvant treatment for uterine carcinoma with successful salvage brachytherapy: a case report. AB - PURPOSE: Although the majority of recurrences occur within the first 3 years of hysterectomy for endometrioid carcinoma, we report herein a successful salvage vaginal brachytherapy in a patient with endometrioid uterine carcinoma which recurred more than 17 years after initial treatment. MATERIALS AND METHODS: A 61 year-old female was diagnosed with endometrioid adenocarcinoma of the uterus and treated with TAH-BSO, followed by adjuvant external beam radiation therapy (EBRT) to the whole pelvis. After remaining free of any recurrent or metastatic disease for more than 17 years, she was diagnosed with isolated vaginal cuff recurrence and successfully treated with a salvage high-dose-rate intracavitary vaginal brachytherapy. RESULTS: The patient remained disease free until her death from unrelated causes 7 years later. CONCLUSION: To the best of our knowledge, this case represents the longest time to recurrence of endometrial cancer in someone who had been treated with TAH-BSO and adjuvant pelvic EBRT. This case highlights that even with adjuvant therapy, late recurrences may occur, and successful salvage brachytherapy is very effective. PMID- 21589886 TI - Emergence of switch-like behavior in a large family of simple biochemical networks. AB - Bistability plays a central role in the gene regulatory networks (GRNs) controlling many essential biological functions, including cellular differentiation and cell cycle control. However, establishing the network topologies that can exhibit bistability remains a challenge, in part due to the exceedingly large variety of GRNs that exist for even a small number of components. We begin to address this problem by employing chemical reaction network theory in a comprehensive in silico survey to determine the capacity for bistability of more than 40,000 simple networks that can be formed by two transcription factor-coding genes and their associated proteins (assuming only the most elementary biochemical processes). We find that there exist reaction rate constants leading to bistability in ~90% of these GRN models, including several circuits that do not contain any of the TF cooperativity commonly associated with bistable systems, and the majority of which could only be identified as bistable through an original subnetwork-based analysis. A topological sorting of the two-gene family of networks based on the presence or absence of biochemical reactions reveals eleven minimal bistable networks (i.e., bistable networks that do not contain within them a smaller bistable subnetwork). The large number of previously unknown bistable network topologies suggests that the capacity for switch-like behavior in GRNs arises with relative ease and is not easily lost through network evolution. To highlight the relevance of the systematic application of CRNT to bistable network identification in real biological systems, we integrated publicly available protein-protein interaction, protein-DNA interaction, and gene expression data from Saccharomyces cerevisiae, and identified several GRNs predicted to behave in a bistable fashion. PMID- 21589887 TI - Transcriptional regulation: effects of promoter proximal pausing on speed, synchrony and reliability. AB - Recent whole genome polymerase binding assays in the Drosophila embryo have shown that a substantial proportion of uninduced genes have pre-assembled RNA polymerase-II transcription initiation complex (PIC) bound to their promoters. These constitute a subset of promoter proximally paused genes for which mRNA elongation instead of promoter access is regulated. This difference can be described as a rearrangement of the regulatory topology to control the downstream transcriptional process of elongation rather than the upstream transcriptional initiation event. It has been shown experimentally that genes with the former mode of regulation tend to induce faster and more synchronously, and that promoter-proximal pausing is observed mainly in metazoans, in accord with a posited impact on synchrony. However, it has not been shown whether or not it is the change in the regulated step per se that is causal. We investigate this question by proposing and analyzing a continuous-time Markov chain model of PIC assembly regulated at one of two steps: initial polymerase association with DNA, or release from a paused, transcribing state. Our analysis demonstrates that, over a wide range of physical parameters, increased speed and synchrony are functional consequences of elongation control. Further, we make new predictions about the effect of elongation regulation on the consistent control of total transcript number between cells. We also identify which elements in the transcription induction pathway are most sensitive to molecular noise and thus possibly the most evolutionarily constrained. Our methods produce symbolic expressions for quantities of interest with reasonable computational effort and they can be used to explore the interplay between interaction topology and molecular noise in a broader class of biochemical networks. We provide general purpose code implementing these methods. PMID- 21589888 TI - An imperfect dopaminergic error signal can drive temporal-difference learning. AB - An open problem in the field of computational neuroscience is how to link synaptic plasticity to system-level learning. A promising framework in this context is temporal-difference (TD) learning. Experimental evidence that supports the hypothesis that the mammalian brain performs temporal-difference learning includes the resemblance of the phasic activity of the midbrain dopaminergic neurons to the TD error and the discovery that cortico-striatal synaptic plasticity is modulated by dopamine. However, as the phasic dopaminergic signal does not reproduce all the properties of the theoretical TD error, it is unclear whether it is capable of driving behavior adaptation in complex tasks. Here, we present a spiking temporal-difference learning model based on the actor-critic architecture. The model dynamically generates a dopaminergic signal with realistic firing rates and exploits this signal to modulate the plasticity of synapses as a third factor. The predictions of our proposed plasticity dynamics are in good agreement with experimental results with respect to dopamine, pre- and post-synaptic activity. An analytical mapping from the parameters of our proposed plasticity dynamics to those of the classical discrete-time TD algorithm reveals that the biological constraints of the dopaminergic signal entail a modified TD algorithm with self-adapting learning parameters and an adapting offset. We show that the neuronal network is able to learn a task with sparse positive rewards as fast as the corresponding classical discrete-time TD algorithm. However, the performance of the neuronal network is impaired with respect to the traditional algorithm on a task with both positive and negative rewards and breaks down entirely on a task with purely negative rewards. Our model demonstrates that the asymmetry of a realistic dopaminergic signal enables TD learning when learning is driven by positive rewards but not when driven by negative rewards. PMID- 21589889 TI - Epistasis in a model of molecular signal transduction. AB - Biological functions typically involve complex interacting molecular networks, with numerous feedback and regulation loops. How the properties of the system are affected when one, or several of its parts are modified is a question of fundamental interest, with numerous implications for the way we study and understand biological processes and treat diseases. This question can be rephrased in terms of relating genotypes to phenotypes: to what extent does the effect of a genetic variation at one locus depend on genetic variation at all other loci? Systematic quantitative measurements of epistasis--the deviation from additivity in the effect of alleles at different loci--on a given quantitative trait remain a major challenge. Here, we take a complementary approach of studying theoretically the effect of varying multiple parameters in a validated model of molecular signal transduction. To connect with the genotype/phenotype mapping we interpret parameters of the model as different loci with discrete choices of these parameters as alleles, which allows us to systematically examine the dependence of the signaling output--a quantitative trait--on the set of possible allelic combinations. We show quite generally that quantitative traits behave approximately additively (weak epistasis) when alleles correspond to small changes of parameters; epistasis appears as a result of large differences between alleles. When epistasis is relatively strong, it is concentrated in a sparse subset of loci and in low order (e.g. pair-wise) interactions. We find that focusing on interaction between loci that exhibit strong additive effects is an efficient way of identifying most of the epistasis. Our model study defines a theoretical framework for interpretation of experimental data and provides statistical predictions for the structure of genetic interaction expected for moderately complex biological circuits. PMID- 21589890 TI - Quantitative epistasis analysis and pathway inference from genetic interaction data. AB - Inferring regulatory and metabolic network models from quantitative genetic interaction data remains a major challenge in systems biology. Here, we present a novel quantitative model for interpreting epistasis within pathways responding to an external signal. The model provides the basis of an experimental method to determine the architecture of such pathways, and establishes a new set of rules to infer the order of genes within them. The method also allows the extraction of quantitative parameters enabling a new level of information to be added to genetic network models. It is applicable to any system where the impact of combinatorial loss-of-function mutations can be quantified with sufficient accuracy. We test the method by conducting a systematic analysis of a thoroughly characterized eukaryotic gene network, the galactose utilization pathway in Saccharomyces cerevisiae. For this purpose, we quantify the effects of single and double gene deletions on two phenotypic traits, fitness and reporter gene expression. We show that applying our method to fitness traits reveals the order of metabolic enzymes and the effects of accumulating metabolic intermediates. Conversely, the analysis of expression traits reveals the order of transcriptional regulatory genes, secondary regulatory signals and their relative strength. Strikingly, when the analyses of the two traits are combined, the method correctly infers ~80% of the known relationships without any false positives. PMID- 21589891 TI - Chromosome-biased binding and gene regulation by the Caenorhabditis elegans DRM complex. AB - DRM is a conserved transcription factor complex that includes E2F/DP and pRB family proteins and plays important roles in development and cancer. Here we describe new aspects of DRM binding and function revealed through genome-wide analyses of the Caenorhabditis elegans DRM subunit LIN-54. We show that LIN-54 DNA-binding activity recruits DRM to promoters enriched for adjacent putative E2F/DP and LIN-54 binding sites, suggesting that these two DNA-binding moieties together direct DRM to its target genes. Chromatin immunoprecipitation and gene expression profiling reveals conserved roles for DRM in regulating genes involved in cell division, development, and reproduction. We find that LIN-54 promotes expression of reproduction genes in the germline, but prevents ectopic activation of germline-specific genes in embryonic soma. Strikingly, C. elegans DRM does not act uniformly throughout the genome: the DRM recruitment motif, DRM binding, and DRM-regulated embryonic genes are all under-represented on the X chromosome. However, germline genes down-regulated in lin-54 mutants are over-represented on the X chromosome. We discuss models for how loss of autosome-bound DRM may enhance germline X chromosome silencing. We propose that autosome-enriched binding of DRM arose in C. elegans as a consequence of germline X chromosome silencing and the evolutionary redistribution of germline-expressed and essential target genes to autosomes. Sex chromosome gene regulation may thus have profound evolutionary effects on genome organization and transcriptional regulatory networks. PMID- 21589892 TI - Quantitative subcellular proteome and secretome profiling of influenza A virus infected human primary macrophages. AB - Influenza A viruses are important pathogens that cause acute respiratory diseases and annual epidemics in humans. Macrophages recognize influenza A virus infection with their pattern recognition receptors, and are involved in the activation of proper innate immune response. Here, we have used high-throughput subcellular proteomics combined with bioinformatics to provide a global view of host cellular events that are activated in response to influenza A virus infection in human primary macrophages. We show that viral infection regulates the expression and/or subcellular localization of more than one thousand host proteins at early phases of infection. Our data reveals that there are dramatic changes in mitochondrial and nuclear proteomes in response to infection. We show that a rapid cytoplasmic leakage of lysosomal proteins, including cathepsins, followed by their secretion, contributes to inflammasome activation and apoptosis seen in the infected macrophages. Also, our results demonstrate that P2X7 receptor and src tyrosine kinase activity are essential for inflammasome activation during influenza A virus infection. Finally, we show that influenza A virus infection is associated with robust secretion of different danger-associated molecular patterns (DAMPs) suggesting an important role for DAMPs in host response to influenza A virus infection. In conclusion, our high-throughput quantitative proteomics study provides important new insight into host-response against influenza A virus infection in human primary macrophages. PMID- 21589893 TI - The antiviral efficacy of HIV-specific CD8+ T-cells to a conserved epitope is heavily dependent on the infecting HIV-1 isolate. AB - A major challenge to developing a successful HIV vaccine is the vast diversity of viral sequences, yet it is generally assumed that an epitope conserved between different strains will be recognised by responding T-cells. We examined whether an invariant HLA-B8 restricted Nef90-97 epitope FL8 shared between five high titre viruses and eight recombinant vaccinia viruses expressing Nef from different viral isolates (clades A-H) could activate antiviral activity in FL8 specific cytotoxic T-lymphocytes (CTL). Surprisingly, despite epitope conservation, we found that CTL antiviral efficacy is dependent on the infecting viral isolate. Only 23% of Nef proteins, expressed by HIV-1 isolates or as recombinant vaccinia-Nef, were optimally recognised by CTL. Recognition of the HIV-1 isolates by CTL was independent of clade-grouping but correlated with virus specific polymorphisms in the epitope flanking region, which altered immunoproteasomal cleavage resulting in enhanced or impaired epitope generation. The finding that the majority of virus isolates failed to present this conserved epitope highlights the importance of viral variance in CTL epitope flanking regions on the efficiency of antigen processing, which has been considerably underestimated previously. This has important implications for future vaccine design strategies since efficient presentation of conserved viral epitopes is necessary to promote enhanced anti-viral immune responses. PMID- 21589894 TI - Novel and conserved protein macoilin is required for diverse neuronal functions in Caenorhabditis elegans. AB - Neural signals are processed in nervous systems of animals responding to variable environmental stimuli. This study shows that a novel and highly conserved protein, macoilin (MACO-1), plays an essential role in diverse neural functions in Caenorhabditis elegans. maco-1 mutants showed abnormal behaviors, including defective locomotion, thermotaxis, and chemotaxis. Expression of human macoilin in the C. elegans nervous system weakly rescued the abnormal thermotactic phenotype of the maco-1 mutants, suggesting that macoilin is functionally conserved across species. Abnormal thermotaxis may have been caused by impaired locomotion of maco-1 mutants. However, calcium imaging of AFD thermosensory neurons and AIY postsynaptic interneurons of maco-1 mutants suggest that macoilin is required for appropriate responses of AFD and AIY neurons to thermal stimuli. Studies on localization of MACO-1 showed that C. elegans and human macoilins are localized mainly to the rough endoplasmic reticulum. Our results suggest that macoilin is required for various neural events, such as the regulation of neuronal activity. PMID- 21589896 TI - Evolution of Th2 immunity: a rapid repair response to tissue destructive pathogens. PMID- 21589895 TI - Genome of Herbaspirillum seropedicae strain SmR1, a specialized diazotrophic endophyte of tropical grasses. AB - The molecular mechanisms of plant recognition, colonization, and nutrient exchange between diazotrophic endophytes and plants are scarcely known. Herbaspirillum seropedicae is an endophytic bacterium capable of colonizing intercellular spaces of grasses such as rice and sugar cane. The genome of H. seropedicae strain SmR1 was sequenced and annotated by The Parana State Genome Programme--GENOPAR. The genome is composed of a circular chromosome of 5,513,887 bp and contains a total of 4,804 genes. The genome sequence revealed that H. seropedicae is a highly versatile microorganism with capacity to metabolize a wide range of carbon and nitrogen sources and with possession of four distinct terminal oxidases. The genome contains a multitude of protein secretion systems, including type I, type II, type III, type V, and type VI secretion systems, and type IV pili, suggesting a high potential to interact with host plants. H. seropedicae is able to synthesize indole acetic acid as reflected by the four IAA biosynthetic pathways present. A gene coding for ACC deaminase, which may be involved in modulating the associated plant ethylene-signaling pathway, is also present. Genes for hemagglutinins/hemolysins/adhesins were found and may play a role in plant cell surface adhesion. These features may endow H. seropedicae with the ability to establish an endophytic life-style in a large number of plant species. PMID- 21589897 TI - An E2F1-mediated DNA damage response contributes to the replication of human cytomegalovirus. AB - DNA damage resulting from intrinsic or extrinsic sources activates DNA damage responses (DDRs) centered on protein kinase signaling cascades. The usual consequences of inducing DDRs include the activation of cell cycle checkpoints together with repair of the damaged DNA or induction of apoptosis. Many DNA viruses elicit host DDRs during infection and some viruses require the DDR for efficient replication. However, the mechanism by which DDRs are activated by viral infection is poorly understood. Human cytomegalovirus (HCMV) infection induces a DDR centered on the activation of ataxia telangiectasia mutated (ATM) protein kinase. Here we show that HCMV replication is compromised in cells with inactivated or depleted ATM and that ATM is essential for the host DDR early during infection. Likewise, a downstream target of ATM phosphorylation, H2AX, also contributes to viral replication. The ATM-dependent DDR is detected as discrete, nuclear gammaH2AX foci early in infection and can be activated by IE proteins. By 24 hpi, gammaH2AX is observed primarily in HCMV DNA replication compartments. We identified a role for the E2F1 transcription factor in mediating this DDR and viral replication. E2F1, but not E2F2 or E2F3, promotes the accumulation of gammaH2AX during HCMV infection or IE protein expression. Moreover, E2F1 expression, but not the expression of E2F2 or E2F3, is required for efficient HCMV replication. These results reveal a novel role for E2F1 in mediating an ATM-dependent DDR that contributes to viral replication. Given that E2F activity is often deregulated by infection with DNA viruses, these observations raise the possibility that an E2F1-mediated mechanism of DDR activation may be conserved among DNA viruses. PMID- 21589898 TI - A flurry of folding problems: an interview with Susan Lindquist by Jane Gitschier. PMID- 21589899 TI - Assembly of Drosophila centromeric chromatin proteins during mitosis. AB - Semi-conservative segregation of nucleosomes to sister chromatids during DNA replication creates gaps that must be filled by new nucleosome assembly. We analyzed the cell-cycle timing of centromeric chromatin assembly in Drosophila, which contains the H3 variant CID (CENP-A in humans), as well as CENP-C and CAL1, which are required for CID localization. Pulse-chase experiments show that CID and CENP-C levels decrease by 50% at each cell division, as predicted for semi conservative segregation and inheritance, whereas CAL1 displays higher turnover. Quench-chase-pulse experiments demonstrate that there is a significant lag between replication and replenishment of centromeric chromatin. Surprisingly, new CID is recruited to centromeres in metaphase, by a mechanism that does not require an intact mitotic spindle, but does require proteasome activity. Interestingly, new CAL1 is recruited to centromeres before CID in prophase. Furthermore, CAL1, but not CENP-C, is found in complex with pre-nucleosomal CID. Finally, CENP-C displays yet a different pattern of incorporation, during both interphase and mitosis. The unusual timing of CID recruitment and unique dynamics of CAL1 identify a distinct centromere assembly pathway in Drosophila and suggest that CAL1 is a key regulator of centromere propagation. PMID- 21589900 TI - Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface. AB - Helicobacter pylori (Hp) injects the CagA effector protein into host epithelial cells and induces growth factor-like signaling, perturbs cell-cell junctions, and alters host cell polarity. This enables Hp to grow as microcolonies adhered to the host cell surface even in conditions that do not support growth of free swimming bacteria. We hypothesized that CagA alters host cell physiology to allow Hp to obtain specific nutrients from or across the epithelial barrier. Using a polarized epithelium model system, we find that isogenic DeltacagA mutants are defective in cell surface microcolony formation, but exogenous addition of iron to the apical medium partially rescues this defect, suggesting that one of CagA's effects on host cells is to facilitate iron acquisition from the host. Hp adhered to the apical epithelial surface increase basolateral uptake of transferrin and induce its transcytosis in a CagA-dependent manner. Both CagA and VacA contribute to the perturbation of transferrin recycling, since VacA is involved in apical mislocalization of the transferrin receptor to sites of bacterial attachment. To determine if the transferrin recycling pathway is involved in Hp colonization of the cell surface, we silenced transferrin receptor expression during infection. This resulted in a reduced ability of Hp to colonize the polarized epithelium. To test whether CagA is important in promoting iron acquisition in vivo, we compared colonization of Hp in iron-replete vs. iron-deficient Mongolian gerbils. While wild type Hp and DeltacagA mutants colonized iron-replete gerbils at similar levels, DeltacagA mutants are markedly impaired in colonizing iron-deficient gerbils. Our study indicates that CagA and VacA act in concert to usurp the polarized process of host cell iron uptake, allowing Hp to use the cell surface as a replicative niche. PMID- 21589901 TI - A component of the Xanthomonadaceae type IV secretion system combines a VirB7 motif with a N0 domain found in outer membrane transport proteins. AB - Type IV secretion systems (T4SS) are used by Gram-negative bacteria to translocate protein and DNA substrates across the cell envelope and into target cells. Translocation across the outer membrane is achieved via a ringed tetradecameric outer membrane complex made up of a small VirB7 lipoprotein (normally 30 to 45 residues in the mature form) and the C-terminal domains of the VirB9 and VirB10 subunits. Several species from the genera of Xanthomonas phytopathogens possess an uncharacterized type IV secretion system with some distinguishing features, one of which is an unusually large VirB7 subunit (118 residues in the mature form). Here, we report the NMR and 1.0 A X-ray structures of the VirB7 subunit from Xanthomonas citri subsp. citri (VirB7(XAC2622)) and its interaction with VirB9. NMR solution studies show that residues 27-41 of the disordered flexible N-terminal region of VirB7(XAC2622) interact specifically with the VirB9 C-terminal domain, resulting in a significant reduction in the conformational freedom of both regions. VirB7(XAC2622) has a unique C-terminal domain whose topology is strikingly similar to that of N0 domains found in proteins from different systems involved in transport across the bacterial outer membrane. We show that VirB7(XAC2622) oligomerizes through interactions involving conserved residues in the N0 domain and residues 42-49 within the flexible N terminal region and that these homotropic interactions can persist in the presence of heterotropic interactions with VirB9. Finally, we propose that VirB7(XAC2622) oligomerization is compatible with the core complex structure in a manner such that the N0 domains form an extra layer on the perimeter of the tetradecameric ring. PMID- 21589902 TI - The hexamer structure of Rift Valley fever virus nucleoprotein suggests a mechanism for its assembly into ribonucleoprotein complexes. AB - Rift Valley fever virus (RVFV), a Phlebovirus with a genome consisting of three single-stranded RNA segments, is spread by infected mosquitoes and causes large viral outbreaks in Africa. RVFV encodes a nucleoprotein (N) that encapsidates the viral RNA. The N protein is the major component of the ribonucleoprotein complex and is also required for genomic RNA replication and transcription by the viral polymerase. Here we present the 1.6 A crystal structure of the RVFV N protein in hexameric form. The ring-shaped hexamers form a functional RNA binding site, as assessed by mutagenesis experiments. Electron microscopy (EM) demonstrates that N in complex with RNA also forms rings in solution, and a single-particle EM reconstruction of a hexameric N-RNA complex is consistent with the crystallographic N hexamers. The ring-like organization of the hexamers in the crystal is stabilized by circular interactions of the N terminus of RVFV N, which forms an extended arm that binds to a hydrophobic pocket in the core domain of an adjacent subunit. The conformation of the N-terminal arm differs from that seen in a previous crystal structure of RVFV, in which it was bound to the hydrophobic pocket in its own core domain. The switch from an intra- to an inter-molecular interaction mode of the N-terminal arm may be a general principle that underlies multimerization and RNA encapsidation by N proteins from Bunyaviridae. Furthermore, slight structural adjustments of the N-terminal arm would allow RVFV N to form smaller or larger ring-shaped oligomers and potentially even a multimer with a super-helical subunit arrangement. Thus, the interaction mode between subunits seen in the crystal structure would allow the formation of filamentous ribonucleocapsids in vivo. Both the RNA binding cleft and the multimerization site of the N protein are promising targets for the development of antiviral drugs. PMID- 21589903 TI - CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope. AB - Cytotoxic CD8+ T cells (CTLs) play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also against cryptic epitopes encoded by viral alternative reading frames (ARF). We studied here the mechanisms of HIV-1 escape from CTLs targeting one such cryptic epitope, Q9VF, encoded by an HIVgag ARF and presented by HLA-B*07. Using PBMCs of HIV-infected patients, we first cloned and sequenced proviral DNA encoding for Q9VF. We identified several polymorphisms with a minority of proviruses encoding at position 5 an aspartic acid (Q9VF/5D) and a majority encoding an asparagine (Q9VF/5N). We compared the prevalence of each variant in PBMCs of HLA-B*07+ and HLA-B*07- patients. Proviruses encoding Q9VF/5D were significantly less represented in HLA-B*07+ than in HLA-B*07- patients, suggesting that Q9FV/5D encoding viruses might be under selective pressure in HLA-B*07+ individuals. We thus analyzed ex vivo CTL responses directed against Q9VF/5D and Q9VF/5N. Around 16% of HLA-B*07+ patients exhibited CTL responses targeting Q9VF epitopes. The frequency and the magnitude of CTL responses induced with Q9VF/5D or Q9VF/5N peptides were almost equal indicating a possible cross-reactivity of the same CTLs on the two peptides. We then dissected the cellular mechanisms involved in the presentation of Q9VF variants. As expected, cells infected with HIV strains encoding for Q9VF/5D were recognized by Q9VF/5D-specific CTLs. In contrast, Q9VF/5N-encoding strains were neither recognized by Q9VF/5N- nor by Q9VF/5D-specific CTLs. Using in vitro proteasomal digestions and MS/MS analysis, we demonstrate that the 5N variation introduces a strong proteasomal cleavage site within the epitope, leading to a dramatic reduction of Q9VF epitope production. Our results strongly suggest that HIV-1 escapes CTL surveillance by introducing mutations leading to HIV ARF-epitope destruction by proteasomes. PMID- 21589904 TI - A family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides. AB - Over the last decade a significant number of studies have highlighted the central role of host antimicrobial (or defence) peptides in modulating the response of innate immune cells to pathogen-associated ligands. In humans, the most widely studied antimicrobial peptide is LL-37, a 37-residue peptide containing an amphipathic helix that is released via proteolytic cleavage of the precursor protein CAP18. Owing to its ability to protect against lethal endotoxaemia and clinically-relevant bacterial infections, LL-37 and its derivatives are seen as attractive candidates for anti-sepsis therapies. We have identified a novel family of molecules secreted by parasitic helminths (helminth defence molecules; HDMs) that exhibit similar biochemical and functional characteristics to human defence peptides, particularly CAP18. The HDM secreted by Fasciola hepatica (FhHDM-1) adopts a predominantly alpha-helical structure in solution. Processing of FhHDM-1 by F. hepatica cathepsin L1 releases a 34-residue C-terminal fragment containing a conserved amphipathic helix. This is analogous to the proteolytic processing of CAP18 to release LL-37, which modulates innate cell activation by classical toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS). We show that full-length recombinant FhHDM-1 and a peptide analogue of the amphipathic C-terminus bind directly to LPS in a concentration-dependent manner, reducing its interaction with both LPS-binding protein (LBP) and the surface of macrophages. Furthermore, FhHDM-1 and the amphipathic C-terminal peptide protect mice against LPS-induced inflammation by significantly reducing the release of inflammatory mediators from macrophages. We propose that HDMs, by mimicking the function of host defence peptides, represent a novel family of innate cell modulators with therapeutic potential in anti-sepsis treatments and prevention of inflammation. PMID- 21589905 TI - Misregulation of AUXIN RESPONSE FACTOR 8 underlies the developmental abnormalities caused by three distinct viral silencing suppressors in Arabidopsis. AB - In Arabidopsis, micro (mi)RNAs and trans-acting (ta-si)RNAs synthesized directly or indirectly through the DICER-LIKE-1 (DCL1) ribonuclease have roles in patterning and hormonal responses, while DCL2,3,4-dependent small-interfering (si)RNAs are mainly involved in silencing of transposable elements and antiviral defense. Viral suppressors of RNA silencing (VSRs) produced by phytoviruses to counter plant defense may perturb plant developmental programs because of the collision of their inhibitory effects with the regulatory action of endogenous miRNAs and ta-siRNAs. This could explain the similar developmental aberrations displayed by Arabidopsis miRNA/ta-siRNA pathway mutants, including dcl1, and by some VSR-expressing plants. Nonetheless, the molecular bases for these morphological aberrations have remained mysterious, and their contribution to viral disease symptoms/virulence unexplored. The extent of VSR inhibitory actions to other types of endogenous small RNAs remains also unclear. Here, we present an in-depth analysis of transgenic Arabidopsis expressing constitutively HcPro, P19 and P15, three unrelated VSRs. We show that VSR expression has comparable, yet modest effects on known miRNA and ta-siRNA target RNA levels, similar to those observed using an hypomorphic dcl1 mutation. However, by combining results of transcriptome studies with deep-sequencing data from immuno-precipitated small RNAs, additional, novel endogenous targets of miRNA and ta-siRNA were identified, unraveling an unsuspected complexity in the origin and scope-of-action of these molecules. Other stringent analyses pinpointed misregulation of the miR167 target AUXIN RESPONSE FACTOR 8 (ARF8) as a major cause for the developmental aberrations exhibited by VSR transgenic plants, but also for the phenotypes induced during normal viral infection caused by the HcPro-encoding Turnip mosaic virus (TuMV). Neither RNA silencing, its suppression by VSRs, nor the virulence/accumulation of TuMV was altered by mutations in ARF8. These findings have important implications for our understanding of viral disease symptoms and small RNA-directed regulation of plant growth/development. PMID- 21589906 TI - A large and intact viral particle penetrates the endoplasmic reticulum membrane to reach the cytosol. AB - Non-enveloped viruses penetrate host membranes to infect cells. A cell-based assay was used to probe the endoplasmic reticulum (ER)-to-cytosol membrane transport of the non-enveloped SV40. We found that, upon ER arrival, SV40 is released into the lumen and undergoes sequential disulfide bond disruptions to reach the cytosol. However, despite these ER-dependent conformational changes, SV40 crosses the ER membrane as a large and intact particle consisting of the VP1 coat, the internal components VP2, VP3, and the genome. This large particle subsequently disassembles in the cytosol. Mutant virus and inhibitor studies demonstrate VP3 and likely the viral genome, as well as cellular proteasome, control ER-to-cytosol transport. Our results identify the sequence of events, as well as virus and host components, that regulate ER membrane penetration. They also suggest that the ER membrane supports passage of a large particle, potentially through either a sizeable protein-conducting channel or the lipid bilayer. PMID- 21589908 TI - Selection and validation of reference genes for quantitative real-time PCR in buckwheat (Fagopyrum esculentum) based on transcriptome sequence data. AB - Quantitative reverse transcription PCR (qRT-PCR) is one of the most precise and widely used methods of gene expression analysis. A necessary prerequisite of exact and reliable data is the accurate choice of reference genes. We studied the expression stability of potential reference genes in common buckwheat (Fagopyrum esculentum) in order to find the optimal reference for gene expression analysis in this economically important crop. Recently sequenced buckwheat floral transcriptome was used as source of sequence information. Expression stability of eight candidate reference genes was assessed in different plant structures (leaves and inflorescences at two stages of development and fruits). These genes are the orthologs of Arabidopsis genes identified as stable in a genome-wide survey gene of expression stability and a traditionally used housekeeping gene GAPDH. Three software applications--geNorm, NormFinder and BestKeeper--were used to estimate expression stability and provided congruent results. The orthologs of AT4G33380 (expressed protein of unknown function, Expressed1), AT2G28390 (SAND family protein, SAND) and AT5G46630 (clathrin adapter complex subunit family protein, CACS) are revealed as the most stable. We recommend using the combination of Expressed1, SAND and CACS for the normalization of gene expression data in studies on buckwheat using qRT-PCR. These genes are listed among five the most stably expressed in Arabidopsis that emphasizes utility of the studies on model plants as a framework for other species. PMID- 21589907 TI - Human neutrophil clearance of bacterial pathogens triggers anti-microbial gammadelta T cell responses in early infection. AB - Human blood Vgamma9/Vdelta2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vgamma9/Vdelta2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vgamma9/Vdelta2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vgamma9/Vdelta2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-alpha dependent proliferation of Vgamma9/Vdelta2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting gammadelta T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis--characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity--show a selective activation of local Vgamma9/Vdelta2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The gammadelta T cell-driven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of gammadelta T cells and TNF-alpha and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive gammadelta T cells in early infection and suggest novel diagnostic and therapeutic approaches. PMID- 21589910 TI - Niche as a determinant of word fate in online groups. AB - Patterns of word use both reflect and influence a myriad of human activities and interactions. Like other entities that are reproduced and evolve, words rise or decline depending upon a complex interplay between their intrinsic properties and the environments in which they function. Using Internet discussion communities as model systems, we define the concept of a word niche as the relationship between the word and the characteristic features of the environments in which it is used. We develop a method to quantify two important aspects of the size of the word niche: the range of individuals using the word and the range of topics it is used to discuss. Controlling for word frequency, we show that these aspects of the word niche are strong determinants of changes in word frequency. Previous studies have already indicated that word frequency itself is a correlate of word success at historical time scales. Our analysis of changes in word frequencies over time reveals that the relative sizes of word niches are far more important than word frequencies in the dynamics of the entire vocabulary at shorter time scales, as the language adapts to new concepts and social groupings. We also distinguish endogenous versus exogenous factors as additional contributors to the fates of words, and demonstrate the force of this distinction in the rise of novel words. Our results indicate that short-term nonstationarity in word statistics is strongly driven by individual proclivities, including inclinations to provide novel information and to project a distinctive social identity. PMID- 21589909 TI - Systematic and evolutionary insights derived from mtDNA COI barcode diversity in the Decapoda (Crustacea: Malacostraca). AB - BACKGROUND: Decapods are the most recognizable of all crustaceans and comprise a dominant group of benthic invertebrates of the continental shelf and slope, including many species of economic importance. Of the 17635 morphologically described Decapoda species, only 5.4% are represented by COI barcode region sequences. It therefore remains a challenge to compile regional databases that identify and analyse the extent and patterns of decapod diversity throughout the world. METHODOLOGY/PRINCIPAL FINDINGS: We contributed 101 decapod species from the North East Atlantic, the Gulf of Cadiz and the Mediterranean Sea, of which 81 species represent novel COI records. Within the newly-generated dataset, 3.6% of the species barcodes conflicted with the assigned morphological taxonomic identification, highlighting both the apparent taxonomic ambiguity among certain groups, and the need for an accelerated and independent taxonomic approach. Using the combined COI barcode projects from the Barcode of Life Database, we provide the most comprehensive COI data set so far examined for the Order (1572 sequences of 528 species, 213 genera, and 67 families). Patterns within families show a general predicted molecular hierarchy, but the scale of divergence at each taxonomic level appears to vary extensively between families. The range values of mean K2P distance observed were: within species 0.285% to 1.375%, within genus 6.376% to 20.924% and within family 11.392% to 25.617%. Nucleotide composition varied greatly across decapods, ranging from 30.8 % to 49.4 % GC content. CONCLUSIONS/SIGNIFICANCE: Decapod biological diversity was quantified by identifying putative cryptic species allowing a rapid assessment of taxon diversity in groups that have until now received limited morphological and systematic examination. We highlight taxonomic groups or species with unusual nucleotide composition or evolutionary rates. Such data are relevant to strategies for conservation of existing decapod biodiversity, as well as elucidating the mechanisms and constraints shaping the patterns observed. PMID- 21589911 TI - Livelihood security and adherence to antiretroviral therapy in low and middle income settings: a systematic review. AB - INTRODUCTION: We sought to examine the association between livelihood security and adherence to antiretroviral therapy (ARVs) in low- and middle-income countries (LIMC). METHODS: Performing a systematic review, we searched, independently and in duplicate, 7 electronic databases and 2 conference websites for quantitative surveys that examined the association between indicators of livelihood security and adherence to ARVs in LIMC between 2000-2010. Criteria for relevance were applied to complete papers (quantitative study with estimates of associations) and quality assessment was conducted on those deemed relevant. We performed three regressions to measure the association between each type of livelihood and adherence. RESULTS: Twenty original studies and 6 conference abstracts were included, the majority from Africa (n = 16). Seventeen studies and 3 conference abstracts were cross-sectional and 3 studies and 3 abstracts were prospective clinical cohort studies, with considerable variation in quality for studies of each design type. Among the diverse populations represented, we observed considerable variation in associations between measurements of livelihood indicators and increasingly accepted adherence measures, irrespective of study design or quality. A financial capital indicator, financial constraints/payment for ARV medication, was more commonly associated with non adherence (3/5 studies). A human capital indicator, educational level, was most commonly associated with adherence (11/20 studies). DISCUSSION: Additional better quality research examining livelihood security is required to inform provision of optimal supports for adherence and mitigation of the impacts of HIV/AIDS. PMID- 21589912 TI - Validation of World Health Organisation HIV/AIDS clinical staging in predicting initiation of antiretroviral therapy and clinical predictors of low CD4 cell count in Uganda. AB - INTRODUCTION: The WHO clinical guidelines for HIV/AIDS are widely used in resource limited settings to represent the gold standard of CD4 counts for antiviral therapy initiation. The utility of the WHO-defined stage 1 and 2 clinical factors used in WHO HIV/AIDS clinical staging in predicting low CD4 cell count has not been established in Uganda. Although the WHO staging has shown low sensitivity for predicting CD4<200 cells/mm(3), it has not been evaluated at for CD4 cut-offs of <250 cells/mm(3) or <350 cells/mm(3). OBJECTIVE: To validate the World Health Organisation HIV/AIDS clinical staging in predicting initiation of antiretroviral therapy in a low-resource setting and to determine the clinical predictors of low CD4 cell count in Uganda. RESULTS: Data was collected on 395 participants from the Joint Clinical Research Centre, of whom 242 (61.3%) were classified as in stages 1 and 2 and 262 (68%) were females. Participants had a mean age of 36.8 years (SD 8.5). We found a significant inverse correlation between the CD4 lymphocyte count and WHO clinical stages. The sensitivity the WHO clinical staging at CD4 cell count of 250 cells/mm(3) and 350 cells/mm(3) was 53.5% and 49.1% respectively. Angular cheilitis, papular pruritic eruptions and recurrent upper respiratory tract infections were found to be significant predictors of low CD4 cell count among participants in WHO stage 1 and 2. CONCLUSION: The WHO HIV/AIDS clinical staging guidelines have a low sensitivity and about half of the participants in stages 1 and 2 would be eligible for ART initiation if they had been tested for CD4 count. Angular cheilitis and papular pruritic eruptions and recurrent upper respiratory tract infections may be used, in addition to the WHO staging, to improve sensitivity in the interim, as access to CD4 machines increases in Uganda. PMID- 21589913 TI - Behavior of QQ-plots and genomic control in studies of gene-environment interaction. AB - Genome-wide association studies of gene-environment interaction (GxE GWAS) are becoming popular. As with main effects GWAS, quantile-quantile plots (QQ-plots) and Genomic Control are being used to assess and correct for population substructure. However, in G x E work these approaches can be seriously misleading, as we illustrate; QQ-plots may give strong indications of substructure when absolutely none is present. Using simulation and theory, we show how and why spurious QQ-plot inflation occurs in G x E GWAS, and how this differs from main-effects analyses. We also explain how simple adjustments to standard regression-based methods used in G x E GWAS can alleviate this problem. PMID- 21589914 TI - Altered mRNA editing and expression of ionotropic glutamate receptors after kainic acid exposure in cyclooxygenase-2 deficient mice. AB - Kainic acid (KA) binds to the AMPA/KA receptors and induces seizures that result in inflammation, oxidative damage and neuronal death. We previously showed that cyclooxygenase-2 deficient (COX-2(-/-)) mice are more vulnerable to KA-induced excitotoxicity. Here, we investigated whether the increased susceptibility of COX 2(-/-) mice to KA is associated with altered mRNA expression and editing of glutamate receptors. The expression of AMPA GluR2, GluR3 and KA GluR6 was increased in vehicle-injected COX-2(-/-) mice compared to wild type (WT) mice in hippocampus and cortex, whereas gene expression of NMDA receptors was decreased. KA treatment decreased the expression of AMPA, KA and NMDA receptors in the hippocampus, with a significant effect in COX-2(-/-) mice. Furthermore, we analyzed RNA editing levels and found that the level of GluR3 R/G editing site was selectively increased in the hippocampus and decreased in the cortex in COX 2(-/-) compared with WT mice. After KA, GluR4 R/G editing site, flip form, was increased in the hippocampus of COX-2(-/-) mice. Treatment of WT mice with the COX-2 inhibitor celecoxib for two weeks decreased the expression of AMPA/KA and NMDAR subunits after KA, as observed in COX-2(-/-) mice. After KA exposure, COX 2(-/-) mice showed increased mRNA expression of markers of inflammation and oxidative stress, such as cytokines (TNF-alpha, IL-1beta and IL-6), inducible nitric oxide synthase (iNOS), microglia (CD11b) and astrocyte (GFAP). Thus, COX-2 gene deletion can exacerbate the inflammatory response to KA. We suggest that COX 2 plays a role in attenuating glutamate excitotoxicity by modulating RNA editing of AMPA/KA and mRNA expression of all ionotropic glutamate receptor subunits and, in turn, neuronal excitability. These changes may contribute to the increased vulnerability of COX-2(-/-) mice to KA. The overstimulation of glutamate receptors as a consequence of COX-2 gene deletion suggests a functional coupling between COX-2 and the glutamatergic system. PMID- 21589915 TI - Alphacoronaviruses in New World bats: prevalence, persistence, phylogeny, and potential for interaction with humans. AB - Bats are reservoirs for many different coronaviruses (CoVs) as well as many other important zoonotic viruses. We sampled feces and/or anal swabs of 1,044 insectivorous bats of 2 families and 17 species from 21 different locations within Colorado from 2007 to 2009. We detected alphacoronavirus RNA in bats of 4 species: big brown bats (Eptesicus fuscus), 10% prevalence; long-legged bats (Myotis volans), 8% prevalence; little brown bats (Myotis lucifugus), 3% prevalence; and western long-eared bats (Myotis evotis), 2% prevalence. Overall, juvenile bats were twice as likely to be positive for CoV RNA as adult bats. At two of the rural sampling sites, CoV RNAs were detected in big brown and long legged bats during the three sequential summers of this study. CoV RNA was detected in big brown bats in all five of the urban maternity roosts sampled throughout each of the periods tested. Individually tagged big brown bats that were positive for CoV RNA and later sampled again all became CoV RNA negative. Nucleotide sequences in the RdRp gene fell into 3 main clusters, all distinct from those of Old World bats. Similar nucleotide sequences were found in amplicons from gene 1b and the spike gene in both a big-brown and a long-legged bat, indicating that a CoV may be capable of infecting bats of different genera. These data suggest that ongoing evolution of CoVs in bats creates the possibility of a continued threat for emergence into hosts of other species. Alphacoronavirus RNA was detected at a high prevalence in big brown bats in roosts in close proximity to human habitations (10%) and known to have direct contact with people (19%), suggesting that significant potential opportunities exist for cross species transmission of these viruses. Further CoV surveillance studies in bats throughout the Americas are warranted. PMID- 21589916 TI - The relationship between anogenital distance, fatherhood, and fertility in adult men. AB - BACKGROUND: Anogenital distance (AGD), a sexually dimorphic measure of genital development, is a marker for endocrine disruption in animal studies and may be shorter in infant males with genital anomalies. Given the correlation between anogenital distance and genital development, we sought to determine if anogenital distance varied in fertile compared to infertile adult men. METHODS: A cross sectional study of consecutive men being evaluated for infertility and men with proven fertility was recruited from an andrology clinic. Anogenital distance (the distance from the posterior aspect of the scrotum to the anal verge) and penile length (PL) were measured using digital calipers. ANOVA and linear regression were used to determine correlations between AGD, fatherhood status, and semen analysis parameters (sperm density, motility, and total motile sperm count). FINDINGS: A total of 117 infertile men (mean age: 35.3+/-17.4) and 56 fertile men (mean age: 44.8+/-9.7) were recruited. The infertile men possessed significantly shorter mean AGD and PL compared to the fertile controls (AGD: 31.8 vs 44.6 mm, PL: 107.1 vs 119.5 mm, p<0.01). The difference in AGD persisted even after accounting for ethnic and anthropomorphic differences. In addition to fatherhood, on both unadjusted and adjusted linear regression, AGD was significantly correlated with sperm density and total motile sperm count. After adjusting for demographic and reproductive variables, for each 1 cm increase in a man's AGD, the sperm density increases by 4.3 million sperm per mL (95% CI 0.53, 8.09, p = 0.03) and the total motile sperm count increases by 6.0 million sperm (95% CI 1.34, 10.58, p = 0.01). On adjusted analyses, no correlation was seen between penile length and semen parameters. CONCLUSION: A longer anogenital distance is associated with fatherhood and may predict normal male reproductive potential. Thus, AGD may provide a novel metric to assess reproductive potential in men. PMID- 21589917 TI - Phylogeography and genetic structuring of European nine-spined sticklebacks (Pungitius pungitius)-mitochondrial DNA evidence. AB - As a consequence of colonisation from different glacial refugia, many northern European taxa are split into distinct western and eastern lineages. However, as for the nine-spined stickleback (Pungitius pungitius), the exact location of the contact zone between lineages often remains poorly known. We assessed the genetic differentiation and diversity in the nine-spined stickleback within Europe using 1037 base pairs of cytochrome b sequence for 320 individuals from 57 locations, including pond, lake, river, and coastal habitats. Our main aims were (i) to locate the contact zone between the previously recognized western and eastern lineages, (ii) investigate latitudinal patterns in genetic diversity, (iii) compare genetic diversity among different habitat types, and (iv) date the known split between eastern and western lineages. The data revealed the split between eastern and western to be located across the Danish Straits and roughly following the Norway/Sweden border to the North. Reference sites from Canada form their own clades, and one of the Canadian sites was found to have a haplotype common to the Eastern European lineage, possibly representing an ancestral polymorphism. The split between the two European clades was dated to approximately 1.48 million years ago (Mya), and between Canada and Europe to approximately 1.62 Mya. After controlling for habitat effects, nucleotide (but not haplotype) diversity across populations decreased with increasing latitude. Coastal populations showed significantly higher haplotype diversity (but not nucleotide diversity) than pond populations, but there were no detectable differences in haplotype diversity among different freshwater habitat types (viz. river, lake and pond populations), or between coastal and lake/river populations. Sequences were found to cluster according to their geographic proximity, rather than by habitat type, and all habitat types were found within each major clade, implying that colonisation and adaptation between the coastal and freshwater environments in different regions must have occurred in parallel. PMID- 21589918 TI - The influence of reproductive experience on milk energy output and lactation performance in the grey seal (Halichoerus grypus). AB - Although evidence from domestic and laboratory species suggests that reproductive experience plays a critical role in the development of aspects of lactation performance, whether reproductive experience may have a significant influence on milk energy transfer to neonates in wild populations has not been directly investigated. We compared maternal energy expenditures and pup growth and energy deposition over the course of lactation between primiparous and fully-grown, multiparous grey seal (Halichoerus grypus) females to test whether reproductive experience has a significant influence on lactation performance. Although there was no difference between primiparous females in milk composition and, thus, milk energy content at either early or peak lactation primiparous females had a significantly lower daily milk energy output than multiparous females indicating a reduced physiological capacity for milk secretion. Primiparous females appeared to effectively compensate for lower rates of milk production through an increased nursing effort and, thus, achieved the same relative rate of milk energy transfer to pups as multiparous females. There was no difference between primiparous and multiparous females in the proportion of initial body energy stores mobilised to support the costs of lactation. Although primiparous females allocated a greater proportion of energy stores to maternal maintenance versus milk production than multiparous females, the difference was not sufficient to result in significant differences in the efficiency of energy transfer to pups. Thus, despite a lower physiological capacity for milk production, primiparous females weaned pups of the same relative size and condition as multiparous females without expending proportionally more energy. Although reproductive experience does not significantly affect the overall lactation performance of grey seals, our results suggest that increases in mammary gland capacity with reproductive experience may play a significant role in the age-related increases in neonatal growth rates and weaning masses observed in other free-ranging mammals. PMID- 21589920 TI - Effectiveness of action in India to reduce exposure of Gyps vultures to the toxic veterinary drug diclofenac. AB - Contamination of their carrion food supply with the non-steroidal anti inflammatory drug diclofenac has caused rapid population declines across the Indian subcontinent of three species of Gyps vultures endemic to South Asia. The governments of India, Pakistan and Nepal took action in 2006 to prevent the veterinary use of diclofenac on domesticated livestock, the route by which contamination occurs. We analyse data from three surveys of the prevalence and concentration of diclofenac residues in carcasses of domesticated ungulates in India, carried out before and after the implementation of a ban on veterinary use. There was little change in the prevalence and concentration of diclofenac between a survey before the ban and one conducted soon after its implementation, with the percentage of carcasses containing diclofenac in these surveys estimated at 10.8 and 10.7%, respectively. However, both the prevalence and concentration of diclofenac had fallen markedly 7-31 months after the implementation of the ban, with the true prevalence in this third survey estimated at 6.5%. Modelling of the impact of this reduction in diclofenac on the expected rate of decline of the oriental white-backed vulture (Gyps bengalensis) in India indicates that the decline rate has decreased to 40% of the rate before the ban, but is still likely to be rapid (about 18% year(-1)). Hence, further efforts to remove diclofenac from vulture food are still needed if the future recovery or successful reintroduction of vultures is to be feasible. PMID- 21589921 TI - The insulin-mediated modulation of visually evoked magnetic fields is reduced in obese subjects. AB - BACKGROUND: Insulin is an anorexigenic hormone that contributes to the termination of food intake in the postprandial state. An alteration in insulin action in the brain, named "cerebral insulin resistance", is responsible for overeating and the development of obesity. METHODOLOGY/PRINCIPAL FINDINGS: To analyze the direct effect of insulin on food-related neuronal activity we tested 10 lean and 10 obese subjects. We conducted a magnetencephalography study during a visual working memory task in both the basal state and after applying insulin or placebo spray intranasally to bypass the blood brain barrier. Food and non food pictures were presented and subjects had to determine whether or not two consecutive pictures belonged to the same category. Intranasal insulin displayed no effect on blood glucose, insulin or C-peptide concentrations in the periphery; however, it led to an increase in the components of evoked fields related to identification and categorization of pictures (at around 170 ms post stimuli in the visual ventral stream) in lean subjects when food pictures were presented. In contrast, insulin did not modulate food-related brain activity in obese subjects. CONCLUSIONS/SIGNIFICANCE: We demonstrated that intranasal insulin increases the cerebral processing of food pictures in lean whereas this was absent in obese subjects. This study further substantiates the presence of a "cerebral insulin resistance" in obese subjects and might be relevant in the pathogenesis of obesity. PMID- 21589922 TI - Allocating logging rights in Peruvian Amazonia--does it matter to be local? AB - BACKGROUND: The fate of tropical forests is a global concern, yet many far reaching decisions affecting forest resources are made locally. We explore allocation of logging rights using a case study from Loreto, Peruvian Amazonia, where millions of hectares of tropical rainforest were offered for concession in a competitive tendering process that addressed issues related to locality. METHODOLOGY/PRINCIPAL FINDINGS: After briefly presenting the study area and the tendering process, we identify and define local and non-local actors taking part in the concession process. We then analyse their tenders, results of the tendering, and attributes of the concession areas. Our results show that there was more offer than demand for concession land in the tendering. The number of tenders the concession areas received was related to their size and geographic location in relation to the major cities, but not to their estimated timber volumes or median distances from transport routes. Small and Loreto-based actors offered lower yearly area-based fees compared to larger ones, but the offers did not significantly affect the results of the tenders. Local experience in the form of logging history or residence near the solicited concession areas, as well as being registered in the region of Loreto, improved the success of the tenders. CONCLUSIONS/SIGNIFICANCE: The allocation process left a considerable number of forest areas under the management of small and local actors, and if Peru is to reach its goal of zero deforestation rate by safeguarding 75 per cent of its forests by 2020, the small and the local actors need to be integrated to the forest regime as important constituents of its legitimacy. PMID- 21589923 TI - Lizards cooperatively tunnel to construct a long-term home for family members. AB - Constructing a home to protect offspring while they mature is common in many vertebrate groups, but has not previously been reported in lizards. Here we provide the first example of a lizard that constructs a long-term home for family members, and a rare case of lizards behaving cooperatively. The great desert skink, Liopholis kintorei from Central Australia, constructs an elaborate multi tunnelled burrow that can be continuously occupied for up to 7 years. Multiple generations participate in construction and maintenance of burrows. Parental assignments based on DNA analysis show that immature individuals within the same burrow were mostly full siblings, even when several age cohorts were present. Parents were always captured at burrows containing their offspring, and females were only detected breeding with the same male both within- and across seasons. Consequently, the individual investments made to construct or maintain a burrow system benefit their own offspring, or siblings, over several breeding seasons. PMID- 21589924 TI - Small worlds and semantic network growth in typical and late talkers. AB - Network analysis has demonstrated that systems ranging from social networks to electric power grids often involve a small world structure-with local clustering but global ac cess. Critically, small world structure has also been shown to characterize adult human semantic networks. Moreover, the connectivity pattern of these mature networks is consistent with lexical growth processes in which children add new words to their vocabulary based on the structure of the language learning environment. However, thus far, there is no direct evidence that a child's individual semantic network structure is associated with their early language learning. Here we show that, while typically developing children's early networks show small world structure as early as 15 months and with as few as 55 words, children with language delay (late talkers) have this structure to a smaller degree. This implicates a maladaptive bias in word acquisition for late talkers, potentially indicating a preference for "oddball" words. The findings provide the first evidence of a link between small-world connectivity and lexical development in individual children. PMID- 21589919 TI - Evidence that the human pathogenic fungus Cryptococcus neoformans var. grubii may have evolved in Africa. AB - Most of the species of fungi that cause disease in mammals, including Cryptococcus neoformans var. grubii (serotype A), are exogenous and non contagious. Cryptococcus neoformans var. grubii is associated worldwide with avian and arboreal habitats. This airborne, opportunistic pathogen is profoundly neurotropic and the leading cause of fungal meningitis. Patients with HIV/AIDS have been ravaged by cryptococcosis--an estimated one million new cases occur each year, and mortality approaches 50%. Using phylogenetic and population genetic analyses, we present evidence that C. neoformans var. grubii may have evolved from a diverse population in southern Africa. Our ecological studies support the hypothesis that a few of these strains acquired a new environmental reservoir, the excreta of feral pigeons (Columba livia), and were globally dispersed by the migration of birds and humans. This investigation also discovered a novel arboreal reservoir for highly diverse strains of C. neoformans var. grubii that are restricted to southern Africa, the mopane tree (Colophospermum mopane). This finding may have significant public health implications because these primal strains have optimal potential for evolution and because mopane trees contribute to the local economy as a source of timber, folkloric remedies and the edible mopane worm. PMID- 21589925 TI - MCP-1 upregulates amylin expression in murine pancreatic beta cells through ERK/JNK-AP1 and NF-kappaB related signaling pathways independent of CCR2. AB - BACKGROUND: Amylin is the most abundant component of islet amyloid implicated in the development of type 2 diabetes. Plasma amylin levels are elevated in individuals with obesity and insulin resistance. Monocyte chemoattractant protein 1 (MCP-1, CCL2) is involved in insulin resistance of obesity and type 2 diabetes. We investigated the effect of MCP-1 on amylin expression and the underlying mechanisms with murine pancreatic beta-cell line MIN6 and pancreatic islets. METHODOLOGY/PRINCIPAL FINDINGS: We found that MCP-1 induced amylin expression at transcriptional level and increased proamylin and intermediate forms of amylin at protein level in MIN6 cells and islets. However, MCP-1 had no effect on the expressions of proinsulin 1 and 2, as well as prohormone convertase (PC) 1/3 and PC2, suggesting that MCP-1 specifically induces amylin expression in beta-cells. Mechanistic studies showed that although there is no detectable CCR2 mRNA in MIN6 cells and islets, pretreatment of MIN6 cells with pertussis toxin inhibited MCP-1 induced amylin expression, suggesting that alternative Gi-coupled receptor(s) mediates the inductive effect of MCP-1. MCP-1 rapidly induced ERK1/2 and JNK phosphorylation. Inhibitors for MEK1/2 (PD98059), JNK (SP600125) or AP1 (curcumin) significantly inhibited MCP-1-induced amylin mRNA expression. MCP-1 failed to induce amylin expression in pancreatic islets isolated from Fos knockout mice. EMSA showed that JNK and ERK1/2 were involved in MCP-1-induced AP1 activation. These results suggest that MCP-1 induces murine amylin expression through AP1 activation mediated by ERK1/2 or JNK. Further studies showed that treatment of MIN6 cells with NF-kappaB inhibitor or overexpression of IkappaBalpha dominant-negative construct in MIN6 cells significantly inhibited MCP-1-induced amylin expression, suggesting that NF-kappaB related signaling also participates in MCP-1-induced murine amylin expression. CONCLUSIONS/SIGNIFICANCE: MCP-1 induces amylin expression through ERK1/2/JNK-AP1 and NF-kappaB related signaling pathways independent of CCR2. Amylin upregulation by MCP-1 may contribute to elevation of plasma amylin in obesity and insulin resistance. PMID- 21589927 TI - Genomic markers reveal introgressive hybridization in the Indo-West Pacific mangroves: a case study. AB - Biodiversity of mangrove ecosystems is difficult to assess, at least partly due to lack of genetic verification of morphology-based documentation of species. Natural hybridization, on the one hand, plays an important role in evolution as a source of novel gene combinations and a mechanism of speciation. However, on the other hand, recurrent introgression allows gene flow between species and could reverse the process of genetic differentiation among populations required for speciation. To understand the dynamic evolutionary consequences of hybridization, this study examines genomic structure of hybrids and parental species at the population level. In the Indo-West Pacific, Bruguiera is one of the dominant mangrove genera and species ranges overlap extensively with one another. Morphological intermediates between sympatric Bruguiera gymnorrhiza and Bruguiera sexangula have been reported as a variety of B. sexangula or a new hybrid species, B. * rhynchopetala. However, the direction of hybridization and extent of introgression are unclear. A large number of species-specific inter-simple sequence repeat (ISSR) markers were found in B. gymnorrhiza and B. sexangula, and the additive ISSR profiling of B. * rhynchopetala ascertained its hybrid status and identified its parental origin. The varying degree of scatterness among hybrid individuals in Principal Coordinate Analysis and results from NewHybrids analysis indicate that B. * rhynchopetala comprises different generations of introgressants in addition to F(1)s. High genetic relatedness between B. * rhynchopetala and B. gymnorrhiza based on nuclear and chloroplast sequences suggests preferential hybrid backcrosses to B. gymnorrhiza. We conclude that B. * rhynchopetala has not evolved into an incipient hybrid species, and its persistence can be explained by recurrent hybridization and introgression. Genomic data provide insights into the hybridization dynamics of mangrove plants. Such information can assist in biodiversity assessment by helping detect novel taxa and/or define species boundaries. PMID- 21589926 TI - Knowledge-driven multi-locus analysis reveals gene-gene interactions influencing HDL cholesterol level in two independent EMR-linked biobanks. AB - Genome-wide association studies (GWAS) are routinely being used to examine the genetic contribution to complex human traits, such as high-density lipoprotein cholesterol (HDL-C). Although HDL-C levels are highly heritable (h(2)~0.7), the genetic determinants identified through GWAS contribute to a small fraction of the variance in this trait. Reasons for this discrepancy may include rare variants, structural variants, gene-environment (GxE) interactions, and gene-gene (GxG) interactions. Clinical practice-based biobanks now allow investigators to address these challenges by conducting GWAS in the context of comprehensive electronic medical records (EMRs). Here we apply an EMR-based phenotyping approach, within the context of routine care, to replicate several known associations between HDL-C and previously characterized genetic variants: CETP (rs3764261, p = 1.22e-25), LIPC (rs11855284, p = 3.92e-14), LPL (rs12678919, p = 1.99e-7), and the APOA1/C3/A4/A5 locus (rs964184, p = 1.06e-5), all adjusted for age, gender, body mass index (BMI), and smoking status. By using a novel approach which censors data based on relevant co-morbidities and lipid modifying medications to construct a more rigorous HDL-C phenotype, we identified an association between HDL-C and TRIB1, a gene which previously resisted identification in studies with larger sample sizes. Through the application of additional analytical strategies incorporating biological knowledge, we further identified 11 significant GxG interaction models in our discovery cohort, 8 of which show evidence of replication in a second biobank cohort. The strongest predictive model included a pairwise interaction between LPL (which modulates the incorporation of triglyceride into HDL) and ABCA1 (which modulates the incorporation of free cholesterol into HDL). These results demonstrate that gene gene interactions modulate complex human traits, including HDL cholesterol. PMID- 21589928 TI - An ecological study of the determinants of differences in 2009 pandemic influenza mortality rates between countries in Europe. AB - BACKGROUND: Pandemic A (H1N1) 2009 mortality rates varied widely from one country to another. Our aim was to identify potential socioeconomic determinants of pandemic mortality and explain between-country variation. METHODOLOGY: Based on data from a total of 30 European countries, we applied random-effects Poisson regression models to study the relationship between pandemic mortality rates (May 2009 to May 2010) and a set of representative environmental, health care associated, economic and demographic country-level parameters. The study was completed by June 2010. PRINCIPAL FINDINGS: Most regression approaches indicated a consistent, statistically significant inverse association between pandemic influenza-related mortality and per capita government expenditure on health. The findings were similar in univariable [coefficient: -0.00028, 95% Confidence Interval (CI): -0.00046, -0.00010, p = 0.002] and multivariable analyses (including all covariates, coefficient: -0.00107, 95% CI: -0.00196, -0.00018, p = 0.018). The estimate was barely insignificant when the multivariable model included only significant covariates from the univariate step (coefficient: 0.00046, 95% CI: -0.00095, 0.00003, p = 0.063). CONCLUSIONS: Our findings imply a significant inverse association between public spending on health and pandemic influenza mortality. In an attempt to interpret the estimated coefficient ( 0.00028) for the per capita government expenditure on health, we observed that a rise of 100 international dollars was associated with a reduction in the pandemic influenza mortality rate by approximately 2.8%. However, further work needs to be done to unravel the mechanisms by which reduced government spending on health may have affected the 2009 pandemic influenza mortality. PMID- 21589929 TI - Urate oxidase purification by salting-in crystallization: towards an alternative to chromatography. AB - BACKGROUND: Rasburicase (Fasturtec(r) or Elitek(r), Sanofi-Aventis), the recombinant form of urate oxidase from Aspergillus flavus, is a therapeutic enzyme used to prevent or decrease the high levels of uric acid in blood that can occur as a result of chemotherapy. It is produced by Sanofi-Aventis and currently purified via several standard steps of chromatography. This work explores the feasibility of replacing one or more chromatography steps in the downstream process by a crystallization step. It compares the efficacy of two crystallization techniques that have proven successful on pure urate oxidase, testing them on impure urate oxidase solutions. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigate the possibility of purifying urate oxidase directly by crystallization from the fermentation broth. Based on attractive interaction potentials which are known to drive urate oxidase crystallization, two crystallization routes are compared: a) by increased polymer concentration, which induces a depletion attraction and b) by decreased salt concentration, which induces attractive interactions via a salting-in effect. We observe that adding polymer, a very efficient way to crystallize pure urate oxidase through the depletion effect, is not an efficient way to grow crystals from impure solution. On the other hand, we show that dialysis, which decreases salt concentration through its strong salting-in effect, makes purification of urate oxidase from the fermentation broth possible. CONCLUSIONS: The aim of this study is to compare purification efficacy of two crystallization methods. Our findings show that crystallization of urate oxidase from the fermentation broth provides purity comparable to what can be achieved with one chromatography step. This suggests that, in the case of urate oxidase, crystallization could be implemented not only for polishing or concentration during the last steps of purification, but also as an initial capture step, with minimal changes to the current process. PMID- 21589930 TI - Nrt1 and Tna1-independent export of NAD+ precursor vitamins promotes NAD+ homeostasis and allows engineering of vitamin production. AB - NAD(+) is both a co-enzyme for hydride transfer enzymes and a substrate of sirtuins and other NAD(+) consuming enzymes. NAD(+) biosynthesis is required for two different regimens that extend lifespan in yeast. NAD(+) is synthesized from tryptophan and the three vitamin precursors of NAD(+): nicotinic acid, nicotinamide and nicotinamide riboside. Supplementation of yeast cells with NAD(+) precursors increases intracellular NAD(+) levels and extends replicative lifespan. Here we show that both nicotinamide riboside and nicotinic acid are not only vitamins but are also exported metabolites. We found that the deletion of the nicotinamide riboside transporter, Nrt1, leads to increased export of nicotinamide riboside. This discovery was exploited to engineer a strain to produce high levels of extracellular nicotinamide riboside, which was recovered in purified form. We further demonstrate that extracellular nicotinamide is readily converted to extracellular nicotinic acid in a manner that requires intracellular nicotinamidase activity. Like nicotinamide riboside, export of nicotinic acid is elevated by the deletion of the nicotinic acid transporter, Tna1. The data indicate that NAD(+) metabolism has a critical extracellular element in the yeast system and suggest that cells regulate intracellular NAD(+) metabolism by balancing import and export of NAD(+) precursor vitamins. PMID- 21589931 TI - Are nested networks more robust to disturbance? A test using epiphyte-tree, comensalistic networks. AB - Recent research on ecological networks suggests that mutualistic networks are more nested than antagonistic ones and, as a result, they are more robust against chains of extinctions caused by disturbances. We evaluate whether mutualistic networks are more nested than comensalistic and antagonistic networks, and whether highly nested, host-epiphyte comensalistic networks fit the prediction of high robustness against disturbance. A review of 59 networks including mutualistic, antagonistic and comensalistic relationships showed that comensalistic networks are significantly more nested than antagonistic and mutualistic networks, which did not differ between themselves. Epiphyte-host networks from old-growth forests differed from those from disturbed forest in several topological parameters based on both qualitative and quantitative matrices. Network robustness increased with network size, but the slope of this relationship varied with nestedness and connectance. Our results indicate that interaction networks show complex responses to disturbances, which influence their topology and indirectly affect their robustness against species extinctions. PMID- 21589932 TI - Reproducibility and relative validity of a food frequency questionnaire developed for female adolescents in Suihua, North China. AB - BACKGROUND: This study aims to evaluate the reproducibility and validity of a food frequency questionnaire (FFQ) developed for female adolescents in the Suihua area of North China. The FFQ was evaluated against the average of 24-hour dietary recalls (24-HRs). METHODOLOGY/PRINCIPAL FINDINGS: A total of 168 female adolescents aged 12 to 18 completed nine three consecutive 24-HRs (one three consecutive 24 HRs per month) and two FFQs over nine months. The reproducibility of the FFQ was estimated using intraclass correlation coefficients (ICCs), and its relative validity was assessed by comparing it with the 24-HRs. The mean values of the 24-HRs were lower than those of the FFQs, except for protein (in FFQ1) and iron (in FFQ2). The ICCs for all nutrients and food groups in FFQ1 and FFQ2 were moderately correlated (0.4-0.8). However, all the ICCs decreased after adjusting for energy. The weighted kappa statistic showed moderate agreement (0.40-0.6) for all nutrients and food groups, except for niacin and calcium, which showed poor agreement (0.35). The relative validity results indicate that the crude Spearman's correlation coefficients of FFQ1 and the 24-HRs ranged from 0.41 (for Vitamin C) to 0.65 (for fruit). The coefficients of each nutrient and food group in FFQ2 and the 24-HRs were higher than those in FFQ1 and the 24-HRs, indicating good correlation. Although all energy-adjusted Spearman's correlation coefficients were lower than the crude coefficients, de-attenuation to correct for intra-individual variability improved the correlation coefficients. The weighted kappa coefficients of nutrients and food groups ranged from 0.32 for beans to 0.52 for riboflavin in FFQ1 and the 24-HRs, and 0.32 for Vitamin C to 0.54 for riboflavin in FFQ2 and the 24-HRs. CONCLUSION: The FFQ developed for female adolescents in the Suihua area is a reliable and valid instrument for ranking individuals within this study. PMID- 21589933 TI - Association between HSV1 seropositivity and obesity: data from the National Health and Nutritional Examination Survey, 2007-2008. AB - BACKGROUND: Herpes simplex virus (HSV) is among the most common sexually transmitted pathogens in the United States and worldwide. HSV has a high incidence of undetected cases. In addition, there is no treatment, and there is a lack of knowledge why disparities among populations exist. Research studies suggest that fat tissue may participate in body's immune responses, and the impact of obesity on susceptibility to HSV1 infection is not clear. The purpose of this study was to examine whether obesity is a risk factor for HSV1 infection using a large sample from the general population. METHODS/PRINCIPAL FINDINGS: This cross-sectional study used data from the National Health and Examination and Nutritional Examination Survey (NHANES) from 2007-2008. Variables, gender, age, race/ethnicity, marital status, education, poverty level, and diabetes represented potential confounders and were included in analyses. The two-tailed Pearson's chi square, student's t test, and a multiple logistic regression analysis were applied to evaluate associations using a significance value of p<=0.05. Adjusted odds ratios with 95% confidence interval represented the degree of these associations. The prevalence of HSV1 infection in US population between 20 and 49 years old was 60.3% (n = 1,536). In this study, having a BMI classified as the obese group (BMI 30-39.9) was significantly associated with HSV1 infection before [unadjusted OR = 1.74 (95% CI 1.20-2.51), p = 0.006] and after controlling for socio-demographic factors [adjusted OR = 1.50 (95%CI 1.06-2.13)], p = 0.026]. This association was stronger than three already established risk factors of age, female gender, and poverty level. CONCLUSIONS/SIGNIFICANCE: This study provides evidence that obesity may play a role in the susceptibility to HSV1 infection. Findings from this study suggest that obesity should be considered when designing preventive measures for HSV1 infection. These results may also explain why some people acquire HSV1 infections and some do not. Further, these findings may justify an increased emphasis on the control and prevention of HSV1 transmission and other pathogens in overweight and obese populations. PMID- 21589934 TI - Water contamination reduces the tolerance of coral larvae to thermal stress. AB - Coral reefs are highly susceptible to climate change, with elevated sea surface temperatures (SST) posing one of the main threats to coral survival. Successful recruitment of new colonies is important for the recovery of degraded reefs following mortality events. Coral larvae require relatively uncontaminated substratum on which to metamorphose into sessile polyps, and the increasing pollution of coastal waters therefore constitutes an additional threat to reef resilience. Here we develop and analyse a model of larval metamorphosis success for two common coral species to quantify the interactive effects of water pollution (copper contamination) and SST. We identify thresholds of temperature and pollution that prevent larval metamorphosis, and evaluate synergistic interactions between these stressors. Our analyses show that halving the concentration of Cu can protect corals from the negative effects of a 2-3 degrees C increase in SST. These results demonstrate that effective mitigation of local impacts can reduce negative effects of global stressors. PMID- 21589935 TI - Degradation of the disease-associated prion protein by a serine protease from lichens. AB - The disease-associated prion protein (PrP(TSE)), the probable etiological agent of the transmissible spongiform encephalopathies (TSEs), is resistant to degradation and can persist in the environment. Lichens, mutualistic symbioses containing fungi, algae, bacteria and occasionally cyanobacteria, are ubiquitous in the environment and have evolved unique biological activities allowing their survival in challenging ecological niches. We investigated PrP(TSE) inactivation by lichens and found acetone extracts of three lichen species (Parmelia sulcata, Cladonia rangiferina and Lobaria pulmonaria) have the ability to degrade prion protein (PrP) from TSE-infected hamsters, mice and deer. Immunoblots measuring PrP levels and protein misfolding cyclic amplification indicated at least two logs of reductions in PrP(TSE). Degradative activity was not found in closely related lichen species or in algae or a cyanobacterium that inhabit lichens. Degradation was blocked by Pefabloc SC, a serine protease inhibitor, but not inhibitors of other proteases or enzymes. Additionally, we found that PrP levels in PrP(TSE)-enriched preps or infected brain homogenates are also reduced following exposure to freshly-collected P. sulcata or an aqueous extract of the lichen. Our findings indicate that these lichen extracts efficiently degrade PrP(TSE) and suggest that some lichens could have potential to inactivate TSE infectivity on the landscape or be a source for agents to degrade prions. Further work to clone and characterize the protease, assess its effect on TSE infectivity and determine which organism or organisms present in lichens produce or influence the protease activity is warranted. PMID- 21589936 TI - A translational regulator, PUM2, promotes both protein stability and kinase activity of Aurora-A. AB - Aurora-A, a centrosomal serine-threonine kinase, orchestrates several key aspects of cell division. However, the regulatory pathways for the protein stability and kinase activity of Aurora-A are still not completely understood. In this study, PUM2, an RNA-binding protein, is identified as a novel substrate and interacting protein of Aurora-A. Overexpression of the PUM2 mutant which fails to interact with Aurora-A, and depletion of PUM2 result in a decrease in the amount of Aurora A. PUM2 physically binds to the D-box of Aurora-A, which is recognized by APC/C(Cdh1). Overexpression of PUM2 prevents ubiquitination and enhances the protein stability of Aurora-A, suggesting that PUM2 protects Aurora-A from APC/C(Cdh1)-mediated degradation. Moreover, association of PUM2 with Aurora-A not only makes Aurora-A more stable but also enhances the kinase activity of Aurora A. Our study suggests that PUM2 plays two different but important roles during cell cycle progression. In interphase, PUM2 localizes in cytoplasm and plays as translational repressor through its RNA binding domain. However, in mitosis, PUM2 physically associates with Aurora-A to ensure enough active Aurora-A at centrosomes for mitotic entry. This is the first time to reveal the moonlight role of PUM2 in mitosis. PMID- 21589937 TI - Proliferative hypothalamic neurospheres express NPY, AGRP, POMC, CART and Orexin A and differentiate to functional neurons. AB - Some pathological conditions with feeding pattern alterations, including obesity and Huntington disease (HD) are associated with hypothalamic dysfunction and neuronal cell death. Additionally, the hypothalamus is a neurogenic region with the constitutive capacity to generate new cells of neuronal lineage, in adult rodents. The aim of the present work was to evaluate the expression of feeding related neuropeptides in hypothalamic progenitor cells and their capacity to differentiate to functional neurons which have been described to be affected by hypothalamic dysfunction. Our study shows that hypothalamic progenitor cells from rat embryos grow as floating neurospheres and express the feeding-related neuropeptides Neuropeptide Y (NPY), Agouti-related Protein (AGRP), Pro OpioMelanocortin (POMC), Cocaine-and-Amphetamine Responsive Transcript (CART) and Orexin-A/Hypocretin-1. Moreover the relative mRNA expression of NPY and POMC increases during the expansion of hypothalamic neurospheres in proliferative conditions.Mature neurons were obtained from the differentiation of hypothalamic progenitor cells including NPY, AGRP, POMC, CART and Orexin-A positive neurons. Furthermore the relative mRNA expression of NPY, CART and Orexin-A increases after the differentiation of hypothalamic neurospheres. Similarly to the adult hypothalamic neurons the neurospheres-derived neurons express the glutamate transporter EAAT3. The orexigenic and anorexigenic phenotype of these neurons was identified by functional response to ghrelin and leptin hormones, respectively. This work demonstrates the presence of appetite-related neuropeptides in hypothalamic progenitor cells and neurons obtained from the differentiation of hypothalamic neurospheres, including the neuronal phenotypes that have been described by others as being affected by hypothalamic neurodegeneration. These in vitro models can be used to study hypothalamic progenitor cells aiming a therapeutic intervention to mitigate feeding dysfunction that are associated with hypothalamic neurodegeneration. PMID- 21589938 TI - Targeted assembly of short sequence reads. AB - As next-generation sequence (NGS) production continues to increase, analysis is becoming a significant bottleneck. However, in situations where information is required only for specific sequence variants, it is not necessary to assemble or align whole genome data sets in their entirety. Rather, NGS data sets can be mined for the presence of sequence variants of interest by localized assembly, which is a faster, easier, and more accurate approach. We present TASR, a streamlined assembler that interrogates very large NGS data sets for the presence of specific variants by only considering reads within the sequence space of input target sequences provided by the user. The NGS data set is searched for reads with an exact match to all possible short words within the target sequence, and these reads are then assembled stringently to generate a consensus of the target and flanking sequence. Typically, variants of a particular locus are provided as different target sequences, and the presence of the variant in the data set being interrogated is revealed by a successful assembly outcome. However, TASR can also be used to find unknown sequences that flank a given target. We demonstrate that TASR has utility in finding or confirming genomic mutations, polymorphisms, fusions and integration events. Targeted assembly is a powerful method for interrogating large data sets for the presence of sequence variants of interest. TASR is a fast, flexible and easy to use tool for targeted assembly. PMID- 21589939 TI - Insulin resistance in non-obese subjects is associated with activation of the JNK pathway and impaired insulin signaling in skeletal muscle. AB - BACKGROUND: The pathogenesis of insulin resistance in the absence of obesity is unknown. In obesity, multiple stress kinases have been identified that impair the insulin signaling pathway via serine phosphorylation of key second messenger proteins. These stress kinases are activated through various mechanisms related to lipid oversupply locally in insulin target tissues and in various adipose depots. METHODOLOGY/PRINCIPAL FINDINGS: To explore whether specific stress kinases that have been implicated in the insulin resistance of obesity are potentially contributing to insulin resistance in non-obese individuals, twenty healthy, non-obese, normoglycemic subjects identified as insulin sensitive or resistant were studied. Vastus lateralis muscle biopsies obtained during euglycemic, hyperinsulinemic clamp were evaluated for insulin signaling and for activation of stress kinase pathways. Total and regional adipose stores and intramyocellular lipids (IMCL) were assessed by DXA, MRI and (1)H-MRS. In muscle of resistant subjects, phosphorylation of JNK was increased (1.36+/-0.23 vs. 0.78+/-0.10 OD units, P<0.05), while there was no evidence for activation of p38 MAPK or IKKbeta. IRS-1 serine phosphorylation was increased (1.30+/-0.09 vs. 0.22+/-0.03 OD units, P<0.005) while insulin-stimulated tyrosine phosphorylation decreased (10.97+/-0.95 vs. 0.89+/-0.50 OD units, P<0.005). IMCL levels were twice as high in insulin resistant subjects (3.26+/-0.48 vs. 1.58+/-0.35% H(2)O peak, P<0.05), who also displayed increased total fat and abdominal fat when compared to insulin sensitive controls. CONCLUSIONS: This is the first report demonstrating that insulin resistance in non-obese, normoglycemic subjects is associated with activation of the JNK pathway related to increased IMCL and higher total body and abdominal adipose stores. While JNK activation is consistent with a primary impact of muscle lipid accumulation on metabolic stress, further work is necessary to determine the relative contributions of the various mediators of impaired insulin signaling in this population. PMID- 21589940 TI - Somatostatin inhibits cell migration and reduces cell counts of human keratinocytes and delays epidermal wound healing in an ex vivo wound model. AB - The peptide hormone somatostatin (SST) and its five G protein-coupled receptors (SSTR1-5) were described to be present in the skin, but their cutaneous function(s) and skin-specific signalling mechanisms are widely unknown. By using receptor specific agonists we show here that the SSTRs expressed in keratinocytes are functionally coupled to the inhibition of adenylate cyclase. In addition, treatment with SSTR4 and SSTR5/1 specific agonists significantly influences the MAP kinase signalling pathway. As epidermal hormone receptors in general are known to regulate re-epithelialization following skin injury, we investigated the effect of SST on cell counts and migration of human keratinocytes. Our results demonstrate a significant inhibition of cell migration and reduction of cell counts by SST. We do not observe an effect on apoptosis and necrosis. Analysis of signalling pathways showed that somatostatin inhibits cell migration independent of its effect on cAMP. Migrating keratinocytes treated with SST show altered cytoskeleton dynamics with delayed lamellipodia formation. Furthermore, the activity of the small GTPase Rac1 is diminished, providing evidence for the control of the actin cytoskeleton by somatostatin receptors in keratinocytes. While activation of all receptors leads to redundant effects on cell migration, only treatment with a SSTR5/1 specific agonist resulted in decreased cell counts. In accordance with reduced cell counts and impaired migration we observe delayed re-epithelialization in an ex vivo wound healing model. Consequently, our experiments suggest SST as a negative regulator of epidermal wound healing. PMID- 21589941 TI - Prey capture behavior in an arboreal African ponerine ant. AB - I studied the predatory behavior of Platythyrea conradti, an arboreal ponerine ant, whereas most species in this subfamily are ground-dwelling. The workers, which hunt solitarily only around dusk, are able to capture a wide range of prey, including termites and agile, nocturnal insects as well as diurnal insects that are inactive at that moment of the Nyctemeron, resting on tree branches or under leaves. Prey are captured very rapidly, and the antennal palpation used by ground dwelling ponerine species is reduced to a simple contact; stinging occurs immediately thereafter. The venom has an instant, violent effect as even large prey (up to 30 times the weight of a worker) never struggled after being stung. Only small prey are not stung. Workers retrieve their prey, even large items, singly. To capture termite workers and soldiers defending their nest entrances, ant workers crouch and fold their antennae backward. In their role as guards, the termites face the crouching ants and end up by rolling onto their backs, their legs batting the air. This is likely due to volatile secretions produced by the ants' mandibular gland. The same behavior is used against competing ants, including territorially-dominant arboreal species that retreat further and further away, so that the P. conradti finally drive them from large, sugary food sources. PMID- 21589942 TI - Using satellite tracking to optimize protection of long-lived marine species: olive ridley sea turtle conservation in Central Africa. AB - Tractable conservation measures for long-lived species require the intersection between protection of biologically relevant life history stages and a socioeconomically feasible setting. To protect breeding adults, we require knowledge of animal movements, how movement relates to political boundaries, and our confidence in spatial analyses of movement. We used satellite tracking and a switching state-space model to determine the internesting movements of olive ridley sea turtles (Lepidochelys olivacea) (n = 18) in Central Africa during two breeding seasons (2007-08, 2008-09). These movements were analyzed in relation to current park boundaries and a proposed transboundary park between Gabon and the Republic of Congo, both created to reduce unintentional bycatch of sea turtles in marine fisheries. We additionally determined confidence intervals surrounding home range calculations. Turtles remained largely within a 30 km radius from the original nesting site before departing for distant foraging grounds. Only 44.6 percent of high-density areas were found within the current park but the proposed transboundary park would incorporate 97.6 percent of high-density areas. Though tagged individuals originated in Gabon, turtles were found in Congolese waters during greater than half of the internesting period (53.7 percent), highlighting the need for international cooperation and offering scientific support for a proposed transboundary park. This is the first comprehensive study on the internesting movements of solitary nesting olive ridley sea turtles, and it suggests the opportunity for tractable conservation measures for female nesting olive ridleys at this and other solitary nesting sites around the world. We draw from our results a framework for cost-effective protection of long-lived species using satellite telemetry as a primary tool. PMID- 21589943 TI - Exogenous expression of human apoA-I enhances cardiac differentiation of pluripotent stem cells. AB - The cardioprotective effects of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (apoA-I) are well documented, but their effects in the direction of the cardiac differentiation of embryonic stem cells are unknown. We evaluated the effects of exogenous apoA-I expression on cardiac differentiation of ESCs and maturation of ESC-derived cardiomyocytes. We stably over-expressed full-length human apoA-I cDNA with lentivirus (LV)-mediated gene transfer in undifferentiated mouse ESCs and human induced pluripotent stem cells. Upon cardiac differentiation, we observed a significantly higher percentage of beating embryoid bodies, an increased number of cardiomyocytes as determined by flow cytometry, and expression of cardiac markers including alpha-myosin heavy chain, beta-myosin heavy chain and myosin light chain 2 ventricular transcripts in LV apoA-I transduced ESCs compared with control (LV-GFP). In the presence of noggin, a BMP4 antagonist, activation of BMP4-SMAD signaling cascade in apoA-I transduced ESCs completely abolished the apoA-I stimulated cardiac differentiation. Furthermore, co-application of recombinant apoA-I and BMP4 synergistically increased the percentage of beating EBs derived from untransduced D3 ESCs. These together suggests that that pro-cardiogenic apoA-I is mediated via the BMP4-SMAD signaling pathway. Functionally, cardiomyocytes derived from the apoA-I transduced cells exhibited improved calcium handling properties in both non caffeine and caffeine-induced calcium transient, suggesting that apoA-I plays a role in enhancing cardiac maturation. This increased cardiac differentiation and maturation has also been observed in human iPSCs, providing further evidence of the beneficial effects of apoA-I in promoting cardiac differentiation. In Conclusion, we present novel experimental evidence that apoA-I enhances cardiac differentiation of ESCs and iPSCs and promotes maturation of the calcium handling property of ESC-derived cardiomyocytes via the BMP4/SMAD signaling pathway. PMID- 21589946 TI - Belimumab, a BLyS-specific inhibitor for the treatment of systemic lupus erythematosus. AB - As B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), therapies targeting them may provide a valuable treatment for patients with SLE. One of the therapeutic strategies for B-cell targeting is through the inhibition of factors involved in the survival or differentiation of B cells. B-cell-activating factor (BAFF) or B-lymphocyte stimulator (BlyS; trademark of Human Genome Sciences, Rockville, MD, USA) has proven to be a key factor in the selection and survival of B cells. Belimumab is a fully human monoclonal antibody (immunoglobulin G1) that binds to soluble BAFF and inhibits it from binding to its receptors. To date, two phase III trials have demonstrated that belimumab in combination with standard of care significantly reduced SLE disease activity and SLE flare rates in patients with active SLE. In addition, it was generally well tolerated. This article reviews the immune mechanisms induced by the inhibition of BAFF/BLyS and the evidence-based clinical effectiveness of belimumab in SLE patients. PMID- 21589945 TI - Exhaustive sampling of docking poses reveals binding hypotheses for propafenone type inhibitors of P-glycoprotein. AB - Overexpression of the xenotoxin transporter P-glycoprotein (P-gp) represents one major reason for the development of multidrug resistance (MDR), leading to the failure of antibiotic and cancer therapies. Inhibitors of P-gp have thus been advocated as promising candidates for overcoming the problem of MDR. However, due to lack of a high-resolution structure the concrete mode of interaction of both substrates and inhibitors is still not known. Therefore, structure-based design studies have to rely on protein homology models. In order to identify binding hypotheses for propafenone-type P-gp inhibitors, five different propafenone derivatives with known structure-activity relationship (SAR) pattern were docked into homology models of the apo and the nucleotide-bound conformation of the transporter. To circumvent the uncertainty of scoring functions, we exhaustively sampled the pose space and analyzed the poses by combining information retrieved from SAR studies with common scaffold clustering. The results suggest propafenone binding at the transmembrane helices 5, 6, 7 and 8 in both models, with the amino acid residue Y307 playing a crucial role. The identified binding site in the non energized state is overlapping with, but not identical to, known binding areas of cyclic P-gp inhibitors and verapamil. These findings support the idea of several small binding sites forming one large binding cavity. Furthermore, the binding hypotheses for both catalytic states were analyzed and showed only small differences in their protein-ligand interaction fingerprints, which indicates only small movements of the ligand during the catalytic cycle. PMID- 21589947 TI - Lorcaserin for the treatment of obesity. AB - Obesity is a worldwide epidemic and there is an urgent need for the development of effective pharmacological therapies that target the metabolic and behavioral factors of body weight regulation. Serotonin (5-HT) has been implicated as a critical factor in the short-term (meal-by-meal) regulation of food intake and pharmaceutical companies have invested millions of dollars to discover and develop drug targets for the serotonergic pathway. Lorcaserin is a novel selective agonist of the 5-HT(2C) receptor for weight loss therapy. Preclinical and clinical studies indicate lorcaserin is well tolerated and not associated with cardiac valvulopathy or pulmonary hypertension suggesting that lorcaserin is a selective 5-HT(2C) receptor agonist and has little or no activation of the 5 HT(2B) and 5-HT(2A) receptors, respectively. Lorcaserin acts to alter energy balance through a reduction in energy intake and without an increase in energy expenditure and achieved the U.S. Food and Drug Administration guidelines for weight loss efficacy. It remains to be determined whether or not lorcaserin will be approved for the long-term management of obesity. PMID- 21589948 TI - New beta2-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease. AB - beta-Adrenoceptor agonists are central to the management of chronic obstructive pulmonary disease (COPD). They contribute both as rescue medications and as controller agents. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines indicate that they are useful at all stages of the disease. Current use of beta-adrenoceptor agonists emphasizes the rapidity of their onset of action and the duration of their effect. The development of newer agents seeks to improve these properties. Concern about the side effects of beta-adrenoceptor agonists-has limited their use in asthma. In view of their potential for cardiovascular effects and the prevalence of comorbidities in COPD, careful attention needs to be given when using these agents in COPD patients. PMID- 21589949 TI - An overview of pharmacotherapy for anti-neutrophil cytoplasmic antibody associated vasculitis. AB - A number of recently published prospective clinical trials have enabled the definition of the type, duration and intensity of immunosuppressive treatment in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Patients with early or localized nonrenal disease should receive an induction therapy consisting of oral prednisone in combination with oral or parenteral methotrexate. Patients with generalized or severe disease, including those with renal vasculitis, should receive 6-10 pulses of cyclophosphamide over 3-6 months or 3-6 months of daily oral cyclophosphamide plus tailing doses of prednisone. Remission therapy consists of azathioprine plus low-dose prednisone given for at least 18-24 months after the achievement of remission. Despite their efficacy, treatment with conventional agents is associated with a number of problems, including a high number of relapses and considerable morbidity. To overcome these issues, research has focused on novel immunosuppressive drugs, such as mycophenolate mofetil and leflunomide, and on molecular targeted therapy. B-cell depletion with rituximab has been shown to be at least as effective as cyclophosphamide in inducing remission in AAV, but it is not safer. TNF-alpha blockade with infliximab is a promising strategy for refractory disease, but evidence from controlled trials is still lacking. With increased understanding of the disease, novel agents and therapy principles are rapidly emerging and undergoing clinical testing. PMID- 21589950 TI - The role of inflammation and infection in prostate cancer: Importance in prevention, diagnosis and treatment. AB - It is currently estimated that infections and inflammatory responses are linked to 15-20% of all deaths from cancer worldwide. Many studies point to an important role of inflammation in prostate growth, although the contribution of inflammation to benign prostatic hyperplasia and prostate cancer is not completely understood. There is an unmet need for epidemiologic and molecular pathologic approaches to address the issue of inflammation and prostate cancer. Here we review the published evidence with respect to the involvement of inflammation and infection in prostate cancer. We also present an overarching hypothesis that chronic inflammation associated with aging and infection may play an important role in the etiology and progression of prostate cancer. As such, chronic inflammation may represent an important therapeutic target in prostate cancer. PMID- 21589951 TI - A report from the XVIII International AIDS Conference. (July 18-23, 2010-Vienna, Austria). AB - Political and social issues have a major impact on how and when HIV infection and AIDS are treated, and were a major component of the meeting in Vienna. Many discussions were held on aspects such as epidemiology, risk behavior, public health, human rights, political responses to the epidemics challenge, social stigma and discrimination, use of and recommendations on the use of condoms and other preventive measures... However, the availability of drugs and/or other therapies is a crucial issue, and while it was not the main focus of attention during this year's international AIDS conference, it will be the focus of the following report. Indeed, intensive research for new antiretrovirals continues, with new active compounds presented during the poster sessions at the Wien Messe convention center, but a wide armamentarium is currently already available, including late-generation agents such as darunavir, etravirine, raltegravir and maraviroc that provide reliable effectiveness as rescue therapy for patients failing older drug-containing highly active regimens (Azkune Galparsoro, H. et al., Abst THPE0141). All information across the meeting related to therapies for HIV infection are briefly reviewed in the following report, which complements and guides through the extensive information available on the organizing society's website. PMID- 21589952 TI - Monte Carlo simulations of protein amyloid formation reveal origin of sigmoidal aggregation kinetics. AB - Severe conditions and lack of cure for many amyloid diseases make it highly desired to understand the underlying principles of formation of fibrillar aggregates (amyloid). Here, amyloid formation from peptides was studied using Monte Carlo simulations. Systems of 20, 50, 100, 200 or 500 hexapeptides were simulated. Association kinetics were modeled equal for fibrillar and other (inter and intra-peptide) contacts and assumed to be faster the lower the effective contact order, which represents the distance in space. Attempts to form contacts were thus accepted with higher probability the lower the effective contact order, whereby formation of new contacts next to preexisting ones is favored by shorter physical separation. Kinetic discrimination was invoked by using two different life-times for formed contacts. Contacts within amyloid fibrils were assumed to have on average longer life-time than other contacts. We find that the model produces fibrillation kinetics with a distinct lag phase, and that the fibrillar contacts need to dissociate on average 5-20 times slower than all other contacts for the fibrillar structure to dominate at equilibrium. Analysis of the species distribution along the aggregation process shows that no other intermediate is ever more populated than the dimer. Instead of a single nucleation event there is a concomitant increase in average aggregate size over the whole system, and the occurrence of multiple parallel processes makes the process more reproducible the larger the simulated system. The sigmoidal shape of the aggregation curves arises from cooperativity among multiple interactions within each pair of peptides in a fibril. A governing factor is the increasing probability as the aggregation process proceeds of neighboring reinforcing contacts. The results explain the very strong bias towards cross beta-sheet fibrils in which the possibilities for cooperativity among interactions involving neighboring residues and the repetitive use of optimal side-chain interactions are explored at maximum. PMID- 21589953 TI - DNA-guided display of proteins and protein ligands for the interrogation of biology. AB - The self-assembly of nanosized DNA templates--based on formation of duplex, triplex, quadruplex or even pentaplex structures--provides unique opportunities for the controlled presentation of appended functional units. Recently, researchers have recognized the potential of such DNA scaffolds to address questions in the life sciences. In this critical review the focus is on the exploration of proteins. It is shown how different scaffolds can be used to control localization, structure and bioactivity of proteins and protein ligands. Further examples demonstrate that DNA-based recognition can even be used to trigger the formation of protein targeted molecules. Potential and existing applications in protein detection, drug discovery, structural characterization of protein targets as well as in the design of nucleic acid responsive pharmacophores are discussed (107 references). PMID- 21589954 TI - Metallatriangles and metallasquares: the diversity behind structurally characterized examples and the crucial role of ligand symmetry. AB - Reports on spontaneous self-assembly processes between metal fragments and organic ligands frequently tend to ignore the fact that the product isolated and structurally characterized in most cases is only one out of a more or less large series of feasible ones. This is true even for rings containing as few as three or four metal ions. Here we shall review metallatriangles and metallasquares containing predominantly cis-square-planar metal entities and a range of bidentate bridging ligands. The most significant features contributing to the number of possible stereoisomers appear to be ligand symmetry and flexibility, viz. rotation of two halves of a ligand about a single bond, or rotation of the whole ligand about the metal-donor atom bonds. With low-symmetry bidentate ligands the number of isomers increases dramatically with ring size as a consequence of an increase in possible connectivity patterns, hence linkage isomers, and an increase in possible rotamer states of the bridging ligands. In this tutorial review it is demonstrated how complexity increases as the symmetry of the bridging ligands is lowered from D(infinityh) and D(2h) to C(infinityv), C(2v), C(2h) and C(s). Special attention will be paid to cyclic tri- and tetranuclear complexes of substituted pyrimidine ligands (C(2v) and C(s) symmetries) as well as the flexible 2,2'-bipyrazine, which can adopt states of either C(2v) or C(2h) symmetry. Uses of these complexes and ways to reduce the number of isomers will be pointed out. PMID- 21589955 TI - Preparation of secondary and tertiary amines from nitroarenes and alcohols. AB - Various secondary amines were obtained selectively from the reaction of nitroarenes with primary alcohols in the presence of ruthenium(II) complexes having phosphine-amine ligands as the catalyst. Secondary amines could be further alkylated with a primary alcohol using the same catalyst, but different conditions. PMID- 21589956 TI - Novel titania hollow nanospheres of size 28 +/- 1 nm using soft-templates and their application for lithium-ion rechargeable batteries. AB - We report a novel protocol to prepare titania hollow nanospheres of size about 28 +/- 1 nm with micelles of asymmetric triblock copolymers. The hollow particles exhibit unique electrochemical properties in lithium ion rechargeable batteries such as high capacity, very low irreversible capacity loss, and high cycling performance. PMID- 21589957 TI - Quantitative label-free RNA detection using surface-enhanced Raman spectroscopy. AB - Surface-Enhanced Raman Spectroscopy (SERS) was performed to detect label-free RNA. We defined conditions which make it possible to probe the four bases of RNA, in single strands of polyadenosine (pA), polyuridine (pU), polycytosine (pC) and polyguanosine (pG). We therefore present below a quantitative analysis of mixtures of non-hybridized single strands, based on the deconvolution of the SERS mixture spectrum into the relative contributions of the SERS spectra of each constituent. PMID- 21589958 TI - Imides: forgotten players in the Ugi reaction. One-pot multicomponent synthesis of quinazolinones. AB - Up to now, the synthesis of quinazolinones has required lengthy synthetic procedures. Here, we describe an innovative one-pot multicomponent reaction leading to highly substituted quinazolinones. We believe that this novel transformation may open the door for the generation of new and pharmacologically active quinazolinones, but, most important of all, the resurrection of the imide Ugi scaffold paves the way for the synthesis of novel molecular architectures. PMID- 21589959 TI - Formation of nitric oxide and nitrous oxide in electron-irradiated H(2)18O/N2 ice mixtures--evidence for the existence of free oxygen atoms in interstellar and solar system analog ices. AB - We investigated the irradiation of low temperature H(2)(18)O/N(2) ice mixtures with energetic electrons in an ultrahigh vacuum chamber. The newly formed species, such as nitric oxide (N(18)O), nitrous oxide (NN(18)O), hydrogen peroxide (H(2)(18)O(2)) and hydrazine (N(2)H(4)), were identified in the experiments with infrared absorption spectroscopy and mass spectrometry. The results suggest that the unimolecular decomposition of water molecules within water ices at 10 K can lead to the formation of transient, suprathermal oxygen atoms. These oxygen atoms may play an important role in the formation of oxygen containing biomolecules such as amino acids and sugar, as well as the decomposition of the biomolecules in the ices. PMID- 21589960 TI - Thermal isomerization of eta6-arene ferradicarbolllides. Experimental proof for isolobal relation between (eta6-arene)Fe and (eta5-cyclopentadienyl)Co cluster units. AB - The heating of selected [1-(eta(6)-arene)-closo-1,2,3-FeC(2)B(9)H(11)] complexes resulted in the thermal rearrangement and isolation of the corresponding 1,2,4-, 1,2,7-, and 1,2,8-cage isomers. Demonstrated here is a similar rearrangement and the NMR behaviour for isostructural [1-(eta(5)-cyclopentadienyl)-closo-1,2,3 CoC(2)B(9)H(11)] compounds. PMID- 21589961 TI - Systematic investigation of droplet generation at T-junctions. AB - Droplet microfluidics has attracted much attention in recent years. For many droplet-based applications, researchers want to predict the size of the droplets in a certain experimental condition. To meet this need, van Steijn and colleagues proposed an elegant theoretical model that predicts the volume of droplets generated in a common channel configuration for forming a steady-state, continuous stream of droplets, the T-junction geometry. To determine the accuracy of this model in predicting droplet volume, we performed a systematic experimental study over two orders of magnitude in capillary number. We found that this model, albeit elegant, has a limited range of interfacial tension over which it can predict accurately the droplet volume. Our experimental results, together with fluid dynamic simulations, allowed us to highlight the importance of physical fluid properties when employing theoretical models. PMID- 21589962 TI - Correlation of crystal structure, dielectric properties and lattice vibration spectra of (Ba(1-x)Sr(x))(Zn(1/3)Nb(2/3))O3 solid solutions. AB - (Ba(1-x)Sr(x))(Zn(1/3)Nb(2/3))O(3) (BSZN) (x = 0.0, 0.50, 0.60, 0.65, 0.70, 1.0) solid solutions were synthesized by a conventional solid-state sintering technique. Vibration spectra (Raman spectroscopy and Fourier transform far infrared reflection spectroscopy, FTIR) and X-ray diffraction (XRD) were employed to evaluate the crystal structures and phonon modes of these solid solutions. Dielectric constants (epsilon(r)) and temperature coefficient of capacitances (tau(c)) were examined to reveal the correlation of the dielectric properties and the crystal structures. The results show that with the increase in Sr(2+) content, the lattice structures of ceramics turn gradually from disordered cubic structure to ordered structure because antiphase tilting of the oxygen octahedra occurs where x>= 0.65, which is the main reason for the phase transitions and variation of crystal structure. The appearance of the phase transitions is associated with variation of the symmetry structure, from cubic (Pm 3m, where x = 0) to pseudocubic (I4/mcm, where 0.65 <=x < 1.0) and then to hexagonal (P 3ml, where x = 1.0). New phonon modes appear at around 250 cm(-1) in Raman spectra where x>= 0.65, and there is also a different phonon mode appearing at 156 cm(-1) in the FTIR spectra at the same x range. The appearance of the new phonon modes is the characteristic of ceramics whose oxygen octahedra have tilted with Sr(2+) concentration where x>= 0.65. The Raman shifts are related to the rigidity of the oxygen octahedra, while the widths of peaks are correlated with tau(c). The FTIR spectra were subjected to the Kramers-Kronig analysis, and the imaginary part of the dielectric constant was analyzed in detail. PMID- 21589963 TI - Preparation of hexacoordinating benzimidazole containing ligand and hexakis(benzimidazole-ruthenium(II)) complex. Molecular structure of C6{CH2-(N benzimidazole-RuCl2(p-cymene))}6. AB - A hexabenzimidazole ligand was synthesised and used to prepare a hexakis{benzimidazole-ruthenium(II)} complex containing six RuCl(2)(arene) units of which the X-ray structure analysis shows a helical arrangement with alternating up and down benzymidazole-ruthenium(II) branches attached to a central benzene ring. The reactivity of the prepared complex with phosphite and carbonate was investigated and revealed the weakness of (benzimidazole)N-Ru bonds and the release of the polydentate ligand. PMID- 21589964 TI - A tumor mRNA-dependent gold nanoparticle-molecular beacon carrier for controlled drug release and intracellular imaging. AB - We demonstrate a tumor mRNA-dependent drug carrier for controlled release of doxorubicin (Dox) and intracellular imaging based on gold nanoparticle-molecular beacon. Fluorescent Dox is released effectively and induces apoptosis in breast cancer cells but not in normal cells. Significantly, the release of Dox is correlated positively with the quantities of tumor mRNA, which is according to various stages of tumor progression, and so can decrease effectively side effects of Dox. PMID- 21589965 TI - Reversible luminescence switch in a photochromic metal-organic framework. AB - Eu(III) ions have been introduced into a photoactive viologen system to yield a polyrotaxane-like metal-organic framework, which exhibits reversible photochromism and luminescence modulation with a non-destructive readout capability in the solid state. PMID- 21589966 TI - Exo-cyclopamine--a stable and potent inhibitor of hedgehog-signaling. AB - The combination of theoretical and computational studies with organic synthesis and biological investigations has led to exo-cyclopamine. This stable and highly potent derivative of cyclopamine promises big potential as an experimental drug against several types of human cancer. PMID- 21589967 TI - Sensing of biologically relevant d-metal ions using a Eu(III)-cyclen based luminescent displacement assay in aqueous pH 7.4 buffered solution. AB - 1.Eu.BPS was developed as a luminescent lanthanide sensor for use in displacement assays for detection of d-metal ions by monitoring the changes in the europium emission, which was quenched for iron(II), with a detection limit of ~10 pM (0.002 MUg L(-1)) for Fe(II) in buffered pH 7.4 solution. PMID- 21589968 TI - Large scale assembly of ordered donor-acceptor heterojunction molecular wires using the Langmuir-Blodgett technique. AB - Unidirectionally aligned photoconductive donor-acceptor heterojunction molecular wires spanning over fifty square microns are fabricated using the Langmuir Blodgett technique. PMID- 21589969 TI - ATRP, subsequent azide substitution and 'click' chemistry: three reactions using one catalyst in one pot. AB - This communication describes a novel and fast reaction to substitute the living chain end after Atom Transfer Radical Polymerization (ATRP) by an azide functionality. The reaction is catalyzed by the ATRP catalyst at room temperature in aqueous solution and can be followed by a 'click' reaction using again the same catalyst. PMID- 21589974 TI - Applications of bismuth(III) compounds in organic synthesis. AB - This review article summarizes the applications of bismuth(III) compounds in organic synthesis since 2002. Although there are an increasing number of reports on applications of bismuth(III) salts in polymerization reactions, and their importance is acknowledged, they are not included in this review. This review is largely organized by the reaction type although some reactions can clearly be placed in multiple sections. While every effort has been made to include all relevant reports in this field, any omission is inadvertent and we apologize in advance for the same (358 references). PMID- 21589975 TI - Determination of response of real-time SidePak AM510 monitor to secondhand smoke, other common indoor aerosols, and outdoor aerosol. AB - The amount of light scattered by airborne particles inside an aerosol photometer will vary not only with the mass concentration, but also with particle properties such as size, shape, and composition. This study conducted controlled experiments to compare the measurements of a real-time photometer, the SidePak AM510 monitor (SidePak), with gravimetric mass. PM sources tested were outdoor aerosols, and four indoor combustion sources: cigarettes, incense, wood chips, and toasting bread. The calibration factor for rescaling the SidePak measurements to agree with gravimetric mass was similar for the cigarette and incense sources, but different for burning wood chips and toasting bread. The calibration factors for ambient urban aerosols differed substantially from day to day, due to variations in the sources and composition of outdoor PM. A field evaluation inside a casino with active smokers yielded calibration factors consistent with those obtained in the controlled experiments with cigarette smoke. PMID- 21589976 TI - Determination of melamine in milk powder based on the fluorescence enhancement of Au nanoparticles. AB - We have developed a new analytical method to detect melamine (MA) in milk powder based on the fluorescence enhancement of Au nanoparticles (AuNPs). AuNPs with the average diameter of ~16 nm can emit stable fluorescence at 370 nm when the excitation wavelength was selected at 252 nm. The AuNPs could assemble with melamine to form larger aggregates (AuNPs-MA) through electrostatic interaction and coordinating interaction in acidic conditions, which led to the significant enhancement of the fluorescence intensity. Under the optimized conditions, the enhancement of the fluorescence intensity exhibited a good linear dependence on melamine concentration in the range from 8.0 * 10(-10) to 8.0 * 10(-8) M, and the detection limit is 6.1 * 10(-10) M (3sigma). This proposed method showed high precision and accuracy when applied to the real sample analyses. In conclusion, a simple, rapid, accurate and sensitive method to detect melamine has been suggested. PMID- 21589978 TI - Role of 5-thio-(2-nitrobenzoic acid)-capped gold nanoparticles in the sensing of chromium(vi): remover and sensor. AB - This study describes a simple, rapid method for sensing Cr(vi) using 5-thio-(2 nitrobenzoic acid) modified gold nanoparticles (TNBA-AuNPs) as a remover for Cr(iii) and as a sensor for Cr(vi). We discovered that TNBA-AuNPs were dispersed in the presence of Cr(vi), whereas Cr(iii) induced the aggregation of TNBA-AuNPs. Due to this phenomenon, TNBA-AuNPs can be used as a sorbent material for the removal of >90% Cr(iii), without removing Cr(vi). After centrifuging a solution containing Cr(iii), Cr(vi), and TNBA-AuNPs, Cr(iii) and Cr(vi) were separately present in the precipitate and supernatant. In other words, TNBA-AuNPs are capable of separating a mixture of Cr(iii) and Cr(vi). The addition of ascorbic acid to the supernatant resulted in a reduction of Cr(vi) to Cr(iii), driving the aggregation of TNBA-AuNPs. The selectivity of this approach is more than 1000 fold for Cr(vi) over other metal ions. The minimum detectable concentration of Cr(vi) was 1 MUM using this approach. Inductively coupled plasma mass spectrometry provided an alternative for the quantification of Cr(iii) and Cr(vi) after a mixture of Cr(iii) and Cr(vi) had been separated by TNBA-AuNPs. The applicability of this approach was validated through the analysis of Cr(vi) in environmental water samples. PMID- 21589977 TI - Determination of dissolved zinc in seawater using micro-Sequential Injection lab on-valve with fluorescence detection. AB - This paper introduces the preliminary design and optimization of a micro Sequential Injection lab-on-valve system (MUSI-LOV) with fluorescence detection for the direct determination of trace Zn(2+) in an unacidified seawater matrix. The method capitalizes on the sensitivity and selectivity of FluoZin-3, which was originally designed to measure zinc in living cells. The optimum reaction conditions, sources of blank signal and physical parameters of the MUSIA-LOV are evaluated with the requirements of trace metal analysis in mind, namely high sensitivity and low background signals. A detailed investigation of the effect of sample and reagent sequencing on sensitivity is presented for the first time using MUSIA-LOV. We find that the order of sequencing greatly influences peak shape and analytical sensitivity with the highest and smoothest peaks obtained when a large volume of sample (75 MUL) is aspirated last in the sequence prior to flow reversal and detection. The optimized reaction conditions and reagent/sample sequencing protocol yield a detection limit of 0.3 nM Zn(2+), high precision (RSD < 2.5%), a linear quantification range up to 40 nM and an analytical cycle of ~1 min per sample. This work demonstrates that MUSI-LOV is capable of attaining detection limits that are close to those needed for open ocean determinations of Zn(2+) without preconcentration or separation of the analyte from the seawater matrix. The low reagent consumption (50 MUL per sample), full automation and minimal maintenance requirements of MUSI-LOV make it well suited for shipboard analysis and, eventually, for development to meet the pressing need for trace element measurements in unattended locations. PMID- 21589979 TI - Hexaphenylbenzene-based polymers of intrinsic microporosity. AB - Microporous polymers derived from the 1,2- and 1,4-regioisomers of di(3',4' dihydroxyphenyl)tetraphenylbenzene have very different properties with the former being composed predominantly of cyclic oligomers whereas the latter is of high molar mass suitable for the formation of robust solvent-cast films of high gas permeability. PMID- 21589980 TI - Colorimetric and fluorescent dual probe based on a polythiophene derivative for the detection of cysteine and homocysteine. AB - Colorimetric and fluorescent dual detection of cysteine (Cys) and homocysteine (Hcy) has been realized based on the ionic self-assembly of a cationic polythiophene derivative with aromatic derivatives of Cys and Hcy formed in situ. PMID- 21589981 TI - A molecular dynamics study and molecular level explanation of pressure dependence of ionic conductivity of potassium chloride in water. AB - Experimental ionic conductivity of different alkali ions in water shows markedly different dependences on pressure. Existing theories such as that of Hubbard Onsager are unable to explain these dependences on pressure of the ionic conductivity for all ions. We report molecular dynamics investigation of potassium chloride solution at low dilution in water at several pressures between 1 bar and 2 kbar. Two different potential models have been employed. One of the models successfully reproduces the experimentally observed trend in ionic conductivity of K(+) ions in water over the 0.001-2 kbar range. We also propose a theoretical explanation, albeit at a qualitative level, to account for the dependence of ionic conductivity on pressure in terms of the previously studied Levitation Effect. It also provides a microscopic picture in terms of the pore network in liquid water. PMID- 21589982 TI - How does CO capture process on microporous NaY zeolites? A FTIR and DFT combined study. AB - Reliable experimental IR and theoretical approaches, both investigating CO adsorption on NaY faujasites, are supporting that CO capture occurs through the completion of the vacant coordination of Na(+) cations located in the accessible S(II) sites. As a result, carbonyl adsorbed species are formed by the capture of one, two or three CO molecules and are experimentally discernable by their respective IR positions that are down-shifted by an average 11-12 cm(-1) value for each captured CO molecule. DFT analysis is proposed for comparison and reproduces well the observed experimental shift of the nu(CO) positions of the different polycarbonyls of interest. In addition, the effect of Si or Al composition surrounding the SII Na(+) cation is investigated and results suggest that polycarbonyls that are formed might be in connection with the acidic strength of the cationic sites. This combined study completes and improves the understanding of the complex issue of CO adsorption at 80 K widely used as a model to explain how physical adsorption takes place in NaY faujasites working as an efficient industrial adsorbent in gas separation or gas purification processes. PMID- 21589983 TI - Effects of deposited Pt particles on the reducibility of CeO2(111). AB - The interaction of Pt particles with the regular CeO(2)(111) surface has been studied using Pt(8) clusters as representative examples. The atomic and electronic structure of the resulting model systems have been obtained through periodic spin-polarized density functional calculations using the PW91 exchange correlation potential corrected with the inclusion of a Hubbard U parameter. The focus is on the effect of the metal-support interaction on the surface reducibility of ceria. Several initial geometries and orientations of Pt(8) with respect to the ceria substrate have been explored. It has been found that deposition of Pt(8) over the ceria surface results in spontaneous oxidation of the supported particle with a concomitant reduction of up to two Ce(4+) cations to Ce(3+). Oxygen vacancy formation on the CeO(2)(111) surface and oxygen spillover to the adsorbed particle have also been considered. The presence of the supported Pt(8) particles has a rather small effect (~0.2 eV) on the O vacancy formation energy. However, it is predicted that the spillover of atomic oxygen from the substrate to the metal particle greatly facilitates the formation of oxygen vacancies: the calculated energy required to transfer an oxygen atom from the CeO(2)(111) surface to the supported Pt(8) particle is only 1.00 eV, i.e. considerably smaller than 2.25 eV necessary to form an oxygen vacancy on the bare regular ceria surface. This strongly suggests that the propensity of ceria systems to store and release oxygen is directly affected by the presence of supported Pt particles. PMID- 21589984 TI - Do salmon farms increase the concentrations of mercury and other elements in wild fish? AB - Earlier assessments have suggested that salmon farms may act as a source of mercury (Hg) and other elements in local marine environments. In this study, we measured 30 elements in the livers of demersal Atlantic cod (Gadus morhua) and pelagic saithe (Pollachius virens) caught in association with salmon farms (farm associated [FA]; n = 75) or at reference locations (control; n = 80) in three regions throughout the latitudinal extent of Norway (59-70 degrees N). Concentrations of most elements (24 of 30) were higher (20-70%) in cod compared to saithe. In particular, Hg was 6.8 times higher in cod than saithe. Nine elements were significantly different between FA saithe and control saithe, but only four (Hg, U, Cr and Mn) were highest in FA saithe, and this pattern was only detected consistently across all locations for Hg. Thirteen elements differed in concentration between FA cod and control cod, but only three elements (U, Al and Ba) were higher in FA cod than controls, and this pattern was only detected consistently across all locations for Al. After controlling for a set of potentially confounding variables, the estimated concentrations of Hg in saithe livers were ~80% higher in FA fish compared to controls. In contrast, Hg concentrations were ~40% higher in control cod compared to FA cod. Our results do not support the notion that salmon farms in general increase the concentrations of potentially harmful elements in wild fish, and the distribution of Hg and other elements in cod and saithe in Norwegian coastal waters may be more influenced by habitat use, diet, geochemical conditions and water chemistry. PMID- 21589985 TI - Highly efficient hydrogen storage with PdAg nanotubes. AB - Hydrogen storage is one of the vital and challenging issues for the commercialization of hydrogen-powered fuel cells. In this report, the synthesized PdAg nanotubes exhibit enhanced hydrogen-storage ability. The highest capacity for hydrogen absorption obtained on the PdAg nanotubes with 15% of Pd was over 200 times greater than the pure Pd nanoparticles. PMID- 21589986 TI - Fabrication of transparent and conductive carbon nanotube/polyvinyl butyral films by a facile solution surface dip coating method. AB - We present a simple solution surface dip coating method for fabricating transparent and conductive carbon nanotube/polyvinyl butyral (CNT/PVB) composite films. This fabrication process is simple to scale production and requires only ethanol and water as solvents, which is green and environment friendly. PMID- 21589987 TI - Fabrication of size-controllable Fe2O3 nanoring array via colloidal lithography. AB - Tailed-Fe(2)O(3) ring arrays are fabricated by solution-dipping on a colloidal monolayer template. The influence of synthesis parameters on the quality of nanostructures has been investigated. The ring size can be controlled by changing the precursor concentration and varying the annealing time of the polystyrene sphere colloidal monolayer. In addition, the edge of the rings is sensitive to the surface tension of precursor solution, and high quality ordered ring arrays can be obtained by tuning the surface tension. This strategy allows the fabrication of specific metal oxides ring arrays with high quality and uniform morphology. PMID- 21589988 TI - Alternating chemical ligation reactivity of S-acyl peptides explained with theory and computations. AB - Previously discovered alternating reactivity of S-acyl di-, tri-, and tetrapeptide in internal chemical ligation reactions is rationalised using conformational search, virtual screening methods and quantum chemical calculations. Conformational preorganisation is shown to be the major controller of reactivity, with hydrogen bonding providing additional stabilisation for the tetrapeptide structure. PMID- 21589989 TI - Incorporation of chemical functionalities in the framework of mesoporous silica. AB - Mesoporous silica, which shows well-defined pore systems, tunable pore diameters (2-30 nm), narrow pore size distributions and high surface areas (>600 m(2) g( 1)), is frequently modified using different methodologies (including in situ and post-synthetic strategies) to introduce various chemical functionalities useful in applications like catalysis, separation, drug delivery, and sensing. This contribution aims to provide a critical overview of the various strategies to incorporate chemical functionalities in mesoporous silica highlighting the advantages of the in situ methods based on the bottom-up construction of mesoporous silica containing various chemical functionalities in its structure. PMID- 21589990 TI - Label-free fluorescent detection of Cu(II) ions based on DNA cleavage-dependent graphene-quenched DNAzymes. AB - We developed a novel and general methodology to design a label-free fluorescent Cu(II) sensor based on internal DNA cleavage and an extrinsic fluorophore in a graphene/DNAzymes complex with high sensitivity and selectivity. PMID- 21589991 TI - Silver(I) pyrophosphonates: structural, photoluminescent and thermal expansion studies. AB - The solvothermal reactions of silver(I) salts with mono-organophosphonic acids, i.e. 3-thienylphosphonic acid (3-TPA), phenylphosphonic acid (PPA), alpha naphthylphosphonic acid (alpha-NPA) and cyclohexylphosphonic acid (CPA), yield four new silver(I) pyrophosphonates, namely: [Ag(2)(ptp)] (1), [Ag(2)(ppp)] (2), [Ag(3)(CH(3)CN)(pnp)(pnpH)] (3), and [Ag(3)(pcp)(pcpH)] (4) [ptp(2-) = pyro-3 thienylphosphonate, ppp(2-) = pyrophenylphosphonate, pnp(2-) = pyro-alpha naphthylphosphonate, pcp(2-) = pyrocyclohexylphosphoante]. In all cases, the pyrophosphonate ligands are generated in situ from their relative mono organophosphonic acids, mediated by silver(I) ions. Single crystal structural determinations reveal that compounds 1 and 2 display two-dimensional layer architectures, while 3 and 4 show one-dimensional chain structures. Structure 1 can be best described as a layer made up of Ag(4)O(P)(6) clusters linked by O-P-O units and AgAg contacts, with the organic groups grafted on the two sides of the inorganic layer. A similar layer structure is found in 2 except that the AgAg interactions are absent. Compound 3 shows a chain structure where the silver ions are bridged by the phosphonate oxygen atoms forming an infinite Ag-O(P) chain which is decorated by the pyrophosphonate ligand and CH(3)CN. Compound 4 has another type of chain structure made up of Ag-O(P) with extensive Ag...Ag argentophilic interactions. Solid state photoluminescent properties and thermal expansion behaviors are also investigated. PMID- 21589992 TI - Transcriptional regulation by miRNA mimics that target sequences downstream of gene termini. AB - Transcriptome studies have revealed that protein-coding loci within the human genome are overlapped at their 3'-termini by noncoding RNA (ncRNA) transcripts. Small duplex RNAs designed to be fully complementary to these 3' ncRNAs can modulate transcription of the upstream gene. Robust regulation by designed RNAs suggests that endogenous small RNAs might also recognize 3' ncRNAs and regulate gene expression. A genome-wide evaluation revealed that sequences immediately downstream of protein-coding genes are enriched with miRNA target sites. We experimentally tested miRNA mimics complementary to the well-characterized 3' terminus of the human progesterone receptor (PR) gene and observed inhibition of PR transcription. These results suggest that recognition of ncRNA transcripts that overlap gene termini may be a natural function of endogenous small RNAs. PMID- 21589993 TI - Synchrotron radiation X-ray fluorescence microscopy reveals a spatial association of copper on elastic laminae in rat aortic media. AB - Copper, an essential trace metal in humans, plays an important role in elastic formation. However, little is known about the spatial association between copper, elastin, and elastin producing cells. The aorta is the largest artery; the aortic media is primarily composed of the elastic lamellae and vascular smooth muscle cells, which makes it a good model to address this issue. Synchrotron radiation X ray fluorescence microscopy (SRXRF) is a new generation technique to investigate the spatial topography of trace metals in biological samples. Recently, we utilized this technique to determine the topography of copper as well as other trace elements in aortic media of Sprague Dawley rats. A standard rat diet was used to feed Sprague Dawley rats, which contains the normal dietary requirements of copper and zinc. Paraffin embedded segments (4 MUm of thickness) of thoracic aorta were analyzed using a 10 keV incident monochromatic X-ray beam focusing on a spot size of 0.3 MUm * 0.2 MUm (horizontal * vertical). The X-ray spectrum was measured using an energy-dispersive silicon drift detector for elemental topography. Our results showed that phosphorus, sulfur, and zinc are predominately distributed in the vascular smooth muscle cells, whereas copper is dramatically accumulated in elastic laminae, indicating a preferential spatial association of copper on elastic laminae in aortic media. This finding sheds new light on the role of copper in elastic formation. Our studies also demonstrate that SRXRF allows for the visualization of trace elements in tissues and cells of rodent aorta with high spatial resolution and provides an opportunity to study the role of trace elements in vasculature. PMID- 21589994 TI - Natural products containing a diazo group. AB - Although diazo compounds are probably best known for their involvement as versatile intermediates in modern synthetic organic chemistry, a small number of such compounds also occur naturally. Many of the early examples, such as azaserine, originally isolated in the 1950s, have antitumour properties and consist of modified alpha-amino acids. More recently, other more complex diazo compounds have been isolated from natural sources, and these include diazobenzoquinones, diazonaphthoquinones, such as the SF2415 and A80915 antibiotics, and the diazofluorene-based kinamycins and lomaiviticins. This report will cover the isolation, biosynthesis, biological activity and synthesis of natural products containing a diazo group. PMID- 21589995 TI - Multiplexed arrays of chemosensors by parallel dip-pen nanolithography. AB - Miniaturized combined arrays of three different pH indicators allowing for sensitive, robust and broad-range acidity detection are prepared by parallel dip pen nanolithography, which proves the potential of this technique to fabricate multiplexed platforms at the micro- and nanoscale that can act as sensors. PMID- 21589996 TI - Avoiding spurious correlation in analysis of chemical kinetic data. AB - This communication demonstrates that improperly formulated data analyses can inflate the strength of statistical correlations and result in drawing incorrect conclusions. The widespread misuse of a second-order kinetic model in the recent literature reveals that many chemists are not aware of the dangers of spurious correlation. PMID- 21589997 TI - Observing 13C-13C connectivities at high magnetic fields and very high spinning frequencies. AB - We report the application of a dipolar recoupling sequence for the observation of (13)C-(13)C connectivities in biomolecules at high magnetic fields (B(0)>= 21.1 T) and ultra-high magic angle spinning frequencies (nu(R) = 60 kHz). The efficiency and the robustness of this double-quantum technique are demonstrated on the YajG protein (19.6 kDa). PMID- 21589998 TI - Formation of alpha-helix-based twisted ribbon-like fibrils from ionic complementary peptides. AB - Ionic-complementary peptides (ICPs) are well known for their strong propensity to form amyloid-like beta-sheet fibrils. Here, we present the first example that alpha-helical based ICPs can self-assemble into a highly ordered fibrillar structure. Intriguingly, the individual alpha-helices in such fibrils are arranged shoulder-to-shoulder, making them distinct from conventional coiled-coil based fibrils. PMID- 21589999 TI - Core-shell effects in the ionization of doped helium nanodroplets. AB - Core-shell particles with water clusters as the core and surrounded by an atomic or molecular shell have been synthesized for the first time by adding water and a co-dopant sequentially to helium nanodroplets. The co-dopants chosen for investigation were Ar, O(2), N(2), CO, CO(2), NO and C(6)D(6). These co-dopants have been used to investigate the effect of an outer shell on the ionization of the core material by charge transfer in helium nanodroplets. The specific aim was to determine how the identity of the shell material affects the fragmentation of water cluster ions, i.e. whether it helps to stabilize parent ion ((H(2)O)(n)(+)) formation or increases fragmentation (to form (H(2)O)(n)H(+)). N(2), O(2), CO(2) and C(6)D(6) all show a marked softening effect, which is consistent with the formation of a protective shell around the water cluster core. For CO and NO co dopants, the response is complicated by secondary reactions which actually favour water cluster ion fragmentation for some water cluster sizes. PMID- 21590000 TI - Towards the synthesis of sugar amino acid containing antimicrobial noncytotoxic CAP conjugates with gold nanoparticles and a mechanistic study of cell disruption. AB - Cationic antimicrobial peptides are potent inhibitors of growth of a broad spectrum of micro-organisms but often have large cytotoxic effects. We prepared some novel sugar amino acid containing cyclic cationic peptides and their Au nanoparticle attached counterparts and studied their antimicrobial activities and cytotoxic behaviour, including an investigation of the mechanism of the cytotoxicity. PMID- 21590001 TI - Landfills as risk factors for respiratory disease in children. AB - OBJECTIVE: To investigate the relationship between exposure to a landfill site closed 6 years previously and respiratory symptoms in children aged up to 13 years. METHOD: This was a cross-sectional study conducted in Varzea Paulista, in the state of Sao Paulo, Brazil. One adult in every household in a neighborhood close to the landfill and from a randomized sample of households in another neighborhood with similar socioeconomic characteristics but no landfill were interviewed and asked about respiratory symptoms and other variables relating to children aged up to 13. A logistic regression model was used to study this relationship. RESULTS: The likelihood of a child having respiratory symptoms was a function of -2.36 + 0.43 if the child was less than 2 years old; + 0.24 if the child lived in the landfill area; -0.67 if there was a computer at home; + 0.54 if firewood was burnt in the home in the last year; + 0.94 if the child was diagnosed with asthma; + 0.87 if the child visited a health service in the previous 30 days. CONCLUSION: The authors conclude that living near to a landfill closed 6 years previously may be a risk factor for respiratory disease in children. PMID- 21590002 TI - Anthropometric midarm measurements can detect systemic fat-free mass depletion in patients with chronic obstructive pulmonary disease. AB - Our objective was to determine whether anthropometric measurements of the midarm (MA) could identify subjects with whole body fat-free mass (FFM) depletion. Fifty five patients (31% females; age: 64.6 +/- 9.3 years) with mild/very severe chronic obstructive pulmonary disease (COPD), 18 smokers without COPD (39% females; age: 49.0 +/- 7.3 years) and 23 never smoked controls (57% females; age: 48.2 +/- 9.6 years) were evaluated. Spirometry, muscle strength and MA circumference were measured. MA muscle area was estimated by anthropometry and MA cross-sectional area by computerized tomography (CT) scan. Bioelectrical impedance was used as the reference method for FFM. MA circumference and MA muscle area correlated with FFM and biceps and triceps strength. Receiver operating characteristic curve analysis showed that MA circumference and MA muscle area cut-off points presented sensitivity and specificity >82% to discriminate FFM-depleted subjects. CT scan measurements did not provide improved sensitivity or specificity. For all groups, there was no significant statistical difference between MA muscle area [35.2 (29.3-45.0) cm2] and MA cross-sectional area values [36.4 (28.5-43.3) cm2] and the linear correlation coefficient between tests was r = 0.77 (P < 0.001). However, Bland-Altman plots revealed wide 95% limits of agreement (-14.7 to 15.0 cm2) between anthropometric and CT scan measurements. Anthropometric MA measurements may provide useful information for identifying subjects with whole body FFM depletion. This is a low-cost technique and can be used in a wider patient population to identify those likely to benefit from a complete body composition evaluation. PMID- 21590003 TI - Effects of a bis(benzyl)spermine analog on MCF-7 breast cancer cells in culture and nude mice xenografts. AB - We studied the effects of a polyamine analog, N,N'-bis{3 [(phenylmethyl)amino]propyl}-1,7-diaminoheptane (MDL 27695) on MCF-7 cells, as part of an attempt to develop new drugs for breast cancer treatment. Using [H-3] thymidine incorporation assay and long-term growth curves, we found that MDL 27695 inhibited the growth of MCF-7 cells in a dose-dependent manner in the low mu M range. G1 synchronized cells progressing in cell cycle showed delayed and inefficient entry into S phase in the presence of 4 mu M MDL 27695. Consistent with a G1 arrest, MDL 27695 significantly reduced estradiol-mediated increase in the expression of cyclin D1. HPLC analysis showed that treatment of MCF-7 cells with MDL 27695 reduced the accumulation of natural polyamines, putrescine, spermidine, and spermine, by 43, 38, and 45%, respectively, at 8 h after the initiation of cell cycle. This decrease in polyamine levels was not associated with a decrease in the activity of polyamine biosynthetic (ornithine decarboxylase, ODC; s-adenosylmethionine decarboxylase, SAMDC) or catabolizing (spermidine/spermine acetyltransferase, SSAT) enzymes. However, there was a 40% decrease in the uptake of putrescine and spermidine, in cells treated with MDL 27695. Our studies also showed that MDL 27695, at a dose of 20 mg/kg, caused a significant inhibition of tumor growth in nude mice harboring MCF-7 cell derived tumors, without overt symptoms of toxicity. These data indicate that the polyamine analog MDL 27695 is an efficient inhibitor of MCF-7 breast cancer cell growth in vitro and in vivo. Our results suggest that polyamines are critical factors in cell cycle regulation of breast cancer cells and potential targets for therapy. PMID- 21590004 TI - Estrogenic regulation of a novel 34 kDa protein associated with cyclin B1 in MCF 7 breast cancer cells. AB - Recent studies have revealed altered regulation of cyclins in breast cancer cells. To understand the role of aberrant cyclin B1 expression in the proliferation of breast cancer cells, we examined cyclin B1-associated proteins in estrogen-responsive MCF-7 cells in a cell cycle-dependent manner. Immunoprecipitation of cell lysate with a monoclonal anti-human cyclin B1 antibody, followed by Western blot probing with an anti-human cdc2 (PSTAIR) antibody revealed the presence of a 34 kDa protein in estradiol-treated cells at 16 h after initiation of cell cycle progression. Flow cytometry and [H-3] thymidine (Thd) incorporation experiments showed a dramatic increase in the percentage of S phase cells at this time point. This protein was suppressed by an antiestrogen, 4-hydroxytamoxifen. It was not found in MCF-1OA, a normal breast epithelial cell line. The 34 kDa protein was not reactive with antibodies raised against other cyclin dependent kinases (CDKs), including p34(cdc2(Carboxy terminal)). This protein was functionally active as determined by histone H1 kinase activity. These data suggest that the induction of a cyclin B1-associated 34 kDa protein during the G1 --> S transition might be a positive regulator of cell cycle progression in estrogen-responsive breast cancer cells. PMID- 21590005 TI - Neoadjuvant intra-arterial infusion chemotherapy for invasive thymoma. AB - Four patients with stage III or IVa invasive thymoma successfully underwent surgical intervention and radiotherapy following neoadjuvant intra-arterial chemotherapy including 50 mg/m(2) of cisplatin and 20 mg/m(2) of adriamycin. Remarkable reduction rates (60% or more) of the tumor size were obtained without significant side effects. About 4 weeks after neoadjuvant chemotherapy, an extended thymectomy including invaded organs was easily performed with a small amount of intraoperative bleeding. All patients but one are currently alive and disease-free. This method may be a new therapeutic strategy in the management of invasive thymoma. PMID- 21590006 TI - Analysis of the proliferative and phenotypic properties of tumor infiltrating lymphocytes expanded in vitro in the course of the clinical trial of adoptive immunotherapy of metastatic melanoma. AB - Adoptive immunotherapy with in vitro expanded tumor infiltrating lymphocytes (TIL) and recombinant interleukin-2 (rIL-2) is a recent option in the treatment of advanced melanoma resistant to conventional chemotherapy. In the course of a protocol of treatment of advanced melanoma with in vitro expanded TIL and rIL-2, we obtained 38 samples from 27 different patients. Lymphocytes derived were cultured in the presence of rIL-2 in vitro for a 4-6 week period and 23 resulted in proliferative cultures. Eighteen samples were infused in the course of the clinical trial. The median number of lymphocytes obtained was 18x10(9) (range 1 43x10(9)) cells. Phenotypic analysis showed that all samples contained a pure population of T cells. These data confirm that lymphocytes can be expanded from advanced metastatic sites, have peculiar characteristics and are suitable to be infused in vivo. PMID- 21590007 TI - Low and high molecular weight cytokeratins in invasive breast carcinoma. AB - Low molecular weight cytokeratin (LCK) and high molecular weight cytokeratin (HCK) were analyzed by immunohistochemistry using two monoclonal antibodies in 90 patients with operable invasive breast carcinoma (IBC). Fifty-nine (65.6%) of 90 tumors were LCK-positive, and 19 (21.1%) were HCK-positive. The incidence of LCK positivity was inversely correlated with nuclear or histological grade, however, the incidence of HCK positivity was positively correlated. The positive correlation of the incidence of LCK positivity with estrogen receptor (ER) status was observed, however, the inverse correlation was found between the incidence of HCK positivity and ER status. The mean of ER content (101.9 fmol/mg protein) in LCK-positive tumors was significantly higher than that (20.8 fmol/mg protein) in LCK-negative tumors. To the contrary, the mean of ER content (10.1 fmol/mg protein) in HCK-positive tumors was significantly lower than that (91.3 fmol/mg protein) in HCK-negative tumors. Overall survival (OS) and relapse-free survival (RFS) of patients with LCK-positive tumors tended to be better than those of patients with LCK-negative tumors. No difference was demonstrated between OS and RFS of patients with HCK-positive tumors and those of patients with HCK-negative tumors. LCK-positive IBC can be well differentiated and HCK-positive IBC poorly differentiated. The immunohistochemical analysis for LCK and HCK can be utilized to evaluate the differentiation of IBC. Furthermore, LCK immunoreactivity might be one of the prognostic factors of IBC, and HCK immunoreactivity could be useful for the histological diagnosis for carcinoma with metaplasia, such as squamous cell or spindle cell carcinoma. PMID- 21590008 TI - Low toxicity of inhaled interferon-gamma in four patients with lung metastasis from renal cell carcinoma. AB - Inhalation of interferon-gamma (IFN-gamma) was used in four patients with pulmonary metastasis from renal cell carcinoma. Three million JRU IFN-gamma were inhaled every day (3 patients) or 5 times per week (1 patient). One patient achieved no change after IFN-gamma inhalation and three patients had no response. No drug-related side effects were observed. These findings point to the clinical feasibility of inhalation of IFN-gamma. However, further studies are needed to establish the anti-tumor efficacy of IFN-gamma inhalation therapy. PMID- 21590009 TI - The effect of continuous infusion IL-1 alpha on carboplatin-induced thrombocytopenia and anti-tumor activity in RIF-1 tumor bearing mice. AB - Interleukin-1 alpha (IL-1 alpha) has potent effects on hematopoiesis and can significantly enhance the anti-tumor activity of cytotoxic drugs. Studies were undertaken here to determine whether IL-1 alpha, administered by continuous infusion, could prevent carboplatin (CBDCA)-mediated thrombocytopenia and enhance CBDCA-mediated anti-tumor effects. RIF-1 tumor bearing mice were treated with CBDCA and IL-1 alpha either by a single bolus injection or by continuous infusion through the use of ALZET pumps. The duration and extent of CBDCA-induced thrombocytopenia in tumor-bearing mice was diminished when IL-1 alpha was administered continuously as compared to CBDCA alone or CBDCA plus a single bolus injection of IL-1 alpha. In addition, IL-1 alpha induced potentiation of CBDCA anti-tumor activity in vivo was significantly increased when IL-1 alpha was administered by continuous infusion. These results demonstrate the potential efficacy of IL-1 alpha by continuous infusion. PMID- 21590010 TI - Histochemical characteristics of calcium binding S100 proteins and bone morphogenetic proteins in chondro-osseous tumors. AB - Immunohistochemical distribution of the Ca2+ binding proteins S100A1, S100A2, S100A4, S100A6, S100B, and bone morphogenetic protein (BMP) in chondro-osseous tumors and lesions, both benign and malignant, was investigated using specific anti S100 protein and BMP antibodies. Chondrogenic tumor cells of chondro-osseous lesions were characterized by the presence of marked staining for S100B and BMP, while they were only faintly reactive for S100A1, S100A2, S100A4 and S100A6. Dense fibrous connective tissue in osseous tumor and ossifying fibroma showed moderate immunoreactivity for S100A1, S100A4 and BMP. Immunoreactivity of S100A2, prominent in epidermal basal cells and associated or homologous cells of epidermal tumors or skin appendages tumors, was not found in cartilage and bone forming cells. Biological roles of S100B in chondroid cells may involve Ca2+ signaling in precalcified tissue, cytoskeletal protein organization and matrix formation since glycosaminoglycan synthesis is mediated by calcium ions. S100B positive cells in chondro-osseous structures also strongly expressed BMP. The present study allowed us to conclude that among the S100 proteins, the S100B in particular and S100A1, S100A4 and S100A6 but not S100A2 may be involved in the process of tumorigenesis of chondro-osseous tumors and BMP may have an important role in the chondroid and osseous differentiation. The detailed biological role of S100 proteins in chondro-osseous tumors is under investigation. PMID- 21590011 TI - Thymidine phosphorylase activity required for tumor angiogenesis and growth. AB - Thymidine phosphorylase (TP) is identical to platelet-derived endothelial cell growth factor (PD-ECGF), and has angiogenic activity. We examined the involvement of TP activity in tumor growth and angiogenesis. KB cells were transfected with wild-type or mutant (L148R) PD-ECGF cDNA, and two sublines with high TP activity, KB/wt4 and KB/wt6, and one subline with no TP activity, KB/L148R, were cloned, respectively. The doubling times of these subclones in vitro were similar to that of KB cells. However, the growth of KB/wt4 and KB/wt6 cells was significantly faster when xenografted into nude mice than that of control cells with no TP activity. The tumors with high TP activity (KB/wt4 and KB/wt6) had significantly more microvessels than those with no TP activity (KB/-, KB/CV and KB/L148R) (P<0.01). These results, taken together with previous reports, suggest that the TP enzyme activity itself is involved in angiogenesis and growth of the KB tumors. PMID- 21590013 TI - The role of cell membrane-associated urinary trypsin inhibitor in tumor cell invasion and metastasis. AB - Tumor cells (human choriocarcinoma SMT-cc1 cells and human promyeloid leukemia U937 cells) express urinary trypsin inhibitor (UTI)-like immunoreactive substance. Because of the prominent inhibitory effects of exogenous UTI on tumor cell invasive and metastatic potential, it is important to determine whether there is endogenous UTI production by these cells. Most of cell-associated UTI is located on the cell surface. Immuno-precipitates of the particulate fraction contained three different polypeptide chains including M(r) >200 kDa, 125 kDa, and a polydisperse band of M(r) 40 kDa, which is confirmed to be UTI by amino acid sequence analysis. In SMT-cc1 cells pulse-labeled with [S-35]sulfate, a polyclonal antibody against UTI precipitated labeled proteins of >200 kDa, 125 kDa, 93 kDa, 69 kDa, and 40 kDa. Upon chase, very low levels of 40 kDa band could be detected in lysates. On the other hand, although UTI was immunoprecipitated from U937 cells and the cells were immunohistochemically positive with anti-UTI antibody, UTI remained unlabeled even after long incubation of the cells with [S 35]sulfate. This suggests that SMT-cc1 cells may produce endogenous UTI, but U937 cell-associated UTI, which may not be generated by U937 cells themselves, may be taken up onto the cell surface from the serum. SMT-cc1 cells were invasive on the Matrigel in an in vitro assay. Exogenously applied UTI efficiently inhibits tumor cell invasion in a dose-dependent manner. Furthermore, addition of anti-UTI antibody to the cells enhanced cell-associated caseinolytic activity. Anti-UTI antibody produced biphasic, concentration-dependent changes in tumor cell invasion. Although invasion by the cells was enhanced by addition of lower concentrations (<0.5 mu g/ml) of anti-UTI antibody to the in vitro assay system, higher concentrations (>0.5 mu g/ml) of antibody blocked tumor cell invasion, suggesting that too much cell-associated proteolytic activity may cause uncontrolled matrix degradation. Our results suggest that certain tumor cells express UTI on their cell surface and that membrane-bound UTI may control proteolysis and contribute to prevent the excessive fibrinolysis in condition such as tumor invasion. PMID- 21590012 TI - Postoperative prognosis of pulmonary adenocarcinoma subtypes correlates with HLA DR expression and the number of tumor-infiltrating cells. AB - Human pulmonary adenocarcinomas (AC) can be divided into two types with special morphologic and immunohistologic properties and a different number of tumor infiltrating cells as shown by previous investigations. In the present study the relevance of this subdivision for patients' survival was investigated. 42 surgically resected pulmonary AC of stage I and II were subclassified using light and electron microscope. For immunohistologic phenotypization, reactions with monoclonal antibodies against HLA-DR, CD1 and CD3 were studied on fresh tumor specimens. Postoperative survival was evaluated after at least 24 months. AC of type I (N=23) with mucin production and ultrastructural properties of goblet cells showed almost no HLA-DR expression. Infiltration by CD1-positive dendritic cells Langerhans cells and CD3-positive T lymphocytes was significantly lower than in AC of type II (N=19), which expressed HLA-DR homogeneously and showed, ultrastructurally, Clara cell and/or type II pneumocyte properties. Patients' outcome was similar in stage I AC of both types: about 70% of patients were still alive after 24 months. However, significant differences were found between the two types in stage II AC with regional lymph node metastases: survival of patients with AC of type II corresponded roughly with stage I tumors (67%) but only 20% of patients with type I AC were still alive after 24 months. These results indicate that postoperative prognosis for patients with pulmonary AC of type II is more favourable than for mucinous AC of type I. This may be due to the homogeneous HLA-DR expression and higher number of immunologically competent tumor-infiltrating cells which possibly results in better tumor surveillance. PMID- 21590014 TI - The clinical application of an ATP assay to predict the chemosensitivity of gastric cancer. AB - The chemosensitivity of human xenografts in nude mice and fresh surgical specimens of gastric cancer was evaluated in vitro using the ATP assay and the MTT assay. The in vitro sensitivity of 6 human xenografts was detected by the ATP assay and compared with the in vivo sensitivity of the xenografts in nude mouse. The assay showed a 56.3% true-positive rate and a 85.7% true-negative rate, with 90.0% sensitivity and 46.2% specificity. When 10 surgical specimens obtained from gastric cancer patients were divided into two groups and sensitivities assessed by the ATP and the MTT assays, the overall correlation of both assays was 81.3%. The ATP assay might be useful in evaluating the chemosensitivity of human gastric carcinomas. PMID- 21590015 TI - Keratin expression in normal uterine cervical epithelium and carcinomas of cervical origin. AB - The immunohistochemical expression of keratins 7, 8, 10, 13, 14, 17, 18 and 19 was examined in formalin-fixed paraffin-embedded tissues of normal uterine cervical epithelium and carcinomas of cervical origin (4 squamous cell carcinoma in situ, 17 squamous cell carcinoma, 9 adenocarcinoma, and 1 adenoid basal carcinoma). A panel of 8 monoclonal antibodies capable of recognizing 8 individual keratin subtypes was employed using microwave oven heating and a labeled streptavidin biotin method. Ectocervical squamous epithelium expressed keratins 14 and 19 in the basal cell layer, and keratins 10 and 13 in the suprabasal cell layer. Endocervical columnar cells were found to express keratins 7, 8, 18 and 19, whereas the reserve cells expressed keratins 7, 8, 14, 17, 18 and 19. Most of the squamous cell carcinomas, both keratinizing and non keratinizing, as well as the carcinoma in situ revealed a keratin phenotype detected in normal ectocervical squamous cells (keratins 10, 13, 14 and 19) and endocervical subcolumnar reserve cells (keratins 7, 17 and 18). The adenocarcinomas, both endocervical and endometrial type, were positive for keratins 7, 8, 17, 18 and 19. The adenoid basal carcinoma expressed all the keratins examined including the expression of reserve cell keratin. Reserve cell keratins were found mostly in squamous cell carcinomas, adenocarcinomas and adenoid basal carcinoma of cervical origin. Therefore, the keratin expression pattern indicates the origin of a variety of carcinomas of the uterine cervix from a common progenitor, endocervical reserve cells. PMID- 21590016 TI - Immunostaining of human glioblastomas with various PCNA antibodies. AB - The aim of the study was to compare various PCNA clones (PC10, 19A2, and 19F4) on frozen and paraffin wax sections of ten human glioblastomas. Standard immunohistochemical methods were used (avidin-biotin-peroxidase technique). Half of the paraffin sections were pretreated in a microwave oven. With few exceptions positive staining was achieved only on paraffin sections after microwave treatment. Staining with the 19A2 antibody revealed few (<1%) positively stained tumor nuclei in only three cases whereas staining with 19F4 was positive in eight cases with a labeling index (LI) in the range of <1-3.5%. All cases showed positive staining with the PC10 antibody with an LI of <1% in three cases and in the range of 2.0-17.2% in the remaining seven. However, most of the PC10 stained sections showed a disturbing unspecific background staining. Thus, in spite of the background staining we conclude that PC10 offered the best immunostaining of the antibodies tested. PMID- 21590017 TI - Relation between CA125 levels and second-look operation for ovarian cancer. AB - We investigated the relationship between the serum level of CA125 before a second look operation (SLO) and SLO findings in 196 patients with adenocarcinoma of the ovary. SLO findings were positive in 38 (19.4%) of 196 patients. The positive rate tended to increase with the clinical stage, but SLO findings were positive even in a patient with stage Ia disease. The pre-SLO serum level of CA125 was positive in 11 patients before SLO, SLO findings were positive in 8 of these 11 patients. The highest diagnostic accuracy (37.9%) for the pre-SLO serum level of CA125 was obtained at a cut-off value of 11 U/ml. Our findings suggest that a positive pre-SLO serum level of CA125 does not necessarily indicate tumor positivity. In addition, we suggest that the cut-off value for prediction of SLO findings should be below 35 U/ml, which is a commonly used cut-off value. PMID- 21590018 TI - Study of angiotensin II-induced hypertensive chemotherapy for ovarian cancer in rats. AB - We investigated the usefulness of angiotensin II (AT II)-induced hypertensive chemotherapy for adenocarcinoma of the ovary, which was induced with dimethylbenzantracene (DMBA) in rats. Ovaries with DMBA-induced cancer had poor blood flow, while normal ovaries had abundant brood flow when blood pressure was normal. The brood flow of the normal ovaries was suppressed by AT II-induced hypertension, while the blood flow in ovarian cancer was more than doubled. Tissue levels of the anticancer drug cisplatin (CDDP) were almost the same in the normal ovary in the presence or absence of induced hypertension. However, the CDDP level in ovarian cancer tissue was significantly higher with AT II-induced hypertension than with normotension. Comparison of the ratio of the enlarged tumor to the primary tumor and the histopathologic antitumor effects, showed that AT II-induced hypertension treatment with CDDP was highly effective. Angiotensin II-induced hypertensive chemotherapy for adenocarcinoma of the ovary in rat was highly effective in comparison with normotension. PMID- 21590019 TI - Overexpressed cyclin D1 protein related to p53 and retinoblastoma proteins in transitional cell carcinoma of the urinary tract. AB - We employed immunohistochemical methods to investigate the overexpression of cyclin D1 protein as well as p53 protein and retinoblastoma protein (pRb) in 57 patients with transitional cell carcinoma (TCC) of the urinary tract, in order to determine their frequency and significance, and also association with the clinicopathological behavior of this tumor. Nuclear immunostaining with cyclin D1 antibody revealed 7 homogeneously stained tumors (12.3%), including 4 heterogeneous pRb expressions, of which only one was also positive for p53. Positive immunostaining with each antibody to p53 or pRb was obtained in 15 (26.3%) and 49 (86%) tumors, respectively. The 49 pRb-positive tumors included 6 homogeneous and 43 heterogeneous nuclear immunostaining patterns. The remaining pRb-negative 8 tumors included 5 cyclin D1-negative tumors. The prevalence of p53 staining was higher in high-grade (P<0.05) and invasive types of tumors (P<0.05) than the other types studied. On the other hand, no significant relationship was found between cyclin D1- or pRb-immunoreactivity and clinicopathological factors. These findings provide evidence for infrequent cyclin D1 protein overexpression in TCC independently associated with p53 protein and/or pRb overexpression. PMID- 21590020 TI - High incidence of Helicobacter pylori infection detected serologically in the residual stomach caused by gastric cancer. AB - Helicobacter pylori (HP) may be involved in the pathogenesis of chronic gastritis, gastric ulcer and intestinal-type gastric cancer. In the present study, we detected HP infection serologically after gastric surgery by measuring the serum anti-HP IgG levels and determining their correlation with the serum gastrin levels. The HP-infection rate after distal gastrectomy was 81.5% (75/92), which was higher than that after total gastrectomy 17.2% (5/29). The serum gastrin levels after distal gastrectomy were within the normal range and there was no significant correlation between the serum gastrin level and serologically detected HP infection, nor between the number of days after distal gastrectomy and HP infection. The high HP infection incidence after distal gastrectomy was confirmed serologically and endoscopically, suggesting HP infection plays some role in the superficial gastritis of the residual stomach without correlating with the serum gastrin levels. PMID- 21590021 TI - Prognosis of patients with primary epithelial ovarian carcinoma who were not successfully cytoreduced. AB - The aim of this study was to determine prognostic factors of patients with advanced ovarian carcinoma who were not successfully cytoreduced at first surgery. Twenty patients with incomplete initial cytoreduction surgery (12 patients with stage IIIc and 8 patients with stage IV), were analyzed for prognostic factors. The survival time of 13 patients with second reduction surgery (SRS) was significantly (P<0.005) longer than that of 7 patients in whom SRS was not applicable. According to the histologic types, the survival time of patients with serous cystadenocarcinoma or endometrioid adenocarcinoma was significantly (P<0.0001) longer than that of patients with clear cell carcinoma, mucinous cystadenocarcinoma or undifferentiated carcinoma. Size of residual tumor after SRS was correlated with response to combination chemotherapy consisting of cyclophosphamide, epirubicine and cis-diamminedichloroplatinum (II) (CAP therapy). The survival time of patients with less than 2 cm residual tumor after SRS was significantly (P<0.05) longer than that of patients with 2 cm or more residual tumor after SRS. Patients in whom CA125 normalized in response to CAP therapy after first surgery had less than 2 cm residual tumor after SRS and survived longer, compared to patients in whom CA125 did not normalize. These results suggest that even if initial cytoreduction surgery failed, patients with good response to CAP therapy and less than 2 cm residual tumor after SRS can be expected to have relatively good prognosis. PMID- 21590022 TI - The increase of apoptosis and the decrease of proliferation by angiogenesis inhibitor in rat mammary tumors. AB - We have investigated the change of balance between proliferating and apoptotic tumor cells in dimethylebenz(a)-anthracene (DMBA)-induced rat mammary tumors by using anti-angiogenic drug, AGM-1470 and anticancer drug, 5'-deoxy-5 fluorouridine (5'-DFUR). The rate of PCNA positive proliferating cells was decreased in the tretment groups, especially in AGM-1470 and in the combination of AGM-1470 and 5'-DFUR. And apoptotic index evaluated by TUNEL method was increased in 5'-DFUR and in the combination group. The ratio of proliferating cells/apoptotic cells was markedly decreased in AGM-1470 and AGM+5'-DFUR group compared to control group. These data suggested that anti-angiogenic drugs might regulate the growth behavior of tumor cells by changing the microenvironments. PMID- 21590023 TI - The 67 kD laminin-receptor in high and low metastatic melanoma cell lines. AB - Four melanoma cell lines with different metastatic potential were used to study the expression of 67 kD laminin receptor (LnR) gene by traditional immunohistochemistry and polymerase chain reaction techniques. Intensive labeling of LnR protein was found in cells with high metastatic potential. Also, the result from PCR and RT-PCR proved the correlation between LnR gene and metastatic potential of melanoma cells in addition to other cell types from previous studies. It is, thus, suggested that the expression of LnR gene can be used as an early marker for the malignancy of melanoma cells. PMID- 21590024 TI - Comparison of effectiveness between chemotherapy alone versus chemo-radiotherapy in stage III non-small cell lung cancer. AB - Combined chemotherapy with radiotherapy has been claimed to be superior to radiotherapy alone in stage III non-small cell lung cancer (NSCLC). The present study was designed to give chemo-radiotherapy with 300 cGy only on the day the cytotoxic drugs are administered. The aim was to exploit the cell cycle synergism between the two treatments. Forty-five patients of stage IIIA+B with inoperable NSCLC were randomized in two groups. Group A to be treated with chemotherapy only and group B to be treated with chemotherapy plus radiotherapy. Drugs for group A were: cisplatinum 90 mg/m(2), vindesine 3 mg/m(2) and epirubicin 40 mg/m(2) once every 3 weeks for 8 courses. Group B: cisplatinum 60 mg/m(2), vindesine 3 mg/m(2) and epirubicin 30 mg/m(2) plus 300 cGy radiation, every two weeks for 8 cycles. Then, estimation of response was done. Toxicity was tolerable. In group A the response rate was 52%, in group B 90% (partial and complete). The difference was statistically significant. Additional radiotherapy up to 5,400 cGy was given in patients of group B while patients of group A had palliative radiation on recurrence. Survival rate was significantly longer for patients of group B. PMID- 21590025 TI - Cystosarcoma phyllodes of the breast. AB - Forty-nine patients with cystosarcoma phyllodes (CP), aged 13-81 years, (mean 35.2 years) were studied. Tumor size ranged from 1.9 to 14 cm (mean 5.2 cm). Mean follow-up period was 11.3 years. Tumors were histopathologically graded as benign, borderline or malignant. Forty-two tumors were diagnosed as benign; 4 borderline and 3 malignant. Six patients had recurrent disease within 6 years of their first surgery. Statistical analysis showed that age was not a significant factor for predicting recurrence or malignant histopathology. Five patients with relapse had borderline or malignant tumors larger than 4 cm. The histopathologic diagnosis was concordant with the clinical course. Multivariate analysis showed that tumor size and histology were significant and independent factors for disease-free interval. Breast-conserving surgery with a wide tumor-free margin is preferred in CP, and close follow-up is advised in cases with malignant or borderline histopathology and tumors larger than 4 cm. PMID- 21590026 TI - Paclitaxel (taxol) in pretreated, relapsed and/or metastatic adult soft tissue sarcomas (STS). AB - Twelve patients suffering from recurrent or metastatic, previously treated, STS were given paclitaxel as a 3-hour infusion, with prophylactic medication, in 3 week cycles, at two different dosages: 135 mg/m(2) or 175 mg/m(2) in patients pretreated with less than or equal to 2 or greater than or equal to 3 chemotherapy regimens, respectively. A total of 39 courses was given (median 3, range 2-5). Overall, treatment was relatively well tolerated, major toxicity consisting of grade 2-3 neutropenia (33%); The adopted schedule was feasible in day-hospital setting, with satisfactory patient compliance. Only a partial response was obtained (8%), lasting 4 months; six patients had stable disease and five progressed while on treatment. Our results suggest a lack of activity of paclitaxel in this tumor type. However, the very advanced stage of disease and the strong pretreatment in the evaluated series probably partially account for some of the resistance and such a poor response rate. Further studies might be appropriate with paclitaxel, alone or in combination with other agents, on selected patients in less advanced stage of disease. PMID- 21590027 TI - Rare activation of ras oncogenes in radiation induced rat skin tumors. AB - We examined a large panel of radiation induced rat skin tumors for activation of the H- or K-ras oncogenes. Using oligonucleotide hybridization analysis of tumor DNA we found that only 1 out of 96 tumors tested had an activated K-ras gene, and none of the 78 tumors examined for H-ras mutations were positive. Tumors were induced by high and low LET, and included lesions of various sizes and histologic type. DNA sequencing of tumors and NIH3T3 transfectants from a previous study gave results consistent with a rare occurence of ras activation in this system. PMID- 21590028 TI - Interleukin-2 (IL-2) gene therapy with allogeneic fibroblasts in the CT-26 model of murine colorectal carcinoma. AB - We previously demonstrated the efficacy of a genetically engineered vaccine composed of syngeneic tumor cells mixed with syngeneic, IL-2 gene transduced fibroblasts in the CT-26 model of murine colorectal carcinoma. In this report, we describe a more practical approach to fibroblast mediated IL-2 gene therapy that employs syngeneic tumor cells mixed with allogeneic, IL-2 gene transduced fibroblasts. BALB/c mice were challenged with an injection of CT-26, 14 days following immunization with IL-2 modified syngeneic BALB/c 3T3 (H-2(d)) or allogeneic C3H 3T3 (H-2(k)) fibroblasts mixed with irradiated CT-26. Both syngeneic and allogeneic IL-2 modified fibroblasts provided significantly better protection compared to animals treated with control fibroblasts (syngeneic IL-2 fibroblasts 32/40-80% vs. control 15/45-33%, p<0.01; allogeneic IL-2 fibroblasts 25/37-68% vs. control 15/45-3345, p<0.01). There was no statistically significant difference between the groups immunized with syngeneic or allogeneic IL-2 modified fibroblasts. These findings support the evaluation of allogeneic IL-2 modified fibroblasts as a practical form of cytokine gene therapy for cancer. PMID- 21590030 TI - Chemotherapy with DMXAA (5,6-dimethylxanthenone-4-acetic acid) in combination with CI-1010 (1H-imidazole-1-ethanol,alpha-[[(2-bromoethyl)amino]methyl]-2-nitro ,mon o-hydrobromide (R isomer)) against advanced stage murine colon carcinoma 26. AB - Because an enhanced therapeutic gain might be expected with co-administration of a hypoxic cell selective cytotoxin and a compound that induces hemorrhagic necrosis in tumors, the combination of CI-1010 (a potent bioreductive hypoxia selective cyto toxin) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) has been evaluated against advanced stage (>150 mg) murine colon carcinoma 26 (C26). CI 1010 and DMXAA were administered intraperitoneally over a range of toxic to ineffective doses as single agents and in combination to adult BALB/c x DBA/2 F1 hybrid mice bearing s.c. implants of C26. Both CI-1010 and DMXAA were ineffective as single agents, but regimens combining these two agents were highly active. The administration of DMXAA at 20 mg/kg/inj on days 9, 13, and 17 and CI-1010 at 65 mg/kg/inj on days 9-17 resulted in 60% of the animals tumor free on day 92 of the study. The remaining animals that were not tumor free survivors achieved a delay in tumor growth of 22.4 days. However, this treatment regimen was also considered toxic resulting in 2/10 treatment related deaths. Modification of the CI-1010 treatment schedule to intermittent delivery 24 h after each scheduled dose of DMXAA reduced treatment related toxicity while retaining efficacy. On this schedule the combination of CI-1010 (95 mg/kg/inj) given 24 h after DMXAA (20 mg/kg/inj) on days 9, 13, and 17 resulted in 60% of the treated animals tumor free on day 98 of the study. Treatment failures experienced a tumor growth delay of 11.6 days. Combination chemotherapy with CI-1010 and DMXAA was ineffective when DMXAA was administered 1 h prior to CI-1010, simultaneously with CI-1010, or 1 h after the administration of CI-1010. These results suggest that an enhanced therapeutic interaction between CI-1010 and DMXAA is achievable in vivo and that this interaction requires the development of substantial DMXAA induced tumor hypoxia prior to administration of CI-1010. PMID- 21590029 TI - Prevention of skin tumors induced by 7,12-dimethylbenz(a)anthracene in mice by black seed oil. AB - The effect of topical application of black seed oil on 7,12 dimethylbenz(a)anthracene (DMBA)-induced skin tumors in BALB/c mice was investigated. Topical application of chemically extracted oil (C.O.) and naturally extracted oil (N.O.) highly prevented the appearance of skin tumors in experimental animals. Skin tumors (papillomas and carcinomas) were initiated by application of 300 mu g DMBA (on days 1,8) followed by applying 0.5 mg croton oil, biweekly until the end of the experiment (25 weeks). The application of N.O. completely prevented the appearance of skin tumors in mice of group 3 versus a tumor incidence of 78.9% in animals of group 1 (carcinogenic control) (cc). Painting the skin of mice with C.O. (group 2) significantly reduced the tumor incidence to 14.2%. Moreover, a significant decrease was observed in number of mice bearing tumors, and number of tumors per mouse in group 2. Multiplicity was also decreased but insignificantly in the same group. The treatment with C.O. and N.O. insignificantly increased the rate of mice survival as compared to that of animals of group 1. PMID- 21590031 TI - Gestational trophoblastic disease in a fifty-one year old woman. AB - Molar pregnancy has always been of interest to physicians because of the diagnostic and management challenges it presents. Its occurrence in patients older than 50 years of age is rare and misdiagnosis is common. A 51 year old black female presented to the gynecology emergency room with vaginal bleeding for twenty days. She was diagnosed with a molar pregnancy by a pelvic ultra-sound. Prior to presenting to the emergency room she had a negative work-up for hyperthyroidism, including a biopsy of a benign thyroid nodule and was also started on Inderal for new onset hypertension. She underwent a primary hysterectomy and subsequently required five courses of actinomycin D for plateauing of the BhCG. The different forms of presentation of gestational trophoblastic disease should be kept in mind so that the diagnosis can be made promptly and appropriate treatment started early, especially in patients with advanced age. PMID- 21590032 TI - The effect of a single therapeutic dose of cisplatin on GFR in dogs. AB - This study prospectively describes the late effect of a single dose of cisplatin on GFR in tumor-bearing dogs. GFR (measured by quantitative renal scintigraphy), BUN, creatinine, and urine specific gravity values were obtained in 19 tumor bearing dogs prior to and four weeks after a single dose of cisplatin. Eleven tumor-bearing dogs were given a known non-nephrotoxic anticancer drug, dexniguldipine, as control. No significant differences in pretreatment GFR, serum chemistry, or urinalysis values were observed between cisplatin-treated and control dogs. GFR was significantly decreased four weeks following cisplatin administration. The average percent change in GFR was -13.49% for all cisplatin treated dogs. No significant alterations of BUN, serum creatinine, or urine specific gravity were observed following treatment. In the control group, the average percent change in GFR was +3.98% which was not significantly different from pretreatment values. PMID- 21590033 TI - Immunotherapy with low-dose interleukin-2 in association with melatonin as salvage therapy for metastatic soft tissue sarcomas. AB - Polychemotherapy represents the only standard medical therapy of metastatic soft tissue sarcomas (STS), whereas the recent biotherapies with cytokines, such as interleukin-2 (IL-2), seem not to have a relevant therapeutic role. The pineal hormone melatonin (MLT), whose immunomodulating activity is well known, would seem to exert a direct cytostatic action on STS cell proliferation. Moreover, MLT has been proven to amplify IL-2 efficacy. On this basis, a pilot phase II study with low-dose IL-2 plus MLT has been performed in untreatable metastatic STS patients. The study included 13 evaluable metastatic STS patients with poor PS, who progressed on at least one previous polychemotherapeutic line. IL-2 was injected subcutaneously at 3 million IU/day for 6 days/week for 4 weeks and MLT was given orally at 40 mg/day in the evening. A partial response was achieved in one patient with leiomyosarcoma. Eight other patients had a stable disease (SD) whereas the remaining 4 patients progressed. A survival longer than 1 year was achieved in 6/13 patients and the percent of 1-year survival was significantly higher in patients with response or SD than in the progressed ones (6/9 vs 0/4). Mean increases in lymphocyte and eosinophil numbers were significantly higher in patients with response or SD than in the progressed ones. These preliminary results would suggest that immunotherapy with low-dose IL-2 plus MLT may have some impact at least on the survival time of untreatable metastatic STS patients with poor clinical conditions. PMID- 21590034 TI - Frequent microsatellite instability in oral cancer. AB - In oder to confirm whether microsatellite instability (MI) contributes to oral carcinogenesis, we studied 30 unrelated patients with oral cancer by PCR-MI assay with 14 microsatellite markers. MI was detected in 60% of 30 primary tumors. Tn particular, 12 of these cases presented at least two loci with MI, which were considered as patients with replication error (RER). Moreover, an additional MI, which was not observed in the primary tumor and normal tissue, was observed in one lymph node metastasis. We found significant correlation between RER and lymph node metastasis. These results suggest that RER is a common event in the oncogenesis of oral cancer and may be correlated with the progression of this disease. PMID- 21590035 TI - Hepatic arterial infusion of the nitrosourea derivate fotemustine for the treatment of liver metastases from colorectal carcinoma. AB - The chloroethylnitrosourea derivate diethyl-1-(3-(2-chloroethyl)-3-nitroso ureido)-ethyl phosphonate fotemustine (FM) was investigated in a open monocentric clinical-pharmacological trial. Seventeen patients, with a median age of 57 years and progressive hepatic metastases from colorectal carcinoma received regional treatment with a stepwise dose-escalated regimen of FM to define the maximally tolerated dose. Thrombo- and leukocytopenia were dose-limiting with median nadir at day 29 (range, 19-79) and day 39 (range, 19-78), respectively. Local side effects in the liver were mild with only transiently elevated enzymes. No other severe side-effects, except pain (WHO grade III) in one patient after the infusion of FM was noted. The maximally tolerated dose was 125 mg/m(2)/day. Plasma profiles followed a mono-exponential law (one-compartment-model). Systemic concentrations measured as area under the time-concentration curve (AUG) indicated a short plasma half-life (t(1/2)=25.8+/-11.5 min) and a high body clearance (C-L=2.193+/-870 ml/min) with large inter- and intra-individual variations. Of fifteen evaluable patients examined with CT-scan, one complete, three partial, one minor response and seven patients with stable disease were observed [ORR=27%, IC95% (4.5-49.5%)]. In summary, hepatic arterial infusion of FM appears to be effective treatment for liver metastases from colorectal carcinoma. Considering the absence of mucositis/diarrhea and hepatic toxicity, FM could be explored as an alternative to 5-FUDR or 5-FU in previously untreated patients with isolated liver metastases. PMID- 21590036 TI - Sex hormones in patients with liver cirrhosis and hepatocellular carcinoma. AB - Sex hormones have been proposed to play an important role in promoting liver cancer transformation. The aim of our study was to evaluate changes in circulating levels of estradiol (EII), testosterone (T) and the EII/T relationship (ETR) in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) of viral origin compared with a group of healthy controls (C). The study population included 64 patients (41 M) mean age 62.5 years with HCC; 68 patients (41 M) mean age 61.3 years suffering from LC, while the C included 59 subjects (39 M) mean age 60.0 years recruited from voluntary blood donors. EII and T were assayed using the IEMA method; ultrasonography was performed using a Toshiba SSA 240 A scanner with a convex 3.75 MHz probe. Serum EII levels progressively increased from C to LC and HCC with statistically significant values (H=36.9, p<0.0001). Serum values of T progressively decreased from C to LC and HCC but the difference was not significant (H=3.84, p=ns). ETR values differed in the three groups, with a significant difference between C vs LC and HCC (p<0.0001). There was also a significant difference for EII, with values decreasing as the neoplasm dimension increased (p<0.04), and in particular there were differences between HCC <5 cm vs >5 cm (p<0.05). In contrast, ETR progressively increased as the diameter of neoplasm increased, but differences were significant only between <3 cm vs >5 cm (p<0.05). In conclusion, our data confirm that in LC and HCC there is an increase in serum EII levels, which can be important in the genesis of liver carcinoma. Progressive serum reduction in T may be due to increased androgen uptake and progressive accumulation within the neoplastic mass. Further studies are necessary to determine whether subjects with LC and elevated serum levels of estrogens are at higher risk of developing HCC. PMID- 21590037 TI - Expression of epidermal growth factor and its receptor in gestational trophoblastic diseases. AB - Gestational trophoblastic diseases (GTD) is an abnormal condition of the placenta, the incidence of which is very high in the State of Kerala, India. Placentae of normal (50) and molar pregnancy (122) including 52 showing persistent disease were used for the study. EGFR and EGF expression was analyzed by immunohistochemistry using monoclonal antibodies. EGF receptors were quantitated using the I-125 EGF-binding assay and that of EGF was quantitated using isotope labelled antibody to EGF. Tumours with histological diagnosis of invasive moles and choriocarcinoma showed very strong binding of both EGF and EGFR. The present observations also suggest the possibility of presence of mutated EGF receptors in persistent trophoblastic disease. PMID- 21590038 TI - Evaluation of outcome by race in early-stage non-small cell lung cancer. AB - Most studies of outcome by race in cancer have shown that blacks have a shorter survival compared to whites, both overall and within each TNM stage. We endeavored to evaluate the difference in survival by race in US military veterans treated for early stage non-small cell lung cancer (NSCLC). This retrospective analysis of overall survival by race, looking at all-cause mortality in a group of consecutively treated veterans with stage I-II NSCLC, was carried out at a 1,000-bed tertiary care Department of Veterans Affairs Medical Center. The study included 143 white and 45 black patients treated with curative intent for stage I II NSCLC between January 1982 through August 1994. Nineteen patients received radiotherapy alone for their treatment while the remaining 169 underwent a complete surgical resection. There were no significant differences in patient characteristics for important prognostic variables. An overall survival analysis of all-cause mortality found no significant difference between the two groups. With equal access to health care, as is available for eligible patients in Department of Veterans Affairs Medical Centers, racial differences in lung cancer treatment outcome may be diminished or eliminated. PMID- 21590039 TI - Interphase nucleolar organizer region distribution in the tissues of oral leukoplakia, oral submucous fibrosis and oral cancer. AB - The AgNOR technique, was applied to oral tissue sections of 185 oral cancer, 42 oral leukoplakia, 37 oral submucous fibrosis and 10 normal subjects to investigate whether any correlation held good in these different tissues. Compared to the AgNOR counts in normal oral epithelium, there was a gradation in increase in the mean AgNOR counts from oral leukoplakia to oral submucous fibrosis to oral carcinoma (P<0.01). This suggests that AgNOR count parallels with the degree of neoplastic transformation of oral epithelium. Three oral submucous fibrosis patients who showed very high AgNOR counts as that of oral cancer patients, later developed oral carcinoma. Among the oral cancer tissues, the moderately and poorly differentiated subtypes showed higher AgNOR counts and scattered distribution pattern than the well differentiated subtype which showed a clustered distribution pattern. These results suggest that AgNOR technique can be utilised as a diagnostic and prognostic indicator in premalignant and malignant oral tissues. PMID- 21590041 TI - Interference of papilloma viruses with p53-dependent and -independent apoptotic pathways. AB - Papillomavirus infection interferes with four distinct and dominant levels of intra- and intercellular control of oncogenesis, three of which are based on the induction of apoptosis. Papillomaviruses cause abrogation of the cellular senescence program and interfere with p53-dependent DNA repair or apoptosis triggered by DNA damage. As a result, spontaneous or induced mutations are not eradicated and the transformed state may be established through oncogene activation and tumor suppressor gene inactivation. The interference of papillomaviruses with a recently described p53-independent intercellular control step, in which nontransformed cells induce apoptosis specifically in their transformed neighbouring cells, allows survival of papillomavirus-expressing transformed cells. Finally, p53-dependent hypoxia-triggered apoptosis in microtumors may be overcome by papillomaviruses and thus lead to efficient and rapid tumor progression. PMID- 21590040 TI - Chromosome 13 poly(ADP-ribose) polymerase polymorphisms and lung cancer risk. AB - A 193 base pair repeat polymorphism in the human poly(ADP-ribose) polymerase (PADPRP) pseudogene found on chromosome 13 has been associated with lung cancer, endemic Burkitt lymphoma, B-cell lymphoma, breast cancer and colorectal carcinoma. We investigated the frequency of the PADPRP genetic polymorphism in a hospital-based case-control study of lung cancer for 54 cases and 47 controls. There was a statistically significant difference in allelic frequency between Caucasians and African Americans (p<0.001). For African Americans, the odds ratio for lung cancer and the 'B' allele was 2.38 (95% C.I.=0.73, 7.69) and for Caucasians 0.44 (95% C.I.=0.11, 1.77). The results for the African Americans, however, were not in Hardy-Weinberg equilibrium, although the Caucasians were. Thus, this study, albeit small, does not find that the PADPRP pseudogene duplicated region located on chromosome 13 is a risk factor for lung cancer. PMID- 21590042 TI - Increased polysomy 3 and 17 detected by fluorescence in situ hybridization (FISH) in oral squamous cell carcinoma. AB - Numerical chromosome aberrations were studied by fluorescence in situ hybridization (FISH) using pericentromeric DNA probes specific for chromosomes 3 and 17 in 18 oral squamous cell carcinomas (SCCs) and 3 lymph nodes as control. Disomy 3 and 17 was detected in approximately 90% of control cells, and in 60.9 +/- 4.0% and 62.7 +/- 3.6% of SCCs, respectively. Polysomy 3 and 17 significantly increased in SCCs when compared to controls. The pattern of chromosome aberrations varied considerably between cases. There was no obvious relationship between the degree of polysomies and clinicopathological factors such as tumor differentiation, stage of the disease and clinical outcome. Chromosome aberrations by FISH did not correlate with DNA aneuploidy by flow cytometry. Our results indicate that oral SCCs are more frequently associated with the increased copy number of chromosomes 3 and 17 than previously thought, and that a correlation between chromosome aberrations by FISH and DNA aneuploidy by flow cytometry is not obvious. PMID- 21590043 TI - Surgical technical details improving sentinel node identification in breast cancer. AB - Between January and July 1996, 50 females underwent a sentinel axillary lymphadenectomy with intraoperative lymphatic mapping for breast cancer. The blue stained lymph node was focused in 39 of 51 (76.5%) procedures. The mapped sentinel lymph node identified the axillary nodal status in 92.3% (36/39) of cases. Histologic metastasis in the sentinel node was focused in 41% (16/39) and in 50% (8/16) the blue stained sentinel node was solely invaded. The overall sensitivity of the procedure was 84% and the specificity 100%. The authors stress the importance of surgical details to improve the sentinel node identification and the development of this new minimally invasive alternative, especially in small-sized breast carcinomas. PMID- 21590044 TI - Immunohistochemical detection of nm23-H1/NDP kinase in childhood thyroid carcinoma. AB - Childhood thyroid cancer is known to be aggressive. High incidence of lymph node and distant metastasis are characteristic features of these cases. In adult, reduced expression of nm23-H1/nucleoside diphosphate (NDP) kinase has been correlated with cancer invasion and metastasis in some tumor types. Therefore, we examined the expression of nm23-H1 gene product in childhood thyroid carcinomas in Japan. 27 primary thyroid carcinomas and 8 metastatic lymph nodes were analyzed by immunohistochemistry using monoclonal antibody H1-229. 21 out of 23 cases (91%) of papillary carcinomas were positively immunostained, whereas none of the 4 follicular carcinomas showed any immunoreactivity. No correlation was found between the nm23-H1/NDP kinase antigen expression and nodal involvement or distant metastasis in primary tumors. However, only 50% (4 out of 8) of metastatic lymph nodes from papillary carcinoma were positively stained, demonstrating a significant decrease comparing to those of primary sites. These data indicate that the expression of nm23-H1/NDP kinase cannot predict tumor metastatic potential in childhood thyroid cancer. PMID- 21590045 TI - Mediterranean and immunodeficiency associated Kaposi's sarcoma - Does micromorphology reflect clinical patterns? AB - Kaposi's sarcoma (KS) follows a different clinical course in Mediterranean and immunodeficiency related cases and has a poorer prognosis in the latter. We investigated 40 patients with Mediterranean and eight with immunodeficiency related KS by histomorphology and immunohistology in comparision to the clinical presentation in order to identify characteristic patterns distinctive for each of these KS forms. We also evaluated oncoprotein activation and phosphotyrosine activity. Tissue sections were stained with hematoxylin-eosin (H&E), Mallory's phosphotungstick acid hematoxylin (PTAH), Hotchkiss-McManus' periodic acid - Schiff reaction (PAS), Masson's trichrome, Pinkus' orcein-Giemsa, Lapham's method for myelin, Bielschowski-Gomori's silver impregnation for reticular fibres, Bodian's silver impregnation for neurofibrils, and Wartin-Starry silver impregnation for fungi and bacteria. Immunohistochemistry was performed on deparaffinated sections using the microwave technique with avidin-peroxidase and 3-amino-ethyl-carbazole for alpha smooth muscle actin, CD34, phosphotyrosine, p53, and bcl-2. Mediterranean KS was characterized by pseudocapsule formation around nodules, which has been lost in immunodeficiency related KS. The latter, additionally, showed outstanding infiltrative growth with lace-like involvement of subcutaneous fat, colonization of perineuronal-periadnexal adventitial dermis, irregular vascular lacunae encircling vessels and/or adnexa, collections of histiocytoid-like cells, intravascular papillary projections of atypical endothelia cells. Both types could further be characterized by presence of alpha smooth muscle actin and CD34 expressing cells, high levels of phosphotyrosinase in plump spindle cells and variable expression of p53, sometimes coexpressed with phosphotyrosinase indicating cellular activation. The oncoprotein bcl-2 was not detected in this tumor material. The particular clinical features of Mediterranean and immunodeficiency related forms of KS may be reflected, at least in part, in characteristic histomorphological findings. PMID- 21590046 TI - The expression of MDM2 and p53 protein breast carcinoma. AB - We studied the expression of MDM2 protein and p53 protein in 67 cases of the breast carcinoma. The result demonstrated no significant relationship between the MDM2 protein expression and any of the clinicopathological parameters except for the estrogen receptor status (p=0.033). Furthermore, in p53 protein negative cases, there was a significant relationship between MDM2 protein expression and the ER status (p=0.027). This study showed the expression of ER to be associated with MDM2 protein in p53 protein negative breast carcinoma. These results thus suggested that an investigation of both p53 and MDM2 gene alteration revealed precise information regarding breast carcinoma. PMID- 21590047 TI - p53 protein expression in adenoid cystic carcinoma of the head and neck. AB - Forty-one adenoid cystic carcinomas were investigated retrospectively with the polyclonal antibody CM-1 against the p53 protein and the results compared with clinicopathological parameters and the proliferative activity estimated by Ki-67 expression. p53 acted as a significant explanation variable in simple linear regression with Ki-67 as the dependent variable (r=0.39, p<0.02). High p53 expression was observed in tumors with violated margins during primary surgery. No significant correlations were demonstrated with other clinicopathological parameters or treatment outcome. Alterations in the p53 gene may be responsible for increased proliferative activity in the tumors, but elevated antigen expression has little prognostic value. PMID- 21590048 TI - Correlation between human papillomavirus infection and clinicopathological parameters in anal canal carcinoma. AB - We evaluated human papillomavirus (HPV) DNA in 17 anal canal tumors and its correlation with symptomatology, tumor extension and prognosis. Five squamous carcinomas and 4 cloacogenic tumors resulted HPV+. Statistical analysis showed no correlation between HPV infection and tumor morphology, lymph node involvement or prognosis, and no significant difference in the duration of symptoms between HPV+ and HPV- patients. HPV are involved in the pathogenesis of the tumors, but are not responsible for an increased neoplastic malignancy. Anoscopy with brushing or biopsy is a suitable screening method to identify HPV. PMID- 21590049 TI - The clinical implications of glutathione S-transferase-pi expression in lung cancer. AB - We performed immunohistochemical staining of glutathione S-transferase-pi (GST pi) in 97 lung cancer specimens. In untreated patients, 86% (48/56) of NSCLC and none (0/8) of SCLC stained for GST-pi, and all squamous cell carcinomas were positive (28/28). The proportion of positive NSCLC with preoperative chemotherapy was similar to that of the untreated NSCLC, but the proportion of treated SCLC positive for GST-pi (14/18) was significantly higher than untreated tumors. GST pi in NSCLC may be a tumor marker rather than being involved in drug resistance, and GST-pi-induction by chemotherapy may relate to acquired resistance in SCLC. PMID- 21590050 TI - p53 nuclear accumulation in preneoplastic lesions and stage I uterine endometrioid adenocarcinoma. AB - A total of 118 endometrial neoplastic and preneoplastic lesions comprising 43 uterine endometrioid adenocarcinoma at stage I, 40 complex (adenomatous) hyperplasias and 35 atypical hyperplasias were examined for p53 nuclear accumulation to assess the incidence of p53 alterations in infiltrating carcinomas and to verify if p53 aberrations may allow the identification of a subset of premalignant cases with high risk of progression. No specific immunostaining was observed in the cases of complex hyperplasia without atypias. One (3%) of 35 atypical hyperplasias showed focal areas of p53 immuno-reactivity. The overall frequency of p53 overexpression in endometrial carcinomas was 54%. The distribution of cases with nuclear accumulation of p53 was significantly different (p=0.01) in tumours with different degree of invasiveness. In addition, p53 nuclear accumulation was observed more often in tumours with moderate (G2) or poor differentiation (G3) (p=0.03). Our data indicate that p53 aberrations are not early events in endometrial carcinogenesis and may be related with tumour progression and aggressiveness. PMID- 21590051 TI - Lactation, lactation suppression hormones and breast cancer. AB - One hundred and fifty-four parous women with pathologically confirmed newly diagnosed breast cancer in National Taiwan University Hospital were selected as the case group. Three hundred and eighty-six parous inpatient controls were individually matched for each case by age and date of admission. Information was collected from questionnaire interview and medical record. Effects of lactation and lactation suppression hormone were assessed with conditional logistic regression analysis. In univariate analysis, lactation had a weak protective effect, after adjusting for educational level, body mass index, family history of breast cancer, reproductive factors, oral contraceptive and lactation suppression hormone use, the weak negative associations changed to weak positive ones. The use of lactation suppression hormone was consistently associated with a higher breast cancer risk. The major confounders between lactation and breast cancer risk were parity and age at first full-term birth. Lower breast cancer risks were found in high parity - long lactation, and in younger ages at first full-term birth - long lactation groups. The differences among different lactation lengths within each parity and age at first full-term birth category were small. The protective effects disappeared after adjusting for other potential confounders. The results of this study questions the independent protective effect of lactation in a population having both a variable duration of lactation and rapid socioeconomic change. The role of lactation suppression hormones needs further study. PMID- 21590052 TI - Breast cancer. AB - Seasonal variation has been demonstrated in connection with several aspects of primary breast carcinoma. This report describes a seasonal variation in the growth of breast carcinoma in the axillary nodes that has not been reported previously and has prognostic implications. The nodes from a series of 301 node positive breast cancer patients were investigated prospectively for the presence/absence of tumour cells in their efferent lymphatic vessels, the former being of poor prognosis. Their presence, i.e. positive EV-status, is common in nodes with established tumour growth. Many more patients coming to operation in the first 6 months of the year showed such findings, while more of negative EV status were found in the second half (chi(2)=13, P<0.0005). Positive EV-status was, as expected, associated with poor prognosis relative to EV-negative (chi(2)=14). Its prognostic impact did not alter with season. It may be of note that seasonal variation in the arrival of micrometastases at the nodes has also been reported recently. These two phenomena may have a common pathogenesis. PMID- 21590053 TI - Effects of gelonin immunoconjugate of monoclonal antibody MSN-1 to endometrial adenocarcinoma on antigen-producing tumor cells in vitro. AB - Missile therapy, which destroys cancer cells specifically, has been considered to be an effective modality for treatment of carcinoma. We have developed a monoclonal antibody MSN-1 (immunoglobulin class: IgM), of which the immunogen is the endometrial adenocarcinoma cell line SNG-II, which strongly reacts with endometrial adenocarcinomas. We describe an immunoconjugate consisting of the MSN 1 and a plant hemitoxin named gelonin which has revealed to assume selective cytotoxicity against the SNG-II in a colony formation assay in vitro. The results of our study suggest that the 'inhibitory concentration' or IC50, of the MSN-1 gelonin immunoconjugate against the SNG-II was 188 fold that of gelonin alone. These results indicated that the MSN-1-gelonin immunoconjugate exhibited highly selective cytotoxicity to endometrial adenocarcinoma, which expressed an epitope against the MSN-1, and it is suggested that the MSN-1-gelonin immunoconjugate has possibility of clinical application to treatment of endometrial adenocarcinomas. PMID- 21590054 TI - Immunogenicity of the hydrophilic region of the MUC1 mucin protein core. AB - This report is an analysis of data relating to the epitopes of 28 murine monoclonal antibodies reactive with the protein core of human carcinoma associated MUC1 mucins. All anti-MUC1 antibodies define epitopes of linear sequences of 3, 4 or 5 amino acids within the hydrophilic domain, APDTRPAP, which is expressed multiple times in a highly conserved 20 amino acid repeat sequence of the MUC1 core. The R residue is present in the epitopes defined by all of the 28 anti-MUC1 monoclonal antibodies. Epitopes of antibodies originally prepared against immunogens containing human milk fat globule membranes include the motif DTR in over 90% of the examples studied. PMID- 21590055 TI - Effects of highly purified anthraquinoid compounds from Aloe vera on sensitive and multidrug resistant leukemia cells. AB - Folk medicine has attributed antitumor properties to preparations from Aloe vera. We have studied the effects of five purified compounds from the plant on human K562 leukemia and on its multidrug resistant (MDR) variant, K562/R. The glycosides aloin A and B, aloesin and aloeresin were devoid of antitumor activity up to 200 mu M concentrations. Only the aglycone aloe emodin produced reproducible antitumor effects, which, interestingly, were more pronounced in the MDR, P-glycoprotein overexpressing, cell line. Its IC50 was in fact 29 mu M in K562 and 10.5 mu M in K562/R. Aloe emodine caused mainly cytostasis and accumulation of the cells in the S and G(2)-M phases of the cell cycle during the first 48 h of treatment. Thereafter, massive cell death ensued. Research on the antitumor activity of compounds extracted from Aloe vera probably deserves continuation. PMID- 21590056 TI - Combination of CPT-11 with cisplatin as first-line chemotherapy in advanced epithelial ovarian cancer. AB - As CPT-11 was shown to be efficacious in recurrent ovarian cancer, a phase II trial has been undertaken at a recommended dose determined in the phase I trials of combination therapy of CPT-11 with cisplatin (CDDP). As first-line chemotherapy, 60 mg/m(2) of CPT-11 (on days 1, 8, and 15) and 60 mg/m(2) of CDDP (on day 1) were intravenously administered to patients with epithelial ovarian cancer with residual lesions larger than 2 cm, and patients who underwent exploratory laparotomy. Case 1 and 2 achieved CR and PR after completion of the first and second courses, respectively. After the third course when CA125 values turned negative, secondary cytoreductive surgery was performed in both cases, and the tumor was completely extirpated. Dose limiting toxicity was neutropenia, which was managed by administration of granulocyte stimulating factor or by skipping the administration of CPT-11. In Case 2, the number of platelets decreased with repetition of the courses. Grade 3 or worse diarrhea was not observed. The combination therapy of CPT-11 with CDDP is considered to be safe and efficacious in treatment of epithelial ovarian cancer. PMID- 21590057 TI - Clinical significance of serum c-erbB-2 protein in patients with primary breast cancer. AB - We measured serum c-erbB-2 protein concentration in 167 patients with primary breast cancer. The rate of positive results was 6%. The positivity rate of serum c-erbB-2 protein did not differ among stages I, II, IIIa and IIIb. However the positivity rate on stage IV was 50% (3/6) and significantly higher than the other stages (p=0.0006). The rate of;positive results correlated significantly with lymph node status (p=0.0037). We concluded that the level of serum c-erbB-2 protein reflected the malignant characteristics of primary breast cancer and its measurement may be useful for a preoperative evaluation of primary breast cancer. PMID- 21590058 TI - Lung cancer angiogenesis. AB - Recent advances in our understanding of angiogenesis in solid tumor growth and metastasis has also led to intense investigation of angiogenesis and its clinical significance in lung cancer. This investigation has shown that angiogenesis is an important prognostic indicator for lung carcinoma and will become increasingly important when investigating new therapies aimed at inhibiting the formation of new blood vessels or targeting the tumor vasculature. PMID- 21590059 TI - Detection of p53 mutations in gynecologic tumors by means of a simple, nonradioactive minigel method of PCR-SSCP analysis. AB - We studied 22 gynecological tumors for mutations in exons 5 through 8 of the p53 gene by means of SSCP analysis, using a simplified, nonradioactive technique developed at our laboratory. In order to test the procedure, we carried it out in parallel with the usual radioactive one. Two coincident mutations (in exons 5 and 8) were found by means of both methods. However, an additional one in exon 6 was found by means of our nonradioactive technique. This simplified method for SSCP analysis of the p53 gene in human tumors is faster, easier and cheaper to perform than the conventional radioactive method, and yields equivalent results. It could be thus an excellent candidate for routine use in the clinical setting. PMID- 21590060 TI - Effect of specific activity on neuroblastoma uptake of I-123-meta iodobenzylguanidine in nude mice xenografted with SK-N-SH cells. AB - The effect of specific activity of meta[I-123]iodobenzylguanidine ([I-123]MIBG) on neuroblastoma uptake was studied in a nude mouse model (NMRI nu/nu) xenografted subcutaneously with SK-N-SH cells. Groups of eight animals received [I-123]MIBG intravenously with a specific activity of greater than or equal to 260 GBq/mu mol (no-carrier-added), 3.7 GBq/mu mol, 37 MBq/mu mol, and 0.37 MBq/mu mol, respectively. All animals in the group injected with 0.37 MBq/mu mol died immediately after the injection. Al 4 and 24 h, there was no significant effect of specific activity on tumor uptake of [I-123]MIBG in the different groups. The uptake of non-tumor tissue was in general lower with 37 MBq/mu mol compared to higher specific activities. The differences in blood, heart, liver, spleen and lungs were statistically significant at 24 h, whereas at 4 h significant differences were only present in the heart, liver and lungs. The results suggest that for the treatment of children with neuroblastoma a lower specific activity of radioiodinated MIBG may minimize the radiation exposure to non-tumor tissue but not to the tumor. Higher mass of MIBG >0.5 mu mol/g, however, is considered as lethal dose in our nude mice model and corresponding doses may cause toxic side effects in human. PMID- 21590061 TI - Novel sequence tagged sites from the human 8p12-p21 chromosomal region involved in breast cancer. AB - Seventeen sequence-tagged sites (STSs) from the human 8p12-p21 chromosomal region were identified in a subset of nonchimeric yeast artificial chromosomes (YACs). YAC ends were cloned, sequenced and a PCR primer pair was designed for each of the STSs thus generated. STSs were mapped by means of PCR on somatic cell hybrids specific for chromosome 8. These STSs will contribute to the construction of physical, high-resolution genetic and transcriptional maps necessary to clone potential tumor suppressor genes of the 8p12-p21 region involved in breast cancer. PMID- 21590062 TI - The relationship between the epidemiological and hormonal aspects of 6 human neoplasias - An introduction to the concept of steroid carcinogenesis. AB - The purpose of the present study is to test the validity of our steroid carcinogenesis hypothesis that the outer environment is conditioning the risks of various human neoplasias by sending carcinogenic signals to their target tissues by way of the steroid generating system (the gonads and the adrenal). Practically, we attempted a case-control study for each of the 6 human neoplasia types as regards the excretions of 14 urinary steroids. From both mathematical and endocrinological reasons, case-control comparison was carried out by use of 13 log-transformed steroid ratios in place of 14 original steroid excretion data. The urinary steroid deviation profile was prepared for each of the 8 cancer populations in such a way as to include 13 t-values of the Student's t-test with the above 13 steroid parameters. The names and sizes (in parenthesis) of the normal- and cancer-populations used in this study are, given as follows: a) the male normal group (n=104); b) the female normal group (n=127); c) the female breast cancer group (n=245); d) the cervical cancer group (n=345); e) the endometrial cancer group (n=68); f) the ovarian cancer group (n=160); male gastric cancer group (n=421); h) the female gastric cancer group (n=615); i) the male esophageal cancer group (n=434); j) the female esophageal cancer group (n=123). The regression analysis technic was employed for the pattern analysis of the urinary steroid deviation profiles of the 8 cancer populations. The hormonal data were collated with the epidemiological data for each tumor population. The results obtained are as follows: a) the urinary steroid deviation profiles of 8 cancer populations were highly specific and were distinguishable from one another at the young age (20 years). The above specificities of the hormonal traits of the 8 cancer populations decreased with the progression of host age in the order of the young age, the middle age (40 years) and the old age (60 years). b) Evidence was presented to indicate that the difference of the hormonal trait between the male- and female-esophageal cancer groups was to be classified as qualitative, whereas the inter-sex difference of the hormonal trait of 2 gastric cancer populations was quantitative rather than qualitative, c) A parallelism between the epidemiological- and hormonal data of the 8 cancer groups was observed in that 3 high-morbidity cancer populations (the female breast cancer group and the gastric cancer groups of both sexes) were distinguished from other low morbidity cancer populations by their relative stability of both the steroid deviation pattern and the amplitude of steroid deviation. The significance of the observed findings was discussed with special emphasis on their relevance to the steroid carcinogenesis hypothesis in the light of recent information from our and other laboratories. PMID- 21590063 TI - Vascular endothelial growth factor expression correlates with hematogenous metastasis and prognosis in colorectal carcinoma. AB - We investigated the expression of vascular endothelial growth factor (VEGF) in 175 colorectal carcinomas by immunohistochemistry. VEGF expression was correlated with advanced TNM stage (III, IV), advanced T stage (T3, T4), vessel involvement, lymph node metastasis, and liver metastasis. With regard to the prognosis, both overall and relapse-free survival was significantly poorer, and furthermore, the hematogenous recurrences were significantly more commonly found in the patients with VEGF-positive tumors. VEGF expresion in colorectal carcinomas may have a substantial value in predicting those patients at high risk for hematogenous recurrence after surgery. PMID- 21590064 TI - Duodenal carcinoid tumor resected by strip biopsy. AB - The patient was a 56-year-old male in whom gastroscopy during a health check-up revealed a protruding lesion on the anterior wall of the duodenum. Biopsy was performed, examination of the specimen yielded a diagnosis of carcinoid tumor, and the patient was referred to our hospital. Two-channel endoscopy demonstrated a 4-mm-diameter tumor. The tumor together with normal tissue surrounding it was resected by the strip biopsy method. Strip biopsy is a type of endoscopic mucosal resection that appears to be an excellent technique for reliable and complete tumor removal. PMID- 21590065 TI - Microsatellite instability in Japanese colorectal carcinoma. AB - Recent studies have shown that microsatellite instability (MSI) play an important role in the development of various types of cancer. To clarify the clinicopathologic significance of MSI in colorectal carcinoma (CRC), the presence of MSI was examined in 54 Japanese cases of CRC using the polymerase chain reaction-based method. The incidence of MSI in CRC cases was 13 out of 54 cases (24%). CRC with MSI also showed a significant tendency not to have lymph node metastasis (P<0.05), although neither the survival nor the prognosis of the cases examined in this study were available due to the short period of follow-up. The present study showed that the incidence of MSI in Japanese CRC was 24% and suggests that CRC with MSI may behave in a less malignant manner. PMID- 21590066 TI - Evaluation of DNA polymerase beta gene mutation as a genetic marker for colorectal carcinoma. AB - DNA polymerase beta is known to be involved in repair of DNA damage. Frequent mutation of its gene in the segment encoding amino acids 149-297 has been reported in colorectal cancer. To investigate whether mutation in this region is available as a genetic marker for colorectal cancer, 11 primary tumors and 4 liver metastases from 11 patients were examined by fragment length analysis and single-strand conformation polymorphism (SSCP) analysis of reverse-transcription polymerase chain reaction (RT-PCR) products. Although allelic imbalance in the p53 and DCC genes were observed in ten out of eleven primary tumors and all liver metastases using a dinucleotide repeat polymorphism, mutation was not detected in the DNA polymerase beta mRNA. Neither was it detected in seven colon cancer cell lines. Present results suggest that mutation in this region is uncommon in colorectal cancers and is not a useful genetic marker for colorectal cancer. PMID- 21590067 TI - Chemotherapy of human alpha-fetoprotein-producing gastric carcinomas grown in nude mice. AB - We have examined the effects of chemotherapeutic drugs on tumor growth and metastasis of human alpha-fetoprotein-producing gastric carcinoma (AFPGC) xenografts growing in nude mice. These xenografts consisted of 3 hepatoid adenocarcinomas and 2 non-hepatoid, poorly differentiated adenocarcinomas. Mitomycin C and cisplatin inhibited the tumor growth and liver metastasis of hepatoid adenocarcinomas in nude mice. 5-fluorouracil also inhibited the growth of hepatoid adenocarcinomas but did not exhibit a significant antimetastatic action. Doxorubicin was effective only against non-hepatoid adenocarcinomas. These results indicate that chemotherapeutic drugs for AFPGC should be used according to the subtype of the tumor. PMID- 21590068 TI - The expression of E-cadherin as a prognostic factor in breast cancer. AB - We examined the clinical significance of E-cadherin expression in 98 patients with breast cancer. E-cadherin expression significantly correlated with histologic grade (p=0.0323) and tended to correlate with the absence of axillary lymph node metastases (p=0.0646). The expression of E-cadherin was associated significantly with the recurrence rate (p=0.0334) and marginally associated with disease-free (p=0.0597) but not overall survival, in univariate analysis. The association between E-cadherin expression and disease-free survival was lost in multivariate analysis. The prognostic value of E-cadherin expression in breast cancer appears to be limited. A larger, prospective study with long-term follow up is needed. PMID- 21590069 TI - Differences in repair of potentially lethal damage in Chinese hamster ovary cells exposed to 65 MeV proton beams and (137)Cesium gamma-rays. AB - Our study aimed to establish whether there are differences in the repair of potentially lethal damage (PLD) resulting from exposure to 65 MeV proton beams and (137)Cesium (Cs-137) gamma-rays. Irradiation with proton beams was carried out at the plateau and Bra,og peak in unmodulated beams, and at the spread-out Bragg peak (SOBP) for modulated beams. After irradiation, Chinese hamster ovary (CHO) cells in plateau phase were either plated immediately or kept in their own spent medium at 37 degrees C for various times up to 8 hours before plating to dishes or microplates. Survival was assessed with two methods: clonogenic and metabolic activity (MTT) assay. Obvious repair was observed in response to both kinds of irradiation beams, including different irradiation positions in proton beams. The clonogenic assay showed the PLD recovery ratios of 2.05, 1.79, 1.66 and 1.32 at two hours after 5 Gy irradiation for Cs-137 gamma-rays, plateau, SOBP and Bragg peak of proton beams, respectively. Recovery ratios for the SOBP and Bragg peak were significantly lower than that for gamma-rays (p<0.05 or p<0.01). There were no significant differences in the recovery ratios assessed by different methods (clonogenic and MTT assay), except for the Bragg peak. PLD repairs for proton beams and Cs-137 gamma-rays were not found at lower dose irradiation (3 Gy). Our results indicate that PLD repair in response to 65 MeV proton beams (SOBP and Bragg peak) is less and occurs later than for Cs-137 gamma rays. The MTT assay was found to be a useful method in radiobiological research of proton beams. PMID- 21590070 TI - Bcl-2 and p53 expressions in large-cell lymphoma. AB - Bcl-2 and p53 regulate apoptosis in a see-saw fashion and are expressed abnormally in a variety of malignant tumors. We investigated the frequency and prognostic significance of both bcl-2 and p53 expression in 31 large-cell lymphomas. Immunoreaction of bcl-2 and p53 was found in 74% (23/31) and 65% (20/31) of large-cell lymphomas, respectively. Overall survival was not significantly associated with immunoreactivity for either bcl-2 or p53. Frequent association with both p53 and bcl-2 in large-cell lymphomas confirms the existence of a multistep genetic deregulation in lymphomagenesis, but their clinical significance remains to be elucidated in a larger study. PMID- 21590071 TI - Validation of breast cancer prognostic models. AB - Besides classic prognostic factors in breast cancer, there are numerous variables without fully established prognostic value. The use of all these factors in daily clinical practice may prove difficult. In this study we investigated the validity of certain reported prognostic models in our own population of patients. In a retrospective series of 244 breast cancer patients, we determined certain clinical, morphological and immunohistochemistry variables. Validity analysis of the prognostic models reported by other authors was performed by the use of their corresponding Cox equations calculated from the data published. The validation made with the Paik model without prognostic value has obtained statistical significance in our series, and variables predicting the evolution of their patients was not confirmed. The application of the Lovekin prognostic model did appear to be valid in our group of patients. It has not been possible to verify as prognostic in our patients all the models proposed by other authors. PMID- 21590072 TI - Effect of basic fibroblast growth factor-saporin mitotoxin on breast cancer cell lines in vitro. AB - Fibroblast growth factor receptors are widely expressed on breast cancer cells and we report a preliminary study to determine whether these could be useful as potential targets for delivery of a cytotoxic fibroblast growth factor 2-saporin conjugate. We show that this mitotoxin conjugate can displace I-125-fibroblast growth factor 2 binding though with reduced affinity compared to unlabeled fibroblast growth factor 2. For 4 out of 5 cell lines it is an effective inhibitor of cell growth, and cytotoxic for at least 2 of the lines. Inhibitory effects did not depend on responsiveness of cells to fibroblast growth factor 2. This activity was not achieved with free saporin. There may be potential uses for this conjugate in both experimental systems to study receptor function and subsequent processing, and also in clinical settings to eliminate breast cancer cells. PMID- 21590073 TI - Nodular lymphocyte predominant Hodgkin's disease progressing to a large B-cell lymphoma without previous treatment. AB - The nodular form of lymphocyte predominance Hodgkin's disease presents particular clinical and biological features that have set it apart as a distinct clinicopathological entity. It has an indolent course with long-term survival despite frequent localized relapses, and a remarkable tendency to progress into a B-cell non-Hodgkin's lymphoma. Biological evidence strongly point to a B-cell proliferation from the start. We report the unique case of a patient with nodular lymphocyte predominant Hodgkin's disease in stage I who had all disease removed for diagnosis and did not receive fu;ther treatment. He relapsed in the same lymph node area twelve years later, and the biopsy was now consistent with a large B-cell lymphoma. The histopathological and immunophenotypic profiles clearly show the identity of the two lymph node proliferations. This phenomenon exemplifies the growing inter-relashionship between Hodgkin's disease and non Hodgkin's lymphomas. PMID- 21590074 TI - Persistent alpha 1 integrin subunit expression in human neuroblastoma cell lines which overexpress N-myc and downregulate other integrin subunits. AB - Neuroblastoma is characterized by amplification and overexpression of N-myc. N myc down-regulates expression of the beta 1 integrin extracellular matrix receptor, however, some beta 1 was found on the surface of N-myc overexpressing neuroblastoma cell lines. It was determined that the alpha 1 subunit is expressed in the cells, associates with beta 1 and is present on the cell surface. Interestingly, the level of alpha 1 was reduced marginally when compared to beta 1. Finally, overexpression of N-myc alters cell morphology on extracellular matrix proteins with persistence of alpha 1 beta 1-dependent responses. Our work supports the conclusion that altered integrin expression may be an important factor in human neuroblastoma. PMID- 21590075 TI - Solitary intracranial plasmacytomas. AB - We present two cases of an unusal localised extramedullary plasmacytoma with a long survival period: a 42-year-old woman with left temporal and a 25-year-old woman with left parietal intracranial plasmacytoma. The tumor masses were totally removed in both patients and their histological, histochemical (PAS and methyl green pyronin positive granules) and immunohistochemical (positive light chains mostly lambda, and negative stains for GFAP, NSE and S-100 protein) properties showed that the tumor tissues consisted of monoclonal population of plasma cells. Our cases were diagnosed as solitary cerebral plasmacytomas since the presence-of underlying multiple myeloma has been ruled out by the clinical, laboratory, radiographic and immunological investigations. Postoperatively the patients were given 40 Gy to the whole cranium and additional 20 Gy focused on the tumor site. Complete remissions were achived 7.5 and 5.5 years, respectively. PMID- 21590076 TI - DNA ploidy in hepatic cirrhosis, dysplasia and carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common and aggressive form of primary liver tumors. The evolution and the putative association of this neoplasm with hepatic cirrhosis and liver cell dysplasia remain uncertain. We analyzed the DNA ploidy by flow cytometry in a cohort of 130 liver specimens representing liver cirrhosis, hepatic cell dysplasia and hepatocellular carcinoma to determine the incidence and potential biological relevance of this feature. Our results show that four (8.0%) of the 50 cirrhotic lesions, four (26.7%) of 15 dysplastic, and 51 (78.5%) of the 65 HCC manifested DNA aneuploidy. Moreover, DNA aneuploidy was manifested in 60% of histologically negative hepatic resection margins of HCC. Our results indicate that: i) the presence of DNA aneuploidy in some cirrhotic livers and liver cell dysplasias support the potential evolution of HCC from a subset of these lesions that harbor such clonal alterations, ii) DNA aneuploidy in histologically negative resection margins of HCC in some cases support the concept of field cancerization in these tumors and iii) the predominance of DNA aneuploidy and high proliferative index (PI) in liver cell carcinomas underscore their aggressive biological behavior. PMID- 21590077 TI - Levels of plasma cysteine-proteinase activity in bladder cancer patients. AB - Plasma activity of a Cathepsin B like (CB) cystine protease was evaluated employing a chromogenic assay in citrated plasma samples of 21 patients with transitional bladder cancer (TBC), and 36 healthy blood donors. The median value of total CB activity was significantly higher in the group of patients bearing bladder carcinoma (103.4 mU/ml) as compared to the control group (77.7 mU/ml). 57% of patients showed high values of total CB while only 25% of the controls showed values over the cut-off levels (97.0 mU/ml). When the proenzyme (pro-CB) was analyzed, the median value was also significantly higher in the TBC patients (42.2 mU/ml) as compared to the control group (20.6 mU/ml). While 62% of TBC group showed values over pro-CB cut-off level (35.0 mU/ml) only 31% of controls did so. Total CB median value from other 29 patients succesfully treated from TBC without evidence of disease at the moment of blood colection was near the cut-off (97.6 mU/ml) while pro-CB median values were lower than the cut-off levels (33.2 mU/ml). PMID- 21590078 TI - Changes in c-src activity in a human colon cancer cell line during differentiation. AB - Sodium butyrate is a potent agent inducing transient differentiation of colorectal carcinoma cell line HT29. Besides an increase in the level of alkaline phosphatase and morphological changes, this differentiation is followed by a great reduction of kinase activity of the c-src gene product (pp60(c-src)), combined with a sharp decrease in binding of pp60(c-src) to GST-src SH2+SH3 fusion proteins. This finding suggests that the cause of the reduction of pp60(c src) kinase activity could be an inactive conformation of the pp60(c-src) molecule in sodium butyrate-treated HT29 cells. PMID- 21590079 TI - Descriptive epidemiological assessment of cancers of the breast, ovary and uterine corpus in Greater Bombay. AB - An attempt has been made to make a descriptive epidemiological assessment of cancers of the breast, uterine corpus and ovary in Greater Bombay. The descriptive epidemiology has been discussed in relation to age and demographic and socio-economic composition of the population, utilising the recent 5 year data. The incidence of these cancers in Bombay has been compared with national and international findings. Time trend analysis of these cancers has also been discussed, using the data for the past 30 years. The basic data was collected by the Bombay Cancer Registry. A linear regression model based on the logarithms of the incidence rates was utilised for studying the time trends. In Bombay, during the period 1989-1993, 4,110 breast cancer cases were registered representing 11.2% of the total number of cancers seen and 23.5% of all cancers in females. The average A.A.R. for incidence and mortality of breast cancer was found to be 29.4 and 12.5 per 100,000 population respectively. During the same period 326 cases of uterine corpus cancers and 1,096 ovarian cancers were recorded in Bombay. Breast cancer is extremely rare in the premenarchal age. The age specific incidence is seen to vary for each of these cancers. The incidence is seen to be very high, of all the three cancers in the Parsis, when compared with the other religious groups. Breast and ovarian cancers were found to the highest in Gujratis, whereas, cancer of the uterine corpus was predominant in Marathi speaking women. The incidence of all the three cancers was found to be increasing with a rise in the educational level of the patients. This was found to be maximum for married women followed by the widows and is lowest in unmarried women. The trend of incidence data for all these three cancers in Greater Bombay, confirms the impression and parallel changes in age-adjusted incidence rate in the corresponding sites observed in other registries throughout of the world. PMID- 21590080 TI - Regulation of genes associated with angiogenesis, growth, and metastasis by specific p53 point mutations in a murine melanoma cell line. AB - K1735 murine melanoma cells transfected with p53 cDNAs bearing specific point mutations are metastatic in nude mice, whereas the parent and control-transfected cells are nonmetastatic. To determine whether p53 gene mutations regulate genes associated with angiogenesis, growth, and metastasis, we examined expression of vascular endothelial growth factor I, IGF-I receptor, epidermal growth factor insulin-like growth factor I, IGF-I receptor, epidermal growth factor receptor, c MET, and thrombospondin 1 in K1735 cells transfected with one of four different mutant p53 cDNAs. Northern blot analysis demonstrated differential upregulation of these genes in cells transfected with different mutant p53 cDNAs. Up regulation of angiogenesis-, growth-, and metastasis-related genes by mutant p53 may contribute to metastasis formation. PMID- 21590081 TI - Induction of p53 protein by carbon-ion and proton beam irradiation in two close human lymphoblastoid cell lines with different p53 status. AB - In this study, we compared the kinetics of the postirradiation p53 protein expression for carbon ion beam (290 MeV/n, LET 75 keV/mu m) and proton beam (65 MeV) with that of (13)7Cs-gamma ray. We used two human lymphoblastoid cell lines derived from the same donor with different p53 status. Wild-type p53 protein increased after irradiation and it was dose-dependent. Meanwhile, the mutated p53 protein level did not show any increase with irradiation. With the three forms of radiation, there was no significant difference as regards the p53 protein kinetics. PMID- 21590082 TI - The receptor super-antagonist Sant7. AB - Interleukin-6 (IL-6) plays a central role in the pathogenesis of multiple myeloma, acting both as a growth and a survival factor for myeloma cells. IL-6 has been recently shown to possess three topologically distinct receptor binding sites: site 1 for binding to the subunit specific chain IL-6R alpha and sites 2 and 3 for the interaction with two separate subunits of the signalling chain gp130. We have generated a set of IL-6 receptor antagonists carrying substitutions that abolish interaction with gp130 at either site 2 alone (site 2 antagonist) or at both sites 2 and 3 (site 2+3 antagonist). In addition, substitutions were introduced at site 1 that increased affinity for IL-6R alpha. When tested as growth inhibitors on a representative set of IL-6-dependent human myeloma cell lines (XG-1, XG-2, XG-4 and XG-6), although site 2 antagonists were effective on 3 out of 4 of the cell lines, only the site 2+3 antagonist Sant7 showed full antagonism on the entire spectrum of cells tested. Moreover, IL-6 receptor antagonists were also pro-apoptotic factors for myeloma cells. Their capacity to induce cell death was directly related to the impairment of binding to gp130 and to their ability to fully block intracellular signalling. In fact, the most potent inducer of apoptosis was again Sant7, which also counteracted the protective autocrine effect excercised by the endogenously produced IL-6. On the basis of these results we propose the super-antagonist Sant7 as a possible candidate for the immunotherapy of multiple myeloma. PMID- 21590083 TI - Insulin-like growth factor (IGF)-I and IGF-II protein expression in pulmonary adenocarcinoma. AB - Insulin-like growth factor (IGF)-I and IGF-II expression was studied immunologically in tissue specimens from 120 patients with pulmonary adenocarcinoma and was correlated with patient prognosis. Multivariate analysis showed that IGF-II expression had a significant influence on prognosis. Our findings suggest that IGF-I and IGF-II play an important role in tumor progression and that IGF-II is a useful prognostic marker for pulmonary adenocarcinomas. PMID- 21590084 TI - Heparin coating of human breast carcinoma cells in vivo. AB - Mast cells, the only source of heparin in the body, are common in breast carcinoma. Due to metachromatic staining of heparin-proteoglycans released from the mast cells toluidine blue may stain connective tissue a reddish-purple. This study shows that tumour cells in the vicinity may also be coated with metachromatic substance. Such bl vivo coating does not appear to have been reported previously. In experimental studies in vitro coating has been described following suspension of mouse tumour cells in a heparin solution and preincubation of ascitic tumour cells in heparin has given reduction in survival time after transplantation. In human breast carcinoma stromal metachromasia may under certain circumstances be indicative of poor prognosis. The biological implications of in vivo tumour cell coating with heparin are under investigation. PMID- 21590085 TI - Advanced mucinous adenocarcinoma in pregnancy. AB - The incidence of masses in pregnancy is estimated to occur in 1/81 to 1/2,500 pregnancies. The development of colorectal carcinoma during pregnancy is a more rare event, with less than 30 cases above the peritoneal reflection reported in the last 70 years. The differential diagnosis of mucinous adenocarcinoma of ovarian vs. gastrointestinal origin is often difficult. We report a pregnant patient affected by advanced colorectal cancer, who presented with an asymptomatic unilateral adnexal mass on ultrasound. A 28-year old woman was referred to our hospital after a routine ultrasound examination at 26 weeks gestation showing a right adnexal mass. At elective exploratory laparotomy, the patient was found to have metastatic mucinous adenocarcinoma. Diagnostic and treatment choices of such a cancer in a pregnant patient were explored. The final diagnosis of colorectal cancer was made only at the time of a subsequent emergency laparotomy. The goal of an obstetrician/gynecologist and other care givers of pregnant patients, is to achieve a healthy mother and child. Unfortunately, physicians may unwillingly sacrifice the health of the mother by denying or delaying her procedures or treatments simply because she is pregnant. It is especially important in the case of adnexal masses and their related pathology, due to the difficulty in detection and management of such cases during pregnancy, that doctors actively assume the responsibility of assuring that pregnant patients receive the proper care they need. PMID- 21590087 TI - Intrahepatic fluorodeoxyuridine to treat unresectable hepatocellular carcinoma patients. AB - Of 16 HCC patients who received intrahepatic FdUrd at a dose of 0.3 mg/kg/day for 14 consecutive days by continuous infusion, every 28 days, no one achieved a complete response, while 3 patients achieved partial response (18.75%), lasting 6, 9 and 18 months, respectively. Seven patients (43.75%) exhibited stable disease and their mean time to progression was 4.28 months; in the extant 6 patients (37.5%) the disease progressed. Major biliary toxicity was observed. On the basis of these data, intra-arterial chemotherapy should not yet be considered the standard treatment of unresectable HCCs. PMID- 21590086 TI - Human SAK related to the PLK/polo family of cell cycle kinases shows high mRNA expression in testis. AB - We identified the nucleotide sequence of a cDNA encoding a polypeptide with a kinase domain that is related to the catalytic region of Drosophila melanogaster polo, Saccharomyces cerevisiae CDC5 as well as human FNK and PLK. The novel gene seems to represent the human counterpart of the mouse gene sak. The sequence of SAK predicts a serine/threonine kinase of 970 aa. The distribution of SAK mRNA in adult organs is restricted to certain tissues such as testis and thymus. Northern analyses of tumor tissues (lung, breast, brain) and corresponding normal tissues from the same patient did not reveal SAK expression. Comparing the mRNA distribution of the proliferation-associated polo-like kinase (PLK) with the expression of SAK we observed distinct differences. Thus, we suggest that these kinases have unique physiological roles in different cells or in response to different signals. PMID- 21590088 TI - Cytogenetical observations in a mucoepidermoid carcinoma arising from heterotopic intranodal salivary gland tissue. AB - The cytogenetical observations in a mucoepidermoid carcinoma (MEG) arising from heterotopic intranodal salivary gland tissue are presented. The MEC was characterized by two reciprocal translocations, viz, t(1;7) (p36;q11) and t(11;19) (q14-21;p11). The present and the previous studies show that the last rearrangement or related deviations characterize about 40% of all MEG. The remaining cases form a subgroup distinguished by trisomies with or without concomitant structural deviations other than those affecting 11q14-22. At least MEC of the first subgroup show neither predilection for any specific anatomical site nor for any age group or particular sex. Inducing agent(s) and genotypic status of the tissue of origin seem to be the decisive factors for the chromosomal patterns in MEG. PMID- 21590089 TI - Colon tissue implanted into the glandular stomach in rats lack susceptibility to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) carcinogenesis. AB - The present study was undertaken to determine the response of colon mucosa implanted into the fundus of stomach in 6-week old male F344 rats to oral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Samples of colonic tissue about 8 mm in diameter were obtained from various colon sites and surgically implanted into the anterior wall of the fundus by isografting. MNNG was chronically administered at a concentration of 100 mg/l in the drinking water for 16 weeks starting 4 weeks after the operation and the grafted colon mucosa was examined at 12 months after the operation. Control rats received a sham operation and the same amount of MNNG. In the MNNG administered groups, only one adenoma containing Paneth cells was noted in the implanted colon tissue whereas over 40% incidence of gastric tumors was observed in the pyloric mucosa. In the operated rats not given MNNG no gastric tumors were observed in either the grafted site or the pylorus. PMID- 21590090 TI - Growth-suppressive activities of serine protease inhibitors, FOY-305, ONO-3403 and FO-349 toward human carcinoma cells. AB - FOY-305 is a synthetic serine protease inhibitor and ONO-3403 and FO-349 are its derivatives. The effects of these compounds on the proliferation of several human carcinoma cell lines were investigated in vitro by MTT colorimetric assay. ONO 3403 showed the most potent growth-inhibitory activity among these protease inhibitors. The half maximum inhibition concentrations of ONO-3403 toward BxPC-3 pancreatic carcinoma, T24 bladder carcinoma and A431 epidermoid carcinoma cells were 20-30 mu g/ml whereas those toward pancreatic carcinomas, PANC-1 and Mia PaCa-2, were 60-80 mu g/ml. Since FOY-305 has been shown to be effective in chemotherapy for human oral cancer, ONO-3403 is expected to be a more effective anticancer drug. PMID- 21590091 TI - Hepatocellular carcinoma with sarcomatous change. AB - We studied clinicopathological and immunohistochemical features of hepatocellular carcinoma (HCC) with sarcomatous change among surgically resected HCC cases. Among 308 HCC cases, 6 (1.9%) showed partial (5 cases) or entire (1 case) sarcomatous change. Only 1 case received preoperative anti-cancer therapy among the 6 cases, suggesting that sarcomatous change is not always related to anti cancer therapy. Immunohistochemically, the sarcomatous components were positive for albumin and alpha 1-antichymotrypsin and negative for alpha-fetoprotein in all cases. Expressions of intermediate filament-related proteins (e.g., cytokeratin and vimentin) in the sarcomatous components were heterogeneous. The sarcomatous components showed stronger expressions of p53 protein and/or mouse double minute-2 protein, and higher proliferating cell nuclear antigen labeling index, suggesting their high proliferative activity and high malignant potential. PMID- 21590092 TI - Apoptosis induced by ultraviolet B irradiation of leukemia cells and macrophages. AB - In this study, we examined the effects of ultraviolet-B (UV-B) irradiation on a variety of cultured cells including human (HL-60, U937) and mouse (MI, WEHI3B/D) leukemia cells, and mouse macrophages (P388-D1, J744). UV-B irradiation for 15 min variably induced apoptosis in all of the cell lines examined, except for J744. Apoptosis was apparently prevented by the treatment of a panel of anti oxygen reagents. WEHI3B/D, M1 and HL-60 induced cell differentiation showed delayed induction of apoptosis. Protein kinase C and bcl-2 protein expression did not change during the process of apoptosis. These results indicate that (1) UV-B irradiation induces apoptosis of leukemia cells and macrophages via direct and/or indirect DNA damage, and (2) cell differentiation results in less frequent apoptosis. PMID- 21590093 TI - V-onc product expression in early phase post perinatal retrovirus infection predictive of malignancy of induced lesions. AB - Sixteen sarcomas developed in rats within 40 days post perinatal infection with feline sarcoma virus of Snyder-Theilen strain were examined to elucidate the association of the viral oncogene product (P85) expression with malignancy of developed sarcomas. Of these, 6 grew up to index-finger-tip-size, consisted of spindle shaped sarcoma cells and had no metastasis (group A), and 10 grew over thumb-tip-size, consisted of polygonal shaped sarcoma cells and had frequent metastasis (group B). One group A tumor and 8 group B tumors expressed P85. The v onc product expression was thus found to be predictive of malignancy of induced tumors. PMID- 21590094 TI - Measurements of cellular proliferation by H-3-thymidine-labeling index and flow cytometry in breast cancer patients. AB - In 50 node negative breast cancer patients, tumor S-phase fraction (SPF) was determined by H-3-thymidine labeling index ((HTLI)-H-3) or flow cytometry (FC). Forty-five patients had tumor cell kinetics measured by both techniques. Twenty three patients were classified as having high proliferative activity and 22 low by (HTLI)-H-3, while 32 as highly proliferating and 13 low proliferating by FC. In 30 patients only, both indices agreed on identifying high or low proliferative activity. These results suggest the need of more careful attention to standardization and quality control of cell kinetic data before carrying out clinical trials based on these parameters. PMID- 21590095 TI - Human papillomavirus 16 E6 and E7 are associated with the nuclear matrix of cervical carcinoma cells. AB - Carcinoma of uterine cervix is closely associated with human papillomavirus (HPV) infection and HPV16 DNA has been shown to integrate into the genome of host cancer cells. The subgenomic fragments (E6E7) were found to be present in nuclear matrix (NM)-associated DNA by novel PCR. Further investigation showed the absence of E6 open reading frame (protein encoding sequence) in NM-associated DNA. DNA protein binding assay (Southwestern blotting) labeled 2 groups of NM proteins that bound commonly to E6E7 DNA and specifically to either E6 or E7 DNA. Complex protein formation that was recognized by E6E7 was suggested. Further investigation into properties of these NM proteins may provide a better understanding of the role of HPV in cervical carcinogenesis. PMID- 21590096 TI - Correlation of peritoneal dissemination and integrin alpha 3 expression in gastric cancer. AB - To clarify the interrelationship between alpha 3 integrin, subunit/E-cadherin expression and peritoneal dissemination in gastric cancer, alpha 3 integrin subunit and E-cadherin expression gas were immunohistochemically examined and were correlated with clinicopathologic parameters. Among 150 primary gastric cancers, alpha 3 integrin subunit and E-cadherin were strongly expressed in 96 (65%) and 88 (59%) tumors, respectively. Integrin alpha 3 expression was closely associated with peritoneal dissemiantion, but there was no relationship between integrin alpha 3 expression and histologic type, nodal status, macroscopic type or wall invasion. Furthermore, 22 (84%) of 26 tumors which recurred in peritoneum overexpressed integrin alpha 3 expression in primary tumors. All seven peritoneal foci obtained from peritoneal dissemination expressed integrin alpha 3 expression despite no integrin alpha 3 expression in two of these 7 primary tumors. Reduced E-cadherin expression in primary tumors was intimately associated with large tumor size (>6 cm), nodal involvement, peritoneal dissemination and positive serosal invasion. Peritoneal dissemination was most frequently found in the tumors with positive integrin alpha 3 expression and reduced E-cadherin expression. Patients with these type of tumor [E-cadherin expression (-), and integrin alpha 3 subunit (+)] showed the poorest prognosis as compared with the other groups of patients. These results indicate that upregulation of integrin alpha 3 expression and down regulation of E-cadherin might have an important role in the formation of peritoneal dissemination. These tumors have characteristics of easy detachment from the serosal surface via downregulation of E-cadherin and strong adhesion capacity to the peritoneum via up-regulation of integrin alpha 3 expression. The immunohisto-chemical combination analysis of E-cadherin and integrin alpha 3 expression on the primary gastric cancer may be a good screening method to predict peritoneal recurrence. PMID- 21590097 TI - Possible association between immunocompetence and enhanced risk of multicentric carcinogenesis in both the stomach and other organs in patients with gastric cancer. AB - In a retrospective study, we analyzed the association between the immunocompetence and multicentric carcinogenesis in both the stomach and organs other than the stomach in patients with single gastric cancer (SGC) and those with multiple gastric cancers (MGC). The incidence of primary cancers in other organs in patients with MGC (4/17, 23.5%) was significantly higher than that with SGC (15/202, 7.4%). Our analysis of the immunocompetence revealed a trend towards decreased activity of NK cells and of mitogen-induced blastogenesis in patients with MGC as compared to those with SGC. In patients with SGC, patients with primary cancers in other organs had significantly lower levels of both PHA induced blastogenesis and CD4/CDs, and revealed a greater trend towards decreased activity of both NK cells and Con A-induced blastogenesis than patients without other primary cancers. These findings may suggest that immunocompetence plays a role in the enhanced multicentric carcinogenesis not only in the stomach but also in cancers of other organs. PMID- 21590098 TI - The influence of gemcitabine on the CD4/CD8 ratio in patients with solid tumours. AB - Gemcitabine (dFdC) is a novel pyrimidine antimetabolite with documented antineoplastic activity against metastatic non-small cell lung cancer (NSCL), pancreatic carcinoma, ovarian and breast cancer. The side effects of gemcitabine are generally mild; severe infections are reported in less than Ilo of patients. In contrast, other new nucleoside analogues such as the purine antimetabolite fludarabine lead to a significant alteration of the CD4/CD8 lymphocyte ratio associated with an increased risk for opportunistic infections. This study investigates the effect of gemcitabine on different lymphocyte subsets during consecutive applications. 16 patients with solid rumours (3 non-small cell lung cancer, 3 pancreas, 3 testicular, 2 breast, ovarian germ-cell, 1 ovarian, 1 small cell lung, 1 gastric cancer, 1 carcinoma of unknown primary); 15 patients were previously treated, received at least 3 applications of gemcitabine (1,000 mg/m(2) as a 30 min infusion, at days 1, 8, 15; q 4 weeks). Lymphocytes surface antigens were analysed by standard technique flow cytometry prior to every infusion. The median number of leukocytes before therapy was 7823/mu l, with lymphocytes 875/mu l, including 68% T-cells (CD3(+)), 9% B-cells (CD19(+); CD20(+)) and 15% NK-cells (CD56(+); CD16(+); CD3(-)), the CD4/CD8 ratio was 1.7. After gemcitabine therapy the median number of leukocytes was 5136/mu l, with lymphocytes 1012/mu l, including 77% T-cells, 8% B-cells and 10% NK-cells and a CD4/CD8 ratio of 2.2. Severe complications or opportunistic infections were not seen in these 16 patients. No significant change of CD4/CD8 ratios and NK-ccll numbers was seen in our patients with solid tumours during weekly treatment with gemcitabine. A severely increased risk for opportunistic infections following treatment with the new antimetabolite gemcitabine appears unlikely. PMID- 21590099 TI - Fertility-preserving treatment for advanced malignant germ cell tumors of the ovary. AB - We retrospectively studied 26 patients with stage Ic or greater malignant germ cell tumors of the ovary. Sixteen of the 26 underwent fertility-preserving treatment and 10 underwent total hystero-oophorectomy. There were 3 deaths in each group, but none among the stage Ic cases. The survival curves for stage II to IV disease did not significantly differ in the two groups. Seven patients in the fertility-preserving group were married, and had children. All patients in the hystero-oophorectomy group remained single except for one who was married before surgery. These results suggest that fertility-preserving treatment should be offered even in advanced cases. PMID- 21590100 TI - p53 immunohistochemical analysis of the lymph nodes in node-negative breast cancer patients who had subsequent relapse. AB - We performed a genetic dignosis using p53 immunohistochemistry for the detection of lymph node micrometastasis. Immunohistochemical analysis was performed in 12 node-negative patients with breast cancer who subsequently showed relapse. There was no p53 immunostaining in 197 lymph nodes from 12 patients, while 2 were positive in the 12 primary lesions. p53 immunohistochemistry is not an alternative method for detecting lymph node micrometastasis in node-negative breast cancer. PMID- 21590102 TI - Enhancement of sensitivity to CDDP in human pharyngeal carcinoma cells by H-7, a protein kinase inhibitor. AB - We investigated the synergetic effects of 1-(5-isoquinolinesulfonyl)-2 methylpiperazine dihydrochloride (H-7) on cis-diamminedichloroplatinum(II) (CDDP) cytotoxicity to KB cells, a human pharyngeal carcinoma cell line, and explored the possible mechanism whereby it exerted these effects. In vitro treatment with H-7 markedly decreased protein kinase C (PKC) activity in KB cells and significantly sensitized the cells to CDDP. Treatment of KB cells with H-7 induced a dose-dependent depletion of intracellular glutathione (GSH) levels. These results suggest that the decreased GSH content induced by H-7 may be involved in sensitizing KB cells to CDDP. PMID- 21590101 TI - Three-day intravesical instillation of anti-cancer drugs for prophylaxis of bladder cancer. AB - In this study, evaluation was made of the longterm outcome of 3-day intravesical instillation as adjuvant treatment immediately after transurethral resection of superficial transitional cell carcinoma of the bladder. Antitumor solution was instilled intravesically for 3 consecutive days following TUR of the primary lesion in 71 patients. All patients were randomly divided into three treatment groups. Mean intervals to the first recurrence for BLM (50.2 months) was statistically significant compared with the MMC (18.1 months) group (p=0.0485). Disease-free survival as determined by the Kaplan-Meier method in MMC, DOX and BLM was 55.0%, 60.4% and 76.2% at 2 years and 45.3%, 41.2% and 40.7% at 10 years, respectively. Postoperative 3-day intravesical instillation was found safe and may be useful for prophylaxis of bladder cancer recurrence. PMID- 21590103 TI - Clinical effects of chemoimmunotherapy for patients with peritoneal carcinomatosis. AB - The present study was undertaken to determine whether chemoimmunotherapy using activated killer cells is better than chemotherapy alone for cancer patients with peritoneal carcinomatosis. Thirty-one cancer patients received adoptive immunotherapy by activated killer cells and chemotherapy by anticancer drugs selected by a chemosensitivity test (chemoimmunotherapy group), and another 31 cancer patients received chemotherapy (chemotherapy group). The regimen of chemotherapy was determined by the results of a chemosensitivity test in both groups. The clinical effects including response rate and survival were assessed. Five patients (16.1%) achieved complete response (CR), and 17 patients (54.8%) partial response (PR) in the chemoimmunotherapy group (response rate: 22/31 patients = 71.0%), whereas 4 patients (12.9%) achieved CR, and 5 patients (16.1%) PR in the chemotherapy group (response rate: 9/31 patients = 29.0%). The response rate was higher in chemoimmunotherapy group than in chemotherapy group (p<0.05). However, no difference was observed in survival between the two groups. Therefore, it is necessary to develop methods to induce more potent killer cells for adoptive immunotherapy. PMID- 21590104 TI - Pharmacokinetics of consecutive low-dose cisplatin. AB - The present study investigated the optimal mode of cisplatin (CDDP) dosing in terms of pharmacokinetics. Ten patients with stage Ic ovarian cancer were randomly assigned to receive either bolus-CDDP (70 mg/m(2), 2-h infusion on day 1) or consecutive low-dose (CLD)-CDDP (10 mg/m(2), 4-h infusion for 7 consecutive days) in the adjuvant setting. Maximum concentration (C-max) of total and filterable platinum for the bolus-CDDP group were significantly higher than those for the CLD-CDDP group. Whereas, filterable drug exposure defined by the area under the concentration-time curve (AUC) was approximately 2-fold higher for the CLD-CDDP group. Urine excretion rates, which were considered to be related with nephrotoxicities, were significantly lower for the CLD-CDDP. Anti-tumor effect of CDDP has been reported to be dependent on the AUC rather than C-max of filterable platinum. Thus, CLD-CDDP dosing may possibly deliver an improved therapeutic index as compared to the usual bolus dosing method, especially for patients with pelvic tumors which eventually involve the urinary tract leading to impaired renal function. PMID- 21590105 TI - High urinary hydroxyproline excretion in patients with advanced head and neck cancer. AB - We studied the urinary excretion of hydroxyproline, measured as the hydroxyproline-to-creatinine ratio (HOP/Cr), in sixty-six patients with head and neck disease including, 18 patients with head and neck cancer. Urinary hydroxyproline excretion was determined before treatment by the linear gradient elution method. Although the urinary excretion of hydroxyproline is considered to be useful in monitoring cancer tissue such as prostate carcinomas, no studies have been performed on the urinary excretion of hydroxyproline in patients with head and neck cancer. The HOP/Cr was significantly higher in cancer patients than in the healthy control. The ratio of patients with T3/T4 cancers was higher than in patients with benign tumors (p<0.05), chronic inflammatory diseases (p<0.01) or T1/T2 cancer (p<0.05). The high HOP/Cr with T3/T4 head and neck cancer corresponded to the extent of tumor invasion into the surrounding tissues such as muscles and bone. This suggests that HOP/Cr may be useful as a supplementary parameter for the assessment of tumor invasiveness which is masked in head and neck carcinomas such as skull base or maxillary carcinomas. PMID- 21590106 TI - Endodermal sinus tumor of the ovary in pregnancy. AB - The ultrasonographic evidence of an irregular mixed mass, cystic and solid, in retrouterine area and the high levels of alpha(1)-FP values in a young pregnant woman, indicated the possibility of an ovarian germ cell neoplasia. Respecting the patient's will, pregnancy was protracted until the 36th week. A cesarian section allowed the releasing of a vital fetus and the removal of a neoplastic mass which proved to be an endodermal sinus tumor (EST) at stage Ia. Then the patient, the 12th case of EST in pregnancy reported in the literature, underwent 5 PVB chemotherapy cycles and, 3 years after the intervention, appears disease free. PMID- 21590107 TI - Treatment of human cancers by NO-releasing reagents related to Mn-SOD. AB - Nitric oxide (NO) plays various roles in organisms, including its anti-tumor effect. But it was not well known how NO actually influences human cancer cells and destroys them. We investigated the relation between NO and SODs using S nitroso-N-acetyl penicillamine (SNAP), an NO releasing reagent. In several cancer cells treated with SNAP, the expression of manganese-superoxide dismutase (Mn SOD) mRNA and the enzymatic activity of Mn-SOD were both enhanced. These results suggest that some human cancers which are resistant to NO may enhance the expression of Mn-SOD in order to protect themselves against NO radicals. Such mechanism is also expected to offer a clue to the practical use of NO donors as an anti-cancer drug. PMID- 21590108 TI - The role of growth factors in proliferation and invasion of thyroid cancer. AB - A growing literature has established the close association between tumor progression and growth regulatory aberrations in cancer cells. Most studies have focused on the phenomenon, that advanced tumors or metastases have lost the sensitivity to growth inhibitors. Metastasis are the primary cause of death in patients with differentiated thyroid cancer. Proliferation and differentiation of the thyroid was supposed to be under the major control of only a single hormone (thyroid stimulating hormone). However, we and others have shown that a complex network of various growth factors regulates growth and invasion of thyroid cancer cells. Our findings highlight two aberrations of growth regulation which may favour progression of malignancy and acquisition of metastatic competence: i) resistence to growth factor inhibitors and ii) growth autonomy of metastatic thyroid cancer cells. PMID- 21590109 TI - Refinement and distinction of the chromosome 10p candidate tumor suppressor region in human gliomas. AB - Our recent studies have shown that telomeric 10p is frequently deleted in both low and high grade gliomas. Other studies have shown an invariant association of erb-b amplification and loss of chromosome 10. It has not been determined whether this association was specific for a particular locus on chromosome 10. We sought to assess this by examining tumors, for both 10p loss and gene amplification. 55% of tumors showed some degree of allelic imbalance at 10p15. Amplification of erb b, c-myc, and a mitochondrial cDNA probe, recently found to be amplified in diverse grades of gliomas was assessed. erb-b and the mitochondrial cDNA probe showed amplification in 28% of the tumors; c-myc gene was amplified in only one astrocytoma. No significant association was noted when comparing the presence of a specific amplified gene, and loss of loci on chromosome. Chromosome 10p15 shows significant loss in glial tumors, and is independent of the chromosome 10 region associated with erb-b amplification. The region at 10p15 is distinct in harboring a putative tumor suppressor gene in gliomas, and is involved earlier in the multi step pathway to glial tumor malignancy. PMID- 21590110 TI - Increased levels of urinary basic fibroblast growth factor in bladder cancer patients. AB - Urinary basic fibroblast growth factor (bFGF) was determined by a competitive sandwich ELISA test in 26 patients with transitional bladder cancer and 26 normal volunteers or subjects with benign urological diseases. The median bFGF value in the patient group was 3.41 ng bFGF/g creatinine (range: 0-153.6), significantly higher than the median levels in the control group (1.39 ng/g creatinine; range: 0-4.5). On the basis of the optimal cut-off point of 2.64 ng bFGF/g creatinine, the sensitivity of the test for detecting bladder cancer was 61.5% and the specificity 76.9%. We also studied 17 individuals successfully treated for a previous bladder cancer and with no evidence of disease at the moment of urine collection (NED group). These subjects showed similar urinary bFGF levels as those observed in the control group (median 0.24 ng bFGF/g creatinine, range 0 5.1). Our data suggest that the dosage of urinary bFGF could be a non-invasive useful assay in the management of bladder cancer patients. PMID- 21590111 TI - Early detection of recurrent mono-metastases of breast cancer to endocrine tissues by following CEA levels. AB - CEA and CA 15-3 are the most commonly used biological markers for detection of recurrences and metastases of breast carcinoma. According to the literature CA 15 3 is the more sensitive of the two markers. Herein, we describe a case of a 50 year old woman with breast cancer, who had multiple mono recurrence of endocrine organ metastases. The CEA levels, rather than CA 15-3, proved to be the more accurate predictor of her disease recurrence. We describe the unique behaviour of her carcinoma, which emphasizes our opinion that the combination of CEA and CA 15 3 could be used to rule out recurrences or metastases of breast cancer. PMID- 21590112 TI - Tamoxifen-induced hypertriglyceridaemia. AB - We report seven cases of breast adenocarcinoma and hypertriglyceridaemia associated with the use of tamoxifen. Two cases presented with life-threatening acute pancreatitis. Two cases show a rise in serum triglycerides (TG) after starling tamoxifen. Five patients had some degree of insulin resistance or diabetes which may have aggravated the hypertriglyceridaemia. One additional patient had an apolipoprotein phenotype associated with hypertriglyceridaemia. Fibrates effectively reduced serum TG levels. In general, tamoxifen improves the lipid profile and this may account for the reduction in coronary events in patients taking this drug. However, a rise in serum TG levels has been documented in several studies. Our reports suggest that it is important to screen patients on tamoxifen since hypertriglyceridaemia could cause potentially fatal acute pancreatitis or increase the risk of developing ischaemic heart disease. PMID- 21590113 TI - Cytogenetic analysis of rat cells, transformed by human papillomavirus genes. AB - Chromosomal analysis of immortalized rat embryo fibroblasts (IE5) and transformed by HPV18 E6+E7 genes (A4E5) or HPV16 E7 alone (trB4; trF8; trC2) variants have been done. Transformed cell lines represented heterogeneous cell populations containing neardiploid subpopulations with 41-44 chromosomes and also heterogeneous polyploid cells in contrast to immortal cells IE5 that contained normal number of chromosomes-42. In transformed cells the abnormalities of interphase nuclei (giant-, micro-, apoptotic nuclei) were observed which could reflect genomic instability of polyploid cells. Several chromosomal alterations were revealed in immortal IE5 cells, but only reciprocal translocation t(8; 10) (q22q12.3) was stable and kept in cells transformed by HPV18 E6+E7 genes or HPV16 E7 alone. We can conclude that genomic instability and clonal expansion of the cells with specific chromosomal alterations contribute to HPV-mediated transformation. PMID- 21590114 TI - Diurnal rhythmicity of endogenous TNF alpha concentration in plasma of advanced gastrointestinal cancer patients. AB - The objective of this study was to test the hypothesis of a diurnal fluctuation of circulating levels of endogenous tumor necrosis factor alpha (TNF alpha) in patients with advanced gastrointestinal cancer. Serum levels of TNF alpha were measured at 8 am., 2 p.m., 6 p.m., 10 p.m., and 2 a.m, in 40 patients with advanced gastro-intestinal cancer. In the control group TNF alpha plasma levels were low and did not exhibit regular patterns. On the contrary serum TNF alpha levels were substantially increased in patients with advanced cancer. Peak value appeared at 2 a.m. In contrast, the levels were low in the afternoon (2 p.m.). The presence of circadian rhythm was found with an acrophase at 0 h 36 min. PMID- 21590115 TI - Tumor proliferative compartment in non-Hodgkin's lymphoma. AB - The extent of cell proliferation is an important biological aspect of a tumor cell population that can affect clinical outcome. Besides other well established clinical and histopathological prognostic criteria, cell kinetic data may therefore be of significant prognostic value. This study evaluated the proliferative activity of various grades of non-Hodgkin's lymphoma, by analyzing the expression of the proliferating cell nuclear antigen (PCNA). PCNA is a 36 kD nuclear protein associated with the cell cycle and is directly involved in DNA synthesis during cell proliferation. Our study revealed a good correlation (p=0.000) between PCNA expression and tumor grade. The highest levels of PCNA expression (mean=43%) were seen in the high grade lesions and the lowest (mean=19%) in low grade lesions. These results suggest that PCNA immunostaining may be used to evaluate proliferative index in various grades of NHL, which in turn could be used to monitor response to treatment. PMID- 21590116 TI - Quality of life in Dukes' B and C colorectal carcinoma. AB - Adjuvant chemotherapy (ACT) is standard therapy in Dukes' C colorectal carcinoma (CRC) in several countries. Several studies have documented a significant improvement in overall survival, but the clinical efficacy on quality of life (QoL) has been doubted. To clarify this item, we performed a study on QoL in 94 CRC patients diagnosed between 1993-96 and randomised to surgery with or without ACT. 82 'survivors' were mailed the EORTC QLQ C-30. Sixty-two patients (76%) responded. They reported a high level of functioning and a low frequency of symptoms. ACT did not improve global QoL, and tended to cause less pain (p=0.023) and more nausea/vomiting (p=0.065). PMID- 21590117 TI - Primary liver tumors in China. AB - Until now, no large series studies on the clinicopathological features of primary liver tumors (PLTs) in mainland China have been reported. The authors retrospectively investigated 3,160 cases of PLTs surgically resected at Shanghai Oriental Hospital of Hepatobiliary Surgery between January 1982 and January 1996. Most of them are true neoplasms, others are tumor-like lesions. The 3,160 cases of PLTs could be divided into 3 groups of 25 types arising from three germinal layers, of which tumor-like lesions (Group 1) were of 4 types involving 112 cases (3.5%), benign PLTs (Group 2) were of 10 types involving 499 cases (15.8%) and malignant PLTs (Group 3) were of 11 types involving 2,549 cases (80.7%). The most common type of lesion in each group was solitary necrotic nodule, cavernous hemangioma and hepatocellular carcinoma (HCC), accounting for 73.2%, 74.3% and 96.6% of their respective groups. The patients ranged in age from 5 months to 79 years (mean, 45.7 years), but the age distribution and sex ratio varied reciprocally from group to group and from lesion to lesion. For example, the mean age of the patients in Group 1 was 39.1 years of age, whereas in Group 2 and Group 3, it was 45.9 years and 49.6 years, respectively. The sex ratio of men to women was 2.6:1 in Group 1, 1:1.1 in Group 2 and 7.7:1 in Group 3. The rates of serum HBsAg positivity and concomitant liver cirrhosis in the patients with HCC were 74.4% and 72%, respectively, and the concomitant rate of cirrhosis in small HCC (<3 cm in diameter) was as high as 83.3% (P<0.05), demonstrating a close relationship of HCC with HBV infection and liver cirrhosis. HCC amounts to 78.4% of the total 3,160 PLTs in this series, indicating that HCC is the most common malignant tumor of the liver in China. PMID- 21590118 TI - Decreased expression of MLH1, MSH2, PMS1 and PMS2 in pigmented lesions indicates accumulation of failed DNA repair along with malignant transformation and tumour progression. AB - The tumorigenesis of human nonpolyposis colorectal cancer was reported to be connected with the mutations in DNA mismatch repair genes. The main aim of this study was to check the epression of 4 proteins MLH1, MSH2, PMS1 and PMS2 responsible for mismatch DNA repair in naevi and melanomas. Fifty-one naevi, 78 primary melanomas, 30 lymphatic and 7 organ melanoma metastases were stained for the presence of MLH1, MSH2, PMS1 and PMS2. All proteins were preserved in 88% of naevi and only in 37% of primary melanomas, 17% of lymphatic metastases and in none of the distant metastases. The difference of expression of all 4 proteins between naevi and melanomas was highly significant (p<0.01). MLH1 and MSH2 correlated significantly with each other as well with the follow-up of patients. On the basis of our results one can conclude that the defect of mismatch DNA repair plays an important role in both tumorigenesis of melanoma and metastatic spread of tumour. PMID- 21590119 TI - The use of toads (Bufo regularis) in a new biological assay for screening chemicals or drugs which induce leukaemia in man. AB - Injection of Egyptian toads Bufo regularis, with adriamycin subcutaneously in the dorsal lymph sac at a dose level of 0.1 mg/toad, once every 3 weeks for 3 months induced pronounced alterations in the blood cells. These alterations were more or less similar to the criteria reported in human leukaemia. These changes were all comparable to those observed after the treatment of the experimental animals with the chemical carcinogen 7,12-dimethylbenz(a)anthracene. It is speculated that toads (Bufo regularis) can be used as biological test animals for screening chemicals or drugs which induce leukaemia in man. PMID- 21590120 TI - Enhancement of apoptosis in irradiated glioblastoma cells by pentoxifylline. AB - The p53 gene is frequently mutated in human glioblastomas, which are highly resistant to radiation and chemotherapy. Pentoxifylline has recently been shown to sensitize breast cancer cells in which the wild-type p53 function was abrogated to cisplatin-induced apoptosis. In this study, the effect of pentoxifylline on three irradiated human glioblastoma cell lines, U87MG, which has the wild-type p53; U251, which has a mutant p53; and LN-Z308, which has no p53, was examined. After radiation, even at a dose as high as 20 Gy, typical apoptotic cells were rarely produced. G(2) cell cycle arrest was observed with all three cell lines. Significant G(1) cell population was only observed with U87MG cells, in which increased levels of p21/WAF1/Cip1 occurred. Pentoxifylline increased the amount of radiation-induced DNA fragmentation and apoptosis in p53 defective U251 and LN-Z308 cells. Colony formation assay demonstrated that pentoxifylline moderately enhanced the cell killing effect of irradiation in these cells. PMID- 21590121 TI - De novo germline mutations of the p53 gene in young children with sarcomas. AB - Germline p53 mutations are associated with cancer predisposition in Li-Fraumeni families as well as in individuals with component tumors of the syndrome. In the majority of cases these mutations have been shown to be inherited rather than de novo. We screened 59 children with primary bone or soft tissue sarcomas. Germline p53 mutations were identified in 2 patients. Interestingly, analysis revealed that both mutations were de novo. Although the frequency of germline p53 mutations in primary pediatric sarcoma patients is low, there is evidence for the importance of considering pediatric patients for testing for de novo mutations. PMID- 21590122 TI - Preparation of the antibodies against recombinant human thymidylate synthase for the detection of its intratumoral levels and the application to sensitivity-study of 5-fluorouracil. AB - Thymidylate synthase (TS) is a rate-limiting enzyme in de novo DNA biosynthesis and also a primary target for 5-fluorouracil (5-FU)-based chemotherapy. To estimate the con-elation between the expression of TS in the tumor, clinical response and prognosis in cancer patients treated with 5-FU, we have prepared recombinant human TS (rhTS) protein by culturing of E. coli transfected with the plasmid (pGEX-2TH) encoding the nucleotide sequence of hTScDNA and then obtained a highly purified polyclonal antibody against rhTS protein. Using this anti-TS antibody, it was revealed that the content of TS protein, as determined by Western blot analysis, correlated with the enzyme activity (gamma=0.973) and cytotoxicity of 5-FU, expressed as IC50 value (gamma=0.954) against human colon tumor cells, sensitive to and with acquired-resistance to 5-fluoropyrimidines and other cancer cells. On immunochemical evaluation, it was also confirmed that the tumor cells overexpressing TS proteins were strongly stained by the polyclonal antibody when compared to the cell lines expressing TS to lower extent both in vitro and in vivo conditions. These results indicate that this purified polyclonal antibody to rhTS is applicable to prospective and retrospective clinical studies on immunochemical TS expression in various tumors as a prognostic factor and 5-FU response-predicting parameter. PMID- 21590123 TI - Establishment and characterization of a new cell line derived from a human chondrosarcoma. AB - A new human cell line, CAL 78, derived from a dedifferentiated chondrosarcoma of the muscle of the thigh has been established in culture. Fibroblastoid morphology, vimentin expression and lack of epithelial antigens are in agreement with mesodermic origin of these cells. The xenograft of CAL 78 cells in nude mouse showed the characteristics of hyaline cartilaginous differentiation. Cytogenetic changes were numerous and complex, all the metaphases were tetraploid and no alterations described by other authors have been found. CAL 78 constitutes an appropriate model to evaluate efficiency of a new therapy for chondrosarcomas. Moreover, this cell line may be used to study some stage of chondrocytic differentiation. PMID- 21590124 TI - Expression and localization of matrix metalloproteinases and tissue inhibitors of metalloproteinases as a prognostic factor in advanced colorectal carcinomas. AB - To clarify the usefulness of matrix metallo-proteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) as prognostic factors in advanced colorectal carcinoma, the immunohistochemical expressions of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1 and TIMP-2 were examined. Specimens were selected from 67 consecutive patients undergoing surgery for advanced colorectal carcinoma. The patterns of expression were compared with the prognoses of the patients. The patients with TIMP-2 expression in stroma adjacent to the tumor mass had better prognoses than those of the patients who had no TIMP-2 expression in normal stroma adjacent to the tumor (p<0.05), which probably acted as a block of cancer cell invasion. However, the expression of MMP-2, presumably acting as an antagonist to TIMP-2 was not related to the prognosis, and the MMP-1, MMP-2, MMP 3, MMP-9 and TIMP-1 expressions were not related to any clinicopathological factors examined. PMID- 21590125 TI - nm23-H1 expression in salivary adenoid cystic carcinoma in relation to metastasis and survival. AB - The expression of nm23-H1, product of putative metastasis suppressor gene, was evaluated immunohistochemically in 31 cases of adenoid cystic carcinoma (ACC) of salivary glands and correlated with their clinicopathologic features. All benign salivary gland tumors of various types, which were used as a non-metastatic control, showed obvious nm23-H1 expression. The immunoreactivity of tumor cells was stronger than that of normal salivary gland components, although the distribution patterns of positive cells considerably varied between tumor types. In ACC, 16 cases (52%) showed the reduction of nm23-H1 immunoreactivity either in positive cell frequency or staining intensity. These cases were referred to as negative cases. The incidence of negative cases was 67% (10/15) and 38% (6/16) of the cases with and without metastasis, respectively. Furthermore, metastatic tumors showed decreased immunoreactivity of this protein compared with their primary tumors. The prognosis of patients with a nm23 negative tumor was generally poorer than that with a positive tumor. These results may suggest that the reduction of nm23-H1 protein has an implication for metastasis of ACC. PMID- 21590126 TI - Inguinal lymph node recurrence of mucosal cancer of the stomach. AB - Metastasis to the inguinal lymph node from early gastric cancer is rare. We report a case of 63-year-old Japanese male with gastric mucosal cancer which metastasized to the left inguinal lymph nodes 4 years after a curative gastrectomy. The importance of routine examination of inguinal lymph nodes for cases with gastric cancer is suggested. PMID- 21590127 TI - Clinical efficacy of leuprorelin acetate monthly depot in premenopausal patients with metastatic breast cancer. AB - We included 58 premenopausal patients with metastatic breast cancer in an open study with leuprorelin acetate monthly depot. The overall response rate was 15/50 patients (30%). The median duration to tumour progression according to Kaplan Meier analysis was 12 months. After leuprorelin acetate treatment permanent suppression of ovarian function was recorded with oestradiol levels below 30 pg/ml. The side effects were acceptable. The most common were: menopausal complaints, headache, dizziness and nausea. Changes of laboratory parameters were caused by cessation of ovarian function and progression of the underlying disease. Leuprorelin acetate is an effective drug for first line palliative treatment of premenopausal, metastatic breast cancer. The objective response rate is similar to other GnRH analogues and to reported data on surgical oophorectomy. PMID- 21590128 TI - Hydroxyurea as a modulator of multidrug resistance in resistant solid tumor. AB - We enrolled 11 consecutive pre-treated resistant advanced cancer patients to receive hydroxyurea (HU) (as modulator of MDR) 10 mg/kg/day (d) p.o. d 1-14 in association with DXR (d 15) alone or in combination with VDS (d 15) or VP16 (d 15 17) in presence, respectively, of soft tissue sarcoma, breast carcinoma, lung and gastric carcinoma. We obtained a stabilization of disease (NC) in 62.5% of patients, with a mean duration of 6 months. The mean survival was 12.2+ months for NC and 6 months for progressive disease (PD). No severe or unexpected adverse events were reported over 34 cycles administered; the most frequently recorded side effects were haematological and gastrointestinal toxicity. It seems that at the dosage we used, HU is poorly active in overcoming MDR; further studies with larger number of patients and different dosage are needed. PMID- 21590129 TI - Amifostine (WR-2721, Ethyol(TM)) can protect human endothelial but not tumor cells from cisplatin-induced cytotoxicity. AB - Amifostine (WR-2721, Ethyol(TM)) is a chemo-and radioprotective agent which is increasingly used in clinical practice to minimize antitumor therapy-induced toxicities. The key of this property of amifostine is certainly its selective action in terms of differential protection of normal tissue and not of tumor cells. Using HUVEC cells and three different cancer cell lines (A549 non-small cell lung cancer, DND-1A melanoma and HeLa cervical carcinoma) we provide evidence that amifostine could protect normal, and not cancer cells, from cisplatin (CDDP)-induced cytotoxicity in vitro. Furthermore, low doses of amifostine, easily attainable in vivo, can protect 50% of normal cells in vitro from CDDP-induced cytotoxicity. PMID- 21590130 TI - Enhancement by aminoguanidine of gastric carcinogenesis induced by N-methyl-N' nitro-N-nitrosoguanidine in Wistar rats. AB - The effects of prolonged administration of aminoguanidine on gastric carcinogenesis induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG), the ornithine decarboxylase activity of the gastric wall, and the labeling index of the gastric mucosa were investigated in inbred Wistar rats. The rats received 12.5 or 25.0 mg/kg body weight of aminoguanidine s.c. every other day after oral MNNG treatment for 25 weeks. Prolonged administration of aminoguanidine at 25.0 mg/kg body weight, but not at 12.5 mg/kg body weight, significantly increased the incidence of gastric cancers in experimental week 52. However, it did not influence the histologic types of gastric cancers. Aminoguanidine at 25.0 mg/kg body weight also significantly increased the ornithine decarboxylase activity of the antral portion of the gastric wall and the labeling index of the antral epithelial cells. These findings indicate that aminoguanidine enhances gastric carcinogenesis and suggest that its effect may be related to increased proliferation of antral epithelial cells. PMID- 21590131 TI - Lack of prognostic significance for p53-overexpression and Ki-67-immunoreactivity in oral T1-2 squamous cell carcinomas. AB - Previous investigations on squamous cell carcinomas (SCC) of the head and neck region have failed to reveal a significant correlation between p53-overexpression or Ki-67-immunoreactivity and survival. Contrary to these studies we restricted the evaluation to T1-2 SCC from the oral cavity. Immunohistochemically identified p53-overexpression was observed in 69% of the tumours, and Ki-67-positive cancer cells ranged from 12 to 83% in individual rumours (median 37%). No significant correlation was found between p53-overexpression or Ki-67-positivity and survival. Although the degree of tumour differentiation and the pattern of invasion correlated with prognosis (p=0.0387 and 0.0319 respectively), these associations were too weak to be used as prognostic markers. PMID- 21590132 TI - E-cadherin and c-met expression as a prognostic factor in gastric cancer. AB - E-cadherin has an important role in the cell-cell adhesion and is known as an invasion suppressor gene. The c-met, which is a receptor of hepatocyte growth factor receptor, is involved in the proliferative and motile activity in cancer cells. The invasive and metastatic capacities of gastric cancer were studied from the immunohistochemically examined expression of MET and E-cadherin. Among 127 primary gastric cancers, 47 (34%) tumors were found to have preserved E-cadherin expression and the other 84 tumors showed reduced E-cadherin expression. MET expression was found in 55 (43%) tumors. A strong correlation was found between reduced E-cadherin expression and a larger tumor, positive serosal invasion, lymph node metastases or poor prognosis. Tumors with MET expression have the tendencies to invade deeply, to metastasize in more remote lymph nodes or peritoneum and to run a poor prognosis. MET over-expression and reduced E cadherin expression were strongly associated with lymph node metastasis, peritoneal dissemination and poor prognosis. This group of patients with simultaneously abnormal expressions of these genes had a sixfold relative risk of death, as compared with patients with tumors showing MET negative or preserved E cadherin expression. These results indicate that immunohistochemical combined analyses of MET and E-cadherin expression may be a powerful tool for the evaluation of invasive capacity and the prognosis of gastric cancer patients. PMID- 21590133 TI - Prognostic value of AgNOR counting. AB - The prognostic significance of the argyrophilic nucleolar organizer regions (AgNORs) in tumour pathology is still a matter of debate. A prospective study was performed in a series of renal cell carcinomas to clarify the prognostic value of AgNOR counting. Sections from 21 renal cell carcinomas were stained in 1990 with the method of Ploton. Black dots within the nucleus from 200 tumour cells were counted: the mean AgNOR count for the whole series was 6.13, the median 5.94 and the SD 1.78. Patients were then followed up for at least 6 years or to death: at the time of the survival analysis (June 1996), 13 patients were alive without evidence of recurrence or metastasis, 6 had died of the disease and 2 of myocardial infarction. All the patients with 5.94 AgNORs per cell or fewer were alive at 6-year follow-up, while only 60% of patients with more than 5.94 AgNORs per cell survived (p=0.01). In the multivariate analysis, only AgNOR count (p=0.015) retained an independent prognostic significance. With the limitation due to the small number of cases, this prospective study clearly indicates that AgNOR count has a significant prognostic role, at least in renal cell carcinoma. PMID- 21590134 TI - Suppression of tumor metastasis by manganese superoxide dismutase is associated with reduced tumorigenicity and elevated fibronectin. AB - We have examined the tumorigenicity and the level of extracellular matrix proteins in fibrosarcoma cells expressing low (SOD-L) and high (SOD-H) MnSOD activities as well as the fibrosarcoma cells transfected with the selectable marker alone (NEO). When the cells derived from each tumor cell line were injected into syngeneic mice., the number of tumor cells required to make a tumor in one-half of the mice (TD50) was markedly increased in MnSOD-transfected cells. The decrease in the tumorigenicity of the MnSOD-transfected cells was associated with an increase in the fibronectin level. These results support the hypothesis that MnSOD is a new type of tumor-suppressor gene. PMID- 21590135 TI - Alterations of cholesteryl ester metabolism characteristic for cancer. AB - Earlier as well as recent evidence obtained in our laboratory is reviewed indicating that specific changes in cholesteryl ester metabolism are related to tumor growth. Some properties of cholesteryl 14-methylhexadecanoate, an unknown lipid discovered and identified in our laboratory are described and its fundamental role as an essential cofactor in protein synthesis is emphasized. Increased quantities of this ester are present in tissues of tumor-bearing animals and the elevation of its level in serum is proportional to the tumor growth. Evidence has been presented that it may be a useful and reliable marker of malignant tumors in humans. This compound is synthesized in liver cells by enzymes that were recently purified to homogeneity from rat liver. The activity of these enzymes is significantly enhanced in tumor-bearing rats in a close proportion to the tumor growth. Activity of these preparations from normal rat liver may be greatly enhanced by the addition in vitro of serum from cancer patients. Since the enzymes are of lecithin-cholesterol acyl transferase type, apparently cancer serum contains some peculiar molecular species of these phospholipids. Because these lipids may be specific products of tumor cells, attempts are now in progress in this laboratory to identify them and the possibility is studied for their utilization as specific tumor markers. PMID- 21590136 TI - Overexpression of p53 associated with tumor angiogenesis, tumor cell proliferation, and prognosis in gastric carcinoma. AB - Mutations in the p53 gene seem to be the most common genetic change in human malignancies. Recently, it was reported that p53 mutation was significantly associated with prognosis in various cancers. In this study, we investigated the correlation between p53 overexpression and prognosis of gastric carcinoma using immunohistochemical staining with an anti-p53 antibody. Although there was no significant association between p53 status and various clinicopathologic factors, prognosis of patients with p53-positive tumors was significantly worse than of those with p53-negative: tumors. Both microvessel count (MVC; the mean number of microvessels in the five areas of highest vascular density at 200x magnification) and PCNA labeling index (PCNA LI; percentage of positive cells per more than 500 tumor cells) were significantly higher in p53-positive tumors than in p53 negative tumors. In summary, it is suggested that p53 overexpression is closely associated with tumor angiogenesis, tumor cell proliferation and prognosis of gastric carcinoma. PMID- 21590137 TI - Are CD44 spliced variants involved in human breast cancer metastasis? AB - Expression of CD44 isoforms has been investigated on normal breasts, fibroadenomas, cysts and breast cancers. Carcinomas express additional variants in comparison with normal breasts while fibroadenomas and cysts do not. Invasive cancers also express more variants than in situ carcinomas. Recent studies tend to demonstrate that overexpression of CD44 is not a survival prognostic factor whereas expression of exon 2v and/or 3v could be. Results for exons 4v to 10v are presently conflicting. Further studies will then be necessary to clarify the role of CD44 isoforms in mammary carcinogenesis and metastasis. Metastatic capacity could be linked with expression of additional variants but also with no transcription of variants associating exon 6v with either exon 10v or both exons 9 and 10v. PMID- 21590138 TI - Human achaete-scute homolog-1 is highly expressed in a subset of neuroendocrine tumors. AB - Human achaete-scute homolog-1 (hASH1) is critical for establishing the neuroendocrine (NE) phenotype of small cell lung cancer. To define its role in other neoplasms, we analyzed 33 tumors for hASH1 by Northern blotting. Significant levels of hASH1 mRNA were detected in 4 pheochromocytomas, 2 medullary thyroid cancers, and 1 thymic carcinoid. hASH1 transcripts were undetectable in 8 parathyroid lesions, 6 gastrinomas, 4 insulinomas, and 7 thyroid neoplasms, as well as in normal thyroid, adrenal, or pancreas tissue. Therefore, hASH1 mRNA is highly abundant in a subset of human tumors and may play a role in dictating their NE phenotype. PMID- 21590140 TI - Oral vehicle administration before radiation causes radioprotection of murine SCCVII tumors. AB - The effect of administering various vehicles on the response to radiation of SCCVII tumors in C3H mice was investigated. When saline, 0.5% carboxymethyl cellulose solution, or 1% hydroxypropylmethyl cellulose (HPMC) solution was given orally 30 min before single 15 Gy irradiation, the tumor regrowth was significantly faster than that seen after 15 Gy treatment alone. There was no difference in this radioprotective response due to the type of vehicle. On the other hand, the tumor regrowth was similar to that seen after 15 Gy alone when saline was given intravenously 20 min before irradiation or intraperitoneally 30 min beforehand, or when 1% HPMC was given orally 2 h beforehand. Oral vehicle administration shortly before irradiation can cause radioprotection of murine tumors, probably by increasing the hypoxic fraction. PMID- 21590139 TI - Vitamins A and E in neoplastic disease. AB - Vitamins A and E play an important role against 'free radicals' (FRs). Their antioxidant action is evident in neoplastic disease (ND) that is known to have a FRs pathology. This finding has been supported by previous research showing increased lipid peroxidation of the erythrocyte membrane with increased permeability and higher hemoglobin susceptibility to oxidative stress. Connections exist between the two vitamins and FRs lipid peroxidation of the membranes. In order to study A and E vitamin behaviour in ND, they were assayed in the sera of 88 cancer patients versus 94 healthy subjects. In the 88 cancer cases, without considering variables such as age, sex and smoking habits, the average amount of vitamin A was 47.44+/-19.60 mu g/dl versus 71.77+/-18.30 in controls (P<0.0001). The average amount of vitamin E was 1144.42+/-507.45 in ND versus 1497.45+/-397.74 in controls (P<0.0001). The two vitamins were simultaneously assayed in the same serum by high pressure liquid chromatography. The method is rapid and gave exact and repeatable results. Reasons for vitamin decrease are discussed. PMID- 21590141 TI - Relationship between microsatellite instability and histologic types of colorectal carcinoma. AB - To evaluate the relationship between microsatellite instability (MIN) and histologic types of carcinomas in different organs, we analyzed how often MIN occurred in signet ring cell carcinomas of the colon (7 cases), stomach (13 cases), urinary bladder (5 cases), and prostate (3 cases). We also analyzed MIN and the expression of Epstein-Barr virus encoded RNA (EBER) transcripts in undifferentiated carcinoma with lymphoid stroma: 18 cases of lymphoepithelioma like carcinoma (LELC) of the colorectum and 8 of the stomach and 9 cases of lymphoepithelial nasopharyngeal carcinoma (NPC). MIN was frequently observed in the signet ring cell carcinomas (4/7, 57%) and LELCs (12/18, 67%) of the colorectum, but was not found in the signer ring cell carcinomas of the urinary bladder or prostate or in NPCs and occurred significantly (p<0.05) less often in both gastric signer ring cell carcinoma (1/13, 8%) and gastric LELCs (1/8, 13%). Most of the gastric LELCs (5/6) and all of the NPCs in which MIN was not identified expressed EBER transcripts. Thus, MIN appear to be specific for signer ring cell carcinomas and LELCs of the colorectum, but there was no strong correlation between MIN and carcinomas in other organs. Different genetic alterations in the different organs could result in the formation of carcinomas of similar types. PMID- 21590142 TI - The influence of pyrimidine nucleoside phosphorylase activity on metastasis of breast cancer. AB - The activity of pyrimidine nucleoside phosphorylase (PyNPase) was analyzed in thirty-six cases of resected breast cancer and 9 cases of resected benign breast tumor. PyNPase is an enzyme which converts 5'-DFUR to 5-FU in tumor tissue and has been reported to be identical to the platelet-derived endothelial cell growth factor (PD-ECGF) that has angiogenic activity. PyNPase activity was significantly elevated in cancer and metastatic lymph nodes compared to normal lesions of the same breast. PyNPase activity was higher in T2 and T3 breast cancer than of T1 breast cancer. Furthermore, cases of high PyNPase activity (>200 mu g FU/mg protein/h) were significantly more likely to develop distant metastasis (p<0.01) than those of low PyNPase activity. These results suggest an important role of PyNPase activity in the progression of breast cancer. PMID- 21590143 TI - Combination chemoendocrine therapy containing vindesine for refractory metastatic breast cancer. AB - Metastatic breast cancer has ultimately failed to respond to the multiple prior therapies, and thus new therapeutic regimens are required. Nine patients with metastatic breast cancer previously treated with multiple therapeutic regimens were enrolled. The treatment schedule was as follows: vindesine was given intravenously at a dose of 2 mg/m(2) every four weeks. Etoposide and medroxyprogesterone acetate was orally administered at a dose of 25 mg/day for 14 consecutive days and 600 mg/day every day. Only one patient with exclusive bone metastasis showed partial response and the objective response rate for the combination of agents was 11%. Pain derived from the metastatic lesions was reduced in four (80%) among five patients with bone metastasis. For patients with refractory breast cancer, especially with bone metastasis, chemoendocrine therapy containing vindesine might have therapeutic efficacy with low toxicity and favorable quality of life. PMID- 21590144 TI - A case of liver metastasis of malignant peritoneal mesothelioma successfully treated by surgery. AB - We herein report a very rare case of liver metastasis of malignant peritoneal mesothelioma occurring in a 47-year-old old woman, who had undergone a right lobectomy of the liver, and is still alive and well more than 2 years after the initial surgery. There is little information on how to successfully treat liver metastasis of this disease. Since mesothelioma cells rarely respond to chemotherapy cr radiation, we conclude that surgery plays an important role in the management of liver metastasis of malignant peritoneal mesothelioma. PMID- 21590145 TI - A primary cardiac leiomyosarcoma with mutation at H-ras codon 12. AB - The presence of activating ras mutations in a cardiac leiomyosarcoma which occurred in the right atrium of the heart of a female patient was examined. The tumor had the appearance of leiomyosarcoma in rutine histopathological examination and the definite diagnosis was confirmed by a positive immunohistochemical reaction to smooth muscle actin. Molecular analysis by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) technique showed a point mutation of H-ras gene at codon 12. To the best of our knowledge, this is the first report describing ras gene mutation in a cardiac leiomyosarcoma implying a role for the ras oncogenes in the development of this tumor. PMID- 21590146 TI - Helicobacter pylori, atrophic fundal gastritis and risk for gastric adenocarcinoma. AB - Fundal atrophic gastritis and Helicobacter pylori have been implicated as possible etiologic factors in gastric cancer. This case-control study was performed to determine which risk factor is more closely related to gastric cancer. The endoscopic Congo red test was performed to evaluate the extent of fundal atrophic gastritis in 43 patients with gastric cancer and 86 cancer-free control subjects, who were individually matched by age, sex, and date of endoscopy (within 3 months). The prevalance of H. pylori infection and severe fundal gastritis were significantly higher in patients with differentiated adenocarcinoma, but not with undifferentiated adenocarcinoma, than in control subjects. The odds ratios for differentiated and undifferentiated adenocarcinomas were 6.85 (95% confidence interval, 1.94-11.82) and 1.50 (95% CI, 0.84-3.11), respectively. However, the odds ratio of H. pylori infection was greater than that of severe fundal gastritis. Moreover, multivariate analysis provided similar results. H. pylori infection is an independent indicator of a higher risk of the differentiated adenocarcinomas of the stomach than is severe fundal gastritis. PMID- 21590147 TI - Expression of variant CD44, exon 6 in patients with metastatic pulmonary tumor. AB - High expression ratios of CD44 variant 6 (CD44 V6) in patients with metastatic pulmonary tumor were found in those with primary lesions of cancer of the colon, uterus, larynx, liver and osteosarcoma. It was clarified that patients showing expression of CD44 variant 6 likely revealed pulmonary metastasis at earlier time following operations of primary cancer (p<0.05). CD44 V6, an adhesion molecule, was a factor to participate in pulmonary metastases from various organ cancers. No significant correlation was observed in survival between patients with CD44 V6 positive versus negative tumors, except laryngeal tumor after resection of primary or metastatic lung tumor. CD44 V6 related to its invasive and further metastatic functions in metastatic lung tumor. We suggest that cancer cells expressing the CD44 molecule especially V6 may adhere to vascular endothelium and hyaluronic acid in the lung. And cancer cells without this molecule liberated from the primary focuses hardly adhere to the pulmonary tissues supposedly resulting in delayed metastases and proliferations in the pulmonary tissues. PMID- 21590148 TI - Prognostic values of serum CA19-9 and CEA levels for colorectal cancer. AB - CA19-9 and CEA are associated with gastrointestinal malignancy as adhesion molecules. We measured serum CA19-9 and CEA levels in 328 patients with colorectal cancer. Both serum CA19-9 and CEA levels correlated significantly with recurrence and survival, respectively. Serum CA19-9 levels correlated significantly with survival according to Astler-Coller stage and multivariate analysis. Serum CEA levels showed no such correlations, although the combination of CEA with CA19-9 improved the sensitivity for predicting recurrence. Assessment of serum CA19-9 levels is more important than that of CEA in the clinical management of patients with colorectal cancer. PMID- 21590149 TI - Acute acalculous cholecystitis complicating oral recontamination after allogeneic bone marrow transplantation. AB - Acalculous cholecystitis (AAC) is a well known complication in critically ill patients. Risk factors include mechanical ventilation, total parenteral nutrition and multiple blood transfusions. AAC has very rarely been described in patients undergoing allogeneic BMT. We report a case of AAC in a 25-year old female occuring after successful allografting for acute myeloid leukemia. The patient presented with leukocytosis, acute abdominal pain, right upper quadrant guarding and laboratory signs of liver dysfunction coincidentally with oral recontamination 38 days after BMT. AAC was diagnosed during explorative laparatomy and cholecystectomy was performed. Following surgery the patient developed acute graft versus host disease but recovered completely. PMID- 21590150 TI - P53 protein overexpression in lung adenocarcinomas in non-smokers. AB - Greater than 55% of all lung cancers contain mutations in the p53 tumor suppressor gene, and the frequency of p53 mutations has been directly correlated with the use of tobacco and the smoking of cigarettes. To determine if environmental tobacco smoke (ETS) is associated with changes in p53 expression in human lung cancer in never-smokers, we determined the degree of p53 protein expression in ten lung tumors from never-smokers exposed to ETS. We show that 5 of 8 (62.5%) adenocarcinomas contained significant levels of p53 protein overexpression as detected by immunohistochemical staining. While these findings suggest that ETS is a possible inducer of altered p53 expression in lung adenocarcinoma in non-smokers, larger studies are needed to confirm this relationship. PMID- 21590151 TI - Elevated breast cancer serum markers in otherwise healthy women. AB - A high value of mucin-like carcinoma associated antigen (MCA), CA-15.3 or H23, in a woman known to have a diagnosis of breast cancer, may reflect presence of disease. A low level in a breast cancer patient may be accepted for remission, but a false negative result cannot be excluded. On the other hand, a low level of serum tumor marker in the general population actually lacks any significance. However, what is the meaning of an elevated level of marker, known to have a relatively high sensitivity and specificity, in an otherwise healthy woman? Does it mean an occult breast cancer or a false positive? Sera samples were obtained from 155 consecutive, otherwise healthy women, who were referred for mammography, and assayed for tumor markers. MCA was elevated in 15-24% of patients with normal mammogram, depending on their ages. Lack of elevation of a second marker in most of the cases supported the assumption that the elevation of the MCA was insignificant. Elevation of H23 occurred more frequently in younger women than in the elders, but was not associated with elevation of a second marker. In the cases with abnormal mammogram due to histologically proven benign disorders, serum tumor markers were generally within the normal ranges. Our results pointed to the lack of diagnostic significance of an elevated level of serum tumor marker, as far as the mammogram was normal or benign, there was no history of cancer nor any other systemic disease (including malignancy), and a second tumor marker was within the normal range. The women with presently false positive marker level may, however, be followed, because of the possible risk for future development of breast cancer. PMID- 21590152 TI - Lack of correlation between cisplatin cytotoxic effect and potential Na, K adenosine triphosphatase (Na, K-ATPase) activity or intracellular level of glutathione. AB - The use of cisplatin as a cancer chemotherapeutic agent is limited by its dose dependent nephrotoxicity. It has been suggested that the differential toxic effects of cisplatin may be related to differences in Na+/K+ ATPase activity or levels of glutathione (GSH). The present study evaluated these possibilities by testing cells from different tissue origins for their sensitivities to cisplatin and the numbers of Na+/K+ ATPase, affinities to ouabain and intracellular glutathione levels. Our results have shown that the cytotoxic effect of cisplatin was in the order of Calu-1>U-138MG>HEK>SK-HEp1>AGS>TL cells. Dissociation contants (K-d) of the different cell lines to ouabain revealed that the U-138MG cells (29 pM) had the highest affinity while the SK-HEp1 cells (123 pM) had the lowest. In addition the most number of ouabain binding sites was detectable on the Calu-1 cells (2.388x10(5)/cell) with the lowest in the U-138MG (5.22x10(4)/cell) cells. Linear regression analysis of these data indicate that there is no correlation between toxicity of cisplatin to the density (p=0.6563) or affinity (p=0.5499) of the Na+/K+ ATPase to ouabain on the responding cells. Nor is there a direct correlation between cisplatin toxicity and the level of intercellular GSH. These results suggest that activity of Na+/K+ ATPase or level of GSH alone is not sufficient to account fbr the differential toxicity of cisplatin nor is it a necessary trait of cisplatin resistance. PMID- 21590153 TI - Chemotherapy-induced severe thrombocytopenia in gynecologic oncology and its treatment with interleukin-3. AB - Six patients suffering from various gynecologic malignancies developed severe thrombocytopenia (WHO IV) after normal-dose chemotherapy. All patients were treated with platelet transfusions but the results on hematopoietic recovery were not satisfactory. Therefore treatment with a new hematopoietic substance (rh interleukin-3) was initiated. All patients received a dosage of 5 mu g/kg/bw daily s.c. up to 10 days depending on the response of platelet counts. In two women, who had suffered from severe hemorrhage (epistaxis resp. ankle joint hematoma), symptoms disappeared after approximately three days of rhIL-3 use. Whereas platelet transfusions were ineffective in all patients, IL-3 led to a significant increase of the platelet count after 3-5 days of application. Side effects were mild, when seen in one case, where G-CSF was given at the same time. Our experience supports the idea of using new growth factors like rhIL-3 to cure chemotherapy-induced myelosuppression, such as severe thrombocytopenia. PMID- 21590154 TI - Tamoxifen for disease-negative but MCA-positive breast cancer patients. AB - Increased levels of mucin-like carcinoma-associated antigen (MCA) in breast cancer patients with no evidence of disease following the treatment of the primary disease created a dilemma of 'to treat' or 'wait and see'. One might assume that early treatment of clinically undetectable disease on the basis of an elevated serum level of a sensitive and reliable tumor marker, may improve the treatment results, and even prolong the patient's survival. 'Wait and see' on acceptance of the notion that even early metastatic disease, still manifested only by uprising MCA levels, is incurable, and treatment should be kept in reserve for palliation of symptomatic disease. Sixty-one breast cancer patients with increasing MCA levels but without evidence of metastatic disease were randomized for tamoxifen 20 mg b.i.d. or to follow-up till relapse. The results for a median follow-up period of one year were encouraging. The non-treated patients experienced a significantly higher relapse rate (24.1%) than the tamoxifen-treated subjects (0%; p=0.012). The results for a median follow-up of 5 years were disappointing. The overall relapse rate was 22.2%. The relapse rate among the control patients was 25.8% while in the treatment arm it was 17.4% (p=0.46). The event-free survival and the pattern of relapse were similar in both arms. Tamoxifen may therefore be reserved for overt metastases, and not wasted on asymptomatic subclinical disease. It seems that there is no yield in terms of event-free survival for MCA measurements in breast cancer patients during the 5 year follow-up period. PMID- 21590155 TI - Salvage chemotherapy with cladribine in a patient with recurrent malignant oligodendroglioma. AB - Oligodendrogliomas appear to be the most chemoresponsive subtype of gliomas. PCV (procarbazine, CCNU, vincristine) chemotherapy produces significant response rates and probable prolongation of survival. Unfortunately there is no well defined second line chemotherapy. There is evidence that the purine analogue cladribine has activity in astrocytomas, which are much less sensitive to chemotherapy than oligodendrogliomas, but the use of cladribine in oligodendrogliomas has never been reported. We describe the unsuccessful use of cladribine as third line chemotherapy in a young man with an aggressive oligodendroglioma. The literature pertaining to chemotherapy for oligodendrogliomas is reviewed. PMID- 21590156 TI - Urokinase-type plasminogen activator and its inhibitor plasminogen activator inhibitor-1. AB - Tumor associated proteolysis is an essential mechanism in invasion and metastasis of cancer. The influence of the serine protease urokinase-like plasminogen activator (u-PA) and its inhibitor plasminogen activator inhibitor-1 (PAI-1) on the clinical prognosis of squamous carcinoma of the head and neck region (HNSCC) was evaluated. U-PA and PAI-1 levels were measured in tumor biopsies of 41 HNSCC patients and 6 biopsies of healthy oral mucosa using ELISA technique. Patients were followed for an average of 24 months. U-PA concentration in tumor tissue was four times higher than in healthy mucosa (4.96 ng/mg protein versus 1.32 ng/mg). PAI-1 levels were 22 times higher (69.55 ng/mg versus 3.18 ng/mg). Univariate Cox regression analysis revealed significant correlation (p=0.022) of PAI-1 with recurrence of the disease and no significance for u-PA. PAI-1 might become a new functional risk factor reflecting clinical prognosis. PMID- 21590157 TI - Comparison of topoisomerase I and II expression in primary brain tumor and lung cancer. AB - Topoisomerase I (TOP I) and II (TOP II) activities and their corresponding levels were analyzed in 27 primary brain tumors and 32 lung cancers (28 NSCLC, 4 SCLC). The TOP I and II activities in primary brain tumors varied from 500-2,000 units/mg and 100-3,000 units/mg respectively. Their corresponding levels varied from <0.01-3.30 (TOP I) and 0.24-8.30 (TOP II) arbitrary units. In lung cancer, the TOP I and II activities ranged from 1,000-4,000 and 500-4,000 units/mg respectively with their levels ranging from 0.30-61.60 and 0.2-14.2 arbitrary units respectively. These parameters were compared in both tumors using the Wilcoxon rank sums test, the difference were statically significance for all four parameters with a p<0.0001 for TOP I and II activities and TOP I levels and p<0.09 for TOP II levels. Using linear regression analysis, there was no correlation between TOP I and II activities and their corresponding levels in primary brain tumor. However, in lung cancer, the relationship between TOP I activities and levels were linear with r(2)=0.2 and p<0.0094, but not for TOP II activity and their levels. There was no relationship between TOP I and TOP II levels in the same tumor for both types of cancer. The future clinical implication of these findings are discussed. PMID- 21590158 TI - Concomitant 5-FU, hydroxyurea and cisplatin with external beam radiation therapy for locally advanced pancreatic cancer. AB - The aim of the study was to determine the efficacy and toxicity of alternate week concurrent 5-fluorouracil, hydroxyurea, and cisplatin with radiotherapy for locally advanced pancreatic adenocarcinoma. Patients received 5-fluorouracil, hydroxyurea and cisplatin with radiotherapy on an alternate week basis. Chemoradiotherapy was given day 1-5, and no therapy given day 6-14 for each 14 day cycle. Chemotherapy doses were as follows: hydroxyurea 1 mg every 12 h starting day 0, 5-fluorouracil 800 mg/m(2)/day for 5 days starting day 1, and cisplatin 20 mg/m(2) daily for 5 days every other cycle. A radiation dose of 6000 cGy was prescribed. Acute toxicities were monitored and therapy modified for hematologic toxicity. Nine patients enrolled, however eight were evaluable; one patient expired prior to therapy. The median radiation dose delivered was 5540 cGy. Sixty-three percent required a chemotherapy dose reduction. Fifty percent achieved local control by radiographic imaging after completion of therapy. Median survival was 12 months. Acute toxicity included: 38% grade 2-3 nausea, 37% grade 2-3 vomiting, 63% grade 2-3 mucositis, 63% grade 2-3 neutropenia, and 88% grade 3-4 thrombocytopenia. Other sequelae included hand-foot syndrome, deep venous thrombosis, hearing loss, seizures, and anorexia. Patients achieved the same median survival as compared to other reported studies of radiation therapy with single agent 5-fluorouracil. We do not recommend this protocol due to the significant toxicity. Future studies to incorporate conformal radiation therapy with more active, less toxic chemotherapeutic agents should be investigated. PMID- 21590159 TI - Local anergy rather than systemic anti-tumour immunity to explain tumour growth in an animal model of oral squamous cell carcinoma. AB - A chemically induced syngeneic hamster tumour model of human oral squamous cell carcinoma (OSCC) was used to investigate the possible influence of locally transplanted growing rumours on the immune system of the recipient. Cell activation and cell cytotoxicity assays were performed in vitro using the colorimetric MTT assay to measure any possible changes. The fast growing nature of the tumour model if grafted locally as a fragment was confirmed but not if injected as a single cell suspension (SCS). Stimulation (Concanavalin A) of spleen cells from normal and from tumour bearing animals showed that there was a minor though statistically significant decrease in the mitogenic response of the latter. Thus, the respective stimulatory indices (SI) were 4.06+/-1.61 and 2.06+/ 0.87 (0.02

0.01). No significant difference was observed when spleen cells were stimulated with interleukin-2 (IL-2), although there was a similar trend. Pre immunisation of animals with irradiated autologous SCS three weeks prior to grafting, resulted in a significant decrease in the tumour growth rate of subsequently grafted tumour. Thus, the mean If: SD (weight of takes in mg) for the successful takes of untreated (n=10) and treated (n=9) groups were 52.0+/ 52.2 and 25.7+/-19.4 (0.02

0.05) respectively. The number of cases with no tumour takes were 2 of 10 (20%) and 6 of 9 (66%) respectively. In a separate experiment groups of 5 animals were immunized with an increasing number of cells as irradiated SCS, the results of which demonstrated an inverse correlation between the rate of tumour growth and the number of injected tumour cells. The addition of irradiated SCS to IL-2 activated normal spleen cells (LAK cells) in vitro led to a dose-related decrease in the efficiency of cytotoxicity of latter when tested against an xenogeneic super-sensitive surrogate tumour target cell line (Fen cells). Thus, the percent killing by IL-2-activated normal spleen cells was 56.4%. The corresponding mean values for IL-2 activated normal spleen cells in the presence of tumour SCS at 25/1 and 50/1 ratios were 35.9% (p<0.05) and 11.9% (p<0.001) respectively. Ln an attempt to establish the presence of T suppressor cells, spleen cells from tumour bearing animals were injected concomitantly with SCS into 5 recipients. After four weeks no tumour growth had occurred. In conclusion we demonstrated that the presence of injected or grafted tumour had only a minor effect on systemic immune function but induced a strong local anergic effect. This local anergic effect was demonstrable as blocking of LAK activity and thus perhaps allowed suppression of the functional activities of incoming immunocompetent cells. PMID- 21590160 TI - Relationship between microlymphatic vessel density within tumors and lymph node metastasis. AB - We assessed the relationship between microlymphatic vessel density (MLD) within tumors and lymph node metastasis. The SCID mice were injected subcutaneously with various human tumor cells. DNA was extracted from lymph nodes for specific detection of a human beta-globin-related sequence. The discrimination of lymphatic vessels was done by enzyme-histochemistry for 5'-nucleotidase in endothelial cells after an adequate inhibition of the activity. The nodal metastasis could be detected in mice with PC-14, and they developed high MLD. Mice without metastasis had low MLD excepting OST cells. Experimentally, we have observed high MLD within PC-14 tumors and its tendency toward lymph node metastasis. PMID- 21590161 TI - Expression of alpha-smooth-muscle actin antigen in thymoma and thymic cancer. AB - Using specimens from 95 patients with thymoma and 6 with thymic cancer, we studied the expression of an alpha-smooth-muscle actin antigen immunohistochemically. It was mainly identified in the cytoplasm of small spindle cells within stroma and in the cytoplasm of tumor cells excepting vessels. In thymomas, the stromal expression is related to poor survival, while the cytoplasmic expression within tumor cells correlate with good outcome. Our data indicate that significance of the smooth muscle differentiation may be different between stromal and tumor cells. This antigen may be a useful indicator of survival in thymic neoplasms, especially in thymoma. PMID- 21590162 TI - Expression of CA19-9, SLX, STN and CEA in relatively early gastric carcinoma. AB - Expression and presence of the carbohydrate antigens CA19-9, SLX and STN, and CEA in tissues and serum were examined in 132 patients with early or propria muscle invaded gastric cancer. The seropositive rate was not different in patients with cancer or gastritis. In tumor tissue, the positive rate for these antigens was 28.8% in CA19-9, 9.1% in SLX, 47.0% in STN and 72.9% in CEA. Results showed that gastric cancers, even at an early stage, produce abnormal carbohydrate antigens not detected in normal tissues. However, transfer of antigens into the circulation was not observed in patients with early gastric cancer, suggesting the possibility that number of carcinoma cells may be involved in the transfer of antigens into blood. PMID- 21590163 TI - Demonstration of a polymorphism in the gene ERCC1 by two DNA sequencing methods. AB - New methodology is important to the advancement of biomedical science. We recently described a polymorphism within exon IV of the ERCC1 gene, which is associated with an approximate 50% decrease in codon usage in some biological systems. In this report we show that this polymorphism can be readily demonstrated by standard manual DNA sequencing, and by a recently developed methodology which relies on spectrophotometric principles. The major advantage of this new methodology is that several-fold more samples can be assessed per unit time, at reduced cost. PMID- 21590164 TI - Antibacterial activity of adriamycin against bacillus Calmette-Guerin. AB - Although intravesical instillation of bacillus Calmette-Guerin (BCG) or adriamycin (ADR) is an established and effective therapy for superficial bladder cancer, the current major problems are BCG-resistant and ADR-resistant bladder cancer and recurrence after the instillation therapy. Combination therapy with BCG and ADR might overcome the drug-resistance of bladder cancer. However, before combined used of BCG and ADR, it should be clarified whether ADR has bactericidal and bacteriostatic effects on BCG or not, since only alive BCG has a potential antitumor effect. In the current study, the in vitro antibacterial activity of ADR was assessed on BCG by the standard serial two-fold dilution method. When BCG was treated with ADR at 0.13-125 mu g/ml for two hours, ADR had no effect on the viability and the growth of BCG. However, ADR at 250-1,000 mu g/ml had a bactericidal effect on BCG. Epirubicin (EPI) at 0.13-15.6 mu g/ml did not affect the viability and the growth of BCG, however, EPI at 31.3-1,000 mu g/ml had a bactericidal activity. Pirarubicin (THP) at 125-1,000 mu g/ml also had a bactericidal activity. The minimal inhibitory concentrations of ADR, EPI and THP were 250, 250 and 125 mu g/ml, respectively. This study demonstrates that ADR at high concentrations had bactericidal and bacteriostatic effects on BCG. These findings suggest that combination treatment with BCG and low dose ADR could be used and overcome the resistance of bladder cancer to BCG and ADR. The possible clinical implications of the combined use of BCG and ADR are discussed. PMID- 21590165 TI - Cisplatin, etoposide and bleomycin infusion (PEBi regimen) in good-risk patients with germ cell tumors. AB - Patients with good-risk germ cell tumors have an approximately 85-95% chance of cure with standard chemotherapy. However, acute and late toxicity may be severe and negatively influence the quality of life. In an attempt to reduce toxicity, we evaluated a new schedule including bleomycin administered-as a continuous infusion in patients with low and intermediate volume metastatic disease. Patients were treated as follows: cisplatin, 100 mg/m(2) day 4; etoposide, 100 mg/m(2) days 1 through 5; bleomycin, 15 unit bolus on day 1 followed by 30 mg as a continuous infusion for 72 h, with cycles repeated every 21 days. Between 1992 and 1996, 25 patients entered the study and were assessable for response and side effects. Major patient characteristics were: performance status ECOG 0-1; minimal disease, 13 patients, intermediate disease, 12; median age, 33 years (range 15 50). Twenty-one of 25 patients (84%) achieved a complete remission, 2 patients achieved a partial remission, and 2 patients did not respond to the regimen. At a median follow-up of 24 months, 24/25 patients were alive, 23 were without evidence of disease, and I had persistent disease. Grade III/IV side effects included leuko/neutropenia (8 patients), anemia (3 patients), and nausea/vomiting (3 patients). No drug-related deaths were observed, and no evidence of pulmonary toxicity was registered. In conclusion, the PEBi regimen is an effective and well tolerated regimen in patients with good-risk germ cell tumors and may be considered as a front-line chemotherapy. PMID- 21590166 TI - p53 protein overexpression in infiltrating ductal carcinoma of female breast and its association with lymph node metastasis. AB - Traditionally, prognosis in carcinoma of the breast is evaluated based on size and differentiation of the tumor and status of lymph node metastasis. In addition to these established markers, in this molecular age other parameters such as overexpression of p53, c-erbB-2 and c-myc proteins are increasingly used to assess the prognosis. At present, the prognostic value of the molecular markers, at best, is controversial and conflicting. In this study, we examined 67 infiltrating ductal. carcinomas of female breast with and without lymph node metastasis for p53 protein overexpression by immunohistochemistry on formalin fixed, paraffin-embedded tissue sections to ascertain if p53 positive tumors have greater metastatic potential than p53 negative tumors. In addition, p53 overexpression was also correlated with tumor size, grade, expression of estrogen and progesterone receptors, and age of the patient to clarify the issue of relevance of p53 overexpression in prognostication, p53 overexpression was observed in 39% of tumors and showed strong correlation only with the histological grade of the tumor. The incidence of p53 overexpression in grade 1, grade 2 and grade 3 tumors was 0%, 33% and 58% respectively. Lymph node metastasis was less frequent in tumors that overexpressed p53 protein. Twenty seven percent of primary tumors with lymph node metastasis showed p53 protein overexpression, in contrast to 44% of tumors without metastasis. No correlation was observed between p53 overexpression and all the other parameters evaluated except progesterone receptor negative status. These results suggest that p53 overexpression is not an independent prognostic indicator and should not be used to predict lymph node metastasis or aggressive behavior of the tumor. PMID- 21590167 TI - Experimental study of the effect of IL-6 on cancer cachexia. AB - Several cytokines, including IL-1, TNF, LIF and IL-6 have recently been proposed as cachexia inducers. We experimentally examined the participation of cytokines, particularly, IL-6, in cancer cachexia using the human digestive cancer cell lines MKN 28, MKN 45, MKN 74, Kato-III, OCUM-2M (gastric cancer), SW1990, Panc-1 (pancreatic cancer), and OCUG (gallbladder cancer). A high level of IL-6 was detected in the OCUG culture medium. Nude mice bearing OCUG tumor had reduced body weight even when the tumor was relatively small. Loss of both muscle and adipose tissue, anemia, hypoglycemia, and a high serum level of human IL-6 were observed in these mice. However, body weight recovered rapidly to the level of that of nontumor-bearing mice after resection of OCUG tumor. Antihuman IL-6 but not anti-murine IL-6 receptor antibodies significantly suppressed the development of cachexia as measured by various indicators of cachexia including loss of both muscle and adipose tissue, anemia and hypoglycemia, as well as weight loss. These results suggest that OCUG-bearing mice exhibited cancer cachexia mediated by IL 6, and that of OCUG cell line might be useful as a human digestive cancer cachexia model. PMID- 21590168 TI - Cisplatin modulates tumor cell susceptibility to tumor-infiltrating lymphocytes in vivo. AB - We investigated the in vivo augmentation of susceptibility of tumor cells to tumor-infiltrating lymphocytes (TILs) with cisplatin (CDDP). TILs showed cytotoxicity against autologous and established tumor cells. Pretreatment of tumor cells with CDDP 2 mu g/ml for 12 h enhanced the susceptibility of tumor cells to TILs in vitro. TILs and autologous tumor cells were obtained from malignant ascites of patients, before and after the intraperitoneal administration of CDDP. TILs had higher cytotoxicity against autologous tumor cells of CDDP treated as compared to untreated control tumor cells, providing direct evidence of in vivo immunomodulatory effect of CDDP in cancer patients. PMID- 21590169 TI - Carcinogenesis by the cultivated baked Agaricus bisporus mushroom in mice. AB - The mushroom of commerce in the Western hemisphere, Agaricus bisporus, was administered orally to Swiss mice that were 6 weeks old at the start of the experiment The mushrooms were baked at 220-230 degrees C for 10 min. Subsequently, the mushrooms were fed to the animals for 3 days and were followed by a semisynthetic diet for 4 days each week, for life. The treatment induced tumors in the forestomach, glandular stomach, duodenum, and ovaries in the following incidences: 20, 12, 14 and 12% in females and 16, 20, 4 and 0% in males. In the tissues of the untreated controls, only an ovarian tumor was found in a female. Histopathologically, the neoplasms were classified as squamous cell papillomas and carcinomas of the forestomach, and adenomas and adenocarcinomas of the glandular stomach, duodenum, and ovaries. Since Agaricus bisporus is mainly eaten in baked form in the United States, the findings may carry useful implications. PMID- 21590170 TI - Overexpression of manganese superoxide dismutase gene changes the metastasis associated-character of the mouse fibrosarcoma, FSa-II. AB - The tumor metastatic ability and tumorigenicity of the mouse fibrosarcoma cell line (FSa-II) were significantly reduced due to overexpression of manganese superoxide dismutase (MnSOD) as reported previously. We investigated changes in the in vitro basic character of FSa-II cells transfected with the human MnSOD cDNA which was employed in the previous studies. FSa-II and the control vector transfected cell line NEO, had no detectable MnSOD activity. SOD-H, into which MnSOD cDNA was transfected, is the cell line with high MnSOD activity. The malignant phenotype, characterized by serum-independence, was suppressed with elevated MnSOD activity. A quantitative comparison of transferrin receptor (TfR) by flow cytometry showed the amount of TfR on the membrane of SOD-H cells to be significantly less than that on the membrane of NEO cells. The amount of CD44 expression on SOD-H cells was almost the same as that on NEO cells. The results of this study suggest that the overexpression of MnSOD is related to suppression of the malignant phenotype and that changes of iron metabolism may play an important role in this process. PMID- 21590171 TI - Microsatellite instability occurs infrequently in sporadic renal cell carcinoma. AB - Forty-nine sporadic renal cell carcinomas were screened for instability at nine different microsatellite loci. Three tumors (6.1%) showed alterations at more than one locus. One chromophobe-cell renal carcinoma showed microsatellite instability at 3 loci and was considered to exhibit a replication error-positive phenotype. Two of the tumors with clear-cell histology showed minor alterations at one of the nine loci examined, These data indicate that microsatellite instability occurs infrequently in sporadic RCC and that the mutator phenotype may be involved in rare instances such as the chromophobe-cell carcinoma. PMID- 21590172 TI - Activity of cytotoxic agents against clear cell carcinoma of the ovary which is intrinsically platinum-refractory. AB - The aim of the present study was to evaluate cytotoxic agents active for clear cell carcinoma of the ovary (OCCA) which is intrinsically platinum-resistant. We first conducted in vitro chemosensitivity tests assessing antitumor activities of Various agents against OCCA using two cell lines (HAC-2 and KK) established from ascites of patients with pure OCCA. The most potent single agent was SN-38 (active substance of CPT-11 in vivo) in both cell lines. The second most potent agent was mitomycin-C (MMC) followed by doxorubicin (DOX) in HAC-2 and DOX followed by MMC in KK, respectively. In vivo chemosensitivity test of agents on HAC-2 transplanted into BALB/C nude mice demonstrated that MMC was most potent, followed by DOX and CPT-11. Moreover, a combination of CPT-11 and MMC exhibited the highest anti-tumor activity in this animal model. Cisplatin, etoposide, and paclitaxel were found to be ineffective in either the in vitro or in vivo experimental system. Clinical trial with a combination of MMC and CPT-11 are warranted in patients with OCCA. PMID- 21590173 TI - Autocrine motility factor receptor expression as a prognostic factor in pulmonary adenocarcinoma. AB - Autocrine motility factor receptor (AMF-R) expression was studied immunologically in tissue specimens from 121 patients with pulmonary adenocarcinoma. AMF-R expression was correlated with lymph node metastasis and stage. The prognosis of AMF-R positive patients was poorer than that of AMF-R negative patients. Multivariate analysis showed that AMF-R expression had a significant influence on prognosis. Our findings suggest that AMF-R plays an important role in tumor progression and that AMF-R expression is a useful prognostic marker for pulmonary adenocarcinomas. PMID- 21590174 TI - Smoking enhanced the expression of MDR-1 in rat prostatic carcinoma. AB - Smoking is associated with the development of different malignancies, especially lung carcinoma. Considerably less interest has been devoted whether the outcome of cancer treatment can be affected by ongoing smoking. In the present study, the effects of ongoing smoking was evaluated on the expression of classical multidrug resistance (MDR-1) in a tumour tissue not usually related to smoking, prostatic carcinoma in rats. The expression of mdr1 was evaluated by quantitative RNA-RNA solution hybridisation and the distribution of the glycoprotein P-170 was examined by immunohistochemistry using the monoclonal antibodies C219 and C494. A group of animals was exposed to cigarette smoke in a nose-only exposure system for 1 h/day, 5 days/week for four weeks. The results demonstrated a significant enhanced expression of mdr1 RNA in the rumours from smoke exposed animals and the immunohistochemical analysis also displayed an increase of the positively stained cells following smoking. These results indicate that alteration at least at the level of transcription is involved in the overexpression of P-170 following smoking. An effect on translation or post-translation cannot be excluded. The observations might add to the experience of drug resistance seen in the clinical situation in tumours associated with carcinogens such as smoking. PMID- 21590175 TI - A flow cytometric analysis of the nuclear DNA content between primary and recurrent colorectal cancers. AB - We compared the DNA content in both the primary and recurrent lesions of 12 cases with colorectal cancer. The DNA ploidy agreed in 10 cases (83.3%) between the primary and recurrent lesions. The mean DNA index was similar between both lesions. The DNA content seems to remain stable during recurrence in many cases of colorectal cancer. However, the existence of variations in the content also suggests that the specimens should be investigated for both primary and recurrent lesions in order to obtain more information on the biological or clinical behavior of the tumor. PMID- 21590176 TI - Curative radiotherapy (RT) using limited RT treatment fields in elderly patients with non-small cell lung cancer in clinical stage IIIA. AB - We report a prospective phase II study utilizing limited radiotherapy (RT) treatment fields in elderly (greater than or equal to 75 years) patients (pts) with non-small cell lung cancer (NSCLC) in clinical stage IIIA. Sixteen good risk pts with histologically confirmed NSCLC in clinical stage IIIA, age greater than or equal to 75 years (yr) (range 75-83; median age 77) were entered in the study. All pts were treated with Limited RT fields (including T and N1-2 usually with a 1.5 cm, radiographic margin) and received a minimum of 54 Gy (range 54-62 Gy, median 60 Gy, dose/fraction 2 Gy/5 dd a week). All pts have been followed-up for a median time of 3.5 years (range 1.75-6.58). Median survival (MS) was 18 months (range 7-52 months). No acute and/or late significant toxicity was recorded. Univariate analysis showed a better survival in pts receiving a radiation dose greater than or equal to 60 Gy, with an MS of 34 vs 14 months (p=0.017) and in pts with Karnofsky Performance Status greater than or equal to 80, with an MS of 34 vs 12 months (p=0.0O2). There are scarce data available on survival in elderly pts with NSCLC in clinical stage IIIA. Pts submitted to 'standard' RT in unresectable NSCLC have a poor median survival time and 5-year survival rates. The results obtained in our pts encourage us to use 'limited' RT in elderly but the results require a phase III study before definitive recommendations can be made. PMID- 21590177 TI - Macrophage colony-stimulating factor as a marker of ovarian carcinoma. AB - Macrophage colony stimulating factor (M-CSF) is a cytokine which stimulates the proliferation and differentiation of phagocytic cells. We evaluated the usefulness of M-CSF as a serum tumor marker for ovarian malignancies and also assessed M-CSF production by tumor cells and the role of an autocrine system in such M-CSF production. The findings obtained were as follows: i) Serum M-CSF was a useful marker for malignant ovarian tumors. ii) M-CSF was a marker for both epithelial stromal tumors and for germ cell tumors. It was also a marker for dysgerminoma, for which no specific tumor marker is currently available. iii) The value of combined assays employing M-CSF was confirmed. iv) M-CSF production was demonstrated in various malignant ovarian tumor cell lines, but the presence of an autocrine system for M-CSF was not confirmed. PMID- 21590178 TI - Family history in participants of breast cancer screening. AB - Of 12,337 participants of mass screening for breast cancer (screenees) in Gunma Prefecture between 1980 to 1985, 1,000 participants' records in Gunma Prefecture were investigated. The records of screenees who had already developed breast cancer were excluded. The rate of screenees who had a family history (FH) of cancer in first- and second-degree relatives was compared with that of 1,248 breast cancer patients (controls) using the conditional logistic regression model. The mean age of screenees (49 y.o.) was similar to that of controls (51 y.o.). The number of screenees with positive FH of cancer including other malignancies was 530 with the odds ratio of 2.68. This was statistically significant with chi-square test. The rates of screenees with positive FH of cancer were quite similar in the seven districts. Screenees had a significantly larger number of relatives with a positive FH of breast cancer compared with the controls. The rate of positive breast cancer history in parents of screenees was significantly higher than in the parents of controls. Rates of positive breast cancer history in grandmothers and aunts of screenees were also significantly higher than that in the controls. The rate of breast cancer history in sisters was not different between the two groups. Screenees had a higher rate of positive FH of cancer in parents, especially in mothers. Family histories of stomach, liver, lung, and uterus cancer in parents were more frequently observed in screenees compared with the controls and those cancer histories were also frequently observed in other family members of screenees. These data showed that a FH of cancer is one of the primary motivations of participation in the breast cancer screening program. Participants seemed to be intrinsically a high risk group of breast cancer. PMID- 21590179 TI - Long-term follow-up for patients with Ewing's sarcoma of bone treated with adjuvant and neoadjuvant chemotherapy. AB - The long-term results obtained in 252 patients with non-metastatic Ewing's sarcoma of bone treated between March 1972 and June 1988 according to three sequential protocols of treatment were evaluated. Primary tumor was treated with radiotherapy in 125 cases, with surgery in 52 and with surgical resection followed by radiotherapy in 75. In the first protocol (REA 1; 1972-78) chemotherapy was performed with a 3-drug regimen (VCR, CPM, ADM), whereas in the REA 2 protocol (1979-82) and in the REN 1 protocol (1983-88) a 4-drug regimen was used (VCR, CPM, ADM, ACTD). Chemotherapy was delivered as adjuvant treatment in REA 1 and 2, and as neoadjuvant in the last study. At a mean follow-up of 14.8 years, with the 95% of patients with a minimum FU of 10 years, 101 pts (40%) remained continuously free of disease, 144 patients relapsed, two patients died of adriamycin cardiotoxicity and 5 patients developed a second neoplasm. 6% of the patients relapsed 5 or more years after the diagnosis with the latest recurrence registered at the tenth year. Type of local treatment, LDH serum level, chemotherapy protocol and sex were predictive factors of DFS after a multivariate analysis. The possibility of late relapse in Ewing's sarcoma has been confirmed by our retrospective study and for patients with Ewing's sarcoma, a 10-year follow up should be recommended. PMID- 21590180 TI - Further analysis of the relationship between the epidemiological and hormonal aspects of 6 human neoplasias with special emphasis on the presentation of the topological features of oncogene activation tumor suppressor gene inactivation of individual neoplasias. AB - The purpose of this study was to test the validity of the steroid carcinogenesis hypothesis by comparatively investigating the endocrinological and epidemiological aspects of cancers of the breast, uterine cervix, endometrium, stomach, esophagus and ovary. The emphasis of this study was placed on the extraction of the information on the topological feature of oncogene activation tumor suppressor gene inactivation for each of 6 neoplasias using the data stock of the age-adjusted incidence rates (AAIRs) of 19 neoplasias from 47 population units of the world. Our investigation was started on the basis of the recognition that the world statistics data of cancer risk should include information on the interaction of oncogene activation-tumor suppressor gene inactivation for each human neoplasia, and that the sophisticated application of statistical analysis technics may allow us to assess separately the implications of oncogene activation and tumor suppressor gene inactivation in the genesis of a given neoplasia. In designing mathematical strategies, we had in mind the premise that oncogene activation and tumor suppressor gene inactivation represent 2 distinct entities in the world of chemistry, and that they should have each their own equilibrium models with 2 distinct equilibrium points. The details of the mathematical principles and procedures are presented in the text. The results were as follows: i) There was a good agreement of results between the observed value and the expected value of thermodynamics as regards the location of the equilibrium point in both instances - a finding to support the validity of our mathematical strategies. ii) One of our mathematical strategies (the use of the original coordinates and its variant coordinates in parallel) was found to be useful for assessing separately the implication of oncogene activation (the original coordinates) and that of tumor suppressor gene inactivation (the variant coordinates). iii) The correlation study of the endocrinological data with the epidemiological data in breast cancer strongly suggests the possibility that sex steroid may play a cardinal role in the oncogene activation at the initiation step of breast carcinogenesis. iv) Evidence is available to indicate that glucocorticoid under certain circumstances may play a crucial role in the process of tumor suppressor gene inactivation at the promotion step of breast carcinogenesis. v) The philosophical distinction between the steroid carcinogenesis theory and the random mutation criminal theory of carcinogenesis is discussed in the light of recent information on chemical carcinogenesis. PMID- 21590181 TI - Eating habits and colorectal cancer. AB - In order to investigate the relation between the occurrence of colorectal cancer and food consumption in Hokkaido, Japan, etiological factors of colorectal cancer were investigated through an ecologic study using official food consumption and mortality statistics concerning colorectal cancer, and through a community-based case-control study. The ratio of 'animal foods' to 'plant foods' and that of 'animal protein' to 'plant protein' had a significant correlation with the mortality rate in colorectal cancer. The percentage of fat energy was much more contributory than the absolute amount of fat. Traditional Japanese foods tended to prevent while Western foods tended to promote colorectal cancer. Odds ratios for Japanese foods were low for colon cancer, and those for Western foods were high for rectum cancer. Relative amounts of foods are more contributory than their absolute amounts. An increase of colorectal cancer in Japanese people may be attributable to the increase in the relative amounts of Western foods. Reduction of the ratio of animal foods to plant foods (i.e., a reduction in relative amounts of Western foods or an increase in relative amounts of Japanese foods) may lend to the prevention of colorectal cancer. PMID- 21590182 TI - Identification of the flame retardants polybrominated diphenyl ethers in adipose tissue from patients with non-Hodgkin's lymphoma in Sweden. AB - We have recently reported increased concentrations of polychlorinated biphenyls and chlordane compounds in adipose tissue from patients with non-Hodgkin's lymphoma (NHL) compared with surgical controls. As a feasibility project we have now studied the occurrence of polybrominated diphenyls ethers (PBDE) in the same study population. Four samples of adipose tissue were selected at random from the case and control series. We were able to identify PBDEs in all samples. PBDEs are environmental contaminants and the levels are increasing in sediment and biological samples. Our results indicate that human beings are also exposed, mainly through the food chain, resulting in ng/g concentrations of PBDEs in the adipose tissue. This has not been previously reported from Sweden. Any health consequences are so far not studied. The environmental situation for PBDEs is thus similar to that of PCBs a few decades ago. PMID- 21590183 TI - Aggressive angiomyxoma of the inguinal region. AB - Aggressive angiomyxoma is a distinctive and very rare soft tissue tumor occurring almost exclusively in women. Only seven cases occurring in men have been previously reported. We herein report a case of a 74-year-old man who was admitted to our hospital presenting with a huge right inguinal mass that had grown over a 14-year period, in order to undergo surgical treatment for gastric cancer. The inguinal tumor was well-defined and demonstrated a glistening appearance on the cut surface. Histologically, the tumor was composed of bland looking spindle and stellate cells with delicate cytoplasmic processes, which sparsely populated the fibromyxoid matrix. A prominent vascular component was also present. Immunohistochemically, the stromal cells stained consistently for vimentin and variably for muscle-specific actin, but not for alpha-smooth muscle actin, desmin, and S-100 protein. The gastric cancer was microscopically diagnosed to be papillary adenocarcinoma with serosal invasion and showing immunoreactivity for p53 protein, but not for aggressive angiomyxoma. PMID- 21590184 TI - A variable neovascularization threshold in tumor-bearing mice. AB - The development of solid tumors is dependent on angiogenesis in such a way that a restriction in neovascularization would cause secondary tumor implants to remain in dormant state, establishing an apparent paradox. In this study an attempt has been made to demonstrate that in the tumor-host relationship a variable threshold of angiogenic response is generated which can be normal, enhanced or diminished depending on the intensity of the stimulus. The latter was determined by the number of PEM, semiallogeneic lynphocytes or irradiated tumor cells which were intradermally injected to induce the host angiogenic response. As compared to the normal controls, in tumor-bearing mice, capillary neoformation i) induced by a low angiogenic stimulus was progressively inhibited by tumor growth; ii) when induced by higher stimuli, in 9 day tumor-bearing mice the response was enhanced while in those of 12 days it was normal being completely inhibited in 15 day tumor-bearing mice; iii) when in a specific day of tumor growth (9, 12 or 15) progressively higher angiogenic stimuli were applied, the response was higher in tumor-bearing mice than in the corresponding controls. Similar results were obtained with PEM induced granulomas, suggesting the participation of a phenomenon of counter-inflammation. It can be concluded that there is an angiogenic threshold that increases as a function of tumor growth so that the response will depend on whether the stimulus attains or surpasses the threshold. PMID- 21590185 TI - Changing site distribution of Japanese colorectal cancer. AB - To clarify the time trends in the characteristics of colorectal cancer, we investigated 1,286 Japanese patients with colorectal cancer who underwent a resection of the disease between 1972 and 1995 at our hospital. Based on our findings, this carcinoma tended to shift to the more proximal colon in the second 11-year period in comparison to the first 11-year period (P=0.0001). This tendency was also found in elderly patients (P=0.0001), but not in young ones. These findings thus suggest the need for targeted examinations for the early detection of the proximal colon cancer, especially in the elderly. PMID- 21590186 TI - Early detection of peritoneal dissemination of gastrointestinal cancers by reverse-transcriptase polymerase chain reaction. AB - We examined the usefulness of the reverse-transcriptase polymerase chain reaction (RT-PCR) analysis for E-cadherin mRNA in the early diagnosis of peritoneal dissemination of gastric and colorectal cancers. The RT-PCR analysis was performed on RNA samples extracted from cells which were collected preoperatively from ascites or intraperitoneally infused fluid. E-cadherin mRNA was detected in 2/2 cases (100%) graded into P-1 peritoneal dissemination, indicating the presence of metastatic cells. In the cases with P-2 and P-3 dissemination the gene expression was detected in 2/3 (67%) and 3/5 (60%), respectively. The RT-PCR analysis was more sensitive for P-1 dissemination than cytological examination. These results suggest that determination of E-cadherin gene expression is useful for the early detection of peritoneal dissemination in gastrointestinal cancer because of its high sensitivity and specificity. PMID- 21590187 TI - Effect of quercetin on the in vitro and in vivo growth of mouse hepatoma cells. AB - Quercetin has been reported to have tumor growth inhibition effect. We have examined the in vitro and in vivo effects of quercetin on the growth of ML-3 murine hepatoma cells. Our results showed that quercetin dose dependently inhibited the growth of ML-3 cells. Flow cytometric analysis showed that quercetin-treated cells were mainly arrested at G(0)-G(1) phases of the cell cycle. For the in vivo experiment, BALB/c mice were transplanted intrasplenicly with ML-3 hepatoma cells and fed with 2% quercetin in the diet. The survival of tumor-bearing mice and the size of hepatic tumor were recorded at 40 days after implantation of ML-3 cells. Significant increase in survival of tumor-bearing mice was found by quercetin treatment, all mice in the quercetin group survived to the end of the experiment while only 50% of the mice in control group survived. These results suggested that quercetin has potential for hepatoma treatment. PMID- 21590188 TI - Prognostic factors in patients with hepatocellular carcinoma submitted to chemoembolization. AB - The prognosis of unresectable hepatocellular carcinoma is poor. Encouraging response rates have been reported with chemoembolization, but no survival advantage has been demonstrated. Assessment of the impact of the treatment modality on prognosis is complicated by a poor understanding of the prognostic factors in the disease. We therefore evaluated, through univariate and multivariate analysis, the role on prognosis of 16 variables in 63 patients submitted to chemoembolization. Patients were treated with epirubicin (50 mg) plus ethiodized oil and gelatin sponge (22 cases) or with a new program combining i.a, chemotherapy with chemoembolization (41 cases) as follows: L-leucovorin, 100 mg/m(2) i.v.; fluorouracil, 800 mg/m(2) i.a.; carboplatin, 250 mg/m(2) i.a. Chemoembolization with mitoxantrone, 10 mg/m(2), plus ethiodized oil and gelatine sponge was performed immediately after. Median survival for the whole group of patients was 294 days. A multivariate analysis showed a highly significant influence on survival for Child's status (p=0.002) and for TNM stage (p=0.01). Median survival for patients with Child's A disease was 13.9 months and for patients with TNM stage I-II disease 19 months. In conclusion, our data suggest that patients with limited disease and adequate liver function have a longer survival after chemoembolization. PMID- 21590189 TI - Risk factors for typhlitis. AB - A case-control study was undertaken to identify risk factors for typhlitis in patients with hematological malignancies. A data base file with a total of 410 episodes of fever and neutropenia in patients cared for between May 1987 and 1996 was reviewed. Typhlitis was defined as a symptom complex of fever, intense abdominal pain and tenderness in the presence of neutropenia. Five cases of typhlitis were identified. Three controls for every patient were randomly selected from the same cohort. Diarrhea and jaundice were more frequent in patients than in controls (p=0.03). The presence of mucositis, prolonged duration of profound neutropenia and idarubicin treatment proved to be risk factors for typhlitis. PMID- 21590190 TI - Cost-effectiveness of neoadjuvant multimodal therapy in patients with esophageal adenocarcinoma. AB - We conducted an incremental cost-effectiveness analysis to evaluate an adjuvant multimodal therapy (chemotherapy + radiotherapy) in patients with esophageal adenocarcinoma undergoing surgery. We utilized the clinical data of a published controlled trial comparing preoperative chemotherapy + radiotherapy versus surgery alone. Information on costs was derived from local data and verified against reported values. Multimodal treatment was found to improve life expectancy by 196.9 discounted years every 100 subjects (survival gain of about 2 years per patient). Costs of this neoadjuvant therapy were estimated as $780,010 per 100 patients. Our cost-effectiveness analysis showed that the cost per life year gained was $3,961 for the multimodal therapy in comparison with surgery alone. The pharmacoeconomic profile of this therapeutic modality compares favorably with previous economic data calculated for other types of health care intervention. PMID- 21590191 TI - Ages at different reproductive events, numbers of menstrual cycles in between and breast cancer risk. AB - One hundred and seventy-five pathologically confirmed new cases of female breast cancer in National Taiwan University Hospital were selected as the case group. Four hundred and fifty-seven inpatient controls were individually matched for each case by age and date of admission. Information of reproductive factors and potential confounders were collected from questionnaire interview and medical records. Menstrual cycles before and after first fuIl-term pregnancy were estimated from the questionnaire. Conditional logistic regression was used to estimate the effects of reproductive risk factors and numbers of menstrual cycles before and after first full-term pregnancy. After adjusting for educational level, body mass index, family history of breast cancer and oral contraceptive use, age at menarche and menopause only showed borderline significance. Age at first full-term birth predicted breast cancer risk better. Parity was the most important protective factor. Number of menstrual cycles before first full-term pregnancy was also positively associated with breast cancer risk with linear trends. PMID- 21590192 TI - Endometrial carcinoma in a breast cancer patient treated with tamoxifen. AB - The use of tamoxifen for breast cancer therapy is linked to an increased danger of developing endometrial neoplasias in postmenopausal patients receiving the drug. Understanding the molecular mechanisms of the tumorigenic activity of tamoxifen may be of great prognostic and therapeutic significance. Our study suggests that tamoxifen treatment and alterations of the K-ras proto-oncogene may occur as parallel events in carcinogenesis of the endometrium. PMID- 21590193 TI - Prolonged corrected QT dispersion. AB - The anthracyclines are antibiotics effective in the treatment of many malignancies. However, their usefulness is limited by the development of potentially acute or chronic cardiotoxicity. No definitive guidelines exist for monitoring cardiac function during and after anthracyclines although methods have been suggested. Electrocardiograms and echocardiograms are routinely utilized for noninvasive assessment of myocardial function. The aim of the study was to assess the effects of doxorubicin on ventricular repolarization time indexes, as they have been shown to be effective in the identification of electrical myocardial instability and hence in the identification of the risk for either arrhythmia or heart failure. Electrocardiographic parameters were compared in 27 cancer patients before and after chemotherapy including doxorubicin. The data of the present study show that after only a short period of treatment with doxorubicin there is a significant increase in ventricular recovery time indexes (QTc dispersion and 'Adjusted' QTc dispersion). The relation between the electrophysiological response to doxorubicin and the potential cardiotoxic effect of this drug remains to be established through prospective studies. PMID- 21590194 TI - Cisplatin induces serotonin release from human peripheral blood mononuclear cells of cancer patients and methylprednisolone inhibits this effect. AB - The aim of this study was to verify whether cisplatin (CDDP) can induce serotonin (5HT) release from peripheral blood mononuclear cells (PBMC) of cancer patients and determine whether methylprednisolone (MP) can inhibit such release. Ten patients (mean age 61.8 years) with cancer of different sites, all but one in advanced stage of disease were studied. Our study showed that unstimulated PBMC of cancer patients release a higher amount of 5HT than that of healthy subjects (57+/-5 nM vs 10+/-1 nM, p<0.001) and that similarly the stimulation with PHA or CDDP induces a higher amount of 5HT release by PBMC of cancer patients than that by PBMC of healthy subjects (74+/-6 vs 32+/-3 nM, p<0.001 and 91+/-8 vs 18+/-2 nM, p<0.001, respectively). The addition of MP to the culture in the presence of CDDP induced a significant decrease of 5HT levels: from 91+/-8 to 53+/-7 nM, p=0.002. This result obtained in cancer patients paralleled that previously obtained by us in healthy subjects. Our data confirm a new mechanism through which CDDP could induce emesis and provide a further possible explanation to the anti-emetic activity of corticosteroids, such as MP. PMID- 21590195 TI - Endometrial carcinoma stage I. AB - Standard staging and therapeutic approach to endometrial cancer involves lymph node sampling (LNS) at the time of total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO). Lymphadenectomy prolongs time of surgery and increases the risk of morbidity; where other predictors are available, it may not contribute important supplementary information. 185/247 women with stage I endometrial carcinoma underwent the standard surgery while 62 underwent TAH+BSO. Recurrence and survival were monitored for a mean of 6.5 years and retrospectively reviewed: the rates for groups with and without known lymph node status were alike [13.5% (25/185) recurrence for the former and 12.9% (8/62) for the latter, and 5-year survival rates of 75.7% (140/185) for the former and 74.2 (46/62) for the latter]. Myometrial invasion and histological grade appeared to have been highly accurate predictors without lymph node information. Because information on histological grade is available early and is highly predictive, its use could be incorporated into a revised management algorithm for stage I endometrial cancer which would depend upon ensuring lymphadenectomy for women with low grade histopathology and omitting it for those with high grades on the grounds that no further information is necessary to act appropriately. PMID- 21590196 TI - Amputation of the lower limb as palliative treatment for debilitating musculoskeletal cancer. AB - Limb sparing surgery has replaced amputation surgery for treating sarcomas of the lower limb in most cases. Wide resection followed by postoperative radiation therapy can achieve acceptable local control and survival rates in patients with bone and soft-tissue sarcomas of the lower limb. Recurrent or persistent disease constitutes a major oncological problem. Local symptoms such as agonizing pain, fractures, tumor fungation, inability to walk and inability to maintain daily activities, further impair the patient's quality of life. In this clinical set-up palliative amputation of the limb should be considered. Fourteen patients with soft-tissue or bone sarcomas underwent palliative major amputation. The procedures included: hemipelvectomy, hip disarticulation, knee disarticulation, above or below-knee amputation. Local control of the disease and pain, and improvement of the performance status were observed in 13 evaluable patients. The mobility was restored in 13/14 patients. The median survival following the procedure was 9 months. There was only one case of immediate post-operative death. Severe phantom pain was not reported by any of the patients. Quality of life was reported to be improved by two-thirds of the patients. We found palliative major amputation surgery worth-performing in low-performance status cancer patients with locally advanced disease of the lower limb. PMID- 21590197 TI - Psychological burden of women with mild cervical intraepithelial neoplasia. AB - Forty women with diagnosis of CIN I attending our outpatient colposcopic clinic were evaluated regarding psychological distress and compliance to follow-up after they had been informed about their diagnosis. In our study 52.9% of the women (n=21) (group A) reported that they did not get sufficient information concerning diagnosis, while 47.1% of the women (n=19) received sufficient information (group B). Women with adequate information had less fear of having cancer than women with inadequate information (P=0.03). As expected these women had a statistically increased distress (P=0.004). In group A the patients reported that the follow-up period reinforced the anxiety compared to group B (P=0.04). The compliance for regular attendance of cervical cancer screening programs after treatment was significantly better in group B compared to group A (P=0.02). Our study indicates that adequate information for women about the diagnosis CIN I, reassurance and understanding from medical staff are vital for the success in the treatment of patients with mild dyskaryosis. The gynaecologist's counselling strategy plays a major role in these psychological effects. PMID- 21590198 TI - Structure-activity relationships among the ortho-, meta- and para-isomers of phenylenebis (methylene)seleno cyanate (XSC) as inhibitors of 7,12 dimethylbenz(a)anthracene-DNA binding in mammary glands of female CD rats. AB - As shown earlier p-XSC inhibits DMBA-induced mammary cancer in female CD rats. This inhibition is due, in part, to inhibition of DMBA-DNA adduct formation in the target organ. We have now utilized the DMBA-DNA binding assay to evaluate the chemopreventive potential of positional isomers of XSC (o-, m- and p-XSC) applied at selenium doses of 5 and 15 ppm; p-XTC, the sulfur analog of p-XSC, was used at an equimolar dose to determine whether selenium is required for the observed inhibitory effect. Selenium and sulfur compounds were administered in a semipurified high-fat diet (23.5% corn oil). Rats were fed for 1 week prior to oral administration of a single dose of [H-3]DMBA (5 mg/rat); animals were sacrificed 24 h later, DNA was isolated from mammary fat pads and levels of total binding were determined. All agents produced a dose-dependent inhibition of DMBA DNA binding in the mammary tissues. The inhibition at 5, respectively 15 ppm Se in the form of XSC isomers and at 30 mu M, respectively 90 mu M in the form of p XTC was: o-XSC (27%, 42%); m-XSC (32%, 47%); p-XSC (22%, 29%); and p-XTC (10%, 20%); only inhibition by dietary o-XSC and m-XSC at 15 ppm Se reached statistical significance (p<0.05). Thus, o-XSC and m-XSC equally inhibit DMBA-DNA binding and both are better inhibitors than p-XSC; the latter appears to be slightly more effective than its sulfur analog p-XTC. Clearly, the structure of the selenium containing compound is a critical factor in determining the extent of inhibition of DMBA-DNA binding. The described short-term in vivo assay may constitute the basis for future selection of chemopreventive agents in the rat mammary tumor model system. PMID- 21590199 TI - Radiosensitization by iodo-deoxyuridine in cultured SW-1573 human lung tumor cells. AB - To investigate radiosensitization by halogenated pyrimidines in human cells, SW 1573 lung tumor cells were grown in absence or presence of 4 mu M of iododeoxyuridine (IdUrd). Cell survival after irradiation with gamma-rays from a Cs-137 source with single doses up to 8 Gy, was determined by clonogenic assay, Radiosensitization by IdUrd was observed in both exponentially growing and plateau phase cells. Linear-quadratic analyses of the radiation survival curves demonstrated that radiosensitization was mainly expressed by an increase of the value of alpha (determining the initial slope of the survival curve) which can be interpreted as an enhancement of fixation of potentially lethal damage (PLD). The value of beta (determining the curvature of the survival curve), which might be attributed to enhanced interaction or to fixation of sublethal damage (SLD), was not influenced. In view of clinical applications of IdUrd it is of interest that radiosensitization has its main effect in the low dose region of the cell survival curve, described by the linear term alpha D. PMID- 21590200 TI - Is CT scan monitoring useful in patients with epithelial ovarian cancer and follow-up negative CA 125 serum levels? AB - We retrospectively reviewed our series of ovarian cancers to assess the benefit of routine follow-up abdominal computer tomography (CT) scans in asymptomatic patients with CA 125 levels <35 U/ml. A chart review was undertaken of all patients with a diagnosis of ovarian cancers treated and followed at the Institute of Obstetrics and Gynecology, University of Ancona, from January 1986 to January 1994. In asymptomatic patients, the routine follow-up consisted of physical examination and CA 125 serum level determination every three to four months for the first two years, and every six months thereafter for a minimum of 5 years. At each visit, a history and a bimanual vaginal examination were completed. The pelvic and abdomen CT scans were performed every six months for the first year and then annually. Inclusion criteria were CA 125 levels >35 U/ml prior to surgery or initial chemotherapy, and complete routine follow-up. Fifty two patients (75%) satisfied the inclusion criteria. After surgery, 32 of the 52 CA 125 positive patients (61%) showed a decrease in CA 125 levels; 10 other patients showed a negativity of CA 125 after cisplatinum polychemotherapy. After a median time of 49 months (range 16-117 months), 9 of the 42 patients (21%) developed a relapse. The overall CA 125 sensitivity at the time of relapse was 78%, with a specificity of 94%; the sensitivity for early detection of relapses was 70%. Two-hundred and seventy-six abdominal and pelvic CT scans were performed and 8 were positive for tumor relapse, with an overall sensitivity of 89%. The sensitivity of CT scans was 33% for early detection of relapses. The routine performance of follow-up CT scans did not significantly improve the overall detection of early relapses in ovarian carcinoma. A longitudinal monitoring of serum CA 125 is a reliable method of follow-up. Abdominal and pelvic CT scans should be performed in patients who, after a period in which they have been classified as not having evidence of disease with normal CA 125 serum levels, show elevated and rising CA 125, with the aim of finding and characterizing relapses. PMID- 21590201 TI - Tumor proliferative compartment, multidrug resistance gene product and apoptosis regulatory p53 and bcl-2 proteins in pediatric acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most frequent childhood tumor. Although the cure rate has increased dramatically over the past few years, the molecular and cellular biology of this disease is still not fully understood. Important factors affecting prognosis include age, leucocyte count, cytogenetic abnormalities, immunophenotype and sex. However, the role of cell kinetics, tumor associated genes and drug resistance have rarely been investigated in pediatric ALL. This preliminary study looks at these aspects in this disease. Immunocytochemical analysis of the tumor suppressor protein p53, the anti apoptotic protein bcl-2, the multidrug resistance (MDR) gene product P glycoprotein and the proliferation marker, Ki-67 were done using appropriate monoclonal antibodies. A total of 88 previously untreated children with confirmed ALL diagnosis and 40 age matched controls were included in the study. Ki-67 was expressed in 81% and P-glycoprotein in 68% of all cases. P53 expression was observed in 68% and Bcl-2 in 50% of cases. Fifty percent of all cases also showed concomitant expression of bcl-2 and p53. Since wild-type p53 is known to negatively regulate the expression of bcl-2, the co-expression of these two proteins having contrasting functions suggests that the p53 may be of a mutant variety. In addition, the expression of p53 also correlates to the presence of the multidrug gene product P-glycoprotein. Control samples were negative for all the four markers. P53, bcl-2 and P-glycoprotein can all influence chemotherapy resistance, the first two by regulating programmed cell death and the third by influencing intracellular drug levels. All patients are now being followed up to assess treatment response and to study the prognostic significance of the analyzed markers. PMID- 21590202 TI - Glutathione administration against cisplatin-induced nephrotoxicity does not modify its cytotoxic activity. AB - Glutathione (GSH) is an intracellular thiol compound which has been shown to protect against cisplatin-induced nephrotoxicity, in animal models and clinical trials. In order to determine whether GSH interferes with cisplatin activity, the lymphoma L5178Y was implanted in 50 DBA/2 mice, and then they were treated with cisplatin with or without previous GSH. Two similar experiments were carried out with three different groups: Group 1: Control group without cisplatin; Group 2: Treatment with cisplatin without GSH, and Group 3: GSH administration prior to cisplatin. Tumor area and survival have been considered as parameters to measure the activity of cisplatin. The average Values of tumor areas in the mice pretreated with GSH were not significantly different from those corresponding to the group treated with cisplatin alone. Sixty days survival was 55% and 73% in the groups pretreated with GSH and with cisplatin alone respectively, the difference was not statistically significant. In conclusion, GSH administration prior to cisplatin does not modify its cytotoxic activity. PMID- 21590203 TI - Postoperative irradiation combined with chemotherapy for high-risk rectal cancer patients. AB - In a prospective open-study we evaluated the combination of radiation therapy and adjuvant 5-FU plus levamisole in controlling Modified Astler-Coller (MAC) B2 or C rectal cancer following a curative-intended surgery. Sixty-four consecutive rectal cancer patients were treated by adjuvant radiation therapy (Linac 8 MV, 50 50.4 Gy to an isocentric pelvis brick volume in 5 fractions per week each of 1.8 2 Gy), and 12 monthly courses of 5-fluorouracil (375 mg/m(2)/day for 5 consecutive days) plus levamisole (50 mg t.i.d. for 3 days). Within a median follow-up period of 36 months, 19 patients (29.6%) experienced relapses. The 3 year-DFS of MAC B2 patients was 82%, compared with 60% in MAC C. Early radiation treatment was not associated with a higher proportion of relapses, while late radiation therapy initiation was associated with a significantly higher proportion of relapses. Early radiation therapy, not later than following the 2nd to 4th course of chemotherapy, is associated with the more acceptable proportion of relapses. PMID- 21590204 TI - Telomeric length variation in human testicular germ cell tumours. AB - Telomeric length was studied in 5 cases of human testicular germ cell rumours by measuring the length of the terminal restriction fragments (TRFs) containing the (TTAGCG)(n) sequence. Mean TRF length in human placenta used as a source of reference DNA for assessing the effect of cellular ageing was 14 kbp. TRF length in two classical seminomas and a mixed embryonal carcinoma/atypical seminoma ranged from 4 to 14 kbp and from 4 to 23 kbp, respectively, with the same mean value of 9 kbp in both tumour types. In a mixed teratoma/embryonal carcinoma, telomeric length ranged from 14 to 27 kbp with a mean of 20 kbp. In the single case of spermatocytic seminoma studied, telomeric length was up to 100 kbp with a distinct sharp band at similar to 50 kbp, representing the longest, homogeneous telomeres found so far. PMID- 21590205 TI - Epidermal growth factor and its receptor in cervical cancer. AB - Epidermal growth factor (EGF) is an important growth factor regulating both normal and malignant cells. The present study analyzes the expression pattern of EGF and its receptor (EGF-R) in 424 cases of various stages of tumor progression in the uterine cervix. In all the samples studied, EGF and EGF-R expression was predominant in the basal or basaloid cells. Increased expression of the two proteins correlated with increasing histological abnormality (dysplasia). In invasive cancer, alteration of EGF expression was more evident than EGF-R. The expression pattern showed significant correlation in the basal and spinal cell layers. This increased expression of EGF observed in dysplastic and malignant cells may be due to overexpression of EGF-R and suggests its role in cellular proliferation. PMID- 21590206 TI - Nitric oxide is involved in stimulation of tumor growth. AB - The immune system can inhibit or stimulate tumor growth. Peritoneal cells (PEG) from MM3 mammary tumor-bearing mice (TBM) displayed enhanced capacity to produce nitric oxide (NO) upon stimulation with LPS plus IFN-gamma, as compared to normal mice. The addition of L-Arginine (L-Arg) increased NO release by TBM-PEC but not by normal PEG; this increase could be reversed with N-G-nitro-L-arginine methyl ester (L-NAME). This inhibitor, given systemically, decreased MM3 tumor growth but not lung metastasis. Tumor retardation was associated with inhibition of angiogenesis induced by spleen cells. Conversely, L-Arg potentiated vascular response but not tumor growth. In conclusion, NO synthesis is up regulated in PEC during MM3 tumor progression sustaining tumor growth by mediating the angiogenic cascade. PMID- 21590207 TI - Expression of heat shock protein 70 and p53 in human lung cancer. AB - Bronchial biopsies of 21 patients with lung cancer were analyzed by Western blot for stress protein HSP70 and p53 proteins. Squamous carcinoma was the most common type found. The p53 protein was detectable in 14 cases. The HSP70 was detectable in 17 and overexpressed in 9 patients. Eleven patients showed positivity for both protein expressions, however no statistical significance was found (Kappa's test, p>0.05). Specific associations were not observed for HSP70 overexpression and p53 detection that could be related to clinical finds or tabagism. Our results indicate that the stress protein HSP70 is detectable and may be involved in the tumor development. PMID- 21590208 TI - Involvement of RB kinases and phosphatases in life and death decisions. AB - Previously we found that retinoblastoma protein (RB) became dephosphorylated in an early stage of DNA damage-induced, p53-independent apoptosis. Here, we report that both RB dephosphorylation and apoptosis are regulated by relative levels of RB kinases (cyclin-dependent kinases, or cdks) and phosphatases. Treatment of human Jurkat T cells with roscovitine, a potent and selective synthetic inhibitor of several cdks, rapidly induced RB dephosphorylation, which was followed by induction of apoptosis-associated internucleosomal DNA fragmentation. The roscovitine treatment did not increase levels of the endogenous cdk inhibitor proteins p16(Ink4a), p27(kip1) and p21(Waf1), supporting the idea that the observed RB dephosphorylation was due to a direct inhibition of cdk activities by roscovitine. Treatment with a protein kinase C inhibitor (sphingosine or staurosporine), which leads to suppression of several cdk kinase activities, also induced cellular RB dephosphorylation and apoptosis. Finally, roscovitine- or sphingosine-induced RB dephosphorylation was blocked by a specific inhibitor of protein-serine/threonine phosphatases (calyculin A or okadaic acid). Therefore, RB phosphorylation status and cellular fate are regulated by the ratio of RB kinases to RB phosphatases. PMID- 21590209 TI - Comparative inhibition of prostate cell invasion by conformationally flexible and constrained bis(2,6-dioxopiperazine)s. AB - Inhibition of the migration of human prostate cancer PC-3 cells by a series of 18 conformationally flexible and constrained bis(2,6-dioxopiperazine)s including selected bis(morpholinomethyl) derivatives was investigated in vitro using the Matrigel invasion assay. The anti-invasion effects were compared to the cytotoxic effects of these experimental drugs. The parent conformationally mobile ICRF-159 (razoxane) and its dextrorotatory isomer ICRF-187 (dexrazoxane) inhibited invasion at concentrations that were at least 19-fold lower than their cytotoxic concentrations. This indicates that the anti-invasion effect was achieved independent of cytotoxicity. Seven conformationally constrained compounds were found to have no appreciable anti-invasive activity. Generally, the morpholinomethyl pro-drug derivatives of seven of the dioxopiperazines, exhibited either anti-invasive or cytotoxic activities that were reduced or unchanged relative to the parent molecules. In summary, certain bis(2,6-dioxopiperazine)s exhibit a promising and selective anti-invasion effect in human prostate cells. This activity seems to require a flexible linker allowing for multiple conformational possibilities of the dioxopiperazine rings. PMID- 21590210 TI - Haematopoietic cytokines in the biology and treatment of acute myeloid leukaemia. AB - In acute myeloid leukaemia (AML), age has a definite effect on the biology of the disease and also determines the outcome of chemotherapy. AML cells constitutively express mRNA and produce several haematopoietic cytokines. The haematopoietic cytokines: SCF, IL-3, GM-CSF and G-CSF induce leukaemic colonies or activate DNA synthesis in about 80% of AML cases. Both M-CSF and thrombopoietin stimulated AML cell proliferation is seen in vitro in about 50% of cases. Both IL-6 and IL-11 showed little proliferative activity on primary AML cells. The combinations of these cytokines were synergistic in stimulating the proliferation of AML cells. On the other hand, the inhibitory haematopoietic cytokines: TNF-alpha, TGF-beta, IFN-gamma and IL-4 have shown multiple effects on AML blast cell proliferation. In several in vitro systems, haematopoietic cytokines have failed to induce maturation of AML blasts. Only in AML with t(8;21), G-CSF has induced granulocytic maturation of AML blasts in vitro. AML cells with chromosomal abnormalities involving the 21q22 region differentiate in vitro into eosinophils in the presence of IL-5. IL-6 and IFN-alpha have induced megakaryocytic differentiation of blast cells from acute megakaryoblastic leukemia (M7) patients. The haematopoietic cytokines: SCF, IL-3 and GMCSF have protected in vitro AML cells from chemotherapy-induced apoptosis. Many clinical studies have been recently reported evaluating the effect of the haematopoietic cytokines: GM CSF, G-CSF, IL-3 and PIXY321 as adjuncts to the chemotherapy of AML patients. Most studies have shown these haematopoietic cytokines to be well-tolerated and effective in augmenting neutrophil recovery in elderly AML patients when given after chemotherapy. On the other hand, considerable number of studies using these cytokines before and during chemotherapy to recruit AML cells into cell cycle and thus make them more susceptible to chemotherapy have reaveled no benefit. Several clinical trials have shown promising results after the use of IL-2 either as remission induction therapy in refractory and/or relapsed AML patients or as post remission consolidative immunotherapy. Haematopoietic cytokines administered after chemotherapy can shorten the duration of neutropenia and hospitalisation without a significant effect on treatment outcome. On the other hand, their use before and during chemotherapy has yielded no benefit, and instead have led to delay of platelet recovery and worse survival rate in some elderly AML patients. PMID- 21590211 TI - Taxol induces apoptosis in human colon carcinoma cell lines arrested in G(2)/M phase. AB - We analyzed taxol-induced apoptosis in human colon carcinoma cell lines. Cells expressing Bcl-2 (COLO320) and those that did not (DLD-1), underwent apoptosis after 24 h exposure to 1 mu M taxol. Flow cytometry showed that the numbers of cells arrested in G(2)/M decreased and that of apoptotic cells increased time dependently. The molecular weight of Bcl-2 was increased to above 26 kDa in COLO320 and LoVo cells after a 4 h exposure to taxol. Incubating the cells with genistein, a protein tyrosine kinase inhibitor, inhibited the taxol-induced modified Bcl-2 expression and apoptosis. These results suggest that taxol induces apoptosis in cells arrested in G(2)/M phase which might be partly explained by Bcl-2 inactivation by phosphorylation in human colon carcinoma cell lines. PMID- 21590212 TI - Association of serum autoantibodies to tumor-suppressor gene p53 in patients with ovarian cancer according to status of the disease. AB - Sera from 130 ovarian cancer patients and from 118 normal control volunteers were assayed for serum autoantibodies to p53 using an enzyme-linked immunosorbent assay (ELISA). Overall, autoantibodies were detected in 41% of ovarian cancer patients as compared to 0.9% of healthy individuals (P<0.001). The incidence of autoantibodies was lower in patients with complete remission (20%) as compared to those with recurrence (48%, P<0.01) and before primary surgery (49%, P<0.05). There was no statistically significant correlation between p53 serum autoantibody status and tumor stage, degree of malignancy and histological subtype. Comparing the autoantibody status with p53 antigen expression in the corresponding tissue resulted in 57% consistent results. Thus, serological testing for p53 autoantibodies provides additional information and may be associated with the disease status in patients with ovarian cancer. PMID- 21590213 TI - Tumour inhibitory effects of plasmid DNA. AB - The experiments were designed to examine whether direct in vivo transfer of plasmid DNA not carrying any 'therapeutic' genes ('empty' plasmid DNA) can influence tumour growth. Murine MC-induced sarcoma Mc12 was transplanted i.m. in syngeneic recipients and the tumour-inoculated mice were treated either with repeated peritumoral (i.m.) injections of the naked plasmid DNA or with a single peritumoral (i.m.) injection of plasmid DNA incorporated in liposomes. Two plasmid DNA preparations, BCMGNeo and pON1 were utilized. The direct in vivo transfer of both 'empty' plasmid DNA preparations inhibited tumour growth and significantly prolonged survival of tumour-bearing mice. Our results emphasize the importance of plasmid DNA controls for evaluation of gene therapy of cancer based on the transfer of 'therapeutic' genes in tumour-bearing individuals. PMID- 21590214 TI - Aspiration biopsy cytology of pleuro-pulmonary metastasis from a recurrent meningioma. AB - A transthoracic fine-needle aspiration biopsy, sampled under echographic guidance from a pleuro-pulmonary mass, proved to be a metastatic meningioma. The meningioma had been operated on from the left parietal lobe, twelve years previously. Cytologic specimens showed nests of round-to-spindle-shaped tumor cells with whorl formation; the cells were immunoreactive for vimentin and epithelial-membrane antigen. The cytological appearance of the tumor cells was diagnostic of meningioma. In the course of the clinical staging, a recurrent cerebral meningioma was found and was judged to be inoperable, because of extensive growth and brain infiltration. PMID- 21590215 TI - Prostatic carcinosarcoma. AB - A unique case of carcinosarcoma of the prostate in a 66-year old man is presented. The patient underwent a total prostatectomy under the diagnosis of prostatic carcinoma. Despite adjuvant radiotherapy, the patient died about 3 months after the operation. The surgically resected primary tumor was composed of two histologically distinct elements, an adenocarcinoma and sarcoma with various mesodermal components. These elements were intimately intermingled and transitional forms were often noted. The sarcomatous portion contained areas of chondromatous differentiation. The pathogenesis of this complex neoplasm is discussed. PMID- 21590216 TI - Detection of hepatitis C virus in sera and genotyping according to the 5' non coding region. AB - A reverse transcription (RT)-polymerase chain reaction (PCR) method was used for detection of the RNA of hepatitis C virus (HCV) in 120 samples of sera from Crete, which were positive for HCV-specific antibodies, by ELISA and Western blot analyses. A segment of 255 bp, located in the most conserved region of the HCV genome (the 5' untranslated region, 5' UTR), was amplified. For the identification of sequence variation from the HCV-1 strain, twenty of these samples were sequenced and compared to prototype strain (HCV-1) according to current genotypic classification. We were able to identify fourteen of the twenty as type 1a (i.e. similar to the prototype), two as type 1b, two as type 3a and two as type 4a. These findings generally agree with the geographic distribution of the already identified genotypes, though 3a type has not been reported previously in Crete (Greece). PMID- 21590217 TI - Transformation of human breast epithelial cells by 7, 12, dimethylbenz(a)anthracene, but not by N-methyl-N-nitrosourea, is accompanied by up-regulation of basic fibroblast growth factor. AB - Normal human breast epithelial cells (HBL100) are immortalized by endogenous SV40 genome and are not tumorigenic in nude mice if injected in the first 50 passages in culture. This cell line also depends on the expression of basic fibroblast growth factor (bFGF) for its viability in culture. The present study was designed to transform these cells with chemical carcinogens to establish malignant HBL100 cell lines in order to evaluate the eventual modulation in the expression of bFGF. In the first experiment, HBL100 cells were treated with 2 mu g/ml of 7, 12, dimethylbenz(a)anthracene (DMBA) for two 24 h periods. In a second experiment, HBL100 cells were transformed by exposing them to 20 mu g/ml of N-methyl-N nitrosourea (MNU) twice a day for two days. Unlike the HBL100 parental cell line, the two newly derived cell lines (named respectively HBLTDMBA and HBLTMNU) were tumorigenic when injected in nude mice. The expression of bFGF, as measured by immunocytochemistry and Western blot analysis, was higher in the DMBA-transformed cell line than in the parental HBL100 and MNU-transformed lines. These results differentiate between transformation selectivity by two different carcinogens. The direct-acting carcinogen MNU, which induces point mutation, does not require enhanced expression of bFGF, whereas bFGF may be necessary for early events leading towards transformation by carcinogens requiring metabolism for their action, such as DMBA. PMID- 21590218 TI - Expression of thymidine phosphorylase and angiogenesis in human ovarian tumor. AB - Thymidine phosphorylase (dThdPase) is an enzyme involved in pyrimidine nucleoside metabolism. dThdPase activity is increased in various types of malignant tumors. Recently, we demonstrated that dThdPase is identical to platelet-derived endothelial cell growth factor (PD-ECGF), and has angiogenic activity. We measured the dThdPase activity and the level of thrombomodulin (TM), as a marker for endothelial cells, in ovarian carcinomas, benign tumors and normal ovarian tissues. The average dThdPase activity of ovarian carcinomas (10.86+/-6.98 nmol/100 mu g protein/h) was significantly higher than that of benign tumors (4.66+/-3.91 nmol/100 mu g protein/h) or normal tissues (2.52+/-1.90 nmol/100 mu g protein/h). The expression of dThdPase detected by immunoblot analysis was well correlated with dThdPase activity. In an immunohistochemical study, the expression of dThdPase was more frequently observed in ovarian carcinomas than in benign tumors or normal tissues. dThdPase activity in human ovarian carcinomas was significantly correlated with the expression of TM in human ovarian carcinomas. These findings suggest that dThdPase expression is significantly correlated with angiogenesis in ovarian tumors. PMID- 21590219 TI - Comparison of DNA sequences of the long terminal repeat of human T lymphotropic virus type I in Japanese and Brazilian Amazonian samples. AB - Antibodies to human T lymphotropic virus type I has been detected in subjects of different human ethnicities all around the world. Etiological relationship between the virus and human diseases has been claimed by many investigators. Amplified and sequenced region of the long terminal repeat of human T lymphotropic virus type I obtained from nucleic acid extracted from serum samples of Japanese and Brazilian patients with cancer of uterine cervix and normal Brazilian subjects, all seropositives for the virus, showed minor genetic variations when compared to the Japanese prototype. PMID- 21590220 TI - The analysis of the innate pathways of 5-fluorouracil phosphorylation in human gastrointestinal cancer cell lines in vitro and in vivo. AB - Possible pathways of the phosphorylation of 5-fluorouracil (FUra) were investigated in vitro and in vivo, using certain xenografts, of human gastric and colorectal cancer cell lines. The oxonic acid (Oxo), an inhibitor of orotate phosphoribosyltransferase (OPRTase) that catalyzes the direct production of 5 fluorouridine 5'-monophosphate from FUra (the first pathway) and 2, 6 dihydroxypyridine (DP), an inhibitor of uridine phosphorylase (UPase), the enzyme converting FUra to 5-fluorouridine (the second pathway), were employed to estimate a contribution of these two metabolic pathways in the anabolism of FUra. Ten out of 13 cancer cell lines tested were found to utilize the first route for the phosphorylation of FUra, as revealed by marked inhibition of the phosphorylation of FUra by Oxo in 4 of 5 and in 6 of 8 gastric and colorectal cancer cell lines, respectively. The phosphorylation of FUra in the xenografts of human AZ521 gastric adenocarcinoma and SNU-C2A colorectal carcinoma was also regulated by Oxo, the production of 5-fluoro-nucleotides after i.v. injection of FUra with the Oxo significantly decreased from 0.587 to 0.311 nmol/g and from 1.75 to 0.40 nmol/g in respective xenografts, suggesting that the nature of an anabolic pathway of FUra in the tumor cells in vitro reflects the metabolic pattern found in the in vivo conditions. Moreover, the intracellular concentrations of phosphoribosylpyrophosphate (PPRibP) in DLD-1 and SNU-C(2)A cells were much higher than those found in HCT-15 and MKN-28 cells, leading to the findings that FUra was phosphorylated by OPRTase in the former and by UPase and uridine kinase in the latter cells. These results also may suggest that the intracellular levels of PPRibP in the tumor cells are importantly related to the selection of a proper metabolic pathway of FUra by the cell. PMID- 21590221 TI - Angiographic diagnosis of the degree of invasion in rectal cancer. AB - Inferior mesenteric arteriography was performed prior to surgery on 36 patients with carcinoma of the rectum in order to diagnose the degree of cancer invasion. Results were divided into four categories based on degree of invasion as observed in angiographs, and were compared with results of macroscopic observation and histological studies. A high degree of correlation was seen between observation of pre-operative angiographic abnormalities and macroscopic observation of the degree of cancer invasion (75%). However, comparisons between histological findings and observations of pre-operative angiographic abnormalities yielded a low degree of correlation (41.2%), particularly among the lower three categories of invasion. This is believed to reflect the changes in tissue that accompany cancer, such as inflammation, adhesion, and fibrosis, which also are revealed by angiography. The ability to diagnose the degree of cancer invasion is important in selecting the appropriate surgical procedure for treating rectal cancer, and angiography should be considered for use in such diagnosis. This study showed that pre-operative angiography clearly highlighted changes in rectal arteries in advanced cases (A2, a2 or above) of rectal cancer. The usefulness of angiographic observations in selecting treatment strategies was demonstrated. PMID- 21590222 TI - Proliferating cell nuclear antigen and argyrophilic nucleolar organizer regions in patients with thymic disease. AB - We examined argyrophil nuclear organizer regions (AgNOR) and proliferating cell nuclear antigen (PCNA) in 41 patients with surgically-treated thymic disease. AgNOR count and PCNA labeling index (LI) in thymic carcinoma were significantly higher than those in thymoma and thymic hyperplasia. A positive correlation was observed between the PCNA LI and argyrophilic nucleolar organizer region (AgNOR) counts within all thymic disease (r=0.31, P=0.002). The PCNA LI in invasive thymoma was lower than that in non-invasive thymoma. In survival analysis, the cut-off values for the PCNA LI and AgNOR count were chosen to produce two categories with equal numbers of 26 thymoma patients. There were no significant difference in the survival rate between the lower and higher group patients in relation with AgNOR count and PCNA LI. We conclude that combining AgNOR and PCNA may discriminate the biological activity of thymic disease. These staining methods can be performed with ease and, applied in a clinical laboratory on a routine basis to help predict cytological malignancy of thymic disease. PMID- 21590223 TI - A phase I study of cisplatin, methotrexate, levofolinic acid and 5-fluorouracil in advanced squamous cell carcinoma of the head and neck. AB - Twenty-one chemotherapy-naive patients with unresectable or metastatic squamous cell carcinoma of the head and neck (SCCHN) received a combination chemotherapy including cisplatin (CDDP), methotrexate (MTX), folinic acid (LFA) and 5 fluorouracil (5-FU). The doses of the 3 cytotoxic drugs were escalated until dose limiting toxicity occurred in more than 1/3 of the patients. The treatment was generally well tolerated; no toxic deaths occurred. Only 2 patients showed dose limiting neutropenia. Non-haematologic drug toxicities were infrequent and never reached grade 3. 3/21 (14%) complete responses and 6/21 (29%) partial responses were observed, for an overall response rate of 43%. 5/6 patients treated at step 5 achieved an objective response to treatment and 2 complete responses were observed in this group of patients. Although maximum tolerated doses (MTD) were not reached even at step 5, we decided to stop the escalation and to recommend this level for the phase II study. Our regimen combines a good tolerability with a high level of activity at step 5; a phase II study is currently ongoing. PMID- 21590224 TI - Antineoplaston AS2-1 for maintenance therapy in liver cancer. AB - Antineoplaston AS2-1 exhibits cytostatic growth inhibition of human hepatocellular carcinoma cells in vitro and showed minimum adverse effects in a phase I clinical trial. Liver cancer is difficult to control because of multicentricity and underlying liver disease. We reviewed two clinical cases of liver cancer (hepatocellular carcinoma and multiple liver metastases from colon cancer) in whom we believe antineoplaston A2-1 was useful as a maintenance therapy after transcatheter arterial embolization (TAE) and microwave coagulation necrosis (MCN). The two patients have continued to be in good condition for more than two years without limitation of their normal activities. Antineoplaston AS2 1 may be effective and useful as a maintenance agent after TAE and MCN in patients with liver cancer. PMID- 21590225 TI - Successful pregnancies after malignant ovarian germ cell tumour. AB - The treatment of ovarian germ cell rumours has changed during the past two decades. The use of conservative surgery and adjuvant chemotherapy instead of radiotherapy is now often but not always employed. We report three cases of young patients treated for ovarian germ cell tumours, who were subsequently able to complete successful pregnancies. We think that in view of the possibility of sparing the young patients' childbearing potential with a better quality of life, this therapeutic approach should be utilized whenever applicable. PMID- 21590226 TI - Does smoking or family history influence the prognosis of patients with non-small cell lung cancer? AB - The prognostic significance of pack-years smoked (PY) and family history of cancer (FH) was studied using the Cox proportional hazard model in 970 patients with non-small cell lung cancer. PY influenced survival only in women after other variables were adjusted [Hazard ratio (HR): 1.75 (1.45-2.11)]. FH also influenced survival with marginal significance in women with stage I disease [HR: 2.17 (0.89 5.29), p=0.088]. Furthermore, these two factors operated additively in women [HR for patients with both smoking and family histories over those without either: 2.25 (1.18-4.26)], but not in men. PMID- 21590227 TI - Correlation between expression of urokinase-type plasminogen activator receptor and metastasis in gastric carcinoma. AB - To clarify the interrelationship between urokinase-type plasminogen activator receptor (uPAR) and the progression of gastric cancer, uPAR expression in gastric cancer was studied by the reverse transcription (RT)-PCR and immunohistochemistry. uPAR mRNA was expressed in 44 of 46 primary gastric cancers and uPAR immunoreactivity was found in 21 (14%) of 155 tumors. uPAR immunoreactivity was also observed in the fibroblast-like cells and the inflammatory cells including macrophages. The intensity of uPAR immunoreactivity of these cells was weaker than that of cancer cells. uPAR expression detected by RT-PCR may be from cancer cells and/or non-cancerous stromal cells. uPAR immunoreactivity in cancer cells was closely associated with histologic type, nodal status, and macroscopic type. The uPAR positive tumors were closely associated with the macroscopically infiltrating type, undifferentiated type and stage IV disease. Poorly differentiated carcinomas with rich intestitial fibrosis (scirrhous carcinoma) expressed uPAR with a significantly higher incidence than the other histologic types of carcinoma. Growth of scirrhous carcinoma may be a result of a concerted action of the players in the plasminogen activator system, consisting of cancer cells and stromal elements. Furthermore, there was an intimate relationship between the grade of lymph node metastasis and uPAR tissue status. Patients with a uPAR positive tumor had a significantly poorer prognosis than those with uPAR negative tumor. These results indicate that the immunohistochemical diagnosis of uPAR tissue status on the primary tumor of gastric cancer may be a good predictor for the prognosis of patients with gastric cancer. PMID- 21590228 TI - Dukes' A tumor. AB - Dukes' classification for colorectal cancer is easy to remember and accurate in estimating survival. The Japanese definition of early gastric cancer have some problems, since it includes node-positive cases showing a worse prognosis. The aim of this study was to clarify whether or not Dukes' A tumor can be used as new criteria for early gastric cancer. Using 217 patients who underwent radical gastrectomy and lymph node dissection for primary gastric adenocarcinoma, long term results and cumulative survival rates after operation were examined. Patients consisted of three groups: Group 1, 20 patients with node-negative tumor invading down to the muscularis propria, Group 2, 175 patients with node-negative tumor limited to the mucosa or submucosa, and Group 3, 22 patients with node positive tumor limited to the mucosa or submucosa. The 10-year survival rates for Group 1, Group 2, and Group 3 patients were 94.7%, 96.9%, and 85.1%, respectively. The survival rate of Group 3 patients was significantly lower than that of Group 1 and Group 2 patients (p<0.05). The prognosis of patients with Dukes' A tumor (Group 1 plus Group 2) was excellent, showing 10-year survival rate of 96.6%. Mucosal or submucosal cancer brought a poor prognosis when there was lymph node metastasis. Early gastric cancer would better be defined as a Dukes' A tumor which includes node-negative tumor not beyond the muscularis propria. PMID- 21590229 TI - Increased concentration of hepatocyte growth factor in the sera of patients with gastrointestinal cancer. AB - We measured the concentration of hepatocyte growth factor (HGF) in the sera of 138 patients with gastrointestinal cancer. The mean value and positive rate for this protein (assuming 0.4 ng/ml as the cut-off value) were 0.29 ng/ml (11.4%) in healthy donors (n=44), 0.90 ng/ml(70.8%) in esophageal cancer (n=24), 0.39 ng/ml (33.3%) in gastric cancer (n=39), and 0.40 ng/ml (42.7%) in colorectal cancer (n=75). Thus, the mean values of the esophageal and colorectal cancer group were significantly higher than that of healthy donors. There was a tendency for elevated mean value of serum HGF in the sera of patients with distant metastases, compared to those with no such evidence, i.e., 1.36:0.77 ng/ml in esophageal cancer, 0.69:0.30 ng/ml in gastric cancer, and 0.66:0.37 ng/ml in colorectal cancer. This difference was statistically significant in gastric and colorectal cancer. These findings suggest that serum HGF is useful as a tumor marker with a close correlation to the metastatic state of gastrointestinal cancer. PMID- 21590230 TI - Alteration of polyunsaturated fatty acid pattern of plasma phospholipids and antioxidants in cervical HPV infection and neoplasia. AB - The complex interactions between host immunity and infectious diseases have been documented in literature and they play a role in virus infection. Many clinical experimental reports have stressed the importance of homeostasis of cell membranes and of the 'cell healthy indicators', namely polyunsaturated fatty acids and antioxidants in HIV infection. Today's increased incidence of heterosexual transmission of HIV has showed a strict correlation between HIV and HPV infection. According to some studies, positive HIV subjects have 40-200 times a greater risk of becoming HIV-positive. We have evaluated in 40 women with HIV infection the plasma levels of polyunsaturated fatty acids of phospholipids and vitamin E, determined by GC-MS methods, and the erythrocyte glutathione peroxidase activity (GHS-Px) by spectrophotometric techniques. The alteration of these parameters were correlated with the progression of the infection, i.e. the appearance of dysplastic or neoplastic pathologies on the uterine cervix. The differences were statistically significant (p<0.001) in subjects with cervical cancer with respect to both normal controls and patients with condylomatosis. PMID- 21590231 TI - Induction of apoptosis in ovarian carcinoma cell line by glucocorticoids, and sex steroid hormones. AB - We investigated the interactions in the KOC-2s human ovarian cancer cells on the effect of glucocorticoids, and sex steroid hormones in ovarian carcinomas. At 10( 8) M to 10(-5) M, dexamethasone (Dex) decreased the number of cells by 75-80% (p<0.001). At 10(-8) M and 10(-7) M, hydrocortisone (HC) decreased the number by 50% (p<0.01); at 10(-6) M and 10(-5) M, the decrease in number of cells was 65%. The E-2 decrease in number was not statistically significant. Progesterone (PG) showed at 10(-8) to 10(-6) M an increase in number of cells, however, at 10(-5) M it was decreased by 70% with a significant difference (p<0.001). Dex (10(-8)-10( 5) M), HC (10(-8)-10(-5) M) and PG (10(-5) M) produced internucleosomal cleavage of DNA into fragments with multiples of 180 to 200 bp. The TNF-alpha with addition of Dex (10(-8)-10(-5) M) and HC (10(-8)-10(-5) M) was increased after 24 h, 48 h (p<0.001); however, gradually decrease after 72 h. When PG (10(-8)-10(-5) M) was added, PG (10(-5) M) increased the secretion of TNF-alpha after 72 h. Our findings demonstrate that glucocorticoids, and PG directly induce apoptotic DNA fragmentation of KOC-2s cells. However, the secretion of TNF-alpha and expression of Fas antigen were totally different in these substances. These data provide a basis for future studies on the mechanisms of apoptotic effect of glucocorticoids, and PG and the therapeutic effects of these substances. PMID- 21590232 TI - Regulation of cathepsin B activity by modulators of arachidonic acid metabolism in human monocytes. AB - Cathepsin B (CB), a lysosomal cysteine proteinase, is implicated in tumour invasion and metastasis. Although direct exposure of THP-1 cells to arachidonic acid did not stimulate the induction of CB activity, cells treated with arachidonic acid followed by interferon-gamma (IFN-gamma), as well as concurrently treated cultures with arachidonic acid and lipopolysaccharide (LPS) or phorbol ester (PMA) increased CB activity in a dose-dependent manner. LPS and IFN-gamma-induced increases in CB were down-regulated by dexamethasone, an inhibitor of phospholipase A(2) (PLA(2)). Whereas dibutyryl cAMP, which increases PLA(2) activity, caused elevations in CB in THP-1 cells; inhibition of protein kinase A by H-89, which reduces PLA(2) expression, blocked the effect of dibutyryl cAMP. On the other hand, indomethacin, an inhibitor of cyclooxygenase, and ketoconazole, an inhibitor of lipoxygenase, up-regulated CB activity dose dependently, indicating that the balance among PLA(2), cyclooxygenase and lipoxygenase activities might regulate the levels of CB synthesis. These data suggest that arachidonic acid may be associated with part of the intracellular signal pathway in the induction of CB activity by LPS, PMA and IFN-gamma. PMID- 21590233 TI - Significance of tumor marker SLX in colorectal cancer. AB - We examined serum SLX for its significance as a tumor marker in 109 colorectal cancer patients. There a close correlation with immunohistochemical expression of SLX and serum SLX level. Serum SLX was positive in 16.5% of 109 patients with colorectal cancers. There was no significant correlation between serum SLX level and histologic type or primary tumor status. There were significant correlations between serum SLX positive rates and both lymph node and hematogenous metastasis. In 7 SLX positive cases who underwent curative resection, 4 patients had already recurrence in the liver. Our findings suggest that serum SLX values may be a biologic marker of metastasis. PMID- 21590234 TI - Association of progression and reduced expression of VLA-2 in gastric cancer. AB - We investigated the expression of VLA-2 in gastric cancers by immunohistochemistry using anti-integrin alpha 2 and beta 1 antibodies and the data were compared with the pathological findings of each gastric cancer. The specimens were stained with an immunohistological technique for integrin alpha 2 and beta 1 subunits. Tumors, simultaneously expressing both integrin alpha 2 and beta 1 subunits were defined as positive for VLA-2. Tumors expressing either subunits of integrin alpha 2 or beta 1 or those showing reduced expression of both subunits were defined as VLA-2 negative tumors. In the 77 primary tumors, 55 (71%) were VLA-2 positive. 38 (90%) of 42 tumors showing differentiated type including tubular adenocarcinoma and papillary adenocarcinoma expressed VLA-2, whereas 19 (55%) out of 35 undifferentiated type of cancers including poorly differentiated adenocarcinoma, mucinous carcinoma and signet ring cell carcinoma stained for VLA-2. In the undifferentiated type of cancers, VLA-2 negative tumors had a significantly higher incidence of vessel invasion than VLA-2 positive ones (p<0.05). VLA-2 negative tumors showed a tendency to peritoneal dissemination, lymph node metastases, lymphatic invasion or invasion beyond the subserosal layer. In the specimens of peritoneal dissemination, VLA-2 expression rate was found in 56% (9/16), with a higher expression rate than that of primary lesions. These data indicate that reduced expression of VLA-2 may strongly associate with vessel invasion especially in the undifferentiated type of adenocarcinoma of the stomach. PMID- 21590235 TI - Growth arrest of DMBA-induced mammary carcinogenesis with ibuprofen treatment in female Sprague-Dawley rats. AB - We examined effects of ibuprofen on the growth and development of DMBA-induced mammary cancers in mature female Sprague-Dawley rats. Ibuprofen was added to the standard diet at approximately 1,000 mg/kg rodent chow, resulting in an average daily dose of 25 mg per day per 0.25 kg rat. After five weeks of ibuprofen treatment, there was a 37% reduction in tumor volume compared to a 260% increase in the volume of tumors in untreated rats (p<0.001). These results suggest that ibuprofen may have potential in the chemoprevention and treatment of breast cancer. PMID- 21590236 TI - Molecular analysis of uterine leiomyomas using the probes D7S13(7q) and HSPA2(14q). AB - Human uterine leiomyomas, mostly cytogenetically characterized, were analyzed by Southern blotting. The region 7q22.3-q31.2 was analyzed in 54 leiomyomas using the polymorphic probe D7S13. The region 14q22-24 was investigated in 25 leiomyomas with the probe HSPA2. No evidence of rearrangement or amplification of these DNA-regions was observed. Nor was any loss of polymorphism for the probe D7S13 seen. These, and earlier negative results, motivate further molecular investigation to understand the mechanisms reflected by recurrent chromosome aberrations in myomas. PMID- 21590237 TI - Ovarian tumor complicated by a colo-ovarian fistula. AB - Although a fistula is a rare complication of ovarian tumor, we encountered four patients with cole-ovarian fistulas in three years. The first case was demonstrated by following barium enema by the extravasation of barium from the sigmoid colon, and by a gas-containing lesion in the tumor observed on computed tomography. Mature cystic teratoma was the pathological diagnosis in two cases. A mixed germ cell tumor and a serous cystadenoma of low malignant potential were diagnosed in the other two cases. The etiology and differential diagnosis of cole ovarian fistula are reviewed. PMID- 21590238 TI - Management of malignant lymphoma in two siblings with Bloom's syndrome. AB - Treatment of the malignant neoplasms which develop in patients with chromosome fragile syndrome, such as Bloom's syndrome (BS), requires extremely careful planning of the chemotherapy regime because of the excessive chemosensitivity of patients with such syndromes. Two siblings with BS developed B cell-type non Hodgkin's lymphoma in the third decade of their lives. In both cases a 3-bp homozygous deletion of the BLM gene was detected. Since the lymphoma of the older brother was nasopharyngeal in origin, he was administrated radiation therapy as the primary treatment. However, hepatic metastasis was detected and this was the cause of his death. A 9-bp deletion in exon 7 of the p53 gene was detected in the metastatic lymphoma. His younger sister developed a lymphoma of abdominal lymph node in origin. She received a half dose of the drugs used in the acute lymphoblastic leukemia treatment without radiation, and twenty months after the diagnosis of her lymphoma she continues to be in complete remission and free of treatment complications. The p53 gene mutation was not detected in her lymphoma. These results suggest that radiation therapy and the radiation dose for the treatment for lymphoma in patients with BS should be carefully considered. PMID- 21590239 TI - Reactivity of 87 monoclonal antibodies against tissues in vivo and resting and irradiated endothelial cells in vitro. AB - Altered expression of vascular endothelial cell (EC) surface antigens in response to irradiation is one of the early events of radiation-induced damage. Using flow cytometry, we investigated the immunocytochemical reactivity of a blind panel comprising 87 mAbs submitted to the endothelial section of the 6th International Workshop on Human Leukocyte Differentiation Antigens with irradiated and resting human dermal microvascular endothelial (HDME) and EA cell lines. Monolayers of irradiated cells received a single 5 Gy dose of 72 h prior to staining but were otherwise treated the same as resting cells. For comparative purposes we have also examined the immunohistochemical reactivity of the mAb panel with EC in ovarian tumour, Wilms' tumour and human placenta. In the flow cytometry experiments 42 and 44 mAbs stained HDME and EA cells respectively and while no antibody stained irradiated but not unirradiated cells, upregulation was seen for CD31, CD34, CD141 and CD146 in irradiated cells. The upregulation of thrombomodulin (CD141) is noteworthy since it is a marker of EC damage and thus may be a useful reagent in investigations of vascular injury. Comparison with tissue staining showed that 21 mAbs were reactive with at least one tissue but not with either EA or HDME cells. Nine mAbs showed no cross reactivity with tissue and of these one reacted with EA cells only. PMID- 21590240 TI - Immunohistochemical detection of MAGE tumor-associated antigens in esophageal squamous cell carcinoma. AB - Genes of the MAGE family encode tumor-specific antigens recognized by cytotoxic T lymphocytes in a variety of neoplasms. We investigated the protein expression of these antigens as related to the gene expression, in esophageal squamous cell carcinoma by using monoclonal antibodies recognizing MAGE gene products. Esophageal squamous cell carcinomas were found to express both MAGE-1 (4 out of 15 samples) and MAGE-3 (7 out of 15 samples) genes, by RT-PCR. Immunoblotting revealed MAGE-1 and MAGE-3 gene products in 2 and 6 out of 15 samples, respectively. Immunohistochemistry performed on 12 samples showed MAGE-1 protein expression, limited to single tumor cells, in 2 cases. MAGE-3 gene product was detectable in 7 cases: in 5 of them over 50% of neoplastic cells were positive. Considering the high percentages of tumor cells expressing MAGE-3 antigen, the use of epitope-based vaccines could be envisaged in patients displaying appropriate HLA-class I phenotype. PMID- 21590241 TI - Cytotoxicity of 2-deoxy-D-glucose and its tetra-acetate ester in tumoral cell lines. AB - Mouse Lewis lung carcinoma cells (3LL-HH), mouse leukemic cells (L1210), mouse melanoma cells (B16F1), rat gliosarcoma cells (9L), rat hybrid insulin-producing cells (BRIN-BD11) and human hepatocellular carcinoma cells (HepG2) were cultured for 8 to 96 h in the absence or presence of 2-deoxy-D-glucose or its tetra acetate ester (45 mu M to 0.8 mM). The ester was more efficient than the unesterified glucose analog in decreasing the growth of the tumoral cells, as assessed by either the generation of formazan from 3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyl-tetrazolium bromide or direct cell counting. At high concentration (0.8 mM), the ester even decreased the cell number below its initial value. Even under these conditions, a partial restoration ol-cell growth was observed, however, when the cells were cultured in a control medium after having been exposed for 8 h to 2-deoxy-D-glucose tetraacetate. These findings indicate that such an ester acts as a powerful cytostatic and cytotoxic agent in several tumoral cell lines. PMID- 21590242 TI - Comparative analysis of radiometric and autoradiographic methods in the investigation of DNA synthetic activity of tumor cells in vitro. AB - DNA synthesis in cell cultures of Ehrlich ascites carcinoma (EAC) was studied by means of autoradiography and liquid scintillation radiometry. The following parameters were compared for estimation of DNA synthesis: a) total radioactivity of incorporated [H-3]thymidine registered by a liquid scintillation counter, b) labeling index (LI) reflecting the relative number of cells which synthesize DNA, and c) mean grain count (MGC) indicating average intensity of DNA synthesis in the S-phase of the cell cycle. Kinetics of total radioactivity of incorporated [H 3]thymidine was determined to correlate better with LI. Changes in DNA synthesis in vitro were shown to be monitored with a higher level of significance by the radiometric technique, but autoradiography was more sensitive in some cases. Priority and informative value of the two methods were discussed. Autoradiography and liquid scintillation radiometry were concluded to be mutually complementary for investigation of DNA synthesis in tumor cells in vitro. Combination of the two methods was recommended for investigation of influence of cell proliferation inhibitors on DNA synthesis. PMID- 21590243 TI - Early stage breast cancer. AB - Breast cancer is the most common malignancy seen in women. Due to the increasing awareness for this disease and the increasing use of screening mammography, more patients are now diagnosed with early stage disease. Over the past few years, the indications for adjuvant treatment have expanded considerably, and more women are now candidates for chemotherapy, hormonal therapy, or both. The role of various prognostic factors and their implications on the design of a multidisciplinary therapeutic approach is discussed in this review. Current recommendations regarding the extent of the surgery, the role of radiation, and its integration to the adjuvant treatment are discussed. Guidelines on adjuvant chemotherapy and adjuvant hormonal therapy are also being presented. PMID- 21590244 TI - Lymphomatous meningitis in immunocompetent patients. AB - A prospective study of combined modality therapy of non-AIDS related lymphomatous meningitis was carried out. Lymphomatous meningitis is diagnosed increasingly as anti-lymphoma therapies become more effective and result in prolonged patient survival. Twenty-two patients (range 38-69 years; median 60) with lymphomatous meningitis due to metastatic non-AIDS related non-Hodgkins lymphoma were treated. Neurologic presentation included: headache (n=13); cranial neuropathies (n=9); ataxia (n=5); cauda equina syndrome (n=3); myelopathy (n=1); and meningismus (n=1). All patients underwent radiographic evaluation of the extent of central nervous system disease (CNS) followed by radiotherapy (n=8) and sequential intraventricular chemotherapy (methotrexate in 22 patients; cytarabine in 12; thio-TEPA in 5). CNS imaging demonstrated: interrupted CSF now (n=8); intra cranial subarachnoid nodules (n=2); hydrocephalus (n=2); spinal subarachnoid nodules (2); nerve root enhancement (n=2); and epidural spinal cord compression (n=1). Cytologic responses were seen in 16 patients (73%) to first-, 7 (58%) to second- and 2 (40%) to third-line chemotherapy. Treatment-related toxicity included 14 patients (64%) with aseptic meningitis and 12 patients (55%) with thrombocytopenia or neutropenia (all unrelated to intraventricular chemotherapy). Median survival was 10 months (range: 3-24 months). Fourteen patients (64%) died of their systemic disease, 3 patients (14%) died of progressive lymphomatous meningitis, 4 patients (19%) died of progressive combined systemic disease in lymphomatous meningitis and 1 patient (5%) is disease-free. Fourteen patients (64%) received concurrent systemic chemotherapy and no differences were seen in outcome within this group of patients including 6 patients treated with dose intensive chemotherapy and autologous bone marrow transplantation. Lymphomatous meningitis in patients with non-AIDS related non-Hodgkin's lymphoma may be palliated with combined modality therapy, however, despite the application of standard or dose intensive systemic chemotherapy, therapy remains non-curative. PMID- 21590245 TI - Microsatellite instability is rarely detected in oesophageal adenocarcinoma. AB - Microsatellite instability and the replication error phenotype are characteristic of hereditary non-polyposis colorectal cancer and have also been described in certain sporadic carcinomas. Seventy-four microsatellite DNA markers, covering all non-acrocentric autosomal chromosome arms, were used to determine the frequency of microsatellite instability in adenocarcinoma of the oesophagus. Nine of 23 cases (39%) of oesophageal adenocarcinoma demonstrated microsatellite alterations with at least 1 marker, but only 2 cases (9%) displayed alterations with multiple markers. Hence, microsatellite instability is rarely detected in oesophageal adenocarcinomas and is unlikely to play a major role in its development. PMID- 21590246 TI - De novo expression of P-glycoprotein associated with poor prognosis in high grade non-Hodgkin's lymphoma. AB - Chemotherapy has proven to be effective in the management of high grade non Hodgkin's lymphoma (NHL). However drug resistance remains a major clinical obstacle to effective disease control. One such well documented system involves multidrug resistance (MDR), characterized by the overexpression of a 170 kDa membrane protein termed P-glycoprotein (Pgp). Analysis of P-glycoprotein was done on lymph node biopsies obtained from 109 patients with high grade NHL. Patients were followed up for time periods ranging from 7 to 26 months after chemotherapy or until recurrent/residual disease was diagnosed. Analysis of Pgp in tissue samples was carried out by immunocytochemistry and Western blot. Of the 109 patients, 36 had either residual or recurrent disease. All these patients had a second lymph node biopsy done which was also analyzed for Pgp. P-glycoprotein was detected by immunocytochemistry in only 5 of the 73 patients who remained disease free, while it was expressed in 26 of the 36 patients with residual/recurrent disease. All the 36 tissue samples of the latter group and 42 of the 73 biopsies of the disease-free group were re-analyzed by Western blot. Only one of the 42 samples from the disease-free group showed a positive Western blot reaction while 30 of the 36 samples from patients with recurrent/residual disease gave a positive reaction. Thirty-four of the 36 repeat biopsy samples from patients with recurrent/residual disease were positive for Pgp. Correlation analysis, thus showed significant relationship between prognosis and detection of Pgp by immunocytochemistry (r=0.85, p<0.001) and Western blot (r=0.90, p<0.001). Moreover, the odds ratio of a tumor positive for Pgp not responding to chemotherapy was 35.36 (CI 11.03, 113.37). Thus evaluation for Pgp may prove to be a useful prognostic marker for high grade NHL, and may also prove useful in designing or altering chemotherapy protocols in such patients. PMID- 21590247 TI - Cultured oncogenic osteomalacia tumor cells produce a factor(s) that inhibits osteocalcin production by osteoblastic cells. AB - A 34-year-old patient was diagnosed with oncogenic osteomalacia associated with hypophosphatemia, low levels of serum 1,25-dihydroxyviamin D [1,25(OH)(2)D], and osteocalcin (OC). Resection of the tumor normalized these blood abnormalities. While such tumors produce a humoral factor(s) that affects phosphate reabsorption by the proximal renal tubules, the direct action of such factor(s) on osteoblast function has not been examined previously. We investigated the effect of conditioned medium of cultured osteomalacia tumor cells on OC production by human osteoblastic cell line, MG-63. The conditiond medium inhibited OC production induced by 1,25(OH)(2)D-3. Our results indicate that the humoral factor(s) produced by the tumor has direct effect on osteoblasts and may contribute to development of the characteristic syndrome. PMID- 21590248 TI - 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography of head and neck in patients with nasopharyngeal carcinomas. AB - Positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose (FDG) demonstrates increased tracer uptake in head and neck carcinomas. This study was undertaken to evaluate FDG-PET for the detection of nasopharyngeal carcinoma (NPC) and cervical lymph node metastasis, as well as to determine the effectiveness of FDG-PET for the diagnosis of recurrent or persistent NPC in irradiated fields. Twenty patients with suspected NPC were enrolled in this study. Ten patients had not received treatment for NPC. The remaining 10 patients were suspected to have recurrent or persistent NPC after radiotherapy. Following FDG-PET imaging, each patient underwent biopsy of suspicious lesions to establish a final diagnosis. The FDG-PET studies were analyzed two ways: i) Each tomogram slice was visually inspected. Abnormal FDG uptake on tomogram was compared to sites of suspected NPC, based on clinical examination, as well CT and MRI results. ii) Computer quantified radioactivity within the region of interest was compared to radioactivity in the cerebellum and to radioactivity in the normal aerodigestive mucosa. i) All proven NPC were detected as areas of increased FDG uptake by visual inspection (accuracy 100%). ii) The differences in levels of radioactivity between NPC and normal tissues were very large: radioactivity ratio of NPC/cerebellum ranged from 102% to 294%, and that of NPC/mucosa ranged from 130% to 704%. iii) All 5 cases of cervical lymph node metastasis were detected. FDG-PET studies of head and neck may prove valuable for distinguishing NPC (increased radioactivity) from scar tissue (reduced radioactivity). Its application may facilitate the diagnosis of recurrent NPC, as fibrosis and distortion of normal architecture in irradiated fields do not affect the accuracy of FDG-PET for the detection of NPC. PMID- 21590249 TI - A rigid external prosthesis to improve quality of life after chest wall resection. AB - Chest wall resection (CWR) is occasionally required in cancer patients and may cause significant functional deficits. We report an instance where a rigid orthotic device was useful in rehabilitation. Such custom-made devices can improve the quality of life for cancer patients. PMID- 21590250 TI - A phase II study of vinorelbine in patients with advanced non-small cell lung cancer. AB - Twenty-seven patients with non-small cell lung cancer were recruited into a phase II study of single-agent vinorelbine using a 25 mg/m(2) weekly dose schedule. All patients were inoperable (stage III disease - 11 patients; stage IV disease - 16 patients). Median age was 64 years (range: 37-72 years). Histological sub-types were squamous cell carcinoma (15 patients), adenocarcinoma (8) and large cell carcinoma (4). Partial response was documented in 4 (16%) of 25 evaluable patients, and stable disease in 13 (52%) patients. Median duration of response was 6.5 months (range 3-16 months) and median overall survival for patients with stable disease/partial response was 8 months (range 1-20 months). Vinorelbine was generally well tolerated although WHO grade 3/4 toxicity was noted for lethargy, constipation, alopecia (2 patients each), headache and non-tumour related bone pain (1 patient each). Vinorelbine is a moderately active single-agent in non small cell lung cancer and is currently undergoing evaluation as part of combination chemotherapy regimens. PMID- 21590251 TI - Low molecular thymic peptides improve the deficient immunocytotoxicity of mononuclear cells from tumor patients in vitro. AB - We studied, in vitro, the stimulating effects of a commercial preparation of low molecular thymic peptides (TP) on the immunocytotoxicity of peripheral blood lymphocytes and monocytes from patients with breast tumors, melanoma and colorectal tumors. On average, tumor patients showed a lower natural killer (NK), lymphokine (IL-2) activated killer (LAK) cell and basic tumoristatic activity of monocytes, compared with healthy donors. There was no correlation between the NK cell number and the NK-cell activity of the tumor patients. The TP showed no effects on the NK-cell activity in any group, yet elevated the deficient LAK-cell activity of tumor patients and that of healthy donors. On monocytes, TP enhanced the deranged tumoristatic activity only in tumor patients, while being slightly inhibitory on control monocytes. Dividing the donors on the basis of the TP effects on cytotoxicity of the mononuclear cells into TP-nonresponders and TP responders, a higher number of TP-responders was found among tumor patients, compared with healthy donors. Moreover, a higher number of TP-nonresponders were observed with lymphocytes from colorectal tumor patients at advanced tumor stage. Therefore, on the basis of the applied immunocytotoxic assays, these results may provide a basis for selecting tumor patients, who may respond to TP in immunotherapy protocols. PMID- 21590252 TI - Cloning and partial sequencing of a novel human activin receptor-like kinase. AB - Receptors for the transforming growth factor (TGF)-beta receptor superfamily are transmembrane protein serine/threonine kinases. By using a polymerase chain reaction (PCR)-based strategy to screen for the protein kinase sequences, we isolated a novel complementary DNA (cDNA) clone from a human breast carcinoma and a human brain cDNA libraries. The PCR primers were designed based upon the published sequence of the kinase domain of human activin receptor-like kinase (ALK)-4. The clone has unique nucleotide sequences with 82% identical to the corresponding region of rat ALK-7 and shows 96% identity at the amino acid level; however, was incomplete at the 5' end. Despite the 5' untranslated and ligand binding regions, these results indicate the heterogeneity of a transmembrane kinase domain between the current ALK and the previously cloned human TGF-beta receptor families. The expression of messenger RNA in human tissues varied for the different human ALKs might elicit specific TGF-beta receptors functions. PMID- 21590253 TI - Reversal of multidrug resistance by derivatives of acrivastine. AB - A major obstacle to successful cancer chemotherapy is the development of multidrug resistance (MDR) characterized by the overexpression of the drug transporter P-glycoprotein and the enhanced cellular efflux of many anticancer drugs. The identification and use of agents that reverse the MDR phenotype or drug-resistant tumors could provide an adjuvant to conventional cancer chemotherapy that would significantly enhance treatment efficacy. Several derivatives of acrivastine and a structurally-related benzyl piperazine were used in the present study to establish the utility of structure-activity and in vitro analyses to identify compounds that are effective at sensitizing MDR tumors in vivo. Of the seven compounds evaluated, 5 were identified by structure-activity analyses as inhibitors of P-glycoprotein, 1 was identified as a possible inhibitor, and 1 was deemed a non-interactor. In vitro analyses indicated that all seven compounds could inhibit P-glycoprotein; however, the compound identified by structure-activity analyses as a non-interactor was least potent. In vivo experimentation revealed that the more potent P-glycoprotein inhibitors, as determined by either structure-activity analyses or in vitro testing, also sensitized multidrug-resistant tumor masses implanted into athymic nude mice to treatment with vinblastine; though, efficacy was limited by host toxicity. Results from this study corroborate previously-established relationships between chemical structure and P-glycoprotein inhibition. Results further demonstrate that P-glycoprotein inhibitory potency, as established by structure-activity or in vitro analyses, provides insight into the ability of the agent to sensitize drug-resistant tumors in vivo. PMID- 21590254 TI - Clinically relevant suramin dosing regimen in mice with no effects against PC-3 prostate xenografts. AB - The goal of these studies was to develop a suramin dosing schedule that would maintain suramin plasma concentrations in mice in the 150-250 mu g/ml range. A high pressure liquid chromatography method was used to determine suramin plasma concentrations in mice. For pharmacokinetic studies CD2F(1) mice were treated intraperitoneally with 140 mg/kg of suramin. These pharmacokinetic data were used to develop a clinically relevant dosing regimen. To test the efficacy of this dosing regimen, athymic nude mice were implanted orthotopically with PC-3 prostate carcinoma cells, randomized, and treated intraperitoneally. The pharmacokinetically derived dosing regimen resulted in no antitumor effect against PC-3 prostate tumors. Suramin plasma concentrations ranged from 155 to 258 mu g/ml over the 14-day therapy period with tumor concentrations in the 53 241 mu g/g wet weight range. PMID- 21590255 TI - Expression pattern of gastrointestinal markers in native colorectal epithelium, lesions, and carcinomas. AB - Three small peptides with a typical cysteine-rich domain (TFF or P-domain) display a specific folding structure (trefoil); they are abundantly expressed on mucosal surfaces of normal and neoplastic gastrointestinal tissues. This epithelial location coincides with mucin secretion and, although not proven beyond doubt, this association is suggestive of their function in maintenance of surface integrity. Using normal colon epithelium, premalignant lesions and tumor samples and specific antibodies we studied expression of these peptides in colorectal carcinomas. RT PCR was performed to extend the sensitivity of the assays. While coexpression of pS2, hITF, MUC1 and MUC2 was demonstrated, MUC5 was absent and no simultaneous activity of pS2 and SML1 (as in gastric mucosa and carcinoma) was noted in rectal tumors. Actively transcribed and expressed cytokeratin 20 and GAPDH were used as experimental controls for immunostaining and RT-PCR, respectively. PMID- 21590256 TI - Analysis of K-ras gene mutations in human pancreatic cancer cell lines and in bile samples from patients with pancreatic and biliary cancers. AB - The ras family of oncogenes are the most frequently activated group of dominant transforming genes in both human and experimental cancers. The ras family of genes encode highly similar proteins with molecular weights of 21 kDa which are thought to play a key role in signal transduction. Activation in vivo by point mutations results in the ras p21 protein being maintained in the activated form and stimulating cellular proliferation autonomously. Point mutations at codon 12 of K-ras have been observed in >75% of cases of adenocarcinomas of the exocrine pancreas. The type and frequency of K-ras gene mutations in pancreatic cancer cell lines and in bile samples from patients with cytologically-proven biliary tract malignancies and from patients with non-malignant disorders of the biliary tract were determined. Codons 12, 13 and 61 of the K-ras gene were analysed by using restriction fragment length polymorphisms created through mismatched primers during polymerase chain reaction (PCR) of genomic DNA. A mutation of codon 12 of K-ras was detected in 10 of 13 (77%) human pancreatic cancer cell lines. The amino-acid substitutions were glycine to aspartate (5 samples), arginine (2), valine (2) and cysteine (1). No mutations were found at codons 13 or 61. A mutation at codon 12 of K-ras was detected in 9 of 18 (50%) of bile samples analysed. Eleven bile samples had positive cytology for malignancy of pancreaticobiliary origin, and 4 (36%) of these had a codon 12 mutation. Mutations were detected in 5 of the 7 (71%) cytologically-negative bile samples, although malignancy was subsequently diagnosed in 2 of these patients on further histology, and was suspected in 3 other cases on clinical and radiological criteria. This method provides a rapid determination of K-ras gene mutations in bile samples for patients with pancreatic and biliary tract diseases, which may be useful when considering future therapy directed at inhibition of activated ras induced signal transduction pathways. PMID- 21590257 TI - Chromosome instability in head and neck cancer patients. AB - Genetic changes play a crucial role in the process of neoplastic transformation. Mutations may occur spontaneously, but most of them (60-90%) are induced by mutagens. The epidemiological data indicate that only a part of the population exposed to mutagens/carcinogens develops cancer. Studies of the mechanisms leading to individual sensitivity to mutagens as well as tests allowing to recognize individuals susceptible to cancer have been performed. The bleomycin test is widely used for this purpose. In this classical test introduced by Hsu et al, the mean number of breaks per cell is analysed. In our study we present first results of the bleomycin test in patients suffering from head and neck cancer. In these patients, an increased number of breaks/cell (1.22 +/- 0.5 vs 0.79 +/- 0.3 in the control group) and an increased number of damaged cells (47% vs 36%) were observed. The results were also analysed in regard to the clinical stage of the disease. The data suggest that the chromosome instability does not correlate with the progression of the disease. PMID- 21590258 TI - Pitfalls in the RNA-based PCR amplification of the CDRIII sequence for quantitation of minimal residual disease in multiple myeloma (Commentary). AB - The uniqueness of the complementarity determining region III (CDRIII) has been utilized successfully in the last decade for development of a patient specific, molecular, polymerase chain reaction (PCR)-based assay for determining minimal residual disease in various lymphoid malignancies. There are various approaches for carrying out this test. i) CDRIII primers are used to amplify the corresponding DNA from the same patient and quantitation of the amplified CDRIII bands is done by generation a standard curve of known amounts of purified patient's tumor DNA, followed by a linear regression analysis to quantitate the results. ii) CDRIII primers are used to amplify a serially-diluted patient's sample (unknown), with replicate points. According to Poisson equation, replicate points in each dilution can be either all positive, all negative, or 'mixed', negative and positive. The quantitation, according to this approach is done by determination of the dilution point where there are 'mixed' lanes plus the flanking 'all negative' and 'all positive' lanes, assuming that the test can always detect one tumor cell in 100,000 cells. In this communication we show evidence that the use of the Poisson method can lead to an underestimation of the amount of tumor cells, due to the great variability in the priming and amplification among the various CDRIII primers. This variation is inherent to the size, C/G ratio, melting point of each primer, etc. In a simulated statistical model we show that the magnitude of error in the Poisson method could reach 1-2 logs. In contrast, using the standard curve for each patient and regression analysis eliminate these problems. PMID- 21590259 TI - Tissue polypeptide specific antigen for early prediction of non-small cell lung cancer recurrence. AB - TPS is a new tumor marker immunoassay that indicates tumor proliferative rate rather than tumor burden. Thirty-nine patients with non-small cell lung cancer (NSCLC), including 18 cases with recurrence and 21 cases without recurrence 1 year postoperation, were enrolled in this study. The serial serum levels of tissue polypeptide specific antigen (TPS) were measured before operation and 1 week, 4 weeks, 3 months, 6 months, 9 months, and 12 months after operation, using an immunoradiometric assay (IRMA), for early detection of recurrence. The results revealed that mean serum values of TPS were higher in 18 patients with recurrent cancer (103.5, 69.2, 88.1, 137.0, 108.6, 170.5, and 106.3 U/l) when compared with 21 patients without recurrent cancer (86.7, 53.0, 54.5, 57.4, 52.3, 52.0, and 58.6 U/l), preoperation and at all times after operation. If the TPS serum level 1 week after operation was considered as the baseline level (1x), elevated TPS ratios were higher in 18 patients with recurrence (1.2x, 2.5x, 2.1x, 4.3x, and 3.0x) when compared with 21 patients without recurrence (1.1x, 1.1x, 1.0x, 1.0x, and 1.1x), 4 weeks to 12 months after operation. We conclude that TPS is a suitable marker for early prediction of NSCLC recurrence. Patients with recurrent NSCLC within 1 year postoperation showed higher serum TPS levels and elevated TPS ratios than patients without recurrent NSCLC. PMID- 21590260 TI - The influence of cues and stimulus history on the non-linear frequency characteristics of the pursuit response to randomized target motion. AB - When humans pursue motion stimuli composed of alternating constant velocity segments of randomised duration (RD), they nevertheless initiate anticipatory eye deceleration before stimulus direction changes at a pre-programmed time based on averaging prior stimulus timing. We investigated, in both the time and frequency domains, how averaging interacts with deceleration cues by comparing responses to stimuli composed of segments that were either constant-velocity ramps or half cycle sinusoids. RDs were randomized within 6 ranges, each comprising 8 RDs and having differing mean RD. In sine responses, deceleration cues could be used to modulate eye velocity for long-range stimuli (RD = 840-1,200 ms) but in the shortest range (RD = 240-660 ms) cues became ineffective, so that sine responses resembled ramp responses, and anticipatory timing was primarily dependent on averaging. Additionally, inclusion of short duration (240 ms) segments reduced peak eye velocity for all RDs within a range, even when longer RDs in the range (up to 1,080 ms) would normally elicit much higher velocities. These effects could be attributed to antagonistic interactions between visually driven pursuit components and pre-programmed anticipatory deceleration components. In the frequency domain, the changes in peak velocity and anticipatory timing with RD range were translated into non-linear gain and phase characteristics similar to those evoked by sum-of-sines stimuli. Notably, a reduction in pursuit gain occurred when high-frequency components associated with short duration segments were present. Results appear consistent with an adapted pursuit model, in which pre-programmed timing information derived from an internally reconstructed stimulus signal is stored in short-term memory and controls the initiation of predictive responses. PMID- 21590262 TI - Integration of vestibular and proprioceptive signals for spatial updating. AB - Spatial updating during self-motion typically involves the appropriate integration of both visual and non-visual cues, including vestibular and proprioceptive information. Here, we investigated how human observers combine these two non-visual cues during full-stride curvilinear walking. To obtain a continuous, real-time estimate of perceived position, observers were asked to continuously point toward a previously viewed target in the absence of vision. They did so while moving on a large circular treadmill under various movement conditions. Two conditions were designed to evaluate spatial updating when information was largely limited to either proprioceptive information (walking in place) or vestibular information (passive movement). A third condition evaluated updating when both sources of information were available (walking through space) and were either congruent or in conflict. During both the passive movement condition and while walking through space, the pattern of pointing behavior demonstrated evidence of accurate egocentric updating. In contrast, when walking in place, perceived self-motion was underestimated and participants always adjusted the pointer at a constant rate, irrespective of changes in the rate at which the participant moved relative to the target. The results are discussed in relation to the maximum likelihood estimation model of sensory integration. They show that when the two cues were congruent, estimates were combined, such that the variance of the adjustments was generally reduced. Results also suggest that when conflicts were introduced between the vestibular and proprioceptive cues, spatial updating was based on a weighted average of the two inputs. PMID- 21590263 TI - Reply to the correspondence letter by Dr. Mitra S. to "alendronate for the treatment of hypercalcaemia due to neonatal subcutaneous fat necrosis". PMID- 21590261 TI - Corticomotor plasticity induced by tongue-task training in humans: a longitudinal fMRI study. AB - Corticomotor pathways may undergo neuroplastic changes in response to acquisition of new motor skills. Little is known about the motor control strategies for learning new tongue tasks. The aim of this study was to investigate the longitudinal effect of novel tongue-task training on corticomotor neuroplasticity. Thirteen healthy, right-handed men, aged 24-35 years (mean age +/- SD: 27.3 +/- 0.3 years), performed a training task consisting of standardized tongue protrusion onto a force transducer. The tongue task consisted of a relax protrude-hold-relax cycle with 1.0 N as the target at the hold phase lasting for 1.5 s. Subjects repeated this task for 1 h. Functional magnetic resonance imaging was carried out before the tongue-task training (baseline), 1-h after the training, and one-day and one-week follow-up. During scanning, the subjects performed tongue protrusion in blocks interspersed with rest. A region-of interest (ROI) approach and an explorative search were implemented for the analysis of corticomotor activity across conditions. All subjects completed the tongue-task training (mean success rate 43.0 +/- 13.2%). In the baseline condition, tongue protrusion resulted in bilateral activity in regions most typically associated with a motor task including medial frontal gyrus (supplementary motor area [SMA]), precentral gyrus (tongue motor cortex), putamen, thalamus, and cerebellum. The ROI analysis revealed increased activity in the precentral gyrus already 1 h post-training. One day after the training, increased activity was observed in the precentral gyrus, SMA, putamen, and cerebellum. No increase was found 1 week after training. Correlation analyses between changes in success rates and changes in the numbers of voxels showed robust associations for left Area 4a in primary motor cortex 1 h, 1 day, and 1 week after the tongue-task training and for the left Area 4p in primary motor cortex and the left lateral premotor cortex 1 day after the training. In the unrestricted analysis, increased activity was found in the parahippocampal gyrus 1 h after the tongue-task training and remained for a week. Decreased activity was found in right post-central and middle frontal gyri 1 h and 1 week post training. The results verified the involvement of specific corticomotor areas in response to tongue protrusion. Short-term tongue-task training was associated with longer-lasting (up to 1 week) changes in motor-related brain activity. The results suggested that primary motor areas are involved in the early and late stages, while other motor areas mainly are engaged in the later stage of corticomotor neuroplasticity of the tongue. PMID- 21590264 TI - Tetrasomy and pentasomy of the X chromosome. AB - We describe a newborn girl with a life-threatening laryngomalacia and extreme hypotonia. Genetic analysis revealed the very rare genetic condition mosaicism of 48,XXXX and 49,XXXXX (50/50). We here state that the degree of early hypotonia constitutes an important early prognostic feature in this syndrome. The timely insertion of a gastrostomy is warranted in order to prevent aspiration. CONCLUSION: A karyotype is mandatory in female newborns with moderate to severe hypotonia in order to exclude polyploid mosaicism of the X chromosome. An 'overall prognosis' for 48,XXXX and 49,XXXXX girls is difficult to provide towards parents in line with a well-known, substantial variability in outcome for all polysomy X infants. PMID- 21590265 TI - Isolated congenital tracheal stenosis in a preterm newborn. AB - Severe tracheal stenosis, resulting in functional atresia of the trachea is a rare congenital malformation with an estimated occurrence of two in 100,000 newborns. If no esophagotracheal fistula is present to allow for spontaneous breathing, this condition is usually fatal. We report on a male infant born at 32 weeks of gestation. The patient presented with respiratory distress immediately after delivery due to severe congenital tracheal stenosis resulting in functional atresia of the trachea. Endotracheal intubation failed and even emergency tracheotomy did not allow ventilation of the patient lungs. The patient finally succumbed to prolonged hypoxia due to functional tracheal atresia. The etiology of tracheal atresia and tracheal stenosis is still unclear, but both conditions are frequently combined with other anomalies of the VACTERL (vertebral anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, esophageal atresia, renal/radial anomalies and limb defects) and TACRD (tracheal agenesis, cardiac, renal and duodenal malformations) association. Conclusion Successful treatment of severe congenital tracheal stenosis and tracheal atresia depends on either prenatal diagnosis or recognition of this condition immediately after birth to perform tracheotomy without delay. Nevertheless, despite any efforts, the therapeutical results of severe tracheal stenosis and tracheal atresia are still unsatisfactory. PMID- 21590266 TI - Phenotypic spectrum of 80 Greek patients referred as Noonan syndrome and PTPN11 mutation analysis: the value of initial clinical assessment. AB - Noonan syndrome (NS) is a common multiple congenital anomaly entity, the diagnosis of which, on clinical grounds, is based on a comprehensive scoring system in order to select patients for molecular confirmation. Our aim was to evaluate the phenotypic characteristics in the light of PTPN11 mutations. The study revealed 80 patients who were referred with initial indication of NS or Noonan-like syndrome (NLS) and further assessed by a clinical geneticist; 60/80 index patients, mean age 5.9 +/- 5.3 years, fulfilled the NS criteria. Molecular analysis of PTPN11 gene (exons and their flanking regions) of the total population revealed mutations in 17/80 patients, all belonging in the group of the patients screened with the scoring system. All mutations were heterozygous missense changes, mostly clustering in exon 3 (8/17), followed by exons 13 (3/17), 8 (2/17), 7 (2/17), 2 (1/17) and 4 (1/17). We conclude that (a) most of our clinically diagnosed NS cases were sporadic (b) PTPN11 analysis should be limited to those fulfilling the relevant NS criteria (c) Cardiovascular evaluation should comprise all NS patients, while pulmonary stenosis, short stature, and thorax deformities prevailed among those with PTPN11 mutations. PMID- 21590267 TI - Isolated torsion of the fallopian tube: a case report and review of the literature. AB - Isolated torsion of the fallopian tube is a rare medical emergency, especially in premenarchal girls. We present a 9-year-old girl with right-sided lower abdominal pain. Isolated torsion of the fallopian tube was suspected preoperatively because of the clinical presentation combined with the results of ultrasound and magnetic resonance imaging (MRI). At emergency laparoscopy, the isolated torsion of the fallopian tube could be reduced, and the tube could be salvaged. This case report shows that the use of ultrasonography and MRI or CT is a helpful diagnostic tool to recognize this condition at an early stage. Especially in young girls presenting with abdominal pain, this should be kept in mind, as digital vaginal examination and vaginal ultrasound most often cannot be used in the diagnostic process. In conclusion, because prompt surgical intervention is required to preserve the tube and prevent progression to peritonitis and possible detrimental effects on future fertility, isolated torsion of the fallopian tube should be considered in the differential diagnosis of lower abdominal pain in all female patients regardless of age. PMID- 21590268 TI - Vaccinia virus lacking A17 induces complex membrane structures composed of open membrane sheets. AB - The vaccinia virus (VACV) precursor membrane, the crescent, consists of an open membrane sheet and is formed by rupture of a cellular compartment. Here, we asked whether A17, a viral membrane protein, plays a role in membrane rupture. Without A17 synthesis, crescents are not formed, and instead, tubular and vesicular membranes accumulate (Rodriguez et al. in J Virol 69:4640-4648, 1). We used electron tomography (ET) to analyze whether the viral membranes lacking A17 consist of open membrane sheets. Tubular, vesicular and so far not described onion-shaped membranes, which consisted of open membrane sheets, were seen. Thus, the data show that membrane rupture occurs independently of the A17 protein. PMID- 21590269 TI - Comparison of the sensitivity of imprint and scraping techniques in the diagnosis of American tegumentary leishmaniasis in a referral centre in Rio de Janeiro, Brazil. AB - American tegumentary leishmaniasis (ATL) is an infectious disease that presents a wide spectrum of clinical manifestations making parasitological tests important for its diagnosis. Direct examination, although considered of low sensitivity is still employed mainly in areas with poor laboratory infrastructure. The aim of this study was to standardize the method of collecting and reading the scraping procedure and to then compare sensitivity of this procedure on two sites of the lesion (outer edge-OE and inner edge-IE) and of the imprint against the reference method (isolation in culture) in a group of 110 patients treated at a Referral Center in Rio de Janeiro, Brazil. ATL diagnosis was confirmed in 40 patients (36.4%), 39 cases were caused by L. braziliensis and 1 by L. amazonensis. Imprint was positive in 28 patients and scraping in OE in 17 and in IE in 25 patients, resulting in sensitivity of 70%, 42.5%, and 62.5% respectively. When the three direct examinations were combined, sensitivity value attained 77.5%. Aspects related to ease and quality of the collected material, pain intensity and frequency of bleeding in the scraping procedure were also broached and discussed in this study. The parameters of accuracy presented indicate that the direct methods can be safely used in ATL diagnosis, principally in IE scraping, as it is easy to produce and the examination is not costly, which allows the procedure to be repeated at different moments which, in turn, increases the possibility of finding the parasite. Despite that the direct methods are technically widespread, they are not standardized and the parameters of accuracy are unknown. If we consider the high incidence of leishmaniasis in low-income areas, the implantation of standardized and selective methods would provide advances in the diagnosis of leishmaniasis. PMID- 21590270 TI - The parkin-like human homolog of Drosophila ariadne-1 (HHARI) can induce aggresome formation in mammalian cells and is immunologically detectable in Lewy bodies. AB - Loss of functional Parkin is responsible for the death of midbrain dopaminergic neurons in human autosomal recessive juvenile parkinsonism. Since no cells express functional Parkin, it is unclear why other neuronal and non-neuronal populations are not also endangered. One possible explanation is that other neurons express a redundant ubiquitin-protein ligase (E3) that is absent from dopaminergic neurons. In this study, we demonstrate that human homolog of Drosophila ariadne-1 (HHARI) is a candidate for such a redundant function. In in vitro assays, HHARI binds to many of the same proteins as parkin, including CDCrel-1, synphilin-1, and CASK. In cell culture studies, HHARI forms aggresomes that are indistinguishable from those formed by parkin in terms of morphology, subcellular localization, incorporation of ubiquitin-proteasome components, and dependence on microtubules. In addition, endogenous HHARI is found in human Lewy bodies in both Parkinson's disease and diffuse Lewy body disorder. Taken together, these data suggest that HHARI, and perhaps other Parkin-like E3 ligases, may serve redundant roles for parkin in different cell types. PMID- 21590271 TI - Protection of shrimp against white spot syndrome virus (WSSV) with beta-1,3-D glucan-encapsulated vp28-siRNA particles. AB - White spot syndrome virus (WSSV) is a major shrimp viral pathogen responsible for large economic losses to shrimp aquaculture all over the world. The RNAi mediated by siRNA contributes a new strategy to control this viral disease. However, the efficient approach to deliver the siRNA into shrimp remains to be addressed. In this investigation, an antiviral vp28-siRNA was encapsulated in beta-1,3-D glucan, and then the beta-1,3-D-glucan-encapsulated vp28-siRNA particles (GeRPs) were delivered into Marsupenaeus japonicus shrimp. The results showed that the vp28-siRNA in GeRPs could be released in hemocytes of shrimp. It was found that the GeRPs containing the vp28-siRNA inhibited the replication of WSSV in vivo, which presented a better antiviral activity than the non-encapsulated vp28-siRNA. Further evidence indicated that the mortality of WSSV-infected shrimp was significantly delayed by the GeRPs containing vp28-siRNA. Therefore, our study presented that the glucan-encapsulated siRNA might represent a novel potential therapeutic or preventive approach to control the shrimp disease. PMID- 21590272 TI - Detection of isolated ipsilateral regional lymph node recurrences by F18 fluorodeoxyglucose positron emission tomography-CT in follow-up of postoperative breast cancer patients. AB - Imaging diagnostic methods except for mammograms are not recommended for follow up of postoperative breast cancer patients in order to detect small recurrences because of the poor survival improvement in earlier randomized trials. However, the use of new imaging modalities may improve survival by detection of small isolated regional lymph node recurrences which are potentially curable. Between April 2006 and December 2008, we used PET-CT to find small recurrences in follow up of 1,907 postoperative breast cancer patients. A total of 3,280 PET-CT imagings were performed. The median age at PET-CT imaging was 58 years, with a median 48-month interval from definitive surgery to the PET-CT imaging. Twenty two patients were found to have isolated ipsilateral regional recurrences only by PET-CT (axillary node recurrences in 6, infraclavicular node recurrences in 5, supraclavicular node recurrences in 6, and parasternal node recurrences in 5). All of those recurrences were missed by palpation or were nonpalpable. The pathological lymph node status at the definitive surgery for the primary breast cancer of 22 patients with the isolated ipsilateral regional lymph node recurrences was positive in 17 patients. If patients are limited to those who had pathologically positive node(s) at definitive surgery, the incidence of patients with isolated regional lymph node recurrences found only by PET-CT would be 2.6% (17/663 patients). Seventeen other asymptomatic cancers including contralateral breast cancers were found only by PET-CT. Early detection of isolated loco regional recurrences of breast cancer is suggested to result in improved survival. Therefore, the use of PET-CT in follow-up of postoperative node positive breast cancer patients may improve their survival because of early detection of isolated regional lymph node recurrences which are still potentially curable, and screening of other asymptomatic cancers. PMID- 21590273 TI - Comparison of onset and duration of action of soft tissue and pulpal anesthesia with three volumes of 4% articaine with 1:100,000 epinephrine in maxillary infiltration anesthesia. AB - PURPOSE: This randomized double-blind investigation was conducted to compare the onset and duration of action of soft tissue and pulpal anesthesia with three volumes of 4% articaine with 1:100,000 epinephrine in maxillary infiltration anesthesia. The injection discomfort associated with three volumes of infiltration anesthesia was also assessed. MATERIALS AND METHODS: A total of 10 subjects received 0.6 mL (group 1), 0.9 mL (group 2), and 1.2 mL (group 3) of the anesthetic buccal to the upper canine. Test teeth were assessed with electrical stimulation to determine onset and duration of pulpal anesthesia. Soft tissue anesthesia was assessed by pin-prick test, and injection discomfort was assessed using a visual analogue scale. The statistical analysis of the data recorded was carried out with one-way ANOVA and post-hoc tests. RESULTS: The 1.2-mL dose induced faster onset of pulpal anesthesia, a higher success rate, and a longer duration of soft tissue/pulpal anesthesia than was achieved with 0.6 mL (P < 0.005). No differences in injection discomfort were observed between treatment groups. Group 3 where 1.2 mL of local anesthetic was injected showed faster onset and longer duration of action of articaine. Group 3 also had longer soft tissue anesthesia as compared to groups 1 and 2. CONCLUSION: Maxillary infiltration anesthesia with articaine and epinephrine has a faster onset, a greater success rate, and a longer duration when a volume of 1.2 mL is used than when volumes less than 1.0 mL are used. Palatal tissues were anesthetized with the highest concentration (1.2 mL) in our study (30% of cases). PMID- 21590275 TI - Calreticulin-2 is localized in the lumen of the endoplasmic reticulum but is not a Ca2+ -binding protein. AB - Calreticulin (CRT)-1 is a major Ca(2+)-buffering protein in the lumen of the endoplasmic reticulum. Human and murine CRT-2 was isolated in 2002, but the subcellular localization and function is still unclear. Here, we studied the intracellular localization and function of CRT-2 with hemagglutinin-tagged (HA-) human CRT-2. Western blotting revealed HA-CRT-2 as a single band at 50 kDa. Using immunofluorescence microscopy of cultured fibroblasts and epithelial cells transfected with HA-CRT-2 cDNA, labeling for HA-CRT-2 was seen as a reticular network with a nuclear envelope pattern that colocalized with calnexin and protein disulfide isomerase. Immunoelectron microscopy confirmed that HA-CRT-2 was localized in the lumen of the endoplasmic reticulum. Stains-all staining, a method to detect Ca(2+)-binding proteins, could not stain the immunoprecipitate of HA-CRT-2, although HA-CRT-1 immunoprecipitate was stained blue. These results indicate that the molecular weight of the non-tagged CRT-2 on SDS-PAGE is 49 kDa, and that CRT-2, as well as CRT-1, is localized in the lumen of the endoplasmic reticulum, but that CRT-2 capacity for Ca(2+)-binding may be absent or much lower than that of CRT-1. PMID- 21590274 TI - Electrical stimulation for testing neuromuscular function: from sport to pathology. AB - The use of electrical stimulation (ES) can contribute to our knowledge of how our neuromuscular system can adapt to physical stress or unloading. Although it has been recently challenged, the standard technique used to explore central modifications is the twitch interpolated method which consists in superimposing single twitches or high-frequency doublets on a maximal voluntary contraction (MVC) and to compare the superimposed response to the potentiated response obtained from the relaxed muscle. Alternative methods consist in (1) superimposing a train of stimuli (central activation ratio), (2) comparing the MVC response to the force evoked by a high-frequency tetanus or (3) examining the change in maximal EMG response during voluntary contractions, if this variable is normalized to the maximal M wave, i.e. EMG response to a single stimulus. ES is less used to examine supraspinal factors but it is useful for investigating changes at the spinal level, either by using H reflexes, F waves or cervicomedullary motor-evoked potentials. Peripheral changes can be examined with ES, usually by stimulating the muscle in the relaxed state. Neuromuscular propagation of action potentials on the sarcolemma (M wave, high-frequency fatigue), excitation-contraction coupling (e.g. low-frequency fatigue) and intrinsic force (high-frequency stimulation at supramaximal intensity) can all be used to non-invasively explore muscular function with ES. As for all indirect methods, there are limitations and these are discussed in this review. Finally, (1) ES as a method to measure respiratory muscle function and (2) the comparison between electrical and magnetic stimulation will also be considered. PMID- 21590276 TI - Polymorphisms of the CYP1A1 and CYP2E1 genes in head and neck squamous cell carcinoma risk. AB - Polymorphisms in genes that encode P450 cytochrome enzymes may increase carcinogen activation or decrease their inactivation and consequently, promote the development of cancer. The aims of this study were to identify the MspI CYP1A1, PstI-CYP2E1 and DraI-CYP2E1 polymorphisms in patients with head and neck cancer and to compare with individuals without cancer; to evaluate the association of these polymorphisms with risk factors and clinical histopathological parameters. In the study group, 313 patients were evaluated for CYP1A1, 217 for CYP2E1 (PstI) and 211 for CYP2E1 (DraI) and in the control group 417, 334 and 374 individuals, respectively. Molecular analysis was performed by PCR-RFLP technique, and chi-square and multiple logistic regression tests were used for statistical analysis. The result of analysis regarding individuals evaluated for CYP1A1 (MspI) showed that age (OR: 8.15; 95% CI 5.57-11.92) and smoking (OR: 5.37; 95% CI 3.52-8.21) were predictors for the disease; for the CYP2E1 (PstI and DraI), there were associations with age (PstI-OR: 9.10; 95% CI 5.86-14.14/DraI-OR: 8.07; 95% CI 5.12-12.72), smoking (PstI-OR: 4.10; 95% CI 2.44 6.89/DraI-OR: 5.73; 95% CI 3.34-9.82), alcohol (PstI-OR: 1.93; 95% CI 1.18 3.16/DraI-OR: 1.69; 95% CI 1.02-2.81), respectively, with disease development. CYP2E1 (PstI) was less frequent in patient group (OR: 0.48; 95% CI 0.23-0.98). Regarding clinical histopathological parameters, CYP1A1 polymorphism was less frequent in the larynx primary anatomic site (OR = 0.45; 95% CI = 0.28-0.73; P = 0.014). In conclusion, we confirm that age, smoking and alcohol consumption are risk factors for this disease and the polymorphisms investigated have no association with the development of head and neck cancer. PMID- 21590277 TI - Molecular cloning, expression, sequence analyses of dust mite allergen Der f 6 and its IgE-binding reactivity with mite allergic asthma patients in southeast China. AB - We report the cloning and molecular characterization of a full-length cDNA encoding house dust mite allergen, Der f 6 from D. farinae isolated in China. The full-length Der f 6 cDNA was obtained with 840 nucleotides long. Nucleotide sequencing analyses showed a total of 36 mutations in five Der f 6 cDNA clones, corresponding to 23 incompatible amino acid residues. Recombinant Der f 6 (rDer f 6) protein was successfully expressed in and purified from E. coli BL21. Among 20 asthmatic patients, 45% was positive to rDer f 6 by ELISA. Bioinformatics analyses revealed that the mature Der f 6 was a hydrophobic and extracellular protein with chymotrypsin-like serine protease activity, its secondary structure was composed of alpha helix (7.69%), extended strand (34.62%), random coils (57.69%), and the similarity of Der f 6 to Blo t 6, Sui m 6, Der f 3 and Der f 9 was 64, 65, 35, and 38%, respectively. PMID- 21590278 TI - Differential effects of Cucumber mosaic virus satellite RNAs in the perturbation of microRNA-regulated gene expression in tomato. AB - Viral infections generally cause disease symptoms by interfering with the microRNA (miRNA)-mediated regulation of gene expression of host plants. In tomato leaves, the accumulation levels of eleven miRNAs and ten target mRNAs were enhanced by different degrees upon Cucumber mosaic virus (CMV)-Fny and Tomato aspermy virus (TAV)-Bj infections. The ability of CMV-Fny to interfere with miRNA pathway was dramatically suppressed in the addition of the benign satellite (sat) RNA variant (satYn12), but was slightly affected when CMV-Fny was co-inoculated with the aggressive satRNA variant (satT1). In plants harboring the infection of CMV-FnyDelta2b (a CMV-Fny 2b-deletion mutant), the unaltered miRNAs and target mRNAs levels compared with mock inoculated plants indicated that 2b ORF was essential for perturbation of miRNA metabolism. When the amounts of viral open reading frames (ORFs) in these infections were quantified, we found satYn12 caused a higher reduction of CMV-Fny accumulation levels than satT1. These results indicate the complex mechanism by which satRNAs participate in CMV-tomato interaction, and suggest that the severity of disease symptoms positively correlates to some extent with the perturbation of miRNA pathway in tomato. PMID- 21590279 TI - Acute transverse myelitis in demyelinating diseases among the Chinese. AB - The aim of the study was to characterize the demographic, clinical, and prognostic features of Chinese patients with acute transverse myelitis (ATM). The clinical data from ATM patients in a demyelinating disease database were analyzed retrospectively. Sixty-seven ATM patients with a follow-up duration longer than 2 years were identified. The frequency of neuromyelitis optica-related ATM (NMO ATM) was high in our cohort (40.3%). Recurrent ATM (R-ATM), with a female predominance, was common in total idiopathic ATM (69.0%, 20/29). In R-ATM with longitudinally extensive spinal cord lesions (LESCLs), the high seropositivity of NMO-IgG, spinal cord lesions mostly involved the central gray matter and severer long-term disability were similar to NMO-ATM. In RTM without LESCLs, low seropositivity of NMO-IgG, preferentially involvement of the peripheral white matter and relative better neurological recovery were consistent with multiple sclerosis-related ATM (MS-ATM). The transition rates to MS in patients with acute partial transverse myelitis (APTM) and acute complete transverse myelitis (ACTM) were not significant (16.7 vs. 6.3%, P = 0.753), while LESCLs (OR = 11.4, P = 0.028) were significantly correlated with transition to NMO. The presence of LESCLs was the only variable showing a higher risk for reaching Rankin 3 (hazard ratio: 2.5, 95% CI: 1.0-6.1). Chinese patients with ATM had demographic, clinical, and prognostic features different from those in Western populations. Idiopathic R-ATM, common in Chinese, is a heterogeneous entity that shares partial clinical, spinal MRI and prognostic features with MS-ATM and NMO-ATM. The length of spinal cord lesion, rather than APTM/ACTM, may be a prognostic factor associated with clinical outcome and long-term disability in our population. PMID- 21590280 TI - Will early reconstruction prevent abnormal kinematics after ACL injury? Two-year follow-up using dynamic radiostereometry in 14 patients operated with hamstring autografts. AB - PURPOSE: Previous studies have reported that Anterior Cruciate Ligament (ACL) reconstruction does not restore normal tibial rotation in patients with chronic instability and repeated episodes of giving way. We hypothesised that early ACL reconstruction, using quadruple hamstring autografts, before the pivoting episodes had occurred, would protect the knee joint from developing abnormal kinematics with increased external tibial rotation during flexion. METHODS: Fourteen consecutive patients (8 men, 6 women) with a median age of 24 years (18 43), with a complete, isolated unilateral ACL rupture and an intact contralateral knee, were studied. The operations were performed by one experienced surgeon, using quadruple hamstring autografts. We used dynamic radiostereometry (RSA) with tantalum markers inserted in both the injured and the intact contralateral knee to study the pattern of knee motion during active and weight-bearing knee extension. The patients were evaluated pre-operatively and followed for 2 years after the ACL reconstruction. The anterior-posterior laxity was measured using the KT-1000. RESULTS: Before surgical repair of the ACL, the internal/external tibial rotation or abduction/adduction did not differ significantly between the injured and intact knees (P = 0.27-0.91). Separate studies of the anterior posterior translation of the medial and lateral femoral flexion facet centres (MFC and LFC) relative to a fixed tibia did not reveal any significant differences between the injured and intact knees (P = 0.21-0.59). Pre operatively, the KT-1000 laxity measurements showed a side-to-side difference of 2.5 (1.0-5.5) mm. At 2 years, the laxity side-to-side difference was 0.5 (0-3.0) mm (P = 0.001), and there were still no significant differences between the injured and intact knees in terms of internal/external tibial rotation and abduction/adduction (P = 0.13-0.60). Nor did the anterior-posterior translation of the flexion facet centres differs (P = 0.27-0.97). CONCLUSION: During the first 6-8 weeks after the ACL injury, before pivoting episodes had occurred, the kinematics of the injured knee were normal and did not differ from those of the intact contralateral knee. Reconstruction of the ACL within 10 weeks after injury using quadruple hamstring autografts resulted in unchanged knee kinematics for 2 years and no difference compared with the intact contralateral knee. Surgical repair during the early phase after the injury appears to protect the knee from developing abnormal knee motion after an ACL rupture. LEVEL OF EVIDENCE: III. PMID- 21590282 TI - Response to Rose (2011): nicotine preloading: the importance of a pre-cessation reduction in smoking behavior. PMID- 21590281 TI - Inhibition of cerebral type 1 cannabinoid receptors is associated with impaired auditory mismatch negativity generation in the ketamine model of schizophrenia. AB - RATIONALE: Preclinical and clinical research suggests that the endogenous cannabinoid system is involved in cognitive impairments related to schizophrenia. In particular, the deficient generation of mismatch negativity (MMN) indicating auditory sensory memory is a characteristic finding in schizophrenic patients. Experimental studies implicate deficient N-methyl-D: -aspartate (NMDA) receptor functioning in such abnormalities. OBJECTIVES: The primary aim of this study was to investigate the effects of the cannabinoid CB(1) receptor antagonist rimonabant on MMN deficits in the NMDA receptor antagonist model of schizophrenia by using ketamine. METHODS: Twenty-four healthy male subjects participated in a randomized, double-blind, placebo-controlled cross-over study with subanesthetic doses of intravenous ketamine. The MMNs to frequency and duration deviants were elicited within an auditory oddball paradigm and recorded by a 32-channel EEG. Psychopathology was assessed using the Psychotomimetic States Inventory. RESULTS: Twenty subjects completed both experimental sessions. Ketamine infusion had no significant effect on MMN amplitudes in both deviance conditions. In contrast to placebo, co-administration of rimonabant produced significant deficits in MMN amplitudes to duration deviants at electrode position Fz. CONCLUSIONS: The results point to the involvement of the endogenous cannabinoid system in auditory sensory memory as a cognitive key feature in schizophrenia. They particularly suggest that CB(1) receptor antagonism may impair cognitive performance by a disturbed interaction between endocannabinergic activity and glutamatergic neurotransmission implied in schizophrenia. PMID- 21590283 TI - Stress and cocaine interact to modulate Arc/Arg3.1 expression in rat brain. AB - RATIONALE: The interaction between stress and drugs of abuse is a critical component of drug addiction, but the underlying molecular mechanisms remain elusive. Arc/Arg3.1 is an effector immediate early gene that may represent a bridge connecting short- and long-term neuronal modifications associated with exposure to stress and drugs of abuse. OBJECTIVES: This research aims to study the modulation of Arc/Arg3.1 expression as a marker of neuronal changes associated with exposure to stress and cocaine. MATERIALS AND METHODS: Rats exposed to either single or repeated stress sessions were subjected to a single intraperitoneal injection of cocaine hydrochloride (10 mg/kg) and sacrificed 2 h later. RNase protection assay was used to determine changes in Arc/Arg3.1 gene expression in different brain regions. RESULTS: We found significant stress cocaine interactions in the prefrontal cortex (p < 0.001) and hypothalamus (p < 0.05). In the prefrontal cortex, acute stress potentiated cocaine-induced Arc/Arg3.1 mRNA elevation, whereas prolonged stress attenuated the response to cocaine. In the hypothalamus, although markedly reduced by acute stress, Arc/Arg3.1 gene expression was still increased by cocaine. No interaction was observed following repeated stress. Notably, cocaine-induced Arc/Arg3.1 mRNA levels were not influenced by stress in striatum and hippocampus. CONCLUSIONS: In our experimental model, stress interacted with cocaine to alter Arc/Arg3.1 expression in a regionally selective fashion and in a way that depended on whether stress was acute or repeated. These results point to Arc/Arg3.1 as a potential molecular target modulated by stress to alter cellular sensitivity to cocaine. PMID- 21590284 TI - Methylphenidate increases cigarette smoking in participants with ADHD. AB - RATIONALE: Methylphenidate (Ritalin(r)) is commonly prescribed for behavioral problems associated with attention deficit/hyperactivity disorder (ADHD). The results of previous studies suggest that methylphenidate increases cigarette smoking in participants without psychiatric diagnoses. Whether methylphenidate increases cigarette smoking in participants diagnosed with ADHD is unknown. OBJECTIVE: In this within-subjects, repeated measures experiment, the acute effects of a range of doses of methylphenidate (10, 20, and 40 mg) and placebo were assessed in nine cigarette smokers who were not attempting to quit and met diagnostic criteria for ADHD but no other Axis I psychiatric disorders other than nicotine dependence. METHODS: Each dose of methylphenidate was tested once while placebo was tested twice. One hour after ingesting drug, participants were allowed to smoke ad libitum for 4 h. Measures of smoking included total cigarettes smoked, total puffs, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum; caloric intake during the 4-h smoking session was calculated. RESULTS: Methylphenidate increased the total number of cigarettes smoked, total number of puffs, and carbon monoxide levels. Methylphenidate decreased the number of food items consumed and caloric intake. CONCLUSIONS: The results of this experiment suggest that acutely administered methylphenidate increases cigarette smoking in participants with ADHD, which is concordant with findings from previous studies that tested healthy young adults. These data indicate that clinicians may need to consider non-stimulant options or counsel their patients before starting methylphenidate when managing ADHD diagnosed individuals who smoke. PMID- 21590287 TI - Effects of nitrogen sources on production and composition of sophorolipids by Wickerhamiella domercqiae var. sophorolipid CGMCC 1576. AB - The effects of nitrogen sources on growth of sophorolipid-producing yeast, Wickerhamiella domercqiae var. sophorolipid CGMCC 1576 and on production and composition of sophorolipids were studied. Organic nitrogen sources are more favorable for accumulation of biomass than inorganic ones. Presence of ammonium ion from different inorganic nitrogen sources (except NH(4)HCO(3)) greatly inhibited the production of lactonic sophorolipids. However, when organic nitrogen sources were used, lactonic sophorolipid production was strongly increased. Production of crystalline lactonic sophorolipids from organic/inorganic nitrogen sources was enhanced with the increase of pH value adjusted by sodium hydroxide or sodium citrate solution. Fourier-transform infrared (FT-IR), gas chromatography mass spectrometry (GC-MS), high-performance liquid chromatography (HPLC), and mass spectra (MS) were employed to compare the composition of sophorolipid mixture obtained from different nitrogen sources. More than 15 acidic sophorolipid molecules and only 4 lactonic sophorolipid molecules were produced by using 1.27 g/l ammonium sulfate as nitrogen source; they were separated by preparative HPLC and their structures were elucidated by MS. These results suggest extraordinary regulatory effects of nitrogen source on growth and sophorolipid synthesis of W. domercqiae var. sophorolipid. PMID- 21590285 TI - Antidepressant-like effect of artemin in mice: a mechanism for acetyl-L-carnitine activity on depression. AB - RATIONALE: Depression may be associated with altered plasticity of the nervous system. The importance of neurotrophic factor levels is strongly suggested, and the neuronal-related family is extensively studied with respect to glial-derived one. OBJECTIVES: Aimed to contribute to the study of nervous plasticity modulation as therapeutical target in mood disorders, the role of the glial derived factor artemin (ARTN) in depression and in the pharmacodynamics of the antidepressant and trophic compound acetyl-L: -carnitine (ALCAR) was evaluated. METHODS: Male mice were treated with 100 mg kg(-1) ALCAR daily for 7 days; 0.6 MUg/mouse ARTN was acutely injected intracerebroventricularly. Gene knockdown of ARTN and GDNF family receptor alpha (GFRalpha3) was obtained by oligonucleotide antisense strategy. The forced swimming test was performed to evaluate antidepressant-like effects. RESULTS: Repeated ALCAR administration increased ARTN levels in spinal cord, hippocampus, and prefrontal cortex. No modulatory effect was detected on BDNF and glial cell line-derived neutrotrophic factor (GDNF). ARTN, 30 min after administration, showed a dose-dependent antidepressant like effect. ALCAR needed a 7-day treatment to reach a comparable effect; nevertheless, both substances were able to induce a phosphorylation of the GDNF family receptor Ret. A decrease of the free ARTN level by a specific ARTN antibody impaired the antidepressant-like effect of acute ARTN and repeated ALCAR. Gene knockdown of ARTN or, alternatively, of its receptor GFRalpha3 fully prevented ALCAR effectiveness. CONCLUSIONS: A mechanism for the antidepressant property of ALCAR is proposed, and the novelty of the possible role of ARTN in depression is suggested. PMID- 21590286 TI - Palladium nanoparticles produced by fermentatively cultivated bacteria as catalyst for diatrizoate removal with biogenic hydrogen. AB - A new biological inspired method to produce nanopalladium is the precipitation of Pd on a bacterium, i.e., bio-Pd. This bio-Pd can be applied as catalyst in dehalogenation reactions. However, large amounts of hydrogen are required as electron donor in these reactions resulting in considerable costs. This study demonstrates how bacteria, cultivated under fermentative conditions, can be used to reductively precipitate bio-Pd catalysts and generate the electron donor hydrogen. In this way, one could avoid the costs coupled to hydrogen supply. The catalytic activities of Pd(0) nanoparticles produced by different strains of bacteria (bio-Pd) cultivated under fermentative conditions were compared in terms of their ability to dehalogenate the recalcitrant aqueous pollutants diatrizoate and trichloroethylene. While all of the fermentative bio-Pd preparations followed first order kinetics in the dehalogenation of diatrizoate, the catalytic activity differed systematically according to hydrogen production and starting Pd(II) concentration in solution. Batch reactors with nanoparticles formed by Citrobacter braakii showed the highest diatrizoate dehalogenation activity with first order constants of 0.45 +/- 0.02 h-1 and 5.58 +/- 0.6 h-1 in batches with initial concentrations of 10 and 50 mg L-1 Pd, respectively. Nanoparticles on C. braakii, used in a membrane bioreactor treating influent containing 20 mg L-1 diatrizoate, were capable of dehalogenating 22 mg diatrizoate mg-1 Pd over a period of 19 days before bio-Pd catalytic activity was exhausted. This study demonstrates the possibility to use the combination of Pd(II), a carbon source and bacteria under fermentative conditions for the abatement of environmental halogenated contaminants. PMID- 21590288 TI - Biochemical characterization of the carotenoid 1,2-hydratases (CrtC) from Rubrivivax gelatinosus and Thiocapsa roseopersicina. AB - Two carotenoid 1,2-hydratase (CrtC) genes from the photosynthetic bacteria Rubrivivax gelatinosus and Thiocapsa roseopersicina were cloned and expressed in Escherichia coli in an active form and purified by affinity chromatography. The biochemical properties of the recombinant enzymes and their substrate specificities were studied. The purified CrtCs catalyze cofactor independently the conversion of lycopene to 1-HO- and 1,1'-(HO)(2)-lycopene. The optimal pH and temperature for hydratase activity was 8.0 and 30 degrees C, respectively. The apparent K (m) and V (max) values obtained for the hydration of lycopene were 24 MUM and 0.31 nmol h(-1) mg(-1) for RgCrtC and 9.5 MUM and 0.15 nmol h(-1) mg(-1) for TrCrtC, respectively. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis revealed two protein bands of 44 and 38 kDa for TrCrtC, which indicate protein processing. Both hydratases are also able to convert the unnatural substrate geranylgeraniol (C20 substrate), which functionally resembles the natural substrate lycopene. PMID- 21590289 TI - Long-term preservation of anammox bacteria. AB - Deposit of useful microorganisms in culture collections requires long-term preservation and successful reactivation techniques. The goal of this study was to develop a simple preservation protocol for the long-term storage and reactivation of the anammox biomass. To achieve this, anammox biomass was frozen or lyophilized at two different freezing temperatures (-60 degrees C and in liquid nitrogen (-200 degrees C)) in skim milk media (with and without glycerol), and the reactivation of anammox activity was monitored after a 4-month storage period. Of the different preservation treatments tested, only anammox biomass preserved via freezing in liquid nitrogen followed by lyophilization in skim milk media without glycerol achieved stoichiometric ratios for the anammox reaction similar to the biomass in both the parent bioreactor and in the freshly harvested control treatment. A freezing temperature of -60 degrees C alone, or in conjunction with lyophilization, resulted in the partial recovery of the anammox bacteria, with an equal mixture of anammox and nitrifying bacteria in the reactivated biomass. To our knowledge, this is the first report of the successful reactivation of anammox biomass preserved via sub-zero freezing and/or lyophilization. The simple preservation protocol developed from this study could be beneficial to accelerate the integration of anammox-based processes into current treatment systems through a highly efficient starting anammox biomass. PMID- 21590290 TI - Soybean transcription factor GmMYBZ2 represses catharanthine biosynthesis in hairy roots of Catharanthus roseus. AB - Catharanthus roseus (L.) G. Don is a plant species known for its production of a variety of terpenoid indole alkaloids, many of which have pharmacological activities. Production of catharanthine in cell cultures or in hairy roots established by transformation with Agrobacterium rhizogenes is of interest because catharanthine can be chemically coupled to the abundant leaf alkaloid vindoline to form the valuable anticancer drug vinblastine. Here, we observed a high amount of catharanthine in hairy roots of C. roseus, established by infecting leaf explants with the A. rhizogenes >agropine-type A4 strain carrying plasmid pRi. T-DNA transfer from plasmid pRi into hairy roots was confirmed by PCR for the essential T-DNA genes rolA and rolB and the agropine synthesis gene ags. The results suggest that integration of T-DNA into the plant DNA plays a positive role on the catharanthine pathway in C. roseus hairy roots. Furthermore, co-transformation with the soybean transcription factor GmMYBZ2 indicated that GmMYBZ2 reduces the catharanthine production by alteration of expression of a number of genes linked to the pathway. Transcription levels of the zinc-finger transcription factor 1 gene ZCT1 were high, and the transcription levels of the anthranilate synthase gene ASalpha, the strictosidine synthase gene STR, and the key transcription factor gene octadecanoid-responsive Catharanthus APETALA2/ethylene response factor were low. In addition, GmMYBZ2 had a negative effect on the gene expression levels of A-type cyclin CYSA and B-type cyclin CYSB, which was correlated with a reduced growth rate of the hairy roots. PMID- 21590291 TI - Application of polyhydroxyalkanoate binding protein PhaP as a bio-surfactant. AB - PhaP or phasin is an amphiphilic protein located on surfaces of microbial storage polyhydroxyalkanoates granules. This study aimed to explore amphiphilic properties of PhaP for possible application as a protein surfactant. Following agents were used to conduct this study as controls including bovine serum albumin, sodium dodecyl sulfate (SDS), Tween 20, sodium oleate, a commercial liquefied detergent together with the same amount of PhaP. Among all these tested control surfactants, PhaP showed the strongest effect to form emulsions with lubricating oil, diesel, and soybean oil, respectively. PhaP emulsion stability study compared with SDS revealed that PhaP had a stronger capability to maintain a very stable emulsion layer after 30 days while SDS lost half and two-thirds of its capacity after 2 and 30 days, respectively. When PhaP was more than 200 MUg/ml in the water, all liquids started to exhibit stable emulsion layers. Similar to SDS, PhaP significantly reduced the water contact angles of water on a hydrophobic film of biaxially oriented polypropylene. PhaP was thermally very stable, it showed ability to form emulsion and to bind to the surface of polyhydroxybutyrate nanoparticles after a 60- min heating process at 95 degrees C. It is therefore concluded that PhaP is a protein with thermally stable property for application as natural and environmentally friendly surfactant for food, cosmetic, and pharmaceutical usages. PMID- 21590292 TI - Hybrid 18F-FDG PET-MRI of the hand in rheumatoid arthritis: initial results. AB - 18F-fluorodeoxyglucose PET (18F-FDG PET) is highly sensitive to inflammatory changes within the synovial tissue in rheumatoid arthritis (RA). However, the highest spatial resolution for soft tissue can be achieved with MRI. Here, we report on the first true hybrid PET-MRI examination of the hand in early RA exploiting the advantages of both modalities. PET-MRI was performed with a prototype of an APD-based magneto-insensitive BrainPET detector (Siemens Healthcare, Erlangen, Germany) operated within a standard 3T MR scanner (MAGNETOM Trio, Siemens). PET images were normalized, random, attenuation and scatter corrected, iteratively reconstructed and calibrated to yield standardized uptake values (SUV) of 18F-FDG uptake. T1-weighted TSE in coronal as well as sagittal orientation prior to and following Gadolinium administration were acquired. Increased 18F-FDG uptake was present in synovitis and tenovaginitis as identified on contrast-enhanced MRI. The tracer distribution was surrounding the metacarpophalangeal joints II and III. Maximum SUV of 3.1 was noted. In RA, true hybrid 18F-FDG PET-MRI of the hand is technically feasible and bears the potential to directly visualize inflammation. PMID- 21590293 TI - Yoga for low back pain: a systematic review of randomized clinical trials. AB - It has been suggested that yoga has a positive effect on low back pain and function. The objective of this systematic review was to assess the effectiveness of yoga as a treatment option for low back pain. Seven databases were searched from their inception to March 2011. Randomized clinical trials were considered if they investigated yoga in patients with low back pain and if they assessed pain as an outcome measure. The selection of studies, data extraction and validation were performed independently by two reviewers. Seven randomized controlled clinical trials (RCTs) met the inclusion criteria. Their methodological quality ranged between 2 and 4 on the Jadad scale. Five RCTs suggested that yoga leads to a significantly greater reduction in low back pain than usual care, education or conventional therapeutic exercises. Two RCTs showed no between-group differences. It is concluded that yoga has the potential to alleviate low back pain. However, any definitive claims should be treated with caution. PMID- 21590294 TI - Bone mineral density in ambulatory patients with multiple sclerosis. AB - Multiple sclerosis (MS) may be associated with reduced bone mass and higher frequency of osteoporosis. Femoral and spinal bone mineral density (BMD) in 70 ambulatory MS patients (46 females and 24 males) was compared with 100 sex-, age , and BMI-matched control individuals. BMD was reduced in male patients (lumbar spine 0.976 +/- 0.114 g/cm(2) compared with 1.059 +/- 0.147 g/cm(2) in controls, p = 0.024, total hip 0.946 +/- 0.136 g/cm(2) compared to 1.036 +/- 0.118 g/cm(2) in controls, p = 0.008, femoral neck 0.812 +/- 0.136 g/cm(2) compared with 0.887 +/- 0.135 g/cm(2) in controls p = 0.042), and only in the total hip in female patients (0.88 +/- 0.127 g/cm(2) compared with 0.935 +/- 0.112 g/cm(2) in controls, p = 0.018). Multivariate analysis demonstrated that the predominantly affected site was the hip. MS patients exhibit increased frequency of low bone mass compared with controls. Further studies should assess the etiologic factors and employ appropriate therapies. PMID- 21590295 TI - Pull-out suture in posterior root avulsion fracture of the medial meniscus: 2 cases. PMID- 21590296 TI - Obturator hip dislocation with intrapelvic migration of the femoral head in Ehlers-Danlos syndrome. PMID- 21590297 TI - Bilateral tenosynovial giant cell tumor of the knee accompanied by chronic ACL tear. PMID- 21590298 TI - Fenestration methods for Sylvian arachnoid cysts--endoscopy or microsurgery. AB - INTRODUCTION: Two different approaches to fenestration, endoscopic and microsurgical, are in use for Sylvian arachnoid cysts (SACs), the most frequent among intracranial arachnoid cysts. We presented the clinical data and compared our results, with regard to technique and clinical success, with either microsurgical or neuroendoscopic fenestration of SACs. MATERIALS AND METHODS: Twenty-nine patients who subjected to cysto-cisternostomy by the same team, using either of the two methods, were studied retrospectively. RESULTS: Thirteen patients underwent microsurgery, and 16 had endoscopic cysto-cisternostomy. No reoperation was needed in either of these groups, i.e., full clinical and radiological success was achieved in both. The complication rate was 23% in the microsurgery patients and 47% in the endoscopic surgery group, with no statistically significant difference. CONCLUSIONS: No relevant differences between the two methods are seen either in the published data or in our results. Adding our results to the published data, both techniques were reviewed in a discussion of the one that allows a better controlled or safer fenestration. We conclude that endoscopic fenestration of SACs is not superior to microsurgical cyst fenestration, and the latter seems safer. PMID- 21590299 TI - Combination chemotherapy with ifosfamide, cisplatin, and etoposide for medulloblastoma: single-institute experience and differences in efficacy for subgroups of medulloblastoma. AB - PURPOSE: Treatment for medulloblastoma consists of surgical resection, radiation therapy, and chemotherapy. In Japan, ICE chemotherapy consisting of cisplatin, ifosfamide, and etoposide is one of the most common regimens. Here, we summarize the toxicity and efficacy of ICE chemotherapy and evaluate the usefulness of the recently introduced molecular classification scheme to predict the outcome. METHODS: Seventeen patients with medulloblastoma treated by ICE chemotherapy as an initial therapy at our institute were retrospectively reviewed. Eleven were categorized in the standard-risk group and six in the high-risk group. All patients underwent maximum cytoreductive surgery, radiation therapy, and ICE chemotherapy. Operative specimens were subjected to immunohistochemical staining using four antibodies-DKK1, SFRP1, NPR3, and KCNA1-to classify the cases into four subgroups, WNT group, SHH group, group C, and group D, respectively. RESULTS: ICE chemotherapy following surgery and radiation therapy was tolerable in most patients with appropriate management, although myelosuppression and hearing disturbance occurred. There was no significant difference in survival between patients with standard-risk disease and high-risk disease. Five-year survival and 5-year progression-free survival for the 17 patients were 80.7% and 63.5%, respectively. Three patients were classified as WNT group, 2 as SHH group, 1 as group C, and 11 as group D. Group D tended to have poorer prognosis after ICE chemotherapy. CONCLUSIONS: ICE chemotherapy was tolerable and active against medulloblastomas. Patients categorized as group D tended to have worse outcome after ICE chemotherapy. PMID- 21590300 TI - The lignicolous fungus Coniochaeta pulveracea and its interactions with syntrophic yeasts from the woody phylloplane. AB - The yeast-like fungus Coniochaeta pulveracea was studied with regard to its novel lignocellulolytic activities and the possible effect thereof on yeasts from the woody phylloplane. An enrichment procedure was used to isolate C. pulveracea from a decaying Acacia tree, and the identity of the isolate was confirmed using morphology, as well as molecular and phylogenetic techniques. This isolate, as well as strains representing C. pulveracea from different geographical regions, were compared with regard to optimum growth temperature and enzyme activity to representatives of closely related species. These include strains of Coniochaeta boothii, Coniochaeta rhopalochaeta, and Coniochaeta subcorticalis. Plate assays for cellulase and xylanase activity indicated that all representatives of the above-mentioned species were able to produce extracellular hydrolytic enzymes and were also able to degrade birchwood toothpicks during a 50-day incubation period at 30 degrees C. To test the ability of these fungi and their enzymes to release simple sugars from complex cellulosic substrates, filtrates obtained from liquid cultures of Coniochaeta, cultivated on carboxymethyl cellulose (CMC) as sole carbon source, were analyzed using high-performance liquid chromatography analysis. Consequently, the presence of mono- and disaccharides such as glucose and cellobiose was confirmed in these culture filtrates. Two subsequent experiments were conducted to determine whether these simple sugars released from woody material by Coniochaeta may enhance growth of phylloplane yeasts. In the first experiment, representatives of Coniochaeta were co-cultured with selected yeasts suspended in agar plates containing birchwood toothpicks, followed by examination of plates for colony formation. Results indicated that Coniochaeta growth on the toothpicks enhanced growth of nearby yeast colonies in the agar plates. In the second experiment, representatives of selected yeasts and Coniochaeta species were co-cultured on CMC and xylan-containing plates where after yeast colony formation was recorded on the plates. Saccharomyces cerevisiae strains, engineered to utilize specific wood degradation products, i.e., cellobiose or xylose, as sole carbon source were used as positive controls. While it was found that cellobiose released from CMC was assimilated by the yeasts, no evidence could be obtained that xylose released from xylan was used as carbon source by the yeasts. These ambiguous results could be ascribed to secretion of nutritious metabolic end products, other than the products of fungal xylanases. PMID- 21590301 TI - Bioavailability of copper, cadmium, zinc, and lead in tropical savanna soils assessed by diffusive gradient in thin films (DGT) and ion exchange resin membranes. AB - The technique of diffusion gradient in thin films (DGT) for assessing bioavailable metals has not been tested under field conditions. We assessed the relationships of DGT- and cation exchange resin-membrane-measured concentrations of Cd, Cu, Pb, and Zn with plant uptake of the metals under greenhouse and field conditions. In the greenhouse, the effective concentrations of Cu, Pb, and Zn by DGT correlated significantly with uptake by sorghum (Sorghum bicolor), but cation exchange resin-membrane-measured concentrations of Cd, Pb, and Zn did not correlate with sorghum uptake. In the field, the DGT-measured concentrations of Cd, Pb, and Zn were not linearly related to uptake Cd, Pb, and Zn by lettuce (Lactuca sativa) except for Cu uptake (r = 0.87, p < 0.05). Similarly, it was only the resin-membrane-extractable Pb that correlated with Pb uptake by lettuce (r = 0.77; p < 0.05). However, fitting non-linear regression models improved the plant metal uptake predictions by DGT-measured bioavailable Cd, Cu, Pb, and Zn under field conditions. In conclusion, the DGT technique was fairly predictive of bioavailability in the greenhouse, but not in the field. PMID- 21590302 TI - Characterization of MRNP34, a novel methionine-rich nacre protein from the pearl oysters. AB - Nacre of the Pinctada pearl oyster shells is composed of 98% CaCO3 and 2% organic matrix. The relationship between the organic matrix and the mechanism of nacre formation currently constitutes the main focus regarding the biomineralization process. In this study, we isolated a new nacre matrix protein in P. margaritifera and P. maxima, we called Pmarg- and Pmax-MRNP34 (methionine-rich nacre protein). MRNP34 is a secreted hydrophobic protein, which is remarkably rich in methionine, and which is specifically localised in mineralizing the epithelium cells of the mantle and in the nacre matrix. The structure of this protein is drastically different from those of the other nacre proteins already described. This unusual methionine-rich protein is a new member in the growing list of low complexity domain containing proteins that are associated with biocalcifications. These observations offer new insights to the molecular mechanisms of biomineralization. PMID- 21590303 TI - Support vector machine ensembles for intelligent diagnosis of valvular heart disease. AB - In this work, we investigate the use of ensemble learning for improving Support vector machines (SVM) classifier which is one of the important direction in the current research of machine learning, and thereinto bagging, boosting and random subspace are three powerful and popular representatives. Researchers have so far shown that the ensemble methods are quite well in many practical classification problems. However, for valvular heart disease detection, there are almost no studies investigating their feasibilities. Thus, in this study we evaluate the performance of three popular ensemble methods for diagnosing of the valvular heart disorders. To evaluate the performance of investigated ensemble methodology, a comparative study is realized by using a data set containing 215 samples. To achieve a comprehensive comparison, we consider the previous results reported by earlier methods. Experimental results suggest the feasibilities of ensemble of SVM classification methods, and we also derive some valuable conclusions on the performance of ensemble methods for valvular heart disease detection. PMID- 21590304 TI - Chronic pancreatitis in India: untying the nutritional knot. PMID- 21590305 TI - Molecular cloning and transgenic expression of a synthetic human erythropoietin gene in tobacco. AB - Erythropoietin (EPO) is a hormone belonging to a group of hematopoietic growth factors that control the proliferation and differentiation of bone marrow cells. It induces the production of erythrocytes, thereby increasing the amount of circulating hemoglobin and oxygen. Previous attempts to transgenically express human EPO in plants failed to succeed because the plants exhibited abnormal morphology and infertility. In the present work, we describe the generation of fertile transgenic tobacco plants able to express a synthetic version of human EPO. A 582-bp fragment of the human EPO gene was synthesized using a PCR-based method and ligated into pCR-Blunt. After sequencing, the human EPO fragment was transferred to pWUbi.tm1 and the expression cassette was then transferred to the binary vector pWBVec4a. After Agrobacterium-mediated transformation of Nicotiana tabacum SR1 plants, integration of the transgene into T(0) and T(1) plant genomes was confirmed by PCR. The human EPO gene was found to be expressed in tobacco leaves at the mRNA and protein levels. Self-crossing allowed us to obtain T(1) plants exhibiting Mendelian segregation of the transgene. None of the plants presented any kind of malformation or deformity. PMID- 21590306 TI - Immunomodulatory and therapeutic potential of a mycelial lectin from Aspergillus nidulans. AB - Lectins bind to surface receptors on target cells, and activate a cascade of events, eventually leading to altered immune status of host. The immunomodulatory potential of purified lectin from Aspergillus nidulans was evaluated in Swiss albino mice treated intraperitoneally with seven different doses of purified lectin. Lectin prevented BSA-induced Arthus reaction and systemic anaphylaxis. The enhanced functional ability of macrophages was evident from respiratory burst activity and nitric oxide production in splenocyte cultures. Interferon-gamma and interleukin-6 levels were significantly up-regulated in treated groups. Maximum stimulatory effect was observed at the dose of 1.5 mg/kg body weight. Therapeutic potential of A. nidulans lectin was assessed against trinitrobenzene sulfonic acid-induced ulcerative colitis in male Wistar rats. Rats pre-treated with 80 mg/kg body weight of purified lectin intraperitoneally prior to colitis induction showed lesser disease severity and recovery within 7 days, while rats post treated with the same dose showed recovery in 11 days. The results demonstrate immunomodulatory effects of A. nidulans lectin in Swiss albino mice, resulting in improved immune status of the animals and unfold its curative effect against ulcerative colitis in rat model. This is the first report on immunomodulatory and therapeutic potential of a lectin from microfungi. PMID- 21590307 TI - Characteristics of an immobilized yeast cell system using very high gravity for the fermentation of ethanol. AB - The characteristics of ethanol production by immobilized yeast cells were investigated for both repeated batch fermentation and continuous fermentation. With an initial sugar concentration of 280 g/L during the repeated batch fermentation, more than 98% of total sugar was consumed in 65 h with an average ethanol concentration and ethanol yield of 130.12 g/L and 0.477 g ethanol/g consumed sugar, respectively. The immobilized yeast cell system was reliable for at least 10 batches and for a period of 28 days without accompanying the regeneration of Saccharomyces cerevisiae inside the carriers. The multistage continuous fermentation was carried out in a five-stage column bioreactor with a total working volume of 3.75 L. The bioreactor was operated for 26 days at a dilution rate of 0.015 h(-1). The ethanol concentration of the effluent reached 130.77 g/L ethanol while an average 8.18 g/L residual sugar remained. Due to the high osmotic pressure and toxic ethanol, considerable yeast cells died without regeneration, especially in the last two stages, which led to the breakdown of the whole system of multistage continuous fermentation. PMID- 21590308 TI - Pathology of flupirtine-induced liver injury: a histological and clinical study of six cases. AB - Drug-induced liver injury may cause impairment of liver function and is a leading cause of acute liver failure. Identification of the causative substance in patients receiving several drugs is often difficult in clinical practice. Evaluation of liver biopsies in suspected drug-induced injury is a challenging task that requires close clinico-pathological correlation. Recognizing a characteristic morphological pattern of liver injury may contribute to identification of the causative drug. Flupirtine, a non-opioid analgesic, has been reported to cause liver injury of idiosyncratic type in rare instances. We wished to characterize the histopathological features of flupirtine-induced liver injury, which have not been reported so far. Liver biopsies of five patients with severe liver injury and one explanted liver of a patient with flupirtine-induced acute liver failure that required transplantation were assessed. In addition clinical presentation and course were reviewed and clinical follow up was performed. Extensive perivenular necrosis with associated ceroid pigment-laden macrophages and a mild to moderate lymphocytic infiltrate was a common feature in all cases. Histological extent of liver necrosis corresponded well to serum amino transferase levels. Accidental reexposure of one patient resulted in a plasma cell rich hepatitis with perivenular necrosis. This study provides evidence that flupirtine can cause substantial liver injury of hepatocellular type. Liver damage is associated with a characteristic morphological picture, the recognition of which will aid in causality assessment of drug-induced liver injury. Clinical and histological features raise the possibility of an immune-mediated toxicity. PMID- 21590309 TI - Automatic 3D segmentation of individual facial muscles using unlabeled prior information. AB - PURPOSE: Segmentation of facial soft tissues is required for surgical planning and evaluation, but this is laborious using manual methods and has been difficult to achieve with digital segmentation methods. A new automatic 3D segmentation method for facial soft tissues in magnetic resonance imaging (MRI) images was designed, implemented, and tested. METHODS: A region growing algorithm based on local energy functions, using intensity similarities among neighboring regions as criteria, was developed. This local energy function includes the neighborhood relationships not only in the same dataset but from other training datasets. This approach differs from previous studies where the prior information was represented as manual segmented atlases. In this study, a consensus of many datasets, none of which was labeled a priori, is used to guide the segmentation. The method was tested in MRI scans for adult facial structures. MRI scans were obtained from the Alzheimer's disease neuroimaging initiative database. Comparison was made to results from expert manual segmentation and region growing techniques. RESULTS: The volumetric overlap between automated 3D segmentation results and the ground truth was 82.6% for masseter and 78.8% for temporalis tissues. CONCLUSION: A new automated method to segment various facial soft tissues was implemented and the results compared with standard region growing results. The proposed method shows 3.9% improvement in accuracy over the standard method. Reduction in segmentation errors was consistently achieved in MRI scans. PMID- 21590310 TI - Evaluation of the effects of VKORC1 polymorphisms and haplotypes, CYP2C9 genotypes, and clinical factors on warfarin response in Sudanese patients. AB - OBJECTIVE: African populations, including the Sudanese, are underrepresented in warfarin pharmacogenetic studies. We designed a study to determine the associations between the polymorphisms and haplotype structures of CYP2C9 and VKORC1 and warfarin dose response in Sudanese patients, one of the most genetically diverse populations in Africa. MATERIAL AND METHODS: The effect of the CYP2C9 polymorphisms (*2, *3, *5, *6, *8, *9, and *11), 20 VKORC1 tag SNPs and haplotypes, and clinical covariates were comprehensively assessed in 203 Sudanese warfarin-treated patients. RESULTS: Patients with the CYP2C9*2,*5,*6, or *11 variant required a daily warfarin dose that was 21% lower than those with CYP2C9*1/*1 (4.7 vs 5.8 mg/day, P < 0.001). SNPs around the VKORC1 and POL3S genes were divided into two haplotype blocks in Sudanese populations. According to multiple linear regression results, rs8050984, rs7294, and rs7199949 in the VKORC1 and POL3S genes (P <0.001, <0.001, <0.001, respectively), CYP2C9 genotype (*2, *5, *6, *11; P < 0.001), body weight (P = 0.04), target INR (P = 0.007), and concurrent medications (P = 0.029) could explain about 36.7% of the total warfarin dose variation. CONCLUSION: Our data revealed that VKORC1 and CYP2C9 polymorphisms are important factors that influence warfarin dose response in Sudanese patients. Our data suggest that combinations of the SNPs may improve predictions of warfarin dose requirements. PMID- 21590311 TI - [Spondyloarthritides]. AB - Spondyloarthritides are a group of inflammatory rheumatic disorders related by clinical symptoms and genetic predisposition; the most important subtype is ankylosing spondylitis. The other subtypes include psoriatic spondyloarthritis, after preceding infections, in association with chronic inflammatory bowel diseases, and undifferentiated spondyloarthritis. The most significant clinical symptoms are inflammatory back pain and peripheral, usually asymmetric oligoarthritis and enthesitis. The possibility of other organs being involved is typical to some extent and the frequency varies among the subtypes: particularly affected are the eyes, the skin, and the intestines. Less commonly aortic valve defects and arrhythmias occur. The strongest genetic factor is the MHC class I molecule HLA-B27, which is exhibited by 90% of the patients with ankylosing spondylitis. The diagnostic possibilities for early identification have improved in the last few years. Early determination of HLA-B27 and magnetic resonance imaging have contributed to this development. Conventional radiography still represents the gold standard in the diagnostic workup. New criteria for classification of axial and peripheral spondyloarthritis have recently become available and international recommendations for the management of ankylosing spondylitis were recently published. PMID- 21590312 TI - AS-48 bacteriocin: close to perfection. AB - Bacteriocin AS-48 is an intriguing molecule because of its unique structural characteristics, genetic regulation, broad activity spectrum, and potential biotechnological applications. It was the first reported circular bacteriocin and has been undoubtedly the best characterized for the last 25 years. Thus, AS-48 is the prototype of circular bacteriocins (class IV), for which the structure and genetic regulation have been elucidated. This review discusses the state-of-the art in genetic engineering with regard to this circular protein, with the use of site-directed mutagenesis and circular permutation. Mutagenesis studies have been used to unravel the role of (a) different residues in the biological activity, underlining the relevance of several residues involved in membrane interaction and the low correlation between stability and activity and (b) three amino acids involved in maturation, providing information on the specificity of the leader peptidase and the circularization process itself. To investigate the role of circularity in the stability and biological properties of the enterocin AS-48, two different ways of linearization have been attempted: in vitro by limited proteolysis experiments and in vivo by circular permutation in the structural gene as-48A. The results summarized here show the significance of circularization on the secondary structure, potency and, especially, the stability of AS-48 and point as well to a putative role of the leader peptide as a protecting moiety in the pre-proprotein. Taken all together, the data available on circular bacteriocins support the idea that AS-48 has been engineered by nature to make a remarkably active and stable protein with a broad spectrum of activity. PMID- 21590313 TI - Development of a measure to assess the implementation of children's systems of care: the Systems of Care Implementation Survey (SOCIS). AB - The children's system of care framework has been extensively implemented in the U.S. Since its inception in 1993, the Comprehensive Community Mental Health Services for Children and Their Families Program has invested in excess of $1 billion supporting the development of systems of care in 164 grantee sites across the country. Despite these efforts to implement children's systems of care nationally, little is known about the extent to which the principles and values actually have been put into practice outside of the funded grantee sites. This paper describes the development of the Systems of Care Implementation Survey, a measure designed specifically for the first ever study assessing the level of implementation of factors contributing to effective children's systems of care in a nationally representative sample of counties throughout the U.S. PMID- 21590314 TI - Should we reoperate for recurrent high-grade astrocytoma? AB - Despite optimal treatment of post-operative radiotherapy and chemotherapy for newly diagnosed high-grade astrocytoma, nearly all patients eventually recur. However, the efficacy of reoperation for recurrent astrocytoma is still debatable as to different surgical indications. To investigate the therapeutic effect of reoperation on patients with recurrent high-grade astrocytoma more objectively, a retrospective case-matched study was carried out. The clinical data of 63 cases of recurrent high-grade astrocytoma treated between January 2006 and December 2008 were studied. A total of 21 cases received reoperation immediately after tumor recurrence, while 42 cases without reoperation were matched by gender, age, Karnofsky Performance Scale (KPS) score, histopathology, recurrent interval after the first operation, extent of initial surgery, adjuvant treatment and characteristics of recurrent tumor. The study showed that the median survival time was 7 months in the reoperation group, while in non-reoperation group, it was 4 months. There was significant difference on univariate analysis (P < 0.001). Moreover, the median duration time of progression-free survival (PFS) after tumor recurrence was significantly (P < 0.001) longer in the reoperation group (5 months) than that in the non-reoperation group (2.5 months). The prognostic factors of recurrent high-grade astrocytoma included reoperation, KPS score and tumor location. It was indicated that reoperation could prolong the survival time and improve the quality of survival in patients of recurrent high grade astrocytoma. PMID- 21590315 TI - Evidence for unique threat-processing mechanisms in psychopathic and anxious individuals. AB - Behaviorally, psychopathy and anxiety display opposite patterns of threat sensitivity and response inhibition. However, it is unclear whether this is due to shared or to separate underlying processes. To address this question, we evaluated whether the threat sensitivity of psychopathic and anxious offenders relates to similar or different components of Gray and McNaughton's (2000) Reinforcement Sensitivity Theory using a sample of 87 prisoners and a task that crossed threat onset with attentional focus. Psychopathy was associated with significantly weaker fear-potentiated startle (FPS) under conditions that presented threat cues after alternative, goal-directed cues. Conversely, anxiety was associated with significantly stronger FPS when threat appeared first and was the focus of attention. Furthermore, these differences were statistically independent. The results suggest that the abnormal sensitivity to threat cues associated with psychopathy and anxiety relate to different underlying processes and have implications for understanding the relationship between low- and high anxious psychopathy. PMID- 21590317 TI - Is callose a barrier for lead ions entering Lemna minor L. root cells? AB - Plants have developed a range of strategies for resisting environmental stresses. One of the most common is the synthesis and deposition of callose, which functions as a barrier against stress factor penetration. The aim of our study was to examine whether callose forms an efficient barrier against Pb penetration in the roots of Lemna minor L. exposed to this metal. The obtained results showed that Pb induced callose synthesis in L. minor roots, but it was not deposited regularly in all tissues and cells. Callose occurred mainly in the protoderm and in the centre of the root tip (procambial central cylinder). Moreover, continuous callose bands, which could form an efficient barrier for Pb penetration, were formed only in the newly formed and anticlinal cell walls (CWs); while in other CWs, callose formed only small clusters or incomplete bands. Such an arrangement of callose within root CWs inefficiently protected the protoplast from Pb penetration. As a result, Pb was commonly present inside the root cells. In the light of the results, the barrier role of callose against metal ion penetration appears to be less obvious than previously believed. It was indicated that induction of callose synthesis is not enough for a successful blockade of the stress factor penetration. Furthermore, it would appear that the pattern of callose distribution has an important role in this defence strategy. PMID- 21590316 TI - Feeling bad about screwing up: emotion regulation and action monitoring in the anterior cingulate cortex. AB - This study examined neural features of emotional responses to errors. We specifically examined whether directed emotion regulation of negative emotion associated with error modulates action-monitoring functions of anterior cingulate cortex, including conflict monitoring, error processing, and error prevention. Seventeen healthy adults performed a continuous performance task during assessment by fMRI. In each block, participants were asked either to increase or decrease their negative emotional responses or to react naturally after error commission. Emotion regulation instructions were associated with modulation of rostral and dorsal anterior activity and of their effective connectivity following errors and conflict. Cingulate activity and connectivity predicted subsequent errors. These data may suggest that responses to errors are affected by emotion and that aspects of emotion and cognition are inextricably linked, even during a nominally cognitive task. PMID- 21590318 TI - Clinicopathological analysis for recurrence of stage Ib gastric cancer (according to the second English edition of the Japanese classification of gastric carcinoma). AB - BACKGROUND: The prognosis for patients with stage Ib (second English edition of the Japanese classification of gastric carcinoma) gastric cancer is promising, with an expected 5-year survival of 90%. Despite this relatively high survival rate, the outcome for patients who experience recurrence is poor. To date, however, prognostic and recurrence factors for stage Ib gastric cancer are poorly understood, and appropriate adjuvant chemotherapy protocols have not been developed. METHODS: We retrospectively analyzed data from 86 stage Ib gastric cancer patients who underwent curative gastrectomy to determine the rates and predictive factors of recurrence. RESULTS: Eleven patients showed recurrence, with a 12.8% 5-year cumulative recurrence rate. Nearly all of these patients were initially histologically diagnosed with poorly differentiated adenocarcinoma. Based on univariate analyses, recurrence was associated with gender and histological type. Multivariate analyses revealed that the only independent risk factor for recurrence was histologically undifferentiated-type adenocarcinoma. The 5-year survival rate of patients with undifferentiated-type adenocarcinoma was 84%. The predominant recurrence pattern was peritoneal dissemination, and was typically observed 1-3 years post-resection. CONCLUSION: This retrospective study identified undifferentiated-type adenocarcinoma as the only risk factor for recurrence in stage Ib gastric cancer patients. Although randomized controlled studies are necessary, stage Ib gastric cancer patients with this identified recurrence risk factor would be candidates for adjuvant chemotherapy. PMID- 21590319 TI - Body weight perception among high school students and its influence on weight management behaviors in normal weight students: a cross-sectional study. AB - AIM: This study investigates body weight perception and its influence on weight management behaviors in normal weight adolescents in Timis County, Romania. We hypothesized that misperception of overweight in normal weight adolescents would be positively associated with unhealthy weight control behaviors. METHODS: From 2908 respondents participating in the survey we selected a total of 2093 normal weight high school students for the analysis. Outcome measures included self reported height and weight measurements, overweight misperceptions and weight control behaviors. Weighted prevalence estimates and odds ratios were computed. RESULTS: There were 22.64% of normal weight students who perceived themselves as overweight. Females (36.48%) were more likely to perceive themselves as overweight than males (8.15%) (P < 0.0001). After adjusting for age and gender, students who perceived themselves as overweight were more likely to exercise (OR = 2.85; 95% CI: 2.25-3.61), eat less food, fewer calories or low fat foods (OR = 3.54; 95% CI: 2.78-4.51), fast for 24 hours or more (OR = 1.79; 95% CI: 1.28 2.49), take diet pills, powders or tea (OR = 3.93; 95% CI: 2.62-5.89), vomit or take laxatives (OR = 1.96; 95% CI: 1.15-3.34) to lose weight or to keep from gaining weight, compared to students who did not perceive themselves as overweight. CONCLUSION: A significant proportion of normal weight high school students misperceive themselves as overweight and are engaging in unhealthy weight management behaviors. These results should be considered when establishing prevention programs and educational components that address weight misperceptions and the harmful effects of unhealthy weight control methods should be performed even among normal weight adolescents. PMID- 21590320 TI - Overall survival and extent of surgery in adult versus elderly glioblastoma patients: A population based retrospective study. AB - INTRODUCTION: The purpose of this retrospective population based study was to investigate the effect of the extent of surgery on overall survival in young versus adult glioblastoma patients in Vorarlberg/Austria during the last 4 years. METHODS: Forty-eight patients (median age 62.5 years, ranging from 25-82 years, 19 female and 29 male) with histologically proven glioblastoma received surgery (16 biopsies, 18 partial and 14 complete resections) and postoperative chemo irradiation with concomitant and adjuvant temozolomide. The median follow up of the patient population was 11.7 months (ranging from 3 to 36 months). Postoperative temporary morbidity was found in 5 out of 48 (10.4%) patients, and no mortality or permanent morbidity occurred. One infection led to revision surgery. FINDINGS: Altogether, the 12/24 months overall survival was 54/20.2% with a median survival of 13.7 months. In younger patients (<65 yrs, median 57.5 yrs, 28 patients), the 12/24 months overall survival was 68.4/34.3% with 16.9 months median survival, in the elderly patients (>65 yrs, median 73 yrs, 20 patients) the 12/24 months overall survival was 28.8/5.8%, with 7.7 months median survival (Log-rank, p = 0.0005). Extent of surgery influenced overall survival of the adult group nearly significantly (biopsy versus complete resection: p = 0.06), but did not affect overall survival of the elderly (p = 0.5). CONCLUSIONS: Overall survival of elderly glioblastoma patients treated with surgery and chemo irradiation with concomitant and adjuvant temozolomide is significantly reduced compared to the younger patients. In addition, in the elderly the extent of surgery did not influence the prognosis in our population. PMID- 21590322 TI - [Guidelines for smoking cessation - update 2010]. AB - In 2005, the OGP (Austrian Society of Pneumology) worked out the first standards of smoking cessation. With many new therapies, it is timely to update the guidelines of smoking cessation. This time all relevant professionals who are active in smoking cessation in Austria worked together in a big consensus process, not only the diverse medical professionals such as internists, pneumologists, or gynecologists but also psychotherapists, psychologists, and nurses. The Austrian standards for smoking cessation is closely related to the Update for smoking cessation 2008 of the USDHHS (US Department of Health and Human Services) and the Cochrane Reports. Ten main recommendations for smoking cessation have been worked out. The guidelines for smoking cessation was reviewed by three international reviewers. PMID- 21590323 TI - Inflammatory markers: exhaled nitric oxide and carbon monoxide during the ovarian cycle. AB - Nitric oxide (NO) production and carbon monoxide (CO) production are increased in inflammatory lung diseases. Although there are some pieces of evidence for hormonal modulation by estrogen, little is known about exhaled NO and CO during the ovarian cycle. In 23 subjects, we measured exhaled NO and CO by an online analyzer. Significantly higher levels of exhaled NO were found at the midcycle compared with those in the premenstrual period or during menstruation. Higher levels of CO were after ovulation and reached a peak in the premenstrual phase. The lowest levels of CO were observed in the first days of the estrogen phase. In males, there was no significant variation in exhaled NO and CO. Exhaled NO and CO levels vary during the ovarian cycle in women, and this fact should be taken into account during serial measurements of these markers in the female population. PMID- 21590321 TI - [Growth hormone therapy in adult patients: a review]. AB - Growth hormone deficiency (GHD) can frequently be expected in hypopituitarism of adult patients. If GHD is proven by dynamic testing of the somatotrophic axis, growth hormone substitution is useful for improving quality of life, body composition, bone and lipid metabolism, and myocardial function according to the criteria of evidence-based medicine and is admitted by most national health authorities. There are no other reasonable indications for growth hormone treatment in adulthood. PMID- 21590325 TI - Microvesicles are messengers. PMID- 21590324 TI - Enhanced phosphorylation of MAPKs by NE promotes TNF-alpha production by macrophage through alpha adrenergic receptor. AB - The aim of this study was to investigate whether norepinephrine (NE) could regulate macrophage production of tumor necrosis factor alpha (TNF-alpha) by influencing the phosphorylation of mitogen-activated protein kinases (MAPKs). Primary macrophages from male BALB/c mice were applied to explore the mechanism by which NE influences the the secretion of TNF-alpha when macrophages were activated by lipopolysaccharides (LPS). We found that NE could increase crophage production of TNF-alpha when macrophages were activated by LPS, and this effect could be inhibited by alpha adrenergic antagonist phentolamine. Also, NE could increase the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERK), and p38, through alpha receptor. Furthermore, JNK inhibitor SP600125, ERK inhibitor U0126, and p38 inhibitor SB203580 could all partially counteract NE's effect on the phosphorylation of MAPKs, as well as TNF alpha production by macrophages. This study revealed that as macrophages were activated by LPS, NE promoted the secretion of inflammatory factors by increasing the phosphorylation of MAPKs through an alpha receptor-dependent pathway. Our results provide the evidence of a relationship between stress and diseases, as well as the mechanism by which stress induces or affects the inflammation-related diseases. PMID- 21590326 TI - Racemic resolution of some DL-amino acids using Aspergillus fumigatus L-amino acid oxidase. AB - The ability of Aspergillus fumigatus L-amino acid oxidase (L-aao) to cause the resolution of racemic mixtures of DL-amino acids was investigated with DL alanine, DL-phenylalanine, DL-tyrosine, and DL-aspartic acid. A chiral column, Crownpak CR+ was used for the analysis of the amino acids. The enzyme was able to cause the resolution of the three DL-amino acids resulting in the production of optically pure D-alanine (100% resolution), D-phenylalanine (80.2%), and D tyrosine (84.1%), respectively. The optically pure D-amino acids have many uses and thus can be exploited industrially. This is the first report of the use of A. fumigatus L: -amino acid oxidase for racemic resolution of DL-amino acids. PMID- 21590327 TI - Comparative trial of two intravenous doses of granisetron (1 versus 3 mg) in the prevention of chemotherapy-induced acute emesis: a double-blind, randomized, non inferiority trial. AB - PURPOSE: A single 3 mg or 40 MUg/kg intravenous dose of granisetron combined with dexamethasone is routinely used in several countries, although the antiemetic guidelines have recommended granisetron at the dose of 1 mg or 10 MUg/kg. A randomized, multicenter trial was conducted to determine the optimal intravenous granisetron dose, 1 or 3 mg, in cancer patients receiving emetogenic chemotherapy. METHODS: We enrolled 365 patients and randomly assigned them to receive intravenous granisetron 3 mg (3-mg group) or 1 mg (1-mg group), combined with dexamethasone at an adequate dose fixed as per the emetic risk category. The primary end point was the proportion of patients with a complete response during the first 24 h after chemotherapy. RESULTS: The study demonstrated that 1 mg of granisetron was not inferior in effect to 3 mg. For the primary end point, 359 patients were evaluable according to the modified intention-to-treat (ITT) analysis. Complete protection was achieved in the modified ITT population, 90.6% and 88.8% for the 3- and 1-mg groups, respectively (p < 0.01 for non inferiority). CONCLUSIONS: This study showed that 1 mg granisetron is not inferior to 3 mg when both doses are combined with dexamethasone. Therefore, 1-mg dose of intravenous granisetron should be the recommended prophylactic regimen for the prevention of acute emesis. PMID- 21590329 TI - Single-channel recording from adult Brugia malayi. AB - Lymphatic filariasis is a significant cause of morbidity in humans. One of the causative agents is Brugia malayi a clade III nematode. Current therapeutic agents are effective against the microfilaria but less so against the adults residing in the host lymphatics. A large number of anthelmintics act on nematode ion channels including the nicotinic receptors found on nematode somatic muscle. The purpose of this study was to develop a preparation from adult B. malayi that was amenable to patch-clamp recording to facilitate the study of the ion channels present in this organism. We also present a preliminary characterization of the single-channel properties of nicotinic receptors from the adult musculature. PMID- 21590328 TI - A genome-wide genetic map of NB-LRR disease resistance loci in potato. AB - Like all plants, potato has evolved a surveillance system consisting of a large array of genes encoding for immune receptors that confer resistance to pathogens and pests. The majority of these so-called resistance or R proteins belong to the super-family that harbour a nucleotide binding and a leucine-rich-repeat domain (NB-LRR). Here, sequence information of the conserved NB domain was used to investigate the genome-wide genetic distribution of the NB-LRR resistance gene loci in potato. We analysed the sequences of 288 unique BAC clones selected using filter hybridisation screening of a BAC library of the diploid potato clone RH89 039-16 (S. tuberosum ssp. tuberosum) and a physical map of this BAC library. This resulted in the identification of 738 partial and full-length NB-LRR sequences. Based on homology of these sequences with known resistance genes, 280 and 448 sequences were classified as TIR-NB-LRR (TNL) and CC-NB-LRR (CNL) sequences, respectively. Genetic mapping revealed the presence of 15 TNL and 32 CNL loci. Thirty-six are novel, while three TNL loci and eight CNL loci are syntenic with previously identified functional resistance genes. The genetic map was complemented with 68 universal CAPS markers and 82 disease resistance trait loci described in literature, providing an excellent template for genetic studies and applied research in potato. PMID- 21590330 TI - Competition-colonization trade-offs in a ciliate model community. AB - There is considerable theoretical evidence that a trade-off between competitive and colonization ability enables species coexistence. However, empirical studies testing for the presence of a competition-colonization (CC) trade-off and its importance for species coexistence have found mixed results. In a microcosm experiment, we looked for a CC trade-off in a community of six benthic ciliate species. For each species, we measured the time needed to actively disperse to and colonize an empty microcosm. By measuring dispersal rates and growth rates of the species, we were able to differentiate between these two important components of colonization ability. Competitive ability was investigated by comparing species' growth with or without a competitor in all pairwise species combinations. Species significantly differed in their colonization abilities, with good colonizers having either high growth rates or high dispersal rates or both. Although species showed a clear competitive hierarchy, competitive and colonization ability were uncorrelated. The weakest competitors were also the weakest colonizers, and the strongest competitor was an intermediate colonizer. However, some of the inferior competitors had higher colonization abilities than the strongest competitor, indicating that a CC trade-off may enable coexistence for a subset of the species. Absence of a community-wide CC trade-off may be based on the lack of strong relationships between the traits underlying competitive and colonization ability. We show that temporal effects and differential resource use are alternative mechanisms of coexistence for the species that were both slow colonizers and poor competitors. PMID- 21590331 TI - Increase in water-use efficiency and underlying processes in pine forests across a precipitation gradient in the dry Mediterranean region over the past 30 years. AB - Motivated by persistent predictions of warming and drying in the entire Mediterranean and other regions, we have examined the interactions of intrinsic water-use efficiency (W(i)) with environmental conditions in Pinus halepensis. We used 30-year (1974-2003) tree-ring records of basal area increment (BAI) and cellulose (13)C and (18)O composition, complemented by short-term physiological measurements, from three sites across a precipitation (P) gradient (280-700 mm) in Israel. The results show a clear trend of increasing W(i) in both the earlywood (EW) and latewood (LW) that varied in magnitude depending on site and season, with the increase ranging from ca. 5 to 20% over the study period. These W(i) trends were better correlated with the increase in atmospheric CO(2) concentration, C(a), than with the local increase in temperature (~0.04 degrees C year(-1)), whereas age, height and density variations had minor effects on the long-term isotope record. There were no trends in P over time, but W(i) from EW and BAI were dependent on the interannual variations in P. From reconstructed C(i) values, we demonstrate that contrasting gas-exchange responses at opposing ends of the hydrologic gradient underlie the variation in W(i) sensitivity to C(a) between sites and seasons. Under the mild water limitations typical of the main seasonal growth period, regulation was directed at increasing C(i)/C(a) towards a homeostatic set-point observed at the most mesic site, with a decrease in the W(i) response to C(i) with increasing aridity. With more extreme drought stress, as seen in the late season at the drier sites, the response was W(i) driven, and there was an increase in the W(i) sensitivity to C(a) with aridity and a decreasing sensitivity of C(i) to C(a). The apparent C(a)-driven increases in W(i) can help to identify the adjustments to drying conditions that forest ecosystems can make in the face of predicted atmospheric change. PMID- 21590332 TI - Beyond climate envelopes: effects of weather on regional population trends in butterflies. AB - Although the effects of climate change on biodiversity are increasingly evident by the shifts in species ranges across taxonomical groups, the underlying mechanisms affecting individual species are still poorly understood. The power of climate envelopes to predict future ranges has been seriously questioned in recent studies. Amongst others, an improved understanding of the effects of current weather on population trends is required. We analysed the relation between butterfly abundance and the weather experienced during the life cycle for successive years using data collected within the framework of the Dutch Butterfly Monitoring Scheme for 40 species over a 15-year period and corresponding climate data. Both average and extreme temperature and precipitation events were identified, and multiple regression was applied to explain annual changes in population indices. Significant weather effects were obtained for 39 species, with the most frequent effects associated with temperature. However, positive density-dependence suggested climatic independent trends in at least 12 species. Validation of the short-term predictions revealed a good potential for climate based predictions of population trends in 20 species. Nevertheless, data from the warm and dry year of 2003 indicate that negative effects of climatic extremes are generally underestimated for habitat specialists in drought-susceptible habitats, whereas generalists remain unaffected. Further climatic warming is expected to influence the trends of 13 species, leading to an improvement for nine species, but a continued decline in the majority of species. Expectations from climate envelope models overestimate the positive effects of climate change in northwestern Europe. Our results underline the challenge to include population trends in predicting range shifts in response to climate change. PMID- 21590333 TI - Lactobacillus plantarum prevents bacterial translocation in rats following ischemia and reperfusion injury. AB - BACKGROUND: Bacterial translocation is considered a major cause of initiation and development of systemic sepsis and multiple organ dysfunction in clinic. The aim of this study was to determine the ability of a defined Lactobacillus plantarum to prevent ischemia/reperfusion (I/R) induced intestinal infection. METHODS: Female Sprague-Dawley rats were randomly allocated into three groups: (1) controls (sham-operated, no treatment), (2) ischemia/reperfusion and (3) ischemia/reperfusion and Lactobacillus plantarum treatment. Lactobacillus plantarum L2 was administered daily intragastrically 14 days prior to induction of I/R. Rats were then sacrificed, and tissue and blood samples were cultured to determine bacterial translocation. Cytokines in plasma were detected by ELISA. Ileal segments were removed for morphological examination. RESULTS: Intestinal I/R induced excess pro-inflammatory cytokine secretion and barrier dysfunction (increased epithelial cell apoptosis, cecal flora dysbiosis, disruption of mucosa and multiple erosions) in the intestine, associated with increased bacterial translocation to extraintestinal sites. Approximately 87.5% of rats exposed to I/R had bacterial translocation while there was no bacterial translocation in controls. However, pretreatment of animals with Lactobacillus plantarum completely prevented I/R induced bacterial translocation, reduced pro inflammatory cytokine release, and intestinal epithelial cell apoptosis, resulting in recovered microflora and mucosal integrity. CONCLUSIONS: These findings indicate that Lactobacillus plantarum L2 can prevent I/R-induced bacterial translocation and intestinal barrier dysfunction and, thereby, exert beneficial effects in the intestinal tract. PMID- 21590335 TI - Quality improvement of tuberculosis screening in foreign-born patients. AB - In the United States, a disproportionate percentage of tuberculosis (TB) cases occur in foreign-born persons. We implemented a performance improvement project to improve rates of screening for latent tuberculosis infection in a medical clinic. A questionnaire was developed to identify patients for tuberculosis screening, which was performed as a Tuberculin Skin Test (TST). Patients with positive skin tests underwent further testing. One hundred and sixty-five patients were screened, with 58 TSTs ordered and 36 placed. Twenty-seven patients returned to have the TST read with 12 positive. Eleven of these patients had chest X-rays, 2 revealing findings suggestive of active TB. This project identifies the importance of a standardized TB screening process for high-risk patients and identifies barriers to such a process. PMID- 21590334 TI - Novel biomarker candidates to predict hepatic fibrosis in hepatitis C identified by serum proteomics. AB - BACKGROUND: Liver biopsy remains the gold standard to assess hepatic fibrosis. It is desirable to predict hepatic fibrosis without the need for invasive liver biopsy. Proteomic techniques allow unbiased assessment of proteins and might be useful to identify proteins related to hepatic fibrosis. AIMS: We utilized two different proteomic methods to identify serum proteins as candidate biomarkers to predict hepatic fibrosis stage in patients with chronic hepatitis C virus (HCV) infection. METHODS: Serum was obtained from 24 people with chronic HCV at time of liver biopsy and from 6 normals. Liver biopsy fibrosis was staged 1-4 (Batts Ludwig). Pooled serum samples (six in each of four fibrosis groups and controls) were analyzed with 4- and 8-plex isobaric tags for relative and absolute quantitation (iTRAQ), determining protein identification (ID) and ratios of relative protein abundance. Nonpooled samples were analyzed with two-dimensional (2-D) gels and difference in gel electrophoresis (DIGE) comparing different samples on the same gel and across gels. Spots varying among groups were measured with densitometry, excised, digested, and submitted for tandem mass spectrometry (MS/MS) protein ID. RESULTS: iTRAQ identified 305 proteins (minimum 99% ID confidence); 66 were increased or decreased compared with controls. Some proteins were increased or decreased for specific fibrosis scores. From 704 DIGE protein spots, 66 were chosen, 41 excised, and 135 proteins identified, since one gel spot often identified more than one protein. CONCLUSIONS: Both proteomic methods identified two proteins as biomarker candidates for predicting hepatic fibrosis: complement C4-A and inter-alpha-trypsin inhibitor heavy chain H4. PMID- 21590336 TI - Socioepidemiology of cigarette smoking among Cambodian Americans in Long Beach, California. AB - We examined the prevalence of cigarette smoking among Cambodian Americans in Long Beach, California. A stratified random sample of 1,414 adult respondents was selected from 15 census tracts with high concentrations of Cambodian Americans. The prevalence of current smokers was 13.0%; the sex-specific prevalence of smoking was 24.4% for men and 5.4% for women. The mean age of the sample was 50.5 years; about 60% of the respondents were women. The survey response rate was 90.5% among households in which respondents self-identified as Cambodian American, and at least one person completed the survey. Significant covariates of current smoking were gender, age, education, marital status, and health status. The prevalence of smoking among Cambodian men was higher than among other males in California. Culturally-tailored interventions should consider demographic characteristics of the target population as well as the high level of respect given to religion, elders, and peers. PMID- 21590337 TI - Characterization and evolution of MHC class II B genes in Ardeid birds. AB - Major histocompatibility complex (MHC) is a multi-gene family that is very suitable to investigate a wide range of open questions in evolutionary ecology. In this study, we characterized two expressed MHC class II B genes (DAB1 and DAB2) in the Grey Heron (Aves: Ardea cinerea). We further developed the primer pairs to amplify and sequence two MHC class II B loci in ten ardeid birds. Phylogenetic analysis revealed that different parts of the genes showed different evolutionary patterns. The exon 2 sequences tended to cluster two gene-specific lineages. In each lineage, exon 2 sequences from several species showed closer relationships than sequences within species, and two shared identical alleles were found between species (Egretta sacra and Nycticorax nycticorax; Egretta garzetta and Bubulcus ibis), supporting the hypothesis of trans-species polymorphism. In contrast, the species-specific intron 2 plus partial exon 3 tree suggested that DAB1 and DAB2 were subject to concerted evolution. GENECONV analyses showed the gene exchange played an important role in the ardeid MHC evolution. PMID- 21590338 TI - Morphometric study of the suprascapular notch: proposal of classification. AB - INTRODUCTION: The size and shape of the suprascapular notch (SSN) may be a factor in suprascapular nerve entrapment. The aim of the study was to determine the variation of the SSN of 86 scapulae in the Polish people. METHODS: A total of 86 human scapulae were included in the study. Three measurements were defined and collected for every SSN: maximal depth (MD), superior (STD) and middle (MTD) transverse diameters. The measurements of the SSN were taken using two complementary methods: classical osteometry and a new one based on the analysis of digital photographic documentation of the SSN taken using MultiScanBase v.14.02 software. RESULTS: The analysis allowed determining five types of SSN. Type I has a longer maximal depth than superior transverse diameter (24.4%). Type II has equal MD, STD and MTD (2.3%). Type III has a superior transverse diameter longer than the maximal depth (54.7%). Type IV was a bony foramen (7%). Type V has a discrete notch (11.6%). Types I and III were divided into three subtypes: A (MTD was longer than STD), B (equal, MTD = STD) and C (inversely, MTD < STD). Superior transverse suprascapular ligament was completely and partially ossified in 7 and 23.3%, respectively. CONCLUSION: The presented quantitative classification of the SSN is simple and based on specific geometrical parameters that clearly distinguish five structural types and could be used in the further investigation in computer tomography or ultrasonography. The ossification of the superior transverse scapular ligament (STSL) in the study of the Polish people was similar to that described in Germany, France and Italy. PMID- 21590339 TI - The cleidoatlanticus muscle: a potential pitfall for the practice of ultrasound guided interscalene brachial plexus block. AB - INTRODUCTION: Image interpretation during ultrasound guided interscalene nerve blocks might be difficult and misleading due to rare anatomical variations of the sternocleidomastoid muscle. CASE REPORT: During a routine dissection, we found a cleidoatlanticus muscle, which originated lateral to the regular cleidomastoid portion of the sternocleidomastoid muscle. This muscle separated from the sternocleidomastoid muscle at level of the dorsally crossing omohyoid muscle to fuse with the levator scapulae muscle's origin at the transverse process of the atlas. CONCLUSION: As this muscle crosses at a level, where ultrasound guided interscalene blocks are performed, this unusual structure might lead to misinterpretation of the confusing ultrasound image, resulting in misguided needle positioning and consecutive inefficiency of the block technique. PMID- 21590340 TI - Mineralisation patterns in the subchondral bone plate of the humeral head. AB - PURPOSE: Pathologic changes of the glenohumeral joint, like a long-standing overloading or an accident often lead to severe glenohumeral osteoarthritis, and a glenohumeral joint replacement could be necessary. Joint instability and glenoid loosening are the most common post-operative complications, which can be caused by eccentric loading of the glenoid, if the humeral head is malcentered. If these malcentered cases could be identified pre-operatively, the pathologic position of the humeral head could be fixed intra-operatively and complication may be prevented. Computed tomography osteoabsorptiometry (CT-OAM) is a useful method to determine the distribution of mineralisation in the subchondral bone as a marker for the long-term loading history of a joint. The objective of this study was to gain information about the mineralisation distribution in the subchondral bone plate of the humeral head. METHODS: By the use of CT-OAM, the distribution of the subchondral mineralisation of 69 humeral heads was investigated and groups of mineralisation patterns were built. To evaluate if differences in age exist, the mean values of the two groups were compared using t test. RESULTS: 49 humeral heads (71% of 69 specimens) showed bicentric subchondral mineralisation patterns with ventral and dorsal maxima, 20 humeral heads (29% of 69 specimens) could be classified as monocentric with a centro dorsal maximum. We found no statistical significant difference between the age of the monocentric and the bicentric group on a significance level of 95%. CONCLUSION: We could show that stress distribution at the humeral head is typically bicentric with a ventral and dorsal maximum. However, other mineralisation patterns may occur under pathologic circumstances. The pre operative identification of such cases by the use of CT-OAM could help to improve the post-operative results in shoulder surgery. PMID- 21590341 TI - Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1alpha to exercise training. AB - Low mitochondriogenesis is critical to explain loss of muscle function in aging and in the development of frailty. The aim of this work was to explain the mechanism by which mitochondriogenesis is decreased in aging and to determine to which extent it may be prevented by exercise training. We used aged rats and compared them with peroxisome proliferator-activated receptor-gamma coactivator 1alpha deleted mice (PGC-1alpha KO). PGC-1alpha KO mice showed a significant decrease in the mitochondriogenic pathway in muscle. In aged rats, we found a loss of exercise-induced expression of PGC-1alpha, nuclear respiratory factor-1 (NRF-1), and of cytochrome C. Thus muscle mitochondriogenesis, which is activated by exercise training in young animals, is not in aged or PGC-1alpha KO ones. Other stimuli to increase PGC-1alpha synthesis apart from exercise training, namely cold induction or thyroid hormone treatment, were effective in young rats but not in aged ones. To sum up, the low mitochondrial biogenesis associated with aging may be due to the lack of response of PGC-1alpha to different stimuli. Aged rats behave as PGC-1alpha KO mice. Results reported here highlight the role of PGC-1alpha in the loss of mitochondriogenesis associated with aging and point to this important transcriptional coactivator as a target for pharmacological interventions to prevent age-associated sarcopenia. PMID- 21590342 TI - Association between sleep quality and body mass index among Chinese nonagenarians/centenarians. AB - We examined the individual association between body mass index (BMI) and sleep quality among the very elderly. The present study analyzed data from survey that was conducted on all residents aged 90 years or more in a district, there were 2,311,709 inhabitants in 2005. Subjects were divided into four groups according to quartile of BMI (<16.6, 16.6-18.9, 18.9-21.1, >21.1 kg/m(2)) and according to classification criteria of underweight, normal weight, overweight, and obesity in BMI (<18.5, 18.5-23.0, 23.0-27.5, >27.5 kg/m(2)), respectively. Sleep quality was measured using The Pittsburgh Sleep Quality Index (PSQI). Sleep quality included quality classification and scores, sleep duration, sleep latency, and sleep efficiency. The subjects included in the statistical analysis were 216 men and 444 women. According to quartile of BMI or classification criteria of underweight, normal weight, overweight, and obesity in BMI, none of the differences in sleep quality scores, sleep latency, sleep duration, sleep efficiency percentage, and prevalence of poor sleep quality was significant among different BMI groups. The difference in BMI between subjects with good and poor sleep quality was non-significant. Unadjusted and adjusted multiple logistic regression showed that none of the BMI groups had a function of decreasing the risk for poor quality. Among longevity Chinese, there is no association between BMI and sleep quality. PMID- 21590343 TI - Role of Th-2 cytokines in the development of Barrett's esophagus in rats. AB - BACKGROUND: Barrett's esophagus is characterized by a distinct Th-2-predominant cytokine profile, unlike the pro-inflammatory nature of reflux esophagitis. The aim of this study was to examine the role of Th-2 cytokines during the development of Barrett's esophagus, using a rat model. METHODS: Barrett's esophagus was induced by Levrat's esophagojejunostomy technique in Brown-Norway (BN) rats. Rats were killed at 8, 15, 30, and 50 weeks after the operation. We studied the incidences of esophagitis and Barrett's esophagus, and the mRNA expression of cytokines and CDX2 by real-time reverse transcriptase-polymerase chain reaction and immunohistochemical staining. Finally, we compared the incidence of Barrett's esophagus in BN rats with that in Sprague-Dawley (SD) rats. RESULTS: Esophagitis was found in all rats. Barrett's esophagus appeared 8 weeks after the operation, and its incidence and length increased over time. Levels of Th-2 cytokines such as interleukin (IL)-4, IL-10, and IL-13 were significantly increased in Barrett's esophagus as compared to those in non Barrett's esophagus, while there were no differences in the levels of pro inflammatory cytokines. The peak of elevated IL-4 mRNA was observed before that of CDX2 mRNA. IL-4 was co-localized in CD4-positive cells and CDX2-positive goblet cells. The incidence of Barrett's esophagus was more common in BN rats (8/10, 80%) than in SD rats (2/7, 28%) at 30 weeks. CONCLUSION: Th-2 cytokines, especially IL-4, may play a crucial role in the development of Barrett's esophagus in an early phase. These results provide understanding of the pathogenesis of Barrett's esophagus from the aspect of the Th-2 immune response. PMID- 21590344 TI - Role of endogenous hydrogen sulfide on renal damage induced by adriamycin injection. AB - A single injection of adriamycin (ADR) induces marked and persistent proteinuria in rats that progress to glomerular and tubulointerstitial lesions. It has been shown that ADR-induced nephrotoxicity is mediated, at least in part, by oxidative stress that lead to inflammation. Endogenous hydrogen sulfide (H2S) is synthesized from L-cysteine and is an important signaling molecule in inflammation. This study evaluates the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the evolution of renal damage induced by ADR. The rats were injected i.p. with 0.15 M NaCl or PAG (50 mg/kg) 2 h after ADR injection (3.5 mg/kg). Control rats were injected with 0.15 M NaCl or PAG only. Twenty hours urine samples were collected for albuminuria and creatinine measurements on days 1 and 14 after saline or ADR injections and on days 2 and 15 blood samples were collected to measure plasma creatinine, then the rats were killed. The kidneys were removed for H2S formation evaluation, renal lipid peroxidation and glutathione levels, and histological and immunohistochemical analysis. On day 2 after ADR injection the rats presented increase in oxidative stress associated with neutrophils and macrophages influx in renal tissue. On day 15 the rats also presented increased desmin expression at glomerular edge and vimentin in cortical tubulointerstitium, as well as albuminuria. All these alterations were reduced by PAG injection. The protective effect of PAG on ADR nephrotoxicity was associated to decreased H2S formation and to restriction of oxidative stress and inflammation in the renal cortex. PMID- 21590345 TI - Using a gel/plastic surrogate to study the biomechanical response of the head under air shock loading: a combined experimental and numerical investigation. AB - A combined experimental and numerical study was conducted to determine a method to elucidate the biomechanical response of a head surrogate physical model under air shock loading. In the physical experiments, a gel-filled egg-shaped skull/brain surrogate was exposed to blast overpressure in a shock tube environment, and static pressures within the shock tube and the surrogate were recorded throughout the event. A numerical model of the shock tube was developed using the Eulerian approach and validated against experimental data. An arbitrary Lagrangian-Eulerian (ALE) fluid-structure coupling algorithm was then utilized to simulate the interaction of the shock wave and the head surrogate. After model validation, a comprehensive series of parametric studies was carried out on the egg-shaped surrogate FE model to assess the effect of several key factors, such as the elastic modulus of the shell, bulk modulus of the core, head orientation, and internal sensor location, on pressure and strain responses. Results indicate that increasing the elastic modulus of the shell within the range simulated in this study led to considerable rise of the overpressures. Varying the bulk modulus of the core from 0.5 to 2.0 GPa, the overpressure had an increase of 7.2%. The curvature of the surface facing the shock wave significantly affected both the peak positive and negative pressures. Simulations of the head surrogate with the blunt end facing the advancing shock front had a higher pressure compared to the simulations with the pointed end facing the shock front. The influence of an opening (possibly mimicking anatomical apertures) on the peak pressures was evaluated using a surrogate head with a hole on the shell of the blunt end. It was revealed that the presence of the opening had little influence on the positive pressures but could affect the negative pressure evidently. PMID- 21590346 TI - Dietary protein intake and bariatric surgery patients: a review. AB - Bariatric surgery, a highly successful treatment for obesity, requires adherence to special dietary recommendations to insure the achievement of weight loss goals and weight maintenance. Postoperative consumption of protein is linked to satiety induction, nutritional status, and weight loss. Hence, we conducted an extensive literature review to identify studies focused on the following: protein and nutritional status; recommendations for dietary protein intake; the effects of protein-rich diets; and associations between dietary protein intake and satiety, weight loss, and body composition. We found that there have been few studies on protein intake recommendations for bariatric patients. Dietary protein ingestion among this population tends to be inadequate, potentially leading to a loss of lean body mass, reduced metabolic rates, and physiological damage. Conversely, a protein-rich diet can lead to increased satiety, enhanced weight loss, and improved body composition. The quality and composition of protein sources are also very important, particularly with respect to the quantity of leucine, which helps to maintain muscle mass, and thus is particularly important for this patient group. Randomized studies among bariatric surgery patient populations are necessary to establish the exact quantity of protein that should be prescribed to maintain their nutritional status. PMID- 21590347 TI - Early improvement in albuminuria in non-diabetic patients after Roux-en-Y bariatric surgery. AB - BACKGROUND: Obesity is a growing epidemic in the USA that has been shown to be associated with chronic kidney disease and albuminuria. Bariatric surgery is an effective means of achieving long-term weight loss and improvements in metabolic derangements including albumin excretion over the long term. METHODS: We report changes in urinary albumin excretion levels in the early post-operative period for a euglycemic, predominantly Hispanic American cohort undergoing Roux-en-Y gastric bypass surgery. RESULTS: Our cohort of 38 patients was largely female (89.5%) and predominantly Hispanic (76.3%) with a mean BMI of 46 +/- 8.0 kg/m(2). Over half (53.3%) of the patients with significant preoperative albumin excretion in our cohort lowered their albumin excretion levels to <20 mg/g of creatinine. This early reduction in albumin excretion in our cohort correlated significantly with the level of albumin excretion preoperatively but not with the degree of weight loss experienced in this early post-operative period. CONCLUSIONS: Improvements in microalbuminuria in the early post-operative period after Roux-en Y surgery may result from an interplay between changes in gastrointestinal hormones, insulin sensitivity, blood pressure, and adipose tissue-and needs further study. PMID- 21590348 TI - Acute renal failure due to tobramycin intoxication during selective digestive tract decontamination. PMID- 21590349 TI - Hydralazine-induced ANCA vasculitis with pulmonary renal syndrome: a rare clinical presentation. AB - Hydralazine is a commonly used drug for treatment of hypertension and is known to cause drug-induced lupus erythematosus. It has rarely been reported to cause anti neutrophil cytoplasmic antibody positive vasculitis, a life-threatening complication. Presentation could be extremely variable delaying diagnosis. Although drug-induced vasculitis has been infrequently associated with rapidly progressing glomerulonephritis, pulmonary involvement presenting as pulmonary renal syndrome is extremely rare. We report a case of hydralazine-induced vasculitis presenting as pulmonary renal syndrome with fatal outcome even after aggressive treatment. Numerous antibodies are associated with hydralazine including anti myeloperoxidase antibody, anti-nuclear antibody, anti-histone antibody, and anti-elastase antibody. Additionally, we also report the presence of anti-phospholipid antibodies specific to anti-cardiolipin, anti-beta2 glycoprotein, and anti-phosphatid that have not been previously reported. We conclude that early diagnosis and prompt discontinuation of the drug is necessary for the treatment of hydralazine-induced anti neutrophil cytoplasmic antibody vasculitis. PMID- 21590350 TI - [Transient myopia]. AB - Although transient myopia is an extremely rare symptom, systemic diseases which can also lead to a life-threatening condition should also be considered in cases of sudden deterioration of vision. Therefore, the initial diagnosis in an ophthalmological clinic or practice plays a decisive role. PMID- 21590351 TI - [Graves' ophthalmopathy from the internist's perspective]. AB - Graves' orbitopathy (GO) is the most frequently observed extrathyroidal manifestation of Graves' disease occurring in up to 40% of patients. Most patients with Graves' orbitopathy are tested positive for TSH receptor autoantibodies (TRAb), which are pathognomonic for Graves' disease and also play a central pathogenetic role in the development of GO. For the diagnosis of Graves' disease, symptoms of hyperthyroidism, low TSH and high fT3 and/or fT4 levels and positive TRAbs are typical. All patients with Graves' disease must be regularly examined for extrathyroidal manifestations, especially for Graves' orbitopathy. For hyperthyroidism, treatment with antithyroidal drugs, such as thiamazole or propylthiouracil is initiated to quickly restore euthyroidism, which also frequently leads to improvement of Graves' orbitopathy. Smoking cessation is also heavily mandated. In cases of relapse or ineffective antithyroidal treatment, radioiodine therapy or thyroid surgery is a further definitive therapeutic option to treat hyperthyroidism. The management of Graves' orbitopathy remains clinically challenging and demands involvement of a multidisciplinary team including endocrinologists, ophthalmologists, surgeons, radiotherapists and nuclear medicine specialists. PMID- 21590352 TI - [Drug therapy and radiotherapy in Graves' orbitopathy]. AB - Drug therapy and radiotherapy in Graves' orbitopathy (GO) aim mainly at the inherent soft tissue inflammation. A timely and sustained anti-inflammatory therapy not only alleviates the current symptoms but particularly intends to limit the degree of permanent alterations. It is indicated in active GO of moderate or higher severity. Pharmacologically, glucocorticoids and if appropriate other immunosuppressive agents, such as cyclosporine are given. Adverse effects can complicate the treatment. Retrobulbar irradiation is applied against diplopia due to eye muscle involvement during the active phase. PMID- 21590353 TI - [Electronic patient records and teleophthalmology : part 1: introduction to the various systems and standards]. AB - Electronic storage of patient-related data will replace paper-based patient records in the near future. Some steps in medical practice can even now not be achieved without electronic data processing. Both systems, conventional paper based and electronic-based records, have advantages and disadvantages which have to be taken into consideration. The advantages of electronic-based records are e.g. good availability of data, structured storage of data, scientific analysis of long-term data and possible data exchange with colleagues in the context of teleconsultation systems. Problems have to be solved in the field of data security, initial high investment costs and time consumption in learning to use the system as well as in incompatibility of existing IT systems. PMID- 21590355 TI - Effects of stable knockdown of Aurora kinase A on proliferation, migration, chromosomal instability, and expression of focal adhesion kinase and matrix metalloproteinase-2 in HEp-2 cells. AB - Overexpression of Aurora kinase A (AURKA) is frequently observed in various cancers, including laryngeal squamous cell carcinoma (LSCC). We investigated the effects of knockdown of AURKA on laryngeal cancer HEp-2 cells both in vitro and in vivo. A plasmid containing short hairpin (sh)RNA against AURKA was constructed and transfected into HEp-2. Measurements included the CCK-8 assay for viability and proliferation, flow cytometry for apoptosis and effects on the mitotic checkpoint, a trans-well assay for migration, immunofluorescence for assessment of genomic instability, and western blotting for protein expression. AURKA knockdown inhibited proliferation, migration, and colony formation in vitro and tumorigenicity in vivo. The knockdown induced the accumulation of cells in G2-M phase and eventual apoptosis. Knockdown of AURKA caused delayed entry into mitosis after treatment with nocodazole, reduced chromosomal instability, and decreased expression of focal adhesion kinase (FAK), phosphorylated FAK, and matrix metalloproteinase-2 (MMP-2), key regulators in cell adhesion and invasion. Knockdown of AURKA inhibits the growth and invasiveness of this LSCC cell line both in vitro and in vivo. These effects may partially result from the reduced expression of FAK and MMP-2. Knockdown of AURKA expression may represent a promising therapeutic strategy for the treatment of LSCC. PMID- 21590356 TI - [Sublingual immunotherapy. Where are we now?]. AB - Allergic diseases represent a global health problem. They affect 20% to 30% of the German population, but more than 40% of the group between 20 and 40 years of age. The symptoms have a considerable influence on social life and cause an impairment of sleep and performance at work/school, leading to a high but avoidable economic impact. For over 100 years specific immunotherapy (SIT) has been used to treat IgE-mediated allergic diseases. Numerous well-controlled studies have provided evidence of its efficacy, safety and tolerability. Today SIT represents a well-established treatment of allergic rhinitis, rhinoconjunctivitis and allergic asthma with a positive health economic impact. Initially, SIT was administered subcutaneously (SCIT), but other routes of application have been developed. In particular the sublingual-swallow method (SLIT) has been proven to be effective and well-tolerated in large studies on grass pollen allergies and represents an additional effective route of administration in adults and children. PMID- 21590357 TI - Detection and characterisation of SCCmec remnants in multiresistant methicillin susceptible Staphylococcus aureus causing a clonal outbreak in a Swedish county. AB - The purpose of this study was to investigate if multiresistant methicillin susceptible Staphylococcus aureus (MR-MSSA) causing a clonal outbreak in Ostergotland County, Sweden, were derived from methicillin-resistant S. aureus (MRSA) by carrying remnants of SCCmec, and, if so, to characterise this element. A total of 54 MSSA isolates with concomitant resistance to erythromycin, clindamycin and tobramycin from 49 patients (91% clonally related, spa type t002) were investigated with the BD GeneOhm MRSA assay and real-time polymerase chain reaction (PCR) targeting the SCCmec integration site/SCCmec right extremity junction. DNA sequencing of one isolate representing the MR-MSSA outbreak clone was performed by massive parallel 454 pyrosequencing. All isolates that were part of the clonal outbreak carried SCCmec remnants. The DNA sequencing revealed the carriage of a pseudo-SCC element 12 kb in size, with a genomic organisation identical to an SCCmec type IotaIota element, except for a 41-kb gap. This study demonstrates the presence of a pseudo-SCC element resembling SCCmec type II among MR-MSSA, suggesting possible derivation from MRSA. The presence of SCCmec remnants should always be considered when SCCmec typing is used for MRSA detection, and may not be suitable in locations with a high prevalence of MR MSSA, since this might give a high number of false-positive results. PMID- 21590358 TI - Evaluation of a pulse oximeter sensor tester. AB - OBJECTIVE: The Lightman is intended to test the optical and electrical properties of a pulse oximeter probe including the wavelength of the light emitting diode by means of a micro spectrometer. The aim of this study was to evaluate the ability of the Lightman to detect faulty pulse oximeter finger probes by testing the accuracy of the wavelength of the light emitting diode in isolation from the monitor. METHODS: The pulse oximeter measurements of arterial oxygen saturation from the "accurate" and "inaccurate" probes, as identified by the Lightman, were compared with arterial saturation determined by a co-oximeter. Data was analysed from 63 sets of measurements. In addition, we conducted a national survey to determine the testing procedures used by the Biomedical Engineering departments to evaluate the accuracy of pulse oximeter devices. RESULTS: The bias [95% limits of agreement] for accurate, over-reading and under-reading probes were 0.17% [3.6 to -3.3], 1.44% [5.4 to -2.5] and -1.6% [2.6 to -5.8] respectively. The response rate to the national survey was 75% (142/189); a pulse oximeter tester was used by 93/142 (65%) trusts. CONCLUSIONS: Our findings suggest that the Lightman can detect faulty probes and predict reasonably accurately the direction of the probe's error. The Lightman may be considered as a useful tool to assess the accuracy of pulse oximeters. The national survey highlighted a wide variation in the testing procedure utilised to evaluate the accuracy of pulse oximeters. Introduction of guidelines regarding the testing procedure would promote a uniform practice. PMID- 21590359 TI - Metabolic monitors as a diagnostic tool. AB - Metabolic measurements using indirect calorimetry aid in nutritional assessment and management in intensive care units. They are used during weaning from mechanical ventilator and can calculate work of breathing also. We would like to report a case in which these monitors helped diagnose and manage a child with hypometabolism. PMID- 21590360 TI - Diagnostic value of high spatial and temporal resolution time-resolved MR angiography in the workup of peripheral high-flow vascular malformations at 1.5 Tesla. AB - To evaluate the feasibility and diagnostic impact of time-resolved MR angiography (TR-MRA) combined with parallel imaging and low contrast dose for the assessment of peripheral high-flow vascular malformations (VM) at 1.5 Tesla (T). Twelve consecutive patients (7 female, 5 male, mean age 24.7 +/- 11.1 years) with known or suspected high-flow VM underwent time-resolved MRA. Two readers individually assessed image quality, diagnostic confidence as well as hemodynamic features. Digital subtraction angiography (DSA) correlation was available in 9 patients. TR MRA provided a comprehensive assessment of all VMs with good quality images, allowing reliable differentiation of the early and main arterial phases and of at least the early venous phase. Based on hemodynamic features VM were classified as predominantly arterial malformations in 5 cases (42%), or arteriovenous malformations in the remaining 7 cases (58%). The high-flow component of a VM was confirmed by DSA in 9/9 (100%) cases during the interventional treatment procedure. TR-MRA of peripheral VMs with temporal interpolation and stochastic spiral trajectories is feasible, allowing the assessment of dynamic inflow and vessel-specific information similar to conventional DSA. Therefore, TR-MRA represents a reasonable alternative imaging technique for the pre-treatment evaluation of high-flow VMs. PMID- 21590361 TI - Prevalence, intensity and associated factor analysis of Tropilaelaps mercedesae infesting Apis mellifera in China. AB - Tropilaelaps mercedesae is a serious ectoparasite of Apis mellifera in China. The aim of this study was to investigate the infestation rates and intensity of T. mercedesae in A. mellifera in China, and to explore the relative importance of climate, district, management practices and beekeeper characteristics that are assumed to be associated with the intensity of T. mercedesae. Of the 410 participating apiaries, 379 apiaries were included in analyses of seasonal infestation rates and 352 apiaries were included in multivariable regression analysis. The highest infestation rate (86.3%) of T. mercedesae was encountered in autumn, followed by summer (66.5%), spring (17.2%) and winter (14.8%). In autumn, 28.9% (93) of the infested apiaries were in the north (including the northeast and northwest of China), 71.1% (229) were in the central and south (including east, southeast and southwest China), and 306 apiaries (82.9%) were co infested by both T. mercedesae and Varroa. Multivariable regression analysis showed that geographical location, season, royal jelly collection and Varroa infestation were the factors that influence the intensity of T. mercedesae. The influence of beekeeper's education, time of beekeeping, operation size, and hive migration on the intensity of T. mercedesa was not statistically significant. This study provided information about the establishment of the linkage of the environment and the parasite and could lead to better timing and methods of control. PMID- 21590362 TI - Plant germline development: a tale of cross-talk, signaling, and cellular interactions. PMID- 21590364 TI - Vitamin E tocotrienols: life beyond tocopherols. PMID- 21590363 TI - Differential effects of Zn2+ on activation, deactivation, and inactivation kinetics in neuronal voltage-gated Na+ channels. AB - Whole-cell, patch-clamp recordings were carried out in acutely dissociated neurons from entorhinal cortex (EC) layer II to study the effects of Zn(2+) on Na(+) current kinetics and voltage dependence. In the presence of 200 MUM extracellular Cd(2+) to abolish voltage-dependent Ca(2+) currents, and 100 mM extracellular Na(+), 1 mM Zn(2+) inhibited the transient Na(+) current, I (NaT), only to a modest degree (~17% on average). A more pronounced inhibition (~36%) was induced by Zn(2+) when extracellular Na(+) was lowered to 40 mM. Zn(2+) also proved to modify I (NaT) voltage-dependent and kinetic properties in multiple ways. Zn(2+) (1 mM) shifted the voltage dependence of I (NaT) activation and that of I (NaT) onset speed in the positive direction by ~5 mV. The voltage dependence of I (NaT) steady-state inactivation and that of I (NaT) inactivation kinetics were markedly less affected by Zn(2+). By contrast, I (NaT) deactivation speed was prominently accelerated, and its voltage dependence was shifted by a significantly greater amount (~8 mV on average) than that of I (NaT) activation. In addition, the kinetics of I (NaT) recovery from inactivation were significantly slowed by Zn(2+). Zn(2+) inhibition of I (NaT) showed no signs of voltage dependence over the explored membrane-voltage window, indicating that the above effects cannot be explained by voltage dependence of Zn(2+)-induced channel pore block. These findings suggest that the multiple, voltage-dependent state transitions that the Na(+) channel undergoes through its activation path are differentially sensitive to the gating-modifying effects of Zn(2+), thus resulting in differential modifications of the macroscopic current's activation, inactivation, and deactivation. Computer modeling provided support to this hypothesis. PMID- 21590365 TI - Primary mediastinal large B-cell lymphoma, classic Hodgkin lymphoma presenting in the mediastinum, and mediastinal gray zone lymphoma: what is the oncologist to do? AB - In recent years, an overlap in biologic and clinical features has been identified between classic Hodgkin lymphoma (CHL) and primary mediastinal large B-cell lymphoma (PMBL). Further strengthening this relationship is the identification of lymphomas with clinical and morphologic features transitional between the two, known as gray zone lymphomas (GZL). However, this diagnostic gray zone is not just of theoretical interest: it presents a practical problem, as the treatment approaches for CHL traditionally differ from those for aggressive B-cell lymphomas. This article reviews the treatment approach for mediastinal lymphomas, including CHL of the nodular sclerosis subtype (CHL-NS), PMBL, and mediastinal GZL. Though several trials have evaluated different regimens with or without radiation in PMBL and CHL-NS, there is a lack of prospective experience in treating GZL because of the rarity of these tumors. Historical data indicate that they have done poorly with traditional approaches developed for the treatment of either CHL or diffuse large B-cell lymphoma. PMID- 21590366 TI - Combination therapy with the albumin-binding prodrug of doxorubicin (INNO-206) and doxorubicin achieves complete remissions and improves tolerability in an ovarian A2780 xenograft model. PMID- 21590367 TI - Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. AB - BACKGROUND: The aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors. PATIENTS AND METHODS: Patients aged >= 18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.5 mg/m(2)/day * 3 days or 1.0 mg/m(2)/day * 3 days) intravenously in combination with oral olaparib 50, 100 or 200 mg bid for six cycles. The primary objectives were to determine the safety and tolerability and to establish the MTD of olaparib in combination with topotecan. RESULTS: Twenty one patients were enrolled and 19 received treatment. Dose-limiting toxicities were neutropenia and thrombocytopenia. The MTD was established as topotecan 1.0 mg/m(2)/day * 3 days plus olaparib 100 mg bid. The most common adverse events (AEs) included fatigue and gastrointestinal events. There was an olaparib and topotecan dose-related increase in neutropenia which was dose limiting. CONCLUSIONS: Further development of olaparib and topotecan in combination was not explored due to dose-limiting hematological AEs and the resulting sub-therapeutic MTD. PMID- 21590368 TI - Investigating the potential of conserved inner core oligosaccharide regions of Moraxella catarrhalis lipopolysaccharide as vaccine antigens: accessibility and functional activity of monoclonal antibodies and glycoconjugate derived sera. AB - We investigated the conservation and antibody accessibility of inner core epitopes of Moraxella catarrhalis lipopolysaccharide (LPS) in order to assess their potential as vaccine candidates. Two LPS mutants, a single mutant designated lgt2 and a double mutant termed lgt2/lgt4, elaborating truncated inner core structures were generated in order to preclude expression of host-like outer core structures and to create an inner core structure that was shared by all three serotypes A, B and C of M. catarrhalis. Murine monoclonal antibodies (mAbs), designated MC2-1 and MC2-10 were obtained by immunising mice with the lgt2 mutant of M. catarrhalis serotype A strain. We showed that mAb MC2-1 can bind to the core LPS of wild-type (wt) serotype A, B and C organisms and concluded that mAb MC2-1 defines an immunogenic inner core epitope of M. catarrhalis LPS. We were unsuccessful in obtaining mAbs to the lgt2/lgt4 mutant. MAb MC2-10 only recognised the lgt2 mutant and the wt serotype A strain, and exhibited a strong requirement for the terminal N-acetyl-glucosamine residue of the lgt2 mutant core oligosaccharide, suggesting that this residue was immunodominant. Subsequently, we showed that both mAbs MC2-1 and MC2-10 could facilitate bactericidal killing of the lgt2 mutant, however neither mAb could facilitate bactericidal killing of the wt serotype A strain. We then confirmed and extended the candidacy of the inner core LPS by demonstrating that it is possible to elicit functional antibodies against M. catarrhalis wt strains following immunisation of rabbits with glycoconjugates elaborating the conserved inner core LPS antigen. The present study describes three conjugation strategies that either uses amidases produced by Dictyostelium discoideum, targeting the amino functionality created by the amidase activity as the attachment point on the LPS molecule, or a strong base treatment to remove all fatty acids from the LPS, thus creating amino functionalities in the lipid A region to conjugate via maleimide-thiol linker strategies targeting the carboxyl residues of the carrier protein and the free amino functionalities of the derived lipid A region of the carbohydrate resulted in a high loading of carbohydrates per carrier protein from these carbohydrate preparations. Immunisation derived antisera from rabbits recognised fully extended M. catarrhalis LPS and whole cells. Moreover, bactericidal activity was demonstrated to both the immunising carbohydrate antigen and importantly to wt cells, thus further supporting the consideration of inner core LPS as a potential vaccine antigen to combat disease caused by M. catarrhalis. PMID- 21590369 TI - Trends in health-related quality of life and health service use associated with comorbid diabetes and major depression in South Australia, 1998-2008. AB - PURPOSE: To investigate the trends in health-related quality of life and health service use associated with diabetes and/or major depression in South Australia from 1998 to 2008. METHODS: Data analyzed were from 9,059 persons aged >=15 years who participated in representative surveys of the South Australian population in 1998, 2004 and 2008. Major depression was determined using the mood module of the Primary Care Evaluation of Mental Disorders (PRIME-MD). Diagnosed diabetes and health service use were determined by self-report. Health-related quality of life was assessed using the 36-item Short-Form Health Survey (SF-36) and the 15-item Assessment of Quality of Life (AQoL) instruments. Socio-demographics (including mental health literacy), arthritis, asthma, osteoporosis, and obesity covariates were determined by self-report. Weighted age-standardized and multiple covariate adjusted means of dependent measures were computed. RESULTS: The prevalence of diabetes only, major depression only, and comorbid diabetes and major depression increased by 3.0 (74%), 2.6 (36%), and 0.4 (53%) percentage points, respectively, from 1998 to 2008. Mean health-related quality of life scores were 9 to 41% lower (worse), and health service use was 49% higher for persons with comorbid diabetes and major depression than for those with diabetes only (all P values <0.05) independent of all covariates, consistently over the 10-year period. CONCLUSIONS: If past trends continue, our results suggest that the increased population health and economic burden of comorbid diabetes and major depression could persist over the next decade or so. These trends have important implications for making health policy and resource allocation decisions. PMID- 21590371 TI - [Reconstruction of the distal radioulnar joint using the Herbert ulnar head prosthesis]. AB - OBJECTIVE: To provide painfree forearm rotation in patients with degenerative changes of the distal radioulnar joint (DRUJ). The primary goal is to stabilize the DRUJ in patients with an unstable stump of the distal ulna following resection arthroplasty with the secondary effect of restoring painfree forearm rotation. INDICATIONS: Instability of the distal ulna following various types of resection arthroplasties. Primary or secondary osteoarthritis of the DRUJ. Replacement of an ulnar head destroyed by tumor or trauma. CONTRAINDICATIONS: Longitudinal instability of the forearm (e.g., following an Essex-Lopresti-type of injury, resection of the radial head). Inadequate soft tissue with severe ulnocarpal ligamentous insufficiency. Radial deformity (must be corrected before replacement of the ulnar head). SURGICAL TECHNIQUE: In cases of osteoarthritis of the DRUJ, dorsal exposure of the distal radioulnar joint to the depth of the 5th extensor compartment. Raising of an ulnar-based capsuloretinacular flap by sharp dissection off the ulnar neck proximally and off the dorsal part of the triangular fibrocartilage complex (TFCC) distally. Osteotomy of the distal ulna corresponding to the preoperatively planned size of the prosthesis and removal of the ulnar head, while preserving the attachment of the TFCC within the capsuloretinacular flap. Reaming of the ulnar medullary canal. Insertion of a trial prosthesis. The trial prosthesis has to fit accurately into the shaft with a fluoroscopically documented ulna minus situation of minus 1-2 mm at the wrist joint level. After implanting the definite stem and ulnar head of the Herbert ulnar head prothesis (Martin Medizintechnik(r), Tuttlingen, Germany), the capsuloretinacular flap is reattached to the dorsal rim of the sigmoid notch through drilling holes and under advanced tension. In patients with an unstable distal ulnar stump, the operative procedure is technically more demanding as it is more difficult to raise a sufficient capsuloretinacular flap and due to the loss of the ulnar head as an anatomic landmark. POSTOPERATIVE MANAGEMENT: Long arm cast with 70 degrees elbow flexion, 40 degrees forearm supination, and 20 degrees wrist extension for 2 weeks. Subsequently forearm rotation is limited at 40 degrees in a removable ulnar gutter splint. Six weeks postoperatively unlimited active range of motion is allowed and normal activities are gradually commenced. Return to maximum stress 12 weeks postoperatively. RESULTS: Patient satisfaction is high due to an increased forearm rotation, stronger grip force, and remarkable pain relief. In most patients with an unstable distal ulnar stump following resection arthroplasty of the DRUJ, stability can be restored. PMID- 21590372 TI - [Stoffella metatarsal I osteotomy for Hallux valgus correction : an update]. AB - PROBLEM: A Hallux valgus (bunion) is a complex deformity caused by a dysbalance of the static and dynamic elements of the foot. Thus, the aim of an anatomical reconstruction is to normalize the physiological angle between the first and second metatarsal and to realign the balance of periarticular soft tissues. Modern surgical techniques should allow for very early weight-bearing and, at the same time, make immobilizing casts or other devices unnecessary. SOLUTION: The Stoffella metatarsal I osteotomy is a technique which meets the requirements of statical and dynamic balance in combination with immediate full weight-bearing. SURGICAL TECHNIQUE: After sparingly removing the medial exostosis (bunion), a distal metatarsal osteotomy is performed. To correct the deformity, the metatarsal head is shifted laterally, plantarwards, and rotated, if required. Fixation is performed by a stable DC clip for osteosynthesis, screwed in place to maintain the correction. Soft tissue balancing is achieved by a transarticular lateral release and medial capsular raphing. POSTOPERATIVE MANAGEMENT: Early functional rehabilitation, immediate full weight-bearing, normal heel-to-toe gait, lymphatic drainage, soft bandage for big toe for 6 weeks. RESULTS: A total of 353 patients, thereof 177 patients with simultaneous operation of both sides, were included. Preoperative hallux valgus angle (42 degrees ; range 25-60 degrees ) improved to 16 degrees (range 6-30 degrees ). The intermetatarsal angle averaged 15 degrees (range 10-26 degrees ) preoperatively and 10 degrees (range 7-14 degrees ) postoperatively. The Kitaoka score improved from 47 points preoperatively to 87 points postoperatively. Complications included 4 deep infects (0.8%), 3 dislocations of the metatarsal head (0.6%), 4 necroses of the metatarsal head (0.8%), and 13 arthrofibroses (2.6%). PMID- 21590373 TI - When tumor suppressor TGFbeta meets the HER2 (ERBB2) oncogene. AB - Despite its tumor suppressive role in normal mammary epithelial cells, TGFbeta has been reported to promote the migration, invasion and survival in breast cancer cells overexpressing the HER2 (ERBB2; neu) oncogene, and to accelerate the metastasis of neu-induced mammary tumors in mice. A clearer understanding of the molecular mechanisms underlying the crosstalk between TGFbeta and HER2 has started to emerge. In recent studies reviewed here, the synergistic effect of TGFbeta and HER2 on tumor progression has been shown to likely be a combined result of two distinct features: (1) loss of TGFbeta's tumor suppressive effect through functional alterations in the anti-mitogenic effect of Smad-mediated transcription, and (2) gain of pro-survival and pro-migratory function through HER2-dependent mechanisms. In HER2-overexpressing breast cancer, this crosstalk results in increased cancer cell proliferation, survival and invasion, accelerated metastasis in animal models, and resistance to chemotherapy and HER2 targeted therapy. Thus, the transformed cellular context imparted by constitutively active HER2 signaling, as a consequence of HER2 gene amplification or overexpression, aborts the tumor suppressive role of TGFbeta and facilitated the oncogenic role of this pathway. In turn, TGFbeta potentiates oncogenic HER2 signaling by inducing shedding of the ERBB ligands and clustering of HER2 with integrins. Here we discuss recent studies examining Smad-dependent and independent mechanisms of crosstalk between TGFbeta and HER2. Therefore, blockade of TGFbeta:HER2 crosstalk may suppress breast cancer progression and metastasis, and enhance the efficiency of conventional therapies in patients with HER2 overexpressing breast cancer. PMID- 21590375 TI - Effect of water temperature on the content of essential polyunsaturated fatty acids in freshwater zooplankton. PMID- 21590374 TI - Consequences of epithelial or stromal TGFbeta1 depletion in the mammary gland. AB - Transforming growth factor beta1 (TGFbeta) affects stroma and epithelial composition and interactions that mediate mammary development and determine the course of cancer. The reduction of TGFbeta in Tgfbeta1 heterozygote mice, which are healthy and long-lived, provides an important model to dissect the contribution of TGFbeta in mammary gland biology and cancer. We used both intact mice and mammary chimeras in conjunction with Tgfbeta1 genetic depletion and TGFbeta neutralizing antibodies to evaluate how stromal or epithelial TGFbeta depletion affect mammary development and response to physiological stimuli. Our studies of radiation carcinogenesis have revealed new aspects of TGFbeta biology and suggest that the paradoxical TGFbeta switch from tumor suppressor to tumor promoter can be resolved by assessing distinct stromal versus epithelial actions. PMID- 21590376 TI - Study of the effects of enhancer and insulator on the chromatin structure in Drosophila melanogaster. PMID- 21590377 TI - Short peptides modulate the effect of endonucleases of wheat seedling. PMID- 21590378 TI - Peptides corresponding to intracellular regions of somatostatin receptors with agonist and antagonist activity. PMID- 21590379 TI - Genetic and molecular analysis of gene trans-inactivation caused by homologous eu heterochromatic chromosome rearrangement in Drosophila melanogaster. PMID- 21590381 TI - Alterations in fatty acid composition of mice brain and liver with aging and at savory essential oil administration. PMID- 21590380 TI - Investigation of transport and unpacking mechanisms of polyplexes for transfection efficacy on different cell lines. PMID- 21590382 TI - Melanin pigments in the fungus Paecilomyces lilacinus (Thom) Samson. PMID- 21590383 TI - Fatty acid composition of mitochondrial membranes of pea seedlings under conditions of insufficient moistening and moderate cooling. PMID- 21590384 TI - Identification of single amino acid polymorphisms in MS/MS spectra of peptides. PMID- 21590385 TI - The mechanism of substrate search by base excision repair enzymes. PMID- 21590386 TI - Diagnosis of cancer using microchip-based system for simultaneous quantitation of six tumor markers. PMID- 21590387 TI - Postural muscle recovery under lowered oxygen concentration after prolonged disuse. PMID- 21590388 TI - Genes potentially associated with resistance of lung cancer cells to paclitaxel. PMID- 21590389 TI - Study of influence of prodigiozan-dependent comuton on slow efflux of calcium ions from the matrix of mitochondria of various tissue and species origins. PMID- 21590390 TI - Translational approaches to medication development. AB - Alcohol accounts for major disability worldwide and available treatments are insufficient. A massive growth in the area of addiction neuroscience over the last several decades has not resulted in a corresponding expansion of treatment options available to patients. In this chapter, we describe our experience with building translational research programs aimed at developing novel pharmacotherapies for alcoholism. The narrative is based on experience and considerations made in the course of building these programs, and work on four mechanisms targeted by our libraries: cholinergic nicotine receptors, receptors for corticotropin-releasing hormone (CRH), neurokinin 1 (NK1) receptors for substance P (SP) and hypocretin/orexin receptors. Around this experience, we discuss issues we believe to be critical for successful translation of basic addiction neuroscience into treatments, and complementarities between academic and other actors that in our assessment need to be harnessed in order to bring treatments to the clinic. PMID- 21590391 TI - Introduction to viral vectors. AB - Viral vector is the most effective means of gene transfer to modify specific cell type or tissue and can be manipulated to express therapeutic genes. Several virus types are currently being investigated for use to deliver genes to cells to provide either transient or permanent transgene expression. These include adenoviruses (Ads), retroviruses (gamma-retroviruses and lentiviruses), poxviruses, adeno-associated viruses, baculoviruses, and herpes simplex viruses. The choice of virus for routine clinical use will depend on the efficiency of transgene expression, ease of production, safety, toxicity, and stability. This chapter provides an introductory overview of the general characteristics of viral vectors commonly used in gene transfer and their advantages and disadvantages for gene therapy use. PMID- 21590392 TI - Introduction to gene therapy: a clinical aftermath. AB - Despite three decades of huge progress in molecular genetics, in cloning of disease causative gene as well as technology breakthroughs in viral biotechnology, out of thousands of gene therapy clinical trials that have been initiated, only very few are now reaching regulatory approval. We shall review some of the major hurdles, and based on the current either positive or negative examples, we try to initiate drawing a learning curve from experience and possibly identify the major drivers for future successful achievement of human gene therapy trials. PMID- 21590393 TI - Host cells and cell banking. AB - Gene therapy based on the use of viral vectors is entirely dependent on the use of animal cell lines, mainly of mammalian origin, but also of insect origin. As for any biotechnology product for clinical use, viral -vectors have to be produced with cells derived from an extensively characterized cell bank to maintain the appropriate standard for assuring the lowest risk for the patients to be treated. Although many different cell types and lines have been used for the production of viral vectors, HEK293 cells or their derivatives have been extensively used for production of different vector types: adenovirus, oncorectrovirus, lentivirus, and AAV vectors, because of their easy handling and the possibility to grow them adherently in serum-containing medium as well as in suspension in serum-free culture medium. Despite this, these cells are not necessarily the best for the production of a given viral vector, and there are many other cell lines with significant advantages including superior growth and/or production characteristics, which have been tested and also used for the production of clinical vector batches. This chapter presents basic considerations concerning the characterization of cell banks, in the first part, and, in the second part, practically all cell lines (at least when public information was available) established and developed for the production of the most important viral vectors (adenoviral, oncoretroviral, lentiviral, AAV, baculovirus). PMID- 21590394 TI - Overview of current scalable methods for purification of viral vectors. AB - As a result of the growing interest in the use of viruses for gene therapy and vaccines, many virus-based products are being developed. The manufacturing of viruses poses new challenges for process developers and regulating authorities that need to be addressed to ensure quality, efficacy, and safety of the final product. The design of suitable purification strategies will depend on a multitude of variables including the vector production system and the nature of the virus. In this chapter, we provide an overview of the most commonly used purification methods for viral gene therapy vectors. Current chromatography options available for large-scale purification of gamma-retrovirus, lentivirus, adenovirus, adeno-associated virus, herpes simplex virus, baculovirus, and poxvirus vectors are presented. PMID- 21590395 TI - Methods to construct recombinant adenovirus vectors. AB - The most efficient system to introduce genes of interest within the adenovirus genome is by homologous recombination in microorganisms. In this chapter, the most popular procedures are described: two for homologous recombination in Escherichia coli, and one in yeast. Main differences between procedures are found in the plasmids needed as well as in the selection system used to rapidly identify newly generated recombinant adenovirus. The adenovirus genomes are then analyzed to confirm their identity and integrity, and further linearized to generate a viral pre-stock in permissive human cells. Finally, as a previous step before its amplification at medium or large scale, the viral pre-stock must be analyzed to quantify its potency and infectivity as well as to exclude the presence of unwanted replication competent particles. PMID- 21590396 TI - Manufacturing of adenovirus vectors: production and purification of helper dependent adenovirus. AB - Adenoviral vector (AdV) of the third generation also known as helper-dependent adenoviral vector (HDV) is an attractive delivery system for gene therapy applications. However, obtaining high quality-grade HDV in sufficient amount remains a challenge that hampers the extensive use of this vector in preclinical and clinical studies. Here we review recent progress in the large-scale manufacturing of HDV. The production of HDV is now amenable to large-scale volume with reduced process duration under optimized rescue and co-infection conditions. Also, efficient downstream processing of HDV with acceptable recovery of HDV and minimal contamination by the helper virus is described. PMID- 21590397 TI - Manufacturing of retroviruses. AB - Retrovirus vectors derived from moloney murine leukemia virus (MoMLV) were the first class of viral vectors developed for gene therapy. They have been extensively used in clinical trials, particularly in ex vivo transduction of hematopoietic stem cells. Although there is a vast experience acquired with retroviruses, their manufacturing is still a difficult task due to the low cell productivities and inherent instability of the infective virus. These viral vectors are most commonly produced using stable producer cell lines in adherent monolayer culture systems. In order to obtain high transduction efficiencies and low toxicity in clinical applications, the viral preparations should be purified, concentrated, and well characterized to attain stringent quality specifications. This chapter describes currently used protocols for manufacturing retroviruses. PMID- 21590398 TI - Lentiviral vectors. AB - Lentiviral vectors have evolved over the last decade as powerful, reliable, and safe tools for stable gene transfer in a wide variety of mammalian cells. Contrary to other vectors derived from oncoretroviruses, they allow for stable gene delivery into most nondividing primary cells. In particular, lentivectors (LVs) derived from HIV-1 have gradually evolved to display many desirable features aimed at increasing both their safety and their versatility. This is why lentiviral vectors are becoming the most useful and promising tools for genetic engineering, to generate cells that can be used for research, diagnosis, and therapy. This chapter describes protocols and guidelines, for production and titration of LVs, which can be implemented in a research laboratory setting, with an emphasis on standardization in order to improve transposability of results between laboratories. We also discuss latest designs in LV technology. PMID- 21590399 TI - Adeno-associated viruses. AB - Adeno-associated virus (AAV) vectors have evolved over the past decade as a particularly useful gene -vector for in vivo applications. In contrast to oncoretro- and lentiviral vectors, this vector stays essentially episomal after gene transfer, making it safer because of the absence of insertional mutagenesis. AAV's non-pathogenicity is a further advantage. For decades, this vector could only be produced at a small scale for research purposes and, eventually, used at very small doses for clinical studies, because only transfection methods were available, which have limited scalability. However, since the development of scalable production methods, this bottleneck is resolved and, from a technical point of view, large quantities of AAV vectors can be produced, opening the possibility of using AAV vectors for whole body treatments in gene therapy trials. This chapter presents the basic principles of small- and large-scale production procedures as well as detailed procedure of small-scale production, purification, and analytical protocols for AAV vectors. In Chapter 10, the reader will find a large-scale production method based on the use of the insect cell/baculovirus system. PMID- 21590400 TI - Manufacturing of adeno-associated viruses, for example: AAV2. AB - Adeno-associated virus (AAV) is one of the most promising vectors for gene therapy. There are several ways of producing AAV vectors but large-scale production of this vector remains a major challenge. Virovek developed a novel method of expressing the AAV Rep and Cap genes in insect cells mediated by intron splicing mechanism and producing AAV vectors with these Rep and Cap sequences containing the artificial intron. The recombinant baculoviruses harboring these artificial intron-containing Rep and Cap sequences are very stable and the AAV vectors produced in insect cells with these recombinant baculoviruses are very infectious. PMID- 21590401 TI - Vector characterization methods for quality control testing of recombinant adeno associated viruses. AB - Adeno-associated virus (AAV)-based vectors expressing therapeutic gene products have shown great promise for human gene therapy. A major challenge for translation of promising research to clinical development is the establishment of appropriate quality control (QC) test methods to characterize clinical grade AAV vectors. This chapter focuses on QC testing, providing an overview of characterization methods appropriate for clinical vectors prepared for early phase clinical studies, and detailed descriptions for selected assays that are useful to assess AAV vector safety, potency, and purity. PMID- 21590402 TI - Baculoviruses mediate efficient gene expression in a wide range of vertebrate cells. AB - Baculovirus expression vector system (BEVS) is well known as a feasible and safe technology to produce recombinant (re-)proteins in a eukaryotic milieu of insect cells. However, its proven power in gene delivery and gene therapy is still poorly recognized. The basis of BEVS lies in large enveloped DNA viruses derived from insects, the prototype virus being Autographa californica multiple nucleopolyhedrovirus (AcMNPV). Infection of insect cell culture with a virus encoding a desired transgene under powerful baculovirus promoter leads to re protein production in high quantities. Although the replication of AcMNPV is highly insect specific in nature, it can penetrate and transduce a wide range of cells of other origin. Efficient transduction requires only virus arming with an expression cassette active in the cells under investigation. The inherent safety, ease and speed of virus generation in high quantities, low cytotoxicity and extreme transgene capacity and tropism provides many advantages for gene delivery over the other viral vectors typically derived from human pathogens. PMID- 21590403 TI - Herpes simplex virus type 1-derived recombinant and amplicon vectors. AB - Herpes simplex virus type 1 (HSV-1) is a human pathogen whose lifestyle is based on a long-term dual interaction with the infected host, being able to establish both lytic and latent infections. The virus genome is a 153 kbp double-stranded DNA molecule encoding more than 80 genes. The interest of HSV-1 as gene transfer vector stems from its ability to infect many different cell types, both quiescent and proliferating cells, the very high packaging capacity of the virus capsid, the outstanding neurotropic adaptations that this virus has evolved, and the fact that it never integrates into the cellular chromosomes, thus avoiding the risk of insertional mutagenesis. Two types of vectors can be derived from HSV-1, recombinant vectors and amplicon vectors, and different methodologies have been developed to prepare large stocks of each type of vector. This chapter summarizes (1) the two approaches most commonly used to prepare recombinant vectors through homologous recombination, either in eukaryotic cells or in bacteria, and (2) the two methodologies currently used to generate helper-free amplicon vectors, either using a bacterial artificial chromosome (BAC)-based approach or a Cre/loxP site specific recombination strategy. PMID- 21590404 TI - Manufacture of measles viruses. AB - Measles viruses have shown potent oncolytic activity as a therapeutic against a variety of human cancers in animal models and are currently being tested in clinical trials in patients. In contrast to using measles virus as a vaccine, oncolytic activity depends on high concentrations of infectious virus. For use in humans, the high-titer measles virus preparations must also be purified to remove significant levels of cellular proteins and nucleic acid resulting from the cytolytic products of measles virus replication and release. Pleomorphic measles virus must be treated as >1-MUm particles that are extremely shear sensitive to maximize recoveries and retain infectivity. Therefore, to maximize the recovery of sterile, high titer infectious measles viruses, the entire production and purification process must be done using gentle conditions and aseptic processing. Here we describe a procedure applicable to the production of small (a few liters) to large (50-60 L) batches of measles virus amplified in Vero cells adapted to serum-free growth. Cell culture supernatant containing the measles virus is clarified by filtration to remove intact Vero cells and other debris, and then treated with Benzonase((r)) in the presence of magnesium chloride to digest contaminating nucleic acid. The measles virus in the treated cell culture supernatant is then concentrated and purified using tangential flow filtration (TFF) and diafiltration. The concentrated and diafiltered measles virus is passed through a final clarifying filter prior to final vialing and storage at <-65 degrees C. An infectivity assay to quantify infectious measles virus concentration based on the TCID(50) method is also described. This procedure can be readily adapted to the production and purification of measles viruses using good manufacturing practices (GMP). PMID- 21590405 TI - In vivo gene delivery into hCD34+ cells in a humanized mouse model. AB - In vivo targeted gene delivery to hematopoietic stem cells (HSCs) would mean a big step forward in the field of gene therapy. This would imply that the risk of cell differentiation and loss of homing/-engraftment is reduced, as there is no need for purification of the target cell. In vivo gene delivery also bypasses the issue that no precise markers that permit the isolation of a primitive hHSC exist up to now. Indeed, in vivo gene transfer could target all HSCs in their stem-cell niche, including those cells that are "missed" by the purification criteria. Moreover, for the majority of diseases, there is a requirement of a minimal number of gene-corrected cells to be reinfused to allow an efficient long-term engraftment. This requisite might become a limiting factor when treating children with inherited disorders, due to the low number of bone marrow (BM) CD34(+) HSCs that can actually be isolated. These problems could be overcome by using efficient in vivo HSC-specific lentiviral vectors (LVs). Additionally, vectors for in vivo HSC transduction must be specific for the target cell, to avoid vector spreading while enhancing transduction efficiency. Of importance, a major barrier in LV transduction of HSCs is that 75% of HSCs are residing in the G0 phase of the cell cycle and are not very permissive for classical VSV-G-LV transduction. Therefore, we engineered "early-activating-cytokine (SCF or/and TPO)" displaying LVs that allowed a slight and transient stimulation of hCD34(+) cells resulting in efficient lentiviral gene transfer while preserving the "stemness" of the targeted HSCs. The selective transduction of HSCs by these vectors was demonstrated by their capacity to promote selective transduction of CD34(+) cells in in vitro-derived, long-term culture-initiating cell colonies and long-term NOD/SCID repopulating cells. A second generation of these "early-acting cytokine"-displaying lentiviral vectors has now been developed that is fit for targeted in vivo gene delivery to hCD34(+) cells. In the method presented here, we describe the in vivo gene delivery into hCD34(+) cells by intramarrow injection of these new vectors into humanized BALB/c Rag2( null )/IL2rgc ( null ) (BALB/c RAGA) mice. PMID- 21590406 TI - In vivo evaluation of gene transfer into mesenchymal cells (in view of cartilage repair). AB - Gene transfer of specific growth factors is suitable for inducing chondrogenic differentiation of -mesenchymal cells to be used for cartilage regeneration. However, extent and quality of repair tissue formation also depend on biomechanical and metabolic influences that can only be studied in vivo. We describe three methods to evaluate viral gene transfer into mesenchymal cells in animal models of articular cartilage defects, e.g., mouse, rat and miniature pig models, focussing on the repair of hyaline cartilage tissue. PMID- 21590407 TI - Ethical consideration. AB - The twofold distinction between interventions into the germ line and interventions into somatic cells on the one hand and between the treatment of diseases and enhancement on the other hand resulted in the concept of somatic gene therapy. There is a nearly unanimous agreement that somatic gene therapy has a high-ranking moral objective and uses methods that extend current techniques for treating diseases in a morally acceptable way. In its experimental phase principles of research ethics as the autonomy and the informed consent of the patient or the test person, a fair selection of test persons and a careful weighing of risks and benefits have to be taken into account and several specific points have to be considered. Experimental somatic gene therapy requires a positive vote of a competent and independent ethics committee. PMID- 21590408 TI - Clinical trials of GMP products in the gene therapy field. AB - Advances in gene therapy are increasingly leading to clinical assessment in many fields of medicine with diverse approaches. The basic science stems from approaches aimed at different functions such as correcting a missing/abnormal gene, altering the proportion or expression of normal genes to augment a physiological process or using this principle to destroy malignant or infected cells. As the technology advances, it is increasingly important to ensure that clinical trials answer the questions that need to be asked. In this chapter we review examples of published clinical trials, resources for accessing information about registered trials, the process of regulating trials, good clinical practice, and good manufacturing practice as well as summarising the approach taken by regulatory authorities in reviewing applications for the introduction of products for use in the clinic. PMID- 21590409 TI - Genome sequencing and assembly. AB - Decoding the genome sequence is becoming a fundamental tool for molecular, genetic, and genomic studies. This chapter reviews the history of DNA sequencing and technical principles of different sequencing platforms, and compares the strengths and weaknesses of different techniques for high-throughput genome sequencing applications are compared. It also covers brief descriptions on genome assembly and its validation. PMID- 21590410 TI - Targeted cloning of fungal telomeres. AB - Telomeres are the sequences that form the ends of eukaryotic chromosomes and are essential structures that confer genome stability and guide chromosome behavior. In addition, the terminal regions of the chromosomes tend to house genes with predicted roles in ecological adaptation. Unfortunately, however, most fungal genome assemblies contain very few telomeres and, therefore, the identities of genes residing near the chromosome ends are often unknown. In an effort to develop a complete understanding of the organization and gene content of chromosome ends in a number of fungi, we developed efficient methods for the identification and targeted cloning of telomeres. This chapter describes the basic steps and shows exemplary results from the targeted cloning of Epichloe festucae telomeres. PMID- 21590411 TI - Identification and annotation of repetitive sequences in fungal genomes. AB - Advances in sequencing technologies have fundamentally changed the pace of genome sequencing projects and have contributed to the ever-increasing volume of genomic data. This has been paralleled by an increase in computational power and resources to process and translate raw sequence data into meaningful information. In addition to protein coding regions, an integral part of all the genomes studied so far has been the presence of repetitive sequences. Previously considered as "junk," numerous studies have implicated repetitive sequences in important biological and structural roles in the genome. Therefore, the identification and characterization of these repetitive sequences has become an indispensable part of genome sequencing projects. Numerous similarity-based and de novo methods have been developed to search for and annotate repeats in the genome, many of which have been discussed in this chapter. PMID- 21590412 TI - Next-generation sequencing and potential applications in fungal genomics. AB - Since the first fungal genome was sequenced in 1996, sequencing technologies have advanced dramatically. In recent years, it has become possible to cost effectively generate vast amounts of DNA sequence data using a number of cell- and electrophoresis-free sequencing technologies, commonly known as "next" or "second" generation. In this chapter, we present a brief overview of next generation sequencers that are commercially available now. Their potential applications in fungal genomics studies are discussed. PMID- 21590413 TI - Getting the most out of your fungal microarray data: two cost- and time-effective methods. AB - Advances in genome sequencing technologies have facilitated production of a wealth of fungal data; within the last 5 years, experimental costs and labor have diminished, shifting the production bottleneck from genomic data generation to data analysis. Genome sequences and microarrays now exist for many fungi, and transcriptional profiling has been shown to be an efficient way to examine how the entire genome changes in response to many different environments or treatments. Multiple platforms, programs, and protocols exist for analyzing such data, making this task daunting for the bench-based scientist. Furthermore, many existing programs are expensive and require license renewals on a yearly basis for each user in the laboratory. Costs may be prohibitively high for bench-based scientists in academia. Our combined experiences with this kind of analysis have favored two programs, depending upon whether the scientist is working with single or dual-channel hybridization data. Our protocols are aimed toward helping the bench-based PI get the most possible information from their data, without the need for expensive software or an experienced bioinformaticist. PMID- 21590414 TI - Fusarium graminearum from expression analysis to functional assays. AB - Fusarium graminearum, the causal agent of head blight of wheat, was the third filamentous fungus to have a completed genome sequence. Since the release of the genome sequence in 2003, F. graminearum has become a model for studies of genomics and transcriptomics, mycotoxins, fungal population genetics, gene function, and sexual development. Herein we present the techniques we have used in our laboratory to perform expression analyses on life cycle stages of F. graminearum and techniques to functionally characterize those genes identified as potentially interesting. PMID- 21590415 TI - EST analysis pipeline: use of distributed computing resources. AB - This chapter describes how a pipeline for the analysis of expressed sequence tag (EST) data can be -implemented, based on our previous experience generating ESTs from Trichoderma spp. We focus on key steps in the workflow, such as the processing of raw data from the sequencers, the clustering of ESTs, and the functional annotation of the sequences using BLAST, InterProScan, and BLAST2GO. Some of the steps require the use of intensive computing power. Since these resources are not available for small research groups or institutes without bioinformatics support, an alternative will be described: the use of distributed computing resources (local grids and Amazon EC2). PMID- 21590416 TI - The application of ChIP-chip analysis in the rice blast pathogen. AB - To attempt to gain an understanding of the molecular underpinnings of disease, many researchers have turned to expression profiling of genes during various stages of host recognition, entry, invasive growth, and host responses. While these studies have proven valuable, a deeper level of knowledge of the control circuitry affecting observed gene expression profiles can lead to a better understanding of the host pathogen interaction. Transcription factors are key switches in signal transduction circuits regulating gene expression. One powerful method to define target sequence specificity for this important group of transcription regulators is chromatin immunoprecipitation (ChIP) with microarray chips (chip), commonly called ChIP-chip. A more recent variation of this technique is ChIP-seq where DNA sequencing replaces the microarray chip. Here, we describe how we elucidated the binding sites for the Magnaporthe oryzae Ca(2+)/calcineurin-dependent transcription factor MoCRZ1 with the ChIP-chip approach. PMID- 21590417 TI - Proteome studies of filamentous fungi. AB - The continued fast pace of fungal genome sequence generation has enabled proteomic analysis of a wide variety of organisms that span the breadth of the Kingdom Fungi. There is some phylogenetic bias to the current catalog of fungi with reasonable DNA sequence databases (genomic or EST) that could be analyzed at a global proteomic level. However, the rapid development of next generation sequencing platforms has lowered the cost of genome sequencing such that in the near future, having a genome sequence will no longer be a time or cost bottleneck for downstream proteomic (and transcriptomic) analyses. High throughput, nongel based proteomics offers a snapshot of proteins present in a given sample at a single point in time. There are a number of variations on the general methods and technologies for identifying peptides in a given sample. We present a method that can serve as a "baseline" for proteomic studies of fungi. PMID- 21590418 TI - A bioinformatics pipeline for sequence-based analyses of fungal biodiversity. AB - The internal transcribed spacer (ITS) is the locus of choice with which to characterize fungal diversity in environmental samples. However, methods to analyze ITS datasets have lagged behind the capacity to generate large amounts of sequence information. Here, we describe our bioinformatics pipeline to process large fungal ITS sequence datasets, from raw chromatograms to a spreadsheet of operational taxonomic unit (OTU) abundances across samples. Steps include assembling of reads originating from one clone, identifying primer "barcodes" or "tags," trimming vectors and primers, marking low-quality base calls and removing low-quality sequences, orienting sequences, extracting the ITS region from longer amplicons, and grouping sequences into OTUs. We expect that the principles and tools presented here are relevant to datasets arising from ever-evolving new technologies. PMID- 21590419 TI - Identifying protein complexes by affinity purification and mass spectrometry analysis in the rice blast fungus. AB - Affinity purification and mass spectrometry analyses have been used in various organisms to identify -protein complexes and determine protein-protein interactions in vivo. In comparison with the TAP (tandem affinity purification) tag, the 3* FLAG is a relatively small epitope tag. It has been used to systematically identify protein-protein interactions in the budding yeast. We have used the 3* FLAG tag to isolate proteins co-purified with a number of genes in the rice blast fungus, including TIG1, MST50, PMK1, and MST12. For the example given in the text, five genes homologous to components of the yeast Set3C complex were identified by mass spectrometry analysis. PMID- 21590420 TI - Large scale identification of genes involved in plant-fungal interactions using Illumina's sequencing-by-synthesis technology. AB - Deep transcriptome profiling of pathogen-infected tissues enhances the understanding of molecular mechanisms underlying host-pathogen interactions. Illumina's next generation sequencing technology sequencing-by-synthesis (SBS) is a powerful tool to rapidly sequence genomes and transcriptomes at an affordable rate. We modified the procedure for SBS library construction to significantly increase the efficiency of library construction. Using our improved method, two Sclerotinia homoeocarpa libraries were constructed from mycelia grown in potato dextrose broth (PDB) or potato dextrose agar (PDA) for 96 h, respectively, and two creeping bentgrass libraries were constructed from leaves 96 h after inoculation with S. homoeocarpa or water sprayed, respectively. About 4-7 million mRNA signatures were sequenced from each library. Sequence analysis using BLAST was performed against sequenced fungal genomes and rice genomic sequence to identify the expressed genes in both S. homoeocarpa mycelia and creeping bentgrass. Bioinformatic analysis identified many expressed genes in the pathogen and host. A public database to access the sequence data was developed at http://www.dstidb.org . Our results demonstrate how SBS technology can unravel transcriptome complexity during the creeping bentgrass-S. homoeocarpa interaction. PMID- 21590421 TI - High-throughput production of gene replacement mutants in Neurospora crassa. AB - The model filamentous fungus Neurospora crassa has been the focus of functional genomics studies for the past several years. A high-throughput gene knockout procedure has been developed and used to generate mutants for more than two thirds of the ~10,000 annotated N. crassa genes. Yeast recombinational cloning was incorporated as an efficient procedure to produce all knockout cassettes. N. crassa strains with the Deltamus-51 or Deltamus-52 deletion mutations were used as transformation recipients in order to reduce the incidence of ectopic integration and increase homologous recombination of knockout cassettes into the genome. A 96-well format was used for many steps of the procedure, including fungal transformation, isolation of homokaryons, and verification of mutants. In addition, development of software programs for primer design and restriction enzyme selection facilitated the high-throughput aspects of the overall protocol. PMID- 21590422 TI - Phenotypic analysis of Neurospora crassa gene deletion strains. AB - Phenotypic analysis of Neurospora crassa knockout (KO) mutants was used as a vehicle to introduce students to laboratory research. The availability of gene deletion strains was the impetus for the development of a program designed to introduce beginning science students to basic microbiology, genetics, microscopy and beginning bioinformatics. The goal was to provide a research experience, acquire laboratory skills and phenotype hundreds of KO mutants. The data provided by the students was used to build a phenotype database at the Broad Institute at Harvard/MIT for the fungal scientific community. Each mutant analysis consists of five assays that examine growth and morphology, asexual and sexual development using wild-type (parental) strains as a reference. This information indicates how loss of each gene impacts these basic and important processes. PMID- 21590423 TI - Efficient approaches for generating GFP fusion and epitope-tagging constructs in filamentous fungi. AB - For functional characterization of predicted genes encoding hypothetical proteins in fungal genomes, it is complementary to genetic studies to determine their expression and subcellular localization patterns in different developmental or infection stages. It is also important to identify and characterize other proteins that are physically associated with or functionally related to these genes in vivo by co-immunoprecipitation or affinity purification analyses. In this chapter, we described a set of yeast shuttle vectors and protocols to generate fusion constructs by the yeast gap repair approach. Because of the simplicity and efficiency of yeast gap repair, these vectors and the general methods described in this chapter are suitable for functional genomics studies in filamentous fungi. PMID- 21590424 TI - Large-scale insertional mutagenesis in Magnaporthe oryzae by Agrobacterium tumefaciens-mediated transformation. AB - With genome sequences of more and more fungi become available, high-throughput systematic -mutagenesis is desirable for functional genomics studies. While a number of random insertional mutagenesis and targeted gene disruption approaches have been used in filamentous fungi, Agrobacterium tumefaciens-mediated Transformation (ATMT) remains one of the most effective methods for identifying genes required for specific fungal developmental or infection processes. Because of its simplicity, ATMT is suitable for large-scale insertion mutagenesis in fungi. Magnaporthe oryzae, the rice blast fungus is a model for studying host pathogen interactions. Here, we describe protocols for generating a M. oryzae mutant library consisting of over 70,000 ATMT transformants and for identifying genes -disrupted by T-DNA in the mutants by TAIL-PCR. PMID- 21590425 TI - Molecular methods for studying the Cryphonectria parasitica - hypovirus experimental system. AB - The interaction of the filamentous fungal plant pathogen Cryphonectria parasitica with its virulence-attenuating viruses provides a unique platform to explore the molecular biology and genetics of virus-host interactions. Following the development of transformation procedures for this fungus, subsequent advances include infectious cDNA clones of several members of the Hypoviridae and an imminently complete fungal genome project. Presented here are basic protocols for growth of the organism and the extraction of DNA, RNA, and protein. Additionally, two further protocols are provided for investigations of host protein phosphorylation and for viral genome secondary structure. PMID- 21590426 TI - Metabolic fingerprinting in Fusarium verticillioides to determine gene function. AB - Fusarium verticillioides is a major pathogen of corn and poses a significant risk to human health by producing mycotoxins that accumulate in kernels. Considerable efforts have focused on identifying genes involved in secondary metabolism and pathogenesis. The availability of a sequenced genome accelerates gene discovery and characterization, but functional genomics approaches are hindered when disruption of a gene results in a phenotype that is not readily distinguishable from the wild type. To address this problem, we developed a metabolomics approach to characterize gene function. The technique involves culturing two fungal strains (wild type and a mutant) under identical conditions, extracting as wide a range of metabolites as possible, analyzing the metabolomes by gas chromatography/mass spectrometry, and comparing the unique metabolic fingerprint of each strain. PMID- 21590427 TI - Tapping genomics to unravel ectomycorrhizal symbiosis. AB - Given recent technological advances, we are in a golden era of cell and whole organism research. With the availability of so many sequenced genomes, and the data that has been mined there-in, it is easy to gain the impression that all our work as scientists is complete. Instead, such work and results have now provided oceans of data, but with minimal functional information. We also do not have a full grasp on the working relationships within a number of different plant developmental pathways. This is especially true in the study of the symbiotic interaction between ectomycorrhizal fungi and their plant hosts. One of the current interests in symbiotic and pathogenic interactions between plants and fungi is the role of small, secreted proteins. What makes fungal small secreted proteins so interesting is that only a few of them share sequence homology to any other known proteins, but some may act as effectors modulating plant metabolism and development. Therefore, it is difficult to make predictions as to the action of these proteins without functional analysis. For this reason, we created a pipeline to analyze the role and function of these proteins. Typically, this involves transcriptional analysis of genes followed by protein localization, identification of protein-protein interactions, and functional analysis of the protein through heterologous expression in yeast among many other different procedures. Due to the physiology of mycorrhizal root tips, there are a number of unique challenges that must be overcome to properly study a fungal effector. Here, we outline some of the methods, and hopefully helpful tips, that we are currently using to pursue the study of different effectors in the Laccaria Populus interaction. PMID- 21590428 TI - Delay in the treatment of pulmonary tuberculosis: a report from Afghanistan. AB - OBJECTIVES: The aim of this study was to determine the length of delays and to investigate the factors associated with patient (care-seeking) and health-system (treatment initiation following care-seeking) delays, among smear-positive tuberculosis patients in Kunar province, Afghanistan, as delay in diagnosis and treatment results in more severe disease, higher mortality, and a longer period of infectivity in the community. METHODS: A cross-sectional study of 122 new smear-positive pulmonary tuberculosis patients, aged >=15 years, registered at a hospital and a clinic in Kunar province, was conducted from September 2008 to February 2009 using a structured questionnaire interview. RESULTS: Among the 122 participants, the average patient, health-system, and total delays were 205.2, 150.7, and 356.0 days, respectively. Patient delay was independently associated with an increase in the household size, social stigma linked with tuberculosis (social consequences of having tuberculosis), chest pain, longer time to reach a private health-care facility, initial seeking of alternative services (self treatment with herbs or drugs; obtaining of drugs from pharmacy or drug store; visiting traditional health provider; and visiting community health worker), and initial consultation with a private health-care facility (p < 0.05). The risk of health-system delays increased with multiple visits and with time to reach private health facilities (p < 0.05). The risk of health-system delays decreased as social stigma increased (p < 0.05). CONCLUSIONS: Delays in the initiation of tuberculosis treatment in Kunar province are daunting. Efforts to reduce delays must encourage early visits, reduce tuberculosis-associated stigma, encourage a public-private health-care mix, improve health-care providers' diagnostic capabilities, and encourage active case-finding with recording of symptoms and screening of contacts. PMID- 21590429 TI - Paternal occupational exposures and the risk of congenital malformations--a case control study. AB - OBJECTIVES: This study examined the association between certain paternal occupational exposures during the periconceptional period and the risk of congenital malformations. MATERIALS AND METHODS: A case-control study was carried out from December 2009 to April 2010; on 242 congenital malformation cases and 270 controls. Paternal occupational exposure to certain workplace hazards was assessed by a detailed questionnaire to evaluate the occupational exposure for both fathers and mothers including pesticides, solvents, welding fumes, lead, working with video display terminals (VDTs) and computer monitors. In addition, the questionnaire assessed the presence of other risk factors such as consanguinity, smoking and history of any maternal diseases during the pregnancy with the child. RESULTS: The results revealed that the odds of having a child with congenital malformation was higher (P < 0.01) if the father was occupationally exposed to pesticides (OR: 3.42, 95% CI: 1.97-5.92), solvents (OR: 5.63, 95% CI: 2.77-11.42), or welding fumes (OR: 2.98, 0.99-8.54) during the periconceptional period. However, consanguinity (OR: 1.91, 95% CI: 1.25-2.92) was a risk factor of developing congenital malformations among offspring. CONCLUSION: Control of workplace exposures and adherence to threshold limit values of those hazards should be adopted to minimize the risk of developing congenital malformations among offspring. PMID- 21590430 TI - The influence of single whole body cryostimulation treatment on the dynamics and the level of maximal anaerobic power. AB - OBJECTIVES: The objective of this work was to determine the dynamics of maximal anaerobic power (MAP) of the lower limbs, following a single whole body cryostimulation treatment (WBC), in relation to the temperature of thigh muscles. MATERIALS AND METHODS: The subjects included 15 men and 15 women with an average age (+/- SD) of 21.6 +/- 1.2 years. To evaluate the level of anaerobic power, the Wingate test was applied. The subjects were submitted to 6 WBC treatments at -130 degrees C once a day. After each session they performed a single Wingate test in the 15, 30, 45, 60, 75 and 90th min after leaving the cryogenic chamber. The order of the test was randomized. All Wingate tests were preceded by an evaluation of thigh surface temperature with the use of a thermovisual camera. RESULTS: The average thigh surface temperature (T(av)) in both men and women dropped significantly after the whole body cryostimulation treatment, and next increased gradually. In women T(av) remained decreased for 75 min, whereas in men it did not return to the basal level until 90th min. A statistically insignificant decrease in MAP was observed in women after WBC. On the contrary, a non-significant increase in MAP was observed in men. The course of changes in MAP following the treatment was similar in both sexes to the changes in thigh surface temperature, with the exception of the period between 15th and 30th min. The shorter time to obtain MAP was observed in women till 90th min and in men till 45 min after WBC compared to the initial level. CONCLUSIONS: A single whole body cryostimulation may have a minor influence on short-term physical performance of supramaximal intensity, but it leads to improvement of velocity during the start as evidenced by shorter time required to obtain MAP. PMID- 21590431 TI - Akt/PKB isoforms expression in the human lumbar herniated disc: correlation with clinical and MRI findings. AB - Intervertebral disc (IVD) degeneration suggests a complex process influenced by genetics, lifestyle and biomechanics, which accounts for the development of low back pain (LBP) and lumbar radiculopathy, a major cause of musculoskeletal disability in humans. The family of Akt/PKB kinases is a principal mediator in the signal transduction pathways, which contribute to transcriptional regulation, cell growth, proliferation, apoptosis, and survival ability. The purpose of this study was to evaluate the transcriptional profile of the AKT family genes in human herniated discs and the involvement of the PI3K-Akt signaling pathway in human IVD degeneration. Real-time PCR analysis was used to assess the mRNA expression pattern of the three Akt/PKB isoforms in 63 herniated and 10 control disc specimens. Our results showed a significant positive correlation between AKT1 and AKT3 mRNA in herniated discs suggesting a synergistic action between these isoforms in disc herniation. Interestingly, AKT2 mRNA was up-regulated in patients with acute pain during the first 12 months, indicating that AKT2 transcriptional activation may be associated with acute rather than chronic inflammation and phagocytosis. Finally, Akt1/PKB transcription presented a stepwise activation as disc herniation deteriorated. Our findings provide evidence on the transcriptional activation of the Akt/PKB pathway indicating that it is involved in lumbar disc degeneration. There is need for further studies to elucidate the exact role and down-stream signaling action of Akt/PKB isoforms in the pathogenesis of lumbar disc herniation. PMID- 21590433 TI - Relationship status among parents of children with autism spectrum disorders: a population-based study. AB - Despite speculation about an 80% divorce rate among parents of children with an Autism Spectrum Disorder (ASD), very little empirical and no epidemiological research has addressed the issue of separation and divorce among this population. Data for this study was taken from the 2007 National Survey of Children's Health, a population-based, cross-sectional survey. A total of 77,911 parent interviews were completed on children aged 3-17 years, of which 913 reported an ASD diagnosis. After controlling for relevant covariates, results from multivariate analyses revealed no evidence to suggest that children with ASD are at an increased risk for living in a household not comprised of their two biological or adoptive parents compared to children without ASD in the United States. PMID- 21590432 TI - Can gaze avoidance explain why individuals with Asperger's syndrome can't recognise emotions from facial expressions? AB - Research has shown that individuals with Autism Spectrum Disorders (ASD) have difficulties recognising emotions from facial expressions. Since eye contact is important for accurate emotion recognition, and individuals with ASD tend to avoid eye contact, this tendency for gaze aversion has been proposed as an explanation for the emotion recognition deficit. This explanation was investigated using a newly developed emotion and mental state recognition task. Individuals with Asperger's Syndrome were less accurate at recognising emotions and mental states, but did not show evidence of gaze avoidance compared to individuals without Asperger's Syndrome. This suggests that the way individuals with Asperger's Syndrome look at faces cannot account for the difficulty they have recognising expressions. PMID- 21590434 TI - Access to dental care for low-income adults: perceptions of affordability, availability and acceptability. AB - The objective of this study was to explore access to dental care for low-income communities from the perspectives of low-income people, dentists and related health and social service-providers. The case study included 60 interviews involving, low-income adults (N = 41), dentists (N = 6) and health and social service-providers (N = 13). The analysis explores perceptions of need, evidence of unmet needs, and three dimensions of access--affordability, availability and acceptability. The study describes the sometimes poor fit between private dental practice and the public oral health needs of low-income individuals. Dentists and low-income patients alike explained how the current model of private dental practice and fee-for-service payments do not work well because of patients' concerns about the cost of dentistry, dentists' reluctance to treat this population, and the cultural incompatibility of most private practices to the needs of low-income communities. There is a poor fit between private practice dentistry, public dental benefits and the oral health needs of low-income communities, and other responses are needed to address the multiple dimensions of access to dentistry, including community dental clinics sensitive to the special needs of low-income people. PMID- 21590435 TI - Protective effects of vitamin E against hypercholesterolemia-induced age-related diseases. AB - Hypercholesterolemia is a major risk factor for age-related diseases such as atherosclerosis and Alzheimer's disease (AD). Changes in human plasma cholesterol levels results from the interaction between multiple genetic and environmental factors. The accumulation of excess cholesterol in blood vessels leads to atherosclerosis. Many studies on this field show that differential expression of oxidative stress-related proteins, lipid metabolism-related enzymes, and receptors response to atherogenic diet. Additionally, excess brain cholesterol has been associated with increased formation and deposition of amyloid-beta peptide from amyloid precursor protein which may contribute to the risk and pathogenesis of AD. To consider genetically, more than 50 genes have been reported to influence the risk of late-onset AD. Some of these genes might be also important in cholesterol metabolism and transport. Epidemiological studies have shown an association between high intake and high serum concentrations of antioxidant vitamins like vitamin E and lower rates of ischemic heart diseases. It has been known that vitamin E also inhibits smooth muscle cell proliferation by non-antioxidant mechanism. On the basis of the previous results, vitamin E has been accepted as an important protective factor against hypercholesterolemia induced age-related diseases. PMID- 21590436 TI - Metabolism of tocotrienols in animals and synergistic inhibitory actions of tocotrienols with atorvastatin in cancer cells. AB - Tocotrienols (T3s), members of the vitamin E family, exhibit potent anti-cancer, anti-oxidative, anti-inflammatory, and some other biological activities. To better understand the bioavailability and metabolism of T3s, T3s and their metabolites were identified in urine and fecal samples from mice on diet supplemented with mixed T3s using HPLC/electrochemical detection and liquid chromatography electrospray ionisation mass spectrometry (LC-ESI-MS). Whereas the short-chain metabolites carboxyethyl hydroxychromans (CEHCs) and carboxymethylbutyl hydroxychromans (CMBHCs) were the major metabolites of T3s, several new metabolites with double bonds were also identified. Similar to tocopherols, the majority of T3 metabolites were excreted as sulfate/glucuronide conjugates in mouse urine. The distribution of gamma- and delta-T3 and gamma-T3 metabolites were also determined in different organs as well as in urine and fecal samples from mice on diets supplemented with corresponding T3s. The synergistic anti-cancer actions of gamma-T3 and atorvastatin (ATST) were studied in HT29 and HCT116 colon cancer cell lines. The combination greatly potentiated the ability of each individual agent to inhibit cancer cell growth and to induce cell cycle arrest and apoptosis. The triple combination of gamma-T3, ATST, and celecoxib exhibited synergistic actions when compared with any double combination plus the third agent. Mechanistic studies revealed that the synergistic actions of gamma-T3 and ATST could be attributed to their mediation of 3-hydroxy-3-methyl glutaryl-CoA reductase, and the subsequent inhibition of protein geranylgeranylation. It remains to be determined whether such a synergy occurs in vivo. PMID- 21590437 TI - Lung ultrasonography for the assessment of rapid extravascular water variation: evidence from hemodialysis patients. AB - Chest ultrasonography is a useful tool to assess extravascular lung water at bedside. In presence of interstitial-alveolar imbibition, vertical artifacts arising from the pleura are detected; these are called B-lines. Although a positive linear correlation between B-lines and extravascular lung water has been shown in symptomatic heart failure patients, the subclinical phase of pulmonary imbibition and the clearance of B-lines after rapid body fluid removal have been less investigated. The aim of this study was to assess if chest ultrasound could detect lung water imbibition and its variations induced by dialysis, an experimental model of controlled rapid fluid loss. Forty-one patients undergoing hemodialysis were studied. Total number of B-lines from ultrasound chest scanning and vena cava diameters were measured before and after treatment. Before dialysis, most of the patients presented ultrasound signs of pulmonary imbibition despite the absence of dyspnea; the number of B-lines was associated with the accumulated weight before treatment (p < 0.05) as well as with the residual weight after dialysis (p < 0.01); B-lines and end-inspiratory and end-expiratory vena cava diameters were also significantly reduced after dialysis. Moreover, B lines reduction was significantly related to weight loss. Ultrasound performed at the bedside can detect lung water and intravascular overload and their reduction after dialysis in yet asymptomatic patients. These observations add further evidence regarding the use of lung ultrasound and inferior vena cava measurement in estimating volume overload and monitoring the response to therapy both in hemodialysis and congestive heart failure patients. PMID- 21590438 TI - Emerging problems regarding severity assessment and treatment strategies for patients with pneumonia: controversies surrounding the HCAP concept. PMID- 21590439 TI - A pharmacoepidemiological study of the multi-level determinants, predictors, and clinical outcomes of biosimilar epoetin alfa for renal anaemia in haemodialysis patients: background and methodology of the MONITOR-CKD5 study. AB - Prior longitudinal observational studies have examined the practice patterns and outcomes of anaemia management, including the use of erythropoiesis-stimulating agents (ESAs). Several dimensions of effectiveness remain unaddressed; especially considering the revised ESA label (target Hb levels between 10 and 12 g/dL), the recently published TREAT study, and the European approval of the first ESA biosimilar (HX575). Anecdotal evidence suggests that patient outcomes are influenced by physician-related variables and whether anaemia management is congruent with practice guidelines, but this has not been studied systematically. MONITOR-CKD5 is an international, prospective, observational, pharmacoepidemiological study evaluating the multi-level factors and outcomes of treatment with HX575 for renal anaemia in haemodialysis patients. Driven by a novel, integrated, multi-focal framework for post-approval observational studies, it examines determinants of response at both the patient and the physician level; integrates an advocated statistical methodology here to fore used mainly in the social and behavioural sciences; assesses factors potentially predictive of a poor treatment response; and evaluates the extent to which treatment is congruent with evidence-based guidelines, good practice evidence, and the revised ESA label. This pan-European study will recruit at least 1,000 patients from a minimum of 75 centres, and follow them for up to 24 months following initiation of anaemia management with biosimilar epoetin alfa. MONITOR-CKD5 will not only study the core issues addressed by prior observational studies but also aims to take knowledge discovery a step further by assessing outcomes across varying cohorts of patients, and examining the impact of evidence-based practice on clinical outcomes, differentiating, in the process, between physician-level and patient-level determinants. PMID- 21590440 TI - Retinal vein occlusion: time for action has come. PMID- 21590441 TI - The Nyhus-Wantz lectureship: etiology, herniosis, diverticulosis coli, and cancer. AB - The Nyhus-Wantz Lectureship honors two giants who represent the few who formed a new surgical specialty: herniology. My topics are etiology, herniosis, diverticulosis coli, and cancer. Hippocrates blamed wear and tear for herniation. Russell's (Lancet 1:1519-1523, 1902) explanation was congenital peritoneal "buds" extending down to the pelvis. Harrison (Arch Surg 4:680-689, 1922) attributed herniae to transversalis fascial degradation. Keith (Lancet 2(17):1398-1399, 1906) concluded that pathology was involved, even though Russell (Lancet 1:1519 1523, 1902) had denied it. Nevertheless, the congenital theory prevailed. According to McVay (Christopher's textbook of surgery, W.B. Saunders, Philadelphia, 1960, p. 159), defects arise in normal musculo-aponeurotic structures. Research showed that atrophy was caused by damaged fibroblasts producing less collagen, which was abnormal (having a reduced I/III ratio). The disease was systemic, later named herniosis. Nicotine addiction increased the incidence of herniation by an inflammatory process named metastatic emphysema. In 1948, Saint's Triad, an aggregation of hiatus hernia (later, any primary hernia), gallstones, and diverticulosis coli, was introduced. This association occurred eight times more often than expected, with herniosis appearing to be its cause, abetted by high blood cholesterol causing gallstones. In 2006, Krones et al. (Int J Colorectal Dis 21:18-24, 2006) provided evidence that colon cancer is accompanied by a reduction in diverticula. Klinge et al. (Hernia 8(4):300-301, 2004) showed that these entities require different extracellular matrices (ECMs). Ghajar and Bissell (Histochem Cell Biol 130:1105-1118, 2008) pointed out that the ECM, which comprises 80% of the breast, influences its epithelial genetic expression, likewise with other organs (kidney, skin, lung, colon, and ovaries). Recently, a fundamental change in our understanding of cancer growth and metastasis has taken place. Whereas the degradation of connective tissue was thought to encourage invasion, eliciting concern for the herniated, now, investigators report the reverse, a reactive vascularized stroma resembling wound healing with an increase in fibroblasts and collagen I. Words such as desmoplasia, fibrosis, and stiffening abound. In conclusion, degradation of the ECM may be why herniosis appears to be hostile to the development of cancer throughout the body. Studies are needed of patients with and without a history of hernia to determine their incidence of cancer. Data from smokers should be separated, since they carry their own high risk of malignancy. PMID- 21590442 TI - Non-erotic thoughts and sexual functioning. AB - This study sought to replicate and extend investigations of current models of sexual dysfunction (Barlow, 2002; Janssen, Everaerd, Spiering, & Janssen, 2000) which implicate factors such as spectatoring, failure to use ameliorative strategies, and information processing biases in the development and persistence of sexual difficulties. A sample of 165 (n = 71 men) undergraduates completed measures of sexual dysfunction and relationship satisfaction, and reported on the content and frequency of non-erotic thoughts during sex with a partner (i.e., spectatoring), the emotional impact of non-erotic thoughts, and the strategies used to manage them. They also reported on their main sexual functioning difficulties and the strategies they used to manage those difficulties. Finally, participants were presented with a series of hypothetical sexual scenarios and were asked to report their immediate interpretation of events in the scenario. The content of non-erotic thoughts was similar to previous work (Purdon & Holdaway, 2006), although gender differences in thought content were less pronounced. As in previous research, greater frequency of, and anxiety evoked by, non-erotic thoughts was associated with poorer sexual functioning, but we found that this was over and above relationship satisfaction. Participants both high and low in sexual functioning reported using a variety of strategies to manage their non-erotic thoughts, thought suppression being the least effective, and also used a variety of strategies to manage sexual difficulties. Poorer sexual functioning was associated with more negative interpretations of ambiguous sexual scenarios, but this was mediated by relationship satisfaction. However, positive interpretations were predicted by sexual functioning. Results were discussed in terms of their theoretical and clinical implications. PMID- 21590443 TI - Maximizing benefits from riparian revegetation efforts: local- and landscape level determinants of avian response. AB - With limited financial resources available for habitat restoration, information that ensures and/or accelerates success is needed to economize effort and maximize benefit. In the Central Valley of California USA, riparian habitat has been lost or degraded, contributing to the decline of riparian-associated birds and other wildlife. Active restoration of riparian plant communities in this region has been demonstrated to increase local population sizes and species diversity of landbirds. To evaluate factors related to variation in the rate at which bird abundance increased after restoration, we examined bird abundance as a function of local (restoration design elements) and landscape (proportion of riparian vegetation in the landscape and riparian patch density) metrics at 17 restoration projects within five project areas along the Sacramento River. We developed a priori model sets for seven species of birds and used an information theoretic approach to identify factors associated with the rate at which bird abundance increased after restoration. For six of seven species investigated, the model with the most support contained a variable for the amount of riparian forest in the surrounding landscape. Three of seven bird species were positively correlated with the number of tree species planted and three of seven were positively correlated with the planting densities of particular tree species. Our results indicate that restoration success can be enhanced by selecting sites near existing riparian habitat and planting multiple tree species. Hence, given limited resources, efforts to restore riparian habitat for birds should focus on landscape-scale site selection in areas with high proportions of existing riparian vegetation. PMID- 21590444 TI - Gene polymorphisms, pharmacokinetics, and hematological toxicity in advanced non small-cell lung cancer patients receiving cisplatin/gemcitabine. AB - BACKGROUND: This study quantified the impact of drug pathway-associated genetic variants on the pharmacokinetics (PK) of gemcitabine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Thirty-seven patients with advanced NSCLC were sampled for plasma concentrations of gemcitabine, difluoro-deoxy uridine (dFdU), intracellular gemcitabine triphosphates (dFdCTP), and unbound platinum concentrations after gemcitabine 1,250 mg/m(2) i.v. followed by cisplatin 75 mg/m(2). We analyzed 13 germline single nucleotide polymorphisms and one deletion-glutathione S-transferase (GST) M1-within six drug pathway associated genes (GSTM1, GSTP1, cytidine deaminase (CDA), solute carrier (SLC) 28A1, SLC28A2, and deoxycytidine kinase). PK models were fitted to the data using nonlinear mixed-effects modeling, and genetic data were tested on drug PK and hematological toxicity. RESULTS: Patients carrying the nonsynonymous CDA SNP 79A >C (CDA*2) had a 21% lower gemcitabine clearance as compared to wild-type patients (outcomes and complications.0.0009), but the risk for chemotherapy associated neutropenia (61% vs. 32%, P = 0.07) and severe neutropenia (17% vs. 5%, P = 0.26) was not significantly higher. Other gene polymorphisms were not associated with drug PK parameters or hematological toxicity. The known functional mutant variant CDA*3 was not found in any of the patients. CONCLUSIONS: Although the mutant CDA*2 allele results in an increased exposure to gemcitabine in Caucasian patients, this study gives no definite conclusion on the clinical relevance of this finding. Further studies should look into the relationship between CDA genotypes, plasmatic CDA activity, and clinical outcome in patients receiving gemcitabine-based chemotherapy. PMID- 21590445 TI - Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants. AB - PURPOSE: Folate-metabolizing single-nucleotide polymorphisms (SNPs) are emerging as important pharmacogenetic prognostic determinants of the response to chemotherapy. With high doses of methotrexate (MTX) in the consolidation phase, methylenetetrahydrofolate reductase (MTHFR) polymorphisms could be potential modulators of the therapeutic response to antifolate chemotherapeutics in identifying a possible correlation with the outcome. This study aims to analyse the potential role of the MTHFR C677T and A1298C genetic variants in modulating the clinical toxicity and efficacy of high doses of MTX in a cohort of paediatric ALL patients (n = 151) treated with AIEOP protocols. METHODS: This work includes DNA extraction by slides and RFLP-PCR. RESULTS: The first observation relative to early toxicities (haematological and non-haematological), after the first doses of MTX in all protocols, was an association between the 677T and 1298C carriers and global toxicity. We found that in the 2 g/m(2) MTX group, patients harbouring 677TT homozygously exhibited a substantial 12-fold risk of developing toxicity. In this study, we demonstrate that the MTHFR 677TT variant is associated with an increased risk of relapse when compared to other genotypes. The Kaplan-Meier analysis showed that the 677TT variant had a lower 7-year DFS(disease-free survival) probability compared to the 677C carrier genotype (log-rank test P = 0.003) and OS (overall survival) and also confirms the lower probability of survival for patients with the 677TT variant (log-rank test, P = 0.006). CONCLUSIONS: Our study provides further evidence of the critical role played by folate pathway enzymes in the outcome of ALL, possibly through the interference of MTX. PMID- 21590446 TI - Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients. AB - PURPOSE: There is significant inter-patient variability in the pharmacokinetics of pegylated liposomal doxorubicin (PLD). Identification of factors affecting the pharmacokinetics of PLD would enable personalization of therapy. We previously reported that age, gender, body composition, and monocytes affect the clearance of other liposomal agents. Therefore, we evaluated how these factors affect the pharmacokinetics of PLD. METHODS: Pharmacokinetic studies of PLD were performed as part of phase I and II studies in 70 patients with solid tumors or Kaposi's sarcoma. The effects of monocyte count, age, gender, and body composition on PLD clearance were examined. RESULTS: There was a 15.3-fold variability in PLD clearance. Body surface area-based dosing did not significantly reduce the variability in PLD clearance. The mean +/- SD clearance for patients <60 years old and >=60 years old were 54.6 +/- 28.5 and 23.3 +/- 10.8 mL/h/m(2), respectively (P < 0.0001), and for female and male patients were 23.7 +/- 18.8 and 55.6 +/- 26.8 mL/h/m(2), respectively (P < 0.0001). A reduction in pre-cycle monocyte count was associated with a greater reduction in PLD clearance. CONCLUSIONS: Age, gender, and monocyte counts appear to correlate with PLD clearance. Further investigation of the association between these factors, PLD pharmacokinetics, and clinical outcomes (efficacy and toxicity) is warranted. These effects on the pharmacokinetics of PLD may be an approach for personalizing PLD therapy and may affect other pegylated liposomes and nanoparticle agents. PMID- 21590447 TI - A phase I trial of oral metronomic vinorelbine plus capecitabine in patients with metastatic breast cancer. AB - PURPOSE: To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTD) of oral metronomic vinorelbine with capecitabine in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Escalated doses of oral metronomic vinorelbine (starting dose 30 mg) every other day continuously and capecitabine (starting dose 800 mg/m(2) bid) on days 1-14 every 21 days were administered. DLTs were evaluated during the first cycle. RESULTS: Thirty-six women were enrolled at eight escalating dose levels. For twenty-four patients, treatment was first line, for eight second line, and for four third line. The DLT level was reached at oral metronomic vinorelbine 70 mg and capecitabine 1,250 mg/m(2), and the recommended MTD doses are vinorelbine 60 mg and capecitabine 1,250 mg/m(2). DLTs were febrile neutropenia grade 3 and 4, diarrhea grade 4, and treatment delays due to unresolved neutropenia. There was no treatment-related death. The main toxicities were grade 2-3 neutropenia in 16.6% of patients each, grade 2-3 anemia 16.5%, grade 2-4 fatigue 27.5%, grade 2 3 nausea/vomiting 11%, and grade 3-4 diarrhea 8.2%. Two complete and 10 partial responses were documented. CONCLUSION: Oral metronomic vinorelbine with capecitabine is a well-tolerated and feasible regimen that merits further evaluation in MBC. PMID- 21590448 TI - Pharmacokinetics of orally administered uracil in healthy volunteers and in DPD deficient patients, a possible tool for screening of DPD deficiency. AB - PURPOSE: Dihydropyrimidine dehydrogenase (DPD) deficiency can lead to severe toxicity in patients treated with standard doses of 5-fluorouracil (5-FU). Oral uracil administration and subsequent measurement of uracil and dihydrouracil (DHU) plasma concentrations might detect patients with DPD deficiency. This study compares the pharmacokinetics of uracil and DHU after oral uracil administration in subjects with normal and deficient DPD status. METHODS: Five hundred milligrams of uracil per metre square was administered orally to 11 subjects with normal DPD status and to 10 subjects with reduced DPD activity. Repeated administration (n = 3) of this dose was performed in 4 subjects, and 1,000 mg uracil/m(2) was administered to 4 subjects to assess intra-individual variation and linearity of pharmacokinetics. RESULTS: In subjects with normal DPD status, 500 mg/m(2) uracil resulted in uracil C (max) levels of 14.4 +/- 4.7 mg/L at T (max) = 30.0 +/- 11.6 min, and in DPD-deficient subjects, 20.0 +/- 4.5 mg/L at 31.5 +/- 1.1 min. The uracil AUC(0>180) was 31.2 +/- 5.1 mg L/h in DPD-deficient subjects, which was significantly higher (P < 0.05) than in the subjects with normal DPD status (13.8 +/- 3.9 mg L/h). Repeated uracil dosing showed reproducible uracil PK in subjects with normal DPD status, and dose elevation of uracil suggested linear pharmacokinetics. CONCLUSION: The pharmacokinetics of uracil differs significantly between subjects with a normal DPD activity and those with a deficient DPD status. The AUC and C (max) of uracil can be useful as a diagnostic tool to differentiate patients with regard to DPD status. PMID- 21590449 TI - Population pharmacokinetics of PM00104 (Zalypsis((r))) in cancer patients. AB - OBJECTIVE: The aim of this study was to characterize the population pharmacokinetics of PM00104 (Zalypsis((r))) in cancer patients. METHODS: A total of 135 patients included in four phase I clinical trials who receive intravenous PM00104 at doses ranging from 53 to 5,000 MUg/m(2) and administered as 1-, 3-, or 24-h infusion every 3 weeks or as 1-h infusion on days 1, 8, and 15 of a 28-day cycle, or 1-h infusion daily during 5 consecutive days every 3 weeks were included in the analysis. Pharmacokinetic data were analyzed with non-linear mixed effect model using NONMEM VI software. The effect of selected patient covariates on PM00104 pharmacokinetics was investigated. Model evaluation was performed using predictive checks and non-parametric bootstrap. RESULTS: An open four-compartment catenary linear model with first-order elimination was developed to best describe the data. Plasma clearance and its between-subject variability was 43.7 L/h (34%). Volume of distribution at steady state was 822 L (117%). Within the range of covariates studied, age, sex, body size variables, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, lactate dehydrogenase, creatinine clearance, albumin, total protein, hemoglobin, performance status, liver metastases, dose-limiting toxicity, and stable disease for 3 months were not statistically related to PM00104 pharmacokinetic parameters. Bootstrap and posterior predictive check evidenced the model was deemed appropriate to describe the time course of PM00104 plasma concentrations in cancer patients. CONCLUSIONS: The integration of phase I pharmacokinetic data demonstrated PM00104 linear elimination from plasma, dose proportionality up to 5,000 MUg/m(2), and time-independent pharmacokinetics. No clinically relevant covariates were identified as predictors of PM00104 pharmacokinetics. PMID- 21590450 TI - Recurrence rates and prognostic factors in ypN0 rectal cancer after neoadjuvant chemoradiation and total mesorectal excision. AB - BACKGROUND: Neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy is typically recommended for patients with locally advanced rectal cancer. Patients with pathologically node-negative tumors have an improved prognosis, but recurrence patterns and independent prognostic factors in these patients have been incompletely characterized. METHODS: Using a retrospective cohort study design, we included all rectal cancer patients treated with neoadjuvant chemoradiation and curative surgery from 1993 through 2003, who had ypN0 tumors. We characterized recurrence rates and patterns in patients not treated with adjuvant chemotherapy. Secondarily, we compared them to patients who did receive adjuvant treatment and assessed for independent prognostic factors, using univariate and multivariable survival analyses. RESULTS: Overall, 324 ypN0 patients (ypT0: n = 73; ypT1-2: n = 130; ypT3-4: n = 120) were followed for a median of 5.8 years. The risk of recurrence was associated with pathologic stage 2.7% ypT0, 12.3% ypT1-2, 24.2%ypT3-4. Five-year recurrence-free survival in patients who did not receive adjuvant treatment was 100% (ypT0), 84.4% (ypT1-2) and 75% (ypT3-4). There was no significant difference in 5-year recurrence-free survival between patients who did and did not receive adjuvant treatment. In multivariable analysis, pathologic stage was the factor most strongly associated with recurrence (hazard ratio 3.6 for ypT3-4 vs. ypT0-2, 95% confidence interval 1.9-6.7, P < 0.0001). CONCLUSIONS: The recurrence rates for selected patients with ypT0-2N0 rectal cancer after neoadjuvant chemoradiation and total mesorectal excision are low. Although standard practice remains completion of planned postoperative adjuvant chemotherapy for all patients undergoing chemoradiation, these data suggest prospective trials may be warranted to measure the benefit of adjuvant chemotherapy in favorable subgroups, such as ypT0-2N0. PMID- 21590451 TI - Towards more effective liver allocation criteria for hepatocellular carcinoma: tumor response to locoregional therapy. PMID- 21590452 TI - Early-onset colorectal cancer is an easy and effective tool to identify retrospectively Lynch syndrome. AB - BACKGROUND AND OBJECTIVES: Early age of onset is a marker of a possible hereditary component in colorectal cancer (CRC). We evaluated whether early age of onset is a good marker to identify Lynch syndrome, especially retrospectively, and if there is any other feature that could improve this identification. METHODS: We selected patients with CRC aged 45 years or younger from the pathological reports of three different institutions and different periods of time. Clinical information, family history, and tumor samples were obtained. Cases were classified according to mismatch repair (MMR) proficiency. RESULTS: Of 133 tumors, 22 showed microsatellite instability (MSI). In 15 MSI cases, a germline mutation in 1 of the MMR genes was identified, 7 of which were not identified before. The positive predictive value (PPV) of right colon CRC for a positive genetic MMR test is 30.6%, whereas "signet ring" cells and fulfillment Amsterdam II criteria have PPVs of 42.9% and 47.8%, respectively. Combining right sided CRC with mucin production, with fulfilling Amsterdam II criteria, or with "signet ring" cells, PPVs are 54.5, 64.3, and 100%. The probability of the absence of a mutation when CRC is located in the left colon is 94.7%, whereas absence of aggregation for Lynch-related neoplasm has a 100% probability. CONCLUSIONS: Early age of onset is an effective method to identify retrospectively Lynch syndrome. Taking into account the location and histology features of the tumor, and the familial history of the cases, we notably increase the a priori probability of detecting a germline MMR mutation. PMID- 21590453 TI - MRI predictive factors for long-term outcomes of low rectal tumours. AB - BACKGROUND: Low rectal cancers have poor outcomes. It has been suggested that low tumours are biologically more aggressive and tend to be more locally advanced at presentation. Pre-operative identification of prognostic factors will enable use of selective neoadjuvant therapies and possibly increase sphincter-sparing rates where oncologically safe. METHODS: A subset of 101 patients with low rectal cancer (within 5 cm of the anal verge) in a multicentre trial were studied. MRI images were reviewed by a senior radiologist, blinded to outcome. MRI-predicted tumour spread and MRI tumour regression grade (TRG) were analysed for 5-year recurrence and survival rates using a Cox regression model. RESULTS: On univariate analysis, advanced MRI low rectal tumour stage correlated with greater incidence of recurrence (p=0.013) and death (p=0.029) compared with earlier stage tumours. Good MRI TRG score (good response to pre-operative therapy) correlated with significantly reduced tumour recurrence rates (p=0.008) and increased survival (p=0.008) versus the poor MRI TRG score group. On multivariate analysis, good MRI TRG score was associated with reduced recurrence (p=0.003) but not survival rates. CONCLUSIONS: This study confirms that MRI can be used to predict patients at increased risk of recurrence following surgery in low rectal cancer. This information can be used to direct pre-operative therapies and plan operative strategies. This is the first study to confirm the association between MRI TRG and long-term outcome. Poor response to neoadjuvant therapy can be used to plan use of further therapies prior to surgery to attempt to improve outcome. PMID- 21590454 TI - Clinically relevant biomarkers to select patients for targeted inhibitor therapy after resection of hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a vascular tumor that proliferates through angiogenic pathways mediated, in part, by vascular endothelial growth factor receptor 2 (VEGFR2), and platelet-derived growth factor receptor (PDGFR) alpha and beta. We hypothesized that overexpression of these proteins is associated with decreased survival after resection. METHODS: A total of 57 patients, with available tissue for analysis, who underwent liver resection for HCC between August 2000 and March 2008 at a single institution were identified from a prospectively maintained database. Tumor specimens were assessed with immunohistochemistry for VEGFR2, PDGFR-alpha, and PDGFR-beta expression and were graded by an experienced pathologist. Primary outcome was overall survival (OS). RESULTS: Median patient age was 64 years; 65% (n=37) were male. Median follow-up was 24.5 months, and median OS was 25.5 months. Median tumor size and number were 7 cm and 1, respectively. Macro and microvascular invasion was present in 9% (n=5) and 42% (n=24) of patients, respectively. Seventy-five percent of patients had tumors exceeding Milan criteria. 9% had positive resection margins. Thirty five percent of patients had cirrhosis and the median nonadjusted Model for End Stage Liver Disease (MELD) score was 7.5. Tumors exhibited differential expression of VEGFR2 (low: 79%, high: 21%), PDGFR-alpha (low: 93%, high: 7%), and PDGFR-beta (low: 96%, high: 4%). After excluding all 30-day deaths (n=7), high PDGFR-alpha and PDGFR-beta expression were independently associated with decreased OS (8.7 vs 29.1 months, P=0.01; 2.8 vs 28.8 months, P<0.001; respectively). High VEGFR2 expression displayed a trend toward decreased OS (20.8 vs 27.5 months, P=0.2). When adjusted for tumor burden, vascular invasion, margin status, and MELD score on independent multivariate analyses, both PDGFR-alpha and -beta high expression were independently associated with decreased survival. CONCLUSIONS: High expression of PDGFR-alpha and PDGFR-beta may be independently associated with decreased OS irrespective of margin status, MELD score, and tumor extent. This finding may help to select patients who would benefit from targeted inhibitor therapy in the adjuvant setting. PMID- 21590455 TI - Viable tumor tissue adherent to needle applicators after local ablation: a risk factor for local tumor progression. AB - BACKGROUND: Local tumor progression (LTP) is a serious complication after local ablation of malignant liver tumors, negatively influencing patient survival. LTP may be the result of incomplete ablation of the treated tumor. In this study, we determined whether viable tumor cells attached to the needle applicator after ablation was associated with LTP and disease-free survival. METHODS: In this prospective study, tissue was collected of 96 consecutive patients who underwent local liver ablations for 130 liver malignancies. Cells and tissue attached to the needle applicators were analyzed for viability using glucose-6-phosphate dehydrogenase staining and autofluorescence intensity levels of H&E stained sections. Patients were followed-up until disease progression. RESULTS: Viable tumor cells were found on the needle applicators after local ablation in 26.7% of patients. The type of needle applicator used, an open approach, and the omission of track ablation were significantly correlated with viable tumor tissue adherent to the needle applicator. The presence of viable cells was an independent predictor of LTP. The attachment of viable cells to the needle applicators was associated with a shorter time to LTP. CONCLUSIONS: Viable tumor cells adherent to the needle applicators were found after ablation of 26.7% of patients. An independent risk factor for viable cells adherent to the needle applicators is the omission of track ablation. We recommend using only RFA devices that have track ablation functionality. Adherence of viable tumor cells to the needle applicator after local ablation was an independent risk factor for LTP. PMID- 21590456 TI - Sudden death from superior mesenteric artery thrombosis in a cocaine user. AB - Cocaine-mediated tissue injury is well established, particularly myocardial ischemia and infarction. Gastrointestinal complications including mesenteric ischemia, ischemic colitis and intestinal perforation occur less frequently. Cocaine-induced visceral arterial thrombosis is a rare finding. We report a case of a 49-year-old chronic cocaine user with superior mesenteric artery (SMA) thrombosis. The patient presented with a 24-h history of abdominal pain, nausea and vomiting. Physical examination documented tachycardia and a soft, non-rigid abdomen with voluntary guarding. Abdominal X-ray did not show any evidence of peritoneal free air or bowel obstruction. Laboratory investigations revealed elevated white blood cells and a high anion gap; a blood gas analysis was not done. Three hours after initial presentation, the patient had a cardiac arrest and died. At autopsy, the jejunum was ischemic, without obvious infarction. The SMA was occluded at its origin by significant atherosclerosis with superimposed thrombus. The myocardium had fibrosis, without acute infarction, and severe triple coronary artery atherosclerosis. Toxicological blood analysis confirmed cocaine use. This report emphasizes the need to consider chronic stimulant drug abuse in accelerated atheroma and thrombosis of visceral arteries. PMID- 21590457 TI - Re-oxygenation of post-mortem lividity by passive diffusion through the skin at low temperature. AB - Post-mortem hypostasis develops due to passive settling of the blood under the effect of gravity after death. Due to consumption of oxygen in the tissues by residual cellular activity after the circulation has stopped, lividity is composed of deoxygenated blood. It has been previously shown that cooling of a body causes lividity to oxygenate, changing from a dark red/blue to a pink/red color, due to hemoglobin's increased affinity for oxygen at low temperature. This study has confirmed that this occurs by passive diffusion through the skin, but that this can only occur within a limited time frame. The reasons for this process and its potential forensic application require further investigation. PMID- 21590458 TI - Open versus minimally invasive esophagectomy: what is the best approach? Frame the issue. AB - Surgical resection continues to be the gold standard treatment approach for early invasive and locoregional esophageal cancer. Esophagectomy has historically had a reputation as a complex operation with high mortality and morbidity. Increasingly, results from high-volume specialized centers have demonstrated that mortality rates of below 4% should be expected and that patients can potentially demonstrate excellent levels of quality of life following surgical resection. Up until recently, virtually all surgical resections were done utilizing an open approach utilizing either a transthoracic or a transhiatal operation. Over the past several years, however, a variety of fully minimally invasive or hybrid procedures have been advocated with a view of improving mortality and morbidity outcomes. In the absence of either randomized or controlled prospective comparisons, this series of papers will review current perceptions of the advantages of both minimally invasive and open surgery for the treatment of esophageal cancer. PMID- 21590459 TI - Overexpression of matrix metalloproteinase-21 is associated with poor overall survival of patients with colorectal cancer. AB - INTRODUCTION: Matrix metalloproteinase-21 (MMP-21) is a member of the MMP family, which is overexpressed in some solid tumors and is thought to enhance the tumor invasion and metastasis ability. The aim of the present study is to examine the MMP-21 expression in human colorectal cancer and normal colorectal tissue using tissue microarray technique and to determine its association with clinicopathological characteristics and prognostic value. MATERIALS AND METHODS: Four array blocks including 256 cases of colorectal cancer and adjacent normal tissues were investigated by immunohistochemistry assay. Staining evaluation results were analyzed statistically in relation to various clinicopathological characters and overall survival. RESULTS: High level of MMP-21 expression was detected in colorectal cancer, significantly more than in normal colorectal epithelial cells. In colorectal cancer, MMP-21 was significantly positively correlated with depth of invasion, lymph node metastasis, and distant metastasis. The overall survival rate was significantly lower for patients with MMP-21 positive than those with MMP-21 negative tumors. However, no correlations between MMP-21 expression and patients' age, sex tumor location, or differentiation status were detected. CONCLUSION: Our findings emphasize the important role of MMP-21 in the invasion and metastasis process in human colorectal cancer. It might also serve as a novel prognostic marker that is independent of, and additive to, the TNM staging system. PMID- 21590460 TI - History, goals, and technique of laparoscopic pancreatic necrosectomy. AB - The surgical treatment of severe acute pancreatitis has significantly changed in the last several years with the advent of enhanced imaging techniques and minimally invasive surgery. Criteria for surgical intervention have been influenced by the use of step-up approaches that provide incremental multimodality interventions with repeat imaging. Here, we provide a brief introduction to the history, goals, indications, and technique of laparoscopic pancreatic necrosectomy. The technique requires a fundamental understanding of the natural history of pancreatitis and its complication. Laparoscopic approaches can be useful as primary and adjunctive therapy for the treatment of infected pancreatitic necrosis. PMID- 21590461 TI - [On the importance of health services research: an overview]. AB - In Germany, health services research has become an important area of research. Health services research is a multidisciplinary field of scientific investigation that studies central problems of health care to increase knowledge and understanding and provide solutions for those problems. The paper aims to demonstrate the value of health services research for health care practitioners by defining its central tasks, by describing the development of this research field in Germany and by deriving future challenges for health services researchers. PMID- 21590462 TI - On the representation of intentions: do personally relevant consequences determine activation? AB - The intention-superiority effect describes shorter latencies for reactions to stimuli intended for future enactment, relative to stimuli associated with no enactment or canceled enactment. Previous attempts to demonstrate an intention superiority effect for other types of tasks--for instance, observing the experimenter executing actions--have not yielded an intention-superiority effect. A reason for this could be that the typical enactment task was associated with a higher degree of personal relevance than were other laboratory-based tasks and that task importance or its consequences heighten the accessibility of intention relevant materials. In two experiments, we demonstrate an intention-superiority effect for different types of tasks (e.g., monitoring a video clip) when task realization has personally relevant consequences in terms of a performance evaluation. In contrast, we found no intention-superiority effect when future enactment had no personally relevant consequences for participants. These findings imply that the intention-superiority effect is not restricted to actions but occurs generally for relevant plans. PMID- 21590463 TI - Is there an urban advantage in child survival in sub-saharan Africa? Evidence from 18 countries in the 1990s. AB - Evidence of higher child mortality of rural-to-urban migrants compared with urban nonmigrants is growing. However, less attention has been paid to comparing the situation of the same families before and after they migrate with the situation of urban-to-rural migrants. We use DHS data from 18 African countries to compare child mortality rates of six groups based on their mothers' migration status: rural nonmigrants; urban nonmigrants; rural-to-urban migrants before and after they migrate; and urban-to-rural migrants before and after they migrate. The results show that rural-to-urban migrants had, on average, lower child mortality before they migrated than rural nonmigrants, and that their mortality levels dropped further after they arrived in urban areas. We found no systematic evidence of higher child mortality for rural-to-urban migrants compared with urban nonmigrants. Urban-to-rural migrants had higher mortality in the urban areas, and their move to rural areas appeared advantageous because they experienced lower or similar child mortality after living in rural areas. After we control for known demographic and socioeconomic correlates of under-5 mortality, the urban advantage is greatly reduced and sometimes reversed. The results suggest that it may not be necessarily the place of residence that matters for child survival but, rather, access to services and economic opportunities. PMID- 21590464 TI - Prevention of type 2 diabetes and its complications in developing countries: a review. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a significant global public health problem affecting more than 285 million people worldwide. Over 70% of those with T2DM live in developing countries, and this proportion is increasing annually. Evidence suggests that lifestyle and other nonpharmacological interventions can delay and even prevent the development of T2DM and its complications; however, to date, programs that have been specifically adapted to the needs and circumstances of developing countries have not been well developed or evaluated. PURPOSE: The purpose of this article is to review published studies that evaluate lifestyle and other non-pharmacological interventions aimed at preventing T2DM and its complications in developing countries. METHODS: We undertook an electronic search of MEDLINE, PubMed, and EMBASE with the English language restriction and published until 30 September 2009. RESULTS: Nine relevant publications from seven studies were identified. The reported interventions predominantly used counseling and educational methods to improve diet and physical activity levels. Each intervention was found to be effective in reducing the risk of developing T2DM in people with impaired glucose tolerance, and improving glycemic control in people with T2DM. CONCLUSIONS: The current evidence concerning the prevention of T2DM and its complications in developing countries has shown reasonably consistent and positive results; however, the small number of studies creates some significant limitations. More research is needed to evaluate the benefits of low-cost screening tools, as well as the efficacy, cost-effectiveness, and sustainability of culturally appropriate interventions in such countries. PMID- 21590465 TI - Youth, sexual risk-taking behavior, and mental health: a study of university students in Uganda. AB - BACKGROUND: Little focus has been paid to the role of mental health among young people with regard to risky sexual behavior and HIV prevention in sub-Saharan Africa. The aim of this study was to investigate the relationship between poor mental health and risky sexual behavior (HIV/AIDS) among a population of university students in Uganda. METHODS: In 2005, 980 Ugandan university students completed a self-administered questionnaire (response rate 80%) assessing sociodemographic and religious background factors, mental health, alcohol use, and sexual behavior. Mental health was assessed using items from the Hopkins Symptoms Checklist-25 and the Symptom Checklist-90. RESULTS: High scores on depression and high numbers of sexual partners among both males (odds ratio (OR) 2.0, 95% confidence interval (CI) 1.2-3.3) and females (OR 3.3, 95% CI 1.3-8.6) were significantly associated. Elevated anxiety scores among men were associated with high numbers of sexual partners (OR 1.9, 95% CI 1.1-3.3) and inconsistent condom use (OR 1.9, 95% CI 1.1-3.6). Psychoticism was also significantly associated with high numbers of sexual partners among men. The associations remained statistically significant after controlling for sociodemographic factors and level of alcohol consumption. CONCLUSION: These findings indicate that previous conclusions on the association between sexual behavior and mental health from high- and middle-income countries also are valid in a low-income setting, such as in Uganda. This knowledge has implications for policy formation and HIV/AIDS preventive strategies. Coordinated youth-friendly mental health and sexual and reproductive health services to meet the needs of young people would be desirable. PMID- 21590466 TI - Is ureteral stenting really necessary after ureteroscopic lithotripsy with balloon dilatation of ureteral orifice? A multi-institutional randomized controlled study. AB - PURPOSE: Our aim was to evaluate the role of balloon dilatation of the ureteral orifice on the decision to stent after ureteroscopy. MATERIALS AND METHODS: We prospectively enrolled 505 patients from two clinics, undergoing ureteroscopy (URS) for urolithiasis. Patients having balloon dilatation of the ureteral orifice and uncomplicated ureteroscopy were randomized to be either stented (n = 144) or nonstented (n = 142). Ureteroscopy was done with a 9.8 rigid ureteroscope. For dilatation of ureteral orifice, 18Fr-4 cm balloons were used (UromaxTM, Boston Scientific, USA). Holmium laser or pneumatic devices were used for lithotripsy. In the second postoperative week, patients were asked to assess: pain, dysuria, and urgency using a 10-cm visual analog score (VAS) and unplanned visits. In each visit, urinalysis, urine culture, plain X-ray, and ultrasound examinations were performed. Six months after URS, follow-up IVU was performed to evaluate ureteral narrowing. Results for the separate clinics were not revealed until the end of study. RESULTS: There were no significant differences between the two groups regarding gender, age, preoperative serum creatinine levels, stone size, stone side and location, lithotripsy type, pain, infectious complications, unplanned visits, and ureteral narrowing. However, irritative symptoms were more common in the stented group. Success rates of 97.8 and 97.2% were similar in the unstented and stented groups. CONCLUSION: In uncomplicated URS, balloon dilatation of the ureteral orifice should not significantly affect the decision for or against stent placement. Avoiding stents lowers costs and gives fewer irritative symptoms. PMID- 21590468 TI - Percutaneous nephrolithotomy in children: does age matter? AB - PURPOSE: To compare the outcomes of percutaneous nephrolithotomy (PCNL) in 2 age groups. METHODS: Fifty-one renal units (RU) of 45 patients were operated between January 2006 and December 2010. In all patients, PCNL was performed by pediatric nephroscope of 17F size through a 20F Amplatz sheath. Patients were examined in 2 groups (Group1: <=5 years, Group 2: >5 years) and outcomes were compared accordingly. RESULTS: The mean age was 5.95 +/- 3.63 years and male-to-female ratio was 23/22. The mean stone burden, operative time, and postoperative hospital stay were 4.24 +/- 2.03 cm(2), 94.30 +/- 37.28 min, and 5.18 +/- 2.97 days, respectively. In the postoperative period, 44 renal units (86.2%) were stone-free. Two age groups were similar regarding the postoperative hospital stay, gender distribution, stone location, stone composition, and complication rates. However, stone burden and number of access was less and stone-free rate was higher in younger age group. CONCLUSION: The stone-free rate in preschool children is at least as good as older children without an increase in complication rates. The older children (>5 years) have a higher stone burden and need multiple accesses more frequently. The complications are mostly low grade and can be managed conservatively. Our results showed that PCNL in younger children as safe and effective as in the older children and age should not be considered as a limiting factor. PMID- 21590467 TI - Male circumcision and HIV infection risk. AB - BACKGROUND: Male circumcision is being promoted to reduce human immunodeficiency virus type 1 (HIV) infection rates. This review evaluates the scientific evidence suggesting that male circumcision reduces HIV infection risk in high-risk heterosexual populations. METHODS: We followed the updated International Consultation on Urological Diseases evidence-based medicine recommendations to critically review the scientific evidence on male circumcision and HIV infection risk. RESULTS: Level 1 evidence supports the concept that male circumcision substantially reduces the risk of HIV infection. Three major lines of evidence support this conclusion: biological data suggesting that this concept is plausible, data from observational studies supported by high-quality meta analyses, and three randomized clinical trials supported by high-quality meta analyses. CONCLUSIONS: The evidence from these biological studies, observational studies, randomized controlled clinical trials, meta-analyses, and cost effectiveness studies is conclusive. The challenges to implementation of male circumcision as a public health measure in high-risk populations must now be faced. PMID- 21590469 TI - Update on biofilm infections in the urinary tract. AB - PURPOSE: Biofilm infections have a major role in implants or devices placed in the human body. As part of the endourological development, a great variety of foreign bodies have been designed, and with the increasing number of biomaterial devices used in urology, biofilm formation and device infection is an issue of growing importance. METHODS: A literature search was performed in the Medline database regarding biofilm formation and the role of biofilms in urogenital infections using the following items in different combinations: "biofilm," "urinary tract infection," "bacteriuria," "catheter," "stent," and "encrustation." The studies were graded using the Oxford Centre for Evidence based Medicine classification. RESULTS: The authors present an update on the mechanism of biofilm formation in the urinary tract with special emphasis on the role of biofilms in lower and upper urinary tract infections, as well as on biofilm formation on foreign bodies, such as catheters, ureteral stents, stones, implants, and artificial urinary sphincters. The authors also summarize the different methods developed to prevent biofilm formation on urinary foreign bodies. CONCLUSIONS: Several different approaches are being investigated for preventing biofilm formation, and some promising results have been obtained. However, an ideal method has not been developed. Future researches have to aim at identifying effective mechanisms for controlling biofilm formation and to develop antimicrobial agents effective against bacteria in biofilms. PMID- 21590470 TI - Pediatric sub-specialist controversies in the treatment of congenital heart disease in trisomy 13 or 18. AB - Trisomy 13 and 18 are associated with congenital heart disease. Cardiac palliation has been reported in the literature, but is not usually done in this population. Thus, a multi-disciplinary team may experience controversy in formulating a care plan that includes cardiac intervention. Our objective was to determine differences in recommendations for cardiac intervention in this population between physicians specializing in pediatric cardiac critical care, neonatology, and genetics. A web-based survey was performed between April 2007 and August 2008. This survey evaluated surgical and transcatheter cardiac palliations that had been performed for individuals with trisomy 13 or 18 at the respondent's institution, the respondent's recommendations for cardiac intervention in hypothetical symptomatic patients with trisomy 13 or trisomy 18 and the influence of parental preference on these recommendations. Eight hundred fifty-nine responses were obtained from a primarily academic practice setting (59%). Cardiologists were most likely to recommend intervention; low risk interventions were recommended by 32% of cardiologists, 7% of neonatologists and 20% of geneticists. Parental request to intervene resulted in a 3 fold increased in the likelihood of all specialist recommending intervention. Counseling of families frequently occurred by multiple sub specialists (50%) and there was frequently (71%) a difference in opinion. Individuals with trisomy 13 or 18 are receiving cardiac intervention at many institutions. Cardiologists were more likely than geneticists or neonatologists to recommend intervention on all heart lesions other than single ventricle palliation which no specialists recommended. Parental wishes that "everything be done" significantly influenced all specialists' recommendations. PMID- 21590471 TI - Intermolecular electron transfer in two-iron superoxide reductase: a putative role for the desulforedoxin center as an electron donor to the iron active site. AB - Superoxide reductase (SOR) is a superoxide detoxification system present in some microorganisms. Its active site consists of an unusual mononuclear iron center with an FeN4S1 coordination which catalyzes the one-electron reduction of superoxide to form hydrogen peroxide. Different classes of SORs have been described depending on the presence of an additional rubredoxin-like, desulforedoxin iron center, whose function has remained unknown until now. In this work, we investigated the mechanism of the reduction of the SOR iron active site using the NADPH:flavodoxin oxidoreductase from Escherichia coli, which was previously shown to efficiently transfer electrons to the Desulfoarculus baarsii SOR. When present, the additional rubredoxin-like iron center could function as an electronic relay between cellular reductases and the iron active site for superoxide reduction. This electron transfer was mainly intermolecular, between the rubredoxin-like iron center of one SOR and the iron active site of another SOR. These data provide the first experimental evidence for a possible role of the rubredoxin-like iron center in the superoxide detoxifying activity of SOR. PMID- 21590473 TI - The effect of oral clonidine premedication on blood loss and the quality of the surgical field during endoscopic sinus surgery: a placebo-controlled clinical trial. AB - Bleeding during functional endoscopic sinus surgery (FESS) remains a challenge for both surgeons and anesthesiologists despite several modalities available for improving the surgical field. This study was conducted to evaluate the effect of oral clonidine premedication on blood loss and the quality of the surgical field in FESS. In a placebo-controlled clinical trial, a total of 84 American Society of Anesthesiologists (ASA) physical status I-II patients undergoing endoscopic sinus surgery for chronic sinusitis were randomly allocated to receive either oral clonidine 0.2 mg or identical-looking placebo tablets 90 min before arrival at the operating room. Blood loss in the clonidine group was 214 +/- 67 ml on average and that in the placebo group was 276 +/- 78 ml (mean +/- SD, p < 0.01). The median (range) bleeding score in the clonidine group was significantly lower than that in the placebo group (2 (1-3) vs. 2.5 (2-4), p < 0.0001). Accordingly, the surgeon was more satisfied with the surgical field in the clonidine group than with that in the placebo group (median score, 4 (3-5) vs. 3 (1-5), p < 0.001). In conclusion, premedication with oral clonidine 0.2 mg can effectively reduce bleeding during FESS. PMID- 21590474 TI - [Therapeutic strategies in rheumatoid arthritis]. AB - Rheumatoid arthritis is the most common chronic inflammatory-rheumatic joint disease. If untreated, patients develop radiologically detectable progressive joint destruction. Rheumatoid arthritis has considerable socioeconomic importance, since a majority of patients are affected at employable age and can be significantly disabled over the course of the disease. Therefore, an appropriate early intervention with disease modifying anti-rheumatic drugs as well as ergo- and physiotherapy plays an important role for the prognosis. In the past few years, the introduction of novel drugs has improved the treatment opportunities markedly. This progress was the basis for new treatment strategies of tight disease control with the goal of disease remission. PMID- 21590475 TI - Squamous cell carcinoma in the larynx in a 7-year-child. AB - Squamous cell carcinoma (SCC) involving the larynx in childhood is very rare, especially in the ages younger than 10 years. Most of the reported cases are transformed from the recurrent respiratory papillomatosis (RRP) with human papilloma virus (HPV) infection. Due to the RRP long course, the rarity and the unspecific symptoms of the cancer, they usually are diagnosed at late stages. Controversy exists regarding the causes and the treatments of these kinds of diseases. Here, we reviewed the related reports and presented a case of 7-year old boy who had an advanced well-differentiated SCC of the larynx which transformed from RRP with HPV genotyping test negative. The patient underwent only the resection of involved tissues and no other treatments. Except for hoarseness in his voice, the boy is going well and has had an uneventful course of 10 years following operative treatment. PMID- 21590476 TI - Children with high and intermediate imperforate anus: their experiences of hospital care. AB - PURPOSE: The purpose of this study was to examine the experiences of children with high and intermediate imperforate anus (IA), and specifically their experiences of hospital care. METHODS: Twenty-five children born with high and intermediate IA participated; 9 boys and 16 girls. The mean age was 10.5 years (range 8.0-13.6). Two control groups were involved in the study. A self-report questionnaire was used to gather the data concerning children's experiences of hospital care. Items were scored on a 5-point Likert scale. RESULTS: The children's responses on hospital care items scored high. The children with IA reported being less satisfied with the information given, and understood less why they needed to visit the hospital than did the children in the two control groups. CONCLUSION: The children's experiences of care seemed to be positive even though the children born with IA are subjected to invasive treatment. More research is called for in the unexplored area of information to the children, and particularly to the children born with a defect. Children's views are important and should always be considered, as their answers most certainly reflect a genuine experience, contributing to the further development of their specific care. PMID- 21590477 TI - Patch repair is an independent predictor of morbidity and mortality in congenital diaphragmatic hernia. AB - BACKGROUND: Infants with congenital diaphragmatic hernia (CDH) have variable outcomes. There is a considerable potential benefit in being able to predict perinatally, which infants have severe hypoplasia and are thus more likely to die or survive with significant morbidity. We examine the relationship between a need for patch repair of CDH (PR) and outcome, using a national database. METHODS: Baseline characteristics of patients undergoing PR or non-patch repair (NPR) were compared. Multivariate analysis was performed to determine the association of PR with mortality and morbidity independent of other known predictors. RESULTS: Baseline characteristics of PR and NPR infants were similar although those infants with PR had higher SNAP-II scores. PR was an independent predictor of mortality with an odds ratio of 17.1 (95%CI 2.0-149.2) and was independently associated with secondary outcome measures of morbidity, including the need for oxygen at discharge and the duration of ventilation. CONCLUSIONS: Infants requiring PR have significantly higher mortality and suffer greater morbidity than those undergoing NPR. This association is independent of other known predictors of mortality. Identifying prenatal features associated with this high risk group would be of great clinical value. PMID- 21590478 TI - The cholinergic response is increased in isolated ileum from gastroschisis rat model. AB - INTRODUCTION: Babies with gastroschisis (G) have high morbidity rate and long hospital stay due to bowel hypomotility caused by chronic exposure of the bowel to the amniotic fluid. Our aim was to evaluate the reactivity of isolated ileum in fetal rats selected for experimental gastroschisis. METHOD: G was surgically created at 18.5 days of gestation (term = 22 days). Concentration-dependent curve to the muscarinic agonist methacholine (1-30 MUM) and contractions induced by electrical field stimulation (EFS, 1-16 Hz, 50 V, 1 ms) were carried out in isolated ileum of groups control (C), sham (S) and gastroschisis (G) (n = 30). Protein expression for M(3) was assessed by western blot analysis. RESULTS: The frequency and amplitude of spontaneous contractions were decreased in G (p < 0.001). Methacholine produced concentration-dependent contractions being the maximal response values higher in G (p < 0.01). EFS-induced frequency-dependent contractions showed 1.8 times higher in G as well as an increase of M(3) expression. CONCLUSION: The frequency and the amplitude of rhythmic contractions were reduced along with an increase in the contraction induced by mucarinic agonist and by EFS in G. These results suggest the occurrence of an adaptative supersensitivity to cholinergic response via increases in the protein expression for M(3) receptor. PMID- 21590479 TI - Oral maxillofacial tumors and tumor-like conditions: a Ugandan survey. AB - AIM: Currently, there is very little information from Uganda as to the range and prevalence of oral diseases in children. Most of these studies focus on prevalence of caries, periodontal disease, malocclusions, and trauma to teeth. Since the epidemiology of oral maxillofacial tumors is variable between regions yet there are no publications on this entity in the pediatric population available from Uganda, the authors of this study decided to carry out the first Ugandan retrospective survey. DESIGN: All entries for specimens from children between the ages of 0 and 16 years during the 5-year period from 2006 to 2010 were retrieved and compiled into five diagnostic categories. RESULTS: During the study period, 610 (29.33%) specimens came from children between the ages of 0 and 16 years, with a male to female ratio of 1.29:1. The diagnostic category with the largest number of specimens was malignant (61.08%), followed by inflammatory/reactive lesions (16.07%) and benign tumors (12.13%). In all, there were 51 benign tumors of non-odontogenic origin and 23 odontogenic tumors. The most frequently diagnosed lesions were Burkitt's lymphoma, which accounted for over 55.24% of all cases. This was followed by irritation fibromas that accounted for 5.74% of all cases. CONCLUSIONS: This survey shows that, while nearly 29% of cases biopsied at the authors' unit are from children under 16 years of age, the majority of lesions are malignant. Burkitt's lymphoma took up the lion's share; this entity requires chemotherapeutic treatment, hence there is need to strengthen medical oncology. Odontogenic tumors are relatively rare in this age group; however, certain lesions such as adenomatoid odontogenic tumor are common in children and therefore should be considered when we have failed maxillary canine eruption. PMID- 21590480 TI - Rare cause of a neck mass: successful balloon embolisation of a congenital external carotid artery-internal jugular vein fistula. AB - Congenital arteriovenous fistulas are a rare cause of neck mass in children, but should be considered in the differential diagnosis of paediatric patients presenting with pulsatile neck masses even when there is no history of trauma. Balloon embolisation is the treatment of choice because of the high risk of surgical complications in this region. PMID- 21590481 TI - Varicosities in an adolescent girl on laparoscopy: an unusual presentation of May Thurner syndrome. AB - May-Thurner syndrome is a rare clinical entity involving venous obstruction of the left lower extremity. May-Thurner syndrome most commonly presents with deep vein thrombosis. We describe an unusual presentation of a girl with a dragging abdominal pain mimicking the symptoms of a varicocele. Diagnosis can be made with MR venogram. There are many different treatment options but if compression of the vein is minimal conservative management is possible. PMID- 21590482 TI - Inhibition of fibroblast growth factor receptor 1: influence on tympanic membrane wound healing in rats. AB - An animal model of chronic tympanic membrane (TM) perforation is needed for experiments on supporting healing of TM perforations. The basic fibroblast growth factor is important in TM wound healing. The object of this study was to investigate the efficacy of fibroblast growth factor receptor 1 (FGFR1) inhibition to arrest wound healing of experimental TM perforation. Bilateral instrumental myringotomies were performed in 12 rats. A specific inhibitor of the FGFR1 tyrosine kinase (SU5402) was applied to the left TM (2 mg/ml) and to the right TM (10 mg/ml) of each animal daily for 12 consecutive days. Thereafter, TMs were observed weekly for a total of 30 days. TM healing was delayed in a dose dependent manner. We observed differences in the histologic parameters between both groups. SU 5402 is a strong inhibitor of TM healing but seems not to be suitable to create a chronic TM perforation in rat. PMID- 21590483 TI - A national series of 244 sinonasal cancers in Finland in 1990-2004. AB - Sinonasal cancer is still a somewhat controversial entity because most series are single-center studies. The aim of this study was to give more accurate and generalisable information about treatment of the neck and prognosis of sinonasal cancer. Retrospective, population-based, multicentre study. Altogether 244 patients diagnosed in 1990-2004 were evaluated. The 3- and 5-year disease specific survival (DSS) rates after treatment with curative intent were 68 and 57%, respectively. Regional status at the time of the diagnosis (P < 0.001, log rank) and local recurrence (P = 0.02, log rank) during the follow-up had a statistically significant effect on DSS. Initially 13% of the patients were diagnosed with neck metastasis. The proportion of regional recurrences during the follow-up was 9%, but it did not have a statistically significant impact on DSS (P = 0.68, log rank). Histopathology had no statistically significant impact on survival in this material of 244 patients. In conclusion, routine elective neck treatment of all sinonasal cancer patients is not recommended, but the importance of the treatment of the primary location is emphasised. PMID- 21590484 TI - Do higher hospital-wide nurse staffing levels reduce in-hospital mortality in elderly patients with hip fractures: a pilot study. AB - BACKGROUND: There is increasing recognition that lower nurse staffing levels are associated with higher morbidity and mortality among medical and surgical patients. The degree to which this applies to elderly patients with hip fractures is unclear. QUESTIONS/PURPOSES: We conducted a pilot study using administrative data as an initial step in investigating the relationship between nurse staffing levels and in-hospital mortality among elderly patients with hip fractures. PATIENTS AND METHODS: We retrospectively reviewed administrative data for 13,343 patients 65 years or older with a primary diagnosis of hip fracture admitted to 39 Michigan hospitals between 2003 and 2006. We used logistic regression to calculate the change in predicted probability of in-hospital death conferred by differences in the hospitals' overall number of full-time equivalent registered nursing staff (FTE-RN) per patient day. Regression models controlled for patient age, gender, and comorbid conditions; hospital characteristics including teaching status, hip fracture volume, and income/racial composition of the hospital's zip code; and seasonal influenza. RESULTS: We found an association between hospital wide nurse staffing levels and in-hospital mortality among patients with hip fractures. The odds of in-hospital mortality decreased by 0.16 for every additional FTE-RN added per patient day, even after controlling for covariates. This association suggests the absolute risk of mortality increases by 0.35 percentage points for every one unit decrease of FTE-RN per patient day, a 16% increase in the risk of death. CONCLUSIONS: Decreased hospital-wide nurse staffing levels are associated with increased in-hospital mortality among patients admitted with hip fractures. These observations indicate the need for further studies to characterize this relationship for staffing of units caring for patients with hip fractures. LEVEL OF EVIDENCE: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21590485 TI - Function plateaus by one year in patients with surgically treated displaced midshaft clavicle fractures. AB - BACKGROUND: Based on short-term (1 year or less) followup, primary fixation of displaced midshaft clavicle fractures reportedly results in better function compared with that reported for nonoperative methods. Whether better function persists beyond 1 year is unclear. QUESTIONS/PURPOSES: For displaced midshaft clavicle fractures, do the better mean Disabilities of the Arm, Shoulder and Hand (DASH) and Constant-Murley Shoulder (CSS) scores for operative versus nonoperative treatment at 1 year change between 1- and 2-year followup? PATIENTS AND METHODS: We previously reported 132 patients in a randomized prospective trial at 1 year, and here we report a further followup of 95 of the 132 patients (72%) at 2 years after injury. We evaluated all patients with the DASH and CSS scores. RESULTS: The mean DASH and CSS scores were similar at 2 years compared with 1 year postinjury for both the nonoperated and operated patients. The mean scores for the operated patients remained higher than those in the nonoperative group (DASH operative 4.1 +/- 7.0 versus DASH nonoperative 11.4 +/- 19.7, CSS operative 97.1 +/- 4.5 versus CSS nonoperative 91.6 +/- 14.1) at 2 years postinjury. CONCLUSIONS: The improvement in DASH and CSS scores seen with primary fixation of displaced clavicle fractures persists at 2 years but does not differ from values seen after 1 year of followup, suggesting a clinical steady state has been reached whereby outcome is unlikely to change with time. LEVEL OF EVIDENCE: Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21590486 TI - Influence of gender and fixation stability on bone defect healing in middle-aged rats: a pilot study. AB - BACKGROUND: Gender and stability of fixation independently influence bone regeneration but their combined effects are unclear. QUESTIONS/PURPOSES: In a pilot study we determined the combined influence of gender and fixation stability on the callus of middle-aged rats regarding (1) biomechanical properties; (2) bridging over time; (3) callus formation; and (4) callus size, geometry, mineralization, and microstructure. METHODS: We osteotomized the left femur of 32 Sprague-Dawley rats (12 months old). Femurs were externally fixed with a gap of 1.5 mm in four groups of eight animals each: female semirigid, male semirigid, female rigid, and male rigid. Qualitative and quantitative in vivo radiographic analyses were performed twice weekly. Six weeks postoperatively, harvested femora were evaluated using micro-CT and biomechanical testing. RESULTS: Torsional stiffness and maximum torque at failure were higher in male and in semirigidly fixed fractures. Radiographic analysis revealed earlier bridging and callus formation in both male groups. Micro-CT analysis showed a larger callus size, altered geometry, and microstructure in males and semirigidly fixed animals, whereas mineralization was similar in all animals. CONCLUSION: Our data suggest female gender represents an independent risk factor for bone healing in middle aged rats. Although healing in females was delayed compared with males, they exhibited a similar response (superior callus properties) to a more semirigid fixation. CLINICAL RELEVANCE: While female gender appears to reflect a risk for impaired bone healing in middle-aged female rats, clinical studies would be required to confirm the finding in humans. PMID- 21590487 TI - Delayed fracture healing in growth differentiation factor 5-deficient mice: a pilot study. AB - BACKGROUND: Growth differentiation factor-5 (GDF-5) is a key regulator of skeletogenesis and bone repair and induces bone formation in spinal fusions and nonunion applications by enhancing chondrocytic and osteocytic differentiation and stimulating angiogenesis. Elucidating the contribution of GDF-5 to fracture repair may support its clinical application in complex fractures. QUESTIONS/PURPOSE: We therefore asked whether the absence of GDF-5 during fracture repair impaired bone healing as assessed radiographically, histologically, and mechanically. METHODS: In this pilot study, we performed tibial osteotomies on 10-week-old male mice, stabilized by intramedullary and extramedullary nailing. Healing was assessed radiographically and histologically on Days 1 (n = 1 wild-type; n = 5 bp [brachopodism]), 5 (n = 3 wild-type; n = 3 bp), 10 (n = 6 wild-type; n = 3 bp), 14 (n = 6 wild-type; n = 6 bp), 21 (n = 6 wild-type; n = 6 bp), 28 (n = 7 wild-type; n = 6 bp), and 56 (n = 6 wild-type; n = 6 bp) after fracture. After 10 (n = 7 wild-type; n = 7 bp contralateral and n = 3 bp fractured tibiae), 14 (n = 6 wild-type; n = 6 bp), 21 (n = 6 wild-type; n = 6 bp), 28 (n = 6 wild-type; n = 3 bp), and 56 (n = 8 wild-type; n = 6 bp) days, the callus cross-sectional area was calculated. We characterized the mechanical integrity of the healing fracture by yield stress and Young's modulus at 28 (n = 6 wild-type; n = 3 bp) and 56 (n = 8 wild-type; n = 6 bp) days postfracture. RESULTS: The absence of GDF-5 impaired cartilaginous matrix deposition in the callus and reduced callus cross-sectional area. After 56 days, the repaired bp fracture was mechanically comparable to that of controls. CONCLUSIONS: Although GDF-5 deficiency did not compromise long-term fracture healing, a delay in cartilage formation and remodeling supports roles for GDF-5 in the early phase of bone repair. CLINICAL RELEVANCE: Local delivery of GDF-5 to clinically difficult fractures may simulate cartilage formation in the callus and support subsequent remodeling. PMID- 21590488 TI - Osteogenic induction of bone marrow-derived stromal cells on simvastatin releasing, biodegradable, nano- to microscale fiber scaffolds. AB - Tissue engineering is an effective approach for the treatment of bone defects. Statins have been demonstrated to promote osteoblastic differentiation of bone marrow-derived stromal cells (BMSCs). Electrospun biodegradable fibers have also shown applicability to drug delivery in the form of bone tissue engineered scaffolds with nano- to microscale topography and high porosity similar to the natural extracellular matrix (ECM). The aim of this study was to investigate the feasibility of a simvastatin-releasing, biodegradable, nano- to microscale fiber scaffold (SRBFS) for bone tissue engineering with BMSCs. Simvastatin was released from SRBFS slowly. BMSCs were observed to spread actively and rigidly adhere to SRBFS. BMSCs on SRBFS showed an increase in alkaline phosphatase activity 2 weeks after cell culture. Furthermore, osteoclastogenesis was suppressed by SRBFS in vitro. The new bone formation and mineralization in the SRBFS group were significantly better than in the biodegradable fiber scaffold (BFS) without simvastatin 12 weeks after implantation of the cell-scaffold construct into an ectopic site on the murine back. These results suggest that SRBFS promoted osteoblastic differentiation of BMSCs in vitro and in vivo, and demonstrate feasibility as a bone engineering scaffold. PMID- 21590489 TI - Angiogenesis-associated crosstalk between collagens, CXC chemokines, and thrombospondin domain-containing proteins. AB - Excessive vascularization is a hallmark of many diseases including cancer, rheumatoid arthritis, diabetic nephropathy, pathologic obesity, age-related macular degeneration, and asthma. Compounds that inhibit angiogenesis represent potential therapeutics for many diseases. Karagiannis and Popel [Proc. Natl. Acad. Sci. USA 105(37):13775-13780, 2008] used a bioinformatics approach to identify more than 100 peptides with sequence homology to known angiogenesis inhibitors. The peptides could be grouped into families by the conserved domain of the proteins they were derived from. The families included type IV collagen fibrils, CXC chemokine ligands, and type I thrombospondin domain-containing proteins. The relationships between these families have received relatively little attention. To investigate these relationships, we approached the problem by placing the families of proteins in the context of the human interactome including >120,000 physical interactions among proteins, genes, and transcripts. We built on a graph theoretic approach to identify proteins that may represent conduits of crosstalk between protein families. We validated these findings by statistical analysis and analysis of a time series gene expression data set taken during angiogenesis. We identified six proteins at the center of the angiogenesis associated network including three syndecans, MMP9, CD44, and versican. These findings shed light on the complex signaling networks that govern angiogenesis phenomena. PMID- 21590490 TI - Gastric type I carcinoid: a pilot study with human G17DT immunogen vaccination. AB - CONTEXT: Gastric type I carcinoid is a rare neoplasm, deriving from enterochromaffin-like cells (ECL), mainly affecting women with autoimmune gastritis. The approach to treatment, either endoscopic, medical or surgical, is not well defined, particularly in multifocal tumours or carcinoids with rapid growth/frequent recurrence. OBJECTIVE: To determine whether an anti-G17 vaccination might interfere on the natural history of gastric type I carcinoid. SETTING: Padua teaching Hospital, outpatient clinic. DESIGN AND PATIENTS: Three patients with type I gastric carcinoid in autoimmune gastritis were administered, after informed consent and ethic committee approval, with a vaccine against gastrin 17 (G17), a synthetic peptide that stimulates specific and high-affinity anti-G17 antibodies, and followed up endoscopically and clinically for a mean of 36 months. MAIN OUTCOME MEASURES: Gastric histology and specifically carcinoid growth/recurrence and trend in time in gastrin, G17, pepsinogens, chromogranin A and clinical parameters. RESULTS: Following vaccination, carcinoid regression was observed in 2/3 patients and, in one of the patients, even the disappearance of ECL hyperplasia, with a reduced ECL cells stimulation, confirmed by a significant reduction in chromogranin A levels. Regression was observed in the two patients that showed a more clear local response to the vaccine. Increased autoantibody titre was observed, but no appearance of new autoimmune diseases. CONCLUSIONS: Anti-G17 vaccination induced regression of type I gastric carcinoid and could be considered for the treatment of this tumour, when endoscopic removal is not indicated. PMID- 21590491 TI - Spindle cell oncocytoma of the pituitary gland with follicle-like component: organotypic differentiation to support its origin from folliculo-stellate cells. AB - Spindle cell oncocytoma (SCO) is a rare, non-adenomatous tumor originating from the anterior pituitary gland. Composed of fusiform, mitochondrion-rich cells sharing several immunophenotypic and ultrastructural properties with folliculo stellate cells (FSC), SCO has been proposed to represent a neoplastic counterpart of the latter. To date, however, SCO has failed to meet one criterion commonly used in histological-based taxonomy and diagnostics; that of recapitulating any of FSCs' morphologically defined developmental or physiological states. We describe a unique example of SCO wherein a conventional fascicular texture was seen coexisting with and organically merging into follicle-like arrangements. The sellar tumor of 2.7 * 2.6 * 2.5 cm was transphenoidally resected from a 55-year old female. Preoperative magnetic resonance imaging indicated an isointense, contrast enhancing mass with suprasellar extension. Histology showed multiple rudimentary to well-formed, follicle-like cavities on a classical spindle cell background; while all the participating cells exhibited an SCO immunophenotype, including positivity for S100 protein, vimentin, EMA, Bcl-2, and TTF-1, as well as staining with the antimitochondrial antibody 113-1. Conversely no expression of GFAP, follicular-epithelial cytokeratin, carcinoembryonic antigen, or anterior pituitary hormones was detected. Ultrastructurally, tumor cells facing follicular lumina displayed organelles of epithelial specialization, in particular surface microvilli and apical tight junctions. This constellation is felt to be reminiscent of FSCs' metaplastic transition to follicular epithelium, as observed during embryonic development and physiological renewal of the hormone-secreting parenchyma. Such finding is apt to being read as a supporting argument for SCO's descent from the FSC lineage. PMID- 21590492 TI - SOCS3 promoter methylation is mutually exclusive to EGFR amplification in gliomas and promotes glioma cell invasion through STAT3 and FAK activation. AB - The suppressor of cytokine signaling 3 (SOCS3) gene is one of eight structurally related genes of the SOCS family and has been suggested to function as a tumor suppressor by inhibition of the JAK/STAT signaling pathway. We investigated 60 human gliomas of different histological types for SOCS3 alterations and found frequent SOCS3 promoter hypermethylation and transcriptional downregulation. However, SOCS3 promoter hypermethylation was virtually absent in primary glioblastomas, which are characterized by frequent epidermal growth factor receptor (EGFR) amplification and overexpression. Assessment of the relationship between SOCS3 and EGFR aberrations revealed that SOCS3 promoter hypermethylation was inversely related to both the EGFR gene dosage as well as the EGFR protein expression, thus suggesting SOCS3 inactivation as a mechanism substituting for EGFR activation in a subset of gliomas. In support of this hypothesis, stable shRNA-mediated SOCS3 knock-down in U251 glioblastoma cells resulted in an activation of EGFR-related signaling pathways, i.e. an increase in the activation levels of STAT3, FAK and to a lesser extent MAPK, while the AKT phosphorylation levels remained unaffected. Functionally, SOCS3-depletion caused strongly increased tumor cell invasion with no obvious effect on tumor cell proliferation. In summary, our findings suggest that SOCS3 inactivation by promoter hypermethylation is mutually exclusive to EGFR activation in gliomas and preferentially promotes glioma cell invasion through STAT3 and FAK activation. PMID- 21590493 TI - Religiosity and social support: implications for the health-related quality of life of African American hemodialysis patients. AB - The purpose of this study was to determine whether sociocultural differences have any effect on the health-related quality of life among African American hemodialysis patients. This study examined relationships between religiosity, social support, and the health-related quality of life of African American hemodialysis patients. Four hemodialysis units were selected for the study. The study population consisted of 176 African American hemodialysis patients who had been receiving hemodialysis treatments for at least 1 month. The religiosity variable was measured by the Measure of Religious Involvement. Social Support was measured by the Medical Outcomes Study Social Support Survey, and health-related quality of life was measured by the Medical Outcomes Study 36 Short Form Health Survey (SF-36v2). The investigators found that social support contributed to the emotional and physical health of African American hemodialysis patients in the sample, whereas religiosity was inversely related to the physical health of these patients. PMID- 21590494 TI - Proof of concept: endogenous antiangiogenic factors predict the occurrence of symptomatic vasospasm post subarachnoid hemorrhage. AB - BACKGROUND: The pathogenesis of vasospasm (VS) post aneurysmal subarachnoid hemorrhage (SAH) is multifactorial and not completely understood. The authors hypothesize that circulating antiangiogenic factors play an important role in brain injury post SAH and that elevated levels predict the occurrence of symptomatic vasospasm. METHODS: In this study the authors measured the serum and cerebrospinal fluid (CSF) levels of soluble endoglin (sEng) and soluble fms-like tyrosine kinase 1 (sFlt1) in controls and SAH patients within 48 h of the bleed. Patients were prospectively followed and subcategorized into those with (sVS) and without symptomatic vasospasm (no-sVS). RESULTS: Compared to healthy controls, SAH patients had higher CSF levels of sEng (0.037 vs. 0.251 ng/ml; P = 0.02) and sFlt1 (0.068 vs. 0.679 ng/ml; P = 0.001). In the subgroup analysis, sVS patients had higher CSF levels of sEng and sFlt1 than no-sVS patients (sEng: 0.380 vs. 0.159 ng/ml, P = 0.02; sFlt1: 1.277 vs. 0.343 ng/ml, P = 0.01). The serum levels of sEng and sFlt1 were not statistically different among the different groups. CONCLUSIONS: Based on these results the authors conclude that elevated CSF levels of sFlt1 and sEng herald the occurrence of symptomatic VS post SAH. PMID- 21590495 TI - Prognostic value of intercellular adhesion molecule (ICAM)-1 expression in breast cancer. AB - PURPOSE: The intercellular adhesion molecule (ICAM)-1 is expressed on many cell types including endothelial cells and different cancer cell entities. Experimental data strongly indicate that ICAM-1 can activate intracellular signalling pathways in cancer cells leading to enhanced cell motility, invasion and metastasis. Yet, little is known about the role of ICAM-1 expression during malignant progression in breast cancer patients. METHODS: We investigated ICAM-1 protein and mRNA expression in two partly overlapping cohorts of breast cancer patients. ICAM-1 protein was detected by Western blot analysis in 104 cases and verified by immunohistochemistry. Additionally, ICAM-1 mRNA microarray data from 169 tumours were analysed. RESULTS: With both methods, high ICAM-1 expression was significantly associated with a poorly differentiated phenotype, a negative estrogen receptor (ER) status and positive lymph node involvement. In addition, there was a significant prognostic impact of ICAM-1 protein overexpression on recurrence-free survival (HR = 2.82, P = 0.023), which was most pronounced in ER negative tumours. ICAM-1 mRNA overexpression was associated with high urokinase plasminogen activator (uPA) and uPA-inhibitor protein 1 (PAI 1) protein and mRNA levels as well as high Ki67 protein and vascular endothelial growth factor (VEGF) mRNA expression. CONCLUSIONS: In our group of patients, ICAM-1 expression was associated with a more aggressive tumour phenotype. Because of its association with malignant progression, ICAM-1 might represent a new target in the treatment of breast cancer patients. PMID- 21590496 TI - Spinal epidural abscess: aetiology, predisponent factors and clinical outcomes in a 4-year prospective study. AB - Spinal epidural abscess (SEA) is a rare, but serious, condition with multiple causes. We prospectively studied the aetiology, predisposing factors, and clinical outcomes of SEA in all patients with SEA treated in our hospital's neurosurgical service from 2004 to 2008. For each patient, we recorded the medical history, comorbidities, focus of infection, pathogen(s), and outcome. The 36 patients (19 women and 17 men) ranged in age from 34 to 80 years old (mean 57; median 56). The SEA was primary (i.e., due to haematogenous spread) in 16 patients (44%); it was secondary to elective spinal procedures, either injections or surgery, in 20 patients (56%). The duration of follow-up was 12-60 months (mean 36; median 37.5). The most common pathogen, Staphylococcus aureus, was found in 18 patients (50%). Patients with primary SEA had different underlying diseases and a wider range of pathogens than those with secondary SEA. Only five patients (14%) had no major comorbidity; 16 of the 20 patients with secondary SEA (44% of the overall group) had undergone spinal surgery before developing the SEA; the treatment of the SEA involved multiple surgical operations in all 16 of these patients, and spinal instrumentation in 5 (14%); 22 patients (61% of the overall group) recovered fully. PMID- 21590497 TI - Detecting growth hormone abuse in athletes. AB - It is believed that athletes have been abusing growth hormone (GH) for its anabolic and lipolytic effects since the early 1980s, at least a decade before endocrinologists began to treat adults with GH deficiency. There is an on-going debate about whether GH is performance enhancing. Although many of the early studies were negative, more recent studies suggest that GH improves strength and sprint capacity, particularly when it is combined with anabolic steroids. Although use of GH is banned by the World Anti-Doping Agency (WADA), its detection remains challenging. Two approaches have been developed to detect GH abuse. The first is based on measurement of pituitary GH isoforms; after injection of recombinant human GH, which comprises solely the 22-kDa isoform, endogenous production is down-regulated leading to an increase in the 22-kDa isoform relative to other isoforms. The second is based on measurement of markers of GH action. Insulin-like growth factor-I (IGF-I) and N-terminal pro-peptide of type III collagen (P-III-NP) increase in response to GH administration in a dose dependent manner. When combined with discriminant function analysis, use of these markers differentiates between individuals taking GH and placebo. Subsequent studies have shown that the test is applicable across different ethnicities and is unaffected by injury. WADA regulations state that when analytes are measured by immunoassay, two assays are needed. Final validation of the marker test is currently being undertaken with modern commercially available immunoassays to finalise the threshold values to be used to determine whether a doping offence has been committed. PMID- 21590498 TI - Tropomyosin is in a reduced state in rabbit psoas muscle. AB - Tropomyosin (Tm) purified from skeletal and cardiac muscle often contains disulfide bonds due to oxidation of cysteine groups that are in close proximity in the coiled-coil structure. Are these disulfide crosslinks present in the muscle or produced by oxidation during preparation? To answer this question we reacted one part of freshly dissected rabbit psoas muscle fibers, which was permeabilized with Triton X-100, with N-ethyl maleimide (NEM) to block cysteine groups and another part with 5,5'-dithiobis(2-nitro benzoate) (DTNB) to facilitate disulfide bond formation by interchain sulfhydryl-disulfide exchange. We found, by high resolution gradient SDS polyacrylamide gels, that the NEM treated muscle was only composed of uncrosslinked Tm and the DTNB treated muscle was composed of disulfide-crosslinked Tm. This work indicates that Tm exists in a reduced state in rabbit psoas muscle. PMID- 21590499 TI - Stem cells, mature adipocytes, and extracellular scaffold: what does each contribute to fat graft survival? AB - BACKGROUND: Soft tissue engineering offers new perspectives for improving fat graft survival, for which the appropriate association of cells and scaffold seems essential. This study aimed to analyze the survival of free-cell grafts compared with adipose-derived stem cells (ASCs) seeded on collagen scaffolds. METHODS: Adipose tissue from a single volunteer was used for the following preparations: purified adipose tissue, isolated mature adipocytes (free-cell graft), cultured ASCs without scaffold (free-cell graft), collagen scaffold only, cultured ASCs in collagen scaffold without and with bioactive factors, and freshly-isolated ASCs in collagen scaffold. These were grafted on 18 nude mice for 2 months, after which specimens were evaluated grossly and histologically using hematoxylin phloxine-safran (HPS), Oil-Red-O, and antivimentin labeling. Specimens and animals were weighed before implantation and after explantation, and weight values were statistically analyzed. RESULTS: Free-cell grafts (mature adipocytes and free ASCs) showed complete resorption in 50 and 60% of the animals (remaining weight fraction was 22.5 and 5.3%, respectively). The survival of purified adipose tissue was 81.8% (statistically greater compared with free-cell grafts; p < 0.05). In the ASCs-scaffold association, the remaining weight fractions (87.3 70.4%) were statistically greater than in free-cell grafts (5.3-22.5%; p < 0.05), but the difference between ASC-scaffolds and fat grafts was not statistically significant. These results were confirmed by clinical and histologic observations. CONCLUSION: Three-dimensional collagen scaffolds seem to improve survival of ASCs compared with free-cell grafts (adipocytes and free ASCs). PMID- 21590500 TI - Primum non nocere, deinde philosophare. PMID- 21590501 TI - High-frequency ultrasound probe sonography staging for colorectal neoplasia with superficial morphology: its utility and impact on patient management. AB - BACKGROUND: This prospective study aimed to evaluate the impact of high-frequency ultrasound probe sonography (HFUPS) staging on the management of patients with superficial colorectal neoplasia (SCN) as determined by the endoscopic characteristics of lesions. METHODS: Consecutive patients referred for endoscopic treatment of nonpedunculated SCN were enrolled in this study. A lesion was considered high risk if a depressed area or invasive pit pattern was present. The gold standard for final staging included histology from endoscopic or surgical resection. The impact on treatment was defined as any modification of the therapeutic algorithm based on the result of the HFUPS examination compared with that based on endoscopy alone. RESULTS: In this study, 48 lesions in 48 patients were evaluated. Of these, 28 (58%) were considered high risk, and the remaining 20 (42%) were regarded as low risk. A total of seven lesions (15%) that could not be examined with HFUPS and another non-neoplastic lesion were excluded from final analysis. For the remaining 40 lesions, the overall accuracy of the HFUPS examination to predict the correct T-stage was 90% (95% confidence interval [CI], 77-96%). The HFUPS examination had a positive impact on the treatment of 0 low risk and 11 high-risk (42%) lesions. CONCLUSION: The impact of HFUPS on the treatment of SCN depends on their endoscopic characteristics. It is negligible for low-risk SCNs, and these lesions can be treated on the basis of their endoscopic appearance alone. Nevertheless, compared with endoscopy alone, HFUPS changed the subsequent therapeutic approach in a positive way for up to 42% of high-risk lesions, including those with a depressed component and an invasive pit pattern. These endoscopic features can therefore be recommended as the entry criteria for an HFUPS examination. PMID- 21590502 TI - The impact of preventable disruption on the operative time for minimally invasive surgery. AB - BACKGROUND: Current ergonomic studies show that disruption exposes surgical teams to stress and musculoskeletal disorders. This study considers minimally invasive surgery as a sociotechnical process subjected to a variety of disruption events other than those recognized by ergonomic science. The research takes into consideration the impact of preventable disruption on operating time rather than on the physical and emotional status of the surgical team. METHODS: Events inside operating rooms that disturbed operative time were recorded for 17 minimally invasive surgeries. The disruption events were classified into four main areas: prerequisite requirements, work design, communication during surgery, and other. Each area was further classified according to sources of disruption. Altogether, 11 sources of disruption were identified: patient record, protocol and policy, surgical requirements and surgeon preferences, operating table and patient positioning, arrangement of instruments, lighting, monitor, clothing, surgical teamwork, coordination, and other. RESULTS: Disruption prolonged operative time by more than 32%. Teamwork forms the main source of disruption followed by operating table and patient positioning and arrangement of instruments. These three sources represented approximately 20% of operative time. Failure to follow principles of work design had a significant negative impact, lengthening operative time by approximately 15%. Although lighting and monitors had a relatively small impact on operative time, these factors could create inconvenience and stress within the surgical teams. In addition, the effect of failure to follow surgical protocols and policies or having incomplete patient records may have a limited effect on operative time but could have serious consequences. CONCLUSION: This report demonstrates that preventable disruption caused an increase in operative time and forced surgeons and patients to endure unnecessary delay of more than 32%. Such additional time could be used to deal with the pressure of emergency cases and to reduce waiting lists for elective surgery. PMID- 21590504 TI - Neural activity, neural connectivity, and the processing of emotionally valenced information in older adults: links with life satisfaction. AB - This study examines whether differences in late-life well-being are linked to how older adults encode emotionally valenced information. Using fMRI with 39 older adults varying in life satisfaction, we examined how viewing positive and negative images would affect activation and connectivity of an emotion-processing network. Participants engaged most regions within this network more robustly for positive than for negative images, but within the PFC this effect was moderated by life satisfaction, with individuals higher in satisfaction showing lower levels of activity during the processing of positive images. Participants high in satisfaction showed stronger correlations among network regions-particularly between the amygdala and other emotion processing regions-when viewing positive, as compared with negative, images. Participants low in satisfaction showed no valence effect. Findings suggest that late-life satisfaction is linked with how emotion-processing regions are engaged and connected during processing of valenced information. This first demonstration of a link between neural recruitment and late-life well-being suggests that differences in neural network activation and connectivity may account for the preferential encoding of positive information seen in some older adults. PMID- 21590505 TI - "Smart inhibition": electrophysiological evidence for the suppression of conflict generating task rules during task switching. AB - A major challenge for task switching is maintaining a balance between high task readiness and effectively ignoring irrelevant task rules. This calls for finely tuned inhibition that targets only the source of interference without adversely influencing other task-related representations. The authors show that irrelevant task rules generating response conflict are inhibited, causing their inefficient execution on the next trial (indicating the presence of competitor rule suppression[CRS];Meiran, Hsieh, & Dimov, Journal of Experimental Psychology: Learning, Memory and Cognition, 36, 992-1002, 2010). To determine whether CRS influences task rules, rather than target stimuli or responses, the authors focused on the processing of the task cue before the target stimulus was presented and before the response could be chosen. As was predicted, CRS was found in the event-related potentials in two time windows during task cue processing. It was also found in three time windows after target presentation. Source localization analyses suggest the involvement of the right dorsal prefrontal cortex in all five time windows. PMID- 21590506 TI - En-case-ing the patient: disciplining uncertainty in medical student patient presentations. AB - The problem-oriented medical record is the widespread, standardized format for presenting and recording information about patients, which is taught to future physicians early in their medical training. Based on our participant observation of medical training, we analyze the ways in which the patient presentation operates in medical training as a disciplinary technology that manages uncertainty in the clinical decision-making process. We uncover various mechanisms at work including the construction of a coherent narrative structure in which chaotic experiences are re-organized and re-interpreted to fit neatly in a linear plot with a predictable ending, the atomization of the patient as a whole into separable "problems," the attempt to solve these "problems" as though they are independent of one another, and the mystification of translations in scale, which give rise to much of the uncertainty in medicine. Operating at the boundary of the chaotic and often ungraspable world of the suffering experience of the patient and the highly structured realm of the medical record, a patient presentation is one medium through which both a disciplined record of experience and disciplined medical practitioners are produced. This process functions to transform the human subject patient into a recognizable, generic clinical case, and the medical student into an identifiable, professional future physician. PMID- 21590507 TI - Chloroplast biotechnology, genomics and evolution: current status, challenges and future directions. PMID- 21590508 TI - A cotton group C MAP kinase gene, GhMPK2, positively regulates salt and drought tolerance in tobacco. AB - Mitogen-activated protein kinase (MAPK) cascades play important roles in mediating biotic and abiotic stress responses. In plants, MAPKs are classified into four major groups (A-D) according to their sequence homology and conserved phosphorylation motifs. Compared with well-studied MAPKs in groups A and B, little is known about group C. In this study, we functionally characterised a stress-responsive group C MAPK gene (GhMPK2) from cotton (Gossypium hirsutum). Northern blot analysis indicated that GhMPK2 was induced by abscisic acid (ABA) and abiotic stresses, such as NaCl, PEG, and dehydration. Subcellular localization analysis suggested that GhMPK2 may activate its specific targets in the nucleus. Constitutive overexpression of GhMPK2 in tobacco (Nicotiana tabacum) conferred reduced sensitivity to ABA during both seed germination and vegetative growth. Interestingly, transgenic plants had a decreased rate of water loss and exhibited enhanced drought and salt tolerance. Additionally, transgenic plants showed improved osmotic adjustment capacity, elevated proline accumulation and up regulated expression of several stress-related genes, including DIN1, Osmotin and NtLEA5. beta-glucuronidase (GUS) expression driven by the GhMPK2 promoter was clearly enhanced by treatment with NaCl, PEG, and ABA. These results strongly suggest that GhMPK2 positively regulates salt and drought tolerance in transgenic plants. PMID- 21590509 TI - Novel clinical finding in MECP2 duplication syndrome. PMID- 21590510 TI - Neighborhood foreclosures and self-rated health among breast cancer survivors. AB - PURPOSE: We determined the association of neighborhood foreclosure risk on the health status of a statewide sample of breast cancer survivors (n = 1047) and the extent to which covariates accounted for observed associations. METHODS: Measures of self-rated health and several covariates were obtained by telephone interview 1 year after diagnosis. We used the federal Housing and Urban Development agency's estimated census-tract foreclosure-abandonment-risk score and multilevel, logistic regression to determine the association of foreclosure risk (high, moderate versus low) with self-rated health (fair-poor versus good, very good, excellent) and whether covariates could explain the observed association. RESULTS: Women who resided in high-foreclosure-risk (HFR) areas were 2.39 times (95% CI: 1.83-3.13) more likely to report being in fair-poor health than women who lived in low-foreclosure-risk areas. The odds ratio (OR) was reduced for women who lived in high-foreclosure-risk versus low-foreclosure-risk areas after adjusting for income (HFR OR: 1.78; 95% CI: 1.01-3.15), physical activity (HFR OR: 1.74; 95% CI: 0.98-3.08), and perceived neighborhood conditions (HFR OR: 1.76; 95% CI: 1.02-3.05). CONCLUSIONS: Breast cancer survivors who lived in census tracts with high- versus low-foreclosure risk reported poorer health status. This association was explained by differences in household income, physical activity, and perceived neighborhood conditions. PMID- 21590511 TI - Quality and acceptability of patient-reported outcome measures used in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. AB - PURPOSE: To review the quality and acceptability of condition-specific, domain specific and generic multi-item patient-reported outcome measures (PROMs) used in the assessment of adults with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). METHODS: Systematic literature searches were made to identify PROMs. Quality and acceptability was assessed against an appraisal framework, which captured evidence of both the thoroughness and results of evaluations: evidence of measurement (reliability, validity, responsiveness, interpretability, data quality/precision) and practical properties (feasibility, patient acceptability), and the extent of active patient involvement was sought. RESULTS: A total of 11 CFS/ME-specific, 55 domain-specific and 11 generic measures were reviewed. With the exception of the generic SF-36, all measures had mostly limited evidence of measurement and/or practical properties. Patient involvement was poorly reported and often cursory. CONCLUSIONS: The quality and acceptability of reviewed PROMs is limited, and recommendations for patient-reported assessment are difficult. Significant methodological and quality issues in PROM development/evaluation were identified by the appraisal framework, which must be addressed in future research. Clear discrepancies exist between what is measured in research and how patients define their experience of CFS/ME. Future PROM development/evaluation must seek to involve patients more collaboratively to measure outcomes of importance using relevant and credible methods of assessment. PMID- 21590512 TI - Effects of temporal trial-by-trial cuing on early and late stages of auditory processing: evidence from event-related potentials. AB - Temporal-cuing studies show faster responding to stimuli at an attended versus unattended time point. Whether the mechanisms involved in this temporal orienting of attention are located early or late in the processing stream has not been answered unequivocally. To address this question, we measured event-related potentials in two versions of an auditory temporal cuing task: Stimuli at the uncued time point either required a response (Experiment 1) or did not (Experiment 2). In both tasks, attention was oriented to the cued time point, but attention could be selectively focused on the cued time point only in Experiment 2. In both experiments, temporal orienting was associated with a late positivity in the timerange of the P3. An early enhancement in the timerange of the auditory N1 was observed only in Experiment 2. Thus, temporal attention improves auditory processing at early sensory levels only when it can be focused selectively. PMID- 21590513 TI - Spatial and identity negative priming in audition: evidence of feature binding in auditory spatial memory. AB - Two experiments are reported with identical auditory stimulation in three dimensional space but with different instructions. Participants localized a cued sound (Experiment 1) or identified a sound at a cued location (Experiment 2). A distractor sound at another location had to be ignored. The prime distractor and the probe target sound were manipulated with respect to sound identity (repeated vs. changed) and location (repeated vs. changed). The localization task revealed a symmetric pattern of partial repetition costs: Participants were impaired on trials with identity-location mismatches between the prime distractor and probe target-that is, when either the sound was repeated but not the location or vice versa. The identification task revealed an asymmetric pattern of partial repetition costs: Responding was slowed down when the prime distractor sound was repeated as the probe target, but at another location; identity changes at the same location were not impaired. Additionally, there was evidence of retrieval of incompatible prime responses in the identification task. It is concluded that feature binding of auditory prime distractor information takes place regardless of whether the task is to identify or locate a sound. Instructions determine the kind of identity-location mismatch that is detected. Identity information predominates over location information in auditory memory. PMID- 21590514 TI - New insights into the pathophysiology of pes cavus in Charcot-Marie-Tooth disease type 1A duplication. AB - Forefoot pes cavus is a cardinal sign of Charcot-Marie-Tooth disease (CMT). This review is focused on the pathophysiology of pes cavus in CMT1A duplication, which is the most common subtype of the disease. Assessment of foot deformities in CMT1A, their prevalence and proposed mechanisms, and recent contributions of magnetic resonance imaging studies of lower-leg and foot musculature are revised. Special attention is given to papers on foot deformities at initial stages of the disease. We conclude that pes cavus is an early and age-dependent manifestation of CMT1A duplication. Selective denervation of intrinsic foot musculature, particularly of the lumbricals, and not imbalance of lower-leg muscles, seems to be the initial mechanism causing reduced ankle flexibility and forefoot cavus deformity. PMID- 21590515 TI - AGEs, RAGE, and diabetic retinopathy. AB - Diabetic retinopathy is a major diabetic complication with a highly complex etiology. Although there are many pathways involved, it has become established that chronic exposure of the retina to hyperglycemia gives rise to accumulation of advanced glycation end products (AGEs) that play an important role in retinopathy. In addition, the receptor for AGEs (RAGE) is ubiquitously expressed in various retinal cells and is upregulated in the retinas of diabetic patients, resulting in activation of pro-oxidant and proinflammatory signaling pathways. This AGE-RAGE axis appears to play a central role in the sustained inflammation, neurodegeneration, and retinal microvascular dysfunction occurring during diabetic retinopathy. The nature of AGE formation and RAGE signaling bring forward possibilities for therapeutic intervention. The multiple components of the AGE-RAGE axis, including signal transduction, formation of ligands, and the end-point effectors, may be promising targets for strategies to treat diabetic retinopathy. PMID- 21590516 TI - Enantioselective recognition of tartaric acids with ethynylated carbazole-based chiral bisboronic acid chemosensors with improved response at acidic pH. AB - Chiral bisboronic acid chemosensors based on ethynylated carbazole were prepared. The chiral chemosensors show red-shifted emission than the chemosensors with unsubstituted carbazole fluorophore. a-PET effect was found for the chemosensors, which is different from our previous observation of the d-PET effect for boronic acid chemosensors based on carbazole. Enantioselective recognition of tartaric acids was implicated with these chemosensors. Consecutive fluorescence emission enhancement/diminishment were observed with increasing the concentration of the tartaric acids, which is tentatively assigned to the transition of the binding stoichiometry from 1:1 binding to 1:2 binding. In particularly interesting is the improved fluorescence response at acidic pH for recognition of tartaric acids, which is rarely observed for a-PET chemosensors. We propose that the sensing is due to hybrid mechanism of a-PET/d-PET and conformational restriction upon binding. Our results will be useful for design of chiral boronic acid chemosensors with improved fluorescence response at acidic pH, which are rarely reported. PMID- 21590517 TI - Development and linkage analysis of 104 new microsatellite markers for bay scallop (Argopecten irradians). AB - For genetic analysis and linkage mapping of bay scallop (Argopecten irradians), a set of 120 novel simple sequence repeat markers were developed from microsatellite-enriched libraries and expressed sequence tags. An inter subspecies hybrid bay scallop family (CC5) of 46 progeny was analyzed as the reference population to confirm polymorphism and test the segregation patterns of these loci. A total of 104 microsatellite markers were polymorphic in the reference family, among which 36 in female, 28 in male, and 40 in both parents, respectively. Linkage analysis allowed mapping these markers to 15 linkage groups, which is close to the haploid chromosome number of bay scallop (n = 16). Analysis of the 40 markers segregating in both parents showed a higher recombination rate in the female parent, with the average of female-to-male recombination ratio of 1.09:1 between linked pairs of markers. When null alleles were considered, there were 17 loci showing segregation distortion at the 5% significance level using the chi-square test. The microsatellite markers developed in this study provide a useful resource for future linkage mapping and quantitative loci analysis in A. irradians. PMID- 21590518 TI - Interventional management for cancer pain. AB - Cancer pain is a distressing result of disease, both primary and metastatic, as well as complications caused by cancer treatment. Medication management often is insufficient to adequately treat the ensuing pain or the complications of medical management limit acceptable dosage for pain control. In these instances, interventional modalities are an additional tool in the pain physician's armamentarium. Most commonly employed are intrathecal opioids, local anesthetic and clonidine infusions, neurolytic-nerve and sympathetic-ganglion blockade, and radiofrequency techniques. These are discussed in this article concomitantly with current outcome data as reported in the medical literature. PMID- 21590519 TI - Application of intraoperative indocyanine green videoangiography to brain tumor surgery. AB - BACKGROUND: Videoangiography using indocyanine green (ICG) has been used in the ophthalmologic field for a long time. It was introduced to the neurosurgical field several years ago but has been limited to vascular surgeries. We applied ICG videoangiography to brain tumor surgery and evaluated the usefulness. METHODS: Twenty-three patients with a brain tumor who underwent microsurgical resection were analyzed. The pathological diagnosis was meningioma in 15 patients, metastasis in three, glioma in three, and hemangioblastoma in two. A microscope with a special filter and infrared excitation light to illuminate the operating field was used in this study. The intravascular fluorescence was imaged with a video camera attached to the microscope. ICG was injected intravenously with the dose of 5-25 mg, and overall, ICG was injected intraoperatively 32 times. RESULTS: ICG videoangiography allowed for an excellent evaluation of blood flow in the tumoral and peri-tumoral vessels both before and after the resection in all cases. CONCLUSIONS: ICG videoangiography is a useful method for monitoring blood flow in the exposed vessels during microsurgery for a brain tumor. This noninvasive method is simple, safe, cost-effective, and easily repeatable. Before resection, it provides information on the tumoral and peri-tumoral circulation including sequential visualization of vessels or direction of the blood flow. After resection, it checks the patency of the peri-tumoral vessels and is especially useful for the vein. This ICG videoangiography can be an alternative tool to intraoperative angiography or Doppler ultrasonography in selective cases. PMID- 21590520 TI - Dronabinol, a cannabinoid agonist, reduces hair pulling in trichotillomania: a pilot study. AB - RATIONALE: Trichotillomania is characterized by repetitive pulling causing noticeable hair loss. Pharmacological treatment data for trichotillomania are limited. OBJECTIVE: Dronabinol appears to reduce the exocitotoxic damage caused by glutamate release in the striatum and offers promise in reducing compulsive behavior. METHODS: Fourteen female subjects (mean age = 33.3 +/- 8.9) with DSM IV trichotillomania were enrolled in a 12-week open-label treatment study of dronabinol (dose ranging from 2.5-15 mg/day). The primary outcome measure was change from baseline to study endpoint on the Massachusetts General Hospital Hair Pulling Scale (MGH-HPS). In order to evaluate effects on cognition, subjects underwent pre- and post-treatment assessments using objective computerized neurocognitive tests. Data were collected from November 2009 to December 2010. RESULTS: Twelve of the 14 subjects (85.7%) completed the 12-week study. MGH-HPS scores decreased from a mean of 16.5 +/- 4.4 at baseline to 8.7 +/- 5.5 at study endpoint (p = 0.001). Nine (64.3%) subjects were "responders" (i.e., >= 35% reduction on the MGH-HPS and "much or very much improved" Clinical Global Impression scale). The mean effective dose was 11.6 +/- 4.1 mg/day. The medication was well-tolerated, with no significant deleterious effects on cognition. CONCLUSIONS: This study, the first to examine a cannabinoid agonist in the treatment of trichotillomania, found that dronabinol demonstrated statistically significant reductions in trichotillomania symptoms, in the absence of negative cognitive effects. Pharmacological modulation of the cannabinoid system may prove useful in controlling a range of compulsive behaviors. Given the small sample and open-label design, however larger placebo-controlled studies incorporating cognitive measures are warranted. PMID- 21590521 TI - Effects of continuous positive airway pressure on apnea-hypopnea index in obstructive sleep apnea based on long-term compliance. AB - PURPOSE: Although continuous positive airway pressure (CPAP) is the gold standard in the treatment of obstructive sleep apnea (OSA), its effectiveness depends on the regular use. In this retrospective study, the effectiveness of CPAP with regard to the reduction of the apnea-hypopnea index was calculated based on individual adherence data extracted from a cohort of patients with OSA METHODS: The electronic database was analyzed for follow-up visits of patients receiving CPAP for OSA. The following information was extracted the charts of 750 patients: apnea-hypopnea index (AHI) at diagnosis, AHI with CPAP, duration of therapy, hours of CPAP use, and subjective hours of sleep. Eighty-two successfully treated and stable CPAP patients (AHI/Epworth Sleepiness Scale (ESS) at baseline 35.6 +/- 22.1/10.5 +/- 5.1) could be further evaluated. RESULTS: Mean AHI under CPAP was 2.4 +/- 2.5 with an ESS of 6.9 +/- 4.2. Subjective hours of sleep were 6.5 +/- 1.1. The average treatment period was 584.6 +/- 566.5 days (3,800 h of sleep). Mean hours of use was 2,712 +/- 3,234 (4.69 +/- 2.42 per night). This leads to the following calculated measures: hours of sleep without CPAP, 1,088; number of respiratory events with CPAP, 6508.8; number of respiratory events without CPAP, 38,732.8; total number or respiratory events, 45,241.6; average AHI, 11.91. CONCLUSIONS: Even in an ideal group of patients, CPAP cannot eliminate respiratory events due to limited adherence. Adherence needs to be taken into account when comparing the effects of CPAP on the AHI with alternative treatment methods, especially those with 100% adherence (e.g., surgery). PMID- 21590522 TI - Short-term after-effect of forearm cast removal in children. AB - PURPOSE: To investigate the sensation in the hand after forearm cast removal in children. METHODS: The study group included 33 consecutive children who were treated nonoperatively for a forearm fracture at our center over a 1-year period. The children were asked to report any sensation in the ipsilateral hand after cast removal, and the findings were analyzed against background and fracture related data. RESULTS: The patients ranged in age from 6 to 14 years (median 10.00 years). Seventeen had been immobilized in an above-elbow cast and the remainder in a below-elbow cast. All children treated with an above-elbow cast complained that after cast removal, the hand on that side felt limp, and they had to hold it with the contralateral hand. By contrast, only one child treated with a below-elbow cast reported this sensation (p = 0.0001, Fisher exact test). CONCLUSIONS: Orthopedic surgeons and rehabilitation unit staff should be aware of the possibility of a very short-term sensation of drooping and weakness of the hand after removal of an above-elbow cast in children and prepare the child and parents accordingly in order to lessen unnecessary anxiety. PMID- 21590523 TI - Activation of glial cells in the spinal cord of a model of lumbar radiculopathy. AB - PURPOSE: Glial cells in the spinal cord of a lumbar radiculopathy model were investigated using immunohistochemical methods. Neuropathic pain is a consequence of neural plasticity. In models of neuropathic pain models, roles for glial cells in the development of pain behaviors have been reported. Accumulating evidence suggests that activation of p38 mitogen-activated protein kinase (p38) in glial cells contributes to the pathogenesis of neuropathic pain. We examined whether activation of glial cells is involved in the development of neuropathic pain-like behavior observed in a model of lumbar radicular pain that we developed. However, the pathogenesis of lumbar radiculopathy and in particular the effect of spinal glial activation on pain transmission in the dorsal horn of the spinal cord are still not fully known. METHODS: The left L5 spinal root of Sprague-Dawley rats was ligated proximal to the DRG to produce models of lumbar radiculopathy. Protein levels of phosphorylated-p38 (p-p38) in the spinal cord were quantified by Western blot analysis. Double-immunofluorescense studies of p-p38 and specific markers of glia and neurons were performed to determine when and which types of cells were activated in the spinal cord. RESULTS: We observed p38 activation in hyperactive microglia in the dorsal horn ipsilateral to surgery at 1 and 7 days after root constriction, but not in astrocytes or neurons. CONCLUSIONS: Constriction of the lumbar root activated microglia in the spinal cord at 1 and 7 days after surgery, and then returned to normal state at 28 days after surgery, while pain behavior continued. These findings suggest that development of lumbar radicular pain may be initiated by activation of microglia. PMID- 21590524 TI - Recent stressful life events: Their long term effects. AB - The long-term effects of undesirable life events are reviewed. Two forms of major event that are outside the child's control, divorce and war, are discussed together with the literature investigating the impact of undesirable life events on subsequent risk for psychopathology and maladjustment. The impact of any event cannot be easily predicted without a substantial knowledge of its antecedents, nature and consequences for the child's current environmental circumstances. The indications are that some children may be life event prone as a consequence of either not being protected from adverse circumstances in the family or peer group; or contributing, through their own behavioural style, to an increased likelihood of life event occurrence. The evidence supports the notion that, whatever the origins of life events, they increase the risk of subsequent psychopathology or poor adaptation to subsequent environmental demands such as school achievement. There are marked individual differences in outcome from exposure to similar severe events. The degree of risk for either subsequent psychopathology or poor adaptation is best determined by a knowledge of life events in association with other forms of adverse or ameliorating circumstances rather than by life events alone. Psychological and physiological responses to events, as well as measures of the environment, should be incorporated in future longitudinal research to assist in explaining individual differences in outcome to similar undesirable circumstances. PMID- 21590525 TI - Adolescence and suicide: A review of psychological autopsy studies. AB - Increasing suicide rates among youth in many European and other Western countries have prompted growing public concern. In this article, psychological autopsy studies and complementary results from other studies of adolescent completed suicide are reviewed. These studies show that the majority of adolescent suicide completers has suffered from severe psychosocial symptoms. Approximately two thirds of the victims have communicated their suicidal intentions, and about one third has made a previous suicide attempt. Less than half of the adolescent victims have been under psychiatric care, and even fewer at the time of suicide. Current knowledge on the specific risk factors for adolescent completed suicide is not conclusive. Further research is needed for understanding e.g. the mediating mechanisms of family related risk factors, and the role of antisocial and aggressive behaviour in adolescent suicide. PMID- 21590526 TI - The modification and standardisation of the Harter self-esteem questionnaire with Scottish school children. AB - This paper describes a study to modify an American questionnaire measuring self esteem in children for use in the United Kingdom and also to obtain normative values for this questionnaire with Scottish school children aged 8-15 years. Five thousand children resident in the Lothian Region of Scotland, a 5% sample of the age group, were identified using a cluster sampling technique in order to provide a random sample of the general population for this age group. The main findings were as follows: children usually rated themselves higher than the midpoint on most subscales, indicating that they have a positive regard for themselves; boys tended to rate themselves higher than girls on most subscales except behaviour; scores tended to decline as children get older, especially for girls; global or overall self-esteem was highly correlated with the other subscales, especially physical appearance or attractiveness; self-esteem scores were not influenced by social class, school or religion. The modified Harter questionnaire can be used to measure self-esteem in several situations. These include comparisons between different groups of children, changes in self-esteem following treatment interventions or the effects of illness on children's psychological adjustment. Finally, the study has provided normative values for a Scottish population of school children aged 8-15 years. PMID- 21590528 TI - Three siblings with Asperger syndrome: A family case study. AB - Reports of multiple incidence of Asperger syndrome have suggested links between Asperger syndrome and autism. In this case study, we describe three siblings with Asperger syndrome based on the ICD-10 criteria. There was no family history of mental retardation or of autism. We propose that in some families, Asperger syndrome may occur as a distinct clinical entity and show no overlap with autism. PMID- 21590527 TI - Cognitive functioning in female patients with 21-hydroxylase deficiency. AB - The cognitive functioning of 27 female patients with congenital adrenal hyperplasia (CAH) (aged 11-41 yrs) and 13 of their healthy sisters (13-31 yrs) was compared using short versions of age-appropriate Wechsler scales. In contrast to other studies, neither a higher than average IQ level for CAH patients (mean: 99.0) nor for their sisters (97.7) was found. Unexpectedly, and in contrast to other reports, the subgroup of salt-wasting (SW) patients>16 yrs (N=6; mean score: 111.5) differed from their sisters as well as from simple-virilizing (SV) patients in "full IQ" (p<0.05) and subtest scorings for "Information", "Similarities", and "Picture Completion" (p<0.05-<0.10). SW patients displayed "more masculine" behaviour (vs. SV patients and sisters) which, in turn, was related to differential prenatal hormonal influences. No clear-cut relationships between IQ/cognitive (subtest) findings and gender-role behaviour were found. PMID- 21590529 TI - SPECT (Single Photon Emission Computed Tomography) in 31 children and adolescents with autism and autistic-like conditions. AB - SPECT with Tc-99m-HM-PAO was used in examining 31 patients with autism and autistic-like conditions. Sixteen of these had autistic disorder/autistic-like conditions with associated epilepsy. The autistic disorder group without epilepsy was relatively high functioning. All 31 patients showed reduction of regional cerebral blood flow in the temporal lobes. There was no clear difference between the groups with and without epilepsy, suggesting that seizure disorder per se could not account for the findings. PMID- 21590530 TI - The definition and prevalence of autism: A review. AB - Sixteen studies of the prevalence of autism in childhood, using epidemiological methods in defined populations in Europe, the USA and Japan, in English or with English summaries, were found in the published literature. Age specific rates varied from 3.3 to 16.0 per 10,000. Eight studies gave rates for a sub-group of 'typical' autism varying from 1.2 to 8.4. Reasons for variations were sought by examining geographic and demographic details of the populations screened, methods for initial screening and final examination of possibly autistic children, demographic and clinical details of children identified as autistic, and criteria used for diagnosis. There was evidence, independent of diagnostic criteria, of a higher prevalence among children of first generation immigrants to Europe from 'exotic' countries. Apart from this, all differences could be due to variations in diagnostic practice and increasing awareness of the manifestations of autistic conditions throughout the range of intelligence, from severely retarded to average and above. However, it remains possible, though not proven, that rates do vary over place and/or time. The problems of defining a sub-group with 'typical' autism among the wide spectrum of children with the triad of impairments of social interaction, communication and imagination are discussed and the value of such a sub-grouping questioned. PMID- 21590555 TI - Failure locus of the anterior cruciate ligament: 3D finite element analysis. AB - Anterior cruciate ligament (ACL) disruption is a common injury that is detrimental to an athlete's quality of life. Determining the mechanisms that cause ACL injury is important in order to develop proper interventions. A failure locus defined as various combinations of loadings and movements, internal/external rotation of femur and valgus and varus moments at a 25(o) knee flexion angle leading to ACL failure was obtained. The results indicated that varus and valgus movements were more dominant to the ACL injury than femoral rotation. Also, Von Mises stress in the lateral tibial cartilage during the valgus ACL injury mechanism was 83% greater than that of the medial cartilage during the varus mechanism of ACL injury. The results of this study could be used to develop training programmes focused on the avoidance of the described combination of movements which may lead to ACL injury. PMID- 21590556 TI - Do women and men consider abortion as an alternative to contraception in the United States? An exploratory study. AB - The USA, a country with widespread access to the full range of modern methods of contraception, continues to have one of the highest abortion rates among developed countries. Forty-nine per cent of women reported ever experiencing an unintended pregnancy in 2001; 48% of these conceptions occurred during a month that contraception was used. We explored the extent to which people use contraception and abortion interchangeably to achieve their fertility goals via focus groups (n = 4) and semi-structured in-depth interviews (IDIs) (n = 18) with men and women between the ages of 18 and 35 in New York City in 2006. While there was a consensus that abortion cannot replace contraceptive use, poor couple communication, lack of planning, lack of acceptable contraceptive methods and the pleasures that people associate with having unprotected sex result in the perception that some individuals rely on abortion over contraception to prevent unintended births. Men and women both identified women as solely in charge of avoiding an unwanted pregnancy and resolving it should one occur. No one supported repeat abortions for themselves or others, and many respondents perceived multiple abortions to lead to infertility, which strengthens their position that substituting abortion for contraception is unacceptable. PMID- 21590557 TI - Conflict, displacement and health in the Middle East. AB - Displacement is a hallmark of modern humanitarian emergencies. Displacement itself is a traumatic event that can result in illness or death. Survivors face challenges including lack of adequate shelter, decreased access to health services, food insecurity, loss of livelihoods, social marginalisation as well as economic and sexual exploitation. Displacement takes many forms in the Middle East and the Arab World. Historical conflicts have resulted in long-term displacement of Palestinians. Internal conflicts have driven millions of Somalis and Sudanese from their homes. Iraqis have been displaced throughout the region by invasion and civil strife. In addition, large numbers of migrants transit Middle Eastern countries or live there illegally and suffer similar conditions as forcibly displaced people. Displacement in the Middle East is an urban phenomenon. Many displaced people live hidden among host country populations in poor urban neighbourhoods - often without legal status. This represents a challenge for groups attempting to access displaced populations. Furthermore, health information systems in host countries often do not collect data on displaced people, making it difficult to gather data needed to target interventions towards these vulnerable populations. The following is a discussion of the health impacts of conflict and displacement in the Middle East. A review was conducted of published literature on migration and displacement in the region. Different cases are discussed with an emphasis on the recent, large-scale and urban displacement of Iraqis to illustrate aspects of displacement in this region. PMID- 21590558 TI - The Golden Crescent and HIV/AIDS in Central Asia: deadly interactions. AB - Afghanistan has become the world's largest producer of illicit opiates. Opium and its derivative heroin are widespread substances of use, abuse and dependency in Central Asia. The region is currently undergoing expanding HIV epidemics driven largely by needle sharing among people who use drugs, in contexts where public health interventions to reduce the harms associated with substance use are limited by policy, law and legalistic and repressive approaches to drug users. Evidence-based approaches to drug treatment are lacking or limited in multiple states. Urgent reform is needed. The massive volumes of Afghan's illicit opiate exports are having serious impacts on the health of the region. PMID- 21590559 TI - A sociocognitive approach to service quality and adherence amongst elderly patients: a pilot study. AB - This article examines the relationship between patients' perceptions of emotional intelligence (EI), health competence, service quality, and adherence behavior in the Home Medicines Review (HMR) setting. Participants were purposively recruited from different urban and regional areas in Australia and qualitative data were obtained from in-depth interviews with 20 HMR patients. Service quality is conceptualized from a sociocognitive perspective by incorporating psycho-socio factors such as EI and health competence as moderators to overall service quality and adherence. The findings suggest that EI and health competence influence patient perceptions of service quality and nonadherence at multiple levels of abstraction. Implications are that staff training and development programs that incorporate EI could improve service delivery which could increase patient perceptions of service quality and adherence. Designing intervention initiatives aimed at increasing patient awareness and education of their health conditions could also improve service quality perceptions and adherence behavior. PMID- 21590560 TI - Who are the medical travelers and what do they want?: a qualitative study. AB - The ongoing debate on U.S. healthcare reform fueled by increasing cost and poor access to quality healthcare is spurring interest in medical travel. The topic of medical travel-going abroad to seek medical care-has been widely reported in various news outlets. This issue even resulted in a Senate Hearing before the Special Committee on Aging. Despite this popularity, very little empirical research has been conducted to describe and understand medical travelers. To fill this gap, the present study involves in-depth interviews of medical travel facilitators with extensive exposure to and communication with medical travelers. This article has multiple objectives. It aims to develop a demographic and psychographic profile of medical travelers and identify their underlying motives to seek medical care overseas. Based on these insights, it presents a list of propositions to be tested in further research. Finally, it offers practical implications for the healthcare industry. PMID- 21590561 TI - Asymmetric responsiveness of physician prescription behavior to drug promotion of competitive brands within an established therapeutic drug class. AB - This article examines the impact of direct-to-physician, direct-to-consumer, and other marketing activities by pharmaceutical companies on a mature drug category which is in the later stage of its life cycle and in which generics have accrued a significant market share. The main objective of this article is to quantitatively estimate the impact of pharmaceutical promotions on physician prescribing behavior for three different statin brands, after controlling for factors such as patient, physician and physician practice characteristics, generic pressure, et cetera. Using unique panel data of physicians, combined with patient pharmacy prescription records, the authors developed a physician level generalized linear regression model. The generalized estimating equations method was used to account for within physician serial correlations and estimate physician population averaged effects. The findings reveal that even though on average the marketing efforts affect the brand share positively, the magnitude of the effects is very brand specific. Generally, each statin brand has its own trend and because of this, the best choice of predictors for one brand could be suboptimal for another. PMID- 21590562 TI - Qualitative triadic study of the relational factors influencing the formation of quality in a community-based aged health care service network. AB - A service is produced through the interactions of the various service participants. This study aims to identify the factors that influence the interactions of the service providers, recipients, and enablers of a community based aged health care service, within a single service network. Interviews were conducted with the manager, three care workers, and five clients using the convergent interview technique. Data were analyzed inductively using thematic content analysis. Client focus, client contribution, client empowerment, and provider empowerment were identified as key themes. Whilst these themes are independently supported by the literature, they have previously been studied largely in isolation to each other. PMID- 21590563 TI - Jordanian pharmaceutical companies: are their marketing efforts paying off? AB - The pharmaceuticals industry is one of the main industries in Jordan. Jordanian pharmaceuticals rank third in the export industry of this country. This study aims to examine the strengths that Jordanian pharmaceutical companies have, which, in turn, form their competitiveness base. In addition, this study aims to identify their weaknesses and the effects of marketing their products in the local market. What is the relationship between Jordanian pharmaceutical product quality, price and value, and the competitiveness of pharmaceutical companies in the local market? Our study aims to answer this and other questions. Our results and practical implications are discussed. PMID- 21590564 TI - Generational cohorts hold the key to understanding patients and health care providers: coming-of-age experiences influence health care behaviors for a lifetime. AB - The health care landscape is ever changing. Medical groups are experiencing challenges in recruiting staff, dealing with managing effective clinical teams, and tempering the growing tensions among partnerships and medical groups. Additionally, all clinicians report many patients are now approaching them differently than in the past. They come armed with medical information from the Internet and a more questioning attitude toward the clinician's directive for care. What accounts for these behavioral changes and management challenges within health care organizations? These issues may be best understood and addressed through generational cohort analysis. PMID- 21590565 TI - "Between the devil and the deep blue sea": the beliefs of caregivers of people with dementia regarding the use of in-home respite services. AB - This article details results from qualitative research with caregivers in regard to the beliefs they associate with the use of in-home respite services. Outcomes are perceived by caregivers in relation to care recipient personal safety and the avoidance of negative consequences through the provision of supervision in the caregiver's absence. Use of in-home services challenges normative beliefs for some caregivers, particularly for spousal caregivers who feel it is their role to provide assistance that is needed in the home. Likewise, perceived inflexibility and the inability of in-home services to provide responsive and personalized care make the use of in-home services difficult and may inform control beliefs. Implications are discussed in relation to community care pathways and the promotion and development of in-home respite services to better target caregiver beliefs and respond to caregiver perceived needs. PMID- 21590566 TI - The Minnesota Live Well at Home Project: screening and client satisfaction. AB - The objective of the Minnesota Live Well at Home Program (LWAH) was to develop a screening tool that targets private-pay older persons at risk for nursing home admission or assisted living entry and delivers a multi-component "diversion" service program to support these clients. Two hundred sixty-one clients completed the brief screening protocol, and 3-month telephone surveys (N=119) collected additional pilot evaluation data to determine content of diversion service support and satisfaction with various LWAH components. The preliminary findings showed that the screening tool was delivered efficiently and targeted clients at potential high risk for residential care placement. Clients were also satisfied with the multi-component LWAH service. The results provide support for the feasibility of a LWAH risk management process that links community-residing older persons with community-based long-term care options. PMID- 21590567 TI - Motivating high-risk older adults to exercise: does coaching matter? AB - The aim of the study was to compare two coaching channels--a combination of telephone and face-to-face coaching (combined phone and face-to-face) versus telephone coaching only (phone)--on exercise performances in a home-based low intensity program. Multiple regression models were used to examine if the two coaching channels were associated with different 3-month posttest exercise performances. Individuals with the combined phone and face-to-face coaches had better exercise performances at 3-month posttest, compared to those who received phone coaching only. The evaluation suggests that, in a home-based, low-intensity training program that has been demonstrated to benefit high-risk, ethnically diverse older adults, face-to-face coaching appears to be a more powerful motivator than a phone-based approach only. PMID- 21590568 TI - Occupational risk factors for blood and body fluid exposure among home care aides. AB - This cross-sectional study of home care aides examines self-reported occupational exposure to blood and body fluids to determine if factors that place these workers at risk can be identified. Home care aides working for two agencies in the Chicagoland area were surveyed. A total of 62 (6.3%) of the home care aides reported instances of blood and body fluid exposure either via sharps or mucous membrane contact. Although few aides reported performing health care-related tasks such as colostomy care, caring for a urinary catheter, or bowel stimulation (which were outside their scope of duties), those who did were significantly more likely to experience blood and body fluid exposure (p<=.01). Level of assistance needed by clients in tasks such as feeding, laundry, and transportation was also found to be significantly associated with blood and body fluid exposure (p<=.01). These data highlight the importance of, and need for, home care aid training in the use of universal precautions. PMID- 21590569 TI - Media, social proximity, and risk: a comparative analysis of newspaper coverage of Avian Flu in Hong Kong and in the United States. AB - This study uses the psychometric paradigm (Renn & Rohrmann, 2000; Slovic, 1992) as an analytic framework to analyze the risk dimensions being conveyed in media coverage of Avian flu in Hong Kong and in the United States between 2003 and 2007. A quantitative content analysis of The New York Times and South China Morning Post stories showed different patterns of avian flu related risk content coverage. The differences revealed that dimensions related to dreadfulness, catastrophic potential, uncertainty, and unfamiliarity were more emphasized in The New York Times than in South China Morning Post. The authors discuss the implications. PMID- 21590570 TI - Sensitivity and specificity of the Distress Impact Thermometer for the detection of psychological distress among CRC survivors. AB - This study assessed the relative screening performance of the Distress Impact Thermometer (DIT) and cutoff levels with the established clinical case threshold of the Hospital Anxiety and Depression Scale (HADS) among a sample of colorectal cancer (CRC) survivors. Fifty-nine CRC survivors completed the DIT, HADS, and provided demographic information at baseline, and 45 of these patients completed the same measures at follow-up, giving a total of 104 participant data. Receiver operating characteristic (ROC) analysis was performed to determine the accuracy of the DIT compared to the HADS, with a cutoff score >=8 on each HADS subscale (depression and anxiety) and >=15 on the HADS total scale used to identify patients with psychological distress. The sample comprised slightly more males (63%) than females, with an average age of 59 years (SD = 9.53) and ranging from 33 to 77 years. The optimum DT cutoff score of >=5 yielded a sensitivity of 60% and specificity of 86.1%; the area under the curve was 0.771 (95% confidence interval [CI] [0.646, 0.896]). For the depression subscale, the DT performed better on specificity than sensitivity, however the opposite was true for the anxiety subscale. The addition of an impact thermometer did not enhance screening performance. The results of this study provide support for a DT score of >=5 for detecting psychological distress among CRC survivors and do not support the addition of an impact thermometer. The use of the DT might underestimate depression but overestimate anxiety. PMID- 21590571 TI - Use of psychosocial support services among male Veterans Affairs colorectal cancer patients. AB - The authors describe use of psychosocial services within +/- 3 months of diagnosis among male colorectal cancer (CRC) patients treated within the Veterans Affairs (VA) health care system. Analysis included 1,199 patients with CRC treated at 27 VA medical centers primarily diagnosed between the periods 2005 to 2007. Of the patients, 78.6% received some form of psychosocial support, including 50.5% social work, 58.9% chaplain, 6.2% psychologist, 7.1% psychiatry, 3.5% mental health nurse, and 4.4% other. Logistic regression results indicate that rectal cancer patients were less likely to receive psychosocial services (odds ratio = .65, 95% confidence interval [0.43, 0.97]). The majority of patients in the VA receive some type of psychosocial service at the time of CRC diagnosis. PMID- 21590572 TI - How to be a patient in a palliative life experience? A qualitative study to enhance knowledge about coping abilities in advanced cancer patients. AB - To date there has been little research that reveals and describes the connection between the individual and his or her environment, which is the foundation for the coping process. These findings are part of a grounded theory study. The article shows how "the struggle to be a participant in one's own life" was identified as a central tendency in coping with advanced cancer. It involved a pattern of four life conditions: alleviation from a life-threatening illness, carry on a normal life, live with powerlessness, and find courage and strength, which were characterized by a series of limitations and resources significant to coping. PMID- 21590573 TI - Patient counselling on the risk of infertility and its impact on childhood cancer survivors: results from a national survey. AB - Fertility can be impaired by radiation and chemotherapy among childhood cancer survivors. Therefore, timely and adequate patient counselling about the risk of infertility and preservation methods is needed. The primary study objective was to assess remembered counselling among childhood cancer survivors. As a second objective, the impact of lacking patient counselling on offspring-related attitudes and behaviour was examined. Counselling regarding the late effects of gonadotoxicity that could be recalled by patients was assessed using a questionnaire sent by the German Childhood Cancer Registry. The questionnaire was answered by 2754 adult childhood cancer survivors (53.1% female, mean = 25.7 years). The proportion of patients who could not remember patient counselling about the late effects of chemo-/radiotherapy on fertility decreased significantly over time. In 1980 to 1984 67%, in 2000 to 2004 50% of the patients reported no memories of counselling (p < .001). Counselled patients feared significantly less that their children may have an increased cancer risk (4.4% vs. 6.7%, p = .03). They were also more likely to undergo fertility testing than patients who could not recall counselling (odds ratio = 2.91, 95% confidence interval [2.12, 3.99]). Patients reported an increased memory of patient counselling over the past 25 years. Still, a 50% rate of recalled counselling shows an ongoing need for adequate and especially sustainable counselling of paediatric cancer patients about infertility and other long-term adverse treatment effects. Those who reported a lack of counselling had offspring-related fears more frequently, which stopped them from having children. PMID- 21590574 TI - The impact of specialized oncology nursing on patient supportive care outcomes. AB - Meeting the supportive care needs of cancer patients remains a challenge to cancer care systems around the world. Despite significant improvements in the organization of medical care of patients with cancer, numerous surveys of cancer populations demonstrate that significant proportions of patients fail to have their supportive care needs met. One possible solution is the introduction of a care coordinator role using oncology nursing to help ensure that patients' physical, psychological, and social support needs are addressed. Although having face validity, there is little empirical evidence on the effects of nurse-led supportive care coordinator roles on patient reported supportive care outcomes. In this article the authors present the results of a prospective longitudinal cohort study of 113 patients referred to a community-based specialist oncology nursing program. Using validated instruments they found significant improvements in patient-reported outcomes in key supportive care domains: unmet needs, quality of life, and continuity of care, as well as a shift in patterns of health resource utilization from acute care settings to the community over the course of the intervention. The results of this study are important in supporting the design and development of controlled trials to examine provider roles in the coordination of supportive cancer care. PMID- 21590575 TI - Coping together and apart: exploring how patients and their caregivers manage terminal head and neck cancer. AB - Head and neck cancer (HNC) challenges the physical, social, and psychological well-being of the individual, and their family and friends, with 50% of patients facing the prospect of dying within 5 years of diagnosis. To enhance care at the end of life, further understanding of how patients and their loved ones cope is needed. Findings from a qualitative study are presented which suggest that patients with terminal HNC and their caregivers cope individually, with support and as a dyad. Relationship qualities which might facilitate coping together as a dyad are described. These may aid distinction between coping together and acts of social support. PMID- 21590576 TI - Eliciting adaptive emotion in conversations with parents of children receiving therapy for leukemia. AB - Clinician-parent communication may often be difficult, especially soon after the diagnosis. The aims of this article are to identify the communication strategies associated with expressions of adaptive emotions in parents and to explore the effect of the type of leukemia and of parent's gender on parents' expressions of emotions. The data are obtained from 4.622 conversational turns of 20 videotaped interviews with 10 mothers and 10 fathers of children at their first hospitalization for leukemia. A coding scheme for parent emotional expressions was reliably applied by two independent judges. An original self-report questionnaire on parents' emotional states was used before and after the interview. Positive politeness of interviewer elicits adaptive emotional expressions in parents. Mothers of children with acute myeloid leukemia and fathers of children with acute lymphoblastic leukaemia appear more distressed during the interview. This interview can be identified as an innovative technique of communication with parents of children with cancer. PMID- 21590577 TI - Quadriceps muscle blood flow and oxygen availability during repetitive bouts of isometric exercise in simulated sailing. AB - In this study, we wished to determine whether the observed reduction in quadriceps muscle oxygen availability, reported during repetitive bouts of isometric exercise in simulated sailing efforts (i.e. hiking), is because of restricted muscle blood flow. Six national-squad Laser sailors initially performed three successive 3-min hiking bouts followed by three successive 3-min cycling tests sustained at constant intensities reproducing the cardiac output recorded during each of the three hiking bouts. The blood flow index (BFI) was determined from assessment of the vastus lateralis using near-infrared spectroscopy in association with the light-absorbing tracer indocyanine green dye, while cardiac output was determined from impedance cardiography. At equivalent cardiac outputs (ranging from 10.3+/-0.5 to 14.8+/-0.86 L . min(-1)), the increase from baseline in vastus lateralis BFI across the three hiking bouts (from 1.1+/-0.2 to 3.1+/-0.6 nM . s(-1)) was lower (P = 0.036) than that seen during the three cycling bouts (from 1.1+/-0.2 to 7.2+/-1.4 nM . s(-1)) (Cohen's d: 3.80 nM . s(-1)), whereas the increase from baseline in deoxygenated haemoglobin (by ~17.0+/-2.9 MUM) (an index of tissue oxygen extraction) was greater (P = 0.006) during hiking than cycling (by ~5.3+/-2.7 MUM) (Cohen's d: 4.17 MUM). The results suggest that reduced vastus lateralis muscle oxygen availability during hiking arises from restricted muscle blood flow in the isometrically acting quadriceps muscles. PMID- 21590578 TI - Effect of biological maturation on maximal oxygen uptake and ventilatory thresholds in soccer players: an allometric approach. AB - In this study, we investigated the effect of biological maturation on maximal oxygen uptake ([Vdot]O(2max)) and ventilatory thresholds (VT(1) and VT(2)) in 110 young soccer players separated into pubescent and post-pubescent groups.. Maximal oxygen uptake and [Vdot]O(2) corresponding to VT(1) and VT(2) were expressed as absolute values, ratio standards, theoretical exponents, and experimentally observed exponents. Absolute [Vdot]O(2) (ml . min(-1)) was different between groups for VT(1), VT(2), and [Vdot]O(2max). Ratio standards (ml . kg(-1) . min( 1)) were not significantly different between groups for VT(1), VT(2), and [Vdot]O(2max). Theoretical exponents (ml . kg(-0.67) . min(-1) and ml . kg(-0.75) . min(-1)) were not properly adjusted for the body mass effects on VT(1), VT(2), and [Vdot]O(2max). When the data were correctly adjusted using experimentally observed exponents, VT(1) (ml . kg(-0.94) . min(-1)) and VT(2) (ml . kg(-0.95) . min(-1)) were not different between groups. The experimentally observed exponent for [Vdot]O(2max) (ml . kg(-0.90) . min(-1)) was different between groups (P = 0.048); however, this difference could not be attributed to biological maturation. In conclusion, biological maturation had no effect on VT(1), VT(2) or [Vdot]O(2max) when the effect of body mass was adjusted by experimentally observed exponents. Thus, when evaluating the physiological performance of young soccer players, allometric scaling needs to be taken into account instead of using theoretical approaches. PMID- 21590579 TI - Determinants and patterns of physical activity practice among Spanish university students. AB - The purpose of the present study was to investigate the socio-demographic and lifestyle determinants of physical activity practice, as well as the motivations for being or not being physically active in Spanish university students. A representative sample of students from a Spanish university (n = 2,051; 42.1% males; mean age 21.9, s = 4.8 years) participated in the present cross-sectional study. A questionnaire including questions regarding lifestyle, dietary habits, parents' characteristics, and physical activity habits was administered to the students. The socio-demographic and lifestyle determinants of physical activity practice were assessed using multivariable logistic regression. 68.4% of men and 48.4% of women reported to practise physical activity in the present sample. Those who practised physical activity consumed more fruits and were less likely to be smokers compared to non-physically active students. Also, physically inactive men spent more time in front of the computer and physically inactive women spent more time in front of the TV and were more likely to be frequent alcohol consumers. Maternal educational level and maternal physical activity habits were also important determinants of physical activity practice among men and women respectively. In conclusion, physically active students tended to engage in other healthy habits in the present population, suggesting the clustering of healthy or unhealthy lifestyle factors among specific subgroups. PMID- 21590580 TI - Death and injury from automobile collisions: an overlooked epidemic. AB - Automobile collisions are a major source of injury, death, and disability worldwide. Roadway injuries are affected by societal and cultural influences as much as any other health-related event, but have historically received relatively little attention from the medical anthropology community. The development of safety intervention strategies is affected by notions of responsibility for preventive care, including a balance between regulation, technology, and personal choice. This balance may be affected by perceptions of the risks associated with roadway use, potentially related to notions of individual control and the portrayal of collisions in the popular media and lexicon. Prevention efforts are also affected by the definition of injury as a disease-a biological phenomenon requiring research and intervention efforts from the medical and public health communities. Injury prevention priorities and strategies also differ across cultures and locales, dependent in part on economic constraints, native mobility practices, and the quality and expediency of post-trauma care. Progressing injury prevention worldwide requires multidisciplinary action, including an examination of these various cultural and societal influences. We believe that future efforts will benefit from the expertise and analysis of the medical anthropology community. PMID- 21590581 TI - Aging disaster: mortality, vulnerability, and long-term recovery among Katrina survivors. AB - Data from this multiyear qualitative study of the effects of Hurricane Katrina and flooding in New Orleans suggest differences in how the elderly cope with disaster. At the time of the disaster, the elderly of New Orleans were at greater risk than other groups, and more elderly died than any other group during the storm and in the first year after. Those who did survive beyond the first year report coping with the long-term disaster aftermath better than the generation below them, experiencing heightened stresses, and feeling as if they are "aging" faster than they should. We offer insight on how we might define and characterize disasters, and illustrate that long-term catastrophes "age" in specific ways. PMID- 21590582 TI - Facing victims: forensics, visual technologies, and sexual assault examination. AB - This article analyzes a particular legal-medical artifact: the photos of wounds and injuries collected by forensic nurses who work with sexual assault victim patients. I show how forensic expertise draws on multiple medical practices and adapts these practices with the goal of preserving the integrity of the evidence collection processes. In particular, forensic nurse examiners practice a rigid regime of draping and avoiding the victim-patient's gaze at some points in the forensic routine while engaging the victim's gaze at other points in the examination. Unlike the examination, the photograph itself deliberately pictures the patient's gaze to break the plane of the image, giving the photographic artifact an affective charge as a truth-preserving object within a juridical process. Focusing on forensic photography sheds light on the techno-scientific possibilities that enable forensic encounters as they align therapeutic techniques with legal directives in new and problematic ways. PMID- 21590583 TI - Taking humor seriously: talking about drinking in Native American focus groups. AB - Focus groups provide a source of data that highlight community ideas on a topic of interest. How interview data will be utilized varies by project. With this in mind, we identify ways that focus group data from a particular population (Native American) articulate a health issue of individual tribal concern (alcohol consumption). Taking our analytic framework from linguistics, one of the four fields of inquiry in anthropology, we examine format ties and the performance of humor as stylistic features of tribal focus groups and illustrate how linguistic devices can be used in analyzing aspects of adolescent and adult drinking. Focus group data require systematic review and analysis to identify useful findings that can lead to inquiry points to initiate collaborative work with local experts before the data can be developed and configured into effective program initiatives. PMID- 21590584 TI - Can you keep a secret? Pretences of confidentiality in HIV/AIDS counseling and treatment in Eastern Indonesia. AB - A critical feature of contemporary interventions of HIV is the provision of voluntary counseling and testing. Protecting the confidentiality of the client is a lynchpin of successful counseling. This article explores the teaching and implementation of the concept of confidentiality in highlands Papua, Eastern Indonesia. Results of participant observation and in-depth interviews with clinic staff in 2009 and 2010 show that confidentiality is an ideal poorly taught and systematically violated in practice. Identifying, labeling, and regulating HIV positive persons appears more important than enacting the humanitarian and moral imperative of protecting client rights. Confidentiality becomes the means to enact dividing practices and to create categories of persons-those who choose to adhere to therapies and those who do not. The implications of this pattern are discussed with reference to wider humanitarian initiatives. PMID- 21590585 TI - Functional connectivity between the left and right inferior frontal lobes in a small sample of children with and without reading difficulties. AB - Individuals with dyslexia often demonstrate bilateral inferior frontal lobe activation while performing basic reading tasks. To investigate these findings, functional connectivity analyses were conducted on fMRI data collected from children with dyslexia, who did and did not respond well to treatment, and from non-impaired readers. Analysis of active and resting-state fMRI data across 15 participants revealed functional connections between the inferior frontal regions in non-impaired readers and treatment responders, but not in treatment non responders. Analyses incorporating DTI data revealed associations with anterior corpus callosum structures. These results suggest that bilateral frontal functional connectivity is normative and may facilitate treatment response. PMID- 21590586 TI - Identification of psychopathic individuals using pattern classification of MRI images. AB - BACKGROUND: Psychopathy is a disorder of personality characterized by severe impairments of social conduct, emotional experience, and interpersonal behavior. Psychopaths consistently violate social norms and bring considerable financial, emotional, or physical harm to others and to society as a whole. Recent developments in analysis methods of magnetic resonance imaging (MRI), such as voxel-based-morphometry (VBM), have become major tools to understand the anatomical correlates of this disorder. Nevertheless, the identification of psychopathy by neuroimaging or other neurobiological tools (e.g., genetic testing) remains elusive. METHODS/PRINCIPAL FINDINGS: The main aim of this study was to develop an approach to distinguish psychopaths from healthy controls, based on the integration between pattern recognition methods and gray matter quantification. We employed support vector machines (SVM) and maximum uncertainty linear discrimination analysis (MLDA), with a feature-selection algorithm. Imaging data from 15 healthy controls and 15 psychopathic individuals (7 women in each group) were analyzed with SPM2 and the optimized VBM preprocessing routines. Participants were scanned with a 1.5 Tesla MRI system. Both SVM and MLDA achieved an overall leave-one-out accuracy of 80%, but SVM mapping was sparser than using MLDA. The superior temporal sulcus/gyrus (bilaterally) was identified as a region containing the most relevant information to separate the two groups. CONCLUSION/SIGNIFICANCE: These results indicate that gray matter quantitative measures contain robust information to predict high psychopathy scores in individual subjects. The methods employed herein might prove useful as an adjunct to the established clinical and neuropsychological measures in patient screening and diagnostic accuracy. PMID- 21590587 TI - Where in the brain is morality? Everywhere and maybe nowhere. AB - The neuroscience of morality has focused on how morality works and where it is in the brain. In tackling these questions, researchers have taken both domain specific and domain-general approaches-searching for neural substrates and systems dedicated to moral cognition versus characterizing the contributions of domain-general processes. Where in the brain is morality? On one hand, morality is made up of complex cognitive processes, deployed across many domains and housed all over the brain. On the other hand, no neural substrate or system that uniquely supports moral cognition has been found. In this review, we will discuss early assumptions of domain-specificity in moral neuroscience as well as subsequent investigations of domain-general contributions, taking emotion and social cognition (i.e., theory of mind) as case studies. Finally, we will consider possible cognitive accounts of a domain-specific morality: Does uniquely moral cognition exist? PMID- 21590589 TI - [On the history of one form of social psychiatric care: family care exemplified on the Leipzig-Dosen asylum]. AB - On the basis of archival sources and primary literature the study exemplifies the history of one form of extramural social psychiatric care on the example of one particular institution, the town asylum of Leipzig-Dosen. Family care was introduced in Leipzig in 1904 by Georg Lehmann, primarily as an alternative treatment option. After initial opposition among the local population had been defeated, this form of treatment was soon quite accepted. Due to the socioeconomic changes as a result of World War I, the extent of family care was downsized. From 1940 family care in Dosen was abolished, due to a change in ideology. Part of the patients previously in family care fell victim to the National socialist T-4 programme to murder chronically mental ill. However, this study could also prove that at least one third of these patients survived. It can only be presumed to which extent this was due to their physical work being needed as a result of war shortages. PMID- 21590588 TI - Neural basis of moral verdict and moral deliberation. AB - How people judge something to be morally right or wrong is a fundamental question of both the sciences and the humanities. Here we aim to identify the neural processes that underlie the specific conclusion that something is morally wrong. To do this, we introduce a novel distinction between "moral deliberation," or the weighing of moral considerations, and the formation of a "moral verdict," or the commitment to one moral conclusion. We predict and identify hemodynamic activity in the bilateral anterior insula and basal ganglia that correlates with committing to the moral verdict "this is morally wrong" as opposed to "this is morally not-wrong," a finding that is consistent with research from economic decision-making. Using comparisons of deliberation-locked vs. verdict-locked analyses, we also demonstrate that hemodynamic activity in high-level cortical regions previously implicated in morality--including the ventromedial prefrontal cortex, posterior cingulate cortex, and temporoparietal junction--correlates primarily with moral deliberation as opposed to moral verdicts. These findings provide new insights into what types of processes comprise the enterprise of moral judgment, and in doing so point to a framework for resolving why some clinical patients, including psychopaths, may have intact moral judgment but impaired moral behavior. PMID- 21590590 TI - [A comparison of homicide-suicide and domestic homicide in the region of basle, Switzerland]. AB - BACKGROUND: Homicide-suicide and domestic homicide without consecutive suicide might be regarded as an extreme form of domestic violence. According to the national crime-register, however, there might be some relevant differences between the perpetrators of the two. METHOD: The files of all cases of homicide suicide (n = 24) and of all cases of domestic homicide without suicide (n = 21), which had been examined at the Institute of forensic medicine in Basle between 1987 und 2006, were compared. RESULTS: Perpetrators of domestic homicide without suicide were significantly younger, had a poorer educational background and were rather foreigners. About two thirds of the perpetrators of homicide-suicide used a gun compared with only one third of those committing domestic homicide. DISCUSSION: Measures as they are known from suicide prevention programmes like limiting the access to lethal instruments like guns might be useful in the case of homicide-suicide, measures for the prevention of domestic homicide should aim at better integration and education of the perpetrators and their family. PMID- 21590592 TI - Antenatally detected mature teratoma in an undescended testis. PMID- 21590591 TI - [A case of affective disorder with psychotic symptoms as late manifestation of Huntington's Chorea]. AB - We report about a woman of 60 years who received psychiatric inpatient treatment for an affective disorder with psychotic symptoms on several occasions. As time elapsed symptoms of dementia became more and more obvious. Despite a comprehensive workup with neuroimaging methods (SPECT, PET) the correct diagnosis of Huntington's Chorea was not attained until the characteristic movements appeared. Up till then pathologic movements had hardly occurred and there were no known cases of Huntington's Chorea in the family. This case is remarkable as the patient was not only treated with different antidepressants and antipsychotics but with a course of ECT too. Beyond this it shows the enormous stress this illness imposes on patients and their caregivers. PMID- 21590594 TI - An unusual case of invasive Blastocystis hominis infection. PMID- 21590593 TI - [The plastic surgical treatment of progressive skin lesions caused by calciphylaxis]. PMID- 21590595 TI - Successful salvage treatment of peptic duodenal stenosis with repeat insertion of self-expanding stent after failed balloon dilation. PMID- 21590596 TI - Esophageal obstruction due to a collapsed biodegradable esophageal stent. PMID- 21590597 TI - Severe gastric ischemia after combined sclerotherapy for bleeding gastric ulcer. PMID- 21590598 TI - Novel use of combined Dual Knife and endoloop for resection of a large pedunculated colon polyp. PMID- 21590599 TI - Endosonographic and elastographic features of a rare epidermoid cyst of an intrapancreatic accessory spleen. PMID- 21590600 TI - Benign schwannoma of the hepatoduodenal ligament. PMID- 21590601 TI - Duodenal vascular ectasia (DUVE) associated with hematopoietic stem cell transplant. PMID- 21590602 TI - Fluorescein-aided endomicroscopy for detection of signet ring cell carcinoma. PMID- 21590603 TI - Inverted sessile serrated polyp diagnosed by magnifying image-enhanced colonoscopy. PMID- 21590604 TI - Five interval colorectal cancers. PMID- 21590605 TI - Colonoscopy complicated by arterial avulsion and retroperitoneal hemorrhage. PMID- 21590606 TI - Malignant fibrous histiocytoma of the small bowel with colon metastasis. PMID- 21590607 TI - Spontaneous tension pneumocephalus after esophagogastroscopy. PMID- 21590608 TI - Primary gastric, duodenal, and rectal signet ring cell carcinoma revealed by cutaneous metastasis. PMID- 21590609 TI - Insertion of two overlapping new covered metal stents for closure of a complex biliary leak and description of a safe technique for their removal. PMID- 21590610 TI - Tapered-tip Teflon catheter: another device for sequential dilation in endoscopic ultrasound-guided hepaticogastrostomy. PMID- 21590611 TI - Mucosal tears during colonoscopy in a patient with ulcerative colitis. PMID- 21590613 TI - Mixed cavernous hemangioma-lymphangioma of the jejunum: detection by wireless capsule endoscopy. PMID- 21590612 TI - Disseminated histoplasmosis: a rare cause of multiple ulcers in the gastrointestinal tract. PMID- 21590614 TI - Primary jejunal angiosarcoma: an extremely rare tumor diagnosed by means of anterograde spiral enteroscopy. PMID- 21590615 TI - A rare case of a pancreatic mass due to accessory spleen; when EUS-FNA is not enough. PMID- 21590617 TI - Acute and subacute encephalopathies. PMID- 21590618 TI - Encephalopathies caused by electrolyte disorders. AB - Some of the most common reasons for metabolic neurologic disturbances in the setting of a general hospital are frequently encountered electrolyte and related osmolality disorders. Hyperosmolality is usually related to hypernatremia and/or hyperglycemia. Identifying the cause and carefully calculating the water deficit is crucial to appropriate management. Hyponatremia may be hypertonic, isotonic, or hypotonic. When hypotonic, it may be hypervolemic, euvolemic, or hypovolemic in nature. Determining the precise nature of the hyponatremia allows the clinician to focus the therapy appropriately. The rate of development of hyponatremia is crucial to safe and appropriate treatment. In acutely developing hyponatremia, hypertonic saline is required, whereas in slowly developing hyponatremia, water restriction and slow correction is required to avoid the syndrome of osmotic demyelination. Disorders of potassium metabolism are also common electrolyte disorders seen in the general hospital. Appropriate diagnosis and management of hyperkalemia and hypokalemia are also discussed. PMID- 21590619 TI - Uremic encephalopathy and other brain disorders associated with renal failure. AB - Kidney failure is one of the leading causes of disability and death and one of the most disabling features of kidney failure and dialysis is encephalopathy. This is probably caused by the accumulation of uremic toxins. Other important causes are related to the underlying disorders that cause kidney failure, particularly hypertension. The clinical manifestations of uremic encephalopathy include mild confusional states to deep coma, often with associated movement disorders, such as asterixis. Most nephrologists consider cognitive impairment to be a major indication for the initiation of renal replacement therapy with dialysis with or without subsequent transplantation. Sleep disorders, including Ekbom's syndrome (restless legs syndrome) are also common in patients with kidney failure. Renal replacement therapies are also associated with particular neurologic complications including acute dialysis encephalopathy and chronic dialysis encephalopathy, formerly known as dialysis dementia. The treatments and prevention of each are discussed. PMID- 21590620 TI - Autoimmune encephalopathy. AB - Autoimmune encephalopathy represents a complex category of disease with diverse immunologic associations, clinical manifestations, and therapeutic outcomes. Three main subgroups include autoimmune encephalopathies without cancer but with neural nonspecific serologic evidence of autoimmunity (encompassing "Hashimoto's encephalopathy") that is the main focus of this review, paraneoplastic encephalopathies, and central nervous system (CNS) vasculitis (primary or secondary). Diagnosis of autoimmune encephalopathy can be suspected based on the clinical course, serologic evidence of autoimmunity, severe but nonspecific slowing on electroencephalography, and evidence of intrathecal inflammation in the cerebrospinal fluid. Rarely, there will be evidence of meningeal enhancement or increased fluid attenuated inversion-recovery signal in symptomatic regions on magnetic resonance imaging, but diagnosis may require brain biopsy demonstration of perivascular lymphocytic infiltrates. Nonspecific autoimmune encephalopathies are generally much more therapeutically responsive than paraneoplastic and vasculitic encephalopathies, so that high-dose corticosteroids may produce dramatic improvement within as little as a few days, although exceptional patients can require months of therapy. Paraneoplastic syndromes typically require tumor removal and often prove fatal. CNS vasculitides may respond to steroid therapy, but often require a second agent such as cyclophosphamide. PMID- 21590621 TI - Immune-mediated encephalopathies with an emphasis on paraneoplastic encephalopathies. AB - Recent identification of syndromes encompassing psychiatric symptoms, seizures, and movement disorders has led to effective treatments for several previously obscure conditions now known to be immune-mediated encephalopathies. In contrast to long-recognized paraneoplastic neurologic syndromes associated with antibodies to intracellular antigens, these more recently described disorders are not always paraneoplastic, are associated with cell surface antibodies, and may respond to immunosuppressive therapies. In this review, the author discusses clinical presentations, differential diagnosis, immunologic evaluation, and therapeutic options for both groups of disorders. PMID- 21590622 TI - Acute and subacute encephalopathies: deficiency states (nutritional). AB - Optimal functioning of the central and peripheral nervous system is dependent on a constant supply of essential nutrients. Nutritional deficiencies of thiamine and niacin, rarely vitamin B (12), and possibly folate can cause a wide range of neuropsychiatric manifestations. Neurologic manifestations associated with these deficiency states are the focus of this review. The preventable and potentially treatable nature of these disorders makes this an important subject. Prognosis depends on prompt recognition and institution of appropriate therapy. PMID- 21590623 TI - Toxic encephalopathy. AB - Neurotoxic exposures are common. Although there are myriad substances that can cause encephalopathy, this review focuses on common environmental neurotoxins, such as select heavy metals, organic industrial toxins, and pesticides. The central nervous system is susceptible to toxic injury, and many environmental neurotoxins are capable of causing encephalopathy. When a patient presents with toxic encephalopathy, the differential diagnosis is initially broad. The clinical presentation after exposure to a toxin varies in severity among patients. Arriving at the correct diagnosis is often a diagnostic challenge. The importance of taking a good history and performing a comprehensive examination cannot be overemphasized. Neuroimaging and neurophysiologic testing typically play ancillary roles. Confirmatory laboratory testing is available for some toxins. Treatment of most toxic encephalopathies is not supported by clinical trials; additional research is needed in the field. PMID- 21590624 TI - Seizures and encephalopathy. AB - There is a complex relationship between seizures and encephalopathy. Seizures alone without any underlying neurologic or medical illness can be the sole cause of encephalopathy. Often these patients have a history of epilepsy, in which case accurate diagnosis is straightforward. Acute neurologic conditions often contribute to encephalopathy, but also increase the risk of seizures--many of which are subclinical. In these scenarios, it can be difficult to determine whether the encephalopathy is caused by seizures, the underlying neurologic disorder, or both. In addition, systemic diseases are commonly associated with encephalopathy; they may also increase the risk of seizures, although less commonly than acute neurologic conditions, and therefore may go unrecognized. This review will examine common and uncommon causes of seizures in encephalopathic patients, typical clinical presentations as well as diagnosis and treatment. PMID- 21590625 TI - Posterior reversible encephalopathy syndrome: a review. AB - Encephalopathy due to reversible cerebral edema is an important cause of neurologic morbidity accompanying many disorders. Although controversy remains concerning the pathophysiologic trigger, the mechanism of this disorder ultimately depends on failure of the blood-brain barrier to maintain the compartmentalization of intravascular fluid. This failure of the blood-brain barrier depends primarily on the capillary hydrostatic pressure, under the influence of the systemic blood pressure, and on the integrity of the structures that make up the blood-brain barrier, most importantly the vascular endothelium, under the influence of various diseases and toxic medications. Although typical clinical contexts and presentations have been well defined, many patients have atypical features that pose a diagnostic challenge. Therefore, awareness of this clinical variability is important for prompt diagnosis. This review discusses the history and pathophysiology of posterior reversible encephalopathy syndrome and then addresses its clinical diagnosis and management. PMID- 21590626 TI - Post-cardiac arrest encephalopathy. AB - Brain injury continues to be a leading cause of mortality and morbidity in patients resuscitated after cardiac arrest. During periods of hypoxia and ischemia, numerous mechanisms contribute to the initial and secondary injury of the brain. Though many drugs and therapies have been evaluated for neuroprotection, only therapeutic hypothermia has been proven to be effective. Accurate prognostication after cardiac arrest is essential, and can be achieved with careful neurologic examination and several ancillary tests utilizing neurophysiology, neuroimaging, and biochemistry. Practice guidelines are now available for prognostication and postresuscitation care, with emphasis on improving survival and quality of life. Also reviewed are a wide spectrum of postarrest neurologic complications and their targeted treatments. PMID- 21590627 TI - [Perspectives in diabetes 2011: dialogue - experience - benefit]. PMID- 21590628 TI - [Initial education for parents of children with diabetes: effort and outcomes in children and parents]. AB - INTRODUCTION: Parents are responsible for the therapy and prognosis of their child with diabetes. Thus a structured initial education covering medical and psychosocial aspects of diabetes for parents offered by a multidisciplinary paediatric diabetes team is essential. METHODS: Quality of educational process and outcomes were assessed in 10 German paediatric diabetes units with parents of 81 children (4-14 yrs). A structured diabetes education programme for parents was used. Outcome parameters were parental satisfaction with education, diabetes knowledge (DWT: Typ1), children's quality of metabolic control and health related quality of life (QoL) (KINDL-R) and both parents' well-being (WHO-5) at onset (t0) and 6 (t1) and 12 (t2) months later. RESULTS: On average 30.6 +/- 10.1 lessons were required. Parents were highly satisfied with the education. Their diabetes knowledge at t0 and t1 exceeded the T-norms of the best educated adult patients. Children's QoL at t1 and t2, assessed by their parents, didn't differ from representative healthy norms. Mean HbA1c at t1 was 6.8 +/- 1.0% and 7.2 +/- 1.2% at t2. Compared to standard values of WHO-5 mothers' psychological well being was poor. Scores < 13 (indicating depression) were seen at 50% (t0), 41% (t1) and 29% (t2) of the mothers. DISCUSSION: The comprehensive diabetes education leads to high levels of diabetes knowledge and satisfaction with care. 12 months after diabetes onset the target of metabolic control (HbA1c < 7.5%) was met by 71% of the children, while their QoL was good. However, the great psychological burden of mothers at onset indicates their need for ongoing specialized care. PMID- 21590629 TI - [Clinical parameters for molecular testing of Maturity Onset Diabetes of the Young (MODY)]. AB - BACKGROUND: Monogenic forms of diabetes are often diagnosed by chance, due to the variety of clinical presentation and limited experience of the diabetologists with this kind of diabetes. Aim of this study was to evaluate clinical parameters for an efficient screening. METHODS: Clinical parameters were: negative diabetes specific antibodies at onset of diabetes, positive family history of diabetes, and low to moderate insulin requirements after one year of diabetes treatment. Molecular testing was performed through sequencing of the programming regions of HNF-4alpha (MODY 1), glucokinase (MODY 2) and HNF-1alpha/TCF1 (MODY 3) and in one patient the HNF-1beta/TCF2 region (MODY 5). 39 of 292 patients treated with insulin were negative for GADA and IA2A, and 8 (20.5%) patients fulfilled both other criteria. RESULTS: Positive molecular results were found in five (63%) patients (two with MODY 2, two with MODY 3, one with MODY 5). At diabetes onset, the mean age of the 5 patients with MODY was 10.6 +/- 5.3 yrs (range 2.6-15 yrs), HbA(1c) was 8.4 +/- 3.1 % (6.5-13.9%), mean diabetes duration until diagnosis of MODY was 3.3 +/- 3.6 yrs (0.8-9.6 yrs) with insulin requirements of 0.44 +/- 0.17 U/kg/d (0.2-0.6 U/kg/d). Patients with MODY 3 were changed from insulin to repaglinide, those with MODY 2 were recommended discontinuing insulin treatment. CONCLUSION: In patients with negative diabetes-specific antibodies at onset of diabetes, with a positive family history, and low to moderate insulin needs a genetic screening for MODY is indicated. Watchful consideration of these clinical parameters may lead to an early genetic testing, and to an adequate treatment. PMID- 21590630 TI - [Successful treatment with liraglutide in type 1 diabetes and MODY]. AB - HISTORY AND CLINICAL FINDINGS: A 22 year old obese woman with type 1 diabetes for 17 years and poor metabolic control despite continuous insulin infusion (case 1). Case 2 was a 16 year-old girl of normal weight in whom diabetes mellitus type 1 was diagnosed accidentally. Her 54 year old father was and had been treated for diabetes mellitus type 1 for 10 years. He was poorly controlled and associated with polyneuropathy and history of myocardial infarction (case 3). INVESTIGATIONS: In Case 1 the C-peptide test was negative, glutamic acid decarboxylase- and IA2-antibodies were not demonstrated. Cases 2 and 3 showed normal C-peptide, tests for GAD-, IA2- and ICA antibodies were negative. A nucleotid substitution in intron 1 of the HNF-4alpha gene was demonstrated. TREATMENT AND COURSE: All three patients were treated with liraglutide. There was a reduction in HbA(1c), glucose fluctuations, hypoglycaemia, daily insulin dose and body weight, as well as an improvement of well-being and quality of life. CONCLUSION: These case reports indicate that GLP-1 analogs may reduce postprandial and fasting glucose levels in non-type 2 diabetic patients, independently or residual beta cell function. Further studies are needed to evaluate the benefits of treatment with liraglutide in patients with type 1 or type 3 diabetes. PMID- 21590631 TI - [Complication after percutaneous dilation tracheostomy]. PMID- 21590632 TI - [The beta cell in diabetes]. PMID- 21590633 TI - [Is HbA1c suitable for diagnosis of diabetes? Pro]. PMID- 21590634 TI - [Is HbA1c suitable for diagnosis of diabetes? Contra]. PMID- 21590635 TI - [New perspectives of imaging techniques in islet research]. PMID- 21590636 TI - [Cross-border health care in Europe: will centers of reference for pediatric diabetes serve as a model?]. PMID- 21590637 TI - [Hypo- and hypernatremia]. PMID- 21590638 TI - [Elevation of troponin after epileptic seizures]. PMID- 21590639 TI - Effects of different vibration exercises on bench press. AB - This study was undertaken to analyze the effects of different vibration recovery strategies via feet or hands on the number of repetitions performed and on mean velocity, peak velocity and blood lactate concentration during consecutive bench press sets. 9 elite judo athletes performed 3 sets of bench press at 60% of one repetition maximum (1RM), leading to failure and allowing a 180 s rest period between sets. During the rest period, 1 of the 3 following procedures was performed: 150 s rest plus 30 s push-up vibration exercise (Push-up), 150 s rest plus 30 s squat vibration exercise (Squat) or 180 s only rest (Passive). Statistical analysis revealed that the Squat condition resulted in a significant increase in the number of repetitions achieved, in comparison with all other rest strategies. However, kinematic parameters and blood lactate concentration were not affected by vibration. These data suggest that a vibration stimulus applied to the feet, between sets, can result in positive improvements in upper body resistance exercise performance. Although the mechanisms are not fully understood, this positive effect of vibration could be due to an increased motor cortex excitability and voluntary drive. PMID- 21590640 TI - Maximal lactate steady state is altered in the heat. AB - The aim of this study was to compare the maximal lactate steady state (MLSS) and ventilatory threshold (VT) under different environments (TEMP: 22 degrees C; and HOT: 40 degrees C; 50% RH). 8 male subjects (age 23.9+/-2.4 years, body mass 75.9+/-7.3 kg and VO2(max) 47.8+/-4.9 mL.kg(-1).min(-1)) performed a series of tests to determine the peak workload (W(peak)), VT and MLSS on a cycle ergometer. W(peak) was higher in the TEMP as compared to the HOT condition (225+/-9 W vs. 195+/-8 W, respectively; p<0.05). The workload at MLSS was higher at 22 degrees C (180+/-11 W) than 40 degrees C (148+/-11 W; p<0.05), as well as VT at 22 degrees C (156+/-9 W) was higher than 40 degrees C (128+/-6 W). Likewise, the blood lactate concentration at MLSS was higher at 22 degrees C (5.60+/-0.26 mM) than 40 degrees C (4.22+/-0.48 mM; p<0.05). The mean of heart rate (HR) was not statistically different between TEMP (168+/-3 bpm) and HOT (173+/-3 bpm) at MLSS, despite being different at trials between the 25(th) and the 30(th) min of exercise. The HR at VT was significantly higher in HOT (153+/-4 bpm) as compared to the TEMP (145+/-2 bpm). Our results suggest that environmental conditions may influence the determination of MLSS and VT. Moreover, VT was appropriate for estimation of the workload at MLSS in the HOT. PMID- 21590641 TI - Contextual variables and time-motion analysis in soccer. AB - Using a multi-camera computerised tracking system the present study aimed to provide a detailed analysis of the work-rate profile of a team of elite soccer players during official matches of the Spanish Premier League. Observation-based performance measures were obtained from 434 individual samples. 6 physical parameters involving the distance covered by players were analysed: standing intensity (0-11 km.h (-1)), low-intensity running (11.1-14 km.h (-1)), moderate intensity running (14.1-17 km.h (-1)), high-intensity running (17.1-21 km.h ( 1)), very high-intensity running (21.1-24 km.h (-1)) and sprinting (>24 km.h ( 1)). These intensity thresholds were considered with respect to 4 contextual variables: MATCH STATUS, MATCH LOCATION, OPPONENT LEVEL and MATCH HALF, which were analysed in relation to the EFFECTIVE PLAYING TIME. A descriptive analysis and a multivariate mixed model were employed for the analysis of change processes in soccer. The distance total covered (m) by players at different work intensities during the EFFECTIVE PLAYING TIME was greater when playing at HOME (3 931 vs. 3 887 AWAY), when the reference team was LOSING (3 975 vs. 3 837 DRAWING and 3 921 WINNING) and when the level of the opposing team was HIGHER (4 032 vs. 3 938 MEDIUM and 3 736 BOTTOM). By contrast, their physical performance decreased during the 2NDHALF of matches (3 822 vs. 3 985 1ST HALF). PMID- 21590642 TI - Pre-race dietary carbohydrate intake can independently influence sub-elite marathon running performance. AB - We examined whether selected anthropometric and nutritional factors influenced field-based marathon running performance. An internet-based data collection tool allowed competitors in the 2009 London Marathon (n=257, mean +/- SD age: 39 +/- 8 years, finish time: 273.8 +/- 59.5 min) to record a range of anthropometric, training and nutritional predictors. Multivariate statistical methods were used to quantify the change in running speed mediated by a unit change in each predictor via the 95% confidence interval for each covariate-controlled regression slope ( B). Gender ( B=1.22 to 1.95 km/h), body mass index ( B=-0.14 to -0.27 km/h), training distance ( B=0.01 to 0.04 km/h) and the amount of carbohydrate consumed the day before the race ( B=0.08 to 0.26 km/h) were significant predictors, collectively accounting for 56% of the inter-individual variability in running speed (P<0.0005). Further covariate-adjusted analysis revealed that those competitors who consumed carbohydrate the day before the race at a quantity of >7 g/kg body mass had significantly faster overall race speeds (P=0.01) and maintained their running speed during the race to a greater extent than with those who consumed <7 g/kg body mass (P=0.02). We conclude that, in addition to gender, body size and training, pre-race day carbohydrate intake can significantly and independently influence marathon running performance. PMID- 21590643 TI - The effects of pre-exercise glycemic index food on running capacity. AB - This study examined the effects of pre-exercise food on different glycemic indexes (GI) on exercise metabolism and endurance running capacity. 9 subjects performed 3 exercise trials on different days 15 min after ingesting: lentils, (LGI), potatoes, (HGI), and placebo. Each subject ingested an equal amount of each food (1 g/kg body mass) and ran on a level treadmill for 5 min at 60%, 45 min at 70% and then at 80% of VO (2max) until exhaustion. Serum glucose concentrations were higher ( P<0.01) 15 min after the HGI trial compared to the LGI and placebo trials. In addition, serum glucose levels were higher ( P<0.05) during the LGI trial at the time of exhaustion compared to the HGI and placebo trials. Plasma insulin levels, 15 min after ingestion, were higher ( P<0.001) in the HGI trial as compared to the LGI and placebo trials. Exercise time was longer during the LGI trial ( P<0.05) compared to the placebo, but the time to exhaustion in the HGI condition did not differ from the placebo (LGI: 90.0 +/- 7.9; HGI: 81.8 +/- 5; placebo: 73.0 +/- 6.4 min). These results suggest that lentils, the LGI food, ingested 15 min before prolonged exercise maintained euglycemia during exercise and enhanced endurance running capacity. PMID- 21590644 TI - Injuries and overuse syndromes in powerlifting. AB - Powerlifting is a discipline of competitive weightlifting. To date, no investigations have focused on pain encountered during routine training. The aim of the study was to identify such pain, assign it to particular exercises and assess the data regarding injuries as well as the influence of intrinsic and extrinsic factors. Data of 245 competitive and elite powerlifters was collected by questionnaire. Information regarding current workout routines and retrospective injury data was collected. Study subjects were selected from 97 incorporated powerlifting clubs. A percentage of 43.3% of powerlifters complained of problems during routine workouts. Injury rate was calculated as 0.3 injuries per lifter per year (1 000 h of training=1 injury). There was no evidence that intrinsic or extrinsic factors affected this rate. Most commonly injured body regions were the shoulder, lower back and the knee. The use of weight belts increased the injury rate of the lumbar spine. Rate of injury to the upper extremities was significantly increased based on age >40 years (shoulder/p=0.003, elbow/p=0.003, hand+wrist/p=0.024) and female gender (hand+wrist/p=0.045). The daily workout of a large proportion of powerlifters is affected by disorders which do not require an interruption of training. The injury rate is low compared to other sports. PMID- 21590645 TI - Elite athletes and oral health. AB - Elite athletes follow demanding training regimes to achieve optimal performance. Training incorporates strategies which coincide with risk factors for dental caries and erosion. The important role of a disease-free oral cavity for peak performance is often overlooked and oral health may be compromised. This initial exploratory study aimed to identify risk factors for dental caries and erosion in elite triathletes. Questionnaires regarding training, diet and oral health were distributed to a sample of elite triathletes in New Zealand. A further sample of 10 athletes was randomly selected from the Dunedin triathlon club to participate in a clinical oral examination. Sports drinks were consumed by 83.9% of the triathletes while training; for 48.4% consumption of both sports drinks and water was described as 'little sips often, from a bottle'. Eating during training sessions was reported by 93.5% of participants; of those 62.1% ate only during cycling training. Only 3.2% perceived training as high risk to oral health. All clinical examination cases were assessed as high risk for developing caries. The diet of elite triathletes is consistent with a high risk profile for caries and erosion. Future research should be aimed at oral health promotion programs for the athletes, coaches and oral-health providers. PMID- 21590646 TI - Alpha-lipoic acid inhibits endoplasmic reticulum stress-induced cell death through PI3K/Akt signaling pathway in FRTL5 thyroid cells. AB - Alpha-lipoic acid (ALA) has been shown to modulate cell death via PI3K/Akt signal pathway in various cells. In the present study, the effects of ALA on cell death and PI3K/Akt signal pathway linked to cell death-related proteins during endoplasmic reticulum (ER) stress in FRTL5 thyroid cells were evaluated. In FRTL5 thyroid cells, cell viability increased by ALA pretreatment in tunicamycin (TN) treated cells. When TN was treated, CCAAT/enhancer-binding protein-homologous protein (CHOP) and Bax protein levels were elevated while Bcl-2 protein levels were reduced. ALA diminished CHOP and Bax protein levels, and augmented Bcl-2 protein levels in TN-treated cells. After exposure to TN, phospho-Akt protein levels were repressed whereas total Akt protein levels were not changed. ALA increased phospho-Akt protein levels but not total Akt protein levels in both non TN-treated and TN-treated cells. After LY294002 administration in non-TN-treated cells, cell viability was reduced, and CHOP and Bax protein levels were elevated, and Bcl-2 protein levels were reduced. The CHOP, Bcl-2 and Bax protein levels were not different after LY294002 administration in TN-treated cells. LY294002 and wortmannin decreased cell viability, and increased CHOP and Bax protein levels, and decreased Bcl-2 protein levels in ALA-pretreated and TN-treated cells. In conclusion, these results suggest that ER stress may induce cell death by modulating PI3K/Akt signal pathway linked to cell death-related proteins in FRTL5 thyroid cells. Moreover, these findings imply that ALA may ameliorate ER stress-induced cell death by activating PI3K/Akt signal pathway and attenuating changes of cell death-related proteins in FRTL5 thyroid cells. PMID- 21590647 TI - Prolonged inappropriate TSH suppression during hypothyroidism after thyroid ablation in a patient with nonautoimmune familial hyperthyroidism. AB - Prolonged TSH suppression was reported in a patient with nonautoimmune hyperthyroidism. These observations were made during L-thyroxine treatment and it was not possible to investigate a possible increase in serum TSH concentrations to levels observed in untreated hypothyroidism. We describe nonautoimmune familial hyperthyroidism identified in an Israeli woman, which is remarkable for the prolonged inappropriate TSH suppression after thyroid ablation. After 2 radioiodine treatments for several years, her TSH was always lower than 0.03 mU/l with 1.6 MUg/kg/day (100 MUg) thyroxine. 14 years after the radioiodine treatments, she discontinued thyroxine for 3.5 months and developed myxoedema with fT4 <6.0 and fT3 1.3 pmol/l and TSH of only 4.4 mU/l, which rose to only 8.6 after TRH. Genomic analysis showed a germline substitution M626I in the TSHR gene. Both exons of the thyroid-releasing hormone receptor revealed no mutations in this gene. Functional in vitro characterization of M626I showed a cell surface expression of 70% compared with the wt (100%), a significant increase of basal activity (5-fold over wt basal), which was confirmed by linear regression analysis (LRA) (slope: M626I=7, wt=1). No TRH-receptor mutation was detected. Therefore, this is the first patient with nonautoimmune hyperthyroidism with unequivocal evidence for inappropriately prolonged TSH suppression documented by a clearly insufficient TSH increase during clinical hypothyroidism. The in vitro characterization of the TSH-receptor mutation did not show any explanations for the prolonged TSH suppression. Therefore, other possible candidate genes remain to be investigated for potential explanations for this prolonged TSH suppression. PMID- 21590648 TI - Pioglitazone compared to glibenclamide on lipid profile and inflammation markers in type 2 diabetic patients during an oral fat load. AB - The aim of the study was to evaluate the effect of pioglitazone and glibenclamide on lipid profile and inflammatory parameters during an oral fat load (OFL). A total of 201 type 2 diabetic patients on treatment with metformin were enrolled in the study; pioglitazone was titrated till 45 mg/day and glibenclamide till 15 mg/day, in association with metformin, respectively. The patients underwent an OFL at baseline and after 12 months. The OFL was given between 08.00 and 09.00 h after a 12-h fast. Blood samples were drawn before and 3, 6, 9, and 12 h after the OFL. We evaluated glycemic-metabolic parameters [glycated hemoglobin (HbA (1c)), fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment (Homa) index], total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tgs), interleukin-6 (IL-6), high sensitivity C-reactive protein (Hs-CRP), tumor necrosis factor-alpha (TNF-alpha), and adiponectin (ADN). Pioglitazone was better than glibenclamide in decreasing HbA (1c), FPG, FPI, lipid profile, and in improving inflammatory parameters such as Hs-CRP, and ADN. Comparing the OFL performed at baseline, and the OFL performed at the end of the study, pioglitazone, but not glibenclamide, improved all post-OFL peaks for all parameters. Comparing the 12 months OFL in the group treated with pioglitazone and in the group treated with glibenclamide, the values recorded with pioglitazone were significantly better than the ones obtained with glibenclamide. We can conclude that pioglitazone was better than glibenclamide in mitigating the variations of lipid components and inflammation parameters in type 2 diabetic patients. PMID- 21590649 TI - [Risk assessment for domestic violence]. AB - The aim of the present study is to give a systematic overview of risk assessment instruments for the field of domestic violence. Six instruments were identified, which had been published in a peer-reviewed journal and for which validation studies exist: the Domestic Violent Screening Instrument (DVSI), the Danger Assessment (DA), the Spousal Assault Risk-Assessment (SARA), the Ontario Domestic Assault Risk-Assessment (ODARA), the Violence Risk Appraisal Guide (VRAG), and the Domestic Violence Risk Appraisal Guide (DVRAG). Their validity and practical use are discussed. PMID- 21590650 TI - Hydroxytyrosol induces vascular smooth muscle cells apoptosis through NO production and PP2A activation with subsequent inactivation of Akt. AB - Olive oil has been shown to exhibit beneficial effects in the prevention of cardiovascular diseases although its molecular mechanism still remains unclear. In the present study, we investigated the effect of hydroxytyrosol (HT), a major phenolic component in olive oil and leaves from OLEA EUROPAEA L. (Oleaceae family), on vascular smooth muscle cells (VSMCs) survival, migration, and apoptosis. HT treatment resulted in a dose-dependent decrease of cell survival and migration in the presence or absence of platelet-derived growth factor (PDGF) by inducing apoptosis of VSMCs. HT enhanced nitric oxide (NO) production in a dose-dependent manner, and the NO synthase inhibitor L-NMMA blocked HT-mediated effects on VSMCs survival. HT as well as the NO donor SNAP reduced the phosphorylation levels of Akt, suggesting that HT inactivates Akt via NO production with subsequent apoptosis of VSMCs. Moreover, HT-dependent apoptosis and reduction in the phosphorylation level of Akt were suppressed by okadaic acid, an inhibitor of protein phosphatase 2A (PP2A) that dephosphorylates Akt. In contrast, the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), an upstream activator of Akt, was not affected by HT. Together, these findings indicate that HT could induce VSMCs apoptosis through NO production and PP2A activation followed by inactivation of Akt signaling pathway. PMID- 21590651 TI - Cytotoxic steroids from Sarcococca saligna. AB - Two new C21-steroidal esters, sarsaligates A(1) and B(2), and two new steroidal alkaloids, sarsaligenines A(3) and B(4), together with four known compounds (sarcovagine, sarcorucinine, dimethylamino-3 beta-pregnane-20-one, and beta sitosterol 5- 8, respectively), were isolated from the leaves and stems of Sarcococca saligna. The structures of compounds 1-4 were elucidated by NMR and MS spectroscopic analysis. Of the compounds tested, 5 and 6 were the most cytotoxic against the cell lines K562, SK-BR-3, and PANC-1, with IC50 values in the range of 2.25-5.00 uM, while 3 and 4 selectively inhibited HL-60 cells with IC50 values of 2.87 and 3.61 uM, respectively. Compounds 3-6 therefore deserve further evaluation of their cytotoxic potentials. PMID- 21590652 TI - Monoterpenes isolated from Minthostachys verticillata (Griseb.) Epling essential oil modulates immediate-type hypersensitivity responses in vitro and in vivo. AB - In a previous work, we have demonstrated that Minthostachys verticillata essential oil has immunomodulatory effects in vitro on cells from allergic patients. Here we characterized main components of M. verticillata essential oil and also tested if these compounds modulate In vitro and in vivo the immediate type allergic reaction. Gas chromatography was used to identify main components of the essential oil. Pulegone (63.4 %), menthone (15.9 %), and limonene (2.1 %) were found as main classes. IL-13 levels were evaluated from lymphocytes cultures stimulated with allergen alone or combined with monoterpenes. All compounds stimulated cell proliferation but, interestingly, promoted a reduction of IL-13 values, limonene and the mixture of the three compounds being the most active. beta-Hexosaminidase release was determined from basophils to which essential oil or monoterpenes were added. We observed that, whichever combination of monoterpenes was used, beta-hexosaminidase release was diminished in all cases. Obtained values were even lower than those of antiallergic drug desloratadine. Essential oil and limonene inhibited mast cell activation and degranulation in the skin when testing passive cutaneous anaphylaxis, limonene being the most active. In conclusion, limonene was the compound that showed the most potent immunomodulatory activity. This fact suggests that it constitutes a promising natural alternative for a novel treatment of allergic diseases. PMID- 21590653 TI - Quantitative determination of triperpene saponins and alkenated-phenolics from Labisia pumila using an LC-UV/ELSD method and confirmation by LC-ESI-TOF. AB - This study describes the first analytical method for the determination of four triterpene saponins (ardisicrenoside B, ardisiacrispin A, 3- O- alpha- L rhamnopyranosyl-(1 -> 2)-beta-D-glucopyranosyl-(1 -> 4)-alpha-L-arabinopynanosyl cyclamiretin A and ardisimamilloside H) and three alkenated-phenolics (irisresorcinol, belamcandol B, and demethylbelamcandaquinone B) from the leaves, leaves/stems, and roots of LABISIA PUMILA using an HPLC-UV-ELSD method. The separation was achieved using a reversed-phase (C-18) column, PDA and ELS detection, and a water/acetonitrile gradient as the mobile phase. The major triterpenoid (ardisiacrispin A) and irisresorcinol compounds were detected at a concentration as low as 10.0 and 0.2 ug/mL, respectively. Analysis of various samples showed considerable variation of 0.11-2.46 % for the major triterpenoid compound, ardisiacrispin A. LC-mass spectrometry method coupled with electrospray ionization (ESI) is described for the identification of compounds in plant samples. This method involved the use of the [M + Na]+ and [M + NH4]+ ions for compounds 1-4 in the positive ion mode with extractive ion chromatogram (EIC). PMID- 21590654 TI - [Operative management and techniques of mastectomy in female-to-male transsexuals]. AB - BACKGROUND: Subcutaneous mastectomy in female to male transsexuals is one first important step in gender adjustment. Beside proper surgical technique, operative management of mastectomy procedures is important to allow for an optimised process of gender transformation including all necessary individual operations. METHODS: 126 female-to-male transsexuals were prospectively included in the observation period, all undergoing a step 1 operation of gender adjustment. The mastectomy procedure is conventionally embedded in an overall approach for gender transformation and was regularly combined with procedures like colpectomy, extension of the urethra as well as hysterectomy and ovariectomy. 4 different methods for mastectomy were introduced at our institution, depending on and adjusted to the breast volume, grade of breast ptosis, the breast size and envelope and skin elasticity. For patient evaluation a standardised survey was conducted using a semiquantitative score (1-4) for grading aesthetic results and nipple sensibility. RESULTS: Between 2006 and 2009 a total of 126 patients underwent a step 1 procedure of gender adjustment, 63 had mastectomy and 29 a revision procedure after external prior mastectomy. In 64/126 (50.8%) mastectomy was performed using a one-third edge cut, 30/126 (23.8%) were operated by a submammarian approach and pedicled nipples technique, in another 22/126 cases (17.5%) mastectomy was performed using circular tightening and 10/126 (7.9%) received freely transplanted nipples. For improving the aesthetic results, additional procedures were performed on 29 patients (46%). The patient survey revealed a high level of satisfaction with the aesthetic result, 42/50 (84%) of the patients rated results as good or very good. CONCLUSIONS: We newly introduced an operative concept of mastectomy being embedded and adjusted in an overall approach for gender adjustment (Munich Modular Operative Kit; MMOK). Using the presented individualised surgical techniques of mastectomy, all procedures were conducted in a very scar-saving manner, however, a higher rate of correction procedures was necessary to individually adjust skin shrinking and thereby optimising the prior aesthetic results. The new Munich Modular Operative Kit allows for gender reassignment including breast corrections usually using 4 operative steps. PMID- 21590655 TI - Health-related quality of life in patients reliant upon mitrofanoff catheterisation. AB - OBJECTIVE: Aim of the study was determine health care outcomes from the patients' perspective in patients reliant on Mitrofanoff catheterisation for bladder emptying. SUBJECTS/PATIENTS: Patients over the age of 16 dependent on Mitrofanoff catheterisation for bladder emptying were asked to complete a health care outcome questionnaire, the SF-36 ((r)) Health Survey v2. Quality of life measures for 8 health concepts were compared against published data for the normal population. RESULTS: Out of a total of 25 patients who were eligible for enrolment into our study, we were able to contact 19 patients. The norm-based score for Physical Functioning (PF=50.4), Role Physical (RP=53.8), Bodily Pain (BP=55.6), Vitality (VT=56.9), Social Functioning (SF=51.5), Role Emotional (RE=52.2), and Mental Health (MH=54.6) were all higher than those reported within the normal population (normal=50.0). Physical and mental component summary measures were higher than in the normal population. When compared against age-matched norms our patient group scored higher than the normal population for all measures except Physical Functioning (50.4 vs. 53.4) and physical component summary (51.9 vs. 53.5). The self-reported scores for Vitality, Mental Health and the mental component summary were all statistically significantly better than those seen in the age-matched control population (p<0.01). CONCLUSIONS: Quality of life in patients dependent on Mitrofanoff catheterisation for bladder emptying is good. The SF-36 measures 8 major health care outcomes and in our patients these measures of health were similar to those seen in the general population, rather than the poorer outcomes reported in patients with other chronic medical conditions. PMID- 21590656 TI - Evaluation of orchidopexy with or without opening the external oblique fascia in children with superficial inguinal undescended testis. AB - INTRODUCTION: Orchidopexy is one of the most common pediatric surgeries. In general, the operation for truly undescended testis (UDT) includes opening of the external oblique fascia. The most common location of the testis in UDT is adjacent to the external inguinal canal (superficial inguinal type). Using a new method we performed orchidopexy without opening the fascia. In this clinical trial we compared the outcome after a classic procedure with that obtained using our method. METHODS AND PATIENTS: This clinical controlled trial was undertaken in the Al Zahra hospital between 2008 and 2010. Patients were randomized into either into the closed technique group (group A, n=52) or the open group (group B, n=52). The incidence of short-term and long-term complications was recorded with a specific questionnaire at the time of surgery and at follow-up visits. Data were analyzed with the SPSS 15.0 software using chi-square and t-tests. RESULTS: 104 patients were included in this study. The incidence of short-term complications (surgical site hematoma, surgical wound infection, scrotal hematoma) and long-term complications (testicular atrophy) did not differ significantly between the 2 groups. Procedure duration in group A was significantly shorter than in group B (p=0.001). Medial thigh sensory loss was more common in group B (p=0.05). CONCLUSION: When investigating the surgical management of undescended testes, our study found differences in medial thigh sensory loss rate and procedure duration between the open and closed techniques. Operative treatment of UDT without opening the external oblique fascia is highly recommended. PMID- 21590657 TI - Failure to report ethical approval and informed consent in paediatric surgical publications. AB - INTRODUCTION: Medical research involving human subjects must follow ethical standards as outlined in the Declaration of Helsinki of the World Medical Association. The 3 journals J Ped Surg, Eur J Pediatr Surg and Pediatr Surg Int all require authors' statements regarding ethical approval and the patient or guardian informed consent for studies involving human subjects. It has previously been reported that ethical approval and informed consent is not documented in a considerable proportion of publications in other journals. The aim of this study was to investigate whether ethical approval and informed consent was documented in a consecutive series of publications involving human subjects in the 3 paediatric surgical journals. MATERIAL AND METHODS: All articles involving human subjects or material published in the print and online issues of J Ped Surg, Eur J Pediatr Surg and Pediatr Surg Int in 2010 were systematically reviewed as to whether ethics committee or institutional review board approval and patient or guardian consent to participate in the study was reported. Publications were categorised into prospective studies, retrospective studies, description of new methods and case reports. RESULTS: 579 articles were included in the study (324 J Ped Surg, 103 Eur J Pediatr Surg and 153 Pediatr Surg Int). In case reports (n=142), the lowest level of documentation of ethical approval (1.4%) and informed consent (1%) was observed. The remaining 437 original articles reported ethical approval in 54% of publications (prospective studies 66%, retrospective studies 59%, new methods 27%). Informed consent was documented in 16% of the original articles (prospective studies 50%, retrospective studies 17%, new methods 14%). Detailed investigation of the different journals revealed the highest rate of reporting of ethical approval for J Pediatr Surg (71%), followed by Eur J Pediatr Surg (43%), and Pediatr Surg Int (24%). Patient or guardian informed consent was reported in 15% of the publications in J Pediatr Surg and Pediatr Surg Int, respectively, and in 24% of the papers published in Eur J Pediatr Surg. CONCLUSION: Adherence to ethical principles in paediatric surgical research should be improved. Information on ethical approval and informed consent should be included in all manuscripts accepted for publication. Editors should consider establishing a specific online template asking authors for the necessary information during the submission process. PMID- 21590658 TI - Thoracoscopic lung biopsy during venovenous extracorporeal membrane oxygenation in childhood. PMID- 21590659 TI - Hepatocellular cholestasis and pruritus: beyond clinical treatment. PMID- 21590660 TI - [Evaluation of image quality of two different three-dimensional cone-beam scanners used for orthopedic surgery in the bony structures of the pelvis in comparison with standard CT scans]. AB - AIM: This study evaluated the image quality of two different cone beam CT scanners used in the operation theatre in pelvic trauma surgery in relation to their radiation dosage. Furthermore, the assumption that a higher dosage would result in better image quality was analysed by using the different acquisition scanner modes. MATERIAL AND METHODS: We scanned the acetabulum (n=4) and iliosacral joints (n=4) of two human cadavers with a conventional CT and with two mobile cone beam CT scanners (Siemens Arcadis Orbic 3D and Ziehm Vision Vario 3D). With the two cone beam CT scanners (3D-BV), we used 6 different acquisition modes with different radiation dosages. The axial views of all scans were exported and blinded. Subsequently, the images were evaluated by 7 medical doctors with regard to identifiability of cortical structures (acetabular joint, fovea capitis femoris, cortical bone of the femur head, iliosacral joint, and sacral foramina), and the quality of the cancellous structure of the femur head. The evaluation was performed on axial views by using a defined five-point score. The interrater quality was statistically analysed according to Cohen with the kappa coefficient. In addition, the Wilcoxon test was used to identify significances between the 21 paired results of the evaluators. For determination of the signal-to-noise ratio, a Catphan 600 reference block with two different test elements (Teflon, PMP) was used. RESULTS: Overall, the image quality of the conventional CT scans received the best score. Comparing the two 3D cone beams, the image quality of the Siemens Arcadis Orbic 3D in high-dosage mode received the best score (median: 2.40), the Ziehm Vision Vario 3D in low-dose mode without large patient key received the lowest score (median: 3.16). The differences in the 21 paired results of the two different acquisition modes were significant in 17 cases (p < 0.05) but the size of difference when comparing the different acquisition modes was almost always small. The interobserver agreement in one acquisition mode was low (kappa 0.008-0.134). The overall evaluation results of the same acquisition mode diverged by up to 2 score points. We noted a higher signal-to-noise ratio in the high dosage mode than in the low dosage mode. DISCUSSION: When using intraoperative 3D imaging with the cone beam CT technique for pelvic injury, image acquisition in low-dose mode is adequate in terms of signal-to-noise ratio and image quality. The image quality does not correlate linearly with a higher radiation dosage. Therefore, the pelvic trauma surgeon using this technique is encouraged to gather his own experience with low dose modes thereby reducing patient radiation exposure. PMID- 21590661 TI - [Proximal osseous integration in THR using the cementless Vektor-Titan stem: medium- and long-term results]. AB - OBJECTIVE OF THE STUDY: The objective of this study is to establish the medium term and long-term clinical and radiological results with the cementless Vektor Titan stem. Special consideration has been given to evaluate the extent to which the implant design achieves proximal stress transfer, thus avoiding stress shielding in the proximal femur. MATERIAL AND METHODS: From October 10, 1996, to May 18, 2000, 432 Vektor-Titan stems were implanted in 348 patients in the Wichernhaus Orthopaedic Clinic at Rummelsberg Hospital. The results were evaluated clinically and radiologically within the scope of a retrospective cohort study. The Vektor stem is a titanium straight stem designed for cementless fixation. It has a high proximal volume in the form of a three-dimensional taper with longitudinal ribs. This design achieves strong primary fixation in the proximal metaphysis. RESULTS: The survival probability of the stem was 99.08 % after a mean time of 7.5 years after surgery. One implant had to be replaced due to a traumatic periprosthetic fracture. Another had to be replaced after 9 months due to septic loosening, and a third after 14 months due to a suspected low-grade infection which, however, was not confirmed intraoperatively. The fourth stem required replacement after 75 months, again due to a periprosthetic fracture. Based on the Merle d'Aubigne score , surgery led to very good clinical results in 254 cases (58.8 %) and to good improvement in 130 cases (30.1 %). In 33 cases (7.6 %) there was a moderate improvement in the score, and in 15 cases (3.5 %) there was no improvement. Bone structure was radiologically normal in 421 cases (97.5 % of all cases). No signs of atrophy were found in the proximal femur and the trochanters. On the contrary, there was evidence of an even denser bone structure at the level of the osteotomy and the lateral implant fixation within the greater trochanter. There the trabeculae were visibly aligned towards the surface of the implant, indicative of direct biological fixation at the bone implant interface. These findings remained unchanged over long observation periods. There were no changes along the diaphyseal stem. CONCLUSIONS: Medium term and long-term results with the cementless Vektor-Titan stem show a low rate of implant loosening with stable metaphyseal fixation and preservation of bone structure in the proximal femur and the absence of changes along the diaphyseal stem. PMID- 21590662 TI - [The EbM Commentary at the Annual Meeting of the German Congress of Orthopaedics and Traumatology (DKOU): background, aims and vision]. AB - The critical appraisal of clinical and scientific work to assure the effectiveness and to balance the risks of treatment are mandatory today. Recent innovations in medicine often lead only to minor improvement in patient benefit. For the better understanding of the presented study results, the EbM commentary was introduced in 2007 at the Annual Meeting of the German Society of Orthopaedics and Traumatology. The EbM commentary was developed within the Swiss Orthopaedic Society and is a vital part of the Annual Meetings. The EbM commentary is a carefully prepared critical appraisal of an orally presented study by a specially trained colleague. The commentary consists of three components and begins with a systematic analysis following the SPION principle. What kind of study was carried out? Which patients were enrolled in the investigation? What kind of interventions were compared? How was the outcome measured? What is the benefit of the study for my own practice and what is the benefit for the patient? The reporting and the evaluation of the patient benefit is of great interest. In the second step the strengths and weaknesses of the study were discussed and the study will be rated for their evidence. For the best case the presented study implies direct changes in the usual treatment of patients. In the worst case no changes are necessary and the study is rated "so what" because of methodological weaknesses making the drawn conclusions invalid. For the audience the EbM commentary may support their rating of the quality of the presented study. The congress team selects interesting presentations for the EbM commentary. The EbM commentators receive the oral presentation and in most cases additional information from the selected studies four weeks in advance of the meeting. The EbM commentary is focused on a precise analysis of the presented data in an open and pleasant discussion. The aim of the EbM commentary is to clearly point out the patient benefit and to disclose the biases and weaknesses. The best studies of the DKOU were awarded following the suggestion of the EbM jury. The experiences have shown some methodological improvement of the presentations. The pragmatic style of the EbM commentary has led to good acceptance at the Annual Meeting of the German Society of Orthopaedics and Traumatology. PMID- 21590664 TI - [Modified cochlear implant fixation using a single suture]. PMID- 21590665 TI - The use of remotely sensed environmental data in the study of malaria. AB - Mapping and anticipating risk is a major issue in the fight against malaria, a disease causing an estimated one million deaths each year. Approximately half the world's population is at risk and it is of prime importance to evaluate the burden of malaria at the spatial as well as the temporal level. The role of the environment with regard to the determinants of transmission and burden of the disease are described followed by a discussion of special issues such as urban malaria, human population mapping and the detection of changes at the temporal scale. Risk maps at appropriate scales can provide valuable information for targeted control and the present review discusses the essentials of principles, methods, advantages and limitations of remote sensing along with a presentation of ecological, meteorological and climatologic data which rule the distribution of malaria. The panel of commonly used analytic methods is examined and the methodological limitations are highlighted. A review of the literature details the increasing interest in the use of remotely sensed data in the study of malaria, by mapping or modeling several malariometric indices such as prevalence, morbidity and mortality, which are discussed with reference to vector breeding, vector density and entomological inoculation rate, estimates of which constitute the foundation for understanding endemicity and epidemics. PMID- 21590666 TI - Geospatial tools for the identification of a malaria corridor in Estado Sucre, a Venezuelan north-eastern state. AB - Landscape ecology research relies on frameworks based on geographical information systems (GIS), geostatistics and spatial-feature relationships. With regard to health, the approach consists of systems analysis using a set of powerful tools aimed at the reduction of community vulnerability through improved public policies. The north-oriental malaria focus, one of five such foci in Venezuela, situated in the north-eastern part of the Estado Sucre state, unites several social and environmental features and functions as an epidemiological corridor, i.e. an endemic zone characterised by permanent interaction between the mosquito vector and the human host allowing a continuous persistence of the malaria lifecycle. A GIS was developed based on official cartography with thematic overlays depicting malaria distribution, socio-economic conditions, basic environmental information and specific features associated with the natural wetlands present in the area. Generally, malaria foci are continuously active but when the malaria situation was modelled in the north-oriental focus, a differential, spatio-temporal distribution pattern situation was found, i.e. a situation oscillating between very active and dormant transmission. This pattern was displayed by spatial and statistical analysis based on the model generated in this study and the results were confirmed by municipal and county malaria records. Control of malaria, keeping the incidence at a permanently low level within the regional population, should be possible if these results are taken into account when designing and implementing epidemiological surveillance policies. PMID- 21590667 TI - Spatial distribution of HIV/AIDS in Yunnan province, People's Republic of China. AB - Risk maps for the geographical distribution of human immunodeficiency virus (HIV) and the acquired immune deficiency syndrome (AIDS) are needed for the direction of HIV prevention interventions. Our study, based on county-level data on the numbers of HIV/AIDS patients in the Yunnan province, People's Republic of China, applied trend surface analysis and spatial autocorrelation analysis to demonstrate the geographical distribution of HIV-positive patients in the province. The case load of HIV was found to be most severe in the central-west region of the province. While Kunming county was shown to be negatively correlated with its surrounding counties, many high-burden counties are surrounded by other counties with similar case numbers. We conclude that intervention efforts in Yunnan province should concentrate on the western and northeast regions, targeting the hotspots of infection. PMID- 21590668 TI - Effect of soil surface salt on the density and distribution of the snail Bithynia siamensis goniomphalos in northeast Thailand. AB - Opisthorchis viverrini infection is associated with human cholangiocarcinoma and northeast Thailand has the highest incidence of this disease in the world. Bithynia siamensis goniomphalos is the major freshwater snail intermediate host of O. viverrini in this area and an analysis based on geographical information systems was used to determine the effect of variation in soil surface salt on the density and distribution of this snail. A malacological survey was carried out in 56 water bodies in the Khorat basin, northeast Thailand at locations with various soil surface salt levels. Mollusk samples were collected from 10 ecologically representative water body sites with 10-20 sampling stations in each. The shoreline of clear, shallow water bodies was found to be the preferred B. s. goniomphalos habitat. The snails were exclusively found in water with salinity levels ranging between 0.05 and 22.11 parts per thousand (ppt), which supports the notion that B. s. goniomphalos prefers water with some saline content over pure, freshwater. The highest snail population densities were in rice fields, ponds, road-side ditches and canals within a water salinity range of 2.5-5.0 ppt. However, the presence of B. s. goniomphalos was negatively correlated with water salinity (P <=0.05), both with regard to density and distribution. The areas with the highest density of B. s. goniomphalos were those with less than 1% soil surface salt (potential index = 0.314), while the lowest densities were found in areas exceeding 50% soil surface salt (potential index = 0.015). PMID- 21590669 TI - Socio-geographical factors in vulnerability to dengue in Thai villages: a spatial regression analysis. AB - Focusing on the socio-geographical factors that influence local vulnerability to dengue at the village level, spatial regression methods were applied to analyse, over a 5-year period, the village-specific, cumulative incidence of all reported dengue cases among 437 villages in Prachuap Khiri Khan, a semi-urban province of Thailand. The K-order nearest neighbour method was used to define the range of neighbourhoods. Analysis showed a significant neighbourhood effect (rho = 0.405, P <0.001), which implies that villages with geographical proximity shared a similar level of vulnerability to dengue. The two independent social factors, associated with a higher incidence of dengue, were a shorter distance to the nearest urban area (beta = -0.133, P <0.05) and a smaller average family size (beta = -0.102, P <0.05). These results indicate that the trend of increasing dengue occurrence in rural Thailand arose in areas under stronger urban influence rather than in remote rural areas. PMID- 21590670 TI - Spatial distribution of triatomines (Reduviidae: Triatominae) in urban areas of the city of Salvador, Bahia, Brazil. AB - Environmental changes have a strong influence on the emergence and/or reemergence of infectious diseases. The city of Salvador, Brazil--currently the focus of a housing boom linked to massive deforestation--is an example in point as the destruction of the remaining areas of the Atlantic Forest around the city has led to an increased risk for Chagas disease. Human domiciles have been invaded by the triatomine vectors of Trypansoma cruzi, the flagellate protozoan causing Chagas disease, a problem of particular concern in urban/suburban areas of the city such as the Patamares sector in the north-east, where numbers of both the vector and human cases of the disease have increased lately. To control and prevent further deterioration of the situation, the control programme for Chagas disease, developed by the Bahia Center for Zoonosis Control, has divided the area into a grid of designated surveillance units (ZIs) that are subjected to vector examination. In six out of 98 of these ZIs, 988 triatomes were collected and georeferenced during the 3-year period between 2006 and 2009. The hottest months, that are also generally the driest, showed the highest numbers of triatomines with Triatoma tibiamaculata being the predominant species (98.3%) with Panstrongylus geniculatus present only occasionally (0.6%). Fifty-four percent of all triatomines captured were found inside the homes, and 48.6% out of 479 individuals in the affected ZIs selected for analysis tested positive for T. cruzi infection. The study presented here is a pioneering initiative to map the spatial distribution of triatomines based on geographical information systems with the additional aim of contributing to an expanded knowledge-base about T. cruzi and its vectors in urban areas and raise public health awareness of the risks involved. PMID- 21590671 TI - Incidence of visceral leishmaniasis in the Vaishali district of Bihar, India: spatial patterns and role of inland water bodies. AB - The role of the distribution of inland water bodies with respect to the transmission of visceral leishmaniasis (VL) and its dominant vector, Phlebotomous argentipes, has been studied at the regional scale in Bihar, eastern India. The Landsat TM sensor multispectral scanning radiometer, with a spatial resolution of 30 m in the visible, reflective-infrared and shortwave-infrared (SWIR) bands, was used to identify water bodies using the normalized differential pond index (NDPI) calculated as follows: (Green - SWIR I)/(Green + SWIR I). Nearest neighbour and grid square statistics were used to delineate spatial patterns and distribution of the sandfly vector and the disease it transmits. The female P. argentipes sandfly was found to be associated with the distance from open water and particularly abundant near non-perennial river banks (68.4%; P <0.001), while its association with rivers was focused further away from the water source (chi(2) = 26.3; P <0.001). The results also reveal that the distribution of VL is clustered around non-perennial riverbanks, while the pattern is slightly random around the perennial river banks. The grid square technique illustrate that the spatial distribution of the disease has a much stronger correlation with lower density of open waters surfaces as well as with sandfly densities (chi(2) = 26.0; P <0.001). The results of our study suggest that inland water presence poses a risk for VL by offering suitable breeding sites for P. argentipes, a fact that should be taken into account when attempting to control disease transmission. PMID- 21590672 TI - Geographical information systems in the management of the 2009-2010 emergency oral anti-rabies vaccination of foxes in north-eastern Italy. AB - Emergency oral fox vaccination campaigns, targeting a recent rabies epidemic in wild foxes (Vulpes vulpes) in north-eastern Italy, were implemented twice, first in the winter of 2009 and then in the spring of 2010. Following on an unsuccessful manual bait distribution campaign, vaccine baits were aerially distributed by helicopters using a satellite-navigated, computer-supported, automatic bait drop system. The flight paths were traced with distance of 500 1,000 m from one another to optimise helicopter missions and guarantee homogeneous coverage of the vaccination area. The vaccine distribution was evaluated by superimposing a 1 km-step grid and weighing the number of baits per cell. The implementation of a geographical information system for the management of vaccine distribution proved to be useful, both for the planning and execution phases, of the campaigns. It supported effective management of the flights and allowed near real-time monitoring of the campaigns. In addition, it facilitated the identification of areas with suboptimal bait density that would require additional flights or supplementary, manual distribution. PMID- 21590673 TI - Spatial analysis of bluetongue cases and vaccination of Swiss cattle in 2008 and 2009. AB - Bluetongue (BT) is a vector-borne viral disease of ruminants. The infection is widespread globally with major implications for international animal trade and production. In 2006, BT virus serotype 8 (BTV-8) was encountered in Europe for the first time, causing extensive production losses and death in susceptible livestock. Following the appearance of BTV-8 in Switzerland in 2007, a compulsory vaccination programme was launched in the subsequent year. Due to social factors and difficulties to reach animals on high pasture, the regional vaccination coverage varied across the country in both 2008 and 2009. In this study, the effect of vaccination on the spatial occurrence of BTV-8 and the associated relative disease risk in Switzerland in 2008 and 2009 were investigated by a spatial Bayesian hierarchical approach. Bayesian posterior distributions were obtained by integrated nested Laplace approximations, a promising alternative to commonly used Markov chain Monte Carlo methods. The number of observed BTV-8 outbreaks in Switzerland decreased notably from 2008 to 2009. However, only a non significant association between vaccination coverage and the probability of a spatial unit being infected with BTV-8 was identified using the model developed for this study. The relative disease risk varied significantly across the country, with a higher relative risk of BTV-8 infection in western and north western Switzerland where environmental conditions are more suitable for vector presence and viral transmission. Examination of the spatial correlation between disease occurrence, control measures and associated ecological factors can be valuable in the evaluation and development of disease control programmes, allowing prioritisation of areas with a high relative risk of disease. PMID- 21590674 TI - Towards assessing fine-scale indicators for the spatial transmission risk of Fasciola hepatica in cattle. AB - In order to improve the spatial resolution of current risk maps for fasciolosis in cattle, more knowledge is needed with respect to farm-level factors that determine infection risk. In this study, we visited 39 dairy farms within a predefined low- and high-risk area for fasciolosis in Belgium and assessed their infection status by an indirect bulk tank milk enzyme-linked immunosorbent assay (ELISA). Management factors were collected and all pastured lands of the farms were visited to identify and georeference potential snail habitats. The habitats were visually characterised, investigated for the presence of the intermediate host snails of Fasciola hepatica (i.e. Galba truncatula and Radix spp) and used in a geographical information system (GIS) to construct overlays including information on soil and hydrology. A linear regression model was used to evaluate associations between bulk tank milk ELISA results and farm level management and habitat factors. A logistic, mixed model was used to identify possible risk factors for the presence of intermediate host snails on a potential habitat. Potential snail habitats were found in 35 out of 39 farms. A total of 87 potential habitats were identified and on 29% of these, intermediate host snails were found. The number of potential habitats, the presence of snails, drainage of pastures, month of turnout of the cows, stocking rate, type of watering place and risk area were significantly associated with the bulk tank milk ELISA result and explained 85% of the observed variation. Intermediate host snails were more likely to be present with increasing surface of the potential habitat and on loamy soils. This study confirms the importance of farm management factors in the infection risk for F. hepatica in cattle and highlights that the combination of management factors with characterization of snail habitats is a powerful means to predict the infection risk with F. hepatica at the individual farm level. Further research is needed to investigate how this knowledge can be incorporated in nation-wide spatial distribution models of the parasite. PMID- 21590675 TI - Continent-wide association of H5N1 outbreaks in wild and domestic birds in Europe. AB - The highly pathogenic avian influenza strain H5N1 was first detected in Europe in 2005, and has since been documented continent-wide in wild birds and poultry. However, the relative roles of each host group in transmission remain contentious. Using recently developed tools for analysis of ecological niches and geographic distributions of species, we compared ecological niche requirements for H5N1 between paired host groups (poultry versus wild birds, Anseriformes versus Falconiformes, swans versus non-swan Anseriformes). If environmental signals of different host groups are significantly different, the groups are likely to be involved in distinct transmission cycles. In contrast, models for which similarity cannot be rejected imply no unique ecological niches and no potential linkage of transmission cycles. In 24 similarity tests, we found significant similarity (13/24) or no significant differences (9/24). Although 2 of the 24 analyses showed significant differences, neither was unequivocal, so we conclude an overall signal of niche similarity among groups. We thus could not document distinct ecological niches for H5N1 occurrences in different host groups and conclude that the transmission cycles are broadly interwoven. PMID- 21590676 TI - Mathematical modelling of the impact of climatic conditions in France on Rhipicephalus sanguineus tick activity and density since 1960. AB - Rhipicephalus sanguineus, the brown dog tick, has a worldwide distribution in areas with a relatively warm climate, including mild winters. This tick plays an important role as vector for various animal and human pathogens, including bacteria and protozoa. Based on precise daily meteorological data from the past 40 years, combined with mathematical modelling designed to predict tick activity, two modelling approaches were developed. The first examined the evolution of the number of weeks with favourable biological conditions for ticks in four French cities located at various latitudes of the country: Nimes in the south, Paris in the north, Lyon in the east and Nantes in the west. The second analysed the extension of the geographical surface area in km(2) where the biological conditions favour tick activity for at least 12 weeks per year. Both analyses revealed clear evidence of increased temperatures coupled with an augmented tick activity index in three of the four cities. However, the change was not significant in Nimes, where the climate is Mediterranean and the tick is already endemic. For Paris, Lyon and Nantes, the activity index values have increased significantly, i.e. by 4.4%, 4.0% and 3.4%, respectively. The distribution of the activity index values is evolving strongly with significantly fewer values below 50% since the 1960s and a clear decrease of values between 20% and 50% during the latest decade. Between 1960 and 2000, the theoretical extension of the surface area where the climatic index is suitable for R. sanguineus has increased by 66%. Even though several other important factors, such as changes in biotopes or human activity, are not included in this study, the resulting patterns and trends are noticeable. Our models constitute the first demonstration of the impact of climate change on the activity and distribution of ticks and confirm the observed northward migration trend for this Mediterranean domestic tick. PMID- 21590677 TI - Evaluation of the positional difference between two common geocoding methods. AB - Geocoding, the process of matching addresses to geographic coordinates, is a necessary first step when using geographical information systems (GIS) technology. However, different geocoding methodologies can result in different geographic coordinates. The objective of this study was to compare the positional (i.e. longitude/latitude) difference between two common geocoding methods, i.e. ArcGIS (Environmental System Research Institute, Redlands, CA, USA) and Batchgeo (freely available online at http://www.batchgeo.com). Address data came from the YMCA-Harvard After School Food and Fitness Project, an obesity prevention intervention involving children aged 5-11 years and their families participating in YMCA-administered, after-school programmes located in four geographically diverse metropolitan areas in the USA. Our analyses include baseline addresses (n = 748) collected from the parents of the children in the after school sites. Addresses were first geocoded to the street level and assigned longitude and latitude coordinates with ArcGIS, version 9.3, then the same addresses were geocoded with Batchgeo. For this analysis, the ArcGIS minimum match score was 80. The resulting geocodes were projected into state plane coordinates, and the difference in longitude and latitude coordinates were calculated in meters between the two methods for all data points in each of the four metropolitan areas. We also quantified the descriptions of the geocoding accuracy provided by Batchgeo with the match scores from ArcGIS. We found a 94% match rate (n = 705), 2% (n = 18) were tied and 3% (n = 25) were unmatched using ArcGIS. Forty-eight addresses (6.4%) were not matched in ArcGIS with a match score >=80 (therefore only 700 addresses were included in our positional difference analysis). Six hundred thirteen (87.6%) of these addresses had a match score of 100. Batchgeo yielded a 100% match rate for the addresses that ArcGIS geocoded. The median for longitude and latitude coordinates for all the data was just over 25 m. Overall, the range for longitude was 0.04-12,911.8 m, and the range for latitude was 0.02 37,766.6 m. Comparisons show minimal differences in the median and minimum values, while there were slightly larger differences in the maximum values. The majority (>75%) of the geographic differences were within 50 m of each other; mostly <25 m from each other (about 49%). Only about 4% overall were >=400 m apart. We also found geographic differences in the proportion of addresses that fell within certain meter ranges. The match-score range associated with the Batchgeo accuracy level "approximate" (least accurate) was 84-100 (mean = 92), while the "rooftop" Batchgeo accuracy level (most accurate) delivered a mean of 98.9 but the range was the same. Although future research should compare the positional difference of Batchgeo to criterion measures of longitude/latitude (e.g. with global positioning system measurement), this study suggests that Batchgeo is a good, free-of-charge option to geocode addresses. PMID- 21590678 TI - GeoCREV: veterinary geographical information system and the development of a practical sub-national spatial data infrastructure. AB - This paper illustrates and discusses the key issues of the geographical information system (GIS) developed by the Unit of Veterinary Epidemiology of the Veneto region (CREV), defined according to user needs, spatial data (availability, accessibility and applicability), development, technical aspects, inter-institutional relationships, constraints and policies. GeoCREV, the support system for decision-making, was designed to integrate geographic information and veterinary laboratory data with the main aim to develop a sub-national, spatial data infrastructure (SDI) for the veterinary services of the Veneto region in north-eastern Italy. Its implementation required (i) collection of data and information; (ii) building a geodatabase; and (iii) development of a WebGIS application. Tools for the management, collection, validation and dissemination of the results (public access and limited access) were developed. The modular concept facilitates the updating and development of the system according to user needs and data availability. The GIS management practices that were followed to develop the system are outlined, followed by a detailed discussion of the key elements of the GIS implementation process (data model, technical aspects, inter institutional relationship, user dimension and institutional framework). Problems encountered in organising the non-spatial data and the future work directions are also described. PMID- 21590679 TI - Survived infancy but still vulnerable: spatial-temporal trends and risk factors for child mortality in the Agincourt rural sub-district, South Africa, 1992-2007. AB - Targeting of health interventions to poor children at highest risk of mortality are promising approaches for enhancing equity. Methods have emerged to accurately quantify excess risk and identify space-time disparities. This provides useful and detailed information for guiding policy. A spatio-temporal analysis was performed to identify risk factors associated with child (1-4 years) mortality in the Agincourt sub-district, South Africa, to assess temporal changes in child mortality patterns within the study site between 1992 and 2007, and to produce all-cause and cause-specific mortality maps to identify high risk areas. Demographic, maternal, paternal and fertility-related factors, household mortality experience, distance to health care facility and socio-economic status were among the examined risk factors. The analysis was carried out by fitting a Bayesian discrete time Bernoulli survival geostatistical model using Markov chain Monte Carlo simulation. Bayesian kriging was used to produce mortality risk maps. Significant temporal increase in child mortality was observed due to the HIV epidemic. A distinct spatial risk pattern was observed with higher risk areas being concentrated in poorer settlements on the eastern part of the study area, largely inhabited by former Mozambican refugees. The major risk factors for childhood mortality, following multivariate adjustment, were mother's death (especially when due to HIV and tuberculosis), greater number of children under 5 years living in the same household and winter season. This study demonstrates the use of Bayesian geostatistical models for accurately quantifying risk factors and producing maps of child mortality risk in a health and demographic surveillance system. According to the space-time analysis, the southeast and upper central regions of the site appear to have the highest mortality risk. The results inform policies to address health inequalities in the Agincourt sub-district and to improve access to health services. Targeted efforts to prevent vertical transmission of HIV in specific settings need to be undertaken as well as ensuring the survival of the mother and father in childhood. PMID- 21590680 TI - Interleukin-6 plays an essential role in hypoxia-inducible factor 2alpha-induced experimental osteoarthritic cartilage destruction in mice. AB - OBJECTIVE: Hypoxia-inducible factor 2alpha (HIF-2alpha) (encoded by Epas1) causes osteoarthritic (OA) cartilage destruction by regulating the expression of catabolic factor genes. We undertook this study to explore the role of interleukin-6 (IL-6) in HIF-2alpha-mediated OA cartilage destruction in mice. METHODS: The expression of HIF-2alpha, IL-6, and catabolic factors was determined at the messenger RNA and protein levels in primary culture mouse chondrocytes, human OA cartilage, and mouse experimental OA cartilage. Experimental OA in wild type, HIF-2alpha-knockdown (Epas1+/-), and Il6-/- mice was caused by intraarticular injection of Epas1 adenovirus or destabilization of the medial meniscus. The role of IL-6 was determined by treating with recombinant IL-6 protein or by injecting HIF-2alpha adenovirus (AdEpas1) intraarticularly in mice with or without IL-6-neutralizing antibody. RESULTS: We found that Il6 is a direct target gene of HIF-2alpha in articular chondrocytes. Both Epas1 and Il6 were up-regulated in human and mouse OA cartilage, whereas HIF-2alpha knockdown in mice led to inhibition of both Il6 expression and cartilage destruction. Treatment with IL-6 enhanced Mmp3 and Mmp13 expression; conversely, Il6 knockdown inhibited HIF-2alpha-induced up-regulation of Mmp3 and Mmp13. Injection of IL-6 protein into mouse knee joints triggered OA cartilage destruction, whereas IL-6 neutralization led to blocking of HIF-2alpha-induced cartilage destruction with concomitant modulation of Mmp3 and Mmp13 expression. Moreover, Il6 knockout resulted in inhibition of AdEpas1-induced and destabilization of the medial meniscus-induced cartilage destruction as well as inhibition of Mmp3 and Mmp13 expression. CONCLUSION: Our findings indicate that IL-6 acts as a crucial mediator of HIF-2alpha-induced experimental OA cartilage destruction in mice via regulation of Mmp3 and Mmp13 levels. PMID- 21590682 TI - Clinical image: crystal arthritis induced by intraarticular corticosteroid. PMID- 21590683 TI - T cells stimulated with an analog peptide of type II collagen require the Fc receptor gamma-chain to secrete interleukin-4 and suppress autoimmune arthritis in mice. AB - OBJECTIVE: To explore the characteristics of the T cell population that responds to an analog peptide (A9) of type II collagen and regulates autoimmunity, using the collagen-induced arthritis (CIA) model. METHODS: Analog peptide A9 is a 26 amino acid peptide analogous to the sequence of a segment of type II collagen (CII245-270) but with substitutions at amino acid positions 260 (alanine for isoleucine), 261 (hydroxyproline for alanine), and 263 (asparagine for phenylalanine). We previously showed that A9 profoundly suppressed CIA and immune responses to type II collagen. In order to determine the mechanism of suppression, we used transgenic mice whose T cells express a type II collagen specific receptor (T cell receptor) and performed passive cell transfer experiments. RESULTS: The results demonstrated that suppression of CIA by A9 is dependent on T cells. Using multiparameter flow cytometry, we determined that the cells responsible for suppression were CD4+ and expressed high levels of Fcepsilon receptor Igamma chain (FcRgamma). To establish the significance of this finding, we obtained mice genetically deficient in FcRgamma in order to perform passive transfer experiments. The resulting FcRgamma-/- CD4+ T cells, when primed by culture with A9, could not transfer the suppression of arthritis or secrete cytokines in response to A9. CONCLUSION: Taken together, the results of this study suggest that the suppression of arthritis and the Th2 cytokine profile elicited by A9 is dependent on the presence of FcRgamma in T cells. These findings are novel and may have therapeutic potential for patients with autoimmune arthritis. PMID- 21590684 TI - The transcription factor FBI-1/OCZF/LRF is expressed in osteoclasts and regulates RANKL-induced osteoclast formation in vitro and in vivo. AB - OBJECTIVE: Since transcription factors expressed in osteoclasts are possible targets for regulation of bone destruction in bone disorders, we investigated the expression of the transcription factor FBI-1/OCZF/LRF (in humans, factor that binds to inducer of short transcripts of human immunodeficiency virus type 1; in rats, osteoclast-derived zinc finger; in mice, leukemia/lymphoma-related factor) in patients with rheumatoid arthritis (RA), and assessed its role in osteoclastogenesis in vivo. METHODS: Expression of FBI-1/OCZF was investigated in subchondral osteoclasts in human RA and in rat adjuvant-induced arthritis (AIA) using immunostaining and in situ hybridization, respectively. Transgenic mice overexpressing OCZF (OCZF-Tg) under the control of the cathepsin K promoter were generated, and bone mineral density and bone histomorphometric features were determined by peripheral quantitative computed tomography, calcein double labeling, and specific staining for osteoclasts and osteoblasts. LRF/OCZF expression and the consequence of LRF inhibition were assessed in vitro with RANKL-induced osteoclast differentiation. RESULTS: FBI-1/OCZF was detected in the nuclei of osteoclasts in rat AIA and human RA. RANKL increased the levels of LRF messenger RNA and nuclear-localized LRF protein in primary macrophages. In OCZF Tg mice, bone volume was significantly decreased, the number of osteoclasts, but not osteoblasts, was increased in long bones, and osteoclast survival was promoted. Conversely, inhibition of LRF expression suppressed the formation of osteoclasts from macrophages in vitro. CONCLUSION: FBI-1/OCZF/LRF regulates osteoclast formation and apoptosis in vivo, and may become a useful marker and target in treating disorders leading to reduced bone density, including chronic arthritis. PMID- 21590681 TI - Association of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups. AB - OBJECTIVE: T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin-2 (IL-2). Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac. METHODS: We conducted a trans-ethnic study of 8,695 SLE cases and 7,308 controls of 4 different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time polymerase chain reaction. RESULTS: A 32-kb haplotype comprising multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans, European Americans, and Asians, but not in African Americans. Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, European American, and Hispanic American populations (odds ratio 1.3 [95% confidence interval 1.14-1.31], meta-analysis P=3.8*10(-7)). In European Americans, the largest ethnic data set studied, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-double-stranded DNA, and anti-RNP antibodies. PPP2CA expression was ~2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying the GG genotype (P=0.007). CONCLUSION: Our data provide the first evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in European Americans, Hispanic Americans, and Asians. PMID- 21590685 TI - Surgeon volumes in oesophagogastric and hepatopancreatobiliary resectional surgery. PMID- 21590686 TI - Distinctive chromosomal instability patterns in oral verrucous and squamous cell carcinomas detected by high-resolution DNA flow cytometry. AB - BACKGROUND: Oral verrucous carcinomas (OVCs) are characterized by better prognosis than oral squamous cell carcinomas (OSCCs). Because chromosomal instability (CIN) in solid tumors is indicative of prognosis, this study investigated whether OVCs and OSCCs were characterized by differences in CIN biomarkers. METHODS: Fresh or frozen multiple tissue samples were submitted to high-resolution DNA flow cytometry (hr DNA-FCM). RESULTS: DNA aneuploid sublines were detected in 6 of 9 OVCs (66.7%) and in 20 of 25 OSCCs (80.0%). Multiple DNA aneuploid sublines were observed, respectively, in 2 of 6 (33.3%) DNA aneuploid OVCs and in 14 of 20 (70%) DNA aneuploid OSCCs (P = .163). OVCs were mainly characterized by DNA Index (DI) values in the near-diploid region (DI?1 and DI < 1.4), whereas aneuploid OSCCs carried most frequently multiple aneuploid sublines with high DI values (DI >= 1.4). DNA near-diploid and high aneuploid sublines were, respectively, 87.5% and 12.5% for the OVCs versus 30% and 70% for the OSCCs (P = .004). CONCLUSIONS: Present data suggest that OVCs are characterized by a lower degree of CIN and tumor heterogeneity than OSCCs, such that they appear as "frozen" in an early stage of DNA near-diploid aneuploidy, as previously observed for oral preneoplastic lesions. These DI characteristics, which can easily be obtained by hr DNA-FCM, appear to reflect the well-known differences in aggressiveness and prognosis of OVCs and OSCCs. PMID- 21590687 TI - Perifosine-induced inhibition of Akt attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance in neuroblastoma in vivo. AB - BACKGROUND: Neuroblastoma (NB) tumors expressing high levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB or activated Akt are associated with decreased event-free or overall survival in patients with NB. In the current study, the effect of perifosine, an Akt inhibitor, on the chemosensitivity of TrkB-expressing NB cells or tumors was evaluated. METHODS: A tetracycline regulated TrkB-expressing isogenic NB cell model system was tested. In this system, NB cells were treated with etoposide and/or perifosine both in vitro and in vivo. Inhibition of the target by perifosine was evaluated by Western blot analysis or kinase activity assay. Cell survival and tumor growth were investigated. RESULTS: In vitro BDNF treatment induced Akt phosphorylation and rescued cells from etoposide-induced cell death in cells with high TrkB expression, but not in cells with low TrkB expression. Pretreatment of high TrkB expressing TB3 cells with perifosine blocked BDNF/TrkB-induced Akt phosphorylation and inhibited BDNF's protection of TB3 cells from etoposide treatment. In vivo, tumors with high TrkB expression were found to have elevated levels of phosphorylated Akt and were less sensitive to etoposide treatment compared with tumors with low TrkB expression. Mice treated with a combination of perifosine and etoposide were found to have a statistically significant decrease in tumor growth compared with mice treated with either etoposide or perifosine alone. Activation of Akt through the BDNF/TrkB signaling pathway induced chemoresistance in NB in vivo. CONCLUSIONS: Perifosine-induced inhibition of Akt increased the sensitivity of NB to chemotherapy. The results of the current study support the future clinical evaluation of an Akt inhibitor combined with cytotoxic drugs for the improvement of treatment efficacy. PMID- 21590688 TI - Bisphosphonates and pathologic complete response to taxane- and anthracycline based neoadjuvant chemotherapy in patients with breast cancer. AB - BACKGROUND: Several studies have suggested that bisphosphonates have an antitumor effect. In the current study, the authors sought to evaluate whether the use of bisphosphonates increased the rate of pathological complete response (pCR) in patients with breast cancer. METHODS: The authors identified 1449 patients with breast cancer who were receiving taxane- and anthracycline-based neoadjuvant chemotherapy between 1995 and 2007 at The University of Texas MD Anderson Cancer Center. Patients who received bisphosphonates for osteopenia or osteoporosis while receiving chemotherapy were also identified. The primary outcome was the percentage of patients achieving a pCR. Groups were compared using the chi-square test. A multivariable logistic regression model was fit to examine the relation between the use of bisphosphonates and pCR. An exploratory survival analysis using the Kaplan-Meier method was performed; groups were compared using the log rank test. RESULTS: Of the 1449 patients included, 39 (2.7%) received bisphosphonates. Those receiving bisphosphonates were older (P < .001) and less likely to be obese (P = .04). The pCR rate was 25.4% in the bisphosphonate group and 16% in the nonbisphosphonate group (P = .11). In the multivariable model, patients treated with bisphosphonates tended to have higher rates of pCR (odds ratio, 2.18; 95% confidence interval, 0.90-5.24); however, the difference was not found to be statistically significant. With a median follow-up of 55 months (range, 3 months-145 months), no differences in disease recurrence or survival were observed. CONCLUSIONS: The use of bisphosphonates at the time of neoadjuvant chemotherapy was not found to be associated with a statistically significant increase in the rates of pCR. The observed estimates suggest a positive effect; however, the small percentage of patients receiving bisphosphonates likely affected the power to detect a statistically significant difference. PMID- 21590690 TI - Dispositional optimism buffers combat veterans from the negative effects of warzone stress on mental health symptoms and work impairment. AB - The study examined dispositional optimism s role in buffering the effect of warzone stress on mental health symptoms and mental health symptoms on work impairment. A total of 2,439 soldiers from an active-duty brigade combat team were surveyed following a 12-month deployment to Iraq. Posttraumatic stress disorder (PTSD) symptoms, depression symptoms, combat exposure, deployment demands, and work impairment were measured. Soldiers higher in dispositional optimism showed weaker relationships between combat exposure and PTSD symptoms, and between deployment demands and PTSD and depression symptoms. Dispositional optimism also buffered mental health symptom effects on work impairment. Dispositional optimism may protect soldiers from warzone stress and mental health symptoms. Potential mechanisms explaining how dispositional optimism may serve as a protective factor are discussed. PMID- 21590689 TI - Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. AB - BACKGROUND: The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open-label, single-arm trial was evaluated. METHODS: Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression-free survival at 6 months (PFS-6), and secondary end points included safety and median overall survival (OS). RESULTS: All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0-7.0 months) and PFS-6 rate was 16% (95% CI, 5.0%-32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment-related deaths. CONCLUSIONS: Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously. PMID- 21590692 TI - Poorly differentiated adenocarcinoma arising from a cervical bronchial cyst. AB - Bronchogenic cysts with malignant change are rarely reported. We describe a case of poorly differentiated adenocarcinoma arising from a cervical bronchial cyst in a patient presenting with a thyroid mass, cervical lymphadenopathy, and initial biopsy suggestive of papillary thyroid carcinoma. The clinical presentation, intraoperative findings, radiographic images, and pathology slides are presented. To our knowledge, this is the first report of a poorly differentiated adenocarcinoma arising from a bronchial cyst in the cervical region. PMID- 21590691 TI - One-phase crystal disorder in pharmaceutical solids and its implication for solid state stability. AB - Solid-state disorders of active pharmaceutical ingredients have been characterized by means of X-ray diffraction techniques and solid-state nuclear magnetic resonance spectroscopy. The results determined that the pleuromutilin derivative, I, displays a unique continuous conformational disorder while retaining its long-range crystalline structure. The propionic acid (PA) version of this compound displayed partial crystalline order and site disorder of PA, depending on the quantity of PA incorporated in the structure. Thus, I is a unique example of one-phase crystalline-amorphous model. Physical and chemical stability data was acquired on these disordered systems and discussed in relation with the characterized disorder present in the crystal systems. Analysis of the results showed that in contrast to phase-separated amorphous, restrained disorders do not influence the stability. PMID- 21590693 TI - Bell's palsy during pregnancy: is it associated with adverse perinatal outcome? AB - OBJECTIVE: To determine whether an association exists between Bell's palsy during pregnancy and adverse perinatal outcomes. METHODS: A retrospective study comparing all singleton pregnancies of patients with and without Bell's palsy was conducted. Multiple logistic regression model was performed to control for confounders. RESULTS: Out of 242,216 deliveries, 0.017% (n = 42) were diagnosed with Bell's palsy during pregnancy. Risk factors for Bell's palsy were chronic hypertension (9.5% vs. 1.5%, P < .001) and maternal obesity (7.1% vs. 0.8%, P < .001). Patients with Bell's palsy during pregnancy had higher rates of severe preeclampsia (9.5% vs. 1.1%, P < .001) and Cesarean deliveries (31.0% vs. 13.3%, P = .001) compared to the comparison group. In contrast, no significant association was documented between Bell's palsy and adverse perinatal outcomes such as low Apgar scores (<7) at 5 minutes (4.8% vs. 3.1%; P = .524) and perinatal mortality (2.4% vs. 1.4%; P = .57). Using multivariable analysis, controlling for confounders such as maternal age, fertility treatments, and ethnicity, Bell's palsy during pregnancy was significantly associated with obesity (odds ratio [OR] = 9.08 95% confidence interval [CI] 2.8-29.46; P < .001), chronic hypertension (OR = 6.69 95% CI 2.38-18.76; P < .001), and severe preeclampsia (OR = 9.46 95% CI 3.37-26.53; P < .001). CONCLUSIONS: Chronic hypertension and obesity are independent risk factors for Bell's palsy. Bell's palsy during pregnancy is significantly associated with severe preeclampsia. Nevertheless, no significant association exists between Bell's palsy and adverse perinatal outcomes. PMID- 21590694 TI - Dietary red palm oil protects the heart against the cytotoxic effects of anthracycline. AB - Strong anti-neoplastic anthracyclines like daunorubicin (DNR) and doxorubicin (DOX) have high efficacy against systemic neoplasm and solid tumours. However, clinically, they cause chronic cardiomyopathy and congestive heart failure. Red palm oil (RPO) supplementation can protect the heart against ischemic injury. We therefore hypothesize that supplementation with RPO during chemotherapy may protect the heart. Control rats received a standard diet, and the experimental group received RPO in addition for 4 weeks. Each group was subsequently injected with either saline or DNR over a 12-day period towards the end of 4 weeks. Hearts were excised and perfused on a working heart system. Functional parameters were measured. Tissue samples were collected for analysis of mRNA and protein levels. DNR + RPO increased aortic output by 25% (p < 0.05) compared with DNR only. Furthermore, DNR treatment significantly reduced tissue mRNA levels of superoxide dismutase 1 (SOD1) and nitric oxide synthase 1 (NOS1) compared with untreated controls. Protein expression of SOD1 followed the same pattern as mRNA levels. NOS1 protein levels were significantly increased in DNR treated rats when compared with untreated controls. In addition, DNR increased phosphorylation of p38 and Jun N-terminal kinase compared with untreated controls, whereas DNR + RPO completely counteracted this activation. DNR + RPO significantly up regulated the protein extracellular signal-regulated kinase 1 level compared with DNR only. In this model of DNR treatment, RPO is associated with stabilization of important antioxidant enzymes such NOS and SOD, and inhibition of the 'stress' induced mitogen-activated protein kinase pathways. Dietary RPO also maintained function, similar to control, in DNR treated hearts. PMID- 21590695 TI - Functional roles of superoxide and hydrogen peroxide generated by mitochondrial DNA mutation in regulating tumorigenicity of HepG2 cells. AB - Mitochondria are a major source of reactive oxygen species (ROS). Recent studies have estimated that mitochondrial DNA mutations inducing the overproduction of ROS are associated with human cancer. However, a substantial challenge in elucidating their diverse roles in regulating tumorigenesis is the lack of methods for probing ROS in living systems with molecular specificity. In this study, we reported the application of two fluorescent probes, 2-chloro-1,3 dibenzothiazolinecyclohexene and naphthofluorescein disulfonate, which showed high selectivity for superoxide (O2(*-)) and hydrogen peroxide (H2O2). They were capable of detecting and visualizing O2(*-) and H2O2 overproduction caused by a mutation in the gene encoding nicotinamide adenine dinucleotide dehydrogenase subunit 6 (ND6) in HepG2 cells. The levels of O2(*-) and H2O2 in mitochondria isolated from HepG2 cells were found to be 0.63 +/- 0.07 and 1.13 +/- 0.05 MUM, respectively. Using assays of tumorigenesis in mouse models, we found that treatment of the mice with different ROS scavengers suppressed tumour growth. These findings suggested that ROS generated by ND6 gene mutation do play an important role in regulating tumorigenesis and H2O2 may be a key modulator. PMID- 21590696 TI - Thyroid hormone-induced haemoglobin changes and antioxidant enzymes response in erythrocytes. AB - Thyroid hormones modulate haemoglobin and reactive oxygen species (ROS) production, leading to antioxidant changes. This study evaluated the antioxidant response to ROS in erythrocytes in hypothyroid and hyperthyroid rats. Wistar rats were divided into four groups: control; hyperthyroid (T4-12 mg 1(-1) in drinking water); sham operated (simulation of thyroidectomy); and hypothyroid (thyroidectomized). Four weeks after, blood was collected and haemoglobin and T(4) levels, lipid peroxidation (LPO), protein oxidation, superoxide dismutase (SOD), catalase (CAT) , glutathione S-transferase (GST) and glutathione peroxidase (GPx) activities, and total radical antioxidant potential (TRAP) were measured. SOD, CAT and GST immunocontent was evaluated. Haemoglobin levels were increased in hyperthyroid erythrocytes. LPO and carbonyls were augmented (65% and 55%, respectively) in hyperthyroid and reduced (31% and 56%, respectively) in hypothyroid group. SOD and CAT activities have not changed, as well as CAT immunocontent. TRAP was diminished in both hyperthyroid and hypothyroid groups (36% and 37%, respectively). GST activity and immunocontent, as well as GPx activity, were increased in hyper and hypothyroid rats. The data suggest that thyroid hormone changes determine ROS concentration changes and decrease of some antioxidant defences that would lead to a compensatory answer of the GST and GPx enzymes, which could be consider as credible biomarkers. PMID- 21590698 TI - Aggression, grooming and group-level cooperation in white-faced capuchins (Cebus capucinus): insights from social networks. AB - The form of animal social systems depends on the nature of agonistic and affiliative interactions. Social network theory provides tools for characterizing social structure that go beyond simple dyadic interactions and consider the group as a whole. We show three groups of capuchin monkeys from Barro Colorado Island, Panama, where there are strong connections between key aspects of aggression, grooming, and proximity networks, and, at least among females, those who incur risk to defend their group have particular "social personalities." Although there is no significant correlation for any of the network measures between giving and receiving aggression, suggesting that dominance relationships do not follow a simple hierarchy, strong correlations emerge for many measures between the aggression and grooming networks. At the local, but not global, scale, receiving aggression and giving grooming are strongly linked in all groups. Proximity shows no correlation with aggression at either the local or the global scale, suggesting that individuals neither seek out nor avoid aggressors. Yet, grooming has a global but not local connection to proximity. Extensive groomers who tend to direct their efforts at other extensive groomers also spend time in close proximity to many other individuals. These results indicate the important role that prosociality plays in shaping female social relationships. We also show that females who receive the least aggression, and thus pay low costs for group living, are most likely to participate in group defense. No consistent "social personality" traits characterize the males who invest in group defense. PMID- 21590697 TI - Inhibitory effects of novel integrin-targeting peptides on angiogenesis activity in HUVEC cells in vitro. AB - Integrins are critically involved in many tumour-promoting activities. The development of inhibitors against integrins may suppress tumour growth by inhibiting tumour angiogenic signalling. In this study, we investigated the effects of two novel peptides containing the integrin binding arginine-glycine aspartic acid-motif on inhibiting diverse cell behaviours, including cell adhesion, motility, invasion, tube formation and cell cytoskeleton. Cell adhesion and motility assays demonstrated that cyclopeptides c-Gly and c-Lys might inhibit the adhesive and motile activity at the concentration of 25 MUM. There was no significant effect on cell invasion, indicating the importance of extracellular matrix degradation in modulating the anti-invasive effect of human umbilical vein endothelial cells (HUVECs). More importantly, the tubular network formation of HUVECs was significantly inhibited by cyclopeptide c-Lys besides causing a remarkable inhibition of cytoskeletal organization, disrupting the focal adhesion and actin stress fibres formation. In conclusion, this study results indicated that the novel peptide c-Lys has the ability to inhibit diverse cell behaviours of HUVECs, and the effects may be mediated at different levels of the tumour growth. Therefore, c-Lys is perhaps proposed to be a potent anti-angiogenic drug candidate. PMID- 21590699 TI - Male chimpanzees' grooming rates vary by female age, parity, and fertility status. AB - Copulation preferences in our closest living relative, the chimpanzee, suggest that males prefer older females who have had previous offspring. However, this finding is counter to some behavioral models, which predict that chimpanzee males, as promiscuous breeders with minimal costs to mating, should show little or no preference when choosing mating partners (e.g. should mate indiscriminately). To determine if the preferences indicated by copulations appear in other contexts as well as how they interact, we examined how male chimpanzees' grooming patterns varied amongst females. We found that males' preferences were based on interactions among females' fertility status, age, and parity. First, grooming increased with increasing female parity. We further found an effect of the estrous cycle on grooming; when females were at the lowest point of their cycle, males preferentially groomed parous females at peak reproductive age, but during maximal tumescence, males preferred the oldest multiparous females. Nulliparous females received relatively little grooming regardless of age or fertility. Thus, male chimpanzees apparently chose grooming partners based on both female's experience and fertility, possibly indicating a two-pronged social investment strategy. Male selectivity seems to have evolved to effectively distribute costly social resources in a pattern which may increase their overall reproductive success. PMID- 21590700 TI - Defining and ranking effects of individual agents based on survival times of cancer patients treated with combination chemotherapies. AB - An important problem in oncology is comparing chemotherapy (chemo) agents in terms of their effects on survival or progression-free survival time. When the goal is to evaluate individual agents, a difficulty commonly encountered with observational data is that many patients receive a chemo combination including two or more agents. Because agents given in combination may interact, quantifying the contribution of each individual agent to the combination's overall effect is problematic. Still, if on average combinations including a particular agent confer longer survival, then that agent may be considered superior to agents whose combinations confer shorter survival. Motivated by this idea, we propose a definition of individual agent effects based on observational survival data from patients treated with many different chemo combinations. We define an individual agent effect as the average of the effects of the chemo combinations that include the agent. Similarly, we define the effect of each pair of agents as the average of the effects of the combinations including the pair. Under a Bayesian regression model for survival time in which the chemo combination effects follow a hierarchical structure, these definitions are used as a basis for estimating the posterior effects and ranks of the individual agents, and of all pairs of agents. The methods are illustrated by a data set arising from 224 pediatric brain tumor patients treated with over 27 different chemo combinations involving seven chemo agents. PMID- 21590701 TI - A consistency approach to evaluation of bridging studies and multi-regional trials. AB - Recently, global drug developments have attracted much attention from sponsors as well as regulatory authorities. The ICH E5 guideline defines a bridging study as a supplementary study conducted in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage, and dose regimen to allow extrapolation of the foreign clinical data to the population of the new region. On the other hand, a multi-regional trial may incorporate subjects from many regions around the world under the same protocol so that after showing the overall efficacy of a drug in all global regions, we can simultaneously evaluate the possibility of applying the overall trial results to each region and consequently support drug registration in each region. In this paper, we develop a consistency approach for assessment of similarity between a bridging study conducted in a new region and studies conducted in the original region. A statistical criterion is also established to assess the consistency between the region of interest and overall results in a multi-regional trial. The method for sample size determination for the bridging study is also proposed. Numerical examples illustrate applications of the proposed approaches in different scenarios. PMID- 21590702 TI - Perspectives on genome-wide multi-stage family-based association studies. AB - With the establishment of large consortiums of researchers, genome-wide association (GWA) studies have become increasingly popular and feasible. Although most of these association studies focus on unrelated individuals, a lot of advantages can be exploited by including families in the analysis as well. To overcome the additional genotyping cost, multi-stage designs are particularly useful. In this article, I offer a perspective view on genome-wide family-based association analyses, both within a model-based and model-free paradigm. I highlight how multi-stage designs and analysis techniques, which are quite popular in clinical epidemiology, can enter GWA settings. I furthermore discuss how they have proven successful in reducing analysis complexity, and in overcoming one of the most cumbersome statistical hurdles in the genome-wide context, namely controlling increased false positives due to multiple testing. PMID- 21590703 TI - Sufficient conditions for concluding surrogacy based on observed data. AB - In this paper, we show that Prentice's criteria for surrogates can be strengthened to remedy some weaknesses of the criteria, and we also propose some sufficient conditions under which the treatment effects on a surrogate and on the true endpoint have qualitative implication and equivalence relations. With or without requiring Prentice's criteria, we discuss what conditions are required to qualitatively assess the causal effect of treatment on an unobserved endpoint in terms of an observed surrogate. Rather than a correlation between a surrogate and an endpoint, we require stricter measurements of association for the qualitative assessment. Further we show that these conditions can be satisfied by commonly used models, such as generalized linear models and Cox's proportional hazard models. PMID- 21590704 TI - The isotopic distribution conundrum. AB - Although access to high-resolution mass spectrometry (MS), especially in the field of biomolecular MS, is becoming readily available due to recent advances in MS technology, the accompanied information on isotopic distribution in high resolution spectra is not used at its full potential, mainly because of lack of knowledge and/or awareness. In this review, we give an insight into the practical problems related to calculating the isotopic distribution for large biomolecules, and present an overview of methods for the calculation of the isotopic distribution. We discuss the key events that triggered the development of various algorithms and explain the rationale of how and why the various isotopic distribution calculations were performed. The review is focused around the developmental stages as briefly outlined below, starting with the first observation of an isotopic distribution. The observations of Beynon in the field of organic MS that chlorine appeared in a mass spectrum as two variants with odds 3:1 lie at the basis of the first wave of algorithms for the calculation of the isotopic distribution, based on the atomic composition of a molecule. From here on, we explain why more complex biomolecules such as peptides exhibit a highly complex isotope pattern when assayed by MS, and we discuss how combinatorial difficulties complicate the calculation of the isotopic distribution on computers. For this purpose, we highlight three methods, which were introduced in the 1980s. These are the stepwise procedure introduced by Kubinyi, the polynomial expansion from Brownawell and Fillippo, and the multinomial expansion from Yergey. The next development was instigated by Rockwood, who suggested to decompose the isotopic distribution in terms of their nucleon count instead of the exact mass. In this respect, we could claim that the term "aggregated" isotopic distribution is more appropriate. Due to the simplification of the isotopic distribution to its aggregated counterpart, Rockwood was able to use the convolution for the calculation of the "aggregated" isotopic distribution. Convolution methods are computationally efficient and economic in their memory usage. We spend a section on the work introduced by Rockwood during the 1990s. Due to recent breakthroughs in mass spectrometric technology and the widespread high-resolution instruments (e.g., FTICR-MS, FTOrbitrap-MS, and TOF-MS) that provide high-resolution, isotope-resolved, accurate mass data, there is an emerging need for algorithms that can calculate isotopic distributions for large biomolecules. The number of recent publications on this topic does witness this trend. The new methods are mostly based on complex mathematical developments such as, for example, cellular automata (Meija and Caruso [2004]. J Am Soc Mass Spectrom, 15(5):654-658), dynamic programming (Snider [2007]. J Am Soc Mass Spectrom, 18:1511-1515), and hierarchical models (Li et al. [2008] J Am Soc Mass Spectrom, 19:1867-1874). We also comment on the ideas to use Punnet squares and Pascal's triangle to introduce the concept of the isotopic distribution for educational and didactic purposes. PMID- 21590705 TI - The relationship between calcium and the metabolism of plasma membrane phospholipids in hemolysis induced by brown spider venom phospholipase-D toxin. AB - Brown spider venom phospholipase-D belongs to a family of toxins characterized as potent bioactive agents. These toxins have been involved in numerous aspects of cell pathophysiology including inflammatory response, platelet aggregation, endothelial cell hyperactivation, renal disorders, and hemolysis. The molecular mechanism by which these toxins cause hemolysis is under investigation; literature data have suggested that enzyme catalysis is necessary for the biological activities triggered by the toxin. However, the way by which phospholipase-D activity is directly related with human hemolysis has not been determined. To evaluate how brown spider venom phospholipase-D activity causes hemolysis, we examined the impact of recombinant phospholipase-D on human red blood cells. Using six different purified recombinant phospholipase-D molecules obtained from a cDNA venom gland library, we demonstrated that there is a correlation of hemolytic effect and phospholipase-D activity. Studying recombinant phospholipase-D, a potent hemolytic and phospholipase-D recombinant toxin (LiRecDT1), we determined that the toxin degrades synthetic sphingomyelin (SM), lysophosphatidylcholine (LPC), and lyso-platelet-activating factor. Additionally, we determined that the toxin degrades phospholipids in a detergent extract of human erythrocytes, as well as phospholipids from ghosts of human red blood cells. The products of the degradation of synthetic SM and LPC following recombinant phospholipase-D treatments caused hemolysis of human erythrocytes. This hemolysis, dependent on products of metabolism of phospholipids, is also dependent on calcium ion concentration because the percentage of hemolysis increased with an increase in the dose of calcium in the medium. Recombinant phospholipase-D treatment of human erythrocytes stimulated an influx of calcium into the cells that was detected by a calcium-sensitive fluorescent probe (Fluo 4). This calcium influx was shown to be channel-mediated rather than leak promoted because the influx was inhibited by L-type calcium channel inhibitors but not by a T-type calcium channel blocker, sodium channel inhibitor or a specific inhibitor of calcium activated potassium channels. Finally, this inhibition of hemolysis following recombinant phospholipase-D treatment occurred in a concentration-dependent manner in the presence of L-type calcium channel blockers such as nifedipine and verapamil. The data provided herein, suggest that the brown spider venom phospholipase-D-induced hemolysis of human erythrocytes is dependent on the metabolism of membrane phospholipids, such as SM and LPC, generating bioactive products that stimulate a calcium influx into red blood cells mediated by the L-type channel. PMID- 21590706 TI - Mediation of Rac1 activation by kindlin-2: an essential function in osteoblast adhesion, spreading, and proliferation. AB - Kindlins are focal adhesion proteins that regulate integrin signaling. Although integrin activation is critical for bone development, little is known about the expression and role of kindlins in osteoblasts. We therefore investigated the function of kindlin-2 in osteoblast adhesion, spreading, and proliferation using small interfering RNA. In MC3T3-E1 cells, only kindlin-2 is highly expressed and localizes to focal adhesion. We found that kindlin-2 was involved in integrin activation in MC3T3-E1 cells and that kindlin-2 knockdown osteoblasts resulted in diminished cell adhesion, spreading, and proliferation. In this process, kindlin 2 knockdown impaired transient Rac1 activation, influencing Akt activation and AP 1 activity. In agreement with these data, pharmacological inhibition of Rac1 reduced MC3T3-E1 cell adhesion, spreading, and proliferation. Overall, these findings demonstrated that kindlin-2 governs Rac1 activation, which controls osteoblast function. Our findings provide the first insights concerning the function of kindlin-2 in osteoblast, and suggest that kindlin-2 is a critical mediator for osteoblast physiology. PMID- 21590707 TI - IL-8 increases integrin expression and cell motility in human chondrosarcoma cells. AB - Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Interleukin-8 (IL-8), a chemokine with a defining CXC amino acid motif, is known to possess tumorigenic and proangiogenic properties. Over-expression of IL-8 has been detected in many human tumors. However, the effects of IL-8 in migration and integrin expression in chondrosarcoma cells are largely unknown. In this study, we found that IL-8 increased the migration and the expression of alphavbeta3 integrin in human chondrosarcoma cells. Activations of phosphatidylinositol 3-kinase (PI3K), Akt, and AP-1 pathways after IL-8 treatment were demonstrated, and IL-8-induced expression of integrin and migration activity was inhibited by the specific inhibitor and mutant of PI3K, Akt, and AP-1 cascades. Taken together, our results indicated that IL-8 enhances the migration of chondrosarcoma cells by increasing alphavbeta3 integrin expression through the PI3K/Akt/AP-1 signal transduction pathway. PMID- 21590708 TI - BMP-2 suppresses renal interstitial fibrosis by regulating epithelial-mesenchymal transition. AB - Dysregulation of epithelial-to-mesenchymal transition (EMT) may contribute to renal fibrogenesis. Our previous study indicated that bone morphogenetic protein 2 (BMP-2) significantly reversed transforming growth factor (TGF)-beta1-induced renal interstitial fibrosis. In this study, we examined the underlying mechanism and elucidate the regulation of EMT process under BMP-2 treatment. Cultured renal interstitial fibroblast (NRK-49F) was treated with TGF-beta1 (10 ng/ml) with or without BMP-2 (10-250 ng/ml) for 24 h. The expression of alpha-smooth muscle actin (alpha-SMA), E-cadherin, fibronectin, or Snail transcriptional factors was analyzed by immunofluorescence staining or Western blotting. Cell migration was analyzed by wound-healing assay. NRK-49F treated with TGF-beta1 induced significant EMT including upregulatioin of alpha-SMA, fibronectin, and snail proteins and down-regulation of E-cadherin. Interestingly, co-treatment with BMP 2 dose-dependently reversed TGF-beta1-induced cellular fibrosis, cell migration, and above EMT change. The above effect was closely correlated with Snail since BMP-2 dose- and time-course dependently induced a significant decrease in the level of Snail. Moreover, Snail siRNA significantly reversed TGF-beta1-induced increases in the level of alpha-SMA and fibronectin (intracellular and extracellular). We suppose that BMP-2 have the potential to attenuate TGF-beta1 induced renal interstitial fibrosis by attenuating Snail expression and reversing EMT process. PMID- 21590709 TI - Alkaline stress-induced autophagy is mediated by mTORC1 inactivation. AB - The activation of autophagic pathway by alkaline stress was investigated. Various types of mammalian cells were subjected to alkaline stress by incubation in bicarbonate buffered media in humidified air containing atmospheric 0.04% CO(2) . The induction of autophagy following alkaline stress was evaluated by assessing the conversion of cytosolic LC3-I into lipidated LC3-II, the accumulation of autophagosomes, and the formation of autolysosomes. Colocalization of GFP-LC3 with endolysosomal marker in HeLa GFP-LC3 cells undergoing autophagic process by alkaline stress further demonstrates that autophagosomes triggered by alkaline stress matures into autolysosomes for the lysosome dependent degradation. We found that the inactivation of mTORC1 is important for the pathway leading to the induction of autophagy by alkaline stress since the expression of RhebQ64L, a constitutive activator of mTORC1, downregulates the induction of autophagy after alkaline stress in transfected human 293T cells. These results imply that activation of autophagic pathway following the inactivation of mTORC1 is important cellular events governing alkaline stress-induced cytotoxicity and clinical symptoms associated with alkalosis. PMID- 21590710 TI - The role of Lrp5/6 in cardiac valve disease: LDL-density-pressure theory. AB - Atherosclerosis and osteoporosis are the leading causes of mortality and morbidity in the World. Recent epidemiologic studies have demonstrated that these disease processes develop in parallel. Evidence indicates that hyperlipidemia plays a paradoxical role in both disease processes. However, the mechanism is not understood. This prospectus hypothesizes the role of lipids activate atherosclerosis within the bone and the heart to initiate the development of diseases in both of these tissues. The Prospectus on the Lrp 5/6 receptors provides a foundation for the mechanisms involved in the Lrp5/6 mediated disease biology. The LDL-Density-Pressure theory: the Role of Lrp5/6 provides a biological and a hemodynamic approach towards understanding the development of valvular heart disease and the implications in the field of bone molecular biology. This prospectus will review the current literature, provide a basis for the development of valve disease and indicate future therapeutic pathways for this disease process in the future. PMID- 21590711 TI - Correlates of mercury in female river otters (Lontra canadensis) from Nova Scotia, Canada. AB - Mercury (Hg) can reach toxic concentrations in aquatic habitats, sometimes as a consequence of human activity. Mercury can have deleterious effects, particularly in piscivorous mammals in which it bioaccumulates. Furs from trapper-provided female otter (Lontra canadensis) carcasses in Nova Scotia were analyzed for total Hg. Concentrations of total Hg in fur samples averaged 25 ug/g dry weight, ranging from 1.4 to 137 ug/g; 20 ug/g is the fur concentration at which toxic effects are expected. Mercury concentrations were greater in otters from watersheds with bedrock substrates known to contain more available Hg, from otters trapped farther inland, and from otters trapped on watersheds with hydroelectric dams. Otter reproductive potential was measured by counting the number of blastocysts in reproductive tracts. Tooth annuli were used to age otters. Reproductive potential was not related to Hg concentration, nor was Hg concentration related to age. In a general linear model, 53% of variation in fur Hg was explained by underlying bedrock, distance from the coast at which otters were trapped, and presence/absence of a hydroelectric dam. The proportion of juveniles in a population did not differ relative to bedrock Hg concentration, but was lower on watersheds with hydroelectric dams. Because we found no evidence of reduced reproductive potential from greater Hg concentrations, the low proportion of juveniles suggests that Hg reduced juvenile survival, although our evidence is circumstantial. PMID- 21590712 TI - Acute and chronic toxicity of boron to a variety of freshwater organisms. AB - Boron enters the aquatic environment from various sources, including weathering of borates, sewage effluents, coal combustion, use of cleaning compounds, and agrochemicals. The present study was designed to generate data on acute and chronic boron toxicity in support of an update of water quality standards in Illinois, USA. We examined the acute toxicity of boron to eight different freshwater organisms including a fish, an insect, two crustaceans, and four bivalve mollusks. To our knowledge, this is the first study to present data on the toxicity of boron to freshwater mollusks. We also sought to clarify whether hardness or pH affect boron toxicity to aquatic life, and to quantify chronic effect levels in two freshwater species. Sensitivity among the various species ranged widely, with the fathead minnow (Pimephales promelas) being the most sensitive. Neither pH nor hardness had a consistent effect on acute boron toxicity to two crustaceans (Ceriodaphnia dubia and Hyalella azteca), but we observed evidence that chloride reduces boron toxicity to H. azteca. The fathead minnow, while more acutely sensitive than the other species, had a lower acute to chronic ratio than did H. azteca, which had reduced reproduction at 13 mg/L. While we do not know the extent to which the eight tested species represent the range of sensitivities of native but untested species in Illinois, the current water quality standard for Illinois (1 mg/L) is conservative with regard to the native species tested thus far. PMID- 21590713 TI - Uptake of lead, cadmium, and other metals in the liver and kidneys of cattle near a lead-zinc mine in Kabwe, Zambia. AB - Concentrations of lead, cadmium, and other metals in the liver and kidneys of cattle near a lead-zinc mine in Kabwe (Zambia), which is ranked among the 10 worst polluted places on earth, were compared with other Zambian towns. Metal concentrations were measured in the liver and kidneys of 51 cattle from Kabwe and other Zambian towns. The maximum metal concentrations, expressed in mg/kg and dry weight, in the liver or kidneys were 398.4 (Cu), 252.6 (Zn), 77.81 (Cr), 19.37 (Cd), 7.57 (Ni), 1.8 (Pb), 1.04 (Co), 0.112 (Hg), and 0.05 (As). Concentrations of Pb and Cd in Kabwe cattle were higher than levels in other Zambian towns. The mean concentration of Cd exceeded benchmark values in offal destined for human consumption. Levels of Ni and Cr may also pose public health concerns. Concentrations of Pb and Cr, Pb and Cu, Cd and Zn, Cd and Hg, Zn and Cu, Cu and Co, as well as Co and Ni were positively correlated. The present study also highlighted the dangers of exposure of animals and humans to a mixture of toxic metals. PMID- 21590714 TI - Identification of benzothiazole derivatives and polycyclic aromatic hydrocarbons as aryl hydrocarbon receptor agonists present in tire extracts. AB - Leachate from rubber tire material contains a complex mixture of chemicals previously shown to produce toxic and biological effects in aquatic organisms. The ability of these leachates to induce Ah receptor (AhR)-dependent cytochrome P4501A1 expression in fish indicated the presence of AhR active chemicals, but the responsible chemicals and their direct interaction with the AhR signaling pathway were not examined. Using a combination of AhR-based bioassays, we have demonstrated the ability of tire extract to stimulate both AhR DNA binding and AhR-dependent gene expression and confirmed that the responsible chemicals were metabolically labile. The application of CALUX (chemical-activated luciferase gene expression) cell bioassay-driven toxicant identification evaluation not only revealed that tire extract contained a variety of known AhR-active polycyclic aromatic hydrocarbons but also identified 2-methylthiobenzothiazole and 2 mercaptobenzothiazole as AhR agonists. Analysis of a structurally diverse series of benzothiazoles identified many that could directly stimulate AhR DNA binding and transiently activate the AhR signaling pathway and identified benzothiazoles as a new class of AhR agonists. In addition to these compounds, the relatively high AhR agonist activity of a large number of fractions strongly suggests that tire extract contains a large number of physiochemically diverse AhR agonists whose identities and toxicological/biological significances are unknown. PMID- 21590715 TI - Effects of four rice paddy herbicides on algal cell viability and the relationship with population recovery. AB - Paddy herbicides are a high-risk concern for aquatic plants, including algae, because they easily flow out from paddy fields into rivers, with toxic effects. The effect on algal population dynamics, including population recovery after timed exposure, must be assessed. Therefore, we demonstrated concentration response relationships of four paddy herbicides for algal growth inhibition and mortality, and the relationship between the effect on algal cell viability and population recovery following exposure. We used SYTOX Green dye assay and flow cytometry to assess cell viability of the alga Pseudokirchneriella subcapitata. Live cells could be clearly distinguished from dead cells during herbicide exposure. Our results showed that pretilachlor and quinoclamine had both algicidal and algistatic effects, whereas bensulfuron-methyl only had an algistatic effect, and pentoxazone only had an algicidal effect. Then, a population recovery test following a 72-h exposure was conducted. The algal population recovered in all tests, but the periods required for recovery differed among exposure concentrations and herbicides. The periods required for recovery were inconsistent with the dead cell ratio at the beginning of the recovery test; that is, population recovery could not be described only by cell viability. Consequently, the temporal effect of herbicides and subsequent recovery of the algal population could be described not only by the toxicity characteristics but also by toxicokinetics, such as rate of uptake, transport to the target site, and elimination of the substance from algal cells. PMID- 21590716 TI - Antitumor effects of telomerase inhibitor TMPyP4 in osteosarcoma cell lines. AB - Telomere studies in carcinomas have been extensively reported for prognostic utility and effective methods for targeting telomerase therapy has been described, but efficacy of telomerase inhibitor remained unknown in sarcoma cells. In this study, we investigated the effects of telomerase inhibitor cationic porphyrin TMPyP4 on telomerase activity, telomere length, cell growth, and apoptosis in osteosarcoma cell lines. TMPyP4 significantly inhibited telomerase activity in telomerase positive HOS and Saos-2, but not in MG-63. TMPyP4 significantly induced telomere shortening, and inhibition of the cell growth in HOS and Saos-2 with over 17% apoptosis rates. In terms of MG-63, TMPyP4 did not induce inhibition of both telomerase activity and cell growth, although it induced significant telomere shortening. Telomere length after treatment was 5.60 kb in HOS, 4.00 kb in Saos-2, and 9.89 kb in MG-63. These results may suggest that both telomerase activity loss and sufficient telomere shortening are necessary to inhibit cell growth in telomerase positive osteosarcoma cells. TMPyP4 did not induced telomere shortening but significantly inhibited the growth with 22.6% apoptosis rate in telomerase negative with extremely longer telomere U2OS, may indicating the antitumor effect of TMPyP4 may be related to DNA damage including telomere dysfunction through G-quadruplex stabilization, independent on telomere length. PMID- 21590717 TI - Nanocomposite therapy as a more efficacious and less inflammatory alternative to bone morphogenetic protein-2 in a rodent arthrodesis model. AB - The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spine fusion has led to concerns regarding a potential accompanying inflammatory response. This study evaluates a combination therapy (TrioMatrix(r); Pioneer Surgical, Inc., Marquette, MI) comprised of a demineralized bone matrix (DBM), hydroxyapatite, and a nanofiber-based collagen scaffold in a rodent spine fusion model. Thirty-six athymic rats that underwent a posterolateral intertransverse spinal fusion were randomly assigned to 1 of 5 treatment groups: absorbable collagen sponge alone (ACS, negative control), 10 ug rhBMP-2 on ACS (positive control), TrioMatrix(r), Grafton(r) (Osteotech, Inc., Eatontown, NJ), and DBX(r) (Synthes, Inc., West Chester, PA). Both TrioMatrix(r) and rhBMP-2-treated animals demonstrated 100% fusion rates as graded by manual palpation scores 8 weeks after implantation. This rate was significantly greater than those of the ACS, Grafton(r), and DBX(r) groups. Notably, the use of TrioMatrix(r) as evaluated by microCT quantification led to a greater fusion mass volume when compared to all other groups, including the rhBMP-2 group. T2-weighted axial MRI images of the fusion bed demonstrated a significant host response associated with a large fluid collection with the use of rhBMP-2; this response was significantly reduced with the use of TrioMatrix(r). Our results therefore demonstrate that a nanocomposite therapy represents a promising, cost-effective bone graft substitute that could be useful in spine fusions where BMP-2 is contraindicated. PMID- 21590718 TI - Calcification in human intervertebral disc degeneration and scoliosis. AB - Calcification is a pathological process that may lead to impairment of nutrient supply and disc metabolism in degenerative and scoliotic intervertebral discs (IVDs). The purpose of this study was to assess the calcification potential of IVDs in degenerative disc disease (DDD) and adolescent idiopathic scoliosis (AIS). For this purpose, 34 IVDs from 16 adult patients with DDD and 25 IVDs from 9 adolescent patients with AIS were obtained at surgery. The concave and convex parts of the scoliotic discs were analyzed separately. Von Kossa staining was performed to visualize calcium deposits, while type X collagen (COL X) expression associated with endochondral ossification was measured by immunohistochemistry. Alkaline phosphatase activity and calcium and inorganic phosphate concentrations were used as indicators of calcification potential. Results showed the presence of calcium deposits and COL X in degenerative and scoliotic IVDs, but not in control discs, and the level of the indicators of calcification potential was consistently higher in degenerative and scoliotic discs than in control discs. The results suggest that disc degeneration in adults is associated with ongoing mineral deposition and that mineralization in AIS discs might reflect a premature degenerative process. PMID- 21590719 TI - Relationship of donor variables and graft dimension on biomechanical performance of femoral ring allograft. AB - Structural femoral ring allograft is commonly used in interbody spinal arthrodesis. Fractures of implanted femoral ring allograft have been reported. Data to guide donor screening and tissue processing by allograft tissue banks for factors that affect graft strength are incomplete. Fresh frozen human femora from 34 cadaveric donors were sectioned into ten 20-mm thick specimens. Bone mineral density (BMD), donor age, and graft dimensions were recorded for each specimen. Three hundred twenty-seven specimens were tested in quasi-static axial compression. Linear regression models compared load to failure with BMD, sex specific donor age, minimum/maximum cortical wall thickness, and minimum/maximum outer ring diameter. Correlations between minimum and maximum cortical wall thickness and load to failure were significant (r = 0.73, p < 0.001 and r = 0.74, p < 0.001, respectively). BMD showed a weaker negative correlation with load to failure (r = -0.11, p = 0.05). Correlations between load to failure and minimum and maximum outer ring diameter and age (r = 0.06, p = 0.31) were not significant. We found that the minimum and maximum cortical wall thicknesses of femoral ring allograft are strongly correlated with the axial compressive load to failure of the graft. Other tested parameters did not prove to be effective predictors of resistance to axial loading. PMID- 21590720 TI - Contributions of chemical exchange to T1rho dispersion in a tissue model. AB - Variations in T(1rho) with locking-field strength (T(1rho) dispersion) may be used to estimate proton exchange rates. We developed a novel approach utilizing the second derivative of the dispersion curve to measure exchange in a model system of cross-linked polyacrylamide gels. These gels were varied in relative composition of comonomers, increasing stiffness, and in pH, modifying exchange rates. Magnetic resonance images were recorded with a spin-locking sequence as described by Sepponen et al. These measurements were fit to a mono-exponential decay function yielding values for T(1rho) at each locking-field measured. These values were then fit to a model by Chopra et al. for estimating exchange rates. For low stiffness gels, the calculated exchange values increased by a factor of 4 as pH increased, consistent with chemical exchange being the dominant contributor to T(1rho) dispersion. Interestingly, calculated chemical exchange rates also increased with stiffness, likely due to modified side-chain exchange kinetics as the composition varied. This article demonstrates a new method to assess the structural and chemical effects on T(1rho) relaxation dispersion with a suitable model. These phenomena may be exploited in an imaging context to emphasize the presence of nuclei of specific exchange rates, rather than chemical shifts. PMID- 21590722 TI - Analysis of complex cardiovascular flow with three-component acceleration-encoded MRI. AB - Functional information regarding cardiac performance, pressure gradients, and local flow derangement are available from blood acceleration fields. Thus, this study examines a 2D and 3D phase contrast sequence optimized to efficiently encode three-directional, time-resolved acceleration in vitro and in vivo. Stenosis phantom acceleration measurements were compared to acceleration derived from standard velocity encoded phase contrast-magnetic resonance imaging (i.e., "velocity-derived acceleration"). For in vivo analysis, three-directional 2D acceleration maps were compared to velocity-derived acceleration using regions proximal and distal to the aortic valve in six healthy volunteers at 1.5 and 3.0 T (voxel size = 1.4 * 2.1 * 8 mm, temporal resolution = 16-20 ms). In addition, a 4D acceleration sequence was evaluated for feasibility in a healthy volunteer and postrepair biscuspid aortic valve patient with an ascending aortic aneurysm. The phantom magnetic resonance acceleration measurements were more accurate (nonturbulent root mean square error = 2.2 vs. 5.1 m/s(2) for phase contrast magnetic resonance imaging) and 10 times less noisy (nonturbulent sigma = 0.9 vs. 13.6 m/s(2) for phase contrast-magnetic resonance imaging) than velocity-derived acceleration. Acceleration mapping of the left ventricular outflow tract and aortic arch exhibited signal voids colocated with complex flow events such as vortex formation and high order motion. 4D acceleration data, visualized in combination with the velocity data, may provide new insight into complex flow phenomena. PMID- 21590721 TI - Calibration and validation of TRUST MRI for the estimation of cerebral blood oxygenation. AB - Recently, a T(2) -Relaxation-Under-Spin-Tagging (TRUST) MRI technique was developed to quantitatively estimate blood oxygen saturation fraction (Y) via the measurement of pure blood T(2) . This technique has shown promise for normalization of fMRI signals, for the assessment of oxygen metabolism, and in studies of cognitive aging and multiple sclerosis. However, a human validation study has not been conducted. In addition, the calibration curve used to convert blood T(2) to Y has not accounted for the effects of hematocrit (Hct). In this study, we first conducted experiments on blood samples under physiologic conditions, and the Carr-Purcell-Meiboom-Gill T(2) was determined for a range of Y and Hct values. The data were fitted to a two-compartment exchange model to allow the characterization of a three-dimensional plot that can serve to calibrate the in vivo data. Next, in a validation study in humans, we showed that arterial Y estimated using TRUST MRI was 0.837 +/- 0.036 (N=7) during the inhalation of 14% O2, which was in excellent agreement with the gold-standard Y values of 0.840 +/- 0.036 based on Pulse-Oximetry. These data suggest that the availability of this calibration plot should enhance the applicability of T(2) Relaxation-Under-Spin-Tagging MRI for noninvasive assessment of cerebral blood oxygenation. PMID- 21590724 TI - kT -points: short three-dimensional tailored RF pulses for flip-angle homogenization over an extended volume. AB - With Transmit SENSE, we demonstrate the feasibility of uniformly exciting a volume such as the human brain at 7T through the use of an original minimalist transmit k-space coverage, referred to as "k(T) -points." Radio-frequency energy is deposited only at a limited number of k-space locations in the vicinity of the center to counteract transmit sensitivity inhomogeneities. The resulting nonselective pulses are short and need little energy compared to adiabatic or other B 1+-robust pulses available in the literature, making them good candidates for short-repetition time 3D sequences at high field. Experimental verification was performed on three human volunteers at 7T by means of an 8-channel transmit array system. On average, whereas the standard circularly polarized excitation resulted in a 33%-flip angle spread (standard deviation over mean) throughout the brain, and a static radio-frequency shim showed flip angle variations of 17% and up, application of k(T) -point-based excitations demonstrated excellent flip angle uniformity (8%) for a small target flip angle and with sub-millisecond durations. PMID- 21590723 TI - Magnetic resonance elastography of the lung parenchyma in an in situ porcine model with a noninvasive mechanical driver: correlation of shear stiffness with trans-respiratory system pressures. AB - Quantification of the mechanical properties of lung parenchyma is an active field of research due to the association of this metric with normal function, disease initiation and progression. A phase contrast MRI-based elasticity imaging technique known as magnetic resonance elastography is being investigated as a method for measuring the shear stiffness of lung parenchyma. Previous experiments performed with small animals using invasive drivers in direct contact with the lungs have indicated that the quantification of lung shear modulus with (1) H based magnetic resonance elastography is feasible. This technique has been extended to an in situ porcine model with a noninvasive mechanical driver placed on the chest wall. This approach was tested to measure the change in parenchymal stiffness as a function of airway opening pressure (P(ao) ) in 10 adult pigs. In all animals, shear stiffness was successfully quantified at four different P(ao) values. Mean (+/-STD error of mean) pulmonary parenchyma density corrected stiffness values were calculated to be 1.48 (+/-0.09), 1.68 (+/-0.10), 2.05 (+/ 0.13), and 2.23 (+/-0.17) kPa for P(ao) values of 5, 10, 15, and 20 cm H2O, respectively. Shear stiffness increased with increasing P(ao) , in agreement with the literature. It is concluded that in an in situ porcine lung shear stiffness can be quantitated with (1) H magnetic resonance elastography using a noninvasive mechanical driver and that it is feasible to measure the change in shear stiffness due to change in P(ao) . PMID- 21590725 TI - Optimized double inversion recovery for reduction of T1 weighting in fluid attenuated inversion recovery. AB - Fluid-attenuated inversion recovery (FLAIR) is a routinely used technique in clinical practice to detect long T(2) lesions by suppressing the cerebrospinal fluid. Concerns remain, however, that the inversion pulse in FLAIR imparts T(1) weighting that can decrease the detectability and mischaracterize some lesions. Hence, FLAIR is usually acquired in conjunction with a standard T(2) to guard against these concerns. Recently, double inversion recovery (DIR) preparations have highlighted certain types of lesions by suppressing both cerebrospinal fluid and white matter but produce even stronger T(1) contrast than FLAIR. This work shows that the inversion times in a DIR sequence can be optimized to minimize unwanted T(1) weighting, enabling the acquisition of cerebrospinal fluid suppressed images with pure T(2) weighting. This technique is referred to as T(1) -nulled DIR. The theory to determine the optimized inversion times is discussed and the results are shown by simulations, normal volunteer studies, and multiple sclerosis patient studies. T(1) -nulled DIR provides equivalent or superior contrast between gray and white matters as well as white matter and multiple sclerosis lesion at the same repetition time. Multiple sclerosis lesions appeared sharper on T(1) -nulled DIR compared to FLAIR. T(1) -nulled DIR has the potential to replace the combination of standard T(2) and FLAIR acquisitions in many clinical protocols. PMID- 21590726 TI - Probing mouse brain microstructure using oscillating gradient diffusion MRI. AB - High resolution diffusion tensor images of the mouse brain were acquired using the pulsed gradient spin echo sequence and the oscillating gradient spin echo sequence. The oscillating gradient spin echo tensor images demonstrated frequency dependent changes in diffusion measurements, including apparent diffusion coefficient and fractional anisotropy, in major brain structures. Maps of the rate of change in apparent diffusion coefficient with oscillating gradient frequency revealed novel tissue contrast in the mouse hippocampus, cerebellum, and cerebral cortex. The observed frequency-dependent contrasts resembled neuronal soma-specific Nissl staining and nuclei-specific 4',6-diamidino-2 phenylindole (DAPI) staining in the mouse brain, which suggests that the contrasts might be related to key features of cytoarchitecture in the brain. In the mouse cuprizone model, oscillating gradient spin echo-based diffusion MRI revealed significantly higher frequency-dependence of perpendicular diffusivity (lambda(?) ) in the demyelinated caudal corpus callosum at 4 weeks after cuprizone treatment when compared with control mice and mice at 6 weeks after cuprizone treatment. The elevated frequency-dependence of lambda(?) coincided with the infiltration of activated microglia/macrophages and disruption of axons during acute demyelination in the caudal corpus callosum. The results demonstrate the potential of oscillating gradient spin echo-based diffusion MRI for providing tissue contrasts complimentary to conventional pulsed gradient spin echo-based diffusion MRI. PMID- 21590727 TI - Fast whole-body magnetic resonance angiography in mice. AB - High-throughput magnetic resonance imaging (MRI) tools are required for the longitudinal investigation of vascular diseases in mouse models. Angiographic data from various anatomic regions may be needed in a single experiment. This study involves a three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiography (MRA) method using sequential acquisitions of four data sets corresponding to the head, the thorax, the abdomen, and the hind limbs of a mouse. After repositioning the animal, each anatomic region was acquired in 2 min, and the TOF effect was provided by the spatial selectivity of the radio frequency (RF) resonator. No slab selection was needed and whole-body MRA was performed in a total experiment time of 10 min. The voxel size was equal to or greater than 131 * 195 * 188 MUm(3). To suppress the signal arising from stationary tissues, both inversion recovery and interspersed saturation, used as magnetization preparations, were compared from a theoretical and an experimental perspective. The arterial tree (carotid, aortic, iliac, renal, and smaller arteries) was well visualized by this method, both in control healthy mice and in mice with common carotid artery ligation. The potential interest of this method for evaluating arterial diseases is discussed. PMID- 21590728 TI - In utero phenotyping of mouse embryonic vasculature with MRI. AB - The vasculature is the earliest developing organ in mammals and its proper formation is critical for embryonic survival. MRI approaches have been used previously to analyze complex three-dimensional vascular patterns and defects in fixed mouse embryos. Extending vascular imaging to an in utero setting with potential for longitudinal studies would enable dynamic analysis of the vasculature in normal and genetically engineered mouse embryos, in vivo. In this study, we employed an in utero MRI approach that corrects for motion, using a combination of interleaved gated acquisition and serial coregistration of rapidly acquired three-dimensional images. We tested the potential of this method by acquiring and analyzing images from wildtype and Gli2 mutant embryos, demonstrating a number of Gli2 phenotypes in the brain and cerebral vasculature. These results show that in utero MRI can be used for in vivo phenotype analysis of a variety of mutant mouse embryos. PMID- 21590729 TI - Using indirect covariance processing for structure elucidation of small molecules in cases of spectral crowding. AB - Indirect and unsymmetrical indirect covariance NMR provide powerful tools to compute and visualize correlation information by transforming component spectra into combined spectral data matrices. Sensitive component spectra such as TOCSY, HSQC and NOESY can be quickly converted into experimentally insensitive or time consuming correlation spectra such as HSQC-NOESY. The comparison of illustrative series of spectra from four steroids, dexamethasone, testosterone, allylestrenol and tibolone, renders the effects of resonance overlap on the ease of interpretation visible. The compounds are selected such that signal overlap increases systematically in the proton and carbon domain. Spectra are defined as light, moderate and heavy signal overlap, based on signal density. The investigation suggests that moderate spectral congestion in either proton or carbon domain leads to a number of artifacts that does not hamper signal assignment but lowers the level of confidence on de novo structure elucidation. Since the number of correlations usually increases through covariance processing, component spectra with severe spectral congestion in both dimensions are not suitable for covariance processing and the resulting spectra do not support structure confirmation or structure elucidation. The calculated spectra are compared with the corresponding experimental spectra with respect to their application in structure elucidation laboratory environments. PMID- 21590730 TI - Complete 1H and 13C NMR data assignment of protolimonoids from the stem barks of Aphanamixis grandifolia. AB - Seven new protolimonoids, named aphagranins A-G (1-7), along with four known compounds, were isolated from the ethanol extract of the stem barks of Aphanamixis grandifolia. Structure elucidation and signal assignments were achieved on the basis of spectral and chemical evidences. PMID- 21590732 TI - Concerted actions of insulin-like growth factor 1, testosterone, and estradiol on peripubertal bone growth: a 7-year longitudinal study. AB - A better understanding of how bone growth is regulated during peripuberty is important for optimizing the attainment of peak bone mass and for the prevention of osteoporosis in later life. In this report we used hierarchical models to evaluate the associations of insulin-like growth factor 1 (IGF-1), estradiol (E(2) ), and testosterone (T) with peripubertal bone growth in a 7-year longitudinal study. Two-hundred and fifty-eight healthy girls were assessed at baseline (mean age 11.2 years) and at 1, 2, 3.5, and 7 years. Serum concentrations of IGF-1, E(2) , and T were determined. Musculoskeletal properties in the left lower leg were measured using peripheral quantitative computed tomography (pQCT). Serum levels of IGF-1, E(2) , and T increased dramatically before menarche, whereas they decreased, plateaued, or increased at a lower rate, respectively, after menarche. IGF-1 level was positively associated with periosteal circumference (PC) and total bone mineral content (tBMC) throughout peripuberty but not after adjustment for muscle cross-sectional area (mCSA). On the other hand, IGF-1 was associated with tibial length (TL) independently of mCSA before menarche. T was positively associated with TL, PC, tBMC, and cortical volumetric bone mineral density, independent of mCSA, before menarche but not after. E(2) was associated with TL positively before menarche but negatively after menarche. These findings suggest that during puberty, circulating IGF-1 promotes bone periosteal apposition and mass accrual indirectly, probably through stimulating muscle growth, whereas the effects of sex steroids on bone growth differ before and after menarche, presenting a biphasic pattern. Hence the concerted actions of these hormones are essential for optimal bone development in peripuberty. PMID- 21590731 TI - Relationship of testosterone and osteocalcin levels during growth. AB - Recent studies in mice have demonstrated that osteocalcin (OCN) regulates testosterone (T) production in males but not in females. We hypothesized that this novel bone-testis axis may be most relevant during rapid skeletal growth to help maximize bone size. Thus we measured serum T, total and undercarboxylated (UC) OCN, and periosteal circumference at the radius in 56 boys (bone age 4 to 20 years). T was correlated with OCN (bone-age-adjusted r = 0.30, p = .024), with a similar trend for UC OCN. T began to increase in the boys at bone age 11 years, and OCN peaked at bone age 14 years. Thus we divided the boys into three groups: 4 to 10 years (n = 16), 11 to 14 years (n = 18), and 15 to 20 years (n = 22). In boys of bone age 11 to 14 years (but not the other two groups), OCN was correlated with T (r = 0.57, p = .013), with a similar trend for UC OCN; T, in turn, was correlated with periosteal circumference (r = 0.75, p < .001). Collectively, these findings support the recent observations in mice of a novel bone-testis axis. Moreover, our data suggest that in human males, this axis may be most relevant during rapid skeletal growth, when T levels are rising under the influence of the hypothalamic-pituitary axis and OCN is increasing due to skeletal growth. During this phase, OCN may further stimulate testicular T production, which, in turn, contributes to an increase in bone size. PMID- 21590733 TI - DXA measurements in Rett syndrome reveal small bones with low bone mass. AB - Low bone mass is reported in growth-retarded patients harboring mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene causing Rett syndrome (RTT). We present the first study addressing both bone mineral density (BMD) and bone size in RTT. Our object was to determine whether patients with RTT do have low BMD when correcting for smaller bones by examination with dual-energy X-ray absorptiometry (DXA). We compared areal BMD (aBMD(spine) and aBMD(total hip) ) and volumetric bone mineral apparent density (vBMAD(spine) and vBMAD(neck) ) in 61 patients and 122 matched healthy controls. Further, spine and hip aBMD and vBMAD of patients were associated with clinical risk factors of low BMD, low energy fractures, MECP2 mutation groups, and X chromosome inactivation (XCI). Patients with RTT had reduced bone size on the order of 10% and showed lower values of spine and hip aBMD and vBMAD (p < .001) adjusted for age, pubertal status, and body mass index (BMI). aBMD(spine) , vBMAD(spine) , and aBMD(total hip) were associated with low-energy fractures (p < .05). Walking was significantly associated to aBMD(total hip) and vBMAD(neck) adjusted for age and body mass index (BMI). Further, vBMAD(neck) was significantly associated to a diagnosis of epilepsy, antiepileptic treatment, and MECP2 mutation group, but none of the associations with vBMAD(neck) remained clinically significant in a multiple adjusted model including age and BMI. Neither aBMD(spine) , vBMAD(spine) , nor aBMD(total hip) were significantly associated with epilepsy, antiepileptic treatment, MECP2 mutation group, XCI, or vitamin D status. Low bone mass and small bones are evident in RTT, indicating an apparent low-bone-formation phenotype. PMID- 21590734 TI - Adenosine receptor subtype expression and activation influence the differentiation of mesenchymal stem cells to osteoblasts and adipocytes. AB - Osteoblasts and adipocytes differentiate from a common precursor cell, the mesenchymal stem cell (MSC). Adenosine is known to signal via four adenosine receptor subtypes, and significantly, recent findings indicate that these may play a role in MSC differentiation. We therefore investigated adenosine receptor expression and activation during the differentiation of MSCs to osteoblasts and adipocytes. The A(2B) R was dominant in MSCs, and its expression and activity were transiently upregulated at early stages of osteoblastic differentiation. Both activation and overexpression of A(2B) R induced the expression of osteoblast-related genes [Runx2 and alkaline phosphatase (ALP)], as well as ALP activity, and stimulation increased osteoblast mineralization. The expression of A(2A) R was upregulated during later stages of osteoblastic differentiation, when its activation stimulated ALP activity. Differentiation of MSCs to adipocytes was accompanied by significant increases in A(1) R and A(2A) R expression, and their activation was associated with increased adipogenesis. Enhanced A(2A) R expression was sufficient to promote expression of adipocyte-related genes (PPARgamma and C/EBPalpha), and its activation resulted in increased adipocytic differentiation and lipid accumulation. In contrast, the A(1) R was involved mainly in lipogenic activity of adipocytes rather than in their differentiation. These results show that adenosine receptors are differentially expressed and involved in lineage-specific differentiation of MSCs. We conclude, therefore, that fruitful strategies for treating diseases associated with an imbalance in the differentiation and function of these lineages should include targeting adenosine receptor signal pathways. Specifically, these research avenues will be useful in preventing or treating conditions with insufficient bone or excessive adipocyte formation. PMID- 21590735 TI - Connexin43 deficiency reduces the sensitivity of cortical bone to the effects of muscle paralysis. AB - We have shown previously that the effect of mechanical loading on bone depends in part on connexin43 (Cx43). To determine whether Cx43 is also involved in the effect of mechanical unloading, we have used botulinum toxin A (BtxA) to induce reversible muscle paralysis in mice with a conditional deletion of the Cx43 gene in osteoblasts and osteocytes (cKO). BtxA injection in hind limb muscles of wild type (WT) mice resulted in significant muscle atrophy and rapid loss of trabecular bone. Bone loss reached a nadir of about 40% at 3 weeks after injection, followed by a slow recovery. A similar degree of trabecular bone loss was observed in cKO mice. By contrast, BtxA injection in WT mice significantly increased marrow area and endocortical osteoclast number and decreased cortical thickness and bone strength. These changes did not occur in cKO mice, whose marrow area is larger, osteoclast number higher, and cortical thickness and bone strength lower relative to WT mice in basal conditions. Changes in cortical structure occurring in WT mice had not recovered 19 weeks after BtxA injection despite correction of the early osteoclast activation and a modest increase in periosteal bone formation. Thus BtxA-induced muscle paralysis leads to rapid loss of trabecular bone and to changes in structural and biomechanical properties of cortical bone, neither of which are fully reversed after 19 weeks. Osteoblast/osteocyte Cx43 is involved in the adaptive responses to skeletal unloading selectively in the cortical bone via modulation of osteoclastogenesis on the endocortical surface. PMID- 21590736 TI - Histone deacetylase inhibitor MS-275 stimulates bone formation in part by enhancing Dhx36-mediated TNAP transcription. AB - Histone deacetylases (HDACs) deacetylate both histones and nonhistone proteins and play a key role in the regulation of physiologic and aberrant gene expression. Inhibition of HDACs has emerged as a promising therapeutic target for cancer and neurologic diseases. In this study we investigated the osteogenic effect and mechanism of action of MS-275, a class I HDAC inhibitor with preference for HDAC1. Both local and systemic administration of MS-275 stimulated bone regeneration in animal models. MS-275 stimulated mRNA expression and activity of the early osteogenic marker tissue-nonspecific alkaline phosphatase (TNAP) in bone tissue and osteogenic cells. By using a series of TNAP promoter deletion constructs and a DNA affinity precipitation assay, we identified DExH box helicase Dhx36 as a factor that binds to the MS-275 response element in the TNAP promoter. We also found that Dhx36 binding to the MS-275 response element is crucial for MS-275 induction of TNAP transcription. Dhx36 physically interacted with a subset of HDACs (HDAC1 and -4) whose protein levels were downregulated by MS-275, and forced expression of these HDACs blunted the stimulatory effects of MS-275 by a deacetylase activity-independent mechanism(s). Taken together, the results of our study show that MS-275 induces TNAP transcription by decreasing the interaction of HDAC1/4 with Dhx36, which can at least in part contribute to the bone anabolic effects of MS-275. PMID- 21590737 TI - Volumetric bone mineral density and bone structure in childhood chronic kidney disease. AB - Chronic kidney disease (CKD) is associated with increased fracture risk and skeletal deformities. The impact of CKD on volumetric bone mineral density (vBMD) and cortical dimensions during growth is unknown. Tibia quantitative computed tomographic scans were obtained in 156 children with CKD [69 stages 2 to 3, 51 stages 4 to 5, and 36 stage 5D (dialysis)] and 831 healthy participants aged 5 to 21 years. Sex-, race-, and age- or tibia length-specific Z-scores were generated for trabecular BMD (TrabBMD), cortical BMD (CortBMD), cortical area (CortArea) and endosteal circumference (EndoC). Greater CKD severity was associated with a higher TrabBMD Z-score in younger participants (p < .001) compared with healthy children; this association was attenuated in older participants (interaction p < .001). Mean CortArea Z-score was lower (p < .01) in CKD 4-5 [-0.49, 95% confidence interval (CI) -0.80, -0.18)] and CKD 5D (-0.49, 95% CI -0.83, -0.15) compared with healthy children. Among CKD participants, parathyroid hormone (PTH) levels were positively associated with TrabBMD Z-score (p < .01), and this association was significantly attenuated in older participants (interaction p < .05). Higher levels of PTH and biomarkers of bone formation (bone-specific alkaline phosphatase) and resorption (serum C-terminal telopeptide of type 1 collagen) were associated with lower CortBMD and CortArea Z-scores and greater EndoC Z-score (r = 0.18-0.36, all p <= .02). CortBMD Z-score was significantly lower in CKD participants with PTH levels above versus below the upper limit of the Kidney Disease Outcome Quality Initiative (KDOQI) CKD stage-specific target range: -0.46 +/- 1.29 versus 0.12 +/- 1.14 (p < .01). In summary, childhood CKD and secondary hyperparathyroidism were associated with significant reductions in cortical area and CortBMD and greater TrabBMD in younger children. Future studies are needed to establish the fracture implications of these alterations and to determine if cortical and trabecular abnormalities are reversible. PMID- 21590738 TI - Simultaneous screening for osteoporosis at CT colonography: bone mineral density assessment using MDCT attenuation techniques compared with the DXA reference standard. AB - The purpose of this study was to evaluate the utility of lumbar spine attenuation measurement for bone mineral density (BMD) assessment at screening computed tomographic colonography (CTC) using central dual-energy X-ray absorptiometry (DXA) as the reference standard. Two-hundred and fifty-two adults (240 women and 12 men; mean age 58.9 years) underwent CTC screening and central DXA BMD measurement within 2 months (mean interval 25.0 days). The lowest DXA T-score between the spine and hip served as the reference standard, with low BMD defined per World Health Organization as osteoporosis (DXA T-score <= -2.5) or osteopenia (DXA T-score between -1.0 and -2.4). Both phantomless quantitative computed tomography (QCT) and simple nonangled region-of-interest (ROI) multi-detector CT (MDCT) attenuation measurements were applied to the T(12) -L(5) levels. The ability to predict osteoporosis and low BMD (osteoporosis or osteopenia) by DXA was assessed. A BMD cut-off of 90 mg/mL at phantomless QCT yielded 100% sensitivity for osteoporosis (29 of 29) and a specificity of 63.8% (143 of 224); 87.2% (96 of 110) below this threshold had low BMD and 49.6% (69 of 139) above this threshold had normal BMD at DXA. At L(1) , a trabecular ROI attenuation cut off of 160 HU was 100% sensitive for osteoporosis (29 of 29), with a specificity of 46.4% (104 of 224); 83.9% (125 of 149) below this threshold had low BMD and 57.5% (59/103) above had normal BMD at DXA. ROI performance was similar at all individual T(12) -L(5) levels. At ROC analysis, AUC for osteoporosis was 0.888 for phantomless QCT [95% confidence interval (CI) 0.780-0.946] and ranged from 0.825 to 0.853 using trabecular ROIs at single lumbar levels (0.864; 95% CI 0.752 0.930 at multivariate analysis). Supine-prone reproducibility was better with the simple ROI method compared with QCT. It is concluded that both phantomless QCT and simple ROI attenuation measurements of the lumbar spine are effective for BMD screening at CTC with high sensitivity for osteoporosis, as defined by the DXA T score. PMID- 21590739 TI - The effects of a two-year randomized, controlled trial of whey protein supplementation on bone structure, IGF-1, and urinary calcium excretion in older postmenopausal women. AB - The effects of dietary protein on bone structure and metabolism have been controversial, with evidence for and against beneficial effects. Because no long term randomized, controlled studies have been performed, a two-year study of protein supplementation in 219 healthy ambulant women aged 70 to 80 years was undertaken. Participants were randomized to either a high-protein drink containing 30 g of whey protein (n = 109) or a placebo drink identical in energy content, appearance, and taste containing 2.1 g of protein (n = 110). Both drinks provided 600 mg of calcium. Dual-energy X-ray absorptiometric (DXA) hip areal bone mineral density (aBMD), 24-hour urinary calcium excretion, and serum insulin like growth factor 1 (IGF-1) were measured at baseline and at 1 and 2 years. Quantitative computed tomographic (QCT) hip volumetric bone mineral density (vBMD) and a femoral neck engineering strength analysis were undertaken at baseline and at 2 years. Baseline average protein intake was 1.1 g/kg of body weight per day. There was a significant decrease in hip DXA aBMD and QCT vBMD over 2 years with no between-group differences. Femoral neck strength was unchanged in either group over time. The 24-hour urinary calcium excretion increased significantly from baseline in both groups at 1 year but returned to baseline in the placebo group at 2 years, at which time the protein group had a marginally higher value. Compared with the placebo group, the protein group had significantly higher serum IGF-1 level at 1 and 2 years (7.3% to 8.0%, p < .05). Our study showed that in protein-replete healthy ambulant women, 30 g of extra protein increased IGF-1 but did not have beneficial or deleterious effects on bone mass or strength. The effect of protein supplementation in populations with low dietary protein intake requires urgent attention. PMID- 21590740 TI - Stronger bone correlates with African admixture in African-American women. AB - Osteoporosis affects all populations, but the risk for low bone density and fracture varies greatly by self-reported race and ethnicity. In this article, the relationship between measured percent African admixture and hip structural geometry, estimated from the hip structural analysis (HSA) program, was examined in a subcohort of the Women's Health Initiative (WHI). The study sample included 793 African-American women and 8559 non-Hispanic white women. All the participants were postmenopausal, between the ages of 50 and 79 years, at the time of recruitment and were followed for up to 9 years. Bone density and hip geometry were assessed using dual-energy X-ray absorptiometry. African admixture was measured for African Americans using genetic ancestry informative markers. Multiple regression and mixed-effects models were used for cross-sectional and longitudinal analyses, respectively. Covariates assessed from questionnaires and physical measurements were included in the analysis to control for possible confounding effects. The study results show significant correlations between percent of African admixture and HSA assessments. In comparison with non-Hispanic white women, significantly greater bone strength, as indicated by higher hip bone mineral density and stronger hip geometry, in women with higher African admixture was observed. However, women with higher percent African admixture had larger reductions in bone strength than non-Hispanic white women during the follow-up. PMID- 21590741 TI - The renin-angiotensin system, blood pressure, and heart structure in patients with hereditary vitamin D-resistance rickets (HVDRR). AB - Vitamin D deficiency has been linked to hypertension and an increased prevalence of cardiovascular risk factors and disease. Studies in vitamin D receptor knockout (VDR KO) mice revealed an overstimulated renin-angiotensin system (RAS) and consequent high blood pressure and cardiac hypertrophy. VDR KO mice correspond phenotypically and metabolically to humans with hereditary 1,25 dihydroxyvitamin D-resistant rickets (HVDRR). There are no data on the cardiovascular system in human HVDRR. To better understand the effects of vitamin D on the human cardiovascular system, the RAS, blood pressure levels, and cardiac structures were examined in HVDRR patients. Seventeen patients (9 males, 8 females, aged 6 to 36 years) with hereditary HVDRR were enrolled. The control group included age- and gender-matched healthy subjects. Serum calcium, phosphorous, creatinine, 25-hydroxyvitamin D [25(OH)D],1,25-dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ], parathyroid hormone (PTH), plasma rennin activity (PRA), aldosterone, angiotensin II (AT-II), and angiotensin-converting enzyme (ACE) levels were determined. Ambulatory 24-hour blood pressure measurements and echocardiographic examinations were performed. Serum calcium, phosphorus, and alkaline phosphatase values were normal. Serum 1,25(OH)(2) D(3) and PTH but not PRA and ACE levels were elevated in the HVDRR patients. AT-II levels were higher than normal in the HVDRR patients but not significantly different from those of the controls. Aldosterone levels were normal in all HVDRR patients. No HVDRR patient had hypertension or echocardiographic pathology. These findings reveal that 6- to 36-year-old humans with HVDRR have normal renin and ACE activity, mild but nonsignificant elevation of AT-II, normal aldosterone levels, and no hypertension or gross heart abnormalities. PMID- 21590743 TI - On reducing the duration of untreated illness in unipolar depression. PMID- 21590742 TI - FGF-23/Klotho signaling is not essential for the phosphaturic and anabolic functions of PTH. AB - Parathyroid hormone (PTH) is widely recognized as a key regulator of mineral ion homeostasis. Daily intermittent administration of PTH is the only currently available anabolic therapy for bone disorders such as osteoporosis. Recent studies have shown that PTH increases transcription and secretion of fibroblast growth factor 23 (FGF-23), another important regulator of phosphate homeostasis and skeletal metabolism. However, the full relationship between PTH and FGF-23 is largely unknown. This study evaluated the effect of FGF-23/Klotho signaling on the phosphaturic and anabolic functions of PTH. Eight-day-old wild-type (WT) Fgf23(-/-) and Kl(-/-) mice were injected with 100 ug/kg PTH(1-34) or vehicle daily for a 2-week-period and then euthanized. Intermittent injection of PTH successfully reduced the serum phosphate levels and reversed the hyperphosphatemia of Fgf23(-/-) and Kl(-/-) mice. Bone changes were analyzed in the distal femur metaphysis by peripheral quantitative computed tomography (pQCT), micro-computed tomography (uCT), and histomorphometry. PTH treatment induced substantial increases in bone mineral density (BMD) and trabecular bone volume in each mouse genotype. Expression of osteoblastic marker genes, including Runx2, Col1, Alp, Ocn, and Sost, was similarly altered. In addition, primary osteoblasts were isolated and treated with 100 nM PTH in vitro. PTH treatment similarly induced cAMP accumulation and phosphorylation of ERK1/2 and CREB in the osteoblasts from each genotype. Taken together, our results demonstrate that FGF 23/Klotho signaling is not essential for the phosphaturic and anabolic functions of PTH, suggesting that PTH can function as a therapeutic agent to improve the skeletal quality of patients even in the presence of abnormal serum FGF-23 levels. PMID- 21590744 TI - The role of tyrosine 71 in modulating the flap conformations of BACE1. AB - beta-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is a potential target for treating Alzheimer's disease. BACE1's binding site is partially covered by a flexible loop on its N-terminal domain, known as the "flap," which has been found in several conformations in crystal structures of BACE1 and other aspartyl proteases. The side chain of the invariant residue Tyr71 on the flap adopts several rotameric orientations, leading to our hypothesis that the orientation of this residue dictates the movement and conformations available to the flap. We investigated this hypothesis by performing 220 ns of molecular dynamics simulations of bound and unbound wild-type BACE1 as well as the unbound Y71A mutant. Our findings indicate that the flap exhibits various degrees of mobility and adopts different conformations depending on the Tyr71 orientation. Surprisingly, the "self-inhibited" form is stable in our simulations, making it a reasonable target for drug design. The alanine mutant, lacking a large side chain at position 71, displays significant differences in flap dynamics from wild type, freely sampling very open and closed conformations. Our simulations show that Tyr71, in addition to its previously determined functions in catalysis and substrate binding, has the important role of modulating flap conformations in BACE1. PMID- 21590745 TI - Crystal structure of Bacteroides thetaiotaomicron TetX2: a tetracycline degrading monooxygenase at 2.8 A resolution. PMID- 21590746 TI - Coarse-grained modeling of conformational transitions underlying the processive stepping of myosin V dimer along filamentous actin. AB - To explore the structural basis of processive stepping of myosin V along filamentous actin, we have performed comprehensive modeling of its key conformational states and transitions with an unprecedented residue level of details. We have built structural models for a myosin V monomer complexed with filamentous actin at four biochemical states [adenosine diphosphate (ATP)-, adenosine diphosphate (ADP)-phosphate-, ADP-bound or nucleotide-free]. Then we have modeled a myosin V dimer (consisting of lead and rear head) at various two head-bound states with nearly straight lever arms rotated by intramolecular strain. Next, we have performed transition pathway modeling to determine the most favorable sequence of transitions (namely, phosphate release at the lead head followed by ADP release at the rear head, while ADP release at the lead head is inhibited), which underlie the kinetic coordination between the two heads. Finally, we have used transition pathway modeling to reveal the order of structural changes during three key biochemical transitions (phosphate release at the lead head, ADP release and ATP binding at the rear head), which shed lights on the strain-dependence of the allosterically coupled motions at various stages of myosin V's work cycle. Our modeling results are in agreement with and offer structural insights to many results of kinetic, single-molecule and structural studies of myosin V. PMID- 21590747 TI - Attenuated methamphetamine induced neurotoxicity by modafinil administration in mice. AB - Methamphetamine (METH) is a highly addictive drug that might induce neurotoxicity. Clinical trials have reported that modafinil, a wake-promoting agent used to treat sleep disorders, may have some efficacy for the treatment of psychostimulant addiction. In this study we tested possible neuroprotective effects of modafinil after toxic METH administration in mice. We evaluated the effect of modafinil (two injections of either 90 or 180 mg/kg) and METH binge (3 * 7 mg/kg i.p. injections, 3-h apart) coadministration on DA striatal content, TH immunoreactivity in striatal areas and spontaneous locomotor activity. We also investigated acute locomotor activity and stereotypy profile in mice treated with a single METH dose (2 and 7 mg/kg) pretreated with modafinil (90 and 180 mg/kg). We found that mice treated with a METH binge showed a marked decrease in DA and dopaminergic metabolites as well as lower levels of TH immunoreactivity in the dorsal striatum. Pretreatment with modafinil (both 90 and 180 mg/kg) attenuated these effects but did not prevent METH induced decrease in locomotion. We also found that groups that received the combination of both modafinil and single dose METH showed a decrease in total distance traveled in an open field compared with METH groups. We observed an increment in the time mice expended doing stereotypic movements (continuous sniffing) in the group that received the combination of both METH and modafinil (i.e., decreasing locomotion). Our results suggest a possible protective role of modafinil against METH acute striatal toxicity. PMID- 21590748 TI - "Official" and "practical" kin: Inferring social and community structure from dental phenotype at Neolithic Catalhoyuk, Turkey. AB - The Neolithic site of Catalhoyuk, Turkey (7400-5600 cal BC) is widely acknowledged for its role in the study of early farming communities. To better understand the social and community structure of this setting, an intracemetery biological distance analysis was conducted. Metric and nonmetric observations were recorded in both deciduous and permanent dentitions (n = 266) to explore phenotypic patterning of individuals interred within individual buildings. Specifically, this study tests the hypothesis that individuals within houses and house groupings represent family units and the social structure of Catalhoyuk was largely biological-kin based. Multivariate and univariate statistical procedures were applied to phenotypic dental data. Results indicate that inclusion for interment within a house was only minimally related to biological affinity. Moreover, the site does not appear to be organized into larger, biologically related neighborhoods of houses. These findings suggest that Catalhoyuk may not have been a kin-based society, largely because membership within a house cemetery was not solely defined on the basis of biological affinity, such as in a family group. Rather, it appears that social structure was centered on the house as the unifying social principle. The choice for interment location may have transcended biological lines thereby creating an alternate and more fluid definition of "kin." These findings can be used to understand the transition to settled life and biological patterning in this Neolithic community. PMID- 21590749 TI - Functional and evolutionary significance of the recruitment and firing patterns of the jaw adductors during chewing in Verreaux's sifaka (Propithecus verreauxi). AB - Jaw-muscle electromyographic (EMG) patterns indicate that compared with thick tailed galagos and ring-tailed lemurs, anthropoids recruit more relative EMG from their balancing-side deep masseter, and that this muscle peaks late in the power stroke. These recruitment and firing patterns in anthropoids are thought to cause the mandibular symphysis to wishbone (lateral transverse bending), resulting in relatively high symphyseal stresses. We test the hypothesis that living strepsirrhines with robust, partially fused symphyses have muscle recruitment and firing patterns more similar to anthropoids, unlike those strepsirrhines with highly mobile unfused symphyses. Electromyographic (EMG) activity of the superficial and deep masseter, anterior and posterior temporalis, and medial pterygoid muscles were recorded in four dentally adult Verreaux's sifakas (Propithecus verreauxi). As predicted, we find that sifaka motor patterns are more similar to anthropoids. For example, among sifakas, recruitment levels of the balancing-side (b-s) deep masseter are high, and the b-s deep masseter fires late during the power stroke. As adult sifakas often exhibit nearly complete symphyseal fusion, these data support the hypothesis that the evolution of symphyseal fusion in primates is functionally linked to wishboning. Furthermore, these data provide compelling evidence for the convergent evolution of the wishboning motor patterns in anthropoids and sifakas. PMID- 21590750 TI - Carious lesions and maize consumption among the Prehispanic Maya: an analysis of a coastal community in northern Yucatan. AB - Patterns of carious lesions were analyzed in the Classic period coastal Maya population of Xcambo, a salt production and administration center in northern Yucatan. To this end, the study investigated caries in the permanent dentitions of 163 adult skeletons, 23 from the Early Classic (AD 250-550) and 140 from the Late Classic period (AD 550-750), equally distributed between sexes. The archaeological and bioarchaeological evidence indicates a wealthy and socially homogeneous population dedicated to salt production and administration in the Early Classic that switched to pure administrative functions in the Late Classic. The results indicate an increase in caries from 7.4% and 21.2% (males and females respectively) from the Early Classic to 14.0% in males and 27.4% in females from the Late Classic period. The rate of caries in the Early and in the Late Classic phases of continuous occupation is not consistent with a simple interpretation of a heavier reliance on maize during the latter phase, characterized by a sedentary lifestyle, particularly for the male segment of the society now dedicated completely to the administration of the salt mines. Rather, the increase in caries rates in both sexes is best explained within a broader context of overall food habits, new cariogenic foods for both sexes, and the changes in lifestyle imposed by the increased socioeconomic role of the site. Our conclusions stress the limitations imposed by interpreting carious lesions solely in terms of single dietary components, such as maize consumption, without taking into account broader aspects of cultural and socioeconomic relevance. PMID- 21590751 TI - Forward dynamic simulation of bipedal walking in the Japanese macaque: investigation of causal relationships among limb kinematics, speed, and energetics of bipedal locomotion in a nonhuman primate. AB - Japanese macaques that have been trained for monkey performances exhibit a remarkable ability to walk bipedally. In this study, we dynamically reconstructed bipedal walking of the Japanese macaque to investigate causal relationships among limb kinematics, speed, and energetics, with a view to understanding the mechanisms underlying the evolution of human bipedalism. We constructed a two dimensional macaque musculoskeletal model consisting of nine rigid links and eight principal muscles. To generate locomotion, we used a trajectory-tracking control law, the reference trajectories of which were obtained experimentally. Using this framework, we evaluated the effects of changes in cycle duration and gait kinematics on locomotor efficiency. The energetic cost of locomotion was estimated based on the calculation of mechanical energy generated by muscles. Our results demonstrated that the mass-specific metabolic cost of transport decreased as speed increased in bipedal walking of the Japanese macaque. Furthermore, the cost of transport in bipedal walking was reduced when vertical displacement of the hip joint was virtually modified in the simulation to be more humanlike. Human vertical fluctuations in the body's center of mass actually contributed to energy savings via an inverted pendulum mechanism. PMID- 21590752 TI - Brief communication: the relation between standard error of the estimate and sample size of histomorphometric aging methods. AB - Histomorphometric aging methods report varying degrees of precision, measured through Standard Error of the Estimate (SEE). These techniques have been developed from variable samples sizes (n) and the impact of n on reported aging precision has not been rigorously examined in the anthropological literature. This brief communication explores the relation between n and SEE through a review of the literature (abstracts, articles, book chapters, theses, and dissertations), predictions based upon sampling theory and a simulation. Published SEE values for age prediction, derived from 40 studies, range from 1.51 to 16.48 years (mean 8.63; sd: 3.81 years). In general, these values are widely distributed for smaller samples and the distribution narrows as n increases--a pattern expected from sampling theory. For the two studies that have samples in excess of 200 individuals, the SEE values are very similar (10.08 and 11.10 years) with a mean of 10.59 years. Assuming this mean value is a 'true' characterization of the error at the population level, the 95% confidence intervals for SEE values from samples of 10, 50, and 150 individuals are on the order of +/- 4.2, 1.7, and 1.0 years, respectively. While numerous sources of variation potentially affect the precision of different methods, the impact of sample size cannot be overlooked. The uncertainty associated with SEE values derived from smaller samples complicates the comparison of approaches based upon different methodology and/or skeletal elements. Meaningful comparisons require larger samples than have frequently been used and should ideally be based upon standardized samples. PMID- 21590753 TI - Burden and viability of Borrelia burgdorferi in skin and joints of patients with erythema migrans or lyme arthritis. AB - OBJECTIVE: To determine the burden and viability of Borrelia burgdorferi in the skin and joints of patients with Lyme disease. METHODS: Standard and quantitative polymerase chain reaction (PCR) techniques were used to detect B burgdorferi DNA in skin samples from 90 patients with erythema migrans (EM) and in synovial fluid (SF) from 63 patients with Lyme arthritis (LA) and in synovial tissue from 9 patients. Quantitative PCR determinations of B burgdorferi DNA, messenger RNA (mRNA), and ribosomal RNA (rRNA) were made in 10 skin samples from EM patients and 11 SF samples from LA patients. RESULTS: Skin lesions in most patients with EM had positive PCR results for B burgdorferi DNA. In the majority of patients with LA, a late disease manifestation, PCR results in pretreatment SF samples were positive. In patients with antibiotic-refractory arthritis, positive PCR results persisted for as long as 11 months, but positive results in samples taken during the postantibiotic period did not correlate with relapse or with the subsequent duration of arthritis, and at synovectomy, all results of PCR of synovial tissue were negative. B burgdorferi mRNA, a marker of spirochetal viability, was detected in 8 of 10 skin samples from EM patients, but in none of 11 SF samples from LA patients, even when obtained prior to antibiotic administration. Moreover, the median ratio of spirochetal rRNA to DNA, a measure of ribosomal activity, was 160 in the 10 EM skin samples, but only 0.15 in the 3 LA SF samples with positive results. CONCLUSION: B burgdorferi in the skin lesions of EM patients were active and viable, whereas those in the SF of LA patients were moribund or dead at any time point. Thus, detection of B burgdorferi DNA in SF is not a reliable test of active joint infection in Lyme disease. PMID- 21590756 TI - Preparation of silica-based nanoparticle having surface-bound octanoyl aminopropyl moieties and its applications for the capillary electrochromatography separation of charged and neutral compounds. AB - A kind of novel amphiphilic silica-based nanoparticle having surface-bound octanoyl-aminopropyl moieties (OA-NP) with the diameter of ~250 nm was successfully prepared and characterized by elemental analysis, Fourier transform infrared spectrometry. The potential use of OA-NP as pseudostationary phase in capillary electrochromatography for the separation of aromatic acids, basic, and neutral compounds was investigated. Five aromatic acids were separated rapidly with high column efficiency as they migrate in the same direction with the EOF under optimum experimental conditions. Under a running buffer with the composition of 40% methanol, 10 mM phosphate buffer (pH 5.5) with 1.0 mg/mL OA NPs added, basic compounds investigated were baseline resolved with relatively symmetrical peaks. Due to the existence of polar acyl amide group on the surface of OA-NPs, "silanol effect" that occurs between the positively charged basic analytes and the silanols of the capillary column was greatly suppressed. Furthermore, the newly synthesized OA-NPs were also tried for the separation of some neutral analytes, and satisfactory separations were obtained. PMID- 21590757 TI - Development of internal amplification controls for DNA profiling with the AmpFlSTR((r)) SGM Plus((r)) kit. AB - DNA extracted from forensic samples can be degraded and also contain co-extracted contaminants that inhibit PCR. The effects of DNA degradation and PCR inhibition are often indistinguishable when examining a DNA profile. Two internal amplification controls (IACs) were developed to improve quality control of PCR using the AmpFlSTR(r) SGM Plus(r) kit. The co-amplification of these controls with DNA samples was used to monitor amplification efficiency and detect PCR inhibitors. IAC fragments of 90 and 410 bp (IAC90 and IAC410) were generated from the plasmid pBR322 using tailed primers and then amplified with ROX-labelled primers. Co-amplification of IAC90 and IAC410 was performed with varying amounts of template DNA, degraded DNA and DNA contaminated with humic acid, heme and indigo dye. Both IAC90 and IAC410 were successfully amplified with human DNA without significantly affecting the quality of the DNA profile, even with DNA amounts lower than 0.5 ng. In the presence of inhibitors, the IAC90 signal was still present after all human DNA loci fail to amplify; in contrast, the IAC410 signal was reduced or absent at low levels of inhibition. Amplification of the two IACs provided an internal PCR control and allowed partial profiles caused by inhibition to be distinguished from degraded DNA profiles. PMID- 21590758 TI - Pluronic F68 enhanced the conformational stability of salmon calcitonin in both aqueous solution and lyophilized solid form. AB - The effects of different surfactants on the conformational stability and structural similarity of salmon calcitonin (sCT) in aqueous solution and lyophilized forms were investigated by using microscopic Fourier transform infrared (FTIR) spectroscopy with second-derivative spectral analysis. Six surfactants, HCO-60, sodium dodecyl sulfate (SDS), Tween 80, PEG 400, Pluronic 68, and F127 were selected. The sCT aqueous solution with or without different surfactants was, respectively, incubated at 40 degrees C for up to 35 h. sCT films were casted on the CaF(2) plates and IR spectra were collected as a function of incubation time. Second derivative analysis showed that the native sCT having a major alpha-helical structure was gradually changed to the combination of alpha-helix, random coil, and beta-sheet conformations in aqueous solution at 40 degrees C. Similar conformational changes with delayed beta-sheet formation were obtained for sCT after co-incubation with all the surfactants except Pluronic F68. When the native sCT was freeze-dried alone, a marked conformational alteration was found as illustrated by a poor spectral correlation coefficient (r) value of 0.823 as compared to that of the unlyophilized native sCT. This r value was significantly deviated from 1, strongly indicating the influence of lyophilization stress on the surfactant-free sCT. The r value for sCT after lyophilizing with HCO-60, Pluronic F127, PEG 400, or Pluronic F68 was >0.9, suggesting the possible stabilization of these surfactants in the lyophilization process. The sCT sample after lyophilizing with Pluronic F68 showed a highest r value (>0.968), indicating the most optimal stabilization effect of Pluronic F68 for sCT sample via lyophilization. Pluronic F68 was found to be the preferential surfactant for preventing the secondary structure changes in aqueous solution at 40 degrees C as well as in lyophilized powder. PMID- 21590759 TI - Metal ion-assembled micro-collagen heterotrimers. AB - Collagen mimetic peptides (CMPs) provide critical insight into the assembly, stability, and structure of the triple helical collagen protein. The majority of natural fibrous collagens are aab or abc heterotrimers, yet few examples of heterotrimeric CMPs have been reported. Previously, CMP heterotrimers have only been accessible by total syntheses or by introducing complementary interstrand electrostatic or steric interactions. Here, we describe an abc CMP heterotrimer in which each contributing CMP consists of only three amino acids: glycine, proline and 4-hydroxyproline. Assembly of the heterotrimeric triple helix is directed by a combination of metal-ion coordination to set the relative register of the CMPs, and minimization of valence frustration to direct heterotrimerization. Assembly of the four-component mixture is facile and extremely rapid, and equilibration to the abc heterotrimer occurs within a few hours at modestly elevated temperatures. The melting temperatures of the metal assembled collagen trimers are higher by some 30 degrees C than the apopeptide assemblies. Two iterations of the design are described, and the outcomes suggest possibilities for designing self-assembling abc and abb heterotrimers. PMID- 21590760 TI - Cholecystectomy as a risk factor for oesophageal adenocarcinoma. AB - BACKGROUND: Owing to an increased risk of oesophageal bile exposure after cholecystectomy, an association with oesophageal adenocarcinoma is possible. There are some data in support of this hypothesis, and the aim of this study was to ascertain whether the association could be confirmed. METHODS: A population based cohort study was undertaken to compare the number of cases of oesophageal adenocarcinoma observed in a cohort of patients who have had a cholecystectomy in Sweden during 1965-2008 with the expected number, calculated from the entire Swedish population of corresponding age, sex and year. The risk of oesophageal adenocarcinoma was assessed by calculating the standardized incidence ratio (SIR) with 95 per cent confidence intervals. RESULTS: The cholecystectomy cohort included 345 251 patients who were followed up for a mean of 15 years and contributed 4 854 969 person-years at risk. The total of 126 new cases of oesophageal adenocarcinoma was greater than expected (SIR 1.29, 1.07 to 1.53). The strength of the association between cholecystectomy and oesophageal adenocarcinoma tended to increase with longer follow-up after cholecystectomy. There was no association between cholecystectomy and oesophageal squamous cell carcinoma (SIR 0.93, 0.81 to 1.08), and in an unoperated cohort of 192 960 patients with gallstones no increased risk of oesophageal adenocarcinoma was identified (SIR 0.99, 0.71 to 1.35). CONCLUSION: Cholecystectomy appears to be linked to an increased risk of oesophageal adenocarcinoma, but the absolute risk is small. PMID- 21590761 TI - Sacral nerve stimulation increases activation of the primary somatosensory cortex by anal canal stimulation in an experimental model. AB - BACKGROUND: Sacral and posterior tibial nerve stimulation may be used to treat faecal incontinence; however, the mechanism of action is unknown. The aim of this study was to establish whether sensory activation of the cerebral cortex by anal canal stimulation was increased by peripheral neuromodulation. METHODS: A multielectrode array was positioned over the right primary somatosensory cortex of anaesthetized rats. A brief burst of electrical stimulation was applied to either the left sacral root or the left posterior tibial nerve, and evoked potentials from anal canal stimulation were signal-averaged at intervals over 1 h. At the end of the experiment, the cerebral cortex was removed and probed for polysialylated neural cell adhesion molecule (PSA-NCAM). RESULTS: Sacral nerve root and posterior tibial nerve stimulation significantly increased the peak amplitude of primary cortical evoked potentials by 54.0 and 45.1 per cent respectively. This change persisted throughout the period of observation. The density of PSA-NCAM-positive cells in the somatosensory cortex underlying the electrode array was increased by approximately 50 per cent in the sacral nerve stimulated group. CONCLUSION: Brief sacral neuromodulation induces profound changes in anal canal representation on the primary somatosensory cortex, providing a plausible hypothesis concerning the mechanism of action of neuromodulation in the treatment of faecal incontinence. PMID- 21590762 TI - Randomized clinical trial of epidural, spinal or patient-controlled analgesia for patients undergoing laparoscopic colorectal surgery. AB - BACKGROUND: Epidural analgesia is considered fundamental in enhanced recovery protocols (ERPs). However, its value in laparoscopic colorectal surgery is unclear. The aim of this study was to examine the effects of different analgesic regimens on outcomes following laparoscopic colorectal surgery in fluid-optimized patients treated within an ERP. METHODS: Ninety-nine patients were randomized to receive epidural, spinal or patient-controlled (PCA) analgesia. The primary endpoints were time until medically fit for discharge and length of hospital stay. Secondary endpoints included return of bowel function, pain scores, and changes in pulmonary function and quality of life. RESULTS: Ninety-one patients completed the study. The median length of hospital stay was 3.7 days following epidural analgesia, significantly longer than that of 2.7 and 2.8 days for spinal analgesia and PCA respectively (P = 0.002 and P < 0.001). There was also a slower return of bowel function with epidural analgesia than with spinal analgesia and PCA. Epidural analgesia did not offer better preservation of pulmonary function or quality of life, although pain scores were higher in the PCA group in the early postoperative period. CONCLUSION: Many of the outcomes in the epidural analgesia group were significantly worse than those in the spinal analgesia and PCA groups, suggesting that either of these two modalities could replace epidural analgesia. PMID- 21590764 TI - TCR down-regulation boosts T-cell-mediated cytotoxicity and protection against poxvirus infections. AB - Cytotoxic T (Tc) cells play a key role in the defense against virus infections. Tc cells recognize infected cells via the T-cell receptor (TCR) and subsequently kill the target cells by one or more cytotoxic mechanisms. Induction of the cytotoxic mechanisms is finely tuned by the activation signals from the TCR. To determine whether TCR down-regulation affects the cytotoxicity of Tc cells, we studied TCR down-regulation-deficient CD3gammaLLAA mice. We found that Tc cells from CD3gammaLLAA mice have reduced cytotoxicity due to a specific deficiency in exocytosis of lytic granules. To determine whether this defect was reflected in an increased susceptibility to virus infections, we studied the course of ectromelia virus (ECTV) infection. We found that the susceptibility to ECTV infection was significantly increased in CD3gammaLLAA mice with a mortality rate almost as high as in granzyme B knock-out mice. Finally, we found that TCR signaling in CD3gammaLLAA Tc cells caused highly increased tyrosine phosphorylation and activation of the c-Cbl ubiquitin ligase, and that the impaired exocytosis of lytic granules could be rescued by the knockdown of c-Cbl. Thus, our work demonstrates that TCR down-regulation critically increases Tc cell cytotoxicity and protection against poxvirus infection. PMID- 21590763 TI - NKG2D performs two functions in invariant NKT cells: direct TCR-independent activation of NK-like cytolysis and co-stimulation of activation by CD1d. AB - Invariant NKT cells are important in the activation and regulation of immune responses. They can also function as CD1d-restricted killer cells. However, the role of activating innate NK-cell receptors expressed on NKT cells in triggering cytolytic function is poorly characterized. Here, we initially confirmed that the cellular stress-ligand receptor NKG2D is expressed on CD4- NKT cells, whereas most CD4+ NKT cells lack this receptor. Interestingly, NKG2D+ NKT cells frequently expressed perforin, and both NKG2D and perforin localized at the site of contact with NKG2D ligand-expressing target cells. CD4- NKT cells degranulated in response to NKG2D engagement in a redirected activation assay independent of stimulation via their invariant TCR. NKT cells killed P815 cells coated with anti NKG2D mAb and CD1d-negative K562 tumor target cells in an NKG2D-dependent manner. Furthermore, NKG2D engagement co-stimulated TCR-mediated NKT-cell activation in response to endogenous CD1d-presented ligands or suboptimal levels of anti-CD3 triggering. These data indicate that the CD4- subset of human NKT cells can mediate direct lysis of target cells via NKG2D engagement independent of CD1d, and that NKG2D also functions as a co-stimulatory receptor in these cells. NKG2D thus plays both a direct and a co-stimulatory role in the activation of NKT cells. PMID- 21590765 TI - B lymphocytes acquire and present intracellular antigens that have relocated to the surface of apoptotic target cells. AB - The induction of an effective immune response requires the activation of CD4+ T lymphocytes by APCs. While DCs have been shown to be pivotal in this process, it is now apparent that optimal CD4+ T-cell activation also requires B-lymphocyte APC function. Along with the acquisition of soluble antigens, it is known that B cells also acquire membrane-tethered antigens. Recent reports have described the relocation of intracellular antigens to the cell surface following immunogenic apoptosis. This study was designed to determine whether B cells can acquire and present such antigens to CD4+ T cells. By targeting the model antigen tetanus toxin C fragment to various cellular locations, we show that antigen-specific B cells acquire intracellular antigens that have relocated to the surface of cells undergoing immunogenic apoptosis. Crucially, we also demonstrate that antigen specific B cells acquiring relocated antigen from apoptotic targets are capable of efficiently inducing CD4+ T-cell activation. We propose that the acquisition and presentation of intracellular antigens that have relocated to the cell surface during immunogenic apoptosis represents a novel means by which antigen specific B cells contribute to the generation of immunity. PMID- 21590766 TI - Selection of T-cell receptors with a recurrent CDR3beta peptide-contact motif within the repertoire of alloreactive CD8(+) T cells. AB - Peptide/MHC complexes recognized by alloreactive T lymphocytes (TLs) have been identified, but their contribution to in vivo allo-rejection is not known. We previously characterized the peptide pBM1, highly represented among endogenous H 2K(b) (K(b) )-associated peptides and critically required to induce full activation of H-2(k) monoclonal CD8(+) TLs expressing the cognate TCR-BM3.3. Here, we asked whether a pBM1/K(b) -specific TL subset could be detected within a polyclonal TL population rejecting allogeneic cells in vivo. We show that the proportion of pBM1/K(b) -binding CD8(+) TLs increased from <0.04% in naive mice to 3% of activated CD44(+) CD8(+) TLs in H-2(k) mice rejecting K(b) -expressing cells. Among these, TCR-Vbeta2 usage was greatly enriched, and 75% of them shared a TCR-Vbeta2 CDR3beta motif with the prototype TCR-BM3.3. Fewer than 5% of K(b) reactive CD44(+) CD8(+) TLs not binding pBM1/K(b) displayed this CDR3beta motif. We found that the recurrent CDR3beta motif of pBM1/K(b) -binding TLs was assembled from distinct V/D/J recombination events, suggesting that it is recruited upon immunization for its optimal TCR-peptide/MHC fit. Thus, a CDR3beta motif generated by a process akin to "convergent recombination" accounts for a sizable fraction of the alloreactive anti-K(b) TCR repertoire. PMID- 21590767 TI - T-cell help permits memory CD8(+) T-cell inflation during cytomegalovirus latency. AB - CD4(+) T cells are implied to sustain CD8(+) T-cell responses during persistent infections. As CD4(+) T cells are often themselves antiviral effectors, they might shape CD8(+) T-cell responses via help or via controlling antigen load. We used persistent murine CMV (MCMV) infection to dissect the impact of CD4(+) T cells on virus-specific CD8(+) T cells, distinguishing between increased viral load in the absence of CD4(+) T cells and CD4(+) T-cell-mediated helper mechanisms. Absence of T-helper cells was associated with sustained lytic MCMV replication and led to a slow and gradual reduction of the size and function of the MCMV-specific CD8(+) T-cell pool. However, when virus replication was controlled in the absence of CD4(+) T cells, CD8(+) T-cell function was comparably impaired, but in addition CD8(+) T-cell inflation, a hallmark of CMV infection, was completely abolished. Thus, CD8(+) T-cell inflation during latent CMV infection is strongly dependent on CD4(+) T-cell helper functions, which can partially be compensated by ongoing lytic viral replication in the absence of CD4(+) T cells. PMID- 21590768 TI - Functional evidence that Drosha overexpression in cervical squamous cell carcinoma affects cell phenotype and microRNA profiles. AB - Although gain of chromosome 5p is one of the most frequent DNA copy-number imbalances in cervical squamous cell carcinoma (SCC), the genes that drive its selection remain poorly understood. In a previous cross-sectional clinical study, we showed that the microRNA processor Drosha (located on chromosome 5p) demonstrates frequent copy-number gain and overexpression in cervical SCC, associated with altered microRNA profiles. Here, we have conducted gene depletion/overexpression experiments to demonstrate the functional significance of up-regulated Drosha in cervical SCC cells. Drosha depletion by RNA interference (RNAi) produced significant, specific reductions in cell motility/invasiveness in vitro, with a silent RNAi-resistant Drosha mutation providing phenotype rescue. Unsupervised hierarchical clustering following global profiling of 319 microRNAs in 18 cervical SCC cell line specimens generated two groups according to Drosha expression levels. Altering Drosha levels in individual SCC lines changed the group into which the cells clustered, with gene depletion effects being rescued by the RNAi-resistant mutation. Forty-five microRNAs showed significant differential expression between the groups, including four of 14 that were differentially expressed in association with Drosha levels in clinical samples. miR-31 up-regulation in Drosha-overexpressing samples/cell lines was the highest-ranked change (by adjusted p value) in both analyses, an observation validated by northern blotting. These functional data support the role of Drosha as an oncogene in cervical SCC, by affecting expression of cancer-associated microRNAs that have the potential to regulate numerous protein-coding genes. PMID- 21590769 TI - Active site mutant dimethylarginine dimethylaminohydrolase 1 expression confers an intermediate tumour phenotype in C6 gliomas. AB - Dimethylarginine dimethylaminohydrolase (DDAH) metabolizes the endogenous inhibitor of nitric oxide synthesis, asymmetric dimethylarginine (ADMA). Constitutive over-expression of DDAH1, the isoform primarily associated with neuronal nitric oxide synthase (nNOS) results in increased tumour growth and vascularization, and elevated VEGF secretion. To address whether DDAH1-mediated tumour growth is reliant upon the enzymatic activity of DDAH1, cell lines expressing an active site mutant of DDAH1 incapable of metabolizing ADMA were created. Xenografts derived from these cell lines grew significantly faster than those derived from control cells, yet not as fast as those over-expressing wild type DDAH1. VEGF expression in DDAH1 mutant-expressing tumours did not differ from control tumours but was significantly lower than that of wild-type DDAH1 over-expressing tumours. Fluorescence microscopy for CD31 and pimonidazole adduct formation demonstrated that DDAH1 mutant-expressing tumours had a lower endothelial content and demonstrated less hypoxia, respectively, than wild-type DDAH1-expressing tumours. However, there was no difference in uptake of the perfusion marker Hoechst 33342. Non-invasive multiparametric quantitative MRI, including the measurement of native T(1) and T(2) relaxation times and apparent water diffusion coefficient, was indicative of higher cellularity in DDAH1 expressing xenografts, which was confirmed by histological quantification of necrosis. C6 xenografts expressing active site mutant DDAH1 displayed an intermediate phenotype between tumours over-expressing wild-type DDAH1 and control tumours. These data suggest that enhanced VEGF expression downstream of DDAH1 was dependent upon ADMA metabolism, but that the DDAH1-mediated increase in tumour growth was only partially dependent upon its enzymatic activity, and therefore must involve an as-yet unidentified mechanism. DDAH1 is an important mediator of tumour progression, but appears to have addition roles independent of its metabolism of ADMA, which need to be considered in therapeutic strategies targeted against the NO/DDAH pathway in cancer. PMID- 21590770 TI - Role of miR-150-targeting c-Myb in colonic epithelial disruption during dextran sulphate sodium-induced murine experimental colitis and human ulcerative colitis. AB - Chronic inflammatory bowel diseases (IBDs) are associated with differential expression of genes involved in inflammation and tissue remodelling. We surveyed the expression profile of apoptosis-related microRNAs by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in a dextran sulphate sodium (DSS) murine model of colitis. We found that miR-150 was strongly elevated, whereas c-Myb, a transcription factor and a target gene of miR-150, was significantly reduced in colon tissue after DSS treatment. Interestingly, elevation of miR-150 and down-regulation of c-Myb were also observed in human colon with active ulcerative colitis compared to the normal colon. Supporting the observation of DSS treatment inducing colonic cell apoptosis, Bcl-2, an anti apoptotic protein known to be regulated by c-Myb, was reduced in colon tissue of DSS-treated mice. Furthermore, forced expression of pre-miR-150 in colonic epithelial HT29 cells strongly elevated miR-150 levels and decreased c-Myb and Bcl-2 levels, thus enhancing cell apoptosis induced by serum deprivation. Together, the present study presents the first evidence that miR-150 and its targeting of c-Myb may serve as a new mechanism underlying the colonic epithelial disruption in DSS-induced murine experimental colitis and in active human IBD. PMID- 21590771 TI - Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas. AB - Mutation of the ARID1A gene and loss of the corresponding protein BAF250a has recently been described as a frequent event in clear cell and endometrioid carcinomas of the ovary. To determine whether BAF250a loss is common in other malignancies, immunohistochemistry (IHC) for BAF250a was performed on tissue microarrays (TMAs) in more than 3000 cancers, including carcinomas of breast, lung, thyroid, endometrium, kidney, stomach, oral cavity, cervix, pancreas, colon and rectum, as well as endometrial stromal sarcomas, gastrointestinal stromal tumours, sex cord-stromal tumours and four major types of lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, mantle cell lymphoma and follicular lymphoma). We found that BAF250a loss is frequent in endometrial carcinomas but infrequent in other types of malignancies, with loss observed in 29% (29/101) of grade 1 or 2 and 39% (44/113) of grade 3 endometrioid carcinomas of the endometrium, 18% (17/95) of uterine serous carcinomas and 26% (6/23) of uterine clear cell carcinomas. Since endometrial cancers showed BAF250a loss, we stained whole tissue sections for BAF250a expression in nine cases of atypical hyperplasia and 10 cases of atypical endometriosis. Of the nine cases of complex atypical endometrial hyperplasia, all showed BAF250a expression; however, of 10 cases of atypical endometriosis (the putative precursor lesion for ovarian clear cell and endometrioid carcinoma), one case showed loss of staining for BAF250a in the atypical areas, with retention of staining in areas of non-atypical endometriosis. This was the sole case that recurred as an endometrioid carcinoma, indicating that BAF250a loss may be an early event in carcinogenesis. Since BAF250a loss is seen in endometrial carcinomas at a rate similar to that seen in ovarian carcinomas of clear cell and endometrioid type, and is uncommon in other malignancies, we conclude that loss of BAF250a is a particular feature of carcinomas arising from endometrial glandular epithelium. PMID- 21590772 TI - Activation of telomerase by seminal plasma in malignant and normal cervical epithelial cells. AB - Seminal fluids are involved in the development of cervical cancer but the underlying mechanism is unclear. Because cellular transformation requires telomerase activation by expression of the telomerase reverse transcriptase (hTERT) gene, we examined the role of seminal fluids in telomerase activation. Significantly elevated hTERT mRNA and telomerase activity were observed in cervical cell lines (HeLa, SiHa and Caski) treated with seminal plasma. Normal cervical epithelial cells expressed minimal levels of hTERT mRNA and telomerase activity, and seminal plasma substantially enhanced both expression and activity. The hTERT promoter activity was similarly increased in seminal plasma-treated HeLa cells and this effect was closely correlated with increased Sp1 expression and binding to the hTERT promoter. Cyclooxygenase-2 (COX-2) was simultaneously increased in HeLa cells exposed to seminal plasma, and blockade of COX-2 induction abolished seminal plasma stimulation of the hTERT promoter activity, hTERT expression and telomerase activity. Prostaglandin E2 (PGE2) mimics the effect of seminal plasma, stimulating Sp1 expression, enhancing Sp1 occupancy on the hTERT promoter and promoter activity. Moreover, tumour growth was robustly enhanced when HeLa cells together with seminal plasma were injected into nude mice. Taken together, seminal plasma stimulates COX-2-PGE2-Sp1-dependent hTERT transcription, which provides insights into the putative mechanism underlying telomerase activation in cervical epithelial and cancer cells. PMID- 21590773 TI - Acute exposure to doxorubicin results in increased cardiac P-glycoprotein expression. AB - Doxorubicin is a frequently used anticancer drug, but its use is restricted due to the occurrence of severe side effects, namely strong cardiotoxicity. It is known from cancer cells that doxorubicin enhanced the expression of its efflux pump P-glycoprotein (P-gp), which may modulate local drug concentrations. We therefore studied the cardiac expression of P-gp in doxorubicin-treated mice. Mice were treated with doxorubicin, and P-gp expression was studied after 1, 3, and 5 days. Thereby, we could show a significant upregulation of abcb1a (162 +/- 15% of control) and abcb1b (418 +/- 110% of control) mRNA transcripts after 3 days. On protein level, western blot analysis and immunofluorescence staining revealed a similar finding 5 days after doxorubicin administration. In addition, these results could be confirmed by in vitro models using primary rat cardiomyocytes and the murine cardiomyocyte-like HL-1 cells. Besides an enhanced mRNA and protein expression, doxorubicin-treated HL-1 cells also demonstrated an enhanced P-gp function as assessed by a daunorubicin accumulation assay. Our in vivo and in vitro results demonstrate a cardiac upregulation of P-gp in doxorubicin-treated mice on expression and functional level. This finding may be relevant for cardiac tissue concentrations of P-gp substrates and may represent a mechanism in cardiac self-protection against xenobiotics. PMID- 21590774 TI - Inner blood-retinal barrier mediates l-isomer-predominant transport of serine. AB - D-serine, a coagonist for N-methyl-D-aspartate-type glutamate receptors, which mediate visual signal transmission, is thought to be generated from L-serine via serine racemase in the retina. However, the source of L-serine and D-serine in the retina are yet to be determined. The purpose of the present study was to investigate the characteristics of the blood-to-retina transport of serine at the inner blood-retinal barrier (BRB). In vivo study revealed the blood-to-retina transport of [(3) H]L-serine with an influx clearance of 49.9 MUL/(min.g retina), which is greater than that of [(3) H]D-serine. This was consistent with the L isomer-predominant uptake of serine by conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2 cells), an in vitro inner BRB model. [(3) H]L-Serine and [(3) H]D-serine uptake by TR-iBRB2 cells took place in an Na(+)-dependent and a concentration-dependent manner with Michaelis constant values of 97.5 MUM and 9.63 mM, respectively. The uptake process of [(3) H]L serine and [(3) H]D-serine was significantly inhibited by system ASC (alanine serine-cysteine) substrates. Polymerase chain reaction analysis and immunocytochemistry revealed the expression of ASC transporters ASCT1 and ASCT2 in TR-iBRB2 cells. These results suggest that the system ASC at the inner BRB is a potent pathway for supplying serine in the form of the L-isomer from the circulating blood to the retina. PMID- 21590775 TI - 6-Mercaptopurine transport by equilibrative nucleoside transporters in conditionally immortalized rat syncytiotrophoblast cell lines TR-TBTs. AB - Recently, more women were provided with 6-mercaptopurine (6-MP) during pregnancy. Therefore, we attempted to clarify the transport mechanisms of 6-MP through blood placenta barrier using rat conditionally immortalized syncytiotrophoblast cell lines (TR-TBTs). The uptake of 6-MP was time- and ATP dependent, but sodium independent in TR-TBTs. 6-MP was eliminated over 50% from the cells within 30 min. The uptake of 6-MP was saturable with Michaelis-Menten constant values of 198 MUM and 250 MUM in TR-TBT 18d-1 and TR-TBT 18d-2, respectively. 6 Thioguanine, azathioprine, and hypoxantine, structural analogues of 6-MP, strongly inhibited [(14) C]6-MP uptake. Equilibrative nucleoside transporter (ENT) inhibitors, adenosine and uridine, significantly inhibited [(14) C]6-MP uptake. However, several organic anions and cations had no effect on [(14) C]6-MP uptake in TR-TBTs. These results suggest that sodium-independent transporters, ENTs, may be involved in 6-MP uptake at the placenta. In addition, multidrug resistance protein (MRP) inhibitors, methotrexate, probenecid, cefmetazole, and sulfinpyrazone, significantly increased the accumulation of [(14) C]6-MP in the cells. It is indicated that 6-MP may be eliminated across the blood-placental barrier via MRPs. TR-TBTs expressed mRNA of ENT1, ENT2, MRP4, and MRP5. These findings are important for the therapy of acute lymphoblastic leukemia and autoimmune diseases of pregnant women, and should be useful data in elucidating teratogenicity of 6-MP during pregnancy. PMID- 21590776 TI - Hot water bath treatments assisted by microwave energy to delay postharvest ripening and decay in strawberries (Fragaria * ananassa). AB - BACKGROUND: A lab-scale approach using microwave (MW)-assisted hot water treatments was developed and tested to assess the potential of this heating method to delay postharvest ripening and decay in strawberries. Strawberries (Fragaria * ananassa) immersed in water were exposed to microwaves at a frequency of 2450 MHz for 3 min at 514 W or 1 min 50 s at 763 W to reach an average temperature of 43.8 +/- 0.6 degrees C at the fruit centre. Another batch was treated in hot water at 45 degrees C for 15 min, and a final batch was not treated (control). RESULTS: After 9 days of refrigerated storage (3 degrees C and 90% relative humidity), all heat-treated strawberries showed significant retention of quality parameters such as colour and firmness and significantly lower yeast and mould populations (P < 0.05). CONCLUSION: Strawberries subjected to MW-assisted hot water treatments showed significantly better retention of lightness compared with conventionally treated berries. A short (1 min 50 s) treatment at 763 W was the best choice to prevent strawberry decay. PMID- 21590777 TI - Characteristics of papaya seed oils obtained by extrusion-expelling processes. AB - BACKGROUND: In general, about 300 g kg(-1) of the weight of papaya fruits appears as waste materials during processing, including a considerable amount of papaya seeds. To make a more efficient use of papaya, it is worth investigating the utilization of the seeds. The aim of this study was to comprehensively assess the lipid characteristics of papaya seed oil obtained by expelling processes. RESULTS: Papaya seed oil was found to have several unique characteristics, including its high oleic content, the relative ratio of saturated/monounsaturated/polyunsaturated fatty acids of 29/68/3, the polyunsaturated fatty acids merely accounting for 3.34% and its triacylglycerol composition being very similar to that of olive oil. Also, this oil was rich in chemopreventive benzyl isothiocyanate, the level ranging from 4.0 to 23.3 g kg( 1) dependent on the various processing methods for the pretreatment of papaya seeds. CONCLUSION: On the basis of our results, papaya seed oil can be considered as a high-oleic oil with a chemoprotective effect, and may be viewed as a healthy alternative in the functional food industry. PMID- 21590778 TI - Brazilian red propolis: unreported substances, antioxidant and antimicrobial activities. AB - BACKGROUND: Chloroform, ethyl acetate and methanol extracts of a sample of red propolis from the state of Alagoas (northeast Brazil) were analyzed by gas chromatography-mass spectrometry and high-performance liquid chromatography-diode array detection-electrospray ionization-mass spectrometry. Antimicrobial and antioxidant activities were also obtained. RESULTS: The propolis sample contained low content of narigenin-8-C-hexoside, this being the first report of a C glycoside in propolis. The main constituent found was characterized as 3,4,2',3' tetrahydroxychalcone. Other important constituents were the chalcone isoliquiritigenin, the isoflavans (3S)-vestitol, (3S)-7-O-methylvestitol, the pterocarpan medicarpin, the phenylpropenes trans-anethol, methyl eugenol, elimicin, methoxyeugenol and cis-asarone, and the triterpenic alcohols lupeol and alpha- and beta- amyrins. The methanol extract exhibited high antioxidant activities by 2,2-diphenyl-1-picrylhydrazyl and beta-carotene/linoleic acid assay methods, and antimicrobial activity toward Gram-positive and Gram-negative bacteria. CONCLUSION: Structures are suggested for new substances never before seen in any kind of propolis. This is the first report of 3,4,2',3' tetrahydroxychalcone and a flavone C-glycoside in a propolis sample. PMID- 21590779 TI - The MP2-F12 method in the Turbomole program package. AB - A detailed description of the explicitly correlated second-order Moller-Plesset perturbation theory (MP2-F12) method, as implemented in the TURBOMOLE program package, is presented. The TURBOMOLE implementation makes use of density fitting, which greatly reduces the prefactor for integral evaluation. Methods are available for the treatment of ground states of open- and closed-shell species, using unrestricted as well as restricted (open-shell) Hartree-Fock reference determinants. Various methodological choices and approximations are discussed. The performance of the TURBOMOLE implementation is illustrated by example calculations of the molecules leflunomide, prednisone, methotrexate, ethylenedioxytetrafulvalene, and a cluster model for the adsorption of methanol on the zeolite H-ZSM-5. Various basis sets are used, including the correlation consistent basis sets specially optimized for explicitly correlated calculations (cc-pVXZ-F12). PMID- 21590780 TI - Giant magnetic moment of the core-shell Co13@Mn20 clusters: first-principles calculations. AB - The core-shell clusters Co(13)@TM(20) with TM = Mn, Fe, Co, and Ni are investigated within first-principles simulations in the framework of density functional theory. Huge magnetic moments have been found in the Co(13)@TM(20) clusters especially for the Co(13)@Mn(20) cluster with a giant magnetic moment of 113 MU(B). The large magnetic moments are mainly due to the special core-shell structure and the weak interaction between the TM and other atoms. PMID- 21590781 TI - Ultrastructural effects of cisplatin on the inner ear and lateral line system of zebrafish (Danio rerio) larvae. AB - Zebrafish, Danio rerio, has been a prominent model vertebrate for the study of chemical toxicity and human disease. Zebrafish hair cells (HCs) show significant structural, functional and molecular similarities to the mammalian inner ear HCs. We examined the effects of cisplatin, an anti-cancer drug, on HCs of the inner ear and on HCs and support cells (SCs) of neuromasts in zebrafish using transmission and scanning electron microscopy. Forty-five zebrafish larvae, 12 days post-fertilization, were assessed: 15 unexposed controls, 15 exposed to 10 uM cisplatin solution, and 15 exposed to 50 uM cisplatin solution. Hair cells in the cristae and maculae of the inner ear and of neuromasts were extremely sensitive to cisplatin. The drug was associated with vacuolization and the presence of myelinoid bodies in HC cytoplasm and with a condensation of the nuclear chromatin. The predominant pattern of injury was widespread degeneration of mitochondria, which appeared swollen and less electron-dense with disorganized or reduced cristae. Severity of damage seemed to be concentration-dependent, and the inner ear suffered more damage than the lateral line. Alterations similar to those in HCs were also observed in SCs of the neuromasts. Scanning electron microscopy showed loss of kinocilia in neuromasts of fish exposed to the higher concentration of cisplatin. PMID- 21590784 TI - Toward a physical biology. PMID- 21590786 TI - SUMO meets meiosis: an encounter at the synaptonemal complex: SUMO chains and sumoylated proteins suggest that heterogeneous and complex interactions lie at the centre of the synaptonemal complex. AB - Recent discoveries have identified the small ubiquitin-like modifier (SUMO) as the potential 'missing link' that could explain how the synaptonemal complex (SC) is formed during meiosis. The SC is important for a variety of chromosome interactions during meiosis and appears ladder-like. It is formed when 'axes' of the two homologous chromosomes become connected by the deposition of transverse filaments, forming the steps of the ladder. Although several components of axial and transverse elements have been identified, how the two are connected to form the SC has remained an enigma. Recent discoveries suggest that SUMO modification underlies protein-protein interactions within the SC of budding yeast. The versatility of SUMO in regulating protein-protein interactions adds an exciting new dimension to our understanding of the SC and suggests that SCs are not homogenous structures throughout the nucleus. We propose that this heterogeneity may allow differential regulation of chromosome structure and function. PMID- 21590787 TI - Why is it crucial to reintegrate pathology into cancer research? AB - The integration of pathology with molecular biology is vital if we are to enhance the translational value of cancer research. Pathology represents a bridge between medicine and basic biology, it remains the gold standard for cancer diagnosis, and it plays an important role in discovery studies. In the past, pathology and cancer research were closely associated; however, the molecular biology revolution has shifted the focus of investigators toward the molecular alterations of tumors. The reductionist approach taken in molecular studies is producing great insight into the inner workings of neoplasia, but it can also minimize the importance of histopathology and of understanding the disease as a whole. In turn, pathologists can underestimate the role of molecular studies in developing new ancillary techniques for clinical diagnosis. A multidisciplinary approach that integrates pathology and molecular biology within a translational research system is needed. This process will require overcoming cultural barriers and can be achieved through education, a more effective incorporation of pathology into biological research, and conversely an integration of biological research into the pathology laboratory. PMID- 21590788 TI - Hierarchical spatial modeling of uncertainty in air pollution and birth weight study. AB - In environmental health studies air pollution measurements from the closest monitor are commonly used as a proxy for personal exposure. This technique assumes that air pollution concentrations are spatially homogeneous in the neighborhoods associated with the monitors and consequently introduces measurement error into a resultant model. To model the relationship between maternal exposure to air pollution and birth weight, we build a hierarchical model that accounts for the associated measurement error. We allow four possible scenarios, with increasing flexibility, for capturing this uncertainty. In the two simplest cases, we specify models with a constant variance term and a variance component that allows uncertainty in the exposure measurements to increase as the distance between maternal residence and the location of the closest monitor increases. In the remaining two models, we introduce spatial dependence using random effects. The models are illustrated using Bayesian hierarchical modeling techniques that relate pregnancy outcomes from the North Carolina Detailed Birth Records to air pollution data from the U.S. Environmental Protection Agency. PMID- 21590789 TI - Fitting dynamic models with forcing functions: application to continuous glucose monitoring in insulin therapy. AB - The artificial pancreas is an emerging technology to treat type 1 diabetes (T1D). It has the potential to revolutionize diabetes care and improve quality of life. The system requires extensive testing, however, to ensure that it is both effective and safe. Clinical studies are resource demanding and so a principle aim is to develop an in silico population of subjects with T1D on which to conduct pre-clinical testing. This paper aims to reliably characterize the relationship between blood glucose and glucose measured by subcutaneous sensor as a major step towards this goal. Blood-and sensor-glucose are related through a dynamic model, specified in terms of differential equations. Such models can present special challenges for statistical inference, however. In this paper we make use of the BUGS software, which can accommodate a limited class of dynamic models, and it is in this context that we discuss such challenges. For example, we show how dynamic models involving forcing functions can be accommodated. To account for fluctuations away from the dynamic model that are apparent in the observed data, we assume an autoregressive structure for the residual error model. This leads to some identifiability issues but gives very good predictions of virtual data. Our approach is pragmatic and we propose a method to mitigate the consequences of such identifiability issues. PMID- 21590790 TI - Practical modifications to the time-to-event continual reassessment method for phase I cancer trials with fast patient accrual and late-onset toxicities. AB - The goal of phase I cancer trials is to determine the highest dose of a treatment regimen with an acceptable toxicity rate. Traditional designs for phase I trials, such as the Continual Reassessment Method (CRM) and the 3 + 3 design, require each patient or a cohort of patients to be fully evaluated for the dose-limiting toxicity (DLT) before new patients can be enrolled. As such, the trial duration may be prohibitively long. The Time-to-Event Continual Reassessment Method (TITE CRM, Cheung and Chappell, 2000) circumvents this limitation by allowing staggered patient accrual without the need for complete DLT follow-up of previously treated patients. However, in the setting of fast patient accrual and late-onset toxicities, the TITE-CRM results in overly aggressive dose escalation and exposes a considerable number of patients to toxic doses. We examine a modification to the TITE-CRM proposed by the original TITE-CRM creator and propose an alternative approach useful in this setting by incorporating an accrual suspension rule. A simulation study designed based on a neuro-oncology trial indicates that the modified methods provide a much improved degree of safety than the TITE-CRM while maintaining desirable design accuracy. The practical aspects of the proposed designs are discussed. The modifications presented are useful when planning phase I trials involving chemoradiation therapy. PMID- 21590791 TI - Marginal regression models with time-varying coefficients for recurrent event data. AB - Recurrent event data arise frequently from medical research. Examples include repeated infections, recurrence of tumors, relapse of leukemia, repeated hospitalizations, recurrence of symptoms of a disease, and so on. In the analysis of recurrent event data, the proportional rates model assumes that the regression coefficients are time invariant. In reality, however, these parameters may vary over time, and the temporal covariate effects on the event process are of great interest. In this article, we formulate a class of semiparametric marginal rates models, which incorporate a mixture of time-varying and time-independent parameters, to analyze recurrent event data. For statistical inference on model parameters, an estimation procedure is developed and asymptotic properties of the proposed estimators are established. In addition, we develop tests for investigating whether or not covariate effects vary with time. The finite-sample behaviors of the proposed methods are examined in simulation studies. An example of application of the proposed methodology is illustrated on a set of data from a clinic study on chronic granulomatous disease. PMID- 21590792 TI - Regression analysis with covariates that have heteroscedastic measurement error. AB - We consider the estimation of the regression of an outcome Y on a covariate X, where X is unobserved, but a variable W that measures X with error is observed. A calibration sample that measures pairs of values of X and W is also available; we consider calibration samples where Y is measured (internal calibration) and not measured (external calibration). One common approach for measurement error correction is Regression Calibration (RC), which substitutes the unknown values of X by predictions from the regression of X on W estimated from the calibration sample. An alternative approach is to multiply impute the missing values of X given Y and W based on an imputation model, and then use multiple imputation (MI) combining rules for inferences. Most of current work assumes that the measurement error of W has a constant variance, whereas in many situations, the variance varies as a function of X. We consider extensions of the RC and MI methods that allow for heteroscedastic measurement error, and compare them by simulation. The MI method is shown to provide better inferences in this setting. We also illustrate the proposed methods using a data set from the BioCycle study. PMID- 21590793 TI - Sample size and power determination in joint modeling of longitudinal and survival data. AB - Owing to the rapid development of biomarkers in clinical trials, joint modeling of longitudinal and survival data has gained its popularity in the recent years because it reduces bias and provides improvements of efficiency in the assessment of treatment effects and other prognostic factors. Although much effort has been put into inferential methods in joint modeling, such as estimation and hypothesis testing, design aspects have not been formally considered. Statistical design, such as sample size and power calculations, is a crucial first step in clinical trials. In this paper, we derive a closed-form sample size formula for estimating the effect of the longitudinal process in joint modeling, and extend Schoenfeld's sample size formula to the joint modeling setting for estimating the overall treatment effect. The sample size formula we develop is quite general, allowing for p-degree polynomial trajectories. The robustness of our model is demonstrated in simulation studies with linear and quadratic trajectories. We discuss the impact of the within-subject variability on power and data collection strategies, such as spacing and frequency of repeated measurements, in order to maximize the power. When the within-subject variability is large, different data collection strategies can influence the power of the study in a significant way. Optimal frequency of repeated measurements also depends on the nature of the trajectory with higher polynomial trajectories and larger measurement error requiring more frequent measurements. PMID- 21590794 TI - Bayesian procedures for phase I/II clinical trials investigating the safety and efficacy of drug combinations. AB - Many formal statistical procedures for phase I dose-finding studies have been proposed. Most concern a single novel agent available at a number of doses and administered to subjects participating in a single treatment period and returning a single binary indicator of toxicity. Such a structure is common when evaluating cytotoxic drugs for cancer. This paper concerns studies of combinations of two agents, both available at several doses. Subjects participate in one treatment period and provide two binary responses: one an indicator of benefit and the other of harm. The word 'benefit' is used loosely here: the response might be an early indicator of physiological change which, if induced in patients, is of potential therapeutic value. The context need not be oncology, but might be any study intended to meet both the phase I aim of establishing which doses are safe and the phase II goal of exploring potential therapeutic activity. A Bayesian approach is used based on an assumption of monotonicity in the relationship between the strength of the dose-combination and the distribution of the bivariate outcome. Special cases are described, and the procedure is evaluated using simulation. The parameters that define the model have immediate and simple interpretation. Graphical representations of the posterior opinions about model parameters are shown, and these can be used to inform the discussions of the trial safety committee. PMID- 21590795 TI - Biomedicine in the environment: sorption of the cyclotide kalata B2 to montmorillonite, goethite, and humic acid. AB - Cyclotides are bioactive, stable mini-proteins produced in high amounts in Violaceae and Rubiaceae with promising pharmaceutical and agrochemical applications. Environmental issues must be addressed before large-scale plant cultivation of cyclotides for pharmaceutical or pesticidal purposes can commence. The objective of the present study was to investigate sorption of the cyclotide kalata B2 (kB2), because knowledge of cyclotide biogeochemistry will aid our understanding of environmental fate. The octanol-water partitioning coefficient was determined to be 2.8 +/- 0.6 (log K(OW) = 0.4 +/- 0.1). Sorption of kB2 by montmorillonite, goethite, and humic acid was investigated at different concentrations and under varying acidity and reached equilibrium within minutes. The kB2 sorption at a solution concentration of 0.2 mg/L to montmorillonite was high (120 mg/g) compared to humic acid (0.60 mg/g) and goethite (0.03 mg/g). Kalata B2 intercalated the interlayer space of montmorillonite. The sorption isotherm for humic acid was linear up to a solution concentration of 0.8 mg/L and concave for montmorillonite and goethite up to an equilibrium solution concentration of 1.5 mg/L. Sorption to goethite was unaffected by pH, but sorption to montmorillonite and humic acid at pH near the isoelectric point (pI) was threefold the sorption when pH > the isoelectric point, suggesting that electrostatic interaction/repulsion between kB2 and sorbents play an important role. The strong sorption to montmorillonite reduces exposure to below toxic threshold values. In addition, the transport risk of soluble cyclotides is reduced, but particle-bound cyclotides may be transported to recipient aquatic sediments with the associated risk of adversely affecting sediment-dwelling organisms. PMID- 21590796 TI - Application of chemical toxicity distributions to ecotoxicology data requirements under REACH. AB - The European Union's REACH regulation has further highlighted the lack of ecotoxicological data for substances in the marketplace. The mandates under REACH (registration, evaluation, authorization, and restriction of chemicals) to produce data and minimize testing on vertebrates present an impetus for advanced hazard assessment techniques using read-across. Research in our group has recently focused on probabilistic ecotoxicological hazard assessment approaches using chemical toxicity distributions (CTDs). Using available data for chemicals with similar modes of action or within a chemical class may allow for selection of a screening point value (SPV) for development of environmental safety values, based on a probabilistic distribution of toxicity values for a specific endpoint in an ecological receptor. Ecotoxicity data for acetylcholinesterase inhibitors and surfactants in Daphnia magna and Pimephales promelas were gathered from several data sources, including the U.S. Environmental Protection Agency's ECOTOX and Pesticides Ecotoxicity databases, the peer-reviewed literature, and the Human and Environmental Risk Assessment (HERA) project. Chemical toxicity distributions were subsequently developed, and the first and fifth centiles were used as SPVs for the development of screening-predicted no-effect concentrations (sPNECs). The first and fifth centiles of these distributions were divided by an assessment factor of 1,000, as recommended by REACH guidance. Use of screening values created using these techniques could support the processes of data dossier development and environmental exposure assessment, allowing for rigorous prioritization in testing and monitoring to fill data gaps. PMID- 21590797 TI - Effects of cyclic changes in pH and salinity on metals release from sediments. AB - The effects of dynamic changes in pH and salinity on metal speciation and release are investigated with sediments posed in a simulated estuarine environment. The release of Zn, Cd, Mn, and Fe was studied using sediment from the Anacostia River (Washington, DC, USA) spiked with freshly precipitated amorphous cadmium sulfide to increase Cd content. The sediment was exposed to salt water (high pH, ionic strength) and freshwater (neutral pH, minimal ionic strength) continuously and alternately (to mimic tidal changes) in small microcosms over 100 d. At the conclusion of the experiments, the vertical profiles of acid volatile sulfide (AVS) and simultaneously extracted metals (SEM) as well as porewater metals and anion concentrations were characterized. Acid volatile sulfide oxidation at the sediment surface led to a commensurate increase in dissolved metal species and metal release that was strongly dependent on the changes in the overlying water characteristics. Total Cd release was substantially higher during exposure to salt water, although, as a result of complexation, predicted dissolved Cd(2+) concentration in the overlying water was higher during exposure to freshwater. Total Zn release was little changed during exposure to salt water and freshwater, although the predicted dissolved Zn(2+) concentration was much higher during freshwater exposures. No significant iron was released because of the rapid oxidation of ferrous iron (Fe(2+)) in aerobic surficial sediments and overlying water. The present study suggests that cyclic changes in pH and salinity in the overlying water can dramatically influence metal release from estuarine sediments. PMID- 21590798 TI - An estuarine mudsnail in situ toxicity assay based on postexposure feeding. AB - In situ assays provide more realistic exposure scenarios than laboratory assays, which is particularly pertinent for estuaries because exposure conditions are difficult to simulate. Traditionally, sublethal toxicity testing endpoints, such as growth, emergence, and reproduction, imply time-delayed extrapolations from individuals to populations, communities, and ecosystems. Sublethal responses mechanistically linked to ecosystem functions have been largely neglected. Feeding is an unequivocal ecologically meaningful response because its impairment has direct and immediate effects on ecosystems, by hampering key functions such as organic matter decomposition, long before its effects at the individual level have consequences at successively higher levels of biological organization. The ultimate goal of the present study was to widen the range of ecosystem functions for estuarine quality assessments. Specifically, a short-term in situ assay based on the postexposure feeding of the mudsnail Hydrobia ulvae is presented. Methodologies to quantify precisely postexposure egestion as a surrogate of feeding were achieved. A multiple regression model from laboratory experiments was successfully applied to an in situ assay at reference (Mira River) and contaminated Portuguese estuaries (Sado River) for predicting reference results and allowing unraveling confounding factors during exposure (temperature, salinity, sediment grain size). Sensitivity comparisons of postexposure feeding with survival and growth, after Cu exposure, were carried out and used for a first preliminary appraisal of the relative consequences of ecosystem-level immediate effects. PMID- 21590799 TI - If J doesn't evolve, it won't J-resolve: J-PRESS with bandwidth-limited refocusing pulses. AB - There is increasing interest in the J-PRESS technique, an in vivo implementation of two-dimensional J-spectroscopy combined with PRESS localization, for high field spectroscopy studies of the human brain. The experiment is designed to resolve scalar couplings in the second, indirectly detected dimension, but will only do so if the slice-selective refocusing pulses in the PRESS sequence affect all coupled spins equally. At high magnet field strengths, due to limited RF pulse bandwidth, PRESS-based localization results in spatially dependent evolution of coupling. In some regions of the localized volume, coupling evolves during the PRESS echo time, while in other regions it may be partially or fully refocused. This study investigates the impact of this effect on the appearance of the J-PRESS spectrum for coupled spins, focusing on two commonly observed metabolites, lactate and N-acetyl aspartate, showing that such behavior results in additional peaks in the J-resolved spectrum (termed J-refocused peaks). It is also demonstrated that increasing the bandwidth of refocusing pulses significantly reduces the size of such signals. PMID- 21590800 TI - Improved myo-inositol detection through Carr-Purcell PRESS: a tool for more sensitive mild cognitive impairment diagnosis. AB - A 3-T study is presented, comparing the ability of two (1) H spectroscopy pulse sequences, Carr-Purcell point resolved spectroscopy (CPRESS; TE = 45 msec), and conventional PRESS (TE = 35 msec), to separate between groups of 20 normal control (NC) and 20 mild cognitive impairment (MCI) subjects. Both sequences showed higher myo-inositol (mI) and mI/N-acetyl-aspartate (NAA) levels in the posterior cingulate gyrus of the MCI subjects. The increased intrasubject repeatability of mI and mI/NAA CPRESS measurements (~ 6% vs. 9% for PRESS) translated into decreased intraclass variability. A 22% intraclass mI PRESS variability was reduced to 16% for CPRESS, and an 18% intraclass mI/NAA PRESS variability was reduced to 12% for CPRESS for the group of NC subjects. Similar results were observed for the MCI subjects. Decreased intraclass variability led to improved separation between NC and MCI subjects (P = 0.017 for PRESS and P < 0.0001 for CPRESS mI/NAA, the best NC/MCI discriminant for each method). Seventy five percent sensitivity at eighty percent specificity was demonstrated by mI/NAA CPRESS measurements in separating NC from MCI subjects. High correlations were also observed between subject performance on a number of neuropsychological tests (probing verbal memory, visuoconstruction performance, and visual motor integration) and the mI/NAA ratio; higher correlation coefficients (with stronger statistical significance) were consistently evident for CPRESS than for PRESS data. PMID- 21590801 TI - Iron quantification of microbleeds in postmortem brain. AB - Brain microbleeds (BMB) are associated with chronic and acute cerebrovascular disease and present a source of pathologic iron to the brain proportional to extravasated blood. Therefore, BMB iron content is potentially a valuable biomarker. We tested noninvasive phase image methods to quantify iron content and estimate true source diameter (i.e., unobscured by the blooming effect) of BMB in postmortem human tissue. Tissue slices containing BMB were imaged using a susceptibility weighted imaging protocol at 11.7T. BMB lesions were assayed for iron content using atomic absorption spectrometry. Measurements of geometric features in phase images were related to lesion iron content and source diameter using a mathematical model. BMB diameter was estimated by image feature geometry alone without explicit relation to the magnetic susceptibility. A strong linear relationship (R(2) = 0.984, P < 0.001) predicted by theory was observed in the experimental data, presenting a tentative standardization curve where BMB iron content in similar tissues could be calculated. In addition, we report BMB iron mass measurements, as well as upper bound diameter and lower bound iron concentration estimates. Our methods potentially allows the calculation of brain iron load indices based on BMB iron content and classification of BMB by size unobscured by the blooming effect. PMID- 21590802 TI - Optimization of spiral-based pulse sequences for first-pass myocardial perfusion imaging. AB - Although spiral trajectories have multiple attractive features such as their isotropic resolution, acquisition efficiency, and robustness to motion, there has been limited application of these techniques to first-pass perfusion imaging because of potential off-resonance and inconsistent data artifacts. Spiral trajectories may also be less sensitive to dark-rim artifacts that are caused, at least in part, by cardiac motion. By careful consideration of the spiral trajectory readout duration, flip angle strategy, and image reconstruction strategy, spiral artifacts can be abated to create high-quality first-pass myocardial perfusion images with high signal-to-noise ratio. The goal of this article was to design interleaved spiral pulse sequences for first-pass myocardial perfusion imaging and to evaluate them clinically for image quality and the presence of dark-rim, blurring, and dropout artifacts. PMID- 21590803 TI - PCATMIP: enhancing signal intensity in diffusion-weighted magnetic resonance imaging. AB - Diffusion-weighted MRI studies generally lose signal intensity to physiological motion, which can adversely affect quantification/diagnosis. Averaging over multiple repetitions, often used to improve image quality, does not eliminate the signal loss. In this article, PCATMIP, a combined principal component analysis and temporal maximum intensity projection approach, is developed to address this problem. Data are first acquired for a fixed number of repetitions. Assuming that physiological fluctuations of image intensities locally are likely temporally correlated unlike random noise, a local moving boxcar in the spatial domain is used to reconstruct low-noise images by considering the most relevant principal components in the temporal domain. Subsequently, a temporal maximum intensity projection yields a high signal-intensity image. Numerical and experimental studies were performed for validation and to determine optimal parameters for increasing signal intensity and minimizing noise. Subsequently, a combined principal component analysis and temporal maximum intensity projection approach was used to analyze diffusion-weighted porcine liver MRI scans. In these scans, the variability of apparent diffusion coefficient values among repeated measurements was reduced by 59% relative to averaging, and there was an increase in the signal intensity with higher intensity differences observed at higher b values. In summary, a combined principal component analysis and temporal maximum intensity projection approach is a postprocessing approach that corrects for bulk motion-induced signal loss and improves apparent diffusion coefficient measurement reproducibility. PMID- 21590804 TI - Novel 16-channel receive coil array for accelerated upper airway MRI at 3 Tesla. AB - Upper airway MRI can provide a noninvasive assessment of speech and swallowing disorders and sleep apnea. Recent work has demonstrated the value of high resolution three-dimensional imaging and dynamic two-dimensional imaging and the importance of further improvements in spatio-temporal resolution. The purpose of the study was to describe a novel 16-channel 3 Tesla receive coil that is highly sensitive to the human upper airway and investigate the performance of accelerated upper airway MRI with the coil. In three-dimensional imaging of the upper airway during static posture, 6-fold acceleration is demonstrated using parallel imaging, potentially leading to capturing a whole three-dimensional vocal tract with 1.25 mm isotropic resolution within 9 sec of sustained sound production. Midsagittal spiral parallel imaging of vocal tract dynamics during natural speech production is demonstrated with 2 * 2 mm(2) in-plane spatial and 84 ms temporal resolution. PMID- 21590805 TI - Combined prospective and retrospective motion correction to relax navigator requirements. AB - Prospective motion correction can prevent motion artifacts in magnetic resonance imaging of the brain. However, for high-resolution imaging, the technique relies on precise tracking of head motion. This precision is often limited by tracking noise, which leads to residual errors in the prospectively-corrected k-space data and artifacts in the image. This work shows that it is possible to estimate these tracking errors, and hence the true k-space sample locations, by applying a two sided filter to the tracking data after imaging. A conjugate gradient reconstruction is compared to gridding as a means of using this information to retrospectively correct for the effects of the residual errors. PMID- 21590806 TI - MRI of blood flow of the human retina. AB - This study reports a high-resolution MRI approach to image basal blood flow and hypercapnia-induced blood-flow changes in the unanesthetized human retina on a 3 T MRI scanner. Pseudocontinuous arterial spin labeling technique with static tissue suppression was implemented to minimize movement artifacts and improve blood-flow sensitivity. Turbo spin-echo acquisition was used to achieve high spatial resolution free of susceptibility artifacts. The size, shape, and position of a custom-made receive radiofrequency coil were optimized for sensitivity in the posterior retina. Synchronized eye blink and respiration to the end of each data readout minimized eye movement and physiological fluctuation. Robust high-contrast blood-flow MRI of the unanesthetized human retina was obtained at 500 * 800 MUm(2) in-plane resolution. Blood flow in the posterior retina was 93 +/- 31 mL/(100 mL min) (mean +/- standard deviation, N = 5). Hypercapnic inhalation (5% CO(2)) increased blood flow by 12 +/- 4% relative to air (P < 0.01, N = 5). This study demonstrates the feasibility of blood-flow MRI of the retina of unanesthetized human. Because blood flow is tightly coupled to metabolic function under normal conditions and it is often perturbed in diseases, this approach could provide unique insights into retinal physiology and serve as an objective imaging biomarker for disease staging and testing of novel therapeutic strategies. This approach could open up new avenue of retinal research. PMID- 21590808 TI - Excite and receive solenoid radiofrequency coil for MRI-guided breast interventions. AB - A radiofrequency coil based on a solenoid design was developed and integrated with a novel device for MR-guided breast interventions using a circumferential approach. The transmit/receive tapered solenoid design conforms to the shape of the pendent breast, and provides open circumferential needle access to breast tissue under rotational symmetry. Phantom and in vivo studies using a healthy volunteer demonstrated a superior uniformity using the tapered solenoid coil compared with a commercial 8-channel diagnostic imaging coil. The solenoid coil design has important advantages due to localized transmit/receive such as B(1) homogeneity and reduced specific absorption ratio (SAR) especially at high-field strengths. Because it provides open access and a rotationally symmetric local field, the tapered solenoid design can easily be adapted for bilateral imaging and 3D MR-guided breast interventions. PMID- 21590807 TI - Photoreceptor degeneration changes magnetic resonance imaging features in a mouse model of retinitis pigmentosa. AB - Retinal degeneration-1 (rd1) mice are animal models of retinitis pigmentosa, a blinding disease caused by photoreceptor cell degeneration. This study aims to determine magnetic resonance imaging (MRI) changes in retinas of 1- and 3-month old rd1 mice. Apparent diffusion coefficient in retina was measured using diffusion MRI. The blood-retinal barrier leakage was evaluated using gadolinium diethylenetriaminepentaacetic acid-enhanced T(1)-weighted MRI before and after systemic gadolinium-diethylenetriaminepentaacetic acid injection. Photoreceptor degeneration in rd1 retina was apparent by decreased retinal thickness and loss of water diffusion anisotropy in both 1- and 3-month-old rd1 mice. Furthermore, statistically significant increase of mean retinal apparent diffusion coefficient and gadolinium-diethylenetriaminepentaacetic acid-enhanced T(1)-weighted MRI signals were observed in 3-month-old rd1 mice comparing with age-matched wild type mice. Together, these data suggest that MRI parameter changes can signature common pathological changes in photoreceptor-degenerated eyes, particularly blood retinal barrier leakage-induced retinal edema. PMID- 21590809 TI - Selection of STOP-free sequences from random mutagenesis for 'loss of interaction' two-hybrid studies. AB - The investigation of protein-protein interactions is an essential part of biological research. To obtain a deeper insight into regulatory protein networks, the identification of the components, domains and especially single residues that are involved in these interactions is helpful. A widespread and attractive genetic tool for investigation of protein-protein interactions is the yeast two hybrid system. This method enables large-scale screens and its application is cheap and relatively simple. For identification of the amino acids in a protein sequence that are essential for interaction with a specific partner, yeast two hybrid assays can be combined with random mutagenesis of the sequence of interest. A common problem with such an experiment is the generation of stop codons within the mutagenized fragments, leading to the isolation of many false positives when screening for loss of interaction using the two-hybrid method. To overcome this problem, we modified the yeast two-hybrid system to allow selection for sequences without stop codons. To achieve this, we fused the ScURA3 marker gene in frame to the mutagenized fragments. We show here that this marker is fully functional when fused to a two-hybrid construct with a nuclear localization signal, such as a Gal4 activation domain and a prey protein, thus allowing selection of stop-free sequences on media without uracil. Using the Rho-binding domain from a Bni1-like formin and different Rho-type GTPases from Ashbya gossypii as examples, we further show that our system can be used to screen large numbers of transformants for loss of protein-protein interactions in combination with random mutagenesis. PMID- 21590810 TI - A new colour assay for [URE3] prion in a genetic background used to score for the [PSI+] prion. AB - Most scoring assays for yeast prions are dependent on specific genetic markers and constructs that differ for each prion. Here we describe a simple colour assay for the [URE3] prion that works in the 74D-964 strain frequently used to score the [PSI(+)] prion. Although this assay can only be used to score for [URE3] in the [psi(-)] version of the strain, it makes it easier to examine the effects of host mutations or environmental changes on [URE3] or [PSI(+)] using a colour assay in the identical genetic background. PMID- 21590811 TI - Regulation of the system x(C)- cystine/glutamate exchanger by intracellular glutathione levels in rat astrocyte primary cultures. AB - The system x(C)- (Sx(C)-) transporter functions to mediate the exchange of extracellular cystine (L-Cys(2)) and intracellular glutamate (L-Glu). Internalized L-Cys(2) serves as a rate-limiting precursor for the biosynthesis of glutathione (GSH), while the externalized L-Glu can contribute to either excitatory signaling or excitotoxicity. In the present study the influence of culture conditions (with and without dibutyryl-cAMP) and GSH levels on the expression of Sx(C)- were investigated in primary rat astrocyte cultures. Sx(C)- activity in dbcAMP-treated cells was nearly sevenfold greater than in untreated astrocytes and increased further (~threefold) following the depletion of intracellular GSH with buthionine sulfoximine. This increase in Sx(C)- triggered by GSH depletion was only observed in the dbcAMP-treated phenotype and was distinct from the Nrf2-mediated response initiated by exposure to electrophiles. Changes in Sx(C)- activity correlated with increases in both protein and mRNA levels of the xCT subunit of the Sx(C)- heterodimer, an increase in the V(max) for L-Glu uptake and was linked temporally to GSH levels. This induction of Sx(C) was not mimicked by hydrogen peroxide nor attenuated by nonspecific antioxidants but was partially prevented by the co-administration of the cell-permeant thiols GSH-ethyl ester and N-acetylcysteine. These findings demonstrate that the expression of Sx(C)- on astrocytes is dynamically regulated by intracellular GSH levels in a cell- and phenotype-dependent manner. The presence of this pathway likely reflects the inherent vulnerability of the CNS to oxidative damage and raises interesting questions as to the functional consequences of changes in Sx(C)- activity in CNS injury and disease. PMID- 21590812 TI - A porphyrin-fullerene dyad with a supramolecular "double-cable" structure as a novel electron acceptor for bulk heterojunction polymer solar cells. PMID- 21590813 TI - Artificial muscles based on polypyrrole/carbon nanotube laminates. PMID- 21590814 TI - Silver nanowires: from scalable synthesis to recyclable foldable electronics. PMID- 21590815 TI - Hydrophobic shell loading of biopolyelectrolyte capsules. PMID- 21590816 TI - Ordered zigzag stripes of polymer gel/metal nanoparticle composites for highly stretchable conductive electrodes. PMID- 21590817 TI - Organic-inorganic nanocomposites by placing conjugated polymers in intimate contact with quantum rods. PMID- 21590818 TI - Hierarchically porous TiO2 electrodes fabricated by dual templating methods for dye-sensitized solar cells. PMID- 21590819 TI - Quantum-sized gold nanoclusters: bridging the gap between organometallics and nanocrystals. AB - This Concept article provides an elementary discussion of a special class of large-sized gold compounds, so-called Au nanoclusters, which lies in between traditional organogold compounds (e.g., few-atom complexes, <1 nm) and face centered cubic (fcc) crystalline Au nanoparticles (typically >2 nm). The discussion is focused on the relationship between them, including the evolution from the Au???Au aurophilic interaction in Au(I) complexes to the direct Au-Au bond in clusters, and the structural transformation from the fcc structure in nanocrystals to non-fcc structures in nanoclusters. Thiolate-protected Au(n)(SR)(m) nanoclusters are used as a paradigm system. Research on such nanoclusters has achieved considerable advances in recent years and is expected to flourish in the near future, which will bring about exciting progress in both fundamental scientific research and technological applications of nanoclusters of gold and other metals. PMID- 21590820 TI - NMR spectroscopy of intermetallic compounds: an experimental and theoretical approach to local atomic arrangements in binary gallides. AB - The results of the investigation of MGa(2) with M = Ca, Sr, Ba and of MGa(4) with M = Na, Ca, Sr, Ba by a combined application of NMR spectroscopy and quantum mechanical calculations are comprehensively evaluated. The electric-field gradient (EFG) was identified as the most reliable measure to study intermetallic compounds, since it is accessible with high precision by quantum mechanical calculations and, for nuclear spin I>1/2, by NMR spectroscopy. The EFG values obtained by NMR spectroscopy and quantum mechanical calculations agree very well for both series of investigated compounds. A deconvolution of the calculated EFGs into their contributions reveals its sensitivity to the local environment of the atoms. The EFGs of the investigated di- and tetragallides are dominated by the population of the p(x)-, p(y)-, and p(z)-like states of the Ga atoms. A general combined approach for the investigation of disordered intermetallic compounds by application of diffraction methods, NMR spectroscopy, and quantum mechanical calculations is suggested. This scheme can also be applied to other classes of crystalline disordered inorganic materials. PMID- 21590822 TI - Squaramides: bridging from molecular recognition to bifunctional organocatalysis. AB - In this minireview, squaramides are presented from their roots as artificial anion receptors in molecular recognition studies to their recent advances as powerful bifunctional hydrogen-bonding catalysts in asymmetric organocatalysis. The main features of the squaramido functionality and the direct comparison with the analogous ureas and thioureas are also discussed. PMID- 21590821 TI - Hemoglobin as a nitrite anhydrase: modeling methemoglobin-mediated N2O3 formation. AB - Nitrite has recently been recognized as a storage form of NO in blood and as playing a key role in hypoxic vasodilation. The nitrite ion is readily reduced to NO by hemoglobin in red blood cells, which, as it happens, also presents a conundrum. Given NO's enormous affinity for ferrous heme, a key question concerns how it escapes capture by hemoglobin as it diffuses out of the red cells and to the endothelium, where vasodilation takes place. Dinitrogen trioxide (N(2)O(3)) has been proposed as a vehicle that transports NO to the endothelium, where it dissociates to NO and NO(2). Although N(2)O(3) formation might be readily explained by the reaction Hb-Fe(3+)+NO(2)(-)+NO?Hb-Fe(2+)+N(2)O(3), the exact manner in which methemoglobin (Hb-Fe(3+)), nitrite and NO interact with one another is unclear. Both an "Hb-Fe(3+)-NO(2)(-)+NO" pathway and an "Hb-Fe(3+) NO+NO(2)(-) " pathway have been proposed. Neither pathway has been established experimentally. Nor has there been any attempt until now to theoretically model N(2)O(3) formation, the so-called nitrite anhydrase reaction. Both pathways have been examined here in a detailed density functional theory (DFT, B3LYP/TZP) study and both have been found to be feasible based on energetics criteria. Modeling the "Hb-Fe(3+)-NO(2)(-)+NO" pathway proved complex. Not only are multiple linkage isomeric (N- and O-coordinated) structures conceivable for methemoglobin-nitrite, multiple isomeric forms are also possible for N(2)O(3) (the lowest-energy state has an N-N-bonded nitronitrosyl structure, O(2)N-NO). We considered multiple spin states of methemoglobin-nitrite as well as ferromagnetic and antiferromagnetic coupling of the Fe(3+) and NO spins. Together, the isomerism and spin variables result in a diabolically complex combinatorial space of reaction pathways. Fortunately, transition states could be successfully calculated for the vast majority of these reaction channels, both M(S)=0 and M(S)=1. For a six-coordinate Fe(3+)-O-nitrito starting geometry, which is plausible for methemoglobin-nitrite, we found that N(2)O(3) formation entails barriers of about 17-20 kcal mol(-1) , which is reasonable for a physiologically relevant reaction. For the "Hb-Fe(3+) NO+NO(2) (-) " pathway, which was also found to be energetically reasonable, our calculations indicate a two-step mechanism. The first step involves transfer of an electron from NO(2)(-) to the Fe(3+)-heme-NO center ({FeNO}(6)) , resulting in formation of nitrogen dioxide and an Fe(2+)-heme-NO center ({FeNO}(7)). Subsequent formation of N(2)O(3) entails a barrier of only 8.1 kcal mol(-1) . From an energetics point of view, the nitrite anhydrase reaction thus is a reasonable proposition. Although it is tempting to interpret our results as favoring the "{FeNO}(6)+NO(2)(-) " pathway over the "Fe(3+)-nitrite+NO" pathway, both pathways should be considered energetically reasonable for a biological reaction and it seems inadvisable to favor a unique reaction channel based solely on quantum chemical modeling. PMID- 21590824 TI - Proton-induced tuning of metal-metal communication in rack-type dinuclear Ru complexes containing benzimidazolyl moieties. AB - Ru complexes bearing a bis-tridentate benzimidazolyl ligand have been synthesized. The dinuclear ones act as a bibasic acid with pK(a1)=4.36 and pK(a2)=5.90. The protonated form of the dinuclear complex exhibited two one electron oxidations at +0.91 and +1.02 V versus the ferrocenium/ferrocene (Fc/Fc(+)) couple (the potential difference (DeltaE)=0.11 V), but the di deprotonated form showed two waves at +0.50 and +0.58 V versus Fc/Fc(+) (DeltaE=0.08 V). Since the potential difference between two waves reflects the strength of the metal-metal interaction, the deprotonation of the benzimidazole moieties in the complexes weakened the Ru-Ru communication. The degree of electronic coupling between two metal centers, estimated from the intervalence charge transfer (IVCT) band, was greater for the protonated form. DFT calculations for the protonated and deprotonated forms of the dinuclear complex suggest that the Ru(II)-L(H(2)) pi* interaction plays a key role in the Ru-Ru interaction. PMID- 21590823 TI - The stepwise Diels-Alder reaction of 4-nitrobenzodifuroxan with Danishefsky's diene. AB - The Diels-Alder reaction of 4-nitrobenzodifuroxan (NBDF) with 1-methoxy-3 trimethylsilyloxy-1,3-butadiene has been investigated experimentally and theoretically. Treatment of NBDF with excess diene in chloroform at room temperature was found to afford a single product that contained a carbonyl functionality. Based on an X-ray structure and NMR spectroscopic data, the product appeared to be a result of the hydrolysis of the OSiMe(3) moiety of the thermodynamically more stable endo [2+4] cycloadduct, characterized by a cis arrangement of the MeO and NO(2) functionalities. In situ NMR investigations of the interaction were carried out at room temperature in CDCl(3) and at -40 degrees C in deuterated acetonitrile. Calculations at the B3LYP/6-31G* level in the gas phase and in acetonitrile were carried out under the assumption that the most stable cis conformation of the diene is also the most reactive in the interaction. The analysis revealed the NBDF/cis diene interaction involves the formation of a zwitterionic intermediate. Importantly, this intermediate is formed in two preferred conformations, which correspond to the endo and exo modes of approach of the reagents. Cyclization of these two identified conformations afforded the experimentally characterized endo and exo [2+4] cycloadducts. According to the calculations, the interconversion of the two conformers can either take place through a return to the pre-reaction complexes or it can occur by rotation through an intermediate conformation of lesser stability. In view of the stepwise character of the interaction, the possibility that the intermediate zwitterion is the result of the interaction between NBDF and the trans diene could not be excluded. Calculations carried out with the most stable and more populated s-trans conformer confirmed this idea and supported the role of the zwitterion in the overall interaction. PMID- 21590825 TI - A facile and specific approach to new liquid chromatography adsorbents obtained by ionic self-assembly. AB - A new ionic-liquid monomer, 1-vinyl-3-octadecylimidazolium bromide ([C(18)VIm]Br), was prepared and polymerized on porous silica particles by means of a surface-initiated radical chain-transfer reaction. Further modification for functionalization was performed through the exchange of counteranions from bromide to methyl orange (MO). Two new silica-poly(octadecylimidazolium) (Sil PImC(18)) hybrid materials (Sil-PImC(18)-Br and Sil-PImC(18)-MO) were synthesized and characterized by elemental analysis, thermogravimetric analysis, diffuse reflectance infrared Fourier transform spectroscopy (DRIFT), and solid-state (13)C CP/MAS NMR spectroscopy. Sil-PImC(18)-MO presented ultra-high shape selectivity for constrained isomers of polycyclic aromatic hydrocarbons (PAHs) both in reversed- and normal-phase HPLC when used as the stationary phase. Fundamental aspects of the molecular shape selectivity were evaluated by using Standard Reference Material (SRM) 869b; the column selectivity test mixture for liquid chromatography. The impact of this phase was also demonstrated by the separation of SRM 1647e (16 priority pollutant PAHs) and several steroid isomers. Enhanced selectivity could be explained by the highly oriented arrangement between the octadecylimidazolium chain and a rigid segment of MO. These findings may open a new window of research for the design of materials used in chromatographic supports, solid extraction, catalysis, and electrolytes by simple modifications of the counterions in the poly(ionic liquid) analogous phase. PMID- 21590826 TI - A highly selective, cell-permeable fluorescent nanoprobe for ratiometric detection and imaging of peroxynitrite in living cells. AB - Peroxynitrite (ONOO(-)) is a highly reactive species implicated in the pathology of numerous diseases and there is currently great interest in developing fluorescent probes that can selectively detect ONOO(-) in living cells. Herein, a polymeric micelle-based and cell-penetrating peptide-coated fluorescent nanoprobe that incorporates ONOO(-) indicator dye and reference dye for the ratiometric detection and imaging of ONOO(-) has been developed. The nanoprobe effectively avoids the influences from enzymatic reaction and high-concentration .OH and ClO( ). The improved ONOO(-) selectivity of the nanoprobe is achieved by a delicate complementarity of properties between the nanomatrix and the embedded molecular probe (BzSe-Cy). This nanoprobe also has other attractive properties, such as good water solubility, photostability, biocompatibility, and near-infrared excitation and emission. Fluorescence imaging experiments by confocal microscopy show that this nanoprobe is capable of visualizing ONOO(-) produced in living cells and it exhibits very low toxicity and good membrane permeability. We anticipate that this technique will be a potential tool for the precise pathological understanding and diagnosis of ONOO(-)-related human diseases. PMID- 21590827 TI - Direct one-pot reductive N-alkylation of nitroarenes by using alcohols with supported gold catalysts. PMID- 21590828 TI - Zinc-catalyzed chemoselective reduction of esters to alcohols. PMID- 21590829 TI - Substrate-controlled, phosphine-catalyzed domino reactions of activated conjugated dienes: highly diastereoselective synthesis of bicyclic skeletons. PMID- 21590831 TI - Macromol. Rapid commun. 1/2010. PMID- 21590833 TI - What a great year! PMID- 21590832 TI - Macromol. Rapid commun. 1/2010. PMID- 21590834 TI - Advances in dielectric elastomers for actuators and artificial muscles. AB - A number of materials have been explored for their use as artificial muscles. Among these, dielectric elastomers (DEs) appear to provide the best combination of properties for true muscle-like actuation. DEs behave as compliant capacitors, expanding in area and shrinking in thickness when a voltage is applied. Materials combining very high energy densities, strains, and efficiencies have been known for some time. To date, however, the widespread adoption of DEs has been hindered by premature breakdown and the requirement for high voltages and bulky support frames. Recent advances seem poised to remove these restrictions and allow for the production of highly reliable, high-performance transducers for artificial muscle applications. PMID- 21590835 TI - Using metallo-supramolecular block copolymers for the synthesis of higher order nanostructured assemblies. AB - Many research groups have explored the properties and solution self-assembly of main chain metallo-supramolecular multiblock copolymers. Until recently, these metal complexes have been used to prepare mainly micelle type structures. However, the self-assembly of such copolymers has been exploited further to create more advanced architectures which utilize the reversible supramolecular linkage of their building blocks as a key component in their synthesis. Furthermore, the incorporation of multiple orthogonal interactions and stimuli responsive polymers into their design, enables more precise external control of their properties. This feature article discusses recent developments and provides an insight into their potential exploitation and development for the creation of novel, smart, and responsive nanostructures. PMID- 21590836 TI - Effect of Gold Nanoparticles on the Thermosensitivity, Morphology, and Optical Properties of Poly(acrylamide-acrylic acid) Microgels. AB - Novel positive thermosensitive microgels of poly(acrylamide-acrylic acid) with embedded gold nanoparticles have been synthesized and characterized by means of dynamic light scattering, UV-vis spectroscopy, field emission scanning electron microscopy, and transmission electron microscopy. These systems show temperature (upper critical solution temperature-like volume phase transition) and optical responsiveness making them externally triggered systems. PMID- 21590837 TI - Single-step electrospinning of bimodal fiber meshes for ease of cellular infiltration. AB - Bimodal fiber meshes with fiber diameters differing by one order of magnitude, are electrospun in a simple one-step process, using a standard single syringe electrospin setup. The nano- and microfiber meshes combine the benefits of nanofibers (cell adhesion, proliferation) with those of microfibers (open structure, large pore size) and are therefore interesting as scaffolds for cellular infiltration. PMID- 21590838 TI - Morphology and pH Sensing Characteristics of New Luminescent Electrospun Fibers Prepared from Poly(phenylquinoline)-block-Polystyrene/Polystyrene Blends. AB - New luminescent electrospun (ES) fibers for pH-tunable colorimetric sensors were prepared from binary blends of poly(phenylquinoline)-block-polystyrene (PPQ-b PS)/polystyrene (PS) with a single-capillary spinneret. The PPQ-b-PS aggregated domain sizes in the ES fibers prepared from dichloromethane (CH(2) Cl(2) ), chlorobenzene (CB) and chloroform (CHCl(3) ) were 1.5 +/- 0.5, 2.2 +/- 0.4 and 4.1 +/- 1.1 um, respectively. Such variation on the aggregation size led to the red-shifting photoluminescence spectra changing from green, to yellow, and orange. ES fibers prepared from CH(2) Cl(2) exhibited pH-tunable photoluminescence and the emission maximum varied from 532 to 560 nm as the pH value changed from 7 to 1. The study demonstrated that the ES fibers prepared could have potential applications for sensory devices. PMID- 21590839 TI - Immobilization of Candida antarctica lipase B on Polystyrene Nanoparticles. AB - Polystyrene (PS) nanoparticles were prepared via a nanoprecipitation process. The influence of the pH of the buffer solution used during the immobilization process on the loading of Candida antarctica lipase B (Cal-B) and on the hydrolytic activity (hydrolysis of p-nitrophenyl acetate) of the immobilized Cal-B was studied. The pH of the buffer solution has no influence on enzyme loading, while immobilized enzyme activity is very dependent on the pH of adsorption. Cal-B immobilized on PS nanoparticles in buffer solution pH 6.8 performed higher hydrolytic activity than crude enzyme powder and Novozyme 435. PMID- 21590840 TI - A Novel Type of Vesicles Based on Ionic and pi-pi Interactions. AB - Electrostatic self-assembly can be used to form supramolecular vesicles in aqueous solution. Vesicles consist of cationic G8 poly(amidoamine) dendrimers and the trivalent sulfonate dye Ar27. No classical amphiphiles are present but the interplay of electrostatics, pi-pi interaction and geometric factors influences the structure formation. Labeled guest molecules, both small molecules and peptides, can be included inside these vesicles and vesicles imaged by fluorescence techniques. The structure was studied by dynamic and static light scattering, small-angle neutron scattering, confocal laser scanning microscopy, and fluorescence correlation spectroscopy. The study indicates the prospect of constructing functional nanoobjects by the self-assembly of charged molecules in aqueous solution. PMID- 21590841 TI - Self-Assembled Micelles Based on PEG-Polypeptide Hybrid Copolymers for Drug Delivery. AB - A series of amphiphilic poly(L-leucine)-block-poly(ethylene glycol)-block-poly(L leucine) (PLL-PEG-PLL) hybrid triblock copolymers have been synthesized. All the blocks in this system have good biocompatibility and low toxicity. The PLL-PEG PLL copolymers could self-assemble into micelles with PLL blocks as the hydrophobic core and PEG blocks as the hydrophilic shell, which were characterized by FT-IR, (1) H NMR, and transmission electron microscopy analysis. The critical micellar concentration of the copolymer was 95.0 mg . L(-1) . The circular dichroism spectrum shows that the PLL segments adopt a unique alpha helical conformation, which is found to play an important role in controlling the drug release rate. The drug release could be effectively sustained by encapsulation in the micelles. The copolymers may have potential applications in drug delivery. PMID- 21590842 TI - Fluorinated copolymer nanoparticles for multimodal imaging applications. AB - Nanomaterials have emerged as valuable tools in biomedical imaging techniques. Here, the synthesis and characterization of a novel fluorinated nanoparticle with potential applications as an MRI contrast agent is reported. Particles were synthesized using a free radical polymerization technique. Secondary ion mass spectrometry analysis showed that the particles' surface contained fluorinated groups and nitrogen-containing groups. Solid-state NMR spectroscopy suggested the presence of two distinct fluorine resonances, which conforms to the structure of the fluorinated monomer. Ongoing studies aim to evaluate the performance of the nanoparticles as MRI contrast agents both in vitro and in vivo. PMID- 21590843 TI - Macromol. Rapid commun. 11/2010. PMID- 21590844 TI - Advances in the elegance of chemistry in designing dendrimers. AB - Highly functional and monodisperse macromolecules with tailored architecture constitute the key to designing efficient and smart nanomaterials. Dendrimers offer real potential to achieve this goal, and one of the earlier challenges faced by this novel class of polymers has been addressed by the evolution of synthetic methodologies. This review provides an evaluation of the role played by chemistry in taking these macromolecules of academic relevance to practical industrial and biological applications, in a relatively short period. One can now construct dendrimers in a 'made-to-order' fashion, for numerous applications in a variety of disciplines. PMID- 21590845 TI - Interconversion of planar networks and vesicles triggered by temperature. AB - Dumbbell-shaped amphiphiles based on an elongated rod segment can self-assemble into planar networks with in-plane hexagonally ordered pores in aqueous solution. On increasing temperature, the 2D networks change into hollow capsules passing through the closed sheets as an intermediate structure due to a LCST behavior of the oligoether dendritic exterior. The primary driving force for this interesting feature seems to originate from a consequence of the energy balance between hydrophobic interactions of anisotropic rod segments and alkyl chains, and repulsive interactions between dissimilar blocks. This dynamic structural variation triggered by external stimuli in a self-assembling system can provide a useful strategy to create smart supramolecular materials and biomimetic systems. PMID- 21590846 TI - Synthesis of Aromatic Macrocyclic Amphiphiles and their Self-Assembling Behavior in Aqueous Solution. AB - A triblock amphiphilic macrocycle consisting of a macrocyclic aromatic segment, a hydrophilic oligo(ethylene oxide) branch, and a hydrophobic alkyl dendron is successfully synthesized and characterized. The resulting cyclic amphiphile is observed to self-assemble into hollow double-layered capsules in aqueous solution, as confirmed by dynamic light scattering and cryogenic transmission electron microscopy investigations. The capsules are able to encapsulate hydrophobic guest molecules through aromatic interactions with high stability. PMID- 21590847 TI - Photoinduced microphase separation in block copolymers: exploring shape incompatibility of mesogenic side groups. AB - Photoinduced microphase separation in block copolymers (BCP) was achieved for the first time, using a rationally designed diblock copolymer composed of two side chain liquid crystalline polymers (SCLCP). The miscibility of the two blocks was promoted by the miscibility between the two types of mesognic side groups, while upon UV exposure inducing the trans-cis isomerization of azobenzene mesogens on one SCLCP, the shape incompatibility of bent cis isomers with an ordered liquid crystalline phase drove the separation of the two blocks resulting in a microphase separated morphology. This result shows the perspective of using light to process and organize BCP morphology and related nanostructures in a lithography-free manner. PMID- 21590848 TI - Facile Synthesis of Glycopolypeptides by Combination of Ring-Opening Polymerization of an Alkyne-Substituted N-carboxyanhydride and Click "Glycosylation". AB - Synthetic glycopolypeptides have attracted much interest for application in biomedical field as they are structural mimics to the natural glycopeptides or glycoproteins. However, the synthesis methods toward glycopolypeptides are still few or less efficient. Herein, we present a facile route to preparation of glycopolypeptides with highly effective "glycosylation" by click postpolymerization modification. First, an alkyne-substituted N-carboxyanhydride (NCA) monomer was synthesized and subsequently polymerized to afford the polypeptide with "clickable" alkyne pendants. The alkyne-functionalized polypeptide was then "glycosylated" by click reaction of different sugar azides to the alkyne pendants with high efficiency. All the obtained glycopolypeptides were soluble and preferred alpha-helix conformation in water. Primary studies on the obtained glycopolypeptides binding with Con A lectin were assessed by turbidimetric assay. The more quantitive studies of the interactions between lectin proteins and the synthetic glycopolypeptides, and the application of these materials as the multivalent ligands are in progress. PMID- 21590849 TI - PEO-Covered Nanoparticles by Emulsion Inversion Point (EIP) Method. AB - This study reports the first PEO-coated polymer nanoparticles synthesis by miniemulsion polymerization of nano-emulsions prepared by the low-energy emulsification method called EIP. The surfactant used was Brij 98, a PEO based non ionic commercial surfactant. The partial phase diagram of the system water/Brij 98/styrene was first determined. The Emulsion Inversion Point technique was then used on the water/Brij 98/styrene system to the formation of styrene-in-water nano-emulsions. After miniemulsion polymerization, particle sizes as low as 36 nm were obtained. To the best of our knowledge, this method had not been used for polymerizable system up to now. PMID- 21590850 TI - Combinatorial mapping of substrate step edge effects on diblock copolymer thin film morphology and orientation. AB - We have used a combinatorial gradient technique to map precisely how the terrace structure and microdomain lattice alignment in a thin film of a sphere-forming diblock copolymer are affected by both the thickness of the copolymer film and the height of a series of parallel step edges fabricated on the substrate. We find that for film thicknesses slightly incommensurate with integer numbers of sphere layers, the step edges act as nucleation sites for regions with one more or one fewer layers of spheres. We also find that for our system, the hexagonal lattice formed by a single layer of spheres on the low side of a step edge is aligned along the direction of the step edge only where the film on the high side is sufficiently thin to support only a wetting layer of copolymer material. This work will guide the tuning of film thickness and step height in future studies and applications of graphoepitaxy in block copolymer films. PMID- 21590851 TI - Fabrication of patterned images in photochromic organic microfibers. AB - Photochromic spiropyran molecules were embedded in electrospun polymer microfibers. Electrospinning of a clear viscous chloroform solution containing a spiropyran and a matrix polymer, such as polystyrene and polyethylene oxide, affords polymer microfibers that are photoswitchable. Photomasked, 365 nm UV irradiation of the microfibers results in the generation of patterned color images owing to the selective transformation of the spiropyran molecules from their ring-closed SP to ring-opened MC form. The UV-irradiated areas display brilliant red fluorescence, which changes to green fluorescence upon prolonged irradiation. PMID- 21590853 TI - Macromol. Rapid commun. 12/2010. PMID- 21590852 TI - Micelles-encapsulated microcapsules for sequential loading of hydrophobic and water-soluble drugs. AB - Layer-by-layer (LbL) assembly was conducted on CaCO(3) microparticles pre-doped with polystyrene-block-poly(acrylic acid) (PS-b-PAA) micelles, and resulted in micelles encapsulation in the microcapsules after core removal. Distribution of the micelles in the templates and capsules was characterized by transmission electron microscopy and confocal laser scanning microscopy. The micelles inside the capsules connected with each other to form a chain and network-like structure with a higher density near the capsule walls. The hydrophobic PS cores were then able to load small uncharged hydrophobic drugs while the negatively charged PAA corona could induce spontaneous deposition of water-soluble positively charged drugs such as doxorubicin. PMID- 21590854 TI - Combining living anionic polymerization with branching reactions in an iterative fashion to design branched polymers. AB - This paper reviews the precise synthesis of many-armed and multi-compositional star-branched polymers, exact graft (co)polymers, and structurally well-defined dendrimer-like star-branched polymers, which are synthetically difficult, by a commonly-featured iterative methodology combining living anionic polymerization with branched reactions to design branched polymers. The methodology basically involves only two synthetic steps; (a) preparation of a polymeric building block corresponding to each branched polymer and (b) connection of the resulting building unit to another unit. The synthetic steps were repeated in a stepwise fashion several times to successively synthesize a series of well-defined target branched polymers. PMID- 21590855 TI - Homogeneous Detection of Trypsin in Protein Mixtures Based on Fluorescence Resonance Energy Transfer between Anionic Conjugated Polymer and Fluorescent Probe. AB - Herein we describe a novel and simple conjugated polymer-fluorescent probe based platform for trypsin detection from protein mixtures in homogeneous solution. This platform takes advantage of specific interaction between the probe and the active site of trypsin and the electrostatic interaction between the polymer and the protein to mediate energy transfer between the polymer and the probe. This method does not require any separation steps, which should facilitate high throughput protease screening and drug discovery. PMID- 21590856 TI - Fabrication of diverse microcapsule arrays of high density and good stability. AB - Microcapsule arrays attract a lot of interest due to their potential applications in sensing technology. A strategy for fabricating diverse microcapsule arrays through covalent linking is reported here. The self-assembly of microcapsules was directed by using a poly(allylamine hydrochloride) (PAH)-patterned template, which was created via microcontact printing. The microcapsules with PAH as the outermost layer were treated with glutaraldehyde and then covalently immobilized on the PAH regions, resulting in ordered microcapsule arrays. The arrays had a high density of capsules and the aggregate number in a pattern could be well controlled by adjusting the area of the PAH pattern. A single microcapsule array could be obtained if the diameter of the PAH region was smaller than that of the microcapsules. These covalently assembled arrays could survive through successive incubation in solutions of high ionic strength and extreme pHs. Such good stability ensures further treatments, such as chemical reactions and loading of functional substances. PMID- 21590857 TI - Block copolymer micelles with near infrared metal phthalocyanine dyes for laser induced writing. AB - A route has been developed to disperse metal-containing phthalocyanine dyes in a non-polar medium based on amphiphilic block copolymer micelles of poly[styrene block-(4-vinylpyridine)] (PS-b-P4VP) and poly[styrene-block-(acrylic acid)] (PS-b PAA) copolymers. Polar P4VP and PAA efficiently encapsulate cobalt(II), manganese(II), and nickel(II) phthalocyanine dyes by axial coordination of nitrogen and u-oxo bridged dimerization with the transition metals, respectively. Good dispersion of the dyes is confirmed by the linear enhancement of Q-bands in UV-vis absorption spectra with dye concentration. A thin monolayered PS-b-P4VP micelle film that contained a nickel(II) phthalocyanine dye which efficiently adsorbs a laser beam on a localized area to generate a local heat higher than the glass transition temperatures of both blocks. One-dimensional laser writing on the dye-containing film allows the fabrication of a few submicrometer wide line patterns in which the self-assembled nanostructure of the block copolymer is modified by the directional heat arising from laser scanning. PMID- 21590858 TI - High-density glycosylation of polymer membrane surfaces by click chemistry for carbohydrate-protein recognition. AB - To biologically mimic the carbohydrate-protein interactions in artificial systems, one of the challenges is to construct a glycosylated surface with a high glycosyl density to yield a notable 'glycoside cluster effect'. A novel strategy is presented for high density glycosylation of the surface of a microporous poly(propylene) membrane (MPPM) by click chemistry. It is promising that the surface glycosyl density can be well controlled over a wide range and the maximum value is over 10 umol . cm(-2) . The recognition capability of these glycosylated MPPMs to lectins indicates the occurrence of the 'glycoside cluster effect' when the glycosyl density on the membrane surface exceeds 0.20 umol . cm(-2) . PMID- 21590859 TI - Copolymerization of ethylene with sterically hindered 3,3-dimethyl-1-butene using a chain-walking pd-diimine catalyst. AB - In this Communication, the copolymerization of ethylene with a sterically hindered alpha-olefin comonomer, gamma-trisubstituted 3,3-dimethyl-1-butene (DMB), using a chain-walking Pd-diimine catalyst, [(ArN?C(Me)?(Me)C?NAr)Pd(CH(3) )(N?CMe)]SbF(6) (Ar?2,6-(iPr)(2) C(6) H(3) ) (1) is reported. In spite of its high steric bulkiness in the close proximity of the double bond, appreciable DMB incorporations (up to 3 mol-%) are successfully achieved in the copolymers. The chain microstructure of the copolymers is elucidated, and the effect of DMB incorporation on polymer topology and thermal properties are examined. This work thus demonstrates the high capability of the Pd-diimine catalyst in incorporating sterically encumbered alpha-olefins. PMID- 21590860 TI - Synthesis of new pyridazine-based monomers and related polymers for photovoltaic applications. AB - New aromatic compounds with a pyridazine core have been synthesized. Four electron-withdrawing monomers have been easily prepared from simple condensation reactions and ring closure procedures. Optimized HOMO, LUMO, and bandgap energy levels have been obtained. The resulting conjugated polymers have been tested in organic solar cells. First studies have revealed power conversion efficiencies up to 0.5% for an active area of 1.0 cm(2) . PMID- 21590861 TI - Ultrafast Responsive Poly- (N-isopropylacrylamide) Gel Produced by Cryostructuring of Self-crosslinkable Polymer Microgels. AB - A macroporous material composed of closely aggregated particles was prepared by cryo-structuration of N-isopropylacrylamide-co-N-hydroxymethylacrylamide (NIPA-co HMAm) particle suspensions. The formed structure was maintained by the formation of covalent bonds through self-crosslinking between the particles while the system was in a semi-frozen state thus avoiding the need to freeze-dry the sample. This resulted in macroporous structure composed of closely aggregated thermoresponsive particles which exhibit an ultrafast temperature response. The response rate can be attributed both to the macroporous structure as well as the fast responsive properties of the individual particles. PMID- 21590862 TI - Orientation and Dynamics of ZnO Nanorod Liquid Crystals in Electric Fields. AB - ZnO nanorod polymer hybrids (i.e., ZnO nanorods coated with a block copolymer with a short anchor block (dopamine) and a longer solubilizing block of polystyrene (PS)) form liquid crystalline (LC) phases if they are dispersed at high concentration e.g., in a PS oligomer matrix. Due to the high mobility of the low T(g) -matrix the nanorod polymer hybrids show a switching behavior under an applied AC electric field. Hence, the orientation of the nanorod mesogens can be changed from planar (parallel to the substrate) to homeotropic (perpendicular) in full analogy to the switching of low molecular liquid crystals in an electric field. Dielectric measurements show that such a switching is mainly due to the cooperative LC behavior, because the rods themselves exhibit only a very small effective dipole moment. The process can be investigated by polarizing microscopy. SEM images show the orientations of the individual nanorods, which correspond to the Fredericks transition well known for liquid crystals aligned in an electric field. This was the first time such a transition could be visualized by electron microscopy due to the large nanorod mesogens. The observation is interesting to orient nanorods perpendicular to an electrode and can help to improve optoelectronic devices. PMID- 21590863 TI - Macromol. Rapid commun. 13/2010. PMID- 21590864 TI - Macromolecular synthetic biomaterials for delivery of therapeutics. PMID- 21590865 TI - pH-Responsive Polymers as Gene Carriers. AB - Despite the immense potential of non-viral delivery system in gene therapy its application has been impaired greatly by various impediments having contrasting traits. Therefore it is an absolute necessity to develop some non-viral vectors which are endowed with special characteristics to act differently in intracellular as well as extracellular compartments to surmount these inter conflicting hurdles. Such smart polymers should serve some specific purposes by adjusting their structural or functional traits under the influence of stimuli such as temperature, light, salt concentration or pH. Among all these stimuli responsive polymers pH-responsive polymers have attracted major attention and great impetus has been directed towards utilizing the subtle yet significant change in pH value within the cellular compartments. This review is intended to provide a comprehensive account of the development of pH-responsive polymeric vectors based on their structural features and consequent functional attributes to achieve efficient transfection. The underlying modes of actions relating to structure and differential pH environment have also been discussed in this review. PMID- 21590866 TI - Intracellular Protein Delivery Systems Formed by Noncovalent Bonding Interactions between Amphipathic Peptide Carriers and Protein Cargos. AB - Successful molecular therapy using protein-based therapeutic agents for intracellular targets depends on the development of efficient and safe protein delivery systems that are able to overcome the problem of poor permeability of cell membrane to proteins. Here, we summarize recent studies elucidating how one particular class of peptide-based carriers, amphipathic peptide, has been designed and utilized for intracellular protein delivery in a simple yet effective manner. The unique feature of these delivery systems lies in the noncovalent binding of amphipathic peptides to protein cargos, mainly through hydrophobic interactions. At least five different types of amphipathic peptides have been developed and demonstrated to be able to deliver various biologically active proteins into a variety of cell types without the use of chemical conjugation. In view of their efficiency and presumably low toxicity, we anticipate that amphipathic peptides will continue to be developed as powerful carriers for intracellular delivery of protein therapeutics. PMID- 21590867 TI - Brush-Like Amphoteric Poly[isobutylene-alt-(maleic acid)-graft oligoethyleneamine)]/DNA Complexes for Efficient Gene Transfection. AB - Synthetic gene delivery vectors, especially cationic polymers have attracted enormous attention in recent decades because of their ease of manufacture, targettability, and scaling up. However, certain issues such as high cytotoxicity and low transfection efficiency problems have hampered the advance of nonviral gene delivery. In this study, we designed and synthesized brush-like amphoteric poly[isobutylene-alt-(maleic acid)-graft-oligoethyleneamine] capable of mediating highly efficient gene transfection. The polymers are composed of multiple pendant oligoethyleneimine molecules with alternating carboxylic acid moiety grafted onto poly[isobutylene-alt-(maleic anhydride)]. The polymer formed from pentaethylenehexamine {i.e., poly[isobutylene-alt-(maleic acid)-graft pentaethylenehexamine)]} was able to condense DNA efficiently into nanoparticles of size around 200 nm with positive zeta potential of about 28-30 mV despite its amphoteric nature. Luciferase expression level and percentage of GFP expressing cells induced by this polymer was higher than those mediated with polyethyleneimine (branched, $?overline M _{?rm w} $ 25 kDa) by at least one order of magnitude at their optimal N/P ratios on HEK293, HepG2, and 4T1 cells. In vitro cytotoxicity testing revealed that the polymer/DNA complexes were less cytotoxic than those of PEI, and the viability of the cells after being incubated with the polymer/DNA complexes at the optimal N/P ratios was higher than 85%. This polymer can be a promising gene delivery carrier for gene therapy. PMID- 21590868 TI - Injectable Biodegradable Poly(ethylene glycol)/RGD Peptide Hybrid Hydrogels for in vitro Chondrogenesis of Human Mesenchymal Stem Cells. AB - In this study, an injectable and biodegradable poly(ethylene glycol) (PEG)/arginine-glycine-aspartic (RGD) peptide hybrid hydrogel has been synthesized and used as a biomimetic scaffold for encapsulation of human mesenchymal stem cells (hMSCs). Tetrahydroxyl PEG was functionalized with acrylate, and then reacted with thiol-containing peptide (RGD). Gelation occurred within 30 min with the addition of cells and PEG-dithiol via Michael addition. The hydrogels synthesized with a peptide concentration of 1.0-5.0 mM achieved significantly greater cell viability when compared to the hydrogels without the RGD peptide. However, the effect of RGD on chondrogenesis was found to be dose dependent. Immunohistology studies demonstrated that hMSCs encapsulated in the hydrogel matrix with 1.0 mM RGD and TGF-beta3 showed enhanced positive staining for aggrecan and type II collagen as compared to that with 5.0 mM RGD and unmodified PEG hydrogels. RT-PCR results further revealed that the cells in hydrogels with 1 mM RGD expressed significantly higher levels of type II collagen than those in PEG hydogels without RGD peptide. These findings have demonstrated that the PEG-RGD hydrogels can be a promising scaffold to deliver hMSCs for cartilage repair. PMID- 21590869 TI - Efficient Liposomal Nanocarrier-mediated Oligodeoxynucleotide Delivery Involving Dual Use of a Cell-Penetrating Peptide as a Packaging and Intracellular Delivery Agent. AB - The effective use of oligonucleotide therapeutics, such as antisense oligodeoxynucleotides (ODNs) and small interfering RNAs (siRNAs), requires efficient delivery systems capable of intracellular penetration. Cell-penetrating peptides (CPPs), including arginine-rich peptides, have been extensively studied as tools for enhancing intracellular uptake efficiency of various bioactive molecules, including nanoparticles and liposomes. CPPs also have an ability to form tight complexes with nucleic acids, such as ODNs and siRNAs, making CPPs effective as packaging agents. Here, we constructed a CPP-modified liposome loaded with complexes of nona-arginine (9R) and NF-kappaB decoy ODNs, and evaluated intracellular uptake and anticancer activity in vitro. We found that 9R/ODN complexes were efficiently loaded into liposomes that were effectively internalized into U87MG glioblastoma cells and sensitized cells to the effects of paclitaxel. To the best of our knowledge, this is the first report describing the dual use of 9R CPP as a cell penetrating and a complexing agent within a single nanoparticle. PMID- 21590870 TI - Folate-Conjugated Polymer Micelles with pH-Triggered Drug Release Properties. AB - Folate has been applied as a targeting moiety for various anticancer drug delivery agents to avoid non-specific attack of normal tissues as well as to increase cellular uptake at the target tumor cells. Polymer micelles made of poly[(D,L-lactide)-co-glycolide)]-poly(ethylene glycol)-folate (PLGA-PEG-FOL) was fabricated as a tumor targeting carrier for encapsulating the anticancer drug doxorubicin. To accelerate the drug release in the endosome after folate-mediated cellular uptake, pH-sensitive poly(beta-amino ester)-PEG-FOL (PAE-PEG-FOL) was added together with PLGA-PEG-FOL to form mixed micelles. The results showed that the drug release can be triggered at different pH due to the ionization of PAE. The IC(50) of PLGA-PEG-FOL micelles is 0.46 * 10(-6) M. With 20% PAE in the mixed micelles (20:80 mixed micelles), the IC(50) decreases to 0.34 * 10(-6) M, which is comparable to that of pure PAE-PEG-FOL micelles at pH 7.4. As a result of the pH sensitivity, the PAE-PEG-FOL micelles are not stable at pH 6.5 or lower, and the drug may be released from the micelles into the extracellular environment before uptake by the cells. The 20:80 mixed micelles are relatively stable at this condition. As a result, the micelles retain more drug in the micelles for a higher degree of cellular uptake by folate receptor-mediated endocytosis, and exhibit higher cytotoxicity. PMID- 21590871 TI - Novel triblock oligopeptides as efficient nonviral vectors: characterisation and further insights. AB - The delivery of immunomodulatory genes into the cornea prior to transplantation is one promising strategy to improve graft survival rates. We recently reported a class of novel triblock oligopeptides that could mediate efficient gene transfer into corneal endothelial cells. Now these peptides are characterised further and it is show that they lack distinct secondary structures. Peptide complexes are also demonstrated to be weakly haemolytic and transfection efficiency is shown to be sensitive to several experimental conditions. SEM and FRET confocal images are used to study the particle morphology and to show that they condense their DNA cargo well. PMID- 21590872 TI - Synthesis of guanidinium-modified hyaluronic Acid hydrogel. AB - In this report, a new guanidinylating reagent is presented, which was developed without any protection/deprotection strategy and was successfully employed for linking to hyaluronan in aqueous solution. The dually functionalised HA biopolymer bearing guanidinium and hydrazide groups was synthesised to form hydrogel in less than a minute when mixed with aldehyde-modified HA. This hydrogel exhibited higher storage modulus with enhanced stability in PBS when compared to the non-guanidine-containing gel. The gel shift assay showed that this biopolymer formed a stable complex with DNA as well as efficient gene transfection to cells that express HA-receptor CD44. The toxicity studies of this polymer with fibroblast cells revealed that the cells were almost 80% viable after 4 d of incubation at high HA concentration (2.5 * 10(-3) M). PMID- 21590873 TI - pDNA/poly(L-lysine) Polyplexes Functionalized with a pH-Sensitive Charge Conversional Poly(aspartamide) Derivative for Controlled Gene Delivery to Human Umbilical Vein Endothelial Cells. AB - An efficient endosome-escaping function was integrated into the polyplex of plasmid DNA (pDNA) with poly(L-lysine) (PLys) to improve its gene transfection efficiency through electrostatic coating with charge-conversional polymer (CCP). CCP showed charge-conversional function responding to endosomal pH, leading to the release of pDNA/PLys polyplex into the cytoplasm. The cells took up the intact CCP-integrated ternary polyplex, which exerted appreciably higher transfection efficiency with lower cytotoxicity than pDNA/PLys polyplex against human umbilical vein endothelial cells (HUVECs). This is consistent with the facilitated endosomal escape of the CCP-integrated ternary polyplex compared to the pDNA/PLys polyplex as directly observed with confocal laser-scanning microscopy. PMID- 21590874 TI - Delivery of anticancer drugs using polymeric micelles stabilized by hydrogen bonding urea groups. AB - Polymeric micelles comprising a hydrogen-bonding core were formed from block copolymers with pendant urea groups and explored as drug delivery vehicles. The amphiphilic block copolymers were synthesized by organocatalytic ring opening polymerization (ROP) of urea-functionalized cyclic carbonates from a poly(ethylene glycol) macroinitiator. The urea functionality was incorporated because its ability to increase the hydrophobic core's affinity toward polar organic compounds through intermolecular hydrogen bonding. Doxorubicin (DOX), a lipophilic anticancer drug with hydrogen-bonding functionalities, was systematically incorporated into the micelle's hydrophobic interior via hydrogen bonding to the functionalized monomers. Micelles employing urea groups were found to more efficiently interact with DOX thus allowing increased drug loading capacity while maintaining a desirable micellular size. More importantly, while DOX-loaded micelles were shown to kill HepG2 human liver carcinoma cell lines efficiently, all of the polymers were non-cytotoxic. PMID- 21590875 TI - Formation and degradation of biodegradable triple-layered microparticles. AB - In this work, we report how biodegradable triple-layered microparticles can be fabricated through a simple, reliable, and economical one-step solvent evaporation technique. Characterization of triple-layered PLGA (shell)/PLLA (middle layer)/EVA (core) microparticles was conducted and their formation mechanism was described. Subsequently, in vitro hydrolytic degradation of these microparticles was investigated. It was found that the PLGA shell degraded rapidly leaving behind double-walled microparticles of PLLA/EVA after 40 days. The middle PLLA layer degraded more rapidly than expected because of the migration of PLGA oligomers that created a hydrophilic and acidic microenvironment in the PLLA layer. These degradation results therefore provide important insights into how triple-layered microparticles degrade, and how their degradation characteristics affect the drug releasing properties of these novel microparticles. PMID- 21590876 TI - Core-shell-corona micelle stabilized by reversible cross-linkage for intracellular drug delivery. AB - Reversibly cross-linked core-shell-corona micelles based on a triblock copolymer composed of poly(aliphatic ester), polyphosphoester, and poly(ethylene glycol) are reported. The triblock copolymer is synthesized through consecutive ring opening polymerization of epsilon-caprolactone and 2,4-dinitrophenylthioethyl ethylene phosphate, followed by conjugation of poly(ethylene glycol). After deprotection under mild conditions, the amphiphilic polymer forms core-shell corona micelles with free thiols in the shell. Cross-linking of the micelles within the shell reduces their critical micellization concentration and enhances their stability against severe conditions. The redox-sensitive cross-linkage allows the facilitated release of entrapped anticancer drugs in the cytoplasm in response to the intracellular reductive environment. With enhanced stability during circulation after administration, and accelerated intracellular drug release at the target site, the biocompatible and biodegradable shell-cross linked polymeric micelle is promising as a drug vehicle for cancer chemotherapy. PMID- 21590877 TI - Photocrosslinked DNA nanospheres for drug delivery. AB - DNA has been employed as both a genetic and a generic material. X-shaped DNA (X DNA) in particular has four branched arms, providing multivalent functionalities that can allow for simultaneous multiple crosslinking. Here we report the synthesis of four acrylate-functionalized X-DNA monomers that can be further photocrosslinked to form monodisperse and tunable DNA nanospheres. In particular, the size and surface charge of these nanospheres were precisely controlled in a linear fashion, simply by tuning the monomer concentration in the reaction. The morphology and surface properties of the nanospheres were characterized using FT IR, HPLC, TEM, AFM, zeta potential, and DLS analysis. In vitro studies in mammalian cells revealed that these DNA nanospheres demonstrated significant efficacy in the delivery of doxorubicin. These results highlight the potential of using DNA as material building blocks to design novel nanocarriers with properties tailored for the delivery of drugs in general and DNA/RNA in particular. PMID- 21590878 TI - Design and evaluation of Peptide amphiphiles with different hydrophobic blocks for simultaneous delivery of drugs and genes. AB - In this study, peptides with six different compositions were designed and synthesized to study the effect of the structure of the hydrophobic block in triblock oligopeptide amphiphiles ((A(m) X)(n) H(5) K(15) ) on self-assembly properties, drug loading capacity and gene expression efficiency. The peptides were synthesized using a standard Fmoc-solid phase peptide synthesis protocol, which are A(12) H(5) K(15) , A(11) FH(5) K(15) , (A(5) F)(2) H(5) K(15) , (A(3) F)(3) H(5) K(15) , (AF)(6) H(5) K(15) and (AL)(6) H(5) K(15) . A(12) H(5) K(15) , A(11) FH(5) K(15) , (A(5) F)(2) H(5) K(15) and (A(3) F)(3) H(5) K(15) , formed micelles at concentrations above 200 mg . L(-1) with large size or aggregation. However, (AF)(6) H(5) K(15) and (AL)(6) H(5) K(15) had CMC values of 42 and 49 mg . L(-1) respectively, and the resulting micelles were much smaller in size as compared to the other peptide designs (108 and 233 nm for (AF)(6) H(5) K(15) and (AL)(6) H(5) K(15) , respectively). In addition, both peptides were able to load paclitaxel (PTX) into nanoparticles although PTX-loaded (AF)(6) H(5) K(15) nanoparticles had a smaller size (278 versus 295 nm, respectively). Encapsulation efficiency of PTX with (AF)(6) H(5) K(15) nanoparticles was 74%. Gene transfection studies showed that luciferase expression level induced by (AF)(6) H(5) K(15) micelles in HepG2 cell line was much higher than that mediated by (AL)(6) H(5) K(15) micelles at their respective optimal N/P ratios (3.2 * 10(8) versus 3.9 * 10(7) RLU . mg proteins(-1) ). Therefore, simultaneous delivery of PTX and luciferase-encoding plasmid was conducted using (AF)(6) H(5) K(15) micelles against HepG2 cells, and the results demonstrated that the co-delivery of PTX at 0.01 mg . L(-1) further increased luciferase expression level from 3.2 * 10(8) to 8.0 * 10(8) RLU . mg proteins(-1) at the optimal N/P ratio (i.e., 18). In summary, it is important to optimize the hydrophobic block of the oligopeptide amphiphiles in order to achieve desired properties for co-delivery of drugs and genes. PMID- 21590879 TI - Macromol. Rapid commun. 2/2010. PMID- 21590881 TI - Multifunctional Micro- and Nanoparticles - Quo vadis? PMID- 21590880 TI - Macromol. Rapid commun. 2/2010. PMID- 21590882 TI - Droplet microfluidics for fabrication of non-spherical particles. AB - We describe new developments for controlled fabrication of monodisperse non spherical particles using droplet microfluidics. The high degree of control afforded by microfluidic technologies enables generation of single and multiple emulsion droplets. We show that these droplets can be transformed to non spherical particles through further simple, spontaneous processing steps, including arrested coalescence, asymmetric polymer solidification, polymerization in microfluidic flow, and evaporation-driven clustering. These versatile and scalable microfluidic approaches can be used for producing large quantities of non-spherical particles that are monodisperse in both size and shape; these have great potential for commercial applications. PMID- 21590883 TI - Acorn-shape polymeric nano-colloids: synthesis and self-assembled films. AB - These studies show for the first time that the synthesis of two distinct phase separated copolymers within one colloidal particle, i.e., poly(methyl methacrylate) (PMMA)/n-butylacrylate (nBA) and poly(nBA)/pentafluorostyrene (p PFS) phases, results in unique acorn-shaped morphologies and are capable of coalescence. Spectroscopic and morphological analysis combined with contact angle measurements as well as thermodynamic modeling reveal that in an effort to create stable heterogeneous two-phase particle morphologies it is essential to provide desirable interfacial energetic conditions during polymerization and to utilise monomers that have a similar glass transition temperature (T(g) ). Such colloidal particles are stable and are able to self-assemble during coalescence, depending upon the surface energy of a substrate. When a particle monolayer coalesces on a high surface tension substrate, the p-PFS phase expresses itself near the film air interface, whereas for low surface energy substrates, the p-PFS phase dominates the film-substrate interfacial regions. PMID- 21590884 TI - Squishy non-spherical hydrogel microparticles. AB - Recent advances in the synthesis of polymeric colloids have opened the doors to new advanced materials. There is strong interest in using these new techniques to produce particles that mimic and/or interact with biological systems. An important characteristic of biological systems that has not yet been exploited in synthetic polymeric colloids is their wide range of deformability. A canonical example of this is the human red blood cell (RBC) which exhibits extreme reversible deformability under flow. Here we report the synthesis of soft polymeric colloids with sizes and shapes that mimic those of the RBC. Additionally, we demonstrate that the mechanical flexibility of the colloids can be reproducibly varied over a large range resulting in RBC-like deformability under physiological flow conditions. These materials have the potential to impact the interaction between biological and synthetic systems. PMID- 21590885 TI - Polymer Vesicles with a Red Cell-like Surface Charge: Microvascular Imaging and in vivo Tracking with Near-Infrared Fluorescence. AB - Polymersomes are block copolymer-based vesicles whose long circulation times or "stealth" in vivo coupled with the loading and controlled release of drugs, siRNA, and other compounds has made them attractive for delivery. A brushy corona of non-ionic polyethylene glycol (PEG) likely contributes stealth, but red blood cells (RBCs) possess a negatively charged glycocalyx and circulate much longer. Polyanionic block copolymers were therefore mixed into polymersomes which were also labeled with a near IR fluorophore to quantify biodistribution in live mice and excised organs. Charge shifts tissue distribution, and high resolution imaging of vesicles in blood capillaries further shows that organ cultures can provide deeper insight into microscale transport within tissue microenvironments. PMID- 21590886 TI - Endocytosis and Intracellular Distribution of PLGA Particles in Endothelial Cells: Effect of Particle Geometry. AB - Targeting, internalization, and intracellular trafficking of carriers are key processes in drug delivery to endothelial cells. We synthesized PLGA particles with spherical and elliptical disk geometries and investigated the effect of particle shape on rate of particle endocytosis and their intracellular distribution in endothelial cells. Elliptical disks (aspect ratio of 5) were endocytosed at a slower rate compared to spheres (1.8 um diameter) of the same volume. However, both particles were eventually internalized and accumulated around the nucleus. We quantified the orientation of elliptical disks and found that disks, on average, oriented tangentially with the nuclear membrane. The non spherical geometry of elliptical disks brings unique aspects to the kinetics and equilibrium distribution of these particles in cells. PMID- 21590887 TI - Fabrication, assembly, and application of patchy particles. AB - The site-specific engineering of colloidal surfaces has provided a powerful approach to pushing the boundaries of today's materials research. The resulting surface-anisotropic and patchy particles have become the center of vital research areas, ranging from the need for large-scale fabrication techniques to exploring new applications of these materials. This Review summarizes patchy particle fabrication techniques, including but not limited to particle and nanosphere lithography and glancing-angle deposition. The variety of existing patchy particle fabrication techniques is revealed and the need for a scalable approach to high-volume patchy particle production is identified. Ongoing modeling efforts describing patchy particle interactions and properties are reviewed as potential predictive tools. Research endeavors that deal with the directed assembly of patchy particles in electric and magnetic fields, as well as with supraparticular assembly through chemical interactions, are discussed. The Review is concluded with a note on the future application of patchy particles as phoretic motors. PMID- 21590888 TI - Polymer single crystal templated janus nanoparticles. AB - Top-selective surface modification has been widely used for the synthesis of Janus nanoparticles (NPs). Herein we demonstrate that polymer single crystals can serve as generic substrates to immobilize NPs and the resultant NPs are Janus in nature. This technique is generic because various NPs as well as polymer single crystal substrates can be used. Single crystals of poly(ethylene oxide), polycaprolactone, and polyethylene-block-poly(ethylene oxide) have been successfully used to immobilize gold, magnetic, and semiconducting NPs. Subsequent dissolution of the single crystals led to various types of Janus NPs and NP clusters with different polymer brushes. PMID- 21590889 TI - Compartmentalization of Gold Nanocrystals in Polymer Microparticles using Electrohydrodynamic Co-Jetting. AB - Polymer particles with micro- and nanoscale anisotropy have received increasing interest for their ability to simultaneously present different physical- and chemical properties. In this communication, we demonstrate that gold nanocrystals (NCs) can be selectively incorporated into one compartment of anisotropic polymer particles. Stable bicompartmental particles were prepared via electrohydrodynamic co-jetting of aqueous nanoparticle suspensions followed by thermal cross-linking. Bicompartmental particle populations with different NC densities were obtained by varying the NC concentration in the jetting suspension. While NC-loaded polymer particles showed different optical properties depending on the NC density, they still maintained discrete interfaces between two compartments. Moreover, the fraction of the bicompartmental particles was higher than 98% based on flow cytometry. This study delineates a new approach for preparation of inorganic/organic composite particles with precisely engineered, anisotropic nanoparticle distributions and may contribute to further developments in emerging scientific areas, such as smart materials or particle-based diagnostics. PMID- 21590890 TI - Absorption Properties of Microgel-PVP Composite Nanofibers Made by Electrospinning. AB - The absorption and desorption of water, as well as the retention of certain molecules within a polymeric network, have special interest in a wide range of applications, including drug delivery, biosensing, chemical separation, catalysis, and optics. In this communication, we report the encapsulation by electrospinning of poly(N-isopropylacrylamide)-based monodisperse microgels within microfibers of crosslinked poly(vinylpyrrolidone), which is a hydrogel itself, up to concentrations of 40 wt.-% of the microgels. We present an optical characterization of these composite microfibers and quantify their absorbance, which can be as large as 17 times their de-swollen weight. Interestingly, this absorbance can be tuned by controlling the values of the temperature and the pH of the medium. PMID- 21590891 TI - Anisotropic particle synthesis inside droplet templates on superhydrophobic surfaces. AB - We demonstrate how droplet templates dispensed on superhydrophobic substrates can be used to fabricate both shape-anisotropic ("doughnut") and composition anisotropic ("patchy magnetic") supraparticles. The macroscopic shape of the closely-packed particle assemblies is guided by the droplet meniscus. Aqueous droplets of monodisperse microsphere suspensions dispensed on the substrates initially acquire near-spherical shape due to a high contact angle. During the solvent evaporation, however, silica suspension droplets undergo shape transitions (concaving) guiding the structure of the final assemblies into doughnut supraparticles. Composition anisotropy is achieved by drying a droplet containing a mixed suspension of latex and magnetic nanoparticles, while exposing it to magnetic field gradients. Depending on the pattern of the magnetic fields, the magnetic nanoparticles segregate into single, bilateral, or trilateral, patched spherical supraparticles. The physical effects leading to the development of anisotropy are discussed. Unlike the conventional wet self-assembly (WSA) methods where the final structures need to be extracted from the liquid environment, this efficient one-step procedure produces ready to use "dry" supraparticles. PMID- 21590892 TI - Toward Assembly of Non-close-packed Colloidal Structures from Anisotropic Pentamer Particles. AB - Particles combining multiple anisotropy dimensions offer possibilities for self assembly that have not been extensively explored to date. The scope for assembly of microparticles in which the anisotropy dimensions of internal bond angle and chemical ordering have been varied is investigated. Colloidal assemblies with interesting open (i.e., non-close-packed) structures can be assembled from these building blocks. The structure of the assemblies formed is linked to the building block anisotropy because the steric constraints introduced induce deviations from close packing. Key challenges addressed in pursuit of these structures are parallelization of microfluidic synthesis methods, simulation to efficiently search the available anisotropy space, and methods that characterize the properties of the resulting assemblies. This combined program of synthesis, simulation, assembly, and characterization may be applied to develop design rules that guide efforts to fabricate microparticle building blocks and their assemblies. PMID- 21590893 TI - Multifunctional nanoscale platforms for targeting of the cancer cell immortality spectrum. AB - In the post-genomic era, "omics" platforms and cancer systems biology are greatly advancing our knowledge of the molecular and cellular underpinnings of cancer. In this article, we begin by outlining the factors governing the development of cancer (tumorigenesis) and use this framework to motivate the need for systems approaches to cancer diagnostics and therapeutics. We review recent efforts to tap into the remarkable potential of nanotechnology for (i) systems-surveillance (or "sensing") of the molecular signatures of tumorigenesis, and (ii) spatiotemporally-regulated delivery (or "targeting") of combination therapeutics to cancer cells. Specifically, we highlight the salient role of polymeric biomaterials and describe the physicochemical characteristics that render them attractive for the design of such nanoscale platforms. We conclude with discussions on the emerging role of macromolecular biophysics and computational nanotechnology in engineering spatiotemporally-regulated anti-cancer systems. PMID- 21590894 TI - Ion-selective optodes measure extracellular potassium flux in excitable cells. AB - Optodes have been used for detection of ionic concentrations and fluxes for several years. However, their uses in biomedical applications have not yet been fully explored. This study investigates optodes as a potential sensor platform for monitoring cellular ion flux with attendant implications in the field of drug screening and toxicology. A prototype system was developed to quantitatively measure extracellular potassium flux from a monolayer of cardiomyocytes. Optodes were created and immobilized on a glass coverslip for fluorescent imaging. The system detected potassium (K(+) ) ion flux during the repolarization phase of the cardiac action potential and further detected a decrease in the magnitude of the flux in the presence of a known K(+) channel inhibitor by optically monitoring local K(+) ion concentrations during field stimulation of the cardiomyocyte monolayer. PMID- 21590895 TI - Small, stable, and monodispersed bubbles encapsulated with biopolymers. AB - A microfluidic route to producing small (<10 um) bubbles with a narrow size distribution and long-time (at least, up to one month) stability is reported. The bubbles are encapsulated with a protein-polysaccharide shell. The strategy includes the following events, occurring in sequence: (i) a microfluidic generation of bubbles from a mixture of CO(2) and a minute amount of gases with low solubility in water, in an aqueous solution of lysozyme and sodium alginate; (ii) the dissolution of CO(2) leading to the shrinkage of bubbles and a local increase in acidity of the medium; (iii) the deposition of lysozyme at the gas water interface triggered by the local decrease in pH; (iv) the deposition of alginate onto the lysozyme shell, due to the electrostatically driven complexation of alginate with lysozyme. PMID- 21590897 TI - Macromol. Rapid commun. 3/2010. PMID- 21590896 TI - Multifunctional magnetoplasmonic nanoparticle assemblies for cancer therapy and diagnostics (theranostics). AB - In this work, we describe the preparation and biomedical functionalities of complex nanoparticle assemblies with magnetoplasmonic properties suitable for simultaneous cancer therapy and diagnostics (theranostics). Most commonly magnetoplasmonic nanostructures are made by careful adaptation of metal reduction protocols which is both tedious and restrictive. Here we apply the strategy of nanoscale assemblies to prepare such systems from individual building blocks. The prepared superstructures are based on magnetic Fe(3) O(4) nanoparticles encapsulated in silica shell representing the magnetic module. The cores are surrounded in a corona-like fashion by gold nanoparticles representing the plasmonic module. As additional functionality they were also coated by poly(ethyleneglycol) chains as a cloaking agent to extend the blood circulation time. The preparation is exceptionally simple and allows one to vary the contribution of each function. Both modules can carry drugs and, in this study, they were loaded with the potential anticancer drug curcumin. A comprehensive set of microscopy, spectroscopy and biochemical methods were applied to characterize both imaging and therapeutic function of the nanoparticle assemblies against leukemia HL-60 cells. High contrast magnetic resonance images and high apoptosis rates demonstrate the success of assembly approach for the preparation of magnetoplasmonic nanoparticles. This technology allows one to easily "dial in" the functionalities in the clinical setting for personalized theranostic regiments. PMID- 21590898 TI - Recent developments concerning the dispersion of carbon nanotubes in polymers. AB - The ability to control the dispersion of carbon nanotubes in polymers is key to most applications of nanotube-polymer composites. This feature article describes recent advances in methods used to disperse carbon nanotubes and considers how these methods affect dispersion on different length scales. It is becoming increasing clear that perfect dispersion is not desired for many applications, in particular for electrical conductivity, and controlling the dispersion is key for proper function of the composite in its intended application. PMID- 21590899 TI - Hetero-Multifunctional Poly(ethylene glycol) Copolymers with Multiple Hydroxyl Groups and a Single Terminal Functionality. AB - Hetero-multifunctional poly(ethylene glycol-co-glycerol) random copolymers with multiple hydroxyl functionalities and a single terminal functionality have been prepared by copolymerization of ethylene oxide (EO) and ethoxy ethyl glycidyl ether (EEGE) with the use of a suitable initiator, introducing a protected amino group or a double bond, respectively. Acidic deprotection was used for removal of the acetal protecting groups in the chain, and the terminal amino group was regenerated by catalytic hydrogenation. A series of copolymers with narrow polydispersity was obtained, varying comonomer fractions from 3 to 67% and molecular weights in the range of 5 000-32 000 g . mol(-1) (1.05 < $?overline M _{?rm w} /?overline M _{?rm n}$ < 1.25). Molecular and thermal characterization was carried out using (1) H- and (13) C NMR, SEC and differential scanning calorimetry (DSC). PMID- 21590900 TI - Liquid crystalline period variations in self-assembled block copolypeptides surfactant ionic complexes. AB - We investigate the complexation of ampholytic poly(N-isopropylacylamide)-block poly- (L-glutamic acid)-block-poly(L-lysine) (PNiPAM-b-PLG-b-PLLys) triblock copolymers and PNiPAM-block-(PLG-co-PLLys) diblock copolymers with counter charged anionic and cationic surfactants. Both triblock and diblock copolymers are able to selectively form complexes through either L-glutamic acid-cationic surfactant or L-lysine-anionic surfactant ionic pairs, depending on the protonated or deprotonated states of the ampholytic peptide units. The complexes show ordering at multiple length scales: i) the block copolymer length scale (10(1) nm), ii) the liquid crystalline length scale (10(0) nm), and, iii) the peptidic secondary structures length scale (10(0) nm). We show that the liquid crystalline period can be tuned by varying the random/block copolypeptide architectures and the composition of the ampholytic amino acid species. PMID- 21590901 TI - Fabrication of Patterned Polydiacetylene Composite Films Using a Replica-Molding (REM) Technique. AB - Functional three-dimensional (3D) micropatterns of diacetylene supramolecules embedded in a host polymer have been successfully fabricated by a replica-molding (REM) technique. Dimensional reduction as a result of liquid evaporation during the curing process does not affect the conformational features of the transferred patterns. Polymerization of the diacetylene vesicles using 254 nm UV-light irradiation from the back-side of the transparent substrate induces blue colored polydiacetylene (PDA) micro-images. Interestingly, the polymerization selectively occurs in the molded areas because of the sub-300 nm light blocking property of SU-8. 3D fluorescence patterns are readily obtained by heat treatment of the blue images on the film. PMID- 21590902 TI - Iron-Mediated ICAR ATRP of Styrene and Methyl Methacrylate in the Absence of Thermal Radical Initiator. AB - Initiators for continuous activator regeneration in atom transfer radical polymerization (ICAR ATRP) is a new technique for conducting ATRP. ICAR ATRP has many strong advantages over normal ATRP, such as forming the reductive transition metal species in situ using oxidatively stable transition metal species and a lower amount of metal catalyst in comparison with the normal ATRP system. In this work, the iron-mediated ICAR ATRP of styrene and methyl methacrylate are reported for the first time using oxidatively stable FeCl(3) . 6H(2) O as the catalyst in the absence of any thermal radical initiator. The kinetics of the polymerizations and effect of different polymerization conditions are studied. It is found that the polymerization of styrene can be conducted well even if the amount of iron(III) is as low as 50 ppm. PMID- 21590903 TI - Polymer Brushes via Controlled, Surface-Initiated Atom Transfer Radical Polymerization (ATRP) from Graphene Oxide. AB - A method for growing polymers directly from the surface of graphene oxide is demonstrated. The technique involves the covalent attachment of an initiator followed by the polymerization of styrene, methyl methacrylate, or butyl acrylate using atom transfer radical polymerization (ATRP). The resulting materials were characterized using a range of techniques and were found to significantly improve the solubility properties of graphene oxide. The surface-grown polymers were saponified from the surface and also characterized. Based on these results, the ATRP reactions were determined to proceed in a controlled manner and were found to leave the structure of the graphene oxide largely intact. PMID- 21590904 TI - Controlling the Photoluminescence from a Laser Dye through the Oxidation Level of Polypyrrole. PMID- 21590905 TI - Viscoelastic behavior and force nature of thermo-reversible epoxy dry adhesives. AB - The gecko adhesion phenomenon has stimulated efforts to produce synthetic patterned dry adhesives. Besides introducing surface patterns on dry adhesives, it is also highly desirable to understand their intrinsic material properties. This communication reports the viscoelastic behavior of non-patterned epoxy elastomers exhibiting intrinsic adhesion that is much higher than that of elastomers typically used for structure patterning. The diverse molecular origin of the adhesion is revealed through the study of adhesion against various substrates. PMID- 21590906 TI - Tailoring Polymeric Hydrogels through Cyclodextrin Host-Guest Complexation. AB - A close correllation between molecular-level interactions and macroscopic characteristics of polymer networks exists. The characteristics of the polymeric hydrogels assembled from beta-cyclodextrin (beta-CD) and adamantyl (AD) substituted poly(acrylate)s can be tailored through selective host-guest complexation between beta-CD and AD substituents and their tethers. Dominantly, steric effects and competitive intra- and intermolecular host-guest complexation are found to control poly(acrylate) isomeric inter-strand linkage in polymer network formation. This understanding of the factors involved in polymeric hydrogel formation points the way towards the construction of increasingly sophisticated biocompatible materials. PMID- 21590907 TI - 1,1-diphenyl ethylene-mediated radical polymerisation: a general non-metal-based technique for the synthesis of precise core cross-linked star polymers. AB - This communication details the successful synthesis of low polydispersity core cross-linked star (CCS) polymers via DPE-mediated polymerisation. We demonstrate the ability to produce poly(methyl methacrylate) and poly(acrylonitrile) CCS polymers that are currently inaccessible via the two most common non-metal-based controlled radical polymerisation techniques (NMP and RAFT polymerisations). PMID- 21590908 TI - Observations on Solution Crystallization of Poly(vinyl alcohol) in the Presence of Single-Wall Carbon Nanotubes. AB - PVA/SWNT dispersions yield aloe plant-like crystals, where the leaves are single crystals templated by PVA coated SWNT. Longer growth times (~18 months) lead to hexagonal rod-like crystals. HR-TEM images show evidence that PVA molecules are aligned parallel to the SWNT axis. WAXD, electron diffraction, and HR-TEM observations of these aloe plant and hexagonal crystals suggests evidence for possible PVA-SWNT epitaxy. Wide-angle and electron diffraction data of these crystals also show that the structure seems to mimic the 2D hexagonal crystal packing of SWNT. PVA lattice images and moire fringes were also observed in the leaf-like crystals. PMID- 21590909 TI - Cross-Linked Multilayers of Poly(vinyl amine) as a Single Component and Their Interaction with Proteins. AB - Novel multilayer thin films that consist solely of cross-linked single component layers are generated by a selective cross-linking of the poly(vinyl amine) (PVAm) layers in [PVAm/poly(acrylic acid) (PAA)](n) thin films constructed either on silica particles or silicon wafers, followed by the removal of PAA. The surface topography of the (PVAm)(n) multilayer thin films, before and after the adsorption of human serum albumin (HSA), has been studied by atomic force microscopy on the freeze-dried films. The decrease of the average roughness of the film after the adsorption of HSA showed the protein was adsorbed into the (PVAm)(n) film making these films potential reservoirs for proteins. PMID- 21590910 TI - Macromol. Rapid commun. 4/2010. PMID- 21590911 TI - Metal-containing polymers: building blocks for functional (nano)materials. AB - The incorporation of metallic units into polymer chains has emerged as a promising route towards functional metal-containing (nano)materials. The resulting polymers possess rich functions derived from their metallic elements, such as redox, optical, catalytic and magnetic properties. In addition, the directional and dynamic nature of metal coordination interactions provides further variables for the exploration of novel materials with designed nanostructures. These types of polymers can be synthesized through direct metal ligand coordination or chain polymerization of metal containing monomers. Depending on the polymerization techniques and starting components, the resulting polymers, akin to their organic counterparts, can be produced in the form of insoluble networks, processible chain structures, gels or colloids. Research into this rising multidisciplinary subject has benefited from recent progress in several related areas such as supramolecular chemistry, colloidal chemistry etc., with the combination of the relative merits of each ensuring further developments in each individual discipline. For example, as a result of studies into organometallic block copolymers self-assembly behavior, living supramolecular polymerization has been unprecedentedly realized for the architectural design of micelles (see image on the right). Nevertheless, the field is still in a developmental stage and offers ample opportunities for fundamental research, as well as material exploration. In this Feature Article, we intend to overview the field with a brief survey of recent literature. PMID- 21590912 TI - Self-complementary nucleoside-thiophene hybrid systems: synthesis and supramolecular organization. AB - Versatile synthetic methods towards a variety of thiophene-nucleobase hybrid systems are reported. Adenine- and thymine-based modified nucleosides characterized by a bithiophene unit linked to the C5' or C8 position through an ethylenamino or an ethylensulfanyl bridge were synthesized and successfully polymerized in the presence of FeCl(3) . The self-organization properties of the pure polymers as well as their mixtures - with complementary nucleobases - were investigated by means of optical microscopy and AFM in cast film showing complex supramolecular structures resulting from the interplay of multiple intermolecular interactions. PMID- 21590913 TI - Impact of Nanoscale Confinement on Crystal Orientation of Poly(ethylene oxide). AB - Using a layer-multiplying coextrusion process to fabricate films with thousands of alternating polymer nanolayers, we report here a new crystalline morphology in confined polymer nanolayers and an abrupt transition in the crystallization habit. At higher temperatures, poly(ethylene oxide) crystallizes as large, in plane lamellae. A 5 degrees C change in the crystallization temperature produces an on-edge lamellar orientation. The results point to a transition from heterogeneous nucleation to substrate-assisted nucleation. This may be a general phenomenon that accounts for previously unexplained differences in the preferred chain alignment of confined polymer crystals. PMID- 21590914 TI - Synthesis with Single Macromolecules: Covalent Connection between a Neutral Dendronized Polymer and Polyelectrolyte Chains as well as Graphene Edges. AB - Single chains of a neutral, dendronized polymer with peripheral azide groups (PG3A) are co-deposited onto molecularly modified graphite substrates with a positively charged dendronized polymer (PG2) as well as with negatively charged plasmid dsDNA. PG3A is also prepared near graphite step-edges. Single PG3A chains are moved with a scanning force microscope tip, into close contact with either of the two polyelectrolytes, as well as the step-edge at predetermined positions. Treating these structures in situ with UV light leads to photochemically induced cross-linking between the PG3A chains carrying azide groups and PG2, dsDNA, and graphite step-edges, respectively, which is proven by mechanically challenging the "welding" points by pulling on the molecules with the SFM-tip. PMID- 21590915 TI - Studying and Suppressing Olefin Isomerization Side Reactions During ADMET Polymerizations. AB - Olefin isomerization side reactions that occur during ADMET polymerizations were studied by preparing polyesters via ADMET and subsequently degrading these polyesters via transesterification with methanol. The resulting diesters, representing the repeating units of the previously prepared polyesters, were then analyzed by GC-MS. This strategy allowed quantification of the amount of olefin isomerization that took place during ADMET polymerization with second generation ruthenium metathesis catalysts. In a second step, it was shown that the addition of benzoquinone to the polymerization mixture prevented the olefin isomerization. Therefore, second generation ruthenium metathesis catalysts may now be used for the preparation of well-defined polymers via ADMET with very little isomerization, which was not possible before. PMID- 21590916 TI - Poly(vinyl phosphonic acid): Hydrodynamic Properties and SEC-Calibration in Aqueous Solution. AB - Poly(vinyl phosphonic acid) (PVPA) as obtained by free radical polymerization of aqueous vinyl phosphonic acid was studied by light scattering (SLS, DLS) and size exclusion chromatography (SEC) in dilute aqueous solutions containing sufficient salt in order to screen long range electrostatic interactions. Samples of 37<$?overline M _{?rm w}$< 110 * 10(3) were studied. The polymers showed positive A(2) -values in aqueous NaH(2) PO(4) solution (0.04 M), and self-diffusion behavior and R(H) /R(G) -ratios indicative of the structure of random coiled chains. A comparison of the SEC-elugrams of the PVPA-samples with those of commercially available standards of poly(acrylic acid) sodium salt gave a fit to the same calibration curve described by log P(n(PVPA)) = -0.21nu(e) + 7.0(+0.1) which correlates the number average degree of polymerization (P(n) ) with the elution volume nu(e) . This indicates that PVPA and PAA have the same hydrodynamic structure under given solution conditions. PMID- 21590917 TI - Reduced Graphene Oxide/Poly(3-hexylthiophene) Supramolecular Composites. AB - Poly(3-hexylthiophene) (P3HT) supramolecular structures are fabricated on P3HT dispersed reduced graphene oxide (RGO) monolayers and surfactant-free RGO monolayers. P3HT is able to disperse RGO in hot anisole/N,N-dimethylformamide solvents, and forms nanowires on RGO surfaces through a RGO induced crystallization process. The TEM and AFM investigation of the resultant P3HT/RGO composites shows that P3HT nanowires grow from RGO, and connect individual RGO monolayers. Raman spectroscopy confirms the interaction between P3HT and RGO, which allows the manipulation of the RGO electrical properties. Such a bottom-up approach provides interesting graphene-based composites for nanometer-scale electronics. PMID- 21590918 TI - A novel high throughput method to investigate polymer dissolution. AB - The dissolution behavior of polystyrene (PS) in biodiesel was studied by developing a novel high throughput approach based on Fourier-transform infrared (FTIR) microscopy. A multiwell device for high throughput dissolution testing was fabricated using a photolithographic rapid prototyping method. The dissolution of PS films in each well was tracked by following the characteristic IR band of PS and the effect of PS molecular weight and temperature on the dissolution rate was simultaneously investigated. The results were validated with conventional gravimetric methods. The high throughput method can be extended to evaluate the dissolution profiles of a large number of samples, or to simultaneously investigate the effect of variables such as polydispersity, crystallinity, and mixed solvents. PMID- 21590919 TI - New low bandgap dithienylbenzothiadiazole vinylene based copolymers: synthesis and photovoltaic properties. AB - Two new low-bandgap block copolymers derived from dithienylbenzothiadiazole (DTBT) and different electron-rich functional groups (dioctoxyl benzene and N octyl-diphenylamine), poly(1,4-dioctoxyl-2,5-divinylbenzene-co-4,7-dithiophene-2' yl-2,1,3-benzothiadiazole) (PPV-DTBT), poly(3,8-divinyl-N-octyl-diphenylamine-co 4,7-dithiophene-2'-yl-2,1,3-benzothiadiazole) (PDPAV-DTBT), were synthesized by Heck cross-coupling polymerization. PPV-DTBT and PDPAV-DTBT are easily soluble in common organic solvents such as o-dichlorobenzene and chloroform. DSC and TGA results indicate that these copolymers possess good thermal stabilities. PPV-DTBT and PDPAV-DTBT films exhibit broad absorption bands at 300-765 nm (with an optical bandgap of 1.62 eV) and 300-733 nm (with an optical bandgap of 1.69 eV), respectively. The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of PPV-DTBT were estimated by cyclic voltammetry to be -5.43 and -3.74 eV, respectively, and the HOMO and LUMO of PDPAV-DTBT were -5.37 and -3.7 eV, respectively. Preliminary photovoltaic cells based on the composite structure of ITO/PEDOT: PSS/PPV-DTBT:PCBM (1: 2, w/w)/Al showed an open-circuit voltage of 0.75 V, a power conversion efficiency of 0.6%, and a short circuit current of 1.7 mA . cm(-2) . PMID- 21590920 TI - Formation of Vesicular Morphologies via Polymerization Induced Self-Assembly and Re-Organization. AB - A facile and feasible strategy for the preparation of vesicular morphologies has been developed using reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymerization of styrene has been performed in a selected solvent, methanol, using S-1-dodecyl-S-(alpha,alpha'-dimethyl-alpha"-acetic acid)trithiocarbonate (TC)-terminated poly(4-vinylpyridine) as chain transfer agent and stabilizer. Various morphologies including spherical vesicles, nanotubes, and compound vesicles with different shapes are obtained by changing the feed ratios and reaction conditions. The final nanostructural materials are formed through formation of the block copolymers, self-assembly, and re organization of the morphology in a one-pot polymerization. The latter two are induced by the propagation of PS blocks. The preparation of nanostructural materials can be performed at a concentration higher than 0.5 g . mL(-1) , thus this method offers a practical approach to prepare nanostructural materials on a large scale. PMID- 21590922 TI - Macromol. Rapid commun. 5/2010. PMID- 21590921 TI - A Novel Approach for Mixing ZnO Nanoparticles into Poly(ethyl methacrylate). AB - A novel and versatile approach for the mixing of ZnO nanofillers into a host polymer matrix, poly(ethyl methacrylate) (PEMA), is reported. Firstly, ZnO nanoparticles are deposited onto the surface of polystyrene (PS) colloidal particles in a "raspberry-like" fashion and subsequently obtained PS/ZnO composite particles are mixed into the PEMA matrix in the range of 0.5 to 5 wt. %. Microscopic analyses reveal a homogenous distribution of PS/ZnO domains into the PEMA matrix even at 5 wt.-% loading level. Thermogravimetric analysis and differential scanning calorimetry results indicate an improvement in thermal stability of PEMA matrix after mixing with PS/ZnO filler particles. A significant enhancement in mechanical properties of PEMA matrix in the presence of PS/ZnO particles has been evidenced by dynamic mechanical analysis and three point bending measurements. PMID- 21590923 TI - Molecular aspects of radical polymerizations-the propagation frequency. AB - The product of the propagation rate constant and monomer concentration is a central issue of radical polymerization. Both quantities are strongly interrelated as the determination of a reliable value of the propagation rate constant requires exact knowledge of the monomer concentration. Even for homogeneous polymerization conditions, exact knowledge of the monomer concentration at the reaction site from the molecular perspective is not trivial. For emulsion polymerizations the situation is additionally complicated by mass transfer events and colloid-chemical effects. Molecular modeling appears as an attractive alternative or complement to the deterministic kinetic description of radical polymerizations. PMID- 21590924 TI - Controlling the Optical Properties of Hyperbranched Conjugated Polyazomethines through Terminal-Backbone Interactions. AB - A simple approach to tune the optical properties of the hyperbranched conjugated polymers by only adjusting the terminal-backbone interactions has been reported in this article. Hyperbranched conjugated polyazomethines have been successfully prepared by the reaction of tetramine and dialdehyde. Not only varying the monomer feed ratio to change the quantity of terminal amino groups, but also adopting protonation or complexion with proper dopants (SnCl(2) and beta cyclodextrin), can alter the interactions between amino terminals and imine bonds in the backbone. Correspondingly, the optical properties of the resulting hyperbranched polymers are controlled. PMID- 21590925 TI - Sphere-to-Rod Transition of Micelles formed by the Semicrystalline Polybutadiene block-Poly(ethylene oxide) Block Copolymer in a Selective Solvent. AB - We present a morphological study of the micellization of an asymmetric semicrystalline block copolymer, poly(butadiene)-block-poly(ethylene oxide), in the selective solvent n-heptane. The molecular weights of the poly(butadiene) (PB) and poly(ethylene oxide) (PEO) blocks are 26 and 3.5 kg . mol(-1) , respectively. In this solvent, micellization into a liquid PEO-core and a corona of PB-chains takes place at room temperature. Through a thermally controlled crystallization of the PEO core at -30 degrees C, spherical micelles with a crystalline PEO core and a PB corona are obtained. However, crystallization at much lower temperatures (-196 degrees C; liquid nitrogen) leads to the transition from spherical to rod-like micelles. With time these rod-like micelles aggregate and form long needles. Concomitantly, the degree of crystallinity of the PEO-cores of the rod-like micelles increases. The transition from a spherical to a rod-like morphology can be explained by a decrease of solvent power of the solvent n-heptane for the PB-corona chains: n-Heptane becomes a poor solvent at very low temperatures leading to a shrinking of the coronar chains. This favors the transition from spheres to a morphology with a smaller mean curvature, that is, to a cylindrical morphology. PMID- 21590926 TI - Gold Nanoparticles Functionalized by a Dextran-Based pH- and Temperature Sensitive Polymer. AB - A dextran-based dual-sensitive polymer is employed to endow gold nanoparticles with stability and pH- and temperature-sensitivity. The dual-sensitive polymer is prepared by RAFT polymerization of N-isopropylacrylamide from trithiocarbonate groups linked to dextran and succinoylation of dextran after polymerization. The functionalized nanoparticles show excellent stability under various conditions and can be stored in powder-form. UV and DLS measurements confirm that the temperature-induced optical changes and aggregation behaviors of the particles are strongly dependent on pH. PMID- 21590927 TI - Design of Organoiron Macromolecules Based on Upper Rim Functionalized Calix[4]arenes. AB - The versatility of cationic cyclopentadienyliron complexes is demonstrated for the generation of calix[4]arene-based dendrimers and polymers. Dendrimers were prepared from a branched organoiron calix[4]arene through subsequent reactions of azo dyes and organoiron complexes. The resulting azo dye-containing metallocalix[4]arenes were soluble in polar organic solvents and displayed lambda(max) ranging between 430 and 456 nm. Upon addition of various acids, the lambda(max) shifted to higher wavelengths (513-535 nm). In the solid state and in solution, the azo dye-containing metallocalix[4]arenes reversibly changed colour in the presence of acid and base, indicating their potential use as acid sensors. Cyclic voltammetric studies showed that the iron centres of the metallocalix[4]arenes were reversibly reduced at E(1/2) = -1.49 V. When non branching organoiron-based calix[4]arene were reacted with dithiols, polymers containing calix[4]arenes either in their side chains or main chains were obtained. The polymers possessed weight average molecular weights between 35 000 and 53 000. The polymers were determined to be thermally stable with backbone decomposition occurring above 500 degrees C. PMID- 21590928 TI - Electron Beam-Based Functionalization of Poly(ethersulfone) Membranes. AB - Poly(ethersulfone) membranes were surface modified in a one-step procedure. For this purpose, the membranes were soaked with aqueous solutions of different low molecular weight molecules bearing diverse hydrophilic functionalities and subject to electron beam treatment. No catalysts, photoinitiators, organic solvents or other toxic reagents were used, and no additional synthetic or purification steps were required. PMID- 21590929 TI - Bis(germyl)ketones: Toward a New Class of Type I Photoinitiating Systems Sensitive Above 500 nm? AB - The ability of a bis(germyl)ketone Ph(3) GeCOGePh(3) to act as a photoinitiator of free radical polymerization under visible light is investigated. The results suggest that this compound could be the starting point of a new high performance class of photoinitiators. The excited state processes, as well as the generation and the reactivity of the germyl radicals, are studied by laser flash photolysis, ESR spin trapping experiments, and molecular orbital calculations; they are compared to the results obtained on a mono- (germyl)ketone CH(3) COGePh(3) . Time dependent density functional theory calculations allow discussion of the strongly red-shifted ground state absorption of Ph(3) GeCOGePh(3) . PMID- 21590930 TI - In situ Photopolymerization of a Gel Ionic Liquid Electrolyte in the Presence of Iodine and Its Use in Dye Sensitized Solar Cells. AB - We report for the first time an in situ photopolymerization of model co-monomers, 2-hydroxyethyl methacrylate (HEMA) and tetra (ethylene glycol) diacrylate (TEGDA), in an IL electrolyte containing I(2) for DSSCs. TiO(2) nanoparticles were used as the photo-initiator and co-gelator in a charge transfer polymerization reaction. The gel-IL polymer obtained was characterized in terms of the diffusion properties of the electrolyte. Preliminary results from DSSCs assembled using the gel-IL electrolyte showed energy conversion efficiency of 3.9% at 1 sun (AM1.5) and 5.0% at 0.39 sun illumination. PMID- 21590931 TI - Sequential polymer precipitation of core-shell microstructured composites with giant permittivity. AB - Polymeric core-shell microstructures have been constructed through a new method, namely sequential precipitation, which is intrinsically a self-assembly and phase separation process. High-quality poly(vinyldene fluoride)-polycarbonate-lithium perchlorate composite films with spherical core-shell microstructures have been prepared and determined to consist of conducting cores and insulating shells. Because of the percolation effect, the resulting materials present a dielectric constant as high as 10(4) -10(7) at the threshold. PMID- 21590932 TI - Two types of block copolymer micelles with ion-containing cores. AB - We report a combined experimental and theoretical study of micellization of block copolymer with hydrophilic nonionic corona-forming blocks and weak polyelectrolyte (wPE) core-forming blocks with pH-triggered solubility in aqueous solutions. We demonstrate that in addition to micelles with neutral cores, there exist two other types of micelles with PE- or ionomer-like cores, in which monovalent counterions are released or condensed on core wPE block, respectively. The transition between the two types of micelles occurred upon changes in ionization of the PE core block and resulted in nonmonotonous changes of aggregation number as a function of pH. Such micelles with stimulus responsive cores represent promising nanocarriers for controlled delivery applications. PMID- 21590934 TI - Macromol. Rapid commun. 6/2010. PMID- 21590933 TI - Novel Spectrally Stable Saturated Blue-Light-Emitting Poly[(fluorene)-co (dioctyldibenzothiophene-S,S-dioxide)]s. AB - Novel poly[(fluorene)-co-(2,8-dioctyldibenzothiophene-S,S-dioxide-3,7-diyl)]s were synthesized. The octyl group on the 2,8-dioctyldibenzothiophene-S,S-dioxide (DOSO) unit improved the solubility of the polymers and broadened the optical band gap from 2.95 to 3.20 eV as the content of DOSO unit increases. The electroluminescence (EL) spectra of polymers show CIE coordinates around (0.16, 0.07) independent of the ratio of DOSO units in the polymers, owing to the ICT and steric hindrance dual-function. A high efficiency of 3.1 cd . A(-1) (EQE = 3.9%) was obtained with the configuration of ITO/PEDOT:PSS/polymer/Ba/Al. The results indicate that PF-3,7DOSOs could be a promising candidate for saturated blue-emitting polymers with spectral stability and high efficiency. PMID- 21590935 TI - Poly(2-oxazoline)s as Smart Bioinspired Polymers. AB - Poly(2-alkyl-2-oxazoline)s can be regarded as pseudo-peptides or bioinspired polymers, which are available through living/controlled cationic polymerization and polymer ("click") modification procedures. Materials and solution properties may be adjusted via the nature of the side chain (hydrophilic-hydrophobic, chiral, bio-functional, etc.), opening the way to stimulus-responsive materials and complex colloidal structures in aqueous environments. Herein, we give an overview over the macromolecular engineering of polyoxazolines, including the synthesis of biohybrids, and the "smart"/bioinspired aggregation behavior in solution. PMID- 21590936 TI - Holes and ledges created by multilayer assembly on polyelectrolyte brushes: a novel route for the three-dimensional nanoscale design of surfaces. AB - The layer-by-layer (LBL) assembly of poly(diallyldimethylammonium chloride) and poly(sodium styrene sulfonate) on poly(sulfo propyl methacrylate) brushes resulted in films with nanometer- and micrometer-sized holes and ledges, observed by atomic force microscopy and scanning electron microscopy. Polyelectrolyte assembly was followed by the quartz microbalance technique. The formation of ledges and holes is explained by the interaction of the brush polymers with the incoming polyelectrolytes during the LBL assembly, inducing a spatially localized and self-organized accumulation of the assembled polymers. PMID- 21590937 TI - Crystallization-Induced Phase Segregation Based on Double-Crystalline Blends of Poly(3-hexylthiophene) and Poly(ethylene glycol)s. AB - Crystallization-induced vertical stratified structures were constructed based on double-crystalline poly(3-hexylthiophene) (P3HT)/poly(ethylene glycol)s (PEG) systems at room temperature, in which the P3HT crystallinity and the mechanism were investigated. Vertical stratified microstructures with highly crystalline P3HT network on the surface were formed when depositing from marginal solvents, while lateral phase-separated structures or low P3HT crystallinity were observed for good solvents. The morphological differences came from the solvent effect. In marginal solvents, p-xylene and dichloromethane, P3HT large-scale microcrystallites were generated in solution, which ensured the priority of P3HT crystalline sequence, and phase separation began in the liquid states. When the PEG matrix began to crystallize, great energy from which the second phase separation was induced drove P3HT crystallites to the surface, resulting in the formation of vertical stratified microstructures with highly crystalline P3HT network on the surface. The method, crystallization-induced phase segregation of crystalline-crystalline blends in marginal solvent, provides a facile way to construct vertically stratified structures, in which P3HT highly crystalline network is favored. PMID- 21590938 TI - Direct structuring of a biomimetic anti-reflective, self-cleaning surface for light harvesting in organic solar cells. AB - A one-step method to fabricate a biomimetic dual-scale hierarchical structure for a transparent anti-reflective, self-cleaning layer for organic solar cells is reported. Template-mediated UV replica molding is used to directly create a multi functional surface with an acrylate-functionalized perfluoropolyether without complicated processing steps. The surface exhibits superhydrophobic properties and self-cleaning characteristics. In addition, the surface leads to an enhancement of photovoltaic power conversion efficiency by ~10% as a result of reflection suppression and transmittance enhancement. The method can easily be applied to large area substrates (22 cm * 24 cm) in a cost-effective manner. Furthermore, the solar cell can withstand harsh outdoor conditions for a long time, without a notable change in the device performance, owing to robust surface layer and non-fouling properties. PMID- 21590939 TI - Direct Synthesis of Poly(dimethylsiloxane) Copolymers with TPE-Properties via CuAAC (Click Chemistry). AB - Poly(dimethylsiloxane) copolymers were synthesized directly from AA/BB monomers employing a CuAAC reaction (click chemistry) in a polyaddition approach. Using organic dialkynes and oligo(siloxane)s end-functionalized with azide moieties it was possible to obtain siloxane-based copolymers with TPE properties by click chemistry for the first time. As seen from DSC experiments, properties were strongly dependent on the incorporated organic comonomer. PMID- 21590940 TI - Solid-State Synthesis of Silver Nanoparticles at Room Temperature: Poly(vinylpyrrolidone) as a Tool. AB - Silver nanoparticles have been used for a long time and recently various methods have been additionally developed for their production. Here we report for the first time a solid-state high-speed vibration milling method for the synthesis of silver nanoparticles, in which poly(vinylpyrrolidone) is used for the reduction of the silver salt. The synthesis is performed at room temperature and no surfactant to direct the anisotropic growth of the nanoparticles is required. The formation of the nanoparticles was studied by UV-Visible spectroscopy, transmission electron microscopy, and powder X-ray diffraction techniques. The nanoparticles synthesized were found to be uniform in size and shape with an average diameter of less than 5 nm. In addition, the antimicrobial activity of these silver nanoparticles was investigated against Escherichia coli and found to be positive. PMID- 21590941 TI - Complexation of syndiotactic polystyrene with 12-crown-4. AB - Solid-state complexation of syndiotactic polystyrene (sPS) with a crown ether compound, 1,4,7,10-tetraoxa-cyclododecane (12-crown-4), took place when a film of sPS/chloroform clathrate was subjected to a guest exchange procedure assisted with a plasticizing agent. The new guest 12-crown-4 molecules were incorporated into the crystalline region of the sPS film, without causing a large conformational change of host sPS helices. X-ray diffraction and thermogravimetric investigations showed that sPS/12-crown-4 complex had a clathrate complex structure which contained four 12-crown-4 molecules per unit cell. IR and Raman data suggested that 12-crown-4 took a C(i) -type conformation in the sPS complex phase. PMID- 21590942 TI - The advantages of in situ surfactant generation for miniemulsions. AB - The stabilisation of miniemulsions using an in situ generated surfactant is presented. This surfactant, prepared from of a water-soluble base and an oil soluble long chain acid was successfully used to create stable miniemulsions with up to 60 vol.-% organic phase. It is shown that the creation of a surface active species at the oil-water interface allowed stable miniemulsions to be generated more rapidly than when using conventional surfactant. In addition, polymerised miniemulsions exhibited less secondary nucleation when in situ surfactants were used. PMID- 21590943 TI - Toward Tailor-Made Biocide Materials Based on Poly(propylene)/Copper Nanoparticles. AB - A set of poly(propylene) composites containing different amounts of copper nanoparticles (CNP) were prepared by the melt mixed method and their antimicrobial behavior was quantitatively studied. The time needed to reduce the bacteria to 50% dropped to half with only 1 v/v % of CNP, compared to the polymer without CNP. After 4 h, this composite killed more than 99.9% of the bacteria. The biocide kinetics can be controlled by the nanofiller content; composites with CNP concentrations higher than 10 v/v % eliminated 99% of the bacteria in less than 2 h. X-ray photoelectron spectroscopy did not detect CNP at the surface, therefore the biocide behavior was attributed to copper in the bulk of the composite. PMID- 21590944 TI - Gold Tailored Photosensitive Elastin-like Polymer: Synthesis of Temperature, pH and UV-vis Sensitive Probes. AB - Here, we describe a procedure to manufacture smart hybrid probes that exhibit tunable optical properties as a function of multiple environmental variations. Initially, we achieved a one-pot synthesis of gold-PREP (photo-responsive elastin like polymer) conjugate Gold-AzoGlu15 via reduction of auric acid in the presence of PREP AzoGlu15. Outstandingly, Gold-AzoGlu15 exhibited pH and temperature sensitiveness. However, Gold-AzoGlu15 was not UV-vis sensitive. We noticed that photo-isomerisation of azobenzene moieties in Gold-AzoGlu15 could not be detected by UV-vis spectroscopy. In a subsequent step, we explored the use of cyclodextrins and the formation of alkanethiol mixed-monolayers over mother Gold AzoGlu15 by thiol-place exchange reactions in order to decouple photo isomerisation of azobenzene from the bulk phase absorption. In this sense we achieved the synthesis of beta-cyclodextrin capped Gold-CD-AzoGlu15. Notable was that cis-trans photo-conversion of azobenzene groups in Gold-CD-AzoGlu15 could be successfully detected. Finally, we present the optical properties exhibited by multi-sensitive probe Gold-CD-AzoGlu15 as a function of pH, temperature and UV vis irradiation. We think that gold-PREP hybrids could be of great interest in the design of multi-functional chromophore-metal nanocomposites that operate in aqueous media for the development of multi-stimuli sensitive detectors for biosensing applications. PMID- 21590945 TI - Functionalization of Carbon Materials using the Diels-Alder Reaction. AB - A simple and efficient Diels-Alder (DA) reaction on carbon material has been demonstrated. The present work involves single and multiwall carbon nanotubes (CNTs), as well as Herringbone carbon nanofiber. The CNTs show a dual nature of reactivity in DA reaction, i.e., they behave both as dienophile and diene with furfuryl groups and maleic anhydride derivatives, respectively. Various functional groups, including alcohol, amine, epoxy, carboxylic and ester, have been introduced on the carbon materials. The results suggest that the reactivity of CNT in DA reaction may resemble the chemistry of small molecules. PMID- 21590946 TI - Macromol. Rapid commun. 7/2010. PMID- 21590947 TI - Microphase separation of block copolymer thin films. AB - Today, high-ordered micro- and nano-patterned surfaces are widely used in many areas, such as in the preparation of super-thin dielectric films, photonic crystals, antireflective films, super-non-wetting surfaces, bio-compatible surfaces and microelectric devices. Considering the critical fabrication conditions and the irreducible high cost of the photolithography technique in patterning nano-scale structures (<100 nm), the development of other micro- and nano-patterning techniques that can be used to fabricate long-range ordered features - especially nanoscale arrays - is a promising subject in surface science. In contrast to the traditional photolithography patterning technique, block copolymers can spontaneously phase separate into arrays of periodic patterns with length-scales of 10-50 nm, which provides an efficient pathway to pattern nanoscale features. Today, preparing long-range ordered arrays by block copolymer microphase separation is one of the most promising techniques for the fabrication of nanoscale arrays, not only being a simple process but also having a lower cost than traditional methods. In this feature article, we first summarize the many techniques developed to induce ordering in the microphase separation of the block copolymer thin films. Then, evolution, order-order transitions and reversible switching microdomains are considered, since they are very important in the ordered engineering of microphase separation of the block copolymer thin films. Finally, the outlook of this research area will be given. PMID- 21590948 TI - Colloid-Assisted Self-Assembly of Robust, Three-Dimensional Networks of Carbon Nanotubes over Large Areas. AB - Natural materials, such as bone and spider silk, possess remarkable properties as a result of sophisticated nanoscale structuring. They have inspired the design of synthetic materials whose structure at the nanoscale is carefully engineered or where nanoparticles, such as rods or wires, are self-assembled. Although much work has been done in recent years to create ordered structures using diblock copolymers and template-assisted assembly, no reports describe highly ordered, three-dimensional nanotube arrays within a polymeric material. There are only reports of two-dimensional network structures and structures on micrometer-size scales. Here, we describe an approach that uses plasticized colloidal particles as a template for the self-assembly of carbon nanotubes (CNTs) into ordered, three-dimensional networks. The nanocomposites can be strained by over 200% and still retain high conductivity when relaxed. The method is potentially general and so may find applications in areas such as sensing, photonics, and functional composites. PMID- 21590949 TI - Supramolecular Nanocycles Comprising beta-Cyclodextrin-click-Ferrocene Units: Rings of Rings of Rings. AB - We applied 1,3-dipolar cycloaddition to bind ethynylferrocene onto 6I-azido-6I deoxycyclomaltoheptaose under microwave assisted conditions. The process was investigated by (1) H NMR, FT-IR spectroscopy, and MALDI-TOF mass spectrometry. The ability of the synthesized compound to self-organize to cyclic supramolecular structures was investigated by dynamic light scattering measurements and cryo transmission electron microscopy. PMID- 21590950 TI - Preparation of Clickable Poly(3-hydroxyalkanoate) (PHA): Application to Poly(ethylene glycol) (PEG) Graft Copolymers Synthesis. AB - A new synthesis of amphiphilic biodegradable copolymers consisting of hydrophobic poly(3-hydroxyalkanoate) (PHA) backbone and hydrophilic poly(ethylene glycol) (PEG) units as side chains is described. Poly[(3-hydroxyoctanoate)-co-(3 hydroxyundecenoate)] (PHOU) was first methanolyzed and its unsaturated side chains were quantitatively oxidized to carboxylic acid. Esterification with propargyl alcohol led to an alkyne-containing "clickable" PHA in 71% conversion. Its reactivity was successfully demonstrated by grafting azide-terminated PEG chains of 550 and 5 000 g . mol(-1) , respectively. All products were fully characterized using GPC, (1) H, and COSY NMR. PMID- 21590951 TI - Use of a profluorophore for visualization of the rupture of capsules in self healing coatings. AB - An important category of self-healing materials relies on the release of a healing agent from a capsule upon the occurrence of damage to the material. Visualization of the release of the healing agent is difficult to accomplish. Here we show that a profluorophore can successfully be used to visualize the local release of a healing agent in a self-healing coating. A tetra-functional thiol compound encapsulated in nanocapsules or microcapsules is dispersed in a poly(methyl acrylate) film, in which the profluorophore is molecularly dispersed. A strong fluorescence signal is observed when a cut is introduced in the film. This fluorescence provides clear evidence that the capsules rupture locally during the introduction of a cut. In a more general sense, it proves that profluorophores can be very useful in materials science. PMID- 21590952 TI - Effects of Temperature and Solvent on the Energy Transfer and beta-Phase Formation in the Iridium(III) Complex-Containing Polyfluorene in Solutions and as Suspended Nano-Particles. AB - The effects of temperature and solvent on the beta-phase formation and energy transfer in an Ir(III) complex-containing polyfluorene were investigated. Efficient energy transfer from polyfluorenes host to Ir complexes guest can be realized at low temperature. The formation of beta-phase was observed both in THF solution at low temperature and as suspended nano-particles at room temperature. In addition, phosphorescent polymer nanoparticles were prepared successfully and exhibited efficient phosphorescent emission. PMID- 21590953 TI - Induction of molecular organization of oligomers by low-energy electrons. AB - We reveal that a beam of low-energy electrons (18 eV) can directly trigger long range molecular ordering of an amorphous, semi-flexible oligomer in a few minutes without the prerequisite of pre-orientation. A strong endothermic transition was detected with a micro-thermal analyzer on the areas that had been exposed to the electron irradiation while the areas that were shielded from the irradiation by a protective mask remained amorphous as usual. This result suggests that long-range molecular ordering only develops in the area of the oligomer film under electron irradiation. This is the first-time effort to use electron irradiation to control the long-range ordering of an amorphous organic thin film above the glass transition temperature. PMID- 21590954 TI - Dual Responsive Block Copolymer Micelles Functionalized by NIPAM and Azobenzene. AB - A novel amphiphilic diblock copolymer composed of a hydrophilic poly(ethylene oxide) block and a hydrophobic block copolymerized by azobenzene-containing methacrylate and N-isopropylacrylamide was synthesized using ATRP. The polymer micelles showed dual responsiveness to heat and light. The size of the micelles was dependent on temperature and the encapsulated substance in the hydrophobic cores was released during heating and cooling processes. The hydrophobicity of the micellar cores appeared as a reversible change in response to light with neither disruption of the micelles nor leakage of the encapsulated substance while H-aggregation of the azobenzene moieties was detected. PMID- 21590955 TI - Highly ordered hexagonal arrays of hybridized micelles from bimodal self assemblies of diblock copolymer micelles. AB - We demonstrate the formation of highly ordered hexagonal arrays of hybridized polystyrene-poly(4-vinyl pyridine), PS-PVP, micelles with controllable size by solvent annealing techniques. Because the formation of hybridized micelles was prohibited in the mixture solutions of two different-sized PS-PVP micelles, single-layered films with bimodal self-assemblies of small and large micelles were fabricated from the mixture solutions by adjusting their mixing ratios. When the single-layered films were solvent annealed by saturated vapor of tetrahydrofuran (THF), on the other hand, small and large PS-PVP micelles in the bimodal self-assemblies merged together to form hybridized micelles. In addition, the hybridized micelles arranged themselves in a highly ordered hexagonal array, the diameter and center-to-center distance of which were precisely adjusted by varying the mixing ratio of small to large micelles in the bimodal assemblies. PMID- 21590956 TI - Electronic Properties and Photovoltaic Performances of a Series of Oligothiophene Copolymers Incorporating Both Thieno[3,2-b]thiophene and 2,1,3-Benzothiadiazole Moieties. AB - A series of donor-acceptor alternated conjugated copolymers, composed of thiophene, bithiophene, thieno[3,2-b]thiophene, and 2,1,3-benzothiadiazole units and differing from each other by the nature and the number of 3-alkylthiophene in the backbone, have been synthesized by Stille cross-coupling polymerization. The material's optical and electrochemical properties, in solution and in thin films, have been investigated using UV-Visible absorption and cyclic voltammetry. Bulk heterojunction solar cells using blends of the newly synthesized copolymers, as electron donor, and C60-PCBM or C70-PCBM, as electron transporting material, have been elaborated. A maximum power conversion efficiency of 1.8% is achieved with a 1:4 PPBzT(2) -C12:C70-PCBM weight ratio. PMID- 21590957 TI - A rapid and facile synthesis of nanofibrillar polyaniline using microwave radiation. AB - We present the first fast and facile microwave assisted synthesis of polyaniline (PANI) nanofibers ("MWA synthesis"). Under conventional synthesis (CS), the polymer was produced with 79.7% yield after 5 h at ambient temperature. However, under microwave irradiation, the nanofibers were produced with yield of 76.2% after only 5 min, i.e., with 78.8% after 20 min at ambient temperature. The FTIR and Raman spectra show the PANI structure in all samples either synthesized conventionally or in the microwave. SEM and TEM confirm the nanofibrillar morphology. PMID- 21590958 TI - Macromol. Rapid commun. 8/2010. PMID- 21590959 TI - Recent Progress on the Photonic Properties of Conjugated Organometallic Polymers Built Upon the trans-Bis(para-ethynylbenzene)bis(phosphine)platinum(II) Chromophore and Related Derivatives. AB - This review article surveys the electronic and photophysical properties of conjugated organometallic polymers built upon the title compound and its related derivatives focussing primarily on systems investigated in our laboratories. The general structure of the polymers is (trans-bis(para ethynylbenzene)bis(phosphine)platinum(II)-G)(n) where G is a conjugated group such as thiophene, fluorene, carbazole, substituted silole, quinone derivative, and metalloporphyrin residue, or a non-conjugated main-group moiety. Systems based on substituted phenylene units and other related fused rings are also discussed. The phosphine ligands are generally triethyl- or tri-n-butylphosphine groups. These trans-platinum(II) polymers and the corresponding model compounds are compared to the corresponding ortho-derivatives in the quinone series, and the newly prepared paracyclophane-containing polymers. For the porphyrin series, a comparison of fully conjugated oligomers exhibiting the general structure (trans-bis(para-ethynyl(zinc(porphyrin)))bis(phosphine)platinum(II))(n) (i.e., the C(6) H(4) group is absent from the main chain) will be made. This contribution also includes a description of the properties of the mononuclear chromophore itself, properties that define those of the polymers. Potential applications with regard to electronic and optical devices will be highlighted. These soluble and stable materials feature both the processing advantages of polymers and the functionality provided by the presence of metal centers. These multifunctional organometallic polyyne polymers exhibit convenient structural variability as well as optical and electronic properties, which renders them important for use in different research domains as chemical sensors and sensor protectors, as converters for light/electricity signals, and as patternable precursors to magnetic metal alloy nanoparticles. PMID- 21590960 TI - Nano Grape Formation by isotactic-Poly(methacrylic acid)-block-Poly(butyl acrylate). AB - A novel approach is employed to produce core-corona nanospheres, which introduces a stereoregular hydrophilic part to an amphiphilic block copolymer. The resultant morphology is reported using isotactic-poly(methacrylic acid)-block-poly(butyl acrylate). Infrared spectroscopy revealed a supramolecular interaction, and X ray diffraction revealed the crystallization of the outer isotactic-poly(methacrylic acid) part. The nanostructure, which looks like a nanosized 'grape', was formed when nanospheres and nanofibers coexisted simultaneously and partially fused. PMID- 21590961 TI - Molecular Characteristics of Poly(N-isopropylacrylamide) Separated from Nanocomposite Gels by Removal of Clay from the Polymer/Clay Network. AB - The extraordinary mechanical and swelling/deswelling properties of nanocomposite (NC) gels are attributed to their unique organic (polymer)/inorganic (clay) network structure. In this study, poly(N-isopropylacrylamide) (PNIPA) was successfully separated from an NC gel network by decomposing the clay (hectorite) using hydrofluoric acid (HF). A very low HF concentration (0.2 wt.-%) was adequate for the decomposition of the clay without causing any damage to PNIPA. The separated PNIPA had a high $?overline M _{?rm w}$ (=5.5 * 10(6) g . mol(-1) ). Also, $?overline M _{?rm w}$ was almost constant regardless of the clay concentration (C(clay) = 1-25 * 10(-2) mol . l(-1) ), even though the properties of the NC gel varied widely over this C(clay) range. Comparisons of NC gels, PNIPA, and SiO(2) -NC gels indicated that the clay platelets specifically play an important role in NC gels. PMID- 21590962 TI - The Effect of Hofmeister Salts on the LCST Transition of Poly(2-oxazoline)s with Varying Hydrophilicity. AB - The influence of Hofmeister salts was investigated on the cloud point of three poly(2-oxazoline)s, namely poly(2-ethyl-2-oxazoline) [PEtOx], poly(2-n-propyl-2 oxazoline) [PnPropOx], and poly(2-isopropyl-2-oxazoline) [PiPropOx]. In addition, a comb polymer based on oligo-2-ethyl-2-oxazoline side chains and a methacrylate backbone (POEtOxMA) was included in this investigation. It was found that the ionic response of the poly(2-oxazoline)s strongly depends on their hydrophilicity. The comb polymer POEtOxMA revealed a strikingly similar response to the salts as linear PEtOx even though the cloud points of the polymers in water differ. This indicates that the architecture does not significantly influence the effect of the Hofmeister ions, even though there is a difference in the absolute cloud point. PMID- 21590963 TI - Block Copolymer Micellar Nanoreactors for the Directed Synthesis of ZnO Nanoparticles. AB - We report the simple one-pot synthesis of size tunable zinc oxide nanoparticles (ZnO NPs) out of an organometallic ZnO precursor using the self-assembly of solution phase polystyrene-block-poly(2-vinylpyridine) micelles. The resulting hybrid material could be deposited on various substrates in a straightforward manner with the NPs showing size-dependent absorption and photoluminescence due to the quantum-size effect. We compare the results to the assembly of preformed NPs which are selectively incorporated in the poly(2-vinylpyridine) core of the micelles due to the high affinity of ZnO to vinylpyridine. PMID- 21590964 TI - Self-aligned micropatterns of bifunctional polymer surfaces with independent chemical and topographical contrast. AB - Bifunctional surfaces are micropatterned using a self-aligned, dual-purpose lithographic mask and pairs of conformally deposited iCVD polymers. A first layer is deposited, then physically masked and etched in oxygen plasma. A second layer is deposited with the mask still in place. Lift-off reveals the micropatterned surface. The thicknesses of the two layers are independently controlled so that the resultant surface displays both chemical and topographical contrast. The patterning scheme is independent of the polymers used and order of deposition. We use this scheme to create surfaces that spatially confine microcondensation, as well as chemical functionality. We also demonstrate microwells whose depth can be altered in response to a water stimulus. PMID- 21590965 TI - Heterogeneous "Organoclick" Derivatization of Polysaccharides: Photochemical Thiol-ene Click Modification of Solid Cellulose. AB - A simple and direct method for derivatization of solid polysaccharides is presented. The novel methodology is based on the combination of organic acid catalyzed esterification or etherification and photochemical thiol-ene click derivatization of a heterogeneous polysaccharide. The solid cellulose was "organoclick" modified with aryl, alkyl and polyester groups, respectively. The modification allows for a highly modular and metal free surface modification of solid polysaccharides. PMID- 21590966 TI - Electrostatic Assembly of Poly(ethylene glycol) Nanotubes. AB - Poly(ethylene glycol) (PEG)-based films, nanotubes, and nanotube arrays were successfully made using layer-by-layer (LbL) assembly ion-containing PEO derivatives on porous templates and planar substrates. PEG nanotubes are challenging to produce because PEG dissolves into solutions and solvents used during nanotube processing, but our techniques circumvent the issue. Nanotube dimensions were verified using microscopy and the average observed diameter was 155 nm. The PEG-based structures showed remarkable stability in water, salt water, and sodium hydroxide solution. PMID- 21590967 TI - Poly(p-phenylenevinylene) Derivatives with Defined Conjugation Segments and Post Polymerization Modification with Sterically Enshrouded Chromophores. AB - Two poly(p-phenylenevinylene) derivative alternating copolymers (P1-I and P2-I) have been prepared featuring iodo substituents and m-phenylene units to periodically disrupt conjugation. P1-I was derivatized with various chromophores to yield P1a-f. In P1a-f, the chromophores were positioned within a sterically protected pocket shielding them from interchain interactions so that intrachain interactions between polymer segments could be observed. Solution and film properties of polymers have been examined. Post-polymerization chromophore modification leads to new photophysical properties such as intramolecular charge transfer and fluorescent resonance energy transfer processes in some cases. PMID- 21590968 TI - Macromol. Rapid commun. 9-10/2010. PMID- 21590969 TI - Metal-containing and metallo-supramolecular polymers and materials. PMID- 21590970 TI - Poly(ferrocenylsilane) Gels and Hydrogels with Redox-Controlled Actuation. AB - This concise paper discusses poly(ferrocenylsilane) (PFS)-based organometallic gels and hydrogels as a novel class of redox-responsive materials. First, the use of silicon-bridged spirocyclic [1]ferrocenophane crosslinkers for creating PFS networks swellable in organic solvents is described. Optical properties of PFS composite colloidal crystal films, composed of monodisperse silica spheres embedded in such PFS networks, are shown to be influenced by solvent swelling or redox chemistry, allowing the use of these composites in photonic crystal full color displays. The synthesis of networks composed of water-soluble PFS polyanions or polycations is discussed. In response to redox stimuli, a polyanionic PFS-hydrogel exerted a pressure, which could render it useful as an actuator. PMID- 21590971 TI - Metal-ligand-containing polymers: terpyridine as the supramolecular unit. AB - New and interesting properties can be obtained from macromolecular architectures functionalized with supramolecular moieties, particularly metal-ligand complexes. Self-assembly, based on the selective control of noncovalent interactions, guides the creation of hierarchically ordered materials providing access to novel structures and new properties. This field has expanded significantly in the last two decades, and one of the most ubiquitous functionalities is terpyridine. Despite its wide-spread use, much basic knowledge regarding the binding of terpyridine with metal ions remains unknown. Here, the binding constants of PEG substituted terpyridine in relation to other literature reports are studied and a few examples of supramolecular materials from our laboratory are summarized. PMID- 21590972 TI - Promising Optoelectronic Materials: Polymers Containing Phosphorescent Iridium(III) Complexes. AB - As one of the most promising optoelectronic materials, polymers that contain phosphorescent Ir(III) complexes have attracted more and more interest in recent years. They are a class of well-known electroluminescent materials with excellent performance. So far, efficient green-, red-, and white-emitting polymer light emitting diodes based on polymers with on-chain Ir(III) complexes have been realized successfully. For the realization of this class of polymer material, Ir(III) complexes (as energy guest) can be introduced into the main-chain or side chain of polymers (as energy host). In this article, we summarize the design principles, synthetic routes, structure-property relationships, and applications in optoelectronic devices of polymers that contain phosphorescent Ir(III) complexes. PMID- 21590973 TI - Luminescent coordination polymers built upon cu(4) x(4) (x=br,i) clusters and mono- and dithioethers. AB - This paper focuses on the syntheses, structures, and luminescence properties of 1D, 2D, and 3D coordination polymers built upon the tetranuclear Cu(4) X(4) clusters and mono- and dithioether assembling ligands. A review of the relevant literature is presented along with our own results stressing on the salient features of the interactions between the CuI salt as the starting material and the thioethers. Among the features, the solvato- (lost or gain of a monothioether or solvent molecule) and luminescence thermochromism (temperature dependence of the emission) of the solids, and the enhanced versatility of the CuI salt to form clusters of different nuclearity (Cu(2) I(2) , Cu(4) I(4) , Cu(6) I(6) ) and structures (closed cubane, partially open "flower-basket-like" cubane, and open cubane) upon the reaction conditions and ligands, are described. The steady state and time-resolved solid-state emission and excitation spectra (at 298 and 77 K) as well as the emission lifetimes are examined. Simple and apparently "innocent" modification may have a drastic effect on the polymer network and cluster structures, but this paper finds no obvious trend for the moment except for the ligand rigidity. The rhombic Cu(2) I(2) and closed-cubane Cu(4) I(4) clusters are the most encountered motifs whereas the open-flower-basket Cu(4) I(4) cubane and the hexagonal Cu(6) I(6) clusters are scarce. PMID- 21590974 TI - RAFT Polymerization Meets Coordination Chemistry: Synthesis of a Polymer-Based Iridium(III) Emitter. AB - A synthetic approach toward the synthesis of well-defined copolymers with attached phosphorescent iridium(III) emitters is presented. A reactive u-hydroxy bridged precursor complex has been utilized to coordinate suitable ligand sites of a methacrylate-based copolymer. The starting copolymer has been synthesized via the reversible addition fragmentation chain transfer (RAFT) polymerization technique. Using a reactive complex species, the coordination reaction at the copolymer could be performed under very mild conditions in the absence of any supporting additives. PMID- 21590976 TI - Supramolecular Star-Shaped Poly(ethylene glycol) Based on a [2 * 2] Grid-Like Metal Complex. AB - Supramolecular star-shaped polymers are a class of materials that are formed by self-assembly of polymeric precursors. The resulting structures combine the beneficial properties of conventional star-shaped polymers and (reversible) supramolecular interactions. We previously introduced [2 * 2] copper(I) grids of 3,6-di(2-pyridyl)-pyridazine (DPP) as structural motif to form the core of supramolecular star-shaped polymers. In the current work, this concept is expanded to star-shaped poly(ethylene glycol) (PEG) by end-functionalization of amine-functionalized PEG with DPP. The synthesis and characterization of PEG-DPP as well as the self-assembly into star-shaped supramolecular polymers upon copper(I) complexation are discussed in detail. PMID- 21590975 TI - Aggregation-Induced Emission in a Hyperbranched Poly(silylenevinylene) and Superamplification in Its Emission Quenching by Explosives. AB - A silicon-containing hyperbranched polymer (hb-P1/2) with sigma*-pi* conjugation was prepared in a good yield and high molecular weight by rhodium-catalyzed alkyne polyhydrosilylation of 1,2-bis(4-ethynylphenyl)-1,2-diphenylethene (1) with tris(4-dimethylsilylphenyl)amine (2). The polymer was thermally stable, losing merely 5% of its weight when heated to ~445 degrees C. Whereas hb-P1/2 was weakly luminescent when molecularly dissolved, it became highly emissive when supramolecularly aggregated, showing an aggregation-induced emission (AIE) phenomenon. A superamplification effect was observed when the AIE nanoaggregates were used as fluorescent chemosensor for explosive detection: the quenching efficiency was greatly increased in a nonlinear fashion with increasing quencher concentration. PMID- 21590977 TI - Organometallic complexes for nonlinear optics, 47 - synthesis and cubic optical nonlinearity of a stilbenylethynylruthenium dendrimer. AB - The synthesis of the 1st generation dendrimer 1,3,5-{trans-[Ru(C=C-3,5-(trans [Ru(C=CPh)(dppe)(2) (C=CC(6) H(4) -4-(E)-CH?CH)])(2) C(6) H(3) )(dppe)(2) (C=CC(6) H(4) -4-(E)-CH?CH)]}(3) C(6) H(3) proceeds by a novel route that features Emmons-Horner-Wadsworth coupling of 1,3,5-C(6) H(3) (CH(2) PO(OEt)(2) )(3) with trans-[Ru(C=CC(6) H(4) -4-CHO)Cl(dppe)(2) ] and 1-I-C(6) H(3) -3,5 (CH(2) PO(OEt)(2) )(2) with trans-[Ru(C=CPh)(C=CC(6) H(4) -4-CHO)(dppe)(2) ] as key steps. The stilbenylethynylruthenium dendrimer is much more soluble than its ethynylated analog 1,3,5-{trans-[Ru(C=C-3,5-(trans-[Ru(C=CPh)(dppe)(2) (C=CC(6) H(4) -4-C=C)])(2) C(6) H(3) )(dppe)(2) (C=CC(6) H(4) -4-C=C)]}(3) C(6) H(3) and, in contrast to the ethynylated analog, is a two-photon absorber at telecommunications wavelengths. PMID- 21590978 TI - Shape-Persistent, Truxene-Based, Nano-Sized Bisterpyridine Ruthenium(II) Complexes: Synthesis and Photophysical Properties. AB - A new series of shape-persistent metallomacromolecules G0 and G1 as well as corresponding ligands, based on thiophene-functionalized bisterpyridine-Ru(II) with truxene moieties, as the nodes, were developed. All new compounds were fully characterized by (1) H, COSY, and (13) C NMR, as well as MALDI-TOF MS. Their photophysical properties revealed that the branched scaffold resulted in high molar absorption coefficients and broad absorption making these materials potential candidates for light-harvesting. PMID- 21590979 TI - Synthesis of Prussian Blue Coordination Polymer Nanocubes via Confinement of the Polymerization Field Using Miniemulsion Periphery Polymerization (MEPP). AB - Miniemulsion periphery polymerization (MEPP) has been used for the synthesis of Prussian blue (PB) nanocubes. Pentacyano ferrate functionalized surfactant in combination with a co-surfactant containing 4-(dimethylamino)-pyridine (DMAP) or OH end groups in lieu of ferrate functionality (EPE-DMAP or EPE-OH) were used to prepare a miniemulsion system comprising 20 wt.-% toluene and 0.5 wt.-% total surfactant. On addition of Fe(3+) to the miniemulsion, metal coordination polymerization occurred with nanocubes generated when the ratio of EPE-Fe:EPE DMAP (or EPE-OH) was 60:40 (w/w). The resulting nanocubes are apparently amorphous. Particles with irregular shape have been observed on reacting EPE-Fe and Fe(3+) directly in water, thus suggesting that confinement of the polymerization field on the periphery of the miniemulsion droplets is a primary factor in the formation of cubic structures. PMID- 21590980 TI - Very-low-bandgap metallopolyynes of platinum with a cyclopentadithiophenone ring for organic solar cells absorbing down to the near-infrared spectral region. AB - Two solution-processable metallopolyynes of platinum functionalized with the electron-deficient 4H-cyclopenta[2,1-b:3,4-b']dithiophen-4-one spacer and their model molecular complexes were synthesized and developed for the applications of polymer solar cells. These metallated polymers possess extremely low bandgaps of 1.44-1.53 eV which extend toward the near-infrared (NIR) range of the solar spectrum, and represent the lowest optical bandgap yet reported for platinum(II) metallopolyynes to date. The structural flexibility, processibility, and good photovoltaic performance make cyclopentadithiophenone-containing polymers prominent candidates for NIR photovoltaic applications. PMID- 21590981 TI - pi-Conjugated Donor and Donor-Acceptor Metallo-Polymers. AB - Two zinc(II)- and two ruthenium(II) containing pi-conjugated metallo-polymers were synthesized and characterized in detail. We could prove by SEC, analytical ultracentrifugation (AUC) and viscosimetry the ruthenium(II) metallo-polymers to be high molar mass materials (M(fs) = 20 000 g . mol(-1) Ru1-2; M(fs) = 34 000 g . mol(-1) Ru1) exhibiting intrinsic viscosities of up to [eta] = 192 . cm(3) . g(-1) . Applying spin-coating we produced homogeneous films of the polymers and could, subsequently, investigate the photophysical properties in the solid state. Introducing the Ru(II) metallo-polymers mixed with PCBM[60] as photoactive layer in bulk-heterojunction solar cells resulted in very low efficiencies due to morphology problems. PMID- 21590982 TI - Conjugated copolymers containing low bandgap rhenium(i) complexes. AB - Conjugated copolymers with novel low bandgap rhenium(I) complexes on the polymer main-chain are reported. The low bandgap metal-containing polymers were synthesized by Suzuki cross-coupling polycondensation or Stille coupling polymerization. The metal free copolymers are conjugatively-linked with functionalized intramolecular charge transfer units, which exhibited prominent absorption band in the UV-vis region. These functionalized charge transfer units not only broadened the absorption spectrum, but also functioned as a bidentate ligand. Upon the complexation of rhenium(I) pentacarbonyl chloride, the absorption spectrum of the resulting polymers was further boardened, and the bandgap was reduced. The material design of this work has opened up a new approach in developing low bandgap metal-containing polymers as light harvesting materials. PMID- 21590983 TI - Dual emission from highly conjugated 2,2':6':2"-terpyridine complexes-a potential route to white emitters. AB - Here, we present a new class of terpyridine complexes of the transition-metal ions, iron(II), ruthenium(II), and osmium(II), overcoming the poor emission properties typical for this class of polypyridyl complexes. These complexes show, besides an increased room-temperature emission quantum yield and a prolonged lifetime of the metal-to-ligand charge-transfer (MLCT) states, dual emission from two well-separated excited states of the same molecule. These experimental findings are attributed to a highly stabilized ligand chromophore, where photoinduced excited-state planarization causes an enhancement of electron delocalization. This planarization, in turn, reduces the potential energy of the S(1) state and minimizes electronic coupling to the MLCT state, which is prone to non-radiative deactivation via metal-centered excited states. Due to their dual emission the complexes presented here show emission covering the entire Vis spectral range upon excitation of the pipi* states in the near UV. Thus, by structurally tuning the electronic coupling of the pipi* and the MLCT states a new synthetic route toward white emitters, which can subsequently be incorporated into polymers, is opened. PMID- 21590984 TI - Silacyclobutane-based diblock copolymers with vinylferrocene, ferrocenylmethyl methacrylate, and [1]dimethylsilaferrocenophane. AB - Well-defined diblock copolymers have been prepared in which three different ferrocene-based monomers are combined with 1,1-dimethylsilacyclobutane (DMSB) and 1-methylsilacyclobutane, respectively, as their carbosilane counterparts. Optimized procedures are reported for the living anionic chain growth following sequential monomer addition protocols, ensuring narrow polydispersities and high blocking efficiencies. The DMSB-containing copolymers show phase segregation in the bulk state, leading to micromorphologies composed of crystalline DMSB phases and amorphous polymetallocene phases. PMID- 21590985 TI - Monte carlo simulations of metallo-supramolecular micelles. AB - Using Monte Carlo simulations we show that the equilibrium properties of metallo supramolecular micelles are determined by the competition of 2:1 and 1:1 metal ligand complexation in the bulk and on the surface as well as steric interactions between the neighboring corona blocks attached to the surface. We predict that by increasing the association energy for the second metal-ligand bond, or decreasing the corona block length one can achieve a larger core surface coverage for metallo-supramolecular micelles. Compared to covalently bonded block copolymer micelles, we show that metallo-supramolecular micelles have smaller monomer and end group density, especially in the vicinity of the core, which may lead to experimentally observed aggregation. PMID- 21590986 TI - Electropolymerization of a Ruthenium(II) Bis(pyrazolyl)pyridine Complex to Form a Novel Ru-Containing Conducting Metallopolymer. AB - A new derivative of 2,6-bis(pyrazol-1-yl)pyridine (bpp) symmetrically substituted with 3,4-ethylenedioxy-thienyl (EDOT) substituent groups, and the corresponding ruthenium(II) complex was synthesized and characterized by NMR spectroscopy, elemental analysis, mass spectrometry, and single-crystal X-ray diffraction. A new linear conducting metallopolymer consisting of [Ru(bpp-(EDOT)(2) )(terpy)](2+) fragments was deposited directly on to electrode surfaces as a transparent, deep red film by electrochemical coupling of the pendant EDOT moieties. XPS analysis reveals that the film has the expected structure consisting of monomer repeats without degradation or loss of metal ions. Additionally, the absorption spectrum of the polymer film shows a broad absorption range from 310 to 700 nm. PMID- 21590987 TI - Photooxidation of Nanopatterned Poly(chloromethylstyrene): Direct Formation of Crosslinked Aldehyde-Functionalized Films for Chemical Functionalization and Bioconjugation. AB - UV irradiation of chloromethyl styrene simultaneously crosslinks the polymer and generates aldehyde groups that can be employed for polymer surface functionalization through aldehyde-imine/hydrazone chemistry. Using this method, we successfully have functionalized nanoimprinted polymer patterns with dyes, nanoparticles, and enzymes. These surfaces were characterized by infrared (ATR IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), fluorescence microscopy, and enzymatic activity assays. PMID- 21590988 TI - Donor-pi-Acceptor Polymer with Alternating Triarylborane and Triphenylamine Moieties. AB - A luminescent main chain donor-pi-acceptor-type polymer (4) was prepared via organometallic polycondensation reaction followed by post modification. With both electron-rich amine and electron-deficient borane moieties embedded in the main chain, 4 exhibits an interesting ambipolar character: it can be reduced and oxidized electrochemically at moderate potentials and shows a strong solvatochromic effect in the emission spectra. Complexation studies show that 4 selectively binds to fluoride and cyanide; quantitative titration with cyanide reveals a two-step binding process. PMID- 21590989 TI - Complexation of terpyridine-containing dextrans: toward water-soluble supramolecular structures. AB - Dextran was functionalized with 6-(2,2':6',2"-terpyridin-4'-yloxy)-hexanoic acid using two different ratios of terpyridine to dextran, leading to terpyridine functionalized dextran esters possessing different degrees of substitution (DS = 0.23-0.41). The intra- and intermolecular complexation behavior of both functionalized biopolymers was studied using Fe(II) metal ions as well as activated Ru(III) complexes. The complexation behavior in the first case was studied by UV-visible and viscosity titration experiments. In the latter case, a water soluble comb-polymer could be obtained when using a PEG- functionalized terpyridine Ru(II) moiety for complexation. Moreover, nanoprecipitation was applied to self-assemble the functionalized dextrans into nanoparticles. PMID- 21590990 TI - Seeded growth and solvent-induced fragmentation of fiberlike polyferrocenylsilane polyisoprene block copolymer micelles. AB - Addition of a concentrated solution of PI(1000) -PFS(50) dissolved in THF to a solution of PI(1000) -PFS(50) seed micelles in decane led to the formation of uniform elongated fiberlike micelles with a narrow length distribution. When additional THF (>10 vol.-%) was added to the micelles, the micelle length decreased and the contour-length distribution broadened. This effect was shown to be inconsistent with a transition to an equilibrium, in which individual polymer molecules dissociated from and added to existing micelles. Rather, it appears that the polar solvent induced fragmentation of the fiberlike micelles. PMID- 21590991 TI - Fiberlike micelles formed by living epitaxial growth from blends of polyferrocenylsilane block copolymers. AB - Poly(ferrocenyldimethylsilane) (PFS) block copolymers form fiberlike micelles by a seeded growth process. This paper describes the effect of adding similar amounts of PFS block copolymers, PFS-PDMS and PFS-PI, to a common micelle seed. The lengths of the micelles obtained were strongly influenced by the degree of polymerization of the corona-forming blocks. The change in length was due to a change in the number of polymer molecules per unit length of the micelle. PMID- 21590992 TI - Synthesis and characterization of cytocompatible sulfonated polyanilines. AB - We report here that by good design, polyaniline (PANI) can be cytocompatible and formed into usable scaffolds for bio-medical applications. By adjusting the ratio of two monomers, aniline (AN) and metanilic acid (MA), a series of copolymers with different sulfonation degrees have been synthesized. Four-probe conductivity measurements showed that as the sulfonation degree increased, the conductivity decreased. XPS analysis was used to determine the sulfur/nitrogen ratio. In vitro cell culture study was conducted with human osteosarcoma (HOS) cells. Microscopic observation did not show abnormal cellular behavior when sulfonated polyaniline (SPAN) was put in direct contact with HOS cells. Cells growing on the non transparent dark green SPAN films were observed with fluorescence by laser scanning cytometry (LSC). In proliferation studies more than 70% of cells were found viable on SPAN compared to 88% for poly(L-lactic acid) with the number of cells growing on glass as a control, indicating generally good biocompatibility. We expect these polymers would have great potential in biological applications of conducting polymers as we determine that a variety of physical and chemical properties can be controlled through synthesis. PMID- 21590993 TI - Scanning force microscopy as applied to conformational studies in macromolecular research. AB - The modern state of SFM research on polymer nano-objects including single chains is discussed in comparison with other similar high-resolution microscopy techniques. The range of problems to be solved preferentially by SFM is highlighted. Promising methodology to describe quantitatively the morphology of macromolecular objects is proposed. The main benefits of this algorithm seem to be the apparent mathematical correctness as well as the possibility to estimate errors and the confidence of the numbers obtained. Special attention is paid to the dynamic observations of conformational transitions on a substrate in real time regime. This approach allows one to realise direct control of the adsorbed macromolecules by means of exposure to different vapours. Driving forces of the vapour-induced reorganisation are discussed. PMID- 21590995 TI - Magnetic resonance imaging evaluation of renal structure and function related to disease: technical review of image acquisition, postprocessing, and mathematical modeling steps. AB - Kidney disease represents a leading cause of morbidity, with high healthcare costs. The existing methods used to evaluate renal function include measures of glomerular filtration rate (GFR), yet the clinical methods are generally inaccurate and poorly reproducible. A method that improves measures of renal function as part of a comprehensive examination that also evaluates renal structure represents an important unmet clinical need. Use of dynamic contrast enhanced magnetic resonance imaging (MRI) for the evaluation of renal function has been undergoing development by several groups. The methodology has been referred to as MR Urography (MRU) or MR Nephro-urography (MRNU). MRU/MRNU shows promise for providing new insights into the evaluation of renal structure and function in relation to important disease processes, including urinary obstruction and in relation to renal transplantation. MRU/MRNU generally requires consideration of imaging acquisition technique, image postprocessing strategies, and subsequent kinetic mathematical modeling of the data in reference to specific physiological renal processes, such as renal blood flow and GFR. Here we review the specifics of proposed methods in light of the overall strengths and limitations of each of these strategies. The overall objective is to provide a roadmap for future developments in this evolving field of novel MRI applications. PMID- 21590996 TI - Detection of early response to temozolomide treatment in brain tumors using hyperpolarized 13C MR metabolic imaging. AB - PURPOSE: To demonstrate the feasibility of using DNP hyperpolarized [1-(13)C] pyruvate to measure early response to temozolomide (TMZ) therapy using an orthotopic human glioblastoma xenograft model. MATERIALS AND METHODS: Twenty athymic rats with intracranial implantation of human glioblastoma cells were divided into two groups: one group received an oral administration of 100 mg/kg TMZ (n = 10) and the control group received vehicle only (n = 10). (13)C 3D magnetic resonance spectroscopic imaging (MRSI) data were acquired following injection of 2.5 mL (100 mM) hyperpolarized [1-(13)C]-pyruvate using a 3T scanner prior to treatment (day D0), at D1 (days from treatment) or D2. RESULTS: Tumor metabolism as assessed by the ratio of lactate to pyruvate (Lac/Pyr) was significantly altered at D1 for the TMZ-treated group but tumor volume did not show a reduction until D5 to D7. The percent change in Lac/Pyr from baseline was statistically different between the two groups at D1 and D2 (P < 0.008), while percent tumor volume was not (P > 0.2). CONCLUSION: The results from this study suggest that metabolic imaging with hyperpolarized [1-(13)C]-pyruvate may provide a unique tool that clinical neuro-oncologists can use in the future to monitor tumor response to therapy for patients with brain tumors. PMID- 21590997 TI - Dual-temporal resolution dynamic contrast-enhanced MRI protocol for blood-brain barrier permeability measurement in enhancing multiple sclerosis lesions. AB - PURPOSE: To design a more accurate and reproducible technique for the measurement of blood-brain barrier (BBB) permeability in gadolinium-enhancing multiple sclerosis (MS) lesions. MATERIALS AND METHODS: Four MS patients were scanned using a new dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) protocol based on an uninterrupted two-part acquisition consisting of an initial part at high temporal and low spatial resolutions and a second part at low temporal and high spatial resolutions. The method preserves both the high spatial resolution needed for the often small size of lesions and the high temporal resolution required during the first minute after injection to sufficiently sample the first-pass bolus. Simulations compared the performance of this new protocol with the conventional one at low temporal and high spatial resolutions throughout. RESULTS: The BBB permeability estimates changed by up to 33% between the two protocols. The new protocol led to simulated error on K(trans) of 7%-10%, versus 7%-30% with the conventional protocol, and was more robust with respect to offsets between acquisition and injection start times, differences in shape of the first-pass peak, and permeability values. CONCLUSION: The dual-temporal resolution protocol produces improved BBB permeability estimates and provides a more complete view of active inflammatory MS lesion pathology. PMID- 21590998 TI - Preclinical use of longitudinal MRI for screening the efficacy of S nitrosoglutathione in treating spinal cord injury. AB - PURPOSE: To evaluate the therapeutic efficacy of S-nitrosoglutathione (GSNO) in spinal cord injury (SCI) using in vivo MRI in combination with neuorobehavioral testing and postmortem tissue analysis. MATERIALS AND METHODS: Sixteen female rats were mildly injured at the vertebral T10 level and randomized into control (n = 8) and GSNO-treatment (n = 8) groups. GSNO was delivered at 0.05 mg/kg dose in saline by means of tail vein at 1 hr postinjury and then given orally on the following days. On postinjury days 1, 3, 7, and 28, the rats were tested behaviorally, then scanned using sagittal T2-weighted MRI for the quantification of lesion, edema, and hemorrhagic regions at the injury site. Excised cords were analyzed using histology and immunohistochemistry. RESULTS: Treatment with GSNO was feasible in rats with SCI. On the average, the GSNO group at each scan day 1, 3, 7, and 28 exhibited better functional recovery as indicated by the behavioral performance of 52%, 33%, 19%, and 18%, and had smaller lesions of -4%, -16%, 20%, and -17% compared with the controls, respectively. Edema trend was parallel to the lesion volumes in both groups. Ex vivo data demonstrated that GSNO plays a role in neuronal tissue preservation and sparing. CONCLUSION: The data collectively provided the preliminary evidence that the injured rats responded favorably to GSNO treatment. Longitudinal MRI provides critical quantitative information regarding the changes in lesion properties, which helps evaluating the efficacy of an exogenous intervention in SCI. PMID- 21590999 TI - Quantitative assessment of the cervical spinal cord damage in neuromyelitis optica using diffusion tensor imaging at 3 Tesla. AB - PURPOSE: To investigate whether quantitative MRI measures of cervical spinal cord white matter (WM) using diffusion tensor imaging (DTI) in neuromyelitis optica (NMO) differed from controls and correlated with clinical disability. MATERIALS AND METHODS: Ten referred patients and 12 healthy volunteers were imaged on a 3 Tesla scanner and patients were clinically assessed on the Expanded Disability Status Scale (EDSS). Two raters quantified DTI-derived indices from all participants, including fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity (lambda[parallel]) and perpendicular diffusivity (lambda[perpendicular]) at C1-C6 for lateral and dorsal columns. After the inter rater reliability test, univariate correlations between DTI measures and disability were assessed using the Spearman's rho correlation coefficient. Multiple regression analysis was performed to investigate which DTI measures independently correlated with the clinical score. RESULTS: Statistical test results indicated high reliability of all DTI measurements between two raters. NMO patients showed reduced FA, increased MD and lambda[perpendicular] compared with controls while lambda[parallel] did not show any significant difference. The former three DTI metrics also showed significant correlations with disability scores, and especially FA was found to be sensitive to mild NMO (EDSS <= 3) CONCLUSION: FA is a potentially useful quantitative biomarker of otherwise normal appearing WM damage in NMO. Such damage is associated with clinical disability. PMID- 21591000 TI - Measurement of aortic arch pulse wave velocity in cardiovascular MR: comparison of transit time estimators and description of a new approach. AB - PURPOSE: To investigate the efficiency of a new method (TT-Upslope) for transit time (Deltat) estimation from cardiovascular MR (CMR) velocity curves. MATERIALS AND METHODS: Fifty healthy volunteers (40 +/- 15 years) underwent applanation tonometry to estimate carotid-femoral pulse wave velocity (cf-PWV) and carotid pressure measurements, and CMR to estimate aortic arch-PWV and ascending aorta distensibility (AAD). The Deltat was calculated with TT-Upslope by minimizing the area delimited by two sigmoid curves fitted to the systolic upslope of the ascending (AAC) and descending (DAC) aorta velocity curves, and compared with previously described methods: TT-Point using the half maximum of AAC and DAC, TT Foot using AAC and DAC feet, and TT-Wave by minimizing the area between AAC and DAC curves using cross correlation. RESULTS: All the Deltat methods provided a high reproducibility of arch-PWV. However, TT-Upslope and TT-Wave resulted in better correlations with aging (r = 0.83/r = 0.83 versus r = 0.47/r = 0.72), cf PWV (r = 0.69/r = 0.70 versus r = 0.34/r = 0.59), and AAD (r = 0.81/r = 0.71 versus r = 0.61/r = 0.60). Furthermore, TT-Upslope resulted in stronger relationship between arch-PWV and AAD according to a theoretical model and provided better characterization of older subjects compared with TT-Wave. CONCLUSION: Arch-PWV estimated with CMR using the TT-Upslope method was found to be reproducible and accurate, providing strong correlations with age and aortic stiffness indices. PMID- 21591001 TI - Practical signal-to-noise ratio quantification for sensitivity encoding: application to coronary MR angiography. AB - PURPOSE: To develop and evaluate a practical method for the quantification of signal-to-noise ratio (SNR) on coronary MR angiograms (MRA) acquired with parallel imaging. MATERIALS AND METHODS: To quantify the spatially varying noise due to parallel imaging reconstruction, a new method has been implemented incorporating image data acquisition followed by a fast noise scan during which radiofrequency pulses, cardiac triggering and navigator gating are disabled. The performance of this method was evaluated in a phantom study where SNR measurements were compared with those of a reference standard (multiple repetitions). Subsequently, SNR of myocardium and posterior skeletal muscle was determined on in vivo human coronary MRA. RESULTS: In a phantom, the SNR measured using the proposed method deviated less than 10.1% from the reference method for small geometry factors (<=2). In vivo, the noise scan for a 10 min coronary MRA acquisition was acquired in 30 s. Higher signal and lower SNR, due to spatially varying noise, were found in myocardium compared with posterior skeletal muscle. CONCLUSION: SNR quantification based on a fast noise scan is a validated and easy to-use method when applied to three-dimensional coronary MRA obtained with parallel imaging as long as the geometry factor remains low. PMID- 21591002 TI - Cardiovascular MR dobutamine stress in adult tetralogy of Fallot: disparity between CMR volumetry and flow for cardiovascular function. AB - PURPOSE: To evaluate the MR agreement of cardiac function parameters between volumetric (cine SSFP) and phase contrast flow (PC-flow) assessment in patients with repaired tetralogy of Fallot (r-TOF) and chronic pulmonary regurgitation (PR) at rest and under dobutamine stress (DS-MR). MATERIALS AND METHODS: We studied 18 patients with r-TOF and severe chronic PR (34 +/- 12.7 years, PR fraction([flow]) 44 +/- 15%) by cardiac MR at rest, 10 and 20 MUg/kg/min of dobutamine. We compared analogous functional parameters by volumetry and PC-flow: (i) Systemic output [left ventricle stroke volume (LV(SV)) versus aortic forward flow (AO(FF))], (ii) Pulmonary output [right ventricle stroke volume (RV(SV)) versus pulmonary forward flow (PA(FF))], (iii) PR volume [(RV(SV)-LV(SV)) versus pulmonary backward flow (PA(BF))], (iv) PR fraction [(RV(SV)-LV(SV)/RV(SV)) versus (PA(BF)/PA(FF))]. RESULTS: We found excellent Bland-Altman agreement (mean difference +/- limits of agreement, mL/beat/m(2)) at rest for both the systemic ( 0.8 +/- 5.7) and pulmonary strokes volumes (-0.1 +/- 7.6), which slightly deteriorates during DS-MR. The PR volume showed acceptable agreement at rest ( 3.6 +/- 15.1), but also further deteriorated during stress (5.4 +/- 24). In contrast, the PR fraction showed poor agreement equally at rest (-5.6 +/- 22.8) and DS-MR (3.2 +/- 19.2). CONCLUSION: In r-TOF with chronic PR, analogous functional parameters should not be used interchangeably between volumetric and PC-flow assessment during DS-MR evaluation. PMID- 21591003 TI - MR elastography of human lung parenchyma: technical development, theoretical modeling and in vivo validation. AB - PURPOSE: To develop a novel MR-based method for visualizing the elastic properties of human lung parenchyma in vivo and to evaluate the ability of this method to resolve differences in parenchymal stiffness at different respiration states in healthy volunteers. MATERIALS AND METHODS: A spin-echo MR Elastography (MRE) pulse sequence was developed to provide both high shear wave motion sensitivity and short TE for improved visualization of lung parenchyma. The improved motion sensitivity of this approach was modeled and tested with phantom experiments. In vivo testing was then performed on 10 healthy volunteers at the respiratory states of residual volume (RV) and total lung capacity (TLC). RESULTS: Shear wave propagation was visualized within the lungs of all volunteers and was processed to provide parenchymal shear stiffness maps for all 10 subjects. Density corrected stiffness values at TLC (1.83 +/- 0.22 kPa) were higher than those at the RV (1.14 +/- 0.14 kPa) with the difference being statistically significant (P < 0.0001). CONCLUSION: (1)H-based MR elastography can noninvasively measure the shear stiffness of human lung parenchyma in vivo and can quantitate the change in shear stiffness due to respiration. The values obtained were consistent with previously reported in vitro assessments of cadaver lungs. Further work is required to increase the flexibility of the current acquisition and to investigate the clinical potential of lung MRE. PMID- 21591004 TI - Early onset of retrograde flow in the main pulmonary artery is a characteristic of pulmonary arterial hypertension. AB - PURPOSE: To evaluate if early onset of retrograde flow in the main pulmonary artery is a characteristic of pulmonary arterial hypertension (PAH). MATERIALS AND METHODS: Fifty-five patients with suspected pulmonary hypertension (PH) underwent right-sided heart catheterization and retrospectively ECG-gated MR phase-contrast velocity quantification in the main pulmonary artery. Pulmonary hypertension was defined by a mean pulmonary artery pressure being larger than 25 mmHg. The onset time of the retrograde flow relative to the cardiac cycle duration (Relative Onset Time = ROT) was compared with mean pulmonary artery pressure. RESULTS: By the catheterization, 38 patients were identified as having PAH. The ROT for these PAH patients was significantly different from those found in the 17 non-PH subjects (0.14 +/- 0.06 versus 0.37 +/- 0.06, P < 0.001). The mean pulmonary artery pressure was related to the ROT (r(2) = 0.62, P < 0.001) and could be estimated from the ROT with a standard deviation of 11.7 mmHg. With a cutoff value of 0.25, the ROT distinguished PAH patients from non-PH subjects. CONCLUSION: Early onset of retrograde flow in the main pulmonary artery is a characteristic of pulmonary arterial hypertension and is visible by standard MR phase-contrast velocity quantification. PMID- 21591005 TI - Morphological manifestations of nonpuerperal mastitis on magnetic resonance imaging. AB - PURPOSE: To investigate the morphological features of nonpuerperal mastitis on magnetic resonance imaging (MRI). MATERIALS AND METHODS: MRI results of 27 patients diagnosed with nonpuerperal mastitis were retrospectively analyzed according to the Breast Imaging Reporting and Data System (BI-RADS). RESULTS: According to the enhanced MRI results, 22 cases presented as nonmass-like enhancements and five cases presented as masses. For the 22 nonmass-like enhancement lesions, one case showed as a homogeneous enhancement and 21 cases showed as heterogeneous enhancements. In the 21 heterogeneous enhancement cases, 13 contained lesions of rim-like enhancement. With regard to the number of lesions with rim-like enhancement, 11 presented as multiple and two as single. In the five mass lesions, three presented as rim enhancements. Indications of rim or rim-like enhancement accounted for 59% (16/27) of all cases. For the 16 cases that presented with signs of rim or rim-like enhancement, the central hypointensity area surrounded by enhanced rim or rim-like entity showed as hyperintensity in 14 cases and hypointensity or heterointensity in two cases on T2-weighted imaging. CONCLUSION: On contrast-enhanced MRI, most nonpuerperal mastitis presented as nonmass-like lesion with heterogeneous signal intensity. The observation of signs of rim or rim-like enhancement on contrast-enhanced MRI with central hypointensity areas showing as hyperintensity on T2-weighted imaging is suggestive of the possibility of nonpuerperal mastitis. PMID- 21591006 TI - Breast diffusion-weighted MRI: comparison of tetrahedral versus orthogonal diffusion sensitization for detection and localization of mass lesions. AB - PURPOSE: To evaluate the potential of tetrahedral diffusion-weighted imaging (DWI) compared to orthogonal DWI for detection and localization of early enhanced breast mass lesions at 1.5T. MATERIALS AND METHODS: Sixty-seven consecutive patients (mean age 51.7 years, range 14-84 years) with 68 solitary early enhanced breast lesions suspicious for cancer on dynamic contrast-enhanced magnetic resonance imaging (MRI) were enrolled in this retrospective study. Two radiologists independently observed maximum intensity projection images of orthogonal and tetrahedral DWI and the diagnostic accuracy and background tissue visibility between two DWI techniques were compared. Contrast-enhanced MRI was used as the reference standard. Background tissue visibility was assessed based on whether the "breast quadrant" and "skin line" were determined. A phantom validation study for apparent diffusion coefficient (ADC) values was also conducted. RESULTS: Sensitivity (93%) and specificity (96%) on tetrahedral DWI were equivalent to those on orthogonal DWI (sensitivity, 88%; specificity, 95%). Background tissue was more easily determined with tetrahedral DWI (breast quadrant, 90%; skin lines, 95%) than with orthogonal DWI (breast quadrant, 61%; skin lines, 16%). ADC values of tetrahedral DWI were highly correlated with those of orthogonal DWI. CONCLUSION: Tetrahedral DWI provided equivalent detectability of mass lesions with improved visibility of surrounding anatomical structure. PMID- 21591008 TI - Hepatic fat quantification using chemical shift MR imaging and MR spectroscopy in the presence of hepatic iron deposition: validation in phantoms and in patients with chronic liver disease. AB - PURPOSE: To compare the accuracy of four chemical shift magnetic resonance imaging (MRI) (CS-MRI) analysis methods and MR spectroscopy (MRS) with and without T2-correction in fat quantification in the presence of excess iron. MATERIALS AND METHODS: CS-MRI with six opposed- and in-phase acquisitions and MRS with five-echo acquisitions (TEs of 20, 30, 40, 50, 60 msec) were performed at 1.5 T on phantoms containing various fat fractions (FFs), on phantoms containing various iron concentrations, and in 18 patients with chronic liver disease. For CS-MRI, FFs were estimated with the dual-echo method, with two T2*-correction methods (triple- and multiecho), and with multiinterference methods that corrected for both T2* and spectral interference effects. For MRS, FF was estimated without T2-correction (single-echo MRS) and with T2-correction (multiecho MRS). RESULTS: In the phantoms, T2*- or T2-correction methods for CS MRI and MRS provided unbiased estimations of FFs (mean bias, -1.1% to 0.5%) regardless of iron concentration, whereas the dual-echo method (-5.5% to -8.4%) and single-echo MRS (12.1% to 37.3%) resulted in large biases in FFs. In patients, the FFs estimated with triple-echo (R = 0.98), multiecho (R = 0.99), and multiinterference (R = 0.99) methods had stronger correlations with multiecho MRS FFs than with the dual-echo method (R = 0.86; P <= 0.011). The FFs estimated with multiinterference method showed the closest agreement with multiecho MRS FFs (the 95% limit-of-agreement, -0.2 +/- 1.1). CONCLUSION: T2*- or T2-correction methods are effective in correcting the confounding effects of iron, enabling an accurate fat quantification throughout a wide range of iron concentrations. Spectral modeling of fat may further improve the accuracy of CS-MRI in fat quantification. PMID- 21591007 TI - The diverse pathology and kinetics of mass, nonmass, and focus enhancement on MR imaging of the breast. AB - PURPOSE: To compare the pathology and kinetic characteristics of breast lesions with focus-, mass-, and nonmass-like enhancement. MATERIALS AND METHODS: A total of 852 MRI detected breast lesions in 697 patients were selected for an IRB approved review. Patients underwent dynamic contrast enhanced MRI using one pre- and three to six postcontrast T(1)-weighted images. The "type" of enhancement was classified as mass, nonmass, or focus, and kinetic curves quantified by the initial enhancement percentage (E(1)), time to peak enhancement (T(peak)), and signal enhancement ratio (SER). These kinetic parameters were compared between malignant and benign lesions within each morphologic type. RESULTS: A total of 552 lesions were classified as mass (396 malignant, 156 benign), 261 as nonmass (212 malignant, 49 benign), and 39 as focus (9 malignant, 30 benign). The most common pathology of malignant/benign lesions by morphology: for mass, invasive ductal carcinoma/fibroadenoma; for nonmass, ductal carcinoma in situ (DCIS)/fibrocystic change(FCC); for focus, DCIS/FCC. Benign mass lesions exhibited significantly lower E(1), longer T(peak), and lower SER compared with malignant mass lesions (P < 0.0001). Benign nonmass lesions exhibited only a lower SER compared with malignant nonmass lesions (P < 0.01). CONCLUSION: By considering the diverse pathology and kinetic characteristics of different lesion morphologies, diagnostic accuracy may be improved. PMID- 21591009 TI - MRI findings of recurrent hepatocellular carcinoma after liver transplantation: preliminary results. AB - PURPOSE: To describe the patterns of recurrence and serial magnetic resonance imaging (MRI) features of hepatocellular carcinoma (HCC) after liver transplantation. MATERIALS AND METHODS: All cases of recurrent HCC after transplantation between September 2002 and August 2009 that underwent MRI including precontrast T1, T2-weighted images, and postgadolinium dynamic images were reviewed. On MRI we evaluated the characteristics and patterns of recurrent HCC after transplantation. RESULTS: A total 7 of 76 transplanted patients (four men, three women, age range, 45-63, mean 52.7 years) were included in this study. Four patients (57.1%) were identified to have a pattern of persistent local disease (PLD) near the transplanted liver, hepatorenal space, or suture site within 2.75 years (range, 2-4 years). Two patients showed recurrent HCC in the allograft alone within 5 years. One patient showed an intraperitoneal seeding (IPS) pattern which demonstrated diffuse peritoneal infiltration and thickening within 9 months. The diffuse metastatic disease (DMD) pattern was observed as a late manifestation of PLD and IPS. The most prominent volume of recurrent tumor burden was found in an extrahepatic (5 of 7 patients) compared to an intrahepatic (2 of 7 patients) location. The signal intensities and enhancement patterns did not exhibit change with disease progression. CONCLUSION: We describe four patterns of recurrence of HCC following transplant. The most prominent tumor burden was located in an extrahepatic compared to an intrahepatic location. PMID- 21591010 TI - Vascular staging of renal and adrenal malignancies with a noncontrast enhanced steady state free precession technique. AB - PURPOSE: To compare a noncontrast enhanced balanced steady state free precession (bSSFP) MRI technique with a conventional dynamic contrast-enhanced (DCE) three dimensional (3D) spoiled gradient recalled echo (SPGR) imaging in the vascular staging of renal and adrenal malignancies. MATERIALS AND METHODS: Sixty-three MRIs with both bSSFP and DCE acquisitions performed for initial staging of renal and adrenal malignancies were retrospectively evaluated for presence and extent of thrombus in the renal veins and inferior vena cava (IVC). Thrombus characterization was also evaluated. DCE imaging was used as the standard-of reference. Histopathology was available in 46 of 63 cases as an additional external standard. RESULTS: There is very good agreement between bSSFP and DCE imaging for determining the presence or absence of thrombus in the renal veins (r = 0.95; P < 0.0001) and IVC (r = 0.91; P < 0.0001). BSSFP is less successful at distinguishing bland from tumor thrombus. CONCLUSION: Noncontrast enhanced bSSFP is an acceptable alternative to DCE imaging for vascular staging of locally advanced renal/adrenal malignancies, with somewhat limited ability to distinguish bland from tumor thrombus. PMID- 21591012 TI - Segmentation of the quadratus lumborum muscle using statistical shape modeling. AB - PURPOSE: To compare automated segmentation of the quadratus lumborum (QL) based on statistical shape modeling (SSM) with conventional manual processing of magnetic resonance (MR) images for segmentation of this paraspinal muscle. MATERIALS AND METHODS: The automated SSM scheme for QL segmentation was developed using an MR database of 7 mm axial images of the lumbar region from 20 subjects (cricket fast bowlers and athletic controls). Specifically, a hierarchical 3D-SSM scheme for segmentation of the QL, and surrounding psoas major (PS) and erector spinae+multifidus (ES+MT) musculature, was implemented after image preprocessing (bias field correction, partial volume interpolation) followed by image registration procedures to develop average and probabilistic MR atlases for initializing and constraining the SSM segmentation of the QL. The automated and manual QL segmentations were compared using spatial overlap and average surface distance metrics. RESULTS: The spatial overlap between the automated SSM and manual segmentations had a median Dice similarity metric of 0.87 (mean = 0.86, SD = 0.08) and mean average surface distance of 1.26 mm (SD = 0.61) and 1.32 mm (SD = 0.60) for the right and left QL muscles, respectively. CONCLUSION: The current SSM scheme represents a promising approach for future automated morphometric analyses of the QL and other paraspinal muscles from MR images. PMID- 21591011 TI - Reproducibility of renal perfusion MR imaging in native and transplanted kidneys using non-contrast arterial spin labeling. AB - PURPOSE: To examine both inter-visit and intra-visit reproducibility of a MR arterial spin labeling (ASL) perfusion technique in native and transplanted kidneys over a broad range of renal function. MATERIALS AND METHODS: Renal perfusion exams were performed at 1.5 T in a total of 24 subjects: 10 with native and 14 with transplanted kidneys. Using a flow-sensitive alternating inversion recovery (FAIR) ASL scheme, 32 control/tag pairs were acquired and processed using a single-compartment model. Two FAIR-ASL MR exams were performed at least 24 h apart on all the subjects to assess inter-visit reproducibility. ASL perfusion measurements were also repeated back-to-back within one scanning session in 8 native subjects and in 12 transplant subjects to assess intra-visit reproducibility. Intra-class correlations (ICCs) and coefficients of variation (CVs) were calculated as metrics of reproducibility. RESULTS: Intra-visit ICCs ranged from 0.96 to 0.98 while CVs ranged from 4.8 to 6.0%. Inter-visit measurements demonstrated slightly more variation with ICCs from 0.89 to 0.94 and CVs from 7.6 to 13.1%. Medullary perfusion demonstrated greater variability compared with cortical blood flow: intra-visit ICCs from 0.72 to 0.78 and CVs from 16.7 to 26.7%, inter-visit ICCs from 0.13 to 0.63 and CVs from 19.8 to 37%. CONCLUSION: This study indicates that a FAIR-ASL perfusion technique is reproducible in the cortex of native and transplanted kidneys over a broad range in renal function. In contrast, perfusion measurements in the medulla demonstrated moderate to poor reproducibility for intra-visit and inter-visit measures respectively. PMID- 21591013 TI - Noncontrast MR angiography for comprehensive assessment of abdominopelvic arteries using quadruple inversion-recovery preconditioning and 3D balanced steady-state free precession imaging. AB - PURPOSE: To develop a noncontrast magnetic resonance angiography (MRA) method for comprehensive evaluation of abdominopelvic arteries in a single 3D acquisition. MATERIALS AND METHODS: A noncontrast MRA (NC MRA) pulse sequence was developed using four inversion-recovery (IR) pulses and 3D balanced steady-state free precession (b-SSFP) readout to provide arterial imaging from renal to external iliac arteries. Respiratory triggered, high spatial resolution (1.3 * 1.3 * 1.7 mm(3)) noncontrast angiograms were obtained in seven volunteers and ten patients referred for gadolinium-enhanced MRA (CE MRA). Images were assessed for diagnostic quality by two radiologists. Quantitative measurements of arterial signal contrast were also performed. RESULTS: NC MRA imaging was successfully completed in all subjects in 7.0 +/- 2.3 minutes. In controls, image quality of NC MRA averaged 2.79 +/- 0.39 on a scale of 0-3, where 3 is maximum. Image quality of NC MRA (2.65 +/- 0.41) was comparable to that of CE MRA (2.9 +/- 0.32) in all patients. Contrast ratio measurements in patients demonstrated that NC MRA provides arterial contrast comparable to source CE MRA images with adequate venous and excellent background tissue suppression. CONCLUSION: The proposed noncontrast MRA pulse sequence provides high-quality visualization of abdominopelvic arteries within clinically feasible scan times. PMID- 21591014 TI - Diagnostic value of the flow profile in the distal descending aorta by phase contrast magnetic resonance for predicting severe coarctation of the aorta. AB - PURPOSE: To compare aortic flow profiles at the level of the proximal descending (PDAo) and distal descending aorta (DDAo) in patients investigated for coarctation of the aorta (CoA), and compare their respective diagnostic value for predicting severe CoA. Diastolic flow decay in the PDAo predicts severe CoA, but flow measurements at this level are limited by flow turbulence, aliasing, and stent-related artifacts. MATERIALS AND METHODS: We studied 49 patients evaluated for CoA with phase contrast magnetic resonance imaging (PC-MRI). Parameters of diastolic flow decay in the PDAo and DDAo were compared. Their respective diagnostic value was compared with the standard reference of transcatheter peak gradient >=20 mmHg. RESULTS: Flow measurement in the PDAo required repeated acquisition with adjustment of encoding velocity or location of the imaging plane in 69% of patients; measurement in the DDAo was achieved in single acquisition in all cases. Parameters of diastolic flow decay in the PDAo and DDAo, including rate-corrected (RC) deceleration time and RC flow deceleration yielded a good correlation (r = 0.78; P < 0.01, and r = 0.92; P < 0.01), and a similar diagnostic value for predicting severe CoA. The highest diagnostic accuracy was achieved by RC deceleration time at DDAo (sensitivity 85%, specificity 85%). CONCLUSION: Characterization of aortic flow profiles at the DDAo offers a quick and reliable noninvasive means of assessing hemodynamically significant CoA. PMID- 21591015 TI - Adiabatic localized correlation spectroscopy (AL-COSY): application in muscle and brain. AB - PURPOSE: To describe an enhanced version of a localized correlation spectroscopy (L-COSY) by introducing adiabatic radiofrequency (RF) pulses for localization in two dimensions. Adiabatic pulses will improve slice selection profile and reduce chemical shift artifacts. Optimized Mao and adiabatic hyperbolic secant pulses are tested in vivo. MATERIALS AND METHODS: Region of interest is localized by a 90 degrees nonselective adiabatic RF pulse followed by two pairs of adiabatic RF pulses and a terminal 90 degrees RF sinc pulse. Slice profiles for both refocusing pulses and chemical shift artifacts are measured in a water-oil phantom for L-COSY and AL-COSY. In vivo results of both COSY sequences are shown from muscle and brain on a 3 Tesla (T) scanner. RESULTS: Chemical shift artifacts were reduced with AL-COSY compared with L-COSY. Slice profiles of adiabatic pulses were found to be sharper and more symmetrical than those of traditional Mao pulses. One-dimensional (1D) phantom studies showed longer T2 values using AL COSY sequence. Comparison of 2D spectra obtained revealed spectroscopic peak volume improvements in AL-COSY and less residual water. In vivo 1D comparison showed more inphase and sharper peaks in AL-COSY spectrum. CONCLUSION: The AL COSY sequence is an improved sequence due to sharper slice selection profiles, reduction of chemical shift artifacts, peak volume improvements in 2D techniques, and less J-modulation. PMID- 21591016 TI - Signal to noise ratio and uncertainty in diffusion tensor imaging at 1.5, 3.0, and 7.0 Tesla. AB - PURPOSE: To compare diffusion tensor imaging (DTI) measurements at ultra high field strength (7 Tesla [T]) in human volunteers with DTI measurements performed at 1.5 and 3 Tesla. MATERIALS AND METHODS: The signal to noise ratio (SNR) and the uncertainty in fitted DTI parameters fractional anisotropy and primary eigenvector are assessed with tractography based regions of interest, measured in nine volunteers at 1.5T, 3T, and 7T with clinically available hardware configurations. RESULTS: An increase in SNR is observed on the 7T system compared with the 1.5 or 3T system. The measured increase in SNR at 7T is larger than expected from field strength alone, indicating the large influence of improved receive coil hardware. Additionally, while the average fractional anisotropy remains relatively constant across field strengths, a decrease in uncertainty in the fitted values for fractional anisotropy and the principal eigenvector of the DTI tensor was found. Increased spatial heterogeneity of signal intensities is observed at 7T. CONCLUSION: Given the current hardware constraints, DTI at ultra high field strengths is possible with improved performance in selected regions of interest. PMID- 21591017 TI - Fast lipid and water levels by extraction with spatial smoothing (FLAWLESS): three-dimensional volume fat/water separation at 7 Tesla. AB - PURPOSE: To quickly and robustly separate fat/water components of 7T MR images in the presence of field inhomogeneity for the study of metabolic disorders in small animals. MATERIALS AND METHODS: Starting with a Markov random field (MRF) based formulation for the 3-point Dixon separation problem, we incorporated new implementation strategies, including stability tracking, multiresolution image pyramid, and improved initial value generation. We term the new method FLAWLESS (Fast Lipid And Water Levels by Extraction with Spatial Smoothing). RESULTS: Compared with non-MRF techniques, FLAWLESS decreased the fat-water swapping mistakes in all of the three-dimensional (3D) animal volumes that we tested. FLAWLESS converged in approximately 1/60th of the computation time of other MRF approaches. The initial value generation of FLAWLESS further improved robustness to field inhomogeneity in 3D volume data. CONCLUSION: We have developed a novel 3 point Dixon technique found to be useful for high field small animal imaging. It is being used to assess lipid depots and metabolic disorders as a function of genes, diet, age, and therapy. PMID- 21591018 TI - Proton resonance frequency shift-weighted imaging for monitoring MR-guided high intensity focused ultrasound transmissions. AB - PURPOSE: To combine temperature-related information of phase images and magnitude images acquired from an MR spoiled gradient echo sequence using a postprocessing method referred to as PRF-shift-weighted imaging (PRFSWI). MATERIALS AND METHODS: Phase images are capable of detecting shifts in proton resonance frequency (PRF) caused by local changes in temperature. Magnitude images provide anatomical information for treatment planning and positioning as well as temperature-related contrast. We used PRFSWI to produce a phase-mask and performed multiplication on the magnitude image to increase temperature-related contrast. RESULTS: Through MRI-guided focused ultrasound (MRIgFUS) experiments (both ex vivo and in vivo), we determined that PRFSWI is capable of enhancing the contrast of a heated area even in the initial stages of transmitting high-intensity focused ultrasound energy. CONCLUSION: The PRFSWI images are sensitive to changes in temperature and display the heated spot directly in the magnitude images. Although the images do not provide quantitative data related to temperature, this method could be used as a complement to the phase temperature mapping method in the real-time monitoring of MRIgFUS experiments. PMID- 21591019 TI - Comparison of a single shot T1-weighted in- and out-of-phase magnetization prepared gradient recalled echo with a standard two-dimensional gradient recalled echo: preliminary findings. AB - PURPOSE: To compare in-phase (IP)/out-of-phase (OP) single shot magnetization prepared gradient-recalled-echo (MP-GRE) with a standard two-dimensional gradient recalled-echo (2D-GRE), and to compare image quality of MP-GRE in cooperative and noncooperative subjects. MATERIALS AND METHODS: Ninety-six consecutive subjects (52 males, 44 females; mean age, 53.2 +/- 16.7 years), both cooperative (n = 73) and noncooperative (n = 23) subjects who had MRI examinations including precontrast T1-weighted IP/OP MP-GRE with or without IP/OP 2D-GRE were included in the study. The sequences were independently qualitatively evaluated by two radiologists. Quantitative analysis of liver fat index, signal-to-noise ratio (SNR) and liver-lesion contrast-to-noise ratio (CNR) was also performed. Data were subjected to statistical analysis. RESULTS: The visual detection of the presence or absence of liver steatosis showed no differences between 2D-GRE and MP-GRE imaging (k = 1). Minor differences were observed on image quality between MP-GRE and 2D-GRE in cooperative subjects, and between MP-GRE sequences performed in cooperative and noncooperative subjects. Liver fat index results were strongly positively correlated (r = .98; 95% confidence interval [CI] 0.97 to 0.98; P < .0001). Intercept (.14; 95% CI .13 to .15; P < .0001) and slope (.83; 95% CI .79 to .86; P < .0001) were statistically significant. CONCLUSION: IP/OP MP-GRE and 2D-GRE comparably demonstrate the presence or absence of hepatic steatosis. Image quality of MP-GRE was also comparable to 2D-GRE, and was not substantially adversely affected if subjects were unable to cooperate with breathholding instructions. PMID- 21591020 TI - Impact of outliers on diffusion tensor and Q-ball imaging: clinical implications and correction strategies. AB - PURPOSE: To measure the impact of corrupted images often found to occur in diffusion-weighted magnetic resonance imaging (DW-MRI). To propose a robust method for the correction of outliers, applicable to diffusion tensor imaging (DTI) and q-ball imaging (QBI). MATERIALS AND METHODS: Monte Carlo simulations were carried out to measure the impact of outliers on DTI and QBI reconstruction in a single voxel. Methods to correct outliers based on q-space interpolation and direction removal were then implemented and validated in real image data. RESULTS: Corruption in a single voxel led to clear variations in DTI and QBI metrics. In real data, the method of q-space interpolation was successful in identifying corrupted voxels and restoring them to values consistent with those of uncorrupted images. CONCLUSION: For images containing few gradient directions, where outlier removal was either impossible due to limited volumes or resulted in large changes in DTI/QBI metrics, q-space interpolation proved to be the method of choice for image restoration. A simple decision support system is proposed to assist clinicians in the correction of their corrupted DW data. PMID- 21591021 TI - Comparative study of standard space and real space analysis of quantitative MR brain data. AB - PURPOSE: To compare the robustness of region of interest (ROI) analysis of magnetic resonance imaging (MRI) brain data in real space with analysis in standard space and to test the hypothesis that standard space image analysis introduces more partial volume effect errors compared to analysis of the same dataset in real space. MATERIALS AND METHODS: Twenty healthy adults with no history or evidence of neurological diseases were recruited; high-resolution T(1) weighted, quantitative T(1), and B(0) field-map measurements were collected. Algorithms were implemented to perform analysis in real and standard space and used to apply a simple standard ROI template to quantitative T(1) datasets. Regional relaxation values and histograms for both gray and white matter tissues classes were then extracted and compared. RESULTS: Regional mean T(1) values for both gray and white matter were significantly lower using real space compared to standard space analysis. Additionally, regional T(1) histograms were more compact in real space, with smaller right-sided tails indicating lower partial volume errors compared to standard space analysis. CONCLUSION: Standard space analysis of quantitative MRI brain data introduces more partial volume effect errors biasing the analysis of quantitative data compared to analysis of the same dataset in real space. PMID- 21591022 TI - Reduced transverse relaxation rate (RR2) for improved sensitivity in monitoring myocardial iron in thalassemia. AB - PURPOSE: To evaluate the reduced transverse relaxation rate (RR2), a new relaxation index which has been shown recently to be primarily sensitive to intracellular ferritin iron, as a means of detecting short-term changes in myocardial storage iron produced by iron-chelating therapy in transfusion dependent thalassemia patients. MATERIALS AND METHODS: A single-breathhold multi echo fast spin-echo sequence was implemented at 3 Tesla (T) to estimate RR2 by acquiring signal decays with interecho times of 5, 9 and 13 ms. Transfusion dependent thalassemia patients (N = 8) were examined immediately before suspending iron-chelating therapy for 1 week (Day 0), after a 1-week suspension of chelation (Day 7), and after a 1-week resumption of chelation (Day 14). RESULTS: The mean percent changes in RR2, R2, and R2* off chelation (between Day 0 and 7) were 11.9 +/- 8.9%, 5.4 +/- 7.7% and -4.4 +/- 25.0%; and, after resuming chelation (between Day 7 and 14), -10.6 +/- 13.9%, -8.9 +/- 8.0% and -8.5 +/- 24.3%, respectively. Significant differences in R2 and RR2 were observed between Day 0 and 7, and between Day 7 and 14, with the greatest proportional changes in RR2. No significant differences in R2* were found. CONCLUSION: These initial results demonstrate that significant differences in RR2 are detectable after a single week of changes in iron-chelating therapy, likely as a result of superior sensitivity to soluble ferritin iron, which is in close equilibrium with the chelatable cytosolic iron pool. RR2 measurement may provide a new means of monitoring the short-term effectiveness of iron-chelating agents in patients with myocardial iron overload. PMID- 21591023 TI - Targeted single-shot methods for diffusion-weighted imaging in the kidneys. AB - PURPOSE: To investigate the feasibility of combining the inner-volume-imaging (IVI) technique with single-shot diffusion-weighted (DW) spin-echo echo-planar imaging (SE-EPI) and DW-SPLICE (split acquisition of fast spin-echo) sequences for renal DW imaging. MATERIALS AND METHODS: Renal DWI was performed in 10 healthy volunteers using single-shot DW-SE-EPI, DW-SPLICE, targeted-DW-SE-EPI, and targeted-DW-SPLICE. We compared the quantitative diffusion measurement accuracy and image quality of these targeted-DW-SE-EPI and targeted DW-SPLICE methods with conventional full field of view (FOV) DW-SE-EPI and DW-SPLICE measurements in phantoms and normal volunteers. RESULTS: Compared with full FOV DW-SE-EPI and DW-SPLICE methods, targeted-DW-SE-EPI and targeted-DW-SPLICE approaches produced images of superior overall quality with fewer artifacts, less distortion, and reduced spatial blurring in both phantom and volunteer studies. The apparent diffusion coefficient (ADC) values measured with each of the four methods were similar and in agreement with previously published data. There were no statistically significant differences between the ADC values and intravoxel incoherent motion (IVIM) measurements in the kidney cortex and medulla using single-shot DW-SE-EPI, targeted-DW-EPI, and targeted-DW-SPLICE (P > 0.05). CONCLUSION: Compared with full-FOV DWI methods, targeted-DW-SE-EPI and targeted DW-SPLICE techniques reduced image distortion and artifacts observed in the single-shot DW-SE-EPI images, reduced blurring in DW-SPLICE images, and produced comparable quantitative DW and IVIM measurements to those produced with conventional full-FOV approaches. PMID- 21591025 TI - Interaction of electrical stimulation and voluntary hand movement in SII and the cerebellum during simulated therapeutic functional electrical stimulation in healthy adults. AB - The therapeutic application of functional electrical stimulation (FES) has shown promising clinical results in the rehabilitation of post-stroke hemiplegia. It appears that the effect is optimal when the patterned electrical stimulation is used in close synchrony with voluntary movement, although the neural mechanisms that underlie the clinical successes reported with therapeutic FES are unknown. One possibility is that therapeutic FES takes advantage of the sensory consequences of an internal model. Here, we investigate fMRI cortical activity when FES is combined with voluntary effort (FESVOL) and we compare this activity to that produced when FES and voluntary activity (VOL) are performed alone. FESVOL revealed greater cerebellar activity compared with FES alone and reduced activity bilaterally in secondary somatosensory areas (SII) compared with VOL alone. Reduced activity was also observed for FESVOL compared with FES alone in the angular gyrus, middle frontal gyrus and inferior frontal gyrus. These findings indicate that during the VOL condition the cerebellum predicts the sensory consequences of the movement and this reduces the subsequent activation in SII. The decreased SII activity may reflect a better match between the internal model and the actual sensory feedback. The greater cerebellar activity coupled with reduced angular gyrus activity in FESVOL compared with FES suggests that the cortex may interpret sensory information during the FES condition as an error-like signal due to the lack of a voluntary component in the movement. PMID- 21591026 TI - The less BOLD, the wiser: support for the latent resource hypothesis after traumatic brain injury. AB - Previous studies of the BOLD response in the injured brain have revealed neural recruitment relative to controls during working memory tasks in several brain regions, most consistently the right prefrontal cortex and anterior cingulate cortices. We previously proposed that the recruitment observed in this literature represents auxiliary support resources, and that recruitment of PFC is not abnormal or injury specific and should reduce as novelty and challenge decrease. The current study directly tests this hypothesis in the context of practice of a working memory task. It was hypothesized that individuals with brain injury would demonstrate recruitment of previously indicated regions, behavioral improvement following task practice, and a reduction in the BOLD signal in recruited regions after practice. Individuals with traumatic brain injury and healthy controls performed the n-back during fMRI acquisition, practiced each task out of the scanner, and returned to the scanner for additional fMRI n-back acquisition. Statistical parametric maps demonstrated a number of regions of recruitment in the 1-back in individuals with brain injury and a number of corresponding regions of reduced activation in individuals with brain injury following practice in both the 1-back and 2-back. Regions of interest demonstrated reduced activation following practice, including the anterior cingulate and right prefrontal cortices. Individuals with brain injury demonstrated modest behavioral improvements following practice. These findings suggest that neural recruitment in brain injury does not represent reorganization but a natural extension of latent mechanisms that engage transiently and are contingent upon cerebral challenge. PMID- 21591024 TI - The rs2910164:G>C SNP in the MIR146A gene is not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. AB - The rs2910164:G>C SNP is located in the gene for miR-146a, a microRNA that binds the 3' UTR of the BRCA1 transcript. Preliminary data based on the analysis of a small number of cases suggested that this single nucleotide polymorphism (SNP) might be associated with the age of onset of familial breast and ovarian cancer. This effect was not confirmed on a large series of familial breast cancer cases negative for a BRCA1 or BRCA2 mutation. We show here a lack of association of the rs2910164:G>C SNP with breast cancer risk in a series of 1,166 BRCA1 and 560 BRCA2 mutation carriers. In conclusion, the polymorphism in the miR-146a gene is unlikely to be of substantial significance regarding breast cancer risk. PMID- 21591027 TI - Light microscopy with doughnut modes: a concept to detect, characterize, and manipulate individual nanoobjects. AB - Higher order laser modes, mainly called doughnut modes (DMs) have use in many different branches of research, such as, bio-imaging, material science, single molecule microscopy, and spectroscopy. The main reason of their increasing importance is that recently, the techniques to generate well-defined DMs have been refined or rediscovered. Although their potential is still not fully utilized, their specifically polarized field distribution gives rise to a wide field of applications. They are contributing to complete our fundamental knowledge of the optical properties of single emitting species, such as molecules, nanoparticles, or quantum dots, offering insight into the three dimensional dipole or particle orientation in space. The perfect zero intensity in the focus center qualifies some DMs for stimulated emission depletion (STED) microscopy. For the same reason, they have been suggested for trapping and tweezing applications. PMID- 21591028 TI - Profiling of active thrombin in human blood by supramolecular complexes. PMID- 21591029 TI - A planar {Mn19(OH)12}26+ unit incorporated in a 60-tungsto-6-silicate polyanion. PMID- 21591031 TI - Palladium-catalyzed oxidative borylative carbocyclization of enallenes. PMID- 21591030 TI - Ultrasensitive near-infrared Raman reporters for SERS-based in vivo cancer detection. PMID- 21591032 TI - Direct palladium-catalyzed intermolecular allylation of highly electron-deficient polyfluoroarenes. PMID- 21591033 TI - Multivalent nanoparticle networks as ultrasensitive enzyme sensors. PMID- 21591034 TI - The amyloid-Congo red interface at atomic resolution. PMID- 21591035 TI - Electron transport through single molecules comprising aromatic stacks enclosed in self-assembled cages. PMID- 21591036 TI - Porous hollow carbon@sulfur composites for high-power lithium-sulfur batteries. PMID- 21591038 TI - Synthesis of isoquinolines from alpha-aryl vinyl azides and internal alkynes by Rh-Cu bimetallic cooperation. PMID- 21591039 TI - A metastable metal with decagonal local symmetry obtained by low-temperature pseudomorphosis. PMID- 21591040 TI - Suzuki-Miyaura cross-coupling reactions in flow: multistep synthesis enabled by a microfluidic extraction. PMID- 21591041 TI - Self-activation in de novo designed mimics of cell-penetrating peptides. PMID- 21591042 TI - Synthesis and direct imaging of ultrahigh molecular weight cyclic brush polymers. PMID- 21591043 TI - Total chemical synthesis of a 304 amino acid K48-linked tetraubiquitin protein. PMID- 21591045 TI - Science in a changing world. PMID- 21591044 TI - Enantioselective N-H functionalization of indoles with alpha,beta-unsaturated gamma-lactams catalyzed by chiral Bronsted acids. PMID- 21591046 TI - An efficient route to selective bio-oxidation catalysts: an iterative approach comprising modeling, diversification, and screening, based on CYP102A1. AB - Perillyl alcohol is the terminal hydroxylation product of the cheap and readily available terpene, limonene. It has high potential as an anti-tumor substance, but is of limited availability. In principle, cytochrome P450 monooxygenases, such as the self-sufficient CYP102A1, are promising catalysts for the oxidation of limonene or other inert hydrocarbons. The wild-type enzyme converts (4R) limonene to four different oxidation products; however, terminal hydroxylation at the allylic C7 is not observed. Here we describe a generic strategy to engineer this widely used enzyme to hydroxylate exclusively the exposed, but chemically less reactive, primary C7 in the presence of other reactive positions. The approach presented here turns CYP102A1 into a highly selective catalyst with a shifted product spectra by successive rounds of modeling, the design of small focused libraries, and screening. In the first round a minimal CYP102A1 mutant library was rationally designed. It contained variants with improved or strongly shifted regio-, stereo- and chemoselectivity, compared to wild-type. From this library the variant with the highest perillyl alcohol ratio was fine-tuned by two additional rounds of molecular modeling, diversification, and screening. In total only 29 variants needed to be screened to identify the triple mutant A264V/A238V/L437F that converts (4R)-limonene to perillyl alcohol with a selectivity of 97 %. Focusing mutagenesis on a small number of relevant positions identified by computational approaches is the key for efficient screening for enzyme selectivity. PMID- 21591047 TI - Open-shell characters and second hyperpolarizabilities of one-dimensional graphene nanoflakes composed of trigonal graphene units. AB - The impact of topology on the open-shell characters and the second hyperpolarizabilities (gamma) has been addressed for one-dimensional graphene nanoflakes (GNFs) composed of the smallest trigonal graphene (phenalenyl) units. The main results are: 1) These GNFs show not only diradical but also multiradical characters when increasing the number of linked units. 2) GNFs composed of an equivalent number of units can exhibit a wide range of open-shell characters-from nearly closed-shell to pure multiradical characters-depending on the linking pattern of the trigonal units. 3) This wide variation in open-shell characters is explained by their resonance structures and/or by their (HOMO-i)-(LUMO+i) gaps deduced from the orbital correlations. 4) The change in the linking structure of the units can effectively control their open-shell characters as well as their gamma values, of which the longitudinal components are significantly enhanced for the singlet GNFs having intermediate open-shell characters. 5) Singlet alternately linked (AL) systems present intermediate multiradical characters even in the case of a large number of units, which creates a significant enhancement of gamma with increasing the size, whereas nonalternately linked (NAL) systems, which present pure multiradical characters, possess much smaller gamma values. Finally 6) by switching from the singlet to the highest spin states, the gamma values of NAL systems hardly change, whereas those of AL systems exhibit large reductions. These fascinating structure-property relationships between the topology of the GNFs, their open-shell characters, and their gamma values not only deepen the understanding of open-shell characters of GNFs but aim also at stimulating further design studies to achieve giant NLO responses based on open shell graphene-like materials. PMID- 21591048 TI - We have a new publisher: John Wiley & Sons. PMID- 21591049 TI - Protein engineering: Case studies of commercialized engineered products. AB - Programs in biochemistry invariably encompass the principles of protein engineering. Students often display increased understanding and enthusiasm when theoretical concepts are underpinned by practical example. Herein are presented five case studies, each focusing upon a commercial protein product engineered to enhance its application-relevant functionality. The case studies may be incorporated into a standard lecture series detailing protein engineering or may form the basis of a class-led post-lecture series discussion. PMID- 21591050 TI - Design and implementation of an interdepartmental bioinformatics program across life science curricula. AB - Over the past 10 years, there has been a technical revolution in the life sciences leading to the emergence of a new discipline called bioinformatics. In response, bioinformatics-related topics have been incorporated into various undergraduate courses along with the development of new courses solely focused on bioinformatics. This report describes the design and implementation of an interdepartmental bioinformatics program throughout several life science programs. Using elements of the backward curricular design process, nine faculty members from the Biology, Microbiology, and Chemistry Departments at the University of Wisconsin - La Crosse incorporated bioinformatics in a coordinated manner into 10 courses. Key molecular biology concepts were first identified followed by development of bioinformatics exercises that centered on these concepts. An overview of how the program was constructed and implemented and a summary of the exercises that were designed will be presented. PMID- 21591051 TI - Assessment of a bioinformatics across life science curricula initiative. AB - At the University of Wisconsin-La Crosse, we have undertaken a program to integrate the study of bioinformatics across the undergraduate life science curricula. Our efforts have included incorporating bioinformatics exercises into courses in the biology, microbiology, and chemistry departments, as well as coordinating the efforts of faculty within those departments. Here, we assess student confidence in solving and ability to solve bioinformatics-related problems. Assessment data show increases in student performance on bioinformatics related problems and more confidence in solving such problems with increased exposure to the field of bioinformatics. Additionally, the faculty perceive an increased awareness of the applications of bioinformatics among the students in their courses. The combination of three different assessment tools, a student self-assessment of learning, a content exam, and faculty survey, was an effective and efficient approach for evaluating this multi-departmental program. PMID- 21591052 TI - Education resources for guiding discussions on ethics in science. AB - Faculty, staff, and students at all levels of educational institutions are becoming more aware about ethical issues in the classroom and in research. As educators, it is our responsibility to provide an opportunity to discuss these issues so that future scientists will be prepared to face the many ethical challenges they may encounter. Often, unfortunately, we are reticent to engage in this discussion due solely to the lack of our own repertoire of resources regarding ethics. Thus, this summary of educational resources was compiled to promote ethics discussions in science classrooms and research programs. PMID- 21591053 TI - Learning in a gene technology laboratory with educational focus: Results of a teaching unit with authentic experiments. AB - In an effort to overcome deficiencies in teaching molecular biology at school, a workshop in an out-of-school laboratory including only authentic experiments was developed. Evaluation of 337 A-level 12th graders followed a quasi-experimental design, with one hands-on group, two non-experimental control groups (at school/in the laboratory), and one group with no intervention. Their cognitive achievement was monitored by pre-, post-, and retention tests and analyzed for inter-group differences. Test items were differentiated into the "updated prior knowledge" and the "project-oriented" set relating to new knowledge. All intervention groups increased knowledge either as a whole or in relation to the project, whereas updating of prior knowledge was observed only in the laboratory, independently of experimenting. The hands-on group provided a higher learning success as regards knowledge acquisition as a whole, whereas the non-experimental laboratory group was more successful in updating prior knowledge, both groups in comparison with the school group. Nevertheless, the hands-on group's achievement scores dropped more than those of the school group. Learning motivation may have been higher in the laboratory, furthered by the involvement in experiments, as shown by correlation analysis. However, the experimental situation may comply with the cognitive load theory by a substantially higher contribution of extraneous load. PMID- 21591054 TI - Ribosome recycling: An essential process of protein synthesis. AB - A preponderance of textbooks outlines cellular protein synthesis (translation) in three basic steps: initiation, elongation, and termination. However, researchers in the field of translation accept that a vital fourth step exists; this fourth step is called ribosome recycling. Ribosome recycling occurs after the nascent polypeptide has been released during the termination step. Despite the release of the polypeptide, ribosomes remain bound to the mRNA and tRNA. It is only during the fourth step of translation that ribosomes are ultimately released from the mRNA, split into subunits, and are free to bind new mRNA, thus the term "ribosome recycling." This step is essential to the viability of cells. In bacteria, it is catalyzed by two proteins, elongation factor G and ribosome recycling factor, a near perfect structural mimic of tRNA. Eukaryotic organelles such as mitochondria and chloroplasts possess ribosome recycling factor and elongation factor G homologues, but the nature of ribosome recycling in eukaryotic cytoplasm is still under investigation. In this review, the discovery of ribosome recycling and the basic mechanisms involved are discussed so that textbook writers and teachers can include this vital step, which is just as important as the three conventional steps, in sections dealing with protein synthesis. PMID- 21591055 TI - Formulation of questions followed by small group discussion as a revision exercise at the end of a teaching module in biochemistry. AB - Undergraduate medical students get fewer opportunities to clarify their doubts and to reinforce their understanding of concepts after lecture classes. There is no information available in the literature that addresses the question of usefulness of prior formulation of questions followed by small group discussion by undergraduate medical students as a revision exercise. The purpose of this work is to evaluate the effect of formulation of objective type short answer questions by undergraduate medical students followed by small group discussion on the answers of the questions prepared as a revision exercise on their understanding of the topic "amino acid metabolism" and the retention of the gain after 15 days. At the end of a regular teaching module on the topic of amino acid metabolism, undergraduate medical students were asked to prepare 16 objective type short answer questions on the various aspects of the topic as homework. Small group discussions involving 12-14 students in each group and lasting one hour were conducted on the questions and answers prepared by them in the presence of a faculty member. The effects on low, medium, and high achievers were evaluated with multiple choice questions by pre-test and post-tests before and after the group discussion. Formulation of questions was highly effective in improving understanding on the topic for all the students. The overall mean post test scores after the formulation of questions (12.6) and after the small group discussion that followed (14.7) were significantly higher than the mean pre-test score (8.5). For high achievers, the gain from formulation of questions was higher than the gain from small group discussion. Small group discussion was highly effective for all students. The gain from small group discussion was higher among the low and medium achievers in comparison with the high achievers. The gain from the exercise was retained among the low, medium, and high achievers after 15 days. In conclusion, formulation of short answer questions followed by small group discussion on the answers of the questions prepared by the undergraduate medical students is an effective revision exercise for improving their understanding on a selected topic. PMID- 21591056 TI - Accessible NMR experiments studying the hydrodynamics of (15) N-enriched ubiquitin at low fields. AB - We have recently developed and implemented two experiments in biomolecular NMR for an undergraduate-level biophysical chemistry laboratory with commercially available (15) N-enriched human ubiquitin. These experiments take advantage of (15) N direct detection of the NMR signal. The first experiment develops skills in acquiring and interpreting one-dimensional and two-dimensional NMR data of an aqueous protein sample (D. Rovnyak, L. E. Thompson (2005) An accessible two dimensional solution nuclear magnetic resonance experiment on human ubiquitin, Biochem. Mol. Biol. Educ. 33, 117-122). In the second experiment, discussed here, students examine the overall dynamics of a protein in solution. Students measure spin relaxation times T(1) and T(2) and use these data to estimate a rotational correlation time, tau(c) , and the diameter of ubiquitin using the Stokes Einstein relation. This is a fast and simple experiment, requiring about 1 h of instrument time, and a valuable opportunity to provide a hands-on experience in studying macromolecular size and dynamics. This experiment is conducted in synchrony with lecture material on hydrodynamics and sedimentation. PMID- 21591057 TI - Surface plasmon resonance label-free monitoring of antibody antigen interactions in real time. AB - Detection of biologically active compounds is one of the most important topics in molecular biology and biochemistry. One of the most promising detection methods is based on the application of surface plasmon resonance for label-free detection of biologically active compounds. This method allows one to monitor binding events in real time without labeling. The system can therefore be used to determine both affinity and rate constants for interactions between various types of molecules. Here, we describe the application of a surface plasmon resonance biosensor for label-free investigation of the interaction between an immobilized antigen bovine serum albumin (BSA) and antibody rabbit anti-cow albumin IgG1 (anti-BSA). The formation of a self-assembled monolayer (SAM) over a gold surface is introduced into this laboratory training protocol as an effective immobilization method, which is very promising in biosensing systems based on detection of affinity interactions. In the next step, covalent attachment via artificially formed amide bonds is applied for the immobilization of proteins on the formed SAM surface. These experiments provide suitable experience for postgraduate students to help them understand immobilization of biologically active materials via SAMs, fundamentals of surface plasmon resonance biosensor applications, and determination of non-covalent biomolecular interactions. The experiment is designed for master and/or Ph.D. students. In some particular cases, this protocol might be adoptable for bachelor students that already have completed an extended biochemistry program that included a background in immunology. PMID- 21591058 TI - A simple experiment to show photodynamic inactivation of bacteria on surfaces. AB - New suitable approaches were investigated to visualize the photodynamic inactivation (PDI) of bacteria immobilized on agar surfaces. The PDI capacities of a cationic photosensitizer (5,10,15,20-tetra(4-N,N,N trimethylammoniumphenyl)porphyrin) and an anionic photosensitizer (5,10,15,20 tetra(4-sulfonatophenyl)porphyrin) were analyzed on a typical Gram-negative bacterium Escherichia coli following two procedures. In Experiment I, the E. coli cells were grown as lawn on agar surface containing the sensitizers spread in a small area (10 nmol in ~0.6 cm(2) ). After irradiation with visible light (10 min, 90 milliwatts/cm(2) ), no cells were grown in the area containing the cationic porphyrin. In Experiment II, small colonies (~2-mm diameter) of E. coli on agar were treated with a solution of sensitizer (10 nmol) and irradiated with visible light for 3 h. Overnight incubation at 37 degrees C shows a growth delay of E. coli colonies treated with the cationic photosensitizer. In contrast, the anionic porphyrin did not produce appreciable photodamage. These experiments could be either used in an undergraduate project for natural science advance students or used for a postgraduate practical training course. This methodology illustrates the application of PDI to treat bacteria growing as localized foci of infection. PMID- 21591059 TI - Commentary: Do biology and chemistry educators talk to each other? PMID- 21591060 TI - Chromatographic separation of two proteins. AB - Terms to be familiar with before you start to solve the test: ion exchange chromatography, gel filtration, column chromatography, elution, chromatography fractions, void volume (V(o) ), elution volume (V(e) ), SDS-polyacrylamide gel electrophoresis, isoelectric point, isoelectric focusing, CsCl gradient centrifugation. PMID- 21591061 TI - Commentary: The seven challenges of stem cell education in biochemistry. PMID- 21591063 TI - Websites of note. PMID- 21591062 TI - Commentary: Just in time learning with radio frequency identification devices (RFIDs). PMID- 21591064 TI - Song: When acids get oxidized (to the tune of "When Johnny Comes Marching Home"). PMID- 21591066 TI - Coupled reactions versus connected reactions: Coupling concepts with terms. AB - A hallmark of living matter is its ability to extract and transform energy from the environment. Not surprisingly, biology students are required to take thermodynamics. The necessity of coupling exergonic reactions to endergonic processes is easily grasped by most undergraduate students. However, when addressing the thermodynamic concept of coupled reactions, both students and textbook authors often make claims that clash with the Second Law of Thermodynamics. Herein, I point out the most common flaws, analyze the causes leading to these mistakes, and suggest a few rules to avoid them. PMID- 21591067 TI - The personal response: A novel writing assignment to engage first year students in large human biology classes. AB - The teaching of highly valued scientific writing skills in the first year of university is challenging. This report describes the design, implementation, and evaluation of a novel written assignment, The Personal Response and accompanying Peer Review, in the course, Human Biology (BIOL1015) at The University of Queensland. These assignments were the first assessment tasks of the course and were set early in the first semester of university. BIOL1015 had a diverse cohort of 319 first year students from five bachelor degree programs, primarily from Pharmacy and Human Movement Studies. Audio files in the form of interviews with eminent biomedical scientists were obtained from a leading public radio program. Students used these files as triggers to submit a short but highly structured assignment written from a personal perspective and in an expressive style. Evaluations revealed that overall, students found the task interesting and challenging. Students performed well, regardless of their background knowledge, disciplinary interest, or preference for topics within human biology. This study demonstrated that The Personal Response was an appropriate task for these first year students of human biology. It represents an alternative to traditional essay writing. PMID- 21591068 TI - Students' ability to organize biochemical and biochemistry-related terms correlates with their performance in a biochemical examination. AB - Organization is believed to be related to understanding and memory. Whether this belief was applicable in biochemical education was examined about two years after students had experienced biochemistry classes in their first year. The ability of organizing information in biochemistry was judged from the number of correct links of 886 biochemical and biochemistry-related terms to 14 headings, and the level of understanding and memory on biochemical material was determined from the number of correct answers to biochemical items. The result showed a statistically significant positive correlation between the ability of organization and the level of understanding and memory. Thus, biochemistry teachers need to show the organization of what they teach for the help of the students who have a low level of understanding and memory. PMID- 21591069 TI - The news of science, a colloquium-style course designed to promote lifelong scientific awareness. AB - It is generally agreed that informed citizens in a republic such as the United States should maintain broad awareness of current developments in science and technology. This paper describes a colloquium-style course, The News of Science, designed to stimulate in undergraduate students a desire for such awareness, and to present a convenient means for doing so. The course, which has been offered since 2000 at Oregon State University, requires students to read Science magazine and to present oral reports on articles of their choosing. Each student in the course is required to read all of the articles selected for oral presentation, and to contribute toward discussion of each talk. PMID- 21591070 TI - Reversible ligand binding reactions: Why do biochemistry students have trouble connecting the dots? AB - Adaptive chemical behavior is essential for an organism's function and survival, and it is no surprise that biological systems are capable of responding both rapidly and selectively to chemical changes in the environment. To elucidate an organism's biochemistry, its chemical reactions need to be characterized in ways that reflect the normal physiology in vivo. This is a challenging experimental problem because biological systems are inherently complex with myriads of interlinked chemical networks orchestrating processes that are mostly irreversible in nature. One successful approach for simplifying the study of biochemical reactions is to analyze them under controlled reversible equilibrium conditions in vitro that approximate the range of physiological conditions found in vivo. Because this approach has helped elucidate some of the chemical mysteries of complex biological systems, many topics presented in modern biochemistry courses are essentially rooted in the chemistry of reversible equilibrium reactions. Since most undergraduate biochemistry courses typically require students to complete year-long general and organic chemistry courses, biochemistry instructors may assume that entering students have sufficient understanding of basic reversible equilibrium chemistry to move forward into more advanced biochemical topics. However, this assumption is at odds with our experience in that many entering students seem confused by the conventions, language, symbolic formalism, and/or mathematical tools normally use to describe reversible equilibrium reactions. Part of the problem here may stem from how certain basic chemical concepts are taught (or are not taught) in their prerequisite chemistry courses. Here, we identify some conceptual barriers that many students seem to confront and we discuss instructional strategies designed to help students "connect the dots," so to speak, and better understand how dynamic biological processes can be analyzed in terms of reversible equilibrium chemistry. PMID- 21591071 TI - Introductory bioinformatics exercises utilizing hemoglobin and chymotrypsin to reinforce the protein sequence-structure-function relationship. AB - We describe two bioinformatics exercises intended for use in a computer laboratory setting in an upper-level undergraduate biochemistry course. To introduce students to bioinformatics, the exercises incorporate several commonly used bioinformatics tools, including BLAST, that are freely available online. The exercises build upon the students' background knowledge of hemoglobin and chymotrypsin, and foster a better understanding of how protein sequence relates to structure and function. PMID- 21591072 TI - Teaching the role of mitochondrial transport in energy metabolism. AB - Studies from our laboratories over recent years have uncovered the existence, and established the properties of a variety of mitochondrial transporters. The properties of these transporters throw light on a variety of biochemical phenomena that were previously poorly understood. In particular the role of mitochondrial transport in energy metabolism has been investigated under a variety of physio-pathological conditions. Consistently we describe the procedure to investigate mitochondrial traffic in isolated mitochondria as a model system for students to learn. Here we report some observations that contribute to novel knowledge of the role of mitochondria in glycolysis, urea and purine nucleotide cycle, and nitrogen metabolism with particular reference to the malate/oxaloacetate shuttle and fumarate, glutamine, and lactate metabolism. PMID- 21591073 TI - Western blot analysis to illustrate relative control levels of the lac and ara promoters in Escherichia coli. AB - The lactose operon and its control is a fundamental transcriptional regulatory concept presented in introductory and many advanced molecular biology courses. Much is known about the positive and negative control mechanisms that govern levels of expression of this operon. One basic principle that is taught about the lac operon is that it is "leaky," meaning that the transcriptional control of the operon is not 100% efficient and that in wild-type cells, transcription from the promoter is never completely "off," but there is always some basal transcription. In contrast, the arabinose operon is often used as an example of a tightly controlled operon, and transcription from the ara promoter is very low in the absence of inducer. The relative levels of control of these two operons can be illustrated using Western blots of proteins expressed in the presence and absence of the appropriate inducers and antibodies against the gene products. Different times of growth and the addition of inducer can also be examined. The results are very dramatic and help to reinforce the principles of promoter control. PMID- 21591074 TI - HPLC determination of caffeine and paraxanthine in urine: An assay for cytochrome P450 1A2 activity. AB - Cytochrome P450 enzymes are a family of heme-containing proteins located throughout the body with roles in metabolism of endogenous and exogenous compounds. Among exogenous compounds, clinically relevant pharmaceutical agents are nearly all metabolized by P450 enzymes. However, the activity of the different cytochrome P450 enzymes varies among individuals and, therefore, so does drug efficacy as well as susceptibility to side effects and toxicity. Thus, assessing P450 activity is of great interest in drug development and clinical pharmacology. This study investigates the phenotyping of a single P450 activity by analyzing urine samples using isocratic reverse-phase HPLC. Specifically, the activity of human P450 1A2, which converts caffeine into paraxanthine, can be investigated by measuring the change in caffeine and paraxanthine concentrations in urine over time following a single dose of caffeine. There is an observable relationship between caffeine intake and paraxanthine formation that varies among individuals. This laboratory exercise provides a means for simple assessment of P450 1A2 metabolic activity using an HPLC method without additional extraction or purification steps and introduces students to the complexities of individualized medicine as well as the basic biochemical techniques of sample preparation and quantitative HPLC. Furthermore, students may design and test their own hypothesis using these methods. PMID- 21591075 TI - Utilization of integrated Michaelis-Menten equation to determine kinetic constants. AB - Students of biochemistry and related biosciences are urged to solve problems where kinetic parameters are calculated from initial rates obtained at different substrate concentrations. Troubles begin when they go to the laboratory to perform kinetic experiments and realize that usual laboratory instruments do not measure initial rates but only substrate or product concentrations as a function of reaction time. To overcome this problem we present a methodology which uses the integrated form of Michaelis-Menten equation. The method presented has a theoretical and pedagogic basis which is not as arbitrary as other approaches. Here we present and describe the methodology for analyzing time course data together with some examples of the essential computer procedures to implement these analyses. To simplify the understanding of this methodology the experimental examples are confined to linear inhibitions and experimental points utilized are the same from which the initial rates are determined. PMID- 21591076 TI - Commentary: Putting students in our place. PMID- 21591077 TI - Analysis of the cell cycle by flow cytometry. AB - Terms to be familiar with before you start to solve the test: Cell cycle, flow cytometry, cell culture, fluorescent DNA dye, diploid and tetraploid cells, mitosis, phases of the cell cycle, growth factors, microtubules, apoptosis, DNA synthesis, proteasome, [(3) H]thymidine, pulse labeling, histones, protein phosphorylation, M-phase promoting factor (MPF), cyclins, cyclin-dependent kinases (Cdks), synchronized culture. PMID- 21591078 TI - Commentary: Translational research curricula. PMID- 21591079 TI - Commentary: Clickers (personal response units) may add value to lectures. PMID- 21591080 TI - Websites of note. PMID- 21591082 TI - Biochemistry and undergraduate liberal education. PMID- 21591083 TI - Chemical complexities in a crime novel. PMID- 21591084 TI - Lecture-free biochemistry: A Process Oriented Guided Inquiry Approach. AB - Biochemistry courses at Seattle University have been taught exclusively using process oriented guided inquiry learning (POGIL) without any traditional lecture component since 1997. In these courses, students participate in a structured learning environment, which includes a preparatory assignment, an in-class activity, and a follow-up skill exercise. Instructor-designed learning activities provide the content of the course while the cooperative learning structure provides the content-free procedures that promote development of critical process skills needed for learning. This format enables students to initially explore a topic independently, work together in groups to construct and refine knowledge, and eventually develop deep understanding of the essential concepts. These stages of exploration and concept development form the foundation for application to high level biochemical problems. At the end of this course, most students report feeling confident in their knowledge of biochemistry and report substantial gains in independence, critical thinking, and respect for others. PMID- 21591085 TI - A case-based approach increases student learning outcomes and comprehension of cellular respiration concepts. AB - This study investigated student learning outcomes using a case-based approach focused on cellular respiration. Students who used the case study, relative to students who did not use the case study, exhibited a significantly greater learning gain, and demonstrated use of higher-order thinking skills. Preliminary data indicate that after engaging with the case study, students were more likely to answer a question addressing misconceptions about cellular respiration correctly when compared with students who did not use the case study. More rigorous testing is needed to fully elucidate whether case-based learning can effectively clarify student misconceptions related to biological processes. PMID- 21591086 TI - Open-ended assignments and student responsibility. AB - An inquiry-based laboratory course was created in an effort to increase student responsibility in learning and to improve teaching in areas related to molecular medicine. Authentic medical cases with both scientific and clinical aspects formed the basis of a project-oriented course that also included student laboratory work focused on the disease-related proteins. Students used basic biochemical techniques to develop and test hypotheses relating their results to the clinical findings. The course also included patient demonstrations to personalize students' knowledge of case presentations, lectures on basic biochemical principles relevant to the molecular basis of the cases, and seminars by invited guests with expertise in translational medicine. Students developed proposals for future research as part of the final examination. An inquiry matrix was used to evaluate the degree of learning responsibility taken during the course. By allowing for openness in how to explore the case including choice of methods and interpretation of unexpected results, students gained confidence in their ability to solve problems, formulate and test hypotheses, and collaborate with both clinical and non-clinical professionals. PMID- 21591087 TI - Virtual office hours using a tablet PC: E-lluminating biochemistry in an online environment. AB - The availability of online collaboration software has provided new opportunities for instructors to interact with students outside the classroom. This report describes how Elluminate Live!(r), a particular conferencing software package, can be used with a tablet PC to conduct virtual office hours in a biochemistry course. The educational value of engaging students in an online environment, with text messaging, voice-over-internet protocol (VoIP), and application sharing is also discussed. A student perspective is provided to illustrate the advantages of conducting virtual office hours and how the combination of online collaboration software and tablet PC technology can provide an enhanced learning experience. PMID- 21591088 TI - Proper reporting of results. PMID- 21591089 TI - Using restriction mapping to teach basic skills in the molecular biology lab. AB - Digestion of DNA with restriction enzymes, calculation of volumes and concentrations of reagents for reactions, and the separation of DNA fragments by agarose gel electrophoresis are common molecular biology techniques that are best taught through repetition. The following open-ended, investigative laboratory exercise in plasmid restriction mapping allows students to gain technical expertise while simultaneously exploring the utility of gel electrophoresis and restriction mapping. Because of its interpretive nature, this project also provides data suitable for a written report, and can thus be used to reinforce lessons on figure presentation and science writing skills. PMID- 21591090 TI - Accumulation of monoterpenoid indole alkaloids in periwinkle seedlings (Catharanthus roseus) as a model for the study of plant-environment interactions. AB - Alkaloids are part of the chemical arsenal designed to protect plants against an adverse environment. Therefore, their synthesis and accumulation are frequently induced in response to certain environmental conditions and are mediated by chemical signals, which are formed as the first responses to the external stimulus. A set of experiments using Catharanthus roseus seedlings is presented to illustrate this interaction. Using the well characterized induction of monoterpenoid indole alkaloid synthesis in response to methyl jasmonate, one chemical mediator; simple and reproducible experiments are proposed to demonstrate this type of plant-environment interaction to plant physiology or biochemistry B.Sc. students. After exposure to the inducer, seedlings are analyzed for alkaloid accumulation and for the increase of tryptophan decarboxylase (TDC) enzyme activity by means of thin layer chromatography, followed by UV spectrophotometry. Alkaloids should increase as a result of the exposure to the inducer, as well as TDC activity, which plays a critical role in channeling carbon skeletons from primary to secondary metabolism in this plant. PMID- 21591091 TI - Commentary: What do students say about problem-based learning? PMID- 21591093 TI - Problem-solving test: The role of a chromatin-remodeling complex. PMID- 21591092 TI - The eyes have it: A Problem-Based Learning Exercise in Molecular Evolution. AB - Molecular evolution provides an interesting context in which to use problem-based learning because it integrates a variety of topics in biology, biochemistry, and molecular biology. This three-stage problem for advanced students deals with the structure, multiple functions, and properties of lactate dehydrogenase isozymes, and the related evolutionary trade offs of gene sharing versus gene duplication among their corresponding genes. It has directive elements that require students to find and read classic articles, review thermodynamic principles, and apply their understanding to a mythical world wherein dinosaurs continued to evolve. The science fiction writing assignment that brings closure to the problem transformed the problem with respect to student interest and engagement. PMID- 21591094 TI - Commentary: A "Biofuels" teaching moment. PMID- 21591095 TI - Commentary: The best pointing and manipulating device in the world, our ten fingers. PMID- 21591096 TI - Websites of note. PMID- 21591097 TI - Song: The tao of hormones (to the tune of "The Sound of Silence"). PMID- 21591099 TI - An alternative presentation of metabolism: Enzyme-catalyzed reactions can be viewed as atoms flowing through sluice gates. AB - Why should we think of enzymes as sluice gates? We are used to talk about "metabolic flux": I should like to suggest that we should indeed envision metabolism as a "liquid" flowing in different channel segments, each of which contains a single metabolite. Enzymes facilitate chemical reactions without affecting the reaction equilibrium, creating, or destroying matter: they can be visualized as "sluice gates" (mobile metal or wooden plates that control water flow in channels and sluices: Fig. 1), or, rather, as openings in metal or wooden plates that block the channel. Metabolism control and homeostasis maintenance are equivalent to controlling the water flux while maintaining the water level in each channel segment approximately constant. The "gates" representing non cooperative (Michaelis-Menten) and cooperative enzymes have very different shapes, reflecting their different roles in metabolic regulation: the activity of noncooperative enzymes catalyzing irreversible reactions has the greater effect over the flux, but cooperative enzymes are necessary to maintain homeostasis when irreversible reactions are involved. PMID- 21591100 TI - Molecular modeling of estrogen receptor using molecular operating environment. AB - Molecular modeling is pervasive in the pharmaceutical industry that employs many of our students from Biology, Chemistry and the interdisciplinary majors. To expose our students to this important aspect of their education we have incorporated a set of tutorials in our Biochemistry class. The present article describes one of our tutorials where undergraduates use modeling experiments to explore the structure of an estrogen receptor. We have employed the Molecular Operating Environment, a powerful molecular visualization software, which can be implemented on a variety of operating platforms. This tutorial reinforces the concepts of ligand binding, hydrophobicity, hydrogen bonding, and the properties of side chains and secondary structure taught in a general biochemistry class utilizing a protein that has importance in human biology. PMID- 21591101 TI - Locks and keys: An analysis of biochemistry students' use of analogies. AB - Analogies can be powerful teaching tools because they can make abstract material intelligible to students by comparing it to material with which the students are already familiar. In this study, we interviewed 43 students to determine the specific ways they use analogies to learn and function in their biochemistry classes. We found that students use analogies in a variety of unique ways to promote understanding, visualization, recall, and motivation in their biochemistry clases. However, their uses of analogies did not always correlate well with their instructors' purposes for using analogies. We also discuss the teaching implications of these findings. PMID- 21591102 TI - Biohorizons: An eConference to assess human biology in large, first-year classes. AB - We detail the design, implementation and evaluation of an eConference entitled "Biohorizons", using a presage-process-product model to describe the development of an eLearning community. Biohorizons was a summative learning and assessment task aiming to introduce large classes of first-year Human Biology students to the practices of professional scientists. It was implemented in semester 1 for students enrolled in Pharmacy and Human Movement Studies degree programs, and in semester 2, for Science students. Pairs of students selected a topic of interest in Human Biology, registered into on-line clusters, then developed and wrote a short scientific paper and accompanying PowerPoint presentation. They then individually participated in an online Discussion. All three tasks were assessed using standards-referenced assessment rubrics. Learning was supported by eTutors, working in asynchronous mode. Biohorizons was evaluated by analyzing student achievement data, surveys and focus group interviews. Most students were able to achieve high academic standards (global mean scores for semester 1, 85-96%; semester 2, 81-90%). Student evaluations support: 1) the successful integration of eLearning into large classes of Human Biology, 2) the engagement of first-year students through collaborative learning, and 3) the fostering of learning through challenging assessment relevant to the core practices of professional scientists. PMID- 21591103 TI - Students' preferred teaching techniques for biochemistry in biomedicine and medicine courses. AB - The aim of this study was to investigate the students' preferred teaching techniques, such as traditional blackboard, power-point, or slide-projection, for biochemistry discipline in biomedicine and medicine courses from Sao Paulo State University, UNESP, Botucatu, Sao Paulo, Brazil. Preferences for specific topic and teaching techniques were determined from questionnaires on a Liquert scale from 1 to 5 (strongly disagree; disagree; neither agree, nor disagree; agree; strongly agree) distributed at the end of biochemistry discipline to 180 biomedical students (30 students/year) and 540 medical students (90 students/year), during the years 2000-2005. Despite of the different number of hours applied to the course topics for the two groups of students, the majority of undergraduates from biomedicine and medicine preferred metabolic topics. Although the perception of a medical student is expected to be different than that of a biomedical student, as the aims of the two programs are different, 92.4% of students from each course agreed or strongly agreed with the biochemistry topics, and 92.1% thought highly on this subject. The majority of students, a number of 139 undergraduates from biomedicine and 419 from medicine course, preferred traditional blackboard teaching than slide-projection, or power point class. In conclusion, it is imperative that the health courses reflect on sophisticated technology and data presentation with high density of information in biochemistry discipline. The traditional classes with blackboard presentation were most favored by students from biomedicine and medicine courses. The use of students' preferred teaching techniques might turn biochemistry more easily understood for biomedical and medical students. PMID- 21591104 TI - An integrated strategy for teaching biochemistry to biotechnology specialty students. AB - The faculty of biochemistry established an integrated teaching strategy for biotechnology specialty students, by intermeshing the case-study method, web assistant teaching, and improved lecture format with a brief content and multimedia courseware. Teaching practice showed that the integrated teaching strategy could retain the best features of each pedagogy and better solve the main difficulties that lay in the teaching of biochemistry to biotechnology specialty students in the East China University of Science and Technology. PMID- 21591105 TI - A project-based biochemistry laboratory promoting the understanding and uses of fluorescence spectroscopy in the study of biomolecular structures and interactions. AB - A laboratory project for a first semester biochemistry course is described, which integrates the traditional classroom study of the structure and function of biomolecules with the laboratory study of these molecules using fluorescence spectroscopy. Students are assigned a specific question addressing the stability/function of lipids, proteins, or nucleic acids, and asked to design an experiment to answer the question using fluorescence methodologies. Students study phase equilibria and determine the critical micelle concentration of single chain amphiphiles, the melting point of multilamellar vesicles, and the melting points and thermodynamic constants (K(eq) , DeltaG(0) , DeltaH(0) and DeltaS(0) ) for denaturation of ds-DNA and proteins. In addition, they examine binding properties of proteins. These laboratory experiments are designed to support student learning of the major themes of structure and function in the course. PMID- 21591106 TI - From egg to crystal: A practical on purification, characterization, and crystallization of lysozyme for bachelor students. AB - A practical hands-on course encompassing enzyme purification, biochemical characterization, and crystallization that completed the course work of 350 second-year bachelor students enrolled in molecular biology/biochemistry was given at the Universite Louis Pasteur of Strasbourg (France). The experimental part of the practical dealt entirely with the model protein lysozyme isolated from hen egg-white. It was designed as a research project to give students the possibility to practice biochemical methods such as chromatography, electrophoresis, and spectrophotometry. It also included enzyme activity assay and protein crystal growth that are usually taught in master-level courses. The organization of the practical work and the related experimental procedures are described and discussed. PMID- 21591107 TI - Lactate dehydrogenase kinetics and inhibition using a microplate reader. AB - A lactate dehydrogenase (LDH) enzyme kinetics laboratory experiment has been developed in which students obtain kinetic data using a microplate spectrophotometer (reader). These instruments have the capability of reading absorbances of many samples in a very short time frame. In this experiment 12 samples are prepared at a time and the absorbances read in less than 1 min. In a 3-hr laboratory period, students collect data at five different substrate concentrations without inhibitor and also in the presence of two different concentrations of inhibitor. Students have enough time to repeat each part if they obtain too much scatter in their data. The enzyme examined, LDH, correlates with the study of metabolism and has particular relevance for students who are interested in medical careers. The LDH assay itself is not new, but the microplate format and the use of urea as a quench reagent are novel features. Students plot Michaelis-Menten and Lineweaver-Burk plots and calculate values for V(max) , apparent V(max) (V(max) (app) ), K(m) , apparent K(m) (K(m) (app) ), k(cat) , and K(I) . Students typically obtain results correctly showing that oxalic acid is a competitive inhibitor and oxamic acid is a noncompetitive inhibitor when lactate is the substrate of the reaction. PMID- 21591108 TI - From purines to basic biochemical concepts: Experiments for high school students. AB - Many high school biology courses address mainly the molecular and cellular basis of life. The complexity that underlies the most essential processes is often difficult for the students to understand; possibly, in part, because of the inability to see and explore them. Six simple practical experiments on purine catabolism as a part of a biochemistry course for 16-18 years students that require only simple equipment for thin layer chromatography have been developed, tried, and tested. These include detection and measurement of enzyme activities in biological extracts, detection of reversible and irreversible reactions, creating a pathway from consecutive reactions. They focus on purines because of their multifunctionality in biochemical processes. They allow students to grasp specific concepts and to use them as a framework for approaching metabolic complexity. PMID- 21591109 TI - Commentary: tribute to herman T. Epstein (1920-2007). PMID- 21591110 TI - Problem-solving Test: alpha1-antitrypsin deficiency: An example for a protein folding disease. AB - Terms to be familiar with before you start to solve the test: protein conformation, protein folding, proteases, protein synthesis, protein glycosylation, glycoproteins, N-linked and O-linked oligosaccharides, endoplasmic reticulum, Golgi complex, secretory pathway, microsomes, pulse/chase labeling, SDS-polyacrylamide gel electrophoresis, immunoprecipitation, chaperones, protein translocation. PMID- 21591111 TI - Commentary: Bioprocessing and the essentials of biochemistry. PMID- 21591112 TI - Commentary: Many students benefit from listening to lecture recordings. PMID- 21591113 TI - Websites of note. PMID- 21591115 TI - Why the linkage of glycogen to glycogenin was so difficult to determine. AB - Glycogenin is the self-glucosylating enzyme that primes mammalian and yeast glycogen synthesis. It proved to be the long-suspected, covalently bound protein component of glycogen. One of the most difficult aspects in elucidating the role of glycogenin was to learn the nature of its covalent bond to glycogen. PMID- 21591116 TI - Improving Thai students' understanding of concepts in protein purification by using Thai and English versions of a simulation program*. AB - To support student learning in biochemistry and related courses, a simulation program, the Protein Purification Program, offers an alternative multimedia-based tool. This program has now been translated to produce a Thai version. However, translation from the original into the Thai language is limited by the differences between the language characteristics of English and Thai. Therefore, use of the program with Thai students had a twofold purpose. It helped their understanding of the concepts of protein purification by allowing code switching between the languages, but it also improved their understanding of, and competence in scientific English, which is a vital skill for functioning as a modern biochemist. According to the results of the questionnaires, undergraduates using the Thai/English program scored significantly higher than those using only the English language program (p < 0.05). In addition, the interview data suggested that the Thai/English program had improved student understanding of the concepts of protein purification to a greater extent than a single language (English) program. Students' overall preference in terms of their learning using the Thai/English program was 4.15 on a 1-5 Likert scale. PMID- 21591117 TI - Participation in research program: A Novel Course in Undergraduate Education of Life Science. AB - A novel course, "Participation in Research Program (PRP)" in life sciences is open for 1st to 3rd year undergraduates. PRP introduces the principles of a variety of biological methods and techniques and also offers an opportunity to explore some specific knowledge in more detail prior to thesis research. In addition, the PRP introduces some methodologies that have been proven to be successful at each institution to participants. Through disciplines crossing, students were trained theoretically and practically about modern techniques, facilitating the efficient commutation of general laboratory skills and modern laboratory skills, and the possession of higher research ability. Therefore, during some basic training (e.g., usage and maintenance of equipments, designing and completing experiments, analyzing data and reporting results, etc.), a series of capabilities are strengthened, such as basic experimental skills, searching appropriate methods, explaining unknown biological phenomena, and the capacity of solving problems. To determine the efficiency of these strategies, we carefully examined students' performance and demonstrated the progress in students' basic abilities of scientific research in their training. PMID- 21591118 TI - Blackboard electrophoresis: An Inexpensive Exercise on the Principles of DNA Restriction Analysis. AB - Undergraduates with little training on molecular biology may find the technical level of the typical introductory restriction laboratory too challenging and have problems with mastering the underlying concepts and processes. Blackboard electrophoresis is an active learning exercise, which focuses student attention on the sequences and principles of DNA restriction. Students convert short strings of letters of A, C, G, and Ts into blackboard electrophoresis profiles analogous to gel electrophoresis of restriction digests. Students work in teams to i) invent short strings of letters representing polynucleotides; ii) identify and count the number of specific restriction sequences in each string; iii) fractionate the strings in restriction fragments and count their size; and iv) predict blackboard electrophoretic patterns in which fragments are represented by sizes. The exercise is inexpensive, since it does not require laboratory equipment or supplies and accommodates a plethora of introductory contexts that can be explored to bring in relevance to students. The exercise has been used with high school and university audiences with very positive outcomes. Blackboard electrophoresis is a valuable complement or alternative to other instructional approaches to teach restriction analysis and DNA diversity. PMID- 21591119 TI - Using "ethics labs" to set a framework for ethical discussion in an undergraduate science course. AB - Teaching ethics across the curriculum is a strategy adopted by many universities. One of the fundamental aims of teaching ethics across the curriculum is to get students to see ethics as truly relevant to the subjects they are studying. Ideally, students will come to see that ethics is a thread woven deeply in the fabric of all knowledge and practice. The standard approach, in which students are required to take a separate ethics course, is not especially well suited to this task, but incorporating ethics into science courses presents significant challenges and is likely to meet with resistance, if only because professors in the sciences are often untrained in the teaching of ethics. In an effort to raise the standard of science education as well as comply with a university-wide curricular mandate, we as a team developed the concept of an "ethics lab." We discuss the design of the exercises done during laboratory sections, the training of the graduate students who run the exercises, and the iterations of the exercises over time. We report unanticipated rapid positive outcomes of an attempt to integrate ethics education into a sophomore/junior level science course, Introduction to Genetics. PMID- 21591120 TI - Demonstration of REBASE-assisted restriction mapping to determine the recognition site of unknown restriction endonucleases. AB - An important step in the characterization of a new restriction enzyme involves determination of its recognition site. Comparison of its DNA substrate digestion fragment patterns with those obtained using enzymes of known specificity indicates whether the enzyme recognizes a novel sequence or is an isoschizomer of already existing prototype. REBASE (Restriction Enzyme dataBASE: http://www.neb.com/rebase)-assisted restriction mapping is described in this paper for a rare cutter [TspMI (REBASE No. 7191)] and a frequent cutter [BflI (REBASE No. 4910)] as a practical exercise for undergraduate students to understand how to determine recognition sequence of a REase. PMID- 21591121 TI - Gel electrophoresis: DNA Science Without the DNA! AB - The aim of this project is to develop a simple system for the teaching and demonstration of DNA gel electrophoresis. DNA gel electrophoresis requires the use of specialized apparatus, toxic reagents, expensive agarose gel, and DNA samples, as well as a considerable amount of valuable classroom time to complete. A systematic evaluation of suitable alternative materials and components for the simulation of DNA gel electrophoresis was undertaken. A tried and tested set of combinations is presented here for educators to use in hands-on classroom teaching, which does not require DNA, agarose, or Tris-borate-EDTA buffer. The use of common biological stains in place of DNA samples, agar-agar-based gels, and weak electrolyte solutions provides a simple, inexpensive, and highly reproducible system that is adaptable to instructional needs. The migration of multicolored bands during electrophoresis provides an intuitive, compelling demonstration of the concept of electrophoresis. PMID- 21591122 TI - Investigation of the properties of wild type and mutant alkaline phosphatase variants: A laboratory project linking genotype and phenotype. AB - An understanding of the link between genotype and phenotype is essential for biology students. A 3-wk laboratory project aimed at demonstrating this link and introducing early year students to some aspects of the research process is described. Students investigate the properties of wild type and mutant variants of alkaline phosphatase using the techniques of both biochemistry and molecular biology. Changes in enzyme activity are correlated with the changes in DNA sequence that introduce restriction enzyme sites. Mutants are also used to analyze the regulation of phoA gene expression. The application of different techniques to the same experimental system helps students to integrate information from different parts of the course. PMID- 21591123 TI - Isolation of RNA and RT-PCR, cloning, and sequencing of noncoding RNAs from fungi*. AB - RNomics, the understanding of functional RNAs and their interactions at a genomic level, is of utmost practical and theoretical importance in modern life sciences. To introduce our students to the techniques and promise of this emerging field, a practical class activity for advanced undergraduate students in biochemistry and molecular biology is described. In these exercises, students first identify noncoding RNA from different fungi by computational methods and analyze their transcription regulation signals and splice signals by bioinformatics tools, then isolate total RNA from these fungi, and finally verify these noncoding RNA gene expressions by reverse transcriptase-polymerase chain reaction, cloning, and sequencing. This activity not only introduces students to the concept of RNomics, noncoding RNA, and RNA splicing, but also introduces students to the practice of basic molecular techniques. The natural combination of the genome projects and bioinformatics with modern molecular biology techniques is considered a major advantage of this laboratory course. PMID- 21591124 TI - Teaching lactose metabolism: A Complex Challenge Faced with a Simple Kit. AB - We developed an experimental didactic proposal to teach both carbohydrate metabolism and lactose intolerance as the disease related to that metabolism. Therefore, we implemented an empirical strategy consisting of inexpensive and nontoxic components for which students do not need to know any of the laboratory techniques. The fact that students were able to discuss their own results obtained from the experiments performed in their classroom gave them an additional motivation to learn the subject. PMID- 21591125 TI - Screening of lactic acid bacteria for bacteriocins by microbiological and PCR methods. AB - We describe a practical laboratory designed for third-year undergraduate students of Biotechnology as part of a Microbial Physiology and Genetics course. It comprises a five-session laboratory module to screen foods for lactic acid bacteria (LAB)1 and to test isolated LAB for the presence of bacteriocins. Traditional Thai fermented foods are first screened for bacteriocin-producing LAB using microbiological methods. This is followed by a simple and rapid DNA extraction and by a multiplex polymerase chain reaction (PCR) using three pairs of specific primers to test for the presence or absence of various bacteriocin genes in the isolated LAB. PCR amplicons of 332, 412, and 608 bp indicate the presence of pediocin, enterocin, and nisin genes, respectively, whereas no amplicon band indicates the absence of these bacteriocins. The laboratory provides the students with experience in the use of microbiological and multiplex PCR methods and shows how the molecular biology techniques can be related to their daily lives. The module could easily be adapted to the study of fermented foods from other countries. PMID- 21591127 TI - Information literacy as a core value. PMID- 21591126 TI - Commentary: Introducing the language of biochemistry. PMID- 21591128 TI - Engaging the learner: Embedding information literacy skills into a biotechnology degree. AB - One of the challenges of the Biotechnology industry is keeping up to date with the rapid pace of change and that much of the information, which students learn in their undergraduate studies, will be out of date in a few years. It is therefore crucial that Biotechnology students have the skills to access the relevant information for their studies and critically evaluate the vast volume of information and its sources. By developing information literacy skills, which are part of lifelong learning, Biotechnology graduates are better prepared for their careers. Students also need to understand the issues related to the use of information such as social, political, ethical, and legal implications. This paper will outline the embedding of information literacy skills within the Biotechnology degree at the University of South Australia. Examples of specific activities and their link to assessment will be discussed. PMID- 21591129 TI - Commentary: Biochemistry, the game: A strategy to capture the gaming generation. PMID- 21591130 TI - Websites of note. PMID- 21591132 TI - BAMBED launches the "Bridging the Gap" series. PMID- 21591133 TI - You be the examiner!: "Model answers" that require critical thinking. AB - "You be the examiner!" is an online approach to providing students with immediate, readily accessible, and nonthreatening feedback on their understanding of key biochemical concepts. The feedback aims to affirm correct understanding and, where further study appears necessary, direct the student to the relevant sections of their textbook and/or lecturer-provided study notes. Rather than providing model answers to previous examination questions, "You be the examiner" asks the students to evaluate typical "student" answers to such questions. Instead of a single "correct" answer, students encounter a range of answers that they must assess for accuracy and appropriateness. PMID- 21591134 TI - How to create successful discussions in science classrooms. AB - Professors often expect students to have the skills that are necessary to participate in discussions. Students, on the other hand, have been trained to glean information from the lecture format; their prior experiences in discussions are likely to be limited to personal opinions on topics such as stem-cell research or evolution. Sudden changes in expectations are jarring and unwelcome at any stage of life but especially when it affects our performance. Thus, bringing any new pedagogy into the classroom has to come with proper preparation for both the students and the faculty. Here, I present my guidelines for bringing discussions into small classrooms. A great deal of structure and preparation are needed to make a discussion-based class successful. To teach using a discussion based format requires creating pedagogical links to every aspect of the course. It requires changing not only what we teach but also what we value. Various components that are needed for a successful discussion-based course are outlined here. PMID- 21591135 TI - Web-based analysis for student-generated complex genetic profiles. AB - A simple, rapid method for generating complex genetic profiles using Alu-based markers was recently developed for students primarily at the undergraduate level to learn more about forensics and paternity analysis. On the basis of the Cold Spring Harbor Allele Server, which provides an excellent tool for analyzing a single Alu variant, we present a new web-based system for analyzing several genetic loci, including Hardy-Weinberg equilibrium, genetic drift, and Fst genetic-distance calculations, as well as analyzing eight loci profiles simultaneously for forensic purposes. By analyzing several loci, students can determine more precisely the relatedness of populations as well as develop a greater appreciation for the use of DNA markers in forensic analysis by concurrently assessing the frequencies of genotypes for eight genetic loci. PMID- 21591136 TI - Developing a new interdisciplinary lab course for undergraduate and graduate students: Plant cells and proteins. AB - Studies of protein function increasingly use multifaceted approaches that span disciplines including recombinant DNA technology, cell biology, and analytical biochemistry. These studies rely on sophisticated equipment and methodologies including confocal fluorescence microscopy, mass spectrometry, and X-ray crystallography that are beyond the scope of traditional laboratory courses. To equip the advanced undergraduate and beginning graduate students with an enabling base of knowledge and initial experience with advanced protein research methodologies, a laboratory course entitled Plant Cells and Proteins was developed in a partnership between Washington University and the Donald Danforth Plant Science Center in St. Louis. In this one semester course, 10-12 students obtain hands-on experience with plant tissue culture, gene transformation, subcellular localization of fluorescent recombinant proteins using confocal microscopy, purification of affinity-tagged recombinant proteins, isolation of total protein extracts, enzymatic assays, one- and two-dimensional gel electrophoresis, MALDI-TOF and ESI-Q-TOF mass spectrometry, protein crystallization, and X-ray diffraction. The course is taught as a series of modules, each led by an expert researcher. Students are evaluated based on a series of graded written reports and tests of their mastery of key concepts, interpretations, and the limitations of the experimental methods. PMID- 21591137 TI - Introducing DNA concepts to Swiss high school students based on a Brazilian educational game. AB - Subjects such as techniques for genetic diagnosis, cloning, sequencing, and gene therapy are now part of our lives and raise important questions about ethics, future medical diagnosis, and such. Students from different countries observe this explosion of biotechnological applications regardless of their social, academic, or cultural backgrounds, although they are not usually familiar with their theoretical genetic bases. To introduce some molecular biology concepts for high school students, we developed a new problem for the Brazilian board game "Discovering the cell" ("Celula Adentro(c)" in Portuguese), a pedagogic tool based on inquiry-, cooperative-, and problem-based learning. This problem (Case) is based on the forensic DNA, which represents an interesting theme for students, as it recurrently appears on newspapers and television series. In this work, we tested this game with secondary students and teachers from Switzerland. Our results indicate that the game "Discovering the cell" is well accepted by both students and teachers and may represent a good pedagogical approach to help teaching complex themes in molecular biology, even with students from different socioeconomical, cultural, and academic backgrounds. PMID- 21591138 TI - Teaching biochemistry at Lisbon University-Facing the challenge of the Bologna Declaration in the 25th anniversary of the biochemistry course. AB - The biochemistry degree has been taught at Lisbon University for 25 years. Since its creation, the curriculum is characterized for being widely eclectic and multidisciplinary. The adoption of the concepts proposed in Europe by the Declaration of Bologna and incorporation of these ideas at Lisbon University is discussed here for the biochemistry degree. PMID- 21591139 TI - Identification of bacteria using matrix-assisted laser desorption ionization time of-flight mass spectrometry. AB - Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS or simply MALDI)1 has become ubiquitous in the identification and analysis of biomacromolecules. As a technique that allows for the molecular weight determination of otherwise nonvolatile molecules, MALDI has had a profound impact in the molecular biosciences, especially in the field of proteomics. MALDI analysis of whole organisms allows for the generation of a phenotypic profile or "molecular fingerprint;" once established, these fingerprints can be used for identification purposes. PMID- 21591140 TI - An undergraduate laboratory exercise to study the effect of darkness on plant gene expression using DNA microarray. AB - DNA microarrays are microscopic arrays on a solid surface, typically a glass slide, on which DNA oligonucleotides are deposited or synthesized in a high density matrix with a predetermined spatial order. Several types of DNA microarrays have been developed and used for various biological studies. Here, we developed an undergraduate laboratory exercise using an Arabidopsis DNA microarray to study the gene expression of Brassica rapa, Wisconsin Fast Plant. Genes involved in senescence, cell wall loosening/degradation, and sugar transport were the most upregulated, while those involved in photosynthesis, the elimination of reactive oxygen intermediates associated with photooxidative stress and auxin synthesis, were the most downregulated. Students were able to complete the experiment successfully. Throughout the exercise, they learned various important molecular techniques including RNA isolation, quantification, reverse transcription, cRNA synthesis, labeling and purification, and microarray hybridization, washing, scanning, and feature extraction. The exercise can be integrated into a college-level molecular biology laboratory. The procedure used can be adapted to examine other effects on other organisms. PMID- 21591141 TI - Conjugation in Escherichia coli: A laboratory exercise. AB - Bacterial conjugation is a genetic transfer that involves cell-to-cell between donor and recipient cells. With the current method used to teach students in genetic courses at the undergraduate level, the transconjugants are identified using bacterial physiology and/or antibiotic resistance. Using physiology, however, is difficult for both first-year undergraduates and special science students at the high school levels, who do not have the basic knowledge. We have developed a laboratory exercise that comprises a simple and rapid technique for transferring bacterial DNA by conjugation and examining the transconjuants using only antibiotic resistance on agar. The identity of the right transconjuants is confirmed by agarose gel electrophoresis. This exercise is designed to help students understand how horizontal gene transfer occurs in bacteria by conjugation using Escherichia coli as a hands-on learning model. Students should be able to draw concept maps of three DNA transfer methods on their own after carrying out the experiment and getting some additional information. PMID- 21591142 TI - Commentary: Ph.D. in biochemistry education? PMID- 21591143 TI - Effectiveness of problem-based learning on academic performance in genetics. AB - This study aimed at comparing the effectiveness of problem-based learning (PBL)1 and traditional lecture-based instruction on elementary school students' academic achievement and performance skills in a science unit on genetics while controlling for their reasoning ability. For the specified purpose, twoinstructional methods were randomly assigned to intact classes of two different teachers. Each teacher had both PBL classes and traditional classes. Although students in PBL classes (n = 126) worked on ill-structured problems cooperatively with the guidance of the teacher, students in traditional classes (n = 91) received instruction based on teacher's explanations, discussions, and textbooks. Genetics Achievement Test was developed by researchers to measure the academic achievement and performance skills. Multivariate Analysis of Covariance results showed that the PBL students had higher academic achievement and performance skills scores (M = 11.44 and M = 2.67, respectively) when compared with those in traditional classes (M = 10.91 and M = 2.20, respectively). This indicated that the PBL students tend to better acquire scientific conceptions related to genetics and integrate and organize the knowledge. Moreover, it was found that the reasoning ability explained a significant portion of variance in the scores of academic achievement and performance skills. PMID- 21591144 TI - Analysis of mutant Ras proteins. AB - Terms to be familiar with before you start to solve the test: growth-factor signaling; Ras proteins; Raf proteins; G proteins; protein kinases; GTPase; GEFs (guanine nucleotide exchange factors); GAPs (GTPase activating proteins); transfection; expression plasmid; mitogen-activated protein kinase (MAPK); extracellular signal-regulated kinase (ERK); constitutively active mutant; dominant inhibitory mutant. PMID- 21591145 TI - Commentary: The prodigious growth and maturation of Wikipedia. PMID- 21591147 TI - Websites of note. PMID- 21591146 TI - Audio podcasting in a tablet PC-enhanced biochemistry course. AB - This report describes the effects of making audio podcasts of all lectures in a large, basic biochemistry course promptly available to students. The audio podcasts complement a previously described approach in which a tablet PC is used to annotate PowerPoint slides with digital ink to produce electronic notes that can be archived. The fundamentals of this approach are described, and data from student attitudinal and informational surveys are presented. The survey data suggest that the students have a positive attitude toward the combination of tablet-based instruction and audio podcasting. In addition, three students provide testimonials on how these technological tools allowed them to utilize their preferred learning styles to succeed in the course. Possible negative consequences of this approach, in terms of class attendance and note taking, are also analyzed and discussed. PMID- 21591148 TI - Bridging the educational research-teaching practice gap: The importance of bridging the gap between science education research and its application in biochemistry teaching and learning: Barriers and strategies. AB - There is a large body of educational research results available in the science education literature that could be usefully applied for the improvement of teaching practice in biochemistry and molecular biology. Unfortunately, for a great variety of reasons, such applications are relatively limited in our discipline. In this first paper in the series, "Bridging the Gap", I describe some of the barriers that are hampering the bridging of this gap and suggest some possible strategies that colleagues might wish to try in order to promote the wider use of this excellent educational resource. PMID- 21591149 TI - Bridging the educational research-teaching practice gap: The power of assessment. AB - Student assessment, in all its forms, is central to the educational process. In this paper in the series, "Bridging the Gap", I describe how assessment can be used as a powerful instrument for influencing how and what students learn and how and what instructors teach in a manner that is conducive to educationally sound curriculum change and improvement. In this way assessment is seen as a useful strategy for colleagues interested in bridging the gap between educational research and its application in teaching practice. PMID- 21591150 TI - Hemoglobin's moving around (to the tune of "Santa Claus is Coming to Town"). PMID- 21591152 TI - A birth-to-death view of mRNA from the RNA recognition motif perspective. AB - RNA binding proteins are a large and varied group of factors that are the driving force behind post-transcriptional gene regulation. By analogy with transcription factors, RNA binding proteins bind to various regions of the mRNAs that they regulate, usually upstream or downstream from the coding region, and modulate one of the five major processes in mRNA metabolism: splicing, polyadenylation, export, translation and decay. The most abundant RNA binding protein domain is called the RNA Recognition Motif (RRM)1. It is probably safe to say that an RRM containing protein is making some contact with an mRNA throughout its existence. The transcriptional counterpart would likely be the histones, yet the multitude of specific functions that are results of RRM based interactions belies the universality of the motif. This complex and diverse application of a single protein motif was used as the basis to develop an advanced graduate level seminar course in RNA:protein interactions. The course, utilizing a learner-centered empowerment model, was developed to dissect each step in RNA metabolism from the perspective of an RRM containing protein. This provided a framework to discuss the development of specificity for the RRM for each required process. PMID- 21591153 TI - Improvement of student understanding of how kinetic data facilitates the determination of amino acid catalytic function through an alkaline phosphatase structure/mechanism bioinformatics exercise. AB - Laboratory exercises, which utilize alkaline phosphatase as a model enzyme, have been developed and used extensively in undergraduate biochemistry courses to illustrate enzyme steady-state kinetics. A bioinformatics laboratory exercise for the biochemistry laboratory, which complements the traditional alkaline phosphatase kinetics exercise, was developed and implemented. In this exercise, students examine the structure of alkaline phosphatase using the free, on-line bioinformatics protein-modeling program Protein Explorer. Specifically, students examine the active site residues of alkaline phosphatase and propose functions for these residues. Furthermore, by examining the mechanism of alkaline phosphatase and by using the published kinetic data, students propose specific roles for several active-site residues. Paired t-test analysis of pre- versus postexercise assessment data shows that the completion of the exercise improves student's ability to use kinetic data correctly thereby determining a probable catalytic function for an active site amino acid. PMID- 21591154 TI - Student assessment in large-enrollment biology classes. AB - Enrollments into first-year university biology courses may be very large, and therefore evaluating student learning can represent quite a challenge. In this article, we present our experience in assessing students by means of an assessment instrument called "Understand Before Choosing" (UBC). It has been used for six semesters, and its performance has been compared with two other common means of assessment, the use of multiple-choice questions and the use of open ended questions. UBC consists of a text (100 lines, nearly 700 words) on the subject being tested, and a set of carefully worded questions that require the selection of one of five crafted options to be answered. To choose the best option, a student needs to understand the concepts embedded in the text. PMID- 21591155 TI - Team-teaching a current events-based biology course for nonmajors. AB - Rice University has created a team-taught interactive biology course for nonmajors with a focus on cutting edge biology in the news-advances in biotechnology, medicine, and science policy, along with the biological principles and methodology upon which these advances are based. The challenges inherent to teaching current topics were minimized by team-teaching the course, providing knowledgeable and enthusiastic lecturers for every topic while distributing the effort required to update material. Postdoctoral associates and advanced graduate students served as lecturers, providing an opportunity for them to develop their teaching skills and learn to communicate effectively with nonscientists on newsworthy topics related to their research. Laboratory tours, in-class demonstrations, and mock-ups helped lecturers convey surprisingly advanced ideas with students who lacked a strong theoretical or practical science background. A faculty member and co-coordinator administer the class, organize class activities, and mentor the speakers on teaching techniques and lecture design. Course design, lecture topics, hands-on activities, and approaches to successfully solve the difficulties inherent to team teaching are discussed. Course evaluations reflect student involvement in, and enjoyment of, the class. PMID- 21591156 TI - Teaching undergraduate research: The one-room schoolhouse model. AB - Undergraduate research in the biochemistry, cell, and molecular biology program at Drake University uses apprenticeship, cooperative-style learning, and peer mentoring in a cross-disciplinary and cross-community educational program. We call it the one-room schoolhouse approach to teaching undergraduate research. This approach is cost effective, aids learning, supports the development of science and transferable management skills, is productive, and supports diversity. It allows a small set of faculty to involve large numbers of students in research and maintain a productive scholarship program. It provides students with skills in scientific research and transferable skills that they apply to a wide set of careers. PMID- 21591157 TI - Cooperative learning combined with short periods of lecturing: A good alternative in teaching biochemistry. AB - The informal activities of cooperative learning and short periods of lecturing has been combined and used in the university teaching of biochemistry as part of the first year course of Optics and Optometry in the academic years 2004-2005 and 2005-2006. The lessons were previously elaborated by the teacher and included all that is necessary to understand the topic (text, figures, graphics, diagrams, pictures, etc.). Additionally, a questionnaire was prepared for every chapter. All lessons contained three parts: objectives, approach and development, and the assessment of the topic. Team work, responsibility, and communication skills were some of the abilities developed with this new methodology. Students worked collaboratively in small groups of two or three following the teacher's instructions with short periods of lecturing that clarified misunderstood concepts. Homework was minimized. On comparing this combined methodology with the traditional one (only lecture), students were found to exhibit a higher satisfaction with the new method. They were more involved in the learning process and had a better attitude toward the subject. The use of this new methodology showed a significant increase in the mean score of the students' academic results. The rate of students who failed the subject was significantly inferior in comparison with those who failed in the previous years when only lecturing was applied. This combined methodology helped the teacher to observe the apprenticeship process of students better and to act as a facilitator in the process of building students' knowledge. PMID- 21591158 TI - The French paradox: Determining the superoxide-scavenging capacity of red wine and other beverages. AB - Plant-derived phenolic compounds such as those found in red wine, tea, and certain fruit juices may protect against cardiovascular disease by detoxifying (scavenging) superoxide and other unstable reactive oxygen species. We present a laboratory exercise that can be used to assess the superoxide-scavenging capacity of beverages. Among the beverages examined, only those known to be rich in phenolic compounds (red wine, green tea, blueberry juice, and stout beer) exhibited appreciable superoxide scavenging. White wine and a 10% ethanol solution served as controls and did not scavenge superoxide. PMID- 21591159 TI - Using green and red fluorescent proteins to teach protein expression, purification, and crystallization. AB - We have designed a laboratory curriculum using the green and red fluorescent proteins (GFP and RFP) to visualize the cloning, expression, chromatography purification, crystallization, and protease-cleavage experiments of protein science. The EGFP and DsRed monomer (mDsRed)-coding sequences were amplified by PCR and cloned into pMAL (MBP-EGFP) or pT7His (His(10) -mDsRed) prokaryotic expression vectors. Then the fluorescent proteins were expressed in Rosetta (DE3) pLysS by IPTG induction or autoinduction. We purified the fluorescent proteins by affinity chromatography (Amylose and metal ion-chelating column), anion-exchange chromatography (High Q column), size exclusive chromatography (Sephacryl S-200 column), and hydrophobic interaction chromatography (Methyl HIC column) to exhibit the protein-purification techniques. After purification, the fusion protein MBP-EGFP was cleaved by TEV protease. The recombinant mDsRed protein was crystallized by hanging drop vapor diffusion technique to show students the basic operation of crystallization. The whole procedure can be monitored real time by naked eyes when using fluorescent proteins. The demonstration of expression, purification, crystallization, and protease cleavage became much more vivid and interesting, which greatly deepened the students' understanding of modern protein science techniques. PMID- 21591160 TI - Actin immobilization on chitin for purifying myosin II: A laboratory exercise that integrates concepts of molecular cell biology and protein chemistry. AB - This article presents our experience on teaching biochemical sciences through an innovative approach that integrates concepts of molecular cell biology and protein chemistry. This original laboratory exercise is based on the preparation of an affinity chromatography column containing F-actin molecules immobilized on chitin particles for purifying skeletal myosin II. It favors the active learning of protein extraction and purification, the learning of concepts such as muscle contraction, cytoskeleton structure, and its importance for the living cell. This laboratory exercise also promotes learning biotechnological applications of chitin and the applications of protein immobilization in different industrial fields. Furthermore, the activities target the development of laboratorial abilities, problem-solving skills, and the ability to write a scientific report, following the model of a scientific article. The trials are mainly proposed for either an undergraduate project for advanced students in the life sciences or a postgraduate practical training course. In both the cases, the students must have had biochemistry as part of their regular curriculum. Alternatively, the affinity chromatography method can fit in any regular biochemistry course if active chitin, F-actin, and a myosin II extract are provided. It is very important to mention that this laboratory exercise can be used even in places where a facility such as ultracentrifugation is lacking. For that, the steps of actin purification are skipped, and actin is commercially obtained. Therefore, it is an adequate approach for the active learning of biochemical and molecular cell biology principles and techniques even in poor countries. PMID- 21591162 TI - Commentary: Lecturing with stone-age technology. PMID- 21591161 TI - Use of a laboratory exercise on molar absorptivity to help students understand the authority of the primary literature. AB - To promote understanding of the authority of the primary literature in students taking our biochemistry laboratory courses, a biochemistry laboratory exercise on the determination of an acceptable molar absorptivity value of 2-nitrophenol (2 NP) was developed. This made the laboratory course much more relevant by linking to a thematic thread, beta-galactosidase, that scaffolds concepts in one exercise with those in later exercises. The substrate for the continuous assay of beta galactosidase is the chromogenic 2-nitrophenyl-beta-D-galactopyranoside that produces 2-NP. In an early laboratory exercise, students determine the wavelength of maximum absorption for the protonated and deprotonated form of 2-NP at various pH values and then determine the molar absorptivity of 2-NP. Students were encouraged to discuss apparent discrepancies not only in their own determinations of molar absorptivity values for 2-NP, but also in the published molar absorptivity values for 2-NP (2,150-21,300 M(-1) cm(-1) ) at almost the same pH and at 420 nm. Finally, the students were led to a publication that serves as an authentic source for molar absorptivity of 2-NP. PMID- 21591163 TI - Problem-solving test: The effect of in vitro bisulfite treatment on genomic DNA. AB - Terms to be familiar with before you start to solve the test: polymerase chain reaction, primer, promoter, restriction endonucleases, agarose gel electrophoresis, ethidium bromide staining, DNA methylation, Taq polymerase, single nucleotide polymorphisms, CpG islands, tumor suppressor genes, protooncogenes, epigenetic regulation. PMID- 21591164 TI - Critical skills in biotechnology education. PMID- 21591165 TI - Introducing principles of validation into biochemistry and biotechnology courses: Practical concepts and a framework for active learning. AB - Although undergraduate biochemistry and biotechnology courses teach the concept of accuracy and precision during practical laboratory sessions, the formal teaching of validation methodologies receives little attention. An increasing number of biochemistry and biotechnology graduates are finding work in industry in the area of industrial validation associated with biopharmaceutical, diagnostics, biomedical device, and pharmaceutical validation. We have introduced a structured introduction to validation into our undergraduate industrial biochemistry programme to illustrate the importance of validation within a framework of good manufacturing practice (GMP) and to show how validation is essential for regulatory compliance. PMID- 21591166 TI - Commentary: Interactive whiteboards. PMID- 21591168 TI - Websites of note. PMID- 21591167 TI - Interactive computer simulations of genetics, biochemistry, and molecular biology. AB - This article describes three interactive software simulations targeted to key domains of modern molecular genetics: genetics, biochemistry, and molecular biology. These simulations allow students to deepen their understanding of key principles in these domains by setting up crosses, designing proteins, and designing genes; the simulations then apply these principles to produce results that the students can interpret. Using this software, students can confront their misconceptions and connect these disciplines in a way that is difficult if not impossible without an interactive environment. We present lab exercises that guide the students as they use the software in a series of activities that begin by introducing the tools and build towards more open inquiry. Preliminary evaluation shows that students enjoy the software and that it promotes active engagement and application of the material. The open-source Java software and the relevant lab manuals are available free of charge on line. PMID- 21591169 TI - Song: Translation [to the tune of "Maria" (From West Side Story)]. PMID- 21591171 TI - Overcome inertia and publish your science education scholarship. PMID- 21591172 TI - Expanding ecological possibilities: Biological nitrogen fixation updated. AB - Biological Nitrogen Fixation (BNF)1 is classically understood as a process restricted to the rhyzosphere and carried out by only few free-living organisms. Recent reports present a variety of new representatives of diazotrophs as well as the presence of known nitrogen-fixing organisms in new habitats. These data were systematized to expand the view on the diazotrophs' ecology and capabilities, bringing new insights on the biogeochemical cycle of nitrogen and its implications on the ecologic chain. With these new discoveries regarding BNF occurrence, we herein bring a brief review systematizing the available new data aiming to help teachers and students in updating their view on this subject, which has been underestimated in most textbooks. PMID- 21591173 TI - Implementation and assessment of a molecular biology and bioinformatics undergraduate degree program. AB - The Department of Biological Sciences at the University of Wisconsin-Parkside has developed and implemented an innovative, multidisciplinary undergraduate curriculum in Molecular Biology and Bioinformatics (MBB). The objective of the MBB program is to give students a hands-on facility with molecular biology theories and laboratory techniques, an understanding of mathematical and physical concepts, an ability to apply these concepts to MBB, and a proficiency with the computational tools and skills related to bioinformatics. We hypothesized that a greater exposure to bioinformatics methods, more rigorous requirements in math and computer science, and a constant demand for integrating information in hands on laboratory courses would help students develop better analytical skills. Indeed, the assessment data support these predictions. Interestingly, 80% of MBB majors apply and are accepted into graduate schools. PMID- 21591174 TI - Biochemical thermodynamics under near physiological conditions. AB - The recommendations for nomenclature and tables in Biochemical Thermodynamics approved by IUBMB and IUPAC in 1994 can be easily introduced after the chemical thermodynamic formalism. Substitution of the usual standard thermodynamic properties by the transformed ones in the thermodynamic equations, and the use of appropriate thermodynamic tables can be easily employed in the study of the energetics of biochemical equations, regulatory systems, and metabolic pathways under near physiological conditions. PMID- 21591175 TI - Just working with the cellular machine: A high school game for teaching molecular biology. AB - Molecular biology is a difficult comprehension subject due to its high complexity, thus requiring new teaching approaches. Herein, we developed an interdisciplinary board game involving the human immune system response against a bacterial infection for teaching molecular biology at high school. Initially, we created a database with several questions and a game story that invites the students for helping the human immunological system to produce antibodies (IgG) and fight back a pathogenic bacterium second-time invasion. The game involves answering questions completing the game board in which the antibodies "are synthesized" through the molecular biology process. At the end, a problem-based learning approach is used, and a last question is raised about proteins. Biology teachers and high school students evaluated the game and considered it an easy and interesting tool for teaching the theme. An increase of about 5-30% in answering molecular biology questions revealed that the game improves learning and induced a more engaged and proactive learning profile in the high school students. PMID- 21591176 TI - An integrated protein chemistry laboratory: Chlorophyll and chlorophyllase. AB - Chlorophyll, the most abundant pigment in nature, is degraded during normal plant growth, when leaves change color, and at specific developmental stages. Chlorophyllase catalyzes the first chemical reaction in this process, that is, the hydrolysis of chlorophyll into chlorophyllide. Here, we describe a series of laboratory sessions designed to illustrate a sequence of experiments used as part of the scientific research process and to convey key biochemical concepts. The format guides students through the process of biochemical protein analysis, starting from a recombinant protein expression vector and working through a kinetic analysis of the purified protein. Over the course of these experiments, students learn protocols in basic protein chemistry that allow them to design and conduct a related experiment of their own interest. The described set of laboratories can be tailored to fit either a 4- or an 8-week series of experiments for use in either introductory or advanced biochemistry laboratory courses, respectively. PMID- 21591177 TI - Use of molecular dynamics data in biochemistry courses: An amphipathy scale to determine protein alpha-helix transmembrane segments. AB - The aim of this manuscript is to explain the application of an amphipathy scale obtained from molecular dynamics simulations and to demonstrate how it can be useful in the protein structure field. It is shown that this scale is easy to be used with the advantage of revealing domains of transmembrane alpha-helix of proteins without the need of knowing anything besides the protein primary structure. In addition, it allows the students to correlate concepts of protein structure and function, energy minimization, molecular dynamics simulations, and protein location. PMID- 21591178 TI - Measuring intracellular enzyme concentrations: Assessing the effect of oxidative stress on the amount of glyoxalase I. AB - Enzymology is one of the fundamental areas of biochemistry and involves the study of the structure, kinetics, and regulation of enzyme activity. Research in this area is often conducted with purified enzymes and extrapolated to in vivo conditions. The specificity constant, k(S) , is the ratio between k(cat) (the catalytic constant) and K(m) (Michaelis-Menten constant), and expresses the efficiency of an enzyme as a catalyst. This parameter is usually determined for purified enzymes, and in this work, we propose a classroom experiment for its determination in situ, in permeabilized yeast cells, based on a method of external enzyme addition, which was previously reported. Under these conditions, which resemble the in vivo state, enzyme concentrations and protein interactions are preserved. The students are presented with a novel approach in enzymology, based on the titration methods that allow the measurement of the enzyme amount, and thus the k(cat) and k(S) . The method will also be used to investigate the effect of exposure to oxidative stress conditions on yeast glyoxalase I. PMID- 21591179 TI - A laboratory exercise to determine human ABO blood type by noninvasive methods. AB - Analysis of single-nucleotide polymorphisms and their association with diseases and nondisease phenotypes is of growing importance in human biology studies. In this laboratory exercise, students determine the genetic basis for their ABO blood type; however, no blood is drawn. Students isolate genomic DNA from buccal mucosa cells that are present in saliva and analyze the DNA on an agarose gel. Subsequently, this DNA is used as a PCR template to amplify exons 6 and 7 of the gene that determines the human ABO phenotype. These PCR products are digested and run on agarose gels to examine the restriction fragment length polymorphisms. A deletion in the O(1) allele converts the BstE II site in exon 6 into a Kpn I site, and this feature is used to determine the presence of O(1) alleles. The pattern of exon 7 digest products allows students to distinguish among four other common ABO alleles: A(1) , A(2) , B, and O(2) . This exercise introduces students to commonly used molecular biology techniques, such as genomic DNA isolation, PCR, gel electrophoresis, and restriction digests. PMID- 21591180 TI - Commentary: Five-minute University. PMID- 21591181 TI - Experimental approaches to microarray analysis of tumor samples. AB - Comprehensive measurement of gene expression using high-density nucleic acid arrays (i.e. microarrays) has become an important tool for investigating the molecular differences in clinical and research samples. Consequently, inclusion of discussion in biochemistry, molecular biology, or other appropriate courses of microarray technologies has become essential in training the modern scientist. The following article offers preparatory and problem-solving questions for engaging students in the understanding of microarray technologies for use in conjunction with other course materials relating to discussions of microarray technology. PMID- 21591182 TI - Problem-solving test: RNA and protein synthesis in bacteriophage-infected E. coli cells. AB - Terms to be familiar with before you start to solve the test: Bacteriophage, E. coli, template, translation, density labeling, radioactive labeling, ribosomes, ribosomal fraction, ribosomal subunits, cesium chloride density gradient centrifugation, sucrose density gradient centrifugation, ribosomal RNA (rRNA), messenger RNA (mRNA). PMID- 21591183 TI - Commentary: Genomic snake oil. PMID- 21591184 TI - Crossing over: An undergraduate service learning project that connects to biotechnology education in secondary schools. AB - The importance of engaging students in science and helping them to become informed citizens has been highlighted by many groups invested in science education. This report describes a project that furthers both academic and civic goals through the integration of a service learning component into an undergraduate course. This nonmajors class covers the biology underlying the use of genetic information in today's society and provides students with the opportunity to discuss related ethical and political issues. The service learning project itself involved the creation of instructional materials dealing with the above topics and issues for use in local secondary school classrooms. Students developed materials in a digital media format to allow for revision in response to peer and community feedback. Outcomes of this pilot project suggest benefits to undergraduates as well as high school educators and students. Interdisciplinary collaborations and local educational partnerships have also been developed and strengthened through this work. PMID- 21591185 TI - Commentary: The 60 million users of Facebook include our students and colleagues. PMID- 21591186 TI - Websites of note. PMID- 21591188 TI - Calcium and signal transduction. AB - Cell signaling is an essential process in which a variety of external signals, defined as first messengers, are translated inside the cells into specific responses, which are mediated by a less numerous group of second messengers. The exchange of signals became a necessity when the transition from monocellular to pluricellular life brought with it the division of labor among the cells of the organisms: unicellular organisms do not depend on the mutual exchange of signals, as they essentially only compete with each other for nutrients. Calcium (Ca2+) was selected during evolution as second messenger, because its chemistry made it a much more flexible ligand than the other abundant cations in the primordial environment (Na+, K+, Mg2+ ). Ca2+ can accept binding sites of irregular geometries and is thus ideally suited to be a carrier of biological information. The Ca2+ signal has properties that set it apart from those of all other biological messengers: they will be reviewed in this contribution. Among them, the ambivalent character of the Ca2+ signal is the most important: while essential to the viability of the cells, it can also easily become a conveyor of doom. PMID- 21591189 TI - A research project-based and self-determined teaching system of molecular biology techniques for undergraduates. AB - Molecular biology techniques play a very important role in understanding the biological activity. Students who major in biology should know not only how to perform experiments, but also the reasons for performing them. Having the concept of conducting research by integrating various techniques is especially important. This paper introduces a research project-based and self-determined teaching system of molecular biology techniques for undergraduates. Its aim is to create an environment mimicking real research programs and to help students build up confidence in their research skills. The students are allowed to explore a set of commonly used molecular biology techniques to solve some fundamental problems about genes on their own. They find a gene of interest, write a mini-proposal, and give an oral presentation. This course provides students a foundation before entering the research laboratory and allows them to adapt easily to real research programs. PMID- 21591190 TI - A novel tool to facilitate the learning of buffering mechanism by undergraduate students of the biological area. AB - In this study, the application and evaluation of a novel didactic tool (buffer kit) is described to make it easy for students in the biological area to overcome their conceptual deficiencies that render the learning of the buffering mechanism difficult. The buffer kit was constructed with double-face EVA cards with a conjugated acid formula (H2CO3 or H2O or H3 O+ ) printed on one face and the respective conjugated base formula (HCO -3 or OH- or H2O) printed on the reverse face. The conjugated acid and base faces were exposed after adding extra H+ and OH- cards, representing the addition of strong acids and bases, respectively. The buffer kit was evaluated with regard to the efficiency of content comprehension and retention of the gain by challenging the students to answer four subjective questions one week after a regular teaching module about the buffering mechanism. For each evaluation round, the buffering mechanism was taught to the control student group without the support of the buffer kit and, to the test student group, an identical content was taught, however, supported by the buffer kit. The overall mean scores obtained by the students who accessed the buffer kit (5.0) were significantly higher (p < 0.01) than the mean score of the control group (3.0), and the buffer kit increased twofold the percentage of students who gave more than 50% right answers. The use of the buffer kit was highly effective in improving the understanding of undergraduate students of the biological area about the buffering mechanism and the application of the Henderson-Hasselbalch equation. PMID- 21591191 TI - The effect of access time on online quiz performance in large biology lecture courses. AB - To better understand the dynamics of online student test taking, including the likelihood of cheating by large numbers of students, we examined test-taking patterns and outcomes of weekly online quizzes in two large undergraduate biology lecture courses. Students taking a quiz late in a 1-3-day quiz access period performed 10-15% worse on quizzes than the students who completed the quiz early. Quiz access time was also negatively correlated with performance in other course components and course grades. These patterns suggest that academic dishonesty was not a determinant in unsupervised online quiz performance. Students generally completed quizzes in late afternoon or evening hours, but students who completed quizzes between midnight and 8 a.m. had significantly lower quiz grades than their peers. In addition, upper-division students were more likely to characterize weekly online quizzes as more helpful for their learning than the lower-division students. PMID- 21591192 TI - Tonal interface to MacroMolecules (TIMMol): A textual and tonal tool for molecular visualization. AB - We developed the three-dimensional visualization software, Tonal Interface to MacroMolecules or TIMMol, for studying atomic coordinates of protein structures. Key features include audio tones indicating x, y, z location, identification of the cursor location in one-dimensional and three-dimensional space, textual output that can be easily linked to speech or Braille output, and the ability to scroll along the main chain backbone of a protein structure. This program was initially designed for visually impaired users, and it already has shown its effectiveness in helping a blind researcher study X-ray crystal structure data. Subsequently, TIMMol has been enhanced with a graphical display to act as a bridge to ease communication between sighted and visually impaired users as well as to serve users with spatial visualization difficulties. We performed a pilot study to assess the efficacy of the program in conveying three-dimensional information about proteins with and without graphical output to a general scientific audience. Attitudes regarding using TIMMol were assessed using Rasmol, a common visualization package, for comparison. With the use of text and tones exclusively, a majority of users were able to identify specific secondary structure elements, three-dimensional relationships among atoms, and atoms coordinating a ligand. In addition, a majority of users saw benefits in using TIMMol and would recommend it to those having difficulty with standard tools. PMID- 21591193 TI - A streamlined molecular biology module for undergraduate biochemistry labs. AB - Site-directed mutagenesis and other molecular biology techniques, including plasmid manipulation and restriction analysis, are commonly used tools in the biochemistry research laboratory. In redesigning our biochemistry lab curricula, we sought to integrate these techniques into a term-long, project-based course. In the module presented here, students use structural data to design a site directed mutant and make the mutation using the Kunkel method. A second, silent mutant, that creates or removes a restriction site, is simultaneously introduced. Restriction digestion and agarose gel electrophoresis are used to assess the success of mutagenesis. Placing these procedures in the context of continuous, student-driven project serves to create a "research style" laboratory environment. PMID- 21591194 TI - Cloning yeast actin cDNA leads to an investigative approach for the molecular biology laboratory. AB - The emergence of molecular tools in multiple disciplines has elevated the importance of undergraduate laboratory courses that train students in molecular biology techniques. Although it would also be desirable to provide students with opportunities to apply these techniques in an investigative manner, this is generally not possible in the classroom because of the preparation, expense, and logistics involved in independent student projects. The authors have designed a 10-week lab series that mimics the research environment by tying separate fundamental lab techniques to a common goal: to build a plasmid with yeast actin cDNA cloned in a particular orientation. In the process of completing this goal, a problem arises in that students are unable to obtain the target plasmid and instead only recover the gene cloned in the opposite orientation. To address this problem, students identify four plausible hypotheses and work in teams to address them by designing and executing experiments. This project reinforces the utility and flexibility of techniques covered earlier in the class and serves to develop their skills in experimental design and analysis. As the project is focused on one problem, the diversity of experimental approaches is limited and may be prepared in advance with little additional expense in reagents or technical support. PMID- 21591195 TI - Teaching the toolkit: A laboratory series to demonstrate the evolutionary conservation of metazoan cell signaling pathways. AB - A major finding of comparative genomics and developmental genetics is that metazoans share certain conserved, embryonically deployed signaling pathways that instruct cells as to their ultimate fate. Because the DNA encoding these pathways predates the evolutionary split of most animal groups, it should in principle be possible to clone representatives of such signaling pathways from almost any species, demonstrating their sequence conservation. Here I describe an 8-week laboratory series that tests this prediction by attempting to clone multiple members of a known signaling pathway from a species where the targets are unknown. Beginning with the molecular components of a signaling pathway and publicly available sequence information from related taxa, students designed partially degenerate PCR primers to amplify the corresponding mRNA sequences from a "new" organism, in this case a turtle (Trachemys scripta). Using a single round of degenerate PCR and standard DNA cloning techniques, we were able to retrieve 6 out of 16 species-specific homologs on the first attempt (~40% success rate). To conclude the project, the novel sequences were submitted back into the original public database. The molecular methods of the lab can be adapted to any combination of pathway and organism, demonstrating the conserved components of cellular signaling in any biological process, from gastrulation to aging. The linked labs offer intensive research-based training in bioinformatics and molecular biology, while empirically demonstrating the ubiquity of the metazoan cell-signaling toolkit. PMID- 21591196 TI - Commentary: Critiquing final examination practices. PMID- 21591197 TI - Problem-solving test: Expression cloning of the erythropoietin receptor. AB - Terms to be familiar with before you start to solve the test: cytokines, cytokine receptors, cDNA library, cDNA synthesis, poly(A)+ RNA, primer, template, reverse transcriptase, restriction endonucleases, cohesive ends, expression vector, promoter, Shine-Dalgarno sequence, poly(A) signal, DNA helicase, DNA ligase, topoisomerases, [125I] labeling, transfection, mock transfection, SDS polyacrylamide gel electrophoresis, beta-mercaptoethanol, autoradiography. PMID- 21591198 TI - Commentary: Enhancing assessment in the biological sciences. PMID- 21591199 TI - Websites of note. PMID- 21591200 TI - Song: When acids are synthesized (to the tune of "When Johnny Comes Marching Home"). PMID- 21591202 TI - Ph.D. in biochemistry (education)! PMID- 21591203 TI - Ph.D. in biochemistry with research in education. PMID- 21591204 TI - Primordial soup, fool's gold, and spontaneous generation: A brief introduction to the theory, history, and philosophy of the search for the origin of life. AB - This study provides a concise background to the biochemical search for the origin of life, as grounded in the field of prebiotic chemistry. It is intended to provide a good summary of competing theories and place them in a broader context, raising questions about weaknesses in any particular theory. This material is relevant for science educators at all levels, and will stimulate interest in a wide variety of students. PMID- 21591205 TI - Teaching noncovalent interactions using protein molecular evolution. AB - Noncovalent interactions and physicochemical properties of amino acids are important topics in biochemistry courses. Here, we present a computational laboratory where the capacity of each of the 20 amino acids to maintain different noncovalent interactions are used to investigate the stabilizing forces in a set of proteins coming from organisms adapted to different environments. Using protein sequence and structure information it is possible to evaluate the noncovalent contributions to the stabilization of a given protein fold. As a case study, we use the protein lumazine synthase from three different organisms adapted to live in extreme temperatures: one psychrophilic (optimal growth temperature, 0-20 degrees C), one mesophilic (optimal growth temperature, 20-50 degrees C), and one thermophilic (optimal growth temperature, 80-110 degrees C). We found that this computational laboratory for biochemistry and molecular biology courses enhances student amino acid noncovalent interaction understanding and how these interactions are involved in protein stability. PMID- 21591206 TI - A laboratory demonstration illustrating bioseparations using colorful proteins. AB - A simple in class laboratory illustrating the principles of ion exchange chromatography as a bioseparation technique is described. A protein's isoelectric point as a driving force for ion exchange chromatography is easily demonstrated by using combinations of proteins with natural color or fluorescence, such as DsRed2, enhanced green fluorescent protein (EGFP), and flavodoxin. Simple equipment is required for this separation which can be performed on a desk top. The experiment can stimulate a range of discussion about process parameters that would create a more efficient separation of the proteins, other types of chromatography, and bioseparations in general. PMID- 21591207 TI - Design-based learning for biology: Genetic engineering experience improves understanding of gene expression. AB - Gene expression is a difficult topic for students to learn and comprehend, at least partially because it involves various biochemical structures and processes occurring at the microscopic level. Designer Bacteria, a design-based learning (DBL) unit for high-school students, applies principles of DBL to the teaching of gene expression. Throughout the 8-week unit, students genetically engineer bacteria to meet a need in their own lives. Through a series of investigations, discussions, and design modifications, students learn about the molecular processes and structures involved in gene expression, and how these processes and structures are dependent upon various environmental variables. This article is intended to describe the Designer Bacteria unit and report preliminary results of student progress and performance on pre-unit and post-unit assessments. Teacher experiences and student progress indicate that Designer Bacteria successfully taught core aspects of gene expression through DBL. PMID- 21591209 TI - Commentary: A rare opportunity. PMID- 21591208 TI - Problem-solving test: Targeted gene disruption. AB - Terms to be familiar with before you start to solve the test: mutation, vector, plasmid, origin of replication, promoter, introns/exons, open reading frame, transfection, circular and linear DNA, DNA integration, homologous recombination, DNA replication, gene expression, heterozygote, homozygote. PMID- 21591210 TI - Commentary: plagiarism. PMID- 21591211 TI - Websites of note. PMID- 21591212 TI - Bridging the educational research-teaching practice gap: Conceptual understanding, part 1: The multifaceted nature of expert knowledge. AB - The term "conceptual understanding" has been used rather loosely over the years in educational practice, with a tendency to focus on a few aspects of an extremely complex phenomenon. In this first article of a two-part miniseries on conceptual understanding, we describe the nature of expert (versus novice) knowledge and show how the conceptual understanding of experts is multifaceted in nature requiring competence in a wide range of cognitive skills. We then discuss five such facets of conceptual understanding that require competence in the cognitive skills of memorization, integration, transfer, analogical reasoning, and system thinking. We also argue for the importance of explicitly teaching and assessing such facets of understanding as part of all molecular life science curricula so as to better prepare our students to become experts in the field. Examples of the assessment tasks that can be used to promote the development of multifaceted conceptual understanding in students are presented in Part 2 of this series. PMID- 21591214 TI - Phosphoenolpyruvate: An end to hand-waving. AB - The conversion of phosphoenolpyruvate (PEP) in glycolysis is coupled with the formation of ATP. This note discusses the origin of the energy required for ATP formation as arising from redistribution of energy in PEP when compared with its precursor, 2-phosphoglycerate. PMID- 21591215 TI - A portable bioinformatics course for upper-division undergraduate curriculum in sciences. AB - This article discusses the challenges that bioinformatics education is facing and describes a bioinformatics course that is successfully taught at the California State Polytechnic University, Pomona, to the fourth year undergraduate students in biological sciences, chemistry, and computer science. Information on lecture and computer practice topics, free for academic use software and web links required for the laboratory exercises and student surveys for two instances of the course, is presented. This course emphasizes hands-on experience and focuses on developing practical skills while providing a solid knowledge base for critically applying these skills. It is designed in blocks of 1-hour lecture followed by 2 hours of computer laboratory exercises, both covering the same general topic, for a total of 30 hours of lecture and 60 hours of computer practice. The heavy computational aspect of this course was designed to use a single multiprocessor computer server running Linux, accessible from laptops through Virtual Network Computing sessions. The laptops can be either provided by the institution or owned by the individual students. This configuration avoids the need to install and maintain bioinformatics software on each laptop. Only a single installation is required for most bioinformatics software on the Linux server. The content of this course and its software/hardware configuration are well suited for institutions with no dedicated computer laboratory. This author believes that the same model can be successfully implemented in other institutions, especially those who do not have a strong instructional computer technology support such as community colleges and small universities. PMID- 21591216 TI - Teaching glycoproteins with a classical paper: Knowledge and methods in the course of an exciting discovery: The story of discovering HK-ATPASE beta-subunit. AB - To integrate research into the teaching of glycoproteins, the story of discovering hydrogen-potassium ATPase (HK-ATPase) beta subunit is presented in a way covering all the important teaching points. The interaction between the HK ATPase alpha subunit and a glycoprotein of 60-80 kDa was demonstrated to support the existence of the beta subunit. On revealing the strategies and experimental designs of this discovery, the knowledge of glycoproteins is delivered. The purpose of this effort was to facilitate the teaching of scientific thinking in the science classroom, to make the biochemistry classroom a more interesting place, and to attract uncertain minds into the career of biochemistry research. PMID- 21591217 TI - Using FRET to measure the angle at which a protein bends DNA: TBP binding a TATA box as a model system. AB - An undergraduate biochemistry laboratory experiment that will teach the technique of fluorescence resonance energy transfer (FRET) while analyzing protein-induced DNA bending is described. The experiment uses the protein TATA binding protein (TBP), which is a general transcription factor that recognizes and binds specific DNA sequences known as TATA boxes. When TBP binds to a TATA box, it bends the DNA. Such bending will be detected using FRET to measure the distance between two fluorophores located on the ends of the DNA. When TBP binds and bends the DNA, the fluorophores move closer together, reflected by an increase in FRET. At the completion of the experiment, three parameters will be determined: 1) the efficiency of the FRET, 2) the end-to-end distance between the fluorophores, and 3) the angle at which TBP bends the DNA. In performing this experiment, students will be introduced to FRET, gain experience in quantitative biophysical measurements, and appreciate how a protein can induce a dramatic change in DNA conformation. PMID- 21591218 TI - Biochemistry and molecular biology techniques for person characterization. AB - Using the traditional serological tests and the most novel techniques for DNA fingerprinting, forensic scientists scan different traits that vary from person to person and use the data to include or exclude suspects based on matching with the evidence obtained in a criminal case. Although the forensic application of these methods is well known, the procedures and techniques used to obtain these results are not so well studied. Here, we report a laboratory exercise aimed to familiarize the students in several of the methods and markers employed for people individualization. With this exercise, students have to characterize themselves and an unknown sample according to the following characteristics: ABO blood group, presence or absence of Y chromosome, and their polymorphism for a variable number of tandem repeats (VNTR). This exercise has been originally developed for students of the course "Techniques in Criminology" within the Bachelor of Criminology. Although the schedule and procedures have been addressed to students who are faced for their first time with a laboratory of molecular biology, the exercise can also be adapted to students in more specialized courses and studies. PMID- 21591219 TI - Fly diversity revealed by PCR-RFLP of mitochondrial DNA. AB - In this article, we describe an inexpensive, two-session undergraduate laboratory activity that introduces important molecular biology methods in the context of biodiversity. In the first session, students bring tentatively identified flies (order Diptera, true flies) to the laboratory, extract DNA, and amplify a region of the mitochondrial gene NADH dehydrogenase subunit 1. In the second session, the students digest the PCR product with a restriction enzyme, visualize the resulting fragments by agarose gel electrophoresis, and analyze their results with comparison to known sequences. The diversity of flies and their importance as disease vectors, agriculture pests, pollinators, models of speciation, and in the case of Drosophila melanogaster, as a genetic model organism, offer many perspectives with which to appeal to students' interests. The laboratory exercise can be linked as a module to topics in biodiversity, bioinformatics, entomology, evolution, and mutagenesis. PMID- 21591220 TI - Of tacit knowledge, texts and thing-based learning (TBL). AB - Practical knowledge has two dimensions- a visible, codified component that resembles the tip of an iceberg. The larger but crucial tacit component which lies submerged consists of values, procedures and tricks of the trade and cannot be easily documented or codified. Undergraduate science students were given an opportunity to explore this component through an inquiry-based course. PMID- 21591221 TI - Commentary: The professional masters degree. PMID- 21591222 TI - Commentary: 2400 Years of education. PMID- 21591223 TI - Websites of note. PMID- 21591224 TI - Bridging the educational research-teaching practice gap: Conceptual understanding, part 2: Assessing and developing student knowledge. AB - The first paper [1] in this two-part miniseries on conceptual understanding discussed expert and novice conceptual knowledge, the multifaceted nature of conceptual understanding, and the cognitive skills essential for constructing it. This second article presents examples of instruments for the assessment and development of five facets of conceptual understanding that require competence in the cognitive skills of mindful memorization, integration, transfer, analogical reasoning, and system thinking. We also argue for the importance of explicitly assessing these facets of conceptual understanding as part of all biochemistry and molecular biology curricula so as to develop expert knowledge in our students. PMID- 21591225 TI - Song: Biochemistry pie (to the tune of "American Pie"). PMID- 21591227 TI - Applying innovative educational principles when classes grow and resources are limited: Biochemistry experiences at Muhimbili University of Allied Health Sciences. AB - Teaching to large classes is often challenging particularly when the faculty and teaching resources are limited. Innovative, less staff intensive ways need to be explored to enhance teaching and to engage students. We describe our experience teaching biochemistry to 350 students at Muhimbili University of Health and Allied Sciences (MUHAS) under severe resource limitations and highlight our efforts to enhance the teaching effectiveness. We focus on peer assisted learning and present three pilot initiatives that we developed to supplement teaching and facilitate student interaction within the classroom. These included; instructor facilitated small group activities within large group settings, peer-led tutorials to provide supplemental teaching and peer-assisted instruction in IT skills to enable access to online biochemistry learning resources. All our efforts were practical, low cost and well received by our learners. They may be applied in many different settings where faculties face similar challenges. PMID- 21591228 TI - Multimedia presentations on the human genome: Implementation and assessment of a teaching program for the introduction to genome science using a poster and animations. AB - Genome science, including topics such as gene recombination, cloning, genetic tests, and gene therapy, is now an established part of our daily lives; thus we need to learn genome science to better equip ourselves for the present day. Learning from topics directly related to the human has been suggested to be more effective than learning from Mendel's peas not only because many students do not understand that plants are organisms, but also because human biology contains important social and health issues. Therefore, we have developed a teaching program for the introduction to genome science, whose subjects are focused on the human genome. This program comprises mixed multimedia presentations: a large poster with illustrations and text on the human genome (a human genome map for every home), and animations on the basics of genome science. We implemented and assessed this program at four high schools. Our results indicate that students felt that they learned about the human genome from the program and some increases in students' understanding were observed with longer exposure to the mixed multimedia presentations. PMID- 21591229 TI - Teaching of biochemistry in medical school: A well-trodden pathway? AB - Biochemistry and molecular biology occupy a unique place in the medical school curriculum. They are frequently studied prior to medical school and are fundamental to the teaching of biomedical sciences in undergraduate medical education. These two circumstances, and the trend toward increased integration among the disciplines, have led to reconsideration of biochemistry instruction in many medical schools. We conducted a survey to explore the evolving trends in biochemistry education. A broad diversity was evident in parameters including course content, faculty, governance, prerequisites, and teaching methods. Notably, sharp differences were apparent between freestanding biochemistry courses and those in which biochemistry is integrated with other subjects. Furthermore, the data imply a likely trend toward increased integration of biochemistry with other disciplines in the medical school curriculum. PMID- 21591230 TI - Glucose as the sole metabolic fuel: The possible influence of formal teaching on the establishment of a misconception about energy-yielding metabolism among students from Rio de Janeiro, Brazil. AB - Energy-yielding metabolism is an important biochemistry subject that is related to many daily experiences and health issues of students. An adequate knowledge of the general features of EYM is therefore important, both from an academic and social point of view. In a previous study, we have shown that high-school students present the misconception that carbohydrates, especially glucose, are the sole metabolic fuel for ATP production by human cells. In the present work, we investigated the possible origins of the occurrence of this misconception among students. The analysis of students' answers to questionnaires indicated that the misconception appears as soon as in the 8th grade and remains unchanged throughout subsequent school years. The analysis of grade textbooks showed that the misconception is likely to be a consequence of the teaching of nutrition in the 8th grade, when a single function is emphasized for each nutrient. The energetic function is mainly associated with carbohydrates, while proteins and lipids are considered structural and storage molecules, respectively. An extreme similarity was observed between students' knowledge of nutrient's function and textbook contents. Analysis of high-school textbooks suggested that the misconception would be reinforced because of the detailed teaching only of glucose metabolism, with rare mention of lipids or amino acids as metabolic fuels. The consequences of that approach are discussed and suggestions are made on an alternative teaching of energy-yielding metabolism. PMID- 21591231 TI - Caenorhabditis elegans as an undergraduate educational tool for teaching RNAi. AB - Discovery of RNA-mediated interference (RNAi) is widely recognized as one of the most significant molecular biology breakthroughs in the past 10 years. There is a need for science educators to develop teaching tools and laboratory activities that demonstrate the power of this new technology and help students to better understand the RNAi process. C. elegans is an ideal model organism for the undergraduate laboratory because of the simplicity of worm maintenance, its well studied genetic background, and the fact that it can be employed as a model organism in laboratory environments where vertebrate research is restricted. Certain unique features of C. elegans make it a very suitable organism for RNAi studies. Specifically, nematode strains highly sensitive to RNAi are readily available from public sources, and RNAi induction by a feeding method is an uncomplicated procedure that lends itself readily as an educational tool. In this article, we provide a detailed depiction of the use of C. elegans as an RNAi educational tool, describing two separate RNAi-based experiments. One is a qualitative experiment where students can examine the effects of knocking down the unc-22 gene involved in the regulation of muscle contraction, which results in a "twitching" phenotype. The other experiment is a quantitative RNAi experiment, where students measure the effect of knocking down the lsy-2 gene involved in neuronal development. Although these experiments are designed for a college-level study, nematode research projects can also be accomplished in secondary school facilities. PMID- 21591232 TI - Thermal and chemical denaturation of Bacillus circulans xylanase: A biophysical chemistry laboratory module. AB - A number of institutions have been, or are in the process of, modifying their biochemistry major to include some emphasis on the quantitative physical chemistry of biomolecules. Sometimes this is done as a replacement for part for the entire physical chemistry requirement, while at other institutions this is incorporated as a component into the traditional two-semester biochemistry series. The latter is the model used for biochemistry and molecular biology majors at the University of Richmond, whose second semester of biochemistry is a course entitled Proteins: Structure, Function, and Biophysics. What is described herein is a protein thermodynamics laboratory module, using the protein Bacillus circulans xylanase, which reinforces many lecture concepts, including: (i) the denatured (D) state ensemble of a protein can be different, depending on how it was populated; (ii) intermediate states may be detected by some spectroscopic techniques but not by others; (iii) the use and assumptions of the van't Hoff approach to calculate DeltaH(o) , DeltaS(o) , and DeltaG(o) (T) for thermal protein unfolding transitions; and (iv) the use and assumptions of an approach that allows determination of the Gibb's free energy of a protein unfolding transition based on the linear dependence of DeltaG(o) on the concentration of denaturant used. This module also requires students to design their own experimental protocols and spend time in the primary literature, both important parts of an upper division lab. PMID- 21591233 TI - Commentary: Putting ourselves in the students' place. PMID- 21591234 TI - Commentary: Teaching cognitive skills in the biochemistry classroom-A community effort. PMID- 21591235 TI - Problem-solving test: A mutation causing cystic fibrosis. AB - Terms to be familiar with before you start to solve the test: cystic fibrosis, pedigree analysis, transmembrane protein, channel protein, polymerase chain reaction, primers, polyacrylamide gel electrophoresis, fluorescent DNA staining, autosomal vs. sex-linked inheritance, recessive vs. dominant inheritance, homozygote, heterozygote, frame-shift mutation, deletion. PMID- 21591236 TI - Commentary: Web 2.0-The users take control in the age of wikis and blogs. PMID- 21591237 TI - Websites of note. PMID- 21591238 TI - Song: Gluconeogenesis (to the tune of "Supercalifragilisticexpialidocious"). PMID- 21591240 TI - Safrole induces cell death in human tongue squamous cancer SCC-4 cells through mitochondria-dependent caspase activation cascade apoptotic signaling pathways. AB - Safrole is one of important food-borne phytotoxin that exhibits in many natural products such as oil of sassafras and spices such as anise, basil, nutmeg, and pepper. This study was performed to elucidate safrole-induced apoptosis in human tongue squamous carcinoma SCC-4 cells. The effect of safrole on apoptosis was measured by flow cytometry and DAPI staining and its regulatory molecules were studied by Western blotting analysis. Safrole-induced apoptosis was accompanied with up-regulation of the protein expression of Bax and Bid and down-regulation of the protein levels of Bcl-2 (up-regulation of the ratio of Bax/Bcl-2), resulting in cytochrome c release, promoted Apaf-1 level and sequential activation of caspase-9 and caspase-3 in a time-dependent manner. We also used real-time PCR to show safrole promoted the mRNA expressions of caspase-3, -8, and -9 in SCC-4 cells. These findings indicate that safrole has a cytotoxic effect in human tongue squamous carcinoma SCC-4 cells by inducing apoptosis. The induction of apoptosis of SCC-4 cells by safrole is involved in mitochondria- and caspase dependent signal pathways. PMID- 21591242 TI - Prevalence, risk factors and complications associated with type 2 diabetes in migrant South Asians. AB - It is estimated that type 2 diabetes (T2D) currently affects about 246 million people worldwide, with South Asians, especially Indians, having both the largest number of cases and the fastest growing prevalence. South Asian ethnicity has been identified as a major risk factor for the development of T2D with central adiposity, insulin resistance and an unfavourable lipid profile being identified as predominant signals of alarm. Leading databases, including Web of Science, Medline, PubMed and Science Direct, were consulted and manual searches were conducted for cited references in leading diabetes-related journals. In all, 152 articles were included for the final assessment reported in this review. Genetic predisposition, central adiposity and unfavourable lifestyle, including physical inactivity and an unhealthy diet, were associated with the prevalence of T2D in migrant South Asians. 'Westernization', acculturation, socio-economic factors and lack of knowledge about the disease have also been identified as contributors to the development of T2D in this population. Higher prevalence of T2D in migrant South Asians may not be entirely attributed to genetic predisposition; hence, ethnicity and associated modifiable risk factors need further investigation. Preventive measures and appropriate interventions are currently limited by the lack of ethnic-specific cut-off points for anthropometric and biological markers, as well as by the absence of reliable methods for dietary and physical activity assessment. This article describes the prevalence rate, risk factors and complications associated with T2D in migrant South Asians living in different countries. PMID- 21591241 TI - Effects of different protein content and glycaemic index of ad libitum diets on diabetes risk factors in overweight adults: the DIOGenes multicentre, randomized, dietary intervention trial. AB - BACKGROUND: Dietary regimens providing different levels of protein and glycemic index (GI) foods when prescribed for weight management may also influence insulin sensitivity. PROCEDURES AND OUTCOMES: Overweight/obese adults in 8 European countries who lost >= 8% of initial body-weight (BW) after following a low calorie diet (LCD) were later randomly assigned with a 2x2 factorial design into 4 ad libitum dietary groups with two different protein content levels and dissimilar glycemic index, which were compared to a healthy reference diet. Specific markers assessing insulin resistance were measured. The LCD was initially applied to 932 adults and 773 were randomised to the 5 ad libitum diets. The 6-months programme was completed by 548 participants. The assignment to the Low Protein /High Glycemic Index diet induced a statistically higher HOMA IR increase during the 6 months period as compared to the control. Contrariwise, the insulin response was lower in the High Protein/Low Glycemic Index diet after 60 and 90 min of an Oral Glucose Tolerance test subsequently carried out after the 6-months intervention. The Low Glycemic Index diets (either with high or low protein content) also lead to a decrease in fructosamine levels during the trial. CONCLUSION/INTERPRETATION: After a weight loss period, an increase in the dietary protein proportions and a decrease in the consumption of foods with a high Glycemic Index within an ad libitum dietary intervention aiming to weight maintenance produced favorable effects on glycaemic control and insulin sensitivity in overweight/obese subjects. PMID- 21591243 TI - Tooth evolution and dental defects: from genetic regulation network to micro-RNA fine-tuning. AB - Teeth, like all epithelial appendages, form via a sequential and reciprocal series of inductive signals between the epithelium and the underlying mesenchyme. The genes involved in this signaling network regulating ectodermal organ development have been highly conserved during evolution and are gaining more understanding in great detail. The specific functions of numerous genes during embryogenesis are known, and the involvement of their mutations in the pathogenesis of congenital defects is being extensively studied. Recently, the micro-RNA (miRNA) pathway has been associated with various aspects of embryogenesis including ectodermal organ formation and odontogenesis. In this review, I presented the genetic network involved during tooth formation and evolution, and several mutations that give rise to dental defects. The possible impact of fine-tuning and network regulation by miRNAs on development, evolution of teeth, and defects are, therefore, discussed. PMID- 21591244 TI - Tbx1, subpulmonary myocardium and conotruncal congenital heart defects. AB - Conotruncal congenital heart defects, including defects in septation and alignment of the ventricular outlets, account for approximately a third of all congenital heart defects. Failure of the left ventricle to obtain an independent outlet results in incomplete separation of systemic and pulmonary circulation at birth. The embryonic outflow tract, a transient cylinder of myocardium connecting the embryonic ventricles to the aortic sac, plays a critical role in this process during normal development. The outflow tract (OFT) is derived from a population of cardiac progenitor cells called the second heart field that contributes to the arterial pole of the heart tube during cardiac looping. During septation, the OFT is remodeled to form the base of the ascending aorta and pulmonary trunk. Tbx1, the major candidate gene for DiGeorge syndrome, is a critical transcriptional regulator of second heart field development. DiGeorge syndrome patients are haploinsufficient for Tbx1 and present a spectrum of conotruncal anomalies including tetralogy of Fallot, pulmonary atresia, and common arterial trunk. In this review, we focus on the role of Tbx1 in the regulation of second heart field deployment and, in particular, in the development of a specific population of myocardial cells at the base of the pulmonary trunk. Recent data characterizing additional properties and regulators of development of this region of the heart, including the retinoic acid, hedgehog, and semaphorin signaling pathways, are discussed. These findings identify future subpulmonary myocardium as the clinically relevant component of the second heart field and provide new mechanistic insight into a spectrum of common conotruncal congenital heart defects. PMID- 21591245 TI - Maternal folate, vitamin B12 and homocysteine levels in pregnancies affected by congenital malformations other than neural tube defects. PMID- 21591246 TI - Maternal alcohol drinking pattern during pregnancy and the risk for an offspring with an isolated congenital heart defect and in particular a ventricular septal defect or an atrial septal defect. AB - BACKGROUND: This cohort study examines the possible association between maternal alcohol intake, including binge drinking, during pregnancy, and the subsequent risk of having a child with an isolated congenital heart defect and, more specifically, with the isolated form of ventricular septal defect (VSD) or of an atrial septal defect (ASD). METHODS: Participants were 80,346 pregnant women who were enrolled into the Danish National Birth Cohort in 1996-2002 and gave birth to a live-born singleton without any chromosome anomalies. Twice during pregnancy these women were asked about their intake of alcohol. Few (if any) women with an excessive/abusive intake of alcohol were enrolled into the Danish National Birth Cohort. RESULTS: Through linkage with the National Hospital Discharge Registry, we identified 477 infants with a diagnosis of isolated congenital heart defect registered at any time during their first 31/2-years of life; they included 198 infants with a VSD and 145 with an ASD. Neither the number of episodes of binge drinking nor binge drinking during three different developmental periods was associated with VSD or ASD. Women drinking 1/2-11/2, 2, and 3+ drinks of alcohol per week had adjusted prevalence ratios of delivering an infant with a VSD of 1.22 (95% CI = 0.90-1.66); 1.38 (95% CI = 0.83-2.28); and 1.10 (95% CI = 0.54 2.23), respectively. The test for trend was 0.29. CONCLUSIONS: Prenatal exposure to low-to-moderate levels of alcohol on a weekly basis or occasional binge drinking during the early part of pregnancy was not statistical significantly associated with the prevalence of isolated VSD and ASD in offspring. PMID- 21591247 TI - Current state of congenital heart research and clues to future directions. PMID- 21591248 TI - Fully connected Bayesian belief networks: a modeling procedure with a case study of the Ganges river basin. AB - The use of Bayesian Belief Networks (BBNs) in modeling of environmental and natural resources systems has gradually grown, and they have become one of the mainstream approaches in the field. They are typically used in modeling complex systems in which policy or management decisions must be made under high uncertainties. This article documents an approach to constructing large and highly complex BBNs using a matrix representation of the model structure. This approach allows smooth construction of highly complicated models with intricate likelihood structures. A case study of the Ganges river basin, the most populated river basin of the planet, is presented. Four different development scenarios were investigated with the purpose of reaching the Millennium Development Goals and Integrated Water Resources Management goals, both promoted by the United Nations Agencies. The model results warned against the promotion of economic development policies that do not place strong emphasis on social and environmental concerns. PMID- 21591249 TI - Estimating the designated use attainment decision error rates of US Environmental Protection Agency's proposed numeric total phosphorus criteria for Florida, USA, colored lakes. AB - The utility of numeric nutrient criteria established for certain surface waters is likely to be affected by the uncertainty that exists in the presence of a causal link between nutrient stressor variables and designated use-related biological responses in those waters. This uncertainty can be difficult to characterize, interpret, and communicate to a broad audience of environmental stakeholders. The US Environmental Protection Agency (USEPA) has developed a systematic planning process to support a variety of environmental decisions, but this process is not generally applied to the development of national or state level numeric nutrient criteria. This article describes a method for implementing such an approach and uses it to evaluate the numeric total P criteria recently proposed by USEPA for colored lakes in Florida, USA. An empirical, log-linear relationship between geometric mean concentrations of total P (a potential stressor variable) and chlorophyll a (a nutrient-related response variable) in these lakes-that is assumed to be causal in nature-forms the basis for the analysis. The use of the geometric mean total P concentration of a lake to correctly indicate designated use status, defined in terms of a 20 ug/L geometric mean chlorophyll a threshold, is evaluated. Rates of decision errors analogous to the Type I and Type II error rates familiar in hypothesis testing, and a 3rd error rate, E(ni) , referred to as the nutrient criterion-based impairment error rate, are estimated. The results show that USEPA's proposed "baseline" and "modified" nutrient criteria approach, in which data on both total P and chlorophyll a may be considered in establishing numeric nutrient criteria for a given lake within a specified range, provides a means for balancing and minimizing designated use attainment decision errors. PMID- 21591250 TI - Biomedical nanocomposites of poly(lactic acid) and calcium phosphate hybridized with modified carbon nanotubes for hard tissue implants. AB - Degradable polymer-based materials are attractive in orthopedics and dentistry as an alternative to metallic implants for use as bone fixatives. Herein, a degradable polymer poly(lactic acid) (PLA) was combined with novel hybrid nanopowder of carbon nanotubes (CNTs)-calcium phosphate (CP) for this application. In particular, CNTs-CP hybrid nanopowders (0.1 and 0.25% CNTs) were prepared from the solution of ionically modified CNTs (mCNTs), which was specifically synthesized to be well-dispersed and thus to effectively adsorb onto the CP nanoparticles. The mCNTs-CP hybrid nanopowders were then mixed with PLA (up to 50%) to produce mCNTs-CP-PLA nanocomposites. The mechanical tensile strength of the nanocomposites was significantly improved by the addition of mCNTs-CP hybrid nanopowders. Moreover, nanocomposites containing low concentration of mCNTs (0.1%) showed significantly stimulated biological responses including cell proliferation and osteoblastic differentiation in terms of gene and protein expressions. Based on this study, the addition of novel mCNT CP hybrid nanopowders to PLA biopolymer may be considered a new material choice for developing hard tissue implants. PMID- 21591251 TI - Implantation of green tea catechin alpha-tricalcium phosphate combination enhances bone repair in rat skull defects. AB - The purpose of the present study is to investigate effects of the combination of epigallocatechin-3-gallate (EGCG) and alpha-tricalcium phosphate (alpha-TCP) on bone regenerative capacity in a bilateral rat calvarial bone defect model. MATERIALS AND METHODS: Bilateral 5-mm-diameter calvarial defects were created in adult male Wistar rats and filled with preparations of EGCG (0, 0.1, 0.2, 0.4 mg) combined with alpha-TCP particles. This was done by dissolving EGCG in 100% ethanol (50 MUL/14 mg) and dropping under sterile condition. The control group was left unfilled (n = 8). The animals were sacrificed at 2 and 4 weeks. Radiological images were taken, and histological analysis was done. Six animals from control (0 mg EGCG + alpha-TCP) group and (0.2 mg EGCG+ alpha-TCP) group were labeled with fluorescent dyes and histomorphometrically analyzed (n = 6) at 2 and 4 weeks. RESULTS: Histomorphometric analysis revealed that the combination of EGCG and alpha-TCP at doses of 0.1 and 0.2 mg yielded significantly more new bone formation than untreated control group at 2 and 4 weeks (p > 0.05). Mineral apposition rate at 0.2-TCP group was enhanced compared with the one of the positive control alpha-TCP group at 4 weeks (p > 0.05). CONCLUSION: The combination of alpha-TCP particles and 0.2 mg EGCG stimulates maximum bone regeneration in rat calvarial defects, and this combination would be potentially effective as bone graft material. PMID- 21591252 TI - Synthesis of periodically structured titania nanotube films and their potential for photonic applications. PMID- 21591253 TI - Fabrication of hierarchically porous inorganic nanofibers by a general microemulsion electrospinning approach. PMID- 21591254 TI - Lithographically fabricated optical antennas with gaps well below 10 nm. PMID- 21591255 TI - Probing a bifunctional luminomagnetic nanophosphor for biological applications: a photoluminescence and time-resolved spectroscopic study. PMID- 21591256 TI - A novel procedure for protein extraction from formalin-fixed paraffin-embedded tissues. AB - Most of the archived pathological specimens in hospitals are kept as formalin fixed paraffin-embedded tissues (FFPE) for long-term preservation. Up to now, these samples are only used for immunohistochemistry in a clinical routine as it is difficult to recover intact protein from these FFPE tissues. Here, we report a novel, short time-consuming and cost-effective method to extract full-length, non degraded proteins from FFPE tissues. This procedure is combined with an effective and non-toxic deparaffinisation process and an extraction method based on antigen retrieval, high concentration of SDS and high temperature. We have obtained enough intact protein to be detected by Western blotting analysis. This technique will allow utilising these stored FFPE tissues in several applications for protein analysis helping to advance the translational studies in cancer and other diseases. PMID- 21591257 TI - The role of statistical power analysis in quantitative proteomics. AB - Designing an experiment for quantitative proteomic analysis is not a trivial task. One of the key factors influencing the success of such studies is the number of biological replicates included in the analysis. This, along with the measured variation will determine the statistical power of the analysis. Presented is a simple yet powerful analysis to determine the appropriate sample size required for reliable and reproducible results, based on the total variation (technical and biological). This approach can also be applied retrospectively for the interpretation of results as it takes into account both significance (p value) and quantitative difference (fold change) of the results. PMID- 21591258 TI - Nitrogen-rich plasma-polymerized coatings on PET and PTFE surfaces improve endothelial cell attachment and resistance to shear flow. AB - Low seeding efficiency and poor cell retention under flow-induced shear stress limit the effectiveness of in vitro endothelialization strategies for small diameter vascular grafts. Primary-amine-rich plasma-polymerized coatings (PPE:N) deposited using low- and atmospheric-pressure plasma discharges on PET and PTFE are evaluated for their ability to improve endothelial cells' kinetics and strength of attachment. PPE:N coatings increase cell adhesion and adhesion rate, spreading, focal adhesion, and resistance to flow-induced shear compared with bare and gelatin-coated PET and PTFE. In particular, about 90% of the cells remain on coated surfaces after 1 h exposure to shear. These coatings, therefore, appear as a promising versatile approach to improve cell seeding strategies for vascular grafts. PMID- 21591259 TI - A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis. AB - Sepsis is a deadly disease characterized by the inability to regulate the inflammatory-coagulation response in which the endothelium plays a key role. The cause of this perturbation remains poorly understood and has hampered the development of effective therapeutics. Matrix metalloproteases (MMPs) are involved in the host response to pathogens, but can also cause uncontrolled tissue damage and contribute to mortality. We found that human sepsis patients had markedly elevated plasma proMMP-1 and active MMP-1 levels, which correlated with death at 7 and 28 days after diagnosis. Likewise, septic mice had increased plasma levels of the MMP-1 ortholog, MMP-1a. We identified mouse MMP-1a as an agonist of protease-activated receptor-1 (PAR1) on endothelial cells. MMP-1a was released from endothelial cells in septic mice. Blockade of MMP-1 activity suppressed endothelial barrier disruption, disseminated intravascular coagulation (DIC), lung vascular permeability as well as the cytokine storm and improved survival, which was lost in PAR1-deficient mice. Infusion of human MMP-1 increased lung vascular permeability in normal wild-type mice but not in PAR1 deficient mice. These findings implicate MMP-1 as an important activator of PAR1 in sepsis and suggest that therapeutics that target MMP1-PAR1 may prove beneficial in the treatment of sepsis. PMID- 21591260 TI - The first MMP in sepsis. PMID- 21591263 TI - Coverage-dependent variation of adsorption configurations of methionine on Ge(100). AB - The adsorption configurations of methionine molecules on the Ge(100) surface have been studied by using DFT calculations, core-level photoemission spectroscopy (CLPES), and low-energy electron diffraction (LEED) to scrutinize the adsorption structure as a function of coverage. At first, we obtained two important and stable structures. One is the most stable structure between these structures described as an "O-H dissociated-N dative-S dative-bonded structure" and the other is a less stable adsorption structure of these indicating an "O-H dissociated-S dative-bonded structure" by using DFT calculations. We also performed CLPES to clarify our DFT calculation results. Through the spectral analysis of the S 2p, C 1s, N 1s, and O 1s core-level spectra, we acquired the reasonable results that also revealed quite different bonding configurations depending on the methionine coverage. At low coverage (ca. 0.30 ML), a single type of sulfur and charged nitrogen peaks, which indicate an "O-H dissociated-N dative-S dative-bonded structure", were observed. On the other hand, two types of sulfur peaks with thiol formation and two nitrogen peaks with neutralized and charged characteristics were monitored at a higher coverage (0.60 ML and above), which can be described as an "O-H dissociated-S dative-bonded structure". Hence, we can clearly demonstrate that our results obtained from CLPES spectra and DFT calculations are matched well with each other. Moreover, we additionally confirmed that the relative population of the two types of thiols and amines being included in methionine in between half monolayer induces a surface reorientation in the ordering from 2*1 to 1*1 employing LEED. This interesting variation of the methionine adsorbed on the Ge(100) surface by coverage dependence will be precisely discussed by using DFT calculations, CLPES, and LEED. PMID- 21591262 TI - The role of the N-terminal domain in the regulation of the "constitutively active" conformation of protein kinase CK2alpha: insight from a molecular dynamics investigation. AB - Protein kinase CK2 is an extremely well-conserved pleiotropic protein kinase with a growing list of substrates, the majority of which are proteins implicated in signal transduction, gene expression, and transcription-related functions. Protein kinase CK2 is a ubiquitous heterotetrameric serine/threonine protein kinase made up of two alpha or alpha' catalytic subunits and two beta regulatory subunits. Moreover, protein kinase CK2 is defined as a "constitutively active" protein kinase in contrast to most other protein kinases characterized by the presence of distinct conformations associated with the active and inactive states. As previously demonstrated by in vitro mutation studies, CK2 activity is substantially regulated by the interaction between the N-terminal tail and the kinase domain. In fact, progressive deletions of the N-terminal tail show a decrease in the activity of the kinase. Even if the detrimental effects of Delta2 12 deletion can be partially reversed by the addition of a CK2beta subunit, deletions Delta2-12 and Delta2-30 progressively decrease the basal activity of CK2. In particular, as experimentally demonstrated, the Delta2-12 N-terminal deletion affects both the K(M) value for ATP and for the substrate peptide, and the k(cat) value of CK2alpha. In this work, molecular dynamics (MD) simulations were carried out on wild-type (wt), Delta2-12 and Delta2-30 deletion mutants of CK2alpha in order to explore the role of the N-terminal tail on the conformational behavior of CK2. Furthermore, classical MD simulations were carried out to assess the anticipated impact of conformational changes in a novel set of CK2alpha mutant forms, such as the triple mutant Y206F-R10A-Y261F and the single mutant Y125F. PMID- 21591261 TI - Haematopoietic stem cell differentiation promotes the release of prominin-1/CD133 containing membrane vesicles--a role of the endocytic-exocytic pathway. AB - The differentiation of stem cells is a fundamental process in cell biology and understanding its mechanism might open a new avenue for therapeutic strategies. Using an ex vivo co-culture system consisting of human primary haematopoietic stem and progenitor cells growing on multipotent mesenchymal stromal cells as a feeder cell layer, we describe here the exosome-mediated release of small membrane vesicles containing the stem and cancer stem cell marker prominin-1 (CD133) during haematopoietic cell differentiation. Surprisingly, this contrasts with the budding mechanism underlying the release of this cholesterol-binding protein from plasma membrane protrusions of neural progenitors. Nevertheless, in both progenitor cell types, protein-lipid assemblies might be the essential structural determinant in the release process of prominin-1. Collectively, these data support the concept that prominin-1-containing lipid rafts may host key determinants necessary to maintain stem cell properties and their quantitative reduction or loss may result in cellular differentiation. PMID- 21591264 TI - Female urinary proteomics: New insight into exogenous and physiological hormone dependent changes. AB - PURPOSE: In the frame of a research study on possible urinary markers related to physiological hormones cycle, 33 volunteer, healthy, normotensive fertile women were selected. Clinical parameters and renin-angiotensin-aldosterone system (RAAS) components were also investigated, on the basis of the well-known relation linking sex female hormones and renin and aldosterone levels. EXPERIMENTAL DESIGN: A classic proteomic approach was applied to investigate urinary protein changes at different stages of menstrual cycle, specifically mid-cycle phase (G1), luteal phase (G2) and after 2 months of contraceptive therapy (G3). Analysis of urinary proteome was performed by SDS-PAGE, 2-D PAGE, Western blotting, and protein identification by HPLC-MS/MS. RESULTS: In the four comparisons examined (G1 vs. G2; G1 vs. G3; G2 vs. G3 and G(G1+G2) vs. G3), a total of 115 protein spots were differentially represented among the subgroups. Data validation was performed by replicated experiments of immunoblotting. CONCLUSIONS AND CLINICAL RELEVANCE: The present work highlights for the first time variations with menstrual cycle or estroprogestin pill of newly discovered, or never related, urinary proteins. In particular, possible protein markers could be useful for further applications in contraceptive target research and RAAS modulation-related topics. PMID- 21591266 TI - Discovery and initial validation of alpha 1-B glycoprotein fragmentation as a differential urinary biomarker in pediatric steroid-resistant nephrotic syndrome. AB - PURPOSE: In this cross-sectional pilot study we set out to discover a non invasive biomarker that could distinguish steroid-resistant nephrotic syndrome (SRNS) from steroid-sensitive nephrotic syndrome (SSNS). EXPERIMENTAL DESIGN: Urine and clinical data were collected from patients with idiopathic nephrotic syndrome and healthy controls. Using SELDI-TOF-MS, we identified an 11-fold upregulated 13.8 kDa fragment of alpha 1-B glycoprotein (A1BG) in urine in SRNS. To validate our findings, A1BG was detected by Western blot. Creatinine was measured and transformed to glomerular filtration rate (GFR) by the new Schwartz formula and classified to chronic kidney disease (CKD) stage. p-Values were determined by unpaired t-test and Mann-Whitney rank sum test. Microalbumin was also measured to determine albumin/creatinine ratios. RESULTS: The 13.8 kDa A1BG was present in 7 of 19 patients with SRNS; but absent in all SSNS (n=15) and controls (n=10). The A1BG(+) patients had lower GFR than A1BG(-) patients (p<0.009) and tended to have higher CKD stage. CONCLUSION AND CLINICAL RELEVANCE: The 13.8 kDa A1BG fragment had a high discriminatory power for steroid resistance in pediatric nephrotic syndrome, but is only present in a subset of patients. Additional longitudinal studies are required to determine the usefulness of this biomarker as a non-invasive predictive marker of therapeutic response. PMID- 21591265 TI - Elevated expression levels of ANXA11, integrins beta3 and alpha3, and TNF-alpha contribute to a candidate proteomic signature in urine for kidney allograft rejection. AB - PURPOSE: Kidney transplantation is the treatment of choice for end stage renal disease, with long-term allograft loss being the major obstacle, and for which potential treatments are based on a histological diagnosis. The problem is that markers for predicting graft rejection are limited in number, are invasive, and are quite non-specific. We have hypothesized that protein biomarkers might be discovered in the urine of patients when acute or chronic rejection might be occurring. EXPERIMENTAL DESIGN: We have established a workflow in which initial screening for candidate biomarkers is first performed using urine samples on large-scale antibody microarrays. This approach generated several dozen candidates. The next step is to qualify some of the strongest signals using the high-throughput Reverse Capture Protein Microarray platform. RESULTS: Four top candidates including ANXA11, Integrin alpha3, Integrin beta3 and TNF-alpha, initially identified by the antibody microarray platform, were all qualified using Reverse Capture Protein Microarrays. We also used receiver operating condition (ROC) curves to independently quantify the specificity and sensitivity of these four analytes. CONCLUSIONS AND CLINICAL RELEVANCE: The present data suggest that these novel four analytes in the urine, together or independently, may contribute to a robust and quantitative urine proteomic signature for diagnosing acute or chronic rejection of renal allografts. PMID- 21591267 TI - Urine proteomics in kidney and urogenital diseases: Moving towards clinical applications. AB - To date, multiple biomarker discovery studies in urine have been conducted. Nevertheless, the rate of progression of these biomarkers to qualification and even more clinical application is extremely low. The scope of this article is to provide an overview of main clinically relevant proteomic findings from urine focusing on kidney diseases, bladder and prostate cancers. In addition, approaches for promoting the use of urine in clinical proteomics including potential means to facilitate the validation of existing promising findings (biomarker candidates identified from previous studies) and to increase the chances for success for the identification of new biomarkers are discussed. PMID- 21591268 TI - Human urinary peptide database for multiple disease biomarker discovery. AB - PURPOSE: Human urine is an ideal candidate for use in clinical diagnostics. It is easily available, as untrained personnel can collect it. It correlates well with the pathophysiology of a number of diseases, making it a useful source for clinical proteomics. EXPERIMENTAL DESIGN: In this article, we give an update of the human urinary peptide database derived from over 13,000 data sets of CE-MS by now. RESULTS: Urine samples from both patients and healthy subjects were analyzed by CE-MS; these included 47 different pathophysiological conditions. Besides defining biomarkers by their experimental parameters, information on their sequences provides fundamental data into the pathological pathways of diseases. Therefore, we have sequenced 953 urinary peptides by using state-of-the-art top down MS/MS. Identified biomarkers of all clinical proteomic CE-MS studies including their regulation are also listed in this work. CONCLUSIONS AND CLINICAL RELEVANCE: Biomarker discovery can be used in the management of a wide range of diseases, by combining these data sets of the database. Taking this approach, we can reveal details, at a molecular level, on the pathogenesis of a number of diseases, in particular those associated with urine production and excretion. PMID- 21591269 TI - Bisquinoxaline-fused porphyrins for dye-sensitized solar cells. AB - 5,10,15,20-Tetrakis(2,4,6-trimethylphenyl)-6'-carboxylquinoxalino[2,3 b]quinoxalino[12,13-b']porphyrinatozinc(II) (ZnPBQ) is synthesized to evaluate the effects of pi elongation of quinoxaline-fused porphyrins on the optical, electrochemical, and photovoltaic properties. ZnPBQ showed an intensified Soret band as well as red-shifted Soret and Q bands relative to 5,10,15,20 tetrakis(2,4,6-trimethylphenyl)-6'-carboxylquinoxalino[2,3-b]porphyrinatozinc(II) (ZnPQ), demonstrating the improved light-harvesting property of ZnPBQ. The optical and electrochemical HOMO-LUMO gaps were consistent with those estimated by DFT calculations. The photovoltaic properties were compared under optimized conditions, in which a sealed device structure with TiCl(4) -treated, TiO(2) double layers was used. The ZnPBQ cell exhibited a relatively high power conversion efficiency (eta) of 4.7%, which was smaller than that of the ZnPQ cell (eta=6.3%). The weaker electronic coupling between the LUMO of ZnPBQ and conduction band (CB) of TiO(2) or more tilted geometry of ZnPBQ on the TiO(2) surface may result in the low electron injection/charge collection efficiency as well as the low incident photon-to-current efficiency (IPCE) for the ZnPBQ cell (maximum IPCE=56%) relative to the ZnPQ cell (maximum IPCE=75%), leading to the lower eta value of the ZnPBQ cell than that of the ZnPQ cell. In addition, the open-circuit potential of the ZnPBQ cell also slightly decreased with the effect of charge recombination from the electrons injected into the CB of TiO(2) to I(3)(-). PMID- 21591270 TI - Fine-tuning of triarylamine-based photosensitizers for dye-sensitized solar cells. AB - The synthesis of a series of novel organic photosensitizers based on modified triarylamine motives has been achieved. The new "push-pull" dyes, bearing one to three naphthyl units in place of phenyl rings, have been successfully obtained following original synthetic routes. The structural, optical and electrochemical properties of these chromophores were studied by combining crystallographic, experimental and theoretical data. We further present a systematic study of this series of dyes. When embedded in dye-sensitized solar cell devices, the new photosensitizers showed good spectral response with IPCE greater than 85% from 470 to 580 nm and overall power conversion efficiencies reaching 6.6%. One of these new sensitizers, containing one naphthyl attached to the pi-conjugated linker and having phenyl rings on the outside, led to the highest molar extinction coefficient and energy conversion efficiency of the series while exhibiting higher electron lifetime. PMID- 21591271 TI - Acid-catalyzed etherification of glycerol with long-alkyl-chain alcohols. PMID- 21591273 TI - False-positive FDG PET/CT uptake in Warthin tumor in head and neck oncological patients confirmed by a fine needle aspiration. PMID- 21591274 TI - Toxoplasmosis in a post-transplant bronchoalveolar lavage: a case report. AB - Toxoplasma gondii usually causes an asymptomatic and then latent infection in human adults; however, a potentially fatal disseminated form can occur in immunocompromised patients. Given that the diagnosis of acute Toxoplasma infection, as opposed to latent disease, relies on finding direct evidence of T. gondii infection in tissue, pathologic examination is critical. There have only been a few reports describing the cytomorphology of Toxoplasma in exfoliative cytology, and no reports of the findings in Thin Prep. In this report, we describe a fatal case of toxoplasmosis in a cardiac transplant patient that was diagnosed by respiratory cytopathology. Although the extracellular organisms were well visualized on the Wright-Giemsa stained cytospin, they were only faintly seen on the Pap-stained cytospin trapped within mucin and were not easily appreciated on the ThinPrep slides nor the H&E stained cell block sections. An immunohistochemical stain for Toxoplasma performed on the cell block was strongly positive, and an autopsy performed on the patient confirmed disseminated infection. Our case illustrates that the diagnosis of Toxoplasma in exfoliative cytology specimens can be challenging since organisms are not well visualized on ThinPrep or Pap-stained material; therefore, Wright-Giemsa stained material can be particularly helpful. PMID- 21591275 TI - Cytopathic effects of human papillomavirus infection and the severity of cervical intraepithelial neoplasia : A frequency study. AB - Cytopathic effects related to the human papillomavirus (HPV) infection are more frequently found in cervical intraepithelial neoplasia (CIN) 1; however, there are indications that at least half the histological diagnoses of CIN2 and CIN3 include koilocytosis areas. The objective of this study was to evaluate the frequency of the cytological criteria suggestive of HPV infection in the cervical smears of women with a histological diagnosis of CIN. One hundred and sixty-two women with abnormal cervical smears and a diagnosis of CIN confirmed by histopathology were selected, including 46 cases of CIN 1, 42 of CIN 2 and 74 cases of CIN 3. Koilocytosis was found in 63% of the smears from women with a histopathological diagnosis of CIN 1. This sign was observed in 26.2% and 25.7% of smears of women with a diagnosis of CIN 2 and CIN 3, respectively. Cytomegaly also was frequent in cervical smears of women with histopathological diagnosis of CIN 1 (71.8%). On the other hand, spindle cells and atypical metaplasia were more frequent in women with CIN 2 and CIN 3. Atypical parakeratosis showed similar frequency in all grades of CIN diagnosis. Koilocytois and cytomegaly were inversely correlated with the diagnosis of CIN2 or CIN 3, with OR values respectively of 0.30 (95%CI 0.13-0.68) and 0.26 (95%CI 0.11-0.58). The others signs analyzed did not show any significant association. Koilocitosis and cytomegaly can provides good reassurance that a patient with atypical cervical smear have CIN 1. PMID- 21591276 TI - The cytomorphologic spectrum of salivary gland type tumors in the lung and mediastinum: a report of 16 patients. AB - In the lung and mediastinum, salivary gland type tumors (SGTTs) can occur as either primary tumors or metastases from tumors arising in the major or minor salivary glands. This study reviewed the cytology cases of SGTTs in the lung and mediastinum diagnosed over a six-year period at our institution. The specimens included a total of 22 exfoliative or aspiration cytology specimens identified in 16 patients. Two of the cases were primary tumors: adenoid cystic carcinoma (ACC) of the trachea and mucoepidermoid carcinoma (MEC) of the thymus. The remaining 20 tumors were metastases from the parotid, submandibular gland, tongue, nasal cavity, or soft palate. Eight of the 16 patients (50%) had a diagnosis of ACC, four (25%) had salivary duct carcinomas, two (12.5%) had MECs, one (6.25%) was a basaloid tumor, and one (6.25%) was polymorphous low grade adenocarcinoma. In our series, these SGTTs were more commonly metastatic in the lung or mediastinum (87.5% of the patients), and the most common histological subtype was ACC, followed by SDC. This study also illustrates the cytomorphologic features and diagnostic pitfalls of these unusual SGTTs. PMID- 21591277 TI - Research. Adding drugs to regimen reduces mother-to-infant transmission. PMID- 21591278 TI - Research reveals that stigmas about HIV/AIDS persist. PMID- 21591280 TI - Prisons. Denial of ART did not violate rights of HIV-positive inmate. PMID- 21591279 TI - Disability. Terminated worker was 'regarded as' disabled by company. PMID- 21591281 TI - [Amalgam can be an illness inducing material for many people]. PMID- 21591282 TI - [Basal cell carcinoma]. PMID- 21591283 TI - Collaboration works to improve stroke outcomes in Ghana. PMID- 21591284 TI - The rise of open-source electronic health records. PMID- 21591285 TI - Listening to narratives from the Tuskegee syphilis study. PMID- 21591286 TI - The enhanced recovery programme in colorectal surgery. PMID- 21591287 TI - A Code of Conduct is published for live case demonstrations. AB - Dr Greg Dehmer discusses the history and development of this new document, in this area of medical teaching. PMID- 21591289 TI - Thermography is providing new insights into the pathophysiology of disease. AB - Just 10 years after thermal heterogeneity within human atherosclerotic coronary arteries was observed in vivo, a novel non-invasive thermography technique is being developed. PMID- 21591290 TI - Collaborative learning in PBL. PMID- 21591291 TI - Care needed when interpreting the importance of competency-based assessments. PMID- 21591292 TI - Spirituality and medicine: views and opinions of teachers in a Brazilian medical school. PMID- 21591293 TI - Patterns of approaches to studying of pre-clinical, clinical and post graduate students from a setting in a developing country in Asia. PMID- 21591294 TI - A competence-based curriculum for vocational training in general practice in Germany: nearby or far away? PMID- 21591295 TI - Benchmarks of Toxicology, with Peter Goering. PMID- 21591296 TI - [Salvage surgery for upper aerodigestive tract tumours]. AB - Salvage surgeries of head and neck tumors are considered as poor satisfactory either for disease control results or for aesthetic and functional outcomes. Several improvements have been made possible since few years in all fields of oncologic treatments. A new approach must be initiated in that context, moreover since take in charge for head and neck region (exclusive initial medical treatment) let us consider an increasement of clinical situations for which a salvage therapy could be performed. The new surgery techniques have to be considered, reconstructive and guided by systems, which can improve surgical skills (navigation, robotic, sentinel node procedure, nervous detection and so on), the help of reirradiation techniques, the use of medical therapy during surgical procedure, the photodynamic therapy and all the help provided by new medical imaging and modern biology, which can determine more precisely the status of the cancer when it is taken in charge. The mastery of those techniques improvements must follow on an evolution of the concepts in the field of combined salvage treatments performed by multidisciplinary teams. Those treatments have to be realized in structures, which have the techniques and the multiple skills for allowing increasement of outcomes of those severe diseases. PMID- 21591297 TI - [Surgery after. . .]. PMID- 21591298 TI - [The importance of a SNiP of the MDM2 gene to modulate the p53 pathway and the predisposition to cancer]. PMID- 21591299 TI - [RB, guardian of prostatic tumor progression]. PMID- 21591300 TI - [Hormone therapy of locally advanced cancer of the prostate validated by several randomized trials]. PMID- 21591301 TI - [Her2 positive breast cancer: practices]. AB - The molecular classification of Perou and Sorlie breast tumors has to streamline, systematize and make effective use of targeted therapies against specific molecular subtypes, including breast HER2 positive. Trastuzumab and lapatinib are currently the two therapies targeting HER2, which have demonstrated their effectiveness in clinical practice. This literature review aims to make the data points on pertinent and useful data for physicians in daily. PMID- 21591302 TI - The "other diseases" of the Millennium Development Goals: rhetoric and reality of free drug distribution to cure the poor's parasites. AB - The sixth MDG aims 'to combat HIV/AIDS, TB, malaria and other diseases'. The residual category of 'other diseases' has become the focus of intense interest, partly because it has provided an opportunity to increase resources for the control of the mostly parasitic 'neglected tropical diseases' (NTDs). Intense lobbying has secured large amounts of funding from donors, as well as generous donations of medicines from the major drug companies. A massive programme is now underway to treat the parasites of the poor in Africa via integrated vertical interventions of mass drug administration in endemic areas. The approach has been hailed as remarkably effective, with claims that there is now a real prospect of complete control and, for some NTDs, even elimination. However, a closer look at evaluation and research data reveals that much less is known about what is being achieved than is suggested. Competition between implementing organisations is leading to potentially counterproductive exaggerations about treatment coverage. Detailed local-level research in Uganda and Tanzania shows that actual rates of drug take-up among target populations are often lower than is necessary to effectively control the diseases, and that methods of drug distribution may even lead to active resistance to treatment. If current trends are not corrected, declining rates of NTD infection will not be sustained. Much more rigorous and effective monitoring is essential. PMID- 21591303 TI - Food security politics and the Millennium Development Goals. AB - This article reviews proposals regarding the recent food crisis in the context of a broader, threshold debate on the future of agriculture and food security. While the MDGs have focused on eradicating extreme poverty and hunger, the food crisis pushed the hungry over the one billion mark. There is thus a renewed focus on agricultural development, which pivots on the salience of industrial agriculture (as a supply source) in addressing food security. The World Bank's new 'agriculture for development' initiative seeks to improve small-farmer productivity with new inputs, and their incorporation into global markets via value-chains originating in industrial agriculture. An alternative claim, originating in 'food sovereignty' politics, demanding small-farmer rights to develop bio-regionally specific agro-ecological methods and provision for local, rather than global, markets, resonates in the IAASTD report, which implies agribusiness as usual ''is no longer an option'. The basic divide is over whether agriculture is a servant of economic growth, or should be developed as a foundational source of social and ecological sustainability. We review and compare these different paradigmatic approaches to food security, and their political and ecological implications. PMID- 21591304 TI - The "AIDS and MDGs" approach: what is it, why does it matter, and how do we take it forward? AB - Progress towards the Millennium Development Goals (MDGs) has been mixed, and many observers have noted the tendency for development actors to address individual MDGs largely in isolation from one another. This in turn has resulted in missed opportunities to catalyse greater interdisciplinary collaboration and innovation towards MDG achievement. The term 'AIDS and MDGs' is gaining currency as an approach that aims to explore, strengthen and leverage the links between AIDS and other health and development issues. Drawing from academic literature and from MDG country reports, this article sets out three important pillars to an AIDS and MDGs approach: 1) understanding how AIDS and the other MDGs affect one another; 2) documenting and exchanging lessons learned across MDGs; and 3) creating cross- MDG synergy. We propose broader policy level implications for this approach and how UNDP and other partners can take this agenda forward. Because the MDGs explicitly locate HIV within a broader international commitment to human development targets, they provide a critical platform for development partners to galvanise resources, political will and momentum behind a broader, systematic and structural approach to HIV, health and development. PMID- 21591305 TI - Constructing interethnic conflict and cooperation: why some people harmed Jews and others helped them during the Holocaust in Romania. AB - The authors draw on a natural experiment to demonstrate that states can reconstruct conflictual interethnic relationships into cooperative relationships in relatively short periods of time. The article examines differences in how the gentile population in each of two neighboring territories in Romania treated its Jewish population during the Holocaust. These territories had been part of tsarist Russia and subject to state-sponsored anti-Semitism until 1917. During the interwar period one territory became part of Romania, which continued anti Semitic policies, and the other became part of the Soviet Union, which pursued an inclusive nationality policy, fighting against inherited anti-Semitism and working to integrate its Jews. Both territories were then reunited under Romanian administration during World War II, when Romania began to destroy its Jewish population. The authors demonstrate that, despite a uniform Romanian state presence during the Holocaust that encouraged gentiles to victimize Jews, the civilian population in the area that had been part of the Soviet Union was less likely to harm and more likely to aid Jews as compared with the region that had been part of Romania. Their evidence suggests that the state construction of interethnic relationships can become internalized by civilians and outlive the life of the state itself. PMID- 21591306 TI - Electoral reform and public policy outcomes in Thailand: the politics of the 30 Baht health scheme. AB - How do changes in electoral rules affect the nature of public policy outcomes? The current evidence supporting institutional theories that answer this question stems almost entirely from quantitative cross-country studies, the data of which contain very little within-unit variation. Indeed, while there are many country level accounts of how changes in electoral rules affect such phenomena as the number of parties or voter turnout, there are few studies of how electoral reform affects public policy outcomes. This article contributes to this latter endeavor by providing a detailed analysis of electoral reform and the public policy process in Thailand through an examination of the 1997 electoral reforms. Specifically, the author examines four aspects of policy-making: policy formulation, policy platforms, policy content, and policy outcomes. The article finds that candidates in the pre-1997 era campaigned on broad, generic platforms; parties had no independent means of technical policy expertise; the government targeted health resources to narrow geographic areas; and health was underprovided in Thai society. Conversely, candidates in the post-1997 era relied more on a strong, detailed national health policy; parties created mechanisms to formulate health policy independently; the government allocated health resources broadly to the entire nation through the introduction of a universal health care system, and health outcomes improved. The author attributes these changes in the policy process to the 1997 electoral reform, which increased both constituency breadth (the proportion of the population to which politicians were accountable) and majoritarianism. PMID- 21591307 TI - Faith-based social services: saving the body or the soul? A research note. AB - Faith-based organizations might be ideal social service providers, claiming to transform clients' lives with holistic support while meeting immediate needs. While organizations have such goals, their success is impacted by constituencies with differing goals for the organization. Clients with goals not commensurate with an organization's may compromise its ability to attain its goals. Three questions are examined here: What are the goals of faith-based service providers? When asked what they think about the services, do clients share the organizational goals? Are organizations likely to meet either set of goals? Homeless persons patronizing faith-based soup kitchens were interviewed; service activities of organizations were observed. Clients' goals focused on survival in their current situation. Organizations' goals ranged from meeting clients' immediate needs to transforming clients through spiritual restoration. Congregations studied met clients' immediate needs. However, clients' accommodational goals were potentially problematic for organizations with spiritual goals. PMID- 21591308 TI - The BP oil spill and the bounty of Plaquemines Parish. AB - The source of 25 to 30 percent of America's seafood, the Mississippi River Delta's cornucopian world is now uncertain. And yet, even if shrimp, oysters, and finfish are unaffected by the BP Oil Spill - a big if - one can already reflect on the passing of the culture once built upon gathering them. For almost three centuries, levees made life possible along the riverbanks and in the wetlands beyond. Those same levees also ensured the wetlands would eventually melt away into the Gulf. Cutting off the silt left behind during annual river inundations subjected the fragile land to erosion. Sulfur, natural gas, and oil production companies dug twenty thousand miles of canals to gain more direct routes to their fields and to pump out their mineral wealth. This caused salt-water intrusion that killed off plant life and caused more erosion. The world that sustained my Plaquemines ancestors was less subject to collapse following disasters not only because the ecosystem before the wetlands' ongoing loss was then more vibrant, complex, and robust; but also because their lives, especially their culinary lives, were more vibrant, complex, and robust. Life was hard, but when it came to putting food on the table, life followed the seasons. PMID- 21591309 TI - "In bacteria land": the battle over raw milk. AB - Beginning at around 1893, America's initial raw milk wars pitted proponents of pasteurized milk against advocates of a complex scheme for "certifying" clean, uncontaminated raw milk. The certification program, unsuited to modern commercial economies of scale, soon faded into obscurity. When a new version of the raw milk movement began gathering strength in the 1970s, scarcely anyone remembered the terms on which a certain amount of rational debate had once taken place. Part of the reason is that over the course of the twentieth century, the scale and structure of the fluid milk industry had undergone drastic changes that turned a highly variable, fragile product into a nearly featureless one poorly understood by consumers, regulators, or polemicists. Meanwhile, new dairying and processing practices had begun creating hospitable conditions for pathogens that were unknown during the first controversies but that urgently need to be considered today. Unfortunately, discussion of the raw milk question is now almost wholly dictated by intolerant ideologues on both sides, in an atmosphere of profound historical amnesia. Given the great complexity of the issues involved and the serious implications for public health, the general tone of debate is at best counterproductive. PMID- 21591310 TI - High-end dining in the nineteenth-century United States. AB - A look at what fine restaurants served in mid-nineteenth century America, using the New York Public Library's collection of menus from the Fifth Avenue Hotel in New York City for the years 1859 to 1865. With particular paid attention to the entree category, 1,250 menus were analyzed. There are 900 different dishes mentioned, and the article discusses what were the most popular and the setting and customs governing such meals. PMID- 21591311 TI - The struggle for Sunday lunch: gastropolitics in the life of Nelson Mandela. AB - This paper explores the political, economic, and social life of Nelson Mandela through his food choices from 1918 to the present. A description of the minutiae of one particular 1950s Sunday lunch is used to examine the broader role of first colonial and later apartheid legislation in determining the dietary choices and options of South Africans past and present. How such policies shaped attitudes and access to Nelson Mandela's ancestral Xhosa cuisine is assessed. The long-term cultural, economic, and political impact of a lack of access to core indigenous African ingredients is evaluated. Most of all this paper offers a snapshot portrayal of two families (one white, one black) trying to sustain a normal friendship within a grossly abnormal society. PMID- 21591312 TI - Between plenty and poverty foraging in the Salento with Patience Gray. AB - Patience Gray was one of the first food writers to celebrate the culinary and cultural significance of edible weeds and plants. In 1970 she and her husband, the Belgian sculptor Norman Mommens, settled in the far south of Italy. It was the endpoint of their Mediterranean odyssey, which had taken them to the Greek island of Naxos, Carrara, in northwestern Tuscany, Catalonia, the Veneto, and finally Puglia. Gray's Honey from a Weed, the product of those travels, remains one of the best texts on wild foods and on edible weeds in particular. Drawing on Gray's unpublished letters and manuscripts this essay explores the life of one of the twentieth century's most unusual and often overlooked food writers. The contemporary uses and significance of edible weeds and plants are also discussed through foraging trips and interviews with Gray's friends and neighbors. Though Gray warned that traditional ways of life were dying out, it is clear that foraging is still an important part of the Salentine diet. PMID- 21591313 TI - To market, to market!: Riding shotgun with the tomato man. PMID- 21591314 TI - Jean-Louis Vignes: California's forgotten winemaker. AB - This article represents a first step in the process of restoring the legacy of pioneer California winemaker Jean-Louis Vignes (1780-1862). Vignes was a native of France who established and operated a commercial winery (El Aliso) in Los Angeles for 22 years (1833-1855). The article includes the first known photograph of Vignes discovered by the author. While prominent twentieth-century American wine historians have acknowledged Vignes, the author emphasizes a key distinction made by French historian Leonce Jore. Vignes left France to go to the Sandwich Islands as part of a commercial enterprise that traveled with Catholic missionaries (Picpus Fathers). Only after five years of frustration did Vignes move to Los Angeles and establish a winery. The author uses the remembrances of well-known nineteenth-century commentator William Heath Davis [Seventy-Five Years in California (San Francisco, 1929)] to give some personal insights into Vignes as a winemaker. Davis visited him at El Aliso three times as a young man and lived long enough (1909) to validate Vignes's vision for the potential of winemaking in California. The article also includes the first known full citation for Vignes's gravesite at Evergreen Cemetery in Los Angeles. PMID- 21591315 TI - Recipes: beyond the words. AB - This paper explores recipes and food writing from the perspective of linguistics or, more specifically, pragmatics. It looks briefly at the discourse of recipes, at how they work and what kinds of linguistic structures are typically involved. The main theme of the paper, however, is that the best food writing is as much about the images and feelings the writer wants to conjure in the mind of the reader as it is about the words it contains, or the way that discourse is set out. In order to shed any real light on recipe writing, then, we need to explain how they manage to convey moods, impressions, emotions, and feelings. We need to go beyond the words. The paper features examples from, among others, the work of Elizabeth David and Edouard de Pomaine, serving to illustrate the theoretical points made. PMID- 21591316 TI - [Treatment of acid-fast bacterial infection based on the PK/PD theory]. PMID- 21591318 TI - [Vaccination--new facts from basic research]. PMID- 21591317 TI - [Toxic epidermal necrolysis--a rare, but life-threatening disease]. PMID- 21591319 TI - [High-density lipoprotein (HDL) and cholesteryl ester transfer protein (CETP): role in lipid metabolism and clinical meaning]. AB - Large epidemiological studies have consistently shown that plasma levels of high density lipoprotein (HDL) correlate inversely with cardiovascular risk. The apparent cardioprotective role of HDL has primarily been attributed to its participation in reverse cholesterol transport (RCT) but there is also substantial evidence that supports the concept of HDL and apoA-I preventing oxidative damage, inhibiting systemic inflammation, promoting vascular integrity and preventing thrombosis. Besides conventional therapy to increase HDL like physical exercise, weight loss and dietary changes new strategies to intervene at various steps of its metabolism have been proposed and are in development. One of the most promising approaches is inhibiting cholesteryl ester transfer protein (CETP)which plays a central role in RCT by transferring cholesteryl esters from HDL to apoB containing lipoproteins in exchange for triglycerides. The failure of the CETP inhibitor torcetrapib, however, to cause any benefit on cardiovascular outcomes despite significantly increased HDL levels in several clinical trials casted doubts upon the concept of CETP inhibition. Meanwhile, off target toxicity could be shown for torcetrapib and a new generation of CETP inhibitors stands ready to be tested in large clinical trials. This article describes the formation and remodeling of HDL, how HDL is thought to be beneficial for the vasculature and what options we have today to increase HDL levels with a special focus on CETP inhibition. PMID- 21591320 TI - [Hawthorn extract WS 1442 in the treatment of patients with heart failure and LVEF of 25%-35%]. PMID- 21591321 TI - [The transdermal 7-day buprenorphine patch--an effective and safe treatment option, if tramadol or tilidate/naloxone is insufficient. Results of a non interventional study]. AB - The transdermal 7-day buprenorphine matrix patch provides a constant and user friendly pain management when chronic musculoskeletal pain requires opioids. This analysis of clinical routine data evaluated the benefit of this treatment for patients previously receiving oral long-term treatment with weak opioids alone. Data of 310 patients previously treated with tramadol or tildate/naloxone and part of a multicentre observational study with 3295 patients were analyzed. In 89.7% of the 310 patients oral treatment with weak opioids was replaced by the 7 day buprenorphine patch due to insufficient analgesia. During treatment with the 7-day buprenorphine patch there was a clinically significant decrease of the mean pain intensity at rest during the day from 5.7 to 2.9, on physical effort during the day from 7.3 to 3.8 and at night from 5.2 to 2.3 (11-point NRS scale, p < or = 0.001). In addition, quality of life aspects such as mobility, self-reliance and quality of sleep improved, which are relevant for individual patient satisfaction with pain management. For patients with previous long-term tramadol or tilidate/naloxone treatment the switch to the 7-day buprenorphine matrix patch proved to be effective and safe for the management of chronic pain. The user friendly 7-day application interval contributes to improving compliance and a reducing exposure to tablets. PMID- 21591322 TI - [Benefit assessment in conventional and complementary medicine]. PMID- 21591323 TI - [Therapy of patellar dislocation]. PMID- 21591324 TI - [Neuropathological research on organs of patients of the "Heil- und pflegeanstalt" (state hospital) Gunzburg]. AB - BACKGROUND: The two Kaiser Wilhelm-Institutes (KWI) in Berlin (1914, new building 1931) and in Munich (1917, new building 1926-28), specialized on pathologic anatomical as well as psychiatric genetic research, were set up before times of National Socialism. METHODS: Data evaluation is based on patient documents and annual reports of the archive of today's district hospital Gunzburg and on patient documents (copies) of the historical archive of today's Max-Planck Institute of Psychiatry. RESULTS: The KWI in Munich was indirectly provided with brain material by Bavarian "Heil- und Pflegeanstalten" (state hospitals) including the state hospital Gunzburg. CONCLUSIONS: During National Socialism patients' organs were sent from the "Heil- und Pflegeanstalt" (state hospital) Gunzburg to the KWI in Munich for the purpose of conducting research. Commemorating patients' fates and clarifying what happened defines a place of remembrance. PMID- 21591325 TI - [Peculiarities of schizophrenic diseases in prelingually deaf persons]. AB - Diagnostic criteria of schizophrenia, according to Kurt Schneider's first and second range symptoms appear in spoken language. This raises the question of how symptoms of schizophrenia are manifested in prelingually deaf people who mainly communicate with sign language. The article shows that acoustic hallucinations of normal hearing schizophrenic people correspond to visual and tactile hallucinations of the prelingually deaf. An additional similarity is found in a disorder of the structure of the language. These similarities show that schizophrenia does not depend on the acoustic part of language or the acquisition of spoken language. PMID- 21591326 TI - [Vitamin E for gonarthrosis and coxarthrosis--results of a postmarketing surveillance study]. AB - BACKGROUND: Inflammatory processes release reactive oxygen species, destroying cartilage tissue. Vitamin E is an antioxidant and protects cartilage tissue. Dietary intake of vitamin E is often low in patients with osteoarthrosis, and short term clinical studies have shown symptomatic relief in pain. Therefore, efficacy and tolerability of vitamin E are investigated in routine use of medical practitioners. PATIENTS AND METHODS: Open, multicentric observational study including 151 patients with osteoarthritis (knee, hip): 85 patients were treated with 333,5 mg RRR-alpha-tocopherol (monotherapy), 61 patients with 333,5 mg RRR alpha-tocopherol and a further analgesic (combination therapy). 5 patients (2 monotherapy, 3 combination) failed to turn up for follow-up (dropout). According to the study design, the physician was free in his treatment (assignment to treatment, choice of analgesic). After 4, 8, and 12 weeks the efficacy and tolerability were determined by physicians and by patients. RESULTS: Demographic data were comparable in both groups, however clinical condition was slightly worse in the combination group. In the course of the treatment, all parameters improved in both groups. Monotherapy was somewhat less effective and set on later. There were two adverse events in the monotherapy group (total endoprosthesis, itching). Tolerability of monotherapy was rated slightly better than combination therapy by physicians and by patients. CONCLUSIONS: For patients with gonarthrosis or coxarthrosis the supplementation of Vitamin E to an analgetic medication is reasonable and well tolerated. PMID- 21591327 TI - [Persistence and adherence: Comparison between the five classes diuretics, beta blocker, calcium channel blockers, ACE-inhibitors and angiotensin receptor blockers as the first line in antihypertensive therapy]. PMID- 21591328 TI - [Medical treatment of hypertension in inpatients. Role of fixed dose combinations]. PMID- 21591329 TI - [Fixed dose combination of an ARB calcium antagonist lowers blood pressure effectively and improves quality of life]. PMID- 21591330 TI - [Ponderance over tissue regeneration and regenerative medicine]. AB - Research in the field of tissue regeneration is a new focus in life science and medicine in the 21st century, hereby I express my personal expectations of its research and translational application in the future. PMID- 21591331 TI - [Attach importance to research on lymph circulation system after burns]. AB - A series of pathophysiological changes in lymph circulation system occur after severe burns. We try to elucidate the importance through summarizing our experiments on some of the changes in lymph circulation based on rat and goat lymphatic fistula model since 1998. The lymphatic contraction frequency decreased while the lymph flow speed increased during burn shock stage. Contents of several key inflammatory factors, such as TNF-alpha, IL-6, IL-8, IL-10, IL-18, and HMGB 1, were increased in lymph or lymph nodes, and they were higher than those in blood and liver. The protein concentration increased in lymph while decreased in plasma. The endotoxin was translocated to lymph earlier than to blood, therefore, the number of E. coli or the number of endotoxin translocated via lymph route were more than those via blood. The bacteria and endotoxin of pseudomonas aeruginosa could invade through local lymphatic route from infected burn wound. Th2 shift from Th1/Th2 occurred in lymph and the ratio of CD4+/CD8+ T lymph cells decreased in lymph nodes after burns, denoting local immunosuppression. The apoptosis of lymphocytes in lymph organ might contribute to this immunosuppression. PMID- 21591332 TI - [Tissue regeneration is a key tool for burn tissue repair]. AB - Regenerative medicine is presently one of the hottest areas in medical research. Regenerative medicine is to search for effective biotherapeutic strategies to promote self-repair and regeneration, or to construct new tissues and organs hopefully to improve or restore the function of the injured tissues and organs. Regenerative repair, including nonstructural and functional repair, may be classified into exogenous and endogenous regenerative repair when considering its cellular or molecular origin. To strengthen researches on regenerative medicine may precipitate the application of new clinical therapeutic strategies, and supply effective therapeutic means for treatment of severe burns. PMID- 21591333 TI - [The practice of wound healing center construction in China]. AB - The construction of wound healing or wound care center in China is necessary for patients and about 10 wound healing or care centers have already been established during the past years. In this paper, we summarize their experience and expect their development in the future. PMID- 21591334 TI - [Effect of particulate allogeneic acellular dermal matrix (PADM) combined with autologous split-thickness skin (STS) on wound healing in rats]. AB - OBJECTIVE: To evaluate the effects of mixed grafting of allogeneic PADM and autologous STS on wound healing of full-thickness defect in rats. METHODS: Full thickness defects with size of 6 cm x 4 cm were produced on the back of 12 SD rats, and they were divided into E group (n = 6) and C group (n = 6) according to the random number table. The wounds in E group were grafted with a mix of allogeneic PADM (expansion rate 10: 5) and autologous STS with thickness of 0.2 mm, while those in C group were grafted with autologous STS in the same thickness. The wound healing rate, survival rate, contraction rate, and expansion rate of transplanted skin were observed at post operation week (POW) 2, 3, 4, 6, 8, 12, 20. Tissue samples form wounds and surrounding normal skin were harvested at POW 20 for histopathological observation as follows. The structure of collagen fiber bundle was observed by HE staining, the diameter and gap rate of collagen fiber bundle were also measured. The distribution of type I and III collagen was observed by sircus red staining, and the contents of type I, III collagen and their ratio were also examined. Data were processed with independent samples t test, Levene test, and t' test. RESULTS: Survival rate of transplanted skin in E group at POW 2 [(76.1 +/- 13.1)%] was obviously lower than that in C group [(94.5 +/- 1.3)%, t' = 3.440, P = 0.018]. Contraction rate of transplanted skin in E, C groups at POW 3 showed significant difference [(34 +/- 8)% vs. (16 +/- 12)%, t = 3.211, P = 0.009]. Compared with those in peri-wound normal skin, collagen fiber bundles in C group showed signs of homogenization, and collagen fibers were thin with irregular arrangement. Collagen fiber structure and arrangement of composite skin in E group were similar to those surrounding normal skin with incomplete degradation of PADM. Diameter of collagen fiber bundle [(9.6 +/- 0.8) microm], gap rate between collagen bundle [(24 +/- 5)%], content of type I collagen [(80.2 +/- 5.4)%] and the ratio of type I to type III collagen (4.3 +/- 1.2) in E group were all increased as compared with those in C group [(7.3 +/- 1.4) microm (t = 3.562, P = 0.005), (17 +/- 4)% (t = -2.760, P = 0.020), (68.1 +/- 8.4)% (t = 2.981, P = 0.014), 2.3 +/- 1.0 (t = -3.204, P = 0.009)], while content of type III collagen [(19.8 +/- 5.4)%] in E group was lower than that in C group [(32.0 +/- 8.4)%, t = 2. 981, P = 0.014]. Above-mentioned indexes of collagen in wound of E group were similar to those of normal skin surrounding the wound. CONCLUSIONS: Allogeneic PADM used as dermal regeneration template is beneficial in improving collagen fiber bundle structure in dermis layer of rats with full thickness skin wounds when repaired with autologous STS, and it accelerates maturation of regenerative dermal tissue. PMID- 21591335 TI - [Design and biological evaluation of poly-lactic-co-glycolic acid (PLGA) mesh/collagen-chitosan hybrid scaffold (CCS) as a dermal substitute]. AB - OBJECTIVE: To design and construct a kind of dermal regeneration template with mesh, and to preliminarily evaluate its biological characteristics. METHODS: PLGA mesh was integrated into CCS with freeze-drying method for constructing PLGA mesh/CCS composite (PCCS). The micromorphologies and mechanical properties among PLGA mesh, CCS, and PCCS were compared. PCCS and CCS was respectively implanted into subcutaneous tissue of SD rats (PCCS and CCS groups, 9 rats in each group). The tissue samples were collected at post operation week (POW) 1, 2, and 4 for histopathological and immunohistochemical observation. Protein levels of CD68, MPO, IL-1beta, IL-10 were examined by Western blot, with expression of gray value. Data were processed with one-way analysis of variance and t test. RESULTS: Three-dimensional porous structure of PCCS was similar to that of CCS. Mechanical property of PLGA mesh and PCCS was respectively (3.07 +/- 0.10), (3.26 +/- 0.15) MPa, and they were higher than that of CCS [(0.42 +/- 0.21) MPa, F = 592.3, P < 0.0001)]. The scaffolds were filled with newly formed tissue in PCCS group at POW 2, while those in CCS group were observed at POW 4. A large accumulation of macrophages was observed in both groups, especially at POW 2, and more macrophage infiltration was observed in CCS group. The protein level of IL-10 in PCCS group at POW 2 was obviously higher than that in CCS group, while the protein levels of CD68, MPO, IL-1beta were significantly decreased as compared with those in CCS group (with t value from -4.06 to 2.89, P < 0.05 or P < 0.01). CONCLUSIONS: PCCS has excellent mechanical property with appropriate three-dimensional porous structure. Meanwhile, it can rapidly induce formation of new tissue and vascularization, and it has a prospect of serving as a dermal substitute. PMID- 21591336 TI - [Effect of topical application of aminoguanidine cream on skin tissue of rats with diabetes]. AB - OBJECTIVE: To investigate the effects of aminoguanidine cream on the proliferation of keratinocytes (KC), content of advanced glycosylation end products (AGE) and oxidative stress in skin tissue of rats with diabetes. METHODS: Stearic acid, liquid paraffin, vaseline, lanolin, isopropyl myristate fat, glycerol, 50 g/L alcohol paraben, aminoguanidine hydrochloride etc. were mixed in certain proportion to make aminoguanidine cream, and cream without aminoguanidine was used as matrix. The dorsal skin of normal rats were harvested and treated by aminoguanidine cream with dose of 5, 10 g/L, or 5 g/L together with 10 g/L azone. The transdermal effect was respectively measured at post treatment hour 2, 4, 7, 10, 12, 24. Thirty SD rats were divided into normal control (NC, n = 6), diabetes (D, n = 8), aminoguanidine cream-interfered (AI, n = 8), matrix cream-interfered groups (MI, n = 8) according to the random number table. Diabetes was reproduced by intraperitoneal injection of STZ (65 mg/kg) in rats of D, AI, and MI groups, and rats in NC group were injected with 0.05 mmol/L citrate buffer as control. One week later, dorsal skin of rats in AI and MI groups were respectively treated with 10 g/L aminoguanidine cream and matrix cream by external use for 4 weeks. AGE content was determined with fluorescence detection from skin collagen extract. KC cell cycle was detected by flow cytometry. Skin tissue specimens were obtained for determination of levels of superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO), and total antioxidant capacity. Data were processed with t test. RESULTS: Transdermal effect of aminoguanidine cream with dose of 10 g/L was better than that with 5 g/L or 5 g/L + 10 g/L azone cream. One rat was not induced successfully in MI group. Four weeks after model reproduction, 4 rats died in D group and 1 rat died in AI group. The AGE content in D group was obviously higher than that in NC group [(36.8 +/- 2.6), (24.6 +/- 2.7) U per milligram hydroxyproline, respectively, t = 7.2, P < 0.01], and that in AI group [(28.6 +/- 3.7) U per milligram hydroxyproline] was also lower as compared with that in D group (t = 3.9, P < 0.05). There was no significant difference in AGE content between MI [(32.2 +/- 5.2) U per milligram hydroxyproline] and D groups (t = 1.6, P > 0.05). The percentage of KC in S phase was obviously lower in D group than in NC group [(5.3 +/- 0.6)%, (7.6 +/- 0.9)%, respectively, t = 4.50, P < 0.01], while that in MI group [(9.2 +/- 1.5)%] was higher as compared with that in D group ( t = 4.90, P < 0.01). It was more higher in AI group than in D group on KC percentage in S and G2/M phase (with t value respectively 6.80, 3.17, P values all below 0.01). The oxidative stress indexes of skin tissue in D group were all higher than those in NC group, in which levels of MPO and SOD showed statistical difference (with t value respectively 4.4, 3.7, P values all below 0.05). The oxidative stress indexes were all lower in AI group than in D group, especially in SOD level (t = 1.4, P < 0.05). Levels of MAD, MPO in MI group were significantly lower than those in D group (with t value respectively 2.6, 2.9, P values all below 0.05). CONCLUSIONS: Aminoguanidine cream can promote KC proliferation and appropriately reduce oxidative stress through inhibiting AGE formation to a certain extent in skin tissue of rats with diabetes. Signal use of matrix cream can also reduce oxidative stress in skin tissue of rats with diabetes. PMID- 21591337 TI - [Screening of differential expression genes of human skin epidermal stem cells at different development stages by cDNA microarray technique]. AB - OBJECTIVE: To analyze expression characteristics of human skin epidermal stem cell at different developmental stages, and to explore its biological significance. METHODS: Health skin samples from 28-32 w fetuses (F group), 4-12 y children (C group), and 35-55 y adult (A group) were harvested, with 10 cases in each group. Epidermis were separated using trypsin digestion and EDTA, and human epidermal stem cells were isolated and purified with type IV collagen attachment method. The monoclonal antibody of integrin beta1 and keratin 19 were used for detection and identification of epidermal stem cells by immunohistochemical staining. Total RNA was extracted from above cells by Trizol one-step method, and were detected by formaldehyde denaturing agarose gel electrophoresis. Probes were prepared and hybridized into cDNA microarray for scanning fluorescent signals and analysis of images, with two-fold differential expression value for screening. Significantly up/down-regulated genes were selected for verification by real time RT-PCR. RESULTS: By comparing expression profile between A and C groups, a total of 1808 genes with differential expression were detected, including 1089 up regulated genes and 719 down-regulated genes, and they were classified into 128 categories. Among them, 1462 genes were known (found in GeneBank), 346 genes were unknown. A total of 4534 genes with differential expression were detected between C and F groups, in which 1783 genes were up-regulated and 2751 genes were down regulated, and they were classified into 216 categories. Among them, 3577 genes were known (found in GeneBank), and 957 genes were unknown. There were 1104 genes with differential expression consistently detected in F, C and A groups, which were classified into 32 categories according to gene function. Among them, 94 genes were consistently up-regulated and 75 genes consistently down-regulated. Test results of real time RT-PCR were in accordance with above-mentioned results. CONCLUSIONS: Gene expression profiles of epidermal stem cells cultured in vitro, harvested from fetuses, children, and adult, exhibit obvious difference. This may be closely related to different stages of proliferation and differentiation of human epidermal stem cell and self-repair ability of wound at different developmental stages. PMID- 21591338 TI - [Biological effects of paracrine from insulin stimulated adipose-derived stem cells (ADSC) on human vascular endothelial cells]. AB - OBJECTIVE: To study the biological effects of the paracrine from ADSC after being stimulated by insulin on vascular endothelial cells. METHODS: (1) ADSC was isolated from human adipose tissue and cultured in vitro. The third generation cells were collected and divided into insulin group (I, cultured with serum-free DMEM containing 1 x 10(-7) mol/L insulin) and control group (C, cultured with serum-free DMEM) according to the random number table, with 6 slots in each group. Three days later, ADSC culture medium (ADSC-CM) was collected for determination of levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) by ELISA. (2) Human umbilical vein endothelial cells (HUVEC) were cultured to the third generation, and they were cultured with special nutrient solution and divided into ADSC-CM with insulin stimulation group (AI), ADSC-CM without insulin stimulation group (AC), insulin group (I, with same concentration as above), blank control group (BC) according to the random number table. Three days later, proliferation of HUVEC was determined with MTT method (with expression of absorbance value). Another two samples of HUVEC were respectively divided into 4 groups as above for determination of apoptosis rate with Annexin V/FITC double-staining 12 hours after culture, and HUVEC migration with scratch adhesion test at post scratch hour (PSH) 12, 24, 36, 48. Data were processed with t test. RESULTS: (1) Compared with those in C group [(287 +/- 47), (577 +/- 84) pg/mL, respectively], the secretion levels of VEGF and HGF in I group [(643 +/- 64), (930 +/- 68) pg/mL, respectively] were significantly increased (with t value respectively 18.869, 18.475, P values all below 0.05). (2) The absorbance value of HUVEC in AI and AC groups was 0.847 +/- 0.042, 0.798 +/- 0.022, respectively, which were higher than that in I and BC groups [0.665 +/ 0.028 (with t value respectively 4.579, 3.732), 0.674 +/- 0.031 (with t value respectively 3.761, 4.073), P values all below 0.01], and that in AI group was higher than that in AC group (t = 2.576, P < 0.05). The apoptosis rates of HUVEC in AI and AC groups [(5.8 +/- 1.9)%, (9.0 +/- 2.0)%, respectively] were obviously lower as compared with that in I and BC groups [(30.4 +/- 6.0)% (with t value respectively 12.891, 10.417), (31.4 +/- 7.4)% (with t value respectively 11.474, 9.783), P values all below 0.05 ], and that in AC group was higher than that in AI group (t = 8.548, P < 0.05). The distance of migration of HUVEC in AI and AC groups were greater than that in I and BC groups at PSH 36, 48, and that in AI group was greater as compared with that in AC group (with t value respectively 4.076, 4.573, P values all below 0.05). CONCLUSIONS: Paracrine from ADSC after being stimulated by insulin can promote proliferation and migration of HUVEC, and suppress its apoptosis, and it is beneficial for tissue vascularization. PMID- 21591339 TI - [Present status and prospects of professional facilities for wound healing]. AB - It is essential for the development of modern clinical medicine to establish a professional facility and team for wound healing. There is some successful experience of constructing and running the wound healing center to be mirrored at home and abroad. The construction of the facility and team for wound healing will be promoted by guideline issuing, profession certification, and others, which would push forward the clinical treatment and basic research of wound healing. PMID- 21591340 TI - [Establishment of wound care center and development of burns and plastic surgery discipline]. AB - To study the interaction between establishment of wound care center and development of discipline of burns and plastic surgery. The changes in number of outpatient, time for dressing change per patient, outpatient service income, number of inpatients and operations in our hospital were summarized and retrospectively analyzed before and after establishment of wound care center. The proportion of patients with chronic wounds and skin and soft tissue defects after trauma among all inpatients in the same term were investigated. Meanwhile, the development of discipline of burns and plastic surgery before and after establishment of wound care center was analyzed. Compared with those in the year before establishment of wound care center, outpatient number, time for dressing change per patient, outpatient service income, inpatient number, and amount of operations were all increased (with increase rate of 330%, 569%, 325%, 161%, and 173%, respectively) in the year after establishment of wound care center. The ratio of patients with chronic wounds and skin and soft tissue defects after trauma among all inpatients was respectively increased from 4.3% and 4.5% in the year before establishment of wound care center to 9.2% and 12.4% in the year after establishment of wound care center. Patient satisfaction, bed utilization rate, levels of wound treatment and repair were all improved after establishment of wound care center. So we come to conclusions as follows. Establishment of wound care center can promote development of the standard of burns and plastic surgery. Comprehensive use of multidisciplinary theories and techniques concerning burns, plastic and aesthetic surgery, medical aesthetics, etc. can be beneficial for improvement of quality of wound healing and achievement of cosmetic effect, and wound care center may be further developed. PMID- 21591341 TI - [Exploration on the linkage mechanism between wound healing department and community health system]. AB - Discipline of wound healing, has been emerged with the demand of patients suffering from various wounds. A unique way different from traditional medical system, in accordance with the incidence of wound diseases, medical demand, and current medical system of China, should be operated for the specialty, so as to benefit medical service for patients, rational allocation of medical resources. An overall layout with characteristic of "small ward, big clinic" is likely to meet the discipline demand associated with wound diseases, which present the linkage mechanism between wound healing department and community health system. By means of jointing wound healing clinic in community, two-way referral pathway for patients, training for general practitioner in community, guarantee and incentive system, an new operation pattern of wound healing discipline would be formed, described as linkage mechanism of wound healing department and community health system. PMID- 21591342 TI - [Probe into construction mode of wound care center]. AB - Relevant data including diagnosis and treatment model, operation situation, etc. are analyzed in our wound care center and compared with abroad based-on literature retrieval, to find out a suitable way for setting up wound care centers in our country. Wound care center with mode of multidisciplinary cooperation that is "specialist-oriented" was established in our hospital, mirroring the experience of foreign wound care centers. The investigation showed the demands of patients could be met, their psychological and economic pressures as well as social burden might be greatly relieved in our center. For an example, we achieved our purpose readily by setting up a clinical pathway of diabetic foot according to the features of our hospital. The model of multidisciplinary cooperation, with minor adjustments, may be applicable for wound care centers at home and abroad. Our wound care center will establish better system of diagnosis and treatment to conform to the situation in our country. PMID- 21591343 TI - [Role of lymphatics in bacterial translocation from intestine in burn rats]. AB - OBJECTIVE: To investigate the role of lymphatics in bacterial translocation from intestine of rats with burn. METHODS: Escherichia coli (E. coli) labeled with chloromethylbenzamidodialkylcarbocyanine (CM-DIL) were prepared. Sixty adult male Wistar rats were randomly divided into scald group and sham injury group according to the envelope method, with 30 rats in each group. Rats in both groups were gavaged with 0.5 mL fluid containing CM-DIL-labeled E. coli. Rats in scald group were inflicted with 30% TBSA deep partial-thickness scald (verified by pathological section) and resuscitated with fluid. Rats in sham injury group were sham injured by bathing in 25 degrees C water for 10 s (verified by pathological section) and also received with fluid infusion. Mesenteric lymph node (MLN), liver, mesenteric lymph fluid (MLF), and liver vein blood (LVB) were harvested at post injury hour (PIH) 2, 24, and 72. Bacteria translocation was detected with fluorescent tracing technique and bacteria culture. The endotoxin content in above-mentioned four kinds of specimens was quantitatively determined with chromogenic substrate limulus amebocyte lysate. The carrying capacity of endotoxin in MLF and LVB was calculated. Data were processed with t test or one way analysis of variance. RESULTS: (1) Living bacteria were in short-stick form, and they were seen moving in single or in doubles or triples in sample fluid. Dead bacteria were in irregular aggregates. Labeled bacteria in small amount were detected in sham injury group, their number peaked at PIH 24. A large amount of labeled bacteria were detected in scald group at PIH 2, which peaked at PIH 24 and decreased at PIH 72. The largest amount of labeled bacteria were found in MLN in scald group as compared to those in the other samples, and the number peaked at PIH 24 [(5872 +/- 1976) x 10(3) CFU/g], which was obviously higher than that [(216 +/- 110) x 10(3) CFU/g, t = 30.129, P = 0.000] in sham injury group. The number of bacteria decreased at PIH 72, but it was still significantly different from that in sham injury group ( t = 4.323, P = 0.000). The number of bacteria in LVB was the smallest. (2) 29 (24.2%) samples out of the 120 samples in sham injury group were positive for bacteria. 72 (60.0%) samples out of the 120 samples in scald group were positive for bacteria. No alive bacterium was detected at any time point in LVB sample in both group; the other three samples were detected with alive bacteria since PIH 2. There were more alive bacteria detected in MLN and liver as compared with the other two kinds of samples in scald group. The amount of bacteria in MLN, liver, and MLF in scald group were higher than those in sham injury group (with t value respectively 4.353, 4.354, 4.965, P values all equal to 0.000). (3) The endotoxin level in each kind of sample at each time point was obviously higher in scald group than that in sham injury group, and it peaked at PIH 2 in liver and MLF. The difference of endotoxin level among 4 kinds of samples in scald group at PIH 2 was statistically significant ( F = 258.47, P = 0.000), and the endotoxin level was higher in liver, MLN, and MLF. They were obviously higher than those in sham injury group (with t value respectively 43.378, 43.123, 22.423, P values all equal to 0.000). The endotoxin level in MLF was 9 times of that in LVB. (4) The carrying capacity of endotoxin in LVB and MLF at each time point in scald group was higher than that in sham injury group. CONCLUSIONS: CM-DIL marked bacteria can reflect the microbial translocation condition. The lymphatic route is an important pathway for bacteria translocation. PMID- 21591344 TI - [Influence of hydrogen sulfide on important organs in rats with severe burn]. AB - OBJECTIVE: To investigate the changes in hydrogen sulfide (H2S) and cystathionine gamma-lyase (CSE) in rats with severe burn, and to analyze the effects on important organs. METHODS: One hundred and four healthy male SD rats were divided into normal control group (NC, n = 8), burn group (B, n = 48), and H2S intervention group (HI, n = 48) according to the random number table. SD rats in HI group were intraperitoneally injected with NaHS (56 micromol/kg) once a day for 5 days. Then rats in HI and B groups were subjected to 30% TBSA full thickness burn. Blood sample as well as heart, liver, lung, kidney, and stomach tissue samples were harvested from rats in B group at post burn hour (PBH) 2, 6, 12, 24, 48, and 96 respectively for determination of serum content of H2S and CSE activity. Serum content of alanine transaminase (ALT), aspartate aminotransferase (AST), MB isoenzyme of creatine kinase (CK-MB), urea nitrogen (BUN), and creatinine (Cr) in HI and B groups were examined at each time point. Samples were harvested from above organs in each group for histomorphological observation. Above-mentioned indexes were also determined in NC group as control. Data were processed with SNK- q test, t test, correlation analysis (between serum content of H2S and CSE activities, biochemical indexes). RESULTS: Serum content of H2S and CSE activities of above organs (except for lung tissue at PBH 48, 96) in B group within PBH 96 were lower than those in NC group, reaching minimum values at PBH 6 or 12. Compared with those in NC group, serum contents of all biochemical indexes in B group were obviously increased within PBH 48, in which serum contents of BUN [(32.5 +/- 9.8) mmol/L] and Cr [(65 +/- 9) micromol/L] reached peak at PBH 6, and serum contents of ALT [(423 +/- 59) U/L], AST [(993 +/- 60) U/L], and CK-MB [(49 261 +/- 6637) U/L] peaked at PBH 12. Serum contents of all biochemical indexes in HI group at each time point were significantly decreased as compared with those in B group, but the same change tendencies were showed in both groups. Histomorphological observation showed that all the organs were severely injured in B group at PBH 24, whereas those in HI group were markedly ameliorated. Serum content of H2S in B group was respectively correlated with CSE activities of all organs (with r value from 0.639 to 0.894, P values all below 0.005) and serum contents of biochemical indexes (with r value from 0.301 to 0.585, P values all below 0.001). CONCLUSIONS: H2S/CSE system may take part in pathophysiological process in rats with severe burn. Exogenous H2S replacement therapy can protect important organs of rats with severe burn. PMID- 21591345 TI - [Coincidence of HCV and HGV infections in hemodialysis patients]. AB - HCV and HGV were recognized as highly prevalent in maintenance dialysis population and variable from country to country and unit to unit. The introduction of serologic tests, for detecting antibodies to HCV (anti-HCV) and HGV (anti-HGV) antigens, has facilitated the study of the epidemiology as well as clinical significance of HCV and HGV infections in patients on maintenance dialysis. The implementation of molecular biology techniques (polymerase chain reaction) for detecting HCV and HGV viremia (HCV-RNA, HGV-RNA) facilitate diagnosis and transmission routes of the infection. The aim of the study was to evaluate the coincidence of HCV and HGV infections in dialysis population and relationship between current and overcome infections and markers of liver damage. The study was performed in the group of 215 patients aged 26-81 years (mean 53.2) on 3 x week maintenance hemodialysis from 33 to 301 months (mean 101.8 months) in the Department of Nephrology, University Hospital, Cracow. Anti-HCV and anti-HGV antibodies were determined based on immunoenzymatic, IIIrd generation, methods. HCV-RNA and HGV-RNA were estimated using polymerase chain reaction (PCR). The anti-HCV antibodies were present (+) in 40 (18.6%) of patients. From the group of patients with anti-HCV (+) antibodies 42.5% were also HCV-RNA (+) whereas from the patients with anti-HCV (-) antibodies 10.4% were HCV-RNA (+). Anti-HGV antibodies tested in the group of 93 patients: 32 anti-HCV (+) and 61 anti-HCV ( ) were positive in 20 (62.5%) and 22 (36.1%) patients, respectively. In the group of patients with anti-HGV (+) antibodies HGV-RNA (+) were detected in 63.6%. Anti HCV (+) and anti-HGV (+) patients were dialysed longer as compared with negative ones: 144.5 vs. 83.5 months, p < 0.001 and 119 vs. 96.4 months, p-NS, respectively. CONCLUSIONS: 1. The prevalence of HCV and HGV infections in the dialysis population is very high. 2. The coincidence of HCV and HGV infections is frequent. 3. Our results showed that even anti-HCV (-) and anti-HGV (-) patients carry the risk of viral infection due to detected HCV-RNA and HGV-RNA in some patients. PMID- 21591346 TI - [Adaptation of Vespide Allergy Quality of Life Questionnaire for Polish children with venom allergy and for their parents]. AB - Aim of the study was to assess validity and reliability of adaptations of VQLQ for Polish children with Hymenoptera venom allergy and their parents. Sample under study consisted of 73 children aged up to 14 years, who were treated with specific venom immunotherapy (VIT) in 2008 in centres conducting this procedure in Poland, and their parents. Theoretical validity of the scales was assessed with exploratory factor analysis using principal component analysis method. Reliability of the scales was assessed in terms of internal consistency with Cronbach alpha coefficient. Results of analysis showed that both scales measure 4 dimension of quality of life and reliability of scales measuring particular dimensions is at least acceptable in case of scale for children, and high in case of scale for parents. Both adapted scales are valid and reliable tools measuring quality of life in children with Hymenoptera venom allergy and their parents' quality of life in the face of child's allergy. PMID- 21591347 TI - [Health-related quality of life in children with Hymenoptera venom allergy treated with VIT and quality of life of their parents]. AB - Hymenoptera venom allergy, although rare in children, by its potential fatalities, leads to many psychosocial consequences, influencing quality of life of children and their parents. Aim of this paper is the estimation of health related quality of life of venom allergic children treated with specific immunotherapy, and their parents. Assessment of factors influencing health related quality of life levels was also performed. MATERIAL AND METHODS: Sample under study consisted of 73 children: mean age 10.6, SD 2, 4, treated because of Hymenoptera venom allergy in 5 clinical allergy centers in Poland. Data was collected using VQLQ questionnaire adapted for children and their parents. Determinants of quality of life were assessed with multivariate linear and logistic regression models. Analysis were done with SPSS 15 for Windows package. RESULTS: Girls reported higher level of anxiety than boys (B = 0.47; 95% CI = (0.01; 0.94)). Level of caution in children increased along with increase of their anxiety against re-sting (B = 0.49; 95% CI = (0.27; 0.71)). Level of anxiety of children who were under treatment from 6 months to 2 years was lower than level of anxiety of parents of children treated shorter than 6 months (B = 1.21; 95% CI = (-2.16; -0.25)). The lowest level of caution was reported by parents of children aged 10 year or less (B = -0.86; 95% CI = (-1.67; -0.05)), while the highest was reported by parents of children aged 11 years (B = 0.86; 95% CI = (0.20; 1.53)) in comparison to parents of children aged 12 years or more. Parents' caution increased along with increase of their anxiety (B = 0.61; 95% CI = (0.40; 0.83)). Higher level of limitations was imposed by parents of children treated with rush or ultra rush method, in comparison to parents of children treated with conventional method (B = 1.27; 95% CI = (0.21; 2.33)). Levels of quality of life in children and their parents were strongly dependent in the same dimensions. CONCLUSIONS: 1. Levels of quality of life in particular dimension in children is related to level of the same dimension in parents. 2. Age of children influenced level of caution of their parents. 3. Treatment duration influenced level of anxiety of parents. 4. Safety feeling acquired by parents at the beginning of treatment improves their quality of life in all dimensions. PMID- 21591348 TI - [Heart rate variability in type 1 diabetic patients with retinopathy. Part I. Frequency analysis]. AB - Cardiovascular autonomic function is measured as heart rate variability (HRV). The aim of the study was the HRV comparison between type 1 diabetic patients without (R0) and with diabetic retinopathy (R1). The group R0 was significantly younger (36.08 +/- 13.52 years) than group R1 (42.90 +/- 10.42 years). Diabetes duration was significantly longer in the group R1 as compared to group R0 (22.60 +/- 8.72 years vs 16.72 +/- 11.54 years, p < 0.04). Also HbA1c level in the group R1 was significantly higher as compared to the group R0 (p = 0.006). The data demonstrated that abnormal HR variability measured over a 24-h period provides information on the risk of sudden death. To assess HR variability twenty four hour EKG monitoring were performed in all examined patients. RR intervals were significantly longer between 2.00 a.m. and 5.00 a.m. In each hour of 24-h EKG Holter monitoring VLF and LF were significantly lower in the group R1. In the group R1 - HF was also significantly lower but only during sleeping time (between 11 p.m. and 7 a.m.). 24-h EKG monitoring is a useful and promising tool in diabetic patients with different microvascular complications. PMID- 21591349 TI - [Miniinvasive Mitchell-Kramer method in the operative treatment of the hallux valgus deformity--preliminary report]. AB - The aim of this study was to evaluate the preliminary results of miniinvasive Mitchell-Kramer distal osteotomy of the first metatarsal. METHODS: We evaluated 5 patients, all women, who underwent miniinvasive distal metatarsal osteotomy of the first metatarsal with preservation of lateral cortex of distal fragment. We made reposition and percutaneous stabilization using of 2-mm K-wire. We did not use cast immobilization and allowed to go to offload of the forefoot. Radiological (AP and lateral foot standing X-ray picture) VAS scale and The American Orthopaedic Foot and Ankle Society (AOFAS) hallux-metatarsophalangeal interphalangeal scale was used for the clinical assessment. RESULTS: Preoperatively mean hallux valgus angle (HVA) was 32.4 degrees, intermetatarsal angle (IM) 14,3 degree, VAS 8.9/10 and AOFAS 40.2/100. Postoperatively HVA was 14.7, IM 9.1, VAS 3.6/10 and AOFAS 91.2/100. We did not notice complication and all patients were satisfied. CONCLUSIONS: The miniinvasive Mitchell-Kramer method is good surgical treatment of mild-to-moderate hallux valgus deformity. Cast immobilization is unnecessary, there are good clinical and cosmetic results. Using the minioscillating saw reduces surgical exposure. PMID- 21591350 TI - [Neopterin in assessing the activity of inflammatory bowel diseases: ulcerative colitis and Crohn's disease]. AB - The increase in the incidence of non-specific inflammatory bowel disease (IBD): ulcerative colitis (UC) and Crohn's disease (CD) makes the research of finding new biochemical markers, which were characterized by a high sensitivity and specificity for an objective assessment of severity of the inflammatory process and the effectiveness of treatment of patients. The aim of this study was to estimate the usefulness of neopterin in serum in assessing the disease activity in comparison to other markers of inflammation such as C-reactive protein (CRP) and TNF-alpha in patients with exacerbation of IBD and healthy volunteers. The study included 32 patients with UC and 31 with CD. The control group consisted of 30 healthy volunteers matched for age and gender. Disease activity in patients with UC was assessed based on a point system Mayo. In patients with CD disease activity was calculated based on the CDAI (Crohn's Disease Activity Index). Serum concentrations of neopterin, CRP and TNF-alpha were measured. For determination of CRP were used immunochemical nephelometric method. TNF-alpha and neopterin was measured by ELISA. RESULTS: In patients with UC and CD increased concentration of serum neopterin was significantly higher compared to the control group (p < 0.005). We observed a positive correlation between increased concentrations of neopterin in serum and increased levels of TNF-alpha and CRP, increasing the number of leukocytes and platelets count and the degree of disease activity in patients with both UC and CD, but was no statistically significant differences between the two groups of patients. CONCLUSIONS: Measurement of neopterin concentration in serum may be a useful marker to assess disease activity in patients with IBD. PMID- 21591351 TI - [Gastrointestinal tract polyps in acromegaly patients]. AB - Acromegaly is a rare, chronic disease due to hypersecretion of growth hormone (GH) by pituitary adenoma arising from somatotrophs. The course of the disease is related to long-term organ and systemic complications and malignancies. Colon polyps seem to constitute the most frequent tumours in acromegaly apart from thyroid nodules. The aim of this study was to evaluate the prevalence of colon polyps in patients with acromegaly. Thirty one acromegaly patients, 22 females and 9 males (mean age 46.3 +/- 11.9 yrs), were enrolled to the study. Colonoscopy with histopathological assessment of specimens taken during examination was carried out in all patients. Colon polyps were found in 13 patients (41.9%) i.e. 8 females and 5 males. In two patients multiple polyps were discovered (2 and 3 respectively). Polyps were histopatologically verified as tubular adenoma with low-grade dysplasia (10 patients, 76.9%) and hyperplastic polyps (3 patients, 23.1%). The prevalence of colon polyps was significantly related to the duration of uncontrolled acromegaly (p < 0.01). Median duration of uncontrolled acromegaly in patients with and without colon polyps were 10.0 (IQR = 2.0) yrs and 6.5 (IQR = 5.0) yrs, respectively. IGF-1, GH basic and in 120 min of OGTT serum concentrations on diagnosis were not significantly related to the prevalence of colon polyps. Our study indicates that duration of uncontrolled acromegaly, contrary to IGF-1, GH basic and in OGTT serum concentrations at diagnosis are essential for the colon polyps development. Colonoscopy is considered to be routine in patients with acromegaly. PMID- 21591352 TI - [Retrospective hormonal analysis of incidentally discovered and operated adrenal tumors for subclinical Cushing's syndrome]. AB - In the last twenty years the introduction of new imaging techniques has caused increasing incidence of accidental detection of adrenal tumors, which are usually mild and in most cases are hormonally inactive adenomas. Among hormonal disorders in patients with adrenal incidentalomas the hypercortisolism is often described, which, if not treated properly, leads to multiple organ complications, and further to the patient's death. The aim of the study was the retrospective analysis of the group of patients with adrenal incidentaloma, verified by histopathology for assessment of subclinical Cushing's syndrome. Among the group of 225 patients: 62 men and 163 women with incidentally detected adrenal tumors in age from 19 to 81 years diagnosed and treated in the Department of Clinical Endocrinology, University Hospital in Krakow, 59 patients was sent to surgery: 15 men and 42 women. Two groups of patients were analysed, divided on the basis of histopathological examination result. Group A consisted of patients with adrenal cortical adenoma: 38 people (11 men and 27 women). In group B there were people with so-called other hormonal inactive adrenal tumors - 17 people (4 men and 13 women). The average age of the patients in group A was 52.05 +/- 11.52 years, in group B 51.44 +/- 14.14 years. In group A the mean morning level of cortisol was 18.23 +/- 6.42 ug/dl and did not differ statistically significantly from the results of group B (mean morning cortisol level of 15.86 +/- 4.6 ug/dl). However a significantly higher nocturnal cortisol levels in the blood serum of patients with group A versus group B was observed (6.78 +/- 5.65 ug/dl vs. 3.57 +/- 1.77 ug/dl). There was no cortisol diurnal rhythm disorders in group B, while in group A slightly disrupted cortisol diurnal rhythm was found in 17 people. Mean values of 24-hour urine 17-OHCS and free cortisol were statistically higher in group A than in group B, although mean values remained within normal limits. In 24 patients from group A where abnormalities in the screening test with 1 mg DXA were found, a test with 2 and 8 mg was performed, which showed incomplete suppression of the excretion of steroid metabolites in the urine after administration of 8 mg in 17 subjects, and 3 of the total absence of suppression. In group B in 4 people there was no suppression in 1 mg of DXA test, while the suppression test with 8 mg of DXA was normal. A detailed analysis of the clinical signs, meticulously carried out and repeated hormonal diagnosis with the use of functional tests should be focused on the detection of subclinical hormonal disorders, which is crucial in preventing organ damage and making a decision of the right treatment of the patient, which is surgical. PMID- 21591353 TI - [Diagnostic difficulties in recognizing of pheochromocytoma]. AB - Pheochromocytoma (PH) is a tumour of chromaffin cells of the sympathetic nervous system and its clinical symptoms are associated with excessive production and release of catecholamines. The main criterion for clinical diagnosis of PH is finding increased concentrations of catecholamines or their metabolites in serum and/or urine. The largest diagnostic and therapeutic problems are patients with slightly elevated levels of methoxycatecholamines in serum and/ or urine. Aim of this study was to determine the cut-off point for elevated methoxycatecholamine in the collection of daily urine, which would give the basis for determining the reasonable recommendations of the biochemical criteria for diagnosis of PH. Retrospectively we analysed the results of 45 patients sent to laparoscopic adrenalectomy to the Department of General Surgery II with the preoperative diagnosis of pheochromocytoma. The diagnosis of pheochromocytoma was based on the finding of elevated 24-hour urine methoxycatecholamines. Based on the results of the histopathological examination patients were divided into two groups. Group 1 included 27 patients (14 women and 13 men) with histopathologically confirmed pheochromocytoma of adrenal gland. Group 2 consisted of 18 patients (11 women and 7 men), in which histopathological examination did not confirm the presence of pheochromocytoma. Mean age of patients in group 1: 46.8 +/- 14.4 years, in group 2: 55.7 +/- 13.7 years. Hypertension was diagnosed in 77.8% of those with group 1 and 94.4% from group 2. Based on the analyzed results of the CT, we found that the average tumor size in group 1 (4.2 +/- 1.9 cm) was statistically higher than in group 2 (2.9 +/- 1.1 cm). The average concentration of normetanephrine (NMN) in 24-hour urine in group 1 was statistically significantly higher than in group 2 (2,686 +/- 870.4 vs. 2375.1 +/- 754 mg/24h), as well as the average concentration of metanephrine (MN) (2533.4 +/- 3269.3 +/- 491.6 vs. 371.5 mg/24 hrs), and the sum of both methoxycatecholamines (NMN + MN) (5219.3 +/- 5190.6 vs. 1241.8 +/- 1202.2). The highest sensitivity in diagnosing pheochromocytoma with the rate of 81.5% was obtained for the sum of normetanephrine and metanephrine in 24-hour urine, while the sensivity for levels of each methoxycatecholamine separately was similar (63%). The highest specificity in the exclusion of PH was shown for 24-hour urine metanephrine (94.4%). The highest positive predictive value was found for the level of metanephrine in 24-hour urine (94.4%). The diagnostic cutoff concentrations of NMN, MN and NMN + MN for the diagnosis of pheochromocytoma were set. For the 24-hour urine NMN- cut-off > 1500 ug/24 h, for MN > 700 ug/24h and for NMN + MN > 1350 ug/24h. Shown above cut-off levels of methoxycatecholamines urine concentration will allow to pose a more accurate preoperative diagnosis of PH. PMID- 21591354 TI - [Evaluation of hematopoietic chimerism after allogeneic bone marrow transplantation by modern molecular techniques (STR-PCR and RQ-PCR)--single center]. AB - Allogeneic hematopoietic stem cell transplantation (alloSCT) is a curative treatment for many patients suffering from malignant and non-malignant hematological disorders. Successful transplantation is a process that requires the engraftment of transplanted pluripotent hematopoietic stem cells which re establish normal hematological and immunological systems. Distinguishing between host and donor origin of bone marrow and blood cells is vitally important for monitoring of the engraftment process. One of the most useful tools for engraftment monitoring is the assessment of hematopoietic chimerism. Which occurs after alloHSCT and describes the percentage of donor hematopoietic and lymphoid cells in a transplant recipient. 38 adult patients, after alloSCT performed in Katedra i Klinika Hematologii Collegium Medicum UJ entered the study and the total number of transplantations was 43. The evaluation of hematopoietic chimerism was based on PCR amplification of polymorphic non-coding DNA sequences- short tandem repeats (STR-PCR). The main tool was a semiquantitative method- fragment length analysis. The product of amplification was analyzed using the sequencer. The second method was based on a quantitative Real Time PCR technique (RQ-PCR) based on SYBRgreen chemistry. There were performed amplification of biallelic non-coding DNA sequences with short insertions or deletions. Hematopoietic chimerism evaluations were performed on +30, +60, +90, +120, +150, +180, +270 and +360 day and then every 6 months post alloSCT on peripheral blood or bone marrow samples. STR-PCR and RQ-PCR chimerism assays were compared and results evidenced the greater sensitivity of RQ-PCR method. There were not crucial differences in the results of chimerism evaluation obtained by means of these two methods. The analysis of chimerism kinetics after allogeneic stem cell transplantation allowed to modify the post-transplantation-treatment in 3 patients after alloNMSCT leading to increase of donor-origin hematopoiesis in transplant recipients (in 2 pts decision of DLI, 1 of them withdrawal of immunosuppression, 1 pt giving G-CSF). The results of chimerism monitoring confirmed that the failure of achieving a CC or lost of CC can predict the relapse of the disease. PMID- 21591355 TI - [Implementation of direct sequencing as a method of ABL gene mutations analysis in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitor]. AB - Chronic Myeloid Leukemia (CML), belonging to mieloproliferative syndromes, is one of the myeloproliferative clonal hyperplasia. It is caused by the Philadelphia chromosome resulting from the reciprocal translocation, t(9;22) between the long arms of chromosomes 9 and 22. This results in the production of fusion BCR-ABL transcript and chimeric protein--tyrosine kinase activity. This protein leads to increased proliferation, resistance to apoptosis, and worse adhesion of CML cells. Molecular analysis are very important in the era treatment of CML by tyrosine kinase inhibitors (TKI). Constant monitoring of the level of BCR-ABL transcript aimed at monitoring response to medical treatment as well as early detection of resistance to TKI therapy. The most common causes of resistance are point mutations ABL kinase domain of the BCR-ABL gene. In this aim, the biological material used (peripheral blood) derived from 58 patients of the Department of Hematology, Jagiellonian University Collegium Medicum. The isolated RNA was performed in successive stages: RT-PCR, RQ-PCR to a semi-nested PCR. In order to detect point mutations ABL kinase domain technique used direct sequencing of the product obtained in response to a semi-nested PCR. Using this technique allow in do not only a rapid detection of point mutations but also identification of its position in the ABL domain, type of mutation (e.g., T3151), as well as nucleotide and the amino acid substitution. The most common point mutations detected were T3151 and M244V. PMID- 21591356 TI - [Quality of life in patients treated for cancer of paranasal sinus and other area at head and neck]. AB - AIM: The oncology efficiency and quality of life are both important for patients with head and neck cancer in every-day life. MATERIAL AND METHODS: Evaluation of the dysphagia discomfort was made of 240 patients (190 male and 50 female). The primary location of the tumor was: paranasal sinuses, oral cavity, oropharynx, hypopharynx and larynx. The treatment was surgical or sugical and radiotherapy. Patient's quality of life was evaluated according to the self-administered questionnaire (M.D. Anderson Dysphagia Inventory MDADI). RESULTS: The comparison of the influence of dysphagia on the quality of life was made in two groups of patients. The first group consist of maxillectomy patients wearing obturator protheses, the second one were treated for cancer located in other mentioned area. Patients with primary tumors of the oral cavity, oropharynx, hypopharynx and larynx had significantly greater swallowing disability with an adverse impact on their quality of life compared with patients after maxillectomy. Method of treatment and stage of head and neck cancer greatly affected dysphagia-related quality of life. The longer the interval between completion of treatment and assessment by the MDADI, the higher the total score, thus reflecting a higher quality of life and funcional status as related to swallowing. CONCLUSION: The MDADI is the validated and reliable self-administered questionnaire designed specifically for evaluating the impact of dysphagia on the quality of life of patients with head and neck cancer. PMID- 21591357 TI - [The Polish version of the SF-36v2 questionnaire for the quality of life assessment]. AB - The American questionnaire SF-36 Health Survey is a worldwide tool used to assess the quality of life. It becomes increasingly popular also in Poland. Unfortunately, the existing Polish studies that used the questionnaire are not entirely reliable because different linguistic versions have been applied in the studies. The basic psychometric properties, like reliability and validity estimates of these versions have not been defined. The goal of the paper is to present the study aimed at evaluating the Polish version that has been acquired at The Qualitymetric--the unique entitled distributor of the SF-36v2--in terms of its utility for the Polish population. One thousand seventy six people took part in the study. On the basis of this study, the factor analysis, discriminant validity of the items and reliability and validity tests have been performed. The results showed that the factor structure of the Polish version of SF-36v2 differs from its original American version. However, it has been decided to maintain the original subscales in the Polish version of SF-36v2 in order to make comparisons between the Polish data and the data available abroad. The reasonable indicators of validity and reliability of the Polish version of SF-36v2 do support this decision. Nevertheless, some caution is recommended while interpreting the results of this version. PMID- 21591358 TI - [The influence of renal replacement therapy and patient education on circadian blood pressure values]. AB - The aim of study was to evaluate the influence of the dialysis method and patients knowledge about disease and therapy on the 24 hour blood pressures (BP) values. MATERIAL AND METHODS. The study group consisted of 62 dialysed patients- 27 with peritoneal dialysis (PD) and 35 with hemodialysis (HD). The questionnaire including sociodemographic data, information about disease and questions assessing patients knowledge about disease was carried out. Additionally, 24 hour ambulatory blood pressure monitoring (ABPM) and medical record analysis was performed. Results. Patients with PD had lower BP, especially systolic (SBP), than did patients with HD, (p < 0.05). PD patients treated > 3 years were more often non-dippers. The higher SBP (183.3 < or = 34.6 vs 149.9 +/- 18.4 mmHg, p < 0.05), MAP (105.9 +/- 16.7 vs 92.1 +/- 12.6 mmHg, p < 0.05) and BP fluctuations were also observed in HD women in comparison with PD women. Diastolic BP negatively correlated with age of the patients. The level of knowledge about disease was higher in PD patients, however, there was no relationship between knowledge and BP values. There was also no correlation between patients compliance with therapeutic regimen and BP values, although persons who adhered more systematically to the dietician recommendations had advantageous drop's in BP at night (p < 0.05). CONCLUSIONS: The results suggest that high BP values and its fluctuations are more often observed in HD patients, especially in females. The influence of patients knowledge and compliance on BP values should be verified by further research. PMID- 21591360 TI - [The predicting role of high sensitive troponin testing after coronary artery bypass graft surgery]. AB - An article is a short review which summarize the utility of high sensitive cardiac troponins measurements after coronary artery bypass grafting surgery and their prognostic value in the short- and the long-term survival. PMID- 21591359 TI - [The plasma levels and diagnostic utility of selected hematopoietic growth factors (HGFs) in breast cancer patients]. AB - BACKGROUND: Hematopoietic growth factors (HGFs) are involved in the regulation of hematopoietic cells growth. Few clinical investigations have shown their autologous production both in vitro by human cell lines and in vivo by tumors, for example in breast cancer. We have investigated the plasma levels of selected cytokines (M-CSF, G-CSF, GM-CSF) and commonly accepted tumor marker (CA 15-3) before treatment of breast cancer patients in relation to the healthy controls. Additionally, the diagnostic criteria: sensitivity, specificity, the predictive value of positive and negative results were defined. MATERIAL AND METHODS: Tested group--80 patients with breast cancer, control group--20 healthy women. M-CSF, G CSF and GM-CSF were determined using ELISA method, CA 15-3--was measured by chemiluminescence immunoassay--CMIA (ABBOTT). RESULTS: Median values of HGFs and CA 15-3 plasma levels were significantly higher in breast cancer patients comparing to the control group. The diagnostic sensitivity of M-CSF was higher than CA 15-3 (59% and 44% respectively), and for the other tested cytokines. The combined analysis of all tested cytokines resulted also in the increased sensitivity range (81%), especially with CA 15-3 (91%). The diagnostic specificities were higher for M-CSF and CA 15-3 (equal 95%) and for other tested cytokines (equal 90%). Positive predictive values (PPV) were high for all tested parameters, and negative predictive values (NPV) were higher to exclude breast cancer. CONCLUSIONS: This study suggests that tested cytokines can be clinically useful in diagnostics of breast cancer patients, especially with CA 15-3, but further investigation and confirmation by a prospective study are necessary. PMID- 21591361 TI - [Oral cavity changes in patients after kidney transplantation and preventive treatment algorithms]. AB - Kidney transplantation is the best option of treatment for patients with end stage renal failure. However, following kidney transplantation many stomatological abnormalities are frequently reported. It is mainly due to immunosuppressive therapy and subsequent impaired immune response. There is an increased risk of infections and malignancies. The most frequent findings in the oral cavity include: aphthae, erosions of bacterial, viral and fungal origin, lichen-like or leukoplakia-like changes. The another type of change is gingival hyperplasia and its periodontologial consequences. In this review etiology, clinical symptoms of periodontological changes are described together with algorithm of pre- and posttransplant management of oral healthy is provided. PMID- 21591362 TI - [Clinical symptoms variety in adults with celiac disease]. AB - Celiac disease, called gluten enteropathy, is a chronic disorder, characterized by the immunologic answer to the gluten contained in the wheat, barley and oat in genetically predisposed patients. The frequency of celiac disease is estimated on 0.5-1% in the adult population and proportion of diagnosed to non-diagnosed cases is 1 to 7. The clinical picture of that disease in adults presents wide spectrum of gastrointestinal and extraintestinal symptoms. There is 5-10 fold increased risk of its coexistence with other autoimmune diseases, such as diabetes mellitus type I, juvenile arthritis or autoimmune thyroiditis. Abnormal liver function or vascular thrombosis are also observed. Acute abdominal pain as the leading symptom is present in 16.3% of celiac cases. Moreover the increased frequency of the microscopic colitis and gastritis may influence on the persistence of clinical symptoms. PMID- 21591363 TI - [The role of tissue Doppler imaging in diagnosis of pulmonary embolism]. AB - Pulmonary embolism (PE), despite improvement of diagnostic methods often remains undiagnosed. Importantly, the lack of correct diagnosis is one of major factors negatively influencing the prognosis of PE for patients. Echocardiography is frequently performed on patients suspected of PE. However, the majority of signs reported by echocardiography only indirectly indicate PE. However, new parameters characteristic of pulmonary embolism by means of novel echo-cardiographic methods may increase the probability of a correct diagnosis, thus improving the prognosis in this group of patients. The aim of this study was to present a potential role of echo-cardiography with tissue Doppler imaging in diagnosing pulmonary embolism. Tissue Doppler echocardiography (TDE) is a based on the Doppler effect in order to assess movements of the heart structures. Due to a selective measurements of the velocities of selected fragments of myocardium, TDE allows for a fully quantitative and objective assessment of the regional myocardial function. One of the new parameters helpful in PE diagnosis is M-index, which is ratio of early diastolic mitral inflow velocity and right ventricular Tei index. M-index < 112, showed 92% sensitivity and 92% specificity for the PE diagnosis. Another parameter V-index, which is the ratio of right ventricular Tei index to left ventricular Tei index was assessed in PE diagnosis in patients with pulmonary hypertension (PH). The value of V-index > 1.2 confirmed PE with a sensitivity of 82% and a specificity of 83%. In our study, it was shown that patients with PE manifest hyperkinetic left ventricular function. Peak systolic velocity of the mitral annulus lateral portion (SmLV) = 5.5 cm/s had a sensitivity of 60% and a specificity of 86% in diagnosing PE in patients with congestive heart failure (CHF), whereas the ratio of peak systolic velocity of the tricuspid annulus to peak systolic velocity of the mitral annulus (SmRV/LV) = 1.2 showed a sensitivity of 76% and a specificity of 93% in diagnosing PE. The mentioned above date showing that echocardiography combined with tissue Doppler imaging may be useful in diagnosing PE. PMID- 21591364 TI - [Lipodystrophy and metabolic disturbances as complications of antiretroviral therapy]. AB - Effective treatment of HIV infection with antiretroviral drugs significantly improve prognosis. Reduction of mortality and life prolongations in patients receiving such therapy have been also connected with the risk of side effects development. Among these complications metabolic disturbances such as lipodystrophy, dyslipidaemia, and insulin resistance which are present according some authors in up to 50% of patients receiving HAART play an important role. In spite of different investigations molecular basis of lipodystrophy development during HAART have not be fully understood, and the latest research revealed a lot of new aspects connected w adipocyte tissue pathophysiology, which were not taken up to know into consideration. In the presented publication the most important information about pathogenesis of lipodystrophy development in HIV infected patients treated with ARV drugs have been presented. PMID- 21591365 TI - [The impact of polichlorinated biphenyls on neoplastic processes]. AB - The structure and turnover of polichlorinated biphenyls (PCB) in environment was presented. The PCB absorption and metabolism in organisms as well as the PCB influence on neoplastic process. PMID- 21591366 TI - [Does medical practice make life shorter?]. AB - In the present paper, an average age of death of medical doctors, separately for men and women, was compared with the average age of death across the Polish population. Obtained data indicate a higher mortality of women doctors in relation to the entire Polish population. PMID- 21591367 TI - [C1-C2 transarticular screw fixation of atlanto-axial instability with tetraparesis in rheumatoid patient--case report]. AB - A case of a 50-year-old patient with C1-C2 subluxation and concomitant neurological deficits in the course of rheumatoid arthritis has been described. In the article the diagnostic and therapeutic procedures, consisting mainly of surgical treatment, have been presented. Indications for the surgery were: a rapid disease progression observed during the last six months, and tetraparesis. The authors propose the choice of applied surgical technique by taking into account difficulties consequential to the anatomy of this region, as well as additional complications regarding the chronic inflammation process. The use of transarticular screw fixation method, together with concurrent spinal cord decompression allowed the stabilization of C1-C2 subluxation and improvement of the neurological state of the patient. PMID- 21591368 TI - [Inflammatory changes of oral cavity proceeding appearance of clinical symptoms of Crohn's disease]. AB - Crohn's disease belongs to the inflammatory bowel diseases. Inflammatory changes can be located in any part of the gastrointestinal tract including rarely oral cavity. We present a case of a 21 years old woman with unhealed by the local treatment, and verified by histological examination, inflammatory changes of oral cavity. These changes had proceed the diagnosis of typical changes in gastrointestinal tract for 6 months. Changes were located in terminal ileum and colon and were confirmed by colonoscopic, histologic and radiologic studies. Standard therapy of Crohn's disease with antiinflammatory and immunosuppressive drugs led to the healing of oral changes. We point out on the necessity of proper differential diagnosis of problematic unhealing changes, particularly with ulcerations of oral mucosa in young patients. Dental examination with histological confirmation of mucosal changes may be helpful in proper diagnosis of Crohn's disease in the young group of patients. PMID- 21591369 TI - [140-year anniversary of Medical Society in Tarnow 1870-2010 ]. PMID- 21591370 TI - [Deviations?]. PMID- 21591371 TI - [Psychiatry and justice, current debates]. PMID- 21591372 TI - [Financing expert centers for bipolar disorders in question]. PMID- 21591373 TI - [The therapeutic stay, a clinical, ethical and political act]. PMID- 21591375 TI - [A trip with the Pierre Bleue club and institutional psychotherapy]. AB - The Pierre Bleue therapeutic club is an association which forms part of the Trelaze day centre. Its missions involve organising therapeutic stay, highlights in the institutional dynamics of the centre. PMID- 21591374 TI - [The therapeutic stay, an "institutional regulator"]. AB - A therapeutic stay acts as a "regulator" of the undesirable effects of the institutional setting. It relies on the commitment of the members of the group who are no longer identified by their status. It is a paradigmatic act of a concept of care inherited from the policy of local sector healthcare and institutional psychotherapy. In the current context, it is an act which advocates patient-centred care. PMID- 21591376 TI - [Arc-en-ciel in Guadeloupe, a therapeutic stay]. AB - Participants in a workshop organised by a therapeutic care centre visited Guadeloupe with the two nurses who supervise the group throughout the year. The workshop, the work carried out prior to the trip and the stay itself are very much part of the care and the life of the patients involved in this project. The personal accounts and the follow-up of this initiative testify to its success. PMID- 21591377 TI - [From teaching and care to creativity, a therapeutic stay project]. AB - A group of young patients led by teachers and caregivers decided to organise a therapeutic stay. The objective of the stay was to visit historical sites to act out scenes from a fictional play written in a workshop. This stay enabled patients to develop their autonomy and strengthened the therapeutic alliance. PMID- 21591378 TI - [The therapeutic stay, the clinic's "nuggets of care"]. AB - A therapeutic stay is an adventure which represents a commitment on the part of caregivers and patients. A break of this type, during which relations are different to those within the institutional setting, gives rise to a questioning of an institution's ways of being and doing. It leads to clinical reflection and a therapeutic boost. PMID- 21591379 TI - [Bibliography]. PMID- 21591380 TI - [Early stages of schizophrenia, challenges and prospects]. AB - Despite a relatively extensive treatment armamentarium, the evolution of schizophrenic patients overall remains unfavourable. Early treatment is essential and influences the prognosis. Facilitating access to care through the creation of specialised assessment centres to complement the current system of care is one of the possible avenues for improvement. PMID- 21591381 TI - [Caring for suicide attempters in twelve healthcare institutions in Picardie]. AB - Simple tools to help in caring for people having attempted to commit suicide are often lacking or are unsuitable. Faced with this situation, a standardised questionnaire was sent to practitioners in all public institutions in Picardie which care for suicide attempters. A real effort must be made by healthcare professionals in order to improve the care provided to these patients. PMID- 21591382 TI - [7/7 liaison psychiatry]. PMID- 21591383 TI - [Land of asylum]. PMID- 21591385 TI - [Dynamics of biochemical markers of reparative fibrosis in uncomplicated course of myocardial infarction]. AB - Dynamics of biochemical markers of reparative fibrosis in patients with myocardial infarction (MI) with complicated course did not differ from that in the group of patients without complications. Development of complications was associated with elevation of blood serum content of glucosaminoglycans in phase 3 of reparative fibrosis compared with group of patients without complications. This elevation was significant in the group of patients with rhythm disturbances. Statistically significant increase of total urinal oxyproline was found in patients with cardiac aneurism in phase 1 and in patients with cardiogenic shock in phase 3 of reparative fibrosis. These subject allow to speak about participation of reparative fibrosis in development of complications. Complications of myocardial infarction developed in patients aged 58 years and older. PMID- 21591384 TI - [Antiarrhythmic activity of omega-3 polyunsaturated fatty acids in patients with stable ischemic heart disease and ventricular rhythm disturbances]. AB - The purpose of this investigation is to evaluate the influence of purified highly concentrated omega-3 polyunsaturated fatty acids (90% omega-3 polyunsaturated fatty acids 1 g/day) on the severe ventricular arrythmias in patients with stable coronary heart disease (CHD) without concomitant left ventricular contractivity impairment. MATERIALS AND METHODS: 43 patients with stable CHD (26 male and 17 female, aged 66.2 +/- 8.3) with ejection fraction above 45% with unstable paroxysms of ventricular tachycardia detected at Holter ECG monitoring that received 1 g/day omega-3 polyunsaturated fatty acids during 1 month. 23 patients continued treatment for one month extra, while 20 stopped receiving after one month. ECG monitoring was repeated monthly. RESULTS: In one month after started receiving 90% omega-3 polyunsaturated fatty acids the mean heart rate reduced by 2.4%, the number of single extrasystoles reduced by 20.1% (p=0.01), the number of paired extrasystoles reduced by 47% (p=0.0018) and the number of paroxysms reduced by 49% (p=0.0029). In 41.9% patients no paroxysms have been registered after one month. When continuously receiving omega-3 polyunsaturated fatty acids during the second month, the treatment efficiency increases, while the receiving been stopped after one month, the effect is reduced but remains. CONCLUSION: 1 g/day omega-3 polyunsaturated fatty acids application in patients with stable CHD without myocardium contraction dysfunction suffering from ventricular arrhythmias (4B grade after B.Lown) with no direct indications for implantable cardioverter defibrillator therapy results in significant reduction of arrhythmia. PMID- 21591386 TI - [Efficacy of ramipril, carvedilol, and trimetazidine MR in improvement of quality of life of patients after myocardial infarction]. PMID- 21591387 TI - [Assessment of quality of life after inclusion of coenzyme Q10 in the scheme of treatment of women with arterial hypertension and elevated risk of cardiovascular complications]. PMID- 21591388 TI - [Efficacy of shock-wave therapy in the treatment of chronic ischemic heart failure]. AB - INTRODUCTION: Shock-wave therapy (SWT) has proved its efficacy and safety in a number of studies in stable effort angina. METHODS: Twenty-four patients (20 men, 4 women; mean age 63.3 +/- 6.1 years) with chronic heart failure (CHF) of ischemic origin (>6 months after AMI) and left ventricular (LV) ejection fraction (EF) <40% received SWT in addition to their stable treatment. SWT was performed in 9 sessions with 100 shocks per spot in viable segments detected by low dose dobutamine stress echocardiography. Patients were examined at baseline and at 3 and 6 months after SWT. Troponin T level was measured after each week of treatment. RESULTS: Class of CHF significantly decrease from 2.2 +/- 0.8 to 1.7 +/- 0.7 at 3 and at 6 months after SWT (p<0.01). Six-minute walk test improved from 414 +/- 141 to 509 +/- 141 and 538 +/- 116 m (p<0.01) at 3 and 6 months, respectively. Significant augmentation of LVEF at rest was noted at 3 and 6 months after SWT (from 32.2 +/- 6.0 to 34.8 +/- 9.6 and 37.7 +/- 9.5, respectively p=0.03). Troponin T was negative in all cases. Significant increase of LV longitudinal deformation was registered at 6 months (from -8.84 +/- 0.38 to -9.72 +/- -0.44%, p<0.01) what evidenced for improvement of LV contractility. The latter was a result of restored hibernating segments function (longitudinal deformation of these segments rose from initial -7.52 +/- -0.5 to -9.18 +/- 0.53 and -9.63 +/- 0.59% at 3 and 6 months after SWT, respectively, p<0.01). CONCLUSIONS: In patients with CHF SWT caused significant clinical improvement as well as increases in LV EF and distance walked during 6-min walk test. These results justify conduct of a placebo controlled study. PMID- 21591389 TI - [Qualitative and quantitative changes of circulating in blood endotheliocyte precursor cells in patients with hypercholesterolemia]. AB - Aim of this study was elucidation of diagnostic value of qualitative and quantitative parameters of circulating endotheliocyte precursor cells (EPC), in the state of apoptosis (apoptotic endotheliocytes A AE), as well as effect of main risk factors on the studied parameters in patients with coronary atherosclerosis and hypercholesterolemia. We examined 24 patients with ischemic heart disease (14 men, 10 women, mean age 58.4 +/- 2.3 years) with stenoses >75% in coronary arteries according to angiography data and hypercholesterolemia (main group). Control group comprised 15 healthy volunteers. Circulating EPC in peripheral blood were evaluated by cytofluorimetry. Functional parameters of isolated EPC were assessed after cultivation in human fibronectin. Adhesive properties were studied in cell culture by immunehistochemical method after 7 days of incubation. Proliferation capacity was assessed by number of EPC in 1 mm3 of medium at day 7 of incubation. Determination and counting of AE was carried out using cytofluorimetry with immunostaining of cells by anexin B and CDA31 after preliminary treatment of endotheliocyte culture with H2O2 and comparing the results with control culture of endotheliocytes. Number of circulating EPC in patients with IHD was 58.% less than in healthy persons. Adhesive capacity of EPC in patients with IHD was lowered by 43%. Number of EPC surviving in cell culture was 80.9% less than in control group. At the same time number of circulating AE in patients with IHD was 2.5 times greater. Reduction of number of EDC, adhesive capacity, and rise of number of AE correlated significantly with number of involved coronary arteries, presence of diabetes, and smoking status. Presence of arterial hypertension and blood cholesterol level did not correlate with quantitative and qualitative parameters of EPC. Thus qualitative and qualitative parameters of circulating EPC and apoptotic cells can be considered as markers of dysfunction of endothelium and predictors of atherosclerotic vascular lesions in patients with hypercholesterolemia. PMID- 21591390 TI - [Some markers of endothelial dysfunction in patients with type 1 diabetes mellitus and ketoacidosis]. PMID- 21591391 TI - [Neonatal gastroenteritis triggers long-term cardiomyocyte atrophy, remodeling and irreversible hyperpolyploidization]. AB - Growth retardation, inflammation and cardiac overload in early childhood are linked with hypertension and infarction in adults. This link was termed as developmental programming. Exact mechanisms and critical time frames for development of the heart are still unknown. To elucidate these questions, we developed a model of moderate cryptosporidial gastroenteritis triggering main programming factors. Sliding the time point of infection day by day (from day 4 to day 18), we tested complete rat neonatal period. Also, we repeated all experiments 30 days after infection. Using methods of cytometry, immunocytochemistry and confocal microscopy, we compared sensitivity of ventricular cardiomyocyte shape, protein content and ploidy. Our data indicated that gastroenteritis lasting four days triggered cardiomyocyte atrophy, almost doubling cell length to width ratio, and premature and excessive polyploidization. Surprisingly, nucleus and cytoplasm reacted to the disease differently. Cardiomyocytes accumulated genomes only when the disease covered the time period between 6 and 14 days after birth, when cells substitute proliferative growth with hypertrophy. Contractile proteins and cell shape on the contrary, showed high sensitivity in the course of complete neonatal period. After restoration, ploidy did not regress, whereas cell shape and protein content revealed moderate restoration. Taking into account that somatic polyploidy is irreversible and that it alters global gene expression pattern, we may suggest that genome duplication is one of the instruments of developmental programming and that gastroenteritis is one if the triggers of this programming. PMID- 21591392 TI - [Acute and postponed action of adriamycin on the contractile function and antioxidant status of the myocardium]. AB - Functional, biochemical and morphological studies of rat cardiac muscle after single injection of adriamycin (2.2 mg/kg) were carried out. The myocardium was taken for studies in 2 hours and in 2-3 weeks after adriamycin injection. The isolated heart was perfused retrogradely with Krebs solution and left ventricular isovolumic pressure and perfusion pressure were continuously monitored. Two-fold increase in perfusion rate was accompanied by raised developed pressure, heart rate and perfusion pressure which in the given conditions reflected a tone of coronary vessels. The cardiac contractile function of rats that received adriamycin 2 hours before, remained unaltered as compared to control group, however, perfusion pressure was raised by 26%. These hearts responded to H2O2 introduction (100 microM) into coronary vessels by more profound fall in developed pressure, which fell to 31 +/- 8% after 40 minutes vs. 61 +/- 5% in the control group (p<0.01). In two-three weeks after adriamycin injection, both cardiac contractile function and its responsiveness to oxidative stress induced by H2O2 introduction did not differ from the control, however, perfusion pressure remained elevated and this was accompanied by slowed myocardial relaxation. The myocardial concentration of malonic dialdehyde was moderately increased in adriamycin-treated group in both terms while the activity of antioxidant enzymes (SOD, GPHx and catalase) remained unaltered. Results showed an absence of the direct connection between myocardial antioxidant status and the contractile function changes at adriamycin action. PMID- 21591393 TI - [Independent predictors of deep vein thrombosis (results of prospective 18 months study)]. AB - We followed for 18 months 90 patients who had had deep vein thrombosis (DVE) and/or pulmonary embolism (PE) and received therapy with anticoagulants either for 3-12 months or for indefinitely long time. During follow-up rate of recurrent DVE was 16.7%, no recurrences of PE were registered. Predictors of recurrent PE were selected among 165 demographic, anthropometric, anamnestic, clinical, genetic, instrumental, and laboratory parameters, as well as risk factors of development of thromboembolic complications. According to results of multifactorial regression analysis we established the following independent predictors recurrent DVE during 18 months of follow-up: elevated level of DAdimer after 1 month of anticoagulant therapy (p=0.005; relative risk--relative risk [RR] 8.1, 95% confidence interval [CI] 1.9 to 34.8), homozygosity for C249T polymorphism in beta-fibrinogen gene (p=0.044; RR 8.4 95% CI 1.1 to 65.7), and percentage of all values of international normalized ratio within therapeutic interval 2.0-3.0 (p=0.009; RR 0.94, 95 CI 0.89 to 0.98). PMID- 21591394 TI - [Drug correction of hormonal disturbances and risk factors of cardiovascular complications in women of reproductive age with polycystic ovary syndrome]. PMID- 21591395 TI - [Interrelationship between antibodies to enzymes of antioxidant system and cardiac involvement in patients with systemic scleroderma]. AB - In blood of patients with systemic scleroderma we detected antibodies to the antioxidant system enzymes. Level of specific immunoglobulins rose with increase of the disease activity. Antioxidant system of the body is represented by a number of enzymes called to negate pathogenic effect of active forms of oxygen. In pathological states balance between factors of aggression and defense is disturbed. This leads to even more deep damage of tissues. Taking into consideration important role of immunological shifts in development of atherosclerosis one can suggest that autoantibodies to enzymes represent one of mechanisms of derangement of the work of enzymatic systems. Significantly higher levels of antibodies were detected in patients with symptoms of involvement of the cardiovascular system. We measured blood serum antibodies according to elaborated by us method of indirect immuno enzyme analysis with the use of immobilized antigenic forms of enzymes. PMID- 21591396 TI - [Nitrous oxide and atherosclerosis. Pharmacotherapy of atherosclerosis and nitrous oxide]. PMID- 21591397 TI - [Russian National Congress of Cardiology, 5-7 October, 2010]. PMID- 21591398 TI - [Evolution of oral drug forms of metoprolol: advantages of long acting modified release forms with modified release]. AB - Review oral modified release drug forms of beta-adrenoblocker metoprolol which is used in arterial hypertension and ischemic heart disease is presented. Metoprolol has salts such as tartrate which is used for production of immediate release (IR) and sustained release (SR) forms and succinate used for production of controlled release form (CR/XL). Metoprolol SR has monolith matrix type, metoprolol CR/XL system of multiple pellets. Effect of metoprolol tartrate (IR) on mortality was demonstrated in a number of studies in patients with arterial hypertension (AH) (MAPHY), myocardial infarction (SMT, GMT, MIAMI), dilated cardiomyopathy and heart failure (MDC). Studies of efficacy of metoprolol SR are scarce. Antihypertensive efficacy of metoprolol SR in patients with AH did not exceed that of a metoprolol IR or CR/XL. First retrospective analysis of efficacy of metoprolol tartrate and succinate (CR/XL) in patients after myocardial infarction allowed to obtain comparable results of 34% mortality lowering. In a prospective study in patients with chronic heart failure (COMET) metoprolol tartrate IR was not superior to carvedilol when mortality lowering was concerned. At the same time administration of controlled release metoprolol (CR/XL) in 2 large clinical trials (RESOLVD, MERITAHF) was advantageous in patients with chronic heart failure relative to lowering of mortality and rate of hospitalizations. A novel controlled release form of metoprolol has been created as a tartrate salt on the basis of pellet technology (CD/ERT) and its bioequivalence to metoprolol CR/XL has been proved. PMID- 21591399 TI - [Inhibitors of HMG-Co-A reductase (statins) in the treatment of dyslipidemia and atherosclerosis at the turn of decades]. PMID- 21591400 TI - [Spontaneous coronary artery dissection]. PMID- 21591401 TI - [A case of Asperger's disorder with catatonia originally suspected of being catatonic schizophrenia]. AB - We report the case of an adolescent male who presented with mutism, immobility, catalepsy, and mannerisms. The patient was admitted to our hospital with suspected catatonic schizophrenia; however, he was subsequently diagnosed with catatonia due to Asperger's disorder. The patient was a 16-year-old male. More than six months before presentation, his grandfather displayed bizarre and violent behavior. Subsequently, he began to experience catatonia, which eventually led to hospitalization. Treatment with diazepam improved his condition and, as no causal disorders other than Asperger's disorder were identified, he was diagnosed with catatonia. The patient had experienced persistent abuse by his mother during childhood; therefore, it is important to consider reactive attachment disorder (DSM-IV-TR) as a differential diagnosis. Among child and adolescent psychiatrists, catatonia is considered to occur at a high frequency among patients with autistic spectrum disorders. In contrast, general psychiatrists tend to consider catatonia as related to schizophrenia, which may be the reason why the diagnosis of our patient was difficult. We assume that the pathogenesis of catatonia in this case was death mimicry due to the subjective perception of a life-threatening situation. For the treatment of catatonia with autistic spectrum disorders, the efficacy of benzodiazepines and electroconvulsive therapy has been established. When a patient with an autistic spectrum disorder presents with motor functional disturbances, it is important to consider these disturbances as catatonia. Furthermore, it is also important to begin the treatment mentioned above even in the presence of definite psychogenic or situational factors. PMID- 21591402 TI - [Considering residency programs in psychiatry in a private hospital]. AB - Postgraduate education in psychiatry is comprised of three years of residency training. The residency program consists of Post-Graduate Year One (PGY-1), Post Graduate Year Two (PGY-2), and Post-Graduate Year Three (PGY-3). Psychiatry residents must write case reports in order to be accredited as mental health physicians by the Ministry of Health, Labour and Welfare, and to be psychiatric specialists of the Japanese Society of Psychiatry and Neurology. A residency training administration committee coordinates residency programs, residency training leadership, and the invitation of residents. It is crucial that hospital faculty members interact with residents. PMID- 21591403 TI - [Views on the new psychiatric specialist certification system from the perspective of those experiencing the postgraduate psychiatric training system in Japan]. AB - The psychiatric specialist certification system of the Japanese Society of Psychiatry and Neurology was established in 2005, with a transitional period that ran until 2008. A three-year postgraduate training scheme was started in connection with the new psychiatric specialist certification system, and the first formal examination under the new system was held in 2010. A resident desiring certification as a psychiatric specialist must purchase a psychiatric specialist certification handbook and present it when taking the examination. There are many differences between the new examination and the transitional period examination, in terms of both the handbook and the number of case reports to be submitted. Results of a survey conducted on 360 psychiatrists belonging to either university or national hospitals, all of whom had undergone psychiatric training within the past eight years, revealed that there was currently a lack of knowledge, and low rate of utilization, of the handbook. The primary author was in the first cohort of those who began postgraduate psychiatric training in a university hospital and subsequently took the first examination administered after the transition period. The author has maintained that, based on personal experience, a number of issues need improvement, such as the large number of grading items to be signed off on by supervising psychiatrists, and complications involving the outline of cases to be experienced. Additionally, it was thought to be difficult for supervisors who had obtained their specialist certification via the transitional period examination to have an adequate understanding of the outline of the new examination. Therefore, it is important that residents themselves take a more assertive attitude to becoming specialists. In the future, in order to establish a sound specialist certification system, the results of this survey of physicians who took the new examination should be taken into account. PMID- 21591404 TI - [Approach to side effects of psychotropic drugs by a team]. AB - Providing safer and more effective medication is the mission of a clinical pharmacist. A clinical pharmacist will never succeed in this mission if medicines are dispensed without considering these objectives. Clinical pharmacists must audit prescriptions, and they have a duty to inquire with the physician if anything warrants clarification. In other words, clinical pharmacists cannot function without collaboration by physicians. It is well known that antipsychotic drugs can induce various side effects, such as extrapyramidal symptoms and autonomic nervous system dysfunction. Such side effects were reported in 23.7 percent of 1123 patients treated with psychotropic medicines in general medicine wards, in a survey conducted by the Japanese Society of Hospital Pharmacists. Side effects are detrimental to patients' quality of life and indirectly affect their medication adherence rate. The physicians, pharmacists, nurses, and occupational therapists at the hospital where this study was conducted are researching these problems, with a particular focus on extrapyramidal symptoms. This study describes their efforts and discusses collaboration with physicians from a clinical pharmacist's perspective. PMID- 21591405 TI - [Further challenges in collaboration and cross-specialization work in psychiatric services]. AB - Using a case illustrating cognitive behavioral treatment for a patient with obsessive-compulsive disorder, clinical tips and challenges are described in the context of collaboration between multiple health professionals from different backgrounds in a psychiatric hospital. Furthermore, after reviewing the current status of education and training issues related to collaboration, and introducing the fundamental concept of cross-specialization work, existing tasks and future challenges involved in the education and training of multiple health professions are discussed. PMID- 21591406 TI - [Psychiatric occupational therapy practice in Shinshu University Hospital- collaboration with psychiatrist]. AB - This report describes psychiatric occupational therapy practice and collaboration between occupational therapists and psychiatrists at Shinshu University Hospital. Collaboration with psychiatrists enables us to provide the following occupational therapy programs. (1) Individual occupational therapy approaches for patients at the early recovery stage in the psychiatric ward. (2) Psychoeducational interventions by a multi-disciplinary team (MDs, nurses, OTRs, PSWs, CPs). (3) Occupational therapy approaches used in combination with m-ECT for severe psychiatric disorders. (4) Recovery support programs for psychiatric outpatients. It is suggested that occupational therapists should collaborate with psychiatrists in order to facilitate rehabilitation services for people with psychiatric disorders. PMID- 21591407 TI - [The development of the ICD-11]. AB - The ICD-10 will have been used for approximately twenty years by the time the new revision of the ICD (ICD-11) is completed, and the revision process is being implemented. Accordingly, the WHO has organized groups of experts designated to deal with issues in each field, and the International Advisory Group for the Revision of ICD-10 Mental and Behavioral Disorders has been launched for the field of psychiatry. Regarding the revision, this group is responsible for ultimate decision-making in establishing a framework for the new version. We reported processes of the ICD-11 by the above mentioned group and its coordinating groups and working groups. In addition, we reported the WHO-WPA Survey which was distributed to 500 members of the Japanese Society for Psychiatry and Neurology. PMID- 21591408 TI - [Flow of basic life support and advanced cardiovascular life support in cardiopulmonary resuscitation and emergency cardiovascular care]. PMID- 21591409 TI - [The impact of 2010 international consensus on CPR and ECC science with treatment recommendations on Japan]. AB - New guidelines on cardiopulmonary resuscitation(CPR) and emergency cardiovascular care (ECC) were published in October 2010 from International Liaison Committee on Resuscitation (ILCOR). Changes of these guidelines will have dramatic effects on Japan. Starting with chest compressions first will increase by-stander CPR. Cases of recovery of spontaneous heartbeat could increase as a result. Intensive care and radical treatments for cardiovascular emergency and brain damage after cardiopulmonary arrest would be essential. Education, implementation and teams (EIT) will be the third subject. PMID- 21591410 TI - [Historical review from beginning of CPR to CPCR (cardiopulmonary resuscitation to cardiopulmonary-cerebral resuscitation)]. AB - This 2010 is a memorial year for CPR, as in 1960 closed chest cardiac massage was first introduced in clinical setting. Jude, Kouwenhoven are the pioneer of this method. However, Prof. Peter Safar was also distinguished pioneer of articial respiration and airway management. Manual chest compression is not efficient to maintain oxygenation and impossible to airway patent. Applying both respiration by mouth-to-mouth breathing and closed chest cardiac massage, it started the new era of CPR. CPR has been expanded to every countries, however, it has not been successful to obtain a good survival rate in out -of-hospital cardiac arrest. BLS is the most important to increase the survival rate. It is the problem how to recover brain function after cardiac arrest then followed with recovery of spontaneous circulation. Brain oriented resuscitation is the target for CPR. Chain of survival is still very useful to treat cardiac arrest. Post cardiac arrest syndrome should be well recognized and hypothermia therapy is introduced as one of the best treatment. PMID- 21591411 TI - [New evidences in the 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care with Treatment Recommendations]. AB - Key changes in Guideline 2010 by Japanese Resuscitation Council were described and the reasons of the change were explained based on 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care with Treatment Recommendations. In BLS, the value of chest compression was further emphasized and it became an initial skill of CPR In ALS, post resuscitation care was systemized by incorporating hypothermia, PCI, and other diagnostic and therapeutic modalities. Indication of hypothermia was further expanded to non-VF categories. Use of AED was expanded to infant. Education, Implementation and Teams were newly included as a chapter to promote the knowledge and skill of resuscitation science into the society. PMID- 21591412 TI - [BLS in adults]. AB - This manuscript expresses viewpoints on future pre-hospital care, mainly focusing on basic life support (BLS) by ambulance crew at emergency scenes, following recommendations of G2010. Ambulance workers need to have an ability to decide instantly "what you can do now to others" in every emergency scenes. Also it is necessary to always treat patients with the spirit of "generosity". PMID- 21591413 TI - [Pediatric basic life support]. AB - The new international consensus and guidelines were published by American Heart Association in October 2010. These guidelines include many important changes in pediatric basic life support(BLS) based on many evidences. Especially in children, asphyxial cardiac arrest has been more common than cardiac arrest and only one third to one half victims can receive bystander cardiopulmonary resuscitation(CPR). According to new guidelines, "CAB" (Chest compressions/Circulation, Airway, and Breathing/ventilation) is recommended instead of "ABC" sequence. In addition, pediatric chain of survival is revised and the section of "Look, Listen, Feel" is deleted. These changes are recommended in order to simplify training with the hope that more pediatric victims will consequently receive bystander CPR. PMID- 21591414 TI - [Advanced cardiovascular life support in AHA Guidelines 2010: Key changes from Guidelines 2005]. AB - In cardiopulmonary cerebral resuscitation (CPCR), advanced cardiovascular life support(ACLS) is a part of "chain of survival" and effects on resuscitation outcome as the interventions which increase the likehood of ROSC and as the continuing step to the post -cardiac arrest care. In order to build effective ACLS intervention, quality of basic life support is essential throughout the resuscitation effort. Based on quality CPR, ACLS providers should optimize the outcome by the integrated strategy that is consist of appropriate "drug therapy", qualified"advanced airway management", and accurate "physiologic monitoring". In this article, ACLS in American Heart Association(AHA) 2010 guidelines was reviewed and key changes from the 2005 guidelines are extracted. Not only guideline itself but training designed on the valid recommendations of guidelines are important to achieve competency of ACLS teams and better outcome of resuscitation. PMID- 21591415 TI - [Pediatric advanced life support]. AB - Important changes or points of emphasis in the recommendations for pediatric advanced life support are as follows. In infants and children with no signs of life, healthcare providers should begin CPR unless they can definitely palpate a pulse within 10 seconds. New evidence documents the important role of ventilations in CPR for infants and children. Rescuers should provide conventional CPR for in-hospital and out-of-hospital pediatric cardiac arrests. The initial defibrillation energy dose of 2 to 4J/kg of either monophasic or biphasic waveform. Both cuffed and uncuffed tracheal tubes are acceptable for infants and children undergoing emergency intubation. Monitoring capnography/capnometry is recommended to confirm proper endotracheal tube position. PMID- 21591416 TI - [Percutaneous cardiopulmonary support (PCPS)]. AB - The percutaneous cardiopulmonary support (PCPS) allows maintaining the patient's cardiac and pulmonary status with low cardiac or pulmonary performance due to acute myocardial infarction, pulmonary thromboembolism, postoperative phase of great blood vessels/open heart surgery or percutaneous coronary intervention, and so on. This system consists of a centrifugal pump with its control system, membrane oxygenator, measure devices for blood flow and pressure and a heating system for temperature conditioning of blood. The potential effectiveness is suggested using PCPS for cardiopulmonary resuscitation(CPR), so called extracorporeal cardiopulmonary resuscitation(ECPR). The single center studies suggesting the utility of ECPR appear, but ECPR is contents to have possibilities to improve prognosis in limited adaptation because there is not yet enough evidence in CoSTR 2010 by ILCOR. However, multicenter study about the utility of ECPR used PCPS for the out-of-hospital cardiac arrest(Study of Advanced life support for Ventricular fibrillation with Extracorporeal circulation in Japan: SAVE-J) is started in April 2007, and it is said that ECPR may improve neurological outcome comparing with that of the conventional CPR by the interim report. Further studies will determine its efficacy and adequate criteria. PMID- 21591417 TI - [Therapeutic hypothermia]. AB - The International Liaison Committee on Resuscitation (ILCOR) recommended therapeutic hypothermia treatment as follows. Comatose adult patients with spontaneous circulation after out-of-hospital VF cardiac arrest should be cooled to 32 to 34 degrees C for 12 to 24 hours. Induced hypothermia might also benefit comatose adult patients with spontaneous circulation after out-of-hospital cardiac arrest from a nonshockable rhythm, or cardiac arrest in hospital. Therapeutic hypothermia may be beneficial for adolescents who remain comatose following resuscitation from sudden witnessed out-of-hospital VF cardiac arrest, and may be considered for infants and children who remain comatose following resuscitation from cardiac arrest. Newly born infants born at or near-term with evolving moderate to severe hypoxic-ischemic encephalopathy should be offered therapeutic hypothermia. PMID- 21591418 TI - [Application of hyperbaric oxygen therapy for post-cardiac arrest syndrome]. AB - Therapeutic mechanisms of hyperbaric oxygen therapy (HBOT) are based on elevation of both the partial pressure of oxygen and hydrostatic pressure. It has been reported that HBOT supply much amount of oxygen and might prevent from brain tissue after global ischemia in patients with post-cardiac arrest syndrome(PCAS). On the other hand, high levels of oxygen produce reactive oxygen species(ROS). ROS occurs secondary brain damage after ischemia. The clinical evidence of HBOT has not been established. In this paper, we review some reports about the advantages and disadvantages of HBOT after global ischemia with PCAS. PMID- 21591419 TI - [Consideration of early rehabilitation in the treatment of post-cardiac arrest syndrome]. AB - Resumption of spontaneous circulation (ROSC) after cardiac arrest is an unnatural pathophysiological state. In 2008, ILCOR has proposed "post-cardiac arrest syndrome (PCAS)". Clinicians must focus on treating to reverse the pathophysiological manifestations of PCAS in bed. Immobility, deconditioning, and weakness are common problems in patients with critical illness. Therapeutic strategies have to be identified to give patients after ROSC the best chance for survival with good neurological function. Concerning the beneficial effects of early mobilization after stroke, and the efficacy of a strategy for whole-body rehabilitation in the earliest days of critical illness on functional outcomes, the intervention of early rehabilitation care by an interdisciplinary team seems to contribute to good long-time outcome of post-cardiac arrest patients. PMID- 21591420 TI - [CPR education in Japan--past, present and future]. AB - the last 7 years, more than 300,000 automated external defibrillators(AEDs) installed nationwide in Japan, and at least one AED has placed in 38,634 schools. Therefore, only 0.7% of bystanders used the AEDs(By-AED) in all OHCA cases with th 48 % of ROSC. In recent years, elementary and junior high school student has interested in AED results in each school has at least one AED. Therefore, introduction of CPR education starting from elementary school was extremely important. CPR education is not yet ubiquitous, and the promotion of AEDs and CPR education on a nationwide scale remains an urgent issue. Therefore, to solve this problem, we investigated the status of CPR education in schools teachers. We conducted surveys targeting for school teachers in Tokyo. Question; "What age do you think suitable for CPR training ?" Most of teachers answered"Suitable age for start CPR education from the upper grades of elementary school to a junior high school". Reason is, physically, continuous high quality chest compression could performed age of junior high. However, 'Importance of life' could teach from lower grade of elementary school because of child have a good long time memory. In this reason, CPR education is extremely important. Also teachers need 'more time', 'curriculum for CPR education and 'good CPR instruction tool for teaching'. The solution to teacher's request, we prepared follows. A 90 minutes hands only CPR curriculum should be introduced to elementary school CPR for basic CPR education. CPR +AED education should be started in lower grade of elementary school with AED trainer. In conclusion, school CPR programs are extremely important for awareness both in skill and knowledge of CPR among the entire school. Future research is warranted to improve the resuscitation rate by school CPR program. PMID- 21591421 TI - [The basic life support guidance of American Heart Association (AHA)]. AB - The American Heart Association (AHA) and other member councils of International Liaison Committee on Resuscitation (ILCOR) complete review of resuscitation science every 5 years. And ILCOR publishes Consensus on Science with Treatment Recommendations(CoSTR). The AHA published "American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation(CPR) and Emergency Cardiovascular Care (ECC)" (G2010), that basis on CoSTR 2010 on Oct. 18th, 2010. The switchover to new curriculum based on G2010 on and after Mar. 1st, 2011 is the policy of AHA in their all training courses. The AHA maintains the quality of their training courses by some systems. AHA instructors are trained by some steps of instructor courses and monitoring systems and update their scientific knowledge on resuscitation by e-learning. The authors introduce an outline of basic life support for healthcare providers, the instructor training systems of AHA and summary of basic life support basis on G2010. PMID- 21591422 TI - [A schema of PALS provider course and a role of the instructors; from 2005 to 2010]. PMID- 21591423 TI - [Immediate Cardiac Life Support (ICLS) course developed by Japanese Association for Acute Medicine]. AB - The Immediate Cardiac Life Support (ICLS) course was developed and launched by Japanese Association for Acute Medicine (JAAM) for resident training, in April 2002. The ICLS course is designed as multi-professional one-day (8 hours) resuscitation course and teaches the essential skills and team dynamics required to manage a patient in cardiac arrest for 10 minutes before the arrival of a cardiovascular specialist. The course consists of skill stations and scenario stations. The skill stations provide basic life support (BLS) with automated external defibrillator (AED), basic airway management and in-hospital management with electrocardiographic (ECG) monitoring with manual external defibrillator. In total, 117,246 candidates attended 6,971 ICLS courses until the end of December 2010. Furthermore, we developed additional course of ICLS to manage stroke, Immediate Stroke Life Support (ISLS). We also describe the development and structure of, and rationale for the ICLS course. PMID- 21591424 TI - [Handling of automated external defibrillator (AED)]. AB - It is medical equipment in "Advanced managed care equipment and specific maintenance medical equipment" for around and the life support though is thought that AED operates if it always turns on power like the television not used by the sense like home appliance as a result of spreading in general widely. It is management that it is important to always check the expiration date etc. of the indicator and the articles of consumption of AED to use it at any time when AED is set up, and requested by those who set it up. PMID- 21591425 TI - [Usage of a defibrillator]. AB - Guideline 2010 for cardiopulmonary resuscitation was released the other day. There is no big change in the use of a defibrillator. Asynchronous defibrillation is used as a therapy for VF and pulseless VT. When you find a patient, start CPR immediately and prepare a defibrillator. About the value of energy, comply a recommended value of defibrillator's manufacturer with biphasic waveform, on the other hand, deliver 360J shock with monophasic waveform. Cardioversion is used as a therapy for supraventricular arrhythmia like atrial fibrillation. It is important to synchronize with QRS complex on ECG surely and deliver a shock. If it is not synchronized surely, there is a possibility to occur VF. Transcutaneous pacing is used as a therapy for bradycardia. It produces a depolarization of myocardium by giving current stimulus from a surface of a body, and force a heart to contract. It is usually carried out at demand mode, and confirmed that a heart contracts certainly. Defibrillator is an only device to terminate VF and pulseless VT and it is important to test defibrillator usually so that it can be used any time it is necessary. PMID- 21591426 TI - [Implementation and management of cardiopulmonary support system]. AB - The cardiopulmonary support with percutaneous cannula and centrifugal pump (percutaneous cardiopulmonary support, PCPS) has been applied to the cardiac arrest patient. Since the introduction of it, PCPS has made many improvements as it is assisted by maneuverable closed circuit with centrifugal pump, and the invention of thin-wall cannula also supported the development of it. Now, PCPS is utilized as cardiopulmonary support for resuscitation. A combination of PCPS and intra-aortic balloon pumping(IABP) reduces afterload and promotes adequate organ perfusion. This manuscript describes attachment to PCPS and IABP, and methods of management. It is continue to be important to have a thorough knowledge of these devices, of which there is the increase in use frequency. PMID- 21591427 TI - [Monitoring of jugular venous oxygen saturation]. AB - The continuous monitoring of jugular venous oxygen saturation(SjO2) has become a practical method for monitoring global cerebral oxygenation and metabolism. SjO2 reflects the balance between the cerebral blood flow and the cerebral metabolic rate for oxygen (CMRO2), if arterial oxyhemoglobin saturation, hemoglobin concentration remain constant. Normal SjO2 values range between 55% and 75%. Low SjO2 indicates cerebral hypoperfusion or ischemia. Conversely, an increased SjO2 indicates either cerebral hyperemia or a disorder that decreases CMRO2. In minimizing secondary brain damage following resuscitation from cardiopulmonary arrest, SjO2 monitoring is thus considered to be an integral part of multimodality monitoring and can provide important information for the management of patients in neurointensive care. PMID- 21591428 TI - [Intracranial pressure monitoring of cerebral resuscitation]. PMID- 21591429 TI - [Statistics concerning patients of out-of-hospital cardiac arrests in Japan]. AB - The Fire and Disaster Management Agency (FDMA) of Japan started a nationwide, population-based, cohort study in 2005 and keeps collecting the ambulance transportation records of out-of-hospital cardiac arrests in Japan based on the standardized Utstein style. By analyzing the outcomes of bystander-witnessed arrests among patients who had ventricular fibrillation and arrests, the rate of survival at 1 month is 11.4% and the rate of survival with minimal neurologic impairment at 1 month is 7.1%. The rate of survival at 1 month and the rate of survival with minimal neurologic impairment at 1 month are improved by bystander (family member or other) CPR, early CPR by EMS personnel, and the administration of a shock with the use of a public-access AED. It is important to improvement the ambulance service system by using these statistical data. PMID- 21591430 TI - [Current situation and future scope of the cardiopulmonary cerebral resuscitation in Japan]. AB - New guidelines for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC) were released in October 2010. The 2010 Guidelines changed a core concept of basic life support from traditional A-B-C (Airway, Breathing, Chest compressions) procedure to C-A-B (Chest compressions, Airway, Breathing) procedure. In the change of concept, it is emphasized that rescuer should start CPR with chest compression immediately. Japanese researchers contributed to the revision of the guidelines from a stage of establishment of a CoSTR(2005 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations) which gives the guidelines theoretical evidences. It is expected for us to promote resuscitation science even in traditional theoretical field but also in the field of education, implementation, and team approach. PMID- 21591431 TI - [Medical ethics in terminal stage viewed from emergency and critical care in Japan]. AB - In Japan, several types of the proposal for terminal care have been published by Medical Association, Ministry of Health, Labor and Welfare, etc. Among them, the guidelines proposed by Japanese Association for Acute Medicine (JAAM) are appreciated as most concretely expressed ethically as well as practically regarding the judgment of terminal stages, the medical ethics needed through the processes thereafter and the methods on withdrawal or withholding in terminal care. The author explained and considered the terminal care provided by medical professionals for the absolutely desperate including the brain dead following post-cardiac arrest syndrome for instance, according to the guidelines by JAAM. The best practice selected for the terminally ill ought to be reasonable and suitable from the aspects of both medical science and ethics. PMID- 21591432 TI - [Progress and perspectives in treatment of chronic hepatitis B]. AB - In Japan there are four approved anti-hepatitis B virus drugs available. Interferon has both antiviral and immune-modulatory effects. When it is effective, the durable treatment responses can be obtained. Three nucleoside and nucleotide analogues, lamivudine, adefovir, and entecavir, are potent oral inhibitors of HBV replication and well-tolerable. Though these drugs have greatly improved clinical course of chronic hepatitis B, it is still difficult to eradicate HBV from carriers. Several trials of combination of nucleoside analogues and interferon have been reported and some showed improved treatment responses. Further studies are needed to explore the best way to combine several drugs or to discover new anti-HBV drugs. PMID- 21591433 TI - [Association between hemostasis/coagulation-system parameters and clinicopathological factors in patients with primary lung cancer]. AB - Previous studies have gradually clarified the relationship between cancer and blood coagulation disorder and its mechanism. Various studies have also reported the association between lung cancer and coagulation disorder. However, it is rare to measure most hemostasis/coagulation-system test parameters in clinical practice. In this study, we investigated the association of hemostasis/coagulation-system test parameters, such as the prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time, and platelet count, which are routinely measured as preoperative examination parameters in patients with lung cancer, with the histopathologically evaluated stage of lung cancer. Although the mean values of hemostasis/coagulation-system parameters in all subjects were within the normal ranges, there were significant changes with respect to the clinico-pathological factors, showing a specific tendency. In patients in whom the histopathological stage was advanced, the APTT was prolonged, or the platelet count was increased. PMID- 21591434 TI - [Full-thickness resection of the focus site for adolescent idiopathic ventricular tachycardia]. AB - We present a case of a 14-year-old male with incessant idiopathic ventricular tachycardia for which both pharmacological and catheter ablation treatments failed. Curative surgery was performed on this patient. By intraoperative epicardial isochronous mapping, arrhythmogenic focus was identified in the right ventricular infundibulum between the large conus branch and the proximal right ventricular coronary branch. After cryoablation both from the epi- and endo cardial sides failed to terminate the arrhythmia, subsequent full-thickness resection of the identified focus was performed. There was no postoperative recurrence of tachyarrhythmia In idiopathic ventricular tachycardia, arrhythmogenic focus is not always situated on the endo- or epicardial side. Full thickness resection of the focus site might be necessary in such patients as we experienced this time. PMID- 21591435 TI - [Surgical treatment of postinfarction ventricular septal rupture]. AB - BACKGROUND: Postinfarction ventricular septal rupture (VSR) is a lethal complication with high mortality. The aim of this study was to evaluate our surgical strategy and results of VSR. PATIENTS AND METHODS: Between 1996 and 2008, 13 consecutive patients underwent operation for VSR at our hospital. All patients required emergent operation because of severe cardiogenic shock. Surgical procedure consisted of endocardial patch repair with infarct exclusion, so called "Komeda-David operation". In patients with multiple coronary artery disease, myocardial revascularization was done simultaneously. RESULTS: These patients were divided into 2 groups according to the location of VSR. There were 9 patients of anterior VSR. Two of them could not be weaned from cardiopulmonary bypass and died of severe low output syndrome (LOS) at early postoperative period. The site of infarction in both patients was broad anteroseptal region including right ventricle. On the other hand, there were 4 patients of inferior VSP. Two of these patients were lost due to LOS. One patient was complicated with left ventricular free wall rupture. In another patient, infarction was extended proximally toward the mitral annulus and papillary muscles. Both cardiopulmonary bypass time and aortic crossclamp time were significantly longer in inferior VSR than in anterior region. There was no late death in 2 groups. CONCLUSIONS: Despite improvements of surgical procedures, such as infarct exclusion technique, the operative mortality remains high in cases with broad infarction and/or right ventricular infarction. In these particular circumstances, in should be mandatory to consider the optimal timing of operation and the modification of surgical technique itself. PMID- 21591436 TI - [Surgical therapy for left ventricular pseudoaneurysm]. AB - Left ventricular pseudoaneurysm is a rare complication of myocardial infarction. However, the risk of rupture and heart failure are high, especially in a case of rapidly expanding aneurysm. As for left ventricular pseudoaneurysm, the risk of operation is high, and the long-term results are not good. We experienced 2 cases The 1st case was lost due to methicillin-resistant Staphylococcus aureus (MRSA) pneumonia The 2nd case is alive and has been free from heart failure for 3 years. The early diagnosis and surgery is necessary for a pseudoaneurysm. PMID- 21591437 TI - [Bronchial injury due to double-lumen endobronchial tube]. AB - A 68-years-old and 148 cm tall female with lung cancer was operated on a left lower lobectomy via posterolateral thoracotomy. A 35 Fr double-lumen endobronchial tube was smoothly inserted and the tip was placed in the left main bronchus whose position was confirmed by fiberoptic bronchoscope. After lobectomy and lymph node dissection were completed, 1-lung ventilation was terminated, the left chest cavity was filled with saline, and an air-leak test was performed. Immediately after the initiation of bilateral lung ventilation, massive air-leak was observed in the left hilar region and the saline in the chest regurgitated into the airway, and she fell into critical ventilatory insufficiency. After sucking the saline in the chest, thorough observation revealed a 3 cm-long rupture of the membranous portion of the left main bronchus. The rupture was manually occluded and ventilatory insufficiency was avoided, then the tip of the endobronchial tube was re-inserted into the right main bronchus and right single lung ventilation was initiated. The rupture was closed by a 4-0 polydioxanone (PDS) running suture with no coverage. The patient was extubated immediately after the operation. Ten days later, she had a tiny bronchial fistula, and it was cured by chest drainage only, and she discharged home on the 48th postoperative day. PMID- 21591438 TI - [Median re-sternotomy for aortic valve re-replacement assisted by video-assisted thoracic surgery]. AB - Cardiac reoperation via a median re-sternotomy is associated with a high risk of injury to cardiac structures and the great vessels, and may result in massive bleeding. We report a case of aortic valve re-replacement, and severe adhesion was suspected between the sternum and the left brachiocephalic vein by preoperative computed tomography (CT) scans. To avoid injury to the vein, the adhesive tissue was dissected under video-assisted thoracic surgery (VATS). Then median re-sternotomy was performed safely, and the aortic valve was replaced again. The patient's postoperative course was uneventful. Since sternal adhesions are checked and dissected visually, concomitant VATS might be a very useful option after previous cardiac surgery. PMID- 21591439 TI - [One-stage coronary artery bypass grafting and revascularization in a patient with ischemic heart disease and arteriosclerosis obliterans]. AB - With the overall increase in ischemic heart disease (IHD), cases combining arteriosclerosis obliterans (ASO) of the lower extremities and IHD are on the rise. Therefore, it is necessary to consider methods and timing of operation. These cases have occasionally large collateral pathways from the internal thoracic artery (ITA) to the femoral artery via the epigastric artery. To prevent irreversible ischemia of the lower limbs after harvesting of ITA, we planned to perform a one-stage operation for ASO-combined IHD. Revascularization of the lower extremities was performed 1st. Subsequently coronary artery bypass grafting with ITA was completed. The operative courses were uneventful. PMID- 21591440 TI - [Application of the lower partial sternotomy approach to patients who may need tracheostomy in the early period after cardiac surgery]. AB - Recent good results of cardiovascular surgery have led to expansion of its indication to elderly patients and patients with serious complications. Such patients may have serious respiratory complications after cardiac surgery and need to undergo tracheostomy relatively early in the postoperative period. Although the full sternotomy approach is the standard in almost all cardiac surgeries, superficial and deep sternal infections are rather common after early tracheostomy in full sternotomy patients. The lower partial sternotomy approach is a safer and more useful procedure in patients who will need tracheostomy in the early period after cardiac surgery. We report on 2 patients who were successfully tracheostomized within a week after cardiac surgery, with a review of the literature. PMID- 21591441 TI - [Subscapular elastofibroma]. AB - Elastofibroma is a tumor that is localized mainly at the subscapular region. We report 2 cases of subscapular elastofibromas. Case 1, 75-year-old woman was seen at the hospital because of a left dorsal tumor. Computed tomography (CT) scan revealed the tumor of 6 cm in diameter in the inferior angle of left scapula. The patient underwent excision of the tumor. Case 2, 90-year-old man underwent excision a tumor of 5 cm in diameter in the inferior angle of right scapula simultaneously with the operation of right lung cancer. Histological examinations showed increased elastic fiber with elastica van Gieson staining. These specimens confirmed the diagnosis of elastofibroma There have been no signs of recurrence after surgery. PMID- 21591443 TI - [Extended thymectomy and intraoperative-intrapleural perfusion hyperthermo chemotherapy for stage IVa invasive thymoma with myasthenia gravis]. AB - A 37-year-old woman diagnosed with ocular myasthenia gravis was referred to our department. Chest computed tomography (CT) showed anterior mediastinal tumor and right pleural dissemination. Extended thymectomy and right intraoperative intrapleural perfusion hyperthermo-chemothrapy (IPHC) were performed. Pathological diagnosis was invasive thymoma type B2 and stage IVa based on Masaoka's classification. The post operative course was uneventful. The patient underwent 4 cycles of adjuvant chemotherapy with doxorubicin, cisplatin, vincristine, and cyclophosphamide (ADOC), and is free from recurrence at 12 months postoperatively. PMID- 21591442 TI - [Surgical resection of a pulmonary pleomorphic carcinoma involving the azygos vein]. AB - We report a case of surgical treatment of pulmonary pleomorphic carcinoma invading the azygos vein. Chest computed tomography (CT) revealed a mass of 6 cm in size, in the upper lobe of the right lung. He underwent the right upper lobectomy and lymph node dissection with combined resection of the involved azygos vein. Histological examination revealed pleomorphic carcinoma (pT3N0M0, stage IIB). The postoperative course was uneventful, and he was alive without recurrence 26 months after the operation. Six cases of pleomorphic carcinoma have been surgically treated between June 2008 and August 2009 in our institute. Early diagnose with complete resection is suggested to be essential in the improvement of survival for this disease based on review of our experience. PMID- 21591444 TI - [Stanford type A acute aortic dissection with congenital complete absence of the left pericardium; report of a case]. AB - A 52-year-old woman who presented with acute onset of chest pain was diagnosed with Stanford type A acute aortic dissection by computed tomography at another hospital. She was referred to our department for emergency surgery. The left pericardium visualized via a median sternotomy was clearly defective, and the left phrenic nerve was located ventral to the defect. The ascending aorta and total arch were replaced with an aortic valve and a prosthetic graft, respectively. Postoperative chest radiography excluded left phrenic nerve palsy. The postoperative course was uneventful and the patient was discharged on postoperative day 17. PMID- 21591445 TI - [Volume reduction surgery for giant coronary sinus with valvular heart disease; report of a case]. AB - A 64-year-old male with giant left atrium and giant coronary sinus, who had aortic valve regurgitation, prosthesis valve paravalvular leakage in mitral position and prosthesis valve malfunction in tricuspid valve position, was successfully treated with double valve replacement, paravalvular leakage repair and volume reduction of left atrium and coronary sinus. Giant coronary sinus was about 70 mm in diameter and was thought to be induced by persistent left superior vena cava, high right atrium pressure and prosthesis valve malfunction in tricuspid valve position. Lung volume was so much increased by volume reduction of left atrium and coronary sinus and patient's symptoms were much improved. PMID- 21591446 TI - [Intermittent opening of a mechanical mitral valve prosthesis due to pannus formation; report of a case]. AB - A 76-year-old woman with a history of severe mitral valve stenosis had undergone mitral valve replacement with a 27 mm St. Jude Medical (SJM) valve in 1991. Follow-up transthoracic echocardiography revealed an increase in the pressure gradient across the mitral prosthesis 16 years after the surgery. Prosthetic valve dysfunction was suspected, but transesophageal echocardiography and cineradiography failed to show mechanical valve dysfunction. Two years later, she presented with dyspnea on exertion and leg edema. Cineradiography revealed intermittent restriction of the opening of the mechanical valve leaflet approximately every 10 beats. Thus, we diagnosed intermittent prosthetic valve dysfunction and performed a reoperation. On inspection of the prosthesis, we observed semicircular pannus formation around the posterior leaflet in the ventricular side. It was considered that the pannus tissue had interfered with 1 leaflet opening of the mitral valve prosthesis, resulting in intermittent valve dysfunction. We replaced the prosthesis with a new 25 mm SJM valve. The patient was discharged after confirmation of normal prosthetic function. PMID- 21591447 TI - [Surgical treatment of iatrogenic cardiac injury induced by pericardiocentesis; report of a case]. AB - We reported a case of surgical treatment of iatrogenic cardiac injury. A 67-year old man with cardiac tamponade was treated by pericardiocentesis. At night he was transferred to our hospital for emergent treatment of shock state. We found the pericardiocentesis drainage tube perforated left ventricle on computed tomography (CT). This perforation was repaired on the beating heart state using 5-0 monofilament mattress sutures reinforced by felt pledgets. Fatal complications might not occur when appropriate procedures are followed during the placement of a catheter for pericardiocentesis. Iatrogenic cardiac injury is rare but nevertheless requires caution. PMID- 21591448 TI - [Three primary cancers of pulmonary cancer, malignant melanoma and esophageal cancer; report of a case]. AB - A 61-year-old man, who had medical history of hepatitis type C, surgery for malignant melanoma of the lower limb, endoscopic mucosal resection for esophageal cancer, was pointed out a pulmonary nodule in the right middle lobe by surveillance computed tomography after 5 years of surgery for melanoma. Pathology of esophageal cancer was squamous cell carcinoma limited in mucosa without lymphatic nor venous invasion. The nodule gradually enlarged and respiratory endoscopic examination could not establish pathological diagnosis. Thoracoscopy assisted pulmonary biopsy revealed squamous cell carcinoma, and right middle lobectomy with mediastinal node dissection was performed. Histological examination showed moderately differentiated squamous cell carcinoma without lymph node involvement. The stage of lung cancer was T1N0M0, stage IA. Although 9 months have passed since surgery for lung cancer, recurrence of each malignancy has not been detected. PMID- 21591449 TI - [Pleomorphic carcinoma of the lung; report of a case]. AB - A 83-year-old male was referred to our hospital for further examination of abnormal shadow on chest radiography. Chest computed tomography (CT) showed a tumor mass in his right lung. Bronchoscopy brushing cytology revealed non-small cell lung carcinoma and right middle lobectomy was performed. Histological findings showed large cell carcinoma comprised of spindle cell component, finally diagnosing as pleomorphic carcinoma of the lung. Although he was diagnosed as pT2N0M0 (stage IA) after the operation, massive liver metastasis was found 7 months later. We report this case with references to the literatures on pleomorphic carcinoma of the lung. PMID- 21591450 TI - [Catamenial pneumothorax due to diaphragmatic endometriosis confirmed by histological examination; report of a case]. AB - We reported a case of catamenial pneumothorax caused by diaphragmatic endometriosis that was histologically confirmed. A 49-year-old female who had recurrent chest pain and cough appearing on the day preceding each menstruation from 5 years ago. These episode suggested catamenial pneumothorax. Thoracotomy revealed the characteristic appearances of catamenial pneumothorax such as blueberry spots and multiple small holes on the central tendon of the right diaphragm. But there were no lesions on the visceral pleura of the lung. Partial resection of the diaphragm including these lesions were performed. Histological examination showing positive for estrogen receptor and progesterone receptor confirmed the presence of endometrial tissue on the diaphragm. The patient has been well controlled by therapy with gonadotropin releasing hormone, without recurrence of catamenial pneumothorax. PMID- 21591451 TI - [Effectiveness of the HighFO novel oxygen nebulizer for respiratory failure patients with severe hypoxia]. AB - Optimal oxygen delivery is an essential component of therapy for patients with respiratory failure. Reservoir masks or air entrainment nebulizers have often been used for patients who require highly concentrated oxygen, but these may not actually deliver a sufficient fraction of inspired oxygen if there is a marked increase in the patient's ventilatory demands, or if oxygen flow becomes limited due to high resistance in the nebulizer nozzles. The HighFO nebulizer is a novel air entrainment nebulizer equipped with unique structures which reduce nozzle resistance, and as a result, it is possible to supply a sufficient flow of highly concentrated-oxygen. The purpose of this study was to evaluate the effectiveness and usefulness of the HighFO nebulizer in 10 respiratory failure patients with severe hypoxemia who used a reservoir mask and required more than 10 L/min of oxygen supply. In each case, the reservoir mask was replaced with the HighFO nebulizer, and changes in percutaneous oxygen saturation (SpO2) were monitored using pulse oximetry. Oxygenation improved promptly after the reservoir mask was substituted for the HighFO nebulizer (SpO2 : 83.7% +/- 8.5%-94.2% +/- 3.2%, p = 0.007). This finding suggests that the HighFO nebulizer was reasonably effective in delivering highly concentrated oxygen, sufficient for patient demands. The HighFO nebulizer may be the beginning of a new strategy for oxygen therapy. PMID- 21591452 TI - [The prevalence of sleep-disordered breathing among commercial drivers and analysis of predictive factors based on health examinations]. AB - Sleep-disordered breathing (SDB) is associated with a range of manifestations of cardiovascular disease such as stroke, ischemic heart disease and heart failure, and it is known to cause excessive daytime somnolence and be associated with traffic accidents. Therefore, it is important to detect SDB in the early stages. We investigated the prevalence of SDB using a portable monitoring system in 81 commercial drivers. We then analyzed predictive factors for SDB using their health examination records of the same fiscal year. The prevalence of moderate to severe levels of SDB reached 28.3% in all subjects. Multivariate analysis showed that the predictive factors which significantly correlated with SDB were : presence of glucose metabolism disorders (odds ratio [OR] 6.745), weight gain greater than 10 kg from age 20 (OR 5.374), and aging (OR 1.136). These results suggest that health examination records could help detect a high-risk group of SDB, which is important because its early diagnosis could prevent commercial driver traffic accidents. PMID- 21591453 TI - [Comparison between pandemic H1N1 2009 influenza pneumonia and seasonal influenza pneumonia in adults]. AB - We compared 126 cases of seasonal influenza pneumonia (seasonal flu) reported between January, 1996 and March, 2009, with 10 cases of laboratory-confirmed pandemic influenza (H1N1) 2009 influenza virus pneumonia (novel flu), based on clinical condition, computed tomography (CT) findings, severity, treatment, and prognosis, to clarify the characteristics of this novel flu. The mean age of subjects was 52.4 years in the novel flu group and 64 years in the seasonal flu group, and novel flu patients were younger than seasonal flu patients. Seasonal flu patients had more underlying diseases than did novel flu patients. The median duration from illness onset to hospitalization was 4 days in both groups. Primary viral pneumonia was present in 70% of novel flu cases and 31% of seasonal flu cases. The proportion of primary virus pneumonia was higher in novel flu patients, and the disease severity of the seasonal flu group was more severe than that of the novel flu group. White blood cell and lymphocyte counts were lower in novel flu patients, and chest CT images showed bilateral shadows and pure ground glass opacities more frequently in the novel flu cases. There were no differences in treatment, number of days required for the fever to subside, or mortality between the groups. PMID- 21591455 TI - [A case of benign metastasizing leiomyoma medicating for 14 years]. AB - We report a case of benign metastasizing leiomyoma medicated for 14 years after the diagnosis. A 47-year-old woman, who had undergone hysterectomy for uterine myoma at age 40 in 1989, was readmitted in 1996 because of abnormal shadows found on a chest X-ray film. Computed tomography (CT) and further chest X-ray films showed multiple nodules in bilateral lung fields. Open lung biopsy revealed leiomyomatous nodules histologically similar to those found at age 40. Tests for both estrogen and progesterone receptors in the biopsied specimen were positive. We diagnosed the lung nodules as benign metastasizing leiomyoma (BML) and gave her progesterone. Apart from 2 occasions when the patient elected to stop receiving medication, we obtained decreases in the size and number of tumors for 10 years from the start of treatment. However, despite continued administration of progesterone, the tumors continued to grow slowly during the next 4 years. We believe that the effectiveness of progesterone may have gradually decreased in this case, and thus are considering a change in treatment. BML is rare, and it must be carefully followed up long-term in post-menopausal patients. PMID- 21591454 TI - [A case of pulmonary multicentric Castleman disease which appeared as a very large lesion]. AB - A 31-year-old man visited our hospital with a persistent cough. Computed tomography (CT) scans of his chest showed a very large mass and multiple nodular lesions in the right lung field, mediastinal and hilar lymph node enlargement and splenomegaly. Laboratory analysis showed polyclonal hyperimmunoglobulinemia and increased levels of serum C-reactive protein (14.05 mg/dl) and interleukin-6 (44.2 pg/ml). The pathological findings of lung specimens obtained using video assisted thoracoscopy revealed hyperplasia of the lymphoid follicles with germinal centers, plasma cell infiltration which stained positively with either anti-kappa chain or anti-lambda chain antibodies, and fibrosis in the alveolar septum. We made a diagnosis of multicentric Castleman disease based on high levels of serum IL-6, multiple lymph node enlargement and splenomegaly, although this case had histological findings in common not only with Castleman disease but also with inflammatory myofibroblastic tumor. His abnormal chest radiography findings and laboratory data significantly improved 6 months after his first visit, without any treatment. Multicentric Castleman disease showing a very large mass is extremely rare. PMID- 21591456 TI - [An autopsy case of asbestos-related pleomorphic carcinoma of the lung]. AB - A 50-year-old man with a history of asbestos inhalation developed symptoms related to a metastatic brain tumor was admitted. Chest X-ray images showed an opacity in the left lower lung field. We were unable to differentiate between lung cancer and malignant pleural tumor using either transbronchial lung biopsy or computed tomography (CT)-guided needle biopsy. After 3 months the patient died from rapid disease progression despite radiation therapy, drainage of large quantities of the pleural effusion and chemotherapy. A diagnosis of asbestos related pleomorphic carcinoma of the lung was made after autopsy and immunohistochemical examination of the tumor. PMID- 21591457 TI - [A case of adenocarcinoma of the lung with a pulmonary thromboembolism which improved with gefitinib]. AB - A 56-year-old man was admitted, and was given a diagnosis of adenocarcinoma of the lung (T2N0M0, clinical stage IB), but pleural dissemination was found during surgery. A computed tomography (CT) scan 10 months after surgery revealed enlargement of the mediastinal lymph nodes and a thrombus in the pulmonary artery. Although the patient was immediately given warfarin and heparin, the warfarin was discontinued due to liver dysfunction, and the thromboembolism in his pulmonary artery recurred. The epidermal growth factor receptor (EGFR) mutation investigation of the surgical specimen revealed an EGFR point mutation at exon 21 (L858R). Gefitinib treatment was started and his levels of plasma D dimer immediately decreased. The mediastinal lymph nodes shrank, and the thrombus in the pulmonary artery had disappeared on a CT scan 2 months after gefitinib treatment. Tumor regression was observed, and no recurrence of the pulmonary embolism was found 10 months after gefitinib treatment. Gefitinib was therefore a very effective treatment not only for lung cancer, but also for pulmonary embolism due to lung cancer. PMID- 21591458 TI - [A case of sarcoidosis with bilateral pleural effusion treated with high-dose steroids]. AB - A 25-year-old man was admitted with elevated fever, dyspnea, cough, dorsal chest pain, and multiple nodular shadows and pleural effusion found on chest X-ray films. There were multiple swollen superficial lymph nodes, and non-caseating epithelioid cell granulomas with Langhans giant cells were detected on a biopsy specimen of a right inguinal lymph node. Bronchoscopy findings demonstrated mucosal irregularity, telangiectasia and small nodules, and another biopsy specimen was similar to that of the inguinal lymph node. The number of lymphocytes and the CD4/CD8 ratio were elevated in his bronchoalveolar lavage fluid, and serum ACE and lysozymes levels were also elevated. These findings are compatible with sarcoidosis. Although his symptoms and pleural effusion improved with the administration of 30 mg/day prednisolone (PSL), these findings recurred after about 4 weeks. Therefore, we increased the PSL dose to 60 mg/day, and his symptoms, pleural effusions and laboratory data improved again. There were no signs of relapse after tapering and discontinuance of PSL. PMID- 21591459 TI - [A case of Paragonimus westermani with elevated FDG uptake into a pulmonary nodular lesion and right hilar and mediastinal lymph nodes on FDG-positron emission tomography]. AB - A 47-year-old Chinese woman living in Japan was referred with a 2-month history of cough with hemoptysis. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) showed increased FDG uptake into a pulmonary nodular lesion 25 mm in greatest dimension in the right upper lobe, and right hilar and mediastinal lymph nodes. Laboratory investigation did not reveal either eosinophilia or a marked elevation of serum IgE titer. A culture of bronchial lavage fluid was sterile and culture for mycobacteria was negative. Cytological examination results of transbronchial brushing samples were Class III. A partial resection of the right upper lobe was performed because of the possibility of primary lung cancer. Pathological examination of the nodular lesion showed helminthic eggs surrounded by dense inflammatory infiltrates, which mainly consisted of lymphocytes and eosinophils. Based on the findings of a serological study for helminth, the morphological characteristics of the eggs and the patient's history of eating raw crab, the patient was given a diagnosis of Paragonimus westermani, which can mimic primary lung cancer. PMID- 21591460 TI - [A case of interstitial pneumonia possibly associated with polyarteritis nodosa]. AB - A 71-year-old man was admitted due to persistent pyrexia of over 2 weeks duration, dry cough, and chest computed tomographic (CT) findings of interstitial pneumonia. On admission, his body temperature was 38.0 degrees C, and there was mild livedo reticularis observed on the trunk and skin of the extremities. Fine crackles were detected in the lower lung fields. Laboratory examinations showed high levels of an inflammatory reaction and a positive rheumatoid factor, but the findings were negative for any other autoantibodies, including the antineutrophil cytoplasmic antibody. His bronchoalveolar lavage fluid revealed an increase in CD4+ lymphocytes. A biopsy specimen of the abdominal skin showed necrotizing vasculitis of the muscular arteries. Lung biopsy specimens showed necrotizing and granulomatous vasculitis of the pulmonary arteries in the usual interstitial pneumonia pattern, with numerous lymphoid follicles. Therefore, a diagnosis of polyarteritis nodosa was clinically and pathologically established. This case of interstitial pneumonia associated with polyarteritis nodosa was difficult to discriminate from microscopic polyarteritis. PMID- 21591461 TI - [A case of sarcomatoid carcinoma of the lung successfully treated with carboplatin, paclitaxel and bevacizumab]. AB - A 63-year-old male smoker with left chest pain was admitted for examination of an abnormal chest shadow. A chest computed tomography (CT) scan revealed a tumor in S6 of the left lung, and left pleural effusion. Histological examination by CT guided needle biopsy revealed a proliferation of spindle-shaped tumor cells with sarcomatous features. Immunohistochemical staining confirmed the tumor cells to be of epidermal origin, indicating a diagnosis of sarcomatoid carcinoma of the lung. No distant metastases were found, and his disease was judged to be clinical stage IV (T3N2M1a). He received 5 courses of systemic chemotherapy consisting of carboplatin, paclitaxel and bevacizumab, and the tumor shrank. Systemic chemotherapy is generally ineffective for sarcomatoid carcinoma of the lung. However, in the present case this chemotherapy was effective with the addition of bevacizumab. PMID- 21591462 TI - [A case of pulmonary-limited Wegener granulomatosis mimicking bacterial pneumonia caused by Staphylococcus aureus]. AB - A 56-year-old woman who had suffered from systemic lupus erythematosus and Sjogren syndrome was admitted complaining of persistent cough. Chest X-ray films showed an infiltrative shadow in the right middle lung field. Her serum PR3-ANCA titer was high, and granulomatous inflammation with Langhans giant cell was noted in a transbronchial biopsy specimen. About 3 months later, purulent sputum and high grade fever developed, with a new infiltrative shadow in the left upper lung field noted on a chest X-ray film. We treated her based on a diagnosis of bacterial pneumonia caused by methicillin-resistant Staphylococcus aureus, but her condition did not improve. We finally gave her a diagnosis of pulmonary limited Wegener's granulomatosis. Her condition improved with the administration of sulfamethoxazole-trimethoprim, prednisolone and cyclophosphamide. We report a case of pulmonary-limited Wegener granulomatosis which mimicked bacterial pneumonia caused by methicillin-resistant Staphylococcus aureus. This case suggests that Wegener's granulomatosis should be considered on encountering pneumonia caused by Staphylococcus aureus. PMID- 21591463 TI - [A case of secondary pulmonary cryptococcosis presenting with multiple cystic shadows]. AB - An 80-year-old woman with a history of rheumatoid arthritis and steroid diabetes had been given a diagnosis of multiple bilateral pulmonary cystic lesions 16 months previously, and these lesions were observed to gradually increase on follow-up. She presented with a fever of 38 degrees C, cough, and sputum for 2 weeks, and the pulmonary cystic lesions had enlarged, and therefore she was admitted. A chest X-ray film revealed multiple cystic lesions 4 cm in greatest dimension in both the left upper and middle lung fields, and chest computed tomography (CT) scans revealed that the lesions of the left S1+2 had niveau formation with a partially thickened wall. However, the lesions in the left S4 and S5 areas and the right S8 area had thin, smooth walls. Transbronchial lung biopsy of the left S4 lesion yielded granuloma formation and yeast-like fungus bodies within multinucleated giant cells, while bronchial lavage fluid culture showed cryptococcus neoformans. It is known that pulmonary cryptococcosis presents various images and histopathologic findings, according to the immune interactions between the fungus body and the host. We report a rare case that presented with multiple cryptococcal cystic lesions. PMID- 21591464 TI - [A case of pulmonary MALT lymphoma with multiple nodules and ground-glass opacities]. AB - An asymptomatic 77-year-old woman was referred in 2000 because multiple nodular shadows were found on chest X-ray films on a medical checkup. Chest computed tomography (CT) showed bilateral multiple ground-glass opacities and ill-defined nodules. A transbronchial lung biopsy was performed via bronchoscopy, but the specimens did not yield any specific findings. She was then monitored without therapy as an outpatient. In November 2005, chest CT imaging showed that the size and density of the ground-glass opacities and nodules had increased. In January, 2006 video-assisted thoracic surgery (VATS) was performed to obtain a definitive diagnosis. Based on histological and immunohistochemical examinations, primary pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma was diagnosed. She has been followed up without any additional treatment since. CONCLUSION: Multiple ground glass opacities and nodules are rare chest CT findings in pulmonary MALT lymphoma. PMID- 21591465 TI - [Lung cancer in Japan: analysis of lung cancer registry cases resected in 2004]. AB - The Japan Lung Cancer Society, Japanese Association for Chest Surgery, and Japanese Respiratory Society jointly established the Japanese Joint Committee for Lung Cancer Registration. In 2010, analyses of 11,663 cases of lung cancer that underwent surgical resection in 2004 were performed, then the findings were registered and collected for analysis by the committee. The survival rate for all cases was 69.6%, while the 5-year survival rate in males (n = 7.369) was 63.0% and 80.9% in females (n = 4,294). The 5-year survival rates by c-stage (UICC Ver. 6 and Ver. 7) were as follow: IA (n = 6,295, 6,295), 82.0% and 82.0%; IB (n = 2,788, 2,339), 63.4% and 66.1%, IIA (n = 203, 819), 55.4% and 54.5%; IIB (n = 899, 648), 48.6% and 46.4%: IIIA (n = 940, 1,216), 43.3% and 42.8%; IIIB (n = 407, 90), 41.6% and 40.3% and IV (n = 131, 256), 29.1% and 31.4%, respectively. The 5-year survival rates by p-stage (UICC Ver. 6 and Ver. 7) were as follow: IA (n = 5,611, 4,978), 85.9% and 86.8%; IB (n = 2,398, 2,552), 69.3% and 73.9%; IIA (n = 336, 941), 60.9% and 61.6%; IIB (n = 977, 848), 51.1% and 49.8%; IIIA (n = 1354, 1804), 41.0% and 40.9%; IIIB (n = 799, 106), 36.7% and 27.8%, and IV (n = 188, 434), 27.8% and 27.9%, respectively. The 5-year survival rates by histological type were as follow: adenocarcinoma, 74.9% squamous cell carcinoma, 59.1%; large cell carcinoma, 53.3% small cell carcinoma, 52.6%; and adenosquamous cell carcinoma, 50.8%. Operative death occurred in 48 cases (0.4%) and hospital death in 46 (0.4%). PMID- 21591466 TI - [Recognition of viruses by inflammasomes]. PMID- 21591467 TI - [Imaging of pulmonary tuberculosis--valuable educational resources for the study of diagnostic imaging of the respiratory tract]. PMID- 21591468 TI - [The Patients' Charter for tuberculosis care]. PMID- 21591469 TI - [Therapeutic strategy for tuberculous empyema--trends in plombage]. PMID- 21591470 TI - [The role of specialists on tuberculosis and acid-fast bacterial infections at general hospitals]. PMID- 21591471 TI - Quality Management in healthcare--a bureaucratic evil or an indispensable medical duty? PMID- 21591473 TI - Assisted dying: reply to Connoly and Larkin. PMID- 21591472 TI - PROCAM-, FRAMINGHAM-, SCORE- and SMART-risk score for predicting cardiovascular morbidity and mortality: a comment. PMID- 21591474 TI - [Guideline for diagnosis, follow-up and treatment of mucopolysaccharidoses type II or Hunter disease]. PMID- 21591475 TI - [Private health insurance--it's enough now!]. PMID- 21591476 TI - [Clozapine card]. PMID- 21591477 TI - [Cryotherapy of prostatic cancer]. PMID- 21591478 TI - Industry-funded research. PMID- 21591479 TI - Findings from the Council of State and Territorial Epidemiologists' 2008 assessment of state reportable and nationally notifiable conditions in the United States and considerations for the future. AB - CONTEXT: The State Reportable Conditions Assessment (SRCA) is an annual assessment of reporting requirements for reportable public health conditions. The Council of State and Territorial Epidemiologists (CSTE) and the Centers for Disease Control and Prevention have gained valuable experience in developing a centralized repository of information about reportable conditions across US states and territories. OBJECTIVE: This study examines the reporting status in states of nationally notifiable conditions used to inform public health and national surveillance initiatives. DESIGN: Conditions included in SRCA are updated annually by using a Web-based tool created by the CSTE. SETTING: SRCA information for 2008 was reported from all US states, 2 cities, and 4 territories. PARTICIPANTS: Respondents included state or territorial epidemiologists (or designees) for reporting jurisdictions. MAIN OUTCOME MEASURE: Conditions were classified as explicitly reportable, implicitly reportable, or not reportable. RESULTS were tabulated to determine reporting statistics for the conditions nationwide. RESULTS: The SRCA included 101 conditions recommended for national notification: 93 (92%) were infectious conditions, and 8 (8%) were other (noninfectious or crosscutting) conditions. Of nationally notifiable infectious conditions, 61 (66%) were explicitly reportable in 90% or more jurisdictions; only 2 (25%) noninfectious or crosscutting nationally notifiable conditions were explicitly reportable in 90% or more jurisdictions. Furthermore, 3 nationally notifiable infectious conditions were explicitly reportable in less than 70% of jurisdictions. CONCLUSIONS: Although most nationally notifiable conditions were explicitly reportable, we found that many of these conditions have implicit reporting authority in states. As notifiable condition surveillance moves toward an informatics-driven approach, automated electronic case-detection systems will need explicit information about what conditions are reportable. Future work should address the feasibility of standardizing the format of reportable disease lists and nomenclature used to facilitate data aggregation and interpretation across states. PMID- 21591481 TI - [L-incision of the sternum]. PMID- 21591482 TI - [Transplantation of autologous pulmonary valve to the aortic valve and human frozen pulmonary valve to the position of the pulmonary valve (Ross surgery) in a patient with aortic valve regurgitation with a single coronary artery]. PMID- 21591483 TI - Finding health care; preparing for the future. PMID- 21591484 TI - Well implemented, President Obama's national HIV/AIDS strategy is precisely what is needed to further control HIV/AIDS. PMID- 21591485 TI - The goal of relevance. PMID- 21591486 TI - Calculating the ROI for analog to digital mammography conversion. PMID- 21591487 TI - Improving employee engagement. PMID- 21591488 TI - The times they are a-changin'. PMID- 21591489 TI - An effective approach for choosing an electronic health record. AB - With government stimulus money becoming available to encourage healthcare facilities to adopt electronic health record (EHR) systems, the decision to move forward with implementing an EHR system has taken on an urgency not previously seen. The EHR landscape is evolving rapidly and the underlying technology platform is becoming increasingly interconnected. One must make sure that an EHR decision does not lock oneself into technology obsolescence. The best approach for evaluating an EHR is on the basis of:usability, interoperability, and affordability. PMID- 21591490 TI - Achieving high performance through organizational culture transformation: key concepts and best practices, Part 1. AB - This article outlines a road map to achieving organizational excellence by identifying the structures, conditions, and practices necessary to institutionalize both the core values of diversity transformation (inclusion, respect, fairness, and equity) and the core clinical and administrative practices that drive organizational high performance and improvement. Fundamentally, this approach takes as a given the interrelatedness of clinical quality, operational efficiency, and work culture. Cultural competence requires the transformation of not just clinical practice but the systems by which care is organized and delivered. PMID- 21591491 TI - Quiet heroes. PMID- 21591492 TI - Obtaining ABNs and implementing an effective process. AB - In the current healthcare environment, it is critical that healthcare providers get every penny to which they are entitled. It seems that each year healthcare providers are forced to do more with less and imaging services in particular have taken a huge hit in reimbursement starting back in 2005 with the implementation of the Deficit Reduction Act (DRA). Payment reductions will likely continue over the next several years. One way to optimize revenue is to ensure that Advance Beneficiary Notices (ABNs) are being obtained in an effort to receive payment for services that may not be medically necessary. This article focuses on requirements for using the ABN and provides tips for implementing an effective process for monitoring medical necessity denials. PMID- 21591493 TI - The influence of workforce behavior on organizational performance. AB - Individual attitudes, values, personalities, ethics, and cultural differences all have an influence in organizational behavior. The formation of a culturally harmonious organization leads to new levels of management and structure, transcending the distinct cultures of individual team members. Leaders must be able to improve group process by facilitating interaction among group members and by maximizing group dynamics, which can only develop when there is positive interdependence, accountability, constructive interaction, and social skills. PMID- 21591494 TI - Capital budgeting: the characteristics of imaging projects, Part 4. PMID- 21591495 TI - Kinetic Care. PMID- 21591496 TI - Survival of the fittest. PMID- 21591497 TI - CTAs and PET modifiers... what they have in common? PMID- 21591498 TI - Renewing the process of mentoring: why our industry requires it. AB - Due to the nature of modern business organizations and the ever increasing competiveness and corporatization associated with the business environment, the number of individuals working without a mentor is growing. For individuals at the beginning of their careers or those expanding their responsibilities to include additional service lines, the lack of a strong and willing mentor can increase the learning curve and frustration of the leader. Successful mentoring, along with certain professional organizations, will allow us to make successful strides toward renewing and growing leadership within the imaging field. PMID- 21591499 TI - Teleradiology deal breakers. PMID- 21591501 TI - The pro from Dover. PMID- 21591500 TI - CR/PACS for scoliosis: a turn for the better? AB - As radiology departments convert to digital imaging, the acquisition, reading,and management of scoliosis studies pose unique challenges. This case study assesses the actual impact on efficiency,file management, cost, and clinical acceptability after a conversion to see whether goals were accomplished. As digital imaging for scoliosis studies became the new standard of care in the Children's Hospital of Philadelphia radiology department, it renewed interest and attention to these disorders and facilitated improved patient care. PMID- 21591502 TI - What followers want from leaders, yesterday and today. AB - Throughout the recent past, some of the needs of followers have remained static while others have evolved with industry trends. Several studies exploring both aspects are analyzed in this article while pointing out the distinct difference between managers and leaders. While the core needs of followers may appear basic in concept, leaders must be aware and responsive to the changing needs of their staff whether the change is a consequence of the uncertain economy or whether the need is an inherent trait of a generation. Leaders must develop the skills necessary to identify changing needs while instilling confidence and trust in followers all the while piloting departments and business units into the future. PMID- 21591503 TI - Reducing inpatient procedure turnaround times using a value analysis approach. AB - Productivity, efficiency, and effective utilization of staff resources have become critical ingredients in reducing expenses with a rapidly diminishing pot of capital and operating dollars. When seeking process improvement, patient safety and quality clinical care must never be compromised. This article explores how one facility approached and developed performance standards using a "value analysis" team structure and applying analytical tools to track and monitor performance activity over time,as well examining the financial impact when operational efficiencies and turnaround time (TAT) improves and its potential impact on inpatient length of stay (LOS). PMID- 21591504 TI - Importance of auditing: an ounce of prevention is worth a pound of cure. PMID- 21591505 TI - No passing hurricane. PMID- 21591506 TI - A tribute to professor Edward George Kasili. PMID- 21591507 TI - Outcome and haemato-toxicity of two chemotherapy regimens for childhood non Hodgkin's lymphoma in a Kenyan hospital. AB - BACKGROUND: Effectiveness and toxicity of childhood cancer treatments have never been evaluated in Kenya since introduction of structured care in the early seventies. OBJECTIVE: To evaluate effectiveness and toxicity of two treatment protocols for Non-Hodgkin's lymphoma (NHL). DESIGN: Historical cohort study using medical records. SETTING: Kenyatta National Hospital, a tertiary care and medical teaching hospital. SUBJECTS: Children < or =15 years with diagnosis of non Hodgkin's Lymphoma. MAIN OUTCOME MEASURES: Primary outcomes were median survival, event free survival and toxicity. RESULTS: Out of 101 records, only 26 (25.7%) met inclusion criteria. Baseline characteristics were similar in the two treatment arms. Median survival was 0.75 months (95% CI = 0.54-0.96) and 1.0 months (95% CI = 0.29-1.71) for short and long arm groups. There was no difference in event free survival and haematological toxicity. CONCLUSION: No clear difference in effectiveness and toxicity between the intensive-short and the less aggressive long course chemotherapy regimens was evident. Though lack of difference may be attributed to the small sample size, suboptimal supportive care for intensive treatment would increase risk of toxic deaths. As the short course protocol did not demonstrate obvious deterioration of median and event free survival, a strong case may be made for a randomised clinical trial within a context of improved supportive care. PMID- 21591509 TI - Prevalence of iron deficiency in children with cyanotic heart disease seen at Kenyatta National Hospital and Mater Hospital Nairobi. AB - OBJECTIVE: To establish the prevalence of iron deficiency among children with cyanotic heart disease. DESIGN: Cross-sectional study. SETTING: The study was carried out at Kenyatta National Hospital and Mater Hospital from August to December of 2007. A total of 112 children meeting the eligibility criteria were recruited from the wards and the cardiac clinics. SUBJECTS: These were children less than 18 years of age, with cyanotic heart disease confirmed on ECHO, presenting at the paediatric cardiac clinic of the two hospitals or admitted in the wards at Kenyatta National Hospital. These were patients who had not undergone surgical correction. RESULTS: The prevalence of iron deficiency was found to be 16.9% (95% CI 9.8-24.1%). CONCLUSION: There is a high prevalence of iron deficiency among patients with congenital heart disease with cyanosis in the two institutions. Routine screening for iron deficiency is recommended for these children and those found to be deficient should be treated. PMID- 21591508 TI - Clinico-pathologic characteristics and treatment outcomes in children with neuroblastoma at the Kenyatta National Hospital, Nairobi. AB - OBJECTIVE: To determine clinical-pathologic characteristics, treatment modalities and treatment outcomes of children diagnosed with neuroblastoma. DESIGN: Cross sectional descriptive study based on secondary data from patient records. SETTING: Records department of Kenyatta National Hospital (KNH), a tertiary teaching and referral hospital based in Nairobi. SUBJECTS: Children aged 15 years and below, admitted with the diagnosis of neuroblastoma, between January 1997 and December 2005. MAIN OUTCOME MEASURES: Presenting clinical features, diagnostic modalities including laboratory and imaging data, treatment modalities, response to treatment and patient survival. RESULTS: Twenty six patients were eligible for the study; 13 males and 13 females giving a M:F ratio of 1:1. The age range was 5 days to 12 years, with a median age of five years. Abdominal swelling (53.8%), inability to walk due to bone pains, (50%), and cranial or periorbital swelling, (38.5%) were the commonest presenting features. Diagnosis of neuroblastoma was based on tissue biopsy in 50% (95% CI 40.6-79.8%) of the patients, and on fine needle aspiration cytology of mass or bone marrow in the rest. Bone marrow involvement was present in 16, (75%). Anaemia, was common with 72.7% patients having a haemoglobin (HB) <8 g/dl at presentation. Immunohistochemistry and cytological grading were done in two, (8%), patients. Urinary vanilly 1 mandelic acid (VMA), screening was positive in 50% (95% CI 29.9%-70.1%). The most frequently involved organs were abdomen (88.9%), and skeleton, (84.6%). Majority of patients, (92.3%), presented with advanced stage IV disease. Three patients died before commencement of treatment. All treated patients (100%), received cytotoxic therapy. Only two patients (8.6%) had surgery as part of treatment while one, (4.3%) was treated with radiotherapy. The initial treatment regimen was similar for all the patients. Although most patients had a complete initial response to treatment, early relapse, treatment failure, death or loss to follow up of patients with progressive disease were common. Overall survival (OS) at one year and two years were 19.2% (95% CI 6.6-39.4%) and 7.7% (95% CI 0.9%-25.1%) respectively. Only one patient was alive, (also free of disease), five years after diagnosis. CONCLUSION: Although other clinical-pathologic findings of the patients were similar to those reported elsewhere, virtually all study patients presented with advanced stage IV disease, which would be associated with poor prognosis irrespective of quality of care. Priority must therefore be on ensuring early diagnosis and referral of patients with neuroblastoma before any other interventions can be expected to positively impact on outcome. The limited role of surgery and radiotherapy observed over the study period may be attributed to late presentation of the patients. Pathologic evaluation of important information could have been availed at minimal extra cost. To be at par with current internationally accepted treatment approaches that have been associated with improved survival, there is need to base choice of regimens for individual patients on clinical and readily accessible pathologic markers. PMID- 21591510 TI - Risk factors for cardiac dysfunction in children on treatment for cancer at Kenyatta National Hospital, Nairobi. AB - OBJECTIVE: To determine the point prevalence of abnormal cardiac function and to assess the risk factors for cardiac dysfunction in paediatric oncology patients on treatment at Kenyatta National Hospital. DESIGN: Descriptive cross-sectional study with a nested case control. SETTING: Kenyatta National Hospital between February and April 2006. MAIN OUTCOME MEASURES: Left ventricular dysfunction if ejection fraction (EF) <55% or fractional shortening (FS) <29% defined cases. Controls had EF >55% or FS >29%. RESULTS: One hundred and eleven patients were enrolled of whom 32 had abnormal cardiac function and were classified as cases while 79 had normal cardiac function. About a third, point prevalence 29% (95% CI 21.2-37.9), had cardiac dysfunction. Cumulative anthracycline dose was a risk factor for cardiac dysfunction in this population. Above 200 mg/m2 the attributable risk percentage of cardiac dysfunction was 77%. CONCLUSIONS: Serial echocardiography should be performed to identify patients at risk. Alternative treatment protocols should be used when the cumulative anthracycline dose exceeds 200 mg/m2 due to the high attributable risk. Studies to further assess the other associated risk factors and long term effects of anthracycline are recommended. PMID- 21591511 TI - Prevalence of cytomegalovirus antibodies in blood donors at the National Blood Transfusion Centre, Nairobi. AB - BACKGROUND: Cytomegalovirus (CMV) infection in susceptible patients is associated with serious morbidity and a high mortality. Transmission of cytomegalovirus infection through blood transfusion is markedly reduced by transfusion of CMV seronegative blood products, or by transfusion of leucodepleted blood products. OBJECTIVE: To determine the prevalence CMV IgG and IgM antibodies among blood donors at the National Blood Transfusion Services (NBTS), Nairobi. DESIGN: Cross sectional descriptive study. SETTING: Four hundred participants were recruited from blood donors at the NBTS and testing was done at the Kenyatta National Hospital (KNH) immunology laboratories and the NBTC. MAIN OUTCOME MEASURES: Social demographic data and the CMV serologic status for the participants was determined and documented as being positive or negative for immunoglobulin G (IgG) and immunoglobulin M (IgM). The age, gender, marital status, education level and geographical area of residence of the participants were documented. Corresponding results of HIV, hepatitis B antigen, hepatitis C antibody from the patients were obtained from the NBTS. RESULTS: Majority of the blood donors recruited were male at 57.9%. Most blood donors were aged 16-20 years (42.5%) and only 17.2% were above 30 years of age. Unmarried blood donors, those with secondary school education and an income between Kshs 5000 (US $67) and KShs 50,000 (US$ 667) monthly were the majority at 78.5%, 54.8% and 66.1% respectively. Sexually active blood donors constituted 60.5% of the donors recruited. Positivity for transfusion transmissible infections (TTI) tested was 1.3%, 0.3%, 2.3% and 1.0% for human immunodeficiency virus (HIV), syphilis, hepatitis B and hepatitis C respectively. Anti- CMV IgG and IgM positivity was 97.0%, (95% CI 96.45-97.53%), and 3.6% (95% CI 1.7-5.2%), respectively. There was no statistical difference between different ages, marital status, salary, individual's sexuality in the prevalence of CMV antibodies. However females had a higher prevalence of CMV antibodies. CONCLUSION: There is a very high prevalence of cytomegalovirus antibodies among blood donors at the NBTS, with virtually all blood donors having been exposed to the virus. Since the CMV remains latent within leucocytes after infection inspite of the prescence of antibodies in seropositive individuals, leucoreduction of blood products is recommended before transfusion to seronegative susceptible patients. In Kenya, susceptible groups of patients include very low birthweight babies, patients with acquired immune deficiency syndrome (AIDS) due to human immunodeficiency virus infections (HIV) patients, patients on myelosuppressive cancer therapy and recipients of kidney transplants. Further studies are recomended to determine the prevalence of CMV antibodies in these patients in order to establish the magnitude of the demand for CMV safe blood. PMID- 21591512 TI - Heparin-induced thrombocytopaenia/thrombosis: a clinicopathologic review. AB - BACKGROUND: Heparin is widely used for the prophylaxis of venous thrombo-embolism and pulmonary embolism. Thrombocytopaenia and the sequale of thrombosis are uncommon adverse effects of therapy which are associated with high morbidity and mortality. OBJECTIVE: To review the clinical-pathologic features of heparin induced thrombocytopaenia/thrombosis. DATA SOURCES: Reputable haematology journals and the internet in English. Searches included thrombosis, heparin, and heparin induced thrombocytopaenia. DATA SELECTION: Only relevant journals and internet sources were selected for this review. In particular leading journals in thrombosis and anticoagulants. DATA EXTRACTION: High quality abstracts, papers and internet articles were the main source of information. DATA SYNTHESIS: Information from the selected abstracts and papers was used'for the paper. CONCLUSION: The clinical effects of heparin induced thrombocytopaenia/thrombosis (HIT/T) include venous and arterial events the latter of which include limb ischaemia, myocardial infarction and stroke. The pathogenesis of this complication is related the formation of heparin-platelet factor 4 antibodies which can be demonstrated in the laboratory by functional and immunoassays. Management requires alternative anticoagulation with agents that have no cross reactivity with heparin platelet factor 4 antibodies. These agents include danapranoid, direct thrombin inhibitors and newer agents like fondaparinux and rivaroxaban with anti Xa activity. PMID- 21591513 TI - Radiation synovectomy: treatment option for haemophilia patients with chronic haemarthrosis: a review. AB - BACKGROUND: Ablation of the synovium with radiopharmaceuticals, referred to as radiation synovectomy, (RS), has emerged as a simple affordable and safe procedure that is highly effective in preventing chronic disabling end stage arthritis in haemophilia patients. OBJECTIVE: To provide a review of the principles and role of radiation synovectomy, (RS), in the management of haemophiliac patients with chronic haemarthrosis, and to consider the possibility of this treatment option in Kenyan patients with haemophilia. DATA SOURCES: A literature search through the internet using Boolean commands, PubMed interface to MEDLINE, Evidence, the Cochrane library. Papers from reputable haematology and radiation medicine journals, as well as conference presentations of the World Federation of Hemophilia were also included. DATA SELECTION: The searches for papers, abstracts and reviews were limited to English language, haemophilia, haemarthrosis, synovectomy, RS, radiopharmaceuticals for RS and safety of RS. DATA EXTRACTION: All abstracts, and most of the papers were reviewed. Only those abstracts, papers and conference materials from reputable sources were used for this paper. DATA SYNTHESIS: All available papers and abstracts were reviewed for the most up to date information. The indications, requirements, procedure and safety aspects of RS were examined. The merits of alternative forms of synovectomy were considered. In the light of this information, the feasibility of RS as a treatment option for haemophilia patients in Kenya was considered. CONCLUSION: Radiation synovectomy has been carried out on thousands of haemophilia patients with chronic haemathrosis over the last 20 years. Experience accumulated in numerous centres in America, Europe, Asia, North and South Africa indicates that majority of haemophilia patients undergoing RS are spared life long crippling arthritis and deformity. The principle safety concern of the potential for late radiation-related malignancy has been mitigated by appropriate choice of radiopharmaceuticals, and carefully executed procedure. The effectiveness, simplicity and affordability of RS make it particularly suitable for treatment of haemophilia patients in developing countries like Kenya. PMID- 21591514 TI - Clinical application of tumour markers: a review. AB - BACKGROUND: Tumour markers have made a difference to oncology practice. They can be used in screening, diagnosis, prognostication and assessment of treatment efficacy. Reports on tumour marker usage suggest that many clinicians assume that a biomarker for a particular cancer can be effectively used for all these indications. This assumption is incorrect. Several guidelines have been published to inform clinicians on effective utilisation of these tests. OBJECTIVE: To outline the recommended uses of the most commonly requested tumours markers in clinical practice. DESIGN: A hand search of literature on the recommended use of carcinoembryonic antigen (CEA), alphafetoprotein (AFP), prostate specific antigen (PSA), CA-125 and CA-19.9. Systematic reviews and prospective randomised clinical trials of tumour marker applications were also looked at. DATA SOURCES: Five key journals and reference lists of relevant studies were considered. DATA EXTRACTION AND SYNTHESIS: Two authors abstracted relevant data independently. Emphasis was given to guidelines from expert panels. The quality of the guidelines was assessed by availability of level of evidence supporting the recommendations. RESULTS: Several national and international expert groups have developed guidelines for use of markers for most cancers. CEA, AFP, PSA, CA-125 and CA-19.9 are validated for use in treatment monitoring of colorectal, hepatocellular, prostatic, ovarian and pancreatic carcinomas respectively. AFP and PSA are also useful for cancer screening in high risk groups. CA-125 has limited role in screening while CEA and CA 19.9 are not recommended for cancer screening. CONCLUSIONS: Not all currently available tumour markers can be used for screening and diagnosis of malignancies. Adherence to recommendations on tumour marker utilisation will improve the cost-effectiveness of these tests. PMID- 21591515 TI - Management of immune thrombocytopaenia in children: a review. AB - OBJECTIVE: To provide an overview of the various treatment options available in the rational management of ITP in children. DATA SOURCE: Published original research findings and reviews. DATA SELECTION: On-line searches for published data on immune thrombocytopaenia, idiopathic thrombocytopaenia, thrombocytopaenic purpura. DATA EXTRACTION: Abstracts of selected articles were read and analysed to determine their relevance to this article. DATA SYNTHESIS: All relevant articles were read in full and necessary contribution extracted for this review. CONCLUSION: Immune thrombocytopaenic purpura is a common disorder affecting children and adults. Ongoing research into the pathogenesis is providing the basis for future treatment options. Greater consensus as to appropriate treatment strategies is needed to improve outcomes. PMID- 21591516 TI - Immunophenotyping of acute leukaemias by flow cytometry: a review. AB - OBJECTIVE: To provide an overview of the utility of flow cytometry for phenotyping of acute leukaemias and selection-of monoclonal antibodies. DATA SOURCES: The literature review was obtained through internet, journals and chapters in the relevant books. DATA SELECTION: Relevant articles and chapters on immunophenotyping of acute leukaemias were selected from respected international journals and books in the field of haematology and were reviewed. DATA EXTRACTION AND SYNTHESIS: Complete articles relevant to the topic were selected and reviewed and the necessary information extracted for this review. CONCLUSIONS: Flow cytometry has been used extensively in recent years to characterise haemopoeitic malignancies and done routinely in the developed world. This technique has greatly improved the diagnosis and classification of haemopoeitic malignancies and has been recommended by World Health Organisation classification (WHO) of tumours of haemopoeitic and lymphoid tissue. Application of flow cytometry for the diagnosis of leukaemias has been recently introduced in Kenya and is currently being undertaken in research using limited but appropriate panels of monoclonal antibodies. It is hoped that findings of this research will inform the use of flow cytometry as an ancillary diagnostic technique in our resource constrained set up. PMID- 21591517 TI - Approaches to advancing blood safety through haemovigilance: a review. AB - BACKGROUND: Blood transfusion is always associated with some level of risk. Haemovigilance is a risk monitoring system integral to the practice of transfusion medicine whose ultimate purpose is to improve the quality and safety of transfusion therapy. OBJECTIVE: To examine the contribution of haemovigilance to blood safety, including the approaches that some countries have taken to institute haemovigilance, and explore routes through which countries without such systems can achieve them. DATA SOURCES: The internet and journals on the topic of haemovigilance and development of haemovigilance systems in the English language. DATA SELECTION: Reputable journals on the topic of haemovigilance were examined for abstracts and papers. Abstracts based on known credible and distinguished sources were selected. DATA EXTRACTION: Information on haemovigilance and the processes of developing haemovigilance in various countries was reviewed. DATA SYNTHESIS: The information from selected papers and abstracts was used for writing this paper. CONCLUSION: Varying processes for haemovigilance have been adopted by different countries. The more advanced systems have national/regional coordinating mechanisms. Availability of haemovigilance data has given transfusion services a clear understanding of problems associated with transfusion that need to be solved so as to improve transfusion safety. Although countries in sub-Saharan Africa have made considerable progress in enhancing blood safety in the recent past, nationally coordinated haemovigilance systems are lacking. Focus on haemovigilance systems is considered the next frontier to be conquered in enhancing blood safety in the region. PMID- 21591518 TI - Progress in blood transfusion services in Kenya from the 1980's: a review. AB - BACKGROUND: Provision of safe and adequate supplies of blood is dependent on a well organised blood transfusion service with dedicated well-trained manpower and resources for the service. OBJECTIVE: To provide an overview of the evolution of blood transfusion services in Kenya, from the 1980s to date. DATA SOURCES: Various Government of Kenya publications and websites on blood transfusion related issues. Publications and websites of stakeholders including donors and other partners as well. PERSONAL EXPERIENCE: The author has been in national blood transfusion administration for over five years. DATA SELECTION: Data related to blood transfusion in Kenya on websites and publication were scrutinised. DATA EXTRACTION: All selected articles were read. DATA SYNTHESIS: All the collected data together with the author's experience were used for this publication. CONCLUSION: As part of the effort by the Ministry of Health to reform the health sector, there was need to reorganise departments and divisions within the Ministry. The reorganisation of the blood transfusion service was one such consideration and it was hoped that following this change, there would be better, safer and more efficient provision of blood for transfusion service snation wide. This article documents the evolution of blood transfusion services from the early 1980s to date. PMID- 21591519 TI - Disseminated histoplasmosis diagnosed on bone marrow aspirate cytology: report of four cases. AB - Histoplasmosis, caused by two varieties of dimorphic fungi, Histoplasma capsulatum variant capsulatum and Histoplasma capsulatum variant duboisii is a systemic fungal infection. It has a worldwide distribution and is shown to be more prevalent in North America and Central America. Both variants occur in Africa. Disease spectrum ranges from asymptomatic primary infection to disseminated disease in immunocompromised patients. Since the upsurge of acquired immune deficiency syndrome (AIDS) and despite the availability of high active anti-retroviral therapy (HAART) many patients still present with opportunistic infections of which histoplasmosis is one. Four cases are presented; two infants and two adults. All had disseminated disease with multiple organ involvement and the disease was not suspected clinically. Diagnosis was made incidentally on bone marrow aspirate cytology. The two adult cases were HIV positive, one with CD4 counts of 132 cells/microlitre and was not on HAART. The other was on HAART but the CD4 had not been determined. One of the infants tested HIV negative and the others status was unknown. A high index of suspicion is required for diagnosis as the disease may mimic tuberculosis(TB) and other causes of hepatosplenomegaly such as visceral leishmaniasis. Laboratory diagnosis includes culture, direct staining, antigen and antibody detection. Antibody detection may give false negative in the immunocompromised patient. The infection responds well to antifungal agents (amphotericin B is the drug of choice) and life long maintenance therapy may be required in AIDS especially if CD4 counts remain less than 150 cells/microlitre. Histoplasmosis should be a differential diagnosis in immunosuppressed patients with unexplained fever, weight loss, hepatosplenomegaly and chest findings especially if not responding to anti-TB treatment. PMID- 21591520 TI - The GLIVEC international patient assistance programme: the Nairobi experience. AB - Glivec is a drug used in the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GISI). It is an expensive drug which would be out of reach for most patients in Kenya. Norvatis Pharmaceutical together with Axios International a healthcare management company and Max Foundation have made it possible for patients in developing countries to get access to the drug at no cost. Patients meet the cost of the confirmatory test and are recruited into the programme to receive the drug at no cost. A total of 201 patients are in the programme in Nairobi, mainly drawn from Kenyatta National Hospital the major referral hospital in Kenya. The age range is nine years to 75 years with a mean age of 39.5 years. Males make up 56.5% while females are 43.5%. CML are 173 (86%) while GIST patients are 28 (13.9%). Most of the CML cases are referred in the chronic stable phase (87.8%) and 85.7% have been on hydroxyurea as the initial treatment. Compliance rates are approximately 80%. PMID- 21591521 TI - The case for venous thromboembolism prophylaxis in Africa. AB - While venous thromboembolism (VTE) is a well recognised occurrence in clinical practice in the developed world, with event rates of at least 2-3 million per year, little attention is paid to this entity in the developing world where the burden of infectious diseases and limited access to care have not recognised VTE as a significant cause of morbidity and mortality. The opportunity for Africa to do better as the inevitable recognition of the consequence of VTE becomes more apparent is available using basic tools and therapies. PMID- 21591522 TI - The Nairobi Hospice--tribute to the late professor Edward George Kasili. AB - Professor Edward George Kasili is regarded as the father of the hospice movement in Kenya. In 1990, he together with Ruth Wooldridge and Jane Moore founded the Nairobi Hospice which takes care of patients with life limiting illnesses from all walks of life. This was of course not easy since even now the mentality of people towards dying is still the same, where people fear talking about death. The hospice movement tries to help somebody die well, die with dignity. The Nairobi Hospice had the privilege of caring for Professor Kasili in his last days before he passed on due to complications of cancer. This article is a tribute to this great man for his forward thinking and for starting the hospice movement. PMID- 21591523 TI - Effectiveness of paracervical block versus intravenous morphine during uterine curettage: a randomized controlled trial. AB - BACKGROUND: Abnormal uterine bleeding is a common gynecologic problem. Fractional curettage, evacuation and curettage, and dilatation curettage are common gynecologic procedures for investigation and treatment of abnormal uterine bleeding. To perform all these procedures, anesthesia is needed but technique varies among hospitals. The standard procedure of uterine curettage was performed after paracervical block or intravenous morphine injection. OBJECTIVE: To compare pain scores during and after uterine curettage using intravenous morphine versus paracervical block MATERIAL AND METHOD: A randomized controlled trial study was performed. Sixty-four patients with abnormal uterine bleeding and indication for curettage were enrolled in the present study. Simple randomized procedure was used to distribute the patients into two groups. Intravenous morphine was carried out in 32 patients as the group A while paracervical block was used in the other 32 patients of the group B before uterine curettage. The main outcome measurement was pain score, which assessed by Numerical rating scale ranging from 0-10. RESULTS: The median pain score during uterine curettage were 7.5 and 6 (p = 0.103), immediately after uterine curettage were 3 and 3 (p = 0.822) and 30 minutes after uterine curettage were 1 and 1 (p = 0.206) in the control and treatment group, respectively. CONCLUSION: Pain scores in patients who received paracervical block were not statistically different from those who received intravenous morphine. Paracervical block could be used as another choice for pain relief during uterine curettage. PMID- 21591524 TI - Factors associated with severe complications in unsafe abortion. AB - OBJECTIVE: To assess factors associated with severe complications in unsafe abortion and to compare the complications in unsafe abortions with spontaneous or therapeutic induced abortion at Khon Kaen Hospital. MATERIAL AND METHOD: Four hundred sixty two medical records with the diagnosis of abortion at Khon Kaen Hospital between January and December 2008 were reviewed. Patient characteristics, complications and treatment outcomes were collected. The complications from abortion were classified into mild and severe group. Qualitative data were presented as frequencies and percentage. Comparison data was analyzed by using Pearson Chi-square test. RESULTS: Out of 462 cases of abortion observed over the study period, 170 (36.8%) women had undergone an unsafe abortion. Twenty-seven (16%) women had severe complications and included 18 cases with hemorrhage requiring blood transfusions (66.6%), 17 cases with shock (63%), six cases with acute renal failure (22.2%), two cases with sepsis with DIC (7.4%) and two death cases. Ninety-five women (56%) in the unsafe abortion did not use any contraception. When compared between the mild and severe complication in the unsafe abortion group, there were statistical differences in the marital status, level of education and the method used (p = 0.003, p = 0.019, p < 0.001, respectively). Severe complications from unsafe abortion more frequently occurred in married, low educated women where intrauterine chemical injection was the most often used. CONCLUSION: The unsafe abortion had more severe complications than the spontaneous or therapeutic abortion, which had affected the women's health. Level of education, marital status, and method used were factors associated with severe complications in unsafe abortion. PMID- 21591525 TI - Mode of delivery and outcomes in preterm births. AB - OBJECTIVE: To compare maternal and neonatal outcomes by mode of delivery in preterm births. MATERIAL AND METHOD: This prospective study was a part of SEA ORCHID project of 9,263 pregnant women. The subjects were all women admitted for preterm birth (20 to 36 weeks) in nine hospitals in four Southeast Asian countries (Thailand, Malaysia, Indonesia, and the Philippines) between June 2007 and December 2009. Deliveries were classified into vaginal delivery and caesarean delivery. We obtained data from women's medical and delivery records. RESULTS: There were 765 preterm births in this analysis, 294 (38.4%) were delivered by caesarean section with a mean weight of 1,988 +/- SD 629 g and 471 (61.6%) were delivered vaginally with a mean weight of 1,982 +/- SD 699 g. There were two maternal deaths in caesarean delivery group. Caesarean delivery was significantly associated with increased risk of blood loss > 500 ml and > 1,000 ml, adjusted ORs: 11.7, CI 95%: 5.7-24.1 and 12.0, CI 95%: 2.2-65.3, respectively. Infants delivered vaginally had a significantly shorter length of hospital stay than infant delivered by caesarean delivery (adjusted mean difference 3.4, CI 95%: 1.2 5.5). The risk of respiratory distress syndrome, birth asphyxia (low Apgar scores (< 7) at 5 minutes) and early neonatal death were not statistically different between caesarean delivery and vaginal delivery. CONCLUSION: In preterm births, caesarean delivery significantly increases the risk of postpartum hemorrhage and had longer neonatal length of hospital stay compared to vaginal delivery. PMID- 21591526 TI - Efficacy and safety of high dose generic sildenafil in Thai patients with pulmonary arterial hypertension. AB - OBJECTIVE: Sildenafil, an orally administered phosphodiesterase type 5 (PDE-5) inhibitor, was known for enhancing the downstream effects of NO. It was approved for treatment in patients with pulmonary arterial hypertension (PAH). Recently, a generic sildenafil (Unison Laboratories, Thailand) was proved to have the same bioequivalent as in the original formula. The authors conducted a 12-week case series to study the efficacy and safety of Elonza (generic sildenafil) in PAH patients. MATERIAL AND METHOD: Comparison of both hemodynamic data from cardiac catheterization and clinical outcome such as six minute walk test (6MWT) were performed to assess the efficacy of generic sildenafil at the dosage of 50 mg given orally three times daily in patients with PAH over a 12 weeks period. RESULTS: There were 20 patients whose average age was 31.4 +/- 14.3 years old (13 58) and their average weight was 48.1 +/- 11.9 kg (31-79). There were three idiopathic pulmonary artery hypertensions (IPAH) and 17 congenital left to right shunts. There was a 15.1% decrease in pulmonary vascular resistance index (PVRi) from 20.5 +/- 13.9 to 17.4 +/- 2.9 Wood unit m2 at the end of 12 weeks (p = 0.044). The ratio of pulmonary to systemic vascular resistance (PVR/SVR) was also decreased from 0.71 +/- 0.57 to 0.52 +/- 0.41 (p = 0.014). 6MWT increased significantly from 271 +/- 59 meters (m) at baseline to 297 +/- 48 m, 307 +/- 43 m and 321 +/- 52 m at week 2, 6 and 12, respectively (p = 0.01). There was no significant change in other hemodynamic parameter, Borg dyspnea score, and functional class. CONCLUSION: At the end of the 12-week treatment, a 50 mg three times daily of generic sildenafil given to patients with PAH was shown to have benefit on decreasing PVRi, PVR/SVR ratio. There was also an increase in mean average of 6MWT at the end of 12 weeks. PMID- 21591527 TI - Prevalence of stroke and stroke risk factors in Thailand: Thai Epidemiologic Stroke (TES) Study. AB - OBJECTIVE: To assess stroke prevalence and stroke risk factors in Thailand. MATERIAL AND METHOD: Thai Epidemiologic Stroke (TES) Study is an ongoing, community based cohort study that has been conducted in five geographic regions of Thailand. Baseline health status survey was started in 2004 and enrollment continued until the end of 2006. All participants who were suspicious of being stroke victims were verified. In this analysis, baseline data of 19,997 participants aged 45 to 80 years were identified and analyzed as a cross sectional analysis. RESULTS: Three hundred and seventy six subjects were proved to have a stroke thus resulting the crude prevalence of stroke to be 1.88% (95% CI, 1.69 to 2.07). Age standardization to Segi world standard population was 1.81% (95% CI, 1.62 to 1.99). Crude prevalence among adults aged > or = 65 years was 2.70% (95% CI, 2.28 to 3.11). Stroke prevalence differed among five geographic regions of the country (Bangkok 3.34%, Central region 2.41%, Southern 2.29%, Northern 1.46% and Northeastern 1.09%). Using multiple logistic regression analysis, factors associated with higher stroke prevalence were male gender (p < 0.001), occupational class (p < 0.001), geographic region (p < 0.001), hypertension (p < 0.001), diabetes mellitus (p = 0.002) and hypercholesterolemia (p = 0.026). CONCLUSION: Stroke prevalence in Thailand from TES study is higher than previous studies, but it is lower than developed countries, probably due to high case fatality rate in Thai population. Geographic variation in stroke prevalence is found more in Bangkok, Central and Southern regions. Longitudinal follow-up of TES cohort study will provide further information on risk factors and incidence of stroke. PMID- 21591528 TI - Acute pancreatitis: assessment severity with Ranson score and CT evaluation. AB - BACKGROUND: Severe acute pancreatitis is a complex and challenging problem. The aim of the present study was to assess severe acute pancreatitis (SAP) with Ranson score and CT scan. MATERIAL AND METHOD: Between January 2000 and December 2005, all patients who had each of the following criteria (1) first-time diagnosis of acute pancreatitis, (2) acute pancreatitis as the primary admitting diagnosis and (3) contrasted-enhanced computed tomography (CE-CT) were retrospectively reviewed. RESULTS: Ninety-eight patients that met the present study criteria were identified. Of these patients, 27 were defined as SAP by using Ranson criteria and/or CE-CT. Within SAP group, factors showing significance (p < 0.05) in the patients that had a Ranson score between > or = 3 and < 3 were age and biliary tract stone. CONCLUSION: The incidence of severe acute pancreatitis in Srinagarind Hospital was 27.5%. Biliary disease and alcohol abuse together accounted for 81:48% of severe acute pancreatitis patients. PMID- 21591529 TI - Alvarado score for the acute appendicitis in a provincial hospital. AB - OBJECTIVE: To assess the accuracy of Alvarado Score in predicting acute appendicitis in Chachoengsao Hospital. MATERIAL AND METHOD: The prospective study involved 1, 000 patients with suspected acute appendicitis. It was carried out between April 2008 and March 2010. The patients were given specific scores according to variables of Alvarado Scoring System. The signs, symptoms, laboratory values and pathology reports of each patient were collected and evaluated. The diagnosis was confirmed by operative findings and histopathological examination of specimens. The sensitivity, specificity, positive and negative predictive values and receiver operator characteristic (ROC) curves of each indicator were also calculated. RESULTS: Out of total 1,000 patients (407 males, 593 females), 838 underwent surgery (352 males, 486 females) and specimens of 715 patients (313 males, 402 females) were confirmed by histopathological examination, thus giving negative appendectomy rate of 14.7% (11.08% males, 17.28% females). The overall sensitivity of Alvarado Score was 87.41% and the specificity was 74.39%, while the positive predictive value was 83.7%. The area under the curve was 0.74. CONCLUSION: Though the diagnosis of acute appendicitis remains mainly clinical evaluation, Alvarado Score can be recommended as a helpful tool for the admission criteria and further management in order to reduce unnecessary admission, morbidity and mortality, length of stay, and cost of treatment. PMID- 21591530 TI - National survey of pediatric anesthesia practice in Thailand. AB - OBJECTIVE: To assess current pediatric anesthesia practice for further education from Royal College of Anesthesiologists of Thailand. MATERIAL AND METHOD: A questionnaire was sent to 500 anesthetists in public hospitals in January 2010 to investigate preoperative data, intraoperative data, postoperative pain management, ambulatory anesthesia, and pediatric anesthesia training requirement. RESULTS: Response rate was 30.6%. Preoperative fasting and infective endocarditis (IE) prophylaxis were appropriate except that half the anesthesiologists preferred giving antibiotics in non-cyanotic heart diseases and ordering complete blood count as a routine investigation in healthy patients undergoing minor surgery. Premedication was preferred in children and adolescents. Parental presence during induction was most often selected in children (74.5%). Modified Ayre T-piece was the most popular breathing circuit used during induction while circle circuit was more likely used during maintenance period. Manual ventilation was preferred in neonates. Scavenging system was rarely used Intraoperative fluid was given based on Holliday & Segar Law (> 90%). Isotonic fluid without glucose was preferred for replacement of third space loss and hypotonic fluid with glucose was preferred for maintenance fluid. Transfusion trigger was inversely correlated with age. Postoperative pain scales were more often used in children and adolescents. Fentanyl was more popular in younger age group. Intermittent intravenous administration was the most preferred route. Age group of infants and older were predominantly accepted to be anaesthetized on an ambulatory basis. Pediatric advanced life support was seldom performed. Intermittent training was more popular than certified fellowship training. CONCLUSION: Routine investigation in healthy patients, IE prophylaxis in non-cyanotic patients, intraoperative fluid replacement, and pediatric advanced life support and postoperative pain management were the issues recommended for further education. PMID- 21591531 TI - Perioperative pulmonary aspiration: an analysis of 28 reports from the Thai Anesthesia Incident Monitoring Study (Thai AIMS). AB - OBJECTIVE: To study the patients' characteristics, outcomes, contributory factors, factors minimizing the incidence and suggested corrective strategies for perioperative pulmonary aspiration in Thailand. MATERIAL AND METHOD: This is a prospective descriptive research design. The relevant data was extracted from the incident reports on aspiration from 51 hospitals across Thailand during the study period between January 1 and June 30, 2007 from the Thai Anesthesia Incident Monitoring Study (Thai AIMS) database. Descriptive statistics was used. Each incident report was reviewed by three senior anesthesiologists. Any disagreement was discussed to achieve a consensus. RESULTS: From 1,996 incident reports, there were 28 reports (1.4%) that met the definition of pulmonary aspiration. Most of the incidents occurred in patients with ASA 1-2 (85.7%), during the official hour (64.3%) and the anesthesiologists were in charge (67.9%). Eleven incidents (39.3%) occurred during induction, seven (25%) during maintenance and seven (25%) during emergence phases. Anesthetic factors played an important role in 26 incidents (92.9%). All the incidents except one (96.4%) were considered human errors and 25 (89.2%) were preventable. Of the incidents caused by human errors, nine (32.1%) were caused by skill-based errors. Thirteen patients (46.4%) had major physiologic changes and 10 (35.7%) of them needed unplanned ICU admission. Ten patients (35.7%) needed prolonged ventilator support and two (7.14%) of them died. CONCLUSION: The contributing factors that might lead to the incidents were improper decision (75%), lack of experience (53.5%) and lack of knowledge (21.4%). Factors minimizing incident, were vigilance (85.7%), having experienced assistant (50%) and experience in that situation (25%). Suggested preventive strategies were guidelines practice in anesthetic management (67.8%), improvement of supervision (57.1%), additional training (42.8%) and quality assurance activity (28.6%). PMID- 21591532 TI - Clinical response and safety of malathion shampoo for treatment of head lice in a primary school. AB - OBJECTIVE: Help eradicate or at least alleviating head lice in a primary school with malathion shampoo and to study clinical response and safety of malathion shampoo. MATERIAL AND METHOD: All students were examined by using a fine-toothed lice comb to help detect live lice. Direct visual examination and the collection of nits for microscopic examination were performed to differentiate viable nits from empty nits. Diagnosis of head lice was made by the presence of lice. All students that had lice and/or nits were treated with malathion shampoo. Malathion shampoo was also provided for all family members. Pediculocidal efficacy was by the presence or absence of live lice. Blood for red blood cell cholinesterase activity was drawn in 32 volunteers before treatment and after the second treatment. RESULTS: At the first visit, 629 students were examined and 48 students had live head lice. The infestation rate was 13% in girls and 1.3% in boys. The cure rate was 93% after the first treatment. The reported side effects were nausea, a burning sensation, and irritation that was found in five (4%), 10 (7%) and three (2%) students respectively. The mean of RBC cholinesterase activity before and after two applications showed significant changes (p = 0.03). It was -7.5 +/- 4.1% reduction from the initial, but all were in the normal range. There was no report of clinical manifestation of malathion toxicity. CONCLUSION: Malathion shampoo is safe and effective in the treatment of head lice. There is significant skin absorption so a scalp examination for head lice should be done before subsequent application to avoid unnecessary exposure. PMID- 21591533 TI - Developing standard reference data for Thai children from a six-minute walk test. AB - BACKGROUND: The six-minute walk test (6MWT) is a useful test for pre-and post treatment comparisons, measuring functional status and predicting morbidity and mortality. The test is not widely used with children because the exact reference data in healthy children are often not known and the test requires concentration and co-operation from the participants, which is harder to manage in children. Data for children have been studied in many countries, but data for Thai children is limited. OBJECTIVE: To establish reference values for a six-minute walking distance (6MWD) of healthy Thai children aged between 9 and 12 years. MATERIAL AND METHOD: A cross-sectional study was conducted in healthy children attending the 4 to 6 grades of seven primary schools in Songkla province in southern Thailand. The tests were conducted according to the American Thoracic Society (ATS) guidelines between June and September 2008. The potential variables were evaluated for their relations and confounding factors. Reference curves were developed. RESULTS: Seven hundred thirty nine students were recruited for the study, 403 boys (54.5%) and 336 girls (45.5%). Only one girl could not complete the test. The mean 6MWD was 677 (+/- 62.2) meters. The average walking distance was 36.4 meters greater in boys than girls (693.5 and 657.1 meters, respectively). The walking distance increased with age from 9 to 12 years of age in boys, but it decreased with age in girls after 11 years old. There were no unexpected events during or after the tests. Multivariate analysis showed that the 6MWD correlated to age, sex, weight and heart rate differences. Age-specific centile curves of 9 to 12 years for the 6MWD in each sex were developed. CONCLUSION: 6MWT a practical simple test, is one of several modalities for objective evaluation of functional exercise capacity. The reference value of 6MWT for healthy Thai children aged 9 to 12 years was calculated and reported. PMID- 21591534 TI - Gait symmetrical indexes and their relationships to muscle tone, lower extremity function, and postural balance in mild to moderate stroke. AB - OBJECTIVE: To investigate asymmetrical gait characteristics and degree of associations between gait symmetrical indexes and clinical measures in a stroke population. MATERIAL AND METHOD: Thirty patients with stroke participated in the present study. Clinical measures included muscle tone of affected hip adductors (HA), hip extensors (HE), knee extensors (KE), ankle plantar flexors (AP) and ankle invertors (AI), lower extremity function and postural balance. Symmetrical indexes of gait biomechanics included braking peak force (Y1), propulsive peak force (Y2), first peak vertical force (Z1) and second peak vertical force (Z2), step length, single support time (SST), step time, stance time and swing time were determined. RESULTS: The symmetrical index of force was significantly related with muscle tone and lower extremity function. Temporospatial variables significantly related to muscle tone and lower extremity function, but not to postural balance. CONCLUSION: Muscle tone and lower extremity function were important for walking efficiency as the presented relationships with symmetrical gait characteristic in patients with a stroke. PMID- 21591535 TI - RAPID progression: tool for screening aggressive course of disease (ACD) in Alzheimer dementia. AB - OBJECTIVE: There is a need for a tool in clinical practice to assess the rate of progression of Alzheimer's disease (AD) patients. The present study purpose was to develop a tool for screening and progression assessing of AD patients with Aggressive Course of Disease (ACD). MATERIAL AND METHOD: The Thai Realtime Assessment of Progression In Dementia (RAPID) was developed for screening AD patients with ACD through a caregiver questionnaire. At baseline and at a 6-month follow up visit, patients were tested by the Alzheimer's Disease Assessment Scale cognitive component (ADAS-Cog), while their caregivers completed the Thai RAPID. The tests were run by a team of psychiatrists in the Department of Psychiatry, Chulalongkorn Memorial Hospital. RESULTS: Fifty patients with cognitive impairment were recruited. As a screening tool, the Thai RAPID cut-off point of 9 points yielded a fair sensitivity and specificity (0.625 and 0.643, respectively) for rapid progression as defined by 4 point or greater deterioration in ADAS-Cog. As a progression assessment tool, a cutoff point of 3-points yielded a good sensitivity and specificity (0.875 and 0.810, respectively). CONCLUSION: The present pilot study suggests that the Thai RAPID can be a valuable tool for the ACD screening and for progression assessment in AD patients. PMID- 21591536 TI - Validity and reliability study of the Thai version of WHO Schedules for Clinical Assessment in Neuropsychiatry: Eating Disorders Section. AB - OBJECTIVE: To determine the validity and reliability of the Thai version of the WHO Schedules for Clinical Assessment in Neuropsychiatry (SCAN) Version 2.1, Eating Disorders Section MATERIAL AND METHOD: The SCAN interview version 2.1 Eating Disorders Section (section 9) was translated into Thai. The content validity of the translation was verified by comparing the back-translation to the English original. Whenever inconsistencies were encountered, the Thai version was adapted so that it correctly conveyed the meaning of the original English version. The revised Thai version was then field-tested in four regions (Suanprung Psychiatric Hospital, Jitavejkhonkaen Hospital, Srithanya Hospital and Suansaranrom Psychiatric Hospital, each place comprised 20 volunteers) for comprehensibility of the relatively technical language. Re-edition of the Thai version was made in accordance with suggestions from the field trial. The reliability study was done between October 2005 and September 2008 in which 30 persons (4 males; 26 females) were recruited. Fifteen persons (1 males and 14 females) were eating disorders patients (4 anorexia nervosa and 11 bulimia nervosa patients) and the other 15 (3 males and 12 females) were normal. The number of years of formal education varied widely and occupations were diverse. Subjects were interviewed using SCAN eating disorders section by a psychiatrist competent in using the Thai version of SCAN. The interviews were recorded on video so that the material could be re-rated. RESULTS: Regarding validity of WHO SCAN eating disorders section, based on the response from Thai subjects and consultations with competent psychiatrists, the content validity was established. Regarding the reliability study, the time taken to interview an eating disorder patient averaged 23.80 +/- 5.15 minutes (range, 18.35-34.26) versus 17.27 +/- 4.05 minutes (range, 9.07-22.37) for a normal subject. The mean of inter-rater reliability (kappa) of the eating disorder section was 0.73, standard error (SE) = 0.02, 95% confident interval (CI = 0.68-0.77). Seventy-eight point five percent of the items in the section had a substantial kappa. The mean of intra-rater reliabilities was 0.76, SE = 0.03, 95% CI = 0.70-0.82. Sixty-eight point four percent and 31.58% of the items had a substantial and almost perfect kappa respectively. CONCLUSION: The Thai version of the Eating Disorders Sections of SCAN version 2.1 proved to be a valid and reliable tool for assessing eating disorders among Thai speakers. PMID- 21591537 TI - Case report: severe CMV colitis in a patient with follicular lymphoma after chemotherapy. AB - BACKGROUND: Cytomegalovirus (CMV) can infect immuno-compromised host, especially in HIV and bone marrow transplantation patients. CMV colitis was reported after receiving chemotherapy in a solid tumor and aggressive Non-Hodgkin's lymphoma, but not yet in indolent lymphoma patients. CASE REPORT: In the present report, a 64-year-old woman was re-admitted with watery diarrhea after eight cycles of chemotherapy for Follicular lymphoma. She had hyponatremia, hypokalemia, and hypocalcemia, which were the consequences of severe diarrhea. After two weeks of continuous diarrhea, she was set for colonoscopy, which showed multiple ulcers along the colon. Pathological results were found to be consistent with CMV colitis. Her diarrhea symptom improved after receiving ganciclovir. CONCLUSION: CMV colitis could occur in indolent lymphoma patients who receive R-CVP regimen (rituximab, cyclophosphamide, vincristine, and prednisolone). Patients exhibiting severe and prolonged diarrhea should be investigated for definite diagnosis in order to receive proper treatment. PMID- 21591538 TI - Lactic acidosis associated with severe neuromuscular weakness and stavudine therapy. AB - Nucleoside analogue reverse-transcriptase inhibitors (NRTIs) especially stavudine, used for the treatment of HIV infection have been rarely associated with lactic acidosis syndrome (LAS) and severe neuromuscular weakness mimicking Guillain Barre syndrome. A 36-year-old man presented with a one-week history of nausea, vomiting, epigastric pain, dyspnea associated with progressive muscle weakness and numbness in glove and stocking pattern. He had symptomatic HIV infection, diagnosed 2 years before the admission and was treated with GPOvir (lamivudine, stavudine and nevirapine). Physical examination revealed afebrile dyspnic drowsy man with crepitation in both lungs and hepatomegaly. Neurological examination showed areflexic symmetrical weakness of both extremities and decreased pin-prick sensation in glove and stocking pattern as well as loss of vibration and touch sensation in both hands and feet. He developed cardiopulmonary arrest and was intubated. Investigations revealed severe lactic acidosis (lactic acid = 21.1 mg/dl). Electrophysiological studies revealed severe sensorimotor axonopathy predominantly involved the lower extremities. Stavudine was discontinued. Severe LAS dramatically improved and polyneuropathy gradually recovered with symptomatic as well as supportive interventions. Monitoring of LAS and neuromuscular weakness is advocated in HIV patient who receive stavudine therapy. Immediate discontinuation of the medication after detection of these complications may prevent this fatal complications. PMID- 21591539 TI - Neurofibromatosis type I associated multiple sclerosis. AB - Neurofibromatosis (NF) type I is a common autosomal dominant disease that principally affects the skin and peripheral nervous system. Neurofibromatosis type I associated multiple sclerosis is a very rare condition. A 28-year old NF1 man developed progressive spastic-ataxic gait, left side dysmetria, right internuclear ophthalmoplegia, spastic dysarthria. MRI of the brain depicted Dawson finger appearance demyelination of the corpus callosum and other multifoci demyelinating lesions typical for MS. CSF revealed high CSF protein with negative oligoclonal band. Visual evoked potential showed prolonged P100 latency, abnormal waveform and temporal dispersion bilaterally. The syndrome partially responded and stabilized with corticosteroid. Six months later progression of the syndrome characterized by paraparesis, bilateral cerebellar hemispheric syndrome and bilateral internuclear ophthalmoplegia occurred. Repeated MRI revealed more extensive white matter lesions extended into centrum semiovale. The progressive syndrome did not respond to corticosteroid. Primary progressive multiple sclerosis was diagnosed. Only thirteen cases with NF1 and multiple sclerosis have been described in the literature. The association has been hypothesized to be related to mutations in the neurofibromin protein or oligodendrocyte-myelin glycoprotein (OMgp) gene. PMID- 21591540 TI - Management of a large, recurrent simple cyst of the liver by total excision: a case report. AB - Simple cysts are common benign lesions of the liver. Treatment is reserved for symptomatic patients. Current management includes percutaneous aspiration with instillation of sclerosing agents, wide excision or unroofing, or fenestration of the cyst wall (> 50%) either by open or laparoscopic surgery. Total excision of the cyst wall is infrequently mentioned. The authors report a case of a large, recurrent simple cyst of the liver that was successfully treated by total excision. PMID- 21591541 TI - The use of imipramine in a child with Hinman's syndrome: case report. AB - BACKGROUND: The Hinman's syndrome is a serious and unusual outcome of the dysfunctional elimination syndrome. The data about treatment of this syndrome is very limited. OBJECTIVE: To describe an unusual treatment of the Hinman's syndrome in a child by using imipramine. MATERIAL AND METHOD: A 7-year-old Thai boy presented with both diurnal and nocturnal enuresis and dribbling for one year. After many investigations were performed, the diagnosis of Hinman's syndrome was established. Finally, imipramine was used for the treatment. RESULTS: The patient had a good response to the treatment by imipramine. Before the treatment was started, he had both diurnal and nocturnal enuresis almost every day. After one month of treatment, he became dry 4 to 5 days/week in daytime and 5 to 7 days/week at night. CONCLUSION: This report shows that imipramine may play a role in the treatment of Hinman's syndrome. PMID- 21591542 TI - Basic knowledge of transcranial direct current stimulation. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) was a neurophysiologic technique using weak electrical currents (1-2 mA) to modulate the activity of neurons in the brain. It was discovered in the 1960s, and then reintroduced by the reasonably well-controlled experiments 12 years ago. They suggested that electrodes placed on the head can produce noticeable neurological changes depended on the current direction. OBJECTIVE: To review a basic technique of the instrument, mechanism of action, and application in clinical researches of tDCS. MATERIAL AND METHOD: The tDCS studies were thoroughly reviewed in MEDLINE database using the key words "Transcranial direct current stimulation, tDCS, noninvasive brain stimulation, neurophysiologic technique" from 1998 to 2010. RESULTS: The basic technique of the instrument, mechanism of action, application in clinical researches such as stroke, pain syndrome and craving; safety, side effect, and precaution of tDCS are described. CONCLUSION: tDCS study is rapidly increasing and accepted as a noninvasive technique. It is easy to use and safe. The outcomes of tDCS in clinical researches are preferable with very little side effects. PMID- 21591543 TI - Comparative study on mineral elements in the roots of Rheum tanguticum from Qinghai-Plateau. AB - In the present paper, the authors analysed 10 mineral elements in the roots of Rheum tanguticum collected from 30 different habitats. The mean concentration values of the 10 elements decreased as follows: Ca>Mg>K>Fe>Mn>Cr>Zn>Ni>Cu>Se. Ca, Mg, K and Fe were abundant in this herb. Most elements varied over a wide range depending on the different habitats. The mineral element data were evaluated by principal component analysis to reveal the distribution pattern of elements in root. Four principal components (K-Ca factor, Cu factor, Mg factor and Zn-Se factor) of plant elements were selected. The authors' study provided a new scientific foundation for further studies and general application of this Chinese herb. PMID- 21591545 TI - Drug treatments for skin disease introduced in 2010. PMID- 21591544 TI - Therapeutic advances in cutaneous T-cell lymphoma. AB - A variety of novel therapeutic modalities have recently become available for patients with cutaneous T cell lymphoma (CTCL). In particular, with recent FDA approvals of the three new agents vorinostat (Zolinza), romidepsin (Istodax), and pralatrexate (Folotyn) CTCL treatment has been transformed. Here, we offer a brief overview of these agents and discuss their place in the spectrum of current therapies for CTCL. PMID- 21591546 TI - The stability of miniscrew placement. PMID- 21591547 TI - Factors contributing to the success or failure of skeletal anchorage devices: an informal JCO survey. PMID- 21591548 TI - A modified palatal anchorage plate for simple and efficient distalization. PMID- 21591549 TI - A simple technique for mandibular symphyseal distraction osteogenesis. PMID- 21591550 TI - A cast-metal Haas-type expander for the deciduous dentition. PMID- 21591551 TI - A precise bracket gauge for indirect bonding. PMID- 21591552 TI - Rotation wedges for forsus treatment. PMID- 21591553 TI - The importance of socio-environmental and personal factors related with smoking among high school seniors in western Kanagawa Prefecture, Japan. AB - OBJECTIVES: The purpose of this study was to identify socio-environmental and personal variables associated with high school students smoking behavior by applying multilevel analyses. METHODS: A cross-sectional survey of the first-year students of five public senior high schools in western Kanagawa Prefecture, Japan was conducted using multilevel logistic regression analyses with students at level 1 and schools at level 2. Self-administered questionnaires were returned by 517 out of 597 enrolled students, and information was collected regarding the prevalence of previous and current smoking and socio-environmental, educational and personal variables. RESULTS: The rates of past and current smoking were found to be 25.2% and 12.6% in males and 16.9% and 5.2% in females, respectively. Maternal smoking, having friends or older school-mates who smoked and lower probabilities of high school academic achievement potential were significantly associated with both past (adjusted ORs of 2.37, 4.28 and 2.98, respectively) and current (adjusted ORs 2.46, 5.57 and 3.02) smoking. CONCLUSIONS: It is recommended that health professionals in charge of school-based educational programs should tailor the teaching methods to fit the students' backgrounds and specific vulnerabilities. Educational programs for smoking prevention focusing on the students' mothers and classmates or students in high schools with reduced academic achievement potential should be developed. PMID- 21591554 TI - Too much for small hospitals. PMID- 21591555 TI - Staffing. Will you be ready if nurses strike? PMID- 21591557 TI - Patient education. Facebook isn't just for status updates or playing games anymore. PMID- 21591558 TI - Other voices. More clinicians speak up about flawed care, but silence still kills. PMID- 21591556 TI - Patient satisfaction. Satisfaction surveys start to focus on the whole picture. PMID- 21591559 TI - Patient satisfaction. Project runway: hospital gowns get some fashion sense. PMID- 21591560 TI - Fulfilling a final request. PMID- 21591561 TI - The season of hope. PMID- 21591562 TI - mHealth. AB - More than 17,000 mHealth apps now are available for smart phones and other devices, and they do everything from monitoring urine flow for patients with enlarged prostates to reminding people prone to kidney stones to drink more water. And that's just on the consumer side. Countless apps are avail-able for use by clinicians and hospitals. Mobile apps are changing health care in dramatic ways. PMID- 21591563 TI - Turning nurses into health IT superusers. AB - Just training nurses and hoping they're happy with health information technology is a losing proposition. Most Wired hospitals find it best to get nurses involved in digital decisions early on. PMID- 21591564 TI - Long-term care: your new priority. PMID- 21591565 TI - Best practices for recruitment & retention. AB - The recession temporarily eased the health care workforce shortage, but our aging population will boost both retirements and demand for your services. Here are tips for hiring and keeping staff. PMID- 21591566 TI - A path to nursing excellence. PMID- 21591567 TI - Driving out errors,. AB - Eastern Maine Healthcare Systems has an ambitious goal: Zero medical errors. Its strategy: Highly involved leaders, processes that "couldn't fail if you tried" and one heart-hitting image. PMID- 21591568 TI - The FTC vs. Lake Wobegon. PMID- 21591569 TI - The Belgian Society of Cardiology: a view on its strength, weakness, opportunities and threats. PMID- 21591570 TI - Evidence-based selection of contrast media in interventional cardiology: implications of the updated guidelines. PMID- 21591571 TI - Implantable cardioverter/defibrillator interventions in primary prevention: do current implantation criteria really predict ICD interventions? AB - BACKGROUND: Randomized controlled trials have proven the efficacy of implantable cardioverter/defibrillators (ICDs) to prevent sudden cardiac death (SCD) in primary prevention. However,long-term data on the incidence of appropriate and inappropriate interventions in real life and on the predictive value of commonly used clinical variables to guide patient selection are scarce. METHODS: We retrospectively studied 101 patients who received an ICD for primary prophylaxis of SCD: 63.4% with ischaemic heart disease (IHD) and 36.6% with idiopathic dilated cardiomyopathy (IDCM). The mean follow-up period was 26.2 (+/- 14.8; median 27.8; range 5.6-70.5) months. Age, left ventricular ejection fraction (LVEF), QRS duration, NYHA class and electrophysiological study (EPS) outcome were evaluated as predictors of ICD intervention. RESULTS: At 2 years the cumulative incidence of appropriate (17.5% in IHD; 28% in IDCM; P= 0.63) and inappropriate (12.8% in IHD, 15.4% in IDCM; P = 0.62) interventions was similar in both groups. Atrial fibrillation was the most common cause of inappropriate interventions in the IHD group, sinus tachycardia in the IDCM group. Advanced age was associated with less inappropriate interventions (HR: 0.96 (95% confidence interval (CI) 0.94-0.98); P < 0.01), and a better LVEF with less appropriate interventions (HR: 0.97 (95% Cl 0.94-0.99); P < 0.01). This amounted in a significant absolute difference in the number of appropriate interventions between the group with a LVEF < 25% and 25-34% after 3 years of follow-up of 42% in IHD (48% vs 6%). A prolonged QRS duration was associated with a slightly elevated risk for appropriate interventions only in the IHD group (HR: 1.01 (95% CI 1.00-1.03); P = 0.04). On the other hand, increased NYHA class was only associated with increased risk for appropriate interventions in the IDCM group (HR: 5.24 (95% CI1.11-24.74); P= 0.04). No significant statistical association was found between a positive EPS and appropriate or inappropriate interventions. CONCLUSIONS: In primary prevention, during a mean follow-up of 2 years, one in five patients had a possibly live-saving appropriate intervention. However, the incidence of inappropriate interventions was substantial. Predictors for appropriate interventions were: (i) LVEF in the total study group, (ii) NYHA class in the IDCM group and (iii) QRS duration in the IHD group. PMID- 21591572 TI - Left atrial size and left ventricular hypertrophy correlate with myocardial fibrosis in patients with hypertrophic cardiomyopathy. AB - INTRODUCTION: In hypertrophic cardiomyopathy (HCM) risk assessment with respect to sudden cardiac death (SCD) is currently based on the presence or absence of different risk markers (RM). Recently, myocardial fibrosis as detected by gadolinium-enhanced magnetic resonance imaging (GE-MRI) has been suggested as additional RM. We evaluated the prevalence of myocardial fibrosis and examined correlations with other risk markers in patients considered to be at increased risk. METHODS: We included 50 patients with HCM with > 1 (2-4) RM who underwent GE-MRI to check for myocardial fibrosis. Late enhancement was assessed semi quantitatively using a 17-segment model of the LV (from 0 = absent, 1 = point shaped, 2 = limited to 1 LV segment, 3 = involving > or = 2 segments). Outflow obstruction was present in 25 patients, the other 25 (1 after septal ablation and after myectomy) were non-obstructive. RESULTS: Patients (33 men; mean age 44 +/- 13 years; NYHA class: 2.0 +/- 0.9) had a number of RM of 1.7 +/- 0.8. Evidence of myocardial fibrosis > or = 2 was found in 39 patients (mean score: 2.3 +/- 0.9). Correlations were found between left atrial diameter (eta = 0.5), septum thickness (eta = 0.6), and severity of fibrosis. Patients with fibrosis 2 had larger left atria (50 +/- 7 vs 43 +/- 7 mm, P = 0.007) and a thicker septum both on echocardiography (25 +/- 6 vs 17 +/- 5 mm, P < 0.001) and on GE-MRI (28 +/- 5 vs 20 +/- 4 mm, P = 0.01). No correlations were found between fibrosis score and other RM, global LV mass on GE-MRI, or other clinical variables. CONCLUSIONS: Left ventricular hypertrophy and left atrial size, as two markers for global disease severity, correlate with the severity of fibrosis on GE-MRI. PMID- 21591574 TI - Metabolic syndrome with or without diabetes contributes to left ventricular diastolic dysfunction. AB - OBJECTIVE: Left ventricular diastolic dysfunction (LVDD) is considered a precursor of diabetic cardiomyopathy, while the metabolic syndrome (MetS) is associated with an increased risk of cardiovascular morbidity and mortality. This study aimed to evaluate the association between LVDD, MetS and glucose metabolism disturbances classified by oral glucose tolerance testing (oGTT). METHODS AND RESULTS: The presence of LVDD was evaluated in 166 subjects with normal ejection fraction, 43 (26%) of whom had type 2 diabetes at inclusion. In subjects without diabetes, an oGTT was performed. The MetS was diagnosed as indentified by the NCEPIII-criteria, while LVDD was verified and graded according to the current guidelines. MetS was diagnosed in 97 (59%) patients, 44% of whom had known diabetes. The prevalence of LVDD was 68% in subjects with MetS vs. 19% in patients without MetS, respectively (P < 0.001). A severe form of LVDD was observed in 34% and 15% of patients with and without MetS, respectively (P = 0.001), whereupon the prevalence of mild and severe diastolic dysfunction increased with the number of MetS criteria (P= 0.001). In the MetS group, early diastolic tissue relaxation velocity (E') was significantly reduced (6.9 +/- 1.8 cm/s vs. 7.7 +/- 2.1 cm/s; P= 0.009) and the E/E' ratio was significantly higher (10.5 +/- 3.9 vs. 9.1 +/- 3.0 cm/s, P = 0.015) as compared to the group without MetS (n = 69). CONCLUSION: MetS was associated with a higher prevalence and severity of LVDD, whereupon coexisting diabetes aggravates these inding.Patients displaying MetS with concomitant LVDD might represent a target population in which appropriate medical care for early heart failure prevention should be initiated. PMID- 21591573 TI - Heart structure and function in patients with generalized autoimmune diseases: echocardiography with tissue Doppler study. AB - OBJECTIVE: Heart pathology strongly influences the course and prognosis of patients with generalized autoimmune diseases. In spite of autoimmunity being a common denominator of these diseases, systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and dermato/polymyositis (DPM) differ significantly in the pathogenesis of organ damage. The aim of the study was to compare pathologic changes in heart structure and function in these diseases by means of standard echocardiography and tissue Doppler (TDE). MATERIAL AND METHODS: Four groups were examined: 60 SSc, 60 SLE and 15 DPM patients in stable clinical conditions and 30 healthy control subjects. Echocardiography with TDE was performed with the assessment of systolic (S) and diastolic (E) velocities of mitral and tricuspid annuli. RESULTS: Heart in SSc was characterized by significant diastolic left ventricular dysfunction (mitral E 8.61 +/- 2.3 cm/s vs. 12.4 +/- 3.5 cm/s in the control group; P < 0.01) with preserved systolic function (mitral S 7.85 +/- 1.5 cm/s vs. 7.95 +/- 0.9 cm/s in control group; ns). SLE and DPM resulted mainly in pathologic thickening of valvular leaflets and/or pericardium [mitral or aortic leaflets thickened in 38 (63.3%) of SLE patients, 7 (46.7%) of DPM patients; pericardium thickened in 36 (60%) of SLE patients]. Pulmonary capillary wedge pressure was elevated in SSc (13.8 +/- 3.5 mmHg) and DPM (13.2 +/- 2.5 mmHg) patients as compared to the control group (9.2 +/- 3.7 mmHg, P < 0.01). Right ventricular systolic and diastolic dysfunction was frequent irrespective of the presence or absence of pulmonary hypertension. CONCLUSIONS: Echocardiography with TDE reveals characteristic pathology in different forms of generalized autoimmune diseases reflecting their different pathogenetic mechanisms. Overproduction of collagen in SSc results in diastolic left ventricular dysfunction, while generalized inflammation in SLE and DPM leads mainly to pathologic changes on valvular leaflets and/or pericardium. Interestingly, right ventricular dysfunction is common in all diseases analyzed, regardless of the presence of pulmonary hypertension. Echocardiography, preferably with TDE, could add valuable information about usually asymptomatic heart pathology in an individual patient with generalized autoimmune disease. PMID- 21591575 TI - Electrical remodelling in cardiac resynchronization therapy: decrease in intrinsic QRS duration. AB - INTRODUCTION: Cardiac resynchronization therapy (CRT) provides a therapeutic option for patients with congestive heart failure (CHF) and left bundle-branch block. Structural myocardial remodelling due to CRT has been described extensively. We hypothesized that CRT might also induce electrical remodelling, thus decreasing the intrinsic QRS duration. METHODS: In 38 patients with CHF (ejection fraction (EF): 26 +/- 7%) a CRT device was implanted. 18 patients suffered from ischaemic cardiomyopathy (ICM) and 20 from dilated cardiomyopathy (DCM). Echocardiography and 12-lead ECGs without pacing were obtained prior to implantation and after 6 and 12 months. Patients were classified as responders in case of an increase in EF > or = 25% in combination with an increase in NYHA class > or = 1. Variance analysis was performed to determine the impact of response or underlying heart disease (ICM/DCM) on the extent of change in QRS duration (delta QRS duration). RESULTS: The EF increased to 36 +/- 10% (P < 0.0001) after 6 months and 40 +/- 12% (P < 0.0001) after 12 months of CRT. Intrinsic QRS duration decreased from 171 +/- 18 ms before CRT to 164 +/- 23 ms (P = 0.027) after 6 months and 161 +/- 25 ms (P = 0.002) after 12 months of CRT. 22 patients (58%) were classified as responders. Whereas a significant decrease in intrinsic QRS duration was observed in responders, only a slight decrease was seen in non-responders. However, two-factorial variance analyses did not show a significant influence of response or underlying heart disease (ICM/DCM) on delta QRS duration (P = 0.7). CONCLUSION: CRT results in an electrical remodelling with a reduction of the intrinsic QRS duration. PMID- 21591576 TI - Association between cardiac functional capacity and parameters of tissue Doppler imaging in patients with normal ejection fraction. AB - OBJECTIVE: Patients with normal ejection fraction (EF) by conventional echocardiography may present with symptoms and findings of decreased cardiac functional capacity. We aimed to investigate the association between cardiac functional capacity determined by cardiopulmonary exercise test (CPET) and parameters of tissue Doppler (TD) imaging in patients with normal EF. METHODS: In all, 52 patients with normal EF were included. Conventional and TD imaging were performed. Peak systolic (S), early (E') and late (A') diastolic velocities were obtained from septal and lateral mitral annulus and tricuspid annulus by pulsed wave TD. CPET was performed. Exercise time, peak oxygen consumption (peak VO2), anaerobic threshold (AT), metabolic equivalents (MET) values were determined and were compared with TD imaging parameters. RESULTS: We did not find any association between conventional echocardiographic measurements and cardiac functional capacity. However, peak S, E' and A velocity from the septal and tricuspid annulus and E' velocity from the lateral annulus correlated with exercise time, peak VO2, AT and MET (all P < 0.05). E/E' from the left ventricle correlated inversely with exercise time, peak VO2, AT and MET (all P < 0.05). S, E, A' velocities from septal and tricuspid annulus, E' velocity from lateral annulus were lower in patients with MET < or = 7 than in patients with MET > 7 (all P < 0.05). CONCLUSION: Systolic and diastolic velocities measured byTD imaging correlated with cardiac functional capacity as determined by CPET in patients with normal EF by conventional echocardiography. TD imaging could be more susceptible to determine cardiac functional capacity in these patients. PMID- 21591577 TI - Are all criteria of metabolic syndrome equally harmful? AB - OBJECTIVE: The metabolic syndrome (MS) is associated with subclinical damage of different organs.The aim of this study was to determine which risk factors of MS were independently associated with left ventricular structure and function (diastolic and global). METHODS: The study included 204 subjects with MS and 88 control subjects with no risk factors. The metabolic syndrome was defined by the presence of three or more of ATP-NCEP III criteria. All subjects underwent laboratory blood tests, and complete two-dimensional echocardiography which also included tissue Doppler. The echocardiography was used to assess left ventricular (LV) structure (LVmass/Ht2.7), systolic (LVEF, Ssepptal, Slateral) and diastolic function, by pulse-wave Doppler (E/A ratio) and tissue Doppler imaging (E/e'average), and global function (Tei index). Appropriate time intervals for the estimation of the Tei index were obtained by tissue Doppler. RESULTS: The LV mass index, E/e'average and Tei index were significantly higher in the MS group, whereas there was no difference in LV systolic function. Multiple regression analysis showed that LVmass/Ht2 was independently associated with systolic blood pressure (beta = 0.41, P < 0.001) and waist circumference (beta = 0.22, P = 0.016).The same analysis revealed that E/e'verage was independently associated with systolic blood pressure (3 = 0.35, P < 0.001), waist circumference (beta = 0.24,P = 0.004) and triglycerides level (3 = 0.21,P = 0.012); while theTei index was independently associated with systolic blood pressure (beta = 0.42, P < 0.001) and fasting glucose (beta = 0.31, P < 0.001). CONCLUSION: MS impairs left ventricular structure and diastolic and global function. Systolic blood pressure was the only MS criterion which was, at the same time, independently associated with LVmass/Ht27, E/e'averag3, and the Tei index. PMID- 21591578 TI - Plasma osteopontin levels in prediction of prognosis in acute myocardial infarction. AB - OBJECTIVE: We sought to explain the clinical importance of the osteopontin (OPN) in the setting of acute ST-elevation myocardial infarction (STEMI). METHODS: Eighty consecutive patients (55 = 11 years, 12 women and 68 men) and sixty healthy control subjects were included in the study. In all patients, plasma OPN levels were assessed on admission and on the third day (peak value). Creatinine kinase (CK)/CK-myocardial band (MB), troponin I and N-terminal pro-brain natriuretic factor levels and echocardiographic findings were also recorded. Patients were classified into high and low OPN groups according to the median OPN value, and monitored for the occurrence of major adverse cardiovascular events (MACE). RESULTS: Patients with STEMI had higher OPN levels (23.8 [16.7-41.3] ng/ml) on admission than the control subjects (18.0 [11.3-31.5] ng/ml, P = 0.004).The third day value of OPN was significantly higher (39.2 [27.2-56.0] ng/ml) than the OPN level on admission (23.8 [16.7-41.3] ng/ml, P < 0.001). Admission and peak OPN levels were not correlated with CK/CK-MB, white blood cell counts, troponin I and the N-terminal pro-brain natriuretic factor. The plasma OPN levels were not correlated with left ventricular wall motion score index either. In the subgroups of infarct localization and reperfusion strategy, plasma OPN levels were similar. When the patients were compared according to the median OPN values, there were no differences in the occurrence of MACE between the high and low OPN groups. CONCLUSION: This study suggests, for the first time, that the plasma OPN level increases in the first hours of the acute STEMI; however, it could not be used as a prognostic biomarker of STEMI. PMID- 21591579 TI - Bleeding complications with acute coronary syndrome in six Middle Eastern countries. AB - OBJECTIVE: Little is known about the prevalence and prognostic implications of major bleeding complications among patients admitted with acute coronary syndrome (ACS) in the Middle East. We describe the prevalence and outcome of ACS in Middle Eastern patients with and without major bleeding complications. METHODS: The Gulf Registry of Acute Coronary Events (Gulf RACE) is a prospective, multinational registry conducted for 6 months in 2007 for patients hospitalized with the final diagnosis of ACS in 65 centres in six adjacent Middle Eastern countries. There were no exclusion criteria. A total of 8166 patients were stratified according to the development of major bleeding complications during the index admission. RESULTS: Compared to patients without bleeding complications, patients with major bleeding (68 patients, 0.83%) were significantly older, and had ST-segment elevation myocardial infarction. However, there were no significant differences between the two groups with regard to sex, other cardiovascular risk factors, or use of antiplatelet and antithrombotic therapy. Patients with bleeding complications had worse in-hospital outcomes including death, congestive heart failure, cardiogenic shock, recurrent myocardial infarction, and stroke. After adjusting for baseline characteristics, major bleeding was independently associated with a more than 5-fold increase in in-hospital mortality (odds ratio 5.2, 95% confidence interval 2.8-10.1, P < 0.001). CONCLUSION: Similar to Western studies, bleeding in the setting of ACS is a powerful and independent predictor of poor in-hospital outcomes in patients admitted with ACS in the Middle East. PMID- 21591580 TI - The combination of 64 multislice CT angiography and optical coherence tomography optimally characterizes coronary plaques. AB - OBJECTIVE: The European Society of Cardiology designated 2008 as the year of imaging. However, despite the intense focus on the many types of imaging and the relative benefits of each one, the optimal modalityfor the diagnosis of coronary artery disease remains controversial. Among the currently available techniques, coronary angiography (CA) is the most widely used. In light of the many recent improvements in imaging, a comparison of the different modalities for CAD diagnosis and treatment evaluation is urgently needed. MATERIAL AND METHODS: of the 1583 patients examined by computed tomography CA (CTCA) in the past 2 years, 28 with unstable angina also underwent CA and optical coherence tomography (OCT) evaluation. The coronary artery indices obtained with the three modalities were compared in this subset of patients. RESULTS: Minimal lumen diameter and reference lumen diameter were calculated independently based on the data obtained from each modality. The diameters measured by CTCA were significantly larger than those measured by CA or OCT (p < 0.05). Minimal cross-section area calculation was feasible only from the CTCA and OCT data, but not from the CA data. Again, the cross-sectional area measured by CTCA was significantly larger than that measured by OCT. Plaque diameter, remodelling index, plaque volume, and CT value could be measured only by CTCA. Disease extent was measured by CTCA using the method of J.K. Min and by CA using the Syntax Score. Intimal thickness and the thickness of the thrombus and fibrous cap could be evaluated only by OCT. CONCLUSION: A comparison of the three different imaging modalities (CA, CTCA, and OCT) in CAD pointed out the benefits as well as the limits. A combination of CA, CTCA, and OCT was found to provide the best approach to evaluating the coronary arteries. CTCA best revealed the vessel wall while OCT provided optimal visualization of the intima. The extent of coronary artery disease was best detered with CA and CTCA. PMID- 21591581 TI - Lack of beneficial effects of granulocyte colony-stimulating factor in patients with subacute myocardial infarction undergoing late revascularization: a double blind, randomized, placebo-controlled clinical trial. AB - BACKGROUND: Early clinical studies have suggested that administration of granulocyte-colony stimulating factor (G-CSF) may improve the clinical condition of patients suffering from myocardial infarction (MI).This prospective, randomized, double-blind, placebo-controlled single-centre trial aims to assess the safety and clinical efficacy of G-CSF administration in patients with subacute MI and impaired LV function undergoing delayed primary percutaneous coronary intervention (PCI). METHODS: A total of 16 patients (13 men, mean age 51 years) with subacute ST-segment elevation MI and a left ventricular (LV) ejection fraction (EF) of less than 45% at baseline who underwent late revascularization, were included in the study. Patients were randomized in a double-blind fashion to receive either G-CSF (at a dose of 10 microg/kg body weight) or placebo for five consecutive days. End points consisted of assessment of safety parameters as well as changes of global and regional myocardial function from baseline until six months following PCI. RESULTS: G-CSF administration resulted in a significant mobilization of different cell populations (four-fold increase in WBC count and a six-fold increase in CD34+ cells). G-CSF treatment was well tolerated in most patients and no major adverse cardiac events or severe G-CSF-related side effects were identified during hospitalization and at follow-up. No significant differences were observed between the G-CSF and placebo groups regarding global and regional myocardial function parameters. CONCLUSION: G-CSF administration is safe, but not effective, in improving impaired LV functional parameters in patients with subacute MI who had an impaired baseline EF of less than 45%. PMID- 21591582 TI - Ventricular septal rupture following acute myocardial infarction. AB - OBJECTIVE: Ventricular septal rupture (VSR) is a complication of acute myocardial infarction (AMI) that is associated with significant mortality. We aim to review the clinical outcome in the current era. METHODS AND RESULTS: Patients admitted to a single tertiary centre from 1997 to 2008 with VSR post-AMI were identified from the local cardiac registry. We performed a retrospective review on 25 patients. Mean age (15 women) was 71 years. Most patients had cardiovascular risk factors (84%); the commonest was hypertension (72%). Anterior AMI (80%) and apical VSR (84%) formed the majority of the cases. Eleven patients (44%) received prior coronary reperfusion therapy either via thrombolysis or PCI. Median time to rupture was 1 day from diagnosis of infarction. More than half (60%) of the patients were in Killip class 3 or 4 at diagnosis of rupture. Mean left ventricular ejection fraction (LVEF) was 33 +/- 10%. Most patients (80%) required IABP for haemodynamic support. All patients who underwent surgery had ventricular septal repair; amongst them 47% had concomitant CABG. Those managed conservatively were older (P = 0.01). Overall mortality rate was 44%. Most died within the first four days (82%). Surgical and non-surgical survival rates were 68% and 17%, respectively (P= 0.039). Patient demographics, prior coronary reperfusion techniques, Killip class status and LVEF were not significant predictors of mortality. However, non-anterior wall AMI and non-apical VSR were significantly associated with poorer survival (P = 0.009, P = 0.026 respectively). CONCLUSIONS: While the occurrence ofVSR post-AMI appears to be low compared to earlier studies, it continues to be associated with significant mortality. Non-anterior wall AMI and non-apical VSR were associated with poorer survival and surgical repair conferred survival advantage over conservative management. PMID- 21591583 TI - Differential effect of ATP binding cassette transporter A1 R219K and cholesteryl ester transfer protein TaqIB genotypes on HDL-C levels in overweight/obese and non-obese Chinese subjects. AB - OBJECTIVES: ATP-binding cassette transporter A1 (ABCA1) and cholesteryl ester transfer protein (CETP) are involved in the HDL metabolism and play a key role in reverse cholesterol transport. The study aim was mainly to examine the possible association of the ABCA1 and CETP polymorphisms with overweight/obesity in a South-West Chinese population. METHODS AND RESULTS: Three hundred and thirty eight Han Chinese (206 overweight/obese and 132 normal control subjects) in Chengdu area were studied using the PCR-RFLP analysis. The genotype and allele frequencies of the ABCA1 R219K, CETP Taq IB and -629C > A polymorphisms in cases of overweight/obesity showed no significant statistical difference compared to those of the control subjects. However, on analysis of the HDL-C levels, cases showed statistically higher levels among those carrying the ABCA 1 KK genotype compared to RR genotype carriers, and controls having the CETP B2B2 genotype had a marginally significantly higher serum HDL-C concentration than those of the B1B1 genotype. In addition, the combined genotype effect of the ABCA1 R219K and the CETP Taq IB polymorphisms on HDL-C levels was evident in the control subjects: the carriers of the KK/B2B2 genotype showed the highest levels of HDL-C (2.23 +/- 0.91 mmol/L), whereas those of the RR/B1B1 genotype showed the lowest (1.32 +/- 0.33 mmol/L). There were significant differences of the HDL-C levels between subjects with genotype KK/B2B2 and those with each of the other genotype combinations (all P < 0.05). CONCLUSION: Polymorphisms of theABCA1 and CETP genes are associated with altered plasma HDL-C concentrations.These associations on HDL C levels are modified by BMI in a Chinese population of the Chengdu area. PMID- 21591584 TI - Transradial approach in myocardial infarction. AB - OBJECTIVE: This study investigates the feasibility, efficacy, and safety of routine primary percutaneous coronary intervention via transradial approach in patients with acute ST-elevation myocardial infarction. METHODS AND RESULTS: From 2005 to 2007,122 consecutive patients with acute ST-elevation myocardial infarction within 12 hours, including those experiencing cardiogenic shock, were eligible for primary transradial PCI if the radial artery pulse could be felt. Efficacy, safety, and major adverse cardiac events regarding mortality, recurrent non-fatal myocardial infarction, and revascularization were recorded. Eighty-five of 122 patients underwent transradial PCI, and 37 had transfemoral PCI. Older women, haemodynamic instability, and the presence of severe chronic kidney disease (stages 4 and 5) or end-stage renal disease were significantly related to choice of transfemoral approach (P < 0.05). Glycoprotein IIb/IIIa inhibitors were used more often in patients who underwent transradial PCI than in those who underwent transfemoral PCI (37% vs 16%; P = 0.043). The incidence of major bleeding complications requiring blood transfusion was significantly higher in the transfemoral group (P = 0.004). A similar procedural success rate was achieved in both groups (P = 0.737). During follow-up of 580 days, the total major adverse cardiac events were similar in both groups (P = 0.299). CONCLUSIONS: Routine transradial primary PCI can be safely and successfully performed on up to 70% of acute ST-elevation myocardial infarction patients and, compared with transfemoral approach, is associated with a significantly reduced rate of major bleeding complications. PMID- 21591585 TI - Flecainide. PMID- 21591586 TI - Purulent pericarditis and pericardial abscess one year after LAD-stenting. PMID- 21591587 TI - Acute cardiac tamponade: presenting sign of acute leukaemia. AB - Cardiac tamponade is a life-threatening emergency that has to be promptly recognised. We report the case of a young adult patient with an acute cardiac tamponade as a rare presenting symptom of T-cell acute leukaemia. An emergency pericardiocentesis was performed with immediate relief of the symptoms. The aetiology was diagnosed on the basis of the serological hyperleucocytosis and the anatomopathological analysis of the pericardial fluid. The patient was subsequently referred for chemotherapy. Acute leukaemia presenting with pericardial tamponade as a first sign is rare, and described only in a few case reports. Furthermore, we discuss the diagnostic and therapeutic measures of haemodynamic unstable cardiac tamponade. PMID- 21591588 TI - Anomalous right coronary artery causing inferior myocardial infarction, diagnosed on the occasion of a life-insurance medical exam. AB - We present a case of an anomalous right coronary artery (RCA) originating from the opposite aortic sinus causing a transmural inferior myocardial infarction in a former competitive cyclist, followed by a brief discussion of the epidemiology, presentation, diagnosis and treatment of this coronary anomaly. PMID- 21591589 TI - The use of ivabradine for inappropriate sinus tachycardia. AB - We present a 47-year-old woman with inappropriate sinus tachycardia. Initial treatment with beta blockers was not successful. The patient became asymptomatic and tachycardia resolved with ivabradine. In this report we review the potential role of ivabradine in the treatment of inappropriate sinus tachycardia. PMID- 21591590 TI - Treating humoral rejection after cardiac transplantation. AB - Whereas effective strategies are available to treat acute cellular cardiac rejection, humoral rejection, also called vascular or antibody-mediated rejection, is more difficult to manage. Antibody-mediated (non-cellular) rejections (AMR) are rare and few successfully treated cases have been described in the literature. We report on a female patient, diagnosed with humoral rejection, leading to severe ventricular dysfunction and haemodynamic compromise, two months after transplantation. The patient received a combination therapy, consisting of plasmapheresis and immunoglobulins, which resulted in complete resolution of immunohistochemical signs of AMR. In this report, we will overview AMR and discuss several treatment modalities. PMID- 21591591 TI - Ventricular tachycardia: first manifestation of myotonic dystrophy. AB - Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy in adults. It is a multisystem disorder also affecting the heart with an increased incidence of sudden cardiac death. We present a young female patient with ventricular tachycardia (VT) who had no cardiac complaints previously. In this patient, the phenotypic characteristics implying DM1, neuromuscular testing and genetic analysis all confirmed the diagnosis of DM1 and because of the malignant nature of VT, she received an implantable cardioverter/defibrillator. PMID- 21591592 TI - Synovial sarcoma in the right atrium and right ventricle. AB - A metastatic synovial sarcoma in the right atrium and ventricle is described. A 36-year-old man was admitted to our hospital with generalized fatigue, dyspnoea, and precordial pain. Transthoracic echocardiography demonstrated a metastatic tumour in both the right atrium and right ventricle and revealed obstruction of the inflow tract of the right ventricle caused by a metastatic right atrial tumour. Thoracic computed tomography revealed a pleural-based paravertebral mass in the left intrathoracic cavity and multiple pulmonary nodules in both lungs. Cardiac surgery was performed for palliative treatment due to right cardiac failure and a risk of fatal embolization. The patient died 12 months after the cardiac surgery. PMID- 21591593 TI - Right-sided coronary artery origin: interarterial or intraseptal course? PMID- 21591594 TI - BMI status in Swedish children and young adults in relation to caries prevalence. AB - Overweight and obesity are increasing as health problems at global level. Dental caries and obesity are both multifactorial diseases and are associated with dietary habits. The aim of the present study was to investigate the relationship between body weight status and caries prevalence in an unselected population followed from pre-school years to young adulthood. The present investigation was designed as a longitudinal analysis of the association between overweight/obesity and dental caries in one population at 3, 6, 15 and 20 years of age. The result shows that adolescents (15 years) and young adults (20 years) who are overweight/obese had a statistically significantly higher caries prevalence than normal-weight young people. At 6 years of age, the odds (OR) of having caries among obese children are 2.5 times higher than the odds for caries among six-year old children of normal weight (p = 0.04). At 3 years of age, no association between overweight/obesity and caries was found. To conclude, overweight and obese adolescents and young adults had more caries than normal-weight individuals. The present study emphasises the need for multidisciplinary approaches to change the lifestyle factors causing both overweight/obesity and dental caries. PMID- 21591595 TI - Comparison between high concentration EDTA (24%) and low concentration EDTA (3%) with surfactant upon removal of smear layer after rotary instrumentation: a SEM study. AB - This in vitro study compare cleanliness of tooth canal walls regarding smear layer after final treatment with 24% ethylenediaminetetraaceticacid (EDTA) and 3% EDTA with or without surfactant. Sixty extracted teeth, randomly distributed into four groups, were prepared using ProFile instruments (DENTSPLY, Maillefer, Ballaigues, Switzerland), and subjected to different final irrigation solutions: group A, 24% EDTA; group B, 3% EDTA with surfactant; group C (positive control), 3% EDTA; and group D (negative control), 0.5% sodium hypochlorite. Roots were sectioned, examined and evaluated under scanning electron microscope; microphotographs were taken for the coronal, middle and apical third of each specimen. Statistical analysis showed no difference regarding presence of smear layer between test groups in the coronal and apical sections. They were cleaned in the coronal sections and uncleaned in the apical sections. In the middle section, group B was significantly cleaner (p < 0.05) than the other groups. In conclusion, surfactant in combination with EDTA did not improve root canal cleanliness and there is no difference between different EDTA concentrations in removing the smear layer. PMID- 21591596 TI - Effect of post-brushing mouthrinse solutions on salivary fluoride retention. AB - Fluoride (F) toothpaste is one of the most effective means of caries prevention. There is also evidence that mouthrinse solutions with antimicrobial agents reduce plaque formation and gingivitis and may be used as adjuncts to daily self performed oral hygiene for risk patients. The authors hypothesize that using these solutions--without or with just a low F concentration after brushing--will have a "wash-out" effect on F toothpaste. Mouthrinse solutions with more F might be beneficial in this respect. Two groups of 10 (Series 1) and 12 (Series II) healthy subjects were recruited. They brushed for 1 min with toothpastes containing either 1450 or 5000 ppm F. After brushing and spitting out the toothpaste, the participants in Series I rinsed for 30 sec with 10 ml of a variety of products with various F concentrations (0, 100, 226 or 900 ppm F). In Series II, they first rinsed with water after the brushing and directly thereafter with 20 ml of the post-brushing rinsing solution for 30 sec. Saliva samples in both series were collected at different time points up to 1 h and the F concentration was measured. There was significantly less F in saliva after rinsing with no F or with a low F concentration (100 ppm) compared with just brushing with a F toothpaste. Rinsing with 226 ppm F displayed significantly higher F concentrations in saliva compared with only toothbrushing. Products with a high F concentration (i.e. toothpaste with 5000 ppm F or a mouthrinse solution with 900 ppm F) produced the highest F retention in saliva compared with all other protocols. The quantity of mouthrinse solution (20 vs. 10 ml) did not seem to have any effect on the F retention. The results from both test series show that a post-brushing rinsing solution without F or with just 100 ppm F exerts a "wash-out" effect on toothbrushing with either 1450 or 5000 ppm F, which may be negative for all patients, especially those with a risk of caries. The general population will benefit more from higher concentrations of F in mouthrinse solutions and, based on the results of the present investigation, 226 ppm F (corresponding to 0.05% NaF) should be the lowest concentration used. Furthermore, caries risk patients are recommended to use a high-F toothpaste (5000 ppm F) or a post-brushing mouthrinse solution with 900 ppm F (corresponding to 0.2% NaF). PMID- 21591597 TI - Firing temperature accuracy of four dental furnaces. AB - In spite of using recommended firing and displayed temperatures, low-fired dental porcelain more often demonstrates unsatisfactory results after firing than porcelain fired at higher temperatures. It could therefore be anticipated that temperatures shown on the display are incorrect, implying that the furnace does not render correct firing programs for low-fired porcelain. The purpose of this study is to investigate deviations from the real temperature during the firing process and also to illustrate the service and maintenance discipline of furnaces at dental laboratories. Totally 20 units of four different types of dental furnaces were selected for testing of temperature accuracy with usage of a digital temperature measurement apparatus, Therma 1. In addition,the staffs at 68 dental laboratories in Sweden were contacted for a telephone interview on furnace brand and on service and maintenance program performed at their laboratories. None of the 20 different dental furnaces in the study could generate the firing temperatures shown on the display, indicating that the hypothesis was correct. Multimat MCII had the least deviation of temperature compared with displayfigures. 62 out of 68 invited dental laboratories chose to participate in the interviews and the result was that very few laboratories had a service and maintenance program living up to quality standards. There is room for improving the precision of dental porcelain furnaces as there are deviations between displayed and read temperatures during the different steps of the firing process. PMID- 21591599 TI - Outcome of a scheme for specialist orthodontic care, a follow-up study in 31-year olds. AB - Changes in the occlusion after orthodontic treatment have in several studies been analyzed by the use of the PAR Index developed by Shaw & Richmond. The use of the PAR Index has been shown by O'Brien & Shaw to be a reliable and reproducible method to evaluate orthodontic treatment results. The purpose of the study was to examine the long-range orthodontic treatment outcome by following a group of patients into adulthood to the age of 31 years. For the study 115 individuals from a previous randomized study were invited for follow-up examination at age 31 years. Seventy-two individuals, 32 males (44.4%) and 40 females (55.6%) of the original sample attended for clinical examination. Study casts were obtained and questionnaires addressing the patient's awareness and opinion of the treatment were distributed. In addition twenty-four subjects responded by returning filled in questionnaires. The mean change in wPAR scores from start to retention represents a mean relative improvement in occlusion of 78.7%. The mean wPar score improvement from age 19 to 31 years was 11.9%. The relative mean wPar score change dropped to 53.5% at age 31 years. The differences in wPAR recordings between the recorded stages were all statistically significant. The treatment outcome as expressed by mean wPAR scores at age 31 years was significantly better among individuals treated with extractions compared to those treated without extractions. The mean wPAR scores of the individuals with retainers at age 31 years were significantly lower when compared to the mean score for those without retainers (unpaired t-test, p = 0.020). This clearly indicates the benefit of long-term retention. The changes in the concern scores from 19 to 31 years of age were small. At age 31 years only 8 of the 96 respondents (8.3%) expressed concern about the treatment outcome. PMID- 21591600 TI - Tesamorelin update. PMID- 21591598 TI - Alpha-1-antitrypsin deficiency and periodontitis, a pilot study. AB - The aim of this study was to investigate if periodontal parameters and elastase in gingival crevicular fluid (GCF) are different in alpha-1-antitrypsin deficient (AATD) subjects compared to subjects with normal AAT level. Thirty subjects were included, 20 of whom with severe AATD, phenotype PiZZ. Ten AATD subjects suffered from chronic obstructive pulmonary disease (COPD, group 1) and 10 were asymptomatic (group 2). Ten control subjects, phenotype PiMM, (group 3) were recruited from a public dental clinic. The examination comprised of sampling of GCF, Gingival Index (GI), Plaque Index (PlI), probing pocket depth (PPD) and radiography. GCF was collected with paper strips (Periopaper). Plasma AAT concentration was measured by nephelometry and AAT in GCF with ELISA. Elastase activity and protein in GCF were determined by spectrophotometry. The mean values for GI, PlI, PPD and the radiological measurements did not show any statistically significant differences between the groups. AAT in plasma and GCF demonstrated very low values in groups 1 and 2 with no significant difference between these groups but a statistical difference in comparison with group 3. Elastase in GCF did not show any difference between the three groups. In conclusion, neither the periodontal parameters nor the elastase in GCF were different in AATD subjects, phenotype PiZZ, when compared to subjects with normal AAT level, phenotype PiMM, in this material. PMID- 21591601 TI - Sex work, criminalization, and HIV: lessons from advocacy history. PMID- 21591602 TI - A glass half full: cancer risk for people living with HIV. PMID- 21591603 TI - Emerging issues in research, treatment, and care. PMID- 21591604 TI - The iPrEx results: lifting hopes, raising questions. PMID- 21591605 TI - Structure-based design of a new series of D-glutamic acid based inhibitors of bacterial UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase (MurD). AB - MurD ligase is one of the key enzymes participating in the intracellular steps of peptidoglycan biosynthesis and constitutes a viable target in the search for novel antibacterial drugs to combat bacterial drug-resistance. We have designed, synthesized, and evaluated a new series of D-glutamic acid-based Escherichia coli MurD inhibitors incorporating the 5-benzylidenethiazolidin-4-one scaffold. The crystal structure of 16 in the MurD active site has provided a good starting point for the design of structurally optimized inhibitors 73-75 endowed with improved MurD inhibitory potency (IC(50) between 3 and 7 MUM). Inhibitors 74 and 75 showed weak activity against Gram-positive Staphylococcus aureus and Enterococcus faecalis. Compounds 73-75, with IC(50) values in the low micromolar range, represent the most potent D-Glu-based MurD inhibitors reported to date. PMID- 21591607 TI - Synthesis and characterization of novel forward osmosis membranes based on layer by-layer assembly. AB - Forward osmosis (FO) has received considerable interest for water- and energy related applications in recent years. FO does not require an applied pressure and is believed to have a low fouling tendency. However, a major challenge in FO is the lack of high performance FO membranes. In the current work, novel nanofiltration (NF)-like FO membranes with good magnesium chloride retention were synthesized using layer-by-layer (LbL) assembly. The membrane substrate was tailored (high porosity, finger-like pores, thin cross-section, and high hydrophilicity) to achieve a small structural parameter of 0.5 mm. Increasing the number of polyelectrolyte layers improved the selectivity of the LbL membranes while reducing their water permeability. The more selective membrane 6#LbL (with 6 polyelectrolyte layers) had much lower reverse solute transport compared to 3#LbL and 1#LbL. Meanwhile, the FO water flux was found to be strongly affected by both membrane water permeability and solute reverse transport. Severe solute reverse transport was observed for the active-layer-facing-draw-solution membrane orientation, likely due to the suppression of Donnan exclusion as a result of the high ionic strength of the draw solution. In contrast, the active-layer-facing feed-solution orientation showed remarkable FO performance (15, 20, and 28 L/m2.h at 0.1, 0.5, and 1.0 M MgCl2, respectively, for membrane 3#LbL using distilled water as feed solution), superior to other NF-like FO membranes reported in the literature. To the best of the knowledge of the authors, this is the first work on the synthesis and characterization of LbL based FO membranes. PMID- 21591606 TI - Fenretinide derivatives act as disrupters of interactions of serum retinol binding protein (sRBP) with transthyretin and the sRBP receptor. AB - Serum retinol binding protein (sRBP) is released from the liver as a complex with transthyretin (TTR), a process under the control of dietary retinol. Elevated levels of sRBP may be involved in inhibiting cellular responses to insulin and in generating first insulin resistance and then type 2 diabetes, offering a new target for therapeutic attack for these conditions. A series of retinoid analogues were synthesized and examined for their binding to sRBP and their ability to disrupt the sRBP-TTR and sRBP-sRBP receptor interactions. A number inhibit the sRBP-TTR and sRBP-sRBP receptor interactions as well as or better than Fenretinide (FEN), presenting a potential novel dual mechanism of action and perhaps offering a new therapeutic intervention against type 2 diabetes and its development. Shortening the chain length of the FEN derivative substantially abolished binding to sRBP, indicating that the strength of the interaction lies in the polyene chain region. Differences in potency against the sRBP-TTR and sRBP sRBP receptor interactions suggest variant effects of the compounds on the two loops of sRBP guarding the entrance of the binding pocket that are responsible for these two protein-protein interactions. PMID- 21591608 TI - Deposition of silver nanoparticles in geochemically heterogeneous porous media: predicting affinity from surface composition analysis. AB - The transport of uncoated silver nanoparticles (AgNPs) in a porous medium composed of silica glass beads modified with a partial coverage of iron oxide (hematite) was studied and compared to that in a porous medium composed of unmodified glass beads (GB). At a pH lower than the point of zero charge (PZC) of hematite, the affinity of AgNPs for a hematite-coated glass bead (FeO-GB) surface was significantly higher than that for an uncoated surface. There was a linear correlation between the average nanoparticle affinity for media composed of mixtures of FeO-GB and GB collectors and the relative composition of those media as quantified by the attachment efficiency over a range of mixing mass ratios of the two types of collectors, so that the average AgNPs affinity for these media is readily predicted from the mass (or surface) weighted average of affinities for each of the surface types. X-ray photoelectron spectroscopy (XPS) was used to quantify the composition of the collector surface as a basis for predicting the affinity between the nanoparticles for a heterogeneous collector surface. A correlation was also observed between the local abundances of AgNPs and FeO on the collector surface. PMID- 21591609 TI - Stimulus-responsive self-assembly: reversible, redox-controlled micellization of polyferrocenylsilane diblock copolymers. AB - In depth studies of the use of electron transfer reactions as a means to control the self-assembly of diblock copolymers with an electroactive metalloblock are reported. Specifically, the redox-triggered self-assembly of a series of polystyrene-block-polyferrocenylsilane (PS-b-PFS) diblock copolymers in dichloromethane solution is described. In the case of the amorphous polystyrene(n)-b-poly(ferrocenylphenylmethylsilane)(m) diblock copolymers (PS(n) b-PFMPS(m): n = 548, m = 73; n = 71, m = 165; where n and m are the number averaged degrees of polymerization), spherical micelles with an oxidized PFS core and a PS corona were formed upon oxidation of more than 50% of the ferrocenyl units by [N(C(6)H(4)Br-4)(3)][SbX(6)] (X = Cl, F). Analogous block copolymers containing a poly(ferrocenylethylmethylsilane) (PFEMS) metalloblock, which has a lower glass transition temperature, behaved similarly. However, in contrast, on replacement of the amorphous metallopolymer blocks by semicrystalline poly(ferrocenyldimethylsilane) (PFDMS) segments, a change in the observed morphology was detected with the formation of ribbon-like micelles upon oxidation of PS(535)-b-PFDMS(103) above the same threshold value. Again the coronas consisted of fully solvated PS and the core consisted of partially to fully oxidized PFS associated with the counteranions. When oxidation was performed with [N(C(6)H(4)Br-4)(3)][SbF(6)], reduction of the cores of the spherical or ribbon like micelles with [Co(eta-C(5)Me(5))(2)] enabled full recovery of the neutral chains and no significant chain scission was detected. PMID- 21591610 TI - Supramolecular aggregation of block copolymers in the solid state as assisted by the selective formation of inclusion crystals. AB - Supramolecular self-assembly of a host molecule with selected blocks of triblock copolymers enabled the formation of inclusion 2D nanocrystals that connect consecutive copolymer chains. Indeed, the selective inclusion of ethylene oxide (EO) blocks in inclusion crystals and the phase segregation of PO blocks of poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) (EO(n)PO(m)EO(n)) triblock copolymers provide an efficient route to create alternated crystalline lamellae and amorphous layers, forming a well-organized material. The spontaneous formation of the supramolecular architectures was realized by a solvent-free mechanochemical approach or by thermal treatment of the copolymer and host (tris o-phenylenedioxycyclotriphosphazene), as demonstrated by in situ synchrotron X ray diffraction. The driving force for the fabrication of crystalline inclusion compounds with selected EO segments is based on the establishment of cooperative noncovalent intermolecular interactions, while steric effects prevent the formation of the inclusion crystal with the remaining PO blocks. The 2D (1)H (13)C solid state and fast-(1)H MAS NMR provide direct evidence of the intimate interactions between the host and EO block and the topology of the block copolymer in the material. The large magnetic susceptibility generated by the aromatic host nanochannels surrounding the included EO chains was interpreted by ab initio calculations (HF-GIAO/DGDZVP) that carefully reproduce the chemical shifts associated with the effects of guest-host interactions. The theoretical calculations enable the measurement of short intermolecular distances between the host and the target block, demonstrating the existence of a diffuse network of multiple CH...pi host-guest interactions that improve the robustness of the supramolecular architecture. The overall evidence enforces the strategy of combining the use of block copolymers and clathrate-forming molecules to fabricate organized materials through noncovalent interactions. PMID- 21591612 TI - Diastereoselective intramolecular Friedel-Crafts alkylation of tetralins. AB - An efficient and versatile synthesis of cis-hexahydrobenzophenanthridines starting from readily available tetralins has been developed using an intramolecular Friedel-Crafts alkylation as a key step. The substrates were prepared via a highly stereocontrolled rhodium-catalyzed ring-opening reaction of meso-oxabicyclic alkenes and a hydrogenation sequence. Thus, a wide variety of complex tetracyclic compounds have been isolated with a high level of regio-, diastereo-, and enantioselectivity. PMID- 21591611 TI - Discovery and biological evaluation of a novel class of dual microsomal prostaglandin E2 synthase-1/5-lipoxygenase inhibitors based on 2-[(4,6 diphenethoxypyrimidin-2-yl)thio]hexanoic acid. AB - Various inflammatory diseases are associated with the excessive formation of leukotrienes (LTs) and prostaglandins (PGs). Herein, we present a novel class of dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E(2) synthase-1 (mPGES-1), key enzymes in the formation of LTs and PGE(2), respectively. On the basis of the structure of 2-[(4,6-diphenethoxypyrimidin-2 yl)thio]hexanoic acid (1), we performed a detailed SAR analysis, and mechanistic studies were carried out to elucidate the mode of 5-LO inhibition. Interestingly, the pyrimidine ring including the thioether of 1 could be replaced by a simple benzyl or a benzylidene moiety yielding a novel series of bioactive 2-benzylidene and 2-benzylhexanoic acids exemplified by 2-(2,3 diphenethoxybenzylidene)hexanoic acid, 29 (IC(50) 5-LO = 0.8 MUM; mPGES-1 = 1.1 MUM). Importantly, none of the novel bioactive derivatives strongly inhibited cyclooxygenase activities. Together, we provide novel promising lead compounds for the treatment of inflammatory diseases valuable for further investigations in vivo. PMID- 21591613 TI - Sulfoxide-alkene hybrids: a new class of chiral ligands for the Hayashi-Miyaura reaction. AB - Sulfoxide-alkene hybrids are introduced as a new class of chiral heterodentate ligands for the Hayashi-Miyaura reaction. The synthesis of these ligands was achieved without the use of protecting groups. A chiral resolution was performed via simple column-chromatographic separation of the diastereomeric ligands. Both diastereomers proved to be excellent ligands in Rh-catalyzed 1,4-addition reactions, furnishing chiral products with high enantioselectivities and, remarkably, opposite stereoconfigurations. PMID- 21591614 TI - Simple and clear evidence for positive feedback limitation by bipolar behavior during scanning electrochemical microscopy of unbiased conductors. AB - On the basis of an experimentally validated simple theoretical model, it is demonstrated unambiguously that when an unbiased conductor is probed by a scanning electrochemical tip (scanning electrochemical microscopy, SECM), it performs as a bipolar electrode. Though already envisioned in most recent SECM theories, this phenomenon is generally overlooked in SECM experimental investigations. However, as is shown here, this may alter significantly positive feedback measurements when the probed conductor is not much larger than the tip. PMID- 21591616 TI - Conformational dynamics in a truncated epidermal growth factor receptor ectodomain. AB - Structural studies have revealed two forms of the monomeric epidermal growth factor receptor (EGFR) ectodomain: a compact (tethered) form stabilized by interdomain interactions and an extended (untethered) form in the presence of ligand. An important question is whether the ligand induces a conformational transition from a tethered to untethered form or whether there is a preexisting conformational equilibrium between tethered and untethered states. To distinguish between these two possibilities, we investigated a truncated receptor, EGFR501 (spanning residues 1-501), that contains the minimal elements required for high affinity ligand binding in solution. Conformational transitions and dynamics were inferred by means of fluorescence from five internal tryptophan residues that are located within or close to the ligand-binding domains of EGFR501. A preexisting conformational equilibrium between tethered and untethered states in EGFR501 was deduced from (1) the nonlinear Arrhenius temperature dependence of fluorescence and (2) fluorescence polarization showing independently mobile domains. In contrast, the ligand-EGFR501 complex revealed a linear Arrhenius temperature dependence of fluorescence and increased fluorescence polarization due to a lack of significant interdomain motions. The data suggest that the role of the ligand is to trap the EGFR501 in the untethered state that is transiently formed in solution through a preexisting conformational equilibrium. PMID- 21591615 TI - Identification of flame retardants in polyurethane foam collected from baby products. AB - With the phase-out of PentaBDE in 2004, alternative flame retardants are being used in polyurethane foam to meet flammability standards. However, insufficient information is available on the identity of the flame retardants currently in use. Baby products containing polyurethane foam must meet California state furniture flammability standards, which likely affects the use of flame retardants in baby products throughout the U.S. However, it is unclear which products contain flame retardants and at what concentrations. In this study we surveyed baby products containing polyurethane foam to investigate how often flame retardants were used in these products. Information on when the products were purchased and whether they contained a label indicating that the product meets requirements for a California flammability standard were recorded. When possible, we identified the flame retardants being used and their concentrations in the foam. Foam samples collected from 101 commonly used baby products were analyzed. Eighty samples contained an identifiable flame retardant additive, and all but one of these was either chlorinated or brominated. The most common flame retardant detected was tris(1,3-dichloroisopropyl) phosphate (TDCPP; detection frequency 36%), followed by components typically found in the Firemaster550 commercial mixture (detection frequency 17%). Five samples contained PBDE congeners commonly associated with PentaBDE, suggesting products with PentaBDE are still in-use. Two chlorinated organophosphate flame retardants (OPFRs) not previously documented in the environment were also identified, one of which is commercially sold as V6 (detection frequency 15%) and contains tris(2 chloroethyl) phosphate (TCEP) as an impurity. As an addition to this study, we used a portable X-ray fluorescence (XRF) analyzer to estimate the bromine and chlorine content of the foam and investigate whether XRF is a useful method for predicting the presence of halogenated flame retardant additives in these products. A significant correlation was observed for bromine; however, there was no significant relationship observed for chlorine. To the authors knowledge, this is the first study to report on flame retardants in baby products. In addition, we have identified two chlorinated OPFRs not previously documented in the environment or in consumer products. Based on exposure estimates conducted by the Consumer Product Safety Commission (CPSC), we predict that infants may receive greater exposure to TDCPP from these products compared to the average child or adult from upholstered furniture, all of which are higher than acceptable daily intake levels of TDCPP set by the CPSC. Future studies are therefore warranted to specifically measure infants exposure to these flame retardants from intimate contact with these products and to determine if there are any associated health concerns. PMID- 21591617 TI - Inherently chiral resorcin[4]arenes: a new concept for improving the functionality. AB - A new reactive postion at the upper rim of inherently chiral resorcin[4]arenes was introduced through cleavage of an up to now unreactive methoxy group through the demethylating reagent 9-I-9-BBN. Conservation of the inherent chirality was warranted through the use of a protecting group at the free phenol group. PMID- 21591618 TI - New experimental conditions for tandem hydroalumination/Cu-catalyzed asymmetric conjugate additions to beta-substituted cyclic enones. AB - Readily available alkenylalanes, arising from hydroalumination of unprotected terminal alkynes, have been directly employed for the copper-catalyzed asymmetric conjugate addition (ACA) to beta-substituted cyclic enones. The desired products, containing a quaternary stereogenic center, are generally obtained in good yields and enantioselectivities. PMID- 21591619 TI - A glucose-insensitive T7 expression system for fully-induced expression of proteins at a subsaturating level of L-arabinose. AB - The L-arabinose (Ara)-controlled T7 expression system was previously constructed by creation of an Escherichia coli BL21(BAD) strain. The production of recombinant proteins in this strain was stringently regulated and reached a high level upon induction with Ara. Nevertheless, this system is still associated with inherent problems of interference with glucose and of the all-or-nothing induction profile at a subsaturating level of Ara. In this study, these problems were circumvented by modifying the physiological traits of BL21(BAD) strain. This was followed by deletion of ptsG gene and the araFGH and araBAD operon. The former encodes the glucose transporter while the latter two gene operons produce proteins responsible for Ara uptake and catabolism. In addition, the expression of genomic araE (encodes the Ara transporter) was constitutively enhanced. The resulting strain was designated BAD-5. By expression of the faster degrader GFP(LAA) at a subsaturating level of Ara, 80% of BAD-5 strain was found visually bright in the presence or absence of glucose. A further analysis by flow cytometry showed a uniform distribution of GFP expression for BAD-5 strain. In marked contrast, BL21(BAD) strain exhibiting visual brightness was less than 10% of the cell population and remained dark in the presence of glucose. Moreover, a saturated level of luciferase from Renilla reniformis (Rluc) could be readily obtained in BAD-5 strain at 20 MUM Ara regardless of glucose. Rluc in BL21(BAD) strain was produced in an Ara dose-dependent manner, and the protein production became arrested when glucose was present. Overall, it illustrates the usefulness of the improved system for overproduction of recombinant proteins in an efficient, homogeneous, and glucose-insensitive way. PMID- 21591620 TI - Continuous high-yield production of vertically aligned carbon nanotubes on 2D and 3D substrates. AB - Vertically aligned carbon nanotubes (VACNTs) have certain advantages over bulk CNT powders and randomly oriented CNT mats for applications in flexible electronic devices, filtration membranes, biosensors and multifunctional aerospace materials. Here, a machine and a process to synthesize VACNTs in a continuous manner are presented showing uniform growth on 2D and 3D substrates, including alumina fibers, silicon wafer pieces, and stainless steel foils. Aligned multiwalled carbon nanotubes (MWNT) are synthesized at substrate feed rates of up to 6.8 cm/min, and the CNTs reach up to 60 MUm in length depending on residence time in the reactor. In addition to the aligned morphology indicative of high yield growth, transmission electron microscopy and Raman spectroscopy reveal that the CNTs are of comparable quality to CNTs grown via a similar batch process. A significant reduction in time, reaction products, gases, and energy is demonstrated relative to batch processing, paving the way for industrial production of VACNTs. PMID- 21591621 TI - Synthesis of directly connected BODIPY oligomers through Suzuki-Miyaura coupling. AB - Treatment of a meso-arylboron dipyrrin (BODIPY) with NBS provides mono- and dibrominated BODIPYs at the 2- and 6-positions in excellent yields with high regioselectivity. Brominated products can be employed as a nice building block for the synthesis of a variety of BODIPY derivatives through Suzuki-Miyaura coupling. Because of a lack of substituents at the 1,3,5,7-positions, a directly beta-beta-linked BODIPY dimer exhibits a completely coplanar conformation of BODIPY units, offering effective pi-conjugation. PMID- 21591622 TI - Asymmetric synthesis of alpha-alkyl alpha-selenocarbonyl compounds catalyzed by bifunctional organocatalysts. AB - A new organocatalytic approach for the synthesis of a variety of alpha-alkyl, alpha-phenylselenyl ketones as well as their corresponding esters and amides, by the addition of alpha-selenocarbonyl derivatives to nitroalkenes catalyzed by thiourea or squaramide cinchona catalysts, is presented. This catalytic system allows the preparation in high yields of enantiomerically enriched selenocarbonyl derivatives bearing two chiral centers with excellent ee's and dr's by using catalytic loadings of 3 mol%. PMID- 21591623 TI - Copper-mediated annulative direct coupling of o-alkynylphenols with oxadiazoles: a dehydrogenative cascade construction of biheteroaryls. AB - A copper-mediated annulative direct coupling of o-alkynylphenols with 1,3,4 oxadiazoles proceeds smoothly even under ambient conditions to afford the corresponding biheteroaryls. The reaction system represents a new avenue for the construction of biheteroaryl molecules of interest in their biological and physical properties. PMID- 21591625 TI - Tuning of charge balance in bipolar host materials for highly efficient solution processed phosphorescent devices. AB - A novel bipolar host material, which meets the requirements of high triplet energy, good charge carrier transport properties, high solubility, and film forming ability at the same time, has been designed and synthesized. Utilizing a new compound as host material, high-efficiency solution-processed blue and white phosphorescent organic light-emitting diodes (PHOLEDs) have been achieved. PMID- 21591624 TI - The first total synthesis of (+/-)-cyclophostin and (+/-)-cyclipostin P: inhibitors of the serine hydrolases acetyl cholinesterase and hormone sensitive lipase. AB - Cyclophostin, a structurally unique and potent naturally occurring acetyl cholinesterase (AChE) inhibitor, and its unnatural diastereomer were prepared in 6 steps and 15% overall yield from hydroxymethyl butyrolactone. The unnatural diastereomer of cyclophostin was converted into cyclipostin P, a potent naturally occurring hormone sensitive lipase (HSL) inhibitor, using a one pot dealkylation alkylation process. The inhibition [IC(50)] of human AChE by cyclophostin and its diastereomer are reported, as well as constituent binding (K(I)) and reactivity (k(2)) constants. PMID- 21591626 TI - Grating-coupled surface plasmon enhanced short-circuit current in organic thin film photovoltaic cells. AB - In this study, we demonstrate the fabrication of grating-coupled surface plasmon resonance (SPR) enhanced organic thin-film photovoltaic cells and their improved photocurrent properties. The cell consists of a grating substrate/silver/P3HT:PCBM/PEDOT:PSS structure. Blu-ray disk recordable substrates are used as the diffraction grating substrates on which silver films are deposited by vacuum evaporation. P3HT:PCBM films are spin-coated on silver/grating substrates. Low conductivity PEDOT:PSS/PDADMAC layer-by-layer ultrathin films deposited on P3HT:PCBM films act as the hole transport layer, whereas high conductivity PEDOT:PSS films deposited by spin-coating act as the anode. SPR excitations are observed in the fabricated cells upon irradiation with white light. Up to a 2-fold increase in the short-circuit photocurrent is observed when the surface plasmon (SP) is excited on the silver gratings as compared to that without SP excitation. The finite-difference time-domain simulation indicates that the electric field in the P3HT:PCBM layer can be increased using the grating-coupled SP technique. PMID- 21591627 TI - Unprecedented directing group ability of cyclophanes in arene fluorinations with diaryliodonium salts. AB - For the first time it is shown that exceptionally electron-rich arene rings can be fluorinated exclusively during the reductive elimination reactions of diaryliodonium fluorides. The 5-methoxy[2.2]paracyclophan-4-yl directing group simultaneously reduces unproductive aryne chemistry and eliminates ligand exchange reactions by a combination of steric and electronic effects. Use of the cyclophane directing group permits an unprecedented degree of control in fluorination reactions of diaryliodonium salts. PMID- 21591628 TI - Bile acid-based cage compounds with lipophilic outer shells and inner cavities. AB - The uniquely functionalized steroid-based cyclodimers 4, cis-5, and trans-5 have been synthesized and fully characterized.The cyclodimer 5, with a cis-trans ratio of 3:1, is obtained by coupling the terminal alkenes of two 4-pentenoate groups on a cyclodimer 4 via Grubbs' intramolecular ring-closing metathesis. The crystal structure shows cis-5 to be a cagelike cyclic oligomer bridged by the flexible oct-4-enedioate link. PMID- 21591629 TI - Unprecedented Cu-catalyzed coupling of internal 1,3-diynes with azides: one-pot tandem cyclizations involving 1,3-dipolar cycloaddition and carbocyclization furnishing naphthotriazoles. AB - A one-pot protocol for the synthesis of triazole-annulated polyheterocycles via metal-catalyzed coupling of internal 1,4-disubstituted 1,3-diynes and organic azides has been described. The mechanistic rationale for the reaction suggests tandem cyclizations involving copper-catalyzed cycloaddition and 6-endo carbocyclization reactions. The cascade cyclization leads to an increase in molecular complexity to furnish naphtho[1,2-d]triazoles in satisfactory yields. The generality of the method has been demonstrated by using a series of aromatic/aliphatic azides and symmetrical internal 1,3-diynes. PMID- 21591630 TI - Regioselective alkylation of carbohydrate derivatives catalyzed by a diarylborinic acid derivative. AB - Regioselective, catalyst-controlled monoalkylations of cis-vicinal diol motifs in carbohydrate derivatives, using a diphenylborinic ester precatalyst, are described. Selective installation of benzyl, naphthylmethyl, 4-bromobenzyl and benzyloxymethyl protective groups at a single secondary hydroxy group of ten representative carbohydrate derivatives illustrates the scope of this method. This new mode of catalytic reactivity represents an operationally simple method to access useful monoalkylated building blocks while avoiding the use of stoichiometric quantities of organotin reagents. PMID- 21591631 TI - Synthesis of 2-mercaptobenzothiazoles via DBU-promoted tandem reaction of o haloanilines and carbon disulfide. AB - An efficient strategy for the synthesis of a variety of 2-mercaptobenzothiazole derivatives has been developed. The reaction proceeded from o-haloaniline derivatives and carbon disulfide via a tandem reaction in the presence of 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU) to afford the corresponding 2 mercaptobenzothiazole derivatives in good to excellent yields. PMID- 21591632 TI - Interfacing multicellular organisms with polyelectrolyte shells and nanoparticles: a Caenorhabtidis elegans study. AB - We report the surface modification of microscopic live multicellular nematodes Caenorhabtidis elegans with polyelectrolyte multilayers (pure and doped with 20 nm gold nanoparticles) and the direct magnetic functionalization of nematodes with biocompatible magnetic nanoparticles. Magnetically functionalized "ironoxideclad" nematodes can be effectively separated and moved using an external magnetic field. The surface-functionalized nematodes preserve their viability and reproduction. PMID- 21591633 TI - Spectral dependence of nanocrystal photoionization probability: the role of hot carrier transfer. AB - We conduct measurements of photocharging of PbSe and PbS nanocrystal quantum dots (NQDs) as a function of excitation energy (homega). We observe a rapid growth of the degree of photocharging with increasing homega, which indicates an important role of hot-carrier transfer in the photoionization process. The corresponding spectral dependence exhibits two thresholds that mark the onsets of weak and strong photocharging. Interestingly, both thresholds are linked to the NQD band gap energy (E(g)) and scale as ~1.5E(g) and ~3E(g), indicating that the onsets of photoionization are associated with specific nanocrystal states (tentatively, 1P and 2P, respectively) and are not significantly dependent on the energy of external acceptor sites. For all samples, the hot-electron transfer probability increases by nearly 2 orders of magnitude as photon energy increases from 1.5 to 3.5 eV, although at any given wavelength the photoionization probability shows significant sample-to-sample variations (~10(-6) to 10(-3) for 1.5 eV and ~10(-4) to 10(-1) for 3.5 eV). In addition to the effect of the NQD size, these variations are likely due to differences in the properties of the NQD surface and/or the number and identity of external acceptor trap sites. The charge separated states produced by photoionization are characterized by extremely long lifetimes (20 to 85 s) that become longer with increasing NQD size. PMID- 21591634 TI - Inducible site-selective bottom-up assembly of virus-derived nanotube arrays on RNA-equipped wafers. AB - Tobacco mosaic virus (TMV) is a tube-shaped, exceptionally stable plant virus, which is among the biomolecule complexes offering most promising perspectives for nanotechnology applications. Every viral nanotube self-assembles from a single RNA strand and numerous identical coat protein (CP) subunits. Here we demonstrate that biotechnologically engineered RNA species containing the TMV origin of assembly can be selectively attached to solid surfaces via one end and govern the bottom-up growth of surface-linked TMV-like nanotubes in situ on demand. SiO(2) wafers patterned by polymer blend lithography were modified in a chemically selective manner, which allowed positioning of in vitro produced RNA scaffolds into predefined patches on the 100-500 nm scale. The RNA operated as guiding strands for the self-assembly of spatially ordered nanotube 3D arrays on the micrometer scale. This novel approach may promote technically applicable production routes toward a controlled integration of multivalent biotemplates into miniaturized devices to functionalize poorly accessible components prior to use. Furthermore, the results mark a milestone in the experimental verification of viral nucleoprotein complex self-assembly mechanisms. PMID- 21591635 TI - Spray-layer-by-layer assembly can more rapidly produce optical-quality multistack heterostructures. AB - Automated spray-layer-by-layer (LbL) assembly was used to create highly reflective structurally colored thin films with high reflectance at near-UV light wavelengths. Reflectance peaks were tuned by fabricating alternating stacks of high (TiO(2) nanoparticles) and low (SiO(2) nanoparticles) refractive index materials using a non-quarter-wave design. Spray-assembled multilayer heterostructures fabricated with up to 840 individual polymer or nanoparticle deposition steps presented similar roughness and refractive index values compared to Bragg stacks obtained via immersion LbL assembly. Such complex multilayer heterostructures, however, could be fabricated in significantly shorter times; the time required to deposit a complete bilayer was only about 90 s, compared to 36 min for the immersion assembly of the same system. Optimization of the experimental parameters was performed to achieve uniform coatings and relatively smooth interfaces and surfaces. We observed that the spraying times of the nanoparticle and polymer solutions are the main parameters that determine the thickness, optical properties, and uniformity of the assembled films. Ellipsometry, atomic force microscopy (AFM), UV-vis spectroscopy, and transmission electron microscopy (TEM) were used to characterize the samples. The nanoparticle thin films were iridescent and presented relatively narrow peaks of high reflectance (~90%) at visible and near-UV wavelengths of light. PMID- 21591636 TI - Comparison of structure and reactivity of phosphine-amido and hemilabile phosphine-amine chelates of rhodium. AB - A series of mono- and binuclear rhodium(I) complexes bearing ortho phosphinoanilido and ortho-phosphinoaniline ligands has been synthesized. Reactions of the protic monophosphinoanilines, Ph(2)PAr or PhPAr(2) (Ar = o C(6)H(4)NHMe), with 0.5 equiv of [Rh(MU-OMe)(COD)](2) result in the formation of the neutral amido complexes, [Rh(COD)(P,N-Ph(2)PAr(-))] or [Rh(COD)(P,N-PhP(Ar( ))Ar)] (Ar(-) = o-C(6)H(4)NMe(-)), respectively, through stoichiometrically controlled deprotonation of an amine by the internal methoxide ion. Similarly, the binuclear complex, [Rh(2)(COD)(2)(MU-P,N,P',N'-mapm(2-))] (mapm(2-) = Ar(Ar( ))PCH(2)P(Ar(-))Ar), can be prepared by reaction of the protic diphosphinoaniline, mapm (Ar(2)PCH(2)PAr(2)), with 1 equiv of [Rh(MU OMe)(COD)](2). An analogous series of hemilabile phosphine-amine compounds can be generated by reactions of monophosphinoanilines, Ph(2)PAr' or PhPAr'(2) (Ar' = o C(6)H(4)NMe(2)), with 1 equiv of [Rh(NBD)(2)][BF(4)] to generate [Rh(NBD)(P,N Ph(2)PAr')][BF(4)] or [Rh(NBD)(P,N-PhPAr'(2))][BF(4)], respectively, or by reactions of diphosphinoanilines, mapm or dmapm (Ar'(2)PCH(2)PAr'(2)), with 2 equiv of the rhodium precursor to generate [Rh(2)(NBD)(2)(MU-P,N,P',N' mapm)][BF(4)](2) or [Rh(2)(NBD)(2)(MU-P,N,P',N'-dmapm)][BF(4)](2), respectively. Displacement of the diolefin from [Rh(COD)(P,N-Ph(2)PAr(-))] by 1,2 bis(diphenylphosphino)ethane (dppe) yields [Rh(P,P'-dppe)(P,N-Ph(2)PAr(-))] which, while unreactive to H(2), reacts readily and irreversibly with oxygen to form the peroxo complex, [RhO(2)(P,P'-dppe)(P,N-Ph(2)PAr(-))], and with iodomethane to yield [RhI(CH(3))(P,P'-dppe)(P,N-Ph(2)PAr(-))]. Hemilabile phosphine-amine compounds can also be prepared by reactions of [Rh(P,P'-dppe)(P,N Ph(2)PAr(-))] with Me(3)OBF(4) or HBF(4).Et(2)O, resulting in (thermodynamic) additions at nitrogen to form [Rh(P,P'-dppe)(P,N-Ph(2)PAr')][BF(4)] or [Rh(P,P' dppe)(P,N-Ph(2)PAr)][BF(4)], respectively. The nonlabile phosphine-amido and hemilabile phosphine-amine complexes were tested as catalysts for the silylation of styrene. The amido species do not require the use of solvents in reaction media, can be easily removed from product mixtures by protonation, and appear to be more active than their hemilabile, cationic congeners. Reactions catalyzed by either amido or amine complexes favor dehydrogenative silylation in the presence of excess olefin, showing modest selectivities for a single vinylsilane product. The binuclear complexes, which were prepared in an effort to explore possible catalytic enhancements of reactivity due to metal-metal cooperativity, are in fact somewhat less active than mononuclear species, discounting this possibility. PMID- 21591637 TI - A functionally integrated device for effective and facile oil spill cleanup. AB - In this Letter, we have fabricated a multifunctional device for highly efficient and inexpensive oil spill cleanup by combining electroless metal deposition with self-assembled monolayers, which has integrated the functions of oil containment booms, oil-sorption materials, oil skimmers, and water-oil separating devices. This functionally integrated device has a lower density than that of water, which leads to a potential application as oil containment booms; it can take up oil that is 3.5 times its own weight, which shows excellent oil-sorption properties, with the water-oil separating yield of the as-prepared device being up to 92%. The device has the advantages of high efficiency, capacity of antiwave, and reproducibility, which is suitable for many types of organic solvents or oils, even for emulsion of petroleum and water, and thus is a proof-of-principle idea to be applied in marine spilt oil cleanup and other water-oil separating systems. PMID- 21591638 TI - Selective targeting of antibody conjugated multifunctional nanoclusters (nanoroses) to epidermal growth factor receptors in cancer cells. AB - The ability of smaller than 100 nm antibody (Ab) nanoparticle conjugates to target and modulate the biology of specific cell types may enable major advancements in cellular imaging and therapy in cancer. A key challenge is to load a high degree of targeting, imaging, and therapeutic functionality into small, yet stable particles. A versatile method called thin autocatalytic growth on substrate (TAGs) has been developed in our previous study to form ultrathin and asymmetric gold coatings on iron oxide nanocluster cores producing exceptional near-infrared (NIR) absorbance. AlexaFluor 488 labeled Abs were used to correlate the number of Abs conjugated to iron oxide/gold nanoclusters (nanoroses) with the hydrodynamic size. A transition from submonolayer to multilayer aggregates of Abs on the nanorose surface was observed for 54 Abs and an overall particle diameter of ~60-65 nm. The hydrodynamic diameter indicated coverage of a monolayer of 54 Abs, in agreement with the prediction of a geometric model, by assuming a circular footprint of 16.9 nm diameter per Ab molecule. The targeting efficacy of nanoclusters conjugated with monoclonal Abs specific for epidermal growth factor receptor (EGFR) was evaluated in A431 cancer cells using dark field microscopy and atomic absorbance spectrometry (AAS) analysis. Intense NIR scattering was achieved from both high uptake of nanoclusters in cells and high intrinsic NIR absorbance of individual nanoclusters. Dual mode imaging with dark field reflectance microscopy and fluorescence microscopy indicates the Abs remained attached to the Au surfaces upon the uptake by the cancer cells. The ability to load intense multifunctionality, specifically strong NIR absorbance, conjugation of an Ab monolayer in addition to a strong r2 MRI contrast that was previously demonstrated in a total particle size of only 63 nm, is an important step forward in development of theranostic agents for combined molecular specific imaging and therapy. PMID- 21591640 TI - Applying the oligomer approach to luminescent conjugated organoboranes. AB - A series of highly luminescent monodisperse fluoreneborane oligomers (n=1-6) were prepared using a new iterative synthetic procedure that takes advantage of the highly selective and differential reactivity of bromoboranes with arylsilanes and arylstannanes. Cyclic and square wave voltammetry revealed a gradual decrease of the LUMO energy levels with increasing chain length, while absorption and emission data showed a bathochromic shift and increase in quantum efficiency. An extended conjugation length of n(ECL)=5 was derived. PMID- 21591639 TI - Homoleptic hexa and penta gallylene coordinated complexes of molybdenum and rhodium. AB - The reactions of molybdenum(0) and rhodium(I) olefin containing starting materials with the carbenoid group 13 metal ligator ligand GaR (R = Cp*, DDP; Cp* = pentamethylcyclopentadienyl, DDP = HC(CMeNC(6)H(3)-2,6-(i)Pr(2))(2)) were investigated and compared. Treatment of [Mo(eta(4)-butadiene)(3)] with GaCp* under hydrogen atmosphere at 100 degrees C yields the homoleptic, hexa coordinated, and sterically crowded complex [Mo(GaCp*)(6)] (1) in good yields >=50%. Compound 1 exhibits an unusual and high coordinated octahedral [MoGa(6)] core. Similarly, [Rh(GaCp*)(5)][CF(3)SO(3)] (2) and [Rh(GaCp*)(5)][BAr(F)] (3) (BAr(F) = B{C(6)H(3)(CF(3))(2)}(4)) are prepared by the reaction of GaCp* with the rhodium(I) compound [Rh(coe)(2)(CF(3)SO(3))](2) (coe = cyclooctene) and subsequent anion exchange in case of 3. Compound 2 features a trigonal bipyramidal [RhGa(5)] unit. In contrast, reaction of excess Ga(DDP) with [Rh(coe)(2)(CF(3)SO(3))](2) does not result in a high coordinated homoleptic complex but instead yields [(coe)(toluene)Rh{Ga(DDP)}(CF(3)SO(3))] (4). The common feature of 2 and 4 in the solid state structure is the presence of short CF(3)SO(2)O...Ga contacts involving the GaCp* or rather the Ga(DDP) ligand. Compounds 1, 2, and 4 have been fully characterized by single crystal X-ray diffraction, variable temperature (1)H and (13)C NMR spectroscopy, IR spectroscopy, mass spectrometry, as well as elemental analysis. PMID- 21591641 TI - Highly enantioselective partial hydrogenation of simple pyrroles: a facile access to chiral 1-pyrrolines. AB - A highly enantioselective Pd-catalyzed partial hydrogenation of simple 2,5 disubstituted pyrroles with a Bronsted acid as an activator has been successfully developed, providing chiral 2,5-disubstituted 1-pyrrolines with up to 92% ee. PMID- 21591642 TI - Fast and stable photochromic oxazines for fluorescence switching. AB - The stringent limitations imposed by diffraction on the spatial resolution of fluorescence microscopes demand the identification of viable strategies to switch fluorescence under optical control. In this context, the photoinduced and reversible transformations of photochromic compounds are particularly valuable. In fact, these molecules can be engineered to regulate the emission intensities of complementary fluorophores in response to optical stimulations. On the basis of this general design logic, we assembled a functional molecular construct consisting of a borondipyrromethene fluorophore and a nitrospiropyran photochrome and demonstrated that the emission of the former can be modulated with the interconversion of the latter. This fluorophore-photochrome dyad, however, has a slow switching speed and poor fatigue resistance. To improve both parameters, we developed a new family of photochromic switches based on the photoinduced opening and thermal closing of an oxazine ring. These compounds switch back and forth between ring-closed and -open isomers on nanosecond-microsecond timescales and tolerate thousands of switching cycles with no sign of degradation. In addition, the attachment of appropriate chromophoric fragments to their switchable oxazine ring can be exploited to either deactivate or activate fluorescence reversibly in response to illumination with a pair of exciting beams. Specifically, we assembled three dyads, each based on either a borondipyrromethene or a coumarin fluorophore and an oxazine photochrome, and modulated their fluorescence in a few microseconds with outstanding fatigue resistance. The unique photochemical and photophysical properties of our fluorophore-photochrome dyads can facilitate the development of switchable fluorophores for superresolution imaging and, ultimately, provide valuable molecular probes for the visualization of biological samples on the nanometer level. PMID- 21591643 TI - Determination of binding energy and solubility parameters for functionalized gold nanoparticles by molecular dynamics simulation. AB - The binding energy, density, and solubility of functionalized gold nanoparticles in a vacuum are computed using molecular dynamics simulations. Numerous parameters including surface coverage fraction, functional group (-CH(3), -OH, NH(2)), and nanoparticle orientation are considered. The analysis includes computation of minimum interparticle binding distances and energies and an analysis of mechanisms that may contribute to changes in system potential energy. A number of interesting trends and results are observed, such as increasing binding distance with higher terminal group electronegativity and a minimum particle-particle binding energy (solubility parameter) based upon surface coverage. These results provide a fundamental understanding of ligand-coated nanoparticle interactions required for the design and processing of high-density polymer composites. The computational model and results are presented as support for these conclusions. PMID- 21591644 TI - Counterion exchange to achieve reversibly switchable hydrophobicity and oleophobicity on fabrics. AB - We describe a simple layer-by-layer (LbL) technology and counterion exchange procedure to tune the liquid wettability of commercially available cotton fabrics. A polyelectrolyte multilayer is deposited on the fabric surface by the LbL technology, and counterion exchange is used to control the surface composition and thereby to modulate the solid surface energy. The tunability of the solid surface energy, along with the inherent re-entrant texture of the cotton fabric, results in simultaneously switchable wettability between a nonwetting state and a fully wetted state for water and hexadecane. This switchable hydrophobicity and oleophobicity can be explained within a robustness factor, which is a quantitative criterion for the transition between the two states. The counterion exchange can be confirmed by X-ray photoelectron spectroscopy analysis. PMID- 21591645 TI - Shapes of sulfur, oxygen, and nitrogen mustards. AB - Thorough conformational analyses have been performed on representative sulfur, oxygen, and nitrogen mustards. A total of 23, 18, and 38 unique conformers have been located for SM, OM, and NM, respectively, at the MP2/aug-cc-pVDZ level of theory. Despite the fact that these molecules differ only in the identity of the central heteroatom, comparison of their low energy conformations reveals that the shapes they adopt are distinctive to each molecule. Potential energy surfaces for CH(2)-X (X = S, O, and N-CH(3)) and CH(2)-CH(2) bond rotations are presented and, where possible, compared with dihedral angle distributions observed in crystal structure data. These results were used to benchmark and improve the performance of the MM3 and MMFF94 force fields. PMID- 21591646 TI - Surface modification of silicon nanowires via copper-free click chemistry. AB - A two-step process based on copper-free click chemistry is described, by which the surface of silicon nanowires can be functionalized with specific organic substituents. A hydrogen-terminated nanowire surface is first primed with a monolayer of an alpha,omega-diyne and thereby turned into an alkyne-terminated, clickable platform, which is subsequently coupled with an overlayer of an organic azide carrying the desired terminal functionality. The reactive, electron deficient character of the employed diyne enabled a quantitative coupling reaction at 50 degrees C without metal catalysis, which opens up a simple and versatile route for surface functionalization under mild conditions without any potentially harmful additives. PMID- 21591648 TI - Kinetico-mechanistic information about alkene hydroamination with aniline in bromide-rich ionic media: importance of solvolysis. AB - The study of the [PtBr(4)](2-) reactivity with hexene and aniline in highly ionic (Bu(4)P)Br/CH(2)Br(2) media has been studied from a Kinetico-Mechanistic perspective. The results indicate bromide ion association to the square-planar starting material to produce a stable diamagnetic compound that can be described as an ion pair of a [PtBr(5)](3-) square-pyramidal complex stabilized by several phosphonium countercations. While this species reacts rapidly with aniline, producing the known square-planar complex [PtBr(3)(PhNH(2))](-) with release of the apical bromide of the square-pyramidal intermediate, the reaction with hexene, producing the square-planar [PtBr(3)(hexene)](-) complex, is much slower. The thermal and pressure activation parameters determined for these processes fully agree with the proposed reactivity. The gross features of the platinum catalyzed hydroamination mechanism, occurring via much higher energy transition states, are not necessarily altered by these new findings, given the fact that all ligand exchange reactions occur with relatively low activation barriers. Nevertheless, the nature of the catalyst resting state needs revision as demonstrated. The importance of explicitly considering the solvent for reactions conducted in noninnocent highly organized media is also highlighted. PMID- 21591647 TI - Responsive glyco-poly(2-oxazoline)s: synthesis, cloud point tuning, and lectin binding. AB - A new sugar-substituted 2-oxazoline monomer was prepared using the copper catalyzed alkyne-azide cycloaddition (CuAAC) reaction. Its copolymerization with 2-ethyl-2-oxazoline as well as 2-(dec-9-enyl)-2-oxazoline, yielding well-defined copolymers with the possibility to tune the properties by thiol-ene "click" reactions, is described. Extensive solubility studies on the corresponding glycocopolymers demonstrated that the lower critical solution temperature behavior and pH-responsiveness of these copolymers can be adjusted in water and phosphate-buffered saline (PBS) depending on the choice of the thiol. By conjugation of 2,3,4,6-tetra-O-acetyl-1-thio-beta-d-glucopyranose and subsequent deprotection of the sugar moieties, the hydrophilicity of the copolymer could be increased significantly, allowing a cloud-point tuning in the physiological range. Furthermore, the binding capability of the glycosylated copoly(2 oxazoline) to concanavalin A was investigated. PMID- 21591649 TI - Iron-catalyzed preparation of trifluoromethyl substituted vinyl- and alkynylcyclopropanes. AB - A convenient iron-catalyzed procedure to prepare trifluoromethylated vinyl- and alkynylcyclopropanes in a chemo- and diastereoselective manner is presented. The active diazo compound (trifluoromethyl diazomethane) is generated in situ and used in the concomitant cyclopropanation reaction. PMID- 21591650 TI - Solubilization of oils or addition of monoglycerides drives the formation of wormlike micelles with an elliptical cross-section in cholesterol-based surfactants: a study by rheology, SANS, and cryo-TEM. AB - We report the formation of wormlike micelles (WLM) in poly(oxyethylene) cholesteryl ether (ChEO(10)) aqueous solutions by the addition of lipophilic monoglycerides at room temperature (monolaurin (ML), monocaprin (MC), and monocaprylin (MCL)) bearing 12-, 10-, and 8-carbon alkyl chains, respectively. A combination of rheology, small-angle neutron scattering (SANS), and cryo-TEM was used to study their viscoelastic properties and structure. With the successive addition of cosurfactant, a significant increase in viscosity and a clear solidlike behavior is obtained, suggesting the formation of a viscoelastic network of wormlike micelles. Only for MCL is typical Maxwellian behavior obtained. The onset of micellar growth, as detected by the occurrence of solidlike behavior and a significant increase in viscosity, is obtained for 0.30 (1 wt%), 0.34 (1 wt%), and 0.60 (1.5 wt%) cosurfactant/ChEO(10) molar ratios with ML, MC, and MCL, respectively. With ML and MC, extremely long relaxation times (exceeding 20 s) compared to those of MCL are obtained, and zero-shear viscosity values are more than 1 order of magnitude higher than with MCL. These results show that cosurfactants with longer alkyl chain lengths (ML and MC) induce the formation of longer wormlike micelles and do so at lower concentrations. SANS measurements on dilute solutions confirm that the viscoelastic behavior correlates with an increase in contour length and reveals an elliptical cross section with an axial ratio of around 2. Cryo-TEM images provide visual evidence of the wormlike micelles and confirm the elliptical shape of the cross-section. The addition of small amounts of aliphatic oils (ethyl butyrate, EB, and ethyl caprylate, EC) and cyclic oils (peppermint, PP, and tea tree, TT, oils) to ChEO(10) solutions induces wormlike micelle formation at a lower cosurfactant concentration or even in its absence (for PP, TT, and EC) because of their probable localization in the palisade layer. The viscosity peak and height of the plateau modulus occur at increasing monoglyceride concentration following the order PP ~ TT > EC > EB > no oil. PMID- 21591651 TI - Contrasting effect of gold nanoparticles and nanorods with different surface modifications on the structure and activity of bovine serum albumin. AB - Nanoparticles exposed to biofluids become coated with proteins, thus making protein-nanoparticle interactions of particular interest. The consequence on protein conformation and activity depends upon the extent of protein adsorption on the nanoparticle surface. We report the interaction of bovine serum albumin (BSA) with gold nanostructures, particularly gold nanoparticles (GNP) and gold nanorods (GNR). The difference in the geometry and surface properties of nanoparticles is manifested during complexation in terms of different binding modes, structural changes, thermodynamic parameters, and the activity of proteins. BSA is found to retain native-like structure and properties upon enthalpy-driven BSA-GNP complexation. On the contrary, the entropically favored BSA-GNR complexation leads to substantial loss in protein secondary and tertiary structures with the release of a large amount of bound water, as indicated by isothermal calorimetry (ITC), circular dichroism (CD), and Fourier transform infrared (FTIR) and fluorescence spectroscopies. The esterase activity assay demonstrated a greater loss in BSA activity after complexation with GNR, whereas the original activity is retained in the presence of GNP. The formation of large assemblies (aggregates) and reduced average lifetime, as evidenced from dynamic light scattering and fluorescence decay measurements, respectively, suggest that GNR induces protein unfolding at its surface. The effect of temperature on the CD spectra of BSA-GNP was found to be similar to that of pristine BSA, whereas BSA GNR shows distortion in CD spectra at lower wavelengths, strengthening the perception of protein unfolding. High binding constant and entropy change for BSA GNR complexation determined by ITC are consistent with large surfacial interaction that may lead to protein unfolding. The present work highlights the differential response of a protein depending on the nature of the nanostructure and its surface chemistry, which need to be modulated for controlling the biological responses of nanostructures for their potential biomedical applications. PMID- 21591652 TI - Chemical sensitivity of graphene edges decorated with metal nanoparticles. AB - Graphene is a novel two-dimensional nanomaterial that holds great potential in electronic and sensor applications. By etching the edges to form nanoribbons or introducing defects on the basal plane, it has been demonstrated that the physical and chemical properties of graphene can be drastically altered. However, the lithographic or chemical techniques required to reliably produce such nanoribbons remain challenging. Here, we report the fabrication of nanosensors based on holey reduced graphene oxide (hRGO), which can be visualized as interconnected graphene nanoribbons. In our method, enzymatic oxidation generated holes within the basal plane of graphene oxide, and after reduction with hydrazine, hRGO was formed. When decorated with Pt nanoparticles, hRGO exhibited a large and selective electronic response toward hydrogen gas. By combining experimental results and theoretical modeling, we propose that the increased edge to-plane ratio, oxygen moieties, and Pt nanoparticle decoration were responsible for the observed gas sensing with hRGO nanostructures. PMID- 21591653 TI - Surfactant adsorption kinetics by total internal reflection Raman spectroscopy. 2. CTAB and Triton X-100 mixtures on silica. AB - Total internal reflection (TIR) Raman spectroscopy has been used to study the kinetics of adsorption, desorption, and displacement of mixed surfactant systems at the silica-water interface. The limited penetration depth of the evanescent wave provides surface sensitivity while the chemical sensitivity of Raman scattering permits the determination of the time-dependent composition of the adsorbed film. Principal component analysis is used to deconvolute the Raman spectra with a time resolution of 2 s and a precision of 5% of a monolayer. Both equilibrium and kinetic measurements are presented for the cetyltrimethylammonium bromide (CTAB)/Triton X-100 system over a range of concentrations and compositions. For a total concentration of 2 mM, the adsorption isotherm shows strong synergistic behavior with the addition of small amounts of CTAB (~2% of the total surfactant) doubling the adsorbed amount of Triton X-100. This synergism has a marked influence on the kinetics: for example, when Triton X-100 replaces CTAB, the Triton X-100 surface excess overshoots its equilibrium value and returns only very slowly to equilibrium. For systems above the cmc, the repartitioning of surfactant between micelles and monomers results in unexpected behavior during exchange or rinsing of mixed surfactant solutions. For example, during rinsing, the more rapid diffusion of CTAB away from the surface leads to a local increase in the monomer concentration of Triton X-100, resulting in a temporary spike in the Triton X-100 surface excess. Displacement kinetics of CTAB by TX-100 and vice versa are generally slower than the adsorption or desorption of the pure surfactants but cover a wide range of kinetic time scales, depending on the details of the compositions and concentrations of the initial and final solutions. PMID- 21591654 TI - Surfactant adsorption kinetics by total internal reflection Raman spectroscopy. 1. Pure surfactants on silica. AB - Total internal reflection Raman spectroscopy provides a sensitive probe of surfactants adsorbed at an interface. A visible laser passes through a silica hemisphere and reflects off the flat silica-water interface. An evanescent wave probes ~100 nm of solution below the surface, and the Raman scattering from this region provides chemically specific information on the molecules present. Here we look at both equilibrium and kinetic aspects of the adsorption of the cationic surfactant cetyltrimethylammonium bromide (CTAB) and the nonionic surfactant Triton X-100 in single-component systems. We use the well-defined wall jet geometry to provide known hydrodynamics for the adsorption process. The well defined hydrodynamics allows us to model the mass transport of surfactant to the surface which is coupled with a kinetic model consistent with the Frumkin isotherm to produce a complete model of the adsorption process. The fit between this model and the experimental results provides insight into the interactions on the surface. PMID- 21591655 TI - Hybrid Si nanowire/amorphous silicon FETs for large-area image sensor arrays. AB - Silicon nanowire (SiNW) field-effect transistors (FETs) were fabricated from nanowire mats mechanically transferred from a donor growth wafer. Top- and bottom gate FET structures were fabricated using a doped a-Si:H thin film as the source/drain (s/d) contact. With a graded doping profile for the a-Si:H s/d contacts, the off-current for the hybrid nanowire/thin-film devices was found to decrease by 3 orders of magnitude. Devices with the graded contacts had on/off ratios of ~10(5), field-effect mobility of ~50 cm(2)/(V s), and subthreshold swing of 2.5 V/decade. A 2 in. diagonal 160 * 180 pixel image sensor array was fabricated by integrating the SiNW backplane with an a-Si:H p-i-n photodiode. PMID- 21591656 TI - Direct measurement of individual deep traps in single silicon nanowires. AB - The potential of the metal nanocatalyst to contaminate vapor-liquid-solid (VLS) grown semiconductor nanowires has been a long-standing concern, since the most common catalyst material, Au, is known to induce deep gap states in several semiconductors. Here we use Kelvin probe force microscopy to image individual deep acceptor type trapping centers in single undoped Si nanowires grown with an Au catalyst. The switching between occupied and empty trap states is reversibly controlled by the back-gate potential in a nanowire transistor. The trap energy level, i.e., E(C) - E(T) = 0.65 +/- 0.1 eV was extracted and the concentration was estimated to be ~2 * 10(16) cm(-3). The energy and concentration are consistent with traps resulting from the unintentional incorporation of Au atoms during the VLS growth. PMID- 21591658 TI - Empirical correlation methods for temporary anions. AB - A temporary anion is a short-lived radical anion that decays through electron autodetachment into a neutral molecule and a free electron. The energies of these metastable species are often predicted using empirical correlation methods because ab initio predictions are computationally very expensive. Empirical correlation methods can be justified in the framework of Weisskopf-Fano-Feshbach theory but tend to work well only within closely related families of molecules or within a restricted energy range. The reason for this behavior can be understood using an alternative theoretical justification in the framework of the Hazi Taylor stabilization method, which suggests that the empirical parameters do not so much correct for the coupling of the computed state to the continuum but for electron correlation effects and that therefore empirical correlation methods can be improved by using more accurate electronic structure methods to compute the energy of the confined electron. This idea is tested by choosing a heterogeneous reference set of temporary states and comparing empirical correlation schemes based on Hartree-Fock orbital energies, Kohn-Sham orbital energies, and attachment energies computed with the equation-of-motion coupled-cluster method. The results show that using more reliable energies for the confined electron indeed enhances the predictive power of empirical correlation schemes and that useful correlations can be established beyond closely related families of molecules. Certain types of sigma* states are still problematic, and the reasons for this behavior are analyzed. On the other hand, preliminary results suggest that the new scheme can even be useful for predicting energies of bound anions at a fraction of the computational cost of reliable ab initio calculations. It is then used to make predictions for bound and temporary states of the furantrione and croconic acid radical anions. PMID- 21591657 TI - Total synthesis of (+)-grandifloracin by iron complexation of a microbial arene oxidation product. AB - (+)-Grandifloracin was synthesized from sodium benzoate by means of a dearomatizing dihydroxylation that proceeds with unusual regioselectivity. Iron diene complexes formed from the arene oxidation product permit the use of otherwise inaccessible transformations. The synthetic material was shown to be antipodal to the natural product, thus determining the absolute configuration of grandifloracin for the first time. PMID- 21591659 TI - Relativistic four-component DFT calculations of 1H NMR chemical shifts in transition-metal hydride complexes: unusual high-field shifts beyond the Buckingham-Stephens model. AB - State-of-the-art relativistic four-component DFT-GIAO-based calculations of (1)H NMR chemical shifts of a series of 3d, 4d, and 5d transition-metal hydrides have revealed significant spin-orbit-induced heavy atom effects on the hydride shifts, in particular for several 4d and 5d complexes. The spin-orbit (SO) effects provide substantial, in some cases even the dominant, contributions to the well known characteristic high-field hydride shifts of complexes with a partially filled d-shell, and thereby augment the Buckingham-Stephens model of off-center paramagnetic ring currents. In contrast, complexes with a 4d(10) and 5d(10) configuration exhibit large deshielding SO effects on their hydride (1)H NMR shifts. The differences between the two classes of complexes are attributed to the dominance of pi-type d-orbitals for the true transition-metal systems compared to sigma-type orbitals for the d(10) systems. PMID- 21591661 TI - Comprehensive core-level study of the effects of isomerism, halogenation, and methylation on the tautomeric equilibrium of cytosine. AB - Core-level X-ray photoemission and near-edge X-ray absorption fine structure spectra of 5-methylcytosine, 5-fluorocytosine, and isocytosine are presented and discussed with the aid of high-level ab initio calculations. The effects of the methylation, halogenation, and isomerization on the relative stabilities of cytosine tautomers are clearly identified spectroscopically. The hydroxy-oxo tautomeric forms of these molecules have been identified, and their quantitative populations at the experimental temperature are calculated and compared with the experimental results and with previous calculations. The calculated values of Gibbs free energy and Boltzmann population ratios are in good agreement with the experimental results characterizing tautomer equilibrium. PMID- 21591662 TI - Small molecule activation by uranium tris(aryloxides): experimental and computational studies of binding of N2, coupling of CO, and deoxygenation insertion of CO2 under ambient conditions. AB - Previously unanticipated dinitrogen activation is exhibited by the well-known uranium tris(aryloxide) U(ODtbp)(3), U(OC(6)H(3)-Bu(t)(2)-2,6)(3), and the tri tert-butyl analogue U(OTtbp)(3), U(OC(6)H(2)-Bu(t)(3)-2,4,6)(3), in the form of bridging, side-on dinitrogen complexes [U(OAr)(3)](2)(MU-eta(2):eta(2)-N(2)), for which the tri-tert-butyl N(2) complex is the most robust U(2)(N(2)) complex isolated to date. Attempted reduction of the tris(aryloxide) complex under N(2) gave only the potassium salt of the uranium(III) tetra(aryloxide) anion, K[U(OAr)(4)], as a result of ligand redistribution. The solid-state structure is a polymeric chain formed by each potassium cation bridging two arenes of adjacent anions in an eta(6) fashion. The same uranium tris(aryloxides) were also found to couple carbon monoxide under ambient conditions to give exclusively the ynediolate [OCCO](2-) dianion in [U(OAr)(3)](2)(MU-eta(1):eta(1)-C(2)O(2)), in direct analogy with the reductive coupling recently shown to afford [U{N(SiMe(3))(2)}(3)](2)(MU-eta(1):eta(1)-C(2)O(2)). The related U(III) complexes U{N(SiPhMe(2))(2)}(3) and U{CH(SiMe(3))(2)}(3) however do not show CO coupling chemistry in our hands. Of the aryloxide complexes, only the U(OC(6)H(2)-Bu(t)(3) 2,4,6)(3) reacts with CO(2) to give an insertion product containing bridging oxo and aryl carbonate moieties, U(2)(OTtbp)(4)(MU-O)(MU-eta(1):eta(1)-O(2)COC(6)H(2) Bu(t)(3)-2,4,6)(2), which has been structurally characterized. The presence of coordinated N(2) in [U(OTtbp)(3)](2)(N(2)) prevents the occurrence of any reaction with CO(2), underscoring the remarkable stability of the N(2) complex. The di-tert-butyl aryloxide does not insert CO(2), and only U(ODtbp)(4) was isolated. The silylamide also reacts with carbon dioxide to afford U(OSiMe(3))(4) as the only uranium-containing material. GGA and hybrid DFT calculations, in conjunction with topological analysis of the electron density, suggest that the U N(2) bond is strongly polar, and that the only covalent U->N(2) interaction is pi backbonding, leading to a formal (U(IV))(2)(N(2))(2-) description of the electronic structure. The N-N stretching wavenumber is preferred as a metric of N(2) reduction to the N-N bond length, as there is excellent agreement between theory and experiment for the former but poorer agreement for the latter due to X ray crystallographic underestimation of r(N-N). Possible intermediates on the CO coupling pathway to [U(OAr)(3)](2)(MU-C(2)O(2)) are identified, and potential energy surface scans indicate that the ynediolate fragment is more weakly bound than the ancillary ligands, which may have implications in the development of low temperature and pressure catalytic CO chemistry. PMID- 21591660 TI - Electrophilic components of diesel exhaust particles (DEP) activate transient receptor potential ankyrin-1 (TRPA1): a probable mechanism of acute pulmonary toxicity for DEP. AB - Inhalation of environmental particulate matter (PM) is correlated with adverse health effects in humans, but gene products that couple detection with cellular responses, and the specific properties of PM that target different pathways, have not been fully elucidated. TRPA1 and V1 are two cation channels expressed by sensory neurons and non-neuronal cells of the respiratory tract that have been implicated as possible mediators of PM toxicity. The goals of this research were to determine if environmental PM preferentially activated TRPA1 and to elucidate the criteria responsible for selectivity. Quantification of TRPA1 activation by 4 model PM revealed that diesel exhaust PM (DEP) and coal fly ash PM (CFA1) were TRPA1 agonists at concentrations >0.077 mg/mL. DEP was more potent, and approximately 97% of the activity of DEP was recovered by serial extraction of the solid DEP with ethanol and hexane/n-butyl chloride. Modification of the electrophile/agonist binding sites on TRPA1 (C621, C641, C665, and K710) to non nucleophilic residues reduced TRPA1 activation by DEP and abolished activation by DEP extracts as well as multiple individual electrophilic chemical components of DEP. However, responses to CFA1 and DEP solids were not affected by these mutations. Activity-guided fractionation of DEP and high resolution mass spectroscopy identified several new DEP-derived TRPA1 agonists, and activation of mouse dorsal root ganglion neurons demonstrated that TRPA1 is a primary target for DEP in a heterogeneous population of primary sensory nerves. It is concluded that TRPA1 is a specific target for electrophilic chemical components of DEP and proposed that activation of TRPA1 in the respiratory tract is likely to be an important mechanism for DEP pneumotoxicity. PMID- 21591664 TI - Highly efficient green organic light-emitting diodes containing luminescent three coordinate copper(I) complexes. AB - A series of highly emissive three-coordinate copper(I) complexes, (dtpb)Cu(I)X [X = Cl (1), Br (2), I (3); dtpb =1,2-bis(o-ditolylphosphino)benzene], were synthesized and investigated in prototype organic light-emitting diodes (OLEDs). 1-3 showed excellent photoluminescent performance in both degassed dichloromethane solutions [quantum yield (Phi) = 0.43-0.60; lifetime (tau) = 4.9 6.5 MUs] and amorphous films (Phi = 0.57-0.71; tau = 3.2-6.1 MUs). Conventional OLEDs containing 2 in the emitting layer exhibited bright green luminescence with a current efficiency of 65.3 cd/A and a maximum external quantum efficiency of 21.3%. PMID- 21591665 TI - Quasi-classical trajectory-gaussian binning study of the OH + D2 -> HOD(v1',v2',v3') + D angle-velocity and vibrational distributions at a collision energy of 0.28 eV. AB - The angle-velocity and product vibrational state distributions for the OH + D(2) reaction at a collision energy of 0.28 eV have been calculated using the quasi classical trajectory-gaussian binning (QCT-GB) method and the Wu-Schatz-Lendvay Fang-Harding (WSLFH) analytical potential energy surface. Comparison with high resolution molecular beam experiments shows that, differing from what happens when using the standard QCT method (i.e., histogram binning), very good results are obtained for both distributions. Hence, the strong differences previously observed between QCT and experimental results mainly come from an inadequate pseudoquantization of HOD rather than from other quantum effects. This is probably the first time that such a high level of agreement between theory and high resolution experimental data has been found in polyatomic reaction dynamics. PMID- 21591666 TI - Anion modules: building blocks of supramolecular assemblies by combination with pi-conjugated anion receptors. AB - Dipyrrolyldiketone boron complexes, as pi-conjugated acyclic anion receptors, act as building subunits of various assemblies through noncovalent interactions in the form of receptor-anion complexes. Instead of, or in addition to, the modification of receptor structures, the introduction of anion modules as building blocks for the assemblies was found to be useful in forming various soft materials. Gallic carboxylate derivatives 3-n (n = 16, 18, 20), as tetrabutylammonium (TBA) salts, form receptor-anion-module complexes that can be used to fabricate supramolecular assemblies. Combinations of aliphatic anion modules 3-n and receptors 1a,b along with a TBA cation afforded products with mesophases, which were indicated by differential scanning calorimetry and polarized optical microscopy. X-ray diffraction measurements of the solid states and mesophases of 1a.3-n.TBA and 1b.3-n.TBA revealed highly ordered structures including lamellar structures, which could be modulated by the lengths of the alkyl chains of the modules. Functional materials exhibiting electrical conductivity were fabricated by using combinations of anionic building blocks that form assemblies by themselves and pi-conjugated acyclic receptors. PMID- 21591667 TI - Crystallographic snapshots of Tom20-mitochondrial presequence interactions with disulfide-stabilized peptides. AB - Most mitochondrial proteins are synthesized in the cytosol and imported into mitochondria. The Tom20 protein, residing on the mitochondrial surface, recognizes the N-terminal presequences of precursor proteins. We previously determined the crystal structures of the Tom20-presequence complex. The successful crystallization involved tethering the presequence to Tom20 through an intermolecular disulfide bond with an optimized linker. In this work, we assessed the tethering method. The intermolecular disulfide bond was cleaved in crystal with a reducing agent. The pose (i.e., conformation and position) of the presequence was identical to the previously determined pose. In another experiment, a longer linker than the optimized length was used for the tethering. The perturbation of the tether changed the pose slightly, but the interaction mode was preserved. These results argue against the forced interaction of the presequence by its covalent attachment to Tom20. Second, as an alternative method referred to as "molecular stiffening", we introduced a disulfide bond within the presequence peptide to restrict the freedom of the peptide in the unbound states. One presequence analogue exhibited over 100-fold higher affinity than its linear counterpart and generated cocrystals with Tom20. One of the two crystallographic snapshots revealed a known pose previously determined by the tethering method, and the other snapshot depicted a new pose. These results confirmed and extended the dynamic, multiple bound state model of the Tom20-presequence interactions and also demonstrated the validity of the molecular tethering and stiffening techniques in studies of transient protein-peptide interactions. PMID- 21591668 TI - A nanoparticle autocatalytic sensor for Ag+ and Cu2+ ions in aqueous solution with high sensitivity and selectivity and its application in test paper. AB - A novel nanoparticle autocatalytic sensor for the detection of Ag(+) and Cu(2+) has been constructed based on the oxidative ability of Ag(+) and Cu(2+) toward o phenylenediamine (OPDA). Ag(+) and Cu(2+) can be reduced to zerovalent silver and copper, respectively, and then such zerovalent Ag and Cu species form silver and copper nanoparticles that can catalyze the reaction between OPDA and Ag(+) and Cu(2+). In the reaction, OPDA is oxidized to 2,3-diaminophenazine (OPDAox), which has a fluorescence emission at 568 nm. Under the optimal conditions, Ag(+) and Cu(2+) can be detected in the concentration ranges from 60 nM to 60 MUM and from 2.5 nM to 25 MUM, respectively. Through this facile approach, Ag(+) and Cu(2+) can be detected down to 60 nM and 2.5 nM, respectively. In addition, the sensor is utilized for the detection of Ag(+) and Cu(2+) in sewage, and we have obtained very good results that are consistent with those of inductively coupled plasma mass spectroscopy (ICP-MS). Moreover, such a nanoparticle autocatalytic sensor is applied to test paper for the detection of Ag(+) and Cu(2+) with the naked eye. With such test paper, Ag(+) and Cu(2+) could be detected at levels as low as 0.06 nmol and 0.3 nmol, respectively, with detection ranges of 0.06-60 nmol for Ag(+) and 0.3-60 nmol for Cu(2+), under the irradiation of UV light (365 nm). The test paper could be potentially used in the rapid detection of Ag(+) and Cu(2+) in real samples. PMID- 21591669 TI - Lead detoxification activities of a class of novel DMSA--amino acid conjugates. AB - The coupling of the 1-carboxyl of DMSA with l-amino acids led to a class of novel 1-(carbonyl-l-amino-acid)-2,3-dimercaptosuccinic acids (DMSA--amino acid conjugates, DMSA-Gly, -Ser, -Val, -Leu, -Ile, -Asn, -Asp, -Gln, -Glu, -Met, -Phe, and -Trp). In the in vivo evaluation of Pb-loaded mice, 0.4 mmol/kg of the conjugates effectively decreased the Pb levels of the femur, brain, kidney, liver, and blood, greatly enhanced urination, and increased the Pb levels of both urine and feces, while causing no redistributions of Pb to the other organs, especially to the brain. With respect to lowering the bone and brain Pb, DMSA Ile, -Asn, -Gln, and -Met were more effective than DMSA. This benefit was attributed to their high transmembrane ability. In contrast to Pb, the essential metals such as Fe, Cu, Zn, and Ca of the treated mice were not affected by the administration of the conjugates. Silico molecular modeling predicted that the conjugates had little hepatotoxicity, except possibly for DMSA-Phe. PMID- 21591670 TI - Long-term trends and opportunities for managing regional water supply and wastewater greenhouse gas emissions. AB - Greenhouse gas emissions are likely to rise faster than growth in population and more than double for water supply and wastewater services over the next 50 years in South East Queensland (SEQ), Australia. New sources of water supply such as rainwater tanks, recycled water, and desalination currently have greater energy intensity than traditional sources. In addition, direct greenhouse gas emissions from reservoirs and wastewater treatment and handling have potentially the same magnitude as emissions from the use of energy. Centralized and decentralized water supply and wastewater systems are considered for a scenario based upon a government water supply strategy for the next 50 years. Many sources of data have large uncertainties which are estimated following the IPCC Good Practice Guidelines. Important sources of emissions with large uncertainties such as rainwater tanks and direct emissions were identified for further research and potential mitigation of greenhouse gas emissions. PMID- 21591671 TI - A tale of two technologies: hydraulic fracturing and geologic carbon sequestration. PMID- 21591672 TI - Demonstration of combined zero-valent iron and electrical resistance heating for in situ trichloroethene remediation. AB - The effectiveness of in situ treatment using zero-valent iron (ZVI) for nonaqueous phase or significant sediment-associated contaminant mass can be limited by relatively low rates of mass transfer to bring contaminants in contact with the reactive media. For a field test in a trichloroethene (TCE) source area, combining moderate-temperature subsurface electrical resistance heating with in situ ZVI treatment was shown to accelerate TCE treatment by a factor of about 4 based on organic daughter products and a factor about 8 based on chloride concentrations. A mass-discharge-based analysis was used to evaluate reaction, dissolution, and volatilization processes at ambient groundwater temperature (~10 degrees C) and as temperature was increased up to about 50 degrees C. Increased reaction and contaminant dissolution were observed with increased temperature, but vapor- or aqueous-phase migration of TCE out of the treatment zone was minimal during the test because reactions maintained low aqueous-phase TCE concentrations. PMID- 21591673 TI - Benchmarking the environmental performance of the Jatropha biodiesel system through a generic life cycle assessment. AB - In addition to available country or site-specific life cycle studies on Jatropha biodiesel we present a generic, location-independent life cycle assessment and provide a general but in-depth analysis of the environmental performance of Jatropha biodiesel for transportation. Additionally, we assess the influence of changes in byproduct use and production chain. In our assessments, we went beyond the impact on energy requirement and global warming by including impacts on ozone layer and terrestrial acidification and eutrophication. The basic Jatropha biodiesel system consumes eight times less nonrenewable energy than conventional diesel and reduces greenhouse gas emissions by 51%. This result coincides with the lower limit of the range of reduction percentages available in literature for this system and for other liquid biofuels. The impact on the ozone layer is also lower than that provoked by fossil diesel, although eutrophication and acidification increase eight times. This study investigates the general impact trends of the Jatropha system, although not considering land-use change. The results are useful as a benchmark against which other biodiesel systems can be evaluated, to calculate repayment times for land-use change induced carbon loss or as guideline with default values for assessing the environmental performance of specific variants of the system. PMID- 21591674 TI - Comparison of elemental carbon in lake sediments measured by three different methods and 150-year pollution history in Eastern China. AB - Concentrations of elemental carbon (EC) were measured in a 150 yr sediment record collected from Lake Chaohu in Anhui Province, eastern China, using three different thermal analytical methods: IMPROVE_A thermal optical reflectance (TOR), STN_thermal optical transmittance (TOT), and chemothermal oxidation (CTO). Distribution patterns for EC concentrations are different among the three methods, most likely due to the operational definition of EC and different temperature treatments prescribed for each method. However, similar profiles were found for high-temperature EC fractions among different methods. Historical soot(TOR) (high-temperature EC fractions measured by the IMPROVE_A TOR method) from Lake Chaohu exhibited stable low concentrations prior to the late 1970s and a sharp increase thereafter, corresponding well with the rapid industrialization of China in the last three decades. This may suggest that high-temperature thermal protocols are suitable for differentiating between soot and other carbon fractions. A similar soot(TOR) record was also obtained from Lake Taihu (~200 km away), suggesting a regional source of soot. The ratio of char(TOR) (low temperature EC fraction measured by the IMPROVE_A TOR method, after correction for pyrolysis) to soot(TOR) in Lake Chaohu shows an overall decreasing trend, consistent with gradual changes in fuel use from wood burning to increasing fossil fuel combustions. Average higher char(TOR)/soot(TOR) was observed in Lake Taihu than in Lake Chaohu in the past 150 years, consistent with the longer and more extensive industrialization around the Taihu region. PMID- 21591675 TI - Levels of perfluorinated compounds in food and dietary intake of PFOS and PFOA in the Netherlands. AB - This study presents concentrations of perfluorinated compounds in food and the dietary intake of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in The Netherlands. The concentrations of perfluorinated compounds in food were analyzed in pooled samples of foodstuffs randomly purchased in several Dutch retail store chains with nation-wide coverage. The concentrations analyzed for PFOS and PFOA were used to assess the exposure to these compounds in The Netherlands. As concentrations in drinking water in The Netherlands were missing for these compounds, conservative default concentrations of 7 pg/g for PFOS and 9 pg/g for PFOA, as reported by European Food Safety Authority, were used in the exposure assessment. In food, 6 out of 14 analyzed perfluorinated compounds could be quantified in the majority of the food categories (perfluoroheptanoic acid (PFHpA), PFOA, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoro-1-hexanesulfonate (PFHxS), and PFOS). The highest concentration of the sum of these six compounds was found in crustaceans (825 pg/g product, PFOS: 582 pg/g product) and in lean fish (481 pg/g product, PFOS: 308 pg/g product). Lower concentrations were found in beef, fatty fish, flour, butter, eggs, and cheese (concentrations between 20 and 100 pg/g product; PFOS, 29-82 pg/g product) and milk, pork, bakery products, chicken, vegetable, and industrial oils (concentration lower than 10 pg/g product; PFOS not detected). The median long term intake for PFOS was 0.3 ng/kg bw/day and for PFOA 0.2 ng/kg bw/day. The corresponding high level intakes (99th percentile) were 0.6 and 0.5 ng/kg bw/day, respectively. These intakes were well below the tolerable daily intake values of both compounds (PFOS, 150 ng/kg bw/day; PFOA, 1500 ng/kg bw/day). The intake calculations quantified the contribution of drinking water to the PFOS and PFOA intake in The Netherlands. Important contributors of PFOA intake were vegetables/fruit and flour. Milk, beef, and lean fish were important contributors of PFOS intake. PMID- 21591676 TI - Variation in antibiotic-induced microbial recolonization impacts on the host metabolic phenotypes of rats. AB - The interaction between the gut microbiota and their mammalian host is known to have far-reaching consequences with respect to metabolism and health. We investigated the effects of eight days of oral antibiotic exposure (penicillin and streptomycin sulfate) on gut microbial composition and host metabolic phenotype in male Han-Wistar rats (n = 6) compared to matched controls. Early recolonization was assessed in a third group exposed to antibiotics for four days followed by four days recovery (n = 6). Fluorescence in situ hybridization analysis of the intestinal contents collected at eight days showed a significant reduction in all bacterial groups measured (control, 10(10.7) cells/g feces; antibiotic-treated, 10(8.4)). Bacterial suppression reduced the excretion of mammalian-microbial urinary cometabolites including hippurate, phenylpropionic acid, phenylacetylglycine and indoxyl-sulfate whereas taurine, glycine, citrate, 2-oxoglutarate, and fumarate excretion was elevated. While total bacterial counts remained notably lower in the recolonized animals (10(9.1) cells/g faeces) compared to the controls, two cage-dependent subgroups emerged with Lactobacillus/Enterococcus probe counts dominant in one subgroup. This dichotomous profile manifested in the metabolic phenotypes with subgroup differences in tricarboxylic acid cycle metabolites and indoxyl-sulfate excretion. Fecal short chain fatty acids were diminished in all treated animals. Antibiotic treatment induced a profound effect on the microbiome structure, which was reflected in the metabotype. Moreover, the recolonization process was sensitive to the microenvironment, which may impact on understanding downstream consequences of antibiotic consumption in human populations. PMID- 21591677 TI - Functional impact of manipulation on the relative orientation of human prolactin receptor domains. AB - Hormone binding creates active receptor dimers for class 1 cytokine receptors; however, the detailed molecular mechanism by which these receptors are activated by their ligands is not well characterized, and it is unknown if these receptors share common mechanisms. A rotation model has been proposed for the activation of human erythropoietin receptor and human growth hormone receptor and is supported by evidence showing that additions of alanine at the junction of the transmembrane (TM) and intracellular (IC) domains and/or within the TM domain influenced receptor activities. This evidence suggests that alanine additions changed the relative orientations of the IC domains and their subsequent activation. We wished to determine if a similar mechanism was at play with human prolactin receptor (hPRLr). Up to four alanines were added between the TM and either the IC or extracellular (EC) domains to extend the TM helix and to rotate the IC or EC domains. Also, up to four glycines were placed between the TM and IC domains to provide increased flexibility between these two domains. Wild-type hPRLr or various mutant receptors were expressed in human embryonic kidney 293T cells that express endogenous Janus kinase 2. In the absence of human prolactin (hPRL), none of the alanine or glycine additions increased the level of receptor phosphorylation above that of wild-type hPRLr. In the presence of hPRL, both wild type hPRLr and each of the mutant receptors were successfully phosphorylated. These data do not support a rotation mechanism for hPRLr activation or a requirement of a fixed spatial relationship between the TM and IC domains for hPRLr activation. In a second set of experiments, both wild-type hPRLr and either alanine- or glycine-extended receptors were coexpressed in 293T cells. In the absence of hPRL, there was no detectable phosphorylation of hPRLr. Such data do not support a piston movement between the hPRLr pair in their activation. PMID- 21591678 TI - Emergent multistability in assembled nanostructures. AB - Scanning tunneling microscopy (STM) at 5 K reveals that native atoms in the surface layer of a semiconductor crystal become bistable in vertical height when a nanostructure is assembled nearby. The binary switching of surface atoms, driven by the STM tip, changes their charge state. Coupling is facilitated by assembling adatom chains, allowing us to explore the emergence of complex multiple switching. Density-functional theory calculations rationalize the observations and a lattice-gas model predicts the cooperative behavior from first principles. PMID- 21591679 TI - Total synthesis of (-)-salinosporamide A. AB - A concise and stereoselective total synthesis of (-)-salinosporamide A (1), a potent inhibitor of the 20S proteasome that is in clinical development as an anticancer drug candidate, has been accomplished in 14 steps with 19% overall yield from 4-pentenoic acid. Our synthesis features a stereoselective alkylation utilizing a chiral auxiliary, formation of a pyrrolidine unit, and oxidation of the pyrrolidine to a gamma-lactam. To demonstrate the scalability of our synthesis, (-)-salinosporamide A has been synthesized on a gram scale. PMID- 21591681 TI - H-H and N-H bond cleavage of dihydrogen and ammonia with a bifunctional parent imido (NH)-bridged diiridium complex. AB - Hydrogenation and protonation of parent imido complexes have attracted much attention in relation to industrial and biological nitrogen fixation. The present study reports the structure and properties of the highly unsaturated diiridium parent imido complex [(Cp*Ir)(2)(MU(2)-H)(MU(2)-NH)](+) derived from deprotonation of a parent amido complex. Because of the Lewis acid-Bronsted base bifunctional nature of the metal-NH bond, the parent imido complex promotes heterolysis of H(2) and deprotonative N-H cleavage of ammonia to afford the corresponding parent amido complexes under mild conditions. PMID- 21591682 TI - Probing the buried Pb/Si(111) interface with SPA LEED and STM on Si(111) Pbalpha?3*?3. AB - High resolution spot profile analysis low energy electron diffraction (SPA-LEED) and variable temperature scanning tunneling microscopy (STM) have been used to observe the growth of Pb on the Pb/Si(111)-alpha?3*?3 phase, which is driven by quantum size effects (QSE). A change in the rotation of the Pb grown islands with respect to the Si substrate has been observed with increasing coverage theta. At lower coverage, separated two-step islands are grown and are aligned with the [110] axis of the substrate. With increasing coverage above 1.5 ML, of the islands coalesce and form a bilayer, with additional islands grown on top. The preferred Pb island orientation changes to 5.6 degrees with respect to the [110] direction. These changes at the metal/semiconductor buried interface are obtained both with SPA LEED and STM as changes to the period of the Moire pattern. The method of analysis of the corrugation period and rotation angle of the Moire pattern measured with diffraction and STM can be applied to obtain the structure of buried metal/substrate interfaces in other epitaxial systems. PMID- 21591683 TI - 17(R),18(S)-epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: structure-activity relationships and stable analogues. AB - 17(R),18(S)-epoxyeicosatetraenoic acid [17(R),18(S)-EETeTr], a cytochrome P450 epoxygenase metabolite of eicosapentaenoic acid (EPA), exerts negative chronotropic effects and protects neonatal rat cardiomyocytes against Ca(2+) overload with EC(50) ~ 1-2 nM. Structure-activity studies revealed that a cis Delta(11,12)- or Delta(14,15)-olefin and a 17(R),18(S)-epoxide are minimal structural elements for antiarrhythmic activity whereas antagonist activity was often associated with the combination of a Delta(14,15)-olefin and a 17(S),18(R) epoxide. Compared with natural material, the agonist and antagonist analogues are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates. PMID- 21591680 TI - Constructing de novo biosynthetic pathways for chemical synthesis inside living cells. AB - Living organisms have evolved a vast array of catalytic functions that make them ideally suited for the production of medicinally and industrially relevant small molecule targets. Indeed, native metabolic pathways in microbial hosts have long been exploited and optimized for the scalable production of both fine and commodity chemicals. Our increasing capacity for DNA sequencing and synthesis has revealed the molecular basis for the biosynthesis of a variety of complex and useful metabolites and allows the de novo construction of novel metabolic pathways for the production of new and exotic molecular targets in genetically tractable microbes. However, the development of commercially viable processes for these engineered pathways is currently limited by our ability to quickly identify or engineer enzymes with the correct reaction and substrate selectivity as well as the speed by which metabolic bottlenecks can be determined and corrected. Efforts to understand the relationship among sequence, structure, and function in the basic biochemical sciences can advance these goals for synthetic biology applications while also serving as an experimental platform for elucidating the in vivo specificity and function of enzymes and reconstituting complex biochemical traits for study in a living model organism. Furthermore, the continuing discovery of natural mechanisms for the regulation of metabolic pathways has revealed new principles for the design of high-flux pathways with minimized metabolic burden and has inspired the development of new tools and approaches to engineering synthetic pathways in microbial hosts for chemical production. PMID- 21591686 TI - Equilibrium and nonequilibrium features in the morphology and structure of physisorbed polyelectrolyte layers. AB - AFM is used to characterize sodium poly(styrene sulfonate) (PSS) layers physisorbed from NaCl solutions with an ionic strength ranging between 0 and 1 M NaCl. Colloidal probe tapping mode imaging shows that domains of PSS salted brushes coexist with flatly adsorbed PSS. The brush area fraction increases with rising degree of polymerization. The surface forces (as measured with colloidal probe technique) are a superposition of steric and electrostatic forces; their respective contribution is determined by the brush area fraction. Unexpectedly, the internal properties of the brush domains (brush thickness and average chain distance) are independent of the deposition salt concentration. Both properties increase with rising polymer length/degree of polymerization, whereas only the brush thickness can be controlled by the surrounding salt concentration (equilibrium feature). Furthermore, we show that the amount of brush-like physisorbed PSS chains leads to an increase in PSS surface coverage, which is also observed with other techniques after addition of salt to the deposition solution (as is extensively described in literature). PMID- 21591684 TI - Formal synthesis of leustroducsin B via Reformatsky/Claisen condensation of silyl glyoxylates. AB - A formal synthesis of leustroducsin B has been completed. The synthesis relies upon a recently developed Reformatsky/Claisen condensation of silyl glyoxylates and enantioenriched beta-lactones that establishes two of the molecule's three core stereocenters and permits further elaboration to an intermediate in Imanishi's synthesis via reliable chemistry (Prasad reduction, asymmetric pentenylation, Mitsunobu inversion). PMID- 21591685 TI - Bioelectronic delivery of electrons to cytochrome P450 enzymes. AB - Cytochrome P450s (cyt P450s) are the major oxidative enzymes in human oxidative metabolism of drugs and xenobiotic chemicals. In nature, the iron heme cyt P450s utilize oxygen and electrons delivered from NADPH by a reductase enzyme to oxidize substrates stereo- and regioselectively. Significant research has been directed toward achieving these events electrochemically. This Feature Article discusses the direct electrochemistry of cyt P450s in thin films and the utilization of such films for electrochemically driven biocatalysis. Maintaining and confirming structural integrity and catalytic activity of cyt P450s in films is an essential feature of these efforts. We highlight here our efforts to elucidate the influence of iron heme spin state and secondary structure of human cyt P450s on voltammetric and biocatalytic properties, using methodologies to quantitatively describe the dynamics of these processes in thin films. We also describe the first cyt P450/reductase films that accurately mimic the natural biocatalytic pathway and show how they can be used with voltammetry to elucidate key mechanistic features. Such bioelectronic cyt P450 systems have high value for future drug development, toxicity screening, fundamental investigations, and chemical synthesis systems. PMID- 21591688 TI - Mycobacterium behavior in wastewater treatment plant, a bacterial model distinct from Escherichia coli and Enterococci. AB - Mycobacteria are waterborne emerging pathogens causing infections in human. Mycobacteria have been previously isolated from wastewater and sludge, but their densities were not estimated due to cultural biases. In order to evaluate the impact of wastewater treatment processes on mycobacteria removal, we used a real time PCR method. First we compared six DNA extraction methods and second we used the more efficient DNA extraction procedure (i.e., enzymatic lysis combined with hexadecyltrimethylammonium bromide-NaCl procedure) in order to quantify Mycobacterium. With the aim to identify parameters that could serve as indicator of mycobacterial behavior, mycobacterial densities were measured in parallel to those of Escherichia coli and enterococci, and to concentrations of chemical parameters usually monitored in wastewater. Mycobacterium reached 5.5 * 105 +/- 3.9 * 105 copies/L in the influent, but was not detected in the effluent after decantation and biofiltration. Most mycobacteria (98.6 +/- 2.7%, i.e. 2.4 +/- 0.7 log10) were removed by the physical-chemical decantation, and the remaining mycobacteria were removed by biofiltration. In contrast, enterococci and E. coli were lightly removed by decantation step and mainly removed by biofiltration. Our results showed that Mycobacterium corresponds to a hydrophobic behavior linked to insoluble compound removal, whereas enterococci and E. coli refer to hydrophilic behaviors linked to soluble compound removals. PMID- 21591689 TI - Interactions within a [ionic liquid + poly(ethylene glycol)] mixture revealed by temperature-dependent synergistic dynamic viscosity and probe-reported microviscosity. AB - Mixtures of ionic liquid (IL) with poly(ethylene glycol) (PEG) may afford media with favorable properties. Dynamic viscosities of mixtures of a common and popular IL 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF(6)]) with PEGs of average molecular weight (MW) 200 (PEG200), average MW 400 (PEG400), number-average MW M(n) 570-630 (PEG600), and number-average MW M(n) 950-1050 (PEG1000) over a complete composition range at 10 degrees intervals in the temperature range of 10-90 degrees C are measured. The temperature dependence of the dynamic viscosity shows ([bmim][PF(6)] + PEG) mixtures to behave as Newtonian fluids and is found to follow Arrhenius-type behavior. In the IL-rich region, excess logarithmic viscosities for the ([bmim][PF(6)] + PEG200) mixture are found to be negative and independent of the temperature. Mixtures of ([bmim][PF(6)] + PEG600) and ([bmim][PF(6)] + PEG1000) show rare and unusual viscosity "synergism" or "hyperviscosity" in the sense that the mixture viscosity is observed to be significantly higher than the viscosity of both the neat components forming the mixture, giving rise to large positive excess logarithmic viscosities. These positive excess logarithmic viscosities decrease with increasing temperature. Formation of extensive H-bonding between the IL and PEG more than compensates for the losses in Coulombic attractive and van der Waals interactions within [bmim][PF(6)] and PEG600/PEG1000, respectively, giving rise to viscosity synergism. This compensation is not enough for ([bmim][PF(6)] + PEG200) and ([bmim][PF(6)] + PEG400) mixtures. The evidence for H-bonding in the mixtures is provided by FTIR absorbance data. The product of the monomer-to-excimer emission intensity ratio and the lifetime of the intramolecular excimer fluorescence of a microfluidity probe, 1,3-bis(1-pyrenyl)propane (BPP), is used as a reflection of the microviscosity of the mixture at different temperatures. The microviscosity shows synergistic effects in all four ([bmim][PF(6)] + PEG) mixtures. The contribution of H-bonding to the microviscosity reported by BPP is observed to be more then that as compared to contributions of Coulombic and van der Waals interactions. Synergism in the dynamic viscosity and microviscosity of ([bmim][PF(6)] + PEG) mixtures is a complex interplay of inter- and intramolecular H-bonding as well as Coulombic and van der Waals type interactions. PMID- 21591687 TI - Complexes of the outer mitochondrial membrane protein mitoNEET with resveratrol-3 sulfate. AB - Binding of the thiazolidinedione antidiabetic drug pioglitazone led to the discovery of a novel outer mitochondrial membrane protein of unknown function called mitoNEET. The protein is homodimeric and contains a uniquely ligated two iron-two sulfur cluster in each of its two cytosolic domains. Electrospray ionization mass spectrometry was employed to characterize solutions of the soluble cytosolic domain (amino acids 32--108) of the protein. Ions characteristic of dimers containing the cofactors were readily detected under native conditions. mitoNEET responded to exposure to solutions at low pH by dissociation to give monomers that retained the cofactor, followed by dissociation of the cofactor in a concerted fashion. mitoNEET formed complexes with resveratrol-3-sulfate, one of the primary metabolites of the natural product resveratrol. Resveratrol itself showed no tendency to interact with mitoNEET. The formation of complexes was evident in both electrospray ionization mass spectrometry and isothermal titration calorimetry measurements. Up to eight molecules of the compound associated with the dimeric form of the protein in a sequential fashion. Dissociation constants determined by micorcalorimetry were in the range 5-16 MUM for the various binding sites. The only other known naturally occurring binding partner for mitoNEET at present is NADPH. It is very interesting that the iron-sulfur cluster containing protein interacts with two potentially redox active substances at the surface of mitochondria. These findings provide a new direction for research into two poorly understood, yet biomedically relevant, species. PMID- 21591690 TI - Identification of ciguatoxins in Hawaiian monk seals Monachus schauinslandi from the Northwestern and Main Hawaiian Islands. AB - Ciguatoxins are potent algal neurotoxins that concentrate in fish preyed upon by the critically endangered Hawaiian monk seal (Monachus schauinslandi). The only report for Hawaiian monk seal exposure to ciguatoxins occurred during a 1978 mortality event when two seal liver extracts tested positive by mouse bioassay. Ciguatoxins were thus proposed as a potential threat to the Hawaiian monk seal population. To reinvestigate monk seal exposure to ciguatoxins we utilized more selective detection methods, the Neuro-2A cytotoxicity assay, to quantify ciguatoxin activity and an analytical method LC-MS/MS to confirm the molecular structure. Tissue analysis from dead stranded animals revealed ciguatoxin activity in brain, liver, and muscle, whereas analysis of blood samples from 55 free-ranging animals revealed detectable levels of ciguatoxin activity (0.43 to 5.49 pg/mL P-CTX-1 equiv) in 19% of the animals. Bioassay-guided LC fractionation of two monk seal liver extracts identified several ciguatoxin-like peaks of activity including a peak corresponding to the P-CTX-3C which was confirmed present by LC-MS/MS. In conclusion, this work provides first confirmation that Hawaiian monk seals are exposed to significant levels of ciguatoxins and first evidence of transfer of ciguatoxin to marine mammals. This threat could pose management challenges for this endangered marine mammal species. PMID- 21591691 TI - Large-area graphene films by simple solution casting of edge-selectively functionalized graphite. AB - We report edge-selective functionalization of graphite (EFG) for the production of large-area uniform graphene films by simply solution-casting EFG dispersions in dichloromethane on silicon oxide substrates, followed by annealing. The resultant graphene films show ambipolar transport properties with sheet resistances of 0.52-3.11 kOmega/sq at 63-90% optical transmittance. EFG allows solution processing methods for the scalable production of electrically conductive, optically transparent, and mechanically robust flexible graphene films for use in practice. PMID- 21591692 TI - Efficient luminescent down-shifting detectors based on colloidal quantum dots for dual-band detection applications. AB - A colloidal quantum dot (QD) luminescent down-shifting (LDS) layer is used to sensitize an InGaAs short wavelength infrared photodetector to the near UV spectral band. An average improvement in the external quantum efficiency (EQE) from 1.8% to 21% across the near UV is realized using an LDS layer consisting of PbS/CdS core/shell QDs embedded in PMMA. A simple model is used to fit the experimental EQE data. A UV sensitive InGaAs imaging array is demonstrated and the effect of the LDS layer on the optical resolution is calculated. The bandwidth of the LDS detector under UV illumination is characterized and shown to be determined by the photoluminescence lifetime of the QDs. PMID- 21591695 TI - Isolation and characterization of atropisomers of seven-membered-ring benzolactams. AB - The atropisomeric properties of seven-membered-ring benzolactams (7a-c and 8a) [1,5-benzodiazepin-2-one (a), 1,5-benzothiazepin-4-one (b), and 1-benzazepin-2 one (c)] were examined. The atropisomers were isolated as the diastereomers with an (S)-phenethylamide moiety, which were characterized by X-ray crystallography, and the barriers to their interconversion were clarified. PMID- 21591696 TI - Single photon ionization and chemical ionization combined ion source based on a vacuum ultraviolet lamp for orthogonal acceleration time-of-flight mass spectrometry. AB - A novel combined ion source based on a vacuum ultraviolet (VUV) lamp with both single photon ionization (SPI) and chemical ionization (CI) capabilities has been developed for an orthogonal acceleration time-of-flight mass spectrometer (oaTOFMS). The SPI was accomplished using a commercial 10.6 eV krypton discharge lamp with a photon flux of about 10(11) photons s(-1), while the CI was achieved through ion-molecule reactions with O(2)(+) reactant ions generated by photoelectron ionization at medium vacuum pressure (MVP). To achieve high ionization efficiency, the ion source pressure was elevated to 0.3 mbar and the photoionization length was extended to 36 mm. As a result, limits of detection (LODs) down to 3, 4, and 6 ppbv were obtained for benzene, toluene, and p-xylene in MVP-SPI mode, and values of 8 and 10 ppbv were obtained for toluene and chloroform, respectively, in SPI-CI mode. As it is feasible to switch between MVP SPI mode and SPI-CI mode rapidly, this system is capable of monitoring complex organic mixtures with a wide range of ionization energies (IEs). The analytical capacity of this system was demonstrated by measuring dehydrogenation products of long-chain paraffins to olefins through direct capillary sampling and drinking water disinfection byproducts from chlorine through a membrane interface. PMID- 21591693 TI - Unraveling terminal C-domain-mediated condensation in fungal biosynthesis of imidazoindolone metabolites. AB - The fungal peptidyl alkaloids of the tryptoquialanine and fumiquinazoline families are nonribosomally assembled by annulation of the indole side chain of fumiquinazoline F (FQF) with an alaninyl or aminoisobutyryl unit by monomodular NRPS enzymes containing adenylation, thiolation, and condensation (A-T-C) domains. The Af12060 and Af12050 enzyme pair from Aspergillus fumigatus thereby converts FQF to FQA, while the homologous TqaH and TqaB enzyme pair from Penicillium aethiopicum makes the 2'-epi diastereomer of FQA, differing only in the stereochemistry of one of the C-N bonds formed in the annulation with l-Ala. To evaluate the basis for this stereochemical control, we have mixed and matched the flavoprotein oxygenases Af12060 and TqaH with the A-T-C modular enzymes Af12050 and TqaB to show that the NRPS enzymes control the stereochemical outcome. The terminal 50 kDa condensation domains of Af12050 and TqaB are solely responsible for the stereochemical control as shown both by making chimeric (e.g., A-T-C* and A*-T*-C) forms of these monomodular NRPS enzymes and by expression, purification, and assay of the excised C-domains. The Af12050 and TqaB condensation domains are thus a paired set of diastereospecific annulation catalysts that act on the fumiquinazoline F scaffold. PMID- 21591694 TI - Development of beta-amino alcohol derivatives that inhibit Toll-like receptor 4 mediated inflammatory response as potential antiseptics. AB - Toll-like receptor 4 (TLR4) induced proinflammatory signaling has been directly implicated in severe sepsis and represents an attractive therapeutic target. Herein, we report our investigations into the structure-activity relationship and preliminary drug metabolism/pharmacokinetics study of beta-amino alcohol derivatives that inhibit the TLR4 signaling pathway. Lead compounds were identified from in vitro cellular examination with micromolar potency for their inhibitory effects on TLR4 signaling and subsequently assessed for their ability to suppress the TLR4-induced inflammatory response in an ex vivo whole blood model. In addition, the toxicology, specificity, solubility, brain-blood barrier permeability, and drug metabolism of several compounds were evaluated. Although further optimizations are needed, our findings lay the groundwork for the future drug development of this class of small molecule agents for the treatment of severe sepsis. PMID- 21591697 TI - Aqueous suspensions of natural swelling clay minerals. 2. Rheological characterization. AB - We report in this article a comprehensive investigation of the viscoelastic behavior of different natural colloidal clay minerals in aqueous solution. Rheological experiments were carried out under both dynamic and steady-state conditions, allowing us to derive the elasticity and yield stress. Both parameters can be renormalized for all sizes, ionic strength, and type of clay using in a first approach only the volume of the particles. However, applying such a treatment to various clays of similar shapes and sizes yields differences that can be linked to the repulsion strength and charge location in the swelling clays. The stronger the repulsive interactions, the better the orientation of clay particles in flows. In addition, a master linear relationship between the elasticity and yield stress whose value corresponds to a critical deformation of 0.1 was evidenced. Such a relationship may be general for any colloidal suspension of anisometric particles as revealed by the analysis of various experimental data obtained on either disk-shaped or lath- and rod-shaped particles. The particle size dependence of the sol-gel transition was also investigated in detail. To understand why suspensions of larger particles gel at a higher volume fraction, we propose a very simplified view based on the statistical hydrodynamic trapping of a particle by an another one in its neighborhood upon translation and during a short period of time. We show that the key parameter describing this hydrodynamic trapping varies as the cube of the average diameter and captures most features of the sol-gel transition. Finally, we pointed out that in the high shear limit the suspension viscosity is still closely related to electrostatic interactions and follows the same trends as the viscoelastic properties. PMID- 21591698 TI - Ultrathin films of variable polarity and crystallinity obtained from 1,2 polybutadiene nanoparticle dispersions. AB - Characterization of ultrathin films of different polymer nanoparticles obtained at room temperature via spin-coating of aqueous dispersions and their morphology are described. Very small nanoparticles of semicrystalline 1,2-polybutadiene (PB), noncrystalline poly(1-butene) (PH), and poly(1-butenal) (PHF) were prepared via catalytic emulsion polymerization and subsequent hydrogenation or hydroformylation. The prefabricated nanoparticles were used as building blocks. The thin films obtained are continuous and transparent (n=1.5; kappa=0). The properties of these films, formed from different constituents, are analyzed. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) images show that the PB-films are very smooth (rms roughness=10 nm) and polycrystalline. Recrystallization of these PB films reveals that edge-on lamellae are the constituent units. Films with very low roughness values (rms roughness <2 nm) are obtained with PH nanoparticles, due to the soft character of the nanoparticles. The AFM profile of the PHF films reveals that the surface remains structured after drying due to the high degree of the internal cross-linking that occurs in the nanoparticles. Quantification of the films' polarity (I(3)/I(1)=0.89, 1.3, and 2.1 for PHF, PB, and PH, respectively) agrees well with the previous values obtained for the polymer dispersions. Surfactant molecules are desorbed during the film formation; however, these aggregates can be removed by rinsing with water with no undesirable effects observed on the films. PMID- 21591699 TI - Star-shaped MePEGn polymers as H+ conducting electrolytes. AB - Proton conducting electrolytes composed of a mixture of MePEG(7)SO(3)H acid and a four-armed, PEG-based, star molecule were prepared. Four MePEG(n) (n = 3, 7, 12) arms were attached to a pentaerythritol or tetrakis(dimethylsilyl) orthosilicate core to form the star molecules. We have examined the structure of these star electrolytes to observe how the structure of an electrolyte affects the observed ionic conductivity. In terms of structural parameters, these star electrolytes showed large volume fractions of PEG, high fluidities, and large fractional free volumes, all of which predict larger ionic conductivities. Through a comparison of the conductivity and structural parameters in a variety of different star electrolytes, we have shown that each of these three structural parameters are important and can strongly affect the observed ionic conductivity. Walden plots indicated a large extent of ion-pairing in our star electrolytes and that MePEG(7)SO(3)H acid was a weak acid in our star electrolytes. PMID- 21591700 TI - Preparation of monodisperse poly(N-isopropylacrylamide) microgel particles with homogenous cross-link density distribution. AB - Monodisperse microgel latex with homogeneous cross-link density distribution within the particles was prepared by feeding the monomer and cross-linker into the reaction mixture in a regulated way during the polymerization. To determine the appropriate monomer feeding parameters, the kinetics of the particle formation was investigated by HPLC. The swelling and optical characteristics of the prepared homogenously cross-linked microgel particles were compared to the properties of inhomogenously cross-linked microgels prepared by the normal precipitation polymerization method. The distribution of the cross-link density within the particles inserts a great influence on the characteristics of the system. The degree of swelling of the homogeneous particles is significantly higher than that of the heterogeneous microgel particles. Furthermore, at room temperature the pNIPAm latex containing the homogeneously cross-linked particles is transparent, while the heterogeneously cross-linked particles form a highly turbid system at the same 0.1 wt% concentration. PMID- 21591701 TI - Ionic liquid-enhanced photooxidation of water using the polyoxometalate anion [P2W18O62](6-) as the sensitizer. AB - Simple polyoxometalate anions are known to be photoreduced in molecular solvents in the presence of 2-propanol or benzyl alcohol. The use of ionic liquids (ILs) as the solvent is now reported to also allow the photooxidation of water to be achieved. In particular, the photochemistry of the classic Dawson polyoxometalate salt K(6)[P(2)W(18)O(62)] has been studied in detail when water is present in the aprotic IL, 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF(4)]) and the protic IL, diethanolamine hydrogen sulfate (DEAS). In these and other ILs, irradiation with white light (wavelength 275-750 nm) or UV light (wavelength 275 320 nm) leads to overall reduction of the [P(2)W(18)O(62)](6-) anion to [P(2)W(18)O(62)](7-) and concomitant oxidation of water to dioxygen and protons. The modified structure of bulk water present in ILs appears to facilitate its oxidation. Analogous results were obtained in aqueous solutions containing the protic IL as an electrolyte. The photoproducts (reduced polyoxometalate anion, dioxygen, and protons) were identified by, respectively, voltammetry, a Clark electrode, and monitoring of pH. The formal reversible potentials E(0)(F) for [P(2)W(18)O(62)](6-/7-/8-/9-/10-) couples are much more positive than in molecular solvents. The [P(2)W(18)O(62)](8-) and more reduced anions, if formed as intermediates, would efficiently reduce photoproducts H(+) or dioxygen to produce [P(2)W(18)O(62)](7-), rather than reform to [P(2)W(18)O(62)](6-). Thus, under photoirradiation conditions [P(2)W(18)O(62)](7-) acts as a kinetic sink so that in principle indirect splitting of water to produce dioxygen and dihydrogen can be achieved. The equivalent form of photooxidation does not occur in liquid water or in molecular solvents such as MeCN and MeCN/CH(2)Cl(2) containing added water, but does occur for solid K(6)[P(2)W(18)O(62)] in contact with water vapor. PMID- 21591702 TI - Barley intake induces bile acid excretion by reduced expression of intestinal ASBT and NPC1L1 in C57BL/6J mice. AB - To investigate the hypocholesterolemic mechanism of barley in vivo, six-week-old C57BL/6J mice were fed a high-fat diet (HFD) or high-fat diet containing barley (HFD-B) for seven weeks. Total and LDL cholesterol concentrations were significantly reduced in the HFD-B group while fecal cholesterol and bile acid was increased. Real-time PCR and immunoblot analysis revealed the induction of FXR expression, which in turn suppressed the expression of ASBT and NPC1L1 in the HFD-B group compared with the controls. In the liver, the expression of HMG-CoA reductase was significantly reduced while LDL receptor expression was unaltered in the HFD-B group compared with the controls. Our data suggest that the hypocholesterolemic effects of barley are primarily the result of reduced dietary cholesterol uptake and bile acid resorption. Reduced expression of intestinal ASBT and NPC1L1 may play a key role in the regulation of dietary cholesterol and bile acid metabolism in mice consuming a diet containing barley. PMID- 21591703 TI - Studies on imidazolium-based ionic liquids having a large anion confined in a nanoporous silica gel matrix. AB - The properties of large molecules confined in nanopores are expected to be different from those of the bulk. This study reports changes in the phase behavior and vibrational frequencies of an imidazolium-based ionic liquid (IL), namely, 1-butyl-3-methyl imidazolium octyl sulfate ([BMIM][OcSO(4)]) in a nanoporous silica gel matrix. Nanoporous silica gel matrixes have been synthesized by a one-step sol-gel technique using tetraethylorthosilicate (TEOS) as a starting precursor. The synthesized gel has been characterized by differential scanning calorimetry (DSC), BET, TEM and FTIR. The FTIR spectra show shifts in many vibrational bands; particularly, the vibrational bands related to the imidazolium ring, aliphatic chain, and SO(3) of the IL are found to shift significantly upon confinement. The DSC results show significant changes in the melting point (DeltaT(m) ~ 52 degrees C), crystallization temperature (DeltaT(C) ~ 14 degrees C), and glass transition temperature (DeltaT(g) ~ 2 degrees C). The IL used in the present study has a large anion ([OcSO(4)]), and DeltaT(m) for this is much larger than those reported earlier for many other ILs with relatively smaller anions. A new approach, based on the liquid-drop model, has been suggested to explain this. PMID- 21591704 TI - Anomalous behavior of linear hydrocarbon chains in water-DMSO binary mixture at low DMSO concentration. AB - We find that at a mole fraction 0.05 of DMSO (x(DMSO) = 0.05) in aqueous solution, a linear hydrocarbon chain of intermediate length (n=30-40) adopts the most stable collapsed conformation. In pure water, the same chain exhibits an intermittent oscillation between the collapsed and the extended coiled conformations. Even when the mole fraction of DMSO in the bulk is 0.05, the concentration of the same in the first hydration layer around the hydrocarbon of chain length 30 (n=30) is as large as 17%. Formation of such hydrophobic environment around the hydrocarbon chain may be viewed as the reason for the collapsed conformation gaining additional stability. We find a second anomalous behavior to emerge near x(DMSO)=0.15, due to a chain-like aggregation of the methyl groups of DMSO in water that lowers the relative concentration of the DMSO molecules in the hydration layer. We further find that as the concentration of DMSO is gradually increased, it progressively attains the extended coiled structure as the stable conformation. Although Flory-Huggins theory (for binary mixture solvent) fails to predict the anomaly at x(DMSO)=0.05, it seems to capture the essence of the anomaly at 0.15. PMID- 21591705 TI - Structure-activity relationship for quaternary ammonium compounds hybridized with poly(methyl methacrylate). AB - Hybrid films from poly (methylmethacrylate) (PMMA) and dioctadecyldimethylammonium bromide (DODAB), cetyltrimethylammonium bromide (CTAB), or tetrapropylammonium bromide (TPAB) were characterized by determination of wettability, ellipsometry, atomic force microscopy, active compounds diffusion to water, X-ray photoelectron spectroscopy (XPS) with determination of atomic composition on the films surface, and biocidal activity against Pseudomonas aeruginosa or Staphylococcus aureus. QAC mobility in the films increased from DODAB to CTAB to TPAB. Diffusion and optimal hydrophobic-hydrophilic balance imparted the highest bioactivity to CTAB. DODAB sustained immobilization at the film surface killed bacteria upon contact. TPAB ability to diffuse was useless because of its unfavorable hydrophobic-hydrophilic balance for bioactivity. PMID- 21591706 TI - One-dimensional molecular zippers. AB - We synthesized an azobenzene derivative to demonstrate a one-dimensional molecular zipper. The formation and underlying mechanism of the molecular zipper formed by combined hydrogen-bonding and van der Waals interactions between adjacent molecules were investigated on a Au(111) surface using scanning tunneling microscopy and density functional theory calculations. PMID- 21591707 TI - Ionic liquid based lithium battery electrolytes: charge carriers and interactions derived by density functional theory calculations. AB - The solvation of lithium salts in ionic liquids (ILs) leads to the creation of a lithium ion carrying species quite different from those found in traditional nonaqueous lithium battery electrolytes. The most striking differences are that these species are composed only of ions and in general negatively charged. In many IL-based electrolytes, the dominant species are triplets, and the charge, stability, and size of the triplets have a large impact on the total ion conductivity, the lithium ion mobility, and also the lithium ion delivery at the electrode. As an inherent advantage, the triplets can be altered by selecting lithium salts and ionic liquids with different anions. Thus, within certain limits, the lithium ion carrying species can even be tailored toward distinct important properties for battery application. Here, we show by DFT calculations that the resulting charge carrying species from combinations of ionic liquids and lithium salts and also some resulting electrolyte properties can be predicted. PMID- 21591709 TI - Organic redox couples and organic counter electrode for efficient organic dye sensitized solar cells. AB - A series of organic thiolate/disulfide redox couples have been synthesized and have been studied systematically in dye-sensitized solar cells (DSCs) on the basis of an organic dye (TH305). Photophysical, photoelectrochemical, and photovoltaic measurements were performed in order to get insights into the effects of different redox couples on the performance of DSCs. The polymeric, organic poly(3,4-ethylenedioxythiophene) (PEDOT) material has also been introduced as counter electrode in this kind of noniodine-containing DSCs showing a promising conversion efficiency of 6.0% under AM 1.5G, 100 mW.cm(-2) light illumination. Detailed studies using electrochemical impedance spectroscopy and linear-sweep voltammetry reveal that the reduction of disulfide species is more efficient on the PEDOT counter electrode surface than on the commonly used platinized conducting glass electrode. Both pure and solvated ionic-liquid electrolytes based on a thiolate anion have been studied in the DSCs. The pure and solvated ionic-liquid-based electrolytes containing an organic redox couple render efficiencies of 3.4% and 1.2% under 10 mW.cm(-2) light illumination, respectively. PMID- 21591708 TI - Molecular structural differences between type-2-diabetic and healthy glycogen. AB - Glycogen is a highly branched glucose polymer functioning as a glucose buffer in animals. Multiple-detector size exclusion chromatography and fluorophore-assisted carbohydrate electrophoresis were used to examine the structure of undegraded native liver glycogen (both whole and enzymatically debranched) as a function of molecular size, isolated from the livers of healthy and db/db mice (the latter a type 2 diabetic model). Both the fully branched and debranched levels of glycogen structure showed fundamental differences between glycogen from healthy and db/db mice. Healthy glycogen had a greater population of large particles, with more alpha particles (tightly linked assemblages of smaller beta particles) than glycogen from db/db mice. These structural differences suggest a new understanding of type 2 diabetes. PMID- 21591710 TI - Rapid high-resolution characterization of functionally important monoclonal antibody N-glycans by capillary electrophoresis. AB - Characterization of the N-glycosylation present in the Fc region of therapeutic monoclonal antibodies requires rapid, high-resolution separation methods to guarantee product safety and efficacy during all stages of process development. Determination of fucosylated oligosaccharides is particularly important during clone selection, product characterization, and lot release as fucose has been shown to adversely affect the ability of mAbs to induce antibody dependent cellular cytotoxicity (ADCC). Here, we apply a general capillary electrophoresis optimization strategy to separate functionally relevant fucosylated and afucosylated glycans on mononclonal antibody products in the presence of several high mannose oligosaccharides. The N-glycans chosen represent those most commonly reported on CHO cell derived therapeutic antibodies. A rapid (<7 min) high resolution separation of 12 commonly reported and functionally important IgG glycans was developed by systematically evaluating the effects of selectivity (boric acid) and efficiency (linear polyacrylamide) enhancing additives. The approach can be used to rapidly optimize capillary electrophoresis separation of other glycan mixtures. Following optimization, the method was applied to overnight sample processing for automated 96 well plate-based glycosylation analyses of two nonproprietary therapeutic monoclonal antibodies, demonstrating ruggedness and suitability for high-throughput process and product monitoring applications. PMID- 21591712 TI - A room-temperature fluorescence study of organofullerenes: cis-1 bisadduct with unusual blue-shifted emissions. AB - C(60) derivatives have shown enhanced fluorescent emissions with respect to C(60) due to the lowering of molecular symmetry and have demonstrated promising potentials as novel organoelectronic materials for application in light-emitting diodes. Previous work has indicated that the fluorescent properties of functionalized C(60) are mainly affected by the addition patterns, rather than the nature of addends. However, no report on the fluorescence of C(60)cis-1 bisadducts, one of the most favorable types of C(60) bisadducts, has appeared up to date. Herein, the fluorescent properties of two structurally related C(60)cis 1 bisadducts of fullerooxazolines, 1 and 2, are examined at room temperature. It shows that a significant difference exists for the fluorescent spectra of 1 and 2, where 1 displays a rather strong unusual blue-shifted emission band, even though the two compounds have the same addition pattern. Monoadducts bearing individual addends of 1 and 2, along with 1a and 1b, which have one PhCD(2)- positioned either next to the C(60)-N or C(60)-O bond, are also examined in order to gain a better understanding of such difference. The results indicate that the unusual blue-shifted emissions for 1 are likely to originate from the vibrational interactions of the addends, suggesting that the fluorescent emissions of C(60) derivatives can be tuned not only by the addition patterns, but also by the nature of the adducts. Density functional theory and time-dependent density functional theory calculations are performed to rationalize the experimental observations. PMID- 21591711 TI - Lead speciation in house dust from Canadian urban homes using EXAFS, micro-XRF, and micro-XRD. AB - X-ray absorption fine-structure (XAFS) spectroscopy, micro-X-ray fluorescence (MUXRF), and micro-X-ray diffraction (MUXRD) were used to determine the speciation of Pb in house dust samples from four Canadian urban homes having elevated Pb concentrations (>1000 mg Pb kg(-1)). Linear combination fitting of the XAFS data, supported by MUXRF and MUXRD, shows that Pb is complexed in a variety of molecular environments, associated with both the inorganic and organic fractions of the dust samples. The inorganic species of lead identified were as follows: Pb metal, Pb carbonate, Pb hydroxyl carbonate, Pb oxide, and Pb adsorbed to iron oxyhydroxides. Pb carbonate and/or Pb hydroxyl carbonate occurred in all four dust samples and accounted for 28 to 75% of total Pb. Pb citrate and Pb bound to humate were the organic species identified. The results of this study demonstrate the ability of XAFS to identify Pb speciation in house dust and show the potential to identify Pb sources from new homes versus older homes. Understanding Pb speciation and how it influences bioaccessibility is important for human health risk assessment and risk management decisions which aim to improve indoor environmental health. PMID- 21591713 TI - Revisiting fluorenone photophysics via dipolar fluorenone derivatives. AB - The nonradiative decay of four dipolar fluorenone derivatives (FODs) was systematically investigated using steady state and time-resolved UV-vis absorption and fluorescence measurements combined with cyclic voltammetry. Analysis of the frontier orbital localization of the global minimum geometry and the vertical transitions was carried out from DFT calculations. The first singlet excited state was found to be pi-pi* in all derivatives regardless of the polarity of the solvent. Charge separation/recombination dominates the singlet excited state deactivation for carbazole-containing FODs. Intersystem crossing (ISC) operates exclusively in the 3,6-disubstituted variants as evidenced by phosphorescence experiments. In the case of CPAFO36, ISC competes disadvantageously with CT deactivation. PMID- 21591714 TI - Measurement of Raman chi(3) and theoretical estimation of DOVE four wave mixing of hydrogen peroxide. AB - Hydrogen peroxide has strong infrared (IR) transitions nu(6) and its combination band nu(2)+nu(6), which may provide a unique opportunity to implement doubly vibrationally enhanced (DOVE) four wave mixing (FWM) for directly measuring hydrogen peroxide in spectrally overcrowded mixtures. In this work, the magnitude of the DOVE third-order susceptibility chi(3) was theoretically estimated. By using a FWM interferometric method, one of the strongest Raman bands, O-O stretch nu(3) Raman chi(3) of 30 wt % H(2)O(2), was first measured to be 1.2 * 10(-14) esu. The Raman chi(3) of nu(2) was then determined to be 5.3 * 10(-15) esu based on their relative Raman intensities. The resulting Raman chi(3) of nu(2) was used to calculate the DOVE chi(3) of (nu(6), nu(2)+nu(6)), together with the dipolar moments of the two IR transitions determined from IR absorption measurement. The calculated value of DOVE-IR chi(3) was 1.1 * 10(-13) esu for pure H(2)O(2), about 1.5 times larger than that of the strong ring breathing Raman band of benzene. The large DOVE chi(3) suggests the feasibility of direct measurement of hydrogen peroxide in an aqueous environment using DOVE four wave mixing. PMID- 21591715 TI - XUV free-electron laser desorption of NO from graphite (0001). AB - We report results of femtosecond laser induced desorption of NO from highly oriented pyrolytic graphite using XUV photon energies of hnu = 38 eV and hnu = 57 eV. Femtosecond pulses with a pulse energy of up to 40 MUJ and about 30 fs duration generated at FLASH are applied. The desorbed molecules are detected with rovibrational state selectivity by (1 + 1) REMPI in the A(2)Sigma(+) <- X(2)Pi gamma-bands around lambda = 226 nm. A nonlinear desorption yield of neutral NO is observed with an exponent of m = 1.4 +/- 0.2. At a fluence of about 4 mJ/cm(2) a desorption cross section of sigma(1) = (1.1 +/- 0.4) * 10(-17) cm(2) is observed, accompanied with a lower one of sigma(2) = (2.6 +/- 0.3) * 10(-19) cm(2) observable at higher total fluence. A nonthermal rovibrational population distribution is observed with an average rotational energy of = 38.6 meV (311 cm(-1)), a vibrational energy of = 136 meV (1097 cm(-1)) and an electronic energy of = 3.9 meV (31 cm(-1)). PMID- 21591716 TI - A fast method coupling ultrahigh performance liquid chromatography with diode array detection for flavonoid quantification in citrus fruit extracts. AB - Flavonoids are a widely distributed group of polyphenolic compounds present in an extensive range of edible plants, notably Citrus species. This article reports a rapid, optimized, and validated method for the separation and quantification of flavonoids in three Citrus fruit extracts by ultrahigh performance liquid chromatography (UHPLC) using a photodiode array detector. This new procedure allowed the simultaneous separation and quantification of 11 selected flavonoids in 5.5 min, 8.2 times faster than that by HPLC analysis. The solvent consumption for each individual analysis was also reduced almost 6.2-fold. The most abundant component in the analyzed samples was naringin (299.06-544.36 mg 100 g-1), followed by rutin (116.60-256.33 mg 100 g-1) and quercetin (7.78-251.49 mg 100 g 1). Isoquercitrin was found in a lower proportion (60.05-81.88 mg 100 g-1). The method was completely validated, providing a sensitive analysis for flavonoid detection and showing satisfactory data for all the parameters tested. This methodology is cheaper, more environmentally friendly, and easier to perform than others previously described. PMID- 21591717 TI - Carbon-13 NMR chemical shifts in columnar liquid crystals. AB - In this article, we present quantum chemical density functional theory (DFT) calculations of the NMR (13)C chemical shift (CS) tensors in 2,3,6,7,10,11 hexahexylthiotriphenylene (HHTT). The DFT calculations are performed on a smaller model molecule where the hexyl chains were reduced to methyl groups (HMTT). These tensors are compared with our previously reported experimental results carried out under magic-angle spinning (MAS) conditions. The phase diagram of HHTT is K < > H <-> D(hd) <-> I, where H is a helical phase and D(hd) is a columnar liquid crystal. The motivation for the present study was to explain experimentally observed and puzzling thermal history effects, which resulted in different behavior in the helical phase upon cooling and heating. In particular, the CS tensors for the aromatic carbons measured in the helical phase upon heating from the solid phase were essentially unaffected, while the cooling from the columnar liquid crystal resulted in a significant averaging. We investigate the effect on the CS tensors of (i) conformational transitions, and (ii) relative molecular orientations within the columns for dimer and trimer configurations. Finally a motional wobbling (PIZZA) model for the dynamic averaging of the CS tensor in the helical phase is suggested. PMID- 21591718 TI - pH/Temperature-responsive behavior of amphiphilic block copolymer micelles prepared using two different methods. AB - The pH- and temperature-responsive behavior of amphiphilic block copolymer poly(L lactide)-b-poly(2-(dimethylamino)ethyl methacrylate) (PLLA-b-PDMAEMA) in aqueous solutions is investigated using static and dynamic light scattering. Electrostatic force, hydrophobic interaction, and hydrogen bonding coexist in the system. Micelles with different structures are prepared using water addition (WA) and direct dissolution (DD) methods. The aggregation from loose micelles into large micellar clusters is observed above the transition temperature under basic conditions. Only micellar clusters from the DD method could disaggregate when temperature was decreased to 24.3 degrees C after heating. The behavior of the micelles prepared with the DD method indicates that only the outer parts of the PLLA-b-PDMAEMA chains in the corona are solvated. PMID- 21591719 TI - Protein polymer conjugates: improving the stability of hemoglobin with poly(acrylic acid). AB - The synthesis, characterization, and evaluation of a novel polymer-protein conjugate are reported here. The covalent conjugation of high-molecular weight poly(acrylic acid) (PAA) to the lysine amino groups of met-hemoglobin (Hb) resulted in the covalent conjugation of Hb to PAA (Hb-PAA conjugate), as confirmed by dialysis and electrophoresis studies. The retention of native-like structure of Hb in Hb-PAA was established from Soret absorption, circular dichroism studies, and the redox activity of the iron center in Hb-PAA. The peroxidase-like activities of the Hb-PAA conjugate further confirmed the retention of Hb structure and biological activity. Thermal denaturation of the conjugate was investigated by differential scanning calorimetry and steam sterilization studies. The Hb-PAA conjugate indicated an improved denaturation temperature (T(d)) when compared to that of the unmodified Hb. One astonishing observation was that polymer conjugation significantly enhanced the Hb-PAA storage stability at room temperature. After 120 h of storage at room temperature in phosphate-buffered saline (PBS) at pH 7.4, for example, Hb-PAA retained 90% of its initial activity and unmodified Hb retained <60% of its original activity under identical conditions of buffer, pH, and temperature. Our conjugate demonstrates the key role of polymers in enhancing Hb stability via a very simple, efficient, general route. Water-swollen, lightly cross-linked, stable Hb polymer nanogels of 100-200 nm were produced quickly and economically by this approach for a wide variety of applications. PMID- 21591720 TI - Effect of protein environment on electronically excited and ionized states of the green fluorescent protein chromophore. AB - The effect of the protein environment on the electronic structure of the green fluorescent protein (GFP) chromophore is investigated by QM/MM (quantum mechanics/molecular mechanics) calculations. The protein has very small effect on the excitation energy of the bright absorbing and the lowest triplet states of the anionic GFP chromophore, deprotonated 4-hydroxybenzylidene-2,3 dimethylimidazolinone (HBDI) anion, however, it increases vertical detachment energy from 2.5 eV (gas-phase deprotonated HBDI anion) to 5.0 eV (solvated protein). We also investigated possible existence of the charge-transfer-to solvent (CTTS) states associated with the GFP chromophore. Although precursors of such states appear in cluster calculations, a tightly packed structure of the protein prevents the formation of the CTTS states in this system. Motivated by a recently discovered new type of photoconversion, oxidative redding, we characterized the redox properties of GFP. The computed standard reduction potential of the anionic form of GFP is 0.47 V (for the GFP(*) + 1e -> GFP(-) reaction), and the reduction potential at physiological conditions (pH 7, T = 25 degrees C) is 0.06 V. PMID- 21591722 TI - Cu(I)-catalyzed, alpha-selective, allylic alkylation reactions between phosphorothioate esters and organomagnesium reagents. AB - Regiocontrol of allylic alkylation reactions involving hard nucleophiles remains a significant challenge and continues to be an active area of research. The lack of general methods in which alpha-alkylation is favored underscores the need for the development of new processes for achieving this type of selectivity. We report that Cu(I) catalyzes the allylic substitution of phosphorothioate esters with excellent alpha-regioselectivity, regardless of the nature of the Grignard reagent that is used. To the best of our knowledge, the Cu-catalyzed allylic alkylation of phosphorothioate esters has never been described. We have also developed a simple protocol for inducing high alpha selectivity starting from secondary allylic halides. This is accomplished by using sodium phosphorothioates as an additive. PMID- 21591723 TI - Volvalerelactones A and B, two new sesquiterpenoid lactones with an unprecedented skeleton from Valeriana officinalis var. latifolia. AB - Volvalerelactones A and B (1 and 2), two new sesquiterpenoid lactones with an unprecedented 3/7/6 tricyclic ring system, were isolated from the roots of Valeriana officinalis var. latifolia. Their structures and relative configurations were elucidated by spectroscopic data and single-crystal X-ray diffraction crystallography, and the absolute configuration was assigned by computational methods. The possible biosynthetic pathways of 1 and 2 were also proposed. PMID- 21591724 TI - Dimeric and trimeric tetrathiafulvalenes with strong intramolecular interactions in the oxidized states. AB - New dimeric and trimeric TTF derivatives with methylenedithio spacers (1a,b, 2a, and 2b) have been synthesized. X-ray structure analysis revealed that TTF units of the dimer 1b adopted distorted face-to-face overlapping arrangement both in intra- and intermolecular stacking. Cyclic voltammetric study indicated that trimeric 2a was in favor of taking di- and tetracationic states, while the dimeric 1a was in favor of taking a monocation. The absorption spectroscopic study suggested an existence of the strong face-to-face interaction particularly in di-, tri-, and tetracationic state of the trimeric TTF derivatives. PMID- 21591721 TI - Complete budding and asymmetric division of primitive model cells to produce daughter vesicles with different interior and membrane compositions. AB - Asymmetric cell division is common in biology and plays critical roles in differentiation and development. Unicellular organisms are often used as model systems for understanding the origins and consequences of asymmetry during cell division. Although basic as compared to mammalian cells, these are already quite complex. We report complete budding and asymmetric fission of very simple nonliving model cells to produce daughter vesicles that are chemically distinct in both interior and membrane compositions. Our model cells are based on giant lipid vesicles (GVs, 10-30 MUm) encapsulating a polyethylene glycol (PEG)/dextran aqueous two-phase system (ATPS) as a crowded and compartmentalized cytoplasm mimic. Ternary lipid compositions were used to provide coexisting micrometer scale liquid disordered (L(d)) and liquid ordered (L(o)) domains in the membranes. ATPS-containing vesicles formed buds when sucrose was added externally to provide increased osmotic pressure, such that they became not only morphologically asymmetric but also asymmetric in both their interior and their membrane compositions. Further increases in osmolality drove formation of two chemically distinct daughter vesicles, which were in some cases connected by a lipid nanotube (complete budding), and in others were not (fission). In all cases, separation occurred at the aqueous-aqueous phase boundary, such that one daughter vesicle contained the PEG-rich aqueous phase and the other contained the dextran-rich aqueous phase. PEGylated lipids localized in the L(o) domain resulted in this membrane domain preferentially coating the PEG-rich bud prior to division, and subsequently the PEG-rich daughter vesicle. Varying the mole ratio of lipids resulted in excess surface area of L(o) or L(d) membrane domains such that, upon division, this excess portion was inherited by one of the daughter vesicles. In some cases, a second "generation" of aqueous phase separation and budding could be induced in these daughter vesicles. Asymmetric fission of a simple self-assembled model cell, with production of daughter vesicles that harbored different protein concentrations and lipid compositions, is an example of the seemingly complex behavior possible for simple molecular assemblies. These compartmentalized and asymmetrically dividing ATPS-containing GVs could serve as a test bed for investigating possible roles for spatial and organizational cues in asymmetric cell division and inheritance. PMID- 21591725 TI - Encapsulation of conventional and unconventional water dimers by water-binding foldamers. AB - Water-binding foldamers have been rarely studied. By orienting both H-bond donors and acceptors toward their interior, two pyridine-derived crescent-shaped folding oligoamides were found to be capable of trapping both conventional and unconventional water dimer clusters in their cavity (~2.5 A radius). In the unconventional water dimer cluster, the two water molecules stay in contact via an unusual H-H interaction (2.25 A) rather than the typical H-bond. PMID- 21591726 TI - Formation of stable hydrophilic C60 nanoparticles by 2-hydroxypropyl-beta cyclodextrin. AB - A number of papers have reported that the large cavity of gamma-CyD is favorable for inclusion of C(60) and forms a 1:2 (C(60):gamma-CyD) complex, whereas it is thought to be difficult for beta-CyD to form a complex at the molecular level. This is because the cavity size of beta-CyD (0.78 nm) is smaller than the van der Waals diameter of C(60) (1.0 nm). In this paper, we will report on the formation of the stable C(60) nanoparticles by the hydrophilic 2-hydroxypropyl-beta cyclodextrin (HP-beta-CyD) layer through weak interaction on the surface of the nanoparticles. C(60) was coground with beta-CyD, gamma-CyD or HP-beta-CyD mainly in a 1:2 molar ratio by an automatic magnetic agitating mortar, the coground powders were dispersed in water, and the resulting solutions were filtered through a pore size of 0.8 MUm filter. The gamma-CyD and HP-beta-CyD systems gave transparent colloidal solutions consisting of C(60)/CyD nanoparticles with the size lower than 100 nm, with high yields (about 100%). The C(60)/HP-beta-CyD nanoparticles are physically stable, keeping a small size for more than 28 days, whereas the gamma-CyD nanoparticles are readily aggregated to form large particles (>800 nm). Solid and liquid NMR spectroscopic studies including measurements of spin-lattice relaxation times indicated that C(60) interacted with gamma-CyD and HP-beta-CyD in the solid and colloidal solutions. When compared with the gamma-CyD nanoparticles, adsorption studies of a hydrophobic dye on the surface of C(60)/CyD nanoparticles indicated that the surface of the HP-beta-CyD nanoparticles is largely covered by HP-beta-CyD molecules forming hydrophilic hydration layers. The present results suggest that HP-beta-CyD is useful for the preparation of C(60) nanoparticles and medical applications such as photodynamic therapy, in spite of having a cavity size smaller than that of gamma-CyD. PMID- 21591727 TI - Poloxamines display a multiple inhibitory activity of ATP-binding cassette (ABC) transporters in cancer cell lines. AB - Primary hepatocellular carcinoma is the third most common fatal cancer worldwide with more than 500,000 annual deaths. Approximately 40% of the patients with HCC showed tumoral overexpression of transmembrane proteins belonging to the ATP binding cassette protein superfamily (ABC) which pump drugs out of cells. The overexpression of these efflux transporters confers on the cells a multiple drug resistance phenotype, which is considered a crucial cause of treatment refractoriness in patients with cancer. The aim of this study was to investigate the inhibitory effect of different concentrations of pH- and temperature responsive X-shaped poly(ethylene oxide)-poly(propylene oxide) block copolymers (poloxamines, Tetronic, PEO-PPO) showing a wide range of molecular weights and EO/PO ratios on the functional activity of three different ABC proteins, namely P glycoprotein (P-gp or MDR1), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein MRP1, in two human hepatocarcinoma cell lines, HepG2 and Huh7. First, the cytotoxicity of the different copolymers (at different concentrations) on both liver carcinoma cell lines was thoroughly evaluated by means of apoptosis analysis using annexin V and propidium iodide (PI). Thus, viable cells (AV-/PI-), early apoptotic cells (AV+/PI-) and late apoptotic cells (V-FITC+/PI+) were identified. Results pointed out copolymers of intermediate to high hydrophobicity and intermediate molecular weight (e.g., T904) as the most cytotoxic. Then, DiOC2, rhodamine 123 and vinblastine were used as differential substrates of these pumps. HeLa, an epithelial cell line of human cervical cancer that does not express P-gp, was used exclusively as a control and enabled the discerning between P-gp and MRP1 inhibition. Moderate to highly hydrophobic poloxamines T304, T904 and T1301 showed inhibitory activity against P gp and BCRP but not against MRP1 in both hepatic cell lines. A remarkable dependence of this effect on the copolymer concentration and hydrophobicity was found. No inhibitory effect against these ABC pumps was observed with the hydrophilic T1107. These findings further evidence the potential usefulness of these Trojan horses as both drug nanocarriers and ABC inhibitors in hepatic MDR tumors and infections that involve the activity of these efflux transporters. PMID- 21591729 TI - Stepwise "click" chemistry for the template independent construction of a broad variety of cross-linked oligonucleotides: influence of linker length, position, and linking number on DNA duplex stability. AB - Cross-linked DNA was constructed by a "stepwise click" reaction using a bis azide. The reaction is performed in the absence of a template, and a monofunctionalized oligonucleotide bearing an azido-function is formed as intermediate. For this, an excess of the bis-azide has to be used compared to the alkynylated oligonucleotide. The cross-linking can be carried out with any alkynylated DNA having a terminal triple bond at any position of the oligonucleotide, independent of chain length or sequence with identical or nonidentical chains. Short and long linkers with terminal triple bonds were introduced in the 7-position of 8-aza-7-deaza-2'-deoxyguanosine (1 or 2), and the outcome of the "stepwise" click and the "bis-click" reaction was compared. The cross-linked DNAs form cross-linked duplexes when hybridized with single-stranded complementary oligonucleotides. The stability of these cross-linked duplexes is as high as respective individual duplexes when they were ligated at terminal positions with linkers of sufficient length. The stability decreases when the linkers are incorporated at central positions. The highest duplex stability was reached when two complementary cross-linked oligonucleotides were hybridized. PMID- 21591728 TI - Copper-catalyzed tandem reaction of isocyanides with N-(2-haloaryl)propiolamides for the synthesis of pyrrolo[3,2-c]quinolin-4-ones. AB - The copper-catalyzed tandem reaction of isocyanides with N-(2 haloaryl)propiolamides is very efficient for the synthesis of pyrrolo[3, 2 c]quinolin-4-ones. Highly reactive cyclic organocopper intermediates were proposed to be generated in the copper-catalyzed formal [3 + 2] cycloaddition reaction of isocyanides with triple bonds. Intramolecular trapping of the organocopper intermediates can lead to aryl C-C bond formation, which offered an efficient method for constructing fused pyrrole structures. PMID- 21591730 TI - Regioselective direct C-H arylations of protected uracils. Synthesis of 5- and 6 aryluracil bases. AB - A new regioselective synthesis of 5- and 6-aryluracil bases based on direct C-H arylations of diverse 1,3-protected uracils has been developed. Benzyl-protected uracils were selected as the most practical in terms of stability during the arylation and facile cleavage of the benzyl groups. Pd-catalyzed C-H arylations in the absence of CuI gave preferentially 5-aryl-, whereas the reactions in the presence of CuI gave 6-aryl-1,3-dibenzyluracils. Final deprotection either by transfer hydrogenolysis over Pd/C or by treatment with BBr(3) gave the desired free arylated uracil bases in good yields. PMID- 21591731 TI - Switchable conductance in functionalized carbon nanotubes via reversible sidewall bond cleavage. AB - We propose several covalent functionalizations for carbon nanotubes that display switchable on/off conductance in metallic tubes. The switching action is achieved by reversible control of bond-cleavage chemistry in [1 + 2] cycloadditions via the sp(3) ? sp(2) rehybridization that it induces; this leads to remarkable changes of conductance even at very low degrees of functionalization. Reversible bond-cleavage chemistry is achieved by identifying addends that provide optimal compensation between the bond-preserving through-space pi orbital interactions with the tube against the bond-breaking strain energy of the cyclopropane moiety. Several strategies for real-time control, based on redox or hydrolysis reactions, cis-trans isomerization or excited-state proton transfer are proposed. Such designer functional groups would allow for the first time direct control of the electrical properties of metallic carbon nanotubes, with extensive applications in nanoscale devices. PMID- 21591732 TI - Charged diphenylalanine nanotubes and controlled hierarchical self-assembly. AB - Hexagonal hierarchical microtubular structures are produced by diphenylalanine self-assembly and the ratio of the relative humidity in the growth chamber to the diphenylalanine concentration (defined as the RH-FF ratio) determines the microtubular morphology. The hexagonal arrangement of the diphenylalanine molecules first induces the hexagonal nanotubes with opposite charges on the two ends, and the dipolar electric field on the nanotubes serves as the driving force. Side-by-side hexagonal aggregation and end-to-end arrangement ensue finally producing a hexagonal hierarchical microtubular structure. Staining experiments and the external electric field-induced parallel arrangement provide evidence of the existence of opposite charges and dipolar electric field. In this self-assembly, the different RH-FF ratios induce different contents of crystalline phases. This leads to different initial nanotube numbers finally yielding different microtubular morphologies. Our calculation based on the dipole model supports the dipole-field mechanism that leads to the different microtubular morphologies. PMID- 21591733 TI - Ejection of solvated ions from electrosprayed methanol/water nanodroplets studied by molecular dynamics simulations. AB - The ejection of solvated small ions from nanometer-sized droplets plays a central role during electrospray ionization (ESI). Molecular dynamics (MD) simulations can provide insights into the nanodroplet behavior. Earlier MD studies have largely focused on aqueous systems, whereas most practical ESI applications involve the use of organic cosolvents. We conduct simulations on mixed water/methanol droplets that carry excess NH(4)(+) ions. Methanol is found to compromise the H-bonding network, resulting in greatly increased rates of ion ejection and solvent evaporation. Considerable differences in the water and methanol escape rates cause time-dependent changes in droplet composition. Segregation occurs at low methanol concentration, such that layered droplets with a methanol-enriched periphery are formed. This phenomenon will enhance the partitioning of analyte molecules, with possible implications for their ESI efficiencies. Solvated ions are ejected from the tip of surface protrusions. Solvent bridging prior to ion secession is more extensive for methanol/water droplets than for purely aqueous systems. The ejection of solvated NH(4)(+) is visualized as diffusion-mediated escape from a metastable basin. The process involves thermally activated crossing of a ~30 kJ mol(-1) free energy barrier, in close agreement with the predictions of the classical ion evaporation model. PMID- 21591734 TI - Temperature and gate voltage dependent Raman spectra of single-layer graphene. AB - Raman spectra of electrostatically gated single-layer graphene are measured from room temperature to 560 K to sort out doping and thermally induced effects. Repeated heating cycles under Ar led to convergent first-order temperature coefficients of the G-band (chi(G) = -0.03 cm(-1)/K) and the 2D-band (chi(2D) = 0.05 cm(-1)/K) frequencies, which are independent of doping level as long as the Fermi level does not shift with temperature. While the intrinsic behavior may be different (e.g., chi(G) ~ -0.02 cm(-1)/K near room temperature), these values appear more appropriate in describing responses of most graphene samples on SiO(2) substrates. The more negative chi(G) value than theoretical expectations may be explained by interactions with the substrate reducing the lattice thermal expansion contribution to the temperature dependence of G-band frequency. Enhanced interactions with the substrate may also be responsible for zero-charge, room-temperature G-band line width increase and 2D-band frequency downshift. PMID- 21591736 TI - Structural periodicity in plutonium(IV) sulfates. AB - The chemistry of tetravalent Pu with sulfate is explored in a series of single crystal X-ray diffraction studies of the alkali metal plutonium sulfate compounds. Five new structures of Pu(IV) sulfates are presented including the structure for the alpha-phase of Pu(SO(4))(2)(H(2)O)(4), Na(10)Pu(2)(SO(4))(9)(H(2)O)(4), K(8)Pu(2)(SO(4))(8)(H(2)O)(5), Rb(8)Pu(2)(SO(4))(8)(H(2)O)(4), and Cs(4)Pu(SO(4))(4)(H(2)O)(2). Changes in structure and stoichiometry are seen down the alkali-metal series despite identical reaction conditions for each of the complexes. Comparison to the other known An(IV) sulfates, Group IV sulfates, and Ce(IV) reveals limited similarity in stoichiometry and structure across the actinide series and their homologues. Marked color changes are observed down the series indicating strong interactions between the plutonium ions and the ligands in these complexes. PMID- 21591735 TI - Comments on "leave-cluster-out cross-validation is appropriate for scoring functions derived from diverse protein data sets": significance for the validation of scoring functions. PMID- 21591737 TI - In vitro imaging and human serum albumin responsive dimeric lanthanide DO3A complex. AB - Two series of dimeric DO3A (1,4,7,10-tetraazacyclodecane-1,4,7-triacetate) lanthanide complexes (LnL(1)-LnL(2), Ln = Eu, Gd, and Tb) have been synthesized with two different bridged chromophores. The X-ray structures of dimeric LnL(1) (Ln = Gd and Tb) complexes show that each metal ion has nine coordination numbers with eight directly bound donor atoms of the ligand and one oxygen donor from the water molecule. Photophysical measurements indicate that the bridged antenna in LnL(2) gives a higher efficiency than that of LnL(1) and is responsive to the protein Human Serum Albumin (HSA), giving an f-f luminescence signal enhancement with a binding constant log K = 4.84. In vitro imaging of EuL(1) and EuL(2) in HeLa cells has been recorded, and EuL(2) has demonstrated a higher rate of cellular uptake and low cytotoxicity (IC(50) = 3 mM). PMID- 21591738 TI - Synthesis and reactivity of a transition metal complex containing exclusively TEMPO ligands: Ni(eta2-TEMPO)2. AB - The reaction of Ni(COD)(2) with two equivalents of the TEMPO radical at 68 degrees C affords the 16 e(-) "bow-tie" complex Ni(eta(2)-TEMPO)(2), 1, in 78% yield. Compound 1 reacts with tert-butyl isocyanide and phenylacetylene at room temperature to yield the 16 e(-) distorted square planar nickel complexes Ni(eta(2)-TEMPO)(eta(1)-TEMPO)(CN(t)Bu), 2, and Ni(eta(2)-TEMPO)(eta(1) TEMPOH)(CCPh), 4, respectively. The facile reactivity of 1 is aided by the transition of the TEMPO ligand from an eta(2) to eta(1) binding mode. Complex 4 is an unusual example of hydrogen atom transfer from phenylacetylene to a coordinated TEMPO ligand. PMID- 21591739 TI - Plasmonic antennas for directional sorting of fluorescence emission. AB - Spontaneous emission of fluorescent molecules or quantum dots is radiated along all directions when emitters are diluted in a liquid solution, which severely limits the amount of collected light. Besides, the emission direction does not carry any useful information and cannot be used to sort different molecules. To go beyond these limits, optical antennas have been recently introduced as conceptual tools to control the radiation properties for nanoemitters fixed on a substrate. Despite intense recent research, controlling the luminescence directivity remains a challenge for emitters with random positions and orientations, which is a key for several biomolecular screening applications. Here, we present full directional control of the fluorescence emission from molecules in water solution by an optical antenna made of a nanoaperture surrounded by a periodic set of shallow grooves in a gold film. For each emission wavelength, the fluorescence beam can be directed along a specific direction with a given angular width, hereby realizing a micrometer-size dispersive antenna. We demonstrate the fluorescence beaming results from an interference phenomenon and provide physical optics guidelines to control the fluorescence directivity by tuning the groove-nanoaperture distance. This photon-sorting capability provides a new approach for high-sensitivity screening of molecular species in solution. PMID- 21591740 TI - Fate of iprovalicarb, indoxacarb, and boscalid residues in grapes and wine by GC ITMS analysis. AB - The behavior in field and the transfer from grapes to wine during winemaking of iprovalicarb, indoxacarb, and boscalid was studied. The residue levels found in grapes were far below the MRLs set for grapes in EU, accounting at harvest time 0.81, 0.43, and 4.23 mg/kg for iprovalicarb, indoxacarb, and boscalid, respectively. The residue levels in the samples treated with boscalid may have residual problems (due to an accumulation effect) if repeated field treatments will be performed. Winemaking experiments showed a complete transfer of all pesticide from grapes to the must, while in wine the residues were low or negligible due to the adsorbing effect of lees and pomace. The clarification experiments showed a good removal of pesticide residues from the wine media, for all pesticides. The GC-ITMS method showed good performance with adequate recoveries ranging from 75 to 115%, and good method limits of quantitation (LOQs) and of determination (LODs) far below MRLs. PMID- 21591741 TI - Fermented soybean liquid alleviated peptic ulcer through the destruction of acidic proton pump rather than suppression of urease of Helicobacter pylori: a kinetic analysis. AB - Fermented soybean liquid (FSL) has been well cited for its broad spectrum of biological effects, yet its documented gastropeptic ulcer (GPU) ameliorating effect is still lacking. It was hypothesized that to avoid the injury exerted by gastric fluid, HP has to be sheltered in chyme emulsions immediately on infection. The HP urease (HPU) and the acidic proton pump (PP) may act as the "two-point pH modulator" to maintain an optimum pH between 6 and 7, and FSL is able to destroy such a modulating mechanism. FSL exhibited higher contents of isoflavonoids (2.5-17.3-fold) and essential amino acids (1.5-4.0-fold) than the nonfermented. FSL administered at 1 g/20 mL tid for 3 months eradicated Helicobacter pylori (HP) by 82% in 37 volunteers having GPU (p < 0.20); simultaneously, the plasma conjugated diene and TBARs levels were significantly resumed (p < 0.05). Kinetic analysis based on the conventional "urease theory" revealed that a cluster of 2.0 * 10(9) of HP cells is required for a single attack in the gastric lumen at pH 1.0-2.5. To verify the hypothesis, chyme shelter testing was conducted in artificial gastric fluid (pH 2.4 +/- 0.20). Results showed the HP cell viability was time- and size-dependent. At 20 min of contact time, the viability was 100, 4.2, 31.4, 43.3, 57.2, and 82.6%, respectively, in intact, dispersed, and particulate chymes (mesh sizes 80, 60, 40, and 20). The corresponding data became 96.2, 0.0, 14.5, 18.5, 21.3, and 28.6%, respectively, at a contact time of 40 min. Conclusively, the kinetic analysis and the chyme-shelter testing revealed that direct infection by bare HP cells is unlikely in real status. FSL is beneficial to GPU most probably due to its ability to raise blood alkalinity levels, destroying the PP and its ROS suppressing effect. PMID- 21591742 TI - In vitro reconstitution of eukaryotic ion channels using droplet interface bilayers. AB - The ability to routinely study eukaryotic ion channels in a synthetic lipid environment would have a major impact on our understanding of how different lipids influence ion channel function. Here, we describe a straightforward, detergent-free method for the in vitro reconstitution of eukaryotic ion channels and ionotropic receptors into droplet interface bilayers and measure their electrical activity at both the macroscopic and single-channel level. We explore the general applicability of this method by reconstitution of channels from a wide range of sources including recombinant cell lines and native tissues, as well as preparations that are difficult to study by conventional methods including erythrocytes and mitochondria. PMID- 21591743 TI - Continuous flow immobilized enzyme reactor-tandem mass spectrometry for screening of AChE inhibitors in complex mixtures. AB - A method is described for identifying bioactive compounds in complex mixtures based on the use of capillary-scale monolithic enzyme-reactor columns for rapid screening of enzyme activity. A two-channel nanoLC system was used to continuously infuse substrate coupled with automated injections of substrate/small molecule mixtures, optionally containing the chromogenic Ellman reagent, through sol-gel derived acetylcholinesterase (AChE) doped monolithic columns. This is the first report of AChE encapsulated in monolithic silica for use as an immobilized enzyme reactor (IMER), and the first use of such IMERs for mixture screening. AChE IMER columns were optimized to allow rapid functional screening of compound mixtures based on changes in the product absorbance or the ratio of mass spectrometric peaks for product and substrate ions in the eluent. The assay had robust performance and produced a Z' factor of 0.77 in the presence of 2% (v/v) DMSO. A series of 52 mixtures consisting of 1040 compounds from the Canadian Compound Collection of bioactives was screened and two known inhibitors, physostigmine and 9-aminoacridine, were identified from active mixtures by manual deconvolution. The activity of the compounds was confirmed using the enzyme reactor format, which allowed determination of both IC(50) and K(I) values. Screening results were found to correlate well with a recently published fluorescence-based microarray screening assay for AChE inhibitors. PMID- 21591744 TI - Carborane-containing poly(fluorene): response to solvent vapors and amines. AB - Hybrid conjugated polymers containing carborane directly bonded in the aromatic backbone repeat structure have interesting electronic bonding structures and are potentially useful new materials in organic electronics. Conjugated polymers based on o-carborane are particularly interesting for applications in sensing and detection because of the cage's unique bonding scheme and its bent geometry. Poly(fluorene) containing o-carborane displays multiple emission pathways that can be modulated through interactions with small molecules. In this paper, we report that films of poly(fluorene) with o-carborane in the backbone function as vapochromatic photoluminescent sensors toward volatile organic molecules. PMID- 21591745 TI - A new aluminosilicate molecular sieve with a system of pores between those of ZSM 5 and beta zeolite. AB - A new aluminosilicate zeolite (ITQ-39) has been synthesized. This is an extensively faulted structure with very small domains that makes the structure elucidation very difficult. However, a combination of adsorption spectroscopy and reactivity studies with selected probe molecules suggests that the pore structure of ITQ-39 is related to that of Beta zeolite, with a three-directional channel system with large pores (12-MR), but with an effective pore diameter between those of Beta and ZSM-5, or a three-directional channel system with interconnected large (12-MR) and medium pores (10-MR). The pore topology of ITQ 39 is very attractive for catalysis and shows excellent results for the preparation of cumene by alkylation of benzene, while it can be a promising additive for FCC. PMID- 21591748 TI - Role of hydrogen in dimerizaton of aluminum clusters: a theoretical study. AB - We have used density functional theory to investigate how Al(13) cluster dimers can be formed with or without a bridging hydrogen. We have identified several stable dimers in which 0, 1, or 2 hydrogen atoms link two bare clusters together. Each of these structures can adsorb further H atoms in atop sites on the surface of the dimer. Additional dimers were identified with 3 and 4 H atoms linking the clusters but these are only stable in the multihydrogenated form. Reaction profiles for the formation of these dimers from a range of cluster and H atom combinations indicate that the dimer structures are energetically favored over the isolated clusters. This observation may have significant implications for the design of cluster-assembled materials. PMID- 21591746 TI - Design and synthesis of a bombesin peptide-conjugated tripodal phosphino dithioether ligand topology for the stabilization of the fac-[M(CO)3]+ core (M=(99 m)Tc or Re). AB - A new tumor-seeking tridentate topology consisting of a phosphino dithioether ((HOCH(2))(2)PCH(2)CH(2)S(CH(2))(n)CH(2)SR; PS(2)) ligand framework for the production of kinetically inert and in vivo stable facial [(99m)Tc(CO)(3)(PS(2))](+) or [Re(CO)(3)(PS(2))](+) is described. The X-ray crystal structure of fac-Re(CO)(3)(PS(2))PF(6) is reported. The bioconjugation strategies for incorporating bombesin (BBN) peptides on to the PS(2) tripodal framework and, thereby, de novo designing of GRP receptor-seeking Tc(PS(2) BBN)(CO)(3) are developed. PMID- 21591747 TI - Solvent enhancement of reaction selectivity: a unique property of cationic chiral dirhodium carboxamidates. AB - 1,3-Dipolar cycloaddition reactions of nitrones with alpha,beta-unsaturated aldehydes catalyzed by a cationic chiral dirhodium(II,III) carboxamidate with (R) menthyl (S)-2-oxopyrrolidine-5-carboxylate ligands in toluene increase reaction rates, give optimum regioselectivities, and enhance stereoselectivities compared to the same reactions performed in traditionally used halocarbon solvents. Rate and enantioselectivity enhancements were also obtained in hetero-Diels-Alder and carbonyl-ene reactions performed in toluene over those obtained in dichloromethane using the diastereomeric chiral cationic dirhodium(II,III) carboxamidate with (S)-menthyl (S)-2-oxopyrrolidine-5-carboxylate ligands. These enhancements are attributed to diminished or absent association of toluene with the catalyst which lessens the relative importance of the uncatalyzed background reaction, and they may also be a consequence of different coordination angles for aldehyde association with rhodium in the different solvent environments. Overall, the enhancement of reaction rates and selectivities with cationic chiral dirhodium(II,III) carboxamidates in toluene suggests broad applications for them in Lewis acid catalyzed reactions. PMID- 21591749 TI - Determination of glycated and acetylated hemoglobins in cord blood by time-of flight mass spectrometry. AB - The characterization of cord blood hemoglobin at the molecular level is a daunting challenge because hemoglobin F (HbF) and hemoglobin A (HbA) coexist in neonatal blood. We developed and validated a method using electrospray time-of flight mass spectrometry (ES-TOF-MS) that measures, in a single analysis, relative levels of glycated and acetylated hemoglobin and allows the calculation of relative proportions of HbA, HbF(0), and HbF(1) in cord blood. Specific sections of acquired spectra were deconvoluted using a maximum entropy-based approach to true mass scale spectra. Mass precisions were less than 3 ppm with similar accuracies. Intra-interday precisions for alpha- and gamma-chain glycation levels were 2.10%/3.72% and 2.75%/6.79%, respectively. The linearity of the alpha-chain glycation response was excellent (r(2) = 0.9990). We performed sample analysis on 39 cord blood specimens and found that the glycated alpha- and gamma-chain levels were 2.27 +/- 0.21% and 2.38 +/- 0.29%, respectively, while the acetylated (G)gamma and (A)gamma-chain levels were 8.48 +/- 0.53% and 7.14 +/ 0.74%, respectively. We observed three types of HbF distinguishable by the intensities of gamma-chain variants. Two-thirds of cord blood specimens were classified as HbF(I) with an intensity ratio (G)gamma/(A)gamma of 1.90 +/- 0.12. For HbF(II) type (10/39 neonates), the intensity ratio of (G)gamma/(A)gamma was 3.71 +/- 0.28. For three neonates with HbF(III), no (A)gamma-chain was detected. PMID- 21591750 TI - Oil-assisted sample preparation: a simple method for analysis of solid samples using matrix-assisted laser desorption/ionization mass spectrometry. AB - Common mass spectrometric techniques, e.g., electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI), require samples to be soluble in suitable solvents. Samples with solubility problems have difficulties for their mass spectrometric characterization. In this paper, an oil-assisted sample preparation (OASP) method was introduced for the analysis of solid samples using MALDI-MS. The novel method involves the use of a droplet of oil (i.e., paraffin oil) as the mixing and loading media for solid analyte and solid matrix. Using this method, rapid on-target sample preparation can be easily achieved, and only a transferable minimal amount of analyte and matrix is required. This method was demonstrated to be applicable for a wide range of analytes, including poorly soluble organic compounds, polymers, organometallic compounds, membrane peptides, and biological solid samples. The novel method can also be used for the analysis of "wet" and solution samples. The limit of detection of the OASP MALDI-MS was determined to be 1 ng with reserpine. PMID- 21591751 TI - Assessments of thiyl radicals in biosystems: difficulties and new applications. AB - The high reactivity of thiyl radicals (RS(*)), which results in half-lives on the order of microseconds, hinders their analysis in biological systems. This Feature reviews the contemporary approaches to assessment of RS(*) using EPR spin trapping, mass spectrometric, immunological, and HPLC protocols. PMID- 21591753 TI - Photosensitized amino acid degradation in the presence of riboflavin and its derivatives. AB - The addition of photosensitizers to water can accelerate disinfection in sunlight based systems by enhancing oxidation of target compounds through direct reaction with the excited sensitizer or through production of another oxidant, such as singlet oxygen (1O2). The kinetics of the oxidation of selected amino acids in the presence of the sensitizer riboflavin (Vitamin B2), its primary photoproduct lumichrome, and its derivative riboflavin tetraacetate (2',3',4',5' tetraacetylriboflavin; RTA) were quantified and the mechanisms of reaction were determined during exposure to 365 +/- 9 nm light. 1O2-mediated reactions contributed to the rapid photodegradation of the four amino acids, but its contribution was sensitizer-dependent and varied from 5.4-10.2% for tyrosine, 7.1 12.4% for tryptophan, 18.7-69.0% for methionine, and 64.7-100.2% for histidine. Riboflavin was subject to rapid photodegradation (t1/2 < 8 min), while the half lives of lumichrome and RTA were 100 and 30 times longer, respectively. Lumichrome and RTA also were more efficient 1O2 sensitizers (quantum yield (Phi) = 0.63 and 0.66) compared to riboflavin (Phi = 0.48). Of the three flavin-based compounds, RTA shows the most promise as a sensitizer in sunlight-based disinfection systems because it absorbs both visible and UV light, is an efficient 1O2 sensitizer, is a strong oxidant in its triplet state, and exhibits greater photostability. PMID- 21591752 TI - Identification of N-propylnoraporphin-11-yl 5-(1,2-dithiolan-3-yl)pentanoate as a new anti-Parkinson's agent possessing a dopamine D2 and serotonin 5-HT1A dual agonist profile. AB - A series of new aporphine analogues (aporlogues) were synthesized bearing a C-, N , or O-linkage at the C11 position. Lipoic ester (-)-15 was identified as a full agonist at the dopamine D(2) and serotonin 5-HT(1A) receptors with K(i) values of 174 and 66 nM, respectively. It elicited antiparkinsonian action on Parkinsin's disease (PD) rats with minor dyskinesia. Chronic use of (-)-15 reduced L-DOPA induced dyskinesia (LID) without attenuating the antiparkinsonian effect. These results suggest that 5-HT(1A) and D(2) dual-receptor agonist (-)-15 may present a novel candidate drug in the treatment of PD and LID. PMID- 21591755 TI - Size-exclusive nanosensor for quantitative analysis of fullerene C60. AB - This paper presents the first development of a mass-sensitive nanosensor for the isolation and quantitative analyses of engineered fullerene (C60) nanoparticles, while excluding mixtures of structurally similar fullerenes. Amino-modified beta cyclodextrin (beta-CD-NH2) was synthesized and confirmed by 1HNMR as the host molecule to isolate the desired fullerene C60. This was subsequently assembled onto the surfaces of gold-coated quartz crystal microbalance (QCM) electrodes using N-dicyclohexylcarbodiimide/N-hydroxysuccinimide (DCC/NHS) surface immobilization chemistry to create a selective molecular configuration described as (Au)-S-(CH2)2-CONH-beta-CD sensor. The mass change on the sensor configuration on the QCM was monitored for selective quantitative analysis of fullerene C60 from a C60/C70 mixture and soil samples. About ~1014-1016 C60 particles/cm2 were successfully quantified by QCM measurements. Continuous spike of 200 MUL of 0.14 mg C60 /mL produced changes in frequency (-Deltaf) that varied exponentially with concentration. FESEM and time-of-flight secondary-ion mass spectrometry confirmed the validity of sensor surface chemistry before and after exposure to fullerene C60. The utility of this sensor for spiked real-world soil samples has been demonstrated. Comparable sensitivity was obtained using both the soil and purified toluene samples. This work demonstrates that the sensor has potential application in complex environmental matrices. PMID- 21591754 TI - Bird mercury concentrations change rapidly as chicks age: toxicological risk is highest at hatching and fledging. AB - Toxicological risk of methylmercury exposure to juvenile birds is complex due to the highly transient nature of mercury concentrations as chicks age. We examined total mercury and methylmercury concentrations in blood, liver, kidney, muscle, and feathers of 111 Forster's tern (Sterna forsteri), 69 black-necked stilt (Himantopus mexicanus), and 43 American avocet (Recurvirostra americana) chicks as they aged from hatching through postfledging at wetlands that had either low or high mercury contamination in San Francisco Bay, California. For each waterbird species, internal tissue, and wetland, total mercury and methylmercury concentrations changed rapidly as chicks aged and exhibited a quadratic, U-shaped pattern from hatching through postfledging. Mercury concentrations were highest immediately after hatching, due to maternally deposited mercury in eggs, then rapidly declined as chicks aged and diluted their mercury body burden through growth in size and mercury depuration into growing feathers. Mercury concentrations then increased during fledging when mass gain and feather growth slowed, while chicks continued to acquire dietary mercury. In contrast to mercury in internal tissues, mercury concentrations in chick feathers were highly variable and declined linearly with age. For 58 recaptured Forster's tern chicks, the proportional change in blood mercury concentration was negatively related to the proportional change in body mass, but not to the amount of feathers or wing length. Thus, mercury concentrations declined more in chicks that gained more mass between sampling events. The U-shaped pattern of mercury concentrations from hatching to fledging indicates that juvenile birds may be at highest risk to methylmercury toxicity shortly after hatching when maternally deposited mercury concentrations are still high and again after fledging when opportunities for mass dilution and mercury excretion into feathers are limited. PMID- 21591756 TI - Characterizing the Interaction between tartrazine and two serum albumins by a hybrid spectroscopic approach. AB - Tartrazine is an artificial azo dye commonly used in food products. The present study evaluated the interaction of tartrazine with two serum albumins (SAs), human serum albumin (HSA) and bovine serum albumin (BSA), under physiological conditions by means of fluorescence, three-dimensional fluorescence, UV-vis absorption, and circular dichroism (CD) techniques. The fluorescence data showed that tartrazine could bind to the two SAs to form a complex. The binding process was a spontaneous molecular interaction procedure, in which van der Waals and hydrogen bond interactions played a major role. Additionally, as shown by the UV vis absorption, three-dimensional fluorescence, and CD results, tartrazine could lead to conformational and some microenvironmental changes of both SAs, which may affect the physiological functions of SAs. The work provides important insight into the mechanism of toxicity of tartrazine in vivo. PMID- 21591757 TI - Using pyridinyl-substituted diaminotriazines to bind Pd(II) and create metallotectons for engineering hydrogen-bonded crystals. AB - The pyridinyl groups of pyridinyl-substituted diaminotriazines 3a,b and 4a,b can bind metals, and the diaminotriazinyl (DAT) groups serve independently to ensure that the resulting complexes can participate in intercomplex hydrogen bonding according to characteristic motifs. As planned, ligands 3a,b and 4a,b form trans square-planar 2:1 complexes with PdCl(2), and further association of the complexes is directed in part by hydrogen bonding of the DAT groups. Similarly, ligands 3a,b and 4a,b form cationic square-planar 4:1 complexes with Pd(BF(4))(2), Pd(PF(6))(2), and Pd(NO(3))(2), and the complexes again typically associate by hydrogen bonding of the peripheral DAT groups. The observed complexes have predictable constitutions and shared structural features that result logically from their characteristic topologies and the ability of DAT groups to engage in hydrogen bonding. These results illustrate the potential of a hybrid inorganic/organic strategy for constructing materials in which coordinative bonds to metals are used in conjunction with other interactions, both to build the molecular components and to control their organization. PMID- 21591758 TI - A new class of phenazines with activity against a chloroquine resistant Plasmodium falciparum strain and antimicrobial activity. AB - New phenazines were synthesized by oxygenation of 1- and 2-naphthol with transition metal peroxo complexes and in situ reaction with 1,2-diamines. The title compounds were evaluated for in vitro antimalarial activity against Plasmodium falciparum and chloroquine-resistant strains. Phenazines 12, 27, and 28 were most prominent in growth inhibition. In vivo protection against cerebral malaria was observed with the phenazines 11, 12, 20, and 27, whereas partial protection was provided by 19. PMID- 21591759 TI - Bottom-up photonic crystal cavities formed by patterned III-V nanopillars. AB - We report on the formation and optical properties of bottom-up photonic crystal (PC) cavities formed by III-V nanopillars (NPs) via catalyst-free selective-area metal-organic chemical vapor deposition on masked GaAs substrates. This method of NP synthesis allows for precise lithographic control of NP position and diameter enabling simultaneous formation of both the photonic band gap (PBG) region and active gain region. The PBG and cavity resonance are determined by independently tuning the NP radius r, pitch a, and height h in the respective masked areas. Near-infrared emission at 970 nm is achieved from axial GaAs/InGaAs heterostructures with in situ passivation by laterally grown InGaP shells. To achieve out-of-plane optical confinement, the PC cavities are embedded in polydimethylsiloxane (PDMS) and removed from the growth substrate. Spatially and spectrally resolved 77 K photoluminescence demonstrates a strong influence of the PBG resonance on device emission. Resonant peaks are observed in the emission spectra of PC cavities embedded in PDMS. PMID- 21591760 TI - Is stress concentration relevant for nanocrystalline metals? AB - Classical fracture mechanics as well as modern strain gradient plasticity theories assert the existence of stress concentration (or strain gradient) ahead of a notch tip, albeit somewhat relaxed in ductile materials. In this study, we present experimental evidence of extreme stress homogenization in nanocrystalline metals that result in immeasurable amount of stress concentration at a notch tip. We performed in situ uniaxial tension tests of 80 nm thick (50 nm average grain size) freestanding, single edge notched aluminum specimens inside a transmission electron microscope. The theoretical stress concentration for the given notch geometry was as high as 8, yet electron diffraction patterns unambiguously showed absence of any measurable stress concentration at the notch tip. To identify possible mechanisms behind such an anomaly, we performed molecular dynamics simulations on scaled down samples. Extensive grain rotation driven by grain boundary diffusion, exemplified by an Ashby-Verrall type of grain switching process, was observed at the notch tip to relieve stress concentration. We conclude that in the absence of dislocations, grain realignment or rotation may have played a critical role in accommodating externally applied strain and neutralizes any stress concentration during the process. PMID- 21591761 TI - Identification of RNA pseudoknot-binding ligand that inhibits the -1 ribosomal frameshifting of SARS-coronavirus by structure-based virtual screening. AB - Programmed -1 ribosomal frameshifting (-1 RF) is an essential regulating mechanism of translation used by SARS-CoV (severe acute respiratory syndrome coronavirus) to synthesize the key replicative proteins encoded by two overlapping open reading frames. The integrity of RNA pseudoknot stability and structure in the -1 RF site is important for efficient -1 RF. Thus, small molecules interacting with high affinity and selectivity with the RNA pseudoknot in the -1 RF site of SARS-CoV (SARS-pseudoknot) would disrupt -1 RF and be fatal to viral infectivity and production. To discover ligands for the SARS-pseudoknot by virtual screening, we constructed a 3D structural model of the SARS-pseudoknot and conducted a computational screening of the chemical database. After virtual screening of about 80,000 compounds against the SARS-pseudoknot structure, high ranked compounds were selected and their activities were examined by in vitro and cell-based -1 RF assay. We successfully identified a novel ligand 43 that dramatically inhibits the -1 RF of SARS-CoV. This antiframeshift agent is an interesting lead for the design of novel antiviral agents against SARS-CoV. PMID- 21591762 TI - The application of high-content analysis in the study of targeted particulate delivery systems for intracellular drug delivery to alveolar macrophages. AB - With an ever increasing number of particulate drug delivery systems being developed for the intracellular delivery of therapeutics a robust high-throughput method for studying particle-cell interactions is urgently required. Current methods used for analyzing particle-cell interaction include spectrofluorimetry, flow cytometry, and fluorescence/confocal microscopy, but these methods are not high throughput and provide only limited data on the specific number of particles delivered intracellularly to the target cell. The work herein presents an automated high-throughput method to analyze microparticulate drug delivery system (DDS) uptake byalveolar macrophages. Poly(lactic-co-glycolic acid) (PLGA) microparticles were prepared in a range of sizes using a solvent evaporation method. A human monocyte cell line (THP-1) was differentiated into macrophage like cells using phorbol 12-myristate 13-acetate (PMA), and cells were treated with microparticles for 1 h and studied using confocal laser scanning microscopy (CLSM), spectrofluorimetry and a high-content analysis (HCA). PLGA microparticles within the size range of 0.8-2.1 MUm were found to be optimal for macrophage targeting (p < 0.05). Uptake studies carried out at 37 degrees C and 4 degrees C indicated that microparticles were internalized in an energy dependent manner. To improve particle uptake, a range of opsonic coatings were assessed. Coating PLGA particles with gelatin and ovalbumin was found to significantly increase particle uptake from 2.75 +/- 0.98 particles per cell for particles coated with gelatin. Opsonic coating also significantly increased particle internalization into primary human alveolar macrophages (p < 0.01) with a 1.7-fold increase in uptake from 4.19 +/- 0.48 for uncoated to 7.53 +/- 0.88 particles per cell for coated particles. In comparison to techniques such as spectrofluorimetry and CLSM, HCA provides both qualitative and quantitative data on the influence of carrier design on cell targeting that can be gathered in a high-throughput format and therefore has great potential in the screening of intracellularly targeted DDS. PMID- 21591764 TI - Dispersal and attenuation of trace contaminants downstream of the Ajka bauxite residue (red mud) depository failure, Hungary. AB - This paper identifies the spatial extent of bauxite processing residue (red mud) derived contaminants and modes of transport within the Marcal and Raba river systems after the dike failure at Ajka, western Hungary. The geochemical signature of the red mud is apparent throughout the 3076 km2 Marcal system principally with elevated Al, V, As, and Mo. Elevated concentrations of Cr, Ga, and Ni are also observed within 2 km of the source areas in aqueous and particulate phases where hyperalkalinity (pH < 13.1) is apparent. Although the concentrations of some trace elements exceed aquatic life standards in waters (e.g., V, As) and fluvial sediments (As, Cr, Ni, V), the spatial extent of these is limited to the Torna Creek and part of the upper Marcal. Source samples show a bimodal particle size distribution (peaks at 0.7 and 1.3 MUm) which lends the material to ready fluvial transport. Where elevated concentrations are found in fluvial sediments, sequential extraction suggests the bulk of the As, Cr, Ni, and V are associated with residual (aqua-regia/HF digest) phases and unlikely to be mobile in the environment. However, at some depositional hotspots, association of As, Cr, and V with weak acid-extractable phases is observed. PMID- 21591763 TI - GlycoFish: a database of zebrafish N-linked glycoproteins identified using SPEG method coupled with LC/MS. AB - Zebrafish (Danio rerio) is a model organism that is used to study the mechanisms and pathways of human disorders. Many dysfunctions in neurological, development, and neuromuscular systems are due to glycosylation deficiencies, but the glycoproteins involved in zebrafish embryonic development have not been established. In this study, a mass spectrometry-based glycoproteomic characterization of zebrafish embryos was performed to identify the N-linked glycoproteins and N-linked glycosylation sites. To increase the number of glycopeptides, proteins from zebrafish were digested with two different proteases -chymotrypsin and trypsin--into peptides of different length. The N-glycosylated peptides of zebrafish were then captured by the solid-phase extraction of N linked glycopeptides (SPEG) method and the peptides were identified with an LTQ OrbiTrap Velos mass spectrometer. From 265 unique glycopeptides, including 269 consensus NXT/S glycosites, we identified 169 different N-glycosylated proteins. The identified glycoproteins were highly abundant in proteins belonging to the transporter, cell adhesion, and ion channel/ion binding categories, which are important to embryonic, organ, and central nervous system development. This proteomics data will expand our knowledge about glycoproteins in zebrafish and may be used to elucidate the role that glycosylation plays in cellular processes and disease. The glycoprotein data are available through the GlycoFish database (http://betenbaugh.jhu.edu/GlycoFish) introduced in this paper. PMID- 21591765 TI - Endoglycosidase-mediated incorporation of 18O into glycans for relative glycan quantitation. AB - Stable isotopic labeling coupled with mass spectrometry analysis is a promising method of detecting quantitative variations in glycans, which may result in aberrant glycosylation in many disorders and diseases. Although various isotopic labeling methods have been used for relative glycan quantitation, enzymatic (18)O labeling, which offers advantages for glycomics similar to those by protease catalyzed (18)O labeling for proteomics, has not been developed yet. In this study, endoglycosidase incorporated (18)O into the N-glycan reducing end in (18)O water as N-glycans were released from glycoproteins, rendering glycan reducing end (18)O labeling (GREOL) a potential strategy for relative glycan quantitation. This proposed method provided good linearity with high reproducibility within 2 orders of magnitude in dynamic range. The ability of GREOL to quantitatively discriminate between isomeric hybrid N-glycans and complex N-glycans in glycoproteins was validated due to the distinct substrate specificities of endoglycosidases. GREOL was also used to analyze changes in human serum N-glycans associated with hepatocellular carcinoma. PMID- 21591766 TI - Novel yellow-emitting Sr8MgLn(PO4)7:Eu2+ (Ln=Y, La) phosphors for applications in white LEDs with excellent color rendering index. AB - Eu(2+)-activated Sr(8)MgY(PO(4))(7) and Sr(8)MgLa(PO(4))(7) yellow-emitting phosphors were successfully synthesized by solid-state reactions for applications in excellent color rendering index white light-emitting diodes (LEDs). The excitation and reflectance spectra of these phosphors show broad band excitation and absorption in the 250-450 nm near-ultraviolet region, which is ascribed to the 4f(7) -> 4f(6)5d(1) transitions of Eu(2+). Therefore, these phosphors meet the application requirements for near-UV LED chips. Upon excitation at 400 nm, the Sr(8)MgY(PO(4))(7):Eu(2+) and Sr(8)MgLa(PO(4))(7):Eu(2+) phosphors exhibit strong yellow emissions centered at 518, 610, and 611 nm with better thermal stability than (Ba,Sr)(2)SiO(4) (570 nm) commodity phosphors. The composition optimized concentrations of Eu(2+) in Sr(8)MgLa(PO(4))(7):Eu(2+) and Sr(8)MgY(PO(4))(7):Eu(2+) phosphors were determined to be 0.01 and 0.03 mol, respectively. A warm white-light near-UV LED was fabricated using a near-UV 400 nm chip pumped by a phosphor blend of blue-emitting BaMgAl(10)O(17):Eu(2+) and yellow-emitting Sr(8)MgY(PO(4))(7):0.01Eu(2+) or Sr(8)MgLa(PO(4))(7):0.03Eu(2+), driven by a 350 mA current. The Sr(8)MgY(PO(4))(7):0.01Eu(2+) and Sr(8)MgLa(PO(4))(7):0.03Eu(2+) containing LEDs produced a white light with Commission International de I'Eclairage (CIE) chromaticity coordinates of (0.348, 0.357) and (0.365, 0.328), warm correlated color temperatures of 4705 and 4100 K, and excellent color rendering indices of 95.375 and 91.75, respectively. PMID- 21591767 TI - Folding of small proteins using constrained molecular dynamics. AB - The focus of this paper is to examine whether conformational search using constrained molecular dynamics (MD) method is more enhanced and enriched toward "native-like" structures compared to all-atom MD for the protein folding as a model problem. Constrained MD methods provide an alternate MD tool for protein structure prediction and structure refinement. It is computationally expensive to perform all-atom simulations of protein folding because the processes occur on a time scale of microseconds. Compared to the all-atom MD simulation, constrained MD methods have the advantage that stable dynamics can be achieved for larger time steps and the number of degrees of freedom is an order of magnitude smaller, leading to a decrease in computational cost. We have developed a generalized constrained MD method that allows the user to "freeze and thaw" torsional degrees of freedom as fit for the problem studied. We have used this method to perform all-torsion constrained MD in implicit solvent coupled with the replica exchange method to study folding of small proteins with various secondary structural motifs such as, alpha-helix (polyalanine, WALP16), beta-turn (1E0Q), and a mixed motif protein (Trp-cage). We demonstrate that constrained MD replica exchange method exhibits a wider conformational search than all-atom MD with increased enrichment of near-native structures. "Hierarchical" constrained MD simulations, where the partially formed helical regions in the initial stretch of the all torsion folding simulation trajectory of Trp-cage were frozen, showed a better sampling of near-native structures than all-torsion constrained MD simulations. This is in agreement with the zipping-and-assembly folding model put forth by Dill and co-workers for folding proteins. The use of hierarchical "freeze and thaw" clustering schemes in constrained MD simulation can be used to sample conformations that contribute significantly to folding of proteins. PMID- 21591769 TI - Linear and cyclic porphyrin hexamers as near-infrared emitters in organic light emitting diodes. AB - Here we report organic light-emitting diodes incorporating linear and cyclic porphyrin hexamers which have red-shifted emission (lambda(PL) = 873 and 920 nm, respectively) compared to single porphyrin rings as a consequence of their extended pi-conjugation. We studied the photoluminescence and electroluminescence of blends with poly(9,9'-dioctylfluorene-alt-benzothiadiazole), demonstrating a high photoluminescence quantum efficiency of 7.7% for the linear hexamer when using additives to prevent aggregation and achieving high color purity near infrared electroluminescence. PMID- 21591770 TI - Stability of beta-carotene in protein-stabilized oil-in-water delivery systems. AB - Inclusion of liposoluble bioactive compounds in fortified foods represents a complex challenge due to the labile nature of such compounds and the instability of oil-in-water emulsion-based delivery systems. In the present study, dispersions prepared with 10% (w/w) sunflower oil (SO) or hydrogenated palm kernel oil (HPKO) containing 0.05% (w/w) beta-carotene were stabilized by various concentrations of whey protein isolate (WPI) or sodium caseinate (NaCas) (0.1 to 2.0% w/w) in 30% (w/w) sucrose aqueous solutions. Physicochemical characterization of emulsions was done considering the particle size, the particle surface protein coverage, and the physical state of continuous and dispersed phases. Physical stability of the systems and their protection properties on beta-carotene were compared. The lipid carrier type and interfacial structure were investigated as the two key factors which regulate the stability of labile lipophilic bioactive molecules in food model systems. Our results showed high beta-carotene stability when O/W systems were stable (protein concentration >=0.8% w/w.) A (partially) solid lipid carrier (HPKO) enhanced protection compared to the liquid carrier (SO) as the bioactive molecules were entrapped in isolated domains within the solid lattice and kept apart from reactive species in the surroundings. NaCas provided a better barrier than WPI due to the different amino acid composition and interface structure which significantly reduced beta-carotene degradation rate. PMID- 21591768 TI - Highly stereoselective Bronsted acid catalyzed synthesis of spirooxindole pyrans. AB - A Bronsted acid-catalyzed Prins-type cyclization sequence to construct spirooxindole pyrans in high yields and excellent diastereoselectivity has been developed. The combination of a beta-hydroxy dioxinone fragment and isatin dimethyl acetal generate oxa-spirooxindoles efficiently. These compounds are diversifiable scaffolds that tap into the rich chemistry of dioxinones. PMID- 21591771 TI - Piezofluorochromic properties and mechanism of an aggregation-induced emission enhancement compound containing N-hexyl-phenothiazine and anthracene moieties. AB - A fluorescent compound, 9,10-bis(2-(10-hexyl-10H-phenothiazin-3-yl)vinyl) anthracene, has been synthesized and studied. The results show that the compound possesses piezofluorochromic properties as well as aggregation-induced emission enhancement effect. The spectroscopic properties and morphological structures are reversibly exhibited upon pressing (or grinding) or annealing (or fuming). The piezofluorochromic nature is generated through phase transformation under the stimulus of external pressure. The reason for the phase transformation caused by external pressure is ascribed to the twisted conformation of the molecule which leads to poor solid molecular packing and weak interactions in the interfaces of lamellar layers confirmed by its single-crystal X-ray diffraction analysis. PMID- 21591772 TI - Antioxidant activities of Korean rice wine concentrates. AB - The antioxidant activities of six Korean rice wine (KRW) concentrates were measured by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and lipid/malonaldehyde (MA) assays. In the DPPH assay, the antioxidant activities of the KRW concentrates, including Maesilju (MSJ), Kookhwaju-1 (KHJ-1), Kookhwaju-2 (KHJ-2), Gugijaju (GGJ), Sasamju (SSJ), and Sogokju (SGJ), were 40%, 66%, 64%, 35%, 35%, and 63%, respectively. Furthermore, the concentrates inhibited the formation of MA from cod liver oil by 49%, 83%, 75%, 82%, 89%, and 90%, respectively, according to the lipid/MA assay. The sample wines were also analyzed for pH, titratable acidity, soluble solids ( degrees Bx), and reducing sugars. The antioxidant activities of volatile extracts of the KRWs extracted by a solvent assisted flavor evaporation (SAFE) apparatus were evaluated by aldehyde/carboxylic acid assay. The volatile extracts of MSJ, KHJ-1, KHJ-2, GGJ, SSJ, and SGJ inhibited the oxidation of hexanal by 97%, 99%, 90%, 90%, 50%, and 51%, respectively. Among the nonvolatile extracts of KRWs, KHJ-2 showed the highest inhibitory effect on MA formation. PMID- 21591773 TI - Interaction of cesium ions with calix[4]arene-bis(t-octylbenzo-18-crown-6): NMR and theoretical study. AB - Using (1)H, (13)C, and (133)Cs NMR spectra, it is shown that calix[4]arene-bis(t octylbenzo-18-crown-6) (L) forms complexes with one (L.Cs(+)) and two (L.2Cs(+)) Cs(+) ions offered by cesium bis(1,2-dicarbollide) cobaltate (CsDCC) in nitrobenzene-d(5). The ions interact with all six oxygen atoms in the crown-ether ring and the pi electrons of the calixarene aromatic moieties. According to extraction technique, the stability constant of the first complex is log beta(nb)(L.Cs(+)) = 8.8 +/- 0.1. According to (133)Cs NMR spectra, the value of the equilibrium constant of the second complex is log K(nb)((2))(L.2Cs(+)) = 6.3 +/- 0.2, i.e., its stabilization constant is log beta(nb)(L.2Cs(+)) = 15.1 +/- 0.3. Self-diffusion measurements by (1)H pulsed-field gradient (PFG) NMR combined with density functional theory (DFT) calculations suggest that one DCC(-) ion is tightly associated with L.Cs(+), decreasing its positive charge and consequently stabilizing the second complex, L.2Cs(+). Using a saturation-transfer (133)Cs NMR technique, the correlation times tau(ex) of chemical exchange between L.Cs(+) and L.2Cs(+) as well as between L.2Cs(+) and free Cs(+) ions were determined as 33.6 and 29.2 ms, respectively. PMID- 21591774 TI - Hierarchical nanostructures self-assembled from diblock copolymer/homopolymer blends with supramolecular interactions. AB - Self-assembly of AB diblock copolymer/C homopolymer blends with reversible supramolecular interactions was studied by real-space self-consistent field theory. The reversible bond is formed between the B free end of the AB diblock copolymers and one end of the C homopolymers, and thereby the supramolecular blends consist of the AB diblock copolymers, C homopolymers, and supramolecular ABC terpolymers. The constitutions of the blends are dependent on the bonding strength and blend ratio. The change of the bonding strength and blend ratio leads to a series of hierarchically ordered alternating nanostructures. In these alternating nanostructures, the C homopolymers exhibit a swollen effect on the C substructures, and the coordination number of C cylinders decreases as the bonding strength increases. To gain the information about the hierarchical nanostructures in details, one-dimensional density profiles were plotted. The results were finally compared with the existing experimental findings, and an agreement was shown. The obtained results provided an insight into the role of the supramolecular interactions on the hierarchical nanostructure formations. PMID- 21591775 TI - Copper(II)-complex directed regioselective mono-p-toluenesulfonylation of cyclomaltoheptaose at a primary hydroxyl group position: an NMR and molecular dynamics-aided design. AB - Interactions between cyclomaltoheptaose (beta-cyclodextrin, betaCD) and p toluenesulfonyl chloride (TsCl) were investigated using MD simulations, both in vacuum, approximating the hydrophobic environment of the CD cavity, and with water as a solvent. In both cases, the minimum energy adiabatic paths, and the mean force potentials (MFP) for the insertion of TsCl along a reaction coordinate perpendicular to the CD plane, were calculated for the two possible orientations of TsCl. The results show a preferred entry of TsCl in the CD cavity with the sulfonyl chloride group pointing to the primary hydroxyls rim. In each orientation, two energy minima for the complex are detected in vacuum that reflect the H-H contacts between host and guest observed by NMR spectroscopy (ROESY, NOESY). These separate minima collapsed into a single broader minimum, when the solvent was introduced in the simulations. The resulting association constant between TsCl and betaCD (K(a) ~ 100 M(-1)) is in good agreement with the NMR results (K(a) = 102 +/- 12 M(-1)) in deuterated water solution at 298 K. Advantage has been taken of the dynamics of the reagent inclusion to set up a one step process involving a transient Cu(2+) chelate at the secondary hydroxyls rim position for the electrophilic monoactivation of betaCD at the primary hydroxyls rim using water as solvent. PMID- 21591776 TI - Structural effects of insulin-loading into HII mesophases monitored by electron paramagnetic resonance (EPR), small angle X-ray spectroscopy (SAXS), and attenuated total reflection Fourier transform spectroscopy (ATR-FTIR). AB - Insulin entrapment within a monoolein-based reverse hexagonal (H(II)) mesophase was investigated under temperature-dependent conditions at acidic (pH 3) and basic (pH 8) conditions. Studying the structure of the host H(II) system and the interactions of insulin under temperature-dependent conditions has great impact on the enhancement of its thermal stabilization and controlled release for the purposes of transdermal delivery. Small angle X-ray spectroscopy (SAXS) measurements show that pH variation and/or insulin entrapment preserve the hexagonal structure and do not influence the lattice parameter. Attenuated total reflection Fourier transform spectroscopy (ATR-FTIR) spectra indicate that, although insulin interacts with hydroxyl groups of GMO in the interface region, it is not affected by pH variations. Hence different microenvironments within the H(II) mesophase were monitored by a computer-aided electron paramagnetic resonance (EPR) analysis using 5-doxylstearic acid (5-DSA) as a pH-dependent probe. The microviscosity, micropolarity, order of systems, and distribution of the probes in different microenvironments were influenced by three factors: temperature, pH, and insulin solubilization. When the temperature is increased, microviscosity and order parameters decreased at both pH 3 and 8, presenting different decrease trends. It was found that, at pH 3, the protein perturbs the lipid structure while "pushing aside" the un-ionized 5-DSA probe to fit into the narrow water cylinders. At the interface region (pH 8), the probe was distributed in two differently structured environments that significantly modifies by increasing temperature. Insulin loading within the H(II) mesophase decreased the order and microviscosity of both the microenvironments and increased their micropolarity. Finally, the EPR analysis also provides information about the unfolding/denaturation of insulin within the channel at high temperatures. PMID- 21591777 TI - Laser induced fluorescence spectroscopy of tetracene with large Ar, Ne, and H2 clusters in superfluid He nanodroplets. AB - Clusters of tetracene molecules with different numbers of attached (Ar)(N), (Ne)(N) and (H(2))(N) particles (N = 1-2000) are assembled inside superfluid He nanodroplets and studied via laser-induced fluorescence. The frequency shift of the fluorescence spectrum of the tetracene molecules is studied as a function of cluster size and pickup order of tetracene and cluster species. For (Ar)(N) and (Ne)(N) clusters, our results indicate that the tetracene molecules reside inside the clusters when tetracene is captured by the He nanodroplet before the cluster species; conversely, the tetracene molecules stay on the surface of the clusters when tetracene is captured after the cluster species. In the case of (H(2))(N) clusters, however, tetracene molecules reside inside the (H(2))(N) clusters irrespective of the pickup order. We conclude that (Ar)(N) and (Ne)(N) clusters are rigid at T = 0.38 K, while (H(2))(N) clusters of up to N = 2000 remain fluxional at the same temperature. The results may also indicate the occurrence of heterogeneous nucleation of the (H(2))(N) clusters, which is induced by the interaction with tetracene chromophore molecules. PMID- 21591779 TI - Genetic modification of stem cells for improved therapy of the infarcted myocardium. AB - The conventional treatment modalities for ischemic heart disease only provide symptomatic relief to the patient without repairing and regenerating the damaged myocardium. Stem cell transplantation has emerged as a promising alternative therapeutic approach for cardiovascular diseases. Stem cells possess the potential of differentiation to adopt morphofunctional cardiac and vasculogenic phenotypes to repopulate the scar tissue and restore regional blood flow in the ischemic myocardium. These beneficial therapeutic effects make stem cell transplantation the method of choice for the treatment of ischemic heart disease. The efficacy of stem cell transplantation may be augmented by genetic manipulation of the cells prior to transplantation. Not only will insertion of therapeutic transgene(s) into the stem cells support the survival and differentiation of cells in the unfavorable microenvironment of the ischemic myocardium, but also the genetically manipulated stem cells will serve as a source of the transgene expression product in the heart for therapeutic benefits. We provide an overview of the extensively studied stem cell types for cardiac regeneration, the various methods in which these cells have been genetically manipulated and rationale of genetic modification of stem cells for use in regenerative cardiovascular therapeutics. PMID- 21591778 TI - Mass spectrometry evidence for cisplatin as a protein cross-linking reagent. AB - Cisplatin is a potent anticancer drug, which functions by cross-linking adjacent DNA guanine residues. However within 1 day of injection, 65-98% of the platinum in the blood plasma is protein-bound. It is generally accepted that cisplatin binds to methionine and histidine residues, but what is often underappreciated is that platinum from cisplatin has a 2+ charge and can form up to four bonds. Thus, it has the potential to function as a cross-linker. In this report, the cross linking ability of cisplatin is demonstrated by Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) with the use of standard peptides, the 16.8 kDa protein calmodulin (CaM), but was unsuccessful for the 64 kDa protein hemoglobin. The high resolution and mass accuracy of FTICR MS along with the high degree of fragmentation of large peptides afforded by collisionally activated dissociation (CAD) and electron capture dissociation (ECD) are shown to be a valuable means of characterizing cross-linking sites. Cisplatin is different from current cross-linking reagents by targeting new functional groups, thioethers, and imidazoles groups, which provides complementarity with existing cross linkers. In addition, platinum(II) inherently has two positive charges which enhance the detection of cross-linked products. Higher charge states not only promote the detection of cross-linking products with less purification but result in more comprehensive MS/MS fragmentation and can assist in the assignment of modification sites. Moreover, the unique isotopic pattern of platinum flags cross linking products and modification sites by mass spectrometry. PMID- 21591780 TI - Quantification of immunoreactive viral influenza proteins by immunoaffinity capture and isotope-dilution liquid chromatography-tandem mass spectrometry. AB - An immunocapture isotope dilution mass spectrometry (IC-IDMS) method was developed to quantify antibody-bound influenza hemagglutinins (HA) in trivalent influenza vaccines (TIV). Currently, regulatory potency requirements for TIV require HA quantification based on the single radial immunodiffusion (SRID) assay, which is time-consuming, laborious, and requires production of large quantities of reagents globally. In IC-IDMS, antiserum to the HA of interest captured viral proteins that were in the correct conformation to be recognized by the antibodies. The captured proteins were digested, and evolutionarily conserved tryptic peptides were quantified using isotope-dilution liquid chromatography tandem mass spectrometry. IC-IDMS relies on antibody-antigen binding similar to SRID but incorporates the accuracy and precision of IDMS. Polyclonal antibodies (pAb-H3) prepared by injection of sheep with purified H3 HA captured 82.9% (55.26 fmol/MUL) of the total H3 HA (66.69 fmol/MUL) from the commercial TIV and 93.6% (57.23 fmol/MUL) of the total H3 HA (61.14 fmol/MUL) in purified virus. While other HA (H1, B), neuraminidase (N1, N2, NB), viral matrix proteins, and nucleoproteins were also captured by this antiserum, our results were not affected due to the specificity of the mass spectrometer. IC-IDMS is an accurate, precise, sensitive, and selective method to measure antibody-bound HA in purified virus and commercial vaccines. PMID- 21591781 TI - Biosynthesis of methoxypyrazines: elucidating the structural/functional relationship of two Vitis viniferaO-methyltransferases capable of catalyzing the putative final step of the biosynthesis of 3-alkyl-2-methoxypyrazine. AB - 3-Alkyl-2-methoxypyrazines (MPs) are an important food constituent and have been associated with detrimental herbaceous flavors in red wines by consumers and the wine industry. The Vitis vinifera genes O-methyltransferase 1 and 2 (VvOMT1 and VvOMT2) have been isolated in the grapevine cultivar Carmenere. These genes encode S-adenosyl-l-methionine (SAM)-dependent O-methyltransferases, which have the ability to methylate 3-alkyl-2-hydroxypyrazines (HPs)-the putative final step in MPs production. Atomic studies were performed in order to explain the differences in these VvOMT activities through their structural/functional relationship in MPs biosynthesis. Differences in enthalpy energy observed between the proteins may be due to changes of equivalent residues in the active sites of VvOMT1 (F319, L322) and VvOMT2 (L319, V322). However, docking simulations and QM/MM analyses described how residues H272 and M182 could explain the main functional differentiation observed between VvOMT1 and VvOMT2 through steric impediment, which limits the formation of the transition state in enzymes encoded by VvOMT2. Therefore, this finding could explain the decreasing catalytic efficiency observed for VvOMT2. PMID- 21591782 TI - Impact of glutathione on the formation of methylmethine- and carboxymethine bridged (+)-catechin dimers in a model wine system. AB - This study was performed to assess the impact of glutathione on the reaction between (+)-catechin and carbonyl compounds in wine-related conditions. (+) Catechin (0.50 mM) and either glyoxylic acid (0.25 mM) or acetaldehyde (0.25 mM) were added to a model wine system with 0.0, 0.25, and 2.5 mM of glutathione added. UPLC-DAD and LC-MS analysis showed that the formation of carbonyl-bridged (+)-catechin dimers was inhibited in the samples with a glutathione to carbonyl ratio of 10:1 compared to the samples without glutathione. At a ratio of 1:1, glutathione inhibited the acetaldehyde-bridged dimers but only had a minor impact on the glyoxylic acid-bridged dimers. Further investigations showed that this trend of inhibition by glutathione on the glyoxylic acid-derived dimer was independent of temperatures, 20 degrees C vs 45 degrees C, or the presence of metal ions, 0.2 mg/L copper(II) and 5 mg/L iron(II). (1)H NMR analysis and LC-MS analysis provided evidence that glutathione inhibited dimer formation via different mechanisms depending on the carbonyl compound. For acetaldehyde-derived dimers, the main mode of inhibition was the ability of glutathione to form a (methyl-glutathionyl-methine)-(+)-catechin complex. Alternatively, the formation of a glutathione-glyoxylic acid addition product impeded the reaction between glyoxylic acid with (+)-catechin. These results demonstrate that glutathione, at sufficient concentration, can have a substantial impact on carbonyl-derived polymerization reactions in wine-like conditions. PMID- 21591783 TI - Cloning, heterologous expression and properties of a recombinant active turnip peroxidase. AB - Turnip (Brassica napus) roots peroxidase isoforms have been used in diagnostic kits and can also efficiently polymerize phenolic compounds from wastewaters. Heterologous expression of a turnip acidic peroxidase (BnPA) was investigated to increase availability of this widely used enzyme. The mature BnPA was ligated into the pET28a(+) vector and used to transform Escherichia coli Rosetta 2. Recombinant BnPA peroxidase was overexpressed and accumulated in inclusion bodies from which it was purified to homogeneity by immobilized metal affinity chromatography under denaturing conditions. Peroxidase activity was observed after a refolding process under oxidative conditions. The yield of pure recombinant BnPA was 29 mg L(-1) of culture with a specific activity of 981 +/- 20 ABTS units mg(-1) at optimal conditions (pH 6, 45 degrees C). Recombinant BnPA showed similar kinetic properties compared to native turnip peroxidase, and its secondary structure evaluated by circular dichroism comprised 20% alpha helix, 32% beta-sheet and 48% random structure. Recombinant BnPA showed high yield and good kinetic properties which are key steps for future structure function studies and biotechnological applications. PMID- 21591784 TI - Plantain and banana starches: granule structural characteristics explain the differences in their starch degradation patterns. AB - Different banana cultivars were used to investigate the influences of starch granule structure and hydrolases on degradation. The highest degrees of starch degradation were observed in dessert bananas during ripening. Scanning electron microscopy images revealed smooth granule surface in the green stage in all cultivars, except for Mysore. The small and round granules were preferentially degraded in all of the cultivars. Terra demonstrated a higher degree of crystallinity and a short amylopectin chain length distribution, resulting in high starch content in the ripe stage. Amylose content and the crystallinity index were more strongly correlated than the distribution of amylopectin branch chain lengths in banana starches. alpha- and beta-amylase activities were found in both forms, soluble in the pulp and associated with the starch granule. Starch phosphorylase was not found in Mysore. On the basis of the profile of alpha amylase in vitro digestion and the structural characteristics, it could be concluded that the starch of plantains has an arrangement of granules more resistant to enzymes than the starch of dessert bananas. PMID- 21591785 TI - pH-controlled exponential and linear growing modes of layer-by-layer assemblies of star polyelectrolytes. AB - We report the unique layer-by-layer (LbL) assembly behavior of pH-sensitive star shaped polyelectrolytes with both linear and exponential growth modes controlled by star architecture and assembly conditions. Cationic poly[2 (dimethylamino)ethyl methacrylate] and anionic poly(acrylic acid) stars were synthesized via "core-first" atom-transfer radical polymerization (ATRP) based on multifunctional initiators, in addition to their linear analogues. We demonstrated the LbL growth behavior as a function of deposition pH (ranging from 5 to 7), number of layers (up to 30 bilayers), and the method of assembly (dip- vs spin-assisted LbL). The spin-assisted LbL assembly makes it possible to render smoother and thinner LbL films with parameters controlled by the shear rate and pH conditions. In contrast, for dip-assisted LbL assembly, the pH-dependent exponential growth was observed for both linear and star polyelectrolytes. In the case of linear/linear pair, the exponential buildup was accompanied with a notable surface segregation which resulted in dramatic surface nonuniformity, "wormlike" heterogeneous morphology, and dramatic surface roughening. In contrast, star/linear and star/star LbL films showed very uniform and smooth surface morphology (roughness below 2.0 nm on the scale of 10 MUm * 10 MUm) with much larger thickness reaching up to 1.0 MUm for 30 bilayers and rich optical interference effects. Star polyelectrolytes with partially screened charges and high mobility caused by compact branched architecture appear to facilitate fast diffusion and exponential buildup of LbL films. We suggest that the fast buildup prevents long-range lateral diffusion of polyelectrolyte star components, hinders large-scale microphase separation, and thus leads to unique thick, smooth, uniform, transparent, and colorful LbL films from star polyelectrolytes in contrast to mostly heterogeneous films from traditional linear counterparts. PMID- 21591786 TI - Highly enantioselective intramolecular cyanoamidation: (+)-horsfiline, (-) coerulescine, (-)-esermethole. PMID- 21591787 TI - Proton transfer between tryptophan and ionic liquid solvents studied with molecular dynamics simulations. AB - The reaction free energies and associated pK(a) values for proton transfer from positively charged tryptophan (HTrp(+)) to the two pure ionic liquids (ILs) BMIM PF6 and BMIM-BF4 are derived from molecular simulations. IL solvation effects are examined with molecular dynamics simulations together with an empirical force field in which the average charge distribution in the actual IL is taken into account. A combination of molecular mechanical and quantum mechanical description (QM/MM) is used to examine the protonation of the anion constituents of the ILs. A dissociation of the protonated anions is observed into hydrogen fluoride and BF3 or PF5. Finally, pK(a) values of 16.5 and 21.5 in BMIM-BF4 and BMIM-PF6, respectively, are found for proton transfer from HTrp(+) to PF6(-) and BF4(-) anions, which indicates that a deprotonation of HTrp(+) is highly unfavorable compared to aqueous solutions. An examination of the contributions to the reaction free energies demonstrates that a deprotonation of tryptophan is impeded because two ions need to be annihilated for the reaction to occur: HTrp(+) and an anion. While the solvation effects induced by the two ILs are similar, the low proton acceptance of PF6(-) anions leads to the larger pK(a) value in BMIM-PF6. Also, estimates suggest that IL-induced pK(a) shifts are comparably small in proton transfer reactions where the total number of ions remains unchanged. For the first time, pK(a) values of acids were determined computationally in ILs. The obtained results elucidate the role of solvation effects on proton transfer between amino acids and ILs and improve our understanding of the observed pH memory of proteins that are solvated in ILs. PMID- 21591788 TI - Switching of enantioselectivity in the catalytic addition of diethylzinc to aldehydes by regioisomeric chiral 1,3-amino sulfonamide ligands. AB - Twenty chiral 1,3-amino sulfonamides of two classes (2a-i and 3a-k) have been prepared from (-)-cis-2-benzamidocyclohexanecarboxylic acid (1) and studied as ligands for catalytic enantioselective addition of Et(2)Zn to a variety of aromatic and aliphatic aldehydes. The ligands 2 and 3 are regioisomers in which the position of the amine and sulfonamide groups is exchanged. Each class of ligands with the same chirality was shown to afford sec-alcohols with the opposite stereochemistry. Structural surveys revealed that the combination of tertiary amino and p-toluenesufonylamido groups works most effectively for the reaction. Through optimization of the structural and reaction conditions, the best ligands quantitatively provided both enantiomeric secondary alcohols in good to excellent enantioselectivity of up to 94% and 98% ee for (S)- and (R) enantiomers, respectively. PMID- 21591789 TI - Simultaneous monitoring of gaseous CO(2) and ethanol above champagne glasses via micro-gas chromatography (MUGC). AB - In champagne tasting, gaseous CO(2) and volatile organic compounds progressively invade the headspace above glasses, thus progressively modifying the chemical space perceived by the consumer. In this study, a novel, rapid, and nonintrusive method aimed to simultaneously determine the content in gaseous CO(2) and ethanol above a glass poured with champagne, using a micro-gas chromatography technique coupled with a thermal conductivity detector, was presented. The simultaneous quantification of CO(2) and ethanol in the headspace of a champagne glass was monitored, in real tasting conditions, all along the first 15 min following pouring, depending on whether or not the glass shows effervescence. Both CO(2) and ethanol were found to be enhanced by the presence of ascending bubbles, thus confirming the close link between rising bubbles and the release of gaseous CO(2) and volatile organic compounds. PMID- 21591790 TI - Adsorption and association of a symmetric PEO-PPO-PEO triblock copolymer on polypropylene, polyethylene, and cellulose surfaces. AB - The association of a symmetric polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO(19)-PPO(29)-PEO(19)) triblock copolymer adsorbed from aqueous solutions onto polypropylene (PP), polyethylene (PE), and cellulose surfaces was probed using Atomic Force Microscopy (AFM). Significant morphological differences between the polyolefin substrates (PP and PE) and the cellulose surfaces were observed after immersion of the films in the PEO(19)-PPO(29)-PEO(19) solutions. When the samples were scanned, while immersed in solutions of the triblock copolymer, it was revealed that the structures adsorbed on the polyolefin surfaces were smoothed by the adsorbed PEO(19)-PPO(29)-PEO(19). In contrast, those structures on the hydrophilic cellulose surfaces were sharpened. These observations were related to the roughness of the substrate and the energy of interaction between the surfaces and the PEO and PPO polymer segments. The interaction energy between each of the blocks and the surface was calculated using molecular dynamics simulations. It is speculated that the associative structures amply reported in aqueous solution at concentrations above the critical micelle concentration, CMC, are not necessarily preserved upon adsorption; instead, it appears that molecular arrangements of the anchor-buoy type and hemimicelles prevail. The reported data suggests that the roughness of the surface, as well as its degree of hydrophobicity, have a large influence on the nature of the resulting adsorbed layer. The reported observations are valuable in explaining the behavior of finishing additives and lubricants commonly used in textile and fiber processing, as well as the effect of the morphology of the boundary layers on friction and wear, especially in the case of symmetric triblock copolymers, which are commonly used as antifriction, antiwear additives. PMID- 21591791 TI - On the mechanism of crystalline polymorph selection by polymer heteronuclei. AB - The phase-selective crystallization of acetaminophen (ACM) using insoluble polymers as heteronuclei was investigated in a combined experimental and computational effort to elucidate the mechanism of polymer-induced heteronucleation (PIHn). ACM heteronucleates from supersaturated aqueous solution in its most thermodynamically stable monoclinic form on poly(n-butyl methacrylate), whereas the metastable orthorhombic form is observed on poly(methyl methacrylate). When ACM crystals were grown through vapor deposition, only the monoclinic polymorph was observed on each polymer. Each crystallization condition leads to a unique powder X-ray diffraction pattern with the major preferred orientation corresponding to the crystallographic faces in which these crystal phases nucleate from surfaces of the polymers. The molecular recognition events leading to these outcomes are elucidated with the aid of computed polymer crystal binding energies using docking simulations. This investigation illuminates the mechanism by which phase selection occurs during the crystallization of ACM using polymers as heteronuclei, paving the way for the improvement of methods for polymorph selection and discovery based on heterogeneous nucleation promoters. PMID- 21591792 TI - Amphiphilic behavior and membrane solubility of a dicholesteryl-cyclodextrin. AB - Amphiphilic cyclodextrins (CDs) are good candidates to functionalize natural membranes as well as synthetic vesicles. In this paper, we provide a full description of the interfacial behavior of pure 6I,6IV-(beta cholesteryl)succinylamido-6I,6IV-(6-deoxy-per-(2,3,6-O-methyl))cycloheptaose (TBdSC) and how it inserts in dipalmitoyl-l-alpha-phosphatidylcholine (DPPC) monolayers as a membrane model. Langmuir isotherms of pure TBdSC suggest a reorganization upon compression, which could be clarified using X-ray reflectivity. The CD head can adjust its conformation to the available area per molecule. A compatible model involving a rotation around a horizontal axis defined by the two selectively substituted glucose units is proposed. The in plane structure is characterized at all scales by Brewster angle microscopy (BAM) on the water surface and atomic force microscopy (AFM) on monolayers deposited on solid substrates. The same tools are used for its mixtures with DPPC. We show in particular that TBdSC seems to be soluble in the liquid-expanded DPPC. However, phase segregation occurs at higher pressure, allowing for sequentially liquid condensed DPPC and high-pressure conformation of TBdSC. This gives rise to a remarkable contrast inversion in both imaging methods. PMID- 21591793 TI - In situ forming and rutin-releasing chitosan hydrogels as injectable dressings for dermal wound healing. AB - An in situ gel-forming system composed of rutin- and tyramine-conjugated chitosan derivatives, horseradish peroxidase (HRP), and hydrogen peroxide (H(2)O(2)) was prepared and applied to dermal wound repair. Rutin was employed to enhance production and accumulation of extracellular matrix in the healing process. In vitro study demonstrates that released rutin significantly enhanced cell proliferation as compared with media without rutin. In vivo wound healing study was performed by injecting hydrogels on rat dorsal wounds with a diameter of 8 mm for 14 days. Histological results demonstrated that rutin-conjugated hydrogel exhibited enhancement of wound healing as compared with treatments with PBS, hydrogel without rutin, and a commercialized wound dressing (Duoderm). More specifically, rutin-conjugated hydrogels induced better defined formation of neo epithelium and thicker granulation, which is closer to the original epithelial tissue. As a result, this study suggests that the in situ gel-forming system can be a promising injectable gel-type wound dressing. PMID- 21591794 TI - Theoretical study of the equilibrium structure, vibrational spectrum, and thermochemistry of the peroxynitrate CF2BrCFBrOONO2. AB - The results of a theoretical study of the molecular structure and conformational mobilities of the peroxynitrate CF(2)BrCFBrOONO(2) and its radical decomposition product CF(2)BrCFBrOO are reported in this paper. The most stable structures were calculated from ab initio G3(MP2)B3 and G4(MP2) methods and from density functional theory at the B3LYP/6-311+G(d) and B3LYP/6-311+G(3df) levels of theory. The equilibrium conformation of CF(2)BrCFBrOONO(2) indicates that the bromine atoms lie in position anti to each other and possess a COON dihedral angle of 114 degrees . A quantum statistical analysis shows that about 40% of the internal rotors can freely rotate at room temperature. Our best values for the standard enthalpies of formation of CF(2)BrCFBrOONO(2) and CF(2)BrCFBrOO at 298 K obtained from isodesmic reactions at the G3(MP2)//B3LYP/6-311+G(3df) level of theory are -144.7 and -127.0 kcal mol(-1). From these values and the enthalpy of formation of the NO(2) radical, a CF(2)BrCFBrOO-NO(2) bond dissociation enthalpy of 26.0 +/- 2 kcal mol(-1) was estimated. PMID- 21591795 TI - Kinetics of thermal modifications in a grape seed extract. AB - The thermal modification kinetics of a commercial grape seed extract (GSE) was investigated. A GSE was exposed to 60, 90, and 120 degrees C for 5, 10, 15, 30, 45, and 60 min. The antioxidant activity (AA) and the absorbance at 420 nm (A(420)) were measured. (+)-Catechin, (-)-epicatechin, procyanidins B1 and B2, and gallic acid were identified and measured. After the thermal treatments, the AA did not show a significant difference (p > 0.05) and both procyanidins and gallic acid increased as well as A(420). (+)-Catechin and (-)-epicatechin decreased. To obtain the activation energy (E(a)) of the changes, a modified Weibull and a combined zero- and first-order model were compared, both followed by the Arrhenius equation. The Weibull model was more accurate. The E(a) values for browning and (+)-catechin, (-)-epicatechin, gallic acid, and procyanidins B1 and B2 were 170, 286, 42, 102, 249, and 95 kJ/mol, respectively. The results were valid at a confident level of 95%. PMID- 21591796 TI - On the temperature dependence of complex formation between chitosan and proteins. AB - Chitosan is a biocompatible easily degradable polysaccharide, which, because of its positive charge, is able to interact favorably with deprotonated carboxyl groups of proteins. The strength of these charge-charge interactions is generally low, resulting in poor colloidal stability of the complexes. To investigate if other noncovalent forces contribute to stabilizing such systems, we have selected alpha-lactalbumin, beta-lactoglobulin, beta-casein, and human growth hormone, characterized by a common acidic pI value (~ 5) that ensures their overall negative charge at physiological pH. Binding energetics between chitosan and proteins was studied by isothermal titration calorimetry, whereas the thermal stability was assessed by differential scanning calorimetry. Our data show that colloidal stability of the particles depends on protein identity as well as temperature, indicating the involvement of nonelectrostatic interactions (e.g., hydrophobic effect) as driving forces for the complex formation. This suggests that chitosan-protein drug delivery systems can be improved through preparation process optimization with regard to temperature. PMID- 21591797 TI - Signature of mobile hydrogen bonding of lysine side chains from long-range 15N 13C scalar J-couplings and computation. AB - Amino acid side chains involved in hydrogen bonds and electrostatic interactions are crucial for protein function. However, detailed investigations of such side chains in solution are rare. Here, through the combination of long-range (15)N (13)C scalar J-coupling measurements and an atomic-detail molecular dynamics (MD) simulation, direct insight into the structural dynamic behavior of lysine side chains in human ubiquitin has been gained. On the basis of (1)H/(13)C/(15)N heteronuclear correlation experiments selective for lysine NH(3)(+) groups, we analyzed two different types of long-range (15)N-(13)C J-coupling constants: one between intraresidue (15)Nzeta and (13)Cgamma nuclei ((3)J(NzetaCgamma)) and the other between (15)Nzeta and carbonyl (13)C' nuclei across a hydrogen bond ((h3)J(NzetaC')). The experimental (3)J(NzetaCgamma) data confirm the highly mobile nature of the chi(4) torsion angles of lysine side chains seen in the MD simulation. The NH(3)(+) groups of Lys29 and Lys33 exhibit measurable (h3)J(NzetaC') couplings arising from hydrogen bonds with backbone carbonyl groups of Glu16 and Thr14, respectively. When interpreted together with the (3)J(NzetaCgamma)-coupling constants and NMR-relaxation-derived S(2) order parameters of the NH(3)(+) groups, they strongly suggest that hydrogen bonds involving NH(3)(+) groups are of a transient and highly dynamic nature, in remarkably good agreement with the MD simulation results. PMID- 21591798 TI - Spatial distributions and interstellar reaction processes. AB - Methyl formate presents a challenge for the conventional chemical mechanisms assumed to guide interstellar organic chemistry. Previous studies of potential formation pathways for methyl formate in interstellar clouds ruled out gas-phase chemistry as a major production route, and more recent chemical kinetics models indicate that it may form efficiently from radical-radical chemistry on ice surfaces. Yet, recent chemical imaging studies of methyl formate and molecules potentially related to its formation suggest that it may form through previously unexplored gas-phase chemistry. Motivated by these findings, two new gas-phase ion-molecule formation routes are proposed and characterized using electronic structure theory with conformational specificity. The proposed reactions, acid catalyzed Fisher esterification and methyl cation transfer, both produce the less stable trans-conformational isomer of protonated methyl formate in relatively high abundance under the kinetically controlled conditions relevant to interstellar chemistry. Gas-phase neutral methyl formate can be produced from its protonated counterpart through either a dissociative electron recombination reaction or a proton transfer reaction to a molecule with larger proton affinity. Retention (or partial retention) of the conformation in these neutralization reactions would yield trans-methyl formate in an abundance that exceeds predictions under thermodynamic equilibrium at typical interstellar temperatures of <=100 K. For this reason, this conformer may prove to be an excellent probe of gas-phase chemistry in interstellar clouds. Motivated by new theoretical predictions, the rotational spectrum of trans-methyl formate has been measured for the first time in the laboratory, and seven lines have now been detected in the interstellar medium using the publicly available PRIMOS survey from the NRAO Green Bank Telescope. PMID- 21591799 TI - Design and development of functionalized cyclometalated ruthenium chromophores for light-harvesting applications. AB - The syntheses and the electrochemical spectroscopic properties of a suite of asymmetrical bistridentate cyclometalated Ru(II) complexes bearing terminal triphenylamine (TPA) substituents are reported. These complexes, which contain structural design elements common to both inorganic and organic dyes that exhibit superior power conversion efficiencies in the dye-sensitized solar cell (DSSC), are broadly formulated as [Ru(II)(L-2,5'-thiophene-TPA-R(1))(L-R(2))](+) [L = tridentate chelating ligand (e.g., 2,2':6',2''-terpyridine (tpy); deprotonated forms of 1,3-di(pyridin-2-yl)benzene (Hdpb) or 6-phenyl-2,2'-bipyridine (Hpbpy)); R(1) = -H, -Me, -OMe; R(2) = -H, -CO(2)Me, -CO(2)H]. The following structural attributes were systematically modified for the series: (i) electron-donating character of the terminal substituents (e.g., R(1) = -H, -Me, -OMe) placed para to the amine of the "L-2,5'-thiophene-TPA-R(1)" ligand framework; (ii) electron withdrawing character of the tridentate chelate distal to the TPA-substituted ligand (e.g., R(2) = -H, -CO(2)Me, -CO(2)H); and (iii) position of the organometallic bond about the Ru(II) center. UV-vis spectra reveal intense and broad absorption bands arising from a collection of metal-to-ligand charge transfer (MLCT) and TPA-based intraligand charge-transfer (ILCT) transitions that, in certain cases, extend beyond 800 nm. Electrochemical data indicate that the oxidative behavior of the TPA and metal chelate units can be independently modulated except in cases where the anionic phenyl ring is in direct conjugation with the TPA unit. In most cases, the anionic character of the cyclometalating ligands renders a metal-based oxidation event prior to the oxidation of the TPA unit. This situation can, however, be reversed with an appropriately positioned Ru-C bond and electron-rich R(1) group. This finding is important in that this arrangement confines the highest occupied molecular orbital (HOMO) to the TPA unit rather than the metal, which is optimal for sensitizing TiO(2); indeed, a remarkably high power conversion efficiency (eta) in the DSSC (i.e., 8.02%) is measured for the TPA-substituted pbpy(-) chelate where R(1) = -OMe. These results provide a comprehensive strategy for improving the performance of bistridentate Ru sensitizers devoid of NCS(-) groups for the DSSC. PMID- 21591800 TI - Enantiomeric self-recognition in homo- and heterodinuclear macrocyclic lanthanide(III) complexes. AB - The controlled formation of lanthanide(III) dinuclear MU-hydroxo-bridged [Ln(2)L(2)(MU-OH)(2)X(2)](n+) complexes (where X = H(2)O, NO(3)(-), or Cl(-)) of the enantiopure chiral macrocycle L is reported. The (1)H and (13)C NMR resonances of these complexes have been assigned on the basis of COSY, NOESY, TOCSY, and HMQC spectra. The observed NOE connectivities confirm that the dimeric solid-state structure is retained in solution. The enantiomeric nature of the obtained chiral complexes and binding of hydroxide anions are reflected in their CD spectra. The formation of the dimeric complexes is accompanied by a complete enantiomeric self-recognition of the chiral macrocyclic units. The reaction of NaOH with a mixture of two different mononuclear lanthanide(III) complexes, [Ln(1)L](3+) and [Ln(2)L](3+), results in formation of the heterodinuclear [Ln(1)Ln(2)L(2)(MU-OH)(2)X(2)](n+) complexes as well as the corresponding homodinuclear complexes. The formation of the heterodinuclear complex is directly confirmed by the NOESY spectra of [EuLuL(2)(MU-OH)(2)(H(2)O)(2)](4+), which reveal close contacts between the macrocyclic unit containing the Eu(III) ion and the macrocyclic unit containing the Lu(III) ion. While the relative amounts of homo- and heterodinuclear complexes are statistical for the two lanthanide(III) ions of similar radii, a clear preference for the formation of heterodinuclear species is observed when the two mononuclear complexes contain lanthanide(III) ions of markedly different sizes, e.g., La(III) and Yb(III). The formation of heterodinuclear complexes is accompanied by the self-sorting of the chiral macrocyclic units based on their chirality. The reactions of NaOH with a pair of homochiral or racemic mononuclear complexes, [Ln(1)L(RRRR)](3+)/[Ln(2)L(RRRR)](3+), [Ln(1)L(SSSS)](3+)/[Ln(2)L(SSSS)](3+), or [Ln(1)L(rac)](3+)/[Ln(2)L(rac)](3+), results in mixtures of homochiral, homodinuclear and homochiral, heterodinuclear complexes. On the contrary, no heterochiral, heterodinuclear complexes [Ln(1)L(RRRR)Ln(2)L(SSSS)(MU OH)(2)X(2)](n+) are formed in the reactions of two different mononuclear complexes of opposite chirality. PMID- 21591801 TI - In vivo osseointegration of nano-designed composite coatings on titanium implants. AB - This is the first in vivo study of plasma-sprayed carbon nanotube (CNT) reinforced hydroxyapatite (HA) coating on titanium implants embedded in rodents' bone. No adverse effect or cytotoxicity of CNT addition on bone tissues and cells was observed. Normal bone growth was observed around HA-CNT-coated implants. CNT addition induces higher osseointegration as compared to HA. Elastic modulus of new bone was compared with the modulus of HA-CNT/bone interface to understand the mechanical integrity of the implant. PMID- 21591802 TI - Discrimination of breast cancer by measuring prostate-specific antigen levels in women's serum. AB - Prostate-specific antigen (PSA) has been reported to be a potential biomarker of breast cancer. Serum PSA of normal women is around 1 pg/mL, which is usually undetectable by current assay methods; thus an ultrasensitive measurement of PSA expression in women's serum is necessary to distinguish normal from malignant breast diseases. To enhance the sensitivity of conventional immunoassay technology for the detection of PSA in sera, we adopted a localized surface plasmon coupled fluorescence fiber-optic biosensor, which combines a sandwich immunoassay with the localized surface plasmon technique. The concentration of total PSA (t-PSA) (from 0.1 to 1000 pg/mL) in phosphate-buffered saline solution and the normalized fluorescence signal exhibit a linear relationship where the correlation coefficient is 0.9574. In addition, the concentration of additional t PSA in 10-fold-diluted healthly women's serum across a similar range was measured. The correlation coefficient for this measurement is 0.9142. In clinical serum samples, moreover, the experimental results of t-PSA detection show that both the mean value and median of normalized fluorescence signals in the breast cancer group (155.2 and 145.7, respectively) are higher than those in the noncancer group (46.6 and 37.1, respectively). We also examined the receiver operating characteristic curve for t-PSA, and the area under the curve (AUC) is estimated to be 0.9063, the AUC being used to measure the performance of a test to correctly identify diseased and nondiseased subjects. PMID- 21591803 TI - Chiral Lewis base-assisted Bronsted acid (LBBA)-catalyzed enantioselective cyclization of 2-geranylphenols. AB - Chiral Lewis base-assisted Bronsted acids (Chiral LBBAs) have been designed as new organocatalysts for biomimetic enantioselective cyclization. A salt of a chiral phosphonous acid diester with FSO(3)H catalyzes the enantioselective cyclization of 2-geranylphenols to give the desired trans-fused cyclized products with high diastereo- and enantioselectivities (up to 98:2 dr and 93% ee). PMID- 21591804 TI - An efficient synthesis of imidazolinium salts using vinyl sulfonium salts. AB - The synthesis of imidazolinium salts from the reaction of formamidines and (2 bromoethyl)diphenylsulfonium triflate is described. A variety of symmetrical and unsymmetrical imidazolinium triflate salts were synthesized in high yield in short reaction times under mild conditions. Aromatic and aliphatic N-substituents work well. The reaction is proposed to proceed via generation of a vinyl sulfonium salt intermediate from the bromoethylsulfonium triflate. PMID- 21591805 TI - Syntheses and characterization of new mid-infrared transparency compounds: centric Ba2BiGaS5 and acentric Ba2BiInS5. AB - Two new mid-infrared transparency compounds, centric Ba(2)BiGaS(5) (1) and acentric Ba(2)BiInS(5) (2), were synthesized from a high-temperature solid-state reaction in evacuated closed silica tubes. Their crystal structures were determined by a single crystal X-ray diffraction method at 293 K. The results of crystal structure solution indicate that compound 1 crystallizes in the centrosymmetric space group Pnma with trans- (1)(infinity)[BiGaS(5)](4-) chain structure, while compound 2 crystallizes in the noncentrosymmetric polar space group Cmc2(1) with cis- (1)(infinity)[BiInS(5)](4-) chain structure. Two types of lone-pair electrons alignment fashions within (1)(infinity)[BiMS(5)](4-) chains result in destructive (for 1) or constructive (for 2) dipole moments, as illustrated in the crystal structures and the partial electron density maps based on the first-principles electronic structure computations. Powder second-harmonic generation (SHG) experiments with a 2.05 MUm pumping laser show that the SHG efficiency of the polar compound 2 is approximately 0.8 times that of KTiOPO(4) (KTP) reference. Furthermore, SHG signal intensity measurements using different size particles of powder samples indicate that compound 2 can also achieve type I phase-matching, which makes the compound promising for practical applications. PMID- 21591806 TI - A facile route to isotropic conductive nanocomposites by direct polymer infiltration of carbon nanotube sponges. AB - Fabrication of high-performance nanocomposites requires that the nanoscale fillers be dispersed uniformly and form a continuous network throughout the matrix. Direct infiltration of porous CNT sponges consisting of a three dimensional nanotube scaffold may provide a possible solution to this challenge. Here, we fabricated CNT sponge nanocomposites by directly infiltrating epoxy fluid into the CNT framework while maintaining the original network structure and CNT contact, with simultaneous improvement in mechanical and electrical properties. The resulting composites have an isotropic structure with electrical resistivities of 10 to 30 Omega.cm along arbitrary directions, much higher than traditional composites by mixing random CNTs with epoxy matrix. We observed reversible resistance change in the sponge composites under compression at modest strains, which can be explained by tunneling conduction model, suggesting potential applications in electromechanical sensors. PMID- 21591807 TI - Efficient and controllably selective preparation of esters using uronium-based coupling agents. AB - Carboxylic acid esters can be prepared in excellent yields at room temperature from an acid and either a phenol or an aliphatic alcohol using the peptide coupling reagents, TBTU, TATU, or COMU, in the presence of organic bases. Reactions using TBTU and TATU are faster but do not occur with tertiary alcohols. Selectivity between reaction with primary or secondary alcohols in diols and polyols can be achieved with choice of base and coupling agent. PMID- 21591809 TI - Adsorption of lead(II) ions from aqueous solution on low-temperature exfoliated graphene nanosheets. AB - Graphene nanosheets (GNSs) that were obtained by vacuum-promoted low-temperature exfoliation were used to adsorb lead ions from an aqueous system. The pristine and thermally modified GNSs were characterized with scanning electron microscopy observation and X-ray photoelectron spectroscopy analysis. It was interestingly found that the adsorption against lead ions was enhanced by heat treatment, although the oxygen complexes of GNSs showed a significant decrease. In addition, lead ion uptake resulted in an increase in the pH value of the solution. It is supposed that the Lewis basicity of GNSs is improved by heat treatment under a high vacuum, in favor of simultaneous adsorption of lead ions and protons onto GNSs. PMID- 21591808 TI - p-hydroxyacetophenone amides from Cystobacter ferrugineus, strain Cb G35. AB - A family of six novel p-hydroxyacetophenone amides, 1-6, was isolated from Cystobacter ferrugineus, strain Cb G35. Their structures were elucidated by ESI TOF mass spectrometry and NMR spectroscopy. Feeding experiments with labeled [13C9,15N]-tyrosine and [d10]-leucine identified the biosynthetic precursors of 1. PMID- 21591810 TI - The importance of NO+ (H2O)4 in the conversion of NO+ (H2O)n to H3O+ (H2O)n: I. Kinetics measurements and statistical rate modeling. AB - The kinetics for conversion of NO(+)(H(2)O)(n) to H(3)O(+)(H(2)O)(n) has been investigated as a function of temperature from 150 to 400 K. In contrast to previous studies, which show that the conversion goes completely through a reaction of NO(+)(H(2)O)(3), the present results show that NO(+)(H(2)O)(4) plays an increasing role in the conversion as the temperature is lowered. Rate constants are derived for the clustering of H(2)O to NO(+)(H(2)O)(1-3) and the reactions of NO(+)(H(2)O)(3,4) with H(2)O to form H(3)O(+)(H(2)O)(2,3), respectively. In addition, thermal dissociation of NO(+)(H(2)O)(4) to lose HNO(2) was also found to be important. The rate constants for the clustering increase substantially with the lowering of the temperature. Flux calculations show that NO(+)(H(2)O)(4) accounts for over 99% of the conversion at 150 K and even 20% at 300 K, although it is too small to be detectable. The experimental data are complimented by modeling of the falloff curves for the clustering reactions. The modeling shows that, for many of the conditions, the data correspond to the falloff regime of third body association. PMID- 21591811 TI - Graphene-on-paper sound source devices. AB - We demonstrate an interesting phenomenon that graphene can emit sound. The application of graphene can be expanded in the acoustic field. Graphene-on-paper sound source devices are made by patterning graphene on paper substrates. Three graphene sheet samples with the thickness of 100, 60, and 20 nm were fabricated. Sound emission from graphene is measured as a function of power, distance, angle, and frequency in the far-field. The theoretical model of air/graphene/paper/PCB board multilayer structure is established to analyze the sound directivity, frequency response, and efficiency. Measured sound pressure level (SPL) and efficiency are in good agreement with theoretical results. It is found that graphene has a significant flat frequency response in the wide ultrasound range 20-50 kHz. In addition, the thinner graphene sheets can produce higher SPL due to its lower heat capacity per unit area (HCPUA). The infrared thermal images reveal that a thermoacoustic effect is the working principle. We find that the sound performance mainly depends on the HCPUA of the conductor and the thermal properties of the substrate. The paper-based graphene sound source devices have highly reliable, flexible, no mechanical vibration, simple structure and high performance characteristics. It could open wide applications in multimedia, consumer electronics, biological, medical, and many other areas. PMID- 21591812 TI - Remote triggered release of doxorubicin in tumors by synergistic application of thermosensitive liposomes and gold nanorods. AB - Delivery of chemotherapeutic agents after encapsulation in nanocarriers such as liposomes diminishes side-effects, as PEGylated nanocarrier pharmacokinetics decrease dosing to healthy tissues and accumulate in tumors due to the enhanced permeability and retention effect. Once in the tumor, however, dosing of the chemotherapeutic to tumor cells is limited potentially by the rate of release from the carriers and the size-constrained, poor diffusivity of nanocarriers in tumor interstitium. Here, we report the design and fabrication of a thermosensitive liposomal nanocarrier that maintains its encapsulation stability with a high concentration of doxorubicin payload, thereby minimizing "leak" and attendant toxicity. When used synergistically with PEGylated gold nanorods and near-infrared stimulation, remote triggered release of doxorubicin from thermosensitive liposomes was achieved in a mouse tumor model of human glioblastoma (U87), resulting in a significant increase in efficacy when compared to nontriggered or nonthermosensitive PEGylated liposomes. This enhancement in efficacy is attributed to increase in tumor-site apoptosis, as was evident from noninvasive apoptosis imaging using Annexin-Vivo 750 probe. This strategy affords remotely triggered control of tumor dosing of nanocarrier-encapsulated doxorubicin without sacrificing the ability to differentially dose drugs to tumors via the enhanced permeation and retention effect. PMID- 21591813 TI - Effect of organic P forms and P present in inorganic colloids on the determination of dissolved P in environmental samples by the diffusive gradient in thin films technique, ion chromatography, and colorimetry. AB - The speciation of P in environmental samples is operationally defined, since it depends on the analytical method used. In this study, we compared four methods to measure P in solution: ion chromatography (IC), the malachite green colorimetric method (CM), the diffusive gradient in thin films technique (DGT) and, for total dissolved P, optical inductively coupled plasma (ICP). These methods were compared on three sets of solutions (filtered over <0.45 MUm): solutions with model organic P compounds, suspensions of synthesized inorganic Fe and Al colloids loaded with P, and environmental samples. The environmentally relevant organic P compounds were only marginally detected by CM and IC. Substantial fractions of certain organic P compounds contributed to the DGT measurement. Colorimetric analysis of DGT eluates detected in general less P than ICP analysis, indicating that these organic P compounds sorbed on the zero sink layer. Phosphorus associated with inorganic colloids was completely recovered by CM, but not by IC and least by DGT. Measurements on a wide set of 271 environmental samples (soil pore waters, groundwaters, and surface waters) suggest that surface water P is largely present as orthophosphate and phosphate sorbed onto inorganic colloids, whereas organic P contributes more in groundwaters. PMID- 21591814 TI - Regiochemistry in cobalt-mediated intermolecular Pauson-Khand reactions of unsymmetrical internal heteroaromatic alkynes with norbornene. AB - The intermolecular Pauson-Khand (PK) reactions of sterically comparable (2 phenylethynyl)heteroaromatic compounds with norbornene, mediated by Co(2)(CO)(8) to give cyclopentenone products, were examined in this study. A synthetic protocol utilizing focused-microwave dielectric heating proved indispensable in the efficient synthesis of the PK cyclopentenone products. "pi-Deficient" heteroaromatic substrates, e.g., 2-pyrones, and some "pi-excessive" heteroaromatics such as 2- and 3-thiophene and 2-furan favor the beta-position in the newly formed cyclopentenone ring. Other pi-excessive heteroaromatics such as 2-pyrrole or 2-indole favor the alpha-position. A pi-excessive 3-indole derivative gave a nearly equal mixture of regioisomers. The position of the nitrogen in pyridyl-containing alkyne substrates also affects the regiochemical outcome of the PK reaction. A 2-pyridyl alkyne, possessing a proximal nitrogen, influences the regioselectivity relative to a 4-pyridyl variant quite dramatically, favoring the beta-position in the newly formed cyclopentenone ring. A 2-pyrimidylalkyne exhibits similar behavior to the 2-pyridylalkyne. Compounds that do not participate in PK reactions with norbornene include (2 phenylethynyl)imidazoles and the related benzimidazoles, which promote rapid decomposition of the in situ generated (MU(2)-alkyne)Co(2)(CO)(6) complexes. This stands in contrast with other nitrogen-containing heteroaromatics, e.g., pyrrole , indole-, and pyrimidine-derived compounds, which effectively undergo PK reactions. Overall, the type of heteroaromatic group dramatically influences PK regioselectivity, which can in part be explained by rationalization of the current reaction mechanism, but not fully. PMID- 21591815 TI - Direct HRTEM observation of ultrathin freestanding ionic liquid film on carbon nanotube grid. AB - Direct imaging of liquids by electron microscopy has been extremely difficult due to their high volatility. Ionic liquids are a unique liquid material with almost zero vapor pressure, which allows us to characterize them under high-vacuum conditions. Here we report the first direct observation of the microstructure and phase behavior of an imidazolium-based room-temperature ionic liquid by high resolution transmission electron microscopy with the aid of a special carbon nanotube network, which is able to support a freestanding ultrathin ionic liquid film on its nanosized holes. It was found that the existence of cluster structures is one of the intrinsic properties of the ionic liquid in its whole liquid phase range. Furthermore, the size and mobility of the clusters play an important role during phase transition of the ionic liquid. We show that the direct HRTEM imaging on freestanding liquid film is a powerful technique to obtain insight into the structure of ionic liquids and their phase behavior. The present study can provide an important starting point for more sophisticated structural studies on the microstructure of liquidus materials. PMID- 21591816 TI - UV-ozone cleaning of supported poly(vinylpyrrolidone)-stabilized palladium nanocubes: effect of stabilizer removal on morphology and catalytic behavior. AB - Poly(vinylpyrrolidone) (PVP)-stabilized Pd nanocubes were synthesized, deposited on a carbon-based support, and subsequently treated with UV-ozone (UVO) in order to eliminate the traces of PVP still present on the surface. Cubes, being a thermodynamically unfavorable shape, are very prone to restructuring to minimize the interfacial free energy and thus allow the assessment of their morphological stability during UVO cleaning. The process of PVP removal was monitored by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and in situ attenuated total reflection infrared spectroscopy (ATR-IR). High-resolution scanning electron microscopy (SEM) imaging was used to evaluate the morphology of the nanocubes. The effect of PVP removal was also studied in the hydrogenation of acetylene, showing a 4-fold increase of activity. This method can be applied to nanoparticles of other common shapes, which expose different crystal planes, in order to study the structure sensitivity of chemical reactions. PMID- 21591817 TI - Comparison of virtual high-throughput screening methods for the identification of phosphodiesterase-5 inhibitors. AB - Reliable and effective virtual high-throughput screening (vHTS) methods are desperately needed to minimize the expenses involved in drug discovery projects. Here, we present an improvement to the negative image-based (NIB) screening: the shape, the electrostatics, and the solvation state of the target protein's ligand binding site are included into the vHTS. Additionally, the initial vHTS results are postprocessed with molecular mechanics/generalized Born surface area (MMGBSA) calculations to estimate the favorability of ligand-protein interactions. The results show that docking produces very good early enrichment for phosphodiesterase-5 (PDE-5); however, in general, the NIB and the ligand-based screening performed better with or without the added electrostatics. Furthermore, the postprocessing of the NIB screening results using MMGBSA calculations improved the early enrichment for the PDE-5 considerably, thus, making hit discovery affordable. PMID- 21591819 TI - Combination of low-dose isotretinoin and pulsed oral azithromycin in the management of moderate to severe acne: a preliminary open-label, prospective, non comparative, single-centre study. AB - BACKGROUND: The conventionally used dose of isotretinoin in acne causes significant dose-related adverse effects. Low-dose isotretinoin has been used successfully in mild to moderate papulopustular acne. Although isotretinoin acts against all mechanisms of acne formation, it has no significant direct antimicrobial effect. OBJECTIVE: To test whether the addition of an antibacterial enables use of isotretinoin in low doses even in moderate to severe acne. METHODS: This was a preliminary open-label, prospective, non-comparative, single centre study carried out in a tertiary-care referral hospital. Seventy patients with grade 3 and 4 acne according to the US FDA global score were included in the study between October 2005 and December 2007. These patients were treated with a combination of low-dose isotretinoin (0.3 mg/kg/day) and pulsed oral azithromycin (500 mg/day over three consecutive days every 2 weeks). Response to treatment was assessed at monthly intervals and was recorded as a percentage decrease in overall severity of disease. Treatment was continued to complete clearance of lesions or to 16 weeks, whichever came later. RESULTS: Sixty-two (93.9%) of 66 eligible patients had complete clearance of disease activity after a mean treatment duration of 21 weeks. The mean total cumulative dose of isotretinoin was 49.6 mg/kg. Seven (11.3%) patients had a relapse of disease during the post treatment follow-up period. Fifty-three adverse effects were observed. Three patients had initial aggravation of disease that was managed with prednisolone and disappeared with continuation of treatment. CONCLUSION: A combination of low dose isotretinoin and oral azithromycin pulse is effective in severe acne and has a reasonably acceptable adverse-effect profile and low post-treatment relapse rates. PMID- 21591818 TI - Efficacy and tolerability of long-acting nifedipine GITS/OROS monotherapy or combination therapy in hypertensive patients: results of a 12-week international, prospective, multicentre, observational study. AB - BACKGROUND: Achieving the maximum reduction in cardiovascular morbidity and mortality is the primary goal of blood pressure (BP) control. Current guidelines recommend several antihypertensive classes as first-line therapy for this purpose but the decision on which agent/s to use will likely be based upon the treating physician's clinical experience. Observational studies provide a useful way of ascertaining the efficacy and tolerability of an antihypertensive in a real-life clinical setting. OBJECTIVE: The aim of this observational study was to determine the efficacy, tolerability and physician/patient satisfaction with long-acting nifedipine (gastrointestinal therapeutic system [GITS]/osmotic-controlled release oral delivery system [OROS]) in a large multinational cohort of hypertensive patients. METHODS: This observational study was conducted in adults (aged >=18 years) with previously untreated or treated hypertension. The decision to prescribe nifedipine 30 or 60 mg once daily was made by the treating physician. Patients then attended up to three clinic visits any time over a 12-week period when medication could be up- or down-titrated or switched. The mean reduction in systolic BP (SBP)/diastolic BP (DBP) from first visit and whether target BP (<140/<90 mmHg or <130/<80 mmHg [for patients with diabetes mellitus]) had been achieved were recorded at the final visit and stratified according to hypertension grade and presence of cardiovascular risk factors. Subjective assessment of efficacy was reported by physicians and patients. All adverse events and their possible relationship to study drug were recorded. All assessments were performed on patients who received at least one dose of nifedipine GITS/OROS. RESULTS: A total of 14 344 patients received nifedipine GITS/OROS treatment (58.7% male; 77.7% non-diabetic; mean age 57.5 years); 14 266 had at least one follow-up visit over a mean 10.2-week period, and 8000 patients had three visits over a mean 12-week period. Initially, 12 826 (89.4%) patients received nifedipine 30 mg, and 6912 patients (48.2%) overall received concomitant antihypertensive agents. The overall mean reduction in SBP/DBP was -27.7/-14.1 mmHg; BP reduction was linked to hypertension grade, age, the presence of five or more cardiovascular risk factors, and prior treatment. Target BP was achieved in 2485/7432 patients (33.4%) receiving nifedipine GITS/OROS monotherapy and in 1751/6912 (25.3%) receiving combination therapy (i.e. GITS/OROS plus any other antihypertensive agent). Non-diabetic patients with moderate (n = 3413) and high (n = 1138) risk reached their target BP goal in 62.5% and 54.2% of cases, respectively; the corresponding values in diabetic patients (moderate-added risk n = 8; high-added risk n = 684) were 75.0% and 54.8%, respectively. A total of 229 patients (1.6%) reported experiencing 286 adverse events. Physician/patient satisfaction with treatment was high. CONCLUSION: Long-acting nifedipine GITS/OROS, alone or in combination with other antihypertensive agents, provides effective and well tolerated treatment of hypertension in a broad spectrum of patients routinely seen in day-to-day clinical practice. PMID- 21591821 TI - Effect of Thuja occidentalis and its polysaccharide on cell-mediated immune responses and cytokine levels of metastatic tumor-bearing animals. AB - CONTEXT: Tumor microenvironment induces an active immune tolerance and escapes immune surveillance. In order to achieve an effective antitumor immune response, appropriately activated immune cells should maintain their antitumor activity to overcome the immune suppressive tumor microenvironment. OBJECTIVES: This study focuses on the effect of Thuja occidentalis L. (Cupressaceae) extract and its polysaccharide (TPS) on cell-mediated immune response (CMI) in metastasis bearing mice. MATERIALS AND METHODS: Metastasis was induced by injecting B16F-10 melanoma cells in mice through the tail vein and effector mechanisms of CMI was studied by analyzing cytotoxic T-lymphocyte (CTL) activity, natural killer (NK) cell activity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody dependent complement-mediated cytotoxicity (ACC). The effect of T. occidentalis and TPS on pro-inflammatory cytokines and tissue inhibitor matrix metalloproteinases (TIMP) levels were also analyzed. RESULTS AND DISCUSSION: Administration of T. occidentalis and TPS enhanced the NK cell activity, ADCC and ACC much earlier than the control tumor-bearing animals. T. occidentalis and TPS were also found to decrease the elevated level of pro-inflammatory cytokines such as interleukin (IL)-1beta, IL-6, GM-CSF and tumor necrosis factor (TNF)-alpha in the serum of metastatic tumor-bearing animals. The level of antitumor factors such as IL-2 and TIMP was elevated by the treatment with T. occidentalis and TPS in the serum, which was lowered in the untreated tumor-bearing animals. CONCLUSION: This study clearly suggests that T. occidentalis and TPS effectively stimulate cell-mediated immune system and decrease pro-inflammatory cytokines, thereby inhibiting metastasis of tumor cells. PMID- 21591820 TI - Resource utilization and cost of treatment with anidulafungin or fluconazole for candidaemia and other forms of invasive candidiasis: focus on critically ill patients. AB - BACKGROUND: Candidaemia and other forms of invasive candidiasis (C/IC) are serious and costly events for hospitalized patients, particularly those in the ICU. Both fluconazole and the echinocandins are recommended as first-line therapy for C/IC. Resource use and cost considerations are important in selecting appropriate treatment but little information is available on the economic implications of using echinocandins in this setting. OBJECTIVE: To compare resource utilization and treatment costs (in $US) associated with the echinocandin anidulafungin (200 mg intravenously on day 1, then 100 mg intravenously daily) versus those of fluconazole (800 mg intravenously on day 1, then 400 mg intravenously daily) as first-line treatment for C/IC. METHODS: Available charts from patients enrolled in a recent clinical trial comparing anidulafungin and fluconazole for C/IC were reviewed. Patients who were in the ICU at study entry were identified, and the following data, collected during the 13-week study period, were compared between treatment groups: global response at end of study treatment, number of days patients survived after hospital discharge ('hospital-free' days), hospital resource use, and C/IC-related costs (year 2008 values) to a US hospital payer. These comparisons were also conducted for all non ICU hospitalized patients, and for survivors in both study populations. Sensitivity analyses explored the cost impact of variability in the hospitalization costs between ICUs and non-ICU wards and of reduced duration intravenous therapy. Statistical comparisons between the two treatment groups were conducted for clinical outcomes, resource use and cost measures, using regression models. All statistical comparisons were adjusted for baseline co variates (Acute Physiology and Chronic Health Evaluation [APACHE] II score, absolute neutrophil count and catheter removal status). RESULTS: For ICU patients with C/IC (n = 63), global response was significantly higher for anidulafungin than fluconazole (68.6% vs 42.9%; p = 0.03). ICU patients treated with anidulafungin had an average of 13.9 more hospital-free days (18.2 vs 4.3 days; p = 0.04) than those treated with fluconazole. After adjustment for co-variates, although lower costs were observed for anidulafungin vs fluconazole in ICU patients and in ICU patients who survived, no statistical differences were found. For all hospitalized patients (n = 159), global response was also higher for anidulafungin (78.3% vs 60.5%; p < 0.01). There was no difference in average length of hospitalization (29.6 days) or hospital-free days. After adjustment for co-variates, anidulafungin treatment resulted in an incremental C/IC-related cost of $US2680 (p = 0.73). For hospitalized patients who survived (anidulafungin 81.9%, fluconazole 69.7%), anidulafungin treatment was associated with an incremental cost of $US231 (p = 0.98). CONCLUSION: Anidulafungin as first-line treatment of C/IC appears to be of particular benefit to ICU patients, improving clinical outcomes and possibly decreasing costs, driven by reduced ICU and hospital stay, when compared with fluconazole. Anidulafungin also yielded significantly improved treatment outcomes in the general inpatient population, with total costs similar to fluconazole. PMID- 21591822 TI - Putting Indigenous cultural training into nursing practice. AB - The provision of Indigenous cultural training for non-Indigenous health workers has been widely promoted as a method of improving health service provision to 'close the gap' in Indigenous health. However, in the absence of strong evidence, the power of Indigenous cultural training to meaningfully contribute to the health of Aboriginal and Torres Strait Islander peoples remains questionable. This research explored how six hospital-based nurses consider the role of Indigenous cultural training and the impact it has had on their practice through individual semi-structured interviews. Thematic analysis revealed the significance of individual professionals' attitudes in determining the impact of Indigenous cultural training, as well as the need for institutional support to assist in translating Indigenous cultural training into practice. Utilising post colonial theory, two key findings emerge. First, the way in which Indigenous cultural training conceptualises 'identity' and 'culture' is critical to its ultimate outcomes. Second, deficits in institutional support limit the efficacy of Indigenous cultural training by placing the onus for institutional change on the shoulders of individual health workers. PMID- 21591823 TI - Closing the Gap: cultural safety in Indigenous health education. AB - The challenge for the future is to embrace a new partnership aimed at closing the gap between Indigenous and non-Indigenous Australians on life expectancy, educational achievement and employment opportunities. Significant improvements in contemporary Indigenous health care can be achieved through culturally safe health education programs for Indigenous students. However, while participation rates of Australian Indigenous students in the higher education sector are increasing, attrition rates are markedly higher than those of the general student population. This paper focuses on a unique degree program that is offered exclusively to Indigenous students in the field of mental health in the School of Nursing, Midwifery and Indigenous Health, Charles Sturt University. This qualitative exploratory study aimed to identify strategies that were especially helpful in sustaining students in the program and to identify and address barriers to the retention of students, to empower students to better prepare for the university environment and to inform academics within the course about areas that could be improved to provide a more culturally safe learning environment. The first stage of the study utilised focus group interviews with 36 Indigenous students across all three years of the program. The findings of the study addressing the issues of culturally appropriate pedagogy, curricula and cultural safety in the mental health degree program are discussed. PMID- 21591824 TI - Understanding culture in practice: reflections of an Australian Indigenous nurse. AB - Most health care organisations aspire to develop a culturally competent workforce. Australian nurses are bound by professional standards to achieving this goal and there is a clear commitment by lead organisations to deliver nursing care that is mindful about respecting cultural diversity (ANMC, 2005). The development of a nursing workforce that is equipped with knowledge and an embedded attitude of cultural sensitivity and safety is a nursing workforce that will bring about positive change and improved consumer experiences (Chenoweth, Jeon, Goff, & Burke, 2006). This paper will reflect on current discussion about cultural competence from the perspective of an Indigenous nurse, and present a personal learning pathway toward a goal of cultural competence. PMID- 21591825 TI - Tjirtamai--'to care for': a nursing education model designed to increase the number of Aboriginal nurses in a rural and remote Queensland community. AB - In 2009, a nursing education model was locally designed and delivered to support the interest of a group of Aboriginal community members living in a rural and remote town in Queensland, specifically to prepare for entry into further nursing education. Named 'Tjirtamai' by the traditional owners of the area, the program was offered in recognition of the challenges faced by Aboriginal people when they enter nursing education courses and as a way to increase the local number of Aboriginal nurses. This program, while funded by the Government, had unprecedented support and involvement from both the local Aboriginal and wider community. The model offered multiple exit points, assistance with financial and other known challenges for Aboriginal and Torres Strait Islander students, and included contextualised literacy and numeracy. Of the 38 Aboriginal students who enrolled in the course, 26 students completed. Of those students, 18 have since enrolled in a bachelor degree in nursing while another 4 enrolled in a diploma of nursing. This paper provides an overview of the course and its outcomes. PMID- 21591826 TI - Tackling tobacco: a call to arms for remote area nurses. AB - Tobacco-related conditions contribute significantly to the health gap between Indigenous and non-Indigenous Australians. Smoking rates in Australia's Indigenous population has failed to decline even though smoking rates in Australia have declined in general. In some Indigenous communities, smoking rates remain very high. This paper outlines a project to investigate appropriate strategies to assist Indigenous smokers to quit and the important role nurses can play. PMID- 21591827 TI - Identity matters: Aboriginal mothers' experiences of accessing health care. AB - This paper reports on research examining how service providers' perceptions of Aboriginal women's identities contributes to their experiences of accessing preventive care during pregnancy and parenting in an urban setting. An intersectionality paradigm was adopted to conduct a secondary analysis of purposively selected transcripts of exploratory interviews with Aboriginal women. Findings indicate that how Aboriginal women identity as mothers was perceived by service providers was the focal point at which women described positive or negative experiences of accessing care. These conclusions challenge nurses' understandings of developing therapeutic relationships with marginalised populations and highlight the necessity of examining how perceptions of identity shape issues of oppression and discrimination within therapeutic relationships. PMID- 21591828 TI - The experiences of nurses in caring for circumcised initiates admitted to hospital with complications. AB - The circumcision of males is a ritual that is performed in the veld, out of the public eye. Traditionally, it has to be attended by circumcised men only; no one is allowed to see the initiates before they are officially released or discharged. In recent times, initiates have been admitted to hospitals following complications during the circumcision process. In the hospitals, they are cared for by nurses. Hospitalisation of initiates creates problems for the elders who accompany the initiates as well as the nurses who are expected to care for them. The purpose of the study was to explore and describe the experiences of nurses who care for initiates who have been admitted into hospital with medical and physical complications. A qualitative approach was adopted for this study, and the data was collected by means of unstructured interviews. A purposively selected sample of nurses of different categories from a rural hospital in the Nkangala district in Mpumalanga Province, South Africa, participated in the study. The data was analysed, and five major categories were developed. The major categories were: conflicting cultural practices, emotions, common complications, ethical issues and possible solutions. Based on the findings of the study, it is recommended that traditional circumcision should be regulated to avoid complications that lead to the admission of initiates into hospitals. Also, a collaborative partnership should be established between the health institutions and the traditional surgeons and healers in caring for initiates. PMID- 21591829 TI - Exploring indigenous health using the clinical reasoning cycle: a student paper. AB - As a requirement for a third year nursing subject based on Australian Indigenous Health and Community Nursing, an assessment was undertaken based on the clinical reasoning cycle. The clinical reasoning cycle refers to clinical judgements and clinical decision-making which can be conceptualised as a logical process of cue collection, processing information, understanding the situation, planning and implementing interventions, evaluating outcomes and reflecting on the process (Levett-Jones et al., 2009). The clinical reasoning cycle for this assessment relates to interactions with Murray (pseudonym), an Australian Indigenous male being treated for alcohol dependence within a community setting. This paper will explore the nursing care of Murray through the clinical reasoning cycle, focusing on community-based, culturally appropriate nursing care. PMID- 21591830 TI - The best bang for our buck: recommendations for the provision of training for tobacco action workers and Indigenous health workers. AB - While smoking rates among Australians in general have declined over the past two decades, rates for Aboriginal Australians have remained high and continue to contribute to the overall poor health of Aboriginal people. Aboriginal health workers are proposed as one way to help reduce smoking rates for Aboriginal people however there is a need for specifically developed courses to train health workers to deliver smoking interventions. PMID- 21591831 TI - Indigenous community participation: how does it relate to student centered learning and embrace primary health care philosophies? AB - The health and well-being of Indigenous Australians has been identified as a critical problem with high levels of chronic illness, morbidity and mortality compared to other Australian population groups. However, as health professionals we continue to discuss and theorise components of Indigenous health addressing issues in a piecemeal way. The concept of primary health care has been shown to have an independent effect on improving the health status of populations and having the ability to reduce health inequalities. Countries with well developed primary care systems have healthier populations and reduced health care costs (Macinko et al., 2003, p. 407). Primary health care combined with a community holistic approach and the defined use of student centered learning in Indigenous education has the potential to provide optimal health care and thus be an effective way to improve Indigenous Community health (McMurray, 2003, p. 296). PMID- 21591832 TI - Two Aboriginal registered nurses show us why black nurses caring for black patients is good medicine. AB - In Queensland, Aboriginal nurses are limited in number in comparison to the mainstream nursing workforce. More Aboriginal registered nurses are needed to cater for Aboriginal patients in our Australian healthcare system in view of today's burgeoning Indigenous health crisis. It is a foregone conclusion that Aboriginal nurses are the most suitable nurses to provide optimal cross cultural care for Aboriginal patients, due to having similar cultural backgrounds. The following paper will show how two Aboriginal registered nurses are optimistic about the possibilities of expanding the ranks of Aboriginal registered nurses through role modelling, and are channelling their research to achieve this with the aim of promoting better health outcomes for their people. A qualitative research approach has been used to examine the subjective human experience of the participants. Three dominant themes emerged from the research and will be expanded upon within the body of this paper to support the authors' thesis that Aboriginal nurses are a valuable commodity to address the Aboriginal health crisis. PMID- 21591833 TI - Indigenous higher degree research students making a difference to the Indigenous health agenda. AB - While research has been seen to perpetuate rather than improve the ongoing health disadvantage of Indigenous Australians, more recently we have witnessed a transformation in the way research is undertaken with Indigenous people. A more collaborative and inclusive approach has made research more appropriate to the needs of Indigenous people and more Indigenous people undertaking higher degree research study. Insights about research with Indigenous people are provided by four Indigenous students undertaking research in health and nursing who discuss 'closing the gap', cultural care, and the current situation surrounding access to and experiences in the health service in Australia for Indigenous people. PMID- 21591834 TI - Antihyperlipidemic activity of Ichnocarpus frutescens in triton WR-1339-induced and high-fat diet animals. AB - CONTEXT: Ichnocarpus frutescens (L.) R.Br. (Apocynaceae) is used to treat diabetes and hyperlipidemia in folk medicine. OBJECTIVE: The crude methanol extract and fractions of I. frutescens were investigated for antihyperlipidemic effect. MATERIALS AND METHODS: Fresh leaves of I. frutescens were extracted with methanol and fractionated with hexane, benzene, ethyl acetate, acetone, and methanol. The active acetone fraction was subfractionated, which resulted in active fraction 3. The antihyperlipidemic effects of the methanol extract and fractions of I. frutescens were studied in triton WR-1339-induced and high-fat diet (HFD) obese animals. Further, lipid absorption and excretion were studied. RESULTS AND DISCUSSION: The methanol extract significantly reduced total cholesterol (TC) by 29.63% and triglyceride (Tg) by 51.10% at 400 mg/kg in triton WR-1339-induced animals and significantly reduced TC (27.81%) and Tg (37.03%) at 400 mg/kg in HFD animals. Fraction 3 showed significant reduction in TC (25.03%) and Tg (58.05%) at 200 mg/kg. Feeding of HFD consisting 3% of fraction 3 increased feces weight and Tg level in mice. Fraction 3, showed significant decrease in plasma Tg level at the second hour, after oral administration of the lipid emulsion to rats. CONCLUSION: The observed properties apparently validate the folk medicinal use of this plant in amelioration of hyperlipidemia. PMID- 21591836 TI - Infants' symptoms of illness assessed by parents: impact and implications. AB - OBJECTIVES. Some parents with a sick infant contact a doctor, while others do not. The reasons underlying such parental decisions have not been thoroughly studied. The purpose of this study was to explore how the actual symptoms in the infant were associated with parent-rated illness, illness severity, and the probability of the parents contacting a doctor. DESIGN. A retrospective questionnaire and a prospective diary study covering 14 months of the participating infants' lives. SETTING AND SUBJECTS. The 194 participating infants were followed for three months prospectively from the age of 11 to 14 months using diary cards, and retrospectively from birth until the age of 11 months by a questionnaire. RESULTS. During the three months of the diary card prospective follow-up, the infants had symptoms on average every second day, and the vast majority (92%) had 10 or more days with at least one symptom; 38% of the infants were reported to have had five or more symptoms for more than five days. Fever, earache, and vomiting were the symptoms most likely to cause parents to rate their infant as ill. Earache was the symptom that triggered doctor contact most immediately. The parent-rated illness severity was strongly related to the tendency to contact a doctor. However, this association was markedly weaker when adjustment was made for the infant not eating normally, having a cough, or running a fever. CONCLUSION. Specific symptoms such as fever, earache, and vomiting were strongly associated with the probability of parents rating the infant as ill. An earache would cause the parents to contact a doctor. Fever and vomiting were other symptoms triggering doctor contacts. First, these symptoms could cause the parents to want a doctor's expert evaluation of the infant's illness; second, the parents could expect medication to be necessary; or third, it could just be difficult for the parents to handle the ill infant. PMID- 21591837 TI - ENT problems in Dutch children: trends in incidence rates, antibiotic prescribing and referrals 2002-2008. AB - BACKGROUND. Ear, nose, and throat (ENT) problems are common in childhood and are important reasons to visit the general practitioner. OBJECTIVE. To examine trends in incidence rates, antibiotic prescribing, and referrals of five common ENT problems in children. DESIGN. Netherlands Information Network of General Practice (LINH), a nationally representative general practice database. Setting. A total of 50 000 children, aged 0-17 years, registered in Dutch general practice over the period 2002-2008. METHODS. Incidence rates were calculated and trends were analysed using linear regression analysis, with incidence rates per age group, proportion treated with antibiotics, and referrals as dependent variables and year of observation as independent variable. RESULTS. In general, incidence rates of acute otitis media, serous otitis, sinusitis, tonsillitis, and tonsil hypertrophy remained stable over the period 2002-2008. An increasing trend was observed for serous otitis media in children aged 0-4 years (RR = 1.04, p < 0.001). A decreasing trend was observed for sinusitis in children aged 5-11 and for tonsillitis in children aged 11-17 years (RR 0.99, p < 0.001 and RR 0.94, p < 0.001, respectively). Antibiotics were prescribed in 10-60% of the diagnoses. An increasing trend for antibiotic prescription was found for acute otitis media (beta = 0.07, p < 0.001), mainly on account of amoxicillin. Although antibiotic treatment of tonsillitis remained stable, pheneticillin prescriptions showed a downward trend (beta = -0.10, p < 0.001). First-choice antibiotics were prescribed in >80% of cases. CONCLUSIONS. This study showed remarkably stable trends in incidence rates, antibiotic prescribing, and referrals of common ENT problems. The low proportion of antibiotic treatment in ENT problems did not show negative consequences. PMID- 21591839 TI - Treatment of acute asthma. PMID- 21591838 TI - Silymarin selectively protects human renal cells from cisplatin-induced cell death. AB - CONTEXT: Cisplatin-induced nephrotoxicity has been accepted as an important obstacle for efficient cisplatin-based chemotherapy. Silymarin from seeds of milk thistle [Silybum marianum L. (Asteraceae)] has been shown to possess various potential pharmacological properties; however, whether or not this agent selectively protects renal cells from cisplatin-induced cell death with no interfering effect on cancer cells is not clear. OBJECTIVE: Potential of silymarin in protection of cisplatin-induced renal cell death without compromising effect on anticancer activity of cisplatin was demonstrated in this study. MATERIALS AND METHODS: Cisplatin-induced cell death was evaluated in human proximal tubular HK-2, lung carcinoma H460, and melanoma G361 cells using MTT, Hoechst 33342, and propidium iodide assays. RESULTS: Cisplatin induced both apoptosis and necrosis in HK-2 cells and caused a decrease in cell viability by ~40% and 60% at the doses of 25 and 100 uM, respectively. Pretreatment with 25 200 uM of silymarin significantly protected against cisplatin-induced cell death in a dose-dependent manner. In contrast, pretreatment of silymarin (25-100 uM) caused no significant change on cisplatin-induced cell death in H460 cells but significantly potentiated cisplatin-induced apoptosis in G361 cells. DISCUSSION AND CONCLUSION: These findings reveal the selectivity of silymarin in protection of renal cells from cisplatin-induced cell death and could be beneficial for the development of this considerately safe compound as a renoprotective agent. PMID- 21591840 TI - Anticandidal activity of Cassia fistula and its effect on ergosterol biosynthesis. AB - CONTEXT: Cassia fistula Linn. (Caesalpiniaceae) has been used in folk medicine. Anthraquinone derivative rhein having antimicrobial properties is actively present in C. fistula fruit. Although, as yet there has been no study of its anticandidal potential. OBJECTIVE: The present study was conducted to determine the phytochemical composition of fruit pulp and seed extract and their effect on Candida albicans ATCC 10261, Candida glabrata ATCC 90030 and Candida tropicalis ATCC 750, respectively. MATERIALS AND METHODS: The fruit pulp and seed extracts were tested for phytochemicals by various standard methods and rhein was identified by thin-layer chromatography. The anticandidal activity was determined by minimum inhibitory concentration (MIC), growth curve studies, cytotoxicity and ergosterol estimation assay. RESULTS: The fruit pulp and seed extracts showed high content of phenolic compounds. Rhein was identified in both extracts, Rf 0.38. MICs of seed extract obtained with C. albicans, C. tropicalis and C. glabrata is 350, 300 and 300 MUg/ml. However, for fruit pulp extract, these values significantly reduced to 150, 250 and 100 MUg/ml, respectively. Comparative MIC values for fluconazole were 16, 16 and 04 ug/ml. At MICs, pulp reduced ergosterol content in cell membrane of C. albicans, C. tropicalis and C. glabrata by 54.42, 48.78 and 68.0%, seed extract by 38.11, 47.0 and 45.0%, whereas, fluconazole showed 93.56, 89.21 and 98.0%, respectively. DISCUSSION AND CONCLUSION: C. fistula fruit pulp and seed extract possessed anticandidal activity. The result was significantly correlated between the MICs, cytotoxicity and ergosterol inhibition. It was concluded that the crude extract is a promising source for anticandidal compounds. PMID- 21591841 TI - Drug delivery systems in the treatment of African trypanosomiasis infections. AB - INTRODUCTION: Animal African trypanosomiasis (AT) is treated and controlled with homidium, isometamidium and diminazene, whereas human AT is treated with suramin, pentamidine, melarsoprol and eflornithine (DFMO), or a combination of DFMO and Nifurtimox. Monotherapy can present serious side effects, for example, melarsoprol, the more frequently used drug that is effective for both hemolymphatic and meningoencephalic stages of the disease, is so toxic that it kills 5% of treated patients. These treatments are poorly efficient, have a narrow safety index and drug resistance is a growing concern. No new drug has been developed since the discovery of DFMO in the 1970s. There is a pressing need for an effective, safe drug for both stages of the disease, and recent research is focused on the development of new formulations in order to improve their therapeutic index. AREAS COVERED: This review shows the potential interest of using nanoparticulate formulations of trypanocidal drug to improve parasite targeting, efficacy and, potentially, safety while being cost-effective. EXPERT OPINION: The design of drug formulations relevant to the treatment of AT must include a combination of very specific properties. In summary, the drug delivery system must be compatible with the physicochemical properties of the drug (charge, lipophilicity and molecular mass) in order to allow high drug payloads while being biocompatible for the patient. PMID- 21591843 TI - Cognitive development and Down syndrome: age-related change on the Stanford-Binet test (fourth edition). AB - Growth models for subtests of the Stanford-Binet Intelligence Scale, 4th edition ( R. L. Thorndike, E. P. Hagen, & J. M. Sattler, 1986a , 1986b ) were developed for individuals with Down syndrome. Models were based on the assessments of 208 individuals who participated in longitudinal and cross-sectional research between 1987 and 2004. Variation in performance among individuals was large and significant across all subtests except Memory for Sentences. Scores on the Memory for Sentences subtest remained low between ages 4 to 30 years. Greatest variation was found on the Pattern Analysis subtest, where scores continued to rise into adulthood. Turning points for scores on the Vocabulary and Comprehension subtests appeared premature relative to normative patterns of development. The authors discuss development at the subdomain level and analyze both individual and group trajectories. PMID- 21591844 TI - Sexual understanding and development of young people with intellectual disabilities: mothers' perspectives of within-family context. AB - The sexual development of young people with intellectual disabilities is a marker of their transition to adulthood and affects their sense of well being and identity. Cognitive impairments and a socially marginalized position increase dependence on their families to assist with sexual matters. In this study, the authors adopted a novel interpretive phenomenological analysis approach, asking 8 mothers to contrast their experience of supporting similarly aged siblings with and without intellectual disabilities. Acknowledgment of their nondisabled offspring's sexuality was demanded by increasing autonomy, whereas continuing dependence of the offspring with intellectual disabilities hindered mothers who were addressing this intensely private and sensitive issue with them. The topic of sexuality brought to the forefront mothers' fears about their offspring's ability to cope with the challenges of adulthood. PMID- 21591845 TI - Physical activity benefits and needs in adults with intellectual disabilities: systematic review of the literature. AB - Regular physical activity is vital for adult individuals with intellectual disabilities. The purpose of this review was to assess critically the evidence on effectiveness of physical activity interventions for adults with intellectual disability. An electronic database search was conducted. Research was then assessed for methodological rigor, and strength of the evidence was determined. Eleven clinical studies met inclusion criteria. Interventions studied included a variety of physical activity modes. Critical review revealed moderate to strong evidence that physical activity positively affected balance, muscle strength, and quality of life in individuals with intellectual disability. The authors also found that the research in this area needs to be translated into practice, specifically the development of physical activity programs that are adaptable to the needs of individuals with intellectual disability. PMID- 21591846 TI - Subsequent births in families of children with disabilities: using demographic data to examine parents' reproductive patterns. AB - The authors determined family reproductive patterns after the birth of a child with (vs. without) a disability. Using Tennessee birth records, the authors examined families of children with Down syndrome (N = 1,123), spina bifida (N = 368), and population group (N = 734,189). Families of children with Down syndrome and with spina bifida were more likely to have subsequent children and larger family sizes than the population group. When a 1st-born target child was born, 28.8% of families had a 2nd child in the population group compared with 37.1% and 45.7% when the child had spina bifida or Down syndrome, respectively. Families of children with disabilities were more likely to have subsequent children regardless of maternal race, marital status, and educational level. PMID- 21591847 TI - Modeling the social determinants of caregiver burden among families of children with developmental disabilities. AB - This study described predictors of caregiver burden among parents of children with developmental disabilities. The sample, obtained from the 2005-2006 National Survey of Children With Special Health Care Needs, included 12,225 children, aged 5 to 17 years, with a developmental disability. Structural equation modeling assessed the relationships between the factors of Caregiver Burden, Ease of Accessing and Navigating the Health Care System, and Unmet Health Care Needs. Caregiver burden was inversely associated with ease of accessing and navigating the health care system (beta = -0.094, SE (beta) = 0.045) and positively associated with unmet health care needs (beta = 0.428, SE (beta) = 0.036). Parents of poor, minority, and uninsured children experienced significantly greater caregiver burden. Bolstering services, particularly for vulnerable families, may ameliorate caregiver burden. PMID- 21591849 TI - Aurora kinase inhibitor patents and agents in clinical testing: an update (2009 10). AB - INTRODUCTION: Mitosis is a key step in the cell cycle and is controlled by several cell cycle regulators, including aurora kinases. Aurora family members A, B and C are essential for spindle assembly, centrosome maturation, chromosomal segregation and cytokinesis. Overexpression/amplification of aurora kinases has been implicated in oncogenic transformation, including the development of chromosomal instability in cancer cells. Hence, the use of aurora kinase small molecule inhibitors as a potential molecular-targeted therapeutic intervention for cancer is being pursued by various researchers. AREA COVERED: This review provides an update on aurora kinase inhibitors based on developments from 2009 to 2010. The medicinal chemistry aspects of aurora kinase inhibitors, with a particular emphasis on the patent literature, are reviewed. Databases such as PubMed, SCOPUS(r), Scifinder(r) and www.clinicaltrials.gov database were used to search for literature in the preparation of this review. EXPERT OPINION: Around a dozen aurora kinase inhibitors are currently undergoing various Phase I-II evaluations for different human cancers. Instead of being applied as a monotherapy, combinations of aurora kinase inhibitors and existing chemotherapeutic compounds seem to give better therapeutic outcomes and are, therefore, a promising future cancer therapy. PMID- 21591851 TI - Patient experience and satisfaction with awake craniotomy for brain tumours. AB - Awake craniotomy is increasingly used to facilitate safe maximal resection of brain tumours. Very little published data is available to determine patient experiences and satisfaction. This knowledge may lead to improvement in technique and enhance future patient care. In 2006, we began to use conscious sedation ('full awake technique') for craniotomies for tumour resection. A questionnaire designed with reference to Royal College of Surgeons (RCS) guidelines was sent out to 60 consecutive patients. Four areas of care were explored. These included the out-patient consultation with the neurosurgeon, anaesthetic consultation, operation and the post-operative period. Fourty-five responses were received. Ninety-three percent of the patients in our study felt involved sufficiently in the decision for awake surgery and felt they were given enough information when seen in the surgical consultation. However, only 64% of patients received written information in advance of their surgical date. Ninety-one percent of patients were confident that they would be looked after during surgery following their anaesthetic consultation. Eighty-seven percent of patients felt at ease during surgery. Twenty-four percent experienced some discomfort during surgery, some of which was related to positioning of the patient rather than surgical technique. Fifty-six percent of our patients reported no post-operative pain. Eighty-four percent of patients were happy with timing of their discharge. Eighty percent felt well supported post-discharge. This study demonstrates high levels of patient satisfaction and provides surgeons with useful data for consenting patients. We identified no difference in levels of patient satisfaction comparing day-case patients with those admitted. We identified areas for improvement including provision of written information, enhancing post-discharge support and allowing more time for anaesthetic discussion before surgery. PMID- 21591852 TI - Primary gliosarcoma--clinical experience from a regional cancer centre in north India. AB - AIMS: We intended to assess the clinicopathological features and treatment outcome in patients of primary gliosarcoma, a rare malignant brain tumour. MATERIALS AND METHODS: Medical records were reviewed and data collected on primary gliosarcoma over an 8-year period (2002-2009) from the departmental archives. Overall survival (OS) was analysed by Kaplan-Meier method. RESULTS: Seventeen patients met the study criterion (male:female = 9:8). Median age and performance status at presentation were 50 years and Karnofsky performance scale (KPS) 70, respectively. Symptoms of raised intracranial tension (in 100%) and motor impairment (in 64.7%) were commonly observed. Tumour location was frontal in four patients, temporal in three, parietal in three, thalamic in one, multilobed in five and multicentric in one. All patients underwent maximal safe surgery (total excision-10, near-total excision-2, subtotal excision and decompression-5). On histopathology, all tumours showed biphasic pattern, glial component positive for glial fibrillary acidic protein (GFAP) and mesenchymal component positive for vimentin and reticulin. Atypia, mitoses, necrosis and endothelial proliferation were identified in the glial component. Post-operative radiotherapy (median dose--60 Gy/30#/6 weeks) was used in 15 patients (88.2%). Concurrent and adjuvant chemotherapy with temozolomide (TMZ) were used in two patients depending upon affordability. After the completion of treatment, 35.3% patients were asymptomatic, 23.5% had symptomatic improvement, while 41.2% deteriorated. Salvage therapy for local recurrence was used in three patients (temporal lobectomy-1; total excision-1; TMZ+bevacizumab-1). At last follow-up (FU), eight patients were alive, seven patients dead and two patients lost to FU with symptom. Median overall survival in the evaluable patients (N = 15) was noted to be 8.27 months (6 month survival 60.76%). CONCLUSIONS: Primary gliosarcoma, a variant of glioblastoma poses clinical challenge because of rarity, poor prognosis and limited experience. In our centre, principle of therapy is akin to that of glioblastoma--surgery followed by radiation along with concurrent and adjuvant TMZ. However, chemotherapy is often cost-prohibitive in our setting as mirrored by limited use (17.6%). Median survival of only 8.27 months in our series is in concert with the existing survival result of primary gliosarcoma in world literature (6.25-11.5 months). PMID- 21591853 TI - Difficulties with recruiting into neurosurgical clinical trials: Surgical Trial in IntraCerebral Haemorrhage II as an example. PMID- 21591854 TI - Paraplegia due to drop metastases from anaplastic oligodendroglioma. AB - In this article, we report on a rare case of spinal seeding from a cerebral anaplastic oligodendroglioma presenting with signs of medullar compression. We discuss the prevalence, mechanisms and imaging findings of spinal seeding in various gliomas. A suitable clinical treatment and follow up for these patients is suggested. PMID- 21591855 TI - Pseudomeningocele presenting with cauda equina syndrome: is a 'ball-valve' theory the answer? AB - Pseudomeningocele is an uncommon complication of spinal surgery. The condition is most often asymptomatic and self-limiting. A proportion of patients may present with lower back pain, dural fistulas, radiculopathy or myelopathy. Cauda equina syndrome due to a pseudomeningocele has been reported due to herniation of the Cauda equina roots through the dural defect. We report a case of large pseudomeningocele causing an impending Cauda equina syndrome by acting as an extradural mass lesion. PMID- 21591856 TI - Depression and post-traumatic stress disorder after aneurysmal subarachnoid haemorrhage in relation to lifetime psychiatric morbidity. AB - INTRODUCTION: Little is known about the roles that lifetime psychiatric disorders play in psychiatric and vocational outcomes of aneurysmal subarachnoid haemorrhage (SAH). MATERIALS AND METHODS: Eighty-three SAH patients without apparent cognitive dysfunction were assessed using the Structured Clinical Interview for DSM-IV axis I disorders (SCID-I) after their SAH. Diagnoses were assessed for three time periods, 'lifetime before SAH', '12 months before SAH' and '7 months after SAH'. RESULTS: Forty-five percentage of patients with SAH reported at least one lifetime psychiatric disorder. After SAH, symptoms of depression and/or post-traumatic stress disorder (PTSD) were seen in 41%, more often in those with a psychiatric history prior to SAH (p = 0.001). In logistic regressions, depression after SAH was associated with a lifetime history of major depression, or of anxiety or substance use disorder, as well as with lifetime psychiatric comorbidity. Subsyndromal or full PTSD was predicted by a lifetime history of major depression. After the SAH, 18 patients (22%) had received psychotropic medication and/or psychological treatment, 13 of whom had a disorder. Those with a lifetime history of major depression or treatment with antidepressants before SAH had lower return to work rates than others (p = 0.019 and p = 0.031, respectively). This was also true for those with symptoms of depression and/or PTSD, or with antidepressant treatment after SAH (p = 0.001 and p = 0.031, respectively). CONCLUSIONS: Depression and PTSD are present in a substantial proportion of patients 7 months after SAH. Those with a history of psychiatric morbidity, any time before the SAH, are more at risk and also constitute a risk group for difficulties in returning to work. PMID- 21591857 TI - Prospective study of outcome of foramen magnum decompressions in patients with syrinx and non-syrinx associated Chiari malformations. AB - OBJECTIVE: To assess the outcome in patients with syrinx and non-syrinx associated Chiari malformations undergoing Foramen Magnum Decompression (FMD). METHODS: Sixty-one patients undergoing FMD for Chiari malformations were prospectively studied with disease specific, generic (SF 36) and subjective (patient reported) outcomes. Of these, 34 patients had objective outcome data including SF36, visual analogue pain scores, Neck and Myelopathy disability indices and the Hospital anxiety and depression score. SF 36 scores were compared to normative data. Data were collected pre-operatively, at 3 months and during long-term follow up (12-60 months). RESULTS: Patient reported improvements in headache and neck pain post-operatively was reported in both syrinx and non syrinx associated patients. Visual Analogue scores showed improvements in arm pain, paresthesia and hand tingling at 3 months in the syrinx group only. Non syrinx patients showed significant improvements post-operatively in the Neck disability index and the SF-36 domains for physical function, role physical and bodily pain. Comparison with SF-36 normative data indicates that patients still have significantly impaired quality of life 12 months post-operatively. CONCLUSION: FMD is able to relieve symptoms and improve quality of life in patients with both syrinx and non-syrinx associated Chiari malformations. In syrinx patients we observed symptomatic improvement in limb symptoms as well as radiological resolution of the syrinx. The use of SF-36 allows the health gain associated with FMD to be quantified. SF 36 is not adequate as a stand alone measure of outcome in this complex disorder and we advocate the concurrent use of disease specific measures and post-operative imaging of the syrinx. PMID- 21591858 TI - Involvement of interleukin 18 in lens opacification of Otsuka Long-Evans Tokushima Fatty rats, a model of human type 2 diabetes. AB - PURPOSE: Mature interleukin 18 (IL-18) leads to the production of interferon gamma, nuclear factor kappa B, and inducible nitric oxide synthase, and we previously reported that the enhancement of IL-18 in lens of hereditary cataract model rats was involved in lens opacification. In this study, we investigated whether the expression of IL-18 relates to lens opacification in Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. METHODS: Male Long-Evans Tokushima Otsuka (LETO) and OLETF rats at 60 weeks of age were used in this study. Expression of IL-18 mRNA was measured by quantitative real time RT-PCR method, and IL-18 and interferon-gamma levels were determined using the ELISA method. The transparency of the lenses was monitored using an EAS-1000, and analyzed by image analysis software connected to the EAS-1000. RESULTS: The plasma levels of glucose, triglycerides and cholesterol in the OLETF rats were significantly higher than in LETO rats as normal controls, and the development of diabetes mellitus was observed. The gene expression levels causing IL-18 activation (IL-18, IL-18 receptor, and caspase-1) are increased at 60 weeks of age, and the levels of IL-18 and interferon-gamma in 60-week-old OLETF rat lenses were also higher than those in the 60-week-old LETO rat. Furthermore, the interferon-gamma levels increased with increasing IL-18 levels in the lenses of OLETF rat, and a close relationship was observed between the levels of IL-18 and opacity. CONCLUSION: The expression of IL-18 was increased in the lenses of OLETF rat. It is possible that activated IL-18 in the lenses of OLETF rat may be related to the lens epithelial cell apotosis and lens opacification. PMID- 21591859 TI - Two-year outcome of partial lacrimal punctal occlusion in the management of dry eye related to Sjogren syndrome. AB - PURPOSE: To analyze the influence of thermal partial punctal occlusion on the ocular surface of dry eye related to Sjogren syndrome. MATERIAL AND METHODS: Thirty-seven eyes of 19 patients (3 male and 16 female; 49.11 +/- 14.33 years old) with keratoconjunctivitis sicca were enrolled in this study. Superior and inferior partial occlusion were performed in both eyes under topical anesthesia using thermal cautery with a sterile tip to obtain lacrimal punctum smaller than 0.5 mm. Schirmer I, break-up-time, diameter of lacrimal puncta, corneal fluorescein, and rose Bengal staining scores were analyzed before and after 24 weeks and after 24 months of the procedure. All measurements were performed under controlled climate. RESULTS: The average lacrimal punctum diameter before the procedure was 0.65 +/- 0.134 mm. All lacrimal puncta were successfully reduced to less than 0.5 mm after 4 weeks of the procedure. The average Schirmer I test values improved statistically after 24 weeks and maintained stable after 24 months. Average break-up-time, rose Bengal, and fluorescein staining score values improved statistically after 24 weeks and improved even more after 24 months. Average Schirmer I test, break-up-time, rose Bengal, and fluorescein staining scores showed significant improvement (p < 0.0001) after 24 months of partial thermal punctal occlusion. CONCLUSION: Our study showed that reducing the punctum diameter to 0.5 mm can improve vital staining scores, break-up-time, and Schirmer I test in dry eye related to Sjogren syndrome. PMID- 21591860 TI - Spontaneous high myopia in one eye will affect the development of form deprivation myopia in the fellow eye. AB - PURPOSE: Whether there is an interaction between eyes of individual subjects in refractive development is an important issue to guide experimental designs and help understand mechanisms involved in development of refractive errors. This study investigated whether spontaneous high myopia in one eye will affect refractive development of the fellow eye treated with form deprivation. METHODS: Thirty-four guinea pigs were divided into four groups: MD (monocularly form deprived animals with a pre-treatment anisometropia <= 2D, n = 8), anisometropic MD (monocular form deprivation on a relatively hyperopic eye in animals with a pre-treatment anisometropia >= 10D, n = 9), normal control (non-form deprivation in animals with a pre-treatment anisometropia <= 2D, n = 8), and anisometropic control (non-form deprivation in animals with a pre-treatment anisometropia >= 10D, n = 9). All eyes in different groups underwent biometric measurements on days 0, 12, 24, and 36 of the experiment. RESULTS: High myopia in one eye reduced form deprivation myopia in the fellow treated eye. The change in refraction from 0 to 36 days in the deprived eyes was -3.07D for the MD group, but -1.22D for the anisometropic MD group (-3.07D vs. -1.22D: p = 0.009, independent sample t-test). The amount of vitreous chamber lengthening over the same period in the deprived eyes was 0.19 mm for the MD group, but 0.12 mm for the anisometropic MD group (0.19 mm vs. 0.12 mm: p = 0.038, independent sample t-test). Myopic development in the anisometropic animals is mainly inhibited within the first 12 days compared to normal MD animals. CONCLUSIONS: These results indicate that an interaction in refractive development may exist temporarily between two eyes of a highly anisometropic animal if the visual environment has been changed. PMID- 21591861 TI - Tear meniscus analysis with Fourier-domain optical coherence tomography in keratoconus. AB - PURPOSE: To measure the lower tear meniscus dynamics with Fourier domain-optical coherence tomography (FD-OCT) in keratoconus patients without dry eye findings to evaluate the effects of the corneal ectasia on lower tear meniscus parameters, and to determine the most affected meniscus variable from the corneal ectasia in keratoconus. METHODS: Prospective, clinical study. Forty-one eyes of 25 keratoconus patients without dry eye and 40 eyes of 20 healthy subjects were included. The lower tear meniscus analysis with FD-OCT, and corneal topography, keratometry, and pachymetry measurements were performed in all eyes. The main outcomes, including the lower tear meniscus height (TMH), depth (TMD), area (TMA), and angle between cornea and the tear meniscus (alpha-angle), were assessed. The results were compared between the patients and the control subjects. RESULTS: The average keratometric power was 53.94 +/- 5.76 D (between 44.46 to 63.75 D) in keratoconic eyes. It was 43 +/- 0.8 D (between 40.50 to 45.94 D) in the controls. The average TMH, TMD, and TMA values did not show any statistically significant difference between the patients and the controls (p = 0.39, p = 0.824, p = 0.516, respectively). However, the average value of the alpha-angle was significantly higher in keratoconic eyes when compared to controls (p = 0.031). It was positively correlated with the keratometric power (r = 0.577, p = 0.001). CONCLUSIONS: The TMH, TMD, and TMA did not show any change with the corneal protrusion; however, the alpha-angle had positive correlation with the keratometric power in keratoconic eyes. PMID- 21591862 TI - Predictability of vitreous detachment following intravitreal plasmin injection in diabetic macular edema associated with vitreomacular traction. AB - PURPOSE: To assess preoperative factors associated with postoperative posterior vitreous detachment (PVD) following intravitreal autologous plasmin injection in diabetic macular edema associated with vitreomacular traction. METHODS: Twenty five eyes with diabetic macular edema associated with vitreomacular traction as documented with optical coherence tomography were included. Approximately 0.2 IU/0.2 ml of autologous plasmin was injected intravitreally. Condition of the posterior vitreous face (degree of detachment, thickness, reflectivity, and diameter of attached vitreous base) was evaluated preoperatively and postoperatively up to 3 months. RESULTS: PVD was achieved in ten eyes (41.7%). There was a significant difference (P = 0.03) in mean posterior vitreous face thickness between the eyes with PVD and the eyes with failed PVD. There was a significant correlation between PVD and both posterior vitreous face thickness (P < 0.03%) and degree of posterior vitreous face reflectivity (P = 0.002). CONCLUSION: In diabetic eyes with vitreomacular traction, the prediction of PVD after plasmin injection is governed by the condition of posterior vitreous face; mainly posterior vitreous face thickness and reflectivity. Eyes with thinner, less reflective posterior vitreous face are more likely to develop PVD. PMID- 21591863 TI - Connective tissue growth factor and tissue inhibitor of matrix metalloproteinase 2 in patients with exfoliative glaucoma. AB - PURPOSE: To investigate the aqueous humor levels of connective tissue growth factor (CTGF), matrix metalloprotinease-2 (MMP-2), and tissue inhibitor of matrix metalloprotinease-2 (TIMP-2) in human eyes with exfoliative glaucoma, primary open-angle glaucoma, and senile cataract patients. PATIENTS AND METHODS: This was a prospective, comparative study. Sixty patients with glaucomas and 25 patients with senile cataract of matched age and gender were enrolled in this study. Patients were classified into three groups: group I comprised 30 patients with exfoliative glaucoma (XFG), group II comprised 30 patients with primary open angle glaucoma (POAG), and group III comprised 25 patients with senile cataract (controls). Aqueous humor samples were obtained by paracentesis at the time of elective surgery for glaucomatous and cataractous patients. CTGF, MMP-2, and TIMP 2 were measured in aqueous humor by specific enzyme linked immunosorbent assay (ELISA) kits, and total aqueous humor protein content was assessed by the Lowry method. RESULTS: There were significant increases in aqueous humor levels of CTGF and TIMP-2 in XFG patients compared to the corresponding values of POAG patients or controls. The MMP-2 aqueous humor level was significantly increased in the XFG patients when compared with controls (P < 0.001). Moreover, the total protein level in the aqueous humor of eyes of the XFG patients was significantly higher than in POAG patients or controls (P < 0.001). A positive correlation was found between CTGF and MMP-2 in aqueous humor samples of XFG patients (P < 0.001). CONCLUSION: Increased levels of aqueous humor of CTGF and TIMP-2 may promote the abnormal extracellular matrix accumulation and may be involved in the pathogenesis of XFG. PMID- 21591864 TI - Epithelial membrane protein-2 (EMP2) and experimental proliferative vitreoretinopathy (PVR). AB - PURPOSE: Proliferative vitreoretinopathy (PVR) is believed to result in part from de-differentiation of retinal pigment epithelium (RPE) with cellular migration in the vitreous cavity, membrane formation, and contraction in an aberrant wound healing strategy. In an in vitro collagen-gel contraction assay, epithelial membrane protein 2 (EMP2) controls contraction through activation of focal adhesion kinase (FAK) in a RPE cell line (ARPE-19). The purpose of this study was to investigate how blocking or altering the level of EMP2 expression changed clinical PVR in an in vivo model. METHODS: Using the ARPE-19 cell line, the levels of EMP2 modulated through stable transfections of an EMP2 overexpressing construct, EMP2 ribozyme, or vector alone. These transfected cell lines were used in a rabbit model of PVR. The severity of PVR was classified by two masked observers. An EMP2 blocking antibody was also used to decrease functional EMP2 in the PVR model. Immunohistochemistry was used to evaluate EMP2 expression in vivo. RESULTS: The transfectants with lower levels of EMP2 had significantly less PVR severity than the degree of PVR induced by wild-type cells (p = 0.05). Also, the transfectants with a low-level of EMP2 expression showed a strong trend of less PVR severity than the high-levels EMP2 transfectants (p = 0.06). Blocking EMP2 with a specific polyclonal antibody significantly decreased the level of PVR severity (p = 0.02). PVR membranes were found to be positive for EMP2 expression. CONCLUSIONS: These in vivo studies support a direct correlation between EMP2 expression and severity of PVR. These results validate the potential for controlling RPE biology through a change in EMP2 expression, and provide a potential therapeutic target for this disease. PMID- 21591865 TI - Quantification of human sebum on skin and human meibum on the eye lid margin using Sebutape(r), spectroscopy and chemical analysis. AB - PURPOSE: The purpose of this study was to determine if the variability in the amount of lid margin meibum is from donor-to-donor or from day-to-day variations and to determine if meibum from donors with meibomian gland dysfunction (MGD) had altered levels of casual eyelid meibum or skin sebum. METHODS: Lipid absorbent Sebutape((r)) was used to collect sebum or meibum. Samples were collected from six donors without dry eye and 21 donors with MGD. Lipid absorbed to Sebutape((r)) was quantified using infrared and visible absorbance spectroscopy. RESULTS: The amount of sebum from donors with MGD and donors without MGD was not significantly different. The amount of casual meibum from normal donors was 50% lower than that for donors with MGD using the spectroscopic assay, but was not significantly different using the chemical assay. The frequency and bandwidth of the infrared carbonyl band from sebum samples was significantly higher than that for meibum samples which indicates the carbonyls are in a different "dielectric" environment. The average relative standard deviation for the casual level of meibum and the level of sebum suggests that the 49% relative standard deviation of casual meibum measured once for each subject using a meibometer may have been due to day-to-day variations and not necessarily due to variations between individuals. The values measured using two different assays were correlated and therefore reliable. CONCLUSIONS: The idea that tear film instability is associated with the quantity of lid margin lipid is not supported by this study because the quantity did not change with MGD. The amount of forehead sebum was not a bio-marker for MGD. Sebutape((r)) is an excellent vehicle to remove tenths of a milligram of meibum from the eyelid and sebum from skin for experimental analysis. PMID- 21591866 TI - Metabolomics of rabbit aqueous humor after administration of glucocorticosteroid. AB - PURPOSE: The purpose of this study was to evaluate metabolic changes in the aqueous humor of rabbits after the administration of glucocorticosteroids. METHODS: Twenty-four New Zealand white rabbits were divided into the following three groups: control (intravitreal injection of sterile saline solution), TA (intravitreal injection of triamcinolone acetonide), and DEX (subconjunctival injection of dexamethasone). Intraocular pressure (IOP), flash electroretinogram (FERG), and flash visual evoked potential (FVEP) were tested. The aqueous humor was acquired pre-injection and at 1 and 30 days post-injection. The samples were detected by (1)H NMR, and then the spectrum was analyzed by principal component analysis (PCA). RESULTS: A significant elevation of IOP was observed in the TA group (1, 7, 14, 21, and 30 days post-injection) and the DEX group (14, 21, and 30 days post-injection) compared to the controls (P < 0.01). In FERG, the amplitudes were decreased, and the implicit time was prolonged in the TA group at 7, 14, and 30 days post-injection compared to the controls (P < 0.05). In FVEP, the amplitudes were decreased, and the implicit time was prolonged in the TA group at 30 days post-injection (P < 0.05). The concentrations of 12 metabolites (including lipid, protein, sugar, antioxidant, and acute phase reaction protein) were significantly changed after intravitreal TA, while 11 metabolites were changed after subconjunctival DEX, compared to the controls. PCA showed that alanine and acetate were the highest value contributions, while sugar metabolism was the major metabolic difference between TA and DEX. CONCLUSIONS: The main metabolic change in the aqueous humor of rabbits after the administration of glucocorticosteroids is sugar metabolism, and the function of the retina and the optic nerve was impaired after intravitreal TA. PMID- 21591868 TI - Retraction. Results of spectral-domain optical coherence tomography by preferential hyperacuity perimeter in patients after idiopathic epiretinal membrane surgery. PMID- 21591867 TI - Tomography-based customized IOL calculation model. AB - PURPOSE: To provide a mathematical calculation scheme for customized intraocular lens (IOL) design based on high resolution anterior segment optical coherence tomography (AS-OCT) of anterior eye segment and axial length data. MATERIAL AND METHODS: We use the corneal and anterior segment data from the high resolution AS OCT and the axial length data from the IOLMaster to create a pseudophakic eye model. An inverse calculation algorithm for the IOL back surface optimization is introduced. We employ free form surface representation (bi-cubic spline) for the corneal and IOL surface. The merit of this strategy is demonstrated by comparing with a standard spherical model and quadratic function. Four models are calculated: (1) quadratic cornea + quadratic IOL; (2) spline cornea + quadratic IOL; (3) spline cornea + spline IOL; and (4) spherical cornea + spherical IOL. The IOL optimization process for the pseudophakic eye is performed by numerical ray-tracing method within a 6-mm zone. The spot diagram on the fovea (forward ray tracing) and wavefront at the spectacle plane (backward ray-tracing) are compared for different models respectively. RESULTS: The models with quadratic (1) or spline (3) surface representation showed superior image performance than the spherical model 4. The residual wavefront errors (peak to valley) of models 1, 2, and 3 are below one micron scale. Model 4 showed max wavefront error of about 15 um peak to valley. However, the combination of quadratic best fit IOL with the free form cornea (model 2) showed one magnitude smaller wavefront error than the spherical representation of both surfaces (model 3). This results from higher order terms in cornea height profile. CONCLUSIONS: A four-surface eye model using a numerical ray-tracing method is proposed for customized IOL calculation. High resolution OCT data can be used as a sufficient base for a customized IOL characterization. PMID- 21591869 TI - On-call neurosurgery: can this continue as a free service? AB - Since 2005, Acute National Health Service (NHS) Trusts have been funded using a system called Payment by Results. This provides a national or regionally set tariff per patient treated, according to a health resource group code. Health resource group codes vary according to diagnosis or procedures carried out and patient co-morbidities. This only funds trusts admitting patients rather than those advising remotely, as neurosurgical centres do for the majority of emergency referrals. Numbers of referrals and emergency admissions to our unit were analysed for the last 4 years in addition to consultant and secretarial time devoted to these cases. This demonstrated an increase in the number of referrals and time spent advising. For the trust hosting the neurosurgical department, this represents a funding deficit for services offered. In our region, this has been remedied by charging neighbouring trusts a fee for emergency neurosurgical referral advice. However, this is difficult to administrate and would be better served as a service-level agreement with our commissioners. Only when this has been achieved, can neurosurgical centres provide a comprehensive consultant-led emergency service without it being to the detriment of the host trust. PMID- 21591870 TI - Debate--does a reversible penumbra exist in intracerebral haemorrhage? AB - Intracerebral haemorrhage is a devastating condition lacking effective therapies, with an uncertain role for surgery in many. Early research described an ischaemic penumbra around the haematoma, representing an area of potential therapeutic intervention. This article discusses the evidence for and against the existence of an ischaemic penumbra in ICH, with particular reference to recent imaging studies. PMID- 21591871 TI - Validation of prognostic scores for clinical use in patients with alcoholic hepatitis. AB - OBJECTIVE: In patients with alcoholic hepatitis, assessment of mortality risk is a key factor in the clinical management. Within the last decade, several prognostic scores have emerged. We aimed to evaluate and compare the predictive performances of the Glasgow alcoholic hepatitis score (GAHS); the model of end stage liver disease (MELD); the MELD-Na; the Lille model; and the age, bilirubin, international normalized ratio, and creatinine (ABIC) score in a population-based unselected cohort of patients with alcoholic hepatitis. MATERIAL AND METHODS: We applied the scoring systems to all 274 patients hospitalized and diagnosed with alcoholic hepatitis (1999-2008) in a Danish region of 1.1 million inhabitants. The ability of each score to predict mortality was evaluated using receiver operating characteristics curves, and the area under the receiver operating characteristics curves (AUROCs) were used to compare the scores. RESULTS: The 28 day mortality was 16%, 84-day 27%, and 180-day 40%. The models had similar predictive properties with AUROC = 0.74-0.78 for 28-day mortality, 0.69-0.77 for 84-day mortality, and 0.65-0.75 for 180-day mortality. There were no statistically significant differences in the models' performances (p > 0.9). Re scoring on day seven improved the AUROCs of the models (AUROC for 28-day, 0.75 0.83; 84-day, 0.75-0.79; and 180-day, 0.72-0.74). CONCLUSIONS: The MELD, the MELD Na, the GAHS, the Lille-model, and the ABIC scores each predicted the 28-, 84-, and 180-day mortality of our patients with alcoholic hepatitis and to the same degree, although not as well as in the original cohorts. Re-scoring on day seven improved the models' predictions. PMID- 21591872 TI - Pharmacokinetic parameters of morroniside in iridoid glycosides of Fructus corni processing based on back-propagation neural network. AB - CONTEXT: Fructus Corni is derived from the dry ripe sarcocarp of Cornus officinalis Sieb. et Zucc. (Cornaceae). Morroniside is an active constituent of Fructus Corni used in many traditional Chinese medicines (TCMs). This article describes a sensitive and specific assay for the quantitation of morroniside in rat plasma after oral administration of iridoid glycosides from Fructus Corni. MATERIALS AND METHODS: In this article, back-propagation (BP) neural network method was fist developed for the prediction of pharmacokinetic (PK) parameters of morroniside in Fructus Corni. RESULTS: The results show that mean square error (MSE) of neural network model with 11 hidden neurons and 90% training data is 0.092. DISCUSSION AND CONCLUSION: This article provides a new method to calculate PK data, one do not need to figure out all the compartment parameters to acquire PK data of morroniside. Therefore, the BP neural network method would be useful for guiding the holistic PK study in consistence with the intrinsic theory and characteristics of TCM. PMID- 21591873 TI - Potential of Vitex negundo roots in the treatment of ulcerative colitis in mice. AB - CONTEXT: Vitex negundo Linn. (Verbenaceae) is an indigenous tree species in India. This tree species has been of interest to researchers because traditionally its roots are reported in the treatment of ulcer and colic pain. OBJECTIVE: The present work was undertaken to validate its folk use in the treatment of ulcerative colitis (UC) by using the method of acetic acid-induced colitis in mice. MATERIALS AND METHODS: Ethanol and aqueous extracts of roots of V. negundo (100 mg/kg) were screened for use in the treatment of UC by the method of acetic acid-induced UC in mice. Macroscopical study of the colon, level of myeloperoxidase (MPO), malondialdehyde (MDA) in colon tissue and blood and histopathology of the colon tissue were studied for the assessment. RESULTS: Ethanol extract (100 mg/kg) reduced the level of MPO in blood from 355 +/- 0.39 to 240 +/- 0.36 U/mL and from 385 +/- 0.35 to 257 +/- 0.36 U/mg in tissue. Similarly, it reduced the level of MDA in blood from 9.40 +/- 0.42 to 6.10 +/- 0.36 nmol/mL and from 9.38 +/- 0.56 to 5.89 +/- 0.56 U/mg in tissue. Both the results are comparable with the standard drug, prednisolone (5 mg/kg). This preventive effect was observed by morphological and histopathological study. DISCUSSION AND CONCLUSION: Results showed that ethanol extract of V. negundo root is effective in the treatment of UC and results are comparable with the standard drug, prednisolone, and thus possessing a great potential in the treatment of UC. PMID- 21591874 TI - Evaluation of a physiological in vitro system to study the transport of nanoparticles through the buccal mucosa. AB - A buccal physiological in vitro testing system for the evaluation of the permeability, the transport route and toxic effects of nanoparticles was developed. Carboxyl polystyrene (CP, 20 nm, 200 nm) and amine modified polystyrene (AP, 200 nm) particles were used as reference particles and characterized in biological media. The permeability through excised porcine buccal mucosa was investigated with Franz diffusion cells. To evaluate the transport route, particle uptake into oral H376 cells was recorded and the cell damage was measured. All particles immediately formed aggregates once dispersed in saliva. 20 nm CP particles permeated the mucus layer and penetrated into the stratum superficiale of the top third region of the epithelium by the transcellular route. The positively-charged 200 nm AP particles permeated the mucus-layer and penetrated into deeper regions of the tissue. By decreasing the temperature to 4 degrees C, particle uptake was inhibited for 20 nm CP and 200 nm AP particles. 200 nm CP particles interacted with the mucus, formed agglomerates and did not penetrate into the epithelium. It can be concluded that the presented system serves as a valuable tool to evaluate the behavior of nanoparticles in the buccal mucosa. PMID- 21591875 TI - Importance of surface coatings and soluble silver in silver nanoparticles toxicity to Daphnia magna. AB - Silver nanoparticles (AgNPs) are now widely used in antibacterial and personal care products. However, the underlying physicochemical mechanisms leading to the toxicity of AgNPs are still under debate. The present study revealed the different effects of three surface coatings (including lactate, polyvinylpyrrolidone, and sodium dodecylbenzene sulfonate, as AgNPs-L, AgNPs-P and AgNPs-S, respectively) on the acute toxicity of AgNPs to a model freshwater cladoceran Daphnia magna. Significant difference in mortality was observed among these three surface coatings of AgNPs, with the 48-h 50% lethal concentrations (48-h LC50s) of AgNPs-L, AgNPs-P and AgNPs-S being 28.7, 2.0 and 1.1 MUg/L, respectively. In contrast, when the daphnids were exposed to soluble Ag released from AgNPs-L and AgNPs-P, the difference in the 48-h LC50s between the two surface coatings (1.1 MUg/L and 0.57 MUg/L, respectively) decreased significantly. These 48-h LC50s were comparable to that of AgNO3 (0.88 MUg/L), indicating that soluble Ag was the primarily cause of the observed toxicity of AgNPs. Indeed, the surface coatings influenced the dissolution of AgNPs into soluble Ag, resulting in the different toxicities of AgNP to the daphnids. Additionally, the 48-h bioaccumulation of AgNPs in daphnids was also dependent on the characteristics of the nanoparticles, such as particle size and surface coating. Our results point to the need to consider the effects of surface coating on the toxicity of AgNPs in environmental risk assessments. PMID- 21591876 TI - Insights into the search for new drugs from traditional knowledge: an ethnobotanical and chemical-ecological perspective. AB - CONTEXT: The variety of pathways for the introduction of a species into the medical collection of traditional communities has led many researchers to question the processes of selection and the use of these resources. A better comprehension of these processes will allow us to understand the cultural dynamics that are related to traditional medical practices, as well as to provide us with new ways in which to facilitate the exploration of natural products. OBJECTIVE: This study aims to test the predictive power of the plant apparency hypothesis as it relates to medicinal plant selection by the rural communities of the Caatinga and the Atlantic Forest in northeast Brazil. MATERIAL AND METHODS: Initially, a survey of the medicinal plants used by these communities was conducted using semistructured interviews. Subsequently, data on the life strategies and the habits of each species were collected. More detailed data on the specific plant parts indicated in interviews were also collected. A phytochemical screening for seven classes of chemical compounds was carried out to test the predictions of the plant apparency hypothesis. RESULTS: The medicinal plants from the Caatinga (especially those that are considered to be trees in habit) have a strong ability to accumulate quantitative compounds, and these species are most likely to be plants with significant biological activity related to these compounds; the medicinal plants from the Atlantic Forest, on the other hand, tend to have a high occurrence of qualitative compounds, especially in herbaceous life forms. DISCUSSION AND CONCLUSION: It was concluded that the plant apparency hypothesis does not adequately explain the selection of medicinal plants in the two environments studied. Our findings highlight some important implications for bioprospecting that need to be further tested experimentally, and through systematic studies, in different regions. PMID- 21591883 TI - Modeling web-based information seeking by users who are blind. AB - PURPOSE: This article describes website information seeking strategies used by users who are blind and compares those with sighted users. It outlines how assistive technologies and website design can aid users who are blind while information seeking. METHOD: People who are blind and sighted are tested using an assessment tool and performing several tasks on websites. The times and keystrokes are recorded for all tasks as well as commands used and spatial questioning. RESULTS: Participants who are blind used keyword-based search strategies as their primary tool to seek information. Sighted users also used keyword search techniques if they were unable to find the information using a visual scan of the home page of a website. A proposed model based on the present study for information seeking is described. CONCLUSIONS: Keywords are important in the strategies used by both groups of participants and providing these common and consistent keywords in locations that are accessible to the users may be useful for efficient information searching. The observations suggest that there may be a difference in how users search a website that is familiar compared to one that is unfamiliar. PMID- 21591884 TI - An expert review of the scientific literature on independent wheelchair transfers. AB - PURPOSE: The purpose of this study was to perform a literature review and seek expert opinion on the relevance and strength of the evidence concerning setup and transfer performance. METHODS: Scientific literature databases were searched until June 2009 using 43 keywords resulting in 339 articles. These were internally reviewed and narrowed to 41 articles which were formally assessed by 13 external experts. Articles that 80% or more of the reviewers scored as moderately or highly relevant were included in the final results. RESULTS: Nineteen articles met the relevancy criteria. The aspects of setup that experts felt were addressed to some degree included vertical transfer distance, transferring across a gap and position of the mobility device relative to target destination. None of the 19 articles were scored as having strong to very strong resulting evidence. CONCLUSIONS: There is a consensus among studies that transferring to a higher surface implies greater exertion of the upper limb. However, there is no evidence concerning how high or low, how close, and how much space is needed next to the target surface so it can be accessible by a majority of wheelchair users. PMID- 21591886 TI - A continuing black hole? The FDA boxed warning: an appeal to improve its clinical utility. AB - The boxed warning is increasingly utilized by the Food and Drug Administration (FDA) as a clinical warning to prescribers of dangerous adverse drug reactions. As these warnings have expanded, we feel the utility and application of boxed warnings are becoming more nebulous. The use of drugs following issuance of a boxed warning has been variable. Droperidol sales decreased 10-fold in the year following the warning, yet there has been essentially no change in the methadone usage over a similar time period after its boxed warning. Including more information, such as estimation of incidence for the adverse drug reaction, would be more clinically useful to the prescriber. Reasonable standards using supplemental databases outside of the FDA (such as national poison center data) could be helpful in developing an integrated and balanced approach to boxed warnings. PMID- 21591887 TI - Deductive sort and climbing sort: new methods for non-dominated sorting. AB - In recent years an increasing number of real-world many-dimensional optimisation problems have been identified across the spectrum of research fields. Many popular evolutionary algorithms use non-dominance as a measure for selecting solutions for future generations. The process of sorting populations into non dominated fronts is usually the controlling order of computational complexity and can be expensive for large populations or for a high number of objectives. This paper presents two novel methods for non-dominated sorting: deductive sort and climbing sort. The two new methods are compared to the fast non-dominated sort of NSGA-II and the non-dominated rank sort of the omni-optimizer. The results demonstrate the improved efficiencies of the deductive sort and the reductions in comparisons that can be made when applying inferred dominance relationships defined in this paper. PMID- 21591888 TI - Multimodal optimization using a bi-objective evolutionary algorithm. AB - In a multimodal optimization task, the main purpose is to find multiple optimal solutions (global and local), so that the user can have better knowledge about different optimal solutions in the search space and as and when needed, the current solution may be switched to another suitable optimum solution. To this end, evolutionary optimization algorithms (EA) stand as viable methodologies mainly due to their ability to find and capture multiple solutions within a population in a single simulation run. With the preselection method suggested in 1970, there has been a steady suggestion of new algorithms. Most of these methodologies employed a niching scheme in an existing single-objective evolutionary algorithm framework so that similar solutions in a population are deemphasized in order to focus and maintain multiple distant yet near-optimal solutions. In this paper, we use a completely different strategy in which the single-objective multimodal optimization problem is converted into a suitable bi objective optimization problem so that all optimal solutions become members of the resulting weak Pareto-optimal set. With the modified definitions of domination and different formulations of an artificially created additional objective function, we present successful results on problems with as large as 500 optima. Most past multimodal EA studies considered problems having only a few variables. In this paper, we have solved up to 16-variable test problems having as many as 48 optimal solutions and for the first time suggested multimodal constrained test problems which are scalable in terms of number of optima, constraints, and variables. The concept of using bi-objective optimization for solving single-objective multimodal optimization problems seems novel and interesting, and more importantly opens up further avenues for research and application. PMID- 21591889 TI - Evolution of cartesian genetic programs for development of learning neural architecture. AB - Although artificial neural networks have taken their inspiration from natural neurological systems, they have largely ignored the genetic basis of neural functions. Indeed, evolutionary approaches have mainly assumed that neural learning is associated with the adjustment of synaptic weights. The goal of this paper is to use evolutionary approaches to find suitable computational functions that are analogous to natural sub-components of biological neurons and demonstrate that intelligent behavior can be produced as a result of this additional biological plausibility. Our model allows neurons, dendrites, and axon branches to grow or die so that synaptic morphology can change and affect information processing while solving a computational problem. The compartmental model of a neuron consists of a collection of seven chromosomes encoding distinct computational functions inside the neuron. Since the equivalent computational functions of neural components are very complex and in some cases unknown, we have used a form of genetic programming known as Cartesian genetic programming (CGP) to obtain these functions. We start with a small random network of soma, dendrites, and neurites that develops during problem solving by repeatedly executing the seven chromosomal programs that have been found by evolution. We have evaluated the learning potential of this system in the context of a well known single agent learning problem, known as Wumpus World. We also examined the harder problem of learning in a competitive environment for two antagonistic agents, in which both agents are controlled by independent CGP computational networks (CGPCN). Our results show that the agents exhibit interesting learning capabilities. PMID- 21591890 TI - Extremely low-frequency electromagnetic fields affect lipid-linked carbonic anhydrase. AB - In the last years, the effect of extremely low-frequency electromagnetic fields (ELF-EMF) on the activity of different enzymes were investigated. Only the membrane-anchored enzymes did decrease their activity, up to 50%. In this work, the effect of ELF-EMF on bovine lung membrane carbonic anhydrase (CA) were studied. Carbonic anhydrases are a family of 14 zinc-containing isozymes catalyzing the reversible reaction: CO(2)+H(2)O = HCO(3)(- )+H(+). CA differ in catalytic activity and subcellular localization. CA IV, IX, XII, XIV, and XV are membrane bound. In particular, CA IV, which is expressed in the lung, is glycosyl phosphatidyl inositol-linked to the membrane, therefore it was a candidate to inhibition by ELF-EMF. Exposure to the membranes to a field of 75 Hz frequency and different amplitudes caused CA activity to a reproducible decrease in enzymatic activity by 17% with a threshold of about 0.74 mT. The decrease in enzymatic activity was independent of the time of permanence in the field and was completely reversible. When the source of enzyme was solubilized with Triton, the field lost its effect on CA enzymatic activity, suggesting a crucial role of the membrane, as well as of the particular linkage of the enzyme to it, in determining the conditions for CA inactivation. Results are discussed in terms of the possible physiologic effects of CA inhibition in target organs. PMID- 21591891 TI - Occupational exposure to magnetic fields from transformer stations and electric enclosures in Turkey. AB - We aimed to provide a systematic evaluation of magnetic field (MF) exposure of staff working in the offices located above or close to transformer stations (TS) and electric enclosures (EE). Occupational short-term "spot" measurements with Narda EFA-300 and isotropic magnetic field probe were carried out in two National Banks and one Industrial Company having more than 500 employees. Extremely low frequency (ELF) MFs up to several tens of MUT were measured in the mentioned working environments. 25% of the measured MFs were found less than 0.3 MUT, the background exposure level that staff receive at home, 75% were above 0.3 MUT with the highest value of 6.8 MUT. The mean and median personal exposures were calculated to be 1.19 MUT and 0.56 MUT, respectively. Most of the staff (83%) is under risk based on epidemiological studies that reported a statistically significant association between risk of leukemia and averaged magnetic fields of 0.2 MUT or over. Results showed that risk evaluation should be considered to minimize the possibility of the workers being harmed due to exposure to work related electromagnetic sources. PMID- 21591892 TI - Effects of a low-intensity electromagnetic field on fibroblast migration and proliferation. AB - The aim of this study was to test if an extremely weak 1 GHz electromagnetic field (EMF), known to be in resonance with clusters of water molecules, has biological effects on human fibroblasts. We demonstrated that in an in vitro model of wound healing, this EMF can activate fibroblast migration. [(3)H]thymidine incorporation experiments demonstrated that the EMF could also activate fibroblast proliferation. Activation of the expression of human fibroblast growth factor 1 (HFGF1) after EMF exposure showed that molecular wound healing pathways are activated in response to this water-resonant EMF. PMID- 21591893 TI - Effect of physiological parameters of blood on magnetophoretic mobility of erythrocytes. AB - Magnetophoresis is the process of the particle motion under the influence of a magnetic field. The magnetic particle and medium are considered responsive to the imposed magnetic field, and the material property that describes the response to the external magnetic field is relative magnetic permeability, and the magnetic susceptibility. The present work aims to evaluate the effect of internal and external physiological parameters on the erythrocytes' magnetophoretic mobility (MM) using Cell Tracking Velocimetry (CTV). The results of this study showed that there are a strong correlation between MM and several physiological blood parameters such as mean corpuscle hemoglobin (MCH), red blood cells distribution width (RDW), mean corpuscle hemoglobin concentration (MCHC), and fibrinogen. PMID- 21591894 TI - Endogenous electromagnetic fields in plant leaves: a new hypothesis for vascular pattern formation. AB - Electromagnetic (EM) phenomena have long been implicated in biological development, but few detailed, practical mechanisms have been put forth to connect electromagnetism with morphogenetic processes. This work describes a new hypothesis for plant leaf veination, whereby an endogenous electric field forming as a result of a coherent Frohlich process, and corresponding to an EM resonant mode of the developing leaf structure, is capable of instigating leaf vascularisation. In order to test the feasibility of this hypothesis, a three dimensional, EM finite-element model (FEM) of a leaf primordium was constructed to determine if suitable resonant modes were physically possible for geometric and physical parameters similar to those of developing leaf tissue. Using the FEM model, resonant EM modes with patterns of relevance to developing leaf vein modalities were detected. On account of the existence of shared geometric signatures in a leaf's vascular pattern and the electric field component of EM resonant modes supported by a developing leaf structure, further theoretical and experimental investigations are warranted. Significantly, this hypothesis is not limited to leaf vascular patterning, but may be applicable to a variety of morphogenetic phenomena in a number of living systems. PMID- 21591895 TI - The embryonic and post-embryonic development in two Drosophila species exposed to the static magnetic field of 60 mT. AB - In this study, a static magnetic field influence on development and viability in two different species, Drosophila melanogaster and Drosophila hydei, was investigated. Both species completed development (egg-adult), in and out of the static magnetic field induced by double horseshoe magnet. Treated vials with eggs were placed in the gap between magnetic poles (47 mm) and exposed to the average magnetic induction of 60 mT, while control ones were kept far enough from magnetic field source. We found that exposure to the static magnetic field reduced development time in both species, but statistical significance was found only for D. hydei. Furthermore, we found that the average viability of both Drosophila species exposed to the magnetic field was significantly weaker compared to control ones. These results indicate that 60 mT static magnetic field could be considered as a potential stressor, influencing on different levels the embryonic and post-embryonic development of individuals. PMID- 21591896 TI - Thermal aspects of exposure to radiofrequency energy: report of a workshop. AB - This special issue contains papers presented at an international workshop entitled 'Thermal Aspects of Radio Frequency Exposure' convened in Gaithersburg, Maryland, USA on 11-12 January 2010, and co-sponsored by the Mobile Manufacturers Forum, the GSM Association, and the US Food and Drug Administration. The goals of the workshop were to (1) identify appropriate health endpoints associated with thermal hazards and their time-dependence thresholds, and (2) outline future directions for research that might lead to an improved understanding of health and safety implications of human exposure to radiofrequency energy and design of improved exposure limits for this energy. This present contribution summarises some of the major conclusions of the speakers, and offers comments by one of the present authors on proposed research priorities and the implications of the material presented at the workshop for setting improved thermally based limits for human exposure to RF energy. PMID- 21591897 TI - Thresholds for thermal damage to normal tissues: an update. AB - The purpose of this review is to summarise a literature survey on thermal thresholds for tissue damage. This review covers published literature for the consecutive years from 2002-2009. The first review on this subject was published in 2003. It included an extensive discussion of how to use thermal dosimetric principles to normalise all time-temperature data histories to a common format. This review utilises those same principles to address sensitivity of a variety of tissues, but with particular emphasis on brain and testis. The review includes new data on tissues that were not included in the original review. Several important observations have come from this review. First, a large proportion of the papers examined for this review were discarded because time-temperature history at the site of thermal damage assessment was not recorded. It is strongly recommended that future research on this subject include such data. Second, very little data is available examining chronic consequences of thermal exposure. On a related point, the time of assessment of damage after exposure is critically important for assessing whether damage is transient or permanent. Additionally, virtually no data are available for repeated thermal exposures which may occur in certain recreational or occupational activities. For purposes of regulatory guidelines, both acute and lasting effects of thermal damage should be considered. PMID- 21591899 TI - Hyperthermic effects on behavior. AB - This review focuses upon the past 8 years of research on hyperthermic effects on behavior. Heat stress and heat stoke become severe conditions when body temperatures exceed 40 degrees C as this can lead to delirium, convulsions, coma, and death. The animal literature indicates that hyperthermia can increase glutamatergic and decrease GABAergic neurotransmission. Interestingly, u-opiate receptor antagonists can attenuate the morphological and biochemical changes in brain, as well as, ameliorate some behavioral deficits induced by heart stress. In humans, heat stress can produce detrimental effects on motor and cognitive performance. Since most cognitive tasks require a motor response, some cognitive deficiencies may be attributed to decreased motor performance. Although hyperthermia may exert more deleterious effects on complex than simple cognitive tasks, systematic studies are needed to examine the effects of different levels and durations of hyperthermia (irrespective of dehydration) on cognition. Additionally, body temperatures should be carefully monitored where controls are run for baseline or brief exposures to a hyperthermic environment. Acute radiofrequency exposure can disrupt behavior when body temperatures increase >1 degrees C with whole body SAR between 3.2-8.4 W/kg and time-averaged power densities at 8-140 mW/cm(2). Effects of lower levels of radiation are conflicting and some experiments fail to replicate even with the original investigators. This suggests either that brief exposure to the radiation is at a threshold where some individuals are affected while others are not, or that these levels are innocuous. Nevertheless, thermal changes appear to account for almost all of the behavioral effects reported. PMID- 21591898 TI - Toward establishment of temperature thresholds for immunological impact of heat exposure in humans. AB - There is interest in understanding the health impact of thermal effects as a result of exposure of humans to radiofrequency/microwave (RF/MW) fields. Immune cells and responses are affected by modest changes in temperature and it is important to quantify these effects and establish safety thresholds similar to what has been done with other tissue targets. Since previous summaries of thresholds for thermal damage to normal tissues have not focused much attention to cells of the immune system, this summary highlights recent studies which demonstrate positive and some negative effects of temperature shifts on human immune cells. We emphasise literature reporting adverse immunological endpoints (such as cell damage, death and altered function) and provide the temperature at which these effects were noted. Whereas there have been many in vitro studies of adverse temperature effects on immune cells, there has been limited validation of these temperature effects in vivo. However, data from heat stress/stroke patients do provide some information regarding core temperatures (40 degrees C) at which thermal damage to immunological processes can begin to occur. We conclude that there is considerable need for more quantitative time temperature assessments using relevant animal models, more complete kinetic analyses to determine how long immunological effects persist, and for analysis of whether frequency of exposure has impact on immune function. To date, no attempt to categorise effects by using cumulative thermal dose measurements (e.g. cumulative equivalent minutes at a given temperature) has been conducted for cells or tissues of the immune system, representing a major gap in this field. PMID- 21591900 TI - Thermal thresholds for teratogenicity, reproduction, and development. AB - The human embryo and foetus may be especially vulnerable to chemical and physical insults during defined stages of development. In particular, the scheduled processes of cell proliferation, cell migration, cell differentiation, and apoptosis that occur at different times for different organ structures can be susceptible to elevated temperatures. With limited ability to regulate temperature on its own, the developing embryo and foetus is entirely dependent upon the mother's thermoregulatory capacity. As a general rule, maternal core body temperature increases of ~2 degrees C above normal for extended periods of time, 2-2.5 degrees C above normal for 0.5-1 h, or >=4 degrees C above normal for 15 min have resulted in developmental abnormalities in animal models. Significant differences in thermoregulation and thermoneutral ambient temperatures make direct extrapolation of animal data to humans challenging, and the above temperatures may or may not be reasonable threshold predictions for adverse developmental effects in humans. Corresponding specific absorption rate (SAR) values that would be necessary to cause such temperature elevations in a healthy adult female would be in the range of >=15 W/kg (whole body average or WBA), with ~4 W/kg required to increase core temperature 1 degrees C. However, smaller levels of thermal stress in the mother that are asymptomatic might theoretically result in increased shunting of blood volume to the periphery as a heat dissipation mechanism. This could conceivably result in altered placental and umbilical blood perfusion and reduce heat exchange with the foetus. It is difficult to predict the magnitude and threshold for such an effect, as many factors are involved in the thermoregulatory response. However, a very conservative estimate of 1.5 W/kg WBA (1/10th the threshold to protect against measurable temperature increases) would seem sufficient to protect against any significant reduction in blood flow to the embryo or foetus in the pregnant mother. This is more than three times above the current WBA limit for occupational exposure (0.4 W/kg) as outlined in both IEEE C95.1-2005 and ICNIRP 1998 international safety standards for radiofrequency (RF) exposures. With regard to local RF exposure directly to the embryo or foetus, significant absorption by the mother as well as heat dissipation due to conductive and convective exchange would offer significant protection. However, a theoretical 1 W/kg exposure averaged over the entire 28-day embryo, or averaged over a 1-g volume in the foetus, should not elevate temperature more than 0.2 degrees C. Because of safety standards, exposures to the foetus this great would not be attainable with the usual RF sources. Foetal exposures to ultrasound are limited by the US Food and Drug Administration (FDA) to a maximum spatial peak temporal average intensity of 720 mW/cm(2). Routine ultrasound scanning typically occurs at lower values and temperature elevations are negligible. However, some higher power Doppler ultrasound devices under some conditions are capable of raising foetal temperature several degrees and their use in examinations of the foetus should be minimised. PMID- 21591901 TI - Sensing hot and cold with TRP channels. AB - The past decade has witnessed the cloning of a new family of ion channels that are responsive to temperature. Six of these transient receptor potential (TRP) channels are proposed to be involved in thermosensation and are located in sensory nerves and skin. The TRPV1, TRPV2, TRPV3, and TRPV4 channels have incompletely overlapping functions over a broad thermal range from warm to hot. Deletion of the individual TRPV1, TRPV3, and TRPV4 channels in mice has established their physiological role in thermosensation. In all cases thermosensation is not completely abolished - suggesting some functional redundancy among the channels. Notably, the TRPV2 channel is responsive to hot temperatures in heterologous systems, but its physiological relevance in vivo has not been established. Cool and cold temperatures are sensed by TRPM8 and TRPA1 family members. Currently, the pharmaceutical industry is developing agonists and antagonists for the various TRP channels. For instance, TRPV1 receptor agonists produce hypothermia, while antagonists induce hyperthermia. Recent investigations have found that different regions of the TRPV1 receptor are responsive to temperature, nociceptive stimuli, and various chemical agents. With this information, it has been possible to develop a TRPV1 compound that blocks responses to capsaicin and acid while leaving temperature sensitivity intact. These channels have important implications for hyperthermia research and may help to identify previously unexplored mechanisms in different tissues that are responsive to thermal stress. PMID- 21591902 TI - Health Council of The Netherlands: no need to change from SAR to time-temperature relation in electromagnetic fields exposure limits. AB - The Health Council of the Netherlands (HCN) and other organisations hold the basic assumption that induced electric current and the generation and absorption of heat in biological material caused by radiofrequency electromagnetic fields are the only causal effects with possible adverse consequences for human health that have been scientifically established to date. Hence, the exposure guidelines for the 10 MHz-10 GHz frequency range are based on avoiding adverse effects of increased temperatures that may occur of the entire human body at a specific absorption rate (SAR) level above 4 W/kg. During the workshop on Thermal Aspects of Radio Frequency Exposure on 11-12 January 2010 in Gaithersburg, Maryland, USA, the question was raised whether there would be a practical advantage in shifting from expressing the exposure limits in SAR to expressing them in terms of a maximum allowable temperature increase. This would mean defining adverse time temperature thresholds. In this paper, the HCN discusses the need for this, considering six points: consistency, applicability, quantification, causality, comprehensibility and acceptability. The HCN concludes that it seems unlikely that a change of dosimetric quantity will help us forward in the discussion on the scientific controversies regarding the existence or non-existence of non thermal effects in humans following long duration, low intensity exposure to electromagnetic fields. Therefore, the HCN favours maintaining the current approach of basic restrictions and reference levels being expressed as SAR and in V/m or uT, respectively. PMID- 21591903 TI - ARPANSA, standards development, and the need for thermal effects research. PMID- 21591905 TI - A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens. AB - Quantitative methods for estimation of cancer risk have been developed for daily, lifetime human exposures. There are a variety of studies or methodologies available to address less-than-lifetime exposures. However, a common framework for evaluating risk from less-than-lifetime exposures (including short-term and/or intermittent exposures) does not exist, which could result in inconsistencies in risk assessment practice. To address this risk assessment need, a committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute conducted a multisector workshop in late 2009 to discuss available literature, different methodologies, and a proposed framework. The proposed framework provides a decision tree and guidance for cancer risk assessments for less-than-lifetime exposures based on current knowledge of mode of action and dose-response. Available data from rodent studies and epidemiological studies involving less-than-lifetime exposures are considered, in addition to statistical approaches described in the literature for evaluating the impact of changing the dose rate and exposure duration for exposure to carcinogens. The decision tree also provides for scenarios in which an assumption of potential carcinogenicity is appropriate (e.g., based on structural alerts or genotoxicity data), but bioassay or other data are lacking from which a chemical specific cancer potency can be determined. This paper presents an overview of the rationale for the workshop, reviews historical background, describes the proposed framework for assessing less-than-lifetime exposures to potential human carcinogens, and suggests next steps. PMID- 21591906 TI - When is adult hippocampal neurogenesis necessary for learning? evidence from animal research. AB - The hippocampus is a key brain structure involved in the short- and long-term processing of declarative memory. Since adult hippocampal neurogenesis was first found, numerous studies have tried to establish the contribution of newborn neurons to hippocampus-dependent cognitive functions. However, this large amount of research has generated contradictory results. In this paper, we review the body of evidence investigating the relationship between hippocampal neurogenesis and learning to conclude the functional role of adult-born hippocampal neurons. First, factors that could explain discrepancies among experiments are taken into account. Then, in addition to methodological differences, we emphasize the importance of the age of the newborn neurons studied, as to how their maturation influences both their properties and potential functionality. Next, we discuss which declarative memory components could require involvement of adult hippocampal neurogenesis, taking into consideration the representational demands of the task, its difficulty and the level of performance reached by the subject. Finally, other factors that could modulate neurogenesis and memory, such as stress levels or previous experience of the animal, should also be taken into consideration in interpreting experiments focused on neurogenesis. In conclusion, our analysis of published studies suggests that new adult-born neurons, under certain circumstances, have a crucial and irreplaceable role in hippocampal learning. PMID- 21591907 TI - Current perspectives on potential role of albumin in neuroprotection. AB - Albumin is the most abundant plasma protein synthesised mainly in the liver. It is also a major component of extracellular fluids including cerebrospinal fluid, interstitial fluid and lymph. Albumin has several biochemical properties including regulation of colloid osmotic pressure of plasma, transportation of hormones, fatty acids, drugs and metabolites across plasma, regulation of microvascular permeability, antioxidant activity, anti-thrombotic activity and anti-inflammatory activity. This multifunctional protein has been implicated in many neurological diseases owing to its ability to regulate hemodynamic properties of the brain circulation as well as the direct neuroprotective actions on neuronal and glial cells. In this review, we summarise various neuroprotective actions of the albumin in the brain. In experimental ischemic stroke, exogenous human serum albumin administration has been found to be neuroprotective via reducing brain swelling, prevention of post-ischemic thrombosis, anti-oxidant activity, hemodilution and increasing the perfusion to the ischemic tissue. Also, human serum albumin administration is currently under clinical trials for treatment of cerebral ischemia. In the experimental models of Alzheimer's disease, albumin has been implicated in neuroprotection by inhibiting polymerisation and enhancing the clearance of amyloid beta. The direct neuroprotective actions on neuronal and glial cells are mediated via endogenously produced albumin or cellular uptake of blood derived albumin. These neuroprotective effects of albumin are partly attributed to anti-oxidant property and modulation of intracellular signalling of neuronal or glial cells. The recent finding of de novo synthesis of albumin in microglial cells directs us to explore newer roles of this endogenously produced multifunctional protein in normal as well as pathological conditions of the brain. PMID- 21591908 TI - Spontaneously hypertensive rat (SHR) as an animal model for ADHD: a short overview. AB - Diverse studies indicate that attention-deficit hyperactivity disorder (ADHD) is associated with alterations in encoding processes, including working or short term memory. Some ADHD dysfunctional domains are reflected in the spontaneously hypertensive rat (SHR). Because ADHD, drugs and animal models are eliciting a growing interest, hence the aim of this work is to present a brief overview with a focus on the SHR as an animal model for ADHD and memory deficits. Thus, this paper reviews the concept of SHR as a model system for ADHD, comparing SHR, Wistar-Kyoto and Sprague-Dawley rats with a focus on the hypertension level and working, short-term memory and attention in different behavioral tasks, such as open field, five choice serial reaction time, water maze, passive avoidance, and autoshaping. In addition, drug treatments (d-amphetamine and methylphenidate) are evaluated. PMID- 21591910 TI - Impoverished environment, cognition, aging and dementia. AB - Animals living in an impoverished environment, i.e., without the possibility of physical and social activity, perform worse on cognitive tests compared to animals in an enriched environment. The same cognitive difference is also observed in humans. However, it is not clear whether this difference is caused by a decrease in cognition due to an impoverished environment or an increase due to an enriched environment. This review discusses the impact of an impoverished environment on cognition in animal experimental studies and human experimental studies with community-dwelling and institutionalized older people. Results show that the cognitive functioning of old rats is more affected by an impoverished environment than young rats. Similarly, sedentary and lonely people (impoverished environment) have worse cognitive functioning and show a faster cognitive decline than physically and socially active people. Institutionalization further aggravates cognitive decline, probably due to the impoverished environment of nursing homes. In institutions, residents spend an unnecessary and excessive amount of time in bed; out of bed they show mainly sedentary or completely passive behavior. In conclusion, older people, especially those that have been institutionalized, have poor levels of physical and social activity, which in turn has a negative impact on cognitive functioning. PMID- 21591909 TI - Role of the basolateral amygdala and NMDA receptors in higher-order conditioned fear. AB - Laboratory rats learn to fear relatively innocuous stimuli which signal the imminent arrival of an innate source of danger, typically brief but aversive foot shock. Much is now known about the neural substrates underlying the acquisition, consolidation and subsequent expression of this fear. Rats also learn to fear stimuli which signal learned sources of danger but relatively little is known about the neural substrates underlying this form of fear. Two Pavlovian conditioning paradigms used to study this form of fear are second-order conditioning and sensory preconditioning. In second-order conditioning, rats are first exposed to a signaling relationship between one stimulus, such as a tone, and aversive foot shock, and then to a signaling relationship between a second stimulus, such as a light, and the now dangerous tone. In sensory preconditioning, these phases are reversed: rats are first exposed to a signaling relationship between the light and the tone and then to a signaling relationship between the tone and the foot shock. In both paradigms, rats exhibit fear when tested with the light. In this review paper, we describe the evidence for higher order forms of conditioning, the conditions which promote this learning and its contents. We compare and contrast the substrates of the learning underlying second-order and sensory preconditioning fear with those known to underlie the better studied first-order conditioned fear. We conclude with some comments as to the role of higher-order processes in anxiety disorders. PMID- 21591923 TI - Paramedic accuracy using SALT triage after a brief initial training. AB - OBJECTIVE: To determine paramedics' understanding of and accuracy using SALT (sort-assess-lifesaving interventions-treatment/transport) triage, a proposed national guideline for primary triage during mass-casualty incidents, immediately and four months after training. METHODS: A 20-minute lecture on SALT triage was provided to all paramedics (n = 320) from a single county during mandatory continuing education. Triage concepts were reemphasized during a 10-minute small group lecture throughout the study period as part of standard refresher training. After the initial training, all paramedics were asked to complete a posttest consisting of three general knowledge questions about SALT triage and 10 patient scenarios in which they had to assign a triage category. The same test was administered four months after the original educational session. Demographic and job experience information was also obtained. Responses were scored and matched for each paramedic and compared using paired t-test. RESULTS: A total of 290 (91%) paramedics completed the initial posttest. They correctly answered an average (+/- standard deviation) of 10.7 +/- 2.3 of the 13 questions (82%). For the 10 patient scenarios, they correctly triaged an average of 8.1 +/- 2.0 patients. A total of 159 paramedics completed both tests. Sixty-seven percent had more than 10 years of emergency medical services (EMS) experience; 72% had prior mass-casualty drill experience; 51% had prior actual mass-casualty experience; and 23% had heard of SALT triage prior to the training. There were no statistically significant differences in initial test scores for any of these demographic groups. For those subjects who completed both tests, the mean overall score for the initial test was 10.9 +/- 1.9 (84%) and for the later test was 11.0 +/- 1.9 (85%) (p < 0.770; 95% confidence interval [CI] -0.3 to 0.3). For the 10 patient scenarios, the paramedics correctly triaged an average of 8.3 +/- 1.7 patients on the initial test and 8.3 +/- 1.4 patients on the later test (p < 0.565; 95% CI -0.4 to 0.2). CONCLUSION: Following a short didactic course, paramedics were able to accurately perform SALT triage during a written scenario. Four months after the training, they had retained their understanding of and accuracy using SALT triage. It appears that a brief educational tool was effective for training EMS providers in SALT triage. PMID- 21591927 TI - Quantification of stiffness change in degenerated articular cartilage using optical coherence tomography-based air-jet indentation. AB - Articular cartilage is a thin complex tissue that covers the bony ends of joints. Changes in the composition and structure of articular cartilage will cause degeneration, which may further lead to osteoarthritis. Decreased stiffness is one of the earliest symptoms of cartilage degeneration and also represents the imperfect quality of repaired cartilage. An optical coherence tomography (OCT) based air-jet indentation system was recently developed in our group to measure the mechanical properties of soft tissues. In this study, this system was applied to quantify the change of mechanical properties of articular cartilage after degeneration induced by enzymatic digestions. Forty osteochondral disks (n = 20 * 2) were prepared from bovine patellae and treated with collagenase and trypsin digestions, respectively. The apparent stiffness of the cartilage was measured by the OCT-based air-jet indentation system before and after the degeneration. The results were also compared with those from a rigid contact mechanical indentation and an ultrasound water-jet indentation. Through the air-jet indentation, it was found that the articular cartilage stiffness dropped significantly by 84% (p < 0.001) and 63% (p < 0.001) on average after collagenase and trypsin digestions, respectively. The stiffness measured by the air-jet indentation system was highly correlated (R > 0.8, p < 0.001) with that from the other two indentation methods. This study demonstrated that the OCT-based air-jet indentation can be a useful tool to quantitatively assess the mechanical properties of articular cartilage, and this encourages us to further develop a miniaturized probe suitable for arthroscopic applications. PMID- 21591928 TI - Inner meniscus cells maintain higher chondrogenic phenotype compared with outer meniscus cells. AB - Meniscus cells have several distinct properties in cellular morphology and extracellular matrix production. Inner meniscus cells are considered to have more chondrocytic phenotype compared with outer meniscus cells. However, the chondrogenic property of each meniscus cell has not been elucidated in detail. In this study, we investigated the difference between human inner and outer meniscus derived cells in extracellular matrix deposition and chondrogenic potential. Monolayer-cultured inner meniscus cells showed small and ovoid shapes though slender and fibroblastic cells were obtained from outer half of human meniscus. The syntheses of type II collagen and safranin O-stained proteoglycans were increased in chondrogenic pellets derived from inner meniscus cells, rather than in outer meniscus cell-derived pellets. On the other hand, adipogenic lipid vacuoles were equally accumulated in both inner and outer meniscus cells after adipogenic treatment. Chondrogenic treatments also enhanced the expression of chondrogenic marker genes, such as Sry-type HMG box (SOX) 9, Scleraxis, and alpha1(II) collagen, in inner meniscus cells. However, SOX9 expression was not increased in outer meniscus cells even after chondrogenic treatment. This study demonstrated that inner meniscus cells maintained higher chondrogenic potential compared with outer meniscus cells. Our results suggest that the difference between inner and outer meniscus cells in chondrogenic property might have an essential role in preserving a zone-specific meniscal feature. PMID- 21591929 TI - Enforced bipedal downhill running induces Achilles tendinosis in rats. AB - Enforced downhill running has been reported to induce tendinosis in the rat supraspinatus tendon but similar exercise failed to induce Achilles tendinosis in this animal. Due to the presence of acromial arch in the shoulder, accessing the supraspinatus tendon with physical modalities is difficult; thus this model may not be suitable for studying the treatment for tendinosis. To develop a rat model for Achilles tendinosis, we tested 14 mature Sprague-Dawley rats by dividing them into 2 groups of 7 each. The experimental group was subjected to a daily enforced downhill bipedal running program by suspending their upper bodies so that they ran with their hind limbs on a treadmill for 1 hr/day for 8 weeks. The downward inclination was 20 degrees and the speed was 17 m/min. The animals in the control group did not undergo any exercise. After 8 weeks, the Achilles tendons were harvested and subjected to histological and biomechanical analysis. Histological examination revealed tenocyte proliferation, change in tenocytes appearance, and collagen bundle disintegration in the running group. The biomechanical testing revealed significant decrease in stiffness (p = 0.002) and ultimate tensile strength (p = 0.016) in the running group than in the control group. Both the histological and biomechanical findings are suggestive of changes in the tendon of the running group that resembled the pathological changes of tendinosis in human. This new model of Achilles tendinosis in rat will be useful for studying the etiology and subsequent management strategies of this condition. PMID- 21591930 TI - Age-related increases of macroautophagy and chaperone-mediated autophagy in rat nucleus pulposus. AB - OBJECTIVE: Excessive apoptosis plays an important role in the progression of intervertebral disc degeneration. However, the effect of autophagy, another type of programmed cell death, on the pathogenesis of disc degeneration is still unclear. Macroautophagy and chaperone-mediated autophagy (CMA) change and intervertebral disc degeneration aggravates with age. This study aims at examining the expression changes of light chain 3 (LC3), lysosome-associated membrane protein 2A (LAMP-2A), and Hsc70, the indicator substrates of macroautophagy and CMA, in rat nucleus pulposus (NP) to prove that macroautophagy and CMA are both related with age. METHODS: Female Sprague-Dawley rats of 3, 12, and 24 months (n = 8 per age) were used in this study. Autophagic vacuoles in NP cells were detected by transmission electron microscopy. In NP, the expressions of LC3-II and LAMP-2A protein and mRNA were examined by immunohistochemistry and reverse transcription polymerase chain reaction, respectively. LC3-II, LC3-I, and LAMP-2A protein were also measured by western blot. The mRNA and protein level of myocyte enhancer factor-2D regulated by LAMP-2A and Hsc70 were detected by reverse transcriptase polymerase chain reaction and western blot, respectively. RESULTS: Transmission electron microscopy showed more autophagic vacuoles in 12- and 24-month groups than in 3-month group. Expression of LC3-II and LC3-II/LC3-I in 24-month group was significantly higher than in 3-month group (p < 0.05). Meanwhile, LAMP-2A expression was significantly higher in 24-month group than in 3-month group (p < 0.05). However, lower expression of Hsc70 and myocyte enhancer factor-2D was found in the 24-month rats than in 3-month group (p < 0.05, p < 0.05, respectively). CONCLUSION: Macroautophagy and CMA were present and increased with age in rat NP. PMID- 21591931 TI - A novel proteolytic processing of prolysyl oxidase. AB - Lysyl oxidase (LOX) is an amine oxidase that is critical for the stability of connective tissues. The secreted proLOX is enzymatically quiescent and is activated through proteolytic cleavage between residues Gly(162) and Asp(163) (residue numbers according to the mouse LOX) by bone morphogenetic protein (BMP) 1 gene products. Here we report a novel processing of proLOX identified in vitro and in vivo. Two forms of mature LOX were identified and characterized by their immunoreactivity to specific antibodies, amine oxidase activity, and mass spectrometry. One form was identified as a well-characterized BMP-1 processed LOX protein. Another was found to be a truncated form of LOX resulting from the cleavage at the carboxy terminus of Arg(192). The truncated form of LOX still appeared to retain amine oxidase activity. The results from the proLOX gene deletion and mutation experiments indicated that the processing occurs independent of the cleavage of proLOX by BMP-1 gene products and likely requires the presence of LOX propeptide. These results indicate that proLOX could be processed by two different mechanisms producing two forms of active LOX. PMID- 21591932 TI - Stronger accent following a stroke: the case of a trilingual with aphasia. AB - This study documents patterns of change in speech production in a multilingual with aphasia following a cerebrovascular accident (CVA). EC, a right-handed Hebrew-English-French trilingual man, had a left fronto-temporo-parietal CVA, after which he reported that his (native) Hebrew accent became stronger in his (second language) English. Recordings of his pre- and post-CVA speech permitted an investigation of changes in his accent. In sentence- and segment-listening tasks, native American English listeners (n = 13 and 15, respectively) judged EC's pre- and post-CVA speech. EC's speech was perceived as more foreign accented, slow, strained and hesitant, but not less intelligible, post-CVA. Acoustic analysis revealed less coarticulation and longer vowel- and word durations post-CVA. This case extends knowledge about perceptual and acoustic changes in speech production in multilinguals following CVAs. It is suggested that EC's stronger accent post-CVA may have resulted from damage to the neuronal networks that led to impairment in his other language domains. PMID- 21591933 TI - Electropalatography in the description and treatment of speech disorders in five children with cerebral palsy. AB - Some children with cerebral palsy have articulation disorders that are resistant to conventional speech therapy. The aim of this study was to investigate whether the visual feedback method of electropalatography (EPG) could be an effective tool for treating five children (mean age of 9.4 years) with dysarthria and cerebral palsy and to explore whether training improved the posteriorly placed articulation of the Swedish dental/alveolar target consonants /t/, /d/, /n/ and /s/ produced in different positions. An EPG analysis was conducted and some of the data were combined with a perceptual analysis. A more anterior placement was seen after treatment for the target sounds. Features of diagnostic importance revealed were unusual tongue-palate contacts, such as double articulation and abnormally retracted articulation. A possible change in stop closure duration was indicated. The results suggest that EPG could be of potential benefit for diagnosing, treating and describing articulation errors associated with cerebral palsy. PMID- 21591934 TI - The transition from the core vowels to the following segments in Japanese children who stutter: the second, third and fourth syllables. AB - Shimamori and Ito (2007 , Syllable weight and phonological encoding in Japanese children who stutter. Japanese Journal of Special Education, 44, 451-462; 2008, Syllable weight and frequency of stuttering: Comparison between children who stutter with and without a family history of stuttering. Japanese Journal of Special Education, 45, 437-445; 2009, Difference in frequency of stuttering between light and heavy syllables in the production of monosyllables: From the viewpoint of phonetic transition. The Japanese Journal of Logopedics and Phoniatrics, 50, 116-122 (in Japanese)) proposed the hypothesis that in Japanese the transition from the core vowels (CVs) to the following segments affected the occurrence of stuttering. However, the transition we investigated was in the first syllables only, and the effect of the transition in second, third and fourth syllables was not addressed. The purpose of this study was to investigate whether the transition from the CVs in the second, third and fourth syllables affected the occurrence of stuttering. The participants were 21 Japanese children. A non-word naming task and a non-word reading task were used. The frequency of stuttering was not significantly different where the number of transitions from the CVs differed on either task. These results suggest that the transition from the CVs in the second, third and fourth syllables does not have a significant effect on the occurrence of stuttering in Japanese. PMID- 21591935 TI - Minimal pair distinctions and intelligibility in preschool children with and without speech sound disorders. AB - Listeners' identification of young children's productions of minimally contrastive words and predictive relationships between accurately identified words and intelligibility scores obtained from a 100-word spontaneous speech sample were determined for 36 children with typically developing speech (TDS) and 36 children with speech sound disorders (SSD) of unknown origin in three age groups (3+, 4+ and 5+ years). Each child's productions of 78-word stimuli were recorded and presented to unfamiliar adults for forced-choice identification. Results of a two-way MANOVA (two groups by three ages) indicated that the TDS group had significantly higher (p < 0.001) percent consonant items correct (PCIC) and percent syllable shape items correct. Stepwise regression analyses revealed significant predictors of intelligibility scores to be PCIC (adjusted R(2) = 0.10, p = 0.04) for the TDS group and PCIC and percent vowel items correct (adjusted R(2) = 0.63, p < 0.001) for the SSD group. PMID- 21591936 TI - Sudden death for a challenge to federal funding of stem-cell research. PMID- 21591937 TI - Human embryonic stem-cell research under siege--battle won but not the war. PMID- 21591938 TI - The $640 billion question--why does cost-effective care diffuse so slowly? PMID- 21591939 TI - Videos in clinical medicine. Fiberoptic intubation. PMID- 21591940 TI - Images in clinical medicine. Hydropic gallbladder. PMID- 21591941 TI - The Palliative Care Information Act in real life. PMID- 21591942 TI - Revisiting E&M visit guidelines--a missing piece of payment reform. PMID- 21591944 TI - Selenium and the course of mild Graves' orbitopathy. AB - BACKGROUND: Oxygen free radicals and cytokines play a pathogenic role in Graves' orbitopathy. METHODS: We carried out a randomized, double-blind, placebo controlled trial to determine the effect of selenium (an antioxidant agent) or pentoxifylline (an antiinflammatory agent) in 159 patients with mild Graves' orbitopathy. The patients were given selenium (100 MUg twice daily), pentoxifylline (600 mg twice daily), or placebo (twice daily) orally for 6 months and were then followed for 6 months after treatment was withdrawn. Primary outcomes at 6 months were evaluated by means of an overall ophthalmic assessment, conducted by an ophthalmologist who was unaware of the treatment assignments, and a Graves' orbitopathy-specific quality-of-life questionnaire, completed by the patient. Secondary outcomes were evaluated with the use of a Clinical Activity Score and a diplopia score. RESULTS: At the 6-month evaluation, treatment with selenium, but not with pentoxifylline, was associated with an improved quality of life (P<0.001) and less eye involvement (P=0.01) and slowed the progression of Graves' orbitopathy (P=0.01), as compared with placebo. The Clinical Activity Score decreased in all groups, but the change was significantly greater in the selenium-treated patients. Exploratory evaluations at 12 months confirmed the results seen at 6 months. Two patients assigned to placebo and one assigned to pentoxifylline required immunosuppressive therapy for deterioration in their condition. No adverse events were evident with selenium, whereas pentoxifylline was associated with frequent gastrointestinal problems. CONCLUSIONS: Selenium administration significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves' orbitopathy. (Funded by the University of Pisa and the Italian Ministry for Education, University and Research; EUGOGO Netherlands Trial Register number, NTR524.). PMID- 21591943 TI - Alemtuzumab induction in renal transplantation. AB - BACKGROUND: There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. METHODS: In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 3 years for safety and efficacy end points. RESULTS: The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P<0.001) and 12 months (5% vs. 17%, P<0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P=0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, P=0.63). Adverse-event rates were similar among all four treatment groups. CONCLUSIONS: By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. (Funded by Astellas Pharma Global Development; INTAC ClinicalTrials.gov number, NCT00113269.). PMID- 21591945 TI - Genomics and the eye. PMID- 21591947 TI - Images in clinical medicine. Graves' disease. PMID- 21591946 TI - Acute HIV-1 Infection. PMID- 21591948 TI - Case records of the Massachusetts General Hospital. Case 15-2011. A 19-year-old South African woman with headache, fatigue, and vaginal discharge. PMID- 21591949 TI - Alemtuzumab in kidney-transplant recipients. PMID- 21591950 TI - Fatty acids and retinopathy. PMID- 21591951 TI - Farm microbiome and childhood asthma. PMID- 21591952 TI - Farm microbiome and childhood asthma. PMID- 21591954 TI - AIP mutation in pituitary adenomas. PMID- 21591956 TI - Hypoxia and inflammation. PMID- 21591957 TI - Hypoxia and inflammation. PMID- 21591958 TI - Hypoxia and inflammation. PMID- 21591960 TI - Radioiodine therapy for hyperthyroidism. PMID- 21591961 TI - Radioiodine therapy for hyperthyroidism. PMID- 21591963 TI - More on NK-cell and B-cell deficiency with a thymic mass. PMID- 21591965 TI - Anaphylaxis from passive transfer of peanut allergen in a blood product. PMID- 21591969 TI - Mandibular asymmetry in unilateral and bilateral posterior crossbite patients using cone-beam computed tomography. AB - OBJECTIVE: To test the hypotheses that (1) there is no difference in mandibular asymmetry between the crossbite and normal side in a unilateral crossbite group (UCG) and between the right and left sides in a bilateral crossbite group (BCG) and a control group (CG); and (2) there is no significant difference in mandibular asymmetry among crossbite groups and control group. MATERIALS AND METHODS: The cone-beam computed tomography scans of three groups were studied: (1) 15 patients (6 male, 9 female; mean age: 13.51 +/- 2.03 years) with unilateral posterior crossbite; (2) 15 patients (8 male, 7 female; mean age: 13.36 +/- 2.12 years) with bilateral posterior crossbite; and (3) 15 patients (8 male, 7 female; mean age: 13.46 +/- 1.53 years) as a control group. Fourteen parameters (eight linear, three surface, and three volumetric) were measured. Side comparisons were analyzed with paired samples t-test, and for the intergroup comparison, analysis of variance (ANOVA) and Tukey tests were used at the P < .05 level. RESULTS: According to side comparisons, no statistically significant difference was found in the UCG. There were statistically significant differences in hemimandibular (P = .008) and ramal (P = .004) volumes for the BCG and in ramal height (P = .024) and body length (P = .021) for the CG. Intergroup comparisons revealed significant differences in hemimandibular (P = .002) and body volume (P < .001) for the normal side of the UCG and left sides of the other groups, and in angular unit length (P = .025) and condylar width (P = .007) for the crossbite side of the UCG and the right sides of the other groups. CONCLUSIONS: Contrary to UCG, CG and BCG were found to have side-specific asymmetry. Skeletal components of the mandible have significant asymmetry among the crossbite groups and the CG. PMID- 21591970 TI - A preliminary study describing body position in daily life in children with severe cerebral palsy using a wearable device. AB - PURPOSE: The effects of gravity and immobilisation are regarded as factors in the development of spinal deformity in cerebral palsy (CP). This study was to assess the body positions in daily life of children with CP using a wearable device. METHOD: Four institutionalised children with severe quadriplegic CP participated in this study. Four age-matched children without disability also participated as healthy controls. The participants wore a body position recorder throughout their normal daily activities for a period of 24 h. After the body position data were recorded, the amount of time spent by each subject in upright, supine, prone, and left and right lateral lying positions and the frequency of positional change were computed. RESULTS: The pattern of body position change in daily life was clearly different among children with CP and between children with CP and healthy controls. Children with CP spent less time in the upright position and remained in one position for longer periods of time than the control children. CONCLUSIONS: Twenty-four-hour monitoring could provide quantitative information about body position, the frequency of body position changes and the period of time spent in a preferred body position, with possible implications for preventing spinal deformity. PMID- 21591971 TI - Stress and anxiety in pregnant women exposed to ultrasound. AB - AIM: To investigate the levels of anxiety and stress during pregnancy among women who are routinely offered ultrasound at first and second trimesters. METHODS: This is a cross-sectional study involving 296 women, in which 146 pregnant women without any medical problem were compared with 150 nonpregnant women. Both groups were submitted to the Lipp Inventory of Stress Symptoms for Adults and to the State-Trait Anxiety Inventory. Logistic regression analysis was used to evaluate the effect of pregnancy on the anxiety and stress levels. RESULTS: There was no statistical difference between pregnant and nonpregnant women [56.8% (83/146) vs. 48.6% (73/150), odds ratio (OR) 1.39 95% confidence interval (CI) 0.88-2.19] regarding the level of stress. Logistic regression analysis demonstrated that the only significant independent predictor of stress was maternal age (OR 0.95, 95% CI 0.91-0.96; P = 0.045) for the pregnant women and monthly income and religious belief for the nonpregnant group. Pregnant women had a higher level of anxiety compared with the nonpregnant (15.7% vs. 2.6%, P = 0.0002) and ultrasound examination decreased the anxiety level. CONCLUSION: Pregnant women did not have a higher level of stress compared with the nonpregnant women, and maternal age is the only significant independent predictor of stress. Pregnant women are more anxious, and after the ultrasound examination, the level of anxiety decreased. PMID- 21591972 TI - Invasive fetal therapies: approach and results in treating fetal ovarian cysts. AB - OBJECTIVE: To show the validity of prenatal invasive surgical intervention when a fetal ovarian cyst is diagnosed, compared to a wait and see attitude, in order to avoid possible prenatal and postnatal complications. PATIENTS: Fourteen cases of intra-abdominal cysts monitored in our center between April 2005 and November 2010. All cases were first diagnosed in the third trimester, and were monitored for the remainder of the pregnancy and after delivery (2 months-3 years postnatally). SURGICAL INTERVENTION: Upon maternal and fetal cutaneous anesthesia performed trans-amniotically, the cystic fluid (mean contents 43.85 cc, DS 46.27) was extracted for cytological, biochemical, and hormonal examination. RESULTS: Thirteen cases of intra-abdominal cysts (92.8%) were fetal ovarian cysts. Ninety two percent of pregnancies bearing such a condition were successfully concluded (n = 12). Sixty-nine percent concluded in vaginal delivery (n = 9). None experienced maternal and/or fetal complications. Every drained cyst had an estradiol concentration higher than 10,000 pg/ml. CONCLUSIONS: The aspiration of ovarian cysts exceeding a 40 mm diameter, performed as early as possible, allows a good longitudinal treatment of this fetal affection, thus avoiding torsion, tissue necrosis, and invasive postnatal surgery, as well as giving hope of future gestational capability to the fetus/newborn. PMID- 21591973 TI - The role of cytokines IL-6 and IL-8 in the pathogenesis of spontaneous abortions. AB - OBJECTIVE: The aim of this study was to investigate the role of interleukin-6 and interleukin-8 in the spontaneous abortion of the first and second trimester of pregnancy and the possibility of IL-6 and IL-8 being used as markers for the pregnancy outcome. METHOD: The patients were divided into three groups: group 1, women at the time of first trimester miscarriage (n = 35); group 2, women at the time of second trimester miscarriage (n = 35); group 3 included the women without previous history of abortions submitted to hysterectomy (n = 10). Plasma levels of interleukin-6 and interleukin-8 were measured by bioassays method (ELISA). Mann-Whitney U test and Kruskal-Wallis test were used to assess differences between two or more groups of patients, respectively. Post hoc analysis was performed using Mann-Whitney U test with Bonferroni's correction. RESULTS: Interleukin 6 levels in women who had a second trimester abortion were statistically higher compared to those who had a first trimester abortion. Interleukin-8 levels in patients with second trimester abortion were also statistically higher compared to the control group. No significant differences between women with first trimester abortions and those without previous history of abortions were found. CONCLUSIONS: Our data suggest that IL-6 and IL-8 might be crucial factors which take part in the defensive reaction of maternal organization during the 2nd trimester of pregnancy. PMID- 21591974 TI - Neonatal intensive care unit admissions and their associations with late preterm birth and maternal risk factors in a population-based study. AB - OBJECTIVE: To assess the association of late preterm births (LPB [34(0/7) 36(6/7)]) and maternal risk factors with Neonatal Intensive Care Unit (NICU) admissions. METHODS: A retrospective cross-sectional analysis was conducted using data of all who delivered between 2000 and 2008. Statistical analysis was done using Chi-square and multivariable logistic regression. RESULTS: During the study period, 259,576 babies were delivered, and 11.6% were admitted to the NICU. Using logistic regression (NICU admission vs. no NICU admission), there was a 9-fold increased risk associated with preterm labor including preterm premature rupture membranes (PTL/PPROM) while LPB and essentially all other maternal risk factors were not significant. CONCLUSIONS: In our study, NICU admissions are more associated with PTL/PPROM rather than LPB and maternal risk factors. PMID- 21591975 TI - Challenges in Monte Carlo track structure modelling. AB - PURPOSE: Although great progress has been made, numerous challenges remain in the development of Monte Carlo (MC) charged-particle track structure simulation models. Such models have evolved from the simple gas phase target models to those using condensed phase interaction data coupled with complex targets representing cellular and molecular constituents of mammalian tissue. A wide choice of MC models is now available ranging from those based on the physics of continuous slowing down, to simulations following each interaction on an event-by-event basis. The choice of code depends largely on requirements for computational speed, and the degree of detail required; however, one must be continuously vigilant to recognise the inherent limitations of the model chosen. CONCLUSIONS: There remain numerous questions of the accuracy and completeness of the interaction physics that present challenges to MC modellers. Recent evidence suggests that the yields of electrons with energies less than a few hundred eV might be substantially overestimated by the elastic and inelastic cross-sections used in many codes. Densely ionising heavy ions present modelling challenges when the rate of energy loss is sufficient to ionise essentially 'every' atom along the ion path. Effects of electron capture and loss by moving heavy ions present significant challenges for modellers particularly for accurate simulation for ions heavier than protons and helium ions? The average effective-charge provides an inadequate description for estimating differential cross-sections for energy loss. These and other questions are considered. PMID- 21591976 TI - Capillary-tube-based oxygen/argon micro-plasma system for the inactivation of bacteria suspended in aqueous solution. AB - PURPOSE: An aqueous solution containing Escherichia coli can be completely inactivated within a short treatment time using a capillary-tube-based oxygen/argon micro-plasma source. MATERIALS AND METHODS: A capillary-tube-based oxygen/argon micro-plasma system with a hollow inner electrode was ignited by a 13.56 MHz radio frequency power supply with a matching network and characterised by optical emission spectroscopy. An aqueous solution containing E. coli was then treated at various the working distances, plasma exposure durations, and oxygen ratios in argon micro-plasma. The treated bacteria were then assessed and qualitatively investigated. The morphologies of treated bacteria were examined using a scanning electron microscope (SEM). RESULTS: In the proposed oxygen/argon micro-plasma system, the intensities of the main emission lines of the excited species, nitric oxide (NO), hydrated oxide (OH), argon (Ar), and atomic oxygen (O), fluctuated with the addition of oxygen to argon micro-plasma. Under a steady state of micro-plasma generation, the complete inactivation of E. coli in aqueous solution was achieved within 90 s of argon micro-plasma exposure time with a working distance of 3 mm. SEM micrographs reveal obvious morphological damage to the treated E. coli. The addition of oxygen to argon micro-plasma increased the variety of O-containing excited species. At a given supply power, the relative intensities of the excited species, NO and OH, correlated with the ultraviolet (UV) intensity, decreased. CONCLUSION: For the proposed capillary-tube-based micro-plasma system with a hollow inner electrode, the oxygen/argon micro-plasma source is efficient in inactivating E. coli in aqueous solution. The treatment time required for the inactivation process decreases with decreasing working distance or the increasing synthesised effect of reactive species and UV intensity. PMID- 21591977 TI - Are all human-derived follicle-stimulating hormone products the same? A systematic review and meta-analysis using direct and adjusted indirect analyses, to determine whether Fostimon(r) is more efficient than Metrodin-HP(r). AB - BACKGROUND: Randomized trials (RCTs) and systematic reviews have challenged the claim for superiority of recombinant follicle-stimulating hormone (recFSH) compared with human-derived FSH (hFSH). Even so, much of the evidence comes from unavailable products. If the efficacy of the currently available Fostimon((r)) is superior, the off-market Metrodin-HP((r)), then data from the latter should not be used, gauge of the former. METHODS: Electronic/hand searches were performed to identify RCTs comparing Fostimon((r)) vs. Metrodin-HP((r)) or either product with recFSH. Primary outcomes were live-birth rate (LBR), ongoing pregnancy rate (OPR), and OPR/LBR. Secondary outcomes were clinical pregnancy rate (CPR), multiple pregnancy rate (MPR), ovarian hyperstimulation syndrome (OHSS), abortion rates, and cycle demographics. Data were extracted, allowed for an intention-to treat analysis, and meta-analyzed using combined direct/adjusted indirect methods. RESULTS: Twenty-two RCTs met the inclusion criteria: Fostimon((r)) vs. Metrodin-HP((r)) (n = 2); Fostimon((r)) vs. recFSH (n = 8); and Metrodin-HP((r)) vs. recFSH (n = 12). LBR (odds ratio = 1.72; 95% confidence interval = 1.05 2.80), OPR/LBR, and CPR were all significantly higher favoring Fostimon((r)). OPR, MPR, OHSS, and miscarriage rates were not significantly different. Pooled results for cycle demographics were not reported due to high heterogeneity. Conclusions. Fostimon((r)) is superior to Metrodin-HP((r)) regarding clinical outcomes. Therefore, care should be taken not to assume that all hFSH products have the same efficacy. PMID- 21591978 TI - Correlation between depression, anxiety, and nausea and vomiting during pregnancy in an in vitro fertilization population: a pilot study. AB - The study objective is to compare the prevalence of nausea and vomiting of pregnancy (NVP) in singleton and twin gestations conceived via in vitro fertilization (IVF), and to analyze the impact of associated psychological factors. A cohort study on 45 singleton and 12 twin gestations was conducted at an academic practice. Three validated questionnaires assessing anxiety; depression; and NVP at baseline, 10-12 weeks, and 20-22 weeks gestation were used. The prevalence of NVP was compared between twins and singletons and its association with depression and anxiety was determined. Significantly more subjects with twin pregnancies reported NVP at 10-12 weeks of gestation. NVP was not associated with baseline depression or anxiety scores. There were no differences in depression scores between the groups at any time. A trend toward higher anxiety scores among twin gestations at 10-12 weeks was significant at 20 22 weeks. Within the twin group, anxiety scores remained stable, but scores for singletons decreased significantly from 10-12 weeks to 20-22 weeks. NVP is more common in the first trimester in twins compared with singletons following IVF. In IVF pregnancies, anxiety scores, but not depression scores, are higher in women with twin gestations. Women undergoing infertility treatment should be counseled accordingly when discussing the risks associated with multiple gestations. PMID- 21591979 TI - Anticipation of presbyopia in Portuguese familial amyloidosis ATTR V30M. AB - The aim of this study was to evaluate if Portuguese patients with familial amyloidosis, liver transplanted and not, have an earlier development of presbyopia compared with a normal population and its relation with the presence or the absence of anterior capsule opacification of the lens. This study was performed to evaluate if Portuguese patients with familial amyloidosis and in a blood donors population (control group). Three hundred and fifty-six subjects, 144 amyloidotic patients and 212 healthy individuals, were evaluated for the need of plus lenses for normal near reading (Jaeger chart 1 at 33 cm). In familial amyloidosis patients, the value of the add-power was related to age, liver transplantation status, and presence of visible anterior capsule opacification of the lens. In both groups, the value of add-power was positively correlated with age (r=0.91; P<0.005). Familial amyloidosis patients require more add-power than control individuals of similar age, and need to use reading glasses at earlier ages. The age of onset of presbyopia in familial amyloidosis patients was significantly lower than in control individuals (32 years vs. 42 years). Adjusting for age, no significant difference was observed in add-power values between liver transplanted and not transplanted amyloidotic patients, suggesting that liver transplantation has no influence on presbyopia evolution in these patients. Familial amyloidosis patients had an earlier onset of presbyopia, probably related to amyloid deposition on the anterior capsule of the lens, which is not halted by liver transplantation. PMID- 21591980 TI - The effects of continuous positive airway pressure therapy on mean platelet volume in patients with obstructive sleep apnea. AB - Previous studies have reported increased platelet activation and aggregation in patients with obstructive sleep apnea (OSA). Continuous positive airway pressure (CPAP) treatment has been shown to decrease platelet activation. We aimed to study the effects of nasal CPAP therapy has on MPV values in patients with severe OSA. Thirty-one patients (21 men; mean age 53.8 +/- 9.2 years) with severe OSA (AHI > 30 events/hour) constituted the study group. An age, gender and body mass index (BMI) matched control group was composed 25 subjects (14 men; mean age 49.6 +/- 8.5 years) without OSA (AHI < 5 events/hour). We measured MPV values in patients with severe OSA and control subjects and we measured MPV values after 6 months of CPAP therapy in severe OS patients. The median (IQR) MPV values were significantly higher in patients with severe OSA than in control group (8.5 [8.3 9.1] vs. 8.3 [7.5-8.8] fL; p = 0.03). The platelet counts were significantly lower in patients with severe OSA than in control group (217.8 +/- 45.9 vs. 265.4 +/- 64.0 * 109/L; p = 0.002). The six months of CPAP therapy caused significant reductions in median (IQR) MPV values in patients with severe OSA (8.5 [8.3-9.1] to 7.9 [7.4-8.2] fL; p < 0.001). Six months of CPAP therapy caused significant increase in platelet counts when compared with baseline values (217.8 +/- 45.9 to 233.7 +/- 60.6 * 109/L; p < 0.001). We have found that the MPV values of patients with severe OSA were significantly higher than those of the control subjects and 6 months CPAP therapy caused significant reductions in the MPV values in patients with severe OSA. PMID- 21591981 TI - P2Y12 and EP3 antagonists promote the inhibitory effects of natural modulators of platelet aggregation that act via cAMP. AB - Several antiplatelet drugs that are used or in development as antithrombotic agents, such as antagonists of P2Y12 and EP3 receptors, act as antagonists at G(i)-coupled receptors, thus preventing a reduction in intracellular cyclic adenosine monophosphate (cAMP) in platelets. Other antiplatelet agents, including vascular prostaglandins, inhibit platelet function by raising intracellular cAMP. Agents that act as antagonists at G(i)-coupled receptors might be expected to promote the inhibitory effects of agents that raise cAMP. Here, we investigate the ability of the P2Y12 antagonists cangrelor, ticagrelor and prasugrel active metabolite (PAM), and the EP3 antagonist DG-041 to promote the inhibitory effects of modulators of platelet aggregation that act via cAMP. Platelet aggregation was measured by platelet counting in whole blood in response to the TXA2 mimetic U46619, thrombin receptor activating peptide and the combination of these. Vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) was measured using a cytometric bead assay. Cangrelor always increased the potency of inhibitory agents that act by raising cAMP (PGI2, iloprost, PGD2, adenosine and forskolin). Ticagrelor and PAM acted similarly to cangrelor. DG-041 increased the potency of PGE1 and PGE2 as inhibitors of aggregation, and cangrelor and DG-041 together had more effect than either agent alone. Cangrelor and DG-041 were able to increase the ability of agents to raise cAMP in platelets as measured by increases in VASP P. Thus, P2Y12 antagonists and the EP3 antagonist DG-041 are able to promote inhibition of platelet aggregation brought about by natural and other agents that raise intracellular cAMP. This action is likely to contribute to the overall clinical effects of such antagonists after administration to man. PMID- 21591982 TI - Platelet response to aspirin and clopidogrel in patients with peripheral atherosclerosis. AB - Aspirin and clopidogrel are important drugs in the secondary prevention of ischemic events. A considerable individual variation in platelet response to these drugs has, however, been reported, and high residual platelet reactivity despite treatment may be an independent risk factor for ischemic events. Most studies have been undertaken in patients with coronary heart disease, but patients with peripheral artery disease (PAD) may exhibit greater residual platelet reactivity, possibly because of platelet activation by a larger area of diseased endothelium. It is yet unsettled which method that best measures platelet reactivity and an eventual lack of response to aspirin. Several instruments are promoted to measure platelet response and low-response to platelet inhibitors, but it is questionable if they measure this in comparable ways. We studied the comparability of three tests of platelet reactivity for the assessment of low-response to aspirin and clopidogrel in patients with PAD. In 263 patients, platelet function was assessed twice, 3 months apart, by the Platelet Function Analyzer-100 (PFA), light transmission aggregometry (LTA), and whole blood impedance aggregometry (IA). In a subgroup of 43 patients, we studied the effect of a single dose of 600 mg clopidogrel on platelet function. Low response to aspirin assessed by analyses targeting cyclooxygenase-1 activity (LTA, IA) was rare (<= 8.1%). With the PFA, we found 17% with low response at both visits, and 60% who were consistently responsive, whereas 23% were categorized differently at the two visits. Low response to clopidogrel, occurred in 0-23%, depending on the method and the criteria used. A low-response to aspirin, defined by lack of COX-1 inhibition, is a rare phenomenon whereas high residual platelet reactivity as determined by PFA may be a rather frequent finding but is not consistent over time in all patients. A low-response to clopidogrel depends very much on the method and definition used. PMID- 21591983 TI - Investigation of TNF-alpha, TGF-beta 1, IL-10, IL-6, IFN-gamma, MBL, GPIA, and IL1A gene polymorphisms in patients with idiopathic thrombocytopenic purpura. AB - Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by the presence of autoantibodies developing against thrombocyte membrane glycoproteins (GPs), such as GPIIa/IIIa and GPIb/IX. Single nucleotide polymorphisms (SNPs) of inflammatory cytokine genes were investigated in 71 patients with chronic ITP and 71 healthy controls, and they were compared with the clinical parameters. The polymorphisms in the SNPs were investigated with the polymerase chain reaction, polymerase chain reaction with sequence specific primer, and polymerase chain reaction-restriction fragment length polymorphism methods. It was found that the high expression of TNF-alpha (-308) AG phenotype significantly increased in cases with ITP (odds ratio, OR: 0.318, 95% confidence intervals, CI: 0.103-0.987, p < 0.05). TT genotype in TGF-beta 1 (codon 10) significantly decreased in ITP in comparison with the controls (OR: 0.342, 95% CI: 0.149-0.787, p = 0.016). IFN-gamma (+874) TT genotype was detected to be high in cases with ITP (OR: 3.301, 95% CI: 1.400-7.784, p < 0.05), whereas AA genotype was found to be significantly lower (OR: 4.993, 95% CI: 1.586-15.721, p < 0.05). MBL (codon 54) BB genotype (OR: 1.164, 95% CI: 1.059-1.279, p < 0.05) and IL1A A1/A2 genotype (OR: 0.249, 95% CI: 0.076-0.815, p < 0.05) were found to be significantly higher in cases with ITP than in healthy controls. TNF-alpha (-308) AG phenotype was detected to be significantly higher in steroid-refractory and splenectomized cases at the end of the first year than in the steroid-responsive (complete response (CR) and remission (R)) cases (OR: 4.137, 95% CI: 1.156 14.807, p < 0.05). When we compared the cases, from whom we obtained a CR at their first steroid response, with 12 cases, who entered R but from whom we could not obtain any CR, the frequencies of IFN-gamma (+874) AA genotype were found as 12 (20.3%) and 6 (50%) (OR: 0.082, 95% CI: 0.009-0.793, p < 0.05). MBL (codon 54) AB genotype was detected to be significantly higher in CR patients than in R cases (OR: 1.273, 95% CI: 1.110-1.459, p < 0.05). With these findings, it was found that TNF-alpha/AG, TGF-beta 1/TT, IFN-gamma/TT, MBL/BB, and IL-1RA A1/A2 genotypes were detected as the genes of susceptibility to ITP, while TNF alpha/AG, IFN-gamma/AA, and MBL/AB genotypes might be important in response to steroid treatment. PMID- 21591984 TI - Access to New Zealand Sign Language interpreters and quality of life for the deaf: a pilot study. AB - PURPOSE: This paper aims to: (1) explore usage and accessibility of sign language interpreters, (2) appraise the levels of quality of life (QOL) of deaf adults residing in New Zealand, and (3) consider the impact of access to and usage of sign language interpreters on QOL. METHOD: Sixty-eight deaf adults living in New Zealand participated in this study. Two questionnaires were employed: a 12-item instrument about access and use of New Zealand sign language interpreters and the abbreviated version of the World Health Organization Quality of Life questionnaire (WHOQOL-BREF). RESULTS: The results showed that 39% of this sample felt that they were unable to adequately access interpreting services. Moreover, this group scored significantly lower than a comparable hearing sample on all four WHOQOL-BREF domains. Finally, the findings revealed that access to good quality interpreters were associated with access to health services, transport issues, engagement in leisure activities, gaining more information, mobility and living in a healthy environment. CONCLUSIONS: These findings have consequences for policy makers and agencies interested in ensuring that there is an equitable distribution of essential services for all groups within New Zealand which inevitably has an impact on the health of the individual. PMID- 21591985 TI - Effects of NUTRIOSE(r) dietary fiber supplementation on body weight, body composition, energy intake, and hunger in overweight men. AB - The objective of the present study was to determine the effectiveness of a soluble dietary fiber, NUTRIOSE((r)), on body weight, body composition, energy intake and hunger in overweight Chinese men. The volunteers were randomized in double-blind fashion to 250 ml fruit juice supplemented with NUTRIOSE((r)) (Test, n = 60) or a maltodextrin (Control, n = 60) at a dosage of 17 g twice daily for 12 weeks. Body weight, body composition were performed at 0, 4, 8 and 12 weeks while daily energy intake and hunger were assessed every 3 days. Test subjects had reductions in body weight (1.5 kg, P < 0.001), body mass index (0.5 kg/m(2), P < 0.001) and body fat percentage (0.3%, P < 0.001) versus Controls. NUTRIOSE((r)) supplementation resulted in a lower daily energy intake (3,079 kJ/day, P < 0.001) with group differences noted as early as 3 days. Test subjects reported less hunger across the study period versus Controls (P < 0.01). NUTRIOSE((r)) supplementation for 12 weeks results in body composition improvements and reduces body weight, energy intake and hunger in overweight men. PMID- 21591986 TI - Differential effect of cheese fatty acid composition on blood lipid profile and redox status in normolipidemic volunteers: a pilot study. AB - The present study investigated the effect of the consumption of two cheese varieties differing for fat quality on blood lipid profile and redox status biomarkers in 30 selected healthy volunteers, consuming either the experimental cheese (from milk produced by cows fed a grass and maize silage based diet with 5% of linseed oil added) or the control cheese (from normal cows' milk) for 4 weeks according to a crossover design. The experimental cheese had a lower content of medium-chain saturated fatty acids and a higher content of stearic acid and polyunsaturated fatty acids; its consumption led to higher levels of vitamins C and E and stearic acid in blood, while myristic acid and oxidized low density lipoprotein concentrations were significantly lower. As myristic acid and oxidized low-density lipoprotein are highly correlated with increased atherogenic risk and vitamins C and E with antioxidant activity, the enrichment of cows' diet with linseed oil could provide a dietary option to prevent cardiovascular diseases risk. PMID- 21591987 TI - Oxidative stability of fermented Italian-type sausages using mate leaves (Ilex paraguariensis St. Hil) extract as natural antioxidant. AB - The objective of this work is to evaluate the effects of the addition of dried extract from mate leaves on the oxidative stability (lipid and protein), microbiological characteristics (lactic and Micrococcaceae bacteria) and sensory attributes of formulations of Italian-type sausages. The different Italian-type sausages formulations tested in this work were in agreement with the legislation in terms of chemical and microbiological parameters. During storage, the formulation with 0.4 wt% of mate leaves extract presented lower thiobarbituric acid reactive substances and carbonyl values compared with the control, proving the antioxidant action of the extract. The sensory characteristics of flavour, texture and global acceptation were not affected by the addition of mate extract compared with the formulation with artificial antioxidant. PMID- 21591988 TI - Antiretroviral drug resistance mutations among treated and treatment-naive patients in Pakistan: diversity of the HIV type 1 pol gene in Pakistan. AB - Pakistan is experiencing a growing HIV epidemic. Antiretroviral drugs (ARV) have been smuggled into the country and available without prescription since the early 1990s, but are now provided free of cost by the government. We assessed the prevalence of HIV-1, drug resistance, and subtype distributions. Blood specimens were collected from HIV-1-infected participants registered in Sindh Province on dry blood spot (DBS) cards in 2008. Pol, protease, and partial reverse transcriptase regions were sequenced after reverse transcriptase PCR (RT-PCR). HIV-1 subtype was assigned by phylogenetic analysis. Primary drug resistance was analyzed by the Calibrated Population Resistance (CPR) tool using the Stanford Surveillance Drug Resistance Mutation (SDRM) major mutation list. Out of 100 blood samples collected, 42 were suitable for testing. Out of 42, 11 were ARV receiving and 31 ARV-naive patients. Among them, 24 were injection drug users (IDUs), four immigrants, two hijras (male transvestites), two men who have sex with men (MSM), four prisoners, one female sex workers, two spouses of HIV infected persons, and four from the general population. ARV resistance among naive patients was 2/31 (6.5%) and 36.4% (4/11) among ARV-experienced patients making an overall resistance of 14.2%. HIV-1 subtype A1 was the predominant subtype found in 35/42 (83.3%) followed by CRF35_AD and C, 6.5% each. Subtype D and G were found in one (2.4%) each. A significant proportion of Pakistani HIV patients has ARV drug resistance. Physicians treating patients should consider the magnitude of drug resistance while selecting regimens, and address drug adherence aggressively. PMID- 21591989 TI - Beverages have an appreciable contribution to the intake of soluble dietary fibre: a study in the Spanish diet. AB - Beverages are generally not taken into account to determine the intakes of dietary fibre (DF) in diets. Soluble dietary fibre (SDF) content was determined in common alcoholic and non-alcoholic beverages - ranging from 0.18 g/l in white wine to 9.01 g/l in instant coffee - and their contribution to the DF intake in the Spanish Mediterranean diet was estimated as 2.13 g/person/day. It is concluded that beverages provide an appreciable amount of SDF in the diet, and the omission of its contribution may lead to underestimate DF intakes. PMID- 21591990 TI - Ginsenoside Rb3 ameliorates myocardial ischemia-reperfusion injury in rats. AB - CONTEXT: Panax ginseng C. A. Mey (Araliaceae) has been widely used in clinic for treatment of cardiovascular diseases in China. Ginsenoside Rb3 is the main chemical component of Panax ginseng. OBJECTIVE: The aim of this study was to evaluate the effect of ginsenoside Rb3 on myocardial ischemia-reperfusion injury in rats. METHODS: Sprague--Dawley rats were orally treated with Rb3 (5, 10 or 20 mg/kg) daily for 3 days followed by subjecting to left anterior descending coronary artery ligation for 30 min and reperfusion for 24 h. RESULTS: This study showed that ginsenoside Rb3 treatment resulted in a reduction in myocardial infarct size. Ginsenoside Rb3 significantly attenuated the changes of creatine kinase activity and lactate dehydrogenase activity. The cardioprotective effect of ginsenoside Rb3 was further confirmed by histopathological examination. Ginsenoside Rb3 alleviated the increase of malondialdehyde content and the decrease of superoxide dismutase activity in left ventricle. Treatment with ginsenoside Rb3 also decreased plasma endothelin and angiotensin II levels. CONCLUSION: These findings suggested that ginsenoside Rb3 possesses the effect against myocardial IR injury and the underlying mechanism is related to its antioxidant activity and microcirculatory improvement. PMID- 21591991 TI - Antibacterial activity of essential oils from Eucalyptus and of selected components against multidrug-resistant bacterial pathogens. AB - CONTEXT: Eucalyptus globulus Labill (Myrtaceae) is the principal source of eucalyptus oil in the world and has been used as an antiseptic and for relieving symptoms of cough, cold, sore throat, and other infections. The oil, well known as 'eucalyptus oil' commercially, has been produced from the leaves. Biological properties of the essential oil of fruits from E. globulus have not been investigated much. OBJECTIVE: The present study was performed to examine the antimicrobial activity of the fruit oil of E. globulus (EGF) and the leaf oils of E. globulus (EGL), E. radiata Sieber ex DC (ERL) and E. citriodora Hook (ECL) against multidrug-resistant (MDR) bacteria. Furthermore, this study was attempted to characterize the oils as well as to establish a relationship between the chemical composition and the corresponding antimicrobial properties. MATERIALS AND METHODS: The chemical composition of the oils was analyzed by GLC-MS. The oils and isolated major components of the oils were tested against MDR bacteria using the broth microdilution method. RESULTS: EGF exerted the most pronounced activity against methicillin-resistant Staphylococcus aureus (MIC ~ 250 ug/ml). EGF mainly consisted of aromadendrene (31.17%), whereas ECL had citronellal (90.07%) and citronellol (4.32%) as the major compounds. 1,8-cineole was most abundant in EGL (86.51%) and ERL (82.66%). DISCUSSION AND CONCLUSION: The activity of the oils can be ranked as EGF > ECL > ERL ~ EGL. However, all the oils and the components were hardly active against MDR Gram-negative bacteria. Aromadendrene was found to be the most active, followed by citronellol, citronellal and 1,8-cineole. PMID- 21591992 TI - Phylogenetic and similarity analysis of HTLV-1 isolates from HIV-coinfected patients from the south and southeast regions of Brazil. AB - HTLV-1 is endemic in Brazil and HIV/HTLV-1 coinfection has been detected, mostly in the northeast region. Cosmopolitan HTLV-1a is the main subtype that circulates in Brazil. This study characterized 17 HTLV-1 isolates from HIV coinfected patients of southern (n=7) and southeastern (n=10) Brazil. HTLV-1 provirus DNA was amplified by nested PCR (env and LTR) and sequenced. Env sequences (705 bp) from 15 isolates and LTR sequences (731 bp) from 17 isolates showed 99.5% and 98.8% similarity among sequences, respectively. Comparing these sequences with ATK (HTLV-1a) and Mel5 (HTLV-1c) prototypes, similarities of 99% and 97.4%, respectively, for env and LTR with ATK, and 91.6% and 90.3% with Mel5, were detected. Phylogenetic analysis showed that all sequences belonged to the transcontinental subgroup A of the Cosmopolitan subtype, clustering in two Latin American clusters. PMID- 21591993 TI - Recent advances in the discovery of small-molecule ATP competitive mTOR inhibitors: a patent review. AB - INTRODUCTION: The mammalian target of rapamycin (mTOR) is a protein kinase and a key component of the PI3K/Akt/mTOR signaling pathway, and is deregulated in half of all human cancers. Rapamycin and its analogs (rapalogs) are allosteric inhibitors of one functional mTOR complex, mTORC1, and are clinically proven therapeutic agents for the treatment of certain cancers. However, rapalogs mainly partially inhibit mTORC1, while ATP competitive inhibitors suppress both mTORC1 and mTORC2, and therefore may offer advantages in the clinic. Recently, small molecule inhibitors have entered clinical trials that are mTOR-selective or dual mTOR/PI3K inhibitors. AREAS COVERED: This review focuses on ATP-competitive mTOR inhibitors that have appeared in the patent literature in 2010. Many inhibitors with new structural motifs have been discovered as well as inhibitors that are related to previously disclosed structures. This review endeavors to put into perspective the diverse structural elements that make up these compounds. Patent applications are covered that include either selective mTOR inhibitors or dual mTOR/PI3K inhibitors. EXPERT OPINION: The PI3K/mTOR signaling pathway is an exciting target for the development of pharmaceuticals to treat cancer and other diseases, due to the unique combination of a clinically and commercially validated pathway approach (i.e., rapalogs), combined with a biological rationale for further increased efficacy (i.e., ATP-competitive inhibitors). With the number of candidate drugs currently in development or at earlier stages of the drug discovery pipeline, we are bound to see small-molecule inhibitors reach pivotal trials, and hopefully the market, in the near future. PMID- 21591994 TI - Amonafide: a potential role in treating acute myeloid leukemia. AB - INTRODUCTION: Amonafide is a novel topoisomerase II (Topo II) inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA. Amonafide retains cytotoxic activity even in the presence of P glycoprotein (Pgp)-mediated multi-drug resistance (MDR), a major contributor to clinical treatment failure. AREAS COVERED: In vitro, Pgp-mediated transport (efflux) of amonafide from myeloblasts obtained from patients with secondary acute myeloid leukemia (sAML) was significantly less than efflux of daunorubicin. Amonafide has shown efficacy in patients with sAML, as well as in patients with poor prognostic characteristics such as older age and unfavorable cytogenetics, all associated with MDR. Improved antileukemic activity is observed when amonafide is given together with cytarabine, rather than as monotherapy, with a complete remission rate of ~ 40% in a recent Phase II trial in sAML. The efficacy of amonafide was maintained among poor-risk subsets of patients, including older patients and patients who had previous myelodysplastic syndrome or previous leukemogenic therapy. The safety profile was acceptable and manageable. EXPERT OPINION: Amonafide plus cytarabine may have clinical utility in patients with sAML and in other poor-risk subgroups of acute myeloid leukemia (AML). Ongoing trials will help define the role for amonafide in the treatment of poor-risk AML. PMID- 21591997 TI - Clofarabine for myelodysplastic syndromes. AB - INTRODUCTION: Treatment options in myelodysplastic syndromes (MDS) remain limited. The introduction of novel therapies that can improve response rates and survival outcomes in MDS remains a challenge. Clofarabine is a purine nucleoside analog that works primarily via inhibition of DNA biosynthesis and the ribonucleotide reductase enzyme with recent evidence suggesting that at low doses it may affect DNA methylation. It has been successfully used in the treatment of acute myeloid leukemia (AML) and is under investigation in MDS. AREAS COVERED: A PubMed search for articles pertaining to clofarabine was conducted and streamlined to only include data on MDS or AML that evolved from MDS. Also included were clofarabine-related response and safety data from presentations at the 52(nd) Annual American Society of Hematology Meeting in Orlando, Florida, USA. EXPERT OPINION: Clinical trials using clofarabine in MDS and MDS/myeloproliferative neoplasms have produced overall response rates of 31 - 43% including complete responders. Although myelosuppression is an important side effect, clofarabine is generally well tolerated in MDS. Clofarabine is currently available in an intravenous form with an oral formulation presently under investigation, either as a single agent or in combination therapy in MDS. Larger studies may help clarify the viability of clofarabine in the treatment of MDS patients. PMID- 21591995 TI - Socioeconomic inequalities in height, leg length and trunk length among children aged 6.5 years and their parents from the Republic of Belarus: evidence from the Promotion of Breastfeeding Intervention Trial (PROBIT). AB - BACKGROUND: Lower socioeconomic position is associated with shorter stature, in particular shorter leg length, but the magnitude of these associations in non Western countries has received little attention. AIM: To examine socioeconomic differentials in height, leg and trunk length in 6.5 year olds from the Republic of Belarus and compare these to differentials in parental height. METHODS: Multivariable linear regression was used to examine associations in a cohort of 13 889 children. RESULTS: Children from non-manual households were 1.0 cm (95% confidence interval: 0.7-1.3 cm) taller than those from manual households. Mothers and fathers from non-manual backgrounds were 0.7 cm (0.5-0.8) and 1.8 cm (1.6-2.0) taller than those from manual backgrounds, respectively. Associations with higher parental educational attainment were similar. The magnitudes of the associations of socioeconomic position with leg length were similar to those with trunk length. Adjusting for mid-parental height and number of older siblings attenuated associations markedly. CONCLUSIONS: In Belarus, similar socioeconomic differentials in height were observed in both children and their parents. Among children, height differentials were partly explained by mid-parental height and number of older siblings. Leg length was not a more sensitive indicator of childhood socioeconomic conditions than trunk length. PMID- 21591998 TI - Role of TGF-beta and BMP7 in the pathogenesis of oral submucous fibrosis. AB - To understand the molecular pathogenesis of oral submucous fibrosis (OSF), which is a chronic inflammatory disease, gene expression profiling was performed in 10 OSF tissues against 8 pooled normal tissues using oligonucleotide arrays. Microarray results revealed differential expression of 5,288 genes (P <= 0.05 and fold change >= 1.5). Among these, 2,884 are upregulated and 2,404 are downregulated. Validation employing quantitative real-time PCR and immunohistochemistry confirmed upregulation of transforming growth factor-beta1 (TGF-beta1), TGFBIp, THBS1, SPP1, and TIG1 and downregulation of bone morphogenic protein 7 (BMP7) in OSF tissues. Furthermore, activation of TGF-beta pathway was evident in OSF as demonstrated by pSMAD2 strong immunoreactivity. Treatment of keratinocytes and oral fibroblasts by TGF-beta confirmed the regulation of few genes identified in microarray including upregulation of connective tissue growth factor, TGM2, THBS1, and downregulation of BMP7, which is a known negative modulator of fibrosis. Taken together, these data suggest activation of TGF-beta signaling and suppression of BMP7 expression in the manifestation of OSF. PMID- 21591999 TI - Drug safety evaluation of amlodipine. AB - INTRODUCTION: Despite the availability of a wide range of antihypertensive medications, in European countries the number of patients not reaching blood pressure control target varies from 59.7% in England to 81.3% in Spain demonstrating substantial unmet need in the effective treatment of arterial hypertension. AREAS COVERED: The authors conducted a review analyzing clinical efficacy and safety of amlodipine, both alone and in combination with other antihypertensive drugs, including the most important studies about amlodipine in the last 15 years. Readers will have a clearer idea of the use of amlodipine, its indications and contraindications, and they will know if amlodipine is a better or worse choice compared to the other antihypertensive drugs. EXPERT OPINION: Amlodipine is not inferior to the other antihypertensive drugs in reducing hypertension and has additional biological effects that are not mediated through blood pressure reduction, including antioxidant activity, inhibition of smooth muscle cell proliferation and enhancement in endothelial NO production. Amlodipine, besides being effective on left ventricular hypertrophy, appears beneficial in slowing down the progression of carotid hypertrophy and atherosclerosis, and can be used in patients with angina pectoris, even if the first choice for angina treatment is beta-blockers. PMID- 21592000 TI - NK-1 as a melanoma target. AB - INTRODUCTION: Melanoma expresses both neurokinin-1 (NK-1) receptors and substance P (SP). After binding to the NK-1 receptor, SP induces tumor cell proliferation in melanoma cells, whereas after binding to the same NK-1 receptor, antagonists inhibit melanoma cell proliferation and cause tumor cell death by apoptosis. Thus, the NK-1 receptor could be a new and promising target in melanoma therapy. AREAS COVERED: This review provides an overview of the underlying mechanism of action of the SP/NK-1 receptor system, and NK-1 receptor antagonists in human melanoma, over the last 7 years. EXPERT OPINION: In stages III - IV, no effective treatment exists for melanoma and hence there is an urgent need to improve therapy in melanoma patients. The NK-1 receptor is a promising new target in human melanoma treatment, since preclinical assays (most of them in vitro assays) have reported that NK-1 receptor antagonists exert an antitumor action against melanoma. The NK-1 receptor antagonist aprepitant is used in clinical practice and exerts an antitumor action against human melanoma in vitro. In the future, such antitumor action should be tested in human clinical trials. This should be faster compared with less investigated NK-1 receptor antagonists, because a great part of the required safety and characterization studies for aprepitant have already been carried out. PMID- 21592001 TI - Chemical composition, antibacterial activity and cytotoxicity of essential oils of Tanacetum parthenium in different developmental stages. AB - CONTEXT: Tanacetum parthenium Schultz Bip. (Asteraceae) is an aromatic perennial plant, widely distributed in the northern hemisphere. This species traditionally has been used in insecticides, cosmetics, balsams, dyes, medicines and preservatives. MATERIAL AND METHODS: The essential oil of T. parthenium was obtained by hydrodistillation in three developmental stages and analyzed by gas chromatography-mass spectrometry. The antibacterial activity of the oils was investigated against four Gram-positive and four Gram-negative bacteria. The oil was tested for cytotoxicity against THP-1 cells using the Trypan blue assay. RESULTS: Twenty-nine components were identified in the essential oil; the highest amount was extracted at the flowering stage. The main component, in the flowering stage, was camphor (18.94%) and other major components were bornyl acetate (18.35%), camphene (13.74%), bornyl isovalerate (3.15%), borneol (10.93%), juniper camphor (6.23%) and beta-eudesmol (2.65%). Minimum inhibitory concentration of essential oil was evaluated from 4 uL mL(-1) against Staphylococcus subtilis to 38 uL mL(-1) against Entrobacter aerogenes. Toxicity assay showed that the oil has no significant toxicity at 5-15% v/v concentrations on THP-1 cells. DISCUSSION AND CONCLUSION: This study demonstrates the occurrence of camphor/bornyl acetate chemotype of T. parthenium in western regions of Iran. The finding showed also the studied oils have relatively good antibacterial activity without significant toxicity, thus have great potentiality to be used as natural health product. PMID- 21592002 TI - Situational and psychosocial factors mediating coordinated joint attention with augmentative and alternative communication systems with beginning communicators without disabilities. AB - This study examined how infants' age, joint attention (JA) skills, caregiver ratings of language and temperament, and caregiver JA style related to JA in a structured literacy task with an augmentative and alternative communication (AAC) system. Sixteen infants (mean = 10.6 months) without disabilities participated in two storybook reading interactions with an experimenter in two conditions where the AAC system was either aligned or divided from the experimenter's eye gaze. Individual differences in JA skills, caregiver JA style, and temperament were associated with coordinated JA across both conditions. The findings suggest it is important to examine both extrinsic and intrinsic factors, which may not only reduce attention demands but also mediate the success of JA interactions with AAC systems. PMID- 21592003 TI - "He cares about me and I care about him." Children's experiences of friendship with peers who use AAC. AB - Typically developing children face multiple challenges in developing friendships with peers who have severe physical disabilities and use augmentative and alternative communication (AAC), especially when these peers experience restrictions in mobility, educational participation, physical access, and communication. In this small qualitative study, six typically developing children were interviewed about their friendships with classmates who have cerebral palsy and use AAC. Data were analyzed according to Riessman's narrative methodology (2008). Overall, participants viewed these friendships positively. In this article, we discuss the main themes that characterized these friendships: communication, learning, helping, and shared time. This knowledge may help to facilitate friendships between children without disabilities and their peers who use AAC within mainstream educational settings. PMID- 21592004 TI - Visual supports for shared reading with young children: the effect of static overlay design. AB - This study examined the effects of two types of static overlay design (visual scene display and grid display) on 39 children's use of a speech-generating device during shared storybook reading with an adult. This pilot project included two groups: preschool children with typical communication skills (n = 26) and with complex communication needs (n = 13). All participants engaged in shared reading with two books using each visual layout on a speech-generating device (SGD). The children averaged a greater number of activations when presented with a grid display during introductory exploration and free play. There was a large effect of the static overlay design on the number of silent hits, evidencing more silent hits with visual scene displays. On average, the children demonstrated relatively few spontaneous activations of the speech-generating device while the adult was reading, regardless of overlay design. When responding to questions, children with communication needs appeared to perform better when using visual scene displays, but the effect of display condition on the accuracy of responses to wh-questions was not statistically significant. In response to an open ended question, children with communication disorders demonstrated more frequent activations of the SGD using a grid display than a visual scene. Suggestions for future research as well as potential implications for designing AAC systems for shared reading with young children are discussed. PMID- 21592005 TI - The ComAlong communication boards: parents' use and experiences of aided language stimulation. AB - This study evaluated parents' use and experiences of the ComAlong communication boards, which were provided to them during a parental course on communication development, responsive strategies, and augmentative and alternative communication (AAC). Quantitative and qualitative data was collected through a survey of 65 parents and an in-depth case study of four of the parents. Questionnaires, interviews, logbooks, and video recordings showed that parents used the ComAlong boards and experienced an increased understanding of augmentative and alternative communication. Most parents reported that their children showed an interest in the boards and that in some cases started to use the boards functionally in communication. Parents' views, in terms of gains and difficulties of using graphic communication at home, are discussed. PMID- 21592006 TI - Announcing the AAC-RERC white paper on mobile devices and communication Apps ( www.aac-rerc.com ). PMID- 21592007 TI - Adaptation process for standing postural control in individuals with hemiparesis. AB - PURPOSE: To study the adaptation process for standing postural control in patients with hemiparesis after stroke. METHODS: The changes of a standing posture developed in nine hemiparetic patients who had never maintained an upright stance alone (aged 48-62 years; 6-19 days after stroke) was evaluated by recording ground reaction forces and surface electromyographic (EMG) from lower limbs. A 60-s standing trial without any instruction about body alignment was repeated five times, and the experience-related changes of centre of pressure (COP) and integrated EMG data were estimated. RESULTS: In the early standing trials, patients balanced themselves by managing the average COP position around the midline of both feet, accompanied by increased muscular activity of the non paretic leg. COP displacement gradually decreased in the later standing trials (P < 0.05). Postural adaptations were achieved by shifting the centre of body sway to the side of the non-paretic foot (P < 0.05) while reducing biceps femoris muscular activity (P < 0.01) in the non-paretic leg. CONCLUSIONS: This study revealed that weight-bearing asymmetry might contribute to improving increased body sway and muscular over-activity of the non-paretic leg. When planning rehabilitative treatment for hemiparetic patients, we should consider that weight bearing asymmetry may be a result of systematic postural control. PMID- 21592008 TI - Subcutaneous antifungal screening of Latin American plant extracts against Sporothrix schenckii and Fonsecaea pedrosoi. AB - CONTEXT: Subcutaneous mycoses are chronic infections caused by slow growing environmental fungi. Latin American plants are used in folk medicine to treat these afflictions. Moreover, the potential of the rich Latin American biodiversity for this purpose has not been fully explored. OBJECTIVES: The aim of the study was to screen Latin American plant extracts against two species of subcutaneous fungi: Sporothrix schenckii and Fonsecaea pedrosoi. MATERIALS AND METHODS: One hundred ninety-five organic extracts from 151 Latin American plants were screened against two subcutaneous fungi by the agar dilution method at a concentration of 100 ug/mL, and minimum inhibitory concentrations (MICs) of active extracts were determined. Positive (amphothericin B) and negative (50% ethanol) controls were used. RESULTS AND DISCUSSION: Twenty eight extracts showed activity at <=100 ug/mL. Of these, four extracts from Gnaphalium gaudichaudianum DC (Asteraceae), Plumeria rubra L (Apocynaceae), Tecoma stans (L.) Juss. ex Kunth. (Bignoniaceae), and Trichostigma octandum (L.), H. Walter showed activity against F. pedrosoi at MIC 12.5 ug/mL; and, four extracts from Bourreria huanita (Lex.) Hemsl. (Boraginaceae), Phytolacca bogotensis Kunth (Phytolaccaceae), Monnina xalapensis Kunth (Polygalaceae) and Crataegus pubescens (C. Presl) C. Presl (Rosaceae) against S. schenckii. This is the first report on antifungal activity of the Latin American plants against these two subcutaneous fungi. CONCLUSION: S. schenkii and F. pedrosoi were inhibited by B. huanita (MIC: 12.5 and 25 ug/mL), G. gaudichaudianum (MIC: 50 and 12.5 ug/mL) and T. triflora (MIC: 25 ug/mL). PMID- 21592009 TI - Selection and use of contraceptive methods among internal migrant workers in three large Chinese cities: a workplace-based survey. AB - OBJECTIVES: To describe the current status of the decision-making process with regard to the use of contraceptive methods among internal migrant workers in three large Chinese cities. METHODS: A total of 4313 sexually active internal migrant workers were recruited in Beijing, Shanghai, and Chengdu. Information on contraceptive use was collected by means of questionnaires. RESULTS: Contraceptive prevalence was 86% among unmarried sexually active migrant workers and 91% among married workers. The main contraceptive methods used by married migrants were the intrauterine device (51%), condoms (25%) and female/male sterilisation (17%); the main methods resorted to by unmarried, sexually active migrants were condoms (74%) and oral contraceptives (11%). The contraceptive method applied by 20% of married respondents had been selected by other people, without they themselves having their share in an informed choice. Adopting the contraceptive decisions made by others was associated with being a married migrant, a construction or service worker, a rural-urban migrant, a migrant living in collective or rented rooms, or a migrant with more children. CONCLUSIONS: Many internal migrants in these large cities did not choose their contraceptive method on their own. Efforts enabling and encouraging migrants to make informed choices are needed. PMID- 21592010 TI - Abstracts of the Canadian Nutrition Society's 2nd Annual Scientific Meeting, Guelph, Ontario, Canada, 2-4 June 2011. PMID- 21592011 TI - Antioxidant and antimicrobial activities of branches extracts of five Juniperus species from Turkey. AB - CONTEXT: Several Juniperus species (Cupressaceae) are utilized in folk medicine in the treatment of infections and skin diseases. OBJECTIVE: This work was designed to evaluate the antioxidant and antimicrobial potential of methanol and water branches extracts of Juniperus species from Turkey: Juniperus communis L. var. communis (Jcc), Juniperus communis L. var. saxatilis Pall. (Jcs), Juniperus drupacea Labill. (Jd), Juniperus oxycedrus L. subsp. oxycedrus (Joo), Juniperus oxycedrus L. subsp. macrocarpa (Sibth. & Sm.) Ball. (Jom). MATERIALS AND METHODS: Total phenolics, total flavonoids and condensed tannins were spectrophotometrically determined. The antioxidant properties were examined using different in vitro systems. The toxicity was assayed by Artemia salina lethality test. The antimicrobial potential against bacteria and yeasts was evaluated using minimum inhibitory concentration and minimum bactericidal concentration (MIC/MBC) measurements. The effect on bacteria biofilms was tested by microtiter plate assay. RESULTS: Both in the DPPH (1,1-diphenyl-2-picrylhydrazyl) and TBA (thiobarbituric acid) test Jom resulted the most active (IC(50) = 0.034 +/- 0.002 mg/mL and 0.287 +/- 0.166 ug/mL). Joo exhibited the highest reducing power (1.78 +/- 0.04 ASE/mL) and Fe(2+) chelating activity (IC(50) = 0.537 +/- 0.006 mg/mL). A positive correlation between primary antioxidant activity and phenolic content was found. The extracts were potentially non-toxic against Artemia salina. They showed the best antimicrobial (MIC = 4.88-30.10 ug/mL) and anti-biofilm activity (60-84%) against S. aureus. DISCUSSION AND CONCLUSION: The results give a scientific basis to the traditional utilization of these Juniperus species, also demonstrating their potential as sources of natural antioxidant and antimicrobial compounds. PMID- 21592012 TI - Antiproliferative effects of extracts from Iranian Artemisia species on cancer cell lines. AB - OBJECTIVE: Different species of Artemisia (Asteraceae) have shown to exhibit antitumor activity. The aim of this study was to identify the antiproliferative effect of some Artemisia species from Iran on cultured human cancer cells. MATERIALS AND METHODS: Methanol, ethyl acetate, dichloromethane and n-hexane extracts from aerial parts of seven species of Artemisia were prepared and their antiproliferative effects on four cancer (AGS, HeLa, HT-29 and MCF-7) and normal cell line (L929) were determined. Different concentrations of extracts were added to cultured cells and incubated for 72 h. 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay was employed to assess the cell viability. RESULTS: Different extracts exert various growth inhibitory effects. In case of AGS cells, dichloromethane and methanol extracts of A. ciniformis Krasch. & Popov ex Poljak. (IC(50) values: 35 and 60 ug/ml, respectively) showed the highest growth inhibitory effects. HeLa cells were more sensitive to both A. diffusa Krasch. ex Poljak. dichloromethane (IC(50) value: 71 ug/ml) and A. ciniformis ethylacetate (IC(50) value: 73 ug/ml) extracts. Dichloromethane extracts of A. diffusa, A. santolina Schrenk and A. ciniformis (IC(50) values: 42, 91 and 94 ug/ml, respectively) exhibited more inhibition on HT-29 cells in comparison to other extracts. MCF-7 cells were best inhibited by A. ciniformis dichloromethane (IC(50) value: 29 ug/ml) and A. vulgaris L. ethyl acetate (IC(50) value: 57 ug/ml) extracts. DISCUSSION AND CONCLUSION: This study shows the antiproliferative effects of Artemisia extracts on malignant cell lines. Artemisia could be also considered as a promising chemotherapeutic agent in cancer treatment. PMID- 21592013 TI - Anti-inflammatory, free radical-scavenging, and metal-chelating activities of Malva parviflora. AB - CONTEXT: Malva parviflora L. (Malvaceae) is widely distributed throughout Africa. It has several uses in traditional medicinal practice. Leaves of this plant are used in the treatment of some inflammatory disorders. OBJECTIVE: The anti inflammatory and the antioxidant activities of the methanol extract (Met. E) and aqueous extract (Aq. E) of M. parviflora leaves were investigated. MATERIALS AND METHODS: Croton oil-induced ear edema and acetic acid-induced vascular permeability were applied as acute inflammatory models to evaluate the anti inflammatory activity of the extracts. The antioxidant effects were evaluated using the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical assay and the measurement of the metal-chelating activity. RESULTS: Results demonstrated that Met. E inhibited the croton oil-induced ear edema by 57%. In contrast, the Aq. E did not show any activity. Furthermore, Met. E and Aq. E inhibited significantly the acetic acid-induced vascular permeability by 36 and 40%, respectively. However, Met. E and Aq. E exerted a strong scavenging activity with IC(50) values of 89.03 +/- 2.65 and 76.67 +/- 0.29 ug/mL, respectively. Moreover, Met. E and Aq. E were able to chelate ferrous ions in a concentration-dependent manner. DISCUSSION AND CONCLUSION: These findings demonstrate that M. parviflora leaf extracts possess anti-inflammatory and antioxidant activities and thus have great potential as an interesting source for natural health products. PMID- 21592014 TI - Reduction of metabolic and behavioral signs of acute stress in male Wistar rats by saffron water extract and its constituent safranal. AB - CONTEXT: Saffron extract can inhibit the metabolic disorders induced by stress but the mechanism of action of saffron extract in the central nervous system is not clear. OBJECTIVE: The present research investigated the effects of saffron water extract and its constituent, safranal on the behavioral and metabolic signs induced by electroshock stress in male Wistar rats (W: 250-300 g). MATERIALS AND METHODS: Dried saffron material and maceration method was used for extraction. Animals received intra-amygdala (1, 5, and 10 ug/rat) or intraperitoneal (1, 5, and 10 mg/kg) administration of the extract, safranal (Fluka, Germany), or saline 5 or 30 min before stress induction, respectively. RESULTS: The result showed that stress elevated the corticosterone plasma (115 nmol/L) concentration in the control and intra-amygdala (1, 5, and 10 ug/rat)-treated groups but not in groups that received extract or safranal (55 nmol/L) intraperitoneally (1, 5, and 10 mg/kg). Moreover, anorexia was reduced only in groups that received the extract (1, 5, and 10 mg/kg) or safranal (1, 5, and 10 mg/kg) intraperitoneally (50 sec). Stress increased sniffing, rearing, locomotion, and coping time, which were decreased by intraperitoneal (1, 5, and 10 mg/kg) but not by intra-amygdala (1, 5, and 10 ug/rat) administration of saffron extract and safranal. DISCUSSION AND CONCLUSION: The results revealed that saffron water extract and safranal had an important impact on the reduction of both metabolic and behavioral signs of stress in male Wistar rats. Moreover, the involvement of the amygdala in this observation can be ruled out. PMID- 21592015 TI - Horizontal gaze palsy and progressive scoliosis due to a deleterious mutation in ROBO3. AB - PURPOSE: To describe a family with horizontal gaze palsy and progressive scoliosis with a deleterious mutation in the ROBO3 gene. METHODS: All family members had full ophthalmologic, neurologic, and orthopedic examinations and complete sequencing of the ROBO3 gene. RESULTS: Four affected members had complete loss of horizontal gaze with progressive scoliosis that varied between family members. ROBO3 sequencing revealed a novel 15 base deletion (c.2_16 delTGCTGCGCTACCTGC) in exon 1 that segregated in homozygous form with the phenotype and probably alters the shape and ionic charge of the extracellular immunoglobulin motif 1. This mutation was not detected in 100 control chromosomes. CONCLUSIONS: The novel ROBO3 mutation in this family may be among the most deleterious yet reported. Family members in general were severely affected, but comparison of this family to other families with ROBO3 mutations did not yield a definitive phenotype-genotype correlation. PMID- 21592016 TI - Moving a formative test from a paper-based to a computer-based format. A student viewpoint. AB - BACKGROUND: A paper-based test was changed to a computer-based format. Students completed the test over a 2-week period on any computer with internet access. AIM: To determine the acceptability to students of the computer-based format, whether resources were used by students during the test, the value of receiving an immediate score, positive aspects of the computer format and areas for improvement. METHODS: Students completed an online survey containing closed questions (Likert scale) and free text questions. RESULTS: A large majority of respondents had easy access to a computer, found it easy to complete the test in the time given and did not use resources to answer the test questions. The most cited benefits were flexibility and convenience in being able to choose both the location and time for taking the test. A smaller majority found it useful to get immediate feedback. The possibility of students 'cheating' because of the ability to use resources during the test was seen as problematic. Some students felt that the test appeared to lack importance because of the flexibility permitted. CONCLUSIONS: From a student perspective, the computer was an acceptable platform for delivering a formative assessment comprising multiple choice questions (MCQs). PMID- 21592017 TI - Lessons from medical students' perceptions of learning reflective skills: a multi institutional study. AB - BACKGROUND: A core competency during undergraduate medical training is the development of reflective learning. The current literature is limited to demonstrating how reflective learning has been implemented or the approaches to its development. There is a lack of insight into students' perceptions of reflection and the factors that support development of reflective practice. Bridging this gap may provide insight into how reflective learning within the curriculum can be better developed to increase engagement from learners. METHODS: Eight focus group interviews with second year students from four UK medical schools were held. Results were thematically analysed. KEY FINDINGS: Students have a high level of understanding of the purpose of reflection in practice but they perceive that there is a tension between public and private reflections. Assessment of the reflective process was perceived to be useful for developing reflective skills but grading of their reflective writing was not considered to be useful. Staff who champion the development of reflective skills and mentor students were perceived to play key roles in aiding the development of reflective skills. Appropriate experiences were seen to be a key part of developing reflective skills. CONCLUSION: These findings highlight potential ways to revise and improve engagement with the reflective learning components of undergraduate courses. PMID- 21592018 TI - A 3-year experience implementing blended TBL: active instructional methods can shift student attitudes to learning. AB - Medical educators have been encouraged to adopt active instructional strategies that require learners to engage in and direct their own learning. These innovations may be seen as disruptive and face early challenges due to student resistance. We report 3 years of experience implementing a blend of team-based learning (TBL) and online learning modules in an undergraduate medical course. Three sequential cohorts of first year medical students were surveyed exploring how they valued different instructional methods during a period of evolving curricular design. In addition to a demonstrated increase in acceptance of new teaching methods, there was a shift in student perceptions of the relative merits of didactic, online and TBL teaching. Medical students' appreciations of different instructional methods are influenced by the maturity of instructional design. Educational change is best viewed through a longer term lens, acknowledging the necessity for teachers to develop experience in implementing new methods in the context of their institution. PMID- 21592019 TI - Comparison of three clinical environments for pre-clinical clinical skills training. AB - OBJECTIVES: Primary health care (PHC), secondary health care (SHC), and tertiary health care (THC) were compared in search of the most suitable setting for clinical skills training of pre-clinical students. METHODS: The Dundee Ready Educational Environment Measure questionnaire was presented to 300 clerkship students of the Faculty of Medicine at Gadjah Mada University, Indonesia who were attached to PHC, SHC, and THC settings. Students were asked to assess their current attachment for suitability for training of pre-clinical students. Semi structured interviews were held with 46 clinical supervisors based on the three types of settings. RESULTS: Clerkship students preferred PHC centers over SHC and THC hospitals for clinical skills training of pre-clinical students (p < 0.05). PHC staff felt their centers to be well-equipped to train pre-clinical students, including availability of supervisors' time for teaching, adequate physical facilities and equipment, and suitable patient cases. CONCLUSION: In the developing country context, PHC centers seemed more appropriate for clinical skills training of pre-clinical students than SHC and THC hospitals. However, the skills laboratory must guard that clinical skills are trained and performed in the same way in that facility, in PHC centers and in teaching hospitals. PMID- 21592020 TI - Bridging the global health training gap: Design and evaluation of a new clinical global health course at Harvard Medical School. AB - BACKGROUND: Medical student and resident interest in global health has been growing rapidly. Meanwhile, educational opportunities for trainees remain limited, and many trainees participate in global health experiences abroad without adequate preparation. Medical institutions are attempting to respond to this training gap by developing global health curricula. AIMS: We describe a novel clinical skills-based curriculum recently established among Harvard medical students and residents with the primary objective of providing essential clinical knowledge and skills to work effectively in resource-limited settings. METHODS: The course consisted of 10 evening sessions taught by a multidisciplinary faculty and focusing on practical management of the leading causes of the global burden of disease. Didactic discussions were reinforced by case studies and practical skills sessions, such as tropical microscopy, basic bedside ultrasound, simple dental extraction, and newborn resuscitation. RESULTS: Student mean knowledge scores increased significantly, from 64.5% (SD 8.9) before the course to 79.5% (SD 8.6) after the course (p < 0.001). Students also gave strongly positive evaluations and particularly valued the course's practical skills-building and the horizontal and vertical mentorship that developed among the diverse student, resident, and faculty participants. CONCLUSIONS: This clinical course in global health may serve as one model for more effectively preparing trainees to work in developing countries. PMID- 21592021 TI - Introduction of real patients into problem-based learning in preclinical first year anatomy curriculum. AB - BACKGROUND: Early patient contacts are considered important in medical education. AIMS: We studied the influence of a real patient trigger on study motivation and learning in problem-based study groups of first-year medical and dentistry students. METHODS: 156 eligible students were allocated into 17 groups. Six randomly selected groups received both the real patient and paper trigger, and 11 groups received only the paper trigger. The immediate and later effects of the trigger were assessed with qualitative and quantitative questionnaires and exam scores. The tutors answered questionnaires concerning learning outcomes. RESULTS: The students reported that the real patient trigger significantly improved their study motivation, understanding of the learning objectives and confidence in future patient encounters. The real patient trigger was considered significantly more interesting than the paper case. No statistically significant difference was observed in the exam scores. The tutors observed that groups with poor previous performance gained better results in study sessions. CONCLUSIONS: Real patient triggers motivate students to learn basic medical sciences. Ways to present real patients to students should be considered in medical curricula from early on. PMID- 21592022 TI - Academic dishonesty among undergraduates from private medical schools in India. Are we on the right track? AB - BACKGROUND: Though doctors are considered to be respectful role models of professionalism and ethics, medical students are no strangers to academic dishonesty. AIM: To assess the academic dishonesty practices among undergraduate students from private medical schools in India. METHODS: A pre-tested and validated questionnaire containing 10 commonly done academic misconducts were administered and responses were collected. RESULTS: Out of 166 medical students enrolled in the study, 75% have given proxy for attendance and 49% have copied from others record book. During a theory exam, 74% of students have copied from their friends, 2% have tried to get the question paper before exam and 5% have influenced their teachers by unfair means to get more marks. During clinical/practical exam, 81% have got technical help, 45% had prior knowledge about the exam case, and 54% of them have falsely documented clinical findings. CONCLUSIONS: The prevalence of academic dishonesty is high. Academic integrity and ethics should be emphasized to the students which might help them in becoming professional and honest doctors. PMID- 21592023 TI - The educational and financial impact of using patient educators to teach introductory physical exam skills. AB - PURPOSE: Physical exam skills are essential to core competencies for physicians in training. It is increasingly difficult to secure time and funding for physician faculty to teach these critical skills. This study was designed to determine whether Patient Educators (PE) (non-physician instructors) in an introductory clinical medicine (ICM) course (1) were as effective as physician faculty in teaching the physical exam, (2) impacted consistency of student performance on a final practical exam, and (3) whether this model was cost effective. METHOD: PE were introduced into an ICM course at the University of Minnesota from 2006 to 2008. Each year, students' physical exam competencies were evaluated by a performance-based head-to-toe examination and 6 months later by an objective structured clinical examination (OSCE). Differences in test scores between years and variability (i.e., consistency) among yearly scores were assessed. The cost per student was calculated by considering a stable compensation cost per hour for the required number of physician faculty, standardized patients, and PE in each year. RESULTS: Mean student performance was statistically lower with PE, but only by two percentage points. The amount of variation within the medical student classes' physical exam skills remained stable as the use of PE expanded. Total educator salary costs per student declined from $449 in 2006 to $196 in 2008. CONCLUSIONS: In terms of sustainability and student performance, the use of trained lay educators has equivalent outcomes and is less costly for physical exam instruction in the pre clinical years. PMID- 21592024 TI - Admission selection criteria as predictors of outcomes in an undergraduate medical course: a prospective study. AB - BACKGROUND: In 1998, a new selection process which utilised an aptitude test and an interview in addition to previous academic achievement was introduced into an Australian undergraduate medical course. AIMS: To test the outcomes of the selection criteria over an 11-year period. METHODS: 1174 students who entered the course from secondary school and who enrolled in the MBBS from 1999 through 2009 were studied in relation to specific course outcomes. Regression analyses using entry scores, sex and age as independent variables were tested for their relative value in predicting subsequent academic performance in the 6-year course. The main outcome measures were assessed by weighted average mark for each academic year level; together with results in specific units, defined as either 'knowledge'-based or 'clinically' based. RESULTS: Previous academic performance and female sex were the major independent positive predictors of performance in the course. The interview score showed positive predictive power during the latter years of the course and in a range of 'clinically' based units. This relationship was mediated predominantly by the score for communication skills. CONCLUSIONS: Results support combining prior academic achievement with the assessment of communication skills in a structured interview as selection criteria into this undergraduate medical course. PMID- 21592026 TI - Did you ever? PMID- 21592027 TI - Elephants and quality care. PMID- 21592028 TI - Be prudent of ketamine in treating resistant depression in patients with cancer. PMID- 21592029 TI - Palliative medicine and the surgeon. PMID- 21592030 TI - Making the case for palliative care in developing countries: the Republic of Georgia. PMID- 21592031 TI - Rehabilitation of the hospice and palliative care patient. AB - Disability is a common problem among hospice and palliative care patients. It leads to depression, poor quality of life, increased caregiver needs, health care resource utilization, and need for institutionalization. There is a growing body of evidence that rehabilitation interventions improve functional status, quality of life, and symptoms such as pain and anxiety in this population. Having adequate knowledge about rehabilitation is essential for the provision of comprehensive end-of-life care. The goals of this article are to review the role and benefits of rehabilitation in hospice and palliative care; to discuss the elements of patient assessment for rehabilitation including the use of functional assessment tools; and to review the roles of physical, occupational, and speech therapy in hospice and palliative care patients. PMID- 21592032 TI - The joys and complications of working on a team. PMID- 21592033 TI - Palliative care for patients with Huntington's disease #201. PMID- 21592034 TI - Genetic screening and DNA banking at the end of life #206. PMID- 21592035 TI - Tyrell and Tonya: an ICU experience. PMID- 21592045 TI - Returning to work after spinal cord injury: exploring young adults' early expectations and experience. AB - PURPOSE: The study sought to explore experience and expectations about paid work among young adults on sick leave after spinal cord injury (SCI). METHOD: Eight participants with traumatic SCI, who were 20-34 years of age, and had not yet returned to work 1-5 years post-injury, were interviewed. Selection was made with purposive sampling. Data were analysed using a constant comparative method. RESULTS: Four main themes emerged as relevant: 'finding your way to an everyday life where work is possible', 'at the crossroads, expectations of work through education', 'expectations of paid work as part of a desired future life' and 'expectations of finding a solution within oneself or with help from others'. The findings reveal high expectations of work ability but at the same time difficulties to plan for return to work and lack of support in this process. CONCLUSIONS: The participants represent a vulnerable group in vocational rehabilitation due to their young age and recent injury. Without formal training or suitable work experience, they need tailored work support as part of their general rehabilitation. PMID- 21592046 TI - Recent achievements in nanostructured photovoltaic devices. AB - This mini-review summarizes some key interesting applications and perspectives of nanostructured devices for future nanoelectronics, among them are photonic circuits, carbon nanostructures for chemisensors, unique Ag-Cu-nanocluster contacts for high-effective solar cells. Recent patents in the field are also discussed. PMID- 21592044 TI - Triggering receptor expressed on myeloid cells-1 (TREM-1) modulates immune responses to Aspergillus fumigatus during fungal asthma in mice. AB - Triggering receptor expressed on myeloid cells-1 (TREM-1) expression is increased during pulmonary fungal infection suggesting that this receptor might be involved in anti-fungal immune responses. To address the role of TREM-1 in a murine model of fungal allergic airway disease, A. fumigatus-sensitized CBA/J mice received by intratracheal injection a mixture of live A. fumigatus conidia and one of a control adenovirus vector (Ad70), an adenovirus containing a gene encoding for the extracellular domain of mouse TREM-1 and the F(c) portion of human IgG (AdTREM-1Ig; a soluble inhibitor of TREM-1 function), or an adenovirus containing mouse DAP12 (AdDAP12; DAP12 is an intracellular adaptor protein required for TREM 1 signaling), and examined at various days after challenge. Whole lung TREM-1 levels peaked at day 3 whereas circulating TREM-1 levels peaked at day 30 in this fungal asthma model. AdTREM-1Ig-treated mice exhibited significantly higher airway hyperresponsiveness following methacholine challenge compared with Ad70- and AdDAP12-treated mice. Whole lung analysis of AdTREM-1Ig treated mice revealed markedly higher amounts of fungal material compared with the other groups. ELISA analysis of whole lung and bronchoalveolar lavage samples indicated that several pro-allergic cytokine and chemokines including CCL17 and CCL22 were significantly increased in the AdTREM-1Ig group compared with the other groups. Finally, Pam3Cys and soluble Aspergillus antigens induced TREM-1 transcript expression in macrophages in a TLR2 dependent manner. In conclusion, TREM-1 modulates the immune response directed against A. fumigatus during experimental fungal asthma. PMID- 21592047 TI - Mild cognitive impairment (MCI) - the novel trend of targeting Alzheimer's disease in its early stages - methodological considerations. AB - While much uncertainty exists in the estimates of the global burden of Alzheimer's disease and about the potential impact of various interventions, there is a widespread acceptance of the fact that the steady increase in the incidence and prevalence of the condition worldwide is becoming a massive public health problem as well as a huge economic burden for all healthcare systems and societies. These heavy demands are further compounded by the poor quality of life of the affected individuals, of their families and of their caregivers. The epidemic proportion of Alzheimer's disease has triggered relentless attempts for development of treatment approaches during the past two decades by a multitude of pharmaceuticals and biotech companies. Commercial development of the acetylcholinesterase inhibitors has, until recently, virtually dominated the field and, although efficacy has been demonstrated for five different products, the longterm clinical results suggested that alternate approaches were warranted. Disease modifying strategies targeting the beta- amyloid plaques (e.g., decreasing beta-amyloid formation through beta- and gamma-secretase inhibition, diminishing beta-amyloid aggregation through anti-aggregants or enhancement of beta-amyloid clearance through active/passive immunization), targeting the neurofibrillary tangles through inhibition of tau protein hyperphosphorilation or, more recently, by increasing mitochondrial permeability, all these potential treatment modalities are facing major methodological challenges during the conduct of a myriad of clinical trials meant to bring the novel therapies to the market. Failure of more than 400 products tested in more than 800 clinical trials to date, with many of these failures occurring in late stage development (phase III) have triggered a paradigm shift toward targeting of the early stages of cognitive deficiencies (mild cognitive impairment- MCI) and a refinement of the investigative methodologies. The great heterogeneity of the disease entity itself (MCI) coupled with inadequate sensitivity, specificity and positive/negative predictive values of the many common diagnostic outcome scales, outcome measures, and of many of the currently used biomarkers expose the drug development professionals to the risk of methodological flaws rendering the products explored ineffective, while very expensive. PMID- 21592048 TI - Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. AB - INTRODUCTION: Two phase 3 studies evaluated the efficacy and safety of rosiglitazone (RSG), a type 2 diabetes treatment, in an extended release (RSG XR) form as adjunctive therapy to ongoing acetylcholine esterase inhibitor (AChEI) treatment in AD (REFLECT-2, adjunctive to donepezil; REFLECT-3, to any AChEI). An open-label extension study (REFLECT-4) assessed RSG XR long-term safety. METHODS: In these two double-blind, placebo-controlled studies, subjects with mild-to moderate probable AD were randomized within 2 apolipoprotein E (APOE) allelic strata (APOE epsilon4-positive, APOE epsilon4-negative) to once daily placebo, 2 mg RSG XR, or 8 mg RSG XR for 48 weeks (REFLECT-2, N=1,496; REFLECT-3, N=1,485). Co-primary efficacy endpoints were change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) scores at week 48. Three populations were analyzed: APOE4 negative, all subjects except APOE epsilon4 homozygotes, and the full intent-to treat population. RESULTS: No statistically or clinically relevant differences between treatment groups were observed on the a priori primary endpoints in REFLECT-2 or REFLECT-3. Edema was the most frequent adverse event with RSG in each study (14% and 19%, respectively, at 8 mg RSG XR). CONCLUSIONS: No evidence of statistically or clinically significant efficacy in cognition or global function was detected for 2 mg or 8 mg RSG XR as adjunctive therapy to ongoing AChEIs. There was no evidence of an interaction between treatment and APOE status. Safety and tolerability of RSG XR was consistent with the known profile of rosiglitazone. PMID- 21592049 TI - Effects of coenzyme Q and creatine supplementation on brain energy metabolism in rats exposed to chronic cerebral hypoperfusion. AB - It is known that oxidative stress and mitochondrial dysfunction both play an important role in animal models of brain ischemia. The present study was undertaken to test whether oral supplementation of coenzyme Q10 (ubiquinone) or creatine citrate could protect against brain ischemia-induced mitochondrial damage in the rats model. Brain ischemia was induced for 50 minutes with three vessel occlusion (3-VO). Coenzyme Q10 was administered for 30 days before the ischemic event and coenzyme Q10 or creatine citrate for 30 days post-ischemia. Moreover, the concentrations of coenzyme Q10 and alpha-, gamma- tocopherols as well as the formation of thiobarbituric acid reactive substances (TBARS) were measured in brain mitochondria and in plasma. Transient hypoperfusion revealed significant impairment in brain energy metabolism as detected by mitochondrial oxidative phosphorylation as well as decreased concentrations of brain and plasma endogenous antioxidants and increased formation of TBARS in plasma. When compared with the ischemic group, supplementation of coenzyme Q10 was ineffective as a preventive agent. However, the positive effect of therapeutic coenzyme Q10 supplementation was supported by the oxygen consumption values (p < 0.05) and ATP production (p < 0.05) in brain mitochondria, as well as by increased concentration of coenzyme Q9 (p < 0.05) and concentration of alpha-tocopherol (p < 0.05) in brain mitochondria and by increased concentration of alpha-tocopherol (p < 0.05) and gamma-tocopherol in plasma. This suggests that coenzyme Q10 therapy involves resistance to oxidative stress and improved brain bioenergetics, when supplemented during reperfusion after ischemic brain injury. PMID- 21592050 TI - Left anterior temporal lobe sustains naming in Alzheimer's dementia and mild cognitive impairment. AB - Cognitive decline in degenerative dementia is paralleled by progressive brain atrophy, with the localization of atrophy reflecting specific cognitive impairment. Confrontation naming deficits are frequently observed in dementia across etiologies. In this study we aimed to identify the brain regions underlying this deficit. In patients with clinically diagnosed dementia or mild cognitive impairment (MCI) we investigated the relationship between gray matter volume (GMV) and performance on a standardized confrontation naming test. 268 patients with one of three probable etiologies were included: Alzheimer's Dementia (AD), AD with signs of cerebrovascular pathology, and frontotemporal dementia. Applying voxel-based morphometry using a diffeomorphic registration algorithm we contrasted GMV of patients performing within the normal range with those of patients with pathological performance. Further, differential effects of gray matter atrophy on impaired performance in AD versus MCI of AD type were investigated. Results revealed significantly reduced GMV in the left anterior temporal lobe (ATL) in pathological performers compared to normal performers. The subgroup analysis confined to MCI of AD type and AD patients confirmed this relationship. While left ATL atrophy is known to be implicated in naming deficits in semantic dementia, our data confirm the same in AD and MCI of AD type. PMID- 21592051 TI - Abeta(1-42) aggregates into non-toxic amyloid assemblies in the presence of the natural polyphenol oleuropein aglycon. AB - Amyloid aggregation starts with the initial misfolding of peptide/protein precursors, with subsequent structural rearrangement into oligomers and protofibrils; the latter eventually organize into fibrils with shared basic structural features, found deposited in amyloid diseases. Mounting evidence indicates early oligomers as the most toxic amyloid species; accordingly, the search of inhibitors of their growth is considered a promising target to prevent amyloid toxicity. We recently showed that oleuropein aglycon, a polyphenol abundant in the extra virgin olive oil, interferes with the aggregation of amylin (involved in type-2 diabetes), eliminating its cytotoxicity. Here we report that oleuropein aglycon also hinders amyloid aggregation of Abeta(1-42) and its cytotoxicity, suggesting a general effect of such polyphenol. In particular, by using a wide panel of different spectroscopic, immunologic, cell viability and imaging techniques we provide a more detailed description of Abeta(1-42) structural modifications arising in the presence of the inhibitor and the resulting cytotoxicity. We here report that the polyphenol eliminates the appearance of early toxic oligomers favouring the formation of stable harmless protofibrils, structurally different from the typical Abeta(1-42) fibrils. We also show that oleuropein aglycon is maximally effective when is present at the beginning of the aggregation process; furthermore, when added to preformed fibrils, it does not induce the release of toxic oligomers but, rather, neutralizes any residual toxicity possibly arising from the residual presence of traces of soluble oligomers and other toxic aggregates. The possible use of this polyphenol as anti-aggregation molecule is discussed in the light of these data. PMID- 21592052 TI - Transgenic mice as a model for Alzheimer's disease. AB - During the last few decades, numerous stable transgenic mouse strains have been developed in order to mimic a range of Alzheimer's disease (AD)-related pathologies. Although none of the models fully replicates the human disease, the models have been a key feature in translational research, providing significant insights into the pathophysiology of AD. They have also been widely used in the preclinical testing of potential therapies. The choice of transgenic mouse model, as well as the stage of Abeta pathology, significantly contributes to the outcome of the studies. Therefore, it is important to combine studies in different transgenic mouse models and detailed in vitro experiments to obtain a complete understanding of the origin of the disease, the actual sequences of early pathological events as well as being able to evaluate the effects of new drugs in the treatment of AD. PMID- 21592053 TI - Amyloid beta peptide levels increase in brain of AbetaPP Swedish mice after exposure to chlorpyrifos. AB - Chlorpyrifos (CPF) is an organophosphate pesticide widely used in intensive agriculture. Various studies have demonstrated delayed neurotoxic effects in adult mammals after acute CPF exposure. This pesticide induces oxidative stress and neuronal damage, which suggests a possible relationship between CPF exposure and Alzheimer's disease (AD). In the present study, we examined in a mice model of AD, long-term changes in the behavior and brain levels of amyloid beta after acute CPF exposure. Fifty mg/kg of CPF were subcutaneously injected to Tg2576 (Tg) mice carrying the Swedish amyloid-beta protein precursor (AbetaPP) mutation for AD. General status, body weight, acetyl cholinesterase (AChE) inhibition, and behavioral changes were assessed. Amyloid beta fragment (1-40 and 1-42) levels were also measured in the cortical and hippocampal brain regions. A significant and transient decrease in body weight was observed 72 hr after treatment, while no autonomic effects were noted. Motor activity was decreased in Tg mice seven months after CPF treatment. Acquisition learning in a water maze task was not affected, but retention was ameliorated in CPF-exposed Tg mice. Amyloid beta levels increased in the brains of treated Tg mice eight months after CPF exposure. The results of this study show that some behavioral changes persisted or emerged months after acute CPF exposure, while amyloid beta levels increased. These findings raise concern about the risk of developing neurodegenerative diseases following moderate exposure to CPF in vulnerable subjects. PMID- 21592054 TI - Dysregulated NF-kappaB pathway in peripheral mononuclear cells of Alzheimer's disease patients. AB - Diagnosis and therapeutic strategies in Alzheimer's disease (AD) might greatly benefit of the present multidisciplinary approach for studying the molecular pathogenesis of the disorder. Gene expression profile at peripheral level could be a promising tool for pathogenic studies as well as for early diagnosis of AD. A dysregulated inflammatory response, as well as other systemic disorders, have been described in AD. Therefore, we investigated the expression, at peripheral level, of a number of genes involved in the inflammatory, oxidative stress and proliferative response of a well defined, small cohort of sporadic AD patients. Firstly, the mRNA expression of inflammatory, stress and proliferation/ differentiation genes were evaluated, using SuperArray, in mitogen-stimulated peripheral blood mononuclear cells (PBMC) from a group of 12 well-characterized, sporadic AD patients with various levels of dementia, by comparison with aged matched controls. Real-time RT-PCR confirmed the trend of alteration in 16 genes out of the 36 supposed to be dysregulated in AD patients, by the preliminary screening. The expression level of the NFKB1(p105/50Kd) gene was significantly higher in AD with respect to adult age-matched controls (AA) and was related to the Mini-Mental State Examination (MMSE) score of the same patients. In addition, the expression of various NF-kappaB target genes and of both NF-kappaBp50 and NF kappaBp65 DNA-binding activity were increased in PBMC from AD patients in comparison with those from AA. Our results suggest that NF-kappaB activation at peripheral blood cell level could be a potential new hallmark of AD progression and sustain a rationale to more deeply investigate the therapeutic potential of specific NF-kappaB inhibitors in AD. PMID- 21592055 TI - Anti-beta-amyloid immunotherapy for Alzheimer's disease: focus on bapineuzumab. AB - Recent advances in our understanding of the neurobiology of Alzheimer's disease (AD) have led to the development of putative disease-modifying treatments. The most revolutionary of these approaches consists in the removal of brain beta amyloid (Abeta) via anti-Abeta antibodies. Brain imaging and neuropathological studies have shown the ability of both active and passive anti-Abeta immunotherapies of clearing Abeta deposits from the brain of the AD patients. An active anti-Abeta vaccine preparation, AN1792, has been used in AD patients with some clues of clinical efficacy but causing meningoencephalitis in about 6% of patients and it has been abandoned. Several second-generation active Abeta vaccines and passive Abeta immunotherapies have been developed and are under clinical investigation with the aim of accelerating Abeta clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Abeta monoclonal antibodies, that has been tested in two Phase II trials, demonstrating to reduce Abeta burden in the brain of AD patients. However, the preliminary cognitive efficacy of bapineuzumab appears uncertain. The occurrence of vasogenic edema, especially in apolipoprotein E 4 carriers, may limit its clinical use and have led to abandon the highest dose of the drug (2 mg/kg). The results of four ongoing large Phase III trials on bapineuzumab will tell us if passive anti-Abeta immunization is able to alter the course if this devastating disease. PMID- 21592056 TI - Follow-up study of olfactory deficits, cognitive functions, and volume loss of medial temporal lobe structures in patients with mild cognitive impairment. AB - BACKGROUND: At 3 years after diagnosis, the risk of Alzheimer disease (AD) for patients with mild cognitive impairment (MCI) is estimated to be 18% to 30%. To improve treatment of patients at high dementia risk there is a need for a better prediction of the risk for transition from MCI to AD. Olfactory deficits are a hypothetical predictor of conversion form MCI to AD. Furthermore, several studies point at volumetric reduction of medial temporal lobe structures as predictors of conversion form MCI to AD. The primary aim of this study was to evaluate whether investigations of odor deficits in MCI combined with neuropsychological tests and MRI examinations can improve prediction of the development of dementia. METHODS: Changes in olfactory functions, cognitive functions, and volume of medial temporal lobe structures (hippocampus, parahippocampal gyrus, and amygdala) were evaluated in a 24-month follow-up study in 49 MCI patients and 33 controls. RESULTS: In the MCI group, a prediction of strong cognitive functions deterioration based on poor performance in Olfactory Identification tests shows sensitivity of 57% and specificity of 88%. The test based on cognitive functions only shows a sensitivity of 44%, and 89%, respectively. Combined tests having a criteria of poor olfactory identification performance AND poor results of neuropsychological tests showed a sensitivity of 100% and specificity of 84%. Furthermore, correlation was found between the results of Olfactory Identification tests at baseline and deterioration of cognitive functions at follow up. Odor identification threshold did not appear to be a dementia predictor. A correlation of progress of cognitive function deterioration, odor identification deterioration, and decrease of volume of the hippocampus was also observed. CONCLUSIONS: Prediction of MCI to dementia conversion can be improved by supplementing the neuropsychological tests with odor identification tests. A follow up study of hippocampus volume reduction, OI performance and cognitive functions deterioration will further increase prediction accuracy. PMID- 21592057 TI - Mobilization and redistribution of default mode network from resting state to task state in amnestic mild cognitive impairment. AB - Brain task-negative networks (default mode network, DMN) and task-positive networks appear to operate largely in opposition, such that task-negative networks show activation during resting states, whilst task-positive networks are deactivated with the reverse being true during goal-oriented behavior. Altered DMN and task-positive network activity has been observed in amnestic mild cognitive impairment (aMCI) subjects. However, no study has directly linked the patterns of between-state differences in the same aMCI cohort regarding these two types of functional networks. The spatial and temporal characteristics of intrinsic, low frequency BOLD signal fluctuations both during resting state and episodic memory fMRI task were assessed in 28 aMCI subjects and 23 matched healthy controls, using a posterior cingulate cortex- based temporal correlation analysis. aMCI subjects showed impaired attenuation in the DMN between rest and task state, and greater cognitive impairment was associated with decreased ability to attenuate DMN during task engagement. Moreover, more redistributed resource from DMN appeared to be required in aMCI to maintain the similar task performance possibly to offset their inability to engage task-positive networks. In order to complete a given task, mobilized and redistributed resources of DMN appeared to replace task-positive network function to some degrees in aMCI subjects. This may represent an inability to control the switching of functional modes between these types of network. PMID- 21592059 TI - Editorial [hot topic: ischemic stroke in very old patients (guest editor: Maria Cristina Zurru)]. PMID- 21592058 TI - Effect of cholinergic stimulation in early Alzheimer's disease - functional imaging during a recognition memory task. AB - Treatment of Alzheimer's disease (AD) with acetylcholinesterase inhibitors (AChEI) enhances cholinergic activity and alleviates clinical symptoms. In the present functional magnetic resonance imaging (fMRI) study, we investigated the effect of the AChEI rivastigmine on cognitive function and brain activation patterns during a face recognition memory task. Twenty patients with newly diagnosed mild AD were administered a single oral dose of placebo, a single dose of rivastigmine (acute), and twice-daily treatment with rivastigmine for 4 weeks (chronic). After each treatment, the patients underwent a facial recognition task during fMRI. The prefrontal areas known to be involved in face recognition memory processing demonstrated greater fMRI activity in both the acute and chronic rivastigmine conditions compared to the placebo condition. In the same brain areas, differences in both fMRI activation at the map level and regional fMRI signal intensity measures between the placebo and chronic treatment conditions correlated negatively with the Mini- Mental State Examination score. In the chronic rivastigmine condition, patients with better preserved cognitive abilities demonstrated less enhanced prefrontal activity, whereas patients with poorer cognition showed greater prefrontal activity. These findings suggest that the prefrontal attention/working memory systems are already impaired in the early stages of AD and that the effect of cholinergic medication in the brain areas involved in recognition memory, i.e., increased or decreased fMRI activation patterns, depends on the severity of the disease. These findings also suggest the importance of early AChEI treatment in the course of AD, at the point when there is still some cognitive reserve available and the therapy has the highest potential efficacy. PMID- 21592060 TI - Calcium metabolic disorders and treatment of these - boning up for the future. PMID- 21592061 TI - Antidepressants and suicidal thought. PMID- 21592062 TI - From treatment adherence to advanced shared decision making: new professional strategies and attitudes in mental health care. AB - Treatment adherence is related to "self-regulation" of prescribed drugs. Patients organise their drug intake around their own priorities, which may be very different from prescribers' priorities, since most of the patients value their personal concerns and/or their social roles more than the benefits of a prescribed treatment. A gap exists between patients' and professionals' views. This gap is mainly related to patients' health beliefs and physicians' attitudes. A number of strategies can help professionals overcome gaps between their treatment options for depression and schizophrenia and the "real world" alternatives shared by the lay public, patients, their relatives, and political stakeholders. These strategies include integrated care and recovery, family engagement, and the development of a mutualistic patient/physician relationship with the adoption of advance directives and appropriate guidelines that incorporate the patient's choices. The effective implementation of these combined strategies within the person-centred care model empowers patients to collaborate with mental health professionals and their families in making complex health care choices. Barriers to this process include factors affecting the control, contact and communication facets of the patient/physician relationship. PMID- 21592063 TI - Patient involvement and shared decision-making in mental health care. AB - There is growing interest in shared decision-making (SDM) in which the provider and patient go through each phase of the decision-making process together, share treatment preferences, and reach an agreement on treatment choice. Although a majority of the research evaluating SDM has been conducted under "physical" health conditions, patients' participation and SDM for mental health conditions has received increasing interest since the mid 1990s. SDM in mental health care can be more complex than in general health care because that several patient characteristics, health care provider, and system level factors may hinder normalization and implementation of this model into clinical practice. To date, in comparison with other health problems, there are few studies which have assessed SDM in this context. In spite of that, evidence points favorably towards the inclusion of SDM in mental health treatment decisions, given that the majority of patients with mental illness prefer to be involved in the process and wish to have information. However, more studies are needed to provide evidence about the impact of SDM on treatment compliance and health care outcomes. In this overview, the authors present the current state and the future perspectives of SDM in mental health. PMID- 21592064 TI - Users perception of risk and benefits of mood modifying drugs. AB - This article presents a narrative review of qualitative research about reasons users consuming mood modifying drugs have to continue or discontinue medicine taking. Qualitative research provides insight to the phenomena of interest and has been used to understand how patients take medicines and identifies explicative models. Researchers have looked at how mood modifying drugs consumption fit in different models of medicine taking. Consumption of medicines involves frequently two sides from the point of view of the patients, the consideration of benefits and risk. Patients have to balance their perceptions and experiences of both sides and make decisions. It became clear that individual decisions composing the "personal career" of taking mood-modifier drugs is similar to other treatments of chronic conditions but with different limiting or adjuvant social forces at work. Mood modifying drugs produce not only concerns in relation to the drugs reactions but also to the perception that society has about them. Understanding the patient's perspective and the factors involved in the evaluation process for decision making about continuation or discontinuation of mood modifying drugs can help professionals to avoid longer than necessary consumption or early dropouts. PMID- 21592065 TI - Determinants of medicine-taking in psychiatric patients. AB - Lack of adherence is a universal risk in medicine. Its consequences in terms of outcome, suffering and economic costs are immense. This is a selective review of the putative factors involved in medicine taking behavior. Adherence is multidetermined by a number of variables ranging from patient sociodemographic characteristics to factors related to patient/ psychiatrist interaction, drug tolerability and organization of care. A relevant piece of responsibility comes from the drug itself and the patient's subjective tolerability which together with the characteristics of long term treatment and insufficient insight and support result in poor or lack of adherence. The context of the patient/professional therapeutic alliance, the patient's capacities and health system availability are ultimately decisive. PMID- 21592066 TI - Cost-effectiveness of interventions to enhance medication adherence in psychiatric patients: a systematic review. AB - It was conducted a systematic review of economic evaluations that assessed the cost-effectiveness of interventions to enhance the medication adherence in psychiatric patients. Several bibliographic databases were searched: MEDLINE, MEDLINE in process, PSYCINFO, EMBASE, Cochrane Controlled Trials Register, CINAHL, CRD, EconLit, Science Citation Index and Social Science Citation Index. Full economic evaluations which assessed interventions to enhance the adherence to drug therapy in adult patients with a mental illness were included. Data were extracted and the methodological quality of selected studies was assessed. The information was synthesized through narrative procedures. Four clinical trials and two ongoing studies fulfilled the selection criteria. Two studies did not find significant differences in adherence between the interventions (a compliance enhancing program, a therapeutic drug monitoring and a pharmacy-based intervention) and the control groups; one study found that a compliance program was more effective than a non-specific counselling intervention over 18 months in psychotic patients; another study found better results in terms of adherence among high-severity depressed patients receiving a stepped collaborative care during 12 months in comparison to a control group; in moderate-severity patients the differences disappeared after the first 6 months. None of the four studies found significant differences in costs between groups because of the low statistical power. In summary, adherence enhancing programs could be cost effective in psychiatric patients although this statement is based on few studies with limited methodological quality. It is necessary more and better research on the cost-effectiveness of interventions in the field of mental health. PMID- 21592067 TI - Towards a clarification of terminology in medicine taking behavior: compliance, adherence and concordance are related although different terms with different uses. AB - Medical terminology is at continuous process of change since the language of medicine needs the rapid incorporation of new terms or changing the existing ones to be in touch with new ideas, concepts and practices. The evolution of the terms "compliance", "adherence" and "concordance" in the field of medicine-taking represents a good example of this. Although these three terms are frequently used interchangeably generating some confusion, compliance, adherence and concordance mean different things and must be used in different ways. Compliance refers to the extent to which patients follow doctors' prescription about medicine taking; adherence refers to the extent to which patients follow through decisions about medicine taking; and concordance refers to the extent to which patients are successfully supported both in decision making partnerships about medicines and in their medicines taking. This terminology evolution may actually be more important than mere semantics since better adherence to a treatment regimen could be achieved through open-ended physician-patient communication, incorporating the beliefs and preferences of the patient in the decision-making process. At present time, concordance could be useful as a normative or aspirational term while compliance and adherence must be the terms used for scientific measurement in medicine-taking field. PMID- 21592069 TI - Compliance, adherence and concordance in medicine taking of psychiatric patients. PMID- 21592068 TI - It is now personal: recent views on the assessment of therapeutic infidelity in severe mental illness. AB - This paper starts with an attempt to chart the contemporary history of the term "Compliance" and its cognates. It also discusses the recently published guidelines concerning the assessment of adherence in patients with serious mental illnesses, dedicating its middle part to comment on the research and clinical methods to assess adherence in patients. The current consensus amongst experts can be summarized, from a clinical point of view, in a simple rule of thumb: enhancing adherence should depend on simple interventions originating from a multidisciplinary perspective and should include patients' input. Despite its apparent simplicity, improving the assessment of adherence and favouring its enhancement can generate interesting ethical quandaries that will be approached in the light of the relatively new emergent notion of "moral distress.". PMID- 21592070 TI - Designer drugs on the internet: a phenomenon out-of-control? the emergence of hallucinogenic drug Bromo-Dragonfly. AB - Based on the material available in both the scientific literature and on the web, the present paper provides an updated pharmacological, chemical, toxicological and behavioural overview of Bromo-Dragonfly (1-(8-bromobenzo[1,2-b;4,5-b']difuran 4-yl)-2-aminopropane; 'B-fly'). B-Fly is a powerful, long lasting, LSD-like, hallucinogenic drug, which has been associated with a number of acute intoxications and fatalities in a number of countries. A critical discussion of the potential of misuse of B-fly but also of the methodological limitations, which are intrinsically associated with the analysis of online, non-peer reviewed, material, is presented. It is concluded that the availability of online information on novel psychoactive drugs, such as B-fly, may constitute a public health challenge. Better international collaboration levels may be needed to tackle this novel and fast growing phenomenon. PMID- 21592071 TI - Patent review. PMID- 21592072 TI - Mapping fragmental drug-likeness in the MoStBioDat environment: intramolecular hydrogen bonding motifs in beta-ketoenols. AB - A detailed knowledge of hydrogen bond geometry and its directional preferences is vital for in silico investigations of the ligand-receptor short-range non covalent interactions. The spatial arrangement of the carbonyl and hydroxyl groups seems to determine the capability of beta-ketoenol derivatives to recognize the surrounding environment by forming inter- and intra-molecular hydrogen bonds (IHB). In the current study we examined the application of the MoStBioDat platform for a massive database screening of the IHB motifs in beta ketoenol subunits (O=C-C=C-OH). Then, the virtual 3D structural data derived from ZINC and PubChem repository were compared to the experimentally determined CSD data. Differences specific for each database were discovered, which indicated inaccuracies in the simulated data. PMID- 21592073 TI - ? PMID- 21592074 TI - Prediction of Michaelis-Menten constant of beta-glucosidases using nitrophenyl beta-D-glucopyranoside as substrate. AB - In this study, we attempted to use the neural network to model a quantitative structure-K(m) (Michaelis-Menten constant) relationship for beta-glucosidase, which is an important enzyme to cut the beta-bond linkage in glucose while K(m) is a very important parameter in enzymatic reactions. Eight feedforward backpropagation neural networks with different layers and neurons were applied for the development of predictive model, and twenty-five different features of amino acids were chosen as predictors one by one. The results show that the 20-1 feedforward backpropagation neural network can serve as a predictive model while the normalized polarizability index as well as the amino-acid distribution probability can serve as the predictors. This study threw lights on the possibility of predicting the K(m) in beta-glucosidases based on their amino-acid features. PMID- 21592075 TI - Analysis of rate-limiting long-range contacts in the folding rate of three-state and two-state Proteins. AB - In the past decade, when compared to models describing the folding rates of two state proteins, models describing the folding mechanism of three-state proteins remain quite limited due to the complexity present in the folding mechanism and lack in their experimental data. In the present work, rate-limiting long-range contacts were classified into various bins based on sequence separation distance between the contacting residues and the role of these bins were analyzed for their importance in a data set of 35 three-state proteins. Predicting the folding rates of these proteins have been carried out by relating experimental folding rates and long-range contacts obtained from various sequence separation bins. For comparison, using the present model, prediction of the folding rates of 45 two state proteins also resulted with good accuracy. Our method shows that long-range contacts observed in the final 3-D structure of proteins at various sequence separation bins are found to be an important descriptor in explaining the folding rates of three-state proteins and suggest that formation of contacts between residues present at these sequence separation distance may be a crucial factor in deciding structure formation and folding rates of these proteins. The aim of our present work is not to construct a new descriptor for the folding rates of three state proteins, nor is to provide improved means of folding-rate prediction for these proteins. We tend to elucidate that how long-range contacts play a crucial role in the folding mechanism of three state proteins belonging to three major structural classes and implication of these observations due to rate-limiting long-range contacts has been discussed in the light of other experimental studies of protein folding. PMID- 21592076 TI - Molecular cloning, sequence and structural analysis of dehairing Mn(2+) dependent alkaline serine protease (MASPT) of Bacillus pumilus TMS55. AB - Leather industries release a large amount of pollution-causing chemicals which creates one of the major industrial pollutions. The development of enzyme based processes as a potent alternative to pollution-causing chemicals is useful to overcome this issue. Proteases are enzymes which have extensive applications in leather processing and in several bioremediation processes due to their high alkaline protease activity and dehairing efficacy. In the present study, we report cloning, characterization of a Mn2+ dependent alkaline serine protease gene (MASPT) of Bacillus pumilus TMS55. The gene encoding the protease from B. pumilus TMS55 was cloned and its nucleotide sequence was determined. This gene has an open reading frame (ORF) of 1,149 bp that encodes a polypeptide of 383 amino acid residues. Our analysis showed that this polypeptide is composed of 29 residues N-terminal signal peptide, a propeptide of 79 residues and a mature protein of 275 amino acids. We performed bioinformatics analysis to compare MASPT enzyme with other proteases. Homology modeling was employed to model three dimensional structure for MASPT. Structural analysis showed that MASPT structure is composed of nine alpha-helices and nine beta-strands. It has 3 catalytic residues and 14 metal binding residues. Docking analysis showed that residues S223, A260, N263, T328 and S329 interact with Mn2+. This study allows initial inferences about the structure of the protease and will allow the rational design of its derivatives for structure-function studies and also for further improvement of the enzyme. PMID- 21592077 TI - Sucrose isomerase and its mutants from Erwinia rhapontici can synthesise alpha arbutin. AB - Sucrose isomerase (SI) from Erwinia rhapontici is an intramolecular isomerase that is normally used to synthesise isomaltulose from sucrose by a mechanism of intramolecular transglycosylation. In this study, it was found that SI could synthesise alpha-arbutin using hydroquinone and sucrose as substrates, via an intermolecular transglycosylation reaction. Five phenylalanine residues (F185, F186, F205, F297, and F321) in the catalytic pocket of SI were chosen for sitedirected mutagenesis. Mutants F185I, F321I, and F321W, whose hydrolytic activities were enhanced after the mutation, could synthesise alpha-arbutin through intermolecular transglycosylation with a more than two-fold increase in the molar transfer ratio compared with wild type SI. The F297A mutant showed a strong ability to synthesise a novel alpha-arbutin derivative and a four-fold increase in its specific activity for intermolecular transglycosylation over the wild type. Our findings may lead to a new way to synthesise novel glucoside products such as alpha-arbutin derivatives by simply manipulating the Phe residues in the catalytic pocket. From the structure superposition, our strategy of manipulating these Phe residues may be applicable to other similar transglycosylating enzymes. PMID- 21592078 TI - Docking and molecular dynamics simulations of peroxisome proliferator activated receptors interacting with pan agonist sodelglitazar. AB - PPAR (peroxisome proliferator-activated receptor) pan agonists play a critical role in treating metabolic diseases, especially the Type-2 diabetes mellitus (T2DM). GlaxoSmithKline's sodelglitazar (GW677954) is one of the potent PPAR pan agonists, which is currently being investigated in Phase II clinical trials for the treatment of T2DM and its complications. The present study was aimed at investigation into the effect of sodelglitazar at the binding pockets of PPARs. The Schrodinger Suite program (2009) was used for the molecular docking, while the GROMACS program used for the molecular dynamics (MD) simulations. The results thus obtained showed that sodelglitazar being docked well in the active site of PPARs. It was revealed by the MD simulations that the structures of the receptors remained quite stable during the simulations and that the important AF-2 helix showed less flexibility after binding with sodelglitazar. Also, it was observed that sodelglitazar could periodically form hydrogen bonds with the AF-2 helix of PPARs to stabilize the AF-2 helix in an active conformation. Our findings have confirmed that GlaxoSmithKline's sodelglitazar can activate the PPARs, which is quite consistent with the previous biological studies. PMID- 21592079 TI - 3dswap-pred: prediction of 3D domain swapping from protein sequence using Random Forest approach. AB - 3D domain swapping is a protein structural phenomenon that mediates the formation of the higher order oligomers in a variety of proteins with different structural and functional properties. 3D domain swapping is associated with a variety of biological functions ranging from oligomerization to pathological conformational diseases. 3D domain swapping is realised subsequent to structure determination where the protein is observed in the swapped conformation in the oligomeric state. This is a limiting step to understand this important structural phenomenon in a large scale from the growing sequence data. A new machine learning approach, 3dswap-pred, has been developed for the prediction of 3D domain swapping in protein structures from mere sequence data using the Random Forest approach. 3Dswap-pred is implemented using a positive sequence dataset derived from literature based structural curation of 297 structures. A negative sequence dataset is obtained from 462 SCOP domains using a new sequence data mining approach and a set of 126 sequencederived features. Statistical validation using an independent dataset of 68 positive sequences and 313 negative sequences revealed that 3dswap-pred achieved an accuracy of 63.8%. A webserver is also implemented using the 3dswap-pred Random Forest model. The server is available from the URL: http://caps.ncbs.res.in/3dswap-pred. PMID- 21592080 TI - Free energy calculations and binding analysis of two potential anti- influenza drugs with Polymerase basic protein-2 (PB2). AB - Influenza viruses cause a significant level of morbidity and mortality in the population every year. Their resistance to current anti-influenza drugs increases the difficulty of flu treatment. Thus, development of new anti-influenza drugs is necessary in regards of prevent the tragedy of influenza pandemic. The Polymerase basic protein 2 (PB2) subunit of influenza virus RNA polymerase is one of potential targets for new drugs because the binding of PB2 with the 5' cap of the host pre-mRNAs is the initial step of the virus' protein synthesis. In this study, we compared the binding potency of PB2 cap binding domain with two small molecules, i.e., RO and PPT28, with that of PB2 with cap analog m7GTP. The calculated binding energies showed that RO and PPT28 had higher binding affinity with PB2. Further interaction analysis showed that the important parts for binding were the five- and six-member heterocyclic rings (the 6/5-member rings) of small molecules, as well as the hydrophobic parts of RO and PPT28 which had good interactions with the hydrophobic residues in the binding cavity. Thus, RO and PPT28 are two potential anti-influenza drugs targeted PB2, which may inhibit the growth of influenza virus by competitively binding with the cap structure binding domain of PB2. PMID- 21592081 TI - Predicting protein-ligand binding sites based on an improved geometric algorithm. AB - Knowledge of protein-ligand binding sites is very important for structure-based drug designs. To get information on the binding site of a targeted protein with its ligand in a timely way, many scientists tried to resort to computational methods. Although several methods have been released in the past few years, their accuracy needs to be improved. In this study, based on the combination of incremental convex hull, traditional geometric algorithm, and solvent accessible surface of proteins, we developed a novel approach for predicting the protein ligand binding sites. Using PDBbind database as a benchmark dataset and comparing the new approach with the existing methods such as POCKET, Q-SiteFinder, MOE SiteFinder, and PASS, we found that the new method has the highest accuracy for the Top 2 and Top 3 predictions. Furthermore, our approach can not only successfully predict the protein-ligand binding sites but also provide more detailed information for the interactions between proteins and ligands. It is anticipated that the new method may become a useful tool for drug development, or at least play a complementary role to the other existing methods in this area. PMID- 21592082 TI - Analysis and statistics of crystallisation success increase by composition modification of protein and precipitant mixing ratio. AB - The nucleation zone has to be reached for any crystal to grow, and the search for crystallization conditions of new proteins is a trial and error process. Here a convenient screening strategy is studied in detail that varies the volume ratio of protein sample to the reservoir solution in the drop to initiate crystallization that is named "composition modification". It is applied after the first screen and has been studied with twelve proteins. Statistical analysis shows a significant improvement in screening using this strategy. The average improvement of "hits" at different temperatures is between 32 and 42%, for examples, 41.8% +/- 14.0% and 35.7% +/- 12.4% (+/- standard deviation) at 288 K and 300 K, respectively. Remarkably, some new crystals were found by composition modification which increased the probability of reaching the nucleation zone to initiate crystallization. This was confirmed by a phase diagram study. It is also demonstrated that composition modification can further increase crystallisation success significantly (1.3 times) after the improvement of "hits" by temperature screening. The trajectories of different composition modifications during vapour diffusion were plotted, further demonstrating that protein crystallizability can be increased by hitting more parts of the nucleation zone. It was also found to facilitate the finding of initial crystals for proteins of low solubility. These proteins gradually become more concentrated during the vapour diffusion process starting from a larger protein solution ratio in the initial mixture. PMID- 21592083 TI - Analyses of protein sequences using inter-residue average distance statistics to study folding processes and the significance of their partial sequences. AB - One of the goals of molecular bioinformatics is decoding amino acid sequences to extract information on the principles of protein folding. However, this is difficult to perform with standard bioinformatics techniques such as multiple sequence alignment and so on. Thus, we propose a technique based on inter-residue average distance statistics to make predictions regarding the protein folding mechanisms of amino acid sequences. Our method involves constructing a kind of predicted contact map called an Average Distance Map (ADM) based on average distance statistics to pinpoint regions of possible folding nuclei for proteins. Only information on the amino acid sequence of a given protein is required for the present method. In this article, we summarize the results of studies using our method to analyze how specific protein sequences affect folding properties. In particular, we present studies on proteins in the phage lysozyme, such as the globin, fatty acid binding protein-like, and the cupredoxin-like fold families. In the present review, we characterize the 3D architectures of these proteins through the properties of the protein ADMs. Furthermore, we combine the information on the conserved residues within the regions predicted by the ADMs with our results obtained so far. Such information may help identify the folding characteristics of each protein. We discuss this possibility in the present review. PMID- 21592084 TI - The structural determinations of the leucine zipper coiled-coil domains of the cGMP-dependent protein kinase Ialpha and its interaction with the myosin binding subunit of the myosin light chains phosphase. AB - Physiologic relaxation of vascular smooth muscle is induced by the cyclic guanosine monophosphate (cGMP)- dependent protein kinase Ialpha enzyme (cGKIalpha), which activates myosin phosphatase (MLCP). This activation process is thought to occur through the interaction involving both N- and C-terminal leucine zipper coiled-coil (LZCC) domains of the kinase enzyme (cGKIalpha) with the myosin binding subunit (MBS) of MLCP. In this review, I summarize how to define the LZCC domains in both N-terminal cGKIalpha(1-59) and C-terminal MBS proteins using predictive and experimental methods, how to make a rapid and accurate structure determination of a cGKIalpha(1-59) molecule using NMR's residual dipolar coupling (RDC) measurements, and how to indentify the existence of a weak protein interaction between N-terminal LZCC domain (cGKIalpha(1-59)) and a LZCC domain (MBSCT42) within the C-terminal MBS. In addition, the location and orientation of the residues in LZCC proteins can be readily visualized using a novel diagram, the so-called "wenxiang diagram", which is more advantageous than traditional helical wheel diagrams in analyzing LZCC protein structures and their action mechanisms. Using the composed wenxiang diagrams, we have characterized the interaction between cGKIalpha(1- 59) and another LZCC molecule (MBSCT42), and deduced that the most affected residues of these two LZCC molecules might be at the positions d, a, e and g. These studies and findings are also covered in this review. It is intriguing to see that the successful incorporation of wenxiang diagrams and NMR spectroscopy in the LZCC structural and functional studies may provide some insights into protein-protein interaction mechanisms. PMID- 21592085 TI - Patentable subject matter: morally neutral and context free. AB - AMP v. USPTO otherwise known as the ACLU/Myriad "gene patenting" case has famously pitted the American Civil Liberties Union (ACLU) against Myriad Genetics. DNA patent litigation is not novel, but this case is distinct from typical cases involving commercial rivals; heretofore neither side has an interest in the commercially suicidal attacking of the underlying concept of DNA patents. The ACLU, representing the plaintiffs, has no such qualms. And the ACLU is fighting dirty: the United States patent system is effectively moral and social-context neutral, but the ACLU has succeeded in making social and political concerns the highlight of their legal case, even reframing DNA as per our human understanding, as information, and as distinct from a simple double helical macromolecule. The relevance of the case exceeds the bounds of DNA patents, as reflected in the number of amicus briefs filed, and threatens many other industries, particularly those that rely on extracted biomaterials. PMID- 21592086 TI - From cell to cognition: can changes in telomere length indicate patterns of cognitive aging? PMID- 21592087 TI - Ceramide synthase 4 and de novo production of ceramides with specific N-acyl chain lengths are involved in glucolipotoxicity-induced apoptosis of INS-1 beta cells. AB - Pancreatic beta-cell apoptosis induced by palmitate requires high glucose concentrations. Ceramides have been suggested to be important mediators of glucolipotoxicity-induced beta-cell apoptosis. In INS-1 beta-cells, 0.4 mM palmitate with 5 mM glucose increased the levels of dihydrosphingosine and dihydroceramides, two lipid intermediates in the de novo biosynthesis of ceramides, without inducing apoptosis. Increasing glucose concentrations to 30 mM amplified palmitate-induced accumulation of dihydrosphingosine and the formation of (dihydro)ceramides. Of note, glucolipotoxicity specifically induced the formation of C(18:0), C(22:0) and C(24:1) (dihydro)ceramide molecular species, which was associated with the up-regulation of CerS4 (ceramide synthase 4) levels. Fumonisin-B1, a ceramide synthase inhibitor, partially blocked apoptosis induced by glucolipotoxicity. In contrast, apoptosis was potentiated in the presence of D,L-threo-1-phenyl-2-palmitoylamino-3-morpholinopropan-1-ol, an inhibitor of glucosylceramide synthase. Moreover, overexpression of CerS4 amplified ceramide production and apoptosis induced by palmitate with 30 mM glucose, whereas down-regulation of CerS4 by siRNA (short interfering RNA) reduced apoptosis. CerS4 also potentiates ceramide accumulation and apoptosis induced by another saturated fatty acid: stearate. Collectively, our results suggest that glucolipotoxicity induces beta-cell apoptosis through a dual mechanism involving de novo ceramide biosynthesis and the formation of ceramides with specific N-acyl chain lengths rather than an overall increase in ceramide content. PMID- 21592088 TI - Intrinsic membrane association of the cytoplasmic tail of influenza virus M2 protein and lateral membrane sorting regulated by cholesterol binding and palmitoylation. AB - The influenza virus transmembrane protein M2 is a proton channel, but also plays a role in the scission of nascent virus particles from the plasma membrane. An amphiphilic helix in the CT (cytoplasmic tail) of M2 is supposed to insert into the lipid bilayer, thereby inducing curvature. Palmitoylation of the helix and binding to cholesterol via putative CRAC (cholesterol recognition/interaction amino acid consensus) motifs are believed to target M2 to the edge of rafts, the viral-budding site. In the present study, we tested pre-conditions of this model, i.e. that the CT interacts with membranes, and that acylation and cholesterol binding affect targeting of M2. M2-CT, purified as a glutathione transferase fusion protein, associated with [3H]photocholesterol and with liposomes. Mutation of tyrosine residues in the CRAC motifs prevented [(3)H]photocholesterol labelling and reduced liposome binding. M2-CT fused to the yellow fluorescent protein localized to the Golgi in transfected cells; membrane targeting was dependent on CRAC and (to a lesser extent) on palmitoylation. Preparation of giant plasma membrane vesicles from cells expressing full-length M2-GFP (green fluorescent protein) showed that the protein is partly present in the raft domain. Raft targeting required palmitoylation, but not the CRAC motifs. Thus palmitoylation and cholesterol binding differentially affect the intrinsic membrane binding of the amphiphilic helix. PMID- 21592089 TI - Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK. AB - T2Rs (bitter taste-sensing type 2 receptors) are expressed in the oral cavity to prevent ingestion of dietary toxins through taste avoidance. They are also expressed in other cell types, including gut enteroendocrine cells, where their physiological role is enigmatic. Previously, we proposed that T2R-dependent CCK (cholecystokinin) secretion from enteroendocrine cells limits absorption of dietary toxins, but an active mechanism was lacking. In the present study we show that T2R signalling activates ABCB1 (ATP-binding cassette B1) in intestinal cells through a CCK signalling mechanism. PTC (phenylthiocarbamide), an agonist for the T2R38 bitter receptor, increased ABCB1 expression in both intestinal cells and mouse intestine. PTC induction of ABCB1 was decreased by either T2R38 siRNA (small interfering RNA) or treatment with YM022, a gastrin receptor antagonist. Thus gut ABCB1 is regulated through signalling by CCK/gastrin released in response to PTC stimulation of T2R38 on enteroendocrine cells. We also show that PTC increases the efflux activity of ABCB1, suggesting that T2R signalling limits the absorption of bitter tasting/toxic substances through modulation of gut efflux membrane transporters. PMID- 21592090 TI - Acute changes in temperature or oxygen availability induce ROS fluctuations in Daphnia magna linked with fluctuations of reduced and oxidized glutathione, catalase activity and gene (haemoglobin) expression. AB - BACKGROUND INFORMATION: ROS (reactive oxygen species) as well as components of the antioxidant redox systems may act as signals. To link acute environmental change with gene expression, changes in ROS and GSH/GSSG (reduced/oxidized glutathione) level were measured upon acute changes in temperature or oxygen availability in the aquatic key species Daphnia magna together with HIF-1 (hypoxia-inducible factor 1)-mediated Hb (haemoglobin) expression. RESULTS: Acute exposures to 30 degrees C or hypoxia, which induced tissue hypoxia (and possibly elevated mitochondrial ROS production), caused resembling fluctuations of ROS and GSH levels, with frequency and number of peaks increasing and their delay decreasing with the magnitude of environmental change (size of tissue hypoxia). Acute hyperoxia induced an initial decrease in ROS level. Evidence is also provided for the promoting effects of ROS on catalase activity. A signalling function of the ROS fluctuations upon acute changes in temperature was found in the case of Hb, the expression of which is known to respond to temperature changes, by detecting corresponding time courses of both transcription and protein formation. CONCLUSION: ROS-dependent signalling was affected by changes in temperature or oxygen availability. Feedback interactions between ROS and the glutathione redox system, possibly driven by elevated mitochondrial ROS production, likely contributed to the appearance of the ROS and GSH fluctuations upon acute environmental change. Fluctuating ROS levels, which reflect for the magnitude of environmental change, could be a way to transfer information on ROS production to subsequent processes (gene expression) while avoiding too-high and damaging ROS levels. PMID- 21592091 TI - Characterization of bone-marrow-derived rat mesenchymal stem cells depending on donor age. AB - It is generally accepted that autologous transfers, as non-immunogenic, constitute the safest approach in cellular transplantations. However, this attitude is often associated with the need for isolation and extracorporeal propagation of cells derived from aged patients. Thus the knowledge about relationship between aging and the properties of MSCs (mesenchymal stem cells) is crucial in developing new clinical strategies. The aim of this study was to perform complex comparison of MSC derived from young and aged individuals, which included phenotype, proliferating rate, osteogenic and adipogenic potential and secretory activity. Evaluated populations were isolated from bone marrow of 3 month-old and 24-month-old rats. There was no significant difference in membrane antigen expression and PDT (population doubling time). Additionally, the adipogenic and osteogenic potential did not vary between studied populations. The reaction of MSCs to either mitogen [bFGF (basic fibroblas t growth factor)] or oxidative stress (H2O2) in vitro displayed a very similar pattern in both analysed populations. There was no difference in TGFbeta1 (transforming growth factor beta1) and VEGF (vascular endothelial growth factor) secretion measured by ELISA test and gene expression evaluated by real-time PCR. However, the expression of the gene for IL-1alpha (interleukin-1alpha) was 8-fold lower in oMSC (MSC isolated from old rats). These results indicate that aging individuals can be considered as candidates for autologous transplantation of bone-marrow derived MSCs. PMID- 21592092 TI - FA2H-related disorders: a novel c.270+3A>T splice-site mutation leads to a complex neurodegenerative phenotype. AB - Homozygous mutations in the gene for fatty acid 2-hydroxylase (FA2H) have been associated in humans with three neurodegenerative disorders: complicated spastic paraplegia (SPG35), leukodystrophy with spastic paraparesis and dystonia, and neurodegeneration with brain iron accumulation. Here, we describe a novel homozygous c.270+3A>T mutation in an Italian consanguineous family. In two affected brothers (age at molecular diagnosis 22y and 15y; age at last follow-up 24y and 17y), altered FA2H function led to a severe phenotype, with clinical features overlapping those of the three FA2H-associated disorders. Both patients showed childhood onset progressive spastic paraparesis, mild pyramidal and cerebellar upper limb signs, severe cognitive impairment, white-matter disease, and cerebellar, brainstem, and spinal cord atrophy. However, absence of dystonia, drowsiness episodes, and a subtle globus pallidus involvement suggested that FA2H mutations result in a clinical spectrum, rather than causing distinct disorders. Although clinical heterogeneity is apparent, larger numbers of patients are needed to establish more accurate genotype-phenotype correlations. PMID- 21592094 TI - Comparative predictive validity of the Harris Infant Neuromotor Test and the Alberta Infant Motor Scale. PMID- 21592096 TI - Post-traumatic stress disorder and migraine: epidemiology, sex differences, and potential mechanisms. AB - Migraine is a common, often disabling disorder associated with a significant personal and societal burden. The presence of post-traumatic stress disorder (PTSD) may increase this disability substantially. Migraine and PTSD are both up to 3 times more common in women than in men. The divergence in prevalence rates of migraine and PTSD that occurs between the sexes after puberty suggests that gonadal hormones play an important role. In addition, the preponderance of PTSD in women may be related to their higher rates of interpersonal trauma, the most common cause of PTSD. However, recent data suggest that although the odds of PTSD are increased in both women and men with episodic migraine, this association is stronger in men than women. In this paper, we examine the epidemiology of PTSD and migraine, with an emphasis on the known sex differences. We then discuss the neurobiological changes associated with PTSD, the current hypotheses for the mechanisms relating PTSD and migraine, and the treatment implications of these findings. PMID- 21592097 TI - Treatment outcomes of chronic post-traumatic headaches after mild head trauma in US soldiers: an observational study. AB - BACKGROUND: he effectiveness of medical therapies for chronic post-traumatic headaches (PTHs) attributable to mild head trauma in military troops has not been established. OBJECTIVE: To determine the treatment outcomes of acute and prophylactic medical therapies prescribed for chronic PTHs after mild head trauma in US Army soldiers. METHODS: A retrospective cohort study was conducted with 100 soldiers undergoing treatment for chronic PTH at a single US Army neurology clinic. Headache frequency and Migraine Disability Assessment (MIDAS) scores were determined at the initial clinic visit and then again by phone 3 months after starting headache prophylactic medication. Response rates of headache abortive medications were also determined. Treatment outcomes were compared between subjects with blast-related PTH and non-blast PTH. RESULTS: Ninety-nine of 100 subjects were male. Seventy-seven of 100 subjects had blast PTH and 23/100 subjects had non-blast PTH. Headache characteristics were similar for blast PTH and non-blast PTH with 96% and 95%, respectively, resembling migraine. Headache frequency among all PTH subjects decreased from 17.1 days/month at baseline to 14.5 days/month at follow-up (P = .009). Headache frequency decreased by 41% among non-blast PTH compared to 9% among blast PTH. Fifty-seven percent of non blast PTH subjects had a 50% or greater decline in headache frequency compared to 29% of blast PTH subjects (P =.023). A significant decline in headache frequency occurred in subjects treated with topiramate (n = 29, -23%, P = .02) but not among those treated with a low-dose tricyclic antidepressant (n = 48, -12%, P = .23). Seventy percent of PTH subjects who used a triptan class medication experienced reliable headache relief within 2 hours compared to 42% of subjects using other headache abortive medications (P = .01). Triptan medications were effective for both blast PTH and non-blast PTH (66% response rate vs 86% response rate, respectively; P = .20). Headache-related disability, as measured by mean MIDAS scores, declined by 57% among all PTH subjects with no significant difference between blast PTH (-56%) and non-blast PTH (-61%). CONCLUSIONS: Triptan class medications are usually effective for aborting headaches in military troops with chronic PTH attributed to a concussion from a blast injury or non-blast injury. Topiramate appears to be an effective headache prophylactic therapy in military troops with chronic PTH, whereas low doses of tricyclic antidepressants appear to have little efficacy. Chronic PTH triggered by a blast injury may be less responsive to commonly prescribed headache prophylactic medications compared to non-blast PTH. These conclusions require validation by prospective, controlled clinical trials. PMID- 21592098 TI - Multi-center comparison of response to a single tablet of sumatriptan 85 mg and naproxen 500 mg vs usual therapy treating multiple migraine attacks as measured by the completeness of response survey. AB - OBJECTIVE: To investigate a broad definition of migraine resolution that extends beyond specific migraine-associated diagnostic symptoms as measured by the Completeness of Response Survey. METHODS: Conducted at 8 sites, 135 subjects treated migraines with SumaRT/Nap over 2 months. To measure subjects' experiences with SumaRT/Nap compared to their usual migraine medication, the Headache Impact Test, Revised Patient Perception of Migraine Questionnaire, and Completeness of Response Survey were administered at baseline and at 2 months. RESULTS: The effects of the study medicine compared to the subjects' usual migraine medicine reached statistical significance in decreasing headache severity, lessening of associated symptoms, and attaining complete relief with a single dose (60.04% of attacks resolved at 2 hours post-treatment). CONCLUSION: Compared to a subject's usual treatment, SumaRT/Nap used early and consistently for treatment of acute migraine offers important clinical improvements, including lessening of associated symptoms beyond International Headache Society criteria. CLINICAL TRIAL REGISTRATION NUMBER: NCT00893737. PMID- 21592099 TI - OnabotulinumtoxinA for treatment of chronic migraine: a response. PMID- 21592100 TI - Glucose transporters are expressed in taste receptor cells. AB - In the intestine, changes of sugar concentration generated in the lumen during digestion induce adaptive responses of glucose transporters in the epithelium. A close matching between the intestinal expression of glucose transporters and the composition and amount of the diet has been provided by several experiments. Functional evidence has demonstrated that the regulation of glucose transporters into enterocytes is induced by the sensing of sugar of the enteroendocrine cells through activation of sweet taste receptors (T1R2 and T1R3) and their associated elements of G-protein-linked signaling pathways (e.g. alpha-gustducin, phospholipase C beta type 2 and transient receptor potential channel M5), which are signaling molecules also involved in the perception of sweet substances in the taste receptor cells (TRCs) of the tongue. Considering this phenotypical similarity between the intestinal cells and TRCs, we evaluated whether the TRCs themselves possess proteins of the glucose transport mechanism. Therefore, we investigated the expression of the typical intestinal glucose transporters (i.e. GLUT2, GLUT5 and SGLT1) in rat circumvallate papillae, using immunohistochemistry, double-labeling immunofluorescence, immunoelectron microscopy and reverse transcriptase-polymerase chain reaction analysis. The results showed that GLUT2, GLUT5 and SGLT1 are expressed in TRCs; their immunoreactivity was also observed in cells that displayed staining for alpha gustducin and T1R3 receptor. The immunoelectron microscopic results confirmed that GLUT2, GLUT5 and SGLT1 were predominantly expressed in cells with ultrastructural characteristics of chemoreceptor cells. The presence of glucose transporters in TRCs adds a further link between chemosensory information and cellular responses to sweet stimuli that may have important roles in glucose homeostasis, contributing to a better understanding of the pathways implicated in glucose metabolism. PMID- 21592103 TI - Nomenclature for factors of the HLA system, update January 2011. PMID- 21592102 TI - The development of the olfactory organs in newly hatched monotremes and neonate marsupials. AB - Olfactory cues are thought to play a crucial role in the detection of the milk source at birth in mammals. It has been shown that a marsupial, the tammar wallaby, can detect olfactory cues from its mother's pouch at birth. This study investigates whether the main olfactory and accessory olfactory system are similarly well developed in other marsupials and monotremes at birth/hatching as in the tammar. Sections of the head of various marsupial and two monotreme species were investigated by light microscopy. Both olfactory systems were less well developed in the kowari and Eastern quoll. No olfactory or vomeronasal or terminal nerves could be observed; the main olfactory bulb (MOB) had only two layers while no accessory olfactory bulb or ganglion terminale were visible. All other investigated marsupials and monotremes showed further developed olfactory systems with olfactory, vomeronasal and terminal nerves, a three-layered MOB, and in the marsupials a prominent ganglion terminale. The main olfactory system was further developed than the accessory olfactory system in all species investigated. The olfactory systems were the least developed in species in which the mother's birth position removed most of the difficulty in reaching the teat, placing the neonate directly in the pouch. In monotremes they were the furthest developed as Bowman glands were found underlying the main olfactory epithelium. This may reflect the need to locate the milk field each time they drink as they cannot permanently attach to it, unlike therian mammals. While it still needs to be determined how an odour signal could be further processed in the brain, this study suggests that marsupials and monotremes possess well enough developed olfactory systems to be able to detect an odour cue from the mammary area at birth/hatching. It is therefore likely that neonate marsupials and newly hatched monotremes find their way to the milk source using olfactory cues, as has been previously suggested for the marsupial tammar wallaby, rabbits, rats and other eutherians. PMID- 21592104 TI - Nomenclature for factors of the HLA system, update February 2011. PMID- 21592101 TI - Fate of neuron-glia synapses during proliferation and differentiation of NG2 cells. AB - Progenitor cells expressing proteoglycan NG2 (also known as oligodendrocyte precursor cells or polydendrocytes) are widespread in the grey and white matter of the CNS; they comprise 8-9% of the total cell population in adult white matter, and 2-3% of total cells in adult grey matter. NG2 cells have a complex stellate morphology, with highly branched processes that may extend more than 100 MUm around the cell body. NG2 cells express a complex set of voltage-gated channels, AMPA/kainate and/or gamma-aminobutyric acid (GABA)(A) receptors, and receive glutamatergic and/or GABAergic synaptic input from neurons. In every region of the brain NG2 cells are found as proliferative cells, and the fraction of actively cycling NG2 cells is quite high in young as well as in adult animals. During development NG2 cells either differentiate into myelinating oligodendrocytes (and possibly also few astrocytes and neurons) or persist in the brain parenchyma as NG2 cells. This review highlights new findings related to the morphological and electrophysiological changes of NG2 cells, and the fate of synaptic input between neurons and NG2 cells during proliferation and differentiation of these cells in the neonatal and adult nervous system of rodents. PMID- 21592107 TI - The lucky and the unlucky. PMID- 21592108 TI - Diversification of the ADH1B gene during expansion of modern humans. AB - A variant allele, ADH1B*48His, also known as ADH1B*2, at the human Alcohol Dehydrogenase 1B gene (ADH1B) is strongly associated with alcoholism in some populations and has an unusual geographic distribution. Strong evidence implies selection has increased the frequency of this allele in some East Asian populations but does not fully explain its geographic pattern. We have studied haplotypes of 10 single nucleotide polymorphisms (SNPs) and two short tandem repeat polymorphisms (STRPs) in the ADH1B region in 2,206 individuals from a worldwide set of populations. These SNPs and STRPs define nine common haplogroups most of which have distinct geographic patterns. The haplogroups H5 and H6, both with the derived ADH1B*48His allele, appear restricted to the Middle East and East Asia, respectively. The positively selected H7 is derived from H6 by a new regulatory region variant defining SNP rs3811801 restricted to East Asia. Age estimates of the haplogroups based on the STRPs also agree with the time of the migration events estimated by other studies. H7 is estimated to have expanded recently, around 2,800 years ago, and ancient DNA samples from North China confirm its presence about that time. The dating of the H7 expansion may help understand the selective force on the ADH1B gene. PMID- 21592109 TI - Wide disparity in genetic admixture among Mexican Americans from San Antonio, TX. AB - We studied 706 participants of the San Antonio Family Diabetes Study (SAFDS) and 586 male samples from the San Antonio Center for Biomarkers of Risk of Prostate Cancer (SABOR) and used 64 ancestry informative markers to compare admixture proportions between both groups. Existence of population substructure was demonstrated by the excess association of unlinked markers. In the SAFDS sample, ancestral proportions were estimated at 50.2 +/- 0.6% European, 46.4 +/- 0.6% Native American, and 3.1 +/- 0.2% West African. For the SABOR sample, the proportions were 58.9 +/- 0.7%, 38.2 +/- 0.7%, and 2.9 +/- 0.2%, respectively. Additionally, in the SAFDS subjects a highly significant negative correlation was found between individual Native American ancestry and skin reflectance (R(2) = 0.07, P= 0.00006). The correlation was stronger in males than in females but clearly showed that ancestry only accounts for a small percentage of the variation in skin color and, conversely, that skin reflectance is not a robust surrogate for genetic admixture. Furthermore, a substantial difference in substructure is present in the two cohorts of Mexican American subjects from the San Antonio area in Texas, which emphasizes that genetic admixture estimates should be accounted for in association studies, even for geographically related subjects. PMID- 21592110 TI - Long-term safety and efficacy of deferasirox (Exjade) for up to 5 years in transfusional iron-overloaded patients with sickle cell disease. AB - To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19.4 +/- 6.3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33.5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23.8%), lost to follow-up (9.2%) and adverse events (AEs) (7.6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14.6%), diarrhoea (10.8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with >= 4 years deferasirox exposure significantly decreased by -591 MUg/l (95% confidence intervals, -1411, -280 MUg/l; P = 0.027; n = 67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years. PMID- 21592111 TI - Blocking the immunosuppressive axis with small interfering RNA targeting interleukin (IL)-10 receptor enhances dendritic cell-based vaccine potency. AB - Improving dendritic cell (DC) functions is highly promising for therapeutic intervention of diverse diseases, including cancer. Immunosuppressive cytokines such as interleukin (IL)-10 produced by DCs themselves (autocrine) and other regulatory immune cells (paracrine) down-regulate functional profiles of DCs through specific cell surface receptors such as IL-10R. Here, we tried to improve DC functions using small interfering RNA (siRNA) technology to block an IL-10R mediated immunosuppressive axis. DCs modified with siRNA targeting against IL-10R or IL-10 (DC/siIL-10R or DC/siIL-10) led to up-regulation of major histocompatibility complex (MHC) class II, CD40 co-stimulatory molecule, and IL 12 proinflammatory cytokine after lipopolysacharide (LPS) stimulation compared to DC/siGFP. Notably, the LPS-induced functional profiles of DC/siIL-10R were strongly resistant to the addition of recombinant IL-10, which mimicked paracrine IL-10. In contrast, those of DC/siIL-10 were reversed by adding exogenous IL-10. Consistently, DC/siIL-10R generated more human papilloma virus (HPV) E7-specific CD8(+) T cells and stronger anti-tumour effects against E7-expressing TC-1 tumour cells in vaccinated mice than DC/siGFP, as well as DC/siIL-10. Taken together, these results provide the groundwork for future clinical translation of siRNA mediated strategy targeting IL-10R to enhance DC-based vaccine potency. PMID- 21592112 TI - The role of indoleamine 2, 3-dioxygenase in lepromatous leprosy immunosuppression. AB - To elucidate further the possible role of the tryptophan, rate-limiting enzyme indoleamine 2, 3-dioxygenase (IDO) in leprosy, the distribution of IDO-positive cells and IDO activity in the skin biopsies and sera of these patients representing the entire spectrum of the disease were studied. An increased number of macrophages/dendritic cells (DC-lineage IDO(+) cells were found in lepromatous (LL) compared to tuberculoid (BT) and reversal reaction (RR) patients. IDO positive cells showing CD68 and CD86 surface markers predominated in LL lesions, while higher levels of IDO activity were observed in the sera of LL versus BT patients. Tests revealed an increased IDO message in Mycobacterium leprae stimulated peripheral blood mononuclear cells (PBMC) by real-time polymerase chain reaction (PCR) and increased IDO expression in M. leprae-stimulated CD14(+) cells of both healthy controls (HC) and LL patients, as evaluated via flow cytometry. Increased M. leprae-induced IDO-protein synthesis was also confirmed by Western blot. Based on our in vitro studies, it was confirmed that M. leprae up-regulated IDO expression and activity in HC and LL monocytes. Interferon (IFN) gamma synergized with M. leprae in promoting IDO expression and activity in monocytes. IDO expression induced by both IFN-gamma and M. leprae was abrogated by 1-methyltryptophan (1-MT). Our data suggest that M. leprae chronic infection activates the suppressive molecule IDO which, in turn, contributes to the specific immunosuppression observed in LL leprosy. PMID- 21592113 TI - Association of functional GITR gene polymorphisms related to expression of glucocorticoid-induced tumour necrosis factor-receptor (GITR) molecules with prognosis of autoimmune thyroid disease. AB - The glucocorticoid-induced tumour necrosis factor (TNF)-receptor (GITR) affects the functions of regulatory T (T(reg)) and effector T (T(eff)) cells, but the significance of this phenomenon is still unclear. To examine the association of single nucleotide polymorphisms (SNPs) in the GITR gene with the expression of GITR molecules on T cells and with the pathological conditions in patients with autoimmune thyroid disease (AITD), we examined the frequencies of four candidate SNPs in AITD patients and healthy volunteers by restriction enzyme analysis and direct sequence analyses. We also analysed the GITR expression on peripheral T(reg) and T(eff) cells in AITD patients by three-colour flow cytometry. The CC genotype in the rs3753348 C/G SNP was significantly more frequent in patients with mild Hashimoto's disease (HD) than in those with severe HD [P = 0.0117, odds ratio (OR) = 3.13]. The AA genotype in the rs2298213 A/G SNP was significantly more frequent in patients with mild HD than in patients with severe HD (P = 0.010, OR = 4.43). All patients and healthy individuals had the GG genotype in rs60038293 A/G and rs11466696 A/G SNPs. The proportions of GITR(+) cells in T(reg) and T(eff) cells were significantly higher in AITD patients with the CC genotype of the rs3753348 SNP than in those with the GG genotype (P = 0.004 and P = 0.011, respectively). In conclusion, the rs3753348 C/G SNP in the GITR is associated with HD prognosis and expression on T(reg) and T(eff) cells. PMID- 21592114 TI - alpha-Fetoprotein impairs activation of natural killer cells by inhibiting the function of dendritic cells. AB - alpha-Fetoprotein (AFP) is a tumour-associated antigen in hepatocellular carcinoma (HCC). The biological properties of AFP have been identified in its regulatory effects on immune responses of T cells and B cells. However, AFP effects on natural killer (NK) cells are still unclear. In this study, we examined the immunoregulation of AFP on NK activity. The cytolytic activity against K562 cells and Huh7 cells of NK cells co-cultured with AFP-treated dendritic cells (DCs) (AFP-DCs) was lower than that with albumin-treated DCs (Alb DCs). Direct addition of AFP to NK cells did not alter the cytolytic activity of NK cells. Adding AFP inhibited the interleukin (IL)-12 production of DCs after stimulation with lipopolysaccharide (LPS) [Toll-like receptor (TLR)-4 ligand], or Poly(I:C) (TLR-3 ligand), but not IL-18 production. The mRNAs of IL-12p35 and IL 12p40 were significantly inhibited in AFP-DCs compared with Alb-DCs, but those of TLR-4 or TLR-3 were not. Transwell experiments revealed that soluble factors derived from DCs played roles in inhibition of the ability of activating NK cells by AFP-DCs. Adding the neutralizing antibody of IL-12 to NK cells co-cultured with Alb-DCs resulted in a decrease of cytolytic activity to the levels of NK cells co-cultured with AFP-DCs. Adding IL-12 to NK cells co-cultured with AFP-DCs resulted in an increase of cytolytic activity to the levels of NK cells co cultured with Alb-DCs. These demonstrated that the impairment of IL-12 production from AFP-DCs resulted in inhibition of the ability of the activation of NK cells by DCs, and thus suggests a role of AFP in HCC development. PMID- 21592117 TI - Paroxysmal EEG pattern in a child with N-methyl-D-aspartate receptor antibody encephalitis. AB - A previously healthy 8-year-old male presented with cognitive regression, sleep disturbance, hallucinations, and severe attacks of agitation and oligoclonal bands in the cerebrospinal fluid. N-methyl-d-aspartate receptor (NMDAR) antibodies in serum and cerebrospinal fluid were detected 2 months after onset of symptoms. Bursts of agitation were initially considered to be epileptic leading to the administration of a high dose of benzodiazepines. Video electroencephalography (EEG) failed to disclose any correlation between the episodes of agitation and paroxysmal rhythmic slow activity on EEG persisting throughout and after attacks of agitation. Clinical improvement and EEG normalization followed an initial plasma exchange performed 3 months after onset of disease. This particular paroxysmal EEG pattern in NMDAR antibody encephalitis suggests that it may result from the combination of reduced NMDAR function and major gamma-aminobutyric acid (GABA)-ergic activation. PMID- 21592118 TI - Elevated VGKC-complex antibodies in a boy with fever-induced refractory epileptic encephalopathy in school-age children (FIRES). AB - Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a clinically recognized epileptic encephalopathy of unknown aetiology. Presentation in previously healthy children is characterized by febrile status epilepticus. A pharmacoresistant epilepsy ensues, occurring in parallel with dramatic cognitive decline and behavioural difficulties. We describe a case of FIRES in a 4-year-old boy that was associated with elevated voltage-gated potassium channel (VGKC) complex antibodies and a significant clinical and immunological response to immunomodulation. This case, therefore, potentially expands the clinical phenotype of VGKC antibody-associated disease to include that of FIRES. Prior to immunomodulation, neuropsychology assessment highlighted significant attention, memory, and word-finding difficulties. The UK version of the Wechsler Preschool and Primary Scale of Intelligence assessment indicated particular difficulties with verbal skills (9th centile). Immunomodulation was initially administered as intravenous methylprednisolone (followed by maintenance oral prednisolone) and later in the disease course as regular monthly intravenous immunoglobulin infusions and low-dose azathioprine. Now aged 6 years, the seizure burden in this child is much reduced, although increased seizure frequency is observed in the few days before his monthly immunoglobulin infusions. Formal IQ assessment has not been repeated but there is no clinical suggestion of further cognitive regression. VGKC complex antibodies have been reported in a range of central and peripheral neurological disorders (predominantly presenting in adulthood), and the identification of elevated VGKC complex antibodies, combined with the response to immunotherapies in this child, supports an autoimmune pathogenesis in FIRES with potential diagnostic and therapeutic implications. PMID- 21592119 TI - In vitro CNS tissue analogues formed by self-organisation of reaggregated post natal brain tissue. AB - In this paper, we report the characterization of 'Hi-Spot' cultures formed by the re-aggregation of dissociated postnatal CNS tissue grown at an air-liquid interface. This produces a self-organised, dense, organotypic cellular network. Western blot, immunohistochemical, viral transfection and electron microscopy analyses reveal neuronal and glial populations, and the development of a synaptic network. Multi-electrode array recordings show synaptically driven network activity that develops through time from single unit spiking activity to global network bursting events. This activity is blocked by tetanus toxin and modified by antagonists of glutamatergic and GABAergic receptors suggesting tonic activity of excitatory and inhibitory synaptic signaling. The tissue-like properties of these cultures has been further demonstrated by their relative insensitivity to glutamate toxicity. Exposure to millimolar concentrations of glutamate for hours is necessary to produce significant excitotoxic neuronal death, as in vivo. We conclude that 'Hi-Spots' are biological analogues of CNS tissue at a level of complexity that allows for detailed functional analyses of emergent neuronal network properties. PMID- 21592120 TI - Glycogen synthase kinase 3beta in the basolateral amygdala is critical for the reconsolidation of cocaine reward memory. AB - Exposure to cocaine-associated conditioned stimuli elicits craving and increases the probability of cocaine relapse in cocaine users even after extended periods of abstinence. Recent evidence indicates that cocaine seeking can be inhibited by disrupting the reconsolidation of the cocaine cue memories and that basolateral amygdala (BLA) neuronal activity plays a role in this effect. Previous studies demonstrated that glycogen synthase kinase 3beta (GSK-3beta) plays a role in the reconsolidation of fear memory. Here, we used a conditioned place preference procedure to examine the role of GSK-3beta in the BLA in the reconsolidation of cocaine cue memories. GSK-3beta activity in the BLA, but not central amygdala (CeA), in rats that acquired cocaine (10 mg/kg)-induced conditioned place preference increased after re-exposure to a previously cocaine-paired chamber (i.e., a memory reactivation procedure). Systemic injections of the GSK-3beta inhibitor lithium chloride after memory reactivation impaired the reconsolidation of cocaine cue memories and inhibited subsequent cue-induced GSK-3beta activity in the BLA. Basolateral amygdala, but not central amygdala, injections of SB216763, a selective inhibitor of GSK-3beta, immediately after the reactivation of cocaine cue memories also disrupted cocaine cue memory reconsolidation and prevented cue-induced increases in GSK-3beta activity in the BLA. The effect of SB216763 on the reconsolidation of cocaine cue memories lasted at least 2 weeks and was not recovered by a cocaine priming injection. These results indicate that GSK-3beta activity in the BLA mediates the reconsolidation of cocaine cue memories. PMID- 21592121 TI - Carnitine palmitoyltransferase-1c gain-of-function in the brain results in postnatal microencephaly. AB - Carnitine palmitoyltransferase-1c (CPT1c) is a newly identified and poorly understood brain-specific CPT1 homologue. Here, we have generated a new animal model that allows the conditional expression of CPT1c in a tissue specific and/or temporal manner via Cre-lox mediated recombination. Brain-specific, exogenous expression of CPT1c was achieved by crossing transgenic CPT1c mice to Nestin-Cre mice. The resulting double transgenic mice (CPT1c-TgN) displayed severe growth retardation in the postnatal period with a stunted development at 2 weeks of age. CPT1c-TgN mice had a greater than 2.3-fold reduction in brain weight. Even with this degree of microencephaly, CPT1c-TgN mice were viable and fertile and exhibited normal post-weaning growth. When fed a high fat diet CPT1c-TgN mice were protected from weight gain and the difference in body weight between CPT1c TgN and control mice was further exaggerated. Conversely, low fat, high carbohydrate feeding partially reversed the body weight defects in CPT1c-TgN mice. Analysis of total brain lipids of low fat fed mice revealed a depletion of total very long chain fatty acids in adult CPT1c-TgN mice which was not evident in high fat fed CPT1c-TgN mice. These data show that CPT1c can elicit profound effects on brain physiology and total fatty acid profiles, which can be modulated by the nutritional composition of the diet. PMID- 21592123 TI - Implementing and evaluating a school-based program to improve childhood vision. PMID- 21592122 TI - Transport systems of serine at the brain barriers and in brain parenchymal cells. AB - D-Serine is a co-agonist for NMDA-type glutamate receptors. Although D-serine levels in CSF and interstitial fluid (ISF) affect CNS function, the regulatory system remains to be fully understood. Therefore, the purpose of this study was to investigate d-serine transport across the blood-brain barrier (BBB) and blood CSF barrier (BCSFB) and in brain parenchymal cells. D-Serine microinjected into the cerebrum was not eliminated, suggesting a negligible contribution of D-serine efflux transport at the BBB. In contrast, D-serine was taken up from the circulating blood across the BBB via a carrier-mediated process. D-Serine elimination clearance from CSF was fourfold greater than that of d-mannitol, which is considered to reflect CSF bulk flow. The characteristics of D-serine uptake by isolated choroid plexus were consistent with those of Na(+)-independent alanine-serine-cysteine transporter 1 (asc-1). Uptake of D-serine by brain slices appeared to occur predominantly via asc-1 and Na(+)-dependent alanine-serine cysteine transporter 2. These findings suggest that the regulatory system of D serine levels in ISF and CSF involves (i) asc-1 at the BCSFB, acting as a major pathway of D-serine elimination from the CSF, (ii) blood-to-brain and blood-to CSF influx transport of D-serine across the BBB and BCSFB, and (iii) concentrative uptake of D-serine by brain parenchymal cells. PMID- 21592124 TI - Correlates of 2009 pandemic H1N1 influenza vaccine acceptance among middle and high school teachers in rural Georgia. AB - BACKGROUND: Teachers play an essential role in the school community, and H1N1 vaccination of teachers is critical to protect not only themselves but also adolescents they come in contact within the classroom through herd immunity. School-aged children have a greater risk of developing H1N1 disease than seasonal influenza. The goal of this study was to assess the relationship between attitudes toward H1N1 vaccination and vaccine acceptance among middle and high school teachers in rural Georgia. METHODS: Participants were recruited from 2 counties participating in a school-based influenza vaccination intervention in rural Georgia. Data were collected from surveys distributed to middle and high school teachers in participating counties in September 2009 prior to implementing the interventions to increase vaccination against seasonal influenza. Multivariate logistic regression was used to assess the association between teachers' attitudes toward H1N1 vaccination and H1N1 vaccine acceptance, controlling for demographic variables. RESULTS: Among participants, 52.9% indicated that they would get the H1N1 vaccine. In multivariate analyses, H1N1 vaccine acceptance was associated with male gender (odds ratio[OR] = 3.67, p = .016), fear of contracting H1N1 (OR = 3.18, p = .025), and receipt of a seasonal influenza vaccine in the past year (OR = 3.07, p = .031). H1N1 vaccine acceptance was not significantly associated with age, race, perceived severity of H1N1, belief that the H1N1 vaccine would cause illness, or talking about H1N1 with friends. CONCLUSIONS: Teachers may play a pivotal role in school-based H1N1 vaccinations. Understanding and addressing teachers' attitudes toward H1N1 vaccination may assist in future immunization efforts. PMID- 21592125 TI - Adolescent attitudes toward influenza vaccination and vaccine uptake in a school based influenza vaccination intervention: a mediation analysis. AB - BACKGROUND: School-based vaccination programs may provide an effective strategy to immunize adolescents against influenza. This study examined whether adolescent attitudes toward influenza vaccination mediated the relationship between receipt of a school-based influenza vaccination intervention and vaccine uptake. METHODS: Participants were recruited from 2 counties participating in a school-based influenza vaccination intervention trial in rural Georgia (N = 337). Data were collected from surveys distributed to adolescents at pre- and post-intervention time points and from documents indicating vaccine uptake. Guided by the Health Belief Model and the Integrated Behavioral Model, surveys assessed demographic, behavioral, and psychosocial variables. A mediation analysis was used to test whether changes in psychosocial variables from baseline to follow-up mediated the relationship between study condition and influenza vaccine uptake. RESULTS: Controlling for background variables, step 1 of the mediation analysis revealed a significant relationship between study condition and vaccine uptake (odds ratio = 1.77, p = .038). Step 2 of the mediation analysis revealed a significant relationship between study condition and changes in psychosocial variables from baseline to follow-up. Steps 3 and 4 of the mediation analysis revealed that there was full mediation of the relationship between study condition and receipt of an influenza vaccination by intention to receive an influenza vaccination. CONCLUSION: Findings suggest that the success of our school-based influenza vaccination intervention in increasing vaccine uptake was mediated by adolescents' intention to receive an influenza vaccination. Future influenza vaccination efforts geared toward rural adolescents may benefit from addressing adolescent attitudes toward influenza vaccination, particularly increasing intention to receive a vaccine. PMID- 21592126 TI - Immigrant parents' perceptions of school environment and children's mental health and behavior. AB - BACKGROUND: Research has increasingly identified the perception of school environment as an influential factor in children's lives. There has been sparse research attention, however, on the potential importance of parents' perceptions of school environment on child adjustment. This study examined the relationship between parents' perceptions of school environment and children's emotional and behavioral problems. METHODS: Data were derived from the New Canadian Children and Youth Study, a study of the children (aged 4-6 and 11-13) of immigrant parents. Analyses focused on a subsample of Mainland Chinese, Hong Kong Chinese, and Filipino immigrants in a large metropolitan area. RESULTS: Parental perception of school environment was negatively associated with physical aggression in children even after controlling for child age and gender, parental characteristics, family functioning, and aspects of acculturation. In contrast, parental perception was not significantly related to symptoms of emotional distress in children. There were some ethnic differences in perception of school environment. CONCLUSIONS: Parental perception of school environment is important to the well-being of the children of immigrant parents, and reinforces the relevance of initiatives to improve the dynamics between parents and schools. PMID- 21592127 TI - Promoting mental health and preventing substance abuse and violence in elementary students: a randomized control study of the Michigan Model for Health. AB - BACKGROUND: In elementary grades, comprehensive health education curricula mostly have demonstrated effectiveness in addressing singular health issues. The Michigan Model for Health (MMH) was implemented and evaluated to determine its impact on multiple health issues, including social and emotional skills, prosocial behavior, and drug use and aggression. METHODS: Schools (N = 52) were randomly assigned to intervention and control conditions. Participants received 24 lessons in grade 4 (over 12 weeks) and 28 more lessons in grade 5 (over 14 weeks), including material focusing on social and emotional health, interpersonal communication, social pressure resistance skills, drug use prevention, and conflict resolution skills. The 40-minute lessons were taught by the classroom or health teacher who received curriculum training and provided feedback on implementation fidelity. Self-report survey data were collected from the fourth grade students (n = 2512) prior to the intervention, immediately after the intervention, and 6 weeks after the intervention, with the same data collection schedule repeated in fifth grade. RESULTS: Students who received the curriculum had better interpersonal communication skills, social and emotional skills, and drug refusal skills than the control group students. Intervention students also reported lower intentions to use alcohol and tobacco, less alcohol and tobacco use initiated during the study and in the past 30 days, and reduced levels of aggression. CONCLUSION: The effectiveness of the MMH in promoting mental health and preventing drug use and aggression supports the call for integrated strategies that begin in elementary grades, target multiple risk behaviors, and result in practical and financial benefits to schools. PMID- 21592128 TI - Prioritizing the school environment in school violence prevention efforts. AB - BACKGROUND: Numerous studies have demonstrated an association between characteristics of the school environment and the likelihood of school violence. However, little is known about the relative importance of various characteristics of the school environment or their differential impact on multiple violence outcomes. METHODS: Primarily African-American students (n = 27) from Baltimore City high schools participated in concept mapping sessions, which produced interpretable maps of the school environment's contribution to school violence. Participants generated statements about their school environment's influence on school violence and, with the assistance of quantitative methods, grouped these statements according to their similarity. Participants provided information about the importance of each of these statements for the initiation, cessation, and severity of the violence that occurs at school. RESULTS: More than half of the 132 statements generated by students were rated as school environment characteristics highly important for the initiation, cessation, and/or severity of school violence. Participants identified students' own actions, expectations for disruptive behavior, and the environment outside the school as the characteristics most important for the initiation and increased severity of violence that occurs in school. Participants had a more difficult time identifying school environment characteristics important for the cessation of school violence. CONCLUSION: This study provides support from students for the role of the school environment in school violence prevention, particularly in preventing the initiation and reducing the severity of school violence. Schools can utilize the information presented in this article to begin discussions with students and staff about prioritizing school environment changes to reduce school violence. PMID- 21592129 TI - Obesity and other predictors of absenteeism in Philadelphia school children. AB - BACKGROUND: Limited data indicate that obese children are absent from school more than their normal-weight peers. We analyzed administrative data from a large urban school district to investigate the association of obesity and student sociodemographic characteristics with absenteeism. METHODS: We analyzed 291,040 records, representing 165,056 unique students (grades 1-12). Obesity status was classified according to Centers for Disease Control and Prevention age- and sex specific percentiles for body mass index (BMI) and analyses were based on negative binomial regression. RESULTS: Overall rates of overweight and obesity were 17% and 20%, respectively, and the estimated absence rate was 17 absences per 180 student-days. Obesity was weakly associated with increased school absences. The association was present mainly among the most obese students (BMI >99th percentile), who had an 11% greater absence rate compared to normal-weight students. Compared to white students, Hispanics and African Americans had higher absence rates (14% and 10%, respectively), and Asians had lower absence rates (43%). Students eligible for free or reduced-cost meals had 24% higher absence rates than those who were not eligible. CONCLUSIONS: Overweight and obesity do not seem strongly associated with school absence, except among extremely obese children. Race and poverty appear to affect absences to a greater extent than overweight and obesity. Additional research is needed to investigate the contribution of contextual factors in schools and neighborhoods. This study suggests that data routinely collected in schools could be used to track childhood obesity and to efficiently evaluate public health interventions designed to decrease childhood obesity. PMID- 21592130 TI - Uses of Youth Risk Behavior Survey and School Health Profiles data: applications for improving adolescent and school health. AB - BACKGROUND: To monitor priority health risk behaviors and school health policies and practices, respectively, the Centers for Disease Control and Prevention (CDC) developed the Youth Risk Behavior Surveillance System (YRBSS) and the School Health Profiles (Profiles). CDC is often asked about the use and application of these survey data to improve adolescent and school health. The purpose of this article is to describe the importance and potential impact of Youth Risk Behavior Survey (YRBS) and Profiles data based on examples from participating sites. METHODS: The authors spoke with representatives from 25 state and 8 local agencies funded by CDC to learn how data from the YRBS, Profiles, and other data sources are used. The authors identified common themes in the responses and categorized the responses accordingly. RESULTS: Representatives indicated survey data are used to describe risk behaviors and school health policies and practices, inform professional development, plan and monitor programs, support health-related policies and legislation, seek funding, and garner support for future surveys. Examples presented highlight the range of possible uses of survey data. CONCLUSIONS: State and local agencies use YRBS and Profiles data in many ways to monitor and address issues related to adolescent and school health. Innovative uses of survey data are encouraged, although it is also crucial to continue the more fundamental uses of survey data. If the data are not disseminated, the current health needs of students may not be adequately addressed. PMID- 21592131 TI - School nurse inspections improve handwashing supplies. AB - BACKGROUND: Handwashing in the school setting is important for infectious disease control, yet maintaining adequate handwashing supplies is often made difficult by lack of funds, limited staff time, and student vandalism. This study measured the availability of handwashing supplies for students in New Mexico public schools and determined the impact of scheduled school nurse inspections on the availability of handwashing supplies. METHODS: Participating school districts in New Mexico were matched by size and randomized into intervention and control groups. Baseline inspections were conducted in November 2008 followed by 2 subsequent bimonthly inspections. For each student bathroom, the presence or absence of soap and either paper towels or hand dryers was indicated on an inspection checklist. The intervention group reported findings to the New Mexico Department of Health (NMDOH) and to school administrative and custodial staff requesting that any identified problems be addressed. The control group reported inspection findings to the NMDOH only. Descriptive analyses were conducted to determine the proportion of bathrooms with soap and either paper towels or hand dryers. Comparisons were made between the intervention schools and the control schools at baseline and during the intervention period. RESULTS: The intervention group had significantly higher probability of bathrooms being supplied with soap (p < .05) and paper towels/hand dryers (p < .02) during the intervention period. CONCLUSIONS: Regularly scheduled school nurse inspections of hand hygiene supplies, with reporting to appropriate school officials, can improve the availability of handwashing supplies for students. PMID- 21592132 TI - Alcohol and tobacco counter-ads: stealing a page from billboard utilizing graffitists against unhealthy promotions. PMID- 21592133 TI - Mining for treatment-specific and general changes in target compounds and metabolic fingerprints in response to herbivory and phytohormones in Plantago lanceolata. AB - Induction studies focusing on target metabolites may not reveal metabolic changes occurring in plants after various challenges. By contrast, metabolic fingerprinting can be a powerful tool to find patterns that are either treatment specific or general and was therefore used to depict plant responses after various challenges. Plants of Plantago lanceolata were challenged by mechanical damage, specialist herbivores (aphids or sawfly larvae), generalist herbivores (Lepidopteran caterpillars) or phytohormones (jasmonic or salicylic acid). After 3 d of treatment, local and systemic leaves were analyzed for characteristic target metabolites (iridoid glucosides and verbascoside) by gas chromatography coupled with mass spectrometry (GC-MS) and for metabolic fingerprints by liquid chromatography coupled with time of flight mass spectrometry (LC-TOF-MS). Whereas only marginal changes in target metabolite concentrations were found, metabolic fingerprints were substantially affected especially by generalist and phytohormone treatments. By contrast, mechanical damage and specialist herbivory caused fewer changes. Responses to generalists partly overlapped with the changes caused by jasmonic acid, but many additional peaks were up-regulated. Furthermore, many peaks were co-induced by jasmonic and salicylic acid. The surprisingly high co-induction of peaks by both phytohormones suggests that the signaling pathways regulate a set of common targets. Furthermore, only metabolic fingerprinting could reveal that herbivores induce additional species-specific pathways beyond these phytohormone responses. PMID- 21592134 TI - Leaf and root pectin methylesterase activity and 13C/12C stable isotopic ratio measurements of methanol emissions give insight into methanol production in Lycopersicon esculentum. AB - Plant production of methanol (MeOH) is a poorly understood aspect of metabolism, and understanding MeOH production in plants is crucial for modeling MeOH emissions. Here, we have examined the source of MeOH emissions from mature and immature leaves and whether pectin methylesterase (PME) activity is a good predictor of MeOH emission. We also investigated the significance of below-ground MeOH production for mature leaf emissions. We present measurements of MeOH emission, PME activity, and MeOH concentration in mature and immature tissues of tomato (Lycopersicon esculentum). We also present stable carbon isotopic signatures of MeOH emission and the pectin methoxyl pool. Our results suggest that below-ground MeOH production was not the dominant contributor to daytime MeOH emissions from mature and immature leaves. Stable carbon isotopic signatures of mature and immature leaf MeOH were similar, suggesting that they were derived from the same pathway. Foliar PME activity was related to MeOH flux, but unexplained variance suggested PME activity could not predict emissions. The data show that MeOH production and emission are complex and cannot be predicted using PME activity alone. We hypothesize that substrate limitation of MeOH synthesis and MeOH catabolism may be important regulators of MeOH emission. PMID- 21592135 TI - A novel B(weak) hybrid allele lacks three enhancer repeats but generates normal ABO transcript levels. AB - BACKGROUND AND OBJECTIVES: Weak expression of A/B histo-blood group antigens is often explained by single nucleotide substitutions at the ABO locus. However, hybrid alleles containing segments from different ABO alleles can result in unexpected phenotypes and may complicate genotype analysis. We investigated the basis of weak B phenotype in a referred sample. MATERIALS AND METHODS: A healthy young woman was serologically phenotyped as AB(weak) and RBCs were characterized by flow cytometry. All seven ABO exons, five introns plus the 5'-region including the CCAAT-binding factor/Nuclear Factor Y (CBF/NF-Y) binding enhancer were sequenced. ABO transcript levels were measured in fresh peripheral blood samples. Expression of B antigen was semiquantified following transfection of HeLa cells. RESULTS: A new B(weak) allele with 53G>T resulted in a characteristic pattern of moderately weakened B antigen expression on RBCs. Its sequence revealed a novel hybrid between O(2) [O03] and B [B101] alleles with a crossingover region in intron 4 as defined by allele-specific polymorphisms. B transcript levels were similar to normal controls despite the O(2) -related single CBF/NF-Y-binding 43 bp motif in the enhancer region. Expression of the glycosyltransferase including the O(2) -specific Arg18Leu substitution resulted in a slight decrease in B antigen-positive cells. CONCLUSION: We describe here the first hybrid between an O(2) and a B allele and characterized the associated decrease in B antigen expression. Although it lacks three enhancer repeat units compared to common B alleles, the resulting transcript level was unaltered. This study challenges previous suggestions that the number of 43-bp motifs in the ABO enhancer determines transcription rates in erythroid cells. PMID- 21592138 TI - Prevalence of hepatitis B virus infection among Cercopithecidae monkeys in Cameroon. PMID- 21592136 TI - Prevalence and specificity of red-blood-cell antibodies in a multiethnic South and East Asian patient population and influence of using novel MUT+Mur+ kodecytes on its detection. AB - BACKGROUND AND OBJECTIVES: Appropriate screening for irregular red-cell antibodies is essential for ensuring transfusion compatibility and for antenatal management of mothers at risk of haemolytic disease of the foetus and newborn. Screening for all relevant antibodies is, however, limited by screening cells that do not express antigens present in the patient and donor population. Technology to artificially incorporate antigens into red cells is currently available and may be an option for customizing screening cells. MATERIALS AND METHODS: We sought to identify retrospectively the changing patterns of alloantibody prevalence in our multiethnic population on change of screening cells. Antibody screening records of 143 501 patients tested from 2004 to 2010 were retrieved and divided into two groups: period-1 (2004-2008) and period-2 (2009-2010). During period-1, standard screening cells were used while in period 2, MUT+Mur+ KODE(TM) transformed red cells (kodecytes) were used. RESULTS: Four per cent of samples tested during period-2 were positive on antibody screening compared to 3.2% in period-1. Specific antibodies, excluding anti-D, were identified in 1.66% and 1.52% of patients in period-2 and -1, respectively. When confined to antibodies of clinical significance only, period-2 showed higher alloantibody prevalence of 1.16% as compared to 0.66% in period-1. Antibodies to glycophorin variants of MNS (vMNS) were more commonly detected while antibodies to Lewis antigens declined during period-2. CONCLUSION: Antibodies to vMNS antigens are common in South and East Asian populations and are often missed when using standard screening cells. Use of specifically engineered screening cells to express red-cell antigens artificially is beneficial in detecting the diverse alloantibodies present in our population. PMID- 21592139 TI - Emotional words impact the mind but not the body: evidence from pupillary responses. AB - Pupillary responses have been shown to be sensitive to both task load and emotional content. We investigated the interplay of these factors in the processing of single words that varied in emotional valence and arousal. Two tasks of different cognitive load, uninstructed reading and a lexical decision task, were employed, followed by an unannounced recognition task. Reaction times were faster and incidental memory performance was better for high-arousing than for low-arousing words. In contrast to previous findings for pictures and sounds, high-arousing words elicited smaller pupillary responses than low-arousing words; these effects were independent of task load, which increased pupil diameter. Therefore, emotional arousal attributed to words does not mandatorily activate the autonomic nervous system, but rather works on a cognitive level, facilitating word processing. PMID- 21592140 TI - The rumouring of SARS during the 2003 epidemic in China. AB - By analysing rumour content as covered by major Chinese newspapers, this article explores the multiple dimensions of SARS-related rumouring throughout China during the 2003 epidemic. Findings indicate a strong correlation between the scale of SARS infections and level of rumour activities across regions. As for channels of dissemination, the rumour process still found a natural habitat in word of mouth, while internet-based platforms and cell phone text messaging emerged as viable grapevines. Our particular typology of SARS-incurred rumours leads us to identify four distinct types of rumours: legendary rumours; aetiological narratives; proto-memorates; and bogies. The four types of rumours are discussed against the background of superstitious beliefs, folklore practices, popular mentalities, and China's particular socio-political information environment. PMID- 21592141 TI - Tissue donation to biobanks: a review of sociological studies. AB - Collections of human tissue (biobanks) are thought to be an essential resource for biomedical research. Biobanks have, however, been a source of debate in both bioethics and sociology. In recent years this theorising has been supplemented with empirical research, including a significant body of qualitative research, into donors' experiences and attitudes. To date, this literature has not been synthesised. We report the findings of a review of qualitative literature regarding the ways in which lay people construct and experience the process of donation to biobanks. Our aim was to determine what the qualitative research literature tells us about the process of donating to biobanks, and how this can enrich existing insights from quantitative research and from theoretical sociology and bioethics. Qualitative research shows that donation to biobanks is a complex process shaped by donors' embeddedness in a number of social contexts; by complex relations of trust in biomedicine; and by the ambiguous status of human tissue. While these findings are theoretically and practically useful, current sociological theorising is very general. A more detailed and nuanced 'sociology of biobanking' is needed, and this might be best achieved by exploring specific theoretical questions in a variety of biobanking settings. PMID- 21592142 TI - Self-directed and interpersonal male violence in adolescence and young adulthood: a 30-year follow up of a Stockholm cohort. AB - In line with Wilkinson's theory on inequality and health, this study simultaneously analyses self-directed and interpersonal violence among men in a Stockholm birth cohort born in 1953 with respect to their early life experiences of stress, their lack of social connectedness and their relative deprivation. Multinomial logistic regressions with cluster-robust variance estimates were used. Self-directed violence was found to be related to self-rated loneliness and non-membership of voluntary associations but not to a lack of friendship in school at the age of 12-13, while the opposite was shown to be true for interpersonal violence. Growing up in a family that received means-tested social assistance at least once during the period 1953-1965 was taken as an objective indicator of relative deprivation and proved to be correlated with both self directed and interpersonal violence. Disadvantaged social comparison at the age of 12-13, taken as a subjective indicator of relative deprivation, was only statistically related to a subsequent risk of interpersonal violence. It is suggested that different types of social connectedness and relative deprivation, respectively, explain these different patterns of violence. Furthermore, the study speculates on the possibility of frequent social comparison itself being a factor to consider when trying understanding violence in general. PMID- 21592143 TI - Perceiving the target's state or state provoked by the target? An analysis of the descriptive and evaluative knowledge in person perception. AB - In line with the theory of traits as generalized affordances, the present article argues that target's states (TSs) and states provoked by a target (other's states (OSs) towards target) are two components of the meaning of traits referring, respectively, to a descriptive and to an evaluative knowledge of people. A preliminary study confirmed that TS and OS were equally representative of a trait. Two studies were designed to study the effects of practising the use of traits as either TS or OS categories (an induction procedure) on a subsequent person perception task, requiring participants to rate photographed targets on a series of traits. Results show that both the differentiation between targets and evaluative consistency of ratings were enhanced under the OS condition compared to TS and control (with no practice of traits) conditions. Importantly, Study 2 tends to show that the effects of the induction procedure are not limited to the practised traits but also generalize to unpractised traits. Implications of these findings for social perception research are discussed. PMID- 21592144 TI - Low cyanobacterial diversity in biotopes of the Transantarctic Mountains and Shackleton Range (80-82 degrees S), Antarctica. AB - The evolutionary history and geographical isolation of the Antarctic continent have produced a unique environment rich in endemic organisms. In many regions of Antarctica, cyanobacteria are the dominant phototrophs in both aquatic and terrestrial ecosystems. We have used microscopic and molecular approaches to examine the cyanobacterial diversity of biotopes at two inland continental Antarctic sites (80-82 degrees S). These are among the most southerly locations where freshwater-related ecosystems are present. The results showed a low cyanobacterial diversity, with only 3-7 operational taxonomic units (OTUs) per sample obtained by a combination of strain isolations, clone libraries and denaturing gradient gel electrophoresis based on 16S rRNA genes. One OTU was potentially endemic to Antarctica and is present in several regions of the continent. Four OTUs were shared by the samples from Forlidas Pond and the surrounding terrestrial mats. Only one OTU, but no internal transcribed spacer (ITS) sequences, was common to Forlidas Pond and Lundstrom Lake. The ITS sequences were shown to further discriminate different genotypes within the OTUs. ITS sequences from Antarctic locations appear to be more closely related to each other than to non-Antarctic sequences. Future research in inland continental Antarctica will shed more light on the geographical distribution and evolutionary isolation of cyanobacteria in these extreme habitats. PMID- 21592145 TI - Practising gender: children's relationships and the development of gendered behaviour and beliefs. PMID- 21592146 TI - The emergence of gender differences in physical aggression in the context of conflict between young peers. AB - It is well known that a gender difference in physical aggression emerges by the preschool years. We tested the hypothesis that the gender difference is partly due to changing tactics in peer interaction. Observations of girls' and boys' social initiatives and reactions to opportunities for conflict were made, using the Peer Interaction Coding System (PICS) in four independent samples of children between 9 and 36 months of age, which were aggregated to form a summary data set (N= 323), divided into two age bands (below or above 24 months of age). Linear mixed-model analyses revealed significant age by gender interactions in the use of bodily force in response to peers' initiatives and in the tendency to use bodily force at later stages of conflicts with peers. The gender difference in use of force was not explained by differences in the use of verbal tactics. These cross-sectional findings suggest that girls are initially more likely than boys to use reactive aggression, but then desist, whereas boys increase their use of force to defend their territory and possessions. The difference between older and younger girls likely reflects girls' abilities to regulate their behaviour in response to social challenges and the fact that girls are explicitly socialized to yield to peers' demands. PMID- 21592147 TI - Gender differences in children's problem behaviours in competitive play with friends. AB - Disruptive behaviour disorders are much more common in boys than girls (Office of National Statistics, 1999); in contrast, gender differences in normative problem behaviours are poorly understood. To address this issue, 228 6-year-olds (134 boys, 94 girls) were each observed playing a board game with a same-gender friend. Ratings of aggression, disruption, arousal and negativity were used to index problem behaviours. Multiple-groups confirmatory factor analyses demonstrated that the latent factor had the same metric for boys and girls, but a mean that was approximately half a standard deviation higher for boys than girls. In addition, the association between the latent factor and teachers' ratings of total difficulties was significantly stronger for boys than girls. PMID- 21592148 TI - Peer socialization of masculinity and femininity: differential effects of overt and relational forms of peer victimization. AB - Although peer influence has been implicated in recent theories of gender socialization, few investigations have tested whether children's gendered behaviours change over time as a function of peer experiences and whether some peer experiences may exacerbate, rather than dampen, gender non-conformity. Accordingly, the current study examined prospective links between specific forms of peer victimization and children's adherence to traditional gender roles. Peer reports of victimization and self-reports of engagement in stereotypically masculine and feminine activities were collected from 199 children (104 girls; 95 boys) in the Fall and Spring of their fifth-grade year. Multi-group path analysis was used to explore the relations between forms of victimization and masculinity and femininity for girls and boys. For girls, peer victimization predicted withdrawal from both feminine and masculine behaviours. For boys, physical, verbal, and general victimization predicted lower levels of feminine behaviours, but social exclusion forecast heightened engagement in traditionally feminine activities. These findings underscore how social experiences can amplify, as well as reduce, gender non-conformity. PMID- 21592149 TI - Gender and racial favouritism in black and white preschool girls. AB - The authors examined gender and racial preferential behaviour in 108 3- and 5 year-old Black and White girls. Children set up a birthday party for dolls that differed in gender and racial physical characteristics. Whereas White girls showed favouritism towards the doll most closely resembling themselves in both gender and race, Black girls showed most favouritism towards the White girl doll. Black girls were more likely to show preference based on gender rather than race, whereas White girls were equally likely to show race- or gender-based favouritism. Among White 5-year-olds, greater prior interaction with Blacks was positively associated with race-related favouritism (i.e., secondary preference to the White boy doll rather than the Black girl doll). Interracial contact was unrelated to racial favouritism among the other three groups. Results demonstrate the salience of gender identity during the preschool years, and indicate that majority/minority status and intergroup contact shape the development of collective identity and social behaviour. PMID- 21592150 TI - 'It's not that we hate you': understanding children's gender attitudes and expectancies about peer relationships. AB - Widespread gender segregation, evident throughout elementary school, seems to imply that girls and boys have negative feelings and thoughts about one another, and classic theories of inter-group processes support this idea. However, research has generally overlooked children's feelings and perceptions about gender-related interpersonal interactions. This paper investigates the nature of children's attitudes about same- and other-gender peers, and explores how those attitudes relate to the expectancies and beliefs children hold about same- and other-gender peer interactions. Children (N= 98 fifth graders) completed questionnaires assessing their global liking of own- and other-gender peers (Yee & Brown, 1994), positive and negative attitudes about own- and other-gender peers, and outcome expectancies related to interacting with own- and other-gender peers. Results indicated that rather than being characterized by out-group negativity, children's inter-group gender attitudes are best characterized by an in-group positivity bias. Children's positive and negative affective attitudes were also significantly associated with outcome expectancies. In contrast, global liking of own- and other-gender peers was less predictive of outcome expectancies. Thus, the greater specificity of the affective attitude measures appeared to be a more predictive and potentially fruitful gauge of children's feelings about own- and other-gender peers. Results are discussed in terms of the need for finer grained and more extensive studies of children's gender-related feelings and cognitions about own- and other-gender peers. PMID- 21592151 TI - The constructive role of gender asymmetry in social interaction: further evidence. AB - Two hundred and sixty-four children aged 6.5-7.5 years (first graders) took part in a pre-test, interaction, and post-test experiment working on a spatial transformation task known as the 'village task'. Cognitive progress was assessed by pre- to post-test gains in both an immediate and delayed post-test in dyads and individual participants as a control. The results indicate clear links between particular pair types with both communication processes and with learning and cognitive developmental outcomes. The present study demonstrates that gender can act as a source of status asymmetry in peer interaction to influence communication, learning, and cognitive development in same- and mixed-sex dyads. PMID- 21592152 TI - Social reasoning about 'second-shift' parenting. AB - The present study investigated children's and adolescents' social reasoning about parenting roles in the home, specifically 'second-shift parenting' by a mother or father. Surveys were administered to children (age 10) and adolescents (age 13), nearly evenly divided by gender (N= 200) in which two hypothetical scenarios were evaluated. Participants were asked to evaluate and justify second-shift parenting arrangements for the family overall, for the parent in the role, and for the child in the family. Results showed that participants expected mothers rather than fathers to take on the second-shift role, and second-shift parenting was evaluated as more unfair for fathers than for mothers. Personal choice reasoning was used for justifying arrangements for the second-shift parent and moral reasoning was used for justifying arrangements for the child. Social reasoning about the context of parental caretaking roles was multifaceted and varied by age and gender of participant more so than by self-reported personal family arrangements. PMID- 21592153 TI - Breadwinner and caregiver: a cross-sectional analysis of children's and emerging adults' visions of their future family roles. AB - Participants were 150 school-age boys and girls, 58 high school students, and 145 university students drawn from communities in the Southeastern United States. In this cross-sectional study, family role attitudes and expectations were examined across development. Parental work traditionality (occupational prestige and traditionality, and employed hours) predicted daughters' social role attitudes and plans for future family roles, such that daughters' envisioned families resembled that of their parents. Sons' and daughters' own attitudes about adult family roles predicted their plans to work or stay home with their future children; however, mothers' work traditionality predicted daughters' future plans over and above daughters' own attitudes. The only exception to this was in the case of university daughters, where university women's attitudes about social roles fully mediated this relationship. It may be that, as young women approach adulthood and the formation of families, they adjust their vision of their future self to match more closely their own attitudes about the caregiving role. PMID- 21592154 TI - Research in developmental psychology on gender and relationships: reflections on the past and looking into the future. AB - Recent historical trends and current directions in the study of children's gender and relationships are reviewed using Maccoby and Jacklin's (1974) The Psychology of Sex Differences as a reference point. Since the publication of Maccoby and Jacklin's review, researchers have questioned the extent and the magnitude of gender differences in social behaviour as well as the degree to which parents play a primary role in gender development. More attention is now paid to the impact of gender-segregated peer groups and other social relationships (e.g., friendships, romantic relationships) as well as cognitive-motivational and biological processes. Furthermore, the role of the larger social-structural context is addressed in studies of sexism and gender bias during childhood and adolescence. Recommendations for future research are offered. PMID- 21592155 TI - Determinants of tick-borne encephalitis virus antibody presence in roe deer (Capreolus capreolus) sera. AB - In order to identify variables associated with the presence of the tick-borne encephalitis (TBE) virus, we conducted a serological survey of roe deer [Capreolus capreolus (Artiodactyla: Cervidae, Linnaeus 1758)] in three forest districts of southern Hesse, Germany. Overall, 24 out of 105 (22.9%) of the sera were positive (>=1 : 10 plaque reduction neutralization test). Using a logistic regression approach, we found that unexplained spatial variation, indexed roe deer density (positive correlation), hind foot length of the tested roe deer (positive correlation) and infestation with female Ixodes spp. ticks (negative correlation) predicted the probability of TBE virus antibody presence in individual roe deer sera. Spring temperature increase and host sex were rejected as explanatory variables. We found considerable differences in TBE virus antibody seroprevalence (50.0% vs. 17.6%) between two forest districts located in the same county; this finding questions the current county-resolution of public health recordings. Given the high seroprevalence of roe deer and the considerable explanatory power of our model, our approach appears suitable to delineate science-based risk maps at a smaller spatial scale and to abandon the current human incidence per county criterion. Importantly, using roe deer as sentinels would eliminate the inherent bias of risk maps based on human incidence (varying levels of immunization and exposure of humans). PMID- 21592156 TI - Spatial stratification of host-seeking Diptera in boreal forests of northern Europe. AB - The stratification of haematophagous Diptera was assessed in two boreal forests in northern Sweden by placing traps baited with carbon dioxide at 1.5 m, 5.0 m and 10.0 m above the ground. More than 40 000 specimens were captured, including 617 biting midges (Ceratopogonidae), 4029 mosquitoes (Culicidae) and 36 092 black flies (Simuliidae). Catches at the various trap heights reflected the general vertical distribution of the preferred hosts, with mammalophilic flies predominating (68.6%) in catches at 1.5 m and ornithophilic flies (42.4%) in catches at 10.0 m; however, most flies that use host birds at ground level were caught in the lowest traps (e.g. 85.1% of Simulium annulus were collected at 1.5 m). Within-species variation in vertical patterns between forests suggests plasticity in responses to environmental factors such as vegetative structure. PMID- 21592157 TI - A patient's perspective: the impact of adverse drug reactions on patients and their views on reporting. AB - WHAT IS KNOWN AND OBJECTIVE: Adverse drug reactions to prescribed medication are relatively common events. However, the impact such reactions have on patients and their attitude to reporting such events have only been poorly explored. Previous studies relying on self-reporting patients indicate that altruism is an important factor. In the United Kingdom, patient reporting started in 2005; though, numbers of serious reports remain low. METHOD: A purposive sample of fifteen patients who had been admitted to an inner city hospital with an adverse drug reaction were interviewed using a semi-structured questionnaire. Patients were asked to relate in their own words their experience of an adverse drug reaction. Patient's reactions to the information leaflet, adherence to treatment and use of other sources of information on medication were assessed. Interviews were recorded, and a thematic analysis of patients' responses was performed. RESULTS AND DISCUSSION: Analysis of the patient interviews demonstrated the reality of being admitted to hospital is often a frightening process with a significant emotional cost. Anger, isolation, resentment and blame were common factors, particularly when medicines had been prescribed for acute conditions. For patients with chronic conditions, a more phlegmatic approach was seen especially with conditions with a strong support networks. Patients felt that communication and information should have been more readily available from the health care professional who prescribed the medication, although few had read the patient information leaflet. Only a minority of patients linked the medication they had taken to the adverse event, although some had received false reassurance that the drug was not related to their illness creating additional barriers. In contrast to previous studies, many patients felt that adverse drug reporting was not their concern, particularly as they obtained little direct benefit from it. The majority of patients were unaware of the Yellow Card Scheme in the UK for patient reporting. Even when explained, the scheme was felt too cold and impersonal and not a patient's 'job'. WHAT IS NEW AND CONCLUSION: Patients having a severe adverse drug reaction following an acute illness felt negative emotions towards their health care provider. Those with a chronic condition rationalized the event and coped better with its impact. Neither group felt that reporting the adverse reaction was their responsibility. Encouraging patients to report remains important but expecting patients to report solely for altruistic purposes may be unrealistic. PMID- 21592158 TI - Survey to assess public awareness of patient reporting of adverse drug reactions in Great Britain. AB - WHAT IS KNOWN AND OBJECTIVE: Patient reporting to the Yellow Card Scheme (YCS) for reporting adverse drug reactions (ADR) has been available in the UK since 2005. By the end of 2009, 18% of the ADRs reported were submitted by patients. Thus, some patients are aware of the scheme, but we do not know how much awareness exists in the general population and hence the true impact of patient reporting. METHODS: We added eight questions to a telephone omnibus survey of the adult population of the UK, administered over two weekends in January 2009. RESULTS AND DISCUSSION: Results are based on 2028 completed interviews. Of respondents, 8.5% (n=172) had heard of the YCS, but only three individuals had self-reported to the scheme. People of a higher social grade and those with further education were significantly more likely to be aware of the YCS. Those who reported a preference for online reporting were more likely to be men, younger, of middle social grade with further education and in full-time employment. Those suggesting a preference for telephone reporting tended to be women, of working class and with a lower level of education, as did those who expressed a preference for postal reporting, but in addition they were more likely to be older and retired. Each of the three current methods of reporting was preferred by some respondents and could be continued. This is supported by reports that each of the three methods is currently used. WHAT IS NEW AND CONCLUSION: This first survey of awareness of the YCS in the general population of the UK indicates awareness is low and could be improved. PMID- 21592159 TI - Persistence and compliance of deferoxamine versus deferasirox in Medicaid patients with sickle-cell disease. AB - WHAT IS KNOWN AND OBJECTIVE: Patients with sickle-cell disease (SCD) receiving chronic transfusions of red blood cells are at risk of developing serious adverse effects. Iron chelation therapy (ICT) helps eliminate iron overload by binding with plasma iron to form a non-toxic conjugate that can be safely excreted from the body. Two iron chelating agents are currently available in the United States: Deferoxamine (DFO) is an injectable formulation, and deferasirox (Exjade((r)) ) is an oral suspension. This study compared the frequency of hospitalizations, persistence and compliance of patients with SCD from Medicaid programmes treated with DFO vs. deferasirox. METHODS: Health care claims from Medicaid Florida (1998 2007), Missouri (1993-2008) and New Jersey (1996-2008) were analysed. Patients with continuous enrolment for >=6months prior to ICT initiation and >=1 SCD diagnosis were included in the analysis. Patients were divided into four cohorts: patients treated with DFO (any-DFO group) and patients treated with deferasirox (any-deferasirox group); the latter was further divided into patients initiated on DFO and then switched to deferasirox (deferasirox switchers), and patients treated with deferasirox-only (deferasirox-only group). Frequency of hospitalization for crisis conditions related to SCD as well as length of stay pre- and post-ICT treatment initiation were assessed. Persistence was defined as time to drug discontinuation with >=1 Rx gap, using Kaplan-Meier approach. Compliance was estimated using a medication possession ratio (MPR) based on the drug exposure approach. Adjusted analyses of persistence and compliance were also conducted. RESULTS: A total of 217 (mean age: 19.4years, 39.2 men), 275 (20.1years, 41.5% men), 105 (19.4years, 42.9% men) and 166 (20.4years, 41.6% men) patients were included in the any-DFO, any-deferasirox, deferasirox switchers and deferasirox-only groups, respectively. After ICT initiation, the any-deferasirox and deferasirox-only groups experienced a statistically significant reduction in the frequency of hospitalizations relative to pretreatment [any-deferasirox: from 0.09 to 0.06 hospitalizations per patient per month (pmpm), P=0.0105; deferasirox only: from 0.11 to 0.07 hospitalizations pmpm, P=0.0188], whereas it remained stable in the any-DFO group at 0.08 hospitalizations pmpm (P=0.9483). The Kaplan Meier rates of medication persistence assessed at 6 and 12months of follow-up were significantly lower for DFO patients (6 months: 0.34, 12months: 0.21) as compared to all deferasirox (0.51, 0.29, P=0.0002), deferasirox switchers (0.56, 0.37, P=0.0002) and deferasirox-only (0.47, 0.24, P=0.0176) patients. Similarly, compliance to treatment was significantly lower for patients treated with DFO (mean MPR: 0.64) compared with any-deferasirox (0.78, P<0.0001), deferasirox switchers (0.75, P=0.0002) and deferasirox-only (0.80, P<0.0001) patients. Adjusted analyses of persistence and compliance yielded similar results. WHAT IS NEW AND CONCLUSIONS: Based on a Medicaid population, patients treated with deferasirox were more compliant and persistent with their treatment than those treated with DFO. Frequency of hospitalizations was significantly reduced after treatment initiation for the any-deferasirox and deferasirox-only groups. Prospective studies controlling for potential clinical and treatment pattern differences between deferasirox and DFO patients are needed to assess whether the decreased hospitalizations after initiation of deferasirox are related to better treatment compliance. PMID- 21592160 TI - Special Care in Dentistry. Editorial. PMID- 21592161 TI - An intervention to reduce care-resistant behavior in persons with dementia during oral hygiene: a pilot study. AB - The primary purpose of this pilot study was to test the feasibility of an intervention designed to reduce care-resistant behaviors (CRBs) in persons with moderate-to-severe dementia during oral hygiene activities. The intervention, Managing Oral Hygiene Using Threat Reduction (MOUTh), combined best oral hygiene practices with CRB reduction techniques. Oral health was operationalized as the total score obtained from the Oral Health Assessment Tool (OHAT). CRB was measured using a refinement of the Resistiveness to Care Scale. Seven nursing home residents with dementia received twice daily mouth care for 14 days. The baseline OHAT mean score of 7.29 (SD = 1.25) improved to 1.00 (SD = 1.26, p < .001); CRB improved from 2.43 CRBs/minute (SD = 4.26) to 1.09 CRBs/minute (SD = 1.56, t = 1.97, df 41, p= .06). The findings from this pilot study suggest that the MOUTh intervention is feasible and reduced CRBs, thus allowing more effective oral care. PMID- 21592162 TI - Comparison of perceptions of oral health-related quality of life in adolescents affected with ectodermal dysplasias relative to caregivers. AB - The objective of this study was to assess the perceived oral health-related quality of life (OHQoL) of adolescents affected with one of the ectodermal dysplasias (EDs). Data were collected from 2003 to 2007 in a cross-sectional study of a convenience sample of individuals affected by ED (n = 35) using the Child Perceptions Questionnaire (CPQ11-14) for children and the Parent-Caregiver Perceptions Questionnaire for their caregivers. The main findings of this study were that individuals who were affected with ED in the older age group (15- to 19 year-olds) perceived more functional problems than younger individuals (11- to 14 year-olds) (p= .04). Females with ED (n = 13) perceived more emotional problems than males (n = 22; p= .01). Although caregivers tended to report slightly higher OHQoL scores (indicating worse OHQoL), no significant differences were observed between children's and parents' total OHQoL and individual domains' median scores (p > .05). Thus, the perceptions of oral health and well-being may vary by age and gender for children who have ED. Caution is warranted concerning using parents as proxies for their children when assessing the child's OHQoL. PMID- 21592163 TI - Dental treatment needs in Dutch nursing homes offering integrated dental care. AB - The purpose of this study was to determine the dental treatment needs of the residents in nursing homes (NHs) where integrated dental care has been offered without financial barriers. The dental status and surgical, prosthetic, restorative, and periodontal treatment needs were determined for 432 residents (average age 78.8 years) in three Dutch NHs. Although the subjects had no complaints, 72% had dental treatment needs. It was determined that treatment was necessary for 64% of the edentulous subjects (N = 316), 100% of the partially dentate subjects (N = 76), and 87% of the fully dentate subjects (N = 40). We concluded that when residents can no longer carry out oral hygiene independently, it is very difficult for them to maintain a level of oral health where their dental treatment needs have been met, especially for dentate residents. PMID- 21592165 TI - Management of the oral manifestations of senile purpura in an edentulous patient: a case report. AB - Senile purpura occurs because of a weakness of the vascular supporting tissues mainly caused by aging and is most often seen on the dorsal surface of the hands and the extensor surfaces of the forearms, and has also been observed in the oral mucosa of elderly patients. These red lesions present as sharply margined subcutaneous hemorrhagic spots and are due to trauma, such as damage to the endothelium of small blood vessels, or a coagulation defect. They can also be due to reduced perivascular support, or capillary fragility and permeability, or a combination of all of these factors. Oral manifestation of senile purpura can also be induced by long periods of medication use leading to fragile areas of the mucosa. The presence of senile purpura requires continuous follow-up since drug induced purpura may cause plaque function alterations. An accurate diagnosis in elderly complete denture wearers can minimize bleeding and prevent possible development of ulcerations under the dentures, especially during the adaptation period to the prosthesis. This case report, presents the care and 3-year follow up of a 66-year-old woman with complete dentures who presented with the oral manifestations of senile purpura caused by the continued use of several medications. PMID- 21592164 TI - Oral care and sensory sensitivities in children with autism spectrum disorders. AB - Children with autism spectrum disorders (ASD) are at high risk for oral disease. The aim of this study was to examine the contribution of sensory processing problems to challenges in receiving oral care for children with ASD. A questionnaire was sent to the parents of 206 children with disabilities to test the hypotheses that children with ASD, relative to children with other disabilities, experience greater difficulty with home-based and professional oral care, and that these difficulties may relate in part to sensory processing problems. The results partially supported these hypotheses. Compared to children with other disabilities, those with ASD had greater behavioral difficulties and sensory sensitivities that parents believed interfered with their child's oral care. Among children with ASD, sensory sensitivities were associated with oral care difficulties in the home and dental office, and with behavioral difficulties in the dental office. Utilizing strategies to modify the sensory environment may help facilitate oral care in children with ASD. PMID- 21592166 TI - Successful prevention of oral self-mutilation using a lip guard: a case report. AB - Self-injurious behavior (SIB) is causing deliberate harm to the body without suicidal intent; this problem occurs in a number of psychiatric, behavioral, and developmental disorders. This report describes the case of a girl, aged 19 months, whose lower lip injuries due to SIB were successfully treated through the use a combination of extraoral and intraoral prostheses. A custom-made lip guard with a custom-made adjustable head strap was effective in the management of the lip trauma. SIB was prevented and there was no recurrence even at the 17-month follow-up appointment. PMID- 21592168 TI - A prospective study of lymphocyte subpopulations and regulatory T cells in patients with chronic hepatitis C virus infection developing interferon-induced thyroiditis. AB - OBJECTIVE: One of the side effects of interferon-alpha (IFN-alpha) therapy is interferon-induced thyroiditis (IIT). The role of lymphocyte subpopulations in IIT remains to be defined. The aim of this study was to assess different peripheral blood lymphocyte subpopulations, mainly CD4(+) CD25(+) CD127low/ FoxP3(+) regulatory T cells (Tregs), in patients with chronic hepatitis C virus (HCV) infection who developed IIT. DESIGN, PATIENTS AND METHODS: From 120 patients with chronic HCV who started antiviral treatment, those who developed IIT (IIT patients) were selected and compared with patients who did not develop IIT (Co-HCV). Peripheral blood mononuclear cells were obtained before treatment (BT), mid-treatment (MT), end of treatment (ET), 24 weeks post-treatment (PT) and at appearance of IIT (TT). RESULTS: Eleven patients developed IIT: three Hashimoto's thyroiditis, one Graves'disease, one positive antithyroidal antibodies, one nonautoimmune hypothyroidism and five destructive thyroiditis. During antiviral treatment, an increase in CD8(+) and in Tregs was observed in both groups. A decrease in CD3(+) , CD19(+) and NKT lymphocyte subpopulations was also observed (all P < 0.05). However, no changes were observed in the percentage of CD4(+) , CD3(+) gammadelta(+) and iNKT lymphocytes, Th1/Th2 balance and Bcl2 expression on B cells when BT was compared with ET. At the appearance of IIT (TT), IIT patients had a higher Th1 response (CCR5(+) CCR7(-) ) (P < 0.01) and a higher Tregs percentage (P < 0.05) than Co-HCV. CONCLUSIONS: Our results point to the immunomodulatory effects of IFN-alpha on different lymphocyte subpopulations and a possible role of Th1 response and Tregs in patients with HCV who developed IIT. PMID- 21592169 TI - The lack of association between polycystic ovary syndrome and metabolic syndrome: Iranian PCOS prevalence study. AB - OBJECTIVE: This study was designed to evaluate the prevalence of the metabolic syndrome (MetS) and insulin resistance (IR) in a large population-based study in Iran. RESEARCH DESIGN AND METHODS: Anthropometric measurements, biochemical parameters and IR were compared between 136 polycystic ovary syndrome (PCOS) subjects and 423 healthy controls recruited from among 1126 reproductive aged women (18-45 year). PCOS and MetS were diagnosed using the Rotterdam criteria and Joint Interim Statement, respectively. IR was defined using the homeostatic model assessment-IR). RESULTS: Among the PCOS subjects, the mean +/- SD age, body mass index (BMI) and waist circumference were 31 +/- 7.7 years, 26.4 +/- 5.8 kg/m(2) and 84 +/- 13.3 cm, respectively; corresponding values among healthy controls were 36 +/- 7.5 years, 26.4 +/- 5.0 kg/m(2) and 85 +/- 11.9 cm, respectively. Age and BMI adjusted prevalences of MetS in PCOS subjects and controls were 18.5% (CI 95%, 15.3-21.7%) and 18.3% (CI 95%, 15.1-21.5%), respectively [P = not significant (NS)]. Age and BMI adjusted prevalences of IR in PCOS and healthy controls were 27.2% (CI 95%, 23.5-30.9%) and 24.2% (CI 95%, 20.6-27.8%), respectively (P < 0.01). CONCLUSIONS: Metabolic syndrome was no more frequent in a representative sample of PCOS Iranian population than in healthy controls. However, the prevalence of IR in PCOS appears to be higher than in controls. It seems that the association between PCOS and MetS needs more consideration. PMID- 21592170 TI - Development of the two-stage rapid estimate of adult literacy in dentistry. AB - OBJECTIVE: This work proposes a revision of the 30 item Rapid Estimate of Adult Literacy in Dentistry (REALD-30), into a more efficient and easier-to-use two stage scale. METHODS: Using a sample of 1405 individuals (primarily women) enrolled in a Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), the present work utilizes principles of item response theory and multi-stage testing to revise the REALD-30 into a two-stage test of oral health literacy, named Two-Stage REALD or TS-REALD, which maximizes score precision at various levels of participant ability. RESULTS: Based on the participant's score on the five-item first-stage (i.e., routing test), one of three potential stage two tests is administered: a four-item Low Literacy test, a six-item Average Literacy test, or a three-item High Literacy test. CONCLUSIONS: The reliability of scores for the TS-REALD is >0.85 for a wide range of ability. The TS-REALD was found to be predictive of perceived impact of oral conditions on well-being, after controlling for educational level, overall health, dental health, and a general health literacy measure. While containing approximately one-third of the items on the original scale, the TS-REALD was found to maintain similar psychometric qualities. PMID- 21592171 TI - Effect of methanol extract of Basella alba L. (Basellaceae) on the fecundity and testosterone level in male rats exposed to flutamide in utero. AB - We evaluated the effect of the methanol extract of Basella alba (MEBa) on testosterone level and fecundity/fertility in male rats exposed in utero to flutamide - an androgen receptor antagonist. For this purpose, 1.5- and 2.5 month-old male rats exposed in utero to flutamide were treated with the MEBa (1 mg kg(-1) ) for 2 and 1 month respectively. Five days before the end of treatment, rats were housed with females to assess their fecundity/fertility. Thereafter, rats were sacrificed and blood collected for the quantification of testosterone. Flutamide-exposed male rats showed a decrease in their ano-genital distance (AGD, P < 0.05) and were infertile. In normal (methylcellulose-exposed) animals, MEBa provoked an increase in testosterone level in 1.5- (P < 0.008) and 2.5 -month-old rats (P < 0.01) concomitantly with the improvement in their fecundity by 25%. In flutamide-exposed male rats, MEBa increased testosterone level in 1.5 -month-old rats (P < 0.001) without any effect on their fecundity; while in 2.5- month-old rats, MEBa did not affect the testosterone level but improved fecundity (by 25%) and fertility (P < 0.001). This study demonstrated the positive effect of MEBa to enhance fecundity/fertility in normal male rats and in rats exposed to the antiandrogen flutamide during their foetal life. PMID- 21592172 TI - DNA sperm damage correlates with nuclear ultrastructural sperm defects in teratozoospermic men. AB - Sperm morphology has consistently been the best indicator of male fertility. Transmission electron microscopy currently provides the most information on the subcellular details of sperm structure. Recently, assessment of sperm DNA damage has been employed to assess fertility potential. The purpose of this work was to link sperm DNA damage, evaluated by an intercalated fluorescent dye, with the structural characteristics of sperm. Conventional semen analysis was performed on samples from men undergoing fertility evaluation. Thirty men were evaluated and assigned to three subgroups based on strict criteria for sperm morphology: normal morphology (>14% normal forms), intermediate morphology (5-14% normal forms), and poor morphology (<5% normal forms). By quantifying acridine orange-positive cells and ultrastructural sperm defects, we found that the poor morphology pattern group showed a positive association between sperm carrying damaged DNA and the percentage of sperm nucleus with vacuoles (P = 0.01). No statistically significant correlations were established in other ultrastructural characteristics of sperm, including immature chromatin, lytic changes, or abnormal sperm tails. These results suggest that zones without chromatin in the sperm nucleus reflect underlying chromosomal or DNA defects in severe teratozoospermic men. This association should be considered in the evaluation of male fertility. PMID- 21592173 TI - Rehabilitation of the cavernous smooth muscle in patients with organic erectile dysfunction. AB - This study aimed at assessing the effect of regular use of intracorporeal injection (ICI), sildenafil citrate and vacuum constriction device (VCD) on cavernous smooth muscle and erectile activity. One hundred and sixty-five patients with organic erectile dysfunction were investigated for 3 months. The patient and his partner were classified prospectively after proper counselling: group I (n = 56) received ICI twice per week; group II (n = 55) received sildenafil 100 mg twice per week; and group III (n = 54) used VCD twice per week. Duplex ultrasound was carried out before and after treatment, and then, the patients were followed up for a month to assess the resumption of unaided erection. The results showed that there was significant improvement in mean peak systolic velocity (PSV) and mean cavernosal artery diameter (CAD) at the end of the treatment in all groups, being higher in the ICI group than in the other two groups. Also, the percentage of patients who resumed unaided intercourse were higher in the ICI group compared with the other two groups (17.9%, 9.1% and 3.7% respectively). It is concluded that repeated regular use of ICI, sildenafil or VCD by patients with organic erectile dysfunction has a positive impact on their cavernous blood flow and erectile activity. PMID- 21592174 TI - Temperature-induced sperm nuclear vacuolisation is dependent on sperm preparation. AB - The influence of temperature during incubation on the degree of sperm nuclear vacuolisation was assessed by two different experiments. In a first experiment, motile spermatozoa from 24 patients were prepared by the swim-up technique and incubated either at room temperature or at 37 degrees C for up to 4 h. The presence of sperm nuclear vacuoles was determined by contrast-enhanced high magnification microscopy. No statistically significant difference was found in the degree of sperm nuclear vacuoles in both groups (RT: 45.6 +/- 17.6%; 37 degrees C: 48.4 +/- 17.0%) following 4 h of incubation. In a second experiment, spermatozoa from six patients were either prepared by swim-up or washed and incubated at 37 degrees C. After 4 h of incubation, a significant increase in sperm nuclear vacuolisation was found in washed sperm (from 51.5 +/- 15.4% to 68.6 +/- 9.0%; P < 0.05) but not in swim-up sperm (from 51.5 +/- 15.4% to 48.2 +/ 17.1%; n.s.). Our data show that the mode of sperm preparation does influence sperm nuclear vacuolisation at 37 degrees C (Experiment II). However, sperm nuclear vacuolisation is unaffected by temperature in motile sperm after preparation and isolation by swim-up. PMID- 21592175 TI - Effect of different doses of Malaysian honey on reproductive parameters in adult male rats. AB - The aim of this study was to evaluate the effect of different doses of Malaysian honey on male reproductive parameters in adult rats. Thirty-two healthy adult male Sprague-Dawley rats were randomly divided into four groups (eight rats per group). Group 1 (control group) was given 0.5 ml of distilled water. Groups 2, 3 and 4 were given 0.2, 1.2 and 2.4 g kg(-1) body weight of honey respectively. The rats were treated orally by gavage once daily for 4 weeks. Honey did not significantly alter body and male reproductive organs weights. The rats in Group 3 which received honey at 1.2 g kg(-1) had significantly higher epididymal sperm count than those in Groups 1, 2 and 4. No significant differences were found for the percentage of abnormal sperm, elongated spermatid count, reproductive hormonal levels as well as the histology of the testis among the groups. In conclusion, Malaysian honey at a dose of 1.2 g kg(-1) daily significantly increased epididymal sperm count without affecting spermatid count and reproductive hormones. These findings might suggest that oral administration of honey at this dose for 4 weeks may enhance spermiogenesis in adult rats. PMID- 21592176 TI - DNA content of Ovis musimon spermatozoa. AB - To our knowledge, the value of the haploid DNA content (C-value) of Ovis musimon (mouflon) has not been previously published. Therefore, the aim of the present work was to determine the C-value and the nuclear area of O. musimon sperm cells and compare both parameters with those of Ovis aries. Feulgen reaction, which is specific and stoichiometric for DNA, was carried out on semen smears. The C-value and sperm nuclear area were determined using microspectrophotometry and Gallus domesticus erythrocytes as standard species. The C-value of O. musimon was 3.02 +/- 0.04 pg, and the sperm nuclear area was 23.92 +/- 0.89 MUm(2). The C-value and the sperm nuclear area of O. aries were 3.07 +/- 0.03 pg and 22.98 +/- 0.86 MUm(2) respectively. The O. musimon C-value was not significantly different (P > 0.05) from that of O. aries, indicating that both species may have a very close phylogenetic relation. PMID- 21592177 TI - In vitro initiated sperm forward motility in caput spermatozoa: weak and transient. AB - Testicular spermatozoa during journey through epididymis acquire forward motility, which is essential for fertility. To understand the biochemistry of sperm motility initiation, various initiation media have been developed that permitted high level of motility induction (55-60%) in the immature caput spermatozoa in presence of activating principles: theophylline, bicarbonate and epididymal plasma (EP) when analysed microscopically. Here, we show for the first time using caprine model that stability and quality of in vitro-induced motility in the caput spermatozoa is insignificant in contrast to naturally induced motility in mature cauda spermatozoa. In vitro-induced motility of the immature spermatozoa was lost completely upon the removal of these activators by centrifugation. Selective withdrawal of either EP or HCO(3) by dilution retains 50-60% of the in vitro-induced motility. Spectrophotometric analysis revealed that in vitro-induced vertical motility in immature spermatozoa is too little when compared to mature spermatozoa. In in vitro-initiated caput spermatozoa, cyclic adenosine monophosphate level becomes doubled but lesser than cauda spermatozoa. This revelation concludes that scientific knowledge generated over the years on the basis of in vitro initiation method is insignificant and needs improvisation to delineate biochemical regulation of sperm motility which in turn has remarkable potential in wide biological fields, especially in infertility treatment. PMID- 21592178 TI - Butyl paraben-induced changes in DNA methylation in rat epididymal spermatozoa. AB - Parabens have been shown to affect male rodent reproductive parameters, including testosterone levels and sperm production. In this study, we examined the effect of long-term exposure to butyl paraben (BP) on rat epididymal sperm DNA methylation. Adult male rats were exposed to BP (0, 10, 100 and 1000 mg kg(-1) per day) according to OECD TG407 for a repeated 28-day oral toxicity study. Sperm DNA methylation was examined by differential display random amplification of polymorphic DNA (RAPD) following methylation-specific restriction digestion of DNA. Among the 57 RAPD amplicons, six were methylation specific. Of these, five amplicons increased by 1.4- to 3.8-fold in epididymal sperm DNA at testing dose of BP. This indicates that BP can cause DNA hypermethylation in germ cells from the mitotic through post-meiotic stage in adult rat testes. To our knowledge, this is the first report on the epigenetic modification of sperm DNA by parabens. PMID- 21592179 TI - Effect of spermatic vein ligation on seminal total antioxidant capacity in terms of varicocele grading. AB - We aimed to assess the effect of spermatic vein ligation on seminal total antioxidant capacity (TAC) in patients with varicocele. Twenty infertile male patients with varicocele and 20 normal fertile men (control group) were included in the study. All the male patients were diagnosed with primary infertility and varicocele. The patients with varicocele were divided into two groups as nonpalpable (GI) (eight patients) and palpable (GII-III) (12 patients) varicocele groups. All the patients underwent microsurgical spermatic vein ligation. Seminal TAC levels and sperm parameters were evaluated in all the patients. Preoperative sperm count, sperm motility, sperm morphology and seminal TAC levels with equivalent figures 3-6 months after spermatic vein ligation and the same values of the control group were compared. There was a statistically significant increase in the total seminal antioxidant capacity level after spermatic vein ligation, and there was a statistically significant increase in the sperm count, sperm motility and spermatozoa with normal morphology. However, evaluation of the patients for varicocele grade showed a statistically significant increase in the TAC level only in the GII-III varicocele group. Spermatic vein ligation can improve the total seminal antioxidant capacity levels especially in patients with middle and high grade varicocele. PMID- 21592180 TI - Amyloidosis cutis dyschromica: a rare pigmentary disorder. AB - Amyloidosis cutis dyschromica represents a rare type of primary cutaneous amyloidosis with few reported cases worldwide. It is characterized by asymptomatic, generalized hyperpigmentation with intermingled hypopigmented macules without atrophy or telangiectasia. We report herein a 19-year-old female who developed this pigmentary abnormality at 4 years of age. Her aunt and great grandfather also had similar skin pigmentation. An unusual finding in our patient was the presence of papules in addition to characteristic macules. Amyloid deposits were shown histopathologically in both dyschromic macules and papules. PMID- 21592181 TI - Benign cephalic histiocytosis with S-100 protein positivity. PMID- 21592183 TI - Intradermal proliferative fasciitis. PMID- 21592182 TI - Palisaded neutrophilic and granulomatous dermatitis presenting in a patient with rheumatoid arthritis on adalimumab. AB - Rheumatoid arthritis (RA) is a chronic inflammatory arthritis that can present with many unique cutaneous manifestations including palisaded neutrophilic and granulomatous dermatitis (PNGD). The authors present a case of PNGD in a RA patient on adalimumab therapy. The potential association of PNGD and adalimumab therapy is discussed as well as a review of the literature of granulomatous eruptions involving patients with RA who are receiving tumor necrosis factor alpha inhibitor therapy. PMID- 21592184 TI - Paracetamol prescribing in primary care: too little and too much? AB - AIMS: To assess the level of paracetamol off label prescribing in the community and the potential for paracetamol under or overdosing. METHODS: The Scottish Practice Team Information (PTI) database containing prescribing data for approximately 35,839 children aged (0-12 years) was analysed for paracetamol prescriptions for the year 2006. Off label prescribing was defined as prescribing outside the BNFc age and dose recommendations. RESULTS: Two thousand seven hundred and sixty-one children aged 0-12 years were issued with 4423 prescriptions for paracetamol. (1446 males). Children 1-5 years (1329, 42.2%) accounted for 48.9% (2164) of all paracetamol prescriptions. Eighteen per cent (793) of individual prescriptions were off label and after accounting for repeat prescriptions 625 (22.75%) individuals were exposed to off label prescriptions. A further 15% (668) of prescriptions contained insufficient dosage data to determine their status, 13.3% (368) being underdosed and 4.4% (121) overdosed at least once during the study year. In total 11.3% (502) of all prescriptions were classified as underdose, 2.9% (127) as overdose and 15% (667) had no dosage instructions. Age was significantly related to non recommended dosage (chi(2) test, P < 0.001). Children 1-3 months old were at highest risk of being overdosed; 27% of prescriptions recommended actual or potential overdosage and 25% (354) of children aged 6-12 years were prescribed an actual or potential underdose. Overall 57.2% of all prescriptions failed to comply with current BNFc recommendations. CONCLUSION: Paracetamol off label prescribing is common in primary care, with relatively high levels of potential overdosing in the youngest children and potential underdosing in the oldest children. PMID- 21592185 TI - Drug-disease interaction: Crohn's disease elevates verapamil plasma concentrations but reduces response to the drug proportional to disease activity. AB - AIM: Inflammation is involved in the pathogenesis of cardiovascular diseases that includes reduced response to pharmacotherapy due to altered pharmacokinetics and pharmacodynamics. It is not known if these effects exist in general in all inflammatory conditions. It also remains unknown whether in a given population the effect is a function of disease severity. We investigated whether pharmacokinetics and pharmacodynamics of a typical calcium channel inhibitor are influenced by Crohn's disease (CD), a disease for which the disease severity can be readily ranked. METHODS: We administered 80 mg verapamil orally to (i) healthy control subjects (n= 9), (ii) patients with clinically quiescent CD (n= 22) and (iii) patients with clinically active CD (n= 14). Serial analysis of verapamil enantiomers (total and plasma unbound), blood pressure and electrocardiograms were recorded over 8 h post dose. The severity of CD was measured using the Harvey-Bradshaw Index. RESULTS: CD substantially and significantly increased plasma verapamil concentration and in a stereoselective fashion (S, 9-fold; R, 2 fold). The elevated verapamil concentration, however, failed to result in an increased verapamil pharmacodynamic effect so that the patients with elevated verapamil concentration demonstrated no significant increase in response measured as PR interval and blood pressure. Instead, the greater the disease severity, the lower was the drug potency to prolong PR interval (r= 0.86, P < 0.0006), CONCLUSIONS: CD patients with severe disease may not respond to cardiovascular therapy with calcium channel blockers. Reducing the severity increases response despite reduced drug concentration. This observation may have therapeutic implication beyond the disease and the drug studies herein. PMID- 21592187 TI - Development and psychometric evaluation of an instrument to assess venous leg ulcer lifestyle knowledge among nurses. AB - AIM: Development and psychometric testing of an instrument to assess venous leg ulcer lifestyle knowledge. BACKGROUND: Nurses often lack knowledge to provide adequate leg ulcer advice. No valid and reliable instruments are available to assess knowledge on venous leg ulcer advice among nurses. METHODS: The instrument was developed based on a literature review and patient cases. Content validity was evaluated in a Delphi procedure by nine leg ulcer experts. Item-analysis, construct validity and stability were assessed. A sample of 350 nurses and student nurses participated. Data collection took place between February and April 2009. RESULTS: The instrument included four topics: (1) Compression therapy, (2) Physical activity/leg exercises, (3) Leg elevation and (4) Pain management. Multiple-choice questions were developed to assess factual knowledge. Patient cases were developed to assess more complex cognitive skills. Content validity was established. The quality of the response alternatives varied between 0.01 and 0.68. The difficulty index for questions evaluating factual knowledge ranged from 0.12 to 0.78. Patient cases' questions had a difficulty index between 0.07 and 0.60. The score of participants with (theoretically expected) more expertise was significantly higher than the score of participants with (theoretically expected) less expertise. The intraclass correlation coefficients ranged between 0.71 and 0.77. Eleven questions had moderate kappa-values (0.41 0.60), and in eight questions, there was fair agreement (0.30-0.40). CONCLUSION: An instrument with an acceptable content validity and construct validity was developed. The instrument can be applied in nursing education, nursing practice and nursing research to evaluate venous leg ulcer advice knowledge. PMID- 21592186 TI - The effect of a cryotherapy gel wrap on the microcirculation of skin affected by chronic venous disorders. AB - AIM: The aim of this randomized clinical trial was to investigate a cryotherapy (cooling) gel wrap applied to lower leg skin affected by chronic venous disorders to determine whether therapeutic cooling improves skin microcirculation. BACKGROUND: Chronic venous disorders are under-recognized vascular health problems that result in severe skin damage and ulcerations of the lower legs. Impaired skin microcirculation contributes to venous leg ulcer development, thus new prevention therapies should address the microcirculation to prevent venous leg ulcers. METHODS: Sixty participants (n = 30 per group) were randomized to receive one of two daily 30-minute interventions for four weeks. The treatment group applied the cryotherapy gel wrap around the affected lower leg skin, or compression and elevated the legs on a special pillow each evening at bedtime. The standard care group wore compression and elevated the legs only. Laboratory pre- and post-measures included microcirculation measures of skin temperature with a thermistor, blood flow with a laser Doppler flowmeter, and venous refill time with a photoplethysmograph. Data were collected between 2008 2009 and analysed using descriptive statistics, paired t-tests or Wilcoxon signed ranks tests, logistic regression analyses, and mixed model analyses. RESULTS: Fifty seven participants (treatment = 28; standard care = 29) completed the study. The mean age was 62 years, 70% female, 50% African American. In the final adjusted model, there was a statistically significant decrease in blood flow between the two groups (-6.2[-11.8; -0.6], P = 0.03). No statistically significant differences were noted in temperature or venous refill time. CONCLUSION: Study findings suggest that cryotherapy improves blood flow by slowing movement within the microcirculation and thus might potentially provide a therapeutic benefit to prevent leg ulcers. PMID- 21592188 TI - Effects of a blended learning module on self-reported learning performances in baccalaureate nursing students. AB - AIMS: This article is a report of a quasi-experimental study of the effects of blended modules on nursing students' learning of ethics course content. BACKGROUND: There is yet to be an empirically supported mix of strategies on which a working blended learning model can be built for nursing education. METHODS: This was a two-group pretest and post-test quasi-experimental study in 2008 involving a total of 233 students. Two of the five clusters were designated the experimental group to experience a blended learning model, and the rest were designated the control group to be given classroom lectures only. The Case Analysis Attitude Scale, Case Analysis Self-Evaluation Scale, Blended Learning Satisfaction Scale, and Metacognition Scale were used in pretests and post-tests for the students to rate their own performance. RESULTS: In this study, the experimental group did not register significantly higher mean scores on the Case Analysis Attitude Scale at post-test and higher mean ranks on the Case Analysis Self-Evaluation Scale, the Blended Learning Satisfaction Scale, and the Metacognition Scale at post-test than the control group. Moreover, the experimental group registered significant progress in the mean ranks on the Case Analysis Self-Evaluation Scale and the Metacognition Scale from pretest to post test. CONCLUSIONS: No between-subjects effects of four scales at post-test were found. Newly developed course modules, be it blended learning or a combination of traditional and innovative components, should be tested repeatedly for effectiveness and popularity for the purpose of facilitating the ultimate creation of a most effective course module for nursing education. PMID- 21592189 TI - Medication discussion between nurse prescribers and people with diabetes: an analysis of content and participation using MEDICODE. AB - AIM: This paper is a report of a study to identify the content of, and participation in, medicine discussion between nurse prescribers and people with diabetes in England. BACKGROUND: Diabetes affects 246 million people worldwide and effective management of medicines is an essential component of successful disease control. There are now over 20,000 nurse independent prescribers in the UK, many of whom frequently prescribe for people with diabetes. With this responsibility comes a challenge to effectively communicate with patients about medicines. National guidelines on medicines communication have recently been issued, but the extent to which nurse prescribers are facilitating effective medicine-taking in diabetes remains unknown. METHODS: A purposive sample of 20 nurse prescribers working with diabetes patients audio-recorded 59 of their routine consultations and a descriptive analysis was conducted using a validated coding tool: MEDICODE. Recordings were collected between January and July 2008. The unit of analysis was the medicine. RESULTS: A total of 260 instances of medicine discussion identified in the audio-recordings were analysed. The most frequently raised themes were 'medication named' (raised in 88.8% of medicines), 'usage of medication' (65.4%) and 'instructions for taking medication' (48.5%). 'Reasons for medication' (8.5%) and 'concerns about medication' were infrequently discussed (2.7%). Measures of consultation participation suggest largely dyadic medicine discussion initiated by nurse prescribers. CONCLUSION: MEDICODE discussion themes linked to principles of recent guidelines for effective medicine-taking were infrequently raised. Medicine discussion was characterized by a one statement-one response style of communication led by nurses. Professional development is required to support theoretically informed approaches to effective medicines management. PMID- 21592190 TI - Clinical nurse research consultant: a clinical and academic role to advance practice and the discipline of nursing. AB - AIMS: This article presents a proposal for the Clinical Nurse Research Consultant, a new nursing role. BACKGROUND: Although healthcare delivery continues to evolve, nursing has lacked highly specialized clinical and research leadership that, as a primary responsibility, drives evidence-based practice change in collaboration with bedside clinicians. DATA SOURCES: International literature published over the last 25 years in the databases of CINAHL, OVID, Medline Pubmed, Science Direct, Expanded Academic, ESBSCOhost, Scopus and Proquest is cited to create a case for the Clinical Nurse Research Consultant. DISCUSSION: The Clinical Nurse Research Consultant will address the research/practice gap and assist in facilitating evidence-based clinical practice. To fulfil the responsibilities of this proposed role, the Clinical Nurse Research Consultant must be a doctorally prepared recognized clinical expert, have educational expertise, and possess advanced interpersonal, teamwork and communication skills. This role will enable clinical nurses to maintain and share their clinical expertise, advance practice through research and role model the clinical/research nexus. IMPLICATIONS FOR NURSING: Critically, the Clinical Nurse Research Consultant must be appointed in a clinical and academic partnership to provide for career progression and role support. CONCLUSION: The creation of the Clinical Nurse Research Consultant will advance nursing practice and the discipline of nursing. PMID- 21592191 TI - Medication administration via enteral tubes: a survey of nurses' practices. AB - AIM: This article is a report of a study examining the practices of acute care nurses when administering medication via enteral tubes. BACKGROUND: Administering medication via enteral tubes is predominantly a nursing responsibility across countries. It is important to establish what nurses actually do when giving enteral medication to inform policy and continuing education development. METHOD: In 2007, a survey was conducted using a random sample of acute care nurses at two large metropolitan hospitals in Melbourne, Australia. There were 181 Registered Nurses who participated in the study; 92 (50.8%) practised in intensive care units, 52 (28.7%) in surgical areas, 30 (16.6%) in medical areas and 7 (3.9%) were from combined medical-surgical areas. The questionnaire was developed by the researchers and a pilot study was conducted in August 2006 to test reliability, face validity and user-friendliness of the tool. RESULTS: Nurses reported using a range of methods to verify enteral tube position prior to administering enteral medication; some were unreliable methods. A majority reported administering enteric-coated and slow or extended release forms of medication, and giving solid forms of medication when liquid form was available. Nearly all (96%) reported flushing a tube after giving medication, 28% before, and 12% always flushed between each medication. CONCLUSION: Enteral medication administration practices are inconsistent. Some nurses are using unsafe practices and may therefore compromise patient care. PMID- 21592192 TI - Lectin histochemical study on the olfactory bulb of the newt, Cynops pyrrhogaster. AB - The function and/or morphological features of the vomeronasal olfactory system remain unclear in aquatic animals, although the system appeared first in urodeles based on phylogenic data. We examined the lectin binding patterns in the olfactory bulb of a semi-aquatic urodele, the Japanese red-bellied newt, Cynops pyrrhogaster, using 22 different lectins. Eleven of the lectins showed specific binding to the nerve fibres and glomeruli in the olfactory bulb. Among these, Wheat germ agglutinin, pokeweed and peanut agglutinin preferentially bound the main olfactory bulb, reflecting variation in the expression of glycoconjugates between the main and accessory olfactory bulbs. By contrast, the types of lectins bound to the Cynops olfactory bulb were considerably different from those reported in other urodele families. These results suggest a histochemical distinction between the main and accessory olfactory bulbs, and that glycoconjugate expression may differ significantly among urodele families. PMID- 21592193 TI - Distribution of the lingual lymphoid tissue in domestic ruminants. AB - The distribution and organisation of the intralingual lymphoid tissue was studied in sheep, goat and cattle. For each species, the tongues of two animals were harvested and divided in sample blocks extending over the total surface of the tongue. With 2.5 mm intervals, ten serial histological sections were made for conventional histological staining (haematoxylin-eosin, Van Gieson, Masson's trichrome) and immunohistochemical staining of lymphoid cells (anti-CD3, anti CD21, anti-CD45). Lymphocytes were scattered in the subepithelial propria submucosa and in the connective tissue cores of the lingual papillae. The connective tissue cores of fungiform papillae, including those located on the lingual apex, and vallate papillae showed relatively more lymphocytes than the propria-submucosa. Lymphoid cell aggregations were even more abundant beneath the grooves surrounding the vallate papillae in small ruminants. In cattle, a well organised lingual tonsil was additionally found at the root of the tongue. CD3 positive lymphocytes were observed in all species examined. CD21-positive lymphocytes were numerous in the lymphoid nodules of the bovine lingual tonsil but very scarce in the ovine and caprine tongues. Therefore, the lymphoid cell aggregations in the tongues of small ruminants should not be referred to by the term 'lingual tonsil'. PMID- 21592194 TI - A holin remnant protein encoded by STY1365 is involved in envelope stability of Salmonella enterica serovar Typhi. AB - We characterized STY1365, a small ORF of Salmonella enterica serovar Typhi. This 174-bp ORF encodes a putative product of 57 amino acid residues with a premature stop codon. Nevertheless, bioinformatic analyses revealed that the predicted product of STY1365 has similarity to putative holin genes of Escherichia coli and bacteriophage PhiP27. STY1365 showed a high-level expression at the early log phase and a small corresponding protein product was detected mainly in the inner membrane fraction. Cloning of STY1365 in pSU19 mid-copy-vector produced retardation in S. Typhi growth, increased cell permeability to crystal violet and altered the inner membrane protein profile. Similar results were obtained when STY1365 was induced with isopropyl-beta-d-thio-galactoside in pCC1(TM) single copy vector. Our results support the fact that S. Typhi STY1365 encodes a holin remnant protein that is involved in the stability of the bacterial envelope. PMID- 21592195 TI - Inhibitory effects of broccoli extract on Escherichia coli O157:H7 quorum sensing and in vivo virulence. AB - Broccoli extract (BE) has numerous beneficial effects on human health including anticancer activity. Quorum sensing (QS), mediated by self-produced autoinducer (AI) molecules, is a key process for the production of virulence determinants in pathogenic bacteria. BE suppressed AI-2 synthesis and AI-2-mediated bacterial motility in a dose-dependent manner in Escherichia coli O157:H7. In addition, expression of the ler gene that regulates AI-3 QS system was also diminished in response to treatment with BE. Furthermore, in an in vivo efficacy test using Caenorhabditis elegans as a host organism, C. elegans fed on E. coli O157:H7 in the presence of BE survived longer than those fed solely on the pathogenic bacteria. Quantitative real-time PCR analysis indicated that quercetin was the most active among the tested broccoli-derived compounds in downregulating virulence gene expression, while treatment with myricetin significantly suppressed the expression of the eae gene involved in type III secretion system. These data suggest that BE and its flavonoid constituents can inhibit expression of QS-associated genes, thereby downregulating the virulence attributes of E. coli O157:H7 both in vitro and in vivo. This study clearly elucidates BE's QS inhibitory activity and suggests that BE has the potential to be developed as an anti-infective agent. PMID- 21592196 TI - Endolysin of bacteriophage BFK20: evidence of a catalytic and a cell wall binding domain. AB - A gene product of ORF24' was identified on the genome of corynephage BFK20 as a putative phage endolysin. The protein of endolysin BFK20 (gp24') has a modular structure consisting of an N-terminal amidase_2 domain (gp24CD) and a C-terminal cell wall binding domain (gp24BD). The C-terminal domain is unrelated to any of the known cell wall binding domains of phage endolysins. The whole endolysin gene and the sequences of its N-terminal and C-terminal domains were cloned; proteins were expressed in Escherichia coli and purified to homogeneity. The lytic activities of endolysin and its catalytic domain were demonstrated on corynebacteria and bacillus substrates. The binding activity of cell wall binding domain alone and in fusion with green fluorescent protein (gp24BD-GFP) were shown by specific binding assays to the cell surface of BFK20 host Brevibacterium flavum CCM 251 as well as those of other corynebacteria. PMID- 21592197 TI - Prognostic factors in methylprednisolone pulse therapy for alopecia areata. AB - Many treatments induce remission in patients with alopecia areata. Systemic steroids, for example, are effective in the treatment of severe alopecia areata but have many side-effects. To avoid these side-effects, high-dose bolus infusions of methylprednisolone have been used to treat severe alopecia areata. The purpose of this study was to evaluate the prognostic factors associated with pulse therapy and to establish proper indications for methylprednisolone pulse therapy. Seventy patients with severe alopecia areata were treated i.v. with methylprednisolone on 3 consecutive days. All of the patients had rapid and extensive hair loss with the bald area exceeding 50% of the scalp. Seventy percent of the patients showed terminal hair growth and 41.4% showed complete responses with acceptable cosmetic outcomes. The prognostic factors that influenced successful outcome were the disease duration before treatment and the type of alopecia areata. Based on these two factors, a good response was obtained for all types of alopecia areata with a duration of 3months or less before treatment and for the plurifocal type of alopecia areata with a duration of 4 6months. Methylprednisolone pulse therapy is indicated for those alopecia areata patients who fall within our good response group. PMID- 21592198 TI - Pellagra-like erythema on sun-exposed skin of patients with anorexia nervosa. PMID- 21592199 TI - Successful treatment of xanthoma disseminatum with simvastatin. PMID- 21592200 TI - Supraumbilical skin rash after transcatheter arterial chemoembolization: successful treatment with pentoxifylline. PMID- 21592201 TI - Allergic contact dermatitis caused by gum rosin and wood rosin in Tako-no Suidashi ointment. AB - Tako-no-Suidashi ointment (TSO) is an old Japanese over-the-counter drug, used for the drainage of infectious pustular disease, such as furuncles, carbuncles and infectious atheroma, although whether it works well or not is unknown. The ingredients of the TSO compound commonly include rapeseed oil, gum rosin, wood rosin, Japanese wax, paraffin, petrolatum, copper sulfate, Peru balsam, acetic acid, salicylic acid and trace amounts of Guinea green B. We report a case of contact dermatitis in a 38-year-old Japanese woman caused by TSO. The patient presented to our hospital with pruritic erythema on her left cheek. In order to remove a subcutaneous tumor, she had applied TSO 4 days prior to presentation. Clinical examination showed a well-demarcated exudative erythematous macule with yellowish crusts and scales on her left cheek. Patch testing showed a positive reaction to TSO (++), gum rosin (++) and wood rosin (++) at 72 h. As TSO includes highly allergenic material, caution should be made in applying this topical therapy. PMID- 21592202 TI - Immunohistochemical findings of sebaceous carcinoma and sebaceoma: retrieval of cytokeratin expression by a panel of anti-cytokeratin monoclonal antibodies. AB - This study examined immunohistochemical findings of sebaceous carcinoma and sebaceoma. An immunohistochemical study using 13 anti-cytokeratin (CK) antibodies (anti-CK1, 5-8, 10 and 14-20) and 35 cases of sebaceous carcinoma (16 cases on ocular and 19 cases on extraocular regions) and 10 cases of sebaceoma (no cases arose on the eyelids) was performed. Overall, those in ocular lesions were almost the same as those for extraocular lesions in sebaceous carcinoma other than CK8. The findings in sebaceous carcinoma were almost equal to those of sebaceoma. Over 75% of cases with sebaceous carcinoma were positive with anti-CK5 and anti-CK14 antibodies and negative with anti-CK1, CK10, CK15, CK17, CK18 and CK20 antibodies. Most cases (50-75%) of those were positive with CK7 and negative with CK6, CK16, CK19 and CK8. The sensitivity and specificity of immunohistochemical detection of sebaceous carcinoma using the panel of anti-cytokeratin antibodies were lower than those of other antibodies. Immunohistochemical detection of cytokeratins in diagnosing sebaceous carcinoma should be considered to be ancillary to conventional microscopic findings and those of other antibodies. PMID- 21592203 TI - The Horserace Betting Levy Board: 50 years of advances in equine veterinary science, education and practice. PMID- 21592204 TI - Facing the threat of equine parasitic disease. AB - Horses worldwide are exposed to a complex mixture of intestinal parasitic helminths. When burdens are high, these parasites can seriously compromise health and welfare. Some helminth species have an extremely high prevalence and are difficult to control, not least because there is a limited understanding of their most basic biology. Furthermore, levels of resistance to some of the commonly used anthelmintics are widespread and increasing. The cyathostomins are the most common nematode species affecting equids worldwide. Within this group of parasites are more than 50 different species. Until recent research activities, little was known about the contribution that individual species make to clinical disease, parasite epidemiology and anthelmintic resistance. This review describes some of the recent research advances in the understanding of cyathostomins in these areas. As part of the research effort, molecular tools were developed to facilitate identification of the non-parasitic stages of cyathostomins. These tools have proved invaluable in the investigation of the relative contributions that individual species make to the pathology and epidemiology of mixed infections. At the more applied level, research has also progressed in the development of a diagnostic test that will allow numbers of cyathostomin encysted larvae to be estimated. This test utilises cyathostomin-specific serum antibody responses as markers of infection. As anthelmintic resistance will be the major constraint on parasite control in future, researchers are actively investigating mechanisms of drug resistance and how to improve the detection of resistance in the field. Recent developments in these areas are also outlined. PMID- 21592205 TI - Putative intestinal hyperammonaemia in horses: 36 cases. AB - REASONS FOR PERFORMING THE STUDY: Intestinal hyperammonaemia (HA) has been infrequently reported in individual horses; however, there have been no studies describing clinical and laboratory data as well as short- and long-term outcome in a larger number of cases. OBJECTIVES: To describe clinical and laboratory data and short- and long-term outcome in a large group of horses with intestinal HA. METHODS: Multi-centred, retrospective study; case records of horses with HA were reviewed and any horse with a clinical or post mortem diagnosis of intestinal HA was included. Hyperammonaemia was defined as a blood ammonium (NH(4) (+)) concentration >=60 umol/l and horses with a diagnosis of primary hepatic disease were excluded. Relevant data were recorded and, if appropriate, data from survivors were compared to nonsurvivors to identify potential prognostic indicators. RESULTS: Thirty-six cases, 26 mature horses and 10 foals with intestinal HA were identified. Case histories included diarrhoea, colic and neurological signs and the most common clinical diagnosis was colitis and/or enteritis. The most common clinical and laboratory abnormalities included tachycardia, increased packed cell volume, hyperlactataemia and hyperglycaemia. Fourteen horses (39%) survived to discharge; NH(4) (+) concentration on admission was the only parameter significantly associated with survival. All surviving horses and foals for which follow-up information was available recovered completely and returned to their intended use without further complications. CONCLUSIONS AND POTENTIAL RELEVANCE: Intestinal HA occurs in mature horses and foals and can be associated with severe clinical and laboratory abnormalities; further studies are required to investigate predisposing factors and delineate possible differences in aetiologies. PMID- 21592206 TI - Prevalence of gastric ulcer syndrome in high-level endurance horses. AB - REASONS FOR PERFORMING THE STUDY: Equine gastric ulcers syndrome (EGUS) prevalence studies are rare in the endurance horse and none has been carried out to date in horses competing at high level. OBJECTIVES: To determine the prevalence of EGUS in high-level endurance horses. METHODS: Thirty endurance horses competing at high level were selected and submitted to 2 gastroscopic examinations. The first gastroscopy was performed during the interseason period, and the second during the competition season within 2-3 days following a ride of 90-160 km. Data related to housing, feeding, training system as well as age, breed and gender were recorded for each horse. RESULTS: The prevalence of squamous gastric ulcers was 48% during the interseason period (mean score 0.85 +/ 0.13 on a scale from 0-4) and 93% during the competition season (mean score 1.60 +/- 1.15) with a highly significant difference between the seasons (P = 0.001). Most of the lesions were situated in the squamous portion of the stomach but 33.3% of horses showed also glandular lesions. Significant influence of training and performance level on the gastric score (according to the distance of the ride preceding the second gastroscopy) was shown (P = 0.038). There was also a significant influence of housing on the gastric score (P = 0.002) showing higher scores in the horses kept totally on pasture (mean score: 2.14 +/- 0.14) vs. horses housed in a mixed environment (stable + pasture, mean score: 1.43 +/- 0.17). Both the pastured and (stabled + pastured) groups were receiving a grain supplement but the pastured group received a higher daily starch intake, which might explain the higher ulcer prevalence. There was no influence of age, breed or gender on the gastric scores. CONCLUSIONS: The high prevalence of gastric lesions observed in this study is probably related to the high level of training and performance of the horses examined compared to the population of horses included in the prior study. POTENTIAL RELEVANCE: This prevalence of EGUS in high level endurance horses is comparable to the prevalence established in racing horses. The equine veterinarians may take into consideration EGUS as a potential cause of poor performance. PMID- 21592207 TI - Evaluation of a risk-screening questionnaire to detect equine lung inflammation: results of a large field study. AB - REASONS FOR PERFORMING STUDY: The diagnosis of equine recurrent airway obstruction (RAO) and inflammatory airway disease (IAD) is based on clinical signs and increased inflammatory cell percentages in the bronchoalveolar lavage (BAL) fluid. Since a BAL is an invasive procedure, a risk-screening questionnaire (RSQ) would be a valuable screening tool for lung inflammation. OBJECTIVE: To evaluate the accuracy of a RSQ to detect lower airway inflammation (LAI) in a large population of horses. METHODS: A standardised BAL was performed in the field on 167 horses in Alberta, Canada. Horses were separated into 3 categories: 1) BAL normal; 2) BAL mild to moderate LAI (MLAI), and 3) BAL severe LAI (SLAI). The horse owners were asked to complete a RSQ. The RSQ scores were compared to the BAL results to determine the likelihood of a horse having MLAI, SLAI or no LAI. RESULTS: Based on BAL cytology, 28 (17%) horses were normal and 139 (83%) were abnormal, with 110 (66%) showing MLAI and 29 (17%) SLAI. Horses with SLAI and MLAI had a mean RSQ score of 0.95 and 0.70, respectively, compared to 0.60 for normal BAL horses. Horses with SLAI showed more clinical signs than normal and MLAI horses. The sensitivity and negative predictive values of the RSQ for detecting SLAI using a cut-off score of 0.87, were excellent at 0.90 (95%CI 0.73 0.98) and 0.96 (95%CI 0.82-1.00). Questions on the clinical signs typically found in RAO cases differed significantly between horses with BAL SLAI and those with BAL normal. CONCLUSIONS: Prevalence of MLAI was high in this population. Although the RSQ did not allow differentiating normal horses from horses with MLAI, it has a high sensitivity to detect horses with SLAI and is therefore a good screening tool for SLAI. PMID- 21592208 TI - Owner assessment in judging the efficacy of airway disease treatment. AB - REASONS FOR PERFORMING STUDY: Efficacy of medications for recurrent airway obstruction is typically tested using clinical, cytological and lung function examinations of severely affected animals. These trials are technically challenging and may not adequately reflect the spectrum of disease and owner complaints encountered in clinical practice. OBJECTIVE: To determine if owners of horses with chronic airway disease are better able to detect drug efficacy than a veterinarian who clinically examines horses infrequently. METHOD: In a double blinded randomised controlled trial, owners and a veterinarian compared the efficacy of dexamethasone (0.1 mg/kg bwt per os, q. 24 h, for 3 weeks; n = 9) to placebo (n = 8) in horses with chronic airway disease. Before and after treatment, owners scored performance, breathing effort, coughing and nasal discharge using a visual analogue scale (VAS). The clinician recorded vital parameters, respiratory distress, auscultation findings, cough and nasal discharge, airway mucus score, bronchoalveolar lavage fluid (BALF) cytology and arterial blood gases. RESULTS: The VAS score improved significantly in dexamethasone- but not placebo-treated horses. In contrast, the clinician failed to differentiate between dexamethasone- and placebo-treated animals based on clinical observations, BALF cytology or endoscopic mucus score. Respiratory rate (RR) and arterial oxygen pressure (PaO(2)) improved with dexamethasone but not placebo. CONCLUSIONS AND CLINICAL RELEVANCE: In the design of clinical trials of airway disease treatments, more emphasis should be placed on owner-assessed VAS than on clinical, cytological and endoscopic observations made during brief examinations by a veterinarian. Quantifiable indicators reflecting lung function such as RR and PaO(2) provide a good assessment of drug efficacy. PMID- 21592209 TI - Endoscopic examination of the nasolacrimal duct in ten horses. AB - REASONS FOR PERFORMING STUDY: No endoscopic examination of the nasolacrimal duct has been described before. In contrast with other imaging techniques, endoscopy provides a direct inspection of the intralumen and ductal mucosa in standing sedation. OBJECTIVES: To provide a reference against which the endoscopic and clinical features of obstructive nasolacrimal disease in the horse may be compared. METHODS: Endoscopic examination of the nasolacrimal duct was performed in 10 French Thoroughbred bay mares with a 3 mm shaft diameter flexible fibrescope. The duct was divided into 3 zones (1, 2 and 3) from the nostril to the lacrimal sac. RESULTS: Endoscopic examination of the nasolacrimal duct appeared to be quite easy to perform in Zones 1 and 2, while the ease or difficulty of examining Zone 3 depended on the weight and size of the horse for the position of the endoscope in the lacrimal canal. CONCLUSIONS: Endoscopic inspection has provided the possibility of a novel diagnostic approach to conditions of the nasolacrimal duct in horses. POTENTIAL RELEVANCE: Endoscopic examination of the nasolacrimal duct could help to diagnose and treat nasolacrimal diseases by performing sample withdrawal and duct irrigation. PMID- 21592210 TI - An anatomical study to evaluate the risk of pulpar exposure during mechanical widening of equine cheek teeth diastemata and 'bit seating'. AB - REASONS FOR PERFORMING STUDY: Cheek teeth (CT) diastemata are a major equine dental disorder that can be treated by mechanically widening the diastemata. There is limited anatomical knowledge of the spatial relationships of the individual pulps to the adjacent interproximal surfaces; on the risks of exposing the 6th pulp horn when performing the clinically unproven 'bit seating' procedure on Triadan 06s. OBJECTIVES: To describe the anatomical relationships between the occlusal and interproximal surfaces of CT and the adjacent pulp horns; and between the 6th pulp horn and the occlusal and rostral surfaces of Triadan 06s. METHODS: The CT from 30 skulls of horses subjected to euthanasia for non-dental reasons were sectioned to expose the rostrally and caudally situated pulp horns to allow the anatomical relationships between the pulp horns and the occlusal and interproximal aspects of the CT to be assessed. RESULTS: Pulp horns were mean +/- s.d. of 5.74 +/- 1.45 (range 1.3-10.8 mm) from the nearest interproximal surface, with 5.3% of pulp horns being <3.5 mm from the interproximal surface. In contrast to expectations, pulps tended to became closer to the interproximal surface (and also to the occlusal surface) with increasing age. Teeth with physiologically tall clinical crowns, and also those in the Triadan 09 position had pulps that were closer to the interproximal surfaces than the remaining CT. The more caudally situated pulp horns, i.e. in particular, the 4th maxillary and 5th mandibular pulp horns were closer to the interproximal surfaces than the remaining pulp horns and these pulp horns also had the thinnest sub-occlusal secondary dentine. Pulps that were close to the interproximal surface were also found to be close to the occlusal surface of the CT. CONCLUSIONS AND POTENTIAL RELEVANCE: While diastema widening is theoretically safe between the majority of CT, a small proportion of pulp horns are only 1.3 mm from an interproximal surface and others lie just 1.6 mm beneath the occlusal surface, and such pulps are at risk of pulpar exposure and to thermal injury during this procedure. The risk of pulpar exposure increases when dental tissue is removed from the caudal aspects of CT. PMID- 21592211 TI - Investigation of the sensitivity and specificity of radiological signs for diagnosis of periapical infection of equine cheek teeth. AB - REASONS FOR PERFORMING STUDY: Radiography is commonly used for the diagnosis of equine cheek teeth (CT) infection but, to our knowledge, no study to date has evaluated the relative values of individual specific radiographic signs when making a diagnosis. OBJECTIVES: To investigate the sensitivity and specificity of individual radiographic signs identified from the literature for the diagnosis of CT apical infection using a retrospective case-control study. METHODS: Cropped radiographs taken using computed radiography of 41 apically infected CT and 41 control CT were independently blindly evaluated by 3 clinicians for the presence of 12 predetermined radiographic signs associated with CT apical infection. A final diagnosis of either noninfected or infected was made. Sensitivity and specificity were calculated for the presence or absence of each radiographic sign for each clinician. Uni- and multivariable conditional logistic regression were used to determine strength of association of the 12 radiographic signs with apical infection. RESULTS: Median sensitivity and specificity for the diagnosis of CT apical infection were 76 and 90%, respectively. Periapical sclerosis, clubbing of one or 2 roots, degree of clubbing and periapical halo formation had the highest sensitivities (73-90%), with moderate specificity (61-63%). Multivariable conditional logistic regression revealed that severity of periapical sclerosis and extensive periapical halo were strongly associated with CT apical infection. CONCLUSIONS: The presence of periapical sclerosis and formation of a periapical halo were strongly associated with CT apical infection. Computed radiography appears to have a higher sensitivity but similar specificity to previously published results using film radiography to detect CT apical infection. POTENTIAL RELEVANCE: These findings may aid practitioners when interpreting radiographs of equine CT as to the relative significance of their findings. PMID- 21592212 TI - Seminal parameters and field fertility of cryopreserved donkey jack semen after insemination of horse mares. AB - REASONS FOR PERFORMING STUDY: As mule production is often concentrated in remote areas of the world, a simplified semen cryopreservation protocol is required. AIM: To compare the seminal parameters of cryopreserved donkey semen in lactose EDTA and lactose-yolk extenders and the fertility rates on horse mares. METHODS: TRIAL 1: Sperm total and progressive motility, vigour (scale 0-5), morphology (major and minor defects) and plasma membrane integrity (HOST) were evaluated in 25 ejaculates from 5 donkey jacks immediately after collection (raw), after chilling to 5 degrees C (chilled) and after freezing/thawing. The semen was mixed with skimmed-milk extender, centrifuged, and then re-suspended in lactose-EDTA or lactose-yolk extender. Semen was loaded into 0.5 ml straws and chilled to 5 degrees C for 1 h, after which samples were either evaluated (chilled semen) or placed above liquid nitrogen for 20 min prior to immersion. Seminal parameters were evaluated by ANOVA and Tukey's test. TRIAL 2: Cryopreserved semen from 3 males was used to inseminate 53 mares at 60 oestrous cycles randomly assigned to lactose-yolk (n = 30 cycles) or lactose-EDTA (n = 30 cycles) extenders. Pregnancy diagnosis was performed 15 and 25 days post ovulation. The pregnancy rates were compared using Chi-squared tests. RESULTS: TRIAL 1: No significant differences were evident in any seminal parameters between extenders after either chilling or cryopreservation. Total and progressive motility were significantly (P<0.05) lower in cryopreserved semen than raw and chilled semen for both extenders. TRIAL 2: Pregnancy rates did not significantly differ between extenders (lactose-EDTA extender 53.33 and 43.33%; lactose-yolk 50.0 and 46.66% for Days 15 and 25 post ovulation, respectively). CONCLUSIONS: Cryopreservation of donkey semen using the simplified lactose-yolk extender resulted in similar seminal parameters and fertility rates when compared to lactose-EDTA extender. POTENTIAL RELEVANCE: Lactose-yolk extender may be advocated as a simple, easy to prepare extender, for use in geographically isolated enterprises producing mules throughout the world. PMID- 21592213 TI - Vimentin expression in testes of Arabian stallions. AB - REASONS FOR PERFORMING STUDY: Specific patterns of cytoskeletal filaments reflect a functional state of the cell. In testicular cells intermediate filaments (IFs) are of the vimentin type. Since it is known that Sertoli cells regulate the spermatogenic function in the male gonad, it became important to propose a system that could quantify the state of seminiferous tubular quality. To date, a Johnsen score system has never been used to equine testes. OBJECTIVES: To demonstrate the expression pattern of vimentin in testes of mature Arabian stallions and correlate its distribution with grade of seminiferous tubule impairment as indicated by a Johnsen score. METHODS: For histological examination by the Johnsen method, routine haematoxylin-eosin staining was used. Vimentin expression and its presence in testicular sections and testicular homogenates were detected by immunohistochemistry and western blot, respectively. Both analyses were performed qualitatively and quantitatively and further validated by ANOVA tests. RESULTS: Distinct morphology of seminiferous tubules was found in testes harvested from 3 stallions. Vimentin in IFs was immunolocalised to the cytoplasm of Sertoli, Leydig and peritubular-myoid cells. The intensity and pattern of the IFs staining was different in individual seminiferous tubules suggesting a correlation between vimentin expression and the severity of tubule degeneration. Qualitative results by immunohistochemistry and western blot were confirmed by further quantitative analyses. CONCLUSIONS: In equine testes, differential expression of vimentin was found to be correlated with the impairment of seminiferous tubules indicated by a decrease in Johnsen score. POTENTIAL RELEVANCE: The Johnsen score system may be a useful method to facilitate the identification of tubular alterations in the stallion testes. Combined histological and immunohistochemical approach may provide a detailed phenotypic classification of stallions with decreased fertility. PMID- 21592214 TI - Horizontal moment around the hoof centre of pressure during walking on right and left circles. AB - REASONS FOR PERFORMING STUDY: Recent research indicates that the digital joints experience some degree of extrasagittal motion during stance and that the moments under the hoof are asymmetric in horses walking in a straight line. On a circle, these have not been defined. OBJECTIVES: To quantify the amplitude and symmetry of horizontal twisting moments around the vertical axis through the hoof's centre of pressure on left and right circles at walk. METHODS: Six Thoroughbred horses were led at walk across a Kistler force platform on a left and a right circle of 5 m radius. The resultant moment around the hoof was calculated from the 4 horizontal forces and their moment arms. RESULTS: Five of the 6 horses exerted an internal moment around their left forehoof, and 4 exerted an internal moment around their right forehoof on the left circle. On the right circle, 5 of the 6 exerted an internal moment around the left forehoof and a weak external moment around the right forehoof. The moments under the hind hooves were bilaterally similar for right and left circles. CONCLUSION: Intrahorse variability in the applied moments is low, but there is some interhorse variability, especially in the forelimb moments, that indicates future studies of movements of the distal limb joints should be bilateral to account for mechanical asymmetry. POTENTIAL RELEVANCE: The finding that horizontal moments vary between forelimbs in some horses will apply to how exercise on a circle is approached, especially in rehabilitation programmes for horses with orthopaedic injury of the distal limb. PMID- 21592215 TI - Glucose transport in the equine hoof. AB - REASONS FOR PERFORMING STUDY: Several conditions associated with laminitis in horses are also associated with insulin resistance, which represents the failure of glucose uptake via the insulin-responsive glucose transport proteins in certain tissues. Glucose starvation is a possible mechanism of laminitis, but glucose uptake mechanisms in the hoof are not well understood. OBJECTIVES: To determine whether glucose uptake in equine lamellae is dependent on insulin, to characterise the glucose transport mechanism in lamellae from healthy horses and ponies, and to compare this with ponies with laminitis. METHODS: Study 1 investigated the effects of insulin (300 uU/ml; acute and 24 h) and various concentrations of glucose up to 24 mmol/l, on 2-deoxy-D-[2,6-(3)H] glucose uptake in hoof lamellar explants in vitro. Study 2 measured the mRNA expression of GLUT1 and GLUT4 transport proteins by PCR analysis in coronary band and lamellar tissue from healthy horses and ponies, ponies with insulin-induced laminitis, and ponies suffering from chronic laminitis as a result of equine Cushing's syndrome. RESULTS: Glucose uptake was not affected by insulin. Furthermore, the relationship between glucose concentration and glucose uptake was consistent with an insulin-independent glucose transport system. GLUT1 mRNA expression was strong in brain, coronary band and lamellar tissue, but was weak in skeletal muscle. Expression of GLUT4 mRNA was strong in skeletal muscle, but was either absent or barely detectable in coronary band and lamellar tissue. CONCLUSIONS: The results do not support a glucose deprivation model for laminitis, in which glucose uptake in the hoof is impaired by reduced insulin sensitivity. Hoof lamellae rely on a GLUT1-mediated glucose transport system, and it is unlikely that GLUT4 proteins play a substantial role in this tissue. POTENTIAL RELEVANCE: Laminitis associated with insulin resistance is unlikely to be due to impaired glucose uptake and subsequent glucose deprivation in lamellae. PMID- 21592216 TI - Consistent detection of bovine papillomavirus in lesions, intact skin and peripheral blood mononuclear cells of horses affected by hoof canker. AB - REASONS FOR PERFORMING THE STUDY: Equine hoof canker is a chronic proliferative pododermatitis of as yet unknown aetiology. Like equine sarcoid disease, canker is a therapy-resistant disorder characterised by hyperkeratosis, acanthosis and a marked tendency to recur. HYPOTHESIS: There is an association of sarcoid-inducing bovine papillomaviruses of types 1 and 2 (BPV-1, BPV-2) with hoof canker disease. METHODS: Using PCR-based techniques, we assessed canker tissue, intact skin and/or peripheral blood mononuclear cells (PBMCs) of 25 canker-affected horses for the presence of sarcoid-associated BPV-1 and -2. RESULTS: Conventional PCR revealed BPV-1/-2 DNA in 24/24 canker, 12/13 skin and 10/11 PBMC DNA isolates. Using inverse PCR, full-length BPV episomes were detected in 1/5 canker specimens. Sequencing of viral early and late genes amplified from canker, intact skin and PBMC DNA of 2 cases revealed an overall identity of 98% to BPV-1. Viral DNA loads amounted to <=16 copies per cell in canker tissue and intact skin, and to <=0.35 copies per PBMC, as determined by quantitative PCR. Using RT-PCR, the viral major oncogene E5 was shown to be transcribed in 2/4 canker tissue specimens and 5/7 PBMC isolates. Immunocapture PCR from 7 canker and 6 skin extract supernatants revealed capsomere-associated viral DNA in one canker and one skin sample. Hoof tissue, skin and PBMCs collected from 13 individuals with no signs of canker or BPV-related malignancies scored negative throughout the experiments. CONCLUSION: These findings suggest that the observed presence of BPV 1/-2 in canker-affected horses is not coincidental but indicative of an active contribution to hoof canker disease. POTENTIAL RELEVANCE: The use of antivirals and/or immune modulators may help improving canker therapy. PMID- 21592217 TI - Swing phase kinematic and kinetic response to weighting the hind pasterns. AB - REASONS FOR PERFORMING STUDY: It is considered that specific exercises to strengthen limb musculature would be helpful. OBJECTIVE: To describe swing phase kinematic and kinetic changes in the hindlimbs of trotting horses in response to the addition of leg weights to the hind pasterns. METHODS: Six horses were prepared by placing reflective skin markers on the hindlimbs, the withers and fore hooves. Horses were evaluated at trot for 6 trials with and without leg weights (700 g) attached around the pasterns, with the 2 conditions applied in random order. The markers were tracked to determine peak heights of the flight arc of the hind hooves and swing phase joint angulations. Inverse dynamic analysis was used to calculate positive and negative work done across each joint in the first and second halves of the swing phase. Comparisons between conditions were made using paired t tests (normally distributed data) or the Wilcoxon rank sum test (non-normally distributed data). RESULTS: Peak height of the flight arc of the hind hooves was significantly higher with leg weights as a result of increased flexions of the stifle, tarsal and metatarsophalangeal joints. Increased positive (concentric) work was performed by the hip and tarsal musculature to protract and raise the limb in early swing, then to retract and lower the limb in late swing. Increased negative (eccentric) work was performed across the stifle and metatarsophalangeal joints to control their movements in response to increases in inertia and momentum due to the weights. CONCLUSIONS: The addition of weight to the hind pasterns stimulates increased muscular activity across all the hindlimb joints from the hip to the metatarsophalangeal joint. CLINICAL SIGNIFICANCE: The addition of weight to the hind pasterns may have therapeutic applications in activating and strengthening the hindlimb musculature. This is particularly relevant in the hip region, which appears more sensitive and responsive to the effect of weights than to tactile stimulation alone. PMID- 21592218 TI - High speed field kinematics of foot contact in elite galloping horses in training. AB - REASONS FOR PERFORMING STUDY: Mechanical characterisation of the high speed gallop has significant importance for animal welfare and basic biology. Kinematic parameters such as the velocity of each foot at contact can inform theories of why animals gallop, and supplant epidemiological investigation into the mechanisms of musculoskeletal injury. OBJECTIVE: To determine the velocity at which the fore and hind hooves of elite galloping horses impact the surface. METHODS: High speed videography was used to measure the horizontal and vertical velocity of the hoof immediately prior to impact, and the subsequent sink (vertical) and slip (horizontal) distances travelled by the hoof into the surface. Horse speed ranged from 11-19 m/s. In total 170 forelimb and 168 hindlimb foot falls from 89 horses were analysed. RESULTS: Horizontal and vertical hoof velocity increased with speed (P<0.001). Horizontal hoof velocity was significantly greater in the hindlimbs compared to the forelimbs (P<0.001) and was greater in the nonlead limbs compared to the lead limbs (P<0.001). Vertical hoof velocity was significantly greater in the lead limb than the nonlead limb (P<0.001). Overall, forelimbs contacted the ground with a more acute velocity vector angle than hindlimbs (P<0.001). Lead limbs contacted the ground at more acute angles than nonlead limbs (P<0.001). Vertical and horizontal velocities were highly correlated to sink and slip distance. CONCLUSION: Hindlimbs impact the surface at higher velocity than forelimbs, which is likely to result in higher peak impact forces in the hindlimbs. This runs counter to the finding of lower incidence of injury in hindlimbs. POTENTIAL RELEVANCE: Explanations consistent with these findings include the hindlimbs more effectively dampening peak impact forces, or that other injury mechanisms, such as limb vibration and limb load at mid stance, play an important role in injury. PMID- 21592219 TI - Rein tension acceptance in young horses in a voluntary test situation. AB - REASONS FOR PERFORMING THE STUDY: During riding, horses are frequently exposed to pressure from the rider, e.g. through the bit and reins, but few studies have investigated at which point rein tension becomes uncomfortable for the horse. OBJECTIVES: To investigate how much rein tension young inexperienced horses are willing to accept in order to obtain a food reward; whether the tension acceptance changes during 3 consecutive test days; and whether rein tension correlates with the expression of conflict behaviour and heart rate. HYPOTHESES: Pressure-naive horses will apply only little rein tension in the first voluntary trial, but their acceptance will gradually increase. High levels of rein tension will lead to expression of conflict behaviour and increases in heart rate. METHODS: Fifteen 2-year-old, bridle-naive mares were encouraged to stretch their head forward (across a 0.95 m high metal bar) to obtain a food reward in a voluntary test situation. On each test day, each horse was exposed to 2 control sessions (loose reins), an intermediate and a short rein session (1 min/session). Rein tension, heart rate and behaviour were recorded. RESULTS: The horses applied significantly more tension on the first day (mean rein tension: 10.2 N), compared to the second and third test day (Day 2: 6.0 and Day 3: 5.7 N). The horses showed significantly more conflict behaviour in the short rein treatment. There was no treatment effect on heart rate. CONCLUSIONS AND POTENTIAL RELEVANCE: The horses applied the highest rein tension on the first day, and apparently learned to avoid the tension, rather than habituate to it. Rein tension correlated with expression of conflict behaviour, indicating that the horses found the tension aversive. Further studies should focus on the correlation between rein tension and conflict behaviour in ridden horses. PMID- 21592220 TI - Analysis of conformational variations of the cricoid cartilages in Thoroughbred horses using computed tomography. AB - REASONS FOR PERFORMING STUDY: Loss of arytenoid abduction is a common post operative complication of laryngoplasty without a definitive cause. It has been a clinical impression during laryngoplasty surgery that there is great conformational variability along the caudal edge of the Thoroughbred cricoid cartilage that could impact post operative retention of suture position. A change in suture position would probably lead to some loss of abduction. Defining any structural variability of the cricoid would be an initial step in determining whether this variability could impact on the retention of suture position. HYPOTHESIS: Anatomical variations in the larynx of Thoroughbred horses may be detected and measured using objective analysis and computed tomography. METHODS: Larynges were harvested from 15 mature Thoroughbred horses. Helical CT scans were performed on each specimen. Three independent observers performed a series of measurements on 2D and 3D reconstruction images using digital software. Measurements included the lateral cricoid angle, the caudal cricoid prominences, the distance to the cricoid slope, the angle of the cricoarytenoid joints (CAJ), the cricoid thickness and the suture angle. Mean, standard deviation, coefficient of variation and linear regression analysis were performed among all observers and all measurements. RESULTS: Notable conformational differences were evident on the 3D reconstructions. The highest degree of variability was found in 3 measurements: the distance to the lateral cricoid slope, the lateral cricoid angle and the cricoid thickness. A larger left CAJ angle directly and significantly correlated with a larger suture angle. CONCLUSIONS: There are notable conformational differences among cricoid specimens in the Thoroughbred larynx. POTENTIAL RELEVANCE: The morphometric differences identified may impact on optimal prosthesis placement and long-term retention. Since a larger lateral cricoid angle may facilitate abduction loss secondary to a displaced and loosened suture, alternative techniques for suture placement may be of value to prevent arytenoid abduction loss. PMID- 21592221 TI - Cross-sectional area of the tendons of the tarsal region in Standardbred trotter horses. AB - REASONS FOR PERFORMING STUDY: The assessment of a normal range for cross sectional area (CSA) of tendons in the tarsal region is important in order to use them as reference values in the identification of pathological changes of dimensions. OBJECTIVES: To provide normal reference values for the CSA of the tendons of the tarsus of Standardbred trotter horses (STH) by means of ultrasonography. METHODS: Transverse echographic images of the tendons were obtained at different levels proximodistally; these images were digitised and CSA values (mean +/- s.d.) were obtained for each structure. RESULTS: The largest structure corresponded with the lateral digital flexor/caudal tibial tendon complex at Level 1 and the smallest was the medial digital flexor tendon at Level 4. Almost all tendons showed a slight decreasing in their CSA when crossing the tarsus. CONCLUSIONS: The normal CSA values of tendinous structures in the tarsal region of the STH are reported. These data could be used as anatomical references. POTENTIAL RELEVANCE: The establishment of reference values could serve as a tool to discriminate between normal and abnormal dimensions of tarsal tendons in STH. Other horse breeds should need their own reference values. PMID- 21592222 TI - Epidemiological and genetic study of exertional rhabdomyolysis in a Warmblood horse family in Switzerland. AB - REASONS FOR PERFORMING STUDY: Exertional rhabdomyolysis (ER) and its familial basis in Warmblood horses is incompletely understood. OBJECTIVES: To describe the case details, clinical signs and management of ER-affected Warmblood horses from a family with a high prevalence of ER, to determine if histopathological signs of polysaccharide storage myopathy (PSSM) and the glycogen synthase (GYS1) mutation are associated with ER in this family, and to investigate potential risk factors for development of ER. METHODS: A family consisting of a sire with ER and 71 of his descendants was investigated. History of episodes of ER, husbandry, feeding and use was assessed by interviewing horse owners using a standardised questionnaire. All horses were genotyped for GYS1. In 10 ER-affected horses, muscle histopathology was evaluated. RESULTS: Signs of ER were reported in 39% of horses and 51% of the entire family possessed the GYS1 mutation. Horses possessing the GYS1 mutation had a 7.1-times increased risk for developing ER compared to those with the normal genotype (95% confidence interval [CI] 2.37 21.23, P = 0.0005). All muscle samples from horses in the family with ER showed polysaccharide accumulation typical for PSSM, amylase-resistant in 9/10 cases. There was evidence (odds ratio 5.6, CI 1.00-31.32, P = 0.05) that fat or oil feeding improved clinical signs of ER. No other effects of environmental factors associated with clinical signs of ER were identified. CONCLUSION AND POTENTIAL RELEVANCE: PSSM associated with the GYS1 mutation is one identifiable cause of ER in Warmblood horses. Signs of ER are not always manifest in GYS1 positive horses and there are also other causes for ER in Warmblood horses. Breeding animals with the GYS1 mutation results in a high prevalence of ER due to its dominant mode of inheritance. PMID- 21592224 TI - Parent-reported food allergy requiring an avoidance diet in children starting elementary school. AB - AIM: To evaluate the prevalence of parent-reported food allergies requiring avoidance diet at early school age. METHODS: The school health nurses interviewed, by using a structured questionnaire on the required diet at school, the parents of all the 1542 children starting elementary school in a Finnish town with 210,000 inhabitants. RESULTS: An allergy to basic foods was found in 41 (2.7%) children: 1.5% to milk, 1.1% to eggs and 1.0% to grains. An allergy to nuts was present in 3.1% and to fruits and vegetables in 5.8%, both with known cross-sensitization to pollens. In all, 9.2% of the children reported some allergy. Milk, egg and grain allergies were associated with soy, nut and spice allergies. CONCLUSION: Over 2% of the 1542 Finnish first-graders reported allergies to basic foods (milk, eggs or grains) requiring special avoidance diets at school. The figure suggests that avoidance diets started in the first years of life still unnecessarily continued. PMID- 21592225 TI - Prediction of obesity from infancy to adolescence. AB - AIM: To examine the development of childhood obesity and to determine the earliest age when estimating body mass using only weight and height data is associated with a corresponding estimate at the age of 15. METHODS: Subjects included are all children born in 1991 in Ostergotland County, Sweden. Weight and height data collected during regular check-ups at well-child centres and school health care assessments up to 15 years of age were assembled from health records. Correlations between childhood estimates of body mass and the body mass index (BMI) at 15 years of age were computed pairwise. Correlations with r > 0.5 were defined as reliably strong. RESULTS: Complete data were available for 3579 children (62%). Fewer girls (2.6%; C.I. 1.9-3.3) than boys (4.6%; C.I. 3.7-5.5) were obese at 15 years of age. Correlations with BMI at 15 years of age were strong (significantly higher than 0.5) from 5 years of age. Only 23% of girls and 8% of boys found to be obese at 5 years of age were of normal weight at the age of 15. CONCLUSION: From 5 years of age, point estimates of body mass using only weight and height data are strongly associated with BMI at the age of 15. More data sources are needed to predict weight trajectories in younger children. PMID- 21592226 TI - Management of cancer risk in Barrett's esophagus. AB - The importance of Barrett's esophagus (BE) lies in its potential to give rise to esophageal adenocarcinoma (EAC), postulated to be through a series of progressive degrees of dysplasia; from intestinal metaplasia to low-grade dysplasia, high grade dysplasia, and subsequently, to cancer. The management strategies for the detection and treatment of dysplasia and early esophageal cancer on a background of BE have changed significantly in the last few decades, with the emergence of newer and less invasive non-operative alternatives. This review aims to outline BE and its relation to EAC, the rationale and cost-effectiveness of both screening and surveillance programs, methods of diagnosing and identifying dysplasia and early cancer in Barrett's, and approaches to individualizing their endoscopic and surgical management based on best-available staging techniques. PMID- 21592228 TI - Portal venous invasion: the single most independent risk factor for immediate postoperative recurrence of hepatocellular carcinoma. AB - BACKGROUND AND AIM: Despite improvements of treatment in hepatocellular carcinoma (HCC), the recurrence rate after curative hepatic resection still remains remarkably high. An immediate recurrence of HCC after surgery is frustrating. We tried to clarify risks of immediate postoperative recurrence of HCC; that is, within 4 months after curative hepatic resection. METHODS: A total of 167 patients with HCC underwent hepatic resection; 60 had immediate postoperative recurrences (IPR group), and 107 had disease-free survival for more than 5 years (DFS group). Variables were compared between the two groups. RESULTS: Univariate analysis showed the following variables were significant risk factors for immediate postoperative recurrence of HCC: male sex, elevated serum aspartate aminotransferase level, greater amount of blood loss, longer operation time, worse tumor differentiation, higher tumor node metastasis stage, and presence of any of the following: intrahepatic metastasis, tumor-rupture, portal venous invasion, or microvascular invasion. In multivariate analysis, only portal venous invasion was a significant risk factor (odds ratio=3.2, P=0.03, standard error=0.5, Logistic regression analysis). CONCLUSIONS: Portal venous invasion may be the most significant risk factor for immediate postoperative recurrence of HCC. However, accurate assessment of this risk factor may require histological examination, limiting its utility as a preoperative predictor. Further research is necessary to definitively identify preoperative predictors. PMID- 21592227 TI - Prevalence of two homologous genes encoding glycosyltransferases of Helicobacter pylori in the United States and Japan. AB - BACKGROUND AND AIM: jhp0562 and beta-(1,3)galT (jhp0563) of Helicobacter pylori have been suggested as novel virulent factors; however, the clinical associations and functions of these genes remain unclear. We examined the prevalence of jhp0562, beta-(1,3)galT, and cagA in the United States (US) and Japanese populations. METHODS: A total of 308 strains (171 from the US and 137 from Japan) were examined for the status of jhp0562, beta-(1,3)galT, and cagA by polymerase chain reaction. RESULTS: There were significant differences in the status of jhp0562, beta-(1,3)galT and cagA between the US and Japanese populations (P < 0.001). In the US, the prevalence of beta-(1,3)galT was significantly lower in strains isolated from patients with duodenal ulcer (DU) or gastric ulcer (GU) than those with gastritis (47.8% and 32.1% vs 72.0%, P < 0.01), and the absence of beta-(1,3)galT was an independent factor discriminating DU and GU from gastritis (adjusted odds ratios, 4.21 and 8.52; 95% confidence intervals, 1.75 to 10.12 and 2.76 to 26.33, respectively). In the US, the prevalence of the jhp0562 positive/beta-(1,3)galT-negative genotype was significantly higher in strains from DU and GU patients than in those from gastritis patients (50.0%, 67.9%, and 24.4%, P < 0.01) and the cagA status was significantly correlated with that of jhp0562 and inversely correlated with that of beta-(1,3)galT. In contrast, the prevalence of these three genes was not significantly different in Japan. CONCLUSIONS: jhp0562 or beta-(1,3)galT can be used to discriminate peptic ulcers from gastritis in the US, but not in Japan. PMID- 21592229 TI - Role of hepatic stellate cells on graft injury after small-for-size liver transplantation. AB - BACKGROUND AND AIM: Small-for-size grafts are prone to mechanical injury and a series of chemical injuries that are related to hemodynamic force. Hepatic stellate cells activate and trans-differentiate into contractile myofibroblast like cells during liver injury. However, the role of hepatic stellate cells on sinusoidal microcirculation is unknown with small-for-size grafts. METHODS: Thirty-five percent of small-for-size liver transplantation was performed with rats as donors and recipients. Endothelin-1 levels as well as hepatic stellate cells activation-related protein expression, endothelin-1 receptors, and ultrastructural changes were examined. The cellular localizations of two types of endothelin-1 receptors were detected. Furthermore, liver function and sinusoidal microcirculation were analyzed using two different selective antagonists of endothelin-1 receptor. RESULTS: Intragraft expression of hepatic stellate cells activation-related protein such as desmin, crystallin-B and smooth muscle alpha actin was upregulated as well as serum endothelin-1 levels and intragraft expression of the two endothelin receptors. The antagonist to endothelin-1 A receptor not to the endothelin-1 B receptor could attenuate microcirculatory disturbance and improve liver function. CONCLUSIONS: Small-for-size liver transplantation displayed increased hepatic stellate cells activation and high level of endothelin-1 binding to upregulation of endothelin-1 A receptor on hepatic stellate cells, which contracted hepatic sinusoid inducing graft injury manifested as reduction of sinusoidal perfusion rate and elevation of sinusoidal blood flow. PMID- 21592230 TI - Th17 cells are increased with severity of liver inflammation in patients with chronic hepatitis C. AB - BACKGROUND AND AIM: As a newly identified subset of T helper cells, T-helper 17 cells (Th17) are major mediators of inflammation-associated disease. Some reports have revealed significantly increased Th17 cells in hepatitis B virus-infected patients, and a recent study has demonstrated that hepatitis C virus (HCV) specific Th17 cells can be induced in vitro and regulated by transforming growth factor-beta. This study attempted to characterize the role of Th17 cells in the disease progression of chronic hepatitis C (CHC). METHODS: The current study enrolled 53 patients with CHC and 23 healthy controls, in which the circulating and liver-infiltrating Th17 cells were monitored. RESULTS: We found that CHC patients had increased proportions of both circulating and liver-infiltrating Th17 cells compared to healthy individuals, and both measures of Th17 cells were correlated with severity of liver inflammation. We further demonstrated that the HCV-specific Th17 cells were correlated with liver damage but not HCV viral replication. CONCLUSIONS: Such a correlation between the severity of liver damage of CHC and Th17 cells illustrated in this study sheds some light on the understanding of the pathogenesis of CHC. PMID- 21592231 TI - Proliferation signal inhibitors and post-transplant malignancies in heart transplantation: practical clinical management questions. AB - Although malignancy is a major threat to long-term survival of heart transplant (HT) recipients, clear strategies to manage immunosuppression in these patients are lacking. Several lines of evidences support the hypothesis of an anticancer effect of proliferation signal inhibitors (PSIs: mammalian target of rapamycin [mTOR] inhibitors) in HT recipients. This property may arise from PSI's ability to replace immunosuppressive therapies that promote cancer progression, such as calcineurin inhibitors or azathioprine, and/or through their direct biological actions in preventing tumor development and progression. Given the lack of randomized studies specifically exploring these issues in the transplant setting, a collaborative group reviewed current literature and personal clinical experience to reach a consensus aimed to provide practical guidance for the clinical conduct in HT recipients with malignancy, or at high risk of malignancy, with a special focus on advice relevant to potential role of PSIs. PMID- 21592232 TI - Tadalafil versus solifenacin for persistent storage symptoms after prostate surgery in patients with erectile dysfunction: a prospective randomized study. AB - OBJECTIVES: The occurrence of residual storage symptoms after surgical relief of bladder outlet obstruction as a result of benign prostatic enlargement (BPE) underlines the intricate mechanism involved in lower urinary tract symptoms (LUTS). The aim of the present study was to compare tadalafil with solifenacin in modifying symptoms and uroflowmetric parameters in patients with erectile dysfunction (ED) and residual storage symptoms after prostate surgery. METHODS: From May 2007 to April 2009, we evaluated 68 patients who had undergone prostate surgery at least 6months earlier, and presented with ED and persistence of storage symptoms. A total of 56 patients were randomized to receive tadalafil 5mg (group 1) or solifenacin 5mg (group 2), both given daily for 12weeks. International Prostate Symptoms Score (IPSS), IPSS Quality of Life, International Index of Erectile Function-5 (IIEF-5) and uroflowmetry parameters were collected at baseline and after 12weeks of treatment. RESULTS: A total of 26 patients in group 1 and 25 patients in group 2 completed the study. Each group showed a significant and comparable improvement of urinary symptoms with a decrease of IPSS value. Only in group 1 did the treatment with tadalafil result in a significant increase of IIEF-5. No statistically significant variations were noted in uroflowmetric parameters in both groups. CONCLUSIONS: In patients suffering from ED and storage symptoms after surgical treatment for LUTS-BPE, tadalafil 5mg given once daily for 12weeks provided a comparable improvement in IPSS to solifenacin 5mg given for the same period of time. PMID- 21592233 TI - Incidental prostate cancer revisited: early outcomes after holmium laser enucleation of the prostate. AB - Incidental prostate cancer (PCa) after treatment of benign prostate hyperplasia (BPH) is becoming less common. This is a result of the changing patterns of BPH treatment. The purpose of the present research was to re-examine the clinical outcomes and importance of cT1a and cT1b PCa in a contemporary cohort after holmium laser enucleation of the prostate (HoLEP). All patients with newly diagnosed PCa after HoLEP were retrospectively identified. Pre- and postoperative prostate-specific antigen (PSA), biopsy history, pathological features and disease progression were examined. Patients were matched to a control group with benign pathology for outcome comparisons. The database consisted of 240 consecutive patients, aged 52-90 years with prostate sizes from 25 to 375 cm(3) . A total of 28 patients were identified with incidental PCa (14 cT1a and 14 cT1b). Median follow up was 11 months and 13 months for cT1a and cT1b, respectively. Hospitalization time, catheterization time, complications and functional outcomes were similar. Three patients with cT1b required additional treatment as a result of PSA progression. All other cancers are being closely followed. The functional benefits of HoLEP are well established. The incidental PCa detection rate of 11.7% shows the potential benefit of pathological analysis. Just 10.7% of these patients received additional treatment, but this might be significant as these patients would otherwise go untreated. The impact on disease-specific survival and progression requires a longer follow up. PMID- 21592234 TI - Medical expulsive therapy using alfuzosin for patient presenting with ureteral stone less than 10mm: a prospective randomized controlled trial. AB - OBJECTIVES: To assess the spontaneous passage rate for patients being treated with alfuzosin 10mg daily after presenting with an acute ureteral stone compared with a control group, and to assess the respective pain control status. METHODS: This was a prospective randomized controlled trial. Patients presenting with an acute ureteral stone (size 5-10mm) were enrolled and randomized into a medical expulsive therapy (MET) group or control group. The MET group received alfuzosin slow release (SR) 10mg daily for 4weeks and dologesic (paracetamol+dextropropoxyphene, four tablets daily on demand) for 2weeks. The control group received the same analgesics for 2weeks only. Diclofenac sodium SR 100mg daily for 2weeks was added in case of suboptimal pain control. All the patients were assessed through phone interview at week 2 and with kidney-ureter bladder X-ray at week 5 to check for any evidence of stone passage. RESULTS: A total of 67 patients were included in the analysis. The overall spontaneous passage rate was increased by 31.8% with MET (P=0.006). For an upper ureteral stone, the rate was increased by 51.3% (P=0.01). The MET group used significantly less dicolofenac sodium (1.5 tablets vs 6.7 tablets, P=0.031). CONCLUSIONS: MET using alfuzosin SR 10mg daily is effective to enhance the ureteral stone spontaneous passage rate, particularly for upper ureteral stones. Fewer analgesic drugs are consumed and more patients can avoid ureteroscopic lithotripsy and/or extracorporeal shock wave lithotripsy. PMID- 21592235 TI - 17beta-oestradiol regulation of gonadotrophin-releasing hormone neuronal excitability. AB - 17beta-Oestradiol (E(2)) is essential for cyclical gonadotrophin-releasing hormone (GnRH) neuronal activity and secretion. In particular, E(2) increases the excitability of GnRH neurones during the afternoon of pro-oestrus in the rodent, which is associated with increased synthesis and secretion of GnRH. It is well established that E(2) regulates the activity of GnRH neurones through both presynaptic and postsynaptic mechanisms. E(2) significantly modulates the mRNA expression of numerous ion channels in GnRH neurones and alters the associated endogenous conductances, including potassium (K(ATP) , A-type) currents and low voltage T-type and high-voltage L-type calcium currents. Notably, K(ATP) channels are critical for maintaining GnRH neurones in a hyperpolarised state for recruiting the T-type calcium channels, which are important for burst firing in GnRH neurones. In addition, there are other critical channels contributing to burst firing pattern, including the small conductance Ca(2+) -activated K(+) channels that may be modulated by E(2) . Despite these advances, the cellular mechanisms underlying the cyclical GnRH neuronal activity and GnRH release are largely unknown. Ultimately, the ensemble of both pre- and postsynaptic targets of the actions of E(2) will dictate the excitability and activity pattern of GnRH neurones. PMID- 21592237 TI - Sex steroids control neuroinflammatory processes in the brain: relevance for acute ischaemia and degenerative demyelination. AB - Sex steroids have been demonstrated as powerful compounds to protect neurones and neural tissue from neurotoxic challenges and during neurodegeneration. A multitude of cellular actions have been attributed to female gonadal steroid hormones, including the regulation of pro-survival and anti-apoptotic factors, bioenergetic demands and radical elimination, growth factor allocation and counteracting against excitotoxicity. In recent years, immune-modulatory and anti inflammatory characteristics of oestrogen and progesterone have also come under scrutiny. To date, each of these physiological responses has been considered to be partially and selectively integrated in the mediation of steroid-mediated cell protection and tested in suitable animal models and in vitro systems. To what extent these individual effects contribute to the overall neural protection remains sketchy. One idea is that a battery of cellular mechanisms operates at the same time. On the other hand, interactions and the control of the brain intrinsic and peripheral immune system may play an additional and perhaps pioneering function in this scenario, notwithstanding the importance of secondary adjuvant mechanisms. In the present review, we highlight neuroprotective effects of oestrogen and progesterone in two different disease models of the brain, namely acute ischaemic and demyelination damage, which represent the most common acute and degenerative neurological disorders in humans. Besides other inflammatory parameters, we discuss the idea that chemokine expression and signalling appear to be early hallmarks in both diseases and are positively affected by sex steroids. In addition, the complex interplay with local brain resident immune-competent cells appears to be controlled by the steroid environment. PMID- 21592238 TI - Corticotropin-releasing factor neurogenesis during midlife development in salmon: genetic, environmental and thyroid hormone regulation. AB - Salmon parr-smolt transformation (smoltification) is a mid-life transitional stage between life in freshwater and seawater that entails a wide range of neural, endocrine and physiological modifications. In salmon, the neuroendocrine corticotropin-releasing factor (CRF) system regulates pituitary adrenocorticotrophic hormone and thyrotrophin release. Four experimental groups of Atlantic salmon, Salmo salar, were used to investigated CRF neurogenesis and its regulation during smoltification. We compared: (i) developmental stages (parr and early-smolt) in anadromous controls; (ii) a developmentally arrested model: anadromous reared under continuous light (LL) with anadromous controls; (iii) a natural hypoendocrine/incomplete smolt development salmon model (landlocked) with anadromous controls; and (iv) landlocked treated with thyroxine to anadromous control smolt levels. CRF neurogenesis between groups was studied with bromodeoxyuradine (BrdU) incorporation followed by double-labelling CRF and BrdU immunhistochemistry. The rate of CRF neurogenesis in the preoptic area (POA) increased from parr to early-smolts in anadromous salmon. By contrast, neurogenesis was inhibited in the LL group and reduced in the landlocked salmon. The administration of thyroxine in landlocked salmon to match anadromous levels increased the rate of CRF neurogenesis to anadromous levels. In conclusion, newly formed CRF cells in the POA during smoltification are associated with increased retinal innervation to the POA and endocrine responsiveness to increased photoperiod. Both genetic and environmental factors influence the degree of salmon brain development. Thyroid hormones increase CRF neurogenesis during this critical period of development in salmon. We hypothesise that a positive-feedback of thyroid hormones on CRF neurogenesis may be an important event in reaching the developmental climax during critical periods. PMID- 21592240 TI - Risk of cancer in women with cervical precancer: improving risk assessment and management protocols. PMID- 21592241 TI - Reply to: The danger to cytopathology of overspecialization and its relevance for histopathology. PMID- 21592236 TI - The role of kisspeptin and RFamide-related peptide-3 neurones in the circadian timed preovulatory luteinising hormone surge. AB - Many aspects of female reproduction often require intricate timing, ranging from the temporal regulation of reproductive hormone secretion to the precise timing of sexual behaviour. In particular, in rodents and other species, ovulation is triggered by a surge in pituitary luteinising hormone (LH) secretion that is governed by a complex interaction between circadian signals arising in the hypothalamus and ovarian-derived oestradiol signals acting on multiple brain circuitries. These circadian and hormonal pathways converge to stimulate a precisely-timed surge in gonadotropin-releasing hormone (GnRH) release (i.e. positive-feedback), thereby triggering the preovulatory LH surge. Reflecting its control by afferent circadian signals, the preovulatory LH surge occurs at a specific time of day, typically late afternoon in nocturnal rodents. Although the specific mechanisms mediating the hormonal and circadian regulation of GnRH/LH release have remained poorly understood, recent findings now suggest that oestradiol and circadian signals govern specific reproductive neuropeptide circuits in the hypothalamus, including the newly-identified kisspeptin and RFamide-related peptide (RFRP)-3 neuronal populations. Neurones producing kisspeptin, the protein product of the Kiss1 gene, and RFRP-3 have been shown to provide excitatory and inhibitory input to GnRH neurones, respectively, and are also influenced by sex steroid and circadian signals. In the present review, we integrate classic and recent findings to form a new working model for the neuroendocrine regulation of the circadian-timed preovulatory LH surge in rodents. This model proposes kisspeptin and RFRP-3 neuronal populations as key nodal points for integrating and transducing circadian and hormonal signals to the reproductive axis, thereby governing the precisely-timed LH surge. PMID- 21592243 TI - Commitment to health: a predictor of dietary change. AB - AIMS AND OBJECTIVES: To determine the predictive validity of three behavioural variables on changes in diet: commitment to health (commitment), confidence in ability to change dietary behaviours (confidence) and belief about the importance of changing dietary behaviours (importance). BACKGROUND: Literature supports the Transtheoretical Model of Behavior Change as a framework for understanding dietary behaviour change. Less certain are behavioural variables associated with stage movement for action to maintenance stage for dietary behaviour change. This research considered three variables: self-efficacy ('confidence'), decisional balance scale ('importance') and 'commitment'. Published literature supports the importance of each of these behavioural variables, but not their predictive abilities. DESIGN: A cross-sectional survey was used for 499 manufacturing workers from multiple work-sites. METHODS: Subjects' dietary health behaviours were measured by determining how long they consistently ate a low-fat diet, with analysis of variance addressing the stages-of-change model: precontemplation, contemplation, preparation, action, maintenance. RESULTS: Commitment best predicted change from action to maintenance stage (p < 0.05). Importance (p < 0.05) was somewhat significant, but confidence (p > 0.05) was not. CONCLUSIONS: Commitment was the best predictor of dietary change, from the action to the maintenance stage of change. RELEVANCE TO CLINICAL PRACTICE: Clinicians working with patients in the action stage of dietary change can use a stage-based approach and should evaluate commitment to health as part of an overall assessment. Those with high-level commitment will successfully change from action to maintenance with minimal professional assistance. Those with middle-level commitment risk relapse to a pre-action stage will benefit most from professional intervention. Those in the lower level of commitment are most likely to revert to a pre-action stage of change and may be not be ready for dietary change. PMID- 21592244 TI - Cardiac risk scores in high-risk Hispanics and the predictive value of BNP. AB - AIMS: The purpose of this study was to calculate cardiac risk scores in Hispanic subjects and to determine the predictive value of adding B-type natriuretic peptide in identifying those with asymptomatic left ventricular dysfunction as a measure of cardiovascular disease. BACKGROUND: Hispanics have higher rates of cardiovascular risk factors leading to coronary heart disease, asymptomatic left ventricular dysfunction and cardiovascular events. Assessing cardiac risk in these groups is important to identify those at high risk for future cardiovascular events. The use of biomarkers such as B-type natriuretic peptide may increase the accuracy of risk prediction. DESIGN: This study used a descriptive, cross-sectional study design to determine the utility of the standard risk assessment tools (Adult Treatment Panel III and the Framingham Risk Scores risk calculator) and the B-type natriuretic peptide biomarker to estimate coronary heart disease risk in low-income, Hispanic participants. METHODS: A sample of 71 patients (age 52 SD 11, 69% female) with multiple cardiovascular risk factors seen at an ambulatory clinic at a county facility was enrolled in the study. Sociodemographic and medical history information were obtained. Two widely used risk calculators (Adult Treatment Panel III and Framingham Risk Scores) were used to estimate 10-year coronary heart disease risk in each subject. Baseline B-type natriuretic peptide measurement and echocardiography were performed with each subject to evaluate presence of asymptomatic left ventricular dysfunction. Receiver operating curve analyses were performed to compare predictability, sensitivity and specificity of the traditional risk scores against the B-type natriuretic peptide level to detect asymptomatic left ventricular dysfunction. RESULTS: Overall mean risk scores were 5% (SD 5%) (Adult Treatment Panel III) and 10% (SD 7%) (Framingham Risk Scores). Mean B-type natriuretic peptide levels were 108.5 (SD 191.5) pg/ml. Echocardiogram results revealed a high proportion of subjects with asymptomatic left ventricular dysfunction (74.6%). The receiver operating curves showed an area under the curve of 0.67 for B-type natriuretic peptide (p < 0.05), 0.64 (p = NS) for Adult Treatment Panel III and 0.56 (p = NS) for Framingham Risk Scores, evidence that B type natriuretic peptide does significantly better than Adult Treatment Panel or Framingham Risk Scores in predicting asymptomatic left ventricular dysfunction. CONCLUSION: The inclusion of B-type natriuretic peptide with traditional risk scores may be helpful in predicting risk and asymptomatic left ventricular dysfunction in high-risk Hispanics. RELEVANCE TO CLINICAL PRACTICE: Cardiac risk scores can assist clinicians in identifying patients at high risk for developing coronary heart disease. PMID- 21592245 TI - Depression is associated with poor functioning in activities of daily living among nursing home residents without cognitive impairment. AB - AIM: To explore depressive symptoms among nursing home residents without cognitive impairment and the relationship between their depressive symptoms and dependence on activities of daily living, comorbidity and sociodemographic variables. BACKGROUND: Depression has become a major health care concern among older people, but depression and its association with functioning in activities of daily living among nursing home residents without cognitive impairment has previously not been studied in Norway. DESIGN: A cross-sectional comparative design. METHODS: The sample comprised older residents (age 65-102 years; n = 227) from 30 nursing homes with at least six months of residence. All nursing home residents had a Clinical Dementia Rating scale score <=0.5 and were capable of conversation. Scores on the Geriatric Depression Scale (15 items) and demographic variables were collected during face-to-face interviews. The activities of daily living were assessed using the Katz Index based on nurses' observation, and medical diagnoses were obtained from the patient records. Pearson's chi-square test and ordinal logistic regression were used to identify possible associations between activities of daily living and depression. RESULTS: After adjustment for age, sex, marital status, length of stay per year and education, more dependence on activities of daily living was associated with depression [odds ratio (OR): 1.18; 95% confidence interval (CI): 1.04-1.37; p = 0.02]. Higher age was associated with less depression (OR: 0.64; 95% CI: 0.43-0.94; p = 0.02), that is, the odds of depression declined by 36% for each 10-year increase in age. CONCLUSIONS: Our results suggest that depression symptoms are a major health problem among nursing home residents without cognitive impairment and that younger residents are more prone to having depressive symptoms. RELEVANCE TO CLINICAL PRACTICE: Nursing home staff should communicate with and observe residents closely for signs of depression, especially younger residents with high dependence on activities of daily living. In addition, formal screening of all residents for depression using an instrument that is sensitive to older people is recommended. PMID- 21592246 TI - Predictors of pain in nursing home residents with dementia: a cross-sectional study. AB - AIM: The aim of this study was to investigate the association between care activities and pain and restraint and pain in residents with dementia. BACKGROUND: If pain in people with dementia is not identified or alleviated in a timely manner, it could lead to an adverse effect on their physical, mental, social health and quality of life. Care activities and restraint might cause pain, but little is known as to whether they are true risk-factors of pain in people with dementia. DESIGN: A cross-sectional research design was employed. METHODS: One hundred and twelve people with dementia were chosen from two nursing homes located in northern Taiwan. The demographic and clinical data collected included diagnoses, analgesics, restraints, recent falls, etc. The severity of dementia was assessed using the Clinical Dementia Rating Scale. The researchers observed every participant immediately following instances of routine care and then recorded the level of pain using the Chinese version of the Pain Assessment in Advanced Dementia scale. RESULTS: About 36.6% of the participants had a Chinese version of the Pain Assessment in Advanced Dementia scale score above two points and an overall mean score of 1.50 (SD 1.81) with a range from 0-8. Only one resident with dementia received regular analgesic. Pain level in residents with dementia that needed assisted care was higher than in residents who were able to move about freely. It showed a positive correlation between level of pain and the severity of dementia among residents. The major predictors for pain in residents with dementia included restraint, assisted bathing and assisted transfer. CONCLUSION: The findings confirm the association between care activities and pain and between restraint and pain in residents with dementia. RELEVANCE TO CLINICAL PRACTICE: Formal caregivers need to minimise the triggering of pain when they assist residents' daily activities and avoid unnecessary restraints, while offering personalised, conventional nursing care to residents with late-stage dementia. PMID- 21592247 TI - Nursing experience and preference for intuition in decision making. AB - AIMS AND OBJECTIVES: This article examines the relationship between domain specific and domain-general intuition among practicing nurses and student nurses to determine the role of intuition in nurses' decision making. BACKGROUND: Measures of nursing intuition have not been compared with one another or to measures of general preference for intuition in the psychological literature. Prior research has shown that experienced nurses rely on intuition in clinical judgement, but the various aspects of intuition associated with experience have not been fully explored. DESIGN: A correlational design was used to examine the factor structures and interrelationships of self-reported measures of intuition, as well as their relationship to experience. METHOD: A web-based survey was given to 175 practicing nurses and student nurses in the fall of 2007 using measures of intuition from the nursing and psychological literatures. Quantitative analyses employed descriptive and inferential statistics. RESULTS: Measures of preference for intuition were combined, resulting in the identification of two independent aspects of nursing intuition uniquely related to general intuition and nursing experience. Results revealed that preference for intuition in nursing was not solely due to general preference for intuition and that use of nursing intuition increased with experience. CONCLUSION: These results strengthen the knowledge base of decision making in clinical practice by examining differences in preference for use of intuition among nurses. Further interdisciplinary collaboration is recommended. RELEVANCE TO CLINICAL PRACTICE: Understanding the use of intuition in clinical judgement will promote professional practice and favourable patient outcomes. If experience simply leads to increased self confidence and preference for the use of intuition, this may not actually be related to accuracy in judgement. However, if experience provides valuable information on associations between patient symptoms and outcomes, then the use of intuition in clinical practice should be encouraged. PMID- 21592248 TI - Polysomnography and actigraphy concordance in juvenile idiopathic arthritis, asthma and healthy children. AB - The aims of this study were to evaluate sensitivity, specificity and accuracy with an epoch-by-epoch comparison of polysomnography (PSG) and actigraphy with activity counts scored at low, medium and high thresholds, and to compare PSG derived total sleep time (TST), sleep efficiency (SE) and wake after sleep onset (WASO) to the same variables derived from actigraphy at low, medium and high thresholds in 9- to 11-year-old children with juvenile idiopathic arthritis (JIA), asthma and healthy control children. One night of PSG and actigraphy were recorded. Pairwise group comparisons for sensitivity showed significant differences at the low [Tukey's honest significant difference (HSD) P < 0.002], medium (P < 0.001) and high thresholds (P < 0.001) between JIA and asthma groups, and at the high threshold between JIA and controls (P < 0.009). Significant differences were found for specificity at the low (P < 0.001), medium (P < 0.001) and high thresholds (P < 0.001) between JIA and asthma groups, and between JIA and controls (low, P < 0.002: medium, P < 0.002: high, P < 0.008 threshold). PSG TST, WASO and SE were not significantly different among the groups, but significant group differences were found for actigraphy TST, WASO and SE at all three thresholds. Actigraphy showed the least overestimation or underestimation of sleep or wakefulness at the medium threshold for TST and WASO for all three groups. Compared to PSG, actigraphy was most accurate in the identification of sleep from wakefulness in 9- to 11-year-old healthy children, and less accurate in children with JIA and asthma. PMID- 21592249 TI - Planned quit attempts among Ontario smokers: impact on abstinence. AB - AIMS: To examine the use and role of planned quit attempts by smokers and their impact on abstinence. DESIGN: Retrospective, using longitudinal data from the Ontario Tobacco Survey. SETTING: Ontario, Canada. PARTICIPANTS: A total of 551 adult smokers who reported having made a quit attempt during 2007-08. MEASUREMENTS: Reported planning of the most recent quit attempt (i.e. unplanned or planned some time in advance), engaging in preparatory behaviours believed to be related to planning (i.e. use of quit aids such as pharmacotherapy, formal support or health professionals) and abstinence at 1 week and 1 month following the attempt. FINDINGS: Of the smokers, 73.6% planned their quit attempt in advance. Reported planning was more likely among those who thought they were very addicted, compared with those who were less addicted [odds ratio (OR)=2.22, 95% confidence interval (CI): 1.15-4.28]. Smokers who planned a quit attempt were much more likely to use a quit aid (OR=3.50, 95% CI: 1.80-6.79), particularly pharmacotherapy (OR=6.13, 95% CI: 3.05-12.34). The odds of abstaining for 1 week were lower among those who planned (OR=0.45, 95% CI: 0.22-0.89), independent of perceived addiction. No significant difference was observed for abstinence lasting 1 month. Other factors associated with abstinence were smoking fewer cigarettes per day and having personal support. CONCLUSIONS: Although most quit attempts were planned and planners had higher odds of using quit aids, planning did not increase the likelihood of success. PMID- 21592250 TI - The timing of smoking onset, prolonged abstinence and relapse in men: a prospective study from ages 18 to 32 years. AB - AIM: To describe the rate and timing of smoking onset, prolonged abstinence (>=1 year) and relapses from ages 18 to 32 years in initially smoking and non-smoking men. DESIGN: A 23-year longitudinal study. SETTING: Untreated community sample. PARTICIPANTS: A total of 154 American boys were recruited at age 10 years to a larger study (n=206) of delinquency risk; 71 participants who smoked cigarettes and did not use smokeless tobacco and 83 participants who initially did not use tobacco were followed from age 18 to 32 years. MEASUREMENTS: Frequency of tobacco use and weekly cigarettes smoked in the past year were assessed annually. Onset (>6 cigarettes/week), abstinence (0 tobacco uses in the past year) and relapse (>0 cigarettes/week) were tracked annually. FINDINGS: Of smokers, 36% achieved 1 or more years of abstinence by age 32 years; 52% who reached abstinence relapsed at least once. One-half of men who showed onset after age 18 years were smoking at the end of the study, compared to nearly three-quarters of men who were smokers at age 18 years. Risk for relapse following prolonged abstinence was strongest initially and diminished thereafter. Transition probabilities were stronger for the second period of abstinence than for the first. Models were limited by sample size and statistical power. CONCLUSIONS: Relapses continue to erode men's quit success even after long periods of abstinence from smoking. Long term abstinence, despite intervening relapse, bodes well for eventual abstinence. Adolescent onset appears relevant to the likelihood of adult abstinence and relapse patterns. PMID- 21592251 TI - The effect of neighborhood deprivation and residential relocation on long-term injection cessation among injection drug users (IDUs) in Baltimore, Maryland. AB - AIMS: To determine the incidence of long-term injection cessation and its association with residential relocation and neighborhood deprivation. DESIGN: ALIVE (AIDS Linked to the Intravenous Experience) is a prospective cohort with semi-annual follow-up since 1988. Multi-level discrete time-to-event models were constructed to investigate individual and neighborhood-level predictors of long term injection cessation. SETTING: Baltimore, USA. PARTICIPANTS: A total of 1697 active injectors from ALIVE with at least eight semi-annual study visits. MEASUREMENTS: Long-term injection cessation was defined as 3 consecutive years without self-reported injection drug use. FINDINGS: A total of 706 (42%) injectors achieved long-term cessation (incidence=7.6 per 100 person-years). After adjusting for individual-level factors, long-term injection cessation was 29% less likely in neighborhoods in the third quartile of deprivation [hazard ratio (HR)=0.71, 95% CI: 0.53, 0.95) and 43% less likely in the highest quartile of deprivation (HR=0.57, 95% CI: 0.43, 0.76) compared to the first quartile. Residential relocation was associated with increased likelihood of long-term injection cessation (HR=1.55, 95% CI: 1.31, 1.82); however, the impact of relocation varied depending on the deprivation in the destination neighborhood. Compared to those who stayed in less deprived neighborhoods, relocation from highly deprived to less deprived neighborhoods had the strongest positive impact on long-term injection cessation (HR=1.96, 95% CI: 1.50, 2.57), while staying in the most deprived neighborhoods was detrimental (HR=0.76, 95% CI: 0.63, 0.93). CONCLUSIONS: Long-term cessation of injection of opiates and cocaine occurred frequently following a median of 9 years of injection and contextual factors appear to be important. Our findings suggest that improvements in the socio economic environment may improve the effectiveness of cessation programs. PMID- 21592252 TI - Mephedrone: use, subjective effects and health risks. AB - AIMS: To assess the patterns of use, subjective effect profile and dependence liability of mephedrone, supported by corroborative urine toxicology. DESIGN: Cross-sectional structured telephone interview. SETTING: UK-based drug users associated with the dance music scene. PARTICIPANTS: A total of 100 mephedrone users, recruited through their involvement with the dance music scene. MEASUREMENTS: Assessment of pattern of use, acute and after effects, DSM dependence criteria and gas chromatography-mass spectrometry urinalysis. FINDINGS: Mephedrone consumption results in typical stimulant-related subjective effects: euphoria, increased concentration, talkativeness, urge to move, empathy, jaw clenching, reduced appetite and insomnia. Thirty per cent of the sample potentially met criteria for DSM-IV dependence and there was evidence of a strong compulsion to use the drug (47% had used the drug for 2 or more consecutive days). Self-reported recent consumption of mephedrone was confirmed by toxicological analysis in all of the 14 participants who submitted a urine sample. CONCLUSION: Mephedrone has a high abuse and health risk liability, with increased tolerance, impaired control and a compulsion to use, the predominant reported dependence symptoms. PMID- 21592253 TI - Electronic cigarette: users profile, utilization, satisfaction and perceived efficacy. AB - AIMS: To assess the profile, utilization patterns, satisfaction and perceived effects among users of electronic cigarettes ('e-cigarettes'). DESIGN AND SETTING: Internet survey in English and French in 2010. MEASUREMENTS: Online questionnaire. PARTICIPANTS: Visitors of websites and online discussion forums dedicated to e-cigarettes and to smoking cessation. FINDINGS: There were 3587 participants (70% former tobacco smokers, 61% men, mean age 41 years). The median duration of electronic cigarette use was 3 months, users drew 120 puffs/day and used five refills/day. Almost all (97%) used e-cigarettes containing nicotine. Daily users spent $33 per month on these products. Most (96%) said the e cigarette helped them to quit smoking or reduce their smoking (92%). Reasons for using the e-cigarette included the perception that it was less toxic than tobacco (84%), to deal with craving for tobacco (79%) and withdrawal symptoms (67%), to quit smoking or avoid relapsing (77%), because it was cheaper than smoking (57%) and to deal with situations where smoking was prohibited (39%). Most ex-smokers (79%) feared they might relapse to smoking if they stopped using the e-cigarette. Users of nicotine-containing e-cigarettes reported better relief of withdrawal and a greater effect on smoking cessation than those using non-nicotine e cigarettes. CONCLUSIONS: E-cigarettes were used much as people would use nicotine replacement medications: by former smokers to avoid relapse or as an aid to cut down or quit smoking. Further research should evaluate the safety and efficacy of e-cigarettes for administration of nicotine and other substances, and for quitting and relapse prevention. PMID- 21592255 TI - Neonatal cystitis-induced colonic hypersensitivity in adult rats: a model of viscero-visceral convergence. AB - BACKGROUND: The objective of this study was to determine if neonatal cystitis alters colonic sensitivity later in life and to investigate the role of peripheral mechanisms. METHODS: Neonatal rats received intravesical zymosan, normal saline, or anesthesia only for three consecutive days [(postnatal (PN) days 14-16)]. The estrous cycle phase was determined prior to recording the visceromotor response (VMR) to colorectal distension (CRD) in adult rats. Eosinophils and mast cells were examined from colon and bladder tissues. CRD- or urinary bladder distension (UBD)-sensitive pelvic nerve afferents (PNAs) were identified and their responses to distension were examined. The relative expression of N-methyl-d-aspartic acid (NMDA)-NR1 subunit in the lumbo-sacral (L6 S1) spinal cord was examined using Western blot. KEY RESULTS: The VMR to CRD (>=10mmHg) in the neonatal zymosan group was significantly higher than control in both the diestrus, estrus phase and in all phases combined. There was no difference in the total number of eosinophils, mast cells or number of degranulated mast cells between groups. The spontaneous firing of UBD, but not CRD-sensitive PNAs from the zymosan-treated rats was significantly higher than the saline-treated control. However, the mechanosensitive properties of PNAs to CRD or UBD were no different between groups (P>0.05). The expression of spinal NR1 subunit was significantly higher in zymosan-treated rats compared with saline treated rats (P<0.05). CONCLUSIONS & INFERENCES: Neonatal cystitis results in colonic hypersensitivity in adult rats without changing tissue histology or the mechanosensitive properties of CRD-sensitive PNAs. Neonatal cystitis does result in overexpression of spinal NR1 subunit in adult rats. PMID- 21592257 TI - Factor VIII inhibitors: a 50-year perspective. AB - Inhibitors of factor VIII (FVIII) have been studied for more than 50 years, but diagnostic and therapeutic challenges remain. To describe the features that distinguish alloantibodies from autoantibodies, list predisposing factors, and review methods for tolerance induction and autoantibody suppression. Review of key articles published during the past half-century that have advanced knowledge in this field. Alloantibodies generally bind to the A2 or C2 domains of FVIII and disrupt the formation of the FVIII-FIX complex. They exhibit type 1 reaction kinetics, are saturable by FVIII, and display anamnesis. In contrast, autoantibodies usually bind to the C2 domain of FVIII, interfering with phospholipid and von Willebrand factor binding. They have type-2 kinetics and are poorly neutralized by FVIII. Repeated exposures to FVIII induce tolerance in 70 80% of haemophiliacs with inhibitors, whereas drugs that deplete B-lymphocytes restore self-tolerance to FVIII in a similar percentage of non-haemophiliacs. Future work should focus on improving assays that detect and quantify inhibitors, examining the pathophysiology of inhibitor formation using contemporary immunologic tools, and investigating new treatment modalities. These should include agents to control bleeding with less thrombotic risk, more specific immunomodulating drugs to curtail antibody formation, and, for haemophilia patients, genetic therapies to provide FVIII resistant to or protected from inactivation by inhibitors. PMID- 21592256 TI - Diagnosis of supra-esophageal gastric reflux: correlation of oropharyngeal pH with esophageal impedance monitoring for gastro-esophageal reflux. AB - BACKGROUND: Oropharyngeal (OP) pH monitoring has been developed as a new way to diagnose supra-esophageal gastric reflux (SEGR), but has not been well validated. Our aim was to determine the correlation between OP pH and gastro-esophageal reflux (GER) events detected by multichannel intraluminal impedance-pH (MII-pH). METHODS: Fifteen patients (11 males, median age 10.8 years) with suspected GER were prospectively evaluated with ambulatory 24-h OP pH monitoring (positioned at the level of the uvula) and concomitant esophageal MII-pH monitoring. Potential OP events were identified by the conventional pH threshold of <4 and by the following alternative criteria: (i) relative pH drop >10% from 15-min baseline and (ii) absolute pH drop below thresholds of <5.5, 5.0, and 4.5. The 2-min window preceding each OP event was analyzed for correlation with an episode of GER detected by MII-pH. KEY RESULTS: A total of 926 GER events were detected by MII-pH. Application of alternative pH criteria increased the identification of potential OP pH events; however, a higher proportion of OP events had no temporal correlation with GER (45-81%), compared with the conventional definition of pH < 4 (40%). A total of 306 full-column acid reflux episodes were detected by MII-pH, of which 10 (3.3%) were also identified by OP pH monitoring. CONCLUSIONS & INFERENCES: Use of extended pH criteria increased the detection of potential SEGR events, but the majority of decreases in OP pH were not temporally correlated with GER. Oropharyngeal pH monitoring without concurrent esophageal measurements may overestimate the presence of SEGR in children. PMID- 21592258 TI - C1272F: a novel type 2A von Willebrand's disease mutation in A1 domain; its clinical significance. AB - Most mutations identified in 2A VWD patients are localized in the A2 domain, although missense substitutions have also been recognized in the A1 domain. We describe a novel heterozygous missense mutation in the A1 domain of VWF gene responsible for type 2A phenotype. Analysis of the complete exon 28 was carried out in a patient and his mother with life-long histories of moderate to severe bleeding and laboratory data of type 2A VWD. The analysis of exon 28 of VWF gene showed a 3815 G -> T transversion resulting in C1272F mutation. It is probably associated with a group I mechanism according to patients' clinical symptoms, and, in the case of the propositus, the lack of clinical response to treatment with desmopressin. The mutation was not found in 100 normal alleles. This substitution affected the normal S-S bound between C1272 and C1458, which is involved in A1 loop structure, altering the normal multimerization and function of VWF. The VWFpp/VWF:Ag ratio in the propositus and his mother was >3, suggesting a shortened survival of VWF. We believe it is important to report the complete clinical phenotype corresponding to the new mutation to increase the knowledge in the clinical field. PMID- 21592259 TI - DDAVP responsiveness in children with mild or moderate haemophilia A correlates with age, endogenous FVIII:C level and with haemophilic genotype. AB - In most individuals with moderate/mild haemophilia A, FVIII:C levels increase following DDAVP administration to a haemostatic range, thus avoiding the need for FVIII concentrates. We sought to determine the relationship between responsiveness to DDAVP in boys (<18 years old) with mild/moderate haemophilia and patient age, haemophilic severity and haemophilic genotype. Our cohort consisted of 13 boys with moderate and 61 boys with mild haemophilia who, between them, had 38 different mutations; 21 had unique mutations not shared by any other clinic patient, whereas 53 shared one of 17 mutations with some other clinic patient (included 26 boys with >= 1 haemophilic brother). Patient age and endogenous FVIII:C levels were strong predictors of response to DDAVP. Younger patients responded less well to DDAVP and 10 of the 11 patients, when retested at an older age, showed an improved response to DDAVP. Only 1 patient with moderate haemophilia responded to DDAVP, whereas 80% of patients with mild haemophilia responded (including all patients with an endogenous FVIII:C of >0.15 U mL(-1)). Almost all patients with the same mutation had the same response to DDAVP or only a minor discordance in response. Patient's age, disease severity and genotype all are predictors of response to DDAVP. PMID- 21592260 TI - Misnomers in oral pathology. PMID- 21592261 TI - Oral medicine in German-speaking countries. PMID- 21592262 TI - Philosophy, health services and research. PMID- 21592263 TI - Philosophy, health services and research: the importance of keeping conversations open. PMID- 21592264 TI - Shared decision making: trade-offs between narrower and broader conceptions. AB - Shared decision-making approaches, by recognizing the autonomy and responsibility of both health professionals and patients, aim for an ethical 'middle way' between 'paternalistic' and 'consumerist' models of clinical decision making. Shared decision making has been understood in various ways. In this paper, we distinguish narrow and broader conceptions of shared decision making and explore their relative strengths and weaknesses. In the first part of the paper, we construct a summary characterization of an archetypal narrow conception of shared decision making (a conception that does not coincide with any specific published model but which reflects features of a variety of models). We show the shortcomings of such a conception and highlight the need to broaden out our thinking about shared decision making if the ethical (and instrumental) goals of shared decision making are to be realized. In the second part of the paper, we acknowledge and explore the advantages and disadvantages of operating with broader conceptions of shared decision making by considering the analogies between health professional-patient relationships and familiar examples of 'open ended' relationships (e.g. friendships). We conclude by arguing that the illustrated 'trade-offs' between narrow conceptions (which may protect patients from inappropriately paternalistic professionals but preclude important forms of professional support) and broad conceptions (which render more forms of professional support legitimate but may require skills or virtues that not all health professionals possess) suggest the need to find ways, in principle and in practice, of taking seriously both patient autonomy and autonomy-supportive professional intervention. PMID- 21592265 TI - Public and patient participation in health care and health policy in the United Kingdom. PMID- 21592266 TI - Does one's sense of coherence change after an acute myocardial infarction? A two year longitudinal study in Sweden. AB - The aim of this study was to assess changes in the sense of coherence of patients who had suffered their first myocardial infarction. Out of 100 patients at the start of the study, these changes were evaluated in 66 men and 18 women aged 36 70 years. Generally, the sense of coherence was found to be stable among the whole group, but there were significant individual variations in its development in some of the participants over the following years. Even the individuals with an initally high sense of coherence could experience a decrease in its level. The changes that were found in the men can be explained by their marital status, level of treatment satisfaction, disease perception/quality of life, physical limitation, and alcohol intake and/or tobacco use at the baseline. An unexpected finding was that the single men with an initially high sense of coherence experienced a decreased level over time. In order to maintain or increase patients' sense of coherence, it is important for nurses to help them identify their risk factors and to provide conditions for individualized cardiac rehabilitation in order to avoid another myocardial infarction. PMID- 21592267 TI - Sudden cardiac death: the perspectives of Spanish survivors. AB - Sudden cardiac death is an episode of sudden death from cardiac causes in previously healthy patients. The aim of this study was to investigate the life experiences of patients who were resuscitated successfully following a sudden cardiac death. Purposeful sampling was used to recruit the nine participants through the snowball technique. Unstructured interviews were carried out until data saturation was reached. The Giorgi method of analysis, which seeks to reduce the participant's experience to minimal thematic units, common thematic groups, and essential themes in order to describe it, was used. Four essential themes were found: "facing fear"; "the search for meaning"; "feeling death up close and personal"; and "loneliness and estrangement". Nurses must integrate the lifestyle changes of patients who survive a cardiac death in order to provide adequate care following hospital discharge. Patients should undertake follow-up programs in order to receive counseling from health professionals. As a result, the creation of interdisciplinary support groups and the implementation of follow-up programs after hospital discharge are fundamental. Survivors' experiences can inform the development of nursing programs and hospital follow-up services that address the survival of cardiac death. PMID- 21592268 TI - Factors affecting older persons' adherence to prescription drugs in Israel. AB - Despite the significance of patients' adherence to prescription drug treatments, it is estimated that > 30% of the drugs that are prescribed to older persons are not self-administered in accordance with the instructions. This research examines which factors affect the adherence to prescription drugs of older Israelis and tests whether the Theory of Planned Behavior (TPB) can explain their adherence. In this cross-sectional survey design, a reliable and valid structured questionnaire, based on the TPB, was administered to a convenience sample of 207 independent older persons who were taking prescription drugs. One-fifth of the sample reported that they did not adhere to their medication regime. The older persons' self-reported adherence to treatment was related to the quantity of drugs that they were required to take and to whether or not they received the support of a primary caregiver. The more confidence that the older persons had in their physician's level of professionalism, the greater their self-reported adherence to the prescription drugs. Behavioral beliefs, behavioral attitudes, perceived behavioral control, and subjective norms were related to the older persons' intention to self-administer medication. We conclude that nurses have an important responsibility in assessing the medication-taking behaviors of older adults. PMID- 21592269 TI - Factor analysis on oral health care for acute hospitalized patients in Japan. AB - AIM: We conducted a survey to investigate the status regarding the implementation of oral health care for inpatients aged 65 years and older who were in the acute stages of stroke and to examine the factors related to the details of excellent model hospitals. METHODS: We sent a questionnaire on oral health care targeting all 8089 hospitals in Japan. On the basis of the responses obtained from the hospitals, we conducted a survey to analyze the factors defining what are known to be excellent model hospitals. We then conducted a logistic regression analysis using a stepwise procedure. RESULTS: Replies were received from 2444 of the 8089 hospitals (30.2%): 91.8% of the hospitals reported that oral health care was a part of the daily nursing routine while 91.2% of the hospitals considered that aspiration pneumonia could be prevented by appropriate oral health care. Only 30% of the nurses had undergone oral hygiene training. Among the factors involved in excellent model hospitals, we observed a strong correlation with a sense of the necessity for oral health care, oral hygiene training for nurses and a large number of hospital beds. CONCLUSION: Large scale hospitals tend to be more interested in oral health care than smaller hospitals. Providing oral health care is already common in acute hospitals in Japan. There is a great demand for oral hygiene training and obtaining information from dental professionals. It is important to promote the cooperation between dental and nursing personnel within hospitals regarding oral hygiene training. PMID- 21592270 TI - Evaluation of delirium in elderly: a hospital-based study. AB - AIM: The study aimed to study the prevalence, etiologies, clinical profile and outcome of delirium in hospitalized elderly in medicine wards. METHODS: Four hundred elderly patients of more than 60years of age admitted with delirium in the emergency and medicine wards of Sir Sunderlal Hospital Varanasi, India, were evaluated and managed. The Hindi version of the Mini-Mental Status Examinations, a vernacular (Hindi) version of the Mini-Mental State Examination, was used for evaluation of cognitive function status of patients and Confusion Assessment Method (CAM), a screening instrument based on the third edition of the Diagnostic and Statistical Manual of Mental Disorders was used for diagnosis of delirium. RESULTS: A total of 400 hospitalized elderly delirious patients were included in the study aged 61-105years. The mean age of the subjects was 70.87+/-9.26years and 70.81+/-8.4years amongst males and females, respectively. The mortality rate was 14.75%. Out of nine CAM features, all the cases had all three essential features, 78.75% had four features, 58.5% had five features, 44.5% had six features and 9.25% had all nine features. There was a high prevalence of hypoactive delirium (65%) as compared to hyperactive (25%) or mixed (10%). Most common etiologies were sepsis followed by metabolic abnormalities. 70% had 2 or more etiologies. CONCLUSION: Sepsis and metabolic abnormalities were the most common etiologies of delirium in this study. The maximum patients had more than one etiology and this emphasizes the multifactorial nature of delirium and need for thorough evaluation to unravel them. Most of the causes were treatable and have favorable outcome (83% recovered). PMID- 21592271 TI - Factors associated with a protracted hospital stay after hip fracture surgery in Japan. AB - AIM: Hip fracture is a major injury in the elderly and has a high impact on quality of life and use of health-care resources. In this study, we aimed to identify the factors related to prolonged hospital stay and poor outcome after hip fracture surgery. METHODS: We evaluated data from 8920 cases at 398 acute care hospitals in Japan. Multivariate logistic regression analysis was used to determine the factors associated with the length of postoperative hospital stay. RESULTS: A shorter postoperative hospital stay was associated with admission to a high surgical volume hospital (P<0.001). On the other hand, a longer postoperative hospital stay was associated with infective complications, admission to a private hospital, an interval of more than 3days between admission and surgery (P<0.001 for all), and an interval of more than 1day between surgery and start of rehabilitation (P=0.01). Further analysis revealed that infective complications were more likely in older patients (P=0.003) and patients with comorbidities (P=0.03). CONCLUSION: The results imply that hospital stay, and, therefore, use of medical resources, can be decreased by performing surgeries shortly after patients are admitted, preventing postoperative infections, and starting rehabilitation on the next day of the surgery. One of the limitations of our study was that data of the length of hospital stay at transferred hospitals were not available. Therefore, further prospective studies will be needed to address significance of early surgery and rehabilitation. PMID- 21592272 TI - Effects of insulin and amyloid beta(1-42) oligomers on glucose incorporation and mitochondrial function in cultured rat hippocampal neurons. AB - AIM: The molecular basis for impaired glucose metabolism in patients with Alzheimer's disease (AD) has not been fully clarified. We tested whether insulin and amyloid (A)beta(1-42) oligomers would regulate glucose metabolism and energy homeostasis directly in cultured rat hippocampal neurons and evaluated possible interactions between insulin signaling and Abeta(1-42) oligomers. METHODS: Dissociated hippocampal neurons were prepared from Wistar rat embryos at day 21 of gestation and cultured for 14days. Cultured neurons were exposed to insulin (1uM) for 30min, and Abeta(1-42) oligomers (1uM) were added to culture media for 10-30min. The glucose uptake of cultured neurons was measured by enzymatic fluorescence assay using 2-deoxy-d-glucose (2DG), and adenosine triphosphate (ATP) contents were quantified using a luciferin/luciferase luminescence assay. RESULTS: Abeta(1-42) oligomers did not suppress 2DG uptake, reflecting the activities of glucose transporters and/or hexokinase, but led to disrupted ATP contents in the presence and absence of monocarboxylates (lactate/pyruvate). Insulin and C-peptide did not change glucose uptake or ATP concentrations. CONCLUSION: The primary target of Abeta(1-42) oligomers might be mitochondria, which could explain the reduced cerebral glucose levels in patients with AD. Moreover, insulin signaling was not directly linked to glucose metabolism or energy homeostasis in cultured rat hippocampal neurons. PMID- 21592273 TI - Opioid replacement therapy: a wait unmanaged. AB - There has been a rapid increase in members of the Australian population using opioids in recent years. The flow-on effect has been an increase in demand for treatments, particularly opioid replacement therapy (ORT), but the availability of treatments has not increased. This has frequently resulted in delays before treatment can be commenced. Outcomes could improve if health-care professionals had clearer guidelines on how to prioritize access to ORT. This review investigates the triage of consumers in ORT within Australia. Information on triage in ORT was not available, and an understanding of how consumer needs are managed when they present for ORT triage was not identified. In the absence of research to guide this practice, the body of evidence regarding ORT treatment access is weighted on government policies. Triage, as applied in general health and mental health-care service delivery, was reviewed to consider the components of triage and how these might pertain to triage in ORT. Failure to facilitate the needs of consumers accessing ORT can result in further harm to consumers and increased social and financial costs for society. Research is required to investigate how this issue is currently being managed and to lead the way for needed improvements in service delivery. PMID- 21592274 TI - Ecological impacts of invasive alien plants: a meta-analysis of their effects on species, communities and ecosystems. AB - Biological invasions cause ecological and economic impacts across the globe. However, it is unclear whether there are strong patterns in terms of their major effects, how the vulnerability of different ecosystems varies and which ecosystem services are at greatest risk. We present a global meta-analysis of 199 articles reporting 1041 field studies that in total describe the impacts of 135 alien plant taxa on resident species, communities and ecosystems. Across studies, alien plants had a significant effect in 11 of 24 different types of impact assessed. The magnitude and direction of the impact varied both within and between different types of impact. On average, abundance and diversity of the resident species decreased in invaded sites, whereas primary production and several ecosystem processes were enhanced. While alien N-fixing species had greater impacts on N-cycling variables, they did not consistently affect other impact types. The magnitude of the impacts was not significantly different between island and mainland ecosystems. Overall, alien species impacts are heterogeneous and not unidirectional even within particular impact types. Our analysis also reveals that by the time changes in nutrient cycling are detected, major impacts on plant species and communities are likely to have already occurred. PMID- 21592275 TI - Indirect plant-mediated interactions among parasitoid larvae. AB - Communities are riddled with indirect species interactions and these interactions can be modified by organisms that are parasitic or symbiotic with one of the indirectly interacting species. By inducing plant responses, herbivores are well known to alter the plant quality for subsequent feeders. The reduced performance of herbivores on induced plants cascades into effects on the performance of higher trophic level organisms such as parasitoids that develop inside herbivores. Parasitoids themselves may also, indirectly, interact with the host plant by affecting the behaviour and physiology of their herbivorous host. Here, we show that, through their herbivorous host, larvae of two parasitoid species differentially affect plant phenotypes leading to asymmetric interactions among parasitoid larvae developing in different hosts that feed on the same plant. Our results show that temporally separated parasitoid larvae are involved in indirect plant-mediated interactions by a network of trophic and non-trophic relationships. PMID- 21592276 TI - Impacts of shrub encroachment on ecosystem structure and functioning: towards a global synthesis. AB - Encroachment of woody plants into grasslands has generated considerable interest among ecologists. Syntheses of encroachment effects on ecosystem processes have been limited in extent and confined largely to pastoral land uses or particular geographical regions. We used univariate analyses, meta-analysis and structural equation modelling to test the propositions that (1) shrub encroachment does not necessarily lead to declines in ecosystem functions and (2) shrub traits influence the functional outcome of encroachment. Analyses of 43 ecosystem attributes from 244 case studies worldwide showed that some attributes consistently increased with encroachment (e.g. soil C, N), and others declined (e.g. grass cover, pH), but most exhibited variable responses. Traits of shrubs were associated with significant, though weak, structural and functional outcomes of encroachment. Our review revealed that encroachment had mixed effects on ecosystem structure and functioning at global scales, and that shrub traits influence the functional outcome of encroachment. Thus, a simple designation of encroachment as a process leading to functionally, structurally or contextually degraded ecosystems is not supported by a critical analysis of existing literature. Our results highlight that the commonly established link between shrub encroachment and degradation is not universal. PMID- 21592278 TI - When 'dueling technologies' are mistaken for progress. PMID- 21592279 TI - Low-cost telemedicine. PMID- 21592280 TI - Pelvic organ prolapse (POP) surgery: the evidence for the repairs. AB - What is known on the subject? and What does the study add? Substantial experience of the outcomes has been gathered regarding the acute and sub-acute experience with various types of corrective procedures for POP. These include long-term POP correction as well as more recent recognition of improvement in functional disorders associated with POP such as UI, colorectal dysfunction, and sexual dysfunction. Long-term follow-up is available for some of the older types of interventions and current multicentre trials are being accrued with longer term follow-up for new interventions including mesh-type repairs. The study adds a condensed and summarized version of the current literature regarding the various interventions for POP and also provides an overview of the current controversies and areas where knowledge is incomplete and in need of further elaboration for definitive answers regarding optimization of surgical care for POP. Our aim is to summarise the available data on the transvaginal placement of synthetic mesh for pelvic organ prolapse (POP) repair, with a focus on the outcomes and complications of commercial POP-repair kits. As the stability and durability of autologous tissues may be questionable, nonabsorbable, synthetic materials are an attractive alternative for providing additional support during POP surgery. These materials are not novel, and most have been used for many years in surgical applications, e.g. hernia repairs. While theoretically appealing, the implantation of synthetic mesh in the pelvis may be associated with inherent adverse consequences, such as erosion, extrusion, and infection. Additionally, the routine use of these materials may carry potential long-term complications, such as dyspareunia, chronic pelvic pain, and vaginal distortion. The success and failure of mesh-augmented POP repair is related not only to the synthetic material itself, but also to patient- and surgeon-related factors. Recent warnings by the USA Food and Drug Administration and other groups regarding adverse events further complicate the decision to use synthetic mesh. PMID- 21592281 TI - Sexual dysfunction as the last bastion of urological drug commercialisation within the pharmaceutical industry. PMID- 21592282 TI - 'Mohs surgery of the prostate': the utility of in situ frozen section analysis during robotic prostatectomy. PMID- 21592284 TI - Outcomes of scrotal exploration for acute scrotal pain suspicious of testicular torsion: a consecutive case series of 173 patients. PMID- 21592283 TI - Fibrosis and evidence for epithelial-mesenchymal transition in the kidneys of patients with staghorn calculi. PMID- 21592287 TI - Adult hydrocele and spermatocele. PMID- 21592291 TI - Peripheral neuropathy: an underdiagnosed cause of erectile dysfunction. AB - OBJECTIVES: * To assess the prevalence of peripheral neuropathy in patients with erectile dysfunction (ED). * To evaluate the reliability of clinical tests such as the five-item version of the International Index of Erectile Function (IIEF-5) and the Neuropathy Symptom Score (NSS) classification system in predicting the concurrence of peripheral neuropathy. PATIENTS AND METHODS: * We studied 90 patients who were consecutively recruited from the Department of Andrology of the Central Hospital of Asturias. * Anamnesis included questions about risk factors related to ED. * The severity of ED was classified according to IIEF-5 scores and symptoms of peripheral neuropathy were assessed using the NSS. * Neurophysiological tests included electromyography, nerve conduction studies, evoked potentials from pudendal and tibial nerves as well as bulbocavernosus reflex. * Small fibre function was assessed using quantitative sensory tests and sympathetic skin response. Statistical analysis was performed using the SPSS-11 program. RESULTS: * Patients with more severe symptoms of peripheral neuropathy showed lower (worse) IIEF-5 scores (P= 0.015) and required more aggressive therapies (P < 0.001). * Neurophysiological exploration confirmed neurological pathology in 68.9% of patients, of whom 7.8% had myelopathy and 61.1% peripheral neuropathy. * Polyneuropathy was found in 37.8% of the patients, of whom 8.9% had pure small fibre polyneuropathy, and pudendal neuropathy was diagnosed in 14.4%. * No association between neurophysiological diagnosis and IIEF-5 score was detected, but a statistical association was found between neuropathy and NSS scores. CONCLUSIONS: * Up to now, the impact of peripheral neuropathy in the pathogenesis of ED has been underestimated. The combination of anamnesis and an ad hoc neurophysiological protocol showed its high prevalence and provided a more accurate prognosis. * In future, clinical practice should optimize the assessment of pelvic small fibre function. PMID- 21592292 TI - Infective complications after transrectal ultrasound-guided prostate biopsy following a new protocol for antibiotic prophylaxis aimed at reducing hospital acquired infections. AB - OBJECTIVE: To compare the infective complications between two different antibiotic regimens used as prophylaxis for transrectal ultrasound-guided prostate biopsy (TRUSP Bx). PATIENTS AND METHODS: The records of 709 consecutive patients undergoing TRUSP Bx over a period of 20 months at a UK teaching hospital were examined retrospectively. All clinic letters, microbiology reports and admission records were examined for each patient. RESULTS: Within the study period a total of 454 patients received prophylaxis with ciprofloxacin; 11 of these patients (2.4%) developed an infective complication within 4 weeks of the TRUSP Bx. A total of 255 patients received prophylaxis with co-amoxiclav and gentamicin; 33 patients (12.9%) in this group had an infective complication. No cases of Clostridium difficile infection were recorded for any of these patients within 1 month of receiving antibiotics. Re-introduction of the original regimen led to a fall in infective complications. CONCLUSION: Understandable concerns about the development of hospital-acquired infection led to a new protocol for antibiotic prophylaxis which in turn led to a number of patients being put at increased risk of potentially serious infective complications. Antibiotic prophylaxis must reflect tissue penetration, the organisms encountered and their susceptibilities, as well as being based on objective evidence. PMID- 21592293 TI - Predictors for clinically relevant Gleason score upgrade in patients undergoing radical prostatectomy. AB - OBJECTIVE: To evaluate clinical predictors for Gleason score upgrade (GSU) in radical prostatectomy (RP) specimen, especially in patients with 'very' low risk PCA (T1c and biopsy Gleason score <=6 and PSA <10 ng/ml and <=2 positive biopsy cores and PSA density <0.15). PATIENTS AND METHODS: 402 consecutive patients undergoing RP between 2004 and 2006, including a subgroup of 62 patients with 'very' low risk PCA, were examined. Patients were categorized for clinically relevant GSU (defined as upgrade into a higher PCA risk category). Parameters including number of biopsy cores obtained, positive biopsy cores, prostate weight, PSA, DRE and pathology department were evaluated for their role as predictors. Furthermore, GSU in RP specimen was analyzed for its impact on pT stage. RESULTS: Clinically relevant GSU occurred in 38.1% in the whole cohort and in 32.3% in the 'very' low risk PCA subgroup. Gleason score downgrade (GSD) occurred in 4.7%. Number of biopsy cores obtained and prostate weight were independent negative predictors of GSU in all 402 patients (P = 0.02 and P = 0.03, respectively). In the 'very' low risk group, only number of biopsy cores obtained revealed as an independent negative predictor of GSU (P = 0.02). PSA, DRE, number of positive cores or pathology department were not associated to GSU. In the 'very' low risk group, GSU was related with extracapsular tumor extension (P = 0.05). CONCLUSIONS: Clinically relevant GSU in RP specimen is still a challenging problem. Increasing the number of biopsy cores lower this risk significantly. GSD is rare and thus of minor importance for treatment decisions. PMID- 21592294 TI - Management of the bladder in traumatic injuries of the spinal cord during the First World War and its implications for the current practice of urology. AB - What's known on the subject? and What does the study add? Prior to the First World War, traumatic injuries to the spinal cord rapidly led to death from severe infections of the bladder. During the Second World War, Ludwig Guttmann resurrected the use of intermittent catheterisation at Stoke Mandeville Hospital, by meticulous attention to detail and was so successful, that this method was introduced into general urological practice. Historical review of the management of the bladder in patients with spinal injuries. Spinal injury patients- literature review--personal experience at Stoke Mandeville Hospital. Review of the different methods of catheterisation from the 19th century to today. Methods learned from the management of the bladder of spinal injuries patients were adopted into mainstream urology. PMID- 21592295 TI - Non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). AB - What's known on the subject? and What does the study add? Silodosin administered by 4 mg twice daily is as effective as tamsulosin 0.2 mg daily in treating patients with LUTS associated with BPH. Relative to tamsulosin, silodosin has less cardiovascular side effects as judged by the minimal changes of blood pressure and pulse rats after treatment. OBJECTIVE: * To test the hypothesis that the efficacy of silodosin would not be inferior to tamsulosin in treating patients with lower urinary tract symptoms associated with benign prostate hyperplasia (BPH). PATIENTS AND METHODS: * At nine medical centres, 209 patients with an International Prostate Symptom Score (IPSS) of >=13 were randomized to silodosin (4 mg twice daily) or tamsulosin (0.2 mg once daily) for 12 weeks. * The primary efficacy measure was the mean change from baseline to endpoint in IPSS. * The non-inferiority margin of the IPSS change was set at 1.0. * Secondary efficacy measures included change in maximal urinary flow rate (Q(max)) and health-related quality of life (HRQL) score. RESULTS: * Of the 170 (81.3%) patients who completed the study, 86.2% in the silodosin group vs 81.9% in the tamsulosin group achieved a >=25% decrease in IPSS (P= 0.53). * The mean difference (silodosin minus tamsulosin) in IPSS change from baseline was -0.60 (95% confidence interval -2.15, 0.95), inferring the non-inferiority of silodosin to tamsulosin. * The mean changes in the Q(max) and HRQL score from baseline were comparable between the groups (both, P > 0.05). Although patients receiving silodosin had a significantly higher incidence of abnormal ejaculation (9.7% vs tamsulosin 1.0%, P= 0.009), only 1.9% discontinued treatment. * Tamsulosin treatment resulted in a significant reduction in mean systolic blood pressure ( 4.2 mmHg, within-group P= 0.004) relative to the negligible change of silodosin ( 0.1 mmHg, within-group P= 0.96) CONCLUSION: * The trial shows the non-inferiority of silodosin 4 mg twice daily to tamsulosin 0.2 mg once daily in patients with symptoms of BPH. PMID- 21592296 TI - Effect of varicocele on sperm function and semen oxidative stress. AB - OBJECTIVE: To assess the effect of varicocele on sperm DNA integrity, mitochondrial activity, lipid peroxidation and acrosome integrity. PATIENTS AND METHODS: In all, 30 patients with a clinically diagnosed varicocele of grade II or III and 32 men without a varicocele were evaluated for sperm DNA fragmentation (comet assay), mitochondrial activity (3,3'-diaminobenzidine assay), lipid peroxidation (malondialdehyde) and acrosome integrity (fluorescent probe labelled peanut agglutinin). RESULTS: The varicocele group showed fewer spermatozoa with intact DNA (grade II, P= 0.040), more cells with inactive mitochondria (class III, P= 0.001), fewer cells with active mitochondria (class I, P= 0.005) and fewer spermatozoa with intact acrosomes (P < 0.001). Finally, no significant differences were observed in lipid peroxidation levels. CONCLUSION: Men with varicocele showed an increase in sperm DNA fragmentation and a reduction in mitochondrial activity and acrosome integrity. However, lipid peroxidation levels remained unchanged. PMID- 21592297 TI - Second to fourth digit ratio, adult testosterone level and testosterone deficiency. AB - OBJECTIVES: The ratio of the second and fourth finger lengths (2D/4D) is related to intrauterine exposure to testosterone. The relationship between 2D/4D and adult hormonal pattern is controversial. The aim of our study was to determine if there was a relationship between adult serum testosterone levels and the 2D/4D ratio. PATIENTS AND METHODS: We prospectively recruited 204 consecutive patients referred for transrectal prostate biopsy between January 2008 and June 2009. The same physician performed clinical examinations, 2D/4D measurements and the transrectal biopsy in all cases. Cut-off points of 231 and 346 ng/dL testosterone (8 and 12 nmol/L) were used. 2D/4D determination was done with a vernier calliper on the left hand. The hormonal profile (testosterone and sexual hormone binding globulin) of the patients was determined between 7.00 am and 11.00 am. Age, weight, height, body mass index, toxic habits, digital rectal examination, prostate-specific antigen and 2D and 4D measurements were recorded prospectively. RESULTS: The mean age was 67 +/- 7 years and the mean testosterone level was 413 +/- 18 ng/dL (14.33 +/- 0.62 nmol/L). The percentages of patients with testosterone <231 ng/dL (8 nmol/L) and testosterone <346 ng/dL (12 nmol/L) were 6.1 and 30.6 respectively. Univariate analysis showed that low 2D/4D ratios were related to higher levels of testosterone (B=-741.98; beta=-0.165, P= 0.045) and also with low prevalence of biochemical hypogonadism (testosterone <346 ng/dL). Mean 2D/4D ratio in patients with testosterone >346 ng/dL was lower than in patients with testosterone <346 ng/dL (2D/4D 0.97 +/- 0.037 vs 0.99 +/- 0.043 depending on their hormonal status, P= 0.05). High 2D/4D ratio was associated with low testosterone serum levels (P= 0.046). CONCLUSIONS: The 2D/4D ratio is related to adult testosterone levels and the presence of testosterone deficiency syndrome. Patients with high 2D/4D ratios have lower testosterone levels and higher risk of testosterone deficiency syndrome. PMID- 21592298 TI - Histopathological variables and biomarkers enhancer of zeste homologue 2, Ki-67 and minichromosome maintenance protein 7 as prognosticators in primarily endocrine-treated prostate cancer. AB - OBJECTIVE: * To evaluate the prognostic value of histopathological variables and immunostainings of biomarkers enhancer of zeste homologue 2 (EZH2), Ki-67 and minichromosome maintenance protein 7 (MCM7) from core biopsies of hormonally treated patients with prostate cancer. PATIENTS AND METHODS: * Biopsies of 247 primarily endocrine-treated patients were analysed for histopathological characteristics and Gleason scores (GS) according to the revised guidelines of International Society of Urologic Pathology (ISUP) consensus conference 2005. * Immunohistochemical stainings were analysed with the aid of digital image analysis. * The prognostic value of the histopathological variables and the biomarkers was analysed with univariate and multivariate Cox regression analysis, with biochemical recurrence as an endpoint. RESULTS: * Biomarkers EZH2 (relative risk [RR] 2.0, 95% confidence interval 1.2-3.3), Ki-67 (3.4, 2.1-5.5) and MCM7 (2.4, 1.5-3.9) were significantly associated with progression-free survival in a univariate analysis. * Ki-67 immunostaining index detected high-risk patients with GS of 7 (9.1, 8.0-10.3). * In a multivariate analysis with non-conventional GS groups 5-7 (3 + 4), 7(4 + 3)-8, and 9-10, the independent prognostic markers were pretreatment GS (2.2, 1.5-3.2), prostate-specific antigen (PSA) level (2.1, 1.1-4.2), perineural invasion (PNI) (1.6, 1.2-2.2), and clinical T-stage (cT) (1.9, 1.0-3.7). * Combination of the independent markers (PSA level > 20 ng/mL or GS >3 + 4 or PNI >3 or cT >2) yielded best risk stratification (RR 11.6, 10.4 12.7). CONCLUSIONS: * GS remains one of the most important prognostic factors in prostate cancer. However, the refined guidelines by ISUP 2005 might have shifted the threshold between low-grade and high-grade cancers from GS 6 vs 7 to GS 3 + 4 vs 4 + 3. * PNI is an independent prognostic marker superior to cT. * Ki-67 is the most useful biomarker in detecting patients with GS = 7 at high risk for progression. PMID- 21592299 TI - Feasibility of optical coherence tomography imaging to characterize renal neoplasms: limitations in resolution and depth of penetration. AB - What's known on the subject? and What does the study add? Optical coherence tomography has been used for the diagnosis of retinal disease and has been used experimentally for imaging of vascular plaques, gastrointestinal pathology, bladder cancer, prostate cancer, and recently to examine benign kidney microanatomy. It has not been previously used to image kidney cancer. This study presents the first data on the utility of OCT in the imaging for renal neoplasms. It found that OCT was most successful in distinguishing AML and TCC from normal parenchyma. OCT had more limited success at differentiating oncocytoma. Clear cell tumors and other renal cancer subtypes had a more heterogenous appearance, precluding reliable identification using OCT. The study shows that higher resolution versions of OCT, such as OCM, will be needed to allow optical coherence imaging to reach clinical utility in the assessment of renal neoplasms. OBJECTIVES: * To determine the appearance of normal and neoplastic renal tissue when imaged with optical coherence tomography (OCT). * To preliminarily assess the feasibility of using OCT to differentiate normal and neoplastic renal tissue. PATIENTS AND METHODS: * After radical or partial nephrectomy in 20 subjects, normal renal parenchyma and neoplastic tissue samples were obtained. * The tissue was evaluated with light microscopy and using a bench-top laboratory OCT system with a lateral resolution of 10 um. * OCT images were compared with histological slides to evaluate the ability of OCT to differentiate renal neoplasms. RESULTS: * Pathological subtypes included eight clear-cell, three papillary and two chromophobe renal carcinomas; two oncocytomas; one angiomyolipoma (AML); two transitional cell carcinomas (TCCs); and one haematoma. * Using OCT, benign renal parenchyma showed recognizable glomeruli and tubules. * TCC had a distinctive appearance on OCT whereas AML showed a unique identifiable signature because of its fat content. Oncocytomas had a lobulated appearance, which appeared subtly different from renal carcinoma. * Renal carcinoma lacked recognizable anatomical elements and had a heterogeneous appearance making differentiation from normal parenchyma at times difficult. * Subtypes of renal cancer appeared to vary on OCT imaging although discrimination was unreliable. CONCLUSIONS: * OCT imaging for renal neoplasms was most successful in distinguishing AML and TCC from normal parenchyma and malignant tumours. Oncocytoma differed subtly from renal carcinoma, making distinction more challenging. * Clear-cell tumours and other renal carcinoma subtypes had a heterogeneous appearance on OCT, which precluded reliable differentiation from normal parenchyma and between renal carcinoma subtypes. * Higher resolution versions of optical coherence imaging, such as optical coherence microscopy, will be necessary to achieve clinical utility. PMID- 21592300 TI - Changing patterns of bladder cancer in the USA: evidence of heterogeneous disease. AB - OBJECTIVE: To test the hypothesis that bladder cancer is a heterogeneous disease. PATIENTS AND METHODS: We examined the temporal trends of bladder cancer by histological subtype and by disease stage and grade using the National Cancer Institute's Surveillance, Epidemiology, and End Results data collected in 1973 2007. RESULTS: The age-adjusted incidence rates of bladder cancer showed a slight decrease from 1973 to 2007 (annual percentage change [APC] = -0.4, P < 0.05). Although the age-adjusted incidence rates of non-papillary transitional cell carcinoma decreased by about 53% from 7.9 per 100,000 in 1973 to 3.7 per 100,000 in 2007 (APC = -2.2, P < 0.05), the age-adjusted incidence rates of papillary transitional cell carcinoma increased by about 56% from 6.8 per 100,000 in 1973 to 10.6 per 100,000 in 2007 (APC = 0.5, P < 0.05). Among other rare histological subtypes, except for small cell carcinoma which showed a slightly rising trend, squamous cell carcinoma, adenocarcinoma and others all presented a decreasing trend. Similar patterns were found for different stages (localized, regional and distant), but a dramatic increasing trend of grade IV was found between 1998 and 2007 when a corresponding decreasing trend was shown for grades I, II and III. CONCLUSION: The results support the hypothesis that bladder cancer is a heterogeneous disease and taking disease heterogeneity into consideration in future epidemiological studies is essential. PMID- 21592301 TI - Role of combination of L-arginine and alpha-tocopherol in renal transplantation ischaemia/reperfusion injury: a randomized controlled experimental study in a rat model. AB - What's known on the subject? and What does the study add? Renal ischaemia/reperfusion (I/R) injury is an inevitable consequence of kidney transplantation. It contributes to delayed graft function (DGF), acute renal failure and graft rejection. The present study investigates for the first time the impact of a combination of L-arginine and alpha tocopherol on the renal ischemia/reperfusion injury in a rodent model of kidney transplantation. We found that concomitant administration of L-arginine and alpha-tocopherol has a more protective effect and synergistic antioxidant effect on ischaemia/reperfusion injury in transplanted rat kidneys. OBJECTIVES: To investigate the role of L arginine and alpha-tocopherol in ischaemia/reperfusion injury in a kidney transplanted rat model. MATERIALS AND METHODS: In total, 40 male Sprague-Dawley rats subjected to renal transplantation received FK506 (tacrolimus) to overcome early acute rejection episodes. Animals were divided randomly into four groups (ten rats each). Group I were treated with FK506 (2 mg/kg/bw/day) and served as the control group. Group II were treated with L-arginine 300 mg/kg/bw. Group III were treated with alpha-tocopherol 30 mg/kg/bw. Group IV were treated with L arginine and alpha-tocopherol. Urine and blood samples were taken at 0 (before operation), 2, 7 and 14 days post-transplantation for estimation of urine sodium, creatinine, fractional excretion of sodium, serum creatinine, sodium and blood urea nitrogen. Histological examination and measurement of malondialdehyde in kidney tissues were also performed. RESULTS: Serum creatinine and blood urea nitrogen significantly decreased in L-arginine and alpha-tocopherol, as well as combination groups, compared to the control group. Malondialdehyde was significantly decreased in the combination group compared to L-arginine and alpha tocopherol alone. Histological examination of the control group showed that acute tubular necrosis was markedly decreased in transplanted kidneys treated with a combination of both L-arginine and alpha-tocopherol. CONCLUSIONS: Concomitant administration of l-arginine and alpha-tocopherol has a more protective effect and synergistic antioxidant effect on ischaemia/reperfusion injury in transplanted rat kidneys. PMID- 21592302 TI - Low temperature S(0) biomineralization at a supraglacial spring system in the Canadian High Arctic. AB - Elemental sulfur (S(0) ) is deposited each summer onto surface ice at Borup Fiord pass on Ellesmere Island, Canada, when high concentrations of aqueous H(2) S are discharged from a supraglacial spring system. 16S rRNA gene clone libraries generated from sulfur deposits were dominated by beta-Proteobacteria, particularly Ralstonia sp. Sulfur-cycling micro-organisms such as Thiomicrospira sp., and epsilon-Proteobacteria such as Sulfuricurvales and Sulfurovumales spp. were also abundant. Concurrent cultivation experiments isolated psychrophilic, sulfide-oxidizing consortia, which produce S(0) in opposing gradients of Na(2) S and oxygen. 16S rRNA gene analyses of sulfur precipitated in gradient tubes show stable sulfur-biomineralizing consortia dominated by Marinobacter sp. in association with Shewanella, Loktanella, Rubrobacter, Flavobacterium, and Sphingomonas spp. Organisms closely related to cultivars appear in environmental 16S rRNA clone libraries; none currently known to oxidize sulfide. Once consortia were simplified to Marinobacter and Flavobacteria spp. through dilution-to extinction and agar removal, sulfur biomineralization continued. Shewanella, Loktanella, Sphingomonas, and Devosia spp. were also isolated on heterotrophic media, but none produced S(0) alone when reintroduced to Na(2) S gradient tubes. Tubes inoculated with a Marinobacter and Shewanella spp. co-culture did show sulfur biomineralization, suggesting that Marinobacter may be the key sulfide oxidizer in laboratory experiments. Light, florescence and scanning electron microscopy of mineral aggregates produced in Marinobacter experiments revealed abundant cells, with filaments and sheaths variably mineralized with extracellular submicron sulfur grains; similar biomineralization was not observed in abiotic controls. Detailed characterization of mineral products associated with low temperature microbial sulfur-cycling may provide biosignatures relevant to future exploration of Europa and Mars. PMID- 21592303 TI - Coffee consumption and the risk of venous thromboembolism: the Tromso study. AB - BACKGROUND: Several studies have investigated the association between coffee consumption and cardiovascular disease, but little is known about coffee intake and the risk of venous thromboembolism (VTE). OBJECTIVE: The aim of this prospective cohort study was to investigate the association between coffee consumption and the risk of incident VTE in a general population. METHODS: Information about coffee consumption habits was obtained with a self-administered questionnaire in 26, 755 subjects, aged 25-97 years, who participated in the fourth survey of the Tromso study (1994-1995). Incident VTE events were registered until the end of follow-up, 1 September 2007. RESULTS: There were 462 incident VTE events (1.60 per 1000 person-years, 95% confidence interval [CI] 1.46-1.75) during a median of 12.5 years of follow-up. A daily consumption of three to four cups was borderline associated (hazard ratio [HR] 0.70; 95% CI 0.48 1.02) and a daily consumption of five to six cups (HR 0.67; 95% CI 0.45-0.97) was significantly associated with reduced risk of VTE as compared with coffee abstainers in multivariable analysis adjusted for age, sex, body mass index (BMI), smoking status, physical activity, diabetes, history of cardiovascular disease and cancer. Similar risk estimates were found for provoked and unprovoked VTE, and in sex-stratified analyses. CONCLUSION: Our findings suggest a possible U-shaped relationship between coffee consumption and VTE, and that moderate coffee consumption may be associated with a reduced risk of VTE. However, more studies are needed to establish whether moderate coffee consumption is inversely associated with the risk of VTE. PMID- 21592304 TI - Non-steroidal anti-inflammatory drug use and risk of venous thromboembolism. AB - BACKGROUND: The association between the use of non-selective non-steroidal anti inflammatory drugs (NSAIDs) or cyclooxygenase-2-selective inhibitors (COX2Is) and the risk of venous thromboembolism (VTE) remains unclear. OBJECTIVES: To examine this association. PATIENTS/METHODS: We conducted a population-based case-control study in northern Denmark (population of 1.7 million). Using the National Patient Registry, we identified patients with a first hospital VTE diagnosis during 1999 2006 (n = 8368) and their comorbidities. For each case, we selected 10 controls (n = 82, 218) matched by age and sex. From the prescription database, we ascertained the use of NSAIDs at the time of diagnosis (current use) or before (recent use), and comedications. Current use was further classified as new use (first-ever prescription redemption within 60 days before diagnosis date) or long term use. We used odds ratios from a logistic regression model to estimate incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: As compared with no use, the adjusted IRR associating current non-selective NSAID use with VTE was 2.51 (95% CI 2.29-2.76), and that for current COX2I use was 2.19 (95% CI 1.99-2.41). Recent users had substantially smaller increases than current users. The adjusted IRRs among long-term users were 2.06 for non-selective NSAIDs (95% CI 1.85-2.29) and 1.92 for COX2Is (95% CI 1.72-2.15). Similarly increased risks were found for unprovoked VTE (occurrence in the absence of pregnancy, cancer, major trauma, fracture or surgery within 3 months preceding the VTE), deep vein thrombosis, pulmonary embolism, and individual NSAIDs. CONCLUSIONS: The use of non-selective NSAIDs or COX2Is was associated with a two-fold or more increased risk of VTE. PMID- 21592305 TI - Molecular structures and functional relationships in clostridial neurotoxins. AB - The seven serotypes of Clostridium botulinum neurotoxins (A-G) are the deadliest poison known to humans. They share significant sequence homology and hence possess similar structure-function relationships. Botulinum neurotoxins (BoNT) act via a four-step mechanism, viz., binding and internalization to neuronal cells, translocation of the catalytic domain into the cytosol and finally cleavage of one of the three soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) causing blockage of neurotransmitter release leading to flaccid paralysis. Crystal structures of three holotoxins, BoNT/A, B and E, are available to date. Although the individual domains are remarkably similar, their domain organization is different. These structures have helped in correlating the structural and functional domains. This has led to the determination of structures of individual domains and combinations of them. Crystal structures of catalytic domains of all serotypes and several binding domains are now available. The catalytic domains are zinc endopeptidases and share significant sequence and structural homology. The active site architecture and the catalytic mechanism are similar although the binding mode of individual substrates may be different, dictating substrate specificity and peptide cleavage selectivity. Crystal structures of catalytic domains with substrate peptides provide clues to specificity and selectivity unique to BoNTs. Crystal structures of the receptor domain in complex with ganglioside or the protein receptor have provided information about the binding of botulinum neurotoxin to the neuronal cell. An overview of the structure-function relationship correlating the 3D structures with biochemical and biophysical data and how they can be used for structure based drug discovery is presented here. PMID- 21592306 TI - Modular metabolic control analysis of large responses in branched systems- application to aspartate metabolism. AB - Organisms subject to changing environmental conditions or experimental protocols show complex patterns of responses. The design principles behind these patterns are still poorly understood. Here, modular metabolic control analysis is developed to deal with large changes in branched pathways. Modular aggregation of the system dramatically reduces the number of explicit variables and modulation sites. Thus, the resulting number of control coefficients, which describe system responses, is small. Three properties determine the pattern for large changes in the variables: the values of infinitesimal control coefficients, the effect of large rate changes on the control coefficients and the range of rate changes preserving feasible intermediate concentrations. Importantly, this pattern gives information about the possibility of obtaining large variable changes by changing parameters inside the module, without the need to perform any parameter modulations. The framework is applied to a detailed model of Asp metabolism. The system is aggregated in one supply module, producing Thr from Asp (SM1), and two demand modules, incorporating Thr (DM2) and Ile (DM3) into protein. Their fluxes are: J(1), J(2), and J(3), respectively. The analysis shows similar high infinitesimal control coefficients of J(2) by the rates of SM1 and DM2 (C(v1)(J2) = 0.6 and C(v2)(J2) = 0.7, respectively). In addition, these coefficients present only moderate decreases when the rates of the corresponding modules are increased. However, the range of feasible rate changes in SM1 is narrow. Therefore, for large increases in J(2) to be obtained, DM2 must be modulated. Of the rich network of allosteric interactions present, only two groups of inhibitions generate the control pattern for large responses. PMID- 21592307 TI - Membrane protein integration into the endoplasmic reticulum. AB - Most integral membrane proteins are targeted, inserted and assembled in the endoplasmic reticulum membrane. The sequential and potentially overlapping events necessary for membrane protein integration take place at sites termed translocons, which comprise a specific set of membrane proteins acting in concert with ribosomes and, probably, molecular chaperones to ensure the success of the whole process. In this minireview, we summarize our current understanding of helical membrane protein integration at the endoplasmic reticulum, and highlight specific characteristics that affect the biogenesis of multispanning membrane proteins. PMID- 21592308 TI - Absence of adverse effects of oseltamivir on sleep: a double-blind, randomized study in healthy volunteers in Japan. AB - Influenza-associated neuropsychiatric symptoms include parasomnias such as sleepwalking which is a common sleep disturbance in childhood. Oseltamivir is a widely used antiviral drug for influenza. Recently, sleepwalking-like events have been reported in patients with influenza receiving oseltamivir. We investigated whether oseltamivir itself has effects on sleep. In this crossover study, healthy Japanese male volunteers were randomized into two treatment groups, each of which comprised two double-blind 4-day treatment periods. In the first period, group A received 75 mg oseltamivir (evening dose) on day 3, followed by 75 mg b.i.d. on day 4, and placebo in the second period. Group B received the same treatments, but in reverse order. Polysomnographic assessments were performed on all four nights of each treatment period. Pharmacokinetics were assessed during a 2-day open-label phase beginning on day 12. Thirty-one volunteers aged 20-24 years were enrolled. No volunteer had electroencephalographic abnormalities, and no abnormal behaviour was observed. Sleep parameters measured over the whole night and during early- and late sleep periods (first and last thirds of the night) were very similar for oseltamivir and placebo, although the amount of stage 2 sleep in the middle sleep period was slightly greater with oseltamivir. Pharmacokinetics for oseltamivir phosphate in groups A and B were very similar, but for oseltamivir carboxylate, AUC and C(max) values were higher in group B, probably because this group received oseltamivir on the evening of day 11. Oseltamivir was well tolerated. Oseltamivir did not produce clinically relevant changes on nocturnal polysomnographic variables in young Japanese men. PMID- 21592309 TI - Is electrical brain activity a reliable biomarker for opioid analgesia in the gut? AB - The effects of morphine on brain potentials after experimental gut pain have never been investigated. This study explored whether multi-channel-evoked brain potentials (EP) and corresponding dipole sources in the brain would reflect the effects of morphine on experimental oesophageal pain. In a crossover study, the effects of oral morphine (30 mg) or corresponding placebo on pain from electrical oesophageal stimulation were tested in 12 healthy male volunteers. The electroencephalographic (EEG) activity was monitored with 64 surface recordings. Pain was assessed by subjective scores on a visual analogue scale, amplitude and latency of the vertex-EP as well as on multi-channel recordings of EPs. Finally, electrical brain sources after pain stimuli were modelled from the EEG data. Morphine attenuated subjective pain scores (p = 0.008). The amplitude of the P2 peak (230 msec. post-stimulus) in the vertex EPs was unaltered after treatment with morphine, whereas after placebo treatment, it decreased (p = 0.03). However, the overall topography changed and the source of P1 (100 msec. post-stimulus), possibly originating from areas near the cingulate gyrus, changed localization in an upward, posterior direction (p = 0.04). The length of the vector describing this shift correlated inversely with the magnitude of the subjective pain relief (r = -0.7; p = 0.02). With the potential of becoming a useful biomarker in analgesic trials, the localization of the dipole sources reflected the analgesic action of morphine after pain stimuli of the gut. Even though further evaluation of the method is necessary, it has the potential to be a valid objective biomarker for opioid analgesia. PMID- 21592310 TI - Kakusan4 and Aminosan: two programs for comparing nonpartitioned, proportional and separate models for combined molecular phylogenetic analyses of multilocus sequence data. AB - Proportional and separate models able to apply different combination of substitution rate matrix (SRM) and among-site rate variation model (ASRVM) to each locus are frequently used in phylogenetic studies of multilocus data. A proportional model assumes that branch lengths are proportional among partitions and a separate model assumes that each partition has an independent set of branch lengths. However, the selection from among nonpartitioned (i.e., a common combination of models is applied to all-loci concatenated sequences), proportional and separate models is usually based on the researcher's preference rather than on any information criteria. This study describes two programs, 'Kakusan4' (for DNA sequences) and 'Aminosan' (for amino-acid sequences), which allow the selection of evolutionary models based on several types of information criteria. The programs can handle both multilocus and single-locus data, in addition to providing an easy-to-use wizard interface and a noninteractive command line interface. In the case of multilocus data, SRMs and ASRVMs are compared at each locus and at all-loci concatenated sequences, after which nonpartitioned, proportional and separate models are compared based on information criteria. The programs also provide model configuration files for mrbayes, paup*, phyml, raxml and Treefinder to support further phylogenetic analysis using a selected model. When likelihoods are optimized by Treefinder, the best-fit models were found to differ depending on the data set. Furthermore, differences in the information criteria among nonpartitioned, proportional and separate models were much larger than those among the nonpartitioned models. These findings suggest that selecting from nonpartitioned, proportional and separate models results in a better phylogenetic tree. Kakusan4 and Aminosan are available at http://www.fifthdimension.jp/. They are licensed under gnugpl Ver.2, and are able to run on Windows, MacOS X and Linux. PMID- 21592311 TI - Molecular profiling of diatom assemblages in tropical lake sediments using taxon specific PCR and Denaturing High-Performance Liquid Chromatography (PCR-DHPLC). AB - Here we present a protocol to genetically detect diatoms in sediments of the Kenyan tropical Lake Naivasha, based on taxon-specific PCR amplification of short fragments (approximately 100 bp) of the small subunit ribosomal (SSU) gene and subsequent separation of species-specific PCR products by PCR-based denaturing high-performance liquid chromatography (DHPLC). An evaluation of amplicons differing in primer specificity to diatoms and length of the fragments amplified demonstrated that the number of different diatom sequence types detected after cloning of the PCR products critically depended on the specificity of the primers to diatoms and the length of the amplified fragments whereby shorter fragments yielded more species of diatoms. The DHPLC was able to discriminate between very short amplicons based on the sequence difference, even if the fragments were of identical length and if the amplicons differed only in a small number of nucleotides. Generally, the method identified the dominant sequence types from mixed amplifications. A comparison with microscopic analysis of the sediment samples revealed that the sequence types identified in the molecular assessment corresponded well with the most dominant species. In summary, the PCR-based DHPLC protocol offers a fast, reliable and cost-efficient possibility to study DNA from sediments and other environmental samples with unknown organismic content, even for very short DNA fragments. PMID- 21592312 TI - Field guide to next-generation DNA sequencers. AB - The diversity of available 2(nd) and 3(rd) generation DNA sequencing platforms is increasing rapidly. Costs for these systems range from < $100,000 to more than $1,000,000, with instrument run times ranging from minutes to weeks. Extensive trade-offs exist among these platforms. I summarize the major characteristics of each commercially available platform to enable direct comparisons. In terms of cost per megabase (Mb) of sequence, the Illumina and SOLiD platforms are clearly superior (<= $0.10/Mb vs. > $10/Mb for 454 and some Ion Torrent chips). In terms of cost per nonmultiplexed sample and instrument run time, the Pacific Biosciences and Ion Torrent platforms excel, with the 454 GS Junior and Illumina MiSeq also notable in this regard. All platforms allow multiplexing of samples, but details of library preparation, experimental design and data analysis can constrain the options. The wide range of characteristics among available platforms provides opportunities both to conduct groundbreaking studies and to waste money on scales that were previously infeasible. Thus, careful thought about the desired characteristics of these systems is warranted before purchasing or using any of them. Updated information from this guide will be maintained at: http://dna.uga.edu/ and http://tomato.biol.trinity.edu/blog/. PMID- 21592313 TI - Identifying the true oysters (Bivalvia: Ostreidae) with mitochondrial phylogeny and distance-based DNA barcoding. AB - Oysters (family Ostreidae), with high levels of phenotypic plasticity and wide geographic distribution, are a challenging group for taxonomists and phylogenetics. As a useful tool for molecular species identification, DNA barcoding might offer significant potential for oyster identification and taxonomy. This study used two mitochondrial fragments, cytochrome c oxidase I (COI) and the large ribosomal subunit (16S rDNA), to assess whether oyster species could be identified by phylogeny and distance-based DNA barcoding techniques. Relationships among species were estimated by the phylogenetic analyses of both genes, and then pairwise inter- and intraspecific genetic divergences were assessed. Species forming well-differentiated clades in the molecular phylogenies were identical for both genes even when the closely related species were included. Intraspecific variability of 16S rDNA overlapped with interspecific divergence. However, average intra- and interspecific genetic divergences for COI were 0-1.4% (maximum 2.2%) and 2.6-32.2% (minimum 2.2%), respectively, indicating the existence of a barcoding gap. These results confirm the efficacy of species identification in oysters via DNA barcodes and phylogenetic analysis. PMID- 21592314 TI - Analysing recombination in nucleotide sequences. AB - Throughout the living world, genetic recombination and nucleotide substitution are the primary processes that create the genetic variation upon which natural selection acts. Just as analyses of substitution patterns can reveal a great deal about evolution, so too can analyses of recombination. Evidence of genetic recombination within the genomes of apparently asexual species can equate with evidence of cryptic sexuality. In sexually reproducing species, nonrandom patterns of sequence exchange can provide direct evidence of population subdivisions that prevent certain individuals from mating. Although an interesting topic in its own right, an important reason for analysing recombination is to account for its potentially disruptive influences on various phylogenetic-based molecular evolution analyses. Specifically, the evolutionary histories of recombinant sequences cannot be accurately described by standard bifurcating phylogenetic trees. Taking recombination into account can therefore be pivotal to the success of selection, molecular clock and various other analyses that require adequate modelling of shared ancestry and draw increased power from accurately inferred phylogenetic trees. Here, we review various computational approaches to studying recombination and provide guidelines both on how to gain insights into this important evolutionary process and on how it can be properly accounted for during molecular evolution studies. PMID- 21592315 TI - Rapid development and screening of microsatellite loci for Artibeus lituratus and their utility for six related species within Phyllostomidae. AB - Microsatellites are often the marker of choice for population genetic studies at intermediate spatial and temporal scales. Developing large numbers of markers has traditionally been technically difficult, and this has limited our ability to investigate evolutionary phenomena that emerge across short temporal scales. Moreover, few markers tend to successfully amplify across species boundaries. As rapid advancements in high-throughput sequencing make microsatellite development cost- and time-effective, new avenues for evolutionary, population genetic and chromosome linkage mapping research are emerging. We used a published PERL script and second-generation sequencing to rapidly and affordably develop microsatellite loci for a widespread phyllostomid bat, Artibeus lituratus, for which no markers were previously available. We used Roche FLX (Titanium) Genome Sequencing to randomly sequence ~101 Mb (255,065 unique reads) of genomic DNA for A. lituratus, within which we discovered 30,100 microsatellite loci. We designed primers for 19,395 loci that contained suitable flanking regions. We ordered primers for 96 loci, 90 of which produced a single PCR product in A. lituratus. We genotyped 52 loci, and 45 were polymorphic in A. lituratus. We tested cross-species amplification for 96 loci in six additional phyllostomid species: A. planirostris, A. fimbriatus, A. phaeotis, Enchisthenes hartii, Sturnira lilium, and Carollia perspicillata. Cross-species amplification was successful for at least one species for 87 loci (A. fimbriatus), and in all species, at least 66 loci were amplified. These markers will not only facilitate future work on these seven species, but also illustrate the utility of this high-throughput method for development of primers across many species simultaneously. PMID- 21592317 TI - Melanoma researchers have a reason to GRIN: melanoma yields more of its secrets to exome sequencing. PMID- 21592316 TI - Effective inhibition of melanoma by BI-69A11 is mediated by dual targeting of the AKT and NF-kappaB pathways. AB - In melanoma, the activation of pro-survival signaling pathways, such as the AKT and NF-kappaB pathways, is critical for tumor growth. We have recently reported that the AKT inhibitor BI-69A11 causes efficient inhibition of melanoma growth. Here, we show that in addition to its AKT inhibitory activity, BI-69A11 also targets the NF-kappaB pathway. In melanoma cell lines, BI-69A11 inhibited TNF alpha-stimulated IKKalpha/beta and IkappaB phosphorylation as well as NF-kappaB reporter gene expression. Furthermore, the effective inhibition of melanoma growth by BI-69A11 was attenuated upon NF-kappaB activation. Mechanistically, reduced NF-kappaB signaling by BI-69-A11 is mediated by the inhibition of sphingosine kinase 1, identified in a screen of 315 kinases. Significantly, we demonstrate that BI-69A11 is well tolerated and orally active against UACC 903 and SW1 melanoma xenografts. Our results demonstrate that BI-69A11 inhibits both the AKT and the NF-kappaB pathways and that the dual targeting of these pathways may be efficacious as a therapeutic strategy in melanoma. PMID- 21592318 TI - Suppression of alpha5 gene expression is closely related to the tumorigenic properties of uveal melanoma cell lines. AB - Cancer aggressiveness is related to the ability of cancer cells to escape the anchorage dependency toward the extracellular matrix, a process regulated by the integrin alpha5beta1 and its ligand fibronectin. Here, we characterized the expression of the alpha5 gene in human uveal melanoma cell lines with distinct tumorigenic properties and investigated some of the mechanisms underlying the variations of their malignancy. Strong and weak expression of alpha5 was observed in cells with no (T108/T115) and high (T97/T98) tumorigenic properties, respectively. Expression and DNA binding of the transcription factors Sp1, activator protein 1 (AP-1) (both acting as activators), and nuclear factor I (NFI) (a strong repressor) to the alpha5 promoter were demonstrated in all cell lines. A reduced expression of AP-1 combined with a dramatic increase in NFI correlated with the suppression of alpha5 expression in T97 and T98 cells. Restoring alpha5 expression in T97 cells entirely abolished their tumorigenicity in immunodeficient mice. These uveal melanoma cell lines might therefore prove particularly useful as cellular models to investigate alpha5beta1 function in the pathogenesis of invasive uveal melanoma. PMID- 21592319 TI - Test-retest reliability during fear acquisition and fear extinction in humans. AB - AIMS: Classical fear conditioning and extinction has been used to understand the neurobiology of fear learning and its inhibition. The recall of an extinction memory involves the ventromedial prefrontal cortex and the amygdala, and patients with posttraumatic stress disorder (PTSD) have been shown to exhibit deficits in this process. Furthermore, extinction forms the basis of exposure therapies commonly used to treat PTSD patients. It is possible that effective pharmacological and/or psychological treatment regimens could influence the activity of these regions, and thereby increase the ability to retain an extinction memory. However, to test this, a fear conditioning and extinction paradigm must demonstrate within-subject reproducibility over time. We, therefore, sought to test the within-subject reliability of a previously used 2 day, classical fear conditioning and extinction paradigm. METHODS: Eighteen healthy participants participated in a 2-day paradigm on three occasions, each separated by at least 12 weeks. Conditioning and extinction took place on Day 1, and extinction recall and fear renewal were evaluated on Day 2 on each of the three occasions. The conditioned stimulus was a visual cue and the unconditioned stimulus was a mild electric shock to the fingers. Skin conductance was recorded throughout the experiment to measure conditioned responses. RESULTS: We found that conditioning and extinction recall were not significantly different across time and were correlated within subjects. CONCLUSION: These data illustrate the reliability of this paradigm and its potential usefulness in evaluating the influence of a given treatment on the fear extinction network in longitudinal within-subject designs. PMID- 21592320 TI - Hallucinations in neurodegenerative diseases. AB - Patients with neurodegenerative disease frequently experience hallucinations and illusionary perceptions. As early symptoms, hallucinations may even have diagnostic relevance (i.e., for the diagnosis of Lewy Body Dementia). In the later course of the disease, hallucinations may appear as characteristic symptoms and often constitute a particular challenge for therapeutic endeavors. Here, the distinction of disease-inherent hallucinations from medication-associated perceptual disturbances is particularly relevant. Synucleinopathies and tauopathies have different risk profiles for hallucinations. In synucleinopathies hallucinations are much more frequent and phenomenology is characterized by visual, short-lived hallucinations, with insight preserved for a long time. A "double hit" theory proposes that dysfunctionality of both associative visual areas and changes of limbic areas or the ventral striatum are required. In contrast, in tauopathies the hallucinations are more rare and mostly embedded in confusional states with agitation and with poorly defined or rapidly changing paranoia. The occurrence of hallucinations has even been proposed as an exclusion criterion for tauopathies with Parkinsonian features such as progressive supranuclear palsy. To date, treatment remains largely empirical, except the use of clozapine and cholinesterase inhibitors in synucleinopathies, which is evidence-based. The risk of increased neuroleptic sensitivity further restricts the treatment options in patients with Lewy Body Dementia. Coping Strategies and improvement of visual acuity and sleep quality may be useful therapeutic complements. PMID- 21592321 TI - Zac1 plays a key role in the development of specific neuronal subsets in the mouse cerebellum. AB - BACKGROUND: The cerebellum is composed of a diverse array of neuronal subtypes. Here we have used a candidate approach to identify Zac1, a tumor suppressor gene encoding a zinc finger transcription factor, as a new player in the transcriptional network required for the development of a specific subset of cerebellar nuclei and a population of Golgi cells in the cerebellar cortex. RESULTS: We found that Zac1 has a complex expression profile in the developing cerebellum, including in two proliferating progenitor populations; the cerebellar ventricular zone and the external granular layer overlying posterior cerebellar lobules IX and X. Zac1 is also expressed in some postmitotic cerebellar neurons, including a subset of GABAergic interneurons in the medial cerebellar nuclei. Notably, GABAergic interneurons in the cerebellar nuclei are derived from the cerebellar ventricular zone, where Zac1 is also expressed, consistent with a lineage relationship between these two Zac1+ populations. Zac1 is also expressed in a small subset of cells in the posterior vermis, including some neurogranin immunoreactive (NG+) Golgi cells, which, based on short-term birthdating, are derived from the EGL, where Zac1 is also expressed. However, Zac1+ cells and NG+ Golgi cells in the cerebellar cortex also display unique properties, as they are generated within different, albeit overlapping, time windows. Finally, consistent with the expression profile of Zac1, two conspicuous abnormalities were found in the cerebellum of Zac1 null mice: the medial cerebellar nuclei, and not the others, were significantly reduced in size; and the number of Golgi cells in cerebellar lobule IX was reduced by approximately 60% compared to wild-type littermates. CONCLUSIONS: The data presented here indicate that the tumor suppressor gene Zac1 is expressed in a complex fashion in the developing cerebellum, including in two dividing progenitor populations and in specific subsets of postmitotic neurons, including Golgi cells and GABAergic neurons in the medial nuclei, which require Zac1 for their differentiation. We thus conclude that Zac1 is a critical regulator of normal cerebellar development, adding a new transcriptional regulator to the growing list of factors involved in generating neuronal diversity in the developing cerebellum. PMID- 21592323 TI - Array-based techniques for fingerprinting medicinal herbs. AB - Poor quality control of medicinal herbs has led to instances of toxicity, poisoning and even deaths. The fundamental step in quality control of herbal medicine is accurate identification of herbs. Array-based techniques have recently been adapted to authenticate or identify herbal plants. This article reviews the current array-based techniques, eg oligonucleotides microarrays, gene based probe microarrays, Suppression Subtractive Hybridization (SSH)-based arrays, Diversity Array Technology (DArT) and Subtracted Diversity Array (SDA). We further compare these techniques according to important parameters such as markers, polymorphism rates, restriction enzymes and sample type. The applicability of the array-based methods for fingerprinting depends on the availability of genomics and genetics of the species to be fingerprinted. For the species with few genome sequence information but high polymorphism rates, SDA techniques are particularly recommended because they require less labour and lower material cost. PMID- 21592322 TI - Do hospitalist physicians improve the quality of inpatient care delivery? A systematic review of process, efficiency and outcome measures. AB - BACKGROUND: Despite more than a decade of research on hospitalists and their performance, disagreement still exists regarding whether and how hospital-based physicians improve the quality of inpatient care delivery. This systematic review summarizes the findings from 65 comparative evaluations to determine whether hospitalists provide a higher quality of inpatient care relative to traditional inpatient physicians who maintain hospital privileges with concurrent outpatient practices. METHODS: Articles on hospitalist performance published between January 1996 and December 2010 were identified through MEDLINE, Embase, Science Citation Index, CINAHL, NHS Economic Evaluation Database and a hand-search of reference lists, key journals and editorials. Comparative evaluations presenting original, quantitative data on processes, efficiency or clinical outcome measures of care between hospitalists, community-based physicians and traditional academic attending physicians were included (n = 65). After proposing a conceptual framework for evaluating inpatient physician performance, major findings on quality are summarized according to their percentage change, direction and statistical significance. RESULTS: The majority of reviewed articles demonstrated that hospitalists are efficient providers of inpatient care on the basis of reductions in their patients' average length of stay (69%) and total hospital costs (70%); however, the clinical quality of hospitalist care appears to be comparable to that provided by their colleagues. The methodological quality of hospitalist evaluations remains a concern and has not improved over time. Persistent issues include insufficient reporting of source or sample populations (n = 30), patients lost to follow-up (n = 42) and estimates of effect or random variability (n = 35); inappropriate use of statistical tests (n = 55); and failure to adjust for established confounders (n = 37). CONCLUSIONS: Future research should include an expanded focus on the specific structures of care that differentiate hospitalists from other inpatient physician groups as well as the development of better conceptual and statistical models that identify and measure underlying mechanisms driving provider-outcome associations in quality. PMID- 21592324 TI - Impact of a multifaceted program to prevent postoperative delirium in the elderly: the CONFUCIUS stepped wedge protocol. AB - BACKGROUND: Postoperative delirium is common in the elderly and is associated with a significant increase in mortality, complications, length of hospital stay and admission in long care facility. Although several interventions have proved their effectiveness to prevent it, the Cochrane advises an assessment of multifaceted intervention using rigorous methodology based on randomized study design. Our purpose is to present the methodology and expected results of the CONFUCIUS trial, which aims to measure the impact of a multifaceted program on the prevention of postoperative delirium in elderly. METHOD/DESIGN: Study design is a stepped wedge cluster randomized trial within 3 surgical wards of three French university hospitals. All patients aged 75 and older, and admitted for scheduled surgery will be included. The multifaceted program will be conducted by mobile geriatric team, including geriatric preoperative consultation, training of the surgical staff and implementation of the Hospital Elder Life Program, and morbidity and mortality conference related to delirium cases. The primary outcome is based on postoperative delirium rate within 7 days after surgery. This program is planned to be implemented along four successive time periods within all the surgical wards. Each one will be affected successively to the control arm and to the intervention arm of the trial and the order of program introduction within each surgical ward will be randomly assigned. Based on a 20% reduction of postoperative delirium rate (ICC = 0.25, alpha = 0.05, beta = 0.1), three hundred sixty patients will be included i.e. thirty patients per service and per time period. Endpoints comparison between intervention and control arms of the trial will be performed by considering the cluster and time effects. DISCUSSION: Better prevention of delirium is expected from the multifaceted program, including a decrease of postoperative delirium, and its consequences (mortality, morbidity, postoperative complications and length of hospital stay) among elderly patients. This study should allow better diagnosis of delirium and strengthen the collaboration between surgical and mobile geriatric teams. Should the program have a substantial impact on the prevention of postoperative delirium in elderly, it could be extended to other facilities. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01316965. PMID- 21592325 TI - MicroRNA expression in multiple myeloma is associated with genetic subtype, isotype and survival. AB - BACKGROUND: MicroRNAs are small RNA species that regulate gene expression post transcriptionally and are aberrantly expressed in many cancers including hematological malignancies. However, the role of microRNAs in the pathogenesis of multiple myeloma (MM) is only poorly understood. We therefore used microarray analysis to elucidate the complete miRNome (miRBase version 13.0) of purified tumor (CD138+) cells from 33 patients with MM, 5 patients with monoclonal gammopathy of undetermined significance (MGUS) and 9 controls. RESULTS: Unsupervised cluster analysis revealed that MM and MGUS samples have a distinct microRNA expression profile from control CD138+ cells. The majority of microRNAs aberrantly expressed in MM (109/129) were up-regulated. A comparison of these microRNAs with those aberrantly expressed in other B-cell and T-cell malignancies revealed a surprising degree of similarity (~40%) suggesting the existence of a common lymphoma microRNA signature. We identified 39 microRNAs associated with the pre-malignant condition MGUS. Twenty-three (59%) of these were also aberrantly expressed in MM suggesting common microRNA expression events in MM progression. MM is characterized by multiple chromosomal abnormalities of varying prognostic significance. We identified specific microRNA signatures associated with the most common IgH translocations (t(4;14) and t(11;14)) and del(13q). Expression levels of these microRNAs were distinct between the genetic subtypes (by cluster analysis) and correctly predicted these abnormalities in > 85% of cases using the support vector machine algorithm. Additionally, we identified microRNAs associated with light chain only myeloma, as well as IgG and IgA-type MM. Finally, we identified 32 microRNAs associated with event-free survival (EFS) in MM, ten of which were significant by univariate (logrank) survival analysis. CONCLUSIONS: In summary, this work has identified aberrantly expressed microRNAs associated with the diagnosis, pathogenesis and prognosis of MM, data which will prove an invaluable resource for understanding the role of microRNAs in this devastating disease. PMID- 21592326 TI - In vitro-generated interspecific recombinants between bovine herpesviruses 1 and 5 show attenuated replication characteristics and establish latency in the natural host. AB - BACKGROUND: Interspecific recombinant viruses R1DeltagC and R2DeltagI were isolated after in vitro co-infection with BoHV-1 and BoHV-5, two closely related alphaherpesviruses that infect cattle. The genetic characterization of R1DeltagC and R2DeltagI showed that they are composed of different sections of the parental genomes. The aim of this study was the characterization of the in vivo behavior of these recombinants in the natural host. RESULTS: Four groups of four 3-month old calves of both genders were intranasally inoculated with either the recombinant or parental viruses. A control group of two animals was also included. Viral excretion and clinical signs were monitored after infection. Histopathological examination of the central nervous system (CNS) was performed and the establishment of latency in trigeminal ganglia was analyzed by PCR. The humoral response was also evaluated using ELISA tests. Three out of four animals from the BoHV-5 infected group excreted virus for 4-10 days. Two calves shed R1DeltagC virus for one day. In R2DeltagI and BoHV-1.2DeltagCDeltagI groups, infectious virus was isolated only after two or three blind passages. None of the infected animals developed neurological signs, although those infected with BoHV 5 showed histopathological evidence of viral infection. Latent viral DNA was detected in at least one calf from each infected group. Serum and/or mucosal antibodies were detected in all groups. CONCLUSION: Both BoHV-1/-5 recombinants and the BoHV-1 parental strain are attenuated in calves, although they are able to replicate in animals at low rates and to establish latent infections. PMID- 21592327 TI - The casualty chain inventory: a new scale for measuring peritraumatic responses: a cross-sectional study. AB - BACKGROUND: Peritraumatic psychological- and sensory impressions in victims of civilian accidents are only partly understood. This study scrutinizes the level and duration of perceived psychological threat at scene of injury as well as in hospital (the casualty chain) measured by the Casualty Chain Inventory (CCI). The purpose of the study was to assess and validate the CCI, and to examine the correlations between the new instrument and stress responses measured by the Impact of Event Scale (IES) and the Post-traumatic Stress Scale-10 (PTSS-10) METHODS: Three hundred and fifteen injured, conscious, hospitalised patients were assessed with a self-report questionnaire. The CCI consists of eight items including sensory impressions and well-known psychological responses to trauma. RESULTS: The internal consistency of the CCI was solid (Cronbach's alpha: .83 .85). A factor analysis revealed two components, "perception" and "dissociation". The instrument correlates significantly with the Impact of Event Scale (r = 0.47 0.54) and the Posttraumatic Stress Scale-10 (r = 0.32 - 0.50). The explained variance is high both at the scene of injury (61%) and in the hospital (65%). Dissociation and perception either used as a two-factor solution or as a sum score measured in the hospital, gave the strongest prediction for later psychological distress. CONCLUSIONS: The CCI appears to be a useful screening instrument for, at an early state, identifying patients hospitalized after a physical incident at risk for subsequent psychological distress. PMID- 21592328 TI - The influence of both individual and area based socioeconomic status on temporal trends in Caesarean sections in Scotland 1980-2000. AB - BACKGROUND: Caesarean section rates have risen over the last 20 years. Elective Caesarean section rates have been shown to be linked to area deprivation in England, women in the most deprived areas were less likely to have an elective section than those in the most affluent areas. We examine whether individual social class, area deprivation or both are related to Caesarean sections in Scotland and investigate changes over time. METHODS: Routine maternity discharge data from live singleton births in Scottish hospitals from three time periods were used; 1980-81 (n = 133,555), 1990-91 (n = 128,933) and 1999-2000 (n = 102,285). Multilevel logistic regression, with 3 levels (births, postcode sector and Health Board) was used to analyse emergency and elective Caesareans separately; analysis was further stratified by previous Caesarean section. The relative index of inequality (RII) was used to assess socioeconomic inequalities. RESULTS: Between 1980-81 and 1999-2000 the emergency section rate increased from 6.3% to 11.9% and the elective rate from 3.6% to 5.5%. In 1980-81 and 1990-91 emergency Caesareans were more likely among women at the bottom of the social class hierarchy compared to those at the top (RII = 1.14, 95%CI 1.00-1.25 and RII = 1.13, 1.03-1.23 respectively) and also among women in the most deprived areas compared to those in the most affluent (RII = 1.18, 1.05-1.32 and RII = 1.13, 1.02-1.26 respectively). In 1999-2000 the odds of an elective section were lower for women at the bottom of the social class hierarchy than those at the top (RII = 0.87, 0.76-1.00) and also lower in women in the most deprived areas compared to those in the most affluent (RII = 0.85, 0.73-0.99). CONCLUSIONS: Both individual social class and area deprivation are independently associated with Caesarean sections in Scotland. The tendency for disadvantaged women to be more likely to receive emergency sections disappeared at the same time as the likelihood of advantaged groups receiving elective sections increased. PMID- 21592329 TI - MU-Slide Chemotaxis: a new chamber for long-term chemotaxis studies. AB - BACKGROUND: Effective tools for measurement of chemotaxis are desirable since cell migration towards given stimuli plays a crucial role in tumour metastasis, angiogenesis, inflammation, and wound healing. As for now, the Boyden chamber assay is the longstanding "gold-standard" for in vitro chemotaxis measurements. However, support for live cell microscopy is weak, concentration gradients are rather steep and poorly defined, and chemotaxis cannot be distinguished from migration in a single experiment. RESULTS: Here, we describe a novel all-in-one chamber system for long-term analysis of chemotaxis in vitro that improves upon many of the shortcomings of the Boyden chamber assay. This chemotaxis chamber was developed to provide high quality microscopy, linear concentration gradients, support for long-term assays, and observation of slowly migrating cells via video microscopy. AlexaFluor 488 dye was used to demonstrate the establishment, shape and time development of linear chemical gradients. Human fibrosarcoma cell line HT1080 and freshly isolated human umbilical vein endothelial cells (HUVEC) were used to assess chemotaxis towards 10% fetal calf serum (FCS) and FaDu cells' supernatant. Time-lapse video microscopy was conducted for 48 hours, and cell tracking and analysis was performed using ImageJ plugins. The results disclosed a linear steady-state gradient that was reached after approximately 8 hours and remained stable for at least 48 hours. Both cell types were chemotactically active and cell movement as well as cell-to-cell interaction was assessable. CONCLUSIONS: Compared to the Boyden chamber assay, this innovative system allows for the generation of a stable gradient for a much longer time period as well as for the tracking of cell locomotion along this gradient and over long distances. Finally, random migration can be distinguished from primed and directed migration along chemotactic gradients in the same experiment, a feature, which can be qualified via cell morphology imaging. PMID- 21592330 TI - Cyclooxygenase 2-dependent and independent activation of Akt through casein kinase 2alpha contributes to human bladder cancer cell survival. AB - BACKGROUND: Survival rate for patients presenting muscle invasive bladder cancer is very low, and useful therapeutic target has not been identified yet. In the present study, new COX2 downstream signals involved in urothelial carcinoma cell survival were investigated in vitro and in vivo. METHODS: COX2 gene was silenced by siRNA transfection. Orthotopic implantation animal model and transurethral instillation of siRNA with atelocollagen was constructed to examine the effects of COX2 knockdown in vivo. Cell cycle was examined by flowcytoketry. Surgical specimens derived from patients with urinary bladder cancer (all were initially diagnosed cases) were used for immunohistochemical analysis of the indicated protein expression in urothelial carcinoma cells. RESULTS: Treatment with the COX2 inhibitor or knockdown of COX2 reduced expression of casein kinase (CK) 2 alpha, a phophorylated Akt and urokinase type plasminogen activator (uPA), resulting in p27 induction, cell cycle arrest at G1 phase and cell growth suppression in human urothelial carcinoma cell lines expressing COX2. Silencing of CK2alpha exhibited the similar effects. Even in UMUC3 cells lacking the COX2 gene, COX2 inhibition also inhibited cell growth through down-regulation of the CK2alpha-Akt/uPA axis. The mouse orthotropic bladder cancer model demonstrated that the COX2 inhibitor, meloxicam significantly reduced CK2alpha, phosphorylated Akt and uPA expression, whereas induced p27 by which growth and invasiveness of bladder cancer cells were strongly inhibited. Immunohistochemically, high expression of COX2, CK2alpha and phosphorylated form of Akt was found in high grade, invasive carcinomas as well as carcinoma in situ, but not in low-grade and noninvasive phenotypes. CONCLUSIONS: COX2-dependent and independent activation of CK2alpha-Akt/uPA signal is mainly involved in urothelial carcinoma cell survival, moreover, not only COX2 but also CK2alpha could be direct targets of COX2 inhibitors. PMID- 21592331 TI - There is no age limit for methadone: a retrospective cohort study. AB - BACKGROUND: Data from the US indicates that methadone-maintained populations are aging, with an increase of patients aged 50 or older. Data from European methadone populations is sparse. This retrospective cohort study sought to evaluate the age trends and related developments in the methadone population of Basel-City, Switzerland. METHODS: The study included methadone patients between April 1, 1995 and March 31, 2003. Anonymized data was taken from the methadone register of Basel-City. For analysis of age distributions, patient samples were split into four age categories from '20-29 years' to '50 years and over'. Cross sectional comparisons were performed using patient samples of 1996 and 2003. RESULTS: Analysis showed a significant increase in older patients between 1996 and 2003 (p < 0.001). During that period, the percentage of patients aged 50 and over rose almost tenfold, while the proportion of patients aged under 30 dropped significantly from 52.8% to 12.3%. The average methadone dose (p < 0.001) and the 1-year retention rate (p < 0.001) also increased significantly. CONCLUSIONS: Findings point to clear trends in aging of methadone patients in Basel-City which are comparable, although less pronounced, to developments among US methadone populations. Many unanswered questions on medical, psychosocial and health economic consequences remain as the needs of older patients have not yet been evaluated extensively. However, older methadone patients, just as any other patients, should be accorded treatment appropriate to their medical condition and needs. Particular attention should be paid to adequate solutions for persons in need of care. PMID- 21592332 TI - Heterogeneous decrease in malaria prevalence in children over a six-year period in south-western Uganda. AB - BACKGROUND: Malaria is a major public health problem, especially for children. However, recent reports suggest a decline in the malaria burden. The aim of this study was to assess the change in the prevalence of malaria infection among children below five years of age between 2004 and 2010 in a mesoendemic area of Uganda and to analyse the risk factors of malaria infection. METHODS: Two cross sectional surveys were conducted in 2004 and in 2010 at the end of the rainy and dry seasons to measure the prevalence of P. falciparum infection among children less than five years of age. Rapid diagnostic tests and blood smears were used to diagnose malaria infection. In 2010, sampling was stratified by urban and rural areas. In each selected household, knowledge of malaria and bed nets, and bed net ownership and use, were assessed. RESULTS: In 2004 and 2010, respectively, a total of 527 and 2,320 (999 in the urban area and 1,321 in rural areas) children less than five years old were enrolled. Prevalence of malaria infection declined from 43% (95% CI: 34-52) in 2004, to 23% (95% CI: 17-30) in rural areas in 2010 and 3% (95% CI: 2-5) in the urban area in 2010. From the rainy to dry season in 2010, prevalence decreased from 23% to 10% (95% CI: 6-14) in rural areas (P = 0.001) and remained stable from 3% to 4% (95% CI: 1-7) in the urban area (P = 0.9). The proportion of households reporting ownership and use of at least one bed net increased from 22.9% in 2004 to 64.7% in the urban area and 44.5% in rural areas in 2010 (P < 0.001). In 2010, the risk of malaria infection was consistently associated with child age and household wealth. In rural areas, malaria infection was also associated with geographic factors. CONCLUSIONS: This study reports a significant drop in the prevalence of malaria infection among children below five years of age, paralleled by an uptake in bed-net use. However, prevalence remains unacceptably high in rural areas and is strongly associated with poverty. PMID- 21592333 TI - Thermostable recombinant xylanases from Nonomuraea flexuosa and Thermoascus aurantiacus show distinct properties in the hydrolysis of xylans and pretreated wheat straw. AB - BACKGROUND: In the hydrolysis of lignocellulosic materials, thermostable enzymes decrease the amount of enzyme needed due to higher specific activity and elongate the hydrolysis time due to improved stability. For cost-efficient use of enzymes in large-scale industrial applications, high-level expression of enzymes in recombinant hosts is usually a prerequisite. The main aim of the present study was to compare the biochemical and hydrolytic properties of two thermostable recombinant glycosyl hydrolase families 10 and 11 (GH10 and GH11, respectively) xylanases with respect to their potential application in the hydrolysis of lignocellulosic substrates. RESULTS: The xylanases from Nonomuraea flexuosa (Nf Xyn11A) and from Thermoascus aurantiacus (Ta Xyn10A) were purified by heat treatment and gel permeation chromatography. Ta Xyn10A exhibited higher hydrolytic efficiency than Nf Xyn11A toward birchwood glucuronoxylan, insoluble oat spelt arabinoxylan and hydrothermally pretreated wheat straw, and it produced more reducing sugars. Oligosaccharides from xylobiose to xylopentaose as well as higher degree of polymerization (DP) xylooligosaccharides (XOSs), but not xylose, were released during the initial hydrolysis of xylans by Nf Xyn11A, indicating its potential for the production of XOS. The mode of action of Nf Xyn11A and Ta Xyn10A on glucuronoxylan and arabinoxylan showed typical production patterns of endoxylanases belonging to GH11 and GH10, respectively. CONCLUSIONS: Because of its high catalytic activity and good thermostability, T. aurantiacus xylanase shows great potential for applications aimed at total hydrolysis of lignocellulosic materials for platform sugars, whereas N. flexuosa xylanase shows more significant potential for the production of XOSs. PMID- 21592334 TI - Use and feasibility of delayed prescribing for respiratory tract infections: a questionnaire survey. AB - BACKGROUND: Delayed prescribing of antibiotics for respiratory tract infections (RTIs) lowers the amount of antibiotics consumed. Several national treatment guidelines on RTIs recommend the strategy. When advocating treatment innovations, the feasibility and credibility of the innovation must be taken into account. The objective of this study was to explore GPs use and patients uptake of wait-and see prescriptions for RTIs, and to investigate the feasibility of the strategy from GPs' and patients' perspectives. METHODS: Questionnaire survey among Norwegian GPs issuing and patients receiving a wait-and-see-prescription for RTIs. Patients reported symptoms, confidence and antibiotics consumption, GPs reported diagnoses, reason for issuing a wait-and-see-prescription and their opinion about the method. RESULTS: 304 response pairs from consultations with 49 GPs were received. The patient response rate was 80%. The most common diagnosis for the GPs to issue a wait-and-see prescription was sinusitis (33%) and otitis (21%). 46% of the patients reported to consume the antibiotics. When adjusted for other factors, the diagnosis did not predict antibiotic consumption, but both being 16 years or more (p = 0,006) and reporting to have a fever (p = 0,012) doubled the odds of antibiotic consumption, while feeling very ill more than quadrupled the odds (p = 0,002). In 210 cases (69%), the GP found delayed prescribing a very reasonable strategy, and 270 patients (89%) would prefer to receive a wait-and-see prescription in a similar situation in the future. The GPs found delayed prescribing very reasonable most frequently in cases of sinusitis (79%, p = 0,007) and least frequently in cases of lower RTIs (49%, p = 0,002). CONCLUSION: Most patients and GPs are satisfied with the delayed prescribing strategy. The patients' age, symptoms and malaise are more important than the diagnosis in predicting antibiotic consumption. The GP's view of the method as a reasonable approach depends on the patient's diagnosis. In our setting, delayed prescribing seems to be a feasible strategy, especially in cases of sinusitis and otitis. Educational efforts to promote delayed prescribing in similar settings should focus on these diagnoses. PMID- 21592335 TI - Explicit and implicit information needs of people with depression: a qualitative investigation of problems reported on an online depression support forum. AB - BACKGROUND: Health management is impeded when consumers do not possess adequate knowledge about their illness. At a public health level, consumer knowledge about depression is particularly important because depression is highly prevalent and causes substantial disability and burden. However, currently little is known about the information needs of people with depression. This study aimed to investigate the explicit and implicit information needs of users of an online depression support forum. METHODS: A sample of 2680 posts was systematically selected from three discussion forums on an online depression bulletin board (blueboard.anu.edu.au). Data were examined for evidence of requests for information (reflecting explicit needs) and reports of past or current problems (implicit needs). Thematic analysis was conducted using a data-driven inductive approach with the assistance of NVivo 7, and instances of questions and people reporting particular types of problems were recorded. RESULTS: A total of 134 participants with personal experience of depression contributed to the data analysed. Six broad themes represented participant queries and reported problems: Understanding depression; disclosure and stigma; medication; treatment and services; coping with depression; and comorbid health problems. A variety of specific needs were evident within these broad thematic areas. Some people (n = 46) expressed their information needs by asking direct questions (47 queries) but the majority of needs were expressed implicitly (351 problems) by the 134 participants. The most evident need for information related to coping with depression and its consequences, followed by topics associated with medication, treatment and services. CONCLUSIONS: People with depression have substantial unmet information needs and require strategies to deal with the difficulties they face. They require access to high quality and relevant online resources and professionals; thus, there is a need to rectify current gaps in the provision of information and limitations of dissemination. Greater knowledge about depression and its treatment is also needed at the general community level. PMID- 21592336 TI - The patient perspective in research on major depression. AB - Although thousands of studies have examined the genetics, epidemiology, etiology, biology, treatment and prevention of major depressive disorder, we still lack very basic knowledge about what patients with depressive disorders need. Despite the thousands of studies that have been conducted on major depression and the hundreds of randomized trials that have examined the effects of treatments, many patients still do not know how to cope with the daily problems caused by depressive disorders. In this Commentary the need for more research on the perspectives of patients is described. This research should guide treatment studies as well as basic research much more than it currently does. This perpective is especially important to understand and solve the undertreatment of depression, one of the major problems in this area. Up to 50% of depressed patients do not seek treatment, resulting in huge avoidable disease burden and economic costs. In order to solve this problem we need a better understanding of the problems patients encounter in daily life, and what factors contribute to the reasons for seeking treatment or not. Research from the patients' perspective is also necessary to meet the currently unmet information needs of patients, including information about the nature and causes of depression, stigma, medication, treatment and coping with the daily problems of having depression. PMID- 21592338 TI - Factors associated with female genital mutilation in Burkina Faso and its policy implications. AB - BACKGROUND: Female genital mutilation (FGM) usually undertaken between the ages of 1-9 years and is widely practised in some part of Africa and by migrants from African countries in other parts of the world. Laws prohibit FGM in almost every country. FGM can cause immediate complications (pain, bleeding and infection) and delayed complications (sexual, obstetric, psychological problems). Several factors have been associated with an increased likelihood of FGM. In Burkina Faso, the prevalence of FGM appears to have increased in recent years. METHODS: We investigated social, demographic and economic factors associated with FGM in Burkina Faso using the 2003 Demographic Health Survey (DHS). The DHS is a nationally representative cross-sectional survey (multistage stratified random sampling of households) of women of reproductive age (15-49 years). Associations between potential risk factors and the prevalence of FGM were explored using chi2 and t-tests and Mann Whitney U-test as appropriate. Logistic regression modelling was used to investigate social, demographic and economic risk factors associated with FGM. MAIN OUTCOME MEASURES: i) whether a woman herself had had FGM; ii) whether she had one or more daughters with FGM. RESULTS: Data were available on 12,049 women. Response rates by region were at least 90%. Women interviewed were representative of the underlying populations of the different regions of Burkina Faso. Seventy seven percent (9267) of the women interviewed had had FGM. 7336 women had a daughter of whom 2216 (30.2%) had a daughter with FGM and 334 (4.5%) said that they intended that their daughter should have it. Univariate analysis showed that age, religion, wealth, ethnicity, literacy, years of education, household affluence, region and who had responsibility for health care decisions in the household had (RHCD) were all significantly related to the two outcomes (p < 0.01). Multivariate analysis stratified by religion mainly confirmed these findings, however, education is significantly associated with a reduced likelihood of FGM only for Christian women. CONCLUSIONS AND POLICY IMPLICATIONS: Factors associated with FGM are varied and complex. Younger women and those from specific groups and religions are less likely to have had FGM. A higher level of education may be protective for women from certain religions. Policies should capitalize on these findings and religious leaders should be involved in continuing programmes of action. PMID- 21592337 TI - Pitfalls in the statistical examination and interpretation of the correspondence between physician and patient satisfaction ratings and their relevance for shared decision making research. AB - BACKGROUND: The correspondence of satisfaction ratings between physicians and patients can be assessed on different dimensions. One may examine whether they differ between the two groups or focus on measures of association or agreement. The aim of our study was to evaluate methodological difficulties in calculating the correspondence between patient and physician satisfaction ratings and to show the relevance for shared decision making research. METHODS: We utilised a structured tool for cardiovascular prevention (arribaTM) in a pragmatic cluster randomised controlled trial. Correspondence between patient and physician satisfaction ratings after individual primary care consultations was assessed using the Patient Participation Scale (PPS). We used the Wilcoxon signed-rank test, the marginal homogeneity test, Kendall's tau-b, weighted kappa, percentage of agreement, and the Bland-Altman method to measure differences, associations, and agreement between physicians and patients. RESULTS: Statistical measures signal large differences between patient and physician satisfaction ratings with more favourable ratings provided by patients and a low correspondence regardless of group allocation. Closer examination of the raw data revealed a high ceiling effect of satisfaction ratings and only slight disagreement regarding the distributions of differences between physicians' and patients' ratings. CONCLUSIONS: Traditional statistical measures of association and agreement are not able to capture a clinically relevant appreciation of the physician-patient relationship by both parties in skewed satisfaction ratings. Only the Bland Altman method for assessing agreement augmented by bar charts of differences was able to indicate this. TRIAL REGISTRATION: ISRCTN: ISRCT71348772. PMID- 21592339 TI - Geographic profiling as a novel spatial tool for targeting infectious disease control. AB - BACKGROUND: Geographic profiling is a statistical tool originally developed in criminology to prioritise large lists of suspects in cases of serial crime. Here, we use two data sets--one historical and one modern--to show how it can be used to locate the sources of infectious disease. RESULTS: First, we re-analyse data from a classic epidemiological study, the 1854 London cholera outbreak. Using 321 disease sites as input, we evaluate the locations of 13 neighbourhood water pumps. The Broad Street pump--the outbreak's source--ranks first, situated in the top 0.2% of the geoprofile. We extend our study with an analysis of reported malaria cases in Cairo, Egypt, using 139 disease case locations to rank 59 mosquitogenic local water sources, seven of which tested positive for the vector Anopheles sergentii. Geographic profiling ranks six of these seven sites in positions 1-6, all in the top 2% of the geoprofile. In both analyses the method outperformed other measures of spatial central tendency. CONCLUSIONS: We suggest that geographic profiling could form a useful component of integrated control strategies relating to a wide variety of infectious diseases, since evidence based targeting of interventions is more efficient, environmentally friendly and cost-effective than untargeted intervention. PMID- 21592340 TI - Identification of two internal signal peptide sequences: critical for classical swine fever virus non-structural protein 2 to trans-localize to the endoplasmic reticulum. AB - BACKGROUND: The membrane topology and molecular mechanisms for endoplasmic reticulum (ER) localization of classical swine fever virus (CSFV) non-structural 2 (NS2) protien is unclear. We attempted to elucidate the subcellular localization, and the molecular mechanisms responsible for the localization of this protein in our study. The NS2 gene was amplified by reverse transcription polymerase chain reaction, with the transmembrane region and hydrophilicity of the NS2 protein was predicted by bioinformatics analysis. Twelve cDNAs of the NS2 gene were amplified by the PCR deletion method and cloned into a eukaryotic expression vector, which was transfected into a swine umbilical vein endothelial cell line (SUVEC). Subcellular localization of the NS2 protein was characterized by confocal microscopy, and western blots were carried out to analyze protein expression. RESULTS: Our results showed that the -NH2 terminal of the CSFV NS2 protein was highly hydrophobic and the protein localized in the ER. At least four transmembrane regions and two internal signal peptide sequences (amino acids103 138 and 220-262) were identified and thought to be critical for its trans localization to the ER. CONCLUSIONS: This is the first study to identify the internal signal peptide sequences of the CSFV NS2 protein and its subcellular localization, providing the foundation for further exploration of this protein's function of this protein and its role in CSFV pathogenesis. PMID- 21592341 TI - Challenging the role of social norms regarding body weight as an explanation for weight, height, and BMI misreporting biases: development and application of a new approach to examining misreporting and misclassification bias in surveys. AB - BACKGROUND: Cultural pressures to be thin and tall are postulated to cause people to misreport their body weight and height towards more socially normative (i.e., desirable) values, but a paucity of direct evidence supports this idea. We developed a novel non-linear approach to examining weight, height, and BMI misreporting biases and used this approach to examine the association between socially non-normative weight and misreporting biases in adults. METHODS: The Survey of Lifestyles, Attitudes, and Nutrition 2007 (SLAN 2007), a nationally representative survey of the Republic of Ireland (N = 1942 analyzed) was used. Self-reported weight (height) was classified as under-reported by >= 2.0 kg (2.0 cm), over-reported by >= 2.0 kg (2.0 cm), or accurately reported within 2.0 kg (2.0 cm) to account for technical errors of measurement and short-term fluctuations in measured weight (height). A simulation strategy was used to define self-report-based BMI as under-estimated by more than 1.40 kg/m2, over estimated by more than 1.40 kg/m2, or accurately estimated within 1.40 kg/m2. Patterns of biases in self-reported weight, height, and BMI were explored. Logistic regression was used to identify factors associated with mis-estimated BMI and to calculate adjusted odds ratios (AOR) and 99% confidence intervals (99%CI). RESULTS: The patterns of bias contributing the most to BMI mis estimation were consistently, in decreasing order of influence, (1) under reported weight combined with over-reported height, (2) under-reported weight with accurately reported height, and (3) accurately reported weight with over reported height. Average bias in self-report-based BMI was -1.34 kg/m2 overall and -0.49, -1.33, and -2.66 kg/m2 in normal, overweight, and obese categories, respectively. Despite the increasing degree of bias with progressively higher BMI categories, persons describing themselves as too heavy were, within any given BMI category, less likely to have under-estimated BMI (AOR 0.5, 99%CI: 0.3-0.8, P < 0.001), to be misclassified in a lower BMI category (AOR 0.3, 99%CI: 0.2-0.5, P < 0.001), to under-report weight (AOR 0.5, 99%CI: 0.3-0.7, P < 0.001), and to over report height (OR 0.7, 99%CI: 0.6-1.0, P = 0.007). CONCLUSIONS: A novel non linear approach to examining weight, height, and BMI misreporting biases was developed. Perceiving oneself as too heavy appears to reduce rather than exacerbate weight, height, and BMI misreporting biases. PMID- 21592342 TI - Self-reported history of sexually transmissible infections (STIs) and STI-related utilization of the German health care system by men who have sex with men: data from a large convenience sample. AB - BACKGROUND: In Germany, testing and treatment of sexually transmissible infections (STIs) services are not provided by one medical discipline, but rather dispersed among many different providers. Common STIs like gonorrhoea or Chlamydia infection are not routinely reported. Although men who have sex with men (MSM) are particularly vulnerable to STIs, respective health care utilization among MSM is largely unknown. METHODS: A sexual behaviour survey among MSM was conducted in 2006. Questions on self-reported sexual behaviour, STI-related health care consultation and barriers to access, coverage of vaccination against hepatitis, screening for asymptomatic STIs, self-reported history of STIs, and partner notification were analysed. Analysis was stratified by HIV-serostatus (3,511 HIV-negative/unknown versus 874 positive). RESULTS: General Practitioners, particularly gay doctors, were preferred for STI-related health care. Low threshold testing in sex-associated venues was acceptable for most respondents. Shame and fear of homophobic reactions were the main barriers for STI-testing. More than half of the respondents reported vaccination against hepatitis A/B. HIV positive MSM reported screening offers for STIs three to seven times more often than HIV-negative or untested MSM. Unlike testing for syphilis or hepatitis C, screening for asymptomatic pharyngeal and rectal infections was rarely offered. STIs in the previous twelve months were reported by 7.1% of HIV negative/untested, and 34.7% of HIV-positive respondents. CONCLUSIONS: Self reported histories of STIs in MSM convenience samples differ significantly by HIV serostatus. Higher rates of STIs among HIV-positive MSM may partly be explained by more testing. Communication between health care providers and their clients about sexuality, sexual practices, and sexual risks should be improved. A comprehensive STI screening policy for MSM is needed. PMID- 21592343 TI - A survey of primary care physician practices in antibiotic prescribing for the treatment of uncomplicated male gonoccocal urethritis. AB - BACKGROUND: The development of resistance to antimicrobial therapy by Neisseria gonorrhoeae causes on-going problems for individual case management of gonorrhoea. Surveillance data about N. gonorrhoeae have indicated an increase in the incidence of gonorrhoea in France in 2006. As a consequence of the development of antibiotic resistance in N. gonorrhoeae, French guidelines excluded fluoroquinolones as a standard treatment for N. gonorrhoeae. Ceftriaxone became the recommended treatment, associated with azithromycin for Clamydia trachomatis infection. Our aim was to describe the practice patterns of general practitioners (GPs) in managing the antibiotic treatment of patients with symptoms suggestive of uncomplicated male urethritis. METHODS: We developed a clinical vignette describing a man with typical gonococcal urethritis symptoms to elicit questions about antibiotic treatment. We mailed the electronic questionnaire to a random sample of 1000 French GPs belonging to the Sentinelles Network. RESULTS: By the end of the survey period, 350 vignettes were received, yielding a response rate of 35%. Sixty-six GPs (20.2%) prescribed the recommended antibiotics for the simultaneous treatment of N. gonorrhoeae and C. trachomatis infections, while 132 GPs (40.4%) prescribed only non-recommended antibiotics, including ciprofloxacin in 69 cases (21.1%). General practitioners with less than 10 years in practice showed better compliance to guidelines than those with more years in practice (p<0.05). CONCLUSIONS: The results suggest a mismatch between the guidelines and the antibiotic treatment of male uncomplicated urethritis by French GPs, mostly among the subgroup of physicians who have been in practice longer. Educational approaches based on practice feedback need to be developed to improve these deficits in the quality of care. PMID- 21592344 TI - Enhancing the effect of repetitive I-wave paired-pulse TMS (iTMS) by adjusting for the individual I-wave periodicity. AB - BACKGROUND: Repeated application of paired-pulse TMS over the primary motor cortex (M1) in human subjects with an inter-pulse interval (IPI) of 1.5 ms (iTMS(1.5 ms)) has been shown to significantly increase paired-pulse MEP (ppMEP) amplitudes during the stimulation period and increased single-pulse MEP amplitudes for up to 10 minutes after termination of iTMS. RESULTS: Here we show in a cross-over design that a modified version of the iTMS(1.5 ms) protocol with an I-wave periodicity adjusted to the individual I1-peak wave latency (iTMS(adj)) resulted in a stronger effect on ppMEPs relative to iTMS(1.5 ms). CONCLUSIONS: Based on these findings, our results indicate that the efficiency of iTMS strongly depends on the individual choice of the IPI and that parameter optimization of the conventional iTMS(1.5 ms) protocol might improve the outcome of this novel non-invasive brain stimulation technique. PMID- 21592345 TI - Optimal tumor sampling for immunostaining of biomarkers in breast carcinoma. AB - INTRODUCTION: Biomarkers, such as Estrogen Receptor, are used to determine therapy and prognosis in breast carcinoma. Immunostaining assays of biomarker expression have a high rate of inaccuracy; for example, estimates are as high as 20% for Estrogen Receptor. Biomarkers have been shown to be heterogeneously expressed in breast tumors and this heterogeneity may contribute to the inaccuracy of immunostaining assays. Currently, no evidence-based standards exist for the amount of tumor that must be sampled in order to correct for biomarker heterogeneity. The aim of this study was to determine the optimal number of 20X fields that are necessary to estimate a representative measurement of expression in a whole tissue section for selected biomarkers: ER, HER-2, AKT, ERK, S6K1, GAPDH, Cytokeratin, and MAP-Tau. METHODS: Two collections of whole tissue sections of breast carcinoma were immunostained for biomarkers. Expression was quantified using the Automated Quantitative Analysis (AQUA) method of quantitative immunofluorescence. Simulated sampling of various numbers of fields (ranging from one to thirty five) was performed for each marker. The optimal number was selected for each marker via resampling techniques and minimization of prediction error over an independent test set. RESULTS: The optimal number of 20X fields varied by biomarker, ranging between three to fourteen fields. More heterogeneous markers, such as MAP-Tau protein, required a larger sample of 20X fields to produce representative measurement. CONCLUSIONS: The optimal number of 20X fields that must be sampled to produce a representative measurement of biomarker expression varies by marker with more heterogeneous markers requiring a larger number. The clinical implication of these findings is that breast biopsies consisting of a small number of fields may be inadequate to represent whole tumor biomarker expression for many markers. Additionally, for biomarkers newly introduced into clinical use, especially if therapeutic response is dictated by level of expression, the optimal size of tissue sample must be determined on a marker-by-marker basis. PMID- 21592346 TI - Production of antibodies with peptide-CpG-DNA-liposome complex without carriers. AB - BACKGROUND: The screening of peptide-based epitopes has been studied extensively for the purpose of developing therapeutic antibodies and prophylactic vaccines that can be potentially useful for treating cancer and infectious diseases such as influenza virus, malaria, hepatitis B, and HIV. To improve the efficacy of antibody production by epitope-based immunization, researchers evaluated liposomes as a means of delivering vaccines; they also formulated adjuvants such as flagella and CpG-DNA to enhance the magnitude of immune responses. Here, we provide a potent method for peptide-based epitope screening and antibody production without conventional carriers. RESULTS: We present that a particular form of natural phosphodiester bond CpG-DNA encapsulated in a specific liposome complex (Lipoplex(O)) induces potent immunomodulatory activity in humans as well as in mice. Additionally, Lipoplex(O) enhances the production of IgG2a specific to antigenic protein in mice. Most importantly, immunization of mice with several peptides co-encapsulated with Lipoplex(O) without carriers significantly induces each peptide-specific IgG2a production in a TLR9-dependent manner. A peptide specific monoclonal antibody produced against hepatocellular carcinoma-associated antigen has functional effects on the cancer cells. CONCLUSIONS: Our overall results show that Lipoplex(O) is a potent adjuvant and that complexes of peptide and Lipoplex(O) are extremely useful for B cell epitope screening and antibody production without carriers. Therefore, our strategy may be promptly used for the development of therapeutic antibodies by rapid screening of potent B cell epitopes. PMID- 21592347 TI - Culturally-tailored smoking cessation for American Indians: study protocol for a randomized controlled trial. AB - BACKGROUND: Cigarette smoking is the number one cause of preventable death among American Indian and Alaska Natives, AI/ANs. Two out of every five AI/AN will die from tobacco-related diseases if the current smoking rates of AI/ANs (40.8%) persist. Currently, there is no proven, effective culturally-tailored smoking cessation program designed specifically for a heterogeneous population of AI.The primary aim of this group randomized clinical trial is to test the efficacy of "All Nations Breath of Life" (ANBL) program compared to a non-tailored "Current Best Practices" smoking cessation program among AI smokers. METHODS: We will randomize 56 groups (8 smokers per group) to the tailored program or non-tailored program for a total sample size of 448 American Indian smokers. All participants in the proposed study will be offered pharmacotherapy, regardless of group assignment. This study is the first controlled trial to examine the efficacy of a culturally-tailored smoking cessation program for American Indians. If the intervention is successful, the potential health impact is significant because the prevalence of smoking is the highest in this population. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01106456. PMID- 21592348 TI - Objective identification of residue ranges for the superposition of protein structures. AB - BACKGROUND: The automation of objectively selecting amino acid residue ranges for structure superpositions is important for meaningful and consistent protein structure analyses. So far there is no widely-used standard for choosing these residue ranges for experimentally determined protein structures, where the manual selection of residue ranges or the use of suboptimal criteria remain commonplace. RESULTS: We present an automated and objective method for finding amino acid residue ranges for the superposition and analysis of protein structures, in particular for structure bundles resulting from NMR structure calculations. The method is implemented in an algorithm, CYRANGE, that yields, without protein specific parameter adjustment, appropriate residue ranges in most commonly occurring situations, including low-precision structure bundles, multi-domain proteins, symmetric multimers, and protein complexes. Residue ranges are chosen to comprise as many residues of a protein domain that increasing their number would lead to a steep rise in the RMSD value. Residue ranges are determined by first clustering residues into domains based on the distance variance matrix, and then refining for each domain the initial choice of residues by excluding residues one by one until the relative decrease of the RMSD value becomes insignificant. A penalty for the opening of gaps favours contiguous residue ranges in order to obtain a result that is as simple as possible, but not simpler. Results are given for a set of 37 proteins and compared with those of commonly used protein structure validation packages. We also provide residue ranges for 6351 NMR structures in the Protein Data Bank. CONCLUSIONS: The CYRANGE method is capable of automatically determining residue ranges for the superposition of protein structure bundles for a large variety of protein structures. The method correctly identifies ordered regions. Global structure superpositions based on the CYRANGE residue ranges allow a clear presentation of the structure, and unnecessary small gaps within the selected ranges are absent. In the majority of cases, the residue ranges from CYRANGE contain fewer gaps and cover considerably larger parts of the sequence than those from other methods without significantly increasing the RMSD values. CYRANGE thus provides an objective and automatic method for standardizing the choice of residue ranges for the superposition of protein structures. PMID- 21592349 TI - Public claims about automatic external defibrillators: an online consumer opinions study. AB - BACKGROUND: Patients are no longer passive recipients of health care, and increasingly engage in health communications outside of the traditional patient and health care professional relationship. As a result, patient opinions and health related judgements are now being informed by a wide range of social, media, and online information sources. Government initiatives recognise self delivery of health care as a valuable means of responding to the anticipated increased global demand for health resources. Automated External Defibrillators (AEDs), designed for the treatment of Sudden Cardiac Arrest (SCA), have recently become available for 'over the counter' purchase with no need for a prescription. This paper explores the claims and argumentation of lay persons and health care practitioners and professionals relating to these, and how these may impact on the acceptance, adoption and use of these devices within the home context. METHODS: We carry out a thematic content analysis of a novel form of Internet based data: online consumer opinions of AED devices posted on Amazon.com, the world's largest online retailer. A total of #83 online consumer reviews of home AEDs are analysed. The analysis is both inductive, identifying themes that emerged from the data, exploring the parameters of public debate relating to these devices, and also driven by theory, centring around the parameters that may impact upon the acceptance, adoption and use of these devices within the home as indicated by the Technology Acceptance Model (TAM). RESULTS: Five high-level themes around which arguments for and against the adoption of home AEDs are identified and considered in the context of TAM. These include opinions relating to device usability, usefulness, cost, emotional implications of device ownership, and individual patient risk status. Emotional implications associated with AED acceptance, adoption and use emerged as a notable factor that is not currently reflected within the existing TAM. CONCLUSIONS: The value, credibility and implications of the findings of this study are considered within the context of existing AED research, and related to technology acceptance theory. From a methodological perspective, this study demonstrates the potential value of online consumer reviews as a novel data source for exploring the parameters of public debate relating to emerging health care technologies. PMID- 21592350 TI - Why eukaryotic cells use introns to enhance gene expression: splicing reduces transcription-associated mutagenesis by inhibiting topoisomerase I cutting activity. AB - BACKGROUND: The costs and benefits of spliceosomal introns in eukaryotes have not been established. One recognized effect of intron splicing is its known enhancement of gene expression. However, the mechanism regulating such splicing mediated expression enhancement has not been defined. Previous studies have shown that intron splicing is a time-consuming process, indicating that splicing may not reduce the time required for transcription and processing of spliced pre-mRNA molecules; rather, it might facilitate the later rounds of transcription. Because the densities of active RNA polymerase II on most genes are less than one molecule per gene, direct interactions between the splicing apparatus and transcriptional complexes (from the later rounds of transcription) are infrequent, and thus unlikely to account for splicing-mediated gene expression enhancement. PRESENTATION OF THE HYPOTHESIS: The serine/arginine-rich protein SF2/ASF can inhibit the DNA topoisomerase I activity that removes negative supercoiling of DNA generated by transcription. Consequently, splicing could make genes more receptive to RNA polymerase II during the later rounds of transcription, and thus affect the frequency of gene transcription. Compared with the transcriptional enhancement mediated by strong promoters, intron-containing genes experience a lower frequency of cut-and-paste processes. The cleavage and religation activity of DNA strands by DNA topoisomerase I was recently shown to account for transcription-associated mutagenesis. Therefore, intron-mediated enhancement of gene expression could reduce transcription-associated genome instability. TESTING THE HYPOTHESIS: Experimentally test whether transcription associated mutagenesis is lower in intron-containing genes than in intronless genes. Use bioinformatic analysis to check whether exons flanking lost introns have higher frequencies of short deletions. IMPLICATIONS OF THE HYPOTHESIS: The mechanism of intron-mediated enhancement proposed here may also explain the positive correlation observed between intron size and gene expression levels in unicellular organisms, and the greater number of intron containing genes in higher organisms. REVIEWERS: This article was reviewed by Dr Arcady Mushegian, Dr Igor B Rogozin (nominated by Dr I King Jordan) and Dr Alexey S Kondrashov. For the full reviews, please go to the Reviewer's Reports section. PMID- 21592351 TI - Electronic feedback in a diet- and physical activity-based lifestyle intervention for weight loss: a randomized controlled trial. AB - BACKGROUND: The SenseWearTM Armband (SWA) (BodyMedia, Inc. Pittsburgh, PA) is a physical activity and lifestyle monitor that objectively and accurately measures free-living energy balance and sleep and includes software for self-monitoring of daily energy expenditure and energy intake. The real-time feedback of the SWA can improve individual self-monitoring and, therefore, enhance weight loss outcomes. METHODS: We recruited 197 sedentary overweight or obese adults (age, 46.8 +/- 10.8 y; body mass index (BMI), 33.3 +/- 5.2 kg/m(2); 81% women, 32% African American) from the greater Columbia, South Carolina area. Participants were randomized into 1 of 4 groups, a self-directed weight loss program via an evidence-based weight loss manual (Standard Care, n = 50), a group-based behavioral weight loss program (GWL, n = 49), the armband alone (SWA-alone, n = 49), or the GWL plus the armband (GWL+SWA, n = 49), during the 9-month intervention. The primary outcome was change in body weight and waist circumference. A mixed-model repeated-measures analysis compared change in the intervention groups to the standard care group on weight and waist circumference status after adjusting for age, sex, race, education, energy expenditure, and recruitment wave. RESULTS: Body weight was available for 62% of participants at 9 months (52% standard care, 70% intervention). There was significant weight loss in all 3 intervention groups (GWL, 1.86 kg, P = 0.05; SWA-alone, 3.55 kg, P = 0.0002; GWL+SWA, 6.59 kg, P < 0.0001) but not in the Standard Care group (0.89 kg, P = 0.39) at month 9. Only the GWL+SWA group achieved significant weight loss at month 9 compared to the Standard Care group (P = 0.04). Significant waist circumference reductions were achieved in all 4 groups at month 9 (Standard Care, 3.49 cm, P = 0.0004; GWL, 2.42 cm, P = 0.008; SWA-alone, 3.59 cm, P < 0.0001; GWL+SWA, 6.77 cm, P < 0.0001), but no intervention group had significantly reduced waist circumference compared to the Standard Care group. CONCLUSIONS: Continuous self-monitoring from wearable technology with real-time feedback may be particularly useful to enhance lifestyle changes that promote weight loss in sedentary overweight or obese adults. This strategy, combined with a group-based behavioral intervention, may yield optimal weight loss. PMID- 21592352 TI - Concordance of self-reported and medical chart information on cancer diagnosis and treatment. AB - BACKGROUND: Self-reported information is an important tool for collecting clinical information for epidemiologic studies and in clinical settings where electronic medical records are not employed and shared. METHODS: Using data collected from the Shanghai Breast Cancer Survival Study (SBCSS), a population based, prospective cohort study of 5,042 women diagnosed with breast cancer in Shanghai, China, we compared the concordance of patient questionnaire responses to a survey administered approximately 6 months after cancer diagnosis with medical chart information obtained from the diagnostic hospitals for several disease and treatment-related variables. RESULTS: Of 5,042 SBCSS participants, medical chart information was available for 4,948 women (98.1%). Concordance between patient self-reported and medical chart information was high for the majority of disease-related variables, including: diagnosing hospital (agreement: 98.7%, kappa: 0.99), type of surgery conducted (94.0%, 0.53), ER/PR status (94.5%, 0.91), and tumor position (98.2%, 0.97), as well as for important calendar dates, such as date of diagnosis, surgery, and first chemotherapy treatment. The 10 most commonly used chemotherapeutic drugs were all reported with agreement rates of at least 82%, with associated kappa values that ranged from 0.41 for calcium folinate to 0.76 for vinorelbine. CONCLUSIONS: Our study found high validity for patient self-reported information for a variety of disease and treatment-related variables, suggesting the utility of self-reports as an important source of clinical information for both epidemiological research and patient care. PMID- 21592353 TI - Increased serum myeloid-related protein 8/14 level is associated with atherosclerosis in type 2 diabetic patients. AB - BACKGROUND: Myeloid-related protein 8/14 (MRP8/14) is a stable heterodimer formed by two different calcium-binding proteins (MRP8 and MRP14). Studies have identified that MRP8/14 regulates vascular inflammation and serves as a novel marker of acute coronary syndrome. In this study, we evaluated the correlation between serum levels of MRP8/14, hsCRP, endogenous secretory receptor for advanced glycation end-products (esRAGE) and the occurrence of coronary artery disease (CAD), or carotid intima-media thickness (IMT) when CAD was not yet developed in diabetic patients. METHODS: Serum levels of MRP8/14, esRAGE and hsCRP were measured in 375 diabetic patients. Then the results of those who had CAD were compared against who had not. Also, we investigated the associations between above-mentioned indicators and IMT of subjects without CAD in both diabetic group and non-diabetic one. RESULTS: Serum MRP8/14 was significantly higher in CAD than in non-CAD group (9.7 +/- 3.6 ug/ml vs. 8.2 +/- 3.0 ug/ml, P < 0.001). It was associated with severity of CAD (r = 0.16, P = 0.026). In non-CAD group, MRP8/14 was associated with IMT in patients with (r = 0.30, P < 0.001) or without diabetes (r = 0.26, P = 0.015). The areas under the curves of receiver operating characteristic for CAD were 0.63 (95% CI 0.57-0.68) for MRP8/14, 0.76 (95% CI 0.71-0.81) for hsCRP and 0.62 (95% CI 0.56 -0.67) for esRAGE. CONCLUSION: In summary, we report that diabetic patients with CAD had elevated plasma MRP8/14 levels which were also positively correlated with the severity of CAD and carotid IMT in patients without clinically overt CAD. PMID- 21592354 TI - Induction of inflammatory cytokines and Toll-like receptors in chickens infected with avian H9N2 influenza virus. AB - H9N2 influenza virus is endemic in many Asian countries and is regarded as a candidate for the next human pandemic. Knowledge of the induction of inflammatory responses and toll-like receptors (TLRs) in chickens infected with H9N2 is limited. Here, we show that H9N2 induces pro-inflammatory cytokines such as transforming growth factor-beta 3; tumor necrosis factor-alpha; interferon-alpha, -beta, and gamma; and TLR 1, 2, 3, 4, 5, 7, and 15 in trachea, lung, and intestine of infected chickens. In the lung, TLR-15 was dominantly induced. Taken together, it seems that H9N2 infections efficiently induce inflammatory cytokines and TLRs in trachea, lung and intestine of chickens. PMID- 21592355 TI - Detection of prions in the faeces of sheep naturally infected with classical scrapie. AB - Classical scrapie is a naturally transmitted prion disease of sheep and goats. Contaminated environments may contribute to the spread of disease and evidence from animal models has implicated urine, blood, saliva, placenta and faeces as possible sources of the infection. Here we sought to determine whether sheep naturally infected with classical scrapie shed prions in their faeces. We used serial protein misfolding cyclic amplification (sPMCA) along with two extraction methods to examine faeces from sheep during both the clinical and preclinical phases of the disease and showed amplification of PrP(Sc) in 7 of 15 and 14 of 14 sheep respectively. However PrP(Sc) was not amplified from the faeces of 25 sheep not exposed to scrapie. These data represent the first demonstration of prion shedding in faeces from a naturally infected host and thus a likely source of prion contamination in the environment. PMID- 21592356 TI - Analysis of the acute phase responses of serum amyloid a, haptoglobin and type 1 interferon in cattle experimentally infected with foot-and-mouth disease virus serotype O. AB - A series of challenge experiments were performed in order to investigate the acute phase responses to foot-and-mouth disease virus (FMDV) infection in cattle and possible implications for the development of persistently infected "carriers". The host response to infection was investigated through measurements of the concentrations of the acute phase proteins (APPs) serum amyloid A (SAA) and haptoglobin (HP), as well as the bioactivity of type 1 interferon (IFN) in serum of infected animals. Results were based on measurements from a total of 36 infected animals of which 24 were kept for observational periods exceeding 28 days in order to determine the carrier-status of individual animals. The systemic host response to FMDV in infected animals was evaluated in comparison to similar measurements in sera from 6 mock-inoculated control animals.There was a significant increase in serum concentrations of both APPs and type 1 IFN in infected animals coinciding with the onset of viremia and clinical disease. The measured parameters declined to baseline levels within 21 days after inoculation, indicating that there was no systemically measurable inflammatory reaction related to the carrier state of FMD. There was a statistically significant difference in the HP response between carriers and non-carriers with a lower response in the animals that subsequently developed into FMDV carriers. It was concluded that the induction of SAA, HP and type 1 IFN in serum can be used as markers of acute infection by FMDV in cattle. PMID- 21592357 TI - On the genome constitution and evolution of intermediate wheatgrass (Thinopyrum intermedium: Poaceae, Triticeae). AB - BACKGROUND: The wheat tribe Triticeae (Poaceae) is a diverse group of grasses representing a textbook example of reticulate evolution. Apart from globally important grain crops, there are also wild grasses which are of great practical value. Allohexaploid intermediate wheatgrass, Thinopyrum intermedium (2n = 6x = 42), possesses many desirable agronomic traits that make it an invaluable source of genetic material useful in wheat improvement. Although the identification of its genomic components has been the object of considerable investigation, the complete genomic constitution and its potential variability are still being unravelled. To identify the genomic constitution of this allohexaploid, four accessions of intermediate wheatgrass from its native area were analysed by sequencing of chloroplast trnL-F and partial nuclear GBSSI, and genomic in situ hybridization. RESULTS: The results confirmed the allopolyploid origin of Thinopyrum intermedium and revealed new aspects in its genomic composition. Genomic heterogeneity suggests a more complex origin of the species than would be expected if it originated through allohexaploidy alone. While Pseudoroegneria is the most probable maternal parent of the accessions analysed, nuclear GBSSI sequences suggested the contribution of distinct lineages corresponding to the following present-day genera: Pseudoroegneria, Dasypyrum, Taeniatherum, Aegilops and Thinopyrum. Two subgenomes of the hexaploid have most probably been contributed by Pseudoroegneria and Dasypyrum, but the identity of the third subgenome remains unresolved satisfactorily. Possibly it is of hybridogenous origin, with contributions from Thinopyrum and Aegilops. Surprising diversity of GBSSI copies corresponding to a Dasypyrum-like progenitor indicates either multiple contributions from different sources close to Dasypyrum and maintenance of divergent copies or the presence of divergent paralogs, or a combination of both. Taeniatherum-like GBSSI copies are most probably pseudogenic, and the mode of their acquisition by Th. intermedium remains unclear. CONCLUSIONS: Hybridization has played a key role in the evolution of the Triticeae. Transfer of genetic material via extensive interspecific hybridization and/or introgression could have enriched the species' gene pools significantly. We have shown that the genomic heterogeneity of intermediate wheatgrass is higher than has been previously assumed, which is of particular concern to wheat breeders, who frequently use it as a source of desirable traits in wheat improvement. PMID- 21592358 TI - Host range, host specificity and hypothesized host shift events among viruses of lower vertebrates. AB - The successful replication of a viral agent in a host is a complex process that often leads to a species specificity of the virus and can make interspecies transmission difficult. Despite this difficulty, natural host switch seems to have been frequent among viruses of lower vertebrates, especially fish viruses, since there are several viruses known to be able to infect a wide range of species. In the present review we will focus on well documented reports of broad host range, variations in host specificity, and host shift events hypothesized for viruses within the genera Ranavirus, Novirhabdovirus, Betanodavirus, Isavirus, and some herpesvirus. PMID- 21592359 TI - Traditional and non-traditional treatments for autism spectrum disorder with seizures: an on-line survey. AB - BACKGROUND: Despite the high prevalence of seizure, epilepsy and abnormal electroencephalograms in individuals with autism spectrum disorder (ASD), there is little information regarding the relative effectiveness of treatments for seizures in the ASD population. In order to determine the effectiveness of traditional and non-traditional treatments for improving seizures and influencing other clinical factor relevant to ASD, we developed a comprehensive on-line seizure survey. METHODS: Announcements (by email and websites) by ASD support groups asked parents of children with ASD to complete the on-line surveys. Survey responders choose one of two surveys to complete: a survey about treatments for individuals with ASD and clinical or subclinical seizures or abnormal electroencephalograms, or a control survey for individuals with ASD without clinical or subclinical seizures or abnormal electroencephalograms. Survey responders rated the perceived effect of traditional antiepileptic drug (AED), non-AED seizure treatments and non-traditional ASD treatments on seizures and other clinical factors (sleep, communication, behavior, attention and mood), and listed up to three treatment side effects. RESULTS: Responses were obtained concerning 733 children with seizures and 290 controls. In general, AEDs were perceived to improve seizures but worsened other clinical factors for children with clinical seizure. Valproic acid, lamotrigine, levetiracetam and ethosuximide were perceived to improve seizures the most and worsen other clinical factors the least out of all AEDs in children with clinical seizures. Traditional non-AED seizure and non-traditional treatments, as a group, were perceived to improve other clinical factors and seizures but the perceived improvement in seizures was significantly less than that reported for AEDs. Certain traditional non-AED treatments, particularly the ketogenic diet, were perceived to improve both seizures and other clinical factors.For ASD individuals with reported subclinical seizures, other clinical factors were reported to be worsened by AEDs and improved by non-AED traditional seizure and non-traditional treatments. The rate of side effects was reportedly higher for AEDs compared to traditional non-AED treatments. CONCLUSION: Although this survey-based method only provides information regarding parental perceptions of effectiveness, this information may be helpful for selecting seizure treatments in individuals with ASD. PMID- 21592360 TI - Improved triacylglycerol production in Acinetobacter baylyi ADP1 by metabolic engineering. AB - BACKGROUND: Triacylglycerols are used in various purposes including food applications, cosmetics, oleochemicals and biofuels. Currently the main sources for triacylglycerol are vegetable oils, and microbial triacylglycerol has been suggested as an alternative for these. Due to the low production rates and yields of microbial processes, the role of metabolic engineering has become more significant. As a robust model organism for genetic and metabolic studies, and for the natural capability to produce triacylglycerol, Acinetobacter baylyi ADP1 serves as an excellent organism for modelling the effects of metabolic engineering for energy molecule biosynthesis. RESULTS: Beneficial gene deletions regarding triacylglycerol production were screened by computational means exploiting the metabolic model of ADP1. Four deletions, acr1, poxB, dgkA, and a triacylglycerol lipase were chosen to be studied experimentally both separately and concurrently by constructing a knock-out strain (MT) with three of the deletions. Improvements in triacylglycerol production were observed: the strain MT produced 5.6 fold more triacylglycerol (mg/g cell dry weight) compared to the wild type strain, and the proportion of triacylglycerol in total lipids was increased by 8-fold. CONCLUSIONS: In silico predictions of beneficial gene deletions were verified experimentally. The chosen single and multiple gene deletions affected beneficially the natural triacylglycerol metabolism of A. baylyi ADP1. This study demonstrates the importance of single gene deletions in triacylglycerol metabolism, and proposes Acinetobacter sp. ADP1 as a model system for bioenergetic studies regarding metabolic engineering. PMID- 21592361 TI - Latent Membrane Protein 1 as a molecular adjuvant for single-cycle lentiviral vaccines. AB - BACKGROUND: Molecular adjuvants are a promising method to enhance virus-specific immune responses and protect against HIV-1 infection. Immune activation by ligands for receptors such as CD40 can induce dendritic cell activation and maturation. Here we explore the incorporation of two CD40 mimics, Epstein Barr Virus gene LMP1 or an LMP1-CD40 chimera, into a strain of SIV that was engineered to be limited to a single cycle of infection. RESULTS: Full length LMP1 or the chimeric protein LMP1-CD40 was cloned into the nef-locus of single-cycle SIV. Human and Macaque monocyte derived macrophages and DC were infected with these viruses. Infected cells were analyzed for activation surface markers by flow cytometry. Cells were also analyzed for secretion of pro-inflammatory cytokines IL-1beta, IL-6, IL-8, IL-12p70 and TNF by cytometric bead array. CONCLUSIONS: Overall, single-cycle SIV expressing LMP1 and LMP1-CD40 produced a broad and potent T(H)1-biased immune response in human as well as rhesus macaque macrophages and DC when compared with control virus. Single-cycle SIV-LMP1 also enhanced antigen presentation by lentiviral vector vaccines, suggesting that LMP1 mediated immune activation may enhance lentiviral vector vaccines against HIV-1. PMID- 21592362 TI - An unusual case of a microscopic alveolar adenoma coexisting with lung carcinoma: a case report and review of the literature. AB - INTRODUCTION: Alveolar adenomas are extremely rare, benign, primary lung tumors of unknown histogenesis that are characterized by proliferative type II alveolar epithelium and septal mesenchyma. Mostly incidental, they are clinically important as they can imitate benign primary and secondary malignant tumors and at times are difficult to differentiate from early-stage lung cancer. We describe the case of a 59-year-old man with an incidental microscopic alveolar adenoma coexisting with poorly differentiated lung carcinoma. CASE PRESENTATION: A 59 year-old Caucasian man with a medical history of smoking and chronic obstructive pulmonary disease was incidentally found to have a right upper lobe mass while undergoing a computed tomographic chest scan as part of a chronic obstructive pulmonary disease clinical trial. Our patient underwent a right upper lobectomy after a bronchoscopic biopsy of the mass revealed the mass to be a carcinoma. A pathological examination revealed an incidental, small, 0.2 cm, well circumscribed lesion on the staple line margin of the lobectomy in addition to the carcinoma. Histopathological and immunohistochemical examinations revealed the lesion to be an alveolar adenoma. CONCLUSIONS: We report the rare presentation of a microscopic alveolar adenoma coexisting with lung carcinoma. Alveolar adenoma is an entirely benign incidental neoplasm that can be precisely diagnosed using immunohistochemical analysis in addition to its unique histopathological characteristics. PMID- 21592363 TI - alpha-Linolenic acid prevents endoplasmic reticulum stress-mediated apoptosis of stearic acid lipotoxicity on primary rat hepatocytes. AB - AIMS: Lipid accumulation in non-adipose tissues leads to cell dysfunction and apoptosis, a phenomenon known as lipotoxicity. Unsaturated fatty acids may offset the lipotoxicity associated with saturated fatty acids. Stearic acid induced endoplasmic reticulum (ER) stress and caused apoptotic and necrotic cell death in the primary rat hepatocytes. METHODS: Cell viability was investigated using MTT assay, and apoptosis was evaluated with Hoechst 33342 staining. Western blot analysis was used to examine the changes in the expression levels of glucose regulated protein 78 (GRP78), glucose regulated protein 94 (GRP94), and C/EBP homologous protein (CHOP). Caspase-3 activity was evaluated using a Caspase-3 substrate kit. RESULTS: We have studied the ability of alpha-linolenic acid to prevent endoplasmic reticulum stress-mediated apoptosis of rat hepatocytes elicited by stearic acid and thapsigargin. Incubation of primary rat hepatocytes for 16 h with stearic acid produced a significant increase in cell death. Stearic acid also increased levels of three indicators of ER stress -- GRP78, CHOP, and GRP94. alpha-Linolenic acid distinctly reduced cell death and levels of all three indicators of ER stress brought about by stearic acid. Thapsigargin, which induces ER stress produced similar effects to those obtained using stearic acid; its effects were partly reversed by alpha-linolenic acid. CONCLUSION: These results suggest that alpha-linolenic acid prevents ER stress-mediated apoptosis of stearic acid lipotoxicity on primary rat hepatocytes might become a target to develop new antiapoptotic compounds in nonalcoholic fatty liver disease (NAFLD). PMID- 21592364 TI - Chronic breast abscess due to Mycobacterium fortuitum: a case report. AB - INTRODUCTION: Mycobacterium fortuitum is a rapidly growing group of nontuberculous mycobacteria more common in patients with genetic or acquired causes of immune deficiency. There have been few published reports of Mycobacterium fortuitum associated with breast infections mainly associated with breast implant and reconstructive surgery. CASE PRESENTATION: We report a case of a 51-year-old Caucasian woman who presented to our one-stop breast clinic with a two-week history of left breast swelling and tenderness. Following triple assessment and subsequent incision and drainage of a breast abscess, the patient was diagnosed with Mycobacterium fortuitum and treated with antibiotic therapy and surgical debridement. CONCLUSION: This is a rare case of a spontaneous breast abscess secondary to Mycobacterium fortuitum infection. Recommended treatment is long-term antibacterial therapy and surgical debridement for extensive infection or when implants are involved. PMID- 21592366 TI - Bionomics of the malaria vector Anopheles farauti in Temotu Province, Solomon Islands: issues for malaria elimination. AB - BACKGROUND: In the Solomon Islands, the Malaria Eradication Programmes of the 1970s virtually eliminated the malaria vectors: Anopheles punctulatus and Anopheles koliensis, both late night biting, endophagic species. However, the vector, Anopheles farauti, changed its behaviour to bite early in the evening outdoors. Thus, An. farauti mosquitoes were able to avoid insecticide exposure and still maintain transmission. Thirty years on and the Solomon Islands are planning for intensified malaria control and localized elimination; but little is currently known about the behaviour of the vectors and how they will respond to intensified control. METHODS: In the elimination area, Temotu Province, standard entomological collection methods were conducted in typical coastal villages to determine the vector, its ecology, biting density, behaviour, longevity, and vector efficacy. These vector surveys were conducted pre-intervention and post intervention following indoor residual spraying and distribution of long-lasting insecticidal nets. RESULTS: Anopheles farauti was the only anopheline in Temotu Province. In 2008 (pre-intervention), this species occurred in moderate to high densities (19.5-78.5 bites/person/night) and expressed a tendency to bite outdoors, early in the night (peak biting time 6-8 pm). Surveys post intervention showed that there was little, if any, reduction in biting densities and no reduction in the longevity of the vector population. After adjusting for human behaviour, indoor biting was reduced from 57% pre-intervention to 40% post intervention. CONCLUSION: In an effort to learn from historical mistakes and develop successful elimination programmes, there is a need for implementing complimentary vector control tools that can target exophagic and early biting vectors. Intensified indoor residual spraying and long-lasting insecticide net use has further promoted the early, outdoor feeding behaviour of An. farauti in the Solomon Islands. Consequently, the effectiveness of IRS and the personal protection provided by bed nets is compromised. To achieve elimination, any residual transmission should be targeted using integrated vector control incorporating complementary tools such as larviciding and/or zooprophylaxis. PMID- 21592365 TI - Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice. AB - INTRODUCTION: The purpose of this study was to elucidate the effects of histone deacetylase inhibition on the phenotype and function of dendritic cells and on arthritis in SKG mice. METHODS: Arthritis was induced in SKG mice by zymosan A injection. Trichostatin A, a histone deacetylase inhibitor, was administered and its effects on arthritis were evaluated by joint swelling and histological evaluation. Interleukin-17 production in lymph node cells was determined by an enzyme-linked immunosorbent assay (ELISA). Foxp3 expression in lymph node cells and the phenotypes of splenic dendritic cells were examined by fluorescence activated cell sorting (FACS). Bone marrow-derived dendritic cells (BM-DC) were generated with granulocyte macrophage colony-stimulating factor. The effects of trichostatin A on cell surface molecules, cytokine production, indoleamine 2,3 dioxygenase (IDO) expression and T cell stimulatory capacity were examined by FACS, ELISA, quantitative real-time polymerase chain reaction and Western blot, and the allo-mixed lymphocyte reaction, respectively. RESULTS: Trichostatin A, when administered before the onset of arthritis, prevented SKG mice from getting arthritis. Trichostatin A treatment also showed therapeutic effects on arthritis in SKG mice, when it was administered after the onset of arthritis. Trichostatin A treatment reduced Th17 cells and induced regulatory T cells in lymph node, and also decreased co-stimulatory molecule expression on splenic dendritic cells in vivo. In vitro, trichostatin A markedly suppressed zymosan A-induced interleukin 12 and interleukin-6 production by BM-DC and up-regulated IDO expression at mRNA and protein levels. Trichostatin A-treated BM-DC also showed less T cell stimulatory capacity. CONCLUSIONS: Histone deacetylase inhibition changes dendritic cells to a tolerogenic phenotype and ameliorates arthritis in SKG mice. PMID- 21592367 TI - Risk of metabolic syndrome among children living in metropolitan Kuala Lumpur: a case control study. AB - BACKGROUND: With the increasing prevalence of childhood obesity, the metabolic syndrome has been studied among children in many countries but not in Malaysia. Hence, this study aimed to compare metabolic risk factors between overweight/obese and normal weight children and to determine the influence of gender and ethnicity on the metabolic syndrome among school children aged 9-12 years in Kuala Lumpur and its metropolitan suburbs. METHODS: A case control study was conducted among 402 children, comprising 193 normal-weight and 209 overweight/obese. Weight, height, waist circumference (WC) and body composition were measured, and WHO (2007) growth reference was used to categorise children into the two weight groups. Blood pressure (BP) was taken, and blood was drawn after an overnight fast to determine fasting blood glucose (FBG) and full lipid profile, including triglycerides (TG), high-density lipoprotein cholesterol (HDL C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). International Diabetes Federation (2007) criteria for children were used to identify metabolic syndrome. RESULTS: Participants comprised 60.9% (n = 245) Malay, 30.9% (n = 124) Chinese and 8.2% (n = 33) Indian. Overweight/obese children showed significantly poorer biochemical profile, higher body fat percentage and anthropometric characteristics compared to the normal-weight group. Among the metabolic risk factors, WC >=90th percentile was found to have the highest odds (OR = 189.0; 95%CI 70.8, 504.8), followed by HDL-C<=1.03 mmol/L (OR = 5.0; 95%CI 2.4, 11.1) and high BP (OR = 4.2; 95%CI 1.3, 18.7). Metabolic syndrome was found in 5.3% of the overweight/obese children but none of the normal-weight children (p < 0.01). Overweight/obese children had higher odds (OR = 16.3; 95%CI 2.2, 461.1) of developing the metabolic syndrome compared to normal weight children. Binary logistic regression showed no significant association between age, gender and family history of communicable diseases with the metabolic syndrome. However, for ethnicity, Indians were found to have higher odds (OR = 5.5; 95%CI 1.5, 20.5) compared to Malays, with Chinese children (OR = 0.3; 95%CI 0.0, 2.7) having the lowest odds. CONCLUSIONS: We conclude that being overweight or obese poses a greater risk of developing the metabolic syndrome among children. Indian ethnicity is at higher risk compared to their counterparts of the same age. Hence, primary intervention strategies are required to prevent this problem from escalating. PMID- 21592369 TI - The World Starts With Me: a multilevel evaluation of a comprehensive sex education programme targeting adolescents in Uganda. AB - BACKGROUND: This paper evaluates the effect of the World Starts With Me (WSWM), a comprehensive sex education programme in secondary schools in Uganda. The aim of the present study was to assess the effects of WSWM on socio-cognitive determinants of safe sex behaviour (delay; condom use and non-coercive sex). METHODS: A survey was conducted both before and immediately after the intervention among students in intervention (N = 853) and comparison (N = 1011) groups. A mixed model repeated measures analysis was performed to assess the effectiveness of the WSWM programme on the main socio-cognitive determinants of safe sex behaviour at post-test. A similar post-hoc comparison was made between schools based on completeness and fidelity of implementation of WSWM. RESULTS: Significant positive effects of WSMW were found on beliefs regarding what could or could not prevent pregnancy, the perceived social norm towards delaying sexual intercourse, and the intention to delay sexual intercourse. Furthermore, significant positive effects of WSWM were found on attitudes, self-efficacy and intention towards condom use and on self-efficacy in dealing with sexual violence (pressure and force for unwanted sex). A reversed effect of intervention was found on knowledge scores relating to non-causes of HIV (petting, fondling and deep kissing). A follow-up comparison between intervention schools based on completeness of the programme implementation revealed that almost all significant positive effects disappeared for those schools that only implemented up to 7 out of 14 lessons. Another follow-up analysis on the basis of implementation fidelity showed that schools with a "partial" fidelity score yielded more significant positive effects than schools with a "full" fidelity of implementation score. CONCLUSIONS: The study showed an intervention effect on a number of socio cognitive determinants. However, the effectiveness of WSWM could be improved by giving more systematic attention to the context in which such a programme is to be implemented. Implications for the systematic development and implementation of school-based safe sex interventions in Uganda will be discussed. PMID- 21592368 TI - HIV infection and sexual risk behaviour among youth who have experienced orphanhood: systematic review and meta-analysis. AB - BACKGROUND: Previous research has suggested that orphaned children and adolescents might have elevated risk for HIV infection. We examined the state of evidence regarding the association between orphan status and HIV risk in studies of youth aged 24 years and younger. METHODS: Using systematic review methodology, we identified 10 studies reporting data from 12 countries comparing orphaned and non-orphaned youth on HIV-related risk indicators, including HIV serostatus, other sexually transmitted infections, pregnancy and sexual behaviours. We meta analyzed data from six studies reporting prevalence data on the association between orphan status and HIV serostatus, and we qualitatively summarized data from all studies on behavioural risk factors for HIV among orphaned youth. RESULTS: Meta-analysis of HIV testing data from 19,140 participants indicated significantly greater HIV seroprevalence among orphaned (10.8%) compared with non orphaned youth (5.9%) (odds ratio = 1.97; 95% confidence interval = 1.41-2.75). Trends across studies showed evidence for greater sexual risk behaviour in orphaned youth. CONCLUSIONS: Studies on HIV risk in orphaned populations, which mostly include samples from sub-Saharan Africa, show nearly two-fold greater odds of HIV infection among orphaned youth and higher levels of sexual risk behaviour than among their non-orphaned peers. Interventions to reduce risk for HIV transmission in orphaned youth are needed to address the sequelae of parental illness and death that might contribute to sexual risk and HIV infection. PMID- 21592370 TI - Effects on quality of life, anti-cancer responses, breast conserving surgery and survival with neoadjuvant docetaxel: a randomised study of sequential weekly versus three-weekly docetaxel following neoadjuvant doxorubicin and cyclophosphamide in women with primary breast cancer. AB - BACKGROUND: Weekly docetaxel has occasionally been used in the neoadjuvant to downstage breast cancer to reduce toxicity and possibly enhance quality of life. However, no studies have compared the standard three weekly regimen to the weekly regimen in terms of quality of life. The primary aim of our study was to compare the effects on QoL of weekly versus 3-weekly sequential neoadjuvant docetaxel. Secondary aims were to determine the clinical and pathological responses, incidence of Breast Conserving Surgery (BCS), Disease Free Survival (DFS) and Overall Survival (OS). METHODS: Eighty-nine patients receiving four cycles of doxorubicin and cyclophosphamide were randomised to receive twelve cycles of weekly docetaxel (33 mg/m2) or four cycles of 3-weekly docetaxel (100 mg/m2). The Functional Assessment of Cancer Therapy-Breast and psychosocial questionnaires were completed. RESULTS: At a median follow-up of 71.5 months, there was no difference in the Trial Outcome Index scores between treatment groups. During weekly docetaxel, patients experienced less constipation, nail problems, neuropathy, tiredness, distress, depressed mood, and unhappiness. There were no differences in overall clinical response (93% vs. 90%), pathological complete response (20% vs. 27%), and breast-conserving surgery (BCS) rates (49% vs. 42%). Disease-free survival and overall survival were similar between treatment groups. CONCLUSIONS: Weekly docetaxel is well-tolerated and has less distressing side effects, without compromising therapeutic responses, Breast Conserving Surgery (BCS) or survival outcomes in the neoadjuvant setting. TRIAL REGISTRATION: ISRCTN: ISRCTN09184069. PMID- 21592372 TI - Clinical characteristics and therapeutic outcomes of nosocomial super-infection in adult bacterial meningitis. AB - BACKGROUND: Super-infection in adult bacterial meningitis (ABM) is a condition wherein the cerebrospinal fluid (CSF) grows new pathogen(s) during the therapeutic course of meningitis. It is an uncommon but clinically important condition rarely examined in literature. METHODS: Twenty-seven episodes of super infection states in 21 ABM patients collected in a 9.5-year study period (January 2001 to June 2010) were evaluated. The clinical characteristics, implicated pathogens, results of antimicrobial susceptibility tests, and therapeutic outcomes were analyzed. RESULTS: Twenty-one patients (13 men, 8 women) aged 25-73 years (median, 45 years) had post-neurosurgical state as the preceding event and nosocomial infection. The post-neurosurgical states included spontaneous intracranial hemorrhage (ICH) with craniectomy or craniotomy with extra ventricular drainage (EVD) or ventriculo-peritoneal shunt (VPS) in 10 patients, traumatic ICH with craniectomy or craniotomy with EVD or VPS in 6 patients, hydrocephalus s/p VPS in 2 patients, and one patient each with cerebral infarct s/p craniectomy with EVD, meningeal metastasis s/p Omaya implant, and head injury. All 21 patients had EVD and/or VP shunt and/or Omaya implant during the whole course of ABM. Recurrent fever was the most common presentation and the implicated bacterial pathogens were protean, many of which were antibiotic resistant. Most patients required adjustment of antibiotics after the pathogens were identified but even with antimicrobial therapy, 33.3% (7/21) died. Morbidity was also high among survivors. CONCLUSIONS: Super-infection in ABM is usually seen in patients with preceding neurosurgical event, especially insertion of an external drainage device. Repeat CSF culture is mandatory for diagnostic confirmation because most of the implicated bacterial strains are non-susceptible to common antibiotics used. Unusual pathogens like anaerobic bacteria and fungi may also appear. Despite antimicrobial therapy, prognosis remains poor. PMID- 21592371 TI - Comprehensive assessment of sequence variation within the copy number variable defensin cluster on 8p23 by target enriched in-depth 454 sequencing. AB - BACKGROUND: In highly copy number variable (CNV) regions such as the human defensin gene locus, comprehensive assessment of sequence variations is challenging. PCR approaches are practically restricted to tiny fractions, and next-generation sequencing (NGS) approaches of whole individual genomes e.g. by the 1000 Genomes Project is confined by an affordable sequence depth. Combining target enrichment with NGS may represent a feasible approach. RESULTS: As a proof of principle, we enriched a ~850 kb section comprising the CNV defensin gene cluster DEFB, the invariable DEFA part and 11 control regions from two genomes by sequence capture and sequenced it by 454 technology. 6,651 differences to the human reference genome were found. Comparison to HapMap genotypes revealed sensitivities and specificities in the range of 94% to 99% for the identification of variations.Using error probabilities for rigorous filtering revealed 2,886 unique single nucleotide variations (SNVs) including 358 putative novel ones. DEFB CN determinations by haplotype ratios were in agreement with alternative methods. CONCLUSION: Although currently labor extensive and having high costs, target enriched NGS provides a powerful tool for the comprehensive assessment of SNVs in highly polymorphic CNV regions of individual genomes. Furthermore, it reveals considerable amounts of putative novel variations and simultaneously allows CN estimation. PMID- 21592373 TI - An unusual case of hypothermia associated with therapeutic doses of olanzapine: a case report. AB - INTRODUCTION: We report a case of a 42-year-old man who had symptomatic hypothermia as a result of taking olanzapine for paranoid schizophrenia. According to published data, only a few cases of hypothermia associated with olanzapine have been reported since its introduction into clinical use. CASE PRESENTATION: A 42-year-old Sri Lankan man with schizophrenia who was being treated with a therapeutic dose of olanzapine presented with reduced level of consciousness. He had a core temperature of 32 degrees C and was bradycardic. At the time of admission, the electrocardiogram showed sinus bradycardia with J waves. He did not have any risk factors for developing hypothermia except the use of olanzapine. There was improvement in his clinical condition with reversal of electrocardiogram changes following gradual rewarming and the omission of olanzapine. CONCLUSION: Hypothermia induced by antipsychotic medications is not uncommon, but olanzapine-induced hypothermia is rare and occurrence has been reported during initiation or increasing the dose. But here the patient developed hypothermia without dose adjustment. PMID- 21592374 TI - Concordance and robustness of quality indicator sets for hospitals: an analysis of routine data. AB - BACKGROUND: Hospitals are increasingly being evaluated with respect to the quality of provided care. In this setting, several indicator sets compete with one another for the assessment of effectiveness and safety. However, there have been few comparative investigations covering different sets. The objective of this study was to answer three questions: How concordant are different indicator sets on a hospital level? What is the effect of applying different reference values? How stable are the positions of a hospital ranking? METHODS: Routine data were made available to three companies offering the Patient Safety Indicators, an indicator set from the HELIOS Hospital Group, and measurements based on Disease StagingTM. Ten hospitals from North Rhine-Westphalia, comprising a total of 151,960 inpatients in 2006, volunteered to participate in this study. The companies provided standard quality reports for the ten hospitals. Composite measures were defined for strengths and weaknesses. In addition to the different indicator sets, different reference values for one set allowed the construction of several comparison groups. Concordance and robustness were analyzed using the non-parametric correlation coefficient and Kendall's W. RESULTS: Indicator sets differing only in the reference values of the indicators showed significant correlations in most of the pairs with respect to weaknesses (maximum r = 0.927, CI 0.714-0.983, p < 0.001). There were also significant correlations between different sets (maximum r = 0.829, CI 0.417-0.958, p = 0.003) having different indicators or when different methods for performance assessment were applied. The results were weaker measuring hospital strengths (maximum r = 0.669, CI 0.068 0.914, p = 0.034). In a hospital ranking, only two hospitals belonged consistently either to the superior or to the inferior half of the group. Even altering reference values or the supplier for the same indicator set changed the rank for nine out of ten hospitals. CONCLUSIONS: Our results reveal an unsettling lack of concordance in estimates of hospital performance when different quality indicator sets are used. These findings underline the lack of consensus regarding optimal validated measures for judging hospital quality. The indicator sets shared a common definition of quality, independent of their focus on patient safety, mortality, or length of stay. However, for most of the hospitals, changing the indicator set or the reference value resulted in a shift from the superior to the inferior half of the group or vice versa. Thus, while taken together the indicator sets offer the hospitals complementary pictures of their quality, on an individual basis they do not establish a reliable ranking. PMID- 21592375 TI - Femoral nerve palsy caused by ileopectineal bursitis after total hip replacement: a case report. AB - INTRODUCTION: Infectious ileopectineal bursitis is a rare complication after total hip replacement and is associated mainly with rheumatoid arthritis. The main complications are local swelling and pain, but communication of the inflamed bursa with the joint can occur, leading to subsequent cartilage damage and bone destruction. CASE PRESENTATION: We report a case of a 47-year-old Caucasian woman without rheumatoid arthritis who reported pain and palsy in her left leg almost one year after total hip replacement. She was diagnosed with an ileopectineal bursitis after total hip replacement, leading to femoral nerve palsy. The diagnosis was obtained by thorough clinical examination, the results of focused computed tomography and magnetic resonance imaging. CONCLUSION: To the best of our knowledge, this is the first report of non-infectious ileopectineal bursitis in a patient without rheumatoid arthritis as a complication of total hip replacement. This rare case underlines the importance of proper neurologic examination of persistent conditions after orthopedic intervention in otherwise healthy individuals. We believe this case should be useful for a broad spectrum of medical specialties, including orthopedics, neurology, radiology, and general practice. PMID- 21592376 TI - Mapping randomized controlled trials of treatments for eczema--the GREAT database (the Global Resource of EczemA Trials: a collection of key data on randomized controlled trials of treatments for eczema from 2000 to 2010). AB - BACKGROUND: Massive duplication of effort occurs when researchers all over the world undertake extensive searches for randomized controlled trials when preparing systematic reviews, when developing evidence-based guidelines and when applying for research funding for eczema treatments. Such duplication wastes valuable resources.Searching for randomized controlled trials of eczema is a laborious task involving scrutiny of thousands of individual references from diverse electronic databases in order to obtain a few papers of interest. Clinicians and patients who wish to find out more about a particular treatment are at risk of missing the relevant evidence if they are not trained in electronic bibliographic searching. Systematic reviews cannot be relied upon to comprehensively inform current optimal eczema treatments due to incomplete coverage and because many may be out of date.An international, publically available and comprehensive resource which brings together all randomized controlled trials on eczema treatment using a highly sensitive search has the potential to release more filtered knowledge about patient care to those who need it most and to significantly shorten the duration and costs of many clinical eczema research and guideline projects. DESCRIPTION: The Global Resource of EczemA Trials brings together information on all randomized controlled trials of eczema treatments published from the beginning of 2000 up to the end of 2010 and will be updated every month.We searched the Cochrane Central Register of Controlled Trials in The Cochrane Library and the Cochrane Skin Group Specialised Register, MEDLINE, EMBASE, LILACS, AMED and CINHAL databases. We included 268 RCTs (24th March 2011) covering over 70 different treatment interventions.The structure of the Global Resource of Eczema Trials allows the user as much, or as little, specificity when retrieving information on trials as they wish, in an easy to use format. For each trial, the database gives the citation for the published report and also provides enough information to enable a user to decide whether the trial is worth further scrutiny. CONCLUSIONS: The Global Resource of Eczema Trials has been created to facilitate knowledge mobilization into healthcare and to reduce wastage of research time through unnecessary duplication. The collective time saved by research groups around the world can now be used to make strides in optimising the treatment of eczema, in order to further benefit people with eczema. The database can be accessed free of charge at http://www.greatdatabase.org.uk. PMID- 21592377 TI - Preferential regulation of miRNA targets by environmental chemicals in the human genome. AB - BACKGROUND: microRNAs (miRNAs) represent a class of small (typically 22 nucleotides in length) non-coding RNAs that can degrade their target mRNAs or block their translation. Recent disease research showed the exposure to some environmental chemicals (ECs) can regulate the expression patterns of miRNAs, which raises the intriguing question of how miRNAs and their targets cope with the exposure to ECs throughout the genome. RESULTS: In this study, we comprehensively analyzed the properties of genes regulated by ECs (EC-genes) and found miRNA targets were significantly enriched among the EC-genes. Compared with the non-miRNA-targets, miRNA targets were roughly twice as likely to be EC-genes. By investigating the collection methods and other properties of the EC-genes, we demonstrated that the enrichment of miRNA targets was not attributed to either the potential collection bias of EC-genes, the presence of paralogs, longer 3'UTRs or more conserved 3'UTRs. Finally, we identified 1,842 significant concurrent interactions between 407 miRNAs and 497 ECs. This association network of miRNAs-ECs was highly modular and could be separated into 14 interconnected modules. In each module, miRNAs and ECs were closely connected, providing a good method to design accurate miRNA markers for ECs in toxicology research. CONCLUSIONS: Our analyses indicated that miRNAs and their targets played important roles in cellular responses to ECs. Association analyses of miRNAs and ECs will help to broaden the understanding of the pathogenesis of such chemical components. PMID- 21592378 TI - Determinants of changes in dietary patterns among Chinese immigrants: a cross sectional analysis. AB - BACKGROUND: Chinese individuals who have immigrated to a Western country initially tend to have a lower risk of cardiovascular disease (CVD) compared to people who are already living there. Some studies have found, however, that CVD risk increases over time in immigrants and that immigration to a western country is associated with changes in dietary patterns. This could have unfavourable effects on the risk of CVD. There is limited knowledge on the food patterns, awareness and knowledge about healthy nutrition among Chinese immigrants. The objective for this study is to explore changes in food patterns, and levels of awareness and knowledge of healthy nutrition by length of residence among Chinese immigrants to Canada. METHODS: 120 Chinese individuals born in China but currently living in Canada completed an assessment on socio-demographic characteristics, changes in dietary patterns and variables of awareness and knowledge about healthy foods. With ordinal logistic regression the associations between the quartiles of length of residence and dietary patterns, variables of awareness and knowledge about healthy foods were explored, adjusting for age, sex, education and body mass index. RESULTS: More than 50% of the participants reported increasing consumption of fruits and vegetables, decreasing the use of deep-frying after immigration. Increased awareness and knowledge about healthy foods was reported by more than 50% of the participants. Ordinal regression indicated that Chinese immigrants who lived in Canada the longest, compared to Chinese immigrants who lived in Canada the shortest, consumed significant greater portion sizes (OR: 9.9; 95% CI: 3.11 - 31.15), dined out more frequently (OR: 15.8; 95% CI: 5.0 - 49.85), and consumed convenience foods more often (OR: 3.5; 95% CI: 1.23 - 10.01). CONCLUSIONS: Chinese immigrants reported some favourable changes in their dietary intake and greater awareness and more knowledge about healthy foods after immigration. However, an increase in portion size, an increased frequency of dining out and an increased consumption of convenience foods could indicate some unfavourable changes. These results suggest that health promotion strategies should build on the observed benefits of improved nutritional knowledge and target areas of portion size and convenience eating. PMID- 21592379 TI - Sequence analysis of fusion protein gene of Newcastle disease virus isolated from outbreaks in Egypt during 2006. AB - BACKGROUND: Newcastle disease virus represents APMV-1 and is the most characterized among all APMV types. The F protein cleavage site sequence is a well-characterized determinant of NDV pathogenicity in chickens. In this study, the sequences of fusion protein (F) gene of three Newcastle disease virus (NDV) strains isolated from outbreak in chickens in the Al-Sharkia province of Egypt in 2006 were determined. FINDINGS: The viral genomic RNAs were extracted from the infective allantoic fluid and F gene is amplified using primer sets designed from the available sequences of NDV strains from GenBank. The pathogenicity of NDV strains was determined by three internationally recognized tests mean death time, intracerebral pathogenicity index, and intravenous pathogenicity index. The phylogenetic analysis showed that the Egypt isolates are closely related with the genotype II of class II NDV strains. CONCLUSIONS: The sequences of the F genes of the 2006 Egypt isolates are closely related to that of the 2005 Egypt isolate from the same province suggesting that these strains are probably circulating in the vaccinated bird population in Egypt until development of an outbreak. PMID- 21592380 TI - Prevalence and risk factors of malaria among children in southern highland Rwanda. AB - BACKGROUND: Increased control has produced remarkable reductions of malaria in some parts of sub-Saharan Africa, including Rwanda. In the southern highlands, near the district capital of Butare (altitude, 1,768 m), a combined community-and facility-based survey on Plasmodium infection was conducted early in 2010. METHODS: A total of 749 children below five years of age were examined including 545 randomly selected from 24 villages, 103 attending the health centre in charge, and 101 at the referral district hospital. Clinical, parasitological, haematological, and socio-economic data were collected. RESULTS: Plasmodium falciparum infection (mean multiplicity, 2.08) was identified by microscopy and PCR in 11.7% and 16.7%, respectively; 5.5% of the children had malaria. PCR-based P. falciparum prevalence ranged between 0 and 38.5% in the villages, and was 21.4% in the health centre, and 14.9% in the hospital. Independent predictors of infection included increasing age, low mid-upper arm circumference, absence of several household assets, reported recent intake of artemether-lumefantrine, and chloroquine in plasma, measured by ELISA. Self-reported bed net use (58%) reduced infection only in univariate analysis. In the communities, most infections were seemingly asymptomatic but anaemia was observed in 82% and 28% of children with and without parasitaemia, respectively, the effect increasing with parasite density, and significant also for submicroscopic infections. CONCLUSIONS: Plasmodium falciparum infection in the highlands surrounding Butare, Rwanda, is seen in one out of six children under five years of age. The abundance of seemingly asymptomatic infections in the community forms a reservoir for transmission in this epidemic-prone area. Risk factors suggestive of low socio economic status and insufficient effectiveness of self-reported bed net use refer to areas of improvable intervention. PMID- 21592381 TI - Characters of homogentisate oxygenase gene mutation and high clonality of the natural pigment-producing Vibrio cholerae strains. AB - BACKGROUND: Some microorganisms can produce pigments such as melanin, which has been associated with virulence in the host and with a survival advantage in the environment. In Vibrio cholerae, studies have shown that pigment-producing mutants are more virulent than the parental strain in terms of increased UV resistance, production of major virulence factors, and colonization. To date, almost all of the pigmented V. cholerae strains investigated have been induced by chemicals, culture stress, or transposon mutagenesis. However, during our cholera surveillance, some nontoxigenic serogroup O139 strains and one toxigenic O1 strain, which can produce pigment steadily under the commonly used experimental growth conditions, were obtained in different years and from different areas. The genes VC1344 to VC1347, which correspond to the El Tor strain N16961 genome and which comprise an operon in the tyrosine catabolic pathway, have been confirmed to be associated with a pigmented phenotype. In the present study, we investigated the mechanism of pigment production in these strains. RESULTS: Sequencing of the VC1344, VC1345, VC1346, and VC1347 genes in these pigmented strains suggested that a deletion mutation in the homogentisate oxygenase gene (VC1345) may be associated with the pigmented phenotype, and gene complementation confirmed the role of this gene in pigment production. An identical 15-bp deletion was found in the VC1345 gene of all six O139 pigment-producing strains examined, and a 10-bp deletion was found in the VC1345 gene of the O1 strain. Strict sequence conservation in the VC1344 gene but higher variance in the other three genes of this operon were observed, indicating the different stress response functions of these genes in environmental adaption and selection. On the basis of pulsed-field gel electrophoresis typing, the pigment-producing O139 strains showed high clonality, even though they were isolated in different years and from different regions. Additionally all these O139 strains belong to the rb4 ribotype, which contains the O139 strains isolated from diarrheal patients, although these strains are cholera toxin negative. CONCLUSION: Dysfunction of homogentisate oxygenase (VC1345) causes homogentisate accumulation and pigment formation in naturally pigmented strains of V. cholerae. The high clonality of these strains may correlate to an environmental survival advantage in the V. cholerae community due to their pigment production, and may imply a potential protective function of melanin in environmental survival of such strains. PMID- 21592382 TI - Recombinant HPV16 E7 assembled into particles induces an immune response and specific tumour protection administered without adjuvant in an animal model. AB - BACKGROUND: The HPV16 E7 protein is both a tumour-specific and a tumour-rejection antigen, the ideal target for developing therapeutic vaccines for the treatment of HPV16-associated cancer and its precursor lesions. E7, which plays a key role in virus-associated carcinogenesis, contains 98 amino acids and has two finger type structures which bind a Zn++ ion. The ability of an Escherichia coli produced E7-preparation, assembled into particles, to induce protective immunity against a HPV16-related tumour in the TC-1-C57BL/6 mouse tumour model, was evaluated. METHODS: E7 was expressed in E. coli, purified via a one-step denaturing protocol and prepared as a soluble suspension state after dialysis in native buffer. The presence in the E7 preparation of particulate forms was analysed by non-reducing SDS-PAGE and negative staining electron microscopy (EM). The Zn++ ion content was analysed by mass-spectrometry. Ten MUg of protein per mouse was administered to groups of animals, once, twice or three times without adjuvant. The E7-specific humoral response was monitored in mice sera using an E7 based ELISA while the cell-mediated immune response was analysed in mice splenocytes with lymphoproliferation and IFN-gamma ELISPOT assays. The E7 immunized mice were challenged with TC-1 tumour cells and the tumour growth monitored for two months. RESULTS: In western blot analysis E7 appears in multimers and high molecular mass oligomers. The EM micrographs show the protein dispersed as aggregates of different shape and size. The protein appears clustered in micro-, nano-aggregates, and structured particles. Mice immunised with this protein preparation show a significant E7-specific humoral and cell mediated immune response of mixed Th1/Th2 type. The mice are fully protected from the tumour growth after vaccination with three E7-doses of 10 MUg without any added adjuvant. CONCLUSIONS: This report shows that a particulate form of HPV16 E7 is able to induce, without adjuvant, an E7-specific tumour protection in C57BL/6 mice. The protective immunity is sustained by both humoral and cell mediated immune responses. The E. coli-derived HPV16 E7 assembled in vitro into micro- and nanoparticles represents not only a good substrate for antigen presenting cell uptake and processing, but also a cost-effective means for the production of a new generation of HPV subunit vaccines. PMID- 21592383 TI - Canada's Compassionate Care Benefit: is it an adequate public health response to addressing the issue of caregiver burden in end-of-life care? AB - BACKGROUND: An increasingly significant public health issue in Canada, and elsewhere throughout the developed world, pertains to the provision of adequate palliative/end-of-life (P/EOL) care. Informal caregivers who take on the responsibility of providing P/EOL care often experience negative physical, mental, emotional, social and economic consequences. In this article, we specifically examine how Canada's Compassionate Care Benefit (CCB)--a contributory benefits social program aimed at informal P/EOL caregivers--operates as a public health response in sustaining informal caregivers providing P/EOL care, and whether or not it adequately addresses known aspects of caregiver burden that are addressed within the population health promotion (PHP) model. METHODS: As part of a national evaluation of Canada's Compassionate Care Benefit, 57 telephone interviews were conducted with Canadian informal P/EOL caregivers in 5 different provinces, pertaining to the strengths and weaknesses of the CCB and the general caregiving experience. Interview data was coded with Nvivo software and emerging themes were identified by the research team, with such findings published elsewhere. The purpose of the present analysis was identified after comparing the findings to the literature specific to caregiver burden and public health, after which data was analyzed using the PHP model as a guiding framework. RESULTS: Informal caregivers spoke to several of the determinants of health outlined in the PHP model that are implicated in their burden experience: gender, income and social status, working conditions, health and social services, social support network, and personal health practises and coping strategies. They recognized the need for improving the CCB to better address these determinants. CONCLUSIONS: This study, from the perspective of family caregivers, demonstrates that the CCB is not living up to its full potential in sustaining informal P/EOL caregivers. Effort is required to transform the CCB so that it may fulfill the potential it holds for serving as one public health response to caregiver burden that forms part of a healthy public policy that addresses the determinants of this burden. PMID- 21592384 TI - Toxoplasma gondii down modulates cadherin expression in skeletal muscle cells inhibiting myogenesis. AB - BACKGROUND: Toxoplasma gondii belongs to a large and diverse group of obligate intracellular parasitic protozoa. Primary culture of mice skeletal muscle cells (SkMC) was employed as a model for experimental toxoplasmosis studies. The myogenesis of SkMC was reproduced in vitro and the ability of T. gondii tachyzoite forms to infect myoblasts and myotubes and its influence on SkMC myogenesis were analyzed. RESULTS: In this study we show that, after 24 h of interaction, myoblasts (61%) were more infected with T. gondii than myotubes (38%) and inhibition of myogenesis was about 75%. The role of adhesion molecules such as cadherin in this event was investigated. First, we demonstrate that cadherin localization was restricted to the contact areas between myocytes/myocytes and myocytes/myotubes during the myogenesis process. Immunofluorescence and immunoblotting analysis of parasite-host cell interaction showed a 54% reduction in cadherin expression at 24 h of infection. Concomitantly, a reduction in M-cadherin mRNA levels was observed after 3 and 24 h of T. gondii-host cell interaction. CONCLUSIONS: These data suggest that T. gondii is able to down regulate M-cadherin expression, leading to molecular modifications in the host cell surface that interfere with membrane fusion and consequently affect the myogenesis process. PMID- 21592386 TI - Primary atypical carcinoid of the breast: a case report and brief overview of evidence. AB - Primary atypical carcinoid of the breast is rare. Herein we present a case of atypical carcinoid of the breast treated with surgery. The management plan is commented. Moreover an overview of the current evidence is presented. All the evidence is classified as level IV (opinion-based evidence) since there is no satisfactory case series to support a certain therapeutic decision. The treatment for an atypical carcinoid of the breast is the same one offered in patients diagnosed with primary infiltrating breast cancer. A multi-centric approach is needed in order to gather enough data to confidently support a certain management plan for these patients. PMID- 21592385 TI - Transcellular migration of neutrophil granulocytes through the blood cerebrospinal fluid barrier after infection with Streptococcus suis. AB - BACKGROUND: A critical point during the course of bacterial meningitis is the excessive influx of polymorphnuclear neutrophils (PMNs) from the blood into the brain. Both paracellular and transcellular routes of leukocyte transmigration through the blood-brain barrier have been described in CNS diseases so far. Thus, we investigated the mechanism of PMN transmigration through the blood-CSF barrier under inflammatory conditions. METHODS: In an "inverted" Transwell culture model of the blood-CSF barrier, the zoonotic agent Streptococcus suis (S. suis) was used to stimulate porcine choroid plexus epithelial cells (PCPECs) specifically from the physiologically relevant basolateral side. Barrier function was analyzed by measuring TEER and TR-dextran-flux, and tight junction morphology was investigated by immunofluorescence. Route and mechanism of PMN transmigration were determined by immunofluorescence, electron microscopy and FACS analysis. Quantitative real time-PCR was used to determine expression levels of ICAM-1 and VCAM-1. RESULTS: Here, we show that the transmigration of PMNs through PCPECs was significantly higher after stimulation with TNFalpha or infection with S. suis strain 10 compared to its non-encapsulated mutant. Barrier function was not significantly affected by PMN migration alone, but in combination with S. suis infection. Tight junction and cytoskeletal actin reorganisation were also observed after stimulation with S. suis or TNFalpha. Most strikingly, PMNs preferentially migrated across PCPECs via the transcellular route. Extensive sequential analyses of the PMN transmigration process with Apotome((r))-imaging and electron microscopy revealed that paracellular migrating PMNs stop just before tight junctions. Interestingly, PMNs subsequently appeared to proceed by transcellular migration via funnel-like structures developing from the apical membrane. It is noteworthy that some PMNs contained bacteria during the transmigration process. Flow cytometric and transmigration inhibition studies with integrin-specific antibodies showed that PMN traversal is dependent on CD11b/CD18. Analysis of cell adhesion molecules in PCPECs revealed a significant increase of ICAM-1 and VCAM-1 expression after TNFalpha and S. suis stimulation. CONCLUSION: Our data underline the relevance of the blood-CSF barrier as a gate for leukocyte entry into the CNS and suggest a novel transcellular migration step during the pathogenesis of bacterial meningitis. PMID- 21592387 TI - A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterials. AB - BACKGROUND: The most common causes of granulomatous inflammation are persistent pathogens and poorly-degradable irritating materials. A characteristic pathological reaction to intratracheal instillation, pharyngeal aspiration, or inhalation of carbon nanotubes is formation of epithelioid granulomas accompanied by interstitial fibrosis in the lungs. In the mesothelium, a similar response is induced by high aspect ratio nanomaterials, including asbestos fibers, following intraperitoneal injection. This asbestos-like behaviour of some engineered nanomaterials is a concern for their potential adverse health effects in the lungs and mesothelium. We hypothesize that high aspect ratio nanomaterials will induce epithelioid granulomas in nonadherent macrophages in 3D cultures. RESULTS: Carbon black particles (Printex 90) and crocidolite asbestos fibers were used as well-characterized reference materials and compared with three commercial samples of multiwalled carbon nanotubes (MWCNTs). Doses were identified in 2D and 3D cultures in order to minimize acute toxicity and to reflect realistic occupational exposures in humans and in previous inhalation studies in rodents. Under serum-free conditions, exposure of nonadherent primary murine bone marrow derived macrophages to 0.5 MUg/ml (0.38 MUg/cm2) of crocidolite asbestos fibers or MWCNTs, but not carbon black, induced macrophage differentiation into epithelioid cells and formation of stable aggregates with the characteristic morphology of granulomas. Formation of multinucleated giant cells was also induced by asbestos fibers or MWCNTs in this 3D in vitro model. After 7-14 days, macrophages exposed to high aspect ratio nanomaterials co-expressed proinflammatory (M1) as well as profibrotic (M2) phenotypic markers. CONCLUSIONS: Induction of epithelioid granulomas appears to correlate with high aspect ratio and complex 3D structure of carbon nanotubes, not with their iron content or surface area. This model offers a time- and cost-effective platform to evaluate the potential of engineered high aspect ratio nanomaterials, including carbon nanotubes, nanofibers, nanorods and metallic nanowires, to induce granulomas following inhalation. PMID- 21592388 TI - A randomised controlled trial for overweight and obese parents to prevent childhood obesity--Early STOPP (STockholm Obesity Prevention Program). AB - BACKGROUND: Overweight and obesity have a dramatic negative impact on children's health not only during the childhood but also throughout the adult life. Preventing the development of obesity in children is therefore a world-wide health priority. There is an obvious urge for sustainable and evidenced-based interventions that are suitable for families with young children, especially for families with overweight or obese parents. We have developed a prevention program, Early STOPP, combating multiple obesity-promoting behaviors such unbalanced diet, physical inactivity and disturbed sleeping patterns. We also aim to evaluate the effectiveness of the early childhood obesity prevention in a well characterized population of overweight or obese parents. This protocol outlines methods for the recruitment phase of the study. DESIGN AND METHODS: This randomized controlled trial (RCT) targets overweight and/or obese parents with infants, recruited from the Child Health Care Centers (CHCC) within the Stockholm area. The intervention starts when infants are one year of age and continues until they are six and is regularly delivered by a trained coach (dietitian, physiotherapist or a nurse). The key aspects of Early STOPP family intervention are based on Swedish recommendations for CHCC, which include advices on healthy food choices and eating patterns, increasing physical activity/reducing sedentary behavior and regulating sleeping patterns. DISCUSSION: The Early STOPP trial design addresses weaknesses of previous research by recruiting from a well characterized population, defining a feasible, theory-based intervention and assessing multiple measurements to validate and interpret the program effectiveness. The early years hold promise as a time in which obesity prevention may be most effective. To our knowledge, this longitudinal RCT is the first attempt to demonstrate whether an early, long-term, targeted health promotion program focusing on healthy eating, physical activity/reduced sedentary behaviors and normalizing sleeping patterns could be effective. If proven so, Early STOPP may protect children from the development of overweight and obesity. TRIAL REGISTRATION: The protocol for this study is registered with the clinical trials registry clinicaltrials.gov, ID: ES-2010). PMID- 21592389 TI - Identification of tissue-specific, abiotic stress-responsive gene expression patterns in wine grape (Vitis vinifera L.) based on curation and mining of large scale EST data sets. AB - BACKGROUND: Abiotic stresses, such as water deficit and soil salinity, result in changes in physiology, nutrient use, and vegetative growth in vines, and ultimately, yield and flavor in berries of wine grape, Vitis vinifera L. Large scale expressed sequence tags (ESTs) were generated, curated, and analyzed to identify major genetic determinants responsible for stress-adaptive responses. Although roots serve as the first site of perception and/or injury for many types of abiotic stress, EST sequencing in root tissues of wine grape exposed to abiotic stresses has been extremely limited to date. To overcome this limitation, large-scale EST sequencing was conducted from root tissues exposed to multiple abiotic stresses. RESULTS: A total of 62,236 expressed sequence tags (ESTs) were generated from leaf, berry, and root tissues from vines subjected to abiotic stresses and compared with 32,286 ESTs sequenced from 20 public cDNA libraries. Curation to correct annotation errors, clustering and assembly of the berry and leaf ESTs with currently available V. vinifera full-length transcripts and ESTs yielded a total of 13,278 unique sequences, with 2302 singletons and 10,976 mapped to V. vinifera gene models. Of these, 739 transcripts were found to have significant differential expression in stressed leaves and berries including 250 genes not described previously as being abiotic stress responsive. In a second analysis of 16,452 ESTs from a normalized root cDNA library derived from roots exposed to multiple, short-term, abiotic stresses, 135 genes with root-enriched expression patterns were identified on the basis of their relative EST abundance in roots relative to other tissues. CONCLUSIONS: The large-scale analysis of relative EST frequency counts among a diverse collection of 23 different cDNA libraries from leaf, berry, and root tissues of wine grape exposed to a variety of abiotic stress conditions revealed distinct, tissue-specific expression patterns, previously unrecognized stress-induced genes, and many novel genes with root-enriched mRNA expression for improving our understanding of root biology and manipulation of rootstock traits in wine grape. mRNA abundance estimates based on EST library-enriched expression patterns showed only modest correlations between microarray and quantitative, real-time reverse transcription-polymerase chain reaction (qRT-PCR) methods highlighting the need for deep-sequencing expression profiling methods. PMID- 21592390 TI - Public health emergency preparedness and response communications with health care providers: a literature review. AB - BACKGROUND: Health care providers (HCPs) play an important role in public health emergency preparedness and response (PHEPR) so need to be aware of public health threats and emergencies. To inform HCPs, public health issues PHEPR messages that provide guidelines and updates, and facilitate surveillance so HCPs will recognize and control communicable diseases, prevent excess deaths and mitigate suffering. Public health agencies need to know that the PHEPR messages sent to HCPs reach their target audience and are effective and informative. Public health agencies need to know that the PHEPR messages sent to HCPs reach their target audience and are effective and informative. We conducted a literature review to investigate the systems and tools used by public health to generate PHEPR communications to HCPs, and to identify specific characteristics of message delivery mechanisms and formats that may be associated with effective PHEPR communications. METHODS: A systematic review of peer- and non-peer-reviewed literature focused on the following questions: 1) What public health systems exist for communicating PHEPR messages from public health agencies to HCPs? 2) Have these systems been evaluated and, if yes, what criteria were used to evaluate these systems? 3) What have these evaluations discovered about characterizations of the most effective ways for public health agencies to communicate PHEPR messages to HCPs? RESULTS: We identified 25 systems or tools for communicating PHEPR messages from public health agencies to HCPs. Few articles assessed PHEPR communication systems or messaging methods or outcomes. Only one study compared the effectiveness of the delivery format, device or message itself. We also discovered that the potential is high for HCPs to experience "message overload" given redundancy of PHEPR messaging in multiple formats and/or through different delivery systems. CONCLUSIONS: We found that detailed descriptions of PHEPR messaging from public health to HCPs are scarce in the literature and, even when available are rarely evaluated in any systematic fashion. To meet present-day and future information needs for emergency preparedness, more attention needs to be given to evaluating the effectiveness of these systems in a scientifically rigorous manner. PMID- 21592391 TI - Causal graph-based analysis of genome-wide association data in rheumatoid arthritis. AB - BACKGROUND: GWAS owe their popularity to the expectation that they will make a major impact on diagnosis, prognosis and management of disease by uncovering genetics underlying clinical phenotypes. The dominant paradigm in GWAS data analysis so far consists of extensive reliance on methods that emphasize contribution of individual SNPs to statistical association with phenotypes. Multivariate methods, however, can extract more information by considering associations of multiple SNPs simultaneously. Recent advances in other genomics domains pinpoint multivariate causal graph-based inference as a promising principled analysis framework for high-throughput data. Designed to discover biomarkers in the local causal pathway of the phenotype, these methods lead to accurate and highly parsimonious multivariate predictive models. In this paper, we investigate the applicability of causal graph-based method TIE* to analysis of GWAS data. To test the utility of TIE*, we focus on anti-CCP positive rheumatoid arthritis (RA) GWAS datasets, where there is a general consensus in the community about the major genetic determinants of the disease. RESULTS: Application of TIE* to the North American Rheumatoid Arthritis Cohort (NARAC) GWAS data results in six SNPs, mostly from the MHC locus. Using these SNPs we develop two predictive models that can classify cases and disease-free controls with an accuracy of 0.81 area under the ROC curve, as verified in independent testing data from the same cohort. The predictive performance of these models generalizes reasonably well to Swedish subjects from the closely related but not identical Epidemiological Investigation of Rheumatoid Arthritis (EIRA) cohort with 0.71-0.78 area under the ROC curve. Moreover, the SNPs identified by the TIE* method render many other previously known SNP associations conditionally independent of the phenotype. CONCLUSIONS: Our experiments demonstrate that application of TIE* captures maximum amount of genetic information about RA in the data and recapitulates the major consensus findings about the genetic factors of this disease. In addition, TIE* yields reproducible markers and signatures of RA. This suggests that principled multivariate causal and predictive framework for GWAS analysis empowers the community with a new tool for high-quality and more efficient discovery. REVIEWERS: This article was reviewed by Prof. Anthony Almudevar, Dr. Eugene V. Koonin, and Prof. Marianthi Markatou. PMID- 21592392 TI - Validation of actigraphy to assess circadian organization and sleep quality in patients with advanced lung cancer. AB - BACKGROUND: Many cancer patients report poor sleep quality, despite having adequate time and opportunity for sleep. Satisfying sleep is dependent on a healthy circadian time structure and the circadian patterns among cancer patients are quite abnormal. Wrist actigraphy has been validated with concurrent polysomnography as a reliable tool to objectively measure many standard sleep parameters, as well as daily activity. Actigraphic and subjective sleep data are in agreement when determining activity-sleep patterns and sleep quality/quantity, each of which are severely affected in cancer patients. We investigated the relationship between actigraphic measurement of circadian organization and self reported subjective sleep quality among patients with advanced lung cancer. METHODS: This cross-sectional and case control study was conducted in 84 patients with advanced non-small cell lung cancer in a hospital setting for the patients at Midwestern Regional Medical Center (MRMC), Zion, IL, USA and home setting for the patients at WJB Dorn Veterans Affairs Medical Center (VAMC), Columbia, SC, USA. Prior to chemotherapy treatment, each patient's sleep-activity cycle was measured by actigraphy over a 4-7 day period and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire. RESULTS: The mean age of our patients was 62 years. 65 patients were males while 19 were females. 31 patients had failed prior treatment while 52 were newly diagnosed. Actigraphy and PSQI scores showed significantly disturbed daily sleep-activity cycles and poorer sleep quality in lung cancer patients compared to healthy controls. Nearly all actigraphic parameters strongly correlated with PSQI self-reported sleep quality of inpatients and outpatients. CONCLUSIONS: The correlation of daily activity/sleep time with PSQI-documented sleep indicates that actigraphy can be used as an objective tool and/or to complement subjective assessments of sleep quality in patients with advanced lung cancer. These results suggest that improvements to circadian function may also improve sleep quality. PMID- 21592393 TI - Protein attributes contribute to halo-stability, bioinformatics approach. AB - Halophile proteins can tolerate high salt concentrations. Understanding halophilicity features is the first step toward engineering halostable crops. To this end, we examined protein features contributing to the halo-toleration of halophilic organisms. We compared more than 850 features for halophilic and non halophilic proteins with various screening, clustering, decision tree, and generalized rule induction models to search for patterns that code for halo toleration. Up to 251 protein attributes selected by various attribute weighting algorithms as important features contribute to halo-stability; from them 14 attributes selected by 90% of models and the count of hydrogen gained the highest value (1.0) in 70% of attribute weighting models, showing the importance of this attribute in feature selection modeling. The other attributes mostly were the frequencies of di-peptides. No changes were found in the numbers of groups when K Means and TwoStep clustering modeling were performed on datasets with or without feature selection filtering. Although the depths of induced trees were not high, the accuracies of trees were higher than 94% and the frequency of hydrophobic residues pointed as the most important feature to build trees. The performance evaluation of decision tree models had the same values and the best correctness percentage recorded with the Exhaustive CHAID and CHAID models. We did not find any significant difference in the percent of correctness, performance evaluation, and mean correctness of various decision tree models with or without feature selection. For the first time, we analyzed the performance of different screening, clustering, and decision tree algorithms for discriminating halophilic and non-halophilic proteins and the results showed that amino acid composition can be used to discriminate between halo-tolerant and halo-sensitive proteins. PMID- 21592395 TI - Changes in thermal nociceptive responses in dairy cows following experimentally induced Escherichia coli mastitis. AB - BACKGROUND: Mastitis is a high incidence disease in dairy cows. The acute stage is considered painful and inflammation can lead to hyperalgesia and thereby contribute to decreased welfare. The aim of this study was to examine changes in nociceptive responses toward cutaneous nociceptive laser stimulation (NLS) in dairy cows with experimentally induced Escherichia coli mastitis, and correlate behavioral changes in nociceptive responses to clinical and paraclinical variables. METHODS: Seven Danish Holstein-Friesian cows were kept in tie-stalls, where the E. coli associated mastitis was induced and laser stimulations were conducted. Measurements of rectal temperature, somatic cell counts, white blood cell counts and E. coli counts were conducted. Furthermore, scores were given for anorexia, local udder inflammation and milk appearance to quantify the local and systemic disease response. In order to quantify the nociceptive threshold, behavioral responses toward cutaneous NLS applied to six skin areas at the tarsus/metatarsus and udder hind quarters were registered at evening milking on day 0 (control) and days 1, 2, 3, 6 and 10 after experimental induction of mastitis. RESULTS: All clinical and paraclinical variables were affected by the induced mastitis. All cows were clinically ill on days 1 and 2. The cows responded behaviorally toward the NLS. For hind leg stimulation, the proportion of cows responding by stepping was higher on day 0 than days 3 and 6, and the frequency of leg movements after laser stimulation tended to decrease on day 1 compared to the other days. After udder stimulation, the proportion of cows responding by stepping was higher on day 1 than on all other days of testing. Significant correlations between the clinical and paraclinical variables of disease and the behavioral responses toward nociceptive stimulation were found. CONCLUSIONS: Changes in behavioral responses coincide with peaks in local and systemic signs of E. coli mastitis. During the acute stage of E. coli mastitis nociceptive thermal stimulation on hind leg and mammary glands results in decreased behavioral responses toward nociceptive stimulation, which might be interpreted as hypoalgesia. PMID- 21592394 TI - Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. AB - BACKGROUND: There is evidence from epidemiological and in vitro studies that the biological effects of testosterone (T) on cell cycle and survival are modulated by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in prostate cancer. To investigate the cross talk between androgen- and vitamin D-mediated intracellular signaling pathways, the individual and combined effects of T and 1,25(OH)2D3 on global gene expression in LNCaP prostate cancer cells were assessed. RESULTS: Stringent statistical analysis identifies a cohort of genes that lack one or both androgen response elements (AREs) or vitamin D response elements (VDREs) in their promoters, which are nevertheless differentially regulated by both steroids (either additively or synergistically). This suggests that mechanisms in addition to VDR- and AR-mediated transcription are responsible for the modulation of gene expression. Microarray analysis shows that fifteen miRNAs are also differentially regulated by 1,25(OH)2D3 and T. Among these miR-22, miR-29ab, miR-134, miR-1207 5p and miR-371-5p are up regulated, while miR-17 and miR-20a, members of the miR 17/92 cluster are down regulated. A number of genes implicated in cell cycle progression, lipid synthesis and accumulation and calcium homeostasis are among the mRNA targets of these miRNAs. Thus, in addition to their well characterized effects on transcription, mediated by either or both cognate nuclear receptors, 1,25(OH)2D3 and T regulate the steady state mRNA levels by modulating miRNA mediated mRNA degradation, generating attenuation feedback loops that result in global changes in mRNA and protein levels. Changes in genes involved in calcium homeostasis may have specific clinical importance since the second messenger Ca2+ is known to modulate various cellular processes, including cell proliferation, cell death and cell motility, which affects prostate cancer tumor progression and responsiveness to therapy. CONCLUSIONS: These data indicate that these two hormones combine to drive a differentiated phenotype, and reinforce the idea that the age dependent decline in both hormones results in the de-differentiation of prostate tumor cells, which results in increased proliferation, motility and invasion common to aggressive tumors. These studies also reinforce the potential importance of miRNAs in prostate cancer progression and therapeutic outcomes. PMID- 21592396 TI - Transcriptome analysis by GeneTrail revealed regulation of functional categories in response to alterations of iron homeostasis in Arabidopsis thaliana. AB - BACKGROUND: High-throughput technologies have opened new avenues to study biological processes and pathways. The interpretation of the immense amount of data sets generated nowadays needs to be facilitated in order to enable biologists to identify complex gene networks and functional pathways. To cope with this task multiple computer-based programs have been developed. GeneTrail is a freely available online tool that screens comparative transcriptomic data for differentially regulated functional categories and biological pathways extracted from common data bases like KEGG, Gene Ontology (GO), TRANSPATH and TRANSFAC. Additionally, GeneTrail offers a feature that allows screening of individually defined biological categories that are relevant for the respective research topic. RESULTS: We have set up GeneTrail for the use of Arabidopsis thaliana. To test the functionality of this tool for plant analysis, we generated transcriptome data of root and leaf responses to Fe deficiency and the Arabidopsis metal homeostasis mutant nas4x-1. We performed Gene Set Enrichment Analysis (GSEA) with eight meaningful pairwise comparisons of transcriptome data sets. We were able to uncover several functional pathways including metal homeostasis that were affected in our experimental situations. Representation of the differentially regulated functional categories in Venn diagrams uncovered regulatory networks at the level of whole functional pathways. Over Representation Analysis (ORA) of differentially regulated genes identified in pairwise comparisons revealed specific functional plant physiological categories as major targets upon Fe deficiency and in nas4x-1. CONCLUSION: Here, we obtained supporting evidence, that the nas4x-1 mutant was defective in metal homeostasis. It was confirmed that nas4x-1 showed Fe deficiency in roots and signs of Fe deficiency and Fe sufficiency in leaves. Besides metal homeostasis, biotic stress, root carbohydrate, leaf photosystem and specific cell biological categories were discovered as main targets for regulated changes in response to- Fe and nas4x-1. Among 258 differentially expressed genes in response to--Fe and nas4x-1 five functional categories were enriched covering metal homeostasis, redox regulation, cell division and histone acetylation. We proved that GeneTrail offers a flexible and user-adapted way to identify functional categories in large scale plant transcriptome data sets. The distinguished feature that allowed analysis of individually assembled functional categories facilitated the study of the Arabidopsis thaliana transcriptome. PMID- 21592398 TI - Syndromic surveillance for influenza in two hospital emergency departments. Relationships between ICD-10 codes and notified cases, before and during a pandemic. AB - BACKGROUND: Interest in the use of emergency department (ED) data by syndromic surveillance systems to detect influenza outbreaks has been growing. Evaluations of these systems generally focus on events during influenza seasons. The aims of this study were to identify which emergency department disease codes best correlated with confirmed influenza cases and to determine if these same codes would be useful in the non-influenza season. The 2009 influenza pandemic in Victoria, Australia, provided further opportunity to examine the performance of the syndromic surveillance system during this event. METHODS: We undertook a retrospective analysis of data from the Victorian Department of Health's pilot syndromic surveillance programme, 'SynSurv'. SynSurv automatically captures patient information as it is entered by ED staff. This information includes patient demographics, their presenting symptoms and a preliminary diagnosis using ICD-10 coding. To determine which codes were best correlated with influenza notifications, weekly counts for each of the ICD-10 diagnosis codes ever used in the dataset were calculated and compared with the corresponding weekly count of confirmed influenza cases. Correlations between these codes and confirmed influenza cases in the non-influenza season were then undertaken. The data covered the period from July 2001 until August 2009 and included the 2009 influenza pandemic. RESULTS: There was a marked increase in weekly counts of both laboratory-confirmed influenza cases and relevant ICD-10 codes during the influenza pandemic period. The increase in laboratory confirmed cases was more than four times greater than the previous highest number reported, in 2007, even though the influenza-like-illness activity in the community was considered comparable to 2003 and 2007. We found five ICD-10 codes to be moderately and significantly correlated with influenza cases. None of these codes was correlated with laboratory confirmed influenza notifications outside the influenza season, at least in part because of the small number of influenza cases notified during that period. CONCLUSIONS: This study suggests that the choice of codes made by ED staff to record a case of influenza-like illness is influenced by their perceptions of how much influenza is circulating at the time. The ability of syndromic surveillance to detect outbreaks early may be impeded because case diagnosis is influenced by what ED staff believes to be occurring in the community. PMID- 21592397 TI - Adaptive molecular evolution of the Major Histocompatibility Complex genes, DRA and DQA, in the genus Equus. AB - BACKGROUND: Major Histocompatibility Complex (MHC) genes are central to vertebrate immune response and are believed to be under balancing selection by pathogens. This hypothesis has been supported by observations of extremely high polymorphism, elevated nonsynonymous to synonymous base pair substitution rates and trans-species polymorphisms at these loci. In equids, the organization and variability of this gene family has been described, however the full extent of diversity and selection is unknown. As selection is not expected to act uniformly on a functional gene, maximum likelihood codon-based models of selection that allow heterogeneity in selection across codon positions can be valuable for examining MHC gene evolution and the molecular basis for species adaptations. RESULTS: We investigated the evolution of two class II MHC genes of the Equine Lymphocyte Antigen (ELA), DRA and DQA, in the genus Equus with the addition of novel alleles identified in plains zebra (E. quagga, formerly E. burchelli). We found that both genes exhibited a high degree of polymorphism and inter-specific sharing of allele lineages. To our knowledge, DRA allelic diversity was discovered to be higher than has ever been observed in vertebrates. Evidence was also found to support a duplication of the DQA locus. Selection analyses, evaluated in terms of relative rates of nonsynonymous to synonymous mutations (dN/dS) averaged over the gene region, indicated that the majority of codon sites were conserved and under purifying selection (dN = 35 degrees C for three or more days) occurring in 2008 and 2009 and previous heatwaves occurring between 1993 and 2008 were compared with rates during all non-heatwave days (1 October to 31 March). Incidence rate ratios (IRRs) were established for ambulance call-outs, hospital admissions, emergency department presentations and mortality. Dose response effects of heatwave duration and intensity were examined. RESULTS: Ambulance call-outs during the extreme 2008 and 2009 events were increased by 10% and 16% respectively compared to 4.4% during previous heatwaves. Overall increases in hospital and emergency settings were marginal, except for emergency department presentations in 2008, but increases in specific health categories were observed. Renal morbidity in the elderly was increased during both heatwaves. During the 2009 heatwave, direct heat-related admissions increased up to 14-fold compared to a three-fold increase seen during the 2008 event and during previous heatwaves. In 2009, marked increases in ischaemic heart disease were seen in the 15-64 year age group. Only the 2009 heatwave was associated with considerable increases in total mortality that particularly affected the 15-64 year age group (1.37; 95% CI, 1.09, 1.71), while older age groups were unaffected. Significant dose-response relationships were observed for heatwave duration (ambulance, hospital and emergency setting) and intensity (ambulance and mortality). CONCLUSIONS: While only incremental increases in morbidity and mortality above previous findings occurred in 2008, health impacts of the 2009 heatwave stand out. These findings send a signal that the intense and long 2009 heatwave may have exceeded the capacity of the population to cope. It is important that risk factors contributing to the adverse health outcomes are investigated to further improve preventive strategies. PMID- 21592411 TI - Spontaneous remission of Crohn's disease following a febrile infection: case report and literature review. AB - Crohn's disease is a chronic illness that may often follow a relapsing-remitting course. Many of the factors that may be associated with the spontaneous remission of this disease (i.e. not related to specific treatment) remain to be determined. In the present report, we review the medical history of a patient with a long history of moderate to severe Crohn's whose complete remission immediately followed the development of a febrile infection.The patient first developed symptoms of Crohn's in her late adolescent years. At the time of diagnosis at age 23, she was placed on mesalamine--without effective control her disease symptoms. Due to progressive deterioration, the patient underwent a bowel resection at age 25. Soon afterwards symptoms recurred, gradually increasing in severity. In February 2005, at age 36, the patient developed a painful abscess associated with a rectal fistula. Other symptoms at the time included chronic bone and stomach pain, swollen joints, and debilitating fatigue. Surgical correction was scheduled in mid-March. In late February, the patient developed a respiratory infection associated with fevers of 103-104 degrees F. After the onset of fever, the abscess pain disappeared and this was soon followed by a disappearance of all other disease symptoms. By the time the corrective surgery occurred, she had no Crohn's symptoms. Her remission lasted 10 weeks when the previous symptoms then reappeared. The patient has subsequently used a variety of conventional therapies, but still suffers from severe symptoms of her disease.In recent years, a growing body of literature has emphasized the important role that innate immunity plays in the etiology of Crohn's disease; however, a key component of innate immunity, the febrile response, has been overlooked. Other cases of spontaneous remission following febrile infection in inflammatory bowel disease have been reported. Moreover, induction of a febrile response was in the past used as a treatment for inflammatory bowel disease, but was later replaced by surgery and corticosteroids. Further exploration of this arm of the innate immune response may provide new opportunities for patients where conventional therapies fail to secure relief. PMID- 21592412 TI - TAFFEL: Independent Enrichment Analysis of gene sets. AB - BACKGROUND: A major challenge in genomic research is identifying significant biological processes and generating new hypotheses from large gene sets. Gene sets often consist of multiple separate biological pathways, controlled by distinct regulatory mechanisms. Many of these pathways and the associated regulatory mechanisms might be obscured by a large number of other significant processes and thus not identified as significant by standard gene set enrichment analysis tools. RESULTS: We present a novel method called Independent Enrichment Analysis (IEA) and software TAFFEL that eases the task by clustering genes to subgroups using Gene Ontology categories and transcription regulators. IEA indicates transcriptional regulators putatively controlling biological functions in studied condition. CONCLUSIONS: We demonstrate that the developed method and TAFFEL tool give new insight to the analysis of differentially expressed genes and can generate novel hypotheses. Our comparison to other popular methods showed that the IEA method implemented in TAFFEL can find important biological phenomena, which are not reported by other methods. PMID- 21592413 TI - Urine culture doubtful in determining etiology of diffuse symptoms among elderly individuals: a cross-sectional study of 32 nursing homes. AB - BACKGROUND: The high prevalence of bacteriuria in elderly individuals makes it difficult to know if a new symptom is related to bacteria in the urine. There are different views concerning this relationship and bacteriuria often leads to antibiotic treatments. The aim of this study was to investigate the relationship between bacteria in the urine and new or increased restlessness, fatigue, confusion, aggressiveness, not being herself/himself, dysuria, urgency and fever in individuals at nursing homes for elderly when statistically considering the high prevalence of asymptomatic bacteriuria in this population. METHODS: In this cross-sectional study symptoms were registered and voided urine specimens were collected for urinary cultures from 651 elderly individuals. Logistic regressions were performed to evaluate the statistical correlation between bacteriuria and presence of a symptom at group level. To estimate the clinical relevance of statistical correlations at group level positive and negative etiological predictive values (EPV) were calculated. RESULTS: Logistic regression indicated some correlations at group level. Aside from Escherichia coli in the urine and not being herself/himself existing at least one month, but less than three months, EPV indicated no clinically useful correlation between any symptoms in this study and findings of bacteriuria. CONCLUSIONS: Urinary cultures provide little or no useful information when evaluating diffuse symptoms among elderly residents of nursing homes. Either common urinary tract pathogens are irrelevant, or urine culture is an inappropriate test. PMID- 21592414 TI - Accuracy and quality assessment of 454 GS-FLX Titanium pyrosequencing. AB - BACKGROUND: The rapid evolution of 454 GS-FLX sequencing technology has not been accompanied by a reassessment of the quality and accuracy of the sequences obtained. Current strategies for decision-making and error-correction are based on an initial analysis by Huse et al. in 2007, for the older GS20 system based on experimental sequences. We analyze here the quality of 454 sequencing data and identify factors playing a role in sequencing error, through the use of an extensive dataset for Roche control DNA fragments. RESULTS: We obtained a mean error rate for 454 sequences of 1.07%. More importantly, the error rate is not randomly distributed; it occasionally rose to more than 50% in certain positions, and its distribution was linked to several experimental variables. The main factors related to error are the presence of homopolymers, position in the sequence, size of the sequence and spatial localization in PT plates for insertion and deletion errors. These factors can be described by considering seven variables. No single variable can account for the error rate distribution, but most of the variation is explained by the combination of all seven variables. CONCLUSIONS: The pattern identified here calls for the use of internal controls and error-correcting base callers, to correct for errors, when available (e.g. when sequencing amplicons). For shotgun libraries, the use of both sequencing primers and deep coverage, combined with the use of random sequencing primer sites should partly compensate for even high error rates, although it may prove more difficult than previous thought to distinguish between low-frequency alleles and errors. PMID- 21592415 TI - 454 sequencing of pooled BAC clones on chromosome 3H of barley. AB - BACKGROUND: Genome sequencing of barley has been delayed due to its large genome size (ca. 5,000 Mbp). Among the fast sequencing systems, 454 liquid phase pyrosequencing provides the longest reads and is the most promising method for BAC clones. Here we report the results of pooled sequencing of BAC clones selected with ESTs genetically mapped to chromosome 3H. RESULTS: We sequenced pooled barley BAC clones using a 454 parallel genome sequencer. A PCR screening system based on primer sets derived from genetically mapped ESTs on chromosome 3H was used for clone selection in a BAC library developed from cultivar "Haruna Nijo". The DNA samples of 10 or 20 BAC clones were pooled and used for shotgun library development. The homology between contig sequences generated in each pooled library and mapped EST sequences was studied. The number of contigs assigned on chromosome 3H was 372. Their lengths ranged from 1,230 bp to 58,322 bp with an average 14,891 bp. Of these contigs, 240 showed homology and colinearity with the genome sequence of rice chromosome 1. A contig annotation browser supplemented with query search by unique sequence or genetic map position was developed. The identified contigs can be annotated with barley cDNAs and reference sequences on the browser. Homology analysis of these contigs with rice genes indicated that 1,239 rice genes can be assigned to barley contigs by the simple comparison of sequence lengths in both species. Of these genes, 492 are assigned to rice chromosome 1. CONCLUSIONS: We demonstrate the efficiency of sequencing gene rich regions from barley chromosome 3H, with special reference to syntenic relationships with rice chromosome 1. PMID- 21592416 TI - The impact of husbands' gender equity awareness on wives' reproductive health in rural areas of China. AB - OBJECTIVE: The aim of this study was to investigate the effect of husbands' gender equity awareness on wives' reproductive health in rural areas of China. METHODS: A qualitative study of 1919 wives aged from 18 to 69 years and their husbands was conducted in rural China. Data were collected through 3838 structured interviews. We quantified "belief in gender equity" based on responses to 7 specific statements and graded the responses according to a system scoring the strength of the overall belief (a total score 19 or higher, strong; 15-18, moderate; and 14 or less, weak). Data were recorded by bi-input with EpiData 3.1 after being carefully checked. chi(2) tests and logistic regression were performed in this study. RESULTS: Only 20.0% of the husbands demonstrated strong convictions about gender equity. Husbands' gender equity awareness is related to wives' receiving any prenatal care, the number of prenatal visits to a healthcare provider, having a hospital delivery of a newborn, and having gynecological examination one time per year. CONCLUSION: Raising husbands' gender awareness on wives' reproductive health and reducing female illiteracy were very necessary. The whole community should participate actively in the progress of reproductive health promotion. China's Health System requires an integration of its various sectors, including family planning, maternal and child care in resource sharing, and service delivery. TARGET AUDIENCE: Obstetricians & gynecologists. LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to evaluate the impact of husbands' gender equity awareness on wives' reproductive health in rural areas of China; assess how raising husbands' gender awareness on wives' reproductive health and reducing female illiteracy will improve wives' reproductive health; and analyze how China's Health System can integrate its various sectors, including family planning, maternal, and childcare in resource sharing, and service delivery, to improve wives' reproductive health. PMID- 21592417 TI - Lymphocytic adenohypophysitis. AB - Lymphocytic adenohypophysitis is a rare but important cause of decreased pituitary function, which predominantly affects young women in pregnancy or the peripartum period. It is an autoimmune disease of the pituitary gland which can present with varying degrees of pituitary hormonal impairment and/or with symptoms related to pituitary enlargement. TARGET AUDIENCE: Obstetricians & gynecologists. LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to describe the given clinical features of lymphocytic hypophysitis, conduct a differential diagnosis, and select the appropriate treatments for patients with lymphocytic hypophysitis. PMID- 21592418 TI - Transient Horner syndrome following epidural anesthesia for labor: case report and review of the literature. AB - Epidural anesthesia is a widely used method for pain control during labor; nevertheless, it is not without risks. Horner syndrome is an uncommon related complication. We report a case of transient Horner syndrome following epidural anesthesia and a review of the literature. We discuss the pathophysiologic and contributing factors to this syndrome and its potential complications. TARGET AUDIENCE: Obstetricians & gynecologists, family physicians. LEARNING OBJECTIVES: After completion of this activity, physicians will be able to educate healthcare professionals working on the labor ward to be able to estimate the small incidence of Horner Syndrome following epidural anesthesia administered in labor. This will result in optimal management and will minimize the need for costly and inappropriate diagnostic investigations. The reader will also be able to compare the difference in the incidence of Horner syndrome following epidural anesthesia, as reported in the literature; appraise the clinical presentation, the pathophysiology, and the mechanism of Horner syndrome developing as a complication of regional anesthesia; and analyze the different theories proposed in the reported cases in the literature. PMID- 21592419 TI - Adult obesity prevalence in Canada and the United States. AB - Obesity is a public health challenge throughout the world. Ongoing monitoring of trends in obesity is important to assess interventions aimed at preventing or reducing the burden of obesity. Since the 1960s, measured height and weight have been collected in the United States as part of the National Health and Nutrition Examination Survey (NHANES). In Canada, data on measured height and weight have been collected from nationally representative samples of the population less regularly. This changed in 2007 with the launch of the Canadian Health Measures Survey (CHMS), the scope and purpose of which are similar to those of NHANES. The objective of this report is to compare estimates of the prevalence of obesity between Canadian and American adults. PMID- 21592420 TI - Health insurance affects diagnosis and control of hypercholesterolemia and hypertension among adults aged 20-64: United States, 2005-2008. AB - Lack of health insurance presents a barrier to obtaining routine preventive care and early diagnosis and management of chronic conditions. In 2005-2008, approximately 23% of adults aged 20-64 had no health insurance. Hypercholesterolemia (high total cholesterol or taking medication to lower cholesterol) and hypertension (high blood pressure or taking medication to lower blood pressure) are major risk factors for cardiovascular disease, particularly when untreated and uncontrolled and are common among nonelderly adults. In 2005 2008, 23% of adults aged 20-64 had hypercholesterolemia and 23% had hypertension. The objective of this report is to quantify the association between health insurance coverage and the diagnosis and control of hypercholesterolemia and hypertension among persons with those conditions. The criteria used to define these conditions are provided in the "Definitions" section of the report. PMID- 21592421 TI - U.S. teenage birth rate resumes decline. AB - Teenage childbearing has been the subject of long-standing concern among the public and policy makers. Teenagers who give birth are much more likely to deliver a low birthweight or preterm infant than older women, and their babies are at elevated risk of dying in infancy. The annual public costs associated with teen childbearing have been estimated at $9.1 billion. The U.S. teen birth rate fell by more than one-third from 1991 through 2005, but then increased by 5 percent over two consecutive years. Data for 2008 and 2009, however, indicate that the long-term downward trend has resumed. Although the recent declines have been widespread by age, race and ethnicity, and state, large disparities nevertheless persist in these characteristics. The most current data available from the National Vital Statistics System are used to illustrate trends and variations through 2009. PMID- 21592422 TI - Vitamin D status: United States, 2001-2006. AB - The Institute of Medicine (IOM) recently released new dietary reference intakes for calcium and vitamin D. The IOM defined four categories of vitamin D status based on serum 25-hydroxyvitamin D (25OHD): (i) risk of deficiency, (ii) risk of inadequacy, (iii) sufficiency, and (iv) above which there may be reason for concern. This brief presents the most recent national data on vitamin D status in the U.S. population based on these IOM categories. Results are presented by age, sex, race and ethnicity, and, for women, by pregnancy and lactation status. PMID- 21592423 TI - Recent decline in births in the United States, 2007-2009. AB - KEY FINDINGS: From 2007 through 2009, birth rates for women aged 15-44 (fertility rates) fell for most states and nearly all major population subgroups. Birth rates declined for all women under age 40 with some of the largest decreases for women in their peak childbearing years. Fertility rates dropped for all major racial and Hispanic groups with the largest declines among Hispanic women. Birth rates by live-birth order also fell with the largest declines for third-order births and progressively smaller declines for second- and first-order births. Fertility rates decreased or were unchanged in every state and the District of Columbia with the largest declines among western and southeastern states. The number of births in the United States reached an all-time high of 4,316,233 in 2007, but that number has since fallen. From 2007 through 2009, births fell 4 percent to 4,131,019; and the provisional count of births through June 2010 indicated continued declines. Fertility rates--which relate the number of births to women aged 15-44 (i.e., the childbearing years)--also fell during this time frame.This report takes a more detailed look at the decline in births from 2007 through 2009 by mother's age, race and ethnicity, birth order, and state. The analysis is based on a comparison of 2007 final and 2009 preliminary birth data from the National Vital Statistics System (NVSS), and are the most current detailed birth data available. PMID- 21592424 TI - Dietary supplement use among U.S. adults has increased since NHANES III (1988 1994). AB - KEY FINDINGS: Use of dietary supplements is common among the U.S. adult population. Over 40% used supplements in 1988-1994, and over one-half in 2003 2006. Multivitamins/multiminerals are the most commonly used dietary supplements, with approximately 40% of men and women reporting use during 2003-2006. Use of supplemental calcium increased from 28% during 1988-1994 to 61% during 2003-2006 among women aged 60 and over. Use of supplements containing folic acid among women aged 20-39 did not increase since 1988-1994. In 2003-2006, 34% of women aged 20-39 used a dietary supplement containing folic acid. Use of dietary supplements containing vitamin D increased from 1988-1994 through 1999-2002 for men and women in most age groups. Dietary supplements can contain nutrients in amounts as high as or higher than the Institute of Medicine's Recommended Dietary Reference Intakes, therefore contributing substantially to total nutrient intake. Dietary supplements are widely available to U.S. consumers, and monitoring their use over time is an important component of the National Nutrition Monitoring System. Failure to include these nutrients when assessing the adequacy of diets and nutrition in the U.S. population may lead to inaccurate and misleading results. This report provides estimates of dietary supplement use for specific population groups over time. In addition to overall use of dietary supplements, this report focuses on estimates for specific nutrients consumed through dietary supplement use. PMID- 21592426 TI - The emerging role of antiretroviral agents in HIV prevention. PMID- 21592427 TI - Should we start screening for anal squamous intra-epithelial lesions in HIV infected homosexual men? PMID- 21592428 TI - A review of the epidemiology, diagnosis and evidence-based management of Mycoplasma genitalium. AB - Mycoplasma genitalium is attracting increasing recognition as an important sexually transmitted pathogen. Presented is a review of the epidemiology, detection, presentation and management of M. genitalium infection. Accumulating evidence suggests that M. genitalium is an important cause of non-gonococcal, non chlamydial urethritis and cervicitis, and is linked with pelvic inflammatory disease and, possibly, obstetric complications. Although there is no standard detection assay, several nucleic acid amplification tests have >95% sensitivity and specificity for M. genitalium. To date, there is a general lack of established protocols for screening in public health clinics. Patients with urethritis or cervicitis should be screened for M. genitalium and some asymptomatic sub-groups should be screened depending on individual factors and local prevalence. Investigations estimating M. genitalium geographic prevalence document generally low incidence, but some communities exhibit infection frequencies comparable to that of Chlamydia trachomatis. Accumulating evidence supports an extended regimen of azithromycin for treatment of M. genitalium infection, as data suggest that stat 1 g azithromycin may be less effective. Although data are limited, azithromycin-resistant cases documented to date respond to an appropriate fluoroquinolone (e.g. moxifloxacin). Inconsistent clinical recognition of M. genitalium may result in treatment failure and subsequent persistence due to ineffective antibiotics. The contrasting nature of existing literature regarding risks of M. genitalium infection emphasises the need for further carefully controlled studies of this emerging pathogen. PMID- 21592429 TI - Unveiling the hidden epidemic: a review of stigma associated with sexually transmissible infections. AB - Stigma has long accompanied sexually transmissible infections (STI) and hindered prevention and control efforts. It not only acts as a formidable barrier to STI testing, treatment and disclosure, but has a multitude of consequences for the health and quality of life of infected individuals. This review summarises the literature related to STI stigma and offers practical approaches to counter STI associated stigma through multi-level efforts. Specifically, it describes the key sources that breed and perpetuate stigma, outlines how STI-associated stigma has been conceptualised and measured in the literature, documents the impact of stigma on infected and uninfected individuals, and summarises the stigma reduction strategies recommended in the literature. Gaps in the literature are identified and areas for further research are suggested, along with practical strategies for moving forward. PMID- 21592430 TI - Measuring human papillomavirus (HPV) vaccination coverage and the role of the National HPV Vaccination Program Register, Australia. AB - Accurate estimates of HPV vaccination coverage are critical for determining the proportion of the target female population that is not protected by the vaccine, as well as for monitoring the performance of vaccine delivery programs. The implementation of an HPV vaccination register, either as part of an existing immunisation register or stand-alone, can add substantial benefits to an HPV vaccination program. In Australia, the National HPV Vaccination Program Register supports the HPV vaccination program by providing information to consumers and providers about incomplete courses as well as estimates of vaccination coverage by age and area. Future monitoring of vaccine effectiveness will be facilitated by cross-linking to Pap test registries. PMID- 21592431 TI - HIV seroconversions among male non-occupational post-exposure prophylaxis service users: a data linkage study. AB - BACKGROUND: Despite widespread prescription of non-occupational post-exposure prophylaxis (NPEP) in Victoria, little is known about subsequent HIV acquisition among NPEP users. We linked the Victorian NPEP Service (VNPEPS) database and the Victorian HIV Surveillance Registry to determine the number, incidence rate and predictive factors of HIV seroconversions among users of the VNPEPS. METHODS: Records from male patients that received NPEP in the VNPEPS database (n = 1420) between January 2001 and February 2008 were linked with all entries in the Victorian HIV Surveillance Registry up to May 2008. RESULTS: Sixty-one men who presented to the VNPEPS were identified as HIV seropositive; 16 of these were diagnosed at initial presentation for NPEP. The incidence of HIV seroconversion in males who were HIV seronegative at first presentation for NPEP was 1.27 (95% confidence interval 0.95-1.70) per 100 person-years. There was no association between HIV seroconversion and number of NPEP presentations or age. The median age of seroconversion was 34.6 years. CONCLUSION: The incidence of HIV infection among men presenting to the VNPEPS is slightly lower than the HIV incidence in NPEP users in a recent Australian cohort study of men who have sex with men, but higher than HIV incidence in general gay male populations. Frequency of NPEP use was not associated with risk of HIV seroconversion. Examination of risk behaviour before and after NPEP use in this population is required to further assess the impact of NPEP availability and use on HIV incidence rates and risk behaviour in Australia. PMID- 21592432 TI - HIV serosorting among HIV-positive men who have sex with men is associated with increased self-reported incidence of bacterial sexually transmissible infections. AB - BACKGROUND: We aimed to quantify the frequency of HIV serosorting among men who have sex with men (MSM) in Germany, and evaluate the association of serosorting with other sexual risk management approaches (RMA) and with the frequency of bacterial sexually transmissible infections (STI). METHODS: An anonymous, self administered questionnaire was distributed through German online sexual networking sites and medical practices in 2006. The analysis was based on 2985 respondents who reported an HIV test result. Based on two questions on RMA, serosorting was classified as tactical (an event-based decision) or strategic (a premeditated search for a seroconcordant partner). The analysis was stratified by HIV serostatus and seroconcordant partnership status. RESULTS: HIV serosorting patterns were different for HIV-positive and HIV-negative participants. Tactical serosorting ranked second after RMA based on condom use (HIV-positive: 55.1%, HIV negative: 45.1%; P < 0.001). While the overlap of strategic and tactical HIV serosorting among HIV-positive MSM was substantial (58.0%), HIV-negative strategic and tactical serosorting were more distinct (18.1% overlap). Among HIV positive and HIV-negative respondents, tactical serosorting was associated with reduced condom use. Compared with respondents using RMA other than serosorting, HIV-positive men reporting serosorting had a three-fold increased risk for bacterial STI (strategic: odds ratio (OR) = 2.62; 95% confidence interval (CI): 1.76-3.89; tactical: OR = 3.19; 95% CI: 2.14-4.75; both for respondents without HIV seroconcordant partners). CONCLUSIONS: HIV serosorting has emerged as a common RMA among MSM. For HIV-positive MSM, it may contribute to high rates of bacterial STI that may lead to elevated per-contact risks for HIV transmission. PMID- 21592433 TI - Evaluation of Health Map: a patient-centred web-based service for supporting HIV infected patients. AB - BACKGROUND: Our aim was to describe the use of and responses to a self-management website, 'Health Map', established to address the key chronic health issues of HIV-positive people. METHODS: Health Map assessed health issues against current recommendations for: treatment adherence, monitoring CD4 counts and viral load, psychological health and physical activity, vaccination, cholesterol, fasting blood sugar, blood pressure, alcohol consumption, smoking, body mass index, and cervical screening for women and sexually transmissible infection (STI) screening for men who have sex with men (MSM). RESULTS: A total of 552 people, with a mean age of 37 years, completed the full 'Health Map' program, of whom 536 (97%) were Australian, 425 (77%) were male, including 268 (63%) MSM. Online responses to several health indices were of concern: 49% missed at least one dose of antiretroviral therapy per month and only 41% had had an HIV viral load test in the 4 months prior. Only 43% reported regular physical activity, and 49% and 61% reported vaccination for hepatitis A and B. The proportion tested within the recommended periods for fasting cholesterol (40%), fasting blood sugar (35%) and cervical screening (43%) in women or STI screening for MSM (53%) were low. CONCLUSIONS: A substantial proportion of individuals completing the online survey reported information that would suggest their HIV and more general health care is suboptimal. These data are consistent with community surveys and indicate the need for improvement in the chronic management of HIV. PMID- 21592435 TI - Symptomatic and asymptomatic early neurosyphilis in HIV-infected men who have sex with men: a retrospective case series from 2000 to 2007. AB - BACKGROUND: The rise in serious complications of early syphilis, including neurosyphilis, particularly in those with HIV infection and in men who have sex with men (MSM), is of concern. OBJECTIVES: To review the manifestations and management of neurosyphilis in a population of HIV-infected MSM. METHODS: Retrospective review of patients with HIV and early neurosyphilis in three centres in Melbourne, Australia, in 2000-07. RESULTS: Eighteen male HIV patients met the criteria for diagnosis of early neurosyphilis. Thirteen patients (72.2%) had neurological symptoms: six with headache (33.3%), four with tinnitus (22.2%) and five with impaired vision (27.8%), and one patient each with ataxia, leg weakness and anal discharge with faecal incontinence. Five patients (27.8%) reported no neurological symptoms. All had serum rapid plasma reagin (RPR) titres >=1:32 and all except one had cerebrospinal fluid positive for syphilis fluorescent treponemal antibodies-absorbed. After treatment with 14-15 days of 1.8 g intravenous benzylpenicillin 4-hourly, 12 of 17 patients (71%) demonstrated a four-fold drop in serum RPR titre over 6-12 months and were considered successfully treated. A rise in RPR was noted in three patients during the 12 month follow-up period, suggesting re-infection or recurrence. CONCLUSION: HIV infected patients found to have syphilis either because of symptoms or by routine screening should be carefully assessed for neurological, ophthalmic and otological symptoms and signs. A low threshold for a diagnostic lumbar puncture to exclude the diagnosis of neurosyphilis enables appropriate administration and dose of penicillin for treatment, which appears successful in ~75% of cases. PMID- 21592434 TI - Primary prevention lessons learned from those with HIV in Chennai, India. AB - BACKGROUND: As each HIV-infected individual represents a breakdown of HIV primary prevention measures, formative data from representative individuals living with HIV can help shape future primary prevention interventions. Little is known about sexual behaviours and other transmission risk factors of high-risk group members who are already HIV-infected in Chennai, India. METHODS: Semi-structured qualitative interviews were conducted with 27 HIV-infected individuals representing each high-risk group in Chennai (five men who have sex with men (MSM), five female commercial sex workers (CSW), four truckers and other men who travel for business, four injecting drug users (IDU), five married male clients of CSW, and four wives of CSW clients, MSM, truckers, and IDU). RESULTS: Themes relevant to HIV primary prevention included: (1) HIV diagnosis as the entry into HIV education and risk reduction, (2) reluctance to undergo voluntary counselling and testing, (3) gender and sexual roles as determinants of condom use, (4) misconceptions about HIV transmission, and (5) framing and accessibility of HIV education messages. CONCLUSIONS: These qualitative data can be used to develop hypotheses about sexual risk taking in HIV-infected individuals in South India, inform primary prevention intervention programs, and improve primary prevention efforts overall. PMID- 21592436 TI - Changes in depression in a cohort of Danish HIV-positive individuals: time for routine screening. AB - BACKGROUND: The aim of this study was to follow a cohort of HIV-positive individuals for 3 years in order to assess changes in depression, adherence, unsafe sex and emotional strains from living with HIV. METHODS: Participants were assessed for depression, adherence, emotional strain and unsafe sex via a questionnaire. The Beck Depression Inventory II (BDI) was used to assess the prevalence and severity of depressive symptoms. Patients with a BDI score of 20 or above (moderate to major depression) were offered a clinical evaluation by a consultant psychiatrist. RESULTS: In 2005, 205 HIV-positive individuals participated in the study. Symptoms of depression (BDI >14) were observed in 77 (38%) and major depression (BDI >=20) in 53 (26%) individuals. In 2008, 148 participants were retested (72% of original sample). Depression (BDI >14) was observed in 38 (26%) and symptoms of major depression (BDI >=20) in 24 (16%) individuals. Patients at risk of moderate to major depression were more likely to be non-adherent to medications, to practice unsafe sex and to suffer from emotional strains compared with patients not at risk of depression, both at baseline (2005) and follow-up (2008). CONCLUSION: This study demonstrated a decline in depression scores over time and an association between the risk of depression and low medication adherence, stress and unsafe sex. We recommend routine screening for depression to be conducted regularly to provide full evaluations and relevant psychiatric treatment. PMID- 21592437 TI - Effects of periodic presumptive treatment on three bacterial sexually transmissible infections and HIV among female sex workers in Port Moresby, Papua New Guinea. AB - BACKGROUND: Sexually transmissible infections (STI) are common in female sex workers (FSW). AIM: To determine if 3-monthly periodic presumptive treatments (PPT) would reduce the prevalence of STI in FSW. METHODS: In a cohort study conducted between November 2003 and September 2004, FSW were enrolled, counselled and interviewed. Informed consent was obtained. Testing by using polymerase chain reaction (PCR) for Chlamydia trachomatis (Ct), Neisseria gonorrhoeae (Ng) and Trichomonas vaginalis (Tv), and serology for HIV were performed at baseline and final follow-up visits. Each FSW received 3-monthly oral amoxicillin, probenecid, a combination of amoxicillin and clavulanic acid, and azithromycin. Tinidazole was administered once. RESULTS: The cohort consisted of 129 FSW at baseline and 71 at final follow-up visit. Of these 71 FSW, there was a significant decline in the proportion with positive PCR results for Ct from 38% to 16% (P=0.001), Ng from 56% to 23% (P=<0.001) and Tv from 62% to 30% (P=<0.001) between baseline and the final follow-up visit. HIV prevalence increased from 15% to 21% (P=0.125). CONCLUSIONS: PPT was statistically effective in reducing STI but rates rebounded rapidly. Several new HIV infections occurred. If PPT is to be very effective in FSW where the prevalence of STI is so high, then 100% condom use with clients and regular sexual partners (RSP), and high rates of notification of RSP would be required if low incidence and prevalence of STI were to be achievable. PMID- 21592438 TI - Hepatitis B virus and hepatitis C virus infections among female sex workers and men who have sex with men in Lebanon: prevalence, risk behaviour and immune status. AB - BACKGROUND: The aim of our study was to study the prevalence of and the risk behaviours associated with the hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among two high-risk groups: female sex workers (FSW) and men who have sex with men (MSM). Furthermore, since vaccination is a key component of HBV prevention programs, the immune status of HBV infection in these two high-risk groups was evaluated. METHODS: Participants included in this study were part of a bio-behavioural surveillance study done to assess HIV prevalence among four vulnerable groups in Lebanon. Participants were recruited using a respondent driven sampling method. The total number of eligible participants were 101 MSM and 103 FSW. Blood samples were collected as dried blood spots and then eluted to be tested for HCV, HBV and HIV by enzyme-linked immunosorbent assay. RESULTS: None of the 204 individuals tested has been exposed to HCV. In the 101 MSM, only one (0.99%) was an HBsAg carrier and one (0.99%) was confirmed as anti-HIV positive. Among FSW, 30% showed they were immune to HBV compared with only ~10% among MSM. The distribution of socio-demographic characteristics and potential risk factors in both groups were shown. CONCLUSION: Our results highlight the urgent need to raise awareness among FSW and MSM and their health care providers of the availability and benefits of HBV vaccination in Lebanon. In addition, and due to the absence of vaccines against HCV and HIV, education programs aiming at behavioural changes should be intensified. PMID- 21592439 TI - Impact evaluation of a youth sexually transmissible infection awareness campaign using routinely collected data sources. AB - BACKGROUND: Young people are at high risk of sexually transmissible infections (STI) and notifications of chlamydia are rising rapidly. In 2007, a Victorian multimedia campaign aimed to increase STI testing and condom use among 18-25-year olds. We conducted a retrospective impact evaluation using multiple sources of routinely collected data. METHODS: Population-level chlamydia testing data from general practice, chlamydia testing data from five government primary care clinics with a high caseload of young people, and behavioural data from an annual youth behavioural survey were analysed. Analyses included time-series regression to assess trends in testing levels, Kruskal-Wallis tests to assess changes in positivity, and chi(2)-tests to assess knowledge and behaviour change. RESULTS: There was no significant difference in the slope of monthly chlamydia testing in population-level or clinic-based surveillance during the campaign compared with before or after the campaign, and no changes in chlamydia positivity. Between 2007 and 2008, there was a significant increase in STI knowledge among females (P<0.01) and in the proportion of females reporting always using a condom with casual (P=0.04) and new sexual partners (P<0.01) in the annual behavioural survey. CONCLUSIONS: Our findings suggest the campaign had no impact on STI testing but may have contributed to an increase in knowledge and condom use among females; however, this increase could not be directly attributed to the campaign. Future campaigns targeting young people for STI testing should consider alternative messages and approaches, and include robust evaluation mechanisms to measure campaign impact prospectively. PMID- 21592441 TI - Improving Chlamydia trachomatis retesting rates by mailed self-collection kit. AB - BACKGROUND: To assess a mailed self-collection kit for chlamydia testing as an intervention to increase post-treatment retesting rates. METHODS: This prospective intervention study took place at a sexual health clinic in Townsville, North Queensland (Australia) between 2006 and 2008. The intervention consisted of offering to mail a self-collection kit for retesting 3 months after treatment. The achieved retesting rates were compared to those from the previous year and to concurrent controls who did not participate in the intervention. Both control groups received standard advice on retesting. RESULTS: Of the 46 participants in the intervention group, 34.8% returned the sample for retesting 3 to 4 months after initial treatment, in comparison to 6.8% of the historic control groups (n=206) and 1.4% of the concurrent control group (n=142) (P<0.001, respectively). CONCLUSIONS: Retesting rates for Chlamydia trachomatis were substantially and significantly improved using the mailed self-collection kit evidencing that the kit could deliver a much needed intervention to improve notoriously low retesting rates. PMID- 21592440 TI - Re-testing for chlamydia at sexual health services in Australia, 2004-08. AB - OBJECTIVE: To describe the frequency of the 3-month test for re-infection among sexual health service patients in Australia. METHODS: We assessed the re-testing rates at 30-120 days after chlamydia infection in men who have sex with men (MSM), heterosexual males and females attending sexual health services across Australia between 2004 and 2008. A chi(2)-test was used to determine significant differences in re-testing rates according to demographic characteristics and trends over time. RESULTS: In the 5-year period, 10207 MSM, 28530 heterosexual males and 31190 heterosexual females were tested for chlamydia. Of those tested, 9057 (13.0%) were positive. The proportion of patients with chlamydia infection who were re-tested in 30-120 days was 8.6% in MSM, 11.9% in heterosexual males and 17.8% in heterosexual females. Among MSM, chlamydia re-testing rates were lower in men aged <30 years (8.4%) than >=30 years (12.5%) (P=0.04) and lower in travellers and migrants (2.9%) than non-travellers (9.9%) (P=0.002). In heterosexual males, chlamydia re-testing rates were lower in men in regional and rural areas (10.5%) than metropolitan areas (13.5%) (P=0.017). There was no increasing trend in re-testing rates between 2004 and 2008 (P=0.787). Of the patients re-tested, 44.1% of MSM were positive, 21.0% of heterosexual males and 16.1% of females. DISCUSSION: The high chlamydia positivity at 30-120 days support recommendations that call for a 3-month test for re-infection following a positive test. The low re-testing rates highlight the need for innovative strategies to increase re-testing. PMID- 21592442 TI - Anal intercourse among female sex workers in East Africa is associated with other high-risk behaviours for HIV. AB - INTRODUCTION: Epidemiological and HIV prevention studies in sub-Saharan Africa have almost exclusively focussed on vaginal transmission of HIV, the primary mode of transmission in the region. Little is known about the prevalence of heterosexual anal intercourse (AI), its correlates and its role in the spread of HIV. Prevention messaging seldom, if ever, includes AI. METHODS: Sexual and other risk behaviours (including frequency of AI) were assessed in two cross-sectional surveys of female sex workers (FSW) in Kigali, Rwanda (n=800) and Mombasa, Kenya (n=820). In addition, a subset of FSW surveyed in Kigali attended seven focus group discussions and four in-depth interviews. RESULTS: AI was reported by 5.5% and 4.3% of FSW in the cross-sectional surveys, in Kigali and Mombasa, respectively. FSW practising AI reported multiple risk factors for HIV transmission: inconsistent condom use (odds ratio (OR) Kigali 5.9 (95% CI 1.4 24.7); OR Mombasa 2.1 (1.1-4.2)); more than five sexual partners in the past week (OR Kigali 4.3 (1.5-12.4); OR Mombasa 2.2 (1.1-4.3)); alcohol use before sex (OR Kigali 2.8 (1.4-5.8)); more than 5 years of female sex work (OR Mombasa 2.4 (1.2 4.9)); and history of genital symptoms in the past year (OR Mombasa 3.6 (1.7 7.9)). AI was, however, not associated with HIV prevalence (OR Kigali 0.9 (0.5 1.9); OR Mombasa 0.5 (0.2-1.2)). Negative connotations and stigma associated with AI were expressed during qualitative interviews. CONCLUSIONS: AI was associated with several indicators of sexual risk behaviour. Prevalence of AI was probably underreported due to social desirability bias. Stigma associated with AI poses methodological challenges in obtaining valid data. PMID- 21592443 TI - Participants' perspectives of high resolution anoscopy. PMID- 21592444 TI - Participants' perspectives of self-collected anal cytological swabs. PMID- 21592445 TI - Prevalence and correlates of inconsistent condom use among female sex workers in Armenia. PMID- 21592446 TI - Acceptability of female condom use in money boys compared with other men who have sex with men in Chengdu, China: a comparative study. AB - We conducted a clinical trial to compare sexual behaviours and attitudes regarding female condoms among money boys and other men who have sex with men in Chengdu, China, with a particular focus on factors influencing use of female condoms. PMID- 21592447 TI - HIV results: practice at public sexual health clinics in New South Wales. AB - New South Wales (NSW) Health guidelines recommend all HIV results be given in person, however this practice fails to achieve high levels of result collection. Fourteen of all 38 NSW public sexual health clinics (37%) surveyed offer HIV results by telephone to low-risk patients, although all positive results are given in person. Efficiency of result-giving, accessibility to results, patient acceptability and awareness of more flexible national guidelines were cited as reasons for varying practice from state guidelines. NSW guidelines require revision to allow clinicians to determine the most effective and efficient mode of HIV result delivery to their patients. PMID- 21592448 TI - Should we change the focus of health promotion in sexual health clinics? AB - In a response to the recent article by Rudiger Pitroff and Elizabeth Goodburn on changing the focus of health promotion in sexual health clinics, Crouch and Fagan draw attention to the confusion among practitioners between brief interventions in clinics (health education) and the actual nature and scope of sexual health promotion. The response refocuses attention on the Ottawa Charter for Health Promotion and on the social determinants of sexual health inequity as appropriate design drivers of a pilot initiative proposed by Pitroff and Goodburn to re orient sexual health service provision around the real needs of its clients. PMID- 21592449 TI - [Tinea capitis in elderly women: a report of 4 cases]. AB - Tinea capitis is a condition usually found only in children. However, its epidemiological profile has changed in recent decades, with regard to age at onset and the causative microorganisms. We report the cases of 4 women over 65 years of age diagnosed with tinea capitis. One presented plaques of alopecia with desquamation and the other 3 developed crusted inflammatory lesions. Cultures were positive for Trichophyton tonsurans (2 patients), Trichophyton rubrum, and Trichophyton mentagrophytes. The relative rarity of tinea capitis in the elderly and the frequently atypical presentation in this age group can delay diagnosis, leading to irreversible sequelae and increasing the risk of contagion. Fungal culture should be included in the study of persistent, atypical dermatoses of the scalp, particularly in the elderly. PMID- 21592450 TI - Effect of aspirin on mortality in the primary prevention of cardiovascular disease. AB - OBJECTIVE: The lack of a mortality benefit of aspirin in prior meta-analyses of primary prevention trials of cardiovascular disease has contributed to uncertainty about the balance of benefits and risks of aspirin in primary prevention. We performed an updated meta-analysis of randomized controlled trials of aspirin to obtain best estimates of the effect of aspirin on mortality in primary prevention. METHODS: Eligible articles were identified by searches of electronic databases and reference lists. Outcomes of interest were all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and bleeding. Data were pooled from individual trials using the DerSimonian-Laird random effects model, and results are presented as relative risk (RR) and 95% confidence intervals (CIs). RESULTS: Nine randomized controlled trials enrolling 100,076 participants were included. Aspirin reduced all-cause mortality (RR 0.94; 95% CI, 0.88-1.00), myocardial infarction (RR 0.83; 95% CI, 0.69-1.00), ischemic stroke (RR 0.86; 95% CI, 0.75-0.98), and the composite of myocardial infarction, stroke, or cardiovascular death (RR 0.88; 95% CI, 0.83-0.94), but did not reduce cardiovascular mortality (RR 0.96; 95% CI, 0.84-1.09). Aspirin increased the risk of hemorrhagic stroke (RR 1.36; 95% CI, 1.01-1.82), major bleeding (RR 1.66; 95% CI, 1.41-1.95), and gastrointestinal bleeding (RR 1.37; 95% CI, 1.15-1.62). A lack of availability of patient-level data precluded exploration of benefits and risks of aspirin in key subgroups. CONCLUSION: Aspirin prevents deaths, myocardial infarction, and ischemic stroke, and increases hemorrhagic stroke and major bleeding when used in the primary prevention of cardiovascular disease. PMID- 21592451 TI - Cognitive screening in community-dwelling elders: performance on the clock-in-the box. AB - BACKGROUND: The Clock-in-the-Box is a rapid (2-minute) cognitive screening tool. The purpose of this study was to compare the Clock-in-the-Box with the Mini Mental State Exam and neuropsychologic tests; to determine Clock-in-the-Box score normative values by age and education group; and to determine if the Clock-in-the Box score is associated with measures of physical function. METHODS: Community dwelling older participants in the Boston area were recruited for a prospective, longitudinal study in which they completed a variety of cognitive and functional assessments. RESULTS: At baseline, participants (n=798; mean age [+/- standard deviation]=78.2 [+/-5.5] years; 14 [+/-3] mean years of education) completed in home assessments of cognition (Clock-in-the-Box and Mini-Mental State Exam), measures of independent function (Activities of Daily Living and Instrumental Activities of Daily Living), and measures of physical function (Short Physical Performance Battery). The mean Mini-Mental State Exam score was 27.1 (+/-1.6; range 0-30 [0 worst]), and the mean Clock-in-the-Box score was 6.2 (+/-1.6; range 0-8 [0 worst]). Performance on the Clock-in-the-Box was correlated (Spearman) with the Mini-Mental State Exam (r=0.49, P<.001) and neuropsychologic measures (r=0.37-0.50; P<.001). Higher Clock-in-the-Box score was significantly associated with no difficulty in Activities of Daily Living (chi(2) = 39.6, P<.001) and Instrumental Activities of Daily Living (chi(2) = 35.5, P<.001). In addition, higher Clock-in-the-Box scores were associated with higher scores on the Short Physical Performance Battery (F=5.4, P<.001). CONCLUSION: The Clock-in-the-Box is a brief cognitive screening test that is correlated with the Mini-Mental State Exam, neuropsychologic tests, and measures of independent and physical function in community-dwelling older adults. PMID- 21592452 TI - Increasing use of vena cava filters for prevention of pulmonary embolism. AB - PURPOSE: To test whether the use of vena cava filters continues to increase in the era of retrievable filters, suggesting that indications for insertion are broadening. METHODS: Data from 1979 through 2006 are from the National Hospital Discharge Survey. RESULTS: From 1979 through 1984, 17,000 vena cava filters were inserted; 8000 in patients with pulmonary embolism, 4000 in patients with deep venous thrombosis only, and 5000 in patients at risk of pulmonary embolism who had neither. From 1985 through 2006, 803,000 vena cava filters were inserted: 285,000 in patients with pulmonary embolism, 360,000 in patients with deep venous thrombosis only, and 158,000 in patients who had neither. The largest proportional increases in the use of vena cava filters since the introduction of retrievable filters was in patients at risk of pulmonary embolism but who had neither pulmonary embolism nor deep venous thrombosis. The trend toward increased use in this group began before retrievable filters were introduced. There was a 3 fold increase from 2001-2006. CONCLUSION: Extensive use of permanent and retrievable vena cava filters in the US indicates liberalization of indications. It would seem that a more discriminate use of vena cava filters would be appropriate at the present time, keeping an open mind for broadened indications as data accrue. PMID- 21592453 TI - The DRESS syndrome: a literature review. AB - The Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe adverse drug-induced reaction. Diagnosing DRESS is challenging due to the diversity of cutaneous eruption and organs involved. We used the RegiSCAR scoring system that grades DRESS cases as "no," "possible," "probable," or "definite" to classify cases reported in the literature. We also analyzed the clinical course and treatments of the cases. A total of 44 drugs were associated with the 172 cases reported between January 1997 and May 2009 in PubMed and MEDLINE. The most frequently reported drug was carbamazepine, and the vast majority of cases were classified as "probable/definite" DRESS cases. Hypereosinophilia, liver involvement, fever, and lymphadenopathy were significantly associated with "probable/definite" DRESS cases, whereas skin rash was described in almost all of the cases, including "possible cases." Culprit drug withdrawal and corticosteroids constituted the mainstay of DRESS treatment. The outcome was death in 9 cases. However, no predictive factors for serious cases were found. This better knowledge of DRESS may contribute to improve the diagnosis and management of this syndrome in clinical practice. PMID- 21592454 TI - [Novel adipokines: links between obesity and atherosclerosis]. AB - Today, cardiovascular diseases (CVD) remain the principal cause of death in industrialized countries and are linked to obesity and metabolic syndrome. Metabolic syndrome is characterized by changes in arterial blood pressure, glucose metabolism, lipid and lipoprotein profiles in addition to inflammation. Adipose tissue produces many cytokines and secretory factors termed adipokines. Intra-abdominal (visceral) adipose tissue in particular, rather than peripheral, appears to be associated with global cardiometabolic risk. The present article summarizes information on five recently discovered adipokines: vaspin, visfatin, apelin, acylation stimulating protein (ASP) and retinol-binding protein 4 (RBP4) and their potential beneficial or deleterious roles in obesity and atherosclerosis. Vaspin may have antiatherogenic effects through its potential insulin-sensitizing properties. Similarly, visfatin has been suggested to enhance insulin sensitivity, but its potential role in plaque destabilization may counteract this. Apelin, via inhibition of food intake, and increases in physical activity and body temperature, may promote weight loss, resulting in a beneficial antiatherogenic effect. Further, favourable effects on vasodilatation and blood pressure add to this positive effect. Considering its increased levels in subjects with demonstrated atherosclerosis, RBP4 may constitute a biomarker. Lastly, ASP, often increased in obesity and metabolic disorders, may be contributing to efficient lipid storage, and decreasing or blocking ASP may provide a potential antiobesity target. Adipokines may further contribute to obesity-atherosclerosis relationships, the full understanding of which will require further research. PMID- 21592455 TI - Right ventricular outflow tract reconstruction with an allograft conduit in patients after tetralogy of Fallot correction: long-term follow-up. AB - BACKGROUND: In tetralogy of Fallot (TOF) pulmonary regurgitation is a frequent complication after initial repair. The objective of the present study was to describe the long-term experience with the use of allograft conduits for right ventricular outflow tract (RVOT) reconstruction after correction of TOF in our institution. METHODS: Between 1987 and 2009, 133 allografts were implanted in 126 patients (mean age, 27.8 years). The mean time from initial TOF repair to allograft implantation was 20.8+/-8.8 years. Kaplan-Meier analyses were done for patient survival, freedom from allograft replacement and freedom from any cardiovascular event. RESULTS: Hospital mortality was 1.5% (2 patients). Mean follow-up was 8.1 years. Ten other patients died during late follow-up, in 8 patients the cause was heart failure. Patient survival was 95% at 5 years, 91% at 10 years, and 80% at 15 years. Male sex, older patient age at the time of operation, and the use of preoperative diuretics were associated with increased risk of mortality during follow-up. Freedom from allograft replacement was 83% at 10 years and 70% at 15 years. Freedom from any valve-related event was 80% at 10 years and 67% at 15 years. CONCLUSIONS: Right ventricular outflow tract reconstruction after previous TOF repair can be performed with low risk and a low reintervention rate. Allograft conduits function satisfactorily in the pulmonary position at longer-term follow-up. Functional status after allograft implantation in patients with a previous correction of TOF remains good. There is concern about the long-term survival and the occurrence of heart failure. PMID- 21592456 TI - Accuracy of FDG-PET to diagnose lung cancer in a region of endemic granulomatous disease. AB - BACKGROUND: The 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) is used to evaluate suspicious pulmonary lesions due to its diagnostic accuracy. The southeastern United States has a high prevalence of infectious granulomatous lung disease, and the accuracy of FDG-PET may be reduced in this population. We examined the diagnostic accuracy of FDG-PET in patients with known or suspected non-small cell lung cancer treated at our institution. METHODS: A total of 279 patients, identified through our prospective database, underwent an operation for known or suspected lung cancer. Preoperative FDG-PET in 211 eligible patients was defined by standardized uptake value greater than 2.5 or by description ("moderate" or "intense") as avid. Sensitivity, specificity, positive and negative predictive values, likelihood ratios, and decision diagrams were calculated for FDG-PET in all patients and in patients with indeterminate nodules. RESULTS: In all eligible patients (n=211), sensitivity and specificity of FDG-PET were 92% and 40%, respectively. Positive and negative predictive values were 86% and 55%. Overall FDG-PET accuracy to diagnose lung cancer was 81%. Preoperative positive likelihood ratio for FDG-PET diagnosis of lung cancer in this population was 1.5 compared with previously published values of 7.1. In 113 indeterminate lesions, 65% had lung cancer and the sensitivity and specificity were 89% and 40%, respectively. Twenty-four benign nodules (60%) had false positive FDG-PET scans. Twenty-two of 43 benign nodules (51%) were granulomas. CONCLUSIONS: In a region with endemic granulomatous diseases, the specificity of FDG-PET for diagnosis of lung cancer was 40%. Clinical decisions and future clinical predictive models for lung cancer must accommodate regional variation of FDG-PET scan results. PMID- 21592457 TI - Endobronchial ultrasound-guided transbronchial needle aspiration in the management of previously treated lung cancer. AB - BACKGROUND: This study evaluated the role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the assessment of newly developed mediastinal/hilar abnormalities in patients with previously treated lung cancer. METHODS: All EBUS-TBNA cases between July 2008 and October 2010 were retrospectively reviewed. Results of EBUS-TBNA in previously treated lung cancer patients were analyzed. Cancer treatments, numbers of stations biopsied, and pathologic results were recorded. Nonmalignant cytopathology was confirmed with clinical follow-up for benign results. RESULTS: Of 450 patients who underwent EBUS-TBNA, 44 (9.8%) had previous lung cancer treatment, comprising non-small cell lung cancer in 40, small-cell lung cancer in 3, and typical carcinoid in 1. No EBUS-TBNA was performed for lung cancer restaging. Primary treatments included surgical resection in 22, resection with adjuvant/neoadjuvant therapy in 11, chemoradiation in 5, chemotherapy in 4, and radiotherapy in 2. At the primary treatment, 23 of 44 patients had mediastinoscopy. EBUS-TBNA of mediastinal lymph nodes was performed in 40. An average of 1.7 stations were biopsied (range, 1 to 5). The positive EBUS-TBNA in 28 included mediastinal/hilar recurrence of primary lung cancer (ie, same cell type as primary cancer) in 21, and possible new primary lung cancer (ie, different cell type from primary lung cancer) in 7. The sensitivity, specificity, and diagnostic accuracy were 93.1%, 100%, and 95.1%, respectively. CONCLUSIONS: EBUS-TBNA can differentiate a new primary lung cancer from recurrence of previously treated lung cancer, which will facilitate treatment strategy. PMID- 21592458 TI - Postoperative anemia and exercise tolerance after cardiac operations in patients without transfusion: what hemoglobin level is acceptable? AB - BACKGROUND: Restrictive transfusion strategies have been suggested for cardiac surgical patients, leading to various degrees of postoperative anemia. This study investigates the exercise tolerance during rehabilitation of cardiac surgical patients who did not receive transfusions, with respect to their level of postoperative anemia. METHODS: This observational study started in January 2010 and ended in May 2010 in 2 rehabilitation hospitals and 2 large-volume cardiac surgical hospitals. The study population was 172 patients who did not receive transfusions during cardiac surgical operations with cardiopulmonary bypass and subsequently followed a rehabilitation program in 1 of the 2 rehabilitation hospitals. No patient received a transfusion during the rehabilitation hospital stay. Exercise tolerance was measured using the 6-minute walk test at admission and discharge from the rehabilitation hospital. The level of anemia at admission to the rehabilitation hospital was tested as an independent predictor of exercise tolerance within a model inclusive of other possible confounders. RESULTS: Patients with values of hemoglobin less than 10 g/dL at admission to the rehabilitation institute had a significantly (p=0.007) worse performance on the 6 minute walk test than patients with higher values (258+/-106 vs 306+/-101 meters). This functional gap was completely recovered during a normal rehabilitation period. Other independent factors affecting exercise tolerance were age, sex, and albumin concentration. CONCLUSIONS: Postoperative anemia with hemoglobin levels of 8 to 10 g/dL is well tolerated in patients who have not received a transfusion and induces only a transient impairment of exercise tolerance. PMID- 21592459 TI - Anemia before coronary artery bypass surgery as additional risk factor increases the perioperative risk. AB - BACKGROUND: A negative relationship between anemia before coronary artery bypass graft (CABG) surgery and the perioperative mortality has been shown. We tried to clarify whether anemia only expresses an increased perioperative risk or is a risk factor per se in a two-institution database. METHODS: In the years 2005 and 2006, 185 of 3,311 patients undergoing isolated first-time CABG surgery had anemia defined as hematocrit less than 33% or Hb<=11 g/dL. Preoperative and postoperative data of patients having anemia and patients having normal hematocrit were compared using chi2-tests or Fisher's exact tests regarding structural group differences. To determine factors influencing perioperative mortality, methods of logistic regression were used. RESULTS: The 30-day mortality of anemic patients (12.9%) was significantly higher (p<0.001) than the mortality of nonanemic patients (2.2%). Patients having anemia, though, had a worse risk profile before surgery: high European System for Cardiac Operative Risk Evaluation values (median, 7 in anemic patients versus 4 in nonanemic patients), acute myocardial infarction (9.7% in anemic versus 2% in nonanemic patients), diabetes mellitus (45.4% in anemic versus 33.3% in nonanemic patients), and cardiogenic shock (5.4% in anemic versus 0.8% in nonanemic patients) were significantly more frequent in the anemic group. However, taking these risks in account, the logistic regression revealed preoperative anemia still to be a mortality-increasing factor in patients undergoing CABG surgery (odds ratio 3.727, confidence interval: 2.196 to 6.324). Furthermore, anemia was a risk factor for perioperative morbidity (major adverse cardiovascular events) after CABG surgery (odds ratio 2.199, confidence interval: 1.423 to 3.397). CONCLUSIONS: In our patient group undergoing CABG surgery, preoperative anemia increased the mortality risk by 3.4, even when taking the higher perioperative risk of anemic patients into consideration. PMID- 21592460 TI - Risk of stent-related aortic erosion after endoscopic stent insertion for intrathoracic anastomotic leaks after esophagectomy. AB - BACKGROUND: Intrathoracic anastomotic leakage after esophagectomy is associated with high morbidity and mortality. Because of disappointing results after surgical reexploration endoscopic stent implantation was introduced as primary treatment option with improved outcome. Aortoesophageal fistula is a very rare complication and has thus far only anecdotally been reported after esophagectomy. The aim of this retrospective study was to investigate if endoscopic stent implantation increases the incidence of postoperative aortoesophageal fistula by reason of stent-related erosion of the thoracic aorta. METHODS: Between January 2004 and October 2010, 213 patients underwent esophageal resection mainly for esophageal cancer. An intrathoracic esophageal anastomotic leak was endoscopically verified in 25 patients. Seventeen patients received endoscopic implantation of a self-expanding stent as primary treatment. In 8 patients a rethoracotomy was mandatory. RESULTS: After successfully accomplished endoscopic stent placement, complete closure of the anastomotic leak was radiologically proven in all 17 patients. In 13 cases, definitive closure and healing of the leak was achieved and the stent could subsequently be removed. In 1 patient, because of early recurrence of very malignant small cell cancer, the stent remained in situ. Three patients developed an erosion of the thoracic aorta with subsequent massive hemorrhage. The mean time between stent insertion and occurrence of aortoesophageal fistula was 26 days. All 3 patients died of exsanguination with severe hypovolemic shock. Postmortem examination confirmed an aortoesophageal fistula in each case. CONCLUSIONS: While endoscopic stent implantation seems to be effective in the control of intrathoracic anastomotic leakage, nevertheless the incidence of aortoesophageal fistula caused by stent related aortic erosion exceeds the thus far reported numbers. Awareness of this life-threatening complication after stent insertion is therefore mandatory. PMID- 21592461 TI - Reoperation and mechanical circulatory support after repair of anomalous origin of the left coronary artery from the pulmonary artery: a twenty-year experience. AB - BACKGROUND: Although outcomes for repair of anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) have improved, early postoperative mechanical circulatory support is occasionally still required. This study was undertaken to determine whether long-term outcomes for children supported with extracorporeal membrane oxygenation (ECMO) after ALCAPA repair differ from those in children who did not require ECMO. METHODS: Between 1989 (when our ECMO program began) and 2010, 26 consecutive patients (median age of 0.26 years) underwent surgical repair of ALCAPA mainly with a strategy to produce a dual coronary system. Among the 26 patients, 21 did not require ECMO postoperatively (non-ECMO group) and 5 were supported by ECMO (ECMO group). Hospital and clinic records were reviewed to determine endpoints of early or late death, cardiac transplantation, and late reoperation. RESULTS: There were no early or late deaths in either study group, at a mean follow-up of 6.5+/-6.5 years. Mean duration of ECMO support was 10.7+/-6.7 days. There was no difference in age or weight between the two groups. Two patients, one in each group, required cardiac transplantation at 6 days and 21 months, respectively. Four other patients required 6 reoperations (5 for mitral regurgitation and 1 for an atrial septal defect with pulmonary stenosis). Actuarial freedom from cardiac transplantation or reoperation at 5 years was 0% in the ECMO group and 92% in the non-ECMO group (p<0.001; log-rank test). CONCLUSIONS: Overall survival is excellent after ALCAPA repair. However, those patients who require mechanical support after repair appear to be at higher risk for transplantation or reoperation, typically for mitral regurgitation. PMID- 21592462 TI - Prevalence of dental caries and tooth wear in a Neolithic population (6700-5600 years BP) from northern China. AB - OBJECTIVES: The purpose of this study was to assess the prevalence, distribution and intensity of dental caries as well as tooth wear in Neolithic population of northern China to increase our knowledge about the type of food, dietary habit and social stratification in this Neolithic population. MATERIALS AND METHODS: The samples analysed were dental remains of 1007 permanent teeth from 79 adult individuals, who were excavated from three Yangshao archaeological sites in the Xi'an district and adjacent Counties (northern China). The sex and the age-at death of the samples were estimated. RESULTS: The frequency of antemortem tooth loss in the samples was 1.6%. The proportion of individuals with at least one carious tooth reached 41.8%, and the frequency of carious lesion was 5.7%. The most frequent carious lesions were occlusal lesions (4.4%), followed by interproximal (1.4%) and buccal/lingual lesions (0.4%). All 79 individuals were affected by attrition (100%) with various degrees of dental wear observed. The anterior teeth were much more worn than the posterior ones. The frequency of caries in men (3.9%) was significantly lower than that in women (8.1%), but the prevalence of tooth wear in men (99.0%) was significantly higher than that in women (95.2%). CONCLUSIONS: These findings indicate that both caries and tooth wear may be related to the subsistence and diet of this Neolithic population. PMID- 21592463 TI - Gold catalyzed glycosidations for the synthesis of sugar acrylate/acrylamide hybrids and their utility. AB - Propargyl glyco 1,2-orthoesters were exploited for the efficient synthesis of interesting glycomonomers such as glyco-acrylates and acrylamides using gold catalysts. It was observed that propargyl glyco 1,2-orthoesters with hydroxyethyl acrylates gives very good yield of the corresponding glyco-acrylates in a single step in the presence of catalytic amount of gold(III) catalyst; whereas, gold catalyzed glycosidation reaction on hydroxyethyl acrylamides was found to yield the corresponding acrylamidoyl 1,2-orthoester which was then converted to the corresponding glycol-acrylamide in the presence of catalytic amount of TMSOTf. Synthesized glyco-acrylate/acrylamide monomers are shown to undergo thiolate addition as well as free radical polymerization. PMID- 21592464 TI - Studies of a furanoside as antimycobacterial agent loaded into a biodegradable PBAT/sodium caseinate support. AB - An improved synthesis of n-octyl beta-D-galactofuranoside was described using micro-wave activation. The resulting alkyl furanoside showed antibacterial activity against Mycobacterium smegmatis, a non-pathogenic model of Mycobacterium tuberculosis. It was further incorporated into a biodegradable PBAT/sodium caseinate polymer. The resulting biomaterial loaded with 5% of the pharmacophore retained the mycobacteriostatic properties and developed a mycobactericidal activity on contact and at the periphery of the film. PMID- 21592465 TI - En route to sugar-alkaloid conjugates. AB - After stereoselective addition of N-iodosuccinimide to glycals subsequent dehalogenation results in formation of N-glycopyranosyl succinimides. By UV irradiation both azepindiones and preferentially [5.3.1.0(2,6)] tricyclic oxalactams could be obtained. Their transformation into a number of novel sugar conjugates resembling some prominent alkaloid N-pyrrol components by thiation and reduction is reported. PMID- 21592466 TI - Transformation of aldose formazans. Novel synthesis of 2-acetamido-2 deoxypentonolactones and a new pent-2-enose formazan. AB - 2-Acetamido-2-deoxypentonolactones were synthesized from per-O-acetylated formazans of D-ribose, D- and L-arabinose, respectively. In dimethyl sulfoxide, a novel spontaneous transformation of the per-O-acetyl-pentose formazans into new 3,4,5-tri-O-acetyl-pent-2-enose formazans has been recognized. Additional examples for the occurrence of the isomerism between pseudo-aromatic chelate and open phenylazo-phenylhydrazone system were demonstrated by (1)H NMR spectroscopy in both the unprotected pentose formazans and 3,4,5-tri-O-acetyl-pent-2-enose formazans. Computational calculations supported higher stability of the ring form. PMID- 21592467 TI - Investigation of glycosylating properties of 1-deoxy-1-ethoxysulfonyl-hept-2 ulopyranosyl derivatives. Synthesis of a new sulfonic acid mimetic of the sialyl Lewis X tetrasaccharide. AB - Glycosylation reactions of the ethylthio, bromo and chloro derivatives of 1-deoxy 1-ethoxysulfonyl-hept-2-ulopyranose were studied applying different acceptors under different conditions. Elimination side-reactions affording exo- and endoglycals occured in all cases, however, with different proportions. Glycosyl chloride donor was applied to glycosylate a trisaccharide acceptor obtaining a new sulfonic acid mimetic of the sialyl Lewis X tetrasaccharide in high yield. PMID- 21592469 TI - Structure activity relationship analysis of phenolic acid phenethyl esters on oral and human breast cancers: the grey GM(0, N) approach. AB - This paper presents grey structure activity relationship analysis for phenolic acid phenethyl esters from the bioactivity on oral cancer SAS, OEC-M1 and human breast cancer MCF-7. First of all, 14 compounds of phenolic acid phenethyl esters are synthesized, while the bioactivity (cytotoxicity) on the cancer cells SAS, OEC-M1, MCF-7 is tested. Next, the relationship weighting of functional groups of phenolic acid phenethyl esters is found by applying the grey GM(0, N) model on the measured data. Moreover, evident structure activity relationships are established to rule the biological effect of such compounds, e.g., the most important functional group affecting the cytotoxicity on the cancer cells is found. It is interesting that the analyzed result is consistent with the actual circumstance. In comparison with traditional methods, this paper using grey theory indicates more characteristic information about the structure activity relationships of phenolic acid phenethyl esters while using fewer data samples. PMID- 21592468 TI - Effective connectivity analysis of fMRI and MEG data collected under identical paradigms. AB - Estimation of effective connectivity, a measure of the influence among brain regions, can potentially reveal valuable information about organization of brain networks. Effective connectivity is usually evaluated from the functional data of a single modality. In this paper we show why that may lead to incorrect conclusions about effective connectivity. In this paper we use Bayesian networks to estimate connectivity on two different modalities. We analyze structures of estimated effective connectivity networks using aggregate statistics from the field of complex networks. Our study is conducted on functional MRI and magnetoencephalography data collected from the same subjects under identical paradigms. Results showed some similarities but also revealed some striking differences in the conclusions one would make on the fMRI data compared with the MEG data and are strongly supportive of the use of multiple modalities in order to gain a more complete picture of how the brain is organized given the limited information one modality is able to provide. PMID- 21592470 TI - Extracting biomarkers of autism from MEG resting-state functional connectivity networks. AB - The present study is a preliminary attempt to use graph theory for deriving distinct features of resting-state functional networks in young adults with autism spectrum disorder (ASD). Networks modeled neuromagnetic signal interactions between sensors using three alternative interdependence measures: (a) a non-linear measure of generalized synchronization (robust interdependence measure [RIM]), (b) mutual information (MI), and (c) partial directed coherence (PDC). To summarize the information contained in each network model we employed well-established global graph measures (average strength, assortativity, clustering, and efficiency) as well as graph measures (average strength of edges) tailored to specific hypotheses concerning the spatial distribution of abnormalities in connectivity among individuals with ASD. Graph measures then served as features in leave-one-out classification analyses contrasting control and ASD participants. We found that combinations of regionally constrained graph measures, derived from RIM, performed best, discriminating between the two groups with 93.75% accuracy. Network visualization revealed that ASD participants displayed significantly reduced interdependence strength, both within bilateral frontal and temporal sensors, as well as between temporal sensors and the remaining recording sites, in agreement with previous studies of functional connectivity in this disorder. PMID- 21592471 TI - [Indications of digoxin for the treatment of atrial fibrillation]. PMID- 21592472 TI - The interpretation of intra-abdominal pressures from animal models: the rabbit to human example. AB - INTRODUCTION: The importance of the abdominal wall characteristics in intraabdominal pressure (IAP), intraabdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are poorly understood. The applicability of laboratory research findings to human scenarios is unknown due to the potential differences in abdominal wall elastance (AWE) amongst species. The aims of the study are to describe the AWE curve in rabbits and to compare it to the available human data. MATERIALS AND METHODS: Prospective experimental animal study in the setting of research laboratory. Male New Zealand White rabbits weighting 2.7 kg +/- 0.1 kg, were anesthetized and the AWE was determined by infusion of lactated Ringer's solution into the peritoneal cavity whilst the IAP was measured. A meta-analysis of peer-reviewed studies was conducted to define human AWE. RESULTS: The described AWE was lower in the rabbit than in humans. The function comparing human and rabbit was: log(e) human IAP = (0.58 log(e) rabbit IAP+1.6). CONCLUSIONS: The AWE can vary amongst species. This study determined the relationship to allow the comparison of rabbit and human IAP. The proposed mathematical function is important for the advancement of interpretation and understanding of animal research into IAH and ACS. We recommend developing model specific functions comparing individual animal models' IAP and that of humans. PMID- 21592473 TI - The use of hook plate in type III and V acromio-clavicular Rockwood dislocations: clinical and radiological midterm results and MRI evaluation in 42 patients. AB - BACKGROUND: Acromio-clavicular (AC) joint dislocations are very common following falls on the shoulder or an overstretched hand. The best treatment for such lesions remains a matter of debate. Several studies have, however, lent support to the surgical role of the hook plate in Rockwood type III and V AC dislocations. The aim of this study was to evaluate the midterm clinical results and magnetic resonance imaging (MRI) features of coraco-clavicular ligaments 18 months after an AC dislocation treated with an AC Dreithaler hook plate. PATIENTS AND METHODS: The cohort was made up of a consecutive series of 42 patients, who underwent surgery between November 2002 and December 2006 for an AC dislocation. They were classified, according to the Rockwood classification, as 22 grade III and 20 grade V dislocations. Surgical treatment consisted of open reduction and stabilisation with an AC Dreithaler hook plate. A clinical and radiological follow-up examination was performed 1 and 3 months after surgery, that is, before removal of the plate, and 12 months following removal. Eighteen months after the trauma, an MRI and a clinical examination were performed and the Constant-Murley scores calculated. RESULTS: An acceptable joint alignment was achieved in all the patients after surgery; 1 year after plate removal, five cases (12%) of dislocation recurrence were reported. MRI showed the coraco-clavicular ligaments had healed in the remaining 37 cases (88%). CONCLUSION: An AC plate is a useful technique in acromio-clavicular dislocations because it is easy to implant, requires mini-invasive access and results in early resumption of normal activity. MRI can be used to evaluate healing of coraco-clavicular ligaments. A long-term follow-up study is, however, warranted to assess the likelihood of recurrence. LEVEL OF EVIDENCE: Level IV, therapeutic cases series. PMID- 21592474 TI - Epidemiology of electrical injury: findings from a community based national survey in Bangladesh. AB - OBJECTIVES: The objective of this study is to explore the magnitude and pattern of electrical injury in Bangladesh. METHOD: A national survey was conducted between January and December 2003 in Bangladesh. Nationally representative data were collected from 171,366 rural and urban households comprising a 819,429 population. The survey was conducted at a household level with a structured questionnaire. RESULTS: The incidence of fatal and non-fatal injury was found to be 1.6 and 73.7 per 100,000 population year respectively. Compared to females, males were found at a higher risk (RR 1.62; 95% CI 1.37-1.91) and rural people found more vulnerable compared to urban people (RR 5.97; 95% CI 4.71-7.57). The home was found as the most common place for electrical injury, with more than 50% of injury taking place at home. The household source of electricity was found as the most common source of electrical injury. Lightning was also found as major source for electrical injury which constituted more than 25% of the injuries cause by electrical current. More than 80% of electrical injuries occurred between 6a.m. and 6p.m. CONCLUSION: Electrical injury is an emerging cause of mortality and morbidity in both urban and rural areas of Bangladesh. Males and rural people were the more vulnerable group for electrical injury compared to women and the urban population. The home is the most common place for injury occurrence. PMID- 21592475 TI - Efficacy of peripartum antiviral treatment for hepatic failure due to hepatitis B virus. AB - OBJECTIVE: To investigate the efficacy of oral nucleosides in preventing hepatic failure during pregnancy (HFP) caused by hepatitis B virus (HBV) infection. METHODS: Besides receiving standard treatment, 70 women with HFP caused by HBV infection joined a study group (n = 40) or a control group (n = 30) according to their preference. In the study group, 14 women were given lamivudine in the third trimester and an antiviral treatment was continued postpartum. The 26 remaining patients were treated postpartum only, with lamivudine (n = 16) or entecavir (n = 10). RESULTS: In the study group, the values for serum HBV DNA and hepatitis B envelope antigen were markedly lower at 1 and 2 months than they were at baseline (P < 0.001 and P < 0.001, respectively). Moreover, the HBV DNA values at 1 and 2 months were significantly lower in the study than in the control group (P < 0.05). Overall mortality and incidence of intrauterine infection were also significantly lower in the study group (P < 0.05). No newborns had any apparent abnormalities in either group. CONCLUSION: Treatment with nucleosides suppressed the replication of HBV DNA and led to biochemical improvement. It also reduced maternal mortality and safely decreased mother-to-child HBV transmission. PMID- 21592476 TI - Organizational factors impacting on patient satisfaction: a cross sectional examination of service climate and linkages to nurses' effort and performance. AB - BACKGROUND: Patient satisfaction is influenced by the setting in which patients are treated and the employees providing care. However, to date, limited research has explained how health care organizations or nurses influence patient satisfaction. OBJECTIVES: The purpose of this study was to test the model that service climate would increase the effort and performance of nursing groups and, in turn, increase patient satisfaction. METHOD: This study incorporated data from 156 nurses, 28 supervisors, and 171 patients. A cross-sectional design was utilized to examine the relationship between service climate, nurse effort, nurse performance and patient satisfaction. Structural equation modeling was conducted to test the proposed relationships. RESULTS: Service climate was associated with the effort that nurses directed towards technical care and extra-role behaviors. In turn, the effort that nurses exerted predicted their performance, as rated by their supervisors. Finally, task performance was a significant predictor of patient satisfaction. CONCLUSIONS: This study suggests that both hospital management and nurses play a role in promoting patient satisfaction. By focusing on creating a climate for service, health care managers can improve nursing performance and patient satisfaction with care. PMID- 21592477 TI - Cost-effectiveness of enhancing adherence to therapy with statins in the setting of primary cardiovascular prevention. Evidence from an empirical approach based on administrative databases. AB - AIM: To estimate the cost-effectiveness of enhancing adherence to statin therapy across a large population without signs of pre-existing cardiovascular disease. METHODS AND RESULTS: The cohort of 84,262 patients aged 40-79 years, resident in the Italian Lombardia Region, who were newly treated with statins during 2002 2003, was followed from index prescription until 2007. During follow-up the 1397 patients who experienced a hospitalization for ischemic heart disease (IHD) were identified (outcome). Adherence from index prescription until the date of hospitalization or censoring was measured by the proportion of days covered by the therapy with statins (PDC). Cost-effectiveness of enhancing adherence was measured through the incremental cost-effectiveness ratio (ICER). The robustness of findings was tested in a sensitivity analysis. Interventions to increase the average level of adherence from 45% (baseline) to 50% ("soft" intervention) or to 90% ("hard" intervention) reduced the number of patients who experience IHD (from 38.9 to 38.4 or 35.8 events every 10,000 person-year, respectively), and increased the cost for drug therapy (from 1326 to 1452 or 2626 thousand euros every 10,000 person-year, respectively). ICER ranged from 243 (95% CI: 230-259) to 413 (391-439) thousand euros every 10,000 person-year for the soft and hard interventions, respectively. CONCLUSIONS: Interventions aimed at enhancing adherence to statin therapy in the setting of primary cardiovascular prevention might offer important benefits in reducing the risk of cardiovascular outcome, but at a substantial cost. PMID- 21592479 TI - Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. AB - BACKGROUND: Recent data suggest that non-targeted treatment with fibrates modestly reduces the risk of incident cardiovascular events. However the effect of fibrate treatment may be particularly beneficial in patients with guideline endorsed indications for therapy due to evidence of atherogenic dyslipidemia. We conducted a systematic review and meta-analysis to investigate the influence of fibrates on vascular risk reduction in persons with atherogenic dyslipidemia. METHODS: Systematic search of Pubmed, CENTRAL and recent reviews was conducted to identify atherogenic dyslipidemia (serum high density lipoprotein cholesterol [HDL-C]<40 mg/dl or triglycerides >200 mg/dl) cohorts from randomized controlled trials. RR with 95% CI was used as a measure of the association between fibrate therapy and risk of cardiovascular diseases, after pooling data across trials in a random-effects model. RESULTS: Six trials met selection criteria. Compared to placebo, the greatest benefit with fibrate treatment was seen in 7389 subjects with high triglycerides, fibrate therapy reduced risk of vascular events (RR 0.75, 95% CI 0.65 to 0.86, P<0.001); and in 5068 subjects with both high triglycerides and low HDL-C (RR 0.71, 95% CI 0.62 to 0.82, P<0.001). Less benefit was noted in 15,303 subjects selected for low HDL-C (RR 0.84, 95% CI 0.77 to 0.91, P<0.001). Among 9872 subjects with neither high triglycerides nor low HDL C, fibrate therapy did not reduce subsequent vascular events (RR 0.96, 95% CI 0.85 to 1.09, P=0.53). CONCLUSIONS: Fibrate treatment directed at markers of atherogenic dyslipidemia substantially reduce subsequent vascular event risk. PMID- 21592478 TI - Meta analysis of candidate gene variants outside the LPA locus with Lp(a) plasma levels in 14,500 participants of six White European cohorts. AB - BACKGROUND: Both genome-wide association studies and candidate gene studies have reported that the major determinant of plasma levels of the Lipoprotein (a) [Lp(a)] reside within the LPA locus on chromosome 6. We have used data from the HumanCVD BeadChip to explore the contribution of other candidate genes determining Lp(a) levels. METHODS: 48,032 single nucleotide polymorphisms (SNPs) from the Illumina HumanCVD BeadChip were genotyped in 5059 participants of the Whitehall II study (WHII) of randomly ascertained healthy men and women. SNPs showing association with Lp(a) levels of p<10(-4) outside the LPA locus were selected for replication in a total of an additional 9463 participants of five European based studies (EAS, EPIC-Norfolk, NPHSII, PROCARDIS, and SAPHIR). RESULTS: In Whitehall II, apart from the LPA locus (where p values for several SNPs were <10(-30)) there was significant association at four loci GALNT2, FABP1, PPARGC1A and TNFRSFF11A. However, a meta-analysis of the six studies did not confirm any of these findings. CONCLUSION: Results from this meta analysis of 14,522 participants revealed no candidate genes from the HumanCVD BeadChip outside the LPA locus to have an effect on Lp(a) levels. Further studies with genome-wide and denser SNP coverage are required to confirm or refute this finding. PMID- 21592480 TI - Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction. AB - OBJECTIVE: Postprandial hyperlipemia has been shown to impair endothelial function and contribute to the development of atherosclerosis. We investigated the association between postprandial lipid profiles and endothelial function, and we examined the effects of ezetimibe on postprandial hyperlipemia and lipemia induced endothelial dysfunction. METHODS: A randomized prospective trial in which 10 mg/day of ezetimibe was administered to 10 subjects for 4 weeks and not administered to 10 subjects (control group) was performed. Lipid profiles and endothelial function, assessed by brachial artery flow-mediated dilation (FMD) during a fasting state and at 2, 4, 6 and 8 h after an oral cookie loading test, were determined before and after treatment for 4 weeks. RESULTS: In all subjects before treatment, the maximum reduction in postprandial %FMD was significantly correlated with the maximum increases in postprandial triglyceride (TG) (r= 0.499, P<0.05) and apolipoprotein B-48 (apoB-48) concentrations (r=-0.551, P<0.05). Ezetimibe treatment for 4 weeks significantly suppressed postprandial elevation in TG (area under the incremental curve, from 1419+/-594 to 968+/-32 1 mg h/dl, P<0.05), remnant lipoprotein cholesterol (from 66.9+/-27.6 to 38.9+/ 15.4 mg h/dl, P<0.01) and apoB-48 (from 58.8+/-27.5 to 36.2+/-17.0 MUg h/ml, P<0.05) concentrations, and postprandial endothelial dysfunction assessed by %FMD (maximum reduction in %FMD, from -2.6+/-1.1% to -1.2+/-0.8%, P<0.05), whereas no significant changes were observed in the control group. CONCLUSION: Postprandial hyperlipemia is closely correlated with transient endothelial dysfunction. Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction. PMID- 21592481 TI - Near-terminal creep damage does not substantially influence fatigue life under physiological loading. AB - Cortical bone specimens were damaged using repeated blocks of tensile creep loading until a near-terminal amount of creep damage was generated (corresponding to a reduction in elastic modulus of 15%). One group of cortical bone specimens was submitted to the near-terminal damage protocol and subsequently underwent fatigue loading in tension with a maximum strain of 2000 MUepsilon (Damage Fatigue, n=5). A second group was submitted to cyclic fatigue loading but was not pre-damaged (Control Fatigue, n=5). All but one specimen (a damaged specimen) reached run-out (10 million cycles, 7.7 days). No significant differences in microscopic cracks or other tissue damage were observed between the two groups or between either group and additional, completely unloaded specimens. Our results suggest that damage in cortical bone allograft that is not obvious or associated with a stress riser may not substantially affect its fatigue life under physiologic loading. PMID- 21592483 TI - The effects of modeling simplifications on craniofacial finite element models: the alveoli (tooth sockets) and periodontal ligaments. AB - Several finite element models of a primate cranium were used to investigate the biomechanical effects of the tooth sockets and the material behavior of the periodontal ligament (PDL) on stress and strain patterns associated with feeding. For examining the effect of tooth sockets, the unloaded sockets were modeled as devoid of teeth and PDL, filled with teeth and PDLs, or simply filled with cortical bone. The third premolar on the left side of the cranium was loaded and the PDL was treated as an isotropic, linear elastic material using published values for Young's modulus and Poisson's ratio. The remaining models, along with one of the socket models, were used to determine the effect of the PDL's material behavior on stress and strain distributions under static premolar biting and dynamic tooth loading conditions. Two models (one static and the other dynamic) treated the PDL as cortical bone. The other two models treated it as a ligament with isotropic, linear elastic material properties. Two models treated the PDL as a ligament with hyperelastic properties, and the other two as a ligament with viscoelastic properties. Both behaviors were defined using published stress strain data obtained from in vitro experiments on porcine ligament specimens. Von Mises stress and strain contour plots indicate that the effects of the sockets and PDL material behavior are local. Results from this study suggest that modeling the sockets and the PDL in finite element analyses of skulls is project dependent and can be ignored if values of stress and strain within the alveolar region are not required. PMID- 21592482 TI - Quadriceps strength and weight acceptance strategies continue to improve two years after anterior cruciate ligament reconstruction. AB - The anterior cruciate ligament (ACL) is the most commonly-injured knee ligament during sporting activities. After injury, most individuals experience episodes of the knee giving way during daily activities (non-copers). Non-copers demonstrate asymmetrical quadriceps strength and movement patterns, which could have long term deleterious effects on the integrity of the knee joint. The purpose of this study was to determine if non-copers resolve their strength and movement asymmetries within two years after surgery. 26 Non-copers were recruited to undergo pre-operative quadriceps strength testing and 3-dimensional gait analysis. Subjects underwent surgery to reconstruct the ligament followed by physical therapy focused on restoring normal range of motion, quadriceps strength, and function. Subjects returned for quadriceps strength testing and gait analysis six months and two years after surgery. Acutely after injury, quadriceps strength was asymmetric between limbs, but resolved six months after surgery. Asymmetric knee angles, knee moments, and knee and hip power profiles were also observed acutely after injury and persisted six months after surgery despite subjects achieving symmetrical quadriceps strength. Two years after surgery, quadriceps strength in the involved limb continued to improve and most kinematic and kinetic asymmetries resolved. These findings suggest that adequate quadriceps strength does not immediately resolve gait asymmetries in non-copers. They also suggest that non-copers have the capacity to improve their quadriceps strength and gait symmetry long after ACL reconstruction. PMID- 21592484 TI - Field-flow fractionation of magnetic particles in a cyclic magnetic field. AB - Although magnetic field-flow fractionation (MgFFF) is emerging as a promising technique for characterizing magnetic particles, it still suffers from limitations such as low separation efficiency due to irreversible adsorption of magnetic particles on separation channel. Here we report a novel approach based on the use of a cyclic magnetic field to overcome the particle entrapment in MgFFF. This cyclic field is generated by rotating a magnet on the top of the spiral separation channel so that magnetic and opposing gravitational forces alternately act on the magnetic particles suspended in the fluid flow. As a result, the particles migrate transversely between the channel walls and their adsorption at internal channel surface is prevented due to short residence time which is controlled by the rotation frequency. With recycling of the catch release process, the particles follow saw-tooth-like downstream migration trajectories and exit the separation channel at velocities corresponding to their sedimentation coefficients. A retention model has been developed on the basis of the combined effects of magnetic, gravitational fields and hydrodynamic flow on particle migration. Two types of core-shell structured magnetic microspheres with diameters of 6.04- and 9.40-MUm were synthesized and used as standard particles to test the proposed retention theory under varying conditions. The retention ratios of these two types of particles were measured as a function of magnet rotation frequency, the gap between the magnet and separation channel, carrier flow rate, and sample loading. The data obtained confirm that optimum separation of magnetic particles with improved separation efficiency can be achieved by tuning rotation frequency, magnetic field gradient, and carrier flow rate. In view of the widespread applications of magnetic microspheres in separation of biological molecules, virus, and cells, this new method might be extended to separate magnetically labeled proteins or organisms for multiplex analyte identification and purification. PMID- 21592485 TI - Theory of membrane capacitive deionization including the effect of the electrode pore space. AB - Membrane capacitive deionization (MCDI) is a technology for water desalination based on applying an electrical field between two oppositely placed porous electrodes. Ions are removed from the water flowing through a channel in between the electrodes and are stored inside the electrodes. Ion-exchange membranes are placed in front of the electrodes allowing for counterion transfer from the channel into the electrode, while retaining the coions inside the electrode structure. We set up an extended theory for MCDI which includes in the description for the porous electrodes not only the electrostatic double layers (EDLs) formed inside the porous (carbon) particles, but also incorporates the role of the transport pathways in the electrode, i.e., the interparticle pore space. Because in MCDI the coions are inhibited from leaving the electrode region, the interparticle porosity becomes available as a reservoir to store salt, thereby increasing the total salt storage capacity of the porous electrode. A second advantage of MCDI is that during ion desorption (ion release) the voltage can be reversed. In that case the interparticle porosity can be depleted of counterions, thereby increasing the salt uptake capacity and rate in the next cycle. In this work, we compare both experimentally and theoretically adsorption/desorption cycles of MCDI for desorption at zero voltage as well as for reversed voltage, and compare with results for CDI. To describe the EDL structure a novel modified Donnan model is proposed valid for small pores relative to the Debye length. PMID- 21592486 TI - Fabrication of split-ring resonators by tilted nanoimprint lithography. AB - An efficient fabrication technique for large area periodic metallic split-ring arrays has been demonstrated by the combination of tilted nanoimprint lithography and nanotransfer imprinting. The feature size of the split-rings can be adjusted by varying the key geometry parameters of the original imprinting mold. Due to the flexible nature of PDMS molds, these arrays can be patterned on curved surfaces. The molds for nanoimprint lithography and nanotransfer imprinting can be used multiple times without a loss of fidelity. PMID- 21592487 TI - Synthesis of palladium colloids within polydimethylsiloxane and their use as catalysts for hydrogenation. AB - The presence of unreacted silanes within cured polydimethylsiloxane (PDMS) leads to the reduction of tetrachloropalladate(II) ions, generating encapsulated palladium colloids. The resulting colloids had varied morphology and were typically less than 80 nm in size. The Pd/PDMS vessels, which contained 0.10+/ 0.01% Pd, were effective catalysts for the hydrogenation of carbon-carbon multiple bonds for at least ten successive runs with no loss of catalytic activity, and the catalyst does not exhibit the same pyrophoric behavior as Pd on carbon after use in hydrogenation reactions. In addition, storage of previously used Pd/PDMS vessels for 6 months in air did not affect the catalytic activity, and the overall morphology of the catalysts after use was the same as those that have not been involved in catalytic reactions. PMID- 21592488 TI - The influence of plant stanol on phospholipids monolayers--the effect of phospholipid structure. AB - This work is aimed at investigating the influence of a plant stanol (beta sitostanol) on Langmuir monolayers from various phospholipids and comparing the effect of phytostanol versus its unsaturated analog--phytosterol (beta sitosterol). The studied phospholipids differed in the structure of polar head (phosphatidylcholine--PC, phosphatidylethanolamine--PE, phosphatidylserine--PS) as well as in the number of monounsaturated chains in PC molecule. It was found that the introduction of stanol into PC monolayers is thermodynamically favorable, contrary to its effect on PE and PS films. The magnitude of condensing and ordering effect of stanol depends both on the number of monounsaturated chains in PC molecule and on the composition of stanol-PC mixture. The analysis of BAM images evidenced phase separation of immiscible components in stanol/DPPS systems. The results of Langmuir monolayer studies for stanol/phospholipids mixtures compared with those for corresponding sterol/phospholipids systems proved quite a similar effect of both compounds on the investigated phospholipid monolayers, despite differences in the structure of tetracyclic ring skeleton. PMID- 21592490 TI - CD11c+ cells are significantly decreased in the duodenum, ileum and colon of dogs with inflammatory bowel disease. AB - CD11c serves as a marker for human and murine dendritic cells (DCs) and cells expressing this marker have been shown to have similar morphological and functional characteristics in the canine immune system. The aim of this study was to quantify CD11c(+) cells in the duodenum, ileum and colon of healthy dogs and dogs with inflammatory bowel disease (IBD). Endoscopic biopsies from the duodenum (n=12 cases), ileum (n=8 cases) and colon (n=12 cases) were obtained from dogs diagnosed with IBD. Intestinal tissue from 10 healthy beagle dogs was used as control. Immunofluorescence microscopy was carried out using an anti-canine CD11c monoclonal antibody. Labelled cells were recorded as cells per 120,000 MUm(2). The canine chronic enteropathy clinical activity index (CCECAI) was calculated for all dogs with IBD. In addition, sections from all dogs with IBD were evaluated according to the guidelines of the World Small Animal Veterinary Association Gastrointestinal Standardization Group. The number of CD11c(+) cells in the duodenum, ileum and colon of dogs with IBD was significantly reduced compared with controls (P<0.01, P<0.01 and P<0.05, respectively). There was a significant negative correlation between the number of CD11c(+) cells in the colon of dogs with IBD and the CCECAI (P=0.044, r(2)=-0.558). Chronic inflammation in canine IBD appears to involve an imbalance in the intestinal DC population. Future studies will determine whether reduced expression of CD11c could be a useful marker for the diagnosis and monitoring of canine IBD. PMID- 21592489 TI - Speech characteristics associated with three genotypes of ataxia. AB - PURPOSE: Advances in neurobiology are providing new opportunities to investigate the neurological systems underlying motor speech control. This study explores the perceptual characteristics of the speech of three genotypes of spino-cerebellar ataxia (SCA) as manifest in four different speech tasks. METHODS: Speech samples from 26 speakers with SCA were perceptually rated by experienced listeners. The genotypes were: SCA1, SCA5, or SCA6. The speech tasks were: diadochokinesis, word repetition, sentence reading, and picture description. The speech samples were rated using two sets of dimensions characterized as primary (e.g., articulation, rate, and rhythm) or secondary (e.g., imprecise consonants, excess and equal stress, and harsh voice). RESULTS: On primary dimensions, SCA6 was the most impaired generally. Articulation was the most severely affected dimension and the diadochokinesis task was most effective in revealing speech impairments. On secondary dimensions, picture description was the task most likely to produce abnormal speech. The SCA groups shared articulatory problems but differed with respect to abnormal voice features. CONCLUSIONS: These results support previous characterizations of ataxic dysarthria, and provide further information about the speech characteristics of genetic subtypes. Task demands affect perceptual ratings. Voice characteristics may be key to differentiating ataxic subtypes. As the genetic disorders that affect speech become better understood, more detailed characterizations of motor control systems should emerge. PMID- 21592491 TI - Benign placental mass with fetal growth retardation in a bull mastiff. AB - A 4-year-old bull mastiff presented due to premature labour. The referring veterinarian elected to perform a caesarian delivery and at the time of surgery a 4*4*2 cm round, smooth, red to tan, lobulated soft mass was identified attached to the allantoic surface of the zonary placenta of one pup. Microscopically, this mass was composed of loosely arranged confluent undulating cords of polygonal to columnar epithelioid cells separated by a fine fibrovascular stroma resembling the placental labyrinth. The labyrinthine structure and epithelioid nature of the cells suggested that the mass was of trophoblastic origin. Due to the non invasive nature of the mass and relatively low mitotic activity, this proliferative trophoblastic mass was considered to be benign. The absence of morphological features supporting malignant behaviour and the recapitulation of the normal labyrinthine architecture led to the diagnosis of a trophoblastic hamartoma. To the authors' knowledge this is the first report of a placental hamartoma in the dog. PMID- 21592492 TI - Methods and measures in developmental emotions research: some assembly required. AB - The remarkable contributors to this special issue highlight the importance of developmental research on emotion and its regulation, as well as its conceptual and methodological challenges. This commentary offers some additional thoughts, especially concerning alternative views of the convergence of multiple measures of emotional responding, the conceptualization of emotion and emotion regulation, and future directions for work in this field. In the end, in light of the complex construction of emotion and its development, we may learn from studying the divergence among multiple components of emotional responding as we do from expectations of their convergence. In each case, some assembly is required. PMID- 21592493 TI - Home environment, asthma, and obesity: how are they related? PMID- 21592494 TI - Pharmacokinetics of levetiracetam in neonates with seizures. AB - The pharmacokinetics of levetiracetam were determined prospectively in 18 neonates with seizures. Neonates were found to have lower clearance, higher volume of distribution, and a longer half-life as compared with older children and adults. Mild somnolence was the only adverse effect. PMID- 21592495 TI - Risk of hyperbilirubinemia in breast-fed infants. AB - OBJECTIVE: To investigate the risk factors for hyperbilirubinemia in infants who are exclusively breast-fed. STUDY DESIGN: A prospective study was conducted to investigate the effects of birth body weight, sex, mode of delivery, glucose-6 phosphate dehydrogenase (G6PD) deficiency, variant UDP-glucuronosyltransferase 1A1 (UGT1A1) gene, and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) gene on hyperbilirubinemia in neonates who were breast-fed. Hyperbilirubinemia was diagnosed when a full term neonate had a bilirubin level ?15.0 mg/dL (256.5 MUM) in serum at 3 days old. The polymerase chain reaction restriction fragment length polymorphism method was used as a means of detecting the known variant sites in the UGT1A1 and SLCO1B1 gene. RESULTS: Of 252 infants born at term who were exclusively breast-fed, 59 (23.4%) had hyperbilirubinemia. The significant risk factors were a variant nucleotide 211 in UGT1A1 (2.48; 95% CI, 1.29 to 4.76; P = .006), G6PD deficiency (12.24; 95% CI, 1.08 to 138.62; P < .05), and vaginal delivery (3.55; 95% CI, 1.64 to 7.66; P < .001). CONCLUSION: Breast-fed neonates who are 211 variants in the UGT1A1, G6PD deficiency, and vaginal delivery are at high-risk for hyperbilirubinemia. PMID- 21592496 TI - Infant feeding matters. PMID- 21592497 TI - Discoid lupus erythematosus in a teenager. PMID- 21592498 TI - The care of children with medically complex chronic disease. PMID- 21592499 TI - Postoperative surveillance and detection of postprandial hypoglycemia after fundoplasty in children. AB - OBJECTIVE: To evaluate the prevalence of postprandial hypoglycemia (PPH) after fundoplasty after the initiation of a universal postoperative glucose surveillance plan in the neonatal intensive care unit (NICU). STUDY DESIGN: This was a retrospective chart review of children (newborn to 18 years) who underwent fundoplasty at The Children's Hospital of Philadelphia during the 2-year-period after the launch of a surveillance protocol in the NICU and other units. The rate of screening, frequency of PPH (postprandial blood glucose <60 mg/dL [3.3 mmol/L] on 2 occasions), frequency of postprandial hyperglycemia preceding PPH, timing of PPH presentation, and related symptoms were evaluated. RESULTS: A total of 285 children were included (n = 64 in the NICU; n = 221 in other units). Of the children screened in all units, 24.0% showed evidence of PPH, compared with 1.3% of unscreened children. Hyperglycemia preceded PPH in 67.7% (21/31) of all screened children. Within the NICU, most children had PPH within 1 week, but only 53.3% exhibited symptoms of dumping syndrome. CONCLUSIONS: This study supports the use of universal postoperative blood glucose surveillance in identifying PPH in children after fundoplasty. Earlier identification of PPH would lead to earlier treatment and minimize the effects of unidentified hypoglycemic events. PMID- 21592500 TI - Natural history of idiopathic diabetes insipidus. AB - OBJECTIVE: To determine what percentage of diabetes insipidus (DI) in childhood is idiopathic and to assess the natural history of idiopathic DI. STUDY DESIGN: We conducted a retrospective chart review of 105 patients with DI who were born or had DI diagnosed between 1980-1989 at 3 medical centers. A second cohort of 30 patients from 6 medical centers in whom idiopathic DI was diagnosed after 1990 was evaluated retrospectively for subsequent etiologic diagnoses and additional hypothalamic/pituitary deficiencies and prospectively for quality of life. RESULTS: In the first cohort, 11% of patients had idiopathic DI. In the second cohort, additional hypothalamic/pituitary hormone deficiencies developed in 33%, and 37% received an etiologic diagnosis for DI. Health-related quality of life for all the patients with idiopathic DI was comparable with the healthy reference population. CONCLUSIONS: Only a small percentage of patients with DI will remain idiopathic after first examination. Other hormone deficiencies will develop later in one-third of those patients, and slightly more than one-third of those patients will have an etiology for the DI diagnosed. Long-term surveillance is important because tumors have been diagnosed as long as 21 years after the onset of DI. Quality of life for these patients is as good as the reference population. PMID- 21592501 TI - Transient creatine phosphokinase elevations in children: a single-center experience. AB - OBJECTIVES: To determine the etiologies and evolution of rhabdomyolysis in children. STUDY DESIGN: We performed a retrospective study of patients with rhabdomyolysis who were seen in our tertiary care university-affiliated pediatric hospital. Patients in outpatient clinics, seen in the emergency department, or admitted from 2001 to 2002 were selected. With a standardized case report form, we collected predetermined data from each patient's chart. RESULTS: A total of 130 patients with rhabdomyolysis were included in the study (male, 56%; mean age, 7.5 +/- 5.9 years). The median elevation of creatine phosphokinase was 2207 IU/L (range, 1003 to 811 428 IU/L). The most frequent diagnoses were viral myositis (29, 22.3%), trauma (24, 18.4%), surgery (24, 18.4%), hypoxia (12 , 9.2%), and drug reaction (8, 6.2%). Metabolic myopathy was found only in one patient (0.8%). In 17 patients (13.1%), no definite diagnosis could be made. CONCLUSIONS: Etiologies of rhabdomyolysis in children are varied and differ from those reported in adults. In most patients, rhabdomyolysis is benign and without recurrence. In our series, rhabdomyolysis was the initial symptom of a metabolic myopathy in only one patient. PMID- 21592503 TI - White urine in an asymptomatic child. PMID- 21592502 TI - Increased resting energy expenditure is associated with failure to thrive in infants with severe combined immunodeficiency. AB - OBJECTIVES: To measure resting energy expenditure (REE) and determine whether increased REE (hypermetabolism) is associated with failure to thrive (FTT) in patients with severe combined immunodeficiency (SCID) at diagnosis. STUDY DESIGN: REE was measured in 26 patients with SCID in a single transplant center. Predicted REE was determined with World Health Organization standards. Measured REE >110% of predicted REE was classified as hypermetabolism. Other data collected included FTT status, infections, genotype, phenotype, and the feeding methods used. RESULTS: Fifteen of 26 patients (57.7%) had FTT, and 18 of 26 patients (69.2%) were hypermetabolic. Hypermetabolism occured in 14 of 15 patients (93%) with FTT, and only 4 of 11 patients (36%) without FTT had hypermetabolism (P = .003). There was a significant difference between the measured REE (71.75 +/- 16.6 kcal/kg) and the predicted REE (52.85 +/- 2.8 kcal/kg; P < .0001). Eleven of 17 patients (65%) required nasogastric feeding, parenteral nutrition, or both to meet their energy needs. CONCLUSIONS: Hypermetabolism is common in patients with SCID and may contribute to the development of FTT. The hypermetabolism in these patients may necessitate intensive nutrition support. PMID- 21592505 TI - A dopamine receptor (DRD2) but not dopamine transporter (DAT1) gene polymorphism is associated with neurocognitive development of Mexican preschool children with lead exposure. AB - OBJECTIVE: To investigate the effects of prenatal and postnatal lead exposure and polymorphisms in dopamine metabolism genes on neurocognitive development of Mexican children at 24 months (n = 220) and 48 months (n = 186) of age. STUDY DESIGN: We genotyped the dopamine transporter gene (DAT1; SLC6A3) variable nucleotide tandem repeat and the dopamine receptor D2 (DRD2) Taq1A single nucleotide polymorphism. Children were assessed at 24 months with Bayley Scales of Infant Development (Mental Development Index and Psychomotor Development Index) and at 48 months with McCarthy Scales of Children's Abilities. RESULTS: Blood lead concentration (BLL) in umbilical cord was 6.6 +/- 3.3 MUg/dL (measured in 1995-96), 8.1 +/- 4.4 MUg/dL at 24 months, and 8.1 +/- 3.6 MUg/dL at 48 months. Cord BLL was negatively associated with Mental Development Index (P < .01) and Psychomotor Development Index (P < .1), but not McCarthy scores. The 48 month BLL, but not the 24-month BLL, was negatively associated with children's scores. Children with DRD2 TT genotype (variant) scored higher than children with CC genotype (wild type) on the Mental Development Index and McCarthy memory scale. Neither polymorphism modified the relationship between BLL (either prenatal or postnatal) and neurocognitive development. CONCLUSION: Lead exposure was adversely associated with neurocognitive measures, whereas the DRD2 Taq1A TT variant was positively associated with neurocognitive measures. We found no evidence of gene-environment interactions on developmental outcomes in early childhood. PMID- 21592506 TI - Optimizing protein in the diets of critically ill children: time for re evaluation. PMID- 21592507 TI - Efficacy of hypertonic nebulized saline in bronchiolitis: improved outcome measures needed. PMID- 21592508 TI - Zinc, vitamin A, and micronutrient supplementation in children with diarrhea: a randomized controlled clinical trial of combination therapy versus monotherapy. AB - OBJECTIVE: To compare the clinical efficacy of supplementation of zinc, zinc plus vitamin A, and zinc plus combination of micronutrients and vitamins (iron, copper, selenium, vitamin B(12), folate, and vitamin A) on acute diarrhea in children. STUDY DESIGN: This was a double-blind, randomized, placebo-controlled trial. Children aged 6 to 24 months with diarrhea and moderate dehydration were randomized to receive zinc plus placebo vitamin A (group 1), zinc plus other micronutrients plus vitamin A (group 2), zinc plus vitamin A (group 3), or placebo (group 4) as an adjunct to oral rehydration solution. Duration, volume of diarrhea, and consumption of oral rehydration solution were compared as outcome variables within the supplemented groups and with the placebo group. RESULTS: The 167 study subjects included 41 in group 1, 39 in group 2, 44 in group 3, and 43 in group 4. All 3 supplemented groups demonstrated a significant reduction in outcome variables (P < .0001) compared with the placebo group. Group 3 had the lowest reduction of outcome variables and group 2 had a speedy recovery, but differences among the supplemented groups were not statistically significant. CONCLUSIONS: Supplementation with a combination of micronutrients and vitamins was not superior to zinc alone, confirming the clinical benefit of zinc in children with diarrhea. PMID- 21592509 TI - Necrotizing enterocolitis and red blood cell transfusion. PMID- 21592511 TI - Chronic kidney disease, pediatric nephrologists, and tobacco counseling: perceptions and practice patterns. A study from the Midwest Pediatric Nephrology Consortium. AB - We sought to identify practice patterns of pediatric nephrologists for tobacco counseling, because of a high incidence of secondhand smoke exposure and tobacco use in adolescents with chronic kidney disease. Counseling was minimal for several reasons, thus increasing the risk for heart disease inherent in children with chronic kidney disease. PMID- 21592512 TI - Gestational alloimmune liver disease in cases of fetal death. AB - OBJECTIVE: To determine whether alloimmune liver disease can be identified as a cause of fetal death. STUDY DESIGN: This is a retrospective examination of the autopsy tissue of 6 stillborn fetuses and 2 extreme preterm infants (gestational age, 20 to 34 weeks) drawn from families referred for suspected neonatal hemochromatosis. Thirteen appropriate nondisease controls and 8 cases of neonatal acute liver failure with known etiology were also examined. Liver sections were immunostained using anti-human C5b-9 complex. RESULTS: All of the study cases had died with no preceding evidence of fetal distress. Histopathology showed findings of acute liver injury, including global hepatocyte necrosis with minimal reticulum collapse and no fibrosis. Hepatocytes in cases stained strongly positively for C5b-9 complex, suggesting premortem lgG complement-mediated liver injury. Hepatocytes in acute liver failure case controls did not demonstrate a similar mechanism of liver injury. CONCLUSIONS: Alloimmune liver disease is sometimes associated with fetal death. PMID- 21592513 TI - Developmental trajectories of metabolic control among White, Black, and Hispanic youth with type 1 diabetes. AB - OBJECTIVE: To examine race/ethnicity and neighborhood income differences in longitudinal patterns of deterioration in hemoglobin A1c (HbA1c) values among youth (age 10 to 18 years) with type 1 diabetes. STUDY DESIGN: A sample of 225 youth (50.2% female), including 81 White, 81 Black, and 63 Hispanic youth with type 1 diabetes, was matched initially on age and sex. Neighborhood median family income was obtained through public census databases. Self-identified race/ethnicity and all HbA1c values (grand mean, 9.09% +/- 2.02%) available in patients' medical records between age 10 and 18 years were recorded and analyzed. RESULTS: Hierarchical linear modeling revealed age-related deterioration in HbA1c values that differed by race/ethnicity and income. Controlling for income, White and Hispanic youth had similar HbA1c values at the start of adolescence (age 10) and demonstrated similar rates of deterioration across adolescence. Blacks had higher initial HbA1c values compared with Whites and Hispanics, but a similar rate of deterioration. Higher neighborhood income was associated with slower deterioration in HbA1c value among White teens, but not among Hispanic or Black teens. CONCLUSIONS: Longitudinally, Black youth appear to experience disproportionate risks compared with White and Hispanic youth when income is statistically controlled. Neither Black nor Hispanic youth appear to benefit from living in higher-income neighborhoods. PMID- 21592514 TI - Esophageal pH study: rumors of its death are greatly exaggerated. PMID- 21592510 TI - Impact of delivery room resuscitation on outcomes up to 18 months in very low birth weight infants. AB - OBJECTIVE: To examine the relationships between intensity of delivery room resuscitation and short- and long-term outcomes of very low birth weight infants enrolled in the Caffeine for Apnea of Prematurity (CAP) Trial. STUDY DESIGN: The CAP Trial enrolled 2006 infants with birthweights between 500 and 1250 g who were eligible for caffeine therapy. All levels of delivery room resuscitation were recorded in study participants. We divided infants in 4 groups of increasing intensity of resuscitation: minimal, n = 343; bag-mask ventilation, n = 372; endotracheal intubation, n = 1205; and cardiopulmonary resuscitation (chest compressions/epinephrine), n = 86. We used multivariable logistic regression models to compare outcomes across the 4 groups. RESULTS: The observed rates of death or disability, death, cerebral palsy, cognitive deficit, and hearing loss at 18 months increased with higher levels of resuscitation. Risk of bronchopulmonary dysplasia, severe retinopathy of prematurity, and brain injury also increased with higher levels of resuscitation. Adjustment for prognostic variables reduced the differences between the groups for most outcomes. Only the adjusted rates of bronchopulmonary dysplasia and severe retinopathy remained significantly higher after more intense resuscitation. CONCLUSIONS: In CAP Trial participants, the risk of death or neurodevelopmental disability at 18 months did not increase substantially with increasing intensity of delivery room resuscitation. PMID- 21592516 TI - Medico-legal claims for cerebral damage caused by hypocarbia in neonates with hypoxic-ischemic encephalopathy. PMID- 21592517 TI - Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia. AB - OBJECTIVE: To determine the extent of growth impairment resulting from imatinib treatment in children with chronic myeloid leukemia (CML). STUDY DESIGN: Clinical records of 48 chronic-phase CML children administered imatinib as the first-line therapy between 2001 and 2006 were analyzed retrospectively. Cumulative change in height was assessed using the height height-SDS and converted height data from age- and sex-adjusted Japanese norms. RESULTS: A decrease in height-SDS was observed in 72.9% of children, with a median maximum reduction in height-SDS of 0.61 during imatinib treatment. Median follow-up time was 34 months (range, 10-88 months). Growth impairment was seen predominantly in children who started imatinib at a prepubertal age compared with those who started at pubertal age. Growth velocity tended to recuperate in prepubertal children with growth impairment, as they reached pubertal age, suggesting that imatinib had little impact on growth during puberty. CONCLUSIONS: Growth impairment was a major adverse effect of long-term imatinib treatment in children with CML. We report the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML. We should be aware of growth deceleration in children, especially in young children given imatinib before puberty and subjected to prolonged exposure. PMID- 21592519 TI - Ischemic stroke in children: new aspects of treatment. PMID- 21592518 TI - Management of the non-toxic-appearing acutely febrile child: a 21st century approach. PMID- 21592521 TI - Impact of antipsychotics on cytokine production in-vitro. AB - OBJECTIVE: A growing body of data from genetic, immunological and clinical studies indicates an involvement of the immune system in the pathophysiology of schizophrenia and suggests that the modulation of the cytokine system by antipsychotics may be one cause for the improvement of psychotic symptoms. However, the influence of the typical antipsychotics chlorpromazine and haloperidol, and the effect of typical and atypical antipsychotics on the TSST-1 stimulated blood cell secretion of cytokines, and specifically the interleukin (IL)-17 production have not been studied so far, although IL-17 is a leading pro inflammatory cytokine. METHOD: We measured levels of IL-1beta, IL-2, IL-4, IL-6, IL-17 and tumor necrosis factor-alpha (TNF-alpha) in stimulated blood of 10 healthy female subjects in a whole blood assay using the toxic shock syndrome toxin TSST-1 as stimulant. Blood was either supplemented with antipsychotics (chlorpromazine, haloperidol, clozapine, N-desmethylclozapine and quetiapine with four different concentrations each) or not. RESULTS: Under TSST-1 stimulation, antipsychotics as a group had no influence on IL-1beta or IL-6 concentrations but increased IL-4 levels. The most consistent findings were seen regarding IL-17. Mean IL-17 concentrations differed significantly between blood with and without antipsychotic supplements and were increased over all antipsychotics and almost all of the applied antipsychotic concentrations. TNF-alpha levels were increased by chlorpromazine; N-desmethylclozapine and quetiapine reduced IL-2 production. CONCLUSIONS: Antipsychotics might, among other mechanisms, act as such by increasing the production of IL-17. PMID- 21592522 TI - State-dependent changes in the expression of DNA methyltransferases in mood disorder patients. AB - Aberrant transcriptional regulation may be one of the key components of the pathophysiology of mood disorders. DNA methylation generally acts as an epigenetic gene silencing mechanism and is catalyzed by a group of enzymes known as DNA methyltransferases (DNMTs). Several lines of evidence have suggested aberrant DNA methylation in patients with neuropsychiatric disorders and in animal models for psychiatric disorders. However, the involvement of DNMTs in the pathophysiology of mood disorders is not completely understood. In this study, we aimed to determine whether there are alterations in the expression of DNMTs mRNA in mood disorder patients. We used quantitative real-time PCR to measure the mRNA expression of four DNMT isoforms in the peripheral white blood cells of major depressive disorder (MDD) and bipolar disorder (BPD) patients during a depressive and a remissive episode. We found that the levels of DNMT1 mRNA were significantly decreased in a depressive but not in a remissive state of MDD and BPD. In addition, the levels of DNMT3B mRNA in MDD were significantly increased in a depressive but not in a remissive state. Thus, our data suggest that the altered expression of DNMTs is state dependent and that the aberrant epigenetic gene regulations caused by the altered expression of DNMT1 and DNMT3B may be associated with the pathophysiology of mood disorders. PMID- 21592523 TI - A biphasic response to nitric oxide donation in an ex vivo model of donation after cardiac death renal transplantation. AB - BACKGROUND: Donation after cardiac death (DCD) donors are vital to maximize the organ donor pool. Reperfusion injury (RI) is an important sequela in DCD organs due to warm and cold ischemia. RI manifests clinically as a high incidence of delayed graft function (DGF) and primary non-function (PNF) compared with donation after brain death organs. The importance of nitric oxide (NO) in the generation of reperfusion injury is pivotal. METHODS: Using an ex vivo porcine model of kidney transplantation the effects of reperfusion with and without NO supplementation on initial renal blood flow and function were compared. Real-time hemodynamic measurements were recorded and biochemical samples taken at set time points. Molecular markers of reperfusion injury were also measured. Sodium nitroprusside was chosen as the NO donor. RESULTS: Results showed that NO donation initially improved renal blood flow significantly over controls; at the end of reperfusion this benefit was lost. In addition, there was an improvement in creatinine clearance, fractional excretion of sodium and renal oxygen consumption. There were observed to be higher levels of urinary nitrite/nitrate excretion, but no difference in isoprostane levels. CONCLUSION: This study represents a good model for the initial reperfusion period in large animal renal transplantation. The improvement in renal blood flow observed in the NO supplemented groups represents NO mediated vasodilatation. Later in reperfusion, accumulation of nitrogenous free radicals impairs renal blood flow. Clinically, NO supplementation during initial reperfusion of DCD kidneys improves renal blood flow but should be considered with caution due to potential deleterious effects of nitrogenous compound accumulation. PMID- 21592524 TI - Varying effects of hemodynamic forces on tissue factor RNA expression in human endothelial cells. AB - BACKGROUND: Atherosclerotic lesions predominantly localize in areas exposed to distinct hemodynamic conditions. In such lesions, tissue factor (TF) is over expressed. Therefore, we hypothesized that varying types of mechanical forces may induce different effects on TF expression in endothelial cell, and may also influence the effects of chemical stimuli. MATERIALS AND METHODS: TF RNA expression in human umbilical vein endothelial cells (HUVEC) exposed to mechanical stress in the presence or absence of chemical stimulation with thrombin (Th) was determined. The forces examined were: steady unidirectional laminar flow (LF), pulsatile unidirectional laminar flow (PF), constant oscillatory flow (OF), pulsatile to-fro flow (TFF), and cyclic strain (CS). RESULTS: Mechanical stimulation of HUVEC with LF for 2 h induced an 8.7 +/- 0.7 fold increase in TF RNA expression, while PF induced 4.7 +/- 0.9 and TFF induced 8.6 +/- 1.7-fold, respectively. These responses were significantly higher than static controls. Exposure to OF or CS did not result in any significant increase, whereas chemical stimulation with Th led to significant TF expression (4.9 +/- 0.3-fold). The combination of mechanical-chemical stimuli induced significantly higher TF expression than mechanical stresses alone, and this effect was synergistic. Combination of LF+Th for 2 h induced significantly increased TF expression (16.6 +/- 1.7-fold), as did PF+Th (14.8 +/- 2.4) and TFF+Th (17.4 +/- 1.0). Furthermore, after 6 h exposure, only TFF demonstrated significantly higher TF expression both with and without Th. CONCLUSIONS: While uniform laminar flow resulted in transient TF expression, disturbed flow induced sustained amplification of TF expression. Further investigation is needed to elucidate the mechanism of localized atherosclerosis in areas exposed to disturbed flow. PMID- 21592525 TI - Descending aortic diameter of 5.5 cm or greater is not an accurate predictor of acute type B aortic dissection. AB - OBJECTIVE: The risk of acute type B aortic dissection is thought to increase with descending thoracic aortic diameter. Currently, elective repair of the descending thoracic aorta is indicated for an aortic diameter of 5.5 cm or greater. We sought to investigate the relationship between aortic diameter and acute type B aortic dissection, and the utility of aortic diameter as a predictor of acute type B aortic dissection. METHODS: We examined the descending aortic diameter at presentation of 613 patients with acute type B aortic dissection who were enrolled in the International Registry of Acute Aortic Dissection between 1996 and 2009, and analyzed the subset of patients with acute type B aortic dissection with an aortic diameter less than 5.5 cm. RESULTS: The median aortic diameter at the level of acute type B aortic dissection was 4.1 cm (range 2.1-13.0 cm). Only 18.4% of patients with acute type B aortic dissection in the International Registry of Acute Aortic Dissection had an aortic diameter of 5.5 cm or greater. Patients with Marfan syndrome represented 4.3% and had a slightly larger aortic diameter than patients without Marfan syndrome (4.68 vs 4.32 cm, P = .121). Complicated acute type B aortic dissection was more common among patients with an aortic diameter of 5.5 cm or greater (52.2% vs 35.6%, P < .001), and the in hospital mortality for patients with an aortic diameter less than 5.5 cm and 5.5 cm or greater was 6.6% and 23.0% (P < .001), respectively. CONCLUSIONS: The majority of patients with acute type B aortic dissection present with a descending aortic diameter less than 5.5 cm before dissection and are not within the guidelines for elective descending thoracic aortic repair. Aortic diameter measurements do not seem to be a useful parameter to prevent aortic dissection, and other methods are needed to identify patients at risk for acute type B aortic dissection. PMID- 21592527 TI - Surgical palliation of primary pulmonary arterial hypertension by a unidirectional valved Potts anastomosis in an animal model. AB - OBJECTIVE: Patients with idiopathic pulmonary hypertension are at risk for right sided heart failure and sudden death. Despite improvement in pharmacologic management, some still require lung transplantation. Potts anastomosis has been demonstrated as a good palliation in children to alleviate symptoms and medical therapy despite desaturation in the lower part of the body. Young adult patients with pulmonary hypertension and isosystemic pressure remain at risk, particularly at exercise. The goal of this research was to find a palliation for patients in whom suprasystemic pulmonary hypertension developed at exercise. Creating a Potts anastomosis involved a unidirectional valve between the left pulmonary artery and the descending aorta. METHODS: Experimental study was performed on 14 pigs. A prosthetic patch of polytetrafluoroethylene (Gore-Tex; WL Gore & Associates Inc, Newark, Del) was used to create the unidirectional valve and implanted in the Potts anastomosis. Via a left thoracotomy, an aorto-aortic shunt between the aortic isthmus and the distal descending thoracic aorta was instituted, allowing a safe surgical procedure. Intrapulmonary injection of Erciplex glue (Peters Surgical, Bobigny, France), diluted in 70% alcohol, was used to create acute pulmonary hypertension. The right to left shunt across the unidirectional valvular patch was evaluated after clamping the aorta in the acute phase of pulmonary hypertension by echo-pulsed Doppler at the level of the descending thoracic aorta by withdrawal of blood gas (arterial carbon dioxide tension, alveolar carbon dioxide tension) and assessment of peripheral oxygen saturation. Similar reevaluation of the shunt was performed at a mean interval of 13 +/- 2.5 weeks. RESULTS: In the first series, Erciplex glue increased pulmonary artery pressure from 15.3 +/- 3.1 mm Hg to 38.7 +/- 6.0 mm Hg. Mean peripheral oxygen saturation decreased from 100% to 85% +/- 1.5%. Mean partial pressure of carbon dioxide increased from 31.9 +/- 9.1 mm Hg to 46.2 +/- 12.5 mm Hg after shunt opening (P < .01), and mean peripheral oxygen decreased from 435.1 +/- 109.4 mm Hg to 261.9 +/- 77.9 mm Hg (P < 0.05), indicating right to left shunt through the Potts valve (P < .013). Pulsed Doppler showed a mean peak laminar flow of 133.3 +/- 35.3 cm/s before aortic clamping, turbulent flow of 234.9 +/- 40.1 cm/s after glue injection, and return of laminar flow 128.5 +/- 30.1 cm/s after aortic isthmus unclamping. In the second series, the same results were obtained but with a lesser peak flow velocity because of the endothelialization on the valvular patch. Gross analysis of the patch did not show thrombosis, aneurysm, or fissure. CONCLUSIONS: Palliation of exercise suprasystemic pulmonary hypertension was demonstrated by a unidirectional valved Potts anastomosis. This technique can be of help in young adult patients with pulmonary hypertension and isosystemic pressure but with exercise intolerance. PMID- 21592528 TI - The use of the HeartWare HVAD for long-term right ventricular support after implantation of the HeartMate II device. PMID- 21592529 TI - Atrioventricular valve repair in patients with functional single-ventricle physiology: impact of ventricular and valve function and morphology on survival and reintervention. AB - OBJECTIVE: This study was to determine whether atrioventricular valve repair modifies natural history of single-ventricle patients with atrioventricular valve insufficiency and to identify factors predicting survival and reintervention. METHODS: Fifty-seven (13.5%) of 422 single-ventricle patients underwent atrioventricular valve repair. Valve morphology, regurgitation mechanism, and ventricular morphology and function were analyzed for effect on survival, transplant, and reintervention with multivariate logistic and Cox regression models. Comparative analysis used case-matched controls. RESULTS: Atrioventricular valve was tricuspid in 67% and common in 28%. Ventricular morphology was right in 83%. Regurgitation mechanisms were prolapse (n = 24, 46%), dysplasia (n = 18, 35%), annular dilatation (n = 8, 15%), and restriction or cleft (n = 2, 4%). Postrepair insufficiency was none or trivial in 14 (26%), mild in 33 (61%), and moderate in 7 (13%). Survival in repair group was lower than in matched controls (78.9% vs 92.7% at 1 year, 68.7% vs 90.6% at 3 years, P = .015). Patients with successful repair and normal ventricular function had equivalent survival to matched controls (P = .36). Independent predictors for death or transplant included increased indexed annular size (P = .05), increased cardiopulmonary bypass time (P = .04), and decreased postrepair ventricular function (P = .01). Ventricular dilation was a time-related factor for all events, including failed repair. CONCLUSIONS: Survival was lower in single ventricle patients operated on for atrioventricular valve insufficiency than in case-matched controls. Patients with little postoperative residual regurgitation and preserved ventricular function had equivalent survival to controls. Lower grade ventricular function and ventricular dilation correlated with death and repair failure, suggesting that timing of intervention may affect outcome. PMID- 21592530 TI - Early clinical outcomes after transapical aortic valve implantation: a propensity matched comparison with conventional aortic valve replacement. AB - OBJECTIVE: Aortic valve replacement remains the standard treatment for symptomatic severe aortic stenosis. However, catheter-based approaches have recently emerged as therapeutic options for high-risk surgical candidates. The objective of this study is to use propensity scoring to compare early clinical outcomes after transapical aortic valve implantation and conventional aortic valve replacement. METHOD: Propensity scoring based on logistic regression modeling of 16 preoperative patient characteristics was used to identify a group of very high-risk patients undergoing isolated conventional aortic valve replacement comparable to those patients undergoing transapical aortic valve implantation. McNemar's test was used to compare early clinical outcomes between the 2 treatment groups, including 30-day mortality and in-hospital postoperative complications. RESULTS: Ninety-two patients receiving transapical aortic valve implantation between October 2005 and April 2010 met inclusion criteria for this study. Half of these patients were successfully matched 1:1 to a patient receiving conventional aortic valve replacement. Baseline characteristics were similar between the 2 treatment groups after propensity matching. There were 4 perioperative deaths (8.7%) in the conventional aortic valve replacement group and 6 perioperative deaths (13%) in the transapical aortic valve implantation group (P > .05). There were no significant differences in the rates of cerebrovascular accidents, wound infections, reoperation for bleeding, or length of postoperative hospital stay between the 2 groups (P > .05). CONCLUSIONS: Among high-risk propensity-matched patients, early clinical outcomes are similar after transapical aortic valve implantation and conventional aortic valve replacement. However, given the likelihood of residual selection bias, a prospective randomized trial is necessary to adequately compare the clinical outcomes after these 2 aortic valve procedures. PMID- 21592531 TI - On North Pacific circulation and associated marine debris concentration. AB - Marine debris in the oceanic realm is an ecological concern, and many forms of marine debris negatively affect marine life. Previous observations and modeling results suggest that marine debris occurs in greater concentrations within specific regions in the North Pacific Ocean, such as the Subtropical Convergence Zone and eastern and western "Garbage Patches". Here we review the major circulation patterns and oceanographic convergence zones in the North Pacific, and discuss logical mechanisms for regional marine debris concentration, transport, and retention. We also present examples of meso- and large-scale spatial variability in the North Pacific, and discuss their relationship to marine debris concentration. These include mesoscale features such as eddy fields in the Subtropical Frontal Zone and the Kuroshio Extension Recirculation Gyre, and interannual to decadal climate events such as El Nino and the Pacific Decadal Oscillation/North Pacific Gyre Oscillation. PMID- 21592532 TI - A simple osmium post-fixation paraffin-embedment technique to identify lipid accumulation in fish liver using medaka (Oryziaslatipes) eggs and eleutheroembryos as lipid rich models. AB - Hepatic lipidosis is a non-specific biomarker of effect from pollution exposure in fish. Fatty liver is often misdiagnosed or overlooked in histological assessments due to the decreasing application of specific fat procedures and stains. For example, ethanol dehydration in standard paraffin processing removes lipids, leaving vacuoles of which the precise nature is unknown. Lipids can be identified using osmium post-fixation in semi-thin resin sections or transmission electron microscopy. However, both are expensive and technically demanding procedures, often not available for routine environmental risk assessment and monitoring programs. The current emphasis to reduce and refine animal toxicity testing, requires refinement of the suite of histopathological techniques currently available to maximize information gained from using fish for toxicity testing and as bio-indicators of environmental quality. This investigation has successfully modified an osmium post-fixation technique to conserve lipids in paraffin-embedded tissues using medaka (Oryzias latipes) eleutheroembryos and eggs (embryos) as lipid rich models. PMID- 21592533 TI - Influence of multiple stressors on the auto-remediation processes occurring in salt marshes. AB - Due to increasing global population, salt marshes have been subjected to multiple stressors such as increasing nutrient loadings and historical contamination. In order to better understand how does the salt marsh plants auto-remediation capacity (phytoaccumulation of metals) is affected by cultural eutrophication, an experiment was performed under controlled conditions. Plants were exposure to equal metal concentrations (Zn, Cu, and Ni - micronutrients, and Cd - class B metal) simulating historical contamination and three different concentrations of nitrogen (nitrate) simulating steps of cultural eutrophication. According to our study, under the tested concentrations, cultural eutrophication does not seem to affect Zn, Cu and Ni phytoremediation of H. portulacoides, but the ecosystem service of Cd phytoremediation seems to be promoted. Nevertheless, Cd high toxicity and bioaccumulation should be taken into account, as well as the vulnerability of salt marsh ecosystems, whose reduction will have drastic consequences to the ecosystem health. PMID- 21592534 TI - [Women physicians and health research]. PMID- 21592535 TI - [Calcium-alkali syndrome: update of an old clinical problem]. PMID- 21592536 TI - [Acute appendicitis after colonoscopy]. PMID- 21592537 TI - Expression of secreted mucins (MUC2, MUC5AC, MUC5B, and MUC6) and membrane-bound mucin (MUC4) in the lungs of pigs experimentally infected with Actinobacillus pleuropneumoniae. AB - The expression patterns of different secreted (MUC2, MUC5AC, MUC5B, and MUC6) and membrane-bound (MUC4) mucins were determined immunohistochemically in the lungs of pigs experimentally infected with Actinobacillus pleuropneumoniae. Forty-seven week-old colostrum-deprived pigs were randomly allocated to infected (n=20) or control groups (n=20). Five infected and uninfected pigs were euthanized at 0, 6, 12, and 48 h post-inoculation (hpi). In the infected pigs, the expression of both types of mucins, which were invariably observed, was associated with bronchiolar and respiratory bronchiolar lesions. Strong positive mucin signals were seen on the surface of bronchiolar and respiratory bronchiolar epithelium with neutrophil infiltration. The mean mucin-positive area peaked at 6 hpi and decreased significantly to control levels by 48 hpi on the surface of the bronchiolar and respiratory bronchiolar epithelium. Further studies are needed to establish the functional relationship between mucin expression and the host defense mechanism against A. pleuropneumoniae in the lungs of infected pigs. PMID- 21592538 TI - Endoscopic transcervical intrauterine artificial insemination in Labrador Retriever bitches. AB - Besides post-thawing reduced semen quality, there are some difficulties in the execution of the endoscopic transcervical intrauterine artificial insemination (AI) with frozen-thawed semen in bitches. Therefore, the aims of the present study were to evaluate behavioral and reproductive parameters (i.e., vaginal cytology and serum progesterone level) to determine time of insemination and to investigate the particularities and difficulties of this technique in bitches using fresh semen. Ten Labrador Retriever bitches were submitted to three endoscopic transcervical intrauterine AIs (with 48 h intervals). Oestrus and ovulation period were established by behaviour evaluation, progesterone assays and vaginal cytology, enabling optimal timing for AI during oestrus. During AI, the following aspects were evaluated: cervical os catheterization difficulty, semen deposition resistance, occurrence of semen backflow, and time required to perform the AI. In this study, it was possible to catheterize the cervical os in all bitches, with different degrees of difficulty, by manipulating the equipment to allow cervical visualization and catheter introduction in the cervical canal. Serial serum progesterone assays enabled estimation of LH surge day, and thus of ovulation. The pregnancy rate was 90%, with a litter size of 5.0 +/- 2.6 puppies per bitch. It was concluded that the difficulties in the execution of the endoscopic transcervical intrauterine AI technique in Labrador Retriever bitches were minimized by the equipment manipulation and practical experience. PMID- 21592539 TI - [Familial and non-familial benign infantile seizures: A homogeneous entity?]. AB - Among the epileptic syndromes occurring during infancy, which are mostly non idiopathic and associated with a poor prognosis, benign infantile convulsions are characterized by a favourable evolution. This work aims to analyse and compare the clinical, EEG and outcome characteristics of familial benign infantile convulsions (FBIC) and non-familial benign infantile convulsions (NFBIC). This is a retrospective study, conducted between 1988 and 2008, in 40 infants who presented benign infantile seizures during the two first years of life. All of them had no personal history, normal psychomotor development, normal neurological examinations, no abnormalities on biological and radiological investigations and a favourable outcome. In 14 cases, there was a familial history of familial benign infantile convulsions. However, among the 26 cases with non-familial benign infantile convulsions, 11 children had a familial history of other epileptic syndrome. That may suggest a genetic familial susceptibility. In the two groups, the clinical features and the electroencephalography were similar. The seizures had short duration and occurred most often in clusters. Twenty-nine children had secondarily generalized partial seizures and 11 infants had generalized seizures but a focal onset cannot be excluded. The antiepileptic drugs allowed rapid resolution of seizures. One child necessitated a prolonged antiepileptic treatment. In the other cases, seizures cured in the first year without recurrence of seizures after treatment discontinuation. The evolution was characterised in five children by a later occurrence of dystonia. This subgroup was described as infantile convulsion and choreoathetosis syndrome (ICCA). Benign infantile convulsions are probably an underestimated epileptic syndrome. The diagnosis is relatively easy in the familial forms with dominant autosomal transmission. In contrast, in sporadic forms, the diagnosis can be confirmed only by the evolution. The good prognosis must be tempered by the subsequent onset of dystonia consisted in the ICCA syndrome and justifies a prolonged follow-up. PMID- 21592540 TI - [Spinal cord compression due to multiple extramedullary haematopoiesis in a patient with drepanothalassaemia]. PMID- 21592541 TI - A novel scenario for biofouling control of spiral wound membrane systems. AB - Current strategies to control biofouling in nanofiltration and reverse osmosis membrane systems such as chemical cleaning and use of low fouling membranes are not always successful. Based on recent studies, an alternative approach is derived, combining a lower linear flow velocity in lead modules and adapted designs for feed spacer with an advanced cleaning strategy. This approach can be realized by small adaptations in current plant design. A lower linear flow velocity in lead spiral wound membrane modules results in (i) lower energy use, (ii) lower impact of biomass on the feed channel pressure drop, and (iii) more fluffy biofilm that may be easier to remove from the lead membrane modules, especially when adapted feed spacers combined with a reversed enhanced flush are applied. This rational scenario can result in effective biofouling control at low energy requirements, minimal chemical use and minimal cost. PMID- 21592542 TI - Application of an ELISA to the quantification of carbamazepine in ground, surface and wastewaters and validation with LC-MS/MS. AB - Carbamazepine is a psychiatric pharmaceutical widely detected in aquatic environments. Due to its generalized occurrence and environmental persistence it might be considered as an anthropogenic pollution indicator. In this research, a previously developed enzyme-linked immunosorbent assay (ELISA), based on a commercial monoclonal antibody, was applied to the quantification of carbamazepine in ground, surface and wastewaters and results were validated by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The performance of the applied ELISA methodology was tested in the presence of high concentrations of sodium chloride and dissolved organic matter. The method was not significantly affected by matrix effects, being adequate for the quantification of carbamazepine in environmental samples, even without sample pre-treatment. This method allows the quantification of carbamazepine in the range of 0.03-10 MUg L( 1), with a relative error lower than 30%. Due to a pH dependent cross-reactivity with cetirizine, an antihistaminic drug, the assay also enabled the quantification of cetirizine in the samples. The application of the developed method to the quantification of carbamazepine was performed by using environmental samples with very different matrices, collected in the geographical area of Ria de Aveiro, an estuarine system located in the North of Portugal. Carbamazepine was detected in all analyzed wastewater samples and in one surface water with concentrations between 0.1 and 0.7 MUg L(-1). Validation with LC-MS/MS revealed that results obtained by ELISA are 2-28% overestimated, which was considered highly satisfactory due to the absence of sample pre-treatments. PMID- 21592543 TI - Photochemical reactivity of perfluorooctanoic acid (PFOA) in conditions representing surface water. AB - Potential of perfluorooctanoic acid (PFOA) to degrade via indirect photolysis in aquatic solution under conditions representing surface water was studied. Globally distributed and bioaccumulative PFOA does not absorb solar radiation by itself, but may be potentially photochemically transformed by the natural sensitizers such as dissolved organic matter (DOM), nitrate or ferric iron. Reaction solutions containing purified water, fulvic acid (representing DOM), nitrate, ferric iron or sea water from the Baltic Sea were spiked with PFOA and irradiated with an artificial sun (290-800 nm). In comparison similar samples were also irradiated under UV radiation at 254 nm in order to study the direct photolysis. UV radiation at 254 nm decomposed PFOA to perfluoroheptanoic-, perfluorohexanoic- and perfluoropentanoic acids. The samples irradiated with an artificial sun contained no decomposition products and no decrease in PFOA concentration was observed. According to the detection limit of the products and typical solar radiation at the surface of ocean, the photochemical half-life for PFOA was estimated to be at least 256 years at the depth of 0 m, >5000 years in the mixing layer of open ocean and >25,000 years in coastal ocean. This is significantly more than the previously reported photochemical half-life of PFOA (>0.96 years). PMID- 21592544 TI - Fatty involution of the gluteus medius muscles: a late-onset girdle myopathy? AB - BACKGROUND: Involvement of the gluteus medius muscle has been reported in girdle myopathies or facioscapulohumeral myopathies. Camptocormia, or Bent spine syndrome, characterized by involuntary forward flexion of the trunk in the standing position, may be secondary to a late-onset myopathy essentially involving the spinal erector muscles. In this article, we report the observations of patients with severe deficiency of the gluteus medius, suggesting a late-onset myopathy. METHODS: Computed tomography and magnetic resonance imaging (MRI) were performed in 17 patients, with a mean age 76 years, 3 men and 14 women, presenting a Trendelenburg limp related to fatty infiltration of the gluteus medius muscles. Eight of these patients also had camptocormia. RESULTS: Computed tomographic scan and MRI appearance differed from that of age-matched controls and suggested myopathy. MRI excluded an inflammatory disorder or disinsertion of the gluteus medius muscle. Biopsies of gluteus medius and paravertebral muscles showed marked septal fibrosis and adiposis, whereas control biopsies were normal. Creatine phosphokinase was moderately increased in two thirds of patients. CONCLUSIONS: Involvement of the gluteus medius muscles, like involvement of the paravertebral muscles with which it is frequently associated, may be a form of late-onset girdle myopathy. PMID- 21592545 TI - Pharmacogenomics of clopidogrel: evidence and perspectives. AB - Clopidogrel has become the mainstay oral antiplatelet regimen to prevent recurrent ischemic events after acute coronary syndromes or stent placement. However, there is marked interindividual variability in the antiplatelet effects of clopidogrel, and a reduced response to this drug may be a risk factor for ischemic complications. Pharmacogenomic analyses, including candidate-gene and genome-wide association studies, have confirmed that genetic polymorphisms in the hepatic cytochrome P450 (CYP) 2C19 dominantly affect the antiplatelet effects of clopidogrel. CYP2C19 reduced-function alleles have been associated with a significant decrease in clopidogrel responsiveness and a higher risk of adverse cardiac events including stent thrombosis, myocardial infarction, and death in several prospective studies, although these effects were not reproduced in a recent large randomized study that included a randomized control group. The US Food and Drug Administration addressed this issue by adding a boxed warning to the clopidogrel label and suggesting that adjusting the clopidogrel dose or using alternative antiplatelet agents should be potentially implemented for high-risk individuals who are identified based on the CYP2C19 genotype. Although it is promising that CYP2C19 genotyping could be used to guide personalized antiplatelet clopidogrel therapy, currently there is insufficient evidence to recommend routine genetic testing. Prospective randomized clinical trials are necessary to validate this pharmacogenomic approach to clopidogrel therapy. In the most recent trial, paraoxonase-1 (PON1) was identified as a crucial new enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite and the clinical activity of clopidogrel. Further studies are needed to investigate the comprehensive influence of a number of different polymorphisms of CYP2C19 and PON1 variant alleles or other genetic variants on clopidogrel in various ethnic populations. PMID- 21592546 TI - The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog. AB - OBJECTIVE: Cisplatin is a DNA-damaging antitumor agent that is highly effective in treating ovarian cancer. It activates the p53/p21 pathway for its cytotoxic mode of action, but it does not induce p21-dependent cell cycle arrest in G1. Therefore, we investigated this paradox, and used the model analog DAP as a positive control for p21-dependent G1-arrest. METHODS: Studies were conducted in p53-proficient ovarian A2780 tumor cells to examine Cdk activity, cell cycle distribution and DNA damage signaling after cisplatin or DAP in combination with the mitotic inhibitor nocodazole. RESULTS: Cisplatin consistently induced transient S-phase arrest by inhibiting Cdk2/cyclin A complex in S-phase at 12 h and then a durable G2/M-arrest by inhibiting Cdc2/cyclin B complex at 12-18 h. These inhibitions were associated with Chk1 and Chk2 activation and resultant increase in inhibitory tyrosine phosphorylation of Cdk2 and Cdc2. Cisplatin also potently inhibited G1-phase Cdk4/cyclin D1 and Cdk2/cyclin E activities at ~18 h. In agreement, exposure of cisplatin-treated A2780, HCT-116(p53-/-) and HCT 116(p21-/-) tumor cells to nocodazole revealed limited G1-arrest that was dependent on p53 and p21. In contrast, the durable G1-arrest by DAP, which failed to activate Chk1 and Chk2, was unaffected by nocodazole. CONCLUSIONS: Cisplatin induced G1-arrest, but at an attenuated level. This was primarily due to orchestration of Cdk inhibition in S-phase first, then in G2, and finally in G1 that effectively blocked cells in G2 and prevented cells from progressing and arresting in G1. These studies demonstrate that cisplatin unequivocally activates G1-checkpoint response, but the fidelity of G1-arrest is compromised by Chk1/2 activation and checkpoint response in S- and G2/M-phase. PMID- 21592547 TI - Mitochondrial DNA genotyping reveals synchronous nature of simultaneously detected endometrial and ovarian cancers. AB - Simultaneous independent primary tumors of the female genital tract occur in 1-2% of gynecological cancer patients, 50-70% of which are synchronous tumors of the endometrium and ovary. Guidelines for determining the nature of simultaneously detected tumors, based on surgical and histopathological findings, are often ambiguous and may require further molecular analyses. Such approach is necessary to indicate correct prognosis and hence treatment. We here demonstrate how mitochondrial DNA sequencing may provide a cheap and useful tool to contribute to indisputably recognize the synchronous nature of simultaneously detected endometrial and ovarian carcinomas. We further confirm our findings by means of Comparative Genomic Hybridization array analysis, which strengthens the informative potential of mitochondrial DNA genotyping in diagnosing synchrony. PMID- 21592548 TI - New classification system of radical hysterectomy: emphasis on a three dimensional anatomic template for parametrial resection. AB - OBJECTIVE: The international acceptance of a universal classification system for radical hysterectomy is one of the important challenges in gynecologic oncology. The recently published classification system by Querleu and Morrow is a relevant proposal that has been well received by the professional community. However, it does not include a description of parametrial resection in three dimensions, which mostly determines post-operative morbidity. METHODS: The intention of this follow-up paper was to further develop the classification system based on the four proposed types of radical hysterectomy (A-D) into a three-dimensional model using standard anatomical landmarks for definition of resection margins in longitudinal and transverse dimensions and demonstrate it on pictures. RESULTS: Resection margins were defined in longitudinal and transverse dimensions for each suggested type of radical hysterectomy on all three parts of the parametria. Besides precise description using stable anatomical landmarks, all resection lines have been shown on intra-operative photographs. CONCLUSION: Four types of radical hysteretomy can be precisely defined on a three-dimensional anatomical template, including nerve sparing procedure. Our paper should contribute to better standardization (including nomenclature) of the radical hysterectomy, enhancing harmonization of clinical practice in gynecological oncology. PMID- 21592549 TI - Synthesis and study of properties of dental resin composites with different nanosilica particles size. AB - OBJECTIVES: The aim of this work was the synthesis of light-cured resin nanocomposites using nanosilica particles with different particle size and the study of some physical-mechanical properties of the composites. METHODS: Various types of silica nanoparticles (Aerosil) with average particle size of 40, 20, 16, 14, and 7 nm, used as filler were silanized with the silane 3-methacryloxypropyl trimethoxysilane (MPS). The total amount of silane used was kept constant at 10 wt% relative to the filler weight to ensure the complete silanization of nanoparticles. The silanizated silica nanoparticles were identified by FT-IR spectroscopy and thermogravimetric analysis (TGA). Then the silanized nanoparticles (55 wt%) were mixed with a photoactivated Bis-GMA/TEGDMA (50/50 wt/wt) matrix. Degree of conversion of composites was determined by FT-IR analysis. The static flexural strength and flexural modulus were measured using a three-point bending set up. The dynamic thermomechanical properties were determined by dynamic mechanical analyzer (DMA). Sorption, solubility and volumetric change were determined after storage of composites in water or ethanol/water solution 75 vol% for 30 days. The TGA for composites was performed in nitrogen atmosphere from 30 to 700 degrees C. RESULTS: As the average silica particle size decreases, the percentage amount of MPS attached on the silica surface increases. However, the number of MPS molecules attached on the silica surface area of 1 nm(2) is independent of filler particle size. As the average filler particles size decreases a progressive increase in the degree of conversion of composites and an increase in the amount of sorbed water is observed. SIGNIFICANCE: The prepared composites containing different amount of silica filler, with different particle size, but with the same amount of silanized silica and organic matrix showed similar flexural strength and flexural modulus, except composite with the lowest filler particle size, which showed lower flexural modulus. PMID- 21592550 TI - Influence of connector design and material composition and veneering on the stress distribution of all-ceramic fixed dental prostheses: a finite element study. AB - OBJECTIVES: Finite element analysis is a standard method to simulate the stress distribution in all-ceramic dental restorations in order to estimate the loading capacity of the brittle components. The hypothesis of this study was that stresses in the connector area of a veneered FDP are strongly influenced by the framework dimensions and the veneering material. METHODS: Finite element analyzes of bilayered fixed dental prostheses with three different framework-designs and three different veneering materials were conducted, applying the loads onto the veneering as well as directly onto the framework. The outer shape of the veneering ceramic remained constant for all cases. RESULTS: The maximum first principal stresses in the framework of the fixed dental prostheses (FDP) decreased with smaller framework dimensions when the load was applied on the veneering. By applying the load directly onto the framework of the FDP without veneering a converse tendency was found. The variation of the veneering material lead to the conclusion that stresses in the framework became higher with decreasing Young's modulus of the veneer, while the stresses in the veneer increased at the same time. SIGNIFICANCE: The veneering material plays a significant role for the failure of a FDP and cannot be neglected neither in testing nor in simulation. Thus the loading capacity of dental restorations can only be reasonably evaluated when the whole restoration is taken into account, including framework and veneering. PMID- 21592551 TI - A novel array chip to monitor in situ composite degradation using electrochemical impedance spectroscopy. AB - OBJECTIVES: This paper presents a novel array-chip technology used to monitor the physical properties of dental composites in situ. The DECAY chip (Degradation via Electrochemical Array) leverages microfabrication techniques to construct a uniform array of recessed wells that may be filled with dental restorative materials (e.g. composite or amalgam) and analyzed electrochemically in solution. METHODS: The array enables the uniform preparation of multiple specimens and reference controls on a common substrate, all of which may be simultaneously evaluated. The DECAY-chip presented here consists of a 3 * 3 array of 100 MUm deep wells, and is used to monitor the degradation of a common dental composite as a function of time. RESULTS: The data correlate changes in the measured dielectric properties to surface and bulk changes as the composite is exposed to an ethanol:DI mixture (75% ethanol). A model for the system is presented, as are future plans to simplify the methodology for rapid materials screening and in vitro analyses. SIGNIFICANCE: This in situdiagnostic chip will enable evaluation of composite specimens, tested under a wide range of simulated oral environments. It may also serve as a screening platform for new composite formulations and aid in the study of materials degradation and failure mechanisms. PMID- 21592552 TI - The PACE trial in chronic fatigue syndrome. PMID- 21592553 TI - Patients' power and PACE. PMID- 21592554 TI - The PACE trial in chronic fatigue syndrome. PMID- 21592555 TI - The PACE trial in chronic fatigue syndrome. PMID- 21592556 TI - The PACE trial in chronic fatigue syndrome. PMID- 21592558 TI - The PACE trial in chronic fatigue syndrome. PMID- 21592559 TI - The PACE trial in chronic fatigue syndrome. PMID- 21592560 TI - The PACE trial in chronic fatigue syndrome. PMID- 21592561 TI - The PACE trial in chronic fatigue syndrome. PMID- 21592563 TI - The dependence of autologous chondrocyte transplantation on varying cellular passage, yield and culture duration. AB - Matrix-assisted chondrocyte transplantation (m-ACI) still lacks any standardization in its execution in terms of cell passage (P), cell yield (C) and in vitro membrane-holding time (T). It was the goal of this study to analyze the effect of shifting cell culture parameters (P, C, T) on the in vitro as well as in vivo effort of a regulated animal m-ACI. Autologous rabbit knee articular chondrocytes were seeded within bilayer collagen I/III 3-D matrices in variation of P, C and T. Each time, 2 PCT-identical by 2 PCT-identical cell-matrix constructs (CMC)/animal were created. Simultaneously 2 (PCT-distinct) were re implanted (CMC-e) autologous into artificial trochlear pristine chondral defects in vivo to remain for 12 weeks while the remaining 2 were harvested (CMC-i) for immediate in vitro analysis at the time of transplantation of their identical twins. mRNA of both, CMC-e regenerates and CMC-i membranes, was analyzed for Collagen-1,-2,-10, COMP, Aggrecan, Sox9 expression by use of a mixed linear model, multiple regression analysis. Generally, CMC-i values were higher than CMC e values for differentiation targets; the opposite was true for dedifferentiation targets. Regarding individual gene expression, in vivo regenerate cell-matrix properties were significantly dependent on initial cell-matrix in vitro values as a sign of linearity. The parameter membrane-holding time (T) had strongest effects on the resulting mRNA expression with slightly less impact of the parameter passage (P), whereas cell yield (C) had clearly less effects. Noting differences between in vitro and in vivo data, in general, optimal expression patterns concerning chondrogenic differentiation were achieved by few passages, medium cellular yield, short membrane-holding time. Clinical m-ACI may benefit from optimal orchestration of the cell culture parameters passage, yield and time. PMID- 21592562 TI - Role of the Toll-like receptor pathway in the recognition of orthopedic implant wear-debris particles. AB - The inflammatory response to prosthetic implant-derived wear particles is the primary cause of bone loss and aseptic loosening of implants, but the mechanisms by which macrophages recognize and respond to particles remain unknown. Studies of innate immunity demonstrate that Toll-like receptors (TLRs) recognize pathogen associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS). All TLRs signal through myeloid differentiation factor 88 (MyD88), except TLR3 which signals through TIR domain containing adapter inducing interferon-beta (TRIF), and TLR4 which signals through both MyD88 and TRIF. We hypothesized that wear-debris particles may act as PAMPs/DAMPs and activate macrophages via TLRs. To test this hypothesis, we first demonstrated that inhibition of MyD88 decreases polymethylmethacrylate (PMMA) particle-induced production of TNF-alpha in RAW 264.7 macrophages. Next we compared particle induced production of TNF-alpha among MyD88 knockout (MyD88(-/-)), TRIF knockout (TRIF(-/-)), and wild type (WT) murine macrophages. Relative to WT, disruption of MyD88 signaling diminished, and disruption of TRIF amplified the particle-induced production of TNF-alpha. Gene expression data indicated that this latter increase in TNF-alpha was due to a compensatory increase in expression of MyD88 associated components of the TLR pathway. Finally, using an in vivo model, MyD88(-/-) mice developed less particle-induced osteolysis than WT mice. These results indicate that the response to PMMA particles is partly dependent on MyD88, presumably as part of TLR signaling; MyD88 may represent a therapeutic target for prevention of wear debris-induced periprosthetic osteolysis. PMID- 21592564 TI - Basement membrane-like matrix sponge for the three-dimensional proliferation culture of differentiated retinal horizontal interneurons. AB - As the neurons in the central nervous system (CNS) form a neuronal network in a three-dimensional (3D) manner, a 3D proliferation culture system for differentiated neurons has been desired. Although differentiated neurons were previously thought to never proliferate, differentiated horizontal interneurons of Rb-/-; p107+/-; p130-/- (p107-single) retina clonally proliferated without dedifferentiation in vivo. In the present study, we developed a basement membrane like matrix sponge (BM-sponge) for the 3D proliferation culture of differentiated horizontal interneurons. p107-single horizontal interneurons, but not other types of retinal neurons, proliferated in the BM-sponge in a 3D manner. These interneurons expressed presynaptic marker and developed synaptic vesicles. These data demonstrated that p107-single horizontal interneurons cultured in the BM sponge proliferate while maintaining their differentiated features. We described here the 3D proliferation culture system for differentiated neurons. PMID- 21592565 TI - Effects of biomimetic surfaces and oxygen tension on redifferentiation of passaged human fibrochondrocytes in 2D and 3D cultures. AB - Due to its limited healing potential within the inner avascular region, functional repair of the meniscus remains a significant challenge in orthopaedic surgery. Tissue engineering of a meniscus implant using meniscal cells offers the promise of enhancing the reparative process and achieving functional meniscal repair. In this work, using quantitative real-time reverse transcriptase polymerase chain reaction (RT-qPCR) analysis, we show that human fibrochondrocytes rapidly dedifferentiate during monolayer expansion on standard tissue culture flasks, representing a significant limit to clinical use of this cell population for meniscal repair. Previously, we have characterized and described the feasibility of a tailored biomimetic surface (C6S surface) for reversing dedifferentiation of monolayer-expanded rat meniscal cells. The surface is comprised of major meniscal extracellular matrix (ECM) components in the inner region, namely collagen I/II (at a 2:3 ratio) and chondroitin-6-sulfate. We thus have further evaluated the effects of the C6S surface, alongside a number of other tailored surfaces, on cell adhesion, proliferation, matrix synthesis and relevant marker gene expression (collagen I, -II, aggrecan and Sox-9 etc) of passaged human fibrochondrocytes in 2D (coated glass coverslips) and 3D (surface modified polymeric scaffolds) environments. We show that the C6S surface is permissive for cell adhesion, proliferation and ECM synthesis, as demonstrated using DNA quantification, 1,9-dimethylmethylene blue (DMMB) assay, histology and immunohistochemistry. More importantly, RT-qPCR analyses corroborate the feasibility of the C6S surface for reversing phenotypic changes, especially the downregulation of collagen II, of dedifferentiated human fibrochondrocytes. Furthermore, human fibrochondrocyte redifferentiation was enhanced by hypoxia in the 3D cultures, independent of hypoxia inducible factor (HIF) transcriptional activity and was shown to potentially involve the transcriptional activation of Sox-9. PMID- 21592566 TI - The influence of elastin-like recombinant polymer on the self-renewing potential of a 3D tissue equivalent derived from human lamina propria fibroblasts and oral epithelial cells. AB - Three-dimensional epithelial tissue equivalents tend to lose their self-renewing potential progressively during culture as their epithelial cells lose their proliferative capacity with time. Even though the tissue engineered construct can mimic the native tissue well, it rapidly degrades after implantation due to the insufficient number of proliferating cells in the equivalent. In the present study we demonstrate for the first time that the use of an elastin-like recombinant polymer (ELR) engineered to contain the cell adhesion peptide RGD can result in a 3D tissue equivalent with high self-renewing potential, containing as many proliferative cells as the native tissue itself. The 3D tissue equivalent was reconstructed by the coculture of human lamina propria fibroblasts and oral epithelial cells in the nanofibrous ELR-collagen scaffold. Histological, immunohistological and transmission electron microscopic analyses of this oral mucosa equivalent demonstrated the expression of markers characteristic of epithelial proliferation (Ki67) and differentiation (keratin 13), and also the presence of a pluristratified epithelium and an ultrastructurally well-organized basement membrane expressing laminin 332. The synthesis of new extracellular matrix by the fibroblasts was also demonstrated. The scaffold proposed here presents great potential for tissue engineering applications, and also for studies of epithelial proliferation, and epithelial disorders including carcinogenesis. PMID- 21592567 TI - Fetus specific T cell modulation during fertilization, implantation and pregnancy. AB - Recently there is an increasing interest in aspects of a more specific immunoregulation during pregnancy. Understanding these mechanism might have a broader application not only for reproductive immunology but also in general for biology and medicine. Especially the induction, already before conception, of feto-specific T cells with a possibly regulatory function gives a biological explanation of local immunotolerance at the maternal fetal interface, supporting the epidemiological evidence of a feto/paternal-specific immuneregulation. Understanding the expression of specific HLA-classes on trophoblast and the crosstalk of these antigens with various cell types, specifically modulated in the decidua, resulting in the secretion of cytokines and (angiogenic) chemokines has given us a more and more detailed understanding of this regulation. This regulation could be induced by fetal cells circulating in the mother (microchimerism) and from the interaction with fetal subcellular fractions as exosomes, but also from paternal antigens present in seminal fluid. Molecular interaction between paternal and fetal antigens and receptors in endometrium and the decidua are discussed. This review highlights besides uNK cells, especially the function of CD4+ and CD8+ T cells with a regulatory function in the context of recurrent miscarriage and pre-eclampsia. Besides HLA, also male-specific minor histocompatibility antigens and the genetic background for these pregnancy complications are discussed. PMID- 21592568 TI - Cyclosporine-A as a neuroprotective agent against stroke: its translation from laboratory research to clinical application. AB - Stoke remains a leading cause of death and disability with limited treatment options. Extensive research has been aimed at studying cell death events that accompany stroke and how to use these same cell death pathways as potential therapeutic targets for treating the disease. The mitochondrial permeability transition pore (MPTP) has been implicated as a major factor associated with stroke-induced neuronal cell death. MPTP activation and increased permeability has been shown to contribute to the events that lead to cell death. Cyclosporine A (CsA), a widely used immunosuppressant in transplantation and rheumatic medicine, has been recently shown to possess neuroprotective properties through its ability to block the MPTP, which in turn inhibits neuronal damage. This newfound CsA-mediated neuroprotection pathway prompted research on its use to prevent cell death in stroke and other neurological conditions. Preclinical studies are being conducted in hopes of establishing the safety and efficacy guidelines for CsA use in human trials as a potential neuroprotective agent against stroke. In this review, we provide an overview of the current laboratory and clinical status of CsA neuroprotection. PMID- 21592570 TI - PRAME: from diagnostic marker and tumor antigen to promising target of RNAi therapy in leukemic cells. PMID- 21592569 TI - Clinical significance of aberrant DNA methylation in childhood acute lymphoblastic leukemia. AB - Methylation profile was analyzed in ninety-five patients with childhood acute lymphoblastic leukemia (ALL). Methylation of both MGMT and p16 genes were associated with higher age (p=0.01 and p=0.03, respectively). Methylation of both p15 and SHP1 genes occurred more frequently in T-ALL than in precursor B-ALL (p=0.02 and p=0.01, respectively). In contrast, methylation of the DAPK gene was more frequent in precursor B-ALL (p=0.01). Patients with methylation of multiple genes more likely had T cell phenotype, and are classified as medium/high risk (p=0.004 and p=0.03, respectively). These results suggest that methylation status is associated with clinicopathological features in childhood ALL. PMID- 21592571 TI - CD7-positive acute myelomonocytic leukemia with trisomy 21 as a sole acquired chromosomal abnormality in two adolescents. PMID- 21592572 TI - Focal adhesion kinase as a target in the treatment of hematological malignancies. AB - Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that plays important regulatory roles in several basic cellular activities. During normal development, FAK is a critical mediator of the integrin signaling cascade, which modulates cell proliferation, apoptosis, adhesion, spreading and migration. Importantly, FAK overexpression is found in a large number of cancer types and FAK expression levels generally correlate with increased tumor malignancy. Though FAK has been a popular potential target for treatment of solid tumors, its roles in leukemias and lymphomas have not been well defined. Here, I briefly summarize the multifaceted functions of FAK in tumor progression, and discuss current efforts and exciting future directions of using RNAi-mediated knockdown of FAK as a potential therapy against leukemia and lymphomas. PMID- 21592574 TI - Specialized heart failure nurses in a high-tech world. PMID- 21592573 TI - Effects of repeated field applications of two formulations of Bacillus thuringiensis var. israelensis on non-target saltmarsh invertebrates in Atlantic coastal wetlands. AB - Bacillus thuringiensis var. israelensis (Bti) is commonly used for selective control of larval populations of mosquitoes in coastal wetlands. A two year-study was implemented to investigate whether repeated treatments with Bti applied either as a liquid (VectoBac(r) 12AS) or a water-dispersible granule (VectoBac(r) WG) formulation may affect the abundance and diversity of non-target aquatic invertebrates in saltmarsh pools. Taxonomic composition of the invertebrate communities was typical of brackishwater intermittent ecosystems, with a dominance of annelids, crustaceans and nematocerans. Conditions were contrasted between the two years of the survey, both in terms of annual cumulative rainfall and rainfall distribution throughout the year. As a consequence, the hydroperiod and some other environmental characteristics associated with pool drying played a major role in the dynamics of the invertebrate community. In summer 2006, pool drying reduced the abundance of the polychaete worm Nereis diversicolor, of the amphipod crustacean Corophium volutator and of chironomid larvae. These taxa were able to recolonize rapidly the pools after flooding in September 2006. In 2007, rainfall was more regularly distributed across the year, and the pools did not get dry. Hydrozoans, Chironomini and Orthocladiinae larvae, and oligochaetes were more abundant in treated than in control pools, especially in VectoBac(r) WG treated pools. No adverse effects of the treatments were shown on the abundance of N. diversicolor, C. volutator and midge larvae, suggesting that the availability of these food sources for birds was not negatively affected by Bti applications. It is concluded that, as currently performed in Western France coastal wetlands, land-based treatments of saltmarsh pools for larval mosquito control with Bti, used either as VectoBac(r) 12AS or VectoBac(r) WG, did not adversely impact non-target aquatic invertebrate communities. PMID- 21592575 TI - Family caregiving in pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating disease that places a significant burden on patients and their families. However, family caregiving, to the best of our knowledge, has never been described in this population. This study sought to describe depressive symptoms, types of performed care tasks, social support, and the impact of caregiving among family caregivers of patients with PAH. METHODS AND RESULTS: Data were obtained from 35 dyads of patients with PAH (mean age, 51 years; 63% were female; 54% had World Health Organization functional class III symptoms) and their family caregivers (mean age, 52 years; 60% were female; 68% were spouses). Five caregivers (14%) were identified as manifesting moderate to severe depressive symptoms. The majority of caregivers reported that their daily activities were centered around caregiving responsibilities. More than 85% of caregivers were involved in managing care for the patient, and more than half helped the patient with self-management activities. The level of caregivers' perceived social support was low, especially for emotional and informational support. Lower levels of social support were significantly associated with more severe depressive symptoms in caregivers (r = .50, P = .002). CONCLUSION: Caregivers of patients with PAH play a significant role in patients' medical care and self-management, yet they lack sufficient emotional support or information to meet the demands of caregiving. These findings underscore the importance of supporting family caregivers of patients with PAH. PMID- 21592576 TI - Montreal Cognitive Assessment and Mini-Mental Status Examination compared as cognitive screening tools in heart failure. AB - BACKGROUND: Heart failure (HF) patients run four times the risk of developing cognitive impairment than does the general population, yet cognitive screening is not routinely performed. METHODS: This cross-sectional study enrolled 90 community-dwelling adults with HF aged 50 years and above. Participants took the Mini Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA), to measure cognitive function in persons with HF. Participants were predominately men (66%) and Caucasian (78%), aged 50-89 years (62 SD, 9 years), and 77% had an ejection fraction <40%. RESULTS: Fifty-four percent of participants scored <=26 on the MoCA, suggesting mild cognitive impairment (MCI), and 17% scored <=22, suggesting moderate cognitive impairment, compared with 2.2% on the MMSE. The MoCA scores were lowest for visuospatial/executive domain, short-term memory, and delayed recall. These findings were similar to those in published reports. CONCLUSION: These preliminary findings support the use of MoCA for cognitive screening in stable HF. PMID- 21592577 TI - Treatment of rats with heat killed cells (HKC) of Cryptococcus neoformans var. grubii induces cellular activation in spleen and lymphatic nodes. AB - Our previous studies showed that the subcutaneous pretreatment of rats with heat killed cells of Cryptococcus neoformans (HKC) emulsified in complete Freund adjuvant (CFA) promotes protection against an intraperitoneal challenge with viable C. neoformans. In this model, an appropriate activation of adherent peritoneal cells after antigenic treatment is very important for the control of the infection. Here, we investigated the immune response developed in spleen and lymphatic nodes as a result of treatment with HKC-CFA, which might also contribute in the protective phenomenon of this treatment against cryptococcal infection. The results show that, compared with adjuvant alone, rats which received treatment with HKC-CFA presented a greater activation of adherent splenic cells, with up-regulation of major histocompatibility complex class II (MHC II) and CD86 expression and secretion of anticryptococcal metabolites. Furthermore, this treatment also induced an increase in the blastogenic response and the secretion of Th1 and Th2 cytokines by spleen cells in comparison with cells from CFA-phosphate-buffered saline (PBS) treated rats. On the other hand, lymph node cells from animals treated with HKC-CFA presented a rise in the expression of MHCII but not of CD86 with respect to control cells from rats treated with CFA-PBS. These cells also showed a high proliferative response and secretion of Th1-related cytokines, interleukin (IL)-12 and tumor necrosis factor (TNF). These results show that treatment of rats with HKC-CFA is able to induce an early immune response in secondary lymphoid organs, which may contribute to the protective effect induced by this treatment. PMID- 21592578 TI - Sex offender punishment and the persistence of penal harm in the U.S. AB - The U.S. has dramatically revised its approach to punishment in the last several decades. In particular, people convicted of sex crimes have experienced a remarkable expansion in social control through a wide-range of post-conviction interventions. While this expansion may be largely explained by general punishment trends, there appear to be unique factors that have prevented other penal reforms from similarly modulating sex offender punishment. In part, this continuation of a "penal harm" approach to sex offenders relates to the past under-valuing of sexual victimization. In the "bad old days," the law and its agents sent mixed messages about sexual violence and sexual offending. Some sexual offending was mere nuisance, some was treatable, and a fraction "deserved" punishment equivalent to other serious criminal offending. In contrast, today's sex offender punishment schemes rarely distinguish formally among gradations of harm or dangerousness. After examining incarceration trends, this article explores the historical context of the current broad brush approach and reviews the unintended consequences. Altogether, this article reinforces the need to return to differentiation among sex offenders, but differentiation based on science and on the experience-based, guided discretion of experts in law enforcement, corrections, and treatment. PMID- 21592580 TI - Structure of the Fab fragment of the anti-murine EGFR antibody 7A7 and exploration of its receptor binding site. AB - The EGF receptor is an important target of cancer immunotherapies. The 7A7 monoclonal antibody has been raised against the murine EGFR, but it cross-reacts with the human receptor. The results from experiments using immune-competent mice can therefore, in principle, be extrapolated to the corresponding scenario in humans. In this work we report the crystal structure of the 7A7 Fab at an effective resolution of 1.4A. The antibody binding site comprises a deep pocket, located at the interface between the light and heavy chains, with major contributions from CDR loops H1, H2, H3 and L1. Binding experiments show that 7A7 recognizes a site on the EGFR extracellular domain that is not accessible in its most stable conformations, but that becomes exposed upon treatment with a tyrosine kinase inhibitor. This suggests a recognition mechanism similar to that proposed for mAb 806. PMID- 21592581 TI - Blockade of TLR9 signaling in B cells impaired anti-dsDNA antibody production in mice induced by activated syngenic lymphocyte-derived DNA immunization. AB - We previously established a systemic lupus erythematosus (SLE) animal model in non-susceptible BALB/c mice by immunizing with activated syngeneic lymphocyte derived DNA (ALD-DNA), manifested by high level of anti-double-stranded DNA (dsDNA) antibodies (Abs), proteinuria, glomerular deposition of immune complex and glomerulonephritis. The production of anti-dsDNA Abs is closely related with the renal inflammation and damage in this model. However, recognition of ALD-DNA and its signaling pathway within antigen-presenting cells (APC) remains not fully clarified. Herein, in this study, Toll-like receptor 9 (TLR9), a well-known pattern-recognition receptor for dsDNA with CpG motif, was found to be dynamically up-regulated in B cells during the process of the SLE disease. Knockdown of TLR9 by short interfering RNA (siRNA) in B cells in vitro and in vivo reduced the production of anti-dsDNA antibody and consequently ameliorated the SLE syndrome in mice while the affinity and isotype of the antibody remained the same. Our results implied that TLR9 signaling of B cells might play an important role in the production of anti-dsDNA Abs triggered by auto dsDNA, which would extend our understanding of TLR9 immune recognition in the pathogenesis of SLE disease. PMID- 21592579 TI - Somatic hypermutation targeting is influenced by location within the immunoglobulin V region. AB - The observed mutation pattern in immunoglobulin (Ig) V genes from peripheral B cells is influenced by several mechanisms, including the targeting of AID to specific DNA motifs, negative selection of B cells unable to express Ig receptor, and positive selection of B cells that carry affinity-increasing mutations. These influences, combined with biased codon usage, produce the well-known pattern of increased replacement mutation frequency in the CDR regions, and decreased replacement frequency in the framework regions. Through the analysis of over 12,000 mutated sequences, we show that the specific location in the V gene also significantly influences mutation accumulation. While this position-specific effect is partially explained by selection, it appears independently of the CDR/FWR structure. To further explore the specific targeting of SHM, we propose a statistical formalism describing the mutation probability of a sequence through the multiplication of independent probabilities. Using this model, we show that C >G (or G->C) mutations are almost as frequent as C->T and G->A mutations, in contrast with C->A (or G->T) mutations, which are as any other mutation. The proposed statistical framework allows us to precisely quantify the effect of V gene position, mutation substitution type, and micro-sequence specificity on the observed mutation pattern. PMID- 21592582 TI - Chronic Pneumocystis jiroveci presenting as asymptomatic granulomatous pulmonary nodules in lymphoma. AB - We present a rare case of chronic Pneumocystis jiroveci infection presenting as multiple persistent granulomatous pulmonary nodules over a 12 month period in a patient with follicular lymphoma undergoing treatment with Rituximab, Cyclophosphamide, Vincristine, and Prednisolone chemotherapy. Remarkably during this period the patient remained asymptomatic. This is the first case to combine these atypical histological, radiological, and clinical manifestations of P. jiroveci infection highlighting unusual manifestations of the disease. PMID- 21592583 TI - The role of alpha oscillations in temporal attention. AB - Our brain does not process incoming sensory stimuli mechanistically. Instead the current brain state modulates our reaction to a stimulus. This modulation can be investigated by cognitive paradigms such as the attentional blink, which reveal that identical visual target stimuli are correctly reported only on about half the trials. Support for the notion that the fluctuating state of the brain determines stimulus detection comes from electrophysiological investigations of brain oscillations, which have shown that different parameters of ongoing oscillatory alpha activity (~10 Hz) can predict whether a visual stimulus will be perceived or not. The present article reviews recent findings on the role of prestimulus alpha oscillatory activity for visual perception and incorporates these results into a neurocognitive model that is able to account for various findings in temporal attention paradigms, specifically the attentional blink. PMID- 21592584 TI - Altered empathic responding in major depressive disorder: relation to symptom severity, illness burden, and psychosocial outcome. AB - Individuals with major depressive disorder (MDD) demonstrate deficits in multiple social cognitive domains; however, systematic investigations of empathic responding have not been performed. Twenty patients with MDD completed two measures of empathy, the Interpersonal Reactivity Index (IRI: Davis, 1980, 1983) and the Toronto Empathy Questionnaire (TEQ: Spreng et al., 2009). Relative to matched controls, patients with MDD reported significantly reduced levels of empathy measured broadly on the TEQ and specifically in cognitive ('Perspective Taking') and affective ('Empathic Concern') domains captured by the IRI. A higher illness burden (i.e., greater number of past depressive episodes) was associated with greater reductions in perspective taking ability. This study provides early evidence of impaired empathic abilities in patients with MDD that may worsen with illness progression. Alternatively, reductions in perspective taking ability may contribute to a more severe course of illness in this population. Further longitudinal work is needed to characterize the relation between social cognitive performance and social functioning in this population. PMID- 21592585 TI - Evaluation of a nanobody phage display library constructed from a Brucella immunised camel. AB - Brucella are invasive gram-negative bacteria that multiply and survive within eukaryotic cells causing brucellosis. Syrian (and Middle East) health and economy sectors are still affected by this disease causing a serious national problem that needs to be solved. Here, a strategy was developed to introduce a new generation of binders, known as Nanobodies (Nbs) in our combat against Brucella. These Nbs, recombinant single-domain variable fragments derived from camelid heavy-chain antibodies are very stable and highly soluble, making them a useful tool in numerous biotechnological and medical applications. In this work and without having access to purified antigens (Ags), a camel was immunised successfully with heat-killed Brucella melitensis strain Riv1 as demonstrated by the high titer of Ag-specific heavy-chain antibodies in the serum. Lymphocytes of the immunised camel were isolated and their Nb genes were cloned in a relatively large library of 10(8) individual transformants, of which 81% contained an insert with the proper size of a Nb gene. Phage display expression of the Nbs from this library and pannings on the Brucella lysate resulted in a clear enrichment of three distinct Nb-displaying phages (phage-Nbs), referred to as NbBruc01, 02 and 03, with specificity for Brucella. Producing these binders in a pure, soluble form, as well as identifying their specific targets, which are likely to be immunodominant Ags in Brucella, is expected to open wide perspectives for following the vaccination, diagnosis and treatment of brucellosis. PMID- 21592586 TI - Cell-mediated immune response in swine infected with Mycobacterium avium subsp. avium. AB - The zoonotic characteristic of Mycobacterium avium subsp. avium (MAA) represents a veterinary and economic problem in infected pigs. In this study, we analysed cell-mediated immunity six months after experimental infection by measuring interferon-gamma (IFN-gamma) production and by performing lymphocyte transformation tests after in vitro re-stimulation with the MAA-derived antigen. At the same time, IFN-gamma-producing cells were characterised by flow cytometry. In MAA-infected animals, the production of IFN-gamma increased in response to the MAA antigen in the blood, spleen and mesenteric lymph nodes. Similarly, a positive antigen-driven response was detected by the proliferation assay. In contrast, IFN-gamma production and proliferation was undetectable after stimulation with the MAA antigen in uninfected control animals. These results indicate that both methods can be used for the identification of individual MAA infected pigs. Using flow cytometry, we found that double-positive CD4(+)CD8(+) lymphocytes were the major T lymphocyte subset producing IFN-gamma after in vitro re-stimulation. PMID- 21592587 TI - ADEM as a niche variant of post infectious neurological syndromes. PMID- 21592588 TI - Long-term follow-up of chronic suppurative otitis media in a high-risk children cohort. AB - OBJECTIVE: Chronic suppurative otitis media (CSOM) is the leading cause of mild to moderate hearing impairment in children worldwide and a major public health problem in many indigenous populations. There is a lack of basic epidemiological facts and knowledge on the development of CSOM, as the disease primarily affects developing countries where research capacities often are limited. The purpose of this study was to determine the long-term outcome of CSOM in a high-risk population and to identify risk factors. METHODS: Follow-up study (2008) on a population-based cohort of 465 children in Greenland, initially examined (1996-8) between the ages 0 and 4 years. Follow-up was attempted among 307 children living in the two major towns. Binomial logistic regression analysis was made to identify risk factors for developing CSOM and for maintaining disease in to adolescence (odds ratios). Log linear binomial regression was used to estimate risk ratios and absolute risks. RESULTS: At follow-up 236 participated (77% of those available). The prevalence of CSOM was 32/236 (14%) at age group 0-4 years and 21/236 (9%) at age group 11-15 years. Thirteen had disease debut after the initial study. Of those with CSOM in the initial study 24/32 (75%) healed spontaneously. Risk factors for the development of CSOM at any time in childhood was the mother's history of CSOM OR 2.55 (95% CI 1.14-5.70; p=0.02), and mothers with low levels of schooling OR 1.57 (1.03-2.40; p=0.04). Once CSOM had developed boys were more likely to have persistent disease OR 5.46 (95% CI 1.47-20.37; p=0.01). The absolute risk of CSOM if the mother had both a history of CSOM and low schooling was for boys 45.4% (95% CI 26.5-77.7) and for girls 30.7% (95% CI 17.8-53.10). The cumulative risk of CSOM was 19% at follow-up. CONCLUSIONS: Even though a large number of CSOM cases seemed to heal spontaneously, the prevalence of untreated CSOM among school-age children in Greenland remained high as new cases were found at follow-up. Increased focus on prevention and identification of children at special risk could reduce the high prevalence of CSOM. PMID- 21592589 TI - The effect of saccular function on static balance ability of profound hearing impaired children. AB - OBJECTIVE: Researches have shown that in clinical practice, balance disorders in children with congenital or early acquired severe to profound hearing loss are probable. The purposes of present study were to specify the percentage of vestibular evoked myogenic potential (VEMP) and an acoustically evoked, short latency negative response (ASNR) recordings and the relation between their presence and static balance ability and postural control of children with profound sensorineural hearing loss (SNHL). METHODS: Thirty children with profound SNHL, with an average age of 6.93 years, underwent the VEMP and auditory brainstem response (ABR) tests. Both VEMP and ABR were recorded at the threshold level through air-conduction stimulation via an insert receiver. The static balance performance of the hearing-impaired children was tested with six exercises and compared with that of 30 age- and sex-matched normal-hearing children as controls. RESULTS: VEMP was recorded in 53.3% of ears and ASNR in 40.0%. VEMP was revealed in all ears with ASNR, and a significant correlation was shown between their presence (p=0.005) and also between the ASNR wave latency and P1 (p=0.0001) and N1 (p=0.004) wave amplitude of VEMP. There was a significant correlation between the presence of VEMP and ASNR with the performance of the children in two static balance skills, namely standing on one leg with eyes open on a line and the same practice on the balance beam (p<=0.008). CONCLUSION: There was a close relation between the presence of VEMP and ASNR. Additionally, when ASNR was present, the recording of VEMP could be expected. Successful performance in the static balance exercises with reduced vestibular and somatosensory inputs increased the possibility of the recording of ASNR and VEMP. PMID- 21592590 TI - Effect of Ginkgo biloba extract on endotoxin-induced labyrinthitis. AB - OBJECTIVE: There are no reports on the therapeutic effect of Ginkgo biloba extract (GBE) on otitis media-induced labyrinthitis. The present study examined whether GBE can protect against cochlear damage induced by intratympanic instillation of lipopolysaccharide (LPS)-induced labyrinthitis. MATERIALS AND METHODS: Experiments were performed in 20 healthy young male guinea pigs. The control group (n=10) received an intratympanic instillation of LPS (20 MUl, 3mg/ml). The experimental group (n=10) received intratympanic instillation of LPS immediately after instillation of GBE (10mg/kg) and then experimental groups received GBE (100mg/kg) by intraperitoneal injection every day for 3 days. Instillation of LPS or LPS immediately after GBE was done in the right ear; the untreated left ear was considered normal. Physiological and morphological changes were evaluated. RESULTS: Statistical analysis of treatment of GBE revealed significantly less hearing loss than LPS group (p<0.05). The ratio of the value of cochlear blood flow (CBF) compared to untreated left side was significantly higher in the GBE treated group than in the LPS-treated group (p<0.05). This result indicated the recovery of CBF in GBE treated group compared to LPS treated group. In the LPS group, scanning electron microscopy revealed hair cell damage with edema. Missing stereocilia in the third layer of the outer hair cell was revealed. However, both the inner hair cells and the outer hair cells had normal appearance in the GBE group. LPS group showed that cochlear Evans blue extravasation was increased strongly in the stria vascularis, spiral limbus, and in the spiral ligament compared with the GBE treated group. CONCLUSION: GBE significantly minimizes cochlear damage against LPS-induced otitis media with labyrinthitis in a guinea pig model. GBE has potential as an adjunctive therapy to antibiotics in the treatment of acute otitis media with complicated labyrinthitis. PMID- 21592591 TI - The development of auditory skills in infants with isolated Large Vestibular Aqueduct Syndrome after cochlear implantation. AB - OBJECTIVE: The purpose of this study was to investigate the auditory performance of infants with isolated Large Vestibular Aqueduct Syndrome (LVAS) after cochlear implantation, compare their performance with those of infants with a normal inner ear, and establish a database of auditory development. METHOD: 435 infants with congenital severe to profound hearing loss participated in this study. 62 infants in group A were diagnosed with isolated LVAS. 373 infants in group B had a normal inner ear. Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) was used to evaluate the development of auditory skills. RESULTS: The mean scores for auditory ability showed no significant difference between groups A and B. The mean scores for the three different auditory skills increased significantly over time. The differences were statistically significant in mean scores among the three different auditory skills for group B. CONCLUSION: Auditory skills of infants with isolated LVAS developed rapidly after cochlear implantation, in a similar manner to those of infants with a normal inner ear. Cochlear implantation is an effective interventional approach and an established therapeutic option for infants with isolated LVAS. PMID- 21592592 TI - Ototoxicity caused by topical administration of gentamicin versus tobramycin in rabbits. AB - AIM: To investigate the possible differences in cochleotoxic effects in rabbits between twice-daily administration of topical gentamicin and tobramycin throughout the perforated tympanic membrane with the use of distortion-product otoacoustic emissions (DPOAEs). MATERIALS AND METHODS: Twenty female rabbits were studied prospectively daily for 21 days. The rabbits' ears were divided into two groups: right and left ear groups. Twice-daily for 21 days after paracentesis, 0.3% gentamicin was administered topically in the left ears, and 0.3% tobramycin was administered topically in the right ears. For 21 days, the cochlear activity of the right and left ears of all rabbits was examined every 7 days using DPOAEs. The numerical values of the distortion product (DP) intensity recorded on days 7, 14 and 21 of drug administration were compared between the two groups. RESULTS: Cochlear activity was reduced earlier in the gentamicin group in the 2-4kHz frequencies compared to the tobramycin group in the second DPOAE measurement (day 7 of the experiment). In two rabbits in the gentamicin group, the third DPOAE measurement showed that cochlear activity was reduced in all frequencies. In six rabbits in the tobramycin group, the third DPOAE measurement showed that cochlear activity was reduced in all frequencies. There was no statistical significance between the two groups except day 7 in the 2 and 3kHz frequencies (p<0.05). CONCLUSION: We concluded that low frequencies (2 and 3kHz) are more sensitive to the administration of topical gentamicin than to topical tobramycin. Early cessation of tobramycin drops may be minimally cochlear toxic compared to gentamicin within the first 7 days when these drugs are misused in treating chronic otitis media. PMID- 21592593 TI - Distal airway foreign bodies: Importance of a stepwise approach, knowledge of equipment and utilization of other services' expertise. AB - Many distal airway foreign bodies present as obstructive atelectasis and may be removed using instruments passed through rigid bronchoscopes. Deeply impacted distal foreign bodies remain problematic and sometimes require thoracotomy. The purpose of this paper is to discuss alternate approaches to avoid open surgical removal. A clinical algorithm is outlined. A young child presented to the hospital with an episode of coughing and oxygen desaturation. A chest radiograph demonstrated a radiopaque foreign body in the right upper lobe with distal atelectasis. The foreign body could not be found using rigid bronchoscopy so a flexible bronchoscope (3.5mm) was used to identify the distal primary tooth that was lodged in the inflamed tertiary segment of the bronchus. The tooth could not be removed using instruments passed through the sideport of the bronchoscope including balloon catheters, ureteral baskets, and biopsy forceps. The catheters were too compliant to reach the upper lobe and the forceps could not engage the tooth. A decision was made to treat the child with steroids and attempt removal 48 h later. The inflammation had resolved and the tooth had shifted positions to a more accessible left lower lobe tertiary segment. Using fluoroscopy with guide wires through the endotracheal tube, the tooth was removed. Tools used by different services are available as well to retrieve foreign bodies and may obviate the need for thoracotomy. Steroids decreased swelling allowing better access to the foreign body. PMID- 21592594 TI - Rare case of unifocal Langerhans cell histiocytosis in four-month-old child. AB - Langerhans cell histiocytosis (LCH) comprises a group of disorders, the common feature of which is Langerhans cell proliferation. The clinical presentation is highly varied. The severity and prognosis of the disease are dependent on the type and extent of organ involvement. This paper reports a rare case of a four month-old white male with unifocal LCH limited exclusively to the mandible, discussing the diagnosis, radiographic and immunohistochemical aspects, treatment and monitoring multidisciplinary of the case. PMID- 21592596 TI - The effectiveness of an integrated pain management program for older persons and staff in nursing homes. AB - This study examined the effects of an 8-week integrated pain management program (IPMP) on enhancing the knowledge and attitude toward pain management among staff; and improving the pain, quality of life, physical and psychosocial functions, and use of non-drug therapies for the elderly in nursing homes. Nursing home staff (N=147) and residents (N=535) were recruited from ten nursing homes. Nursing homes were randomly assigned into an experimental group (N=296) with IPMP or control group (N=239) without IPMP. The IPMP consisted of pain education for staff and physical exercise and multisensory stimulation art and craft therapy for residents. Data were collected before and after the IPMP. The staff demonstrated a significant improvement in knowledge and attitude to pain management, with the survey score increasing from 8.46+/-3.74 to 19.43+/-4.07 (p<0.001). Among the residents, 74% had experienced pain within the previous 6 months, with pain intensity of 4.10+/-2.20. Those in the experimental group showed a significantly better reduction in pain scores than the control group, from 4.19+/-2.25 to 2.67+/-2.08 (p<0.001). Group differences were also found in psychological well-being, including happiness, loneliness, life satisfaction and depression (p<0.05), and the use of non-drug methods (p<0.05). These results suggested that IPMP is beneficial for staff, and is effective in reducing geriatric pain and negative impacts. Management support and staff involvement in the program are important for its long-term continuation. PMID- 21592597 TI - Age- and menopause-related differences in physiological factors of health quality in women aged 35-60. AB - The purpose of this study was to elucidate using time series analysis age and menopause induced differences in selected health quality related physiological factors. The study was conducted, using the Third National Health and Nutrition Examination Survey (NHANES III), and the NHANES 1999-2002 data, on women aged 35 60. Subjects who had not had surgical menopause, did not use contraceptives, did not smoke, and did not breastfeed during the examination, and did not use contraception and for whom follicle stimulating hormone and luteinizing hormone (LH) activity was assessed, were included in the study. Menopausal status was defined by months since the last period (<2, 2-12, and >12 months for pre-, peri , and postmenopause, respectively). The results indicate that postmenopausal women, aged less than 45, are characterized by a decrease in systolic blood pressure (SBP), an increase in high density lipoprotein (HDL) levels, and a decrease in triglyceride (TG) levels. It was also determined that aging is the main factor leading to physiological variability in systolic blood pressure and high density lipoprotein levels, in pre- and perimenopausal women, and in follicle-stimulating hormone (FSH) activity in peri- and postmenopausal women. PMID- 21592595 TI - Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. AB - Angelman syndrome (AS) is a severe genetic disorder caused by mutations or deletions of the maternally inherited UBE3A gene. UBE3A encodes an E3 ubiquitin ligase that is expressed biallelically in most tissues but is maternally expressed in almost all neurons. In this review, we describe recent advances in understanding the expression and function of UBE3A in the brain and the etiology of AS. We highlight current AS model systems, epigenetic mechanisms of UBE3A regulation, and the identification of potential UBE3A substrates in the brain. In the process, we identify major gaps in our knowledge that, if bridged, could move us closer to identifying treatments for this debilitating neurodevelopmental disorder. PMID- 21592598 TI - Neurochemical alterations of the entorhinal cortex in amnestic mild cognitive impairment (aMCI): a three-year follow-up study. AB - The neurochemical alterations in the entorhinal cortex have not yet been measured, even though the entorhinal cortex is the earliest involved brain region in aMCI. In this study, we investigated whether brain regions including the entorhinal cortex would show early involvement of neurochemical abnormalities in aMCI, and whether magnetic resonance spectroscopy (MRS) abnormalities might be a predictive marker of conversion of aMCI to Alzheimer's disease (AD). MRS was performed on 13 aMCI patients and 11 patients with no cognitive impairment (NCI). Localizing voxels were placed within the entorhinal cortex, hippocampus, posterior cingulate gyrus, and occipital white matter in the dominant hemisphere. N-acetyl aspartate/creatinine (NAA/Cr) ratios in the entorhinal cortex were significantly lower in aMCI patients than in NCI subjects. After a three-year follow-up, seven aMCI patients converted to AD and six remained stable. Baseline NAA/Cr ratios of entorhinal cortex were decreased in converters, compared to NCI. Our study suggested the entorhinal cortex is the earliest site that is subject to neurochemical alteration in aMCI patients, and baseline MRS metabolite ratios in the entorhinal cortex can be a marker for predicting conversion of aMCI to AD. PMID- 21592599 TI - Prevalence and clinical characteristics of urinary incontinence in elderly individuals of a low income. AB - To estimate the prevalence of urinary incontinence (UI) in elderly individuals of low income assisted by the primary health care system in Sao Paulo, Brazil. In this community-based, observational, cross-sectional study, participants assisted by the health family program in Sao Paulo, Brazil, were sampled and interviewed face to face by questionnaire. Participants (n=388) were selected from the collaborative program developed by the 10/66 Dementia Research Group, an International Network of investigators. Demographics, health history and a detailed assessment of UI and urinary symptoms were obtained. Prevalence of UI was calculated. Other variables included age, body mass index (BMI), duration of incontinence and characteristics of the symptoms. The association between UI and the variables was estimated using the Kruskal-Wallis test, Chi-squared test and Fisher test (depending on normality of the distribution and expected frequencies). Prevalence of UI was 38.4%. UI was more common in women than in men (50% vs. 18.3%, p<0.001). Diabetes, obesity and hypertension were associated with UI. Almost 36.2% of the cases were of mixed incontinence, 26.8% of urge incontinence and 24.2% of stress incontinence. Men were more likely to have urge incontinence, while women were more likely to have mixed incontinence (p=0.001). UI is prevalent in the elderly of low income living in Sao Paulo and rates are higher than most previous studies. Chronic conditions such as hypertension, diabetes and obesity were associated with UI. PMID- 21592600 TI - Demographic characteristics and clinical benefits of outpatient geriatric evaluation and management service in Taiwan. AB - As Taiwan has become the fastest aging country in the world, developing elderly friendly health care services is of great importance. Compared with traditional health-care service models, healthcare needs of older people may differ extensively. It has been reported that geriatric evaluation and management (GEM), helps to differentiate the atypical presentations of frail older patients, to discover hidden health-social problems, and to promote long-term clinical outcome. The main purpose of this study was to explore the demographic characteristics of older patients visiting outpatient GEM service and its impact to health-care utilization in a tertiary medical center in Taiwan. From January to October of 2008, 1054 patients visited the outpatient GEM service, and comprehensive geriatric assessment was performed for 140 patients (62.9% males with the mean age was 81.0 +/- 6.6 years), and 34.8% of them were college graduates. Overall, the prevalence of functional impairment was 11.4%, depressive symptoms 20.7%, cognitive impairment 32.1%, and abnormal timed up-and-go test 32.1%. During the 12-month follow-up, items of mean oral medications were significantly reduced (3.2 +/- 2.7 vs. 3.8 +/- 2.8, p<0.001) and the health related quality of life was significantly improved (64.6 +/- 8.0 vs. 61.6 +/- 4.0, p<0.001). In conclusion, patients visiting outpatient GEM services in Taiwan are old and well-educated, and they possessed various functional impairments. The outpatient GEM services significantly reduced the items of oral medications and improved quality of life. The possible better compliance of this cohort due to high educational status may overestimate the clinical effectiveness of outpatient GEM services. Further investigations are needed to clarify the long-term benefits of outpatient GEM services. PMID- 21592601 TI - Physical fitness and 6.5-year mortality in an 85-year-old community-dwelling population. AB - Although poor physical fitness is known to be associated with increased mortality in adult and elderly populations, this association is not conclusive in very elderly. The purpose of the present study was to evaluate the association for a very old community-dwelling population. The participants (90 males, 117 females) were 85-year-old individuals residing in Fukuoka, Japan. Baseline examinations including muscle strength of the handgrip and leg extension, one-leg standing, leg stepping rate, and walking were performed in 2003 and these subjects were followed for 6.5 years. During the follow-up period, 81 individuals (49 males and 32 females) died. Handgrip strength and leg extension strength at age 85 were stronger in surviving men than in non-survivors. Total mortality adjusted for both gender and serum level of total cholesterol fell 5-6% with a 1-kg increase in the handgrip strength of a single hand or both hands. Total mortality also decreased 2% with a 1 kg increase in the leg extension strength of both legs. With adjustment for gender and total cholesterol, mortality fell by 57% in participants of the walking test and fell by 45% in participants of the stepping rate test compared to mortality in nonparticipants. No association was found between mortality and participation in the handgrip strength test, leg extension strength test, or one-leg standing time test. In conclusion, not only poor muscle strength in handgrip or leg extension, but also nonparticipation in walking test or leg-stepping test were independent predictors of total mortality in a very elderly population. PMID- 21592602 TI - Melatonin and myocardial protection. PMID- 21592603 TI - Pathogenesis of classical and atypical BSE in cattle. AB - It is known from earlier studies that the pathogenesis of BSE in cattle differs considerably from the TSE pathogenesis in sheep, where the lymphoreticular system (LRS) is majorly involved in the transport and propagation of the agent. In cattle, the BSE agent has only been detected in the Peyer's patches of the distal ileum and in the tonsils, which have both been identified as the portal of entry for the agent after oral uptake. It was shown that as opposed to most other animal species, in cattle the BSE agent amplifies almost exclusively in the central and peripheral nervous system. However, there is growing evidence for a centrifugal spread from the central nervous system into the periphery at the late stage of the disease. Moreover, there are only very limited data available concerning the pathogenesis of both atypical BSE forms, H type and L type BSE, as compared to classical BSE. In this manuscript we summarize the most recent data that we generated on the classical BSE pathogenesis after an oral challenge study that was performed with 56 cattle. Preliminary results on the pathogenesis of both atypical BSE forms are also presented, based on an intracranial challenge of cattle with German isolates of both atypical BSE forms. PMID- 21592604 TI - Efficacy of various plant hydrosols as natural food sanitizers in reducing Escherichia coli O157:H7 and Salmonella Typhimurium on fresh cut carrots and apples. AB - In the present study, inhibitory effects of the hydrosols of thyme, black cumin, sage, rosemary and bay leaf were investigated against Salmonella Typhimurium and Escherichia coli O157:H7 inoculated to apple and carrots (at the ratio of 5.81 and 5.81 log cfu/g for S. Typhimurium, and 5.90 and 5.70 log cfu/g for E. coli O157:H7 on to apple and carrot, respectively). After the inoculation of S. Typhimurium or E. coli O157:H7, shredded apple and carrot samples were washed with the hydrosols and sterile tap water (as control) for 0, 20, 40 and 60 min. While the sterile tap water was ineffective in reducing (P>0.05) S. Typhimurium and E. coli O157:H7, 20 min hydrosol treatment caused a significant (P<0.05) reduction compared to the control group. On the other hand, thyme and rosemary hydrosol treatments for 20 min produced a reduction of 1.42 and 1.33 log cfu/g respectively in the E. coli O157:H7 population on apples. Additional reductions were not always observed with increasing treatment time. Moreover, thyme hydrosol showed the highest antibacterial effect on both S. Typhimurium and E. coli O157:H7 counts. Inhibitory effect of thyme hydrosol on S. Typhimurium was higher than that for E. coli O157:H7. Bay leaf hydrosol treatments for 60 min reduced significantly (P<0.05) E. coli O157:H7 population on apple and carrot samples. In conclusion, it was shown that plant hydrosols, especially thyme hydrosol, could be used as a convenient sanitizing agent during the washing of fresh-cut fruits and vegetables. PMID- 21592605 TI - Physiological parameters of Bacillus cereus marking the end of acid-induced lag phases. AB - During lag phases microbial cells adapt to their environment and prepare to proliferate. Physiological parameters of B. cereus cells upon exposure to near growth-boundary acid stress were investigated and markers for the transition between lag phase and growth were identified using fluorescent probes combined with flow cytometry. Determination of cell counts and optical density revealed lag phases of 1h, 2h and 5h, in cultures shifted to pH 7, pH 5.3 (set with lactic acid) and pH 4.9 (set with sulfuric acid), respectively. The obtained lag phases fitted the trends in ATP levels, which were constant during the lag phase and increased after the onset of growth. Both the percentage of PI-stained cells and cells with a significant membrane potential decreased during the lag phase. This points to repair of membrane damage and the loss of membrane potential. However, both trends extended in the growth phase, thus not suitable to mark the onset of growth. The activity of the electron transfer chain and esterases did allow for assessment of transition between lag and growth phase. These activities were generally low during the lag phase and increased after the onset of growth. Our results show that, independent of the duration of the lag phase, for different conditions the same physiological trends could be observed. The change in signal of selected probes can be used as a marker for transition from lag phase to the growth phase and may aid in identification of novel targets interfering with bacterial exit from lag phase. PMID- 21592606 TI - Assessing the influences on therapeutic intensification in type 2 diabetes mellitus according to career stage. AB - AIM: This study was designed to document the factors influencing therapeutic decisions in the management of diabetes in relation to stage of medical career. METHODS: An anonymous survey was distributed among medical students, resident medical officers (RMOs) and general practitioners (GPs) presenting a hypothetical case of a 58 year old patient with sub-optimally controlled diabetes on metfomin and gliclazide. Participants were then asked for their next step in management and about factors that would influence their decision-making. RESULTS: GPs (n=72) were most likely to add pioglitazone (33.3%). RMOs (n=42) were more likely to add insulin (47.6%, p<0.01 vs. GPs). Medical students (n=40) were more likely to review diet and observe (42.5%, p<0.01 vs. GPs). Significant differences were observed between the 3 groups in what influenced their choice of therapy. GPs were most likely to take into account patient related factors such as patient's motivation to improve glycaemic control. CONCLUSION: GPs were less likely to initiate insulin therapy, and our results suggest that this may be due to their greater awareness of patient related barriers to commencing insulin. These results justify support for continuing medical education of GPs that focuses on evidence based guidelines. PMID- 21592607 TI - Impact of disease management programs on healthcare expenditures for patients with diabetes, depression, heart failure or chronic obstructive pulmonary disease: a systematic review of the literature. AB - OBJECTIVE: Evaluating the impact of disease management programs on healthcare expenditures for patients with diabetes, depression, heart failure or COPD. METHODS: Systematic Pubmed search for studies reporting the impact of disease management programs on healthcare expenditures. Included were studies that contained two or more components of Wagner's chronic care model and were published between January 2007 and December 2009. RESULTS: Thirty-one papers were selected, describing disease management programs for patients with diabetes (n=14), depression (n=4), heart failure (n=8), and COPD (n=5). Twenty-one studies reported incremental healthcare costs per patient per year, of which 13 showed cost-savings. Incremental costs ranged between -$16,996 and $3305 per patient per year. Substantial variation was found between studies in terms of study design, number and combination of components of disease management programs, interventions within components, and characteristics of economic evaluations. CONCLUSION: Although it is widely believed that disease management programs reduce healthcare expenditures, the present study shows that evidence for this claim is still inconclusive. Nevertheless disease management programs are increasingly implemented in healthcare systems worldwide. To support well considered decision-making in this field, well-designed economic evaluations should be stimulated. PMID- 21592608 TI - Women's autonomy and reproductive health care utilisation: empirical evidence from Tajikistan. AB - OBJECTIVE: Women's autonomy is widely considered to be a key to improving maternal health in developing countries, whereas there is no consistent empirical evidence to support this claim. This paper examines whether or not and how women's autonomy within the household affects the use of reproductive health care, using a household survey data from Tajikistan. METHODS: Estimation is performed by the bivariate probit model whereby woman's use of health services and the level of women's autonomy are recursively and simultaneously determined. The data is from a sample of women aged 15-49 from the Tajikistan Living Standard Measurement Survey 2007. RESULTS: Women's autonomy as measured by women's decision-making on household financial matters increase the likelihood that a woman receives antenatal and delivery care, whilst it has a negative effect on the probability of attending to four or more antenatal consultations. The hypothesis that women's autonomy and reproductive health care utilisation are independently determined is rejected for most of the estimation specifications, indicating the importance of taking into account the endogenous nature of women's autonomy when assessing its effect on health care use. CONCLUSIONS: The empirical results reconfirm the assertion that women's status within the household is closely linked to reproductive health care utilisation in developing countries. Policymakers therefore need not only to implement not only direct health interventions but also to focus on broader social policies which address women's empowerment. PMID- 21592609 TI - Interpretation of karyotype evolution should consider chromosome structural constraints. AB - Comparative genetics, genomics and cytogenetics provide tools to trace the evolutionary history of extant genomes. Yet, the interpretation of rapidly increasing genomic data is not always done in agreement with constraints determined by chromosome structural features and by insights obtained from chromosome mutagenesis. The terms 'non-reciprocal chromosome translocation', 'chromosome fusion' and 'centromere shift' used to explain genomic differences among organisms are misleading and often do not correctly reflect the mechanisms of chromosome rearrangements underlying the evolutionary karyotypic variation. Here, we (re)interpret evolutionary genome alterations in a parsimonious way and demonstrate that results of comparative genomics and comparative chromosome painting can be explained on the basis of known primary and secondary chromosome rearrangements. Therefore, some widespread terms used in comparative and evolutionary genomics should be either avoided (e.g. non-reciprocal translocation) or redefined (e.g. chromosome fusion and centromere shift). PMID- 21592611 TI - Comparison of treatment costs of grade 3/4 adverse events associated with erlotinib or pemetrexed maintenance therapy for patients with advanced non-small cell lung cancer (NSCLC) in Germany, France, Italy, and Spain. AB - Objective of this indirect economic comparison was to estimate and compare management costs of grade 3/4 adverse events (AEs) reported for first-line erlotinib or pemetrexed maintenance therapy in patients with advanced non-small cell lung cancer (NSCLC). The economic analysis was performed for Germany, France, Italy and Spain. Types and incidences of reported grade 3/4 AEs observed with erlotinib or pemetrexed maintenance therapy were retrieved from two recently published placebo-controlled trials. Country-specific estimates on standard treatment algorithms and incremental medical resource utilization associated with each of the reported grade 3/4 AEs have been obtained from clinical oncologists practicing in the four countries and co-authoring this article. The resource use items were subsequently assigned country-specific tariffs to estimate total per patients costs associated with the AE profiles of the two compared maintenance regimens. For the economic analysis a customized economic spreadsheet model was employed. Our comparison shows lower total average per-patient AE management costs for erlotinib than for pemetrexed maintenance therapy in all four studied countries. Total estimated cost savings per patient in favour of erlotinib amount to ? 121, ? 237, ? 106, and ? 119 for Germany, France, Italy and Spain, respectively. These AE cost savings for erlotinib when compared to pemetrexed represent a decrease by 80%, 71%, 94%, and 82%, respectively. The study also discovered considerable differences in AE management costs across countries which are primarily due to differences in clinician's estimates of hospitalization referral rates. Erlotinib maintenance therapy in patients with advanced NSCLC causes lower AE management costs than pemetrexed maintenance therapy indicating a potentially superior tolerability profile. PMID- 21592610 TI - MicroRegulators come of age in senescence. AB - Cellular senescence was first reported five decades ago as a state of long-term growth inhibition in viable, metabolically active cells cultured in vitro. However, evidence that senescence occurs in vivo and underlies pathophysiologic processes has only emerged over the past few years. Coincident with this increased knowledge, understanding of the mechanisms that control senescent-cell gene expression programs has also recently escalated. Such mechanisms include a prominent group of regulatory factors (miRNA), a family of small, noncoding RNAs that interact with select target mRNAs and typically repress their expression. Here, we review recent reports that miRNAs are key modulators of cellular senescence, and we examine their influence upon specific senescence-regulatory proteins. We discuss evidence that dysregulation of miRNA-governed senescence programs underlies age-associated diseases, including cancer. PMID- 21592613 TI - Pleural epithelioid hemangioendothelioma in an elderly patient. A case report and review of the literature. AB - Pleural epithelioid hemangioendothelioma is a really rare tumor of vascular origin and potentially aggressive behavior. We report the case of an 85 years old male patient diagnosed of pleural epithelioid hemangioendothelioma, taking advantage to review exhaustively literature and therapy for the disease. PMID- 21592612 TI - Medical treatment choices for patients affected by advanced NSCLC in routine clinical practice: results from the Italian observational "SUN" (Survey on the lUng cancer maNagement) study. AB - Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and the majority of people diagnosed with NSCLC have locally advanced or metastatic disease. Treatment algorithms have rapidly changed in the last 10 years because of the introduction of new chemotherapeutic and targeted agents in clinical practice. SUN is a 1-year longitudinal observational multicenter study that has consecutively enrolled patients affected by stage IIIB or IV NSCLC with the aim to describe the pattern of care and evolving approaches in the treatment of advanced NSCLC. 987 consecutive NSCLC patients were enrolled between January 2007 and March 2008 at the 74 participating centers throughout Italy and a 12-month follow-up was performed. Cyto-histological diagnosis was performed mainly by broncoscopy with only 24% by CT-scan guided fine-needle aspiration biopsy. 91.4% of the patients received a first-line medical treatment and 8.6% supportive care only. Median age of patients receiving first-line treatment was 66 years. First-line chemotherapy consisted of a single agent in 20% of patients and combination chemotherapy in 80%. The most frequently used chemotherapy regimens were cisplatin plus gemcitabine and carboplatin plus gemcitabine. Median survival of patients receiving first-line chemotherapy was 9.1 months. 32% percent of patients received a second-line treatment that consisted of chemotherapy in 71% of cases and erlotinib in 29%. Overall third line treatment was given to 7.3% of patients. These results showed a pattern of care for advanced NSCLC that reflects the current clinical practice in Italy at the study time with a high adherence to the International guidelines by the Italian Oncologists. PMID- 21592614 TI - EGFR and KRAS mutations in Chinese patients with adenosquamous carcinoma of the lung. AB - Adenosquamous carcinoma (ADSQ) is uncommon in non-small cell lung cancer (NSCLC). The frequency rate of ADSQ was 9.7% of 6990 primary lung cancers resected in our department. Many researches have analyzed genetic and molecular alterations in adenocarcinoma (AD) and squamous cell carcinoma (SQ), but few molecular studies have been conducted on heterogeneous ADSQ. The current study was to investigate gene mutations of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene (KRAS) and their correlation with clinical variables in Chinese patients with ADSQ. Histologic features were reviewed, and immunohistochemical (IHC) and molecular (EGFR and KRAS) studies were done in 55 Chinese patients with ADSQ. Microscopically, all the tumors demonstrated dual differentiation with varying proportions of AD and SQ. Based on morphological diagnosis, a combination of multiple IHC markers is helpful for accurately discriminating two undifferentiated histologic subtypes of ADSQ. EGFR mutations were identified in 21 (38.2%) patients: 11 mutations were in exon 19, 1 in exon 20, 7 in exon 21 and double mutations were found in two patients. We also found two new mutations, namely, L747-E749del K754A within exon 19 and H850R within exon 21. Moreover, 16 (29.1%) silent mutations Q787Q in exon 20 were found in the series, five of which coexisted with other mutations. EGFR mutations were more frequently found in patients with size of the tumors >=3cm [19/35 (54.3%); 2/20 (10%); P=0.001] or coexistent double cancer. However, the EGFR mutation was not associated with gender, age, lymph node status, tumor stage and smoking history. KRAS mutations were present in 2 (3.64%) male patients in codon12 (G12C) and none of them showed EGFR mutation. Moreover, identical EGFR and KRAS mutations in both components of ADSQ were further confirmed by microdissection techniques. The data indicated that the incidence of EGFR and KRAS mutations in Chinese patients with ADSQ were similar to those of Asian patients with AD. Furthermore, EGFR silent mutations accounted for a large proportion in ADSQ. Additional prospective studies are needed in order to define the clinical relevance of new and silent mutation variants. PMID- 21592615 TI - Magic traits in speciation: 'magic' but not rare? AB - Speciation with gene flow is greatly facilitated when traits subject to divergent selection also contribute to non-random mating. Such traits have been called 'magic traits', which could be interpreted to imply that they are rare, special, or unrealistic. Here, we question this assumption by illustrating that magic traits can be produced by a variety of mechanisms, including ones in which reproductive isolation arises as an automatic by-product of adaptive divergence. We also draw upon the theoretical literature to explore whether magic traits have a unique role in speciation or can be mimicked in their effects by physically linked trait-complexes. We conclude that magic traits are more frequent than previously perceived, but further work is needed to clarify their importance. PMID- 21592616 TI - Transport and attenuation of metal(loid)s in mine tailings amended with organic carbon: Column experiments. AB - A laboratory-scale column experiment was conducted to evaluate the effect of organic carbon amendments on the mobility of As, Cu, Fe, Mn, Mo, Ni, Pb, Sb, Tl and Zn in mine tailings. Three columns were packed with sulfide- and carbonate rich tailings, which were amended with a 1:1 (vol.) mixture of peat and spent brewing grain at proportions of 0, 2 and 5vol.%. A simulated input solution characterized by circumneutral pH and elevated concentrations of SO(4) and S(2)O(3) was passed through the columns for 540 days. The input solution contained low concentrations of metal(loid)s during the initial 300 days and elevated concentrations thereafter. Decreases in mass transport of S(2)O(3) were observed in all columns; with increased attenuation observed at 5 vol. % organic carbon content. Removal of Mn, Ni, Cu, Sb and Mo was observed in all columns during the initial 300 days. However, during this time, mobilization of Fe, As, Zn and Pb was observed, with the greatest increases in concentration observed at the higher organic carbon content. During the final 240 days, S(2)O(3) removal was enhanced in columns containing organic carbon, and Fe, Mn, Ni, Tl, As and Sb removal also was observed. This study demonstrates the influence of organic carbon amendments on metal(loid) mobility in mine tailings. Decreases in mass discharge of metal(loid)s may be achieved using this technique; however, site specific geochemical conditions must be considered before field-scale implementation. PMID- 21592617 TI - A chloroplast-targeted DnaJ protein AtJ8 is negatively regulated by light and has rapid turnover in darkness. AB - The DnaJ proteins (also called as J proteins, J domain proteins or HSP40 proteins) function as molecular co-chaperones for the HSP70 proteins. We assessed the expression of the small chloroplast-targeted DnaJ protein, the AtJ8 protein, by subjecting the wild type Arabidopsis plants to different illumination conditions. It is shown that the expression of the transcripts and proteins of the ATJ8 gene is primarily regulated at the level of transcription. When plants were incubated under high light for 3h, both the transcripts and proteins were completely abolished. Upon transfer of plants to darkness, the transcripts started rapidly accumulating, and subsequently, the AtJ8 protein became visible after 2h in darkness. Conversely, incubation of plants in darkness or under low light intensities induced expression of the ATJ8 transcripts and proteins. Feeding plants with sugars clearly decreased the transcript and protein levels, and incubation with cycloheximide revealed a rapid turnover for AtJ8 in darkness. Moreover, the AtJ8 protein was found to be nearly missing from the var1 mutant, which lacks the FTSH5 protease. It is concluded that AtJ8 is expressed mainly in darkness, is prone to a rapid turnover but is partially stabilized by the FTSH proteases. PMID- 21592618 TI - Practice of universal precautions and risk of occupational blood-borne viral infection among Congolese health care workers. AB - The extent of occupational injuries among health care workers in central Africa, particularly in the Democratic Republic of Congo, is not documented. We sought to determine the incidence of percutaneous injury and exposure to blood and other body fluids in Congolese urban and rural hospitals in the previous year. Our data show high rates of percutaneous injury and exposure to blood and other body fluids, reflecting poor safety conditions for most Congolese health care workers. PMID- 21592619 TI - [Acute renal failure induced by acquired hemophiliac syndrome]. PMID- 21592620 TI - [Pulmonary hemorrhage due to leptospirosis]. PMID- 21592621 TI - [Splenic rupture after colonoscopy. An unusual complication]. PMID- 21592623 TI - [Hypovolemic shock caused by an aortoenteric fistula: an unusual cause of gastrointestinal bleeding]. PMID- 21592624 TI - [Bone marrow scintigraphy for the evaluaton of a mediastinal nodule in a patient with chronic hematopoietic disorder]. PMID- 21592622 TI - [Pancreatic ascariasis mimicking a pancreatic tumor]. AB - BACKGROUND AND AIM: Ascaris lumbricoides infection in Spain is anecdotal and is usually associated with travel to areas with high endemicity such as India and South America. Biliopancreatic disease caused by this parasite is both rare and one of the most feared complications. There are few publications in the literature about pancreatic involvement in ascariasis. We describe a case of pancreatic ascariasis diagnosed after a pancreaticoduodenectomy was performed for a suspected pancreatic adenocarcinoma. PATIENT: A 58-year-old man consulted for longstanding abdominal pain and diarrhea. Computed tomography and magnetic resonance scans, endoscopy, and endoscopic ultrasound-guided fine-needle cytology were performed. The pathological diagnosis was moderately differentiated adenocarcinoma of the pancreatic head. RESULTS: Cephalic pancreaticoduodenectomy was performed. The postoperative course was favorable. A pancreatic fistula type B (ISGPF classification) developed and was resolved with conservative treatment. Analysis of the surgical specimen revealed the presence of a pancreatic pseudotumor due to Ascaris lumbricoides. After these findings, treatment was completed with oral albendazole. CONCLUSIONS: Pancreatic ascariasis in our environment is unusual, but should be included in the differential diagnosis of tumors and inflammatory processes of the pancreas. PMID- 21592625 TI - Predicted susceptibility of etravirine in HIV patients experiencing virological failure secondary to non-nucleoside reverse transcriptase inhibitor resistance in Argentina. AB - INTRODUCTION: Virological response to etravirine (ETR) is dependent on the type and number of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance associated mutations (RAMs). METHODS: Data on NNRTI used in HAART at the time of failure and the number of NNRTI-RAMs were collected and retrospectively analyzed. ETR-RAMs were defined as V90I, A98G, L100I, K101E/H/P, V106I, E138A, V179D/F/T, Y181C/I/V, G190A/S, and M230L, and were analyzed according to the weighted mutation score to predict susceptibility (Vingerhoets 2008). RESULTS: N=150. Efavirenz (EFV) containing regimen: 76.7%; nevirapine (NVP): 23.3%. Frequency of ETR-RAMs acquired after NNRTI failure: zero=38.7%, one=39.3%, two=17.3%, three=3.3%, four=1.3%. Most frequent ETR-RAMs after failure with EFV: G190A (28.1%), K101E (14.9%), L100I (10.5%); and with NVP: Y181C (41.7%), G190A (30.6%) and A98G (13.9%). Global predicted susceptibility of ETR: highest response: 69.3%, intermediate response: 24.7%, reduced response: 6%. Comparing maximal response with duration of virological failure: EFV-containing regimen: 94.4% (< 24-weeks) vs. 69.8% (>24-weeks) (p=0.02); NVP-containing regimen: 42.9% (< 24 weeks) vs. 56.5% (>24-weeks) (p=0.41). The presence of lamivudine regimen was associated with a better predicted susceptibility (highest response) to ETR (79% vs. 25%; P=.001). DISCUSSION: The majority of patients maintained susceptibility to ETR after the acquisition of NNRTI resistance. Failing with an EFV-containing regimen had a better predicted susceptibility to ETR than with NVP, especially after short-term virological failure. PMID- 21592626 TI - [Profile of children and adolescents with autism spectrum disorders in an institution in Bogota, Colombia]. AB - OBJECTIVE: To determine the profile of children and adolescents diagnosed with autism spectrum disorder (ASD) in a comprehensive care centre in Bogota, Colombia. MATERIAL AND METHODS: A descriptive-correlational study with a sample of patients who had attended the institution from 2003 to 2009. Demographic and clinical aspects were evaluated and a correlation between the diagnosis and severity being analysed in search for risk factors. RESULTS: A total of 138 patients were studied. The average age of onset was 21 months, and diagnosis had been made at 45 months. There was a male predominance (6.15:1). The predominant diagnosis was autistic syndrome (83%), followed by pervasive developmental disorder not otherwise specified (17%). There was no pathological background in the family history, during pregnancy or during the neonatal period. Motor development during the first year was normal but acquisition of language skills was compromised. The specific signs of ASD as regards the disorder in itself, communication skills, spontaneous speech, verbal comprehension, attention, imitation, use of objects, self-care and symbolic play were significantly related to the severity of the disease. CONCLUSIONS: Diagnosis of ASD is still delayed in our population and usually after referral from someone other than a health professional. The most important problems were found in communication skills and relationships with peers. The study did not show significant associated risk factors. PMID- 21592627 TI - Safety profile and practical considerations of monoclonal antibody treatment. AB - INTRODUCTION: Monoclonal antibodies are immunoglobulins specially designed to act against specific targets, in such a way that their administration stops a specific pathogenic process, stimulates a particular cellular action, or changes a cell mechanism to another pathway of interest. Their production is based on the establishment of modified immortal B lymphocytes to produce a specific immunoglobulin. Depending on the level of purity, this immunoglobulin may be murine complement (ending in "o", for example muromonab); chimeric, in which all the immunoglobulin is human, except in the variable region which is murine (ending in "xi", for example, rituximab); humanised, in which all the immunoglobulin is human, except in the variable complement region which remains murine (ending in "zu", for example, natalizumab); and human complement (ending in "u", for example, adalimumab). Therefore, there will be two types of secondary effects: those arising from the action of the antibody, such as opportunistic infections due to immunosuppression, and those arising from the administration of a protein, such as anaphylactic reactions. The sources used for the present articles were articles published in PubMed, located by searching for "Monoclonal antibodies and Secondary effects", and the web pages of the European Medicines Agency (EMEA) and the US Food and Drus Administration (FDA). DEVELOPMENT: The secondary effects arising from the mechanisms of action were opportunistic infections, common infections, development of tumours and autoimmune phenomena, and those arising from the administration of proteins: anaphylactic reaction, cytokine release syndrome, and the development of neutralising antibodies. Finally, the management of monoclonal antibodies in clinical practice and in special situations is discussed, including administering vaccines, pregnancy and paediatric use. Reference will be made to immune recovery syndrome. CONCLUSIONS: Monoclonal antibodies are highly effective drugs when specifically indicated, but they also may incur serious secondary effects, which although incidence is low, require close monitoring of the patients receiving these treatments. PMID- 21592628 TI - Design, synthesis, and antiproliferative activity of new 1H-pyrrolo[3,2 c]pyridine derivatives against melanoma cell lines. AB - Synthesis of a new series of diarylureas and diarylamides having 1H-pyrrolo[3,2 c]pyridine scaffold is described. Their in vitro antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on pyrrolo[3,2-c]pyridine nucleus was investigated. The newly synthesized compounds, except three N-tolyl derivatives (8f, 9f, and 9h), generally showed superior activity against A375P to Sorafenib. Among all of these derivatives, compounds 8b, 8g, and 9a-e showed the highest potency against A375P with IC(50) in nanomolar range. In addition, compounds 8d, 8e, 8h, 9g, 9i, and 9j were more potent than Sorafenib but with IC(50) in micromolar range. Compounds 8b, 8g, 9b d, and 9i demonstrated higher selectivity towards A375P compared with NIH3T3 fibroblasts. The most potent diarylurea 8g and diarylamide 9d were further tested and showed high potency over nine melanoma cell lines at the NCI. PMID- 21592629 TI - [Pulmonary and renal involvement in a TNFalpha antagonist drug-induced sarcoidosis]. AB - Several cases of sarcoidosis with pulmonary, neurological or ophthalmological involvement occurring during a treatment by anti-TNFalpha have been reported in the literature. We report a 66-year-old man who presented with renal failure and hypercalcaemia, associated with fatigue, shortness of breath and dry cough. He was receiving infliximab since 2004 for psoriatic arthritis. The diagnosis of sarcoidosis was obtained with biopsy sampling of a mediastinal lymph node, and the lung involvement was documented with lung function tests, bronchoalveolar lavage and computed tomographic scan. Laboratory tests were suggestive of interstitial sarcoid nephritis. Disease course was favourable with corticosteroids and discontinuation of infliximab. PMID- 21592630 TI - [Acute bowel intussusception revealing celiac disease: a new case and literature review]. AB - INTRODUCTION: Acute bowel intussusception is a rare manifestation in adult, which mainly involves the small intestine. Celiac disease is a frequent small bowel disease that is largely undiagnosed in adults. We report a patient in whom spontaneously regressive small bowel intussusception was the presenting manifestation of celiac disease. CASE REPORT: A 40-year-old man was admitted for a right-sided iliac abdominal pain related to a small bowel intussusception. Laparotomy ruled out a digestive tumor. Persistence of diffuse abdominal pain associated with progressive and unexplained weight loss for several months led to the diagnosis of celiac disease, which was confirmed by the presence of specific serum autoantibodies and histological duodenal villous atrophy. CONCLUSION: The association between small bowel intussusception and celiac disease does not seem to be fortuitous. Based on this report and the literature review, we suggest that celiac disease can favour small bowel intussusception, even in adulthood. Therefore, diagnosis of celiac disease must be discussed in the presence of unexplained intussusception. PMID- 21592631 TI - [Etiology and prognosis of highly elevated C-reactive protein levels (>=500 mg/L): a retrospective study about 168 measures in a series of 113 patients]. AB - PURPOSE: The C-reactive protein (CRP) is a useful inflammatory marker with a rapid kinetics during the inflammatory process. The objective of this study was to determine the etiology and prognosis of extremely elevated CRP values greater or equal to 500 mg/L. METHODS: We performed an exhaustive retrospective study from January 2004 to July 2009, in a general hospital, of all patients with a CRP value above 500 mg/L, admitted in all clinical departments. Clinical data were collected by a single observer using a standardized questionnaire. RESULTS: One hundred and sixty-eight CRP values greater or equal to 500 mg/L were identified amongst 106,758 tests (0.16%) corresponding to 113 patients: 51% were men and their mean age was 59.5 years. Mean CRP value was 561 mg/L (500-772). An immunocompromised condition was observed in 52% of the patients. All but 13 patients presented an infectious disease. Microbiological analysis of the infected patients identified 59 Gram-positive cocci (20 Staphylococcus spp., 35 Streptococcus spp. including 21 Streptococcus pneumoniae), two Gram-negative cocci, 48 Gram-negative bacilli (including 19 Escherichia coli), three Gram positive bacilli, 16 fungal infections, one viral infection. Site of infection was respiratory in 63%, urinary in 17% and abdominal in 16%. At day 30, mortality rate was 27% and only 41% of the patients were discharged at home. CONCLUSION: CRP value above 500 mg/L is highly related to bacterial infections, without over representation of a given microorganism. One-month mortality is high (27%). PMID- 21592632 TI - Orthognathic patients with nasal deformities: case for simultaneous orthognathic surgery and rhinoplasty. AB - Orthognathic surgery is a recognised way of correcting dentofacial deformities and it is common practice to treat problems that affect the chin simultaneously, while deferring or not treating nasal deformities. There is inadequate published information about the prevalence of nasal deformities in such patients, and our aim was to remedy this. We retrospectively studied 75 patients with dentofacial deformities to find out if there was an association between nasal and dentofacial abnormalities. Forty-six of the 75 patients (61%) had mild to prominent cosmetic nasal problems, of whom 27 had deformities of the nasal bridge, 22 of the lobule of the nasal tip, 20 of nasal width, 14 in the width of the alar base, and 11 of the columella; 8 presented with deviation of the nose, and 6 with abnormal nasal length. Skeletal classes II and III had only slightly varied emphasis on nasal deformities. In comparison 14 patients (19%) had problems with the chin that required, or had already had, genioplasty. We also studied 9 patients who had had corrective bimaxillary surgery with simultaneous rhinoplasty. We set no formal questionnaire, but all patients expressed satisfaction with the postoperative results. PMID- 21592633 TI - Effect of alkalinisation of lignocaine for intraoral nerve block on pain during injection, and speed of onset of anaesthesia. AB - Injections of lignocaine as local anaesthetic for pain control in oral and maxillofacial surgery can themselves be painful. The time of onset of anaesthesia is from 3 to 5 min. Sodium bicarbonate has been used worldwide to reduce both these drawbacks to the injection, so making procedures more acceptable. This randomised prospective trial of 100 patients aged 18-55 years who were given 3 nerve blocks (inferior alveolar, lingual, and long buccal) was designed to assess the effect of alkalinisation of the lignocaine solution with sodium bicarbonate. All patients were given 2% lignocaine hydrochloride with adrenaline 1:80,000 and 50 patients were randomly allocated to be given 8.4% sodium bicarbonate in a 1/10 dilution. Pain was measured on a visual analogue scale (VAS). No patient given the injection with sodium bicarbonate complained of pain, compared with 39/50 (78%) not given sodium bicarbonate (p<0.0001). The mean (SD) time (seconds) to onset of local anaesthesia in the group given sodium bicarbonate was 34.4 (9.8) compared with 109.8 (31.6) in the control group (p<0.001). Our results have confirmed the efficacy of the alkalinised local anaesthetic solution in reducing pain on injection and resulting in quicker onset of anaesthesia. PMID- 21592634 TI - What do midwives think about interprofessional working and learning? AB - OBJECTIVE: This study describes the views of midwives and educators regarding interprofessional working and learning within midwifery care. DESIGN: Qualitative methods using semi-structured interviews and focus groups. PARTICIPANTS: 39 participants, drawn from three participant groups--midwifery educators, newly qualified midwives and Heads of Midwifery--from four university sites throughout the U.K. took part in the research. FINDINGS: Midwives are called upon to work collaboratively with other professionals during the daily provision of maternity care. Midwives are aware of the competencies required for effective collaboration and are supportive of the inclusion of interprofessional education in the training of student midwives. However, the relevance of this education was questioned by some participants because it is not apparent whether its inclusion will result in midwives who are better able to collaborate. KEY CONCLUSIONS: Midwives are supportive of interprofessional learning for students but are uncertain whether it will result in changes in practice. IMPLICATIONS FOR PRACTICE: Interprofessional education may support collaboration in practice, but future educational research aimed at understanding how learning is applied to practice is needed. PMID- 21592635 TI - A pilot study to investigate the combined use of Botulinum toxin type-a and ankle foot orthosis for the treatment of spastic foot in chronic hemiplegic patients. AB - BACKGROUND: Botulinum toxin is commonly used to treat spastic equinus foot. This treatment seems to improve gait in hemiplegic patients when used alone or combined with an ankle-foot orthosis. However, the nature and effects of this improvement have until now rarely been studied. The aim of this study was to quantify the impact of a Botulinum toxin injection in the triceps surae of hemiplegic patients with equinus foot, used either alone or in combination with an ankle-foot orthosis, on the kinematics and dynamics of the paretic lower limb, and to determine the advantage of combining an ankle-foot orthosis with this pharmacological treatment. METHODS: Patients were assessed using gait analysis to measure spatio-temporal, kinematic and dynamic parameters of the gait cycle before Botulinum toxin injection and then 3 and 6weeks after injection. Eight chronic hemiplegics following central nervous system lesion were included. FINDINGS: Botulinum toxin injection led to an increase in velocity, peak ankle dorsiflexion during stance phase, and peak knee flexion during swing phase. It also resulted in an increased peak plantarflexion moment. Use of ankle-foot orthosis led to a specific increase in peak ankle dorsiflexion during swing phase and also increased peak plantarflexion moment. INTERPRETATION: The results indicate that combined Botulinum toxin injection of the triceps surae and wearing an ankle-foot orthosis is more effective than the use of Botulinum toxin only. Use of an ankle-foot orthosis increases ankle dorsiflexion during the swing phase and does not reduce the benefits gained by the use of Botulinum toxin in stance phase. PMID- 21592636 TI - Pyrethroid insecticides in urban salmon streams of the Pacific Northwest. AB - Urban streams of the Pacific Northwest provide spawning and rearing habitat for a variety of salmon species, and food availability for developing salmon could be adversely affected by pesticide residues in these waterbodies. Sediments from Oregon and Washington streams were sampled to determine if current-use pyrethroid insecticides from residential neighborhoods were reaching aquatic habitats, and if they were at concentrations acutely toxic to sensitive invertebrates. Approximately one-third of the 35 sediment samples contained measurable pyrethroids. Bifenthrin was the pyrethroid of greatest concern with regards to aquatic life toxicity, consistent with prior studies elsewhere. Toxicity to Hyalella azteca and/or Chironomus dilutus was found in two sediment samples at standard testing temperature (23 degrees C), and in one additional sample at a more environmentally realistic temperature (13 degrees C). Given the temperature dependency of pyrethroid toxicity, low temperatures typical of northwest streams can increase the potential for toxicity above that indicated by standard testing protocols. PMID- 21592637 TI - Toxicity of dispersant application: Biomarkers responses in gills of juvenile golden grey mullet (Liza aurata). AB - Dispersant use in nearshore areas is likely to increase the exposure of aquatic organisms to petroleum. To measure the toxicity of this controversial response technique, golden grey mullets (Liza aurata) were exposed to mechanically dispersed oil, chemically dispersed oil, dispersant alone in seawater, water soluble fraction of oil and to seawater as a control treatment. Several biomarkers were assessed in the gills (enzymatic antioxidant activities, glutathione content, lipid peroxidation) and in the gallbladder (polycylic aromatic hydrocarbons metabolites). The significant differences between chemically dispersed oil and water soluble fraction of oil highlight the environmental risk to disperse an oil slick when containment and recovery can be conducted. The lack of significance between chemically and mechanically dispersed oil suggests that dispersant application is no more toxic than the natural dispersion of the oil slick. The results of this study are of interest in order to establish dispersant use policies in nearshore areas. PMID- 21592638 TI - Arguments against inhaled glucocorticoids in COPD by phenotype instead of by severity. PMID- 21592639 TI - [The changing role of the coronary care unit cardiologist]. PMID- 21592640 TI - Schistosomiasis and tropical endomyocardial fibrosis with pulmonary hypertension. PMID- 21592641 TI - Early selective trans-nasal cooling during CPR improves success of resuscitation in a porcine model of prolonged pulseless electrical activity cardiac arrest. AB - AIM OF STUDY: In the present study, we investigated trans-nasal cooling in settings of pulseless electrical activity (PEA). We hypothesized that early trans nasal cooling during CPR improves outcomes when cardiac arrest is associated with PEA. METHODS: Ventricular fibrillation (VF) was electrically induced in 16 domestic male pigs weighing 40+/-3 kg. After 14 min of untreated VF, PEA was induced following delivery of one or more electrical shocks. One min after onset of PEA, CPR was started, including chest compression and ventilation. Each animal received 5 min of CPR prior to defibrillation attempt. CPR and resuscitation efforts were discontinued at 15 min unless return to spontaneous circulation was achieved. In 8 animals, selective trans-nasal cooling was begun coincident with start of CPR and 8 randomized controls were identically treated except for trans nasal cooling. Mean aortic pressure was continuously measured together with aortic and right atrial pressure and nasal, body and right jugular vein temperatures. Coronary perfusion pressure (CPP) was computed from measured data. RESULTS: Six of eight animals were resuscitated after early trans-nasal cooling, while only one untreated control was resuscitated (p=0.012). Nasal, body and jugular vein temperatures decreased after cooling. At PC (precordial compression) 5 min, the cooled group recorded a higher CPP (25+/-5 mmHg) than the non-cooled group (15+/-4 mmHg, p=0.001). CONCLUSION: When selective trans-nasal cooling was initiated during CPR in the animal model of prolonged cardiac arrest with PEA, CPP was higher and the likelihood of return of spontaneous circulation was improved. PMID- 21592643 TI - Association of the Bedside Shivering Assessment Scale and derived EMG power during therapeutic hypothermia in survivors of cardiac arrest. AB - INTRODUCTION: Shivering during therapeutic hypothermia (TH) after cardiac arrest (CA) is common, but the optimal means of detection and appropriate threshold for treatment are not established. In an effort to develop a quantitative, continuous tool to measure shivering, we hypothesized that continuous derived electromyography (dEMG) power detected by the Aspect A2000 or VISTA monitor would correlate with the intermittent Bedside Shivering Assessment Scale (BSAS) performed by nurses. METHODS: Among 38 patients treated with TH after CA, 853 hourly BSAS measurements were compared to dEMG power measured every minute by a frontal surface electrode. Patients received intermittent vecuronium by protocol to treat clinically recognized shivering (BSAS>0). Mean dEMG power in decibels (dB) was determined for the hour preceding each BSAS measurement. dEMG and BSAS were compared using ANOVA. RESULTS: The median dEMG power for a BSAS score of 0 (no shivering) was 27 dB (IQR 26-31 dB), BSAS 1 was 30.5 dB (IQR 28-35 dB), BSAS 2 was 34 dB (IQR 30-38 dB), and BSAS 3 was 34.5 dB (IQR 32-44.25). The dEMG for BSAS>=1 (shivering) was statistically different from BSAS 0 (p<0.0001). dEMG and BSAS correlated moderately (r=0.66, p<0.001). CONCLUSION: dEMG power measured from the forehead with the Aspect A2000 or VISTA monitor during therapeutic hypothermia correlated with the Bedside Shivering Assessment Scale. Given its continuous trending of dEMG power, the A2000 or VISTA may be a useful research and clinical tool for objectively monitoring shivering. PMID- 21592642 TI - Association between a quantitative CT scan measure of brain edema and outcome after cardiac arrest. AB - BACKGROUND: Cerebral edema is one physical change associated with brain injury and decreased survival after cardiac arrest. Edema appears on computed tomography (CT) scan of the brain as decreased X-ray attenuation by gray matter. This study tested whether the gray matter attenuation to white matter attenuation ratio (GWR) was associated with survival and functional recovery. METHODS: Subjects were patients hospitalized after cardiac arrest at a single institution between 1/1/2005 and 7/30/2010. Subjects were included if they had non-traumatic cardiac arrest and a non-contrast CT scan within 24h after cardiac arrest. Attenuation (Hounsfield Units) was measured in gray matter (caudate nucleus, putamen, thalamus, and cortex) and in white matter (internal capsule, corpus callosum and centrum semiovale). The GWR was calculated for basal ganglia and cerebrum. Outcomes included survival and functional status at hospital discharge. RESULTS: For 680 patients, 258 CT scans were available, but 18 were excluded because of hemorrhage (10), intravenous contrast (3) or technical artifact (5), leaving 240 CT scans for analysis. Lower GWR values were associated with lower initial Glasgow Coma Scale motor score. Overall survival was 36%, but decreased with decreasing GWR. The average of basal ganglia and cerebrum GWR provided the best discrimination. Only 2/58 subjects with average GWR<1.20 survived and both were treated with hypothermia. The association of GWR with functional outcome was completely explained by mortality when GWR<1.20. CONCLUSIONS: Subjects with severe cerebral edema, defined by GWR<1.20, have very low survival with conventional care, including hypothermia. GWR estimates pre-treatment likelihood of survival after cardiac arrest. PMID- 21592645 TI - SRY upregulation of SOX9 is inefficient and delayed, allowing ovarian differentiation, in the B6.Y(TIR) gonad. AB - SRY on the Y-chromosome acts as a transcription factor to initiate testicular differentiation in mammals. Sox9 is a SRY target gene, upregulated immediately after Sry expression, and plays a key role in testicular differentiation. In the present study, we examined the expression of SRY and SOX9 proteins in the B6.Y(TIR) gonad, which undergoes partial or complete sex reversal. The results show that the ontogeny of SRY expression in the B6.Y(TIR) gonad was comparable with that in the B6.XY gonad. On the other hand, while SOX9 expression immediately followed SRY expression in the B6.XY gonad, it was considerably delayed compared to SRY expression in the B6.Y(TIR) gonad or SOX9 expression in the B6.XY gonad. Although SOX9 expression reached the entire gonad at a time point, it was downregulated and became restricted to the central area in which testis cords were organized. MIS, a marker of Sertoli cells, appeared only in well-organized testis cords. We speculate that the SRY protein from the Y(TIR) chromosome is inefficient in upregulating the Sox9 gene on the B6 background, allowing the initiation of ovarian differentiation. PMID- 21592646 TI - Adsorption and degradation of triazophos, chlorpyrifos and their main hydrolytic metabolites in paddy soil from Chaohu Lake, China. AB - Triazophos and chlorpyrifos are organophosphorus pesticides (OPs), and their primary hydrolytic metabolites are 1-phenyl-3-hydroxy-1,2,4-triazole (BZC) and 3,5,6-trichloro-2-pyridinol (TCP). In this study, the adsorption and degradation of triazophos, chlorpyrifos, BZC and TCP were investigated in paddy soil from Chaohu Lake, China. Adsorption tests demonstrated that the adsorption of these compounds to soils could be described by the Freundlich equation. Moreover, chlorpyrifos displayed the highest affinity for adsorption, followed by triazophos, BZC and TCP. Degradation of these compounds in non-sterile soil followed first-order exponential decay kinetics, and the half-life (t(1/2)) of these contaminants ranged from 8.40 to 44.34 d. Sterilization of soil decreased the degradation rate, indicating that microorganisms played a significant role in the degradation of these compounds. The values of t(1/2) and K(oc) were fitted to obtain models that could predict the leaching potential of the contaminants from soil. Compared to their parent compounds, BZC and TCP showed high potential for leaching into groundwater. The inoculation of OPs-degrading bacterium (Diaphorobacter sp. GS-1) removed 95.38%, 100% and 100% of triazophos, chlorpyrifos and BZC in paddy soil after 21 d, respectively. The pollution risk of triazophos, chlorpyrifos and BZC could be greatly decreased by inoculating soil with Diaphorobacter sp. GS-1, which decreases the t(1/2) of the contaminants. PMID- 21592647 TI - Heavy metal content and distribution in surface sediments of the Seyhan River, Turkey. AB - Chemical fractionation of seven heavy metals (Cd, Cr, Cu, Mn, Ni, Pb and Zn) was studied using a modified three-step sequential procedure to assess their impacts in the sediments of the Seyhan River, Turkey. Samples were collected from six representative stations in two campaigns in October 2009 and June 2010, which correspond to the wet and dry seasons, respectively. The total metal concentrations in the sediments demonstrated different distribution patterns at the various stations. Cadmium was the only metal that was below detection at all stations during both sampling periods. Metal fractionation showed that, except for Mn and Pb, the majority of metals were found in the residual fraction regardless of sampling time, indicating that these metals were strongly bound to the sediments. The potential mobility of the metals (non-residual fractions) is reflected in the following ranking: Pb > Mn > Zn > Cu > Ni > Cr in October 2009 and Mn > Pb > Zn > Cu > Ni > Cr in June 2010. The second highest proportion of metals was bound to organic matter/sulfides, originating primarily from anthropogenic activities. Non-residual metal fractions for all stations were highest in June 2010, which may be linked to higher organic matter concentrations in the sediment samples with 1.40% and 15.1% in October 2009 and June 2010, respectively. Potential sediment toxicity was evaluated using the Risk Assessment Code (RAC). Based on RAC classification, Cd and Cr pose no risk, Cu and Ni pose low risk, Pb and Zn were classified as medium risk metals, while the environmental risk from Mn was high. In addition, based on the sediment quality guidelines (SQG), the Seyhan River can be classified as a river with no, to moderate, toxicological risks, based on total metal concentrations. PMID- 21592648 TI - Learning about knowledge management for improving environmental impact assessment in a government agency: the Western Australian experience. AB - How does knowledge management (KM) by a government agency responsible for environmental impact assessment (EIA) potentially contribute to better environmental assessment and management practice? Staff members at government agencies in charge of the EIA process are knowledge workers who perform judgement oriented tasks highly reliant on individual expertise, but also grounded on the agency's knowledge accumulated over the years. Part of an agency's knowledge can be codified and stored in an organizational memory, but is subject to decay or loss if not properly managed. The EIA agency operating in Western Australia was used as a case study. Its KM initiatives were reviewed, knowledge repositories were identified and staff surveyed to gauge the utilisation and effectiveness of such repositories in enabling them to perform EIA tasks. Key elements of KM are the preparation of substantive guidance and spatial information management. It was found that treatment of cumulative impacts on the environment is very limited and information derived from project follow-up is not properly captured and stored, thus not used to create new knowledge and to improve practice and effectiveness. Other opportunities for improving organizational learning include the use of after-action reviews. The learning about knowledge management in EIA practice gained from Western Australian experience should be of value to agencies worldwide seeking to understand where best to direct their resources for their own knowledge repositories and environmental management practice. PMID- 21592649 TI - New therapies for castration-resistant prostate cancer: efficacy and safety. AB - CONTEXT: Prostate cancer (PCa) is the most common noncutaneous malignancy and the second leading cause of cancer mortality amongst men in the Western world. Up to 40% of men diagnosed with PCa will eventually develop metastatic disease, and although most respond to initial medical or surgical castration, progression to castration resistance is universal. The average survival for patients with castration-resistant prostate cancer (CRPC) is 2-3 yr. OBJECTIVE: To discuss the biologic rationale and evidence supporting current management of patients with CRPC and to review promising novel agents. EVIDENCE ACQUISITION: Electronic databases (PubMed, ClinicalTrials.gov), relevant journals, and conference proceedings were searched manually for preclinical studies, clinical trials, and biomarker analyses focused on the treatment of CRPC. Keywords included castrate resistant prostate cancer and: targeted therapy, novel therapy, immunotherapy, androgen therapy, bone therapy, mechanisms, biomarkers, and trial endpoints; no time range was specified. Information pertaining to current studies was discussed with key opinion leaders. EVIDENCE SYNTHESIS: We focus on the efficacy and safety of approved agents, promising therapies that have proceeded to phase 3 evaluation, and those that have enhanced our understanding of the biology of CRPC. Biomarkers are considered in the context of novel targeted agents and immunotherapy. CONCLUSIONS: CRPC has many targets. Four new agents with different mechanisms of action have recently been shown to have positive results in large phase 3 randomized trials, and have already been approved in the United States for CRPC: cabazitaxel, sipuleucel-T, denosumab, and abiraterone acetate. With our improved understanding of tumor biology and the incorporation of new prognostic and molecular biomarkers into clinical trials, we are making progress in the management of patients with CRPC. PMID- 21592650 TI - Inhibition of hydrogen sulfide generation from disposed gypsum drywall using chemical inhibitors. AB - Disposal of gypsum drywall in landfills has been demonstrated to elevate hydrogen sulfide (H(2)S) concentrations in landfill gas, a problem with respect to odor, worker safety, and deleterious effect on gas-to-energy systems. Since H(2)S production in landfills results from biological activity, the concept of inhibiting H(2)S production through the application of chemical agents to drywall during disposal was studied. Three possible inhibition agents - sodium molybdate (Na(2)MoO(4)), ferric chloride (FeCl(3)), and hydrated lime (Ca(OH)(2)) - were evaluated using flask and column experiments. All three agents inhibited H(2)S generation, with Na(2)MoO(4) reducing H(2)S generation by interrupting the biological sulfate reduction process and Ca(OH)(2) providing an unfavorable pH for biological growth. Although FeCl(3) was intended to provide an electron acceptor for a competing group of bacteria, the mechanism found responsible for inhibiting H(2)S production in the column experiment was a reduction in pH. Application of both Na(2)MoO(4) and FeCl(3) inhibited H(2)S generation over a long period (over 180 days), but the impact of Ca(OH)(2) decreased with time as the alkalinity it contributed was neutralized by the generated H(2)S. Practical application and potential environmental implications need additional exploration. PMID- 21592651 TI - Solar photocatalitycal treatment of carbofuran at lab and pilot scale: effect of classical parameters, evaluation of the toxicity and analysis of organic by products. AB - In this work the TiO(2) solar-photocatalytical degradation of the pesticide carbofuran (CBF) in water, at lab and pilot scale, was studied. At lab scale the evaluation of CBF concentration (14-282 MUmol L(-1)) showed that the system followed a Langmuir-Hinshelwood kinetics type. TiO(2) concentration (0.05-2 g L( 1)) and initial pH (3-9) were also evaluated and optimized using the surface response methodology and the Pareto diagram. In the range of variables studied, initial pH 7.60 and 1.43 g L(-1) of TiO(2) favoured the efficiency of the process. Under optimal conditions the evolution of substrate, chemical oxygen demand, dissolved organic carbon, toxicity and organics by-products were evaluated. In the pilot scale tests, using direct sunlight, 55 mg L(-1) of CBF in a commercial formulation was eliminated after 420 min; while after 900 min of treatment 80% of toxicity (1/E(50) on Vibrium Fischeri), 80% of chemical oxygen demand and 60% of dissolved organic carbon were removed. The analysis and evolution of five CBF by-products, as well the evaluation of the treatment in the presence of isopropanol or using acetonitrile as a solvent suggest that the degradation is mainly carried out by OH radical attack. Finally, a schema depicting the main degradation pathway is proposed. PMID- 21592652 TI - Mineralogy and leachability of gasified sewage sludge solid residues. AB - Gasification of sewage sludge produces combustible gases as well as tar and a solid residue as by-products. This must be taken into account when determining the optimal thermal conditions for the gasification process. In this study, the influence of temperature, heating atmosphere and residence time on the characteristics of the gasified sewage sludge residues is investigated. ICP-AES analyses reveal that the major chemical elements in the char residues are phosphorus, calcium, iron and silicon. Heavy metals such as copper, zinc, chromium, nickel and lead are also present at relatively high levels - from 50 to more than 1000 mg/kg of dry matter. The major mineral phases' identification - before and after heating - as well as their morphology and approximate chemistry (XRD and SEM-EDX) demonstrate that a number of transformations take place during gasification. These are influenced by the reactor's temperature and the oxidative degree of its internal atmosphere. The copper-, zinc- and chromium-bearing phases are studied using chemometric tools, showing that the distribution of those metals among the mineral phases is considerably different. Finally, batch leaching tests reveal that metals retained in the residue are significantly stabilized after thermal treatment to a higher or lower extent, depending on the thermal conditions applied. PMID- 21592653 TI - The efficiency of CO2 sequestration via carbonate mineralization with simulated wastewaters of high salinity. AB - Salinity generally strongly affects the solubility of carbon dioxide in aqueous solution. This would seem to involve a reduction of the efficiency of the carbonate mineralization process with the objective to sequester this greenhouse gas. On the contrary, we demonstrate here that with a more concentrated solution of magnesium chloride, the residence time of CO(2) is enhanced in the aqueous medium because of a reduced tendency to produce CO(2(g)). Experiments intended to simulate more closely the Mg-rich wastewaters that are industrially available have been carried out using solutions differing in Mg concentration (7, 16, 32 g L(-1) Mg). A comparison of the efficiency of the CO(2) mineralization process among sets of experiments shows that the reduction of the efficiency, to about 65%, was lower than that expected, as the low degree of CO(2) degassing results in the enhanced availability of carbonic ions to react with Mg ions to form stable carbonate minerals over a longer time. PMID- 21592654 TI - Can a breathing biocover system enhance methane emission reduction from landfill? AB - Based on the aerothermodynamic principles, a kind of breathing biocover system was designed to enhance O(2) supply efficiency and methane (CH(4)) oxidation capacity. The research showed that O(2) concentration (v/v) considerably increased throughout whole profiles of the microcosm (1m) equipped with passive air venting system (MPAVS). When the simulated landfill gas SLFG flow was 771 g m(-3) d(-1) and 1028 g m(-3) d(-1), the O(2) concentration in MPAVS increased gradually and tended to be stable at the atmospheric level after 10 days. The CH(4) oxidation rate was 100% when the SLFG flow rate was no more than 1285 g m( 3) d(-1), which also was confirmed by the mass balance calculations. The breathing biocover system with in situ self-oxygen supply can address the problem of O(2) insufficient in conventional landfill covers and/or biocovers. The proposed system presents high potential for improving CH(4) emission reduction in landfills. PMID- 21592655 TI - Removal of heavy metals using different polymer matrixes as support for bacterial immobilisation. AB - Great attention is focused on the microbial treatment of metal contaminated environments. Three bacterial strains, 1C2, 1ZP4 and EC30, belonging to genera Cupriavidus, Sphingobacterium and Alcaligenes, respectively, showing high tolerance to Zn and Cd, up to concentrations of 1000ppm, were isolated from a contaminated area in Northern Portugal. Their contribution to Zn and Cd removal from aqueous streams using immobilised alginate, pectate and a synthetic cross linked polymer was assessed. In most cases, matrices with immobilised bacteria showed better metal removal than the non-inoculated material alone. For the immobilisation with all the polymers, 1C2 was the strain that increased the removal of Zn the most, whereas EC30 was the most promising for Cd removal, especially when combined with the synthetic polymer with up to a ca. 11-fold increase in metal removal when compared to the polymer alone. Removal of individual metals from binary mixtures showed that there was differential immobilisation. There was greater removal of Cd than Zn (removals up to 40% higher than those showed for Zn). The results show that metal contaminated environments constitute a reservoir of microorganisms resistant/tolerant to heavy metals that have the capacity to be exploited in bioremediation strategies. Capsule immobilisation of bacteria in the naturally occurring alginate and pectate and in a synthetic cross-linked polymer increased the Zn and Cd removal abilities from single and binary contaminated waters; the applications with the synthetic polymer were the most promising for Cd and Zn removal in single and binary mixtures. PMID- 21592656 TI - Sorption behaviour of Co(II) and Cu(II) on chitosan in presence of nitrilotriacetic acid. AB - Separation and isolation of radioactive cobalt ((60)Co), one of the main contributors towards the activity build up in nuclear reactors, is essential for radioactive waste volume reduction during nuclear reactor decontamination procedures. In this context, sorption of free and complexed Co(II), Cu(II) and nitrilotriacetic acid (NTA) on the biosorbent, chitosan was studied. A detailed investigation on the role of pH on sorption of Co(II), Cu(II) and NTA was done. Uptake capacities of the metal ions and NTA were measured within pH range of 2.0 7.0. At pH above 5, the NTA uptake capacities were found to be higher in presence of the metal ions than in their absence. Effect of NTA was found to be more pronounced on copper uptake than on cobalt uptake. Significant change in selectivity of chitosan towards metal ion uptake from NTA medium was observed with respect to change in pH. At pH 2.9, the uptake of cobalt was found to be more than that of copper, while the selectivity was reversed at pH 6.0. The respective selectivity coefficient (k(Co/Cu)) values were found to be 2.06 and 0.072. PMID- 21592657 TI - Chromium behavior during cement-production processes: a clinkerization, hydration, and leaching study. AB - The behavior of chromium during the production of cement clinker, during the hydration of cement and during the leaching of cement mortars was investigated. The microstructures of clinker and mortar properties were investigated using free lime, XRD, SEM/EDS, and TG/DTA techniques. Chromium was found to be incorporated in the clinker phase. The formation of new chromium compounds such as Ca(6)Al(4)Cr(2)O(15), Ca(5)Cr(3)O(12), Ca(5)Cr(2)SiO(12), and CaCr(2)O(7), with chromium oxidation states of +3, +4.6, +5, and +6, respectively, was detected. After the hydration process, additional chromium compounds were identified in the mortar matrix, including Ca(5)(CrO(4))(3)OH, CaCrO(4).2H(2)O, and Al(2)(OH)(4)CrO(4), with chromium oxidation states of +4.6, +6, and +6, respectively. Additionally, some species of chromium, such as Cr(3+) from Ca(6)Al(4)Cr(2)O(15) and Cr(6+) from CaCr(2)O(7), CaCrO(4).2H(2)O, and Al(2)(OH)(4)CrO(4), were leached during leaching tests, whereas other species remained in the mortar. The concentrations of chromium that leached from the mortar following U.S. EPA Method 1311 and EA NEN 7375:2004 leaching tests were higher than limits set by the U.S. EPA and the Environment Agency of England and Wales related to hazardous waste disposal in landfills. Thus, waste containing chromium should not be allowed to mix with raw materials in the cement manufacturing process. PMID- 21592658 TI - Sequencing Batch Reactor (SBR) for the removal of Hg2+ and Cd2+ from synthetic petrochemical factory wastewater. AB - Petrochemical factories which manufacture vinyl chloride monomer and poly vinyl chloride (PVC) are among the largest industries which produce wastewater contains mercury and cadmium. The objective of this research is to evaluate the performance of a lab-scale Sequencing Batch Reactor (SBR) to treat a synthetic petrochemical wastewater containing mercury and cadmium. After acclimatization of the system which lasted 60 days, the SBR was introduced to mercury and cadmium in low concentrations which then was increased gradually to 9.03+/-0.02 mg/L Hg and 15.52+/-0.02 mg/L Cd until day 110. The SBR performance was assessed by measuring Chemical Oxygen Demand, Total and Volatile Suspended Solids as well as Sludge Volume Index. At maximum concentrations of the heavy metals, the SBR was able to remove 76-90% of Hg(2+) and 96-98% of Cd(2+). The COD removal efficiency and MLVSS (microorganism population) in the SBR was affected by mercury and cadmium concentrations in influent. Different species of microorganisms such as Rhodospirilium-like bacteria, Gomphonema-like algae, and sulfate reducing-like bacteria were identified in the system. While COD removal efficiency and MLVSS concentration declined during addition of heavy metals, the appreciable performance of SBR in removal of Hg(2+) and Cd(2+) implies that the removal in SBR was not only a biological process, but also by the biosorption process of the sludge. PMID- 21592659 TI - Degradation of pyridine by one Rhodococcus strain in the presence of chromium (VI) or phenol. AB - A Rhodococcus strain, Chr-9, which has the ability to degrade pyridine and phenol and reduce chromium (VI) (Cr (VI)) was isolated. The strain could grow with pyridine as the sole carbon and nitrogen source, and its pyridine-degradation capability was enhanced by 100 mg l(-1) phenol; however, the degradation of pyridine was inhibited when the phenol concentration was greater than 400 mg l( 1). The hydroxylation of pyridine suggested that the stimulation and inhibition of phenol to the pyridine degradation may be attributed to competition of phenol and pyridine for the hydroxylase gene. Strain Chr-9 was also able to reduce Cr (VI) when glucose and LB was used as the carbon source; however, the Cr (VI) reduction did not occur when pyridine was the sole carbon and energy source. In addition, strain Chr-9 could reduce Cr (VI) and simultaneously degrade pyridine in the presence of glucose. To the best of our knowledge, strain Chr-9 is the first Rhodococcus strain reported to degrade pyridine in the presence of Cr (VI), and the first strain with the pyridine degradation being stimulated by low concentrations of phenol. PMID- 21592660 TI - Predictive hydrogeochemical modelling of bauxite residue sand in field conditions. AB - The suitability of residue sand (the coarse fraction remaining from Bayer's process of bauxite refining) for constructing the surface cover of closed bauxite residue storage areas was investigated. Specifically, its properties as a medium for plant growth are of interest to ensure residue sand can support a sustainable ecosystem following site closure. The geochemical evolution of the residue sand under field conditions, its plant nutrient status and soil moisture retention were studied by integrated modelling of geochemical and hydrological processes. For the parameterization of mineral reactions, amounts and reaction kinetics of the mineral phases natron, calcite, tricalcium aluminate, sodalite, muscovite and analcime were derived from measured acid neutralization curves. The effective exchange capacity for ion adsorption was measured using three independent exchange methods. The geochemical model, which accounts for mineral reactions, cation exchange and activity corrected solution speciation, was formulated in the geochemical modelling framework PHREEQC, and partially validated in a saturated flow column experiment. For the integration of variably saturated flow with multi component solute transport in heterogeneous 2D domains, a coupling of PHREEQC with the multi-purpose finite-element solver COMSOL was established. The integrated hydrogeochemical model was applied to predict water availability and quality in a vertical flow lysimeter and a cover design for a storage facility using measured time series of rainfall and evaporation from southwest Western Australia. In both scenarios the sand was fertigated and gypsum-amended. Results show poor long-term retention of fertilizer ions and buffering of the pH around 10 for more than 5 y of leaching. It was concluded that fertigation, gypsum amendment and rainfall leaching alone were insufficient to render the geochemical conditions of residue sand suitable for optimal plant growth within the given timeframe. The surface cover simulation demonstrates that the soil moisture status in the residue sand can be ameliorated by an appropriate design of the cover layer with respect to thickness, slope and distance between lateral drains. PMID- 21592661 TI - Facilitation of phosphorus adsorption onto sediment by aquatic plant debris. AB - Aquatic plant debris in lakes or rivers may affect phosphorus flux in water sediment systems. In this study, either aquatic plant debris or typical plant components (cellulose or glucose), were added into a system of sediment (50 g) and overlying water (2L) with different initial SRP (soluble reactive phosphorus) concentrations to investigate the impact. After 18 days of treatment with 4 g of plant debris, the SRP in the overlying water for 0.5 and 2 mg L(-1) initial SRP tests at 30 degrees C decreased by 41 and 53%, respectively, compared to the treatments without plant debris. Cellulose and glucose treatments gave similar results as plant debris treatment. When the water-sediment system was sterilized, the cellulose- or glucose-facilitated decrease in SRP vanished. Additionally, in the non-sterilized system, the glucose treatment significantly increased both the microbial biomass carbon and the microbial biomass phosphorous in the sediment. Although total phosphorous in the sediment increased with glucose treatment, its water soluble and iron associated inorganic fractions, two labile phosphorus fractions, were clearly reduced. Our results suggest that the short-term retention of plant debris in water systems facilitates a decrease in overlying water SRP through microbe-mediated mechanisms of phosphorus adsorption and stabilization in sediment. PMID- 21592662 TI - Removal of dimethyl sulfide utilizing activated carbon fiber-supported photocatalyst in continuous-flow system. AB - The present study investigated the adsorptional photocatalytic decomposition (APD) efficiency of activated carbon fiber-supported TiO(2) (ACF/TiO(2)) in a continuous-flow reactor for the removal of dimethyl sulfide (DMS). The SEM analysis identified that the ACF/TiO(2) exhibited the same tridimensional shape as uncovered ACF and that a TiO(2) photocatalyst could be embedded in the surface of the ACF. In the absence of UV light, the time-series removal efficiencies by ACF and the ACF/TiO(2) units exhibited a similar pattern, which decreased gradually as it reached close to zero. However, the APD efficiency determined via the ACF/TiO(2) with UV light remained at nearly 60% during the remaining courses of the 13-h period, after decreasing from a maximum APD of 80%. The APD efficiencies depended upon the weights of the TiO(2) embedded into the ACFs, the UV sources, the relative humidity, and DMS input concentrations. During a long term (219-h) APD test, the APD efficiencies dropped from 80% to ca 60% within 1h after the initiation of the APD process and then fluctuated between 52% and 60%. No byproducts were measurable or observable in the effluent gas or on the ACF/TiO(2) surface. Consequently, the continuous-flow ACF/TiO(2) system could effectively be applied to control DMS without any significant functional deterioration. PMID- 21592663 TI - Enhanced remedial amendment delivery to subsurface using shear thinning fluid and aqueous foam. AB - A major issue with in situ subsurface remediation is the ability to achieve an even spatial distribution of remedial amendments to the contamination zones in an aquifer or vadose zone. Amendment delivery to the aquifer using shear thinning fluid and to the vadose zone using aqueous foam has the potential to enhance the distribution. 2-D saturated flow cell experiments were conducted to evaluate the enhanced fluid sweeping over heterogeneous system, improved contaminant removal, and extended amendment presence in low-permeability zones achieved by shear thinning fluid delivery. Unsaturated column and flow cell experiments were conducted to investigate the improvement on contaminant mobilization mitigation, amendment distribution, and lateral delivery implemented by foam delivery. It was demonstrated that the shear thinning fluid injection enhanced the fluid sweeping and increased the delivery of remedial amendment into low-perm zones. The presence of amendment distributed by the shear thinning fluid in the low permeability zones was increased. Foam delivery was shown to mitigate the mobilization of highly mobile contaminant from sediments. It also achieved more uniform amendment distribution in a heterogeneous unsaturated system, and demonstrated remarkable increasing in lateral distribution of the injected liquid compared to direct liquid injection. PMID- 21592664 TI - Comparison of morphology and photo-physiology with metal/metalloid contamination in Vallisneria neotropicalis. AB - The overarching goal of this in situ study was to investigate the integrated impact(s) that metal/metalloid contamination might have on the overall health and performance of the ecologically important aquatic macrophyte, Vallisneria neotropicalis. Morphological (i.e., shoot growth-based endpoints) and photo physiological (i.e., photosynthetic activity measured as chlorophyll a fluorescence and oxygen exchange) variables, along with aboveground tissue metal/metalloid concentrations, were measured in natural populations of V. neotropicalis that differed with respect to their anthropogenic pressure. With the exception of an overall negative effect on growth, our results suggest that there were no detrimental effects of low/moderate contamination of V. neotropicalis by trace elements (i.e., arsenic As and mercury Hg; 1.04-2.77 MUg g(-1) dry wt. and 3.76-15.18 ng g(-1) dry wt., respectively) on the photosynthetic physiological performance of this species. V. neotropicalis appears to tolerate low/moderate levels of trace element contamination with little impact on plant health and performance. PMID- 21592665 TI - The repellent effect of organic fatty acids on Culicoides midges as determined with suction light traps in South Africa. AB - The efficacy of a 15% (w/w) mixture of octanoic, nonanoic and decanoic acids in light mineral oil to repel Culicoides biting midges (Diptera; Ceratopogonidae) was determined in three replicates of a 4 * 4 Latin square design under South African field conditions. The fatty acids were applied to +/- 0.07 m(2) polyester meshes with a mesh size 2-3mm fitted to 220 V 8 W Onderstepoort downdraught light traps. To reduce the relatively strong attraction of the light trap, the black light tubes in the Onderstepoort trap were replaced with 8 W 23 cm white light tubes. The traps were operating overnight next to cattle. Two traps treated with the mixture of fatty acids collected 1.7 times fewer midges than two untreated traps. Although this mixture of fatty acids had shown a repellent effect against a number of blood-feeding insects this is the first indication that it also has a significant repellent effect against Culicoides species and especially Culicoides (Avaritia) imicola Kieffer when applied to polyester mesh. PMID- 21592666 TI - Skin lesions in sheep infested with fleas. PMID- 21592667 TI - An insect growth inhibitor--lufenuron--enhances albendazole activity against hydatid cyst. AB - The aim of this work was to evaluate the potential of lufenuron, a benzylphenylurea with ability to interfere with the formation of insect exoskeleton, as a therapeutic drug for larval echinococcosis (hydatid disease). For this purpose lufenuron, alone or in combination with albendazole, was administered to CD1 mice bearing Echinococcus granulosus hydatid cysts in the peritoneal cavity. Neither of the drugs alone was able to exert parasiticidal effects. However, in combination with albendazole, lufenuron reduced the growth of cysts (30-40% in cyst diameter respect to control, p<0.05). This effect was associated with ultrastructural alterations of the hydatid cyst wall and a reduction of the content of myo-inositol-hexakisphosphate, the major component of the electron dense granules of the laminated layer. Overall, this work provides evidence that lufenuron could represent a useful compound for the use in chemotherapy against larval echinococcosis, by enhancing albendazole parasiticidal activity. PMID- 21592668 TI - Larvicidal activity of two Algerian Verbenaceae essential oils against Culex pipiens. AB - The purpose of this study was to evaluate the bioactivity of essential oils extracted from the leaves of Verbena officinalis and Lantana camara L. for the control of Culex pipiens. Triplicate bioassays were performed with fourth larval instars of C. pipiens (n=25 per replicate) with solutions at 1, 5, 10, 50, 100 and 500 MUL/L of V. officinalis and L. camara L. extracts. Cumulative mortalities were determined 3, 6, 12 and 24h after treatment. Results showed cumulative mortalities, at three (3) hours to be 30.0 +/- 2.9% and 14.8 +/- 1.5% and achieve 43.3 +/- 1.9% and 44.4 +/- 3.1% after 24h exposure time, at 100mg/L of essential oil from L. camara and V. officinalis, respectively. PMID- 21592669 TI - Cryptic Leishmaniosis by Leishmania infantum, a feature of canines only? A study of natural infection in wild rabbits, humans and dogs in southeastern Spain. AB - An epidemiological study was carried out to investigate asymptomatic Leishmania infantum infection by PCR and ELISA in wild rabbits, humans and domestic dogs in southeastern Spain. Seroprevalence was 0% (0/36) in rabbits, 2% (13/657) in humans and 7% (14/208) in dogs. The prevalence of PCR-positives was 0.6% (1/162) in rabbits tested in a wide range of tissue samples, 2% (8/392) in humans analysed in blood samples and 10% (20/193) and 67% (29/43) in dogs analysed in blood and lymphoid tissue samples, respectively. Results suggest that wild rabbits have a very low risk of becoming chronically infected with L. infantum, and provide further evidence that cryptic L. infantum infection is widespread in the domestic dog population and is also present in a comparatively smaller proportion of healthy humans. The epidemiological and clinical implications of these findings are discussed. PMID- 21592670 TI - Pediatric sarcomas and related tumors of the head and neck. AB - Sarcomas of the head and neck region are a rare group of tumors in children and present challenges with regard to evaluation and treatment. Rhabdomyosarcomas are the most common sarcomas of the head and neck in children. Presence of metastases and complete surgical resectability continue to be the most relevant clinical prognostic factors in patients with sarcomas. However, many patients present with unresectable tumors; these require radiation therapy, which is associated with concerns about immediate and long-term side effects. New technologies, including proton beam therapy (PBT), appear very promising in terms of reducing acute and long-term toxic effects. A multi-disciplinary approach is required for best long term outcomes in children with head and neck sarcomas. PMID- 21592671 TI - Circulating tumor cells as pharmacodynamic biomarker in early clinical oncological trials. AB - Circulating tumor cells (CTCs) have received a lot of attention from both researchers and clinicians because of their prognostic value for progression-free and overall survival in selected tumor types. CTCs are readily available by single venipuncture, thereby posing little burden on the patient and allowing for repeated, sequential sampling during therapy. Nowadays, the sensitivity of several CTC detection and capture techniques allow for further characterization and analysis of specific targets of interest on the CTC itself. These techniques have given CTCs the potential to be used as a pharmacodynamic read-out in drug development. In this review, we explore the utility of CTCs as a pharmacodynamic biomarker in early clinical oncological trials. We present an overview of current literature on assays for CTCs as pharmacodynamic biomarker, their different targets of interest and their level of validation, followed by discussion of their limitations. PMID- 21592672 TI - Chemotherapy treatment for older women with metastatic breast cancer: what is the evidence? AB - While the over-representation of the elderly in the breast cancer population is projected to dramatically increase within the next two decades, data on chemotherapy for elderly patients with metastatic breast carcinoma (MBC) remain very limited. The aim of the present study is to investigate whether elderly patients included in clinical studies for MBC are representative of the population seen during usual clinical practice. Firstly, a review of the literature was performed identifying 39 publications about chemotherapy for MBC focusing on elderly patients and we examined patient characteristics in each of these publications. Comparison of the age distribution of patients included in these studies with that of a large cohort of consecutive MBC patients aged 65years who received chemotherapy in our institution over the last ten years (n=573) indicated that trials tend to include relatively younger patients. Furthermore, criteria to assess external validity of the results are seldom reported. Possible ways to improve the applicability of results such as increasing the minimum age for inclusion and the use of CGA are proposed. PMID- 21592673 TI - Targeted therapies for advanced non-small-cell lung cancer: current status and future implications. AB - Lung cancer remains the leading cause of malignancy-related mortality worldwide, with over one million cases diagnosed yearly. Non-small-cell lung cancer (NSCLC) accounts for >80% of all lung cancers. Because lung cancer is typically diagnosed at an advanced stage, chemotherapy (CT) is the mainstay of management. Conventional treatment of NSCLC has apparently reached a plateau of effectiveness in improving survival of patients, and treatment outcomes must still be considered disappointing. Hence, considerable efforts have been made in order to identify novel targeted agents that interfere with other dysregulated pathways in advanced NSCLC patients. In order to further improve the results of targeted therapy, we should not forget that lung cancer is a heterogeneous disease with multiple mutations, and it is unlikely that any single signaling pathway drives the oncogenic behaviour of all tumours. The relative failure of some targeted therapies may be a result of multilevel cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events. Thus, blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. We summarize the most promising research approaches to the treatment of NSCLC, with particular attention to drugs with multiple targets or combining targeted therapies. PMID- 21592674 TI - Desulfovibrio species are potentially important in regressive autism. AB - Autism is a complex disorder with no specific diagnostic test so the disease is defined by its characteristics including cognitive defects, social, communication and behavioral problems, repetitive behaviors, unusual sensitivity to stimuli such as noise, restricted interests, and self stimulation. The incidence of this disease has increased remarkably in recent years and was 110/10,000 children (~1%) in multiple areas of the US in 2007. The financial burden on families and communities is enormous. In terms of predisposing factors, heredity plays a role in some subjects, but it is clear that environmental factors are also important. Environmental toxins can affect the immune system adversely. Intestinal bacteria are recognized by a few investigators as potentially important and we have proposed that certain antimicrobial drugs may be a key factor in modifying the intestinal bacterial flora adversely, selecting out potentially harmful bacteria that are normally suppressed by an intact normal intestinal flora. We had felt that clostridia in the gut might be involved in autism because they are virulent organisms and spore-formers; spores would resist antibacterial agents so that when antibiotics were discontinued the spores would germinate and by toxin production or another mechanism lead to autism. However, a recent study of ours employing the powerful pyrosequencing technique on stools of subjects with regressive autism showed that Desulfovibrio was more common in autistic subjects than in controls. We subsequently confirmed this with pilot cultural and real time PCR studies and found siblings of autistic children had counts of Desulfovibrio that were intermediate, suggesting possible spread of the organism in the family environment. Desulfovibrio is an anaerobic bacillus that does not produce spores but is nevertheless resistant to aerobic and other adverse conditions by other mechanisms and is commonly resistant to certain antimicrobial agents (such as cephalosporins) often used to treat ear and other infections that are relatively common in childhood. This bacterium also produces important virulence factors and its physiology and metabolism position it uniquely to account for much of the pathophysiology seen in autism. If these results on Desulfovibrio are confirmed and extended in other studies, including treatment trials with appropriate agents and careful clinical and laboratory studies, this could lead to more reliable classification of autism, a diagnostic test and therapy for regressive autism, development of a vaccine for prevention and treatment of regressive autism, tailored probiotics/prebiotics, and important epidemiologic information. PMID- 21592675 TI - Water distribution and mobility in meat during the conversion of muscle to meat and ageing and the impacts on fresh meat quality attributes--a review. AB - This paper reviews current knowledge on the distribution and mobility of water in muscle (myowater) ante- and post mortem and factors affecting these in relation to fresh meat quality parameters; water-holding capacity (WHC), tenderness and juiciness. NMR transverse relaxometry (T(2)) using bench-top Low-Field Nuclear Magnetic Resonance (LF-NMR) has characterised myowater distribution and mobility as well as structural features in meat which directly affect WHC. The current literature demonstrates that WHC is correlated to the water located outside the myofibrillar network (extra-myofibrillar). This review identifies the critical stages which affect the translocation of water into the extra-myofibrillar space and thus the potential for decreased WHC during proteolysis (the conversion of muscle to meat). This review discusses how the intrinsic properties of the water held within the meat could contribute to juiciness and tenderness. Tenderness has been shown to correlate to T(2), however breed and species differences made it difficult to draw firm conclusions. Further understanding of the inherent water properties of fresh meat and the factors affecting water distribution and mobility using NMR technologies will increase the understanding of WHC and tenderisation of fresh meat. PMID- 21592676 TI - Genotypic effects of the Texel Muscling QTL (TM-QTL) on meat quality in purebred Texel lambs. AB - Texel Muscling QTL (TM-QTL) increases loin muscling in lambs inheriting it from their sire only. This study investigated TM-QTL effects on meat quality in 209 Texel lambs that were CT-scanned then slaughtered at 20weeks (carcasses aged for ~1week). Loin meat quality traits included: CT-measured muscle density (predicting intramuscular fat); mechanical tenderness using Volodkevich-type jaws or MIRINZ tenderometer; intramuscular fat; sensory eating quality (sub-sample of 40 lambs). Volodkevich tenderness was also measured in the leg (Vastis lateralis). TM-QTL genotypes were determined, giving 40 non-carriers (+/+), 70 heterozygotes-53 inheriting TM-QTL from the sire (TM/+) and 17 from the dam (+/TM), 34 homozygote TM-QTL lambs (TM/TM) and 65 uncertain. Multiple regression identified no genotype effects on meat quality. For MIRINZ-measured loin tenderness only, contrasts revealed a significant additive effect of TM-QTL (1.27kgF difference between homozygotes). However, the taste panel identified no significant differences between +/+ and TM/TM lambs. Results show little evidence of TM-QTL affecting meat quality. PMID- 21592677 TI - Adenine nucleotide concentrations and glycolytic enzyme activities in longissimus muscle samples of different pig genotypes collected before and after slaughter. AB - Longissimus muscle samples from the pig genotypes Duroc (Du), Pietrain (MHS homozygote negative (PiNN), positive (PiPP)) and a Duroc-Pietrain crossbreed (DuPi) were analyzed. The PiPP samples showed a faster pH drop and higher electrical conductivity, drip loss and lightness values. Before slaughter the concentrations of the adenine nucleotides were comparable between the genotypes, but 40 min after slaughter (p.m.) the ATP concentrations decreased and IMP increased, to a higher extent in the PiPP pigs. The nucleotide values of the 12 h p.m. samples were again comparable. Activities of glycogen phosporylase (GP), phosphofructokinase (PFK) and lactate dehydrogenase (LDH) were nearly similar before slaughter. Forty minutes after slaughter the LDH activities increased in all pigs and the PFK activities in all genotypes but not in the PiPP. GP results were rather inconsistent indicating an earlier activation of this enzyme. The study showed that the reduced meat quality in the PiPP pigs is accompanied with rapid ATP degradation and accelerated enzyme activation. PMID- 21592678 TI - Chemo-IMRT of oropharyngeal cancer aiming to reduce dysphagia: swallowing organs late complication probabilities and dosimetric correlates. AB - PURPOSE: Assess dosimetric correlates of long-term dysphagia after chemo intensity-modulated radiotherapy (IMRT) of oropharyngeal cancer (OPC) sparing parts of the swallowing organs. PATIENTS AND METHODS: Prospective longitudinal study: weekly chemotherapy concurrent with IMRT for Stages III/IV OPC, aiming to reduce dysphagia by sparing noninvolved parts of swallowing-related organs: pharyngeal constrictors (PC), glottic and supraglottic larynx (GSL), and esophagus, as well as oral cavity and major salivary glands. Dysphagia outcomes included patient-reported Swallowing and Eating Domain scores, Observer-based (CTCAEv.2) dysphagia, and videofluoroscopy (VF), before and periodically after therapy through 2 years. Relationships between dosimetric factors and worsening (from baseline) of dysphagia through 2 years were assessed by linear mixed effects model. RESULTS: Seventy-three patients participated. Observer-based dysphagia was not modeled because at >6 months there were only four Grade >=2 cases (one of whom was feeding-tube dependent). PC, GSL, and esophagus mean doses, as well as their partial volume doses (V(D)s), were each significantly correlated with all dysphagia outcomes. However, the V(D)s for each organ intercorrelated and also highly correlated with the mean doses, leaving only mean doses significant. Mean doses to each of the parts of the PCs (superior, middle, and inferior) were also significantly correlated with all dysphagia measures, with superior PCs demonstrating highest correlations. For VF-based strictures, most significant predictor was esophageal mean doses (48+/-17 Gy in patients with, vs 27+/-12 in patients without strictures, p = 0.004). Normal tissue complication probabilities (NTCPs) increased moderately with mean doses without any threshold. For increased VF-based aspirations or worsened VF summary scores, toxic doses (TDs)(50) and TD(25) were 63 Gy and 56 Gy for PC, and 56 Gy and 39 Gy for GSL, respectively. For both PC and GSL, patient-reported swallowing TDs were substantially higher than VF-based TDs. CONCLUSIONS: Swallowing organs mean doses correlated significantly with long-term worsening of swallowing. Different methods assessing dysphagia resulted in different NTCPs, and none demonstrated a threshold. PMID- 21592679 TI - High-grade glioma relationship to the neural stem cell compartment: a retrospective review of 104 cases. AB - PURPOSE: To assess the incidence of involvement of the neural stem cell (NSC) compartment by high-grade astrocytomas in a series of adult patients. METHODS AND MATERIALS: One hundred four initial diagnostic cranial magnetic resonance imaging series were reviewed. For each series, the gross tumor volume (GTV; enhancing tumor on T(1)), edema (hyperintensity on T(2) FLAIR), and the NSC compartment (hippocampal formation and lateral ventricle plus a 5-mm expansion) were identified. Involvement of NSC by GTV and edema was assessed. For tumors not involving NSC, we measured distances from NSC to GTV and edema. Maximum diameters of GTV were measured for each case. Subset analysis was performed for GTV of <= 2 cm and <= 3 cm in maximum diameter to assess the incidence of involvement of NSC by this group of smaller tumors. For 10 representative tumors, minimum distances from GTV center to NSC were calculated. RESULTS: A total of 103/104 (99.0%) tumors, regardless of GTV maximum diameter, demonstrated involvement of NSC. A total of 101/104 (97.1%) tumors had NSC involvement by GTV, and 2/104 (1.9%) patients showed edema only. For GTV not involving NSC, the mean distance from NSC to GTV was 0.8 cm (range, 0.5--1.4 cm). The mean shortest distance from the center of GTV to NSC was 1.5 cm (range, 0.9--2.6 cm). Involvement of NSC by GTV was 90.9% (10/11 tumors) for GTV of <= 2 cm and 95.7% (22/23 tumors) for GTV of <= 3 cm. CONCLUSIONS: Our results support the hypothesis that the NSC compartment represents the putative site of origin for these tumors. NSC involvement does not appear to represent a volumetric phenomenon. PMID- 21592681 TI - Poor response to sertraline in methamphetamine dependence is associated with sustained craving for methamphetamine. AB - BACKGROUND: Depression is common among individuals with methamphetamine (MA) use disorders. As agents that enhance serotonergic function are frequently used to treat depression, one might predict that they would be useful medications for MA dependence. However, clinical trials of serotonergic agents for MA addiction have been unsuccessful. OBJECTIVE: To identify factors that distinguish MA-dependent research participants who increased MA self-administration while receiving treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline from other groups of participants. METHOD: Using a dataset from a 12-week randomized, placebo-controlled trial of sertraline (100mg daily) for MA addiction, we identified participants who had completed at least 8 weeks of the trial (n=61 sertraline, n=68 placebo). We compared the proportions of MA-positive urine tests for weeks 8-12 of the trial for these subjects to their pre-randomization baseline, and identified those subjects who increased MA use during treatment. Using classification trees, we then assessed all data collected during the study to identify factors associated with increasing MA use during treatment with sertraline, compared to placebo. RESULTS: More subjects in the sertraline condition increased MA use during treatment (n=13) than in the placebo condition (n=5; p=0.03). Classification trees identified multiple factors from both pre treatment and in-treatment data that were associated with increased MA use during treatment. Only elevated in-treatment craving for MA specifically characterized subjects in the sertraline group who increased their MA use. CONCLUSIONS: Some MA abusing individuals treated with SSRIs have sustained craving with an increased propensity to relapse during treatment despite psychosocial treatment interventions. PMID- 21592682 TI - Survival of a pathogenic Leptospira serovar in response to combined in vitro pH and temperature stresses. AB - Leptospira interrogans is a zoonotic pathogen hosted commensally by many mammalian species. On the Western Pacific island of American Samoa a seroprevalence survey conducted in 2004 indicated that 17% of subjects tested had been exposed to several Leptospira serovars, including L. interogans icterohaemorrhagiae. Resource management agencies promoted improved animal waste management practices, including composting, to reduce the risk of water contamination and human exposure from small pig husbandry facilities. This study simulated temperature and pH conditions expected in composting. We subjected L. interrogans serogroup icterohaemorrhagiae serovar Copenhageni strain M-20 to temperatures (25-50 degrees C) and pHs (5.2-7.9) for varying durations of exposure (4-96h) to determine survival, indicated by culturing. Temperatures >=45 degrees C were lethal at the shortest duration of exposure (4h). The effects of temperature were enhanced by pH for temperatures <45 degrees C. The results are summarized in a logistic model of the proportions (p(est)) of leptospires surviving the combined stresses of pH and temperature (p(est)=0.071e((1.091 pH 0.183 T( degrees C)))/1+0.071e((1.091 pH-0.183 T( degrees C)))). A graph of this function, with results of other studies carried out with serovar icterohaemorrhagiae, indicates that composting has the potential to kill leptospires, provided that all wastes are fully exposed to temperatures >=45 degrees C for at least 4h. PMID- 21592680 TI - Reduced cortical gray matter volume in male adolescents with substance and conduct problems. AB - Boys with serious conduct and substance problems (Antisocial Substance Dependence (ASD)) repeatedly make impulsive and risky decisions in spite of possible negative consequences. Because prefrontal cortex (PFC) is involved in planning behavior in accord with prior rewards and punishments, structural abnormalities in PFC could contribute to a person's propensity to make risky decisions. METHODS: We acquired high-resolution structural images of 25 male ASD patients (ages 14-18 years) and 19 controls of similar ages using a 3T MR system. We conducted whole-brain voxel-based morphometric analysis (p<0.05, corrected for multiple comparisons at whole-brain cluster-level) using Statistical Parametric Mapping version-5 and tested group differences in regional gray matter (GM) volume with analyses of covariance, adjusting for total GM volume, age, and IQ; we further adjusted between-group analyses for ADHD and depression. As secondary analyses, we tested for negative associations between GM volume and impulsivity within groups and separately, GM volume and symptom severity within patients using whole-brain regression analyses. RESULTS: ASD boys had significantly lower GM volume than controls in left dorsolateral PFC (DLPFC), right lingual gyrus and bilateral cerebellum, and significantly higher GM volume in right precuneus. Left DLPFC GM volume showed negative association with impulsivity within controls and negative association with substance dependence severity within patients. CONCLUSIONS: ASD boys show reduced GM volumes in several regions including DLPFC, a region highly relevant to impulsivity, disinhibition, and decision-making, and cerebellum, a region important for behavioral regulation, while they showed increased GM in precuneus, a region associated with self-referential and self centered thinking. PMID- 21592683 TI - Reassortment among bovine, porcine and human rotavirus strains results in G8P[7] and G6P[7] strains isolated from cattle in South Korea. AB - Group A rotaviruses (GARVs) cause severe acute gastroenteritis in children and young animals. Although zoonotic infections with bovine-like G6 and G8 GARVs have been reported in many countries, there is little evidence for reassortment between bovine GARVs and GARVs from heterologous species. The finding of bovine GARVs with the G6 and G8 genotypes in combination with the typical porcine P[7] prompted us to characterize all 11 genes of 30 bovine GARVs isolated from clinically infected calves. By the comparison of the full-length ORF of VP7 and NSP1-5, and the partial VP1-4 and VP6 nucleotide sequences between the 30 Korean and other known strains, three different genome constellations were found. Twenty seven strains showed the G8-P[7]-I5-R1-C1-M2-A1-N1-T1-E1-H1 genotypes, a single strain possessed the G6-P[7]-I2-R2-C1-M2-A1-N2-T1-E2-H1 genotype constellation and 2 strains the G6-P[7]-I2-R2-C2-M2-A3-N2-T6-E2-H3 genotype constellation. The complete genome of a single reference strains for each of these three genotype constellations (KJ25, KJ9-1 and KJ19-2) was determined and analyzed. A detailed phylogenetic analysis revealed a complicated picture, with several reassortments among bovine-like, porcine-like and human-like GARV strains, resulting in several different reassortant strains successfully infecting cattle. PMID- 21592684 TI - Relevance in pathogenesis research. AB - Research on pathogenesis of bacterial diseases involves exploration of the intricate and complex interactions among pathogen, host, and environment. Host parasite-environment interactions that were relatively simple were the first to be understood. They include intoxications in which ingestion of a powerful bacterial toxin was sufficient to cause disease. In more complex cases bacteria occupy a variety of niches in the host and attack at an opportune time. Some bacterial pathogens have a brief encounter with the host; others are long-term guests. This variety of relationships involves a wide range of strategies for survival and transmission of bacterial pathogens. Molecular genetics, genomics and proteomics have facilitated understanding of the pathogens and hosts. Massive information often results from such studies and determining the relevance of the data is frequently a challenge. In vitro studies often attempt to simulate one or two critical aspects of the environment, such as temperature, pH, and iron concentration, that may provide clues as to what goes on in the host. These studies sometimes identify critical bacterial virulence factors but regulation of bacterial virulence and host response is complex and often not well understood. Pathogenesis is a process of continuous change in which timing and degree of gene expression are critical and are highly regulated by the environment. It is impossible to get the full picture without the use of natural or experimental infections, although experimental infections involve ethical and economic considerations which may act as a deterrent. PMID- 21592685 TI - Identification of candidate host proteins that interact with LipL32, the major outer membrane protein of pathogenic Leptospira, by random phage display peptide library. AB - Leptospirosis is a worldwide zoonotic disease caused by pathogenic Leptospira spp. Rodent species are the major reservoir hosts that can excrete leptospires in their urine leading to environmental contamination. After gaining entry into the host via skin breaks and mucosa, leptospires disseminate through the bloodstream to target organs causing a wide range of disease manifestations in susceptible mammalian hosts. The crucial step of infection requires host-pathogen interactions. LipL32, the major outer membrane protein (OMP) of pathogenic Leptospira, is conserved among pathogenic leptospires, immunogenic, and expressed in target organs during acute infection in animal models. Therefore, it may play a key role in host-microbe interactions. To identify host proteins that interact with LipL32, phage display technology was employed in our study. Recombinant LipL32 was used as a target molecule for biopanning with a random heptapeptide phage library to enrich for phages expressing peptides with high affinity to LipL32. After three rounds of panning, 44 plaques of eluted phages were subjected to pyrosequencing. Six different peptide sequences were identified and used to search for matching proteins in the database. Putative proteins with potential binding to LipL32 are proteins known to be expressed on the surface of target cells of pathogenic Leptospira such as chloride channel accessory 2, glycoprotein VI, scavenger receptor expressed by endothelial cell isoform I (SREC-I), coronin 2A, laminin alpha 5, collagen XX, and prostaglandin receptor EP1. However, interactions of LipL32 with these host proteins and their role in the pathogenesis of leptospirosis requires experimental confirmation. PMID- 21592686 TI - Novel gastric helicobacters and oral campylobacters are present in captive and wild cetaceans. AB - The mammalian gastric and oral mucosa may be colonized by mixed Helicobacter and Campylobacter species, respectively, in individual animals. To better characterize the presence and distribution of Helicobacter and Campylobacter among marine mammals, we used PCR and 16S rDNA sequence analysis to examine gastric and oral samples from ten dolphins (Tursiops gephyreus), one killer whale (Orcinus orca), one false killer whale (Pseudorca crassidens), and three wild La Plata river dolphins (Pontoporia blainvillei). Helicobacter spp. DNA was widely distributed in gastric and oral samples from both captive and wild cetaceans. Phylogenetic analysis demonstrated two Helicobacter sequence clusters, one closely related to H. cetorum, a species isolated from dolphins and whales in North America. The second related cluster was to sequences obtained from dolphins in Australia and to gastric non-H. pylori helicobacters, and may represent a novel taxonomic group. Dental plaque sequences from four dolphins formed a third cluster within the Campylobacter genus that likely represents a novel species isolated from marine mammals. Identification of identical Helicobacter spp. DNA sequences from dental plaque, saliva and gastric fluids from the same hosts, suggests that the oral cavity may be involved in transmission. These results demonstrate that Helicobacter and Campylobacter species are commonly distributed in marine mammals, and identify taxonomic clusters that may represent novel species. PMID- 21592687 TI - Sonographic markers of aneuploidies at 6-10 weeks of gestation. AB - OBJECTIVES: To determine if sonographic features of live embryos at 6-10 weeks' gestation are altered in aneuploidies. METHODS: Embryonic crown rump length (CRL), embryonic heart rate, gestational sac diameter (GSD) and yolk sac diameter (YSD) were measured by transvaginal sonography in 5603 live embryos from singleton pregnancies at 6-10 weeks' gestation. The measurements were expressed as differences from the expected normal mean for CRL (delta values) and median delta values in the aneuploid cases were compared to the euploid group. RESULTS: 5393 pregnancies resulted in the live birth of phenotypically normal neonates and these cases constituted the euploid group. In 55 cases there was subsequent prenatal diagnosis of aneuploidies (trisomy 21, n=28; trisomy 18, n=10; trisomy 13, n=10; triploidy, n=4; Turner syndrome, n=3). The median and interquartile range (IQR) of delta embryonic heart rate in trisomy 18 was -19.44 (-23.77 to 7.20)bpm and in trisomy 13 it was 11.12 (7.25 to 20.39)bpm, which were significantly lower and higher, respectively, than in euploid embryos (median 0.05, IQR -6.18 to 6.21bpm). The median delta YSD in trisomy 21 was higher than in euploid fetuses (median 0.56, IQR 0.23 to 0.79 and median -0.17, IQR -3.11 to 2.82 mm). There were no other significant differences in measurements between the groups. CONCLUSION: At 6-10 weeks' gestation there are sonographically detectable differences between euploid and trisomic embryos. PMID- 21592688 TI - Analysis of the influence of pasteurization, freezing/thawing, and offer processes on human milk's macronutrient concentrations. AB - INTRODUCTION: The macronutrient concentrations of human milk could be influenced by the various processes used in human milk bank. AIMS: To determine the effect of various process (Holder pasteurization, freezing and thawing and feeding method) on the macronutrient concentration of human milk. METHODS: The samples of donated fresh human milk were studied before and after each process (Holder pasteurization, freezing and thawing and feeding method) until their delivery to newborn infants. Fifty-seven raw human milk samples were analyzed in the first step (pasteurization) and 228 in the offer step. Repeated measurements of protein, fat and lactose amounts were made in samples of human milk using an Infrared analyzer. The influence of repeated processes on the mean concentration of macronutrients in donor human milk was analyzed by repeated measurements ANOVA, using R statistical package. RESULTS: The most variable macronutrient concentration in the analyzed samples was fat (reduction of 59%). There was a significant reduction of fat and protein mean concentrations following pasteurization (5.5 and 3.9%, respectively). The speed at which the milk was thawed didn't cause a significant variation in the macronutrients concentrations. However, the continuous infusion delivery significantly reduced the fat concentration. When the influence of repeated processes was analyzed, the fat and protein concentrations varied significantly (reduction of 56.6% and 10.1% respectively) (P<0.05). Lactose didn't suffer significant reductions in all steps. CONCLUSION: The repeated processes that donor human milk is submitted before delivery to newborn infants cause a reduction in the fat and protein concentration. The magnitude of this decrease is higher on the fat concentration and it needs to be considered when this processed milk is used to feed preterm infants. PMID- 21592689 TI - Short-term and long-term outcomes of 214 cases of non-immune hydrops fetalis. AB - Despite advances in diagnosis and management, non-immune hydrops fetalis (NIHF) has a high mortality rate. Perinatal survival depends on the underlying disorder and the gestational age at diagnosis. As prognostic information is limited, this study acquired data regarding the neurological development of perinatal survivors. We performed a retrospective chart review of 214 cases in which NIHF was diagnosed antenatally. We recorded maternal demographic characteristics and interventions and their effectiveness, as well as the short-term outcome (survival) and long-term outcome including developmental quotients. Among the affected fetuses, 91 (42.5%) survived the perinatal period. Fetuses with chylothorax, chyloascites, or meconium peritonitis, and those in whom therapy was effective, had high survival rates irrespective of the type of intrauterine intervention. The subsequent intact survival rate was 28/56 (50.0%), with intact defined as ratio of the number of infants with normal development to the number of all infants followed. In contrast to the perinatal survival rate, the intact survival rate decreased as gestational age at diagnosis advanced. These findings suggest that the long-term intact survival rate depends on the underlying cause of NIHF. Additionally, while survival was improved with intensive perinatal care during the perinatal period, aggressive perinatal intervention was not a prognostic factor for neurological outcome. PMID- 21592690 TI - Removal of virus from boar semen spiked with porcine circovirus type 2. AB - The virus porcine circovirus type 2 (PCV2) is associated with different disease entities, including reproductive failure. The objective of this study was to investigate the use of a semen processing technique for the elimination of infectious PCV2 in semen. PCV2 was chosen as a model virus because of its small size, high resistance to inactivation and as a known risk factor for boar semen contamination. Aliquots of ejaculates were spiked with PCV2 and processed by a double processing technique, consisting of Single Layer Centrifugation on AndrocollTM-P followed by a "swim-up" procedure. Samples were collected from the resulting fractions during the selection process and analyzed for the presence of infectious PCV2. Virus titres were determined by performing a 50% tissue culture infective dose assay (TCID(50)) by end point dilution and with the use of an indirect peroxidise monolayer assay technique. With an initial infectious virus titre of 3.25-3.82 (TCID(50))/50MUL the two-step sperm selection method eliminated 2.92+/-0.23 logs of infectious PCV2, corresponding to more than 99% reduction. Sperm quality was not affected by the selection procedure. PMID- 21592691 TI - Interrelationship of serum testosterone, dominance and ovarian cyclicity status in female African elephants. AB - The African elephant population in North American zoos is not self-sustaining, in part due to the prevalence of ovarian acyclicity. While little is known about the cause of this condition, earlier research has shown that females without cyclic corpus luteum (CL) function rank higher in the dominance hierarchy than females with cyclic CL function. The goal of this study was to measure longitudinal serum testosterone concentrations in captive female African elephants to determine if there is a relationship among serum testosterone concentrations, social dominance rank and ovarian cyclicity status. Weekly blood samples from 49 female African elephants (24 having and 25 not having cyclic CL function at 22 facilities) were collected over a 12-month period and analyzed for serum testosterone using an enzymeimmunoassay. A progesterone radioimmunoassay was used to quantify serum progestagen concentrations and categorize ovarian cyclicity status. The dominance hierarchy of individual elephants within each herd was assessed by a written temperament survey, which identified 19 dominant, 15 middle and 15 subordinate females. No clear patterns of serum testosterone secretion were observed in females with and without cyclic CL function. Furthermore, no significant relationships were found among serum testosterone concentrations, dominance rank, and ovarian cyclicity status. These data suggest that increased circulating testosterone concentrations are not associated with greater rates of ovarian acyclicity or dominance status in captive female African elephants. PMID- 21592692 TI - Economic costs of adult obesity: a review of recent European studies with a focus on subgroup-specific costs. AB - This review aims to provide an update on economic costs of obesity in Europe with a focus on costs in subgroups defined by relevant third variables such as sex, age, socio-economic status, and morbidity factors. A structured search using MeSH vocabulary and Title/Abstract-searches was conducted in PubMed for 2007 to 2010. All cost categories except intangible costs were considered. N = 19 primary cost of illness studies on adults from Europe which had included at least one cost category as an outcome were identified. Nine studies reported costs in specific subgroups. Two studies (both from Germany) took a societal perspective, with total (direct and indirect) costs of obesity accounting for 0.47-0.61% of gross domestic product. Excess per-capita direct costs ranged from ? 117 to ? 1873, depending on cost categories and comparison group (normal weight, non-obese). One study estimated lower lifetime health care costs given obesity. Regarding subgroups, higher costs of obesity were generally found in men, groups with higher socio-economic status (regarding costs of severe obesity), and groups with co-existing abdominal obesity, diabetes (especially type 1), elevated HbA1c (among patients with type 2 diabetes), and physical co-morbidities given BMI >= 27 (compared to a "BMI >= 30 only"-group). In conclusion, while substantial obesity costs were found in most studies, subgroup analyses and lifetime perspectives call for a differentiated approach to the costs of obesity. Findings such as the higher health care costs in severely obese groups with higher socio economic status (despite fewer co-morbidities), and lower lifetime long-term care costs in obese groups (due to reduced life expectancy), may generate hypotheses both on under- vs. overuse of services, and target groups for interventions. PMID- 21592693 TI - Preventing cold-related morbidity and mortality in a changing climate. AB - Winter weather patterns are anticipated to become more variable with increasing average global temperatures. Research shows that excess morbidity and mortality occurs during cold weather periods. We critically reviewed evidence relating temperature variability, health outcomes, and adaptation strategies to cold weather. Health outcomes included cardiovascular-, respiratory-, cerebrovascular , and all-cause morbidity and mortality. Individual and contextual risk factors were assessed to highlight associations between individual- and neighborhood level characteristics that contribute to a person's vulnerability to variability in cold weather events. Epidemiologic studies indicate that the populations most vulnerable to variations in cold winter weather are the elderly, rural and, generally, populations living in moderate winter climates. Fortunately, cold related morbidity and mortality are preventable and strategies exist for protecting populations from these adverse health outcomes. We present a range of adaptation strategies that can be implemented at the individual, building, and neighborhood level to protect vulnerable populations from cold-related morbidity and mortality. The existing research justifies the need for increased outreach to individuals and communities for education on protective adaptations in cold weather. We propose that future climate change adaptation research couple building energy and thermal comfort models with epidemiological data to evaluate and quantify the impacts of adaptation strategies. PMID- 21592694 TI - Sex assessment from carpals bones: discriminant function analysis in a contemporary Mexican sample. AB - Sex assessment is one of the first essential steps in human identification, in both medico-legal cases and bio-archaeological contexts. Fragmentary human remains compromised by different types of burial or physical insults may frustrate the use of the traditional sex estimation methods, such as the analysis of the skull and pelvis. Currently, the application of discriminant functions to sex unidentified skeletal remains is steadily increasing. However, several studies have demonstrated that, due to variation in size and patterns of sexual dimorphism, discriminant functions are population-specific. In this study, in order to improve sex assessment from skeletal remains and to establish population specific discriminant functions, the diagnostic values of the carpal bones were considered. A sample of 136 individuals (78 males, 58 females) of known sex and age was analyzed. They belong to a contemporary identified collection from the Laboratory of Physical Anthropology, Faculty of Medicine, UNAM (Universidad Nacional Autonoma de Mexico, Mexico City). The age of the individuals ranged between 25 and 85 years. Between four and nine measurements of each carpal bone were taken. Independent t-tests confirm that all carpals are sexually dimorphic. Univariate measurements produce accuracy levels that range from 61.8% to 90.8%. Classification accuracies ranged between 81.3% and 92.3% in the multivariate stepwise discriminant analysis. In addition, intra- and inter-observer error tests were performed. These indicated that replication of measurements was satisfactory for the same observer over time and between observers. These results suggest that carpal bones can be used for assessing sex in both forensic and bio archaeological identification procedures and that bone dimensions are population specific. PMID- 21592695 TI - "Vaginal" bleeding in prepubertal age: a rare scaring riddle, a case of the urethral prolapse and review of the literature. AB - The entities responsible for isolated vaginal bleeding are a broad spectrum of diseases. Vaginal bleeding in a prepubertal child is always treated as an alarming symptom both by parents and professionals. Most often, one of the first hypotheses is that a sexual abuse may be occurred and the clinical work up is oriented to explore it and eventually confirm or substantiante another diagnosis. Among the possible differential diagnosis urethral prolapse has to be considered. We report the case of a 6 years-old Caucasian girl referred to our Service for a mild vaginal bleeding and with the suspicion of sexual abuse, excluded after the confirmation of the presence of urethral prolapse. The clinical picture and workup are described and compared with a review of the international literature on the issue. PMID- 21592696 TI - Comparative dental radiographic identification using flat panel CT. AB - A skull without lower jaw was found and brought in for identification. It was suspected to be that of a man reported missing five years ago. An undated antemortal dental chart and two dental films of the 1st and 2nd dental quadrants, both taken about 4 years before the man went missing, were available for comparison. The method of choice in solving the identity question was comparative dental radiography. Despite numerous attempts, it was not possible to obtain radiographs of the upper jaw that duplicated the X-ray beam angulation of the antemortem dental films. The skull was thus scanned with a multislice computed tomography (MSCT) scanner, and virtual radiographs with the desired angulation were generated from the data with the maximum intensity projection (MIP) technique. The resulting virtual radiographs could, however, not be used for superimposition with the antemortem radiographs because of their poor resolution and the occurrence of artifacts caused by metallic dental fillings. The upper jaw was therefore scanned again, this time with a high resolution eLU-CT (eXplore Locus Ultra flat panel CT). The resulting eLU-CT datasets were visualized with the MIP technique and yielded virtual radiographs that could be compared with the antemortem radiographs. Positive identification could be assumed with near certainty after dental features could be matched in the superimposition of antemortem and postmortem radiographs. In the presented case, eLU-CT was used for the first time for a comparative dental radiographic identification. PMID- 21592697 TI - Are patients with severe epistaxis caused by hereditary hemorrhagic telangiectasia satisfied with nostril closure surgery? AB - OBJECTIVE: Recurrent epistaxis as a manifestation of hereditary hemorrhagic telangiectasia (HHT) is usually difficult to control. Although no treatment is regarded to be completely efficacious, nostril closure is considered a modality of choice for the most severe cases. The cessation of airflow resulting from this procedure can stop bleeding by minimizing risk factors. However, loss of nasal functions is a disadvantage of nostril closure. We conducted a questionnaire survey of patients who underwent nostril closure surgery, regarding the effects and disadvantages of the operation. METHODS: Seven patients were asked questions on issues including frequency and severity of epistaxis pre- and post operatively, satisfaction of treatment, and impairment in daily living activities. RESULTS: Most patients reported complete cessation of bleeding. Some still had bleeding, but the frequency and severity were far lower. No transfusions were required in any of the cases. Patients reported some disadvantages, for example, respiratory, olfactory, and phonatory issues. Six out of seven patients were very satisfied with the outcome of surgery. CONCLUSION: Nostril closure surgery can remarkably reduce frequency and volume of epistaxis. Our survey indicated that satisfactory results were achieved. However, difficulties caused by complete nasal obstruction varied. Thus, individualized coping strategies are required. PMID- 21592698 TI - Patterns of intracranial hemorrhage in petrous temporal bone fracture. AB - OBJECTIVE: To study the relationship pattern of intracranial hemorrhage in cases of traumatic petrous temporal bone fracture. METHODS: All head injury cases admitted to the Emergency Department, Hospital Tengku Ampuan Afzan, Pahang, Malaysia in 2008 were assessed. Computerized tomography (CT) scan of the skull base was performed in indicated cases. Patients with a petrous temporal bone fracture were included in the study. Subsequent magnetic resonance imaging (MRI) was performed. Intracranial hemorrhages incidence, management and outcome were recorded. RESULTS: From 1421 cases of head injury, 49(3.4%) patients were diagnosed to have a petrous bone fracture from the CT scan. Only 46 cases underwent MRI scan and were included in this study. Of these, 36(78.3%) cases had associated intracranial hemorrhages (p<0.01). Intracranial hemorrhage was associated with the longitudinal types of petrous fracture (p<0.05). Subdural hematoma was the most prevalent type of bleed (55.6%). There was no association between the types of intracranial bleeding (extradural, subdural, subarachnoid or intracerebral hemorrhage) and the types of petrous bone fracture (longitudinal, oblique or transverse). The mortality rate was 17.4%. The mortality cases were associated with the presence of other skull bone fractures (p<0.05). CONCLUSIONS: Petrous fracture is significantly associated with intracranial hemorrhage. There was no association between the types of petrous fracture and the types of intracranial hemorrhages in our material. PMID- 21592699 TI - Successful treatment of rhino-orbital mucormycosis by a new combination therapy with liposomal amphotericin B and micafungin. AB - Mucormycosis is a rapidly progressive fungal infection that usually occurs in patients with diabetes mellitus or in immunocompromised patients. Sinus involvement is the most common clinical presentation and the rates of mortality increase with the orbital extension. The treatment of mucormycosis includes aggressive surgical debridement and systemic antifungal therapy. Early diagnosis and prompt initiation of effective antifungal drugs are essential for successful outcome. However, the role of orbital exenteration for the case of orbital involvement remains controversial, and the drugs effective against mucormycosis are limited. We present a successfully treated case with rhino-orbital mucormycosis caused by Rhizopus oryzae in a diabetic and dialysis patient. The early diagnosis, surgical debridement and a new combination therapy with liposomal amphotericin B and micafungin were effective. This new combination antifungal therapy will be useful for the treatment of mucormycosis. PMID- 21592700 TI - Sentinel node biopsy for oral and laryngopharyngeal squamous cell carcinoma: a retrospective study of 177 patients in Japan. AB - OBJECTIVE: Sentinel node (SN) biopsy in the head and neck region has not been widely used in Japan, except at a few facilities. However, almost all these facilities perform preoperative localization and intraoperative diagnosis by frozen section analysis of SN to select patients who must undergo neck dissection in a one-stage procedure. The objective of this study was to determine the actual status of SN biopsy at those facilities in Japan that have actively conducted this procedure, and to elucidate the usefulness and drawbacks of this technique in head and neck cancer. METHODS: We retrospectively reviewed 177 patients who had undergone SN biopsy at 7 facilities. The underlying pathology was laryngeal or hypopharyngeal cancer in 20 patients from one hospital, while the remaining 157 patients had oral cancer. Preoperative localization of SN was determined using conventional lymphoscintigraphy with or without single photon emission computed tomography with CT (SPECT-CT). Intraoperative localization and diagnosis of SN were performed by gamma probe and frozen section analysis. RESULTS: Conventional lymphoscintigraphy detected a mean of 2.6 SNs per patient in 137 patients with oral cancer, compared to 2.7 in 71 patients using SPECT-CT and 2.9 in 154 patients using the gamma probe. No significant differences were apparent between techniques. Forty of the 520 SNs (7.7%; 33 in oral cancer and 7 in laryngeal or hypopharyngeal cancer) were pathologically positive in the final diagnosis. Of these, 3 were not processed for frozen sectioning and were diagnosed only with hematoxylin and eosin staining. Among the others, 32 (86.5%) were diagnosed intraoperatively as showing metastasis. In terms of the false negative rate, 144 patients were determined by SN biopsy to have no positive SNs. Of these, 2 patients had non-SN metastases found in their dissected neck and 8 patients without neck dissection showed late nodal recurrence. The false-negative rate was thus 6.9%. CONCLUSION: Frozen section analysis, particularly multislice sectioning, offers a relatively reliable intraoperative diagnostic method. We were able to perform immediate neck dissection based on the results of multislice sectioning as a single-stage procedure. PMID- 21592701 TI - Neurofeedback for subjective tinnitus patients. AB - OBJECTIVE: Previous studies report that enhanced power in the delta range (1.5 4Hz) and reduced power in the alpha frequency band (8-12Hz) were most pronounced in the temporal regions. These studies referred to the 8-12Hz activity as tau activity, and they created a new neurofeedback protocol to treat tinnitus using a temporally generated tau rhythm (8-12Hz) and slow waves in the delta range (3 4Hz) for feedback. This study aims to repeat this protocol and to evaluate its effect on tinnitus. METHODS: Fifteen normal-hearing patients with tinnitus were treated with the neurofeedback protocol. The Tinnitus Handicap Inventory and Visual Analogue Scales were administered before and after treatment and at 1, 3 and 6 months post-treatment. RESULTS: After therapy, all questionnaires scores were significant improved, and the improvements persisted throughout the followup period. Moreover, an increasing trend in the tau/delta ratio was observed; specifically, the trend was more stable respect of the pre-recording measure. However, only in some subjects may the signal alone be enough to develop the correct behaviors. CONCLUSION: Further studies are necessary to characterize the tinnitus subjects who recovered from and adapted to this psychophysical condition and, therefore, responded to neurofeedback therapy. PMID- 21592702 TI - Current understanding and management of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a kind of rare head and neck cancer in Japan. However, NPC has some unique features. It is one of the most popular cancers in southern China, Southeast Asia, the Arctic, and the middle East/north Africa. This distinctive racial, ethnical, and geographic predisposition to NPC implies that both genetic susceptibility and environmental factors contribute to the development of this tumor. NPC is an Epstein-Barr virus - associated tumor. Consistent elevation of EBV antibody titers is a well-established risk factor of development of NPC. Not only pathophysiological relationship, but also molecular mechanism of EBV-mediated carcinogenesis has been enthusiastically investigated. LMP1, an EBV primary oncogene, upregulates each step of metastasis, and contribute to highly metastatic feature of NPC. A tumor suppressor gene p53 is mostly intact and overexpressed in NPC whereas expression of p16, a cyclin dependent kinase inhibitory protein, is downregulated in 2/3 of NPC. Intention modulated radiotherapy (IMRT) is now getting prevalent for the treatment of NPC because of complicated structure and location of nasopharynx. A good therapeutic result can be achieved by distributing a high dose to the tumor while keeping down normal tissue complications by reducing radiation dose to normal tissues. Chemotherapy is important to control distant metastasis of chemoradiosensitive NPC, and thus, should play an important role. However, most effective combination of anti-tumor drugs, protocol of chemoradiotherapy has not well-established. Finally, molecular targeting therapy, including targeting EBV gene product, has been developing and on the way to the clinical use. PMID- 21592703 TI - Voice-related quality of life in patients after total and partial laryngectomy. AB - OBJECTIVE: To assess the voice-related quality of life (V-RQOL) in patients after total and partial laryngectomy. MATERIALS AND METHODS: 96 patients treated for laryngeal cancer were enrolled in the study. The cohort of patients was divided into three groups depending on the surgical procedure carried out: total laryngectomy (TL), supracricoid partial laryngectomy (SCL) and/or horizontal glottectomy (HG). The maximum phonation time (MPT) and syllable diadochokinesis, were used for the aerodynamic assessment; Yanagihara score was used for acoustic analysis of the sustained /a/ and the GRBAS scale was used for perceptual assessment. Each of the patients completed the VHI. The Kruskal-Wallis and Mann Whitney tests were used to analyse the mean difference among the three groups of patients. RESULTS: A comparison with the values found between groups noted that the TL group showed significantly higher scores of G, R and Yanagihara score, while the HG group showed a significantly higher score of B. No differences were found in the aerodynamic and acoustic measures among the 3 groups. The mean+/ standard deviations of VHI total score were 35.3+/-24.5 for TL group, 30.1+/-21.6 for SCL group, 35.8+/-9.6 for HG group. No significant difference was found across the three groups. CONCLUSIONS: V-RQOL seems to be similar in patients who underwent significantly different surgical procedures even if the voice characteristics were different. These findings need to be considered in patient's counselling together with other data on general quality of life after total and partial laryngectomy. PMID- 21592704 TI - Should breast MRI be performed with adjustment for the phase in patients' menstrual cycle? Correlation between mammographic density, age, and background enhancement on breast MRI without adjusting for the phase in patients' menstrual cycle. AB - PURPOSE: The purpose of this study was to assess the correlation between mammographic density, age, and background enhancement on breast MRI without adjusting for the phase in patients' menstrual cycle. MATERIAL AND METHODS: The background enhancement of bilateral breast MRI and the breast density of mammography in 146 consecutive women without adjusting for the phase in patients' menstrual cycle were reviewed. The breast density was classified into four categories according to the American College of Radiology the Breast Imaging Reporting and Data System lexicon. The background enhancement was classified into four categories: minimal, mild, moderate, and marked. The correlations of mammographic breast density as well as age with background enhancement on breast MRI were examined. RESULTS: There was a significant correlation between mammographic breast density and background enhancement (p = 0.011). All nine cases with almost completely fat mammographic breast density showed minimal (78%) or mild (12%) background enhancement on breast MRI. There was a significant inverse correlation between age and background enhancement (p < 0.0001). Younger patients with dense breasts were more likely to demonstrate moderate/marked background enhancement. CONCLUSION: When no adjusting for the phase in patients' menstrual cycle, a significant correlation was observed between background enhancement and mammographic density. A significant inverse correlation was also observed between age and background enhancement. PMID- 21592705 TI - Multidetector row computed tomography of acute pancreatitis: Utility of single portal phase CT scan in short-term follow up. AB - OBJECTIVE: The purpose of this study is to evaluate the question of whether nonenhanced CT or contrast enhanced portal phase CT can replace multiphasic pancreas protocol CT in short term monitoring in patients with acute pancreatitis. MATERIALS AND METHODS: This retrospective study was approved by the Institutional Review Board. From April 2006 to May 2010, a total of 52 patients having acute pancreatitis who underwent initial dual phase multidetector row CT (unenhanced, arterial, and portal phase) at admission and a short term (within 30 days) follow up dual phase CT (mean interval 10.3 days, range 3-28 days) were included. Two abdominal radiologists performed an independent review of three sets of follow up CT images (nonenhanced scan, single portal phase scan, and dual phase scan). Interpretation of each image set was done with at least 2-week interval. Radiologists evaluated severity of acute pancreatitis with regard to pancreatic inflammation, pancreatic necrosis, and extrapancreatic complication, based on the modified CT severity index. Scores of each image set were compared using a paired t-test and interobserver agreement was evaluated using intraclass correlation coefficient statistics. RESULTS: Mean scores of sum of CT severity index on nonenhanced scan, portal phase scan, and dual phase scan were 5.7, 6.6, and 6.5 for radiologist 1, and 5.0, 5.6, and 5.8 for radiologist 2, respectively. In both radiologists, contrast enhanced scan (portal phase scan and dual phase scan) showed significantly higher severity score compared with that of unenhanced scan (P<0.05), while portal phase and dual phase scan showed no significant difference each other. The trend was similar regarding pancreatic inflammation and extrapancreatic complications, in which contrast enhanced scans showed significantly higher score compared with those of unenhanced scan, while no significant difference was observed between portal phase scan and dual phase scan. In pancreatic necrosis analysis, there was no significant difference between the three image sets for both radiologists. However, when only the patients having pancreatic necrosis (n=13) was separately analyzed, significant differences were observed between the unenhanced and portal phase scan (P=0.04, for radiologist 1), or unenhanced and dual phase scan (P=0.013, for radiologist 2). CONCLUSION: For short-term follow up imaging in assessment of patients with acute pancreatitis, single portal phase CT images without adding unenhanced or arterial phase images provide sufficient information, and thereby reduce radiation exposure. PMID- 21592706 TI - An investigation of the anatomical variations of left atrial appendage by multidetector computed tomographic coronary angiography. AB - PURPOSE: The left atrial appendage (LAA) is usually known as a long, tubular, hooked structure derived from the left atrium. However, it varies widely in terms of anatomical shape. In this study, anatomical shape variations of the LAA were investigated and classified in vivo in a large group of patients by multidetector computed tomography (MDCT) coronary angiography. MATERIALS AND METHODS: The study included 320 consecutive patients (223 men and 97 women, with a mean age of 58 years) who underwent MDCT coronary angiography. MDCT was performed with a 64 detector-row computed tomographic scanner. LAA anatomical variations were classified as five main types and further divided into subtypes. In addition, we gave the classifications descriptive names according to the anatomical external appearance of the LAA: horseshoe (type 1), hand-finger (type 2a), fan (type 2b), wing (type 2c), hook (type 3), wedge (type 4) and swan (type 5) shapes. The types and subtypes of the LAA variations and the presence of thrombus were recorded. RESULTS: In our study, the LAA tip orientation was used and the LAA was divided into type 1, type 2a, 2b, 2c, type 3, type 4 and type 5 in 44 (13.8%), 65 (20.3%), 155 (48.4%), 8 (2.5%), 27 (8.4%), 6 (1.9%) and 15 (4.7%) patients, respectively. LAA thrombus was detected in four patients (1.25%), who had classified LAA shapes of type 2a and type 2b. CONCLUSIONS: The LAA has multiple anatomical shape variations. We demonstrated previously undefined new shape types of LAA. Knowledge of LAA variations is important in order to avoid procedure related complications when ablative treatment is to be performed or if surgical procedures are indicated in this region. MDCT coronary angiography provides important and detailed information about determining and evaluating these variations before undertaking a planned procedure in this region. PMID- 21592707 TI - Gadoxetate disodium-enhanced MR imaging: differentiation between early-enhancing non-tumorous lesions and hypervascular hepatocellular carcinomas. AB - PURPOSE: To retrospectively assess imaging features that help differentiate early enhancing non-tumorous (EN) hepatic lesions from hepatocellular carcinomas (HCCs) on gadoxetate disodium-enhanced MR imaging. MATERIALS AND METHODS: Our institutional review board approved this retrospective study. We reviewed the studies of 158 patients (92 men and 65 women; age range: 29-91; mean age: 65.6 years) with chronic liver damage, who underwent gadoxetate disodium-enhanced MR imaging at 3T MR scanner. Hypervascular lesions identified during the hepatic artery phase were selected for a study cohort. The location, shape, size (maximum diameter and maximum area), and contrast enhancement signal intensity characteristics of the lesions were evaluated, then compared between the EN and HCC lesions. RESULTS: A total of 65 EN lesions (range: 3-60mm, mean: 13.6 +/- 10.6 mm) from 35 patients and 33 HCCs (range: 9-61 mm, mean: 19.3 +/- 12.6 mm) from 20 patients were identified. Lesions were more frequently round or oval in shape for HCCs (n=29; 88%) than ENs (n=26; 40%) (P<0.01). Unexpectedly, some ENs (n=12; 18%) showed hypointensity on hepatocyte-phase, and 6 (50%) of them were T2 hyperintense. For lesions smaller than 2 cm (9 ENs and 21 HCCs) on hepatic arterial-phase images, the mean area of hypointensity in hepatocyte-phase (54.2 +/- 33.1 mm(2)) was significantly smaller than those of the corresponding hyperintensity in hepatic arterial-phase (97.1 +/- 42.0 mm(2)) for EN lesions (P=0.019), whereas no significant difference in area was found for HCCs. CONCLUSION: EN lesions may occasionally present with hypointensity during the hepatocyte-phase; presenting a diagnostic dilemma. In this situation, EN lesions may be differentiated from HCCs when a hypointense area in hepatocyte-phase is smaller than the corresponding hypervascular area in hepatic-arterial phase. PMID- 21592708 TI - Multikinase inhibitor sorafenib transiently promotes necrosis after radiofrequency ablation in rat liver but activates growth signals. AB - AIM: To investigate the effects of sorafenib when combined with radiofrequency ablation treatment in liver tissue, the necrosis volume, tissue repair and hepatocellular growth signals were analyzed in rats. Radiofrequency ablation (RFA) is a widely applied treatment for hepatocellular carcinoma (HCC). Radiofrequency ablation is combined with the multi-tyrosinkinase-inhibitor sorafenib in ongoing clinical trials. Whether this combination treatment affects liver tissue repair is unknown. MATERIALS AND METHODS: Male Sprague Dawley (SD) rats received RFA or sham puncture with concomitant sorafenib (5mg/kg qd from day 2) or vehicle. Necrosis volume was calculated from resected specimens. Proliferation and micro vessel density were determined by Ki67 and CD31 immunofluorescence, respectively. mRNA expression of hepatocyte growth factor (HGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) was quantified. RESULTS: While ablation size was identical in all treatment groups at day 1, sorafenib treated animals showed sustained necroses (219 +/- 24 vs. 88 +/- 52 mm(3) in controls; P = 0.03), elevated alanine aminotransferase (ALT) and elevated glutamate dehydrogenase (GLDH) (76 +/- 37 vs. 47 +/- 58 mm(3); P=0.50) at day 3. By day 7 necrosis volumes equalized for the treatment groups. Ki67 and CD31 staining showed reduced proliferation and micro vessel density at days 1 and 3 following sorafenib. Growth factors HGF and EGF were significantly overexpressed in liver tissue after sorafenib. CONCLUSION: Sorafenib initially promotes necrosis after RFA in liver tissue. The delay in tissue repair is overcome at day 7 presumably by transient compensatory overexpression of growth signals. Based on these data from animal studies further investigation of adjuvant sorafenib in humans is warranted. PMID- 21592709 TI - Apparent diffusion coefficient of diffusion weighted MRI in endometrial carcinoma Relationship with local invasiveness. AB - OBJECTIVE: To evaluate the relationship between apparent diffusion coefficient (ADC) value and the local invasiveness of endometrial carcinoma. METHODS AND MATERIALS: The MR imaging of seventy-three patients with endometrial carcinoma proved by post-operative pathology and sixty-four patients with healthy uteri were retrospectively reviewed. All MR examinations included axial T2WI and T1WI, sagittal T2WI and diffusion-weighted sequences (b=0 and b=1000s/mm(2)). Tumor size, mean ADC value (ADCm) and quartile ADC (ADCq) were acquired on post processing workstation using voxel-analysis software. Differences between the ADC values among three layers of normal uterine body and endometrial carcinomas were compared by ANOVA test. Groups were divided according to pathologic type, histologic grade, depth of myometrial infiltration, presence of cervical invasion and lymphovascular space invasion, and lymph node metastasis. Tumor size and ADC values were compared and analyzed. RESULTS: ADC values were different in three zones of uterine body (P<0.001), with the lowest in junctional zone [(1.126+/ 0.190)*10(-3)mm(2)/s] and highest in outer myometrium [(1.496+/-0.196)*10( 3)mm(2)/s]. Mean ADC value of endometrial carcinomas [(1.011+/-0.121)*10( 3)mm(2)/s] was lower than the normal uterine body. Quartile ADC and tumor size were greater in groups with more invasive pathologic factors (P<0.05). Deep myometrial infiltration, cervical invasion, lymphovascular space invasion and lymph node metastasis were more common as quartile ADC values and tumor sizes increased. CONCLUSION: Mean ADC value was lower in endometrial carcinoma was lower than the normal uterus. Quartile ADC, representing the intra-tumor heterogeneity of water movement, had a profound relationship with invasiveness of endometrial carcinomas, while mean ADC value did not. ADC values may serve as a quantitative indicator to complement routine sequences. PMID- 21592710 TI - Nondiffuse fatty infiltration of the liver: does the uptake of iron-oxide increase or decrease at SPIO-enhanced MR imaging? AB - PURPOSE: To clarify whether the uptake of SPIO increases or decreases in areas of fatty change compared with surrounding areas of nonfatty change at SPIO-enhanced MR imaging. MATERIALS AND METHODS: Approval for this retrospective study was obtained from our institutional review board. This study included 14 patients with nondiffuse fatty infiltration of the liver who underwent SPIO-enhanced MR imaging. Additionally, 30 patients without nondiffuse fatty infiltration of the liver were also evaluated. RESULTS: Among 14 patients, areas of fatty change showed relatively high signal intensity in 7 patents, indicating decreased uptake of SPIO in areas of fatty change. In these 7 patients, 4 had mild cirrhosis and 3 did not have cirrhosis. The mean percentage of signal intensity loss (42%) of fatty areas was significantly lower (p<0.007) than that of adjacent areas of nonfatty change (52%). In the remaining 7 of 14 patients, areas of fatty change showed relatively low signal intensity, indicating increased uptake of SPIO in areas of fatty change. Among these 7 patients, 6 had advanced cirrhosis. The mean percentage of signal intensity loss (47%) of fatty areas was significantly higher (p<0.008) than that of adjacent areas of nonfatty change (31%). CONCLUSION: The uptake of SPIO generally decreased in areas of fatty change compared with normal liver parenchyma at SPIO-enhanced MR imaging. However, in patients with advanced cirrhosis, areas of fatty change shows relatively low signal intensity because the uptake of SPIO in surrounding areas of nonfatty change severely decreased probably due to liver fibrosis. PMID- 21592711 TI - Association between magnetic resonance imaging findings of uterine leiomyomas and symptoms demanding treatment. AB - PURPOSE: To evaluate the association between magnetic resonance imaging (MRI) derived uterine and leiomyoma characteristics and symptoms demanding treatment. MATERIALS AND METHODS: Consecutive patients (n=122; mean age, 47.5 years) with symptomatic leiomyomas participated in a prospective study. The leiomyoma/endometrium relationship, sizes of leiomyomas and uteri, and number and enhancement of leiomyomas were determined by MRI. Submucosal leiomyomas were classified as protruding either >=50% or <50% into the uterine cavity. RESULTS: Sixty-nine patients (57%) had menorrhagia and pressure symptoms, while 26 (21%) had only menorrhagia and 27 (22%) pressure symptoms alone. Leiomyomas with >=50% protrusion into the uterine cavity were detected more often in patients with both symptoms or just menorrhagia than in those with pressure symptoms only (18/69 [26%] versus 1/27 [4%], P=0.013; 10/26 [39%] versus 1/27 [4%], P=0.002, respectively). The degree of enhancement of leiomyomas was higher (P=0.005) and leiomyomas were smaller (P=0.002) in patients with menorrhagia than in those with pressure symptoms. Large uterine and leiomyoma measures were associated with increased urinary frequency (P values 0.002-0.032). Urinary stress incontinence, abdominal pain, and pressure on the back were not associated with MRI findings. CONCLUSION: In comparison with pressure symptoms, menorrhagia is associated with smaller uterine and leiomyoma size and with more intense enhancement. While a submucosal leiomyoma largely protruding into the cavity contributes to menorrhagia, significance of a minor submucosal component seems to be unclear. The large leiomyoma and uterine volumes contribute to increased urinary frequency, whereas other mechanisms for urinary stress incontinence and pain symptoms should be considered. PMID- 21592712 TI - Characterization of a novel biosurfactant producing Pseudomonas koreensis lineage that is endemic to Cuatro Cienegas Basin. AB - The aim of this work is the taxonomic characterization of three biosurfactant producing bacterial isolates from the Churince system at Cuatro Cienegas Basin (CCB) in the Mexican State of Coahuila, and the study of the possible role of biosurfactant production in their ecology and evolution. We determined that these isolates belong to a Pseudomonas koreensis lineage endemic to CCB, using standard taxonomical techniques, phylogenetic analysis of three chromosomal loci and phenotypic characterization. This new lineage has the distinct capacity to produce a biosurfactant when compared with previously reported P. koreensis isolates recovered from agricultural soils in Korea. We present evidence suggesting that the biosurfactant secreted by CCB P. koreensis strains is involved in their ability to compete with a CCB Exiguobacterium aurantiacum strain (m5-66) used as a model organism in competition experiments. Furthermore, the ethyl acetate extract of culture supernatant of CCB P. koreensis strains results in growth inhibition not only of E. aurantiacum m5-66, but also of a Bacillus subtilis type strain (ATCC6633). Based on these results we propose that the production of biosurfactant could be of ecological importance and could play a role in the separation of the P. koreensis CCB lineage. PMID- 21592713 TI - Characterization of two new potential impurities of Valsartan obtained under photodegradation stress condition. AB - A photostability study of Valsartan (VAL) is reported. Exposure of the drug to UV vis radiation (lambda > 320 nm) yielded two previously unknown compounds, which were detected by HPLC. Preparative amounts of the new potential degradation products (DP-1 and DP-2) were obtained by submitting VAL bulk drug to extensive photodegradation. The impurities were isolated by preparative normal phase column chromatography. Analytical information from the infrared, nuclear magnetic resonance and mass spectral data of the degradation products revealed their structures as N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-N-isobutylpentanamide (DP-1) and N-(diazirino[1,3-f]phenanthridin-4-ylmethyl)-N-isobutylpentanamide (DP 2). DP-1 arose from decarboxylation of VAL, while DP-2 results from further loss of nitrogen from the tetrazole motif of DP-1, with concomitant cyclization to yield a tetracyclic diazacyclopropene derivative. PMID- 21592714 TI - Wound irrigation before abdominal computed tomography scanning. AB - The management of penetrating abdominal trauma has evolved considerably over the last 30 years. The goal of any algorithm for penetrating abdominal trauma should be to identify injuries requiring surgical repair and avoid unnecessary laparotomy with its associated morbidity. We describe a case where the infusion of povidone-iodine (Videne) and air into the wound uncovered the peritoneal breach clinically and guided the radiologist to the site of the internal injury. This case report raises an intriguing possible role for povidone-iodine and air to be used both for wound toilet and to aid identification of occult wound tracks on computed tomography imaging. We advocate the routine use of wound irrigation with a mixture of povidone-iodine and air as described, in a select group of patients, as an adjunct to diagnosis before abdominal computed tomography scanning. PMID- 21592715 TI - Efficacy of ongoing group based diabetes self-management education for patients with type 2 diabetes mellitus. A randomised controlled trial. AB - OBJECTIVE: To evaluate the efficacy of ongoing group based diabetes self management education (DSME) for patients with type 2 diabetes. METHODS: 146 patients were randomised to either group education or waiting list control. Primary outcomes were A1C and patient activation measured with patient activation measure (PAM). RESULTS: There were no differences in the primary outcomes between the groups at 12 months, but the control group had an increase in A1C of 0.3% points during follow-up. Diabetes knowledge and some self-management skills improved significantly in the intervention group compared to the control group. A sub group analysis was conducted for the quartile with the highest A1C at baseline (>7.7, n=18 in both groups). There were significant improvements within the intervention group at 12 month follow-up for both A1C and PAM and a trend for better outcome in the intervention group compared to the control. CONCLUSIONS: The locally developed ongoing diabetes self-management education programs prevented an increase in A1C and can have an effect on A1C in patients with higher A1C level. PRACTICE IMPLICATIONS: Locally developed programs may be less effective than programs developed for studies. PMID- 21592716 TI - The association of visit length and measures of patient-centered communication in HIV care: a mixed methods study. AB - OBJECTIVE: Patient centered clinical communication may be associated with longer encounters. METHODS: We used the General Medical Interaction Analysis System (GMIAS) to code transcripts of routine outpatient visits in HIV care, and create 5 measures of patient-centeredness. We defined visit length as number of utterances. To better understand properties of encounters reflected in these measures, we conducted a qualitative analysis of the 15 longest and 15 shortest visits. RESULTS: All 5 measures were significantly associated with visit length (p<0.05, rank order correlations 0.21-0.44). In multivariate regressions, association of patient centeredness with visit length was attenuated for 4 measures, and increased for 1; two were no longer statistically significant (p>0.05). Black and Hispanic race were associated with shorter visits compared with White race. Some of the longest visits featured content that could be considered extraneous to appropriate care. CONCLUSION: Patient centeredness is weakly related to visit length, but may reflect inefficient use of time in long encounters. PRACTICE IMPLICATIONS: Efforts to make visits more patient centered should focus on improving dialogue quality and efficient use of time, not on making visits longer. Shorter visits for Black and Hispanic patients could contribute to health disparities related to race and ethnicity. PMID- 21592717 TI - Development and validation of a patient measure of doctor-patient caring. AB - OBJECTIVE: Conceptualising the doctor-patient relationship as a 'window mirror' exposes care delivery from doctor to self, doctor to patient, patient to self, and patient to doctor. These directions have not been measured concurrently. We aimed to develop and validate a patient questionnaire informed by this model. METHODS: A modified-Delphi exercise was conducted to develop, and face and content validate, the questionnaire. Stage 2 surveyed 495 patients in general practice to assess the internal consistency and construct validity of the questionnaire. RESULTS: The questionnaire is face and content valid. Its internal reliability and construct validity appear good. Patients who care more about their doctor also care more about themselves. A patient or doctor who cares about the other person is associated with increased self-care by that person. CONCLUSIONS: Further development and testing of the patient questionnaire is warranted to validate measurement of how patients perceive the caring they and their doctor give, and receive from, each other. PRACTICE IMPLICATIONS: From the patient perspective the questionnaire may increase awareness of the importance of family doctors and patients caring about each other and themselves. It may inform and evaluate medical students, educational programmes and caring in doctor patient relationships. PMID- 21592718 TI - Clinicians' accuracy in perceiving patients: its relevance for clinical practice and a narrative review of methods and correlates. AB - OBJECTIVE: A relatively unexplored aspect of clinicians' communication skill is their interpersonal sensitivity, or ability to perceive their patients accurately with regard to patients' feelings, desires, intentions, needs, physical states, personality, attitudes, beliefs, and values. The present article argues for the importance of this skill in clinical interactions and summarizes supportive research. METHODS: Reviews approaches to measuring interpersonal sensitivity and research on correlates of clinicians' and laypersons' interpersonal sensitivity. RESULTS: Studies on clinicians' interpersonal sensitivity suggest that this skill could be improved. Furthermore, there are important correlates of clinicians' interpersonal sensitivity, including, on the patient's side, satisfaction, appointment-keeping adherence, and learning of conveyed information, and, on the clinician's side, awareness of patients' cues of anxiety and distress, commitment to patient-centered values, self-reported awareness of own emotions, and female gender. Furthermore, a very large non-clinical literature points to many other correlates of interpersonal sensitivity that are relevant to the clinical situation, including empathy, prosocial behavior, skill in negotiating, selling, teaching, and managing, better personal adjustment, and better interpersonal relationships. Research also suggests that interpersonal sensitivity is a trainable skill that could realistically be included in clinical education. CONCLUSION: Clinicians' interpersonal sensitivity is an important component of quality of care and deserves further research. PRACTICE IMPLICATIONS: This important skill should be incorporated into training programs to improve clinician-patient communication. PMID- 21592720 TI - Acetabular revision total hip arthroplasty using an impacted morselized allograft and a cementless cup: minimum 10-year follow-up. AB - This study was undertaken to analyze the clinical and radiologic results of acetabular revision arthroplasty using an impacted morselized allograft and a cementless cup and was performed on 71 hips of 62 patients who were followed up for a minimum of 10 years (10 years to 14 years 8 months; mean, 12 years). The acetabular bone defects were classified using the American Academy of Orthopaedic Surgeons Committee on the Hip and Paprosky classifications. Cementless hemispherical cups were inserted via a press-fit technique, using an impacted morselized allograft. The mean Harris hip score at the last follow-up visit was 92. Only 3 cases were re-revised, and the 12-year survival rate was thus 95.8%. The study shows that acetabular revision arthroplasty using an impacted morselized allograft and a cementless cup is an excellent treatment option. PMID- 21592719 TI - Effects of an interactive tailored patient assessment tool on eliciting and responding to cancer patients' cues and concerns in clinical consultations with physicians and nurses. AB - OBJECTIVE: To test the effect of Choice, an interactive tailored patient assessment tool (ITPA), on cancer patients' expressed cues and concerns (C&Cs), and clinicians' responses to these C&Cs. METHODS: 97 experimental group consultations, where patients used the Choice ITPA to report their symptoms and problems in preparation to their consultation, were compared to 99 control group consultations. All consultations were audio-taped and coded using the Verona Coding Definitions of Emotional Sequences (VR-CoDES). RESULTS: We identified 473 cues and 109 concerns with a mean number of 3.0 (SD=3.2). The most frequent utterance was cue B (45.2%), indicating expression of uncertainty or hope. We found more C&Cs in consultations with the Choice ITPA compared to the control group (p<0.01), and in consultations with nurses compared to physicians (p<0.001). No differences in clinicians' response types in the two groups were found. However, significant differences in response type between nurses and physicians were found. CONCLUSION: The Choice ITPA was an effective tool to disclose cancer patients' cues and concerns. PRACTICE IMPLICATIONS: The Choice ITPA proved to be an effective intervention for cancer patients to express more C&Cs, but should be accompanied with communication skills training to potentially produce more patient-centered responses from the clinicians. (ClinicalTrials.gov number NCT00857103.) PMID- 21592721 TI - Randomized trial of computer-assisted knee arthroplasty: impact on clinical and radiographic outcomes. AB - Computer-assisted surgery in knee arthroplasty is gaining popularity; however, the resulting outcome improvement is controversial. A double-blinded trial was performed with subjects randomized to undergo surgery with either computer assisted or nonassisted instruments. Postoperatively, limb and implant alignment and rotation were assessed using both full-length radiographs and computed tomography in addition to clinical scores. One hundred twenty patients (141 knees) were randomized. No differences in Western Ontario MacMaster Osteoarthritis Score, Short Form-36, or flexion were seen. More varus limb alignment was seen in the computer-assisted group (1.9 degrees ) vs the nonassisted group (0.9 degrees , P = .04) with no improvement in alignment precision. Rotational alignment of the components did not differ between groups. Computer-assisted surgery appeared to have minimal effect on knee implant arthroplasty with no improvement in limb alignment or early functional outcome. PMID- 21592722 TI - Demoralization and depression in patients with advanced cancer: validation of the German version of the demoralization scale. AB - CONTEXT: The concept of demoralization has been widely used to describe states of existential distress and a self-perceived incapacity to deal effectively with a specific stressful situation. OBJECTIVES: To evaluate the psychometric properties of the German adaptation of the Demoralization Scale (DS) in patients with advanced cancer. METHODS: Participants with heterogeneous tumor sites were recruited in several treatment and rehabilitation facilities. Concurrent and divergent validity of the DS was analyzed through associations with and group differences between measures of distress, depression, anxiety, and meaning related life attitudes. RESULTS: From a total sample of 1102 patients, 516 individuals (45%) with advanced cancer were enrolled (male 53%, median age 58 years [range 18-88], breast cancer 21%, prostate cancer 17%). The total mean score of the DS was 29.8 (SD=10.41). Four factors were extracted by exploratory factor analysis, which accounted for 59% of the variation (Cronbach alpha=0.84): loss of meaning and purpose (alpha=0.88), disheartenment (alpha=0.88), dysphoria (alpha=0.80), and sense of failure (alpha=0.76). DS dimensions shared between 12% and 62% of the variance. Demoralization was significantly associated with anxiety (r=0.71), depression (r=0.61), and distress (r=0.42). Fifty-seven percent of patients had high distress, 24% depression, and 11% high anxiety. According to different cutoff values, between 16% and 39% were seriously demoralized and 73% had moderate levels of demoralization. Between 5% and 20% of patients were seriously demoralized but not clinically depressed; 60% of patients with moderate levels of demoralization had no depression. CONCLUSION: Results provide further evidence that the DS is a valid and reliable instrument of high clinical relevance in patients with advanced cancer. PMID- 21592723 TI - The effectiveness of Korean number naming on insight into numbers in Dutch students with mild intellectual disabilities. AB - BACKGROUND: Children from Asian countries score higher on early years' arithmetic tests than children from Europe or the United States of America. An explanation for these differences may be the way numbers are named. A clear ten-structure like in the Korean language method leads to a better insight into numbers and arithmetic skills. This assumption forms the basis of the current study. METHOD: Examined is whether an intervention with number naming in the Korean way influences number awareness of students with mild intellectual disabilities (N=70; mean age: 9;0 years). RESULTS: The results indicate a positive effect of this alternative method of number naming on the insight into numbers up to 20. However, the effect did not generalize to insight into numbers 21-100. CONCLUSIONS: The Korean method of number naming seems to be a promising way to teach students with mild intellectual disabilities insight into numbers. PMID- 21592724 TI - Bimanual force coordination in children with spastic unilateral cerebral palsy. AB - In this study bimanual grip-force coordination was quantified using a novel "Gripper" system that records grip forces produced while holding a lower and upper unit, in combination with the lift force necessary to separate these units. Children with unilateral cerebral palsy (CP) (aged 5-14 years, n=12) were compared to age matched typically developing (TD) children (n=23). Compared to TD, the CP-group is much slower and takes 50% more time to generate grip and lift forces with more fixating force before lifting the upper unit. In addition the coordination between forces in both hands is reduced. The CP-group increases the lift force in the upper hand 2.5 times more than the holding force when pulling the two units apart, while this is only 1.5 times in TD. Moreover, the correlation between forces generated in both hands in the CP-group is lower. The lack of fine tuning of the forces, measured by the linearity error is increased, especially when the magnet load keeping the unit together is low. The results indicate an impaired pull-hold synergy between upper and lower hand and the lift force. Bimanual tasks evaluating bimanual grip and lift forces in children with CP and can give us new insights in the underlying force control mechanisms of the spastic hand. PMID- 21592725 TI - Mechanistic insights into ischemic mitral regurgitation: echocardiographic and surgical implications. AB - Ischemic mitral regurgitation is a common complication of the healing phase of myocardial infarction. A number of mechanisms have been invoked in its pathogenesis, including alterations of papillary muscle position, annular dynamics, and intraventricular synchrony. The echocardiographic hallmark of ischemic mitral regurgitation is systolic tethering of the mitral valve leaflets away from the annular plane. A number of leaflet tethering parameters have been described (tenting height and area, leaflet angles) that provide insight into the mechanism of tethering as well as prognostic information about the durability of mitral valve repair. Restrictive annuloplasty and coronary artery revascularization promote reverse remodeling and remain the most common surgical treatment. Innovative subannular therapies and a number of percutaneous interventions are under investigation. PMID- 21592726 TI - Prediction of exercise pulmonary hypertension in asymptomatic degenerative mitral regurgitation. AB - OBJECTIVE: Exercise systolic pulmonary arterial pressure (SPAP) predicts the occurrence of symptoms in patients with degenerative mitral regurgitation (MR). However, this measurement is not always available. The purpose of this study was to identify resting echocardiographic predictors of exercise SPAP and whether predicted exercise SPAP may predict symptom-free survival. METHODS: We prospectively enrolled 89 consecutive asymptomatic patients with moderate or greater degenerative MR in whom exercise SPAP was measurable. Left ventricular (LV) systolic and diastolic function were assessed by comprehensive transthoracic echocardiography. Tissue Doppler imaging was used to measure Ea- (early diastolic) and Sa- (systolic) wave velocities and time-to-peak (TP) Sa velocity. Multiple linear regression was built to identify resting predictors of exercise SPAP. RESULTS: Patients with exercise pulmonary hypertension (PHT) (n = 45, 51%) were significantly older and more frequently male, and had shorter TP-Sa velocity and higher E/Ea ratio and LV end-diastolic volume than those without exercise PHT. Exercise SPAP was best correlated with resting LV end-diastolic volume (r = 0.55), TP-Sa (r = 0.72), and E/Ea ratio (r = 0.52). Multiple linear regression analysis allowed us to build the following predictive equation with good precision (r(2) = 0.80): By using this formula, predicted exercise SPAP was well correlated with observed exercise SPAP (r = 0.89). Predicted exercise PHT was associated with significant reduced symptom-free survival in both univariate (P = .04) and multivariate (P = .045) analyses. CONCLUSION: In asymptomatic patients with degenerative MR, exercise PHT can be accurately predicted using resting comprehensive echocardiography. PMID- 21592727 TI - Too many cohorts and repeated measurements are a waste of resources. AB - OBJECTIVE: Researchers in Health Sciences and Medicine often use cohort designs to study treatment effects and changes of outcome variables over time period. The costs of these studies can be reduced by choosing an optimal number of repeated measurements over time and by selecting cohorts of subjects more efficiently with optimal design procedures. The objective of this study is to provide evidence on how to design large-scale cohort studies with budget constraints as efficiently as possible. STUDY DESIGN AND SETTING: A linear cost function for repeated measurements is proposed, and this cost function is used in the optimization procedure. For a given budget/cost, different designs for linear mixed-effects models are compared by means of their efficiency. RESULTS: We found that adding more repeated measures is only beneficiary if the costs of selecting and measuring a new subject are much higher than the costs of obtaining an additional measurement for an already recruited subject. However, this gain in efficiency and power is not very large. CONCLUSION: Adding more cohorts or repeated measurements do not necessarily lead to a gain in efficiency of the estimated model parameters. A general guideline for the optimal choice of a cohort design in practice is required and we offer this guideline. PMID- 21592728 TI - Evaluation of the capability of a new water lift system to reduce the risk of Schneiderian membrane perforation during sinus elevation. AB - The purpose of this study was to evaluate the effectiveness of a new water lift system used as a surgical instrument in the crestal approach of the sinus membrane lifting operation and the capability of this technique to reduce the risk of Schneiderian membrane perforation in comparison with a lateral approach using piezoelectric surgery. 50 sinus membrane-lifting operations were performed. Patients were randomized in 2 groups to receive either lateral sinus elevation with piezosurgery or crestal sinus elevation using the new surgical device. Schneiderian membrane perforation was noted in 6 patients (24%) from the group undergoing the lateral sinus floor elevation approach, but no perforation was observed in the group with the crestal infiltration technique (P=0.01). Aside from membrane perforation, haematoma was present in 3 patients (12%) from the group with lateral sinus floor elevation with no cases in the other group. No microbial infections were noted in the 50 consecutives cases. This study demonstrated that maxillary sinus floor elevation using the water lift system via the crestal approach is a predictable procedure with a low complication rate, compared with the lateral approach with piezoelectric surgery. PMID- 21592729 TI - Strong anticonvulsant effect of thalidomide on amygdaloid kindling. AB - Thalidomide was synthesized more than 50 years ago as hypnotic sedative with unique pharmacologic properties. Recently, we have described a notorious anticonvulsant effect of thalidomide on pentylenetetrazole-induced seizures. Here, we report the results of thalidomide administration on amygdaloid kindling. A total of 100 male Wistar rats were implanted with brain electrodes in the basolateral amygdaloid nucleus and the sensory motor cortex. After surgery the animals received a daily electric stimulus through the amygdaline electrode (500 MUA intensity, 60 Hz frequency, 1 ms duration) until seizures appeared. The following treatment groups were made: (a) controls; (b) rats treated daily with thalidomide (10 mg/kg) or with topiramate (80 mg/kg); (c) rats treated with different doses of thalidomide. Significant reduction in the after-discharge and retard of behavioral stages were observed in rats treated with thalidomide or with topiramate as compared with controls (p<0.01): Also, a similar anticonvulsant outcome of thalidomide therapy was obtained with doses of either 2.5, 5, 10 or 50 mg/kg; at 100 mg/kg all epileptic activity was suppressed. Anticonvulsant efficacy of thalidomide was superior in most parameters than that obtained with topiramate. In amygdaloid kindling, which simulates human epilepsy characterized by focal seizures secondarily generalized, low doses of thalidomide display strong anticonvulsant properties. PMID- 21592730 TI - Hippocampal activation correlates with visual confrontation naming: fMRI findings in controls and patients with temporal lobe epilepsy. AB - PURPOSE: In patients with left temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) decreased naming ability is common, suggesting a critical role for the medial left temporal lobe in this task. We investigated the integrity of language networks with functional MRI (fMRI) in controls and TLE patients. EXPERIMENTAL DESIGN: We performed an fMRI verbal fluency paradigm in 22 controls and 66 patients with unilateral mesial TLE (37 left HS, 29 right HS). Verbal fluency and naming ability were investigated as part of the standard presurgical neuropsychological assessment. Naming ability was assessed using a visual confrontation naming test. RESULTS: Left TLE patients had significantly lower naming scores than controls and those with right TLE. Right TLE patients performed less well than controls, but better than those with left TLE. Left TLE had significantly lower scores for verbal fluency than controls. In controls and right TLE, left hippocampal activation during the verbal fluency task was significantly correlated with naming, characterised by higher scores in subjects with greater hippocampal fMRI activation. In left TLE no correlation with naming scores was seen in the left hippocampus, but there was a significant correlation in the left middle and inferior frontal gyri, not observed in controls and right TLE. In left and right TLE, out of scanner verbal fluency scores significantly correlated with fMRI activation for verbal fluency in the left middle and inferior frontal gyri. CONCLUSION: Good confrontation naming ability depends on the integrity of the hippocampus and the connecting fronto-temporal networks. Functional MRI activation in the left hippocampus during verbal fluency is associated with naming function in healthy controls and patients with right TLE. In left TLE, there was evidence of involvement of the left frontal lobe when naming was more proficient, most likely reflecting a compensatory response due to the ongoing epileptic activity and/or underlying pathology. PMID- 21592731 TI - The impact of substance use disorders on the course of schizophrenia--a 15-year follow-up study: dual diagnosis over 15 years. AB - BACKGROUND: This follow-up study compared patients with schizophrenia with co occurring substance use disorder to patients with schizophrenia and no substance use disorder. AIMS: To investigate the prognostic significance of the effects of substance use disorders on the course of schizophrenia. METHOD: Patients with schizophrenia and co-occurring substance use disorder (n=107), and patients with schizophrenia only (n=119) were followed over a 15-year period through the use of national hospitalization registers, data for time and cause of death, and data for homelessness or institutionalization. RESULTS: The median length of psychiatric hospitalization was 12 days for a patient with dual diagnosis, and 21 days for patients with schizophrenia only. Patients with dual diagnosis displayed a significantly elevated usage of all types of hospital contacts except inpatient treatment for non-psychiatric disorders. In three types of hospital contacts, patients with co-occurring substance use had approximately two to three times as many hospitalizations as did patients with schizophrenia only. Rates for homelessness and institutionalization were similar in both groups. Patients with a dual diagnosis were also significantly more at risk of dying during follow-up than were patients with schizophrenia only. CONCLUSIONS: The findings suggest that the long-term course of schizophrenia is considerably more severe in patients who have a dual diagnosis compared to patients with schizophrenia only Substance use disorders have a substantial impact on the hospitalization rates of patients with schizophrenia, as well as on life expectancy. Patients with co morbid substance abuse are more likely to be admitted for treatment during a given year although they have briefer contact with treatment. PMID- 21592732 TI - Cannabis with high cannabidiol content is associated with fewer psychotic experiences. AB - OBJECTIVE: Cannabis is associated with psychotic outcomes in numerous studies, an effect that is commonly attributed to Delta (9)-tetrahydrocannabinol (Delta 9 THC). An increasing number of authors identify cannabidiol, another component of the cannabis plant, as an antipsychotic agent. The objective of the current study is to investigate the role of cannabidiol content in the association between cannabis use and psychiatric symptoms in a large non-clinical population of cannabis users. METHODS: In a web-based cross-sectional study we obtained detailed information about cannabis use and subclinical psychiatric experiences using the Community Assessment of Psychic Experiences (CAPE). Different types of cannabis (i.e. marijuana, hashish etc.) have distinctive proportions of Delta 9 THC and cannabidiol. Since average concentrations of Delta 9-THC and cannabidiol in the most popular types of cannabis sold on the Dutch market are annually measured, we were able to estimate exposure to Delta 9-THC and cannabidiol. RESULTS: We included 1877 subjects (mean age 23, SD 6.0) who used the same type of cannabis in the majority of the occasions (in >60% of occasions). We found a significant inverse relationship (F(1,1877): 14.577, p<0.001) between cannabidiol content and self-reported positive symptoms, but not with negative symptoms or depression. The estimated effect size of cannabidiol content was small. CONCLUSION: Although the observed effects are subtle, using high cannabidiol content cannabis was associated with significantly lower degrees of psychotic symptoms providing further support for the antipsychotic potential of cannabidiol. PMID- 21592733 TI - Neuropsychological performance and auditory event related potentials in schizophrenia patients and their siblings: a family study. AB - BACKGROUND: Various neuropsychological domains, and P300 auditory event-related potentials (ERP) and mismatch negativity (MMN) exhibit abnormalities in schizophrenia patients and their first-degree relatives. The aims of this study were to compare cognitive and P300/MMN measurements in schizophrenia patients, their siblings, and controls, and to identify the degree of familial influence on each measure. METHODS: Thirty patients diagnosed with schizophrenia according to DSM-IV, 20 unaffected siblings and 25 healthy controls were able to complete all neuropsyhological and neurophysiological assessments. All participants were administered SCID-I and the patients were also evaluated regarding symptom severity and functioning. Neuropsychological battery testing results and P300/MMN measurements were obtained for all the participants. RESULTS: Both schizophrenia patients and their siblings had lower working memory, as measured by the Auditory Consonant Trigram Test (ACT), and lower MMN amplitude scores than the controls. In addition, the patients had lower attention, verbal memory, executive function, visuomotor speed, and figural memory scores than both the siblings and controls, and lower verbal fluency scores than controls. MMN and P300 amplitudes were lower and P300 latency longer in the schizophrenia patients, as compared to controls. P300 latency was also longer in the schizophrenia patients as compared to siblings and, MMN amplitudes were significantly lower in the siblings compared to controls. Working memory performance measured by ACT significantly predicted inclusion in both the patient and sibling groups and showed significant familial influence. MMN amplitude significantly predicted inclusion only to the patient group and did not show significant familial influence. CONCLUSION: The schizophrenia patients exhibited impairment in various cognitive domains and P300/MMN measurements, versus impairment only in working memory and MMN amplitude in their siblings. Working memory seems to have a relatively strong familial influence among all the neuropsychological and neurophysiological parameters evaluated. PMID- 21592734 TI - Bowen's disease of the nail apparatus and association with various high-risk human papillomavirus types. PMID- 21592735 TI - Differences in drug resistance profiles of Mycobacterium tuberculosis isolates causing pulmonary and extrapulmonary tuberculosis in a medical centre in Taiwan, 2000-2010. AB - Few studies have investigated the drug resistance profiles of Mycobacterium tuberculosis (MTB) isolates recovered from different sites of infection. A total of 4521 non-duplicate MTB isolates, including 3723 (82.3%) from respiratory specimens and 798 (17.7%) from non-respiratory sources, were recovered from patients treated at a medical centre in Taiwan from 2000 to 2010. Trend analysis showed a significant decrease (P<0.05) in the rates of resistance to isoniazid, rifampicin and ethambutol, a decrease in resistance to any one of four agents, namely isoniazid, rifampicin, ethambutol or streptomycin, and a decrease in resistance to both isoniazid and rifampicin (multidrug resistance) amongst pulmonary MTB isolates. A similar decrease in resistance to isoniazid and ethambutol was noted amongst non-pulmonary isolates. Rates of drug resistance were significantly higher amongst MTB isolates recovered from respiratory specimens than amongst those from non-respiratory specimens to 0.2 MUg/mL isoniazid (15.3% vs. 9.4%; P<0.0001), 1 MUg/mL rifampicin (5.5% vs. 3.3%; P=0.0108), 5 MUg/mL ethambutol (7.3% vs. 3.8%; P=0.0004), and both isoniazid and rifampicin (4.8% vs. 2.5%; P=0.0051). Resistance rates amongst isolates causing tuberculous lymphadenitis were significantly lower than amongst those causing genitourinary tuberculosis (TB) to isoniazid (3.5% vs. 19.4%, P=0.0012) and to isoniazid, rifampicin, ethambutol or streptomycin (9.6% vs. 22.6%, P=0.0003). In conclusion, the rates of resistance to first-line anti-TB agents and to multiple agents differed amongst MTB isolates obtained from different infectious sources. Continuous monitoring of resistance of MTB isolates from various sites is necessary in order to establish an effective TB surveillance programme. PMID- 21592736 TI - Employment and its relationship with functionality and quality of life in patients with schizophrenia: EGOFORS Study. AB - The aim of this study is to investigate the relationship between work/study status and symptom severity, functionality and quality of life (QoL) in schizophrenia patients. METHODS: Two-hundred and ninety-five chronic schizophrenia patients from 11 centres were included in the study. Symptom severity was measured with Positive and Negative Syndrome Scale for schizophrenia. QoL and functionality was assessed with Global Assessment of Functioning Scale, Quality of Life Scale, Personal and Social Performance Scale, Psychosocial Remission in Schizophrenia Scale, Functional Recovery Scale in Schizophrenia, Performance-Based Skills Assessment-Brief Version and Subjective Well-being under Neuroleptics Scales. RESULTS: Two-third of the participants (n=194) were unemployed. Forty (13.6%) of the participants were involved in full time work/study, 29 (9.8%) people were involved in part-time work/study, 13 (4.4%) people were engaged in work/study below 50% of the time, but their job was classified as regular and independent. Those who work/study had lower symptoms, better functioning and higher levels of QoL. Also those who work/study full-time displayed better results on these measures than the participants involved in part time work/study. Age, education, severity of negative symptoms, gender and duration of remission were found to be related to employment status in the logistic regression analysis. CONCLUSIONS: Our findings suggest that work/study status is an important component of functionality. PMID- 21592737 TI - A functional comparison of patients with schizophrenia between the North and South of Europe. AB - INTRODUCTION: The main objective of this study was to compare clinical and functional outcomes of patients with schizophrenia in Italy and Sweden with a special focus on daily functioning performance and real life milestones. Also, to study if outcome is to be regarded as a consequence of premorbid function, the level of symptom control and functional capacity or if other influences, such as cultural differences, must parallel be considered. METHOD: Ninety-five patients from three centres, Milan and Naples in Italy and Trollhattan in Sweden were investigated. The Positive and Negative Syndrome Scale and the UCSD Performance Based Skills Assessment - Brief version were used together with patients' school history and their status of accommodation and occupation. RESULTS: Patients in Trollhattan were more likely to live independently and patients in Naples to have a work or take part in education. Differences in symptoms and the performance test were present but subtle. DISCUSSION: Differences in real life milestones were not explained by corresponding differences in symptoms, premorbid function or the performance-based test. It is therefore not appropriate only to present functional outcome as an expression of how successful treatment has been. PMID- 21592738 TI - Association between flashbacks and structural brain abnormalities in posttraumatic stress disorder. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is reliably associated with reduced brain volume relative to healthy controls, in areas similar to those found in depression. We investigated whether in a PTSD sample brain volumes in these areas were related to reporting specific symptoms of PTSD or to overall symptom severity. METHOD: Structural MRI scans were obtained from 28 participants diagnosed with PTSD according to DSM-IV-TR. Participants reported the extent of individual PTSD symptoms using the Posttraumatic Diagnostic Scale. Voxel-based morphometry applying the Dartel algorithm implemented within SPM5 was used to identify volumetric changes, related to PTSD total, symptom cluster, and individual symptom scores. RESULTS: Brain volume was unrelated to overall PTSD severity, but greater reexperiencing scores predicted reduced volumes in the middle temporal and inferior occipital cortices. Increased reports of flashbacks predicted reduced volume in the insula/parietal operculum and in the inferior temporal gyrus. CONCLUSION: The data illustrate the value of analyses at the symptom level within a patient population to supplement group comparisons of patients and healthy controls. Areas identified were consistent with a neurobiological account of flashbacks implicating specific abnormalities in the ventral visual stream. PMID- 21592739 TI - Remission amongst elderly schizophrenia patients. AB - Remission in elderly patients has been little studied. The present analysis utilized a European database to focus on the elderly. Using five different instruments examining remission, we report that aging did not adversely affect remission in the elderly. Management of elderly schizophrenia patients should thus be targeted towards remission. PMID- 21592740 TI - Planum temporale asymmetry to the right hemisphere in first-episode schizophrenia. AB - In schizophrenia patients reduced cerebral asymmetry is an important finding and this may reflect a disturbance in cortical development. We investigated planum temporale (PT) volume and asymmetry in 23 first-episode schizophrenia patients compared to healthy controls and found for the first time an in vivo volume asymmetry of PT to the right hemisphere. PMID- 21592742 TI - Ultrasound Brain Tissue Pulsatility is decreased in middle aged and elderly type 2 diabetic patients with depression. AB - We used Tissue Pulsatility Imaging (TPI) to compare the Brain Tissue Pulsatility (BTP) in depressed (n=11) and non-depressed (n=13) type-2 diabetic non-demented patients aged 50 years and older. Both maximum and mean BTP were significantly decreased in depressed diabetic subjects compared to non-depressed diabetic subjects. PMID- 21592743 TI - Solid-state nuclear magnetic resonance investigations of the nature, property, and activity of acid sites on solid catalysts. AB - Further progress in the field of heterogeneous catalysis depends on our knowledge of the nature and behavior of surface sites on solid catalysts and of the mechanisms of chemical reactions catalyzed by these materials. In the past decades, solid-state NMR spectroscopy has been developed to an important tool for routine characterization of solid catalysts. The present work gives a review on experimental approaches and applications of solid-state NMR spectroscopy for investigating Bronsted and Lewis sites on solid acids. Studies focusing on the generation of surface sites via post-synthesis modification routes of microporous and mesoporous materials support the development of new and the improvement of existing catalyst systems. High-temperature and flow techniques of in situ solid state NMR spectroscopy allow a deeper insight into the mechanisms of heterogeneously catalyzed reactions and open the way for studying the activity of acidic surface sites. They help to clarify the activation of reactants on Bronsted and Lewis acid sites and improve our understanding of mechanisms affecting the selectivity of acid-catalyzed reactions. PMID- 21592741 TI - Double-blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder: fMRI outcomes. AB - The aim of this research was to determine the relative effects of risperidone and divalproex on brain function in pediatric mania. This is a double-blind 6-week functional magnetic resonance imaging trial with 24 unmedicated manic patients randomized to risperidone or divalproex, and 14 healthy controls (HCs) matched for IQ and demographic factors (mean age: 13.1+/-3.3years). A pediatric affective color matching task, in which subjects matched the color of a positive, negative or neutral word with one of two colored circles, was administered. The primary clinical measure was the Young Mania Rating Scale (YMRS). The risperidone group, relative to HC, showed an increase in activation from pre- to post-treatment in right pregenual and subgenual anterior cingulate cortex and decreased activation in bilateral middle frontal gyrus during the negative condition; and decreased activation in left inferior and medial, and right middle frontal gyri, left inferior parietal lobe, and right striatum with positive condition. In the divalproex group, relative to HC, there was an increased activation in right superior temporal gyrus in the negative condition; and in left medial frontal gyrus and right precuneus with the positive condition. Greater pre-treatment right amygdala activity with negative and positive condition in the risperidone group, and left amygdala activity with positive condition in divalproex group, predicted poor response on YMRS. Risperidone and divalproex yield differential patterns of prefrontal activity during an emotion processing task in pediatric mania. Increased amygdala activity at baseline is a potential biomarker predicting poor treatment response to both the risperidone and divalproex. PMID- 21592744 TI - The perfect slime. AB - The biofilm mode of life is only possible because biofilm organisms are transiently immobilized in a matrix of extracellular polymeric substances (EPS), also known as "slime". The matrix can be considered an emerging property of microorganisms, allowing them to form stable synergistic consortia, supporting interaction by signaling molecules and horizontal gene transfer and, eventually being activated by extracellular enzymes which turn the matrix into an external digestion system. As unsightly it is, this matrix is--although seemingly stochastic--a highly differentiated and functional immediate environment for biofilm cells. PMID- 21592745 TI - An impedimetric biosensor for detection of dengue serotype at picomolar concentration based on gold nanoparticles-polyaniline hybrid composites. AB - In this work, we describe the preparation and characterization of a novel gold nanoparticles-polyaniline hybrid composite (AuNpPANI) with SH-terminal groups that, due to its ability of immobilizing dengue serotype-specific primers 1, 2 and 3 (ST1, ST2 and ST3), can be used for the development of biosensors. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) were performed. CV and EIS results demonstrated that the AuNpPANI can immobilize ST1, ST2 and ST3, forming AuNpPANI-ST complexes. Well-defined cyclic voltammograms characteristic of a diffusion-limited redox process were observed both for the bare gold electrode and after these electrodes have been modified by the adsorption of AuNpPANI or AuNpPANI-ST. The AuNpPANI-ST(1-3) systems were able to recognize the dengue serotype of different patients at picomolar concentrations. Even when small volumes and low concentrations of the analyte were used, the CV and EIS results showed unequivocal evidence of an existing interaction between dengue serotype-specific primers and their complementary genomic DNA targets. PMID- 21592747 TI - Evaluation of the effect of nutrient ratios on biosurfactant production by Serratia marcescens using a Box-Behnken design. AB - The strain SmSA, identified as Serratia marcescens and known as a biosurfactant producer, was isolated from hydrocarbon contaminated soil from Veracruz, Mexico. The interactions among the C/N, C/Mg and C/Fe ratios have not been examined for this microorganism. In this work was evaluated the effect of these nutrients at three levels using a mineral medium with glucose as the carbon source. A Box Behnken experimental design was utilised to maximise biosurfactant production, which was assessed by oil spreading and surface tension tests. The treatment with C/N=5, C/Fe=26,000 and C/Mg=30 showed the best result since the surface tension was reduced to 30 mN m(-1). The multiple regression and response surface analyses indicated that the interaction between C/N and C/Mg had the utmost effect on the reduction of surface tension and biosurfactant production. The conditions of the best treatment were used to scale up biosurfactant production in a 3L bioreactor giving a yield of 4.1 gL(-1) of pure biosurfactant. It was found that the biosurfactant was mainly produced in the exponential phase and decreased the surface tension to 31 mN m(-1). The contact between the biosurfactant with heavy oil (15 degrees API) increased its displacement from 9.3 to 18 cm. PMID- 21592746 TI - Photoluminescence in the characterization and early detection of biomimetic bone like apatite formation on the surface of alkaline-treated titanium implant: state of the art. AB - Photoluminescence (PL) property is particularly important in the characterization of materials that contain significant proportions of noncrystalline components, multiple phases, or low concentrations of mineral phases. In this research, the ability of biomimetic bone-like apatite deposition on the surface of titanium alloy (Ti6Al4V) substrates in simulated body fluid (SBF) right after alkaline treatment and subsequent heat-treatment was studied by the inherent luminescence properties of apatite. For this purpose, the metallic substrates were treated in 5 M NaOH solution at 60 degrees C. Subsequently, the substrates were heat treated at 600 degrees C for 1 h for consolidation of the sodium titanate hydrogel layer. Then, they were soaked in SBF for different periods of time. Finally, the possibility to use of PL monitoring as an effective method and early detection tool is discussed. According to the obtained results, it was concluded that the PL emission peak did not have any significant shift to the shorter or higher wavelengths, and the PL intensity increased as the exposure time increased. This research proved that the observed inherent PL of the newly formed apatite coatings might be of specific interest for histological probing and bone remodelling monitoring. PMID- 21592748 TI - Synthesis of gold and silver nanoparticles using purified URAK. AB - This study aims at developing a new eco-friendly process for the synthesis of silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) using purified URAK. URAK is a fibrinolytic enzyme produced by Bacillus cereus NK1. The enzyme was purified and used for the synthesis of AuNPs and AgNPs. The enzyme produced AgNPs when incubated with 1 mM AgNO3 for 24 h and AuNPs when incubated with 1 mM HAuCl4 for 60 h. But when NaOH was added, the synthesis was rapid and occurred within 5 min for AgNPs and 12 h for AuNPs. The synthesized nanoparticles were characterized by a peak at 440 nm and 550 nm in the UV-visible spectrum. TEM analysis showed that AgNPs of the size 60 nm and AuNPs of size 20 nm were synthesized. XRD confirmed the crystalline nature of the nanoparticles and AFM showed the morphology of the nanoparticle to be spherical. FT-IR showed that protein was responsible for the synthesis of the nanoparticles. This process is highly simple, versatile and produces AgNPs and AuNPs in environmental friendly manner. Moreover, the synthesized nanoparticles were found to contain immobilized enzyme. Also, URAK was tested on RAW 264.7 macrophage cell line and was found to be non-cytotoxic until 100 MUg/ml. PMID- 21592749 TI - A comparative study of morphology, reactivity and stability of synthesized silver nanoparticles using Bacillus subtilis and Catharanthus roseus (L.) G. Don. AB - Large number of papers has been published recently on the eleventh group metallic elements such as Ag, Au and Cu. Our study was focused on biosynthesis of silver nanoparticles, their morphology, reactivity and stability. We were interested to check these properties in two different samples, S1 and S2, respectively. The biosynthesis of silver nanoparticles was achieved by reacting the samples with 1 mM concentration of silver nitrate, one involves bacteria (S1) and the other involves the plant extract (S2). Spectrophotometric analysis revealed that the particles exhibited two peaks, one at 440 nm (for S1) and the other at 390 nm (for S2). It is well known that longer wavelength corresponds to increase in particle size. Since, S1 has got a longer wavelength; it is not known, whether it forms isolated particles or agglomerates? Morphological characterization has been done by adopting the procedures of Negative staining and Wedge smear preparation methods. This hybrid method may be of interest to study agglomerated particles. Microscopic examination of the smear S1 shows predominantly triangular or hexagonal shaped agglomerated particles which were not observed in S2. Hence further characterization was done using SEM, EDAX and XRD. The S2 particles were in the range of 45-70 nm and were stable for even four months. This study indicated that particle size can be controlled from micrometer to nanometer size by varying biological reductants. PMID- 21592750 TI - Why does the silica-binding protein "Si-tag" bind strongly to silica surfaces? Implications of conformational adaptation of the intrinsically disordered polypeptide to solid surfaces. AB - We recently reported that the bacterial 50S ribosomal protein L2 binds strongly to silica surfaces even in the presence of high salt concentrations, detergents, and denaturants such as 8 M urea. We designated L2 as Si-tag, a fusion tag for immobilizing functional proteins on silica materials. Here we discuss the remarkable properties of the Si-tag polypeptide in order to understand the mechanism underlying this binding. Experimental and theoretical studies have shown that the 60-aa N-terminal region and the 71-aa C-terminal region, both of which are rich in positively charged residues, lack a well-defined three dimensional structure under physiological conditions. This lack of a stable tertiary structure suggests that Si-tag belongs to a family of intrinsically disordered (ID) proteins that exist as dynamic ensembles of rapidly fluctuating structures in aqueous solution. Because of its inherent flexibility, Si-tag could form a large intermolecular interface and optimize its structure for surface interactions by conformational adaptation at the binding interface. Such conformational adaptation occurring concomitantly with binding is common to many ID proteins and is called "coupled folding and binding". Through this conformational adaptation, Si-tag could optimize the interactions between its positively charged side chains and ionized surface silanol groups and between its apolar side chains and hydrophobic surface siloxane sites. The cumulative contribution of these contacts would significantly strengthen the binding of Si tag, resulting in strong, virtually irreversible binding. Our study suggests that flexible ID proteins have tremendous potential for connecting biomolecules to inorganic materials. PMID- 21592751 TI - Development and evaluation of orally disintegrating tablets (ODTs) containing Ibuprofen granules prepared by hot melt extrusion. AB - In the current study Ibuprofen was embedded in a methacrylate copolymer (Eudragit(r) EPO) matrix to produce solid dispersions by hot-melt extrusion (HME) processing. The obtained granules were incorporated in orally disintegrating tablets (ODTs). The tablets were developed by varying the ratio of superdisintegrants such as sodium croscarmellose and crosslinked polyvinylpyrrolidone grades while a direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets which included porosity, hardness, friability and dissolution profiles were further evaluated and compared with Nurofen(r) Meltlet ODTs. The taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and improved tablet palatability. PMID- 21592753 TI - Bayesian network approach to detect laboratory errors: focus on likelihood ratio and critical difference. PMID- 21592754 TI - Radiosurgery versus surgery, both with adjuvant whole brain radiotherapy, for solitary brain metastases: a randomised controlled trial. AB - AIMS: This randomised non-inferiority trial was designed to assess whether radiosurgery plus adjuvant whole brain radiotherapy (RS + WBRT) is as effective as surgery plus whole brain radiotherapy (S + WBRT) for cancer patients with a solitary brain metastasis, with respect to overall survival and quality of life. MATERIALS AND METHODS: Major inclusion criteria were a history of systemic cancer within 5 years and enhanced magnetic resonance imaging-confirmed solitary brain metastasis suitable for both radiosurgery and surgery. All patients were to receive WBRT (30 Gy in 10 fractions). Between February 2003 and April 2009, 40 patients were considered eligible, 22 consented to randomisation and 21 were analysed (11 RS + WBRT, 10 S + WBRT). The trial was closed early due to slow accrual. RESULTS: The estimated median overall survival times for RS + WBRT and S + WBRT patients were 6.2 and 2.8 months, respectively (hazard ratio 0.53, 95% confidence interval 0.20-1.43, P = 0.20). Corresponding median failure-free survival times were 3.1 and 1.7 months (P = 0.20). For 19 'per protocol' patients, 2/10 in the RS + WBRT arm had distant intracranial failure (one also had local failure) and 3/9 S + WBRT patients had distant intracranial failure (no local failures). There were no grade 3-4 late radiation toxicities. Two months after starting treatment there were no significant differences in quality of life between the arms. CONCLUSION: This randomised trial encountered the accrual difficulties and consequent low statistical power commonly associated with interdisciplinary studies drawing from a small eligible population, but can contribute to future overviews on the management of solitary brain metastases. PMID- 21592755 TI - Differential association of proinflammatory cytokines with left ventricular diastolic dysfunction in subjects with and without continuous ambulatory peritoneal dialysis. AB - BACKGROUND AND AIMS: The association between inflammation and left ventricular (LV) diastolic dysfunction in continuous ambulatory peritoneal dialysis (CAPD) and non-CAPD patients is not established. The objective of this study was to test the above association and whether inflammation interacts with CAPD to increase LV diastolic dysfunction risks. METHODS AND RESULTS: 120 subjects with normal creatinine levels and 101 CAPD patients were recruited. Echocardiographic parameters were assessed in all patients. The participants were classified as having LV diastolic dysfunction by echocardiographic findings including mitral inflow E/A ratio < 1, deceleration time > 220 cm/s, or decreased peak annular early diastolic velocity in tissue Doppler imaging. Blood was sampled at the baseline for measurement of inflammation markers, including tissue necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Subjects with LV diastolic dysfunction had higher proinflammation cytokines levels in both groups. Inflamed markers correlated significantly with echocardiography parameters for LV diastolic dysfunction in patients receiving CAPD. In a multivariate regression analysis adjusting for all the factors associated with LV diastolic dysfunction, inflammation is still significantly associated with left ventricular diastolic dysfunction (TNF-alpha, OR: 2.6, 95% CI: 2.0-3.35, p < 0.001; IL-6, OR: 1.26, 95% CI: 1.25-1.26, p = 0.01). In addition, the interaction of CAPD and inflammation significantly contributed to the development of LV diastolic dysfunction (CAPD* TNF-alpha: OR: 1.45, 95% CI: 1.13-1.79, P = 0.004). CONCLUSION: We found inflammation plays a vital role for LV diastolic dysfunction especially in CAPD patients. A synergistic effect between CAPD and inflammation, especially TNF alpha, would further aggravate LV diastolic dysfunction. PMID- 21592756 TI - Pepsin and bile acids in induced sputum of chronic cough patients. AB - One of the theories which explain, why gastroesophageal reflux disease (GORD) may provoke cough, is the occurrence of aspiration of gastric content into the airways. The aim of the study was to assess the presence of aspiration markers: pepsin and bile acids (BA) in induced sputum in gastroesophageal reflux-related (GOR-related) chronic cough (CC) patients. Forty-one CC patients and 20 healthy controls were enrolled in the study. GORD as cause of CC was diagnosed by presence of GORD-related symptoms, gastroscopy and/or improvement of cough upon treatment with proton pump inhibitors (PPI). Patients were divided into two groups based on the response to PPI treatment. In all patients and healthy controls induced sputum was obtained and differential cell counts were calculated. Levels of pepsin and BA were measured in sputum supernatants. Pepsin was detectable in 48.8% samples in CC patients and in 60% healthy controls (p = NS). In pepsin positive samples no significant difference in pepsin concentration could be found between CC patients and control subjects. Pepsin levels in pepsin positive samples were significantly decreased in patients treated with PPI compared to non-treated patients. BA were detectable in 56% samples of CC patients and in 70% healthy controls (p = NS). BA concentration in BA positive samples in CC group was not different from healthy controls. There was also no difference when comparing patients who took PPI and those who did not. Patients characterized as PPI-responders and PPI-non-responders had similar pepsin and BA concentrations. Airway cellularity was not significantly different between groups of patients with or without pepsin or BA in induced sputum. Our results demonstrated the lack of differences in gastric content aspiration between patients with probable GOR-related CC and healthy control subjects. This might imply that the reflex cough theory may be more relevant than the reflux associated aspiration theory in the pathophysiology of GORinduced chronic cough. PMID- 21592757 TI - Eukaryotic cells. PMID- 21592758 TI - Ezrin, Radixin and Moesin: key regulators of membrane-cortex interactions and signaling. AB - The cell cortex serves as a critical nexus between the extracellular environment/cell membrane and the underlying cytoskeleton and cytoplasm. In many cells, the cell cortex is organized and maintained by the Ezrin, Radixin and Moesin (ERM) proteins, which have the ability to interact with both the plasma membrane and filamentous actin. Although this membrane-cytoskeletal linkage function is critical to stability of the cell cortex, recent studies indicate that this is only a part of what ERMs do in many cells. In addition to their role in binding filamentous actin, ERMs regulate signaling pathways through their ability to bind transmembrane receptors and link them to downstream signaling components. In this review we discuss recent evidence in a variety of cells indicating that ERMs serve as scaffolds to facilitate efficient signal transduction on the cytoplasmic face of the plasma membrane. PMID- 21592759 TI - The business cycle and drug use in Australia: evidence from repeated cross sections of individual level data. AB - BACKGROUND: This paper examined the implications of the business cycle for cannabis and alcohol use. What little we know about cannabis use suggests that young Americans (teenagers and adults in their early 20s) seem more inclined to use illicit drugs and to use them more frequently with rises in the unemployment rate. In contrast, a more fulsome alcohol literature suggests that participation in drinking is unaffected by the business cycle. Heavy drinkers drink less during economic downturns and their reduced use counteracts the fact that light drinkers might drink a little more. METHOD: Using individual level data from repeated cross-sections of Australia's National Drug Strategy Household Survey (NDSHS), spanning 1991-2007, this study examined the relationship between cannabis and alcohol use of Australians aged 14-49 years and the unemployment rate and real income per capita, two indicators of the business cycle. RESULTS: Australians in their late 20s, 30s and 40s drink less frequently during economic downturns. If unemployment rate rises are accompanied by falls in income per capita, younger Australians will also drink less frequently. Recent participation in cannabis use (within the last year) increases with falls in income per capita regardless of age, although the increase is less marked for young people (14-24 years). Whereas the participation rate of people aged 25-49 years also falls with rising unemployment rates, the participation of younger people increases. Cannabis users younger than 35 will use more frequently as the unemployment rate rises. In contrast, older Australians will use less frequently. CONCLUSION: Australia's recent economic slowdown has been characterised by rising unemployment rates without accompanying falls in income per capita. Based on our findings this slowdown should have encouraged young Australians aged 14-24 years to both drink and use cannabis more frequently. The slowdown would have had little impact on the frequency of drinking of older Australians. However it should have discouraged older Australians from using cannabis, and encouraged people in their late 30s and 40s to use less frequently, whilst encouraging those aged 25-34 years to use more frequently. PMID- 21592760 TI - Enhanced methane production from ultrasound pre-treated and hygienized dairy cattle slurry. AB - The effect of hygienization (70 degrees C, 60 min) and ultrasound (6000 +/- 500 kJ/kg total solids (TS)) pre-treatments on hydrolysis and biological methane (CH(4)) potential (BMP) of dairy cattle slurry was studied. The BMP of the untreated slurry (control) was 210 +/- 10 Nm(3) CH(4)/ton volatile solids (VS) added; after ultrasound pre-treatment it was 250 +/- 10 Nm(3) CH(4)/ton VS(added) and after hygienization 280 +/- 20 Nm(3) CH(4)/ton VS(added). The specific methanogenic activity (SMA) of the inoculum increased from 22 (untreated) to 26 (ultrasound treated) and up to 28 N ml CH(4)/g VS d, after hygienization. However, only hygienization achieved a positive net energy balance. Both pre treatments increased the VS-based hydrolysis of slurry (10-96%), soluble nitrogen (N(sol)) content in digestates (20 +/- 5%) and biodegradability of the slurry (8 +/- 3%) as estimated via elevated VS removal. PMID- 21592761 TI - Evaluation of self-combustion risk in tire derived aggregate fills. AB - Lightweight tire derived aggregate (TDA) fills are a proven recycling outlet for waste tires, requiring relatively low cost waste processing and being competitively priced against other lightweight fill alternatives. However its value has been marred as several TDA fills have self-combusted during the early applications of this technique. An empirical review of these cases led to prescriptive guidelines from the ASTM aimed at avoiding this problem. This approach has been successful in avoiding further incidents of self-combustion. However, at present there remains no rational method available to quantify self combustion risk in TDA fills. This means that it is not clear which aspects of the ASTM guidelines are essential and which are accessory. This hinders the practical use of TDA fills despite their inherent advantages as lightweight fill. Here a quantitative approach to self-combustion risk evaluation is developed and illustrated with a parametric analysis of an embankment case. This is later particularized to model a reported field self-combustion case. The approach is based on the available experimental observations and incorporates well-tested methodological (ISO corrosion evaluation) and theoretical tools (finite element analysis of coupled heat and mass flow). The results obtained offer clear insights into the critical aspects of the problem, allowing already some meaningful recommendations for guideline revision. PMID- 21592762 TI - Silver nanoparticles as redox reporters for the amplified electrochemical detection of the single base mismatches. AB - In this manuscript, a strategy for the amplification of the responses of an electrochemical DNA hybridization biosensor using silver nanoparticles (Ag-NPs) as redox reporters and its capability for the detection of a single base mismatches (SBM) including thermodynamically stable ones, is described. In this assay, Ag-NPs are immobilized on the top of recognition layer and their oxidation signals are followed. Differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) are used to monitoring the electrode response. Only for complementary target sequence, electron can transfer between Electrode surface and nanoparticles via DNA and Ag-NPs can be oxidized. Therefore this DNA biosensor could differentiate between complementary target and one containing either SBM or thermodynamically stable G-A and G-T targets through oxidation signal of Ag-NPs. This biosensor is able to detect SBM by overcome the direct electron transfer of redox reporter with electrode surface and positioning of it before the mismatch position. PMID- 21592763 TI - Bi-enzyme functionlized hollow PtCo nanochains as labels for an electrochemical aptasensor. AB - In this work, a new signal amplification strategy based on hollow PtCo nanochains (HPtCoNCs) functionalized by bi-enzyme-horseradish peroxidase mimicking DNAzyme (HRP-DNAzyme) and glucose oxidase (GOD), as well as ferrocene-labeled secondary thrombin aptamer (Fc-TBA 2), is developed to construct a highly sensitive electrochemical aptasensor. The HRP-DNAzyme contains a special G-quadruplex structure with an intercalated hemin. With the surface area enlarged by HPtCoNCs, the amount of immobilized Fc-TBA 2, hemin and GOD can be enhanced. Under the enzyme catalysis of GOD, d-glucose is rapidly oxidized into gluconic acid accompanying with the generation of H2O2, which is further electrocatalyzed by Pt nanoparticles and HPR-DNAzyme to improve the electrochemical signal of Fc. With several amplification factors mentioned above, a wide linear ranged from 0.001 to 30 nM is acquired with a relatively low detection limit of 0.39 pM for thrombin. The present work demonstrates that using HPtCoNCs as labels is a promising way to amplify the analysis signal and improve the sensitivity of aptasensors. PMID- 21592764 TI - Intravascular glucose/lactate sensors prepared with nitric oxide releasing poly(lactide-co-glycolide)-based coatings for enhanced biocompatibility. AB - Intravenous amperometric needle-type enzymatic glucose/lactate sensors intended for continuous monitoring are prepared with a novel nitric oxide (NO) releasing layer to improve device hemocompatibility. To create an underlying NO release coating, the sensors with immobilized enzymes (either glucose oxidase or lactate oxidase) are prepared with a thin layer of poly(lactide-co-glycolide) (PLGA) loaded with lipophilic diazeniumdiolate species that slowly release NO via a proton driven reaction. An outer thin layer (ca. 30 MUm) of PurSil (polyurethane/dimethylsiloxane copolymer) limits the flux of glucose and lactate to the inner layer of enzyme, to provide the desired linear amperometric response. A 30 MUm coating of PLGA containing 33 wt% of the appropriate NO donor (N-diazeniumdiolated dibutylhexanediamine, DBHD/N2O2) can release NO at a physiologically relevant rate > 1 * 10-10mol min-1 cm-2 for at least 7 days without influencing the analytical performance of the glucose/lactate sensors. In vitro, the sensors exhibit relatively stable amperometric response over a one week period with high selectivity over interferences (e.g., ascorbic acid) required for blood monitoring applications. Glucose sensors implanted in the veins of rabbits for 8h exhibit significantly enhanced hemocompatibility for the NO release sensors vs. corresponding controls (without NO release in same animals), with greatly reduced thrombus formation on their surfaces. Further, the analytical performance of the NO release glucose sensors are superior to controls placed in the veins of the same animals, with a greater accuracy in measuring blood glucose levels as evaluated using a Clarke error grid type analysis. PMID- 21592765 TI - Paper based point-of-care testing disc for multiplex whole cell bacteria analysis. AB - Point-of-care testing (POCT) of infectious bacterial agents offers substantial benefits for disease diagnosis, mainly by shortening the time required to obtain results and by making the test available bedside or at remote care centers. Immunochromatographic lateral flow biosensors offer a low cost, highly sensitive platform for POCT. In this article, we describe the fabrication and testing of a multiplex immuno-disc sensor for the specific detection of Pseudomonas aeruginosa and Staphylococcus aureus. Antibody conjugated gold nanoparticles were used as the signaling agents. The detection range of the bacteria lies within 500-5000 CFU/ml. The advantage of the immuno-disc sensor is that it does not require any preprocessing of biological sample and is capable of whole cell bacterial detection. We also describe the design and fabrication of a compact portable device which converts the color intensity of the gold nanoparticles that accumulate at the test region into a quantitative voltage reading proportional to the bacterial concentration in the sample. The combination of the immuno-disc and the portable color reader provides a rapid, sensitive, low cost, and quantitative tool for the detection of a panel of infectious agents present in the patient sample. PMID- 21592766 TI - Extradiol dioxygenase-SiO2 sol-gel modified electrode for catechol and its derivatives detection. AB - A feasible and sensitive biosensor for catechol and its derivatives using 2,3 dihydroxybiphenyl 1,2-dioxygenase (BphC)-modified glassy carbon electrode was successfully constructed by polyvinyl alcohol-modified SiO2 sol-gel method. The as-prepared biosensor was characterized by electrochemical impedance spectroscopy, and the surface topography of the film was imaged by atomic force microscope. Liquid chromatography-tandem mass spectrometry was applied to reveal the catalytic mechanism. BphC embedded in SiO2 gel maintained its bioactivity well and exhibited excellent eletrocatalytical response to both catechol and some of its derivatives (such as 3-methylcatechol and 4-methylcatechol). The biosensor showed a linear amperometric response range between 0.002 mM and 0.8 mM catechol. And the sensitivity was 1.268 mA/(mM cm2) with a detection limit of 0.428 MUM for catechol (S/N = 3). Furthermore, the BphC biosensor exhibited perfect selectivity for catechol in the mixtures of catechol and phenol. It was suggested that this flexible protocol would open up a new avenue for designing other ring-cleavage enzyme biosensors, which could be widely used for monitoring various kinds of environmental pollutants. PMID- 21592767 TI - Nanoflake-like SnS2 matrix for glucose biosensing based on direct electrochemistry of glucose oxidase. AB - A novel biosensor is developed based on immobilization of proteins on nanoflake like SnS2 modified glass carbon electrode (GCE). With glucose oxidase (GOD) as a model, direct electrochemistry of the GOD/nanoflake-like SnS2 is studied. The prepared SnS2 has large surface area and can offer favorable microenvironment for facilitating the electron transfer between protein and electrode surface. The properties of GOD/SnS2 are characterized by scanning electron microscopy (SEM), X ray diffraction (XRD), UV-vis spectroscopy, Fourier transform infrared spectroscopy (FTIR) and cyclic voltammetry (CV), respectively. The immobilized enzyme on nanoflake-like SnS2 retains its native structure and bioactivity and exhibits a surface-controlled, reversible two-proton and two-electron transfer reaction with the apparent electron transfer rate constant (k(s)) of 3.68 s-1. The proposed biosensor shows fast amperometric response (8s) to glucose with a wide linear range from 2.5 * 10-5 M to 1.1 * 10-3 M, a low detection limit of 1.0 * 10-5 M at signal-to-noise of 3 and good sensitivity (7.6 +/- 0.5 mA M-1 cm-2). The resulting biosensor has acceptable operational stability, good reproducibility and excellent selectivity and can be successfully applied in the reagentless glucose sensing at -0.45 V. It should be worthwhile noting that it opens a new avenue for fabricating excellent electrochemical biosensor. PMID- 21592768 TI - Polypyrrole-based bilayer nitrate amperometric biosensor with an integrated permselective poly-ortho-phenylenediamine layer for exclusion of inorganic interferences. AB - A bilayer amperometric nitrate biosensor with an integrated permselective layer has been developed for exclusion of inorganic anion and cation interferences. The inner PPy(polypyrrole)-NaR-NADH layer of the biosensor is formed by galvanostatic polymerization of pyrrole (Py) in presence of nitrate reductase (NaR) and nicotinamide adenine dinucleotide (NADH), followed by formation of the outer permselective poly-ortho-phenylenediamine (P-o-PDA) layer by potentiodynamic polymerization of ortho-phenylenediamine (o-PDA). The exclusion efficiency (E(eff)) of the outer layer in rejecting inorganic cation and anion interferences is evaluated by a new proposed relationship. 73-87% and 47-84% of anion and cation interferences, respectively, were efficiently rejected with the permselective layer. Further improvement in the exclusion efficiency for cations was accomplished by combining the use of the outer layer with the addition of 1mM EDTA into the measurement solution. The addition of EDTA improved the E(eff) achieved for cation rejection by 10-40% to give net E(eff) of 89-94%. The inclusion of the outer layer also aided the retention of NaR and NADH in the inner PPy-NaR-NADH layer and, hence, enabled improved amperometric detection of nitrate, achieving a detection limit of 0.20 MUM and a linear concentration range of 10-500 MUM with a 3.4%rsd (n=10). PMID- 21592769 TI - Green-synthesized gold nanoparticles decorated graphene sheets for label-free electrochemical impedance DNA hybridization biosensing. AB - Sensitive electrochemical impedance assay of DNA hybridization by using a novel graphene sheets platform was achieved. The graphene sheets were firstly functionalized with 3,4,9,10-perylene tetracarboxylic acid (PTCA). PTCA molecules separated graphene sheets efficiently and introduced more negatively-charged COOH sites, both of which were beneficial to the decoration of graphene with gold nanoparticles. Then amine-terminated ionic liquid (NH2-IL) was applied to the reduction of HAuCl4 to gold nanoparticles. The green-synthesized gold nanoparticles, with the mean diameter of 3 nm, dispersed uniformly on graphene sheets and its outer layer was positively charged imidazole termini. Due to the presence of large graphene sheets and NH2-IL protected gold nanoparticles, DNA probes could be immobilized via electrostatic interaction and adsorption effect. Electrochemical impedance value increased after DNA probes immobilization and hybridization, which was adopted as the signal for label-free DNA hybridization detection. Unlike previously anchoring DNA to gold nanoparticles, this label-free method was simple and noninvasive. The conserved sequence of the pol gene of human immunodeficiency virus 1 was satisfactorily detected via this strategy. PMID- 21592770 TI - An autonomous CMOS hysteretic sensor for the detection of desorption-free DNA hybridization. AB - This paper describes a sensor for label-free, fully electrical detection of DNA hybridization based on capacitive changes in the electrode-electrolyte interface. The sensor measures capacitive changes in real time according to a charging discharging principle that is limited by the hysteresis window. In addition, a novel autonomous searching technique, which exclusively monitors desorption-free hybridized electrodes among electrode arrays, enhances the performance of the sensor compared with conventional capacitive measurement. The sensor system achieves a detection range of 80 dB. The integrated circuit sensor is fabricated with a 0.35 MUm CMOS process. The proposed sensor offers rapid, robust and inexpensive measurement of capacitance with highly integrated detection circuitry. It also facilitates quantitative evaluations of molecular densities on a chip with distinctive impedance variations by monitoring desorption-free hybridized electrodes. Our electrical biosensor has great potential for use with bio analytical tools and point-of-care diagnosis. PMID- 21592771 TI - Glycosyltransferase structural biology and its role in the design of catalysts for glycosylation. AB - Glycosyltransferases (GTs) are ubiquitous in nature and are required for the transfer of sugars to a variety of important biomolecules. This essential enzyme family has been a focus of attention from both the perspective of a potential drug target and a catalyst for the development of vaccines, biopharmaceuticals and small molecule therapeutics. This review attempts to consolidate the emerging lessons from Leloir (nucleotide-dependent) GT structural biology studies and recent applications of these fundamentals toward rational engineering of glycosylation catalysts. PMID- 21592772 TI - Applications of viral nanoparticles in medicine. AB - Several nanoparticle platforms are currently being developed for applications in medicine, including both synthetic materials and naturally occurring bionanomaterials such as viral nanoparticles (VNPs) and their genome-free counterparts, virus-like particles (VLPs). A broad range of genetic and chemical engineering methods have been established that allow VNP/VLP formulations to carry large payloads of imaging reagents or drugs. Furthermore, targeted VNPs and VLPs can be generated by including peptide ligands on the particle surface. In this article, we highlight state-of-the-art virus engineering principles and discuss recent advances that bring potential biomedical applications a step closer. Viral nanotechnology has now come of age and it will not be long before these formulations assume a prominent role in the clinic. PMID- 21592773 TI - Microbial energy conversion revisited. PMID- 21592774 TI - Gene dispensability. AB - Genome-wide mutagenesis studies indicate that up to about 90% of genes in bacteria and 80% in eukaryotes can be inactivated individually leaving an organism viable, often seemingly unaffected. Several strategies are used to learn what these apparently dispensable genes contribute to fitness. Assays of growth under hundreds of physical and chemical stresses are among the most effective experimental approaches. Comparative studies of genomic DNA sequences continue to be valuable in discriminating between the core bacterial genome and the more variable niche-specific genes. The concept of the core genome appears currently unfeasible for eukaryotes but progress has been made in understanding why they contain numerous gene duplicates. PMID- 21592776 TI - Engineering genomes in multiplex. AB - Efficiently engineering robust complex traits is a key challenge facing metabolic engineering efforts to synthesize valuable products in vivo. Recent advances in genome engineering confront this barrier and significantly enhance the ability to map functional changes targeted throughout the genome and combinatorially optimize complex (multigenic) traits using multiplex recombineering. We describe a framework for efficiently searching genome-wide combinatorial space to optimize complex traits and highlight recent advances in genome engineering that enable this approach. PMID- 21592775 TI - Bacterial growth laws and their applications. AB - Quantitative empirical relationships between cell composition and growth rate played an important role in the early days of microbiology. Gradually, the focus of the field began to shift from growth physiology to the ever more elaborate molecular mechanisms of regulation employed by the organisms. Advances in systems biology and biotechnology have renewed interest in the physiology of the cell as a whole. Furthermore, gene expression is known to be intimately coupled to the growth state of the cell. Here, we review recent efforts in characterizing such couplings, particularly the quantitative phenomenological approaches exploiting bacterial 'growth laws.' These approaches point toward underlying design principles that can guide the predictive manipulation of cell behavior in the absence of molecular details. PMID- 21592777 TI - Ecosystems biology of microbial metabolism. AB - The metabolic capabilities of many environmentally and medically important microbes can be quantitatively explored using systems biology approaches to metabolic networks. Yet, as we learn more about the complex microbe-microbe and microbe-environment interactions in microbial communities, it is important to understand whether and how system-level approaches can be extended to the ecosystem level. Here we summarize recent work that addresses these challenges at multiple scales, starting from two-species natural and synthetic ecology models, up to biosphere-level approaches. Among the many fascinating open challenges in this field is whether the integration of high throughput sequencing methods and mathematical models will help us capture emerging principles of ecosystem-level metabolic organization and evolution. PMID- 21592779 TI - FOXP2 and the role of cortico-basal ganglia circuits in speech and language evolution. AB - PURPOSE OF THE REVIEW: A reduced dosage of the transcription factor FOXP2 leads to speech and language impairments probably owing to deficits in cortical and subcortical neural circuits. Based on evolutionary sequence analysis it has been proposed that the two amino acid substitutions that occurred on the human lineage have been positively selected. Here I review recent studies investigating the functional consequences of these two substitutions and discuss how these first endeavors to study human brain evolution can be interpreted in the context of speech and language evolution. RECENT FINDINGS: Mice carrying the two substitutions in their endogenous Foxp2 gene show specific alterations in dopamine levels, striatal synaptic plasticity and neuronal morphology. Mice carrying only one functional Foxp2, show additional and partly opposite effects suggesting that FOXP2 has contributed to tuning cortico-basal ganglia circuits during human evolution. Evidence from human and songbird studies suggest that this could have been relevant during language acquisition or vocal learning, respectively. SUMMARY: FOXP2 could have contributed to the evolution of human speech and language by adapting cortico-basal ganglia circuits. More generally the recent studies allow careful optimism that aspects of human brain evolution can be investigated in model systems such as the mouse. PMID- 21592780 TI - Alternative conceptions of memory consolidation and the role of the hippocampus at the systems level in rodents. AB - We discuss very recent experiments with rodents addressing the idea that long term memories initially depending on the hippocampus, over a prolonged period, become independent of it. No unambiguous recent evidence exists to substantiate that this occurs. Most experiments find that recent and remote memories are equally affected by hippocampus damage. Nearly all experiments that report spared remote memories suffer from two problems: retrieval could be based upon substantial regions of spared hippocampus and recent memory is tested at intervals that are of the same order of magnitude as cellular consolidation. Accordingly, we point the way beyond systems consolidation theories, both the Standard Model of Consolidation and the Multiple Trace Theory, and propose a simpler multiple storage site hypothesis. On this view, with event reiterations, different memory representations are independently established in multiple networks. Many detailed memories always depend on the hippocampus; the others may be established and maintained independently. PMID- 21592778 TI - Control of microRNA biogenesis and transcription by cell signaling pathways. AB - A limited set of cell-cell signaling pathways presides over the vast majority of animal developmental events. The typical raison d'etre for signal transduction is to control the transcription of protein-coding genes. However, with the recent appreciation of microRNAs, growing attention has been paid towards understanding how signaling pathways intertwine with microRNA-mediated regulation. This review highlights recent studies that uncover unexpected modes of microRNA regulation by cell signaling pathways. Not only can miRNA transcription be positively or negatively regulated by cell signaling, the TGF-beta/BMP pathways and Ras/MAPK pathways have now been shown to directly influence microRNA biogenesis to mediate substantial cellular phenotypes. PMID- 21592781 TI - Levels of acute health service use among cancer survivors in the United Kingdom. AB - BACKGROUND: In the United Kingdom, there are approximately two million cancer survivors (3.2% of the entire population), composed of groups of people in different phases of survivorship and with different health service needs. The aim of this study was to quantify the level of acute health service utilisation by cancer survivors in the UK, according to tumour type, age, sex, time since diagnosis, and time until death. METHODS: Linked national cancer registry and hospital activity data were analysed. The data covered all cancer-related admissions to public hospitals operated by the National Health Service in England occurring in 2006 among people diagnosed with cancer in the period 1990-2006. The intensity of cancer-related health service utilisation was categorised as 'none', 'low' (up to 10% of an individual's time), or 'high' (>10% of an individual's time), among groups defined by time since diagnosis and time until death. Results were extrapolated from the population of England in 2006 (51 million) to that of the UK in 2008 (61 million). FINDINGS: Sixty one thousand of the two million cancer survivors (3%) were in the 'high' utilisation category; 240,000 (12%) were in the 'low' category; 1.70 million (85%) had no cancer-related hospital admissions. 147,000 cancer survivors (7%) were in the last year of their life, and it was this group that had the highest levels of hospital utilisation. 1.57 million cancer survivors (78%) were more than 1 year from both diagnosis and death, and had no cancer related hospital admissions. INTERPRETATION: A considerable proportion of cancer survivors in the UK have a high level of hospital utilisation soon after diagnosis or before death, but the large majority of them are neither recently diagnosed nor near the end of their life, and do not utilise acute health services for cancer-related care. PMID- 21592782 TI - Trehalose overproduction affects the stress tolerance of Kluyveromyces marxianus ambiguously. AB - A thermotolerant Kluyveromyces marxianus mutant was developed by exposing yeast cultures repeatedly to 48 degrees C incubation temperature, and the strain was characterized with a significantly increased trehalose content. Unexpectedly, the strain was sensitive to alcohol, osmotic and oxidative stress, which correlated with the increases in the trehalose concentrations. Intracellular glutathione levels declined in both wild-type and mutant cells when exposed to elevating incubation temperatures. Finally, we reached the surprising conclusion that neither trehalose nor glutathione metabolisms should be aimed at in future strain development programs with K. marxianus. PMID- 21592783 TI - Eliminating methanogenic activity in hydrogen reactor to improve biogas production in a two-stage anaerobic digestion process co-digesting municipal food waste and sewage sludge. AB - Laboratory scale two-stage anaerobic digestion process model was operated for 280 days to investigate the feasibility to produce both hydrogen and methane from a mixture feedstock (1:1 (v/v)) of municipal food waste and sewage sludge. The maximum hydrogen and methane yields obtained in the two stages were 0.93 and 9.5 mL/mL feedstock. To eliminate methanogenic activity and obtain substantial hydrogen production in the hydrogen reactor, both feedstock and mixed liquor required treatment. The heat treatment (100 degrees C, 10 min) for feedstock and a periodical treatment (every 2-5 weeks, either heating, removal of biomass particles or flushing with air) for mixed liquor were effective in different extent. The methane production in the second stage was significantly improved by the hydrogen production in the first stage. The maximum methane production obtained in the period of high hydrogen production was more than 2-fold of that observed in the low hydrogen production period. PMID- 21592784 TI - Use of glycerol for producing 1,3-dihydroxyacetone by Gluconobacter oxydans in an airlift bioreactor. AB - 1,3-Dihydroxyacetone can be produced by biotransformation of glycerol with glycerol dehydrogenase from Gluconobacter oxydans cells. Firstly, improvement the activity of glycerol dehydrogenase was carried out by medium optimization. The optimal medium for cell cultivation was composed of 5.6g/l yeast extract, 4.7 g/l glycerol, 42.1g/l mannitol, 0.5 g/l K(2)HPO(4), 0.5 g/l KH(2)PO(4), 0.1g/l MgSO(4).7H(2)O, and 2.0 g/l CaCO(3) with the initial pH of 4.9. Secondly, an internal loop airlift bioreactor was applied for DHA production from glycerol by resting cells of G. oxydans ZJB09113. Furthermore, the effects of pH, aeration rate and cell content on DHA production and glycerol feeding strategy were investigated. 156.3 +/- 7.8 g/l of maximal DHA concentration with 89.8+/-2.4% of conversion rate of glycerol to DHA was achieved after 72h of biotransformation using 10g/l resting cells at 30 degrees C, pH 5.0 and 1.5vvm of aeration rate. PMID- 21592785 TI - Water extraction of pyrolysis oil: the first step for the recovery of renewable chemicals. AB - The interest in biomass as a source of renewable energy and chemicals has been increasing in keeping up with the transition to a sustainable bio-based economy. An important initial step of chemicals recovery from biomass-derived pyrolysis oil is water extraction where most of polar compounds are isolated in the aqueous phase. This study was done to investigate the effects of stirring rate and water to-oil ratio on the extraction capability (distribution coefficient and yield), water content, and atomic composition of both aqueous and organic phases. The results show that the stirring rate above 300 rpm has no influence on the equilibrium. Increasing the water-to-oil ratio dilutes the aqueous phase without changing the atomic distribution. Forest residue-derived pyrolysis oil should be extracted at a water-to-oil ratio of 0.65-0.7, whereas pine-derived pyrolysis oil is preferably extracted at the lowest feasible water-to-oil ratio where complete phase separation occurs, which is 0.5 in this study. PMID- 21592786 TI - NO formation during agricultural straw combustion. AB - NO formation during combustion of four typical kinds of straw (wheat straw, rice straw, cotton stalk and corn stalk) which belong to soft straw and hard straw was studied in a tubular quartz fixed bed reactor under conditions relevant to grate boiler combustion. Regarding the real situation in biomass fired power plants in China, NO formation from blended straw combustion was also investigated. Nitrogen transfer during blended straw pyrolysis was performed using a thermogravimetric analyzer (TGA) coupled with a Fourier transform infrared (FTIR) spectrometer. The results show that NO conversion for the four straws during combustion is distinctive. Over 70% fuel-N converts into NO for cotton stalk, while only 37% for wheat straw under the same condition. When wheat straw and cotton stalk were mixed, N-NO conversion increases. The limestone addition promotes NO emission during cotton stalk combustion. The presence of SO(2) in atmosphere suppresses NO formation from straw combustion. PMID- 21592787 TI - Study on a fixed zeolite bioreactor for anaerobic digestion of ammonium-rich swine wastes. AB - In this study, a fixed zeolite bioreactor was developed for the anaerobic digestion of ammonium-rich swine wastes (NH(4)(+)-N=3770 mg/l). To investigate the performance of the reactor, a sunken zeolite bioreactor and a bioreactor without zeolite were used as controls. The new bioreactor exhibited good performance, with startup time on the 14th day and methane production of 178.5 ml/g-VS during all 32 days of the experiment at 35 degrees C. This bioreactor significantly shortened startup time, enhanced methane gas yield more than twofold and made COD removal more efficient than under the other models. Furthermore, it reduced the inhibition of high ammonium concentration during the anaerobic digestion of ammonium-rich swine wastes via effective ammonium removal and the immobilisation of microorganisms. Because of its simple structure and good performance, the fixed zeolite bioreactor can be recommended for future use. PMID- 21592788 TI - Synthesis and biological evaluation of desmethylveramiline, a micromolar Hedgehog inhibitor. AB - Desmethylveramiline (1), an aza steroid analogue of veramiline was designed as a surrogate for cyclopamine, a reference antagonist of the Sonic Hedgehog (Shh) pathway. Desmethyveramiline (1) was prepared in seven steps from commercially available Fernholtz acid using the hydroformylation of a terminal olefine as the key step for the construction of the piperidine appendage. In two assays (i) the inhibition of the Shh-induced Gli-dependent luciferase activity in Shh-light2 cells, (ii) the inhibition of the SAG-induced differentiation of the mesenchymal C3H10T1/2 cells, desmethylveramiline (1) is an inhibitor in the MUM range comparable to cyclopamine. PMID- 21592789 TI - Indole 5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase with nanomolar potency in cell-based subgenomic replicons (part 2): central amino acid linker and right-hand-side SAR studies. AB - In this part 2, new indole 5-carboxamide Thumb Pocket 1 inhibitors of HCV NS5B polymerase are described. Structure-activity relationships (SAR) were explored at the central amino acid linker position and the right-hand-side of the molecule in an attempt to identify molecules with a balanced overall profile of potency (EC(50)<100 nM), physicochemical properties and ADME characteristics. PMID- 21592791 TI - Switching between agonists and antagonists at CRTh2 in a series of highly potent and selective biaryl phenoxyacetic acids. AB - A novel series of biaryl phenoxyacetic acids was discovered as potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A hit compound 4 was discovered from high throughput screening. Modulation of multiple aryl substituents afforded both agonists and antagonists, with small changes often reversing the mode of action. Understanding the complex SAR allowed design of potent antagonists such as potential candidate 34. PMID- 21592790 TI - Chemoenzymatic synthesis of C8-modified sialic acids and related alpha2-3- and alpha2-6-linked sialosides. AB - Naturally occurring 8-O-methylated sialic acids, including 8-O-methyl-N acetylneuraminic acid and 8-O-methyl-N-glycolylneuraminic acid, along with 8-O methyl-2-keto-3-deoxy-d-glycero-d-galacto-nonulosonic acid (Kdn8Me) and 8-deoxy Kdn were synthesized from corresponding 5-O-modified six-carbon monosaccharides and pyruvate using a sialic acid aldolase cloned from Pasteurella multocida strain P-1059 (PmNanA). In addition, alpha2-3- and alpha2-6-linked sialyltrisaccharides containing Neu5Ac8Me and Kdn8Deoxy were also synthesized using a one-pot multienzyme approach. The strategy reported here provides an efficient approach to produce glycans containing various C8-modified sialic acids for biological evaluations. PMID- 21592792 TI - N-methylimidazolium chloride-catalyzed pyrophosphate formation: application to the synthesis of Lipid I and NDP-sugar donors. AB - N-Methylimidazolium chloride is found to catalyze a coupling reaction between monophosphates and activated phosphorous-nitrogen intermediates such as a phosphorimidazolide and phosphoromorpholidate to form biologically important unsymmetrical pyrophosphate diesters. The catalyst is much more active, cheaper, and less explosive than 1H-tetrazole, known as the best catalyst for the pyrophosphate formation over a decade. The mild and neutral reaction conditions are compatible with allylic pyrophosphate formation in Lipid I syntheisis. (31)P NMR experiments suggest that the catalyst acts not only as an acid but also as a nucleophile to form cationic and electrophilic phosphor-N-methylimidazolide intermediates in the pyrophosphate formation. PMID- 21592794 TI - Glucosides with cyclic diarylpolynoid as novel C-aryl glucoside SGLT2 inhibitors. AB - Novel C-aryl glucoside SGLT2 inhibitors containing cyclic diarylpolynoid motif were designed and synthesized for biological evaluation. Alkylzinc bromides have been efficiently prepared by the direct insertion of zinc metal into alkyl bromides. The organozinc reagents underwent smooth Pd-catalyzed cross-coupling reactions. Subsequent ring closing metathesis using 2nd generation Grubbs catalyst successfully generated novel class of ansa-compounds. These glucosides with cyclic diarylpolynoids demonstrated moderate in vitro inhibitory activity against SGLT2 in this series to date (IC(50)=59.5-103 nM). PMID- 21592793 TI - Synthesis and application of an N-acylated l-homoserine lactone derivatized affinity matrix for the isolation of quorum sensing signal receptors. AB - The design and synthesis of an agarose resin functionalized with a Gram-negative quorum sensing (QS) signaling molecule analogue is described. The modified resin was utilized in affinity pull-down assays to successfully isolate QscR, a LuxR type QS receptor from Pseudomonas aeruginosa. This resin may facilitate the identification of novel QS signal receptors using affinity chromatography techniques. PMID- 21592795 TI - Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromso Study. AB - In this cross-sectional study we assessed the prevalence of hyperCKemia, defined as persistent CK values >=210 U/L in women, >=400 U/L in men <50 years and >=280 U/L in men >=50 years (reference values according to the Nordic Reference Interval Project). Blood samples were obtained from 12,828 participants in the 6th survey of The Tromso Study. We identified 686 (5.3%) individuals with incidentally elevated CK. After a standardized control test, 169 persons (1.3%) had persistent hyperCKemia, i.e. 69.9% normalization. Use of statins or other causes of hyperCKemia were detected in 78 individuals (46.2%), giving a prevalence of "idiopathic hyperCKemia" of 0.71%. CK variation was highest in younger men and in females between 60 and 69 years. This study has identified persistent hyperCKemia in 1.3% of the normal population, and demonstrates the importance of performing controlled CK analyses, also in those with identified risk factors. PMID- 21592796 TI - A new window on neurocognitive dysfunction in the childhood form of myotonic dystrophy type 1 (DM1). AB - Not much is known about the neurocognitive deficits in the childhood phenotypic expression of DM1. Twenty-four children and adolescents with no mental retardation were administered an extensive neuropsychological battery to investigate cognition in terms of memory, executive functions and visuo-spatial abilities. The results showed discrepancies between Wechsler's indexes with higher scores in Verbal Comprehension than Perceptive Organization and Speed of Processing. Memory assessment using Signoret's Memory Battery revealed a clear difference between verbal and visuospatial memory but no impairment between short and long-term memory. Concerning executive abilities, DM1 subjects showed greater deficits in processing speed than in mental flexibility, inhibition or working memory. This pattern of deficits could implicate a frontoparietal circuit in accordance with the neural networks involved in the adult form of DM1 and reopens the question of a continuum between childhood and adulthood neurocognitive impairments. PMID- 21592798 TI - Decompressive craniectomy for malignant middle cerebral artery infarction: evidence and controversies. AB - Malignant middle cerebral artery (MCA) infarction (MMI) is associated with a mortality rate of 80%. Decompressive craniectomy is considered a life-saving procedure for patients with this devastating condition. Preclinical and clinical data suggest that this procedure should be undertaken as early as possible, prompting increasing demand for emergency surgery. This article reviews the pathophysiology of MMI, and the experimental and clinical evidence supporting this procedure. We consider some of the controversies surrounding patient selection for this procedure and discuss the role of intracranial pressure monitoring in MMI. PMID- 21592797 TI - Formation of mammalian erythrocytes: chromatin condensation and enucleation. AB - In all vertebrates, the cell nucleus becomes highly condensed and transcriptionally inactive during the final stages of red cell biogenesis. Enucleation, the process by which the nucleus is extruded by budding off from the erythroblast, is unique to mammals. Enucleation has critical physiological and evolutionary significance in that it allows an elevation of hemoglobin levels in the blood and also gives red cells their flexible biconcave shape. Recent experiments reveal that enucleation involves multiple molecular and cellular pathways that include histone deacetylation, actin polymerization, cytokinesis, cell-matrix interactions, specific microRNAs and vesicle trafficking; many evolutionarily conserved proteins and genes have been recruited to participate in this uniquely mammalian process. In this review, we discuss recent advances in mammalian erythroblast chromatin condensation and enucleation, and conclude with our perspectives on future studies. PMID- 21592799 TI - Cross-cultural adaptation and validation of the Portuguese version of the Oxford Knee Score (OKS). AB - The purpose of this study was to translate and culturally adapt the Oxford Knee Score (OKS) to the Portuguese language and to test its reliability and validity. This new version was obtained with forward/backward translations, consensus panels and a pre-test. The Portuguese OKS and Medical Outcomes Study - 36 item Short Form (SF-36) questionnaires, visual analog scales (VAS) of pain and disability, and a form for the characteristics of the patients were administered to 80 subjects who underwent total knee replacement (TKR) for severe knee osteoarthritis (OA). Reliability was acceptable with a Cronbach's alpha coefficient of 0.87, and an intraclass correlation coefficient (ICC) of 0.97. Construct validity was supported by the confirmation of three predefined hypotheses involving expected significant correlations between OKS scale, SF-36 subscales and VAS that represent similar constructs. The Portuguese OKS exhibited suitable psychometric properties, in terms of internal consistency, reproducibility and construct validity. PMID- 21592800 TI - The square conformation of phenylglycine-incorporated ascidiacyclamide is stabilized by CH/pi interactions between amino acid side chains. AB - We designed a phenylglycine (Phg)-incorporated ascidiacyclamide (ASC) analogue, cyclo(-Phg-oxazoline-d-Val-thiazole-Ile-oxazoline-d-Val-thiazole- ([Phg]ASC), with the aim of stabilizing the square conformation of ASC through interactions between amino acid side chains. X-ray diffraction analysis showed that [Phg]ASC has a square structure, similar to ASC, in which the sec-butyl group of Ile and the benzene ring of Phg are in close proximity. Consistent with that finding, 1H NMR experiments revealed significant high-field shifts in the sec-butyl group of Ile, which suggests a potential for CH/pi interactions between the sec-butyl group of Ile and the benzene ring of Phg. The CD spectra of [Phg]ASC were less affected by TFE titration or increasing temperature than those of ASC. In addition, [Phg]ASC showed approximately three times greater toxicity toward HL-60 cells than ASC. Thus the potently cytotoxic conformation of [Phg]ASC may be stabilized by CH/pi interactions between the side chains of the Ile and Phg residues. PMID- 21592801 TI - Antimycobacterial activity of novel 1,2,4-oxadiazole-pyranopyridine/chromene hybrids generated by chemoselective 1,3-dipolar cycloadditions of nitrile oxides. AB - The 1,3-dipolar cycloaddition of nitrile oxides generated in situ from benzohydroximinoyl chloride and triethylamine to 2-aminopyranopyridine-3 carbonitriles and 2-aminochromene-3-carbonitriles occurred chemoselectively furnishing novel 1,2,4-oxadiazole-pyranopyridine/chromene hybrid heterocycles in moderate yields. In vitro screening of these compounds against Mycobacterium tuberculosis H37Rv (MTB) disclosed that the 1,2,4-oxadiazole-pyranopyridine hybrids display enhanced activity relative to the 1,2,4-oxadiazole-chromene hybrids. Among the compounds screened, 3-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5 yl]-4-(2,4-dichlorophenyl)-8-[(E)-(2,4-dichlorophenyl)-methylidene]-6-methyl 5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (MIC: 0.31 MUM) is 1.2, 15.2 and 24.6 times more active than standard antitubercular drugs, viz. isoniazid, ciprofloxacin and ethambutol, respectively. PMID- 21592802 TI - Electron microscopy and in situ testing of mechanical deformation of carbon nanotubes. AB - In this paper, the electron diffraction technique to determine the helicity and atomic structure of carbon nanotubes is reviewed, as well as different mechanical test methods, tensile test, bending test, compression test and vibration test of carbon nanotubes by in situ electron microscopy are summarized while the relationship between mechanical properties and structures revealed by experiments is addressed. Except for these, the electric current and electron beam irradiation effect and some other novel electron microscopy experiments are also incorporated. PMID- 21592803 TI - Measurement limits to 134Cs concentration in soil. AB - We investigate the caesium concentrations in soils in mountain areas near Gori nuclear power plant in Korea, focusing on the measurement limits to the (134)Cs. In order to lower the minimum detectable amount (MDA) of activity for the (134)Cs, we have used the ammonium molybdophosphate (AMP) precipitation method to get rid of the (40)K existing in natural radioactivity, which reduces the MDA activity about 10 times smaller than those without the AMP precipitation method. The MDA results for the (134)Cs were found to be in the range between 0.015 and 0.044 Bq/kg-dry weight. In order to diminish the background, we also have measured a part of the soil samples in Yangyang, a small town in the east coast of Korea. However, it turns out that in order to detect the (134)Cs in the samples the MDA should be reduced to the level of mBq/kg-dry weight. PMID- 21592804 TI - Artificial neural networks to evaluate the boron concentration decreasing profile in blood-BPA samples of BNCT patients. AB - For the prediction of decay concentration profiles of the p-boronophenylalanine (BPA) in blood during BNCT treatment, a method is suggested based on Kohonen neural networks. The results of a model trained with the concentration profiles from the literature are described. The prediction of the model was validated by the leave-one-out method. Its robustness shows that it is mostly independent on small variations. The ability to fit retrospective experimental data shows an uncertainty lower than the two compartment model used previously. PMID- 21592805 TI - An effective technique for the storage of short lived radioactive gaseous waste. AB - An effective technique is described to deal with volatile, short lived radioactive waste generated as a result of the routinely produced positron emission tomography (PET) radiopharmaceutical 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG). All radioactive gases and aerosols created during the synthesis are collected and stored safely in commercially available TEDLAR gas sampling bags. Once these collected PET by-products decay, the TEDLAR gas bags can be easily emptied and reused. This improved technique is effective, safe, reliable and economical. PMID- 21592806 TI - Design of a beam shaping assembly and preliminary modelling of a treatment room for accelerator-based BNCT at CNEA. AB - This work reports on the characterisation of a neutron beam shaping assembly (BSA) prototype and on the preliminary modelling of a treatment room for BNCT within the framework of a research programme for the development and construction of an accelerator-based BNCT irradiation facility in Buenos Aires, Argentina. The BSA prototype constructed has been characterised by means of MCNP simulations as well as a set of experimental measurements performed at the Tandar accelerator at the National Atomic Energy Commission of Argentina. PMID- 21592807 TI - 10B concentration evaluation in autoradiography images by optical density measurements. AB - The quantification and analysis of the tracks forming the autoradiography image of a tissue section is essential for the measurement of particle emitter concentration and distribution (e.g. (10)B) in the sample. Conventional counting techniques cannot be used when track density is high because of track overlapping. A densitometry supported by image analysis method suitable for these cases has been developed. Optical density measurements obtained for boron solutions of known concentrations showed a linear behavior in the range of concentrations under consideration. PMID- 21592808 TI - Public awareness about prevention and early detection of oral cancer: a population-based study in Northern Germany. AB - INTRODUCTION: This study investigated the knowledge about oral cancer in a representative population sample of the state of Schleswig-Holstein, Germany. MATERIAL AND METHODS: A representative survey (n=1000) was carried out by means of computer-aided phone interviews among the population of Schleswig-Holstein. Descriptive statistics of demographic variables and responses to the questionnaires were reported by means of counts and percentages. Knowledge about diagnostic items and risk factors was further analysed for socioeconomic factors. RESULTS: 66% of the sample was aware that oral cancer lesions are most often diagnosed at an advanced stage. Only 20-40% knew the two most common sites. More than 70% identified tobacco consumption and a prior oral cancer lesion as risk factors, consumption of alcohol and older age were identified by about 50%. The detailed analysis showed a relationship between a low level of knowledge and certain socioeconomic factors, e.g. older age, low level of education and employment. CONCLUSIONS: This survey highlighted a general lack of public awareness about signs and symptoms of oral cancer and its risk factors. A low level of knowledge was associated with a low level of certain socioeconomic factors. These results should have implications for the design of a state-wide public awareness campaign. PMID- 21592809 TI - Safety and feasibility of intra-operative device closure of atrial septal defect with transthoracic minimal invasion. AB - OBJECTIVE: The study aims to evaluate the safety and feasibility of intra operative device closure of atrial septal defect with transthoracic minimal invasion. METHODS: From May 2006 to June 2009, 252 patients with secundum-type atrial septal defect closure were enrolled in our institution. The patients were divided into two groups, with 182 patients in group I with intra-operative device closure and 72 in group II with surgical closure. In group I, the patients' age ranged from 3 months to 62 years (mean+/-standard deviation, 19.0+/-16.7 years). This approach involved a transthoracic minimal invasion that was performed after full evaluation of the atrial septal defect by transthoracic echocardiography, deploying the device through the delivery sheath to occlude the atrial septal defect. RESULTS: In group I, 180 patients were occluded successfully under this approach. The size of the occluder device implanted ranged from 6 to 48 mm. Minor complications occurred, which included transient arrhythmias (n=23) and pleural effusion (n=15). Two patients with postoperative cardiac arrest were successfully cardiopulmonary resuscitated. Another two patients with occluder dislodged back into the right atrium were turned to surgical repair with cardiopulmonary bypass on the postoperative day. In group II, all patients were occluded successfully, and almost all patients needed blood transfusion and suffered from various minor complications. All discharged patients were followed up for 1-5 years. During this period, we found no recurrence, no thrombosis, even no device failure. In our comparative studies, group II had significantly longer intensive care unit (ICU) stay and hospital stay than group I (p<0.05). The cost for group I was less than group II (p<0.05). CONCLUSIONS: Intra-operative device closure of atrial septal defect with transthoracic minimal invasion is a safe and feasible technique. It had the advantages of cost savings, yielding better cosmetic results, and leaving less trauma than surgical closure. PMID- 21592810 TI - Treatment of left main coronary atresia and associated cardiac defects. PMID- 21592811 TI - Thoratec paracorporeal biventricular assist device therapy: the Freiburg experience. AB - OBJECTIVE: The treatment of severe biventricular (BV) contractile failure using mechanical circulatory support is challenging. We analyzed our center's results following implantation of a biventricular assist device (BVAD). METHODS: We implanted 39 BVADs between September 2001 and January 2009. All patients were qualified candidates for heart transplantation, without an organ available at time of BVAD implantation. Fifteen patients without a history of chronic cardiomyopathy suffered from acute BV failure (group 1), whereas the other 24 suffered from severe chronic cardiomyopathy (group 2). The indication for BVAD implantation was determined in reference to echocardiography, the degree of end organ damage, and whether the patient qualified for a heart transplant or was a candidate for bridge to recovery. RESULTS: Both groups were similar regarding their preoperative hemodynamics, intraoperative and early postoperative findings, and adverse events. Patients in group 1 were younger (mean age 37+/-17 years) than those in group 2 (51+/-12 years). Mean duration of support in group 1 was 137+/-109 days, and 65+/-61 days in group 2. In group 1, 33% (5/15) were weaned off the device and 53% (8/15) underwent heart transplantation, whereas 8/24 patients (42%) in the chronic group were transplanted. Group 1's mortality on the device was lower than that of group 2 (13% vs 67%). Furthermore, 11 patients of group 1 survived for 1 year compared with four in group 2 (73% vs 17%). CONCLUSION: Implantation of a BVAD in patients with chronic heart failure and acute decompensation is associated with a high mortality and morbidity rate. By contrast, BVAD implantation can achieve excellent results in patients with acute BV failure without a history of chronic cardiomyopathy, even if they are in cardiogenic shock upon admission. PMID- 21592812 TI - Assessment of a right-ventricular infundibulum-sparing approach in transatrial transpulmonary repair of tetralogy of Fallot. AB - OBJECTIVE: The study aimed to evaluate the outcome of transatrial-transpulmonary repair of tetralogy of Fallot in relation to a right-ventricular outflow tract (RVOT)-sparing surgery. METHODS: Based on the surgical management of right ventricular outflow tract obstruction (RVOTO) at repair of tetralogy of Fallot, 140 children were retrospectively divided into three groups: (1) pulmonary valve (PV)-sparing, (2) infundibulum-sparing and (3) extended trans-annular patch (TAP). Clinical and echocardiographic outcome was assessed with regards to three equally divided study time eras between January 1994 and June 2010. RESULTS: Over a 15-year study period, median age decreased from 11 (2-101) to 5 (1-11) months (p<0.001), whereas type of RVOT repair changed significantly between the first and the last era (group 1: 18-40%, group 2: 25-40% vs group 3: 57-20% (p=0.002)). Mortality was 0%. Complications were mainly related to clinical restrictive RV physiology (27%) and arrhythmia (10%). This cardiac morbidity remained constant over the eras and was associated with younger age (p=0.04), increased postoperative right ventricle/left ventricle (RV/LV) pressure ratio (p=0.01) and type of RVOT repair at the cost of TAP (p=0.03). Median follow-up of 8 years (1 16 years) showed an overall freedom from RVOT re-operation of 84% and 73%, respectively at 5 and 10 years. Most re-operations were for residual/recurrent RVOTO (12%) occurring more frequently in the latter era: 16% versus 7% in era 1 (p=0.08). Late echocardiographic evaluation revealed a strong correlation between severity of pulmonary regurgitation and increased RV/LV size ratio, which was mainly determined by increased TAP length (p<0.001) and duration of follow-up (p=0.06). CONCLUSION: In a 15-year's experience with transatrial-transpulmonary correction of tetralogy of Fallot, a valve- and infundibulum-sparing approach has been advanced by lowering the age for elective repair. This change has been performed without compromising immediate clinical outcome, despite an increased early re-operation rate for residual obstruction. However, longer follow-up will disclose whether this approach is protective against progressive and late RV dysfunction. PMID- 21592813 TI - S1-state Mn4Ca complex of Photosystem II exists in equilibrium between the two most-stable isomeric substates: XRD and EXAFS evidence. AB - Photosynthetic water oxidation reaction driven by Sun and catalyzed by a unique Mn(4)Ca cluster in Photosystem II (PSII) is known to take place in an oxygen evolving complex (OEC) that cycles five serial redox states, named "Kok's S(i) states" (i=0-4). Recently, the atomic crystal structure of PSII from Thermosynechococcus vulcanus was resolved by 1.9 A-resolution XRD data [55]. Interestingly, it revealed an unusual oxo-bridged Mn(4)CaO(5) cluster in the dark stable S(1)-state, e.g. unusual mono-MU(2)-oxo-mono-MU(4)-oxo-mono-MU(2) carboxylato bridges connecting Mn(a) (terminal) and Mn(b) (central) ions with unusual atomic distance of 2.9 A. Using the UDFT/B3LYP/lacvp** geometry optimization method and a truncated cluster model of the chemically-complete OEC put in epsilon=4 dielectric medium, it is shown that the OEC in S(1) must be in thermal equilibrium between the most-stable isomeric substates ("S(1a) and S(1b)") owing to the quasi-reversible structure change induced by proton migration. Coincidentally, it is found that the Mn(a)-Mn(b) distances in the Mn(4)Ca clusters in S(1a) and S(1b) are given by R(ab)=3.32 A and 2.77 A, respectively, so that the apparent distance between Mn(a) and Mn(b) ions in isomeric equilibrium is given by 2.94 A, in agreement with experimental R(ab)~2.9 A. Concomitantly, the first full-k-range EXAFS spectrum from powdered PSII [45] is used to provide the second experimental evidence for the S(1)-state OEC being in thermal equilibrium between S(1a) and S(1b)-isomers. These OEC-isomers consist of all the chemically-essential 11 amino acid residues, six cofactor ions and nine essential hydrated water molecules in their chemical ionic states around physiological pH 7, thus reasonably satisfying the biochemical charge neutrality with four Mn ions staying at the oxidation states (Mn(a)(III)/Mn(b)(IV)/Mn(c)(III)/Mn(d)(IV)) with the skeleton structures of MT-5J type and T-shaped DD-4J type. These H-bonding water molecules are found to fill a cavity connecting possible substrate/products channels so as to be arranged as an indispensable part of the catalytic Mn(4)Ca cluster in the order of "current substrates" (W1/W2 bound to Mn(a)(III)), "next-substrates" (W4/W7) and "next after-next-substrates" (W5/W6 bound to Ca(2+)). Results show that the Jahn-Teller effect due to Mn(a)(III) ion in these isomers can reasonably explain the very slow-exchange and very-fast-exchange processes observed in S(1) by time-resolved (18)O-exchange mass spectroscopy. PMID- 21592814 TI - Investigation of the maximum quantum yield of PS II in Haematococcus pluvialis cell cultures during growth: effects of chemical or high-intensity light treatment. AB - In this study, we investigated the increase in photosynthetic quantum yield that occurs in advance of increased microalgal growth. Haematococcus pluvialis was cultivated under normal conditions; the number of cells, the maximum quantum yield of photosystem II (F(v)/F(m)), and optical density were measured. We observed an increase in F(v)/F(m) approximately 72h prior to the cell growth phase. To confirm the relationship between photosynthetic yield and growth, samples were treated with several chemicals under high-intensity light illumination and control conditions to inhibit photosystem II and induce a decrease in the quantum photosynthetic yield. The samples were exposed to high intensity light at an irradiance of 400MUmol photonsm(-2)s(-1) for varied amount of time and were treated with chemicals such as 3-(3,4-dichlorophenyl)-1,1 dimethylurea, nigericin sodium salt and valinomycin. We observed that both the photooxidation of photosystem II reaction centers and the formation of transmembrane electrochemical gradients led to an initial decrease in fluorescence yield after the onset of high-intensity light illumination. We also observed that treatment of high-intensity light illuminated cells with antibiotics after adaptation to moderate light intensities caused a difference in photosynthetic activity. In conclusion, the maximum quantum yield of photosystem II is obtained prior to the cell growth phase and can therefore be used as a prediction parameter for cell growth. PMID- 21592815 TI - Zinc oxide mediated heterogeneous photocatalytic degradation of organic species under solar radiation. AB - The photocatalytic decomposition of eco-persistent toluene, salicylic acid and 4 chlorophenol with sun light in an oxygenated aqueous suspension has been studied under nanocrystalline hexagonal ZnO photocatalyst. The effect of substrate temperature onto the structural, morphological and photoactive properties has been investigated. The degradation of toluene, salicylic acid and 4-chlorophenol were achieved using a photoelectrochemical reactor module equipped with synthesized ZnO electrodes. Kinetic parameters have been investigated in terms of a first order rate equation. The rate constant (-k) for this heterogeneous photocatalysis was evaluated as a function of the initial concentration of original species. Substantial reduction in concentrations of toluene, salicylic acid and 4-chlorophenol was achieved as analyzed from COD and TOC studies. The mechanism for the degradation of toluene, salicylic acid and 4-chlorophenol could be explained on the basis of Langmuir-Hinshelwood mechanism. PMID- 21592816 TI - What has happened to VBM (vinblastine, bleomycin, and methotrexate) chemotherapy for early-stage Hodgkin lymphoma? AB - The VBM (vinblastine, bleomycin, methotrexate) chemotherapy combined with involved-field radiotherapy in early-stage Hodgkin lymphoma has not become popular in spite of its excellent results. Nine small trials with this combined therapy were carried out and described in eleven reports. VBM+ radiotherapy offered complete remission rates of 94-100%, with 5-year progression-free survival of 75-95% (elderly patients included). Considerable pulmonary toxicity was recorded in the first trials, but was fully controlled in the later studies through slight modifications of the schedule. The pulmonary toxicity was found related to mediastinal radiotherapy, bleomycin dose and administration of chemotherapy after radiotherapy; it is mitigated by low doses of prednisone. The very good results, the abated side effects on the lungs, the low extrapulmonary toxicity, and the anthracycline-free formulation make this combination therapy worth considering for early-stage Hodgkin lymphoma, particularly in the case of mediastinal involvement or in elderly patients. PMID- 21592817 TI - Fat caves: caveolae, lipid trafficking and lipid metabolism in adipocytes. AB - Caveolae are subdomains of the eukaryotic cell surface, so named because they resemble little caves, being small omega-shaped invaginations of the plasma membrane into the cytosol. They are present in many cell types, and are especially abundant in adipocytes, in which they have been implicated as playing a role in lipid metabolism. Thus, mice and humans lacking caveolae have small adipocytes and exhibit lipodystrophies along with other physiological abnormalities. In this review, we examine the evidence supporting the role of caveolae in adipocyte lipid metabolism in the context of the protein and lipid composition of these structures. PMID- 21592818 TI - Determinants of adipophilin function in milk lipid formation and secretion. AB - In many species the lactating mammary gland is one of the most lipogenic organs of the body. The majority of the lipid produced during lactation is secreted into milk by a novel process of membrane envelopment of cytoplasmic lipid droplets (CLDs). Adipophilin (ADRP/ADPH/PLIN2), a member of the perilipin (PAT) family of lipid droplet proteins, is hypothesized to play a pivotal role in both formation and secretion of milk lipids. Production of milk lipids is the only known example of CLD secretion, and the only process in which PAT family members undergo secretion. This review discusses emerging data on the structural and functional properties of adipophilin that determine its physiological actions and mediate its effects on milk lipid formation and secretion. PMID- 21592819 TI - CXCL12 rs1801157 polymorphism and expression in peripheral blood from breast cancer patients. AB - The role of chemokines has been extensively analyzed both in cancer risk and tumor progression. Among different cytokines, CXCR4 and its ligand CXCL12 have been recently subjected to a closer examination. The single-nucleotide polymorphism (SNP) rs1801157 (previously known as CXCL12-A/SDF1-3'A) in the CXCL12 gene and the relative expression of mRNA CXCL12 in peripheral blood were assessed in breast cancer patients, since the chemokine CXCL12 and its receptor CXCR4 regulate leukocyte trafficking and many essential biological processes, including tumor growth, angiogenesis and metastasis of different types of tumors. Genotyping was performed by PCR-RFLP (polymerase chain reaction followed by restriction fragment length polymorphism) using MspI restriction enzyme and the expression analyses by quantitative RT-PCR. No difference in GG genotype and allele A carrier frequencies were observed between breast cancer patients and healthy blood donors and nor when CXCL12 mRNA expression was assessed among patients with different tumor stages. However a significant difference was observed when CXCL12 mRNA relative expression was analyzed in breast cancer patients in accordance to the presence or absence of the CXCL12 rs1801157 allele A. Allele A breast cancer patients presented a mRNA CXCL12 expression about 2.1 fold smaller than GG breast cancer patients. Estrogen positive patients presenting CXCL12 allele A presented a significantly lower expression of CXCL12 in peripheral blood (p=0.039) than GG hormone positive patients. Our findings demonstrated that allele A is associated with low expression of CXCL12 in the peripheral blood from ER-positive breast cancer patients, which suggests implications on breast cancer clinical outcome. PMID- 21592820 TI - Vitamin D(3) down-regulates proinflammatory cytokine response to Mycobacterium tuberculosis through pattern recognition receptors while inducing protective cathelicidin production. AB - A well-known association between vitamin D(3) and infection with Mycobacterium tuberculosis has previously been reported, but little is known regarding the underlying mechanisms. We have investigated how 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] affects the proinflammatory cytokine production induced by M. tuberculosis. Furthermore, we explored whether 1,25(OH)(2)D(3) influence the production of the protective antimycobacterial peptide cathelicidin. Upon in vitro stimulation with M. tuberculosis, 1,25(OH)(2)D(3) induced a dose-dependent down-regulation of IL-6, TNFalpha and IFNgamma, while increasing the production of IL-10 in culture supernatant as well as cathelicidin mRNA expression. This effect on cytokine response was not due to modulation of T-helper cell differentiation, as T-bet, GATA3, Foxp3 and ROR-gammat mRNA expression remained unaffected. Similarly, 1,25(OH)(2)D(3) did not affect suppressor of cytokine signaling (SOCS)1 and SOCS3 mRNA expression. The mechanism whereby 1,25(OH)(2)D(3) inhibited the proinflammatory cytokine response was through reduced expression of the pattern recognition receptors (PRR) - TLR2, TLR4, Dectin-1 and mannose receptor, whose mRNA and protein expression were both reduced. The suppression of PRRs could be restored by a VDR antagonist. Upon M. tuberculosis stimulation, 1,25(OH)(2)D(3) modulates the balance in cytokine production towards an anti-inflammatory profile by repression of TLR2, TLR4, Dectin-1 and mannose receptor expression, while increasing cathelicidin production. These two effects may have beneficial consequences, by reducing the collateral tissue damage induced by proinflammatory cytokines, while the antibacterial effects of cathelicidin are enhanced. PMID- 21592821 TI - Calcitriol stimulates prolactin expression in non-activated human peripheral blood mononuclear cells: breaking paradigms. AB - Calcitriol, the hormonal form of vitamin D(3), exerts immunomodulatory effects through the vitamin D(3) receptor (VDR) and increases prolactin (PRL) expression in the pituitary and decidua. Nevertheless, the effects of calcitriol upon lymphocyte PRL have not been evaluated. Therefore, we investigated calcitriol effects upon PRL in resting and phytohemagglutinin-activated human peripheral blood mononuclear cells (PBMNC) and Jurkat T lymphoma cells. Immunoblots showed constitutive expression of the 50-kDa VDR species in activated PBMNC and Jurkat cells, while a 75-kDa species was recognized in both resting and activated-PBMNC. Only in resting PBMNC calcitriol significantly stimulated PRL expression in a dose-dependent manner. The positive control CYP24A1, a highly VDR-responsive gene, was stimulated by calcitriol, effect that was stronger in resting than in activated-PBMNC (P<0.05), and without effect in Jurkat cells. Calcitriol upregulation of PRL and CYP24A1 was significantly inhibited by the VDR antagonist TEI-9647. EMSA showed that resting PBMNC contain a protein that binds to DR3-type VDRE. Cell activation reduced basal CYP24A1 while induced CYP27B1, VDR and pregnane X receptor (PXR) expression. In summary, calcitriol stimulated PRL and CYP24A1 gene expression in quiescent lymphocytes through a VDR-mediated mechanism. Our results suggest that the 75-kDa VDR species could be participating in calcitriol-mediated effects, and that activation induces factors such as PXR that restrain VDR transcriptional processes. This study supports the presence of a functional VDR in quiescent lymphocytes, providing evidence to reevaluate the VDR paradigm that assumes that lymphocytes respond to calcitriol only after activation. Altogether, our results offer new insights into the mechanisms whereby PRL is regulated in immune cells. PMID- 21592822 TI - IL-27-producing CD14(+) cells infiltrate inflamed joints of rheumatoid arthritis and regulate inflammation and chemotactic migration. AB - Interleukin (IL)-27, a heterodimeric cytokine, has been reported to be involved in the pathogenesis of autoimmune diseases through mediating differentiation of Th1 or Th17 cells and immune cell activity or survival. However, the origin and effects of IL-27 in joints of rheumatoid arthritis (RA) remain unclear. In this study, we investigated the distribution and anti-inflammatory roles of IL-27 in RA synovium. The IL-27 levels in plasma of RA patients, osteoarthritis (OA) patients, or healthy volunteers (n=15 per group) were equivalent and were at most 1 ng/ml, but the IL-27 level in synovial fluid of RA patients (n=15, mean 0.13 ng/ml; range 0.017-0.37 ng/ml) was significantly higher than that in synovial fluid of OA patients (n=15, mean 0.003 ng/ml; range 0-0.033 ng/ml) and potentially lower than in plasma. We analyzed the protein level of IL-27 produced by RA fibroblast-like synoviocytes (FLSs) or mononuclear cells (MNCs) from RA or OA synovial fluid or peripheral blood and showed that IL-27 in RA joints was derived from MNCs but not from FLSs. We also found by flow cytometry that IL-27 producing MNCs were CD14(+), and that these CD14(+)IL-27(+) cells were clearly detected in RA synovium but rarely in OA synovium by immunohistochemistry. Furthermore, we demonstrated that a relatively physiological concentration of IL 27 below 10 ng/ml suppressed the production of IL-6 and CCL20 from RA FLSs induced by proinflammatory cytokines through the IL-27/IL-27R axis. In the synovial fluid of RA, the IL-27 level interestingly had positive correlation with the IFN-gamma level (r=0.56, p=0.03), but weak negative correlation with the IL 17A level (r=-0.30, p=0.27), implying that IL-27 in inflammatory joints of RA induces Th1 differentiation and suppresses the development or the migration of Th17 cells. These findings indicate that circulating IL-27-producing CD14(+) cells significantly infiltrate into inflamed regions such as RA synovium and have anti-inflammatory effects in several ways: both directly through the reduction of IL-6 production, and possibly through the induction of Th1 development and the suppression of Th17 development; and indirectly by regulation of recruitment of CCR6(+) cells, such as Th17 cells, through the suppression of CCL20 production. Our results suggest that such a serial negative feedback system could be applied to RA therapy. PMID- 21592824 TI - Atherectomy of heavily calcified femoropopliteal stenotic lesions. AB - PURPOSE: To investigate 1-year outcomes after atherectomy in patients with peripheral arterial disease (PAD) and heavily calcified stenotic lesions. MATERIALS AND METHODS: Thirty-eight patients (mean age, 70 y +/- 8; 24 men; TransAtlantic Inter-Society Consensus B-D disease; mean lesion length, 7.5 cm +/- 3.5) with PAD (Rutherford score of 2-6) were included in this prospective study. In total, 42 calcified lesions of the superficial femoral artery (SFA) or popliteal artery were treated with the SilverHawk atherectomy device. Thirty-two lesions were located in the proximal or distal 3 cm of the SFA or in the popliteal artery, which were considered segments exposed to high biomechanical stress. Patients were followed up after 6 and 12 months. Clinical reevaluation included measurement of ankle-brachial index (ABI) and duplex sonography. RESULTS: The primary success rate of the procedure was 88%. In five cases, additional balloon angioplasty and/or stent implantation was necessary. Procedure related embolization occurred in three cases and was treated by aspiration. The mean Rutherford score decreased significantly from 4.1 +/- 1.0 to 1.0 +/- 1.3 after 12 months. At the same time, the ABI increased significantly from 0.7 +/- 0.3 to 0.9 +/- 0.3. The primary patency rate was 69% after 1 year. CONCLUSIONS: Atherectomy might be considered as an alternative approach in patients with PAD who have heavily calcified stenotic lesions, especially in areas with high biomechanical stress, where stent implantation is undesirable. Results after 1 year demonstrated a significant decrease of Rutherford score, an increase in ABI, and a reasonable patency rate. PMID- 21592825 TI - Comments regarding 'Influence of use of a vascular closure device on incidence and surgical management of access sites. Complications after percutaneous interventions'. PMID- 21592823 TI - Making sense of regulatory T cell suppressive function. AB - Several types of regulatory T cells maintain self-tolerance and control excessive immune responses to foreign antigens. The major regulatory T subsets described over the past decade and novel function in transplantation will be covered in this review with a focus on CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells. Multiple mechanisms have been proposed to explain how Treg cells inhibit effector cells but none can completely explain the observed effects in toto. Proposed mechanisms to explain suppressive activity of Treg cells include the generation of inhibitory cytokines, induced death of effector cells by cytokine deprivation or cytolysis, local metabolic perturbation of target cells mediated by changes in extracellular nucleotide/nucleoside fluxes with alterations in intracellular signaling molecules such as cyclic AMP, and finally inhibition of dendritic cell functions. A better understanding of how Treg cells operate at the molecular level could result in novel and safer therapeutic approaches in transplantation and immune-mediated diseases. PMID- 21592826 TI - Endovascular repair of aorto-iliac artery injuries after lumbar-spine surgery. AB - OBJECTIVE: This study aims to describe the endovascular management of abdominal aortic- or common-iliac-artery injuries after lumbar-spine surgery. METHODS: Patients treated for abdominal-aortic- or common-iliac-artery injuries after lumbar-spine surgery during a 13-year period were identified from an endovascular database, providing prospective information on techniques and outcome. The corresponding patient records and radiographic reports were analysed retrospectively. RESULTS: Seven patients were treated with acute (n = 3) or subacute (n = 4) injuries of the common iliac artery (n = 6) or abdominal aorta (n = 1) after lumbar-spine surgery. Vascular injuries included arterial lacerations (n = 3), arteriovenous fistulas (n = 2) and pseudo-aneurysms (n = 2). The mean age of the patients was 51.7 years (30-60 years), 71.4% were women. These lesions were repaired by transluminal placement of stent grafts: Passager (n = 3), Viabahn (n = 1), Wallgraft (n = 1), Zenith (n = 1) and Advanta V12 (n = 1). Exclusion of the injury was achieved in all cases. Mortality was nil. There were no procedure-related complications. During a median follow-up of 8.7 years (range 0.3-13 years), all stent grafts remained patent. CONCLUSIONS: Sealing of common iliac artery or abdominal aortic lesions as a complication of lumbar-disc surgery with a stent graft is effective and is suggested as an excellent alternative to open surgery for iatrogenic great-vessel injuries, particularly in critical conditions. PMID- 21592827 TI - Comparative proteomics reveals deficiency of NHE-1 (Slc9a1) in RBCs from the beta adducin knockout mouse model of hemolytic anemia. AB - Hemolytic anemia is one of the most common inherited disorders. To identify candidate proteins involved in hemolytic anemia pathophysiology, we utilized a label-free comparative proteomic approach to detect differences in RBCs from normal and beta-adducin (Add2) knock-out mice. We detected 7 proteins that were decreased and 48 proteins that were increased in the beta-adducin knock-out RBC ghost. Since hemolytic anemias are characterized by reticulocytosis, we compared reticulocyte-enriched samples from phenylhydrazine-treated mice with mature RBCs from untreated mice. Label-free analysis identified 47 proteins that were increased in the reticulocyte-enriched samples and 21 proteins that were decreased. Among the proteins increased in Add2 knockout RBCs, only 11 were also found increased in reticulocytes. Among the proteins decreased in Add2 knockout RBCs, beta- and alpha-adducin showed the greatest intensity difference, followed by NHE-1 (Slc9a1), the sodium-hydrogen exchanger. We verified these mass spectrometry results by immunoblot. This is the first example of a deficiency of NHE-1 in hemolytic anemia and suggests new insights into the mechanisms leading to fragile RBCs. Our use of label-free comparative proteomics to make this discovery demonstrates the usefulness of this approach as opposed to metabolic or chemical isotopic labeling of mice. PMID- 21592828 TI - F-cell levels are altered with erythrocyte density in sickle cell disease. AB - Lighter cells from density fractionated erythrocytes of sickle cell disease (SCD) patients carry higher amount of externalized phosphatidylserine (PS) and cell surface glycophorins compared to the denser counterparts. Further analysis also revealed that the denser cells contained higher levels of fetal hemoglobin (HbF) compared to the lighter cells, supported by the presence of larger number of F cells in these populations. In this report, we have found direct evidence on the higher survival of the HbF rich erythrocytes in SCD. PMID- 21592829 TI - Bovine tuberculosis and udder health in Irish dairy herds. AB - The association between bovine tuberculosis (TB) infection status based on results from the single intradermal comparative tuberculin test (SICTT) and milk production has been described in dairy cows in TB-infected herds in Ireland. The biological basis was uncertain, but could be related to increased TB susceptibility among lower producing dairy cows. In this study, the relationship between somatic cell count (as an objective measure of udder health) and SICTT reactivity (as a proxy for TB infection status) was investigated. Somatic cell counts of TB infected cows, both during and prior to the lactation of diagnosis of TB infection, were examined and compared to non-infected cows. All Irish dairy herds restricted from trading between June 2004 and May 2005 as a result of two or more TB reactors (test positive) to the SICTT were considered for study. Data were collected on 4340 cows from 419 herds. Previous lactation data for the cows were taken into consideration and all lactations on a cow were analysed together with the years of lactations. There was an inherent hierarchical structure in the data, with lactations nested within cows and cows within herds and so a linear mixed model with two random effects was used to describe the data. Milk production (305-day milk yield) was also included in the model as a fixed effect. The results of the study showed that for all lactations and years under investigation, somatic cell counts for SICTT reactor cows when compared to the non-reactor cows were not significantly different. In this study population, TB infection status was not associated with udder health. PMID- 21592830 TI - Emergence of classical swine fever virus in Israel in 2009. AB - Classical swine fever (CSF) re-emerged in Israel in February 2009 after an absence of 62 years. The outbreak occurred on a domestic pig farm in northern Israel and affected domestic pigs and wild boar. On the basis of phylogenetic analysis of a 190 base pair fragment of the E2 glycoprotein gene, the Israeli CSF virus strain belonged to genotype 2.1 and was genetically most similar to a Chinese CSF virus strain. PMID- 21592831 TI - The potential role of leptin and adiponectin in obesity: a comparative review. AB - Leptin and adiponectin are adipokines produced by the white adipose tissue. The adipokines have been shown to be valuable quantitative markers of adiposity in dogs. Leptin positively correlates with body condition score (BCS) in dogs, regardless of age, sex and breed, and is influenced by feeding state, pharmacological treatment and thyroid gland activity. Conversely, adiponectin negatively correlates with body fat mass and is therefore more abundant in lean animals. The implication of leptin and adiponectin in the pathogenesis of metabolic syndrome is well established in humans, but currently lacking in dogs. Additional studies are necessary to demonstrate their potential usefulness for monitoring the progression of obesity-related diseases and response to treatment. To date, measurement of canine leptin and adiponectin has been used in experimental studies only, whereas bodyweight and BCS are considered the first approach parameters for the routine assessment of body fat content in obese dogs. PMID- 21592832 TI - Prevalence of psychiatric disorders in sick listed chronic low back pain patients. AB - BACKGROUND: Previous findings have shown a high degree of comorbid psychopathology in chronic low back pain (CLBP), but less is known about the broad range of comorbid psychiatric disorders. The prevalence is reported to be between 40% and 100% depending on methods being used, sample or setting. AIMS: To assess the prevalence of psychiatric comorbidity in a population of CLBP patients, using a psychiatric diagnostic interview. METHODS: 565 patients sick listed between 2 and 10months for unspecific LBP were included in the study. All were recruited as part of an ongoing trial in secondary care, and were assessed with the Mini-International Neuropsychiatric Interview (MINI), which is a short structured diagnostic interview for DSM-IV and ICD-10 psychiatric disorders. RESULTS: The prevalence of current psychiatric disorders was 31%. The diagnoses included 19 Axis I disorders, with the most common being somatoform disorders (18%) and anxiety disorders (12%). Major depressive disorders were reported in 4%. There were no gender differences in prevalence of psychiatric disorders. CONCLUSIONS: In a large population of CLBP patients, 31% fulfilled the criteria for at least one current psychiatric disorder when measured with a diagnostic interview. The diagnoses included a wide range of psychiatric disorders, with the most common being somatoform disorders (18%) and anxiety disorders (12%). The results imply that screening CLBP patients for psychiatric comorbidity in secondary care is important since psychopathology may have serious consequences for prognosis, outcome and health care utilization. PMID- 21592833 TI - 1H and 13C NMR studies of glycine in anisotropic media: double-quantum transitions and the effects of chiral interactions. AB - The (1)H NMR spectrum of glycine in stretched gelatin gel and in cromolyn liquid crystal displays a well-resolved doublet due to (1)H-(1)H dipolar interaction. Multiple spectra were obtained within a wide range of offset frequencies of partially saturating radio-frequency (RF) radiation to generate steady-state irradiation envelopes or z-spectra of glycine. Maximal suppression of the doublet occurred when the irradiation was applied exactly at the centre frequency, between the two glycine peaks. This phenomenon is due to double-quantum transitions and is similar to our previous work on quadrupolar nuclei (2)H (HDO) and (23)Na(+). When the (13)C isotopomer glycine-2-(13)C was used, the same effect was found in twice, split by (1)J(CH)+2D(CH). Additional signals in (1)H and (13)C NMR due to prochiral-chiral interactions were found when glycine-2 (13)C was dissolved in chiral anisotropic gelatin and kappa-carrageenan gels. The NMR spectra were successfully simulated assuming a (2)J(HH) coupling constant of 16.5Hz and two distinct dipolar coupling constants for the -(13)CH(2)- group (D(C,HA), and D(C,HB)). PMID- 21592834 TI - Reply to Professor Leftheriotis et al. PMID- 21592835 TI - Blood phenylalanine clearance and BH(4)-responsiveness in classic phenylketonuria. AB - Tetrahydrobiopterin (BH(4)) has been shown to decrease blood phenylalanine concentration in selected patients with phenylketonuria who can be identified with use of the BH(4)-loading test. However, the results of the test could be biased due to hydroxylation-independent blood phenylalanine clearance. Considering of this effect is necessary in patients with classic phenylketonuria, particularly in "slow responders," in whom borderline decrease in blood phenylalanine concentration is typically observed as a result of BH(4)-loading. PMID- 21592836 TI - Clinical investigations of a CVD diamond detector for radiotherapy dosimetry. AB - X-ray detectors based on single crystal diamond film made via chemical vapor deposition were investigated to evaluate their performance under clinically relevant conditions for radiotherapy dosimetry. Studies focused on repeatability, dose rate dependence, tissue phantom ratios, output factors and beam profiling. Repeatability experiments revealed a temporary loss in sensitivity due to charge detrapping effects following irradiation, which was modeled to make corrections that improved short-term precision. Dose rate dependence was observed (Fowler fitting parameter Delta = 0.96 +/- 0.2) using dose rates up to ~2 Gy min(-1). The detector statistically distinguished (n = 5, P < 0.05) between dose values separated by 7.7 * 10(-3) Gy (1 MU). Depth dose measurements from 1 to 15 cm and output factors using 3 * 3 to 10 * 10 cm2 field sizes compared well with a Farmer ion chamber (<1.3% difference). Output factor measurements indicate encouraging results for fields sizes <4 * 4 cm2. Off-axis measurements showed that perturbation of the beam could be reduced when the detector is used in the edge on orientation due to its thin-film sandwich configuration and ~200 nm thick Ag contacts. This relatively inexpensive detector has potential to be used for routine dosimetry using conventional radiotherapy instrumentation. PMID- 21592837 TI - [Optimisation of pharmacotherapy in a trauma centre]. AB - OBJECTIVE: To evaluate the results for implementing a pharmaceutical care programme aimed at optimising personalised pharmacotherapeutic treatment in a Trauma Centre with electronic medical records (EMR) and an integral system for personalised medication dispensing (ISPMD). METHOD: A three-year observational, retrospective study (2007-2009). On a daily basis, we checked the pharmaceutical treatment of patients admitted to hospital units with ISPMD. The medication related problems (MRP) and medication errors (ME) were identified and classified by recording them on a standardised document. We also recorded data on the Pharmaceutical Interventions performed in accordance with fitness and level of acceptance. We used the laser method to identify patients with pharmacotherapy improvement opportunities (MRP and/or ME). RESULTS: One thousand nine-hundred and seventy-one pharmaceutical interventions (PI) were found after having reviewed 124 336 treatment lines, resulting in 12 PI for every 100 patients. The prevalence of patients with MRP was 12%, distributed as such: 50.66% were safety related, 22.98% indication-related, 12.23% effectiveness-related and 14.13% adherence-related. The main drug groups involved were: anti-infectious agents (29%), drugs for the musculoskeletal system (21%), drugs for blood and haematopoietic organs (12%), and drugs for the nervous system (11%). The active ingredient that required most PI in 2007 was dexketoprofen (15.6%), followed by ketorolac (12.4%). In 2008, it was dexketoprofen (22.0%) followed by gentamicin (7.3%), and in 2009 enoxaparin (19.0%) followed by dexketoprofen (14.3%). The origin of MRP was due to ME in 91% of cases in 2007 and 81% in 2008, decreasing to 53% in 2009. PI fitness, as percentages (CI 95%) were considered: Important PI [30.29 (10.19-49.95)]; Very important PI [38.36 (35.45-73)]; Acceptable PI [82.10 (52.28-111.10)]. CONCLUSIONS: Optimising personalised pharmacotherapeutic treatment by implementing an interdisciplinary Pharmaceutical Care programme promotes team work, and as a result improves rational and safe medication dispensing. PMID- 21592838 TI - Varicella rates among unvaccinated and one-dose vaccinated healthy children in Izmir, Turkey. AB - OBJECTIVES: We aimed to determine the rate of breakthrough varicella in Turkey, a country with low varicella vaccination coverage. METHODS: This study was conducted between April 2008 and March 2009 at the Well-Child Clinic at Ege University and pediatricians' offices. We collected information on vaccination status and varicella infection using a questionnaire. In order to elicit more details about the severity of illness, we interviewed all parents and reviewed the clinician records. Vaccination status was verified from the medical records or vaccination cards with dates. RESULTS: A total of 2802 children were evaluated. Of these, 1683 had been vaccinated with a single dose of varicella vaccine and 1119 were unvaccinated. Among vaccinated children, 466 (27.7%) had breakthrough varicella. Vaccinated children tended to have mild varicella. However, about 25% of breakthrough cases had moderate or severe disease. Children who were vaccinated >= 5 years previously had a 3.7-fold higher risk of breakthrough disease than those who were vaccinated <5 years before. Vaccination at younger than 15 months of age was not significantly associated with an increased risk of breakthrough infection. CONCLUSIONS: Breakthrough varicella is not rare in Turkey where varicella infections are common. A longer interval since vaccination may be a risk factor for developing breakthrough varicella. Children who had been vaccinated >5 years previously were at risk for breakthrough disease. A two-dose varicella vaccine policy may be needed to provide improved protection. PMID- 21592839 TI - What do we know about atypical femoral fractures? Insights and enigmas. AB - Although the existence of atypical femoral fractures is well established and bisphosphonate therapy is thought to be a major risk factor, the underlying mechanisms are poorly understood. Epidemiological data show that atypical femoral fractures account for only a small proportion of diaphyseal subtrochanteric femoral fractures, being about 100 times less common than proximal femoral fractures. Consequently, the existence of atypical femoral fractures does not call into question the extremely favorable risk/benefit ratio of bisphosphonate therapy in patients with osteoporosis. Clearly, the number of fractures prevented by bisphosphonate therapy far exceeds the number of atypical femoral fractures potentially related to bisphosphonates. PMID- 21592840 TI - [Dupuytren's disease: state of knowledge and research in physiopathology]. AB - From Baron Dupuytren's historical description up to the advent of molecular biology, many hypotheses about the etiology of Dupuytren's disease have been proposed. This bibliography of the last ten years' publications describes tissue anomalies from the macroscopic down to the ultrastructural level of pathology. The myofibroblast, which is the principal cell of the disease, is the seat of genetics anomalies involving proto-oncogenes (c-myc and MafB). Similarly, glycoproteins implicated in cellular adhesion like fibronectins and catenins are modified and overexpressed in the disease. Extracellular proteins of the metalloproteinase family exhibit many dysfunctions responsible for collagenic proliferation. Finally, growth factors like Transforming Growth Factor (TGF) and Epidermal Growth Factor (EGF) receptor maintain and worsen the disease and could be therapeutic targets in the future. PMID- 21592841 TI - A biomechanical study on fracture risks in ulnohumeral arthroplasty. AB - In the Outerbridge-Kashiwagi ulnohumeral arthroplasty, bone strength may be weakened significantly as a result of the humeral fenestration. Therefore, fracture risks may be increased, particularly in the immediate postoperative period. The objective of this biomechanical cadaver study is to study the humeral bone strength after ulnohumeral arthroplasty. A biomechanical cadaveric study was done in which differences in force needed to fracture the humerus with and without fenestration was measured. First, the diaphysis of 12 distal humeri was embedded and a posterior force was applied until a fracture occurred. Second, a similar study was done with fixed humeral columns, to specifically compare the column strength. In the first part, the force needed to fracture was reduced by 17% after ulnohumeral arthroplasty, which was not statistically significant. However, a shift in the fracture pattern occurred: from diaphyseal fracture towards column fractures after the arthroplasty. In the second part, the force needed to fracture the columns proved to be significantly reduced by 41% after humeral perforation. Alterations in the biomechanical properties of the distal humerus after ulnohumeral arthroplasty may lead to a shift in fracture patterns from diaphyseal to column fractures. The strength of the columns is strongly reduced by 41%. PMID- 21592842 TI - [Surgical management of the adult spastic hand]. AB - The adult spastic hand, of varying causes, but dominated by vascular hemiplegia and brain damage, associates motor disorders and problems of tonus. The variety of forms of brain damage explains the wealth and diversity of the symptoms. These symptoms, often the most serious along with cognitive disorders, justify the expression "central neurological hand". Each case is an individual one. The effect on the hands may be unilateral or bilateral with spasticity involving the fingers/thumb/wrist. The clinical evaluation leading to a decision tree must take into account spasticity, retraction and paralysis, for each muscle. When completed by anesthetic motor blocks, spasticity and/or retraction, damage to extrinsic and/or intrinsic muscles of the fingers may be differentiated. This repeated multidisciplinary evaluation makes it possible to distinguish between "non functional hands", "functional hands" and "potentially functional hands". In the first instance, surgery can only improve the esthetic aspect or facilitate nursing. In the second instance, correcting spasticity may improve function. The treatment of spasticity is based on inhibiting spasticity (by injecting botulinum toxin or surgical motor hyponeurotisation) and reinforcing the non-spastic antagonist muscles via tendon transfer or tenodesis. Surgery is indicated to correct muscular retraction and deformities. The functional indications are highly selective and their limited results only allow a "supporting hand" to be constructed at best. The non-functional indications lead to a codified intervention whose results will greatly improve the management of these patients. PMID- 21592844 TI - The unique role of the visual word form area in reading. AB - Reading systematically activates the left lateral occipitotemporal sulcus, at a site known as the visual word form area (VWFA). This site is reproducible across individuals/scripts, attuned to reading-specific processes, and partially selective for written strings relative to other categories such as line drawings. Lesions affecting the VWFA cause pure alexia, a selective deficit in word recognition. These findings must be reconciled with the fact that human genome evolution cannot have been influenced by such a recent and culturally variable activity as reading. Capitalizing on recent functional magnetic resonance imaging experiments, we provide strong corroborating evidence for the hypothesis that reading acquisition partially recycles a cortical territory evolved for object and face recognition, the prior properties of which influenced the form of writing systems. PMID- 21592843 TI - Postmortem endogenous ethanol production and diffusion from the lung due to aspiration of wood chip dust in the work place. AB - We report an autopsy case of postmortem ethanol diffusion into the cardiac blood after aspiration of wood chips, although antemortem ethanol consumption was not evident. A man in his twenties, who was loading a truck with small wood chips in a hot, humid storehouse, was accidentally buried in a heap of chips. At the time the body was discovered, 20 h after the accident, rectal temperature was 36 degrees C. Autopsy showed the cause of death to be asphyxia due to obstruction of the airway by aspiration of wood chips. The ethanol and n-propanol levels were significantly higher in the lungs (left, 0.603 and 0.009 mg/g; right, 0.571 and 0.006 mg/g) than in other tissues. A significant difference in ethanol concentration was observed between the left cardiac blood (0.243 mg/g) and the right femoral blood (0.042 mg/g). Low levels of ethanol and n-propanol were detected in the stomach contents (0.105 and 0.001 mg/g, respectively). In order to determine whether aspiration of wood chips affects postmortem ethanol production in the lung, we measured the ethanol and n-propanol levels of homogenized rabbit lung tissue incubated with autoclaved or non-autoclaved wood chips. Levels of ethanol and n-propanol were significantly higher in the homogenates incubated with non-autoclaved chips for 24h. The results of this animal experiment suggested that the ethanol detected in the lung was produced by putrefactive bacteria within the wood chips. After death, the ethanol produced endogenously in the lung appears to have diffused and affected the ethanol concentration of the left cardiac blood. PMID- 21592845 TI - Loss of heterozygosity of D9S162: molecular predictor for treatment response in oral carcinoma. AB - Inspite of improvements in treatment regimen of oral cancer, locoregional recurrence rates and overall mortality have remained unchanged over the years. This study therefore focused on microsatellite alterations in 9p21 loci, as a possible molecular prognostic marker in oral cancer and to identify the correlation between allelic imbalance, if any, with the recurrence in oral cancer. Eighty-one patients, treated with radiation or combination of surgery with radiotherapy/chemotherapy, were investigated for LOH/MSI at the 9p21 locus using microsatellite assay. Correlations between allelic alterations and prognostic outcomes were assessed. LOH was noted at D9S161 (56%), followed by D9S162 (31%). Both markers were found to be associated with decreased recurrence free survival, D9S162 showed a significant association with overall survival as well. Only LOH at D9S162 was an independent predictor of recurrence free survival and overall survival. Patients positive for LOH at D9S162 were 6 times more likely to experience recurrence than those without LOH irrespective of treatment modality. LOH at D9S162 is a significant molecular alteration in oral carcinoma with unfavorable repercussions for recurrence and overall survival. PMID- 21592846 TI - Differential survival trends for patients with tonsillar, base of tongue and tongue cancer in Sweden. AB - Tonsillar, base of tongue and tongue cancer have similar anatomical and histopathological appearances but present differences in prognosis. Human papillomavirus (HPV) is a known risk factor for tonsillar and base of tongue cancer, and a survival benefit has been shown for these tumors; however, HPV prevalence in tongue cancer is low. Tonsillar, base of tongue and tongue cancer patients registered in the Swedish Cancer Registry between 1960 and 2004 were followed from the date of cancer diagnosis until death, emigration out of Sweden, or the end of a follow-up (5 years since cancer diagnosis), whichever occurred first. The relative survival rate was computed as the ratio of the observed to the expected survival rate, in which the latter was inferred from the survival of the entire Swedish population in the same age, sex and calendar year stratum. The relative survival rate has improved significantly over time for patients with tonsillar and base of tongue cancer although delineated by different patterns. However, the relative survival rate in tongue cancer patients exhibited only a very modest improvement during the same time period. Contrary to the overall improved survival for patients with tonsillar and base of tongue cancer, the patients with tongue cancer show a very modest improvement in Sweden since 1960. Further studies are warranted to elucidate more effective treatment options for tongue cancer patients. PMID- 21592847 TI - Association between metabolic syndrome and oral pre-malignancy: a community- and population-based study (KCIS No. 28). AB - To elucidate the effect of metabolic syndrome (MetS) on oral pre-malignancy (OPM) and also to examine whether the effect is independent of areca nut chewing. We enrolled a total of 79,940 subjects aged 20 years or older undergoing both oral mucous examination and health check-up for MetS within the Keelung Community based Integrated Screening program between 2003 and 2008. We identified 368 leukoplakia, 72 erythroleukoplakia, and 69 oral submucous fibrosis. The multi variable logistic regression was used to assess the association between MetS and OPM with adjustment of age, gender, areca nut chewing, smoking, and alcohol drinking. Subjects with MetS were at increased risk for OPM (adjusted odds ratio (aOR)=1.68, 95% confidence interval (CI): 1.39-2.04) compared with those without MetS after taking all explanatory factors into account. Among the five components of MetS, subjects with hypertriglyceride (aOR=1.43, 95% CI: 1.17-1.75) and hyperglycemia (aOR=1.30, 95% CI: 1.02-1.67) had higher risk of presenting OPM compared with those within normal ranges. The association between MetS and OPM still persisted even in non-chewers (aOR=1.85, 95% CI: 1.42-2.40) while other risk factors were controlled. We demonstrate a positive association between MetS and OPM, which is independent of areca nut chewing and other confounding factors. This finding provides an insight into a new direction of preventing OPM in contrast to conventional viewpoint focusing on the most important factor of area nut chewing. PMID- 21592848 TI - Spectral studies of copper(II) complexes of tridentate acylhydrazone ligands with heterocyclic compounds as coligands: X-ray crystal structure of one acylhydrazone copper(II) complex. AB - Six copper(II) complexes of 2-hydroxy-4-methoxybenzaldehyde nicotinoylhydrazone (H2hmbn), 2-hydroxy-4-methoxyacetophenone nicotinoylhydrazone (H2hman), 2-hydroxy 4-methoxybenzaldehyde benzoylhydrazone (H2hmbb) and 2-hydroxy-4 methoxyacetophenone benzoylhydrazone (H2hmab) have been synthesized. The complexes viz. [Cu(hmbn)](2).2H(2)O (1), [Cu(hman)](2) (2), [Cu(hmbb)](2).2H(2)O (3), [Cu(hmbb)phen].1(1/2)H2O (4), [Cu(hmbb)(bipy).H2O] (5) and [Cu(hmab)phen] (6) were characterized by different physicochemical techniques. The crystal structure of [Cu(hman)phen] is obtained and it has a distorted square pyramidal geometry with pi-pi stacking interactions and significant C-H pi interactions. PMID- 21592849 TI - Raman spectroscopy of newberyite Mg(PO3OH).3H2O: a cave mineral. AB - Newberyite Mg(PO3OH).3H2O is a mineral found in caves such as from Moorba Cave, Jurien Bay, Western Australia, the Skipton Lava Tubes (SW of Ballarat, Victoria, Australia) and in the Petrogale Cave (Madura, Eucla, Western Australia). Because these minerals contain oxyanions, hydroxyl units and water, the minerals lend themselves to spectroscopic analysis. Raman spectroscopy can investigate the complex paragenetic relationships existing between a number of 'cave' minerals. The intense sharp band at 982 cm(-1) is assigned to the PO4(3-)nu1 symmetric stretching mode. Low intensity Raman bands at 1152, 1263 and 1277 cm(-1) are assigned to the PO4(3-)nu3 antisymmetric stretching vibrations. Raman bands at 497 and 552 cm(-1) are attributed to the PO4(3-)nu4 bending modes. An intense Raman band for newberyite at 398 cm(-1) with a shoulder band at 413 cm(-1) is assigned to the PO4(3-)nu2 bending modes. The values for the OH stretching vibrations provide hydrogen bond distances of 2.728 A (3267 cm(-1)), 2.781 A (3374 cm(-1)), 2.868 A (3479 cm(-1)), and 2.918 A (3515 cm(-1)). Such hydrogen bond distances are typical of secondary minerals. Estimates of the hydrogen-bond distances have been made from the position of the OH stretching vibrations and show a wide range in both strong and weak bonds. PMID- 21592850 TI - A phosphorescent copper(I) complex: synthesis, characterization, photophysical property, and oxygen-sensing behavior. AB - In this paper, we report the synthesis, crystal structure, photophysical properties, and electronic nature of a phosphorescent Cu(I) complex of [Cu(Phen Np)(POP)]BF4, where Phen-Np and POP stand for 2-(naphthalen-1-yl)-1H-imidazo[4,5 f][1,10]phenanthroline and bis(2-(diphenylphosphanyl)phenyl) ether, respectively. [Cu(Phen-Np)(POP)]BF4 renders a yellow phosphorescence peaking at 545 nm, with a long excited state lifetime of 4.69 MUs. Density functional calculation reveals that the emission comes from a triplet metal-to-ligand-charge-transfer excited state. We electrospun composite nanofibers of [Cu(Phen-Np)(POP)]BF4 and polystyrene (PS), hoping to explore the possibility of using the composite nanofibers as an oxygen sensing material. The finally obtained samples with average diameter of ~300 nm exhibit a maximum sensitivity of 7.2 towards molecular oxygen with short response time of 7s due to the large surface-area-to volume ratio of nanofibrous membranes. No photobleaching is detected in these samples. PMID- 21592851 TI - Ground state and excited state dipole moments of 6,8-diphenylimidazo[1,2 alpha]pyrazine determined from solvatochromic shifts of absorption and fluorescence spectra. AB - Electronic absorption and dual fluorescence spectra of 6,8-diphenylimidazo[1,2 alpha]pyrazine (68DIP) was recorded in various solvents with different polarity at room temperature. The ground state (MUg) and the excited state (MUg) dipole moments of 68DIP were estimated from solvatochromic shifts of absorption and fluorescence spectra as a function of the dielectric constant (E) and refractive index (n). The results show that the value of excited state dipole moment in SE: MUeSE=2.8772 D and twisted intramolecular charge transfer (TICT) excited equilibrated state dipole moment value of MUeLE=2.9744 D was found. The solvent dependent spectral shifts in absorption and fluorescence spectra were analyzed by the polarizability-polarity and Kamlet-Taft parameters. PMID- 21592852 TI - A localized surface plasmon resonance light scattering-based sensing of hydroquinone via the formed silver nanoparticles in system. AB - In this contribution, a simple strategy for the detection of hydroquinone (HQ) is proposed based on the localized surface plasmon resonance light scattering (LSPR LS) of the silver nanoparticles (AgNPs) formed through the modified silver mirror reaction. The redox reaction between HQ and silver ammonia occurred in the coexistence of sodium hydroxide and ammonia at room temperature, where silver ammonia was reduced by HQ and resulted in the formation of AgNPs without adding the AgNPs seeds. The formed AgNPs were demonstrated to be monodisperse and uniform by transmission electron microscopy (TEM) image. We also studied the localized surface plasmon resonance absorption (LSPR-A) and LSPR-LS spectra using both a UV-vis spectrophotometer and a common spectrofluorometer, and obtained a good agreement between experiments. By carefully optimizing the amount of NaOH and ammonia of the reaction conditions, we were able to obtain the highest net intensity of LSPR-LS on the concentrations of HQ. On the basis of experimental studies, the LSPR-LS intensity enhanced linearly over the range 0.4-2.5 MUmol L( 1) with the corresponding limits of determination (3sigma) of 70.6 nmol L(-1). With that, the present approach was applied to detect HQ in water samples with satisfactory results. PMID- 21592853 TI - Frequency and phylogeny of norovirus in diarrheic children in Istanbul, Turkey. AB - BACKGROUND: Norovirus (NoV) is recognised as one of the most common causes of foodborne infections. Contaminated shellfish, food, water and hospitals are well documented sources of the virus. OBJECTIVE: NoV in diarrheic children has not previously been investigated in Istanbul, Turkey, hence the aim of this study was to detect and investigate the frequency and phylogeny of human NoV genogroups I and II in children with acute gastroenteritis. STUDY DESIGN: 238 stool samples were collected from diarrheic children from 2 hospitals (Cerrahpasa Medical School and Haseki) in Istanbul and analysed by ELISA, RT-PCR and real-time RT-PCR using both SYBR Green and probe-based assays for human NoV. Primers targeting the RNA-polymerase gene were used for RT-PCR to allow DNA sequencing of Turkish NoV strains and phylogenetic analysis to be performed. RESULTS: NoV GII was detected in 36 (15.1%) of 238 samples by SYBR Green real-time RT-PCR, 10.9% by a probe based real-time RT-PCR and 10.5% by ELISA (Ridascreen). Genogroup II (GII) the Turkish NoVs clustered with including GII4 (72.2%), GII16 (5.5%), GIIb (16.7%) and GIIe (5.5%). Two variants of GII4 (GII4-2006b and GII4-2008), GII16 and recombinant noroviruses (GIIb and GIIe) were identified. CONCLUSION: This study shows a high frequency and genetic diversity of NoV GII infections in children with acute gastroenteritis in Istanbul, Turkey. PMID- 21592855 TI - A comparison of two assays for quantification of Hepatitis B surface Antigen in patients with chronic hepatitis B. AB - BACKGROUND AND OBJECTIVES: Serum Hepatitis B surface Antigen (HBsAg) levels correlate with hepatitis B virus intrahepatic covalently closed circular DNA and may predict response to treatment. Currently, 2 commercial platforms are available for HBsAg quantification in clinical practice, the Architect HBsAg QT and the Elecsys HBsAg. We aimed to directly compare the results of these assays. STUDY DESIGN: HBsAg levels were measured in 1427 serum samples from HBeAg positive chronic hepatitis B patients who participated in a randomized trial of peginterferon alfa-2b+/-lamivudine. Samples were extracted from our serum bank, thawed, and subsequently analysed for HBsAg levels using both assays. RESULTS: Of 1427 samples, 242 (17%) were taken before and 1185 during the treatment phase of the study. Distribution of HBV genotypes was 447 (31%) genotype A, 125 (9%) B, 210 (15%) C and 534 (37%) D. Correlation between Architect and Elecsys results was high (r=0.96, p<0.001). By Bland-Altman analysis, agreement between the two assays was close (mean difference between Architect and Elecsys: -0.01logIU/mL, 95% CI: -0.55-0.52logIU/mL), also when analysed separately for HBV genotypes A-D. Additionally, the performance of our recently published stopping rule for HBeAg positive patients treated with peginterferon was comparable: the negative predictive values were 96% and 98% for Elecsys and Architect, respectively. CONCLUSIONS: There is a high correlation and close agreement between quantitative HBsAg measurements conducted with the Architect and the Elecsys. Clinical prediction rules derived from data from one platform can be applied on the other; both can therefore be used in clinical practice. PMID- 21592854 TI - Oseltamivir-resistant pandemic influenza a (H1N1) 2009 viruses in Spain. AB - BACKGROUND: Pandemic influenza A (H1N1) 2009 virus appeared in Spain on April 25, 2009 for the first time. This new virus was adamantane-resistant but it was sensitive to neuraminidase (NA) inhibitors oseltamivir and zanamivir. OBJECTIVES: To detect oseltamivir-resistant pandemic influenza A (H1N1) 2009 viruses by the Spanish Influenza Surveillance System (SISS) and a possible spread of oseltamivir resistant viruses in Spain since starting of the pandemic situation. STUDY DESIGN: A total of 1229 respiratory samples taken from 413 severe and 766 non severe patients with confirmed viral detection of pandemic influenza A (H1N1) 2009 viruses from different Spanish regions were analyzed for the specific detection of the H275Y mutation in NA between April 2009 and May 2010. RESULTS: H275Y NA substitution was found in 8 patients infected with pandemic influenza A (H1N1) 2009 viruses collected in November and December 2009 and in January 2010. All oseltamivir-resistant viruses were detected in severe patients (8/413, 1.93%) who previously received treatment with oseltamivir. Six of these patients were immunocompromised. CONCLUSION: In Spain, the number of oseltamivir-resistant pandemic influenza A (H1N1) 2009 viruses is until now very low. No evidence for any spread of oseltamivir-resistant H1N1 viruses is achieved in our Country. PMID- 21592856 TI - Lempel-Ziv complexity in schizophrenia: a MEG study. AB - OBJECTIVE: The neurodevelopmental-neurodegenerative debate is a basic issue in the field of the neuropathological basis of schizophrenia (SCH). Neurophysiological techniques have been scarcely involved in such debate, but nonlinear analysis methods may contribute to it. METHODS: Fifteen patients (age range 23-42 years) matching DSM IV-TR criteria for SCH, and 15 sex- and age matched control subjects (age range 23-42 years) underwent a resting-state magnetoencephalographic evaluation and Lempel-Ziv complexity (LZC) scores were calculated. RESULTS: Regression analyses indicated that LZC values were strongly dependent on age. Complexity scores increased as a function of age in controls, while SCH patients exhibited a progressive reduction of LZC values. A logistic model including LZC scores, age and the interaction of both variables allowed the classification of patients and controls with high sensitivity and specificity. CONCLUSIONS: Results demonstrated that SCH patients failed to follow the "normal" process of complexity increase as a function of age. In addition, SCH patients exhibited a significant reduction of complexity scores as a function of age, thus paralleling the pattern observed in neurodegenerative diseases. SIGNIFICANCE: Our results support the notion of a progressive defect in SCH, which does not contradict the existence of a basic neurodevelopmental alteration. PMID- 21592857 TI - Oral administration of multispecies microbial supplements to sows influences the composition of gut microbiota and fecal organic acids in their post-weaned piglets. AB - The timings of the administration of microbial supplements to control the populations of gut microbiota of piglets have been poorly understood. Here the effects of temporal administering multispecies microbial supplements to sows on the composition of gut microbiota and on the bacteria-mediated fecal metabolites in their offsprings were investigated. During gestation and lactation, pregnant sows were fed either a normal diet (group A) or a diet with multispecies supplements comprised of nine microbial species such as Lactobacillus delbrueckii subsp. bulgaricus, Bifidobacterium bifidum, Enterococcus faecium, Candida pintolopesii, and Aspergillus oryzae etc. (group B). All of the sows' piglets were temporarily fed with the same supplements around weaning in accordance with the guideline of the farm. This regimen was followed by a normal diet in both groups over one month thereafter. Under such conditions, the concentration of short-chain fatty acids (SCFAs) in fecal samples remarkably increased in group B compared to group A. When 16S rDNA sequences of the fecal bacteria were analyzed, the microbial structure of bacteria was different between both goups. Especially the Clostridium cluster IV and subcluster XIVa were particularly increased in group B, although the administered microbes were undetectable. Thus, temporal administration of multispecies-microbial supplements to pregnant sows changes the composition of SCFAs and gut microbiota in their offsprings. PMID- 21592858 TI - High on treatment platelet reactivity and stent thrombosis. AB - BACKGROUND: Stent thrombosis (ST) remains a major adverse outcome of percutaneous coronary intervention (PCI). We examined potential associations between high on treatment platelet reactivity and the risk of ST and assessed the effects of increased antiplatelet dosage on platelet inhibition. METHODS: Differences in clinical characteristics and the effect of aspirin and clopidogrel on platelet reactivity were determined after angiographically proven ST in 16 patients and in 40 patients without ST. Platelet reactivity was determined using the VerifyNow assays (Accumetrics Inc., San Diego, CA). Patients found with high on treatment platelet reactivity (P2Y12 Reaction Units >= 235 and/or Aspirin Reaction Units >= 550) returned following two weeks of double dose antiplatelet therapy for further analyses. RESULTS: High post aspirin and/or clopidogrel platelet reactivity was significantly more common in patients with ST versus controls (75% vs. 2.5%, p = < 0.001). Overall, ST patients were younger (52.8 +/- 10.5 vs. 59 +/- 9.6 years; p = 0.039), had more pre-existing coronary artery disease (75% vs. 42%; p = 0.028) and smaller reference vessel diameters (2.9 +/- 0.36 vs. 3.2 +/- 0.54 mm; p = 0.047) when compared to controls. After double dose therapy, antiplatelet reactivity improved significantly in ten out of 12 subjects on clopidogrel (83.3%) and the two patients on aspirin who initially had high on treatment platelet reactivity. CONCLUSION: This study demonstrates that high on treatment platelet reactivity with aspirin and/or clopidogrel is common amongst patients who develop stent thrombosis. Additionally this resistance can be improved with doubling the prior dose of antiplatelet therapy. PMID- 21592859 TI - Baseline faecal occult blood concentration as a predictor of incident colorectal neoplasia: longitudinal follow-up of a Taiwanese population-based colorectal cancer screening cohort. AB - BACKGROUND: Despite widespread use of the immunochemical faecal occult blood test (iFOBT), little is known about the subsequent risk of developing colorectal neoplasia for participants with negative iFOBT results. We investigated whether the concentration of faecal haemoglobin at the first screen is predictive of the subsequent incidence of colorectal neoplasia in those with a negative screening result. METHODS: Between 2001 and 2007, we did a prospective cohort study within the Keelung community-based iFOBT screening programme for residents aged 40-69 years, using a cutoff faecal haemoglobin concentration of 100 ng/mL to classify attendees as negative and positive groups for further clinical investigations. 44,324 participants with negative findings and 1668 with a positive result at the first screen (854 non-referrals who refused colonoscopy and 814 with a false positive result as assessed by colonoscopy) were followed up to ascertain cases of colorectal neoplasia. We investigated the association between baseline faecal haemoglobin concentration and risk of incident colorectal neoplasia, after adjusting for possible confounders. FINDINGS: Median follow-up was 4.39 years (IQR 2.53-6.12) for all 45 992 participants, during which the incidence of colorectal neoplasia increased from 1.74 per 1000 person-years for those with baseline faecal haemoglobin concentration 1-19 ng/mL, to 7.08 per 1000 person years for those with a baseline concentration of 80-99 ng/mL. The adjusted hazard ratios (HRs) increased from 1.43 (95% CI 1.08-1.88) for baseline faecal haemoglobin concentration of 20-39 ng/mL, to 3.41 (2.02-5.75) for a baseline concentration of 80-99 ng/mL (trend test p<0.0001), relative to 1-19 ng/mL. These results did not change when we included repeated iFOBT measurements. Non referrals had the highest risk of incident colorectal neoplasia (adjusted HR 8.46 [6.08-11.76]). INTERPRETATION: Quantitative faecal haemoglobin concentration at first screening predicts subsequent risk of incident colorectal neoplasia. During follow-up, risk stratification based on faecal haemoglobin could help clinicians, with particular attention being paid to those with higher initial faecal haemoglobin concentrations, especially those just under the threshold taken to indicate presence of colorectal neoplasia. FUNDING: None. PMID- 21592860 TI - Screening for colorectal neoplasia with faecal tests. PMID- 21592861 TI - The case for a subunit vaccine against malaria. AB - New technologies and some disillusionment with subunit vaccines has led to increased interest in the development of whole parasite vaccines for malaria. Instead, the current priority should be to build on the partial success of the recombinant protein sporozoite vaccine, RTS,S. There are many possible options for delivering a subunit vaccine but the simplest option, formulating recombinant proteins in an adjuvant, should be fully explored. Numerous options exist for inducing heightened immune responses and for tackling the problem of diversity, but development of recombinant protein subunit vaccines requires a more detailed knowledge of the conformation of the leading vaccine candidates. PMID- 21592862 TI - Current results with slow freezing and vitrification of the human oocyte. AB - The past decade has witnessed renewed interest in human oocyte cryopreservation (OCP). This article reviews the two general methods used for OCP, slow freezing and vitrification, compares the outcomes associated with each technique and discusses the factors that might influence success with OCP (such as oocyte selection or day of transfer). Based on available data, OCP offers a reliable, reproducible method for preservation of the female gamete and will find increasing application in assisted reproductive technology. Oocyte cryopreservation can provide a number of advantages to couples undergoing assisted reproduction or to women interested in fertility preservation. Two methods, slow freezing and vitrification, have been used successfully for oocyte cryopreservation. This article reviews and compares these methods, and discusses various factors that can impact upon success of oocyte cryopreservation. PMID- 21592863 TI - The role of interferon alpha in initiation of type I diabetes in the NOD mouse. AB - Type 1 diabetes (T1D) is an autoimmune disease in both humans and the nonobese diabetic (NOD) mouse, in which the insulin-producing-cells of the pancreatic islets are destroyed by a beta islet cell-specific T cell immune response. We recently reported that interferon (IFN)-alpha is an early trigger of the T1D process in NOD mice. Here, we show that extensive blockade of IFN-alpha action by a monoclonal antibody specific to IFN-alpha receptor 1 results in nearly complete prevention of T1D in NOD mice. Whether professional IFN-alpha producing cells, plasmacytoid dendritic cells (pDCs), are responsible for the initiation of T1D has been unclear. Here we demonstrate that depletion of pDCs in NOD mice by a specific mAb given at 15-25 days of age significantly delays the onset and decreases the incidence of T1D. These findings indicate that pDC and pDC-derived IFN-alpha are the prime initiators of the pathogenesis of T1D in NOD mice. PMID- 21592864 TI - NKT-cell-based immunotherapies in clinical trials. PMID- 21592865 TI - Pre-eclampsia in low and middle income countries. AB - Pre-eclampsia and eclampsia are leading causes of maternal and perinatal morbidity and mortality worldwide. The exact prevalence, however, is unknown. The majority of pre-eclampsia related deaths in LMIC occur in the community and therefore, interventions must be focused at this level. There are a number of unique challenges facing LMIC but the principles of care for women with pre eclampsia remain the same as in well resourced settings. Three primary delays lead to an increased incidence of maternal mortality from pre-eclampsia- delays in triage, transport and treatment. There are a number of other challenges facing LMIC and the health care worker shortage is particularly significant. Task shifting is a potential strategy to address this challenge. Community health care workers, specifically lady health care workers, are an integral part of the health care force in many LMIC and can be employed to provide timely care to women with pre-eclampsia. Prevention strategies should be applied to every pregnant woman since we cannot predict who will develop pre-eclampsia given the limitation in resources. Aspirin and calcium are the only two recommended therapies at this time. Measuring blood pressure and proteinuria is challenging in LMIC due to financial cost and lack of training. A detection tool that is affordable and can be easily applied is needed. Magnesium sulfate is the drug of choice for the prevention and treatment of eclampsia but it is underutilized due to barriers on multiple levels. PMID- 21592866 TI - Interdisciplinary geriatric and psychiatric care reduces potentially inappropriate prescribing in the hospital: interventional study in 150 acutely ill elderly patients with mental and somatic comorbid conditions. AB - BACKGROUND: Potentially inappropriate medications and prescription omissions (PO) are highly prevalent in older patients with mental comorbidities. OBJECTIVE: To evaluate the effect of interdisciplinary geriatric and psychiatric care on the appropriateness of prescribing. DESIGN: Prospective and interventional study. SETTING: Medical-psychiatric unit in an academic geriatric department. PARTICIPANTS: Participants were 150 consecutive acutely ill patients aged on average 80.0 +/- 8.1 years suffering from mental comorbidities and hospitalized for any acute somatic condition. INTERVENTION: From admission to discharge, daily collaboration provided by senior geriatrician and psychiatrist working in a usual geriatric interdisciplinary care team. MEASUREMENTS: Potentially inappropriate medications and PO were detected and recorded by a trained independent investigator using STOPP/START criteria at admission and discharge. RESULTS: Compared with admission, the intervention reduced the total number of medications prescribed at discharge from 1347 to 790 (P < .0001) and incidence rates for potentially inappropriate medications and PO reduced from 77% to 19% (P < .0001) and from 65% to 11% (P < .0001), respectively. Independent predictive factors for PIP at discharge were being a faller (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.43-2.09) and for PO, the increased number of medications (OR 1.54; 95% CI 1.13-1.89) and a Charlson comorbidity index greater than 2 (OR 1.85; 95% CI 1.38 - 2.13). Dementia and/or presence of psychiatric comorbidities were predictive factors for both potentially inappropriate medications and PO at discharge. CONCLUSION: These findings hold substantial promise for the prevention of IP and OP in such a comorbid and polymedicated population. Further evaluations are, however, still needed to determine if such an intervention reduces potentially inappropriate prescribing medication-related outcomes, such as incidence of adverse drug events, rehospitalization, or mortality. PMID- 21592867 TI - A research agenda for nursing homes. PMID- 21592869 TI - A history of TFIIH: two decades of molecular biology on a pivotal transcription/repair factor. AB - The TFIIH multiprotein complex is organized into a 7-subunit core associated with a 3-subunit CDK-activating kinase module (CAK). Three enzymatic subunits are present in TFIIH, two ATP-dependent DNA helicases: XPB and XPD, and the kinase Cdk7. Mutations in three of the subunits, XPB, XPD and TTDA, lead to three distinct genetic disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD) predisposing patients not only to cancer and ageing but also to developmental and neurological defects. These heterogeneous phenotypes originate from the dual role of TFIIH in transcription and DNA repair. For twenty years, many molecular studies have been conducted with the aim to unveil the role of TFIIH in DNA repair and transcription as well as the origin of the phenotypes of patients. This review intends to give a non-exhaustive survey of the most prominent discoveries on the molecular functioning of TFIIH. PMID- 21592870 TI - HPLC determination of the distribution of D-amino acids and effects of ecdysis on alanine racemase activity in kuruma prawn Marsupenaeus japonicus. AB - The distribution of D-amino acids was examined on several tissues of kuruma prawn Marsupenaeus japonicus. D-Alanine was found in all tissues, and the ratio of D alanine to total alanine ranged from 18.7 to 43.7% depending on the tissues. Of these tissues, muscle, heart, and gill contained a relatively large amount of D alanine. Nervous tissue and eye, on the other hand, contained a large amount of D aspartate. D-Glutamate was specifically detected in testis. The percentage of D glutamate to total glutamate was over 50% in testis, suggesting the existence of the biosynthetic enzyme in this tissue. The changes of alanine racemase activity were determined in the muscle and hepatopancreas of M. japonicus before and after molting. The activity after molting increased twice in the muscle. On the other hand, it was not changed in the hepatopancreas. These data suggest that D-alanine plays an important role in the muscle during ecdysis. However, the free D-alanine level in the muscle was not changed significantly before and after ecdysis. From these data, several D-amino acids are considered to be utilized in some essential physiological phenomena in the different tissues of the prawn. PMID- 21592868 TI - Regulation of endonuclease activity in human nucleotide excision repair. AB - Nucleotide excision repair (NER) is a DNA repair pathway that is responsible for removing a variety of lesions caused by harmful UV light, chemical carcinogens, and environmental mutagens from DNA. NER involves the concerted action of over 30 proteins that sequentially recognize a lesion, excise it in the form of an oligonucleotide, and fill in the resulting gap by repair synthesis. ERCC1-XPF and XPG are structure-specific endonucleases responsible for carrying out the incisions 5' and 3' to the damage respectively, culminating in the release of the damaged oligonucleotide. This review focuses on the recent work that led to a greater understanding of how the activities of ERCC1-XPF and XPG are regulated in NER to prevent unwanted cuts in DNA or the persistence of gaps after incision that could result in harmful, cytotoxic DNA structures. PMID- 21592871 TI - Anthropometric history of the French Revolution in the Province of Orleans. AB - We estimate the trend in average height of the population of the French province Orleans from 1715 to the beginning of the 19th century using data on recruits who were drafted either through a lottery system or through general conscription. After controlling for age, residence, and occupation, we find a general decline in the biological standard of living in the decades before the French Revolution. The results support a Ricardian-Malthusian interpretation of the causes of the French Revolution. In the debate 'Revolution de la misere ou de la prosperite' our findings support the side which argues that the French Revolution was a culmination of a long-lasting economic malaise during the final phases of the Ancien Regime. PMID- 21592872 TI - Percutaneous transhepatic cholangiodrainage under real-time MRI guidance: initial experience in an animal model. AB - AIMS: To assess percutaneous transhepatic cholangiodrainage (PTCD) under real time MRI-guidance and compare it to procedures performed under fluoroscopy. METHODS: We developed an in vitro model for MRI-guided and conventional PTCD, using an animal organ set including liver and bile ducts placed in an MRI compatible box and tested it in a 1.0-Tesla open MRI-scanner. Prototype 18G needles and guide wires, standard guide wires, dilatation bougies, and drainages were used (MRI-compatible). MRI-visualization was by means of a bFFE real-time sequence using a surface coil (Flex-L). Outcome measurements were success rates and time needed for bile duct puncture using real-time MRI-guidance versus conventional radiologic methods in the model. Cannulation and drainage placement were also analysed. RESULTS: Fifty MRI-guided experiments were performed, leading to rapid (mean: 43s, range: 15-72s) and successful puncture and cannulation in 96% of procedures. Median drainage placement time was 321.5s (range: 241-411s). In 35 control experiments under fluoroscopy, puncture success was 69%, whereas times were significantly longer (mean 273s, range 45-631s). CONCLUSIONS: Initial in vitro experience shows that PTCD can be successfully and rapidly performed under real-time MRI-guidance and demonstrates improved performance compared to the conventional radiologic approach. PMID- 21592873 TI - Endoscopic ultrasound-guided fine needle aspiration with 22- and 25-gauge needles in solid pancreatic masses: a prospective comparative study with randomisation of needle sequence. AB - BACKGROUND: The difference in the diagnostic accuracy of 22- versus 25-gauge needles in EUS-FNA is not clear. AIMS: To compare the rates of technical success, diagnostic accuracy and complications of EUS-FNA performed with 22-gauge and 25 gauge needles on the same solid pancreatic mass. METHODS: All patients with solid pancreatic masses evaluated from September 2007 to December 2008 were enrolled and underwent EUS-FNA with both 22- and 25-gauge needles with randomisation of needle sequence. The accuracy of the EUS-FNA was determined by comparing the cytological results with the final surgical pathological diagnoses or with the results of a clinical follow-up. A cytological score with different qualitative parameters was created, and a comparison between these parameters was carried out for each needle. RESULTS: Fifty patients with 50 pancreatic masses were recruited. Technical success was 100% and no complications occurred. Diagnostic accuracy was 94% and 86% for the 25- and 22-gauge needles, respectively. Analysis of the cytological score showed a tendency towards the 25-gauge needle, although the difference was not statistically significant. CONCLUSIONS: EUS-FNA performed with 22- or 25-gauge needles had the same diagnostic accuracy. Our study results confirm a significant trend towards a better cytological diagnosis for the 25 gauge needle. PMID- 21592874 TI - [Epilepsy versus convulsive syncope: tilt table test as a diagnostic tool]. PMID- 21592875 TI - Developmental expression and alternative splicing of the duck myostatin gene. AB - Myostatin (MSTN) plays a key role in the negative regulation of muscle growth and development during embryogenesis. The MSTN genes have different genetic characteristics in vertebrates: sole gene in mammals, gene duplication in fish, and alternative splicing in birds. To investigate the alternative splicing sites and developmental expression patterns of the duck MSTN genes, the mRNA and genome sequences were cloned, and the expression patterns were detected during breast muscle and leg muscle development by real-time PCR. In our study, four alternatively spliced forms of MSTN mRNA were found in the developing skeletal muscle of Peking duck, including two novel alternatively spliced transcripts, MSTN-c and MSTN-d. As a result of alternative splicing at the common GT-AG processing sites, MSTN-b and MSTN-c retained only the N-terminal TGFbeta propeptide superfamily domains. However, MSTN-d was not missing these domains, in contrast to MSTN-a. The real-time PCR results showed that there was no significant difference between breast muscle and leg muscle in MSTN-a mRNA expression, also in MSTN-b and MSTN-c. MSTN-a and MSTN-b have significant higher expressions than MSTN-c and MSTN-d, suggesting that they play the major role during embryo muscle development. PMID- 21592876 TI - Efficacy of open rhinoplasty approach to foreign body granuloma of the nose. PMID- 21592877 TI - A general method to assess the utility of the X-chromosomal markers in kinship testing. AB - In studies involving pedigree reconstruction and kinship estimation, it is acknowledged that some pedigrees have the same algebraic expressions for the joint genotypic probabilities and are, therefore, indistinguishable when considering only genetic information, no matter what the mode of transmission considered. Indeed, although standard forensic practice considers solely unlinked autosomal markers, the existence of pedigrees with the referred theoretical property (that are then said to belong to the same kinship class) is possible when considering any kind of genetic transmission. The research on genetic relatedness has always been linked to the root concept of identity-by-descent (IBD). However, although the basic theoretical core for autosomal transmission has been long formalised, a general method allowing the decision if two pedigrees linking two non-inbred individuals are distinguishable using unlinked autosomal markers along with the respective IBD partitions (and consequently the algebraic expressions for the joint genotypic probabilities) was only recently published. In this work X-chromosomal transmission will be at stake, considering that the analytical framework for X-chromosomal markers has been recently established and the importance of X-chromosome markers for these questions has been steadily growing, particularly in forensics, as a tool both to complement the information given by autosomes in complex kinship testing cases and to differentiate pedigrees belonging to the same autosomal kinship class. Therefore, here it will be presented a formal and mathematically well supported framework where a general counting rule is given, allowing a secure and expeditious decision on the usefulness of typing (unlinked) X-chromosomal markers on pairwise kinship testing involving two non-inbred individuals. Moreover the counting rule now presented allows the derivation of algebraic expressions for the joint genotypic probabilities associated with any pedigree. PMID- 21592878 TI - Comments on: "meniscus and cartilaginous lesions. Influence of the delay between ACL injury and ligament reconstruction in 40-year-old patients" by T. Gregory and P. Landreau, published in Rev Chir Orthop, 2008;94:566-72. PMID- 21592879 TI - Initial combination therapy with amlodipine/valsartan compared with monotherapy in the treatment of hypertension. AB - Achieving target blood pressure (BP) is influenced by baseline BP. Post hoc analyses of a placebo-controlled trial of amlodipine/valsartan versus monotherapies were conducted to characterize BP control by baseline BP. Hypertensive patients were randomized to amlodipine 10 mg, valsartan 160 or 320 mg, amlodipine/valsartan 10/160 or 10/320 mg, or placebo. Analysis of BP control rates focused on patients receiving the highest combination and monotherapy doses, with adverse events assessed for all doses. Analyses included 834 patients (mean age: 57 years; male: 51.3%; white: 79.4%; stage 2 hypertension: 61%; mean BP: 157/99 mm Hg). Two weeks after starting therapy, BP control (<140/90 mm Hg) rates were greater with amlodipine/valsartan 10/320 mg (49%) versus monotherapies (32%-38%) and placebo (16%). Consistent results were observed in stage 1 and 2 patients. Among patients receiving combination therapy, statistically significant differences were observed at endpoint versus comparators. At all baseline BP levels, the probability of achieving BP lower than 140/90 or lower than 130/80 mm Hg was greater with amlodipine/valsartan than monotherapies and placebo. Overall adverse events incidence was similar with combination versus monotherapies and placebo. Initial therapy with amlodipine/valsartan results in early, more effective BP control compared with monotherapy, irrespective of baseline BP. PMID- 21592880 TI - Are melatonin and its receptor agonist specific antihypertensive modulators of resistant hypertension caused by disrupted circadian rhythm? PMID- 21592881 TI - Modified N-shaped ileal neobladder after radical cystectomy. AB - OBJECTIVE: We report on the feasibility and outcomes of the N-shaped pouch with an afferent tubular isoperistaltic segment as a new technique for creating a capacious, low pressure bladder substitute following radical cystectomy. METHODS: Between April 2000 and April 2006, 42 patients (36 male, 6 female) with invasive bladder cancer were considered good candidates for orthotopic urinary diversion. All had radical cystectomy with bilateral pelvic lymphadenectomy and orthotopic bladder substitution by an ileal low pressure reservoir (N-shaped) with an afferent isoperistaltic tubular segment. Of the 42 patients, 36 (86%) had squamous cell carcinoma; 6 had transitional cell carcinoma. None of the patients had positive lymph nodes after pathologic examination of the specimen. The patients were available for a median follow-up period of 24.8 months. Follow-up included clinical and radiographic studies to determine functional and oncological outcomes. RESULTS: Eleven patients (26.2%) had early complications during the period <= 3 months following surgery. Seven of these patients had complications such as wound infection, prolonged ileus, persistent urinary leakage, and deep venous thrombosis that were treated conservatively. One female patient developed a pouch-vaginal fistula that required repair. The remaining 3 patients had oncologic failures, 1 of which was isolated urethral recurrence. Late complications occurred in 15 patients (35.7%). These included pouch stones, outflow obstruction, mucus retention, and adhesive bowel obstruction. Daytime and night-time continence was achieved in 92% and 80% of the patients, respectively, and ureteroileal stricture was observed in 5%. The upper tracts remained unchanged or improved in nearly 95% of the patients. CONCLUSIONS: Ileal orthotopic bladder substitution (N-shaped) with an afferent ileal tubular segment offers good functional results with good preservation of the renal units. It is considered a safe and technically feasible surgical procedure. PMID- 21592882 TI - [Relevance of practice guidelines in echocardiography]. PMID- 21592883 TI - [Accuracy of the 64 multislice computed tomography in the diagnosis of coronary stent restenosis]. AB - OBJECTIVE: To determine the accuracy of coronary angiography through 64-slice computed tomography in detecting in-stent restenosis. METHOD: Fifty-two patients with 76 coronary stents and suspicion of restenosis were examined. Initially, they underwent coronary angiography through 64-slice computed tomography, and subsequently invasive coronary angiography as gold standard. Diagnostic efficiency indexes were calculated. RESULTS: In the stents of 3 mm or more of diameter, tomography sensitivity, specificity, positive and negative predictive value were 95, 98, 95 and 98% respectively, with positive likelihood ratio of 42 (CI95%, 6 to 290) and negative of 0.05 (CI95%, .01 to .35), validity of 97% and Kappa of 0.93 (CI95%, .83 to 1), (p ? 0.00001). In the stents smaller than 3 mm, the indexes of diagnostic efficiency and Kappa considerably decreased, loosing the statistical significance (p >0.05). CONCLUSIONS: Coronary angiography through 64-slice computed tomography is an accurate, non-invasive clinical technique for the detection of in-stent restenosis, especially with stents of 3 mm or more of diameter, and reliable allows identification of patients who need to undergo or not control invasive coronary angiography. PMID- 21592884 TI - [Evaluation of coronary stent restenosis with multislice computed tomography]. PMID- 21592885 TI - [Design of a multicenter registry to evaluate rhythm versus rate control in atrial fibrillation: Atrial Fibrillation Mexican Registry (ReMeFA)]. AB - Atrial fibrillation is the most common arrhythmia, predominantly affecting individuals older than 70 years of age. There is little information about its management in Mexico, for this purpose the Mexican Registry of Atrial Fibrillation (ReMeFa) was designed. METHODS: ReMeFA is a prospective multicentric, observational registry concerning the treatment of atrial fibrillation in Mexico. It includes patients 18 years and older, from both genders, with documented atrial fibrillation. Patients with secondary atrial fibrillation from a reversible cause, previous treatment with pulmonary vein ablation (percutaneous or surgical), pacemakers or defibrillators, and with a life expectancy of less than one year, physically or mentally impaired for completing the protocol were excluded. Clinical and demographic data were collected at enrollment and in two scheduled visits at 6 and 12 months. Information about pharmacologic treatment for rhythm or rate control was particularly obtained. PRELIMINARY RESULTS: Between December 2008 to July 2009, 1201 patients from 79 centers were enrolled. CONCLUSION: This registry will provide valuable information about the strategy chosen by physicians in Mexico for the treatment of atrial fibrillation. PMID- 21592886 TI - Spontaneous rupture of an aneurysm of the sinus of Valsalva into the right atrium, associated with an atrial septal aneurysm. AB - Aneurysms of the sinus of Valsalva (SV) and the atrial septum are a rare association. We report the case of a 28-year-old woman, who was admitted to our department complaining of progressive dyspnea of 10 days of evolution, five hours previous to her admission to the hospital; she presented sudden oppressive anterior chest pain, accompanied by palpitations. The presence of rupture of the right SV to the right atrium was clinically confirmed, by echocardiography and hemodynamic studies. In addition, an associated atrial septal aneurysm was found. She underwent surgical correction through sinusplasty without requiring aortic valve replacement. The patient presented persistent postoperative atrioventricular block, which required a permanent pacemaker. Clinical evolution was satisfactory. To our knowledge, this case is a rare combination of two isolated malformations, without previous events that could explain the rupture of the right SV. PMID- 21592887 TI - [Intrapericardial teratoma in the neonatal stage: diagnosis and evolution]. AB - Intrapericardial teratomas in fetal and neonatal stages are rare. They invade the mediastinum compromising the venous return to the heart and leading to hydrops. We report a case of a neonate with fetal hydrops who required ventilatory support at birth and urgent surgical treatment due to severe respiratory failure. During surgery, a multicyst mass was resected in the anterior mediastinum, corresponding to an immature teratoma. PMID- 21592888 TI - Intracardiac ultrasound-guided percutaneous mitral valvuloplasty. AB - Intracardiac echocardiography (ICE) is a relatively new method of ultrasound images useful during cardiac percutaneous interventional procedures. The first human experience with this method was published in 2000 and, since then, several original trials have enrolled this useful method, proving similar and more useful than transesophageal echocardiography in percutaneous treatment of several congenital cardiopathies, like interatrial communication, permeable oval foramen, mitral stenosis, and atrial fibrillation ablation. In this presentation, we publish a single case report of percutaneous mitral valvuloplasty under ICE guidance. PMID- 21592889 TI - [Rescue maneuver for entrapped stent in the coronary tree]. AB - We describe two patients in whom stents dislodged from the unexpanded balloon during angioplasty and remained trapped in the coronary tree. In one patient the stent was located in the curvature of the circumflex artery and, in the other patient, it was detected in the distal left main artery. Retrieval of the undeployed stents was accomplished in the first case after advancing a low profile balloon through the stent and, in the second case, after placing a second guidewire exterior to the stent. In both cases, the balloon was inflated distally and the stents were dislodged after pulling the balloon back towards the guiding catheter and then withdrawing the whole system. PMID- 21592890 TI - Myocardial postconditioning: anaesthetic considerations. AB - "Recently, it has been shown that the heart can be protected against the ischemia reperfusion injury if brief coronary occlusions are performed just at the beginning of the reperfusion. This procedure has been called postconditioning (PostC). It can also be elicited by pharmacological interventions, which are named pharmacological PostC. In general, PostC reduces the reperfusion- induced injury, blunts oxidant-mediated damages and attenuates the local inflammatory response to reperfusion, decreases infarct size, diminishes apoptosis, neutrophil activation, and endothelial dysfunction. The mechanisms that participate in PostC are still not completely understood. In this regard, adenosine, glycine, bradykinin, ciclosporin A are involved in PostC triggering. Similar to ischemic preconditioning, PostC triggers several signaling pathways and molecular components, including nitric oxide (NO), protein kinase C, adenosine triphosphate sensitive potassium channels, the Reperfusion Injury Salvage Kinases (RISK) pathway, which comprises phosphatidylinositol-3-OH kinase (PI3K) and extracellular signal-regulated kinase (ERK 1/2), and, finally, the Survivor Activating Factor Enhancement (SAFE) pathway. In this review, we describe the mechanisms of reperfusion-induced injury as well as the proposed protective pathways activated by PostC, which seem to converge in inhibition of mitochondrial permeability transition pores opening. On the other hand, experimental evidence indicates that volatile anesthetics and opioids are capable of exerting cardioprotective effects under certain conditions, constituting a very useful pharmacological PostC. Thus, the first minutes of reperfusion represent a window of opportunity for triggering the aforementioned mediators, which acting in concert lead to protection of the myocardium against reperfusion injury. Pharmacological, especially anesthetic, PostC may have a promising future in the clinical scenarios in the operating room." PMID- 21592891 TI - [Evidence-based cardiology: practical applications from epidemiology I. The evaluation of a novel drug or therapy]. AB - The substantial increase of randomized controlled trials demand familiarity with the essential aspects of their design and performance by the cardiologist, particularly the adequate interpretation and applicability of the results. In this clinically-based review, we discuss some important aspects in the assessment of novel contemporary therapy such as the use and analysis of composite endpoints; implications from early termination of trials and extrapolation of results to the population. PMID- 21592892 TI - [Guidelines for the accreditation in adult echocardiography and of the echocardiography laboratory from the Echocardiography Association of the Inter American Society of Cardiology (ECHOIASC)]. PMID- 21592893 TI - [Antibodies against T. cruzi identification in migrants from endemic areas, a prevention measure against Chagas disease]. PMID- 21592894 TI - [Relevance of society's participation in medicine. The case of pulmonary hypertension in Latin America]. PMID- 21592895 TI - [The language in medical publications: an endeavor in the achievement of excellence]. PMID- 21592896 TI - [Does acquiring a technical skill is enough to perform gastrointestinal endoscopy? A reflection of the experience in a University Training Center]. PMID- 21592897 TI - [Experience in surgical management of rectal prolapse in two hospitals in Mexico City]. AB - BACKGROUND: Rectal prolapse is defined as a falling out of place of the rectum through anus. Surgery is the treatment of choice to reverse abnormal anatomy and to improve anorectal function. OBJECTIVE: To review the experience in recent years of surgical management of rectal prolapse in the Hospital Central Militar and Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. METHODS: All patients with rectal prolapse who underwent surgical treatment between January 1993 through December 2008 at two institutions in Mexico City were included. Clinical information was obtained of the clinical files in both hospitals. Main study variables were age, sex, degree of prolapse, morbility and type of surgery performed. RESULTS: Fifty seven patients were included, predominantly female (59.6%) with a mean age of 45 years. The most frequent diagnosis was complete rectal prolapse. Fifteen patients (26%) were treated by perineal procedure and 42 (74%) through abdomen: 17 (40%) open and 25 (60%) laparoscopic. Morbidity rate was lower in the laparoscopic group with less length of hospital stay and a lower blood loss, but with higher recurrence rate. CONCLUSIONS: Although the laparoscopic surgery showed advantage related with a less morbility, blood loss and hospital stay, it showed higher recurrence rates." PMID- 21592898 TI - [Midazolam versus dexmedetomidine for sedation for upper gastrointestinal endoscopy]. AB - BACKGROUND: The diagnostic upper gastrointestinal endoscopy (UGI) is a safe procedure although 50% to 60% morbidity and mortality due to cardiopulmonary complications. OBJECTIVE: To compare safety and efficacy of dexmedetomidine vs. midazolam in UGI. METHODS: We conducted a randomized controlled, double-blind, clinical trial to compare the two drugs. Patients with an indication of UGI were randomized to receive sedation with dexmedetomidine or midazolam during the procedure. We compared age, sex, physical status (ASA), body mass index (BMI), degree of sedation (Ramsay scale), recovery time and degree of satisfaction with the procedure. RESULTS: Forty patients with an indication of UGI were included (20 in each arm). Both groups showed a similar distribution by sex, age, BMI and ASA physical status. The level of sedation was similar starting and ending the procedure according to the Ramsay scale. The dexmedetomidine group had a shorter recovery time (7.1 vs. 15.8 min, p <0.05) and satisfaction (9.9 vs. 9.0, p <0.05). Adverse effects occurred in similar proportions in both groups. CONCLUSIONS: Midazolam and dexmedetomidine are suitable for endoscopic procedures of upper digestive tract. Dexmedetomidine offers shorter recovery time and better patient's satisfaction. PMID- 21592899 TI - [Relationship between technical difficulty to cannulate papila of Vater and fluoroscopy time]. AB - BACKGROUND: Exposure to radiation during endoscopic retrograde cholangiopancreatography (ERCP) could have adverse effects on the endoscopic team members and patients. There is an inverse relationship between fluoroscopy time and endoscopist experience. OBJECTIVE: To determine the relationship between the technical difficulty to cannulate Vater's papilla, and time to perform the procedure and fluoroscopy time. METHODS: Patients scheduled for ERCP were divided in two groups depending on the degree of difficulty of the process according to Schutz classification: group A (grades 1-3) and group B (grades 4 and 5). We registered demographic variables, reference diagnosis, endoscopic and radiological diagnoses, degree of difficulty to cannulate Vater's papilla (Freeman scale), duration of procedure, fluoroscopy time and endoscopic complications. RESULTS: 213 patients were included: 101 in group A and 112 in group B. Mean fluoroscopy time was 59.15 seconds in group A and 93.59 seconds in group B (p <0.0001). Mean time to perform the procedure was 13.18 minutes in group A and 20.23 minutes in group B (p <0.0001). Factors related to increased fluoroscopy time were technical difficulty for the CPE according to Schutz (p <0.0001), stent placement (p = 0.021) and hydrostatic dilation (p <0.0001). CONCLUSIONS: The fluoroscopy time increased proportionally to technical difficulty to perform the procedure. PMID- 21592900 TI - [CeliacScore 2.0: Up to date of the Score System for the Diagnosis of Celiac Disease: association with DQbeta1*02 and DQbeta1*0302 alleles]. AB - INTRODUCTION: Celiac disease (CD) diagnosis can be improved if a scoring system comprising clinical, nutritional, serological and histopathological elements is applied. DQbeta1*02 and/ or DQbeta1*0302 alleles can be expected to be more frequent among subjects with the highest scores. OBJECTIVES: To assess the relationship between score assigned to the patient by means of the system developed and alleles associated with CD. METHODS: Scores were assigned to 69 patients (Women: 68.1%; Ages <= 60 years: 95.7%) assisted by a multidisciplinary group for management of CD, using an updated version of a previously described score system (CeliacScore 2.0) were correlated with the occurrence of DQbeta1*02 and/or DQbeta1*0302 alleles. CD was diagnosed if the assigned score was >= 10. RESULTS: 17.4% of studied patients were diagnosed as CD. DQbeta1*02 and/or DQbeta1*0302 alleles were present in 56.5% of our cases. Scores assigned to patient's were independent of the presence of alleles of interest (c2 = 2.3; p > 0.319). 75.0% of subjects with a score higher than 10 had the alleles of interest. The probability for the presence of DQbeta1*02 and/or DQbeta1*0302 alleles was 2.7 in patients with scores >= 10. CONCLUSIONS: The described system can be useful in the CD diagnosis. Alleles associated with CD concentrated among those with the highest scores. Scoring system's operating characteristics should be explored in further studies. PMID- 21592901 TI - [Epidemiology and clinical characteristics of ulcerative colitis in north-eastern Mexico]. AB - BACKGROUND: Inflammatory Bowel Disease (IBD) compromises two entities: Ulcerative Colitis (UC) and Crohn Disease (CD). The incidence and prevalence vary widely in relation to ethnicity and demographic localization. Historically it has been considered a rare disease in Mexico. OBJECTIVE: To determine the frequency of new UC cases and their clinical characteristics in a referral hospital of North Eastern Mexico. METHODS: An epidemiological, descriptive and retrospective study was made which included newly diagnosed patients with UC in a five years period. RESULTS: The adjusted rate of patients diagnosed with UC to the number of admissions for year was 2.3, 2.6, 3.0, 3.6 and 4.1/1000 admissions between 2004 and 2008. The rate of newly diagnosed patients with UC has doubled in the year 2008 compared with the year 2004 (p < 0.05). Fifty five percent of the patients showed mild disease, 30% showed moderate disease and 15% showed severe disease. Fifty percent of the patients had pancolitis, left sided colitis was present in 21% and 29% of the patients just had proctitis. Other clinical aspects of UC corresponded to those previously described. CONCLUSION: The frequency of new patients diagnosed with UC has significantly increased in this tertiary-care referral hospital for the last five years. PMID- 21592903 TI - [Unusual Meckel's diverticulum]. PMID- 21592902 TI - [Prevalence of microscopic colitis in patients with irritable bowel syndrome with diarrhea predominance]. AB - BACKGROUND: Microscopic colitis (MC) and irritable bowel syndrome with diarrhea (IBSD) have a similar clinical and endoscopic presentation. The prevalence of MC in Mexican patients with IBS-D is unknown. OBJECTIVES: To find out the prevalence of MC in patients with IBS-D and compare it with the one observed in patients with IBS with constipation (IBS-C). METHODS: All patients with IBS (Rome III) seen consecutively from January 2008 to August 2010 were included. Those with organic disease, alarm signs, mixed IBS or unsubtyped- IBS (Rome III) were excluded. Colonoscopy with biopsies was performed in all patients that were examined by two pathologists who did not know the clinical characteristics of the subjects. MC was defined according with the universally accepted histological criteria. RESULTS: 155 patients with IBS-D and 145 with IBS-C were studied. Both groups were matched from the standpoint of age, gender ratio and time course of disease. MC was detected in 28 patients with IBS-D and in one with IBS-C (18% vs. 0.7%, p <0.0001). Fifteen patients with lymphocytic colitis and 14 with collagenous colitis were detected. The endoscopic appearance of the colon mucosa was normal in 20 of the 29 patients with MC (69%). CONCLUSIONS: The prevalence of MC in patients with IBS-D was 18%, significantly higher than the one observed in patients with IBS-C. Colonic mucosa had a normal appearance in most of the patients with MC. Systematic biopsies are recommended in patients with IBS-D. PMID- 21592904 TI - [Giant colonic diverticulum]. PMID- 21592905 TI - [Endoscopic submucosal dissection of a colonic tubulovillous adenoma with high grade dysplasia]. PMID- 21592906 TI - [The role of the image on the diagnosis of the gastrointestinal stromal tumor (GIST)]. PMID- 21592907 TI - Success of medical therapy in a rare case of cecal ameboma. AB - INTRODUCTION: Colitis caused by Entamoeba histolytica (EH) is prevalent in developing countries. Clinical presentation ranges from mild diarrhoea episodes to dysentery and liver abscess. Ameboma, a complication caused by EH invasion of the intestinal wall, is a rare presentation of amebiasis, occurring approximately in 1.5% of cases. Because of its insidious and variable clinical presentation only few cases are diagnosed previous to surgical intervention. We report a 52 years old Mexican-mestizo female, presenting with a pain-less right lower quadrant abdominal mass and diagnosed of cecal ameboma prior to surgery by colonoscopy and histopathologic examination. The present case highlights the importance of early diagnosis and medical therapy with antiparasitic drugs in order to avoid complications that could lead these patients to unnecessary surgical management. PMID- 21592908 TI - [Perianal cutaneous amebiasis. Report of two cases]. AB - Perianal cutaneous amebiasis is a rare entity, with 0.03% to 0.07% reported incidence. We present two cases of perianal cutaneous amebiasis, both in male patients. Diagnosis was established by biopsy, with demonstration of Entamoeba histolytica trophozoites. Treatment with metronidazol was performed with good outcome. Although incidence of perianal cutaneous amebiasis is low, this entity must be kept in mind when painful atypical ulcers appear in this region. Diagnosis must be confirmed by identification of the parasite and treatment must be established with antiamebic extra-luminal drugs. PMID- 21592909 TI - Ileocolic intussusception secondary to Hodgkin's lymphoma. Report of a case. AB - Intussusception is a rare condition in adults and represents 1% to 5% of the total cases of intestinal obstruction. Preoperative diagnosis occurs only in a few patients and most of the cases are diagnosed during surgery. A demonstrable etiology is found in 70% to 90% of cases in adult intussusceptions, and approximately 40% of them are caused by primary or secondary malignant tumors. We report the case of a 32 year old male patient with an ileocolic intussusception secondary to Hodgkin's lymphoma, as well as the surgical treatment, and outcome. PMID- 21592910 TI - [Retroperitoneal cystic lymphangioma in an adult: case report]. AB - Retroperitoneal cystic lymphangyoma is a benign lesion, extremely rare in adults. In most cases is asymptomatic. The objective of this report is to present the case of an 82 year old woman who presented abdominal pain, food intolerance and a palpable abdominal mass located toward the upper right quadrant. The abdominal CT scan showed a cystic lesion below the liver which extended to the retroperitoneum. The patient underwent laparotomy achieving complete resection of the lesion and she was discharged soon after. After six months of follow up, she has not presented recurrence. The presentation of this lesion is very rare, generally as a consequence of congenital malformations of the lymphatic vessels. These lesions must be considered as part of the differential diagnosis of the cystic type tumors. The ultrasound and abdominal CT scan are useful for diagnosis. Surgical resection is the only therapeutic option. PMID- 21592911 TI - [Ectopic pancreas in the stomach of infrequent localization in the muscularis mucosae]. AB - Heterotopic pancreatic tissue in the stomach is an uncommon gastric subepithelial lesion. Is usually an asymptomatic condition which is found incidentally. As with other gastric subepithelial lesions, diagnosis can be challenging. Endoscopic forceps biopsy specimens are of little value. Endoscopic ultrasound findings are helpful in characterize this lesions, but they cannot absolutely determine the type of lesion or whether a lesion is benign or malignant. The sequence endosonography- cap assisted endoscopic mucosal resection allows en bloc resection of small gastric subepithelial lesions with low complication rates. We report a case of an ectopic pancreas of the antrum in the stomach that arises from the second layer of the gastric wall (muscularis mucosa) at endoscopic ultrasound that was removed en bloc with cap-assisted endoscopic mucosal resection technique in one endoscopic session without complications. PMID- 21592912 TI - Integration of fuzzy spatial information in tracking based on particle filtering. AB - In this paper, we propose a novel method to introduce spatial information in particle filters. This information may be expressed as spatial relations (orientation, distance, etc.), velocity, scaling, or shape information. Spatial information is modeled in a generic fuzzy-set framework. The fuzzy models are then introduced in the particle filter and automatically define transition and prior spatial distributions. We also propose an efficient importance distribution to produce relevant particles, which is dedicated to the proposed fuzzy framework. The fuzzy modeling provides flexibility both in the semantics of information and in the transitions from one instant to another one. This allows one to take into account situations where a tracked object changes its direction in a quite abrupt way and where poor prior information on dynamics is available, as demonstrated on synthetic data. As an illustration, two tests on real video sequences are performed in this paper. The first one concerns a classical tracking problem and shows that our approach efficiently tracks objects with complex and unknown dynamics, outperforming classical filtering techniques while using only a small number of particles. In the second experiment, we show the flexibility of our approach for modeling: Fuzzy shapes are modeled in a generic way and allow the tracking of objects with changing shape. PMID- 21592913 TI - Combined mining: discovering informative knowledge in complex data. AB - Enterprise data mining applications often involve complex data such as multiple large heterogeneous data sources, user preferences, and business impact. In such situations, a single method or one-step mining is often limited in discovering informative knowledge. It would also be very time and space consuming, if not impossible, to join relevant large data sources for mining patterns consisting of multiple aspects of information. It is crucial to develop effective approaches for mining patterns combining necessary information from multiple relevant business lines, catering for real business settings and decision-making actions rather than just providing a single line of patterns. The recent years have seen increasing efforts on mining more informative patterns, e.g., integrating frequent pattern mining with classifications to generate frequent pattern-based classifiers. Rather than presenting a specific algorithm, this paper builds on our existing works and proposes combined mining as a general approach to mining for informative patterns combining components from either multiple data sets or multiple features or by multiple methods on demand. We summarize general frameworks, paradigms, and basic processes for multifeature combined mining, multisource combined mining, and multimethod combined mining. Novel types of combined patterns, such as incremental cluster patterns, can result from such frameworks, which cannot be directly produced by the existing methods. A set of real-world case studies has been conducted to test the frameworks, with some of them briefed in this paper. They identify combined patterns for informing government debt prevention and improving government service objectives, which show the flexibility and instantiation capability of combined mining in discovering informative knowledge in complex data. PMID- 21592914 TI - Perceptual segmentation: combining image segmentation with object tagging. AB - Human observers understand the content of an image intuitively. Based upon image content, they perform many image-related tasks, such as creating slide shows and photo albums, and organizing their image archives. For example, to select photos for an album, people assess image quality based upon the main objects in the image. They modify colors in an image based upon the color of important objects, such as sky, grass or skin. Serious photographers might modify each object separately. Photo applications, in contrast, use low-level descriptors to guide similar tasks. Typical descriptors, such as color histograms, noise level, JPEG artifacts and overall sharpness, can guide an imaging application and safeguard against blunders. However, there is a gap between the outcome of such operations and the same task performed by a person. We believe that the gap can be bridged by automatically understanding the content of the image. This paper presents algorithms for automatic tagging of perceptual objects in images, including sky, skin, and foliage, which constitutes an important step toward this goal. PMID- 21592915 TI - Detection of small bowel polyps and ulcers in wireless capsule endoscopy videos. AB - Over the last decade, wireless capsule endoscopy (WCE) technology has become a very useful tool for diagnosing diseases within the human digestive tract. Physicians using WCE can examine the digestive tract in a minimally invasive way searching for pathological abnormalities such as bleeding, polyps, ulcers, and Crohn's disease. To improve effectiveness of WCE, researchers have developed software methods to automatically detect these diseases at a high rate of success. This paper proposes a novel synergistic methodology for automatically discovering polyps (protrusions) and perforated ulcers in WCE video frames. Finally, results of the methodology are given and statistical comparisons are also presented relevant to other works. PMID- 21592916 TI - A decision-based velocity ramp for minimizing the effect of misclassifications during real-time pattern recognition control. AB - Real-time pattern recognition control is frequently affected by misclassifications. This study investigated the use of a decision-based velocity ramp that attenuated movement speed after a change in classifier decision. The goal was to improve prosthesis positioning by minimizing the effect of unintended movements. Non-amputee and amputee subjects controlled a prosthesis in real-time using pattern recognition. While performing a target achievement test in a virtual environment, subjects had a significantly higher completion rate (p < 0.05) and a more direct path (p < 0.05) to the target with the velocity ramp than without it. Using a physical prosthesis, subjects stacked a greater average number of 1 cubes (p < 0.05) in three minutes with the velocity ramp than without it (76% more blocks for non-amputees; 89% more blocks for amputees). Real-time control using the velocity ramp also showed significant performance improvements above using majority vote. Eighty-three percent of subjects preferred to control the prosthesis using the velocity ramp. These results suggest that using a decision-based velocity ramp with pattern recognition may improve user performance. Since the velocity ramp is a post-processing step, it has the potential to be used with a variety of classifiers for many applications. PMID- 21592917 TI - Improving the gait performance of non-fluid-based swing-phase control mechanisms in transfemoral prostheses. AB - A prosthetic swing-phase control mechanism simulates the action of leg musculature, aiding gait function by controlling the duration of swing, extent of heel-rise, and by allowing the shank to smoothly decelerate into full knee extension without excessive impact. Non-fluid-based mechanisms have the potential to provide a durable and affordable solution as required in many parts of the world, but the design variables that lead to improved performance of non-fluid based swing-phase control technologies are not well established. Seven transfemoral amputees were fitted with a prosthetic knee joint and different non fluid-based swing-phase setups were systematically assessed. Clinical testing included walk tests utilizing a potentiometer (to measure knee flexion angles) and accelerometer (to measure terminal impact decelerations) mounted on the prosthetic limb. As hypothesized, the friction and spring systems improved gait function. This includes an increased walking speed that closely matched high-end hydraulic prosthetic knee joints, decreased and more normal maximum prosthetic knee flexion, decreased flexion duration, and lower terminal impact. Further improvements were obtained using a dual spring system, two springs in series, over the more conventional single spring system. Non-fluid-based swing-phase control mechanisms are simple and significantly improve the performance of prostheses. Their application is ideal where size, weight and cost may be constrained. PMID- 21592918 TI - Cluster synchronization in directed networks via intermittent pinning control. AB - In this paper, we investigate the cluster synchronization problem for linearly coupled networks, which can be recurrently connected neural networks, cellular neural networks, Hodgkin-Huxley models, Lorenz chaotic oscillators, etc., by adding some simple intermittent pinning controls. We assume the nodes in the network to be identical and the coupling matrix to be asymmetric. Some sufficient conditions to guarantee global cluster synchronization are presented. Furthermore, a centralized adaptive intermittent control is introduced and theoretical analysis is provided. Then, by applying the adaptive approach on the diagonal submatrices of the asymmetric coupling matrix, we also get the corresponding cluster synchronization result. Finally, numerical simulations are given to verify the theoretical results. PMID- 21592919 TI - Practical training framework for fitting a function and its derivatives. AB - This paper describes a practical framework for using multilayer feedforward neural networks to simultaneously fit both a function and its first derivatives. This framework involves two steps. The first step is to train the network to optimize a performance index, which includes both the error in fitting the function and the error in fitting the derivatives. The second step is to prune the network by removing neurons that cause overfitting and then to retrain it. This paper describes two novel types of overfitting that are only observed when simultaneously fitting both a function and its first derivatives. A new pruning algorithm is proposed to eliminate these types of overfitting. Experimental results show that the pruning algorithm successfully eliminates the overfitting and produces the smoothest responses and the best generalization among all the training algorithms that we have tested. PMID- 21592920 TI - Enhanced adaptive loop filter for motion compensated frame. AB - We propose an adaptive loop filter to remove the redundancy between current and motion compensated frames so that the residual signal is minimized, thus coding efficiency increases. The loop filter coefficients and offset are optimized for each frame or a set of blocks to minimize the total energy of the residual signal resulting from motion estimation and compensation. The optimized loop filter with offset is applied for the set of blocks where the filtering process gives coding gain based upon rate-distortion cost. The proposed loop filter is used for the motion compensated frame whereas the conventional adaptive interpolation filter (AIF) is applied to the reference frames to interpolate the subpixel values. Another conventional scheme adaptive loop filter (ALF), is used after deblocking filtering to enhance quality of reconstructed frames, not to minimize energy of residual signal. The proposed loop filter can be used in combination with the AIF and ALF. Experimental results show that proposed algorithm provides the averaged bit reduction of 8% compared to conventional H.264/AVC scheme. When the proposed scheme is combined with AIF and ALF, the coding gain increases even further. PMID- 21592921 TI - Binarization of low-quality barcode images captured by mobile phones using local window of adaptive location and size. AB - It is difficult to directly apply existing binarization approaches to the barcode images captured by mobile device due to their low quality. This paper proposes a novel scheme for the binarization of such images. The barcode and background regions are differentiated by the number of edge pixels in a search window. Unlike existing approaches that center the pixel to be binarized with a window of fixed size, we propose to shift the window center to the nearest edge pixel so that the balance of the number of object and background pixels can be achieved. The window size is adaptive either to the minimum distance to edges or minimum element width in the barcode. The threshold is calculated using the statistics in the window. Our proposed method has demonstrated its capability in handling the nonuniform illumination problem and the size variation of objects. Experimental results conducted on 350 images captured by five mobile phones achieve about 100% of recognition rate in good lighting conditions, and about 95% and 83% in bad lighting conditions. Comparisons made with nine existing binarization methods demonstrate the advancement of our proposed scheme. PMID- 21592922 TI - Characterization of the impaired glucose homeostasis produced in C57BL/6 mice by chronic exposure to arsenic and high-fat diet. AB - BACKGROUND: Type 2 diabetes is characterized by glucose intolerance and insulin resistance. Obesity is the leading cause of type 2 diabetes. Growing evidence suggests that chronic exposure to inorganic arsenic (iAs) also produces symptoms consistent with diabetes. Thus, iAs exposure may further increase the risk of diabetes in obese individuals. OBJECTIVES: Our goal was to characterize diabetogenic effects of iAs exposure and high-fat diet (HFD) in weaned C57BL/6 mice. METHODS: Mice were fed HFD or low-fat diet (LFD) while exposed to iAs in drinking water (25 or 50 ppm As) for 20 weeks; control HFD and LFD mice drank deionized water. Body mass and adiposity were monitored throughout the study. We measured glucose and insulin levels in fasting blood and in blood collected during oral glucose tolerance tests (OGTT) to evaluate the diabetogenic effects of the treatment. RESULTS: Control mice fed HFD accumulated more fat, had higher fasting blood glucose, and were more insulin resistant than were control LFD mice. However, these diabetes indicators decreased with iAs intake in a dose dependent manner. OGTT showed impaired glucose tolerance for both control and iAs treated HFD mice compared with respective LFD mice. Notably, glucose intolerance was more pronounced in HFD mice treated with iAs despite a significant decrease in adiposity, fasting blood glucose, and insulin resistance. CONCLUSIONS: Our data suggest that iAs exposure acts synergistically with HFD-induced obesity in producing glucose intolerance. However, mechanisms of the diabetogenic effects of iAs exposure may differ from the mechanisms associated with the obesity-induced type 2 diabetes. PMID- 21592924 TI - [What has AKD done during last month? The HEART Group and commemoration of Dr. Favaloro]. PMID- 21592923 TI - A statement on ethics from the HEART Group. PMID- 21592925 TI - The incognita of the known: the athlete's heart syndrome. AB - Long-term athletic activity causes morphological and functional changes in the heart characterized as left ventricle cavity dimension changes, wall thickness and mass increase and rhythm conduction changes. This condition is identified as "athlete's heart syndrome". The changes that are seen clinically occur as a result of physiological adaptation to exercise. Cardiovascular adaptation depends on the exercise's type as well as its frequency, duration and intensity. In the athlete's physical examination, various changes can be seen that are mistaken with pathological conditions. In addition, there are changes present due to cardiac hypertrophy, increased vagal tone and repolarization. The knowledge and recognition of the organic and functional changes developing in the athlete's heart is being helpful to differentiate physiological changes from cardiac pathologies that can cause sudden death in athletes. PMID- 21592926 TI - Naxos-Carvajal disease: a rare cause of cardiomyopathy with woolly hair and palmoplantar hyperkeratosis. PMID- 21592927 TI - Atrial angiosarcoma imaged by F-18 FDG PET/CT. PMID- 21592928 TI - Incidental multislice computed tomography finding of a congenital submitral ventricular aneurysm. PMID- 21592929 TI - A rare angiographic finding: aortic pseudo-coarctation. PMID- 21592930 TI - Aortic valve aneurysm: a result or reason? PMID- 21592931 TI - Pericarditis as an initial symptom in Takayasu arteritis. PMID- 21592932 TI - [Angiotensin receptor blockers and risk of cancer]. PMID- 21592933 TI - Autonomic nervous system in heart failure: an endless area of research/ The preserved autonomic functions may provide the asymptomatic clinical status in heart failure despite advanced left ventricular systolic dysfunction. PMID- 21592934 TI - Acute renal failure due to fenofibrate monotherapy. PMID- 21592935 TI - Kawasaki disease presenting as meningitis in a two months old infant. PMID- 21592936 TI - Off-pump coronary bypass in a child with familial hypercholesterolemia: premature atherosclerosis of the ascending aorta. PMID- 21592937 TI - Endovascular stents for treatment of coarctation of the aorta. PMID- 21592938 TI - Positive associations primacy in the IAT: a many-facet rasch measurement analysis. AB - Two studies investigated the different contribution of positive and negative associations to the size of the Implicit Association Test (IAT) effect. A Many Facet Rasch Measurement analysis was applied for the purpose. Across different IATs (Race and Weight) and different groups of respondents (White, Normal weight, and Obese people) we observed that positive words increase the IAT effect whereas negative words tend to decrease it. Results suggest that the IAT is influenced by a positive associations primacy effect. As a consequence, we argue that researchers should be careful when interpreting IAT effects as a measure of implicit prejudice. PMID- 21592939 TI - Does evaluative learning rely on the perception of contingency?: manipulating contingency and US density during evaluative conditioning. AB - An experiment is reported studying the impact of objective contingency and contingency judgments on cross-modal evaluative conditioning (EC). Both contingency judgments and evaluative responses were measured after a contingency learning task in which previously neutral sounds served as either weak or strong predictors of affective pictures. Experimental manipulations of contingency and US density were shown to affect contingency judgments. Stronger contingencies were perceived with high contingency and with low US density. The contingency learning task also produced a reliable EC effect. The magnitude of this effect was influenced by an interaction of statistical contingency and US density. Furthermore, the magnitude of EC was correlated with the subjective contingency judgments. Taken together, the results imply that propositional knowledge about the CS-US relationship, as reflected in contingency judgments, moderates evaluative learning. The data are discussed with respect to different accounts of EC. PMID- 21592940 TI - The intention interference effect. AB - Intentions have been shown to be more accessible (e.g., more quickly and accurately recalled) compared to other sorts of to-be-remembered information; a result termed an intention superiority effect (Goschke & Kuhl, 1993). In the current study, we demonstrate an intention interference effect (IIE) in which color-naming performance in a Stroop task was slower for words belonging to an intention that participants had to remember to carry out (Do-the-Task condition) versus an intention that did not have to be executed (Ignore-the-Task condition). In previous work (e.g., Cohen et al., 2005), having a prospective intention in mind was confounded with carrying a memory load. In Experiment 1, we added a digit-retention task to control for effects of cognitive load. In Experiment 2, we eliminated the memory confound in a new way, by comparing intention-related and control words within each trial. Results from both Experiments 1 and 2 revealed an IIE suggesting that interference is very specific to the intention, not just to a memory load. PMID- 21592941 TI - Exaggeration is harder than understatement, but practice makes perfect! AB - Previous research on the fakeability of the Implicit Association Test (IAT) yielded inconsistent results. The present study simultaneously analyses several relevant factors: faking direction, type of instructions, and practice. Furthermore, it takes baseline individual differences into account. After a baseline assessment in a self-esteem IAT without faking instructions (t0), participants in the faking conditions then (t1) faked high or low scores without being provided with recommended strategies on how to do so (i.e., individual strategies). At t2 and t3, they were asked to fake the IAT after having received information on recommended faking strategies. At t4, faking direction was reversed. Without the recommended strategies, faking high scores was not possible, but faking low scores was. With the recommended strategies, participants needed additional practice to fake high scores. When faking directions were reversed, participants were successful without additional practice, suggesting a transfer in faking skills. In most of the faking attempts, faking success was moderated by individual differences in baseline implicit self esteem. This suggests that the complex interplay of factors influencing faking success should be taken into account when considering the issue of fakeability of the IAT. PMID- 21592942 TI - Task-related versus stimulus-specific practice. AB - When people repeatedly practice the same cognitive task, their response times (RT) invariably decrease. Dutilh, Vandekerckhove, Tuerlinckx, and Wagenmakers (2009) argued that the traditional focus on how mean RT decreases with practice offers limited insight; their diffusion model analysis showed that the effect of practice is multifaceted, involving an increase in rate of information processing, a decrease in response caution, adjusted response bias, and, unexpectedly, a strong decrease in nondecision time. In this study, we aim to further disentangle these effects into stimulus-specific and task-related components. The data of a transfer experiment, in which repeatedly presented sets and new sets of stimuli were alternated, show that the practice effects on both speed of information processing and time needed for peripheral processing are partly task-related and partly stimulus-specific. The effects on response caution and response bias appear to be task-related. This diffusion model decomposition provides a perspective on practice that is more detailed and more informative than the traditional analysis of mean RT. PMID- 21592943 TI - Between-task transfer of learning from spatial compatibility to a color stroop task. AB - Responses to a relevant stimulus dimension are faster and more accurate when the stimulus and response spatially correspond compared to when they do not, even though stimulus position is irrelevant (Simon effect). It has been demonstrated that practicing with an incompatible spatial stimulus-response (S-R) mapping before performing a Simon task can eliminate this effect. In the present study we assessed whether a learned spatially incompatible S-R mapping can be transferred to a nonspatial conflict task, hence supporting the view that transfer effects are due to acquisition of a general "respond to the opposite stimulus value" rule. To this aim, we ran two experiments in which participants performed a spatial compatibility task with either a compatible or an incompatible mapping and then transferred, after a 5 min delay, to a color Stroop task. In Experiment 1, responses were executed by pressing one of two keys on the keyboard in both practice and transfer tasks. In Experiment 2, responses were manual in the practice task and vocal in the transfer task. The spatially incompatible practice significantly reduced the color Stroop effect only when responses were manual in both tasks. These results suggest that during practice participants develop a response-selection strategy of emitting the alternative spatial response. PMID- 21592944 TI - A "unity assumption" does not promote intersensory integration. AB - An account of intersensory integration is premised on knowing that different sensory inputs arise from the same object. Could, however, the combination of the inputs be impaired although the "unity assumption" holds? Forty observers viewed a square through a minifying (50%) lens while they simultaneously touched the square. Half could see and half could not see their haptic explorations of the square. Both groups, however, had reason to believe that they were touching and viewing the same square. Subsequent matches of the inspected square were mutually biased by touch and vision when the exploratory movements were visible. However, the matches were biased in the direction of the square's haptic size when observers could not see their exploratory movements. This impaired integration without the visible haptic explorations suggests that the unity assumption alone is not enough to promote intersensory integration. PMID- 21592945 TI - Emotion-induced impairments in speeded word recognition tasks. AB - Recent studies show that emotional stimuli impair the identification of subsequently presented, briefly flashed stimuli. In the present study, we investigated whether emotional distractors (primes) impaired target processing when presentation of the target stimulus was not impoverished. In lexical decision, animacy decision, rhyme decision, and nonword naming, targets were presented in such a manner that they were clearly visible (i.e., targets were not masked and presented until participants responded). In all tasks taboo-sexual distractors caused a slowdown in responding to the subsequent neutral target. Our results indicate that the detrimental effects of emotional distractors are not confined to paradigms in which visibility of the target is limited. Moreover, impairments were obtained even when semantic processing of stimuli was not required. PMID- 21592946 TI - A robust classic. AB - In the present research, we argue for the robustness of illusory correlations (ICs, Hamilton & Gifford, 1976) regarding two boundary conditions suggested in previous research. First, we argue that ICs are maintained under extended experience. Using simulations, we derive conflicting predictions. Whereas noise based accounts predict ICs to be maintained (Fielder, 2000; Smith, 1991), a prominent account based on discrepancy-reducing feedback learning predicts ICs to disappear (Van Rooy et al., 2003). An experiment involving 320 observations with majority and minority members supports the claim that ICs are maintained. Second, we show that actively using the stereotype to make predictions that are met with reward and punishment does not eliminate the bias. In addition, participants' operant reactions afford a novel online measure of ICs. In sum, our findings highlight the robustness of ICs that can be explained as a result of unbiased but noisy learning. PMID- 21592947 TI - The sound of enemies and friends in the neighborhood. AB - Previous studies (e.g., Pecher, Zeelenberg, & Wagenmakers, 2005) found that semantic classification performance is better for target words with orthographic neighbors that are mostly from the same semantic class (e.g., living) compared to target words with orthographic neighbors that are mostly from the opposite semantic class (e.g., nonliving). In the present study we investigated the contribution of phonology to orthographic neighborhood effects by comparing effects of phonologically congruent orthographic neighbors (book-hook) to phonologically incongruent orthographic neighbors (sand-wand). The prior presentation of a semantically congruent word produced larger effects on subsequent animacy decisions when the previously presented word was a phonologically congruent neighbor than when it was a phonologically incongruent neighbor. In a second experiment, performance differences between target words with versus without semantically congruent orthographic neighbors were larger if the orthographic neighbors were also phonologically congruent. These results support models of visual word recognition that assume an important role for phonology in cascaded access to meaning. PMID- 21592948 TI - Mental representations in fraction comparison. AB - In this study, we investigated the mental representations used in a fraction comparison task. Adults were asked to quickly and accurately pick the larger of two fractions presented on a computer screen and provide trial-by-trial reports of the types of strategies they used. We found that adults used a variety of strategies to compare fractions, ranging among just knowing the answer, using holistic knowledge of fractions to determine the answer, and using component based procedures such as cross multiplication. Across all strategy types, regression analyses identified that reaction times were significantly predicted by numerical distance between fractions, indicating that the participants used a magnitude-based representation to compare the fraction magnitudes. In addition, a variant of the problem-size effect (e.g., Ashcraft, 1992) appeared, whereby reaction times were significantly predicted by the average cross product of the two fractions. This effect was primarily found for component-based strategies, indicating a role for strategy choice in the formation of mental representations of fractions. PMID- 21592949 TI - [Prevention of perinatal depression and anxiety with periconceptional care]. AB - In the public mind, pregnancy, childbirth and newborn care is one of the most wonderful living experiences. However, epidemiological studies have shown that the risks of psychiatric disorders in the perinatal period are multiplying. Pregnancy entails with dramatic physical, mental and social role changing. The birth is a big, irreversible life event, and it should also be nominated as "rite of passage". This process represents a normative crisis during life, which needs new coping mechanisms to be developed. The stress and anxiety during the development of the fetus causes negative consequences in the short and long-term and it causes dangerous complications for the mother, too. During postpartum period, the incidence of major depression is approximately 15-20% that most frequently occurs within 6 months after birth but until the child is 2 years old it can develop any time. Serious risks of the postpartum depression are suicide and infanticide. In addition, it also represents serious teratogenic effects of cognitive and psychomotor development of children. It makes harder to recognize that the symptoms are largely the same as in any other stage of depression occurring during lifetime, but some of the symptoms compliant of normal pregnancy and the postpartum period. In addition, the majorities of women recognize heavily the problem and visit a doctor, because based of social expectations they should feel happiness. After the disclosure of risk factors and securing preventive conditions, preparing to be a mother is effective in prevention of development of perinatal depression. The effective therapy is primarily based on the coaching approach, and requires multi-directional approach. PMID- 21592950 TI - [Role of ultrasonography in the urgent differential diagnosis of acute scrotum]. AB - Acute scrotum, when testicular torsion is suspected, needs emergency exploration. However, acute scrotum caused by torsion of the Morgagni hydatid and epididymitis can be managed conservatively. Real time colour Doppler ultrasound is becoming a more and more popular tool in the differential diagnosis, however, its reliability is still not widely accepted and exploration is preferred. MATERIAL AND METHODS: Case notes of 124 patients treated with acute scrotum during the last 10 years have been reviewed, and the result of physical examination, color Doppler ultrasound, operative notes and clinical outcome were analysed. RESULTS: The final diagnosis was torsion of Morgagni hydatid in 100 cases, furthermore 11 testicular torsion, 8 epididymitis and 10 idiopathic cases were identified. Preoperative colour Doppler ultrasound was done in 45 cases, and exploration was performed in 111 cases. In 38 cases the colour Doppler ultrasound excluded and in 7 cases verified the possibility of testicular torsion. Two false positive and 0 false negative cases were identified. The specificity was 95.0%, sensitivity 100.0%, negative predictive value 100.0%, and positive predictive value 71.4%. DISCUSSION: Colour Doppler ultrasound seems to be a reliable tool in the differential diagnosis of acute scrotum. Its routine use could reduce the number of emergency explorations. PMID- 21592951 TI - [Clinical-genetic care of BRCA-mutation carrier women: prevention, diagnosis and therapy]. AB - Predictive genetics opens a considerable perspective in the diagnostics as well as the treatment of breast and ovarian cancer. Current recommendations and guidelines for the management of BRCA 1 and BRCA 2 mutation carriers are not based on controlled randomized trials, but on expert opinions. The existing options of prevention, early diagnosis and treatment must be clearly interpreted to the patient. In the context of a dedicated genetic counseling the participation of all involved professionals (geneticist, oncologist, surgeon, gynecologist) is required. The decision-making process concerning the possibilities of prevention, diagnosis and treatment is always deeply influenced by the patient's own experience with the cancer occurred in the family, as well as by her values and expectations of life. The focused multidisciplinary approach, with the application of results from prospective studies in cohorts of BRCA mutation carriers allow the concerned individuals to benefit from this kind of approach of medical treatment. PMID- 21592952 TI - [Effectiveness of biological treatments based on ACR70 response in rheumatoid arthritis: indirect comparison and meta-regression using Bayes-model]. AB - The therapy of rheumatoid arthritis has been changed by biological treatments. Their efficacy was evaluated in several randomized controlled trials. These trials were different in patient characteristics and the administration regimen. Placebo was the control and direct comparison of biological treatments is missing. OBJECTIVES: In the present study the efficacy of biological treatments in patients with rheumatoid arthritis was compared based on the randomized controlled trials available in the literature. A meta-analysis was conducted and meta-regression was used to explore the relationship between disease characteristic variables and observed efficacy. RESULTS: The related scientific literature is broad. Thirty two trials involving 18,500 patients were included into the current meta-analysis. The relative odds ratios of biological treatments compared to placebo varied between 3.6 and 20.0, and between 6.4 and 35.5 in case of monotherapy and combination with non-biological therapy, respectively. Disease duration and added non-biological therapy were in positive relationship with relative efficacy. More severe disease resulted smaller relative effect. CONCLUSIONS: The results show that the efficacy of biological treatments is similar. The relative efficacy worsens with more severe disease and improves with disease duration. PMID- 21592953 TI - [Spontaneous aortic rupture during pregnancy]. AB - Aortic dissection is a rare entity. Half of the aortic dissection cases occur during pregnancy in women under the age of 40. The authors report a case of a multiparous woman at the third trimester of her sixth pregnancy, who died from a sudden and intractable cardiovascular shock. Autopsy revealed the dissection of the ascending aorta. The case is interesting, especially because in the pregnant woman's family it was not the first sudden death during pregnancy. Authors review the relevant literature regarding the symptoms and the genetic basis of this rare but potentially lethal complication of pregnancy. PMID- 21592955 TI - Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus. AB - Kruppel-like transcription factors (KLFs) have elicited significant attention because of their regulation of essential biochemical pathways and, more recently, because of their fundamental role in the mechanisms of human diseases. Neonatal diabetes mellitus is a monogenic disorder with primary alterations in insulin secretion. We here describe a key biochemical mechanism that underlies neonatal diabetes mellitus insulin biosynthesis impairment, namely a homozygous mutation within the insulin gene (INS) promoter, c.-331C>G, which affects a novel KLF binding site. The combination of careful expression profiling, electromobility shift assays, reporter experiments, and chromatin immunoprecipitation demonstrates that, among 16 different KLF proteins tested, KLF11 is the most reliable activator of this site. Congruently, the c.-331C>G INS mutation fails to bind KLF11, thus inhibiting activation by this transcription factor. Klf11(-/-) mice recapitulate the disruption in insulin production and blood levels observed in patients. Thus, these data demonstrate an important role for KLF11 in the regulation of INS transcription via the novel c.-331 KLF site. Lastly, our screening data raised the possibility that other members of the KLF family may also regulate this promoter under distinct, yet unidentified, cellular contexts. Collectively, this study underscores a key role for KLF proteins in biochemical mechanisms of human diseases, in particular, early infancy onset diabetes mellitus. PMID- 21592956 TI - mTORC2 protein complex-mediated Akt (Protein Kinase B) Serine 473 Phosphorylation is not required for Akt1 activity in human platelets [corrected]. AB - Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. Both PP242 and Torin1 blocked thrombin and insulin-like growth factor 1 mediated Akt Ser(473) phosphorylation with an IC(50) between 1 and 5 nm, whereas the mTORC1 inhibitor rapamycin had no effect. Interestingly, PP242 and Torin1 had no effect on Akt Thr(308) phosphorylation, Akt1 activity, and phosphorylation of the Akt substrate glycogen synthase kinase 3beta, indicating that Ser(473) phosphorylation is not necessary for Thr(308) phosphorylation and maximal Akt1 activity. In contrast, Akt2 activity was significantly reduced, concurrent with inhibition of PRAS40 phosphorylation, in the presence of PP242 and Torin1. Other signaling pathways, including phospholipase C/PKC and the MAPK pathway, were unaffected by PP242 and Torin1. Together, these results demonstrate that mTORC2 is the kinase that phosphorylates Akt Ser(473) in human platelets but that this phosphorylation is dispensable for Thr(308) phosphorylation and Akt1 activity. PMID- 21592957 TI - Inactivation of tesA reduces cell wall lipid production and increases drug susceptibility in mycobacteria. AB - Phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs) are structurally related lipids noncovalently bound to the outer cell wall layer of Mycobacterium tuberculosis, Mycobacterium leprae, and several opportunistic mycobacterial human pathogens. PDIMs and PGLs are important effectors of virulence. Elucidation of the biosynthesis of these complex lipids will not only expand our understanding of mycobacterial cell wall biosynthesis, but it may also illuminate potential routes to novel therapeutics against mycobacterial infections. We report the construction of an in-frame deletion mutant of tesA (encoding a type II thioesterase) in the opportunistic human pathogen Mycobacterium marinum and the characterization of this mutant and its corresponding complemented strain control in terms of PDIM and PGL production. The growth and antibiotic susceptibility of these strains were also probed and compared with the parental wild-type strain. We show that deletion of tesA leads to a mutant that produces only traces of PDIMs and PGLs, has a slight growth yield increase and displays a substantial hypersusceptibility to several antibiotics. We also provide a robust model for the three-dimensional structure of M. marinum TesA (TesAmm) and demonstrate that a Ser-to-Ala substitution in the predicted catalytic Ser of TesAmm renders a mutant that recapitulates the phenotype of the tesA deletion mutant. Overall, our studies demonstrate a critical role for tesA in mycobacterial biology, advance our understanding of the biosynthesis of an important group of polyketide synthase-derived mycobacterial lipids, and suggest that drugs aimed at blocking PDIM and/or PGL production might synergize with antibiotic therapy in the control of mycobacterial infections. PMID- 21592958 TI - Moving Iron through ferritin protein nanocages depends on residues throughout each four alpha-helix bundle subunit. AB - Eukaryotic H ferritins move iron through protein cages to form biologically required, iron mineral concentrates. The biominerals are synthesized during protein-based Fe2+/O2 oxidoreduction and formation of [Fe3+O](n) multimers within the protein cage, en route to the cavity, at sites distributed over ~50 A. Recent NMR and Co2+-protein x-ray diffraction (XRD) studies identified the entire iron path and new metal-protein interactions: (i) lines of metal ions in 8 Fe2+ ion entry channels with three-way metal distribution points at channel exits and (ii) interior Fe3+O nucleation channels. To obtain functional information on the newly identified metal-protein interactions, we analyzed effects of amino acid substitution on formation of the earliest catalytic intermediate (diferric peroxo A(650 nm)) and on mineral growth (Fe3+O-A(350 nm)), in A26S, V42G, D127A, E130A, and T149C. The results show that all of the residues influenced catalysis significantly (p < 0.01), with effects on four functions: (i) Fe2+ access/selectivity to the active sites (Glu130), (ii) distribution of Fe2+ to each of the three active sites near each ion channel (Asp127), (iii) product (diferric oxo) release into the Fe3+O nucleation channels (Ala26), and (iv) [Fe3+O](n) transit through subunits (Val42, Thr149). Synthesis of ferritin biominerals depends on residues along the entire length of H subunits from Fe2+ substrate entry at 3-fold cage axes at one subunit end through active sites and nucleation channels, at the other subunit end, inside the cage at 4-fold cage axes. Ferritin subunit-subunit geometry contributes to mineral order and explains the physiological impact of ferritin H and L subunits. PMID- 21592959 TI - Usp18 regulates epidermal growth factor (EGF) receptor expression and cancer cell survival via microRNA-7. AB - Epidermal growth factor receptor (EGFR) is involved in development and progression of many human cancers. We have previously demonstrated that the ubiquitin-specific peptidase Usp18 (Ubp43) is a potent regulator of EGFR protein expression. Here we report that the 3'-untranslated region (3'-UTR) of the EGFR message modulates RNA translation following cell treatment with Usp18 siRNA, suggesting microRNA as a possible mediator. Given earlier evidence of EGFR regulation by the microRNA miR-7, we assessed whether miR-7 mediates Usp18 siRNA effects. We found that Usp18 depletion elevates miR-7 levels in several cancer cell lines because of a transcriptional activation and/or mRNA stabilization of miR-7 host genes and that miR-7 acts downstream of Usp18 to regulate EGFR mRNA translation via the 3'-UTR. Also, depletion of Usp18 led to a decrease in protein levels of other known oncogenic targets of miR-7, reduced cell proliferation and soft agar colony formation, and increased apoptosis. Notably, all of these phenotypes were reversed by a specific inhibitor of miR-7. Thus, our findings support a model in which Usp18 inhibition promotes up-regulation of miR-7, which in turn inhibits EGFR expression and the tumorigenic activity of cancer cells. PMID- 21592960 TI - Antibody recognition of a human chorionic gonadotropin epitope (hCGbeta66-80) depends on local structure retained in the free peptide. AB - Human chorionic gonadotropin (hCG) is an important biomarker in pregnancy and oncology, where it is routinely detected and quantified by specific immunoassays. Intelligent epitope selection is essential to achieving the required assay performance. We present binding affinity measurements demonstrating that a typical beta3-loop-specific monoclonal antibody (8G5) is highly selective in competitive immunoassays and distinguishes between hCGbeta(66-80) and the closely related luteinizing hormone (LH) fragment LHbeta(86-100), which differ only by a single amino acid residue. A combination of optical spectroscopic measurements and atomistic computer simulations on these free peptides reveals differences in turn type stabilized by specific hydrogen bonding motifs. We propose that these structural differences are the basis for the observed selectivity in the full protein. PMID- 21592961 TI - Gr-1+ CD11b+ myeloid-derived suppressor cells suppress inflammation and promote insulin sensitivity in obesity. AB - Activation of immune cells, including macrophages and CD8(+) T cells, contributes significantly to the advancement of obesity and its associated medical complications, such as atherosclerosis, insulin resistance, and type 2 diabetes. However, how the activation of these immune cells is regulated in vivo remains largely unexplored. Here we show that a group of immature myeloid cells with cell surface markers of Gr-1(+) CD11b(+) are highly enriched in peripheral tissues (i.e. liver and adipose tissues) during obesity. Down-regulation of these cells in obese animals significantly increases inflammation and impairs insulin sensitivity and glucose tolerance, whereas elevation of these cells via adoptive transfer has the opposite effects. Mechanistically, we show that under obese conditions, the Gr-1(+) cells suppress proliferation and induce apoptosis of CD8(+) T cells and are capable of skewing differentiation of macrophages into insulin-sensitizing, alternatively activated M2 macrophages. Taken together, our study demonstrates that immature myeloid cells provide a checks-and-balances platform to counter proinflammatory immune cells in the liver and adipose tissue during obesity to prevent overt immune responses. PMID- 21592962 TI - Comparison of a preQ1 riboswitch aptamer in metabolite-bound and free states with implications for gene regulation. AB - Riboswitches are RNA regulatory elements that govern gene expression by recognition of small molecule ligands via a high affinity aptamer domain. Molecular recognition can lead to active or attenuated gene expression states by controlling accessibility to mRNA signals necessary for transcription or translation. Key areas of inquiry focus on how an aptamer attains specificity for its effector, the extent to which the aptamer folds prior to encountering its ligand, and how ligand binding alters expression signal accessibility. Here we present crystal structures of the preQ(1) riboswitch from Thermoanaerobacter tengcongensis in the preQ(1)-bound and free states. Although the mode of preQ(1) recognition is similar to that observed for preQ(0), surface plasmon resonance revealed an apparent K(D) of 2.1 +/- 0.3 nm for preQ(1) but a value of 35.1 +/- 6.1 nm for preQ(0). This difference can be accounted for by interactions between the preQ(1) methylamine and base G5 of the aptamer. To explore conformational states in the absence of metabolite, the free-state aptamer structure was determined. A14 from the ceiling of the ligand pocket shifts into the preQ(1) binding site, resulting in "closed" access to the metabolite while simultaneously increasing exposure of the ribosome-binding site. Solution scattering data suggest that the free-state aptamer is compact, but the "closed" free-state crystal structure is inadequate to describe the solution scattering data. These observations are distinct from transcriptional preQ(1) riboswitches of the same class that exhibit strictly ligand-dependent folding. Implications for gene regulation are discussed. PMID- 21592963 TI - Effects of inflammatory factors on mesenchymal stem cells and their role in the promotion of tumor angiogenesis in colon cancer. AB - Mesenchymal stem cells (MSCs), which are modulated by cytokines present in the tumor microenvironment, play an important role in tumor progression. It is well documented that inflammation is an important part of the tumor microenvironment, so we investigated whether stimulation of MSCs by inflammatory cytokines would contribute to their ability to promote tumor growth. We first showed that MSCs could increase C26 colon cancer growth in mice. This growth-promoting effect was further accelerated when the MSCs were pre-stimulated by inflammatory factors IFN gamma and TNF-alpha. At the same time, we demonstrated that MSCs pre-stimulated by both inflammatory factors could promote tumor angiogenesis in vivo to a greater degree than untreated MSCs or MSCs pre-stimulated by either IFN-gamma or TNF-alpha alone. A hen egg test-chorioallantoic membrane (HET-CAM) assay showed that treatment of MSC-conditioned medium can promote chorioallantoic membrane angiogenesis in vitro, especially treatment with conditioned medium of MSCs pretreated with IFN-gamma and TNF-alpha together. This mechanism of promoting angiogenesis appears to take place via an increase in the expression of vascular endothelial growth factor (VEGF), which itself takes place through an increase in signaling in the hypoxia-inducible factor 1alpha (HIF-1alpha)-dependent pathway. Inhibition of HIF-1alpha in MSCs by siRNA was found to effectively reduce the ability of MSC to affect the growth of colon cancer in vivo in the inflammatory microenviroment. These results indicate that MSCs stimulated by inflammatory cytokines such as IFN-gamma and TNF-alpha in the tumor microenvironment express higher levels of VEGF via the HIF-1alpha signaling pathway and that these MSCs then enhance tumor angiogenesis, finally leading to colon cancer growth in mice. PMID- 21592964 TI - Cap2-HAP complex is a critical transcriptional regulator that has dual but contrasting roles in regulation of iron homeostasis in Candida albicans. AB - Iron homeostasis is highly regulated in organisms across evolutionary time scale as iron is essential for various cellular processes. In a computational screen, we identified the Yap/bZIP domain family in Candida clade genomes. Cap2/Hap43 is essential for C. albicans growth under iron-deprivation conditions and for virulence in mouse. Cap2 has an amino-terminal bipartite domain comprising a fungal-specific Hap4-like domain and a bZIP domain. Our mutational analyses showed that both the bZIP and Hap4-like domains perform critical and independent functions for growth under iron-deprivation conditions. Transcriptome analysis conducted under iron-deprivation conditions identified about 16% of the C. albicans ORFs that were differentially regulated in a Cap2-dependent manner. Microarray data also suggested that Cap2 is required to mobilize iron through multiple mechanisms; chiefly by activation of genes in three iron uptake pathways and repression of iron utilizing and iron storage genes. The expression of HAP2, HAP32, and HAP5, core components of the HAP regulatory complex was induced in a Cap2-dependent manner indicating a feed-forward loop. In a feed-back loop, Cap2 repressed the expression of Sfu1, a negative regulator of iron uptake genes. Cap2 was coimmunoprecipitated with Hap5 from cell extracts prepared from iron deprivation conditions indicating an in vivo association. ChIP assays demonstrated Hap32-dependent recruitment of Hap5 to the promoters of FRP1 (Cap2 induced) and ACO1 (Cap2-repressed). Together our data indicates that the Cap2-HAP complex functions both as a positive and a negative regulator to maintain iron homeostasis in C. albicans. PMID- 21592965 TI - Structural and biochemical studies on the regulation of biotin carboxylase by substrate inhibition and dimerization. AB - Biotin carboxylase (BC) activity is shared among biotin-dependent carboxylases and catalyzes the Mg-ATP-dependent carboxylation of biotin using bicarbonate as the CO(2) donor. BC has been studied extensively over the years by structural, kinetic, and mutagenesis analyses. Here we report three new crystal structures of Escherichia coli BC at up to 1.9 A resolution, complexed with different ligands. Two structures are wild-type BC in complex with two ADP molecules and two Ca(2+) ions or two ADP molecules and one Mg(2+) ion. One ADP molecule is in the position normally taken by the ATP substrate, whereas the other ADP molecule occupies the binding sites of bicarbonate and biotin. One Ca(2+) ion and the Mg(2+) ion are associated with the ADP molecule in the active site, and the other Ca(2+) ion is coordinated by Glu-87, Glu-288, and Asn-290. Our kinetic studies confirm that ATP shows substrate inhibition and that this inhibition is competitive against bicarbonate. The third structure is on the R16E mutant in complex with bicarbonate and Mg-ADP. Arg-16 is located near the dimer interface. The R16E mutant has only a 2-fold loss in catalytic activity compared with the wild-type enzyme. Analytical ultracentrifugation experiments showed that the mutation significantly destabilized the dimer, although the presence of substrates can induce dimer formation. The binding modes of bicarbonate and Mg-ADP are essentially the same as those to the wild-type enzyme. However, the mutation greatly disrupted the dimer interface and caused a large re-organization of the dimer. The structures of these new complexes have implications for the catalysis by BC. PMID- 21592966 TI - Insights into structure and function of the active site of SoxAX cytochromes. AB - SoxAX cytochromes catalyze the formation of heterodisulfide bonds between inorganic sulfur compounds and a carrier protein, SoxYZ. They contain unusual His/Cys-ligated heme groups with complex spectroscopic signatures. The heme ligating cysteine has been implicated in SoxAX catalysis, but neither the SoxAX spectroscopic properties nor its catalysis are fully understood at present. We have solved the first crystal structure for a group 2 SoxAX protein (SnSoxAX), where an N-terminal extension of SoxX forms a novel structure that supports dimer formation. Crystal structures of SoxAX with a heme ligand substitution (C236M) uncovered an inherent flexibility of this SoxA heme site, with both bonding distances and relative ligand orientation differing between asymmetric units and the new residue, Met(236), representing an unusual rotamer of methionine. The flexibility of the SnSoxAX(C236M) SoxA heme environment is probably the cause of the four distinct, new EPR signals, including a high spin ferric heme form, that were observed for the enzyme. Despite the removal of the catalytically active cysteine heme ligand and drastic changes in the redox potential of the SoxA heme (WT, -479 mV; C236M, +85 mV), the substituted enzyme was catalytically active in glutathione-based assays although with reduced turnover numbers (WT, 3.7 s(-1); C236M, 2.0 s(-1)). SnSoxAX(C236M) was also active in assays using SoxYZ and thiosulfate as the sulfur substrate, suggesting that Cys(236) aids catalysis but is not crucial for it. The SoxYZ-based SoxAX assay is the first assay for an isolated component of the Sox multienzyme system. PMID- 21592967 TI - A genetically tagged Psb27 protein allows purification of two consecutive photosystem II (PSII) assembly intermediates in Synechocystis 6803, a cyanobacterium. AB - Photosystem II (PSII) is a large membrane bound molecular machine that catalyzes light-driven oxygen evolution from water. PSII constantly undergoes assembly and disassembly because of the unavoidable damage that results from its normal photochemistry. Thus, under physiological conditions, in addition to the active PSII complexes, there are always PSII subpopulations incompetent of oxygen evolution, but are in the process of undergoing elaborate biogenesis and repair. These transient complexes are difficult to characterize because of their low abundance, structural heterogeneity, and thermodynamic instability. In this study, we show that a genetically tagged Psb27 protein allows for the biochemical purification of two monomeric PSII assembly intermediates, one with an unprocessed form of D1 (His27DeltactpAPSII) and a second one with a mature form of D1 (His27PSII). Both forms were capable of light-induced charge separation, but unable to photooxidize water, largely because of the absence of a functional tetramanganese cluster. Unexpectedly, there was a significant amount of the extrinsic lumenal PsbO protein in the His27PSII, but not in the His27DeltactpAPSII complex. In contrast, two other lumenal proteins, PsbU and PsbV, were absent in both of these PSII intermediate complexes. Additionally, the only cytoplasmic extrinsic protein, Psb28 was detected in His27PSII complex. Based on these data, we have presented a refined model of PSII biogenesis, illustrating an important role of Psb27 as a gate-keeper during the complex assembly process of the oxygen-evolving centers in PSII. PMID- 21592968 TI - Integrin betanu-mediated phagocytosis of apoptotic cells in Drosophila embryos. AB - To identify molecules that play roles in the clearance of apoptotic cells by Drosophila phagocytes, we examined a series of monoclonal antibodies raised against larval hemocytes for effects on phagocytosis in vitro. One antibody that inhibited phagocytosis recognized terribly reduced optic lobes (Trol), a core protein of the perlecan-type proteoglycan, and the level of phagocytosis in embryos of a Trol-lacking fly line was lower than in a control line. The treatment of a hemocyte cell line with a recombinant Trol protein containing the amino acid sequence RGD augmented the phosphorylation of focal adhesion kinase, a hallmark of integrin activation. A loss of integrin betanu, one of the two beta subunits of Drosophila integrin, brought about a reduction in the level of apoptotic cell clearance in embryos. The presence of integrin betanu at the surface of embryonic hemocytes was confirmed, and forced expression of integrin betanu in hemocytes of an integrin betanu-lacking fly line recovered the defective phenotype of phagocytosis. Finally, the level of phagocytosis in a fly line that lacks both integrin betanu and Draper, another receptor required for the phagocytosis of apoptotic cells, was lower than that in a fly line lacking either protein. We suggest that integrin betanu serves as a phagocytosis receptor responsible for the clearance of apoptotic cells in Drosophila, independent of Draper. PMID- 21592969 TI - Nuclear factor-kappaB (NF-kappaB) p65 interacts with Stat5b in growth plate chondrocytes and mediates the effects of growth hormone on chondrogenesis and on the expression of insulin-like growth factor-1 and bone morphogenetic protein-2. AB - Growth hormone (GH) stimulates growth plate chondrogenesis and longitudinal bone growth with its stimulatory effects primarily mediated by insulin-like growth factor-1 (IGF-1) both systemically and locally in the growth plate. It has been shown that the transcription factor Stat5b mediates the GH promoting effect on IGF-1 expression and on chondrogenesis, yet it is not known whether other signaling molecules are activated by GH in growth plate chondrocytes. We have previously demonstrated that nuclear factor-kappaB p65 is a transcription factor expressed in growth plate chondrocytes where it facilitates chondrogenesis. We have also shown that fibroblasts isolated from a patient with growth failure and a heterozygous mutation of inhibitor-kappaBalpha (IkappaB; component of the nuclear factor-kappaB (NF-kappaB) signaling pathway) exhibit GH insensitivity. In this study, we cultured rat metatarsal bones in the presence of GH and/or pyrrolidine dithiocarbamate (PDTC), a known NF-kappaB inhibitor. The GH-mediated stimulation of metatarsal longitudinal growth and growth plate chondrogenesis was neutralized by PDTC. In cultured chondrocytes isolated from rat metatarsal growth plates, GH induced NF-kappaB-DNA binding and chondrocyte proliferation and differentiation and prevented chondrocyte apoptosis. The inhibition of NF-kappaB p65 expression and activity (by NF-kappaB p65 siRNA and PDTC, respectively) in chondrocytes reversed the GH-mediated effects on chondrocyte proliferation, differentiation, and apoptosis. Lastly, the inhibition of Stat5b expression in chondrocytes prevented the GH promoting effects on NF-kappaB-DNA binding, whereas the inhibition of NF-kappaB p65 expression or activity prevented the GH-dependent activation of IGF-1 and bone morphogenetic protein-2 expression. PMID- 21592971 TI - Probing the HIV gp120 envelope glycoprotein conformation by NMR. AB - The HIV envelope glycoprotein gp120 plays a critical role in virus entry, and thus, its structure is of extreme interest for the development of novel therapeutics and vaccines. To date, high resolution structural information about gp120 in complex with gp41 has proven intractable. In this study, we characterize the structural properties of gp120 in the presence and absence of gp41 domains by NMR. Using the peptide probe 12p1 (sequence, RINNIPWSEAMM), which was identified previously as an entry inhibitor that binds to gp120, we identify atoms of 12p1 in close contact with gp120 in the monomeric and trimeric states. Interestingly, the binding mode of 12p1 with gp120 is similar for clades B and C. In addition, we show a subtle difference in the binding mode of 12p1 in the presence of gp41 domains, i.e. the trimeric state, which we interpret as small differences in the gp120 structure in the presence of gp41. PMID- 21592970 TI - A synthetic S6 segment derived from KvAP channel self-assembles, permeabilizes lipid vesicles, and exhibits ion channel activity in bilayer lipid membrane. AB - KvAP is a voltage-gated tetrameric K(+) channel with six transmembrane (S1-S6) segments in each monomer from the archaeon Aeropyrum pernix. The objective of the present investigation was to understand the plausible role of the S6 segment, which has been proposed to form the inner lining of the pore, in the membrane assembly and functional properties of KvAP channel. For this purpose, a 22 residue peptide, corresponding to the S6 transmembrane segment of KvAP (amino acids 218-239), and a scrambled peptide (S6-SCR) with rearrangement of only hydrophobic amino acids but without changing its composition were synthesized and characterized structurally and functionally. Although both peptides bound to the negatively charged phosphatidylcholine/phosphatidylglycerol model membrane with comparable affinity, significant differences were observed between these peptides in their localization, self-assembly, and aggregation properties onto this membrane. S6-SCR also exhibited reduced helical structures in SDS micelles and phosphatidylcholine/phosphatidylglycerol lipid vesicles as compared with the S6 peptide. Furthermore, the S6 peptide showed significant membrane-permeabilizing capability as evidenced by the release of calcein from the calcein-entrapped lipid vesicles, whereas S6-SCR showed much weaker efficacy. Interestingly, although the S6 peptide showed ion channel activity in the bilayer lipid membrane, despite having the same amino acid composition, S6-SCR was significantly inactive. The results demonstrated sequence-specific structural and functional properties of the S6 wild type peptide. The selected S6 segment is probably an important structural element that could play an important role in the membrane interaction, membrane assembly, and functional property of the KvAP channel. PMID- 21592972 TI - Negative regulation of Gq-mediated pathways in platelets by G(12/13) pathways through Fyn kinase. AB - Platelets contain high levels of Src family kinases (SFKs), but their functional role downstream of G protein pathways has not been completely understood. We found that platelet shape change induced by selective G(12/13) stimulation was potentiated by SFK inhibitors, which was abolished by intracellular calcium chelation. Platelet aggregation, secretion, and intracellular Ca(2+) mobilization mediated by low concentrations of SFLLRN or YFLLRNP were potentiated by SFK inhibitors. However, 2-methylthio-ADP-induced intracellular Ca(2+) mobilization and platelet aggregation were not affected by PP2, suggesting the contribution of SFKs downstream of G(12/13), but not G(q)/G(i), as a negative regulator to platelet activation. Moreover, PP2 potentiated YFLLRNP- and AYPGKF-induced PKC activation, indicating that SFKs downstream of G(12/13) regulate platelet responses through the negative regulation of PKC activation as well as calcium response. SFK inhibitors failed to potentiate platelet responses in the presence of G(q)-selective inhibitor YM254890 or in G(q)-deficient platelets, indicating that SFKs negatively regulate platelet responses through modulation of G(q) pathways. Importantly, AYPGKF-induced platelet aggregation and PKC activation were potentiated in Fyn-deficient but not in Lyn-deficient mice compared with wild-type littermates. We conclude that SFKs, especially Fyn, activated downstream of G(12/13) negatively regulate platelet responses by inhibiting intracellular calcium mobilization and PKC activation through G(q) pathways. PMID- 21592973 TI - Phylogenetic and functional analysis of histidine residues essential for pH dependent multimerization of von Willebrand factor. AB - von Willebrand factor (VWF) is a multimeric plasma protein that mediates platelet adhesion to sites of vascular injury. The hemostatic function of VWF depends upon the formation of disulfide-linked multimers, which requires the VWF propeptide (D1D2 domains) and adjacent D'D3 domains. VWF multimer assembly occurs in the trans-Golgi at pH ~ 6.2 but not at pH 7.4, which suggests that protonation of one or more His residues (pK(a) ~6.0) mediates the pH dependence of multimerization. Alignment of 30 vertebrate VWF sequences identified 13 highly conserved His residues in the D1D2D'D3 domains, and His-to-Ala mutagenesis identified His395 and His460 in the D2 domain as critical for VWF multimerization. Replacement of His395 with Lys or Arg prevented multimer assembly, suggesting that reversible protonation of this His residue is essential. In contrast, replacement of His460 with Lys or Arg preserved normal multimer assembly, whereas Leu, Met, and Gln did not, indicating that the function of His460 depends primarily upon the presence of a positive charge. These results suggest that pH sensing by evolutionarily conserved His residues facilitates the assembly and packaging of VWF multimers upon arrival in the trans-Golgi. PMID- 21592975 TI - Comment accompanying: obstructive sleep apnoea: a stand-alone risk factor for chronic kidney disease by Chou Yu-Ting. AB - Sleep apnoea (SA) is a high priority health problem because it disrupts sleep and reduces quality of life, it is associated with obesity, hypertension, especially resistant hypertension, congestive heart failure, diabetes and it engenders cardiovascular (CV) complications and death. The following types of apnoea can be distinguished: (i) obstructive, (ii) central (i.e. neurally mediated) and (iii) mixed. Obstructive SA (OSA) is characterized by a cessation of airflow caused by occlusion of the oropharyngeal tract and central SA by a transient abolition of the neural drive to respiratory muscles. Mixed apnoea represents a combination of the two forms. SA is one of the most important triggers of high sympathetic activity and it is perhaps the most important non-traditional risk factor underlying the high CV risk of chronic kidney disease (CKD). The high sympathetic activity engenders three intermediate mechanisms, chronic hypertension, left ventricular hypertrophy and arrhythmias, particularly atrial fibrillation, which eventually leads to CV complications and death. SA is common in end-stage renal disease and studies in haemodialysis and peritoneal dialysis patients coherently show that intensive dialysis improves SA in patients with severe sleep disordered breathing. Renal transplantation is in theory the ideal way of correcting SA, because a restored renal function abrogates the uraemic toxicity. In a case control study, the prevalence of mild and severe SA was almost identical in renal transplant patients as compared to age-, sex- and body mass index-matched healthy subjects, supporting the contention that renal transplantation reverses SA. A study published in this issue of Nephrology, Dialysis Transplantation assesses the association between CKD and SA in symptomatic (snorers) patients, excluding by protocol those with hypertension and diabetes, which are well-known risk factors for SA and CKD. The primary hypothesis tested in this study, i.e. whether snorers are at a higher risk for renal dysfunction, is a sensible one. PMID- 21592974 TI - High normal levels of albuminuria and risk of hypertension in Indo-Asian population. AB - BACKGROUND: Urine albumin excretion in the high normal range [urine albumin to creatinine ratio (UACR) 10-29 mg/g)] predicts hypertension in European-origin populations. However, the prognostic significance of UACR in the high normal range for incident hypertension is unclear in Indo-Asians. The objective of this study was to examine the relationship of normal to high normal levels of UACR and incident hypertension. METHODS: We conducted a nested cohort study within a cluster randomized controlled trial in Pakistan on 1272 normotensive non-diabetic adults aged >= 40 years with UACR <30 mg/g. Incident hypertension was defined as new onset of systolic blood pressure (SBP) >= 140 mmHg or diastolic >= 90 mmHg or initiation of antihypertensive therapy. RESULTS: A total of 920 (72.3%) participants completed the 2-year final follow-up. During this time, 105 (11.4%) developed incident hypertension. In the multivariable model, the odds [95% confidence interval (CI)] for incident hypertension were 2.45(1.21-4.98) for those in the fourth (top) quartile (>= 6.1 mg/g) and 2.12 (1.04-4.35) in the third quartile (3.8-6.1 mg/g) compared to those in the lowest quartile (<2.8 mg/g). In addition, a significant interaction between UACR and baseline SBP was observed suggesting that the odds (95% CI) of incident hypertension with UACR were greater at lower baseline SBP (interaction P = 0.044). CONCLUSIONS: High normal levels of albuminuria as measured by UACR predict hypertension in non diabetic Indo-Asians, and this relationship may be enhanced in individuals with low baseline SBP. Further research is needed to assess the clinical applicability of these findings. PMID- 21592976 TI - Outcome of treated and untreated asymptomatic bacteriuria in renal transplant recipients. AB - BACKGROUND: No guidelines exist concerning treatment of asymptomatic bacteriuria in renal transplant recipients (RTR). Because of scarce clinical symptoms and fear of complications, such episodes are frequently treated based on subjective criteria without clear clinical benefit, with the risk of selecting resistant pathogens. METHODS: We retrospectively analysed the outcome of 334 asymptomatic Escherichia coli (E. coli) and Enterococcus faecalis (E. faecalis) bacteriuria that occurred in 77 RTR later than 1 month post-transplantation. We distinguished: Type I, high-grade bacteriuria with pyuria; Type II, high-grade bacteriuria without pyuria; Type III, low-grade bacteriuria with pyuria and Type IV, low-grade bacteriuria without pyuria. RESULTS: None of the 334 episodes was followed by acute rejection or chronic pyelonephritis. One hundred and one (30%) episodes were treated [32 (62%) Type I, 38 (45%) Type II, 13 (36%) Type III and 18 (11%) Type IV]. Evolution to symptomatic urinary tract infection (UTI) was similar between treated and untreated episodes (0/101 versus 4/233, P = 0.32). The four UTI resolved favourably without further complication upon treatment. Persistent asymptomatic bacteriuria occurred in 45 (46%) treated episodes (2 Type I, 27 Type II, 8 Type III and 9 Type IV), with selection of resistant pathogen in 35 cases (78%). Spontaneous bacterial clearance occurred in 138 (59%) untreated episodes (15 Type I, 23 Type II, 9 Type III and 91 Type IV). Negative control cultures tended to be more frequent in treated Type I (P = 0.09) and in untreated Type II episodes (P = 0.08). CONCLUSION: Restricting antibiotic treatments for asymptomatic low-grade bacteriuria and high-grade bacteriuria in the absence of pyuria, occurring later than 1 month posttransplantation, might be safe in RTR. PMID- 21592977 TI - Careful re-evaluation of the impact of stopping inhibitors of the renin angiotensin system in patients with advanced chronic kidney disease. PMID- 21592978 TI - Have we overlooked congenital cytomegalovirus infection as a cause of stillbirth? PMID- 21592979 TI - Could therapeutic vaccination of cytomegalovirus-seropositive persons prevent reinfection and congenital virus transmission? PMID- 21592980 TI - Human cytomegalovirus infection is detected frequently in stillbirths and is associated with fetal thrombotic vasculopathy. AB - BACKGROUND: Human cytomegalovirus (CMV) is the most common congenital infection in developed countries and is a known cause of intrauterine fetal death. We examined CMV infection in stillbirths and the relationship with histopathological findings at autopsy. METHODS: We collected liver, kidney, and placenta specimens from 130 stillbirths. CMV DNA and protein were detected using polymerase chain reaction and immunohistochemistry, along with routine autopsy of stillborn infants. RESULTS: Overall, CMV DNA was detected in 15% of singleton, >20-week stillborn infants. CMV DNA was detected in kidney (9%), liver (11%), and placenta (5%) specimens, with 75% of infections confirmed by immunohistochemistry. Fetal thrombotic vasculopathy was the only histopathological abnormality associated with CMV infection (in 60% CMV-infected vs 28% uninfected stillbirths P = .010). CONCLUSIONS: Stillbirth has multiple etiologies. However, the detection of CMV DNA in 15% of fetal tissues or placentae suggests a strong association between CMV infection in pregnancy and stillbirth. Molecular testing during postmortem investigation has an important role to determine the contribution of CMV infection. PMID- 21592981 TI - Glycoprotein B vaccine is capable of boosting both antibody and CD4 T-cell responses to cytomegalovirus in chronically infected women. AB - Traditionally, vaccines have been utilized to generate immune responses to a pathogen in a naive population. In the setting of congenital cytomegalovirus (CMV) infection, a vaccine that, when administered to women already infected with CMV, could boost the mother's immunity to CMV would most likely be beneficial in diminishing in utero transmission of CMV. However, the ability to boost an immune response in a population of individuals seropositive for a pathogen of interest is not well studied. This study examines the ability of a recombinant CMV glycoprotein B vaccine with MF59 adjuvant to boost both antibody (neutralizing and enzyme-linked immunosorbent assay end point dilution titer) and CD4+ T-cell responses in previously CMV-seropositive women by way of natural infection. These data suggest that this vaccine is capable of boosting immunity in a population of CMV-infected women and warrants additional evaluation to determine whether these boosted responses may prevent mother to child transmission of CMV. PMID- 21592982 TI - Varicella zoster virus DNA at inoculation sites and in saliva after Zostavax immunization. AB - Analysis of 36 individuals over age 60 years who were immunized with Zostavax revealed varicella zoster virus (VZV) DNA in swabs of skin inoculation sites obtained immediately after immunization in 18 (50%) of 36 subjects (copy number per nanogram of total DNA, 28 to 2.1 * 10(6)) and in saliva collected over 28 days in 21 (58%) of 36 subjects (copy number, 20 to 248). Genotypic analysis of DNA extracted from 9 random saliva samples identified vaccine virus in all instances. In some immunized individuals over age 60, vaccine virus DNA is shed in saliva up to 4 weeks. PMID- 21592983 TI - Human leukocyte antigen genotypes in the genetic control of adaptive immune responses to smallpox vaccine. AB - BACKGROUND: The role of human leukocyte antigen (HLA) genes in mediating adaptive immune responses to smallpox vaccine remains unknown. METHODS: We determined genotypes for a group of individuals (n = 1071) who received a single dose of smallpox vaccine (Dryvax, Wyeth Laboratories) and examined associations between HLA alleles and 15 immune outcomes to smallpox vaccine on a per-locus and a per allele level. RESULTS: We found significant associations between the HLA-B and HLA - DQB1 loci and vaccinia-induced antibodies (P = .04 for each locus), with the HLA-B*1302 (P = .036), B*3802 (P = .011), DQB1*0302 (P = .015), and DQB1*0604 (P = .017) alleles being associated with higher levels. Significant global associations were identified between vaccinia-specific interferon (IFN)-gamma and DQA1 (P = .003), interleukin (IL)-1beta and HLA-B (P = .004), tumor necrosis factor (TNF)-alpha and HLA-B (P = .006), and IL-6 and HLA-B locus (P = .016) for secreted cytokines, as well as between CD8alpha(+) IFN-gamma Elispot responses and DQB1 (P = .027). Subjects carrying B*3906 (P = .006) and B*5701 (P < .001) secreted higher levels of IL-1beta than did subjects who did not carry these alleles. Subjects carrying the B*5301 (P = .047) and B*5601 (P = .008) alleles secreted less IL-1beta, compared with subjects who did not carry these alleles. The B*3502 (P = .009), B*5601 (P = .004), and B*5701 (P < .001) alleles were significantly associated with variations in TNF-alpha secretion. CONCLUSIONS: These data suggest that variations in antibody and cellular IFN-gamma, IL-1beta, TNF-alpha, and IL-6 immune responses after receipt of smallpox vaccine are genetically controlled by HLA genes or genes in close linkage disequilibrium to these alleles. PMID- 21592984 TI - A tick-borne encephalitis virus vaccine based on the European prototype strain induces broadly reactive cross-neutralizing antibodies in humans. AB - After vaccination of humans with tick-borne encephalitis virus (TBEV) vaccine, the extent of cross-neutralization between viruses of the European, Far Eastern, and Siberian subtypes of TBEV and Omsk hemorrhagic fever virus (OHFV) was analyzed. Hybrid viruses that encode the TBEV surface proteins for representative viruses within all subtypes, and OHFV, were constructed using the West Nile virus (WNV) backbone as vector. These viruses allow for unbiased head-to-head comparison in neutralization assays because they exhibit the antigenic characteristics of the TBEV strains from which the surface proteins were derived and showed equivalent biologic properties in cell culture. Human serum samples derived from a TBEV vaccine trial were analyzed and revealed comparable neutralizing antibody titers against European, Far Eastern, and Siberian subtype viruses, indicating equally potent cross-protection against these TBEV strains and a somewhat reduced but still protective neutralization capacity against more distantly related viruses, such as OHFV. PMID- 21592985 TI - Identification of human papillomavirus type 58 lineages and the distribution worldwide. AB - BACKGROUND: Human papillomavirus type 58 (HPV-58) accounts for a much higher proportion of cervical cancers in East Asia than other types. A classification system of HPV-58, which is essential for molecular epidemiological study, is lacking. METHODS AND RESULTS: This study analyzed the sequences of 401 isolates collected from 15 countries and cities. The 268 unique concatenated E6-E7-E2-E5 L1-LCR sequences that comprised 57% of the whole HPV-58 genome showed 4 distinct clusters. L1 and LCR produced tree topologies that best resembled the concatenated sequences and thus are the most appropriate surrogate regions for lineage classification. Moreover, short fragments from L1 (nucleotides 6014-6539) and LCR (nucleotides 7257-7429 and 7540-52) were found to contain sequence signatures informative for lineage identification. Lineage A was the most prevalent lineage across all regions. Lineage C was more frequent in Africa than elsewhere, whereas lineage D was more prevalent in Africa than in Asia. Among lineage A variants, sublineage A2 dominated in Africa, the Americas, and Europe, but not in Asia. Sublineage A1, which represents the prototype that originated from a patient with cancer, was rare worldwide except in Asia. CONCLUSIONS: HPV 58 can be classified into 4 lineages that show some degree of ethnogeographic predilection in distribution. The evolutionary, epidemiological, and pathological characteristics of these lineages warrant further study. PMID- 21592986 TI - Fully human monoclonal antibody directed to proteolytic cleavage site in severe acute respiratory syndrome (SARS) coronavirus S protein neutralizes the virus in a rhesus macaque SARS model. AB - BACKGROUND: There is still no effective method to prevent or treat severe acute respiratory syndrome (SARS), which is caused by SARS coronavirus (CoV). In the present study, we evaluated the efficacy of a fully human monoclonal antibody capable of neutralizing SARS-CoV in vitro in a Rhesus macaque model of SARS. METHODS: The antibody 5H10 was obtained by vaccination of KM mice bearing human immunoglobulin genes with Escherichia coli-producing recombinant peptide containing the dominant epitope of the viral spike protein found in convalescent serum samples from patients with SARS. RESULTS: 5H10, which recognized the same epitope that is also a cleavage site critical for the entry of SARS-CoV into host cells, inhibited propagation of the virus and pathological changes found in Rhesus macaques infected with the virus through the nasal route. In addition, we analyzed the mode of action of 5H10, and the results suggested that 5H10 inhibited fusion between the virus envelope and host cell membrane. 5H10 has potential for use in prevention and treatment of SARS if it reemerges. CONCLUSIONS: This study represents a platform to produce fully human antibodies against emerging infectious diseases in a timely and safe manner. PMID- 21592987 TI - Epidemiologic inference from the distribution of tuberculosis cases in households in Lima, Peru. AB - BACKGROUND: Tuberculosis (TB) often occurs among household contacts of people with active TB. It is unclear whether clustering of cases represents household transmission or shared household risk factors for TB. METHODS: We used cross sectional data from 764 households in Lima, Peru, to estimate the relative contributions of household and community transmission, the average time between cases, and the immunity afforded by a previous TB infection. RESULTS: The distribution of cases per household suggests that almost 7 of 10 nonindex household cases were infected in the community rather than in the household. The average interval between household cases was 3.5 years. We observed a saturation effect in the number of cases per household and estimated that protective immunity conferred up to 35% reduction in the risk of disease. CONCLUSIONS: Cross sectional household data can elucidate the natural history and transmission dynamics of TB. In this high-incidence setting, we found that the majority of cases were attributable to community transmission and that household contacts of case patients derive some immunity from household exposures. Screening of household contacts may be an effective method of detecting new TB cases if carried out over several years. PMID- 21592988 TI - Influence of variations in CCL3L1 and CCR5 on tuberculosis in a northwestern Colombian population. AB - We investigated the association of polymorphisms in CCR5, the major human immunodeficiency virus (HIV)-1 coreceptor, and copy number of its potent ligand CCL3L1 with tuberculosis in 298 individuals from Colombia. The CCR5-HHD haplotype, a known genetic determinant of increased susceptibility to HIV-AIDS, and a high copy number of CCL3L1, a known genetic determinant of enhanced CCL3/CCL3L1 chemokine expression, each associated with presence of tuberculosis. Furthermore, CCR5-HHD was associated with higher CCR5 gene and surface expression. These results substantiate the strong link between the pro inflammatory effects of CCR5 and its ligands with active tuberculosis and suggest that chemokine-chemokine receptor genetic determinants may influence tuberculosis in addition to HIV/AIDS. PMID- 21592990 TI - Berberine ameliorates intestinal epithelial tight-junction damage and down regulates myosin light chain kinase pathways in a mouse model of endotoxinemia. AB - BACKGROUND: This study aimed to examine the protective effect of berberine in endotoxin-induced intestinal tight-junction injury in a mice model of endotoxinemia. METHODS: Endotoxinemia was induced by intraperitoneal injection of lipopolysaccharide (10 mg/kg). Mice were randomized to 5 groups: control mice, berberine-treated mice, lipopolysaccharide (LPS)-injected mice, mice pretreated with berberine, and mice administered berberine following LPS injection. Samples were collected 12 h after LPS treatment. RESULTS: Ileal mucosal permeability to fluorescein isothiocyanate dextran assay indicated that berberine reduced the permeability of the gut barrier in endotoxinemia. Transmission electron microscopy revealed that pretreatement with berberine partly prevented ultrastructural disruption of tight junctions by LPS. Immunofluorescence and Western blot analysis were performed, and the results demonstrated that pretreatement with berberine partially reversed the redistribution of tight junction proteins in colon epithelium and in membrane microdomains. Our data also indicated that pretreatement with berberine could suppress translocation, from cytoplasm to the nucleus, of nuclear factor-kappaB and myosin light chain kinase activation in the intestinal epithelium. CONCLUSIONS: Pretreatement with berberine attenuates disruption of tight junctions in intestinal epithelium in a mice model of endotoxinemia. This may possibly have been mediated through down regulation of the nuclear factor-kappaB and myosin light chain kinase pathway. PMID- 21592989 TI - Defense from the Group A Streptococcus by active and passive vaccination with the streptococcal hemoprotein receptor. AB - BACKGROUND: The worldwide burden of the Group A Streptococcus (GAS) primary infection and sequelae is considerable, although immunization programs with broad coverage of the hyper variable GAS are still missing. We evaluate the streptococcal hemoprotein receptor (Shr), a conserved streptococcal protein, as a vaccine candidate against GAS infection. METHODS: Mice were immunized intraperitoneally with purified Shr or intranasally with Shr-expressing Lactococcus lactis. The resulting humoral response in serum and secretions was determined. We evaluated protection from GAS infection in mice after active or passive vaccination with Shr, and Shr antiserum was tested for bactericidal activity. RESULTS: A robust Shr-specific immunoglobulin (Ig) G response was observed in mouse serum after intraperitoneal vaccination with Shr. Intranasal immunization elicited both a strong IgG reaction in the serum and a specific IgA reaction in secretions. Shr immunization in both models allowed enhanced protection from systemic GAS challenge. Rabbit Shr antiserum was opsonizing, and mice that were administrated with Shr antiserum prior to the infection demonstrated a significantly higher survival rate than did mice treated with normal rabbit serum. CONCLUSIONS: Shr is a promising vaccine candidate that is capable of eliciting bactericidal antibody response and conferring immunity against systemic GAS infection in both passive and active vaccination models. PMID- 21592991 TI - Clostridium difficile transcriptome analysis using pig ligated loop model reveals modulation of pathways not modulated in vitro. AB - A pig ligated loop model was used to analyze the in vivo transcriptome response of Clostridium difficile. Bacterial RNA from the loops was retrieved at different times and was used for microarray analysis. Several virulence-associated genes and genes involved in sporulation cascade were differentially expressed (DE). In concordance with observed upregulation of toxin genes in microarray, enzyme linked immunosorbent assay estimation of total toxin showed high amounts of toxin in the loops. Several genes that were absent in primary annotation of C. difficile 630 but annotated in a secondary annotation were found to be DE. Pathway comparison of DE genes in vitro and in vivo showed that when several pathways were expressed in all conditions, several of the C. difficile pathways were uniquely expressed only in vivo. The pathways observed to be modulated only in this study could be targets of new therapeutic agents against C. difficile infection. PMID- 21592992 TI - Low incidence of HIV-1 superinfection even after episodes of unsafe sexual behavior of homosexual men in the Amsterdam Cohort Studies on HIV Infection and AIDS. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) superinfection is infection of an HIV-1 seropositive individual with another HIV-1 strain. The rate at which HIV-1 superinfection occurs might be influenced by sexual behavior. Superinfection might be detected more often by analyzing longitudinal samples collected from time periods of unsafe sexual behavior. METHODS: Envelope C2-C4 and gag sequences were generated from HIV-1 RNA from longitudinal serum samples that were obtained around self-reported sexual risk periods from 15 homosexual therapy-naive men who participated in the Amsterdam Cohort Studies on HIV Infection and AIDS. Maximum likelihood phylogenetic analysis was used to determine whether HIV-1 superinfection had occurred. RESULTS: We studied a total of 124 serum samples from 15 patients with a median of 8 samples and of 5.8 person-years of follow-up per patient. Phylogenetic analysis on 907 C2-C4 env and 672 gag sequences revealed no case of HIV-1 superinfection, resulting in a superinfection incidence rate of 0 per 100 person-years [95%CI: 0 - -4.2]. CONCLUSIONS: We conclude that HIV-1 superinfection incidence is low in this subgroup of homosexual men who reported unsafe sexual behavior. Additional studies are required to estimate the impact of also other factors, which may determine the risk to acquire HIV-1 superinfection. PMID- 21592993 TI - Influence of interleukin-28B single-nucleotide polymorphisms on progression to liver cirrhosis in human immunodeficiency virus-hepatitis C virus-coinfected patients receiving antiretroviral therapy. AB - BACKGROUND: Single-nucleotide polymorphisms (SNPs) near the IL28B gene have recently been associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapies in patients with chronic hepatitis C. Because human immunodeficiency virus (HIV) coinfection appears to accelerate HCV related liver fibrosis progression, any influence of IL28B SNP on the risk of developing cirrhosis might be more easily recognized in the coinfected population. METHODS: All HIV-HCV-coinfected patients who underwent hepatic elastography before initiating a course of pegylated interferon plus ribavirin therapy at 2 Spanish clinics were retrospectively identified. Liver cirrhosis was defined as >14.5 kPa by transient elastography. The IL28B rs12979860 SNP was examined in a blinded fashion. RESULTS: A total of 304 HIV-HCV-coinfected individuals were analyzed (mean age, 43 years; 80% were male; and 85% were receiving antiretroviral therapy), of whom 18% had cirrhosis. IL28B genotype distribution was as follows: CC, 46%; CT, 43%; and TT, 11%. Cirrhosis was more frequent in CC than CT/TT carriers (24% vs 13%; P = .01). Logistic regression analysis revealed that older age (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.99-1.12]; P = .08), past alcohol abuse (OR, 1.97; 95% CI, 0.95-4.06; P = .07), and CC IL28B genotype (OR, 2.32; 95% CI, 1.22-4.41; P = .01) were predictors of cirrhosis. Interestingly, mean (SD) alanine aminotransferase (ALT) levels were greater (90 +/- 53 vs 71 +/- 33 IU/L;, P = .01) in IL28B CC than CT/TT carriers during the prior 4.8 +/- 3.8 years. CONCLUSIONS: The IL28B rs12979860 CC genotype is associated with a higher prevalence of cirrhosis in HIV HCV-coinfected patients than CT/TT genotypes, suggesting that IL28B CC carriers may experience a more rapid progression of HCV-related liver fibrosis, perhaps as result of increased liver inflammation. Thus, access to HCV treatment is of utmost importance in IL28B CC carriers, in whom treatment response is better and in whom progression to cirrhosis might occur more rapidly. PMID- 21592994 TI - Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death. AB - BACKGROUND: Substantial morbidity occurs during the first year of antiretroviral therapy (ART) in persons with advanced human immunodeficiency virus (HIV) disease despite HIV suppression. Biomarkers may identify high-risk groups. METHODS: Pre ART and 1-month samples from an initial ART trial were evaluated for biomarkers associated with AIDS events or death within 1-12 months. Case patients (n = 63) and control patients (n = 126) were 1:2 matched on baseline CD4 cell count, hepatitis status, and randomization date. All had >= 1 log(10) HIV RNA level decrease at 1 month. RESULTS: Case patients had more frequent prior AIDS events, compared with control patients (P = .004), but similar HIV RNA levels at baseline. Pre-ART and 1-month C-reactive protein (CRP), D-dimer, and interleukin 6 (IL-6) levels and pre-ART hyaluronic acid (HA) levels were associated with new AIDS events or death (P <= .01). Patients who experienced immune reconstitution inflammatory syndrome (IRIS) events had higher pre-ART tumor necrosis factor alpha (TNF-alpha) and HIV RNA levels and significant 1-month increases in CRP, D dimer, IL-6, interleukin 8, CXCL10, TNF-alpha, and interferon-gamma levels, compared with patients who experienced non-IRIS events (P <= .03). Individuals with baseline CRP and HA levels above the cohort median (>2.1 mg/L and >50.0 ng/mL, respectively) had increased risk of AIDS or death (OR, 4.6 [95% CI, 2.0 10.3]; P < .001) and IRIS (OR, 8.7 [95% CI, 2.2-34.8] P = .002). CONCLUSIONS: Biomarkers of Inflammation (CRP, IL-6), coagulation (D-dimer), and tissue fibrosis (HA) measured pre-ART and at 1 month are associated with higher risk of AIDS events, IRIS, or death, warranting additional study as risk stratification strategies. PMID- 21592996 TI - Survival and proliferation of CD28- T cells during HIV-1 infection relate to the amplitude of viral replication. AB - BACKGROUND: CD28(-) T lymphocytes progressively increase during aging, autoimmunity, and HIV-1 infection. Expansion of these cells stands in contrast with their senescent phenotype described by several studies. Understanding the functional properties and phenotype of CD28(-) T cell during HIV-1 infection is important, because this subset incorporates T cells specific for HIV-1 and other chronic pathogens. METHODS: Blood samples were obtained from 23 healthy and 43 HIV-1-infected individuals: 26 receiving antiretroviral therapy and 17 naive to treatment. The phenotype of CD28(-) and CD28(+) T cells was determined by flow cytometry. T cells were activated through T-cell receptor before apoptosis and proliferation measurements. Interleukin (IL)-2, tumor-necrosis factor, interferon gamma, and perforin production were analyzed using enzyme-linked immunosorbent assay. RESULTS: CD28(-) T cells from patients receiving antiretroviral therapy exhibited a low sensitivity to apoptosis and enhanced proliferation after TCR stimulation, compared with T cells of uninfected individuals. On the contrary, CD28(-) T cells from viremic patients showed a decreased Bcl-2 expression, a high sensitivity to apoptosis, and poor proliferative ability, compared with treated patients and control subjects. T cells from untreated patients produced less IL 2, possibly underlying their decreased proliferative abilities. CONCLUSIONS: The level of HIV-1 replication and associated immunoactivation represent a critical factor in regulating survival and activation of CD28(-) T cells. PMID- 21592995 TI - Autophagy is increased in postmortem brains of persons with HIV-1-associated encephalitis. AB - BACKGROUND: Autophagy is critical to maintaining cell homeostasis and is implicated in neurodegenerative diseases. This research examined the role of autophagy in human immunodeficiency virus type 1 (HIV-1)-associated encephalitis, the pathologic hallmark of neuroAIDS. METHODS: The frontal cortex from 32 HIV infected persons (12 without evidence HIV-1 encephalitis or clinical signs of central nervous system impairment and 20 with histopathological findings of HIV-1 encephalitis) and 8 persons without HIV infection and any neuropathology were examined postmortem. Green fluorescent protein-labeled (GFP) light chain 3 (LC3) expressing neuroblastoma SK-N-SH cells treated with gp120 from CXCR4 and CCR5 viruses were also examined. Autophagic markers were assessed by means of Western blot analysis, transmission electron microscopy (TEM), and confocal microscopy. RESULTS: Autophagic proteins Beclin 1, Autophagy-related gene (Atg)-5, Atg-7, and LC3-II were significantly increased in brains with HIV-1 encephalitis (P < .05). These findings were confirmed by TEM and immunostaining of brain tissue. Additionally, levels of autophagic proteins and autophagosomes were increased in neuronal cells treated with both CXCR4- or CCR5-tropic HIV-1 gp120. No increase in the level of autophagy was observed in the brains of HIV-infected persons without HIV-1 encephalitis compared with the level in brains of HIV-uninfected persons. CONCLUSIONS: Postmortem brains with HIV-1 encephalitis exhibit increased markers of autophagy compared with brains from HIV-infected persons without HIV-1 encephalitis or HIV-uninfected control brains, which suggests that dysregulation of autophagy may be important in the pathogenesis of neuroAIDS. PMID- 21592998 TI - Positive selection of Plasmodium falciparum parasites with multiple var2csa-type PfEMP1 genes during the course of infection in pregnant women. AB - Placental malaria infections are caused by Plasmodium falciparum-infected red blood cells sequestering in the placenta by binding to chondroitin sulfate A, mediated by VAR2CSA, a variant of the PfEMP1 family of adhesion antigens. Recent studies have shown that many P. falciparum genomes have multiple genes coding for different VAR2CSA proteins, and parasites with >1 var2csa gene appear to be more common in pregnant women with placental malaria than in nonpregnant individuals. We present evidence that, in pregnant women, parasites containing multiple var2csa-type genes possess a selective advantage over parasites with a single var2csa gene. Accumulation of parasites with multiple copies of the var2csa gene during the course of pregnancy was also correlated with the development of antibodies involved in blocking VAR2CSA adhesion. The data suggest that multiplicity of var2csa-type genes enables P. falciparum parasites to persist for a longer period of time during placental infections, probably because of their greater capacity for antigenic variation and evasion of variant-specific immune responses. PMID- 21592997 TI - B and T lymphocyte attenuator down-regulation by HIV-1 depends on type I interferon and contributes to T-cell hyperactivation. AB - BACKGROUND: Nonspecific T-cell hyperactivation is the main driving force for human immunodeficiency virus (HIV)-1 disease progression, but the reasons why the excess immune response is not properly shut off are poorly defined. METHODS: Eighty-five HIV-1-infected individuals were enrolled to characterize B and T lymphocyte attenuator (BTLA) expression and function. Infection and blockade assays were used to dissect the factors that influenced BTLA signaling in vitro. RESULTS: BTLA expression on overall CD4(+) and CD8(+) T cells was progressively decreased in HIV-1 infection, which was directly correlated with disease progression and CD4(+) T-cell differentiation and activation. BTLA(+)CD4(+) T cells from HIV-1-infected patients also displayed an altered immune status, which was indicated by reduced expression of naive markers but increased activation and exhaustion markers. Cross-linking of BTLA can substantially decrease CD4(+) T cell activation in vitro. This responsiveness of CD4(+) T cells to BTLA-mediated inhibitory signaling was further found to be impaired in HIV-1-infected patients. Furthermore, HIV-1 NL4-3 down-regulated BTLA expression on CD4(+) T cells dependent on plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-alpha. Blockade of IFN-alpha or depletion of pDCs prevents HIV-1-induced BTLA down regulation. CONCLUSIONS: HIV-1 infection potentially impairs BTLA-mediated signaling dependent on pDC-derived IFN-alpha, which may contribute to broad T cell hyperactivation induced by chronic HIV-1 infection. PMID- 21592999 TI - Genotypes coding for mannose-binding lectin deficiency correlated with cryptococcal meningitis in HIV-uninfected Chinese patients. AB - BACKGROUND: There is increasing evidence that mannose-binding lectin (MBL) has a complex role in many diseases, particularly in infectious diseases. However, the relationship between MBL deficiency and cryptococcal meningitis has not been clarified. The purpose of this study was to investigate the correlation between MBL polymorphism and non-HIV cryptococcal meningitis. METHODS: A case-controlled genetic association study was conducted. Patients with cryptococcal meningitis and control subjects were genotyped for 6 alleles of MBL2 gene (H/L, Y/X, P/Q, A/D, A/B, and A/C). The distributions in allele frequency, genotypes, haplotypes, and genotype groups were compared between patients and control subjects. RESULTS: Study participants included 103 HIV-uninfected patients with cryptococcal meningitis and 208 healthy control subjects, all of Chinese Han ethnicity. The homozygous mutative genotypes (O/O) of the coding region were associated with cryptococcal meningitis (P = .023; odds ratio [OR], 4.29; 95% confidence interval [CI], 1.11-19.88), the correlation more overt in immunocompetent patients (P = .005; OR, 6.65; 95% CI, 1.49-33.05). MBL-deficient participant group was associated with cryptococcal meningitis (P = .039; OR, 2.09; 95% CI, .96-4.51), particularly in immunocompetent patients (P = .028; OR, 2.51; 95% CI, .96-6.22). CONCLUSIONS: This is the first to show genotypes coding for MBL deficiency are associated with cryptococcal meningitis in nonimmunocompromised hosts. PMID- 21593000 TI - Expectations regarding vaccines and immune therapies directed against Staphylococcus aureus alpha-hemolysin. PMID- 21593002 TI - Inactivated seasonal influenza vaccines increase serum antibodies to the neuraminidase of pandemic influenza A(H1N1) 2009 virus in an age-dependent manner. PMID- 21593005 TI - Disasters and public health concerns. PMID- 21593004 TI - Interleukin 22 serum levels are associated with radiographic progression in rheumatoid arthritis. AB - OBJECTIVES: To study the role of interleukin 22 (IL-22) in rheumatoid arthritis (RA). METHODS: IL-22 serum levels were measured in patients with early, treatment naive RA (n=49) and in 45 age- and sex-matched healthy individuals as controls. Patients were assessed clinically and radiographically at baseline and followed up for 2 years. Correlations of IL-22 serum levels were sought with parameters of disease activity, serological markers, demographic factors and the incidence of erosions. IL-22 production by peripheral blood T cells was investigated by intracellular flow cytometry. RESULTS: 24 of 49 patients with RA demonstrated elevated IL-22 levels compared with the range of healthy controls. At baseline, a high percentage of these patients (8/24, 33%) demonstrated bone erosions, whereas only one patient (4%) from the group with normal IL-22 had erosions. During the 2 years of follow-up, six additional patients with increased IL-22 at baseline developed erosions. In contrast, none of the patients in whom IL-22 levels were normal developed erosions despite similar treatment regimens. Multivariate regression analysis accounting for other parameters predictive for erosions, such as the presence of rheumatoid factor or anti-cyclic citrullinated peptide antibodies and disease activity, showed that elevated IL-22 baseline levels were independently and significantly associated with erosive RA. Cellular analysis demonstrated enhanced expression of IL-22 from CD4 T cells in RA. CONCLUSION: IL 22 is elevated in the serum of half of the patients with RA. Elevated serum IL-22 allows discrimination between patients with different radiographic progression and indicates a possible involvement of IL-22 in the pathophysiology of RA. PMID- 21593006 TI - Determinants of adherence to iron/folate supplementation during pregnancy in two provinces in Cambodia. AB - Iron supplementation can effectively control and prevent anemia in pregnancy. However, limited adherence is thought to be a major reason for the low effectiveness of iron supplementation programs.This research describes the factors influencing the adherence to iron/folate supplementation during pregnancy in Siem Reap and Kampong Cham provinces in Cambodia.Triangulation method, combining the quantitative and qualitative data collection methods, was performed for this study. A total of 177 women who gave birth during the year prior to the interview were selected for the quantitative survey. Ten women who gave birth during the year prior to the interview and 10 pregnant women were interviewed in depth for the qualitative data.The chi2 test and binary logistic regression were used for statistical analysis. The findings showed an adherence rate of 47%. The logistic regression revealed that the number of supplements received, number of prenatal visits, and access to antenatal care were determinants of adherence (P<.05). In conclusion, access to and follow-up of antenatal care were considered elements essential to improve iron/folate supplementation. Community-based interventions, such as nutrition education and distribution of supplements, should be prioritized in the interventions to improve adherence in Cambodia. PMID- 21593008 TI - Complaints against nursing homes: comparing two sources of complaint information and predictors of complaints. AB - PURPOSE OF THE STUDY: Two consumer-derived measures of nursing home quality that have been underutilized by researchers are consumer complaints to the state certification agency between inspections and complaints to the Long-Term Care Ombudsman Program. This article describes these complaints, considers facility level predictors of complaints, and examines how complaints to the 2 entities are related. DESIGN AND METHODS: This article uses North Carolina complaint data from the state certification agency and Ombudsman from 2002 to 2006. First, we outline the similarities and differences in the 2 complaint sources by considering descriptive statistics and examining the structure of the 2 agencies. Second, we examine the relationship between complaints and facility characteristics that have been predictive of traditional quality measures. Finally, we examine the relationships between the 2 types of complaints. RESULTS: We find that complaints to the 2 agencies exhibit distinct differences in substantiation rates, although the top complaint category for both agencies is quality of care. Having a higher proportion of Medicaid residents is generally not predictive of complaint volume, whereas having a higher proportion of Medicare residents is associated with higher complaint levels. IMPLICATIONS: We find a lack of association between complaints to the 2 agencies when examining specific matched categories of complaints in many cases, suggesting that the 2 entities are not duplicating efforts in these categories. PMID- 21593007 TI - Aging prisoners' treatment selection: does prospect theory enhance understanding of end-of-life medical decisions? AB - PURPOSE: With the rapid growth in the older inmate population and the economic impact of end-of-life treatments within the cash-strapped prison system, consideration should be given to inmate treatment preferences. We examined end-of life treatment preferences and days of desired life for several health scenarios among male inmates incarcerated primarily for murder. DESIGN AND METHODS: Inmates over the age of 45 who passed a cognitive screening completed face-to-face interviews (N = 94; mean age = 57.7; SD = 10.68). RESULTS: We found a 3-way interaction indicating that the effect of parole expectation on desire for life sustaining treatment varied by race/ethnicity and treatment. Minority inmates desired cardiopulmonary resuscitation or feeding tubes only if they believed that they would be paroled. The model predicting desire for palliative care was not significant. Future days of desired life were related to prospective health condition, fear of death, negative affect, and trust in prison health care. Caucasian inmates expressed a desire for more days of life out of prison, whereas minority inmates did not differ in days of desired life either in or out of prison. Minorities wanted more days of life than Caucasians but only if they believed that they would be paroled. IMPLICATIONS: End-of-life care for the burgeoning inmate population is costly, and active life-sustaining treatments may not be desired under certain conditions. Specifically, expectation of parole but not current functional ability interacts with future illness condition in explaining inmates' desire for active treatment or days of desired life in the future. PMID- 21593009 TI - Falls after discharge from hospital: is there a gap between older peoples' knowledge about falls prevention strategies and the research evidence? AB - PURPOSE: The aim of this study was to examine whether older people are prepared to engage in appropriate falls prevention strategies after discharge from hospital. DESIGN AND METHODS: We used a semi-structured interview to survey older patients about to be discharged from hospital and examined their knowledge regarding falls prevention strategies to utilize in the post-discharge period. The study was part of a prospective cohort study, nested within a larger, randomized controlled trial. Participants (n = 333) were asked to suggest strategies to reduce their falls risk at home after discharge, and their responses were compared with current reported research evidence for falls prevention interventions. RESULTS: Participants' strategies (n = 629) were classified into 7 categories: behavioral, support while mobilizing, approach to movement, physical environment, visual, medical, and activities or exercise. Although exercise has been identified as an effective falls risk reduction strategy, only 2.9% of participants suggested engaging in exercises. Falls prevention was most often conceptualized by participants as requiring 1 (35.4%) or 2 (40.8%) strategies for avoiding an accidental event, rather than engaging in sustained multiple risk reduction behaviors. IMPLICATIONS: Results demonstrate that older patients have low levels of knowledge about appropriate falls prevention strategies that could be used after discharge in spite of their increased falls risk during this period. Findings suggest that health care workers should design and deliver falls prevention education programs specifically targeted to older people who are to be discharged from hospital. PMID- 21593010 TI - The impact of TCARE(r) on service recommendation, use, and caregiver well-being. AB - PURPOSE OF THE STUDY: Findings are reported from a study that examined the effects of the Tailored Caregiver Assessment and Referral (TCARE(r)) protocol, a care management process designed to help family caregivers, on care planning and caregiver outcomes. DESIGN AND METHODS: A longitudinal, randomized controlled trial was conducted with 97 caregivers enrolled in a demonstration project in Georgia. Data included on care plans pertaining to service recommendations, compliance, and use were reviewed. Caregiver identity discrepancy, objective burden, relationship burden, stress burden, and depressive symptoms were assessed up to 4 times during a 9-month observation period. Chi-square tests, independent samples t tests, random effects regression growth curve analysis, and random intercept regression analysis were conducted. RESULTS: A greater variety of services were recommended to and used by caregivers in the intervention group than in the control group. Caregivers in the intervention group had lower caregiver identity discrepancy, stress burden, and depressive symptoms over time than caregivers in the control group. IMPLICATIONS: Study findings provide initial support for the merits of the TCARE(r) protocol as a process that can be used to effectively target services to individual caregivers' needs. PMID- 21593011 TI - Effects of environmental conditions on onset of xylem growth in Pinus sylvestris under drought. AB - We determined the influence of environmental factors (air and soil temperature, precipitation, photoperiod) on onset of xylem growth in Scots pine (Pinus sylvestris L.) within a dry inner Alpine valley (750 m a.s.l., Tyrol, Austria) by repeatedly sampling micro-cores throughout 2007-10 at two sites (xeric and dry mesic) at the start of the growing season. Temperature sums were calculated in degree-days (DD) >=5 degrees C from 1 January and 20 March, i.e., spring equinox, to account for photoperiodic control of release from winter dormancy. Threshold temperatures at which xylogenesis had a 0.5 probability of being active were calculated by logistic regression. Onset of xylem growth, which was not significantly different between the xeric and dry-mesic sites, ranged from mid April in 2007 to early May in 2008. Among most study years, statistically significant differences (P<0.05) in onset of xylem growth were detected. Mean air temperature sums calculated from 1 January until onset of xylem growth were 230 +/- 44 DD (mean +/- standard deviation) at the xeric site and 205 +/- 36 DD at the dry-mesic site. Temperature sums calculated from spring equinox until onset of xylem growth showed somewhat less variability during the 4-year study period, amounting to 144 +/- 10 and 137 +/- 12 DD at the xeric and dry-mesic sites, respectively. At both sites, xylem growth was active when daily minimum, mean and maximum air temperatures were 5.3, 10.1 and 16.2 degrees C, respectively. Soil temperature thresholds and DD until onset of xylem growth differed significantly between sites, indicating minor importance of root-zone temperature for onset of xylem growth. Although spring precipitation is known to limit radial growth in P. sylvestris exposed to a dry inner Alpine climate, the results of this study revealed that (i) a daily minimum air temperature threshold for onset of xylem growth in the range 5-6 degrees C exists and (ii) air temperature sum rather than precipitation or soil temperature triggers start of xylem growth. Based on these findings, we suggest that drought stress forces P. sylvestris to draw upon water reserves in the stem for enlargement of first tracheids after cambial resumption in spring. PMID- 21593012 TI - End-of-life care for lung cancer patients in the United States and Ontario. AB - BACKGROUND: Both the United States and Canada offer government-financed health insurance for the elderly, but few studies have compared care at the end of life for cancer patients between the two systems. METHODS: We identified care for non small cell lung cancer (NSCLC) patients who died of cancer at age 65 years and older during 1999-2003. Patients were identified from US Surveillance, Epidemiology, and End Results (SEER)-Medicare data (N = 13,533) and the Ontario Cancer Registry (N = 8100). Health claims during the last 5 months of life identified chemotherapy and emergency room use, hospitalizations, and supportive care. We estimated rates per person-months (PM) for short-term survivors (died <6 months after diagnosis) and longer-term survivors (died >=6 months after diagnosis), adjusting for demographic differences. To test whether monthly rates in Ontario were statistically significantly different from the United States, standardized differences were computed, and a 99% confidence interval (CI) was constructed to account for the multiple tests performed. All statistical tests were two-sided. RESULTS: Rates of chemotherapy use were statistically significantly higher for SEER-Medicare patients than Ontario patients in every month before death (short-term survivors at 5 months before death: SEER-Medicare, 33.2 patients per 100 PM vs Ontario, 9.5 per 100 PM, rate difference = 23.7 per 100 PM, 99% CI = 18.3 to 29.1 per 100 PM, P < .001; longer-term survivors at 5 months before death: SEER-Medicare, 24.4 patients per 100 PM vs Ontario, 14.5 per 100 PM, rate difference = 9.9 per 100 PM, 99% CI = 7.7 to 12.1 per 100 PM, P <. 001). During the last 30 days of life, fewer SEER-Medicare than Ontario patients were hospitalized (short-term survivors, 49.9 vs 78.6 patients per 100 PM, rate difference = 28.6 per 100 PM, 95% CI = 22.9 to 34.4 per 100 PM, P <. 001; longer term survivors, 44.1 vs 67.1 patients per 100 PM, rate difference = 23.0 per 100 PM, 95% CI = 18.5 to 27.5 per 100 PM, P < .001). CONCLUSIONS: NSCLC patients in both Ontario and the United States used extensive end-of-life care. Limited availability of hospice care in Ontario and differing attitudes between the United States and Ontario regarding end-of-life care may explain the differences in practice patterns. PMID- 21593013 TI - fNIRS study of walking and walking while talking in young and old individuals. AB - BACKGROUND: Evidence suggests that gait is influenced by higher order cognitive and cortical control mechanisms. However, less is known about the functional correlates of cortical control of gait. METHODS: Using functional near-infrared spectroscopy, the current study was designed to evaluate whether increased activations in the prefrontal cortex (PFC) were detected in walking while talking (WWT) compared with normal pace walking (NW) in 11 young and 11 old participants. Specifically, the following two hypotheses were evaluated: (a) Activation in the PFC would be increased in WWT compared with NW. (b) The increase in activation in the PFC during WWT as compared with NW would be greater in young than in old participants. RESULTS: Separate linear mixed effects models with age as the two level between-subject factor, walking condition (NW vs WWT) as the two-level repeated within-subject factor, and HbO2 levels in each of the 16 functional near infrared spectroscopy channels as the dependent measure revealed significant task effects in 14 channels, indicating a robust bilateral increased activation in the PFC in WWT compared with NW. Furthermore, the group-by-task interaction was significant in 11 channels with young participants showing greater WWT-related increase in HbO2 levels compared with the old participants. CONCLUSIONS: This study provided the first evidence that oxygenation levels are increased in the PFC during WWT compared with NW in young and old individuals. This effect was modified by age suggesting that older adults may under-utilize the PFC in attention-demanding locomotion tasks. PMID- 21593014 TI - Identification of novel genes involved in sarcopenia through RNAi screening in Caenorhabditis elegans. AB - BACKGROUND: Aging in humans is characterized by a progressive loss of muscle mass and strength known as sarcopenia. Although considered to be a normal aspect of aging, the loss of strength can have significant effects on the health, functioning, and independence of elderly individuals. Although these aspects of sarcopenia have been well studied, the molecular mechanisms leading to its development are still unclear. The nematode Caenorhabditis elegans might be a novel animal model for sarcopenia as worms experience sarcopenia during aging and mutations affecting the daf-2/insulin-like signaling pathway are able to delay this process. METHODS: Via the use of RNA interference, we screened a total of 43 genes, most of which have been shown to be required for the enhanced longevity of daf-2 mutants, to assess for the effects of these genes on muscle function and worm mobility during aging. RESULTS: We identified 17 novel genes that are essential for the delay in the onset of sarcopenia in daf-2 mutants. The identified genes include splicing factors, vacuolar sorting proteins, transcription factors, and metabolic enzymes. Using a transgenic strain that only responds to RNA interference in the body wall muscle, we also found that most of the identified genes act in muscle to prevent the onset of sarcopenia. CONCLUSIONS: Our results demonstrate that at least in worms, specific genetic pathways that modify the development of sarcopenia can be identified. Interestingly, almost all the identified genes also have a known human homolog, and hence, our findings may offer significant leads toward the identification of genes involved in sarcopenia in people. PMID- 21593015 TI - Reach distance but not judgment error is associated with falls in older people. AB - BACKGROUND: Reaching is a vital action requiring precise motor coordination and attempting to reach for objects that are too far away can destabilize balance and result in falls and injury. This could be particularly important for many elderly people with age-related loss of sensorimotor function and a reduced ability to recover balance. Here, we investigate the interaction between reaching ability, errors in judging reach, and the incidence of falling (retrospectively and prospectively) in a large cohort of older people. METHODS: Participants (n = 415, 70-90 years) had to estimate the furthest distance they could reach to retrieve a broomstick hanging in front of them. In an iterative dialog with the experimenter, the stick was moved until it was at the furthest distance they estimated to be reached successfully. At this point, participants were asked to attempt to retrieve the stick. Actual maximal reach was then measured. The difference between attempted reach and actual maximal reach provided a measure of judgment error. One-year retrospective fall rates were obtained at initial assessment and prospective falls were monitored by monthly calendar. RESULTS: Participants with poor maximal reach attempted shorter reaches than those who had good reaching ability. Those with the best reaching ability most accurately judged their maximal reach, whereas poor performers were dichotomous and either underestimated or overestimated their reach with few judging exactly. Fall rates were significantly associated with reach distance but not with reach judgment error. CONCLUSIONS: Maximal reach but not error in perceived reach is associated with falls in older people. PMID- 21593016 TI - Preschool children's cardiac reactivity moderates relations between exposure to family violence and emotional adjustment. AB - This study examined relations between cardiac reactivity, family violence exposure (i.e., child maltreatment [CM] and inter-partner violence [IPV]), and preschool children's emotional adjustment. A sample of 92 mother-preschooler dyads was drawn from predominantly low-income, rural communities. Dyads participated in a laboratory session in which children's Electrocardiograph (ECG) monitoring occurred during a resting baseline, joint-challenge, and individual emotional and cognitive tasks. Mothers consented to review of Children & Youth Services (CYS) records for CM and completed an IPV measure. Mothers rated children's emotional adjustment, and observers rated children on their frustration and positive affect. Children's vagal suppression was shown to moderate relations between family violence exposure and emotional adjustment. Findings indicated that children greater in vagal suppression showed better emotional adjustment when from families low in violence. However, regardless of children's level of vagal suppression, all children showed poorer emotional adjustment when from families high in violence. PMID- 21593017 TI - Preventing venous thromboembolism following orthopedic surgery in the United States: impact of special populations on clinical outcomes. AB - Clinical trials of anticoagulants often exclude special populations. We assessed the proportion of special populations in real-world orthopedic surgery and the incidence of venous thromboembolism (VTE)-related outcomes. Data on patients with hip (n = 11 483) or knee replacement (n = 19 390) were extracted from IMS' PharMetrics Patient-Centric Database. There was high prevalence of patients aged >=75 years (20.3%), CYP3A4-inhibitor use (21.5%), and chronic warfarin use (9.5%). Venous thromboembolism events were increased with each increasing year of age (hip: odds ratio [OR] 1.02, 95% confidence interval [CI] = 1.01-1.03; knee: OR 1.01, 95%CI = 1.00-1.02) and chronic warfarin use (hip: OR 1.56, 95%CI = 1.13 2.17; knee: OR 1.33, 95%CI = 1.03-1.72); in hip patients with renal insufficiency (OR1.61, 95%CI=1.11-2.36); and in knee patients with atrial fibrillation (OR 1.41, 95%CI = 1.06-1.88). Major bleeding was higher in hip patients with hepatic impairment (OR 21.99, 95%CI = 2.04-236.62), each increasing year of age (OR 1.08, 95%CI = 1.01-1.15), and chronic warfarin use (OR 7.11, 95%CI = 1.16-43.46). Special populations are prevalent in real-world orthopedic surgery, which may impact VTE-related outcomes. PMID- 21593018 TI - Continuous active state of coagulation system in patients with nonthrombotic inflammatory bowel disease. AB - This study was planned for searching possible changes of the total coagulation and fibrinolysis system in inflammatory bowel disease (IBD) in order to obtain some clues for explaining the relation between IBD and hypercoagulability. A total of 24 patients with ulcerative colitis, 12 patients with Crohn disease, and 20 healthy controls were studied. Platelets; prothrombin time (PT); partial thromboplastin time (PTT); fibrinogen; D-dimer; fibrinogen degradation products; protein C; protein S; antithrombin; thrombin time; von Willebrand factor; coagulation factors V, VII, VIII, IX, XI, and XIII; plasminogen; antiplasmin; tissue plasminogen activator; plasminogen activator inhibitor 1; and prothrombin fragments 1 + 2 were studied. Most of the procoagulants (platelets, fibrinogen, von Willebrand factor, coagulation factor IX, and plasminogen activator inhibitor 1) were found increased together with decreases in some anticoagulants (protein S and antithrombin) in IBD. Also the activation markers of coagulation (D-dimer, fibrinogen degradation products, and prothrombin fragments 1 + 2) were all increased. The parameters of the total coagulation-fibrinolysis system were increased in IBD, regardless of the form and the activity of the disease. PMID- 21593019 TI - Evaluation of soluble P-selectin as a marker for the diagnosis of deep venous thrombosis. AB - OBJECTIVE: The combination of D-dimer and Wells score can exclude, but not confirm, the diagnosis of deep venous thrombosis (DVT). Since thrombosis and inflammation are interrelated, we evaluated the combination of soluble P-selectin (sPsel) with other inflammatory biomarkers for the diagnosis of DVT. METHODS: Sixty-two positive and one hundred and sixteen patients with negative DVT, by duplex scan, were prospectively evaluated for sPsel, D-dimer, C-reactive protein (CRP), microparticles (MPs; total, leukocyte, and platelet-derived and tissue factor positive microparticles), and clinical Wells score. RESULTS: Biomarkers and clinical scores that differentiated DVT positives from negatives were sPsel (87.3 vs 53.4 ng/mL, P < .0001), D-dimer (5.8 vs 2.1 mg/ L, P < .0001), CRP (2.1 vs 0.8 MUg/mL, P < .0005), and Wells score (3.2 vs 2.0, P < .0001). For MP analysis, platelet-derived MPs were found to differentiate DVT from negatives. Using multivariable logistic regression, a combination of sPsel and Wells score could establish the diagnosis of DVT (cut point >= 90 ng/mL + Wells >= 2), with a specificity of 96% and positive predictive value (PPV) of 100%, and could exclude DVT diagnosis (cut point <= 60 ng/mL and Wells <2) with a sensitivity of 99%, a specificity of 33%, and a negative predictive value (NPV) of 96%. CONCLUSION: This study establishes a biomarker and clinical profile combination that can both confirm and exclude the diagnosis of DVT. PMID- 21593020 TI - Heparin platelet factor 4 antibody positivity in pseudothrombocytopenia. AB - Pseudothrombocytopenia (PTCP) is a laboratory event of platelet clustering related to drugs used for anticoagulation. This condition is engendered by autoantibodies against platelets in usually EDTA-anticoagulated blood. Pseudothrombocytopenia has no clinical significance but when evaluated as true thrombocytopenia, this misconception may lead to unnecessary diagnostic procedures. Heparin-induced thrombocytopenia with thrombosis (HITT) is a complication of heparin treatment caused by heparin platelet factor 4 (HPF-4) antibodies, leading to platelet activation and hypercoagulability. In our study, 48 patients with PTCP and 36 healthy volunteers were included. Heparin platelet factor 4 antibody positivity was detected in 12 patients from PTCP group; nobody from control group had. Citrated serum samples and peripheral blood smears showed normal platelet count. Of the 4 patients using heparin derivative, 1 (2.1%) had antibody positivity but without any bleeding symptoms. In conclusion, HPF-4 antibody positivity might be a risk factor for PTCP. Clinicians should be aware of this kind of condition. PMID- 21593022 TI - Predictors of in-hospital mortality in patients receiving thrombolytic therapy for pulmonary embolism. AB - Predictors of in-hospital mortality from massive pulmonary embolism (PE) were retrospectively assessed in 78 patients who received thrombolytic therapy. Mortality from PE was 19% (15 of 78). Mortality from PE was higher in those with shock, 36% (12 of 33) versus no shock, 7% (3 of 45; P = .001), 21% (7 of 34) with right ventricle (RV) hypokinesis, and 20% (13 of 64) with RV enlargement. Mortality was 14% (2 of 14) with normal cardiac troponin I (cTnI), 19% (4 of 21) with intermediate cTnI, and 22% (8 of 36) with high cTnI (comparisons between groups nonsignificant [NS]). Trends with combinations of risk factors showed the highest mortality with shock plus high cTnI plus RV hypokinesis (57%) or shock plus high cTnI plus RV enlargement (54%). In conclusion, among the single risk factors, shock was associated with the highest in-hospital mortality from PE and combinations with high cTnI and RV enlargement were associated with higher mortalities. PMID- 21593021 TI - Real-world rates of in-hospital and postdischarge deep-vein thrombosis and pulmonary embolism in at-risk medical patients in the United States. AB - Hospitalized medical patients are at risk of deep-vein thrombosis (DVT) and pulmonary embolism (PE). We evaluated inpatient and postdischarge DVT/PE and thromboprophylaxis rates in US medical patients, using patient admissions from January 2005 to November 2007 in the Premier PerspectiveTM-i3 Pharma Informatics database. Among 15 721 patients with cancer, congestive heart failure, severe lung disease, and infectious disease, 39.0% received inpatient thromboprophylaxis, with the highest rate in patients with cancer (51.9%). In all, 3.4% received outpatient pharmacological prophylaxis. Mean +/- SD prophylaxis duration was 2.2 +/- 5.7 days. Overall, 3.0% of inpatients had symptomatic DVT/PE, and an additional 1.1% of patients were rehospitalized for DVT/PE or treated in the outpatient setting. Patients with infectious disease had the highest rate of DVT/PE (4.6%). Inpatient DVT/PE and prophylaxis rates of the different medical conditions had a negative correlation (R(2) = 0.72). This analysis demonstrates the burden of DVT/PE and highlights the underuse of thromboprophylaxis across the continuum of care. PMID- 21593023 TI - The impact of age on the delay in diagnosis in patients with acute pulmonary embolism. AB - It has been speculated that the atypical clinical presentation of acute pulmonary embolism (PE) in older patients leads to a late diagnosis and therefore contributes to a worse prognosis. Therefore, we prospectively evaluated the delay in diagnosis and its relation to the in-hospital mortality in 202 patients with acute PE. Patients >65 years presented more often with hypoxia (P = .017) and with a history of syncope (P = .046). Delay in diagnosis was not statistically different in both age groups. Older age was significantly associated with an increased risk for in-hospital mortality (OR 4.36, 95% CI 0.93-20.37, P = .043), whereas the delay in diagnosis was not associated with an increase of in-hospital mortality. We therefore conclude that the clinical presentation of acute PE in older patients cannot be considered as a risk factor for late diagnosis and is not responsible for their higher in-hospital death rate. PMID- 21593024 TI - Identification of patient venous thromboembolism risk across the continuum of care. AB - Venous thromboembolism (VTE) complications are the leading cause of preventable in-hospital mortality and morbidity in the United States. Initiatives by the National Quality Forum, the Joint Commission, and the Surgical Care Improvement Project aim to improve the prevention of VTE and emphasize the need to recognize the risk of the condition in hospitalized patients. In clinical practice, individual risk assessment using a validated scoring system provides patients with the best care in the prevention of VTE. This is accomplished by a weighted scoring of risk factors, selection of the most appropriate prevention strategy for patients at risk, and regular risk review across the continuum of care. All hospitals should have a local, written, care pathway which assesses inpatient risk of VTE as early as possible upon admission and identifies members of the health care team responsible for applying risk assessment. Venous thromboembolism risk should be regularly reassessed for any changes in the level of risk, with extended out-of-hospital prophylaxis considered for patients with continued risk factors, such as prolonged immobility or illness, treated at home, or in a long term care facility. Finally, a mandatory alert system requiring the clinician to address the issue of prophylaxis before any orders are carried out by the nursing staff is one way to protect all hospitalized patients. PMID- 21593025 TI - Evaluation of hypercoagulability in obese children with thrombin generation test and microparticle release: effect of metabolic parameters. AB - Obesity is associated with a hypercoagulable state. Thrombin generation test (TGT) and microparticle levels were not studied in obese children extensively. It is aimed to determine whether any differences in the coagulation system between obese and normal weighed children exist with the use of TGT and microparticles release. A total of 120 obese and 38 healthy children were included to the study. An increase of thrombin generation and microparticles levels were found in obese children. Hyperinsulinism could not find a risk factor for hypercoagulability in our obese children. None of the parameters of TGT has been shown to be related to metabolic parameters and metabolic syndrome. Microparticles release time is found to correlate only to body mass index (BMI) Standard deviation score (SDS) in obese children. Hypercoagulability is associated with childhood obesity. Significant correlation between degree of obesity and microparticles release suggested that high adipokine levels secreted from adipose tissue can stimulate procoagulant status-independent metabolic dearrangements. PMID- 21593026 TI - Health safety nets can break cycles of poverty and disease: a stochastic ecological model. AB - The persistence of extreme poverty is increasingly attributed to dynamic interactions between biophysical processes and economics, though there remains a dearth of integrated theoretical frameworks that can inform policy. Here, we present a stochastic model of disease-driven poverty traps. Whereas deterministic models can result in poverty traps that can only be broken by substantial external changes to the initial conditions, in the stochastic model there is always some probability that a population will leave or enter a poverty trap. We show that a 'safety net', defined as an externally enforced minimum level of health or economic conditions, can guarantee ultimate escape from a poverty trap, even if the safety net is set within the basin of attraction of the poverty trap, and even if the safety net is only in the form of a public health measure. Whereas the deterministic model implies that small improvements in initial conditions near the poverty-trap equilibrium are futile, the stochastic model suggests that the impact of changes in the location of the safety net on the rate of development may be strongest near the poverty-trap equilibrium. PMID- 21593027 TI - Modelling platelet-blood flow interaction using the subcellular element Langevin method. AB - In this paper, a new three-dimensional modelling approach is described for studying fluid-viscoelastic cell interaction, the subcellular element Langevin (SCEL) method, with cells modelled by subcellular elements (SCEs) and SCE cells coupled with fluid flow and substrate models by using the Langevin equation. It is demonstrated that: (i) the new method is computationally efficient, scaling as (N) for N SCEs; (ii) cell geometry, stiffness and adhesivity can be modelled by directly relating parameters to experimentally measured values; (iii) modelling the fluid-platelet interface as a surface leads to a very good correlation with experimentally observed platelet flow interactions. Using this method, the three dimensional motion of a viscoelastic platelet in a shear blood flow was simulated and compared with experiments on tracking platelets in a blood chamber. It is shown that the complex platelet-flipping dynamics under linear shear flows can be accurately recovered with the SCEL model when compared with the experiments. All experimental details and electronic supplementary material are archived at http://biomath.math.nd.edu/scelsupplementaryinformation/. PMID- 21593028 TI - Transmission and dose-response experiments for social animals: a reappraisal of the colonization biology of Campylobacter jejuni in chickens. AB - Dose-response experiments characterize the relationship between infectious agents and their hosts. These experiments are routinely used to estimate the minimum effective infectious dose for an infectious agent, which is most commonly characterized by the dose at which 50 per cent of challenged hosts become infected-the ID(50). In turn, the ID(50) is often used to compare between different agents and quantify the effect of treatment regimes. The statistical analysis of dose-response data typically makes the assumption that hosts within a given dose group are independent. For social animals, in particular avian species, hosts are routinely housed together in groups during experimental studies. For experiments with non-infectious agents, this poses no practical or theoretical problems. However, transmission of infectious agents between co housed animals will modify the observed dose-response relationship with implications for the estimation of the ID(50) and the comparison between different agents and treatments. We derive a simple correction to the likelihood for standard dose-response models that allows us to estimate dose-response and transmission parameters simultaneously. We use this model to show that: transmission between co-housed animals reduces the apparent value of the ID(50) and increases the variability between replicates leading to a distinctive all-or nothing response; in terms of the total number of animals used, individual housing is always the most efficient experimental design for ascertaining dose response relationships; estimates of transmission from previously published experimental data for Campylobacter spp. in chickens suggest that considerable transmission occurred, greatly increasing the uncertainty in the estimates of dose-response parameters reported in the literature. Furthermore, we demonstrate that accounting for transmission in the analysis of dose-response data for Campylobacter spp. challenges our current understanding of the differing response of chickens with respect to host-age and in vivo passage of bacteria. Our findings suggest that the age-dependence of transmissibility between hosts-rather than their susceptibility to colonization-is the mechanism behind the 'lag-phase' reported in commercial flocks, which are typically found to be Campylobacter free for the first 14-21 days of life. PMID- 21593029 TI - Emergent multicellular life cycles in filamentous bacteria owing to density dependent population dynamics. AB - Filamentous bacteria are the oldest and simplest known multicellular life forms. By using computer simulations and experiments that address cell division in a filamentous context, we investigate some of the ecological factors that can lead to the emergence of a multicellular life cycle in filamentous life forms. The model predicts that if cell division and death rates are dependent on the density of cells in a population, a predictable cycle between short and long filament lengths is produced. During exponential growth, there will be a predominance of multicellular filaments, while at carrying capacity, the population converges to a predominance of short filaments and single cells. Model predictions are experimentally tested and confirmed in cultures of heterotrophic and phototrophic bacterial species. Furthermore, by developing a formulation of generation time in bacterial populations, it is shown that changes in generation time can alter length distributions. The theory predicts that given the same population growth curve and fitness, species with longer generation times have longer filaments during comparable population growth phases. Characterization of the environmental dependence of morphological properties such as length, and the number of cells per filament, helps in understanding the pre-existing conditions for the evolution of developmental cycles in simple multicellular organisms. Moreover, the theoretical prediction that strains with the same fitness can exhibit different lengths at comparable growth phases has important implications. It demonstrates that differences in fitness attributed to morphology are not the sole explanation for the evolution of life cycles dominated by multicellularity. PMID- 21593030 TI - Blood flow in the rabbit aortic arch and descending thoracic aorta. AB - The distribution of atherosclerotic lesions within the rabbit vasculature, particularly within the descending thoracic aorta, has been mapped in numerous studies. The patchy nature of such lesions has been attributed to local variation in the pattern of blood flow. However, there have been few attempts to model and characterize the flow. In this study, a high-order continuous Galerkin finite element method was used to simulate blood flow within a realistic representation of the rabbit aortic arch and descending thoracic aorta. The geometry, which was obtained from computed tomography of a resin corrosion cast, included all vessels originating from the aortic arch (followed to at least their second generation) and five pairs of intercostal arteries originating from the proximal descending thoracic aorta. The simulations showed that small geometrical undulations associated with the ductus arteriosus scar cause significant deviations in wall shear stress (WSS). This finding highlights the importance of geometrical accuracy when analysing WSS or related metrics. It was also observed that two Dean-type vortices form in the aortic arch and propagate down the descending thoracic aorta (along with an associated skewed axial velocity profile). This leads to the occurrence of axial streaks in WSS, similar in nature to the axial streaks of lipid deposition found in the descending aorta of cholesterol-fed rabbits. Finally, it was observed that WSS patterns within the vicinity of intercostal branch ostia depend not only on local flow features caused by the branches themselves, but also on larger-scale flow features within the descending aorta, which vary between branches at different locations. This result implies that disease and WSS patterns in the vicinity of intercostal ostia are best compared on a branch-by-branch basis. PMID- 21593032 TI - Population genetic structure and connectivity of the harmful dinoflagellate Alexandrium minutum in the Mediterranean Sea. AB - The toxin-producing microbial species Alexandrium minutum has a wide distribution in the Mediterranean Sea and causes high biomass blooms with consequences on the environment, human health and coastal-related economic activities. Comprehension of algal genetic differences and associated connectivity is fundamental to understand the geographical scale of adaptation and dispersal pathways of harmful microalgal species. In the present study, we combine A. minutum population genetic analyses based on microsatellites with indirect connectivity (C(i)) estimations derived from a general circulation model of the Mediterranean sea. Our results show that four major clusters of genetically homogeneous groups can be identified, loosely corresponding to four regional seas: Adriatic, Ionian, Tyrrhenian and Catalan. Each of the four clusters included a small fraction of mixed and allochthonous genotypes from other Mediterranean areas, but the assignment to one of the four clusters was sufficiently robust as proved by the high ancestry coefficient values displayed by most of the individuals (>84%). The population structure of A. minutum on this scale can be explained by microalgal dispersion following the main regional circulation patterns over successive generations. We hypothesize that limited connectivity among the A. minutum populations results in low gene flow but not in the erosion of variability within the population, as indicated by the high gene diversity values. This study represents a first and new integrated approach, combining both genetic and numerical methods, to characterize and interpret the population structure of a toxic microalgal species. This approach of characterizing genetic population structure and connectivity at a regional scale holds promise for the control and management of the harmful algal bloom events in the Mediterranean Sea. PMID- 21593031 TI - Candidate genes for carotenoid coloration in vertebrates and their expression profiles in the carotenoid-containing plumage and bill of a wild bird. AB - Carotenoid-based coloration has attracted much attention in evolutionary biology owing to its role in honest, condition-dependent signalling. Knowledge of the genetic pathways that regulate carotenoid coloration is crucial for an understanding of any trade-offs involved. We identified genes with potential roles in carotenoid coloration in vertebrates via (i) carotenoid uptake (SR-BI, CD36), (ii) binding and deposition (StAR1, MLN64, StAR4, StAR5, APOD, PLIN, GSTA2), and (iii) breakdown (BCO2, BCMO1). We examined the expression of these candidate loci in carotenoid-coloured tissues and several control tissues of the red-billed quelea (Quelea quelea), a species that exhibits a male breeding plumage colour polymorphism and sexually dimorphic variation in bill colour. All of the candidate genes except StAR1 were expressed in both the plumage and bill of queleas, indicating a potential role in carotenoid coloration in the quelea. However, no differences in the relative expression of any of the genes were found among the quelea carotenoid phenotypes, suggesting that other genes control the polymorphic and sexually dimorphic variation in carotenoid coloration observed in this species. Our identification of a number of potential carotenoid genes in different functional categories provides a critical starting point for future work on carotenoid colour regulation in vertebrate taxa. PMID- 21593033 TI - Developmental modularity and phenotypic novelty within a biphasic life cycle: morphogenesis of a cone snail venom gland. AB - The venom gland of predatory cone snails (Conus spp.), which secretes neurotoxic peptides that rapidly immobilize prey, is a proposed key innovation for facilitating the extraordinary feeding behaviour of these gastropod molluscs. Nevertheless, the unusual morphology of this gland has generated controversy about its evolutionary origin and possible homologues in other gastropods. I cultured feeding larvae of Conus lividus and cut serial histological sections through the developing foregut during larval and metamorphic stages to examine the development of the venom gland. Results support the hypothesis of homology between the venom gland and the mid-oesophageal gland of other gastropods. They also suggest that the mid-region of the gastropod foregut, like the anterior region, is divisible into dorsal and ventral developmental modules that have different morphological, functional and ontogenetic fates. In larvae of C. lividus, the ventral module of the middle foregut transformed into the anatomically novel venom gland of the post-metamorphic stage by rapidly pinching off from the main dorsal channel of the mid-oesophagus, an epithelial remodelling process that may be similar to other cases where epithelial tubes and vesicles arise from a pre-existing epithelial sheet. The developmental remodelling mechanism could have facilitated an abrupt evolutionary transition to the derived morphology of this important gastropod feeding innovation. PMID- 21593034 TI - The influence of humidity on the attachment ability of the spider Philodromus dispar (Araneae, Philodromidae). AB - Hairy attachment devices that are not supplemented with fluid secretion have evolved independently in lizards and spiders. van der Waals forces have previously been shown to be responsible for excellent adhesive properties of these structures, but it has recently been reported that wetting phenomena also play an important role in such 'dry adhesives'. To investigate the effect of ambient humidity on the attachment of the living spider Philodromus dispar, traction force was measured on a smooth epoxy resin surface at relative humidities (RHs) of 15, 50, 70, 80 and 99 per cent. The results show that attachment ability is significantly higher at an intermediate humidity compared with that in a dry atmosphere and at high humidity. Water condensation on the substrate surface almost completely abolishes adhesion. Experimental results obtained may be explained by an increase in capillarity or changes in mechanical properties of setae and spatulae owing to water absorption by the cuticle at an intermediate RH. The results obtained show dry adhesion limits under different environmental conditions and are important for understanding spider biology. PMID- 21593035 TI - Unique genetic variation at a species' rear edge is under threat from global climate change. AB - Global climate change is having a significant effect on the distributions of a wide variety of species, causing both range shifts and population extinctions. To date, however, no consensus has emerged on how these processes will affect the range-wide genetic diversity of impacted species. It has been suggested that species that recolonized from low-latitude refugia might harbour high levels of genetic variation in rear-edge populations, and that loss of these populations could cause a disproportionately large reduction in overall genetic diversity in such taxa. In the present study, we have examined the distribution of genetic diversity across the range of the seaweed Chondrus crispus, a species that has exhibited a northward shift in its southern limit in Europe over the last 40 years. Analysis of 19 populations from both sides of the North Atlantic using mitochondrial single nucleotide polymorphisms (SNPs), sequence data from two single-copy nuclear regions and allelic variation at eight microsatellite loci revealed unique genetic variation for all marker classes in the rear-edge populations in Iberia, but not in the rear-edge populations in North America. Palaeodistribution modelling and statistical testing of alternative phylogeographic scenarios indicate that the unique genetic diversity in Iberian populations is a result not only of persistence in the region during the last glacial maximum, but also because this refugium did not contribute substantially to the recolonization of Europe after the retreat of the ice. Consequently, loss of these rear-edge populations as a result of ongoing climate change will have a major effect on the overall genetic diversity of the species, particularly in Europe, and this could compromise the adaptive potential of the species as a whole in the face of future global warming. PMID- 21593036 TI - Scaling-up anti-predator phenotypic responses of prey: impacts over multiple generations in a complex aquatic community. AB - Non-consumptive effects (NCEs) of predators owing to induced changes in prey traits are predicted to influence the structure of ecological communities. However, evidence of the importance of NCEs is limited primarily to simple systems (e.g. two to four species) over relatively short periods (e.g. less than one generation). We examined the NCEs of a fish predator, arising from phenotypic plasticity in zooplankton prey traits, over multiple generations of a diverse zooplankton community. The presence of fish, caged to remove consumptive effects, strongly influenced zooplankton community structure, through both direct and indirect NCE pathways, altering the abundance of many taxa by magnitudes as large as 3 to 10-fold. Presence of fish affected different species of cladocerans and copepods both positively and negatively. A particularly striking result was the reversal of dominance in copepod taxa: presence of fish reduced the ratio of calanoids to cyclopoids from 6.3 to 0.43. Further, the NCE of fish had a strong negative trophic cascade to zooplankton resources (phytoplankton). To our knowledge, this is the first experiment to show that NCEs can influence the abundance of multiple prey species over time spans of multiple prey generations. Our findings demonstrate that adaptive phenotypic plasticity of individuals can scale-up to affect the structure of ecological communities. PMID- 21593037 TI - Reservoirs of richness: least disturbed tropical forests are centres of undescribed species diversity. AB - In the last few decades, there has been a remarkable discovery of new species of plants, invertebrates and vertebrates, in what have been called the new age of discovery. However, owing to anthropogenic impacts such as habitat conversion, many of the still unknown species may go extinct before being scientifically documented (i.e. 'crypto-extinctions'). Here, by applying a mathematical model of species descriptions which accounts for taxonomic effort, we show that even after 250 years of taxonomic classification, about 3050 amphibians and at least 160 land mammal species remain to be discovered and described. These values represent, respectively, 33 and 3 per cent of the current species total for amphibians and land mammals. We found that tropical moist forests of the Neotropics, Afrotropics and Indomalaya probably harbour the greatest numbers of undescribed species. Tropical forests with minimal anthropogenic disturbance are predicted to have larger proportions of undescribed species. However, the protected area coverage is low in many of these key biomes. Moreover, undescribed species are likely to be at a greater risk of extinction compared with known species because of small geographical ranges among other factors. By highlighting the key areas of undescribed species diversity, our study provides a starting template to rapidly document these species and protect them through better habitat management. PMID- 21593038 TI - Empirical model estimation of relative biological effectiveness for proton beam therapy. AB - A simple model for proton relative biological effectiveness (RBE) is proposed. It describes the RBE as a function of proton depth, the dose and the linear energy transfer (LET) when proton passes through tissue-like materials. Radiobiological parameters were first obtained by fitting the published experimental cell survival data. The dose-averaged LET values were calculated for 250-MeV proton beam in a water phantom by using GEANT4 Monte Carlo simulation code and were then used as input values to calculate the values of RBE as function of depths. The model was also applied to proton spread-out Bragg peak, where the increasing RBE with depth causes an extended RBE-weighted dose in the distal fall-off region. This model was found to be able to reproduce the measured RBE values as a function of LET, depth and dose for a specific cell line. PMID- 21593039 TI - An epidemic of atrial fibrillation? PMID- 21593040 TI - Pulmonary vein variants predispose to atrial fibrillation: a case-control study using multislice contrast-enhanced computed tomography. AB - AIMS: Pulmonary veins (PV) play a pivotal role in atrial fibrillation (AF). Anatomical variants of PV have been described and related to a higher arrhythmogenic potential. The aim of this study was to compare the prevalence of PV variants and diameters of PV ostia in AF patients and controls. METHODS AND RESULTS: Variants of PV were defined as right or left common ostia (RCO, LCO), a right middle or right top PV . A long common trunk (LCT) was defined as an LCO with a distance to the first branching >= 10 mm. Multislice contrast-enhanced thoracic computed tomography was performed prior to AF ablation in 166 consecutive patients, 47.6% with paroxysmal, 52.4% with persistent AF, as well as in a sex- and age-matched control group without AF, for non-cardiological indications. Images were evaluated by two independent observers. The mean age was 59 +/- 10 years, 108 were men (65.1%). A higher prevalence of LCO was found in the AF group: 33.7 vs. 19.9% (P= 0.004), odds ratio (OR) 2.1; 15.4% in patients vs. 10.2% in controls had an LCT (P= 0.14). No differences in other PV variants were found. The ostial diameters were greater in AF-patients (P< 0.001). CONCLUSIONS: To the best of our knowledge, the present study shows for the first time a higher prevalence of an LCO in patients with AF as compared with controls, with an OR of 2.1. This suggests a pre-disposing role of LCO in the development of AF. PMID- 21593041 TI - Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to moderate hyperlipidaemia. AB - AIMS: Mipomersen, an apolipoprotein (apo) B synthesis inhibitor, has been shown to produce potent reductions in apoB and LDL-cholesterol levels in animal models as well as healthy human volunteers. A randomized, double-blind, placebo controlled, dose-escalation study was designed to evaluate the efficacy and safety of mipomersen monotherapy with or without dose loading in subjects with mild-to-moderate hyperlipidaemia. METHODS AND RESULTS: Fifty subjects with LDL cholesterol levels between 119 and 266 mg/dL were enrolled into five cohorts at a 4:1 randomization ratio of active to placebo. Two 13-week dose regimens were evaluated at doses ranging from 50 to 400 mg/week. Mipomersen produced dose dependent reductions in all apoB containing lipoproteins. In the 200 and 300 mg/week dose cohorts, mean reductions from baseline in LDL cholesterol were -45 +/- 10% (P= 0.000) and -61 +/- 8% (P= 0.000), corresponding to a -46 +/- 11% (P= 0.000) and -61 +/- 7% (P= 0.000) decrease in apoB levels. Triglyceride levels were also lowered with median reductions up to 53% (P= 0.021). The most common adverse events were injection site reactions. Seven of 40 subjects (18%) showed consecutive transaminase elevations >3* upper limit of normal. Five of these subjects received 400 mg/week, four of whom had apoB levels below the limit of detection. As a consequence, the 400 mg/week cohort was discontinued. CONCLUSIONS: Mipomersen administered as monotherapy in subjects with mild-to moderate hyperlipidaemia produced potent reductions in all apoB-containing lipoproteins. Higher doses were associated with hepatic transaminase increases. PMID- 21593042 TI - Emphysematous infectious aortitis: a dramatic evolution. PMID- 21593043 TI - DHEA as a miracle drug in the treatment of poor responders; hype or hope? AB - Dehydroepiandrosterone (DHEA) is being presented as a miracle-drug for the treatment of women responding poorly to gonadotrophin stimulation, while the debate on its actual effectiveness is still ongoing. We would like to present how insufficient the current evidence of acceptable quality is to warrant a conclusion that DHEA supplementation is an effective treatment for women with diminished ovarian reserve. We believe that large-scale, well-designed confirmatory studies are necessary to prove the efficacy of DHEA before it can be recommended for routine use. PMID- 21593044 TI - Germ cell numbers in human embryonic and fetal gonads during the first two trimesters of pregnancy: analysis of six published studies. AB - BACKGROUND: The number of germ cells in human embryonic and fetal ovaries in relation to age is currently based on volumetric estimations from one study including a total of 12 ovaries. Six recent publications present stereological estimations of the number of germ cells in ovaries and testes for the first two trimesters. METHODS: Germ cell numbers from 103 human first and second trimester gonads aged 37-133 days post-conception (p.c.), obtained after legal termination of pregnancy, were collected from six independent studies that all used similar validated stereological methods for estimating germ cell numbers as well as somatic cell numbers. RESULTS: Statistically, the six studies estimated similar number of germ cells (P > 0.05) and no interaction between the studies and age was found (P > 0.05), indicating that the increase in cell numbers in relation to age was of comparable magnitude in each study. The number of germ cells increased from a mean of 7200 to 4,933,000 in fetal ovaries and from 3700 to 1,417,000 in fetal testes, from week 5 to week 19 p.c. A higher rate of increase was found for female germ cells as compared with males (P = 0.004). During the same period, the number of somatic cells increased from a mean of 158,000 to 1,017,000 in ovaries and from 154,000 to 2,035,000 in testes, respectively. CONCLUSIONS By the use of validated stereological methods, this study provides more accurate and improved information on human germ and somatic cell numbers in ovaries and testes during the first two trimesters of pregnancy. PMID- 21593045 TI - Do women with ovaries of polycystic morphology without any other features of PCOS benefit from short-term metformin co-treatment during IVF? A double-blind, placebo-controlled, randomized trial. AB - BACKGROUND: Women with ovaries of polycystic morphology (PCO), without any other features of polycystic ovary syndrome (PCOS), respond similarly to women with PCOS when stimulated with exogenous gonadotrophins, and both groups share various endocrinological disturbances underlying their pathology. In women with PCOS, metformin co-treatment during IVF has been shown to increase pregnancy rates and reduce the risk of ovarian hyperstimulation syndrome (OHSS). The aim of this study was to investigate whether metformin co-treatment before and during IVF can also increase the live birth rate (LBR) and lower severe OHSS rates for women with PCO, but no other manifestations of PCOS. METHODS: This study was a double blind, multi-centre, randomized, placebo-controlled trial. The study population included 134 women with ovulatory PCO (and no evidence of clinical or biochemical hyperandrogenism) undergoing IVF treatment at three tertiary referral IVF units. The primary outcome was LBR. RESULTS: In total, 134 women were randomized, 69 to metformin and 65 to placebo. There were no statistically significant differences between the two groups in baseline characteristics. With regard to IVF outcome, no significant improvements were found in the metformin group when compared with the placebo group. In particular, there was no difference between the groups in rates of live birth [metformin n = 27 (39.1%), placebo n = 30 (46.2), (95% confidence interval 0.38, 1.49, odds ratio = 0.75)], clinical pregnancy [metformin n = 29 (42.0%), placebo n = 33 (50.8%)] or severe OHSS [metformin n = 6 (8.7%), placebo n = 5 (7.7%)]. CONCLUSIONS: There appears to be no benefit in metformin co-treatment before and during IVF in women with PCO without any other features of PCOS. Clinical Trials.gov: NCT01046032. PMID- 21593046 TI - Reducing model complexity of the general Markov model of evolution. AB - The selection of an optimal model for data analysis is an important component of model-based molecular phylogenetic studies. Owing to the large number of Markov models that can be used for data analysis, model selection is a combinatorial problem that cannot be solved by performing an exhaustive search of all possible models. Currently, model selection is based on a small subset of the available Markov models, namely those that assume the evolutionary process to be globally stationary, reversible, and homogeneous. This forces the optimal model to be time reversible even though the actual data may not satisfy these assumptions. This problem can be alleviated by including more complex models during the model selection. We present a novel heuristic that evaluates a small fraction of these complex models and identifies the optimal model. PMID- 21593047 TI - A cell-molecular approach predicts vertebrate evolution. AB - In contrast to the conventional use of genes to determine the evolution of phenotypes, we have functionally integrated epithelial-mesenchymal interactions that have facilitated lung phylogeny and ontogeny in response to major geologic epochs. As such, this model reveals the underlying principles of lung physiology based on the evolutionary interactions between internal and external selection pressures, providing a novel understanding of lung biology. As a result, it predicts how cell-molecular changes in this process can cause disease and offers counterintuitive insights to diagnosis and treatment based on evolutionary principles. PMID- 21593049 TI - Another way of knowing: art, disease and illness experience. PMID- 21593050 TI - 'Representing' the pain of others. AB - This article argues that visual images, particularly photographs, can provide an alternative visual language to communicate pain. It suggests that selected photographs of pain placed between clinician and patient can help trigger a more collaborative approach to dialogue within the consulting room. The participatory roles of artist and clinician as well as patient in the co-construction of meaning and narrative are acknowledged. Comparing images from two projects, Perceptions of Pain and face2face, the article uses Barthes' distinction between a 'denoted' and 'connoted' message to suggest the possibility of an underlying generic iconography for pain. By drawing on selected images and audio recordings from both projects, the article demonstrates how visual images re-invigorate verbal language and vice versa. It highlights how, in placing a photograph between two people, meaning is created within a social context as much as via the configuration of signs within the photographic surface. It is suggested that a resource of pain images, such as that created in both the projects described here, could be a valuable communication tool for use in NHS pain clinics. PMID- 21593048 TI - Clinical course of ICU patients with severe pandemic 2009 influenza A (H1N1) pneumonia: single center experience with proning and pressure release ventilation. AB - BACKGROUND: A number of different modalities have been employed in addition to conventional ventilation to improve oxygenation in patients with severe 2009 pandemic influenza A (H1N1) pneumonia. Outcomes with ventilatory and rescue therapies for H1N1 influenza-related acute respiratory distress syndrome (ARDS) have been varied. A single intensive care unit (ICU) experience with management of laboratory-confirmed 2009 pandemic influenza A (H1N1) ARDS with a combination of proning and airway pressure release ventilation (APRV) is described. METHODS: A retrospective review of medical records of ICU patients seen at Utah Valley Regional Medical Center during the first and second waves of the H1N1 influenza pandemic was done. RESULTS: Fourteen ICU patients were managed with invasive ventilation for 2009 pandemic influenza A (H1N1)-related ARDS. Hypoxemia refractory to conventional ventilation was noted in 11 of 14 patients despite application of APRV. Following proning in patients on APRV, improvement of hypoxemia and hemodynamic status was achieved. Only 2 of 11 patients on APRV and proning required continuous dialysis. Mortality in intubated patients receiving a combination of proning and APRV was 27.3% (3/11) with 2 of these dying during the first wave of the H1N1 influenza pandemic. In all, 3 of 11 patients on proning and APRV underwent tracheostomy, with 2 of these undergoing tube thoracostomy. ARDSnet fluid-conservative protocol was safely tolerated in 8 of 11 of the intubated patients following initiation of proning and APRV. CONCLUSIONS: Proning in combination with APRV provides improvement of hypoxemia with limitation of end organ dysfunction and thereby facilitates recovery from severe 2009 pandemic influenza A (H1N1). PMID- 21593051 TI - Speaking to the dead: images of the dead in contemporary art. AB - In this article I explore works by three artists in which we can see images that relate to bereavement. In the work of the first two, Araya Rasdjarmrearnsook and Andres Serrano, we can see photographic images (still and moving) of human corpses, which have been criticized as morbid and unhealthy. However I argue that it is not in fact images of death or the dead that are problematic but those images which present or evoke evidence of the emotions associated with death, and create a situation where we imagine the circumstances of our own deaths or the death of those we love. Images of the dead are acceptable as long as they do not cause pain to the living, as in a video game fantasy or a fiction, or are seen as other and distant. In the second group of works, by Gustgav Metzger, The Absent Dead: The Surrogate Body, the body is not present either because the death has taken place at a distance, either in time or geographically, or both, and a new site must be created. In this section, I discuss Metzger's auto-destructive art and argue that these works, through their ephemerality, embody a form of 'meaning making' and a possibility of the benefits of grief as described by Parkes. PMID- 21593052 TI - Disseminated Salmonella osetomyelitis in a 2-year-old with sickle cell disease. PMID- 21593053 TI - Thoracic tumor mimicking pneumonia. PMID- 21593054 TI - Childhood abuse in pediatric patients with chronic daily headache. PMID- 21593056 TI - Tyr219 of human matrix metalloproteinase 7 is not critical for catalytic activity, but is involved in the broad pH-dependence of the activity. AB - Human matrix metalloproteinase 7 (MMP-7) exhibits a broad bell-shaped pH dependence with the acidic and alkaline pK(e) (pK(e1) and pK(e2)) values of about 4 and 10. Its active-site tyrosyl residue, Tyr219, is conserved in all other MMPs, and thus has been thought for the ionizable group responsible for pK(e2). In this study, we examined the mutational effects of Tyr219 on enzyme activity. Five Tyr219 variants, Y219F (Tyr219 is replaced with Phe), Y219D, Y219A, Y219C and Y219S, were constructed by site-directed mutagenesis. In the hydrolysis of (7 methoxycoumarin-4-yl)acetyl-l-Pro-l-Leu-Gly-l-Leu-[N(3)-(2,4-dinitrophenyl)-l-2,3 diaminopropionyl]-l-Ala-l-Arg-NH(2), all five variants retained the activity, indicating that Tyr219 is not the ionizable group responsible for pK(e2). Unexpectedly, all five variants exhibited narrower pH-dependence than the wild type MMP-7, with the pK(e1) and pK(e2) values in the range of 5.2-5.4 and 8.6 9.4, respectively. Such pH-dependence shifts were not observed in other active site tyrosyl-residue variants, Y193F and Y216F. These results suggest that Tyr219 is not critical for catalytic activity, but is involved in the broad pH dependence of the activity. PMID- 21593057 TI - Crystal structure of the tandem-type universal stress protein TTHA0350 from Thermus thermophilus HB8. AB - The genome sequence of an extremely thermophilic bacterium, Thermus thermophilus HB8, revealed that TTHA0350 is a tandem-type universal stress protein (Usp) consisting of two Usp domains. Usp proteins, which are characterized by a conserved domain consisting of 130-160 amino acids, are inducibly expressed under a large number of stress conditions. The N-terminal domain of TTHA0350 contains a motif similar to the consensus ATP-binding one (G-2 x-G-9x-G-(S/T)), but the C terminal one seems to lack the consensus motif. In order to determine its structural properties, we determined the crystal structures of TTHA0350 in the unliganded form and TTHA0350*2ATP at 2.50 and 1.70 A resolution, respectively. This is the first structure determination of a Usp family protein in both unliganded and ATP-liganded forms. TTHA0350 is folded into a fan-shaped structure which is similar to that of tandem-type Usp protein Rv2623 from Mycobacterium tuberculosis. However, the dimer assembly with C2-symmetry in TTHA0350 is quite different from that with D2-symmetry in Rv2623. The X-ray structure showed that not only the N-terminal but also the C-terminal domain binds one ATP, although the ATP-binding motif could not be detected in the C-terminal domain. The loop interacting with ATP in the C-terminal domain is in a conformation quite different from that in the N-terminal domain. PMID- 21593058 TI - Using a Smartphone while walking: a measure of dual-tasking ability as a falls risk assessment tool. PMID- 21593059 TI - Difficulty and discrimination parameters of Boston naming test items in a consecutive clinical series. AB - The Boston Naming Test is one of the most widely used neuropsychological instruments; yet, there has been limited use of modern psychometric methods to investigate its properties at the item level. The current study used Item response theory to examine each item's difficulty and discrimination properties, as well as the test's measurement precision across the range of naming ability. Participants included 300 consecutive referrals to the outpatient neuropsychology service at Mayo Clinic in Florida. Results showed that successive items do not necessarily reflect a monotonic increase in psychometric difficulty, some items are inadequate to distinguish individuals at various levels of naming ability, multiple items provide redundant psychometric information, and measurement precision is greatest for persons within a low-average range of ability. These findings may be used to develop short forms, improve reliability in future test versions by replacing psychometrically poor items, and analyze profiles of intra individual variability. PMID- 21593061 TI - Assessment of uncertainty in functional-structural plant models. AB - BACKGROUND AND AIMS: Constructing functional-structural plant models (FSPMs) is a valuable method for examining how physiology and morphology interact in determining plant processes. However, such models always have uncertainty concerned with whether model components have been selected and represented effectively, with the number of model outputs simulated and with the quality of data used in assessment. We provide a procedure for defining uncertainty of an FSPM and how this uncertainty can be reduced. METHODS: An important characteristic of FSPMs is that typically they calculate many variables. These can be variables that the model is designed to predict and also variables that give indications of how the model functions. Together these variables are used as criteria in a method of multi-criteria assessment. Expected ranges are defined and an evolutionary computation algorithm searches for model parameters that achieve criteria within these ranges. Typically, different combinations of model parameter values provide solutions achieving different combinations of variables within their specified ranges. We show how these solutions define a Pareto Frontier that can inform about the functioning of the model. KEY RESULTS: The method of multi-criteria assessment is applied to development of BRANCHPRO, an FSPM for foliage reiteration on old-growth branches of Pseudotsuga menziesii. A geometric model utilizing probabilities for bud growth is developed into a causal explanation for the pattern of reiteration found on these branches and how this pattern may contribute to the longevity of this species. CONCLUSIONS: FSPMs should be assessed by their ability to simulate multiple criteria simultaneously. When different combinations of parameter values achieve different groups of assessment criteria effectively a Pareto Frontier can be calculated and used to define the sources of model uncertainty. PMID- 21593060 TI - Auditory memory decrements, without dissimulation, among patients with major depressive disorder. AB - Questions have been raised about whether poor performance on memory tasks by individuals with major depressive disorder (MDD) might be the result of poor or variable effort or disease-related disruption of neural circuits supporting memory functions. The present study examined performance on a measure of task engagement and on an auditory memory task among 45 patients with MDD (M age = 47.82, SD = 19.55) relative to 32 healthy controls (HC; M age = 51.03, SD = 22.09). One-hundred percent of HC and MDD volunteers performed above the threshold for adequate effort on a formal measure of task engagement. The MDD subjects performed significantly more poorly than the HC subjects on an auditory learning and memory test. The present results suggest that auditory memory difficulties do occur among those with MDD and that decrements in performance in this group may be related to factors other than lack of effort. PMID- 21593062 TI - Dynamics of polyploid formation and establishment in the allotetraploid rock fern Asplenium majoricum. AB - BACKGROUND AND AIMS: Successful establishment of newly formed polyploid species depends on several interlinked genetic and ecological factors. These include genetic diversity within and among individuals, chromosome behaviour and fertility, novel phenotypes resulting from novel genomic make-up and expression, intercytotypic and interspecific competition, and adaptation to distinct habitats. The allotetraploid rock fern Asplenium majoricum is known from one small population in Valencia, Spain, and several larger populations on the Balearic island of Majorca. In Valencia, it occurs sympatrically with its diploid parents, A. fontanum subsp. fontanum and A. petrarchae subsp. bivalens, and their diploid hybrid A. * protomajoricum. This highly unusual situation allowed the study of polyploid genetic diversity and its relationship to the formation and establishment of nascent polyploid lineages. METHODS: Genetic variation for isozyme and chloroplast DNA markers was determined for A. majoricum and A. * protomajoricum sampled thoroughly from known sites in Majorca and Valencia. Results were compared with variation determined previously for the diploid parent taxa. KEY RESULTS: A highly dynamic system with recurring diploid hybrid and allotetraploid formation was discovered. High diversity in the small Valencian A. majoricum population indicates multiple de novo origins from diverse parental genotypes, but most of these lineages become extinct without becoming established. The populations on Majorca most probably represent colonization(s) from Valencia rather than an in situ origin. Low genetic diversity suggests that this colonization may have occurred only once. CONCLUSIONS: There is a striking contrast in success of establishment of the Majorcan and Valencian populations of A. majoricum. Chance founding of populations in a habitat where neither A. fontanum subsp. fontanum nor A. petrarchae subsp. bivalens occurs appears to have been a key factor enabling the establishment of A. majoricum on Majorca. Successful establishment of this polyploid is probably dependent on geographic isolation from diploid progenitor competition. PMID- 21593063 TI - Cyclophosphamide-refractory scleroderma-associated interstitial lung disease: remarkable clinical and radiological response to a single course of rituximab combined with high-dose corticosteroids. AB - We would like to report our experience of using rituximab in cyclophosphamide refractory, rapidly progressive interstitial lung disease (ILD) in a patient with limited scleroderma. A 40-year-old man presented with 10-week history of inflammatory polyarthritis, which responded to a short course of oral corticosteroids. However, 3 weeks later, he developed new onset of exertional dyspnoea. High-resolution CT of the thorax was suggestive of early ILD. Surgical lung biopsy showed features of fibrotic non-specific interstitial pneumonia. He was diagnosed with scleroderma on the basis of: presence of anticentromere antibodies, Raynaud's phenomenon, pulmonary fibrosis, digital oedema and hypomotility along with a dilated oesophagus. He was treated aggressively with pulse doses of corticosteroids and cyclophosphamide; however, his ILD continued to deteriorate. At this stage, he received rituximab (two pulses of 1 g each), which led to a gradual clinical improvement. Now, 12 months since his rituximab infusion, he walks 2 miles daily without any exertional dyspnoea. PMID- 21593064 TI - Relapsing polychondritis: a new adverse event secondary to the use of tumour necrosis factor antagonists? PMID- 21593065 TI - Failures of the RM finger prosthesis joint replacement system. AB - In our unit a high failure rate of the RM finger prosthesis joint replacement system was noted, prompting a review of cases. A series of patients underwent implantation under the care of one surgeon and the results were monitored. Twenty one devices were implanted of which 16 were inserted for rheumatoid disease. Patients were reviewed regularly and the implant performance was assessed critically along with survival of the implant to revision, infection or death of the patient. The mean follow-up was 32 months. Unacceptable failure rates at early and medium term stages were identified, with 15 of the implants revised by 2 years. Loosening was the commonest mode of failure. The authors do not recommend the use of this implant, especially in cases of rheumatoid arthritis. PMID- 21593066 TI - Koebner phenomenon following steroid injection for trigger finger. PMID- 21593067 TI - How to prevent the avulsed soft tissues from wrapping around the K-wire. PMID- 21593068 TI - Intraosseous xanthoma of the hand without an underlying lipid disorder. PMID- 21593070 TI - Effects of forearm muscles on carpal stability. AB - Thirty cadaveric forearms were tested using a wrist testing apparatus specifically designed to investigate the mechanisms of muscle stabilization of the wrist. The specimens were set in a jig allowing the distal row to migrate proximally and to rotate around the pronosupination forearm axis. Five wrist motor tendons (FCR, FCU, ECU, ECRL and APL) were loaded with specific weights. Reactive rotations of the scaphoid, triquetrum and capitate were measured by an electromagnetic motion tracking device. When all five tendons were loaded simultaneously, the capitate supinated and the proximal row predominantly supinated and flexed. By contrast, when the ECU was loaded in isolation, it caused pronation to both proximal and distal rows. The FCR exhibited a mixed effect pronating the capitate and triquetrum, whilst supinating the scaphoid. Based on this, a hypothesis is proposed linking wrist stability to the balance of wrist pronators (ECU and FCR) and supinators (FCU, ECRL and APL). PMID- 21593069 TI - Fractures of the distal radius in women aged 50 to 75 years: natural course of patient-reported outcome, wrist motion and grip strength between 1 year and 2-4 years after fracture. AB - Fractures of the distal radius in postmenopausal women may cause prolonged pain and disability, but little is known about their natural course beyond the first year. In this study, women of 50-75 years of age, initially treated with cast or external fixation, were examined 1 year after distal radial fracture and then re evaluated after a mean of 3 (range, 2-4) years. The evaluation included pain, disability (DASH) scores, grip strength and range of motion. In the 49 participating women pain scores, grip strength and range of motion improved significantly, although the mean improvement was moderate or small. In a subgroup of 13 patients with moderate or severe malunion, the 1 year DASH score was significantly worse than in the remaining patients but improved significantly together with grip strength and range of motion. After fractures of the distal radius, pain, grip strength and range of motion continued to improve beyond 1 year, up to 2-4 years. Patients with malunion had more disability at 1 year but showed significant improvement at 2-4 years. PMID- 21593071 TI - Novel method for wound exposure using a sutureless, self-retaining system. PMID- 21593072 TI - Ten years follow-up of health and disability in people with acute traumatic hand injury: pain and cold sensitivity are long-standing problems. AB - The aim of this study was to investigate health and disability in people with acute traumatic hand injury 10 years after the accident. A consecutive sample of patients from the Department of Hand Surgery was followed up by means of a postal questionnaire containing the instruments EQ-5D for assessment of health and DASH for assessment of disability. Questions were added about cold sensitivity, numbness and aesthetic problems. The 97 people with various acute hand injuries had greater problems with impairments of hand function than with limitations of activities and participation in daily life. Pain was more common than among the general Swedish population. Cold sensitivity was reported by 78% and was associated with both worse impairments and greater limitations on activity and participation. Despite problems with pain and cold sensitivity, they reported good health and a low degree of disability. PMID- 21593073 TI - Percutaneous needle fasciotomy for primary Dupuytren's contracture. AB - This study evaluated the effect of percutaneous needle fasciotomy on primary Dupuytren's contracture in 149 patients (213 rays) admitted to our clinic in 2007. Ninety-two patients (130 rays) were followed up for 2 years to compare the change in total passive extension deficit and the passive extension deficit across the individual joint and to note side effects. No tendon rupture or damage to sensory nerves was observed and the rehabilitation period was short (mean, 0.6 days). We found a significant change (p < 0.001) in total passive extension deficit after 2 years, but the effect of the treatment was greater in Tubiana I and II stages and our best results were in correction of MCP joint contractures. Percutaneous needle fasciotomy is an alternative treatment for elderly patients with severe comorbidity or for those patients who do not want open surgery. PMID- 21593074 TI - Accuracy of intrasheath injection techniques for de Quervain's disease: a cadaveric study. AB - The purpose of this study was to assess the accuracy of injections of dye into the first extensor compartment of the wrist using three different techniques in 150 wrists in 75 fresh cadavers. To compare injections, 50 wrists from 25 cadavers were used for each technique. After the injections, the first extensor compartment was dissected and the dispersion of dye around the abductor pollicis longus and extensor pollicis brevis tendons was investigated. In 72 % of all the wrists, acrylic dye was dispersed into one compartment containing both the abductor pollicis longus and extensor pollicis brevis tendons, but in 28% of the wrists there was a separate compartment for extensor pollicis brevis and dye entered only one of the compartments (14% for each compartment). For accurate injections, we think the injections should be made separately over the two tendons, to allow for the possibility of a septum within the compartment. PMID- 21593076 TI - Female sex worker typology: too complicated to be used pragmatically. PMID- 21593077 TI - Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index. AB - BACKGROUND: Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers. METHODS: We stratified nine European study samples by smoking status and, in each stratum, analysed the association between genotype of the 15q25 SNP, rs1051730, and BMI. We meta-analysed the results (n = 24,198) and then tested for a genotype * smoking status interaction. RESULTS: There was no evidence of association between BMI and genotype in the never smokers {difference per T-allele: 0.05 kg/m(2) [95% confidence interval (95% CI): -0.05 to 0.18]; P = 0.25}. However, in ever smokers, each additional smoking-related T-allele was associated with a 0.23 kg/m(2) (95% CI: 0.13-0.31) lower BMI (P = 8 * 10(-6)). The effect size was larger in current [0.33 kg/m(2) lower BMI per T-allele (95% CI: 0.18-0.48); P = 6 * 10(-5)], than in former smokers [0.16 kg/m(2) (95% CI: 0.03-0.29); P = 0.01]. There was strong evidence of genotype * smoking interaction (P = 0.0001). CONCLUSIONS: Smoking status modifies the association between the 15q25 variant and BMI, which strengthens evidence that smoking exposure is causally associated with reduced BMI. Smoking cessation initiatives might be more successful if they include support to maintain a healthy BMI. PMID- 21593079 TI - Ultrastructure of Felis catus whole fetus (Fcwf-4) cell culture following infection with feline coronavirus. AB - Feline coronavirus (FCoV) consists of two biotypes based on their growth in cell culture and their antigenicity. Infections with FCoV are highly prevalent in the cat population worldwide. In this study, Felis catus whole fetus (Fcwf-4)cell culture was infected with FCoV UPM11C/08. Virus multiplication in cell culture was monitored and examined under the transmission electron microscope. The virus particles revealed the characteristic morphology of feline FCoV represented by envelope viruses surrounded by peplomers. Virus attachment and entry into the cell occurred 15 h post-infection (pi), and the myriad of virus particles were observed both extracellularly and intracellularly after 48 h pi. Thereafter, intracellular virus particles were observed to be present in vacuoles or present freely in the cytoplasm. PMID- 21593078 TI - Cohort Profile: the international epidemiological databases to evaluate AIDS (IeDEA) in sub-Saharan Africa. PMID- 21593080 TI - ParkDB: a Parkinson's disease gene expression database. AB - Parkinson's disease (PD) is a common, adult-onset, neuro-degenerative disorder characterized by the degeneration of cardinal motor signs mainly due to the loss of dopaminergic neurons in the substantia nigra. To date, researchers still have limited understanding of the key molecular events that provoke neurodegeneration in this disease. Here, we present ParkDB, the first queryable database dedicated to gene expression in PD. ParkDB contains a complete set of re-analyzed, curated and annotated microarray datasets. This resource enables scientists to identify and compare expression signatures involved in PD and dopaminergic neuron differentiation under different biological conditions and across species. Database URL: http://www2.cancer.ucl.ac.uk/Parkinson_Db2/ PMID- 21593081 TI - 2010 Survey on cell phone use while performing cardiopulmonary bypass. AB - Cell phone use in the U.S. has increased dramatically over the past decade and text messaging among adults is now mainstream. In professions such as perfusion, where clinical vigilance is essential to patient care, the potential distraction of cell phones may be especially problematic. However, the extent of this as an issue is currently unknown. Therefore, the purpose of this study was to (1) determine the frequency of cell phone use in the perfusion community, and (2) to identify concerns and opinions among perfusionists regarding cell phone use. In October 2010, a link to a 19-question survey (surveymonkey.com) was posted on the AmSECT (PerfList) and Perfusion.com (PerfMail) forums. There were 439 respondents. Demographic distribution is as follows; Chief Perfusionist (30.5%), Staff Perfusionist (62.0%), and Other (7.5%), with age ranges of 20-30 years (14.2%), 30-40 years (26.5%), 40-50 years (26.7%), 50-60 years (26.7%), >60 years (5.9%). The use of a cell phone during the performance of cardiopulmonary bypass (CPB) was reported by 55.6% of perfusionists. Sending text messages while performing CPB was acknowledged by 49.2%, with clear generational differences detected when cross-referenced with age groups. For smart phone features, perfusionists report having accessed e-mail (21%), used the internet (15.1%), or have checked/posted on social networking sites (3.1%) while performing CPB. Safety concerns were expressed by 78.3% who believe that cell phones can introduce a potentially significant safety risk to patients. Speaking on a cell phone and text messaging during CPB are regarded as "always an unsafe practice" by 42.3% and 51.7% of respondents, respectively. Personal distraction by cell phone use that negatively affected performance was admitted by 7.3%, whereas witnessing another perfusionist distracted with phone/text while on CPB was acknowledged by 33.7% of respondents. This survey suggests that the majority of perfusionists believe cell phones raise significant safety issues while operating the heart-lung machine. However, the majority also have used a cell phone while performing this activity. There are clear generational differences in opinions on the role and/or appropriateness of cell phones during bypass. There is a need to further study this issue and, perhaps, to establish consensus on the use of various communication modes within the perfusion community. PMID- 21593082 TI - Near Infrared Spectroscopy during pediatric cardiac surgery: errors and pitfalls. AB - As a result of improvements in early outcomes, long-term neurologicalal outcomes are becoming a major issue in pediatric cardiac surgery. The mechanisms of brain injury are numerous, but a vast majority of injuries are impervious to therapy and only a few are modifiable. The quality of perfusion during cardiac surgery is a modifiable factor and cerebral monitoring during bypass is the way to assess the quality of intra-operative cerebral perfusion. Near infrared spectroscopy (NIRS), as a diagnostic tool, has gained in popularity within the perfusion community. However, NIRS is becoming the standard of care before its scientific validation. This manuscript relates four clinical cases, demonstrating the limitations of NIRS monitoring during pediatric cardiac surgery as well as uncertainties about the interpretation of the recorded values. The clinical relevance of cerebral oxymetry is needed before the use of NIRS as a decision making tool. Multimodal brain monitoring with NIRS, trans-cranial Doppler and electroencephalogram are currently under way in several pediatric centers. The benefit of this time-consuming and expensive monitoring system has yet to be demonstrated. PMID- 21593083 TI - Temperature management and monitoring practices during adult cardiac surgery under cardiopulmonary bypass: results of a Canadian national survey. AB - BACKGROUND: Mild to moderate systemic hypothermia is commonly used as a cerebral protective strategy during adult cardiac surgery. The benefits of this strategy for routine cardiac surgery have been questioned and the adverse effects of hyperthermia demonstrated. The purpose of the present study was to examine current temperature management and monitoring practices during adult cardiac surgery using CPB in Canada. METHODS: Web-based survey referring to adult cases undergoing cardiac surgery using CPB without the use of deep hypothermic circulatory arrest. Thirty-two questionnaires were completed, representing a 100% response rate. RESULTS: The usual management is to cool patients during CPB at 30 (94%) centers for low-risk (isolated primary CABG) cases and at 31 (97%) centers for high-risk (all other) cases. The average nadir temperature at the target site achieved on CPB is 34 degrees C (range 28 degrees C - 36 degrees C). At 26 (81%) centers, patients are typically rewarmed to a target temperature between 36 degrees C and 37 degrees C before separation from CPB. Only 6 (19%) centers reported that thermistors and coupled devices used to monitor blood temperature are checked for accuracy or calibrated according to the product operating directive's schedule or more often. CONCLUSIONS: Contemporary management of adult cardiac surgery under CPB still involves induction of mild to moderate systemic hypothermia. Significant practice variation exists across the country with respect to target temperatures for cooling and rewarming, as well as the site for temperature monitoring. This probably reflects the lack of definitive evidence. There is a need for well-conducted clinical trials to provide more robust evidence regarding temperature management. PMID- 21593084 TI - Occupational exposure to sevoflurane during cardiopulmonary bypass. AB - Volatile anaesthetic agents are widely used for maintenance of anaesthesia in all kinds of surgical procedures. Despite the implementation of measures such as adequate ventilation of the operating room and the use of efficient scavenging systems, concern remains about the risks for occupational exposure, especially in situations associated with an increased risk of anaesthetic gas waste, such as with the use of volatile anaesthetic agents on cardiopulmonary bypass. The present contribution reports the results of a preliminary safety assessment involving measurements of sevoflurane concentrations in the ambient air of a cardiac surgery operating room. In 22 cardiac surgical procedures with cardiopulmonary bypass (11 with open and 11 with closed venous reservoir), measurements of trace concentrations were obtained every 10 min at the following sites: at the outlet of the oxygenator, at the outlet of the cardiotomy reservoir, in the breathing zone of the perfusionist and above the surgical field. The concentrations were measured on-line using a photoacoustic infrared spectrometer. Mean sevoflurane waste concentrations remained consistently below the recommended target value of 4.68 ppm throughout the observation period at the different measurement sites. These results indicate that, with the use of sevoflurane on cardiopulmonary bypass, the recommended levels for occupational exposure are not exceeded, provided adequate operation room ventilation and waste gas scavenging is performed. PMID- 21593085 TI - Retrograde autologous priming reduces transfusion requirements in coronary artery bypass surgery. AB - The hypothesis was tested whether retrograde autologous priming (RAP) of the cardiopulmonary bypass system, compared to a standard primed system (NON-RAP group), results in less haemodilution and less transfusion of packed red blood cells. Retrospectively, data was collected from the medical charts of one hundred patients undergoing elective coronary artery bypass grafting using cardiopulmonary bypass. Fifty patients where RAP was used have been compared to fifty patients using NON-RAP. The prime volume in the NON-RAP group was 1,627+/ 108 mL versus 782+/-96 mL in the RAP group (p<0.001). The lowest haematocrit during perfusion was 22% in the NON-RAP group versus 26% when the RAP technique was used (p<0.001). In the NON-RAP group, 26% of the patients received packed red cells in contrast to 6% in the RAP group (p<0.012). A positive association was found between RAP and less transfusion of packed red blood cells (p<0.012). In conclusion, retrograde autologous priming, reducing the prime volume of the cardiopulmonary bypass system, causes less haemodilution and reduces intraoperative transfusion of packed red blood cells. PMID- 21593086 TI - Scintigraphic parameters with emphasis on perfusion appraisal in rest 99mTc sestamibi SPECT in the recovery of myocardial function after thrombolytic therapy in patients with ST elevation myocardial infarction (STEMI). AB - INTRODUCTION: This study was performed to determine the clinical application of rest 99mTc-sestamibi in the assessment of viability and functional improvement of the left ventricle (LV) myocardium in the post-thrombolytic therapy of acute myocardial infarction (AMI). MATERIAL AND METHODS: In 37 patients with AMI who received thrombolytic therapy, 2-dimensional (2D) echocardiography, as well as the resting redistribution of 99mTc-sestamibi, was investigated, both within 1 week and 3-5 months after AMI. The predictive capacity of the perfusion percentage for myocardial function recovery was evaluated. Also, the capacities of the possible variables in the prediction of recovery of myocardial function resulting from a change in LV ejection fraction (EF) were evaluated using stepwise multiple regression analysis. RESULTS: Thirty-seven patients (30 men and 7 women; mean age: 58+/-14 years) with AMI were enrolled in the study. Redistribution was observed in 35 and 50 segments of the initial and follow-up scans, respectively. In addition, 146 segments with reverse redistribution (RR), both in the initial scan (118 segments) and the follow-up scan (86 segments), were also observed. An apparent difference in wall motion scores was seen between the initial and follow-up echocardiographs (p<0.001). Furthermore, using the optimal cut-off point of perfusion percentage in each image set, sensitivity as well as specificity and likelihood ratio (LR) for the improvement of regional wall motion after 3-5 months were defined. CONCLUSION: These data showed that redistribution and reverse redistribution of 99mTc-sestamibi post thrombolytic therapy can be used as a marker of viability to predict the recovery of segmental wall motion abnormality (stunning), as well as the improvement of segmental perfusion uptake. This study also demonstrates that the resting 99mTc-sestamibi SPECT can be used for an approximate assessment of LV function status and can predict the recovery of jeopardized myocardium function after thrombolytic therapy. PMID- 21593088 TI - Investigation of an incidental finding of eosinophilia. PMID- 21593087 TI - Carboxyhemoglobinemia in a pediatric cardiopulmonary bypass patient derived from a contaminated unit of allogenic blood. AB - A 4.3 kg, three-month-old patient, diagnosed with a perimembranous ventricular septal defect, presented for cardiac surgery. Upon initiation of cardiopulmonary bypass (CPB), the patient developed carboxyhemoglobinemia (11.1%). Potential sources for the unexpected acquired carboxyhemoglobinemia were sought quickly. Testing of residual blood from the unit of packed red blood cells (PRBCs) used to prime the CPB circuit revealed a carboxyhemoglobin (COHb) of 15.1 %. A decrease in cerebral oximetry (rSO(2)) on CPB was initially felt to be a result of the elevated COHb levels. When ventilation of the oxygenator with 100% oxygen (O(2)) failed to decrease COHb levels, a partial exchange transfusion was performed with reduction in COHb to 7.1%. The operation was completed successfully and the patient's COHb levels returned to normal within 75 minutes. Post case analysis of events and data collected during the case revealed a broader differential for explaining the compromised patient's O(2) delivery than the transient acquired carboxyhemoglobinemia. A partial obstruction of the superior vena cava could have triggered the drop in rSO(2) on CPB. Follow-up of the donor blood confirmed the donor had previously undiagnosed carboxyhemoglobinemia as a result of chronic carbon monoxide exposure from a faulty vehicle exhaust system. PMID- 21593089 TI - What GPs know about asthma. PMID- 21593091 TI - How to lose friends and alienate people. PMID- 21593094 TI - Falls and fractures services in UK are "unacceptable," audit concludes. PMID- 21593095 TI - Effectiveness of insoles in treating medial osteoarthritis of the knee. PMID- 21593097 TI - Has child protection become a form of madness? Yes. PMID- 21593096 TI - Lateral wedge insoles for medial knee osteoarthritis: 12 month randomised controlled trial. AB - OBJECTIVE: To assess the effect of lateral wedge insoles compared with flat control insoles on improving symptoms and slowing structural disease progression in medial knee osteoarthritis. DESIGN: Randomised controlled trial. SETTING: Community in Melbourne, Australia. PARTICIPANTS: 200 people aged 50 or more with clinical and radiographic diagnosis of mild to moderately severe medial knee osteoarthritis. INTERVENTIONS: Full length 5 degree lateral wedged insoles or flat control insoles worn inside the shoes daily for 12 months. MAIN OUTCOME MEASURES: Primary symptomatic outcome was change in overall knee pain (past week) measured on an 11 point numerical rating scale. Primary structural outcome was change in volume of medial tibial cartilage from magnetic resonance imaging scans. Secondary clinical outcomes included changes in measures of pain, function, stiffness, and health related quality of life. Secondary structural outcomes included progression of medial cartilage defects and bone marrow lesions. RESULTS: Between group differences did not differ significantly for the primary outcomes of change in overall pain (-0.3 points, 95% confidence intervals -1.0 to 0.3) and change in medial tibial cartilage volume (-0.4 mm(3), 95% confidence interval -15.4 to 14.6), and confidence intervals did not include minimal clinically important differences. None of the changes in secondary outcomes showed differences between groups. CONCLUSION: Lateral wedge insoles worn for 12 months provided no symptomatic or structural benefits compared with flat control insoles. Trial registration Australian New Zealand Clinical Trials Registry ACTR12605000503628 and ClinicalTrials.gov NCT00415259. PMID- 21593098 TI - Has child protection become a form of madness? No. PMID- 21593099 TI - World's poorest countries can improve access to medicines through local production, says United Nations. PMID- 21593100 TI - A young man becomes short of breath and yellow. PMID- 21593101 TI - Skin defect in a bedbound patient. PMID- 21593102 TI - Making GRADE accessible: a proposal for graphic display of evidence quality assessments. AB - When generating guidelines, quality of evidence is frequently reported in tabulated form capturing several domains, for example, study design, risk of bias and heterogeneity. Increasingly, this is done using the Grading of Recommendations Assessment, Development and Evaluation approach. As assimilating large amount of tabulated data across several comparisons and outcomes spread over many pages (sometimes hundreds) is not easy, there is a need to present evidence summaries in a more effective way. A graphic display plotting the several domains used in evidence grading on equiangular spokes starting from the same point, the data length of each spoke proportional to the magnitude of the quality, succinctly captures tabulated information. These plots allow easy identification of deficiencies, outliers and similarities in evidence quality for individual and multiple comparisons and outcomes, paving the way for their routine use alongside tabulated information. PMID- 21593103 TI - The Akt-nitric oxide-cGMP pathway contributes to nerve growth factor-mediated neurite outgrowth in apolipoprotein E knockout mice. AB - Apolipoprotein E (apo)-deficient [apoE(-/-)] mice have peripheral sensory nerve defects and a reduced and delayed response to noxious thermal stimuli. However, to date, no report has focused on the influence of apoE deficiency on calcitonin gene-related peptide (CGRP)-containing nerve fiber extensions. We have shown that the density of CGRP-containing nerve fibers decreases in mesenteric arteries of apoE(-/-) mice compared with wild-type mice. Here, we investigated whether apoE deficiency is involved in nerve growth factor (NGF)-induced CGRP-containing nerve regeneration using apoE(-/-) mice. NGF-mediated CGRP-like immunoreactivity (LI) neurite outgrowth in apoE(-/-) cultured dorsal root ganglia (DRG) cells was significantly lower than that in wild-type cultures. However, the level of NGF receptor mRNA in apoE(-/-) DRG cells was similar to that in wild-type mice. To clarify the mechanism of the impaired ability of NGF-mediated neurite outgrowth, we focused on the Akt-nitric oxide (NO)-cGMP pathway. Expression of phosphorylated Akt was significantly reduced in apoE(-/-) DRG. The NO donor, sodium nitroprusside or S-nitroso-N-acetylpenicillamine, did not affect NGF mediated neurite outgrowth in apoE(-/-) cultured DRG cells. However, 8 bromoguanosine 3',5'-cyclic monophosphate sodium salt n-hydrate, a cGMP analog, induced NGF-mediated nerve facilitation similar to wild-type NGF-mediated neurite outgrowth levels. Furthermore, in apoE(-/-) DRG, soluble guanylate cyclase expression was significantly lower than that in wild-type DRG. These results suggest that in apoE(-/-) mice the Akt-NO-cGMP pathway is impaired, which may be caused by NGF-mediated CGRP-LI-neurite outgrowth defects. PMID- 21593104 TI - An integrative genomics approach identifies activation of thioredoxin/thioredoxin reductase-1-mediated oxidative stress defense pathway and inhibition of angiogenesis in obese nondiabetic human subjects. AB - CONTEXT: Obesity is a complex disease that involves both genetic and environmental perturbations to gene networks in adipose tissue and is proposed as a trigger for metabolic sequelae. OBJECTIVE: We hypothesized that expression of adipose tissue transcripts in gene networks for adaptive response would correlate with the percent fat mass (PFAT) in healthy nondiabetic subjects to maintain metabolic equilibrium and would overlap with genes modulated in response to elevated fatty acid. DESIGN, SETTINGS, AND PATIENTS: Genome-wide transcript profiles were determined in sc adipose tissue of 136 nondiabetics and in palmitate-induced cells. Genotype information and gene expression data in nondiabetic subjects were integrated to characterize the function of 41 obesity associated polymorphisms. RESULTS: Genes involved in inflammation-immune response, endoplasmic reticulum stress, and cell-extracellular matrix interactions were significantly correlated with PFAT. The NRF2 (nuclear factor erythroid 2-related factor-2)-mediated oxidative stress response pathway was strongly enriched among genes correlated with PFAT in adipose and also emerged as the most enriched pathway among genes differentially expressed by palmitate in vitro. Thioredoxin reductase-1 (TXNRD1) was the most strongly correlated gene (rho = 0.65). Genes coregulated with TXNRD1 expression indicated a significant interaction network of genes involved in thioredoxin-mediated oxidative stress defense mechanisms and angiogenesis. Pro- and antiangiogenic factors were negatively and positively correlated, respectively, with obesity. Eight obesity genome-wide association study single-nucleotide polymorphisms (SNP) were associated with expression of 10 local transcripts. SNP rs6861681 was the strongest cis-eQTL (expression quantitative trait loci) for CPEB4 (P = 3.02 * 10 9). CONCLUSIONS: Our study suggests a novel interaction of up-regulated TXN TXNRD1 system-mediated oxidative stress defense mechanisms and down-regulated angiogenesis pathways as an adaptive response in obese nondiabetic subjects. A subset of obesity-associated SNP regulated expression of transcripts as cis-eQTL. PMID- 21593105 TI - Primary hyperparathyroidism with low intact PTH levels in a 14-year-old girl. AB - CONTEXT: Primary hyperparathyroidism (PHPT) is usually associated with hypercalcemia and inappropriately elevated serum PTH. OBJECTIVE: Our objective was to identify the reason(s) for a low serum intact PTH in a child with PHPT. SUBJECT AND METHODS: A 14-yr-old Caucasian girl presented with pancreatitis, nephrolithiasis, hypercalcemia ranging from 13.2 to 17.5 mg/dl, and a low serum intact PTH. She had an ultrasound and technetium-99m-sestamibi scintigraphy confirming the presence of a parathyroid adenoma. RESULTS: The preoperative serum intact PTH assays performed at Quest Diagnostics, Nichols Institute, were low even after serial dilutions, whereas the intraoperative turbo PTH assay was elevated at 3618 pg/ml. C-terminal and cyclase-activating PTH assays for PTH were also elevated. PTH gene sequence analysis performed from DNA extracted both from the parathyroid adenoma and the patient's peripheral blood leukocytes was negative for a mutation in the PTH gene sequence. CONCLUSIONS: The contrasting values on the intact PTH assay and the turbo PTH assay suggest that the adenoma was producing an aberrant PTH molecule that was not detected by the routine intact PTH assay. Because there was no change in PTH gene sequence, this could be indicative of a posttranslational change in the PTH molecule that would not be recognized solely by DNA sequencing. Therefore, a low or normal PTH measurement against the backdrop of clinical and biochemical hyperparathyroidism needs measurement with a variety of assays. PMID- 21593106 TI - Higher acute insulin response to glucose may determine greater free fatty acid clearance in African-American women. AB - CONTEXT: Obesity and diabetes are more common in African-Americans than whites. Because free fatty acids (FFA) participate in the development of these conditions, studying race differences in the regulation of FFA and glucose by insulin is essential. OBJECTIVE: The objective of the study was to determine whether race differences exist in glucose and FFA response to insulin. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at a clinical research center. PARTICIPANTS: Thirty-four premenopausal women (17 African Americans, 17 whites) matched for age [36 +/- 10 yr (mean +/- sd)] and body mass index (30.0 +/- 6.7 kg/m2). INTERVENTIONS: Insulin-modified frequently sampled iv glucose tolerance tests were performed with data analyzed by separate minimal models for glucose and FFA. MAIN OUTCOME MEASURES: Glucose measures were insulin sensitivity index (S(I)) and acute insulin response to glucose (AIRg). FFA measures were FFA clearance rate (c(f)). RESULTS: Body mass index was similar but fat mass was higher in African-Americans than whites (P < 0.01). Compared with whites, African-Americans had lower S(I) (3.71 +/- 1.55 vs. 5.23 +/- 2.74 [*10-4 min-1/(microunits per milliliter)] (P = 0.05) and higher AIRg (642 +/- 379 vs. 263 +/- 206 mU/liter-1 . min, P < 0.01). Adjusting for fat mass, African Americans had higher FFA clearance, c(f) (0.13 +/- 0.06 vs. 0.08 +/- 0.05 min-1, P < 0.01). After adjusting for AIRg, the race difference in c(f) was no longer present (P = 0.51). For all women, the relationship between c(f) and AIRg was significant (r = 0.64, P < 0.01), but the relationship between c(f) and S(I) was not (r = -0.07, P = 0.71). The same pattern persisted when the two groups were studied separately. CONCLUSION: African-American women were more insulin resistant than white women, yet they had greater FFA clearance. Acutely higher insulin concentrations in African-American women accounted for higher FFA clearance. PMID- 21593107 TI - 18-oxocortisol measurement in adrenal vein sampling as a biomarker for subclassifying primary aldosteronism. AB - CONTEXT: 18-Oxocortisol (18-oxoF) is a derivative of cortisol (F) that is produced by aldosterone synthase (CYP11B2). The potential for this steroid as a biomarker for differentiating patients with aldosterone-producing adenoma (APA) from those with idiopathic hyperaldosteronism (IHA) has not been examined. OBJECTIVES: We measured 18-oxoF, aldosterone, and F in plasma from adrenal vein sampling (AVS) of patients with primary aldosteronism. We compared 18-oxoF levels and 18-oxoF/F ratios for their potential to differentiate APA from IHA. DESIGN, SETTING, AND SUBJECTS: This study measured 18-oxoF, F, and aldosterone in AVS obtained from patients with unilateral APA (14 cases) or bilateral IHA (seven cases, 14 samples total) using liquid chromatography-tandem mass spectrometry and RIA analyses. RESULTS: The levels of 18-oxoF and the ratios of 18-oxoF/F, before and after ACTH stimulation, were significantly higher in blood-draining APA than in those from the contralateral adrenal glands and from adrenal glands with IHA. CONCLUSIONS: The 18-oxoF levels and ratios of 18-oxoF/F in AVS samples can be a clinically useful biomarker for differentiating APA from IHA and for determining the localization or lateralization of APA in patients with primary aldosteronism. PMID- 21593108 TI - Intact primary mitochondrial function in myotubes established from women with PCOS. AB - CONTEXT: Polycystic ovary syndrome (PCOS) affects 5-8% of fertile women and is often accompanied by insulin resistance, leading to increased risk of developing type 2 diabetes. Skeletal muscle from insulin-resistant PCOS subjects display reduced expression of nuclear encoded genes involved in mitochondrial oxidative metabolism. OBJECTIVE: We aimed to investigate whether there was a primary mitochondrial dysfunction or difference in mitochondria content that might contribute to the in vivo detected insulin resistance. DESIGN: The ATP synthesis with and without ATP use and the mitochondrial mass was determined in mitochondria isolated from myotubes established from PCOS subjects and control subjects. PATIENTS: Myotubes were established from eight insulin-resistant PCOS subjects (verified by euglycemic hyperinsulinemic clamp) and eight healthy weight and age-matched controls. RESULTS: Mitochondrial mass and measurable mitochondrial ATP synthesis, with and without ATP use, were not different between PCOS subjects and control subjects. CONCLUSION: We found no evidence for a primary impaired mitochondrial function or content in myotubes established from PCOS subjects, and our results suggest that reduced expression of oxidative genes in PCOS subjects is an adaptive trait. PMID- 21593109 TI - IgG4-related hypophysitis: a new addition to the hypophysitis spectrum. AB - CONTEXT: Hypophysitis is a chronic inflammation of the pituitary gland that comprises an increasingly complex clinicopathological spectrum. Within this spectrum, lymphocytic and granulomatous hypophysitis are the most common forms, but newer variants have recently been reported. OBJECTIVE: The aims of the study were to describe a new patient with IgG4-related hypophysitis, review the published literature, and provide diagnostic criteria. SETTING: A 75-yr-old man presented with a 1-yr history of frontal headache. Initial studies revealed panhypopituitarism and a mass in both the sella turcica and the sphenoidal sinus. The patient underwent transphenoidal surgery, initiated high-dose prednisone followed by hormone replacement therapy, and was closely monitored for 3 yr. RESULTS: Symptoms improved after prednisone, along with shrinkage of the pituitary and sphenoidal masses, but recurred when prednisone dose was lowered. Histopathology showed a marked mononuclear infiltrate in both the pituitary and sphenoidal specimens, mainly characterized by increased numbers of plasma cells. Many of the infiltrating plasma cells (>10 per high-power field) were IgG4 positive. Review of the literature identified 11 cases of IgG4-related hypophysitis (two diagnosed based on pituitary histopathology). CONCLUSIONS: We describe the first Caucasian patient with biopsy-proven IgG4-related hypophysitis and provide classification criteria for this disease. PMID- 21593110 TI - Leptin therapy in a congenital leptin-deficient patient leads to acute and long term changes in homeostatic, reward, and food-related brain areas. AB - CONTEXT: Mutations that lead to congenital leptin deficiency cause severe obesity, hyperphagia, and impaired satiety due to malfunctions of peripheral and brain-related mechanisms. DESIGN AND PATIENT: In a leptin-deficient adolescent girl, we investigated brain-related changes before and at two time points after leptin therapy (3 d and 6 months). Functional magnetic resonance imaging was performed during visual stimulation with food (high and low caloric) and nonfood pictures. RESULTS: Results show acute and long-term effects in the amygdala, the orbitofrontal cortex, and the substantia nigra/ventral tegmental area for the comparison of food and nonfood pictures. For the comparison of high and low caloric pictures, pure acute effects in the ventral striatum and the orbitofrontal cortex could be observed as well as acute and long-term effects in the hypothalamus. CONCLUSION: This study gives additional insight in the influence of leptin therapy on brain functions in leptin deficiency. PMID- 21593111 TI - Skeletal fluorosis from brewed tea. AB - BACKGROUND: High fluoride ion (F(-)) levels are found in many surface and well waters. Drinking F(-)-contaminated water typically explains endemic skeletal fluorosis (SF). In some regions of Asia, however, poor quality "brick tea" also causes this disorder. The plant source of brick, black, green, orange pekoe, and oolong tea, Camellia sinensis, can contain substantial amounts of F(-). Exposure to 20 mg F(-) per day for 20 yr of adult life is expected to cause symptomatic SF. High F(-) levels stimulate osteoblasts and enhance bone apposition but substitute for OH(-) groups in hydroxyapatite crystals and thereby result in skeletal fragility and perhaps lead to secondary hyperparathyroidism. Beginning in 2005, we showed that daily consumption of 1-2 gallons of instant tea made from this plant can lead to SF. AIM: We describe a 48-yr-old American woman who developed SF from brewed tea. PATIENT AND METHODS: Our patient had elevated bone mineral density revealed by dual-energy x-ray absorptiometry (spine Z-score, +9.9), severe chronic bone and joint pain, and kyphosis after consuming 1-2 gallons of brewed orange pekoe tea daily for more than three decades. F(-) levels were high in her serum, urine, and clippings of fingernails and toenails, as well as in our reproduction of her beverage. Renal function was normal. She had vitamin D deficiency. Elevated serum PTH levels were unresponsive to adequate vitamin D supplementation. Pain resolved over several months when she stopped drinking tea and continued ergocalciferol. CONCLUSION: Our patient shows that SF can result from chronic consumption of large volumes of brewed tea. PMID- 21593113 TI - Cardiovascular complications of patients with aldosteronism associated with autonomous cortisol secretion. AB - CONTEXT: Primary aldosteronism (PA) is sometimes associated with the autonomous secretion of cortisol. OBJECTIVE: Our objective was to investigate the effect of autonomous cortisol secretion on the prevalence of cardiovascular events (CVE) in patients with PA. DESIGN: This was a retrospective cross-sectional study of cases collected from Gunma University Hospital between 2002 and 2010. PATIENTS: Seventy six consecutive patients hospitalized for an evaluation of PA were analyzed. MAIN OUTCOME MEASURES: Rates of CVE dependent on autonomous cortisol secretion were examined. RESULTS: Of the 76 patients with PA, 21 (28%) had a history of CVE, including 14 with stroke, one with myocardial infarction, and six with atrial fibrillation. The multivariate logistic-regression and receiver operating characteristic analyses revealed that PA patients with CVE had significantly higher midnight cortisol levels than those without CVE; the adjusted odds ratio with a cutoff value of 7.4 MUg/dl was 7.0 (95% confidence interval, 1.8-30.6; P = 0.006). In addition, results of the 1-mg dexamethasone suppression test with a cutoff value of 3.0 MUg/dl differed significantly (odds ratio, 5.0; 95% confidence interval, 1.4-20.7; P = 0.018). Conversely, 67 and 50% of the PA patients with a midnight cortisol level of at least 7.4 MUg/dl and 1-mg dexamethasone suppression test of at least 3.0 MUg/dl had a history of CVE. Other factors such as age, expected glomerular filtration rate, blood pressure, glucose intolerance, the serum aldosterone concentration, plasma renin activity, and the duration of hypertension had no effect. CONCLUSION: The patients with PA associated with autonomous cortisol secretion had high incidence of CVE, and this association may further increase the risk of CVE in patients with PA. PMID- 21593112 TI - Cardiovascular disease in diabetes: where does glucose fit in? AB - CONTEXT: Recent prospective clinical trials have failed to confirm a unique benefit from normalization of glycemia on cardiovascular disease outcomes, despite evidence from basic vascular biology, epidemiological, and cohort studies. EVIDENCE ACQUISITION: The literature was searched using the http://www.ncbi.nlm.nih.gov search engine including over 20 million citations on MEDLINE (1970 to present). Keyword searches included: atherosclerosis, cardiovascular, and glucose. Epidemiological, cohort, and interventional data on cardiovascular disease outcomes and glycemic control were reviewed along with analysis of recent reviews on this topic. EVIDENCE SYNTHESIS: High glucose activates a proatherogenic phenotype in all cell types in the vessel wall including endothelial cells, vascular smooth muscle cells, inflammatory cells, fibroblasts, and platelets, leading to a feedforward atherogenic response. EPIDEMIOLOGICAL AND COHORT STUDIES: Epidemiological and cohort evidence indicates a clear and consistent correlation of glycemia with cardiovascular disease. A recent report of over 25,000 subjects with diabetes in the Swedish National Diabetes Registry verifies this relationship in contemporary practice. Interventional Studies: Prospective randomized interventions targeting a hemoglobin A1c of 6-6.5% for cardiovascular disease prevention failed to consistently decrease cardiovascular events or all-cause mortality. CONCLUSIONS: Basic vascular biology data plus epidemiological and cohort evidence would predict that glucose control should impact cardiovascular events. Prospective clinical trials demonstrate that current strategies that improve blood glucose do not achieve this goal but suggest that a period of optimal control may confer long-term cardiovascular disease benefit. Clinicians should target a hemoglobin A1c of 7% for the prevention of microvascular complications, individualized to avoid hypoglycemia. PMID- 21593114 TI - The effects of ronacaleret, a calcium-sensing receptor antagonist, on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mineral density. AB - CONTEXT: Ronacaleret, a calcium-sensing receptor antagonist that stimulates PTH release from the parathyroid glands, was evaluated as an oral osteoanabolic agent for the treatment of osteoporosis. OBJECTIVE: Our objective was to compare the effects of ronacaleret, teriparatide, and alendronate on bone mineral density (BMD) and markers of bone turnover. DESIGN AND SETTING: In this randomized, placebo-controlled, dose-ranging trial, spine and hip BMD were assessed by dual energy x-ray absorptiometry and bone turnover markers were measured. PATIENTS: Patients included 569 postmenopausal women with low BMD. INTERVENTIONS: Subjects were offered open-label 20 MUg teriparatide sc once daily or were randomized to 100, 200, 300, or 400 mg oral ronacaleret once daily, 70 mg alendronate once weekly, or placebo and were followed for up to 12 months. MAIN OUTCOME MEASURE: Percentage change from baseline in lumbar spine BMD was assessed at month 12. RESULTS: With ronacaleret, the increases in lumbar spine BMD at 12 months (0.3 1.6%) were significantly lower than those attained with teriparatide (9.1%) or alendronate (4.5%). There were small decreases in total hip, femoral neck, and trochanter BMD at month 12 with ronacaleret compared with increases in the teriparatide and alendronate arms. Bone turnover markers increased in the ronacaleret and teriparatide arms and decreased in the alendronate arm. PTH elevations with ronacaleret were prolonged relative to those previously reported with teriparatide. CONCLUSION: The densitometric findings in the context of prolonged PTH elevation and increased bone turnover suggest ronacaleret induces mild hyperparathyroidism. Ronacaleret only modestly increased lumbar spine BMD and decreased BMD at hip sites. PMID- 21593115 TI - Incretin hormone and insulin responses to oral versus intravenous lipid administration in humans. AB - CONTEXT: The incretin effect is responsible for the higher insulin response to oral glucose than to iv glucose at matching glucose levels. It is not known whether this effect is restricted to glucose only. OBJECTIVE: The aim of the study was to examine whether insulin and incretin hormone responses are higher after oral vs. iv challenge of a lipid emulsion with matching triglyceride levels in humans. DESIGN, SETTINGS, AND PARTICIPANTS: A lipid emulsion (Intralipid) was administered orally (3 ml/kg) or iv (variable infusion rates to match triglyceride levels after oral ingestion) in healthy lean males (n = 12) at a University Clinical Research Unit. Samples were collected during 300 min. MAIN OUTCOME MEASURES: We measured the suprabasal area under the curve for insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and the insulin secretory rate based on C-peptide levels by deconvolution. RESULTS: Triglyceride levels increased similarly after oral and iv lipid; also, glucose and free fatty acid levels were similar in the two tests. Oral lipid elicited a clear insulin and C-peptide response, whereas no insulin or C-peptide responses were observed during iv lipid. Total and intact GIP and GLP-1 levels both increased after oral lipid administration but were not significantly altered after iv lipid. CONCLUSIONS: At matching triglyceride levels and with no difference in glucose and free fatty acid levels, oral lipid ingestion but not iv lipid infusion elicits a clear insulin response in association with increased GIP and GLP-1 concentrations. This may suggest that the incretin hormones also contribute to the islet response to noncarbohydrate nutrients. PMID- 21593116 TI - Mild primary hyperparathyroidism: vitamin D deficiency and cardiovascular risk markers. AB - CONTEXT: The extent and clinical significance of cardiovascular (CV) abnormalities associated with mild primary hyperparathyroidism (PHPT) are still matters for discussion. OBJECTIVE: The main objective of the present study was to evaluate biochemical CV risk markers in PHPT patients before and after parathyroidectomy (PTX) in comparison with controls. DESIGN AND SUBJECTS: In a prospective case-control design, 49 patients with PHPT and 49 healthy matched controls were included. METHODS: Blood pressure (BP), 25-OH-D, plasminogen activator inhibitor-1 activity, von Willebrand factor antigen, homocysteine, high sensitivity C-reactive protein, IGF-I, and lipid profile were evaluated at baseline and 15 +/- 4 months after PTX. RESULTS: At baseline, the level of 25-OH D was significantly lower in patients compared with controls (40.1 +/- 16.5 vs. 64.6 +/- 20.8 nmol/liter, P < 0.001) and increased after PTX (58.9 +/- 19.5, P < 0.001). Postoperatively, 25-OH-D was inversely correlated to the PTH level (r = 0.34; P < 0.05). Systolic BP (127.2 +/- 17.4 vs. 119.3 +/- 12.5 mm Hg, P < 0.05) and triglyceride (TG; 1.04 +/- 0.60 vs. 0.86 +/- 0.43 mmol/liter, P < 0.05) were higher in patients compared with controls and decreased slightly in patients after PTX (BP, 124.4 +/- 16.8 mm Hg, and TG, 0.94 +/- 0.50 mmol/liter, P < 0.05). Otherwise, there were no intergroup differences in coagulation, inflammatory, metabolic, and lipid status. CONCLUSIONS: Except for a lower 25-OH-D level and slightly higher systolic BP and TG levels, patients with mild PHPT without other CV risk factors did not differ from healthy controls as regards biomarkers predicting CV diseases. PTX had an overall positive effect on TG level, BP, and vitamin D status. PMID- 21593117 TI - Roux-en-Y gastric bypass corrects hyperinsulinemia implications for the remission of type 2 diabetes. AB - CONTEXT: Roux-en-Y gastric bypass (RYGB) has been shown to induce rapid and durable reversal of type 2 diabetes. OBJECTIVE: The aim of the study was to investigate a possible mechanism for the remission of type 2 diabetes after RYGB. DESIGN: A cross-sectional, nonrandomized, controlled study was conducted. Surgery patients were studied before RYGB and 1 wk and 3 months after surgery. SETTING: This study was conducted at East Carolina University. SUBJECTS: Subjects were recruited into three groups: 1) lean controls with no surgery [body mass index (BMI) < 25 kg/m2; n = 9], 2) severely obese type 2 diabetic patients (BMI > 35 kg/m2; n = 9), and 3) severely obese nondiabetic patients (BMI > 35 kg/m2; n = 9). INTERVENTION: Intervention was RYGB. RESULTS: One week after RYGB, diabetes was resolved despite continued insulin resistance (insulin sensitivity index was approximately 50% of lean controls) and reduced insulin secretion during an iv glucose tolerance test (acute insulin response to glucose was approximately 50% of lean controls). Fasting insulin decreased and was no different from lean control despite continued elevated glucose in the type 2 diabetic patients compared with lean. CONCLUSIONS: After RYGB, fasting insulin decreases to levels like those of lean control subjects and diabetes is reversed (fasting blood glucose < 125 mg/dl). This leads us to propose that 1) exclusion of food from the foregut corrects hyperinsulinemia and 2) fasting insulin is dissociated from the influence of fasting glucose, insulin resistance, and BMI. The mechanisms for reversal of diabetes in the face of reduced insulin remain a paradox. PMID- 21593118 TI - Metyrapone administration reduces the strength of an emotional memory trace in a long-lasting manner. AB - CONTEXT: It has recently been demonstrated that the process of memory retrieval serves as a reactivation mechanism whereby the memory trace that is reactivated during retrieval is once again sensitive to modifications by environmental or pharmacological manipulations. Recent studies have shown that glucocorticoids (GCs) have the capacity to modulate the process of memory retrieval. This suggests that GCs could be an interesting avenue to investigate with regard to reduction of emotional memory. OBJECTIVE: The current study assessed whether a pharmacological decrease in GC levels, induced by metyrapone, a potent inhibitor of GC secretion, would affect retrieval of emotional and neutral information in an acute and/or long-lasting manner. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: To do so, 1 * 750 mg dose of metyrapone, 2 * 750 mg dose of metyrapone, or placebo was administered to young normal participants 3 d after the encoding of a slide show having neutral and emotional segments. The experiment took place in a university and a hospital setting. MAIN OUTCOME MEASURE: Memory performance was assessed after treatment and 4 d later. RESULTS: RESULTS showed that retrieval of emotional information was acutely impaired in the double-dose metyrapone group and that this effect was still present 4 d later, when GC levels were not different between groups. CONCLUSIONS: These results show that decreasing GC levels via metyrapone administration is an efficient way to reduce the strength of an emotional memory in a long-lasting manner. PMID- 21593119 TI - Current state and future perspective of molecular diagnosis of fine-needle aspiration biopsy of thyroid nodules. AB - CONTEXT: Fine-needle aspiration biopsy (FNAB) is the most sensitive and specific tool for the differential diagnosis of thyroid malignancy. Some limitations of FNAB can be overcome by the molecular analysis of FNAB. This review analyzes the current state and problems of the molecular analysis of FNAB as well as possible goals for increasing the diagnostic rate, especially in the indeterminate/follicular lesion cytological group. EVIDENCE ACQUISITION: Twenty publications were evaluated for the diagnostic material and assay systems used, the type, and the number of mutations screened. Sensitivity, specificity, and false-negative and false-positive rates were calculated for all publications. EVIDENCE SYNTHESIS: Testing for a panel of somatic mutations is most promising to reduce the number of indeterminate FNAB. A mean sensitivity of 63.7% was achieved for indeterminate lesions. However, there is a broad sensitivity range for the investigation of mutations in the indeterminate lesions. Therefore, additional molecular markers should be defined by mRNA and microRNA expression studies and evaluated in FNAB samples of thyroid carcinomas without known somatic mutations, and especially for the many benign nodules in the indeterminate/follicular lesion fine-needle aspiration cytology category. This approach should improve the differential diagnosis of indeterminate/follicular lesion FNAB samples. CONCLUSION: Testing for a panel of somatic mutations has led to an improvement of sensitivity/specificity for indeterminate/follicular proliferation FNAB samples. Further methodological improvements, standardizations, and further molecular markers should soon lead to a broader application of molecular FNAB cytology for the differential diagnosis of thyroid nodules and to a substantial reduction of diagnostic surgeries. PMID- 21593120 TI - Alcohol use disorders and hazardous drinking among undergraduates at English universities: some limitations of the survey by Heather et al. (2011). PMID- 21593122 TI - Do media messages change people's risk perceptions for binge drinking? AB - AIMS: The current study investigated the effect of a media health message for drinking on risk perception estimates (comparative optimism). METHODS: Sixty-five young adults who regularly drink alcohol watched an anti-drinking scenario (having an accident due to drinking). There were two intervention conditions: 30 participants 'imagined' they were part of the scenario, and 35 'watched' the scenario. They then completed four comparative optimism estimates comparing themselves to those the same age and gender with similar drinking habits. The four comparisons were of their likelihood of being involved in an accident due to drinking; having unprotected sex, when under the influence of alcohol; having a car accident due to drinking (drivers only) and developing cirrhosis. There was also a control group (n = 59) who just completed the questionnaires. RESULTS: Both intervention groups reported significantly lower comparative optimism for accident, unprotected sex and car accident than the control group. The 'imagine' group reported significantly lower comparative optimism than the 'watch' group for accidents. CONCLUSIONS: These results highlighted that media messages can successfully change people's risk perception, and also that imagination can be a powerful tool in changing risk perceptions associated with binge drinking. PMID- 21593123 TI - Diminishing trend in alcohol poisoning mortality in Estonia: reality or coding peculiarity? AB - AIMS: To examine whether the changes in coding practice could reduce alcohol poisoning mortality rates in Estonia. METHODS: Individual death records in 1983 2009 (age at death 25-64) were used to calculate the 3-year moving averages of age-standardized mortality rates. From 2000 onwards, there was a sharp increase in mortality from mental disorders due to alcohol, and at the same time a remarkable decrease in alcohol poisoning mortality. We calculated expected alcohol poisoning mortality rates for 2000-2009, assuming that mortality rate ratio of alcohol poisoning and mental disorders due to alcohol remained stable. RESULTS: Alcohol poisoning mortality rates fluctuated considerably, being the lowest in 1988 and the highest in 1994-1995. A sharp decline started in 2000. Expected alcohol poisoning mortality rates continued their growth from 2000 onwards with a small decrease in 2006-2009. Mortality rates of mental disorders due to alcohol followed the same curve as alcohol poisoning rates up to 1999, being roughly 10 times lower than alcohol poisoning rates in both genders. From 2000 onwards, mortality from mental disorders due to alcohol increased rapidly, exceeding alcohol poisoning mortality in 2006. CONCLUSION: This study demonstrates an obvious misclassification in coding of alcohol poisoning and mental disorders due to alcohol as underlying causes of death in the Estonian Causes of Death Registry. PMID- 21593124 TI - Risk assessment of moderate to severe alcohol withdrawal--predictors for seizures and delirium tremens in the course of withdrawal. AB - AIMS: To develop a prediction model for withdrawal seizures (WS) and delirium tremens (DT) during moderate to severe alcohol withdrawal syndrome (AWS) in a large cohort of inpatients treated for AWS (n = 827). METHODS: Re-analysis of a cohort study population treated between 2000 and 2009. All patients received a score-guided and symptom-triggered therapy for AWS. Multivariable binary logistic regression models with stepwise variable selection procedures were conducted providing odds ratio (OR) estimates. RESULTS: In the multivariable regression, significant predictors of WS during AWS therapy were a delayed climax of withdrawal severity since admission [OR/10 h: 1.23; 95% confidence interval (CI): 1.1-1.4; P < 0.001)], prevalence of structural brain lesions in the patient's history (OR 6.5; 95% CI: 3.0-14.1; P < 0.001) and WS as the cause of admittance (OR 2.6; 95% CI: 1.4-4.8; P = 0.002). Significant predictors at admission for the occurrence of DT were lower serum potassium (OR/1 mmol/l 0.33; 95% CI: 0.17-0.65; P = 0.001), a lower platelet count (OR/100.000 0.42; 95% CI: 0.26-0.69; P = 0.001) and prevalence of structural brain lesions (OR 5.8; 95% CI: 2.6-12.9; P < 0.001). CONCLUSION: In this large retrospective cohort, some easily determinable parameters at admission may be useful to predict a complicated course of alcohol withdrawal regarding the occurrence of WS or DT. Using the provided nomograms, clinicians can estimate the percentage likelihood of patients to develop either WS or DT during their course of withdrawal. Prevalence of structural brain lesions in the patient's history does strongly warrant a careful observation of patients. PMID- 21593125 TI - Genome Surveyor 2.0: cis-regulatory analysis in Drosophila. AB - Genome Surveyor 2.0 is a web-based tool for discovery and analysis of cis regulatory elements in Drosophila, built on top of the GBrowse genome browser for convenient visualization. Genome Surveyor was developed as a tool for predicting transcription factor (TF) binding targets and cis-regulatory modules (CRMs/enhancers), based on motifs representing experimentally determined DNA binding specificities. Since its first publication, we have added substantial new functionality (e.g. phylogenetic averaging of motif scores from multiple species, and a novel CRM discovery technique), increased the number of supported motifs about 4-fold (from ~100 to ~400), added provisions for evolutionary comparison across many more Drosophila species (from 2 to 12), and improved the user interface. The server is free and open to all users, and there is no login requirement. Address: http://veda.cs.uiuc.edu/gs. PMID- 21593126 TI - HMMER web server: interactive sequence similarity searching. AB - HMMER is a software suite for protein sequence similarity searches using probabilistic methods. Previously, HMMER has mainly been available only as a computationally intensive UNIX command-line tool, restricting its use. Recent advances in the software, HMMER3, have resulted in a 100-fold speed gain relative to previous versions. It is now feasible to make efficient profile hidden Markov model (profile HMM) searches via the web. A HMMER web server (http://hmmer.janelia.org) has been designed and implemented such that most protein database searches return within a few seconds. Methods are available for searching either a single protein sequence, multiple protein sequence alignment or profile HMM against a target sequence database, and for searching a protein sequence against Pfam. The web server is designed to cater to a range of different user expertise and accepts batch uploading of multiple queries at once. All search methods are also available as RESTful web services, thereby allowing them to be readily integrated as remotely executed tasks in locally scripted workflows. We have focused on minimizing search times and the ability to rapidly display tabular results, regardless of the number of matches found, developing graphical summaries of the search results to provide quick, intuitive appraisement of them. PMID- 21593127 TI - Signatures of DNA flexibility, interactions and sequence-related structural variations in classical X-ray diffraction patterns. AB - The theory of X-ray diffraction from ideal, rigid helices allowed Watson and Crick to unravel the DNA structure, thereby elucidating functions encoded in it. Yet, as we know now, the DNA double helix is neither ideal nor rigid. Its structure varies with the base pair sequence. Its flexibility leads to thermal fluctuations and allows molecules to adapt their structure to optimize their intermolecular interactions. In addition to the double helix symmetry revealed by Watson and Crick, classical X-ray diffraction patterns of DNA contain information about the flexibility, interactions and sequence-related variations encoded within the helical structure. To extract this information, we have developed a new diffraction theory that accounts for these effects. We show how double helix non-ideality and fluctuations broaden the diffraction peaks. Meridional intensity profiles of the peaks at the first three helical layer lines reveal information about structural adaptation and intermolecular interactions. The meridional width of the fifth layer line peaks is inversely proportional to the helical coherence length that characterizes sequence-related and thermal variations in the double helix structure. Analysis of measured fiber diffraction patterns based on this theory yields important parameters that control DNA structure, packing and function. PMID- 21593129 TI - TT2NE: a novel algorithm to predict RNA secondary structures with pseudoknots. AB - We present TT2NE, a new algorithm to predict RNA secondary structures with pseudoknots. The method is based on a classification of RNA structures according to their topological genus. TT2NE is guaranteed to find the minimum free energy structure regardless of pseudoknot topology. This unique proficiency is obtained at the expense of the maximum length of sequences that can be treated, but comparison with state-of-the-art algorithms shows that TT2NE significantly improves the quality of predictions. Analysis of TT2NE's incorrect predictions sheds light on the need to study how sterical constraints limit the range of pseudoknotted structures that can be formed from a given sequence. An implementation of TT2NE on a public server can be found at http://ipht.cea.fr/rna/tt2ne.php. PMID- 21593128 TI - SDM--a server for predicting effects of mutations on protein stability and malfunction. AB - The sheer volume of non-synonymous single nucleotide polymorphisms that have been generated in recent years from projects such as the Human Genome Project, the HapMap Project and Genome-Wide Association Studies means that it is not possible to characterize all mutations experimentally on the gene products, i.e. elucidate the effects of mutations on protein structure and function. However, automatic methods that can predict the effects of mutations will allow a reduced set of mutations to be studied. Site Directed Mutator (SDM) is a statistical potential energy function that uses environment-specific amino-acid substitution frequencies within homologous protein families to calculate a stability score, which is analogous to the free energy difference between the wild-type and mutant protein. Here, we present a web server for SDM (http://www cryst.bioc.cam.ac.uk/~sdm/sdm.php), which has obtained more than 10,000 submissions since being online in April 2008. To run SDM, users must upload a wild-type structure and the position and amino acid type of the mutation. The results returned include information about the local structural environment of the wild-type and mutant residues, a stability score prediction and prediction of disease association. Additionally, the wild-type and mutant structures are displayed in a Jmol applet with the relevant residues highlighted. PMID- 21593130 TI - Quadruplex formation is necessary for stable PNA invasion into duplex DNA of BCL2 promoter region. AB - Guanine-rich sequences are highly abundant in the human genome, especially in regulatory regions. Because guanine-rich sequences have the unique ability to form G-quadruplexes, these structures may play a role in the regulation of gene transcription. In previous studies, we demonstrated that formation of G quadruplexes could be induced with peptide nucleic acids (PNAs). PNAs designed to bind the C-rich strand upstream of the human BCL2 gene promoted quadruplex formation in the complementary G-rich strand. However, the question whether G quadruplex formation was essential for PNA invasion remained unanswered. In this study, we compared PNA invasion in the native and mutant, i.e. not forming G quadruplex, BCL2 sequences and showed that G-quadruplex is required for effective PNA invasion into duplex DNA. This finding provides strong evidence for not only sequence-specific, but also quadruplex specific, gene targeting with PNA probes. In addition, we examined DNA-duplex invasion potential of PNAs of various charges. Using the gel shift assay, chemical probing and dimethyl sulfate (DMS) protection studies, we determined that uncharged zwitterionic PNA has the highest binding specificity while preserving efficient duplex invasion. PMID- 21593131 TI - FusionMap: detecting fusion genes from next-generation sequencing data at base pair resolution. AB - MOTIVATION: Next generation sequencing technology generates high-throughput data, which allows us to detect fusion genes at both transcript and genomic levels. To detect fusion genes, the current bioinformatics tools heavily rely on paired-end approaches and overlook the importance of reads that span fusion junctions. Thus there is a need to develop an efficient aligner to detect fusion events by accurate mapping of these junction-spanning single reads, particularly when the read gets longer with the improvement in sequencing technology. RESULTS: We present a novel method, FusionMap, which aligns fusion reads directly to the genome without prior knowledge of potential fusion regions. FusionMap can detect fusion events in both single- and paired-end datasets from either RNA-Seq or gDNA Seq studies and characterize fusion junctions at base-pair resolution. We showed that FusionMap achieved high sensitivity and specificity in fusion detection on two simulated RNA-Seq datasets, which contained 75 nt paired-end reads. FusionMap achieved substantially higher sensitivity and specificity than the paired-end approach when the inner distance between read pairs was small. Using FusionMap to characterize fusion genes in K562 chronic myeloid leukemia cell line, we further demonstrated its accuracy in fusion detection in both single-end RNA-Seq and gDNA Seq datasets. These combined results show that FusionMap provides an accurate and systematic solution to detecting fusion events through junction-spanning reads. AVAILABILITY: FusionMap includes reference indexing, read filtering, fusion alignment and reporting in one package. The software is free for noncommercial use at (http://www.omicsoft.com/fusionmap). PMID- 21593132 TI - Java bioinformatics analysis web services for multiple sequence alignment- JABAWS:MSA. AB - SUMMARY: JABAWS is a web services framework that simplifies the deployment of web services for bioinformatics. JABAWS:MSA provides services for five multiple sequence alignment (MSA) methods (Probcons, T-coffee, Muscle, Mafft and ClustalW), and is the system employed by the Jalview multiple sequence analysis workbench since version 2.6. A fully functional, easy to set up server is provided as a Virtual Appliance (VA), which can be run on most operating systems that support a virtualization environment such as VMware or Oracle VirtualBox. JABAWS is also distributed as a Web Application aRchive (WAR) and can be configured to run on a single computer and/or a cluster managed by Grid Engine, LSF or other queuing systems that support DRMAA. JABAWS:MSA provides clients full access to each application's parameters, allows administrators to specify named parameter preset combinations and execution limits for each application through simple configuration files. The JABAWS command-line client allows integration of JABAWS services into conventional scripts. AVAILABILITY AND IMPLEMENTATION: JABAWS is made freely available under the Apache 2 license and can be obtained from: http://www.compbio.dundee.ac.uk/jabaws. PMID- 21593133 TI - An ensemble biclustering approach for querying gene expression compendia with experimental lists. AB - MOTIVATION: Query-based biclustering techniques allow interrogating a gene expression compendium with a given gene or gene list. They do so by searching for genes in the compendium that have a profile close to the average expression profile of the genes in this query-list. As it can often not be guaranteed that the genes in a long query-list will all be mutually coexpressed, it is advisable to use each gene separately as a query. This approach, however, leaves the user with a tedious post-processing of partially redundant biclustering results. The fact that for each query-gene multiple parameter settings need to be tested in order to detect the 'most optimal bicluster size' adds to the redundancy problem. RESULTS: To aid with this post-processing, we developed an ensemble approach to be used in combination with query-based biclustering. The method relies on a specifically designed consensus matrix in which the biclustering outcomes for multiple query-genes and for different possible parameter settings are merged in a statistically robust way. Clustering of this matrix results in distinct, non redundant consensus biclusters that maximally reflect the information contained within the original query-based biclustering results. The usefulness of the developed approach is illustrated on a biological case study in Escherichia coli. AVAILABILITY AND IMPLEMENTATION: Compiled Matlab code is available from http://homes.esat.kuleuven.be/~kmarchal/Supplementary_Information_DeSmet_2011/. PMID- 21593134 TI - Fast accessibility-based prediction of RNA-RNA interactions. AB - MOTIVATION: Currently, the best RNA-RNA interaction prediction tools are based on approaches that consider both the inter- and intramolecular interactions of hybridizing RNAs. While accurate, these methods are too slow and memory-hungry to be employed in genome-wide RNA target scans. Alternative methods neglecting intramolecular structures are fast enough for genome-wide applications, but are too inaccurate to be of much practical use. RESULTS: A new approach for RNA-RNA interaction was developed, with a prediction accuracy that is similar to that of algorithms that explicitly consider intramolecular structures, but running at least three orders of magnitude faster than RNAup. This is achieved by using a combination of precomputed accessibility profiles with an approximate energy model. This approach is implemented in the new version of RNAplex. The software also provides a variant using multiple sequences alignments as input, resulting in a further increase in specificity. AVAILABILITY: RNAplex is available at www.bioinf.uni-leipzig.de/Software/RNAplex. PMID- 21593135 TI - Evaluation of drug-human serum albumin binding interactions with support vector machine aided online automated docking. AB - MOTIVATION: Human serum albumin (HSA), the most abundant plasma protein is well known for its extraordinary binding capacity for both endogenous and exogenous substances, including a wide range of drugs. Interaction with the two principal binding sites of HSA in subdomain IIA (site 1) and in subdomain IIIA (site 2) controls the free, active concentration of a drug, provides a reservoir for a long duration of action and ultimately affects the ADME (absorption, distribution, metabolism, and excretion) profile. Due to the continuous demand to investigate HSA binding properties of novel drugs, drug candidates and drug-like compounds, a support vector machine (SVM) model was developed that efficiently predicts albumin binding. Our SVM model was integrated to a free, web-based prediction platform (http://albumin.althotas.com). Automated molecular docking calculations for prediction of complex geometry are also integrated into the web service. The platform enables the users (i) to predict if albumin binds the query ligand, (ii) to determine the probable ligand binding site (site 1 or site 2), (iii) to select the albumin X-ray structure which is complexed with the most similar ligand and (iv) to calculate complex geometry using molecular docking calculations. Our SVM model and the potential offered by the combined use of in silico calculation methods and experimental binding data is illustrated. PMID- 21593136 TI - Technical advance: Surface plasmon resonance-based analysis of CXCL12 binding using immobilized lentiviral particles. AB - Use of SPR-based biosensors is an established method for measuring molecular interactions. Their application to the study of GPCRs is nonetheless limited to detergent-solubilized receptors that can then be reconstituted into a lipid environment. Using the chemokine receptor CXCR4 and its specific ligand CXCL12, we outline here a highly reproducible biosensor method based on receptor presentation on the surface of lentiviral particles; the approach is simple and does not require the use of antibodies to achieve correct receptor orientation on the sensorchip surface. We measured the kinetic parameters of CXCR4/CXCL12 binding in a single step and in real time and evaluated the effect of GAG presentation of chemokines on this interaction. The data indicate that at low concentrations, soluble heparin modulates CXCR4/CXCL12 interaction and at high concentrations, abrogates binding. These observations suggest that in addition to their known role in modulating local chemokine availability, GAG affect the receptor/ligand interaction, although their influence on affinity parameters is very limited. The method will also be useful for quantifying these biomarkers in biological fluids and for the development of high-throughput screening for their antagonists. PMID- 21593137 TI - Taking personal responsibility for well-being increases birth satisfaction of first time mothers. AB - Birth satisfaction has been found to enhance a mother's capacity to develop a sense of maternal identity. This study used a phenomenological form of thematic analysis to gain in-depth insights into the birth experiences of first-time New Zealand mothers. Taking personal responsibility (the choices participants made in relation to being in control of and accountable for their own birth processes) was a core theme. Those participants who described the neoliberalist ideal of taking personal responsibility to be well informed and well prepared for any birth experience felt more confident that they would be able to work with whatever labour and birth event eventuated. PMID- 21593138 TI - Telomere dysfunction promotes metastasis in a TERC null mouse model of head and neck cancer. AB - Squamous cell carcinoma arises from highly proliferative basal layer epithelial cells, which normally divide for a short time before detaching from the basement membrane and undergoing terminal differentiation. Basal layer cells in stratified epithelia express the reverse transcriptase known as telomerase. Most human cells do not express telomerase and therefore are subject to loss of telomeric DNA with age due to the inability of lagging strand synthesis to completely replicate chromosomal ends. Late generation telomerase deficient mice exhibit signs of premature aging including reduced function of proliferating cellular compartments. We examined development of squamous cell carcinoma in a telomerase deficient murine background with long and short telomeres. G1 Terc-/- mice (long telomeres) had fewer lymph node metastases, which correlated with increased numbers of apoptotic cells in these tumors compared with wild-type mice. However, G5 Terc-/- mice with short telomeres had increased metastatic tumor burden similar to wild type mice. This increased metastasis correlated with genomic instability and aneuploidy in tumor cells from G5 Terc-/- mice. A number of similarities with human SCC were noted in the mouse model, and dramatic differences in global gene expression profiles were shown between primary and metastatic tumors. We concluded that telomere shortening promotes metastatic tumor development in a Terc null mouse model of head and neck cancer. PMID- 21593139 TI - Downregulation of Sec23A protein by miRNA-375 in prostate carcinoma. AB - Prostate carcinoma (CaP) is a leading cause of cancer-related death in men. We have previously determined the microRNA (miRNA) profile of primary CaP in comparison with nontumor prostate tissue. miRNAs are small, noncoding RNAs that inhibit protein synthesis on a posttranscriptional level by binding to the 3' untranslated region (3'-UTR) of their target genes. In primary CaP tissue, we have previously found by miRNA sequencing that miR-375 and miR-200c were upregulated 9.1- and 4.5-fold, respectively. A computational analysis predicted the 3'-UTR of the SEC23A gene as a potential target for both miR-375 and miR 200c. Here, we show that the 3'-UTR of SEC23A mRNA is indeed a target for miR-375 and miR-200c and that both miRNAs downregulate Sec23A protein expression when ectopically expressed in human 293T cells. In primary samples of CaP, we found a direct correlation between reduction of SEC23A mRNA and overexpression of miR-375 but not of miR-200c. The reduced levels of Sec23A protein were inversely correlated to the increased amount of miR-375 in the LNCaP and DU145 CaP cell lines when compared with normal prostate fibroblasts. In primary CaP, we also detected decreased amounts of Sec23A protein when compared with corresponding normal prostate tissue. Ectopically overexpressed Sec23A in LNCaP and DU145 CaP cells significantly reduced the growth properties, indicating that Sec23A might play a role in the induction or growth of prostate carcinoma. Sec23A overexpression reduced cell growth but did not induce apoptosis, whereas inhibition of Sec23A stimulated cell proliferation. PMID- 21593140 TI - Speciation in the sea: overview of the symposium and discussion of future directions. AB - Speciation remains one of the most controversial and least understood topics in evolution. About 75% of the earth's surface is covered by oceans. However, most of what we currently know about speciation is strongly biased toward terrestrial and freshwater organisms. Here, we discuss some of the major advances of the past two decades in our understanding of speciation in the sea and outline promising future directions that were gathered during the 2011 SICB Symposium "Speciation in the Sea." PMID- 21593141 TI - Timing of hatching and release of larvae by brachyuran crabs: patterns, adaptive significance and control. AB - Most semiterrestrial, intertidal and shallow subtidal brachyuran crabs that live in tropical and warm temperate estuaries, bays and protected coasts world-wide release their planktonic larvae near the times of nocturnal high tides on the larger amplitude tides in the biweekly or monthly cycles of tidal amplitude. Crab larvae usually emigrate quickly to the sea where they develop to return as postlarvae to settle in habitats suitable for their survival. Predators of larvae are more abundant where larvae are released than where they develop, suggesting that this migration from estuaries to the sea reduces predation on larvae. Crabs with larvae that are relatively well-protected by spines and cryptic colors do not emigrate and often lack strong reproductive cycles, lending support to this explanation. Adults control the timing of the release of larvae with respect to the biweekly and monthly cycles of tidal amplitude by controlling when they court and mate and females control when development begins by controlling when they ovulate and allow their eggs to be fertilized by stored sperm. By changing the time they breed, fiddler crabs (Uca terpsichores) compensate for the effects of spatial and temporal variation in incubation temperature on development rates so that embryos are ready to hatch at the appropriate time. Control of the diel and tidal timing of hatching and of release of larvae varies with where adults live. Females of the more terrestrial species often move from protected incubation sites, sometimes far from water, and they largely control the precise time, both, of hatching and of release of larvae. Females of intertidal species also may influence when embryos begin to hatch. Upon hatching, a chemical cue is released that stimulates the female to pump her abdomen, causing rapid hatching and release of all larvae in her clutch. Embryos, rather than females, largely control hatching in subtidal species, perhaps because females incubate their eggs where they release their larvae. Topics for further study include the mechanism whereby adults regulate the timing of breeding, the mechanisms by which females control development rates of embryos, the nature of communication between females and embryos that leads to precise and synchronous hatching by the number (often thousands) of embryos in a clutch, and the causes of selection for such precision. The timing of hatching and of release of larvae by cold-temperate, Arctic, and Antarctic species and by fully terrestrial and freshwater tropical species has received little attention. PMID- 21593142 TI - Mastication and the postorbital ligament: dynamic strain in soft tissues. AB - Although the FEED database focuses on muscle activity patterns, it is equally suitable for other physiological recording and especially for synthesizing different types of information. The present contribution addresses the interaction between muscle activity and ligamentary stretch during mastication. The postorbital ligament is the thickened edge of a septum dividing the orbital contents from the temporal fossa and is continuous with the temporal fascia. As a tensile element, this fascial complex could support the zygomatic arch against the pull of the masseter muscle. An ossified postorbital bar has evolved repeatedly in mammals, enabling resistance to compression and shear in addition to tension. Although such ossification clearly reinforces the skull against muscle pull, the most accepted explanation is that it helps isolate the orbital contents from contractions of the temporalis muscle. However, it has never been demonstrated that the contraction of jaw muscles deforms the unossified ligament. We examined linear deformation of the postorbital ligament in minipigs, Sus scrofa, along with electromyography of the jaw muscles and an assessment of changes in pressure and shape in the temporalis. During chewing, the ligament elongated (average 0.9%, maximum 2.8%) in synchrony with the contraction of the elevator muscles of the jaw. Although the temporalis bulged outward and created substantial pressure against the braincase, the superficial fibers usually retracted caudally, away from the postorbital ligament. In anesthetized animals, stimulating either the temporalis or the masseter muscle in isolation usually elongated the ligament (average 0.4-0.7%). These results confirm that contraction of the masticatory muscles can potentially distort the orbital contents and further suggest that the postorbital ligament does function as a tension member resisting the pull of the masseter on the zygomatic arch. PMID- 21593143 TI - Distinct functions of NS5A in hepatitis C virus RNA replication uncovered by studies with the NS5A inhibitor BMS-790052. AB - BMS-790052, targeting nonstructural protein 5A (NS5A), is the most potent hepatitis C virus (HCV) inhibitor described to date. It is highly effective against genotype 1 replicons and also displays robust genotype 1 anti-HCV activity in the clinic (M. Gao et al., Nature 465:96-100, 2010). BMS-790052 inhibits genotype 2a JFH1 replicon cells and cell culture infectious virus with 50% effective concentrations (EC(50)s) of 46.8 and 16.1 pM, respectively. Resistance selection studies with the JFH1 replicon and virus systems identified drug-induced mutations within the N-terminal region of NS5A. F28S, L31M, C92R, and Y93H were the major resistance mutations identified; the impact of these mutations on inhibitor sensitivity between the replicon and virus was very similar. The C92R and Y93H mutations negatively impacted fitness of the JFH1 virus. Second-site replacements at NS5A residue 30 (K30E/Q) restored efficient replication of the C92R viral variant, thus demonstrating a genetic interaction between NS5A residues 30 and 92. By using a trans-complementation assay with JFH1 replicons encoding inhibitor-sensitive and inhibitor-resistant NS5A proteins, we provide genetic evidence that NS5A performs the following two distinct functions in HCV RNA replication: a cis-acting function that likely occurs as part of the HCV replication complex and a trans-acting function that may occur outside the replication complex. The cis-acting function is likely performed by basally phosphorylated NS5A, while the trans-acting function likely requires hyperphosphorylation. Our data indicate that BMS-790052 blocks the cis-acting function of NS5A. Since BMS-790052 also impairs JFH1 NS5A hyperphosphorylation, it likely also blocks the trans-acting function. PMID- 21593144 TI - Viral interleukin-10 expressed by human cytomegalovirus during the latent phase of infection modulates latently infected myeloid cell differentiation. AB - The human cytomegalovirus UL111A gene is expressed during latent and productive infections, and it codes for homologs of interleukin-10 (IL-10). We examined whether viral IL-10 expressed during latency altered differentiation of latently infected myeloid progenitors. In comparison to infection with parental virus or mock infection, latent infection with a virus in which the gene encoding viral IL 10 has been deleted upregulated cytokines associated with dendritic cell (DC) formation and increased the proportion of myeloid DCs. These data demonstrate that viral IL-10 restricts the ability of latently infected myeloid progenitors to differentiate into DCs and identifies an immunomodulatory role for viral IL-10 which may limit the host's ability to clear latent virus. PMID- 21593145 TI - Nipah virus uses leukocytes for efficient dissemination within a host. AB - Nipah virus (NiV) is a recently emerged zoonotic paramyxovirus whose natural reservoirs are several species of Pteropus fruit bats. NiV provokes a widespread vasculitis often associated with severe encephalitis, with up to 75% mortality in humans. We have analyzed the pathogenesis of NiV infection, using human leukocyte cultures and the hamster animal model, which closely reproduces human NiV infection. We report that human lymphocytes and monocytes are not permissive for NiV and a low level of virus replication is detected only in dendritic cells. Interestingly, despite the absence of infection, lymphocytes could efficiently bind NiV and transfer infection to endothelial and Vero cells. This lymphocyte mediated transinfection was inhibited after proteolytic digestion and neutralization by NiV-specific antibodies, suggesting that cells could transfer infectious virus to other permissive cells without the requirement for NiV internalization. In NiV-infected hamsters, leukocytes captured and carried NiV after intraperitoneal infection without themselves being productively infected. Such NiV-loaded mononuclear leukocytes transfer lethal NiV infection into naive animals, demonstrating efficient virus transinfection in vivo. Altogether, these results reveal a remarkable capacity of NiV to hijack leukocytes as vehicles to transinfect host cells and spread the virus throughout the organism. This mode of virus transmission represents a rapid and potent method of NiV dissemination, which may contribute to its high pathogenicity. PMID- 21593146 TI - The requirement for nucleoporin NUP153 during human immunodeficiency virus type 1 infection is determined by the viral capsid. AB - Lentiviruses likely infect nondividing cells by commandeering host nuclear transport factors to facilitate the passage of their preintegration complexes (PICs) through nuclear pore complexes (NPCs) within nuclear envelopes. Genome wide small interfering RNA screens previously identified karyopherin beta transportin-3 (TNPO3) and NPC component nucleoporin 153 (NUP153) as being important for infection by human immunodeficiency virus type 1 (HIV-1). The knockdown of either protein significantly inhibited HIV-1 infectivity, while infection by the gammaretrovirus Moloney murine leukemia virus (MLV) was unaffected. Here, we establish that primate lentiviruses are particularly sensitive to NUP153 knockdown and investigate HIV-1-encoded elements that contribute to this dependency. Mutants lacking functional Vpr or the central DNA flap remained sensitive to NUP153 depletion, while MLV/HIV-1 chimera viruses carrying MLV matrix, capsid, or integrase became less sensitive when the latter two elements were substituted. Two capsid missense mutant viruses, N74D and P90A, were largely insensitive to NUP153 depletion, as was wild-type HIV-1 when cyclophilin A was depleted simultaneously or when infection was conducted in the presence of cyclosporine A. The codepletion of NUP153 and TNPO3 yielded synergistic effects that outweighed those calculated based on individual knockdowns, indicating potential interdependent roles for these factors during HIV-1 infection. Quantitative PCR revealed normal levels of late reverse transcripts, a moderate reduction of 2-long terminal repeat (2-LTR) circles, and a relatively large reduction in integrated proviruses upon NUP153 knockdown. These results suggest that capsid, likely by the qualities of its uncoating, determines whether HIV-1 requires cellular NUP153 for PIC nuclear import. PMID- 21593147 TI - Longer V1V2 region with increased number of potential N-linked glycosylation sites in the HIV-1 envelope glycoprotein protects against HIV-specific neutralizing antibodies. AB - Human immunodeficiency virus type 1 (HIV-1) has the ability to adapt to the host environment by escaping from host immune responses. We previously observed that escape from humoral immunity, both at the individual and at a population level, coincided with longer variable loops and an increased number of potential N linked glycosylation sites (PNGS) in the viral envelope glycoprotein (Env) and, in particular, in variable regions 1 and 2 (V1V2). Here, we provide several lines of evidence for the role of V1V2 in the resistance of HIV-1 to neutralizing antibodies. First, we determined that the increasing neutralization resistance of a reference panel of tier-categorized neutralization-sensitive and -resistant HIV 1 variants coincided with a longer V1V2 loop containing more PNGS. Second, an exchange of the different variable regions of Env from a neutralization-sensitive HIV-1 variant into a neutralization-resistant escape variant from the same individual revealed that the V1V2 loop is a strong determinant for sensitivity to autologous-serum neutralization. Third, exchange of the V1V2 loop of neutralization-sensitive HIV-1 variants from historical seroconverters with the V1V2 loop of neutralization-resistant HIV-1 variants from contemporary seroconverters decreased the neutralization sensitivity to CD4-binding site directed antibodies. Overall, we demonstrate that an increase in the length of the V1V2 loop and/or the number of PNGS in that same region of the HIV-1 envelope glycoprotein is directly involved in the protection of HIV-1 against HIV-specific neutralizing antibodies, possibly by shielding underlying epitopes in the envelope glycoprotein from antibody recognition. PMID- 21593148 TI - Mutation of a C-terminal motif affects Kaposi's sarcoma-associated herpesvirus ORF57 RNA binding, nuclear trafficking, and multimerization. AB - The Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein is essential for virus lytic replication. ORF57 regulates virus gene expression at multiple levels, enhancing transcription, stability, nuclear export, and translation of viral transcripts. To enhance the nuclear export of viral intronless transcripts, ORF57 (i) binds viral intronless mRNAs, (ii) shuttles between the nucleus, nucleolus, and the cytoplasm, and (iii) interacts with multiple cellular nuclear export proteins to access the TAP-mediated nuclear export pathway. We investigated the implications on the subcellular trafficking, cellular nuclear export factor recruitment, and ultimately nuclear mRNA export of an ORF57 protein unable to bind RNA. We observed that mutation of a carboxy-terminal RGG motif, which prevents RNA binding, affects the subcellular localization and nuclear trafficking of the ORF57 protein, suggesting that it forms subnuclear aggregates. Further analysis of the mutant shows that although it still retains the ability to interact with cellular nuclear export proteins, it is unable to export viral intronless mRNAs from the nucleus. Moreover, computational molecular modeling and biochemical studies suggest that, unlike the wild-type protein, this mutant is unable to self-associate. Therefore, these results suggest the mutation of a carboxy-terminal RGG motif affects ORF57 RNA binding, nuclear trafficking, and multimerization. PMID- 21593149 TI - Adenovirus sequesters phosphorylated STAT1 at viral replication centers and inhibits STAT dephosphorylation. AB - Tyrosine phosphorylation and nuclear translocation of STAT1 indicate activation of interferon (IFN) signal transduction pathways. Here, we demonstrate that tyrosine-phosphorylated STAT1 is targeted by a unique mechanism in adenovirus (Ad)-infected cells. Ad is known to suppress IFN-inducible gene expression; however, we observed that Ad infection prolongs the tyrosine phosphorylation of STAT1 induced by alpha IFN in infected cells. To understand this paradoxical effect, we examined the subcellular localization of STAT1 following Ad infection and found that nuclear, tyrosine-phosphorylated STAT1 accumulates at viral replication centers. This form of STAT1 colocalized with newly synthesized viral DNA. Viral DNA replication, but not viral late gene expression, is required for the regulation of STAT1 phosphorylation. Our results indicate that Ad infection regulates STAT1 dephosphorylation rather than STAT1 phosphorylation. Consistent with this idea, we show that Ad infection disrupts the interaction between STAT1 and its cognate protein tyrosine phosphatase, TC45. Our findings indicate that Ad sequesters phosphorylated STAT1 at viral replication centers and inhibits STAT dephosphorylation. This report suggests a strategy employed by Ad to counteract an active form of STAT1 in the nucleus of infected cells. PMID- 21593150 TI - Wild-type measles virus interferes with short-term engraftment of human CD34+ hematopoietic progenitor cells. AB - Transient lymphopenia is a hallmark of measles virus (MV)-induced immunosuppression. To address to what extent replenishment of the peripheral lymphocyte compartment from bone marrow (BM) progenitor/stem cells might be affected, we analyzed the interaction of wild-type MV with hematopoietic stem and progenitor cells (HS/PCs) and stroma cells in vitro. Infection of human CD34(+) HS/PCs or stroma cells with wild-type MV is highly inefficient yet noncytolytic. It occurs independently of CD150 in stroma cells but also in HS/PCs, where infection is established in CD34(+) CD150(-) and CD34(+) CD150(+) (in humans representing HS/PC oligopotent precursors) subsets. Stroma cells and HS/PCs can mutually transmit MV and may thereby create a possible niche for continuous viral exchange in the BM. Infected lymphocytes homing to this compartment may serve as sources for HS/PC or stroma cell infection, as reflected by highly efficient transmission of MV from both populations in cocultures with MV-infected B or T cells. Though MV exposure does not detectably affect the viability, expansion, and colony-forming activity of either CD150(+) or CD150(-) HS/PCs in vitro, it efficiently interferes with short- but not long-term hematopoietic reconstitution in NOD/SCID mice. Altogether, these findings support the hypothesis that MV accession of the BM compartment by infected lymphocytes may contribute to peripheral blood mononuclear cell lymphopenia at the level of BM suppression. PMID- 21593151 TI - Human T cell leukemia virus type 1 Tax inhibits innate antiviral signaling via NF kappaB-dependent induction of SOCS1. AB - Human T cell leukemia virus type 1 (HTLV-1) inhibits host antiviral signaling pathways although the underlying mechanisms are unclear. Here we found that the HTLV-1 Tax oncoprotein induced the expression of SOCS1, an inhibitor of interferon signaling. Tax required NF-kappaB, but not CREB, to induce the expression of SOCS1 in T cells. Furthermore, Tax interacted with SOCS1 in both transfected cells and in HTLV-1-transformed cell lines. Although SOCS1 is normally a short-lived protein, in the presence of Tax, the stability of SOCS1 was greatly increased. Accordingly, Tax enhanced the replication of a heterologous virus, vesicular stomatitis virus (VSV), in a SOCS1-dependent manner. Surprisingly, Tax required SOCS1 to inhibit RIG-I-dependent antiviral signaling, but not the interferon-induced JAK/STAT pathway. Inhibition of SOCS1 by RNA-mediated interference in the HTLV-1-transformed cell line MT-2 resulted in increased IFN-beta expression accompanied by reduced HTLV-1 replication and p19(Gag) levels. Taken together, our results reveal that Tax inhibits antiviral signaling, in part, by hijacking an interferon regulatory protein. PMID- 21593152 TI - The virulence of 1997 H5N1 influenza viruses in the mouse model is increased by correcting a defect in their NS1 proteins. AB - The NS1 protein of human influenza A viruses binds the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), a protein required for 3' end processing of cellular pre-mRNAs, thereby inhibiting production of beta interferon (IFN-beta) mRNA. The NS1 proteins of pathogenic 1997 H5N1 viruses contain the CPSF30-binding site but lack the consensus amino acids at positions 103 and 106, F and M, respectively, that are required for the stabilization of CPSF30 binding, resulting in nonoptimal CPSF30 binding in infected cells. Here we have demonstrated that strengthening CPSF30 binding, by changing positions 103 and 106 in the 1997 H5N1 NS1 protein to the consensus amino acids, results in a remarkable 300-fold increase in the lethality of the virus in mice. Unexpectedly, this increase in virulence is not associated with increased lung pathology but rather is characterized by faster systemic spread of the virus, particularly to the brain, where increased replication and severe pathology occur. This increased spread is associated with increased cytokine and chemokine levels in extrapulmonary tissues. We conclude that strengthening CPSF30 binding by the NS1 protein of 1997 H5N1 viruses enhances virulence in mice by increasing the systemic spread of the virus from the lungs, particularly to the brain. PMID- 21593153 TI - Reduction of CD4+ T cells in vivo does not affect virus load in macaque elite controllers. AB - A small percentage of human immunodeficiency virus (HIV)- and simian immunodeficiency virus (SIV)-infected individuals spontaneously control virus replication. The majority of these elite controllers mount high-frequency virus specific CD4(+) T cell responses. To evaluate the role these responses might play in viral control, we depleted two elite controller macaques of CD4(+) cells. SIV specific CD4(+) T cell responses did not return to baseline levels until 8 weeks postdepletion. Viral loads remained stable throughout the experiment, suggesting that SIV-specific CD4(+) T cell responses may not play a direct role in controlling chronic viral replication in these elite controllers. PMID- 21593154 TI - Epithelial cell retention of transcriptionally active, P3HR-1-derived heterogeneous Epstein-Barr virus DNA with concurrent loss of parental virus. AB - Deleted, rearranged, heterogeneous (het) Epstein-Barr virus (EBV) DNA with the distinctive capability of disrupting EBV latency has been reported in biopsy samples of EBV-associated tumors whose onset in immunocompetent hosts is characteristically preceded by an antibody response indicative of EBV reactivation. Using the EBV P3HR-1 strain, we have reproduced in long-term culture of SVK epithelial cells an unusual pattern of infection previously observed in a subset of tumor biopsy samples: the persistence of het DNA in the absence of the parental helper virus. Fluorescence in situ hybridization (FISH) of infected cell subclones indicated the retention of het DNA in an integrated form. Incorporation of an intact het DNA molecule was confirmed by PCR, using primers that framed junctions of the four rearranged EBV DNA segments comprising P3HR-1-derived het DNA. Structural analysis of EBV terminal repeats revealed a banding pattern consistent with the integration of het DNA as a concatemer. Linkage of concatemeric monomers was defined at a nucleotide level, and that junctional sequence was detected in cell-free P3HR-1 virion DNA, confirming that subgenomic het DNA was packaged into infectious particles in a concatemeric configuration. Stable integration into cells having lost the standard viral genome allowed the unambiguous designation of het DNA as the source for viral gene products potentially encoded by both. Continuous expression of the latency to-lytic switch protein Zta and detection of the BALF4 gene product gB, known to expand the target cell range of standard virus when incorporated at augmented levels into infectious progeny, add to a presumption of het DNA-enhanced pathogenesis in diseases of EBV reactivation. PMID- 21593155 TI - Immune mediators of rotavirus antigenemia clearance in mice. AB - The immunological mediators that clear rotavirus antigenemia or viremia remain undefined. Immunodeficient mice and antibody transfer were used to test whether lymphocytes or rotavirus-specific serum antibodies are essential for resolving antigenemia. Clearance of antigenemia required lymphocytes, but neither T nor B lymphocytes were absolutely required. Transfer of convalescent-phase or nonneutralizing rotavirus-specific serum antibodies to the systemic compartment of severe-combined-immunodeficient (SCID) mice temporarily suppressed the onset or level of chronic rotavirus antigenemia. Our findings provide the first report demonstrating that clearance of rotavirus antigenemia and possibly viremia are mediated by multiple effector lymphocyte subsets and serum antibodies. PMID- 21593156 TI - Comparative pathology in ferrets infected with H1N1 influenza A viruses isolated from different hosts. AB - Virus replication and pulmonary disease pathogenesis in ferrets following intranasal infection with a pandemic influenza virus strain (A/California/4/09 [CA09]), a human seasonal influenza H1N1 virus isolate (A/New Caledonia/20/99 [Ncal99]), a classical swine influenza H1N1 virus isolate (A/Swine/Iowa/15/30 [Sw30]), or an avian H1N1 virus isolate (A/Mallard/MN/A108-2355/08 [Mal08]) were compared. Nasal wash virus titers were similar for Ncal99 and Sw30, with peak virus titers of 10(5.1) 50% tissue culture infectious doses (TCID(50))/ml and 10(5.5) TCID(50)/ml occurring at day 3 postinfection (p.i.), respectively. The mean peak titer for CA09 also occurred at day 3 p.i. but was higher (10(7) TCID(50)/ml). In contrast, the peak virus titers (10(3.6) to 10(4.3) TCID(50)/ml) for Mal08 were delayed, occurring between days 5 and 7 p.i. Disease pathogenesis was characterized by microscopic lesions in the nasal turbinates and lungs of all ferrets; however, Sw30 infection was associated with severe bronchointerstitial pneumonia. The results demonstrate that although CA09 is highly transmissible in the human population and replicates well in the ferret model, it causes modest disease compared to other H1N1 viruses, particularly Sw30 infection. PMID- 21593157 TI - Transforming growth factor beta-induced reactivation of Epstein-Barr virus involves multiple Smad-binding elements cooperatively activating expression of the latent-lytic switch BZLF1 gene. AB - Transforming growth factor beta (TGF-beta) physiologically induces Epstein-Barr virus (EBV) lytic infection by activating the expression of EBV's latent-lytic switch BZLF1 gene. Liang et al. (J. Biol. Chem. 277:23345-23357, 2002) previously identified a Smad-binding element (SBE) within the BZLF1 promoter, Zp; however, it accounts for only 20 to 30% of TGF-beta-mediated activation of transcription from Zp. Here, we identified additional factors responsible for the rest of this activation. The incubation of EBV-positive MutuI cells with a TGF-beta neutralizing antibody or inhibitors of the TGF-beta type I receptor (TbetaRI) or Smad3 eliminated the TGF-beta-induced reactivation of EBV. The coexpression of Smad2, Smad3, and Smad4 together with a constitutively active form of TbetaRI induced 15- to 25-fold transcription from Zp in gastric carcinoma AGS cells. By electrophoretic mobility shift assays, we identified four additional Smad-binding elements, named SBE2 to SBE5. Substitution mutations in individual SBEs reduced Smad-mediated activation of Zp by 20 to 60%; together, these mutations essentially eliminated it. Chromatin immunoprecipitation assays confirmed that Smad4 newly bound the Zp region of the EBV genome following the incubation of MutuI cells with TGF-beta. SBE2 overlaps the ZEB-binding ZV silencing element of Zp. Depending upon posttranslational modifications, Smad4 either competed with ZEB1 for binding or formed a complex with ZEB1 on the Zp ZV element in a cell free assay system. In transiently transfected cells, exogenously expressed ZEB1 inhibited Smad-mediated transcriptional activation from Zp. We conclude that TGF beta induces EBV lytic reactivation via the canonical Smad pathway by activating BZLF1 gene expression through multiple SBEs acting in concert. PMID- 21593158 TI - A Tyr residue in the reverse transcriptase domain can mimic the protein-priming Tyr residue in the terminal protein domain of a hepadnavirus P protein. AB - Hepadnaviruses are the only known viruses that replicate by protein-primed reverse transcription. Beyond the conserved reverse transcriptase (RT) and RNase H domains, their polymerases (P proteins) carry a unique terminal protein (TP) domain that provides a specific Tyr residue, Tyr96 in duck hepatitis B virus (DHBV), to which the first nucleotide of minus-strand DNA is autocatalytically attached and extended by three more nucleotides. In vitro reconstitution of this priming reaction with DHBV P protein and cellular chaperones had revealed strict requirements for the Depsilon RNA stem-loop as a template and for catalytic activity of the RT domain plus RNA-binding competence of the TP domain. Chaperone dependence can be obviated by using a truncated P protein (miniP). Here, we found that miniP with a tobacco etch virus (TEV) protease cleavage site between TP and RT (miniP(TEV)) displayed authentic priming activity when supplied with alpha (32)P-labeled deoxynucleoside triphosphates; however, protease cleavage revealed, surprisingly, that the RT domain was also labeled. RT labeling had identical requirements as priming at Tyr96 and originated from dNMP transfer to a unique Tyr residue identified as Tyr561 in the presumed RT primer grip motif. Mutating Tyr561 did not affect Tyr96 priming in vitro and only modestly reduced replication competence of an intact DHBV genome; hence, deoxynucleotidylated Tyr561 is not an obligate intermediate in TP priming. However, as a first alternative substrate for the exquisitely complex protein-priming reaction, dNMP transfer to Tyr561 is a novel tool to further clarify the mechanism of hepadnaviral replication initiation and suggests that specific priming inhibitors can be found. PMID- 21593159 TI - Virion structure of baboon reovirus, a fusogenic orthoreovirus that lacks an adhesion fiber. AB - Baboon reovirus (BRV) is a member of the fusogenic subgroup of orthoreoviruses. Unlike most other members of its genus, BRV lacks S-segment coding sequences for the outer fiber protein that binds to cell surface receptors. It shares this lack with aquareoviruses, which constitute a related genus and are also fusogenic. We used electron cryomicroscopy and three-dimensional image reconstruction to determine the BRV virion structure at 9.0-A resolution. The results show that BRV lacks a protruding fiber at its icosahedral 5-fold axes or elsewhere. The results also show that BRV is like nonfusogenic mammalian and fusogenic avian orthoreoviruses in having 150 copies of the core clamp protein, not 120 as in aquareoviruses. On the other hand, there are no hub-and-spoke complexes attributable to the outer shell protein in the P2 and P3 solvent channels of BRV, which makes BRV like fusogenic avian orthoreoviruses and aquareoviruses but unlike nonfusogenic mammalian orthoreoviruses. The outermost "flap" domains of the BRV core turret protein appear capable of conformational variability within the virion, a trait previously unseen among other ortho- and aquareoviruses. New cDNA sequence determinations for the BRV L1 and M2 genome segments, encoding the core turret and outer shell proteins, were helpful for interpreting the structural features of those proteins. Based on these findings, we conclude that the evolution of ortho- and aquareoviruses has included a series of discrete gains or losses of particular components, several of which cross taxonomic boundaries. Gain or loss of adhesion fibers is one of several common themes in double-stranded RNA virus evolution. PMID- 21593160 TI - Clinical outcome of henipavirus infection in hamsters is determined by the route and dose of infection. AB - Nipah virus (NiV) and Hendra virus (HeV) are emerging zoonotic viruses and the causative agents of severe respiratory disease and encephalitis in humans. Little is known about the mechanisms that govern the development of respiratory and neurological disease. Using a hamster model of lethal NiV and HeV infection, we describe the role of the route and dose of infection on the clinical outcome and determine virus tropism and host responses following infection. Infection of hamster with a high dose of NiV or HeV resulted in acute respiratory distress. NiV initially replicated in the upper respiratory tract epithelium, whereas HeV initiated infection primarily in the interstitium. In contrast, infection with a low dose of NiV or HeV resulted in the development of neurological signs and more systemic spread of the virus through involvement of the endothelium. The development of neurological signs coincided with disruption of the blood-brain barrier (BBB) and expression of tumor necrosis alpha (TNF-alpha) and interleukin 1 beta (IL-1beta). In addition, interferon-inducible protein 10 (IP-10) was identified as playing an important role in NiV and HeV pathogenesis. These studies reveal novel information on the development and progression of NiV and HeV clinical disease, provide a mechanism for the differences in transmission observed between NiV and HeV outbreaks, and identify specific cytokines and chemokines that serve as important targets for treatment. PMID- 21593161 TI - Disulfide bond formation in the herpes simplex virus 1 UL6 protein is required for portal ring formation and genome encapsidation. AB - The herpes simplex virus 1 (HSV-1) UL6 portal protein forms a 12-subunit ring structure at a unique capsid vertex which functions as a conduit for the encapsidation of the viral genome. We have demonstrated previously that the leucine zipper region of UL6 is important for intersubunit interactions and stable ring formation (J. K. Nellissery, R. Szczepaniak, C. Lamberti, and S. K. Weller, J. Virol. 81:8868-8877, 2007). We now demonstrate that intersubunit disulfide bonds exist between monomeric subunits and contribute to portal ring formation and/or stability. Intersubunit disulfide bonds were detected in purified portal rings by SDS-PAGE under nonreducing conditions. Furthermore, the treatment of purified portal rings with dithiothreitol (DTT) resulted in the disruption of the rings, suggesting that disulfide bonds confer stability to this complex structure. The UL6 protein contains nine cysteines that were individually mutated to alanine. Two of these mutants, C166A and C254A, failed to complement a UL6 null mutant in a transient complementation assay. Furthermore, viral mutants bearing the C166A and C254A mutations failed to produce infectious progeny and were unable to cleave or package viral DNA. In cells infected with C166A or C254A, B capsids were produced which contained UL6 at reduced levels compared to those seen in wild-type capsids. In addition, C166A and C254A mutant proteins expressed in insect cells infected with recombinant baculovirus failed to form ring structures. Cysteines at positions 166 and 254 thus appear to be required for intersubunit disulfide bond formation. Taken together, these results indicate that disulfide bond formation is required for portal ring formation and/or stability and for the production of procapsids that are capable of encapsidation. PMID- 21593162 TI - Demographic processes affect HIV-1 evolution in primary infection before the onset of selective processes. AB - HIV-1 transmission and viral evolution in the first year of infection were studied in 11 individuals representing four transmitter-recipient pairs and three independent seroconverters. Nine of these individuals were enrolled during acute infection; all were men who have sex with men (MSM) infected with HIV-1 subtype B. A total of 475 nearly full-length HIV-1 genome sequences were generated, representing on average 10 genomes per specimen at 2 to 12 visits over the first year of infection. Single founding variants with nearly homogeneous viral populations were detected in eight of the nine individuals who were enrolled during acute HIV-1 infection. Restriction to a single founder variant was not due to a lack of diversity in the transmitter as homogeneous populations were found in recipients from transmitters with chronic infection. Mutational patterns indicative of rapid viral population growth dominated during the first 5 weeks of infection and included a slight contraction of viral genetic diversity over the first 20 to 40 days. Subsequently, selection dominated, most markedly in env and nef. Mutants were detected in the first week and became consensus as early as day 21 after the onset of symptoms of primary HIV infection. We found multiple indications of cytotoxic T lymphocyte (CTL) escape mutations while reversions appeared limited. Putative escape mutations were often rapidly replaced with mutually exclusive mutations nearby, indicating the existence of a maturational escape process, possibly in adaptation to viral fitness constraints or to immune responses against new variants. We showed that establishment of HIV-1 infection is likely due to a biological mechanism that restricts transmission rather than to early adaptive evolution during acute infection. Furthermore, the diversity of HIV strains coupled with complex and individual-specific patterns of CTL escape did not reveal shared sequence characteristics of acute infection that could be harnessed for vaccine design. PMID- 21593163 TI - The internal Kaposi's sarcoma-associated herpesvirus LANA regions exert a critical role on episome persistence. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) is a 1,162-amino-acid protein that acts on viral terminal repeat (TR) DNA to mediate KSHV episome persistence. The two essential components of episome persistence are DNA replication prior to cell division and episome segregation to daughter nuclei. These functions are located within N- and C-terminal regions of LANA. N- and C-terminal regions of LANA are sufficient for TR DNA replication. In addition, N- and C-terminal regions of LANA tether episomes to mitotic chromosomes to segregate episomes to progeny cell nuclei. To generate a tethering mechanism, N-terminal LANA binds histones H2A/H2B to attach to mitotic chromosomes, and C-terminal LANA binds TR DNA and also associates with mitotic chromosomes. Here, we test the importance of the internal LANA sequence for episome persistence. We generated LANA mutants that contain N- and C-terminal regions of LANA but have most of the internal sequence deleted. As expected, the LANA mutants bound mitotic chromosomes in a wild-type pattern and also bound TR DNA as assayed by electrophoretic mobility shift assays (EMSA). The mutants mediated TR DNA replication, although with reduced efficiency compared with LANA. Despite the ability to replicate DNA and exert the chromosome and DNA binding functions necessary for segregating episomes to daughter nuclei, the mutants were highly deficient for the ability to mediate both short- and long-term episome persistence. These data indicate that internal LANA sequence exerts a critical effect on its ability to maintain episomes, possibly through effects on TR DNA replication. PMID- 21593164 TI - Cryptic protein priming sites in two different domains of duck hepatitis B virus reverse transcriptase for initiating DNA synthesis in vitro. AB - Initiation of reverse transcription in hepadnaviruses is accomplished by a unique protein-priming mechanism whereby a specific Y residue in the terminal protein (TP) domain of the viral reverse transcriptase (RT) acts as a primer to initiate DNA synthesis, which is carried out by the RT domain of the same protein. When separate TP and RT domains from the duck hepatitis B virus (DHBV) RT protein were tested in a trans-complementation assay in vitro, the RT domain could also serve, unexpectedly, as a protein primer for DNA synthesis, as could a TP mutant lacking the authentic primer Y (Y96) residue. Priming at these other, so-called cryptic, priming sites in both the RT and TP domains shared the same requirements as those at Y96. A mini RT protein with both the TP and RT domains linked in cis, as well as the full-length RT protein, could also initiate DNA synthesis using cryptic priming sites. The cryptic priming site(s) in TP was found to be S/T, while those in the RT domain were Y and S/T. As with the authentic TP Y96 priming site, the cryptic priming sites in the TP and RT domains could support DNA polymerization subsequent to the initial covalent linkage of the first nucleotide to the priming amino acid residue. These results provide new insights into the complex mechanisms of protein priming in hepadnaviruses, including the selection of the primer residue and the interactions between the TP and RT domains that is essential for protein priming. PMID- 21593165 TI - Jaagsiekte sheep retrovirus and enzootic nasal tumor virus promoters drive gene expression in all airway epithelial cells of mice but only induce tumors in the alveolar region of the lungs. AB - Jaagsiekte sheep retrovirus (JSRV) induces tumors in the distal airways of sheep and goats, while the closely related enzootic nasal tumor virus type 1 (ENTV-1) and ENTV-2 induce tumors in the nasal epithelium of sheep and goats, respectively. When expressed using a strong Rous sarcoma virus promoter, the envelope proteins of these viruses induce tumors in the respiratory tract of mice, but only in the distal airway. To examine the role of the retroviral long terminal repeat (LTR) promoters in determining tissue tropism, adeno-associated virus (AAV) vectors expressing alkaline phosphatase under the control of the JSRV, ENTV-1, or ENTV-2 LTRs were generated and administered to mice. The JSRV LTR was active in all airway epithelial cells, while the ENTV LTRs were active in the nasal epithelium and alveolar type II cells but poorly active in tracheal and bronchial epithelial cells. When vectors were administered systemically, the ENTV 1 and -2 LTRs were inactive in major organs examined, whereas the JSRV showed high-level activity in the liver. When a putative transcriptional enhancer from the 3' end of the env gene was inserted upstream of the JSRV and ENTV-1 LTRs in the AAV vectors, a dramatic increase in transgene expression was observed. However, intranasal administration of AAV vectors containing any combination of ENTV or JSRV LTRs and Env proteins induced tumors only in the lower airway. Our results indicate that mice do not provide an adequate model for nasal tumor induction by ENTV despite our ability to express genes in the nasal epithelium. PMID- 21593166 TI - Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner. AB - NS5A plays a critical, yet poorly defined, role in hepatitis C virus genome replication. The protein consists of three domains, each of which is able to bind independently to the 3' untranslated region (UTR) of the viral positive strand genomic RNA. The peptidyl-prolyl isomerase cyclophilin A (CypA) binds to domain II, catalyzing cis-trans isomerization. CypA inhibitors such as cyclosporine (CsA) have been shown to inhibit hepatitis C virus (HCV) replication. We show here that CypA stimulated domain II RNA binding activity, and this stimulation was abrogated by CsA. An isomerase mutant of CypA (H126Q) failed to bind to domain II and did not stimulate RNA binding. Finally, we demonstrate that the RNA binding of two domain II mutants, the D316E and D316E/Y317N mutants, previously shown to exhibit CypA independence for RNA replication, was unaffected by CypA. This study provides an insight into the molecular mechanism of CypA activity during HCV replication and further validates the use of CypA inhibitors in HCV therapy. PMID- 21593167 TI - Cytomegalovirus pUL96 is critical for the stability of pp150-associated nucleocapsids. AB - Maturation of human cytomegalovirus (HCMV) initiates with nucleocapsids that egress from the nucleus and associate with a juxtanuclear cytoplasmic assembly compartment, where virion envelopment and release are orchestrated. Betaherpesvirus conserved proteins pp150 (encoded by UL32) and pUL96 are critical for HCMV growth in cell culture. pp150 is a capsid-proximal tegument protein that preserves the integrity of nucleocapsids during maturation. pUL96, although expressed as an early protein, acts late during virus maturation, similar to pp150, based on the comparable antigen distribution in UL96, UL32, or UL96/UL32 dual mutant virus-infected cells. pp150 associates with nuclear capsids prior to DNA encapsidation, whereas both pp150 and pUL96 associate with extracellular virus, suggesting that pUL96 is added after pp150. In the absence of pUL96, capsid egress from the nucleus continues; however, unlike wild-type virus infection, pp150 accumulates in the nuclear, as well as in the cytoplasmic, compartment. Ultrastructural evaluation of a UL96 conditional mutant revealed intact nuclear stages but aberrant nucleocapsids accumulating in the cytoplasm comparable to the known phenotype of UL32 mutant virus. In summary, pUL96 preserves the integrity of pp150-associated nucleocapsids during translocation from the nucleus to the cytoplasm. PMID- 21593168 TI - Extensive geographical mixing of 2009 human H1N1 influenza A virus in a single university community. AB - Despite growing interest in the molecular epidemiology of influenza virus, the pattern of viral spread within individual communities remains poorly understood. To determine the phylogeography of influenza virus in a single population, we examined the spatial diffusion of H1N1/09 influenza A virus within the student body of the University of California, San Diego (UCSD), sampling for a 1-month period between October and November 2009. Despite the highly focused nature of our study, an analysis of complete viral genome sequences revealed between 24 and 33 independent introductions of H1N1/09 into the UCSD community, comprising much of the global genetic diversity in this virus. These data were also characterized by a relatively low level of on-campus transmission as well as extensive spatial mixing, such that there was little geographical clustering by either student residence or city ZIP code. Most notably, students experiencing illness on the same day and residing in the same dorm possessed phylogenetically distinct lineages. H1N1/09 influenza A virus is therefore characterized by a remarkable spatial fluidity, which is likely to impede community-based methods for its control, including class cancellations, quarantine, and chemoprophylaxis. PMID- 21593170 TI - Kaposi's sarcoma-associated herpesvirus vFLIP and human T cell lymphotropic virus type 1 Tax oncogenic proteins activate IkappaB kinase subunit gamma by different mechanisms independent of the physiological cytokine-induced pathways. AB - Activation of IkappaB kinase subunit gamma (IKKgamma), a key regulator of the classical NF-kappaB pathway, by the vFLIP protein of Kaposi's sarcoma-associated herpesvirus (KSHV) and the Tax protein of human T cell lymphotropic virus type 1 (HTLV1) is essential for virus-associated cancer. We show that vFLIP and Tax activate this pathway by different interactions with IKKgamma and independently of the ubiquitin-mediated signaling pathways induced by cytokines. Our data provide new insights into the mechanisms by which IKKgamma can be activated and show that NF-kappaB activation by oncogenic viruses can be targeted without affecting physiologically important pathways. PMID- 21593169 TI - Contribution of topology determinants of a viral movement protein to its membrane association, intracellular traffic, and viral cell-to-cell movement. AB - The p7B movement protein (MP) of Melon necrotic spot virus (MNSV) is a single pass membrane protein associated with the endoplasmic reticulum (ER), the Golgi apparatus (GA), and plasmodesmata (Pd). Experimental data presented here revealed that the p7B transmembrane domain (TMD) was sufficient to target the green fluorescent protein (GFP) to ER membranes. In addition, the short extramembrane regions of p7B were essential for subsequent ER export and transport to the GA and Pd. Microsomal partitioning and bimolecular fluorescence assays supported a type II topology of p7B in planta. Mutations affecting conventional determinants of p7B membrane topology, such as the TMD secondary structure, the overall hydrophobicity profile, the so-called "aromatic belt," and the net charge distribution on either side of the TMD, were engineered into infectious RNAs to investigate the relationship between the MP structure and MNSV cell-to-cell movement. The results revealed that (i) the overall hydrophobic profile and the alpha-helix integrity of the TMD were relevant for virus movement, (ii) modification of the net charge balance of the regions flanking both TMD sides drastically reduced cell-to-cell movement, (iii) localization of p7B to the GA was necessary but not sufficient for virus movement, and (iv) membrane insertion was essential for p7B function in virus movement. Our results therefore indicate that MNSV cell-to-cell movement requires sequential transport of p7B from the ER via the GA to Pd, which is modulated by a combination of several signals with different strengths in the extramembrane regions and TMD of the MP. PMID- 21593172 TI - One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for evaluation of new microbicide candidates. AB - Recent iPrEx clinical trial results provided evidence that systemic preexposure prophylaxis (PrEP) with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) can partially prevent rectal HIV transmission in humans. Similarly, we have previously demonstrated that systemic administration of the same FTC-TDF combination efficiently prevented rectal transmission in humanized bone marrow/liver/thymus (BLT) mice. The CAPRISA 004 trial recently demonstrated that topical application of the tenofovir could partially prevent vaginal HIV-1 transmission in humans. To further validate the usefulness of the BLT mouse model for testing HIV prevention strategies, we evaluated the topical administration of tenofovir as used in CAPRISA 004 to prevent vaginal HIV transmission in BLT mice. Our results demonstrate that vaginally administered 1% tenofovir significantly reduced HIV transmission in BLT mice (P = 0.002). Together with the results obtained after systemic antiretroviral PrEP, these topical inhibitor data serve to validate the use of humanized BLT mice to evaluate both systemic and topical inhibitors of HIV transmission. Based on these observations, we tested six additional microbicide candidates for their ability to prevent vaginal HIV transmission: a C-peptide fusion inhibitor (C52L), a membrane-disrupting amphipathic peptide inhibitor (C5A), a trimeric d-peptide fusion inhibitor (PIE12 Trimer), a combination of reverse transcriptase inhibitors (FTC-TDF), a thioester zinc finger inhibitor (TC247), and a small-molecule Rac inhibitor (NSC23766). No protection was seen with the Rac inhibitor NSC23766. The thioester compound TC247 offered partial protection. Significant protection was afforded by FTC-TDF, and complete protection was offered by three different peptide inhibitors tested. Our results demonstrate that these effective topical inhibitors have excellent potential to prevent vaginal HIV transmission in humans. PMID- 21593173 TI - The diversity of torque teno viruses: in vitro replication leads to the formation of additional replication-competent subviral molecules. AB - The family Anelloviridae comprises torque teno viruses (TTVs) diverse in genome structure and organization. The isolation of a large number of TTV genomes (TTV Heidelberg [TTV-HD]) of 26 TTV types is reported. Several isolates from the same type indicate sequence variation within open reading frame 1 (ORF1), resulting in considerably modified open reading frames. We demonstrate in vitro replication of 12 full-length genomes of TTV-HD in 293TT cells. Propagation of virus was achieved by several rounds of infections using supernatant and frozen whole cells of initially infected cells. Replication of virus was measured by PCR amplification and transcription analyses. Subgenomic molecules (MUTTV), arising early during propagation and ranging in size from 401 to 913 bases, were cloned and characterized. Propagation of these MUTTV in in vitro cultures was demonstrated in the absence of full-length genomes. PMID- 21593171 TI - The genetic bottleneck in vertical transmission of subtype C HIV-1 is not driven by selection of especially neutralization-resistant virus from the maternal viral population. AB - Subtype C human immunodeficiency virus type 1 (HIV-1C) continues to cause the majority of new cases of mother-to-child transmission (MTCT), and yet there are limited data on HIV-1C transmission. We amplified env from plasma RNA for 19 HIV 1C MTCT pairs, 10 transmitting in utero (IU) and 9 transmitting intrapartum (IP). There was a strong genetic bottleneck between all mother-infant pairs, with a majority of transmission events involving the transmission of a single virus. env genes of viruses transmitted to infants IP, but not IU, encoded Env proteins that were shorter and had fewer putative N-linked glycosylation sites in the V1-V5 region than matched maternal sequences. Viruses pseudotyped with env clones representative of each maternal and infant population were tested for neutralization sensitivity. The 50% inhibitory concentration of autologous serum was similar against both transmitted (infant) and nontransmitted (maternal) viruses in a paired analysis. Mother and infant Env proteins were also similar in sensitivity to soluble CD4, to a panel of monoclonal antibodies, and to heterologous HIV-1C sera. In addition, there was no difference in the breadth or potency of neutralizing antibodies between sera from 50 nontransmitting and 23 IU and 23 IP transmitting HIV-1C-infected women against four Env proteins from heterologous viruses. Thus, while a strong genetic bottleneck was detected during MCTC, with viruses of shorter and fewer glycosylation sites in env present in IP transmission, our data do not support this bottleneck being driven by selective resistance to antibodies. PMID- 21593174 TI - Role of interleukin-1 and MyD88-dependent signaling in rhinovirus infection. AB - Rhinoviral infection is an important trigger of acute inflammatory exacerbations in patients with underlying airway disease. We have previously established that interleukin-1beta (IL-1beta) is central in the communication between epithelial cells and monocytes during the initiation of inflammation. In this study we explored the roles of IL-1beta and its signaling pathways in the responses of airway cells to rhinovirus-1B (RV-1B) and further determined how responses to RV 1B were modified in a model of bacterial coinfection. Our results revealed that IL-1beta dramatically potentiated RV-1B-induced proinflammatory responses, and while monocytes did not directly amplify responses to RV-1B alone, they played an important role in the responses observed with our coinfection model. MyD88 is the essential signaling adapter for IL-1beta and most Toll-like receptors. To examine the role of MyD88 in more detail, we created stable MyD88 knockdown epithelial cells using short hairpin RNA (shRNA) targeted to MyD88. We determined that IL 1beta/MyD88 plays a role in regulating RV-1B replication and the inflammatory response to viral infection of airway cells. These results identify central roles for IL-1beta and its signaling pathways in the production of CXCL8, a potent neutrophil chemoattractant, in viral infection. Thus, IL-1beta is a viable target for controlling the neutrophilia that is often found in inflammatory airway disease and is exacerbated by viral infection of the airways. PMID- 21593175 TI - Ex vivo bioluminescence detection of alcelaphine herpesvirus 1 infection during malignant catarrhal fever. AB - Alcelaphine herpesvirus 1 (AlHV-1), carried by wildebeest asymptomatically, causes malignant catarrhal fever (WD-MCF) when cross-species transmitted to a variety of susceptible species of the Artiodactyla order. Experimentally, WD-MCF can be reproduced in rabbits. WD-MCF is described as a combination of lymphoproliferation and degenerative lesions in virtually all organs and is caused by unknown mechanisms. Recently, we demonstrated that WD-MCF is associated with the proliferation of CD8(+) cells supporting a latent type of infection in lymphoid tissues. Here, we investigated the macroscopic distribution of AlHV-1 infection using ex vivo bioluminescence imaging in rabbit to determine whether it correlates with the distribution of lesions in lymphoid and nonlymphoid organs. To reach that goal, a recombinant AlHV-1 strain was produced by insertion of a luciferase expression cassette (luc) in an intergenic region. In vitro, the reconstituted AlHV-1 luc(+) strain replicated comparably to the parental strain, and luciferase activity was detected by bioluminescence imaging. In vivo, rabbits infected with the AlHV-1 luc(+) strain developed WD-MCF comparably to rabbits infected with the parental wild-type strain, with hyperthermia and increases of both CD8(+) T cell frequencies and viral genomic charge over time in peripheral blood mononuclear cells and in lymph nodes at time of euthanasia. Bioluminescent imaging revealed that AlHV-1 infection could be detected ex vivo in lymphoid organs but also in lung, liver, and kidney during WD-MCF, demonstrating that AlHV 1 infection is prevalent in tissue lesions. Finally, we show that the infiltrating mononuclear leukocytes in nonlymphoid organs are mainly CD8(+) T cells and that latency is predominant during WD-MCF. PMID- 21593176 TI - CD4+ T lymphocytes are critical mediators of tumor immunity to simian virus 40 large tumor antigen induced by vaccination with plasmid DNA. AB - A mechanistic analysis of tumor immunity directed toward the viral oncoprotein simian virus 40 (SV40) large tumor antigen (Tag) has previously been described by our laboratory for scenarios of recombinant Tag immunization in BALB/c mice. In the present study, we performed a preliminary characterization of the immune components necessary for systemic tumor immunity induced upon immunization with plasmid DNA encoding SV40 Tag as a transgene (pCMV-Tag). Antibody responses to SV40 Tag were observed via indirect enzyme-linked immunosorbent assay following three intramuscular (i.m.) injections of pCMV-Tag and were typified by a mixed Th1/Th2 response. Complete tumor immunity within a murine model of pulmonary metastasis was achieved upon two i.m. injections of pCMV-Tag, as assessed by examination of tumor foci in mouse lungs, without a detectable antibody response to SV40 Tag. Induction-phase and effector-phase depletions of T cell subsets were performed in vivo via administration of depleting rat monoclonal antibodies, and these experiments demonstrated that CD4(+) T lymphocytes are required in both phases of the adaptive immune response. Conversely, depletion of CD8(+) T lymphocytes did not impair tumor immunity in either immune phase and resulted in the premature production of antibodies to SV40 Tag. Our findings are unique in that a dominant role could be ascribed to CD4(+) T lymphocytes within a model of DNA vaccine-induced tumor immunity to Tag-expressing tumor cells. Additionally, our findings provide insight into the general mechanisms of vaccine-induced tumor immunity directed toward tumors bearing distinct tumor-associated antigens. PMID- 21593177 TI - Viral determinants of polarized assembly for the murine leukemia virus. AB - Retrovirus transmission via direct cell-cell contact is more efficient than diffusion through the extracellular milieu. This is believed to be due to the ability of viruses to efficiently coordinate several steps of the retroviral life cycle at cell-cell contact sites (D. C. Johnson et al., J. Virol. 76:1-8, 2002; D. M. Phillips, AIDS 8:719-731, 1994; Q. Sattenau, Nat. Rev. Microbiol. 6:815 826, 2008). Using the murine leukemia virus (MLV) as a model retrovirus, we have previously shown that interaction between viral envelope (Env) and receptor directs viral assembly to cell-cell contact sites to promote efficient viral spreading (J. Jin et al., PLoS Biol. 7:e1000163, 2009). In addressing the underlying mechanism, we observed that Env cytoplasmic tail directs this contact induced polarized assembly. We present here the viral determinants in the Env cytoplasmic tail and Gag that are important in this process. A tyrosine residue within the cytoplasmic tail of Env was identified, which directs polarized assembly. MLV matrix-mediated membrane targeting is required for Gag recruitment to sites of cell-cell contact. Our results suggest that MLV polarized assembly is mediated by a direct or indirect interaction between both domains, thereby coupling Gag recruitment and virus assembly to Env accumulation at the cell-cell interface. In contrast, HIV Gag that assembles outside of cell-cell interfaces can subsequently be drawn into contact zones mediated by MLV Env and receptor, a finding that is consistent with the previously observed lateral movement of HIV into the virological synapse (W. Hubner et al., Science 323:1743-1747, 2009; D. Rudnicka et al., J. Virol. 83:6234-6246, 2009). As such, we observed two distinct modes of virus cell-to-cell transmission that involve either polarized or nonpolarized assembly, but both result in virus transmission. PMID- 21593178 TI - Recognition of cap structure by influenza B virus RNA polymerase is less dependent on the methyl residue than recognition by influenza A virus polymerase. AB - The cap-dependent endonuclease activity of the influenza virus RNA-dependent RNA polymerase cleaves host mRNAs to produce capped RNA fragments for primers to initiate viral mRNA synthesis. The influenza A virus (FluA) cap-dependent endonuclease preferentially recognizes the cap1 structure (m(7)GpppNm). However, little is known about the substrate specificity of the influenza B virus (FluB) endonuclease. Here, we determined the substrate specificity of the FluB polymerase using purified viral RNPs and (32)P-labeled polyribonucleotides containing a variety of cap structures (m(7)GpppGm, m(7)GpppG, and GpppG). We found that the FluA polymerase cleaves m(7)G-capped RNAs preferentially. In contrast, the FluB polymerase could efficiently cleave not only m(7)G-capped RNAs but also unmethylated GpppG-RNAs. To identify a key amino acid(s) related to the cap recognition specificity of the PB2 subunit, the transcription activity of FluB polymerases containing mutated cap-binding domains was examined by use of a minireplicon assay system. In the case of FluA PB2, Phe323, His357, and Phe404, which stack the m(7)GTP, and Glu361 and Lys376, which make hydrogen bonds with a guanine base, were essential for the transcription activity. In contrast, in the case of FluB PB2, the stacking interaction of Trp359 with a guanine base and putative hydrogen bonds using Gln325 and Glu363 were enough for the transcription activity. Taking these results together with the result for the cap-binding activity, we propose that the cap recognition pocket of FluB PB2 does not have the specificity for m(7)G-cap structures and thus is more flexible to accept various cap structures than FluA PB2. PMID- 21593179 TI - Virally expressed interleukin-10 ameliorates acute encephalomyelitis and chronic demyelination in coronavirus-infected mice. AB - The absence of interleukin-10 (IL-10), a potent anti-inflammatory cytokine results in increased immune-mediated demyelination in mice infected with a neurotropic coronavirus (recombinant J2.2-V-1 [rJ2.2]). Here, we examined the therapeutic effects of increased levels of IL-10 at early times after infection by engineering a recombinant J2.2 virus to produce IL-10. We demonstrate that viral expression of IL-10, which occurs during the peak of virus replication and at the site of disease, enhanced survival and diminished morbidity in rJ2.2 infected wild-type B6 and IL-10(-/-) mice. The protective effects of increased IL 10 levels were associated with reductions in microglial activation, inflammatory cell infiltration into the brain, and proinflammatory cytokine and chemokine production. Additionally, IL-10 increased both the frequency and number of Foxp3(+) regulatory CD4 T cells in the infected central nervous system. Most strikingly, the ameliorating effects of IL-10 produced during the first 5 days after infection were long acting, resulting in decreased demyelination during the resolution phase of the infection. Collectively, these results suggest that the pathogenic processes that result in demyelination are initiated early during infection and that they can be diminished by exogenous IL-10 delivered soon after disease onset. IL-10 functions by dampening the innate or very early T cell immune response. Further, they suggest that early treatment with IL-10 may be useful adjunct therapy in some types of viral encephalitis. PMID- 21593180 TI - Molecular epidemiology and phylogeny reveal complex spatial dynamics in areas where canine parvovirus is endemic. AB - Canine parvovirus type 2 (CPV-2) is a severe enteric pathogen of dogs, causing high mortality in unvaccinated dogs. After emerging, CPV-2 spread rapidly worldwide. However, there is now some evidence to suggest that international transmission appears to be more restricted. In order to investigate the transmission and evolution of CPV-2 both nationally and in relation to the global situation, we have used a long-range PCR to amplify and sequence the full VP2 gene of 150 canine parvoviruses obtained from a large cross-sectional sample of dogs presenting with severe diarrhea to veterinarians in the United Kingdom, over a 2-year period. Among these 150 strains, 50 different DNA sequence types (S) were identified, and apart from one case, all appeared unique to the United Kingdom. Phylogenetic analysis provided clear evidence for spatial clustering at the international level and for the first time also at the national level, with the geographical range of some sequence types appearing to be highly restricted within the United Kingdom. Evolution of the VP2 gene in this data set was associated with a lack of positive selection. In addition, the majority of predicted amino acid sequences were identical to those found elsewhere in the world, suggesting that CPV VP2 has evolved a highly fit conformation. Based on typing systems using key amino acid mutations, 43% of viruses were CPV-2a, and 57% CPV-2b, with no type 2 or 2c found. However, phylogenetic analysis suggested complex antigenic evolution of this virus, with both type 2a and 2b viruses appearing polyphyletic. As such, typing based on specific amino acid mutations may not reflect the true epidemiology of this virus. The geographical restriction that we observed both within the United Kingdom and between the United Kingdom and other countries, together with the lack of CPV-2c in this population, strongly suggests the spread of CPV within its population may be heterogeneously subject to limiting factors. This cross-sectional study of national and global CPV phylogeographic segregation reveals a substantially more complex epidemic structure than previously described. PMID- 21593181 TI - Antibody-dependent cell-mediated cytotoxicity in simian immunodeficiency virus infected rhesus monkeys. AB - With the recent demonstration in the RV144 Thai trial that a vaccine regimen that does not elicit neutralizing antibodies or cytotoxic T lymphocytes may confer protection against human immunodeficiency virus type 1 (HIV-1) infection, attention has turned to nonneutralizing antibodies as a possible mechanism of vaccine protection. In the current study, we evaluated the kinetics of the antibody-dependent cell-mediated cytotoxicity (ADCC) response during acute and chronic SIVmac251 infection of rhesus monkeys. We first adapted a flow cytometry based ADCC assay, evaluating the use of different target cells as well as different strategies for quantitation of activated natural killer (NK) cells. We found that the use of SIVmac251 Env gp130-coated target cells facilitates analyses of ADCC activity with a higher degree of sensitivity than the use of simian immunodeficiency virus (SIV)-infected target cells; however, the kinetics of the measured responses were the same using these different target cells. By comparing NK cell expression of CD107a with NK cell expression of other cytokines or chemokine molecules, we found that measuring CD107a expression is sufficient for evaluating the anti-SIV function of NK cells. We also showed that ADCC responses can be detected as early as 3 weeks after SIVmac251 infection and that the magnitude of this antibody response is inversely associated with plasma viral RNA levels in animals with moderate to high levels of viral replication. However, we also demonstrated an association between NK cell-mediated ADCC responses and the amount of SIVmac251 gp140 binding antibody that developed after viral infection. This final observation raises the possibility that the antibodies that mediate ADCC are a subset of the antibodies detected in a binding assay and arise within weeks of infection. PMID- 21593182 TI - The signal peptide of a recently integrated endogenous sheep betaretrovirus envelope plays a major role in eluding gag-mediated late restriction. AB - The exogenous and pathogenic Jaagsiekte sheep retrovirus (JSRV) coexists with highly related and biologically active endogenous retroviruses (enJSRVs). The endogenous enJS56A1 locus possesses a defective Gag polyprotein which blocks the late replication steps of related exogenous and endogenous retroviruses by a mechanism known as JSRV late restriction (JLR). Conversely, enJSRV-26, which most likely integrated into the sheep genome less than 200 years ago, is able to escape JLR. In this study, we demonstrate that the ability of enJSRV-26 to escape JLR is due to a single-amino-acid substitution in the signal peptide (SP) of its envelope glycoprotein. We show that enJSRV-26 SP does not localize to the nucleolus, unlike the functional SPs of related exogenous and endogenous sheep betaretroviruses. In addition, enJSRV-26 SP function as a posttranscriptional regulator of viral gene expression is impaired. enJSRV-26 JLR escape relies on the presence of the functional enJS56A1 SP. Moreover, we show that the ratio between enJSRV-26 and enJS56A1 Gag is critical to elude JLR. Interestingly, we found that the domestic sheep has acquired, by genome amplification, several copies of the enJS56A1 provirus. These data further reinforce the notion that transdominant enJSRV proviruses have been positively selected in domestic sheep, and that the coevolution between endogenous and exogenous sheep betaretroviruses and their host is still occurring. PMID- 21593183 TI - Effect of intra-amniotic lipopolysaccharide on nephron number in preterm fetal sheep. AB - Chorioamnionitis is an antecedent of preterm birth. We aimed to determine the effect of experimental chorioamnionitis in fetal sheep during late gestation on 1) nephron number, 2) renal corpuscle volume, and 3) renal inflammation. We hypothesized that exposure to chorioamnionitis would lead to inflammation in fetal kidneys and adversely impact on the development of nephrons, leading to a reduction in nephron number. At ~121 days of gestation (term ~147 days), pregnant ewes bearing twin or singleton fetuses received a single intra-amniotic injection of lipopolysaccharide (n = 6; 3 singletons, 3 twins); controls were either untreated or received an intra-amniotic injection of saline (n = 8; 4 singletons, 4 twins). One twin was used from each twin-bearing ewe. At ~128 days of gestation, fetuses were delivered via Caesarean section. Kidneys were collected and stereologically analyzed to determine nephron number and renal corpuscle volume. Renal inflammation was assessed using immunohistochemistry. Experimental chorioamnionitis did not affect body weight or relative kidney weight. There was a significant reduction in nephron number but no change in renal corpuscle volume in LPS-exposed fetuses relative to controls. On average, nephron number was significantly reduced by 23 and 18% in singleton and twin LPS-exposed fetuses, respectively. The degree of renal inflammation did not differ between groups. Importantly, this study demonstrates that exposure to experimental chorioamnionitis adversely impacts on nephron number in the developing fetus. PMID- 21593184 TI - Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. AB - Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone considered a promising therapeutic agent for type 2 diabetes because it stimulates beta cell proliferation and insulin secretion in a glucose-dependent manner. Cumulative evidence supports a role for GLP-1 in modulating renal function; however, the mechanisms by which GLP-1 induces diuresis and natriuresis have not been completely established. This study aimed to define the cellular and molecular mechanisms mediating the renal effects of GLP-1. GLP-1 (1 MUg.kg(-1).min(-1)) was intravenously administered in rats for the period of 60 min. GLP-1-infused rats displayed increased urine flow, fractional excretion of sodium, potassium, and bicarbonate compared with those rats that received vehicle (1% BSA/saline). GLP-1 induced diuresis and natriuresis were also accompanied by increases in renal plasma flow and glomerular filtration rate. Real-time RT-PCR in microdissected rat nephron segments revealed that GLP-1 receptor-mRNA expression was restricted to glomerulus and proximal convoluted tubule. In rat renal proximal tubule, GLP-1 significantly reduced Na(+)/H(+) exchanger isoform 3 (NHE3)-mediated bicarbonate reabsorption via a protein kinase A (PKA)-dependent mechanism. Reduced proximal tubular bicarbonate flux rate was associated with a significant increase of NHE3 phosphorylation at the PKA consensus sites in microvillus membrane vesicles. Taken together, these data suggest that GLP-1 has diuretic and natriuretic effects that are mediated by changes in renal hemodynamics and by downregulation of NHE3 activity in the renal proximal tubule. Moreover, our findings support the view that GLP-1-based agents may have a potential therapeutic use not only as antidiabetic drugs but also in hypertension and other disorders of sodium retention. PMID- 21593185 TI - SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53. AB - Nephrotoxicity is one of the important dose-limiting factors during cisplatin treatment. There is a growing body of evidence that activation of p53 has a critical role in cisplatin-induced renal apoptotic injury. The nicotinamide adenine dinucleotide-dependent protein deacetylase SIRT1 decreases apoptosis through deacetylating of p53, and resveratrol is known as an activator of SIRT1. To study the role of SIRT1 in cisplatin-induced renal injury through interaction with p53, mouse proximal tubular cells (MPT) were treated with cisplatin and examined the expression level of SIRT1, acetylation of p53, PUMA-alpha, Bax, the cytosolic/mitochondrial cytochrome c ratio, and active caspase-3. The expression of SIRT1 was decreased by cisplatin. Resveratrol, a SIRT1 activator, ameliorated cisplatin-induced acetylation of p53, apoptosis, and cytotoxicity in MPT cells. In addition, resveratrol remarkably blocked cisplatin-induced decrease of Bcl-xL in MPT cells. Further specific SIRT1 inhibition with EX 527 or small interference RNA specific to SIRT1 reversed the effect of resveratrol on cisplatin-induced toxicity. Inhibition of p53 by pifithrin-alpha reversed the effect of EX527 in protein expression of PUMA-alpha, Bcl-xL, and caspase-3 and cytotoxicity in MPT cells. SIRT1 protein expression after cisplatin treatment was significantly decreased in the kidney. SIRT1 activation by resveratrol decreased cisplatin induced apoptosis while improving the glomerular filtration rate. Taken together, our findings suggest that the modulation of p53 by SIRT1 could be a possible target to attenuate cisplatin-induced kidney injury. PMID- 21593186 TI - Generation and analyses of R8L barttin knockin mouse. AB - Barttin, a gene product of BSND, is one of four genes responsible for Bartter syndrome. Coexpression of barttin with ClC-K chloride channels dramatically induces the expression of ClC-K current via insertion of ClC-K-barttin complexes into plasma membranes. We previously showed that stably expressed R8L barttin, a disease-causing missense mutant, is retained in the endoplasmic reticulum (ER) of Madin-Darby canine kidney (MDCK) cells, with the barttin beta-subunit remaining bound to ClC-K alpha-subunits (Hayama A, Rai T, Sasaki S, Uchida S. Histochem Cell Biol 119: 485-493, 2003). However, transient expression of R8L barttin in MDCK cells was reported to impair ClC-K channel function without affecting its subcellular localization. To investigate the pathogenesis in vivo, we generated a knockin mouse model of Bartter syndrome that carries the R8L mutation. These mice display disease-like phenotypes (hypokalemia, metabolic alkalosis, and decreased NaCl reabsorption in distal tubules) under a low-salt diet. Immunofluorescence and immunoelectron microscopy revealed that the plasma membrane localization of both R8L barttin and the ClC-K channel was impaired in these mice, and transepithelial chloride transport in the thin ascending limb of Henle's loop (tAL) as well as thiazide-sensitive chloride clearance were significantly reduced. This reduction in transepithelial chloride transport in tAL, which is totally dependent on ClC-K1/barttin, correlated well with the reduction in the amount of R8L barttin localized to plasma membranes. These results suggest that the major cause of Bartter syndrome type IV caused by R8L barttin mutation is its aberrant intracellular localization. PMID- 21593187 TI - Angiotensin II-mediated biphasic regulation of proximal tubular Na+/H+ exchanger 3 is impaired during oxidative stress. AB - Angiotensin (ANG) II via AT1 receptors (AT1Rs) maintains sodium homeostasis by regulating renal sodium transporters including Na(+)/H(+) exchanger 3 (NHE3) in a biphasic manner. Low-ANG II concentration stimulates whereas high concentrations inhibit NHE3 activity. Oxidative stress has been shown to upregulate AT1R function that could modulate the ANG II-mediated NHE3 regulation. This study was designed to identify the signaling pathways responsible for ANG II-mediated biphasic regulation of proximal tubular NHE3 and the effect of oxidative stress on this phenomenon. Male Sprague-Dawley rats were chronically treated with a pro oxidant L-buthionine sulfoximine (BSO) with and without an antioxidant tempol in tap water for 3 wk. BSO-treated rats exhibited oxidative stress and high blood pressure. At low concentration (1 pM) ANG II increased NHE3 activity in proximal tubules from all animals. However, in BSO-treated rats, the stimulation was more robust and was normalized by tempol treatment. ANG II (1 pM)-mediated NHE3 activation was abolished by AT1R blocker, intracellular Ca(2+) chelator, and inhibitors of phospholipase C (PLC) and Ca(2+)-dependent calmodulin (CaM) but it was insensitive to Gialpha and protein kinase C inhibitors or AT2R antagonist. A high concentration of ANG II (1 MUM) inhibited NHE3 activity in control and tempol-treated rats. However, in BSO-treated rats, ANG II (1 MUM) continued to induce NHE3 stimulation. Tempol restored the inhibitory effect of ANG II (1 MUM) in BSO-treated rats. The inhibitory effect of ANG II (1 MUM) involved AT1R dependent, cGMP-dependent protein kinase (PKG) activation and was independent of AT2 receptor and nitric oxide signaling. We conclude that ANG II stimulates NHE3 via AT1R-PLC-CaM pathway and inhibits NHE3 by AT1R-PKG activation. Oxidative stress impaired ANG II-mediated NHE3 biphasic response in that stimulation was observed at both high- and low-ANG II concentration. PMID- 21593188 TI - Both high and low maternal salt intake in pregnancy alter kidney development in the offspring. AB - In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life. PMID- 21593189 TI - The L-kynurenine signalling pathway in trigeminal pain processing: a potential therapeutic target in migraine? AB - INTRODUCTION: In recent years the kynurenine family of compounds, metabolites of tryptophan, has become an area of intensive research because of its neuroactive properties. Two metabolites of this family have become of interest in relation to migraine and pain processing. DISCUSSION: Experimental studies have shown that kynurenic acid (KYNA) plays an important role in the transmission of sensory impulses in the trigeminovascular system and that increased levels of KYNA decrease the sensitivity of the cerebral cortex to cortical spreading depression. Furthermore, another metabolite of the kynurenine family, L-kynurenine, exerts vasodilating effects similar to nitric oxide by increasing cyclic guanosine monophosphate. CONCLUSION: This review summarizes current knowledge of the role of kynurenine signalling in trigeminal and central pain processing, including its therapeutic prospects in migraine treatment. PMID- 21593190 TI - Triptan overuse in the Dutch general population: a nationwide pharmaco epidemiology database analysis in 6.7 million people. AB - INTRODUCTION: A population-based observational study was used to assess the prevalence, demographics, risk factors, and costs of triptan overuse, defined as more than 30 (International Headache Society criteria) or 54 (stringent criteria) defined daily doses per 3 months. METHODS: Analysis of the Dutch Health Care Insurance Board Database for 2005, which included prescriptions for 6.7 million people (46% of the total Dutch population). RESULTS: Triptans were used by 85,172 (1.3%) people; of these, 8,844 (10.4%; 95% CI 10.2-10.6) were overusers by International Headache Society and 2,787 (3.3%; 95% CI 3.2-3.4) were overusers by stringent criteria. The triptan-specific odds ratios for the rate of International Headache Society overuse compared with sumatriptan were: 0.26 (95% CI 0.19-0.36) for frovatriptan; 0.34 (95% CI 0.32-0.37) for rizatriptan; 0.76 95% CI 0.68-0.85) for naratriptan; 0.86 (95% CI 0.72-1.02) for eletriptan; 0.97 (95% CI 0.88-1.06) for zolmitriptan; and 1.49 (95% CI 1.31-1.72) for almotriptan. Costs for overuse were 29.7 million euros; for the International Headache Society criteria this was 46% of total costs and for stringent criteria it was 23%. DISCUSSION: In the Dutch general population, 1.3% used a triptan in 2005, of which 10.3% were overusers and accounted for half of the total costs of triptans. Users of frovatriptan, rizatriptan and naratriptan had a lower level of overuse. PMID- 21593192 TI - IL-7 contributes to the progression of human T-cell acute lymphoblastic leukemias. AB - The importance of microenvironmental factors for driving progression in leukemia has been debated. Previous evidence has pointed to interleukin-7 (IL-7), a fundamental cytokine to normal T-cell development and homeostasis, as an important determinant of the viability and proliferation of T-cell acute lymphoblastic leukemia (T-ALL) cells in vitro. In this study, we report that IL-7 is also a critical determinant of T-ALL progression. T-ALL cell lines and primary T-ALL samples initiated leukemia more slowly when engrafted to immunocompromised Rag2(-/-)IL2rg(-/-) mice lacking IL-7. This effect was not related to reduced engraftment or homing of transplanted cells to the bone marrow. Instead, IL-7 deficiency diminished expansion of leukemia cells in the bone marrow and delayed leukemia-associated death of transplanted mice. Moreover, infiltration of different organs by T-ALL cells, which characterizes patients with advanced disease, was more heterogeneous and generally less efficient in IL-7-deficient mice. Leukemia progression was associated with increased Bcl-2 expression and cell viability, reduced p27(Kip1) expression, and decreased cell-cycle progression. Clinical measurements of IL-7 plasma levels and IL-7 receptor (IL 7R) expression in T-ALL patients versus healthy controls confirmed that IL-7 stimulates human leukemia cells. Our results establish that IL-7 contributes to the progression of human T-cell leukemia, and they offer preclinical validation of the concept that targeting IL-7/IL-7R signaling in the tumor microenvironment could elicit therapeutic effects in T-ALL. PMID- 21593191 TI - CCI-779 inhibits cell-cycle G2-M progression and invasion of castration-resistant prostate cancer via attenuation of UBE2C transcription and mRNA stability. AB - The cell-cycle G(2)-M phase gene UBE2C is overexpressed in various solid tumors including castration-resistant prostate cancer (CRPC). Our recent studies found UBE2C to be a CRPC-specific androgen receptor (AR) target gene that is necessary for CRPC growth, providing a potential novel target for therapeutic intervention. In this study, we showed that the G(1)-S cell-cycle inhibitor-779 (CCI-779), an mTOR inhibitor, inhibited UBE2C mRNA and protein expression in AR-positive CRPC cell models abl and C4-2B. Treatment with CCI-779 significantly decreased abl cell proliferation in vitro and in vivo through inhibition of cell-cycle progression of both G(2)-M and G(1)-S phases. In addition, exposure of abl and C4 2B cells to CCI-779 also decreased UBE2C-dependent cell invasion. The molecular mechanisms for CCI-779 inhibition of UBE2C gene expression involved a decreased binding of AR coactivators SRC1, SRC3, p300, and MED1 to the UBE2C enhancers, leading to a reduction in RNA polymerase II loading to the UBE2C promoter, and attenuation of UBE2C mRNA stability. Our data suggest that, in addition to its ability to block cell-cycle G(1) to S-phase transition, CCI-779 causes a cell cycle G(2)-M accumulation and an inhibition of cell invasion through a novel UBE2C-dependent mechanism, which contributes to antitumor activities of CCI-779 in UBE2C overexpressed AR-positive CRPC. PMID- 21593193 TI - A novel function of junctional adhesion molecule-C in mediating melanoma cell metastasis. AB - Hematogenous dissemination of melanoma is a life-threatening complication of this malignant tumor. Here, we identified junctional adhesion molecule-C (JAM-C) as a novel player in melanoma metastasis to the lung. JAM-C expression was identified in human and murine melanoma cell lines, in human malignant melanoma, as well as in metastatic melanoma including melanoma lung metastasis. JAM-C expressed on both murine B16 melanoma cells as well as on endothelial cells promoted the transendothelial migration of the melanoma cells. We generated mice with inactivation of JAM-C. JAM-C(-/-) mice as well as endothelial-specific JAM-C deficient mice displayed significantly decreased B16 melanoma cell metastasis to the lung, whereas treatment of mice with soluble JAM-C prevented melanoma lung metastasis. Together, JAM-C represents a novel therapeutic target for melanoma metastasis. PMID- 21593194 TI - Stem cell quiescence. AB - Adult stem cells are maintained in a quiescent state but are able to exit quiescence and rapidly expand and differentiate in response to stress. The quiescent state appears to be necessary for preserving the self-renewal of stem cells and is a critical factor in the resistance of cancer stem cells (CSCs) to chemotherapy and targeted therapies. Limited knowledge about quiescence mechanisms has prevented significant advances in targeting of drug-resistant quiescent CSCs populations in the clinic. Thus, an improved understanding of the molecular mechanisms of quiescence in adult stem cells is critical for the development of molecularly targeted therapies against quiescent CSCs in different cancers. Recent studies have provided a better understanding of the intrinsic and extrinsic regulatory mechanisms that control stem cell quiescence. It is now appreciated that the p53 gene plays a critical role in regulating stem cell quiescence. Other intrinsic regulatory mechanisms include the FoxO, HIF-1alpha, and NFATc1 transcription factors and signaling through ATM and mTOR. Extrinsic microenvironmental regulatory mechanisms include angiopoietin-1, TGF-beta, bone morphogenic protein, thrombopoietin, N-cadherin, and integrin adhesion receptors; Wnt/beta-catenin signaling; and osteopontin. In this article, we review current advances in understanding normal stem cell quiescence, their significance for CSC quiescence and drug resistance, and the potential clinical applications of these findings. PMID- 21593195 TI - Early G1 cyclin-dependent kinases as prognostic markers and potential therapeutic targets in esophageal adenocarcinoma. AB - PURPOSE: Chromosomal gain at 7q21 is a frequent event in esophageal adenocarcinoma (EAC). However, this event has not been mapped with fine resolution in a large EAC cohort, and its association with clinical endpoints and functional relevance are unclear. EXPERIMENTAL DESIGN: We used a cohort of 116 patients to fine map the 7q21 amplification using SNP microarrays. Prognostic significance and functional role of 7q21 amplification and its gene expression were explored. RESULTS: Amplification of the 7q21 region was observed in 35% of tumors with a focal, minimal amplicon containing six genes. 7q21 amplification was associated with poor survival and analysis of gene expression identified cyclin-dependent kinase 6 (CDK6) as the only gene in the minimal amplicon whose expression was also associated with poor survival. A low-level amplification (10%) was observed at the 12q13 region containing the CDK6 homologue cyclin dependent kinase 4 (CDK4). Both amplification and expression of CDK4 correlated with poor survival. A combined model of both CDK6 and CDK4 expressions is a superior predictor of survival than either alone. Specific knockdown of CDK4 and/or CDK6 by siRNAs shows that they are required for proliferation of EAC cells and that their function is additive. PD-0332991 targets the kinase activity of both molecules and suppresses proliferation and anchorage independence of EAC cells through activation of the pRB pathway. CONCLUSIONS: We suggest that CDK6 is the driver of 7q21 amplification and that both CDK4 and CDK6 are prognostic markers and bona fide oncogenes in EAC. Targeting these molecules may constitute a viable new therapy for this disease. PMID- 21593197 TI - Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer. AB - Etiologic factors for pancreatic cancer, the 4th deadliest malignant neoplasm in the United States, include obesity and abnormal glucose metabolism. Calorie restriction (CR) and rapamycin each affect energy metabolism and cell survival pathways via inhibition of mammalian target of rapamycin (mTOR) signaling. By using a Panc02 murine pancreatic cancer cell transplant model in 45 male C57BL/6 mice, we tested the hypothesis that rapamycin mimics the effects of CR on pancreatic tumor growth. A chronic regimen of CR, relative to an ad libitum-fed control diet, produced global metabolic effects such as reduced body weight (20.6 +/- 1.6 g vs. 29.3 +/- 2.3 g; P < 0.0001), improved glucose responsiveness, and decreased circulating levels of insulin-like growth factor (IGF)-1 (126 +/- 8 ng/mL vs. 199 +/- 11 ng/mL; P = 0.0006) and leptin (1.14 +/- 0.2 ng/mL vs. 5.05 +/- 1.2 ng/mL; P = 0.01). In contrast, rapamycin treatment (2.5 mg/kg intraperitoneal every other day, initiated in mice following 20 weeks of ad libitum control diet consumption), relative to control diet, produced no significant change in body weight, IGF-1 or leptin levels, but decreased glucose responsiveness. Pancreatic tumor volume was significantly reduced in the CR group (221 +/- 107 mm(3); P < 0.001) and, to a lesser extent, the rapamycin group (374 +/- 206 mm(3); P = 0.04) relative to controls (550 +/- 147 mm(3)), and this differential inhibition correlated with expression of the proliferation marker Ki 67. Both CR and rapamycin decreased phosphorylation of mTOR, p70/S6K, and S6 ribosomal protein, but only CR decreased phosphorylation of Akt, GSK-3beta, extracellular signal regulated kinase/mitogen-activated protein kinase, and STAT3(TYR705). These findings suggest that rapamycin partially mimics the anticancer effects of CR on tumor growth in a murine model of pancreatic cancer. PMID- 21593196 TI - Genetic reduction of insulin-like growth factor-1 mimics the anticancer effects of calorie restriction on cyclooxygenase-2-driven pancreatic neoplasia. AB - Risk of pancreatic cancer, the fourth deadliest cancer in the United States, is increased by obesity. Calorie restriction (CR) prevents obesity, suppresses carcinogenesis in many models, and reduces serum levels of IGF-1. In the present study, we examined the impact of CR on a model of inflammation-associated pancreatitis and pancreatic dysplasia, with a focus on the mechanistic contribution of systemic IGF-1. Administration of a 30% CR diet for 14 weeks decreased serum IGF-1 levels and hindered pancreatic ductal lesion formation and dysplastic severity, relative to a higher calorie control diet, in transgenic mice overexpressing COX-2 [bovine keratin-5 promoter (BK5.COX-2)]. These findings in CR mice correlated with reductions in Ki-67-positive cells, vascular luminal size, VEGF expression, and phosphorylation and total expression of downstream mediators of the IGF-1 pathway. Cell lines derived from BK5.COX-2 ductal lesions (JC101 cells) formed pancreatic tumors in wild-type FVB mice that were significantly reduced in size by a 14-week CR regimen, relative to the control diet. To further understand the impact of circulating levels of IGF-1 on tumor growth in this model, we orthotopically injected JC101 cells into liver-specific IGF-1-deficient (LID) mice. The approximate 65% reduction of serum IGF-1 levels in LID mice resulted in significantly decreased burden of JC101 tumors, despite modestly elevated levels of circulating insulin and leptin. These data show that CR prevents development of dysplasia and growth of pancreatic cancer through alterations in IGF-1, suggesting that modulation of this pathway with dietary and/or pharmacologic interventions is a promising pancreatic cancer prevention strategy. PMID- 21593198 TI - Prolonged Tpeak-to-tend interval on the resting ECG is associated with increased risk of sudden cardiac death. AB - BACKGROUND: Early studies indicate that prolongation of the interval between the peak and the end of the T wave (Tpeak to Tend [TpTe]) on the 12-lead ECG is a marker of ventricular arrhythmogenesis. However, community-based studies have not been conducted. METHODS AND RESULTS: TpTe and other ECG predictors were evaluated in the ongoing Oregon Sudden Unexpected Death Study based in the Portland, Oregon, metropolitan area using a case-control design. Cases of sudden cardiac death (SCD) (n = 353; mean age, 66.6 years; 95% CI, 65.1 to 68.1 years; 67% men) were compared with living controls with coronary artery disease (n = 342; mean age, 64.7 years; 95% CI, 63.4 to 66.0 years; 69% men) from the same region. Analysis of TpTe and selected ECG intervals was limited to sinus rhythm 12-lead ECGs. For cases, these were obtained before and unrelated to SCD. Independent samples t tests and multiple logistic regression were used. Mean TpTe was significantly greater in cases (89.4 ms; 95% CI, 87.7 to 91.2 ms; P < 0.0001) than in controls (76.1 ms; 95% CI, 74.8 to 77.4 ms). The other ECG intervals (corrected QT interval [QTc], QRS duration [QRSD], and TpTe/QT ratio) also were significantly prolonged among cases versus controls (P <= 0.01). TpTe remained a significant predictor of SCD after adjusting for age, sex, QTc, QRSD, and left ventricular function. Odds of SCD increased more with a 1-SD increase in TpTe (12 ms) among subjects with prolonged QRSD (odds ratio, 3.49; 95% CI, 2.06 to 5.91) than with a 1-SD increase in TpTe among subjects with normal QRSD (odds ratio, 1.96; 95% CI, 1.65 to 2.32). TpTe remained significantly associated with SCD in subjects with normal QTc. CONCLUSIONS: Prolongation of the TpTe interval measured in lead V5 was independently associated with SCD, with particular utility when the QTc was normal or not measurable because of prolonged QRSD. PMID- 21593199 TI - Cellular localization of glutamate and glutamine metabolism and transport pathways in the rat ciliary epithelium. AB - PURPOSE: To investigate how glutamate and glutamine levels are established in the aqueous humor by identifying the transporters and metabolism pathways that contribute to the differential accumulation of glutamate and glutamine between the distinct epithelial cell layers that constitute the ciliary body. METHODS: Postembedding immunohistochemistry and silver intensification were used to quantify the relative distributions of glutamate, glutamine, and related amino acids (aspartate, alanine, GABA, and glycine) in the pigmented (PE) and nonpigmented (NPE) epithelial cells of the ciliary body. Fluorescent immunocytochemistry was used to localize Na(+)-dependent glutamate transporters (EAAT1-5), glutamine transporters (LAT1, LAT2, and b(0,+)AT), and the enzyme glutamine synthetase (GS) in the ciliary epithelium. Intravitreal injection of the GS inhibitor methionine sulfoximine (MSO) or the EAAT functional probe D aspartate was used to modulate GS activity and indirectly monitor glutamate uptake from the aqueous, respectively. RESULTS: Although glutamate, glutamine, and alanine were preferentially accumulated in NPE relative to PE cells, no such differential distribution of aspartate, GABA, or glycine was observed. This differential distribution of amino acids was abolished by a single injection of MSO that caused a decrease in glutamine and an increase in glutamate levels in NPE compared with PE cells. This amino acid distribution plus an observed strong labeling of EAAT3 in the interface between the PE and the NPE cell layers indicate that EAAT3 mediates the uptake of glutamate from the blood. Weaker EAAT3 labeling of the basolateral membranes of NPE cells, coupled with the accumulation of injected D-aspartate by the ciliary epithelium, indicates that NPE cells also mediate glutamate uptake directly from the aqueous. In contrast, the basolateral localization of LAT1 and b(0,+)AT in NPE cells suggest that these transporters may mediate glutamine efflux from the NPE cells into the aqueous. CONCLUSIONS: The basolateral membrane localization of EAAT3 and LAT1/b(0,+)AT in NPE cells indicates that the low glutamate and high glutamine levels observed in the aqueous are determined by glutamate uptake and glutamine efflux, respectively. Furthermore, the concentration gradient for glutamine efflux appears to be generated by the active accumulation of glutamate by EAAT3, located in the apical membrane of NPE cells and the subsequent conversion of the accumulated glutamate to glutamine by GS in NPE cells. This suggests that in contrast to fluid transport, which uses both the PE and the NPE cell layers, the transepithelial transport of glutamine occurs primarily in the NPE cell layer. PMID- 21593200 TI - Klotho depletion contributes to increased inflammation in kidney of the db/db mouse model of diabetes via RelA (serine)536 phosphorylation. AB - OBJECTIVE: Klotho is an antiaging hormone present in the kidney that extends the lifespan, regulates kidney function, and modulates cellular responses to oxidative stress. We investigated whether Klotho levels and signaling modulate inflammation in diabetic kidneys. RESEARCH DESIGN AND METHODS: Renal Klotho expression was determined by quantitative real-time PCR and immunoblot analysis. Primary mouse tubular epithelial cells were treated with methylglyoxalated albumin, and Klotho expression and inflammatory cytokines were measured. Nuclear factor (NF)-kappaB activation was assessed by treating human embryonic kidney (HEK) 293 and HK-2 cells with tumor necrosis factor (TNF)-alpha in the presence or absence of Klotho, followed by immunoblot analysis to evaluate inhibitor of kappaB (IkappaB)alpha degradation, IkappaB kinase (IKK) and p38 activation, RelA nuclear translocation, and phosphorylation. A chromatin immunoprecipitation assay was performed to analyze the effects of Klotho signaling on interleukin-8 and monocyte chemoattractant protein-1 promoter recruitment of RelA and RelA serine (Ser)(536). RESULTS: Renal Klotho mRNA and protein were significantly decreased in db/db mice, and a similar decline was observed in the primary cultures of mouse tubule epithelial cells treated with methylglyoxal-modified albumin. The exogenous addition of soluble Klotho or overexpression of membranous Klotho in tissue culture suppressed NF-kappaB activation and subsequent production of inflammatory cytokines in response to TNF-alpha stimulation. Klotho specifically inhibited RelA Ser(536) phosphorylation as well as promoter DNA binding of this phosphorylated form of RelA without affecting IKK-mediated IkappaBalpha degradation, total RelA nuclear translocation, and total RelA DNA binding. CONCLUSIONS: These findings suggest that Klotho serves as an anti-inflammatory modulator, negatively regulating the production of NF-kappaB-linked inflammatory proteins via a mechanism that involves phosphorylation of Ser(536) in the transactivation domain of RelA. PMID- 21593201 TI - Inhibition of plasminogen activator inhibitor-1 restores skeletal muscle regeneration in untreated type 1 diabetic mice. AB - OBJECTIVE: Type 1 diabetes leads to impairments in growth, function, and regenerative capacity of skeletal muscle; however, the underlying mechanisms have not been clearly defined. RESEARCH DESIGN AND METHODS: With the use of Ins2(WT/C96Y) mice (model of adolescent-onset type 1 diabetes), muscle regeneration was characterized in terms of muscle mass, myofiber size (cross sectional area), and protein expression. Blood plasma was analyzed for glucose, nonesterified fatty acids, insulin, and plasminogen activator inhibitor-1 (PAI 1). PAI-039, an effective inhibitor of PAI-1, was orally administered to determine if PAI-1 was attenuating muscle regeneration in Ins2(WT/C96Y) mice. RESULTS: Ins2(WT/C96Y) mice exposed to 1 or 8 weeks of untreated type 1 diabetes before chemically induced muscle injury display significant impairments in their regenerative capacity as demonstrated by decreased muscle mass, myofiber cross sectional area, myogenin, and Myh3 expression. PAI-1, a physiologic inhibitor of the fibrinolytic system and primary contributor to other diabetes complications, was more than twofold increased within 2 weeks of diabetes onset and remained elevated throughout the experimental period. Consistent with increased circulating PAI-1, regenerating muscles of diabetic mice exhibited excessive collagen levels at 5 and 10 days postinjury with concomitant decreases in active urokinase plasminogen activator and matrix metalloproteinase-9. Pharmacologic inhibition of PAI-1 with orally administered PAI-039 rescued the early regenerative impairments in noninsulin-treated Ins2(WT/C96Y) mice. CONCLUSIONS: Taken together, these data illustrate that the pharmacologic inhibition of elevated PAI-1 restores the early impairments in skeletal muscle repair observed in type 1 diabetes and suggests that early interventional studies targeting PAI-1 may be warranted to ensure optimal growth and repair in adolescent diabetic skeletal muscle. PMID- 21593202 TI - Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. AB - OBJECTIVE: Comprehensive proteomic profiling of the human adipocyte secretome identified dipeptidyl peptidase 4 (DPP4) as a novel adipokine. This study assessed the functional implications of the adipokine DPP4 and its association to the metabolic syndrome. RESEARCH DESIGN AND METHODS: Human adipocytes and skeletal and smooth muscle cells were used to monitor DPP4 release and assess the effects of soluble DPP4 on insulin signaling. In lean and obese subjects, depot specific expression of DPP4 and its release from adipose tissue explants were determined and correlated to parameters of the metabolic syndrome. RESULTS: Fully differentiated adipocytes exhibit a substantially higher release of DPP4 compared with preadipocytes or macrophages. Direct addition of DPP4 to fat and skeletal and smooth muscle cells impairs insulin signaling. A fivefold higher level of DPP4 protein expression was seen in visceral compared with subcutaneous fat of obese patients, with no regional difference in lean subjects. DPP4 serum concentrations significantly correlated with adipocyte size. By using adipose tissue explants from lean and obese subjects, we observed a twofold increase in DPP4 release that strongly correlated with adipocyte volume and parameters of the metabolic syndrome and was decreased to the lean level after weight reduction. DPP4 released from adipose tissue correlated positively with an increasing risk score for the metabolic syndrome. CONCLUSIONS: DPP4 is a novel adipokine that may impair insulin sensitivity in an autocrine and paracrine fashion. Furthermore, DPP4 release strongly correlates with adipocyte size, potentially representing an important source of DPP4 in obesity. Therefore, we suggest that DPP4 may be involved in linking adipose tissue and the metabolic syndrome. PMID- 21593203 TI - Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. AB - OBJECTIVE: Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed. RESEARCH DESIGN AND METHODS: Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity. RESULTS: FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of beta-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism. CONCLUSIONS: Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis. PMID- 21593204 TI - The phospholipase A2 enzyme complex PAFAH Ib mediates endosomal membrane tubule formation and trafficking. AB - Previous studies have shown that membrane tubule-mediated export from endosomal compartments requires a cytoplasmic phospholipase A(2) (PLA(2)) activity. Here we report that the cytoplasmic PLA(2) enzyme complex platelet-activating factor acetylhydrolase (PAFAH) Ib, which consists of alpha1, alpha2, and LIS1 subunits, regulates the distribution and function of endosomes. The catalytic subunits alpha1 and alpha2 are located on early-sorting endosomes and the central endocytic recycling compartment (ERC) and their overexpression, but not overexpression of their catalytically inactive counterparts, induced endosome membrane tubules. In addition, overexpression alpha1 and alpha2 altered normal endocytic trafficking; transferrin was recycled back to the plasma membrane directly from peripheral early-sorting endosomes instead of making an intermediate stop in the ERC. Consistent with these results, small interfering RNA-mediated knockdown of alpha1 and alpha2 significantly inhibited the formation of endosome membrane tubules and delayed the recycling of transferrin. In addition, the results agree with previous reports that PAFAH Ib alpha1 and alpha2 expression levels affect the distribution of endosomes within the cell through interactions with the dynein regulator LIS1. These studies show that PAFAH Ib regulates endocytic membrane trafficking through novel mechanisms involving both PLA(2) activity and LIS1-dependent dynein function. PMID- 21593205 TI - The eisosome core is composed of BAR domain proteins. AB - Eisosomes define sites of plasma membrane organization. In Saccharomyces cerevisiae, eisosomes delimit furrow-like plasma membrane invaginations that concentrate sterols, transporters, and signaling molecules. Eisosomes are static macromolecular assemblies composed of cytoplasmic proteins, most of which have no known function. In this study, we used a bioinformatics approach to analyze a set of 20 eisosome proteins. We found that the core components of eisosomes, paralogue proteins Pil1 and Lsp1, are distant homologues of membrane-sculpting Bin/amphiphysin/Rvs (BAR) proteins. Consistent with this finding, purified recombinant Pil1 and Lsp1 tubulated liposomes and formed tubules when the proteins were overexpressed in mammalian cells. Structural homology modeling and site-directed mutagenesis indicate that Pil1 positively charged surface patches are needed for membrane binding and liposome tubulation. Pil1 BAR domain mutants were defective in both eisosome assembly and plasma membrane domain organization. In addition, we found that eisosome-associated proteins Slm1 and Slm2 have F-BAR domains and that these domains are needed for targeting to furrow-like plasma membrane invaginations. Our results support a model in which BAR domain protein mediated membrane bending leads to clustering of lipids and proteins within the plasma membrane. PMID- 21593206 TI - Targeted inactivation of integrin-linked kinase in hair follicle stem cells reveals an important modulatory role in skin repair after injury. AB - Integrin-linked kinase (ILK) is key for normal epidermal morphogenesis, but little is known about its role in hair follicle stem cells and epidermal regeneration. Hair follicle stem cells are important contributors to newly formed epidermis following injury. We inactivated the Ilk gene in the keratin 15- expressing stem cell population of the mouse hair follicle bulge. Loss of ILK expression in these cells resulted in impaired cutaneous wound healing, with substantially decreased wound closure rates. ILK-deficient stem cells produced very few descendants that moved toward the epidermal surface and into the advancing epithelium that covers the wound. Furthermore, those few mutant cells that homed in the regenerated epidermis exhibited a reduced residence time. Paradoxically, ILK-deficient bulge stem cells responded to anagen growth signals and contributed to newly regenerated hair follicles during this phase of hair follicle growth. Thus ILK plays an important modulatory role in the normal contribution of hair follicle stem cell progeny to the regenerating epidermis following injury. PMID- 21593207 TI - Mms1 and Mms22 stabilize the replisome during replication stress. AB - Mms1 and Mms22 form a Cul4(Ddb1)-like E3 ubiquitin ligase with the cullin Rtt101. In this complex, Rtt101 is bound to the substrate-specific adaptor Mms22 through a linker protein, Mms1. Although the Rtt101(Mms1/Mms22) ubiquitin ligase is important in promoting replication through damaged templates, how it does so has yet to be determined. Here we show that mms1Delta and mms22Delta cells fail to properly regulate DNA replication fork progression when replication stress is present and are defective in recovery from replication fork stress. Consistent with a role in promoting DNA replication, we find that Mms1 is enriched at sites where replication forks have stalled and that this localization requires the known binding partners of Mms1-Rtt101 and Mms22. Mms1 and Mms22 stabilize the replisome during replication stress, as binding of the fork-pausing complex components Mrc1 and Csm3, and DNA polymerase epsilon, at stalled replication forks is decreased in mms1Delta and mms22Delta. Taken together, these data indicate that Mms1 and Mms22 are important for maintaining the integrity of the replisome when DNA replication forks are slowed by hydroxyurea and thereby promote efficient recovery from replication stress. PMID- 21593208 TI - CDK promotes interactions of Sld3 and Drc1 with Cut5 for initiation of DNA replication in fission yeast. AB - Cyclin-dependent kinase (CDK) plays essential roles in the initiation of DNA replication in eukaryotes. Although interactions of CDK-phosphorylated Sld2/Drc1 and Sld3 with Dpb11 have been shown to be essential in budding yeast, it is not known whether the mechanism is conserved. In this study, we investigated how CDK promotes the assembly of replication proteins onto replication origins in fission yeast. Phosphorylation of Sld3 was found to be dependent on CDK in S phase. Alanine substitutions at CDK sites decreased the interaction with Cut5/Dpb11 at the N-terminal BRCT motifs and decreased the loading of Cut5 onto replication origins. This defect was suppressed by overexpression of drc1(+). Phosphorylation of a conserved CDK site, Thr-111, in Drc1 was critical for interaction with Cut5 at the C-terminal BRCT motifs and was required for loading of Cut5. In a yeast three-hybrid assay, Sld3, Cut5, and Drc1 were found to form a ternary complex dependent on the CDK sites of Sld3 and Drc1, and Drc1-Cut5 binding enhanced the Sld3-Cut5 interaction. These results show that the mechanism of CDK-dependent loading of Cut5 is conserved in fission yeast in a manner similar to that elucidated in budding yeast. PMID- 21593209 TI - Reduced Mad2 expression keeps relaxed kinetochores from arresting budding yeast in mitosis. AB - Chromosome segregation depends on the spindle checkpoint, which delays anaphase until all chromosomes have bound microtubules and have been placed under tension. The Mad1-Mad2 complex is an essential component of the checkpoint. We studied the consequences of removing one copy of MAD2 in diploid cells of the budding yeast, Saccharomyces cerevisiae. Compared to MAD2/MAD2 cells, MAD2/mad2Delta heterozygotes show increased chromosome loss and have different responses to two insults that activate the spindle checkpoint: MAD2/mad2Delta cells respond normally to antimicrotubule drugs but cannot respond to chromosomes that lack tension between sister chromatids. In MAD2/mad2Delta cells with normal sister chromatid cohesion, removing one copy of MAD1 restores the checkpoint and returns chromosome loss to wild-type levels. We conclude that cells need the normal Mad2:Mad1 ratio to respond to chromosomes that are not under tension. PMID- 21593210 TI - CDK-dependent phosphorylation of Mob2 is essential for hyphal development in Candida albicans. AB - Nuclear Dbf2-related (NDR) protein kinases are essential components of regulatory pathways involved in cell morphogenesis, cell cycle control, and viability in eukaryotic cells. For their activity and function, these kinases require interaction with Mob proteins. However, little is known about how the Mob proteins are regulated. In Candida albicans, the cyclin-dependent kinase (CDK) Cdc28 and the NDR kinase Cbk1 are required for hyphal growth. Here we demonstrate that Mob2, the Cbk1 activator, undergoes a Cdc28-dependent differential phosphorylation on hyphal induction. Mutations in the four CDK consensus sites in Mob2 to Ala significantly impaired hyphal development. The mutant cells produced short hyphae with enlarged tips that displayed an illicit activation of cell separation. We also show that Cdc28 phosphorylation of Mob2 is essential for the maintenance of polarisome components at hyphal tips but not at bud tips during yeast growth. Thus we have found a novel signaling pathway by which Cdc28 controls Cbk1 through the regulatory phosphorylation of Mob2, which is crucial for normal hyphal development. PMID- 21593211 TI - Extracellular matrix composition and remodeling in human abdominal aortic aneurysms: a proteomics approach. AB - Abdominal aortic aneurysms (AAA) are characterized by pathological remodeling of the aortic extracellular matrix (ECM). However, besides the well-characterized elastolysis and collagenolysis little is known about changes in other ECM proteins. Previous proteomics studies on AAA focused on cellular changes without emphasis on the ECM. In the present study, ECM proteins and their degradation products were selectively extracted from aneurysmal and control aortas using a solubility-based subfractionation methodology and analyzed by gel-liquid chromatography-tandem MS and label-free quantitation. The proteomics analysis revealed novel changes in the ECM of AAA, including increased expression as well as degradation of collagen XII, thrombospondin 2, aortic carboxypeptidase-like protein, periostin, fibronectin and tenascin. Proteomics also confirmed the accumulation of macrophage metalloelastase (MMP-12). Incubation of control aortic tissue with recombinant MMP-12 resulted in the extensive fragmentation of these glycoproteins, most of which are novel substrates of MMP-12. In conclusion, our proteomics methodology allowed the first detailed analysis of the ECM in AAA and identified markers of pathological ECM remodeling related to MMP-12 activity. PMID- 21593212 TI - Proteomic analysis of schistosoma japonicum schistosomulum proteins that are differentially expressed among hosts differing in their susceptibility to the infection. AB - Schistosomiasis is a tropical, parasitic disease affecting humans and several animal species. The aim of this study was to identify proteins involved in the growth and survival of the parasitic forms inside a host. Schistosomula of Schistosoma japonicum were isolated from three different hosts: the susceptible BALB/c mice; the Wistar rats, which have a considerably lower susceptibility; and the resistant reed vole, Microtus fortis. Soluble proteins of the schistosomula collected from the above three hosts 10 days postinfection were subjected to two dimensional difference gel electrophoresis. Comparative proteomic analyses revealed that 39, 21, and 25 protein spots were significantly differentially expressed between schistosomula from mice and rats, mice and reed voles, or rats and reed voles, respectively (ANCOVA, p < 0.05). Further, the protein spots were identified by liquid chromatography-tandem MS. Bioinformatics analysis showed that the differentially expressed proteins were essentially those involved in the metabolism of proteins, ribonucleotides, or carbohydrates, or in stress response or cellular movement. This study represents the first attempt at profiling S. japonicum living in different states and provides a basis for a better understanding of the molecular mechanisms in the development and survival of S. japonicum in different host environments. PMID- 21593213 TI - Biological qualification of biomarkers of chemical-induced renal toxicity in two strains of male rat. AB - This study reports the evaluation of four urinary biomarkers of renal toxicity, alpha-glutathione-S-transferase (alpha-GST), MU-GST, clusterin, and renal papillary antigen-1 (RPA-1), in male Sprague-Dawley and Han-Wistar rats given cisplatin, gentamicin, or N-phenylanthranilic acid (NPAA). Kidney injury was diagnosed histopathologically, according to site/nature of renal injury, and graded for severity. The area under the receiver operating characteristic (ROC) curve was used to compare the diagnostic accuracy of each exploratory renal biomarker with traditional indicators of renal function and injury (blood urea nitrogen [BUN], serum creatinine [sCr] as well as urinary N-acetyl-beta-D glucosaminidase [NAG] and protein). These analyses showed that increased urinary alpha-GST was superior to BUN, sCr, and NAG for diagnosis of proximal tubular (PT) degeneration/necrosis. Paradoxically, urinary alpha-GST was decreased in the presence of collecting duct (CD) injury without PT injury (NPAA administration). RPA-1 demonstrated high specificity for CD injury, superior to all of the reference biomarkers. The clusterin response correlated well with tubular injury, whatever the location, particularly when regeneration was present (superior to all of the reference markers for cortical tubular regeneration). There was no conclusive evidence for the diagnostic utility of MU-GST. The data were submitted for qualification review by the European Medicines Agency and the US Food and Drug Administration. Both agencies concluded that the data justified the qualification of RPA-1 and increased the level of evidence for, and clarified the context of use of, the previously qualified clusterin for use in male rats. These biomarkers can be used in conjunction with traditional clinical chemistry markers and histopathology in Good Laboratory Practice rodent toxicology studies used to support renal safety studies in clinical trials. Qualification of alpha-GST must await further explanation of the differences in response to PT and CD injury. PMID- 21593214 TI - Highly purified spermatozoal RNA obtained by a novel method indicates an unusual 28S/18S rRNA ratio and suggests impaired ribosome assembly. AB - Human spermatozoal RNA features special characteristics such as a significantly reduced quantity within spermatozoa compared with somatic cells is described as being devoid of ribosomal RNAs and is difficult to isolate due to a massive excess of genomic DNA in the lysates. Using a novel two-round column-based protocol for human ejaculates delivering highly purified spermatozoal RNA, we uncovered a heterogeneous, but specific banding pattern in microelectrophoresis with 28S ribosomal RNA being indicative for the amount of round cell contamination. Ejaculates with different round cell quantities and density purified spermatozoa revealed that 18S rRNA but not 28S rRNA is inherent to a pure spermatozoal fraction. Transmission electron microscopy showed monoribosomes and polyribosomes in spermatozoal cytoplasm, while immunohistochemical results suggest the presence of proteins from small and large ribosomal subunits in retained spermatozoal cytoplasm irrespective of 28S rRNA absence. PMID- 21593215 TI - Ethylene and 1-methylcyclopropene differentially regulate gene expression during onion sprout suppression. AB - Onion (Allium cepa) is regarded as a nonclimacteric vegetable. In onions, however, ethylene can suppress sprouting while the ethylene-binding inhibitor 1 methylcyclopropene (1-MCP) can also suppress sprout growth; yet, it is unknown how ethylene and 1-MCP elicit the same response. In this study, onions were treated with 10 MUL L(-1) ethylene or 1 MUL L(-1) 1-MCP individually or in combination for 24 h at 20 degrees C before or after curing (6 weeks) at 20 degrees C or 28 degrees C and then stored at 1 degrees C. Following curing, a subset of these same onions was stored separately under continuous air or ethylene (10 MUL L(-1)) at 1 degrees C. Onions treated with ethylene and 1-MCP in combination after curing for 24 h had reduced sprout growth as compared with the control 25 weeks after harvest. Sprout growth following storage beyond 25 weeks was only reduced through continuous ethylene treatment. This observation was supported by a higher proportion of down-regulated genes characterized as being involved in photosynthesis, measured using a newly developed onion microarray. Physiological and biochemical data suggested that ethylene was being perceived in the presence of 1-MCP, since sprout growth was reduced in onions treated with 1 MCP and ethylene applied in combination but not when applied individually. A cluster of probes representing transcripts up-regulated by 1-MCP alone but down regulated by ethylene alone or in the presence of 1-MCP support this suggestion. Ethylene and 1-MCP both down-regulated a probe tentatively annotated as an ethylene receptor as well as ethylene-insensitive 3, suggesting that both treatments down-regulate the perception and signaling events of ethylene. PMID- 21593216 TI - Functional characterization of a eukaryotic melibiose transporter. AB - Pathogenic fungi drastically affect plant health and cause significant losses in crop yield and quality. In spite of their impact, little is known about the carbon sources used by these fungi in planta and about the fungal transporters importing sugars from the plant-fungus interface. Here, we report on the identification and characterization of MELIBIOSE TRANSPORTER1 (MBT1) from the hemibiotrophic fungus Colletotrichum graminicola (teleomorph Glomerella graminicola), the causal agent of leaf anthracnose and stalk rot disease in maize (Zea mays). Functional characterization of the MBT1 protein in baker's yeast (Saccharomyces cerevisiae) expressing the MBT1 cDNA revealed that alpha-D galactopyranosyl compounds such as melibiose, galactinol, and raffinose are substrates of MBT1, with melibiose most likely being the preferred substrate. alpha-D-glucopyranosyl disaccharides like trehalose, isomaltose, or maltose are also accepted by MBT1, although with lower affinities. The MBT1 gene shows low and comparable expression levels in axenically grown C. graminicola and upon infection of maize leaves both during the initial biotrophic development of the fungus and during the subsequent necrotrophic phase. Despite these low levels of MBT1 expression, the MBT1 protein allows efficient growth of C. graminicola on melibiose as sole carbon source in axenic cultures. Although Deltambt1 mutants are unable to grow on melibiose, they do not show virulence defects on maize. PMID- 21593218 TI - Functional human artificial chromosomes are generated and stably maintained in human embryonic stem cells. AB - We present a novel and efficient non-integrating gene expression system in human embryonic stem cells (hESc) utilizing human artificial chromosomes (HAC), which behave as autonomous endogenous host chromosomes and segregate correctly during cell division. HAC are important vectors for investigating the organization and structure of the kinetochore, and gene complementation. HAC have so far been obtained in immortalized or tumour-derived cell lines, but never in stem cells, thus limiting their potential therapeutic application. In this work, we modified the herpes simplex virus type 1 amplicon system for efficient transfer of HAC DNA into two hESc. The deriving stable clones generated green fluorescent protein gene-expressing HAC at high frequency, which were stably maintained without selection for 3 months. Importantly, no integration of the HAC DNA was observed in the hESc lines, compared with the fibrosarcoma-derived control cells, where the exogenous DNA frequently integrated in the host genome. The hESc retained pluripotency, differentiation and teratoma formation capabilities. This is the first report of successfully generating gene expressing de novo HAC in hESc, and is a significant step towards the genetic manipulation of stem cells and potential therapeutic applications. PMID- 21593219 TI - Methylation screening of reciprocal genome-wide UPDs identifies novel human specific imprinted genes. AB - Nuclear transfer experiments undertaken in the mid-80's revealed that both maternal and paternal genomes are necessary for normal development. This is due to genomic imprinting, an epigenetic mechanism that results in parent-of-origin monoallelic expression of genes regulated by germline-derived allelic methylation. To date, ~100 imprinted transcripts have been identified in mouse, with approximately two-thirds showing conservation in humans. It is currently unknown how many imprinted genes are present in humans, and to what extent these transcripts exhibit human-specific imprinted expression. This is mainly due to the fact that the majority of screens for imprinted genes have been undertaken in mouse, with subsequent analysis of the human orthologues. Utilizing extremely rare reciprocal genome-wide uniparental disomy samples presenting with Beckwith Wiedemann and Silver-Russell syndrome-like phenotypes, we analyzed ~0.1% of CpG dinculeotides present in the human genome for imprinted differentially methylated regions (DMRs) using the Illumina Infinium methylation27 BeadChip microarray. This approach identified 15 imprinted DMRs associated with characterized imprinted domains, and confirmed the maternal methylation of the RB1 DMR. In addition, we discovered two novel DMRs, first, one maternally methylated region overlapping the FAM50B promoter CpG island, which results in paternal expression of this retrotransposon. Secondly, we found a paternally methylated, bidirectional repressor located between maternally expressed ZNF597 and NAT15 genes. These three genes are biallelically expressed in mice due to lack of differential methylation, suggesting that these genes have become imprinted after the divergence of mouse and humans. PMID- 21593221 TI - FDA approves prostate cancer treatment that inhibits testosterone synthesis. PMID- 21593220 TI - Rescue of ATP7B function in hepatocyte-like cells from Wilson's disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin. AB - Directed hepatocyte differentiation from human induced pluripotent stem cells (iPSCs) potentially provides a unique platform for modeling liver genetic diseases and performing drug-toxicity screening in vitro. Wilson's disease is a genetic disease caused by mutations in the ATP7B gene, whose product is a liver transporter protein responsible for coordinated copper export into bile and blood. Interestingly, the spectrum of ATP7B mutations is vast and can influence clinical presentation (a variable spectrum of hepatic and neural manifestations), though the reason is not well understood. We describe the generation of iPSCs from a Chinese patient with Wilson's disease that bears the R778L Chinese hotspot mutation in the ATP7B gene. These iPSCs were pluripotent and could be readily differentiated into hepatocyte-like cells that displayed abnormal cytoplasmic localization of mutated ATP7B and defective copper transport. Moreover, gene correction using a self-inactivating lentiviral vector that expresses codon optimized-ATP7B or treatment with the chaperone drug curcumin could reverse the functional defect in vitro. Hence, our work describes an attractive model for studying the pathogenesis of Wilson's disease that is valuable for screening compounds or gene therapy approaches aimed to correct the abnormality. In the future, once relevant safety concerns (including the stability of the mature liver-like phenotype) and technical issues for the transplantation procedure are solved, hepatocyte-like cells from similarly genetically corrected iPSCs could be an option for autologous transplantation in Wilson's disease. PMID- 21593222 TI - CDC pushes for elimination of catheter-related infections. PMID- 21593223 TI - Long-awaited opioid REMS affects prescribers more than dispensers. PMID- 21593224 TI - Pain management is target for research. PMID- 21593225 TI - Revising warfarin patient education materials to meet a National Patient Safety Goal. PMID- 21593226 TI - From resident to peer: practicing where you trained. PMID- 21593228 TI - Risk of venous thromboembolism with drospirenone-containing oral contraceptives. AB - PURPOSE: The risk of venous thromboembolism (VTE) with drospirenone-containing oral contraceptives (OCs) is reviewed. SUMMARY: Increasing attention and media have raised awareness and concern about whether drospirenone-containing OCs increase the risk of VTE. Two studies found that when compared with nonuse of OCs, use of drospirenone-containing OCs was associated with a fourfold to over sixfold increased risk of having a thrombotic event. One of these studies found an increased risk associated with short-term use of drospirenone-containing OCs; however, this study was limited by the small number of participants taking drospirenone despite the large number of study participants. The cohort study that found a higher rate of VTE among drospirenone users was only able to indicate an association between drospirenone use and VTE, not a cause-and-effect relationship. Three studies concluded that drospirenone-containing OCs did not appear to cause an increased risk of VTE. The hemostatic studies found no difference in the various variables assessed between drospirenone- and desogestrel-containing OCs or between cyclic and continuous administration of drospirenone-containing OCs. These results should be interpreted cautiously, as each study had limitations, such as not controlling for confounders (e.g., recent surgery, immobility, obesity), not providing p values to assess homogeneity between treatment groups, and not providing total numbers of participants or specific types of OCs. Patients who receive drospirenone-containing OCs should be educated regarding the signs and symptoms of VTE, along with an appropriate action plan. CONCLUSION: The majority of available data does not support the conclusion that drospirenone-containing OCs pose an increased risk of VTE compared with other OCs. PMID- 21593227 TI - Management of HIV infection in treatment-naive patients: a review of the most current recommendations. AB - PURPOSE: The most current guidelines issued by the Department of Health and Human Services (DHHS) on the management of human immunodeficiency virus (HIV) infection in treatment-naive patients are reviewed. SUMMARY: Treatment guidelines are updated frequently because of the emergence of data demonstrating the risks and benefits of antiretroviral therapy. The DHHS guidelines strongly recommend initiating therapy in patients with certain conditions regardless of CD4 cell count and in patients with CD4 cell counts of <350 cells/mm(3). Although supporting data are less definitive, treatment is also recommended for patients with CD4 cell counts of 350-500 cells/mm(3). Treatment for patients with CD4 cell counts of >500 cells/mm(3) is controversial. Although cumulative observational data and biological evidence support treatment at higher CD4 cell counts, randomized controlled trial data to support this are not available, and the risk of antiretroviral toxicities, resistance, non-adherence, and cost should be considered in individual patients. The preferred regimens have been consolidated to four options, including a dual-nucleoside reverse transcriptase inhibitor backbone (tenofovir plus emtricitabine) with a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir plus ritonavir or darunavir plus ritonavir), or an integrase strand transfer inhibitor (raltegravir). Regimens are classified as alternative or acceptable when they have potential safety or efficacy concerns, have higher pill burdens, or require more-frequent administration compared with preferred regimens. CONCLUSION: The DHHS 2011 guidelines advocate earlier antiretroviral therapy initiation than recommended in recent years, and preferred regimens have been refined to maximize efficacy, safety, and quality of life for treatment naive HIV-infected patients. PMID- 21593229 TI - Elevated International Normalized Ratio associated with long-term azithromycin therapy in a child with cerebral palsy. AB - PURPOSE: A case of coagulopathy in a pre-adolescent with cerebral palsy that developed after chronic prophylactic antibiotic use is reported. SUMMARY: An 11 year-old boy with cerebral palsy was brought to the emergency department experiencing restlessness and decreased oxygen saturation. Evaluation of the patient revealed gallstone-related pancreatitis, with elevated serum amylase and lipase concentrations and abnormal liver function test results. At the time of the initial evaluation, the International Normalized Ratio (INR) was 6.54 (normal range, 0.8-1.2), and the activated partial thromboplastin time was 53.8 seconds (normal range, 24.4-34.8 seconds). The boy's medication history included use of azithromycin 200 mg every other day for about two years for antiinflammatory therapy. On confirmation of the elevated INR 2 hours after the initial evaluation, azithromycin was discontinued, and a single dose of phytonadione 2 mg was administered. About 14 hours after phytonadione administration, the INR had declined to 0.94; 43 hours later, the INR remained within the normal range without further phytonadione therapy. Using the probability scale of Naranjo and colleagues, this case was rated as a probable drug-related adverse event. Previous reports have linked the development of vitamin K deficiency and impaired coagulation to long-term antibiotic use, but not specifically to use of azithromycin or other macrolide antibiotics. CONCLUSION: An elevated INR in a child with cerebral palsy was evidently related to long-term therapy with azithromycin. The abnormal INR normalized after discontinuation of azithromycin and administration of one dose of phytonadione. PMID- 21593230 TI - Effect of early clopidogrel discontinuation on rehospitalization in acute coronary syndrome: results from two distinct patient populations. AB - PURPOSE: Results of a study of the association between early discontinuation of clopidogrel therapy and rehospitalization rates among patients with acute coronary syndrome (ACS) are reported. SUMMARY: In a retrospective observational study, analyses of two nationally representative cohorts of adults hospitalized for acute myocardial infarction (AMI) or coronary stent insertion were conducted to assess risk factors for ACS-related adverse outcomes (rehospitalization for AMI or coronary revascularization) during the 12 months after completion of an initial 28-day course of clopidogrel therapy. Case data were sourced from a commercial insurance claims database, a pharmacy administrative claims database, and a combined dataset that linked hospital discharge and outpatient service data; a time-varying method was used to differentiate adverse events occurring "on" and "off" clopidogrel therapy. One cohort analysis (n = 42,757) indicated that patients who discontinued clopidogrel early (i.e., within 12 months of index discharge) were at significantly increased risk for ACS-related rehospitalization during the 12-month study period (hazard ratio [HR] = 1.11; 95% confidence interval [CI], 1.02-1.20; p < 0.05). In the other cohort analysis (n = 3,171), early clopidogrel discontinuation was associated with an increased risk of rehospitalization or inpatient death (HR = 1.75; 95% CI, 1.59-1.91; p < 0.0001). CONCLUSION: Observational evidence from analyses of data on two large cohorts of patients with primarily employer-sponsored health insurance suggests that early discontinuation of clopidogrel therapy after hospitalization for AMI or coronary stent insertion is associated with a significant increase in the risk of ACS related rehospitalization within the 12-month postdischarge period. PMID- 21593231 TI - Effect of bar-code-assisted medication administration on nurses' activities in an intensive care unit: a time-motion study. AB - PURPOSE: The effect of bar-code-assisted medication administration (BCMA) on nurses' activities in an intensive care unit was evaluated. METHODS: A prospective, observational, time-motion study was conducted by considering two approaches to medication administration in an intensive care unit: paper-based medication administration (PBMA) and BCMA. The time spent on nursing activities was measured using a prevalidated time-motion observation instrument and categorized based on workflow factors such as direct patient care, indirect patient care, administration, and miscellaneous or other. A descriptive analysis was conducted with the amount of time spent on each of the nursing activities. A multivariate analysis of covariance was conducted to assess the difference between the two approaches for the amount of time spent on various categorized nursing activities. Covariates included in the analysis were patient characteristics, medication administration characteristics, and number of nurses involved in medication administration. RESULTS: A total of 101 PBMAs and 151 BCMAs were reviewed. The mean duration of total medication administration time was higher in the BCMA phase compared with the PBMA phase, as was the mean time spent on direct patient care activity. However, nurses spent less time on administration activity during BCMA. Statistical analysis revealed that the medication administration approach (BCMA versus PBMA) had a significant effect on time spent on direct patient care and medication administration activities. CONCLUSION: The implementation of BCMA led to a reduction in the time spent by nurses on medication administration activities and increased the time spent on direct patient care activities. PMID- 21593232 TI - Visual compatibility of common nebulizer medications with 7% sodium chloride solution. AB - PURPOSE: The visual compatibility of hypertonic saline solution with various other drugs used for nebulizer therapy in cystic fibrosis (CF) was assessed. METHODS: Nebulized hypertonic saline solution has proved to be an effective adjunctive therapy for management of CF-related respiratory symptoms. Admixing of hypertonic saline solution and standard medications for nebulizer delivery has been suggested as a way to reduce the time-treatment burden on patients with CF, but that practice has been discouraged due to concerns about potential incompatibilities that could lead to precipitate formation (in the nebulizer or airway) and impeded drug delivery. For the study described here, visual and turbidimetric testing was conducted to assess the compatibility of admixtures of hypertonic saline solution and 11 medications widely used in CF (acetylcysteine, albuterol, atropine, cromolyn sodium, dexamethasone, glycopyrrolate, ipratropium, metaproterenol, sodium bicarbonate, terbutaline, and tobramycin). Three samples each of admixtures of the 11 drugs and 7% sodium chloride (experimental samples) or sterile water for injection (control samples) were prepared. The testing procedure entailed four turbidimetry measurements obtained at 15-minute intervals, as well as visual checks for signs of incompatibility (e.g., haze, particle or gas formation, alteration of color); analysis of variance was used to evaluate differences in test results between the experimental and control samples. RESULTS: Ten of the 11 medications assessed were visually compatible with 7% sodium chloride solution, as determined by serial turbidimetric testing and visual inspection; only cromolyn sodium was found to be visually incompatible with hypertonic saline. CONCLUSION: Eleven medications used in nebulizers for the treatment of CF were visually compatible with 7% sodium chloride solution. PMID- 21593233 TI - Social media in health care: the case for organizational policy and employee education. PMID- 21593217 TI - Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. AB - Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 * 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 * 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women. PMID- 21593234 TI - Heterologous prime-boost oral immunization with GK-1 peptide from Taenia crassiceps cysticerci induces protective immunity. AB - Oral immunization is a goal in vaccine development, particularly for pathogens that enter the host through the mucosal system. This study was designed to explore the immunogenic properties of the Taenia crassiceps protective peptide GK 1 administered orally. Mice were orally immunized with the synthetic GK-1 peptide in its linear form with or without the Brucella lumazine synthase (BLS) protein adjuvant or as a chimera recombinantly bound to BLS (BLS-GK-1). Mice were boosted twice with GK-1 only at 15-day intervals. A significant rate of protection of 64.7% was achieved in GK-1-immunized mice, and that rate significantly increased to 91.8 and 96% when mice were primed with GK-1 coadministered with BLS as an adjuvant and BLS as a carrier, respectively. Specific antibodies and T cell activation and proliferation accompanied the protection induced, revealing the potent immunogenicity of GK-1. Through immunohistochemical studies, GK-1 was detected in T and B cell zones of the Peyer's patches (PP) and mesenteric lymph nodes. In the latter, abundant proliferating cells were detected by 5'-bromo-2' deoxyuridine incorporation. No proliferation was detected in PP. Altogether, these results portray the potent immunogenic properties of GK-1 administered orally and reinforce the usefulness of BLS as an adjuvant and adequate vaccine delivery system for oral vaccines. PMID- 21593235 TI - Oral and nasal DNA vaccines delivered by attenuated Salmonella enterica serovar Typhimurium induce a protective immune response against infectious bronchitis in chickens. AB - Several studies have reported that intramuscular injection of DNA vaccines against infectious bronchitis virus (IBV) induces protective immune responses. In the present study, we developed oral and nasal DNA vaccines that carried the S1 gene and N gene of IBV delivered by attenuated Salmonella enterica serovar Typhimurium strains SL/pV-S1 and SL/pV-N, respectively. The safety and stability of recombinant Salmonella vaccine were evaluated. Following oral and nasal administration to chickens, the serum and mucosal samples were collected and antibodies against IBV were measured. Chickens were then challenged with IBV strain M41 by the nasal-ocular route 3 weeks after boosting. The results showed that oral and nasal immunization with coadministered SL/pV-S1 and SL/pV-N elicited significant IBV-specific humoral and mucosal immune responses and conferred protective efficacy against IBV challenge higher than that in chickens immunized only with SL/pV-S1. The current study shows that novel DNA vaccines delivered by attenuated S. Typhimurium may be promising candidates for the prevention of infectious bronchitis (IB).These vaccines are efficacious, easily produced economically, and able to be delivered orally and nasally rather than injected. Coadministration of SL/pV-S1 and SL/pV-N may represent an effective mucosal vaccination regimen. PMID- 21593237 TI - Within-subject variability of Mycobacterium tuberculosis-specific gamma interferon responses in German health care workers. AB - Gamma interferon (IFN-gamma) release assays (IGRAs) are used increasingly for the periodic tuberculosis (TB) screening of health care workers (HCWs), although data regarding the reproducibility and interpretation of serial testing results in countries with a low incidence of TB are scarce. The present study evaluated and compared the within-subject variability of dichotomous and continuous results of two commercial IGRAs, the QuantiFERON-TB Gold In-Tube (QFT) and the T-SPOT.TB (T SPOT), in German HCWs during a 4-week period. Thirty-five immunocompetent HCWs with low or medium TB screening risk and without known recent TB exposure or tuberculin skin test application were tested repeatedly with both IGRAs at weekly intervals. A total of 158 valid results were obtained for each IGRA. Changes of about +/-70% (QFT) and +/-60% (T-SPOT) from the mean IFN-gamma response accounted for 95% of the within-subject variability. However, according to the manufacturers' cutoffs, inconsistent results were observed more frequently for the QFT (28.6%; four conversions, six reversions) than for the T-SPOT (8.6%; three reversions; P < 0.001). The overall agreement between the IGRAs was good. Regression toward the means accounted for a significant decline in mean IFN-gamma responses of about 25% between successive visits for both IGRAs. Although both assays were highly reliable and reproducible, we observed substantial within subject variability and regression toward the means during a 4-week period, which should be considered when interpreting serial testing results in comparable populations and settings. Our data support the use of borderline zones for the interpretation of serial IGRA results and the retesting of borderline positive results before offering preventive chemotherapy. PMID- 21593236 TI - Distinct effects of anti-tumor necrosis factor combined therapy on TH1/TH2 balance in rheumatoid arthritis patients. AB - The immune balance in patients with rheumatoid arthritis (RA), a disease characterized by TH1 dominance, treated by the preferred combined anti-tumor necrosis factor (anti-TNF) and methotrexate (MTX) therapy was evaluated by assessing the chemokine and cytokine receptors as well as apoptosis induction. A meta-analysis of combined therapy by TNF blockers and MTX in 15 RA patients, MTX monotherapy in 20 RA patients, and 11 diagnosed but untreated RA patients was performed by assessing several immune markers in the whole lymphocyte population, as well as in specific CD4 cells, by both flow cytometry and image analysis. A significant downregulation of CXCR3 and IL-12 receptors (both TH1 markers) and a significant increase in the chemokine receptor CCR4 and, to a lesser extent, IL 4R (both TH2 markers) were found; a particularly marked increase was found in patients treated by combined therapy. This phenomenon was pronounced in CD4 cells and was accompanied by a high proportion of apoptotic cells. The therapeutic effect of MTX and TNF blockers may be due to apoptosis induction in lymphocytes infiltrating from the inflammation site and restoring the TH1/TH2 balance. PMID- 21593238 TI - Serological responses to experimental Norwalk virus infection measured using a quantitative duplex time-resolved fluorescence immunoassay. AB - A quantitative duplex time-resolved fluorescence assay, dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA), was developed to measure Norwalk virus (NV)-specific IgA and IgG antibodies simultaneously. The duplex assay showed superior performance by detecting seroconversion following experimental NV infection at an earlier time point than a reference total immunoglobulin enzyme linked immunosorbent assay (ELISA). PMID- 21593239 TI - Serological response of Shiga toxin-producing Escherichia coli type III secreted proteins in sera from vaccinated rabbits, naturally infected cattle, and humans. AB - Escherichia coli O157:H7 is an important zoonotic pathogen, causing hemolytic uremic syndrome (HUS). The colonization of cattle and human hosts is mediated through the action of effectors secreted via a type III secretion system (T3SS). The structural genes for the T3SS and many of the secreted effectors are located on a pathogenicity island called the locus of enterocyte effacement (LEE). We cloned and expressed the genes coding for 66 effectors and purified each to measure the cross-reactivity of type III secreted proteins from Shiga toxin producing Escherichia coli (STEC) serotypes. These included 37 LEE-encoded proteins and 29 non-LEE effectors. The serological response against each protein was measured by Western blot analysis and enzyme-linked immunosorbent assay (ELISA) using sera from rabbits immunized with type III secreted proteins (T3SPs) from four STEC serotypes, experimentally infected cattle, and human sera from six HUS patients. Twenty proteins were recognized by at least one of the STEC T3SP vaccinated rabbits by Western blotting. Several structural proteins (EspA, EspB, and EspD) and a number of effectors (Tir, NleA, and TccP) were recognized by O26 , O103-, O111-, and O157-specific sera. Sera from experimentally infected cattle and HUS patients were tested using an ELISA against each of the proteins. Tir, EspB, EspD, EspA, and NleA were recognized by the majority of the samples tested. A number of other proteins also were recognized by individual serum samples. Overall, proteins such as Tir, EspB, EspD, NleA, and EspA were highly immunogenic in vaccinated and naturally infected subjects and could be candidates for a cross protective STEC vaccine. PMID- 21593241 TI - Bodies politic: somatic politics and 'meaning making' in medicine and literature. PMID- 21593240 TI - Measurement of functional anti-meningococcal serogroup a activity using strain 3125 as the target strain for serum bactericidal assay. AB - Functional anti-N. meningitidis serogroup A (MenA) activity in human serum is detected by serum bactericidal assay (SBA), using either rabbit (rSBA) or human (hSBA) complement, with F8238 as the recommended MenA SBA target strain. However, the F8238 strain may not be optimal for this purpose because, as we show here, it expresses the L11 immunotype, whereas most MenA invasive strains express the L(3,7)9 or L10 immunotype. Moreover, SBA results may be strain dependent, because immunotypes differ in their sensitivity to complement, emphasizing the need to choose the most appropriate strain. Sera from random subsets of infants, toddlers, children, and adolescents in clinical trials of MenA conjugate vaccines were tested by rSBA using strains 3125 (L10) and F8238 (L11). In unvaccinated subjects from all age groups, the percentages of seropositive samples (rSBA-MenA titer, >=1:8) was lower using strain 3125 than using strain F8238. However, in toddlers and adolescents immunized with a conjugate MenA vaccine, the percentages of seropositive samples generally were similar using either strain in the rSBA. In two studies, sera also were tested with hSBA. Using hSBA, the differences in the percentages of seroprotective samples (hSBA-MenA titer, >=1:4) between strains 3125 and F8238 was less apparent, and in contrast with rSBA, the percentage of seroprotective samples from unvaccinated subjects was slightly higher using strain 3125 than using strain F8238. In adults vaccinated with plain MenA polysaccharide, the percentage of seroprotective samples was higher using strain 3125 than with strain F8238, and the vaccine response rates using strain 3125 were better aligned with the demonstrated efficacy of MenA vaccination. In conclusion, SBA results obtained using the MenA L10 3125 strain better reflected vaccine-induced immunity. PMID- 21593242 TI - Performing medicine: the role of theatre in medical education. PMID- 21593243 TI - The hallucinations of Frederic Chopin. AB - Frederic Chopin is the epitome of the romantic artist; he had a chronic pulmonary disease that ultimately caused his death at the age of 39. An overlooked neurological condition is discussed in this paper. We consider the possibility of a temporal lobe epilepsy, as throughout his life Chopin had hallucinatory episodes, which can accompany seizure disorders. PMID- 21593244 TI - Black, white or green: 'race', gender and avatars within the therapeutic space. AB - Personal identity is critical to provider--patient interactions. Patients and doctors tend to self-select, ideally forming therapeutic units that maximise the patients' benefit. Recently, however, 'reality' has changed. The internet and virtual worlds such as Second Life (http://www.secondlife.com/) allow models of identity and provider--patient interactions that go beyond the limits of mainstream personal identity. In this paper some of the ethical implications of virtual patient--provider interactions, especially those that have to do with personal identity, are explored. PMID- 21593245 TI - Royal ruptures: Caroline of Ansbach and the politics of illness in the 1730s. AB - Caroline of Ansbach, wife of George II, occupied a crucial position in the public life of early 18th-century Britain. She was seen to exert considerable influence on the politics of the court and, as mother to the Hanoverian dynasty's next generation, she became an important emblem for the nation's political well-being. This paper examines how such emblematic significance was challenged and qualified when Caroline's body could no longer be portrayed as healthy and life giving. Using private memoirs and correspondence from the time of her death in 1737, the paper explores the metaphorical potential of the queen's strangulated hernia, as well as the particular problems it posed for the public image of her dynasty. Through these investigations, the paper will comment upon the haphazard nature of public discussion in the early 18th century, and reveal the complex relationship between political speculation and medical diagnosis. PMID- 21593246 TI - Telling the patient's story: using theatre training to improve case presentation skills. AB - A medical student's ability to present a case history is a critical skill that is difficult to teach. Case histories presented without theatrical engagement may fail to catch the attention of their intended recipients. More engaging presentations incorporate 'stage presence', eye contact, vocal inflection, interesting detail and succinct, well organised performances. They convey stories effectively without wasting time. To address the didactic challenge for instructing future doctors in how to 'act', the Mayo Medical School and The Mayo Clinic Center for Humanities in Medicine partnered with the Guthrie Theater to pilot the programme 'Telling the Patient's Story'. Guthrie teaching artists taught storytelling skills to medical students through improvisation, writing, movement and acting exercises. Mayo Clinic doctors participated and provided students with feedback on presentations and stories from their own experiences in patient care. The course's primary objective was to build students' confidence and expertise in storytelling. These skills were then applied to presenting cases and communicating with patients in a fresher, more engaging way. This paper outlines the instructional activities as aligned with course objectives. Progress was tracked by comparing pre-course and post-course surveys from the seven participating students. All agreed that the theatrical techniques were effective teaching methods. Moreover, this project can serve as an innovative model for how arts and humanities professionals can be incorporated for teaching and professional development initiatives at all levels of medical education. PMID- 21593247 TI - Literature and disability: the medical interface in Borges and Beckett. AB - Samuel Beckett and Jorge Luis Borges have presented 20th century literature with a distinctive gallery of solitary figures who suffer from a series of physiological ailments: invalidism, decrepitude, infirmity and blindness, as well as neurological conditions such as amnesia and autism spectrum disorders. Beckett and Borges were concerned with the dynamics between illness and creativity, the literary representation of physical and mental disabilities, the processes of remembering and forgetting, and the inevitability of death. This article explores the depiction of physically and mentally disabled characters in Borges' Funes the Memorious (1942)--a story about an Uruguayan gaucho who has been left paralysed after a fall from a horse which simultaneously endowed him with an infallible memory and perception--and Beckett's Trilogy: Molloy (1951), Malone Dies (1951) and The Unnamable (1953). It examines the prodigious memory of Funes and the forgetful minds of Molloy and Malone with reference to influential neuropsychological studies such as Alexander Luria's twofold exploration of memory and forgetfulness in The Mind of a Mnemonist (1968) and The Man with a Shattered World (1972). The article demonstrates that in contrast to Beckett's amnesiacs and Luria's brain-damaged patient, who are able to transcend their circumstances through cathartic writing, Borges' and Luria's mnemonic prodigies fail to achieve anything significant with their unlimited memories and remain imprisoned within their cognitive disabilities. It reveals that medical discourses can provide invaluable insights and lead to a deeper understanding of the minds and bodily afflictions of literary characters. PMID- 21593248 TI - Robert Knox and the anatomy of beauty. AB - Robert Knox (1791-1862) is typically remembered as the Edinburgh anatomist to whom the murderers Burke and Hare sold the bodies of their victims. This association brought Knox infamy and damaged his life and career. Before the Burke and Hare scandal, Knox was one of the most famous, original and influential anatomists in Britain. He was also something of a dandy with a sophisticated appreciation of the visual arts. His most significant writings on artistic subjects were his books A Manual of Artistic Anatomy and Great Artists and Great Anatomists: A Biographical and Philosophical Study. Knox's interesting and independently minded opinions on the central artistic questions of his day were taken seriously by his contemporaries. His demotion in the official history of anatomy following his involvement with Burke and Hare, however, also removed him from the history of art theory in 19th century Britain. Knox was such a magnetic and impressive figure, though, that he has to be brought back to his era and his era is not complete without him. This paper discusses how Knox's writings on anatomy and biology shaped his contributions to art theory. It is a first step towards returning Knox, the art theorist, to the cultural life of 19th century Britain. PMID- 21593249 TI - Teaching reflective competence in medical education using paintings. PMID- 21593250 TI - Clinical effectiveness of orthodontic miniscrew implants: a meta-analysis. AB - The aim of this meta-analysis was to examine the clinical effectiveness of miniscrew implants (MI) used for anchorage reinforcement compared with that of conventional orthodontic means, as well as to assess the success rates of MIs and the possible risk factors affecting their clinical effectiveness. Literature searches were conducted, and, using specific inclusion and exclusion criteria, two independent investigators performed data extraction and analysis. Overall pooled estimates with 95% confidence intervals (CI) were obtained with the random effects model. Eight out of 3183 original papers met the inclusion criteria. The mean difference of anchorage loss between the MI and conventional anchorage group was -2.4 mm (95% CI = -2.9 mm to -1.8 mm, p = 0). MIs significantly decreased or negated loss of anchorage. Anchorage loss seemed to be less in the mandible, when the MIs were inserted between the second premolar and the first molar, when 2 MIs were inserted per patient jaw, when they were directly connected, as well as when treatment lasted more than 12 months. MIs presented a success rate of 87.7%, with no significant differences between the various subgroups. However, the results of this meta-analysis should be interpreted with some caution because of the number, quality, and heterogeneity of the included studies. PMID- 21593251 TI - Tgf-beta-mediated FasL-Fas-Caspase pathway is crucial during palatogenesis. AB - Programmed cell death, or apoptosis, is one of the fates of the medial edge epithelium (MEE) during palatal fusion. Transforming growth factor beta (Tgf beta) signaling (such as Tgf-beta3) is required for the disappearance of the MEE, but the relationship between Tgf-beta3 and apoptosis remains unclear. Here we show that the Fas ligand (FasL)-Fas-Caspase extrinsic apoptosis pathway functions during palatal fusion in wild-type mice, but is not detectable in mice lacking Tgf-beta3 (Tgf-beta3 (-/-) ) or Tgfbetar2 in the MEE (K14-Cre;Tgfbr2 (fl/fl)). Inhibition of the FasL-Fas system results in persistence of the midline epithelial seam (MES) and inhibition of caspase activity during palatal organ culture. Moreover, ectopic FasL protein induces apoptosis in MES of K14 Cre;Tgfbr2 (fl/fl) mice. Thus, we conclude that the FasL-Fas-caspase extrinsic apoptosis pathway is regulated by the Tgf-beta3 signaling cascade and is essential for palatal fusion during craniofacial development. PMID- 21593253 TI - Creating a 21st century global health agenda: the General Assembly of the United Nations High Level Meeting on Non-Communicable Diseases. PMID- 21593252 TI - Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease that causes exercise limitation, heart failure, and death. We aimed to determine the safety and efficacy of aspirin and simvastatin in PAH. METHODS AND RESULTS: We performed a randomized, double-blind, placebo-controlled 2*2 factorial clinical trial of aspirin and simvastatin in patients with PAH receiving background therapy at 4 centers. A total of 92 patients with PAH were to be randomized to aspirin 81 mg or matching placebo and simvastatin 40 mg or matching placebo. The primary outcome was 6-minute walk distance at 6 months. Sixty-five subjects had been randomized when the trial was terminated by the Data Safety and Monitoring Board after an interim analysis showed futility in reaching the primary end point for simvastatin. After adjustment for baseline 6-minute walk distance, there was no significant difference in the 6-minute walk distance at 6 months between aspirin (n=32) and placebo (n=33; placebo-corrected difference -0.5 m, 95% confidence interval -28.4 to 27.4 m; P=0.97) or between simvastatin (n=32) and placebo (n=33; placebo-corrected difference -27.6 m, 95% confidence interval 59.6 to 4.3 m; P=0.09). There tended to be more major bleeding episodes with aspirin than with placebo (4 events versus 1 event, respectively; P=0.17). CONCLUSIONS: Neither aspirin nor simvastatin had a significant effect on the 6 minute walk distance, although patients randomized to simvastatin tended to have a lower 6-minute walk distance at 6 months. These results do not support the routine treatment of patients with PAH with these medications. PMID- 21593254 TI - Rapid identification of Cryptococcus neoformans var. grubii, C. neoformans var. neoformans, and C. gattii by use of rapid biochemical tests, differential media, and DNA sequencing. AB - Rapid identification of Cryptococcus neoformans var. grubii, Cryptococcus neoformans var. neoformans, and Cryptococcus gattii is imperative for facilitation of prompt treatment of cryptococcosis and for understanding the epidemiology of the disease. Our purpose was to evaluate a test algorithm incorporating commercial rapid biochemical tests, differential media, and DNA sequence analysis that will allow us to differentiate these taxa rapidly and accurately. We assessed 147 type, reference, and clinical isolates, including 6 other Cryptococcus spp. (10 isolates) and 14 other yeast species (24 isolates), using a 4-hour urea broth test (Remel), a 24-hour urea broth test (Becton Dickinson), a 4-hour caffeic acid disk test (Hardy Diagnostics and Remel), 40- to 44-hour growth assessment on l-canavanine glycine bromothymol blue (CGB) agar, and intergenic spacer (IGS) sequence analysis. All 123 Cryptococcus isolates hydrolyzed urea, along with 7 isolates of Rhodotorula and Trichosporon. Eighty five of 86 C. neoformans (99%) and 26 of 27 C. gattii (96%) isolates had positive caffeic acid results, unlike the other cryptococci (0/10) and yeast species (0/24). Together, these two tests positively identified virtually all C. neoformans/C. gattii isolates (98%) within 4 h. CGB agar or IGS sequencing further differentiated these isolates within 48 h. On CGB, 25 of 27 (93%) C. gattii strains induced a blue color change, in contrast to 0 of 86 C. neoformans isolates. Neighbor-joining cluster analysis of IGS sequences differentiated C. neoformans var. grubii, C. neoformans var. neoformans, and C. gattii. Based on these results, we describe a rapid identification algorithm for use in a microbiology laboratory to distinguish clinically relevant Cryptococcus spp. PMID- 21593255 TI - Genotype diversity and distribution of Orientia tsutsugamushi causing scrub typhus in Thailand. AB - Scrub typhus, caused by antigenically disparate isolates of Orientia tsutsugamushi, is a widely distributed mite-borne human disease in the Asia Pacific region. Information regarding the heterogeneity of the immunodominant 56 kDa type-specific antigen (TSA) gene is crucial for the design and evaluation of scrub typhus-specific diagnostic assays and vaccines. Using indirect immunofluorescence assays (IFA) and PCR assays, O. tsutsugamushi was detected samples from rodents and patients with fever of unknown origin obtained from six provinces of Thailand during 2004 to 2007. Sequences were determined for a fragment of the 56-kDa TSA gene, and the relationship between these sequences and those previously determined were assessed. The phylogenetic analyses of partial 56-kDa TSA gene sequences demonstrated wide diversity and distribution of O. tsutsugamushi genotypes in Thailand. Furthermore, the genetic diversity grouped the scrub typhus agents into two commonly and five infrequently found genotypes within six provinces of Thailand. The two most commonly found genotypes of O. tsutsugamushi described in this study do not associate with the prototype strains that are widely used for the design and evaluation of diagnostic assays and vaccine candidates. Thus, these new genotypes should be considered for future scrub typhus assay and vaccine development. PMID- 21593256 TI - Acute necrotizing sinusitis caused by Staphylococcus lugdunensis. AB - Staphylococcus lugdunensis is most commonly associated with infections arising from the inguinal region, but here we report this organism as a cause of bacterial sinusitis, highlighting its potential niche as a commensal of the upper airways. The severity of necrosis demonstrates the potential for destructive pathology mimicking Staphylococcus aureus disease. PMID- 21593257 TI - Streptomycin resistance and lineage-specific polymorphisms in Mycobacterium tuberculosis gidB gene. AB - Mutations related to streptomycin resistance in the rpsL and rrs genes are well known and can explain about 70% of this phenotypic resistance. Recently, the gidB gene was found to be associated with low-level streptomycin resistance in Mycobacterium tuberculosis. Mutations in gidB have been reported with high frequency, and this gene appears to be very polymorphic, with frameshift and point mutations occurring in streptomycin-susceptible and streptomycin-resistant strains. In this study, mutations in gidB appeared in 27% of streptomycin resistant strains that contained no mutations in the rpsL or rrs genes, and they were associated with low-level streptomycin resistance. However, the association of certain mutations in gidB with streptomycin resistance needs to be further investigated, as we also found mutations in gidB in streptomycin-susceptible strains. This occurred only when the strain was resistant to rifampin and isoniazid. Two specific mutations appeared very frequently in this and other studies of streptomycin-susceptible and -resistant strains; these mutations were not considered related to streptomycin resistance, but as a polymorphism. We stratified the strains according to the different phylogenetic lineages and showed that the gidB(16) polymorphism (16G allele) was exclusively present in the Latin American-Mediterranean (LAM) genotype, while the gidB(92) polymorphism (92C allele) was associated with the Beijing lineage in another population. In the sample studied, the two characterized single-nucleotide polymorphisms could distinguish LAM and Beijing lineages from the other lineages. PMID- 21593258 TI - Most multidrug-resistant Pseudomonas aeruginosa isolates from hospitals in eastern France belong to a few clonal types. AB - This study aimed to determine the genetic diversity of clinical multidrug resistant Pseudomonas aeruginosa. We used pulsed-field gel electrophoresis and multilocus sequence typing to analyze 187 strains isolated in different French hospitals. To illustrate the diversity of resistance mechanisms to antibiotics in a given clone, we identified beta-lactamases with an extended spectrum by using phenotypic and genotypic methods. Typing results showed that the majority of our multidrug-resistant isolates belong to a few clonal types (ST235, ST111, and ST175) that are already spreading worldwide. These successful international clones sporadically produced extended-spectrum beta-lactamase-encoding genes but mostly became extensively resistant to beta-lactams after derepression of intrinsic resistance mechanisms (i.e., AmpC cephalosporinase). Our results indicate that cross-transmission plays a major role in the spread of multidrug resistant P. aeruginosa in hospital settings. PMID- 21593259 TI - Achromobacter xylosoxidans infection presenting as a pulmonary nodule mimicking cancer. AB - Achromobacter xylosoxidans is typically isolated from pulmonary sources, presenting as pneumonia in immunosuppressed individuals. We describe a novel clinical presentation of A. xylosoxidans infection presenting as multiple spiculated, pulmonary nodules mimicking cancer for which the patient underwent a wedge resection of the lung for diagnosis and staging of presumptive cancer. PMID- 21593260 TI - Design and performance of the CDC real-time reverse transcriptase PCR swine flu panel for detection of 2009 A (H1N1) pandemic influenza virus. AB - Swine influenza viruses (SIV) have been shown to sporadically infect humans and are infrequently identified by the Influenza Division of the Centers for Disease Control and Prevention (CDC) after being received as unsubtypeable influenza A virus samples. Real-time reverse transcriptase PCR (rRT-PCR) procedures for detection and characterization of North American lineage (N. Am) SIV were developed and implemented at CDC for rapid identification of specimens from cases of suspected infections with SIV. These procedures were utilized in April 2009 for detection of human cases of 2009 A (H1N1) pandemic (pdm) influenza virus infection. Based on genetic sequence data derived from the first two viruses investigated, the previously developed rRT-PCR procedures were optimized to create the CDC rRT-PCR Swine Flu Panel for detection of the 2009 A (H1N1) pdm influenza virus. The analytical sensitivity of the CDC rRT-PCR Swine Flu Panel was shown to be 5 copies of RNA per reaction and 10(-1.3 - -0.7) 50% infectious doses (ID(50)) per reaction for cultured viruses. Cross-reactivity was not observed when testing human clinical specimens or cultured viruses that were positive for human seasonal A (H1N1, H3N2) and B influenza viruses. The CDC rRT PCR Swine Flu Panel was distributed to public health laboratories in the United States and internationally from April 2009 until June 2010. The CDC rRT-PCR Swine Flu Panel served as an effective tool for timely and specific detection of 2009 A (H1N1) pdm influenza viruses and facilitated subsequent public health response implementation. PMID- 21593261 TI - Rapid detection and molecular differentiation of toxigenic Corynebacterium diphtheriae and Corynebacterium ulcerans strains by LightCycler PCR. AB - The systemic symptoms of diphtheria are caused by the tox-encoded diphtheria toxin (DT) which is produced by toxigenic Corynebacterium spp. Besides the classical agent C. diphtheriae, the zoonotic pathogen C. ulcerans has increasingly been reported as an emerging pathogen for diphtheria. The reliable detection of toxigenic Corynebacterium spp. is of substantial importance for both diphtheria surveillance in the public health sector and the clinical workup of a patient with diphtherialike symptoms. Since the respective tox genes of C. diphtheriae and C. ulcerans differ from each other in both DNA and amino acid sequence, both tox genes should be covered by novel real-time PCR methods. We describe the development and validation of a LightCycler PCR assay which reliably recognizes tox genes from both C. diphtheriae and C. ulcerans and differentiates the respective target genes by fluorescence resonance energy transfer (FRET) hybridization probe melting curve analysis. PMID- 21593262 TI - Xpert MTB/RIF: a new pillar in diagnosis of extrapulmonary tuberculosis? AB - Approximately 10 to 15% of tuberculosis (TB) cases in India are estimated to have extrapulmonary disease, and due to a lack of diagnostic means, they often remain untreated. The early detection of Mycobacterium tuberculosis and multidrug resistance is a priority in TB diagnosis to improve the successful treatment rate of TB and reduce transmission. The Xpert MTB/RIF (Xpert) test, recently endorsed by the World Health Organization for the detection of pulmonary TB, was evaluated to test its utility in 547 patients with suspected extrapulmonary tuberculosis. Five hundred forty-seven extrapulmonary specimens were split and processed simultaneously for both culture (solid and liquid) and Xpert testing. For culture, the sensitivity was low, 53% (150/283 specimens). Xpert sensitivity and specificity results were assessed in comparison to a composite reference standard made up of smear and culture results and clinical, radiological, and histological findings. The sensitivity of the Xpert assay was 81% (228/283 specimens) (64% [89/138] for smear-negative cases and 96% [139/145] for smear-positive cases), with a specificity of 99.6%. The sensitivity was found to be high for the majority of specimen types (63 to 100%) except for cerebrospinal fluid, the sensitivity of which was 29% (2/7 specimens). The Xpert test correctly identified 98% of phenotypic rifampin (RIF)-resistant cases and 94% of phenotypic RIF susceptible cases. Sequencing of the 6 discrepant samples resolved 3 of them, resulting in an increased specificity of 98%. In conclusion, the results of this study suggest that the Xpert test also shows good potential for the diagnosis of extrapulmonary TB and that its ease of use makes it applicable for countries where TB is endemic. PMID- 21593263 TI - Rapid simultaneous detection of enterovirus and parechovirus RNAs in clinical samples by one-step real-time reverse transcription-PCR assay. AB - Enteroviruses (EVs) are recognized as the major etiological agent in meningitis in children and young adults. The use of molecular techniques, such as PCR, has substantially improved the sensitivity of enterovirus detection compared to that of virus culture methods. PCR-based methods also can detect a much wider range of EV variants, including those within species A, as well as human parechoviruses (HPeVs) that often grow poorly in vitro and which previously have been underdiagnosed by traditional methods. To exploit these developments, we developed a real-time one-step reverse transcription-PCR (RT-PCR) for the rapid and sensitive detection of EV and HPeV in clinical specimens. Two commercially available RT-PCR kits were used (method I, Platinum one-step kit; method II, Express qPCR one-step kit) with primers and probes targeting the EV and HPeV 5' untranslated regions (5'UTR). Amplification dynamics (threshold cycle [C(T)]values and efficiencies) of absolutely quantified full-length RNA transcripts representative of EV species A to D and HPeV were similar, demonstrating the effectiveness of both assays across the range of currently described human EV and HPeV variants. Probit analysis of multiple endpoint replicates demonstrated comparable sensitivities of the assays for EV and HPeV (method I, approximately 10 copies per reaction for both targets; method II, 20 copies per reaction). C(T) values were highly reproducible on repeat testing of positive controls within assays and between assay runs. Considering the sample turnaround time of less than 3 h, the multiplexed one-step RT-PCR method provides rapid diagnostic testing for EV and HPeV in cases of suspected central nervous system infections in a clinically relevant time frame. PMID- 21593264 TI - Rapid and simultaneous detection of Mycobacterium tuberculosis complex and Beijing/W genotype in sputum by an optimized DNA extraction protocol and a novel multiplex real-time PCR. AB - Rapid diagnosis and genotyping of Mycobacterium tuberculosis by molecular methods are often limited by the amount and purity of DNA extracted from body fluids. In this study, we evaluated 12 DNA extraction methods and developed a highly sensitive protocol for mycobacterial DNA extraction directly from sputa using surface-coated magnetic particles. We have also developed a novel multiplex real time PCR for simultaneous identification of M. tuberculosis complex and the Beijing/W genotype (a hypervirulent sublineage of M. tuberculosis) by using multiple fluorogenic probes targeting both the M. tuberculosis IS6110 and the Rv0927c-pstS3 intergenic region. With reference strains and clinical isolates, our real-time PCR accurately identified 20 non-Beijing/W and 20 Beijing/W M. tuberculosis strains from 17 different species of nontuberculosis Mycobacterium (NTM). Further assessment of our DNA extraction protocol and real-time PCR with 335 nonduplicate sputum specimens correctly identified all 74 M. tuberculosis culture-positive specimens. In addition, 15 culture-negative specimens from patients with confirmed tuberculosis were also identified. No cross-reactivity was detected with NTM specimens (n = 31). The detection limit of the assay is 10 M. tuberculosis bacilli, as determined by endpoint dilution analysis. In conclusion, an optimized DNA extraction protocol coupled with a novel multiprobe multiplex real-time PCR for the direct detection of M. tuberculosis, including Beijing/W M. tuberculosis, was found to confer high sensitivity and specificity. The combined procedure has the potential to compensate for the drawbacks of conventional mycobacterial culture in routine clinical laboratory setting, such as the lengthy incubation period and the limitation to viable organisms. PMID- 21593265 TI - Isolation of Nocardia beijingensis from a pulmonary abscess reveals human immunodeficiency virus infection. AB - A strain of Nocardia was isolated from a pulmonary abscess of a human immunodeficiency virus-infected patient in France. Comparative 16S rRNA gene sequence analysis revealed that the isolate represented a strain of Nocardia beijingensis. Antimicrobial susceptibility testing was essential to guide the clinicians to successfully treat this infection. PMID- 21593266 TI - Genotypic prediction of human immunodeficiency virus type 1 tropism by use of plasma and peripheral blood mononuclear cells in the routine clinical laboratory. AB - We developed a sequencing assay for genotypic HIV-1 tropism determination. The assay allows examination of HIV RNA from plasma and HIV DNA from peripheral blood mononuclear cells (PBMC), including PBMC samples from patients with undetectable viral loads. Assessment of 100 pairs of plasma and PBMC samples showed a high concordance of 90%. With the limitations of population-based sequencing, the assay was found to be robust and suitable for the routine clinical laboratory. PMID- 21593268 TI - Encephalitozoon cuniculi genotype I as a causative agent of brain abscess in an immunocompetent patient. AB - A brain abscess caused by Encephalitozoon cuniculi genotype I together with Streptococcus intermedius occurred in a patient without major immunocompromise and with diabetes. The distinguishing clinical signs were hemiparesis and epilepsy. The microsporidium was observed in the abscess aspirate, and its specific DNA was also detected in stool and urine. The patient was successfully treated with albendazole and mebendazole. PMID- 21593267 TI - Adamantane- and oseltamivir-resistant seasonal A (H1N1) and pandemic A (H1N1) 2009 influenza viruses in Guangdong, China, during 2008 and 2009. AB - Adamantane and oseltamivir resistance among influenza viruses is a major concern to public health officials. To determine the prevalence of antiviral-resistant influenza viruses in Guangdong, China, 244 seasonal A (H1N1) and 222 pandemic A (H1N1) 2009 viruses were screened for oseltamivir resistance by a fluorescence based neuraminidase (NA) inhibition assay along with NA gene sequencing. Also, 147 seasonal A (H1N1) viruses were sequenced to detect adamantane resistance markers in M2. Adamantane-resistant seasonal A (H1N1) viruses clustering to clade 2C were dominant in 2008, followed by oseltamivir-resistant seasonal A (H1N1) viruses, clustering to clade 2B during January and May 2009. In June 2009, a lineage of double-resistant seasonal A (H1N1) viruses emerged, until it was replaced by the pandemic A (H1N1) 2009 viruses. The lineage most likely resulted from reassortment under the pressure of the overuse of adamantanes. As all viruses were resistant to at least one of the two types of antiviral agents, the need for close monitoring of the prevalence of antiviral resistance is stressed. PMID- 21593269 TI - Evaluation of a single-tube multiplex real-time PCR for differentiation of members of the Mycobacterium tuberculosis complex in clinical specimens. AB - Members of the Mycobacterium tuberculosis complex (MTBC) differ in virulence attributes, drug resistance patterns, and host preferences. The rapid differentiation of these species to determine zoonotic or human sources of tuberculosis disease or to direct treatment can benefit both public health and patient management. Commercially available assays cannot differentiate these species, and published assays have not been evaluated directly on clinical specimens. A real-time PCR assay for the differentiation of M. tuberculosis, M. bovis, M. bovis BCG, M. africanum, M. microti, and M. canettii was developed. The presence or absence of regions of difference (RD) between the genomes of members of the MTBC allowed for the design of a single-tube five-plex real-time PCR assay to differentiate these species. This assay assesses the presence of RD1, RD4, RD9, RD12, and a region exterior to RD9 which is present in all MTBC members. To evaluate the performance of this assay, 192 clinical specimens positive for MTBC by real-time PCR were tested, resulting in a 94% correlation of the real-time PCR with the identification results obtained with cultured material. Additionally, 727 Bactec MGIT 960-positive cultures were tested, resulting in a 97% concordance between the methods. This real-time PCR is an inexpensive and rapid (2.5-h) method performed in a closed-format system and requiring minimal hands-on time that can be implemented in a clinical laboratory and used directly on clinical specimens. PMID- 21593272 TI - Specific amino acids of Olive mild mosaic virus coat protein are involved in transmission by Olpidium brassicae. AB - Transmission of Olive mild mosaic virus (OMMV) is facilitated by Olpidium brassicae (Wor.) Dang. An OMMV mutant (OMMVL11) containing two changes in the coat protein (CP), asparagine to tyrosine at position 189 and alanine to threonine at position 216, has been shown not to be Olpidium brassicae transmissible owing to inefficient attachment of virions to zoospores. In this study, these amino acid changes were separately introduced into the OMMV genome through site-directed mutagenesis, and the asparagine-to-tyrosine change was shown to be largely responsible for the loss of transmission. Analysis of the structure of OMMV CP by comparative modelling approaches showed that this change is located in the interior of the virus particle and the alanine-to-threonine change is exposed on the surface. The asparagine-to-tyrosine change may indirectly affect attachment via changes in the conformation of viral CP subunits, altering the receptor binding site and thus preventing binding to the fungal zoospore. PMID- 21593270 TI - Human papillomavirus type 16 variant analysis of E6, E7, and L1 [corrected] genes and long control region in [corrected] cervical carcinomas in patients in northeast China. AB - Human papillomavirus type 16 (HPV 16) plays a cardinal role in the pathogenesis of cervical cancer. HPV 16 has intratypic variants which show different geographical distributions and different oncogenic potentials. To analyze the presence of sequence variations of HPV 16 variants in northeast China, 71 cervical carcinomas were identified by HPV typing. HPV 16-positive specimens were analyzed by PCR-directed sequencing in the E6, E7, and L1 genes and the LCR (long control region). The variation data were compared with those of neighboring districts. In this hospital-based study, HPV 16 was the most common type (73.24%). In HPV 16-positive specimens, 67.31% belonged to the European (E) lineage, while 32.69% were Asian (As) variants. The Asian-American (AA), African 1 (Af-1), African-2 (Af-2), and northern American (NA) lineages were not detected. The most frequently observed variation sites were T178G (32.69%) in E6; A647G (34.62%), G666A (38.46%), and T846C (32.69%) in E7; C6826T (36.17%) and G7060A (61.70%) in L1; and G7521A (98.08%) in the LCR. The most prevalent amino acid variations were D25E in E6 and N29S in E7. In addition, 28 novel variations of HPV 16 were reported. Some covariations between different genes were obtained. In this study, HPV 16 variants belonged to the European lineage and the Asian lineage. Compared with neighboring districts, the distribution of HPV 16 variants in northeast China had a typical pattern. As the first report on HPV 16 variants in northeast China, it should be helpful for designing a HPV vaccine and HPV vaccination program in China. PMID- 21593271 TI - The NS1 protein of influenza A virus suppresses interferon-regulated activation of antigen-presentation and immune-proteasome pathways. AB - The NS1 protein of influenza virus counters host antiviral defences primarily by antagonizing the type I interferon (IFN) response. Both the N-terminal dsRNA binding domain and the C-terminal effector domain are required for optimal suppression of host responses during infection. To better understand the regulatory role of the NS1 effector domain, we used an NS1-truncated mutant virus derived from human H1N1 influenza isolate A/Texas/36/91 (Tx/91) and assessed global transcriptional profiles from two independent human lung cell-culture models. Relative to the wild-type Tx/91-induced gene expression, the NS1 mutant virus induced enhanced expression of innate immune genes, specifically NF-kappaB signalling-pathway genes and IFN-alpha and -beta target genes. We queried an experimentally derived IFN gene set to gauge the proportion of IFN-responsive genes that are suppressed specifically by NS1. We show that the C-terminally truncated NS1 mutant virus is less efficient at suppressing IFN-regulated gene expression associated with activation of antigen-presentation and immune proteasome pathways. This is the first report integrating genomic analysis from two independent human culture systems, including primary lung cells, using genetically similar H1N1 influenza viruses that differ only in the length of the NS1 protein. PMID- 21593273 TI - The helper component-proteinase of the Zucchini yellow mosaic virus inhibits the Hua Enhancer 1 methyltransferase activity in vitro. AB - The helper component-proteinase (HC-Pro) is a multifunctional protein found among potyviruses. With respect to its silencing suppressor function, small RNA binding appears to be the major activity of HC-Pro. HC-Pro could also exhibit other suppressor activities. HC-Pro may inhibit the Hua Enhancer 1 (HEN1) activity. There is indirect evidence showing that either transient or stable expression of HC-Pro in plants results in an increase of non-methylated small RNAs. Here, we demonstrated that recombinant Zucchini yellow mosaic virus (ZYMV) HC-Pro inhibited the methyltransferase activity of HEN1 in vitro. Moreover, we found that the HC-Pro(FINK) mutant, which has lost small RNA-binding activity, inhibited HEN1 activity, while the truncated proteins and total soluble bacterial proteins did not. Using the ELISA-binding assay, we provided evidence that the HC Pro(FRNK) wild-type and HC-Pro(FINK) both bound to HEN1, with HC-Pro(FRNK) binding stronger than HC-Pro(FINK). Motif mapping analysis revealed that the amino acids located between positions 139 and 320 of ZYMV HC-Pro were associated with HEN1 interaction. PMID- 21593274 TI - Tibrogargan and Coastal Plains rhabdoviruses: genomic characterization, evolution of novel genes and seroprevalence in Australian livestock. AB - Tibrogargan virus (TIBV) and Coastal Plains virus (CPV) were isolated from cattle in Australia and TIBV has also been isolated from the biting midge Culicoides brevitarsis. Complete genomic sequencing revealed that the viruses share a novel genome structure within the family Rhabdoviridae, each virus containing two additional putative genes between the matrix protein (M) and glycoprotein (G) genes and one between the G and viral RNA polymerase (L) genes. The predicted novel protein products are highly diverged at the sequence level but demonstrate clear conservation of secondary structure elements, suggesting conservation of biological functions. Phylogenetic analyses showed that TIBV and CPV form an independent group within the 'dimarhabdovirus supergroup'. Although no disease has been observed in association with these viruses, antibodies were detected at high prevalence in cattle and buffalo in northern Australia, indicating the need for disease monitoring and further study of this distinctive group of viruses. PMID- 21593275 TI - Structural requirements of virion-associated cholesterol for infectivity, buoyant density and apolipoprotein association of hepatitis C virus. AB - Our earlier study has demonstrated that hepatitis C virus (HCV)-associated cholesterol plays a key role in virus infectivity. In this study, the structural requirement of sterols for infectivity, buoyant density and apolipoprotein association of HCV was investigated further. We removed cholesterol from virions with methyl beta-cyclodextrin, followed by replenishment with 10 exogenous cholesterol analogues. Among the sterols tested, dihydrocholesterol and coprostanol maintained the buoyant density of HCV and its infectivity, and 7 dehydrocholesterol restored the physical appearance of HCV, but suppressed its infectivity. Other sterol variants with a 3beta-hydroxyl group or with an aliphatic side chain did not restore density or infectivity. We also provide evidence that virion-associated cholesterol contributes to the interaction between HCV particles and apolipoprotein E. The molecular basis for the effects of different sterols on HCV infectivity is discussed. PMID- 21593276 TI - Relation of genetic phylogeny and geographical distance of tick-borne encephalitis virus in central Europe. AB - Tick-borne encephalitis virus (TBEV) is the most important arboviral agent causing disease of the central nervous system in central Europe. In this study, 61 TBEV E gene sequences derived from 48 isolates from the Czech Republic, and four isolates and nine TBEV strains detected in ticks from Germany, covering more than half a century from 1954 to 2009, were sequenced and subjected to phylogenetic and Bayesian phylodynamic analysis to determine the phylogeography of TBEV in central Europe. The general Eurasian continental east-to-west pattern of the spread of TBEV was confirmed at the regional level but is interlaced with spreading that arises because of local geography and anthropogenic influence. This spread is reflected by the disease pattern in the Czech Republic that has been observed since 1991. The overall evolutionary rate was estimated to be approximately 8*10(-4) substitutions per nucleotide per year. The analysis of the TBEV E genes of 11 strains isolated at one natural focus in zdar Kaplice proved for the first time that TBEV is indeed subject to local evolution. PMID- 21593278 TI - Modulation of hepatitis C virus replication by iron and hepcidin in Huh7 hepatocytes. AB - Several clinical observations point to an intricate crosstalk between iron (Fe) metabolism and chronic hepatitis C virus (HCV) infection. In this study, we wanted to investigate the molecular control that Fe levels exert on HCV replication at the hepatocyte level. In keeping with previous observations we confirmed that supra-physiological intracellular Fe induced by haemin treatment down-modulated HCV replication from subgenomic replicons. We also found that RNAi mediated knockdown of the key Fe modulator hepcidin increased intracellular ferritin and inhibited HCV replication. Conversely, HCV replication did not modulate ferritin content in hepatocytes. Finally, we demonstrated that hepcidin is modulated at the mRNA level by alpha interferon through STAT3. We propose that in Huh7 cells hepcidin modulation leads to an unfavourable intracellular environment for HCV replication. These data may therefore contribute to a better understanding of the complex interplay between HCV and cellular physiology during infection. PMID- 21593277 TI - A mechanistic basis for potent, glycoprotein B-directed gammaherpesvirus neutralization. AB - Glycoprotein B (gB) is a conserved, essential component of gammaherpes virions and so potentially vulnerable to neutralization. However, few good gB-specific neutralizing antibodies have been identified. Here, we show that murid herpesvirus 4 is strongly neutralized by mAbs that recognize an epitope close to one of the gB fusion loops. Antibody binding did not stop gB interacting with its cellular ligands or initiating its fusion-associated conformation change, but did stop gB resolving stably to its post-fusion form, and so blocked membrane fusion to leave virions stranded in late endosomes. The conservation of gB makes this mechanism a possible general route to gammaherpesvirus neutralization. PMID- 21593279 TI - Direct medical costs of liquid intravenous immunoglobulins in children, adolescents, and adults in Spain. AB - The aim of this study was to determine health care resource utilization and direct medical costs in Spanish patients treated with intravenous immunoglobulins (IVIGs) in 2009. Cost-of-illness analyses were performed to estimate direct medical costs of patients treated with IVIGs. Prevalence data were obtained from the Spanish Primary Immunodeficiency registry. A semi-structured questionnaire was used to collect data on health care resource utilization and patient distribution. Drug, administration, and premedication costs were considered from the payer's perspective. Separate analyses were conducted for children and adolescents versus adults. The numbers of children and adolescents with replacement therapy were 724, with immunomodulation 243, and with allogeneic bone marrow transplantation 30. The numbers of adult patients were, respectively, 3450, 1134, and 172. Mean annual costs for children and adolescents were 6293 ? with Privigen, 6292 ? with Kiovig, 6939 ? with Flebogamma, and 6559 ? with Octagamocta. For adults, estimations were 17 106 ? with Privigen, 17 103 ? with Kiovig, 18 077 ? with Flebogamma, and 17 423 ? with Octagamocta. Direct medical costs for IVIGs were approximately 91.8 million ?. Drug costs represented 94% of total costs. The choice for a certain IVIG treatment depends on individual patient characteristics and cost considerations. PMID- 21593280 TI - Effect of CYP2C19 genetic polymorphism on pharmacokinetics and pharmacodynamics of a new proton pump inhibitor, ilaprazole. AB - It is well known that the CYP2C19 genetic polymorphism influences the pharmacokinetics and pharmacodynamics of proton pump inhibitors (PPIs), but no report has addressed the effects on ilaprazole, a newly developed PPI. To investigate the effects of the CYP2C19 genetic polymorphism on the disposition and pharmacodynamics of ilaprazole, multiple doses of once-daily 10 mg ilaprazole were repeatedly administered for 7 days to 27 healthy Korean participants, comprising 9 homozygous CYP2C19 extensive metabolizers (homo EMs), 10 heterozygous EMs (hetero EMs), and 8 homozygous poor metabolizers (PMs). The plasma concentration and pharmacodynamic response were measured in the last dose interval. Each genotype group was matched for gender and thus was composed of 4 male and 4 female participants when the analysis was conducted. The pharmacokinetic parameters estimated from the plasma concentrations of ilaprazole and its metabolite ilaprazole sulfone, the serum gastrin level, and the 24-hour intragastric pH were compared among the CYP2C19 genotype groups. No statistically significant differences in the maximum plasma concentration at steady state(C(ss,max)) and the area under the concentration-time curve from zero to 24 hours (AUC(tau)) of ilaprazole and ilaprazole sulfone were observed among the homo EM, hetero EM, and PM CYP2C19 genotypes. In addition, the mean 24-hour intragastric pH, the percentage of time at pH >4, and the AUC(tau) of serum gastrin showed no significant differences among the CYP2C19 genotype groups. The data suggests that the pharmacokinetics and pharmacodynamics of ilaprazole are not significantly influenced by the CYP2C19 genetic polymorphism in healthy participants. PMID- 21593281 TI - Evaluation of the quality of publications on randomized clinical trials using the Consolidated Standards of Reporting Trials (CONSORT) statement guidelines in a Spanish tertiary hospital. AB - The main reason for conducting a clinical trial (CT) is to test the effect of a drug or medical procedure to improve treatment of a disease. CTs contribute most when they are rigorously conducted and the results are published adequately. The aim of this study is to assess, using the CONSORT statement guidelines, the quality of reporting of completed CTs conducted at a tertiary hospital to determine which sections of the articles should be improved. CTs published between 2002 and 2008 were identified by searching the MEDLINE and Cochrane Library. Forty of 127 completed CTs were published. There was a marked increase in the number of articles and the quality of the journals that published the CTs over time. Although the articles were published in high-impact index journals, the Consolidated Standards of Reporting Trials (CONSORT) score reporting quality of the articles varied substantially, which indicates that they should be improved. The title, abstract, introduction, and discussion sections received the highest CONSORT scores and need little improvement. Poor reporting of methodological details and discussion on limitations and strengths were observed. In conclusion, much improvement remains to be made in the quality of reporting of CTs to allow reliable quality assessment of published trials. PMID- 21593282 TI - Effects of alcohol on the pharmacokinetics of morphine sulfate and naltrexone hydrochloride extended release capsules. AB - Although contraindicated, coingestion of alcohol and opioids by patients or drug abusers is a major health concern because of dangerous additive and potentially life-threatening sedative and respiratory effects. In addition, alcohol has been shown to disrupt the extended-release characteristics of certain extended-release opioid formulations, releasing a hazardous amount of opioid over a short time period. Morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT), which contain naltrexone sequestered in each pellet core, are indicated for management of chronic, moderate to severe pain. Sequestered naltrexone is designed for release upon product tampering (crushing) to potentially mitigate morphine-induced subjective effects. This open-label, single-dose, 4-way crossover, pharmacokinetic drug interaction study compared the relative bioavailability of morphine and naltrexone when MS-sNT is administered (under fasting conditions) with increasing doses of alcohol. Thirty-two healthy, opioid naive adults were randomized to MS-sNT administered with 240 mL of 4%, 20%, or 40% alcohol or water. No drug interaction was found between morphine in MS-sNT and 4% or 20% alcohol. Administration with 40% alcohol did not affect overall morphine exposure but was associated with a 2-fold increase in C(max) and reduction of t(max) from 9 to 4 hours versus MS-sNT taken with water. Naltrexone sequestering was successful in all treatment arms and not affected by coadministration with alcohol over the dose range tested. PMID- 21593283 TI - Microdosing clinical study: pharmacokinetic, pharmacogenomic (SLCO2B1), and interaction (grapefruit juice) profiles of celiprolol following the oral microdose and therapeutic dose. AB - The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 ug) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC(0-24) of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng.h/mL) than in *1/*3 (1097 ng.h/mL) and *1/*1 (1547 ng.h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype-dependent differences disappeared following the MD. Dose-normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems. PMID- 21593284 TI - Project Wings, a coping intervention for Latina adolescents: a pilot study. AB - The authors examined the feasibility and preliminary outcomes of Project Wings Girls' Groups, a school-based mental health promotion program designed to improve well-being in Latina adolescents, as observed in outcomes, including perceived stress, depressive symptoms, coping, and connectedness. This pilot randomized controlled trial compared outcomes over 9 months postintervention for 42 9th and 10th grade adolescents attending two urban high schools. Girls were randomized to Project Wings Girls' Groups, a 16-session facilitated curriculum, including sharing circles, mind-body exercises, and coping skills building or the attention control (i.e., similar format but focused on general health topics). Feasibility of retention and long-term follow-up data collection was demonstrated, with lessons learned for future study. Although not statistically powered, this trial demonstrated findings in the expected direction, including reduced perceived stress and depression and increased connectedness. A trial with sufficient power is warranted to examine Project Wings' effects on mental health problems among Latina adolescents. PMID- 21593285 TI - Variables affecting learning in a simulation experience: a mixed methods study. AB - The primary purpose of this study was to test a hypothesized model describing the direct effects of learning variables on anxiety and cognitive learning outcomes in a high-fidelity simulation (HFS) experience. The secondary purpose was to explain and explore student perceptions concerning the qualities and context of HFS affecting anxiety and learning. This study used a mixed methods quantitative dominant explanatory design with concurrent qualitative data collection to examine variables affecting learning in undergraduate, beginning nursing students (N = 124). Being ready to learn, having a strong auditory-verbal learning style, and being prepared for simulation directly affected anxiety, whereas learning outcomes were directly affected by having strong auditory-verbal and hands-on learning styles. Anxiety did not quantitatively mediate cognitive learning outcomes as theorized, although students qualitatively reported debilitating levels of anxiety. This study advances nursing education science by providing evidence concerning variables affecting learning outcomes in HFS. PMID- 21593286 TI - Comparison of nonfried apple snacks with commercially available fried snacks. AB - The study was carried out to evaluate the selected quality attributes of a prototype nonfried apple snack produced by application of vacuum impregnation (VI) of maple syrup and vacuum drying. When maple syrup concentration was adjusted to 20-40% in the VI solution, vacuum-dried apple slices are resulted in the greatest textural attributes, whiteness index, and desirable moisture content and water activity. Comparison of the VI-treated, vacuum-dried apple slices with commercially fried apple and potato snacks revealed that the consumer acceptability was greater for the fried snack products due to their flavor and texture; however, in addition to higher oil content (>30%), commercial fried apple and potato snacks possessed lower antioxidant capacity than nonfried apple snacks. VI process enhanced the calcium content of the nonfried apple snack products. PMID- 21593287 TI - Effect of four types of dietary fiber on the technological quality of pasta. AB - The development of dietary fiber-enriched foods permits to obtain products with functional properties but can cause several problems in technological quality. The aim of this study was to study the quality of pasta obtained by replacing bread wheat flour with resistant starch II (RSII), resistant starch IV (RSIV), oat bran (OB) and inulin (IN) with the purpose of improving their nutritional quality. RSII, RSIV, OB and IN were substituted for a portion of bread wheat flour at levels 2.5%, 5.0%, 7.5% and 10.0%. Cooking properties, amylose and inulin losses, color and texture were measured. Finally, nutritional quality of enriched pasta was evaluated by protein losses during cooking and total dietary fiber. Microstructure of pasta was analyzed by scanning electron microscopy. Addition of RSII into pasta formulation improved the quality of the final product. RSIV-enriched pasta presented an improvement in textural characteristics and OB affected cooking properties positively up to 5% of substitution. Inulin was lost during cooking; besides, its addition negatively affected the technological quality of pasta. The results obtained in this study prove that it is possible to elaborate pasta with acceptable cooking quality and with improved nutritional characteristics by adding 10% of RSII and RSIV and 5% of OB. PMID- 21593288 TI - Review: starch matrices and the glycemic response. AB - Starch is the most important source of energy for humans, and it is present in many products derived from cereals, legumes and tubers. Interestingly, some of these food products can have different metabolic effects (e.g. change of postprandial blood glucose concentration) although the total amount of starch is the same. This review focuses on a microstructural perspective of the glycemic response, in search of an alternative and complementary explanation of this phenomenon. Several starch and food microstructures are responsible for the change in starch bioaccessibility. Aspects such as the characterization of the microstructure of starchy products and, its relation to the metabolic problem, the crucial role of the food matrix and other components in the ingested meal, and the gaps in our present knowledge are discussed. PMID- 21593289 TI - Increased risk of hypertension after gestational diabetes mellitus: findings from a large prospective cohort study. AB - OBJECTIVE: Whether a history of gestational diabetes mellitus (GDM) is associated with an increased risk of hypertension after the index pregnancy is not well established. RESEARCH DESIGN AND METHODS: We investigated the association between GDM and subsequent risk of hypertension after the index pregnancy among 25,305 women who reported at least one singleton pregnancy between 1991 and 2007 in the Nurses' Health Study II. RESULTS: During 16 years of follow-up, GDM developed in 1,414 women (5.6%) and hypertension developed in 3,138. A multivariable Cox proportional hazards model showed women with a history of GDM had a 26% increased risk of developing hypertension compared with those without a history of GDM (hazard ratio 1.26 [95% CI 1.11-1.43]; P=0.0004). These results were independent of pregnancy hypertension or subsequent type 2 diabetes. CONCLUSIONS: These results indicate that women with GDM are at a significant increased risk of developing hypertension after the index pregnancy. PMID- 21593290 TI - One-year results of a community-based translation of the Diabetes Prevention Program: Healthy-Living Partnerships to Prevent Diabetes (HELP PD) Project. AB - OBJECTIVE: Although the Diabetes Prevention Program (DPP) and the Finnish Diabetes Prevention Study (FDPS) demonstrated that weight loss from lifestyle change reduces type 2 diabetes incidence in patients with prediabetes, the translation into community settings has been difficult. The objective of this study is to report the first-year results of a community-based translation of the DPP lifestyle weight loss (LWL) intervention on fasting glucose, insulin resistance, and adiposity. RESEARCH DESIGN AND METHODS: We randomly assigned 301 overweight and obese volunteers (BMI 25-40 kg/m(2)) with fasting blood glucose values between 95 and 125 mg/dL to a group-based translation of the DPP LWL intervention administered through a diabetes education program (DEP) and delivered by community health workers (CHWs) or to an enhanced usual-care condition. CHWs were volunteers with well-controlled type 2 diabetes. A total of 42.5% of participants were male, mean age was 57.9 years, 26% were of a race/ethnicity other than white, and 80% reported having an education beyond high school. The primary outcome is mean fasting glucose over 12 months of follow-up, adjusting for baseline glucose. RESULTS: Compared with usual-care participants, LWL intervention participants experienced significantly greater decreases in blood glucose (-4.3 vs. -0.4 mg/dL; P<0.001), insulin (-6.5 vs. -2.7 MUU/mL; P<0.001), homeostasis model assessment of insulin resistance (-1.9 vs. -0.8; P<0.001), weight (-7.1 vs. -1.4 kg; P<0.001), BMI (-2.1 vs. -0.3 kg/m2; P<0.001), and waist circumference (-5.9 vs. -0.8 cm; P<0.001). CONCLUSIONS: This translation of the DPP intervention conducted in community settings, administered through a DEP, and delivered by CHWs holds great promise for the prevention of diabetes by significantly decreasing glucose, insulin, and adiposity. PMID- 21593291 TI - Impaired fasting glucose is associated with renal hyperfiltration in the general population. AB - OBJECTIVE: Increased glomerular filtration rate (GFR), also called hyperfiltration, is a proposed mechanism for renal injury in diabetes. The causes of hyperfiltration in individuals without diabetes are largely unknown, including the possible role of borderline hyperglycemia. We assessed whether impaired fasting glucose (IFG; 5.6-6.9 mmol/L), elevated HbA1c, or hyperinsulinemia are associated with hyperfiltration in the general middle-aged population. RESEARCH DESIGN AND METHODS: A total of 1,560 individuals, aged 50-62 years without diabetes, were included in the Renal Iohexol Clearance Survey in Tromso 6 (RENIS T6). GFR was measured as single-sample plasma iohexol clearance. Hyperfiltration was defined as GFR>90th percentile, adjusted for sex, age, weight, height, and use of renin-angiotensin system inhibitors. RESULTS: Participants with IFG had a multivariable-adjusted odds ratio of 1.56 (95% CI 1.07-2.25) for hyperfiltration compared with individuals with normal fasting glucose. Odds ratios (95% CI) of hyperfiltration calculated for a 1-unit increase in fasting plasma glucose (FPG) and HbA1c, after multivariable-adjustment, were 1.97 (1.36-2.85) and 2.23 (1.30 3.86). There was no association between fasting insulin levels and hyperfiltration. A nonlinear association between FPG and GFR was observed (df=3, P<0.0001). GFR increased with higher glucose levels, with a steeper slope beginning at FPG>=5.4 mmol/L. CONCLUSIONS: Borderline hyperglycemia was associated with hyperfiltration, whereas hyperinsulinemia was not. Longitudinal studies are needed to investigate whether the hyperfiltration associated with IFG is a risk factor for renal injury in the general population. PMID- 21593292 TI - Insulin detemir reduces weight gain as a result of reduced food intake in patients with type 1 diabetes. AB - OBJECTIVE: Insulin detemir lacks the usual propensity for insulin to cause weight gain. We investigated whether this effect was a result of reduced energy intake and/or increased energy expenditure. RESEARCH DESIGN AND METHODS: A 32-week, randomized crossover design trial was undertaken in 23 patients with type 1 diabetes. Patients on a basal-bolus regimen (with insulin aspart as the bolus insulin) were randomly assigned to insulin detemir or NPH insulin as a basal insulin for 16 weeks, followed by the other basal insulin for 16 weeks. At the end of each 16-week period, total energy expenditure, resting energy expenditure, diet-induced thermogenesis, activity energy expenditure, energy intake, weight change, glycemic control, hypoglycemic episodes, and hormones that affect satiety and fuel partitioning were measured. RESULTS: After 16 weeks, weight change was 0.69+/-1.85 kg with insulin detemir and +1.7+/-2.46 kg with NPH insulin (P<0.001). Total energy intake was significantly less with insulin detemir (2,016+/-501 kcal/day) than with NPH insulin (2,181+/-559 kcal/day) (P=0.026). There was no significant difference in any measure of energy expenditure, HbA1c percentage, or number of hypoglycemic episodes. Leptin was lower and resistin was higher with insulin detemir compared with NPH insulin (P=0.039, P=0.047). After the meal, ghrelin and pancreatic polypeptide levels (P=0.002, P=0.001) were higher with insulin detemir. CONCLUSIONS: The reduced weight gain with insulin detemir compared with NPH insulin is attributed to reduced energy intake rather than increased energy expenditure. This may be mediated by a direct or indirect effect of insulin detemir on the hormones that control satiety. PMID- 21593293 TI - Retinal vascular geometry predicts incident retinopathy in young people with type 1 diabetes: a prospective cohort study from adolescence. AB - OBJECTIVE: To examine the association between retinal vascular geometry and subsequent development of incident retinopathy in young patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A prospective cohort study of 736 people with type 1 diabetes aged 12 to 20 years, retinopathy-free at baseline, attending an Australian tertiary care hospital. Retinopathy was determined from seven-field retinal photographs according to the modified Airlie House Classification. Retinal vascular geometry, including length/diameter ratio (LDR) and simple tortuosity (ST), was quantified in baseline retinal photographs. Generalized estimating equations were used to determine risk of retinopathy associated with baseline LDR and ST, adjusting for other factors. RESULTS: After a median 3.8 (interquartile range 2.4-6.1) years of follow-up, incident retinopathy developed in 287 of 736 (39%). In multivariate analysis, lower arteriolar LDR (odds ratio 1.8 [95% CI 1.2-2.6]; 1st vs. 4th quartile) and greater arteriolar ST (1.5 [1.0 2.2]; 4th vs. 1st quartile) predicted incident retinopathy after adjusting for diabetes duration, sex, A1C, blood pressure, total cholesterol, and BMI. In subgroup analysis by sex, LDR predicted incident retinopathy in male and female participants (2.1 [1.1-4.0] and 1.7 [1.1-2.7]; 1st vs. 4th quartiles, respectively) and greater arteriolar ST predicted incident retinopathy in male participants (2.4 [1.1-4.4]; 4th vs. 1st quartile) only. CONCLUSIONS: Lower arteriolar LDR and greater ST were independently associated with incident retinopathy in young people with type 1 diabetes. These vascular geometry measures may serve as risk markers for diabetic retinopathy and provide insights into the early structural changes in diabetic microvascular complications. PMID- 21593294 TI - Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. AB - OBJECTIVE: Overweight and obese individuals are encouraged to lose 5-10% of their body weight to improve cardiovascular disease (CVD) risk, but data supporting this recommendation are limited, particularly for individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted an observational analysis of participants in the Look AHEAD (Action For Health in Diabetes) study (n=5,145, 40.5% male, 37% from ethnic/racial minorities) and examined the association between the magnitude of weight loss and changes in CVD risk factors at 1 year and the odds of meeting predefined criteria for clinically significant improvements in risk factors in individuals with type 2 diabetes. RESULTS: The magnitude of weight loss at 1 year was strongly (P<0.0001) associated with improvements in glycemia, blood pressure, triglycerides, and HDL cholesterol but not with LDL cholesterol (P=0.79). Compared with weight-stable participants, those who lost 5 to <10% ([means+/-SD] 7.25+/-2.1 kg) of their body weight had increased odds of achieving a 0.5% point reduction in HbA1c (odds ratio 3.52 [95% CI 2.81-4.40]), a 5-mmHg decrease in diastolic blood pressure (1.48 [1.20-1.82]), a 5-mmHg decrease in systolic blood pressure (1.56 [1.27-1.91]), a 5 mg/dL increase in HDL cholesterol (1.69 [1.37-2.07]), and a 40 mg/dL decrease in triglycerides (2.20 [1.71-2.83]). The odds of clinically significant improvements in most risk factors were even greater in those who lost 10-15% of their body weight. CONCLUSIONS: Modest weight losses of 5 to <10% were associated with significant improvements in CVD risk factors at 1 year, but larger weight losses had greater benefits. PMID- 21593295 TI - The effect of zoledronic acid on the clinical resolution of Charcot neuroarthropathy: a pilot randomized controlled trial. AB - OBJECTIVE: To investigate the clinical efficacy of zoledronic acid in patients with diabetes and acute Charcot neuroarthropathy. RESEARCH DESIGN AND METHODS: Thirty-nine consecutive patients were randomly assigned to placebo or three intravenous infusions of 4 mg zoledronic acid. The primary outcome was clinical resolution of acute Charcot neuroarthropathy determined by total immobilization time (casting plus orthosis). RESULTS: At baseline, there was no significant difference between the randomly assigned groups with respect to Charcot disease activity or other baseline values. In the zoledronic acid group, the median time for total immobilization was 27 weeks (range 10-62), and in the placebo group it was 20 weeks (20-52) (P=0.02). CONCLUSIONS: Zoledronic acid had no beneficial effect on the clinical resolution of acute Charcot neuroarthropathy in terms of total immobilization time. It is possible that it may prolong the time to clinical resolution of Charcot neuroarthropathy. PMID- 21593296 TI - Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function. AB - OBJECTIVE: To investigate the effect of 4 weeks of treatment with liraglutide on insulin dose and glycemic control in type 1 diabetic patients with and without residual beta-cell function. RESEARCH DESIGN AND METHODS: Ten type 1 diabetic patients with residual beta-cell function (C-peptide positive) and 19 without (C peptide negative) were studied. All C-peptide-positive patients were treated with liraglutide plus insulin, whereas C-peptide-negative patients were randomly assigned to liraglutide plus insulin or insulin monotherapy. Continuous glucose monitoring with identical food intake and physical activity was performed before (week 0) and during (week 4) treatment. Differences in insulin dose; HbA1c; time spent with blood glucose<3.9, >10, and 3.9-9.9 mmol/L; and body weight were evaluated. RESULTS: Insulin dose decreased from 0.50+/-0.06 to 0.31+/-0.08 units/kg per day (P<0.001) in C-peptide-positive patients and from 0.72+/-0.08 to 0.59+/-0.06 units/kg per day (P<0.01) in C-peptide-negative patients treated with liraglutide but did not change with insulin monotherapy. HbA1c decreased in both liraglutide-treated groups. The percent reduction in daily insulin dose was positively correlated with beta-cell function at baseline, and two patients discontinued insulin treatment. In C-peptide-positive patients, time spent with blood glucose<3.9 mmol/L decreased from 3.0 to 1.0 h (P=0.03). A total of 18 of 19 patients treated with liraglutide lost weight during treatment (mean [range] 2.3+/-0.3 kg [-0.5 to -5.1]; P<0.001). Transient gastrointestinal adverse effects occurred in almost all patients treated with liraglutide. CONCLUSIONS: Treatment with liraglutide in type 1 diabetic patients reduces insulin dose with improved or unaltered glycemic control. PMID- 21593297 TI - Loss of RAGE defense: a cause of Charcot neuroarthropathy? AB - OBJECTIVE: This study investigated the relationship between circulating soluble receptor for advanced glycation end products (sRAGE) and parameters of bone health in patients with Charcot neuroarthropathy (CNA). RESEARCH DESIGN AND METHODS: Eighty men (aged 55.3+/-9.0 years), including 30 healthy control subjects, 30 type 2 diabetic patients without Charcot, and 20 type 2 diabetic patients with stage 2 (nonacute) CNA, underwent evaluations of peripheral and autonomic neuropathy, nerve conduction, markers of bone turnover, bone mineral density, and bone stiffness of the calcaneus. RESULTS: CNA patients had worse peripheral and autonomic neuropathy and a lower bone stiffness index than diabetic or control individuals (77.1, 103.3, and 105.1, respectively; P<0.05), but no difference in bone mineral density (P>0.05). CNA subjects also had lower sRAGE levels than control (162 vs. 1,140 pg/mL; P<0.01) and diabetic (162 vs. 522 pg/mL; P<0.05) subjects, and higher circulating osteocalcin levels. CONCLUSIONS: CNA patients had significantly lower circulating sRAGE, with an accompanying increase in serum markers of bone turnover, and reduced bone stiffness in the calcaneus not accompanied by reductions in bone mineral density. These data suggest a failure of RAGE defense mechanisms against oxidative stress in diabetes. Future studies should determine if medications that increase sRAGE activity could be useful in mitigating progression to CNA. PMID- 21593298 TI - Risk factors for hearing impairment among U.S. adults with diabetes: National Health and Nutrition Examination Survey 1999-2004. AB - OBJECTIVE: The objective of this study was to examine the risk factors of low/mid frequency and high-frequency hearing impairment among a nationally representative sample of diabetic adults. RESEARCH DESIGN AND METHODS: Data came from 536 participants, aged 20-69 years, with diagnosed or undiagnosed diabetes who completed audiometric testing during 1999-2004 in the National Health and Nutrition Examination Survey (NHANES). We defined hearing impairment as the pure tone average>25 dB hearing level of pure-tone thresholds at low/mid-frequencies (500; 1,000; and 2,000 Hz) and high frequencies (3,000; 4,000; 6,000; and 8,000 Hz) and identified independent risk factors using logistic regression. RESULTS: Controlling for age, race/ethnicity, and marital status, odds ratios for associations with low/mid-frequency hearing impairment were 2.20 (95% CI 1.28 3.79) for HDL<40 mg/dL and 3.55 (1.57-8.03) for poor health. Controlling for age, race/ethnicity, sex, and income-to-poverty ratio, odds ratios for associations with high-frequency hearing impairment were 4.39 (1.26-15.26) for history of coronary heart disease and 4.42 (1.26-15.45) for peripheral neuropathy. CONCLUSIONS: Low HDL, coronary heart disease, peripheral neuropathy, and having poor health are potentially preventable correlates of hearing impairment for people with diabetes. Glycemic control, years since diagnosis, and type of glycemic medication were not associated with hearing impairment. PMID- 21593299 TI - Trends in lower-extremity amputations in people with and without diabetes in Spain, 2001-2008. AB - OBJECTIVE: To examine trends in nontraumatic lower-extremity amputations (LEAs) over an 8-year period in patients with and without diabetes in Spain. RESEARCH DESIGN AND METHODS: We identified all patients who underwent an LEA using national hospital discharge data. Discharges were grouped by diabetes status: type 1 diabetes, type 2 diabetes, and no diabetes. The incidence of discharges attributed to amputations were calculated overall and stratified by diabetes status and year. We calculated length of stay and in-hospital fatality stratified by diabetes status and type of LEA. RESULTS: From 2001 to 2008, 46,536 minor LEAs and 43,528 major LEAs were performed. In patients with type 1 diabetes, the incidence of minor and major amputations decreased significantly from 2001 to 2008 (0.88-0.43 per 100,000 inhabitants and 0.59-0.22 per 100,000 inhabitants, respectively). In patients with type 2 diabetes, the incidence of minor and major LEAs increased significantly (9.23-10.9 per 100,000 inhabitants and 7.12-7.47 per 100,000 inhabitants). Hospital stay was similar among type 1 diabetic and type 2 diabetic subjects, according to the type of LEA. Only in-hospital mortality for minor LEAs among type 1 diabetic subjects decreased significantly (4.0% in 2001 vs. 1.6% in 2008). CONCLUSIONS: Our national data show a decrease in the incidence of major and minor LEAs in patients with type 1 diabetes and an increase among patients with type 2 diabetes. Further improvement is necessary in the preventive care and early treatment of patients with diabetes. The management of foot lesions, especially among type 2 diabetic patients, is particularly urgent. PMID- 21593300 TI - The Ipswich Touch Test: a simple and novel method to identify inpatients with diabetes at risk of foot ulceration. AB - OBJECTIVE: To promote foot screening of inpatients with diabetes, we simplified sensory testing to lightly touching the tips of the first, third, and fifth toes (the Ipswich Touch Test [IpTT]). RESEARCH DESIGN AND METHODS: Respective performances of the IpTT and 10-g monofilament (MF) were compared with a vibration perception threshold of >=25 V indicating at-risk feet in 265 individuals. The IpTT and MF were also directly compared. RESULTS: With >=2 of 6 insensate areas signifying at-risk feet, sensitivities and specificities, respectively, were IpTT (77 and 90%), MF (81 and 91%); positive predictive values were IpTT (89%), MF (91%); and negative predictive values were IpTT (77%), MF (81%). Directly compared, agreement between the IpTT and MF was almost perfect (kappa=0.88, P<0.0001). Interrater agreement for the IpTT was substantial (kappa=0.68). CONCLUSIONS: The IpTT performs well against a recognized standard for ulcer prediction. Simple to teach, reliable, without expense, and always at hand, it should encourage uptake of screening and detection of high-risk inpatients requiring foot protection. PMID- 21593301 TI - Post hoc subgroup analysis of the HEART2D trial demonstrates lower cardiovascular risk in older patients targeting postprandial versus fasting/premeal glycemia. AB - OBJECTIVE: To identify the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) trial subgroups with treatment difference. RESEARCH DESIGN AND METHODS: In 1,115 type 2 diabetic patients who had suffered from an acute myocardial infarction (AMI), the HEART2D trial compared two insulin strategies targeting postprandial or fasting/premeal glycemia on time until first cardiovascular event (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for acute coronary syndrome). The HEART2D trial ended prematurely for futility. We used the classification and regression tree (CART) to identify baseline subgroups with potential treatment differences. RESULTS: CART estimated the age of >65.7 years to best predict the difference in time to first event. In the subgroup aged>65.7 years (prandial, n=189; basal, n=210), prandial patients had a significantly longer time to first event and a lower proportion experienced a first event (n=56 [29.6%] vs. n=85 [40.5%]; hazard ratio 0.69 [95% CI 0.49-0.96]; P=0.029), despite similar A1C levels. CONCLUSIONS: Older type 2 diabetic AMI survivors may have a lower risk for a subsequent cardiovascular event with insulin targeting postprandial versus fasting/premeal glycemia. PMID- 21593303 TI - Hyperglycemia and death in cystic fibrosis-related diabetes. AB - OBJECTIVE: Diabetes is common in cystic fibrosis and increases the risk of death, yet the role of hyperglycemia remains unproven. An association between glycemia and mortality would provide compelling evidence to support glucose lowering in cystic fibrosis-related diabetes (CFRD). RESEARCH DESIGN AND METHODS: Using the U.K. Cystic Fibrosis Registry, we analyzed longitudinal data from 2006 to 2009 in 520 individuals with diabetes. We tested the association between HbA1c and mortality. RESULTS: During a median follow-up of 2 years, 36 patients died. The median value of HbA1c was higher in those who died (7.3%) than in those who did not (6.7%). An HbA1c value of >=6.5% was associated with a threefold increased risk of death (hazard ratio 3.2 [95% CI 1.4-7.3]; P=0.005) independent of potential confounders. CONCLUSIONS: Hyperglycemia trebles the risk of death in patients with CFRD. These findings provide epidemiologic support for continued efforts to improve glycemic control. PMID- 21593302 TI - Transition from intravenous to subcutaneous insulin: effectiveness and safety of a standardized protocol and predictors of outcome in patients with acute coronary syndrome. AB - OBJECTIVE: The study objectives were 1) to assess the effectiveness and safety of a standardized protocol for the transition to subcutaneous insulin and oral feeding in diabetic or hyperglycemic patients with acute coronary syndrome (ACS) who were receiving intravenous insulin and glucose at the time of the transfer from the intensive cardiac care unit to a general ward and 2) to identify predictors of transition outcome. RESEARCH DESIGN AND METHODS: This was a prospective observational study. The protocol specifies that patients receive a 100% of their daily subcutaneous insulin requirement from the first day of oral feeding, calculated from the intravenous insulin rate during the final 12 h divided into two: 50% basal and 50% prandial. RESULTS: In 142 patients (93 male, 49 female, age range 47-88 years, 135 with known diabetes) the first day after transition, 44.8% of blood glucose (BG) measurements were within the strict range of 100-140 mg/dL before meals and 100-180 mg/dL after meals, and 70.8% were within the broader ranges of 80-160 mg/dL and 80-200 mg/dL, respectively. Pre- or postprandial hypoglycemia (BG<70 mg/dL) occurred in 11 patients (7.7%) on the first day and in 38 patients (26.8%) on the first 3 days after transition. Old age, high doses of intravenous insulin, and wide BG variations in the 24 h before insulin infusion was stopped were predictive of poor BG control after transition. CONCLUSIONS: This study shows the effectiveness and safety of a standardized protocol for the transition from intravenous to subcutaneous insulin in patients with ACS when regular oral feeding was resumed. PMID- 21593305 TI - Creating a 21st century global health agenda: the general assembly of the United Nations High Level Meeting on Non-Communicable Diseases. PMID- 21593304 TI - Peripheral vascular disease and peripheral neuropathy in individuals with cardiometabolic clustering and obesity: National Health and Nutrition Examination Survey 2001-2004. AB - OBJECTIVE: Two lower-extremity diseases (LEDs), including peripheral neuropathy and peripheral vascular disease (PVD), are leading causes of disability in the U.S. Although LEDs can be complications of diabetes, their prevelances and risk factors apart from diabetes are poorly described. This study describes the prevalence of LEDs and examines the association of obesity and cardiometabolic clustering in a population-based sample. RESEARCH DESIGN AND METHODS: Adults aged>=40 years (n=2,514) were evaluated in the 2001-2004 National Health and Nutrition Examination Survey for clustering of two or more cardiometabolic characteristics, including elevated triglycerides or plasma glucose, low HDL cholesterol levels, increased waist circumference, or hypertension. Clustering was combined with BMI (dichotomized at >=30 kg/m2) to generate three groups: obese (with or without clustering); nonobese with clustering; and nonobese without clustering. Multivariate logistic regression procedures incorporated the complex survey sampling design. RESULTS: Overall, 9.0% of individuals had peripheral neuropathy alone, 8.5% had PVD alone, and 2.4% had both LEDs. The obese group was more likely to have peripheral neuropathy (odds ratio 2.20 [95% CI 1.43-3.39]), PVD (3.10 [1.84-5.22]), and both LEDs (6.91 [2.64-18.06]) compared with nonobese subjects without clustering. Within the nonobese group, clustering increased the odds of peripheral neuropathy (1.50 [1.00-2.25]) and PVD (2.48 [1.38-4.44]) compared with no clustering. CONCLUSIONS: Obesity and clustering markedly increased the likelihood of LEDs in this sample and identified a group for whom preventive activities may reduce the risk of future disability. PMID- 21593307 TI - Mind the gap: olfactory trace conditioning in honeybees. AB - Trace conditioning is a form of classical conditioning, where a neutral stimulus (conditioned stimulus, CS) is associated with a following appetitive or aversive stimulus (unconditioned stimulus, US). Unlike classical delay conditioning, in trace conditioning there is a stimulus-free gap between CS and US, and thus a poststimulus neural representation (trace) of the CS is required to bridge the gap until its association with the US. The properties of such stimulus traces are not well understood, nor are their underlying physiological mechanisms. Using behavioral and physiological approaches, we studied appetitive olfactory trace conditioning in honeybees. We found that single-odor presentation created a trace containing information about odor identity. This trace conveyed odor information about the initial stimulus and was robust against interference by other odors. Memory acquisition decreased with increasing CS-US gap length. The maximum learnable CS-US gap length could be extended by previous trace-conditioning experience. Furthermore, acquisition improved when an additional odor was presented during the CS-US gap. Using calcium imaging, we tested whether projection neurons in the primary olfactory brain area, the antennal lobe, contain a CS trace. We found odor-specific persistent responses after stimulus offset. These post-odor responses, however, did not encode the CS trace, and perceived odor quality could be predicted by the initial but not by the post-odor response. Our data suggest that olfactory trace conditioning is a less reflexive form of learning than classical delay conditioning, indicating that odor traces might involve higher-level cognitive processes. PMID- 21593306 TI - ZPK/DLK, a mitogen-activated protein kinase kinase kinase, is a critical mediator of programmed cell death of motoneurons. AB - Activation of mitogen-activated protein kinase pathways is critically involved in naturally occurring programmed cell death of motoneurons during development, but the upstream mediators remain undetermined. We found that mice deficient in ZPK, also called DLK (ZPK/DLK), an upstream kinase in these pathways, have twice as many spinal motoneurons as do their wild-type littermates. Nuclear HB9/MNX1 positive motoneuron pools were generated similarly in the spinal cord of both ZPK/DLK-deficient and wild-type embryos. Thereafter, however, significantly less apoptotic motoneurons were found in ZPK/DLK-deficient embryos compared with wild type embryos, resulting in retention of excess numbers of motoneurons after birth. Notably, these excess motoneurons remained viable without atrophic changes in the ZPK/DLK-deficient mice surviving into adulthood. Analysis of the diaphragm and the phrenic nerve revealed that clustering and innervation of neuromuscular junctions were indistinguishable between ZPK/DLK-deficient and wild-type mice, whereas the proximal portion of the phrenic nerve of ZPK/DLK-deficient mice contained significantly more axons than the distal portion. This result supports the hypothesis that some excess ZPK/DLK-deficient motoneurons survived without atrophy despite failure to establish axonal contact with their targets. This study provides compelling evidence for a critical role for ZPK/DLK in naturally occurring programmed cell death of motoneurons and suggests that ZPK/DLK could become a strategic therapeutic target in motor neuron diseases in which aberrant activation of the apoptogenic cascade is involved. PMID- 21593308 TI - Olfactory trace conditioning in Drosophila. AB - The neural representation of a sensory stimulus evolves with time, and animals keep that representation even after stimulus cessation (i.e., a stimulus "trace"). To contrast the memories of an odor and an odor trace, we here establish a rigorous trace conditioning paradigm in the fruit fly, Drosophila melanogaster. We modify the olfactory associative learning paradigm, in which the odor and electric shock are presented with a temporal overlap (delay conditioning). Given a few-second temporal gap between the presentations of the odor and the shock in trace conditioning, the odor trace must be kept until the arrival of electric shock to form associative memory. We found that memories after trace and delay conditioning have striking similarities: both reached the same asymptotic learning level, although at different rates, and both kinds of memory have similar decay kinetics and highly correlated generalization profiles across odors. In search of the physiological correlate of the odor trace, we used in vivo calcium imaging to characterize the odor-evoked activity of the olfactory receptor neurons in the antennal lobe. After the offset of odor presentation, the receptor neurons showed persistent, odor-specific response patterns that lasted for a few seconds and were fundamentally different from the response patterns during the stimulation. Weak correlation between the behavioral odor generalization profile in trace conditioning and the physiological odor similarity profiles in the antennal lobe suggest that the odor trace used for associative learning may be encoded downstream of the olfactory receptor neurons. PMID- 21593309 TI - Myelination and axonal electrical activity modulate the distribution and motility of mitochondria at CNS nodes of Ranvier. AB - Energy production presents a formidable challenge to axons as their mitochondria are synthesized and degraded in neuronal cell bodies. To meet the energy demands of nerve conduction, small mitochondria are transported to and enriched at mitochondrial stationary sites located throughout the axon. In this study, we investigated whether size and motility of mitochondria in small myelinated CNS axons are differentially regulated at nodes, and whether mitochondrial distribution and motility are modulated by axonal electrical activity. The size/volume of mitochondrial stationary sites was significantly larger in juxtaparanodal/internodal axoplasm than in nodal/paranodal axoplasm. With three dimensional electron microscopy, we observed that axonal mitochondrial stationary sites were composed of multiple mitochondria of varying length, except at nodes where mitochondria were uniformly short and frequently absent altogether. Mitochondrial transport speed was significantly reduced in nodal axoplasm compared with internodal axoplasm. Increased axonal electrical activity decreased mitochondrial transport and increased the size of mitochondrial stationary sites in nodal/paranodal axoplasm. Decreased axonal electrical activity had the opposite effect. In cerebellar axons of the myelin-deficient rat, which contain voltage-gated Na(+) channel clusters but lack paranodal specializations, axonal mitochondrial motility and stationary site size were similar at Na(+) channel clusters and other axonal regions. These results demonstrate juxtaparanodal/internodal enrichment of stationary mitochondria and neuronal activity-dependent dynamic modulation of mitochondrial distribution and transport in nodal axoplasm. In addition, the modulation of mitochondrial distribution and motility requires oligodendrocyte-axon interactions at paranodal specializations. PMID- 21593310 TI - Alzheimer's disease brain-derived amyloid-beta-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. AB - Synthetic amyloid-beta protein (Abeta) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Abeta in vitro is controversial. Here we report that intracerebroventricular injection of Abeta containing aqueous extracts of Alzheimer's disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Abeta. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Abeta-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Abeta. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Abeta, did not significantly affect the Abeta-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Abeta dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Abeta. PMID- 21593311 TI - Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family. AB - The synucleins (alpha, beta, and gamma) are highly homologous proteins thought to play a role in regulating neurotransmission and are found abundantly in presynaptic terminals. To overcome functional overlap between synuclein proteins and to understand their role in presynaptic signaling from mesostriatal dopaminergic neurons, we produced mice lacking all three members of the synuclein family. The effect on the mesostriatal system was assessed in adult (4- to 14 month-old) animals using a combination of behavioral, biochemical, histological, and electrochemical techniques. Adult triple-synuclein-null (TKO) mice displayed no overt phenotype and no change in the number of midbrain dopaminergic neurons. TKO mice were hyperactive in novel environments and exhibited elevated evoked release of dopamine in the striatum detected with fast-scan cyclic voltammetry. Elevated dopamine release was specific to the dorsal not ventral striatum and was accompanied by a decrease of dopamine tissue content. We confirmed a normal synaptic ultrastructure and a normal abundance of SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) protein complexes in the dorsal striatum. Treatment of TKO animals with drugs affecting dopamine metabolism revealed normal rate of synthesis, enhanced turnover, and reduced presynaptic striatal dopamine stores. Our data uniquely reveal the importance of the synuclein proteins in regulating neurotransmitter release from specific populations of midbrain dopamine neurons through mechanisms that differ from those reported in other neurons. The finding that the complete loss of synucleins leads to changes in dopamine handling by presynaptic terminals specifically in those regions preferentially vulnerable in Parkinson's disease may ultimately inform on the selectivity of the disease process. PMID- 21593312 TI - Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes. AB - Oligomannosidic glycans play important roles in nervous system development and function. By performing a phage display screening with oligomannose-specific antibodies, we identified an oligomannose-mimicking peptide that was functionally active in modulating neurite outgrowth and neuron-astrocyte adhesion. Using the oligomannose-mimicking peptide in crosslinking experiments, synapsin I was identified as a novel oligomannose-binding protein in mouse brain. Further analyses not only verified that synapsin I is an oligomannose-binding lectin, but also indicated that it is a glycoprotein carrying oligomannose and Lewis(x). We also found that synapsin I is expressed in glia-enriched cultures and is released from glial cells via exosomes. Incubation of glial-derived exosomes in the presence of high KCl concentrations or subjecting glial cell cultures to either oxygen/glucose deprivation or hydrogen peroxide resulted in release of synapsin I from exosomes. Application of synapsin I promoted neurite outgrowth from hippocampal neurons and increased survival of cortical neurons upon hydrogen peroxide treatment or oxygen/glucose deprivation. Coculture experiments using wild-type hippocampal neurons and wild-type or synapsin-deficient glial cells showed enhanced neurite outgrowth when synapsin was expressed by glial cells. Synapsin-induced neurite outgrowth was dependent on oligomannose on synapsin I and the neural cell adhesion molecule NCAM at the neuronal cell surface. The data indicate that, under conditions of high neuronal activity and/or oxidative stress, synapsin can be released from glial-derived exosomes and promotes neurite outgrowth and neuronal survival by modulating the interactions between glia and neurons. PMID- 21593314 TI - Synaptic glutamate release is modulated by the Na+ -driven Cl-/HCO3- exchanger Slc4a8. AB - On the one hand, neuronal activity can cause changes in pH; on the other hand, changes in pH can modulate neuronal activity. Consequently, the pH of the brain is regulated at various levels. Here we show that steady-state pH and acid extrusion were diminished in cultured hippocampal neurons of mice with a targeted disruption of the Na(+)-driven Cl(-)/HCO(3)(-) exchanger Slc4a8. Because Slc4a8 was found to predominantly localize to presynaptic nerve endings, we hypothesize that Slc4a8 is a key regulator of presynaptic pH. Supporting this hypothesis, spontaneous glutamate release in the CA1 pyramidal layer was reduced but could be rescued by increasing the intracellular pH. The reduced excitability in vitro correlated with an increased seizure threshold in vivo. Together with the altered kinetics of stimulated synaptic vesicle release, these data suggest that Slc4a8 modulates glutamate release in a pH-dependent manner. PMID- 21593313 TI - Dorsal striatal D2-like receptor availability covaries with sensitivity to positive reinforcement during discrimination learning. AB - Deviations in reward sensitivity and behavioral flexibility, particularly in the ability to change or stop behaviors in response to changing environmental contingencies, are important phenotypic dimensions of several neuropsychiatric disorders. Neuroimaging evidence suggests that variation in dopamine signaling through dopamine D(2)-like receptors may influence these phenotypes, as well as associated psychiatric conditions, but the specific neurocognitive mechanisms through which this influence is exerted are unknown. To address this question, we examined the relationship between behavioral sensitivity to reinforcement during discrimination learning and D(2)-like receptor availability in vervet monkeys. Monkeys were assessed for their ability to acquire, retain, and reverse three choice, visual-discrimination problems, and once behavioral performance had stabilized, they received positron emission tomography (PET) scans. D(2)-like receptor availability in dorsal aspects of the striatum was not related to individual differences in the ability to acquire or retain visual discriminations but did relate to the number of trials required to reach criterion in the reversal phase of the task. D(2)-like receptor availability was also strongly correlated with behavioral sensitivity to positive, but not negative, feedback during learning. These results go beyond electrophysiological findings by demonstrating the involvement of a striatal dopaminergic marker in individual differences in feedback sensitivity and behavioral flexibility, providing insight into the neural mechanisms that are affected in neuropsychiatric disorders that feature these deficits. PMID- 21593315 TI - Na+ -Ca2+ exchanger (NCX3) knock-out mice display an impairment in hippocampal long-term potentiation and spatial learning and memory. AB - Long-term potentiation (LTP) depends on the coordinated regulation of an ensemble of proteins related to Ca(2+) homeostasis, including Ca(2+) transporters. One of the major players in the regulation of intracellular Ca(2+) ([Ca(2+)](i)) homeostasis in neurons is the sodium/calcium exchanger (NCX), which represents the principal mechanism of Ca(2+) clearance in the synaptic sites of hippocampal neurons. Because NCX3, one of the three brain isoforms of the NCX family, is highly expressed in the hippocampal subfields involved in LTP, we hypothesized that it might represent a potential candidate for LTP modulation. To test this hypothesis, we first examined the effect of ncx3 gene ablation on NCX currents (I(NCX)) and Ca(2+) homeostasis in hippocampal neurons. ncx3(-/-) neurons displayed a reduced I(NCX), a higher basal level of [Ca(2+)](i), and a significantly delayed clearance of [Ca(2+)](i) following depolarization. Furthermore, measurement of field EPSPs, recorded from the CA1 area, revealed that ncx3(-/-) mice had an impaired basal synaptic transmission. Moreover, hippocampal slices from ncx3(-/-) mice exhibited a worsening in LTP compared with congenic ncx3(+/+). Consistently, immunohistochemical and immunoblot analysis indicated that in the hippocampus of ncx3(-/-) mice both Ca(2+)/calmodulin dependent protein kinase IIalpha (CaMKIIalpha) expression and the phosphoCaMKIIalpha/CaMKIIalpha ratio were significantly reduced compared with ncx3(+/+). Interestingly, ncx3(-/-) mice displayed a reduced spatial learning and memory performance, as revealed by the novel object recognition, Barnes maze, and context-dependent fear conditioning assays. Collectively, our findings demonstrate that the deletion of the ncx3 gene in mice has detrimental consequences on basal synaptic transmission, LTP regulation, spatial learning, and memory performance. PMID- 21593316 TI - Real-world scene representations in high-level visual cortex: it's the spaces more than the places. AB - Real-world scenes are incredibly complex and heterogeneous, yet we are able to identify and categorize them effortlessly. In humans, the ventral temporal parahippocampal place area (PPA) has been implicated in scene processing, but scene information is contained in many visual areas, leaving their specific contributions unclear. Although early theories of PPA emphasized its role in spatial processing, more recent reports of its function have emphasized semantic or contextual processing. Here, using functional imaging, we reconstructed the organization of scene representations across human ventral visual cortex by analyzing the distributed response to 96 diverse real-world scenes. We found that, although individual scenes could be decoded in both PPA and early visual cortex (EVC), the structure of representations in these regions was vastly different. In both regions, spatial rather than semantic factors defined the structure of representations. However, in PPA, representations were defined primarily by the spatial factor of expanse (open, closed) and in EVC primarily by distance (near, far). Furthermore, independent behavioral ratings of expanse and distance correlated strongly with representations in PPA and peripheral EVC, respectively. In neither region was content (manmade, natural) a major contributor to the overall organization. Furthermore, the response of PPA could not be used to decode the high-level semantic category of scenes even when spatial factors were held constant, nor could category be decoded across different distances. These findings demonstrate, contrary to recent reports, that the response PPA primarily reflects spatial, not categorical or contextual, aspects of real-world scenes. PMID- 21593317 TI - Synaptic targeting and functional modulation of GluK1 kainate receptors by the auxiliary neuropilin and tolloid-like (NETO) proteins. AB - Auxiliary proteins modify the biophysical function and pharmacological properties of ionotropic glutamate receptors and likely are important components of receptor signaling complexes in vivo. The neuropilin and tolloid-like proteins (NETO) 1 and NETO2, two closely related CUB domain-containing integral membrane proteins, were identified recently as auxiliary proteins that slowed GluK2a kainate receptor current kinetics without impacting receptor membrane localization. Here we demonstrate that NETO2 profoundly slows the desensitization rate of GluK1 kainate receptors, promotes plasma membrane localization of transfected receptors in heterologous cells and rat hippocampal neurons, and targets GluK1-containing receptors to synapses. Conversely, the closely related protein NETO1 increases the rate of GluK1 receptor desensitization. Incorporation of NETO proteins into kainate receptor-signaling complexes therefore extends the temporal range of receptor gating by over an order of magnitude. The presence of these auxiliary proteins could underlie some of the unusual aspects of kainate receptor function in the mammalian CNS. PMID- 21593318 TI - Eye position effects in oculomotor plasticity and visual localization. AB - For visual localization to remain accurate across changes of gaze, a signal representing the position of the eye in the orbita is needed to code spatial locations in a reference frame that is independent of retinal displacements. Here we report evidence that the localization of visual objects in space is coded in an extraretinal reference frame. In human subjects, we used outward saccadic adaptation, which can be induced artificially by a systematic displacement of the saccade target. This form of oculomotor plasticity is accompanied by changes in spatial perception, thus highlighting the relevance of saccade metrics for visual localization. We tested the reference frame of outward adaptation for reactive and scanning saccades and visual localization. For scanning saccades, adaptation magnitude was drastically reduced at positions distant from the adapted eye position. Changes in visual localization showed a very similar modulation of eye position. These results suggest that scanning saccade adaptation is encoded in a nonretinotopic reference frame. Eye position effects for reactive saccade adaptation were smaller, and the induced mislocalization did not vary significantly between eye positions. The different modulation of reactive and scanning saccade adaptation supports the idea that oculomotor plasticity can occur at multiple sites in the brain. The findings are also consistent with previous evidence for a stronger influence of scanning saccade adaptation on the visual localization of objects in space. PMID- 21593319 TI - Contrasting roles for dopamine D1 and D2 receptor subtypes in the dorsomedial striatum but not the nucleus accumbens core during behavioral inhibition in the stop-signal task in rats. AB - Dopamine and dopamine-receptor function are often implicated in behavioral inhibition, and deficiencies within behavioral inhibition processes linked to attention deficit/hyperactivity disorder (ADHD), schizophrenia, obsessive compulsive disorder, and drug addiction. In the stop-signal task, which measures the speed of the process of inhibition [stop-signal reaction time (SSRT)], psychostimulant-related improvement of SSRT in ADHD is linked with dopamine function. However, the precise nature of dopaminergic control over SSRT remains unclear. This study examined region- and receptor-specific modulation of SSRT in the rat using direct infusions of the dopamine D1 receptor (DRD1) antagonist SCH 23390 or dopamine D2 receptor (DRD2) antagonist sulpiride into the dorsomedial striatum (DMStr) or nucleus accumbens core (NAcbC). DRD1 and DRD2 antagonists had contrasting effects on SSRT that were specific to the DMStr. SCH 23390 decreased SSRT with little effect on the go response. Conversely, sulpiride increased SSRT but also increased go-trial reaction time and reduced trial completion at the highest doses. These results suggest that DRD1 and DRD2 function within the DMStr, but not the NAcbC, may act to balance behavioral inhibition in a manner that is independent of behavioral activation. PMID- 21593320 TI - Syntaxin 1B suppresses macropinocytosis and semaphorin 3A-induced growth cone collapse. AB - Growth cone collapse is a crucial process for repulsive axon guidance and is accompanied by a reduction in growth cone surface area. This process of reduction may be regulated by endocytosis; however, its molecular mechanism is unclear. Macropinocytosis is a clathrin-independent form of endocytosis in which large areas of plasma membrane can be engulfed. We have reported previously that macropinocytosis is induced in growth cones of chick dorsal root ganglion neurons by semaphorin 3A (Sema3A), a repulsive axon guidance cue, and that Sema3A-induced reduction in growth cone surface area and macropinocytic vacuole area were correlated, suggesting a positive role for macropinocytosis in Sema3A-induced growth cone collapse. In the present study, we found that syntaxin 1B (Syx1B), a membrane trafficking protein, is a negative regulator of macropinocytosis, and its expression is downregulated by Sema3A signaling. Macropinocytosis inhibitor ethylisopropylamiloride or Syx1B overexpression suppressed Sema3A-induced macropinocytosis and growth cone collapse. These results indicate that Syx1B couples macropinocytosis-mediated massive internalization of the plasma membrane to Sema3A-induced growth cone collapse. PMID- 21593322 TI - Calcium/calmodulin-dependent protein kinase II mediates group I metabotropic glutamate receptor-dependent protein synthesis and long-term depression in rat hippocampus. AB - Activation of Group I metabotropic glutamate receptors (mGluRs) in rat hippocampus induces a form of long-term depression (LTD) that is dependent on protein synthesis. However, the intracellular mechanisms leading to the initiation of protein synthesis and expression of LTD after mGluR activation are only partially understood. We investigated the role of several pathways linked to mGluR activation, translation initiation, and induction of LTD. We found that Group I mGluR-dependent protein synthesis and associated LTD, as induced by the agonist (RS)-3,5-dihydrophenylglycine (DHPG) or paired-pulse synaptic stimulation, was dependent on activation of calcium/calmodulin-dependent protein kinase IIalpha (CaMKII). DHPG induced a transient increase in the level of phospho-CaMKII (phospho-CaMKII(T286)) in synaptoneurosomes prepared from whole hippocampus and in CA1 minislices. In synaptoneurosomes, DHPG also induced an increase in phosphorylation of eIF4E, and an increase in protein synthesis that was abolished by translation inhibitors and the CaMKII inhibitors 1-[N,O-bis(5 isoquinolinesulphonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine (KN62) and 2-[N-(2 hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)amino-N-(4-chloro-cinnamyl)-N methylbenzylamine (KN93). In field recordings from CA1, both the translation inhibitor cycloheximide and KN62 significantly reduced DHPG-induced LTD. Combined application did not further reduce the LTD, suggesting a common mechanism. In whole-cell recordings, a third CaMKII inhibitor, AIP (autocamtide-2-related inhibitory peptide), significantly reduced the DHPG-induced LTD of synaptic currents. Inhibition of the classical pathway mediating many Group I mGluR effects by blocking PKC (protein kinase C) or PLC (phospholipase C) did not impair DHPG-induced protein synthesis or LTD. Collectively, these findings demonstrate an important role for CaMKII in mediating the initiation of protein synthesis that then supports the postsynaptic expression of DHPG-induced LTD. PMID- 21593321 TI - NeuroD factors regulate cell fate and neurite stratification in the developing retina. AB - Members of the basic helix-loop-helix (bHLH) family of transcription factors have been shown to control critical aspects of development in many tissues. To identify bHLH genes that might regulate specific aspects of retinal cell development, we investigated the expression of bHLH genes in single, developing mouse retinal cells, with particular emphasis on the NeuroD family. Two of these factors, NeuroD2 and NeuroD6/NEX, had not been previously reported as expressed in the retina. A series of loss- and gain-of-function experiments was performed, which suggested that NeuroD genes have both similarities and differences in their activities. Notably, misexpression of NeuroD genes can direct amacrine cell processes to two to three specific sublaminae in the inner plexiform layer. This effect is specific to cell type and NeuroD gene, as the AII amacrine cell type is refractory to the effects of NeuroD1 and NeuroD6, but uniquely sensitive to the effect of NeuroD2 on neurite targeting. Additionally, NeuroD2 is endogenously expressed in AII amacrine cells, among others, and loss of NeuroD2 function results in a partial loss of AII amacrine cells. The effects of misexpressing NeuroD genes on retinal cell fate determination also suggested shared and divergent functions. Remarkably, NeuroD2 misexpression induced ganglion cell production even after the normal developmental window of ganglion cell genesis. Together, these data suggest that members of the NeuroD family are important for neuronal cell type identity and may be involved in several cell type-specific aspects of retinal development, including fate determination, differentiation, morphological development, and circuit formation. PMID- 21593323 TI - Nuclear factor erythroid 2-related factor 2 facilitates neuronal glutathione synthesis by upregulating neuronal excitatory amino acid transporter 3 expression. AB - Astrocytes support neuronal antioxidant capacity by releasing glutathione, which is cleaved to cysteine in brain extracellular space. Free cysteine is then taken up by neurons through excitatory amino acid transporter 3 [EAAT3; also termed Slc1a1 (solute carrier family 1 member 1)] to support de novo glutathione synthesis. Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant responsive element (ARE) pathway by oxidative stress promotes astrocyte release of glutathione, but it remains unknown how this release is coupled to neuronal glutathione synthesis. Here we evaluated transcriptional regulation of the neuronal cysteine transporter EAAT3 by the Nrf2-ARE pathway. Nrf2 activators and Nrf2 overexpression both produced EAAT3 transcriptional activation in C6 cells. A conserved ARE-related sequence was found in the EAAT3 promoter of several mammalian species. This ARE-related sequence was bound by Nrf2 in mouse neurons in vivo as observed by chromatin immunoprecipitation. Chemical activation of the Nrf2-ARE pathway in mouse brain increased both neuronal EAAT3 levels and neuronal glutathione content, and these effects were abrogated in mice genetically deficient in either Nrf2 or EAAT3. Selective overexpression of Nrf2 in brain neurons by lentiviral gene transfer was sufficient to upregulate both neuronal EAAT3 protein and glutathione content. These findings identify a mechanism whereby Nrf2 activation can coordinate astrocyte glutathione release with neuronal glutathione synthesis through transcriptional upregulation of neuronal EAAT3 expression. PMID- 21593324 TI - Serotonin induces long-term depression at corticostriatal synapses. AB - The striatum has important roles in motor control and action learning and, like many brain regions, receives multiple monoaminergic inputs. We have examined serotonergic modulation of rat and mouse corticostriatal neurotransmission and find that serotonin (5-HT) activates 5-HT(1b) receptors resulting in a long-term depression (LTD) of glutamate release and striatal output that we have termed 5 HT-LTD. 5-HT-LTD is presynaptically mediated, cAMP pathway dependent, and inducible by endogenous striatal 5-HT, as revealed by application of a selective 5-HT reuptake inhibitor. 5-HT-LTD is mutually occlusive with dopamine/endocannabinoid-dependent LTD, suggesting that these two forms of LTD act on the same corticostriatal terminals. Thus, serotonergic and dopaminergic mechanisms exist that may interact to persistently sculpt corticostriatal circuits, potentially influencing action learning and striatal-based disorders. PMID- 21593325 TI - Dopamine-galanin receptor heteromers modulate cholinergic neurotransmission in the rat ventral hippocampus. AB - Previous studies have shown that dopamine and galanin modulate cholinergic transmission in the hippocampus, but little is known about the mechanisms involved and their possible interactions. By using resonance energy transfer techniques in transfected mammalian cells, we demonstrated the existence of heteromers between the dopamine D(1)-like receptors (D(1) and D(5)) and galanin Gal(1), but not Gal(2) receptors. Within the D(1)-Gal(1) and D(5)-Gal(1) receptor heteromers, dopamine receptor activation potentiated and dopamine receptor blockade counteracted MAPK activation induced by stimulation of Gal(1) receptors, whereas Gal(1) receptor activation or blockade did not modify D(1)-like receptor mediated MAPK activation. Ability of a D(1)-like receptor antagonist to block galanin-induced MAPK activation (cross-antagonism) was used as a "biochemical fingerprint" of D(1)-like-Gal(1) receptor heteromers, allowing their identification in the rat ventral hippocampus. The functional role of D(1)-like Gal receptor heteromers was demonstrated in synaptosomes from rat ventral hippocampus, where galanin facilitated acetylcholine release, but only with costimulation of D(1)-like receptors. Electrophysiological experiments in rat ventral hippocampal slices showed that these receptor interactions modulate hippocampal synaptic transmission. Thus, a D(1)-like receptor agonist that was ineffective when administered alone turned an inhibitory effect of galanin into an excitatory effect, an interaction that required cholinergic neurotransmission. Altogether, our results strongly suggest that D(1)-like-Gal(1) receptor heteromers act as processors that integrate signals of two different neurotransmitters, dopamine and galanin, to modulate hippocampal cholinergic neurotransmission. PMID- 21593326 TI - Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. AB - Output properties of neurons are greatly shaped by voltage-gated ion channels, whose biophysical properties and localization within axodendritic compartments serve to significantly transform the original input. The hyperpolarization activated current, I(h), is mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and plays a fundamental role in influencing neuronal excitability by regulating both membrane potential and input resistance. In neurons such as cortical and hippocampal pyramidal neurons, the subcellular localization of HCN channels plays a critical functional role, yet mechanisms controlling HCN channel trafficking are not fully understood. Because ion channel function and localization are often influenced by interacting proteins, we generated a knock-out mouse lacking the HCN channel auxiliary subunit, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Eliminating expression of TRIP8b dramatically reduced I(h) expression in hippocampal pyramidal neurons. Loss of I(h)-dependent membrane voltage properties was attributable to reduction of HCN channels on the neuronal surface, and there was a striking disruption of the normal expression pattern of HCN channels in pyramidal neuron dendrites. In heterologous cells and neurons, absence of TRIP8b increased HCN subunit targeting to and degradation by lysosomes. Mice lacking TRIP8b demonstrated motor learning deficits and enhanced resistance to multiple tasks of behavioral despair with high predictive validity for antidepressant efficacy. We observed similar resistance to behavioral despair in distinct mutant mice lacking HCN1 or HCN2. These data demonstrate that interaction with the auxiliary subunit TRIP8b is a major mechanism underlying proper expression of HCN channels and I(h) in vivo, and suggest that targeting I(h) may provide a novel approach to treatment of depression. PMID- 21593327 TI - A new role for the parahippocampal cortex in representing space. AB - The debate surrounding the function of the human posterior parahippocampal cortex (PHC) is currently dominated by two competing theories. The spatial layout hypothesis proposes that PHC processes information about the shape of space embodied in layout-defining scene features. The contextual association hypothesis rejects this notion, proposing instead that PHC responds to highly contextualized, but not necessarily spatial, stimuli. Here we present a novel concept that suggests PHC is primarily concerned with any representation that depicts three-dimensional local space, be it scenes or even single objects. Specifically, we identified space-defining (SD) and space-ambiguous (SA) single objects, where SD objects consistently evoke a strong sense of the surrounding space while SA objects do not, in the absence of any background, spatial layout, or context. We found that participants could easily identify and distinguish between SD and SA objects. This distinction was subsequently affirmed at a neural level, where visualizing or viewing single SD objects compared with SA objects engaged PHC, despite these single SD objects offering no information about the shape or layout of the space. Moreover, this PHC response was robust and not accounted for by other factors, including contextual associations. Instead, it was linked to intrinsic object properties, specifically a combination of perceived object size and portability. By showing that PHC is responsive to the awareness of surrounding local space suggests its role in scene processing is basic and fundamental, such that it is not dependent on complex scene properties such as geometric structure, scene schema, or contextual associations. PMID- 21593328 TI - Excitatory modulation in the cochlear nucleus through group I metabotropic glutamate receptor activation. AB - Activation of group I metabotropic glutamate receptors (mGluRs) has been suggested to modulate development of auditory neurons. However, the acute effects of mGluR activation on physiological response properties are unclear. To address this, we studied the effects of mGluRs in bushy cells (BCs) of the mammalian anteroventral cochlear nucleus (AVCN). Activation of mGluRs with dihydroxyphenylglycine (DHPG) caused depolarization of BCs in mice as old as P42, but did not affect neurotransmitter release by presynaptic auditory nerve (AN) fibers. Application of mGluR antagonists indicated that mGluRs are tonically active, and are highly sensitive to small elevations in ambient glutamate by the glutamate reuptake blocker threo-beta-benzyloxyaspartic acid (TBOA). mGluR mediated depolarization enhanced the firing probability in response to AN stimulation, and reduced the latency and jitter. Furthermore, excitation through postsynaptic mGluRs can significantly counterbalance the inhibitory effects of presynaptic GABA(B) receptors. Thus, interaction between these two modulatory pathways may provide additional flexibility for fine-tuning the BC relay. PMID- 21593329 TI - Developmental sculpting of dendritic morphology of layer 4 neurons in visual cortex: influence of retinal input. AB - Dendritic morphology determines the kinds of input a neuron receives, having a profound impact on neural information processing. In the mammalian cerebral cortex, excitatory neurons have been ascribed to one of two main dendritic morphologies, either pyramidal or stellate, which differ mainly on the extent of the apical dendrite. Developmental mechanisms regulating the emergence and refinement of dendritic morphologies have been studied for cortical pyramidal neurons, but little is known for spiny stellate neurons. Using biolistics to label single cells on acute brain slices of the ferret primary visual cortex, we show that neurons in layer 4 develop in a two-step process: initially, all neurons appear pyramidal, growing a prominent apical dendrite and few small basal dendrites. Later, a majority of these neurons show a change in the relative extent of basal and apical dendrites that results in a gradual sculpting into a stellate morphology. We also find that ~ 22% of neurons maintain the proportionality of their dendritic arbors, remaining as pyramidal cells at maturity. When ferrets were deprived of retinal input at early stages of postnatal development by binocular enucleation, a significant proportion of layer 4 spiny neurons failed to remodel their apical dendrites, and ~ 55% remained as pyramidal neurons. Our results demonstrate that cortical spiny stellate neurons emerge by differential sculpting of the dendritic arborizations of an initial pyramidal morphology and that sensory input plays a fundamental role in this process. PMID- 21593331 TI - In vivo evidence for lactate as a neuronal energy source. AB - Cerebral energy metabolism is a highly compartmentalized and complex process in which transcellular trafficking of metabolites plays a pivotal role. Over the past decade, a role for lactate in fueling the energetic requirements of neurons has emerged. Furthermore, a neuroprotective effect of lactate during hypoglycemia or cerebral ischemia has been reported. The majority of the current evidence concerning lactate metabolism at the cellular level is based on in vitro data; only a few recent in vivo results have demonstrated that the brain preferentially utilizes lactate over glucose. Using voltage-sensitive dye (VSD) imaging, beta probe measurements of radiotracer kinetics, and brain activation by sensory stimulation in the anesthetized rat, we investigated several aspects of cerebral lactate metabolism. The present study is the first in vivo demonstration of the maintenance of neuronal activity in the presence of lactate as the primary energy source. The loss of the voltage-sensitive dye signal found during severe insulin induced hypoglycemia is completely prevented by lactate infusion. Thus, lactate has a direct neuroprotective effect. Furthermore, we demonstrate that the brain readily oxidizes lactate in an activity-dependent manner. The washout of 1 [(11)C]L-lactate, reflecting cerebral lactate oxidation, was observed to increase during brain activation from 0.077 +/- 0.009 to 0.105 +/- 0.007 min(-1). Finally, our data confirm that the brain prefers lactate over glucose as an energy substrate when both substrates are available. Using [(18)F]fluorodeoxyglucose (FDG) to measure the local cerebral metabolic rate of glucose, we demonstrated a lactate concentration-dependent reduction of cerebral glucose utilization during experimentally increased plasma lactate levels. PMID- 21593330 TI - Duration of inhibition of ventral tegmental area dopamine neurons encodes a level of conditioned fear. AB - It is widely accepted that midbrain dopamine (DA) neurons encode actual and expected reward values by phasic alterations in firing rate. However, how DA neurons encode negative events in the environment is still unclear because some DA neurons appear to be depressed and others excited by aversive stimuli. Here, we show that exposing fear-conditioned rats to stimuli predicting electrical shock elicited three types of biphasic responses, each of which contained an inhibitory pause, in neurochemically identified ventral tegmental area (VTA) DA neurons. The duration of the inhibitory pause in these responses of VTA DA neurons was in direct proportion to the increase in respiratory rate reflecting the level of conditioned fear. Our results suggest that the duration of inhibition of VTA DA neurons encodes negative emotional values of signals predicting aversive events in the environment. PMID- 21593333 TI - Homeostatic synaptic plasticity through changes in presynaptic calcium influx. AB - Chronic perturbations of electrical activity within neural circuits lead to compensatory changes in synaptic strength collectively termed homeostatic synaptic plasticity. The postsynaptic mechanisms underlying these modifications have been characterized in some detail, but the presynaptic mechanisms that alter the efficiency of evoked neurotransmitter release are less clear. To investigate the role of presynaptic calcium influx, we have combined the use of two fluorescent proteins in cultured hippocampal neurons: a calcium reporter localized to synaptic vesicles, SyGCaMP2, and a reporter of vesicle fusion, SypHy. We find that a decrease in the activity of the network causes an increase in the amount of calcium entering the synaptic bouton in response to an action potential and an increase in the probability of vesicle fusion. Homeostatic changes in release probability varied as the third power of calcium influx. These results indicate that changes in the number and/or function of presynaptic calcium channels are major determinants of homeostatic changes in synaptic strength. PMID- 21593332 TI - Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300. AB - It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examined the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here we report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. Our results also demonstrate that the HAT p300 is highly expressed within pyramidal neurons of the ILPFC and that the small-molecule p300-specific inhibitor (C646) infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory. C646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that do not evoke long-lasting LTP. These data suggest that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a reduction in the function of this HAT is required for the formation of fear extinction memory. PMID- 21593334 TI - The robustness of Caenorhabditis elegans male mating behavior depends on the distributed properties of ray sensory neurons and their output through core and male-specific targets. AB - Many evolutionarily significant behaviors, such as mating, involve dynamic interactions with animate targets. This raises the question of what features of neural circuit design are essential to support these complex types of behavior. The Caenorhabditis elegans male uses 18 ray sensilla of the tail to coordinate mate apposition behavior, which facilitates a systematic search of the hermaphrodite surface for the vulva. Precisely how ray neuron types, A and B, robustly endow the male with a high degree of spatial and temporal precision is unknown. We show that the appositional postures that drive the search trajectory reflect the complex interplay of ray neuron type-induced motor outputs. Cell-type specific ablations reveal that the A-neurons are required for all appositional postures. Their activity is instructive because the A-neurons can induce scanning and turning-like appositional postures when artificially activated with channel rhodopsin (ChR2). B-neurons are essential only for initiation of the behavior in which they enhance male responsiveness to hermaphrodite contact. When artificially activated using ChR2, A- and B-neurons produce different tail ventral curl postures. However, when coactivated, A-neuron posture dominates, limiting B-neuron contributions to initiation or subsequent postures. Significantly, males lacking the majority of rays retain a high degree of postural control, indicating significant functional resilience in the system. Furthermore, eliminating a large number of male-specific ray neuron targets only partially attenuates tail posture control revealing that gender-common cells make an important contribution to the behavior. Thus, robustness may be a crucial feature of circuits underlying complex behaviors, such as mating, even in simple animals. PMID- 21593335 TI - Probing TARP modulation of AMPA receptor conductance with polyamine toxins. AB - The properties of synaptic AMPA receptors (AMPARs) depend on their subunit composition and association with transmembrane AMPAR regulatory proteins (TARPs). Although both GluA2 incorporation and TARP association have been shown to influence AMPAR channel conductance, the manner in which different TARPs modulate the mean channel conductance of GluA2-containing AMPARs is unknown. Using ultrafast agonist application and nonstationary fluctuation analysis, we found that TARP subtypes differentially increase the mean channel conductance, but not the peak open probability, of recombinant GluA2-containing AMPARs. TARP gamma-8, in particular, enhances mean channel conductance to a greater degree than gamma 2, gamma-3, or gamma-4. We then examined the action of a use-dependent antagonist of GluA2-containing AMPARs, philanthotoxin-74 (PhTx-74), on recombinant AMPARs and on GluA2-containing AMPARs in cerebellar granule neurons from stargazer mice transfected with TARPs. We found that the rate and extent of channel block varies with TARP subtype, in a manner that correlates linearly with mean channel conductance. Furthermore, block of GluA2-containing AMPARs by polyamine toxins varied depending on whether channels were activated by the full agonist glutamate or the partial agonist kainate, consistent with conductance state-dependent block. Block of GluA2-lacking AMPARs by PhTx-433 is also modulated by TARP association and is a function of agonist efficacy. Our data indicate that channel block by polyamine toxins is sensitive to the mean channel conductance of AMPARs, which varies with TARP subtype and agonist efficacy. Furthermore, our results illustrate the utility of polyamine toxins as sensitive probes of AMPAR channel conductance and suggest the possibility that TARPs may influence their channel properties by selectively stabilizing specific channel conformations, rather than altering the pore structure. PMID- 21593336 TI - Long-term effects of repetitive transcranial magnetic stimulation on markers for neuroplasticity: differential outcomes in anesthetized and awake animals. AB - Long-term effects of repetitive transcranial magnetic stimulation (rTMS) have been associated with neuroplasticity, but most physiological studies have evaluated only the immediate effects of the stimulation on neurochemical markers. Furthermore, although it is known that baseline excitability state plays a major role in rTMS outcomes, the role of spontaneous neural activity in metaplasticity has not been investigated. The first aim of this study was to evaluate and compare the long-term effects of high- and low-frequency rTMS on the markers of neuroplasticity such as BDNF and GluR1 subunit of AMPA receptor. The second aim was to assess whether these effects depend on spontaneous neural activity, by comparing the neurochemical alterations induced by rTMS in anesthetized and awake rats. Ten daily sessions of high- or low-frequency rTMS were applied over the rat brain, and 3 d later, levels of BDNF, GluR1, and phosphorylated GluR1 were assessed in the hippocampus, prelimbic cortex, and striatum. We found that high frequency stimulation induced a profound effect on neuroplasticity markers; increasing them in awake animals while decreasing them in anesthetized animals. In contrast, low-frequency stimulation did not induce significant long-term effects on these markers in either state. This study highlights the importance of spontaneous neural activity during rTMS and demonstrates that high-frequency rTMS can induce long-lasting effects on BDNF and GluR1 which may underlie the clinical benefits of this treatment in neuroplasticity-related disorders. PMID- 21593337 TI - Ventromedial frontal lobe damage disrupts value maximization in humans. AB - Recent work in neuroeconomics has shown that regions in orbitofrontal and medial prefrontal cortex encode the subjective value of different options during choice. However, these electrophysiological and neuroimaging studies cannot demonstrate whether such signals are necessary for value-maximizing choices. Here we used a paradigm developed in experimental economics to empirically measure and quantify violations of utility theory in humans with damage to the ventromedial frontal lobe (VMF). We show that people with such damage are more likely to make choices that violate the generalized axiom of revealed preference, which is the one necessary and sufficient condition for choices to be consistent with value maximization. These results demonstrate that the VMF plays a critical role in value-maximizing choice. PMID- 21593339 TI - Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. AB - Chronic pain is associated with reduced brain gray matter and impaired cognitive ability. In this longitudinal study, we assessed whether neuroanatomical and functional abnormalities were reversible and dependent on treatment outcomes. We acquired MRI scans from chronic low back pain (CLBP) patients before (n = 18) and 6 months after (spine surgery or facet joint injections; n = 14) treatment. In addition, we scanned 16 healthy controls, 10 of which returned 6 months after the first visit. We performed cortical thickness analysis on structural MRI scans, and subjects performed a cognitive task during the functional MRI. We compared patients and controls, as well as patients before versus after treatment. After treatment, patients had increased cortical thickness in the left dorsolateral prefrontal cortex (DLPFC), which was thinner before treatment compared with controls. Increased DLPFC thickness correlated with the reduction of both pain and physical disability. Additionally, increased thickness in primary motor cortex was associated specifically with reduced physical disability, and right anterior insula was associated specifically with reduced pain. Left DLPFC activity during an attention-demanding cognitive task was abnormal before treatment, but normalized following treatment. These data indicate that functional and structural brain abnormalities-specifically in the left DLPFC-are reversible, suggesting that treating chronic pain can restore normal brain function in humans. PMID- 21593338 TI - An anatomical basis for opponent process mechanisms of opiate withdrawal. AB - Opponent process theory predicts that the first step in the induction of drug withdrawal is the activation of reward-related circuitry. Using the acoustic startle reflex as a model of anxiety-like behavior in rats, we show the emergence of a negative affective state during withdrawal after direct infusion of morphine into the ventral tegmental area (VTA), the origin of the mesolimbic dopamine system. Potentiation of startle during withdrawal from systemic morphine exposure requires a decrease in opiate receptor stimulation in the VTA and can be relieved by administration of the dopamine receptor agonist apomorphine. Together, our results suggest that the emergence of anxiety during withdrawal from acute opiate exposure begins with activation of VTA mesolimbic dopamine circuitry, providing a mechanism for the opponent process view of withdrawal. PMID- 21593340 TI - Abnormal neuronal migration changes the fate of developing neurons in the postnatal olfactory bulb. AB - Neuronal precursors are continuously integrated into the adult olfactory bulb (OB). The vast majority of these precursor cells originates from the subventricular zone and migrates along the rostral migratory stream (RMS) en route to the OB. This process, called postnatal neurogenesis, results from intricate pathways depending both on cell-autonomous factors and extrinsic regulation provided by the local environment. Using electroporation in postnatal mice to label neuronal precursors with green fluorescent protein (GFP) and to reduce the expression levels of doublecortin (DCX) with short-hairpin (Sh) RNA, we investigated the consequences of impairing migration on the fate of postnatal formed neurons. First, we showed that electroporation of Dcx ShRNA plasmid efficiently knocks down the expression of DCX and disrupts cells migration along the RMS. Second, we found misplaced anomalous migrating cells that displayed defects in polarity and directionality. Third, patch-clamp recordings performed at 5-7 days post-electroporation (dpe) revealed increased density of voltage dependent Na(+) channels and enhanced responsiveness to GABA(A) receptor agonist. At later time points (i.e., 12 and 30 dpe), most of the Dcx ShRNA(+) cells developed in the core of the OB and displayed aberrant dendritic length and branching. Additional analysis revealed the formation of GABAergic and glutamatergic synaptic inputs on the mispositioned neurons. Finally, quantifying fate determination by numbering the proportion of GFP(+)/calretinin(+) newborn neurons revealed that Dcx ShRNA(+) cells acquire mature phenotype despite their immature location. We conclude that altering the pace of migration at early stages of postnatal neurogenesis profoundly modifies the tightly orchestrated steps of neuronal maturation, and unveils the influence of microenvironment on controlling neuronal development in the postnatal forebrain. PMID- 21593341 TI - BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release. AB - Chronic itch accompanying many dermatological, neurological, and systemic diseases is unresponsive to antihistamines. Our knowledge of endogenous chemicals that evoke histamine-independent itch and their molecular targets is very limited. Recently it was demonstrated in behavioral and cellular experiments that bovine adrenal medulla 8-22 peptide (BAM8-22), a proteolytically cleaved product of proenkephalin A, is a potent activator of Mas-related G-protein-coupled receptors (Mrgprs), MrgprC11 and hMrgprX1, and induces scratching in mice in an Mrgpr-dependent manner. To study the sensory qualities that BAM8-22 evokes in humans, we tested the volar forearm of 15 healthy volunteers with heat inactivated cowhage spicules previously soaked in the peptide. BAM8-22 produced itch in each subject, usually accompanied by sensations of pricking/stinging and burning. The sensations were occasionally accompanied by one or more mechanically evoked dysesthesias, namely alloknesis, hyperknesis, and/or hyperalgesia, but no wheal or neurogenic flare in the skin surrounding the application site. The inactive truncated peptide BAM8-18 produced weak or no sensations. Pretreatment of the tested skin with an antihistamine cream (doxepin) inhibited histamine induced sensations, dysesthesias, and skin reactions but not the sensations and dysesthesias evoked by BAM8-22. We show that BAM8-22 produces itch and nociceptive sensations in humans in a histamine-independent manner. Thus, BAM8-22 may be an endogenous itch mediator that activates, in humans, MrgprX1, a novel target for potential anti-itch treatments. PMID- 21593342 TI - Stable brain ATM message and residual kinase-active ATM protein in ataxia telangiectasia. AB - The gene that is mutated in ataxia-telangiectasia (A-T), ATM, is catalytically activated in response to DNA damage. Yet a full accounting for the CNS deficits in human A-T or its mouse models remains elusive. We have analyzed the CNS phenotypes of two mouse Atm alleles--Atm(tm1Bal) (Bal) and Atm(tm1Awb) (Awb). Neither mutant has detectable mRNA or protein in peripheral tissues. In brain, although Bal/Bal mice have no ATM protein, they have nearly normal amounts of Atm mRNA. Bal/Bal neurons exhibit extensive cell cycle reentry and degeneration in both cortex and cerebellum. Unexpectedly, in Awb/Awb mice a novel mRNA is found in which the engineered mutation is excised. This mRNA is apparently translated and produces a catalytically active ATM protein that responds to DNA damage by phosphorylating p53 and Chk2. Prompted by these results, we examined eight cases of human A-T and found evidence for residual ATM protein in seven of them. These findings offer important new insights into the human disease and the role of brain ATM activity in the severity of the neurological symptoms of A-T. PMID- 21593343 TI - Resident education and quality of gross tissue examination practices of benign uteri. AB - INTRODUCTION: In the USA, most anatomical pathology residency training is based on an apprenticeship model in which residents learn directly by watching more senior personnel and then performing the examination. The level and the effect of the standardisation of resident trainee gross tissue examination practices have not been extensively evaluated. METHODS: In this apprenticeship-based training programme, a retrospective report review was performed to measure the level of standardisation of gross description (for 11 mandatory descriptors) and tissue submission (for four mandatory sections) practices for uterine specimens removed for benign conditions (n=78). Practices were examined for significant relationships with error, turnaround time (TAT), resource utilisation and postgraduate year of resident (n=25) training. RESULTS: Residents provided mandatory descriptors from 23.1% to 93.6% of the time and submitted mandatory sections from 82.1% to 96.2% of the time. Cases submitted by less experienced residents had a longer TAT and were associated with more errors, measured by the necessity to submit additional tissues. Less experienced residents used greater resources (submitting 9.5 tissue cassettes per case) compared with more experienced residents (7.3 cassettes per case), and a statistically significant correlation was found between the number of cassettes submitted and TAT. CONCLUSIONS: In this training programme, the model of apprenticeship training leads to less than optimal standardisation of gross examination practices, inefficiency, active errors and a high frequency of latent conditions leading to error. PMID- 21593344 TI - The biology of micrometastases from uveal melanoma. AB - BACKGROUND: The aim of this study was to investigate the possible causes of tumour latency in uveal melanoma primarily through the analysis of micrometastases in tissue obtained from donors postmortem. Various explanations have been proposed but there is no clear answer from animal studies and few human data. The main hypotheses may be divided into several areas--immunological control of metastatic cells, lack of angiogenesis within micrometastases and reduced cell turnover. METHODS: 196 patients were recruited to the study between 2003 and 2007. Patients were invited to take part and their relatives agreed to postmortem examination of their liver and lungs in the event of their death, including tissue sampling to assess the presence of micrometastases and their biology. Metastatic cells were detected by immunohistochemistry using a pan melanoma antibody reagent, and by quantitative reverse transcriptase (qRT)-PCR for three melanoma-associated genes (tyrosinase Melan-A, and gp100) and a housekeeping gene (HMBS/PBGD) in samples stored in RNAlater or as formalin-fixed paraffin-embedded tissue. RESULTS: 22 deaths were investigated at autopsy as part of the study. Sixteen patients died with large deposits of metastatic melanoma, while six patients died of other causes. In addition, a liver resection for hepatic adenoma provided further tissue from a case without clinical evidence of metastasis. Metastatic melanoma cells were identified by immunohistochemistry of the liver samples in one case and by qRT-PCR in two further cases without macrometastases. There was no evidence of multicellular micrometastases sufficiently large to require angiogenesis and no associated inflammation was observed. CONCLUSION: The most likely explanation for latency in this setting is the inability of uveal melanoma cells in metastatic sites to grow. PMID- 21593345 TI - Hereditary thrombophilia in an unselected cohort of venous thrombosis patients in Singapore. AB - AIM: Hereditary thrombophilic markers are commonly screened among patients diagnosed as having venous thromboembolism, but optimal patient selection and the goals of screening may differ between populations. Determining the patterns of hereditary thrombophilia may improve screening strategies. METHOD: An unselected cohort of venous thromboembolism patients in three tertiary institutions in Singapore was prospectively tested for the prevalence of deficiencies of protein C, protein S, antithrombin III, factor V Leiden and prothrombin 20210 gene mutations. RESULTS: Among 384 patients screened, the prevalences of protein S, protein C and antithrombin III were 9.20%, 1.18% and 4.19% respectively. Only one patient was positive for the factor V Leiden mutation and none tested positive for the prothrombin 20210 gene mutation. At least 1 in 9 patients (11.52%, 95% CI 8.20 to 15.93) will test positive for one of the above markers in an unselected group of 269 patients who completed all tests. The exclusion of patients with clinical risk factors did not improve the detection rates, in comparison with those with obvious provoking clinical risk factors (11.72%, 95% CI 7.36 to 18.06 vs 11.29%, 95% CI 6.73 to 18.18). When upper age limits were set for thrombophilia screening by decades, a statistical difference in the likelihood of a positive thrombophilia screen between younger and older patient was seen for patients below 40 (p<0.001). CONCLUSION: In Singapore and countries with similar demographics, hereditary thrombophilia screening should be confined to testing for protein C, protein S and antithrombin III. PMID- 21593346 TI - Fluorescence in situ hybridisation analysis of formalin-fixed paraffin-embedded tissue sections in the diagnostic work-up of non-Burkitt high grade B-cell non Hodgkin's lymphoma: a single centre's experience. AB - AIMS: In recent years the genetic aberrations associated with diffuse large B cell lymphoma and the new subtype described in the 2008 revision of the WHO classification, 'B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma' have been increasingly well defined. Recurrent genetic abnormalities include rearrangements involving MYC (8q24), BCL2 (18q21) and BCL6 (3q27); as the prognostic and therapeutic implications associated with these abnormalities are clarified their accurate identification at diagnosis is becoming increasingly critical. We describe our experience of using a panel of fluorescence in situ hybridisation (FISH) probes on formalin-fixed paraffin-embedded tissue sections in the diagnostic work-up of 162 patients with non-Burkitt high grade B-cell non Hodgkin's lymphomas (HG-BNHL). METHODS: BCL6, IGH-BCL2 and MYC status were determined prospectively in sequential patients presenting with HG-BNHL, with respect to the presence of rearrangements and copy number changes. Small numbers of samples were analysed retrospectively or were studied at relapse in previously untested patients. RESULTS: FISH analysis was successful in 160/162 (99%) cases, with abnormalities detected in 118/160 (74%). CONCLUSIONS: FISH analysis of formalin-fixed paraffin-embedded tissue sections is a highly reproducible technique with an excellent success rate for the detection of genetic abnormalities which will play an increasingly important role in improving risk stratification of patients with HG-BNHL. PMID- 21593347 TI - Follicular patterned lesions of the thyroid gland: a practical algorithmic approach. AB - Follicular patterned lesions of the thyroid are problematic and interpretation is often subjective. While thyroid experts are comfortable with their own criteria and thresholds, those encountering these lesions sporadically have a degree of uncertainty with a proportion of cases. The purpose of this review is to highlight the importance of proper diligent sampling of an encapsulated thyroid lesion (in totality in many cases), examination for capsular and vascular invasion, and finally the assessment of nuclear changes that are pathognomonic of papillary thyroid carcinoma (PTC). Based on these established criteria, an algorithmic approach is suggested using known, accepted terminology. The importance of unequivocal, clear-cut nuclear features of PTC as opposed to inconclusive features is stressed. If the nuclear features in an encapsulated, non-invasive follicular patterned lesion fall short of those encountered in classical PTC, but nonetheless are still worrying or concerning, the term 'uncertain malignant potential or behaviour, most likely benign' is suggested. Indubitable, classical PTC nuclei (whether diffuse or restricted to a single high power field) are diagnostic of a PTC be it classical, non-invasive or invasive follicular variant PTC. Capsular and vascular invasion remain the only reliable predictors of outcome, as non-invasive, encapsulated follicular variant PTC, even with diffuse PTC nuclear change, behaves in an indolent fashion. PMID- 21593348 TI - The hydraulic conductivity of the xylem in conifer needles (Picea abies and Pinus mugo). AB - Main resistances of the plant water transport system are situated in leaves. In contrast to angiosperm leaves, knowledge of conifer needle hydraulics and of the partitioning of resistances within needles is poor. A new technique was developed which enabled flow-meter measurements through needles embedded in paraffin and thus quantification of the specific hydraulic conductivity (K(s)) of the needle xylem. In Picea abies, xylem K(s) of needle and axes as well as in needles of different age were compared. In Pinus mugo, resistance partitioning within needles was estimated by measurements of xylem K(s) and leaf conductance (K(leaf), measured via 'rehydration kinetics'). Mean K(s) in P. abies needles was 3.5*10(-4) m(2) s(-1) MPa(-1) with a decrease in older needles, and over all similar to K(s) of corresponding axes xylem. In needles of P. mugo, K(s) was 0.9*10(-4) m(2) s(-1) MPa(-1), and 24% of total needle resistance was situated in the xylem. The results indicate species-specific differences in the hydraulic efficiency of conifer needle xylem. The vascular section of the water transport system is a minor but relevant resistance in needles. PMID- 21593349 TI - Conjugated linoleic acid supplementation for 8 weeks does not affect body composition, lipid profile, or safety biomarkers in overweight, hyperlipidemic men. AB - The usefulness of conjugated linoleic acid (CLA) as a nutraceutical remains ambiguous. Our objective was, therefore, to investigate the effect of CLA on body composition, blood lipids, and safety biomarkers in overweight, hyperlipidemic men. A double-blinded, 3-phase crossover trial was conducted in overweight (BMI >= 25 kg/m(2)), borderline hypercholesterolemic [LDL-cholesterol (C) >= 2.5 mmol/L] men aged 18-60 y. During three 8-wk phases, each separated by a 4-wk washout period, 27 participants consumed under supervision in random order 3.5 g/d of safflower oil (control), a 50:50 mixture of trans 10, cis 12 and cis 9, trans 11 (c9, t11) CLA:Clarinol G-80, and c9, t11 isomer:c9, t11 CLA. At baseline and endpoint of each phase, body weight, body fat mass, and lean body mass were measured by DXA. Blood lipid profiles and safety biomarkers, including insulin sensitivity, blood concentrations of adiponectin, and inflammatory (high sensitive-C-reactive protein, TNFalpha, and IL-6) and oxidative (oxidized-LDL) molecules, were measured. The effect of CLA consumption on fatty acid oxidation was also assessed. Compared with the control treatment, the CLA treatments did not affect changes in body weight, body composition, or blood lipids. In addition, CLA did not affect the beta-oxidation rate of fatty acids or induce significant alterations in the safety markers tested. In conclusion, although no detrimental effects were caused by supplementation, these results do not confirm a role for CLA in either body weight or blood lipid regulation in humans. PMID- 21593350 TI - Soy protein diet, but not Lactobacillus rhamnosus GG, decreases mucin-1, trefoil factor-3, and tumor necrosis factor-alpha in colon of dextran sodium sulfate treated C57BL/6 mice. AB - The incidence of inflammatory bowel diseases has increased during recent decades. Within the colon, the families of mucins (MUC) and trefoil factors (TFF) facilitate mucosal protection. Probiotic administration influences the intestinal MUC layer. Additionally, food components may affect gut microflora or have direct effects on the MUC barrier. Our objective was to determine whether diet and/or Lactobacillus rhamnosus GG (LGG) would mediate dextran sodium sulfate (DSS) induced colitis by altering expression of the MUC and TFF genes. C57BL/6 mice were fed diets containing 20% (wt:wt) casein, soy, or whey proteins with or without LGG for 12 d. Seven days after starting LGG diets, the mice were given 2% DSS in drinking water for 4 d. Two additional casein groups with or without LGG were given tap water, for a total of 8 groups. One day after the DSS treatment, the mice were killed and the colon and cecum tissues and cecum contents were collected and analyzed by qRT-PCR. Whey protein significantly increased cecal LGG content compared with the other diets. In the casein diet groups, MUC1 and TFF-3 expression in colon was significantly induced by DSS independent of LGG. Compared with other DSS-treated groups, soy protein decreased MUC-1 and TFF-3 in the colon. Similarly, soy protein decreased the impact of DSS on inflammatory scores, TNFalpha gene expression, and colon shortening. There was no overall effect of LGG on these measurements. In conclusion, soy protein suppressed the DSS-induced inflammatory stimulation of MUC, TFF, and TNFalpha gene expression independently of LGG. PMID- 21593351 TI - Characterization of the organic component of low-molecular-weight chromium binding substance and its binding of chromium. AB - Chromium was proposed to be an essential element over 50 y ago and was shown to have therapeutic potential in treating the symptoms of type 2 diabetes; however, its mechanism of action at a molecular level is unknown. One chromium-binding biomolecule, low-molecular weight chromium-binding substance (LMWCr or chromodulin), has been found to be biologically active in in vitro assays and proposed as a potential candidate for the in vivo biologically active form of chromium. Characterization of the organic component of LMWCr has proven difficult. Treating bovine LMWCr with trifluoroacetic acid followed by purification on a graphite powder micro-column generates a heptapeptide fragment of LMWCr. The peptide sequence of the fragment was analyzed by MS and tandem MS (MS/MS and MS/MS/MS) using collision-induced dissociation and post-source decay. Two candidate sequences, pEEEEGDD and pEEEGEDD (where pE is pyroglutamate), were identified from the MS/MS experiments; additional tandem MS suggests the sequence is pEEEEGDD. The N-terminal glutamate residues explain the inability to sequence LMWCr by the Edman method. Langmuir isotherms and Hill plots were used to analyze the binding constants of chromic ions to synthetic peptides similar in composition to apoLMWCr. The sequence pEEEEGDD was found to bind 4 chromic ions per peptide with nearly identical cooperativity and binding constants to those of apoLMWCr. This work should lead to further studies elucidating or eliminating a potential role for LMWCr in treating the symptoms of type 2 diabetes and other conditions resulting from improper carbohydrate and lipid metabolism. PMID- 21593352 TI - Glutamine reduces postprandial glycemia and augments the glucagon-like peptide-1 response in type 2 diabetes patients. AB - Impaired glucagon-like peptide (GLP-1) secretion or response may contribute to ineffective insulin release in type 2 diabetes. The conditionally essential amino acid glutamine stimulates GLP-1 secretion in vitro and in vivo. In a randomized, crossover study, we evaluated the effect of oral glutamine, with or without sitagliptin (SIT), on postprandial glycemia and GLP-1 concentration in 15 type 2 diabetes patients (glycated hemoglobin 6.5 +/- 0.6%). Participants ingested a low fat meal (5% fat) after receiving either water (control), 30 g l-glutamine (Gln 30), 15 g L-glutamine (Gln-15), 100 mg SIT, or 100 mg SIT and 15 g L-glutamine (SIT+Gln-15). Studies were conducted 1-2 wk apart. Blood was collected at baseline and postprandially for 180 min for measurement of circulating glucose, insulin, C-peptide, glucagon, and total and active GLP-1. Gln-30 and SIT+Gln-15 reduced the early (t = 0-60 min) postprandial glycemic response compared with control. All Gln treatments enhanced the postprandial insulin response from t = 60-180 min but had no effect on the C-peptide response compared with control. The postprandial glucagon concentration was increased by Gln-30 and Gln-15 compared with control, but the insulin:glucagon ratio was not affected by any treatment. In contrast to Gln-30, which tended to increase the total GLP-1 AUC, SIT tended to decrease the total GLP-1 AUC relative to control (both P = 0.03). Gln-30 and SIT increased the active GLP-1 AUC compared with control (P = 0.008 and P = 0.01, respectively). In summary, Gln-30 decreased the early postprandial glucose response, enhanced late postprandial insulinemia, and augmented postprandial active GLP-1 responses compared with control. These findings suggest that glutamine may be a novel agent for stimulating GLP-1 concentration and limiting postprandial glycemia in type 2 diabetes. PMID- 21593353 TI - FADS1 genetic variability interacts with dietary alpha-linolenic acid intake to affect serum non-HDL-cholesterol concentrations in European adolescents. AB - Two rate-limiting enzymes in PUFA biosynthesis, Delta5- and Delta6-desaturases, are encoded by the FADS1 and FADS2 genes, respectively. Genetic variants in the FADS1-FADS2 gene cluster are associated with changes in plasma concentrations of PUFA, HDL- and LDL-cholesterol, and TG. However, little is known about whether dietary PUFA intake modulates these associations, especially in adolescents. We assessed whether dietary linoleic acid (LA) or alpha-linolenic acid (ALA) modulate the association between the FADS1 rs174546 polymorphism and concentrations of PUFA, other lipids, and lipoproteins in adolescents. Dietary intakes of LA and ALA, FADS1 rs174546 genotypes, PUFA levels in serum phospholipids, and serum concentrations of TG, cholesterol, and lipoproteins were determined in 573 European adolescents from the HELENA study. The sample was stratified according to the median dietary LA (<=9.4 and >9.4 g/d) and ALA (<=1.4 and >1.4 g/d) intakes. The associations between FADS1 rs174546 and concentrations of PUFA, TG, cholesterol, and lipoproteins were not affected by dietary LA intake (all P-interaction > 0.05). Similarly, the association between the FADS1 rs174546 polymorphism and serum phospholipid concentrations of ALA or EPA was not modified by dietary ALA intake (all P-interaction > 0.05). In contrast, the rs174546 minor allele was associated with lower total cholesterol concentrations (P = 0.01 under the dominant model) and non-HDL-cholesterol concentrations (P = 0.02 under the dominant model) in the high-ALA-intake group but not in the low-ALA-intake group (P-interaction = 0.01). These results suggest that dietary ALA intake modulates the association between FADS1 rs174546 and serum total and non-HDL-cholesterol concentrations at a young age. PMID- 21593355 TI - Dietary counseling to improve fat quality during pregnancy alters maternal fat intake and infant essential fatty acid status. AB - To explore the effect of maternal dietary intervention on infant essential fatty acid (FA) status, we conducted a prospective, single-blind, randomized nutrition intervention study. At the first trimester of pregnancy, 90 women from families with a history of allergy were randomized either to receive intensive dietary counseling to modify dietary intake according to current recommendations or as controls. Infants' cord and 1-mo isolated serum phospholipid FA were identified and quantified by GC. Detectable levels of eicosatrienoic acid [ETA, 20:3(n-9)] were taken as a biochemical marker for essential FA deficiency, and the DHA sufficiency index [22:6(n-3):22:5(n-6)] and the DHA deficiency index [22:5(n 6):22:4(n-6)] were taken as markers for DHA [22:6(n-3)] status. The concentration of ETA was lower in cord blood in the intervention (I) group [median 0.64 (IQR 0.40-0.78) mg/L; 2.09 (1.31-2.54) MUmol/L] than in the control (C) group [0.92 (0.54-1.20) mg/L; 3.00 (1.76-3.92) MUmol/L] (P = 0.048). The proportion of ETA in total FA in the I group [0.73% (0.48-0.85%)] was lower than in the C group [0.93% (0.78-1.22%)] (P = 0.003). A higher DHA sufficiency index and lower DHA deficiency index were detected in cord blood in the I group than in the C group, although the groups did not differ in the DHA concentration or proportion of the total FA. There were no differences among groups at 1 mo for any of the variables measured. Our findings suggest a better supply of essential FA, particularly important during the period of rapid development, in infants whose mothers received dietary counseling. The results thus highlight the importance of maternal diet for child health, calling for dietary counseling for pregnant women in primary health care. PMID- 21593354 TI - Placental expression of the heme transporter, feline leukemia virus subgroup C receptor, is related to maternal iron status in pregnant adolescents. AB - Little is known about the expression of heme transporters in human placenta and possible associations between these transporters and maternal or neonatal iron status. To address this area of research, relative protein expression of 2 heme transporters, Feline Leukemia Virus, Subgroup C, Receptor 1 (FLVCR1) and Breast Cancer Resistance Protein (BCRP), was assessed using Western-blot analysis in human placental tissue in relation to maternal/neonatal iron status and placental iron concentration. Placental FLVCR1 (n = 71) and BCRP (n = 83) expression were assessed at term (36.6-41.7 wk gestation) in a cohort of pregnant adolescents (13 18 y of age) at high-risk of iron deficiency. Both FLVCR1 and BCRP were detected in all placental samples assayed. Placental FLVCR1 expression was positively related to placental BCRP expression (n = 69; R(2) = 0.104; P < 0.05). Adolescents that were anemic at delivery had lower placental FLVCR1 expression (n = 49; P < 0.05). Placental FLVCR1 expression was positively associated with placental iron concentration at delivery (n = 61; R(2) = 0.064; P < 0.05). In contrast, placental BCRP expression was not significantly associated with maternal iron status or placental iron content. Both FLVCR1 and BCRP are highly expressed in human placental tissue, but only FLVCR1 was significantly inversely associated with maternal iron status and placental iron concentration. Further analysis is needed to explore potential functional roles of FLVCR1 in human placental iron transport. PMID- 21593356 TI - Immune responses of female BALB/c and C57BL/6 neonatal mice to vaccination or intestinal infection are unaltered by exposure to breast milk lycopene. AB - Lycopene, a carotenoid produced by some commonly consumed plants such as tomatoes, is not synthesized by animals. Thus, the levels of lycopene found in the breast milk of lactating females reflect the dietary lycopene supply. Lycopene has potent antioxidant activity but has also been implicated in modulating immune function. Therefore, lycopene in breast milk has the potential to affect the development and/or function of the immune system in the suckling pups. Here, we have investigated the impact of breast milk lycopene on systemic and mucosal immunity in mouse neonates. Diets containing 0.3 g/kg lycopene (Lyc) or control (Con) diets were fed to mouse dams beginning at late gestation and continuing throughout lactation. Seven-day-old female BALB/c pups were parenterally immunized with a model vaccine antigen dinitrophenyl-keyhole limpet hemocyanin (DNP-KLH) and then reimmunized as adults. The levels of DNP-KLH specific IgG in the sera as well as keyhole limpet hemocyanin-specific IFNgamma and IL-4 production by splenic CD4(+) cells were similar in the Lyc and Con pups. In addition, female neonatal (d7) C57BL/6 Lyc and Con pups were infected orally with the enteropathogen Yersinia enterocolitica. Breast milk lycopene had no effect on the recruitment of neutrophils to intestinal lymphoid tissues or on bacterial tissue colonization of the intestines, spleens, and livers. Thus, suckling pups exposed to lycopene in breast milk appear to develop normal innate and adaptive responses both systemically and at intestinal mucosal surfaces. PMID- 21593357 TI - Intestinal threonine utilization for protein and mucin synthesis is decreased in formula-fed preterm pigs. AB - Threonine is an essential amino acid necessary for synthesis of intestinal (glyco)proteins such as mucin MUC2 to maintain adequate gut barrier function. In premature infants, reduced barrier function may contribute to the development of necrotizing enterocolitis (NEC). Human milk protects against NEC compared with infant formula. Therefore, we hypothesized that formula feeding decreases the MUC2 synthesis rate concomitant with a decrease in intestinal first-pass threonine utilization, predisposing the preterm neonate to NEC. Preterm pigs were delivered by caesarian section and received enteral feeding with formula (FORM; n = 13) or bovine colostrum (COL; n = 6) for 2 d following 48 h of total parenteral nutrition. Pigs received a dual stable isotope tracer infusion of threonine to determine intestinal threonine kinetics. NEC developed in 38% of the FORM pigs, whereas none of the COL pigs were affected (P = 0.13). Intestinal fractional first-pass threonine utilization was lower in FORM pigs (49 +/- 2%) than in COL pigs (60 +/- 4%) (P = 0.02). In FORM pigs compared with COL pigs, protein synthesis (369 +/- 31 mg.kg(-1).d(-1) vs. 615 +/- 54 mg.kg(-1).d(-1); P = 0.003) and MUC2 synthesis (121 +/- 17%/d vs. 184 +/- 15%/d; P = 0.02) were lower in the distal small intestine (SI). Our results suggest that formula feeding compared with colostrum feeding in preterm piglets reduces mucosal growth with a concomitant decrease in first-pass splanchnic threonine utilization, protein synthesis, and MUC2 synthesis in the distal SI. Hence, decreased intestinal threonine metabolism and subsequently impaired gut barrier function may predispose the formula-fed infant to developing NEC. PMID- 21593358 TI - Radial nerve disruption following application of a hinged elbow external fixator: a report of three cases. PMID- 21593359 TI - Early clinical and radiographic characteristics in fibrodysplasia ossificans progressiva: a report of two cases. PMID- 21593360 TI - Distal femoral physeal implications of an anatomic ACL reconstruction in a skeletally immature soccer player: a case report. PMID- 21593361 TI - Pathological fracture of the fibula due to a late presenting posterior tibial artery pseudoaneurysm: a case report. PMID- 21593362 TI - Managing episodes of care: strategies for orthopaedic surgeons in the era of reform. PMID- 21593363 TI - Commentary on an article by Jacob S. Vandermeer et al.: "Local administration of ibandronate and bone morphogenetic protein-2 after ischemic osteonecrosis of the immature femoral head. A combined therapy that stimulates bone formation and decreases femoral head deformity". PMID- 21593364 TI - Commentary on an article by T. Tomesen, MD, et al.: "Treatment of displaced intra articular calcaneal fractures with closed reduction and percutaneous screw fixation". PMID- 21593365 TI - Local administration of ibandronate and bone morphogenetic protein-2 after ischemic osteonecrosis of the immature femoral head: a combined therapy that stimulates bone formation and decreases femoral head deformity. AB - BACKGROUND: Bisphosphonate therapy has been shown to preserve the osteonecrotic femoral head in experimental and short-term clinical studies. However, a lack of new bone formation within the preserved femoral head due to the inhibition of bone remodeling is a concern. The purpose of this investigation was to determine if combined therapy consisting of ibandronate and bone morphogenetic protein-2 (BMP-2) can preserve the shape of the femoral head and stimulate new bone formation in an immature animal model of ischemic osteonecrosis. METHODS: Ischemic osteonecrosis was surgically induced in immature pigs. Four groups were studied: normal, treated with saline solution, treated with ibandronate, and treated with both ibandronate and BMP-2 (the ibandronate + BMP-2 group). The animals were killed eight weeks after surgery. Radiographic, histological, and histomorphometric assessments were performed. RESULTS: Radiographic assessment showed better preservation of the femoral head shape-i.e., a 54% (CI [95% confidence interval]: 22%, 86%) higher mean epiphyseal quotient-in the ibandronate + BMP-2 group than in the saline group. Histological assessment showed increased trabecular bone in the ibandronate + BMP-2 group as compared with that in the saline group. The mean values for trabecular bone volume, thickness, and number and for osteoblast surface were an average of 400% (CI: 242%, 558%), 212% (CI: 166%, 259%), 71% (CI: 6%, 137%), and 2402% (CI: 2113%, 2693%) higher, respectively, in the ibandronate + BMP-2 group than in the saline group. The osteoclast number was significantly reduced in the ibandronate + BMP-2 group compared with that in the saline group (-59% [CI: -75%, -42%]). The mean osteoblast surface value in the ibandronate + BMP-2 group was significantly higher (2567% [CI: 2258%, 2877%]) than that in the ibandronate group. Heterotopic ossifications were present in the capsule of the hip joint in the ibandronate + BMP-2 group. CONCLUSIONS: A combination of ibandronate and BMP-2 decreased femoral head deformity while stimulating bone formation in an immature animal model of ischemic osteonecrosis. PMID- 21593366 TI - Five to ten-year outcomes of the Universal total wrist arthroplasty in patients with rheumatoid arthritis. AB - BACKGROUND: Implant arthroplasty of the wrist offers pain relief with preservation of motion to patients with rheumatoid arthritis, although few studies have investigated the long-term results of this procedure. The purpose of the present study is to report the prospective results of total wrist arthroplasty with use of the Universal wrist prosthesis in a consecutive series of patients with rheumatoid arthritis who were managed by a single surgeon. METHODS: Twenty-four wrist arthroplasties in twenty patients with rheumatoid arthritis were followed prospectively. Nineteen wrists in fifteen patients were followed clinically and radiographically for a mean of 7.3 years (range, 5.0 to 10.8 years) after the index procedure. Outcome measures included the Disabilities of the Arm, Shoulder and Hand (DASH) score, wrist range of motion, and standard radiographic findings. RESULTS: The average DASH score improved from 62 points preoperatively to 40 points at the time of the latest follow-up. The mean wrist flexion and extension at the time of the latest follow-up were 42 degrees and 20 degrees , respectively, for a mean improvement in the total flexion-extension arc of 14 degrees . A total of nine wrists (45%) in eight patients underwent revision surgery because of a loose carpal component at the time of the latest follow-up. One patient underwent wrist arthrodesis because of recurrent wrist instability. Two additional wrists in two patients had radiographic evidence of carpal component subsidence at the time of the latest follow-up. The implant survival rates at five and seven years for the original prosthetic components were 75% and 60%, respectively. CONCLUSIONS: The results for the Universal wrist prosthesis at a minimum of five years of follow-up include a high rate of failure, most often because of carpal component loosening, resulting in revision of ten (50%) of twenty wrists at the time of the latest follow-up (with the inclusion of one revision in a patient who died before five years). Patients with a stable prosthesis maintained a functional range of motion and had improvement in patient reported outcome measures. PMID- 21593367 TI - Treatment of displaced intra-articular calcaneal fractures with closed reduction and percutaneous screw fixation. AB - BACKGROUND: Surgical treatment of displaced intra-articular fractures of the calcaneus is a standard procedure in many institutions. To avoid soft-tissue complications, several minimally invasive procedures have recently been introduced. The aim of this study was to assess the percutaneous treatment of displaced intra-articular calcaneal fractures with use of one of these techniques. METHODS: All patients who underwent percutaneous screw fixation according to the method of Forgon and Zadravecz between 1998 and 2006 were selected. Postoperative infections were recorded. During follow-up, pain, functional outcome, range of motion, and change in footwear were evaluated with the use of the American Orthopaedic Foot & Ankle Society (AOFAS) score and the Maryland Foot Score (MFS). All patients also completed a general health status form (Short Form-36 [SF-36]) and a visual analog scale (VAS) for patient satisfaction. Subsequent subtalar arthrodesis and the removal of irritating screws were performed when indicated. RESULTS: We reviewed the cases of thirty seven patients who had a combined total of thirty-nine displaced intra-articular calcaneal fractures and a follow-up period of at least twenty-four months. Five wound infections occurred, two of which were superficial and three of which were deep. At a mean follow-up time of sixty-six months, the mean AOFAS and MFS scores were 84 and 86 points, respectively, of 100 possible points. The mean score on the SF-36 was 76 points, and the mean score on the visual analog scale for patient satisfaction was 7.9 points of 10 possible points. Twenty-nine patients (78%) were able to wear normal shoes. At the time of follow-up, subtalar arthrodesis had been performed in two patients and seventeen patients (46%) had undergone an uncomplicated removal of painful screws. No substantial correlation was found between the severity of the fracture (Sanders classification) or the quality of the reduction when correlated with functional outcome parameters. CONCLUSIONS: We consider the technique of Forgon and Zadravecz to be an excellent option for the treatment of displaced intra-articular calcaneal fractures in selected patients despite the frequent need for screw removal following fracture healing. PMID- 21593368 TI - Biomedical and psychosocial factors associated with disability after peripheral nerve injury. AB - BACKGROUND: The purpose of this study was to evaluate the biomedical and psychosocial factors associated with disability at a minimum of six months following upper-extremity nerve injury. METHODS: This cross-sectional study included patients who were assessed between six months and fifteen years following an upper-extremity nerve injury. Assessment measures included patient self-report questionnaires (the Disabilities of the Arm, Shoulder and Hand Questionnaire [DASH]; pain questionnaires; and general health and mental health questionnaires). DASH scores were compared by using unpaired t tests (sex, Workers' Compensation/litigation, affected limb, marital status, education, and geographic location), analysis of variance (nerve injured, work status, and income), or correlations (age and time since injury). Multivariable linear regression analysis was used to evaluate the predictors of the DASH scores. RESULTS: The sample included 158 patients with a mean age (and standard deviation) of 41 +/- 16 years. The median time from injury was fourteen months (range, six to 167 months). The DASH scores were significantly higher for patients receiving Workers' Compensation or involved in litigation (p = 0.02), had a brachial plexus injury (p = 0.001), or were unemployed (p < 0.001). There was a significant positive correlation between the DASH scores and pain intensity (r = 0.51, p < 0.001). In the multivariable regression analysis of the predictors of the DASH scores, the following predictors explained 52.7% of the variance in the final model: pain intensity (Beta = 0.230, p = 0.006), brachial plexus injury (Beta = -0.220, p = 0.000), time since injury (Beta = -0.198, p = 0.002), pain catastrophizing score (Beta = 0.192, p = 0.025), age (Beta = 0.187, p = 0.002), work status (Beta = 0.179, p = 0.008), cold sensitivity (Beta = 0.171, p = 0.015), depression score (Beta = 0.133, p = 0.066), Workers' Compensation/litigation (Beta = 0.116, p = 0.049), and female sex (Beta = -0.104, p = 0.090). CONCLUSIONS: Patients with a peripheral nerve injury report substantial disability, pain, and cold sensitivity. Disability as measured with the DASH was predicted by brachial plexus injury, older age, pain intensity, work status, time since injury, cold sensitivity, and pain catastrophizing. PMID- 21593369 TI - Acute traumatic compartment syndrome of the leg in children: diagnosis and outcome. AB - BACKGROUND: Currently, the most common clinical scenario for compartment syndrome in children is acute traumatic compartment syndrome of the leg. We studied the cause, diagnosis, treatment, and outcome of acute traumatic compartment syndrome of the leg in children. METHODS: Forty-three cases of acute traumatic compartment syndrome of the leg in forty-two skeletally immature patients were collected from two large pediatric trauma centers over a seventeen-year period. All children with acute traumatic compartment syndrome underwent fasciotomy. The mechanism of injury, date and time of injury, time to diagnosis, compartment pressures, time to fasciotomy, and outcome at the time of the latest follow-up were recorded. RESULTS: Thirty-five (83%) of the forty-two patients were injured in a motor vehicle accident and sustained tibial and fibular fractures. The average time from injury to fasciotomy was 20.5 hours (range, 3.9 to 118 hours). In general, the functional outcome was excellent at the time of the latest follow-up. No cases of infection were noted when fasciotomy was performed long after the injury. At the time of the latest follow-up, forty-one (95%) of forty-three cases were associated with no sequelae (such as pain, loss of function, or decreased sensation). The two patients who lost function had fasciotomy 82.5 and eighty-six hours after the injury. CONCLUSIONS: Despite a long period from injury to fasciotomy, most children who are managed for acute traumatic compartment syndrome of the leg have an excellent outcome. This delay may occur because acute traumatic compartment syndrome manifests itself more slowly in children or because the diagnosis is harder to establish in this age group. The results of the present study should raise awareness of late presentation and the importance of vigilance for developing compartment syndrome in the early days after injury. Fasciotomy during the acute swelling phase, even long after injury, produced excellent results with no cases of infection. PMID- 21593370 TI - Gotfried percutaneous compression plating compared with sliding hip screw fixation of intertrochanteric hip fractures: a prospective randomized study. AB - BACKGROUND: The use of a Gotfried percutaneous compression plate provides a minimally invasive technique for the fixation of intertrochanteric proximal femoral fractures. The purpose of this study was to determine if the percutaneous compression plate provided advantages compared with the sliding hip screw for treatment of A1 and A2 AO/OTA intertrochanteric proximal femoral fractures. METHODS: An institutional review board-approved, prospective, randomized, single blinded study was conducted at a level-I trauma center between July 2004 and September 2007. All patients who met the study criteria and provided informed consent were randomized to treatment with a sliding hip screw or percutaneous compression plate. Of the sixty-six patients who consented to participate, thirty three were randomized to be treated with a sliding hip screw and thirty-three, with a percutaneous compression plate. Data evaluated included surgical time, incision length, blood loss, need for blood transfusion, and postoperative functional status. Follow-up included clinical findings, radiographs until healing was confirmed, functional and pain assessment scores, and the Short Form 36. The median follow-up period for surviving patients was thirty-six months. RESULTS: Sixty-six patients, forty-seven women and nineteen men, with a mean age of seventy-seven years were entered into the study. The treatment groups were similar with respect to study variables (p > 0.05). Operative times (forty-eight vs. seventy-eight minutes), incision length (56 vs. 82 mm), and blood loss (41 vs. 101 mL) significantly favored the percutaneous compression plate group (p < 0.001). The groups were similar immediately postoperatively; however, by discharge, fewer patients with a percutaneous compression plate required walking aids (40% vs. 59%). This trend continued throughout the study but was not significant. Pain with activity was lower throughout the study for the percutaneous compression plate group, but the difference was significant only at the three-month interval. CONCLUSIONS: Previously published reports showing shorter operative times and less blood loss with the percutaneous compression plate were reaffirmed. Compared with the sliding hip screw, the percutaneous compression plate resulted in a larger percentage of patients who were able to walk independently, consistently lower levels of pain with activity, and improved quality of life according to multiple scales of the Short Form-36, but the differences were not significant. Significant differences favoring the percutaneous compression plate were found with regard to operating times, incision length, and blood loss. PMID- 21593371 TI - Early death following primary total knee arthroplasty. AB - BACKGROUND: Total knee arthroplasty carries major risks, including death. Conventional studies have compared the mortality rate following total knee arthroplasty with standardized mortality ratios or age and sex-matched populations. The purpose of the present study was to compare the mortality rate in a population of patients who were managed with total knee arthroplasty with that in patients who were awaiting surgery. METHODS: All patients undergoing primary total knee arthroplasty from 2000 to 2007 at a single institution were recorded. In the same period, all patients who were added to the waiting list for total knee arthroplasty were recorded. The mortality rate and time to death were calculated, and death certificates were retrieved for those who died within thirty or ninety days after the index event. RESULTS: Two thousand, six hundred and ninety-five patients undergoing primary total knee arthroplasty were used for the thirty-day mortality calculation, and 2527 were used for the ninety-day mortality calculation. These patients were compared with 5857 and 5689 patients who were added to the waiting list for the thirty-day and ninety-day mortality calculations, respectively. There was no difference between the populations in terms of age or sex (p > 0.05). The thirty-day mortality following surgery was significantly greater for the surgery group (0.371%; 95% confidence interval, 0.202% to 0.682%) than for the waiting list group (0.0683%; 95% confidence interval, 0.0266% to 0.1755%) (odds ratio, 5.45; 95% confidence interval, 1.81 to 16.43). The ninety-day mortality was also significantly greater for the surgery group (0.792%; 95% confidence interval, 0.513% to 1.219%) than for the waiting list group (0.387%; 95% confidence interval, 0.256% to 0.585%) (odds ratio, 2.05; 95% confidence interval, 1.13 to 3.74). CONCLUSIONS: Primary total knee arthroplasty is associated with an increased risk of death at thirty and ninety days after the operation when compared with a population awaiting the same procedure. Increasing age was a risk factor for death following total knee arthroplasty. PMID- 21593372 TI - Patellar subluxation at terminal knee extension: isolated deficiency of the medial patellomeniscal ligament. AB - BACKGROUND: The medial patellomeniscal ligament has been determined in vitro to be the only substantial distal-medial restraint to lateral patellar displacement. The purpose of this study of prospectively collected data was to determine if isolated deficiency of the medial patellomeniscal ligament, resulting in excessive lateral patellar translation and associated symptoms, could be identified. We hypothesized that, if symptoms were associated with isolated deficiency of that ligament, the laxity and symptoms should resolve after plication of that ligament alone. METHODS: Testing for lateral patellar displacement in the extended knee by exertion of force through the distal patellar attachment of the medial patellomeniscal ligament was performed on 745 patients with patellofemoral syndromes during a twenty-eight-month period. In addition, the ability to recognize pathologically increased lateral patellar translation preoperatively with use of such testing was compared with the ability to recognize increased lateral translation with testing in 439 patients undergoing arthroscopy under anesthesia during that period for any reason. Preoperative symptoms and impairment in knees with isolated deficiency of the medial patellomeniscal ligament were documented and compared with the postoperative results. RESULTS: Isolated medial patellomeniscal ligament deficiency was identified with testing under anesthesia in twenty-three of the 439 knees undergoing arthroscopy for any reason, and twenty of those twenty-three cases had been detected preoperatively with use of lateral patellar displacement testing. Isolated medial patellomeniscal ligament plication was performed in these twenty-three cases, and follow-up data at a mean of 30.8 months were available for twenty-one of the cases. The mean International Knee Documentation Committee subjective score increased from 38.9 preoperatively to 84.6 postoperatively, and recurrent symptomatic pathological lateral patellar translation was present in only one patient. CONCLUSIONS: Isolated deficiency of the medial patellomeniscal ligament can be detected by physical examination. Restoration of the normal length of the ligament by plication can lead to resolution of detectable patellar subluxation and its associated symptoms. PMID- 21593373 TI - Complications of ankle arthroscopy utilizing a contemporary noninvasive distraction technique. AB - BACKGROUND: The reported complication rates of ankle arthroscopy, as well as the types of complications, refer to cases performed fifteen to twenty years ago and include a mixture of invasive and noninvasive distraction methods. As ankle arthroscopy has matured with a move away from invasive distraction and the introduction of improved instruments, it is unclear whether the previously reported complications are reflective of contemporary ankle arthroscopy. We sought to evaluate the types and rates of complications that are associated with contemporary ankle arthroscopy that utilizes noninvasive ankle distraction and a padded foot strap. METHODS: We retrospectively reviewed 294 consecutive arthroscopies. All patients underwent the same intraoperative noninvasive distraction protocol. Demographic data, diagnoses, duration of follow-up data, and procedure-related complications were identified, recorded, and analyzed. RESULTS: All 294 cases were eligible for review. There were twenty complications, resulting in an overall complication rate of 6.8%. There were four non-neurologic complications, including one case of deep venous thrombosis, one case of prolonged portal drainage, and two cases of superficial infection. There were sixteen neurologic complications; six were related to the anterolateral portal, and eight patients had dysesthesias involving the dorsal part of the midfoot. When analyzed as a group, patients who were receiving Workers' Compensation had a higher complication rate than patients who were not receiving Workers' Compensation (21% versus 4.7%, respectively). CONCLUSIONS: Contemporary ankle arthroscopy performed with use of a noninvasive distraction technique is a safe procedure. Our observed complication rate of 6.8% is lower than that reported in a previous benchmark study, although our patients who were receiving Workers' Compensation had a significantly higher risk of having nerve symptoms. An important benefit of the use of contemporary ankle arthroscopy, in which small joint arthroscopic instruments and noninvasive distraction techniques are used, is a marked reduction in the rate of non-neurologic complications. PMID- 21593374 TI - Anterior cruciate ligament reconstruction with semitendinosus graft provided similar stability and knee function and fewer problems with kneeling compared with the bone-patellar tendon-bone graft. PMID- 21593375 TI - A splint was not inferior to a cast for distal radial fracture in children. PMID- 21593376 TI - Combined treatment with corticosteroid injection plus exercise and manual therapy was similar to exercise and manual therapy alone for shoulder pain at 12 weeks. PMID- 21593377 TI - Massive rotator cuff tears without arthropathy: when to consider reverse shoulder arthroplasty. PMID- 21593378 TI - What's new in hand surgery. PMID- 21593379 TI - Abnormal trafficking and degradation of TLR4 underlie the elevated inflammatory response in cystic fibrosis. AB - Morbidity and mortality in cystic fibrosis (CF) are due not only to abnormal epithelial cell function, but also to an abnormal immune response. We have shown previously that macrophages lacking CF transmembrane conductance regulator (CFTR), the gene mutated in CF, contribute significantly to the hyperinflammatory response observed in CF. In this study, we show that lack of functional CFTR in murine macrophages causes abnormal TLR4 subcellular localization. Upon LPS stimulation, CFTR macrophages have prolonged TLR4 retention in the early endosome and reduced translocation into the lysosomal compartment. This abnormal TLR4 trafficking leads to increased LPS-induced activation of the NF-kappaB, MAPK, and IFN regulatory factor-3 pathways and decreased TLR4 degradation, which affects downregulation of the proinflammatory state. In addition to primary murine cells, mononuclear cells isolated from CF patients demonstrate similar defects in response to LPS. Moreover, specific inhibition of CFTR function induces abnormal TLR4 trafficking and enhances the inflammatory response of wild-type murine cells to LPS. Thus, functional CFTR in macrophages influences TLR4 spatial and temporal localization and perturbs LPS-mediated signaling in both murine CF models and patients with CF. PMID- 21593380 TI - The A2B adenosine receptor promotes Th17 differentiation via stimulation of dendritic cell IL-6. AB - Adenosine is an endogenous metabolite produced during hypoxia or inflammation. Previously implicated as an anti-inflammatory mediator in CD4(+) T cell regulation, we report that adenosine acts via dendritic cell (DC) A(2B) adenosine receptor (A(2B)AR) to promote the development of Th17 cells. Mouse naive CD4(+) T cells cocultured with DCs in the presence of adenosine or the stable adenosine mimetic 5'-(N-ethylcarboximado) adenosine resulted in the differentiation of IL 17- and IL-22-secreting cells and elevation of mRNA that encode signature Th17 associated molecules, such as IL-23R and RORgammat. The observed response was similar when DCs were generated from bone marrow or isolated from small intestine lamina propria. Experiments using adenosine receptor antagonists and cells from A(2B)AR(-/-) or A(2A)AR(-/-)/A(2B)AR(-/-) mice indicated that the DC A(2B)AR promoted the effect. IL-6, stimulated in a cAMP-independent manner, is an important mediator in this pathway. Hence, in addition to previously noted direct effects of adenosine receptors on regulatory T cell development and function, these data indicated that adenosine also acts indirectly to modulate CD4(+) T cell differentiation and suggested a mechanism for putative proinflammatory effects of A(2B)AR. PMID- 21593382 TI - High levels of adenosine deaminase on dendritic cells promote autoreactive T cell activation and diabetes in nonobese diabetic mice. AB - Adenosine has been established as an important regulator of immune activation. It signals through P1 adenosine receptors to suppress activation of T cells and professional APCs. Adenosine deaminase (ADA) counters this effect by catabolizing adenosine. This regulatory mechanism has not been tested in a disease model in vivo. Questions also remain as to which cell types are most sensitive to this regulation and whether its dysregulation contributes to any autoimmune conditions. We approached this issue using the NOD model. We report that ADA is upregulated in NOD dendritic cells, which results in their exuberant and spontaneous activation. This, in turn, triggers autoimmune T cell activation. NOD DCs deficient in ADA expression have a greatly reduced capacity to trigger type I diabetes. We also provide evidence that although many cell types, particularly T cells, have been implicated as the suppression targets by adenosine in an in vitro setting, DCs also seem to be affected by this regulatory mechanism. Therefore, this report illustrates a role of ADA in autoimmunity and suggests a potential target for therapeutic intervention. PMID- 21593381 TI - Involvement of adenosine A2A receptors in engulfment-dependent apoptotic cell suppression of inflammation. AB - Efficient execution of apoptotic cell death followed by efficient clearance mediated by professional macrophages is a key mechanism in maintaining tissue homeostasis. Removal of apoptotic cells usually involves three central elements: 1) attraction of phagocytes via soluble "find me" signals, 2) recognition and phagocytosis via cell surface-presenting "eat me" signals, and 3) suppression or initiation of inflammatory responses depending on additional innate immune stimuli. Suppression of inflammation involves both direct inhibition of proinflammatory cytokine production and release of anti-inflammatory factors, which all contribute to the resolution of inflammation. In the current study, using wild-type and adenosine A(2A) receptor (A2AR) null mice, we investigated whether A2ARs, known to mediate anti-inflammatory signals in macrophages, participate in the apoptotic cell-mediated immunosuppression. We found that macrophages engulfing apoptotic cells release adenosine in sufficient amount to trigger A2ARs, and simultaneously increase the expression of A2ARs, as a result of possible activation of liver X receptor and peroxisome proliferators activated receptor delta. In macrophages engulfing apoptotic cells, stimulation of A2ARs suppresses the NO-dependent formation of neutrophil migration factors, such as macrophage inflammatory protein-2, using the adenylate cyclase/protein kinase A pathway. As a result, loss of A2ARs results in elevated chemoattractant secretion. This was evident as pronounced neutrophil migration upon exposure of macrophages to apoptotic cells in an in vivo peritonitis model. Altogether, our data indicate that adenosine is one of the soluble mediators released by macrophages that mediate engulfment-dependent apoptotic cell suppression of inflammation. PMID- 21593383 TI - Transcription factor Nkx2-3 controls the vascular identity and lymphocyte homing in the spleen. AB - The vasculature in the spleen and peripheral lymph nodes (pLNs) is considerably different, which affects both homing of lymphocytes and antigenic access to these peripheral lymphoid organs. In this paper, we demonstrate that in mice lacking the homeodomain transcription factor Nkx2-3, the spleen develops a pLN-like mRNA expression signature, coupled with the appearance of high endothelial venules (HEVs) that mediate L-selectin-dependent homing of lymphocytes into the mutant spleen. These ectopic HEV-like vessels undergo postnatal maturation and progressively replace MAdCAM-1 by pLN addressin together with the display of CCL21 arrest chemokine in a process that is reminiscent of HEV formation in pLNs. Similarly to pLNs, development of HEV-like vessels in the Nkx2-3-deficient spleen depends on lymphotoxin-beta receptor-mediated signaling. The replacement of splenic vessels with a pLN-patterned vasculature impairs the recirculation of adoptively transferred lymphocytes and reduces the uptake of blood-borne pathogens. The Nkx2-3 mutation in BALB/c background causes a particularly disturbed splenic architecture, characterized by the near complete lack of the red pulp, without affecting lymph nodes. Thus, our observations reveal that the organ-specific patterning of splenic vasculature is critically regulated by Nkx2 3, thereby profoundly affecting the lymphocyte homing mechanism and blood filtering capacity of the spleen in a tissue-specific manner. PMID- 21593384 TI - Ligation of Notch receptors in human conventional and plasmacytoid dendritic cells differentially regulates cytokine and chemokine secretion and modulates Th cell polarization. AB - Notch signaling is involved in multiple cellular processes. Recent data also support the prominent role of Notch signaling in the regulation of the immune response. In this study, we analyzed the expression and function of Notch receptors and ligands on both human blood conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs). The expression and modulation upon TLR activation of Notch molecules partially differed between cDCs and pDCs, but functional involvement of the Notch pathway in both cell types was clearly revealed by specific inhibition using DAPT. Beyond the induction of Notch target genes and modulation of maturation markers, Notch pathway was also involved in a differential secretion of some specific cytokines/chemokines by DC subsets. Whereas Notch ligation induced IL-10 and CCL19 secretion in cDCs, Notch inhibition resulted in a diminished production of these proteins. With regard to pDCs, Notch activation induced TNF-alpha whereas Notch inhibition significantly abrogated the secretion of CCL19, CXCL9, CXCL10, and TNF-alpha. Additionally, Notch modulation of DC subsets differentially affected Th polarization of allostimulated T cells. Our results suggest that the Notch pathway may function as an additional mechanism controlling human DC responses, with differential activity on cDCs and pDCs. This control mechanism may ultimately contribute to define the local milieu promoted by these cells under the particular conditions of the immune response. PMID- 21593385 TI - Characterization of the oncogenic activity of the novel TRIM59 gene in mouse cancer models. AB - A novel TRIM family member, TRIM59 gene was characterized to be upregulated in SV40 Tag oncogene-directed transgenic and knockout mouse prostate cancer models as a signaling pathway effector. We identified two phosphorylated forms of TRIM59 (p53 and p55) and characterized them using purified TRIM59 proteins from mouse prostate cancer models at different stages with wild-type mice and NIH3T3 cells as controls. p53/p55-TRIM59 proteins possibly represent Ser/Thr and Tyr phosphorylation modifications, respectively. Quantitative measurements by ELISA showed that the p-Ser/Thr TRIM59 correlated with tumorigenesis, whereas the p-Tyr TRIM59 protein correlated with advanced cancer of the prostate (CaP). The function of TRIM59 was elucidated using short hairpin RNA (shRNA)-mediated knockdown of the gene in human CaP cells, which caused S-phase cell-cycle arrest and cell growth retardation. A hit-and-run effect of TRIM59 shRNA knockdown was observed 24 hours posttransfection. Differential cDNA microarrray analysis was conducted, which showed that the initial and rapid knockdown occurred early in the Ras signaling pathway. To confirm the proto-oncogenic function of TRIM59 in the Ras signaling pathway, we generated a transgenic mouse model using a prostate tissue-specific gene (PSP94) to direct the upregulation of the TRIM59 gene. Restricted TRIM59 gene upregulation in the prostate revealed the full potential for inducing tumorigenesis, similar to the expression of SV40 Tag, and coincided with the upregulation of genes specific to the Ras signaling pathway and bridging genes for SV40 Tag-mediated oncogenesis. The finding of a possible novel oncogene in animal models will implicate a novel strategy for diagnosis, prognosis, and therapy for cancer. PMID- 21593386 TI - Oxaliplatin neurotoxicity of sensory transduction in rat proprioceptors. AB - Neurotoxic effects of oxaliplatin chemotherapy, including proprioceptive impairments, are debilitating and dose limiting. Here, we sought to determine whether oxaliplatin interrupts normal proprioceptive feedback by impairing sensory transduction of muscle length and force by neurons that are not damaged by dying-back neuropathy. Oxaliplatin was administered over 4 wk to rats in doses that produced systemic changes, e.g., decreased platelets and stunted weight gain, but no significant abnormality in the terminal ends of primary muscle spindle sensory neurons. The absence of neuropathy enabled the determination of whether oxaliplatin caused functional deficits in sensory encoding without the confounding issue of axon death. Rats were anesthetized, and action potentials encoding muscle stretch and contraction were recorded intra-axonally from dorsal roots. In striking contrast with normal proprioceptors, those from oxaliplatin treated rats typically failed to sustain firing during static muscle stretch. The ability of spindle afferents to sustain and centrally conduct trains of action potentials in response to rapidly repeated transient stimuli, i.e., vibration, demonstrated functional competence of the parent axons. These data provide the first evidence that oxaliplatin causes persistent and selective deficits in sensory transduction that are not due to axon degeneration. Our findings raise the possibility that even those axons that do not degenerate after oxaliplatin treatment may have functional deficits that worsen outcome. PMID- 21593388 TI - Characterization of postsynaptic Ca2+ signals at the Drosophila larval NMJ. AB - Postsynaptic intracellular Ca(2+) concentration ([Ca(2+)](i)) has been proposed to play an important role in both synaptic plasticity and synaptic homeostasis. In particular, postsynaptic Ca(2+) signals can alter synaptic efficacy by influencing transmitter release, receptor sensitivity, and protein synthesis. We examined the postsynaptic Ca(2+) transients at the Drosophila larval neuromuscular junction (NMJ) by injecting the muscle fibers with Ca(2+) indicators rhod-2 and Oregon Green BAPTA-1 (OGB-1) and then monitoring their increased fluorescence during synaptic activity. We observed discrete postsynaptic Ca(2+) transients along the NMJ during single action potentials (APs) and quantal Ca(2+) transients produced by spontaneous transmitter release. Most of the evoked Ca(2+) transients resulted from the release of one or two quanta of transmitter and occurred largely at synaptic boutons. The magnitude of the Ca(2+) signals was correlated with synaptic efficacy; the Is terminals, which produce larger excitatory postsynaptic potentials (EPSPs) and have a greater quantal size than Ib terminals, produced a larger Ca(2+) signal per terminal length and larger quantal Ca(2+) signals than the Ib terminals. During a train of APs, the postsynaptic Ca(2+) signal increased but remained localized to the postsynaptic membrane. In addition, we showed that the plasma membrane Ca(2+) ATPase (PMCA) played a role in extruding Ca(2+) from the postsynaptic region of the muscle. Drosophila melanogaster has a single PMCA gene, predicted to give rise to various isoforms by alternative splicing. Using RT-PCR, we detected the expression of multiple transcripts in muscle and nervous tissues; the physiological significance of the same is yet to be determined. PMID- 21593387 TI - Role of pH in a nitric oxide-dependent increase in cytosolic Cl- in retinal amacrine cells. AB - Nitric oxide (NO) synthase-expressing neurons are found throughout the vertebrate retina. Previous work by our laboratory has shown that NO can transiently convert inhibitory GABAergic synapses onto cultured retinal amacrine cells into excitatory synapses by releasing Cl(-) from an internal store in the postsynaptic cell. The mechanism underlying this Cl(-) release is currently unknown. Because transport of Cl(-) across internal membranes can be coupled to proton flux, we asked whether protons could be involved in the NO-dependent release of internal Cl(-). Using pH imaging and whole cell voltage-clamp recording, we addressed the relationship between cytosolic pH and cytosolic Cl(-) in cultured retinal amacrine cells. We found that NO reliably produces a transient decrease in cytosolic pH. A physiological link between cytosolic pH and cytosolic Cl(-) was established by demonstrating that shifting cytosolic pH in the absence of NO altered cytosolic Cl(-) concentrations. Strong buffering of cytosolic pH limited the ability of NO to increase cytosolic Cl(-), suggesting that cytosolic acidification is involved in generating the NO-dependent elevation in cytosolic Cl(-). Furthermore, disruption of internal proton gradients also reduced the effects of NO on cytosolic Cl(-). Taken together, these results suggest a cytosolic environment where proton and Cl(-) fluxes are coupled in a dynamic and physiologically meaningful way. PMID- 21593390 TI - Questioning the depolarizing effects of GABA during early brain development. AB - During early brain development, gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, has been thought to be an important source of excitatory neurotransmission. This view, however, was recently challenged by a series of studies that claim that the excitatory effect of GABA is due to non-physiological in vitro experimental conditions. In this article, we aim to summarize results that support and challenge the traditional point of view, and indicate some strong and weak points of both positions. PMID- 21593389 TI - Dipole source analyses of laser evoked potentials obtained from subdural grid recordings from primary somatic sensory cortex. AB - The cortical potentials evoked by cutaneous application of a laser stimulus (laser evoked potentials, LEP) often include potentials in the primary somatic sensory cortex (S1), which may be located within the subdivisions of S1 including Brodmann areas 3A, 3B, 1, and 2. The precise location of the LEP generator may clarify the pattern of activation of human S1 by painful stimuli. We now test the hypothesis that the generators of the LEP are located in human Brodmann area 1 or 3A within S1. Local field potential (LFP) source analysis of the LEP was obtained from subdural grids over sensorimotor cortex in two patients undergoing epilepsy surgery. The relationship of LEP dipoles was compared with dipoles for somatic sensory potentials evoked by median nerve stimulation (SEP) and recorded in area 3B (see Baumgartner U, Vogel H, Ohara S, Treede RD, Lenz FA. J Neurophysiol 104: 3029-3041, 2010). Both patients had an early radial dipole in S1. The LEP dipole was located medial, anterior, and deep to the SEP dipole, which suggests a nociceptive dipole in area 3A. One patient had a later tangential dipole with positivity posterior, which is opposite to the orientation of the SEP dipole in area 3B. The reversal of orientations between modalities is consistent with the cortical surface negative orientation resulting from superficial termination of thalamocortical neurons that receive inputs from the spinothalamic tract. Therefore, the present results suggest that the LEP may result in a radial dipole consistent with a generator in area 3A and a putative later tangential generator in area 3B. PMID- 21593391 TI - Nicotinic excitation of serotonergic projections from dorsal raphe to the nucleus accumbens. AB - Tobacco use is a major public health problem, and although many smokers report that they want to quit, only a small percentage succeed. Side effects associated with nicotine withdrawal, including depression, anxiety, and restlessness, certainly contribute to the low success rate. The dorsal raphe nucleus (DRN) is a serotonergic center with many functions, including control of mood and emotional state. We investigated the effect of nicotine on DRN neurons that project to the nucleus accumbens (NAc), an area involved in reward-related behaviors. Using a retrograde labeling method, we found that 75% of DRN-NAc projection neurons are serotonergic. In coronal slices that include the DRN, whole cell recordings were conducted on neurons identified by fluorescent backlabeling from NAc or randomly selected within the nucleus. Nicotine increased action potential firing rates in a subset of DRN neurons. Voltage-clamp recording revealed nicotinic acetylcholine receptor (nAChR)-mediated inward currents that contribute to the nicotine-induced excitation. Nicotinic receptors also indirectly affect excitability by modulating synaptic inputs to these neurons. Nicotine enhanced excitatory glutamatergic inputs to a subset of DRN-NAc projection neurons, while inhibitory gamma aminobutyric acid (GABA)ergic inputs were modulated either positively or negatively in a subset of these neurons. The net effect of nAChR activation is enhancement of serotonergic output from DRN to the NAc, which may contribute to the effects of nicotine on mood and affect. PMID- 21593392 TI - Sensory versus motor loci for integration of multiple motion signals in smooth pursuit eye movements and human motion perception. AB - We have investigated how visual motion signals are integrated for smooth pursuit eye movements by measuring the initiation of pursuit in monkeys for pairs of moving stimuli of the same or differing luminance. The initiation of pursuit for pairs of stimuli of the same luminance could be accounted for as a vector average of the responses to the two stimuli singly. When stimuli comprised two superimposed patches of moving dot textures, the brighter stimulus suppressed the inputs from the dimmer stimulus, so that the initiation of pursuit became winner take-all when the luminance ratio of the two stimuli was 8 or greater. The dominance of the brighter stimulus could be not attributed to either the latency difference or the ratio of the eye accelerations for the bright and dim stimuli presented singly. When stimuli comprised either spot targets or two patches of dots moving across separate locations in the visual field, the brighter stimulus had a much weaker suppressive influence; the initiation of pursuit could be accounted for by nearly equal vector averaging of the responses to the two stimuli singly. The suppressive effects of the brighter stimulus also appeared in human perceptual judgments, but again only for superimposed stimuli. We conclude that one locus of the interaction of two moving visual stimuli is shared by perception and action and resides in local inhibitory connections in the visual cortex. A second locus resides deeper in sensory-motor processing and may be more closely related to action selection than to stimulus selection. PMID- 21593393 TI - Cues to move increased information in superior colliculus tuning curves. AB - Shifts in the location of spatial attention produce increases in the gain and sensitivity of neuronal responses to sensory stimuli. Cues to shift the line of sight have the same effect on sensory responses in a motor area involved in the control of eye movements, the superior colliculus. Evidence has shown that shifts of gaze and shifts of attention are linked, suggesting there may be similar underlying mechanisms. Here, we report on a novel way in which cues to move the eyes (top-down signals) can influence sensory responses of neurons by altering the variability of their discharge rate. We measured the spatial tuning of superior colliculus neuronal activity in trials with cues to either make or withhold saccadic eye movements. We found that tuning curve widths both increased and decreased, but that the information conveyed by the neuronal discharge about the stimulus increased with a cue to make a saccade. The increase in information resulted partly from a decrease in trial-to-trial variability of neuronal discharges for stimuli located at the flanks of the tuning curves rather than from increases in the discharge rate for stimuli located at the peak of the tuning curves. This result is consistent with theoretical work and provides a novel way for cognitive signals to influence sensory responses within motor regions of the brain. PMID- 21593394 TI - Effect of presynaptic membrane potential on electrical vs. chemical synaptic transmission. AB - The growing realization that electrical coupling is present in the mammalian brain has sparked renewed interest in determining its functional significance and contrasting it with chemical transmission. One question of interest is whether the two types of transmission can be selectively regulated, e.g., if a cell makes both types of connections can electrical transmission occur in the absence of chemical transmission? We explore this issue in an experimentally advantageous preparation. B21, the neuron we study, is an Aplysia sensory neuron involved in feeding that makes electrical and chemical connections with other identified cells. Previously we demonstrated that chemical synaptic transmission is membrane potential dependent. It occurs when B21 is centrally depolarized prior to and during peripheral activation, but does not occur if B21 is peripherally activated at its resting membrane potential. In this article we study effects of membrane potential on electrical transmission. We demonstrate that maximal potentiation occurs in different voltage ranges for the two types of transmission, with potentiation of electrical transmission occurring at more hyperpolarized potentials (i.e., requiring less central depolarization). Furthermore, we describe a physiologically relevant type of stimulus that induces both spiking and an envelope of depolarization in the somatic region of B21. This depolarization does not induce functional chemical synaptic transmission but is comparable to the depolarization needed to maximally potentiate electrical transmission. In this study we therefore characterize a situation in which electrical and chemical transmission can be selectively controlled by membrane potential. PMID- 21593395 TI - Opioid receptor modulation of GABAergic and serotonergic spinally projecting neurons of the rostral ventromedial medulla in mice. AB - The rostral ventromedial medulla (RVM) is an important site of opioid actions and forms part of an analgesic pathway that projects to the spinal cord. The neuronal mechanisms by which opioids act within this brain region remain unclear, particularly in relation to the neurotransmitters GABA and serotonin. In the present study, we examined serotonergic and GABAergic immunoreactivity, identified using immunohistochemistry for tryptophan hydroxylase (TPH) and glutamate decarboxylase (GAD), in combination with in vitro whole cell patch clamping to investigate the role of opioids on the mouse RVM with identified projections to the spinal cord. Tyr-d-Ala-Gly-N-Me-Phe-Gly-ol enkephalin (DAMGO) produced MU-opioid receptor-mediated outward currents in virtually all TPH immunoreactive projecting neurons and GAD-immunoreactive nonprojecting neurons (87% and 86%). The other groups of RVM neurons displayed mixed responsiveness to DAMGO (40-68%). Deltorphin II and U-69593 produced delta- and kappa-opioid receptor-mediated outward currents in smaller subpopulations of RVM neurons, with many of the delta-opioid responders forming a subpopulation of MU-opioid sensitive GABAergic nonprojecting neurons. These findings are consistent with prior electrophysiological and anatomic studies in the rat RVM and indicate that both serotonergic and GABAergic RVM neurons mediate the actions of MU-opioids. Specifically, MU-opioids have a direct postsynaptic inhibitory influence over both GABAergic and serotonergic neurons, including those that project to the dorsal spinal cord. PMID- 21593396 TI - Light exposure induces short- and long-term changes in the excitability of retinorecipient neurons in suprachiasmatic nucleus. AB - The suprachiasmatic nucleus (SCN) is the locus of a hypothalamic circadian clock that synchronizes physiological and behavioral responses to the daily light-dark cycle. The nucleus is composed of functionally and peptidergically diverse populations of cells for which distinct electrochemical properties are largely unstudied. SCN neurons containing gastrin-releasing peptide (GRP) receive direct retinal input via the retinohypothalamic tract. We targeted GRP neurons with a green fluorescent protein (GFP) marker for whole cell patch-clamping. In these neurons, we studied short (0.5-1.5 h)- and long-term (2-6 h) effects of a 1-h light pulse (LP) given 2 h after lights off [Zeitgeber time (ZT) 14:00-15:00] on membrane potential and spike firing. In brain slices taken from light-exposed animals, cells were depolarized, and spike firing rate increased between ZT 15:30 and 16:30. During a subsequent 4-h period beginning around ZT 17:00, GRP neurons from light-exposed animals were hyperpolarized by ~15 mV. None of these effects was observed in GRP neurons from animals not exposed to light or in immediately adjacent non-GRP neurons whether or not exposed to light. Depolarization of GRP neurons was associated with a reduction in GABA(A)-dependent synaptic noise, whereas hyperpolarization was accompanied both by a loss of GABA(A) drive and suppression of a TTX-resistant leakage current carried primarily by Na. This suggests that, in the SCN, exposure to light may induce a short-term increase in GRP neuron excitability mediated by retinal neurotransmitters and neuropeptides, followed by long-term membrane hyperpolarization resulting from suppression of a leakage current, possibly resulting from genomic signals. PMID- 21593398 TI - NCATS purrs: emerging signs of form and function. PMID- 21593397 TI - Changes in reward contingency modulate the trial-to-trial variability of hippocampal place cells. AB - Pyramidal cells in the rodent hippocampus often exhibit clear spatial tuning. Theories of hippocampal function suggest that these "place cells" implement multiple, independent neural representations of position (maps), based on different reference frames or environmental features. Consistent with the "multiple maps" theory, previous studies have shown that manipulating spatial factors related to task performance modulates the within-session variability (overdispersion) of cells in the hippocampus. However, the influence of changes in reward contingency on overdispersion has not been examined. To test this, we first trained rats to collect food from three feeders positioned around a circular track (task(1)). When subjects were proficient, the reward contingency was altered such that every other feeder delivered food (task(2)). We recorded ensembles of hippocampal neurons as rats performed both tasks. Place cell overdispersion was high during task(1) but decreased significantly during task(2), and this increased reliability could not be accounted for by changes in running speed or familiarity with the task. Intuitively, decreased variability might be expected to improve neural representations of position. To test this, we used Bayesian decoding of hippocampal spike trains to estimate subjects' location. Neither the amount of probability decoded to subjects' position (local probability) nor the difference between estimated position and true location (decoding accuracy) differed between tasks. However, we found that hippocampal ensembles were significantly more self-consistent during task(2) performance. These results suggest that changes in task demands can affect the firing statistics of hippocampal neurons, leading to changes in the properties of decoded neural representations. PMID- 21593399 TI - Regulatory T cells: customizing for the clinic. AB - Immune-suppressive cellular immunotherapy requires large numbers of antigen specific regulatory T cells (T(reg) cells), lymphocytes that suppress certain immune responses. Together, three papers in this issue of Science Translational Medicine describe protocols for the ex vivo expansion of human T(reg) cells and assess the immune-suppressive function of ex vivo-manipulated T(reg) cells after transfer into humanized mouse disease models. Along with recent phase I clinical trial results, these new data provide a platform for clinical use of T(reg) cells as personalized therapeutic agents for the treatment of autoimmune diseases, graft-versus-host disease, and transplant rejection. PMID- 21593400 TI - Functional regulatory T cells produced by inhibiting cyclic nucleotide phosphodiesterase type 3 prevent allograft rejection. AB - Regulatory T cells (T(regs)) manipulated ex vivo have potential as cellular therapeutics in autoimmunity and transplantation. Although it is possible to expand naturally occurring T(regs), an attractive alternative possibility, particularly suited to solid organ and bone marrow transplantation, is the stimulation of total T cell populations with defined allogeneic antigen presenting cells (APCs) under conditions that lead to the generation or expansion of donor-reactive, adaptive T(regs). Here we demonstrate that stimulation of mouse CD4(+) T cells by immature allogeneic dendritic cells combined with pharmacological inhibition of phosphodiesterase 3 (PDE) resulted in a functional enrichment of Foxp3(+) T cells. Without further manipulation or selection, the resultant population delayed skin allograft rejection mediated by polyclonal CD4(+) effectors or donor-reactive CD8(+) T cell receptor transgenic T cells and inhibited both effector cell proliferation and T cell priming for interferon gamma production. Notably, PDE inhibition also enhanced the enrichment of human Foxp3(+) CD4(+) T cells driven by allogeneic APCs. These cells inhibited T cell proliferation in a standard in vitro mixed lymphocyte assay and, moreover, attenuated the development of vasculopathy mediated by autologous peripheral blood mononuclear cells in a functionally relevant humanized mouse transplant model. These data establish a method for the ex vivo generation of graft reactive, functional mouse and human T(regs) that uses a clinically approved agent, making pharmacological PDE inhibition a potential strategy for T(reg) based therapies. PMID- 21593401 TI - Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity. AB - Graft-versus-host disease (GVHD) is a frequent and severe complication after hematopoietic cell transplantation. Natural CD4(+)CD25(+) regulatory T cells (nT(regs)) have proven highly effective in preventing GVHD and autoimmunity in murine models. Yet, clinical application of nT(regs) has been severely hampered by their low frequency and unfavorable ex vivo expansion properties. Previously, we demonstrated that umbilical cord blood (UCB) nT(regs) could be purified and expanded in vitro using good manufacturing practice (GMP) reagents; however, the initial number of nT(regs) in UCB units is limited, and average yield after expansion was only 1 * 10(9) nT(regs). Therefore, we asked whether yield could be increased by using peripheral blood (PB), which contains far larger quantities of nT(regs). PB nT(regs) were purified under GMP conditions and expanded 80-fold to yield 19 * 10(9) cells using anti-CD3 antibody-loaded, cell-based artificial antigen-presenting cells (aAPCs) that expressed the high-affinity Fc receptor and CD86. A single restimulation increased expansion to ~3000-fold and yield to >600 * 10(9) cells while maintaining Foxp3 expression and suppressor function. nT(reg) expansion was ~50 million-fold when flow sort-purified nT(regs) were restimulated four times with aAPCs. Indeed, cryopreserved donor nT(regs) restimulated four times significantly reduced GVHD lethality induced by the infusion of human T cells into immune-deficient mice. The capability to efficiently produce donor cell banks of functional nT(regs) could transform the treatment of GVHD and autoimmunity by providing an off-the-shelf, cost-effective, and proven cellular therapy. PMID- 21593402 TI - Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells. AB - Graft rejection by the immune system is a major cause of transplant failure. Lifelong immunosuppression decreases the incidence of graft rejection; however, nonspecific immunosuppression results in increased susceptibly to infection and cancer. Regulatory T cells (T(regs)), which suppress the activation of the immune system and induce tolerance, are currently under evaluation for use in clinical transplantation. Ex vivo expanded polyclonal T(regs) that are introduced into transplant recipients alter the balance of T effector cells to T(regs); however, experimental data suggest that alloantigen-specific T(regs) would be more effective at preventing graft rejection. We have developed a method to enrich alloantigen-specific human T(regs) based on the coexpression of activation markers, CD69 and CD71. These T(regs) could be readily expanded in vitro and demonstrated potent antigen-specific suppression. In a humanized mouse model of alloimmune-mediated injury of human skin grafts, alloantigen-specific T(regs) resulted in a significant reduction in clinically relevant indicators of dermal tissue injury when compared with polyclonal T(regs), restoring a histology comparable to healthy skin. This method of human allospecific T(reg) selection should be scalable to the clinic. The improved in vivo efficacy of alloantigen specific T(regs) over polyclonal T(regs) shown here suggests that generating "customized" T(regs) with defined anti-donor allospecificities may improve current practice in clinical immunotherapy. PMID- 21593403 TI - Safety, Tolerability, and Pharmacokinetics of KP-1461 in Phase I Clinical Studies: A Single Oral Dose Study in Non-HIV-Infected Adults, and a 14-Day Dose Escalating Study in Highly Antiretroviral-Experienced HIV-Infected Adults. AB - BACKGROUND: KP-1461 is a prodrug to KP-1212. KP-1212 is a viral mutagen designed to increase viral error rate. METHODS: We describe 2 phase I studies: KP1461-101 (double-blind, placebo-controlled, single, escalating doses, 100 to 1600 mg study in 42 non-HIV-infected participants) and KP-1461-102 (double-blind placebo controlled dose escalation 14-day study in HIV-infected participants, 400-3200 mg). Primary objectives were safety/tolerability. Secondary objectives included pharmacokinetic analysis with exploratory objective to characterize KP-1212 effects on viral load. RESULTS: KP-1461 was well tolerated. Majority of adverse events were grade 1 (neurological, gastrointestinal, cardiovascular). Four participants experienced grade 3 and 1 experienced a grade 4 event. Analysis demonstrated no difference in pharmacokinetic parameters at day 1 or 14. Linear pharmacokinetics found in 1600 mg arm. Compared to placebo, only at the 3200 mg dose demonstrated a marginally statistically significant virologic response. CONCLUSIONS: These studies provide safety/tolerability information and suggest virologic efficacy. KP-1212, a first-in-class antiretroviral, demonstrates the ability to induce viral eradication in vitro. Viral reduction in vivo may foretell a paradigm shift in HIV pharmacotherapy. PMID- 21593404 TI - A case of immune reconstitution syndrome to disseminated histoplasmosis. AB - Histoplasmosis is an uncommon cause of hepatosplenomegaly in South Africa. A case of immune reconstitution syndrome (IRS) to disseminated histoplasmosis in a patient presented to a tertiary hospital in Kwazulu-Natal, South Africa, is described. PMID- 21593405 TI - Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. AB - The colonic epithelium self-renews every 3 to 5 d, but our understanding of the underlying processes preserving wound healing from carcinogenesis remains incomplete. Here, we demonstrate that Nod-like receptor pyrin domain-containing protein 6 (NLRP6) suppresses inflammation and carcinogenesis by regulating tissue repair. NLRP6 was primarily produced by myofibroblasts within the stem-cell niche in the colon. Although NLRP6 expression was lowered in diseased colon, NLRP6 deficient mice were highly susceptible to experimental colitis. Upon injury, NLRP6 deficiency deregulated regeneration of the colonic mucosa and processes of epithelial proliferation and migration. Consistently, absence of NLRP6 accelerated colitis-associated tumor growth in mice. A gene-ontology analysis on a whole-genome expression profiling revealed a link between NLRP6 and self renewal of the epithelium. Collectively, the integrity of the epithelial barrier is preserved by NLRP6 that may be manipulated to develop drugs capable of preventing adenoma formation in inflammatory bowel diseases. PMID- 21593406 TI - Ligand-gated diffusion across the bacterial outer membrane. AB - Ligand-gated channels, in which a substrate transport pathway is formed as a result of the binding of a small-molecule chemical messenger, constitute a diverse class of membrane proteins with important functions in prokaryotic and eukaryotic organisms. Despite their widespread nature, no ligand-gated channels have yet been found within the outer membrane (OM) of Gram-negative bacteria. Here we show, using in vivo transport assays, intrinsic tryptophan fluorescence and X-ray crystallography, that high-affinity (submicromolar) substrate binding to the OM long-chain fatty acid transporter FadL from Escherichia coli causes conformational changes in the N terminus that open up a channel for substrate diffusion. The OM long-chain fatty acid transporter FadL from E. coli is a unique paradigm for OM diffusion-driven transport, in which ligand gating within a beta barrel membrane protein is a prerequisite for channel formation. PMID- 21593407 TI - Crystal structure of lactose permease in complex with an affinity inactivator yields unique insight into sugar recognition. AB - Lactose permease of Escherichia coli (LacY) with a single-Cys residue in place of A122 (helix IV) transports galactopyranosides and is specifically inactivated by methanethiosulfonyl-galactopyranosides (MTS-gal), which behave as unique suicide substrates. In order to study the mechanism of inactivation more precisely, we solved the structure of single-Cys122 LacY in complex with covalently bound MTS gal. This structure exhibits an inward-facing conformation similar to that observed previously with a slight narrowing of the cytoplasmic cavity. MTS-gal is bound covalently, forming a disulfide bond with C122 and positioned between R144 and W151. E269, a residue essential for binding, coordinates the C-4 hydroxyl of the galactopyranoside moiety. The location of the sugar is in accord with many biochemical studies. PMID- 21593408 TI - Discovery of an unusual biosynthetic origin for circular proteins in legumes. AB - Cyclotides are plant-derived proteins that have a unique cyclic cystine knot topology and are remarkably stable. Their natural function is host defense, but they have a diverse range of pharmaceutically important activities, including uterotonic activity and anti-HIV activity, and have also attracted recent interest as templates in drug design. Here we report an unusual biosynthetic origin of a precursor protein of a cyclotide from the butterfly pea, Clitoria ternatea, a representative member of the Fabaceae plant family. Unlike all previously reported cyclotides, the domain corresponding to the mature cyclotide from this Fabaceae plant is embedded within an albumin precursor protein. We confirmed the expression and correct processing of the cyclotide encoded by the Cter M precursor gene transcript following extraction from C. ternatea leaf and sequencing by tandem mass spectrometry. The sequence was verified by direct chemical synthesis and the peptide was found to adopt a classic knotted cyclotide fold as determined by NMR spectroscopy. Seven additional cyclotide sequences were also identified from C. ternatea leaf and flower, five of which were unique. Cter M displayed insecticidal activity against the cotton budworm Helicoverpa armigera and bound to phospholipid membranes, suggesting its activity is modulated by membrane disruption. The Fabaceae is the third largest family of flowering plants and many Fabaceous plants are of huge significance for human nutrition. Knowledge of Fabaceae cyclotide gene transcripts should enable the production of modified cyclotides in crop plants for a variety of agricultural or pharmaceutical applications, including plant-produced designer peptide drugs. PMID- 21593409 TI - Active multistage coarsening of actin networks driven by myosin motors. AB - In cells, many vital processes involve myosin-driven motility that actively remodels the actin cytoskeleton and changes cell shape. Here we study how the collective action of myosin motors organizes actin filaments into contractile structures in a simplified model system devoid of biochemical regulation. We show that this self-organization occurs through an active multistage coarsening process. First, motors form dense foci by moving along the actin network structure followed by coalescence. Then the foci accumulate actin filaments in a shell around them. These actomyosin condensates eventually cluster due to motor driven coalescence. We propose that the physical origin of this multistage aggregation is the highly asymmetric load response of actin filaments: they can support large tensions but buckle easily under piconewton compressive loads. Because the motor-generated forces well exceed this threshold, buckling is induced on the connected actin network that resists motor-driven filament sliding. We show how this buckling can give rise to the accumulation of actin shells around myosin foci and subsequent coalescence of foci into superaggregates. This new physical mechanism provides an explanation for the formation and contractile dynamics of disordered condensed actomyosin states observed in vivo. PMID- 21593410 TI - Forming giant vesicles with controlled membrane composition, asymmetry, and contents. AB - Growing knowledge of the key molecular components involved in biological processes such as endocytosis, exocytosis, and motility has enabled direct testing of proposed mechanistic models by reconstitution. However, current techniques for building increasingly complex cellular structures and functions from purified components are limited in their ability to create conditions that emulate the physical and biochemical constraints of real cells. Here we present an integrated method for forming giant unilamellar vesicles with simultaneous control over (i) lipid composition and asymmetry, (ii) oriented membrane protein incorporation, and (iii) internal contents. As an application of this method, we constructed a synthetic system in which membrane proteins were delivered to the outside of giant vesicles, mimicking aspects of exocytosis. Using confocal fluorescence microscopy, we visualized small encapsulated vesicles docking and mixing membrane components with the giant vesicle membrane, resulting in exposure of previously encapsulated membrane proteins to the external environment. This method for creating giant vesicles can be used to test models of biological processes that depend on confined volume and complex membrane composition, and it may be useful in constructing functional systems for therapeutic and biomaterials applications. PMID- 21593412 TI - Twists and turns of DNA methylation. PMID- 21593411 TI - Integrin activation and internalization on soft ECM as a mechanism of induction of stem cell differentiation by ECM elasticity. AB - The mechanism by which ECM elasticity induces lineage specification of stem cells has not been clearly understood. Integrins are well-documented mechanosensors that are positioned at the beginning of the sensing pathway. By using an antibody specifically recognizing the active conformation of beta1 integrin, we observed that beta1 integrin activation in bone marrow mesenchymal stem cells (BMMSCs) was induced by soft substrate to a significantly greater degree than by stiff substrate. In contrast, however, the level of cell surface integrin on soft substrate was significantly lower than that on stiff substrate. Soft substrate markedly enhanced the internalization of integrin, and this internalization was mediated mainly through caveolae/raft-dependent endocytosis. The inhibition of integrin internalization blocked the neural lineage specification of BMMSCs on soft substrate. Furthermore, soft substrate also repressed the bone morphogenetic protein (BMP)/Smad pathway at least partially through integrin-regulated BMP receptor endocytosis. A theoretical analysis based on atomic force microscopy (AFM) data indicated that integrin-ligand complexes are more easily ruptured on soft substrate; this outcome may contribute to the enhancement of integrin internalization on soft substrate. Taken together, our results suggest that ECM elasticity affects integrin activity and trafficking to modulate integrin BMP receptor internalization, thus contributing to stem cell lineage specification. PMID- 21593413 TI - Key role for IL-21 in experimental autoimmune uveitis. AB - IL-21 is a pleiotropic type 1 cytokine that shares the common cytokine receptor gamma-chain, gamma(c), with IL-2, IL-4, IL-7, IL-9, and IL-15. IL-21 is most homologous to IL-2. These cytokines are encoded by adjacent genes, but they are functionally distinct. Whereas IL-2 promotes development of regulatory T cells and confers protection from autoimmune disease, IL-21 promotes differentiation of Th17 cells and is implicated in several autoimmune diseases, including type 1 diabetes and systemic lupus erythematosus. However, the roles of IL-21 and IL-2 in CNS autoimmune diseases such as multiple sclerosis and uveitis have been controversial. Here, we generated Il21-mCherry/Il2-emGFP dual-reporter transgenic mice and showed that development of experimental autoimmune uveitis (EAU) correlated with the presence of T cells coexpressing IL-21 and IL-2 into the retina. Furthermore, Il21r(-/-) mice were more resistant to EAU development than wild-type mice, and adoptive transfer of Il21r(-/-) T cells induced much less severe EAU, underscoring the need for IL-21 in the development of this disease and suggesting that blocking IL-21/gamma(c)-signaling pathways may provide a means for controlling CNS auto-inflammatory diseases. PMID- 21593414 TI - Serotonin, cytokines, p11, and depression. PMID- 21593415 TI - Important roles of brain-specific carnitine palmitoyltransferase and ceramide metabolism in leptin hypothalamic control of feeding. AB - Brain-specific carnitine palmitoyltransferase-1 (CPT-1c) is implicated in CNS control of food intake. In this article, we explore the role of hypothalamic CPT 1c in leptin's anorexigenic actions. We first show that adenoviral overexpression of CPT-1c in hypothalamic arcuate nucleus of rats increases food intake and concomitantly up-regulates orexigenic neuropeptide Y (NPY) and Bsx (a transcription factor of NPY). Then, we demonstrate that this overexpression antagonizes the anorectic actions induced by central leptin or compound cerulenin (an inhibitor of fatty acid synthase). The overexpression of CPT-1c also blocks leptin-induced down-regulations of NPY and Bsx. Furthermore, the anorectic actions of central leptin or cerulenin are impaired in mice with brain CPT-1c deleted. Both anorectic effects require elevated levels of hypothalamic arcuate nucleus (Arc) malonyl-CoA, a fatty acid-metabolism intermediate that has emerged as a mediator in hypothalamic control of food intake. Thus, these data suggest that CPT-1c is implicated in malonyl-CoA action in leptin's hypothalamic anorectic signaling pathways. Moreover, ceramide metabolism appears to play a role in leptin's central control of feeding. Leptin treatment decreases Arc ceramide levels, with the decrease being important in leptin-induced anorectic actions and down-regulations of NPY and Bsx. Of interest, our data indicate that leptin impacts ceramide metabolism through malonyl-CoA and CPT-1c, and ceramide de novo biosynthesis acts downstream of both malonyl-CoA and CPT-1c in mediating their effects on feeding and expressions of NPY and Bsx. In summary, we provide insights into the important roles of malonyl-CoA, CPT-1c, and ceramide metabolism in leptin's hypothalamic signaling pathways. PMID- 21593416 TI - Evolutionary origin of a novel gene expression pattern through co-option of the latent activities of existing regulatory sequences. AB - Spatiotemporal changes in gene expression underlie many evolutionary novelties in nature. However, the evolutionary origins of novel expression patterns, and the transcriptional control elements ("enhancers") that govern them, remain unclear. Here, we sought to explore the molecular genetic mechanisms by which new enhancers arise. We undertook a survey of closely related Drosophila species to identify recently evolved novel gene expression patterns and traced their evolutionary history. Analyses of gene expression in a variety of developing tissues of the Drosophila melanogaster species subgroup revealed high rates of expression pattern divergence, including numerous evolutionary losses, heterochronic shifts, and expansions or contractions of expression domains. However, gains of novel expression patterns were much less frequent. One gain was observed for the Neprilysin-1 (Nep1) gene, which has evolved a unique expression pattern in optic lobe neuroblasts of Drosophila santomea. Dissection of the Nep1 cis-regulatory region localized a newly derived optic lobe enhancer activity to a region of an intron that has accumulated a small number of mutations. The Nep1 optic lobe enhancer overlaps with other enhancer activities, from which the novel activity was co-opted. We suggest that the novel optic lobe enhancer evolved by exploiting the cryptic activity of extant regulatory sequences, and this may reflect a general mechanism whereby new enhancers evolve. PMID- 21593417 TI - Simple line drawings suffice for functional MRI decoding of natural scene categories. AB - Humans are remarkably efficient at categorizing natural scenes. In fact, scene categories can be decoded from functional MRI (fMRI) data throughout the ventral visual cortex, including the primary visual cortex, the parahippocampal place area (PPA), and the retrosplenial cortex (RSC). Here we ask whether, and where, we can still decode scene category if we reduce the scenes to mere lines. We collected fMRI data while participants viewed photographs and line drawings of beaches, city streets, forests, highways, mountains, and offices. Despite the marked difference in scene statistics, we were able to decode scene category from fMRI data for line drawings just as well as from activity for color photographs, in primary visual cortex through PPA and RSC. Even more remarkably, in PPA and RSC, error patterns for decoding from line drawings were very similar to those from color photographs. These data suggest that, in these regions, the information used to distinguish scene category is similar for line drawings and photographs. To determine the relative contributions of local and global structure to the human ability to categorize scenes, we selectively removed long or short contours from the line drawings. In a category-matching task, participants performed significantly worse when long contours were removed than when short contours were removed. We conclude that global scene structure, which is preserved in line drawings, plays an integral part in representing scene categories. PMID- 21593418 TI - ADAR1 isoform involvement in embryonic lethality. PMID- 21593419 TI - Spontaneous and aging-dependent development of arthritis in NADPH oxidase 2 deficiency through altered differentiation of CD11b+ and Th/Treg cells. AB - Emerging evidence indicates that NADPH oxidase (NOX) and its reactive oxygen species (ROS) products modulate a variety of cellular events, including proliferation, differentiation, and apoptosis. In this study, we investigated the functions of NOX2 and ROS in immune modulation using NOX2 knockout (KO) mice. Interestingly, NOX2 KO mice spontaneously developed arthritis with onset at 6-7 wk of age and high incidence (60%) at 15-18 wk of age. Arthritis severity in NOX2 KO mice was proportionally increased with age and higher in females than in males. Bone destruction was confirmed by microcomputed tomography scanning and histological analyses of joints. Inflammatory factors, including TNF-alpha, IL 1beta, and RANKL, and serum level of anti-type II collagen IgG were significantly increased in NOX2 KO mice. In addition, NOX2 deficiency perturbed the immune system upon aging. NOX2 KO mice demonstrated preferred development of CD11b+Gr-1+ myeloid cells with profound production of proinflammatory cytokines and augmented expression of IL-17 through the activation of STAT3 and RORgammat in vivo. NOX2 deficiency increased differentiation of effector Th cells in vitro and decreased CD25+FoxP3+ Treg cells both in vitro and in vivo. Furthermore, adoptive transfer of NOX2-deficient CD4(+) T cells into RAG KO mice increased arthritic inflammation compared with WT cells. These results demonstrated that NOX2 deficiency affected the development of CD11b+ myeloid cells and Th17/Treg cells, and thus promoted inflammatory cytokine production and inflammatory arthritis development, strongly supporting a crucial role for ROS generation in the modulation of Th17/Treg cell development and its related inflammatory immune response upon aging. PMID- 21593420 TI - Genome-wide network model capturing seed germination reveals coordinated regulation of plant cellular phase transitions. AB - Seed germination is a complex trait of key ecological and agronomic significance. Few genetic factors regulating germination have been identified, and the means by which their concerted action controls this developmental process remains largely unknown. Using publicly available gene expression data from Arabidopsis thaliana, we generated a condition-dependent network model of global transcriptional interactions (SeedNet) that shows evidence of evolutionary conservation in flowering plants. The topology of the SeedNet graph reflects the biological process, including two state-dependent sets of interactions associated with dormancy or germination. SeedNet highlights interactions between known regulators of this process and predicts the germination-associated function of uncharacterized hub nodes connected to them with 50% accuracy. An intermediate transition region between the dormancy and germination subdomains is enriched with genes involved in cellular phase transitions. The phase transition regulators SERRATE and EARLY FLOWERING IN SHORT DAYS from this region affect seed germination, indicating that conserved mechanisms control transitions in cell identity in plants. The SeedNet dormancy region is strongly associated with vegetative abiotic stress response genes. These data suggest that seed dormancy, an adaptive trait that arose evolutionarily late, evolved by coopting existing genetic pathways regulating cellular phase transition and abiotic stress. SeedNet is available as a community resource (http://vseed.nottingham.ac.uk) to aid dissection of this complex trait and gene function in diverse processes. PMID- 21593422 TI - Structure-based approach to rationally design a chimeric protein for an effective vaccine against Group B Streptococcus infections. AB - Structural vaccinology is an emerging strategy for the rational design of vaccine candidates. We successfully applied structural vaccinology to design a fully synthetic protein with multivalent protection activity. In Group B Streptococcus, cell-surface pili have aroused great interest because of their direct roles in virulence and importance as protective antigens. The backbone subunit of type 2a pilus (BP-2a) is present in six immunogenically different but structurally similar variants. We determined the 3D structure of one of the variants, and experimentally demonstrated that protective antibodies specifically recognize one of the four domains that comprise the protein. We therefore constructed a synthetic protein constituted by the protective domain of each one of the six variants and showed that the chimeric protein protects mice against the challenge with all of the type 2a pilus-carrying strains. This work demonstrates the power of structural vaccinology and will facilitate the development of an optimized, broadly protective pilus-based vaccine against Group B Streptococcus by combining the uniquely generated chimeric protein with protective pilin subunits from two other previously identified pilus types. In addition, this work describes a template procedure that can be followed to develop vaccines against other bacterial pathogens. PMID- 21593423 TI - Apoptosis regulator through modulating IAP expression (ARIA) controls the PI3K/Akt pathway in endothelial and endothelial progenitor cells. AB - Endothelial and endothelial progenitor cells (ECs and EPCs) play a fundamental role in angiogenesis that is essential for numerous physiological and pathological processes. The phosphatase and tensin homolog (PTEN)/ phosphoinositide 3-kinase (PI3K) pathway has been implicated in angiogenesis, but the mechanism in the regulation of this pathway in ECs and EPCs is poorly understood. Here we show that ARIA (apoptosis regulator through modulating IAP expression), a transmembrane protein that we recently identified, regulates the PTEN/PI3K pathway in ECs and EPCs and controls developmental and postnatal angiogenesis in vivo. We found that ARIA is abundantly expressed in EPCs and regulates their angiogenic functions by modulating PI3K/Akt/endothelial nitric oxide synthase (eNOS) signaling. Genetic deletion of ARIA caused nonfatal bleeding during embryogenesis, in association with increased small vessel density and altered expression of various vascular growth factors including angiopoietins and VEGF receptors. Postnatal neovascularization induced by critical limb ischemia was substantially enhanced in ARIA-null mice, in conjunction with more bone marrow (BM)-derived ECs detected in ischemic muscles. Administration of PI3K or NO synthase inhibitor completely abolished the enhanced neovascularization in ARIA(-/-) mice. Mechanistically, we identified that ARIA interacts with PTEN at the intracellular domain independently of the PTEN phosphorylation in its C terminal tail. Overexpressed ARIA increased PTEN in the membrane fraction, whereas ARIA-silencing reduced the membrane-associated PTEN, resulting in modified PI3K/Akt signaling. Taken together, our findings establish a previously undescribed mode of regulation of the PTEN/PI3K/Akt pathway by ARIA, and reveal a unique mechanism in the control of angiogenesis. These functions of ARIA might offer a unique therapeutic potential. PMID- 21593424 TI - Prenatal glucocorticoid exposure in the sheep alters renal development in utero: implications for adult renal function and blood pressure control. AB - Treatment of the pregnant ewe with glucocorticoids early in pregnancy results in offspring with hypertension. This study examined whether glucocorticoids can reduce nephron formation or alter gene expression for sodium channels in the late gestation fetus. Sodium channel expression was also examined in 2-mo-old lambs, while arterial pressure and renal function was examined in adult female offspring before and during 6 wk of increased dietary salt intake. Pregnant ewes were treated with saline (SAL), dexamethasone (DEX; 0.48 mg/h) or cortisol (CORT; 5 mg/h) over days 26-28 of gestation (term = 150 days). At 140 days of gestation, glomerular number in CORT and DEX animals was 40 and 25% less, respectively, compared with SAL controls. Real-time PCR showed greater gene expression for the epithelial sodium channel (alpha-, beta-, gamma-subunits) and Na(+)-K(+)-ATPase (alpha-, beta-, gamma-subunits) in both the DEX and CORT group fetal kidneys compared with the SAL group with some of these changes persisting in 2-mo-old female offspring. In adulthood, sheep treated with dexamethasone or cortisol in utero had elevated arterial pressure and an apparent increase in single nephron glomerular filtration rate, but global renal hemodynamics and excretory function were normal and arterial pressure was not salt sensitive. Our findings show that the nephron-deficit in sheep exposed to glucocorticoids in utero is acquired before birth, so it is a potential cause, rather than a consequence, of their elevated arterial pressure in adulthood. Upregulation of sodium channels in these animals could provide a mechanistic link to sustained increases in arterial pressure in cortisol- and dexamethasone-exposed sheep, since it would be expected to promote salt and water retention during the postnatal period. PMID- 21593426 TI - Visualizing ocular lens fluid dynamics using MRI: manipulation of steady state water content and water fluxes. AB - Studies using various MRI techniques have shown that a water-protein concentration gradient exists in the ocular lens. Because this concentration is higher in the core relative to the lens periphery, a gradient in refractive index is established in the lens. To investigate how the water-protein concentration profile is maintained, bovine lenses were incubated in different solutions, and changes in water-protein concentration ratio monitored using proton density weighted (PD-weighted) imaging in the absence and presence of heavy water (D(2)O). Lenses incubated in artificial aqueous humor (AAH) maintained the steady state water-protein concentration gradient, but incubating lenses in high extracellular potassium (KCl-AAH) or low temperature (Low T-AAH) caused a collapse of the gradient due to a rise in water content in the core of the lens. To visualize water fluxes, lenses were incubated in D(2)O, which acts as a contrast agent. Incubation in KCl-AAH and low T-AAH dramatically slowed the movement of D(2)O into the core but did not affect the movement of D(2)O into the outer cortex. D(2)O seemed to preferentially enter the lens cortex at the anterior and posterior poles before moving circumferentially toward the equatorial regions. This directionality of D(2)O influx into the lens cortex was abolished by incubating lenses in high KCl-AAH or low T-AAH, and resulted in homogenous influx of D(2)O into the outer cortex. Taken together, our results show that the water-protein concentration ratio is actively maintained in the core of the lens and that water fluxes preferentially enter the lens at the poles. PMID- 21593425 TI - Ventilatory effects of substance P-saporin lesions in the nucleus tractus solitarii of chronically hypoxic rats. AB - During ventilatory acclimatization to hypoxia (VAH), time-dependent increases in ventilation lower Pco(2) levels, and this persists on return to normoxia. We hypothesized that plasticity in the caudal nucleus tractus solitarii (NTS) contributes to VAH, as the NTS receives the first synapse from the carotid body chemoreceptor afferents and also contains CO(2)-sensitive neurons. We lesioned cells in the caudal NTS containing the neurokinin-1 receptor by microinjecting the neurotoxin saporin conjugated to substance P and measured ventilatory responses in awake, unrestrained rats 18 days later. Lesions did not affect hypoxic or hypercapnic ventilatory responses in normoxic control rats, in contrast to published reports for similar lesions in other central chemosensitive areas. Also, lesions did not affect the hypercapnic ventilatory response in chronically hypoxic rats (inspired Po(2) = 90 Torr for 7 days). These results suggest functional differences between central chemoreceptor sites. However, lesions significantly increased ventilation in normoxia or acute hypoxia in chronically hypoxic rats. Hence, chronic hypoxia increases an inhibitory effect of neurokinin-1 receptor neurons in the NTS on ventilatory drive, indicating that these neurons contribute to plasticity during chronic hypoxia, although such plasticity does not explain VAH. PMID- 21593421 TI - Genetic and expression analysis of cattle identifies candidate genes in pathways responding to Trypanosoma congolense infection. AB - African bovine trypanosomiasis caused by Trypanosoma sp., is a major constraint on cattle productivity in sub-Saharan Africa. Some African Bos taurus breeds are highly tolerant of infection, but the potentially more productive Bos indicus zebu breeds are much more susceptible. Zebu cattle are well adapted for plowing and haulage, and increasing their tolerance of trypanosomiasis could have a major impact on crop cultivation as well as dairy and beef production. We used three strategies to obtain short lists of candidate genes within QTL that were previously shown to regulate response to infection. We analyzed the transcriptomes of trypanotolerant N'Dama and susceptible Boran cattle after infection with Trypanosoma congolense. We sequenced EST libraries from these two breeds to identify polymorphisms that might underlie previously identified quantitative trait loci (QTL), and we assessed QTL regions and candidate loci for evidence of selective sweeps. The scan of the EST sequences identified a previously undescribed polymorphism in ARHGAP15 in the Bta2 trypanotolerance QTL. The polymorphism affects gene function in vitro and could contribute to the observed differences in expression of the MAPK pathway in vivo. The expression data showed that TLR and MAPK pathways responded to infection, and the former contained TICAM1, which is within a QTL on Bta7. Genetic analyses showed that selective sweeps had occurred at TICAM1 and ARHGAP15 loci in African taurine cattle, making them strong candidates for the genes underlying the QTL. Candidate QTL genes were identified in other QTL by their expression profile and the pathways in which they participate. PMID- 21593428 TI - Electroacupuncture improves rectal distension-induced delay in solid gastric emptying in dogs. AB - The aim of this study was to investigate the effects and mechanisms of electroacupuncture (EA) on rectal distension (RD)-induced delay in solid gastric emptying in dogs. Gastric emptying of solids was assessed in 12 dogs chronically implanted with a duodenal cannula by collecting samples at different time points from the cannula and measuring the dried weights of the samples. Bethanechol and atropine were used to qualitatively validate the method. In separate experiments, gastric emptying of solids was measured in a number of sessions: control, RD, RD + sham-EA, RD + EA of 6 mA, RD + EA of 3 mA, and RD + EA + naloxone. The method of gastric emptying by collecting and drying gastric chyme from the duodenal cannula was found to be accurate and reliable. Using the method, we found gastric emptying to be accelerated with bethanechol (70.01 +/- 8.10% vs. 82.61 +/- 4.15%, P = 0.04, vs. control) and delayed with atropine (4.31 +/- 1.57%, P < 0.001, vs. control). RD substantially and significantly delayed gastric emptying. EA, but not sham-EA, attenuated delayed gastric emptying induced by RD (sham-EA: 48.79 +/ 9.47% vs. EA: 74.28 +/- 5.96%, P < 0.01). The effect was more potent with EA of 6 mA than EA of 3 mA and blocked by naloxone. EA is able to attenuate RD-induced delay in gastric emptying of solids, and this ameliorating effect may be mediated via the opioid pathway. EA may have a therapeutic potential for treating delayed gastric emptying attributed to lower gut distension. PMID- 21593427 TI - Cold tolerance, cold-induced hyperphagia, and nonshivering thermogenesis are normal in alpha1-AMPK-/- mice. AB - Recent studies indicate that a substantial amount of metabolically active brown adipose tissue (BAT) exists in adult humans. Given the unique ability of BAT to convert calories to heat, there is intense interest in understanding the regulation of BAT metabolism in hopes that its manipulation might be an effective way of expending excess calories. Because of the established role of AMP activated protein kinase (AMPK) as a "metabolic master switch" and its extremely high levels of activity in BAT, it was hypothesized that AMPK might play a central role in regulating BAT metabolism. To test this hypothesis, whole body alpha(1)-AMPK(-/-) (knockout) and wild-type mice were studied 1) under control (room temperature) conditions, 2) during chronic cold exposure (14 days at 4 degrees C), and 3) during acute nonshivering thermogenesis (injection of a beta(3)-adrenergic agonist). Under control conditions, loss of alpha(1)-AMPK resulted in downregulation of two important prothermogenic genes in BAT, thyrotropin-releasing hormone (-9.2-fold) and ciliary neurotrophic factor (-8.7 fold). Additionally, it caused significant upregulation of alpha(2)-AMPK activity in BAT, white adipose tissue, and liver, but not cardiac or skeletal muscle. During acute nonshivering thermogenesis and chronic cold exposure, body temperature was indistinguishable in the alpha(1)-AMPK(-/-) and wild-type mice. Similarly, the degree of cold-induced hyperphagia was identical in the two groups. We conclude that alpha(1)-AMPK does not play an obligatory role in these processes and that adaptations to chronic loss of alpha(1)-AMPK are able to compensate for its loss via several mechanisms. PMID- 21593429 TI - Evidence for a hyporesponsive limbic-hypothalamic-pituitary-adrenal axis following early-life repetitive hypoglycemia in adult male rats. AB - The developing limbic-hypothalamic-pituitary-adrenal (LHPA) axis is highly vulnerable to programming by early-life environmental factors, including exposure to synthetic glucocorticoids and nutrient deficiencies. Early-life repetitive hypoglycemia (RHG) is a common complication of insulin therapy for type-1 diabetes that may have long-term consequences in adulthood. Recent observations in a rat model of early RHG suggest persistent changes in LHPA axis function, including changes in relevant hormones and affective behaviors, which support a hyperresponsive LHPA axis. Thus, we hypothesized that early RHG would alter the expression of key genes regulating LHPA axis function in adulthood. The present study employed a rat model of insulin-induced RHG spanning postnatal days (P)24 28, a neurodevelopmental equivalent of early childhood in humans, to assess the long-term effects on mRNA levels for proteins relevant to the LHPA function and the corticosterone responses to ACTH stimulation of dispersed adrenocortical cells in vitro and restraint stress in vivo at adulthood. This early RHG model resulted in a hyporesponsive LHPA axis characterized by impaired corticosterone response, increased hippocampal glucocorticoid and mineralocorticoid receptor (GR and MR), decreased hypothalamic corticotropin-releasing hormone, increased adrenal steroidogenic-acute-regulatory protein and GR, and decreased adrenal MR, melanocortin-type-2 receptor and low-density lipoprotein receptor expression. Our findings highlight a complex environmental-gene interaction between RHG and LHPA axis during development that influences regulation of this axis in adulthood. The findings are consistent with the developmental origins of disease and underscore the influences of early-life events on the programming of a major regulatory system. PMID- 21593430 TI - Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat. AB - Contractile reserve decreases with advancing age and chronic isoproterenol (ISO) administration is a well-characterized model of cardiac hypertrophy known to impair cardiovascular function. This study evaluated whether nonsenescent, mature adult rats are more susceptible to detrimental effects of chronic ISO administration than younger adult rats. Rats received daily injections of ISO (0.1 mg/kg sc) or vehicle for 3 wk. ISO induced a greater impairment in contractile reserve [maximum of left ventricular pressure development (Delta+dP/dt(max))] in mature adult ISO-treated (MA-ISO) than in young adult ISO treated rats (YA-ISO) in response to infusions of mechanistically distinct inotropes (digoxin, milrinone; 20-200 MUl.kg(-1).min(-1)), while basal and agonist-induced changes in heart rate and systolic arterial pressure (SAP) were not different across groups. ISO decreased expression of the calcium handling protein, sarco(endo)plasmic reticulum Ca(2+)-ATPase-2a, in MA-ISO compared with YA, YA-ISO, and MA rats. Chronic ISO also induced greater increases in cardiac hypertrophy [left ventricular (LV) index: 33 +/- 3 vs. 22 +/- 5%] and caspase-3 activity (34 vs. 5%) in MA-ISO relative to YA-ISO rats. Moreover, beta-myosin heavy chain (beta-MHC) and atrial natriuretic factor (ANF) mRNA expression was significantly elevated in MA-ISO. These results demonstrate that adult rats develop greater impairments in systolic performance than younger rats when exposed to chronic catecholamine excess. Reduced contractile reserve may result from calcium dysregulation, increased caspase-3 activity, or increased beta-MHC and ANF expression. Although several studies report age-related declines in systolic performance in older and senescent animals, the present study demonstrates that catecholamine excess induces reductions in systolic performance significantly earlier in life. PMID- 21593431 TI - Hypoxia augments muscle sympathetic neural response to leg cycling. AB - It was demonstrated that acute hypoxia increased muscle sympathetic nerve activity (MSNA) by using a microneurographic method at rest, but its effects on dynamic leg exercise are unclear. The purpose of this study was to clarify changes in MSNA during dynamic leg exercise in hypoxia. To estimate peak oxygen uptake (Vo(2 peak)), two maximal exercise tests were conducted using a cycle ergometer in a semirecumbent position in normoxia [inspired oxygen fraction (Fi(O(2)) = 0.209] and hypoxia (Fi(O(2)) = 0.127). The subjects performed four submaximal exercise tests; two were MSNA trials in normoxia and hypoxia, and two were hematological trials under each condition. In the submaximal exercise test, the subjects completed two 15-min exercises at 40% and 60% of their individual Vo(2 peak) in normoxia and hypoxia. During the MSNA trials, MSNA was recorded via microneurography of the right median nerve at the elbow. During the hematological trials, the subjects performed the same exercise protocol as during the MSNA trials, but venous blood samples were obtained from the antecubital vein to assess plasma norepinephrine (NE) concentrations. MSNA increased at 40% Vo(2 peak) exercise in hypoxia, but not in normoxia. Plasma NE concentrations did not increase at 40% Vo(2 peak) exercise in hypoxia. MSNA at 40% and 60% Vo(2 peak) exercise were higher in hypoxia than in normoxia. These results suggest that acute hypoxia augments muscle sympathetic neural activation during dynamic leg exercise at mild and moderate intensities. They also suggest that the MSNA response during dynamic exercise in hypoxia could be different from the change in plasma NE concentrations. PMID- 21593432 TI - Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer's disease-like pathology in amyloid precursor protein-transgenic mice. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) has neuroprotective and neurotrophic properties and is a potent alpha-secretase activator. As PACAP peptides and their specific receptor PAC1 are localized in central nervous system areas affected by Alzheimer's disease (AD), this study aims to examine the role of the natural peptide PACAP as a valuable approach in AD therapy. We investigated the effect of PACAP in the brain of an AD transgenic mouse model. The long-term intranasal daily PACAP application stimulated the nonamyloidogenic processing of amyloid precursor protein (APP) and increased expression of the brain-derived neurotrophic factor and of the antiapoptotic Bcl-2 protein. In addition, it caused a strong reduction of the amyloid beta-peptide (Abeta) transporter receptor for advanced glycation end products (RAGE) mRNA level. PACAP, by activation of the somatostatin-neprilysin cascade, also enhanced expression of the Abeta-degrading enzyme neprilysin in the mouse brain. Furthermore, daily PAC1-receptor activation via PACAP resulted in an increased mRNA level of both the PAC1 receptor and its ligand PACAP. Our behavioral studies showed that long-term PACAP treatment of APP[V717I]-transgenic mice improved cognitive function in animals. Thus, nasal application of PACAP was effective, and our results indicate that PACAP could be of therapeutic value in treating AD. PMID- 21593433 TI - Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson's disease models. AB - Parkinson's disease (PD) is a progressive age-related movement disorder that results primarily from the selective loss of midbrain dopaminergic (DA) neurons. Symptoms of PD can be induced by genetic mutations or by DA neuron-specific toxins. A specific ablation of an essential factor controlling ribosomal RNA transcription, TifIa, in adult mouse DA neurons represses mTOR signaling and leads to progressive neurodegeneration and PD-like phenotype. Using an inducible Cre system in adult mice, we show here that the specific ablation of Pten in adult mouse DA neurons leads to activation of mTOR pathway and is neuroprotective in genetic (TifIa deletion) and neurotoxin-induced (MPTP or 6OHDA) mouse models of PD. Adult mice with DA neuron-specific Pten deletion exhibit elevated expression of tyrosine hydroxylase, a rate-limiting enzyme in the dopamine biosynthesis pathway, associated with increased striatal dopamine content, and increased mRNA levels of Foxa2, Pitx3, En1, Nurr1, and Lmx1b-the essential factors for maintaining physiological functions of adult DA neurons. Pten deletion attenuates the loss of tyrosine hydroxylase-positive cells after 6OHDA treatment, restores striatal dopamine in TifIa-knockout and MPTP-treated mice, and rescues locomotor impairments caused by TifIa loss. Inhibition of Pten dependent functions in adult DA neurons may represent a promising PD therapy. PMID- 21593434 TI - Decrease in antibody somatic hypermutation frequency under extreme, extended spaceflight conditions. AB - Somatic hypermutation diversifies antibody binding sites by introducing point mutations in the variable domains of rearranged immunoglobulin genes. In this study, we analyzed somatic hypermutation in variable heavy-chain (VH) domains of specific IgM antibodies of the urodele amphibian Pleurodeles waltl, immunized either on Earth or onboard the Mir space station. To detect somatic hypermutation, we aligned the variable domains of IgM heavy-chain transcripts with the corresponding VH gene. We also quantified NF-kappaB and activation induced cytidine deaminase transcripts. Results were compared with those obtained using control animals immunized on Earth. Our data show that, as in most species of ectotherms, somatic hypermutation in P. waltl exhibits a mutational bias toward G and C bases. Furthermore, we show for the first time that somatic hypermutation occurs in space following immunization but at a lower frequency. This decrease is not due to a decrease in food intake or of the B-cell receptor/antigen interaction or to the absence of the germinal center-associated nuclear protein. It likely results from the combination of several spaceflight associated changes, such as the severe reduction in T-cell activation, important perturbations of the cytoskeleton, and changes in the distribution of lymphocyte subpopulations and adhesion molecule expression. PMID- 21593435 TI - Perindopril, a centrally active angiotensin-converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer's disease. AB - The purpose of this work was to test whether brain-penetrating angiotensin converting enzyme (ACE) inhibitors (e.g., perindopril), as opposed to non-brain penetrating ACE inhibitors (e.g., enalapril and imidapril), may reduce the cognitive decline and brain injury in Alzheimer's disease (AD). We first compared the effect of perindopril, enalapril, and imidapril on cognitive impairment and brain injury in a mouse model of AD induced by intracerebroventricular (i.c.v.) injection of amyloid-beta (Abeta)1-40. Perindopril, with significant inhibition of hippocampal ACE, significantly prevented cognitive impairment in this AD mouse model. This beneficial effect was attributed to the suppression of microglia/astrocyte activation and the attenuation of oxidative stress caused by iNOS induction and extracellular superoxide dismutase down-regulation. In contrast, neither enalapril nor imidapril prevented cognitive impairment and brain injury in this AD mouse. We next examined the protective effects of perindopril on cognitive impairment in PS2APP-transgenic mice overexpressing Abeta in the brain. Perindopril, without affecting brain Abeta deposition, significantly suppressed the increase in hippocampal ACE activity and improved cognition in PS2APP-transgenic mice, being associated with the suppression of hippocampal astrocyte activation and attenuation of superoxide. Our data demonstrated that the brain-penetrating ACE inhibitor perindopril, as compared to non-brain-penetrating ACE inhibitors, protected against cognitive impairment and brain injury in experimental AD models. PMID- 21593436 TI - Subcortical vascular dementia exists! PMID- 21593437 TI - Identification of pure subcortical vascular dementia using 11C-Pittsburgh compound B. AB - BACKGROUND: Subcortical vascular dementia (SVaD) is considered the most common type of vascular dementia and often follows a slowly progressive course, simulating Alzheimer disease (AD). Whether the progressive cognitive decline is associated with pure SVaD or concomitant AD remains unknown. The purpose of this study was to determine what proportion of patients with SVaD lack abnormal amyloid imaging, and to examine differences in the clinical or MRI features between subjects with SVaD with cortical amyloid deposition and those without. METHODS: We measured brain amyloid deposition using (11)C-Pittsburgh compound B (PiB) PET in 45 patients (men: women = 19:26; mean age 74.2 +/- 7.6 years) with SVaD. They all met DSM-IV criteria for vascular dementia and had severe white matter high signal intensities without territorial infarction or macrohemorrhage on MRI. RESULTS: Thirty-one (68.9%) of 45 patients with SVaD were negative for cortical PiB binding. There was significant difference between (11)C-PiB-positive and (11)C-PiB-negative groups in terms of age (79.5 vs 71.9 years), Mini-Mental State Examination score (18.6 vs 22.6), the number of lacunes (3.9 vs 9.0), and the visual rating scale of hippocampal atrophy (3.1 vs 2.3). The neuropsychological assessments revealed that patients with (11)C-PiB-negative SVaD performed better on the delayed recall of both the verbal and visual memory test than did those with (11)C-PiB-positive scan. CONCLUSION: SVaD without abnormal amyloid imaging was more common than expected. Patients with SVaD with and without abnormal amyloid imaging differed in clinical and MRI features, although there was considerable overlap. PMID- 21593438 TI - Probing consciousness with event-related potentials in the vegetative state. AB - OBJECTIVE: Probing consciousness in noncommunicating patients is a major medical and neuroscientific challenge. While standardized and expert behavioral assessment of patients constitutes a mandatory step, this clinical evaluation stage is often difficult and doubtful, and calls for complementary measures which may overcome its inherent limitations. Several functional brain imaging methods are currently being developed within this perspective, including fMRI and cognitive event-related potentials (ERPs). We recently designed an original rule extraction ERP test that is positive only in subjects who are conscious of the long-term regularity of auditory stimuli. METHODS: In the present work, we report the results of this test in a population of 22 patients who met clinical criteria for vegetative state. RESULTS: We identified 2 patients showing this neural signature of consciousness. Interestingly, these 2 patients showed unequivocal clinical signs of consciousness within the 3 to 4 days following ERP recording. CONCLUSIONS: Taken together, these results strengthen the relevance of bedside neurophysiological tools to improve diagnosis of consciousness in noncommunicating patients. PMID- 21593439 TI - Comment: Costs and consequences of atraumatic dural puncture needles. PMID- 21593441 TI - White matter degeneration in normal and pathologic aging: the pattern matters. PMID- 21593440 TI - Diffusion tensor imaging and cognitive function in older adults with no dementia. AB - OBJECTIVE: To determine the patterns of diffusivity associated with cognitive domain functions in older adults without dementia. METHODS: We studied older adults without dementia (n = 220) who underwent neuropsychometric testing and a diffusion tensor imaging (DTI) examination at 3 T in a cross-sectional study. Memory, language, attention/executive function, and visual-spatial processing domains were assessed within 4 months of the MRI examination. A fluid-attenuated inversion recovery-based DTI sequence that enabled uncontaminated cortical diffusion measurements was performed. Associations between cortical mean diffusivity (MD) and cognitive function were tested using voxel-based regression analysis. Association between tract diffusivity and cognitive function was tested with regions of interest drawn on color-coded fractional anisotropy (FA) maps. RESULTS: Memory function was associated with the medial temporal lobe cortical MD on voxel-based analysis (p < 0.001, corrected for multiple comparisons), and inferior longitudinal fasciculus and posterior and anterior cingulum FA on tract based analysis (p < 0.001). Language function was associated with the left temporal lobe cortical MD (p < 0.001, corrected for multiple comparisons), inferior longitudinal fasciculus, fornix, and posterior cingulum FA (p < 0.05). Attention and executive function was associated with the posterior and anterior cingulum FA, and visual-spatial function was associated with posterior cingulum FA (p < 0.01). CONCLUSION: Specific cognitive domain functions are associated with distinct patterns of cortical and white matter diffusivity in elderly with no dementia. Posterior cingulum tract FA was associated with all 4 cognitive domain functions, in agreement with the hypothesis that the posterior cingulate cortex is the main connectivity hub for cognitive brain networks. Microstructural changes identified on DTI may be associated with neurodegenerative pathologies underlying cognitive changes in older adults without dementia. PMID- 21593443 TI - Creating a 21st century global health agenda: the General Assembly of the United Nations high level meeting on non-communicable diseases. PMID- 21593442 TI - Headache rate and cost of care following lumbar puncture at a single tertiary care hospital. AB - BACKGROUND: American Academy of Neurology guidelines recommend the use of noncutting needles because of lower rates of headache following lumbar puncture in randomized trials. We sought to determine the rate of headache using cutting needles and the potential cost savings of switching to noncutting needles. METHODS: We retrospectively reviewed the charts of all patients who had a lumbar puncture in the outpatient neurology clinic at a single institution between January 2004 and December 2005. Outcome data included occurrence of headache, back pain, or epidural hematomas within 2 weeks of the procedure. Costs associated with the use of the current system were compared with the projected costs of switching to a noncutting needle system. RESULTS: A total of 274 patients underwent lumbar puncture (62% women, mean age 53 +/- 17 years, average weight 178 +/- 43 pounds). Of these, 38 (14%) had a post-lumbar puncture headache. Eight patients (3%) reported back pain. No patients had an epidural hematoma. Twelve patients were admitted for a total of 18 hospital days, mainly for headache. Predictors of headache were younger age and no prior aspirin use. The rate of headache associated with the noncutting needle according to published literature is 4%. The estimated cost savings would have been approximately $20,000 per year (or approximately $73 per person). CONCLUSIONS: In this single institution study, use of a noncutting needle would have potentially been associated with less adverse events and less cost. Further studies are warranted, including the possibility of premedication with aspirin. PMID- 21593444 TI - Long-term efficacy of deferasirox in preventing cardiovascular complications in the iron-overloaded gerbil. AB - Iron-induced cardiovascular disease is the leading cause of death in iron overloaded patients. Deferasirox is a novel tridentate oral chelator that exhibits a half-life suitable for once-daily dosing; however, little is known regarding the effectiveness of this agent in preventing iron-induced cardiovascular disease. Adult male Mongolian gerbils were randomly divided into 3 groups: control, iron overload, and iron overload followed by deferasirox treatment. Iron-overloaded animals received iron dextran 100 mg/kg intraperitoneally (ip)/5 days for 10 weeks, while deferasirox was given 100 mg/kg per d orally (po) for 9 months post iron loading. Cardiac and aortic iron levels were determined by inductively coupled plasma atomic emission spectrometry. Gerbil electro- and echocardiograms were obtained in anesthetized animals at regular intervals. Compared to control animals, iron concentration was 3.3- and 2.4-fold higher in iron-overloaded heart and aorta, respectively (P < .05). Deferasirox treatment reduced cardiac and aortic iron levels by 32% and 35%, respectively (P < .05). These results were consistent with the decrease in cellular iron deposition observed with Prussian Blue iron staining. Iron overloaded gerbils were found to exhibit frequent arrhythmias including premature ventricular contractions, supraventricular tachycardia, and recurrent ventricular tachycardia. In addition, echocardiographic assessment demonstrated iron overload associated increase in left ventricular dimensions including left ventricular posterior wall dimension (LVPWd: 49%), left ventricular internal dimension (LVIDd: 26%), and left ventricular septum thickness (LVSd: 42%). These parameters were significantly reduced with deferasirox treatment (LVPWd: 23%, LVIDd: 24%, and LVSd: 27%). Iron overload was also associated with reduced ejection fraction (EF: by 30%) and fractional shortening (FS: by 23%) in comparison with controls (P < .05). With deferasirox treatment, these values were higher (EF: by 30%, FS: by 28%) compared to iron-overloaded group. These findings suggest that deferasirox may be useful for attenuating iron-induced changes in cardiac structure and function. PMID- 21593445 TI - Constitutive ERK activity induces downregulation of tristetraprolin, a major protein controlling interleukin8/CXCL8 mRNA stability in melanoma cells. AB - Most melanoma cells are characterized by the V600E mutation in B-Raf kinase. This mutation leads to increased expression of interleukin (CXCL8), which plays a key role in cell growth and angiogenesis. Thus CXCL8 appears to be an interesting therapeutic target. Hence, we performed vaccination of mice with GST-CXCL8, which results in a reduced incidence of syngenic B16 melanoma cell xenograft tumors. We next addressed the molecular mechanisms responsible for aberrant CXCL8 expression in melanoma. The CXCL8 mRNA contains multiples AU-rich sequences (AREs) that modulate mRNA stability through the binding of tristetraprolin (TTP). Melanoma cell lines express very low TTP levels. We therefore hypothesized that the very low endogenous levels of TTP present in different melanoma cell lines might be responsible for the relative stability of CXCL8 mRNAs. We show that TTP is actively degraded by the proteasome and that extracellular-regulated kinase inhibition results in TTP accumulation. Conditional expression of TTP in A375 melanoma cells leads to CXCL8 mRNA destabilization via its 3' untranslated regions (3'-UTR), and TTP overexpression reduces its production. In contrast, downregulation of TTP by short hairpin RNA results in upregulation of CXCL8 mRNA. Maintaining high TTP levels in melanoma cells decreases cell proliferation and autophagy and induces apoptosis. Sorafenib, a therapeutic agent targeting Raf kinases, decreases CXCL8 expression in melanoma cells through reexpression of TTP. We conclude that loss of TTP represents a key event in the establishment of melanomas through constitutive expression of CXCL8, which constitutes a potent therapeutic target. PMID- 21593446 TI - Inhibition of suicidal erythrocyte death by blebbistatin. AB - Blebbistatin, a myosin II inhibitor, interferes with myosin-actin interaction and microtubule assembly. By influencing cytoskeletal dynamics blebbistatin counteracts apoptosis of several types of nucleated cells. Even though lacking nuclei and mitochondria, erythrocytes may undergo suicidal cell death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Triggers of eryptosis include energy depletion and osmotic shock, which enhance cytosolic Ca(2+) activity with subsequent Ca(2+)-sensitive cell shrinkage and cell membrane scrambling. The present study explored the effect of blebbistatin on eryptosis. Cell membrane scrambling was estimated from binding of annexin V to phosphatidylserine at the erythrocyte surface, cell volume from forward scatter in fluorescence-activated cell sorting analysis and cytosolic Ca(2+) concentration from Fluo3 fluorescence. Exposure to blebbistatin on its own (1-50 MUM) did not significantly modify cytosolic Ca(2+) concentration, forward scatter, or annexin V binding. Glucose depletion (48 h) was followed by a significant increase of Fluo3 fluorescence and annexin V binding, effects significantly blunted by blebbistatin (Fluo3 fluorescence >= 25 MUM, annexin V binding >= 10 MUM). Osmotic shock (addition of 550 mM sucrose) again significantly increased Fluo3 fluorescence and annexin binding, effects again significantly blunted by blebbistatin (Fluo3 fluorescence >= 25 MUM, annexin V binding >= 25 MUM). The present observations disclose a novel effect of blebbistatin, i.e., an influence on Ca(2+) entry and suicidal erythrocyte death following energy depletion and osmotic shock. PMID- 21593447 TI - Ion channels and transporters in cancer. 4. Remodeling of Ca(2+) signaling in tumorigenesis: role of Ca(2+) transport. AB - The Ca(2+) signal has major roles in cellular processes important in tumorigenesis, including migration, invasion, proliferation, and apoptotic sensitivity. New evidence has revealed that, aside from altered expression and effects on global cytosolic free Ca(2+) levels via direct transport of Ca(2+), some Ca(2+) pumps and channels are able to contribute to tumorigenesis via mechanisms that are independent of their ability to transport Ca(2+) or effect global Ca(2+) homeostasis in the cytoplasm. Here, we review some of the most recent studies that present evidence of altered Ca(2+) channel or pump expression in tumorigenesis and discuss the importance and complexity of localized Ca(2+) signaling in events critical for tumor formation. PMID- 21593448 TI - Enhanced survival of skeletal muscle myoblasts in response to overexpression of cold shock protein RBM3. AB - Cold-inducible RNA-binding protein (RBM3) is suggested to be involved in the regulation of skeletal muscle mass. Cell death pathways are implicated in the loss of muscle mass and therefore the role of RBM3 in muscle apoptosis in C(2)C(12) myoblasts was investigated in this study. RBM3 overexpression was induced by either cold shock (32 degrees C exposure for 6 h) or transient transfection with a myc-tagged RBM3 expression vector. Cell death was induced by H(2)O(2) (1,000 MUM) or staurosporine (StSp, 5 MUM), and it was shown that cold shock and RBM3 transfection were associated with attenuation of morphological changes and an increase in cell viability compared with normal temperature or empty vector, respectively. No changes in proliferation were observed with either cold shock or RBM3 transfection. DNA fragmentation was not increased in response to H(2)O(2), and a cell permeability assay indicated that cell death in response to H(2)O(2) is more similar to necrosis than apoptosis. RBM3 overexpression reduced apoptosis and the collapse of the membrane potential in response to StSp. Moreover, the increase in caspase-3, -8, and -9 activities in response to StSp was returned to control levels with RBM3 overexpression. These results indicate that increased RBM3 expression decreases muscle cell necrosis as well as apoptosis and therefore RBM3 could potentially serve as an intervention for the loss of muscle cell viability during muscle atrophy and muscle diseases. PMID- 21593449 TI - SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization. AB - The secretin-stimulated human pancreatic duct secretes HCO(3)(-)-rich fluid essential for normal digestion. Optimal stimulation of pancreatic HCO(3)(-) secretion likely requires coupled activities of the cystic fibrosis transmembrane regulator (CFTR) anion channel and apical SLC26 Cl(-)/HCO(3)(-) exchangers. However, whereas stimulated human and guinea pig pancreatic ducts secrete ~140 mM HCO(3)(-) or more, mouse and rat ducts secrete ~40-70 mM HCO(3)(-). Moreover, the axial distribution and physiological roles of SLC26 anion exchangers in pancreatic duct secretory processes remain controversial and may vary among mammalian species. Thus the property of high HCO(3)(-) secretion shared by human and guinea pig pancreatic ducts prompted us to clone from guinea pig pancreatic duct cDNAs encoding Slc26a3, Slc26a6, and Slc26a11 polypeptides. We then functionally characterized these anion transporters in Xenopus oocytes and human embryonic kidney (HEK) 293 cells. In Xenopus oocytes, gpSlc26a3 mediated only Cl( )/Cl(-) exchange and electroneutral Cl(-)/HCO(3)(-) exchange. gpSlc26a6 in Xenopus oocytes mediated Cl(-)/Cl(-) exchange and bidirectional exchange of Cl(-) for oxalate and sulfate, but Cl(-)/HCO(3)(-) exchange was detected only in HEK 293 cells. gpSlc26a11 in Xenopus oocytes exhibited pH-dependent Cl(-), oxalate, and sulfate transport but no detectable Cl(-)/HCO(3)(-) exchange. The three gpSlc26 anion transporters exhibited distinct pharmacological profiles of (36)Cl( ) influx, including partial sensitivity to CFTR inhibitors Inh-172 and GlyH101, but only Slc26a11 was inhibited by PPQ-102. This first molecular and functional assessment of recombinant SLC26 anion transporters from guinea pig pancreatic duct enhances our understanding of pancreatic HCO(3)(-) secretion in species that share a high HCO(3)(-) secretory output. PMID- 21593450 TI - COOH-terminal truncation of flightin decreases myofilament lattice organization, cross-bridge binding, and power output in Drosophila indirect flight muscle. AB - The indirect flight muscle (IFM) of insects is characterized by a near crystalline myofilament lattice structure that likely evolved to achieve high power output. In Drosophila IFM, the myosin rod binding protein flightin plays a crucial role in thick filament organization and sarcomere integrity. Here we investigate the extent to which the COOH terminus of flightin contributes to IFM structure and mechanical performance using transgenic Drosophila expressing a truncated flightin lacking the 44 COOH-terminal amino acids (fln(DeltaC44)). Electron microscopy and X-ray diffraction measurements show decreased myofilament lattice order in the fln(DeltaC44) line compared with control, a transgenic flightin-null rescued line (fln(+)). fln(DeltaC44) fibers produced roughly 1/3 the oscillatory work and power of fln(+), with reduced frequencies of maximum work (123 Hz vs. 154 Hz) and power (139 Hz vs. 187 Hz) output, indicating slower myosin cycling kinetics. These reductions in work and power stem from a slower rate of cross-bridge recruitment and decreased cross-bridge binding in fln(DeltaC44) fibers, although the mean duration of cross-bridge attachment was not different between both lines. The decreases in lattice order and myosin kinetics resulted in fln(DeltaC44) flies being unable to beat their wings. These results indicate that the COOH terminus of flightin is necessary for normal myofilament lattice organization, thereby facilitating the cross-bridge binding required to achieve high power output for flight. PMID- 21593451 TI - Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells. AB - CD73-derived adenosine acts as potent inhibitor of inflammation, and regulatory T cells (Treg) have been shown to express CD73 as a novel marker. This study explored the role of endogenously formed adenosine in modulating NF-kappaB activity and cytokine/chemokine release from murine Treg and effector T cells (Teff) including key enzymes/purinergic receptors of extracellular ATP catabolism. Stimulating murine splenocytes and CD4(+) T cells with anti-CD3/anti CD28 significantly upregulated activated NF-kappaB in CD73(-/-) T cells (wild type: 4.36 +/- 0.21; CD73(-/-): 6.58 +/- 0.75; n = 4; P = 0.029). This was associated with an augmented release of proinflammatory cytokines IL-2, TNF alpha, and IFN-gamma. Similar changes were observed with the CD73 inhibitor APCP (50 MUM) on NF-kappaB and IFN-gamma in wild-type CD4(+) T-cells. Treatment of stimulated CD4(+) T-cells with adenosine (25 MUM) potently reduced IFN-gamma release which is mediated by adenosine A2a receptors (A2aR). AMP (50 MUM) also reduced cytokine release which was not inhibited by APCP. In Teff, A2aR activation (CGS21680) potently inhibited the release of IL-1, IL-2, IL-3, IL-4, IL-12, IL-13, IFN-gamma, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), CCL3, and CCL4. However, in Treg, CGS21680 did not alter cytokine/chemokine release. In summary, CD73-derived adenosine tonically inhibits active NF-kappaB in CD4(+) T-cells, thereby modulating the release of a broad spectrum of proinflammatory cytokines and chemokines. Downregulation of P2X7 and upregulation of CD73 in Treg after antigenic stimulation may be an important mechanism to maintain the ability of Treg to generate immunosuppressive adenosine. PMID- 21593452 TI - Differential modulation of the molecular dynamics of the type IIa and IIc sodium phosphate cotransporters by parathyroid hormone. AB - The kidney is a key regulator of phosphate homeostasis. There are two predominant renal sodium phosphate cotransporters, NaPi2a and NaPi2c. Both are regulated by parathyroid hormone (PTH), which decreases the abundance of the NaPi cotransporters in the apical membrane of renal proximal tubule cells. The time course of PTH-induced removal of the two cotransporters from the apical membrane, however, is markedly different for NaPi2a compared with NaPi2c. In animals and in cell culture, PTH treatment results in almost complete removal of NaPi2a from the brush border (BB) within 1 h whereas for NaPi2c this process in not complete until 4 to 8 h after PTH treatment. The reason for this is poorly understood. We have previously shown that the unconventional myosin motor myosin VI is required for PTH-induced removal of NaPi2a from the proximal tubule BB. Here we demonstrate that myosin VI is also necessary for PTH-induced removal of NaPi2c from the apical membrane. In addition, we show that, while at baseline the two cotransporters have similar diffusion coefficients within the membrane, after PTH addition the diffusion coefficient for NaPi2a initially exceeds that for NaPi2c. Thus NaPi2c appears to remain "tethered" in the apical membrane for longer periods of time after PTH treatment, accounting, at least in part, for the difference in response times to PTH of NaPi2a versus NaPi2c. PMID- 21593454 TI - Another important biological function for the aryl hydrocarbon receptor. PMID- 21593455 TI - Vascular calcification: harder than it looks. PMID- 21593453 TI - PDGF-dependent regulation of regulator of G protein signaling-5 expression and vascular smooth muscle cell functionality. AB - Regulator of G protein signaling (RGS) proteins, and notably members of the RGS R4 subfamily, control vasocontractility by accelerating the inactivation of Galpha-dependent signaling. RGS5 is the most highly and differently expressed RGS R4 subfamily member in arterial smooth muscle. Expression of RGS5 first appears in pericytes during development of the afferent vascular tree, suggesting that RGS5 is a good candidate for a regulator of arterial contractility and, perhaps, for determining the mass of the smooth muscle coats required to regulate blood flow in the branches of the arterial tree. Consistent with this hypothesis, using cultured vascular smooth muscle cells (VSMCs), we demonstrate RGS5 overexpression inhibits G protein-coupled receptor (GPCR)-mediated hypertrophic responses. The next objective was to determine which physiological agonists directly control RGS5 expression in VSMCs. GPCR agonists failed to directly regulate RGS5 mRNA expression; however, platelet-derived growth factor (PDGF) acutely represses expression. Downregulation of RGS5 results in the induction of migration and the activation of the GPCR-mediated signaling pathways. This stimulation leads to the activation of mitogen-activated protein kinases directly downstream of receptor stimulation, and ultimately VSMC hypertrophy. These results demonstrate that RGS5 expression is a critical mediator of both VSMC contraction and potentially, arterial remodeling. PMID- 21593456 TI - High-sensitivity C-reactive protein, obesity, and subclinical atherosclerosis: implications of JUPITER from the MESA study. PMID- 21593457 TI - Intravital fluorescence microscopy improves thrombosis phenotype scoring in mice. PMID- 21593458 TI - No superoxide--no stress?: Nox4, the good NADPH oxidase! PMID- 21593459 TI - Bone marrow-derived smooth muscle cells are breaking bad in atherogenesis. PMID- 21593461 TI - Histological and immunohistochemical study of pars tensa retraction pocket. AB - OBJECTIVE: To study the histological and proliferation characteristics of the pars tensa retraction pocket. To investigate the hypothesis that such retraction pockets may demonstrate breaks in the epithelial basement membrane. STUDY DESIGN: Prospective evaluation. Fifty stage II-IV surgically resected retraction pockets. SETTING: Tertiary care academic hospital. METHODS: Paraffin sections stained with hematoxylin and eosin. Basement membrane evaluation by Periodic acid-Schiff (PAS) and silver-methenamine (SM). Evaluation of cellular proliferation by immunohistochemistry (MIB-1 score). RESULTS: Following are findings noted as frequent but not invariable in pars tensa retraction pockets: (1) subepithelial chronic inflammation (86%), (2) proliferation and hyperkeratinization of the outer epithelial layer, (3) epithelial cones with proliferating cells (increased MIB-1 score) in the basal epithelial layer (39%), (4) loss of the middle double collagen layer (71%), and (5) loss of the inner mucosal layer (33%). Inflammation and cellular proliferation were noted as ubiquitous among all grades. A trend was noted along progressive grades of retraction (II-IV) for an increasing incidence of basal epithelial cones, middle collagen layer loss, and inner mucosal layer loss. Focal loss of basement membrane was noted in several cases with PAS staining, but further staining with the SM in all such cases indicated the basement membrane to be intact. CONCLUSION: A continuum of progressive histological features akin to cholesteatoma is noted with increasing grades of retraction (II-IV). Breach of the basement membrane was recently reported as a feature of cholesteatoma but is not a feature of retraction. The near universal presence of inflammation as noted suggests an etiological role. PMID- 21593460 TI - Implementation and testing of research infrastructure for practice-based research in hearing and communication disorders. AB - OBJECTIVE: To describe site capability and experience of the CHEER network (Creating Healthcare Excellence through Education and Research) to rapidly collect descriptive data on patients with tinnitus and dizziness visiting participating CHEER sites. STUDY DESIGN: Prospective observational data collection study over 6 months. SETTING: Twenty one community otology and otolaryngology practices in the United States. SUBJECTS AND METHODS: As proof of concept, a data collection study was developed for patients with tinnitus and dizziness (presenting with or without associated migraine) through a collaborative effort of the CHEER principal investigator (PI) and co-PIs. The 9 page questionnaire included validated instruments and additional patient- and physician-reported information. Information was captured electronically via REDCap by each site's CHEER research coordinator. Site initiation, data entry rates, and research coordinator feedback were also collected. RESULTS: Of the 21 CHEER sites, 15 participated in the study. Nine sites entered a patient within the first 31 days of study initiation, and all 15 sites were entering patients and corresponding clinical data within 72 days. During the 6-month study, 1044 patients were entered into the REDCap database. Research coordinator engagement was a major driver for success, whereas time and resources were deterrents. Incentives included altruism, professional development, and future financial opportunities. CONCLUSION: The CHEER research network has significant capability and infrastructure to collect prospective data in a practice-based environment. Research coordinator engagement undergirds network success; however, future efforts will cultivate stronger collaboration of the coordinator and site PI. Central coordination of practice-based research through a hub and spoke concept can be successful. PMID- 21593462 TI - Physiological assessment of active middle ear implant coupling to the round window in Chinchilla lanigera. AB - OBJECTIVE: To study the effects of various active middle ear implant loading parameters on round window stimulation in an animal model. STUDY DESIGN: Physiological measurements of the cochlear microphonic and stapes velocity were made from active middle ear implant-generated sinusoidal stimuli with controlled changes in loading parameters. SETTING: Prospective study at an academic research institution. SUBJECTS AND METHODS: Cochlear microphonic and stapes velocities (H(EV)) were measured in 6 study subjects (Chinchilla lanigera) in response to active middle ear implant (Otologics MET, Boulder, Colorado) round window stimulation with assessment of effects of varying parameters of loading pressure, interposed connective tissue, and angle of stimulation with respect to the round window membrane. RESULTS: The measured performance variabilities in repeated applications of the active middle ear implant to the round window were 2.5 dB and 5.0 dB for H(EV) and cochlear microphonic thresholds, respectively. Loading pressure applied to the round window (51-574 dynes) and angle of approach (+/-30 degrees with respect to coronal plane) did not have a significant effect on cochlear microphonic thresholds or H(EV). Significant improvements in cochlear microphonic thresholds and H(EV) were observed for interposed connective tissue regardless of tissue type. CONCLUSION: Variability in performance due to repeated couplings of the active middle ear implant to the round window is small and reproducible. Interposition of connective tissue significantly improves vibration energy transfer to the cochlea. Neither changes in loading pressure nor angle of stimulation of the round window affected active middle ear implant performance. PMID- 21593463 TI - Dysphagia and quality of life may improve with mometasone treatment in patients with eosinophilic esophagitis: a pilot study. AB - OBJECTIVE: The treatment of adult patients with eosinophilic esophagitis remains challenging. The aim was to assess dysphagia and health-related quality of life (HRQL) using validated scales and questionnaires before and after treatment with mometasone furoate. STUDY DESIGN: Case series with planned data collection. SETTING: University hospital and secondary referral hospital. SUBJECTS AND METHODS: Newly diagnosed patients with eosinophilic esophagitis were included and given 200 ug of orally administered topical mometasone furoate 4 times daily. Questionnaires incorporating the Watson Dysphagia Scale (WDS), the European Organization for Research and Treatment of Cancer Quality of Life-Oesophageal Module 18 (EORTC QLQ-OES18), and the Short Form-36 (SF-36) were completed before the initiation of treatment and after 2 months of treatment. RESULTS: Thirty-one consecutive patients (23 men; mean age, 45 years; range, 18-89 years) completed the trial. At inclusion, the mean scores of the WDS, the EORTC QLQ-OES18 dysphagia scale, the eating scale and choking item, and the global health and social functioning dimensions of the SF-36 were 21.3, 20.4, 35.0, 38.6, 71.1, and 82.3, respectively. Posttreatment, these scores improved to 8.9 (P < .0001), 4.6 (P < .00001), 17.8 (P < .001), 16.0 (P < .01), 76.1 (P < .05), and 91.9 (P = .0001), respectively. Except for 1 case of oral candidiasis, no significant side effects were reported. CONCLUSION: The dysphagia and impaired HRQL found in untreated patients with eosinophilic esophagitis improved significantly after 2 months of mometasone furoate treatment. A randomized placebo-controlled trial is warranted to assess causality. The scales and questionnaires used are sensitive instruments appropriate for symptom surveillance in individuals with eosinophilic esophagitis. PMID- 21593464 TI - Repair of large traumatic tympanic membrane perforation with a Steri-Strips patch. AB - OBJECTIVE: To investigate the effects of the Steri-Strips patch (3M) on the treatment of large traumatic tympanic membrane perforations (TMP). STUDY DESIGN: Prospective, randomized, controlled. SETTING: Tertiary university hospital. SUBJECTS AND METHODS: A randomized prospective analysis was performed between February 2009 and January 2011 for the treatment of traumatic TMP larger than 50% of the entire tympanic membrane. The results of closure rate, closure time, hearing gain, and rate of otorrhea between conservative observation, paper patching, and Steri-Strips patching groups were compared. RESULTS: In total, 87 patients were analyzed in this study. The closure rates of the perforations in the Steri-Strips patching, paper patching, and observation groups were 93.3%, 84.2%, and 78.9%, respectively. There was no statistically significant difference in tympanic membrane closure rate between the 3 groups. The Steri-Strips technique decreased the need for repeat procedures. Overall, the Steri-Strips and paper patching groups showed shorter healing times compared with the observation group. However, there was an increased rate of otorrhea in the Steri-Strips group compared with the observation group. CONCLUSION: Steri-Strips patching reduced the healing time and need for repeat procedures in patients with large traumatic TMPs. However, the occurrence of otorrhea was significantly more common in patients treated with the Steri-Strips technique. PMID- 21593465 TI - eHIV-STI update. PMID- 21593466 TI - The sexual health of migrants from central and eastern European countries in London: new methods and new data. PMID- 21593467 TI - Capture-recapture methods and respondent-driven sampling: their potential and limitations. PMID- 21593468 TI - Information for action: a method to inform HIV shared care planning in primary care at the PCT level. PMID- 21593469 TI - Fourth generation point of care testing for HIV: validation in an HIV-positive population. PMID- 21593470 TI - Sexual and HIV risk behaviour in central and eastern European migrants in London. AB - BACKGROUND: Accession of 10 Central and Eastern European (CEE) countries to the E.U. resulted in the largest migratory influx in peacetime British history. No information exists on the sexual behaviour of CEE migrants within the U.K. The aim of this study was to assess the sexual lifestyles and health service needs of these communities. METHODS: A survey, delivered electronically and available in 12 languages, of migrants from the 10 CEE accession countries recruited from community venues in London following extensive social mapping and via the Internet. Reported behaviours were compared with those from national probability survey data. RESULTS: 2648 CEE migrants completed the survey. Male CEE migrants reported higher rates of partner acquisition (adjusted OR (aOR) 2.1, 95% CI: 1.3 to 2.1) and paying for sex (aOR 3.2, 95% CI: 2.5 to 4.0), and both male and female CEE migrants reported more injecting drug use (men: aOR 2.2, 95% CI: 1.3 to 3.9; women: aOR 3.0, 95% CI 1.1 to 8.1), than the general population; however, CEE migrants were more likely to report more consistent condom use and lower reported diagnoses of sexually transmitted infections (STI). Just over 1% of respondents reported being HIV positive. Most men and a third of women were not registered for primary care in the U.K. DISCUSSION: CEE migrants to London report high rates of behaviours associated with increased risk of HIV/STI acquisition and transmission. These results should inform service planning, identify where STI and HIV interventions should be targeted, and provide baseline data to help evaluate the effectiveness of such interventions. PMID- 21593471 TI - Getting patients to their lipid targets: a practical approach to implementing therapeutic lifestyle changes. AB - Improving clinical outcomes in patients at high risk for coronary heart disease (CHD) requires a multimodal approach, especially in patients with the metabolic risk factors that constitute the metabolic syndrome, which is associated with an elevated risk of CHD at all levels of low-density lipoprotein cholesterol (LDL C). Achieving optimal clinical outcomes requires a comprehensive and aggressive therapeutic plan that includes pharmacotherapy and lifestyle changes. Effective pharmacotherapy for components of the metabolic syndrome (eg, hypertension, elevated LDL-C levels, prothrombotic state) is important in improving clinical outcomes, as is pharmacotherapy for glycemic control in patients with diabetes. Therapeutic lifestyle changes recommended for treatment of metabolic syndrome include smoking cessation, exercise programs, nutritional counseling, and weight control. Patient questionnaires are an effective way to help tailor recommendations to individual patients and thereby increase compliance. Clinicians can also help motivate patients by offering practical tips for modifying diet and eating habits and explaining all the benefits of exercise. These combined approaches can be used to help more patients achieve their lipid goals, and new pharmacologic therapies currently under investigation may further expand available treatment options. PMID- 21593472 TI - Achieving cholesterol targets: how well are we doing? AB - Elevated low-density lipoprotein cholesterol (LDL-C) levels are a modifiable risk factor for the development of coronary heart disease (CHD), the leading cause of death in the United States. Treatments to lower these levels help decrease the risk of CHD events and reduce mortality rates in patients with existing CHD and those with no history of CHD. Rates of screening and treatment for high cholesterol levels have improved somewhat in recent years, but there is still room for substantial improvement, especially in patients at high risk of CHD, who benefit most from aggressive LDL-C-lowering therapies. The American Osteopathic Association Clinical Assessment Program, a Web-based program that measures physician performance by analyzing data abstracted from patient medical records and helps guide treatment decisions, is a tool to help physicians improve outcomes in patients with elevated LDL-C levels. PMID- 21593473 TI - Rationale for aggressive lipid lowering in high-risk patients. AB - According to current guidelines from the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), the target low-density lipoprotein cholesterol (LDL-C) level for patients with established coronary heart disease (CHD) or CHD risk equivalents is less than 100 mg/dL, with an optional target of less than 70 mg/dL. More recent data suggest, however, that the physiologically normal level of LDL-C and the level at which atherogenesis is initiated is much lower. Overall, the data convincingly demonstrate that LDL-C lowering is associated with a significant reduction in CHD events, regardless of preexisting CHD. The NCEP ATP III treatment guidelines, published in 2002 and updated in 2004, do not reflect more recent findings on intensive lipid-lowering therapy, which are likely be addressed in the NCEP ATP IV guidelines, scheduled to be released in 2011. Drug options for LDL-C lowering include statins (the drug of choice), bile acid sequestrants, nicotinic acid, fibrates, and selective cholesterol absorption inhibitors. PMID- 21593475 TI - Dose-response of female llamas to ovulation-inducing factor from seminal plasma. AB - The present study was designed to determine if the dose of purified ovulation inducing factor (OIF) from llama seminal plasma required to provoke an ovulatory response is physiologically relevant in terms of the proportion present in a normal ejaculate and to test the hypothesis that corpus luteum (CL) form and function are affected by OIF in a dose-dependent manner. Female llamas were assigned randomly to five groups (n = 10 per group) and given a single i.m. dose of 500, 250, 125, or 60 MUg of purified OIF (representative of the amount present in 1/25th to 1/200th of a normal ejaculate) or 1 ml of PBS (control). Ovulation and CL development were monitored by transrectal ultrasonography. Blood samples were taken to measure plasma progesterone concentrations and to determine changes in plasma concentrations of luteinizing hormone (LH). The high dose of OIF (500 MUg) was associated with the highest incidence of ovulation (P < 0.05), the greatest maximum CL diameter (P < 0.05), and the largest day-to-day profiles of CL diameter (P < 0.05) and plasma progesterone concentrations (P < 0.01). A rise in plasma LH concentration was apparent in all llamas that ovulated and was most rapid and highest in the high-dose group (P < 0.01). The low dose of OIF (60 MUg) was minimally effective for induction of ovulation and the least luteotrophic, as evidenced by the smallest maximum CL diameter and the smallest day-to-day profiles for CL diameter and plasma concentrations of progesterone and LH. Responses were intermediate for the middle-dose groups (125 and 250 MUg). We conclude that OIF from llama seminal plasma has a dose-dependent effect on ovulation rate and CL form and function in llamas and that the biological effect of OIF is evident at physiologically relevant doses (i.e., as little as 1/100th of that present in an ejaculate). PMID- 21593474 TI - Short-term storage of human spermatozoa in electrolyte-free medium without freezing maintains sperm chromatin integrity better than cryopreservation. AB - Previous attempts to maintain human spermatozoa without freezing were based on short-term storage in component-rich medium and led to fast decline in motility and increased incidence of chromosome breaks. Here we report a new method in which sperm are maintained without freezing in an electrolyte-free medium (EFM) composed of glucose and bovine serum albumin. Human sperm were stored in EFM or human tubal fluid medium (HTFM) or were cryopreserved, and their motility, viability, and DNA integrity were examined at different intervals. Cryopreservation led to significant decline in sperm motility and viability and induced DNA fragmentation. Sperm stored in EFM maintained motility and viability for up to 4 and 7 wk, respectively, much longer than sperm stored in HTFM (<2 and <4 wk, respectively). DNA integrity, assessed with comet assay, was also maintained significantly better in EFM than in HTFM. One-week storage in EFM yielded motility and viability similar to that of cryopreserved sperm, but DNA integrity was significantly higher, resembling that of fresh sperm. After several weeks of storage in EFM, sperm were able to activate oocytes, undergo chromatin remodeling, and form normal zygotic chromosomes after intracytoplasmic sperm injection. This study demonstrated that human spermatozoa can be stored in EFM without freezing for several weeks while maintaining motility, viability, and chromatin integrity and that 1-wk storage in EFM offers better protection of sperm DNA integrity than cryopreservation. Sperm storage in EFM may become a viable option for the physicians working in assisted reproduction technology clinics, which would avoid cryodamage. PMID- 21593476 TI - The role of autophagy in corpus luteum regression in the rat. AB - Autophagy is associated with luteal cells death during regression of the corpus luteum (CL) in some species. However, the involvement of autophagy or the association between autophagy and apoptosis in CL regression are largely unknown. Therefore, we investigated the role of autophagy in CL regression and its association with apoptosis. Ovaries were obtained from pseudopregnant rats at Days 2 (early), 7 (mid-), and 14 and 20 (late-luteal stage) of the pseudopregnancy; autophagy-associated protein (microtuble-associated protein light chain 3 [LC3]) was immunolocalized and its expression level was measured. Luteal cell apoptosis was evaluated by measuring cleaved caspase 3 expression. LC3 expression increased slightly from early to mid-luteal stage, with maximal levels detected at the late-luteal stage in steroidogenic luteal cells. The expression level of the membrane form of LC3 (LC3-II) also increased during luteal stage progression, and reached a maximum at the end point of late-luteal stage (Day 20). This pattern coincided with cleaved caspase 3 expression. Furthermore, LC3-II expression increased, as did levels of cleaved caspase 3 in luteal cells cultured with prostaglandin F(2alpha) known to induce CL regression. These findings suggest that luteal cell autophagy is directly involved in CL regression, and is correlated with increased apoptosis. In addition, autophagic processes were inhibited using 3-methyladenine or bafilomycin A1 to evaluate the role of autophagy in apoptosis induction. Inhibition of autophagosome degradation by fusion with lysosomes (bafilomycin A1) increased apoptosis and cell death. Furthermore, inhibition of autophagosome formation (3-methyladenine) decreased apoptosis and cell death, suggesting that the accumulation of autophagosomes induces luteal cell apoptosis. In conclusion, these results indicate that autophagy is involved in rat luteal cell death through apoptosis, and is most prominent during CL regression. PMID- 21593477 TI - Placental ATPase expression is a link between multiple causes of spontaneous abortion in mice. AB - The a2 isoform of vacuolar ATPase (ATP6V0A2 referred to as a2V) plays a pivotal role in successful pregnancy and provides a microenvironment to maintain the delicate immunological balance at the feto-maternal interaction. We studied the expression of a2V mRNA in embryos and placenta of abortion-prone (female CBA * male DBA) murine matings or LPS (lipopolysaccharide)-treated mice. The expression of a2V was significantly higher in the placentas of nonabortion-prone (female BALB/c * male BALB/c and female CBA * male BALB/c) matings compared with the abortion-prone (female CBA * male DBA) mating. The expression of a2V was significantly decreased in the placentas treated with LPS in both female CBA * male DBA and female BALB/c * male BALB/c mating combinations with increased Lif, Il1b, and Tnf expression in the placenta. Decreased expression of a2V in the placenta is directly correlated with high percentages of pregnancy loss in abortion-prone mating (female CBA * male DBA) as well as in LPS-treated animals. The normal expression of placental a2V on Day 16 in the nonabortion-prone matings correlated with higher Mcp1 (monocyte chemotactic protein 1) gene expression, markedly higher infiltration of M1 and M2 macrophages, and no significant polarization patterns (M1/M2 = 1.2-1.6). However, in the abortion-prone mating, decreased placental a2V expression correlated with significantly lower Mcp1 gene expression with less infiltration of M1 and M2 macrophages and with polarization patterns skewed to M1 phenotypes (M1/M2 = 3.9-4.2). These data indicate that the higher expression of placental a2V is associated with dynamic infiltration of M1 and M2 macrophages through the induction of Mcp1 expression. This strengthens our hypothesis that a2V regulates the delicate cytokine and chemokine networks that coordinate the recruitment of macrophages for successful placental development and growth at the feto-maternal interface. PMID- 21593478 TI - Efficient and safe recipient preparation for transplantation of mouse spermatogonial stem cells: pretreating testes with heat shock. AB - Recipient preparation is of prime importance for the successful transplantation of spermatogonial stem cells (SSCs). Busulfan destroys endogenous germs cells and is commonly used for recipient preparation. However, busulfan produces significant side effects, including systemic toxicity, and it is lethal in certain species. The side effects associated with busulfan compromise the efficiency of SSC transplantation and threaten the safety of recipients. Here, we show that heat shock treatment of testes can be used as an alternative to busulfan treatment. Fourteen days after heat shock treatment, mice received a testicular injection of donor germ cells expressing enhanced green fluorescent protein (EGFP). Busulfan-treated mice were used as controls. Two months after transplantation, the number (12 +/- 1 mm) and length (30.46 +/- 5.23 mm) of EGFP expressing testicular colonies in heat shock-treated recipients were not significantly different from those in busulfan-treated recipients. Furthermore, healthy EGFP-expressing offspring were obtained after intracytoplasmic injection of round spermatids recovered from heat shock-treated recipients. This result indicates that donor SSCs undergo complete spermatogenesis in the heat shock treated testes of recipients. Our findings demonstrate the feasibility of using heat shock for the preparation of recipients before SSC transplantation in mice. Heat shock may prove to be useful for recipient preparation in mammalian species in which busulfan produces significant toxicity. PMID- 21593479 TI - Oxidative phosphorylation is essential for felid sperm function, but is substantially lower in cheetah (Acinonyx jubatus) compared to domestic cat (Felis catus) ejaculate. AB - Compared with the normospermic domestic cat, sperm metabolic function is compromised in the teratospermic cat and cheetah, but the pathway(s) involved in this deficiency are unknown. Glycolysis is essential for sperm motility, yet it appears to function normally in spermatozoa of either species regardless of structural morphology. We conducted a comparative study to further understand the mechanisms of energy production in felid spermatozoa, with the hypothesis that oxidative phosphorylation is required for normal sperm function and is impaired in teratospermic ejaculates. Electroejaculates from both species were stained with MitoTracker to quantify mitochondrial membrane potential (MMP) or were incubated to assess changes in sperm function (motility, acrosomal integrity, and lactate production) after mitochondrial inhibition with myxothiazol. Sperm midpiece dimensions also were quantified. Sperm mitochondrial fluorescence (directly proportional to MMP) was ~95% lower in the cheetah compared with the normospermic and teratospermic cat, despite the cheetah having a 10% longer midpiece. In both species, MMP was increased 5-fold in spermatozoa with retained cytoplasm compared with structurally normal cells. Inhibition of oxidative phosphorylation impaired sperm function in both species, but a 100-fold higher inhibitor concentration was required in the cat compared with the cheetah. Collectively, findings revealed that oxidative phosphorylation was required for sperm function in the domestic cat and cheetah. This pathway of energy production appeared markedly less active in the cheetah, indicating a species-specific vulnerability to mitochondrial dysfunction. The unexpected, cross-species linkage between retained cytoplasmic droplets and elevated MMP may reflect increased concentrations of metabolic enzymes or substrates in these structures. PMID- 21593480 TI - Evidence for the involvement of zinc in the association of CRISP1 with rat sperm during epididymal maturation. AB - Rat epididymal protein CRISP1 (cysteine-rich secretory protein 1) associates with sperm during maturation and participates in fertilization. Evidence indicates the existence of two populations of CRISP1 in sperm: one loosely bound and released during capacitation, and one strongly bound that remains after this process. However, the mechanisms underlying CRISP1 binding to sperm remain mostly unknown. Considering the high concentrations of Zn(2+) present in the epididymis, we investigated the potential involvement of this cation in the association of CRISP1 with sperm. Caput sperm were coincubated with epididymal fluid in the presence or absence of Zn(2+), and binding of CRISP1 to sperm was examined by Western blot analysis. An increase in CRISP1 was detected in sperm exposed to Zn(2+), but not if the cation was added with ethylenediaminetetra-acetic acid (EDTA). The same results were obtained using purified CRISP1. Association of CRISP1 with sperm was dependent on epididymal fluid and Zn(2+) concentrations and incubation time. Treatment with NaCl (0.6 M) removed the in vitro-bound CRISP1, indicating that it corresponds to the loosely bound population. Flow cytometry of caput sperm exposed to biotinylated CRISP1/avidin-fluorescein isothiocyanate revealed that only the cells incubated with Zn(2+) exhibited an increase in fluorescence. When these sperm were examined by epifluorescence microscopy, a clear staining in the tail, accompanied by a weaker labeling in the head, was observed. Detection of changes in the tryptophan fluorescence emission spectra of CRISP1 when exposed to Zn(2+) supported a direct interaction between CRISP1 and Zn(2+). Incubation of either cauda epididymal fluid or purified CRISP1 with Zn(2+), followed by native-PAGE and Western blot analysis, revealed the presence of high-molecular-weight CRISP1 complexes not detected in fluids treated with EDTA. Altogether, these results support the involvement of CRISP1-Zn(2+) complexes in the association of the loosely bound population of CRISP1 with sperm during epididymal maturation. PMID- 21593481 TI - Swine models of cystic fibrosis reveal male reproductive tract phenotype at birth. AB - Nearly all male cystic fibrosis (CF) patients exhibit tissue abnormalities in the reproductive tract, a condition that renders them azoospermic and infertile. Two swine CF models have been reported recently that include respiratory and digestive manifestations that are comparable to human CF. The goal of this study was to determine the phenotypic changes that may be present in the vas deferens of these swine CF models. Tracts from CFTR(-/-) and CFTR(DeltaF508/DeltaF508) neonates revealed partial or total vas deferens and/or epididymis atresia at birth, while wild-type littermates were normal. Histopathological analysis revealed a range of tissue abnormalities and disruptions in tubular organization. Vas deferens epithelial cells were isolated and electrophysiological results support that CFTR(-/-) monolayers can exhibit Na(+) reabsorption but reveal no anion secretion following exposure to cAMP-generating compounds, suggesting that CFTR-dependent Cl(-) and/or HCO(3)(-) transport is completely impaired. SLC26A3 and SLC26A6 immunoreactivities were detected in all experimental groups, indicating that these two chloride-bicarbonate exchangers were present, but were either unable to function or their activity is electroneutral. In addition, no signs of increased mucus synthesis and/or secretion were present in the male excurrent ducts of these CF models. Results demonstrate a causal link between CFTR mutations and duct abnormalities that are manifested at birth. PMID- 21593482 TI - DNA damage-sensing kinases mediate the mouse 2-cell embryo's response to genotoxic stress. AB - A critical function of cells is the maintenance of their genomic integrity. A family of phosphoinositide-3-kinase-related protein kinases, which includes ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) kinases, play key roles in sensing DNA damage. ATM and ATR were demonstrated in the cleavage stages of mouse embryo development. Genotoxic stress was imposed by exposure to ultraviolet (UV) radiation (causes DNA strand breaks) or cisplatin (causes strand cross-links). UV irradiation or cisplatin treatment of 2-cell embryos in the G(2) phase of the cell cycle caused DNA damage as defined by increased phosphorylation of the H2A histone family, member X (H2AFX; previously H2AX) variant. UV irradiation caused a stable G(2)-M arrest, and cisplatin treatment allowed progression through mitosis followed by activation of a G(1)-S checkpoint. Both checkpoints were transformation-related protein 53 independent. Caffeine (inhibits both ATM and ATR), but not KU55933 (ATM-selective inhibitor), reversed the G(2)-M block induced by UV, inferring a primary role for ATR in sensing this form of DNA damage. Caffeine and KU55933 were equally effective in reversing the cisplatin-induced G(1)-S block, implicating ATM as the primary sensing enzyme. Breaching of either checkpoint by treatment with caffeine or KU55933 allowed embryos to progress through several further cell cycles, yet none developed to blastocysts. The results show, to our knowledge for the first time, that the G(2)-M and G(1)-S cell-cycle checkpoints in the early embryo are differentially regulated by ATM and ATR in response to genotoxic stress and that they act as an initial point for containment of genomic damage. Under conditions of extensive or persistent DNA damage, the demise of the embryo is the ultimate method of protecting genomic integrity. PMID- 21593483 TI - The major proteins of bovine seminal plasma interact with caseins and whey proteins of milk extender. AB - Milk has been used routinely as an extender for sperm preservation. Caseins, the major proteins in milk, are proposed to be the protective constituents of milk during sperm preservation. It is unclear whether the whey proteins in milk are also implicated in the protection of sperm. Our previous studies have shown that the major proteins of bovine seminal plasma (recently named as binder of sperm or BSP, which comprises BSP1, BSP3, and BSP5 proteins) mediate a continuous phospholipid and cholesterol efflux from the sperm plasma membrane that is detrimental for sperm preservation. In this study, we investigated whether the protective effect of milk could be due to an interaction between BSP proteins and milk proteins. The binding of BSP proteins to milk proteins was demonstrated by gel filtration chromatography. Milk was fractionated into three fractions: the first containing whey protein aggregates and kappa-casein, the second containing all milk proteins, and the third containing small peptides, salts, and sugars. BSP1 has a higher affinity for the milk proteins in the milk fractions as compared to BSP3 and BSP5. The binding of BSP proteins to milk proteins was further characterized by isothermal titration calorimetry. We demonstrated that BSP1 binds to caseins and the titration could be simulated with a Scatchard approach, leading to an affinity constant (K(a)) of 350 mM(-1) and a stoichiometric parameter for the association (n) of 4.5 BSP1 per casein. The association between BSP1 and alpha-lactalbumin was characterized by a K(a) of 240 mM(-1) and an n value of 0.8. These results indicate the existence of an interaction between BSP proteins and milk proteins that could be the origin of the protection of sperm during preservation in milk. PMID- 21593484 TI - High-throughput fluorescence polarization assay for the enzymatic activity of GTPase-activating protein of ADP-ribosylation factor (ARFGAP). AB - GTPase-activating proteins of ADP-ribosylation factors (ARFGAPs) play key cellular roles in vesicle production and trafficking, adhesion, migration, and development. Dysfunctional regulation of ARFGAPs has been implicated in various diseases, including cancer, Alzheimer disease, and autism. Unfortunately, there are few mechanistic details describing how ARFGAPs contribute to disease states. In this regard, it would be extremely helpful to have a set of small molecules that selectively and directly modulate specific ARFGAPs as probes to dissect ARFGAP-regulated cell signaling under various conditions. Currently, such probes are lacking, and their identification is hampered by the lack of a suitable high throughput assay to monitor ARFGAP activity. Here, the authors describe and validate a robust high-throughput assay using fluorescence polarization to monitor the ability of diverse ARFGAPs to enhance the capacity of ARF1 to hydrolyze guanosine triphosphate. PMID- 21593485 TI - Developing cell-specific antibodies to endothelial progenitor cells using avian immune phage display technology. AB - This study aims at generating immune chicken phage display libraries and single chain antibodies (scFvs) specifically directed against cell surface markers of cultured peripheral blood mononuclear cells (PBMCs) that contain endothelial progenitor cells (EPCs). In contrast to previous approaches that use well-defined recombinant antigens attached to plastic surfaces that may alter the structure of the proteins, the authors describe a method that maintains the cell surface markers on live cells while providing the opportunity to rapidly screen entire libraries for antibodies that bind to unknown cell surface markers of progenitor/stem cells. Chickens immunized with live EPCs, consisting of a heterogeneous population of lymphocytes and monocytes, demonstrated a robust immune response. After three rounds of biopanning, the authors purified and characterized three unique scFvs called UG1-3. Codon-optimized recombinant UG1 (gUG-1) shows binding by flow cytometry to circulating CD14-positive cells in peripheral blood consistent with predominant expression of a target protein on monocyte subsets. The authors describe the successful use of immunization of chickens for the generation of scFvs against a heterogenous population of EPCs displaying unknown cell surface markers and demonstrate the strong potential of phage display technology in the development of reagents for the isolation and characterization of stem/progenitor cells. PMID- 21593486 TI - Screening for mevalonate biosynthetic pathway inhibitors using sensitized bacterial strains. AB - A simple, optical density-based assay for inhibitors of the mevalonate-dependent pathway for isoprenoid biosynthesis was developed. The assay uses pathway sensitized Staphylococcus aureus strains and is fully compatible with high density screening in a 1536-well format. S. aureus strains were constructed in which genes required for mevalonate-dependent isopentenyl pyrophosphate (IPP) synthesis were regulated by an isopropyl-beta-D-thiogalactopyranoside (IPTG) inducible promoter. Inhibitors of the target enzymes displayed greater antibacterial potency in media containing low concentrations of IPTG, and therefore less induction of mevalonate pathway genes, than in media with high IPTG conditions. This differential growth phenotype was exploited to bias the cell-based screening hits toward specific inhibitors of mevalonate-dependent IPP biosynthesis. Screens were run against strains engineered for regulation of the enzymes HMG-CoA synthase (MvaS) and mevalonate kinase (mvaK1), mevalonate diphosphate decarboxylase (mvaD), and phosphomevalonate kinase (mvaK2). The latter three enzymes are regulated as an operon. These assays resulted in the discovery of potent antibacterial hits that were progressed to an active hit-to lead program. The example presented here demonstrates that a cell sensitization strategy can be successfully applied to a 1.3-million compound high-throughput screen in a high-density 1536-well format. PMID- 21593487 TI - High-content screening for chemical modulators of embryonal carcinoma cell differentiation and survival. AB - Disentangling the complex interactions that govern stem cell fate choices of self renewal, differentiation, or death presents a formidable challenge. Image-based phenotype-driven screening meets this challenge by providing means for rapid testing of many small molecules simultaneously. Pluripotent embryonal carcinoma (EC) cells offer a convenient substitute for embryonic stem (ES) cells in such screens because they are simpler to maintain and control. The authors developed an image-based screening assay to identify compounds that affect survival or differentiation of the human EC stem cell line NTERA2 by measuring the effect on cell number and the proportion of cells expressing a pluripotency-associated marker SSEA3. A pilot screen of 80 kinase inhibitors identified several compounds that improved cell survival or induced differentiation. The survival compounds Y 27632, HA-1077, and H-8 all strongly inhibit the kinases ROCK and PRK2, highlighting the important role of these kinases in EC cell survival. Two molecules, GF109203x and rottlerin, induced EC differentiation. The effects of rottlerin were also investigated in human ES cells. Rottlerin inhibited the self renewal ability of ES cells, caused the cell cycle arrest, and repressed the expression of pluripotency-associated genes. PMID- 21593489 TI - Determination of unmetabolized folic acid in human plasma using affinity HPLC. AB - BACKGROUND: Folic acid (FA) fortification of food created the need to determine whether fortification elevated concentrations of unmetabolized FA in plasma and whether this form of the vitamin in blood is associated with adverse health outcomes. OBJECTIVE: The objective of this research was to devise a simple, rapid method for the measurement of unmetabolized plasma FA in epidemiologic studies. DESIGN: We previously used the affinity/HPLC with electrochemical detection method to measure folate distribution in human plasma and red blood cells (RBCs). We modified this method with the inclusion of synthetic ethyltetrahydrofolate as an internal standard and with the use of 2 affinity columns connected in parallel to the analytic column through a switching valve to allow one column to be loaded while the other column was eluted into the analytic column. RESULTS: We identified FA and 5-methyltetrahydrofolate (5-mTHF) by retention time and characteristic response across the channels of the electrochemical detector. Limits of detection were 0.034 pmol for 5-mTHF and 0.027 pmol for FA per injection, and the recovery was 92.2% (5-mTHF) and 98.9% (FA). CVs for samples were 8.1% (within day) and 6.8% (between day) for 5-mTHF and 3.2% (within day) and 5.9% (between day) for FA. Total folate with the use of this method correlated highly (r(2) = 0.98, P < 0.001) with values from the microbial assay. The run time for the method was 30 min per sample. Researchers can use this method with longer run times to measure the distribution of folate forms in RBCs. CONCLUSION: This updated method allows efficient analysis of folate forms in human plasma and tissues without the loss of sensitivity or precision. PMID- 21593490 TI - Cognitive function after supplementation with B vitamins and long-chain omega-3 fatty acids: ancillary findings from the SU.FOL.OM3 randomized trial. AB - BACKGROUND: Rapid aging of the population worldwide necessitates a heightened concern about preventing cognitive decline. OBJECTIVE: We investigated the effects of B vitamins and omega-3 (n-3) fatty acid supplementation on cognition in a high-risk population. DESIGN: This was an ancillary study of the SU.FOL.OM3 (SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acids) secondary prevention trial conducted in France between 2003 and 2009. The present sample included 1748 men and women aged 45-80 y with a history of myocardial infarction, unstable angina, or ischemic stroke and who were recruited via a network of 417 physicians. With the use of block randomization with stratification by sex, age, prior cardiovascular disease, and city of residence, participants were assigned in a 2 * 2 factorial design to 1 of 4 groups: 1) 5 methyltetrahydrofolate (folate, 0.56 mg) and vitamins B-6 (3 mg) and B-12 (0.02 mg), 2) eicosapentaenoic and docosahexaenoic acids (600 mg) in a 2:1 ratio, 3) B vitamins and omega-3 fatty acids, or 4) placebo. Cognitive function after 4 y of supplementation was assessed with the French version of the modified Telephone Interview for Cognitive Status. RESULTS: No significant main effects of group assignment on cognitive function were found; however, we found some evidence of disease history- and age-specific effects. In the subgroup with prior stroke, for example, participants assigned to receive B vitamins plus omega-3 fatty acids were significantly less likely to have a decreased score on the temporal orientation task than were those assigned to receive placebo (odds ratio: 0.43; 95% CI: 0.21, 0.86). CONCLUSIONS: If present, dietary effects on cognition are likely group-specific. These results could be useful in interventions aimed at preventing cognitive decline in high-risk individuals. This trial is registered at controlled-trials.com as ISRCTN41926726. PMID- 21593491 TI - Controlling for age in studies on coronary heart disease risk. PMID- 21593493 TI - All olive oils are not the same. PMID- 21593492 TI - Long-term habituation to food in obese and nonobese women. AB - BACKGROUND: Habituation is a form of learning in which repeated exposure to a stimulus leads to a decrease in responding. Eating involves repeated presentation of the same food stimulus in a meal, and habituation is reliably observed within a meal such that faster rates of habituation are associated with less energy intake. It is possible that repeated presentation of the same food over days will lead to long-term habituation, such that subjects habituate to foods repeated over meals. However, no research on long-term habituation to food in humans has been conducted. OBJECTIVE: The current study was designed to assess long-term habituation in 16 obese and 16 nonobese premenopausal women. DESIGN: Obese and nonobese women (aged 20-50 y) were randomly assigned to receive a macaroni and cheese meal presented 5 times, either daily for 1 wk or once per week for 5 wk. RESULTS: In both obese and nonobese women, daily presentation of food resulted in faster habituation and less energy intake than did once-weekly presentation of food. CONCLUSIONS: Long-term habituation was observed when the same food was presented at daily meals but not when presented once weekly for 5 wk. These results provide the first evidence of long-term habituation to food in women and show that memory of food over daily meals can increase the rate of habituation and reduce energy intake. This trial was registered at clinicaltrials.gov as NCT01208870. PMID- 21593495 TI - Inconsistent dietary assessment tools may bias results in assessing the relations between specific foods and coronary heart disease risk in the EPICOR Study. PMID- 21593494 TI - Brain responses to food images during the early and late follicular phase of the menstrual cycle in healthy young women: relation to fasting and feeding. AB - BACKGROUND: Food intake fluctuates throughout the menstrual cycle; it is greater during the early follicular and luteal phases than in the late follicular (periovulatory) phase. Ovarian steroids can influence brain areas that process food-related information, but the specific contribution of individual hormones and the importance of the prandial state remain unknown. OBJECTIVE: The objective was to examine whether brain activation during food visualization is affected by changes in estradiol concentration in the fasted and fed conditions. DESIGN: Nine eumenorrheic, lean young women [mean (+/-SD) age: 26.2 +/- 3.2 y; body mass index (in kg/m(2)): 22.4 +/- 1.2] completed 2 visits, one in the early (low estradiol) and one in the late (high estradiol) follicular phase of their menstrual cycle. At each visit, subjects underwent functional magnetic resonance imaging while they viewed food and nonfood images, before and after a standardized meal. Region of-interest analysis was used to examine the effect of follicular phase and prandial state on brain activation (food > nonfood contrast) and its association with estradiol concentration. RESULTS: Differences were identified in the inferior frontal and fusiform gyri. In these areas, visualization of food elicited greater activation in the fed state than during fasting but only in the late follicular phase, when estradiol concentration was high. The change in estradiol concentration across the follicular phase (late minus early) was inversely correlated with the change in fusiform gyrus activation in the fasted state but not in the fed state. CONCLUSION: Our findings suggest that estradiol may reduce food intake by decreasing sensitivity to food cues in the ventral visual pathway under conditions of energy deprivation. This trial was registered at clinicaltrials.gov as NCT00130117. PMID- 21593496 TI - Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. AB - Approximately one-quarter of circulating cobalamin (vitamin B-12) binds to transcobalamin (holoTC) and is thereby available for the cells of the body. For this reason, holoTC is also referred to as active vitamin B-12. HoloTC was suggested as an optimal marker of early vitamin B-12 deficiency >20 y ago. This suggestion led to the development of suitable assays for measurement of the compound and clinical studies that aimed to show the benefit of measurement of holoTC rather than of vitamin B-12. Today holoTC can be analyzed by 3 methods: direct measurement of the complex between transcobalamin and vitamin B-12, measurement of vitamin B-12 attached to transcobalamin, or measurement of the amount of transcobalamin saturated with vitamin B-12. These 3 methods give similar results, but direct measurement of holoTC complex is preferable in the clinical setting from a practical point of view. HoloTC measurement has proven useful for the identification of the few patients who suffer from transcobalamin deficiency. In addition, holoTC is part of the CobaSorb test and therefore useful for assessment of vitamin B-12 absorption. Clinical studies that compare the ability of holoTC and vitamin B-12 to identify individuals with vitamin B-12 deficiency (elevated concentration of methylmalonic acid) suggest that holoTC performs better than total vitamin B-12. To date, holoTC has not been used for population-based assessments of vitamin B-12 status, but we suggest that holoTC is a better marker than total vitamin B-12 for such studies. PMID- 21593497 TI - Folate status assessment history: implications for measurement of biomarkers in NHANES. AB - This article presents a historical perspective on the different methods used to measure folate status in populations and clinical settings. I discuss some of the advantages and limitations of these procedures. For >50 y researchers have used microbiological assay methods to assess folate status in clinical settings and in population-based studies, such as NHANES. Serum and red blood cell folate values obtained with the Lactobacillus casei assay have formed the basis for current ranges and cutoffs for the establishment of folate sufficiency and for the current dietary reference intakes for folate. Over the past 30 y competitive folate protein binding assays, which are available in kit form, have supplanted microbiological assays in many clinical laboratories because of their ease of use. Several NHANES cycles have used these assays. Folate concentrations obtained with these kits are lower than those from microbiological assays and show a wide variation between different protein binding assay kits. This variation has complicated the setting of values for normal ranges of folate status and the comparison of status changes between different NHANES cycles. The recent development of mass spectrometry methods for folate opens up the possibility of measurement of individual folate vitamers such as folic acid. Past experience with microbiological and competitive protein binding assays indicates some of the technical problems that research will need to address before this promise becomes reality. PMID- 21593498 TI - Regarding "Fruit, vegetables, and olive oil and risk of coronary heart disease in Italian women: the EPICOR Study". PMID- 21593499 TI - Long-term effect of low-dose folic acid intake: potential effect of mandatory fortification on the prevention of neural tube defects. AB - BACKGROUND: Understanding the full effect of chronic low-dose folic acid is important in interpreting the effect of the mandatory folic acid fortification program in North America. OBJECTIVE: We aimed to describe the rate of attainment and steady state (plateau) of red blood cell (RBC) folate in response to long term intake of 140 MUg (designed to mimic fortification) and 400 MUg (recommended dose for the primary prevention of neural tube defects) folic acid/d in reproductive-aged women living in a country with minimal fortification. DESIGN: On the basis of pharmacokinetics principles, it was recently proposed that a steady state should be reached after 40 wk. Thus, 144 women aged 18-40 y were randomly assigned to receive a daily folic acid supplement of 140 (n = 49) or 400 (n = 48) MUg or placebo (n = 47) for 40 wk. RBC folate was measured at baseline and at 6, 12, 29, and 40 wk. RESULTS: After 40 wk, RBC folate did not reach a plateau in either treatment group. Kinetic modeling of the data indicated that RBC folate would approximately double from 779 to 1356 nmol/L in response to 140 MUg folic acid/d with only ~50% of model-estimated steady state conditions achieved at 40 wk. An average RBC folate concentration of 1068 nmol/L after 12 wk of supplementation with 400 MUg folic acid/d was readily achieved at 36 wk after continuous intake of 140 MUg/d. CONCLUSION: Our model shows the considerable length of time required to attain the full effect of low-dose folic acid, which suggests that 140 MUg folic acid/d could be as effective as 400 MUg folic acid/d taken during the periconceptional period if given sufficient time. This trial is registered at www.anzctr.org.au as ACTRN12609000215224. PMID- 21593500 TI - Plasma omega-3 fatty acids and incident diabetes in older adults. AB - BACKGROUND: Although long-chain omega-3 fatty acid (n-3 FA) consumption estimated via food-frequency questionnaires has been associated with a higher incidence of diabetes, limited prospective data on diabetes risk are available that use objective biomarkers of n-3 FAs. OBJECTIVE: We sought to examine the relation between plasma phospholipid n-3 FAs and incident diabetes. DESIGN: We prospectively analyzed data in 3088 older men and women (mean age: 75 y) from the Cardiovascular Health Study (1992-2007). Plasma phospholipid n-3 FAs were measured by using gas chromatography, and incident diabetes was ascertained by using information on hypoglycemic agents and serum glucose. We used Cox proportional hazards models to estimate multivariable-adjusted relative risks. RESULTS: During a median follow-up of 10.6 y, 204 new cases of diabetes occurred. In a multivariable model that controlled for age, sex, race, clinic site, body mass index, alcohol intake, smoking, physical activity, LDL cholesterol, and linoleic acid, relative risks (95% CIs) for diabetes were 1.0 (reference), 0.96 (0.65, 1.43), 1.03 (0.69, 1.54), and 0.64 (0.41, 1.01) across consecutive quartiles of phospholipid eicosapentaenoic acid and docosahexaenoic acid (P for trend = 0.05). Corresponding relative risks (95% CIs) for phospholipid alpha linolenic acid (ALA) were 1.0 (reference), 0.93 (0.65, 1.34), 0.99 (0.68, 1.44), and 0.57 (0.36, 0.90) (P for trend = 0.03). CONCLUSIONS: With the use of objective biomarkers, long-chain n-3 FAs and ALA were not associated with a higher incidence of diabetes. Individuals with the highest concentrations of both types of FAs had lower risk of diabetes. PMID- 21593501 TI - Dietary patterns and 14-y weight gain in African American women. AB - BACKGROUND: An inverse association between healthy dietary patterns and weight gain that has been shown in white populations is not evident in the few studies in African Americans, a population at high risk of obesity. OBJECTIVE: We prospectively assessed dietary patterns in relation to weight gain in African American women. DESIGN: The study included 41,351 women aged 21-54 y at enrollment in 1995 in the Black Women's Health Study. Participants reported dietary intake in 1995 and 2001 and current weight every 2 y through mailed questionnaires. By using factor analysis, 2 major dietary patterns were identified: a "vegetables/fruit" pattern and a "meat/fried foods" pattern. Multivariable mixed linear regression models were used to estimate mean weight gain in 14 y of follow-up according to each dietary pattern. RESULTS: Among women who maintained similar dietary patterns in 1995 and 2001, the vegetables/fruit pattern was associated with significantly less weight gain over 14 y (10.88 and 11.94 kg in the highest and lowest quintiles, respectively; P for trend = 0.003), whereas the meat/fried foods pattern was associated with significantly greater weight gain (12.02 and 10.15 kg in the highest and lowest quintiles, respectively; P for trend < 0.001). The associations were stronger among women aged <35 y, whose weight gain was greatest. CONCLUSION: These findings are the first to indicate that African American women may be better able to achieve long term weight maintenance by consuming a diet high in vegetables and fruit and low in red meat and fried foods. PMID- 21593502 TI - Biomarkers of folate status in NHANES: a roundtable summary. AB - A roundtable to discuss the measurement of folate status biomarkers in NHANES took place in July 2010. NHANES has measured serum folate since 1974 and red blood cell (RBC) folate since 1978 with the use of several different measurement procedures. Data on serum 5-methyltetrahydrofolate (5MTHF) and folic acid (FA) concentrations in persons aged >=60 y are available in NHANES 1999-2002. The roundtable reviewed data that showed that folate concentrations from the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA; used in NHANES 1991 1994 and NHANES 1999-2006) were, on average, 29% lower for serum and 45% lower for RBC than were those from the microbiological assay (MA), which was used in NHANES 2007-2010. Roundtable experts agreed that these differences required a data adjustment for time-trend analyses. The roundtable reviewed the possible use of an isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) measurement procedure for future NHANES and agreed that the close agreement between the MA and LC-MS/MS results for serum folate supported conversion to the LC-MS/MS procedure. However, for RBC folate, the MA gave 25% higher concentrations than did the LC-MS/MS procedure. The roundtable agreed that the use of the LC-MS/MS procedure to measure RBC folate is premature at this time. The roundtable reviewed the reference materials available or under development at the National Institute of Standards and Technology and recognized the challenges related to, and the scientific need for, these materials. They noted the need for a commutability study for the available reference materials for serum 5MTHF and FA. PMID- 21593503 TI - The vitamin D status of Canadians relative to the 2011 Dietary Reference Intakes: an examination in children and adults with and without supplement use. AB - BACKGROUND: The 2011 Dietary Reference Intakes (DRIs) for vitamin D use 25 hydroxyvitamin D [25(OH)D] concentrations to define vitamin D deficiency (<30 nmol/L), the Estimated Average Requirement (40 nmol/L), and the Recommended Dietary Allowance (RDA; 50 nmol/L). The Canadian population has not yet been assessed according to these recommendations. OBJECTIVE: We determined the prevalence of meeting DRI recommendations and the role of vitamin D supplement use among Canadians aged 6-79 y. DESIGN: Plasma 25(OH)D from a representative sample of Canadians in the Canadian Health Measures Survey-Cycle 1 (n = 5306) were used. Supplement use was assessed by household interview. Concentrations of 25(OH)D were compared in supplement users and nonusers by season and race. RESULTS: Overall, 5.4%, 12.7%, and 25.7% of the participants had 25(OH)D concentrations below the 30-, 40-, and 50-nmol/L cutoffs, respectively. In white Canadians, plasma 25(OH)D concentrations ranged from an undetectable percentage with concentrations <30 nmol/L in summer to 24.5% with concentrations <50 nmol/L in winter; the corresponding values ranged from 12.5% to 53.1% in nonwhite Canadians. Supplement users had significantly higher 25(OH)D concentrations than did nonusers, and no seasonal differences were found. In nonsupplement users, the prevalence of 25(OH)D concentrations <50 nmol/L in winter was 37.2% overall and was 60.7% in nonwhites. CONCLUSIONS: One-quarter of Canadians did not meet the RDA, but the use of vitamin D supplements contributed to a better 25(OH)D status. Nonwhite Canadians had the highest risk of not achieving DRI recommendations. More than one-third of Canadians not using supplements did not meet the RDA in winter. This suggests that current food choices alone are insufficient to maintain 25(OH)D concentrations of 50 nmol/L in many Canadians, especially in winter. PMID- 21593504 TI - Overview of a roundtable on NHANES monitoring of biomarkers of folate and vitamin B-12 status: measurement procedure issues. AB - A roundtable dialogue to discuss "NHANES Monitoring of Biomarkers of Folate and Vitamin B-12 Status" took place in July 2010. This article provides an overview of the meeting and this supplement issue. Although the focus of the roundtable dialogue was on the measurement of folate and vitamin B-12 status biomarkers in NHANES, this article also describes the relevance and importance of these issues for clinical and research laboratories. The roundtable identified the microbiological assay (MA) as the gold standard for measurement of serum and red blood cell folate concentrations. The roundtable noted that differences in results between the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA) that NHANES 1991-1994 and 1999-2006 used and the MA that NHANES 2007-2010 used will require adjustment equations to evaluate time trends. The roundtable found that the close agreement between the serum results for the MA and liquid chromatography-tandem mass spectrometry (LC-MS/MS) procedures supported the conversion to LC-MS/MS for serum folate in future NHANES. The roundtable recognized the uncertainty about whether subclinical vitamin B-12 deficiency is a public health concern but encouraged reinstatement of at least one circulating vitamin B-12 measure and one functional vitamin B-12 status measure in future NHANES. The use of serum vitamin B-12 and plasma methylmalonic acid would provide continuity with past NHANES. The roundtable supported the continued use of the National Institute of Standards and Technology (NIST) reference materials in NHANES biomarker analyses and the further development of additional reference materials by the NIST. PMID- 21593505 TI - Omega-3 fatty acids and incident type 2 diabetes: the Singapore Chinese Health Study. AB - BACKGROUND: The role of omega-3 (n-3) fatty acids (FAs) in the development of type 2 diabetes is uncertain, especially with regard to any differential influence of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). OBJECTIVE: The objective was to examine the association between total omega-3 FAs, marine omega-3 (EPA, DHA), nonmarine omega 3 (ALA), and omega-6 (n-6) FAs and omega-6:omega-3 ratio and risk of type 2 diabetes in a Chinese population in Singapore. DESIGN: The analysis included 43,176 Chinese men and women free of chronic disease, aged 45-74 y, in the Singapore Chinese Health Study. Baseline data collection occurred between 1993 and 1998, with follow-up interviews between 1999 and 2004. Cox regression models were used to examine the associations between FA intakes at baseline and risk of developing diabetes. RESULTS: Increased intakes of total omega-3 FAs were inversely associated with diabetes incidence [hazard ratio (HR) for the fifth compared with the first quintile: 0.78; 95% CI: 0.65, 0.94; P for trend = 0.02]. Omega-3 FAs from marine sources were not associated with diabetes risk, whereas nonmarine omega-3 FA intake was strongly associated (HR for the fifth compared with the first quintile: 0.79; 95% CI: 0.67, 0.93; P for trend = 0.004). Omega-6 and omega-6:omega-3 ratio were not associated with incidence of type 2 diabetes. CONCLUSION: Consumption of nonmarine sources (ALA) of omega-3 FAs is associated with a decreased risk of type 2 diabetes in Chinese Singaporeans. PMID- 21593506 TI - Maternal and offspring adiposity-related genetic variants and gestational weight gain. AB - BACKGROUND: Gestational weight gain (GWG) is associated with a range of health outcomes, but little is known about the factors that influence it. OBJECTIVE: The objective was to test the hypothesis that maternal and fetal genetic variants that are reliably associated with adiposity are associated with GWG. DESIGN: We examined the association of a risk allele score by using 4 adiposity-related single nucleotide polymorphisms (SNPs; rs9939609 in FTO, rs17782313 near MC4R, rs6548238 near TMEM18, and rs10938397 near GNPDA2) with GWG in a pregnancy cohort in which women had detailed repeated assessment of GWG (median number of weight measurements: 10; interquartile range: 8, 11). The numbers included in our analyses varied between 2324 and 7563 for different variant-outcome analyses. A linear spline random-effects model was used to model weight change with gestational age and to relate genetic variants to this. This modeling confirmed 3 distinct periods of GWG: 0-18, 19-28, and >=29 wk of gestation. RESULTS: Maternal risk allele score and SNPs in FTO, MC4R, and TMEM18 were positively associated with prepregnancy weight. Maternal allele score was inversely associated with GWG in the first 18 wk of pregnancy (-14.46 g/wk per allele; 95% CI: -24.75, -4.17 g/wk per allele) but was not associated with other periods of GWG. Offspring allele score and maternal and offspring individual SNPs were not associated with GWG in any period or with birth weight or postnatal weight retention. CONCLUSIONS: Our findings suggest that neither maternal nor fetal adiposity related genetic variants are associated with greater GWG. The inverse association of maternal allele score with GWG in the first 18 wk requires replication. PMID- 21593507 TI - Dietary macronutrient composition affects beta cell responsiveness but not insulin sensitivity. AB - BACKGROUND: Altering dietary carbohydrate or fat content may have chronic effects on insulin secretion and sensitivity, which may vary with individual metabolic phenotype. OBJECTIVE: The objective was to evaluate the contribution of tightly controlled diets differing in carbohydrate and fat content for 8 wk to insulin sensitivity and beta cell responsiveness and whether effects of diet would vary with race, free-living diet, or insulin response. DESIGN: Healthy overweight men and women (36 European Americans, 33 African Americans) were provided with food for 8 wk and received either a eucaloric standard diet (55% carbohydrate, 27% fat) or a eucaloric reduced-carbohydrate (RedCHO)/higher-fat diet (43% carbohydrate, 39% fat). Insulin sensitivity and beta cell responsiveness were assessed at baseline and 8 wk by using a liquid meal tolerance test. RESULTS: Insulin sensitivity did not change with diet (P = 0.1601). Static beta cell response to glucose (FS) was 28.5% lower after the RedCHO/higher-fat diet. Subgroup analyses indicated that lower FS with the RedCHO/higher-fat diet occurred primarily among African Americans. A significant inverse association was observed for change in glucose area under the curve compared with change in FS. CONCLUSIONS: Consumption of a eucaloric 43% carbohydrate/39% fat diet for 8 wk resulted in down-regulation of beta cell responsiveness, which was influenced by baseline phenotypic characteristics. Further study is needed to probe the potential cause-and-effect relation between change in FS and change in glucose tolerance. This trial is registered at clinicaltrials.gov as NCT00726908. PMID- 21593508 TI - Folate and vitamin B-12 biomarkers in NHANES: history of their measurement and use. AB - NHANES measured folate and vitamin B-12 status biomarkers, starting with serum folate from NHANES I (1974-1975) through 2010. Subsequent NHANES measured additional biomarkers [eg, red blood cell folate, serum vitamin B-12, total homocysteine (tHcy), methylmalonic acid, serum folic acid, and 5 methyltetrahydrofolic acid]. Examples of the uses of these data are wide ranging and include public policy applications, the derivation of reference intervals, and research. Periodically, the National Center for Health Statistics and its federal partners convene expert panels to review the use of the folate- and vitamin B-12-related biomarkers in NHANES. These panels have evaluated the need for results to be comparable across time and with published data and the use of crossover studies and adjustment equations to ensure comparability. With the recent availability of reference methods and materials for serum folate and tHcy, NHANES has started to use traceability approaches to enhance the accuracy and comparability of its results. A major user concern over the years has been the use of cutoffs to estimate the prevalence of inadequate folate and vitamin B-12 status. Because these cutoffs depend on the measurement procedure, several expert panels suggested approaches for dealing with cutoff challenges. This review summarizes the history and use of folate- and vitamin B-12-related biomarkers beginning with NHANES I (1974-1975) through 2010. PMID- 21593509 TI - Cruciferous vegetable consumption is associated with a reduced risk of total and cardiovascular disease mortality. AB - BACKGROUND: Asian populations habitually consume a large amount of cruciferous vegetables and other plant-based foods. Few epidemiologic investigations have evaluated the potential health effects of these foods in Asian populations. OBJECTIVE: We aimed to examine the associations of cruciferous vegetables, noncruciferous vegetables, total vegetables, and total fruit intake with risk of all-cause and cause-specific mortality. DESIGN: The analysis included 134,796 Chinese adults who participated in 2 population-based, prospective cohort studies: the Shanghai Women's Health Study and the Shanghai Men's Health Study. Dietary intakes were assessed at baseline through in-person interviews by using validated food-frequency questionnaires. Deaths were ascertained by biennial home visits and linkage with vital statistics registries. RESULTS: We identified 3442 deaths among women during a mean follow-up of 10.2 y and 1951 deaths among men during a mean follow-up of 4.6 y. Overall, fruit and vegetable intake was inversely associated with risk of total mortality in both women and men, and a dose-response pattern was particularly evident for cruciferous vegetable intake. The pooled multivariate hazard ratios (95% CIs) for total mortality across increasing quintiles of intake were 1 (reference), 0.91 (0.84, 0.98), 0.88 (0.77, 1.00), 0.85 (0.76, 0.96), and 0.78 (0.71, 0.85) for cruciferous vegetables (P < 0.0001 for trend) and 0.88 (0.79, 0.97), 0.88 (0.79, 0.98), 0.76 (0.62, 0.92), and 0.84 (0.69, 1.00) for total vegetables (P = 0.03 for trend). The inverse associations were primarily related to cardiovascular disease mortality but not to cancer mortality. CONCLUSION: Our findings support recommendations to increase consumption of vegetables, particularly cruciferous vegetables, and fruit to promote cardiovascular health and overall longevity. PMID- 21593510 TI - Parental smoking during pregnancy, early growth, and risk of obesity in preschool children: the Generation R Study. AB - BACKGROUND: Maternal smoking during pregnancy seems to be associated with obesity in offspring. Not much is known about the specific critical exposure periods or underlying mechanisms for this association. OBJECTIVE: We assessed the associations of active maternal and paternal smoking during pregnancy with early growth characteristics and risks of overweight and obesity in preschool children. DESIGN: This study was a population-based, prospective cohort study from early fetal life until the age of 4 y in 5342 mothers and fathers and their children. Growth characteristics [head circumference, length, weight, and body mass index (BMI; in kg/m(2))] and overweight and obesity were repeatedly measured at the ages of 1, 2, 3, and 4 y. RESULTS: In comparison with children from nonsmoking mothers, children from mothers who continued smoking during pregnancy had persistently smaller head circumferences and heights until the age of 4 y, whereas their weights were lower only until the age of 3 mo. This smaller length and normal to higher weight led to an increased BMI [SD score difference: 0.11; 95% CI: 0.02, 0.20; P < 0.05)] and an increased risk of obesity (odds ratio: 1.61; 95% CI: 1.03, 2.53; P < 0.05) at the age of 4 y. In nonsmoking mothers, paternal smoking was not associated with postnatal growth characteristics or risk of obesity in offspring. Maternal smoking during pregnancy was associated with a higher BMI at the age of 4 y in children with a normal birth weight and in those who were small for gestational age at birth. CONCLUSION: Our findings suggest that direct intrauterine exposure to smoke until late pregnancy leads to different height and weight growth adaptations and increased risks of overweight and obesity in preschool children. PMID- 21593511 TI - Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: a critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II. AB - Cobalamin deficiency is relatively common, but the great majority of cases in epidemiologic surveys have subclinical cobalamin deficiency (SCCD), not classical clinical deficiency. Because SCCD has no known clinical expression, its diagnosis depends solely on biochemical biomarkers, whose optimal application becomes crucial yet remains unsettled. This review critically examines the current diagnostic concepts, tools, and interpretations. Their exploration begins with understanding that SCCD differs from clinical deficiency not just in degree of deficiency but in fundamental pathophysiology, causes, likelihood and rate of progression, and known health risks (the causation of which by SCCD awaits proof by randomized clinical trials). Conclusions from SCCD data, therefore, often may not apply to clinical deficiency and vice versa. Although many investigators view cobalamin testing as unreliable, cobalamin, like all diagnostic biomarkers, performs satisfactorily in clinical deficiency but less well in SCCD. The lack of a diagnostic gold standard limits the ability to weigh the performance characteristics of metabolic biomarkers such as methylmalonic acid (MMA) and holotranscobalamin II, whose specificities remain incompletely defined outside their relations to each other. Variable cutoff selections affect diagnostic conclusions heavily and need to be much better rationalized. The maximization of reliability and specificity of diagnosis is far more important today than the identification of ever-earlier stages of SCCD. The limitations of all current biomarkers make the combination of >=2 test result abnormalities, such as cobalamin and MMA, the most reliable approach to diagnosing deficiency in the research setting; reliance on one test alone courts frequent misdiagnosis. Much work remains to be done. PMID- 21593513 TI - The natural history of treated Parkinson's disease in an incident, community based cohort. AB - BACKGROUND: Our understanding of the natural history of idiopathic Parkinson's disease (PD) remains limited. In the era of potential disease modifying therapies, there is an urgent need for studies assessing the natural evolution of treated PD from onset so that relevant outcome measures can be identified for clinical trials. No previous studies have charted progression in unselected patients followed from the point of diagnosis. METHODS: A representative cohort of 132 PD patients was followed from diagnosis for up to 7.9 years (mean 5.2 years). Comprehensive clinical and neuropsychological evaluations were performed every 18 months. Disease progression was evaluated using well validated clinical measures (motor progression and development of dyskinesia on the Unified PD Rating Scale and Hoehn-Yahr scale, dementia onset according to DSM-IV criteria). Multi-level linear modelling was used to chart the nature and rate of progression in parkinsonian symptoms and signs over time. The prognostic importance of baseline demogr'aphic, clinical and genetic variables was evaluated using survival analysis. RESULTS: Axial (gait and postural) symptoms evolve more rapidly than other motor features of PD and appear to be the best index of disease progression. Conversely, conventional outcome measures are relatively insensitive to change over time. Earlier onset of postural instability (Hoehn Yahr stage 3) is strongly associated with increased age at disease onset and has a significant impact on quality of life. CONCLUSIONS: Dementia risk is associated with increased age, impaired baseline semantic fluency and the MAPT H1/H1 genotype. The efficacy of disease modifying therapies may be more meaningfully assessed in terms of their effects in delaying the major milestones of PD, such as postural instability and dementia, since it is these that have the greatest impact on patients. PMID- 21593512 TI - Biomarkers of vitamin B-12 status in NHANES: a roundtable summary. AB - A roundtable to discuss the measurement of vitamin B-12 (cobalamin) status biomarkers in NHANES took place in July 2010. NHANES stopped measuring vitamin B 12-related biomarkers after 2006. The roundtable reviewed 3 biomarkers of vitamin B-12 status used in past NHANES--serum vitamin B-12, methylmalonic acid (MMA), and total homocysteine (tHcy)--and discussed the potential utility of measuring holotranscobalamin (holoTC) for future NHANES. The roundtable focused on public health considerations and the quality of the measurement procedures and reference methods and materials that past NHANES used or that are available for future NHANES. Roundtable members supported reinstating vitamin B-12 status measures in NHANES. They noted evolving concerns and uncertainties regarding whether subclinical (mild, asymptomatic) vitamin B-12 deficiency is a public health concern. They identified the need for evidence from clinical trials to address causal relations between subclinical vitamin B-12 deficiency and adverse health outcomes as well as appropriate cutoffs for interpreting vitamin B-12-related biomarkers. They agreed that problems with sensitivity and specificity of individual biomarkers underscore the need for including at least one biomarker of circulating vitamin B-12 (serum vitamin B-12 or holoTC) and one functional biomarker (MMA or tHcy) in NHANES. The inclusion of both serum vitamin B-12 and plasma MMA, which have been associated with cognitive dysfunction and anemia in NHANES and in other population-based studies, was preferable to provide continuity with past NHANES. Reliable measurement procedures are available, and National Institute of Standards and Technology reference materials are available or in development for serum vitamin B-12 and MMA. PMID- 21593514 TI - War exposure, 5-HTTLPR genotype and lifetime risk of depression. AB - BACKGROUND: In 1962 approximately 1.5 million French people living in Algeria were repatriated to France in very poor and often life-threatening conditions. These people constitute a cohort for the study of the long-term impact of gene environment interaction on depression. AIMS: To examine the interaction between a highly stressful life event and subsequent depression, and its modulation by a length polymorphism of the serotonin transporter gene (5-HTTLPR). METHOD: A community sample of people aged 65 years and over residing in the Montpellier region of the south of France was randomly recruited from electoral rolls. Genotyping was performed on 248 repatriated persons and 632 controls. Current and lifetime major and minor depressive disorders were assessed according to DSM-IV criteria. RESULTS: A significant relationship was observed between exposure to repatriation and subsequent depression (P<0.002), but there was no significant effect of gene alone (P = 0.62). After controlling for age, gender, education, disability, recent life events and cognitive function, the gene-environment interaction (repatriation * 5-HTTLPR) was globally significant (P<0.002; OR = 3.21, 95% CI 2.48-5.12). Individuals carrying the two short (s) alleles of 5 HTTLPR were observed to be at higher risk (P<0.005; OR = 2.34, 95% CI 1.24-4.32), particularly when repatriation occurred before age 35 years (P<0.002; OR = 2.91, 95% CI 1.44-5.88), but this did not reach significance in those who were older at the time of the event (P = 0.067). CONCLUSIONS: The association between depression and war repatriation was significantly modulated by 5-HTTLPR genotype but this appeared to occur only in people who were younger at the time of exposure. PMID- 21593515 TI - Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort study. AB - BACKGROUND: Valproate is one of the most used mood stabilisers for bipolar disorder, although the evidence for the effectiveness of valproate is sparse. AIMS: To compare the effect of valproate v. lithium for treatment of bipolar disorder in clinical practice. METHOD: An observational cohort study with linkage of nationwide registers of all people with a diagnosis of bipolar disorder in psychiatric hospital settings who were prescribed valproate or lithium in Denmark during a period from 1995 to 2006. RESULTS: A total of 4268 participants were included among whom 719 received valproate and 3549 received lithium subsequent to the diagnosis of bipolar disorder. The rate of switch/add on to the opposite drug (lithium or valproate), antidepressants, antipsychotics or anticonvulsants (other than valproate) was increased for valproate compared with lithium (hazard ratio (HR) = 1.86, 95% CI 1.59-2.16). The rate of psychiatric hospital admissions was increased for valproate v. lithium (HR = 1.33, 95% CI 1.18-1.48) and regardless of the type of episode leading to a hospital admission (depressive or manic/mixed). Similarly, for participants with a depressive index episode (HR = 1.87, 95% CI 1.40-2.48), a manic index episode (HR = 1.24, 95% CI 1.01-1.51) and a mixed index episode (HR = 1.44, 95% CI 1.04-2.01), the overall rate of hospital admissions was significantly increased for valproate compared with lithium. CONCLUSIONS: In daily clinical practice, treatment with lithium seems in general to be superior to treatment with valproate. PMID- 21593516 TI - Outcomes of Nordic mental health systems: life expectancy of patients with mental disorders. AB - BACKGROUND: People with mental disorders evince excess mortality due to natural and unnatural deaths. The relative life expectancy of people with mental disorders is a proxy measure of effectiveness of social policy and health service provision. AIMS: To evaluate trends in health outcomes of people with serious mental disorders. METHOD: We examined nationwide 5-year consecutive cohorts of people admitted to hospital for mental disorders in Denmark, Finland and Sweden in 1987-2006. In each country the risk population was identified from hospital discharge registers and mortality data were retrieved from cause-of-death registers. The main outcome measure was life expectancy at age 15 years. RESULTS: People admitted to hospital for a mental disorder had a two- to threefold higher mortality than the general population in all three countries studied. This gap in life expectancy was more pronounced for men than for women. The gap decreased between 1987 and 2006 in these countries, especially for women. The notable exception was Swedish men with mental disorders. In spite of the positive general trend, men with mental disorders still live 20 years less, and women 15 years less, than the general population. CONCLUSIONS: During the era of deinstitutionalisation the life expectancy gap for people with mental disorders has somewhat diminished in the three Nordic countries. Our results support further development of the Nordic welfare state model, i.e. tax-funded community based public services and social protection. Health promotion actions, improved access to healthcare and prevention of suicides and violence are needed to further reduce the life expectancy gap. PMID- 21593517 TI - [Renal cell carcinoma in Iceland: 1971-1990. Survival and incidental diagnosis]. AB - Incidence and mortality of renal cell carcinoma (RCC) is very high in Iceland. Studies have shown increased incidence of incidentally diagnosed RCCs. The significans of incidental diagnosis relating to survival of RCC patients is not known. A retrospective population-based study was carried out on all patients diagnosed with RCC between 1971 and 1990 in Iceland. The aim of the study was to evaluate survival of RCC patients in Iceland with emphasis on incidental diagnosis. By incidental diagnosis we mean tumours that were detected due to imaging techniques or an operation for other than RCC symptoms or signs. Of 236 males and 172 females diagnosed, 308 patients underwent radical nephrectomy with operative mortality of 2.6%. The tumours were classified and staged by Robson's method. Crude probability of survival was evaluated for every stage and multivariate analysis used to find prognostic factors. 224 patients presented with symptoms, the most common of which were abdominal pain, hematuria and weight loss. Between 1971 and 1980 15% of the patients were diagnosed incidentally and 20% between 1981 and 1990 (p>0.1), most often because of intravenous urography. Only 5 tumours were detected by ultrasound and 4 by CT-scans. Five year survival was 76% for stage I and 11% for stage IV. Advanced age, low haemoglobin and high ESR at diagnosis are significant independent risk factors of mortality in multivariate analysis. The year of diagnosis is not a significant prognostic factor after correction for stage. Survival of RCC patients in Iceland is comparable to that in neighbouring countries. Patients diagnosed incidentally have better survival because of a lower stage. The use of ultrasound and CT-scans has not significantly increased incidentally diagnosed tumours. Survival has remained the same for the last two decades. PMID- 21593518 TI - [The use of a helicopter for emergency services in Iceland in 1991]. AB - The study objective was to review the utilization of the Icelandic Coast Guard Helicopter Emergency Services and to evaluate the condition and treatment and determine the outcome of patients transported. Retrospective review of the flight physicians' medical records for the year 1991 was made. Additional information was obtained from the medical records of the hospitals to which the patients were admitted and from the log books of the Coast Guard Coordination Center. Using a modification of the ASA-classification, each patient's condition was evaluated. The usefulness of the helicopter as means of transportation and the importance of the flight physician as a crew member was evaluated as well. Seventy two individuals were transported in 57 flights. The majority of those transported, 54 (76%) were males. Of these 36 (56%) were between 20 and 40 years of age. The majority or 44 (61%) of the patients transported were trauma victims. Forty four (61%) were classified as seriously ill or injured (class III to IV). Eighteen (25%) were moderately ill or injured. Most of these patients were rescued from the ocean or the wilderness. Ten (14%) were healthy individuals rescued from danger at sea. Forty three of the flights were directly to the scene, only 14 were interhospital transfers. Approximately one third of the individuals were flown in from rural areas, one third from the wilderness and one third from off shore. A helicopter was found to be a necessary means of transportation for 32 (45%) individuals and important for the transportation of other 39 (54%). Treatment provided by the flight physician was regarded as necessary for the beneficial outcome of 13 (18%) patients and important for 29 (40%). Our conclusion is that helicopters are a vitaly important component of emergency medical services (EMS) and search and rescue (SAR) in Iceland. A flight physician is a necessary crew member on board the helicopter on all EMS- and SAR- runs. Helicopters may not yet be adequately utilized for emergency services in Iceland. PMID- 21593519 TI - [The use of tranquillizers and hypnotics. Quality assessment of drug information from the medical records and from the pharmacy in Egilsstadir district during a four year period]. AB - Different methods have been used to study drug utilisation, i.e. analysis of a)sales statistics from pharmacies, producers and wholesales, b)prescriptions from pharmacies, c)medical records or d)by counting the number of tablets consumed by a patient over a certain period of time. Each of these methods has its advantages and disadvantages, but the reliability of the data and repeatability is of importance. Egilsstadir district is located on the east part of Iceland. The district is geographically isolated from the rest of the island with only one Health Centre and one pharmacy assessable to the inhabitants. A study was performed to measure the use of tranquillizers and sedatives/hypnotics from medical records and the sales statistics by the local pharmacy. The study period was 4 years, 1986-89, with an average study population of 2949. The medical records in the health centre are partly computerized and partly in a paper record. Through the computerized part of the record all individuals prescribed a tranquillizer and/or a hypnotic during the study period were identified. Their records were then pulled and names of drugs and number of tablets and quantity in mg recorded for each of the study year separately. The medical records and nurses diaries in the local nursing home were pulled and studied the same way. The pharmacy provided sales statistics for each of the study year, including names of drugs, number of tablets and quantity in mg sold. All the results are calculated as defined daily doses (DDD) per 1000 inhabitants per day. The results show good relationship between the sales statistics from the pharmacy and the recorded drug utilisation in the medical record from the local Health Centre. Differences are similar year after year. Somewhat higher figures from the pharmacy are considered mostly caused by prescription filled from persons travelling through the area or coming from the capital city from other doctors. This study and several other studies outside hospitals show lower figures of DDD/1000/day than the official figures for the whole island, see figure 3. The question rises therefore whether hospital use explains this difference or the official figures are not right. PMID- 21593520 TI - [Psychiatric epidemiological research in Iceland]. AB - Epidemiological studies of mental disorders in Iceland have a long tradition. The first study was carried out 150 years ago. The results of some of these studies are reviewed to illustrate the uses of epidemiolgy. According to the results of the first study in 1839-1841 mental disorders seemed to be more prevalent in Iceland than in Denmark. The explanation was methodological, it was easier to identify cases in the small population of Iceland. Later studies have shown that the frequency of mental disorders is similar to that in other countries. The frequency of mental disorders have not changed during this century except for alcoholism, which has increased during the last 50-60 years. The prevalence of mental disorders among people aged 5-60 years is about 20%, but increases after the age of 70 years due to organic mental disorders. The incidence of first consultations with psychiatrists has been just under one per cent per year. The disease expectancy until the age of 61 years has been estimated to be 34%, but is probably higher due to increase in alcoholism and the fact that mild anxiety disorders have not been accounted for. The need for service is far from being met. It can be estimated that 40-50 thousand Icelanders suffer from some mental disorder at any time. Psychiatrists see only about eight thousand patients each year. Approximately seven thousand patients receive prescriptions for psychotropic medications, other than hypnotics, each month. Most of these medications are prescribed by general practitioners, which is their main treatment for mental disorders. About 1,600 persons are treated as inpatients each year for alcoholism and other drug abuse. Preventive work could be made more effective by attending to risk groups which have been defined through epidemiological work. It is imperative that the Icelandic Medical Association defends the freedom of research and encourages further epidemiolgical research in all fields of medicine. Such research in Iceland can contribute to the general knowledge about prevention and treatment of medical disorders. PMID- 21593521 TI - [The role of carbon monoxide and ethanol in fire casualties: A retrospective study of carboxyhemoglobin and blood ethanol levels in fire victims]. AB - The study included 36 fire casualties that were submitted to post-mortem pathological and toxicological examination at the Departments of Forensic Medicine and Pharmacology, University of Iceland, during the period 1971-1990. Twenty eight were males and eigth females. The mean age was 45.3 years (range 3 74 years). Carboxyhemoglobin levels ranged from 0-84%, mean 53.5% (fig. 1) and were considered fatal (> approximately 50%) in 24 cases. Fourteen victims with fatal carboxyhemoglobin levels had no significant burn injuries. Death was therefore attributed to carbon monoxide poisoning alone. In these cases carboxyhemoglobin levels (mean 65.5%, range 49-84) were lower than those found in cases of fatal car exhaust poisonings (mean 73.0%, range 47-87%) investigated by us in the same period (8). The difference was statistically significant (t-test, P<0.01). It supports the idea that combustion products, other than carbon monoxide, may contribute to the toxic effect of fires. Ethanol was found in blood in two thirds (24) of the cases. Blood ethanol levels were in the range 0.47 4.37%0 (mean 2.34%o). Blood ethanol levels and prevalence of inebriation were compared to those found in other fatal accidents investigated by us in the same period. Ethanol levels were significantly higher in the fire cases and inebriation more common than in the reference group (t-test, P<0.01; Chi-square, P<0.001, df=l). Although poisoning with carbon monoxide is of major importance in fire casualties it should not be disregarded that inebriation may often be an equally important factor. This was in fact strongly indicated by our results. PMID- 21593522 TI - [The DeltaF508 mutation in cystic fibrosis patients]. AB - Cystic fibrosis is a serious autosomal recessive disorder. It is commonest among the white Caucasian populations in North and Western Europe. However, no information is available on this disease in Iceland. Only 21 patients have been diagnosed with this condition in Iceland since 1958, hence the prevalence is estimated to be around 1/7000. Three young children, aged 6-30 months, with clinical symptoms suggestive of cystic fibrosis: namely recurrent respiratory infections, malabsorption of fat, low trypsin and chymotrypsin activity and positive sweat test, were investigated. Mutational analysis revealed that all three children were homozygous for the AF508 mutation in the cystic fibrosis gene. This is the first report of cystic fibrosis in Iceland. It is expected that 2-3% of the population are carriers of cystic fibrosis. Identification of all disease-causing mutations in the population should be feasible and encouraged. PMID- 21593523 TI - [Laparoscopic cholecystectomies. First 100 attempted cases at Reykjavik City Hospital]. AB - An account is given of the first 100 attempted laparoscopic cholecystectomies at Borgarspitalinn, Reykjavik City Hospital. The mean age of the patients was 48.7 years with a range of 17-86 years. Seventy seven of the patients were women and 23 men. Ten patients (10%) had acute cholecystitis but others had uncomplicated cholelithiasis. In 10 patients the operation was converted to conventional open cholecystectomy, in most cases because of acute inflammation or adhesions from previous surgery but in one case because of haemorrhage. Five patients had complications, all of which can be considered minor. There was no common bile duct injury and no mortality. No patient required reoperation. The mean operative time for the laparoscopic cholecystectomies was 102 minutes (range 50-222 minutes) and 75% of the operations were completed within two hours. The mean operative time for the first 30 laparoscopic cholecystectomies was 109.7 minutes and dropped to 94.3 minutes for the last 30. The operative time has continued to decrease with further experience. Fifty four percent of the patients who underwent laparoscopic cholecystectomies were discharged from hospital on the first postoperative day and a further 32% on the 2nd day after surgery. The hospital stay was on average four days shorter than after the conventional open cholecystectomies performed in the last months prior to commencing laparoscopic surgery. Eighty three percent of the patients were back to work or previous activity within two weeks of surgery compared to only 11.4% of patients who had undergone open cholecystectomies. Laparoscopic cholecystectomy is felt to be a safe procedure and highly cost-effective. PMID- 21593524 TI - [Assessment of left ventricular ejection fraction by echocardiography]. AB - A new simplified echocardiography method to assess left ventricular (LV) ejection fraction (EF), combining routine M-mode and 2-D echo, was used to measure LV size and evaluate regional wall motion. Echocardiography was performed prior to cardiac catheterization in 35 patients aged 38-69 years (mean 53+8 years). Of these, 14 had suffered an anterior myocardial infarction. At catheterization three patients had ventricular extrasystoles and were omitted from data analysis. The new echo method is a simplification of a model used by Quinones et al. Furthermore, the same measurements were also used to calculate EF by the cube, Teichholz, ellipse, and bullet methods. Compared to the average EF determined by LV angiography of 58+/-17%, EF by the above echocardiography methods in the same respective order was 58+/-16, 70+/-14 (p<0.001), 61+/-15 (p<0.05), 62+/-13 (p<0.01) and 62+/-13% (p<0.01), respectively. The respective correlations (r values) with angiography were 0.93, 0.87, 0.87, 0.91 and 0.91. Thus, compared with LV angiography the new simplified echocardiography method showed the best agreement and correlation, while other methods compared less favorably. PMID- 21593525 TI - [Trends in COPD mortality in Iceland 1951-1990]. AB - We collected information about mortality in chronic obstructive pulmonary diseases (COPD) in Iceland during the time period 1951-1990. During these 40 years only nine individuals younger than 45 years died of bronchial asthma (7 women and 2 men). The mean population during that time period was 149,921 and the mean asthma mortality ratio was 0.15/100,000/year in the age group 0-44 years. The mean mortality ratio in asthma was during the time period 1981-1990: 4.7/ 100,000/year for women and 2.4/100,000/year for men. Compared to the time period 1951-1960 there was a threefold increase in the total mortality in chronic bronchitis in 1981-1990 when the mean mortality ratio was 8.7/100,000/year among men and 7.6/ 100,000/year among women. There was even a greater increase in mortality in emphysema during the 40 years time period and during 1981-1990 the mean mortality ratio was 13.0/100,000/year among men and 11.5 for women. There has been a substantial change in age distribution of the Icelandic population during the time period 1951-1990. Examination of standardized mortality ratio (SMR) shows a tenfold increase in SMR among women in emphysema and a threefold increase in mortality in chronic bronchitis. Among men the SMR for both asthma and chronic bronchitis varied during the time period but there was almost a threefold increase in SMR for emphysema. Thus, there was a relatively greater increase in SMR in COPD among women than men. PMID- 21593526 TI - [Carpal tunnel syndrome]. AB - Analysed are the clinical data of 557 involved hands in 383 patients with carpal tunnel syndrome (CTS) diagnosed and treated in a private neurological practice in Reykjavik, Iceland over a seven year period. The subjects form a selected group as the patients are referred by medical practitioners or seek assistance on their own initiative. The study involved 241 females and 142 males. Age ranged from 14 to 91 years, mean 49 +/- 16.5 years at the time of diagnosis. Both hands were involved in 45.5% of patients, judged clinically. Even though the mean age at diagnosis and duration of symptoms were similar to other studies patients in younger age groups were more common in this study (figure 1). Occupation was known for 376 patients. The occupational classes for the patients are shown in table IV compared to a recent national survey on occupational classification in Iceland. Of 239 females 193 (80.6%) were housewives and of those 152 (78.7%) were also employed. Of the employed patients 82.3% males and 48.8% females were in occupational classes involving manual work compared to 49.5% males and 24.3% females in the control group. The dominant hand was the only hand involved or with worse symptoms in 67.2% of patients (table I). Is CTS an occupational disease? Definite conclusions can not be drawn from these results. Manual workers might seek medical attention more frequently for their symptoms. Symptoms and signs in the 577 hands are shown in table II. Further study on the incidence of CTS in Iceland and it's relationship to the patient's occupation is needed. PMID- 21593527 TI - [Surgical thromboprophylaxis]. AB - Deep vein thrombosis (DVT) and pulmonary embolism (PE) are common and serious post-operative complications. The risk depends on age, general condition, length of operation and type of surgery. Properly used prophylactic therapy with unfractionated heparin, low molecular weight heparin or two-step warfarin can reduce post-operative deaths from PE by 70% and reduce DVT by 50-80% without increasing the risk of serious postoperative bleeding. This review article summarizes the outcome of multiple controlled trials of surgical thromboprophylaxis with various medications. PMID- 21593528 TI - [A health survey of elderly people in Reykjavik]. AB - In 1982 a multifactorial population health survey of people aged 80 years and older and living in the community, was carried out. The mortality registry was examined up to the end of year 1988. By this time 67% had died and the mortality was assessed by Cox's regression analysis on serum cholesterol as one of the main variables included in the survey. The original sample contained 170 persons and 148 were alive at the time of examination. Participation rate of sample is 72%. By end of 1988, 35 persons were alive and 71 dead. Excluded were 22 dead before entry. Serum cholesterol was found to be negatively predictive of mortality in both univariate (p < 0.01) and multivariate analysis when triglycerides, age and smoking were also included (p < 0.01). There was a 0.9% decrease in relative risk for each mg/dl increase of serum cholesterol. Ten persons had serum cholesterol of 160 mg/dl or less and they all died within 10 years from the examination, one of disseminated carcinoma and the rest of non-cancer causes. The strong inverse relationship between mortality and serum cholesterol indicates that this risk factor in old people may be of different nature than in other age groups. PMID- 21593529 TI - [Peptic ulcer disease and Helicobacter pylori. A comparative study of two different three-drug regimens]. AB - Helicobacter pylori (H. pylori) is now known to be strongly associated with gastritis type B, duodenal ulcer, gastric ulcer and perhaps gastric cancer. To cure peptic ulcer disease has become reality. This prospective study included 60 patients, 41 male and 19 females, with long history of peptic ulcer disease (1 - 41 yr, mean 16.5 yr), diagnosed with active duodenal ulcer (50) or gastric ulcer (10) during endoscopy of the upper gastrointestinal tract. After a positive CLO test and histologic confirmation as well as positive culture of H. pylori from the antral mucosa, patients were treated with conventional anti-ulcer therapy. After ulcers were healed (usually in 4 - 6 weeks) patients were randomized to take one of two regimens: 1) colloid bismuth sub-citrate 120 mg, four times a day for 28 days, metronidazole 400 mg, three times a day for 10 days and tetracyclin (DMT) 250 mg, four times a day for 14 days, 2) De-Nol 120 mg, four times a day for 28 days, metronidazole 400 mg, three times a day for 10 days and ampicillin 500 mg, four times a day for 14 days (DMA). Careful monitoring of compliance, symptoms, side effects, H. pylori status and ulcer recurrence by endoscopy was performed at one, two, six and 12 months after completion of triple therapy. Duodenal ulcer recurred in all six patients, that remained H. pylori positive (10%). Eradication of H. pylori was achieved in all patients (30) treated with DMT, and they remained H. pylori negative throughout the 12 months follow-up period. The compliance to the treatment regimens was excellent (<95%). Side effects were frequent (38%), but mild in most cases, mainly soft stool and nausea. One patient had to discontinue the treatment. Re-infection rate was 2% (one patient) during the 12 months follow-up period. A triple therapy with DMT was 100% effective in eradicating H. pylori and statistically superior (p = 0.0105) to DMA at 12 months follow-up. No ulcer recurrence occured in H. pylori negative patients. The importance of persistent and marked symptomatic improvement observed in this study as compared to conventional maintenance treatment has not been emphasized enough in the recent debates on ulcer treatment modalities. The ultimate benefit of H. pylori eradication in peptic ulcer disease should be evaluated by long term follow up studies.. PMID- 21593530 TI - [Blood haemoglobin concentration in elderly people seeking doctors clinics: opposite changes in men and women]. AB - Anaemia of uncertain origin is common in elderly people and is reported to be more common in men than women. We have investigated retrospectively a database of haematological and biochemical data on 16.332 people referred to an outpatient laboratory and compared the blood haemoglobin (Hb) concentration of the sexes. In men the mean adult Hb values of 151 g/1 started to decline at the age of 60 to reach the level of 138 g/1 by the age of 80 and older. In women, by contrast, the mean adult Hb concentration of 134 g/1 started to increase at the age of 50 to 137 g/1 then declining after the age of 70. A multiple regression analysis of variables likely to influence measured Hb values indicated that 6,7 g/1 of the observed 13 g/1 decrease in elderly men could not be explained by chance or selection bias and that an increase of Hb values in women was sustained until after 80 years of age. Results would suggest that sex or sex hormone related factors influence haemoglobin concentrations in elderly people. PMID- 21593531 TI - [Who are admitted to an adolescent psychiatric ward and why?]. AB - The University Hospital's adolescent psychiatric ward is the first health service in Iceland exclusively intended for adolescents. The service was opened in order to meet the needs for a better treatment for adolescents with psychiatric disorders. The service was primarily intended for the most severely disordered who had to be admitted for hospital treatment. The paper shows the use of the unit during its first five years by studying the first 100 patients admitted. Slightly more girls than boys were admitted in the age range 11-19 years, the majority being 14-16 years of age, one half of the patients being 15 years or more. That group comprised a greater proportion with shorter stay, less than nine weeks. Almost one half of the group had conspicuous behaviour disorders at admission, and almost one third had shown suicidal behaviour or expressed having suicidal thoughts. Two thirds of the patients had been under a marked psychosocial stress according to a psychosocial stressor scale. The school and social situation of the majority was bad. One third of the patients were diagnosed as having mood or neurotic disorders according to ICD-10 and almost one half had behaviour or personality disorders. Adolescents with primarily behaviour or social problems, who needed longterm teaching and pedagogical support took up too much of the units resources. Therefore it was not possible to admit a number of patients with other disorders who needed treatment. This might be changed by more and improved outpatient service. PMID- 21593532 TI - [Impotence among Icelandic males 1986-1991]. AB - The estimated prevalence of impotence in western societies approximates 7%. A retrospective descriptive study was performed on 282 Icelandic males (mean age 53.5 years, range 19-79) referred for evaluation of impotence during the period 1986-1991. Diagnostic modalities included measurements of nocturnal penile tumescence (NPT) and penilebrachial index (PBI), hormonal profile and cavernosography. In 55% the NPT was abnormal. In contrast, only 8.2% of PBI was abnormally low. By logistic regression abnormal NPT results correlated with increasing age. Measurements of hormonal profile was performed in 73.4% of the patients. Testosterone was found to be below normal in 12.1%. However, primary or secondary hypogonadism was only found in 3.9% and elevated prolactin in 2.8%. By cavernosography, venous leakage was demonstrated in 3.2% of the men and subsequently ligation of the dorsal penile vein was performed. A trial of testosterone treatment was given in 39.4% of the patients. Impotence is a common complaint among men. Psychological factors predominate in young men and the contribution of somatic etiologic factors increases with age. In the majority of patients relatively simple studies can give useful information on the etiology of impotence. PMID- 21593533 TI - [Advanced cardiac life support outside the hospital in Reykjavik and the surrounding area 1987-1990]. AB - The purpose of this study was to evaluate the results of advanced cardiac life support (ACLS) performed by the crew of the emergency ambulance in Reykjavik and surrounding area from 1987 to 1990 and compare these with results of previous studies. During these four years the crew of the emergency ambulance attempted resuscitation in 195 patients with cardiac arrest. Sixty-four (33%) patients were admitted to the CCU and ICU and 31 (16%) survived to be discharged from the hospital. Asystole was the most common initial arrhythmia, seen in 92 (47%) patients, ventricular fibrillation in 77 (40%) and ventricular tachycardia in four (2%). Other arrhythmias, such as electromechanical dissociation and agonal rhythm were seen in 22 cases (11%). Of those 31, who survived the attack, ventricular fibrillation was by far the most common arrhythmia seen in 23 patients, two had ventricular tachycardia and six asystole on the first rhythm strip. The mean response time of the emergency ambulance was 4.6 minutes, but 4.1 minute when the patient survived the attack. In this study there were relatively more patients with asystole and more cases happened at home than was the case in 1982 to 1986 when the emergency ambulance was not operated during nights or on Sundays and holidays. Witnesses to cardiac arrest are not present nearly as often at home and the results of ACLS at home are also not as good as of ACLS elsewhere. No significant difference is between the main results of this study and the first study of ACLS in the prehospital setting in Reykjavik (1). PMID- 21593534 TI - [Mortality and resyncope in group of 111 patients five years after syncopal attack]. AB - Mortality and resyncope were investigated after five years in 111 patients with syncope, a prospective study conducted at the Reykjavik City Hospital 1985-1986. Twenty one (18.9%) patients have died in this interval, 90 living, 81 patients were traced and resyncope occurred among 20 (24.7%) due to the same cause in 14 of 20 patients. Four patients died in the group (11) that was originally diagnosed with CVD disease (36.4% p<0.001) compared to expected mortality corrected for age, similar results were found in the group (22) with orthostatic hypotension as the cause of syncope. In the total group 21 died versus four expected (p<0.001). This confirms previous results by other investigators that mortality is high among this group of patients. In repeated study 1988-1989 we found that near syncope was frequently cardiovascular in origin and was a cause in 28% of patients, and orthostatic hypotension 20%. A syncope or near syncope should be investigated thoroughly to arrive at a diagnosis, especially in elderly people. PMID- 21593535 TI - [Infective endocarditis in Icelandic children]. AB - The aim of this study was to investigate the predisposing conditions and etiology of infective endocarditis (IE) in Icelandic children during the last ten years from 1984 to 1993. Records from all cases of IE in Iceland during this period were sampled. Vegetations were confirmed in all patients by echocardiography and in cases of culture negative IE the diagnosis was made on clinical grounds and on the response to antibiotic treatment. During this period eight children were diagnosed with IE. Five of these cases occurred in a cluster during a two months period last year (1993). Four patients had a known heart defect, three had a central venous catheter (CVC) and one patient had no factors known to predispose IE. The most common site of infection was the tricuspid valve seen in six cases, one in the aortic valve and one in the aortic arch. All patients survived without neurological sequel. A positive blood culture was obtained in six cases. The infective organisms were Staphylococcus aureus (three patients), Staphylococcus epidermitis (one patient), Streptococcus sanguis (one patient) and Candida albicans (one patient). The results show that the spectrum of IE in Icelandic children is similar to the changing spectrum elsewhere where infected CVC's are now responsible for relatively high proportion of the cases. This is most likely due to greater use of CVC's especially in neonatal intensive care units. A relatively few cases of typical IE, i.e. in children with an underlying heart lesion or following cardiac surgery, suggests effective prophylactic therapy and follow up. PMID- 21593536 TI - [Hepatitis C virus infections in Iceland. Identification and transmission]. AB - During the three year period of October 1990 to October 1993, 124 individuals were identified with antibodies against the hepatitis C virus at the Department of Medical Virology, University of Iceland. The large majority of these were intravenous drug users but also some had become infected by receiving infected blood or blood products. A hepatitis C antibody prevalence study on 1537 randomly picked serum samples demonstrated the prevalence of 0.20%. This prevalence is lower than in most other countries. PMID- 21593537 TI - [Thyroid cancer in Iceland. Epidemiology and prognostic factors with special emphasis on the results of nuclear DNA-analysis]. AB - All malignant primary tumours of the thyroid gland in Iceland during the 36 years 1955 to 1990 were studied. In all 494 thyroid carcinomas were diagnosed during that period. A considerable increase in the reported incidence of thyroid cancer was noted around 1965 and a decline around 1980. These changes are mainly due to variability in incidence of papillary carcinomas in females. The survival rate corrected for intercurrent death was similar for both papillary and follicular carcinomas. During the observation period there was a decline in mortality rate for this disease. In this study we also analysed if DNA-ploidy status and S-phase fraction had an effect on the prognosis of patients with carcinoma of the thyroid gland. By analysing tumour material from paraffin blocks we were able to evaluate the ploidy status in 424 tumours and S-phase value in 417 tumours. Univariate analysis showed that both the ploidy status and the S-phase fraction gave significant values. When taking into account known prognostic variables of thyroid carcinoma in a multivariate analysis neither the ploidy status nor the S phase value proved significant. PMID- 21593538 TI - [Hepatic resections. The results of using CUSA]. AB - Hepatic tumours, both primaries and secondaries, are common. They are seldom operable, but curative resections are sometimes possible. The aims of the study were to present the result and experience of liver operations (primaries, secondaries and benign lesions) and to present the result of using CUSA in these operations. A retrospective study was carried out to evaluate the result of elective hepatic resections in Iceland between 1986-1993 with the aid of CUSA. The type of tumour and resection, operative bleeding, transfusions, hospital stay and complications were noted. Kaplan-Meyer lifetable was used to estimate survival. Fourteen patients underwent fifteen operations, followed by six complications which resulted in five reoperations and one percutaneous drainage. Bleeding was 3000 ml (median, range 350-10.600 ml), transfusion was 3000 ml (median, range 0-12.000 ml) and hospital stay was 24 days (range 9-108 days). There was no operative mortality. Four of nine patients operated for secondaries are living (44%), 15, 41, 46 og 72 months postoperatively (two with recurrence). Two patients were operated for hepatomas, and one of those is alive 86 months postoperatively and is considered to be cured. We conclude that hepatic resection can be carried out in small centers with comparable results to large published series. The ultrasonic scalpel CUSA seems to make the resection tecnically easier and to diminish the amount of bleeding. PMID- 21593539 TI - [Fatal accidents among seamen occuring at sea and on shore]. AB - The objective was to study specific mortality of seamen with particular reference to fatal accidents that occurred other than at sea. The study is a retrospective cohort study. Included in the cohort were 27.884 seamen, both fishermen and sailors from the merchant fleet, who had been members of a pension fund during 1958-1986. Most standardised mortality ratios were greater than 1: 1.26 for all causes and 1.83 for all external causes. There was no healthy worker effect. The excess of deaths from all external causes included all subcategories of death from accidents, poisonings and violence, not just accidents at sea. A significant trend was found for length of employment at sea, accidental poisoning, other accidents, and accidental drowning; correlation coefficients for all causes, all accidents, suicide, and injuries undetermined whether accidentally or purposely inflicted were 0.7-0.8. Compared with seamen who started work during 1968-1977, those who started work in 1978 or later had higher mortality from all causes, road traffic accidents, poisoning, other accidents, homicide, and injuries unknown whether accidentally or purposely inflicted, but not from all accidents at sea and accidental drowning. Seamen seem to be a special group with a high risk of fatal accidents occurring not only at sea. The association between fatal accidents other than at sea and employment time as seamen, indicates that seamen are modified by their occupation in the direction of hazardous behaviour or lifestyle. PMID- 21593540 TI - [The treatment of arterial hypertension in elderly men in Iceland]. AB - The choice of antihypertensive therapy in elderly Icelanders is unknown. In the database of the Icelandic Heart Association 1145 men, aged 70-84 were alive in 1994. Eight hundred thirty-four came to the Heart Association Clinic, 429 of whom either had hypertension or were found to be hypertensive on examination. The prevalence of hypertension in elderly Icelandic men was therefore about 50%. One hundred fifty-seven men took drugs for hypertension. Ninety-five of them were treated with a single drug, 49 with two drugs and five with three drugs. The type of drugs was unknown concerning eight men. Diuretics and beta-blockers were dominant. Although the comparison between those two classes of drugs was uncontrolled the blood pressure was significantly lower in systole on diuretics. The most common combination was beta-blockers and diuretics, then angiotensin converting enzyme inhibitors and diuretics, finally beta-blockers and calcium blockers. It is suggested that the use of diuretics should be increased in this age group. PMID- 21593541 TI - [Incidence of injuries resulting from physical violence in Reykjavik 1974-1991]. AB - The purpose of this study was to research the incidence of injuries in Reykjavik among those who had been the victims of physical violence. The study examined the computer data on all injury cases resulting from physical violence among legal residents of Reykjavik, the capital area, who were treated at the Emergency Department (ED) of the Reykjavik City Hospital, University of Iceland, from the time period 1974-1991. Data for the year 1991 were analysed with respect to where and when the violence took place. The age-adjusted incidence for injury following physical violence varied with the time period. It increased from 17.3 per thousand per year for men and 7.2 for women in 1974-1976 to 19.3 and 8.4 respectively in 1977-1979. In the period 1980-1982 there was a 30% drop in such cases for both sexes. Since that time there has been a significant increase, such that the incidence for injury following physical violence in 1989-1991 was 19.8 for men and 7.0 for women. The incidence of injury following physical violence was highest among males and females in the age group 15-19 year or 46 and 15, respectively. The incidence of those hospitalized after physical violence doubled from 0.54 to 1.10 for men and from 0.20 to 0.42 for women during the study period. About half (males 53%, females 43%) of those suffering injury resulting from physical violence sought help at the ED on Saturdays or Sundays: among the women 41% had been victims of physical violence in the home, whereas for the men violent aggression was most common in places of entertainment (25%) or outdoors (33%). PMID- 21593542 TI - [Hypertension in the elderly - changing attitudes toward treatment]. AB - Raised blood pressure in the elderly is a frequent finding and is not a benign occurence. It should not be viewed as a normal or inevitable consequence of aging. Recent major intervention trials against hypertension in the elderly have showed clear benefits from actively lowering elevated arterial pressure in this group of patients and also in those with isolated systolic hypertension. This review emphasises the importance of antihypertensive treatment in the elderley and underlines the strategies and problems in the care of elderly patients with hypertension. PMID- 21593543 TI - [Alcohol consumption, smoking and drug abuse among teenagers - a prospective study]. AB - Many of the social and health problems of teenagers today are related to the use of intoxicating drugs. In 1990 the use of Lions Quest began in primary schools in Iceland. With Lions Quest the young are taught life skills in order to be helped to live a healthy life without tobacco, alcohol or other intoxicating drugs. The aim of this study, therefore, was to try to determine what factors influence teenage use of intoxicants and whether the attitudes and drug consumption of those teenagers who had participated in Lions Quest were any different from those who had not. The research is a continuation of a comparative study where students were administered questionnaires to ascertain their attitudes toward life and toward the use of intoxicating substances. In 1989 the survey covered 566 students 12-13 years of age and three years later in 1992 reached 500 of the former respondents when they were 15-16 years old. "The schools were chosen such that the study reflected the attitudes of students both in sparsely and in densely settled areas. The study showed that of the 15-16 year olds 18.6% smoked daily, 44.4% had felt the effects of alcohol four times or more, and 5% had a history of repeated drug abuse (cannabis, sniffing solvents, etc.) The use of various intoxicating substances is strongly correlated, a fact that supports the hypothesis that attitudes toward life and conditions that lead to the use of one type of drug also support the use of other drugs. Those teenagers who used drugs had a great deal in common as regards attitudes toward life and the pattern of family relations. They were not as close to their families as were teenagers who did not use drugs, were seldom home in the evening and had few interests in common with their parents. The parents were more often divorced, smoking in the home was more common and alcohol consumption had more frequently caused family problems. These teenagers were more easily influenced, were more dependent on their friends, had less self-confidence, and were less apt to participate in sports and scouts. Their academic presentation was also lower. There was no significant difference in the level of drug use of teenagers who had participated in Lions Quest and those in the control group. Research in other countries has shown that programs of this kind have succeeded well in preventing drug abuse. The reason why the present study did not show the same result may be because teaching materials of this kind are so new to the Icelandic school system and also because the instructional material had not been given a real place in the legally required curriculum at the time the survey was carried out. PMID- 21593545 TI - Activation of retinal ganglion cells following epiretinal electrical stimulation with hexagonally arranged bipolar electrodes. AB - We investigated retinal ganglion cell (RGC) responses to epiretinal electrical stimulation delivered by hexagonally arranged bipolar (Hex) electrodes, in order to assess the feasibility of this electrode arrangement for future retinal implant devices. In vitro experiments were performed using rabbit retinal preparations, with results compared to a computational model of axonal stimulation. Single-unit RGC responses to electrical stimulation were recorded with extracellular microelectrodes. With 100 us/phase biphasic pulses, the threshold charge densities were 24.0 +/- 11.2 and 7.7 +/- 3.2 uC cm(-2) for 50 and 125 um diameter Hex electrodes, respectively. Threshold profiles and response characteristics strongly suggested that RGC axons were the neural activation site. Both the model and in vitro data indicated that localized tissue stimulation is achieved with Hex electrodes. PMID- 21593547 TI - Effects of GABA receptor antagonists on thresholds of P23H rat retinal ganglion cells to electrical stimulation of the retina. AB - An electronic retinal prosthesis may provide useful vision for patients suffering from retinitis pigmentosa (RP). In animal models of RP, the amount of current needed to activate retinal ganglion cells (RGCs) is higher than in normal, healthy retinas. In this study, we sought to reduce the stimulation thresholds of RGCs in a degenerate rat model (P23H-line 1) by blocking GABA receptor mediated inhibition in the retina. We examined the effects of TPMPA, a GABA(C) receptor antagonist, and SR95531, a GABA(A) receptor antagonist, on the electrically evoked responses of RGCs to biphasic current pulses delivered to the subretinal surface through a 400 um diameter electrode. Both TPMPA and SR95531 reduced the stimulation thresholds of ON-center RGCs on average by 15% and 20% respectively. Co-application of the two GABA receptor antagonists had the greatest effect, on average reducing stimulation thresholds by 32%. In addition, co-application of the two GABA receptor antagonists increased the magnitude of the electrically evoked responses on average three-fold. Neither TPMPA nor SR95531, applied alone or in combination, had consistent effects on the stimulation thresholds of OFF center RGCs. We suggest that the effects of the GABA receptor antagonists on ON center RGCs may be attributable to blockage of GABA receptors on the axon terminals of ON bipolar cells. PMID- 21593548 TI - Special issue containing contributions from the Sixth Biennial Research Congress of The Eye and the Chip. PMID- 21593549 TI - Retinal ganglion cell responses to voltage and current stimulation in wild-type and rd1 mouse retinas. AB - Retinal prostheses are being developed to restore vision for those with retinal diseases such as retinitis pigmentosa or age-related macular degeneration. Since neural prostheses depend upon electrical stimulation to control neural activity, optimal stimulation parameters for successful encoding of visual information are one of the most important requirements to enable visual perception. In this paper, we focused on retinal ganglion cell (RGC) responses to different stimulation parameters and compared threshold charge densities in wild-type and rd1 mice. For this purpose, we used in vitro retinal preparations of wild-type and rd1 mice. When the neural network was stimulated with voltage- and current controlled pulses, RGCs from both wild-type and rd1 mice responded; however the temporal pattern of RGC response is very different. In wild-type RGCs, a single peak within 100 ms appears, while multiple peaks (approximately four peaks) with ~ 10 Hz rhythm within 400 ms appear in RGCs in the degenerated retina of rd1 mice. We find that an anodic phase-first biphasic voltage-controlled pulse is more efficient for stimulation than a biphasic current-controlled pulse based on lower threshold charge density. The threshold charge densities for activation of RGCs both with voltage- and current-controlled pulses are overall more elevated for the rd1 mouse than the wild-type mouse. Here, we propose the stimulus range for wild-type and rd1 retinas when the optimal modulation of a RGC response is possible. PMID- 21593551 TI - Laser spectroscopy on volatile sulfur compounds: possibilities for breath analysis. AB - There is an emerging interest in the detection of volatile sulfur compounds (VSCs) in the breath environment, given their biological relevance as potential signatures of several pathological conditions. Particularly, laser-based spectroscopic sensors are candidates for conducting accurate breath diagnostics in clinical settings. With these aims in mind, the current status of VSC sensing via laser absorption spectroscopy is reviewed in this paper. Attention has been focused on the most promising exhaled markers of pathological conditions, namely hydrogen sulfide, carbonyl sulfide, methanethiol, carbon disulfide and dimethyl sulfide. Details of the most relevant spectroscopic studies conducted on such molecules are presented, together with suggestions on the future direction of this challenging analytical field. PMID- 21593546 TI - Encoding visual information in retinal ganglion cells with prosthetic stimulation. AB - Retinal prostheses aim to restore functional vision to those blinded by outer retinal diseases using electric stimulation of surviving retinal neurons. The ability to replicate the spatiotemporal pattern of ganglion cell spike trains present under normal viewing conditions is presumably an important factor for restoring high-quality vision. In order to replicate such activity with a retinal prosthesis, it is important to consider both how visual information is encoded in ganglion cell spike trains, and how retinal neurons respond to electric stimulation. The goal of the current review is to bring together these two concepts in order to guide the development of more effective stimulation strategies. We review the experiments to date that have studied how retinal neurons respond to electric stimulation and discuss these findings in the context of known retinal signaling strategies. The results from such in vitro studies reveal the advantages and disadvantages of activating the ganglion cell directly with the electric stimulus (direct activation) as compared to activation of neurons that are presynaptic to the ganglion cell (indirect activation). While direct activation allows high temporal but low spatial resolution, indirect activation yields improved spatial resolution but poor temporal resolution. Finally, we use knowledge gained from in vitro experiments to infer the patterns of elicited activity in ongoing human trials, providing insights into some of the factors limiting the quality of prosthetic vision. PMID- 21593552 TI - Origin of activation energy in a superionic conductor. AB - The characteristics of cation diffusion with many-body effects are discussed using Ag beta-alumina as an example of a superionic conductor. Polarized Raman spectra of Ag beta-alumina have been measured at room temperature. The interatomic potentials were determined by a non-linear least square fitting between the phonon eigenvalues from the Raman observations and a dynamical matrix calculation based on a rigid-ion model. The obtained potential parameters for the model crystal of Ag beta-alumina successfully reproduce the macroscopic properties with respect to the heat capacity, isothermal compressibility and self diffusion constant. A molecular dynamics (MD) calculation has been carried out using the model crystal of Ag beta-alumina to understand the many-body effects for the fast ionic diffusion. It was found that the Ag-Ag repulsion by excess Ag defects significantly reduced the cost of the energy difference of the occupancy between the stable and metastable sites. It is possible for the system to take various configurations of the mobile ions through defects easily, and then the fast ionic diffusion will appear. On the other hand, the Ag-Ag repulsion changes the dynamics of the Ag ions from a random hopping to a cooperative motion. In the cooperative motion, the ionic transport becomes difficult due to the additional energy required for the structural relaxation of the surrounding Ag ions. We propose a new insight into the superionic conduction, that is, the activation energy for the ionic transport is composed of two kinds of elements: a 'static' activation energy and a 'dynamic' one. The static activation energy is the cost of the averaged energy difference in the various structural configurations in the equilibrium state. The dynamic activation energy is the additional energy required for the structural relaxation induced by the jump process. PMID- 21593550 TI - Multiple factors may influence the performance of a visual prosthesis based on intracortical microstimulation: nonhuman primate behavioural experimentation. AB - We hypothesize that a visual prosthesis capable of evoking high-resolution visual perceptions can be produced using high-electrode-count arrays of penetrating microelectrodes implanted into the primary visual cortex of a blind human subject. To explore this hypothesis, and as a prelude to human psychophysical experiments, we have conducted a set of experiments in primary visual cortex (V1) of non-human primates using chronically implanted Utah Electrode Arrays (UEAs). The electrical and recording properties of implanted electrodes, the high resolution visuotopic organization of V1, and the stimulation levels required to evoke behavioural responses were measured. The impedances of stimulated electrodes were found to drop significantly immediately following stimulation sessions, but these post-stimulation impedances returned to pre-stimulation values by the next experimental session. Two months of periodic microstimulation at currents of up to 96 uA did not impair the mapping of receptive fields from local field potentials or multi-unit activity, or impact behavioural visual thresholds of light stimuli that excited regions of V1 that were implanted with UEAs. These results demonstrate that microstimulation at the levels used did not cause functional impairment of the electrode array or the neural tissue. However, microstimulation with current levels ranging from 18 to 76 uA (46 +/- 19 uA, mean +/- std) was able to elicit behavioural responses on eight out of 82 systematically stimulated electrodes. We suggest that the ability of microstimulation to evoke phosphenes and elicit a subsequent behavioural response may depend on several factors: the location of the electrode tips within the cortical layers of V1, distance of the electrode tips to neuronal somata, and the inability of nonhuman primates to recognize and respond to a generalized set of evoked percepts. PMID- 21593553 TI - Magnetic phase diagram of interacting nanoparticle systems under the mean-field model. AB - The disordered random-anisotropy magnetic nanoparticle systems with competing dipolar interactions and ferromagnetic exchange couplings are investigated by Monte Carlo simulations. Superspin glass (SSG) and superferromagnetic (SFM) behaviors are found at low temperatures depending on the interactions. Based on the mean-field approximation, the Curie-Weiss temperature T(CW) = 0 is suggested as the phase boundary between the SSG systems and the SFM systems, which is evidenced by the spontaneous magnetizations and relaxations. The magnetic phase diagram is plotted. PMID- 21593554 TI - Two-phonon processes of intraband relaxation in the terahertz regime in quantum dots. AB - We theoretically investigate the intraband relaxation of quantum dots in the terahertz regime due to two acoustic phonon scattering by applying a lattice relaxation approach based on the deformation potential coupling between electrons and acoustic phonons. In particular, we find that the relaxation time depends strongly on the ratio of two acoustic phonons. The influences of the energy separation between the ground and first excited state, the quantum dot height, and the lattice temperature on the relaxation time are also discussed. Our theoretical results not only give a reasonable explanation for the current experimental measurement but also provide some insight into two-phonon intraband relaxation in quantum dots. PMID- 21593555 TI - A proposal for implementing an n-qubit controlled-rotation gate with three-level superconducting qubit systems in cavity QED. AB - We present a method for implementing an n-qubit controlled-rotation gate with three-level superconducting qubit systems in cavity quantum electrodynamics. The two logical states of a qubit are represented by the two lowest levels of each system while a higher energy level is used for the gate implementation. The method operates essentially by preparing a W state conditioned on the states of the control qubits, creating a single photon in the cavity mode, and then performing an arbitrary rotation on the states of the target qubit with the assistance of the cavity photon. It is interesting to note that the basic operational steps for implementing the proposed gate do not increase with the number of qubits n, and the gate operation time decreases as the number of qubits increases. This proposal is quite general, and can be applied to various types of superconducting devices in a cavity or coupled to a resonator. PMID- 21593556 TI - Plaquette valence bond ordering in a J1-J2 Heisenberg antiferromagnet on a honeycomb lattice. AB - We study an S = 1/2 Heisenberg model on the honeycomb lattice with first and second neighbor antiferromagnetic exchange (J(1)-J(2) model), employing exact diagonalization in both the S(z) = 0 basis and nearest neighbor singlet valence bond (NNVB) basis. We find that for 0.2 < J(2)/J(1) < 0.3, the NNVB basis gives a proper description of the ground state in comparison with the exact results. By analyzing the dimer-dimer as well as the plaquette-plaquette correlations and also defining appropriate structure factors, we investigate possible symmetry breaking states as the candidates for the ground state in the frustrated region. We provide a body of evidence in favor of plaquette valence bond ordering for 0.2 < J(2)/J(1) < 0.3. By further increasing the ratio J(2)/J(1), this state undergoes a transition to the staggered dimerized state. PMID- 21593557 TI - Quantum criticality in the iron pnictides and chalcogenides. AB - Superconductivity in the iron pnictides and chalcogenides arises at the border of antiferromagnetism, which raises the question of the role of quantum criticality. In this topical review, we describe the theoretical work that led to the prediction of a magnetic quantum critical point arising out of a competition between electronic localization and itinerancy, and the proposal for accessing it by using isoelectronic P substitution for As in the undoped iron pnictides. We go on to compile the emerging experimental evidence in support of the existence of such a quantum critical point in isoelectronically tuned iron pnictides. We close by discussing the implications of these results for the physics of the iron pnictides and chalcogenides. PMID- 21593558 TI - The impact of a novel apolipoprotein E and amyloid-beta protein precursor interacting protein on the production of amyloid-beta. AB - Alzheimer's disease (AD) is characterized by disrupted metabolism of the amyloid beta protein precursor (AbetaPP) and deposition of a byproduct, the amyloid-beta (Abeta) peptide, into plaques. AD is also genetically linked to the gene for apolipoprotein E (apoE). We have identified a novel apoE-binding protein (TMCC2) that also forms a complex with AbetaPP. TMCC2 is a neuronal, predominantly ER localized, protein that co-migrated with AbetaPP during native gel electrophoresis of rat brain extracts, and co-immunoprecipitated with AbetaPP from transfected human cell lysates. TMCC2 bound apoE in an isoform-specific manner in vitro and co-immunoprecipitated with apoE from cell lysates. Co expression of apoE and TMCC2 stimulated Abeta production from the "Swedish" variant of AbetaPP (K595 M/N596L) by up to 1.5-fold (p < 0.05), and also from the 99-amino acid C-terminal fragment of AbetaPP (AbetaPP-C99) that is the direct precursor to Abeta by 1.5- to 2-fold (p < 0.0005), this effect was greater with apoE4 than apoE3 (p = 0.02); both apoE3 and apoE4 stimulated a greater increase in Abeta1-42 than Abeta1-40 production from AbetaPP-C99 in the presence of TMCC2. The interaction between TMCC2 and apoE may therefore contribute to disrupted AbetaPP metabolism and altered Abeta production, as observed in AD. PMID- 21593559 TI - Screening for Alzheimer's disease among illiterate elderly: accuracy analysis for multiple instruments. AB - One of the challenges in screening for dementia in developing countries is related to performance differences due to educational and cultural factors. This study evaluated the accuracy of single screening tests as well as combined protocols including the Mini-Mental State Examination (MMSE), Verbal Fluency animal category (VF), Clock Drawing test (CDT), and Pfeffer Functional Activities Questionnaire (PFAQ) to discriminate illiterate elderly with and without Alzheimer's disease (AD) in a clinical sample. Cross-sectional study with 66 illiterate outpatients diagnosed with mild and moderate AD and 40 illiterate normal controls. Diagnosis of AD was based on NINCDS-ADRDA. All patients were submitted to a diagnostic protocol including a clinical interview based on the CAMDEX sections. ROC curves area analyses were carried out to compare sensitivity and specificity for the cognitive tests to differentiate the two groups (each test separately and in two by two combinations). Scores for all cognitive (MMSE, CDT, VF) and functional assessments (PFAQ) were significantly different between the two groups (p < 0.001). The best screening instruments for this sample of illiterate elderly were the MMSE and the PFAQ. The cut-off scores for the MMSE, VF, CDT, and PFAQ were 17.5, 7.5, 2.5, and 11.5, respectively. The most sensitive combination came from the MMSE and PFAQ (94.1%), and the best specificity was observed with the combination of the MMSE and CDT (89%). Illiterate patients can be successfully screened for AD using well-known screening instruments, especially in combined protocols. PMID- 21593560 TI - Interaction between vascular factors and the APOE epsilon4 allele in predicting rate of progression in Alzheimer's disease. AB - Vascular factors have been shown to affect the rate of Alzheimer's disease (AD) progression. However, the effect of the APOE epsilon4 allele on rate of progression has been ambiguous. Little research to date has examined an interaction between vascular factors and the APOE epsilon4 allele in predicting decline among AD patients. 216 participants with incident AD from a population of elderly persons in Cache County, Utah, were followed for a mean of 3.3 years and 4.2 follow-up visits. A history of vascular risk factors and conditions and anti hypertensive use was assessed at the diagnostic visit. Linear mixed effects models tested interactions between the vascular factors, APOE epsilon4, and time as predictors of clinical progression on the Mini-Mental State Exam (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Multiple comparisons were corrected using the Holm-Bonferroni method. There was a 3-way interaction between stroke, APOE epsilon4 and time in predicting MMSE decline (LR chi2 = 10.32, 2 df, p = 0.006). For the CDR-SB, there were 3-way interactions between the APOE epsilon4, time and either myocardial infarction (LR chi2 = 17.83, 2 df, p = 0.0001) or stroke (LR chi2 = 11.48, 2 df, p = 0.003. Results suggest a complex relationship between the APOE epsilon4 and vascular factors in predicting cognitive and functional progression. Among individuals with a history of stroke or myocardial infarction at baseline, progression of AD is influenced by APOE epsilon4 carrier status and varies by time after AD diagnosis. PMID- 21593561 TI - Use of antiepileptic drugs among community-dwelling persons with Alzheimer's disease in Finland. AB - Persons with Alzheimer's disease (AD) may be particularly susceptible to the adverse drug reactions associated with anti-epileptic drugs (AEDs). The objective of this study was to investigate the national pattern of AED use among community dwelling persons with and without AD in Finland. All persons (n = 28,093) with a diagnosis of AD in 2005 were identified by the Social Insurance Institution of Finland (SII). The SII also identified comparison persons without AD individually matched in terms of age (+/- one year), gender, and region. Records of all reimbursed drug purchases in 2005 were extracted from the Finnish National Prescription Register. Conditional logistic regression was used to calculate unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for reimbursed AED use. Persons with and without AD were aged 42 to 101 (mean 80.0) years, with men comprising 32.2% (n = 9,048) of persons. Epilepsy was diagnosed for 2.1% of persons with AD compared to 1.3% of persons without AD (OR 1.66; 95% CI, 1.45 to 1.89). AEDs were used by 5.0% (n = 1417) of persons with AD compared to 3.4% (n = 955) persons without AD (adjusted OR 1.33; 95% CI, 1.21 to 1.46). The annual prevalence of phenytoin, clonazepam, valproic acid, and oxcarbazepine use was higher among persons with AD. In contrast, pregabalin use was lower among persons with AD (adjusted OR 0.83; 95% CI, 0.70 to 0.99). Use of older AEDs is more prevalent among persons with AD, despite persons with AD being particularly vulnerable to adverse drug reactions associated with many older AEDs. PMID- 21593562 TI - Selenium and Alzheimer's disease: a systematic review. AB - Preventing Alzheimer's disease (AD) would require knowledge about its etiology to a degree of detail not yet available. The major hurdle in understanding the disease lies in teasing out the various causes and their complex interactions. Since considerable data have accrued showing that the essential trace element selenium (Se) might play different roles in the progression of AD, we conducted a systematic review of the literature regarding Se and AD. We identified 9 placebo controlled studies (6 were multiple supplement trials including Se, 1 was ongoing), 4 prospective, 4 cross-sectional, 15 case control, 24 autopsy studies, as well studies in animals and cells. There is an absence of consistent clinical evidence as to whether supplementation of Se is beneficial in the treatment of AD and how Se levels are altered in brain, cerebrospinal fluid, and blood of patients with AD. Some longitudinal and cross-sectional studies, however, show an association of Se status and cognitive function. Findings from molecular biology reveal a decisive role of Se in the pathogenesis of AD. In summary, the current state of knowledge provides no evidence for a role of Se in the treatment of AD, but allows speculation on a potential preventive relevance. Large trials of long term duration could provide definitive answers. PMID- 21593563 TI - Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer's disease. AB - Oxidative stress has been associated with normal aging and Alzheimer's disease (AD). However, little is known about oxidative stress in mild cognitive impairment (MCI) patients who present a high risk for developing AD. The aim of this study was to investigate plasma production of the lipid peroxidation marker, malonaldehyde (MDA) and to determine, in erythrocytes, the enzymatic antioxidant activity of catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) in 33 individuals with MCI, 29 with mild probable AD and 26 healthy aged subjects. GR/GPx activity ratio was calculated to better assess antioxidant defenses. The relationship between oxidative stress and cognitive performance was also evaluated by the Mini Mental State Examination (MMSE). AD patients showed higher MDA levels than both MCI and healthy elderly subjects. MCI subjects also exhibited higher MDA levels compared to controls. Catalase and GPx activity were similar in MCI and healthy individuals but higher in AD. GR activity was lower in MCI and AD patients than in healthy aged subjects. Additionally, GR/GPx ratio was higher in healthy aged subjects, intermediate in MCI and lower in AD patients. No differences in GST activity were detected among the groups. MMSE was negatively associated with MDA levels (r = 0.31, p = 0.028) and positively correlated with GR/GPx ratio in AD patients (r = 0.68, p < 0.001). MDA levels were also negatively correlated to GR/GPx ratio (r = -0.31, p = 0.029) in the AD group. These results suggest that high lipid peroxidation and decreased antioxidant defenses may be present early in cognitive disorders. PMID- 21593564 TI - Effect of environmental enrichment on the immunoendocrine aging of male and female triple-transgenic 3xTg-AD mice for Alzheimer's disease. AB - We have previously shown that 3xTgAD mice (triple-transgenic mice for Alzheimer's disease, harboring PS1(M146V), AbetaPP(Swe), tau(P301L) transgenes) suffer detrimental changes in some key lymphocyte functions, described as health and longevity markers, with males being more affected than females and showing higher mortality rates. In the present work, 3xTgAD and wild type 129/C57BL6 male and female non- and environmentally enriched mice were used. The enriched environment (EE) began in the adulthood (6 months) and lasted for 5.5 months. The animals were sacrificed at advanced stages of the disease (15 month-old), and spleen, thymus, and plasma were obtained. The results indicate that 3xTg-AD males are especially benefitted from EE exposure, as shown by the improvement in lymphocyte functional activities such as chemotaxis and natural killer cytotoxicity, as well as in plasma corticosterone levels. By contrast, wild type females seem to be highly sensitive to EE removal, as regards the proliferation capacity of lymphocytes and their intracellular glutathione content. These results support the relevance of gender differences in AD when screening for new strategies for the control of the disease, and suggest that active life, by means of EE, should be maintained until natural death in order to preserve all the positive effects that this strategy exerts on the immune system. PMID- 21593565 TI - The role of CNI-1493 in the function of primary microglia with respect to amyloid beta. AB - Amyloid-beta (Abeta) oligomer toxicity is a crucial factor in the development of Alzheimer's disease. Therefore, the aim of therapeutic research is to target the modification of secretase activity, increase Abeta degradation, reduce Abeta formation, and modulate Abeta-induced neuroinflammation. Recently, the p38 MAP kinase inhibitor CNI-1493 has been shown to reduce plaque load and has led to an improvement in memory performance in a transgenic mouse model. We examined the role of CNI-1493 in the microglial inflammatory response to Abeta using both a microglia cell line as well as primary microglia isolated from mesocortices. MTT assays were performed to quantify cell viability. FACS analysis was used to measure phagocytosis. We used ELISA to analyse cytokine concentrations in response to CNI-1493 treatment. Western-blot/Dot-blot techniques were used to show the interaction of CNI-1493 with Abeta-oligomers as well as to measure apoptosis in microglia cells. RT-PCR was used to analyze secretase expression, and secretase function was determined using fluorimetric assays. CNI-1493 is able to prevent oligomer formation as well as apoptosis in microglia. A significant reduction was found in the Abeta-induced release of IL-6 and TNF-alpha in the presence of CNI-1493. Phagocytosis is an essential Abeta removal mechanism and was enhanced by CNI-1493 in primary microglia. CNI-1493 also influenced the alpha secretase product C83 with an increase in the treated cells, while a simultaneous reduction in Abeta secretion was also observed. We hypothesize that CNI-1493 not only reduces neuroinflammation and consequent neurodegeneration, but also leads to a shift in AbetaPP-processing towards the non-amyloidogenic pathway. Therefore, CNI-1493 is a promising candidate for the treatment of AD. PMID- 21593566 TI - Autoantibodies against amyloid and glial-derived antigens are increased in serum and cerebrospinal fluid of Lewy body-associated dementias. AB - There is increasing evidence that in Lewy body-associated dementias (encompassing Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB)), the adaptive immune system is altered and the degenerative process includes glial cells in addition to neuronal structures. We therefore aimed to determine levels of autoantibodies against amyloid and glial-derived structures in these dementia types. Using a newly developed Enzyme-linked immunosorbent assay (ELISA), we measured levels of IgG autoantibodies against neuronal and glial structures in serum and cerebrospinal fluid of a total of 91 subjects (13 PDD, 14 DLB, 11 Alzheimer's disease (AD), 11 frontotemporal dementia (FTD), 11 vascular dementia patients (VaD), and 31 healthy controls). Autoantibody levels against alpha synuclein, amyloid-beta42 (Abeta42), myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and S100B were determined. In all groups, autoantibody levels were about three magnitudes higher in serum than in CSF. Serum autoantibody levels against alpha-synuclein, Abeta42, MOG, MBP, and S100B were higher in PDD/DLB compared to tau-associated dementias (AD, FTD), VaD, and controls, respectively, with most of them reaching highly significant p-values. In cerebrospinal fluid (CSF), levels of antibodies against oligodendrocyte derived antigens (MOG, MBP) were significantly increased in PDD/DLB. Increased levels of autoantibodies against both neuronal- and glial-derived antigens in serum and CSF of Lewy body-associated dementias indicate an altered activity of the adaptive immune system in these dementia types. The potential of neural derived IgG autoantibodies as part of a biomarker panel for the diagnosis of Lewy body-associated dementias should be further evaluated. PMID- 21593567 TI - TNF and leptin tell essentially the same story in Alzheimer's disease. AB - Both tumor necrosis factor (TNF) and leptin are, independently, under investigation as the central mechanism for Alzheimer's disease. The wider literature provides every indication that both mediators are part of the same pathways thought to cause functional loss in this condition. This association, which has not been specifically addressed in the Alzheimer's disease literature, may be a useful link to expedite future study into the pathogenesis of this condition. PMID- 21593568 TI - Preanalytical sample handling and sample stability testing for the neurochemical dementia diagnostics. AB - Preanalytical sample handling and storage procedures play an extremely important role in reliably measuring neurochemical dementia diagnostics (NDD) biomarkers: Abeta(1-40), Abeta(1-42), Tau, and pTau181. To test different handling and storage conditions, the following protocols were applied: (a) storage at room temperature for one week, (b) deep-freezing and thawing up to three cycles, (c) deep-freezing, thawing and keeping under +4 degrees C for two days before the analysis, and (d) long-term stability of a deeply frozen sample. Between the first and the seventh day of the storage at room temperature, the percentage of the concentrations (compared to the starting concentrations) fluctuated: 104.3 105.3, 97.6-93.2, 100.6-96.8, and 97.9-90.2 for Abeta(1-40), Abeta(1-42), Tau, and pTau181, respectively. Re-freezing cycles resulted in the percentage fluctuations of the concentrations: 101.1-105.5, 95.4-99.7, 98.3-100.0, and 100.5 101.4 for Abeta(1-40), Abeta(1-42), Tau, and pTau181, respectively. Keeping previously frozen/thawed samples under +4 degrees C for two days resulted in the percentage differences of the concentrations: +15.9, +2.2, -1.1, and -0.1 for Abeta(1-40), Abeta(1-42), Tau, and pTau181, respectively. During long-term stability, the coefficients of linear correlation (R(2)) were: Abeta(1-40), 0.007; Abeta(1-42), 0.02; Tau, 0.011; and pTau181, 0.02, and the corresponding inter-assay coefficients of variation: 13.9%, 13.9%, 11.0%, and 10.7% for Abeta(1 40), Abeta(1-42), Tau, and pTau181, respectively. We conclude that the NDD biomarkers are relatively stable when the cerebrospinal fluid sample is kept at room temperature for about four days; one or two thawing/refreezing cycles do not profoundly affect the biomarkers concentrations, however three cycles result in increased unsystematic variation. The four biomarkers seem to be stable in a sample stored deeply frozen for more than two years. PMID- 21593570 TI - Sodium butyrate improves memory function in an Alzheimer's disease mouse model when administered at an advanced stage of disease progression. AB - Dysregulation of histone acetylation has been implicated in the onset of age associated memory impairment and the pathogenesis of neurodegenerative diseases. Elevation of histone acetylation via administration of histone deacetylase (HDAC) inhibitors is currently being pursued as a novel therapeutic avenue to treat memory impairment linked to Alzheimer's disease (AD). Here we show that severe amyloid pathology correlates with a pronounced dysregulation of histone acetylation in the forebrain of APPPS1-21 mice. Importantly, prolonged treatment with the pan-HDAC inhibitor sodium butyrate improved associative memory in APPPS1 21 mice even when administered at a very advanced stage of pathology. The recovery of memory function correlated with elevated hippocampal histone acetylation and increased expression of genes implicated in associative learning. These data advance our understanding of the potential applicability of HDAC inhibitors for the treatment of AD and suggest that HDAC inhibitors may have beneficial effects even when administered long after the onset of disease associated symptoms. PMID- 21593569 TI - Cholinesterase inhibitors improve both memory and complex learning in aged beagle dogs. AB - Similar to patients with Alzheimer's disease (AD), dogs exhibit age-dependent cognitive decline, amyloid-beta (Abeta) pathology, and evidence of cholinergic hypofunction. The present study sought to further investigate the role of cholinergic hypofunction in the canine model by examining the effect of the cholinesterase inhibitors phenserine and donepezil on performance of two tasks, a delayed non-matching-to-position task (DNMP) designed to assess working memory, and an oddity discrimination learning task designed to assess complex learning, in aged dogs. Phenserine (0.5 mg/kg; PO) significantly improved performance on the DNMP at the longest delay compared to wash-out and partially attenuated scopolamine-induced deficits (15 MUg/kg; SC). Phenserine also improved learning on a difficult version of an oddity discrimination task compared to placebo, but had no effect on an easier version. We also examined the effects of three doses of donepezil (0.75, 1.5, and 6 mg/kg; PO) on performance of the DNMP. Similar to the results with phenserine, 1.5 mg/kg of donepezil improved performance at the longest delay compared to baseline and wash-out, indicative of memory enhancement. These results further extend the findings of cholinergic hypofunction in aged dogs and provide pharmacological validation of the canine model with a cholinesterase inhibitor approved for use in AD. Collectively, these studies support utilizing the aged dog in future screening of therapeutics for AD, as well as for investigating the links among cholinergic function, Abeta pathology, and cognitive decline. PMID- 21593572 TI - Amyloid-beta42 is associated with cognitive impairment in healthy elderly and subjective cognitive impairment. AB - The aim of this study was to predict cognitive performance on the basis of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau) and amyloid-beta42 (Abeta42) in controls and patients at various impairment levels. Previous studies have found an association of CSF T-tau levels with cognitive symptoms, but it has been difficult to relate Abeta to cognition, and it has thus been hypothesized that Abeta reaches a plateau level prior to cognitive symptoms. A comprehensive battery of neuropsychological tests was subjected to factor analysis to yield aggregated cognitive domains. Linear regression models were performed for the total sample of the Gothenburg MCI study (n = 435) and for each level of impairment. Abeta42 and T-tau accounted for a significant proportion of performance in all cognitive domains in the total sample. In controls (n = 60) and patients with subjective cognitive impairment (n = 105), Abeta42 predicted a significant proportion of semantic and working memory performance. For patients with mild cognitive impairment (n = 170), T-tau had the most pronounced impact across cognitive domains, and more specifically on episodic memory, visuospatial, and speed/executive performance. For patients with dementia (n = 100), the most pronounced impacts of Abeta42 were found in episodic memory and visuospatial functioning, while T-tau was substantially associated with episodic memory. Our results suggest that cognition is related to CSF biomarkers regardless of impairment level. Abeta42 is associated with cognitive functions from a potentially early to a later disease phase, and T-tau is more indicative of performance in a later disease phase. PMID- 21593571 TI - The presence and origin of autoantibodies against alpha4 and alpha7 nicotinic acetylcholine receptors in the human blood: possible relevance to Alzheimer's pathology. AB - Alzheimer's disease (AD) is characterized by a loss of alpha4beta2 and alpha7 nicotinic acetylcholine receptors (nAChRs) in the brain and severe memory impairments. Previously, we found that antibodies elicited against extracellular domain of alpha7 nAChR subunit decreased the number of alpha7 nAChRs in the brains of mice and impaired episodic memory. Here we show that antibodies capable to bind alpha7(1-208) are present in the blood of both healthy humans and AD patients. In healthy individuals, their capacity to compete with [(125)-I]-alpha bungarotoxin for the binding to alpha7(1-208) increased with age. The level of such antibodies was significantly elevated in children with severe form of obstructive bronchitis and in mice injected with Lewis lung carcinoma cells expressing both alpha4beta2 and alpha7 nAChRs. Elevated antibody levels were accompanied with decreased surface nAChRs on the blood lymphocytes of children and of mice immunized with alpha7(1-208). Among AD patients, the level of alpha7 nAChR-specific antibodies was significantly larger in people 62.5 +/- 1.5 years old with moderate or severe AD stages (15.2 +/- 1.3 MMSE scores) compared to those of 76 +/- 1.5 years old with the mild (22.7 +/- 0.1 MMSE scores) AD stage. We concluded that alpha7(1-208) nAChR-specific antibodies found in the human blood are formed as a result of common infections accompanied with the destruction of respiratory epithelium. Elevated blood plasma levels of alpha7(1 208) nAChR-specific antibodies are characteristic for the early-onset AD and, therefore, are suggested as one of the risk factors for the development of this form of the disease. PMID- 21593573 TI - Stem cell factor plasma levels are decreased in Alzheimer's disease patients with fast cognitive decline after one-year follow-up period: the Pythia-study. AB - Alzheimer's disease (AD) is the most common cause of cognitive decline in the elderly and is characterized by massive neuronal loss in the brain. Stem cell factor (SCF) is a hematopoietic growth factor that promotes neuroprotective effects and supports neurogenesis in the brain. Decreased SCF plasma levels have been described in AD patients. Whether SCF plasma levels are also associated with the rate of cognitive decline in AD patients has not been reported so far. In the present study, we demonstrate that SCF plasma levels are significantly decreased in AD patients with fast cognitive decline (decrease of Mini-Mental State Examination [MMSE] score > 4 after one year; n = 12) compared to AD patients with slow cognitive decline (decrease of MMSE score <= 4 after one year; n = 28) (fast versus slow cognitive decline: mean +/- SD: 1051.1 +/- 178.7 versus 1237.9 +/- 274.2 pg/ml; p = 0.037). Moreover, SCF plasma levels correlated with the rate of cognitive decline after one year follow-up period (r = 0.315; p = 0.048). In a multiple linear regression analysis, independent predictors of the rate of cognitive decline in our study cohort were age, MMSE scores at baseline, SCF plasma levels, as well as brain-derived neurotrophic factor and activated glycoprotein (GP) IIb/IIIa. These results suggest that lower SCF plasma levels are associated with a higher rate of cognitive decline in AD patients. Thus, treatment strategies increasing SCF plasma levels could be useful for delaying the progression of AD. Further prospective studies are needed to elucidate the value of plasma SCF in a multimarker approach determining AD prognosis. PMID- 21593576 TI - Time trend in the prevalence of adult asthma in Japan: findings from population based surveys in Fujieda City in 1985, 1999, and 2006. AB - BACKGROUND: The burden of asthma is recognized as an important public health problem worldwide. In most countries, the prevalence of asthma has been reported to increase in the last few decades. However, more recent epidemiological studies have shown that the prevalence of asthma has been flat or even decreasing after the 1990 s in some developed countries. The recent time trend in the prevalence of adult asthma in Japan is unknown. METHODS: Population-based surveys were conducted three times in the same region, in 1985, 1999, and 2006, at Fujieda City, Shizuoka, Japan, and the results were reported previously. We compared the results of these surveys to reveal the time trend in the prevalence of adult asthma. Although the questionnaires used in these surveys were not exactly the same, the time trend was assessed by comparing the responses to relevant questions between questionnaires. RESULTS: The prevalences of wheeze following a common cold and dyspneal feeling at night increased significantly from 1985 to 1999 (4.2% to 7.6%, and 3.2% to 5.3%, respectively). The prevalences of lifetime asthma and current asthma also significantly increased from 1999 to 2006 (5.1% to 6.7%, and 1.5% to 3.4%, respectively). CONCLUSIONS: The prevalences of asthma among adults in Fujieda City consistently increased from 1985 to 2006. There was no evidence that the prevalences were in plateau or decreasing. These findings suggest that more efforts are required to stop the increase in the burden of this disease in Japan. PMID- 21593577 TI - An early intensive intervention for inducing inactive asthma in adults--a one year follow-up observation study. AB - BACKGROUND: Treatment strategy that reduces dependence on long-term medication for chronic asthma is preferable. The purpose of the study is to investigate the efficacy of an early intensive intervention for inducing inactive asthma in adults and identify factors that affect the efficacy. METHODS: A prospective study was conducted on subjects who had asthma for two years or less. An intensive intervention consisting of systemic corticosteroid treatment for two weeks followed by inhaled corticosteroid for further 16 weeks with concomitant administration of bronchodilator(s) was administrated on 109 subjects. As a control group, 33 subjects were treated according to the current asthma treatment guidelines for 18 weeks. The primary outcome of the intervention was assessed with symptomatology and use of medication during 12 months after the cessation of treatment period. RESULTS: At one year after the intervention, significantly more patients in the intensive intervention group (41%) than in the control group (24%) had no respiratory symptoms and were medication-free or had experienced minor upper respiratory symptoms (inactive asthma) (P = 0.01). The intensive intervention maintained a significant factor associated with one-year inactive asthma (adjusted odds ratio: 3.61, 95% confidence interval: 1.20-10.84; P = 0.02). Infection as onset cause, asthma duration and pre-treatment %FEV(1.0) were also identified independently associated with inactive asthma. As the limitation, the study was not randomized trial. CONCLUSIONS: Intensive therapy in the early stage is very likely to contribute to increasing one-year asthma inactivity, which may reduce patients' dependence on long-term management by medical treatment. PMID- 21593578 TI - Effects of inhalation or incubation of oxitropium bromide on diaphragm muscle contractility in mice. AB - BACKGROUND: Although oxitropium bromide is used clinically as an anticholinergic drug (i.e., parasympathetic antagonist) to relax airway smooth muscle, we examined whether it has or does not have any effects on diaphragm muscle. METHODS: Three treatment sets, an oxitropium bromide inhalation only group, an oxitropium bromide inhalation plus endotoxin injection group (in vivo) and an oxitropium bromide incubation group (in vitro) were studied as to diaphragm muscle contractile properties. RESULTS: Oxitropium bromide inhalation shifted force-frequency curves upward at 2 h after inhalation (p < 0.05) and inhibited the decrease of force-frequency curves due to endotoxin injection in vivo. Incubation with oxitropium bromide of untreated diaphragm muscle and diaphragm muscle injected with endotoxin did not increase the force-frequency curves dose dependently in vitro; however, it caused both types of muscle to be fatigue resistant. CONCLUSIONS: We speculate that the increment of muscle contractility with the inhalation of oxitropium bromide was induced by the antagonization of musucarinic acetylcholine receptors (mAChR). In addition, the changes of fatigue resistance provoked by oxitropium bromide, which also is speculated to antagonize mAChR, may be beneficial in the treatment of patients with COPD. PMID- 21593579 TI - Interleukin-19 downregulates interleukin-4-induced eotaxin production in human nasal fibroblasts. AB - BACKGROUND: Interleukin-19 (IL-19), a member of the IL-10 family, is characterized as the cytokine suppressing the release and function of several proinflammatory cytokines. For regulation of local reaction in allergic rhinitis (AR), IL-19 might play an especially important role. METHODS: We examined effects of IL-19 on IL-4-induced eotaxin production by human nasal fibroblasts. Early receptor-mediated events (expression of the suppressors of cytokine signaling (SOCS) and phosphorylation of signal transducer and activator of transcription 6 [STAT6]) by IL-19 was examined. Knockdown methods by RNAi were administered to investigate the involvement of those signal transductions. RESULTS: Pretreatment with IL-19 downregulates IL-4-induced eotaxin production, but not interferon gamma(IFN-gamma)-induced RANTES. Pretreatment with IL-19 suppressed the IL-4 induced STAT6 phosphorylation. The IL-19 induced SOCS-1, but not SOCS-3 or SOCS 5. The SOCS-1 knockdown by RNAi diminished pretreatment with IL-19-induced down regulation of eotaxin production. CONCLUSIONS: These results suggest that IL-19 down-regulates IL-4-induced eotaxin production via SOCS-1 in human nasal fibroblasts. In non-hematopoietic cells in AR, IL-19 might be an immunosuppressive factor. PMID- 21593580 TI - Pistachio allergy-prevalence and in vitro cross-reactivity with other nuts. AB - BACKGROUND: Tree nut allergy is characterized by a high frequency of life threatening reactions and is typically lifelong persistent. Some people with a pistachio nut allergy, which is common in the pistachio rich area of Iran, develop a hypersensitivity to other tree nuts as well. The aim of this study was to investigate the prevalence of pistachio nut allergy in Iran, the major pistachio cultivation region in the world. The study also addressed the presence of allergenic cross-reactivity between pistachio and other nuts, including almond, peanut, and cashew in pistachio allergic patients. METHODS: A survey was conducted to determine whether the prevalence of pistachio allergy is affected by exposure to this nut in pistachio cultivation regions, as well as possible cross reactivity between pistachio and other nuts including cashew, almond, and peanut. Inhibition Western blot and inhibition ELISA studies were conducted to assess the presence of allergenic cross-reactivity between pistachio and the other tree nuts. RESULTS: Our results revealed that the prevalence of pistachio allergy is twice as much in pistachio cultivation regions than other areas. Western blotting and inhibition ELISA presented high percentages of inhibition with pistachio and cashew, followed by almond and, to some degree, peanut which indicates different levels of allergenic cross-reactivity. CONCLUSIONS: The results indicate that exposure of people to pistachio significantly affects the prevalence of its allergic reactions. In addition, it was observed that, among pistachio allergic subjects, such exposure may affect the co-sensitivities with other nuts, including cashew and almond. The plant taxonomic classification of pistachio and other tree nuts does appear to predict allergenic cross-reactivity. PMID- 21593581 TI - The influence of environmental exposure to formaldehyde in nasal mucosa of medical students during cadaver dissection. AB - BACKGROUND: Environmental exposure to formaldehyde is commonly associated with clinical symptoms such as mucosal irritation and olfactory disorders. However, the impact of such exposure on the development of mucosal inflammation and its outcome has not been carefully evaluated. METHODS: The observational non comparative study was planned. The study population consisted of group of 41 medical students who had signed up for a cadaver dissection course as part of their gross anatomy teaching at the school of medicine Chiba University in Japan. During such dissection course, the students are exposed to variable levels of environmental formaldehyde routinely employed for the preservation the cadavers. The subjects were evaluated by a detailed medical examination. We measured their serum IgE levels. In addition, an olfaction test and nasal mucosal sensitivity to histamine was serially determined, immediately before and after the course and 6 months after the completion of the course. RESULTS: Olfactory abnormalities were observed in 13/41 (32%) subjects and increased nasal mucosal hypersensitivity to histamine was observed in 17/41 (41%) during and immediately after completion of the course. These subjects had evidence of preexisting allergic rhinitis. 6/41 (15%) other students with no prior evidence of allergic rhinitis also exhibited formaldehyde associated clinical symptoms during the dissecting course. However, the symptoms disappeared upon completion of the course in all subjects studied. CONCLUSIONS: Temporary abnormalities in the olfaction test and increased nasal mucosal hypersensitivity to histamine were observed in a few students with preexisting allergic rhinitis after environmental exposure of high concentrations of formaldehyde. These effects appeared to be transient. PMID- 21593582 TI - Implications of RNA virus-produced miRNAs. AB - MicroRNAs (miRNAs) are small noncoding RNAs that fine-tune protein expression through post-transcriptional regulation. Extensive deep sequencing efforts have identified hundreds of miRNAs from diverse eukaryotic lineages, in addition to a number of DNA virus-produced miRNAs. The absence of RNA virus-encoded miRNAs has led to the assumption that miRNA processing is deleterious to genomic integrity and therefore restricted to DNA-based organisms. However, we recently generated both cytoplasmic and nuclear RNA virus capable of producing a functional miRNA without loss of viral fitness. By exploiting the splicing activity of influenza A virus, we engineered the endogenous miR-124-2 locus into an intron of a viral gene product. Processing of viral-derived miR-124 followed canonical processing events and was comparable to its endogenous counterpart, while virus replication was unaffected. Furthermore, grafting the same locus into a duplicated non essential subgenomic area of Sindbis virus, we can observe non-canonical cytoplasmic-based processing that is independent of any nuclear events. Although it remains unknown as to why there is little natural evidence of RNA virus encoded miRNAs, successful generation of these vectors provide important insights into the relationship between miRNAs and RNA viruses and introduces a new delivery vehicle for the rapidly expanding therapeutic use of RNA interference (RNAi). PMID- 21593583 TI - Dynamic RNA structures in the dengue virus genome. AB - Dengue virus is an important human pathogen that belongs to the Flaviviridae family. The viral genome is a single molecule of RNA of positive polarity that plays multiple roles during the viral life cycle. Besides encoding the viral proteins, the genome contains RNA structures that regulate different viral processes. An important feature of dengue and other flavivirus genomes is the presence of inverted complementary sequences at the ends of the molecule that mediate long-range RNA-RNA interaction and genome cyclization. Recent studies have demonstrated that alternative conformations of the genome are necessary for infectivity. In this review, we discuss the current understanding of the function of different RNA elements that modulate dengue virus replication and provide new ideas of how dynamic RNA structures participate in the viral processes. PMID- 21593584 TI - Hepatitis C virus and host cell lipids: an intimate connection. AB - Hepatitis C virus (HCV) is a major human pathogen, persistently infecting more than 170 million individuals worldwide. The recent establishment of fully permissive culture systems allowed unraveling the close link between host cell lipids and HCV, at each step of the viral replication cycle. HCV entry is triggered by the timely coordinated interaction of virus particles with cell surface receptors, including the low-density lipoprotein receptor. Viral RNA replication strictly depends on fatty acids and cholesterol biosynthesis. This process occurs on modified intracellular membranes, forming a membranous web. Their biogenesis is induced by the viral nonstructural proteins (NS) 4B and NS5A and requires the activity of cellular lipid kinases belonging to the phosphatidylinositol-4-kinase III family. A hallmark of HCV-induced membranes is thus the presence of phosphatidylinositol-4-phosphate (PI4P), which is synthesized by these kinases. Intriguingly, certain recently identified HCV dependency factors selectively bind to PI derivatives, suggesting a crucial role for PIPs in viral RNA replication and assembly. The latter occurs on the surface of lipid droplets and is tightly connected to the very low density lipoprotein pathway leading to the formation of unique lipoviro particles. Thus, HCV exploits lipid metabolism in many ways and may therefore serve as a model system to gain insights into membrane biogenesis, lipid droplet formation and lipid trafficking. PMID- 21593586 TI - RNA virus replication, transcription and recombination. PMID- 21593585 TI - Coronaviruses: an RNA proofreading machine regulates replication fidelity and diversity. AB - In order to survive and propagate, RNA viruses must achieve a balance between the capacity for adaptation to new environmental conditions or host cells with the need to maintain an intact and replication competent genome. Several virus families in the order Nidovirales, such as the coronaviruses (CoVs) must achieve these objectives with the largest and most complex replicating RNA genomes known, up to 32 kb of positive-sense RNA. The CoVs encode sixteen nonstructural proteins (nsp 1-16) with known or predicted RNA synthesis and modification activities, and it has been proposed that they are also responsible for the evolution of large genomes. The CoVs, including murine hepatitis virus (MHV) and SARS-CoV, encode a 3'-to-5' exoribonuclease activity (ExoN) in nsp14. Genetic inactivation of ExoN activity in engineered SARS-CoV and MHV genomes by alanine substitution at conserved DE-D-D active site residues results in viable mutants that demonstrate 15- to 20-fold increases in mutation rates, up to 18 times greater than those tolerated for fidelity mutants of other RNA viruses. Thus nsp14-ExoN is essential for replication fidelity, and likely serves either as a direct mediator or regulator of a more complex RNA proofreading machine, a process previously unprecedented in RNA virus biology. Elucidation of the mechanisms of nsp14 mediated proofreading will have major implications for our understanding of the evolution of RNA viruses, and also will provide a robust model to investigate the balance between fidelity, diversity and pathogenesis. The discovery of a protein distinct from a viral RdRp that regulates replication fidelity also raises the possibility that RNA genome replication fidelity may be adaptable to differing replication environments and selective pressures, rather than being a fixed determinant. PMID- 21593588 TI - Downstream of human NDR kinases: impacting on c-myc and p21 protein stability to control cell cycle progression. AB - The mammalian genome encodes four members of the NDR/LATS kinase family: NDR1 (STK38), NDR2 (STK38L), LATS1 and LATS2, which are highly conserved from yeast to man. Members of the NDR/LATS kinase family have been implicated in a variety of biological processes ranging from cell division and morphology to apoptosis and tumor suppression. In mammals, LATS1/2 function as central parts of the HIPPO tumor suppressor pathway by restricting the activity of the YAP/TAZ proto oncogenes. Recent evidence suggested that NDR1/2 are also part of an extended HIPPO tumor suppressor pathway. Apart from functions in apoptosis signaling and tumor suppression, NDR1/2 have been implicated in controlling centrosome duplication and mitotic chromosome alignment downstream of the HIPPO kinase homologs MST1 and MST2. Significantly, we also reported recently that NDR1/2 are controlling G 1/S transition downstream of a third MST family member MST3. Intriguingly, this newly described MST3-NDR1/2 axis promotes G 1 progression by stabilizing c-myc and preventing p21 accumulation, indicating a potential pro tumorigenic role for NDR kinases. Here, we discuss these novel cell cycle functions of NDR kinases in a broader context and elaborate on possible explanations for the opposing functions of NDR kinases in normal and tumor biology. PMID- 21593587 TI - BMI1 suffers a degrading experience. PMID- 21593589 TI - Division of labor of the replication fork protection complex subunits in sister chromatid cohesion and Chk1 activation. PMID- 21593590 TI - Zinc finger protein 521 antagonizes early B-cell factor 1 and modulates the B lymphoid differentiation of primary hematopoietic progenitors. AB - Zinc finger protein 521 (EHZF/ZNF521) is a multi-functional transcription co factor containing 30 zinc fingers and an amino-terminal motif that binds to the nucleosome remodelling and histone deacetylase (NuRD) complex. ZNF521 is believed to be a relevant player in the regulation of the homeostasis of the hematopoietic stem/progenitor cell compartment, however the underlying molecular mechanisms are still largely unknown. Here, we show that this protein plays an important role in the control of B-cell development by inhibiting the activity of early B-cell factor-1 (EBF1), a master factor in B-lineage specification. In particular, our data demonstrate that: (1) ZNF521 binds to EBF1 via its carboxyl-terminal portion and this interaction is required for EBF1 inhibition; (2) NuRD complex recruitment by ZNF521 is not essential for the inhibition of transactivation of EBF1-dependent promoters; (3) ZNF521 represses EBF1 target genes in a human B lymphoid molecular context; and (4) RNAi-mediated silencing of ZNF521/Zfp521 in primary human and murine hematopoietic progenitors strongly enhances the generation of B-lymphocytes in vitro. Taken together, our data indicate that ZNF521 can antagonize B-cell development and lend support to the notion that it may contribute to conserve the multipotency of primitive lympho-myeloid progenitors by preventing or delaying their EBF1-driven commitment toward the B cell lineage. PMID- 21593591 TI - Stimulation of ALK by the growth factor midkine renders glioma cells resistant to autophagy-mediated cell death. AB - Delta9-tetrahydrocannabinol (THC), the main active component of marijuana, promotes cancer cell death via autophagy stimulation. We find that activation of the tyrosine kinase receptor ALK by its ligand midkine interferes with the signaling mechanism by which THC promotes autophagy-mediated glioma cell death. PMID- 21593592 TI - Titrating autophagy in cardiac plasticity. AB - The heart is a highly plastic organ. In a recent study, we found that autophagy is a required element in load-induced cardiomyocyte growth; when autophagy is suppressed, the heart does not grow. Conversely, afterload stress triggers a transient increase in cardiomyocyte autophagic activity which settles to a new- higher--baseline once the heart has re-achieved steady-state size. Our work went on to decipher the role of histone deacetylases in this biology. PMID- 21593593 TI - Regulation of stomatal opening by the guard cell expansin AtEXPA1. AB - Stomatal movement is strictly regulated by various intracellular and extracellular factors in response environmental signals. In our recent study, we found that an Arabidopsis guard cell expressed expansin, AtEXPA1, regulates stomatal opening by altering the structure of the guard cell wall. This addendum proposes a mechanism by which guard cell expansins regulate stomatal movement. PMID- 21593595 TI - Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. AB - DNA methylation is the most studied epigenetic mark and CpG methylation is central to many biological processes and human diseases. Since cancer has highlighted the contribution to disease of aberrant DNA methylation patterns, such as the presence of promoter CpG island hypermethylation-associated silencing of tumor suppressor genes and global DNA hypomethylation defects, their importance will surely become apparent in other pathologies. However, advances in obtaining comprehensive DNA methylomes are hampered by the high cost and time consuming aspects of the single nucleotide methods currently available for whole genome DNA methylation analyses. Following the success of the standard CpG methylation microarrays for 1,505 CpG sites and 27,000 CpG sites, we have validated in vivo the newly developed 450,000 (450K) cytosine microarray (Illumina). The 450K microarray includes CpG and CNG sites, CpG islands/shores/shelves/open sea, non-coding RNA (microRNAs and long non-coding RNAs) and sites surrounding the transcription start sites (-200 bp to -1,500 bp, 5'-UTRs and exons 1) for coding genes, but also for the corresponding gene bodies and 3'-UTRs, in addition to intergenic regions derived from GWAS studies. Herein, we demonstrate that the 450K DNA methylation array can consistently and significantly detect CpG methylation changes in the HCT-116 colorectal cancer cell line in comparison with normal colon mucosa or HCT-116 cells with defective DNA methyltransferases (DKO). The provided validation highlights the potential use of the 450K DNA methylation microarray as a useful tool for ongoing and newly designed epigenome projects. PMID- 21593594 TI - The epigenetics of estrogen: epigenetic regulation of hormone-induced memory enhancement. AB - Epigenetic processes have been implicated in everything from cell proliferation to maternal behavior. Epigenetic alterations, including histone alterations and DNA methylation, have also been shown to play critical roles in the formation of some types of memory, and in the modulatory effects that factors, such as stress, drugs of abuse and environmental stimulation, have on the brain and memory function. Recently, we demonstrated that the ability of the sex-steroid hormone 17beta-estradiol (E(2)) to enhance memory formation is dependent on histone acetylation and DNA methylation, a finding that has important implications for understanding how hormones influence cognition in adulthood and aging. In this article, we provide an overview of the literature demonstrating that epigenetic processes and E(2) influence memory, describe our findings indicating that epigenetic alterations regulate E(2)-induced memory enhancement, and discuss directions for future work on the epigenetics of estrogen. PMID- 21593596 TI - Determination of genomic 5-hydroxymethyl-2'-deoxycytidine in human DNA by capillary electrophoresis with laser induced fluorescence. AB - Recent studies reported the presence of 5-hydroxymethylcytosine (5 hmC) as an additional modification in mammalian genomic DNA. To date, 5 hmC has been detected only in mouse DNA isolated from embryonic stem cells, some adult tissues and in DNA from human bone marrow. Understanding its biological function will require the development of sensitive analytical methods that allow the detection and quantification of 5-hydroxymethylcytosine along with 5-methylcytosine and cytosine. : Here we report the validation of a fast and sensitive method for the quantification of global 5-hydroxymethyl-2'-deoxycytidine (5 hmdC) in DNA. The method is based on a procedure consisting of fluorescence labeling of deoxyribonucleotides and analysis by capillary electrophoresis with laser-induced fluorescence detection (CE-LIF). A double stranded DNA fragment containing a defined number of 5 hmdC residues was used for peak assignment, to establish separation conditions and to determine the limit of detection (LOD). The method yielded a LOD for 5 hmdC of 0.45 amol, which is equivalent to approximately to one 5 hmdC per 4,000 normal nucleotides (0.025%) using 1 MUg of DNA as the matrix. : By applying the calibrated assay to the analysis of various DNAs we show that 5 hmdC is present in human tissue and human cancer cell lines. We demonstrate that by using CE-LIF DNA can be analyzed in one run for both methylation and hydroxymethylation of cytosine with high sensitivity and accuracy. PMID- 21593597 TI - CpG island hypermethylation of BRCA1 and loss of pRb as co-occurring events in basal/triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) occurs in approximately 15% of all breast cancer patients, and the incidence of TNBC is greatly increased in BRCA1 mutation carriers. This study aimed to assess the impact of BRCA1 promoter methylation with respect to breast cancer subtypes in sporadic disease. Tissue microarrays (TMAs) were constructed representing tumors from 303 patients previously screened for BRCA1 germline mutations, of which a subset of 111 sporadic tumors had previously been analyzed with respect to BRCA1 methylation. Additionally, a set of eight tumors from BRCA1 mutation carriers were included on the TMAs. Expression analysis was performed on TMAs by immunohistochemistry (IHC) for BRCA1, pRb, p16, p53, PTEN, ER, PR, HER2, CK5/6, EGFR, MUC1 and Ki-67. Data on BRCA1 aberrations and IHC expression was examined with respect to breast cancer specific survival. The results demonstrate that CpG island hypermethylation of BRCA1 significantly associates with the basal/triple-negative subtype. Low expression of pRb, and high/intense p16, were associated with BRCA1 promoter hypermethylation, and the same effects were seen in BRCA1 mutated tumors. The expression patterns of BRCA1, pRb, p16 and PTEN were highly correlated, and define a subgroup of TNBCs characterized by BRCA1 aberrations, high Ki-67 (>= 40%) and favorable disease outcome. In conclusion, our findings demonstrate that epigenetic inactivation of the BRCA1 gene associates with RB/p16 dysfunction in promoting TNBCs. The clinical implications relate to the potential use of targeted treatment based on PARP inhibitors in sporadic TNBCs, wherein CpG island hypermethylation of BRCA1 represents a potential marker of therapeutic response. PMID- 21593598 TI - Phosphorylation by MPK6: a conserved transcriptional modification mediates nitrate reductase activation and NO production? AB - Nitrate reductase is a central enzyme of nitrogen assimilation in plants. In a recent work, we have revealed MPK6 could phosphorylate Arabidopsis NIA2 at the serine 627 in hinge 2 region, this phosporylation may represent a rapid activation mechnism when plant need excessive nitrate reduction. Interestingly, all eukaryotic NRs have conserved docking sequence in their FAD domains, and many plant NR proteins have the conserved MAPK phosphorylation site. Those results indicated the MAPK cascades, the conserved signaling pathway also involved in lateral root development, mediated of NR phosporylation and NO generation. We noticed that the phosphorylation of S627 residue by MPK6 have a specially influence on the NO generation activity of NIA2. Although no homology of mammalian NOS has been identified in plants, NR may still share a similar regulation mechanism with mammalian NOS. PMID- 21593599 TI - Multilineage stem cells in the adult: a perivascular legacy? AB - Mesenchymal stem cells proliferate extensively in cultures of unselected, total cell isolates from multiple fetal and adult organs. Perivascular cells, principally pericytes surrounding capillaries and microvessels, but also adventitial cells located around larger arteries and veins, have been recently identified as possible originators of mesenchymal stem cells, first by phenotypic analogies and eventually following stringent cell sorting. While it is clear that purified perivascular cells exhibit multiple mesodermal developmental potentials and become indistinguishable from conventionally derived mesenchymal stem cells after in vitro culture, the possible roles played by these blood vessel-bound cells in organogenesis and adult tissue repair remain elusive. Unsolved questions regarding the identity of mesenchymal stem cells have not compromised the consideration of these cells as outstanding candidates for cell therapies. Better knowledge of the lineage affiliation, tissue distribution and molecular identity of mesenchymal stem cells will contribute to the development of more efficient, safer therapeutic cells. PMID- 21593600 TI - Induction of systemic resistance in rice by leaf extracts of Zizyphus jujuba and Ipomoea carnea against Rhizoctonia solani. AB - Plants accumulate a great diversity of natural products, many of which confer protective effects against phytopathogenic attack. Earlier we had demonstrated that the leaf extracts of Zizyphus jujuba and Ipomoea carnea inhibit the in vitro mycelial growth of Rhizoctonia solani, and effectively reduce the incidence of sheath blight disease in rice. Here we demonstrate that foliar application of the aqueous leaf extracts of Z. jujuba and I. carnea followed by challenge inoculation with R. solani induces systemic resistance in rice as evident from significantly increased accumulation of pathogenesis-related proteins such as chitinase, beta-1,3-glucanase and peroxidase, as well as defense-related compounds such as phenylalanine ammonia-lyase and phenolic substances. Thin layer chromatographic separation of secondary metabolites revealed presence of alkaloid and terpenoid compounds in the leaf extracts of Z. jujuba that exhibited toxicity against R. solani under in vitro condition. Thus, the enhanced sheath blight resistance in rice seedlings treated with leaf extracts of Z. jujuba or I. carnea can be attributed to the direct inhibitory effects of these leaf extracts as well as their ability to elicit systemic resistance against R. solani. PMID- 21593601 TI - Potential applications of germline cell-derived pluripotent stem cells in organ regeneration. AB - Impressive progress has been made since the turn of the century in the field of stem cells. Different types of stem cells have now been isolated from different types of tissues. Pluripotent stem cells are the most promising cell source for organ regeneration. One such cell type is the germline cell-derived pluripotent cell, which is derived from adult spermatogonial stem cells. The germline cell derived pluripotent stem cells have been obtained from both human and mouse and, importantly, are adult stem cells with embryonic stem cell-like properties that do not require specific manipulations for pluripotency acquisition, hence bypassing problems related to induced pluripotent stem cells and embryonic stem cells. The germline cell-derived pluripotent stem cells have been induced to differentiate into cells deriving from the three germ layers and shown to be functional in vitro. This review will discuss the plasticity of the germline cell derived pluripotent stem cells and their potential applications in human organ regeneration, with special emphasis on liver regeneration. Potential problems related to their use are also highlighted. PMID- 21593602 TI - The riboflavin analog roseoflavin targets an FMN-riboswitch and blocks Listeria monocytogenes growth, but also stimulates virulence gene-expression and infection. AB - During recent years, riboswitches have emerged as potential targets for novel antibacterial substances. In this study, we investigated how one flavin analog, roseoflavin, affected the gene-expression, growth and infectivity of the human bacterial pathogen Listeria monocytogenes to determine the potential of this analog to function as an antibacterial substance. The results indicate that roseoflavin has a profound inhibiting effect on the growth of L. monocytogenes at very low concentrations. Also, expression of the gene located downstream of the FMN riboswitch, a riboflavin transporter, was blocked by the addition of roseoflavin. Base-substitution mutations in the FMN riboswitch allowed the bacteria to grow in the presence of roseoflavin, showing that roseoflavin targeted the FMN riboswitch directly. Surprisingly, we found that roseoflavin stimulated L. monocytogenes virulence gene expression and infection abilities in a mechanism independent of the FMN riboswitch. Our results suggest that roseoflavin can block growth but also enhance Listeria virulence. PMID- 21593603 TI - Programmed ribosomal frameshifting in the expression of the regulator of intestinal stem cell proliferation, adenomatous polyposis coli (APC). AB - A programmed ribosomal frameshift (PRF) in the decoding of APC (adenomatous polyposis coli) mRNA has been identified and characterized in Caenorhabditis worms, Drosophila and mosquitoes. The frameshift product lacks the C-terminal approximately one-third of the product of standard decoding and instead has a short sequence encoded by the -1 frame which is just 13 residues in C. elegans, but is 125 in D. melanogaster. The frameshift site is A_AA.A_AA.C in Caenorhabditids, fruit flies and the mosquitoes studied while a variant A_AA.A_AA.A is found in some other nematodes. The predicted secondary RNA structure of the downstream stimulators varies considerably in the species studied. In the twelve sequenced Drosophila genomes, it is a long stem with a four-way junction in its loop. In the five sequenced Caenorhabditis species, it is a short RNA pseudoknot with an additional stem in loop 1. The efficiency of frameshifting varies significantly, depending on the particular stimulator within the frameshift cassette, when tested with reporter constructs in rabbit reticulocyte lysates. Phylogenetic analysis of the distribution of APC programmed ribosomal frameshifting cassettes suggests it has an ancient origin and raises questions about a possibility of synthesis of alternative protein products during expression of APC in other organisms such as humans. The origin of APC as a PRF candidate emerged from a prior study of evolutionary signatures derived from comparative analysis of the 12 fly genomes. Three other proposed PRF candidates (Xbp1, CG32736, CG14047) with switches in conservation of reading frames are likely explained by mechanisms other than PRF. PMID- 21593604 TI - Conserved RNA structures in the non-canonical Hac1/Xbp1 intron. AB - The unconventional splicing of Hac1 by the ribonuclease Ire1 is a key event in the activation of the unfolded protein response (UPR) in Saccharomyces cerevisiae. This splicing is independent of the spliceosome and is mediated by a secondary structure at the intron-exon boundaries of the mRNA. Similar unconventional splicing was also described for the gene Xbp1 in human, mouse, C. elegans and D. melanogaster, and for Hac1 in five other fungi. We used reported RNA structures to build a multiple sequence alignment and the Infernal package to search for homologous structures. We identified homologous non-canonical intron structures in 128 out of 156 searched eukaryotic genomes. Our results show that the sequence of the Hac1/Xbp1 intron is highly conserved only around the splice sites recognized by Ire1. The consensus structure of the Hac1/Xbp1 mRNA is well conserved in Fungi and Metazoa and resembles structures previously described. We show that a typical Hac1/Xbp1 intron is very short, only 20-26 bases, whereas yeast species have a long intron (> 100 bases). We identified six species with unambiguous Hac1/Xbp1 homologs that have lost the non-canonical intron structure. We propose that these species use a different mechanism to regulate the UPR. PMID- 21593605 TI - Gene expression profiling indicate role of ER stress in miR-23a~27a~24-2 cluster induced apoptosis in HEK293T cells. AB - Previously, we had reported that overexpression of miR-23a~27a~24-2 cluster induces caspase-dependent and -independent apoptosis via JNK in human embryonic kidney (HEK293T) cells. Herein, we describe the molecular mechanism(s) responsible for miR-23a~27a~24-2 cluster induced apoptosis. Gene expression profiling was used to characterize the transcriptional response to miR-23a~27a~24 2 cluster overexpression in HEK293T cells. The microarray analysis gave 1,025 differentially expressed genes and analysis of the gene expression data with Ingenuity Pathway Analysis (IPA) software revealed p53 signaling, oxidative stress response and mitochondrial dysfunction among the top processes being affected. This data substantiates our previous study where we had reported increase of ROS and the release of proapoptotic factors such as cytochrome c (cyt c) and apoptosis-inducing factor (AIF) from the mitochondria to cytosol. Additionally, components of ER stress-mediated apoptosis pathway i.e., C/EBP homologous protein (CHOP/DDIT3/GADD153) and TRIB3, an Akt inhibitor were found to be significantly enriched. Also, the enhanced expression of ATF3 and ATF4 was observed at RNA as well as protein level in miR-23a~27a~24-2 cluster overexpressed HEK293T cells. Induction of BIM appeared to be specific, because ER stress caused only a minor change in the expression of the related BH3-only proteins BID or PUMA. The fact that miR-23a~27a~24-2 cluster triggered endoplasmic reticulum stress (ER stress) was further established by the increase in cytosolic calcium levels after overexpression of this cluster in HEK293T cells. These findings were also supported by PANTHER analysis wherein biological process categories of apoptosis and stress response were enriched. Taken together, this work underlines the role of ER stress in miR-23a~27a~24-2 cluster mediated apoptosis in HEK293T cells. Since the detailed knowledge of this cluster induced apoptosis has now been elucidated, the in vivo study of this cluster would help evaluate the prospect of its use as a therapeutic in diseases known to occur because of deregulation of apoptosis. PMID- 21593607 TI - Involvement of human ELAC2 gene product in 3' end processing of mitochondrial tRNAs. AB - Accurate tRNA processing is crucial for human mitochondrial genome expression, but the mechanisms of mt-tRNA cleavage and the key enzymes involved in this process are poorly characterized. At least two activities are required for proper mt-tRNA maturation: RNase P cleaving precursor molecules at the 5' end and tRNase Z at the 3' end. In human mitochondria only RNase P has been identified so far. Using RT-PCR and northern blot analyses we found that silencing of the human ELAC2 gene results in impaired 3' end of mt-tRNAs. We demonstrate this for several mitochondrial tRNAs, encoded on both mtDNA strands, including tRNA (Val) , tRNA (Lys) , tRNA (Arg) , tRNA (Gly) , tRNA (Leu(UUR)) and tRNA (Glu) . The silencing of the MRPP1 gene that encodes a subunit of mtRNase P resulted in inhibition of both 5' and 3' processing. We also demonstrate the double mitochondrial/nuclear localization of the ELAC2 protein using immunofluorescence. Our results indicate that ELAC2 functions as a tRNase Z in human mitochondria and suggest that mt-tRNase Z preferentially cleaves molecules already processed by the proteinaceous mtRNase P. PMID- 21593606 TI - tmRNA on its way through the ribosome: two steps of resume, and what next? AB - Trans-translation is a universal quality-control process eubacteria use to degrade incompletely synthesized proteins and rescue ribosome stalled on defective mRNAs. This process is facilitated by a ribonucleoprotein complex composed of transfer-messenger RNA (tmRNA)-a chimera made of a tRNA-like molecule and a short open reading frame (ORF) -and small protein B (SmpB). Determination of the structure of tmRNA and SmpB in complex with the ribosome, at the stage when translation has resumed on tmRNA, has provided an increased understanding of the structure of tmRNA as it transits the ribosome, and unique insights into the complex mechanism of template switching on the ribosome and SmpB-driven selection of the correct reading frame on tmRNA's ORF. PMID- 21593609 TI - MicroRNA based immunoevasion mechanism of human polyomaviruses. AB - Since miRNAs are considered non-immunogenic, it was not too surprising to discover that some herpesviruses, which are masters of immune evasion, developed their own unique miRNAs to escape immune elimination. In this point of view we discuss our recent findings in which we demonstrate that two polyomaviruses, JC and BK, use an identical miRNA to escape immune attack. This identical miRNA targets the stress-induced protein ULBP3, which is recognized by the killer receptor NKG2D and thus, through the usage of a miRNA, JCV and BKV avoid the NKG2D mediated elimination. We further compare the miRNA-based immune evasion mechanisms of herpes and polyomaviruses, offering new insights on the complexity of the stress induced ligands function and recognition. Lastly, we consider the possibility that other viral and cellular mechanisms are also involved in targeting ULBP3 and other NKG2D ligands. PMID- 21593610 TI - Notes from the Editor-in-Chief. PMID- 21593608 TI - CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders. AB - Over 20 genetic loci with abnormal expansions of short tandem repeats have been associated with human hereditary neurological diseases. Of these, specific trinucleotide repeats located in non-coding and coding regions of individual genes implicated in these disorders are strongly overrepresented. Expansions of CTG, CGG and CAG repeats are linked to, respectively, myotonic dystrophy type 1 (DM1), fragile X-associated tremor/ataxia syndrome (FXTAS), as well as Huntington's disease (HD) and a number of spinocerebellar ataxias (SCAs). Expanded CAG repeats in translated exons trigger the most disorders for which a protein gain-of-function mechanism has been proposed to explain neurodegeneration by polyglutamine-rich (poly-Q) proteins. However, the results of last years showed that RNA composed of mutated CAG repeats can also be toxic and contribute to pathogenesis of polyglutamine disorders through an RNA-mediated gain-of function mechanism. This mechanism has been best characterized in the non-coding repeat disorder DM1 and is also implicated in several other diseases, such as FXTAS, spinocerebellar ataxia type 8 (SCA8), Huntington's disease-like 2 (HDL2), as well as in myotonic dystrophy type 2 (DM2), spinocerebellar ataxia type 10 (SCA10) and type 31 (SCA31). In this review, we summarize recent findings that emphasize the participation of coding mutant CAG repeat RNA in the pathogenesis of polyglutamine disorders, and we discuss the basis of an RNA gain-of-function model in non-coding diseases such as DM1, FXTAS and SCA8. PMID- 21593611 TI - Residential long-term care: public solutions to access and quality problems. AB - Residential long-term care in Canada is characterized by unequal access and quality problems largely due to inadequate public funding and regulation, commercial involvement and its exclusion from medicare. Programs are patchwork, with variations across provinces in the availability of services, level of public funding, eligibility criteria and out-of-pocket costs borne by residents. Most provinces have cut long-term care bed capacity relative to the senior population in the past decade, without sufficiently expanding home and community care or adequately increasing staffing to reflect the higher acuity of the remaining residents. As a result, care is often rushed and underfunded, with poor working conditions leading to poor quality of care and quality of life for residents. This relationship between workers' and residents' well-being is well documented but poorly addressed. Also well researched but rarely reported are the negative impacts of privatization, at all levels: financing, ownership, management and delivery. This article describes the state of residential long-term care in Canada and proposes three policy directions: creating a pan-Canadian long-term care program, improving quality and reversing privatization. PMID- 21593612 TI - What does quality look like to the resident? AB - In her thought-provoking and well-researched paper, Irene Jansen presents some of the main challenges within the facility-based long-term care (LTC) sector and advocates for three major policy changes and investments. But her aim in writing the paper is to start the conversation. I am happy to oblige Jansen's call to tackle other critical issues and thank the editors of Healthcare Papers for the opportunity to briefly express my views. I concur that the federal government is not adequately fulfilling its stewardship role in helping to ensure - along with the provinces and territories - that the facility-based LTC system has the ways and means to meet the legitimate needs of LTC residents and the people who care for them. A national dialogue should be convened with an emphasis on what quality looks like to the resident, not to LTC ministries or funding authorities. The resident is the nucleus around which all else revolves. The challenges in the areas of supply and demand, the patchwork of services and health human resources are huge. But additional staffing and more beds will not add real value to the system unless they are closely linked to the principles of culture change - the journey to improving living and working conditions in LTC across the Canadian landscape. And it is here where I make my prime contribution to the conversation. PMID- 21593613 TI - Finding a model that supports quality. AB - While Canadian provinces demonstrate considerable diversity of performance within the non-profit sector and further research is needed to better understand which non-profit models support the best quality, Canadian research has been generally consistent with US research in confirming a relationship between for-profit ownership and inferior quality. The quality concerns arising from public funding to the private for-profit residential long-term care sector are unlikely to be addressed by adopting tighter regulations. With the expansion of private for profit delivery, the organizational goals of the regulator and the facilities being regulated become less aligned. The former is likely to move to a more deterrence-based model of regulation, which is costly, less effective and draws resources away from direct patient care. PMID- 21593614 TI - Can Canada afford a truly pan-Canadian approach to elder care? AB - This commentary is about Canada's ability to afford a comprehensive pan-Canadian approach to elder care. In redefining the universal public system, a broad and more comprehensive definition of universal public care is needed for those whose physical or mental abilities are impaired. The Scandinavian model affirms that this is both effective and affordable. Comparisons of Canada with other nations in the Organisation for Economic Co-operation and Development on taxation and spending levels reveal that there is room for Canada to increase taxation to fund a Scandinavian model while still having competitive tax and spending rates. PMID- 21593615 TI - Long-term care as part of the continuum. AB - Long-term care (LTC) is but one piece of a continuum of care that stretches from living at home completely independently to the 24-hour supervision and care provided in LTC facilities. People want to stay at home as long as possible and to retain as much independence as they can, and they are often aided in doing so with informal care provided by family and friends. These realities should inform the debates around the construction of the continuum of care. Canada's spending on facility-based long-term care puts us in the middle of the pack among OECD countries; if we consider the whole of continuing care, combining LTC, supportive housing/assisted living and home-based healthcare, Canada stands out as spending the highest proportion (among the 15 countries compared) on facility-based care. Predicting the number of new long-term care beds needed in the future is difficult because of shifting needs and changes in service delivery - new stops on the continuum of care. It is quite possible to organize a system of care that includes a continuum from home-based care to supportive housing and assisted living to LTC that de-emphasizes this last step. The increasing elderly population in Canada will not bring an apocalypse to the healthcare system, but caring for this population will require a redistribution of resources to increase the emphasis on home and community-based services. Our planning for just how many (if any) new long-term care beds are needed and our assessment of reasonable access to those beds need to rest on a vision for the full spectrum of care and attention to the desires of the population we are trying to serve. PMID- 21593616 TI - The changing landscape of healthcare and social policy. AB - The problems in traditional residential long-term care settings described in the lead paper are the tip of the iceberg in relation to changes in the landscape of healthcare and social policy in Canada over the past two decades. The primary purpose of this commentary is to identify some of the less visible changes and how these are affecting our perceptions, values and policy directions in "long term care," however it is defined. The secondary purpose is to caution readers of the dangers of trying to resolve all social policy issues through medicare. This temptation is an artifact of our history and fragmented constitutional powers. It is also due to a well-intended but highly problematic shift in the nature and purpose of public health insurance (and government) in Canada during the 1990s. Without a greater understanding of these and other underlying issues, a pan Canadian program dedicated to residential long-term care under the upcoming Health Accord risks adding to existing problems. There is also a desperate need for better understanding of the intergenerational needs of Canadian families in relation to healthcare and eldercare. PMID- 21593617 TI - Alberta's long-term care services are in crisis: government's relentless pursuit to privatize long-term care. AB - Public Interest Alberta's Seniors Task Force members are deeply concerned about the privatization of long-term care in Alberta that began during the Klein era. The move away from publicly funded and publicly administered long-term care is accelerating under the leadership of Premier Ed Stelmach. In making this shift, government will harvest short-term gain that can only result in long-term pain for people in need of such services. PMID- 21593619 TI - Twice-weekly pegylated interferon-alpha-2a and ribavirin results in superior viral kinetics in HIV/hepatitis C virus co-infected patients compared to standard therapy. AB - BACKGROUND: Hepatitis C virus (HCV)/HIV co-infected patients have more rapid progression of liver fibrosis and only modest cure rates (sustained virologic responses, SVRs) when compared to HCV monoinfected patients. METHOD: We compared the virologic responses of either twice-weekly peginterferon-alpha-2a 180 MUg/week (for 4 weeks, followed by weekly dosing) or weekly peginterferon-alpha 2a 180 MUg/week, and weight-based ribavirin (1-1.2 g/day), among HIV/HCV co infected genotype-1 individuals. RESULTS: Patients receiving the investigational dosing had lower levels of HCV RNA at all time points after initiation of therapy. More patients on this arm achieved clinically relevant early virological responses at weeks 1, 2, 4, 12, and 24. The enhanced early virologic response observed with the investigational arm was associated with a higher induction of interferon-stimulated genes. This early double dose regimen also resulted in a rapid normalization of liver enzymes. Twice-weekly peginterferon-alpha-2a was associated with more frequent early virological responses with similar safety profiles when compared with standard therapy. CONCLUSION: Our results, when confirmed in larger randomized clinical trials, may provide a novel therapeutic approach to improve SVR among HIV/HCV co-infected patients, especially African American patients. PMID- 21593620 TI - Are men the losers of the antiretroviral treatment scale-up? PMID- 21593621 TI - Editorial commentary on 'High frequency of poor locomotor performance in HIV infected patients'. PMID- 21593622 TI - Bevacizumab reverts serous retinal detachment caused by tuberculosis-associated immune reconstitution inflammatory syndrome. PMID- 21593623 TI - Maraviroc intensification for suboptimal CD4+ T cell response in a perinatally HIV-infected adolescent. PMID- 21593625 TI - Current concepts in the diagnosis, pathogenesis, and management of nonarteritic anterior ischemic optic neuropathy. PMID- 21593624 TI - HIV in prison in low income countries. PMID- 21593626 TI - Pitfalls in imaging. PMID- 21593628 TI - Update on retinal prosthetic research: the Boston Retinal Implant Project. AB - The field of retinal prosthetic research, now more than 20 years old, has produced many high-quality technical options that have the potential to restore vision to patients with acquired disease of the outer retina. Five companies have performed Phase I clinical trials demonstrating that blind patients can reliably report basic elements of visual percepts induced by electrical stimulation. However, at present patients and observers generally do not consider the results to be useful enough in the performance of tasks of daily living to justify the risks of surgery and chronic implantation or the costs. Having developed a wireless device implanted in the subretinal space, the Boston Retinal Implant Project has focused its efforts on developing scalable technologies to create a hermetic device that can deliver individually controlled pulses of electrical stimulation to each of hundreds of electrodes. An advanced device with such attributes will be needed to justify the risks of implantation. An assessment of long-term biocompatibility for all devices remains to be done. PMID- 21593627 TI - Low-density lipoprotein receptor-related protein is decreased in optic neuropathy of Alzheimer disease. AB - BACKGROUND: Alzheimer disease (AD) is associated with optic nerve degeneration, yet the underlying pathophysiology of this disease and the optic nerve disorder remain poorly understood. Low-density lipoprotein receptor-related protein (LRP) is implicated in the pathogenesis of AD by mediating the transport of amyloid beta (Abeta) out of the brain into the systemic circulation. As a key player in the reaction to central nervous system injury, astrocytes associate with LRP in AD. This study investigates the role of LRP and astrocytes in the pathogenesis of AD optic neuropathy. METHODS: To investigate the role of LRP and astrocytes in the pathogenesis of AD optic neuropathy, we conducted immunohistochemical studies on postmortem optic nerves in AD patients (n = 11) and age-matched controls (n = 10) to examine the presence of LRP. Quantitative analyses using imaging software were used to document the extent of LRP in neural tissues. Axonal integrity was assessed by performing immunohistochemistry on the subjects' optic nerves with an antibody to neurofilament (NF) protein. Double-immunofluorescence labeling was performed to investigate whether LRP colocalized with astrocytes, expressing glial fibrillary acidic protein. RESULTS: LRP expression was decreased in AD optic nerves compared to that in controls (P < 0.001). LRP immunoreactivity was observed in the microvasculature and perivascularly in close proximity to the astrocytic processes. Colocalization of LRP in the astrocytes of optic nerves was also demonstrated. The presence of optic neuropathy was confirmed in the AD optic nerves by demonstrating greatly reduced immunostaining for NF protein as compared to controls. CONCLUSIONS: The reduction of LRP in the AD degenerative optic nerves supports the hypothesis that LRP may play a role in the pathophysiology of AD optic neuropathy. PMID- 21593629 TI - How should patients with indirect traumatic optic neuropathy be treated? PMID- 21593630 TI - Papilledema: the vexing issues. AB - Papilledema has long been recognized as a valuable sign of increased intracranial pressure (ICP). But because papilledema is based on interruption of the energy dependent process of axoplasmic flow, it appears late after a rise in ICP. Papilledema is usually present in chronically high ICP but sometimes asymmetrically in the 2 eyes and rarely in 1 eye only. Distinguishing it from other optic neuropathies that produce elevated optic discs is challenging, especially in the chronic phase, when visual function may be impaired. Papilledema is often an unrecognized cause of optic disc edema in inflammatory and compressive meningeal disorders that interfere with cerebrospinal fluid (CSF) passage through the arachnoid granulations. Its detection is particularly critical in patients with noncompliant ventricles or extraventricular blockage of cerebrospinal flow because imaging may fail to disclose conventional signs of high ICP. Therefore, patients with indwelling CSF shunts, tuberous sclerosis, chronic granulomatous meningitis, or meningiomatosis should be periodically examined for papilledema so that timely ICP-lowering measures can be instituted to preserve vision. PMID- 21593632 TI - Choroidal infarction or cilioretinal artery occlusion in the setting of elevated intracranial pressure due to fulminant idiopathic intracranial hypertension? PMID- 21593634 TI - Magnetic resonance findings in the pregeniculate visual pathways in Leber hereditary optic neuropathy. PMID- 21593638 TI - Neonatal herpetic hepatitis. PMID- 21593639 TI - Helicobacter pylori and effects on iron status in children: delineating causality. PMID- 21593640 TI - Role of eosinophils in inflammatory bowel and gastrointestinal diseases. AB - Inflammatory bowel diseases (IBD) are characterized by the invasion of leukocytes into the intestinal mucosa. However, a mixed inflammatory picture is observed that includes neutrophils, lymphocytes, monocytes, and eosinophils. To this day, the role of eosinophils in health and in disease remains unclear. Investigations into their function stem primarily from allergic diseases, asthma, and parasitic infections. This makes it even more difficult to discern a role for the fascinating eosinophil in IBDs because, unlike the lung or the skin, eosinophils reside in normal intestinal mucosa and increase in disease states; consequently, an intricate system must regulate their migration and numbers. These granulocytes are equipped with the machinery to participate in gastrointestinal (GI) inflammation and in the susceptible microenvironment, they may initiate or perpetuate an inflammatory response. A significant body of literature characterizes eosinophils present in the GI microenvironment where they have the potential to interact with other resident cells, thus promoting intestinal remodeling, mucus production, epithelial barrier, cytokine production, angiogenesis, and neuropeptide release. A number of lines of evidence support both potential beneficial and deleterious roles of eosinophils in the gut. Although studies from the gut and other mucosal organs suggest eosinophils affect mucosal GI inflammation, definitive roles for eosinophils in IBDs await discovery. PMID- 21593641 TI - Role of dietary factors and food habits in the development of childhood obesity: a commentary by the ESPGHAN Committee on Nutrition. AB - This Comment by the Committee on Nutrition of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition aims to provide a summary of the role of nutrition-related factors on obesity prevention in children ages 2 to 18 years. This Comment emphasizes that dietary interventions should be incorporated into a multidisciplinary strategy for obesity prevention. No single nutrient has been unequivocally associated with the development of obesity. Methodological limitations in study design and the complex nature of obesity must be taken into account when interpreting the association with reported dietary factors. Energy intake should be individually determined, taking into account energy expenditure and growth. Preferential intake of slowly absorbed carbohydrates and limiting the ingestion of rapidly absorbed carbohydrates and simple sugars should be promoted. No specific recommendations for macronutrient intakes to prevent obesity can be made. Plant foods can be used as the main food contributors to a well-balanced diet with adequate monitoring of nutrient intake. Plain water should be promoted as the main source of fluids for children instead of sugar-sweetened beverages. Children should eat at least 4 meals, including breakfast, every day. Regular family meals should be encouraged. Regular consumption of fast food with large portion sizes and high energy density should be avoided. Healthy food options should be promoted for snacking. Food portion sizes should be appropriate for age and body size. Nutrition and lifestyle education aimed at the prevention of obesity should be included in the routine care of children by health care professionals. PMID- 21593642 TI - Use of fluoroscopy to study in vivo motility in mouse pups. AB - OBJECTIVES: Few methods exist to noninvasively study in vivo gastrointestinal motility in animal models of enteric infections. None have been used on mouse pups, which often display more severe symptoms during enteric infections than adult mice. This study sought to determine whether digital fluoroscopy could be used to evaluate gastrointestinal motility in mouse pups as well as adult mice. MATERIALS AND METHODS: Fluoroscopic imaging studies were performed on normal 6- to 8-week-old adult mice and 12-day-old pups to develop protocols for evaluating gastric and intestinal wall movements and changes in stomach sizes. These protocols were then applied to evaluate motility in an established rotavirus mouse model. Imaging studies were performed on adult mice at 0, 2, and 4 days postinfection and on 12-day-old pups at 2 days postinfection. RESULTS: Fluoroscopic studies revealed postnatal differences of gastric peristalsis and rates of intestinal contractions between normal mouse pups and adult mice. Studies of the rotavirus mouse model revealed that differences in gastric function occur between rotavirus-infected and control mouse pups, but no discernible difference occurs between infected and control adult mice. In contrast, there were no detectable differences in rates of intestinal wall movements between control pups with normal stools and infected pups with loose stools. CONCLUSIONS: These results demonstrate that fluoroscopy can evaluate in vivo motility in mouse pups and by doing so provide findings that are clinically relevant to the study of enteric infections in young. PMID- 21593643 TI - Do children with IBD really respond better than adults to thiopurines? AB - BACKGROUND AND OBJECTIVES: Children and adolescents with inflammatory bowel disease (IBD) have more extensive and severe disease than adults. Despite a lack of comparative studies, thiopurines are frequently cited as being more efficacious in children. To test this assertion, we compared the efficacy of thiopurines in children with IBD with that in adults matched for disease phenotype. PATIENTS AND METHODS: Fifty paediatric and adult patients with IBD started on a thiopurine were matched for sex, disease type, and extent. Retrospective data were obtained by electronic case note review, and corticosteroid-free clinical remission and tolerance rates at 6 months as well as relapse rates during the subsequent year were recorded. RESULTS: Adverse effects caused discontinuation of thiopurines in 1 of 50 children and 16% (8/50) of adults (P < 0.05). At 6 months, steroid-free remission was achieved in 30% (15/50) of children and 38% (19/50) of adults (P = 0.53). No differences in remission rates were seen according to disease type. At the end of the following year, 73% (11/15) of children and 68% (13/19) of adults remained in remission (P = 1). CONCLUSIONS: Thiopurines are tolerated better by children. When phenotype is matched, there is no difference in the therapeutic response to thiopurines between children and adults with IBD. PMID- 21593644 TI - Agreement between patient- and physician-completed Pediatric Ulcerative Colitis Activity Index scores. AB - OBJECTIVES: Currently validated ulcerative colitis (UC) activity measures are physician based, but incorporate patient reports of symptoms. We aimed to assess whether patient-completed Pediatric UC Activity Index (PUCAI) scores are comparable to those of physician scores. PATIENTS AND METHODS: We performed a single-center prospective study to assess agreement between patient- and physician-completed PUCAI scores. Seventy patients with UC (ages 4-29) representative of all of the disease activity categories (inactive, mild, moderate, and severe) in the currently published physician-completed scoring system were recruited. Agreement was analyzed for PUCAI scores both as continuous and categorical measures. To ascertain validity, we compared both patient- and physician-completed PUCAI scores with the physician global assessment and serum inflammatory markers. RESULTS: Patient- and physician-completed PUCAI summary scores were identical 49% of the time, were different but within the minimal clinically important difference (MCID) of 20 points 48% of the time, and were at or beyond the MCID only 3% of the time. In general, patients reported higher mean disease severity on their questionnaires than did their physicians, with a mean difference in PUCAI scores of 3 +/- 8 (95% confidence interval 2%-5%). A categorical comparison of the 2 sets of questionnaires using the disease activity groups demonstrated perfect agreement for 60 (86%) pairs (kappa coefficient 0.78; 95% confidence interval 0.65%-0.90%). Both patient- and physician-completed PUCAI scores also correlated well with the physician global assessment and serum inflammatory markers. CONCLUSIONS: Our data indicate strong agreement between PUCAI scores obtained directly from patients and those completed by physicians. Hence, a patient-based PUCAI could complement existing instruments in both clinical and research settings. PMID- 21593645 TI - HLA-DQ genotyping combined with serological markers for the diagnosis of celiac disease: is intestinal biopsy still mandatory? AB - OBJECTIVES: The aim of this study was to evaluate the value of HLA-DQ2/DQ8 allelic genotyping combined with serologic testing for the diagnosis of celiac disease (CD). PATIENTS AND METHODS: One hundred seventy children, who underwent jejunal biopsy for digestive symptoms or malnutrition, were tested for HLA DQ2/DQ8 and serologic markers (tTG and/or anti-endomysial antibodies). Children were classified in 2 groups, according to jejunal histology: group 1, when partial or total villous atrophy was associated with an increased intraepithelial lymphocytosis suggesting CD, and group 2, when these histological criteria were absent. RESULTS: Eight children were excluded from the study because their intestinal histology was not informative; 82 children were classified in group 1 and 80 in group 2. Eighty-one of 82 children in group 1 were positive for HLA and serologic testing. The other child had negative HLA and serologic testing but marked villous atrophy, and further investigation showed an allergic disease. Among the 80 children in group 2, 53 were negative for both HLA and serologic testing, 22 were positive for HLA but negative for serologic testing, 2 were negative for HLA and positive for serologic testing, and 3 patients were positive for both HLA and serologic testing. The last 3 children were shown to have an autoimmune background and had probably a latent form of CD. The association of HLA-DQ2/DQ8 and serologic markers had a sensitivity of 98.8%, a specificity of 96.2%, a positive likelihood ratio of 26.3, and a negative likelihood ratio of 0.013. CONCLUSIONS: The association of positive HLA-DQ2/DQ8 and serologic testing has a high predictive value for CD. We suggest that symptomatic children with high titers of immunoglobulin (Ig)A tTG could be diagnosed as patients with CD without performing jejunal biopsy. In other children, HLA-DQ2/DQ8 could be useful to exclude the diagnosis of CD if negative. In cases of low IgA tTG titers or in patients with IgA deficiency, intestinal biopsy remains mandatory. PMID- 21593646 TI - Gene expression profiling reveals upregulated UCA1 and BMF in gallbladder epithelia of children with pancreaticobiliary maljunction. AB - BACKGROUND: Pancreaticobiliary maljunction is usually associated with choledochal cysts and often causes biliary carcinoma; however, the mechanism of carcinogenesis remains unknown. No study has analyzed overall changes in genetic expression beginning during childhood in gallbladder epithelia with pancreaticobiliary maljunction. PATIENTS AND METHODS: The genomewide expression of gallbladder epithelia was analyzed in 6 children with pancreaticobiliary maljunction and in 4 pediatric controls. Selected genes that were expressed differentially were further analyzed by the real-time reverse transcription polymerase chain reaction (RT-PCR). The products of upregulated genes confirmed by real-time RT-PCR were immunohistochemically analyzed using gallbladders from 19 children with pancreaticobiliary maljunction, 5 pediatric controls, and 5 children with gallstones. RESULTS: Microarray analysis identified 188 upregulated and 160 downregulated genes. RT-PCR confirmed upregulation in 5 of 6 genes and downregulation in 1 of 5 genes, including UCA1, DUOX2, DUOXA2, ID1, BMF, and GP2. Immunohistochemistry showed a significantly higher expression of BMF in the pancreaticobiliary maljunction patients than in the controls and gallstone patients. CONCLUSIONS: This study identified several deregulated genes in the gallbladder of children with pancreaticobiliary maljunction, which may contribute to the pathophysiology. UCA1, a noncoding RNA, is an oncofetal gene, and its upregulation may be important for biliary carcinogenesis. The elevated expression of BMF may function as an apoptotic activator in proliferative gallbladder epithelia. PMID- 21593647 TI - Variation in care for children with esophageal varices: a study of physicians', patients', and families' approaches and attitudes. AB - BACKGROUND AND AIMS: Inadequate evidence to guide the management of children with esophageal varices may lead to variation in care and the provision of poor quality care to some children. The aims of the study were to describe approaches taken by pediatric gastroenterologists for the management of esophageal varices in children, and to determine the attitudes of children, parents, and physicians toward screening endoscopy for identification of varices. METHODS: Canadian pediatric gastroenterologists and hepatologists were questioned about their approaches to screening for esophageal varices and therapy to prevent or treat variceal hemorrhage. Consecutive children with portal hypertension and their parents were surveyed about attitudes to screening endoscopy. RESULTS: Forty seven of 72 (65%) physicians responded. Seventy percent of respondents screen for esophageal varices in selected children, most using endoscopy (77%). Fifty-eight percent of respondents who screen for varices would provide primary prophylactic treatment. Most would treat an acute variceal bleed with antibiotics, acid suppression, octreotide, and endoscopy within 24 hours (76%) and then secondary prophylaxis with endoscopic variceal ligation (96%) or beta-blockers (28%). Among 29 families surveyed, 63% of parents and 50% of patients would agree to screening endoscopy to understand their risk of variceal bleeding and 67% if prophylactic therapy were available. Families were more concerned about the risk of endoscopic adverse events than were gastroenterologists. CONCLUSIONS: Pediatric gastroenterologists vary in the care they provide for children at risk for esophageal varices and their attitudes toward the role of screening endoscopy differ from that of their patients. Further evidence is required to support practice guidelines that may reduce variation in care and thus improve its quality. PMID- 21593648 TI - Effect of formula composition on the development of infant gut microbiota. AB - OBJECTIVES: Breast-feeding induces a gut microbiota rich in bifidobacteria, whereas formula-fed babies have a more diverse colonization. This ecosystem contributes to the development of the immune response and the lower incidence of diarrhea and allergy in breast-fed infants. This randomized double-blind controlled trial aimed to evaluate the bifidogenic effect of a mainly whey protein study formula low in phosphate and protein, allowing a composition closer to that of human milk. PATIENTS AND METHODS: One hundred ninety healthy infants exclusively received study formula with or without Bifidobacterium longum (BL999), or a control formula for up to 4 months. Breast-fed infants served as a reference population. Stool samples collected at 2 months of age were analyzed for bacterial counts (log colony-forming unit [CFU]/g). RESULTS: Bifidobacteria counts were significantly higher in infants receiving the study formula alone (10.0[0.8], P < 0.0001, median [interquartile range]) or with BL999 (9.8[1.4], P < 0.01) than control (9.2[3.5]), and were similar to breast-fed infants (10.1[0.4], P > 0.05). The difference between the 2 study groups was 0.16 log CFU/g (90% confidence interval [CI] [0-0.4]), within the predefined equivalence margin. Microbiota profile, as a percentage of total bacteria counts, showed about 50% Bifidobacteria, 8% Enterobacteria, and <10% Clostridia in study formulae and breast-fed infants versus 22%, 13%, and 19% in controls, respectively. There were no significant differences in growth measurements, digestive tolerance, and adverse events between groups. CONCLUSIONS: This study showed that infant formula closer resembling human milk was more bifidogenic than the control formula and led to a microbiota profile similar to that for breast fed infants. PMID- 21593649 TI - Physiological and bifidogenic effects of prebiotic supplements in infant formulae. AB - OBJECTIVES: This randomized controlled trial involving 110 healthy neonates studied physiological and bifidogenic effects of galactooligosaccharides (GOS), oligofructose, and long-chain inulin (fructooligosaccharides, FOS) in formula. METHODS: Subjects were randomized to Orafti Synergy1 (50 oligofructose:50 FOS) 0.4 g/dL or 0.8 g/dL, GOS:FOS (90:10) 0.8 g/dL, or a standard formula according to Good Clinical Practice guidelines. A breast-fed group was included for comparison. Outcome parameters were weight, length, intake, stool characteristics, crying, regurgitation, vomiting, adverse events, and fecal bacterial population counts. Statistical analyses used nonparametric tests. RESULTS: During the first month of life, weight, length, intake, and crying increased significantly in all of the groups. Regurgitation and vomiting scores were low and similar. Stool frequency decreased significantly and similarly in all of the formula groups but was lower than in the breast-fed group. All of the prebiotic groups maintained soft stools, only slightly harder than those of breast-fed infants. The standard group had significantly harder stools at weeks 2 and 4 compared with 1 (P < 0.001 and P = 0.0279). The total number of fecal bacteria increased in all of the prebiotic groups (9.82, 9.73, and 9.91 to 10.34, 10.38, and 10.37, respectively, log10 cells/g feces, P = 0.2298) and more closely resembled the breast-fed pattern. Numbers of lactic acid bacteria, bacteroides, and clostridia were comparable. In the SYN1 0.8 g/dL and GOS:FOS groups, Bifidobacterium counts were significantly higher at D14 and 28 compared with D3 and were comparable with the breast-fed group. Tolerance and growth were normal. CONCLUSIONS: Stool consistency and bacterial composition of infants taking SYN1 0.8 g/dL or GOS:FOS-supplemented formula were closer to the breast-fed pattern. There was no risk of dehydration. PMID- 21593650 TI - Oral viscous budesonide therapy in children with epidermolysis bullosa and proximal esophageal strictures. PMID- 21593651 TI - Is plasma exchange effective in prevention of hepatic transplantation in fulminant Wilson disease with hepatic failure? PMID- 21593652 TI - Esophageal leukemic infiltration in children. PMID- 21593654 TI - "Evaluation of esophageal motility using multichannel intraluminal impedance in healthy children and children with gastroesophageal reflux": comments. PMID- 21593656 TI - Differences in the prevalence of obesity in children with celiac disease. PMID- 21593657 TI - Nissen fundoplication: bridging the gap between pediatric surgeons and gastroenterologists. PMID- 21593658 TI - Spinal manipulative therapy for chronic low-back pain: an update of a Cochrane review. AB - STUDY DESIGN: Systematic review of interventions. OBJECTIVE: To assess the effects of spinal manipulative therapy (SMT) for chronic low-back pain. SUMMARY OF BACKGROUND DATA: SMT is one of the many therapies for the treatment of low back pain, which is a worldwide, extensively practiced intervention. METHODS: Search methods. An experienced librarian searched for randomized controlled trials (RCTs) in multiple databases up to June 2009. Selection criteria. RCTs that examined manipulation or mobilization in adults with chronic low-back pain were included. The primary outcomes were pain, functional status, and perceived recovery. Secondary outcomes were return-to-work and quality of life. Data collection and analysis. Two authors independently conducted the study selection, risk of bias assessment, and data extraction. GRADE was used to assess the quality of the evidence. RESULTS: We included 26 RCTs (total participants = 6070), 9 of which had a low risk of bias. Approximately two-thirds of the included studies (N = 18) were not evaluated in the previous review. There is a high-quality evidence that SMT has a small, significant, but not clinically relevant, short-term effect on pain relief (mean difference -4.16, 95% confidence interval -6.97 to -1.36) and functional status (standardized mean difference 0.22, 95% confidence interval -0.36 to -0.07) in comparison with other interventions. There is varying quality of evidence that SMT has a significant short-term effect on pain relief and functional status when added to another intervention. There is a very low-quality evidence that SMT is not more effective than inert interventions or sham SMT for short-term pain relief or functional status. Data were particularly sparse for recovery, return-to-work, quality of life, and costs of care. No serious complications were observed with SMT. CONCLUSIONS: High-quality evidence suggests that there is no clinically relevant difference between SMT and other interventions for reducing pain and improving function in patients with chronic low-back pain. Determining cost-effectiveness of care has high priority. PMID- 21593660 TI - Unknown case: Low back pain in a patient with cafe au lait spots. PMID- 21593661 TI - A randomized cross-over study to compare raltegravir and efavirenz (SWITCH-ER study). AB - BACKGROUND: Efavirenz (EFV) causes neuropsychiatric side-effects and an unfavorable blood lipid profile. We investigated the effect of replacing EFV with raltegravir (RAL) on patient preference, daytime sleepiness, sleep quality, anxiety, and lipid levels. METHOD: Switch-ER was a randomized, double-blind, cross-over study. Patients who tolerated EFV, with less than 50 copies/ml HIV RNA, were randomized into two groups: the RAL-first group started with RAL (400 mg twice daily) and EFV placebo, and the EFV-first group with EFV (600 mg once daily) and RAL placebo. After 2 weeks, both groups switched to the alternate regimen. The primary endpoint was patient preference for the first or the second regimen, assessed after 4 weeks. RESULTS: Fifty seven participants were enrolled with a median CD4 cell count 600/MUl, and duration of previous EFV therapy 3.4 years. Fifty three participants completed the study. When asked about treatment preference after 4 weeks, 22 preferred RAL and 12 preferred EFV, whereas 19 did not express a preference. A significant difference in anxiety and stress scores favoring RAL (P = 0.04 and 0.03, respectively) was observed. Median plasma cholesterol levels decreased by 0.4 mmol/l (16 mg/dl, P < 0.001), triglycerides by 0.2 mmol/l (18 mg/dl, P = 0.036), and low-density lipoprotein by 0.2 mmol/l (8 mg/dl, P = 0.004) after replacing EFV with RAL. After study completion, 51% of patients switched to RAL. CONCLUSION: Half of patients previously on a stable EFV preferred to switch to RAL, after double-blind exposure to RAL for 2 weeks. Substitution of EFV by RAL significantly impacted on lipid levels, stress, and anxiety scores. PMID- 21593662 TI - The role of periaqueductal gray and cingulate cortex during suppression of pain in complex regional pain syndrome. AB - OBJECTIVE: Complex regional pain syndrome I (CRPS I) is a frequent and debilitating condition with unclear etiology. Hypothesizing that maladaptive central processes play a crucial role in CRPS, the current study set out to explore cerebral activation during a task to suppress the feeling of pain under constant painful stimulation. METHODS: Ten individuals with CRPS I with symptoms on their left hand were subjected to electrical stimulation of both index fingers subsequently in a functional magnetic resonance imaging experiment. Their data were compared with 15 healthy controls. RESULTS: Concerning psychophysical measures, patients succeeded similarly as healthy controls in suppressing the feeling of pain. However, during constant painful stimulation and with the task to suppress the feeling of pain, there were significant differences in the interaction analyses of the corresponding cortical activation. DISCUSSION: Patients differ from healthy controls by the activation pattern of cerebral areas that belong to the descending opioid pain suppression pathway: PAG and cingulate cortex are activated significantly less during suppression of pain, regardless of whether the symptomatic or asymptomatic hand was stimulated. Thus, there is a generalized functional change in individuals with CRPS I. However, it cannot be deducted whether the abnormality is causative or merely an effect, possibly maladaptive. PMID- 21593663 TI - Experimental pain hypersensitivity in schizophrenic patients. AB - OBJECTIVE: Whether schizophrenic patients are hypoalgesic or feel pain in the same manner as unaffected individuals can affect the primary care of schizophrenic patients, which often involves an assessment of pain severity made by a medical provider. This study was developed to explore the pain sensitivity of schizophrenics under conditions similar to those of a medical examination that included investigating for sites of pain. METHODS: We developed 2 experimental models of pain induction using either pressure or ischemia and used them with 35 schizophrenic patients and 35 controls to record: (1) the stimulus intensity required to induce moderate pain; and (2) the pain intensity induced by a predetermined level of pressure. Clinical data were also collected for the schizophrenic group. RESULTS: Schizophrenic patients needed less pressure (P=0.006) and a shorter duration of ischemia (P<0.001) than controls to record moderate pain, and they felt more pain from a fixed pressure stimulus (P<0.001). Pain histories for the previous 6 months and the heart rate variations that occurred during the tests did not differ between the groups. Pain responses were unrelated to the clinical characteristics of the schizophrenic patients, although hallucination production correlated with the pain felt during the fixed pressure test. DISCUSSION: Under these conditions, schizophrenic patients were hypersensitive to pain induction compared with normal individuals. The hypoalgesia typically associated with schizophrenic patients may correspond to fewer than normal reports of pain, rather than to impaired sensations of pain. This should be taken into account during routine medical practice. PMID- 21593664 TI - Relationships among pain, protective parental responses, and disability for adolescents with chronic musculoskeletal pain: the mediating role of pain catastrophizing. AB - OBJECTIVES: Children learn to cope with pain within the context of the family and parental responses to pediatric pain can impact health outcomes. The aim of this study was to examine relationships among pain, protective parental responses to pain, functional disability, and pain catastrophizing for adolescents with chronic musculoskeletal pain syndromes. METHODS: Initial evaluation records for 138 adolescents with chronic musculoskeletal pain who consulted a pediatric multidisciplinary pain management clinic were examined. Measures were collected at the time of the initial evaluation and included adolescent self-reports of their own usual pain intensity, perceived parental responses to their pain, adolescent functional disability, and pain catastrophizing. RESULTS: Pain catastrophizing was significantly correlated with pain intensity, protective parental responses to pain, and functional disability. Multiple regression analyses further suggest that pain catastrophizing serves as a mediator of relationships between: (1) pain and disability and (2) protective parenting responses and disability. Evidence supporting a significant indirect effect for pain catastrophizing on disability was found within both models through bootstrap and Sobel analyses. DISCUSSION: Pain catastrophizing seems to play an important role in understanding relationships between pain, protective parental responses, and disability for adolescents with musculoskeletal pain. Our findings suggest that strategies that help modify adolescent catastrophic pain beliefs and parental responses to pain, may help improve adolescent functioning. PMID- 21593665 TI - Adaptive versus maladaptive coping and beliefs and their relation to chronic pain adjustment. AB - OBJECTIVES: Coping and beliefs are cornerstones to our understanding of adjustment to chronic pain. This study sought to test the hypothesis that maladaptive pain-related coping and beliefs are more strongly related to measures of patient adjustment than are adaptive coping and beliefs. METHODS: A sample of 106 veterans with mixed chronic pain diagnoses in a multidisciplinary pain treatment program were administered measures of pain beliefs and pain coping, and composite scores were computed to reflect adaptive and maladaptive responses. Correlations between the composite scores and outcomes (pain intensity, pain interference, depression) were examined. Hierarchical multiple regressions were also conducted to estimate the independent contributions of adaptive and maladaptive responses. RESULTS: The maladaptive response composite score was found to be significantly related to pain interference and depression, whereas both adaptive and maladaptive response composite scores were found to be significantly related to pain intensity. The maladaptive response composite showed stronger independent associations with pain interference and depression after controlling for demographic variables, pain intensity, and adaptive responses. Contrary to expectations, only the adaptive response composite showed an independent association with pain intensity. DISCUSSION: The findings suggest that the relative importance of adaptive versus maladaptive beliefs and coping may differ as a function of the outcome domain in question. The findings support current cognitive-behavioral interventions that focus on reducing the frequency of maladaptive coping responses and beliefs as a way to improve patient functioning. PMID- 21593666 TI - Spinal cord stimulation for the treatment of Buerger disease: a report on 3 cases. AB - OBJECTIVES: Buerger disease (or thromboangeiitis obliterans) is an inflammatory disease of the medium and small caliber arteries and veins that predominantly affects young males and presents with ischemia in the hands or the feet. It is closely associated with smoking. Critical ischemia of the lower limbs is a threat to the survival of the patient s extremities, and often disables its victims severely. This takes on an even greater significance in younger individuals who are still actively employed, as is the case in patients suffering from Buerger disease. Our aim was to evaluate the efficiency of the spinal cord stimulation as an alternative therapeutic option in acute stages of Buerger disease. RESULTS AND METHODS: We present a case series of males under the age of 45 years, diagnosed with thromboangeiitis obliterans and all of them were in the acute phase of the disease. They were satisfactorily treated with an implantable spinal cord stimulation device. DISCUSSION: Spinal cord stimulation is an accepted therapy for the treatment of chronic ischemic pain and ulcer healing and to avoid amputation in patients with severe, nonrevascularisable peripheral occlusive arteriopathy, and specially in the subgroup of patients with Buerger disease. It should not only be considered as a last resort strategy for pain control, but as a valid therapeutic option to improve perfusion of the limbs in the initial stages of the disease, however larger studies still remain necessary. PMID- 21593667 TI - Altered central sensitization in subgroups of women with vulvodynia. AB - OBJECTIVE: To investigate the clinical correlates of central nervous system alterations among women with vulvodynia. Altered central sensitization has been linked to dysfunction in central nervous system-inhibitory pathways (e.g., gamma aminobutyric acidergic), and metrics of sensory adaptation, a centrally mediated process that is sensitive to this dysfunction, could potentially be used to identify women at risk of treatment failure using conventional approaches. METHODS: Twelve women with vulvodynia and 20 age-matched controls participated in this study, which was conducted by sensory testing of the right hand's index and middle fingers. The following sensory precepts were assessed: (1) vibrotactile detection threshold; (2) amplitude discrimination capacity (defined as the ability to detect differences in intensity of simultaneously delivered stimuli to 2 fingers); and (3) a metric of adaptation (determined by the impact that applying conditioning stimuli have on amplitude discriminative capacity). RESULTS: Participants did not differ on key demographic variables, vibrotactile detection threshold, and amplitude discrimination capacity. However, we found significant differences from controls in adaptation metrics in 1 subgroup of vulvodynia patients. Compared with healthy controls and women with a shorter history of pain [n=5; duration (y) = 3.4 +/- 1.3], those with a longer history [n=7; duration (y) = 9.3 +/- 1.4)] were found to be less likely to have adaptation metrics similar to control values. DISCUSSION: Chronic pain is thought to lead to altered central sensitization, and adaptation is a centrally mediated process that is sensitive to this condition. This report suggests that similar alterations exist in a subgroup of vulvodynia patients. PMID- 21593668 TI - The temporoparietal fascia flap: a versatile tool in head and neck reconstruction. AB - PURPOSE OF REVIEW: The article reviews recent significant advances and current applications of the temporoparietal fascia flap (TPFF) in head and neck surgery. RECENT FINDINGS: The recent literature describes a wide span of new applications of the TPFF in many areas. Significant developments and refinements in the reconstruction of orbitomaxillary composite defects and orbital exenteration cavities are reported. The TPFF combined with alloplastic framework is gaining in importance in external ear reconstruction. Innovative prefabricated skin or soft tissue grafts based on the TPFF are used to restore facial contour or in the reconstruction of complex facial defects. The free TPFF finds a role in laryngotracheal reconstruction as a vascular carrier to support cartilage grafts. SUMMARY: Owing to its reliability and unequalled structural properties, the TPFF still plays a central role in facial reconstruction. Future investigation will likely incorporate the free TPFF as a vascular carrier of bioengineered tissues, such as cartilage and mucosa, for various head and neck indications. PMID- 21593669 TI - The buccinator flap: a review of current clinical applications. AB - PURPOSE OF REVIEW: This article reviews the buccinator flap, its relevant surgical anatomy, surgical technique, and applications in head and neck reconstruction. RECENT FINDINGS: Reconstruction of defects after extirpation of head and neck neoplasms can be challenging and complex. Various reconstructive techniques, including skin grafts, regional flaps, and free tissue transfer, can be employed in restoration of form and function after ablative surgery. Although a wide array of reconstructive options is available, the technique employed will largely depend on the surgeon preference and experience. Commonly used pedicled flaps and free tissue transfer techniques can share several disadvantages, including prolonged operative time, poor cosmesis, donor site morbidity, functional limitations, and excessive tissue bulk for intraoral reconstruction. The ideal reconstructive method would adhere to the plastic surgery principle of replacement of 'like with like'. The ease of dissection and useful application makes the buccinator flap an excellent additional reconstructive option for the head and neck surgeon. SUMMARY: The buccinator myomucosal flap is a versatile and dependable flap for head and neck reconstruction. Its minimal donor site morbidity, pliability, ease of elevation, and flexible usage while offering optimal functional and cosmetic results make it a viable option for select defects. PMID- 21593670 TI - Supraclavicular artery island flap for reconstructing defects in the head and neck region. AB - PURPOSE OF REVIEW: The supraclavicular artery island flap is a rotation flap that offers a versatile reconstructive option for head and neck defects. Recent anatomical studies have improved our understanding of the vascular supply of the supraclavicular artery island flap. Furthermore, several published large series describe the utility and reliability of this flap. In this article, we review the scientific literature describing the vascular anatomy of the supraclavicular artery island flap, its clinical application, and limitations in reconstructing defects in the head and neck region. RECENT FINDINGS: The vascular anatomy and surface markings, optimal flap design, surgical techniques employed to improve reliability, and aesthetic and functional outcomes of the supraclavicular artery island flap in head and neck reconstruction are well documented in the literature. SUMMARY: The supraclavicular artery island flap offers a versatile and well tolerated option in reconstruction of head and neck defects with several advantages over more traditional regional flaps and distant-free flaps. PMID- 21593671 TI - Complex robotic reconstructive surgical procedures in children with urologic abnormalities. AB - PURPOSE OF REVIEW: Robot-assisted laparoscopic surgery (RALS) is evolving rapidly in the pediatric surgical field. The unique attributes of the robotic interface makes this technology ideal for children with congenital anomalies who often require reconstructive procedures. Furthermore, the system can generate extremely delicate movements in a confined working space such as the one generally found in the pediatric population. Herein, we critically review the current experience with RALS placing a special emphasis in children undergoing complex reconstructive surgical procedures worldwide. RECENT FINDINGS: A total of 42 original manuscripts on a variety of robot-assisted urologic surgical procedures in children were identified from a MEDLINE database search. Complex reconstructive procedures that are being currently performed include reoperative pyeloplasty, pyeloplasty in infants, pyelolithotomy, ureteropyelostomy/ureterostomy, bladder augmentation with or without appendico vesicostomy, bladder neck sling procedure, among others. SUMMARY: Initial results with robot assistance are encouraging and have demonstrated safety comparable to open procedures and outcomes at least equivalent to standard laparoscopy. Future development of smaller instruments, incorporating tactile feedback, will likely overcome current limitations and spread out the use of this technique in younger children and more advanced procedures. PMID- 21593672 TI - A comparison of the i-gel and classic LMA insertion in manikins by experienced and novice physicians. AB - OBJECTIVE: Airway management is of utmost importance in critical patients, for whom endotracheal intubation remains the gold standard. However, it is a difficult skill to acquire and success rates in novices are unacceptably low. Supraglottic devices constitute promising alternatives. The aim of this study was to assess the use of laryngeal mask airway (LMA) classic LMA (cLMA) and a relatively new supraglottic device, the i-gel, in experienced and novice doctors in a manikin setting. METHODS: The study population comprised 116 doctors. After a brief educational session and presentation of cLMA and i-gel, participants were randomly allocated to insert both devices in an adult manikin. Insertions were performed using a size-4 cLMA and a size-4 i-gel. The primary endpoints were the success rate for each device and the duration of the insertion attempt. Secondary endpoint was the perception of ease of use with each device. RESULTS: First attempt success rate was 90.5% for i-gel and 63.8% for cLMA (P<0.001). I-gel use reduced insertion times (13.32+/-4.99 s vs. 17.99+/-6.87 s, P<0.001) and was related with significantly higher first attempt success rates than cLMA in novices (90 vs. 48.3%, P<0.001). In addition, i-gel use provided almost equal success rates for experienced and novice doctors (91 vs. 90%, P=not significant), whereas cLMA use resulted in significantly lower success rates for novices (48.3 vs. 80.4%, P<0.001). CONCLUSION: In this manikin setting i-gel significantly improved success rates and insertion time compared with cLMA. Most importantly, i gel use resulted in high first pass success rates for novice doctors, equal to those achieved by experienced doctors. PMID- 21593673 TI - Influence of physical fitness on the performance of 5-minute continuous chest compression. AB - OBJECTIVE: Inadequate chest compressions during cardiopulmonary resuscitation (CPR) may be insufficient to provide the required blood flow to preserve critical organ function. The purpose of this study was to evaluate the influence of the CPR provider's physical fitness on the quality of chest compression and physiological changes during continuous chest compressions for 5 min. We also investigated the possible effects of rescuer's sex, weight, and height on the quality of CPR performed. METHODS: Forty-seven participants performed uninterrupted chest compressions on a manikin for 5 min. Before performing CPR, the physical fitness of every candidate was assessed using common measures of physical fitness, including maximal aerobic exercise capacity, muscle strength, muscle power, muscle endurance, and reactive agility. To evaluate the physical strain, we monitored the ratings of perceived exertion score, heart rate, minute ventilation volume, volume of carbon dioxide production per minute, and volume of oxygen consumption per minute during CPR performance. RESULTS: There was a significant reduction in the percentage of correct compressions after the first minute: 78.8% in the first, 57.2% in the second, 43.4% in the third, 36.5% in the fourth, and 28.0% in the fifth minute (P<0.001). We observed good correlations between the numbers of correct compressions with muscle strength at each minute except the first minute. In multiple regression analyses, only muscle strength affects the quality of correct chest compression (R=49.4%, P<0.05). CONCLUSION: The results of this study suggest that a fitness program, such as muscle strength exercise for CPR providers, should be considered for improving survival from cardiac arrest. PMID- 21593674 TI - Does the use of a variable stiffness colonoscope offer advantages during colonoscopy under deep sedation? Results of a randomized trial. AB - INTRODUCTION: Variable stiffness colonoscope may be useful in performing colonoscopies in nonsedated patients or under endoscopist-controlled sedation. The objective of this study is to evaluate whether this instrument facilitates colonoscopy in patients under deep sedation monitored by an anaesthesiologist. METHODS: Prospective and randomized study enroling consecutive patients referred for colonoscopy under deep sedation monitored by an anaesthesiologist. In group I, a variable stiffness colonoscope was used, whereas in group II, a standard colonoscope was used. The main variable was the need to change the position of the patient during the endoscopy. RESULTS: Fifty-six patients were included in group I (variable stiffness colonoscope) and 54 in group II (standard colonoscope). The caecum was reached in 92.9% of patients in group I and in 90.7% of group II (P=0.7). The time required to reach the caecum was significantly less in group I (6.14+/-3.5 vs. 7.7+/-3.8; P=0.035). The variable stiffness colonoscope was effective in 66.7% of cases. Changing the position of the patient was necessary in 12.5% of cases in group I compared with 33.3% of cases in group II (P=0.01). CONCLUSION: The variable stiffness colonoscope avoids the need to change the patient's position and reduces caecal intubation time in patients undergoing colonoscopy under deep sedation controlled by an anaesthesiologist. PMID- 21593675 TI - Does intravesical electrostimulation improve neurogenic constipation? A case report. AB - An elderly patient affected by incomplete cauda equina syndrome underwent intravesical electrostimulation (IVES) to improve impaired bladder emptying. One month after IVES treatment, which consisted of 20 daily sessions, cistometrography evidenced a normalization of urinary pattern and a concomitant, but unexpected, improvement of constipation (Wexner score from 22 to 4).This report demonstrates that IVES may be considered another viable and less invasive option for controlling constipation secondary to spinal and peripheral nerve lesions. PMID- 21593676 TI - Functional capacity is significantly impaired in primary biliary cirrhosis and is related to orthostatic symptoms. AB - OBJECTIVE: To assess patient-reported functional ability and its relationship with symptoms in primary biliary cirrhosis (PBC). METHODS: Functional status was assessed in a representative cohort of 75 patients with PBC using the Patient Reported Outcome Measure Information System Health-Assessment Questionnaire (PROMIS-HAQ) functional assessment tool and was related to both symptom severity at the point of assessment (assessed using the PBC-40 and Orthostatic Grading Scale) and symptom severity change over the previous 4 years. Functional status in the PBC group was compared with primary sclerosing cholangitis (cholestatic liver disease) and community controls. RESULTS: Functional impairment at follow up (PROMIS-HAQ) was substantial in PBC significantly higher than that in both primary sclerosing cholangitis and community controls. PROMIS-HAQ domain scores confirmed that patients with PBC had significant impairment in arising, eating, walking, reach and grip and activity, but not dressing or hygiene. Functional impairment correlated positively with greater PBC-40 Fatigue, Cognitive and Social and Emotional domains and higher orthostatic symptoms. Over 4 years, total symptom burden increased significantly (P=0.03). The predominant factor was rise in Cognitive domain scores indicating worsening cognitive symptoms (P<0.0001). Change in PBC-40 Cognitive, Social and Emotional scores (2005-2009) strongly predicted functional ability in 2009. Multivariate analysis confirmed that PROMIS HAQ scores were predicted independently by PBC-40 Social and Emotional scores (P=0.02; beta=0.3) and orthostatic symptoms (P=0.04; beta=0.3). CONCLUSION: PBC associates with substantial functional impairment. PBC symptom distribution evolves over time, with cognitive symptoms making ever-greater contribution to overall symptom burden. The major potentially modifiable determinant responsible for the functional impairment appears to be orthostatic symptoms. PMID- 21593677 TI - Tumor necrosis factor-alpha affects blood-brain barrier permeability in acetaminophen-induced acute liver failure. AB - OBJECTIVES: Cerebral edema is a major cause of death during acute liver failure (ALF), but the exact mechanism of this condition is still not entirely clear. The aim of this study was to investigate the role of tumor necrosis factor alpha (TNFalpha) in changing the permeability of the blood-brain barrier (BBB) during acetaminophen (APAP)-induced ALF. MATERIALS AND METHODS: ALF animal models were generated by administering APAP. Anti-TNFalpha-IgG was intravenously injected (100 MUg/mouse) 2 h after administration of APAP. We investigated BBB permeability with Evans blue staining, and structure with electron microscopy. RESULTS: BBB permeability increased in APAP-induced ALF mice and correlated with elevated serum TNFalpha levels. Electron microscopy of mouse brain tissues revealed tight junction (TJ) disruptions and endothelial cell shrinkage, as well as increased vesicles and vacuoles. In addition, the expression of the TJ associated protein, occludin, was significantly decreased in APAP-induced ALF mice. Changes in BBB permeability and occludin expression could be prevented by administering anti-TNFalpha-IgG 2 h after APAP challenge. CONCLUSION: TNFalpha plays a critical role in the development of brain edema in APAP-induced ALF. Increased BBB permeability may be due to the loss of the TJ-associated protein occludin. PMID- 21593678 TI - Adenosine deaminase activity in patients with Crohn's disease: distinction between active and nonactive disease. AB - BACKGROUND: Crohn's disease (CD) is a common chronic inflammatory bowel disease. During the disease a cascade of immunologic events occur including mucosal influx of inflammatory cells like neutrophils. Adenosine deaminase (ADA) is important in inflammatory responses and serves as a marker of activated leukocytes. MATERIALS AND METHODS: In this study, we investigated the activity of total ADA (tADA) and its isoenzymes, ADA1 and ADA2, in serum and neutrophils derived from 20 active patients with CD, 20 patients in remission, as well as in 15 healthy controls. RESULTS: Patients with active disease had significantly (P<0.001) higher levels of tADA in serum (22.9+/-4.9 U/l) than patients in remission or healthy controls (14.0+/-3.4 U/l and 13.2+/-2.4 U/l respectively). ADA2, the main isoenzyme in the serum was higher in active patients by 60% as compared with patients in remission and healthy controls (19.7+/-1.9 U/l, 12.3+/-1.2 U/l, and 12.2+/-0.9 U/l respectively). We did not find a significant difference in these parameters between healthy controls and stable patients. There was a positive correlation (R=0.516) between tADA activity and C-reactive protein levels in patients with CD. Enhanced activity in tADA was also detected in neutrophils that were obtained from all patients with CD as compared with healthy controls (15.3+/-2.9 U/g, 14.1+/-2.3 U/g, and 9.4+/-2.9 U/g protein, respectively). This is mainly due to a significant increment (up to 51%) in ADA1 activity, the main isoenzyme in the neutrophils (84% out of the tADA). The cause of this increment remains to be elucidated. CONCLUSION: The results obtained in this study demonstrated elevated levels of tADA and ADA2 in patients with active disease. As the patient improves and becomes clinically stable these levels decrease, approaching normal values. tADA and ADA2 can be used as markers of inflammation, and provide a supportive indicator of CD activity. PMID- 21593679 TI - Successful pregnancy outcome in decompensated chronic liver disease with portal vein thrombosis: case report and review of literature. AB - Pregnancy is rare in women with decompensated chronic liver disease. In this case report, we describe a case of a young woman who presented with hepatitis B related decompensated chronic liver disease with portal vein thrombosis having successful full-term uneventful pregnancy. PMID- 21593680 TI - Comic books can educate children about burn safety in developing countries. AB - Burns in developing countries account for significant morbidity and many occur within the pediatric population. This study investigates whether a comic book can increase burn awareness in primary school age children, both domestically and abroad. Based on demographic data regarding pediatric burns in developing nations, a comic book was developed to educate primary school age children on key risk factors regarding burn safety, including teaching children to not touch active stoves, not to light fireworks without supervision, and to "stop, drop, and roll" after burn injury. Students, aged 5 to 7 years, in both West Virginia, United States (N = 74), and West Bengal, India (N = 39), answered a three question survey regarding these issues both before and after reading the comic book. Groups were compared using Fisher's exact test and significance was defined as P < .05. Initially, students answered 67.8 and 66.9% of the questionnaire correctly overall in West Virginia and West Bengal, respectively. These scores improved to 81.6 and 99.1% (P < .01 for each group), respectively, after reading the comic as a class. Specifically, there were significant increases in both groups for the questions regarding avoiding hot stoves (P < .01) and fireworks (P < .01). The lesson required 30 minutes total per class. The teachers reported that students enjoyed reading the comic and were engaged during the sessions. This study demonstrates that a comic book has value in teaching children about burn awareness. Comic books may be a cost-effective method as an outreach tool for children. PMID- 21593681 TI - Burn progression secondary to cardioversion. AB - Severe burns result in a profound hypermetabolic response. Catecholaminergic surges secondary to the burn injury itself, particularly if superimposed on premorbid cardiac disease, can result in cardiac arrhythmias. If unstable, these cardiac rhythm disturbances necessitate immediate cardioversion to regain normal sinus rhythm. Because of the high impedance at the skin-paddle interface, superficial cutaneous burns have been known to develop secondary to cardioversion. The authors describe a novel case of the subsequent local progression of a previously sustained superficial flame burn to full-thickness burn injury after cardioversion. PMID- 21593682 TI - Burns in Sulaymaniyah province, Iraq: epidemiology and risk factors for death in patients admitted to hospital. AB - This retrospective study was undertaken to describe the epidemiology of burns in the province of Sulaymaniyah in Iraqi Kurdistan and investigate factors associated with mortality. Hospital records of all patients admitted to the Burns and Plastic Surgery Centre of Sulaymaniyah for a burn incident during the calendar year of 2006 were reviewed retrospectively. A total of 947 acute burn patients were admitted over the year (females 53.5%, males 46.5%) of whom 41% were aged 0 to 14 years. Flame injuries were responsible for 59% and scalds for 37% of injuries. The median TBSA burnt was 19%, the median length of hospital stay was 5 days, and in-hospital mortality rate was 28%. Multivariable logistic regression showed that burn size, inhalation injury, older age, and female sex were significant risk factors for death. The adjusted odds ratios were 4.8 (95% confidence interval [CI] 1.3-20.0) for those aged 60 years or older compared with children aged 0 to 5 years; 2.2 (95% CI 1.2-4.1) for females compared with males; 9.8 (95% CI 4.8-20.0) for presence of inhalation injury; and 112.8 (95% CI 57.4 221.4) for >= 40% TBSA burnt compared with < 40% TBSA burnt. Burn injuries are an important public health problem in Iraq, and further studies are required to investigate circumstances surrounding burns and risk factors to inform planning of prevention programs. PMID- 21593684 TI - Attrition rates of pediatric emergency medicine fellowship graduates. AB - OBJECTIVES: To identify the percentage of alumni of one Pediatric Emergency Medicine (PEM) fellowship program who consider themselves to still practice in the field. METHODS: A brief survey (5 questions) was sent to all physicians who began the PEM fellowship program at the University of Alabama at Birmingham between the years 1986 and 2006. Survey included demographics, length of time out of fellowship, present work location, and whether the respondent considered themselves to be in the field of pediatric emergency medicine. RESULTS: Forty three physicians were identified as beginning fellowship between 1986 and 2006. One physician was excluded as she was deceased. Forty (95%) of the 42 individuals graduated from a PEM fellowship program. Analyzing the 39 responding PEM graduates, 29 (74%) consider themselves practicing pediatric emergency medicine. Six (60%) of those not considered practicing in PEM (n = 10) are women. Four of these 10 individuals are still in academic medicine. Overall attrition rate for this cohort of PEM fellowship-trained physicians is 25.6% (95% confidence interval, 13.0-42.1). CONCLUSION: Overall attrition rates of fellowship-trained PEM physicians seems to mirror that of adult trained counterparts. PMID- 21593683 TI - Inflammatory response in multiple organs in a mouse model of acute alcohol intoxication and burn injury. AB - This study characterized the inflammatory response after burn injury and determined whether ethanol (EtOH) intoxication at the time of burn injury influences this response. To accomplish this, male mice were gavaged with EtOH (2.9 g/kg) 4 hours before 12 to 15% TBSA sham or burn injury. Mice were killed on day 1 after injury; blood, small intestine, lung, and liver were collected to measure interleukin (IL)-6, IL-10, IL-18, and Monocyte chemotactic protein-1 (MCP 1) levels. In addition, neutrophil infiltration, myeloperoxidase activity, and edema formation were also measured in the small intestine, lung, and liver. There was no difference in the inflammatory markers in the small intestine, lung, and liver in mice receiving either sham or burn injury alone except IL-6 that was increased in all four tissue compartments after burn injury alone. However, when compared with EtOH or burn injury alone, EtOH combined with burn injury resulted in a significant increase in cytokines, neutrophil infiltration, myeloperoxidase activity, and edema in the small intestine, liver, and lung tissue. Furthermore, a significant increase in IL-6 and MCP-1 was observed in circulation after EtOH intoxication and burn injury compared with either EtOH intoxication or burn injury alone; no other cytokines were detected in circulation. These findings suggest that acute EtOH intoxication exacerbates the inflammatory response after burn injury. PMID- 21593685 TI - Predictive model for survival among neurosurgical intensive care patients. AB - BACKGROUND: Models for prediction of outcome of intensive care patients greatly help the physician to make decisions and are also important for risk stratification in clinical research and quality improvement. At present, there are no major predictive models for neurosurgical intensive care unit (NSICU) patients. This study aimed to develop a predictive model for survival in NSICU patients. METHODS: This is a prospective observational study in the NSICU at a tertiary-care university hospital. The data were collected within 24 hours of admission in all patients admitted to the NSICU. The parameters collected were demographic variables, systolic blood pressure, arterial oxygen tension after resuscitation (PaO2), Glasgow coma score (GCS) and pupillary signs, blood urea, creatinine, albumin, glucose, sodium, potassium, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, bilirubin, hemoglobin concentration, leukocyte count, platelet count, temperature, and evidence of infection. Mortality or discharge from NSICU was the primary outcome variable. All patients were provided full care until death or discharge from the ICU. Life support was not withdrawn in any of the patient based on the perception of outcome by the treating physician. All variables were compared between survivors and nonsurvivors. Significant variables were analyzed by multivariate logistic regression and a prediction model was developed. RESULTS: Four hundred six patients were included in the study. Three hundred two patients survived and 104 died (mortality of 25.6%). Significant variables on univariate analysis include primary reason for admission, GCS, pupillary reaction, systolic blood pressure, serum albumin, glucose, serum sodium concentration, hypothermia, and infection at the time of admission. Multivariate analysis showed that the significant independent factors for predicting outcome in NSICU patients are age, diagnosis, GCS, pupillary status, albumin, and serum sodium concentration. The predictive model has good discrimination (receiver operating characteristic curve=0.796) and good calibration (P=0.937). The overall accuracy of the model was 81%. CONCLUSIONS: In the current model of prediction of survival in a neurosurgical ICU, age, diagnosis, GCS, pupillary status, serum albumin, and serum sodium are independent predictors of survival in NSICU patients. PMID- 21593688 TI - Obituary: We have lost one of our friends: A Tribute to Robert J. White, MD, PhD, Professor Emeritus of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, Ohio (1926-2010). PMID- 21593686 TI - Propofol upregulates heme oxygenase-1 through activation of ERKs in human umbilical vein endothelial cells under oxidative stress conditions. AB - BACKGROUND: Heme oxygenase-1 (HO-1) is an important cytoprotective agent. We examined the effect of propofol on the regulation of HO-1 expression and its activity in human umbilical vein endothelial cells (HUVECs) under oxidative stress conditions. We further assessed whether extracellular signal-regulated kinases (ERKs), cJun-N-terminal kinases (JNKs), and p38-mitogen-activated protein kinase mediate propofol-induced HO-1 expression. METHODS: Hydrogen peroxide (100 MUmol/L) was used to induce oxidative stress. HUVECs were treated with different concentrations (1025 and 50 MUmol/L) of propofol for various periods of time. Finally, cells were pretreated with SB203580 (10 MUmol/L), a p38-mitogen activated protein kinase inhibitor; PD98059 (25 MUmol/L), an ERKs inhibitor; SP600125 (10 MUmol/L), a JNKs inhibitor; and ZnPPIX (10 MUmol/L), an HO-1 activity inhibitor, followed by propofol incubation. Reverse transcriptase polymerase chain reaction was used to detect HO-1 mRNA expression. HO-1 activity was determined in microsomal fractions from HUVECs by monitoring the conversion of heme into bilirubin. HO-1 protein and phosphorylated ERKs were measured by western blot analysis. Cell apoptosis was detected using terminal transferase deoxyuridine triphosphate-biotin nick-end labeling. RESULTS: Under oxidative stress conditions, HO-1 expression and activity were increased by propofol in a dose-dependent and time-dependent manner. PD98059, but not SB203580 or SP600125, effectively reduced propofol-induced HO-1 protein levels. The phosphorylation of ERKs was significantly increased by propofol, and this process was also inhibited by PD98059. Hydrogen peroxide-induced apoptosis in HUVECs was attenuated by propofol, which was partly reversed by ZnPPIX. CONCLUSIONS: These findings show that, under oxidative stress conditions, propofol induces HO-1 expression in HUVECs and this effect is mediated, at least in part, via ERKs pathways. PMID- 21593689 TI - Feasibility of intraoperative MRI guidance for craniotomy and tumor resection in the semisitting position. AB - BACKGROUND: Intraoperative magnetic resonance imaging (iMRI) has emerged as a reliable and useful tool in intracranial brain tumor surgery. Patient placement in a semisitting position may be advantageous in certain cases, but has so far seemed incompatible with conductance of iMRI-guided procedures. METHODS: The general iMRI setup and the imaging protocol were tested and described earlier. Having performed a preliminary phantom study and a minimally invasive burr-hole procedure in the semisitting position, we have transferred our setup into craniotomy: an iMRI-guided microsurgical tumor resection was performed in a patient with a recurrent glioblastoma in the occipital lobe extending to the corpus callosum using a mobile 0.15 Tesla iMRI system. All safety precautions commonly used in semisitting craniotomy were also applied. RESULTS: Patient positioning as well as preoperative and intraoperative image acquisition could be accomplished. Tumor resection was performed in a standard microsurgical image guided manner using neuronavigation. On intraoperative imaging, we could demonstrate complete resection of enhancing tissue, which was later confirmed by early postoperative high-field MRI. After our established protocol of patient monitoring, no complications or adverse events were noted intraoperatively or in the early or late postoperative phases. CONCLUSIONS: The iMRI-guided brain tumor resection is feasible in combination with semisitting patient positioning. However, special safety precautions must be followed. PMID- 21593691 TI - Bleed and herniation in tumors compressing the ventricular system: perils of preoperative CSF diversion. PMID- 21593692 TI - Cell-free DNA--a marker to predict ischemic brain damage in a rat stroke experimental model. AB - BACKGROUND: The animal model of stroke that is most frequently used is a rat model of focal brain ischemia caused by middle cerebral artery occlusion (MCAO). Several studies have reported a link between levels of cell-free DNA (CFD) and neurologic outcome in human stroke. The purpose of this study was to assess brain injury and measure CFD levels in 2 models of MCAO in rats, and to determine whether brain injury correlates with CFD. METHODS: A total of 60 rats were used for this study. Twenty rats underwent a sham procedure, 20 rats had MCAO using a monofilament, and 20 rats had MCAO with a silicon-coated filament. Groups were further divided into 2 subgroups. In 1 subgroup of 10 rats, neurologic performance [measured as a neurologic severity score, (NSS)] was measured at 1 and 24 hours after the procedure, and brain edema and infarct volume were determined at 24 hours. In the second subgroup of 10 rats, CFD was measured at 0, 1, 2, 4, 8, 12, and 24 hours and at 2, 3, 4, and 5 days. Neurologic performance (measured as a NSS) was measured at 1 and 24 hours after the procedure. RESULTS: The main finding was a significant increase in CFD levels observed 24 hours after the onset of MCAO. The correlation between the total infarct volume and CFD levels of the 3 groups was R=0.78, P<0.0001. Brain edema and NSS also were strongly correlated with CFD levels at 24 hours after MCAO (R=0.91, P<0.0001 and R=0.73, P<0.0001, respectively). CONCLUSIONS: We found that CFD levels correlate well with the extent of ischemic injury, brain edema, and neurologic outcome in rats 24 hours post-MCAO. We have also shown that CFD correlates well with the expected temporal progression of ischemic injury. These findings place CFD in a unique place as a biomarker for stroke, both experimentally and possibly clinically. PMID- 21593693 TI - Intensive insulin therapy increases the risk of hypoglycemia in neurocritical care patients. AB - BACKGROUND: Intensive insulin therapy protocols are widely used in intensive care medicine. A disadvantage of these protocols may be the occurrence of hypoglycemic episodes. Neurocritical care patients are particularly vulnerable to the effects of hypoglycemia. We aimed to study the risk of hypoglycemia in neurocritical care patients in relation to intensive insulin therapy. METHODS: To determine the effects of 2 different intensive insulin therapy protocols on glucose levels and hypoglycemia incidence, we collected data before and after implementation of the protocols in 2 university hospitals. The risk of hypoglycemia (blood glucose level below 3.0 mmol/L) was studied retrospectively with logistic regression analyses. RESULTS: In hospital A, data were obtained on 152 patients before implementation of the protocol and on 649 patients after implementation of the protocol. In hospital B, data were obtained on 111 patients before implementation of the protocol and on 118 patients thereafter. Implementation of intensive insulin therapy protocols increased the time spent in the desired blood glucose range of 4.6 to 6.0 mmol/L in both hospitals, but increased the risk of hypoglycemia: the absolute risk of hypoglycemia during intensive care unit admission increased in hospital A from 14.5% to 20.3% (adjusted odds ratio=1.3; 95% confidence interval: 0.8-2.3) and in hospital B from 3.6% to 29.7% (adjusted odds ratio=28.6; 95% confidence interval: 5.9-138.9). CONCLUSIONS: Implementation of intensive insulin therapy protocols in neurocritical care patients not only seems to increase the time spent in the desired blood glucose range, but also seems to increase the risk of hypoglycemia. The risk of hypoglycemia strongly depends on characteristics of the intensive insulin therapy protocol. PMID- 21593694 TI - PRO: the "Lund concept" for treatment of patients with severe traumatic brain injury. AB - Two different main concepts for the treatment of severe traumatic brain injury have been established during the last 15 years, namely the more conventional concept recommended in well-established guidelines (eg, the US Guideline, European Guideline, Addelbrook's Guideline from Cambridge) on the one hand, and the Lund concept from the University Hospital of Lund, Sweden on the other. Owing to the lack of well-controlled randomized outcome studies comparing these 2 main therapeutic approaches, we cannot conclude that one is better than the other. This study is the PRO part in a PRO-CON debate on the Lund concept in the present journal. Although the Lund concept is based on a physiology-oriented approach dealing with hemodynamic principles of brain volume and brain perfusion regulation, traditional treatments are primarily based on a meta-analytic approach from clinical studies. High cerebral perfusion pressure has been an essential goal in the conventional treatments (the cerebral perfusion pressure guided approach), even though it has been modified in a recent update of US guidelines. The Lund concept has instead concentrated on management of brain edema and intracranial pressure, simultaneously with improvement of cerebral perfusion and oxygenation (the intracranial pressure and perfusion-guided approach). Although conventional guidelines are restricted to clinical data from meta-analytic surveys, the physiological approach of the Lund therapy finds support in both experimental and clinical studies. It offers a wider base and can also give recommendations regarding fluid therapy, lung protection, optimal hemoglobin concentration, temperature control, the use of decompressive craniotomy, and ventricular drainage. This study puts forward arguments in support of the Lund therapy. PMID- 21593695 TI - Effect of autologous blood transfusion on cerebral cytokine expression. AB - BACKGROUND: Autologous blood transfusion (ABT), for example, by means of cell saver equipment, is used to reduce the need for allogenic blood transfusion in patients with high perioperative blood loss. This study investigated the effect of blood/extracorporal surface interaction during withdrawal and retransfusion of shed autologous blood on cerebral inflammation in rats. Rats subjected to hypotension with cerebral ischemia served as positive controls. METHODS: Eighty eight male Sprague-Dawley rats were anesthetized with sevoflurane, instrumented, and randomly assigned to the following groups: sham-operation (SHAM), autologous blood withdrawal/transfusion only (ABT), or bilateral carotid artery occlusion and autologous blood withdrawal/transfusion (BCAO/ABT). Inflammatory gene expression was investigated with real-time RT-polymerase chain reaction at 6, 12, and 24 hours after SHAM, ABT, or BCAO/ABT in brain hippocampal tissue. Naive rats were investigated as reference. RESULTS: ABT alone had no impact on hippocampal inflammatory gene expression, whereas after BCAO/ABT tumor necrosis factor-alpha (10.7 fold at 24 h), interleukin-1beta (2.1 fold at 6 h), interleukin-6 (35.7 fold at 24 h), COX-2 (9.3 fold at 6 h), and inducible nitric oxide synthase (3.4 fold at 24 h) increased compared with SHAM. CONCLUSIONS: ABT by itself did not provoke an inflammatory reaction in the healthy brain. However, in combination with cerebral ischemia the induction of a broad spectrum of inflammatory parameters indicates an inflammatory reaction of the hippocampus beginning after 6 hours and being most pronounced after 24 hours. Therefore, this study shows that cerebral inflammation is not induced by ABT after contact with extracorporal surfaces in rats. PMID- 21593696 TI - Identification of a mechanism for increased cardiovascular risk among individuals with low vitamin D concentrations. AB - OBJECTIVE: The aim of this study was to investigate the plasma concentrations of vitamin D and its association with plasma lipid profiles. METHODS: Plasma vitamin D3 and lipid concentrations were measured in 119 female cynomolgus monkeys (premenopausal, n = 49; ovariectomized, n = 70) consuming approximately 1,000 IU per day of vitamin D3. In a subset of the ovariectomized monkeys (n = 23), vitamin D3 was remeasured after 6 months. The concentrations of vitamin D3 were analyzed as a continuous variable and were divided at the median into high (>=48 ng/mL) versus low (<48 ng/mL) groupings. RESULTS: Among the 119 monkeys, the range of vitamin D3 concentrations was 24.0 to 95.2 ng/mL (mean +/- SD, 48.5 +/- 12.7 ng/mL). Plasma vitamin D3 concentration was positively associated with high density lipoprotein cholesterol (HDL-C; P = 0.003). Monkeys in the high vitamin D3 group had a significantly greater plasma HDL-C concentration (57.9 mg/dL) than did those in the low vitamin D3 group (47.1 mg/dL; P = 0.001). Although the difference was not significant (P = 0.120), the monkeys in the high vitamin D3 group had a decreased total plasma cholesterol-to-HDL-C ratio compared with those in the low vitamin D3 group (5.4 and 6.2, respectively), potentially putting them at lower risk of atherosclerosis development. CONCLUSIONS: Given that the monkeys all consumed a diet replete in vitamin D3, it seems that individual differences in vitamin D absorption or metabolism may have determined whether the monkeys had high or low concentrations of vitamin D3. Lower vitamin D3 was associated with a more atherogenic lipid profile, a major risk factor for progressing to coronary artery atherosclerosis in monkeys and human beings. PMID- 21593698 TI - Treatment of intracranial solitary fibrous tumors with gamma knife radiosurgery: report of two cases and review of literature. AB - BACKGROUND AND IMPORTANCE: Gamma knife radiosurgery (GKRS) as a treatment option has not been described in the management of typical intracranial solitary fibrous tumors. CLINICAL PRESENTATION: After presenting with visual decline, case A underwent a bioccipital craniotomy during which 90% of tumor was thought to have been resected. She unfortunately required re-resection 56 months later for recurrence when she again presented with progressive visual decline, altered mental status, and headaches. A subtotal resection was performed, because there was extensive tumor involvement of the torcula, straight sinus, and bilateral transverse sinuses. She was subsequently referred for GKRS. Although neurologically intact, with the exception of an upper extremity tremor, case B had undergone 7 surgeries for a posterior fossa tumor over the several decades preceding GKRS. The tumors targeted with GKRS were found on serial MRI scans and were thought to be asymptomatic at the time of treatment. At 7 and 14 months after GKRS, case A experienced tumor shrinkage, which remained stable 20 months after treatment. Effective local tumor control was seen in case B with tumor shrinkage at 3, 8, and 13 months after treatment. However, repeat GKRS was required for case B, because an out-of-field recurrence was found 15 months after the initial GKRS. CONCLUSION: Based on this report and available information in the literature, radiosurgery appears to be a reasonable approach for patients with recurrent or residual intracranial solitary fibrous tumors. PMID- 21593697 TI - Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group. AB - BACKGROUND: The Response Assessment in Neuro-Oncology (RANO) Working Group is an international, multidisciplinary effort to develop new standardized response criteria for clinical trials in brain tumors. The RANO group identified knowledge gaps relating to the definitions of tumor response and progression after the use of surgical or surgically based treatments. OBJECTIVE: To outline a proposal for new response and progression criteria for the assessment of the effects of surgery and surgically delivered therapies for patients with gliomas. METHODS: The Surgery Working Group of RANO identified surgically related end-point evaluation problems that were not addressed in the original Macdonald criteria, performed an extensive literature review, and used a consensus-building process to develop recommendations for how to address these issues in the setting of clinical trials. RESULTS: Recommendations were formulated for surgically related issues, including imaging changes associated with surgical resection or surgically mediated adjuvant local therapies, the determination of progression in the setting where all enhancing tumor has been removed, and how new enhancement should be interpreted in the setting where local therapies that are known to produce nonspecific enhancement have been used. Additionally, the terminology used to describe the completeness of surgical resections has been recognized to be inconsistently applied to enhancing vs nonenhancing tumors, and a new set of descriptors is proposed. CONCLUSION: The RANO process is intended to produce end point criteria for clinical trials that take into account the effects of prior and ongoing therapies. The RANO criteria will continue to evolve as new therapies and technologies are introduced into clinical trial and/or practice. PMID- 21593699 TI - Measurements of Eustachian tube dilation by video endoscopy. AB - OBJECTIVES: 1. To create techniques for measurement of parameters of Eustachian tube (ET) dilation as observed with video endoscopy. 2. To study correlations of the parameters between healthy subjects and patients with ET dysfunction to determine if they may be important for clinical or investigational use. STUDY DESIGN: Prospective study in an academic center. 3 groups of adults: healthy subjects, otitis media with effusion (OME), patulous ET. INTERVENTION: Video software analyses were performed on video recordings from subjects' transnasal endoscopy to measure parameters of the tubal dilation cycle. RESULTS: 24 ETs of 15 healthy subjects, 24 ETs of 15 patulous ET and 20 ETs of 13 OME patients. Mean values for healthy subjects: cycle time 995 ms (SD 404.7), valve opening time 10.5 ms (SD 6.34), torus rotation time 176 ms (SD 151.5 and angle of torus rotation 34.2 degrees (SD 14.3). Palatal elevation, measured as a percentage of torus height was 34.8% (SD 16.6) and excursion of the antero-lateral wall 35.5 % (SD 16.3). Lateral excursion of the antero-lateral wall was significantly less in patulous ET (18.7%, SD 15.1, p = 0.001) and in dilatory dysfunction (23.9%, SD 21.7, p = 0.048). The other parameters were not statistically different between healthy subjects and patients. CONCLUSION: Lateral excursion of the ET's antero lateral wall was significantly reduced in OME and patulous ET patients compared with healthy subjects. Evaluation of the excursion of the lateral wall of the ET, which is due to TVP muscle action, may be an important parameter for further clinical and research study. PMID- 21593700 TI - Otitis media with effusion: an underestimated cause of hearing loss in infants. AB - OBJECTIVE: Otitis media with effusion (OME) is the major reason for failure of neonatal hearing screening. However, little is known about the impact on hearing status of OME in infants during the first months of life. PATIENTS: Infants who failed universal newborn hearing screening. METHODS: Prospective evaluation for the presence of OME, the degree of hearing loss and the disease evolution. RESULTS: Between 2007 and 2008, approximately 152 infants were referred because of unilateral or bilateral failure on universal newborn hearing screening with an automated auditory brainstem response device. Eighty-four (55.3%) had OME, 20 of them were lost to follow-up. The remainder 64 infants comprised 37 boys and 27 girls, with a median age of 49 days (range, 40-65 d) at admission. Auditory brainstem response thresholds were 50 dB nHL (range, 40-60) in both ears. A spontaneous resolution of OME was documented in 15 infants. In the remaining, hearing normalized after tympanocentesis or placement of ventilation tubes. Normal hearing could be ascertained in all children at a median age of 4.8 months (range, 3.3-7.8 mo). In the group of infants analyzed, no permanent hearing loss could be detected. CONCLUSION: OME is an important cause of transient, moderately severe hearing loss during the first months of life--a critical period for development of the auditory system. Active treatment should be considered if spontaneous resolution does not occur to prevent any delay in language acquisition and to exclude an underlying sensorineural hearing loss. PMID- 21593701 TI - Combination therapy is preferable for patients with Ramsay Hunt syndrome. AB - OBJECTIVE: To critically appraise the topic, questioning whether administering antiviral medication in case of Ramsay Hunt syndrome improves the restoration of facial nerve function. METHODS: We reviewed the literature on this subject and calculated the odds ratios for the different treatment modalities. RESULTS: Our study clearly shows that antiviral medication in combination with corticosteroids improves the outcome for patients with Ramsay Hunt syndrome. CONCLUSION: Contrary to a recent Cochrane Library review, we conclude that patients with Ramsay Hunt syndrome should be treated with combination therapy including antivirals. PMID- 21593702 TI - Predictor of auditory performance in mandarin chinese children with cochlear implants. AB - OBJECTIVE: The objectives of this investigation were to analyze auditory performance among Mandarin-speaking school-aged children with cochlear implants from their parents' perspective and to derive predictive factors of the performance. STUDY DESIGN: Parental perspective survey of cochlear implant outcome was developed, and factor analysis of auditory performance was performed by analysis of variance. Categorical regression and Pratt measure of relative importance were approached to derive predictive factors of the performance. SETTING: Chung Shan Medical University, School of Speech Language Pathology and Audiology, and 7 major cochlear implant hospitals in Taiwan. PATIENTS: A total of 177 parents of school-aged children with cochlear implants, with a mean age of 11.36 years (range, 6.75-18.75 yr), were included as participants from 7 major cochlear implant centers nationally. INTERVENTION: All children received unilateral multichannel cochlear implants for a 1-year experience. MAIN OUTCOME MEASURES: The CAPR was the measure of auditory performance, and 31 variables from 5 parts of the recipients' information were explored as independent variables. RESULTS: Of all children with implants, 63.8% reached the level of telephone use. Analysis of variance showed that 9 variables correlated significantly with auditory performance (F = 14.04, p < 0.001; multiple R = 0.79, R = 0.63). Categorical regression demonstrated that 5 factors, namely, "no additional disabilities," "oral/aural communication mode at home" and "at school," "educational placement," and "perception of implantation decision" predicted auditory performance. CONCLUSION: Parental perspective survey demonstrated the level of auditory performance among 177 school-aged children with implant. Five factors were found to predict the auditory performance of these children, suggesting the recipient's participation in the environments, oral/aural communication mode, and without additional disabilities significantly contributing auditory performance. The parent's view of cochlear implantation provides not only an important value of children's function in real life but also as another outcome measure. PMID- 21593703 TI - Immunosuppression: does one regimen fit all? AB - There has been considerable interest in the individualization of immunosuppressive regimens in an attempt to avoid side effects and improve long term outcomes. Most available studies have addressed steroid and calcineurin inhibitor minimization in an attempt to prevent the development of chronic allograft dysfunction and cardiovascular mortality. Herein, we evaluate the available evidence for incorporation of these novel strategies in standard clinical care of kidney transplant recipients. Protocol biopsies, pharmacogenetics, and other assays have been developed to guide tailoring of immunosuppression; however, although promising results have been obtained, trials showing their ability to improve long-term outcome are lacking and urgently needed. PMID- 21593704 TI - Living donor liver transplantations in HIV- and hepatitis C virus-coinfected hemophiliacs: experience in a single center. AB - BACKGROUND: Although almost all human immunodeficiency virus (HIV)-infected Japanese hemophiliacs are coinfected with hepatitis C virus (HCV), the outcome of living donor liver transplantation (LDLT) in such patients in terms of survival rate, perioperative complications, and recovery of coagulation activity is poorly understood. PATIENTS AND METHODS: Six HIV-positive hemophiliacs underwent LDLT for HCV-associated advanced cirrhosis. The mean CD4 T-cell count at transplantation was 376+/-227/MUL. RESULTS: The 1-, 3-, and 5-year survival rates were 66%, 66%, and 50%, respectively. Fatal perioperative bleeding related to hemophilia was not observed. Two patients died within 6 months after transplantation due to graft failure. HIV infection was well controlled in all patients who survived longer than 6 months. Two patients (genotype 2a and 2+3a) achieved a sustained viral response and both of them were alive at the end of follow-up period, whereas one patient (genotype 1a+1b) died of decompensated cirrhosis 4 years after transplantation due to recurrent HCV infection. CONCLUSIONS: HIV/HCV-coinfected hemophiliacs can safely undergo LDLT. Hemophilia was clinically cured after successful transplantation. A good outcome can be expected as long as postoperative hepatitis C is controlled with interferon/ribavirin combination therapy. PMID- 21593705 TI - Crowding and other strong predictors of upper respiratory tract carriage of otitis media-related bacteria in Australian Aboriginal and non-Aboriginal children. AB - BACKGROUND: Streptococcus pneumoniae, Moraxella catarrhalis, and nontypeable Haemophilus influenzae is associated with otitis media (OM). Data are limited on risk factors for carriage of these pathogens, particularly for Indigenous populations. We investigated predictors of nasopharyngeal carriage in Australian Aboriginal and non-Aboriginal children. METHODS: Nasopharyngeal aspirates were collected up to 7 times before age 2 years from 100 Aboriginal and 180 non Aboriginal children. Longitudinal modeling estimated effects of environmental factors and concurrent carriage of other bacteria on the probability of bacterial carriage. We present a novel method combining the effects of number of household members and size of house into an overall crowding model. RESULTS: Each additional household member increased the risk of carriage of S. pneumoniae (odds ratio [OR] = 1.45 per additional Aboriginal child in a 4-room house, 95% confidence interval [CI]: 1.15-1.84; OR = 2.34 per additional non-Aboriginal child, 95% CI: 1.76-3.10), with similar effect sizes for M. catarrhalis, and nontypeable Haemophilus influenzae. However, living in a larger house attenuated this effect among Aboriginal children. Daycare attendance predicted carriage of the 3 OM-associated bacteria among non-Aboriginal children. Exclusive breast feeding at 6 to 8 weeks protected against Streptococcus aureus carriage (OR = 0.42, 95% CI: 0.19-0.90 in Aboriginal children and OR = 0.49, 95% CI: 0.25-0.96 in non-Aboriginal children). OM-associated bacteria were more likely to be present if there was concurrent carriage of the other OM-associated species. CONCLUSIONS: This study highlights the importance of household transmission in carriage of OM bacteria, underscoring the need to reduce the crowding in Aboriginal households. PMID- 21593706 TI - Occurrence of acute otitis media during colds in children younger than four years. AB - To determine how frequently acute otitis media (AOM) occurs, we enrolled children between 6 months and 3 years of age who returned several weeks before and 6 to 10 times during a cold for tympanometry and photography of the tympanic membrane. American Academy of Pediatrics (AAP) criteria were used to diagnose AOM. Children visited their physicians at their discretion. AOM occurred in 17 (55%) of 31 colds; in 12 (100%) colds with pre-existing middle ear effusion (MEE); and in 5 (26%) of 19 colds with no pre-existing MEE (P < 0.0001). Four patients received antibiotics from their physicians. Of 17 children with AOM, 12 did not seek care. AOM is common during colds, particularly with pre-existing MEE. PMID- 21593707 TI - Epidemiologic, clinical, laboratory, and therapeutic characteristics of influenza A/H1N1 in Moslem Bedouin and Jewish children hospitalized in southern Israel during 2009. AB - A total of 739 (225 H1N1(+)) children with a diagnosis of acute respiratory infection were hospitalized during July to December 2009. The H1N1(+) children were compared with 225 randomly enrolled H1N1(-) children with an influenza-like illness. As compared with influenza-like illness patients, patients with 2009 influenza A/H1N1 were characterized by older age, more vomiting, less hypoxemia and wheezing, lower white blood cell counts, less neutrophilia, and severe lymphopenia. PMID- 21593708 TI - A three-year experience of the Referral Center for Surgical Treatment of Gastroesophageal Reflux Disease. AB - AIM: Gastro-esophageal reflux disease (GERD) rapresents the fastest growing disease affecting the alimentary and breathing apparatus. Incidence of esophageal adenocarcinoma with Barrett Esophagus (BE) imposes a decision about therapy management. METHODS: Between January 2006 to December 2009, 3 653 patients were subjected to our observation; 2 095 patients underwent endoscopy (57.4%), of these 598 underwent twenty-four hours pH-Metry (16.3%); 1 558 patients (42.6%) had clinical consult. RESULTS: A total of 1 255/2 095 referred typical symptoms (60%), 644 patients typical and atypical symptoms (30.7%), 96 patients atypical symptoms (4.6%); 4.7% had dysfagia and cramps; 1 897 patients (90.5%) had Los Angeles A esophagitis, 62 Los Angeles B (2.96%), 6 had Shatzki Ring (0.3%). NERD in 26 patients (1.24%); 3.4% had Hp Gastritis; 33 had BE (1.6%), 10 intestinalized type (30.3%), 23 gatric type (69.7%). Eighty-five/2 095 patients (4%, 36 M and 49 F, m.a. 42.5 years, range 20-72) underwent laparoscopic Nissen Rossetti Fundoplication (4%), 69 with preoperative typical symptoms (81%), 11 typical and atypical symptoms (13%), 5 atypical symptoms (6%). Twenty-three had BE (27%, 9 intestinal metaplasia, 3 Long and 6 Short Barrett, 14 Gastric metaplasia); 61 with Los Angeles A esophagitis (98.3%), 1 with Shatzki Ring (1.7%). PH-Metries were positive. CONCLUSION: GERD requires specialistic and qualified centers. PMID- 21593709 TI - "Ulm pouch" technique for total gastrectomy. Chinese experiences. AB - AIM: "Ulm pouch" jejunal interposition reconstruction for total gastrectomy was applied in 62 patients in China, and its morphology was observed by virtual endoscopy. METHODS: The study enrolled 220 patients who underwent total gastrectomy. Among them 62 underwent "Ulm pouch" reconstruction. Patients were 34 men and 28 women, with a mean age of 56 years (range 23-79). Twenty-two patients had underlying diseases, including hypertension and coronary disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and malnutrition. An "Ulm pouch" was made from a jejunal segment by using staplers. An esophago-jejuno anastomosis and an end-to-end anastomosis of the distal end of the pouch to the duodenum were also performed by hand sutures or a stapler. The dimensions of the "Ulm pouch" were measured in 10 randomly selected patients, and we observed the pouch's morphology by virtual endoscopy in 13 patients. We performed Roux-Y reconstruction for the remaining patients. Fifty patients received adjuvant chemotherapy and all patients were followed for one to two years postoperatively. RESULTS: All operations were successful. "Ulm pouch" in size and shape were similarly like actual stomach. Patients regained their appetite within three days of the operation. At one- to two-month postoperative follow-up, patients' nutritional condition had improved and they gained 2-5 kg of body weights. Complications included postoperative cholecystitis, jejuno-duodenal anastomosis leakage and upper gastric bleeding. CONCLUSION: "Ulm pouch" for total gastrectomy is a safe procedure for alimentary reconstruction. The use of linear and circular staplers simplifies the procedure and reduces operative time. Virtual endoscopy showed that the morphology of the pouch is similar to the native stomach. "Ulm pouch" reconstruction results in a good postoperative quality of life and favorable prognosis. PMID- 21593711 TI - Outcome following mesenteric artery revascularisation for chronic mesenteric ischemia. AB - AIM: The purpose of this study was to review the clinical presentation and diagnosis of chronic mesenteric ischaemia (CMI) and to evaluate the early results and late outcome of mesenteric revascularisation. METHODS: This retrospective study included 15 patients with CMI diagnosed between January 2000 and September 2006. Mesenteric revascularisation was done using either transluminal angioplasty, stenting, endarterectomy or bypass graft. Patients were followed up with Duplex scan and/or computed tomographic angiogram to confirm graft patency. RESULTS: Sixteen revascularisation procedures were done in 15 patients. Aorto superior mesenteric artery (SMA) bypass in 9 patients, SMA endarterectomy in 2 patients, transluminal angioplasty in 2 patients, stenting in 2 patients and right common iliac to common hepatic artery bypass in 1 patient with previous failed aorto-SMA graft. There were no perioperative deaths or early procedural complication. Two patients had late graft thrombosis and symptomatic recurrence. One of the three late deaths was due to graft thrombosis and bowel infarction, and the other two died of acute myocardial infarction and disseminated bronchogenic carcinoma respectively. CONCLUSION: We conclude that mesenteric revascularisation for CMI is successful for most patients with symptomatic relief, low mortality and a good long term graft patency. PMID- 21593710 TI - Total fundoplication without division of the short gastric vessels: functional evaluation at one year and review of literature. AB - AIM: Gastro-esophageal reflux disease (GERD) has emerged as one of the most common diseases in modern civilization. We investigated functional evaluation after total fundoplication without division of short gastric vessels and review of literature. METHODS: From January 2007 to June 2008 43 patients with chronic gastroesophageal reflux underwent laparoscopic Nissen-Rossetti fundoplication, 7 were lost during the follow-up. Patients underwent endoscopy, 24 hours pH-Metry, preoperatively, 6 months and 12 months after surgery. Articles were sourced from PubMed and Medline, using the MeSH terms "gastroesophageal reflux disease" and "laparoscopic surgery" and "fundoplication technique". Selection of articles were based on peer review, journal, relevance and English language. RESULTS: Endoscopic findings revealed complete healing of esophagitis in all patients. Barrett esophagus was still present. Six patients reported persistence of symptoms but postoperative pH-metry and endoscopy showed the absence of reflux; two patients (5.5%) were still on PPI therapy at 12 months. Seven patients (19.4%) reported dysphagia for solid for at least three months. Re-admission for dysphagia was required for two (5.5%) and one patient underwent to endoscopic dilatation. At six and 12 months no dysphagia was reported. During the follow-up no gas-bloat syndrome was referred. The Johnsson and DeMeester's score reduction from six months to 12 months was statistically significant. Randomized and non randomized studies seem to point out in a precise way that a division of short gastric vessels is unnecessary to perform a "short and floppy" placation. CONCLUSION: Nissen-Rossetti fundoplication is safe and effective for treatment of GERD, with minimal post-operative side effects. PMID- 21593712 TI - Errors in laparoscopic surgery: what surgeons should know. AB - Some two decades after its introduction, minimal access surgery (MAS) is still evolving. Undoubtedly, its significant uptake world wide is due to its clinical benefits to patient outcome. These benefits include reduced traumatic insult, reduction of pain, earlier return to bowel function, decrease disability, shorter hospitalization and better cosmetic results. Nonetheless complications due to the laparoscopic approach are not rare as documented by several studies on task specific or procedure related MAS morbidity. In all these instances, error analysis research has demonstrated that an understanding of the underlying causes of these complications requires a comprehensive approach addressing the entire system related to the procedure for identification and characterization of the errors ultimately responsible for the morbidity. The present review covers definition, taxonomy and incidence of errors in medicine with special reference to MAS. In addition, possible root causes of adverse events in laparoscopy are explored and existing methods to study errors are reviewed. Finally specific areas requiring further human factors research to enhance safety of patients undergoing laparoscopic operations are identified. The hope is that awareness of causes and mechanisms of errors may reduce incidence of errors in clinical practice for the final benefit of the patients. PMID- 21593713 TI - Novel approach to mitral valve repair in childhood dilated cardiomyopathy. AB - Evidence is mounting that mitral valve repair can improve symptoms in adults with dilated cardiomyopathy. Data is currently lacking for children with dilated cardiomyopathy and options for annuloplasty are limited in children. We report on the successful management of a 21 month-old child in heart failure from dilated cardiomyopathy and severe mitral regurgitation. The echocardiogram showed severely dilated left heart cavities, severe mitral regurgitation from a dilated annulus (23 mm, Z-score 1.74) with discrete anterior leaflet tethering, and moderate systolic dysfunction. The mitral valve was repaired using a 16 mm Bioring Kalangos biodegradable annuloplasty ring. The patient was extubated on the third postoperative hour and discharged on the fifth postoperative day with trivial mitral regurgitation and a 5 mmHg mean transvalvular gradient. At 12 months, the patient is in NYHA class I and presents trivial central mitral regurgitation without any transmitral gradient. This represents the first report in successfully managing a child with dilated cardiomyopathy with mitral regurgitation using a novel biodegradable annuloplasty ring, which has the potential to durably remodel the mitral annulus and grow with the patient. PMID- 21593714 TI - Parastomal hernia repair. An update. AB - Repair of parastomal hernia remains controversial. Open suture repair of the fascial defect or stoma resiting are both associated with high morbidity and unacceptably high recurrence rates and are no longer recommended for routine use. Mesh repair appears to provide the best results. Following the first anectodal reports there are accumulating evidence that laparoscopic mesh repair is feasible and has a promising potential in the management of parastomal hernia. Two laparoscopic techniques have emerged, the use of a mesh with a slit and a central keyhole and a mesh without a slit, the latter often termed as a modified Sugarbaker. Published series, however, are observational and often with a short length of follow-up. Most series suffer from small sample size and controlled trials are lacking. The limited data, therefore, make it difficult to draw conclusions. At present none of the methods of open or laparoscopic mesh repair has proved superior. In spite of this laparoscopic repair has gained increasing acceptance. A polypropylene based mesh with an anti-adhesive layer covering the visceral side seems to be applicable using the keyhole technique with a slit as well as the modified Sugarbaker technique. A PTFE mesh should preferably be used with the modified Sugarbaker technique. If a PTFE mesh is used with the keyhole technique parastomal hernia is likely to recur. PMID- 21593715 TI - Tissue engineering in abdominal wall surgery. AB - Abdominal wall defects and tissue loss that result from traumatic injury, surgical resection, failure of abdominal closures (i.e., incisional hernias) or ventral hernias are a common clinical problem. Currently, the repair of these tissue defects represents a reconstructive challenge to surgeons. The goal of abdominal wall reconstruction is to restore and maintain a functional abdominal wall. This article reviews the current and potential tissue engineering strategies for the repair of abdominal wall defects and suggests some innovative approaches for the translation to the clinical setting. PMID- 21593716 TI - Prevention of incisional hernia development. AB - Despite many advances in the field of surgery and surgical technique, the formation of hernias following abdominal wall incisions continues to be a perplexing and prevalent problem. Recently, much of the attention on hernias has been placed on surgical management. This has led to many different surgical options for repair of routine and complex hernias. Less emphasis, however, has been placed on prevention despite its obvious importance. The formations of incisional hernias are multifactorial and are influenced by many patient and technical factors. This review discusses the various factors contributing to incisional hernia development, prevention strategies, education, and future directions in approaches to hernia prevention. PMID- 21593717 TI - Non-traumatic causes and the management of the open abdomen. AB - The open abdomen is increasingly used for the treatment and prevention of abdominal compartment syndrome. The leading non-traumatic conditions that may cause abdominal compartment syndrome requiring surgical decompression include secondary peritonitis, ruptured abdominal aortic aneurysm and severe acute pancreatitis. Patients may also end up with the open abdomen when the laparotomy wound cannot be closed without tension because of excessive visceral swelling. Also, surgical complications such as laparotomy wound dehiscence, may require temporary abdominal closure techniques. In critically ill surgical patients and in situations when second-look laparotomy is mandatory the open abdomen can be utilized in a preventive manner like in damage control trauma surgery. Underlying disease and the indication for the open abdomen significantly contributes to outcome of patient with open abdomen. Non-traumatic aetiology of the open abdomen is associated with lower likelihood of primary fascial closure and higher rate of open abdomen related complications compared with traumatic aetiology. A number of temporal abdominal closure techniques have been described. Ideally, temporal abdominal closure technique should prevent the development of recurrent abdominal compartment syndrome and facilitate later primary fascia closure with low complication rate. Although fascial closure rate varies between techniques, there are few evidence-based data to support one technique over another. However, recent evolution of temporary abdominal closure techniques have decreased the number of patients with frozen abdomen and reduced the need for planned hernia management. Highest fascial closure rates have been achieved with vacuum-assisted closure systems and systems that provide continuous fascial traction. PMID- 21593718 TI - Self-expanding metal stent for benign colonic stricture. A rare case of long-term follow-up in a patient with ischemic colitis due to abdominal aortic aneurysm rupture. PMID- 21593719 TI - Application of levofloxacine in the second phase of sequential therapy regimen for Helicobacter pylori eradication: is it a good choice? AB - AIM: The aim of this study was to evaluate whether modified sequential therapy regimen that consists of an initial phase, including a PPI plus amoxicillin for 5 days followed by a PPI plus only levofloxacin instead of 2 antibiotics for the remaining 5 days increase the eradication rate via decreasing the number and doses of antibiotics, and increasing patient compliance. METHODS: This study included 40 patients who were admitted to Gastroenterology Outpatient Clinic with H. pylori-positive non-ulcer dyspepsia. All patients received lansoprazole 30 mg BID plus amoxicillin 1,000 mg BID for the first five days followed by lansoprazole 30 mg BID plus levofloxacine 500 mg BID for the remaining five days. Eradication rates were calculated using both intention-to-treat (ITT) and per protocol (PP) analysis. RESULTS: In all, 40 patients (21 females, 19 males) were analyzed with ITT analysis and 38 patients completed the study. H.pylori eradication was achieved in 27 (67.5%) of the 40 patients included in the ITT analysis and in 27 (71%) of the 38 patients included in the PP analysis. Mild adverse effects were reported by 8 patients (8.4%). The most frequent side effects were nausea and a metallic taste in the mouth. Any adverse effect that might lead patients to take less than 80% of the prescribed drugs was not reported. CONCLUSION: This levoflaxin-based sequential therapy regimen was not superior over standard sequential therapy regimen in the eradication of H.pylori. However, it yields better eradication rate than standard triple therapy regimen. PMID- 21593720 TI - Determinants of patient satisfaction in postoperative pain management following hand ambulatory day-surgery. AB - AIM: Adequate postoperative analgesia is a prerequisite for successful ambulatory surgery and continues to be a challenge for anesthesiologists. The goal of the study was to analyze what are determinants of patients' overall satisfaction in postoperative pain management after ambulatory hand surgery. METHODS: Patients undergoing ambulatory hand surgery received oral fixed association tramadol/acetaminophen 37.5/325 mg every 6 hours during the first 48 hours after operation. Analgesic efficacy was evaluated by self-assessment of pain intensity by numeric rating scale. Patients also recorded total number of daily study analgesic tablets, frequency and severity of adverse events, sleep pain interference (SPI 0-10), number of rescue doses and patient global assessment (PGA) on a 4-grade scale. Success ratings on the PGA were considered "good" and "excellent". Preoperative pain intensity, analgesic use, and expectation were also recorded. RESULTS: One hundred and forty-three subjects were evaluated in the study. The percentage of patients who reported rating of success on the PGA was 88.8%. The most significant determinant of failure on the PGA was the presence of moderate to severe adverse events (R=-0.85). Determinants of ratings of success on PGA were adequate analgesia and SPI <= 4. Predictors of successful patient satisfaction were preoperative pain <= 4 on NRS, lack of preoperative analgesic consumption, expected pain >6 on NRS, and lower education level. Weak correlation (R=0.26) was observed between mean daily pain intensity and analgesics intake. CONCLUSION: Results indicate that the oral association tramadol/acetaminophen 37,5/325 mg is effective for the management of postoperative pain after ambulatory hand surgery. The lack of adverse events is the most important determinant of patient satisfaction, followed by the analgesic efficacy. PMID- 21593721 TI - Atrial fibrillation: epidemiology, prognosis and therapy. AB - Atrial fibrillation is the most common cardiac tachyarrhythmia encountered in clinical practice affecting 1% of the population. It is characterized by uncoordinated atrial activation that can lead to embolic complications and reduction in cardiac output resulting in significant morbidity, mortality and a reduction in quality of life. The three major goals in the management of atrial fibrillation are rate control, prevention of thromboembolism and correction of rhythm disturbance. This article will review up-to-date thinking about strategies for achieving each of these fundamental goals of AF care, with an emphasis on new drugs such as dabigatran and dronedarone and emerging non-pharmacologic therapies such as catheter ablation and left atrial appendage exclusion. After many years with relatively few new treatments, the past few years have seen a number of exciting developments which will hopefully improve clinician's ability to improve the outcomes of patients with this chronic and troublesome condition. PMID- 21593722 TI - Genetics of cardiac arrhythmias. AB - Continued research into the identification of mutated genes that cause inherited arrhythmogenic diseases has helped forward understanding into their pathophysiology. Over the last two decades the progress that has been made in the realm of genetic arrhythmias has made it possible not only for symptomatic patients to improve their outcomes, but also family members to better understand their risks and allow them in conjunction with their care providers to make the best decisions for their care. With this continued progress, significant changes will continue to occur in clinical practice. The advances in technology coupled with the improving understanding of genetically determined arrhythmias assists in earlier recognition of potentially fatal diseases, which leads to earlier implementation of treatment. It is the aim of this article to abridge the current knowledge of the genetic background of inherited arrhythmogenic diseases, namely long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. Pathogenesis and genotype-phenotype correlations are also discussed. PMID- 21593723 TI - Cardiovascular syncope: diagnostic approach and risk assessment. AB - Cardiovascular syncope, defined as a transient loss of consciousness resulting from a global cerebral hypoperfusion characterized by rapid onset and spontaneous rapid recovery, comprises events due to bradyarrhythmias, tachyarrhythmias, and structural cardiovascular disease. The evaluation of cardiovascular syncope must be careful and thorough as this type of syncope is associated with increased subsequent morbidity and mortality. In this review we provide current data regarding specific causes of cardiovascular syncope, diagnostic approach, risk stratification, and management of patients who experience a syncope event when a cardiovascular disorder is suspected to be a precipitating factor for the syncope event. Multiple risk stratifications studies were carried out to identify patients at high risk for cardiovascular syncope; we provide several prominent examples of such risk stratifications, with special focus on the congenital long QT syndrome (LQTS) as an example of an arrhythmogenic disorder associated with syncope and sudden cardiac death in young individuals without structural heart disease. PMID- 21593724 TI - Sports and arrhythmias. AB - Rhythm disorders represent the main challenge for the sport physician and cardiologist to grant the certificate of sports eligibility to the athletes. Arrhythmias that occur in athletes can be divided into two types. The most common are generally an expression of morphofunctional changes in the athlete's heart and are represented by certain forms of non-complex tachyarrhythmias and bradyarrhythmias. On the other hand you may encounter less frequently more complex arrhythmias that may be an epiphenomenon of cardiomyopathy can cause sudden death during sports activities. By collection of detailed medical history, careful examination, and in particular by the 12-lead electrocardiogram is already possible to understand the arrhythmic risk sporting population. After an analysis of main types of arrhythmias encountered in the athlete and the main diagnostic methods, this study focuses on the interplay between forms of arrhythmias, arrhythmogenic heart diseases and activity sports. Surely the increased adrenergic tone and anatomical and functional alterations sports related favor the development of arrhythmia and sudden death risk in structural cardiomyopathies. But this is not yet resolved the question of whether sport is able to increase the incidence of ventricular arrhythmias in a normal heart. Dangerousness of the arrhythmia is variable depending on the sport is practiced with high intensity or not. Even if it is important considering the possibility of syncope in hazardous environments. Arrhythmias at risk impose the exclusion of the athlete from the practice of sport. In some cases it may be considered a drug treatment, ablation, and in rare and selected cases, the implantation of a pacemaker or an implantable defibrillator. PMID- 21593726 TI - New insights into how chromatin remodellers direct CENP-A to centromeres. PMID- 21593727 TI - Micro-balancing innate immunity to Salmonella. PMID- 21593728 TI - Searching for the 'melano-miRs': miR-214 drives melanoma metastasis. PMID- 21593729 TI - Is PrP the road to ruin? PMID- 21593730 TI - Generalization of fear inhibition by disrupting hippocampal protein synthesis dependent reconsolidation process. AB - Repetitive replay of fear memories may precipitate the occurrence of post traumatic stress disorder and other anxiety disorders. Hence, the suppression of fear memory retrieval may help prevent and treat these disorders. The formation of fear memories is often linked to multiple environmental cues and these interconnected cues may act as reminders for the recall of traumatic experiences. However, as a convenience, a simple paradigm of one cue pairing with the aversive stimulus is usually used in studies of fear conditioning in animals. Here, we built a more complex fear conditioning model by presenting several environmental stimuli during fear conditioning and characterize the effectiveness of extinction training and the disruption of reconsolidation process on the expression of learned fear responses. We demonstrate that extinction training with a single paired cue resulted in cue-specific attenuation of fear responses but responses to other cures were unchanged. The cue-specific nature of the extinction persisted despite training sessions combined with D-cycloserine treatment reveals a significant weakness in extinction-based treatment. In contrast, the inhibition of the dorsal hippocampus (DH) but not the basolateral amygdala (BLA)-dependent memory reconsolidation process using either protein synthesis inhibitors or genetic disruption of cAMP-response-element-binding protein-mediated transcription comprehensively disrupted the learned connections between fear responses and all paired environmental cues. These findings emphasize the distinct role of the DH and the BLA in the reconsolidation process of fear memories and further indicate that the disruption of memory reconsolidation process in the DH may result in generalization of fear inhibition. PMID- 21593731 TI - Epigenetic treatments for cognitive impairments. AB - Epigenetic mechanisms integrate signals from diverse intracellular transduction cascades and in turn regulate genetic readout. Accumulating evidence has revealed that these mechanisms are critical components of ongoing physiology and function in the adult nervous system, and are essential for many cognitive processes, including learning and memory. Moreover, a number of psychiatric disorders and syndromes that involve cognitive impairments are associated with altered epigenetic function. In this review, we will examine how epigenetic mechanisms contribute to cognition, consider how changes in these mechanisms may lead to cognitive impairments in a range of disorders and discuss the potential utility of therapeutic treatments that target epigenetic machinery. Finally, we will comment on a number of caveats associated with interpreting epigenetic changes and using epigenetic treatments, and suggest future directions for research in this area that will expand our understanding of the epigenetic changes underlying cognitive disorders. PMID- 21593732 TI - Variants of the RELA gene are associated with schizophrenia and their startle responses. AB - The pathogenesis of schizophrenia is thought to involve aberrant immune and inflammatory responses. Nuclear factor kappa B (NF-kappaB) has important roles in the immune and inflammatory responses. The v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) gene encodes the major component of the NF-kappaB complex. We genotyped four single-nucleotide polymorphisms (SNPs) in the RELA gene and performed a gene-based association analysis using 1224 patients with schizophrenia and 1663 controls. We found significant associations of three SNPs (rs11820062: p=0.00011, rs2306365: p=0.0031, and rs7119750: p=0.0080) with schizophrenia and stronger evidence for association in a multi-marker sliding window haplotype analysis (the lowest p=0.00006). The association between this gene and schizophrenia was evident in male subjects but not in female subjects, when separately analyzed by gender. In silico genotype-gene expression analysis using web database and the WGAViewer software revealed that these three schizophrenia-associated SNPs might be related to RELA mRNA expression in immortalized B-lymphocytes. In silico analysis also suggested the putative promoter SNP, rs11820062, might disrupt the consensus transcription factor binding sequence of the androgen receptor. The impact of four RELA polymorphisms on pre-pulse inhibition (PPI) was investigated in 53 patients with schizophrenia. We provided evidence that at risk genotypes of three SNPs were associated with deficits in PPI; however, there was no effect of the one non-risk SNP on PPI. These findings suggest that variants of the RELA gene are associated with risk for schizophrenia and PPI deficits in a Japanese population. PMID- 21593735 TI - Impact of smoking, smoking cessation, and genetic polymorphisms on CYP1A2 activity and inducibility. AB - Cytochrome P4501A2 (CYP1A2) is involved in the metabolism of several drugs and is induced by smoking. We aimed to determine the interindividual change in CYP1A2 activity after smoking cessation and to relate it to CYP1A2 genetic polymorphisms. CYP1A2 activity was determined from the paraxanthine:caffeine ratio in 194 smokers and in 118 of them who had abstained from smoking during a 4 week period. The participants were genotyped for CYP1A2*1F, *1D, and *1C polymorphisms. Smokers had 1.55-fold higher CYP1A2 activity than nonsmokers (P < 0.0001). The individual change in CYP1A2 activity after smoking cessation ranged from 1.0-fold (no change) to a 7.3-fold decrease in activity. In five participants with low initial CYP1A2 activity, an increase was observed after smoking cessation. Before smoking cessation, the following factors were found to influence CYP1A2 activity: CYP1A2*1F (P = 0.005), CYP1A2*1D (P = 0.014), the number of cigarettes/day (P = 0.012), the use of contraceptives (P < 0.001), and 163A/-2467T/-3860G haplotype (P = 0.002). After quitting smoking, only CYP1A2*1F (P = 0.017) and the use of contraceptives (P = 0.05) had an influence. No influence of CYP1A2 polymorphisms on the inducibility of CYP1A2 was observed. PMID- 21593734 TI - Role of glycine receptors in glycine-induced LTD in hippocampal CA1 pyramidal neurons. AB - Glycine in the hippocampus can exert its effect on both synaptic NMDA receptors (NMDARs) and extrasynaptic functional glycine receptors (GlyRs) via distinct binding sites. Previous studies have reported that glycine induces long-term potentiation (LTP) through the activation of synaptic NMDARs. However, little is known about the potential role of the activated GlyRs that are largely located in extrasynaptic regions. We report here that relatively high levels of glycine achieved either by exogenous glycine application or by the elevation of endogenous glycine accumulation with an antagonist of the glycine transporter induced long-term depression (LTD) of excitatory postsynaptic currents (EPSCs) in hippocampal CA1 pyramidal neurons. The co-application of glycine with the selective GlyR antagonist strychnine changed glycine-induced LTD (Gly-LTD) to LTP. Blocking the postsynaptic GlyR-gated net chloride flux by manipulating intracellular chloride concentrations failed to elicit any changes in EPSCs. These results suggest that GlyRs are involved in Gly-LTD. Furthermore, this new form of chemical LTD was accompanied by the internalization of postsynaptic AMPA receptors and required the activation of NMDARs. Therefore, our present findings reveal an important function of GlyR activation and modulation in gating the direction of synaptic plasticity. PMID- 21593733 TI - Multilocus genetic profile for dopamine signaling predicts ventral striatum reactivity. AB - Research integrating neuroimaging and molecular genetics has yielded important insights into how variability in brain chemistry predicts individual differences in brain function, behavior and related risk for psychopathology. However, existing studies have been limited by their focus on the independent effects of single polymorphisms with modest impact on brain chemistry. Here, we explored the effects of five functional polymorphisms affecting dopamine (DA) signaling on reward-related ventral striatum (VS) reactivity, measured with BOLD fMRI, in a sample of 69 Caucasians. We also compiled individual multilocus genetic profile scores reflecting the additive effects of alleles conferring relatively increased DA signaling across the five polymorphic loci: DAT1 9-repeat, DRD4 7-repeat, DRD2 -141C Del, DRD2 Taq1A C (A2), and COMT (158)Met. These multilocus DA profile scores accounted for 10.9% of the inter-individual variability in reward-related VS reactivity. In contrast, none of the individual polymorphisms accounted for significant variability. Our results show that biologically informed multilocus genetic profiles have unique promise as indices of variability in brain chemistry that may yield advances in mapping individual differences in behaviorally relevant brain function. In turn, such genetic profiles may fuel gene-environment interactions research establishing trajectories of risk for psychopathology. PMID- 21593737 TI - Circulating progenitor cells are increased in newly diagnosed untreated hypertensive patients with arterial stiffening but normal carotid intima-media thickness. AB - Circulating progenitor cells (CPCs), including endothelial progenitor cells (EPCs), have a key role in endothelium repair. Cellular NADPH oxidase (Nox) enzymes, including Nox-containing gp91phox, represent a source of reactive oxygen species (ROS); ROS trigger protective signals but may also have detrimental effects. Cellular defenses against ROS include the enzymes manganese superoxide dismutase (MnSOD), catalase (CAT) and glutathione peroxidase type-1 (GPx-1). We investigated the relationships of CPCs with cellular gp91phox, MnSOD, CAT, GPx-1 and ROS levels and with carotid intima-media thickness (cIMT) and stiffness in hypertensives without additional risk factors for cardiovascular disease. CPCs from 53 newly diagnosed, untreated hypertensives and from 29 controls were isolated and identified by flow cytometry. gp91phox, MnSOD, CAT, and GPx-1 mRNA and protein expression and ROS generation were evaluated in enriched samples of CD34(+) cells; cIMT and stiffness were assessed. Hypertensives showed higher arterial stiffness (P < 0.001) but no difference in cIMT with respect to controls. ROS generation was slightly increased (P=0.04), whereas gp91phox, MnSOD, CAT and GPx-1 were significantly higher (P < 0.001) with respect to controls, as was CPC number (P < 0.001), but EPCs were no different. CPC and EPC numbers correlated with gp91phox, ROS and fibrinogen (P < 0.001); moreover, gp91phox, MnSOD, CAT and GPx-1 were correlated with CPC number. In early phases of arterial hypertension, before the development of wall thickening and even in the presence of arterial mechanical impairment, CPC number may be increased to maintain an adequate number of EPCs in peripheral blood. PMID- 21593738 TI - CRP induces hypertension in animal models: homo sapiens says no. PMID- 21593739 TI - Salt intake in children. PMID- 21593740 TI - Salt intake in 3-year-old Japanese children. AB - Salt restriction is widely recommended for the prevention and management of hypertension. It is very important to reduce salt intake during childhood. This survey was conducted to investigate salt intake in Japanese children. The study subjects, totalling 1,424, comprised 3-year-old children who received health checkups conducted by a public health center. Using first-morning urine samples, urinary concentrations of sodium, potassium and creatinine were measured. Additionally, the participants' parents filled out a questionnaire regarding their children's dietary habits. Urinary sodium and potassium concentrations were 140 +/- 67 and 67 +/- 41 mmol l(-1), respectively. The estimated urinary sodium excretion values had a wide distribution, with a mean value of 75 +/- 47 mmol per day (4.4 g per day of salt). Sodium excretion exceeded 100 and 200 mmol per day in 336 (24%) and 32 (2.2%) subjects, respectively. Urinary sodium excretion was significantly higher in children who had older siblings than in firstborn children (78 +/- 49 vs. 72 +/- 45 mmol per day, P < 0.05). The urinary sodium/potassium ratio was also higher in the former group (3.0 +/- 2.7 vs. 2.7 +/- 2.2, P < 0.01). Sodium excretion tended to be higher in children who ate daily snacks than in those who did not (76 +/- 48 vs. 71 +/- 44 mmol per day, P=0.07). In contrast, potassium excretion was significantly higher and the sodium/potassium ratio was lower in children who ate fruits daily than those who did not (39 +/- 29 vs. 33 +/- 23 mmol per day and 2.6 +/- 2.0 vs. 3.2 +/- 2.7, P < 0.01, respectively). These results suggest that excess salt intake occurs in a significant number of 3-year-old Japanese children. The presence of older siblings and dietary habits of eating snacks or fruits influence their sodium and potassium intake. PMID- 21593741 TI - Radial pulse transit time is an index of arterial stiffness. AB - Aortic pulse wave velocity, calculated from pulse transit time (PTT), is often used as an indicator of arterial stiffness and suggested to be standardized for heart rate (HR). This study aimed to determine whether PTT obtained directly from radial arterial waveforms could be used to assess arterial stiffness and the effect of HR on it. Measurements of anthropometric parameters, blood pressure (BP) and radial PTT were taken in 266 apparently healthy adults (113 men and 153 women; age 18-78 years). BP and radial PTT were measured in a subgroup of 11 young subjects (seven men and four women, age 24-35 years) in a 3-month follow-up study, which aimed to investigate the effect of HR changes. Radial PTT was significantly higher in men compared with women (0.116 +/- 0.022 s compared with 0.103 +/- 0.031 s, P < 0.001). It was inversely related to age in men and women (r=-0.838 and r=-0.804, respectively, P < 0.01 for both). Multiple regression analysis showed that HR was a potent predictor of radial PTT in addition to age, sex and systolic BP. There was no significant change in radial PTT when HR ranged from 60 to 75 b.p.m. A significant decrease was found in radial PTT when HR was up to 80 b.p.m. (P < 0.01). These findings indicate that the simple and easily obtainable radial PTT could be a useful index of arterial stiffness, and HR changes should be considered when it is up to 80 b.p.m. PMID- 21593742 TI - Automated determination of the ankle-brachial index using an oscillometric blood pressure monitor: validation vs. Doppler measurement and cardiovascular risk factor profile. AB - The ankle-brachial index (ABI) is a method used widely for peripheral arterial disease (PAD) diagnosis and cardiovascular risk prediction. This study validated automated ABI measurements taken using an oscillometric blood pressure (BP) monitor allowing simultaneous arm-leg BP measurements. A total of 93 patients (hypertension 83%; dyslipidemia 72%; diabetes 45%; cardiovascular disease 23%; smoking 15%) were submitted to Doppler and automated ABI measurements, performed using a professional oscillometric BP monitor (Microlife WatchBP Office; triplicate simultaneous arm-leg BP measurements), in a randomized order. The mean difference between the Doppler reading (1.08 +/- 0.17) and (1) the first oscillometric ABI reading was 0.03 +/- 0.11, (2) the average of two oscillometric readings was 0.02 +/- 0.10 and (3) the average of three oscillometric readings was 0.02 +/- 0.09 (P < 0.01 for all). Strong correlations were found between oscillometric and Doppler ABI (r 0.80, 0.85 and 0.86 for single and average of two and three oscillometric readings, respectively; P < 0.001 for all). Agreement between oscillometric and Doppler ABI in diagnosing PAD (Doppler ABI < 0.9) was found in 95% of cases (kappa 0.79; agreement in diabetics: 94%, kappa 0.79). A receiver operating characteristic (ROC) curve revealed area under the curve at 0.98, with a 0.97 oscillometric ABI cutoff for optimal sensitivity (92%) and specificity (92%) in diagnosing PAD. Average time for automated ABI measurement was 5.8 vs. 9.3 min for Doppler (P < 0.001). Doppler and oscillometric ABI were associated and predicted (multivariate regression analysis) by the same cardiovascular risk factors (pulse pressure, smoking and cardiovascular disease history). Automated ABI measurement using a professional BP monitor allowing simultaneous arm-leg BP measurements appears to be a reliable and faster alternative to Doppler measurement. PMID- 21593743 TI - Novel USH2A mutations in Japanese Usher syndrome type 2 patients: marked differences in the mutation spectrum between the Japanese and other populations. AB - Usher syndrome (USH) is an autosomal recessive disorder characterized by retinitis pigmentosa and hearing loss. USH type 2 (USH2) is the most common type of USH and is frequently caused by mutations in USH2A. In a recent mutation screening of USH2A in Japanese USH2 patients, we identified 11 novel mutations in 10 patients and found the possible frequent mutation c.8559-2A>G in 4 of 10 patients. To obtain a more precise mutation spectrum, we analyzed further nine Japanese patients in this study. We identified nine mutations, of which eight were novel. This result indicates that the mutation spectrum for USH2A among Japanese patients largely differs from Caucasian, Jewish and Palestinian patients. Meanwhile, we did not find the c.8559-2A>G in this study. Haplotype analysis of the c.8559-2G (mutated) alleles using 23 single nucleotide polymorphisms surrounding the mutation revealed an identical haplotype pattern of at least 635 kb in length, strongly suggesting that the mutation originated from a common ancestor. The fact that all patients carrying c.8559-2A>G came from western Japan suggests that the mutation is mainly distributed in that area; indeed, most of the patients involved in this study came from eastern Japan, which contributed to the absence of c.8559-2A>G. PMID- 21593745 TI - LCR-initiated rearrangements at the IDS locus, completed with Alu-mediated recombination or non-homologous end joining. AB - Mucopolysaccharidosis type II (MPS II) is caused by mutations in the IDS gene, which encodes the lysosomal enzyme iduronate-2-sulfatase. In ~20% of MPS II patients the disorder is caused by gross IDS structural rearrangements. We identified two male cases harboring complex rearrangements involving the IDS gene and the nearby pseudogene, IDSP1, which has been annotated as a low-copy repeat (LCR). In both cases the rearrangement included a partial deletion of IDS and an inverted insertion of the neighboring region. In silico analyses revealed the presence of repetitive elements as well as LCRs at the junctions of rearrangements. Our models illustrate two alternative consequences of rearrangements initiated by non-allelic homologous recombination of LCRs: resolution by a second recombination event (that is, Alu-mediated recombination), or resolution by non-homologous end joining repair. These complex rearrangements have the potential to be recurrent and may be present among those MSP II cases with previously uncharacterized aberrations involving IDS. PMID- 21593744 TI - Investigation of modifier genes within copy number variations in Rett syndrome. AB - MECP2 mutations are responsible for two different phenotypes in females, classical Rett syndrome and the milder Zappella variant (Z-RTT). We investigated whether copy number variants (CNVs) may modulate the phenotype by comparison of array-CGH data from two discordant pairs of sisters and four additional discordant pairs of unrelated girls matched by mutation type. We also searched for potential MeCP2 targets within CNVs by chromatin immunopreceipitation microarray (ChIP-chip) analysis. We did not identify one major common gene/region, suggesting that modifiers may be complex and variable between cases. However, we detected CNVs correlating with disease severity that contain candidate modifiers. CROCC (1p36.13) is a potential MeCP2 target, in which a duplication in a Z-RTT and a deletion in a classic patient were observed. CROCC encodes a structural component of ciliary motility that is required for correct brain development. CFHR1 and CFHR3, on 1q31.3, may be involved in the regulation of complement during synapse elimination, and were found to be deleted in a Z-RTT but duplicated in two classic patients. The duplication of 10q11.22, present in two Z-RTT patients, includes GPRIN2, a regulator of neurite outgrowth and PPYR1, involved in energy homeostasis. Functional analyses are necessary to confirm candidates and to define targets for future therapies. PMID- 21593747 TI - Adverse drug reactions: moving from chance to science. PMID- 21593750 TI - Is there clear and convincing evidence of cardiovascular risk with rosiglitazone? PMID- 21593751 TI - Rosiglitazone and the risk of adverse cardiovascular outcomes. PMID- 21593752 TI - Hospital systems for the detection and prevention of adverse drug events. AB - In its 2006 report "Preventing Medication Errors," the Institute of Medicine (IOM) estimated that more than 1.5 million preventable adverse drug events (ADEs) occur annually in the United States. Many organizations, including the IOM, the Institute for Safe Medication Practices, the US Food and Drug Administration, and the Leap Frog Group for Patient Safety have advocated the implementation of technologies to reduce ADEs, particularly in the hospital setting. Many technologies have emerged in recent years to reduce ADEs at various points in the medication use process; however, interfacing some of these key technologies with existing hospital systems poses significant challenges. PMID- 21593753 TI - Adverse drug reactions in utero: perspectives on teratogens and strategies for the future. AB - Many think of an adverse drug reaction (ADR) as an adverse event caused by a medication intended for a given subject. However, as we learned from the thalidomide debacle 50 years ago, some of the most devastating ADRs affect not the subject who takes the medication but rather, in the case of pregnancy exposures, an innocent bystander--the fetus--and the ADRs include birth defects. PMID- 21593754 TI - The phenotype standardization project: improving pharmacogenetic studies of serious adverse drug reactions. AB - The ability to predict the risk for serious drug-induced adverse reactions first requires a large patient database for characterization and validation of genetic markers. The Phenotype Standardization Project (PSP) was initiated to standardize phenotypic definitions, thereby facilitating much-needed recruitment without sacrificing the reliability of patient classification. Three phenotypes have been considered in this initial phase: drug-induced liver injury, drug-induced skin injury, and drug-induced torsade de pointes. PMID- 21593755 TI - Exposing fetal drug exposure. AB - Pregnancy neither protects women from susceptibility to illness nor generally decreases drug dosage requirements of preexisting pharmacotherapy. Thus, a major concern of drug use during pregnancy is maintenance of maternal health while minimizing fetal drug exposure. Important assumptions in reproductive medicine are that fetal exposure to any medication can present risks in pregnancy--because not all risks are known, as little exposure as possible is desirable. PMID- 21593756 TI - Drug safety sciences and the bottleneck in drug development. AB - During a recent review of a new drug application for treatment of a chronic disease, US Food and Drug Administration (FDA) regulators agreed with the sponsor's assessment of efficacy. However, it was noted that two subjects receiving active treatment experienced abnormal liver chemistries that possibly, but not definitely, indicated a liver safety liability. The sponsor was told that a prerequisite for approval would be a new clinical trial involving 20,000 patients treated for 1 year, with 10,000 receiving the new drug and 10,000 receiving a comparator treatment. The sponsor is now faced with the substantial costs involved in undertaking such a large study, the loss of patent life during the conduct and analysis of the study, and the prospect of losing in-class market position. If the drug is ultimately approved, this detour will result in costs and potential revenue loss to the sponsor of well over $1 billion. PMID- 21593757 TI - EPHX1 polymorphisms are not associated with warfarin response in an Italian population. PMID- 21593760 TI - Association of lower urinary tract symptoms and erectile dysfunction: pathophysiological aspects and implications for clinical management. AB - There is strong evidence from multiple epidemological studies that lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are correlated, independent of age or comorbidities as diabetes or hypertension. Although a direct causal relationship is not established yet, four pathophysiological mechanisms can explain the relationship. These include alteration in nitric oxide bioavailability, alpha1-adrenergic receptor hyperactivity, pelvic atherosclerosis and sex hormones. This association has different clinical implications on the management of both disorders. Men seeking care for one condition should always be screened for complaints of the other condition. Sexual function should be assessed and discussed with the patient when choosing the appropriate management strategy for LUTS, as well as when evaluating the patient's response to treatment. Multiple large clinical trials have shown an improvement in LUTS after phosphodiesterase-5 (PDE5)-inhibitor treatment. PDE5 inhibitors show promise as a future treatment for LUTS, either in conjunction with existing therapies or as a primary treatment. There may be a potential therapeutic role for testosterone in LUTS treatment in cases of testosterone deficiency that needs to be investigated. Much further investigation is required, but it is evident that the association between LUTS and ED is fundamental for future therapies and possible preventative strategies. PMID- 21593761 TI - Adrenergic alpha-blockers: an infrequent and overlooked cause of priapism. AB - A systematic review of the literature about the causal relationship between priapism and adrenergic alpha-blockers used for the treatment of lower urinary tract symptoms (LUTS) and arterial hypertension was accomplished. While opportunely describing a case of tamsulosin-induced priapism, we reviewed the literature using MEDLINE, COCHRANE and LILACS libraries, selecting all the articles until the present time addressing the association between priapism and alpha-blockers. Our patient was a healthy 32-year-old man who reported LUTS. His prostate was firm and moderately enlarged on digital rectal examination, measuring 30 grams on transabdominal ultrasound. Empirical treatment with tamsulosin was initiated and he developed priapism the day after the first dose of the drug. Erection was reverted by aspiration of the corpora and intracavernosal injection of adrenaline. Despite the late presentation (40 h of erection), he had no ED on follow-up. In the systematic review, among 2157 articles on priapism, only 13 similar cases reported alpha-blockers as the etiology of priapism. Therefore, adrenergic alpha-blockers are effective and safe drugs, with few serious adverse reactions. Nevertheless the association with priapism is well documented and related to substantial morbidity, this is an infrequent event and should not preclude their use, considering that the patient be sufficiently informed. PMID- 21593762 TI - Non-adaptive origins of interactome complexity. AB - The boundaries between prokaryotes, unicellular eukaryotes and multicellular eukaryotes are accompanied by orders-of-magnitude reductions in effective population size, with concurrent amplifications of the effects of random genetic drift and mutation. The resultant decline in the efficiency of selection seems to be sufficient to influence a wide range of attributes at the genomic level in a non-adaptive manner. A key remaining question concerns the extent to which variation in the power of random genetic drift is capable of influencing phylogenetic diversity at the subcellular and cellular levels. Should this be the case, population size would have to be considered as a potential determinant of the mechanistic pathways underlying long-term phenotypic evolution. Here we demonstrate a phylogenetically broad inverse relation between the power of drift and the structural integrity of protein subunits. This leads to the hypothesis that the accumulation of mildly deleterious mutations in populations of small size induces secondary selection for protein-protein interactions that stabilize key gene functions. By this means, the complex protein architectures and interactions essential to the genesis of phenotypic diversity may initially emerge by non-adaptive mechanisms. PMID- 21593764 TI - Interannual atmospheric variability forced by the deep equatorial Atlantic Ocean. AB - Climate variability in the tropical Atlantic Ocean is determined by large-scale ocean-atmosphere interactions, which particularly affect deep atmospheric convection over the ocean and surrounding continents. Apart from influences from the Pacific El Nino/Southern Oscillation and the North Atlantic Oscillation, the tropical Atlantic variability is thought to be dominated by two distinct ocean atmosphere coupled modes of variability that are characterized by meridional and zonal sea-surface-temperature gradients and are mainly active on decadal and interannual timescales, respectively. Here we report evidence that the intrinsic ocean dynamics of the deep equatorial Atlantic can also affect sea surface temperature, wind and rainfall in the tropical Atlantic region and constitutes a 4.5-yr climate cycle. Specifically, vertically alternating deep zonal jets of short vertical wavelength with a period of about 4.5 yr and amplitudes of more than 10 cm s(-1) are observed, in the deep Atlantic, to propagate their energy upwards, towards the surface. They are linked, at the sea surface, to equatorial zonal current anomalies and eastern Atlantic temperature anomalies that have amplitudes of about 6 cm s(-1) and 0.4 degrees C, respectively, and are associated with distinct wind and rainfall patterns. Although deep jets are also observed in the Pacific and Indian oceans, only the Atlantic deep jets seem to oscillate on interannual timescales. Our knowledge of the persistence and regularity of these jets is limited by the availability of high-quality data. Despite this caveat, the oscillatory behaviour can still be used to improve predictions of sea surface temperature in the tropical Atlantic. Deep-jet generation and upward energy transmission through the Equatorial Undercurrent warrant further theoretical study. PMID- 21593763 TI - Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation. AB - Adenosine receptors and beta-adrenoceptors are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins on binding the agonists adenosine or noradrenaline, respectively. GPCRs have similar structures consisting of seven transmembrane helices that contain well-conserved sequence motifs, indicating that they are probably activated by a common mechanism. Recent structures of beta adrenoceptors highlight residues in transmembrane region 5 that initially bind specifically to agonists rather than to antagonists, indicating that these residues have an important role in agonist-induced activation of receptors. Here we present two crystal structures of the thermostabilized human adenosine A(2A) receptor (A(2A)R-GL31) bound to its endogenous agonist adenosine and the synthetic agonist NECA. The structures represent an intermediate conformation between the inactive and active states, because they share all the features of GPCRs that are thought to be in a fully activated state, except that the cytoplasmic end of transmembrane helix 6 partially occludes the G-protein-binding site. The adenine substituent of the agonists binds in a similar fashion to the chemically related region of the inverse agonist ZM241385 (ref. 8). Both agonists contain a ribose group, not found in ZM241385, which extends deep into the ligand binding pocket where it makes polar interactions with conserved residues in H7 (Ser 277(7.42) and His 278(7.43); superscripts refer to Ballesteros-Weinstein numbering) and non-polar interactions with residues in H3. In contrast, the inverse agonist ZM241385 does not interact with any of these residues and comparison with the agonist-bound structures indicates that ZM241385 sterically prevents the conformational change in H5 and therefore it acts as an inverse agonist. Comparison of the agonist-bound structures of A(2A)R with the agonist bound structures of beta-adrenoceptors indicates that the contraction of the ligand-binding pocket caused by the inward motion of helices 3, 5 and 7 may be a common feature in the activation of all GPCRs. PMID- 21593765 TI - Transcriptional activation of ZEB1 by Slug leads to cooperative regulation of the epithelial-mesenchymal transition-like phenotype in melanoma. AB - The E-box-binding zinc finger transcription factors Slug and ZEB1 are important repressors of E-cadherin, contributing to epithelial-mesenchymal transition (EMT) in primary epithelial cancers. Activator or repressor status of EMT transcription factors defines consequences for tumorigenesis. We show that changes in expression levels of Slug in melanoma cell lines lead to concomitant alterations of ZEB1 expression. Electrophoretic mobility shift, luciferase reporter, and chromatin immunoprecipitation assays identified Slug as a direct transcriptional activator at E-boxes of the ZEB1 promoter. Transcriptional activation of ZEB1 was demonstrated to be specific for Slug, as EMT regulators Snail and Twist failed to influence ZEB1 expression. Slug and ZEB1 cooperatively repressed E-cadherin expression resulting in decreased adhesion to human keratinocytes, but promoted migration of melanoma cells. Our results show that the transcriptional activity of ZEB1 is increased by Slug, suggesting a hierarchical organized expression of EMT transcription factors through directed activation, triggering an EMT-like process in melanoma. PMID- 21593766 TI - Blocking MAPK signaling downregulates CCL21 in lymphatic endothelial cells and impairs contact hypersensitivity responses. AB - CCL21 expression by lymphatic endothelial cells (LECs) is essential for migration of CCR7+ immune cells from skin to regional lymph nodes (LNs). We investigated the importance of mitogen-activated protein kinase (MAPK) signaling in CCL21 expression by ECs in vitro and in vivo. Normal human dermal lymphatic microvascular ECs (HMVEC-dLy) stimulated in vitro with oncostatin M (OSM) expressed high amounts of CCL21 mRNA. CCL21 protein expression by HMVEC-dLy was also markedly increased by OSM compared with unstimulated cultures. Marked phosphorylation of MAPK 44/42 was detected in HMVEC-dLy stimulated by OSM. CCL21 expression by HMVEC-dLy was blocked by a JAK inhibitor 1, JAK3 inhibitor, and U0126 (a MAPK kinase inhibitor) in vitro, all of which blocked phosphorylation of MAPK 44/42. In addition, injection of U0126 into murine skin significantly decreased CCL21 mRNA and protein expression. Moreover, injection of U0126 before sensitization decreased migration of dendritic cells to draining LNs and decreased contact hypersensitivity responses. In summary, these results suggest that the MAPK pathway is important for CCL21 expression by LECs in vitro and in vivo. Blocking MAPK signaling within skin may offer a novel approach to treatment of inflammatory skin diseases. PMID- 21593767 TI - Photoprovocation in cutaneous lupus erythematosus: a multicenter study evaluating a standardized protocol. AB - Photosensitivity is an important and distinguishing sign in various subtypes of cutaneous lupus erythematosus (CLE); however, it remains poorly defined. The purpose of this study was to evaluate whether standardized photoprovocation is a reproducible method to assess photosensitivity in subjects with CLE. A total of 47 subjects with CLE (subacute cutaneous lupus erythematosus (SCLE), n=14; discoid lupus erythematosus (DLE), n=20; lupus erythematosus tumidus (LET), n=13) and 13 healthy volunteers underwent photoprovocation at seven European sites. Of these, 22 (47%) subjects (57% SCLE, 35% DLE, and 54% LET) and none of the healthy volunteers developed photoprovoked lesions according to clinical analysis. Of these 22 subjects, 19 (86%) developed lesions that were histopathologically confirmed as specific for lupus erythematosus (LE). In CLE subjects who developed UV-induced lesions, 86% had Fitzpatrick's phototypes I or II, and the mean minimal erythema dose (MED) was significantly lower compared with subjects without UV-induced lesions (P=0.004). No significant differences in photoprovocation results were observed between study sites. Safety parameters showed no clinically meaningful differences between CLE subjects and healthy volunteers after photoprovocation. In conclusion, a standardized, safe, and reproducible protocol for photoprovocation using UVA and UVB radiation induced skin lesions in approximately half of all CLE subjects and showed comparable results across multiple sites. This method may therefore be used for future diagnostic testing and clinical trials. PMID- 21593768 TI - A GPR40 agonist GW9508 suppresses CCL5, CCL17, and CXCL10 induction in keratinocytes and attenuates cutaneous immune inflammation. AB - G-protein coupled receptors (GPCR) exert diverse physiological functions, many of which are exploited therapeutically. The roles of GPCR in keratinocytes in immune response in the skin, however, remain poorly defined. In this study, we focused on Gi-coupled GPCR in keratinocytes and defined their actions in immunoactivation of cultured keratinocytes in vitro and immune reaction in the skin in vivo. We first activated HaCaT cells by tumor necrosis factor (TNF)-alpha and IFN-gamma and examined effects of various ligands for GPCR on production of CCL17 and CCL5. Agonists for Gi-coupled receptors, particularly GW9508 for GPR40, inhibited CCL17 and CCL5 expression in a pertussis toxin-sensitive manner. The inhibitory effect by GW9508 was abrogated by depletion of GPR40 with RNA interference. GW9508 further suppressed expression of IL-11, IL-24, and IL-33 induced in HaCaT cells by TNF-alpha and IFN-gamma. GW9508 also inhibited CCL5 and CXCL10 production by normal human epidermal keratinocytes. Administration of GW9508 topically to the skin in the challenging phase suppressed ear swelling in a repeated hapten application model and contact hypersensitivity with downregulation of CCL5 and CXCL10, respectively. Thus, in the skin, stimulation of Gi-coupled receptors attenuates induction of critical cytokines and chemokines by proinflammatory cytokines in keratinocytes and suppresses allergic inflammation in the skin. PMID- 21593769 TI - Full-thickness human skin models for congenital ichthyosis and related keratinization disorders. PMID- 21593770 TI - Antimicrobial and anti-inflammatory effects of Cecropin A(1-8)-Magainin2(1-12) hybrid peptide analog p5 against Malassezia furfur infection in human keratinocytes. AB - The lipophilic fungus Malassezia furfur (M. furfur) is a commensal microbe associated with several chronic diseases such as pityriasis versicolor, folliculitis, and seborrheic dermatitis. Because M. furfur-related diseases are difficult to treat and require prolonged use of medications, the treatment for M. furfur-related skin diseases is supposed to gain control over M. furfur growth and the inflammation associated with it, as well as to prevent secondary infections. In this study, we investigated the antifungal and anti-inflammatory effects of cecropin A(1-8)-magainin 2(1-12) hybrid peptide analog P5 on M. furfur. The minimal inhibitory concentration of P5 against M. furfur was 0.39 MUM, making it 3-4 times more potent than commonly used antifungal agents such as ketoconazole (1.5 MUM) or itraconazole (1.14 MUM). P5 efficiently inhibited the expression of IL-8 and Toll-like receptor 2 in M. furfur-infected human keratinocytes without eukaryotic cytotoxicity at its fungicidal concentration. Moreover, P5 significantly downregulated NF-kappaB activation and intracellular calcium fluctuation, which are closely related with enhanced responses of keratinocyte inflammation induced by M. furfur infection. Taken together, these observations suggest P5 may be a potential therapeutic agent for M. furfur associated human skin diseases because of its distinct antifungal and anti inflammatory action. PMID- 21593771 TI - Activation of transient receptor potential vanilloid-3 inhibits human hair growth. AB - In the current study, we aimed at identifying the functional role of transient receptor potential vanilloid-3 (TRPV3) ion channel in the regulation of human hair growth. Using human organ-cultured hair follicles (HFs) and cultures of human outer root sheath (ORS) keratinocytes, we provide the first evidence that activation of TRPV3 inhibits human hair growth. TRPV3 immunoreactivity was confined to epithelial compartments of the human HF, mainly to the ORS. In organ culture, TRPV3 activation by plant-derived (e.g., eugenol, 10-1,000 MUM) or synthetic (e.g., 2-aminoethoxydiphenyl borate, 1-300 MUM) agonists resulted in a dose-dependent inhibition of hair shaft elongation, suppression of proliferation, and induction of apoptosis and premature HF regression (catagen). Human ORS keratinocytes also expressed functional TRPV3, whose stimulation induced membrane currents, elevated intracellular calcium concentration, inhibited proliferation, and induced apoptosis. Of great importance, these effects on ORS keratinocytes were all mediated by TRPV3, as small interfering RNA-mediated silencing of TRPV3 effectively abrogated the cellular actions of the above agonists. These findings collectively support the concept that TRPV3 signaling is a significant player in human hair growth control. Therefore, TRPV3 and the related intracellular signaling mechanism might function as a promising target for pharmacological manipulations of clinically relevant hair growth disorders. PMID- 21593773 TI - Interpretation of Skindex-29 scores: cutoffs for mild, moderate, and severe impairment of health-related quality of life. PMID- 21593775 TI - Consequences of two different amino-acid substitutions at the same codon in KRT14 indicate definitive roles of structural distortion in epidermolysis bullosa simplex pathogenesis. AB - Numerous inherited diseases develop due to missense mutations, leading to an amino-acid substitution. Whether an amino-acid change is pathogenic depends on the level of deleterious effects caused by the amino-acid alteration. We show an example of different structural and phenotypic consequences caused by two individual amino-acid changes at the same position. Epidermolysis bullosa simplex (EBS) is a genodermatosis resulting from KRT5 or KRT14 mutations. Mutation analysis of an EBS family revealed that affected individuals were heterozygous for a, to our knowledge, previously unreported mutation of c.1237G>C (p.Ala413Pro) in KRT14. Interestingly, 2 of 100 unrelated normal controls were heterozygous, and 1 of the 100 was homozygous for a different mutation in this position, c.1237G>A (p.Ala413Thr). In silico modeling of the protein demonstrated deleterious structural effects from proline substitution but not from threonine substitution. In vitro transfection studies revealed a significantly larger number of keratin-clumped cells in HaCaT cells transfected with mutant KRT14 complementary DNA (cDNA) harboring p.Ala413Pro than those transfected with wild type KRT14 cDNA or mutant KRT14 cDNA harboring p.Ala413Thr. These results show that changes in two distinct amino acids at a locus are destined to elicit different phenotypes due to the degree of structural distortion resulting from the amino-acid alterations. PMID- 21593776 TI - Mechanisms of resistance to RAF inhibitors in melanoma. AB - The recent RAF inhibitor trial with PLX4032/RG7204 in late-stage mutant B-RAF melanoma patients has been lauded as a success story for personalized cancer therapy since short-term clinical responses were observed in the majority of patients. However, initial responses were followed by subsequent tumor re-growth, and a subset of patients showed intrinsic resistance. Bi-directional translational efforts are now essential to determine the mechanisms underlying acquired/secondary and intrinsic resistance to RAF inhibitors. PMID- 21593777 TI - Association of HLA and TNF polymorphisms with the outcome of HBV infection in the South Indian population. AB - The role of host genetic factors in the pathogenesis and outcome of hepatitis B virus (HBV) infection is not well known. We assessed the association of HLA and TNF (rs361525, rs1800629, rs1799724, rs1800630 and rs1799964) polymorphisms with HBV outcome in the South Indian population. Association of HLA polymorphism was analyzed in 90 individuals from each group, that is, spontaneous recovery (SR) and chronic-HBV (C-HBV) infection. The role of TNF polymorphisms was evaluated in 150 subjects with SR and 137 patients with C-HBV infection. After adjusting for age and sex, HLA-DRB1*07:01 was strongly associated with chronicity (corrected P value (pc) <0.005, odds ratio (OR) 3.76, 95% confidence interval (CI) 1.84-7.68). The rs1800630 genotype was associated with HBV outcome in codominant (pc<0.01, OR=1.99, 95% CI 1.30-3.05) and dominant (pc<0.01, OR=2.28, 95% CI 1.35-3.84) analyzing models after adjusting for age and sex. Similarly, the rs1799964 genotype was associated with HBV outcome in codominant (pc=0.01, OR=1.57, 95% CI 1.09-2.27) and dominant (pc<0.01, OR=2.21, 95% CI 1.27-3.83) analyzing models. Haplotype analysis (rs1799964/rs1800630/rs1799724/rs1800629/rs361525) revealed that the CACGG haplotype was strongly associated with C-HBV infection (P=0.0004). Our study suggests that inheritance of HLA and TNF polymorphisms might explain the outcome of HBV infection in the South Indian population. PMID- 21593778 TI - Evidence for malaria selection of a CR1 haplotype in Sardinia. AB - Complement receptor 1 (CR1) levels have been associated with malarial susceptibility and/or severity of the disease in different population groups, and CR1 is a receptor for Plasmodium falciparum. In this study, multiple CR1 single nucleotide polymorphisms (SNPs) showed strong evidence of population differentiation between Sardinian and other European ethnic groups. Cross population algorithms comparing haplotype structure and differences in haplotype and allele frequency distribution provided additional support for natural selection of CR1 in Sardinia. The predominant Sardinian CR1 haplotype included SNPs that are associated with decreased CR1 levels in Europeans and other population groups. Previous studies have shown that the SNPs within the dominant Sardinian haplotype have a significantly higher frequency in a malaria endemic compared with non-endemic regions in India. Together with the historical evidence of the prevalence of malaria in Sardinia, these data support the role of malaria leading to positive selection of this CR1 haplotype in Sardinia. PMID- 21593779 TI - Molecular characterisation of KIR2DS2*005, a fusion gene associated with a shortened KIR haplotype. AB - KIR2DS2 is an activating homologue of KIR2DL2, an inhibitory killer-cell immunoglobulin-like receptor (KIR) that surveys expression of major histocompatibility complex-C allotypes bearing a C1 epitope. We have studied here its allele KIR2DS2*005, which shows a hybrid structure-it is identical to other KIR2DS2 alleles in the ectodomain, but has transmembrane and cytoplasmic regions identical to those of KIR2DS3(*)001, a short-tailed KIR of uncertain expression and function. Our results reveal that KIR2DS2*005 is a fusion gene-the product of an unequal crossing over by which the genes KIR2DS2 and KIR2DS3 recombined within a 400 base pair region of complete identity in intron 6. Also resulting from that recombination was a shortened KIR haplotype of the B group, in which three genes commonly linked to KIR2DS2 (KIR2DL2, KIR2DL5B and KIR2DS3) are deleted. Population studies indicate that KIR2DS2*005 is still associated to such haplotype, and it can be found in approximately 1.2% of Caucasoids. Using a combination of two monoclonal antibodies, we also demonstrate that KIR2DS2*005 encodes a molecule expressed on the surface of natural killer- and T-lymphocytes. PMID- 21593780 TI - Gene--gene interaction among cytokine polymorphisms influence susceptibility to aggressive periodontitis. AB - Aggressive periodontitis (AgP) is a multifactorial disease. The distinctive aspect of periodontitis is that this disease must deal with a large number of genes interacting with one another and forming complex networks. Thus, it is reasonable to expect that gene-gene interaction may have a crucial role. Therefore, we carried out a pilot case-control study to identify the association of candidate epistatic interactions between genetic risk factors and susceptibility to AgP, by using both conventional parametric analyses and a higher order interactions model, based on the nonparametric Multifactor Dimensionality Reduction algorithm. We analyzed 122 AgP patients and 246 appropriate periodontally healthy individuals, and genotyped 28 polymorphisms, located within 14 candidate genes, chosen among the principal genetic variants pointed out from literature and having a role in inflammation and immunity. Our analyses provided significant evidence for gene--gene interactions in the development of AgP, in particular, present results: (a) indicate a possible role of two new polymorphisms, within SEPS1 and TNFRSF1B genes, in determining host individual susceptibility to AgP; (b) confirm the potential association between of IL-6 and Fc gamma- receptor polymorphisms and the disease; (c) exclude an essential contribution of IL-1 cluster gene polymorphisms to AgP in our Caucasian Italian population. PMID- 21593781 TI - Understanding the effects of chronic kidney disease on cardiovascular risk: are there lessons to be learnt from healthy kidney donors? AB - Chronic kidney disease (CKD) is now a recognized global public health problem. It is highly prevalent and strongly associated with hypertension and cardiovascular disease (CVD); far more patients with a glomerular filtration rate below 60 ml min(-1) per 1.73 m(2) will die from cardiovascular causes than progress to end stage renal disease. A better understanding of the complex mechanisms underlying the development of CVD among CKD patients is required if we are to begin devising therapy to prevent or reverse this process. Observational studies of CVD in CKD are difficult to interpret because renal impairment is almost always accompanied by confounding factors. These include the underlying disease process itself (for example, diabetes mellitus and systemic vasculitis) and the complications of CKD, such as hypertension, anaemia and inflammation. Kidney donors provide an ideal opportunity to study healthy subjects without manifest vascular disease who experience an acute change from having normal to modestly impaired renal function at the time of uninephrectomy. Prospectively examining the cardiovascular consequences of uninephrectomy using donors as a model of CKD may provide useful insight into the pathophysiology of CVD in CKD and, therefore, into how the CVD risk associated with renal impairment might eventually be reduced. PMID- 21593782 TI - Health-related quality of life is worse in individuals with hypertension under drug treatment: results of population-based study. AB - Patients with hypertension usually report lower health-related quality of life (HRQoL), but it is unclear whether this is secondary to high blood pressure (BP) per se, drug treatment or awareness of disease. In a cross-sectional study using a multistage population-based sample, participants were interviewed and examined at home. Hypertension was defined by BP >=140/90 mm Hg or use of BP-lowering drugs. HRQoL was assessed through the Short-Form Health Survey (SF-12) and presented as the physical component summary (PCS), mental component summary (MCS) and the SF-12 eight-domain scale. In total, 1858 individuals were evaluated, being 60.1% women, aged 52.5 +/- 4.1 years old, and 39.9% men, aged 47.2 +/- 9.1 years old. Prevalence of hypertension was 34.2% (95% CI 31.5-36.9). The PCS scores for hypertensive and normotensive participants were 49.4 (CI 48.6-50.2) and 51.06 (CI 50.4-51.7) (P=0.01), respectively, and the MCS scores were 49.1 (CI 47.9-50.3) and 50.5 (CI 49.6-51.2) (P=0.06), respectively. Participants with hypertension and not using BP drugs had higher HRQoL scores (PCS 49.6; MCS 51.9) than those using BP drugs either with uncontrolled (PCS 45.3; MCS 49.4) or controlled BP (PCS 46.2; MCS 47.7; P<0.05). We concluded that individuals with hypertension have worse quality of life, particularly when their BP is controlled by drugs. This perception may lead to lower rates of adherence to treatment. PMID- 21593783 TI - Patterns of sodium and potassium excretion and blood pressure in the African Diaspora. AB - Habitual levels of dietary sodium and potassium are correlated with age-related increases in blood pressure (BP) and likely have a role in this phenomenon. Although extensive published evidence exists from randomized trials, relatively few large-scale community surveys with multiple 24-h urine collections have been reported. We obtained three 24-h samples from 2704 individuals from Nigeria, Jamaica and the United States to evaluate patterns of intake and within-person relationships with BP. The average (+/-s.d.) age and weight of the participants across all the three sites were 39.9+/-8.6 years and 76.1+/-21.2 kg, respectively, and 55% of the total participants were females. Sodium excretion increased across the East-West gradient (for example, 123.9+/-54.6, 134.1+/-48.8, 176.6+/-71.0 (+/-s.d.) mmol, Nigeria, Jamaica and US, respectively), whereas potassium was essentially unchanged (for example, 46.3+/-22.9, 40.7+/-16.1, 44.7+/-16.4 (+/-s.d.) mmol, respectively). In multivariate analyses both sodium (positively) and potassium (negatively) were strongly correlated with BP (P<0.001); quantitatively the association was stronger, and more consistent in each site individually, for potassium. The within-population day-to-day variation was also greater for sodium than for potassium. Among each population group, a significant correlation was observed between sodium and urine volume, supporting the prior finding of sodium as a determinant of fluid intake in free-living individuals. These data confirm the consistency with the possible role of dietary electrolytes as hypertension risk factors, reinforcing the relevance of potassium in these populations. PMID- 21593784 TI - Blood pressure control status and effects of pravastatin on cardiovascular events occurrence in patients with dyslipidaemia. AB - Dyslipidaemia is often associated with hypertension, and many clinical trials have shown that lipid-lowering therapy and strict blood pressure (BP) control are important for preventing cardiovascular disease (CVD). However, few reports describe the effect of statins on CVD occurrence in relation to long-term BP control. In the present analysis, we investigated the effects of baseline BP and follow-up BP control on the occurrence of CVD in patients enrolled in the MEGA Study. We investigated whether BP values provide more accurate prediction of the occurrence of CVD, including cerebrovascular disease/transischemic attack (CVA/TIA), and the effect of pravastatin on CVA/TIA. The risk for CVA/TIA and other CVD increased significantly (P<=0.001) as the severity of hypertension increased. In contrast, pravastatin reduced the onset of CVA/TIA, regardless of the BP controlled. The mean BP was a more accurate predictor of CVD than a one time BP value. In patients with mild-to-moderate dyslipidaemia, elevated BP increases the risk for CVA/TIA and other CVD, and rigorous BP control was important for preventing CVD, in particular CVA/TIA. The 12-month mean BP is useful to avoid attenuation to determine the association between CVD and BP. Pravastatin prevented CVA/TIA, regardless of BP controlled. PMID- 21593785 TI - Assessing the risk of second malignancies after modern radiotherapy. AB - Recent advances in radiotherapy have enabled the use of different types of particles, such as protons and heavy ions, as well as refinements to the treatment of tumours with standard sources (photons). However, the risk of second cancers arising in long-term survivors continues to be a problem. The long-term risks from treatments such as particle therapy have not yet been determined and are unlikely to become apparent for many years. Therefore, there is a need to develop risk assessments based on our current knowledge of radiation-induced carcinogenesis. PMID- 21593786 TI - Human cancers express mutator phenotypes: origin, consequences and targeting. AB - Recent data on DNA sequencing of human tumours have established that cancer cells contain thousands of mutations. These data support the concept that cancer cells express a mutator phenotype. This Perspective considers the evidence supporting the mutator phenotype hypothesis, the origin and consequences of a mutator phenotype, the implications for personalized medicine and the feasibility of ablating tumours by error catastrophe. PMID- 21593788 TI - Ovarian cancer: Model building. PMID- 21593789 TI - PKCeta promotes a proliferation to differentiation switch in keratinocytes via upregulation of p27Kip1 mRNA through suppression of JNK/c-Jun signaling under stress conditions. AB - To maintain epidermal homeostasis, the balance between keratinocyte proliferation and differentiation is tightly controlled. However, the molecular mechanisms underlying this balance remain unclear. In 3D organotypic coculture with mouse keratinocytes and fibroblasts, the thickness of stratified cell layers was prolonged, and growth arrest and terminal differentiation were delayed when PKCeta-null keratinocytes were used. Re-expression of PKCeta in PKCeta-null keratinocytes restored stratified cell layer thickness, growth arrest and terminal differentiation. We show that in 3D cocultured PKCeta-null keratinocytes, p27(Kip1) mRNA was downregulated, whereas JNK/c-Jun signaling was enhanced. Furthermore, inhibition of JNK/c-Jun signaling in PKCeta-null keratinocytes led to upregulation of p27(Kip1) mRNA, and to thinner stratified cell layers. Collectively, our findings indicate that PKCeta upregulates p27(Kip1) mRNA through suppression of JNK/c-Jun signaling. This results in promoting a proliferation to differentiation switch in keratinocytes. PMID- 21593787 TI - Cancer to bone: a fatal attraction. AB - When cancer metastasizes to bone, considerable pain and deregulated bone remodelling occurs, greatly diminishing the possibility of cure. Metastasizing tumour cells mobilize and sculpt the bone microenvironment to enhance tumour growth and to promote bone invasion. Understanding the crucial components of the bone microenvironment that influence tumour localization, along with the tumour derived factors that modulate cellular and protein matrix components of bone to favour tumour expansion and invasion, is central to the pathophysiology of bone metastases. Basic findings of tumour-bone interactions have uncovered numerous therapeutic opportunities that focus on the bone microenvironment to prevent and treat bone metastases. PMID- 21593790 TI - Involvement of lipid rafts in the localization and dysfunction effect of the antitumor ether phospholipid edelfosine in mitochondria. AB - Lipid rafts and mitochondria are promising targets in cancer therapy. The synthetic antitumor alkyl-lysophospholipid analog edelfosine (1-O-octadecyl-2-O methyl-rac-glycero-3-phosphocholine) has been reported to target lipid rafts. Here, we have found that edelfosine induced loss of mitochondrial membrane potential and apoptosis in human cervical carcinoma HeLa cells, both responses being abrogated by Bcl-x(L) overexpression. We synthesized a number of new fluorescent edelfosine analogs, which preserved the proapoptotic activity of the parent drug, and colocalized with mitochondria in HeLa cells. Edelfosine induced swelling in isolated mitochondria, indicating an increase in mitochondrial membrane permeability. This mitochondrial swelling was independent of reactive oxygen species generation. A structurally related inactive analog was unable to promote mitochondrial swelling, highlighting the importance of edelfosine molecular structure in its effect on mitochondria. Raft disruption inhibited mitochondrial localization of the drug in cells and edelfosine-induced swelling in isolated mitochondria. Edelfosine promoted a redistribution of lipid rafts from the plasma membrane to mitochondria, suggesting a raft-mediated link between plasma membrane and mitochondria. Our data suggest that direct interaction of edelfosine with mitochondria eventually leads to mitochondrial dysfunction and apoptosis. These observations unveil a new framework in cancer chemotherapy that involves a link between lipid rafts and mitochondria in the mechanism of action of an antitumor drug, thus opening new avenues for cancer treatment. PMID- 21593791 TI - A functionalized single-walled carbon nanotube-induced autophagic cell death in human lung cells through Akt-TSC2-mTOR signaling. AB - Nanoparticles are now emerging as a novel class of autophagy activators. Functionalized single-walled carbon nanotubes (f-SWCNTs) are valuable nanomaterials in many industries. This article is designed to assess the autophagic response for f-SWCNTs exposure in vitro and in vivo. A few types of f SWCNTs were screened in human lung adenocarcinoma A549 cells for the autophagic response and related pathways in vitro. Formation of autophagosomes and LC3-II upregulation were confirmed on the basis of electron microscopy and LC3 western blotting for COOH-CNT, but not for PABS-CNT and PEG-CNT. MTT assay showed marked increase in cell viability, when COOH-CNT was added to cells in the presence of autophagy inhibitor 3MA, ATG6 or TSC2 siRNA. Consistent with the involvement of the Akt-TSC1/2-mTOR pathway, the phosphorylation levels of mTOR, mTOR's substrate S6 and Akt were shown significantly decreased in A549 cells on treatment with COOH-CNT using western blotting. What's more, autophagy inhibitor 3MA significantly reduced the lung edema in vivo. In a word, COOH-CNT induced autophagic cell death in A549 cells through the AKT-TSC2-mTOR pathway and caused acute lung injury in vivo. Inhibition of autophagy significantly reduced COOH-CNT induced autophagic cell death and ameliorated acute lung injury in mice, suggesting a potential remedy to address the growing concerns on the safety of nanomaterials. PMID- 21593792 TI - Pharmacological activation of a novel p53-dependent S-phase checkpoint involving CHK-1. AB - We have recently shown that induction of the p53 tumour suppressor protein by the small-molecule RITA (reactivation of p53 and induction of tumour cell apoptosis; 2,5-bis(5-hydroxymethyl-2-thienyl)furan) inhibits hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in vivo and induces p53 dependent tumour cell apoptosis in normoxia and hypoxia. Here, we demonstrate that RITA activates the canonical ataxia telangiectasia mutated/ataxia telangiectasia and Rad3-related DNA damage response pathway. Interestingly, phosphorylation of checkpoint kinase (CHK)-1 induced in response to RITA was influenced by p53 status. We found that induction of p53, phosphorylated CHK-1 and gammaH2AX proteins was significantly increased in S-phase. Furthermore, we found that RITA stalled replication fork elongation, prolonged S-phase progression and induced DNA damage in p53 positive cells. Although CHK-1 knockdown did not significantly affect p53-dependent DNA damage or apoptosis induced by RITA, it did block the ability for DNA integrity to be maintained during the immediate response to RITA. These data reveal the existence of a novel p53-dependent S-phase DNA maintenance checkpoint involving CHK-1. PMID- 21593793 TI - The propeptide of yeast cathepsin D inhibits programmed necrosis. AB - The lysosomal endoprotease cathepsin D (CatD) is an essential player in general protein turnover and specific peptide processing. CatD-deficiency is associated with neurodegenerative diseases, whereas elevated CatD levels correlate with tumor malignancy and cancer cell survival. Here, we show that the CatD ortholog of the budding yeast Saccharomyces cerevisiae (Pep4p) harbors a dual cytoprotective function, composed of an anti-apoptotic part, conferred by its proteolytic capacity, and an anti-necrotic part, which resides in the protein's proteolytically inactive propeptide. Thus, deletion of PEP4 resulted in both apoptotic and necrotic cell death during chronological aging. Conversely, prolonged overexpression of Pep4p extended chronological lifespan specifically through the protein's anti-necrotic function. This function, which triggered histone hypoacetylation, was dependent on polyamine biosynthesis and was exerted via enhanced intracellular levels of putrescine, spermidine and its precursor S adenosyl-methionine. Altogether, these data discriminate two pro-survival functions of yeast CatD and provide first insight into the physiological regulation of programmed necrosis in yeast. PMID- 21593794 TI - The use of polyethylenimine-DNA to topically deliver hTERT to promote hair growth. AB - The present study investigates the efficacy of polyethylenimine (PEI)-DNA complex that expressed human telomerase reverse transcriptase (hTERT) to transfect hair follicle stem cells and produce sufficient hTERT to stimulate hair growth. Transfection with pLC-hTERT-DNA-PEI complex (D+P group) in vitro induced expression of proliferating cell nuclear antigen in 35.8% of the purified stem cell population, suggesting enhanced cell proliferation. In vivo transfection efficiency of rat dorsal skin was determined by staining for beta-gal activity. Cells positive for beta-gal were located in the bulge region and dermal sheath of hair follicles. The follicles in the hTERT-transfected region entered anagenon day 15 after transfection, whereas non-transfected (Neg) controls remained in telogen. The similar effect was observed in 50-day-old rat dorsal skin. D+P group displayed a specific expression of hTERT and sufficient to initiate a transition to the anagen phase and promote new hair synthesis 18 days after the transfection. hTERT promoted follicle neogenesis following wounding. In all, 60 days after wounding, tissues of the D+P group showed more newly regenerating hair follicles (83+/-52 regenerated follicles per rat) in contrast to control group tissues (15+/-15 regenerated follicles per rat). These studies provide a potential approach for gene therapy of skin disease. PMID- 21593795 TI - Niche segregation of ammonia-oxidizing archaea and anammox bacteria in the Arabian Sea oxygen minimum zone. AB - Ammonia-oxidizing archaea (AOA) and anaerobic ammonia-oxidizing (anammox) bacteria have emerged as significant factors in the marine nitrogen cycle and are responsible for the oxidation of ammonium to nitrite and dinitrogen gas, respectively. Potential for an interaction between these groups exists; however, their distributions are rarely determined in tandem. Here we have examined the vertical distribution of AOA and anammox bacteria through the Arabian Sea oxygen minimum zone (OMZ), one of the most intense and vertically exaggerated OMZs in the global ocean, using a unique combination of intact polar lipid (IPL) and gene based analyses, at both DNA and RNA levels. To screen for AOA-specific IPLs, we developed a high-performance liquid chromatography/mass spectrometry/mass spectrometry method targeting hexose-phosphohexose (HPH) crenarchaeol, a common IPL of cultivated AOA. HPH-crenarchaeol showed highest abundances in the upper OMZ transition zone at oxygen concentrations of ca. 5 MUM, coincident with peaks in both thaumarchaeotal 16S rDNA and amoA gene abundances and gene expression. In contrast, concentrations of anammox-specific IPLs peaked within the core of the OMZ at 600 m, where oxygen reached the lowest concentrations, and coincided with peak anammox 16S rDNA and the hydrazine oxidoreductase (hzo) gene abundances and their expression. Taken together, the data reveal a unique depth distribution of abundant AOA and anammox bacteria and the segregation of their respective niches by >400 m, suggesting no direct coupling of their metabolisms at the time and site of sampling in the Arabian Sea OMZ. PMID- 21593796 TI - Anaerobic ammonia oxidation in a fertilized paddy soil. AB - Evidence for anaerobic ammonium oxidation in a paddy field was obtained in Southern China using an isotope-pairing technique, quantitative PCR assays and 16S rRNA gene clone libraries, along with nutrient profiles of soil cores. A paddy field with a high load of slurry manure as fertilizer was selected for this study and was shown to contain a high amount of ammonium (6.2-178.8 mg kg(-1)). The anaerobic oxidation of ammonium (anammox) rates in this paddy soil ranged between 0.5 and 2.9 nmol N per gram of soil per hour in different depths of the soil core, and the specific cellular anammox activity observed in batch tests ranged from 2.9 to 21 fmol per cell per day. Anammox contributed 4-37% to soil N2 production, the remainder being due to denitrification. The 16S rRNA gene sequences of surface soil were closely related to the anammox bacteria 'Kuenenia', 'Anammoxoglobus' and 'Jettenia'. Most of the anammox 16S rRNA genes retrieved from the deeper soil were affiliated to 'Brocadia'. The retrieval of mainly bacterial amoA sequences in the upper part of the paddy soil indicated that nitrifying bacteria may be the major source of nitrite for anammox bacteria in the cultivated horizon. In the deeper oxygen-limited parts, only archaeal amoA sequences were found, indicating that archaea may produce nitrite in this part of the soil. It is estimated that a total loss of 76 g N m(-2) per year is linked to anammox in the paddy field. PMID- 21593797 TI - Exposure of phototrophs to 548 days in low Earth orbit: microbial selection pressures in outer space and on early earth. AB - An epilithic microbial community was launched into low Earth orbit, and exposed to conditions in outer space for 548 days on the European Space Agency EXPOSE-E facility outside the International Space Station. The natural phototroph biofilm was augmented with akinetes of Anabaena cylindrica and vegetative cells of Nostoc commune and Chroococcidiopsis. In space-exposed dark controls, two algae (Chlorella and Rosenvingiella spp.), a cyanobacterium (Gloeocapsa sp.) and two bacteria associated with the natural community survived. Of the augmented organisms, cells of A. cylindrica and Chroococcidiopsis survived, but no cells of N. commune. Only cells of Chroococcidiopsis were cultured from samples exposed to the unattenuated extraterrestrial ultraviolet (UV) spectrum (>110 nm or 200 nm). Raman spectroscopy and bright-field microscopy showed that under these conditions the surface cells were bleached and their carotenoids were destroyed, although cell morphology was preserved. These experiments demonstrate that outer space can act as a selection pressure on the composition of microbial communities. The results obtained from samples exposed to >200 nm UV (simulating the putative worst-case UV exposure on the early Earth) demonstrate the potential for epilithic colonization of land masses during that time, but that UV radiation on anoxic planets can act as a strong selection pressure on surface-dwelling organisms. Finally, these experiments have yielded new phototrophic organisms of potential use in biomass and oxygen production in space exploration. PMID- 21593798 TI - Metagenomic mining for microbiologists. AB - Microbial ecologists can now start digging into the accumulating mountains of metagenomic data to uncover the occurrence of functional genes and their correlations to microbial community members. Limitations and biases in DNA extraction and sequencing technologies impact sequence distributions, and therefore, have to be considered. However, when comparing metagenomes from widely differing environments, these fluctuations have a relatively minor role in microbial community discrimination. As a consequence, any functional gene or species distribution pattern can be compared among metagenomes originating from various environments and projects. In particular, global comparisons would help to define ecosystem specificities, such as involvement and response to climate change (for example, carbon and nitrogen cycle), human health risks (eg, presence of pathogen species, toxin genes and viruses) and biodegradation capacities. Although not all scientists have easy access to high-throughput sequencing technologies, they do have access to the sequences that have been deposited in databases, and therefore, can begin to intensively mine these metagenomic data to generate hypotheses that can be validated experimentally. Information about metabolic functions and microbial species compositions can already be compared among metagenomes from different ecosystems. These comparisons add to our understanding about microbial adaptation and the role of specific microbes in different ecosystems. Concurrent with the rapid growth of sequencing technologies, we have entered a new age of microbial ecology, which will enable researchers to experimentally confirm putative relationships between microbial functions and community structures. PMID- 21593799 TI - Response of methanotrophic communities to afforestation and reforestation in New Zealand. AB - Methanotrophs use methane (CH(4)) as a carbon source. They are particularly active in temperate forest soils. However, the rate of change of CH(4) oxidation in soil with afforestation or reforestation is poorly understood. Here, soil CH(4) oxidation was examined in New Zealand volcanic soils under regenerating native forests following burning, and in a mature native forest. Results were compared with data for pasture to pine land-use change at nearby sites. We show that following soil disturbance, as little as 47 years may be needed for development of a stable methanotrophic community similar to that in the undisturbed native forest soil. Corresponding soil CH(4)-oxidation rates in the regenerating forest soil have the potential to reach those of the mature forest, but climo-edaphic fators appear limiting. The observed changes in CH(4)-oxidation rate were directly linked to a prior shift in methanotrophic communities, which suggests microbial control of the terrestrial CH(4) flux and identifies the need to account for this response to afforestation and reforestation in global prediction of CH(4) emission. PMID- 21593802 TI - A randomized trial testing a contingency-based weight loss intervention involving social reinforcement. AB - Even though behavioral weight loss interventions are conducted in groups, a social contingency (SC) paradigm that capitalizes on the social reinforcement potential of the weight loss group has never been tested. We tested a weight loss intervention in which participation in the weight loss group was contingent upon meeting periodic weight goals. We hypothesized that making access to the group dependent upon weight loss would improve weight outcomes. Participants (N = 62; 84% female; 94% white; age = 51.9 +/- 9.0; BMI = 34.7 +/- 4.5) were randomized to 6-months of standard behavioral weight loss (SBWL) or to a behavioral program that included a SC paradigm. Both groups engaged in social cohesion activities. Participants in SC who did not meet weight goals did not attend group meetings; instead, they received individual treatment with a new interventionist and returned to group once their weight goals were met. SC did not improve overall weight loss outcomes (SC: -10.0 +/- 4.9 kg, SBWL: -10.8 +/- 6.4 kg, P = 0.63). Similarly, overall weight loss was not significantly different in the subgroup of participants in the SC and SBWL conditions who did not meet periodic weight loss goals (-7.3 +/- 4.1 kg vs. -7.1 +/- 3.5 kg, P = 0.90). Surprisingly, "successful" SC participants (who met their weight goals) actually lost less weight than "successful" SBWL participants (-12.4 +/- 3.2 kg vs. -14.5 +/- 4.7 kg, P = 0.02). Whereas contingency-based treatments have been tested for other health behaviors (e.g., substance abuse), this is the first study to test a SC intervention for weight loss. This approach did not improve overall weight loss outcomes. Our attempt to offer appropriate clinical care by providing individual treatment to SC participants when needed may have mitigated the effects of the SC paradigm. PMID- 21593801 TI - Interaction of FTO and physical activity level on adiposity in African-American and European-American adults: the ARIC study. AB - Physical inactivity accentuates the association of variants in the FTO locus with obesity-related traits but evidence is largely lacking in non-European populations. Here we tested the hypothesis that physical activity (PA) modifies the association of the FTO single-nucleotide polymorphism (SNP) rs9939609 with adiposity traits in 2,656 African Americans (AA) (1,626 women and 1,030 men) and 9,867 European Americans (EA) (5,286 women and 4,581 men) aged 45-66 years in the Atherosclerosis Risk in Communities (ARIC) study. Individuals in the lowest quintile of the sport activity index of the Baecke questionnaire were categorized as low PA. Baseline BMI, waist circumference (WC), and skinfold measures were dependent variables in regression models testing the additive effect of the SNP, low PA, and their interaction, adjusting for age, alcohol use, cigarette use, educational attainment, and percent European ancestry in AA adults, stratified by sex and race/ethnicity. rs9939609 was associated with adiposity in all groups other than AA women. The SNP * PA interaction was significant in AA men (P <= 0.002 for all traits) and EA men (P <= 0.04 for all traits). For each additional copy of the A (risk) allele, WC in AA men was higher in those with low PA (beta(lowPA): 5.1 cm, 95% confidence interval (CI): 2.6-7.5) than high PA (beta(highPA): 0.7 cm, 95% CI: -0.4 to 1.9); P (interaction) = 0.002). The interaction effect was not observed in EA or AA women. FTO SNP * PA interactions on adiposity were observed for AA as well as EA men. Differences by sex require further examination. PMID- 21593800 TI - Comparison of glucostatic parameters after hypocaloric diet or bariatric surgery and equivalent weight loss. AB - Weight-loss independent mechanisms may play an important role in the improvement of glucose homeostasis after Roux-en-Y gastric bypass (RYGB). The objective of this analysis was to determine whether RYGB causes greater improvement in glucostatic parameters as compared with laparoscopic adjustable gastric banding (LAGB) or low calorie diet (LCD) after equivalent weight loss and independent of enteral nutrient passage. Study 1 recruited participants without type 2 diabetes mellitus (T2DM) who underwent LAGB (n = 8) or RYGB (n = 9). Study 2 recruited subjects with T2DM who underwent LCD (n = 7) or RYGB (n = 7). Insulin supplemented frequently-sampled intravenous glucose tolerance test (fsIVGTT) was performed before and after equivalent weight reduction. MINMOD analysis of insulin sensitivity (Si), acute insulin response to glucose (AIRg) and C-peptide (ACPRg) response to glucose, and insulin secretion normalized to the degree of insulin resistance (disposition index (DI)) were analyzed. Weight loss was comparable in all groups (7.8 +/- 0.4%). In Study 1, significant improvement of Si, ACPRg, and DI were observed only after LAGB. In Study 2, Si, ACPRg, and plasma adiponectin increased significantly in the RYGB-DM group but not in LCD. DI improved in both T2DM groups, but the absolute increase was greater after RYGB (258.2 +/- 86.6 vs. 55.9 +/- 19.9; P < 0.05). Antidiabetic medications were discontinued after RYGB contrasting with 55% reduction in the number of medications after LCD. No intervention affected fasting glucagon-like peptide (GLP)-1, peptide YY (PYY) or ghrelin levels. In conclusion, RYGB produced greater improvement in Si and DI compared with diet at equivalent weight loss in T2DM subjects. Such a beneficial effect was not observed in nondiabetic subjects at this early time-point. PMID- 21593803 TI - Amelioration of lipid abnormalities by alpha-lipoic acid through antioxidative and anti-inflammatory effects. AB - Recent data have revealed that oxidative products and inflammatory mediators are increased in the insulin-resistant states of obesity and type 2 diabetes mellitus (T2DM). Obese patients with impaired glucose tolerance (IGT) are at high risk for developing T2DM and have high incidence of dyslipidemia. alpha-Lipoic acid (ALA) is a potent antioxidant with insulin sensitizing activity. However, it is not clear whether ALA is effective on lipid parameters in humans. This study has investigated 22 obese subjects with IGT (obese-IGT), 13 of whom underwent 2-week ALA treatment, 600 mg intravenously once daily. Before and after the treatment, euglycemic-hyperinsulinemic clamps were used to measure insulin sensitivity. Meanwhile, plasma lipids, oxidative products, and chronic inflammatory markers were measured. After treatment of ALA in obese-IGT patients, insulin sensitivity was improved, insulin sensitivity index (ISI) impressively enhanced by 41%. Plasma levels of free fatty acids (FFAs), triglyceride (TG), total cholesterol (T Chol), low density lipoprotein-cholesterol (LDL-Chol), small dense LDL-Chol (sd LDL), oxidized LDL-Chol (ox-LDL-Chol), very low density lipoprotein-cholesterol (VLDL-Chol) were all significantly decreased (P < 0.01). At the same time, both plasma oxidative products (malondialdehyde (MDA), 8-iso-prostaglandin) and inflammatory markers (tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL 6)) were remarkably decreased (P < 0.01), while adiponectin was increased (P < 0.01). There are significant negative correlations between ISI and plasma FFAs, sd-LDL-Chol, ox-LDL-Chol, MDA, 8-iso-prostaglandin, TNF-alpha, and IL-6, and positive correlations with HDL-Chol and adiponectin in obese-IGT patients. The results indicate that short-term treatment with ALA can improve insulin sensitivity and plasma lipid profile possibly through amelioration of oxidative stress and chronic inflammatory reaction in obese patients with IGT. PMID- 21593804 TI - Work stress, obesity and the risk of type 2 diabetes: gender-specific bidirectional effect in the Whitehall II study. AB - Psychosocial work stress has been linked to higher risk of type 2 diabetes (T2DM), with the effect being consistently higher among women than men. Also, work stress has been linked to prospective weight gain among obese men but weight loss among lean men. Here, we aimed to examine the interaction between work stress and obesity in relation to T2DM risk in a gender-specific manner. We studied 5,568 white middle-aged men and women in the Whitehall II study, who were free from diabetes at analysis baseline (1993). After 1993, diabetes was ascertained at six consecutive phases by an oral glucose tolerance test supplemented by self-reports. Cox regression analysis was used to assess the association between job strain (high job demands/low job control) and 18-year incident T2DM stratifying by BMI (BMI <30 kg/m(2) vs. BMI >=30 kg/m(2)). Overall, work stress was associated with incident T2DM among women (hazard ratio (HR) 1.41: 95% confidence intervals: 1.02; 1.95) but not among men (HR 0.87: 95% confidence interval 0.69; 1.11) (P(INTERACTION) = 0.017). Among men, work stress was associated with a lower risk of T2DM in nonobese (HR 0.70: 0.53; 0.93) but not in obese individuals (P(INTERACTION) = 0.17). Among women, work stress was associated with higher risk of T2DM in the obese (HR 2.01: 1.06; 3.92) but not in the nonobese (P(INTERACTION) = 0.005). Gender and body weight status play a critical role in determining the direction of the association between psychosocial stress and T2DM. The potential effect-modifying role of gender and obesity should not be ignored by future studies looking at stress-disease associations. PMID- 21593805 TI - Clinical correlates of the weight bias internalization scale in a sample of obese adolescents seeking bariatric surgery. AB - The aim of this study was to evaluate psychometric properties and clinical correlates of the Weight Bias Internalization Scale (WBIS) in a sample of obese adolescents seeking bariatric surgery. Sixty five adolescents enrolled in a bariatric surgery program at a large, urban medical center completed psychiatric evaluations, self-report questionnaires including the WBIS and other measures of psychopathology and physical assessments. The WBIS had high internal consistency (Cronbach's alpha = 0.92). As in previous research with adults, the one underlying factor structure was replicated and 10 of the original 11 items were retained. The scale had significant partial correlations with depression (r = 0.19), anxiety (r = 0.465), social, and behavioral problems (r = 0.364), quality of life (r = -0.480), and eating (r = 0.579), shape (r = 0.815), and weight concerns (r = 0.545), controlling for BMI. However, WBIS scores did not predict current or past psychiatric diagnosis or treatment or past suicidal ideation. Overall, the WBIS had excellent psychometric properties in a sample of obese treatment-seeking adolescents and correlated significantly with levels of psychopathology. These findings suggest that the WBIS could be a useful tool for healthcare providers to assess internalized weight bias among treatment-seeking obese youth. Assessment of internalized weight bias among this clinical population has the potential to identify adolescents who might benefit from information on coping with weight stigma, which in turn may augment weight loss efforts. PMID- 21593806 TI - Downregulation of hepatic glucose-6-phosphatase-alpha in patients with hepatic steatosis. AB - Glucose-6-phosphate transporter (G6PT) and microsomal glucose-6-phosphatase-alpha (G6Pase-alpha) perform the terminal step in glycogenolysis and gluconeogenesis. Deficiency of these proteins leads to glycogen storage diseases. Partial inhibition of G6Pase in rats results in increased hepatic triglyceride content and de novo lipogenesis leading to hepatic steatosis. Hepatic steatosis represents hepatic manifestation of the metabolic syndrome. We investigated molecular mechanisms that may explain the relationship between fatty liver and G6Pase-alpha in humans in detail. A total of 27 patients (11 men, 16 women) underwent liver biopsy. Histological diagnosis identified nonfatty liver in seven patients and nonalcoholic fatty liver in 20 patients. We quantified G6Pase-alpha and G6PT mRNA expression by real-time PCR. Anthropometric measurements and analysis of plasma lipids and liver enzymes were performed. Patients with fatty liver showed no significant differences in age, HOMA(IR) (homeostasis model assessment of insulin resistance), BMI, liver enzymes or waist-to-hip ratio compared to those with nonfatty liver, but total plasma cholesterol levels and liver fat content were higher in patients with fatty liver (P < 0.05). G6Pase alpha and G6PT mRNA expressions were significantly downregulated in fatty compared to histologically normal liver (P < 0.05). G6Pase-alpha and G6PT mRNA expressions correlated positively (R(2) = 0.406 P < 0.05). Both expressions did not correlate with age, BMI, aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma-glutamyl transferase, triglycerides or glucose levels. Our data suggest that expression of hepatic G6Pase-alpha and G6PT are closely interlinked. Downregulation of G6Pase-alpha in fatty liver might be associated with hepatic fat accumulation and pathogenesis of hepatic steatosis. PMID- 21593807 TI - Race, childhood insulin, childhood caloric intake, and class 3 obesity at age 24: 14-year prospective study of schoolgirls. AB - The prevalence of Class 3 obesity (BMI >=40 kg/m(2)) has more than doubled in the past 25 years. In a 14-year prospective study from age 10 to 24 of a biracial schoolgirl cohort (293 black, 256 white), we assessed childhood correlates of Class 3 BMI at age 24. Of 42 girls with Class 3 BMI at age 24, 36 (86%) were black. By logistic regression, significant explanatory variables of Class 3 BMI at age 24 included top decile waist circumference at age 11 (odds ratio (OR) 5.7, 95% confidence interval (CI) 2.3-13.9, P = 0.0002), age 10 BMI >= the Center for Disease Control (CDC) 2000 top 15% (OR 7.0, 95% CI 2.5-19.3, P = 0.0002), and a three-way interaction between race, childhood insulin, and average caloric intake from age 10 to age 19 (for each unit increase, OR 1.7 95% CI 1.3-2.2, P = 0.0003). Age 10 BMI, age 11 waist circumference, and interaction of race, childhood insulin, and childhood caloric intake predict Class 3 obesity in young adulthood, facilitating childhood identification of girls at high risk for developing Class 3 obesity. PMID- 21593808 TI - Trends in the prevalence of abdominal obesity and overweight in English adults (1993-2008). AB - The rising prevalence of generalized obesity is well documented, but less is known about trends in abdominal obesity. Levels of abdominal obesity and overweight are reported for adults in the Health Survey for England (HSE) by survey year and age for 1993-2008. HSE is a nationally representative cross sectional population survey using an interviewer-administered questionnaire and measurement of waist circumference (WC) by nurse, allowing calculation of abdominal overweight and obesity (>=94 cm and >=102 cm in men, and >=80 cm and >=88 cm in women). A total of 40,001 men and 46,397 women aged 18-67 provided data on WC in this period. Between 1993 and 2008 abdominal overweight rose from 44.9% to 62.3% in men, and from 46.6% to 66.8% in women, while abdominal obesity rose from 19.2% to 35.7% in men, and from 23.8% to 43.9% women. However, the rates of increase over time in England appear to be slowing down: curves with a less than linear increase each year were a better fit to the data than a linear trend. There was some variation across the age range in the time trend in abdominal obesity and overweight, in that the absolute increases over time were slightly less for younger adults. PMID- 21593809 TI - Selenium supplementation and exercise: effect on oxidant stress in overweight adults. AB - Both obesity and acute high-intensity exercise increase oxidant stress levels. This study investigates whether selenium (Se) supplementation could be a potential effective therapy to reduce obesity-associated oxidant stress and exercise-induced oxidant stress. Ten normal-weight (NW) (22.80 +/- 0.41 kg/m(2)) and ten overweight (OW) healthy subjects (28.00 +/- 0.81 kg/m(2)) were assessed during a randomized double-blind Se supplementation study (200 ug sodium selenite/day for 3 weeks) with a 3-week placebo control and inversion of treatment periods. Blood levels of lipid hydroperoxide (LH), superoxide dismutase (SOD), erythrocyte glutathione (GSH), and total antioxidant status (TAS), were measured at rest, pre-, and postexercise (30 min 70% VO(2) max before and after treatment (pretreatment (week 0 and 12) and post-treatment (week 3 or 15)). At rest, compared to placebo, Se supplementation had no significant effect on LH, SOD, GSH, and TAS levels. However, Se supplementation decreased LH levels in the OW group, immediately postexercise (-0.25 +/- 0.12 umol/l, P = 0.05) compared to placebo treatment. Postexercise, with or without Se supplementation, no changes in TAS, SOD, and GSH levels were observed in both the NW and OW group. This study has highlighted a potential benefit of Se in reducing LH levels postexercise in OW individuals. Given that oxidant stress is a predictor of coronary events, it is imperative to better understand oxidant stress-related responses to lifestyle factors (in particular "high-risk" population groups) and potential antioxidant therapy. PMID- 21593810 TI - Responses of gut microbiota to diet composition and weight loss in lean and obese mice. AB - Maintenance of a reduced body weight is accompanied by a decrease in energy expenditure beyond that accounted for by reduced body mass and composition, as well as by an increased drive to eat. These effects appear to be due--in part--to reductions in circulating leptin concentrations due to loss of body fat. Gut microbiota have been implicated in the regulation of body weight. The effects of weight loss on qualitative aspects of gut microbiota have been studied in humans and mice, but these studies have been confounded by concurrent changes in diet composition, which influence microbial community composition. We studied the impact of 20% weight loss on the microbiota of diet-induced obese (DIO: 60% calories fat) mice on a high-fat diet (HFD). Weight-reduced DIO (DIO-WR) mice had the same body weight and composition as control (CON) ad-libitum (AL) fed mice being fed a control diet (10% calories fat), allowing a direct comparison of diet and weight-perturbation effects. Microbial community composition was assessed by pyrosequencing 16S rRNA genes derived from the ceca of sacrificed animals. There was a strong effect of diet composition on the diversity and composition of the microbiota. The relative abundance of specific members of the microbiota was correlated with circulating leptin concentrations and gene expression levels of inflammation markers in subcutaneous white adipose tissue in all mice. Together, these results suggest that both host adiposity and diet composition impact microbiota composition, possibly through leptin-mediated regulation of mucus production and/or inflammatory processes that alter the gut habitat. PMID- 21593811 TI - Predictors of ectopic fat accumulation in liver and pancreas in obese men and women. AB - The aim of the present study was to determine the relationship between body fat distribution, adipocytokines, inflammatory markers, fat intake and ectopic fat content of liver and pancreas in obese men and women. A total of 12 lean subjects (mean age 47.25 +/- 14.88 years and mean BMI 22.85 +/- 2), 38 obese subjects (18 men and 20 women) with mean age 49.1 +/- 13.0 years and mean BMI 34.96 +/- 4.21 kg/m2 were studied. MEASUREMENTS: weight, height, BMI, waist circumference, as well as glucose, insulin, HOMA (homeostasis model assessment of insulin resistance), cholesterol, triglycerides, high-density lipoprotein cholesterol, high sensitivity C-reactive protein, daily energy intake, leptin, and adiponectin. Magnetic resonance was used to evaluate visceral, subcutaneous adipose tissue (SCAT) as well as liver and pancreas lipid content using in-phase and out-of-phase magnetic resonance imaging (MRI) sequence. Obese subjects had significantly higher weight, waist circumference, SCAT, deep SCAT, visceral adipose tissue (VAT), liver and pancreatic lipid content than lean subjects. Obese women had significantly lower VAT, liver and pancreas lipid content regardless of same BMI. In multiple regression analyses, the variance of liver lipid content explained by gender and VAT was 46%. When HOMA was added into a multiple regression, a small increase in the proportion of variance explained was observed. A 59.2% of the variance of pancreas lipid content was explained by gender and VAT. In conclusion, obese men show higher VAT and ectopic fat deposition in liver and pancreas than obese women despite same BMI. Independent of overall adiposity, insulin resistance, adiponectin and fat intake, VAT, measured with MRI, is the main predictor of ectopic fat deposition in both liver and pancreas. PMID- 21593813 TI - Characteristics of patients who die of necrotizing enterocolitis. AB - OBJECTIVE: Necrotizing enterocolitis (NEC) is associated with high morbidity and mortality among infants admitted for intensive care. The factors associated with mortality and catastrophic presentation remain poorly understood. Our objective was to describe the factors associated with mortality in infants with NEC and to quantify the degree to which catastrophic presentation contributes to mortality in infants with NEC. Catastrophic NEC was defined before data analysis as NEC that led to death within 7 days of diagnosis. STUDY DESIGN: We performed a retrospective review of the Pediatrix's Clinical Data Warehouse (1997 to 2009, n=560,227) to compare the demographic, therapeutic and outcome characteristics of infants who survived NEC vs those who died. Associations were tested by bivariate and multivariate analysis. RESULT: We compared the 5594 infants diagnosed with NEC and who were discharged home with 1505 infants diagnosed with NEC who died. In multivariate analysis, the factors associated with death (P<0.01 in analysis) were lower estimated gestational age, lower birth weight, treatment with assisted ventilation on the day of diagnosis of NEC, treatment with vasopressors at the time of diagnosis, and Black race. Patients who received only ampicillin and gentamicin on the day of diagnosis were less likely to die. Two-thirds of NEC deaths occurred quickly (<7 days from diagnosis), with a median time of death of one day from time of diagnosis. Infants who died within 7 days of diagnosis had a higher birth weight, more often were on vasopressors and high frequency ventilation at the time of diagnosis compared with patients who died at 7 or more days. Although mortality decreased with increasing gestational age, the proportion of deaths that occurred within 7 days was relatively consistent (65 to 75% of the patients who died) across all gestational ages. CONCLUSION: Mortality among infants who have NEC remains high and infants who die of NEC commonly (66%) die quickly. Most of the factors associated with mortality are related to immaturity, low birth weight and severity of illness. PMID- 21593812 TI - Increased adipose protein carbonylation in human obesity. AB - Insulin resistance is associated with obesity but mechanisms controlling this relationship in humans are not fully understood. Studies in animal models suggest a linkage between adipose reactive oxygen species (ROS) and insulin resistance. ROS oxidize cellular lipids to produce a variety of lipid hydroperoxides that in turn generate reactive lipid aldehydes that covalently modify cellular proteins in a process termed carbonylation. Mammalian cells defend against reactive lipid aldehydes and protein carbonylation by glutathionylation using glutathione-S transferase A4 (GSTA4) or carbonyl reduction/oxidation via reductases and/or dehydrogenases. Insulin resistance in mice is linked to ROS production and increased level of protein carbonylation, mitochondrial dysfunction, decreased insulin-stimulated glucose transport, and altered adipokine secretion. To assess protein carbonylation and insulin resistance in humans, eight healthy participants underwent subcutaneous fat biopsy from the periumbilical region for protein analysis and frequently sampled intravenous glucose tolerance testing to measure insulin sensitivity. Soluble proteins from adipose tissue were analyzed using two-dimensional gel electrophoresis and the major carbonylated proteins identified as the adipocyte and epithelial fatty acid-binding proteins. The level of protein carbonylation was directly correlated with adiposity and serum free fatty acids (FFAs). These results suggest that in human obesity oxidative stress is linked to protein carbonylation and such events may contribute to the development of insulin resistance. PMID- 21593816 TI - There's a time to be critical. PMID- 21593815 TI - Getting personal. PMID- 21593814 TI - Outcomes of preterm infants <29 weeks gestation over 10-year period in Canada: a cause for concern? AB - OBJECTIVE: To compare risk-adjusted changes in outcomes of preterm infants <29 weeks gestation born in 1996 to 1997 with those born in 2006 to 2007. STUDY DESIGN: Observational retrospective comparison of data from 15 units that participated in the Canadian Neonatal Network during 1996 to 1997 and 2006 to 2007 was performed. Rates of mortality and common neonatal morbidities were compared after adjustment for confounders. RESULT: Data on 1897 infants in 1996 to 1997 and 1866 infants in 2006 to 2007 were analyzed. A higher proportion of patients in the later cohort received antenatal steroids and had lower acuity of illness on admission. Unadjusted analyses revealed reduction in mortality (unadjusted odds ratio (UAOR): 0.83, 95% confidence interval (CI): 0.63, 0.98), severe retinopathy (UAOR: 0.68, 95% CI: 0.50 to 0.92), but increase in bronchopulmonary dysplasia (UAOR: 1.61, 95% CI: 1.39 to 1.86) and patent ductus arteriosus (UAOR: 1.22, 95% CI: 1.07 to 1.39). Adjusted analyses revealed increases in the later cohort for bronchopulmonary dysplasia (adjusted odds ratio (AOR): 1.88, 95% CI: 1.60 to 2.20) and severe neurological injury (AOR: 1.49, 95% CI: 1.22 to 1.80). However, the ascertainment methods for neurological findings and ductus arteriosus differed between the two time periods. CONCLUSION: Improvements in prenatal care has resulted in improvement in the quality of care, as reflected by reduced severity of illness and mortality. However, after adjustment of prenatal factors, no improvement in any of the outcomes was observed and on the contrary bronchopulmonary dysplasia increased. There is need for identification and application of postnatal strategies to improve outcomes of extreme preterm infants. PMID- 21593817 TI - The human epoch. PMID- 21593818 TI - Add coastal vegetation to the climate critical list. PMID- 21593830 TI - Major reform for climate body. PMID- 21593832 TI - Japan rethinks its energy policy. PMID- 21593831 TI - Shuttle's end spells change at NASA. PMID- 21593833 TI - 'Soap opera' sours cancer chief hunt. PMID- 21593835 TI - Battle of Yucca Mountain rages on. PMID- 21593834 TI - Geneticists bid to build a better bee. PMID- 21593836 TI - Energy: America's top climate cop. PMID- 21593837 TI - Stem cells: The growing pains of pluripotency. PMID- 21593839 TI - Research beyond the recession. PMID- 21593838 TI - Nuclear winter is a real and present danger. PMID- 21593845 TI - Guidelines for HIV in court cases. PMID- 21593846 TI - PhDs: what's left if science abdicates? PMID- 21593847 TI - Crop failure signals biodiversity crisis. PMID- 21593848 TI - PhDs: Israel also trains plenty. PMID- 21593849 TI - China must reduce fertilizer use too. PMID- 21593850 TI - Noisy oil exploration disrupts marine life. PMID- 21593851 TI - Fund experiments on atmospheric hazards. PMID- 21593852 TI - Data archiving is a good investment. PMID- 21593853 TI - Address education inequality in India. PMID- 21593854 TI - William Nunn Lipscomb Jr (1919-2011). PMID- 21593855 TI - Biodiversity: Species loss revisited. PMID- 21593856 TI - Astronomy: Bound and unbound planets abound. PMID- 21593857 TI - Economics: A positive side of disaster. PMID- 21593858 TI - Earth science: A deep foundry. PMID- 21593859 TI - Epigenetics: Tet proteins in the limelight. PMID- 21593860 TI - Plant biology: Unveiling the Casparian strip. PMID- 21593861 TI - Cardiovascular biology. PMID- 21593862 TI - Molecular mechanisms and clinical applications of angiogenesis. AB - Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies. PMID- 21593863 TI - Lessons on the pathogenesis of aneurysm from heritable conditions. AB - Aortic aneurysm is common, accounting for 1-2% of all deaths in industrialized countries. Early theories of the causes of human aneurysm mostly focused on inherited or acquired defects in components of the extracellular matrix in the aorta. Although several mutations in the genes encoding extracellular matrix proteins have been recognized, more recent discoveries have shown important perturbations in cytokine signalling cascades and intracellular components of the smooth muscle contractile apparatus. The modelling of single-gene heritable aneurysm disorders in mice has shown unexpected involvement of the transforming growth factor-beta cytokine pathway in aortic aneurysm, highlighting the potential for new therapeutic strategies. PMID- 21593864 TI - Progress and challenges in translating the biology of atherosclerosis. AB - Atherosclerosis is a chronic disease of the arterial wall, and a leading cause of death and loss of productive life years worldwide. Research into the disease has led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke. Yet, despite these advances, we still lack definitive evidence to show that processes such as lipoprotein oxidation, inflammation and immunity have a crucial involvement in human atherosclerosis. Experimental atherosclerosis in animals furnishes an important research tool, but extrapolation to humans requires care. Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications. PMID- 21593865 TI - Heart regeneration. AB - Heart failure plagues industrialized nations, killing more people than any other disease. It usually results from a deficiency of specialized cardiac muscle cells known as cardiomyocytes, and a robust therapy to regenerate lost myocardium could help millions of patients every year. Heart regeneration is well documented in amphibia and fish and in developing mammals. After birth, however, human heart regeneration becomes limited to very slow cardiomyocyte replacement. Several experimental strategies to remuscularize the injured heart using adult stem cells and pluripotent stem cells, cellular reprogramming and tissue engineering are in progress. Although many challenges remain, these interventions may eventually lead to better approaches to treat or prevent heart failure. PMID- 21593866 TI - Global quantification of mammalian gene expression control. AB - Gene expression is a multistep process that involves the transcription, translation and turnover of messenger RNAs and proteins. Although it is one of the most fundamental processes of life, the entire cascade has never been quantified on a genome-wide scale. Here we simultaneously measured absolute mRNA and protein abundance and turnover by parallel metabolic pulse labelling for more than 5,000 genes in mammalian cells. Whereas mRNA and protein levels correlated better than previously thought, corresponding half-lives showed no correlation. Using a quantitative model we have obtained the first genome-scale prediction of synthesis rates of mRNAs and proteins. We find that the cellular abundance of proteins is predominantly controlled at the level of translation. Genes with similar combinations of mRNA and protein stability shared functional properties, indicating that half-lives evolved under energetic and dynamic constraints. Quantitative information about all stages of gene expression provides a rich resource and helps to provide a greater understanding of the underlying design principles. PMID- 21593867 TI - Unbound or distant planetary mass population detected by gravitational microlensing. AB - Since 1995, more than 500 exoplanets have been detected using different techniques, of which 12 were detected with gravitational microlensing. Most of these are gravitationally bound to their host stars. There is some evidence of free-floating planetary-mass objects in young star-forming regions, but these objects are limited to massive objects of 3 to 15 Jupiter masses with large uncertainties in photometric mass estimates and their abundance. Here, we report the discovery of a population of unbound or distant Jupiter-mass objects, which are almost twice (1.8(+1.7)(-0.8)) as common as main-sequence stars, based on two years of gravitational microlensing survey observations towards the Galactic Bulge. These planetary-mass objects have no host stars that can be detected within about ten astronomical units by gravitational microlensing. However, a comparison with constraints from direct imaging suggests that most of these planetary-mass objects are not bound to any host star. An abrupt change in the mass function at about one Jupiter mass favours the idea that their formation process is different from that of stars and brown dwarfs. They may have formed in proto-planetary disks and subsequently scattered into unbound or very distant orbits. PMID- 21593868 TI - Melting of the Earth's inner core. AB - The Earth's magnetic field is generated by a dynamo in the liquid iron core, which convects in response to cooling of the overlying rocky mantle. The core freezes from the innermost surface outward, growing the solid inner core and releasing light elements that drive compositional convection. Mantle convection extracts heat from the core at a rate that has enormous lateral variations. Here we use geodynamo simulations to show that these variations are transferred to the inner-core boundary and can be large enough to cause heat to flow into the inner core. If this were to occur in the Earth, it would cause localized melting. Melting releases heavy liquid that could form the variable-composition layer suggested by an anomaly in seismic velocity in the 150 kilometres immediately above the inner-core boundary. This provides a very simple explanation of the existence of this layer, which otherwise requires additional assumptions such as locking of the inner core to the mantle, translation from its geopotential centre or convection with temperature equal to the solidus but with composition varying from the outer to the inner core. The predominantly narrow downwellings associated with freezing and broad upwellings associated with melting mean that the area of melting could be quite large despite the average dominance of freezing necessary to keep the dynamo going. Localized melting and freezing also provides a strong mechanism for creating seismic anomalies in the inner core itself, much stronger than the effects of variations in heat flow so far considered. PMID- 21593869 TI - Eocene lizard from Germany reveals amphisbaenian origins. AB - Amphisbaenia is a speciose clade of fossorial lizards characterized by a snake like body and a strongly reinforced skull adapted for head-first burrowing. The evolutionary origins of amphisbaenians are controversial, with molecular data uniting them with lacertids, a clade of Old World terrestrial lizards, whereas morphology supports a grouping with snakes and other limbless squamates. Reports of fossil stem amphisbaenians have been falsified, and no fossils have previously tested these competing phylogenetic hypotheses or shed light on ancestral amphisbaenian ecology. Here we report the discovery of a new lacertid-like lizard from the Eocene Messel locality of Germany that provides the first morphological evidence for lacertid-amphisbaenian monophyly on the basis of a reinforced, akinetic skull roof and braincase, supporting the view that body elongation and limblessness in amphisbaenians and snakes evolved independently. Morphometric analysis of body shape and ecology in squamates indicates that the postcranial anatomy of the new taxon is most consistent with opportunistically burrowing habits, which in combination with cranial reinforcement indicates that head-first burrowing evolved before body elongation and may have been a crucial first step in the evolution of amphisbaenian fossoriality. PMID- 21593870 TI - Species-area relationships always overestimate extinction rates from habitat loss. AB - Extinction from habitat loss is the signature conservation problem of the twenty first century. Despite its importance, estimating extinction rates is still highly uncertain because no proven direct methods or reliable data exist for verifying extinctions. The most widely used indirect method is to estimate extinction rates by reversing the species-area accumulation curve, extrapolating backwards to smaller areas to calculate expected species loss. Estimates of extinction rates based on this method are almost always much higher than those actually observed. This discrepancy gave rise to the concept of an 'extinction debt', referring to species 'committed to extinction' owing to habitat loss and reduced population size but not yet extinct during a non-equilibrium period. Here we show that the extinction debt as currently defined is largely a sampling artefact due to an unrecognized difference between the underlying sampling problems when constructing a species-area relationship (SAR) and when extrapolating species extinction from habitat loss. The key mathematical result is that the area required to remove the last individual of a species (extinction) is larger, almost always much larger, than the sample area needed to encounter the first individual of a species, irrespective of species distribution and spatial scale. We illustrate these results with data from a global network of large, mapped forest plots and ranges of passerine bird species in the continental USA; and we show that overestimation can be greater than 160%. Although we conclude that extinctions caused by habitat loss require greater loss of habitat than previously thought, our results must not lead to complacency about extinction due to habitat loss, which is a real and growing threat. PMID- 21593871 TI - A novel protein family mediates Casparian strip formation in the endodermis. AB - Polarized epithelia are fundamental to multicellular life. In animal epithelia, conserved junctional complexes establish membrane diffusion barriers, cellular adherence and sealing of the extracellular space. Plant cellular barriers are of independent evolutionary origin. The root endodermis strongly resembles a polarized epithelium and functions in nutrient uptake and stress resistance. Its defining features are the Casparian strips, belts of specialized cell wall material that generate an extracellular diffusion barrier. The mechanisms localizing Casparian strips are unknown. Here we identify and characterize a family of transmembrane proteins of previously unknown function. These 'CASPs' (Casparian strip membrane domain proteins) specifically mark a membrane domain that predicts the formation of Casparian strips. CASP1 displays numerous features required for a constituent of a plant junctional complex: it forms complexes with other CASPs; it becomes immobile upon localization; and it sediments like a large polymer. CASP double mutants display disorganized Casparian strips, demonstrating a role for CASPs in structuring and localizing this cell wall modification. To our knowledge, CASPs are the first molecular factors that are shown to establish a plasma membrane and extracellular diffusion barrier in plants, and represent a novel way of epithelial barrier formation in eukaryotes. PMID- 21593873 TI - Synthetic genomes: The next step for the synthetic genome. PMID- 21593875 TI - Minimization of the temperature coefficient of resonance frequency shift in the coherent population trapping clock. AB - We studied the relationship between the frequency shift of coherent population trapping resonance and the cell temperature of (85)Rb. Results show that the temperature coefficient of the frequency shift can be reduced by buffer gas pressure adjustment and light shift optimization. When the contribution of buffer gas collision to temperature coefficient of frequency shift is less than 0.3 Hz/K, the contribution of light shift to the temperature coefficient of frequency shift becomes obvious. Under this cancelling effect, we can reduce the rate of total frequency shift to near zero. PMID- 21593876 TI - Efficient and wideband horn nanoantenna. AB - In this Letter, we present the design of a horn nanoantenna working at near-IR frequencies. The proposed layout consists of an Ag-air-Ag nanotransmission line terminated in a tapered horn. The antenna design is validated through proper full wave numerical simulations, taking into account actual dispersion and losses of the involved materials. The numerical results show that the designed nanohorn is matched over a broad range of frequencies (more than 50% of fractional bandwidth) and radiates efficiently in the same frequency band (the realized gain is greater than 10 dBi). Such promising results may find application in different technical and scientific fields, ranging from smart lighting to optical wireless communications. PMID- 21593872 TI - BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition. AB - Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia initiating subclones. PMID- 21593877 TI - Lateral shearing interferometry of high-harmonic wavefronts. AB - We present a technique for frequency-resolved wavefront characterization of high harmonics based on lateral shearing interferometry. Tilted replicas of the driving laser pulse are produced by a Mach-Zehnder interferometer, producing separate focii in the target. The interference of the resulting harmonics on a flat-field extreme ultraviolet spectrometer yields the spatial phase derivative. A comprehensive set of spatial profiles, resolved by harmonic order, validate the technique and reveal the interplay of single-atom and macroscopic effects. PMID- 21593878 TI - High quality factor in a two-dimensional photonic crystal cavity on silicon-on insulator. AB - We propose a design for high quality factor two-dimensional (2D) photonic crystal cavities on silicon-on-insulator (SOI). A quality factor of up to 1.2*10(7) with a modal volume of 2.35(lambda/n)(3) is simulated. A very high quality factor of 200,000 is experimentally demonstrated for a 2D cavity fabricated on SOI. PMID- 21593879 TI - Humidity sensor based on a single-mode hetero-core fiber structure. AB - Using a small-core single-mode fiber (SCSMF), a novel relative humidity (RH) sensor based on an SMF28-SCSMF-SMF28 fiber structure was proposed in this paper. By depositing a humidity sensitive material, such as poly (ethylene oxide) (PEO) on the bare SCSMF fiber, the proposed structure can act as an RH sensor with high sensitivity. Experiments demonstrated that the proposed RH sensor with PEO coating can achieve a sensitivity of 430 nm per relative humidity unit (RHU) in the RH range from 80% to 83% RH and a sensitivity of 50 nm per RHU in the RH range from 83% to 95% RH. PMID- 21593880 TI - Generation of a vectorial Mathieu-like hollow beam with a periodically rotated polarization property. AB - We propose a promising and practical scheme to generate a vectorial Mathieu-like hollow beam (vMHB) by using an axicon optical system including a dual-mode elliptic hollow fiber (EHF), and calculate the intensity and polarization distributions of the beam and its fractional orbital angular momentum (OAM). We also fit its intensity profile and obtain suitable theoretical expressions to describe three-dimensional (3D) propagation characteristics of such a Mathieu like hollow beam. Our study shows that the generated beam is a vMHB within the propagation distance 1.2-2.2 m, which has an unchanged (diffraction-free) intensity profile and periodically rotated polarization properties as well as an unchanged fractional OAM within 1.2-2.2 m. PMID- 21593881 TI - Coherent quasi-cw 153 nm light source at 33 MHz repetition rate. AB - We present a quasi-cw laser in a vacuum ultraviolet region at megahertz repetition rate. The narrowband pulses generated from an ytterbium-fiber laser system at 33 MHz repetition rate at the central wavelength of 1074 nm are frequency-converted by successive stages of LiB(3)O(5) crystals and KBe(2)BO(3)F(2) crystals. The generated radiation at 153 nm has the shortest wavelength achieved through phase-matched frequency conversion processes in nonlinear optical crystals to our knowledge. PMID- 21593882 TI - Impact of pulse dynamics on timing jitter in mode-locked fiber lasers. AB - We investigate the high-frequency timing jitter spectral density of mode-locked fiber lasers in different mode-locked regimes. Quantum-noise-limited timing jitter spectra of mode-locked-regime-switchable Yb fiber lasers are measured up to the Nyquist frequency with sub-100-as resolution. The integrated rms timing jitter of soliton, stretched-pulse, and self-similar Yb fiber lasers is measured to be 1.8, 1.1, and 2.9 fs, respectively, when integrated from 10 kHz to 40 MHz. The distinct behavior of jitter spectral density related to pulse formation mechanisms is revealed experimentally for the first time. PMID- 21593883 TI - Stable single-photon interference in a 1 km fiber-optic Mach-Zehnder interferometer with continuous phase adjustment. AB - We experimentally demonstrate stable and user-adjustable single-photon interference in a 1 km long fiber-optic Mach-Zehnder interferometer, using an active phase control system with the feedback provided by a classical laser. We are able to continuously tune the single-photon phase difference between the interferometer arms using a phase modulator, which is synchronized with the gate window of the single-photon detectors. The phase control system employs a piezoelectric fiber stretcher to stabilize the phase drift in the interferometer. A single-photon net visibility of 0.97 is obtained, yielding future possibilities for experimental realizations of quantum repeaters in optical fibers and violation of Bell's inequalities using genuine energy-time entanglement. PMID- 21593884 TI - Tunable optofluidic aperture configured by a liquid-core/liquid-cladding structure. AB - Miniaturized and tunable optical components, such as the waveguide, lens, and prism, have been of great interest for lab-on-chip systems. This Letter reports an optofluidic aperture stop formed by the liquid-core/liquid-cladding flow. The aperture size can be tuned accordingly by adjusting the flow rates. Manipulation of the aperture size allows control of the amount of light passing through the corresponding optical system as well as the angular aperture on the image side. This optofluidic aperture enables lab-on-chip optical systems to have a greater flexibility and more functionalities. PMID- 21593885 TI - Tunable continuous-wave laser at quasi-three-level with a disordered Nd:LGS crystal. AB - A diode-pumped tunable CW Nd(3+):LGS laser at quasi-three-level has been demonstrated. The output power up to 403 mW at the central wavelength of 904 nm was obtained, corresponding to a slope efficiency of 29.7%. Taking advantage of the broad emission spectrum of the disordered crystal Nd:LGS, we tuned the laser wavelength within the spectral range of 899.8 to 906.6 nm with an etalon inserted into the V-type cavity. To the best of our knowledge, it is the first time to obtain a tunable laser based on the (4)F(3/2)-(4)I(9/2) transition of Nd(3+) doped crystals. PMID- 21593886 TI - Single resonance monolithic Fabry-Perot filters formed by volume Bragg gratings and multilayer dielectric mirrors. AB - A new class of Fabry-Perot filters produced by a multilayer dielectric mirror deposited on top of a reflecting volume Bragg grating is described. The first fabricated prototype for the 852 nm region demonstrates a 30 pm bandwidth, 90+% transmission at resonance, and a good agreement with theoretical simulation. PMID- 21593887 TI - Laser-induced fluorescence detection of hydroxyl (OH) radical by femtosecond excitation. AB - The development of a laser-induced fluorescence detection scheme for probing combustion-relevant species using a high-repetition-rate ultrafast laser is described. A femtosecond laser system with a 1 kHz repetition rate is used to induce fluorescence, following two-photon excitation (TPE), from hydroxyl (OH) radicals that are present in premixed laminar flames. The experimental TPE and one-photon fluorescence spectra resulting from broadband excitation into the (0,0) band of the OH A(2)?(+)-X(2)Pi system are compared to simulated spectra. Additionally, the effects of non-transform-limited femtosecond pulses on TPE efficiency is investigated. PMID- 21593888 TI - Improved ultraviolet photorefractive properties of vanadium-doped lithium niobate crystals. AB - A series of vanadium-doped lithium niobate (LN:V) crystals has been grown and their photorefractive properties were investigated. For 0.1 mol. % V-doped LiNbO(3), a fast photorefractive response of 160 ms was obtained with a 351 nm laser and a total light intensity of 583 mW/cm(2). The measurements of the x-ray photoelectron spectrum and electron paramagnetic resonance show that V(3+), V(4+), and V(5+) ions exist in these LN:V crystals. V(3+) and V(4+) ions correspond to the 420 and 475 nm absorption peaks, respectively. The fast photorefractive response and high sensitivity indicate that LN:V is a suitable candidate for UV photorefractive applications. PMID- 21593889 TI - Broadband terahertz transmission within the air channel of thin-wall pipe. AB - We report broadband transmissions of terahertz radiations through the air channel of thin-wall pipe. The impacts of the wall thickness and of the refractive index of the material on the transmission window bandwidth are investigated. An extension of the bandwidth by at least 5.5 times is reported with a commercial drinking straw. The salient properties of the antiresonant reflecting guiding mechanism are studied with the terahertz time domain spectroscopy method, including the reduction of the attenuation coefficient of the propagated field by 60 times the material absorption coefficient. PMID- 21593890 TI - Picosecond mid-infrared optical parametric amplifier based on the wide-bandgap GaS(0.4)Se(0.6) pumped by a Nd:YAG laser system at 1064 nm. AB - Operation of a GaS(0.4)Se(0.6) optical parametric amplifier is demonstrated with a 5-11 MUm idler tuning range, maximum energies of ~10 MUJ for sub-30-ps pulse durations, and performance ~3 times better than with pure GaSe. PMID- 21593891 TI - Slow light on a printed circuit board. AB - Slow-light effects induced by stimulated Raman scattering in polymer waveguides on a printed circuit board are shown to enable a widely tunable delay of broadband optical signals, suggesting an advantageous platform for optical information processing and ultrafast optical waveform transformation. PMID- 21593892 TI - Field-resolved characterization of femtosecond electromagnetic pulses with 400 THz bandwidth. AB - We propose and demonstrate an ultrabroadband concept to characterize amplitude and phase changes of femtosecond pulses. The radiation is superimposed with the first subharmonic spectral components from the same laser source. This effective omega/2omega pulse pair induces a coherently controlled charge current in a time integrating semiconductor detector. An interferometric variation of the time delay between the harmonically related components then reveals the electric field of the 2omega part. This method is realized with the second harmonic of a compact Er:fiber source centered at 390 THz and a GaAs-based detector. Most strikingly, it is sensitive to ~pi/20 phase changes and can be utilized to analyze femtojoule pulses. PMID- 21593893 TI - Polarization dependence of quantum-confined Stark effect in Ge/SiGe quantum well planar waveguides. AB - We report room-temperature quantum-confined Stark effect in Ge/SiGe multiple quantum wells (MQWs) with light propagating parallel to the plane of the Ge/SiGe MQWs for applications in integrated photonics. Planar waveguides embedded in a p i-n diode are fabricated in order to investigate the absorption spectra at different reverse bias voltages from optical transmission measurements for both TE and TM polarizations. Polarization dependence of the absorption spectra of the Ge/SiGe MQWs is clearly observed. The planar waveguides exhibit a high extinction ratio and low insertion loss over a wide spectral range for TE polarization. PMID- 21593894 TI - Single polarization transmission in pedestal-supported silicon waveguides. AB - In this Letter, properties of a pedestal-supported silicon waveguide are investigated, showing that it supports single polarization transmission. The pedestal is fabricated easily through a wet-etching process on strip waveguides. Theoretical analysis shows that this property is due to the leakage of quasi-TM mode when the pedestal width is small. A polarization extinction ratio larger than 20 dB at 1550 nm is measured in the pedestal waveguide sample, demonstrating single polarization transmission property experimentally. Thanks to its large single polarization transmission bandwidth, robustness in fabrication tolerance, and simple fabrication process, pedestal waveguides will have potential applications as simple silicon-integrated polarizers. PMID- 21593895 TI - Phase-matching properties and refined Sellmeier equations of the new nonlinear infrared crystal CdSiP2. AB - We directly measured the second harmonic generation and difference frequency generation phase-matching directions of the nonlinear crystal CdSiP(2) until 9.5 MUm using the sphere method. The simultaneous fit of the experimental angular data allowed the Sellmeier equations of the ordinary and extraordinary principal refractive indices to be refined over the entire transparency range of the crystal. PMID- 21593896 TI - Simple method to measure the visual axis of the human eye. AB - We propose a simple method to measure the angle "alpha" that the visual axis (VA) makes with the optical axis of the human eye. In this method, we capture the images of the pupil from three different angles, one along the VA and the other two along angles that are symmetrical with respect to the VA. These views of the pupil are captured simultaneously by a camera in a single photograph using a pair of plane mirrors. Assuming a model eye and with the help of finite ray tracing, we compute the value of alpha from the measured diameters of the three images of the pupil. Having a simple means to measure the value of alpha can be useful for optical modeling and analysis of the human eye. Measurement of the VA may also be useful in monitoring progressive myopia. PMID- 21593897 TI - Pressure-sensitive blackbody point radiation induced by infrared diode laser irradiation. AB - Ultrabroadband radiation from Yb(2)O(3) at ambient and low air pressures was investigated under the excitation of a 980 nm diode laser. The radiation was confirmed to be blackbody radiation, and it is sensitive to environmental air pressure in the way that the integrated radiation intensity decreases linearly with increasing air pressure. An ideal gas model may be employed to interpret the linear dependence. The pressure-sensitive radiation characteristic provides a potential method for noncontact measurement of air pressure with high accuracy. PMID- 21593898 TI - Enhanced efficiency of the second harmonic inhomogeneous component in an opaque cavity. AB - In this Letter, we experimentally demonstrate the enhancement of the inhomogeneous second harmonic conversion in the opaque region of a GaAs cavity with efficiencies of the order of 0.1% at 612 nm, using 3 ps pump pulses having peak intensities of the order of 10 MW/cm(2). We show that the conversion efficiency of the inhomogeneous, phase-locked second harmonic component is a quadratic function of the cavity factor Q. PMID- 21593899 TI - Dielectric shielded nanoscale patch laser resonators. AB - Dielectric shielded nanoscale patch laser resonators are introduced. Low-index dielectric shield layers surrounding a high-index core are shown to significantly reduce both metal and radiation losses. Structures suitable for both optical and electrical pumping and smaller than the vacuum wavelength in all three dimensions are shown to have a low enough threshold gain to lase at room temperature. Shifting the gain medium core provides control over the radiation pattern of the resonator and enables coupling of the laser light into a waveguide, opening opportunities for chipscale integration. PMID- 21593900 TI - Enhanced mid-infrared emissions of Er3+ at 2.7 MUm via Nd3+ sensitization in chalcohalide glass. AB - Nd(3+) sensitized Er(3+):(4)I(13/2) mid-IR emissions around 2.7 MUm were investigated in the transparent Ga(2)S(3)-GeS(2)-CsCl chalcohalide glasses for the first time. Remarkably, it is found that Nd(3+) greatly enhances Er(3+) 2.7 MUm emission by a maximal 20 times, and depopulates the lower level of Er(3+):(4)I(13/2) for population inversion. Based on Judd-Ofelt theory, the 2.7 MUm emission cross section is calculated (as high as 0.66*10(-20) cm(2)) and the gain property of the Er(3+):(4)I(11/2)->(4)I(13/2) transition is discussed. Hopefully, the materials studied here may find potential applications in the fields of fiber amplifiers and mid-IR lasers. PMID- 21593901 TI - Point and planar ultraviolet excitation/detection of hydroxyl-radical laser induced fluorescence through long optical fibers. AB - We demonstrate an all-fiber-coupled, UV, laser-induced-fluorescence (LIF) detection system of the hydroxyl radical (OH) in flames. The nanosecond-pulsed excitation of the (1,0) band of the OH A(2)?(+)-X(2)Pi system at ~283 nm is followed by fluorescence detection from the (0,0) and (1,1) bands around 310 nm. The excitation-laser beam is delivered through a 400 MUm core UV-grade optical fiber of up to 10 m in length, and the fluorescence signal collected is transmitted through a 1.5 mm core 3 m long fiber onto the remote detector. Single laser-shot planar LIF (PLIF) imaging of OH in flames is also demonstrated using fiber-based excitation. The effects of delivering intense UV beams through long optical fibers are investigated, and the system improvements for an all-fiber coupled OH-PLIF imaging system are discussed. Development of such fiber-based diagnostics and imaging systems constitutes a major step in transitioning laser diagnostic tools from research laboratories to reacting flow facilities of practical interest. PMID- 21593902 TI - High response organic deep ultraviolet photodetector with PEDOT:PSS anode. AB - We have fabricated an organic deep ultraviolet photodetector (PD) using PEDOT:PSS (PH 1000) as a transparent anode. NPB and PBD were employed as electron donor and acceptor, respectively. The PD exhibits a dark current of 0.0829 MUA/cm(2) and a photocurrent of 85.3 MUA/cm(2) at -12 V under 280 nm light illumination with an intensity of 0.488 mW/cm(2). A high response at 248-370 nm with its peak of 0.18 A/W at 280 nm and a detectivity of 1.1*10(12) cm Hz(1/2) W(-1) were achieved. The more detailed mechanism of harvesting high performance and the dependence of photocurrent density on illumination intensity are also discussed. PMID- 21593903 TI - Noncritically phase-matched fourth harmonic generation of Nd:glass lasers in partially deuterated KDP crystals. AB - Noncritically phase-matched (NCPM) fourth harmonic generation (FHG) of Nd:glass laser radiation in partially deuterated dihydrogen phosphate (KD*P) crystals has been demonstrated. At an Nd:glass laser wavelength of 1053.0 nm, NCPM FHG is achieved in 70% deuterated KD*P at a crystal temperature of 18.5+/-0.1 degrees C. Tuning the fundamental laser wavelength from 1052.9 to 1053.2 nm, FHG in KD*P is NCPM by changing the crystal temperature from 17.9 degrees C to 20.5 degrees C. When driven with 2.4 J of second harmonic radiation in a 3 ns flat-top pulse, corresponding to 1 GW/cm(2) 2omega drive intensity, 1.9 J of fourth harmonic radiation was generated in a 6 mm long KD*P crystal, yielding a second to fourth harmonic energy conversion efficiency of 79%. PMID- 21593904 TI - Ultrafast reciprocal space investigation of cavity-waveguide coupling. AB - Local information on the coupling mechanism between the photonic crystal nanocavity and the feeding waveguide is crucial to enable further improvements of the performance of these systems. Although several investigations on such a coupling have already been performed, information on the local dynamic properties remains hidden. Here, we present a reciprocal space investigation of the dynamics of light side-coupled to a photonic crystal nanocavity. We find that the coupling is promoted by Bloch harmonics having greater transverse momentum. PMID- 21593905 TI - Temporal cleaning of a high-energy fiber-based ultrafast laser using cross polarized wave generation. AB - We report the use of cross-polarized wave generation to perform both pulse shortening and temporal cleaning of a high-energy ytterbium-doped fiber-based femtosecond laser system. The nonlinear processes allow both a highly efficient nonlinear conversion of 20% and a large compression ratio of 3.5, with inherently improved coherent and incoherent contrasts. This results in the generation of 37 MUJ, 115 fs pulses at a repetition rate of 100 kHz with high temporal quality. PMID- 21593906 TI - High-sensitivity compact ultrasonic detector based on a pi-phase-shifted fiber Bragg grating. AB - A highly sensitive compact hydrophone, based on a pi-phase-shifted fiber Bragg grating, has been developed for the measurement of wideband ultrasonic fields. The grating exhibits a sharp resonance, whose centroid wavelength is pressure sensitive. The resonance is monitored by a continuous-wave (CW) laser to measure ultrasound-induced pressure variations within the grating. In contrast to standard fiber sensors, the high finesse of the resonance--which is the reason for the sensor's high sensitivity--is not associated with a long propagation length. Light localization around the phase shift reduces the effective size of the sensor below that of the grating and is scaled inversely with the resonance spectral width. In our system, an effective sensor length of 270 MUm, pressure sensitivity of 440 Pa, and effective bandwidth of 10 MHz were achieved. This performance makes our design attractive for medical imaging applications, such as optoacoustic tomography, in which compact, sensitive, and wideband acoustic detectors are required. PMID- 21593908 TI - Fiber laser with combined feedback of core and cladding modes assisted by an intracavity long-period grating. AB - We present a fiber laser made in a single piece of conventional doped-core fiber that operates by combined feedback of the fundamental core mode LP((0,1)) and the high-order cladding mode LP((0,10)). The laser is an all-fiber structure that uses two fiber Bragg gratings and a long-period grating to select the modes circulating in the cavity; the laser emits at the coupling wavelength between the core mode LP((0,1)) and the counterpropagating cladding mode LP((0,10)) in the Bragg gratings. This work demonstrates the feasibility of high-order mode fiber lasers assisted by long-period gratings. PMID- 21593907 TI - High-power direct green laser oscillation of 598 mW in Pr(3+)-doped waterproof fluoroaluminate glass fiber excited by two-polarization-combined GaN laser diodes. AB - We demonstrated a high-power and highly efficient Pr-doped waterproof fluoride glass fiber laser at 522.2 nm excited by two-polarization-combined GaN laser diodes and achieved a subwatt output power of 598 mW and slope efficiency of 43.0%. This system will enable us to make a vivid laser display, a photocoagulation laser for eye surgery, a color confocal scanning laser microscope, and an effective laser for material processing. Direct visible ultrashort pulse generation is also expected. PMID- 21593909 TI - Observation of abruptly autofocusing waves. AB - We report on the experimental observation of abruptly autofocusing waves. This interesting family of wave packets has been realized by using a radially symmetric Airy intensity distribution. As demonstrated in our experiments, these waves can exhibit unusual features, such as the ability to autofocus by following a parabolic trajectory toward their focus. PMID- 21593910 TI - Terahertz-wave parametric oscillator with a misalignment-resistant tuning cavity. AB - We demonstrate a terahertz-wave parametric oscillator (TPO) with a corner-cube resonator consisting of a corner-cube prism (CCP) and a flat mirror. By using the cavity configuration proposed in this Letter, the generation of tunable monochromatic terahertz (THz) waves can be achieved just by rotating the flat mirror instead of rotating the TPO cavity relative to the pump beam. The THz-wave output intensity and pulse width can be controlled periodically by rotating the CCP around the cavity axis. The TPO stability against cavity misalignment is significantly improved by at least 1 to 2 orders of magnitude compared with the conventional plane-parallel resonator configuration. PMID- 21593911 TI - Optical solitons and wave-particle duality. AB - We investigate the propagation of optical solitons interacting with linear defects in the medium. We show that solitons exhibit a wave-particle dualism versus power, i.e., depending on the relative size of soliton and defect, responsible for a soliton trajectory dependent on its waist. PMID- 21593912 TI - Proof-of-concept implementation of the massively parallel algorithm for simulation of dispersion-managed WDM optical fiber systems. AB - We perform a proof-of-concept implementation of the massively parallel algorithm [P. M. Lushnikov, Opt. Lett. 27, 939 (2002)] for simulation of dispersion-managed wavelength-division-multiplexed optical fiber systems. Linear scalability of the algorithm with the number of computer cores is demonstrated. Exact result on the accuracy of the implemented algorithm is found analytically and confirmed numerically as well as it is compared with the accuracy of the standard split step algorithm. PMID- 21593913 TI - Silicon photonic crystal filter with ultrawide passband characteristics. AB - We report on what is believed to be the first example of an ultrawide, bandpass filter, based on a high-contrast multicomponent one-dimensional Si photonic crystal (PC). The effect of the disappearance of a limited number of flat stopbands and their replacement with extended passbands is demonstrated over a wide IR range. The passbands obtained exhibit a high transmission of 92% to 96% and a substantial bandwidth of 1800 nm, which is spectrally flat within the passband. The multicomponent PC model suggested can be applied to the design of any micro- or nanostructured semiconductor or dielectric material for application across a wide spectral range. PMID- 21593914 TI - High-power air-cooled SiC-clad Nd:YVO4 slab lasers. AB - We demonstrate a diode-pumped, air-cooled, 100 W class SiC-clad Nd:YVO(4) active slab laser based on diffusion bonding of two SiC plates to a thin Nd:YVO(4) slab. We obtained 83 W of cw output power with a slope efficiency of 27% without water cooling. This demonstration initiates a novel (to the best of our knowledge) cooling design for efficient removal of waste heat generated from the diode edge pumped high-power slab laser at room temperature. PMID- 21593915 TI - High-resolution Fresnel zone plate fabrication by achromatic spatial frequency multiplication with extreme ultraviolet radiation. AB - We used an approach based on the self-imaging property of gratings to fabricate high-resolution Fresnel zone plates (FZPs). Under certain conditions, the illumination of a parent ZP with a wideband EUV beam produces a radially oscillating intensity distribution with double the spatial frequency of the ZP. This intensity distribution is observed in a certain distance range, given by the local zone width, the focal length of the ZP, and the spectral bandwidth of the illuminating beam. This phenomenon has been used to lithographically record daughter ZPs that have approximately half the zone width, thus twice the resolution, of the parent ZP. FZPs with zone widths as low as 30 nm have been fabricated in this way. Use of this technique in the extreme ultraviolet (EUV) region has the potential for high throughput production of FZPs and similar high resolution diffraction optics with variable spatial frequency for the EUV and x ray regions. PMID- 21593916 TI - Measuring orbital angular momentum superpositions of light by mode transformation. AB - We recently reported on a method for measuring orbital angular momentum (OAM) states of light based on the transformation of helically phased beams to tilted plane waves [Phys. Rev. Lett.105, 153601 (2010)]. Here we consider the performance of such a system for superpositions of OAM states by measuring the modal content of noninteger OAM states and beams produced by a Heaviside phase plate. PMID- 21593918 TI - Near-field measurement of amplitude and phase in silicon waveguides with liquid cladding. AB - Heterodyne near-field scanning optical microscopy (H-NSOM) has proven useful as a tool for characterization of both amplitude and phase of on-chip photonic devices in air, but it has previously been unable to characterize devices with a dielectric overcladding, which is commonly used in practice for such devices. Here we demonstrate H-NSOM of a silicon waveguide with a liquid cladding emulating the solid dielectric. This technique allows characterization of practical devices with realistic refractive index profiles. Fourier analysis is used to estimate the effective refractive index of the mode from the measured data, showing an index shift of 0.08 from air to water cladding, which is seen to correspond well to simulations. PMID- 21593919 TI - Linearly polarized fiber laser using a point-by-point Bragg grating in a single polarization photonic bandgap fiber. AB - We present a narrow-linewidth, linearly polarized neodymium-doped fiber laser that incorporates a point-by-point Bragg grating inscribed into the core of a single-polarization all-solid photonic bandgap fiber. The Bragg grating was written within a single-polarization wavelength band of the fiber; thus, the Bragg reflection was polarized. This all-fiber laser produced 7.2 W, linearly polarized output with 25 pm FWHM and 19.6 dB polarization extinction ratio. PMID- 21593917 TI - Circular polarization intrinsic optical signal recording of stimulus-evoked neural activity. AB - Linear polarization intrinsic optical signal (LP-IOS) measurement can provide sensitive detection of neural activities in stimulus-activated neural tissues. However, the LP-IOS magnitude and signal-to-noise ratio (SNR) are highly correlated with the nerve orientation relative to the polarization plane of the incident light. Because of the complexity of orientation dependency, LP-IOS optimization and outcome interpretation are time consuming and complicated. In this study, we demonstrate the feasibility of circular polarization intrinsic optical signal (CP-IOS) measurement. Our theoretical modeling and experimental investigation indicate that CP-IOS magnitude and SNR are independent from the nerve orientation. Therefore, CP-IOS promises a practical method for polarization IOS imaging of complex neural systems. PMID- 21593921 TI - Automated phase retrieval of a single-material object using a single out-of-focus image. AB - Phase retrieval is widely used in phase contrast microscopy. Here we present an autofocus algorithm that allows the phase of the exit wave function, from a single-material object, to be reconstructed at medium resolution from a single phase contrast image without any a priori knowledge of the imaging system or object. The algorithm is demonstrated on coherent out-of-focus electron micrographs of 30 nm latex sphere calibration standards, giving <10% RMS error over a large defocus range. PMID- 21593920 TI - Array of a dye-doped polymer-based microlaser with multiwavelength emission. AB - This Letter reports a convenient method of fabricating a polymer-based microlaser array. Laterally aligned plastic micropillars equipped with an optical resonator were fabricated by using a lithographic technique with an organic-dye-doped photopolymer, which operated as a laser element with a vertical cavity. Under optical pumping, very fine emission spectra showing a Fabry-Perot-type lasing oscillation were observed. Using this technique, integrated laser cavities with desired operation wavebands can be produced easily. PMID- 21593922 TI - Efficient Type II phase-matching second-harmonic generation in Ba:Yb:Nb:RbTiOPO4/RbTiOPO4 waveguides. AB - Efficient Type II phase-matching second-harmonic generation of a 1125 nm fundamental beam has been obtained using Ba:Yb:Nb:RbTiOPO(4)/RbTiOPO(4) waveguides grown by liquid phase epitaxy. The refractive indices of the epitaxial layer have been measured at different wavelengths, and the Sellmeier coefficients of the chromatic dispersion curves have been obtained. The phase-matching curve shows that the Ba(2+) doping in RbTiOPO(4) contributes to increase the phase matching range until 900 nm. The measured effective refractive indices of the propagation modes agree well with the theoretical calculations. PMID- 21593923 TI - Broadband absorption enhancement in randomly positioned silicon nanowire arrays for solar cell applications. AB - In this Letter, the optical properties of randomly positioned silicon nanowire arrays are studied. The result shows that position randomization with a filling ratio larger than 36% renders better absorptance over a broadband ranging from 300 to 1130 nm compared to regular structures. The ultimate efficiency of a 48% filling ratio position randomized nanowire structure is 13.4% higher compared to the optimized regularly arranged nanowire structure with the same thickness. The absorptance enhancement of random structures is attributed to lowered reflectance, more supported resonant modes, and broadening of existing resonance. PMID- 21593924 TI - Pulse shapes reconfigured on a pulse-to-pulse time scale by using an array of injection-locked VCSELs. AB - We demonstrate line-by-line pulse shaping of optical comb lines separated by 6.25 GHz. An array of injection-locked VCSELs independently modulate four optical comb lines at frequencies up to 3.125 GHz, updating the pulse shape on the time scale of the pulse period. PMID- 21593925 TI - Pre-engineered abruptly autofocusing beams. AB - We introduce a new family of (2+1)D light beams with pre-engineered abruptly autofocusing properties. These beams have a circularly symmetric input profile that develops outward of a dark disk and oscillates radially as a sublinear-chirp signal, creating a series of concentric intensity rings with gradually decreasing width. The light rays involved in this process form a caustic surface of revolution that bends toward the beam axis at an acceleration rate that is determined by the radial chirp itself. The collapse of the caustic on the axis leads to a large intensity buildup right before the intended focus. This ray optics interpretation provides valuable insight into the dynamics of abruptly autofocusing waves. PMID- 21593926 TI - High scotopic/photopic ratio white-light-emitting diodes integrated with semiconductor nanophosphors of colloidal quantum dots. AB - We propose and demonstrate single-chip white-light-emitting diodes (WLEDs) integrated with semiconductor nanophosphors of colloidal quantum dots for high scotopic/photopic (S/P) ratio. These color conversion WLEDs achieve S/P ratios over 3.00, which exceeds the current limit of 2.50 in common lighting technologies, while sustaining sufficient levels of color rendering index. PMID- 21593927 TI - Internal resonantly enhanced frequency doubling of continuous-wave fiber lasers. AB - In this Letter we describe a simple method for frequency doubling in high-power CW fiber lasers that offers the prospect of very high conversion efficiency and high power in the visible wavelength regime. Our approach is based on second harmonic generation in an enhancement resonator within the fiber laser cavity and does not require active cavity length stabilization. This technique has been applied to a cladding-pumped Yb-doped fiber laser to generate 19 W of linearly polarized CW green output at 540 nm, with excellent temporal stability for 90 W of absorbed diode pump power at 975 nm. The prospects for further improvement in performance with respect to conversion efficiency and output power are considered. PMID- 21593928 TI - Binary amplitude holograms made from dyed photoresist. AB - A method for fabricating binary amplitude holograms from a dyed photoresist is described. It is of particular interest for holograms that are used as null optics in the form metrology of aspheric surfaces and wavefronts. A pigment that strongly absorbs light near 633 nm was dissolved in a positive photoresist and the dyed resist was spun onto silica glass substrates. Stable resist layers were obtained that were essentially opaque at 633 nm with little effect on the transmittance of the resist in the UV. A Fresnel zone plate was fabricated from the dyed resist layer using contact lithography, and its performance was demonstrated at 633 nm. PMID- 21593929 TI - Optical amplification of Eu(TTA)3Phen solution-filled hollow optical fiber. AB - A liquid core optical fiber (LCOF) composed of hollow fiber and a solution of Eu(TTA)(3)Phen (TTA=2-thenoyltrifluoroacetone, Phen=1, 10-phenanthroline) in dimethyl sulfoxide (DMSO) has been fabricated, in which the concentration of Eu(TTA)(3)Phen in DMSO is 0.8 wt.%, the core diameter of the LCOF is 10 MUm, and the fiber length is 8.1 cm. By the end pumping with a diode-pumped solid-state laser at 355 nm, a small optical signal at 613 nm was amplified with a gain of 8.2 dB at a pump power of 203 mW. Based on this experimental result, a liquid core optical fiber amplifier can be realized by the LCOF, which has wide potential applications in many optical devices. PMID- 21593930 TI - Unidirectional optical transmission in dual-metal gratings in the absence of anisotropic and nonlinear materials. AB - We predict the unidirectional optical transmission in dual-metal grating structures composed of two gratings with different structures in the absence of anisotropy and nonlinearity. The zero-order unidirectional transmission is achieved. Based on the unique property and by modulating the structural parameters, the transmittance approaches to 0% and 60% in the two opposite directions, respectively. PMID- 21593931 TI - Threshold gain analysis in GaN-based photonic crystal surface emitting lasers. AB - We have analyzed threshold gains and lasing modes in GaN-based photonic crystal (PC) surface emitting lasers (PCSELs) by using the multiple scattering method (MSM) for triangular-lattice PC patterns. Moreover, GaN-based PCSELs with different boundary shapes have been fabricated and measured. The lasing mode at the Gamma band edge of GaN-based PCSELs can be identified by using the angled resolved spectroscopy and matched well to the results calculated by MSM. Threshold conditions in the GaN-based PCSELs with different boundary shapes are obtained by optical pumping and agree well with simulation results. PMID- 21593932 TI - Dark-field scanning in situ spectroscopy platform for broadband imaging of resected tissue. AB - A dark-field geometry spectral imaging system is presented to raster scan thick tissue samples in situ in 1.5 cm square sections, recovering full spectra from each 100 MUm diameter pixel. This spot size provides adequate resolution for wide field scanning, while also facilitating scatter imaging without requiring sophisticated light-tissue transport modeling. The system is demonstrated showing accurate estimation of localized scatter parameters and the potential to recover absorption-based contrast from broadband reflectance data measured from 480 nm up to 750 nm in tissue phantoms. Results obtained from xenograft pancreas tumors show the ability to quantitatively image changes in localized scatter response in this fast-imaging geometry. The polychromatic raster scan design allows the rapid scanning necessary for use in surgical/clinical applications where timely decisions are required about tissue pathology. PMID- 21593933 TI - Hollow-fiber compression of 6 mJ pulses from a continuous-wave diode-pumped single-stage Yb,Na:CaF2 chirped pulse amplifier. AB - Here, 200 fs 6 mJ pulses from a cw diode-pumped Yb,Na:CaF(2) amplifier are spectrally broadened in an Ar- or Ne-filled hollow-core fiber and recompressed to 20 fs (Ar) and 35 fs (Ne) using a prism pair. The results of spectral broadening and phase measurement are in excellent agreement with numerical modeling based on the generalized nonlinear Schrodinger equation. The longer laser wavelength of 1030 nm permits favorable energy scaling for the hollow-fiber technique compared to ultrafast amplifiers operating at 800 nm. PMID- 21593934 TI - Light focusing by slot Fabry-Perot photonic crystal nanoresonator on scanning tip. AB - We numerically investigate the propagation of light through the photonic crystal (PhC) waveguide on low refraction index material for near-field light focusing at the visible wavelength (635 nm) by incorporating a center air slot and Fabry Perot resonator on the scanning tip. Perturbations by water and substrate refraction index changes of the PhC are analyzed by the finite-difference time domain method to show minimal impact on light confinement and throughput. Such a total dielectric probe tip design has great potential to complement the current widely used metal-coated optical-fiber-based light confinement probe. PMID- 21593935 TI - Varifocal liquid-filled microlens operated by an electroactive polymer actuator. AB - We designed, fabricated, and characterized varifocal microlenses, whose focal length varies along with the deformation of a transparent elastomer membrane under hydraulic pressure tailored by electroactive polymer actuators. The microfluidic channel of the microlens was designed to be embedded between silicon and glass so that transient fluctuation of the optical fluid and elastomer membrane is effectively suppressed, and thus the microlens is optically stabilized in a reduced time. Multilayered poly(vinylidene fluoride trifluoroethylene-clorotrifluoroethylene) actuators were also developed and integrated onto the microfluidic chambers. We demonstrated that the developed microlenses are suitable for use in microimaging systems to make their foci tunable. PMID- 21593936 TI - High-power pulsed diode-pumped Er:ZBLAN fiber laser. AB - We report on the operation and performance of a gain-switched Er:ZBLAN fiber laser based on an active pulsed diode pump system. The produced laser pulses offer high peak powers while retaining the high average powers and efficiency of the cw regime. The measured pulse duration was about 300 ns and nearly independent of the pump repetition frequency. The maximum obtained 68 W of peak power is the highest reported, to our knowledge, for diode-pumped Er:ZBLAN fiber lasers, and the 2 W of average power at the repetition frequency of 100 kHz is 2 orders of magnitude higher than previously reported average power in a pulsed regime. The obtained slope efficiency was 34%. PMID- 21593938 TI - Terahertz spectroscopy studies on epitaxial vanadium dioxide thin films across the metal-insulator transition. AB - We present results on terahertz (THz) spectroscopy on epitaxial vanadium dioxide (VO(2)) films grown on sapphire across the metal-insulator transition. X-ray diffraction indicates the VO(2) film is highly oriented with the crystallographic relationship: (002)(film)//(0006)(sub) and [010](film)//[2 1 10](sub). THz studies measuring the change in transmission as a function of temperature demonstrate an 85% reduction in transmission as the thin film completes its phase transition to the conducting phase, which is much greater than the previous observation on polycrystalline films. This indicates the crucial role of microstructure and phase homogeneity in influencing THz properties. PMID- 21593939 TI - Plasma-assisted combustion of methane using a femtosecond laser. AB - We first research the effects of femtosecond-laser-induced plasma (FLIP) on a laminar premixed methane/oxygen/nitrogen flame speed with a wide range of equivalence ratios (0.8-2.0) at atmospheric pressure. It is experimentally found that the flame speed increases by 30.8% at equivalence ratio 1.33, and the effects of the FLIP on the flame speed are more remarkable when the methane is rich. The self-emission spectra from the flame and the plasma are studied, and the presence of the oxygen atom is likely to be a key factor in enhancing flame speed. PMID- 21593940 TI - Phase-matched nonlinear diffraction. AB - We report on a new (to our knowledge) configuration incorporating both birefringence and quasi-phase-matching, enabling efficient phase-matched nonlinear diffraction in one-dimensional periodically poled nonlinear crystals. We demonstrate the method experimentally, showing an efficient nonlinear diffraction to the first few orders in two types of crystals, MgO doped congruent lithium niobate and congruent lithium niobate, and characterize its efficiency dependence on the fundamental power, the propagation angle, and the crystal temperature. This configuration can increase efficiencies observed in nonlinear diffraction experiments, enables ferroelectric domain characterization by nonlinear microscopy, and can be used to determine the duty cycles of periodically poled nonlinear crystals. PMID- 21593941 TI - Rotating vortex solitons supported by localized gain. AB - We show that ringlike localized gain landscapes imprinted in focusing cubic (Kerr) nonlinear media with strong two-photon absorption support new types of stable higher-order vortex solitons containing multiple phase singularities nested inside a single core. The phase singularities are found to rotate around the center of the gain landscape, with the rotation period being determined by the strength of the gain and the nonlinear absorption. PMID- 21593942 TI - Detection of a semirough target in turbulent atmosphere by a partially coherent beam. AB - The inverse problem of the interaction of an isotropic Gaussian Schell-model beam with a semirough target in turbulent atmosphere is investigated. It is found that we can determine the target size and the transverse correlation width of the target by measuring the transverse beam widths and the transverse coherence widths of the beams at the source plane and the receiver plane. Our results are useful for remote sensing and bistatic LIDAR system. PMID- 21593943 TI - Mueller matrix differential decomposition. AB - We present a Mueller matrix decomposition based on the differential formulation of the Mueller calculus. The differential Mueller matrix is obtained from the macroscopic matrix through an eigenanalysis. It is subsequently resolved into the complete set of 16 differential matrices that correspond to the basic types of optical behavior for depolarizing anisotropic media. The method is successfully applied to the polarimetric analysis of several samples. The differential parameters enable one to perform an exhaustive characterization of anisotropy and depolarization. This decomposition is particularly appropriate for studying media in which several polarization effects take place simultaneously. PMID- 21593944 TI - Automatic focusing in digital holography and its application to stretched holograms. AB - The searching and recovering of the correct reconstruction distance in digital holography (DH) can be a cumbersome and subjective procedure. Here we report on an algorithm for automatically estimating the in-focus image and recovering the correct reconstruction distance for speckle holograms. We have tested the approach in determining the reconstruction distances of stretched digital holograms. Stretching a hologram with a variable elongation parameter makes it possible to change the in-focus distance of the reconstructed image. In this way, the proposed algorithm can be verified at different distances by dispensing the recording of different holograms. Experimental results are shown with the aim of demonstrating the usefulness of the proposed method, and a comparative analysis has been performed with respect to other existing algorithms developed for DH. PMID- 21593945 TI - Graphene saturable absorber mirror for ultra-fast-pulse solid-state laser. AB - High-quality graphene sheets with lateral size over 20 MUm have been obtained by bath sonicating after subjecting the wormlike graphite marginally to mixed oxidizer. To date, to our knowledge, they are the largest graphene sheets prepared by exfoliation in the liquid phase. A saturable absorber mirror was fabricated based on these sheets. We exploited it to realize mode-locking operation in a diode-pumped Nd:GdVO(4) laser. A pulse duration of 16 ps was produced with an average power of 360 mW and a highest pulse energy of 8.4 nJ for a graphene mode-locked laser. PMID- 21593949 TI - [The EMPHASIS-HF study]. PMID- 21593950 TI - [Diagnosis and treatment of anemia in heart failure patients]. AB - Anemia is a common comorbidity in patients with acute and chronic heart failure (HF) with preserved and reduced systolic function. It is recognized as a new therapeutic goal in HF since the reduction in hemoglobin levels is considered a significant independent predictive factor of mortality and hospitalization. At present, it is difficult to determine the real magnitude of the problem in terms of actual incidence and prevalence as no consistent definition of anemia associated with HF does exist, and a variety of hemoglobin thresholds have been used in clinical trials and epidemiological studies. The etiology of anemia is multifactorial with the main causes including renal failure, gastrointestinal bleeding and nutritional deficiency. Nevertheless, such criteria are not present in some patients, who show a peculiar type of anemia that may be classified as anemia of chronic diseases, likely due to the chronic inflammatory process of HF. No guidelines for the treatment of anemia in HF patients are available. Most of the previous studies in the literature are limited by small sample sizes. The very few randomized multicenter studies that evaluated the effects of erythropoiesis-stimulating agents associated with intravenous iron therapy did not provide the expected results. Indeed, despite an increase in hemoglobin levels, they did not show any improvement of NYHA functional class, nor of left ventricular ejection fraction. In addition, reasonable hemoglobin levels as a goal of therapy have not been established yet, in particular in relation to the side effects and the cardiovascular risk observed after the administration of erythropoiesis-stimulating agents in oncologic patients. Further studies are warranted to define the magnitude of the problem and establish appropriate therapeutic strategies. It is likely that more reliable data will be derived from an ongoing randomized, double-blind, multicenter study, the RED-HF (Reduction Event with Darbepoetin alfa in Heart Failure), which aims at evaluating morbidity and mortality in a cohort of 2600 HF patients with anemia treated with darbepoetin alfa. PMID- 21593951 TI - [Impact of anemia and its treatment in patients with acute coronary syndromes]. AB - Anemia has been reported in 15-30% of patients with acute coronary syndrome. This percentage is even higher during the in-hospital phase, when hemoglobin tends to reach a "nadir" value, and usually a larger number of anemic patients compared to admission are discharged from the hospital. Both retrospective evaluation of randomized clinical trials and data coming from prospective or retrospective observational studies have prompted out a direct relationship between anemia and adverse outcomes in acute coronary syndrome patients. Although anemia has the potential to worsen the myocardial ischemic insult in acute coronary syndromes, it is not yet clear whether it is responsible per se for a higher incidence of death and myocardial infarction or it behaves just like an additional risk factor. Blood transfusions may correct anemia but also accentuate rather than attenuate both short-term and long-term rates of major adverse cardiac events, suggesting the opportunity of a restrictive use of this therapy in patients with low levels of hemoglobin who are hemodynamically stable. PMID- 21593952 TI - [Left ventricular function in patients with chronic heart failure. Practical aspects on echocardiographic timing and structured reports in the out-of-hospital ultrasound laboratory]. AB - This review addresses some practical aspects of Doppler echocardiography and how to perform it in outpatients with heart failure, in an attempt to make the diagnostic protocols more effective and less expensive for the national healthcare system. This problem comes from the relevant percentage of redundant echocardiographic exams that are irrelevant for the appropriate clinical management. The most important echocardiographic indices to be used for making diagnosis of left ventricular systolic and/or diastolic dysfunction are also discussed. In order to warrant the best quality of the healthcare system, correct timing, performance and structured reports are encouraged even in out-of-hospital echocardiography laboratories, driven by solid scientific knowledge and international guidelines. PMID- 21593953 TI - [Non-steroidal anti-inflammatory drugs and risk of stroke in older patients: current controversies and research directions]. AB - Recent professional statements from established bodies, i.e. American Heart Association, European Medicines Agency, and Medicines and Healthcare products Regulatory Agency, have cautioned on the use of non-steroidal anti-inflammatory drugs (NSAIDs) given the potential increase in atherothrombotic risk associated with their long-term use. However, pharmacoepidemiological studies on the association between NSAID use and the risk of stroke, one of the leading causes of death, disability, and institutionalisation in old age, have shown contrasting results. Notably, very few such studies have addressed the risk in the older population, in particular patients >75-80 years, perhaps the biggest consumer group of these drugs. This article reviews the current evidence on the association between NSAIDs and risk of stroke in the older population. It also discusses the potential clinical, demographic, and pathophysiological factors potentially accounting for the discrepancies in the results of the pharmacoepidemiological studies and provides suggestions for future research directions. PMID- 21593954 TI - [The Valsalva maneuver: ancient semeiotics in aid of present technology?]. PMID- 21593956 TI - [Chest pain in the emergency department: benefits of a management model modified from the ANMCO-SIMEU recommendations]. AB - BACKGROUND: The evaluation of chest pain patients in the emergency department remains a costly and difficult challenge, even though a large proportion of them do not suffer from an acute coronary syndrome. We adopted a clinical decision model, modified from the ANMCO-SIMEU recommendations, and tested its clinical usefulness by assessing: a) the rate of unnecessary hospital admissions, b) the rate of inappropriate discharges based on coronary events (unstable angina, myocardial infarction, death) at 6 months. METHODS: Our population included 511 consecutive patients with chest pain for a period of 6 months. On the basis of the chest pain score and individual risk factors, 383 patients with normal ECG and negative troponin were classified into four categories according to the probability of acute coronary syndrome, resulting in different lengths of hospital stay and planning of further diagnostic tests. Stress testing was mandatory within 72 h if 22 risk factors and typical angina were observed. RESULTS: Inappropriate discharges and unnecessary admissions were 1% and 9.5%, respectively. The clinical decision model based on the four categories of probability was correctly applied in 83% of cases. One hundred patients were diagnosed with acute coronary syndrome. After discharge, 6 patients underwent stress testing with subsequent revascularization (mean 34 days later) without experiencing new cardiac events. One patient was readmitted with unstable angina before completing non-invasive diagnostic tests. None of 297 patients with atypical chest pain, discharged without additional testing, had adverse cardiac events. CONCLUSIONS: Our clinical decision model resulted in a low rate of inappropriate discharges with a low risk of adverse events and a standard rate of unnecessary admissions. Although clinical judgment remains of paramount importance, a clinical decision model and the risk stratification of patients with chest pain lead to an improvement of quality of care. PMID- 21593955 TI - [Networks of care for ST-elevation myocardial infarction in Italy. Results of the RETE IMA WEB survey]. AB - BACKGROUND: The organization of a regional system of care (RSC) for ST-elevation myocardial infarction (STEMI) is recommended by the Italian Federation of Cardiology (FIC) and international guidelines in order to increase the number of patients treated with primary coronary angioplasty and, more in general, with reperfusion therapy, speed up the diagnostic and therapeutic processes, and ultimately improve the outcome. METHODS: The "RETE IMA WEB" survey was launched in 2007 from the Italian Society of Invasive Cardiology (SICI-GISE) in collaboration with the FIC, with the aim of evaluating the current state of RSC for STEMI in Italy. The personnel of the 118 Emergency System participated in the survey. Data collection was made using different electronic forms with access limited by personal passwords. We assessed the organization of the RSC together with local resource availability, with specific attention to the distance from a Hub center. RESULTS: The survey ended in December 31, 2008. We censored 701 hospitals admitting STEMI patients, 157 (22.4%) with uninterrupted access (h24/7 days) to the catheterization laboratory (2.67 per million inhabitants). An operative network was present in 36/103 (35.9%) provinces, with important geographic variability. Among hospitals without a full-time primary angioplasty facility, only 46% was within a RSC. ECG was available in 72% of the national territory, telemedicine in 50%. Prehospital fibrinolysis was available in 16% of the country. Overall, 92.4% of the Italian population resides within 60 min of a Hub center. CONCLUSIONS: In 2008, despite an adequate framework, the RSC for STEMI in Italy was heterogeneous and still suboptimal. Healthcare administrators, scientific societies and all operators involved in the process of care for STEMI should make efforts to implement current guidelines. PMID- 21593957 TI - [The "clinical cost" of implantable cardioverter-defibrillators in the primary prevention of sudden cardiac death is underestimated]. PMID- 21593958 TI - [The "clinical cost" of implantable cardioverter-defibrillators in the primary prevention of sudden cardiac death should not restrict their use]. PMID- 21593959 TI - [Cardiomyopathy induced by frequent premature ventricular complexes originating from the right ventricular outflow tract: left ventricular systolic function recovery after transcatheter ablation]. AB - Left ventricular dysfunction due to frequent isolated premature ventricular complexes originating from the right ventricular outflow tract (RVOT) in patients without structural heart disease and in the absence of sustained ventricular tachycardia is a rare and poorly characterized entity. Successful identification and radiofrequency catheter ablation of the focal source of ventricular ectopy is the most effective treatment for these patients, leading to a complete normalization of ventricular dimensions and contractile function. In this article, we report two cases of left ventricular dysfunction resulting from frequent isolated premature ventricular complexes originating from the RVOT. After successful ablation of the ectopic focus, improvement of functional status and left ventricular function was observed in both patients, confirming the initial diagnostic hypothesis of a cardiomyopathy induced by repetitive ventricular ectopic beats from the RVOT. PMID- 21593960 TI - [Tako-tsubo syndrome in a young man with amyotrophic lateral sclerosis. A case report]. AB - A 40-year-old man with amyotrophic lateral sclerosis undergoing home non-invasive ventilation, with no risk factors for coronary artery disease, was admitted with bilateral lung infiltrates. Given the lack of a favorable clinical response, transfer to our department was scheduled. During ambulance transport the patient experienced chest discomfort. Upon arrival at our department, a diagnosis of tako tsubo syndrome was made. In this report, the clinical aspects are taken as a basis to highlight differences with common available findings, and an international registry is proposed to help piece together fractional information present in the literature. PMID- 21593961 TI - [Submitral left ventricular aneurysm: a rare disease in subsaharian African countries]. PMID- 21593962 TI - [Hospitals for intensive care]. PMID- 21593963 TI - Association between Age and Striatal Volume Stratified by CAG Repeat Length in Prodromal Huntington Disease. AB - BACKGROUND: Longer CAG repeat length is associated with faster clinical progression in Huntington disease, although the effect of higher repeat length on brain atrophy is not well documented. METHOD: Striatal volumes were obtained from MRI scans of 720 individuals with prodromal Huntington disease. Striatal volume was plotted against age separately for groups with CAG repeat lengths of 38-39, 40, 41, 42, 43, 44, 45, 46, and 47-54. RESULTS: Slopes representing the association between age and striatal volume were significantly steeper as CAG repeat length increased. DISCUSSION: Although cross-sectional, these data suggest that striatal atrophy, like clinical progression, may occur faster with higher CAG repeat lengths. PMID- 21593965 TI - Neuropharmacology. PMID- 21593964 TI - Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk. AB - Azathioprine (AZA), 6-mercaptopurine (6-MP), and thioguanine (TG) are thiopurine drugs. These agents are indicated for the treatment of various diseases including hematologic malignancies, inflammatory bowel disease (IBD), rheumatoid arthritis, and as immunosuppressants in solid organ transplants. Thiopurine drugs are metabolized, in part, by thiopurine methyltransferase (TPMT). TPMT displays genetic polymorphism resulting in null or decreased enzyme activity. At least 20 polymorphisms have been identified, of which, TPMT *2, *3A, *3B, *3C, and *4 are the most commonly studied. These polymorphisms have been associated with increased myelosuppression risk. TPMT genotyping may be useful to predict this risk. PMID- 21593966 TI - Gastrointestinal pharmacology. PMID- 21593967 TI - HIV, TB, Malaria, Filaria and Kala azar. PMID- 21593968 TI - Immune system and inflammation. PMID- 21593969 TI - Toxicology. PMID- 21593970 TI - Biomodels. PMID- 21593971 TI - Lifestyle diseases. PMID- 21593972 TI - Contemporary teaching approches in pharmacology. PMID- 21593973 TI - Drug policy research & pharmacoeconomics. PMID- 21593974 TI - Miscellaneous. PMID- 21593976 TI - Miscellaneous. PMID- 21593975 TI - Prize sessions. PMID- 21593978 TI - Clinical pharmacology. PMID- 21593977 TI - From the desk of Organizing Secretary. PMID- 21593979 TI - Pharmacogenomics. PMID- 21593980 TI - Pharmacogenomics. PMID- 21593981 TI - Pharmacovigilance and pharmacoepidemiology. PMID- 21593982 TI - Ethnopharmacology. PMID- 21593983 TI - Drug metabolism and pharmacokinetics. PMID- 21593984 TI - Autonomic nervous system and cardiovascular system. PMID- 21593985 TI - Hematopathology in the new decade: what to expect. PMID- 21593987 TI - Medical complicity in torture at Guantanamo Bay: evidence is the first step toward justice. PMID- 21593988 TI - Puncture of a disc and application of nucleus pulposus induces disc herniation like changes and osteophytes. An experimental study in rats. AB - It has been observed that puncture of a lumbar disc may induce formation of a nodule on the surface of the disc and osteophytes. It is not known if this is based on the presence of a foreign tissue or specifically by the presence of nucleus pulposus or on the disc injury. In this study these mechanisms were separated by comparing disc puncture with application of nucleus pulposus without disc injury, with superficial disc injury without nucleus pulposus and with application of fat. Fifty rats underwent facetectomy of the left L4-5 facet. Ten additional rats were used as donor rats. The rats were exposed to disc puncture (n=10), application of homologous nucleus pulposus (n=10), application of homologous fat tissue (n=10), superficial disc injury (n=10) and ten rats served as control. After 3 weeks the rats were examined macroscopically regarding presence of disc nodules and osteophytes. A limited histological analysis was performed to obtain a microscopic overview of any observed changes. In rats with application of fat, superficial disc injury and in sham controls there were almost no changes observed. However, in rats with disc puncture and applied nucleus pulposus there were clear disc nodules and osteophytes noted. Microscopically the nodules comprised granulation tissue and the osteophytes cortical bone. In conclusion, the data indicate that the presence of nucleus pulposus is more likely to be responsible for the formation of disc nodules and osteophytes than disc injury or the presence of a foreign tissue. This may provide new insights in the mechanisms regarding the formation of disc herniations and osteophytes. PMID- 21593986 TI - Phosphorylation-dependent differential regulation of plant growth, cell death, and innate immunity by the regulatory receptor-like kinase BAK1. AB - Plants rely heavily on receptor-like kinases (RLKs) for perception and integration of external and internal stimuli. The Arabidopsis regulatory leucine rich repeat RLK (LRR-RLK) BAK1 is involved in steroid hormone responses, innate immunity, and cell death control. Here, we describe the differential regulation of three different BAK1-dependent signaling pathways by a novel allele of BAK1, bak1-5. Innate immune signaling mediated by the BAK1-dependent RKs FLS2 and EFR is severely compromised in bak1-5 mutant plants. However, bak1-5 mutants are not impaired in BR signaling or cell death control. We also show that, in contrast to the RD kinase BRI1, the non-RD kinases FLS2 and EFR have very low kinase activity, and we show that neither was able to trans-phosphorylate BAK1 in vitro. Furthermore, kinase activity for all partners is completely dispensable for the ligand-induced heteromerization of FLS2 or EFR with BAK1 in planta, revealing another pathway specific mechanistic difference. The specific suppression of FLS2 and EFR-dependent signaling in bak1-5 is not due to a differential interaction of BAK1-5 with the respective ligand-binding RK but requires BAK1-5 kinase activity. Overall our results demonstrate a phosphorylation-dependent differential control of plant growth, innate immunity, and cell death by the regulatory RLK BAK1, which may reveal key differences in the molecular mechanisms underlying the regulation of ligand-binding RD and non-RD RKs. PMID- 21593989 TI - Causal Inference and Observational Research: The Utility of Twins. AB - Valid causal inference is central to progress in theoretical and applied psychology. Although the randomized experiment is widely considered the gold standard for determining whether a given exposure increases the likelihood of some specified outcome, experiments are not always feasible and in some cases can result in biased estimates of causal effects. Alternatively, standard observational approaches are limited by the possibility of confounding, reverse causation, and the nonrandom distribution of exposure (i.e., selection). We describe the counterfactual model of causation and apply it to the challenges of causal inference in observational research, with a particular focus on aging. We argue that the study of twin pairs discordant on exposure, and in particular discordant monozygotic twins, provides a useful analog to the idealized counterfactual design. A review of discordant-twin studies in aging reveals that they are consistent with, but do not unambiguously establish, a causal effect of lifestyle factors on important late-life outcomes. Nonetheless, the existing studies are few in number and have clear limitations that have not always been considered in interpreting their results. It is concluded that twin researchers could make greater use of the discordant-twin design as one approach to strengthen causal inferences in observational research. PMID- 21593990 TI - RSK2 Binding Models Delineate Key Features for Activity. AB - Due to its overexpression and activation in human cancer cells and tissues, an emerging molecular target in cancer therapeutics is p90 ribosomal s6 kinase 2 (RSK2). While a growing number of RSK2 inhibitors have been reported in the literature, only the crystal structure of RSK2 in complex with an AMP analogue provides a structural basis for understanding RSK2 inhibition. To remedy this, we used our fluorescence polarization assay to determine the RSK2 activity for a set of structurally diverse compounds, and followed this by modeling their binding modes in an all-atom, energy refined crystal structure of RSK2. These binding models reveal that Val131 and Leu147 are key interaction sites for potent RSK2 inhibition. This structure-based pharmacophore is an important tool for new lead discovery and refinement. PMID- 21593991 TI - Role of TNFalpha Induced Inflammation in Delay Eyeblink Conditioning in Young and Aged Rats. AB - Tumor necrosis factor alpha (TNF-alpha) is a multifunctional proinflammatory cytokine, which is a critical inflammatory mediator involved in aging and neurodegenerative diseases of aging. Previous work has shown that diets enriched with antioxidants reduce levels of the cytokine TNF-alpha and improve classical eyeblink conditioning performance. Therefore we tested the hypothesis that the proinflamatory cytokine TNF-alpha may be a critical factor that modulates classical conditioning behavior. If increased levels of endogenous cerebellar TNF alpha negatively affect performance on the eyeblink conditioning task in aged rats, then exogenous administration of TNF-alpha in young rats should result in an impaired acquisition and/or retention of eyeblink conditioning memory. On the other hand, the reduction or blockage of the age-related increase in cerebellar TNF-alpha levels in aged rats should result in an improvement in memory. Young (3 month old) F344 rats were pretreated with an intracerebellar injection of recombinant rat (rr)TNF-alpha or denatured (rr)TNF-alpha prior to eyeblink conditioning coupled to microdialysis. The results showed that young rats treated with rrTNF-alpha have a decreased rate of learning compared to the control group. Norepinephrine which has been shown to play a critical role in cerebellar learning tasks presented a shift on training day one of young rats resembling that observed in aged rats. In a second experiment aged (22 month old) F344 rats were pretreated with intracerebellar microinjection of anti-rat TNF-alpha three times a week for 4 weeks prior to eyeblink conditioning training couple to microdialysis. Aged rats showed a better performance in the conditioned responses when compared to controls. The release of norepinephrine in this group reached basal levels sooner than the control group but not as early as the young rats. The results of these experiments demonstrate a critical correlation between TNF alpha and the rate of learning and the pattern of NE release during eyeblink conditioning. PMID- 21593993 TI - A protocol for characterizing the impact of collateral flow after distal middle cerebral artery occlusion. AB - In humans and in animal models of stroke, collateral blood flow between territories of the major pial arteries has a profound impact on cortical infarct size. However, there is a gap in our understanding of the genetic determinants of collateral formation and flow, as well as the signaling pathways and neurovascular interactions regulating this flow. Previous studies have demonstrated that collateral flow between branches of the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) can protect mouse cortex from infarction after middle cerebral artery occlusion. Because the number and diameter of collaterals varies among mouse strains and after transgenic manipulations, a combination of methods is required to control for these variations. Here, we report an inexpensive approach to characterizing the cerebrovascular anatomy, and in vivo monitoring of cerebral blood flow as well. Further, we introduce a new, minimally invasive method for the occlusion of distal MCA branches. These methods will permit a new generation of studies on the mechanisms regulating collateral remodeling and cortical blood flow after stroke. PMID- 21593994 TI - The evolution of concepts of color vision. AB - The evolution of ideas about the way we see color was closely linked to physical theories of light. Proponents of both corpuscular and wave theories viewed light as a continuous spectrum. This was not easily reconciled with the fact that, for the human eye, all colors can be matched by mixture of three primaries. Physicists such as Mayer who described trichromatic color matching often assumed that there were just three types of rays in the spectrum. This argument was finally resolved by Thomas Young, who noted that trichromatic color matching was consistent with a continuous spectrum if there were just three receptors in the eye. This kind of conceptual mistake, in this case the confusion of the properties of the visual system with physical properties of light, has been common in the history of color science. As another example, the idea of trichromacy was disputed by those who viewed color sensations as opponent processes, red-green, blue-yellow and black-white. The discovery of color opponent neurons in the visual pathway has partly resolved this dilemma. Much of the physiological substrate of the way we detect and distinguish colors is now established, but the link between the signals leaving the retina and the way we name and order colors is still poorly defined. PMID- 21593995 TI - Drugs, Women and Violence in the Americas: U.S. Results of a Multi-Centric Pilot Project (Phase 1). AB - OBJECTIVES: To explore the collective and individual experiences that Latin American females in the U. S. have with substance abuse, violence and risky sexual behaviors. METHODS: This study was conducted in two phases that were carried out from July 2006 to June 2007 in south Florida. This paper covers Phase 1. In Phase 1, focus groups were conducted among 93 women in English, Spanish and Portuguese. Through content analyses of the focus group transcriptions, major themes were identified. RESULTS: Participants identified substance abuse, violence and risky sexual behaviors as closely related problems of great concern in Latina women in the U.S. Three important themes emerged from the focus groups. These included "Living in the US and the Devaluing of Latino Culture," the "Vicious Cycle of Abuse" and "Breaking the Silence". CONCLUSIONS: The results from this study suggest that substance abuse, violence and HIV should be addressed in an integrative and comprehensive manner. Recommendations for the development of policies, programs and services addressing substance abuse, violence and risk for HIV among Latinos are provided. PMID- 21593992 TI - Liquid Chromatography Mass Spectrometry-Based Proteomics: Biological and Technological Aspects. AB - Mass spectrometry-based proteomics has become the tool of choice for identifying and quantifying the proteome of an organism. Though recent years have seen a tremendous improvement in instrument performance and the computational tools used, significant challenges remain, and there are many opportunities for statisticians to make important contributions. In the most widely used "bottom up" approach to proteomics, complex mixtures of proteins are first subjected to enzymatic cleavage, the resulting peptide products are separated based on chemical or physical properties and analyzed using a mass spectrometer. The two fundamental challenges in the analysis of bottom-up MS-based proteomics are: (1) Identifying the proteins that are present in a sample, and (2) Quantifying the abundance levels of the identified proteins. Both of these challenges require knowledge of the biological and technological context that gives rise to observed data, as well as the application of sound statistical principles for estimation and inference. We present an overview of bottom-up proteomics and outline the key statistical issues that arise in protein identification and quantification. PMID- 21593996 TI - Do Verbal Interactions with Infants During Electronic Media Exposure Mitigate Adverse Impacts on their Language Development as Toddlers? AB - The goal of this study was to determine whether verbal interactions between mothers and their 6-month-old infants during media exposure ('media verbal interactions') might have direct positive impacts, or mitigate any potential adverse impacts of media exposure, on language development at 14 months. For 253 low-income mother-infant dyads participating in a longitudinal study, media exposure and media verbal interactions were assessed using 24-hour recall diaries. Additionally, general level of cognitive stimulation in the home [StimQ] was assessed at 6 months and language development [Preschool Language Scale-4] was assessed at 14 months. Results suggest that media verbal interactions play a role in the language development of infants from low-income, immigrant families. Evidence showed that media verbal interactions moderated adverse impacts of media exposure found on 14-month language development, with adverse associations found only in the absence the these interactions. Findings also suggest that media verbal interactions may have some direct positive impacts on language development, in that media verbal interactions during the co-viewing of media with educational content (but not other content) were predictive of 14-month language independently of overall level of cognitive stimulation in the home. PMID- 21593997 TI - Relating Scene-Motion Thresholds to Latency Thresholds for Head-Mounted Displays. AB - As users of head-tracked head-mounted display systems move their heads, latency causes unnatural scene motion. We 1) analyzed scene motion due to latency and head motion, 2) developed a mathematical model relating latency, head motion, scene motion, and perception thresholds, 3) developed procedures to determine perceptual thresholds of scene-velocity and latency without the need for a head mounted display or a low-latency system, and 4), for six subjects under a specific set of conditions, we measured scene-velocity and latency thresholds, and compared the relationship between these thresholds. Resulting PSEs and JNDs of latency thresholds are in the same range of Ellis and Adelstein. The results are a step toward enabling scientists and engineers to determine latency requirements before building immersive virtual environments using head-mounted display systems. PMID- 21593998 TI - A Reparametrization Approach for Dynamic Space-Time Models. AB - Researchers in diverse areas such as environmental and health sciences are increasingly working with data collected across space and time. The space-time processes that are generally used in practice are often complicated in the sense that the auto-dependence structure across space and time is non-trivial, often non-separable and non-stationary in space and time. Moreover, the dimension of such data sets across both space and time can be very large leading to computational difficulties due to numerical instabilities. Hence, space-time modeling is a challenging task and in particular parameter estimation based on complex models can be problematic due to the curse of dimensionality. We propose a novel reparametrization approach to fit dynamic space-time models which allows the use of a very general form for the spatial covariance function. Our modeling contribution is to present an unconstrained reparametrization method for a covariance function within dynamic space-time models. A major benefit of the proposed unconstrained reparametrization method is that we are able to implement the modeling of a very high dimensional covariance matrix that automatically maintains the positive definiteness constraint. We demonstrate the applicability of our proposed reparametrized dynamic space-time models for a large data set of total nitrate concentrations. PMID- 21593999 TI - Who would benefit from memory training? A pilot study examining the ceiling effect of concurrent cognitive stimulation. AB - Diverse effects of memory training were observed in the literature. One possible factor is the amount of concurrent cognitive training received during the training program. In this pilot study, we recruited 24 elderly adults with or without concurrent cognitive stimulations to attend a memory-training program. Findings suggested that elderly people without concurrent cognitive stimulation could benefit from a memory-training program in the form of improved initiation and memory functioning. Self-rated quality of life measure also showed improvements alongside the cognitive benefits. Elderly people with regular concurrent cognitive stimulation, on the other hand, seemed to plateau in their level of performance and did not show any significant change. Our preliminary findings suggested nonlinear concurrent cognitive stimulation in the elderly. PMID- 21594000 TI - Role of zoledronic acid in the prevention and treatment of osteoporosis. AB - Taken once a year, intravenous zoledronic acid (Zol) (Reclast(r) or Aclasta(r)) is a third-generation nitrogen-containing bisphosphonate that is effective compared with placebo in reducing the risk of fractures in patients with postmenopausal osteoporosis and recent low-trauma hip fracture. In glucocorticoid induced osteoporosis, there is no significant difference between Zol and risedronate for new fractures. Improvements in bone mineral density and early reduction of bone remodeling markers are observed in postmenopausal osteoporosis, recent low-trauma hip fracture, and glucocorticoid-induced osteoporosis. Given that Zol is generally well tolerated and very convenient, it is an interesting therapeutic option for aging patients who take multiple oral drugs, who have adherence or gastrointestinal tolerance issues, and who have an indication for oral bisphosphonates. Zol is not recommended for patients with severe renal impairment. Vitamin D deficiency should be corrected before the administration of Zol. PMID- 21594002 TI - Ankle arthritis in a 6-year-old boy after a tick bite - a case report. AB - BACKGROUND: Monoarthritis of the ankle is a rare condition in children, and is most often caused by a bacterial infection. Lyme disease is endemic in southern Scandinavia, and diagnosis remains a challenge. The clinical presentation of Lyme disease varies greatly, and often with considerable delay between exposure and presentation. CASE PRESENTATION: We report a case of ankle arthritis in a boy who presented one year earlier with a tick bite on the dorsum of the foot. He was suboptimally treated with oral antibiotics for one week, and developed in the following months a painless limp. Radiographs revealed a severe arthritis of the right ankle joint with necrosis of the talus and deformation of the talocrural and subtalar joints. There was no history of malaise, fever or other systemic symptoms. He remains seronegative for antibodies against B. burgdorferi. CONCLUSIONS: The suboptimal oral antibiotic treatment may have hindered the antibody production against B burgdorferi, while not being therapeutic, resulting in severe ankle arthritis due to seronegative Lyme disease. PMID- 21594001 TI - Effectiveness of simple balancing training program in elderly patients with history of frequent falls. AB - OBJECTIVE: To study the effectiveness of simply-performed balancing exercises in fall prevention. DESIGN: Pre- and post-trial. SETTING: University hospital from January 2009 to May 2010. PARTICIPANTS: Elderly with falls in the previous year. INTERVENTION: Simple balancing exercise was performed at home every day and was recorded in the booklet. MEASUREMENTS: New falling events and a battery of balancing abilities including the Timed Up and Go Test (TUGT), chair stand, functional reach, and Berg balance scale-short form were evaluated at baseline, 3 , 6-, 9-, and 12-month periods. Fear of falling and quality of life scores were assessed at baseline and 12-month periods. RESULTS: 146 subjects were recruited, 116 female (79.5%) with a mean age of 67.1 years. At the end of the study, 49% of participants had not fallen. All of the balancing abilities were compared between frequent and infrequent fallers and were significantly improved (P<0.001) except for functional reach in the frequent fall group. Most subjects (72%-79%) complied well with the exercise program. However, compliance had no effect on balancing abilities. About 36.4% of participants had adverse events from exercise, of which knee pain was the top ranked. The quality of life and the fall efficacy scores increased significantly at the end of the study. Factors affecting falling were compliance with exercise (adjusted odds ratio [OR]: 2.55, 95% confidence intervals [CI]: 1.04, 6.30) and a history of falling >=3 times in the previous year (adjusted OR: 3.76, 95% CI: 1.18, 11.98). CONCLUSION: Performing simply designed balancing exercises, at least 3 days per week, can increase balancing abilities, and decrease fall rates in the elderly with a history of previous falls. However, strategies to encourage elderly compliance may prevent falling. PMID- 21594003 TI - Somatic mutations of the EGF receptor and their signal transducers affect the efficacy of EGF receptor-specific tyrosine kinase inhibitors. AB - Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer that has been the most common and most fatal cancer worldwide. Gefitinib (Iressa) and erlotinib (Tarceva) specific tyrosine kinase inhibitors (TKI) for the epidermal growth factor receptor (EGFR), have been demonstrated to be effective for some NSCLC patients and are pioneering molecular-targeted drugs used in the clinic for cancer. Because many studies indicate that only some patient populations benefit from these drugs, there has been an urgent need to develop diagnostic methods to select appropriate patients for whom treatment with these drugs will be beneficial. Moreover, problems of acquired resistance after long-term treatment with the drugs have emerged. In this review, I summarize the current understanding of the EGFR-activated signal transduction pathway, which plays important roles in tumorigenesis, and of the molecular mechanisms that determine the sensitivity toward EGFR-TKI. PMID- 21594005 TI - A Sociotechnical Approach to Evaluating the Impact of ICT on Clinical Care Environments. AB - INTRODUCTION: Process-supporting information technology holds the potential to increase efficiency, reduce errors, and alter professional roles and responsibilities in a manner which allows improvement in the delivery of patient care. However, clashes between the model of health care work inscribed in these tools with the actual nature of work has resulted in staff resistance and decreased organisational uptake of ICT, as well as the facilitation of unexpected and negative effects in efficiency and patient safety. Sociotechnical theory provides a paradigm against which workflow and transfusion of ICT in healthcare could be better explored and understood. DESIGN: This paper will conceptualise a formative, multi-method longitudinal evaluation process to explore the impact of ICT with an appreciation of the relationship between the social and technical systems within a clinical department. METHOD: Departmental culture, including clinical work processes and communication patterns will be thoroughly explored before system implementation using both quantitative and qualitative research methods. Findings will be compared with post implementation data, which will incorporate measurement of safety and workflow efficiency indicators. DISCUSSION: Sociotechnical theory provides a paradigm against which workflow and transfusion of ICT in healthcare could be better explored and understood. However, sociotechnical and multimethod approaches to evaluation do not exist without criticism. Inherent in the protocol are limitations of sociotechnical theory and criticism of the multimethod approach; testing of the methodology in real clinical settings will serve to verify efficacy and refine the process. PMID- 21594004 TI - Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an opportunistic human pathogen and one of the leading causes of nosocomial infections worldwide. The difficulty in treatment of pseudomonas infections arises from being multidrug resistant (MDR) and exhibits resistance to most antimicrobial agents due to the expression of different mechanisms overcoming their effects. Of these resistance mechanisms, the active efflux pumps in Pseudomonas aeruginosa that belong to the resistance nodulation division (RND) plays a very important role in extruding the antibiotics outside the bacterial cells providing a protective means against their antibacterial activity. Beside its role against the antimicrobial agents, these pumps can extrude biocides, detergents, and other metabolic inhibitors. It is clear that efflux pumps can be targets for new antimicrobial agents. Peptidomimetic compounds such as phenylalanine arginyl beta-naphthylamide (PAbetaN) have been introduced as efflux pump inhibitors (EPIs); their mechanism of action is through competitive inhibition with antibiotics on the efflux pump resulting in increased intracellular concentration of antibiotic, hence, restoring its antibacterial activity. The advantage of EPIs is the difficulty to develop bacterial resistance against them, but the disadvantage is their toxic property hindering their clinical application. The structure activity relationship of these compounds showed other derivatives from PAbetaN that are higher in their activity with higher solubility in biological fluids and decreased toxicity level. This raises further questions on how can we compact Pseudomonas infections. Of particular importance, the recent resurgence in the use of older antibiotics such as polymyxins and probably applying stricter control measures in order to prevent their spread in clinical sittings. PMID- 21594006 TI - The Disparity Information and Communication Technology for Developing Countries has in the Delivery of Healthcare Information. AB - Information and Communication Technologies (ICT) have merged into the world of healthcare slowly but surely. However, the marriage between the use of technology and its full impact in the health sector has not been fully realised. The focus of this paper is to highlight the impact of ICT on revolutionising access to healthcare information and thus quality of health for populations of the developing world. This paper highlights on the importance of being able to access health information and how traditional media methods have been utilised to allow this within a developing country setting, highlighting the clear digital divide. The paper then addresses the impact of convergent communication technologies and mobile technologies in providing a means of addressing existing healthcare problems within a developing country setting. PMID- 21594007 TI - Patients at the centre: methodological considerations for evaluating evidence from health interventions involving patients use of web-based information systems. AB - Building an evidence base for healthcare interventions has long been advocated as both professionally and ethically desirable. By supporting meaningful comparison amongst different approaches, a good evidence base has been viewed as an important element in optimising clinical decision-making and the safety and quality of care. Unsurprisingly, medical research has put considerable effort into supporting the development of this evidence base, and the randomised controlled trial has become the dominant methodology. Recently however, a body of research has begun to question, not just this methodology per se, but also the extent to which the evidence it produces may marginalise individual patient experiences, priorities and perceptions.Simultaneously, the widespread adoption and utilisation of information systems (IS) in health care has also prompted initiatives to develop a stronger base of evidence about their impacts. These calls have been stimulated both by numerous system failures and research expressing concerns about the limitations of information systems methodologies in health care environments. Alongside the potential of information systems to produce positive, negative and unintended consequences, many measures of success, impact or benefit appear to have little to do with improvements in care, health outcomes or individual patient experiences.Combined these methodological concerns suggest the need for more detailed examination. This is particularly the case, given the prevalence within contemporary clinical and IS discourses on health interventions advocating the need to put the 'patient at the centre' by engaging them in their own care and/or 'empowering' them through the use of information systems.This paper aims to contribute to these on-going debates by focusing on the socio-technical processes by which patients' interests and outcomes are measured, defined and evaluated within health interventions that involve them using web-based information systems. The paper outlines an integrated approach that aims to generate evidence about the impact of these types of health interventions that are meaningful at both individual patient and patient cohort levels. PMID- 21594008 TI - CPOE in Non-Surgical Versus Surgical Specialties: A Qualitative Comparison of Clinical Contexts in the Medication Process. AB - BACKGROUND: Computerized provider order entry (CPOE) systems are implemented in various clinical contexts of a hospital. To identify the role of the clinical context in CPOE use, we compared the impact of a CPOE system on the medication process in both non-surgical and surgical specialties. METHODS: We conducted a qualitative study of surgical and non-surgical specialties in a 1237-bed, academic hospital in the Netherlands. We interviewed the clinical end users of a computerized medication order entry system in both specialty types and analyzed the interview transcripts to elicit qualitative differences between the clinical contexts, clinicians' attitudes, and specialty-specific requirements. RESULTS: Our study showed that the differences in clinical contexts between non-surgical and surgical specialties resulted in a disparity between clinicians' requirements when using CPOE. Non-surgical specialties had a greater medication workload, greater and more diverse information needs to be supported in a timely manner by the system, and thus more intensive interaction with the CPOE system. In turn these factors collectively influenced the perceived impact of the CPOE system on the clinicians' practice. The non-surgical clinicians expressed less positive attitudes compared to the surgical clinicians, who perceived their interaction with the system to be less intensive and less problematic. CONCLUSION: Our study shows that clinicians' different attitudes towards the system and the perceived impact of the system were largely grounded in the clinical context of the units. The study suggests that not merely the CPOE system, the technology itself, influences the perceptions of its users and workflow-related outcomes. The interplay between technology and clinical context of the implementation environment also matters. System design and redesigning efforts should take account of different units' specific requirements in their particular clinical contexts. PMID- 21594009 TI - Conceptual challenges for advancing the socio-technical underpinnings of health informatics. AB - This discussion paper considers the adoption of socio-technical perspectives and their theoretical and practical influence within the discipline of health informatics. The paper highlights the paucity of discussion of the philosophy, theory and concepts of socio-technical perspectives within health informatics. Instead of a solid theoretical base from which to describe, study and understand human-information technology interactions we continue to have fragmented, unelaborated understandings. This has resulted in a continuing focus on technical system performance and increasingly managerial outputs to the detriment of social and technical systems analysis. It has also limited critical analyses and the adaptation of socio-technical approaches beyond the immediate environment to the broader social systems of contemporary society, an expansion which is increasingly mandated in today's complex health environment. PMID- 21594010 TI - Towards an integrative cognitive-socio-technical approach in health informatics: analyzing technology-induced error involving health information systems to improve patient safety. AB - The purpose of this paper is to argue for an integration of cognitive and socio technical approaches to assessing the impact of health information systems. Historically, health informatics research has examined the cognitive and socio technical aspects of health information systems separately. In this paper we argue that evaluations of health information systems should consider aspects related to cognition as well as socio-technical aspects including impact on workflow (i.e. an integrated view). Using examples from the study of technology induced error in healthcare, we argue for the use of simulations to evaluate the cognitive-socio-technical impacts of health information technology [36]. Implications of clinical simulations and analysis of cognitive-social-technical impacts are discussed within the context of the system development life cycle to improve health information system design, implementation and evaluation. PMID- 21594011 TI - A UNIFIED FRAMEWORK FOR ESTIMATING DIFFUSION TENSORS OF ANY ORDER WITH SYMMETRIC POSITIVE-DEFINITE CONSTRAINTS. AB - Cartesian tensors of various orders have been employed for either modeling the diffusivity or the orientation distribution function in Diffusion-Weighted MRI datasets. In both cases, the estimated tensors have to be positive-definite since they model positive-valued functions. In this paper we present a novel unified framework for estimating positive-definite tensors of any order, in contrast to the existing methods in literature, which are either order-specific or fail to handle the positive-definite property. The proposed framework employs a homogeneous polynomial parametrization that covers the full space of any order positive-definite tensors and explicitly imposes the positive-definite constraint on the estimated tensors. We show that this parametrization leads to a linear system that is solved using the non-negative least squares technique. The framework is demonstrated using synthetic and real data from an excised rat hippocampus. PMID- 21594012 TI - Acanthodasys caribbeanensis sp. n., a new species of Thaumastodermatidae (Gastrotricha, Macrodasyida) from Belize and Panama. AB - We describe one new species of Acanthodasys (Gastrotricha, Macrodasyida, Thaumastodermatidae) collected from sublittoral sites around Carrie Bow Cay, Belize and Isla Colon in the Bocas del Toro archipelago, Panama. Though eight species of Acanthodasys are currently recognized, no species has yet been reported from the Caribbean. Acanthodasys caribbeanensissp. n. is characterized by the lack of lateral adhesive tubes, the presence of ventrolateral adhesive tubes, and with cuticular armature in the form of both spineless and spined scales. The spineless scales are not elliptical as in other species of Acanthodasys, but are instead variable in shape and closely resemble the spineless scales of species of Diplodasys. Spined scales bear uniancres up to 50 um long and are the largest reported in the genus. Uniancres are arranged dorsally around the mouth rim and distributed in five distinguishable columns. Adult size varies from 325-625 um long. PMID- 21594013 TI - The genus Nelcyndana Stal (Hemiptera, Cicadidae, Taphurini) with description of three new species from Borneo. AB - The type species of Nelcyndana, Nelcyndana tener (Stal, 1870) from the Philippines, is redescribed and illustrated. The taxonomic position of the genus Nelcyndana in the tribe Taphurini is discussed. Three new species from Borneo are described and illustrated: Nelcyndana borneensissp. n., Nelcyndana vantolisp. n., and Nelcyndana mulusp. n. Distributions maps for the three Borneo species are presented and a key for the identification of the four Asian species of the genus is provided. PMID- 21594014 TI - The genus Trichocnemis LeConte, 1851 (Coleoptera, Cerambycidae, Prioninae). AB - The history of the genus Trichocnemis LeConte, 1851 (Coleoptera, Cerambycidae, Prioninae) is discussed. Its taxonomic status in relation to the genera Ergates Audinet-Serville, 1832 and Callergates Lameere, 1904 is clarified. The synonymy of Macrotoma californica White, 1853, Macrotoma spiculigera White, 1853, and Trichocnemis spiculatus LeConte, 1851 is confirmed. A key to all three genera and their species is provided. PMID- 21594015 TI - Two genera of Braconinae (Hymenoptera, Braconidae) in China, with descriptions of four new species. AB - Two genera, namely Dolabraulax Quicke and Scutibracon Quicke of Braconinae (Hymenoptera: Braconidae) from China are studied for the first time, and four new species, namely Dolabraulax jigongshanus Wang & Chen, sp. n., Dolabraulax flavus Wang & Chen, sp. n., Dolabraulax brevivena Wang & Chen, sp. n. and Scutibracon fujianensis Wang & Chen, sp. n. are fully described and illustrated. The examined specimens are deposited in the Parasitic Hymenoptera Collection, Zhejiang University, Hangzhou, China (ZJUH). PMID- 21594016 TI - The genus Arhaconotus Belokobylskij (Hymenoptera, Braconidae, Doryctinae) from China, with description of a new species. AB - The genus Arhaconotus Belokobylskij (Hymenoptera: Braconidae, Doryctinae) is recorded for the first time from China. A new species of this genus, Arhaconotus hainanensis Tang & Chen, sp. n., is described and illustrated. A key to the species of this genus is updated to include the new species. PMID- 21594017 TI - The genus Ptilophora (Lepidoptera, Notodontidae) in China, with description of a new species. AB - The genus Ptilophora Stephens in China is briefly reviewed, with the description of Ptilophora nanlingensissp. n. The new species is most similar to Ptilophora horieaurea in wing pattern and to Ptilophora jezoensis in male genitalia, but they can be distinguished from each other by the following characters: forewing bright reddish brown in Ptilophora nanlingensis, chestnut brown in Ptilophora horieaurea; costa of male genitalia pointed, with a rounded subapical process ventrally in Ptilophora jezoensis, costa rounded, with apex inflated, and with pointed subapical process ventrally in Ptilophora nanlingensis. A key to the Ptilophora species from China and adjacent areas is presented and a distribution map is given. The holotype of the new species is deposited in the Department of Entomology, South China Agricultural University, P. R. China. PMID- 21594018 TI - Catalogue of the ants (Hymenoptera, Formicidae) of Bulgaria. AB - The present catalogue of the ants (Hymenoptera, Formicidae) of Bulgaria is made on a base of critical reconsideration of literature (covering the period from 1892 till 2009 and part of 2010) as well as on examination of the authors' and several museum's collections. A lot of data were omitted in the previous Bulgarian monograph on ants, lots of new data were recently added and many important additions and alterations were made due to taxonomic revisions of Eurasian Formicidae during the last three decades. Two new species are reported for the country [Temnothorax graecus (Forel, 1911) and Temnothorax cf. korbi (Emery, 1924)].This catalogue contains a list of 163 ant species belonging to 40 genera of 6 subfamilies now known from Bulgaria. Synonyms and information on the previously reported names in relevant publications are given. Known localities of the species are grouped by geographic regions. Maps with concrete localities or regions for each species were prepared. The conservation status of 13 ant species is given as they are included in IUCN Red List of Threatened Species and Bulgarian Biodiversity Act. In comparison with adjacent Balkan regions the ant fauna of Bulgaria is quite rich and its core is composed of South European elements. PMID- 21594019 TI - Eight new species and an annotated checklist of Microgastrinae (Hymenoptera, Braconidae) from Canada and Alaska. AB - Based on the study of 12,000+ specimens, an annotated checklist of 28 genera and 225 species of Microgastrinae braconids from Canada and Alaska is provided, increasing by 50% the number of species for the region. The genera Distatrix, Iconella, Protomicroplitis and Pseudapanteles for Canada, and Diolcogaster for Alaska are recorded for the first time; all but Iconella and Protomicroplitis represent the northernmost extension of their known distribution. Eight new species are described: Apanteles huberisp. n., Apanteles jenniferae sp. n., Apanteles masmithisp. n., Apanteles roughleyisp. n., Apanteles samarshallisp. n., Distatrix carolinaesp. n., Pseudapanteles gouletisp. n., and Venanus hebertisp. n. For the more diverse genera, especially Cotesia, Microplitis, Apanteles, Dolichogenidea and Glyptapanteles, many more species are expected to be found. DNA barcode sequences (cytochrome c oxidase I, or CO1) for 3,500+ specimens provided an additional layer of useful data. CO1 sequences were incorporated to the new species descriptions whenever possible, helped to clarify the limits of some species, and flagged cases where further study is needed. Preliminary results on the latitudinal gradient of species/genera richness (45-80 degrees N); as well as biogeographical affinities of the Canadian/Alaska fauna, are discussed. Taking into account the number of specimens in collections still to be studied, data from the barcoded specimens, and extrapolations from Lepidoptera diversity (the host group of the subfamily) the actual diversity of Microgastrinae in the region is estimated to be at least twice that currently known. PMID- 21594020 TI - A new herrerasaurid (Dinosauria, Saurischia) from the Upper Triassic Ischigualasto Formation of northwestern Argentina. AB - Herrerasauridae comprises a basal clade of dinosaurs best known from the Upper Triassic of Argentina and Brazil, which have yielded remains of Herrerasaurus ischigualastensis and Staurikosaurus pricei, respectively. Systematic opinion regarding the position of Herrerasauridae at the base of Dinosauria has varied. Here we describe a new herrerasaurid, Sanjuansaurus gordilloi gen. n., sp. n., based on a partial skeleton from Carnian-age strata of the the Upper Triassic Ischigualasto Formation of northwestern Argentina. The new taxon is diagnosed by numerous features, including long, band-shaped and posterolaterally oriented transverse process on the posterior cervical vertebrae; neural spines of the sixth to eighth dorsal vertebrae, at least, bearing acute anterior and posterior processes; scapula and coracoid with everted lateral margins of the glenoid; and short pubis (63% of the femoral length). Phylogenetic analysis placed Sanjuansaurus within a monophyletic Herrerasauridae, at the base of Theropoda and including Herrerasaurus and Staurikosaurus. The presence of Sanjuansaurus at the base of the Ischigualasto Formation, along with other dinosaurs such as Herrerasaurus, Eoraptor, Panphagia, and Chromogisaurus suggests that saurischian dinosaurs in southwestern Pangea were already widely diversified by the late Carnian rather than increasing in diversity across the Carnian-Norian boundary. PMID- 21594021 TI - A new species of Stenobiella Tillyard (Neuroptera, Berothidae) from Australia. AB - Stenobiella variolasp. n., a new species of beaded lacewing (Neuroptera: Berothidae), is described and figured from south-eastern Australia. A preliminary key to Stenobiella species is presented. PMID- 21594022 TI - The mycetophagidae (coleoptera) of the maritime provinces of Canada. AB - The Mycetophagidae (hairy fungus beetles) of the Maritime Provinces of Canada are surveyed. Seven species in the genera Mycetophagus, Litargus, and Typhaea are found in the region. Six new provincial records are reported including Mycetophagus punctatus and Mycetophagus flexuosus, whichare newly recorded in the Maritime Provinces. The distribution of all species is mapped, colour habitus photographs of all species are figured, and an identification key to species is provided. The discussion notes that four of the species found in the region are apparently rare, possibly due to the history of forest management practices in the region; a situation similar to that of a significant proportion of other saproxylic beetles found in the Maritime Provinces. PMID- 21594023 TI - Description of a new species of the genus Tribasodites Jeannel (Coleoptera, Staphylinidae, Pselaphinae) from East China with a key to world species. AB - A remarkable new species of the genus Tribasodites, 1960, Tribasodites spinacaritussp. n. is described and illustrated from Zhejiang Province, East China. A key to world species of the genus is provided. Systematic position of the new taxon is discussed. PMID- 21594024 TI - New species and new records of Mydidae from the Afrotropical and Oriental regions (Insecta, Diptera, Asiloidea). AB - New Mydidae species are described from the Afrotropical and Oriental regions including the first records of this family from several countries in eastern Africa (Kenya, Tanzania, and Uganda) and Mauritania in western Africa as well as Nepal and Thailand in Asia. The new species are, Leptomydinae: Leptomydas notossp. n. (south-western India), Leptomydas raptisp. n. (south-central Nepal), Leptomydas tigrissp. n. (north-central Thailand); Syllegomydinae: Mydaselpidini: Mydaselpis ngurumanisp. n. (south-eastern Kenya, north-eastern Tanzania), Vespiodes phaiossp. n. (south-eastern Kenya); Syllegomydinae: Syllegomydini: Syllegomydas (Notobates) astrictussp. n. (Kenya), Syllegomydas (Notobates) heothinossp. n. (Kenya and Uganda), Syllegomydas (Syllegomydas) elachyssp. n. (northern Zimbabwe). Syllegomydas (Syllegomydas) proximus Seguy, 1928 is recorded from western Mauritania and re-described. Syllegomydas (Notobates) dispar (Loew, 1852), which was previously listed as incertae sedis in the Afrotropical Diptera catalogue, is re-described and illustrated based on examination of the type specimens and several additional specimens from Mozambique. Cephalocera annulata Brunetti, 1912 and Syllegomydas bucciferus Seguy, 1928, described from north eastern India and previously unplaced in the Oriental Diptera catalogue, are newly combined with Leptomydas Gerstaecker, 1868 and together with Leptomydas indianus Brunetti, 1912, also from north-eastern India, placed in Leptomydinae. Comments on the possible synonymy of the genera of Mydaselpidini are made. Illustrations and photographs are provided to support the descriptions and future identification. A provisional dichotomous key to Mydidae genera occurring in eastern Africa (Kenya, Malawi, Mozambique, Somalia, Tanzania, Uganda) and the Oriental Region is provided. Distribution, occurrence in biodiversity hotspots and high-biodiversity wilderness areas, and seasonal incidence are discussed for all species. PMID- 21594025 TI - A new caddisfly genus (Trichoptera, Odontoceridae) from Vietnam. AB - Cephalopsyche, a new genus of caddisfly (Trichoptera, Odontoceridae), is described from Vietnam. Two new species are placed in the genus: Cephalopsyche gorgonasp. n. and Cephalopsyche neboissisp. n. The adult male and female of each species exhibit distinct sexual dimorphism, especially in head morphology. In males, there are hinged, chamber-like structures on the vertex of the head, containing filamentous, columnar tissue when exposed. Descriptions and illustrations of both species are provided. PMID- 21594026 TI - New or little-known species of the genus Amphimenes Bates, 1873 (Coleoptera, Carabidae, Lebiinae) from Vietnam. AB - Twelve new species of the genus Amphimenes Bates, 1873 are described from Vietnam: Amphimenes maculatussp. n., Amphimenes bidoupensissp. n., Amphimenes gracilissp. n., Amphimenes montanussp. n., Amphimenes giganteussp. n., Amphimenes mediussp. n., Amphimenes minutussp. n., Amphimenes rufipessp. n., Amphimenes reflexicollissp. n., Amphimenes planicollissp. n., Amphimenes nitidussp. n., and Amphimenes kabakovisp. n.. Amphimenes rugulipennis Bates, 1892, comb. n., is transferred from the genus Brachichila Chaudoir, 1869 and is redescribed from fresh material. A key to all congeners is provided, these being arranged into five new species-groups. Adults of the rugulipennis- and piceolus-groups show subcortical habits, while those of the medius-, rufipes- and planicollis- groupsare herpetobiotic, resulting in such morphological adaptations as partly reduced eyes, missing wings and adnate elytra. PMID- 21594027 TI - The adventive genus Xantholinus Dejean (Coleoptera, Staphylinidae, Staphylininae in North America: new records and a synthesis of distributional data. AB - New distributional and bionomic data are provided for species of the genus Xantholinus in North America. Xantholinus elegans (Olivier 1795) (= X. jarrigei Coiffait 1956)is recorded from North America for the first time, based on specimens collected in Ontario, Canada from 2007-2010. The armature of the internal sac of the aedeagus in situ is illustrated to aid in identification. Xantholinus linearis (Olivier 1795), known previously from the Maritime Provinces of Canada and the eastern United States, is newly recorded from Ontario. Xantholinus longiventris Heer 1839 is still only known from western North America. A key is provided to allow recognition of all three species. PMID- 21594028 TI - Discovery of the rare genus Blacometeorus Tobias, 1976 (Hymenoptera, Braconidae, Blacinae) in the Oriental part of China, with description of a new species. AB - The rare genus Blacometeorus Tobias, 1976 (Hymenoptera: Braconidae: Blacinae)is discovered in Yunnan, China, and a new species, Blacometeorus sinicus Chai & Chen, sp. n. is described and illustrated. It represents the first record of this genus both for China and Oriental region. A key to genus Blacometeorus is updated. PMID- 21594029 TI - Agra, arboreal beetles of Neotropical forests: pusilla group and piranha group systematics and notes on their ways of life (Coleoptera, Carabidae, Lebiini, Agrina). AB - Revisions of two new species groups of the genus Agra Fabricius are presented with the following species described as new: pusilla group - Agra cruciariasp. n. (Brazil), Agra gracesp. n. (Ecuador,Peru), Agra maxsp. n. (Brazil), Agra minasianussp. n. (Brazil),Agra notpusillasp. n. (Brazil), Agra pseudopusillasp. n. (Brazil); piranha group - Agra cesp. n. (Peru), Agra risserisp. n. (Bolivia,Brazil), Agra maiasp. n. (Bolivia), Agra piranhasp. n. (Ecuador); Agra tiputinisp. n. (Ecuador). Species of these two groups have adults that are the smallest in the entire genus, although this does not indicate they are closely related based on other attributes. All species are Amazonian in distribution. PMID- 21594030 TI - Annotated checklist of the recent and extinct pythons (Serpentes, Pythonidae), with notes on nomenclature, taxonomy, and distribution. AB - McDiarmid et al. (1999) published the first part of their planned taxonomic catalog of the snakes of the world. Since then, several new python taxa have been described in both the scientific literature and non-peer-reviewed publications. This checklist evaluates the nomenclatural status of the names and discusses the taxonomic status of the new taxa, and aims to continue the work of McDiarmid et al. (1999) for the family Pythonidae, covering the period 1999 to 2010. Numerous new taxa are listed, and where appropriate recent synonymies are included and annotations are made. A checklist and a taxonomic identification key of valid taxa are provided. PMID- 21594031 TI - Palystes kreutzmanni sp. n. - a new huntsman spider species from fynbos vegetation in Western Cape Province, South Africa (Araneae, Sparassidae, Palystinae. AB - Palystes kreutzmannisp. n. is described from habitats close to Kleinmond, in the Western Cape Province, South Africa. Spiders of this new species live in the typical fynbos vegetation of the Western Cape region. They build retreats between apical leaves of Leucadendron bushes. The systematic position of Palystes kreutzmannisp. n. is discussed. Male and female show characters of different species groups, especially the female copulatory organ seems to be unique within the genus Palystes L. Koch, 1875. PMID- 21594032 TI - A new species of Corydalus Latreille from Venezuela (Megaloptera, Corydalidae). AB - A new species of dobsonfly, Corydalus wanningeri, from Venezuela, is described and illustrated. It superficially resembles Corydalus neblinensis Contreras Ramos, with a uniform reddish coloration of body and wings. Yet, because of male genitalic structure it might be closely related to Corydalus crossi Contreras Ramos. Specimens were collected from a rain forest transitional zone between the Orinoco lowlands and the Gran Sabana plateau, in Bolivar state. This is the 15(th) species of Corydalus to be recorded from Venezuela, rendering this the country with the highest number of documented Corydalus species. A key to the sexually dimorphic, long-mandibled Venezuelan species of the genus is provided. PMID- 21594033 TI - Revision of the rove beetle genus Antimerus (Coleoptera, Staphylinidae, Staphylininae), a puzzling endemic Australian lineage of the tribe Staphylinini. AB - The genus Antimerus Fauvel, 1878, endemic to eastern Australia and Tasmania and a phylogenetically enigmatic member of the large rove beetle tribe Staphylinini, is revised. The genus and each of its four previously known species are redescribed, and a lectotype is designated for Antimerus punctipennis Lea, 1906. Five species are described as new: Antimerus metallicussp. n., Antimerus jamesrodmanisp. n., Antimerus gracilissp. n., Antimerus bellussp. n. and Antimerus monteithisp. n., so that the number of known species in this genus now totals nine. For the first time Antimerus larvae are described, tentatively identified as Antimerus smaragdinus Fauvel, 1878, Antimerus punctipennis and Antimerus metallicus. Available distributional and bionomic data are provided for each species and summarized in the discussion. Adult and larval morphology of Antimerus and its distribution patterns are discussed in the broader context of new data on the evolution of the entire tribe Staphylinini, and with respect to the formation of the Australian fauna of this tribe. The phylogenetic position of Antimerus within Staphylinini remains unresolved pending a targeted formal study. However, a majority of currently available data suggests that it could be a basal member of the recently recovered monophyletic clade of Staphylinini tentatively called "Staphylinini propria". PMID- 21594034 TI - A new Tithaeus species from Hainan Island, China (Arachnida, Opiliones, Laniatores, Epedanidae), with a key to the Chinese species. AB - A new species of the harvestmen Tithaeus calyptratussp. n. (Epedanidae, Opiliones) from Hainan Island (China) is diagnosed, described and illustrated. A key to the two Chinese species of Tithaeus is provided. PMID- 21594036 TI - Skeletons in confusion: a review of astrophorid sponges with (dicho-)calthrops as structural megascleres (Porifera, Demospongiae, Astrophorida). AB - We present a review of astrophorid species possessing calthrops megascleres as structural megascleres (including species with dichotriaene modifications, but excluding mesotriaene and trichotriaene bearing species). Radiating oxeas characteristic of most astrophorids are lacking in such sponges, but auxiliary oxeas are apparently present in some species. These sponges are currently assigned to two families, Pachastrellidae with four nominal genera Dercitus, Stoeba, Dercitancorina, Halinastra (the latter two generally considered junior synonyms of Stoeba), and Calthropellidae with nominal genera Calthropella, Corticellopsis (usually considered a junior synonym), Pachataxa and Pachastrissa. Our review of many original specimens and extensive new material demonstrates the existence of considerable morphological similarity in megasclere shape and arrangement, and possible overlap of some microscleres of these sponges: pseudasters in Dercitus resembling euasters in Calthropella, ataxasters and other modified types in Calthropellidae resembling rhabds in a species of Dercitus. Pachastrellid representatives are proposed to be united in a single genus Dercitus, recognizable as (dicho-)calthrops bearing sponges with sanidaster-like microrhabds. Three subgenera, Dercitus s.s., Stoeba and the revived Halinastra are distinguished to accommodate species groups sharing additional characters. Dercitancorina is merged with Dercitus (Stoeba), because the type species, Dercitus lesinensis was found to be barely distinct from Dercitus (Stoeba) plicatus. Similarly, the calthropellid representatives are proposed to be united in a single genus Calthropella recognizable as calthrops bearing sponges with oxyasters. Three subgenera, Calthropella s.s., Pachataxa and Corticellopsis are distinguished to accommodate species groups sharing additional characters. The calthropellid genus Pachastrissa is considered a junior synonym of Calthropella s.s. because its type species, Pachastrella geodioides, is barely distinct from the type species of Calthropella, Calthropella simplex. Two species previously assigned to Dercitus or Stoeba (Dercitus loricatus and Stoeba natalensis) are excluded from the genus Dercitus as they do not fit with the emended and improved definition of the genus. One species assigned to Calthropella, Calthropella digitata, is excluded from that genus and assigned to the ancorinid genus Stelletta. Based on the similarity of the megascleres and their structure-less arrangement, we predict that the two reviewed genera will be found to be closely related and eventually will need to be accomodated in a single family, but independent molecular evidence is awaited before changes in the family classification, including a verdict on the validity of the family Calthropellidae, will be proposed. Our review included 38 valid species among which fourteen species and one subspecies appear to be new to science. Four of these were represented by insufficient material for a proper description, but the remaining ten are described as new species: Dercitus (Stoeba) senegalensissp. n., Dercitus (Stoeba) verdensissp. n., Dercitus (Stoeba) fijiensissp. n., Dercitus (Stoeba) bahamensissp. n., Dercitus (Halinastra) berausp. n., Dercitus (Halinastra) japonensissp. n., Dercitus (Halinastra) arubensissp. n., Dercitus (Halinastra) sibogaesp. n., Calthropella (Calthropella) xavieraesp. n., and Calthropella (Pachataxa) pyriferasp. n. The new subspecies, Dercitus (Dercitus) bucklandi lusitanicusssp. n. is described for southern East Atlantic populations of the nominal species. Several specimens assigned to existing species were found to be deviating to the extent that they are likely members of further undescribed species. These are briefly discussed to facilitate further studies of the diversity of the two genera. Species of both genera and the six subgenera, including deviating or insufficiently characterized specimens belonging to species not yet properly described, are keyed out. Distribution patterns are discussed. PMID- 21594037 TI - A new relictual and highly troglomorphic species of Tomoceridae (Collembola) from a deep Croatian cave. AB - Tritomurus velessp. n. (Tomoceridae) is described from a Croatian cave. It is characterized by troglomorphic features (absence of eyes, reduced pigmentation, slender claw, pointed tibiotarsal tenent hairs) that only compare, among Tomoceridae, to the microendemic species Tritomurus falcifer from the Pyrenees. Tritomurus veles also shares with Tritomurus falcifer the absence of macrochaetae on head, a presumably non-adaptive character that within Tomoceridae is unique to these two species. Both species have no known epigean relatives in their respective distribution areas and can be considered as relictual. PMID- 21594038 TI - A common terminology for the external anatomy of centipedes (Chilopoda). AB - A common terminology for the external morphological characters of centipedes (Chilopoda) is proposed. Terms are selected from the alternatives used in the English literature, preferring those most frequently used or those that have been introduced explicitly. A total of 330 terms are defined and illustrated, and another ca. 500 alternatives are listed. PMID- 21594039 TI - Araneibatrus gracilipes gen. et sp. n., a remarkable Batrisitae (Coleoptera, Staphylinidae, Pselaphinae) from P. R. China. AB - Araneibatrus gracilipesgen. n. and sp. n. from South China is described and illustrated. The systematic position of the genus is discussed. PMID- 21594040 TI - A new species of Megischus Brulle (Hymenoptera, Stephanidae) from China, with a key to the Chinese species. AB - A new species of Megischus Brulle from China, Megischus aplicatussp. n.,is described and illustrated. A key to the Chinese species of Megischus is added. The holotype is deposited in the Parasitic Hymenoptera Collection of Zhejiang University, Hangzhou. PMID- 21594041 TI - Terrestrial molluscs of Pemba Island, Zanzibar, Tanzania, and its status as an "oceanic" island. AB - Pemba is thought to have had a longer and/or stronger history of isolation than its better-known counterpart, Unguja. The extent to which the biota support this hypothesis of greater oceanicity have been debated. Here, Pemba's terrestrial mollusc ("land-snail") fauna is surveyed and reviewed for the first time. We find at best equivocal evidence for the following hallmarks of greater oceanicity: impoverishment, imbalance, and a high rate of endemism. At least 49 species are present, families are represented in typical proportions, and there are only between two and four island-endemic species - i.e. a 4% to 8% rate of endemism. For land-snails, isolation thus seems to have been short (Pleistocene) or, if longer, weak. Nevertheless, Pemba does host endemic and globally rare species. Forty-five percent of the species found, including most of these, is restricted to forest reserves, with Ngezi Forest Reserve particularly rich. A further 45% are able to tolerate the island's woody cultivated habitats. One new snail species (Cyclophoridae: Cyathopoma) and one new slug species (Urocyclidae: Dendrolimax pro tem.) are described. New data and illustrations are provided for other taxa. PMID- 21594042 TI - Five additions to the list of Sepsidae Diptera for Vietnam: Perochaeta cuirassa sp. n., Perochaeta lobo sp. n., Sepsis spura sp. n., Sepsis sepsi Ozerov, 2003 and Sepsis monostigma Thompson, 1869. AB - A recent collecting trip to Vietnam yielded three new species and two new records of Sepsidae (Diptera) for the country. Here we describe two new species in the species-poor genus Perochaeta (Perochaeta cuirassasp. n. andPerochaeta lobosp. n.) and one to the largest sepsid genus Sepsis (Sepsis spurasp. n.) which is also found in Sumatra and Sulawesi. Two additional Sepsis species are new records for Vietnam (Sepsis sepsi Ozerov, 2003; Sepsis monostigma Thompson, 1869). We conclude with a discussion of the distribution of Perochaeta and the three Sepsis species. PMID- 21594043 TI - Revision of Nearctic species of Esagonatopus, with description of a new species from Florida (Hymenoptera, Dryinidae). AB - Esagonatopus floridensissp. n. is described from Florida, Oklaloosa County (USA). A revision of the three Nearctic species of Esagonatopus Olmi, 1984 is presented. New data on geographic distribution, morphologic variability and opposite sexes of Esagonatopus niger (Fenton, 1924) and Esagonatopus perdebilis (Perkins, 1907) are given. A key to the Nearctic species of Esagonatopus is presented. PMID- 21594044 TI - Taxonomic revision and phylogenetic position of Osteocephalus festae (Anura, Hylidae) with description of its larva. AB - Osteocephalus festae is an Amazonian species recently resurrected from a synonymy with Osteocephalus buckleyi. Because few specimens are known, its morphological variation, diagnostic characters, and distribution are poorly understood. Herein we determine its phylogenetic relationships and provide a complete taxonomic account based on recently collected specimens (adults and larvae) from nine localities in Ecuador and Peru. Osteocephalus festae is most similar to Osteocephalus verruciger from which it differs in having less tuberculate dorsal skin on males, smaller tympanum, and more tooth rows in the oral disk of larvae. A phylogeny based on mitochondrial DNA sequences, genes 12S and ND1, shows that Osteocephalus festae is closely related to Osteocephalus buckleyi, Osteocephalus mutabor and Osteocephalus verruciger. A clade consisting of Osteocephalus festae, Osteocephalus verruciger, and Osteocephalus buckleyi is characterized by stream dwelling tadpoles. Surprisingly, we found paraphyly among Ecuadorian populations of Osteocephalus buckleyi and Osteocephalus verruciger. The causes for paraphyly are unknown but in Osteocephalus buckleyi may result from the existence of cryptic species. PMID- 21594045 TI - A remarkable new cave scorpion of the family Pseudochactidae Gromov (Chelicerata, Scorpiones) from Vietnam. AB - A new genus and species of scorpion belonging to the family Pseudochactidaeare described based on four specimens collected in the Tien Son cave at the Phong Nha - Ke Bang National Park, Quang Binh Province, Vietnam. The new species represents a true troglobitic element, the first one known for the family Pseudochactidae. This represents the third known record of a pseudochactid, and the first from Vietnam. PMID- 21594046 TI - Revision of the key characters for the Thricops nigrifrons species-group (Diptera, Muscidae). AB - An analysis of key characters for the separation of Thricops nigrifrons and Thricops longipes (Diptera, Muscidae) is given. A revised key for Thricops nigrifrons and related species, including two species recently described from the Caucasus, is proposed. PMID- 21594047 TI - Systematics of the Neotropical caddisfly genus Notidobiella Schmid (Trichoptera, Sericostomatidae), with the description of 3 new species. AB - Three new species of Notidobiella Schmid (Insecta: Trichoptera) are described from South America: Notidobiella amazonianasp. n. (Brazil), Notidobiella brasilianasp. n. (Brazil), and Notidobiella ecuadorensissp. n. (Ecuador). In addition, the 3 previously described species in the genus, Notidobiella chacayana Schmid, Notidobiella inermis Flint, and Notidobiella parallelipipeda Schmid, all endemic to southern Chile, are redescribed and illustrated, including the females of each species for the first time, and a key to males of the species in the genus is provided. The occurrence of Notidobiella in Brazil and Ecuador represents a significant extension of the range of the genus beyond southern Chile where it previously was thought to be endemic. The biogeography of Sericostomatidae and other austral South American Trichoptera is reviewed. The presence of the family in South America may not be part of a "transantarctic" exchange, but instead may represent an earlier occurence in the region. The distribution of Notidobiella in tropical South America likely represents recent dispersal from southern South America to the north. PMID- 21594048 TI - A revision of the genus Antepione Packard with description of the new genus Pionenta Ferris (Lepidoptera, Geometridae, Ennominae). AB - Based on genitalic studies, the new genus Pionenta is established for two taxa formerly placed under Antepione. The taxa hewesata and ochreata (and previously associated synonyms) are now synonomized as Pionenta ochreata. Three species of Antepione are now recognized: Antepione thisoaria, Antepione imitata, Antepione tiselaaria with the taxa comstocki, constans, and indiscretata synonomized under Antepione imitata. No new species are described. Adults and genitalia are illustrated, including type specimens. PMID- 21594049 TI - A new species of Heser Tuneva, 2005 (Araneae, Gnaphosidae) from the south of India. AB - A new species of Heser Tuneva, 2005 (Gnaphosidae) is described from the south of India. A key is provided to the species of Heser and the importance of Gnaphosidae for the study of world spider biodiversity is briefly discussed. PMID- 21594050 TI - Generic switch-over during ontogenesis in Dimorphacanthella gen. n. (Collembola, Isotomidae) with barcoding evidence. AB - A new genus Dimorphacanthella is established for Tetracanthella anommatos Chen and Yin, 1984 and Dimorphacanthella mediasetasp. n. from China. The new genus exhibits an unusual metamorphosis: small juveniles, previously called Uzelia anommatos Yue & Yin, 1999 get the second pair of anal spines resulted from moulting and become "Tetracanthella". Species identity of forms with two and four anal spines is proved by barcoding analysis. The derivation of anal spines is compared among genera having four anal spines. PMID- 21594051 TI - Taxonomic revision of Ectyphus Gerstaecker, 1868 and Parectyphus Hesse, 1972 with a key to world Ectyphinae (Insecta, Diptera, Mydidae). AB - The Afrotropical Mydidae genera Ectyphus Gerstaecker, 1868 and Parectyphus Hesse, 1972 are revised. Six species of Ectyphus are recognised (Ectyphus abdominalis Bezzi, 1924, Ectyphus armipes Bezzi, 1924, Ectyphus capillatus Hesse, 1969, Ectyphus pinguis Gerstaecker, 1868, and Ectyphus pretoriensis Bezzi, 1924), of which one is newly described from Kenya, Ectyphus amboselisp. n. Two species, Ectyphus bitaeniatus Hesse, 1969 and Ectyphus flavidorsalis Hesse, 1969, are newly synonymised with Ectyphus pinguis. The monotypic genus Parectyphus Hesse, 1972 and the male of its type species Parectyphus namibiensis Hesse, 1972 are re described while the female is described for the first time. Comments on the distribution of all species within biodiversity hotspots are given. A dichotomous identification key to the genera and species of world Ectyphinae is provided and illustrated keys to the world Ectyphinae are made available online in both dichotomous and multi-access, matrix-based formats. PMID- 21594052 TI - A new genus and two new species of Phygadeuontini (Hymenoptera, Ichneumonidae, Cryptinae) from China. AB - Carinityla Sheng & Sun gen. n., Carinityla punctulata Sheng & Sun sp. n. and Carinityla pilosa Sheng & Sun sp. n. belonging to the tribe Phygadeuontini of the subfamily Cryptinae (Hymenoptera, Ichneumonidae), collected from Jiangxi Province, China, are described. A key to the species of the new genus, Carinityla Sheng & Sun, gen. n., is provided and the genus is placed in Townes' key to genera of Endaseina. PMID- 21594054 TI - The scorpions of Yunnan (China): updated identification key, new record and redescriptions of Euscorpiops kubani and E. shidian (Arachnida, Scorpiones). AB - We present an identification key to the scorpion species of Yunnan (China) with notes on the distribution and ecology. Euscorpiops kubani is recorded for the first time for China. The redescriptions of Euscorpiops shidian and Euscorpiops kubani are provided. The number of known scorpion species from Yunnan is raised to nine. PMID- 21594053 TI - Family-group names in Coleoptera (Insecta). AB - We synthesize data on all known extant and fossil Coleoptera family-group names for the first time. A catalogue of 4887 family-group names (124 fossil, 4763 extant) based on 4707 distinct genera in Coleoptera is given. A total of 4492 names are available, 183 of which are permanently invalid because they are based on a preoccupied or a suppressed type genus. Names are listed in a classification framework. We recognize as valid 24 superfamilies, 211 families, 541 subfamilies, 1663 tribes and 740 subtribes. For each name, the original spelling, author, year of publication, page number, correct stem and type genus are included. The original spelling and availability of each name were checked from primary literature. A list of necessary changes due to Priority and Homonymy problems, and actions taken, is given. Current usage of names was conserved, whenever possible, to promote stability of the classification.New synonymies (family-group names followed by genus-group names): Agronomina Gistel, 1848 syn. nov. of Amarina Zimmermann, 1832 (Carabidae), Hylepnigalioini Gistel, 1856 syn. nov. of Melandryini Leach, 1815 (Melandryidae), Polycystophoridae Gistel, 1856 syn. nov. of Malachiinae Fleming, 1821 (Melyridae), Sclerasteinae Gistel, 1856 syn. nov. of Ptilininae Shuckard, 1839 (Ptinidae), Phloeonomini Adam, 2001 syn. nov. of Omaliini MacLeay, 1825 (Staphylinidae), Sepedophilini Adam, 2001 syn. nov. of Tachyporini MacLeay, 1825 (Staphylinidae), Phibalini Gistel, 1856 syn. nov. of Cteniopodini Solier, 1835 (Tenebrionidae); Agronoma Gistel 1848 (type species Carabus familiaris Duftschmid, 1812, designated herein) syn. nov. of Amara Bonelli, 1810 (Carabidae), Hylepnigalio Gistel, 1856 (type species Chrysomela caraboides Linnaeus, 1760, by monotypy) syn. nov. of Melandrya Fabricius, 1801 (Melandryidae), Polycystophorus Gistel, 1856 (type species Cantharis aeneus Linnaeus, 1758, designated herein) syn. nov. of Malachius Fabricius, 1775 (Melyridae), Sclerastes Gistel, 1856 (type species Ptilinus costatus Gyllenhal, 1827, designated herein) syn. nov. of Ptilinus Geoffroy, 1762 (Ptinidae), Paniscus Gistel, 1848 (type species Scarabaeus fasciatus Linnaeus, 1758, designated herein) syn. nov. of Trichius Fabricius, 1775 (Scarabaeidae), Phibalus Gistel, 1856 (type species Chrysomela pubescens Linnaeus, 1758, by monotypy) syn. nov. of Omophlus Dejean, 1834 (Tenebrionidae). The following new replacement name is proposed: Gompeliina Bouchard, 2011 nom. nov. for Olotelina Baguena Corella, 1948 (Aderidae).Reversal of Precedence (Article 23.9) is used to conserve usage of the following names (family-group names followed by genus-group names): Perigonini Horn, 1881 nom. protectum over Trechicini Bates, 1873 nom. oblitum (Carabidae), Anisodactylina Lacordaire, 1854 nom. protectum over Eurytrichina LeConte, 1848 nom. oblitum (Carabidae), Smicronychini Seidlitz, 1891 nom. protectum over Desmorini LeConte, 1876 nom. oblitum (Curculionidae), Bagoinae Thomson, 1859 nom. protectum over Lyprinae Gistel 1848 nom. oblitum (Curculionidae), Aterpina Lacordaire, 1863 nom. protectum over Heliomenina Gistel, 1848 nom. oblitum (Curculionidae), Naupactini Gistel, 1848 nom. protectum over Iphiini Schonherr, 1823 nom. oblitum (Curculionidae), Cleonini Schonherr, 1826 nom. protectum over Geomorini Schonherr, 1823 nom. oblitum (Curculionidae), Magdalidini Pascoe, 1870 nom. protectum over Scardamyctini Gistel, 1848 nom. oblitum (Curculionidae), Agrypninae/-ini Candeze, 1857 nom. protecta over Adelocerinae/-ini Gistel, 1848 nom. oblita and Pangaurinae/-ini Gistel, 1856 nom. oblita (Elateridae), Prosternini Gistel, 1856 nom. protectum over Diacanthini Gistel, 1848 nom. oblitum (Elateridae), Calopodinae Costa, 1852 nom. protectum over Sparedrinae Gistel, 1848 nom. oblitum (Oedemeridae), Adesmiini Lacordaire, 1859 nom. protectum over Macropodini Agassiz, 1846 nom. oblitum (Tenebrionidae), Bolitophagini Kirby, 1837 nom. protectum over Eledonini Billberg, 1820 nom. oblitum (Tenebrionidae), Throscidae Laporte, 1840 nom. protectum over Stereolidae Rafinesque, 1815 nom. oblitum (Throscidae) and Lophocaterini Crowson, 1964 over Lycoptini Casey, 1890 nom. oblitum (Trogossitidae); Monotoma Herbst, 1799 nom. protectum over Monotoma Panzer, 1792 nom. oblitum (Monotomidae); Pediacus Shuckard, 1839 nom. protectum over Biophloeus Dejean, 1835 nom. oblitum (Cucujidae), Pachypus Dejean, 1821 nom. protectum over Pachypus Billberg, 1820 nom. oblitum (Scarabaeidae), Sparrmannia Laporte, 1840 nom. protectum over Leocaeta Dejean, 1833 nom. oblitum and Cephalotrichia Hope, 1837 nom. oblitum (Scarabaeidae). PMID- 21594055 TI - A synopsis of East-Mediterranean Synaphris Simon, 1894 (Araneae, Synaphridae) with a description of a new species from Israel. AB - Three species of Synaphris occurring in the East Mediterranean - Synaphris orientalis Marusik & Lehtinen, 2003, Synaphris lehtineni Marusik, Gnelitsa & Kovblyuk, 2005 and Synaphris letourneuxi (Simon, 1884) - are surveyed; and a new species - Synaphris wunderlichisp. n. - is described from southern Israel on the basis of males. The new species differs from other East- Mediterranean congeners by its smaller size, a smaller lamella with fewer ridges, and a thick palpal femur. Comparative figures are provided for all species from the East Mediterranean. PMID- 21594056 TI - Coulmannia rossensis sp. n. (Isopoda, Asellota, Paramunnidae) from the Ross Sea, Southern Ocean. AB - A new species of Coulmannia, Coulmannia rossensis, is described from the Ross Sea, Antarctica. It is most similar to Coulmannia ramosae Castello, 2004, but can easily be distinguished from this species bythe males yielding a pair of granulate humps on the dorsum of the pereonites 1-6 and a single granulate hump on the pereonite 7 and the free pleonite. Coulmannia rossensissp. n. is sexually dimorphic. The dorsal sculpture of the female bodies yield a single granulate hump on all the pereonites and free pleonite. The species of the genus Coulmannia are restricted to the Southern Ocean, and Coulmannia rossensissp. n. is the fourth species included in it. PMID- 21594057 TI - A new species of Lithobius (Monotarsobius) Verhoeff, 1905 (Lithobiomorpha, Lithobiidae) from China. AB - The present paper deals with a new species of the genus Lithobius Leach, 1814, Lithobius (Monotarsobius) songi sp. n.(Lithobiomorpha: Lithobiidae) recently discovered in Hebei Province, China. Morphologically it resembles Lithobius (Monotarsobius) holstii (Pocock, 1895) from China and Japan but could be well distinguished from latter by havinga Tomosvary's organ slightly smaller than the adjoining ocelli, different leg plectrotaxy and tridentate claw of female gonopods. A key to the Chinese Lithobius (Monotarsobius)species is presented. PMID- 21594058 TI - Taxonomic study of the genus Neurotettix Matsumura (Hemiptera, Cicadellidae, Deltocephalinae) with a description of a new species from China. AB - This paper treats all four known species of the genus Neurotettix Matsumura, 1914 (Hemiptera, Cicadellidae, Deltocephalinae), including one new species: Neurotettix truncatussp. n. from China. A key is given to distinguish all species of the genus, and illustrations of genitalia are provided. PMID- 21594059 TI - Psychosocial dimensions of SLE: implications for the health care team. AB - BACKGROUND: The purpose of this exploratory study was threefold, ie, to clarify the unique psychosocial challenges facing those living with systemic lupus erythematosus (SLE), to distinguish which sociodemographic variables impact the lives of SLE patients, and generate knowledge regarding the way patients perceive SLE medication regimens. METHODS: This was a cross-sectional exploratory study in 378 patients diagnosed with SLE and receiving services from the SLE Lupus Foundation in New York City. In addition to sociodemographic variables, the instrument used consisted of two scales, ie, the Systemic Lupus Erythematosus Needs Questionnaire (SLENQ) and the Multidimensional Health Locus of Control Scale, as well as questions regarding subjective perceptions of side effects from SLE medication. RESULTS: The highest general cause of self-reported depressive and anxious feelings was changes in appearance due to SLE, and limitations in physical abilities due to SLE (primarily from muscle and joint pain). The higher the sense of control over SLE, the less likely respondents were to report feeling depressed and anxious. African-American and Hispanic SLE patients reported a higher level of unmet psychological needs due to SLE than did their other ethnic counterparts. Weight gain and hair loss were the most likely medication side effects and also the most likely causes of SLE-related depression and anxiety. CONCLUSION: Those living with SLE are at risk for feelings of depression and anxiety. African-American and Hispanic women are at higher risk for these emotional states. Comprehensive assessment across the disciplines should screen this group of patients for depression and anxiety, and be prepared to refer them to patient education and social work counseling as indicated. PMID- 21594060 TI - Clinical vocabulary as a boundary object in multidisciplinary care management of multiple chemical sensitivity, a complex and chronic condition. AB - BACKGROUND: Research has shown that accurate and timely communication between multidisciplinary clinicians involved in the care of complex and chronic health conditions is often challenging. The domain knowledge for these conditions is heterogeneous, with poorly categorized, unstructured, and inconsistent clinical vocabulary. The potential of boundary object as a technique to bridge communication gaps is explored in this study. METHODS: A standardized and controlled clinical vocabulary was developed as a boundary object in the domain of a complex and chronic health condition, namely, multiple chemical sensitivity, to improve communication among multidisciplinary clinicians. A convenience sample of 100 patients with a diagnosis of multiple chemical sensitivity, nine multidisciplinary clinicians involved in the care of patients with multiple chemical sensitivity, and 36 clinicians in the community participated in the study. RESULTS: Eighty-two percent of the multidisciplinary and inconsistent vocabulary was standardized using the Systematized Nomenclature of Medicine - Clinical Terms (SNOMED((r)) CT as a reference terminology. Over 80% of the multidisciplinary clinicians agreed on the overall usefulness of having a controlled vocabulary as a boundary object. Over 65% of clinicians in the community agreed on the overall usefulness of the vocabulary. CONCLUSION: The results from this study are promising and will be further evaluated in the domain of another complex chronic condition, ie, chronic pain. The study was conducted as a preliminary analysis for developing a boundary object in a heterogeneous domain of knowledge. PMID- 21594061 TI - How to deal with sociocultural pressures in daily life: reflections of adolescent girls suffering from eating disorders. AB - Adolescent girls with eating disorders experience unattainable and contradictory expectations in daily life, which create stress and negatively affect their self evaluation. Disordered eating may function as a way of seeking control and consistency. In order to make progress in the understanding of eating disorders, the aim of this study was to describe how adolescent girls with eating disorders reflect upon ways of dealing with sociocultural pressures in daily life. Eighteen interviews with girls aged 15-19 years were analyzed using a phenomenographic approach. The results were summarized into three conceptions: "Striving to be oneself " (conception A) was described as the most desirable, but also the hardest. "Adapting to various situations" (conception B) was used without much reflection, as long as it worked, but when this way of dealing with everyday expectations was unsuccessful it was evaluated negatively. "Presenting oneself in a positive light" (conception C) was described negatively even when it was successful. Within these conceptions, the participants described various strategies that could be used more or less effectively depending on the circumstances. A common theme was their difficulties in finding a balance between trying harder to live up to perceived expectations from others on one hand, and trying to accept the situation as it was, without trying to change themselves or the situation, on the other hand. The participants believed that their eating disorder was partly a result of being unable to deal with sociocultural pressures in an effective way, and they experienced a conflict between societal values of being assertive and values of being interpersonally oriented. Implications for treatment are discussed. PMID- 21594062 TI - A multidisciplinary stroke clinic for outpatient care of veterans with cerebrovascular disease. AB - BACKGROUND: Managing cerebrovascular risk factors is complex and difficult. The objective of this program evaluation was to assess the effectiveness of an outpatient Multidisciplinary Stroke Clinic model for the clinical management of veterans with cerebrovascular disease or cerebrovascular risk factors. METHODS: The Multidisciplinary Stroke Clinic provided care to veterans with cerebrovascular disease during a one-half day clinic visit with interdisciplinary evaluations and feedback from nursing, health psychology, rehabilitation medicine, internal medicine, and neurology. We conducted a program evaluation of the clinic by assessing clinical care outcomes, patient satisfaction, provider satisfaction, and costs. RESULTS: We evaluated the care and outcomes of the first consecutive 162 patients who were cared for in the clinic. Patients had as many as six clinic visits. Systolic and diastolic blood pressure decreased: 137.2 +/- 22.0 mm Hg versus 128.6 +/- 19.8 mm Hg, P = 0.007 and 77.9 +/- 14.8 mm Hg versus 72.0 +/- 10.2 mm Hg, P = 0.004, respectively as did low-density lipoprotein (LDL) cholesterol (101.9 +/- 23.1 mg/dL versus 80.6 +/- 25.0 mg/dL, P = 0.001). All patients had at least one major change recommended in their care management. Both patients and providers reported high satisfaction levels with the clinic. Veterans with stroke who were cared for in the clinic had similar or lower costs than veterans with stroke who were cared for elsewhere. CONCLUSION: A Multidisciplinary Stroke Clinic model provides incremental improvement in quality of care for complex patients with cerebrovascular disease at costs that are comparable to usual post-stroke care. PMID- 21594063 TI - A remarkable new species of the sharpshooter genus Egidemia (Insecta, Hemiptera, Cicadellidae, Cicadellinae). AB - A new species of Egidemia China, 1927, Egidemia impudica, is described and illustrated from the Department of Magdalena (Colombia). The male genitalia of the new species have a very peculiar, diagnostic feature: the pygofer is considerably reduced and truncate posteriorly, so that part of the aedeagus is exposed. A key to males of all known Egidemia species is provided. Notes comparing Egidemia impudica with the other nine known species of the genus are also given. PMID- 21594064 TI - Euglossa obrima, a new species of orchid bee from Mesoamerica, with notes on the subgenus Dasystilbe Dressler (Hymenoptera, Apidae). AB - A new species of the orchid bee subgenus Dasystilbe Dressler (Euglossini: Euglossa Latreille) is described and figured from a series of males and females collected broadly in Mesoamerica. Euglossa (Dasystilbe) obrima, sp. n., is differentiated from the one known species of Dasystilbe, Euglossa (Dasystilbe) villosa Moure, which occurs only in Panama and perhaps Costa Rica. The subgenus and its constituent species are diagnosed, and comments provided on Dasystilbe. PMID- 21594065 TI - A second species of Oculogryphus (Coleoptera, Lampyridae), with notes on the phylogenetic affinities of the genus. AB - A second species of the enigmatic lampyrid genus Oculogryphus is described and figured as Oculogryphus bicolorsp. n. from Vietnam. The definition of the genus is slightly modified with consideration of newly detected morphological variation from this species. According to a comprehensive phylogenetic analysis including nearly 80% of documented lampyrid genera, Oculogryphus is the putative sister group to Stenocladius s. str. within the paraphyletic group of Ototretinae Ototretadrilinae.The classification of Stenocladius is briefly discussed in this context. PMID- 21594066 TI - Biology and systematics of the New World Phyllocnistis Zeller leafminers of the avocado genus Persea (Lepidoptera, Gracillariidae). AB - Four New World species of Phyllocnistis Zeller are described from serpentine mines in Persea (Family Lauraceae). Phyllocnistis hyperpersea,new species, mines the upper leaf surfaces of avocado, Persea americana Mill., and red bay, Persea borbonia (L.) Spreng. and ranges over much of the southeastern United States into Central America. Phyllocnistis subpersea,new species, mines the underside and occasionally upper sides of new leaves of Persea borbonia in southeastern United States. Phyllocnistis longipalpa, new species, known only from southern Florida also mines the undersides of new leaves of Persea borbonia. Phyllocnistis perseafolia,new species, mines both leaf surfaces and possibly fruits of Persea americana in Colombia, South America. As in all known species of Phyllocnistis, the early instars are subepidermal sapfeeders in young (not fully hardened) foliage, and the final instar is an extremely specialized, nonfeeding larval form, whose primary function is to spin the silken cocoon, at the mine terminus, prior to pupation. Early stages are illustrated and described for three of the species. The unusual morphology of the pupae, particularly the frontal process of the head, is shown to be one of the most useful morphological sources of diagnostic characters for species identification of Phyllocnistis. COI barcode sequence distances are provided for the four proposed species and a fifth, undescribed species from Costa Rica. PMID- 21594067 TI - A revision of the purse-web spider genus Calommata Lucas, 1837 (Araneae, Atypidae) in the Afrotropical Region. AB - The purse-web spider genus Calommata Lucas, 1837 is revised in the Afrotropical Region. Following examination of the female type material, Calommata transvaalica Hewitt, 1916 is removed from synonymy with Calommata simoni Pocock, 1903 and revalidated. The females of both species are redescribed and their males described for the first time. While Calommata simoni is very widespread across tropical Africa, Calommata transvaalica is endemic to northern South Africa. Four new species are described, all known only from males: Calommata megaesp. n. (Zimbabwe), Calommata meridionalissp. n. (South Africa), Calommata namibicasp. n. (Namibia) and Calommata tibialissp. n. (Ivory Coast and Togo). Notes are presented on the biology of each species. PMID- 21594068 TI - Revision of the stiletto fly genera Acupalpa Krober and Pipinnipons Winterton (Diptera, Therevidae, Agapophytinae) using cybertaxonomic methods, with a key to Australasian genera. AB - Australian stiletto flies of the sister-genera Acupalpa Krober, 1912 and Pipinnipons Winterton, 2001 (Diptera: Therevidae: Agapophytinae) are revised. Twelve new species of Acupalpa are described, while Acupalpa imitans (White, 1915), comb. n. is transferred from Pipinnipons and Acupalpa albimanis (Krober, 1914), comb. n. is transferred from Ectinorhynchus Macquart as a senior synonym of Acupalpa pollinosa Mann. The total number of species of Acupalpa is therefore increased to 19: Acupalpa albimanis (Krober), comb. n., Acupalpa albitarsa Mann, Acupalpa bohartisp. n., Acupalpa divisa (Walker), Acupalpa dolichorhynchasp. n., Acupalpa glossasp. n., Acupalpa imitans (White), comb. n., Acupalpa irwini Winterton, Acupalpa melanophaeossp. n.,Acupalpa miaboolyasp. n., Acupalpa minutasp. n., Acupalpa minutoidessp. n., Acupalpa notomelassp. n., Acupalpa novayamarnasp. n., Acupalpa rostrata Krober, Acupalpa semirufa Mann, Acupalpa westralicasp. n., Acupalpa yalgoosp. n. and Acupalpa yanchepsp. n. Three new species of Pipinnipons are described, increasing the total number of species to five: Pipinnipons chauncyvallissp. n., Pipinnipons fascipennis (Krober), Pipinnipons kampmeieraesp. n., Pipinnipons kroeberi Winterton, and P. sphecodasp. n.Pipinnipons and Acupalpa are rediagnosed in light of the new species presented herein and revised keys to species are included. A dichotomous key to genera of Australasian Therevidae is included. As an empirical example of cybertaxonomy, taxonomic descriptions were composed using a character matrix developed in Lucid Builder (in Structured Descriptive Data (SDD) format) to generate natural language descriptions supplemented by online specimen and image databases. Web resources are provided throughout the document including: a) links to high resolution colour images of all species on Morphbank, b) registration of authors, publications, taxon names and other nomenclatural acts in Zoobank, with assignment of Life Science Identifiers (LSIDs) for each, c) links to Genbank accession records for DNA sequences, and d) assignment of LSIDs to specimen records with links to respective records in an online Therevidae specimen database. PMID- 21594069 TI - Revision of the Taiwanese millipede genus Chamberlinius Wang, 1956, with descriptions of two new species and a reclassification of the tribe Chamberlinini (Diplopoda, Polydesmida, Paradoxosomatidae, Paradoxosomatinae). AB - The millipede genus Chamberlinius is basically confined to Taiwan, with only one of the four known species presumably introduced to southern Japan. Both previously known species are redescribed, based on new material: Chamberlinius hualienensis Wang, 1956 (the type species) and Chamberlinius piceofasciatus (Gressitt, 1941), the latter being a new subjective senior synonym of Chamberlinius shengmui Wang, 1957, syn. n. Two further congeners are described as new: Chamberlinius pessiorsp. n. and Chamberlinius sublaevussp. n. The genus is re-diagnosed, all of its four species are keyed, and their distributions mapped. The tribe Chamberlinini is reclassified and, based on gonopod traits, shown to comprise the following five genera: Chamberlinius Wang, 1956, Haplogonosoma Brolemann, 1916, Riukiupeltis Verhoeff, 1939, Aponedyopus Verhoeff, 1939 and Geniculodesmus Chen, Golovatch and Chang, 2008. PMID- 21594070 TI - Systematics and biology of the new genus Macrosaccus with descriptions of two new species (Lepidoptera, Gracillariidae). AB - The new genus Macrosaccus Davis & De Prins is proposed for three species formerly assigned to the genus Phyllonorycter: Macrosaccus robiniella (Clemens), Macrosaccus morrisella (Fitch), and Macrosaccus uhlerella (Fitch); two new, closely related species: Macrosaccus neomexicanus Davis and Macrosaccus gliricidius Davis, are also proposed. Descriptions of the adults, pupae, larvae, life histories, and distributions are supplemented with photographs, line drawings, and scanning electron micrographs. Larvae of all species are serpentine/blotch leaf miners on various genera of the plant family Fabaceae. The genus is endemic to the New World, with the invasive species Macrosaccus robiniella now widely established in Europe. PMID- 21594071 TI - Notes on the genus Pedionis Hamilton (Hemiptera, Cicadellidae, Macropsinae), and with description of two new species from China. AB - Two new species Pedionis (Pedionis) nankunshanensis Li, Dai & Li sp. n. and Pedionis (Pedionis) tabulatus Li, Dai & Li sp. n. from China are described and illustrated. A key is given to separate all species of this genus (except Pedionis (Pedionis) oeroe and Pedionis (Pedionis) thyia). PMID- 21594072 TI - Miocene honey bees from the Randeck Maar of southwestern Germany (Hymenoptera, Apidae). AB - The Miocene Randeck Maar (southwestern Germany) is one of the only sites with abundant material of fossil honey bees. The fauna has been the focus of much scrutiny by early authors who recognized multiple species or subspecies within the fauna. The history of work on the Randeck Maar is briefly reviewed and these fossils placed into context with other Tertiary and living species of the genus Apis Linnaeus (Apinae: Apini). Previously unrecorded specimens from Randeck Maar were compared with earlier series in an attempt to evaluate the observed variation. A morphometric analysis of forewing venation angles across representative Recent and Tertiary species of Apis as well as various non-Apini controls was undertaken to evaluate the distribution of variation in fossil honey bees. The resulting dendrogram shows considerable variation concerning the wing venation of Miocene Apini, but intergradation of other morphological characters reveals no clear pattern of separate species. This suggests that a single, highly variable species was present in Europe during the Miocene. The pattern also supports the notion that the multiple species and subspecies proposed by earlier authors for the Randeck Maar honey bee fauna are not valid, and all are accordingly recognized as Apis armbrusteri Zeuner. PMID- 21594074 TI - Marine Gastrotricha of the Near East: 1. Fourteen new species of Macrodasyida and a redescription of Dactylopodola agadasys Hochberg, 2003. AB - The near eastern geographical region is almost devoid of reports of macrodasyidan gastrotrichs, the exceptions themselves being part of this study. Here, as Part 1 are described fourteen new Macrodasyida from countries of the Near East (Cyprus, Egypt and Israel, representing both the Mediterranean and the Red Seas), and a redescription of the previously described Dactylopodolidae: Dactylopodola agadasys Hochberg, 2002. The new species are: Cephalodasyidae (2) - Cephalodasys dolichosomus; Cephalodasys saegailus; Dactylopodolidae (1) Dendrodasys rubomarinus; Macrodasyidae (5) - Macrodasys imbricatus; Macrodasys macrurus; Macrodasys nigrocellus; Macrodasys scleracrus; Urodasys toxostylus; Thaumastodermatidae(4) - Tetranchyroderma corallium; Tetranchyroderma rhopalotum; Tetranchyroderma sinaiensis; Tetranchyroderma xenodactylum; Turbanellidae(2) - Paraturbanella levantia; Turbanella erythrothalassia - spp. n. PMID- 21594073 TI - First descriptions of copepodid stages, sexual dimorphism and intraspecific variability of Mesocletodes Sars, 1909 (Copepoda, Harpacticoida, Argestidae), including the description of a new species with broad abyssal distribution. AB - Mesocletodes Sars, 1909a encompasses 37 species to date. Initial evidence on intraspecific variability and sexual dimorphism has been verified for 77 specimens of Mesocletodes elmari sp. n. from various deep-sea regions, and ontogenetic development has been traced for the first time. Apomorphies are a strong spinule-like pinna on the mx seta that is fused to the basis, P2-P4 exp3 proximal outer seta lost, P1-P4 enp2 extremely elongated, furcal rami elongated, female body of prickly appearance, female P2-P4 enp2 proximal inner seta lost. Intraspecific variability involves spinulation, ornamentation and size of the body and setation and spinulation of pereiopods. Sexually dimorphic modifications of adult females include prickly appearance of the body, P1 enp exceeds exp in length, P1 coxa externally broadened, seta of basis arising from prominent protrusion, hyaline frills of body somites ornate. Sexual dimorphism in adult males is expressed in smaller body size, haplocer A1, 2 inner setae on P2-P4 enp2 and on P5 exp, P5 basendopodal lobe with 2 setae. Some modifications allow sexing of copepodid stages. The female A1 is fully developed in CV, the male A1 undergoes extensive modifications at the last molt. P1-P4 are fully developed in CV. Mesocletodes faroerensis and Mesocletodes thielei lack apomorphies of Mesocletodes and are excluded. PMID- 21594075 TI - Rhantus fengi sp. n. from Xizang, China, and notes on Laccoporus nigritulus (Gschwendtner) (Coleoptera, Dytiscidae). AB - Rhantus fengisp. n. from Mount Sejila, Xizang, China is described and illustrated. Laccoporus nigritulus (Gschwendtner, 1936) is redescribed and illustrated; Laccoporus viator Balfour-Browne, 1939, syn. n. is established as its junior subjective synonym. PMID- 21594076 TI - The millipede genus Caucasodesmus Golovatch, 1985, with the description of a new species from the Crimea, Ukraine (Polydesmida, Diplopoda, Trichopolydesmidae). AB - The hitherto monotypic genus Caucasodesmus is new to the Ukrainian list due to the discovery of Caucasodesmus tauricussp. n. in a cave in the Crimea. The new species is easily distinguished from Caucasodesmus inexpectatus Golovatch, 1985, the type, and only other, known species of this genus, in the abundantly setose collum and following metaterga, and more elaborate gonopods. The status of Caucasodesmus, which shows in the superfamily Trichopolydesmoidea where it definitely belongs such evident generic-level apomorphies as the absence of bacilliform sensilla on antennomeres 5 and 7, of a cannula on the gonocoxite, and of a seminal groove on a biramous gononod telopodite (apparently, both latter characters are functionally correlated to each other), is refined by formally reassigning it to the family Trichopolydesmidae. PMID- 21594077 TI - The millipede family Polydesmidae in Taiwan, with descriptions of five new species (Polydesmida, Diplopoda). AB - Polydesmidae are represented in Taiwan by seven species in two genera. Neither of the genera is endemic to Taiwan, but six of the species are, including five new: Nipponesmus minorsp. n., Epanerchodus bispinosussp. n., Epanerchodus curtigonopussp. n., Epanerchodus flagellifersp. n. and Epanerchodus pinguissp. n. In addition, the diagnosis of the hitherto enigmatic genus Nipponesmus Chamberlin & Wang, 1953 is refined vis-a-vis the especially similar, Central Asian, Siberian and Eastern European genus Schizoturanius Verhoeff, 1931, chiefly based on new material of the type-species Nipponesmus shirinensis Chamberlin & Wang, 1953; this species is adequately redescribed and represents still another Taiwanese endemic. A key to all three currently known species of Nipponesmus Chamberlin & Wang, 1953 is given. The highly speciose Central to East Asian genus Epanerchodus Attems, 1901 is represented in Taiwan by five species, all keyed, including Epanerchodus orientalis Attems, 1901, which is long known to be highly variable in Japan and found particularly polymorphous and apparently allochthonous in Taiwan. The following synonymy is formalized: Epanerchodus orientalis orientalis Attems, 1901 = Epanerchodus orientalis takakuwai Verhoeff, 1913, syn. n. The genus Usbekodesmus Lohmander, 1932 is formally synonymized with Epanerchodus Attems, 1901, syn. n., resulting in the following new formal transfers: Epanerchodus redikorzevi (Lohmander, 1932), Epanerchodus swatensis (Golovatch, 1991), Epanerchodus varius (Geoffroy & Golovatch, 2004), Epanerchodus anachoretus (Golovatch, 1986), Epanerchodus buddhis (Golovatch, 1986), Epanerchodus occultus (Golovatch, 1986), Epanerchodus sacer (Golovatch, 1987), Epanerchodus theocraticus (Golovatch, 1990) and Epanerchodus theosophicus (Golovatch, 1986), all comb. n. ex Usbekodesmus. The distributions of all seven species of Polydesmidae occurring in Taiwan are mapped and discussed. PMID- 21594078 TI - New species of Asphalidesmus Silvestri, 1910 from Australia (Diplopoda, Polydesmida, Dalodesmidea). AB - Asphalidesmus allynensissp. n. and Asphalidesmus dorrigensissp. n. are described from New South Wales, Asphalidesmus otwayensissp. n. from Victoria, and Asphalidesmus bellendenkerensissp. n., Asphalidesmus carbinensissp. n., Asphalidesmus magnus sp. n. and Asphalidesmus minorsp. n. from Queensland. The previously endemic Tasmanian genus Asphalidesmus Silvestri, 1910 is now known from 16 degrees S to 43 degrees S in eastern Australia, a north-south range of ca 3000 km. Asphalidesmus spp. throughout this range are very similar in overall appearance. Three of the new species are able to coil in a tight spiral. PMID- 21594079 TI - Long-term outcome of slipped capital femoral epiphysis: a 38-year follow-up of 66 patients. AB - PURPOSE: The purpose of this retrospective study was to evaluate the long-term outcome of different methods of treatment in slipped capital femoral epiphysis (SCFE), to find risk factors for poor outcome, and to assess whether prophylactic fixation is indicated. METHODS: Sixty-six patients (76 hips) treated for SCFE with a mean follow-up of 38 years (range 21-57 years) were evaluated. All except seven patients had chronic SCFE. Ten patients (15%) had bilateral affection. Three methods of treatment had been used: screw fixation (35 hips), bone-peg epiphysiodesis (30 hips), and bone-peg epiphysiodesis combined with corrective femoral osteotomy (11 hips). The long-term clinical outcome was classified as good when the patient had not undergone total hip replacement (THR), when the Harris hip score (HHS) was 85 points or above, or the patient had no pain. Good radiographic outcome was defined as no THR or osteoarthritis (OA). RESULTS: In 51 patients with chronic slip (mean slip angle 32 degrees ) treated with in situ fixation, the clinical outcome was good in 35 patients (69%) and there was no significant difference between screw fixation and bone-peg epiphysiodesis. Eight patients with large chronic slip (mean slip angle 53 degrees ) were treated with bone-peg epiphysiodesis and corrective femoral osteotomy, and the clinical outcome was poor in six patients. Seven patients with acute slip had larger mean slip angle (57 degrees ) and more complications than those with chronic slip, and the long-term outcome was poor in all. Two hips out of 42 (5%) had OA in the contralateral hip at follow-up. CONCLUSION: In situ fixation of chronic SCFE gave satisfactory long-term outcome irrespective of the treatment method. Corrective femoral osteotomy did not improve the outcome in hips with large slip angles. Acute SCFE had poor outcome. Prophylactic fixation of the contralateral hip is barely necessary. PMID- 21594080 TI - Decrease in outpatient department visits and operative interventions due to bisphosphonates in children with osteogenesis imperfecta. AB - INTRODUCTION: Bisphosphonates are currently the medical treatment most often used in children with osteogenesis imperfecta (OI). The purpose of this retrospective pre-post study was to evaluate the efficacy of treatment with bisphosphonates. We measured the effect by evaluating the number of outpatient department consultations and operative interventions before and after treatment with bisphosphonates in children with OI. METHODS AND MATERIALS: Outpatient department consultation and operative intervention frequencies before and after treatment with bisphosphonates were registered. Children who had at least 2 years of medical records before treatment and at least 2 years after treatment were used in this study. RESULTS: Of 118 children who were treated with bisphosphonates, 51 (23 boys and 28 girls) fulfilled the inclusion criteria. Statistical analysis revealed a significant decrease in outpatient department consultations (P < 0.000) and operative intervention (P < 0.003) before and after bisphosphonate treatment. CONCLUSION: The pre-post design of our study shows a significant reduction of the number of outpatient department consultations and operative interventions in patients with OI after treatment with bisphosphonates. PMID- 21594081 TI - Nesticus baeticus sp. n., a new troglobitic spider species from south-west Europe (Araneae, Nesticidae). AB - A new troglobitic species, Nesticus baeticussp. n. (??), inhabiting the karst landscapes of the high part of the Cazorla, Segura and Las Villas Natural Park (NE Jaen, Spain) where it has been found in 8 caves is diagnosed and described, its distribution and habitat are also analyzed.The new species belongs to the Iberian species group that includes Nesticus luquei, Nesticus lusitanicus and Nesticus murgis. Evolutionary relationships of the Iberian Nesticus species are discussed on the basis of morphological and molecular data (cox1 and rrnL). PMID- 21594082 TI - Stylobates birtlesi sp. n., a new species of carcinoecium-forming sea anemone (Cnidaria, Actiniaria, Actiniidae) from eastern Australia. AB - We describe a new species of carcinoecium-forming sea anemone, Stylobates birtlesisp. n., from sites 590-964 m deep in the Coral Sea, off the coast of Queensland, Australia. An anemone of this genus settles on a gastropod shell inhabited by a hermit crab, then covers and extends the shell to produce a chitinous structure termed a carcinoecium. Stylobates birtlesisp. n. is symbiotic with the hermit crab Sympagurus trispinosus (Balss, 1911). The nature of marginal sphincter muscle and nematocyst size and distribution distinguish Stylobates birtlesi sp. n. from other species in the genus. The four known species of Stylobates are allopatric, each inhabiting a separate ocean basin of the Indo West Pacific. We also extend the known range of Stylobates loisetteae in the Indian Ocean off the coast of Western Australia. PMID- 21594083 TI - Mites of the genus Neharpyrhynchus Fain (Acariformes, Harpirhynchidae) from Neotropical birds. AB - Three new species of parasitic mites of the genus Neharpyrhynchus Fain (Acariformes, Harpirhynchidae) are described from Neotropical birds: Neharpyrhynchus chlorospingussp. n. from Chlorospingus pileatus (Passeriformes, Emberizidae) from Costa Rica, Neharpyrhynchus mironovisp. n. from Dacnys cayana (Passeriformes, Thraupidae) and Neharpyrhynchus tangarasp. n. from Tangara cayana (Thraupidae) both from Brazil. Neharpyrhynchus trochilinus (Fain) is recorded from 3 new host species of the family Trochilidae (Apodiformes), Panterpe insignis and Eugenes fulgens from Costa Rica, and Amazilia lactea from Brazil. Emended diagnosis of the genus and a key to species are provided; all records of Neharpyrhynchus species are summarized. PMID- 21594084 TI - First record of the adventive oriental aphid Schizaphis piricola (Matsumura, 1917) (Hemiptera, Aphididae) in Europe. AB - The oriental aphid Schizaphis piricola (Matsumura) is recorded for the first time in Europe, on the ornamental pear tree Pyrus calleryana in landscaped areas in Madrid (Spain). Data on the morphology of the forms on primary host (apterous and alate fundatrigeniae and fundatrices), and their biology and distribution are given. The keys for identifying species of Schizaphis (Schizaphis) in the Iberian Peninsula are updated. Two species of aphids are also recorded for the first time on Pyrus calleryana: Schizaphis piricola and Aphis pomi. PMID- 21594085 TI - A new species of Simulium (Nevermannia) (Diptera, Simuliidae) from Thailand, with keys to members of the Simulium feuerborni species-group in Thailand. AB - Simulium (Nevermannia) maeaiensesp. n. is described on the basis of female, male, pupal and larval specimens collected from Chiang Mai Province, Thailand. This species is assigned to the feuerborni species-group of the subgenus Simulium (Nevermannia), and is distinctive among this species-group in having the female cibarium furnished with numerous dark minute conical processes on the lower part, the female genital fork with a strongly sclerotized horizontal bar on each arm, and six long pupal gill filaments arising nearly at the same level from the common basal stalk and lying in a horizontal plane. Identification keys to seven species of the feuerborni species-group reported from Thailand are provided for females, males, pupae and mature larvae. PMID- 21594086 TI - Planthoppers of Delaware (Hemiptera, Fulgoroidea), excluding Delphacidae, with species Incidence from adjacent States. AB - The number of species of planthoppers (excluding Delphacidae) known from Delaware is updated from 7 (in 4 families) to 62 species (in 9 families). Specimen abundance is tallied by county and seasonally by two week intervals. The Chao1 abundance estimator suggests that the true fauna may be 74 species, although species incidence tallied from adjacent states (MD, NJ, PA and DC) suggests that a total fauna of approximately 100 species may be possible. An artificial key is presented to genus and select species with photos of most included taxa. PMID- 21594087 TI - Taxonomy and biology of two seed-parasitic gracillariid moths (Lepidoptera, Gracillariidae), with description of a new species. AB - A NEW SPECIES AND NEW RECORD OF GRACILLARIID MOTHS FROM CHINA ARE REPORTED: Conopomorpha flueggella Li, sp. n. and Epicephala relictella Kuznetzov, 1979. Specimens were collected on flowers or leaves of Flueggea suffruticosa (Pall.) Baill. (Euphorbiaceae) at night, and reared from fruits in captivity. Larvae of both species feed on the seeds of Flueggea suffruticosa, but they can be differentiated externally by the position of the red pattern on the thorax and abdomen. Morphology of the eggs, larvae, pupae and the life history of the two species are described and compared. Images of the life history and figures of the genital structures are provided. PMID- 21594088 TI - A new species of the leafhopper genus Diomma Motschulsky (Hemiptera, Cidadellidae, Typhlocybinae) from China. AB - In the present paper, a new species is added to the genus Diomma Motschulsky (Hemiptera: Cicadellidae: Typhlocybinae) from Southwest China, Diomma pincersasp. n. At the same time, a key can distinguish all Chinese species of the genus is provided. PMID- 21594089 TI - Three new species of the leafhopper genus Tautoneura Anufriev (Hemiptera, Cicadellidae, Typhlocybinae) from China. AB - In the present paper, three new species are added to the genus Tautoneura Anufriev from China, Tautoneura baiyunshanasp. n., Tautoneura caoisp. n. and Tautoneura yunnanensissp. n. A key to species recorded from China is provided. PMID- 21594090 TI - A new species of Atractides Koch, 1837 (Acari, Hydrachnidia, Hygrobatidae) from Ethiopia, with a discussion on the biodiversity of the genus Atractides in the Afrotropical region. AB - A new species of Atractides Koch, 1837 (Acari, Hydrachnidia) is described from Ethiopia. The world number of Atractides now tallies 297 species. The diversity of the genus Atractides in the Afrotropical region is briefly discussed. PMID- 21594091 TI - On the Austral-Antarctic stenothoids Proboloides, Metopoides, Torometopa and Scaphodactylus (Crustacea Amphipoda) Part 2: the genus Proboloides, with description of two new genera and the transfer of two nominal species to Metopoides. AB - This is the second part of a revision of the most plesiomorphic genera in the amphipod family Stenothoidae sensu lato (see Krapp-Schickel and Koenemann 2006 for an overview and Krapp-Schickel 2008 for the first part). 41 species not belonging to Metopoides were plotted in a matrix using the same 61 characters as in the first part. The resulting group of Proboloides species (most probably not existing in the Austral-Antarctic region) is discussed, a key for the members given and two new genera erected. Some species described as Proboloides are redescribed and 2 species transferred to Metopoides. A key for all actual members of. The remaining species, i.e. those actually being in the genera Torometopa and Scaphodactylus, will be dealt with in the final part of this series, together with a key to all of them. PMID- 21594092 TI - Jacobyana Maulik, an Oriental flea beetle genus new for the Afrotropical Region with description of three new species from Central and Southern Africa (Coleoptera, Chrysomelidae, Alticinae). AB - An Orientalflea beetle genus Jacobyana Maulik, 1926 including 7 species from India, Nepal, Vietnam and Sri Lanka, is reported in the Afrotropical Region for the first time. It is represented there by three new species, Jacobyana bezdekisp. n., Jacobyana centrafricanasp. n., and Jacobyana sudafricanasp. n. Micrographs of male and female genitalia, scanning electron micrographs of some diagnostic morphological characters, a key to identification and distributional data for the new species, are provided. PMID- 21594093 TI - A new species of dialictus from sombrero island, anguilla (hymenoptera, halictidae). AB - A new species of Lasioglossum Curtis subgenus Dialictus Robertson (Halictinae, Halictini) is described and figured from a series of female and males collected on Sombrero Island, Anguilla; the northernmost island of the Lesser Antilles. Lasioglossum (Dialictus) sombrerensesp. n. is distinguished from its congeners and the name made available for a forthcoming work on the arthropod diversity of Sombrero Island. PMID- 21594094 TI - The genus Hygrocrates Deeleman-Reinhold, 1988 (Araneae, Dysderidae) in Turkey. AB - A new species, Hygrocrates deelemanus Kunt & Yagmur sp. n., is described on the basis of both sexes from the Mediterranean region of Turkey. Detailed morphological descriptions, diagnosis and figures of the copulatory organs of both Turkish species are presented. An identification key is presented for all the currently known species of Hygrocrates. PMID- 21594095 TI - Euastacus morgani sp. n., a new spiny crayfish (Crustacea, Decapoda, Parastacidae) from the highland rainforests of eastern New South Wales, Australia. AB - Euastacus morgani sp. n., is described from a highland, rainforest site in Bindarri National Park, in eastern New South Wales, Australia. Euastacus morgani is found living sympatrically with two more common species, Euastacus dangadi Morgan, 1997 and Euastacus neohirsutus Riek, 1956. Systematically, the species belongs in the 'simplex' complex of the genus that includes Euastacus simplex Riek, 1956, Euastacus clarkae Morgan, 1997, Euastacus maccai McCormack and Coughran 2008 and E. morgani. This new species differs from its nearest congenor, Euastacus simplex, in having three mesial carpal spines. A key to the 'simplex' complex is presented. PMID- 21594096 TI - New records of Caribbomerus from Hispaniola and Dominica with redescription of C. elongatus (Fisher) and a key to species of the genus in the West Indies (Coleoptera, Cerambycidae, Cerambycinae, Graciliini). AB - Three species of Caribbomerus Vitali are newly recorded for the Dominican Republic: Caribbomerus decoratus (Zayas), Caribbomerus elongatus (Fisher), and Caribbomerus asperatus (Fisher). The first two also represent first records for Hispaniola. Caribbomerus elongatus (Fisher) is redescribed based on additional material, including the first known males. Caribbomerus similis (Fisher) is newly recorded for Dominica. A key to the species of the genus from the West Indies is provided. PMID- 21594097 TI - New subgenus and new species of Oriental Omophorus (Coleoptera, Curculionidae, Molytinae, Metatygini). AB - The genus Omophorus Schoenherr, 1835 is recorded for the first time from the Oriental Region and a new subgenus and species, Omophorus (Sinomophorus subgen. n.) rongshusp. n. is described from Yunnan province (P.R. China). The new subgenus differs from the subgenus Omophorus by the longer antennal club, the bifid vestiture of the ventral parts, the elongate subtrapezoidal scutellum, the very small size of sclerotizations in the endophallus, the absence of styli in the ovipositor and the absence of the spiculum ventrale on the VIII female sternite, and from the subgenus Pangomophorus Voss, 1960 by the developed metatibial uncus and the lack of a subhumeral tubercle. A detailed description and figures are provided to allow interpretation of characters in ongoing phylogenetic analyses. PMID- 21594098 TI - A new species of Longitarsus Latreille, 1829 (Coleoptera, Chrysomelidae, Galerucinae) pupating inside stem aerenchyma of the hydrophyte host from the Oriental Region. AB - A new species of subaquatic Longitarsus pupating inside the stem aerenchyma of its hydrophyte host plant is described. Eggs are laid on tender leaves and buds and the larvae are open feeders. This is the first report of an Oriental flea beetle pupating inside the stem of its hydrophyte host. A key to the species of southern Indian Longitarsus is provided. PMID- 21594099 TI - A new species of the rare chrysidid subfamily Loboscelidiinae from China: the third species of Rhadinoscelidia Kimsey, 1988 (Hymenoptera, Chrysididae). AB - Rhadinoscelidia delta Liu, Yao & Xu, sp. n. (Chrysididae, Loboscelidiinae) is described and illustrated based on two female specimens from Hainan province. It represents the first record of the genus Rhadinoscelidia Kimsey, 1988 for China. A key to the world species of this genus is given. All specimens are preserved in the Hymenopteran Collection, South China Agricultural University (SCAU). PMID- 21594100 TI - Tanaidaceans (Crustacea) from the Central Pacific Manganese Nodule Province. I. The genera Collettea, Robustochelia and Tumidochelia. AB - Three new species of are described from the manganese nodule province between the Clarion and the Clipperton Fracture Zone of the equatorial North Pacific Ocean, and collected during the Nodinaut expedition on board the r/v l'Atalante in the summer of 2004. The new species belongs to three genera as: Collettea (Collettea longisetosa), Robustochelia (Robustochelia pacifica), and Tumidochelia (Tumidochelia tuberculata). A key to the genus Tumidochelia is presented and the validity of the genera Robustochelia and Collettea is discussed. PMID- 21594101 TI - Two new species of Urothoe (Crustacea, Amphipoda, Gammaridea) from the East Johor Islands Archipelago, Malaysia. AB - Two new species of urothoid amphipods from Pulau Sibu and Pulau Tinggi, Johor are described and illustrated. The specimens of Urothoe sibuensis new species were collected by vertical haul plankton net and is distinctively different from other existing Urothoe species by these combination of special characters; similar gnathopods 1-2 with short and stout propodus expanded into poorly defined palms; large eyes and epimeron 3 smooth. Urothoe tinggiensis new species as collected using an airlift suction sampler at seagrass area is characterized by its different gnathopodal configuration with setose dactylus of 5th pereopod; eyes minute; carpus is wider than merus in the 5th pereopod; subquadrate coxa 4; merus and carpus of pereopods 6-7 are linear. PMID- 21594102 TI - Revision of the endemic Taiwanese millipede genus Aponedyopus Verhoeff, 1939, with descriptions of two new species (Diplopoda, Polydesmida, Paradoxosomatidae). Advances in the systematica of Diplopoda III. AB - The millipede genus Aponedyopus is endemic to Taiwan and contains three species. All previously described nominal species are considered to represent one species: Aponedyopus montanus Verhoeff, 1939 (the type species), including Aponedyopus reesi (Wang, 1957) and Aponedyopus maculatus Takakuwa, 1942, syn. n. Two further species are described as new: Aponedyopus similissp. n. and Aponedyopus latilobatussp. n. The genus is re-diagnosed, all of its three species are keyed, and their distributions mapped. PMID- 21594103 TI - Review of the genus Tylopus Jeekel, 1968, with descriptions of five new species from Thailand (Diplopoda, Polydesmida, Paradoxosomatidae). AB - The genus Tylopus currently contains 41 species, all keyed and mapped, including five new from northern Thailand: Tylopus bispinosussp. n., Tylopus grandissp. n., Tylopus extremussp. n., Tylopus veligersp. n. and Tylopus parajeekelisp. n. Species of Tylopus are predominantly forest-dwellers, especially in montane habitats where up to 9-10 species can coexist per faunule. We expect many more congeners to be discovered in future, in particular from poorly or relatively poorly prospected regions such as Laos (only two species recorded), Cambodia (no species yet), Vietnam (a few species), Myanmar (a few species) and southern China (one species only). Because the genus is so species-rich and as yet so poorly sampled, a phylogenetic analysis of Tylopus would be premature. PMID- 21594104 TI - Interlinking journal and wiki publications through joint citation: Working examples from ZooKeys and Plazi on Species-ID. AB - Scholarly publishing and citation practices have developed largely in the absence of versioned documents. The digital age requires new practices to combine the old and the new. We describe how the original published source and a versioned wiki page based on it can be reconciled and combined into a single citation reference. We illustrate the citation mechanism by way of practical examples focusing on journal and wiki publishing of taxon treatments. Specifically, we discuss mechanisms for permanent cross-linking between the static original publication and the dynamic, versioned wiki, as well as for automated export of journal content to the wiki, to reduce the workload on authors, for combining the journal and the wiki citation and for integrating it with the attribution of wiki contributors. PMID- 21594105 TI - A review of the millipede genus Sinocallipus Zhang, 1993 (Diplopoda, Callipodida, Sinocallipodidae), with notes on gonopods monotony vs. peripheral diversity in millipedes. AB - The millipede genus Sinocallipus is reviewed, with four new cave-dwelling species, Sinocallipus catba, Sinocallipus deharvengi, Sinocallipus jaegeri and Sinocallipus steineri, being described from caves in Laos and Vietnam. With the new records the number of species in the genus reaches six and the genus range is extended to Central Vietnam and North and Central Laos. Both, Sinocallipus jaegeri from Khammouan Province in Laos and Sinocallipus simplipodicus Zhang, 1993 from Yunnan, China, show high level of reduction of eyes, which has not been recorded in other Callipodida. Peripheral characters such as the relative lengths of antennomeres, the number of ocelli, the number of pleurotergites or even the shape of paraprocts and the coloration seem to provide more information for the distinction of the species than do the relatively uniform gonopods. The differences in gonopods mainly concern the shape and length of cannula, the length and shape of coxal processes g and k, and the number of the acicular projections of the femoroid. An explanation is offered for the function of the trochanteral lobe of 9th leg-pair. It provides mechanical support for the cannula and seems to assist sperm charge and insemination during copulation. An identification key to the species in the genus is produced to accommodate the new species. The new species descriptions were automatically exported at the time of publication to a wiki (www.species-id.net) through a specially designed software tool, the Pensoft Wiki Convertor (PWC), implemented here for the first time together with a newly proposed citation mechanism for simultaneous journal/wiki publications. PMID- 21594106 TI - New earthworm species of the genus Amynthas Kinberg, 1867 from Thailand (Clitellata, Oligochaeta, Megascolecidae). AB - Four new species of terrestrial earthworms from the zebrus-group in the genus Amynthas Kinberg, 1867, are described from Nan province, north Thailand: Amynthas phatubensissp. n., from Tham Pha Tub Arboretum, Amynthas tontongsp. n., from Tontong Waterfall, Amynthas borealissp. n., from Chaloemprakiat district, and Amynthas srinansp. n., from Srinan National Park.After comparing with the two closely related Laos species Amynthas chandyi Hong, 2008 and Amynthas namphouinensis Hong, 2008, the four new species show clear morphological differences, and also it is confirmed that there are no previous records of the species described here. Amynthas phatubensissp. n. is the largest (longest) sized of these earthworms and is the only species that lives in limestone habitats. The genital characters are different among them and also from the two Laotian species. Molecular systematics would be a good method for further analysis of the diversity and species boundaries in SE Asian Amynthas. PMID- 21594107 TI - The larva of Eustra (Coleoptera, Paussinae, Ozaenini):a facultative associate of ants. AB - Larvae of the ground beetle genus Eustra Schmidt-Goebel are described and illustrated for the first time and some biological notes are reported. One specimen of an unknown Eustra species was collected while excavating a nest of the ant Pachycondyla javana Mayr, in Taiwan, which is the first report of a paussine associated with a member of the ant subfamily Ponerinae. Several larvae and adults of a second species, Eustra chinensis Banninger, were collected in Shanghai under bark with no association with ants. First instar larvae of the latter species were also reared in the lab. The occurrence of larvae of the genus Eustra both inside and outside ant nests, together with a report of adults collected inside a nest in Taiwan, suggests that members of this genus may be facultative predators or facultative symbionts of ants, an attribute that has never been reported for this genus. The larvae of Eustra show several unique features, including a peculiar bidentate mandibular apex, an extremely long galea, one of two tarsal claws greatly reduced, abdominal setae (including those of terminal disk) elongate and clavate at apex, urogomphi wide and flattened, and inflated sensilla S-I. Larvae were studied by both optical and scanning electron microscopy, their morphological features are compared with those of other described Paussinae larvae, and their potential phylogenetic and functional significance are discussed. PMID- 21594109 TI - A new species of Leucothoid Amphipod, Anamixis bananarama, sp. n., from Shallow Coral Reefs in French Polynesia (Crustacea, Amphipoda, Leucothoidae). AB - Both leucomorph and anamorph developmental stages of Anamixis bananaramasp. n., are illustrated and described from shallow back reef environments of Moorea, French Polynesia. Distinguished by vestigial first gnathopods that persist in post-transformational adult males, this is the second species in the genus to exhibit this unusual character. In other features such as coxae and second gnathopods Anamixis bananaramasp. n. resembles other Pacific Plate endemics of Anamixis known from the region. Specific host association is not documented but suspected to be small calcareous asconoid sponges associated with coral rubble. PMID- 21594108 TI - Taxonomic revision and phylogenetic analysis of the flightless Mancallinae (Aves, Pan-Alcidae). AB - Although flightless alcids from the Miocene and Pliocene of the eastern Pacific Ocean have been known for over 100 years, there is no detailed evaluation of diversity and systematic placement of these taxa. This is the first combined analysis of morphological and molecular data to include all extant alcids, the recently extinct Great Auk Pinguinus impennis, the mancalline auks, and a large outgroup sampling of 29 additional non-alcid charadriiforms. Based on the systematic placement of Mancallinae outside of crown clade Alcidae, the clade name Pan-Alcidae is proposed to include all known alcids. An extensive review of the Mancallinae fossil record resulted in taxonomic revision of the clade, and identification of three new species. In addition to positing the first hypothesis of inter-relationships between Mancallinae species, phylogenetic results support placement of Mancallinae as the sister taxon to all other Alcidae, indicating that flightlessness evolved at least twice in the alcid lineage. Convergent osteological characteristics of Mancallinae, the flightless Great Auk, and Spheniscidae are summarized, and implications of Mancallinae diversity, radiation, and extinction in the context of paleoclimatic changes are discussed. PMID- 21594110 TI - Nomenclatorial changes and redescriptions of three of Navas' Leucochrysa (Nodita) species (Neuroptera, Chrysopidae). AB - Three species that Navas described - Leucochrysa (Nodita) azevedoi Navas, 1913, Leucochrysa (Nodita) camposi (Navas, 1933) and Leucochrysa (Nodita) morenoi (Navas, 1934) - have received recent taxonomic attention. All three have many similar external features; indeed Navas himself, as well as subsequent authors, have confused the species with each other. Here, (a) misidentifications are corrected; (b) a neotype of Leucochrysa azevedoi is designated; (c) Leucochrysa (Nodita) morenoi, previously synonymized with Leucochrysa (Nodita) camposi, is recognized as a valid species [Reinstated status] All three species are redescribed and illustrated, with special emphasis on the types. Leucochrysa (Nodita) azevedoi was found to be relatively common in agricultural areas along Brazil's Atlantic coast. The two other species are known only from their type localities: Leucochrysa (Nodita) camposi - coastal Ecuador, and Leucochrysa (Nodita) morenoi - Quito, Ecuador. PMID- 21594111 TI - Definition and Revision of the Orthrius-group of genera (Coleoptera, Cleridae, Clerinae). AB - An "Orthrius-group" of genera is proposed, and defined to include Aphelochroa Quedenfeldt, 1885; Caridopus Schenkling, 1908; Dozocolletus Chevrolat, 1842; Gyponyx Gorham, 1883; Languropilus Pic, 1940; Orthrius Gorham, 1876; Pieleus Pic, 1940; Xenorthrius Gorham, 1892; plus three new genera Neorthriusgen. n., Nonalatusgen. n. and Pseudoastigmusgen. n. A phylogeny of the 11 constituent Orthrius-group genera (analysis of 22 morphological characters using Clerus Geoffroy as the out-group taxon was performed with TNT v1.1) is proposed. Four genera are synonymised: Burgeonus Pic, 1950, syn. n. (with Aphelochroa Quedenfeldt, 1885); Brinckodes Winkler, 1960, syn. n. and Quasibrinckodes Winkler, 1960, syn. n. (both with Dozocolletus Chevrolat, 1842); and Dedana Fairmaire, 1888, syn. n. (with Orthrius Gorham, 1876). The genera Falsoorthrius Pic, 1940 and Mimorthrius Pic, 1940 are transferred from Clerinae to the subfamily Tillinae. PMID- 21594112 TI - First record of the myrmicine ant genus Carebara Westwood, 1840 (Hymenoptera, Formicidae) from Saudi Arabia with description of a new species, C. abuhurayri sp. n. AB - The myrmicine ant genus Carebara is recorded for the first time in Saudi Arabia from the Arabian Peninsula as a whole. A new species Carebara abuhurayrisp. n. is described based on workers collected from Al Bahah region. One of the smallest ant species known to occur in Arabia, Carebara abuhurayri is found in an area inhabited by many ant species including Tetramorium sericeiventre Emery, 1877, Pheidole minuscula Bernard, 1952, Pheidole sp., Monomorium destructor (Jerdon, 1851), Monomorium exiguum (Forel, 1894) and Monomorium sp. and Crematogaster sp. PMID- 21594114 TI - Streamlining taxonomic publication: a working example with Scratchpads and ZooKeys. AB - We describe a method to publish nomenclatural acts described in taxonomic websites (Scratchpads) that are formally registered through publication in a printed journal (ZooKeys). This method is fully compliant with the zoological nomenclatural code. Our approach supports manuscript creation (via a Scratchpad), electronic act registration (via ZooBank), online and print publication (in the journal ZooKeys) and simultaneous dissemination (ZooKeys and Scratchpads) for nomenclatorial acts including new species descriptions. The workflow supports the generation of manuscripts directly from a database and is illustrated by two sample papers published in the present issue. PMID- 21594113 TI - Semantic tagging of and semantic enhancements to systematics papers: ZooKeys working examples. AB - The concept of semantic tagging and its potential for semantic enhancements to taxonomic papers is outlined and illustrated by four exemplar papers published in the present issue of ZooKeys. The four papers were created in different ways: (i) written in Microsoft Word and submitted as non-tagged manuscript (doi: 10.3897/zookeys.50.504); (ii) generated from Scratchpads and submitted as XML tagged manuscripts (doi: 10.3897/zookeys.50.505 and doi: 10.3897/zookeys.50.506); (iii) generated from an author's database (doi: 10.3897/zookeys.50.485) and submitted as XML-tagged manuscript. XML tagging and semantic enhancements were implemented during the editorial process of ZooKeys using the Pensoft Mark Up Tool (PMT), specially designed for this purpose. The XML schema used was TaxPub, an extension to the Document Type Definitions (DTD) of the US National Library of Medicine Journal Archiving and Interchange Tag Suite (NLM). The following innovative methods of tagging, layout, publishing and disseminating the content were tested and implemented within the ZooKeys editorial workflow: (1) highly automated, fine-grained XML tagging based on TaxPub; (2) final XML output of the paper validated against the NLM DTD for archiving in PubMedCentral; (3) bibliographic metadata embedded in the PDF through XMP (Extensible Metadata Platform); (4) PDF uploaded after publication to the Biodiversity Heritage Library (BHL); (5) taxon treatments supplied through XML to Plazi; (6) semantically enhanced HTML version of the paper encompassing numerous internal and external links and linkouts, such as: (i) vizualisation of main tag elements within the text (e.g., taxon names, taxon treatments, localities, etc.); (ii) internal cross-linking between paper sections, citations, references, tables, and figures; (iii) mapping of localities listed in the whole paper or within separate taxon treatments; (v) taxon names autotagged, dynamically mapped and linked through the Pensoft Taxon Profile (PTP) to large international database services and indexers such as Global Biodiversity Information Facility (GBIF), National Center for Biotechnology Information (NCBI), Barcode of Life (BOLD), Encyclopedia of Life (EOL), ZooBank, Wikipedia, Wikispecies, Wikimedia, and others; (vi) GenBank accession numbers autotagged and linked to NCBI; (vii) external links of taxon names to references in PubMed, Google Scholar, Biodiversity Heritage Library and other sources. With the launching of the working example, ZooKeys becomes the first taxonomic journal to provide a complete XML-based editorial, publication and dissemination workflow implemented as a routine and cost efficient practice. It is anticipated that XML-based workflow will also soon be implemented in botany through PhytoKeys, a forthcoming partner journal of ZooKeys. The semantic markup and enhancements are expected to greatly extend and accelerate the way taxonomic information is published, disseminated and used. PMID- 21594115 TI - The centipede genus Eupolybothrus Verhoeff, 1907 (Chilopoda: Lithobiomorpha: Lithobiidae) in North Africa, a cybertaxonomic revision, with a key to all species in the genus and the first use of DNA barcoding for the group. AB - The centipede genus Eupolybothrus Verhoeff, 1907 in North Africa is revised. A new cavernicolous species, Eupolybothruskahfi Stoev & Akkari, sp. n., is described from a cave in Jebel Zaghouan, northeast Tunisia. Morphologically, it is most closely related to Eupolybothrusnudicornis (Gervais, 1837) from North Africa and Southwest Europe but can be readily distinguished by the long antennae and leg-pair 15, a conical dorso-median protuberance emerging from the posterior part of prefemur 15, and the shape of the male first genital sternite. Molecular sequence data from the cytochrome c oxidase I gene (mtDNA-5' COI-barcoding fragment) exhibit 19.19% divergence between Eupolybothruskahfi and Eupolybothrusnudicornis, an interspecific value comparable to those observed among four other species of Eupolybothrus which, combined with a low intraspecific divergence (0.3-1.14%), supports the morphological diagnosis of Eupolybothruskahfi as a separate species. This is the first troglomorphic myriapod to be found in Tunisia, and the second troglomorph lithobiomorph centipede known from North Africa. Eupolybothrusnudicornis is redescribed based on abundant material from Tunisia and its post-embryonic development, distribution and habitat preferences recorded. Eupolybothruscloudsley-thompsoni Turk, 1955, a nominal species based on Tunisian type material, is placed in synonymy with Eupolybothrusnudicornis. To comply with the latest technological developments in publishing of biological information, the paper implements new approaches in cybertaxonomy, such as fine granularity XML tagging validated against the NLM DTD TaxPub for PubMedCentral and dissemination in XML to various aggregators (GBIF, EOL, Wikipedia), vizualisation of all taxa mentioned in the text via the dynamically created Pensoft Taxon Profile (PTP) page, data publishing, georeferencing of all localities via Google Earth, and ZooBank, GenBank and MorphBank registration of datasets. An interactive key to all valid species of Eupolybothrus is made with DELTA software. PMID- 21594116 TI - Parisognoriste, a new genus of Lygistorrhinidae (Diptera: Sciaroidea) from the Oise amber with redescription of Palaeognoriste Meunier. AB - A new genus and a new species of Lygistorrhinidae, Parisognoristeeocenica is described from the Eocene Oise amber of the Paris Basin. Parisognoristesciariforme Meunier, 1904 and Parisognoristeaffine Meunier, 1912 are re-described. Lectotypes are designated for both species of Palaeognoriste. The phylogenetic positions of the new genus and Palaeognoriste Meunier are discussed. The paper is an example demonstrating a new approach in cybertaxonomy including automatic generation of manuscript within Virtual Research Environment (Scratchpads), semantic enhancements, and parallel release of the publication on paper and on-line accompanied with registration of new taxa with ZooBank. PMID- 21594117 TI - Stomosis arachnophila sp. n., a new kleptoparasitic species of freeloader flies (Diptera, Milichiidae). AB - Stomosisarachnophila Brake sp. n. (Diptera, Milichiidae) is described from Western Australia. The species is kleptoparasitic on araneid spiders. The paper is an example for a new approach in cybertaxonomy which includes generation of manuscripts within a Virtual Research Environment (Scratchpads), semantic enhancement, parallel release of the publication on paper and online accompanied with registration of new taxa with ZooBank. PMID- 21594118 TI - World species of the genus Platyscelio Kieffer (Hymenoptera: Platygastridae). AB - The genus Platyscelio Kieffer (Hymenoptera: Platygastridae, Scelioninae) is a widespread group in the Old World, found from West Africa to northern Queensland, Australia. The species concepts are revised and a key to world species is presented. The genus is comprised of 6 species, including 2 known species which are redescribed: Platyscelioafricanus Risbec (Benin, Cameroon, Central African Republic, Ghana, Guinea, Guinea-Bissau, Ivory Coast, Kenya, Mozambique, Nigeria, Sierra Leone, South Africa, Tanzania, Togo, Uganda, Yemen, Zimbabwe); and Platysceliopulchricornis Kieffer (Australia, Bangladesh, China, India, Indonesia, Japan, Malaysia, Papua New Guinea, Philippines, Solomon Islands, Taiwan, Thailand, Vanuatu, Vietnam). Five species-group names are considered to be junior synonyms of Platysceliopulchricornis: Platyscelioabnormis Crawford syn. n., Platysceliodunensis Mukerjee syn. n., Platysceliomirabilis Dodd syn. n., Platysceliopunctatus Kieffer syn. n., and Platysceliowilcoxi Fullaway. The following species are hypothesized and described as new taxa: Platyscelioarcuatus Taekul & Johnson, sp. n. (Western Australia); Platysceliomysterium Taekul & Johnson, sp. n. (Zimbabwe, Botswana, South Africa); Platysceliomzantsi Taekul & Johnson, sp. n. (South Africa); and Platysceliostriga Taekul & Johnson, sp. n. (Western Australia). PMID- 21594119 TI - A new species of Tegenaria Latreille, 1804 (Araneae, Agelenidae) from Turkey. AB - A new species of the spider genus Tegenaria Latreille, 1804 is described, based on newly collected specimens from Turkey. Detailed morphological descriptions, diagnosis and figures of the copulatory organs of both sexes are presented. Finally, a checklist and distribution maps for Turkish Tegenaria species are provided. PMID- 21594120 TI - Taxonomic study of subgenus Plastus s. str. (Coleoptera, Staphylinidae, Osoriinae) in China, with descriptions of five new species. AB - This paper treats Chinese species of the rove beetle genus Plastus Bernhauer, 1903, subgenus Plastus s. str. (Coleoptera, Staphylinidae, Osoriinae). None of the 87 previously described species of this subgenus are known from China. The following five new species are described and illustrated: Plastus Plastus amplus Wu & Zhou, sp. n. from Xizang, Plastus Plastus rhombicus Wu & Zhou, sp. n. from Guangxi, Plastus Plastus rhombicus Wu & Zhou, sp. n. from Yunnan, Plastus Plastus shanghaiensis Wu & Zhou, sp. n. from Shanghai, and Plastus Plastus tuberculatus Wu & Zhou, sp. n. from Hainan. A key to adults of the five known Chinese species is provided. PMID- 21594121 TI - Revision of the afrotropical species of Zaprionus (Diptera, Drosophilidae), with descriptions of two new species and notes on internal reproductive structures and immature stages. AB - A new classification of the subgenus Zaprionus is proposed in light of recent phylogenetic findings. The boundaries of the armatus and inermis species groups are redefined. The vittiger subgroup is upgraded to the level of a species group. The tuberculatus subgroup is transferred from the armatus to the inermis group. A new monotypic group, neglectus, is erected. Full morphological descriptions of four species belonging to the vittiger group are given: Zaprionus lachaiseisp. n. from Tanzania and Zaprionus santomensissp. n. from Sao Tome and Principe, and two cryptic species of the indianus complex, Zaprionus africanus Yassin & David and Zaprionus gabonicus Yassin & David. Three nominal species are synonymised: Zaprionus beninensis Chassagnard & Tsacas, syn. n. with Zaprionus koroleu Burla, Zaprionus simplex Chassagnard & McEvey, syn. n. with Zaprionus neglectus Collart, and Zaprionus megalorchis Chassagnard & Tsacas, syn. n. with Zaprionus ornatus Seguy. Half of the 46 species of the subgenus are available as laboratory strains and this has allowed full descriptions of the internal structure of their reproductive systems and their immature stages. PMID- 21594122 TI - Insects attracted to Maple Sap: Observations from Prince Edward Island, Canada. AB - The collection of maple sap for the production of maple syrup is a large commercial enterprise in Canada and the United States. In Canada, which produces 85% of the world's supply, it has an annual value of over $168 million CAD. Over 38 million trees are tapped annually, 6.5% of which use traditional buckets for sap collection. These buckets attract significant numbers of insects. Despite this, there has been very little investigation of the scale of this phenomenon and the composition of insects that are attracted to this nutrient source. The present paper reports the results of a preliminary study conducted on Prince Edward Island, Canada. Twenty-eight species of Coleoptera, Lepidoptera, and Trichoptera were found in maple sap buckets, 19 of which are known to be attracted to saps and nectars. The physiological role of sap feeding is discussed with reference to moths of the tribe Xylenini, which are active throughout the winter, and are well documented as species that feed on sap flows. Additionally, 18 of the 28 species found in this study are newly recorded in Prince Edward Island. PMID- 21594123 TI - Ambengana Millidge & Russell-Smith, 1992, a synonym of Neriene Blackwall, 1833 (Araneae, Linyphiidae). AB - The taxonomic status of the genus Ambengana Millidge & Russell-Smith, 1992, is revised on the basis of its original description, illustrations and re examination of the type species. A new synonymy is proposed: Ambengana complexipalpis Millidge & Russell-Smith, 1992 (the type species of Ambengana) syn. n. with Neriene birmanica (Thorell, 1887). Therefore,the genus Ambengana Millidge & Russell-Smith, 1992 syn. n. is synonymized with Neriene Blackwall, 1833. A morphological re-description, diagnosis and comparative illustrations are provided for Neriene birmanica as well. PMID- 21594124 TI - New species and records of ortholasmatine harvestmen from Mexico, Honduras, and the western United States (Opiliones, Nemastomatidae, Ortholasmatinae). AB - The genus Trilasma Goodnight & Goodnight, 1942 is reinstated for Mexican ortholasmatines, and Cladolasma Suzuki, 1963 is reinstated for two species from Japan and Thailand, Cladolasma parvula Suzuki, comb. n. and Cladolasma angka (Schwendinger & Gruber), comb. n. Eight new species in the subfamily Ortholasmatinae Shear & Gruber, 1983 are described, as follows: Ortholasma colossussp. n. is from California, Trilasma tempestadosp. n., Trilasma hidalgosp. n., Trilasma trispinosumsp. n., Trilasma ranchonuevosp. n., Trilasma petersprouseisp. n. and Trilasma chipinquensis, sp. n. are from Mexico, and Trilasma tropicumsp. n. from Honduras, the farthest south for a dyspnoan harvestman in the New World. A new distribution record for Martensolasma jocheni Shear 2006 is given. The recently described Upper Cretaceous amber fossil Halitherses grimaldii Giribet & Dunlop 2005 is not a member of the Ortholasmatinae, but is likely a troguloidean of an undiagnosed family. PMID- 21594126 TI - A new species of Schinia Hubner from the southeastern United States (Lepidoptera, Noctuidae, Heliothinae). AB - Schinia psamatheasp. n. is described from the southern coastal plain in Georgia and the East Gulf coastal plain in Florida and Alabama in habitats associated with sandy soil or dunes. Adult males and females and their genitalia are described and illustrated. Schinia psamathea is compared to Schinia saturata (Grote). PMID- 21594125 TI - The genus Keilbachia Mohrig from Mainland China, with descriptions of two new species (Diptera, Sciaridae). AB - Seven species of Keilbachia Mohrig are recognized, and among them, two new species, Keilbachia subacumina Wu & Zhang, sp. n. and Keilbachia fengyangensis Wu & Zhang, sp. n. are described and illustrated. Five species, Keilbachia orthonema, Keilbachia flagrispina, Keilbachia demssia, Keilbachia oligonema and Keilbachia acumina are reported for the first time from China. A key to the 15 Chinese species of this genus is also provided. PMID- 21594127 TI - A new species of Odaginiceps Fiers, 1995 (Copepoda, Harpacticoida, Tetragonicipitidae) from the Mediterranean coast of Turkey. AB - Male and female of Odaginiceps korykosensissp. n. (Copepoda, Harpacticoida, Tetragonicipitidae), collected in the intertidal zone of Kizkalesi beach along the Mediterranean coast of Turkey (Mersin Province), are described. The new species is the fifth member of the genus and can easily be distinguished from the other species by the presence of four setae/spines on the second endopodal segment of P4 and by the structure of the caudal rami. Previously, representatives of the genus Odaginiceps have been reported from Gulf of Mexico, off Bermuda and Kenya. Odaginiceps korykosensissp. n. is the first record of the genus in the Mediterranean Sea. PMID- 21594128 TI - Discovery of the water scavenger beetle genus Brownephilus Mouchamps in Turkey (Coleoptera, Hydrophilidae, Hydrophilini. AB - The recently described Hydrochara major Incekara, Mart, Polat, & Karaca, 2009 from Turkey is transferred to the genus Brownephilus Mouchamps. New records and habitat information are given for the species, as well as diagnostic features for separating it from the only other described member of the genus, Brownephilus levantinus Balfour-Browne. The discovery of Brownephilus in Turkey marks the first time the lineage has been found since its original description more than seventy years ago. PMID- 21594129 TI - A new species of Myrmedonota Cameron from eastern Kansas (Coleoptera, Staphylinidae, Aleocharinae). AB - Myrmedonota helianthasp. n. is described from eastern Kansas (USA). All specimens were collected from dung. A modified new key to the species of Myrmedonota of America north of Mexico is provided. PMID- 21594130 TI - Redescription of Stenolophus thoracicus Casey (Coleoptera, Carabidae, Harpalini), a valid species. AB - Stenolophus thoracicus Casey is revalidated. The species is redescribed based on a study of the syntypes and of several conspecific specimens from eastern North America. The species differs from the other eastern species of the subgenus Agonoleptus in having the metasternum shorter and the wings reduced to tiny stubs. The dorsal habitus and median lobe of the aedeagus, along with the structures of the internal sac, are illustrated. PMID- 21594131 TI - Review of the genus Thubana Walker (Lepidoptera, Lecithoceridae) from China, with description of one new species. AB - The genus Thubana Walker is reviewed for China. Nine species are recognized, of which Thubana felinaurita Li, sp. n. is described as new; Thubana dialeukos Park, 2003 and Thubana xanthoteles (Meyrick, 1923) are newly recorded for this country; Thubana stenosis (Park, 2003), syn. n. is synonymised with Thubana xanthoteles, and Thubana microcera (Gozmany, 1978), syn. n. with Thubana leucosphena Meyrick, 1931. Images of adults and genitalia are provided. A checklist of Thubana species in China is included, along with a key to these species. PMID- 21594132 TI - Identity of Squalius (Actinopterygii, Cyprinidae) from Istra Peninsula in Croatia (Adriatic Sea basin). AB - A chub of previously ambiguous identity from the Boljunscica and Pazincica rivers (south-eastern Istra Peninsula) was studied and compared with geographically close Squalius squalus, Squalius zrmanja, and Squalius janae recently described from the Dragonja River drainage in the Adriatic Sea basin in Slovenia. It was shown that the chub from the south-eastern Istra Peninsula differs from all know species of Squalius but one: Squalius janae. Three samples examined from Boljunscica and Pazincica rivers and Squalius janae from its type locality, Dragonja River, show the following characters typical for the latter species: a long head (the head length 27-32% SL); a pointed conical snout with a clearly projecting upper jaw; a long straight mouth cleft, the lower jaw length (39-45% HL) exceeding the caudal peduncle depth; a large eye; commonly 9? branched anal fin rays; commonly 44 total vertebrae (24+20 or 25+19); bright silvery colouration, scales easily lost; iris, pectoral, pelvic and anal fin pigmentation with yellow shades. The data on the distribution of Squalius chubs in the northern Adriatic basin support the assumption that the range of Squalius janae is determined by the geology of the Trieste Flysch Basin and the Pazin Flysch Basin forming the base of the Istra Peninsula. The distribution pattern of this species does not support a simple model of fish dispersal and a complete connectivity within the whole Palaeo-Po historical drainage. Indeed, it indicates a disrupted surface palaeohydrography that was heavily fragmented by karstification in the whole Dinaric area. PMID- 21594133 TI - A new species of dactyloid anole (Iguanidae, Polychrotinae, Anolis) from the southeastern slopes of the Andes of Ecuador. AB - We describe a new species of Anolis from the southeastern slopes of the Andes of Ecuador, province of Zamora-Chinchipe, Parque Nacional Podocarpus. It belongs to (1) the aequatorialis species-group by being of moderate to large size with narrow toe lamellae, and (2) the eulaemus sub-group by having a typical Anolis digit, in which the distal lamellae of phalanx II distinctly overlap the proximal scales of phalanx I. The new species is most similar morphologically to Anolis fitchi but differs from it mainly by having a dewlap with longitudinal rows of 2 5 granular, minute scales separated by naked skin (longitudinal rows of one or two keeled, large scales separated by naked skin in Anolis fitchi) and a vertically shorter dewlap (longer dewlap in Anolis fitchi). PMID- 21594134 TI - Revision of the Agathidinae (Hymenoptera, Braconidae) of Vietnam, with the description of forty-two new species and three new genera. AB - The species of seventeen genera of Agathidinae (Braconidae) from Vietnam are revised: Agathis Latreille, 1804, Bassus Fabricius, 1804; Biroia Szepligeti, 1900; Braunsia Kriechbaumer, 1894; Camptothlipsis Enderlein, 1920; Coccygidium de Saussure, 1892; Coronagathisgen. n. (type species: Coronagathis corniferasp. n.); Cremnops Foerster, 1862; Disophrys Foerster, 1862; Earinus Wesmael, 1837; Euagathis Szepligeti, 1900; Gyragathisgen. n. (type species: Gyragathis quyisp. n.), Gyrochus Enderlein, 1920; Lytopylus Foerster, 1862; Therophilus Wesmael, 1837; Troticus Brulle, 1846, and Zelodiagen. n. (type species: Zelomorpha varipes van Achterberg & Maeto, 1990). Keys to the Vietnamese species are given.Sixty five species are recognised, of which twelve species are newly recorded for Vietnam: Bassus albifasciatus (Watanabe, 1934), Coccygidium angostura (Bhat & Gupta, 1977), Cremnops atricornis (Smith, 1874), stat. n., Disophrys erythrocephala Cameron, 1900, Gyrochus yunnanensis Wang, 1984, Lytopylus romani (Shestakov, 1940), comb. n., Therophilus festivus (Muesebeck, 1953), comb. n., Therophilus javanus (Bhat & Gupta, 1977), comb. n., Therophilus lienhuachihensis (Chou & Sharkey, 1989), comb. n., Therophilus marshi (Bhat & Gupta, 1977), comb. n., Zelodia absoluta (Chen & Yang, 1998), comb. n. and Zelodia longidorsata (Bhat & Gupta, 1977), comb. n.Forty-two species are new to science: Agathis citrinisomasp. n., Bassus albobasalissp. n., Bassus albozonatussp. n., Biroia sororsp. n., Braunsia bicoloratasp. n., Braunsia devriesisp. n., Braunsia maculiferasp. n., Braunsia nigrapiculatasp. n., Braunsia pumaticasp. n., Camptothlipsis hanoiensissp. n., Coronagathis corniferasp. n., Earinus aurantiussp. n., Earinus brevistigmussp. n., Euagathis flavosomasp. n., Disophrys maculiferasp. n., Disophrys quymanhisp. n., Disophrys rhinoidessp. n., Gyragathis quyisp. n., Therophilus annuliferussp. n., Therophilus cattienensissp. n., Therophilus contrastussp. n., Therophilus crenulisulcatussp. n., Therophilus depressiferussp. n., Therophilus elongatorsp. n., Therophilus levisomasp. n., Therophilus marucaesp. n., Therophilus mellisomasp. n., Therophilus nigrolineatussp. n., Therophilus nuichuaensissp. n., Therophilus paraspersp. n., Therophilus planifronssp. n., Therophilus punctiscutumsp. n., Therophilus robustussp. n., Therophilus rugosiferussp. n., Therophilus scutellatussp. n., Troticus alloflavussp. n., Troticus giganteussp. n., Zelodia albobasalissp. n., Zelodia anginotasp. n., Zelodia bicoloristigmasp. n., Zelodia brevifemoralissp. n. and Zelodia flavistigmasp. n.THE FOLLOWING NEW SYNONYMS ARE PROPOSED: Euagathis nigrithorax Bhat & Gupta, 1977, Euagathis variabilis Enderlein, 1920, Euagathis variabilis var. tibialis Enderlein, 1920, Euagathis variabilis var. melanopleura Enderlein, 1920 and Euagathis variabilis var. sucarandana Enderlein, 1920 with Euagathis abbotti (Ashmead, 1900); Euagathis jinshanensis Chen & Yang, 2006 and Euagathis sharkeyi Chen & Yang, 2006, with Euagathis forticarinata (Cameron, 1899). The genus Amputostypos Sharkey, 2009, is synonymised with Coccygidium de Saussure, 1892, syn. n.THE FOLLOWING NEW COMBINATIONS ARE GIVEN: Bassus subrasa (Enderlein, 1920), comb. n., Gyragathis angulosa (Bhat & Gupta, 1977), comb. n., Lytopylus romani (Shestakov, 1940), comb. n., Therophilus annulus (Chou & Sharkey, 1989), comb. n., Therophilus asper (Chou & Sharkey, 1989), comb. n., Therophilus cingulipes (Nees, 1812), comb. n., Therophilus daanyuanensis (Chen & Yang, 2006), comb. n., Therophilus fujianicus (Chen & Yang, 2006), comb. n., Therophilus javanus (Bhat & Gupta, 1977), comb. n., Therophilus lanyuensis (Chou & Sharkey, 1989), comb. n., Therophilus luzonicus (Bhat & Gupta, 1977), comb. n., Therophilus muesebecki (Bhat & Gupta, 1977), comb. n., Therophilus rudimentarius (Enderlein, 1920), comb. n., Therophilus similis (Bhat & Gupta, 1977), comb. n., Therophilus sungkangensis (Chou & Sharkey, 1989), comb. n., Therophilus tanycoleosus (Chen & Yang, 2006), comb. n., Therophilus tonghuaensis (Chen & Yang, 2006), comb. n., Therophilus tongmuensis (Chen & Yang, 2006), comb. n., Therophilus transcasperatus (Chen & Yang, 2006), comb. n., Troticus latiabdominalis (Bhat, 1978),comb. n., Zelodia absoluta (Chen & Yang, 1998), comb. n., Zelodia achterbergi (Chen & Yang, 2006), comb. n., Zelodia albopilosella (Cameron, 1908), comb. n., Zelodia chromoptera (Roman, 1913), comb. n., Zelodia nihonensis (Sharkey, 1996), comb. n., Zelodia cordata (Bhat & Gupta, 1977), comb. n., Zelodia diluta (Turner, 1918), comb. n., Zelodia dravida (Bhat & Gupta, 1977), comb. n., Zelodia exornata (Turner, 1918), comb. n., Zelodia longidorsata (Bhat & Gupta, 1977), comb. n., Zelodia longiptera (Yang & Chen, 2006), comb. n., Zelodia maculipes (Cameron, 1911), comb. n., Zelodia nigra (Bhat & Gupta, 1977), comb. n., Zelodia philippinensis (Bhat & Gupta, 1977), comb. n., Zelodia reticulosa (Yang & Chen, 2006), comb. n., Zelodia quadrifossulata (Enderlein, 1920), comb. n., Zelodia ruida (Sharkey, 1996), comb. n., Zelodia similis (Bhat & Gupta, 1977), comb. n., Zelodia penetrans (Smith, 1860), comb. n. and Zelodia varipes (van Achterberg & Maeto, 1990), comb. n. PMID- 21594135 TI - Zoogeography, taxonomy, and conservation of West Virginia's Ohio River floodplain crayfishes (Decapoda, Cambaridae). AB - The crayfish fauna of West Virginia consists of 23 species and several undescribed taxa. Most survey efforts documenting this fauna have been conducted in lotic waterways throughout the Appalachian plateau, Allegheny Mountains, and Ridge and Valley physiographic provinces. Bottomland forests, swamps, and marshes associated with large river floodplain such as the Ohio River floodplain historically have been under-surveyed in the state. These habitats harbor the richest primary burrowing crayfish fauna in West Virginia, and are worthy of survey efforts. In an effort to fill this void, the crayfish fauna of West Virginia's Ohio River floodplain was surveyed from 2004 through 2009. From this survey, nine species from four genera were documented inhabiting the floodplain. Zoogeography, biology, and conservation status is provided for all nine crayfishes. The dominant genus along the floodplain is Cambarus, which includes Cambarus (Cambarus) carinirostris, Cambarus (Cambarus) bartonii cavatus, Cambarus (Procambarus) robustus and Cambarus (Tubericambarus) thomai. Cambarus (Tubericambarus) thomai is the most prevalent burrowing species occurring along the floodplain. The genus Orconectes consists of two native species, Orconectes (Cambarus) obscurus and Orconectes (Cambarus) sanbornii; and two invasive taxa, Orconectes (Gremicambarus) virilis and Orconectes (Procambarus) rusticus. Orconectes (Cambarus) obscurus has experienced a range extension to the south and occupies streams formerly occupied by Orconectes (Cambarus) sanbornii. Both invasive taxa were allied with anthropogenic habitats and disturbance gradients. The genera Fallicambarus and Procambarus are represented by a single species. Both Fallicambarus (Cambarus) fodiens and Procambarus (Orconectes) acutus are limited to the historic preglacial Marietta River Valley. PMID- 21594136 TI - Chordodes mizoramensis (Nematomorpha, Gordiida), a new species of horsehair worm from Mizoram, North-East India. AB - Chordodes mizoramensis, a new species of freshwater gordiid horsehair worm, is described from Mizoram, NE India on the basis of scanning electron microscopic and morphometric studies. The new species can be distinguished from its congeners in that the apical filaments of the crowned areoles are branched several times, a pattern that has not been observed in other species. An additional distinguishing character is that it has more bulging areoles, which are distributed among simple areoles alone or in groups, do not form clear patterns. PMID- 21594137 TI - Coynema gen. n., a new genus of nematode (Thelastomatoidea, Hystrignathidae) parasites of Passalidae (Coleoptera) from Cuba. AB - The new genus Coynemagen. n. is described as parasite of the two passalid beetles from Cuba: Passalus interstitialis Escholtz, 1829 (type host) and Passalus pertyi Kaup, 1869. Females are characterized by the shape of their cephalic end, cervical cuticle unarmed, a sub-cylindrical procorpus with its base abruptly dilated, fore region of intestine dilated as a sac-like structure, genital system didelphic-amphidelphic and eggs markedly ovoid and smooth-shelled. Males have a digestive system similar to females, tail sharply pointed, bearing a Y-like thickening of the dorsal cuticle. They also present a big, median, mammiform pre cloacal papillae and a pair of small, sub-dorsal pre-cloacal papillae anterior to the cuticular thickening of the tail. PMID- 21594138 TI - A new species of Amblyodus Westwood, 1878 (Coleoptera, Melolonthidae, Dynastinae) from South America. AB - A second species of Amblyodus Westwood, 1878, Amblyodus castroisp. n., is described from the northern South America based on 12 specimens from Brazil and Peru (Amazonian subregion). The new species is here compared with the type species of the genus, Amblyodus taurus Westwood, 1878 and both species and their male genitalia are illustrated. Diagnostic characters for the genus are discussed, especially the metatibial teeth. A distribution map including the type species and the new species is provided. The genus Amblyodus is recorded for the first time from Peru and from Brazil states of Para and Rondonia. PMID- 21594139 TI - Contributions to the faunistics and bionomics of Staphylinidae (Coleoptera) in northeastern North America: discoveries made through study of the University of Guelph Insect Collection, Ontario, Canada. AB - Staphylinidae (Rove Beetles) from northeastern North America deposited in the University of Guelph Insect Collection (Ontario, Canada) were curated from 2008 2010 by the first author. The identification of this material has resulted in the recognition of thirty-five new provincial or state records, six new Canadian records, one new record for the United States and two new records for eastern Canada. All records are for subfamilies other than Aleocharinae and Pselaphinae, which will be treated in future publications as collaborative projects. Range expansions of ten exotic species to additional provinces and states are reported. The known distributions of each species in northeastern North America are summarized and presented as maps, and those species with a distinctive habitus are illustrated with color photographs. Genitalia and/or secondary sexual characters are illustrated for those species currently only identifiable on the basis of dissected males. The majority of the new records are in groups that have been recently revised, demonstrating the importance of curation and local insect surveys to the understanding of biodiversity, even for taxa and areas considered 'relatively well-known'. PMID- 21594140 TI - Description of two new Lophocampa Harris from the Dominican Republic (Arctiidae, Arctiinae). AB - Two new species of Lophocampa Harris are described from the Dominican Republic, Lophocampa lineatasp. n. based on two males, and Lophocampa albitegulasp. n. based on three females. The habitus and genitalia are illustrated. The following nomenclatural changes are also proposed: Lophocampa albiguttata Boisduval, 1870, stat. rev. and Lophocampa brunnea Vincent, nom. n. PMID- 21594141 TI - A survey of East Palaearctic Lycosidae (Araneae). 7. A new species of Acantholycosa Dahl, 1908 from the Russian Far East. AB - Acantholycosa azarkinaesp. n. is described from the Maritime Province of Russia on the basis of both sexes. Acantholycosa norvegica (Thorell, 1872) is reported from the Maritime Province for the first time. A key and illustrations to all six species that occur in Far East Asia are provided. PMID- 21594142 TI - A simultaneous journal / wiki publication and dissemination of a new species description: Neobidessodes darwiniensis sp. n. from northern Australia (Coleoptera, Dytiscidae, Bidessini). AB - Here, we describe a new Australian species in journal format and simultaneously open the description in a wiki format on the www.species-id.net. The wiki format will always link to the fixed original journal description of the taxon, however it permits future edits and additions to species' taxonomy and biology. The diving beetle Neobidessodes darwiniensissp. n. (Coleoptera: Dytiscidae, Bidessini) is described based on a single female, collected in a rest pool of the Harriet Creek in the Darwin Area, Northern Territory. Within Neobidessodes the new species is well characterized by its elongate oval body with rounded sides, short and stout segments of antennae, length of body and dorsal surface coloration. In addition to external morphology, we used mitochondrial cox1 sequence data to support generic assignment and to delineate the new species from other Australian Bidessini including all other known Neobidessodes. Illustrations based on digital images are provided here and as online resources. A modified key is provided. Altogether ten species of the genus are now known worldwide, nine from Australia and one from New Guinea. PMID- 21594143 TI - Seven new species within western Atlantic Starksia atlantica, S. lepicoelia, and S. sluiteri (Teleostei, Labrisomidae), with comments on congruence of DNA barcodes and species. AB - Specimens of Starksia were collected throughout the western Atlantic, and a 650 bp portion of the mitochondrial gene cytochrome oxidase-c subunit I (COl) was sequenced as part of a re-analysis of species diversity of western Central Atlantic shorefishes. A neighbor-joining tree constructed from the sequence data suggests the existence of several cryptic species. Voucher specimens from each genetically distinct lineage and color photographs of vouchers taken prior to dissection and preservation were examined for diagnostic morphological characters. The results suggest that Starksia atlantica, Starksia lepicoelia, and Starksia sluiteri are species complexes, and each comprises three or more species. Seven new species are described. DNA data usually support morphological features, but some incongruence between genetic and morphological data exists. Genetic lineages are only recognized as species if supported by morphology. Genetic lineages within western Atlantic Starksia generally correspond to geography, such that members of each species complex have a very restricted geographical distribution. Increasing geographical coverage of sampling locations will almost certainly increase the number of Starksia species and species complexes recognized in the western Atlantic. Combining molecular and morphological investigations is bringing clarity to the taxonomy of many genera of morphologically similar fishes and increasing the number of currently recognized species. Future phylogenetic studies should help resolve species relationships and shed light on patterns of speciation in western Atlantic Starksia. PMID- 21594144 TI - Revision of the Malagasy genus Trichoteleia Kieffer (Hymenoptera, Platygastroidea, Platygastridae). AB - The species of the genus Trichoteleia Kieffer (Hymenoptera: Platygastridae) are revised: 42 species are recognized, of which two were previously named and are redescribed: Trichoteleia afo Talamas, sp. n., Trichoteleia albidipes Kieffer, Trichoteleia bicolor Talamas, sp. n.; Trichoteleia bidentata Talamas sp. n.; Trichoteleia carinata Talamas, sp. n.; Trichoteleia cincta Talamas & Masner, sp. n.; Trichoteleia delilah Talamas, sp. n.; Trichoteleia eburata Talamas, sp. n.; Trichoteleia echinata Talamas, sp. n.; Trichoteleia fisheri Talamas & Masner, sp. n.; Trichoteleia funesta Talamas, sp. n.; Trichoteleia halterata Talamas & Masner, sp. n.; Trichoteleia hemlyae Talamas & Masner, sp. n.; Trichoteleia irwini Talamas & Masner, sp. n.; Trichoteleia janus Talamas, sp. n.; Trichoteleia jiro Talamas, sp. n.; T. ketrona Talamas, sp. n.; Trichoteleia levii Talamas & Johnson, sp. n.; Trichoteleia longiventris Talamas & Masner, sp. n.; Trichoteleia minima Talamas, sp. n.; Trichoteleia nify Talamas & Masner, sp. n.; Trichoteleia oculea Talamas, sp. n.; Trichoteleia orona Talamas & Masner, sp. n.; Trichoteleia parvipennis Talamas & Masner, sp. n.; Trichoteleia pauliani (Risbec); Trichoteleia picturata Talamas, sp. n.; Trichoteleia prima Talamas, sp. n.; Trichoteleia prolixa Talamas, sp. n.; Trichoteleia quazii Talamas, sp. n.; Trichoteleia ravaka Talamas, sp. n.; Trichoteleia rugifrons Talamas & Masner, sp. n.; Trichoteleia solocis Talamas, sp. n.; Trichoteleia sphaerica Talamas, sp. n.; Trichoteleia subtilis Talamas & Masner, sp. n.; Trichoteleia tahotra Talamas & Masner, sp. n.; Trichoteleia takariva Talamas, sp. n.; Trichoteleia tezitra Talamas, sp. n.; Trichoteleia tigris Talamas, sp. n.; Trichoteleia tonsa Talamas, sp. n.; Trichoteleia warreni Talamas & Masner, sp. n.; Trichoteleia xantrox Talamas, sp. n.; Trichoteleia zuparkoi Talamas & Masner, sp. n. A neotype is designated for Trichoteleia albidipes and a lectotype is designated for Trichoteleia pauliani. PMID- 21594145 TI - Twenty-four new species of Polycentropus (Trichoptera, Polycentropodidae) from Brazil. AB - Twenty-four new species of the caddisfly genus Polycentropus (Insecta: Trichoptera: Polycentropodidae) occurring in Brazil are diagnosed, described, and the male genitalia of each are illustrated. Eighteen of the new species are placed in the Polycentropus jorgenseni species complex of the Polycentropus gertschi group of New World Polycentropussensu lato. Furthermore, 6 new species within the Polycentropus gertschi group (Polycentropus ancistrussp. n., Polycentropus boraceiasp. n., Polycentropus cariocasp. n., Polycentropus froehlichisp. n., Polycentropus galharadasp. n., and Polycentropus graciosasp. n.) are placed in an informal diagnostic cluster of species with Polycentropus urubici Holzenthal and Almeida. Ten of the other Polycentropus gertschi group species form a second cluster of diagnostically similar species, the Polycentropus soniae cluster (Polycentropus caaetesp. n., Polycentropus carolaesp. n., Polycentropus cheliceratussp. n., Polycentropus fluminensissp. n., Polycentropus itatiaiasp. n., Polycentropus minerosp. n., Polycentropus santateresaesp. n., Polycentropus soniaesp. n., Polycentropus tripuisp. n., and Polycentropus virginiaesp. n.). Two of the remaining 8 new species are included in the Polycentropus jorgenseni species complex (Polycentropus cipoensissp. n. and Polycentropus verruculussp. n.), while the remaining 6 are unique and cannot be placed in one of the groups at this time (Polycentropus acinaciformissp. n., Polycentropus amphirhamphussp. n., Polycentropus cachoeirasp. n., Polycentropus inusitatussp. n., Polycentropus paprockiisp. n. and Polycentropus rosalysaesp. n.). PMID- 21594146 TI - The species of the Neotropical genus Fractipons Townes, 1970 (Hymenoptera, Ichneumonidae, Cryptinae). AB - In this paper, two new species of the Neotropical genus Fractipons Townes, 1970 (Hymenoptera, Ichneumonidae) are described. A new diagnosis for the genus, a re description of Fractipons cincticornis Townes, 1970 and a key to known species are provided. New distribution records for the genus now include Argentina, Costa Rica, Panama and Peru. PMID- 21594148 TI - Redescription of Marstonia comalensis (Pilsbry & Ferriss, 1906), a poorly known and possibly threatened freshwater gastropod from the Edwards Plateau region (Texas). AB - Marstonia comalensis, a poorly known nymphophiline gastropod (originally described from Comal Creek, Texas) that has often been confused with Cincinnatia integra, is re-described and the generic placement of this species, which was recently allocated to Marstonia based on unpublished evidence, is confirmed by anatomical study. Marstonia comalensis is a large congener having an ovate-conic, openly umbilicate shell and penis having a short filament and oblique, squarish lobe bearing a narrow gland along its distal edge. It is well differentiated morphologically from congeners having similar shells and penes and is also genetically divergent relative to those congeners that have been sequenced (mtCOI divergence 3.0-8.5%). A Bayesian analysis of a small COI dataset resolved Marstonia comalensis in a poorly supported sub-clade together with Marstonia hershleri, Marstonia lustrica and Marstonia pachyta. The predominantly new records presented herein indicate that Marstonia comalensis was historically distributed in the upper portions of the Brazos, Colorado, Guadalupe and Nueces River basins, south-central Texas. The species has been live collected at only 12 localities and only two of these have been re-visited since 1993. These data suggest that the conservation status of this snail, which has a critically imperiled (G1) NatureServe ranking and was recently proposed for federal listing, needs to be re-assessed. PMID- 21594149 TI - On the placement of the Cretaceous orthopteran Brauckmannia groeningae from Brazil, with notes on the relationships of Schizodactylidae (Orthoptera, Ensifera). AB - The fossil orthopteran Brauckmannia groeningae Martins-Neto (Orthoptera, Ensifera) from the Early Cretaceous Crato Formation of Brazil, currently misplaced at both the genus and family level, is transferred to the family Schizodactylidae and assigned to the extant genus Schizodactylus Brulle; ergo, Brauckmannia enters synonymy under Schizodactylus and Brauckmanniidae enters synonymy under Schizodactylidae. Schizodactylus groeningae (Martins-Neto), comb. n. agrees in size and general habitus with extant members of the genus, but can be readily separated by the robust, subovoid form of the metatibiae and the distinctive morphology of the lateral metabasitarsal processes. This species represents the first fossil occurrence of Schizodactylidae and the only New World record of this ancient lineage. Phylogenetic relationships of the schizodactylids are reviewed and a sister-group relationship with Grylloidea advocated based on a reappraisal of morphological and molecular evidence. PMID- 21594150 TI - Review of the European Greenomyia Brunetti (Diptera, Mycetophilidae) with new descriptions of females. AB - The females of the four continental Greenomyia Brunetti species in Europe are associated with the males, diagnosed and keyed, providing the first association and description of the females of Greenomyia baikalica Zaitzev, 1994 and Greenomyia stackelbergi Zaitzev, 1982. Colour photographs of their habitus and line drawings of their female terminalia are provided. Greenomyia mongolica Lastovka & Matile, 1974 is found to be a senior synonym of Greenomyia theresae Matile, 2002. syn. n. The diagnostic characters used to distinguish between Greenomyia and Neoclastobasis Ostroverkhova in keys did not hold up to a closer scrutiny and leave the status of Neoclastobasis as separate genus questionable. PMID- 21594151 TI - Review of the genus Isodemis Diakonoff (Lepidoptera, Tortricidae) from China, with description of three new species. AB - The genus Isodemis Diakonoff, 1952 in China is reviewed, with seven species recognized. Three new species are described: Isodemis quadratasp. n., Isodemis guangxiensissp. n. and Isodemis hainanensissp. n. The female of Isodemis stenotera Diakonoff, 1983 is described for the first time. Variation within Isodemis illiberalis (Meyrick, 1918) and Isodemis stenotera is briefly discussed. Images of the adults and genitalia are provided, along with a key to the described species. PMID- 21594152 TI - Review of the genus Merulempista Roesler, 1967 (Lepidoptera, Pyralidae) from China, with description of two new species. AB - The genus Merulempista Roesler, 1967 is reviewed for China. Of the four species treated in this paper, Merulempista rubriptera Li & Ren, sp. n. and Merulempista digitata Li & Ren, sp. n. are described as new; Merulempista cyclogramma (Hampson, 1896) is newly recorded for China, and its taxonomic position is briefly discussed. Photographs of the adults and genitalia are provided, along with a key to the known Chinese species. PMID- 21594153 TI - On some Cuban species of the genus Longior Travassos & Kloss, 1958 (Oxyurida, Hystrignathidae), with description of a new species. AB - Longior zayasi Coy, Garcia & Alvarez, 1993 is established as incertae sedis because the males (declared as the holotype) are inconsistent with the generic diagnosis, particularly in relation to the morphology of the head and tail. Thus, the females of Longior zayasi species (which agree with the generic diagnosis) are renamed and re-described as Longior longior Morffe & Garcia sp. n. We also described males found in the sample and considered as conspecific with the new species. A comparative table with the measurements of the most of the records of Longior longior is given. The male of Longior similis Morffe, Garcia & Ventosa, 2009 is described from the type locality of the species and compared with the known males of the genus. A key to the females of the Cuban Longior is given. PMID- 21594154 TI - On the identity of the fossil aquatic beetles from the Tertiary localities in the southern part of the Upper Rhine Graben (Coleoptera, Hydrophilidae, Dytiscidae). AB - This study focuses on the fossil beetles assigned previously to the family Hydrophilidae described from the localities in the southern part of the Upper Rhine Graben: Brunstatt (France, Alsace) and Kleinkems (Germany, Baden Wurttemberg) (both dated ca. to Eocene-Oligocene boundary, 34 Ma). The identity of Escheria convexa Forster, 1891 is fixed by the designation of its neotype, the species is redescribed, illustrated, transferred from the hydrophilid genus Hydrobius Leach, 1815 to the genus Copelatus Erichson, 1832 (Coleoptera: Adephaga: Dytiscidae) and compared with other fossil representatives of Copelatus. The identity of the remaining three species, Hydrobius crassipunctatus (Forster, 1891), Hydrobius dimidiatus (Forster, 1891) and Hydrobius punctulatus (Forster, 1891),is briefly evaluated on the basis of the original descriptions and illustrations only, because their types were lost or destroyed during World War II; all three species are removed from the fossil record of the Hydrophiloidea and placed into Polyphagaincertae sedis. The geology and stratigraphy of Brunnstatt and Kleinkems are discussed briefly. PMID- 21594155 TI - Redefinition of the genus Allonychiurus Yoshii, 1995 (Collembola, Onychiuridae) with description of a new species from China. AB - In this paper, we describe a new species of the genus Allonychiurus Yoshii, 1995, characterized by the presence of an apical swelling on the fourth antennal segment as well as a combination of chaetotaxic and pseudocellar characters. The genus Allonychiurus is redefined. Four of its species are considered as incertae sedis: Allonychiurus michelbacheri (Bagnall, 1948), Allonychiurus spinosus (Bagnall, 1949), Allonychiurus caprariae (Dallai, 1969) and Allonychiurus sensitivus (Handschin, 1928). The three species Allonychiurus borensis (Beruete, Arbea & Jordana, 1994), Allonychiurus sensilatus (Thibaud & Massoud, 1979) and Allonychiurus vandeli (Cassagnau, 1960) are removed from Allonychiurus and placed in Micronychiurus Bagnall, 1949, Thalassaphorura Bagnall, 1949 and Spinonychiurus Weiner, 1996 respectively. The synonymy of Thibaudichiurus Weiner, 1996 with Allonychiurus is rejected and Allonychiurus foliatus (Rusek, 1967) and Allonychiurus mariangeae (Thibaud & Lee, 1994) are re-allocated to Thibaudichiurus. List and identification key to the world species of the genus are given. PMID- 21594156 TI - Cachiporrini, a remarkable new tribe of Lamprosomatinae (Coleoptera, Chrysomelidae) from South America. AB - A new genus and species of Lamprosomatinae, Cachiporra extremaglobosa Chamorro & Konstantinov, is described from Brazil. A new tribe, Cachiporrini, is proposed. The first phylogenetic analysis of Lamprosomatinae based on adult morphological caharacters is conducted. Comparisons are made among lamprosomatine tribes and genera. A key to tribes is provided. PMID- 21594157 TI - First record of the genus aprivesa melichar (hemiptera: fulgoromorpha) from South India, with description of one new species. AB - Aprivesa unimaculatasp. n. (Hemiptera: Fulgoromorpha: Ricaniidae) is described and illustrated from Coorg, south India. This represents the first record of the genus Aprivesa Melichar from India and the fourth known species of Aprivesa. The new taxon greatly extends the range of the genus Aprivesa, which was previously known as an endemic Australian genus. A checklist of all known species of the Ricaniidae from India and keys to all the known genera of the Ricaniidae from India and all species in the genus are provided. PMID- 21594158 TI - Volatile compounds released by disturbed and undisturbed adults of Anchomenus dorsalis (Coleoptera, Carabidae, Platynini) and structure of the pygidial gland. AB - Volatile compounds produced by adults of Anchomenus dorsalis under undisturbed and disturbed conditions were investigated with an all-glass aeration apparatus. GC-MS analysis of the crude extracts from undisturbed and disturbed adults highlighted four major volatile compounds, undecane, heneicosane, Z-9 tricosene and tricosane, of which significantly more undecane was released by disturbed adults compared to undisturbed beetles. The pygidial glands of adults of Anchomenus dorsalis were investigated using light and Transmission Electron Microscopy (TEM). Each gland showed dense aggregates of secretory cells organized into visually distinct lobes; a long collecting canal that drains the secretion towards the reservoir, a bean-shaped double lobed muscular reservoir in which secretion is stored and a short duct (efferent duct) through which the secretion is discharged. The function of the pygidial glands and the possible role played by undecane as a defensive allomone and/or chemical signalling molecule are discussed. PMID- 21594159 TI - The first Strigocis Dury (Coleoptera, Ciidae) from the southern Neotropical region and a provisional key to world species. AB - Strigocis vicosensis Lopes-Andrade, sp. n. is described based on specimens from a single locality (type locality: Vicosa, state of Minas Gerais, southeastern Brazil), being the southernmost record of a Strigocis Dury species. Diagnostic to this new species are the dorsal vestiture consisting of stout yellowish bristles, pronotal punctures separated from each other by at least 0.75* puncture-width and sutural flange of elytra not diverging near apex. Males have both frontoclypeal ridge and anterior pronotal margin produced forward and emarginated at middle forming two small subtriangular plates, and a small abdominal sex patch. Among the New World Strigocis, it most resembles Strigocis bilimeki (Reitter), of which images of male terminalia, as far as ventral and dorsal SEM images of males are also provided. The morphological limits of Strigocis are briefly discussed and redefined, and a provisional key to the world species is provided. PMID- 21594160 TI - Review of the genus Fibuloides Kuznetsov in China (Lepidoptera, Tortricidae, Olethreutinae). AB - Species of the genus Fibuloides Kuznetsov that occur in China are reviewed. Fibuloides trapezoidea, sp. n.is described as new; Fibuloides levatana (Kuznetsov) and Fibuloides modificana Kuznetsov are newly recorded for China; Acroclita nigrovenana Kuznetsov, syn. n. is considered as a synonym of Fibuloides corinthia (Meyrick); and Eucoenogenes elongata Zhang & Li and Eucoenogenes wuyiensis Zhang & Li are transferred to Fibuloides, resulting in two new combinations. A key to the nine Chinese species of Fibuloides is given. PMID- 21594161 TI - A new Gephyromantis (Phylacomantis) frog species from the pinnacle karst of Bemaraha, western Madagascar. AB - We describe a new mantellid frog of the subfamily Mantellinae from the karstic Bemaraha Plateau, western Madagascar. The new species belongs to the genus Gephyromantis, subgenus Phylacomantis, which previously included Gephyromantis azzurrae, Gephyromantis corvus and Gephyromantis pseudoasper. Gephyromantis atsingysp. n. has a snout-vent length of 35-43 mm and is a scansorial frog living among the Tsingy de Bemaraha pinnacles and inside the caves present in the area. A morphological analysis and biomolecular comparison revealed the degree of differentiation between these four species of the Phylacomantis subgenus.The new species seems to be endemic to Tsingy de Bemaraha. PMID- 21594162 TI - A new genus of soft coral of the family Alcyoniidae (Cnidaria, Octocorallia) with re-description of a new combination and description of a new species. AB - A new genus, Aldersladum (family Alcyoniidae), is established to accommodate a previously described species, Efflatounaria sodwanae Benayahu, 1993 (family Xeniidae) from Sodwana Bay, South Africa that was wrongly assigned to the latter genus. This species is redescribed and a second new species, Aldersladum jengi from Penghu Is., Taiwan, is described. The diagnostic features of the new genus include the presence of only figure-eight shaped platelets in all parts of the colony, thus differentiating it from all known genera of the Alcyoniidae. Based on examination of additional material from other localities, the zoogeographical distribution of the genus is confirmed to include the coral reefs of South Africa, Kenya, Gulf of Oman, Taiwan and Japan. Phylogenetic analyses of two mitochondrial genes strongly support its placement in the family Alcyoniidae. PMID- 21594163 TI - Notes on the Nazeris fauna of Yunnan Province, China (Coleoptera, Staphylinidae, Paederinae). AB - Two new species of the genus Nazeris Fauvel collected from Nabanhe Nature Reserve, Yunnan Province, are described under the names of Nazeris nabanhensissp. n. and Nazeris caoisp. n. The male sexual characters are described and illustrated. A key to the Nazeris species of Yunnan is provided. A map of the collecting sites is given. PMID- 21594164 TI - Taxonomic redescription and biological notes on Diaugia angusta (Diptera, Tachinidae): parasitoid of the palm boring weevils Metamasius ensirostris and M. hemipterus (Coleoptera, Dryophthoridae). AB - Diaugia angusta Perty, 1833 is a Neotropical species of Tachinidae (Diptera) reported here as a parasitoid of Metamasius ensirostris (Germar, 1824) and Metamasius hemipterus (Linnaeus, 1758) (Coleoptera: Dryophthoridae) in Brazil. Several species of Dryophthoridae and Curculionidae cause damage to bromeliad and palm species, and most are regarded as pests. In the present study, the male and female of Diaugia angusta are morphologically characterized and illustrated to provide a means for the identification of this parasitoid. Data obtained from preliminary field research show that natural parasitism of Metamasius pupae by Diaugia angusta varies by year but can reach nearly 30%. A network of parasitoid host interactions among tachinid parasitoids and coleopteran hosts reported as bromeliad and palm pests (Dryophthoridae and Curculionidae) in the Americas indicates that the species of the tribe Dexiinisensu lato (including Diaugia angusta) might be promising as biological control agents of these pests. PMID- 21594165 TI - Revision of the South American window fly genus Heteromphrale Krober, 1937 (Diptera, Scenopinidae). AB - The Neotropical window fly genus Heteromphrale Krober, 1937 is revised. Two previously described species (Heteromphrale chilensis (Krober, 1937) and Heteromphrale cyanops (Edwards, 1932)) are redescribed while a new species (Heteromphrale blancasp. n.) is described from Argentina. The male of Heteromphrale chilensis and female of Heteromphrale cyanops are described and figured for the first time, and a key to species is presented. PMID- 21594166 TI - Review of the Palaearctic members of the Lispe tentaculata species-group (Diptera, Muscidae): revised key, synonymy and notes on ecology. AB - The taxonomic reasons for regarding Lispe draperi Seguy, 1933, sp. rev., as a valid species instead of a synonym of Lispe tentaculata (De Geer, 1776) and for treating Lispe quaerens Villeneuve, 1936, syn. n., as a junior synonym of Lispe sericipalpis Stein, 1904 are given. A revised key for the Palaearctic members of the Lispe tentaculata species-group is given. Data on ecology, distribution and feeding preferences are provided. PMID- 21594167 TI - Calosota Curtis (Hymenoptera, Chalcidoidea, Eupelmidae) - review of the New World and European fauna including revision of species from the West Indies and Central and North America. AB - Two of three species previously classified in Calosota Curtis (Hymenoptera: Eupelmidae) from the Neotropical region are transferred to Eupelminae. Calosota eneubulus (Walker) from Galapagos Islands is transferred to Eupelmus Dalman as Eupelmus (Eupelmus) eneubulus (Walker), comb. n., and Calosota silvai (Brethes) from Chile is transferred to Brasema Cameron as Brasema silvaicomb. n.Calosota cecidobius (Kieffer) from Argentina is retained in Calosota, with reservation, as an unrecognized species. The species of Calosota from the New World excluding South America are revised. Eleven species are recognized, including the seven newly described species Calosota albipalpussp. n. (Costa Rica, Mexico, USA, Venezuela), Calosota bicoloratasp. n. (USA), Calosota elongatasp. n. (USA), Calosota longivenasp. n. (USA), Calosota panamaensissp. n. (Panama), Calosota setosasp. n. (Bahamas, Dominican Republic, USA), and Calosota speculifronssp. n. (Costa Rica, USA). The 11 regional species and the Palaearctic species Calosota vernalis Curtis are keyed and illustrated. Calosota vernalis is not known to occur in the New World but is included in the key and diagnosed because it has been intercepted in quarantine in Canada. Calosota pseudotsugae Burks is placed in synonymy under Calosota acron (Walker), syn. n.,and Calosota kentra Burks, Calosota montana Burks and Calosota septentrionalis Hedqvist are placed in synonymy under Calosota aestivalis Curtis syn. n.Calosota modesta Bolivar y Pieltain is removed from synonymy under Calosota viridis Masi, stat. rev., and Calosota viridis, Calosota matritensis Bolivar y Pieltain, and Calosota coerulea Nikol'skaya are placed in synonymy under Calosota metallica (Gahan), syn. n.Calosota grylli Erdos is confirmed as a separate species from Calosota metallica based on features of both sexes. It is suggested that Calosota ariasi Bolivar y Pieltain may be a synonym of Calosota aestivalis, Calosota bolivari Askew may be a synonym of Calosota agrili Nikol'skaya, Calosota dusmeti Bolivar y Pieltain may be a synonym of Calosota violascens Masi, and Calosota lixobia Erdos likely is not a junior synonym of Calosota obscura Ruschka, but formal nomenclatural changes are not proposed prior to a comprehensive Palaearctic revision. Previous interpretation of the mesoscutum in Calosota and Balcha Walker is also modified to include the presence of anteroadmedian lines in addition to notauli and parapsidal lines. PMID- 21594168 TI - A festschrift for stephen L. Wood. PMID- 21594169 TI - New species and records of Cactopinus Schwarz with a key to species (Coleoptera, Curculionidae, Scolytinae). AB - Three new species in the genus Cactopinus Schwarz are described from Mexico and the U.S., bringing the total of known species to 21. New host and distribution records and a new key to species are included. PMID- 21594170 TI - Notes on Scolytus fagi Walsh 1867 with the ignation of a neotype, distribution notes and Key to Scolytus Geoffroy of America east the Mississippi River (Coleoptera, Curculionidae, Scolytinae, Scolytini). AB - The identification of Scolytus fagi Walsh has been difficult because of the lack of diagnostic literature, the occurrence of several morphologically similar sympatric Scolytus species and the loss of the syntypes. In an effort to reduce taxonomic confusion, we designate a neotype for Scolytus fagi, redescribe the male and female, add new distributional records and create a key for the identification of eastern Scolytus species. PMID- 21594171 TI - Stevewoodia minutum, a new genus and species of Scolytidae (Coleoptera) from the West Indies. Studies on West Indian Scolytidae (Coleoptera) 6. AB - A new genus of Scolytidae (Coleoptera), Stevewoodia, from St. Lucia in the Lesser Antilles, is herein named and described. The type species, Stevewoodia minutumsp. n. is also named. The genus is named in honor of the late Steven L. Wood for his many contributions to the systematics of the Scolytidae. PMID- 21594172 TI - Resurrection of Dryotomicus Wood and description of two new species from the Amazon River Basin (Coleoptera, Curculionidae, Scolytinae, Phloeotribini). AB - A cladistic analysis based on 20 morphological characters was conducted for 11 species representing two valid and two synonymized Phloeotribini genera. One hundred-eighty most-parsimonious trees were recovered and the Dryotomicus Wood species were monophyletic in a mostly unresolved strict-consensus tree. The unusual antennal morphology, with the length of the first two funicular segments equal to the last three segments and a scape which is twice the length of the funicle, distinguish Dryotomicus from the other Phloeotribini genera. Hence this genus is resurrected because of monophyly and diagnostic characters. Dryotomicus oenophilissp. n. and Dryotomicus woodrexsp. n. are described from Guyana and Peru, respectively. In the male specimen of Dryotomicus oenophilis, the frons has one median and two large lateral carinae and in the male specimen of Dryotomicus woodrex, the frons has three smaller median tubercles arranged transversely. Phloeotribus puberulus Chapuis and Phloeotribus tuberculatus (Eggers) were monophyletic with the new Dryotomicus species and thus are transferred to this genus. Keys to the Phloeotribini genera and Dryotomicus species are given. PMID- 21594173 TI - New data on Neotropical Scolytus Geoffroy, 1762 with description of five new species from Peru (Coleoptera, Curculionidae, Scolytinae). AB - Five new species of Scolytus Geoffroy, 1762 (Coleoptera: Curculionidae: Scolytinae) are described from Peru, namely Scolytus woodi, Scolytus carveli, Scolytus vagabundus, Scolytus lindemani, Scolytus mozolevskae .The following new synonym is established: Scolytus angustatus Browne, 1970 (= Scolytus facialis Schedl, 1973, syn. n.) New records of the Scolytus species in Loreto, Junin ,Cusco and Madre de Dios Provinces are given and the biology of the genus representatives is discussed. PMID- 21594174 TI - Taxonomic changes in palaeotropical Xyleborini (Coleoptera, Curculionidae, Scolytinae). AB - Following the recent reclassification of the Palaeotropic xyleborine genera (Hulcr and Cognato in press), additional species are transferred to correct genera or synonymized based on analysis of their morphological characters. The following species are given new combinations: Debus amphicranoides (Hagedorn), comb. n., Debus birmanus (Eggers, 1930), comb. n., Debus dolosus (Blandford, 1896), comb. n., Debus eximius (Schedl, 1970), comb. n., Debus interponens (Schedl, 1954), comb. n., Debus robustipennis (Schedl, 1954), comb. n., Debus spinatus (Eggers, 1923), comb. n., Microperus alpha (Beeson, 1929), comb. n., Microperus corporaali (Eggers), comb. n., Microperus eucalyptica (Schedl, 1938), comb. n., Microperus nugax (Schedl, 1939), comb. n., Pseudowebbia percorthylus (Schedl, 1935), comb. n., Truncaudum circumcinctus (Schedl, 1941), comb. n.THE FOLLOWING SPECIES ARE SYNONYMIZED: Arixyleborus hirtipennis (Eggers), syn. n., with Arixyleborus puberulus (Blandford); Coptoborus palmeri (Hopkins), syn. n., with Debus emarginatus (Eichhoff); Coptoborus terminaliae (Hopkins), syn. n., with Debus emarginatus (Eichhoff); Cyclorhipidion polyodon (Eggers), syn. n., with Truncaudum agnatum (Eggers); Euwallacea artelaevis (Schedl), syn. n., with Planiculus bicolor (Blandford); Xyleborinus perminutissimus (Schedl), syn. n., with Xyleborinus perpusillus (Eggers); Xyleborus exesus Blandford, syn. n., with Debus emarginatus (Eichhoff); Xyleborus fulvulus (Schedl), syn. n., with Microperus corporaali (Eggers); Xyleborus marginicollis (Schedl), syn. n., with Diuncus justus (Schedl); Xyleborus shoreae Stebbing, syn. n., with Debus fallax (Eichhoff).THE FOLLOWING SPECIES ARE GIVEN NEW STATUS: Streptocranus superbus (Schedl, 1951), restored name; Webbia divisus Browne, 1972, restored name; Webbia penicillatus (Hagedorn, 1910), restored name. Genus Taphrodasus Wood (1980) is declared not valid. PMID- 21594175 TI - The external morphology of Austroplatypus incompertus (Schedl) (Coleoptera, Curculionidae, Platypodinae). AB - Previous descriptions of adult Austroplatypus incompertus (Schedl) are completed by the addition of descriptions and illustrations of the adults and, in particular, their maxillary palps. I describe and illustrate the non-adult phases of the life cycle and provide a key to the larval instars. The sexual dimorphism of Austroplatypus incompertus is atypical and includes a latitudinal cline which obeys Bergmann's rule. The taxonomic position of the genus within the Platypodinae is clarified. Platypus incostatus Schedl is recognised as the male of the species, and hence a new synonym of Austroplatypus incompertus. PMID- 21594176 TI - Revision of the genus Phloeoditica Schedl - with description of two new genera and two new species in Phloeosinini (Coleoptera, Curculionidae, Scolytinae). AB - The genus Phloeoditica Schedl currently includes four species from Southeast Asia. These species vary substantially in important morphological characters and indicate the existence of multiple genera for these species. A revision based on morphological and in part molecular data resulted in the transfer of Phloeoditica setosa to Pseudoxylechinus the erection of a new genus Asiophilus for Phloeoditica phloeosinoides and a new species Asiophilus macropunctatus from Vietnam. Another new genus with affinities to Phloeoditica is described based on the new species Microditica uniseriata from Thailand. The new genera are included in a revised key to the tribe Phloeosinini. PMID- 21594177 TI - Taxonomic notes on the afrotropical genera Hapalogenius Hagedorn, Hylesinopsis Eggers, and Rhopalopselion Hagedorn (Coleoptera, Curculionidae, Scolytinae). AB - Taxonomic confusion among the afrotropical scolytine genera Hapalogenius Hagedorn, Hylesinopsis Eggers and Rhopalopselion Hagedorn, and their synonyms is discussed with especial reference to the catalogues of Wood and Bright (1992), and Alonso-Zarazaga and Lyal (2009). A key is given to separate the three genera recognised, and the species considered to be included in each genus are listed. Hylesinopsis is resurrected from synonymy with Hapalogenius, and shown not to be closely related to it. Chilodendron Schedl is considered to be a synonym of Hylesinopsis and not of Xylechinus Chapuis. The following new synonymy is proposed at specific level: Hapalogenius africanus (Eggers) (= Hapalogenius lesnei Eggers, = Metahylesinus brincki Schedl); Hapalogenius fuscipennis (Chapuis) (= Hapalogenius bimaculatus Eggers); Hapalogenius oblongus (Eggers) (= Metahylesinus striatus Schedl); Hylesinopsis fasciata (Hagedorn) (= Kissophagus punctatus Eggers); Phrixosoma niger Eggers (= Hapalogenius niger Schedl). The following species are returned to Hylesinopsis from Hapalogenius to which they were transferred by Alonso-Zarazaga and Lyal (2009): Hylesinopsis alluaudi (Lepesme), Hylesinopsis angolensis (Schedl), Hylesinopsis arabiae (Schedl), Hylesinopsis atra (Nunberg), Hylesinopsis confusa (Eggers), Hylesinopsis decellei (Nunberg), Hylesinopsis dubia Eggers, Hylesinopsis emarginata (Nunberg), Hylesinopsis fasciata (Hagedorn), Hylesinopsis ficus (Schedl), Hylesinopsis granulata (Lepesme), Hylesinopsis hirsuta (Schedl), Hylesinopsis joveri (Schedl), Hylesinopsis pauliani (Lepesme), Hylesinopsis punctata (Eggers), Hylesinopsis saudiarabiae (Schedl). The following new combination is given: Hylesinopsis leprosula (Browne) from Cryphalus Erichson. New distributional records are given for some species. PMID- 21594178 TI - Scolytus stepheni sp. n. - a new species of bark-beetle (Coleoptera, Curculionidae, Scolytinae) from Northern India with a key to Indian Scolytus Geoffroy, 1762 species. AB - A new species of bark-beetle from Kashmir, Scolytus stephenisp. n., dedicated to the late Professor Emeritus Stephen Lane Wood, is described and figured. Key to Indian Scolytus Geoffroy, 1762 species is provided. PMID- 21594179 TI - Description of new Dryocoetes (Coleoptera, Curculionidae, Scolytinae) speciesfrom Afghanistan and Northern India and redescription of Scolytoplatypus kunala Strohm. AB - A new bark beetle species, Dryocoetes brownei from Northern India and Afghanistan, is described as a new to science and redescription of Scolytoplatypus kunala Strohmeyer, 1908, previously known only from the female holotype, is provided. PMID- 21594180 TI - Five new species of Triotemnus (Coleoptera, Curculionidae, Scolytinae) from Morocco and Yemen. AB - Fivenew species of the genus Triotemnus from Morocco and Yemen are described. Triotemnus is a new genus of Scolytinae for the Yemen region. External morphology of the new species and all morphologically related species of the genus were studied. While the new species from Morocco are morphologically similar to the known species from the corresponding region, all three newly described species from Yemen, mainly two of them living in Socotra, are morphologically very different from all other known species of the genus. Geographical distribution and the probability of endemicity are discussed. PMID- 21594181 TI - The Banded Elm Bark Beetle, Scolytus schevyrewi Semenov (Coleoptera, Curculionidae, Scolytinae) in North America: a taxonomic review and modifications to the Wood (1982) key to the species of Scolytus Geoffroy in North and Central America. AB - In 2003, an Asian bark beetle, Scolytus schevyrewi Semenov (Coleoptera: Curculionidae: Scolytinae), the banded elm bark beetle, was detected for the first time in North America. This paper modifies the Wood (1982) key to the species of Scolytus Geoffroy to enable identification of Scolytus schevyrewi in North and Central America. Variation of diagnostic characters in Scolytus schevyrewi is discussed. PMID- 21594182 TI - First records of Xyleborinus octiesdentatus (Murayama) (Coleoptera, Curculionidae, Scolytinae) from North America. AB - Xyleborinus octiesdentatus (Murayama), an ambrosia beetle native to Asia, is reported for the first time in North America based on specimens from Alabama and Louisiana. This is the twenty-first species of exotic Xyleborina documented in North America. A re-description of the female and a key to the four North American species of Xyleborinus are presented. PMID- 21594184 TI - Observations on sex ratio and behavior of males in Xyleborinus saxesenii Ratzeburg (Scolytinae, Coleoptera). AB - Strongly female-biased sex ratios are typical for the fungalfeeding haplodiploid Xyleborini (Scolytinae, Coleoptera), and are a result of inbreeding and local mate competition (LMC). These ambrosia beetles are hardly ever found outside of trees, and thus male frequency and behavior have not been addressed in any empirical studies to date. In fact, for most species the males remain undescribed. Data on sex ratios and male behavior could, however, provide important insights into the Xyleborini's mating system and the evolution of inbreeding and LMC in general.In this study, I used in vitro rearing methods to obtain the first observational data on sex ratio, male production, male and female dispersal, and mating behavior in a xyleborine ambrosia beetle. Females of Xyleborinus saxesenii Ratzeburg produced between 0 and 3 sons per brood, and the absence of males was relatively independent of the number of daughters to be fertilized and the maternal brood sex ratio. Both conformed to a strict LMC strategy with a relatively precise and constant number of males. If males were present they eclosed just before the first females dispersed, and stayed in the gallery until all female offspring had matured. They constantly wandered through the gallery system, presumably in search of unfertilized females, and attempted to mate with larvae, other males, and females of all ages. Copulations, however, only occurred with immature females. From galleries with males, nearly all females dispersed fertilized. Only a few left the natal gallery without being fertilized, and subsequently went on to produce large and solely male broods. If broods were male-less, dispersing females always failed to found new galleries. PMID- 21594183 TI - Bark beetles and pinhole borers (Curculionidae, Scolytinae, Platypodinae) alien to Europe. AB - Invasive bark beetles are posing a major threat to forest resources around the world. DAISIE's web-based and printed databases of invasive species in Europe provide an incomplete and misleading picture of the alien scolytines and platypodines. We present a review of the alien bark beetle fauna of Europe based on primary literature through 2009. We find that there are 18 Scolytinae and one Platypodinae species apparently established in Europe, from 14 different genera. Seventeen species are naturalized. We argue that Trypodendron laeve, commonly considered alien in Europe, is a native species; conversely, we hypothesize that Xyleborus pfeilii, which has always been treated as indigenous, is an alien species from Asia. We also point out the possibility that the Asian larch bark beetle Ips subelongatus is established in European Russia. We show that there has been a marked acceleration in the rate of new introductions to Europe, as is also happening in North America: seven alien species were first recorded in the last decade.We present information on the biology, origins, and distributions of the alien species. All but four are polyphagous, and 11 are inbreeders: two traits which increase invasiveness. Eleven species are native to Asia, six to the Americas, and one is from the Canary Islands. The Mediterranean is especially favorable for invasives, hosting a large proportion of the aliens (9/19). Italy, France and Spain have the largest numbers of alien species (14, 10 and 7, respectively). We point out that the low numbers for at least some countries is likely due to under-reporting.Finally, we discuss the difficulties associated with identifying newly invasive species. Lack of good illustrations and keys hinder identification, particularly for species coming from Asia and Oceania. PMID- 21594185 TI - Mitochondrial phylogenies in the light of pseudogenes and Wolbachia: re assessment of a bark beetle dataset. AB - Phylogenetic studies based on mtDNA become increasingly questioned because of potential pitfalls due to mitochondrial pseudogenes and mitochondrial selective sweeps. While the inclusion of nuclear markers should preferentially be considered for future studies, there is no need to abandon mtDNA as long as tests for the known mtDNA artefacts are performed. In this study we presentadditionaldata and test previous phylogeographical studies of Pityogenes chalcographus. We did not detect nuclear copies (numts) of the previously used mitochondrial markers by performing a combined long range/nested PCR of the COI gene and by an in silico analysis of the COI sequence data. This confirms the robustness of our previous phylogenetic study of Pityogenes chalcographus. Results of an in-situ hybridization of Wolbachia in Pityogenes chalcographus confirm the presence of this endosysmbiont in this species. However, we did not detect a correlation between infection status, geographical region and mtDNA haplotypes. The hybridisation data also support a previous hypothesis that infections do not result from parasitoids or parasitic nematodes, insect surface or laboratory contaminations and are hence a true infection of Pityogenes chalcographus. We conclude that the deep structure found in mitochondrial populations of Pityogenes chalcographus indeed represents the evolutionary history of European populations. PMID- 21594186 TI - Hystrignathus dearmasi sp. n. (Oxyurida, Hystrignathidae), first record of a nematode parasitizing a Panamanian Passalidae (Insecta, Coleoptera). AB - Hystrignathus dearmasi sp. n. (Oxyurida: Hystrignathidae) is described from an unidentified passalid beetle (Coleoptera: Passalidae) from Panama. It resembles Hystrignathus cobbi Travassos & Kloss, 1957 from Brazil, by having a similar form of the cephalic end, extension of cervical spines and absence of lateral alae. It differs from the latter species by having the body shorter, the oesophagus and tail comparatively larger, the vulva situated more posterior and the eggs ridged. This species constitutes the first record of a nematode parasitizing a Panamanian passalid. PMID- 21594187 TI - Descriptions of two new species in the genus Macrostylis Sars, 1864 (Isopoda, Asellota, Macrostylidae) from the Weddell Sea (Southern Ocean), with a synonymisation of the genus Desmostylis Brandt, 1992 with Macrostylis. AB - Descriptions of Macrostylis antennamagnasp. n. and Macrostylis uniformissp. n. are presented with notes on intraspecific variability and sexual dimorphism. Macrostylis uniformissp. n. showes differences to Macrostylis antennamagnasp. n. in the length of the antenna 2, the shape of the pleotelson and length of uropods.The genus Desmostylis Brandt, 1992 (formerly including the two species Desmostylis obscurus Brandt, 1992 and Desmostylis gerdesi Brandt, 2002) is synonymised with the genus Macrostylis. Based on type material additional remarks and additions to the original descriptions are provided for both species. Results lead to following nomenclatorial changes: Macrostylis obscurus (Brandt, 1992), comb. n. and Macrostylis gerdesi (Brandt, 2002), comb. n. A setal nomenclature is proposed and the diagnosis for the family is revised. PMID- 21594189 TI - A new Antaeotricha species from Southeastern Arizona (Gelechioidea, Elachistidae, Stenomatinae). AB - The new species Antaeotricha arizonensis is described from southeastern Arizona and southwestern New Mexico. Adults and genitalia are illustrated. PMID- 21594188 TI - Raveniola niedermeyeri from Iran: redescription and new data on distribution (Araneae, Nemesiidae). AB - Raveniola niedermeyeri (Brignoli, 1972), a poorly known species, is rediagnosed and redescribed from the types and from recently collected material from northern and central regions of Iran. This species differs from its congeners in having the male embolus curved distally, as well as in the unique conformation of the spermathecae. New data on the distribution of Raveniola niedermeyeri in Iran are also provided. PMID- 21594190 TI - Species of the genus Mastrus Forster (Hymenoptera, Ichneumonidae) of China with descriptions of two new species parasitizing sawflies (Hymenoptera). AB - Four species of Mastrus Forster, 1869 are reported from China. Two, Mastrus nigrus Sheng & Zeng, sp. n. reared from Arge pullata (Zaddach) and Mastrus rugotergalis Sheng & Zeng, sp. n. reared from Diprion jingyuanensis Xiao & Zhang, are new to science. One, Mastrus deminuens (Hartig, 1838), is a parasitoid of Pachynematus itoi Okutani. A key to species of Mastrus Forster known in China is provided. PMID- 21594191 TI - Australian gall-inducing scale insects on Eucalyptus: revision of Opisthoscelis Schrader (Coccoidea, Eriococcidae) and descriptions of a new genus and nine new species. AB - We revise the genus Opisthoscelis Schrader, and erect the genus Tanyscelisgen. n. with Opisthoscelis pisiformis Froggatt as its type species. Species of both genera induce sexually dimorphic galls on Eucalyptus (Myrtaceae) in Australia, with Opisthoscelis subrotunda Schrader also in Papua New Guinea. We synonymise the following taxa (junior synonym with senior synonym): Opisthoscelis fibularis Froggatt, syn. n. with Opisthoscelis spinosa Froggatt; Opisthoscelis recurva Froggatt, syn. n. with Opisthoscelis maculata Froggatt; Opisthoscelis globosa Froggatt, syn. n. (= Opisthoscelis ruebsaameni Lindinger) with Opisthoscelis convexa Froggatt; and Opisthoscelis mammularis Froggatt, syn. n. with Opisthoscelis verrucula Froggatt. We transfer seven Opisthoscelis species to Tanyscelis as Tanyscelis conica (Fuller), comb. n., Tanyscelis convexa (Froggatt), comb. n., Tanyscelis maculata (Froggatt), comb. n., Tanyscelis maskelli (Froggatt), comb. n., Tanyscelis pisiformis (Froggatt), comb. n., Tanyscelis spinosa (Froggatt), comb. n., and Tanyscelis verrucula (Froggatt), comb. n. We redescribe and illustrate the adult female of each named species of Opisthoscelis for which the type material is known, as well as the first-instar nymph of the type species of Opisthoscelis (Opisthoscelis subrotunda) and Tanyscelis (Opisthoscelis pisiformis). We describe four new species of Opisthoscelis: Opisthoscelis beardsleyi Hardy & Gullan, sp. n., Opisthoscelis thurgoona Hardy & Gullan, sp. n., Opisthoscelis tuberculataHardy & Gullan, sp. n., and Opisthoscelis ungulifinis Hardy & Gullan, sp. n., and five new species of Tanyscelis: Tanyscelis grallator Hardy & Gullan, sp. n., Tanuscelis megagibba Hardy & Gullan, sp. n., Tanyscelis mollicornuta Hardy & Gullan, sp. n., Tanyscelis tripocula Hardy & Gullan, sp. n., and Tanyscelis villosigibba Hardy & Gullan, sp. n. We designate lectotypes for Opisthoscelis convexa, Opisthoscelis fibularis, Opisthoscelis globosa Froggatt, Opisthoscelis maculata, Opisthoscelis mammularis, Opisthoscelis maskelli, Opisthoscelis pisiformis, Opisthoscelis recurva, Opisthoscelis serrata, Opisthoscelis spinosa, and Opisthoscelis verrucula. As a result of our taxonomic revision, Opisthoscelis has six species and Tanyscelis has 12 species. We describe the galls of females for all 18 species and galls of males for 10 species of Opisthoscelis and Tanyscelis, and provide photographs of the galls for most species. A key to the adult females of the species of both genera is included. PMID- 21594192 TI - Further observations on scorpion genera Hadrurus and Hoffmannihadrurus (Scorpiones, Caraboctonidae). AB - Multiple populations of Hadrurus pinteri from Baja California Sur, Mexico have been examined. It is demonstrated that the southern populations of this species have a larger number of accessory trichobothria (neobothriotaxy) than the northern populations, numbers exceeding the maximum currently recorded for the genus. Examination of carapace and chela coloration and its patterns show a close affinity between Hadrurus pinteri and the dark phase of Hadrurus concolorous. A new morphometric ratio of the carapace is defined that distinguishes Hadrurus from Hoffmannihadrurus, further supporting the monophyly of the latter genus. PMID- 21594193 TI - A review of the Holarctic genus Tmeticus Menge, 1868 (Araneae, Linyphiidae), with a description of a new genus. AB - Eight species attributed to Tmeticus are reviewed; five are redescribed and illustrated: Tmeticus affinis (Blackwall, 1885), Tmeticus bipunctis (Bosenberg & Strand, 1906), Tmeticus nigriceps Kulczynski, 1916, Tmeticus ornatus (Emerton, 1914) and Tmeticus tolli Kulczynski, 1908. The new genus, Paratmeticus gen. n. is erected for Tmeticus bipunctis, and a new combination is established: Paratmeticus bipunctis (Bosenberg & Strand, 1906), comb. n. Three species names: Gongylidium vile Kulczynski, 1885, syn. n., Tmeticus difficilis Kulczynski, 1926, syn. n. and Tmeticus dubius Kulczynski, 1926, syn. n., are synonymized with Tmeticus tolli Kulczynski, 1908. Although Gongylidium vile has date priority over Tmeticus tolli it is synonymized because of the lack of usage. Three species from Japan attributed to Tmeticus: Tmeticus neserigonoides Saito & Ono, 2001, Tmeticus nigerrimus Saito & Ono, 2001 and Tmeticus vulcanicus Saito & Ono, 2001 are not related to Tmeticus affinis, the type species of the genus, and their affinities remain unclear. The male of Tmeticus nigriceps is described for the first time. PMID- 21594194 TI - A new species of Harpactea (Araneae, Dysderidae) from Aegean region of Turkey. AB - A new species of the spider genus Harpactea Bristowe, 1939 is described from the Aegean region of Turkey - Harpactea ersenisp. n. (males only). Detailed morphological description and illustrations of the new species are provided. The relationships of the new species are discussed. PMID- 21594195 TI - Aleocharine rove beetles (Coleoptera, Staphylinidae) associated with Leptogenys Roger, 1861 (Hymenoptera, Formicidae) I. Review of three genera associated with L. distinguenda (Emery, 1887) and L. mutabilis (Smith, 1861). AB - Three myrmecophilous genera of Aleocharinae (Staphylinidae) associated with Leptogenys distinguenda (Emery, 1887) and Leptogenys mutabilis (Smith, 1861) are reviewed with descriptions of new taxa: Maschwitzia Kistner, 1989, Togpelenys Kistner, 1989 and Witteia Maruyama & von Beeren, gen. n. (type species: Witteia dentilabrumMaruyama & von Beeren, sp. n.). The following new combinations are proposed: Zyras (s. lat.) aenictophila (Kistner, 1997),comb. n. (exMaschwitzia), Zyras (s. lat.) dichthadiaphila (Kistner in Kistner et al., 2003), comb. n. (exMaschwitzia), Maschwitzia derougemonti (Pace, 1984), comb. n. (exWroughtonilla Wasmann, 1899), Maschwitzia watanabei (Maruyama, 2004), comb. n. (exWroughtonilla), Maschwitzia dilatata (Pace, 2005), comb. n. (exWroughtonilla), Witteia borneensis (Pace, 1986), comb. n. (ex Wroughtonilla). These genera belong to the Wroughtonilla genus group of the tribe Lomechusini. PMID- 21594196 TI - Aleocharine rove beetles (Coleoptera, Staphylinidae) associated with Leptogenys Roger, 1861 (Hymenoptera, Formicidae) II. Two new genera and two new species associated with L. borneensis Wheeler, 1919. AB - Two new genera and two new species of Aleocharinae (Staphylinidae) from Malaysia are described: Parawroughtonilla Maruyama, gen. n. (type species: Parawroughtonilla hirsutaMaruyama, sp. n.), Leptogenonia Maruyama, gen. n. (type species: Leptogenonia roslii Maruyama, sp. n.), which are associated with Leptogenys borneensis Wheeler, 1919. They are closely related and share a unique character state of the aedeagus. PMID- 21594197 TI - New data on freshwater psammic Gastrotricha from Brazil. AB - Current knowledge of freshwater gastrotrich fauna from Brazil is underestimated as only two studies are available. The present communication is a taxonomic account of the first-ever survey of freshwater Gastrotricha in Minas Gerais State. Samplings were carried out yielding six species of three Chaetonotidae genera: Aspidiophorus cf. pleustonicus, Ichthydium cf. chaetiferum, Chaetonotus acanthocephalus, Chaetonotus heideri, Chaetonotus cf. succinctus, Chaetonotus sp., and also an undescribed species belonging to the genus Redudasys (incertae sedis): this is the first finding of specimens of Redudasys outside of original type locality. These preliminary observations suggest that the knowledge of the biodiversity of Gastrotricha in the Minas Gerais State, as well as in the whole Brazil, will certainly increase as further investigations are undertaken, and that freshwater Macrodasyida may be more common than previously thought. PMID- 21594198 TI - Parasabella Bush, 1905, replacement name for the polychaete genus Demonax Kinberg, 1867 (Annelida, Polychaeta, Sabellidae). AB - Parasabella Bush, 1905 is reintroduced as a replacement name for Demonax Kinberg, 1867 (Annelida: Polychaeta: Sabellidae) which is a junior homonym of Demonax Thomson, 1860 (Insecta: Coleoptera: Cerambycidae). PMID- 21594199 TI - Korean species of Aleochara Gravenhorst subgenus Xenochara Mulsant & Rey (Coleoptera, Staphylinidae, Aleocharinae). AB - A taxonomic review of Aleochara Gravenhorst subgenus Xenochara Mulsant & Rey in Korea is presented. Five species are recognized, with one species, Aleochara (Baryodma) intricata Mannerheim, newly transferred to the subgenus Xenochara. Aleochara (Xenochara) asiatica Kraatz and Aleochara (Xenochara) peninsulae Bernhauer are reported for the first time in the Korean peninsula. A key, line drawings of diagnostic characters, and redescriptions of Korean Xenochara species are provided. PMID- 21594200 TI - A review of the non-metallic Osmia (Melanosmia) found in North America, with additional notes on palearctic Melanosmia (Hymenoptera, Megachilidae). AB - We review the six species of non-metallic Osmia (Melanosmia) found in North America, including the description of two new species found in Canada and the northern United States: Osmia (Melanosmia) aquilonariasp. n., and Osmia (Melanosmia) nearcticasp. n., respectively belonging to the inermis and xanthomelana species groups. We additionally provide keys to the non-metallic Melanosmia found in North America, and update keys to the palearctic Melanosmia based on study of the type specimens of Osmia disjuncta Tkalcu, Osmia ephippiata Smith, Osmia ishikawai Hirashima, and Osmia pamirensis Gussakovskij. PMID- 21594201 TI - Oral health status of two 12-year-old socially disadvantaged groups in South India: a comparative study. AB - PURPOSE: The aim of the present study was to compare and assess the oral health status of 12-year-old children from two socially disadvantaged groups in the Udupi district of South India. MATERIALS AND METHODS: A total of 327 children were examined in Ashrama schools, and 340 children were randomly selected for comparison from other government schools. Modified WHO proforma was used for clinical examination. Oral hygiene practices, dental fluorosis, periodontal status, dentition status and dentofacial anomalies were assessed and compared. Chi square test was used for comparison between categorical variables and Mann Whitney test for comparison between two groups for quantitative variables. P u 0.05 was considered as statistically significant. RESULTS: Dental fluorosis was detected in 22.9% children from Ashrama schools, whereas in the comparison group 14.4% children had dental fluorosis (P u 0.001). Mean Decayed teeth and DMFT value in Ashrama school children were 1.15 +/- 1.62, and 1.15 +/- 1.62, respectively. In the comparison group, the corresponding values were 0.46 +/- 0.98 and 0.48 +/- 1.04, respectively (P u 0.001). The mean number of sextants in the Ashrama school children with Community Periodontal Index score 2 was 2.00 +/- 1.53, whereas in the comparison group it was 1.31 +/- 1.53 (P u 0.001). No significant differences were noted between two groups with respect to Dental Aesthetic Index scores. CONCLUSIONS: The present study revealed higher levels of dental caries experience, untreated dental disease and social disadvantage of the children attending Ashrama schools, providing evidence for the need to address the health inequalities of these children. PMID- 21594202 TI - Influence of socioeconomic status on the relationship between locus of control and oral health. AB - The objectives of this study were to assess the relationship between Locus of Control (LoC) and oral health among a group of rural adolescent school children and to examine the influence of socioeconomic status (SES) on the association between health, LoC and oral health status. A total of 318 children 15 years of age from a public and private school formed the study population. The children were administered following the Indian translation of the 18-item Multidimensional Health Locus of Control scale, and subsequently examined for caries and oral hygiene. T tests and correlation analyses showed a significant relationship between higher 'Internal' Locus of Control and dental caries. A hierarchical multiple regression analysis was performed to assess the effect of socioeconomic status on LoC and oral health using three interaction models which showed a statistically significant interaction between 'Internal' LoC and socioeconomic status on caries. Socioeconomic stratum-specific estimates of the relationship between the LoC and caries revealed a positive association between Internal LoC and caries in the middle socioeconomic group. The results demonstrated the relationship between Locus of Control and oral health, and the role of socioeconomic status having a strong bearing on this relationship. PMID- 21594203 TI - Gender influence on occlusal characteristics of primary dentition in 4- to 6-year old children of Bagalkot City, India. AB - PURPOSE: To record, determine and discuss the gender influence on the overall prevalence of occlusal characteristics of primary dentition of 4- to 6-year-old children of Bagalkot City, India. MATERIALS AND METHODS: A total of 1000 children (583 boys and 417 girls) 4 to 6 years old were evaluated clinically for primary molars, primary canines, developmental spaces, measurements of overjet and overbite, crowding, anterior or posterior cross bite, midline discrepancies, lateral profile, as well as assessment of the presence of lip incompetency. A stratified cluster random sampling procedure was executed to collect the representative sample. RESULTS: Highly significant differences between males and females were observed for the prevalence of flush terminal plane molar relationship, class I and II canine relationship, overjet and overbite of 0 to 2 mm, and for both convex and straight profile. A significant difference was seen for the occurrence of mesial step and asymmetric molar relationship, presence of developmental and primate spaces, shift in maxillary dental midline, presence of both single tooth anterior and bilateral posterior cross bite, overjet of 2 to 4 mm and convex profile. CONCLUSIONS: The data revealed that most of the children had a malocclusion and that there was a significant difference between male and female occlusal characteristics. This highlights the importance of identifying children who are in need of orthodontic treatment for dental health or aesthetic reasons. The study also indicated that the prevalence of most of the occlusal characteristics were comparable with other communities, but there existed substantial differences in prevalence of some traits. PMID- 21594204 TI - Dental hygienists' self-reported performance of tobacco cessation activities. AB - PURPOSE: Tobacco use is a major risk factor in oral and systemic diseases. Current national guidelines outline activities that positively contribute towards tobacco cessation. Little is known about dental hygienists' role in tobacco cessation activities. This study investigates dental hygienists' performance of tobacco cessation activities in the dental surgery and explores factors associated with this performance. MATERIALS AND METHODS: Dental hygienists in south-east England on the register of the British Society of Dental Hygiene and Therapy completed a postal questionnaire survey in 2008. RESULTS: A total of 439 (61%) questionnaires were returned, representing both part-time (66.7%) and full time (33.3%) hygienists working in the private (69.5%) and non-private sectors (30.5%). Most hygienists recorded positive attitudes towards tobacco cessation. Overall, 162 (41.9%) reported performing four or more tobacco cessation activities. The less-commonly performed activities indicated to patients the value of attending NHS Stop Smoking Services for specialised help, with hygienists referring patients to the NHS Stop Smoking Services and offering assistance to those who do not wish to attend NHS stop Smoking Services. Higher reported numbers of tobacco cessation activities performed were statistically significantly associated with a higher number of positive attitudes held (P = 0.004), while socio-demographic and professional attributes were not. CONCLUSION: Tobacco cessation activities, as recommended by national guidelines, are not always performed by dental hygienists. Efforts are needed to promote the dental hygienist's role in tobacco cessation, especially in relation to referring patients to NHS Stop Smoking services. These efforts should focus on changing the attitudes of dental hygienists, especially on their effectiveness in promoting tobacco cessation. PMID- 21594205 TI - Black stain - a review. AB - The purpose of this review was to summarise the fundamentals about black stain, its diagnosis and possible differential diagnoses as well as its microbiology and therapy. In addition, various studies investigating the relationship between black stain and dental caries are examined. Many studies report lower caries prevalence in children with black stain, but this finding could not be confirmed by all authors. Also, a negative relation between degree of staining and caries severity has been described. Reasons for these results are not yet clear but it was speculated that they are related to the specific oral microflora described in black stain-affected individuals. PMID- 21594206 TI - Association between maternal schooling and caries prevalence: a cross-sectional study in southern Brazil. AB - PURPOSE: To assess the prevalence and severity of dental caries among 12-year-old schoolchildren and to examine its possible association with maternal schooling. MATERIALS AND METHODS: A cross-sectional study involving a representative sample (n = 253) of the 12-year-old schoolchildren enrolled in 14 schools of the municipality of Curitibanos, Brazil was carried out in 2006. Clinical information was obtained through the World Health Organization criteria. Non-clinical data were obtained through interviews with schoolchildren. Associations were analysed using chi-square test or Fisher exact test followed by non-conditional multiple logistic regression analysis to test the independence of associations between outcome and explanatory variables. P-values were set at < 0.05. RESULTS: The prevalence of caries was 81.7% and the mean decayed, missing or filled teeth score was 4.08. Prevalence was significantly higher among girls, with a prevalence ratio of 2.58 (95% CI 1.25, 5.32) (P = 0.010); among schoolchildren from mothers with lower education level, with a prevalence ratio of 3.26 (95% CI 1.32, 8.06) (P = 0.010); and among schoolchildren who had ever visited a dentist, with a prevalence ratio of 2.91 (95% CI 1.14, 7.62) (P = 0.030). CONCLUSIONS: The prevalence and severity of caries were higher than the Brazilian national average. The prevalence was statistically associated with maternal schooling, had visited a dentist, and gender. PMID- 21594207 TI - Total and free fluoride concentrations of African dentifrices marketed in West Africa. AB - OBJECTIVE: To determine the fluoride concentrations of commercial dentifrices marketed in West Africa. DESIGN: In vitro measurement of the total fluoride concentration by liquid gas chromatography, and of the free fluoride concentration with a fluoride sensitive electrode. SETTING: Collection of fluoride dentifrices in public markets and supermarkets in and around the capital of The Republic of The Gambia, Banjul, after a systematic search. MATERIALS: All commercially available different brands sold in The Gambia and produced locally or in other African countries (Egypt, Morocco, Nigeria and South Africa). OUTCOME MEASURES: Total and free fluoride concentrations of dentifrices in parts per million. RESULTS: Seven different dentifrices were detected with NaMFP as the predominant fluoride source. Four dentifrices showed a total fluoride concentration above 1,000 ppm F-. The products showed - in general - a lower free fluoride concentration. Only one product with NaF as fluoride supplement showed both total and free fluoride concentrations above 1,000 ppm F-. Four products contained calcium-based abrasive additives. CONCLUSION: The measurement of total and free fluoride concentrations of dentifrices available in The Gambia (West Africa) showed inhomogeneities. This was particularly verified where fluoride compounds were combined with calcium-based abrasives. If so, it is recommended that the total fluoride content should be measured by gas chromatography. Periodic quality control of dentifrices should be introduced in areas with an under-developed consumer-counselling infrastructure. PMID- 21594208 TI - Comparative evaluation of the efficacy of 10% doxycycline hyclate in the periodontal treatment of smokers - a clinical and microbiological study. AB - PURPOSE: The aim of this present clinical and microbiological study was to evaluate the efficacy of the association of locally delivered 10% doxycycline hyclate (Atridox(r)) with scaling and root planing in the periodontal treatment of smokers. MATERIALS AND METHODS: Forty-five patients with chronic periodontitis having a minimum of two periodontal pockets (>5 mm) and satisfying the inclusion and exclusion criteria were selected. Sites were randomly assigned to scaling and root planing (SRP) or scaling and root planing followed by local application of 10% doxycycline hyclate (SRP-D). Plaque index (PI), gingival index (GI), periodontal pocket depth (PD), clinical attachment level (CAL) and total anaerobic colony count (TACC) were recorded at baseline, one month and three months respectively. Differences between baseline and each period were considered for analysis. RESULTS: There was a significant reduction in plaque score, gingival score, periodontal pocket depth and total anaerobic colony count from baseline in both groups at all time intervals. Clinical attachment level showed a significant gain in both groups. However, PD reduction (P < 0.001) and CAL gain (P < 0.001) were significant in the test group as compared to control at the end of 3 months. Reduction in total anaerobic colony count from baseline was significant (P = 0.02) in the test group compared to control at the end of 3 months. CONCLUSIONS: The use of locally delivered doxycycline may constitute an important adjunct for the treatment of chronic periodontitis in smokers. PMID- 21594209 TI - The periodontal health of adult Nepalese. AB - PURPOSE: There exists meagre information on the prevalence of periodontal conditions among adults in Nepal. Therefore, appropriate data on periodontal conditions are needed to facilitate planning, monitoring and evaluation of oral health programmes. The objective of the present study was to determine the prevalence of periodontal conditions among adults aged between 33 and 97 years in Nepal and also to elucidate any possible risk predictors of periodontal problems. MATERIALS AND METHODS: The total subjects included in the present study were 1210 (33 to 49 years [n = 596] and 50 to 97 years [n = 614]). Community Periodontal Index scores were used to assess the periodontal status of the selected subjects. Self-reported data were used to ascertain oral health behaviour. RESULTS: Logistic regression analyses showed the following observations for the age group 33 to 49 years: (1) bleeding was more likely found among those subjects who resided in rural areas and upper hill terrain, and among those who used non fluoridated dentifrice; (2) bleeding was, however, less likely to be observed among those with primary or unfinished secondary school education (PSE); (3) calculus deposits were accentuated in illiterates, whereas less calculus formation was experienced by alcohol users; (4) periodontal pocket 4 to 5 mm was predominantly seen among illiterates and those with PSE, smokers and those who used non-fluoridated dentifrice; (5) periodontal pocket v 6 mm was observed among illiterates and those with PSE and those who used non-fluoridated dentifrice. With regard to 50 years old and above, the following observations were noticed: (1) bleeding was associated with the use of non-fluoridated dentifrice; (2) chewing betel nut showed a protective effect with regard to calculus formation; (3) being illiterate increased the likelihood of having periodontal pockets 6 mm or more in depth. CONCLUSIONS: Several findings of the present study are in concordance with empirical evidence. However, the protective effect of alcohol and betel nut against calculus formation needs to be investigated further. PMID- 21594210 TI - Is there a relationship between periodontal disease and smoking after adjusting for job classification in Japanese employed males? AB - OBJECTIVES: The objective of this study is to examine whether the well-known association between periodontal disease and smoking persists after adjusting for job classification. METHODS: A sample of 16,110 employed Japanese males aged 20 69 years was included in the study. Periodontal examinations were conducted using the Community Periodontal Index. The association between periodontal disease and smoking status was examined using logistic regression adjusting for age, diabetes and job classification. Job classification was based on criteria of the Japanese Ministry of Health, Labour and Welfare. There are nine major job groups: (1) Professional (professionals, specialists), (2) Managers, (3) Office workers (computer operators, clerks, secretaries), (4) Skilled worker (factory workers, construction workers), (5) Salesperson (shop assistants), (6) Service occupations (superintendents, cleaners or car park attendants), (7) Security (guards), (8) Farmers and fishermen, (9) Transport and telecommunication workers (truck drivers). RESULTS: Current and former smokers were more likely to have periodontal disease than non-smokers. Adjusting for job classification attenuated the association between smoking and periodontal disease but did not eliminate the association. The odds ratios for the association between smoking and Community Periodontal Index score 3 or 4 attenuated from 2.25 to 2.04 and from 2.62 to 2.52 for individuals aged 20 to 39 and 40 to 69 years, respectively. The effect of job classification on the association between periodontal disease and smoking was higher among younger participants aged 20 to 39 years. CONCLUSIONS: Smoking persisted as an important determinant of periodontal disease after adjusting for job classification in Japanese employed males. PMID- 21594211 TI - Necrotic ulcerative changes in Fanconi's anaemia: a case report. AB - SUMMARY: This case report is of a rare occurrence of necrotic ulcerative changes in a female patient with Fanconi's anaemia and its successful periodontal management. BACKGROUND: The response of the periodontium to certain genetic and haematological disorders may vary from bleeding, ulcerations and necrosis to a more severe form of periodontitis. Periodontal management in such conditions still remains an enigma with respect to the timing of the periodontal intervention with regard to the systemic wellbeing of the patient. METHODS: Necrotising ulcerative lesions in a patient with Fanconi's anaemia (FA) progressed rapidly in a week's time necessitating early preliminary periodontal care, which included scaling and root planning using ultrasonic equipment supplemented with hydrogen peroxide irrigation, in conjunction with systemic antibiotics and blood transfusion. RESULTS: Following 1 unit (500ml) of fresh whole blood transfusion 24 hours preoperatively, basic periodontal therapy, comprising of removal of necrotic slough and thorough scaling was done. There was marked resolution of the necrotic ulceration and related symptoms when the patient was followed up for a period of 1 month. CONCLUSION: This report reconfirms most oral manifestations of Fanconi's anaemia and is the first of its kind to associate necrotic ulcerative changes of the gingiva with FA. It also goes a step further to emphasise the clinical significance of multidisciplinary approach towards successful patient management, which was the primary objective. PMID- 21594213 TI - Comments on the statistical analysis of the paper by Albouy et al comparing four different types of implants with respect to 'spontaneous' progression of peri implantitis. PMID- 21594214 TI - Comments on the letter from Kjell Pettersson and Reiner Mengel by the editorial team of EJOI. PMID- 21594215 TI - Clinical and radiological outcomes of 1- versus 2-stage implant placement: 1-year results of a randomised clinical trial. AB - AIM: To compare the clinical and radiological outcomes of 1- versus 2-stage implant placement. MATERIALS AND METHODS: Forty-seven patients were randomly allocated to 1- or 2-stage treatment groups immediately after implant placement. Twenty-nine patients received 38 1-stage early loaded implants and 18 patients received 51 2-stage early loaded implants. Outcome measures were failures of implants and/or prosthesis, complications, pain score, amount of analgesic consumption and periimplant bone level changes at implant loading (12 weeks) and at the 1-year follow-up. RESULTS: After 1 year, no dropout occurred. In the 1 stage group, 2 implants (1 patient) failed to osseointegrate and the implant supported prosthesis could not be placed, versus none in the 2-stage group. Two complications were reported in the 1-stage group versus only one in the 2-stage group. Pain score measurements, analgesic consumption and peri-implant bone level did not show any significant difference between the two groups. All patients would undergo the same procedures again. CONCLUSIONS: The submerged technique is not a prerequisite for osseointegration, though 1-stage implant placement might be at a slightly higher risk for early failures. PMID- 21594216 TI - Rehabilitation of postrior atrophic edentulous jaws: prostheses supported by 5 mm short implants or by longer implants in augmented bone? One-year results from a pilot randomised clinical trial. AB - PURPOSE: To evaluate whether 5 mm short dental implants could be an alternative to augmentation with anorganic bovine bone and placement of at least 10 mm long implants in posterior atrophic jaws. MATERIALS AND METHODS: Fifteen patients with bilateral atrophic mandibles (5-7 mm bone height above the mandibular canal), and 15 patients with bilateral atrophic maxillae (4-6 mm bone height below the maxillary sinus) and bone thickness of at least 8 mm, were randomised according to a splitmouth design to receive one to three 5 mm short implants or at least 10 mm long implants in augmented bone. Mandibles were vertically augmented with interpositional bone blocks and maxillary sinuses with particulated bone via a lateral window. Implants were placed after 4 months, submerged and loaded, after 4 months, with provisional prostheses. Four months later, definitive provisionally cemented prostheses were delivered. Outcome measures were: prosthesis and implant failures, any complication and peri-implant marginal bone level changes. RESULTS: In 5 augmented mandibles, the planned 10 mm long implants could not be placed and shorter implants (7 and 8.5 mm) had to be used instead. One year after loading no patient dropped out. Two long (8.5 mm in the mandible and 13 mm in the maxilla) implants and one 5 mm short maxillary implant failed. There were no statistically significant differences in failures or complications. Patients with short implants lost on average 1 mm of peri-implant bone and patients with longer implants lost 1.2 mm. This difference was statistically significant. CONCLUSIONS: This pilot study suggests that 1 year after loading, 5 mm short implants achieve similar if not better results than longer implants placed in augmented bone. Short implants might be a preferable choice to bone augmentation since the treatment is faster, cheaper and associated with less morbidity, however their long-term prognosis is unknown. PMID- 21594217 TI - Antibiotic prophylaxis and early dental implant failure: a quasi-random controlled clinical trial. AB - PURPOSE: To compare the efficacy of three different antibiotic regimens in reducing early dental implant failure. MATERIALS AND METHODS: In a controlled clinical trial, 270 consecutively treated patients were allocated to three antibiotic groups, alternatively, according to order of participation in the trial: Group A (2 g amoxicillin single preoperative dose), Group B (single preoperative 2 g amoxicillin followed by 500 mg three times daily for 5 days) and Group C (postoperative amoxicillin with clavulanic acid 625 mg three times daily for 5 days). Outcomes were pain, wound infection, dehiscence, adverse events possibly related to antibiotics and early implant failure. The patients were followed postoperatively at 1 week, 1 month and at the beginning of the prosthetic stage. Chi-square test and ANOVA test were used to examine differences. RESULTS: In total, 240 patients were adherent to the trial protocol: Group A, 73 patients (210 implants); Group B, 79 patients (266 implants); and Group C, 88 patients (290 implants). Patients experiencing early implant failure: 12 in Group A (16.4%), 11 in Group B (13.9%) and 13 in Group C (14.8%). No statistically significant differences were observed for any of the outcome measures between the three groups. CONCLUSIONS: It may not be necessary to provide postoperative antibiotics in patients undergoing dental implant placement, however, these preliminary findings need to be confirmed by large multicentre clinical trials. PMID- 21594218 TI - The influence of smoking on the survival of dental implants: a 5-year pragmatic multicentre retrospective cohort study of 1727 patients. AB - PURPOSE: To evaluate the influence of cigarette smoking on the survival of dental implants with a retrospective observational study of 5 years. MATERIALS AND METHODS: A total of 1727 consecutively treated patients at four private practices were divided into non-smokers (NS group, 1178 patients) and smokers (S group; 549 patients) according to what they declared prior to implant placement. Non-smokers received 4460 implants and 2583 implant-supported prostheses, whereas smokers received 2260 implants and 1292 implant supported prostheses. Various implant systems and procedures were used. Outcome measures were prosthesis and implant survival. RESULTS: Over the 5 years after loading, 159 (17%) non-smokers and 91 (13%) smokers were lost to follow-up; 20 (0.9%) prostheses could not be placed or failed in 15 non-smokers and 12 prostheses (1.2%) could not be placed or failed in 12 smokers. One hundred and twelve (2.9%) implants failed in 105 non-smokers and 107 (5.5%) implants failed in 75 smokers. Most of the implant failures (90%) occurred before implant loading. Fitting a logistic regression for early implant failures and total implant failures, taking into account the clustering of implants in patients, there were no statistically significant differences for prosthesis failures (P value not calculated as too few failures) and early implant failures between the two groups (P = 0.13). However, when considering all implant failures up to 5 years after loading, significantly more failures (5.5%) occurred in smokers compared with non-smokers (2.9%) (OR 1.72; 95% CI 1.20 to 2.50; P = 0.003). CONCLUSIONS: Due to the retrospective nature of this study, conclusions have to be interpreted with caution. Five years after loading, smokers experienced almost twice as many implant failures compared with non smokers. Non-statistically significant trends in favour of non-smokers were observed for early implant failures and prosthesis failures. PMID- 21594219 TI - Short implants in posterior jaws. A prospective 1-year study. AB - BACKGROUND: There is limited evidence for the outcome of short implants (7 mm) to rehabilitate posterior jaws. PURPOSE: To report on the outcome of 7 mm short implants in the rehabilitation of posterior areas of atrophic jaws 1 year after loading. MATERIALS AND METHODS: This prospective study included 127 patients treated with 217 implants supporting 165 fixed prostheses. Final abutments were delivered at surgery stage, and in 11 patients (18 implants) a provisional acrylic resin crown or bridge was manufactured and attached to the implants on the same day as the surgery, achieving immediate function. The final prosthesis was typically delivered after 6 months. Outcome measures were implant survival calculated at patient and implant levels, complications and peri-implant marginal bone resorption calculated at patient level. RESULTS: Three patients with 5 implants were lost to follow-up after 7 months. Implant losses occurred in 6 of the 127 patients and 10 of the 217 implants placed failed, giving a success rate of 95% at patient and implant level after 1 year of follow-up. The mean marginal bone resorption after 1 year of follow-up was 1.27 mm (SD = 0.67 mm). The only complication registered was a periimplant pathology at one implant. CONCLUSIONS: One year after loading, 7 mm short implants provided good success rates (95% at patient level and implant level) suggesting that the use of short implants is a viable concept, however longer follow-ups are needed to confirm these preliminary results. PMID- 21594220 TI - Network meta-analysis of randomised controlled trials: direct and indirect treatment comparisons. PMID- 21594221 TI - Shotgun research. PMID- 21594222 TI - Pooling of dentin microtensile bond strength data improves clinical correlation. AB - PURPOSE: To evaluate whether the correlation between in vitro bond strength data and estimated clinical retention rates of cervical restorations after two years depends on pooled data obtained from multicenter studies or single-test data. MATERIALS AND METHODS: Pooled mean data for six dentin adhesive systems (Adper Prompt L-Pop, Clearfil SE, OptiBond FL, Prime & Bond NT, Single Bond, and Scotchbond Multipurpose) and four laboratory methods (macroshear, microshear, macrotensile and microtensile bond strength test) (Scherrer et al, 2010) were correlated to estimated pooled two-year retention rates of Class V restorations using the same adhesive systems. For bond strength data from a single test institute, the literature search in SCOPUS revealed one study that tested all six adhesive systems (microtensile) and two that tested five of the six systems (microtensile, macroshear). The correlation was determined with a database designed to perform a meta-analysis on the clinical performance of cervical restorations (Heintze et al, 2010). The clinical data were pooled and adjusted in a linear mixed model, taking the study effect, dentin preparation, type of isolation and bevelling of enamel into account. A regression analysis was carried out to evaluate the correlation between clinical and laboratory findings. RESULTS: The results of the regression analysis for the pooled data revealed that only the macrotensile (adjusted R2 = 0.86) and microtensile tests (adjusted R2 = 0.64), but not the shear and the microshear tests, correlated well with the clinical findings. As regards the data from a single-test institute, the correlation was not statistically significant. CONCLUSION: Macrotensile and microtensile bond strength tests showed an adequate correlation with the retention rate of cervical restorations after two years. Bond strength tests should be carried out by different operators and/or research institutes to determine the reliability and technique sensitivity of the material under investigation. PMID- 21594223 TI - MMP-inhibitory effect of chlorhexidine applied in a self-etching adhesive. AB - PURPOSE: To evaluate the MMP-inhibitory effect of chlorhexidine when incorporated in the primer of a two-step selfetching adhesive (Clearfil SE Bond). MATERIALS AND METHODS: Powdered dentin made from human teeth was treated with Clearfil SE Bond primers containing chlorhexidine of different concentrations for 20 s or for 2 min. The collagenolytic activity of the dentin powder was assayed using fluorescein-labelled collagen. RESULTS: Untreated dentin powder contains a low but measurable level of intrinsic activity, which was significantly inhibited by 0.05% chlorhexidine. Treating dentin powder for 20 s with SE Bond primers containing chlorhexidine (0.5%, 1.0%, and 2.0%) reduced the collagenolytic activities by 15.6%, 44.9%, and 56.7% respectively. When treated for 2 min, only SE Bond primer containing 2.0% chlorhexidine could inhibit the collagenolytic activity by 41.1%. CONCLUSION: When incorporated in a two-step self-etching adhesive primer (Clearfil SE Bond primer), chlorhexidine can partially maintain its inhibitory effect on MMPs. PMID- 21594224 TI - Exposed collagen in aged resin-dentin bonds produced on sound and caries-affected dentin in the presence of chlorhexidine. AB - PURPOSE: To evaluate the effect of chlorhexidine on the presence of collagen in aged resin-dentin bonds produced on sound and caries-affected dentin. MATERIALS AND METHODS: Flat dentin surfaces were obtained from 16 sound molars, from which 8 were microbiologically processed for induction of caries. Single Bond 2 was applied to both sound and caries-affected substrates. In half of the teeth assigned for 6-month storage in water, the phosphoric acid demineralized dentin was impregnated with 2% chlorhexidine before the application of the adhesive. Specimens (2 x 2 x 5 mm) were produced and stored in water for 24 h, or 6 months in either water or mineral oil. The specimens were subjected to histological processing and sections were stained with Goldner's Trichrome. The thickness of the zone of exposed collagen was measured by optical microscopy and the data were subjected to two-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: There was no statistically significant difference (p > 0.05) between sound and caries-affected dentin regardless of the storage condition. For both substrates, significantly greater collagen exposure was observed after 6 months in water. Chlorhexidine treated groups resulted in similar collagen exposure to that of the control and 6 months in water groups (p > 0.05), while no increase of the exposed collagen zone was observed after mineral oil storage. CONCLUSION: Aging in water resulted in degradation of the resin-dentin bond, as demonstrated by the increase of the zone of exposed collagen. However, the degradation of the exposed collagen was decelerated in the presence of chlorhexidine. PMID- 21594225 TI - Influence of 2-hydroxyethyl methacrylate concentration on polymer network of adhesive resin. AB - PURPOSE: To evaluate the effect of variations in 2-hydroxyethyl methacrylate (HEMA) concentrations in an experimental comonomer blend on degree of conversion, water sorption, solubility, and ultimate tensile strength of adhesive resin. MATERIALS AND METHODS: The effect of HEMA content (0, 15, 30, and 50%wt - control, G15, G30, and G50 groups, respectively) was tested in an experimental comonomer blend of bis-GMA, bis-EMA, TEG-DMA, and HEMA. The degree of conversion, polymerization rate, ultimate tensile strength, water sorption, and solubility of the adhesive resin blends were determined. RESULTS: At 40 s of light activation time, groups G30 and G50 showed a decrease of 30% and 61%, respectively, in degree of conversion compared to control. Water sorption and solubility differed for all groups, and was statistically higher in G50. For ultimate tensile strength, the control and G15 groups showed statistically higher values than the other groups (p < 0.05). CONCLUSION: Higher HEMA content increases dental adhesive resin degradation. PMID- 21594226 TI - Influence of different enamel substrates on microtensile bond strength of sealants after cariogenic challenge. AB - PURPOSE: To evaluate the microtensile bond strength (MUTBS) of resin sealer on enamel substrates after cariogenic challenge. MATERIALS AND METHODS: Enamel blocks were obtained from human third molars and randomly divided into 6 groups (n = 10) according to enamel substrates (S: sound, CL: caries-like lesion, or CLTF: caries-like lesion + topical fluoride application) and sealant material (F: FluroShield, or H: Helioseal Clear Chroma). Sealants were placed on enamel surfaces, stored in 100% humidity (24 h, 37 degrees C), and longitudinally sectioned into hourglass shapes. According to the groups, pH cycling was applied and the MUTBS test was performed. The fracture patterns were assessed by SEM. RESULTS: Regarding substrates, the highest MUTBS values in MPa were observed for CLTF enamel (26.0 +/- 7.6), followed by S (22.0 +/- 7.4) and CL (15.5 +/- 4.9). A significant interaction was found between material and pH cycling (p = 0.0395). F (23.9 +/- 7.6) showed higher MUTBS values than H (18.3 +/- 7.5) when submitted to pH cycling. The majority of samples presented mixed failure. CONCLUSIONS: Enamel substrate significantly affected MUTBS, with the highest values for remineralized caries-like enamel lesions. Furthermore, MUTBS values were dependent on both materials and pH cycling. PMID- 21594227 TI - Effect of dentin age and acid etching time on dentin bonding. AB - PURPOSE: To compare the bond strengths of young and old dentin using a single bottle etch-and-rinse adhesive system with two acid-etching times (15 s and 30 s), and to examine the correlation between dentin hardness and bond strength. MATERIALS AND METHODS: Twenty-four molars from 18- to 22- or 55- to 60-year-old patients were prepared to expose the occlusal dentin, cut into two equal parts, and assigned to four groups (G), varying the etching time (15 s and 30 s) and dentin age (young [Y]or old [O]): G15Y, G30Y, G15O and G30O. After etching, AdperSingleBond (3M ESPE) adhesive was applied and the tooth was built up with a composite (Filtek Z250). The specimens were prepared for the microtensile bond strength test (MUTBS) at a crosshead speed of 0.5 mm/min and the interfaces were observed under SEM. Also, the Knoop hardness (KHN) of young vs old dentin was measured. RESULTS: The mean (+/- SD) MUTBS (MPa) were: G15Y = 45.9 (+/- 10.7)a, G15O = 34.1 (+/- 9.4)b, G30Y = 48.6 (+/- 14.3)a and G30O = 47.7 (+/- 11.0)a. Two way ANOVA showed no difference in MUTBS between young and old dentin. Old dentin acid etched for 15 s (G15O) had a lower MUTBS than when acid etched for 30 s (G30O). Dentin hardness was higher for old dentin (67.0 +/- 4.8KHN) than young dentin (63.7 +/- 2.9KHN) (p < 0.004). No correlation between MUTBS and dentin hardness was observed. Resin tags were larger and more numerous for young dentin. The hybrid layer formed in intertubular old dentin (G15O) was very thin. CONCLUSION: Bonding to old dentin with 30 s of etching time resulted in higher bond strength and more homogeneous hybrid layer formation than dentin acid etched for 15 s. PMID- 21594228 TI - Effect of air-drying pressure and distance on microtensile bond strength of a self-etching adhesive. AB - PURPOSE: To investigate the effect of pressure and distance during air drying on the microtensile bond strength (MUTBS) of a single-step self-etching adhesive to bovine dentin. MATERIALS AND METHODS: A total of 36 bovine molars was used in this study. Twenty-seven teeth were used for MUTBS testing and 9 teeth for the evaluation of the resin/dentin interface. The teeth were divided into 9 groups according to the variation in solvent evaporation pressure and the distance from the dentin surface. The adhesive was applied according to the manufacturer's instructions. The pressure was adjusted using a pressure regulator and the distance was fixed by measuring the distance from the tip of the syringe to the flat dentin surface. Each tooth was restored with a composite crown 6 mm in height and was cut to produce composite/dentin rectangular sticks with a cross sectional area approximately 1 mm2 and 12 mm in length. The sticks were tested in tension until failure at a crosshead speed of 0.5 mm/min. The fracture pattern was evaluated using a stereomicroscope under 40X magnification. For the resin/dentin interface, the samples were gold sputtered and examined using SEM operated at 20 kV. RESULTS: Two-way ANOVA showed that both pressure and distance from the dentin surface significantly affect the MUTBS of the single-step self etching adhesive (p = 0.001). The interaction of the two independent variables (pressure and distance from dentin surface) showed a significant difference (p = 0.001). CONCLUSION: On the basis of the MUTBS data generated in this study, the single-step self-etching adhesive used proved to be technique sensitive. PMID- 21594229 TI - Durability of microtensile bond to nonetched and etched feldspar ceramic: self adhesive resin cements vs conventional resin. AB - PURPOSE: The objective of this study was to evaluate the effect of thermocycling (TC), self-adhesive resin cements and surface conditioning on the microtensile bond strength (MUTBS) between feldspathic ceramic blocks and resin cements. MATERIALS AND METHODS: Fifty-six feldspathic ceramic blocks (10 x 7 x 5 mm) (Vita Mark II) were divided into groups according to the factors "resin cement" (3 cements) and "surface conditioning" (no conditioning or conditioning [10% hydrofluoric acid etching for 5 min + silanization]) (n = 8): group 1: conditioning+Variolink II (control group); group 2: no conditioning+Biscem; group 3: no conditioning+RelyX U100; group 4: no conditioning+Maxcem Elite; group 5: conditioning+ Biscem; group 6: conditioning+RelyX U100; group 7: conditioning+Maxcem Elite. The ceramic-cement blocks were sectioned to produce non-trimmed bar specimens (adhered cross-sectional area: 1 +/- 0.1 mm2), which were divided into two storage conditions: dry, MUTBS immediately after cutting; TC (12,000x, 5 degrees C/55 degrees C). Statistical significance was determined using two-way ANOVA (7 strategies and 2 storage conditions) and the post-hoc Tukey test (p < 0.05). RESULTS: Resin cement and thermocycling affected the MUTBS significantly (p = 0.001). In the dry condition, group 5 (18 +/- 6.5 MPa) presented the lowest values of MUTBS when compared to the other groups. TC decreased the mean MUTBS values significantly (p < 0.05) for all resin cements tested (9.7 +/- 2.3 to 22.1 +/- 6.3 MPa), except for the resin cement RelyX U100 (22.1 +/- 6.3 MPa). In groups 3 and 4, it was not possible to measure MUTBS, since these groups had 100% pre-test failures during sectioning. Moreover, the same occurred in group 2 after TC, where 100% failure was observed during thermocycling (spontaneous failures). CONCLUSION: Hydrofluoric acid etching and silanization of the feldspathic ceramic surface are essential for bonding self adhesive resin cement to a feldspathic ceramic, regardless of the resin cement used. Non-etched ceramic is not recommended. PMID- 21594230 TI - The impact of fissure depth and enamel conditioning protocols on glass-ionomer and resin-based fissure sealant penetration. AB - PURPOSE: To evaluate the effect that fissure depth and enamel conditioning protocols have on penetration abilities of resin-based and glass-ionomer fissure sealants. MATERIALS AND METHODS: Fifty extracted human molars were randomized into 10 experimental groups. Conditioning was performed as follows: groups I and VI, no pretreatment; groups II and VII, 10% polyacrylic acid and 37% phosphoric acid, respectively; groups III and VIII, self-etching adhesive; groups IV and IX, Er:YAG laser; groups V and X, Er:YAG laser/10% polyacrylic acid and laser/37% phosphoric acid, respectively. In groups I to V, teeth were sealed with a glass ionomer material, and in groups VI to X a resin-based sealant was used. The sealed teeth were sectioned and the penetration ability was evaluated using scanning electron microscopy (SEM). RESULTS: Pretreatment with a suitable acid resulted in superior penetration of glass-ionomer and resin-based sealant when compared with other conditioning protocols (p < 0.0001), except for the teeth treated with both Er:YAG laser and acid. Both conditioning protocol and fissure depth significantly affected the sealant penetration (p < 0.0001), but fissure depth had a greater impact on fissure penetration than did conditioning protocol. CONCLUSION: Resin-based and glass-ionomer sealing materials show similar potential for pit-and-fissure penetration. Penetration of a fissure sealant is largely influenced by the fissure depth. Regarding the conditioning protocol, a pretreatment with a suitable acid is essential to obtain an adequate penetration of a sealing material. PMID- 21594231 TI - Bond strength of fiber posts in different root thirds using resin cement. AB - PURPOSE: The aim of the study was to assess the in vitro bond strength (BS) of glass fiber posts (GF) and carbon fiber posts (CF) in the cervical, middle, and apical thirds of root canals cemented with RelyX-Unicem (RX) and Cement-Post (CP). MATERIALS AND METHODS: Forty maxillary canines were divided into 4 groups (n = 10) according to the cement and post used: group 1: GF and RX; group 2: CF and RX; group 3: GF and CP; group 4: CF and CP. The push-out test was applied in the cervical, middle and apical thirds of each specimen to assess bond strength of the cement/post complex to the root canal wall. The data obtained were submitted to ANOVA (Bonferroni test, p < 0.05), and fracture analysis was done with SEM. RESULTS: The GF posts presented the best results when cemented with RX and with CP (p < 0.05). RX presented the highest BS values for both GF and CF (p < 0.05). For all the groups, BS was higher in the cervical third, followed by the middle and apical thirds. Fracture analysis showed a predominance of cohesive fracture of posts for RX, and a predominance of adhesive fracture between dentin/cement, and mixed failure mode for CP. CONCLUSION: GF posts cemented with RX presented the highest BS values in all root thirds. PMID- 21594232 TI - Collagen cross linking increases its biodegradation resistance in wet dentin bonding. AB - PURPOSE: The biodegradation of exposed dentin collagen within the adhesive/dentin (a/d) interface is one of the main reasons for composite restoration failures and seriously affects the durability of dental restorations. In the present study, the objective was to investigate whether the inclusion of the cross-linking reagent (glutaraldehyde, GA) in the adhesive would increase collagen biodegradation resistance within the a/d interface. MATERIALS AND METHODS: The model adhesive consisted of ~60 % monomers (HEMA/bis-GMA, 45/55 wt/wt) and ~ 40 % ethanol as a solvent. 5% GA was added to the above formulation. After the dentin surfaces were etched for 15 s with 35% phosphoric acid, rinsed with water and blotted dry, adhesives both with and without GA were applied and polymerized by visible light for 20 s. These a/d specimens were immersed in the biodegradation solution (prepared by adding 160 mg collagenase in 1 liter of TESCA buffer solution) for up to 30 days after proceeding with the sectioning/fracture to expose the a/d interfaces. The specimens were analyzed using SEM and micro-Raman spectroscopy. RESULTS: SEM results indicated that for the adhesive without GA, there were many voids and a loss of collagen fibrils in the a/d interface after being challenged by the biodegradation solution. The Raman spectra collected from the interface showed that the amide I of collagen at 1667 cm-1 obviously decreased, indicating a removal of collagen fibrils during the degradation process. For the adhesive containing GA, the collagen fibrils within the interface did not degrade at all, which was also confirmed by the Raman results. CONCLUSION: The results corroborate the previous findings that by using the current adhesive system and wet bonding, the collagen fibrils in the a/d interface are largely unprotected and easily undergo biodegradation. Directly including cross-linking agents in the adhesive could protect collagen fibrils from degradation in situ within the a/d interface. PMID- 21594233 TI - Comparison of alternative adhesive cementation concepts for zirconia ceramic: glaze layer vs zirconia primer. AB - PURPOSE: Zirconia-based ceramics offer strong restorations in dentistry, but the adhesive bond strength of resin cements to such ceramics is not optimal. This study evaluated the bond strength of silane/adhesive/resin cement and zirconia primer/resin cement combinations on non-glazed and glazed zirconia surfaces before and after aging. MATERIALS AND METHODS: Disk-shaped zirconia ceramic specimens (diameter: 8 mm; thickness: 2 mm) (N = 80, n = 10 per group) were randomly divided into 2 groups. While half of the specimens received one coat of glaze and were later finished by grinding, the other half was only ground using 1200-grit silicone carbide abrasives under water. The glazed specimens were then conditioned with 9.5% HF acid gel for 60 s, rinsed with water for 90 s, and neutralized. The glazed and non-glazed specimens were further divided into two groups. Two resin cements, namely, Variolink II and Multilink Automix were adhered onto the zirconia surfaces with their corresponding adhesive systems. In the Variolink II group, zirconia surfaces were silanized (Monobond-S), and adhesive resin (Heliobond) was applied and photopolymerized. In the Multilink Automix group, one coat of Metal/Zirconia Primer was applied with a microbrush, left to react for 180 s, and dried using oil-free air. Half of the specimens in each cement group were subjected to 5000 thermocycles (5 degrees C to 55 degrees C) and the other half was kept in the dark for 24 h at 37 degrees C prior to testing. Specimens were mounted in the jig of the universal testing machine, and force was applied to the ceramic/cement interface until failure occurred (1 mm/min). After evaluating all debonded specimens under SEM, the failure types were defined as either "adhesive" with no cement left on the zirconia (score 0) or "mixed" with less than half of the cement left on the surface with no cohesive failure of the substrate (score 1). Data were analyzed using three-way ANOVA and Dunnett-T3 post-hoc tests. RESULTS: Application of a glaze layer significantly improved the bond strength in the silane/adhesive/Variolink II group (p < 0.05), but no significant effect was found in the zirconia primer/Multilink Automix group (p > 0.05) (three-way ANOVA). Interaction terms were also significant (p < 0.05) (Dunnett-T3). Thermocycling did not decrease the results significantly in any of the groups (p > 0.05). Failure analysis revealed exclusively adhesive failures (score 0: 40 out of 40) in the non-glazed groups, but predominantly mixed failures (score 1: 34 out of 40) in the glazed groups. CONCLUSION: The silane (Monobond S)/adhesive (Heliobond)/Variolink II resin cement combination benefitted from glazing the zirconia surface, but the zirconia primer/Multilink Automix resin cement combination alone also provided sufficient bond strength to zirconia. PMID- 21594234 TI - Effect of sodium ascorbate on tag formation in bleached enamel. AB - PURPOSE: This study analyzed the influence of 10% sodium ascorbate (SA) on tag formation in bleached enamel. MATERIALS AND METHODS: Five groups were tested: G1 control; G2 - bleaching with 10% carbamide peroxide (CP) + restoration; G3 - CP + SA + restoration; G4 - bleaching with 35% hydrogen peroxide (HP) + restoration; and G5 - HP + SA + restoration. The teeth were sectioned and decalcified, and the resin tags were analyzed at 400X magnification using an optical light microscope and Axiovision software. RESULTS: The resin tag lengths in um for each group were as follows: G1 - 36.1A; G2 - 5.8C; G3 - 14.4B; G4 - 1.7D; G5 - 6.5C. Different letters indicate statistically significant differences. CONCLUSION: Tooth bleaching with CP or HP impairs the formation of resin tags, and the utilization of sodium ascorbate increases tags length. PMID- 21594235 TI - Effect of curing modes of dual-curing core systems on microtensile bond strength to dentin and formation of an acid-base resistant zone. AB - PURPOSE: To evaluate the microtensile bond strength (MUTBS) and acid-base resistant zone (ABRZ) of two dualcuring core systems to dentin using four curing modes. MATERIALS AND METHODS: Sixty-four caries-free human molars were randomly divided into two groups according to two dual-curing resin core systems: (1) Clearfil DC Core Automix; (2) Estelite Core Quick. For each core system, four different curing modes were applied to the adhesive and core resin: (1) dual cured and dual-cured (DD); (2) chemically cured and dual-cured (CD); (3) dual cured and chemically cured (DC); (4) chemically cured and chemically cured (CC). The specimens were sectioned into sticks (n = 20 for each group) for the microtensile bond test. MUTBS data were analyzed using two-way ANOVA and the Dunnett T3 test. Failure patterns were examined with scanning electron microscopy (SEM) to determine the proportion of each mode. Dentin sandwiches were produced and subjected to an acid-base challenge. After argon-ion etching, the ultrastructure of ABRZ was observed using SEM. RESULTS: For Clearfil DC Core Automix, the MUTBS values in MPa were as follows: DD: 29.1 +/- 5.4, CD: 21.6 +/- 5.6, DC: 17.9 +/- 2.8, CC: 11.5 +/- 3.2. For Estelite Core Quick, they were: DD: 48.9 +/-5.7, CD: 20.5 +/- 4.7, DC: 41.4 +/- 8.3, CC: 19.1 +/- 6.0. The bond strength was affected by both material and curing mode, and the interaction of the two factors was significant (p < 0.001). Within both systems, there were significant differences among groups, and the DD group showed the highest MUTBS (p < 0.05). ABRZ morphology was not affected by curing mode, but it was highly adhesive-material dependent. CONCLUSION: The curing mode of dual-curing core systems affects bond strength to dentin, but has no significant effect on the formation of ABRZ. PMID- 21594236 TI - Bonding of glass ceramic and indirect composite to non-aged and aged resin composite. AB - PURPOSE: Since adhesion of the restorative materials to pre-polymerized or aged resin composites presents a challenge to the clinicians, existing restorations are often removed and remade prior to cementation of fixed dental prostheses (FDPs). This study evaluated bond strength of non-aged and aged resin composite to an indirect resin composite and pressed glass ceramic using two resin cements. MATERIALS AND METHODS: Disk-shaped specimens (diameter: 3.5, thickness: 3 mm) (N = 160) produced from a microhybrid resin composite (Quadrant Anterior Shine) were randomly divided into eight groups. While half of the specimens were kept dry at 37 degrees C for 24 h, the other half was aged by means of thermocycling (6000 times, 5 degrees C to 55 degrees C). The non-aged and aged resin composites were bonded to a highly filled indirect composite (Estenia) and a pressed glass ceramic (IPS Empress II) using either a photopolymerizing (Variolink Veneer) or a dual-polymerizing (Panavia F2.0) resin cement. While cementation surfaces of both the direct and indirect composite materials were silica coated (30 um SiO2, CoJet Sand) and silanized (ESPE-Sil), ceramic surfaces were conditioned with hydrofluoric acid (20 s), neutralized, and silanized prior to cementation. All specimens were cemented under a load of 750 g. Shear force was applied to the adhesive interface in a universal testing machine (1 mm/min). Failure types of the specimens were identified after debonding. RESULTS: Significant effects of aging (p < 0.05), restorative material (p < 0.05), and cement type (p < 0.05) were observed on the bond strength (3-way ANOVA). Interaction terms were also significant (p < 0.05) (Tukey's test). After aging, in terms of bond strength, indirect composite and pressed glass ceramic in combination with both cements showed no significant difference (p > 0.05). Both indirect composite (24.3 +/- 5.1 MPa) and glass ceramic in combination with Variolink (22 +/- 9 MPa) showed the highest results on non-aged composites, but were not significantly different from one another (p > 0.05). On the aged composites, indirect composite and glass ceramic showed no significant difference in bond strength within each material group (p > 0.05), with both Panavia (17.2 +/- 6 and 15 +/- 5.5 MPa, respectively) and Variolink (19 +/- 8, 12.8 +/- 5.3 MPa, respectively), but in all groups, glass ceramic-Variolink on aged composite revealed the lowest results (12.8 +/- 5.3 MPa). Among all groups, predominantly cohesive failures were observed in the indirect resin composite substrate (79 out of 80) as opposed to the ceramic (18 out of 80) (p < 0.05) (Chi square). CONCLUSION: Regardless of the resin cement type, considering the bond values and the failure types, the adhesion quality of indirect composite cemented to non-aged and aged resin composite was superior with both cements compared to that of pressed glass ceramic. PMID- 21594237 TI - Influence of application methods of self-etching adhesive systems on adhesive bond strength to dentin. AB - PURPOSE: To assess the influence of variations in the application technique of self-etching adhesive systems on the shear bond strength to dentin. MATERIALS AND METHODS: The buccal surface of 255 extracted bovine teeth was ground to expose a flat dentin surface; the teeth were divided into four experimental groups. The self-etching adhesive systems One Up Bond F Plus, Clearfil SE Bond, Xeno III, and FuturaBond NR were used, and the etch-and-rinse adhesive Adper Single Bond 2 was used as the control group. One or two layers of the self-etching systems were actively or passively applied. Cylinders of composite resin were bonded to dentin, and after 24 h, specimens were shear tested in a universal testing machine at a crosshead speed of 1 mm/min. The data were submitted to two-way ANOVA, Dunnett's and Tukey's test (5%). RESULTS: There were significant differences for the factors adhesive type, application method, and their interaction. All adhesive systems showed significant differences. The active application of two layers of self-etching bonding systems resulted in a significantly higher mean than the passive application method. CONCLUSION: The active application of self-etching adhesive systems tends to increase the dentin shear bond strength, and the influence of the application method depends on the tested adhesive. PMID- 21594238 TI - A nano-confined charged layer defies the principle of electrostatic interaction. AB - The reactivity between two charged molecules and the activity of charged biomolecules are mainly governed by the principle of electrostatic interaction, i.e., like charges repel and opposite charges attract. In the present study it is shown that the principle of electrostatic interaction is violated in the nano confined biomimetic environment. Thus a positively charged molecule shows more preference to a positively charged surface compared to a negatively charged surface. PMID- 21594239 TI - Palladium-catalyzed synthesis of indoles via ammonia cross-coupling-alkyne cyclization. AB - The synthesis of indoles via the metal-catalyzed cross-coupling of ammonia is reported for the first time; the developed protocol also allows for the unprecedented use of methylamine or hydrazine as coupling partners. These Pd/Josiphos-catalyzed reactions proceed under relatively mild conditions for a range of 2-alkynylbromoarenes. PMID- 21594240 TI - Facile preparation of SERS-active nanogap-rich Au nanoleaves. AB - To simply reduce HAuCl(4) using 2-thiophenemethanol in an aqueous solution at room temperature, a novel metallic Au nanostructure with a high SERS activity was obtained. Flat sheet-like Au nanoleaves possessing many nanogap hotspots bound with a large percentage of high-index facets were obtained. PMID- 21594241 TI - Asymmetric pyrene derivatives for organic field-effect transistors. AB - For the synthesis of an ortho-dithienylpyrene, a K-region bromination of pyrene was developed which enabled the first reported, non-statistical asymmetric functionalization of pyrene at the 4, 5, 9 and 10 positions. Crystal structures, optical and electronic properties and FET characteristics have been investigated. PMID- 21594242 TI - One pot iridium-catalyzed asymmetrical double allylations of sodium sulfide: a fast and economic way to construct chiral C2-symmetric bis(1-substituted allyl)sulfane. AB - One pot asymmetrical double allylations of sodium sulfide catalyzed by an iridium complex along with a combination of caesium fluoride and water in dichloromethane have been realized and the double allylation products with two C-S bond chiral centers were obtained in 67-99% yields with b/l 81/19-99/1, dr 85/15-99/1, and 96 99% ee. PMID- 21594243 TI - Low-energy electron scattering on deuterated nanocrystalline diamond films-a model system for understanding the interplay between density-of-states, excitation mechanisms and surface versus lattice contributions. AB - Electron energy loss spectrum, elastic reflectivity and selected vibrational excitation functions were measured by High Resolution Electron Energy Loss Spectroscopy (HREELS) for deuterated nanocrystalline dc GD CVD diamond films. The electron elastic reflectivity is strongly enhanced at about 13 eV, as a consequence of the second absolute band gap of diamond preserved up to the surface for D-nano-crystallites. The pure bending modes delta(CD(x)) at 88 meV and 107 meV are dominantly excited through the impact mechanism and their vibration excitation functions mimic the electron elastic reflectivity curve. Pure diamond phonon mode nu(CC) can be probed through the resolved fundamental loss located at 152 meV and through the multiple loss located at 300 meV. In addition to the well-known 8 eV resonance, two supplementary resonances located at 4.5 eV and 11.5 eV were identified and clearly resolved for the first time. A comprehensive set of data is now available on low-energy electron scattering at hydride terminated polycrystalline diamond films grown either by HF (microcrystalline) or dc GD (nanocrystalline) chemical vapour deposition. The careful comparison of the vibrational excitation functions for hydrogen/deuterium termination stretching modes nu(sp(3)-CH(x)) and nu(sp(3)-CD(x)), for hydrogen termination bending modes delta(CH(x)) mixed with diamond lattice modes nu(CC), for deuterium termination bending modes delta(CD(x)), and for multiple loss 2nu(CC) demonstrates the close interplay between three characteristics: (i) the density-of-states of the substrate, (ii) the vibrational excitation mechanisms (dipolar and/or impact scattering including resonant scattering) and (iii) the surface versus lattice character of the excited vibrational modes. This work shows clearly that excitation function measurement provides a powerful and sensitive tool to clarify loss attributions, involved excitation mechanisms, and surface versus lattice characters of the excited vibrational modes. PMID- 21594244 TI - A novel baseline-correction method for standard addition based derivative spectra and its application to quantitative analysis of benzo(a)pyrene in vegetable oil samples. AB - In the present work, a baseline-correction method based on peak-to-derivative baseline measurement was proposed for the elimination of complex matrix interference that was mainly caused by unknown components and/or background in the analysis of derivative spectra. This novel method was applicable particularly when the matrix interfering components showed a broad spectral band, which was common in practical analysis. The derivative baseline was established by connecting two crossing points of the spectral curves obtained with a standard addition method (SAM). The applicability and reliability of the proposed method was demonstrated through both theoretical simulation and practical application. Firstly, Gaussian bands were used to simulate 'interfering' and 'analyte' bands to investigate the effect of different parameters of interfering band on the derivative baseline. This simulation analysis verified that the accuracy of the proposed method was remarkably better than other conventional methods such as peak-to-zero, tangent, and peak-to-peak measurements. Then the above proposed baseline-correction method was applied to the determination of benzo(a)pyrene (BaP) in vegetable oil samples by second-derivative synchronous fluorescence spectroscopy. The satisfactory results were obtained by using this new method to analyze a certified reference material (coconut oil, BCR((r))-458) with a relative error of -3.2% from the certified BaP concentration. Potentially, the proposed method can be applied to various types of derivative spectra in different fields such as UV-visible absorption spectroscopy, fluorescence spectroscopy and infrared spectroscopy. PMID- 21594245 TI - Transmembrane anion transport by synthetic systems. AB - This highlight examines recent advances in the development of synthetic membrane transporters for anions, highlighting the underlying principles of transporter design and the promising applications of such transporters to biological systems including potential future treatments for diseases like cystic fibrosis which is caused by dysregulation of chloride transport across epithelial cell membranes. PMID- 21594246 TI - Rapid, sensitive DNT vapor detection with UV-assisted photo-chemically synthesized gold nanoparticle SERS substrates. AB - We report rapid, sensitive, and direct detection of 2,4-dinitrotoluene (DNT) vapor using tailored gold nanoparticles (Au-NPs) as the SERS substrate. The Au NPs were synthesized using the UV-assisted photo-chemical reduction method and subsequently formed a monolayer on the glass slide through polymer-mediated self assembly. The SERS substrate such prepared has high SERS enhancement, high affinity towards DNT vapor, and rapid response to the DNT adsorption/desorption. We systematically studied the effect of the Au-NP size and surface density on the SERS performance such as enhancement factor and response time. With the optimized SERS substrate, an enhancement factor over 5.6 * 10(6) was achieved. Furthermore, real-time detection of DNT vapor with only 0.35 second data acquisition time was demonstrated using a 12 mW laser. Compared to previously reported results, we achieved two orders of magnitude reduction in detection time and more than one order of magnitude reduction in excitation laser power. The detection limit is estimated to be 0.4 attogram, which corresponds to a sub-ppb DNT concentration in air. This work will lead to the development of ultra-fast and ultra-sensitive SERS devices for explosive identification and monitoring. PMID- 21594259 TI - Local chemical composition of nanophase-separated polymer brushes. AB - Using scattering scanning nearfield infrared microscopy (s-SNIM), we have imaged the nanoscale phase separation of mixed polystyrene-poly(methyl methacrylate) (PS PMMA) brushes and investigated changes in the top layer as a function of solvent exposure. We deduce that the top-layer of the mixed brushes is composed primarily of PMMA after exposure to acetone, while after exposure to toluene this changes to PS. Access to simultaneously measured topographic and chemical information allows direct correlation of the chemical morphology of the sample with topographic information. Our results demonstrate the potential of s-SNIM for chemical mapping based on distinct infrared absorption properties of polymers with a high spatial resolution of 80 nm * 80 nm. PMID- 21594260 TI - Modelling molecule-surface interactions--an automated quantum-classical approach using a genetic algorithm. AB - We present an automated and efficient method to develop force fields for molecule surface interactions. A genetic algorithm (GA) is used to parameterise a classical force field so that the classical adsorption energy landscape of a molecule on a surface matches the corresponding landscape from density functional theory (DFT) calculations. The procedure performs a sophisticated search in the parameter phase space and converges very quickly. The method is capable of fitting a significant number of structures and corresponding adsorption energies. Water on a ZnO(0001) surface was chosen as a benchmark system but the method is implemented in a flexible way and can be applied to any system of interest. In the present case, pairwise Lennard Jones (LJ) and Coulomb potentials are used to describe the molecule-surface interactions. In the course of the fitting procedure, the LJ parameters are refined in order to reproduce the adsorption energy landscape. The classical model is capable of describing a wide range of energies, which is essential for a realistic description of a fluid-solid interface. PMID- 21594261 TI - Synchronization of the circadian rhythm generator and the effects of glucagon on hypothalamic mouse neurons detected by acoustic wave propagation. AB - A thickness shear mode acoustic wave sensor has been used to study the reaction of clonal, immortalized hypothalamic murine neurons in response to glucagon and serum shock in a label free, continuous and real time manner under physiological conditions. Two cell lines were examined; these were the mHypoE-38s and the mHypoE-46s. The technique possesses sufficient sensitivity to detect minor neuronal changes and is capable of discerning subtle differences in cellular behaviors under both stimuli. The kinetics and magnitude of the changes observed here are significantly different compared to those instigated upon causing depolarization, cytoskeletal modifications and surface-adhesion specific interaction alterations with the same cells. Interestingly, this technique has the sensitivity and capability of observing all such changes at the neuronal level without the necessity for invasive interrogation. Under the influence of glucagon, the neurons display both short- and long-term changes, in particular the resonant frequency shifts by -23 +/- 8 Hz (n = 13, std. dev.) and the motional resistance decays at a rate of approximately 10 Omega h(-1) over a 2 hour interval. The effect of synchronizing the neurons prior to glucagon stimulation did not influence the cellular changes observed. The process of partial and full synchronization of the cells resulted in different responses. For full synchronization, the addition of the serum bolus triggered resonant frequency and motional resistance shifts of +75 Hz and +18.5 Omega respectively, which decayed back to baseline levels after 30 minutes. The duration of this decay closely matched the time required for full synchronization in a separate study. The changes observed for partial synchronization were significantly different from full synchronization as the baseline levels in both resonant frequency and motional resistance were not re-achieved indicative of the cell sensor system detecting the difference between full and partial synchronization. Preliminary qualitative immunocytochemistry and RT-PCR studies on these cells support the results obtained with the TSM sensor for the glucagon receptor study. PMID- 21594262 TI - Catalytic oxidation and determination of beta-NADH using self-assembly hybrid of gold nanoparticles and graphene. AB - A self-assembly hybrid of gold nanoparticles on graphene modified electrodes for low-potential NADH detection has been achieved. We used the natural polymer chitosan (Chit) to assist the stabilization of graphene in aqueous solution, and immobilize the electronegative Au nanoparticles (NPs) through electrostatic attraction. The synergy of Au NPs with graphene for catalytic oxidation of NADH made the overpotential ca. 220 mV less positive than that on the bare electrode, and remarkably increased the oxidation current. The amperometric sensors based on such modified electrodes for detection of NADH exhibited a good linearity from 1.5 to 320 MUM, and showed high sensitivity with a low detection limit of 1.2 MUM (S/N = 3). It could also exclude common interfering electroactive compounds like ascorbic acid and possessed good reproducibility and operational stability. Such eminent performance of the Au-RGO/Chit film together with the ability of graphene to significantly enhance the electron transfer between enzymes and the electrode suggested its promise for constructing novel graphene based dehydrogenase biosensors. PMID- 21594263 TI - Probing chemical induced cellular stress by non-Faradaic electrochemical impedance spectroscopy using an Escherichia coli capacitive biochip. AB - A new capacitive biochip was developed using carboxy-CNT activated gold interdigitated (GID) capacitors immobilized with E. coli cells for the detection of cellular stress caused by chemicals. Here, acetic acid, H(2)O(2) and NaCl were employed as model chemicals to test the biochip and monitored the responses under AC electrical field by non-Faradaic electrochemical impedance spectroscopy (nFEIS). The electrical properties of E. coli cells under different stresses were studied based on the change in surface capacitance as a function of applied frequency (300-600 MHz) in a label-free and noninvasive manner. The capacitive response of the E. coli biochip under normal conditions exhibited characteristic dispersion peaks at 463 and 582 MHz frequencies. Deformation of these signature peaks determined the toxicity of chemicals to E. coli on the capacitive biochip. The E. coli cells were sensitive to, and severely affected by 166-498 mM (1-3%) acetic acid with declined capacitance responses. The E. coli biochip exposed to H(2)O(2) exhibited adaptive responses at lower concentrations (<2%), while at a higher level (882 mM, 3%), the capacitance response declined due to oxidative toxicity in cells. However, E. coli cells were not severely affected by high NaCl levels (513-684 mM, 3-4%) as the cells tend to resist the salt stress. Our results demonstrated that the biochip response at a particular frequency enabled the determination of the severity of the stress imposed by chemicals and it can be potentially applied for monitoring unknown chemicals as an indicator of cytotoxicity. PMID- 21594264 TI - A novel method for in situ measurement of solubility via impedance scanning quartz crystal microbalance studies. AB - We introduce here a novel in situ measurement method for solubility of solids in various liquids. Without any calibration the saturation point can be obtained in a relative manner. We exemplified the new method at four systems including water, organic carbonates and an ionic liquid as the solvents and various salts as dissolved solids. PMID- 21594265 TI - Support vector machine regression (LS-SVM)--an alternative to artificial neural networks (ANNs) for the analysis of quantum chemistry data? AB - A multilayer feed-forward artificial neural network (MLP-ANN) with a single, hidden layer that contains a finite number of neurons can be regarded as a universal non-linear approximator. Today, the ANN method and linear regression (MLR) model are widely used for quantum chemistry (QC) data analysis (e.g., thermochemistry) to improve their accuracy (e.g., Gaussian G2-G4, B3LYP/B3-LYP, X1, or W1 theoretical methods). In this study, an alternative approach based on support vector machines (SVMs) is used, the least squares support vector machine (LS-SVM) regression. It has been applied to ab initio (first principle) and density functional theory (DFT) quantum chemistry data. So, QC + SVM methodology is an alternative to QC + ANN one. The task of the study was to estimate the Moller-Plesset (MPn) or DFT (B3LYP, BLYP, BMK) energies calculated with large basis sets (e.g., 6-311G(3df,3pd)) using smaller ones (6-311G, 6-311G*, 6-311G**) plus molecular descriptors. A molecular set (BRM-208) containing a total of 208 organic molecules was constructed and used for the LS-SVM training, cross validation, and testing. MP2, MP3, MP4(DQ), MP4(SDQ), and MP4/MP4(SDTQ) ab initio methods were tested. Hartree-Fock (HF/SCF) results were also reported for comparison. Furthermore, constitutional (CD: total number of atoms and mole fractions of different atoms) and quantum-chemical (QD: HOMO-LUMO gap, dipole moment, average polarizability, and quadrupole moment) molecular descriptors were used for the building of the LS-SVM calibration model. Prediction accuracies (MADs) of 1.62 +/- 0.51 and 0.85 +/- 0.24 kcal mol(-1) (1 kcal mol(-1) = 4.184 kJ mol(-1)) were reached for SVM-based approximations of ab initio and DFT energies, respectively. The LS-SVM model was more accurate than the MLR model. A comparison with the artificial neural network approach shows that the accuracy of the LS-SVM method is similar to the accuracy of ANN. The extrapolation and interpolation results show that LS-SVM is superior by almost an order of magnitude over the ANN method in terms of the stability, generality, and robustness of the final model. The LS-SVM model needs a much smaller numbers of samples (a much smaller sample set) to make accurate prediction results. Potential energy surface (PES) approximations for molecular dynamics (MD) studies are discussed as a promising application for the LS-SVM calibration approach. PMID- 21594266 TI - The interface between Au(100) and 1-butyl-3-methyl-imidazolium hexafluorophosphate. AB - The electrochemical interface of Au(100) and 1-butyl-3-methyl-imidazolium hexafluorophosphate has been characterized by cyclic voltammetry, electrochemical impedance spectroscopy and in situ STM, especially in two distinct potential ranges. In the vicinity of the potential of zero total charge--the value of which has been determined by immersion experiments--charging of the double layer is rather slow, it appears as if the ions comprising the ionic liquid would slowly exchange each other at the surface. In the other, very negative region the ordering of the cations has been observed by STM. PMID- 21594267 TI - Computational design of chlorin based photosensitizers with enhanced absorption properties. AB - The porphyrin and chlorin parent compounds constitute the base of many potent photosensitizers aimed to be utilized in photodynamic therapy (PDT). However, the photosensitizers available on the market today are not ideal for use in PDT; many of them suffering from drawbacks such as long-lasting photosensitization or absorption at wavelengths below the optimal tissue penetration. This has emphasized the need of new photosensitizers with improved photodynamic properties. In the present study we have used density functional theory based methods to design new chlorin compounds with conjugated substituents such as vinyl groups and carboxylic acids, aiming for strong absorption in the therapeutic window of PDT. The specific substituent positions were found to have a significant effect on the spectra. A chlorin with four propenoic acids was able to red-shift the absorption the most compared with non-substituted chlorin, generating the red-most absorption at 755 nm, and with significantly enhanced oscillator strengths. The results from the present study constitute a useful starting point for further design of tetrapyrrole derivatives as improved photosensitizers. PMID- 21594268 TI - Kinetic study of the reaction of OH with CH2I2. AB - Flash photolysis (FP) coupled to resonance fluorescence (RF) was used to measure the absolute rate coefficients (k(1)) for the reaction of OH(X(2)Pi) radicals with diiodomethane (CH(2)I(2)) over the temperature range 295-374 K. The experiments involved time-resolved RF detection of the OH (A(2)Sigma(+)->X(2)Pi transition at lambda = 308 nm) following FP of the H(2)O/CH(2)I(2)/He mixtures. The OH(X(2)Pi) radicals were produced by FP of H(2)O in the vacuum-UV at wavelengths lambda > 120 nm. Decays of OH radicals in the presence of CH(2)I(2) are observed to be exponential, and the decay rates are found to be linearly dependent on the CH(2)I(2) concentration. The results are described by the Arrhenius expression k(1)(T) = (4.2 +/- 0.5) * 10(-11) exp[-(670 +/- 20)K/T] cm(3) molecule(-1) s(-1). The implications of the reported kinetic results for understanding the atmospheric chemistry of CH(2)I(2) are discussed. PMID- 21594269 TI - 2-(1-(Arylimino)propyl)quinolin-8-olate half-titanocene dichlorides: synthesis, characterization and ethylene (co-)polymerization behaviour. AB - A series of 2-(1-(arylimino)propyl)quinolin-8-olate half-titanocene dichlorides, Cp'TiCl(2)L (Cp' = eta(5)-C(5)H(5) or eta(5)-C(5)Me(5), L = 2-(1-(2,6-R(1)-4-R(2) phenylimino)propyl)quinolin-8-olate), was synthesized via the stoichiometric reaction of Cp'TiCl(3) with the corresponding potassium 2-(1-(2,6-R(1)-4-R(2) phenylimino)propyl)quinolin-8-olate salt. All titanium compounds were characterized by elemental analysis, (1)H NMR and (13)C NMR spectroscopy; the molecular structures of two representative compounds were determined by single crystal X-ray diffraction. On activation with methylaluminoxane (MAO), all half titanocene compounds showed high activity in ethylene polymerization, and furthermore, performed with good to high activities in the co-polymerization of ethylene with either 1-hexene or 1-octene affording polyethylenes with high co monomer incorporation. Less bulky ortho-substituents (R(1)) on the phenylimino groups were found to enhance the catalytic activities of their titanium compounds. In general, the titanium pro-catalysts containing eta(5)-C(5)Me(5) (C7 C12) exhibited higher activities than did their analogues bearing eta(5)-C(5)H(5) (C1-C6). Some of the resultant polyolefins were ultrahigh molecular weight polyethylene. PMID- 21594270 TI - Highly luminescent complexes [Mo6X8(n-C3F7COO)6]2- (X=Br, I). AB - New complexes (Bu(4)N)(2)[Mo(6)X(8)(n-C(3)F(7)COO)(6)] (X = Br, I) display extraordinarily bright long-lived red phosphorescence both in solution and solid phases, with the highest emission quantum yields and the longest emission lifetimes among hexanuclear metal cluster complexes of Mo, W and Re, hitherto reported. PMID- 21594271 TI - Luminescent isomeric Pr-Ag coordination polymers immobilized with organic sensitizer and Ag-S clusters. AB - A pair of luminescent heterometallic lanthanide-transition-metal coordination polymers, namely, [PrLAg(3)(SCN)(6).H(2)O](n) (1) and [PrLAg(3)(SCN)(6)](n) (2) [L = 2,6-di(pyrazol-1-yl)pyridine], have been obtained with different cooling rates under solvothermal conditions. The two structures are pseudo- supramolecular isomers constructed via the same [PrL(NCS)(6)](3-) subunit and different Ag-S clusters, presenting diverse two-dimensional and three dimensional frameworks, respectively. In both complexes, the tridentate chelate L, acting as an organic chromophore, along with the d(10)-block Ag-S clusters, are simultaneously immobilized, and effectively sensitize the Pr(III)-based luminescence. PMID- 21594273 TI - Thioredoxin-dependent redox regulation of cellular signaling and stress response through reversible oxidation of methionines. AB - The sensitive oxidations of sulfur containing amino acids (i.e., cysteines and methionines) commonly control protein function, and act as important signaling mechanisms to modify metabolic responses to environmental stressors. Mechanisms associated with cysteine oxidation to form sulfenic acid and disulfides (i.e., cystine and glutathione adducts), and their reversibility through thioredoxin dependent mechanisms, are broadly appreciated as important regulatory mechanisms that control the function of a range of different proteins. Less commonly understood are the cellular consequences of methionine oxidation to form methionine sulfoxide, as the structural requirements for their thioredoxin dependent reduction by methionine sulfoxide reductases limit the reversibility of methionine oxidation to sequences within surface exposed and conformationally disordered regions of proteins. Surface exposed methionines are commonly involved in molecular recognition between transient protein signaling complexes, where their oxidation disrupts productive protein-protein interactions linked to a range of cellular responses. Such a signaling protein is calmodulin, which represents an early and central point in calcium signaling pathways important to stress responses in plants. We describe recent work elucidating fundamental mechanisms of reversible methionine oxidation within calmodulin, including the physical basis for differences in the sensitivity of individual methionines within plant and animal calmodulin to reactive oxygen species (ROS), the structural and functional consequences of their oxidation, and the interactions of oxidized calmodulin with methionine sulfoxide reductase enzymes. It is suggested that, in combination with high-throughput proteomic methods and current generation informatics tools, these mechanistic insights permit useful predictions of oxidatively sensitive signaling proteins that act as redox and stress sensors in response to methionine oxidation. PMID- 21594272 TI - Relating protein adduction to gene expression changes: a systems approach. AB - Modification of proteins by reactive electrophiles such as the 4-hydroxy-2 nonenal (HNE) plays a critical role in oxidant-associated human diseases. However, little is known about protein adduction and the mechanism by which protein damage elicits adaptive effects and toxicity. We developed a systems approach for relating protein adduction to gene expression changes through the integration of protein adduction, gene expression, protein-DNA interaction, and protein-protein interaction data. Using a random walk strategy, we expanded a list of responsive transcription factors inferred from gene expression studies to upstream signaling networks, which in turn allowed overlaying protein adduction data on the network for the prediction of stress sensors and their associated regulatory mechanisms. We demonstrated the general applicability of transcription factor-based signaling network inference using 103 known pathways. Applying our workflow on gene expression and protein adduction data from HNE-treatment not only rediscovered known mechanisms of electrophile stress but also generated novel hypotheses regarding protein damage sensors. Although developed for analyzing protein adduction data, the framework can be easily adapted for phosphoproteomics and other types of protein modification data. PMID- 21594274 TI - Syntheses, structures and properties of a series of non-heme alkoxide-Fe(III) complexes of a benzimidazolyl-rich ligand as models for lipoxygenase. AB - The treatment of Fe(ClO(4))(2).6H(2)O or Fe(ClO(4))(3).9H(2)O with a benzimidazolyl-rich ligand, N,N,N',N'-tetrakis[(1-methyl-2-benzimidazolyl)methyl] 1,2-ethanediamine (medtb) in alcohol/MeCN gives a mononuclear ferrous complex, [Fe(II)(medtb)](ClO(4))(2).1/2CH(3)CN.1/2CH(3)OH (1), and four non-heme alkoxide iron(III) complexes, [Fe(III)(OMe)(medtb)](ClO(4))(2).H(2)O (2, alcohol = MeOH), [Fe(III)(OEt)(Hmedtb)](ClO(4))(3).CH(3)CN (3, alcohol = EtOH), [Fe(III)(O(n)Pr)(Hmedtb)](ClO(4))(3).(n)PrOH.2CH(3)CN (4, alcohol = n-PrOH), and [Fe(III)(O(n)Bu)(Hmedtb)](ClO(4))(3).3CH(3)CN.H(2)O (5, alcohol = n-BuOH), respectively. The alkoxide-iron(III) complexes all show 1) a Fe(III)-OR center (R = Me, 2; Et, 3; (n)Pr, 4; (n)Bu, 5) with the Fe-O bond distances in the range of 1.781-1.816 A, and 2) a yellow color and an intense electronic transition around 370 nm. The alkoxide-iron(III) complexes can be reduced by organic compounds with a cis,cis-1,4-diene moiety via the hydrogen atom abstraction reaction. PMID- 21594275 TI - Highly water-dispersible, mixed ionic-electronic conducting, polymer acid-doped polyanilines as ionomers for direct methanol fuel cells. AB - Highly water-dispersible polymer acid-doped polyanilines have been synthesized and evaluated as an alternative for expensive Nafion ionomers in the anode of direct methanol fuel cells (DMFC). These polymers as ionomers lead to higher performance in single cell DMFC compared to Nafion ionomers due to mixed ionic electronic conduction, water dispersibility, and co-catalytic activity. PMID- 21594276 TI - Hexameric polyoxometalates decorated by six 3d-4f heterometallic clusters. AB - Two nanosized hexameric polyoxometalate-based solid state assemblies (H(2)en)(6)Na(15)K(9)[Dy(6)Fe(6)(H(2)O)(12)(SiW(10)O(38))(6)].34H(2)O (1) and K(13)Na(17)[H(2)en](3)[Tb(6)Fe(6)(H(2)O)(12)(SiW(10)O(38))(6)].40H(2)O (2) (en = 1,2-ethylenediamine), decorated by six [Ln-(MU(3)-O)(3)-Fe] 3d-4f heterometallic clusters, have been synthesized by the hydrothermal method, and characterized by IR, element analysis, magnetic studies and the single-crystal X-ray analyses. The detailed study of the synthetic conditions reveals that the use of the organic ligands, pH value and the reaction temperature all play important roles in the synthesis of the 3d-4f heterometallic POMs. Magnetic study suggests the presence of antiferromagnetic interactions in these two compounds. PMID- 21594277 TI - CeO2 nanoparticles/graphene nanocomposite-based high performance supercapacitor. AB - CeO(2) nanoparticles/graphene nanocomposite is fabricated by depositing CeO(2) nanoparticles onto three-dimensional graphene material and its supercapacitor performance is further investigated. The nanocomposite shows a high specific capacitance and power density, demonstrating a strong synergistic effect possibly contributed from improved conductivity of CeO(2) and better utilization of graphene. PMID- 21594278 TI - First observation of light-induced spin change in vacuum deposited thin films of iron spin crossover complexes. AB - Thin films of [Fe(H(2)Bpz)(2)(phen)] (1) and [Fe(H(2)Bpz)(2)(bipy)] (2) are prepared by vacuum deposition and investigated with respect to their spin crossover behaviour. For the first time light-induced excited spin state trapping (LIESST) is observed in such systems. T(1/2) and T(LIESST) in the films are in agreement with the bulk values. PMID- 21594279 TI - Continuous electrowetting via electrochemical diodes. AB - We describe a novel method for droplet transport combining electrowetting on dielectric (EWOD) and the diode-like behavior of valve metals to achieve unique actuation performance. While traditional EWOD droplet transport requires switching of voltage between multiple electrodes, our method, which we term continuous rectified electrowetting, utilizes a simple single electrode and a DC voltage to move a 50 MUl droplet 28 mm with velocities up to 32 mm s(-1). PMID- 21594280 TI - Electrochemically patterning sol-gel structures on conducting and insulating surfaces. AB - A new approach for the local deposition of sol-gel films on conducting and insulating surfaces using scanning electrochemical microscopy (SECM) via the feedback and direct modes is presented. Patterning is based on enhancing sol-gel condensation by altering the local pH due to water electrolysis as a result of applying negative potentials. PMID- 21594281 TI - Squaraine [2]catenanes: synthesis, structure and molecular dynamics. AB - Three squaraine [2]catenanes are synthesized and found to have bright, deep-red fluorescence and high chemical stability. The interlocked molecules undergo two large-amplitude dynamic processes, twisting of the squaraine macrocycle and skipping over the partner tetralactam. PMID- 21594282 TI - Mixed DNA-functionalized nanoparticle probes for surface-enhanced Raman scattering-based multiplex DNA detection. AB - Highly stable silver nanoparticle-oligonucleotide conjugates were prepared. Based on the mixed DNA-functionalized silver nanoparticles (AgNPs), multiplex DNA detections were demonstrated successfully by SERS. PMID- 21594284 TI - A small molecule antagonist of ghrelin O-acyltransferase (GOAT). AB - Using our recently disclosed fluorescence-based assay to monitor acyltransferase activity, the first non-peptidic, small molecule antagonists of ghrelin O acyltransferase (GOAT), a potential anti-obesity and anti-diabetes target, have been discovered. Each exhibits micromolar inhibition of the enzyme, and may be useful probes for future study of the ghrelin-GOAT system. PMID- 21594285 TI - Mechanism and dynamics of intramolecular triplet state decay of 1-propyl-4 thiouracil and its alpha-methyl-substituted derivatives studied in perfluoro-1,3 dimethylcyclohexane. AB - The absorption, phosphorescence and phosphorescence excitation spectra, phosphorescence quantum yields, and T(1) excited state lifetimes of four 4 thiouracil derivatives were measured for the first time in chemically inert and very weakly interacting perfluoro-1,3-dimethylcyclohexane at room temperature. The set of the 4-thiouracil derivatives comprises 1-propyl-4-thiouracil (PTU) and the related compounds having a methyl substituent at the position alpha to the thiocarbonyl group, namely 1-propyl-4-thiothymine (PTT), 1,3-dimethyl-4 thiouracil (DMTU), and 1-methyl-3-trideuteriomethyl-4-thiouracil ([D(3)]DMTU). Quantitative information on the intramolecular decay of the T(1) excited state of the four 4-thiouracil derivatives is presented, and the mechanism and dynamics of this process are discussed. In the absence of self quenching and solvent induced deactivation, the T(1) decay of the four 4-thiouracil derivatives was dominated by intramolecular nonradiative processes (NR). The values of the rate constant k(NR) in DMTU and [D(3)]DMTU are about 4 times larger than that in PTT and about 3 times larger than that in PTU. The reasons for the enhanced nonradiative rate constant in DMTU are discussed. It is concluded that the faster rate of the nonradiative processes in DMTU is related to a larger contribution from mixing of the T(2) (npi*) state into the lowest energy T(1) (pipi*) state, as compared to the analogous coupling in PTU and PTT. This conclusion is supported by ab initio calculations performed at the EOM-CC2/aug-cc-pVDZ level of theory. The energy spacing between the T(2) (npi*) and T(1) (pipi*) states is estimated to be about 500, 1100, and 2000 cm(-1) for DMTU, PTU, and PTT, respectively. Among the three compounds in question, the predicted energy spacing is thus the smallest for DMTU. PMID- 21594286 TI - The synthesis and stereospecific solid-state photodecarbonylation of hexasubstituted meso- and d,l-ketones. AB - Tertiary carbanions were trapped with half an equivalent of diphosgene to give meso- and d,l-hexasubstituted ketones in moderate yields and modest diastereoselectivities. The ketones were also synthesized by a step-wise synthesis in which the carbonyl group was first installed as an acid before activation and the second nucleophilic attack. This second method gave lower yields but similar diastereoselectivites. Steric limits of both methods were also determined. The photolysis of the resulting crystalline ketones gave a mixture of products in solution, but took place chemoselectively and diastereospecifically in the solid-state. PMID- 21594283 TI - Bacterial symbionts and natural products. AB - The study of bacterial symbionts of eukaryotic hosts has become a powerful discovery engine for chemistry. This highlight looks at four case studies that exemplify the range of chemistry and biology involved in these symbioses: a bacterial symbiont of a fungus and a marine invertebrate that produce compounds with significant anticancer activity, and bacterial symbionts of insects and nematodes that produce compounds that regulate multilateral symbioses. PMID- 21594287 TI - Fluorescent gallium and indium bis(thiosemicarbazonates) and their radiolabelled analogues: synthesis, structures and cellular confocal fluorescence imaging investigations. AB - New fluorescent and biocompatible aromatic Ga(III)- and In(III) bis(thiosemicarbazonato) complexes for dual mode optical and PET or SPECT molecular imaging have been synthesised via a synthetic method based on transmetallation reactions from Zn(II) precursors. Complexes have been fully characterised in the solid state by single crystal X-ray diffraction and in solution by spectroscopic methods (UV/Vis, fluorescence, (1)H and (13)C{(1)H} NMR). The bis(thiosemicarbazones) radiolabelled rapidly in high yields under mild conditions with (111)In (a gamma and Auger emitter for SPECT imaging and radiotherapy with t(1/2) = 2.8 d) and (68)Ga (a generator-available positron emitter for PET imaging with t(1/2) = 68 min). Cytotoxicity and biolocalisation studies using confocal fluorescence imaging and fluorescence lifetime imaging (FLIM) techniques have been used to study their in vitro activities and stabilities in HeLa and PC-3 cells to ascertain their suitability as synthetic scaffolds for future multimodality molecular imaging in cancer diagnosis and therapy. The observation that the indium complexes show certain nuclear uptake could be of relevance towards developing (111)In therapeutic agents based on Auger electron emission to induce DNA damage. PMID- 21594288 TI - Optical electron transfer through 2,7-diethynylfluorene spacers in mixed-valent complexes containing electron-rich "(eta2-dppe)(eta5-C5Me5)Fe" endgroups. AB - We report in this communication the study of the intramolecular electron transfer through a 2,7-diethynylfluorenyl spacer in the Fe(II)/Fe(III) mixed-valent (MV) complex [(eta(2)-dppe)(eta(5)-C(5)Me(5))FeC=C(2,7-C(21)H(24))C=CFe(eta(5) C(5)Me(5))(eta(2)-dppe)][PF(6)] (1[PF(6)]). The complex is generated in situ by comproportionation from its homovalent dinuclear Fe(II) and Fe(III) parents (1 and 1[PF(6)](2)). It is shown that electronic delocalization is much more effective through a 2,7-fluorenyl than through a 4,4'-biphenyl bridging unit. PMID- 21594289 TI - A heterometallic sandwich complex of europium(II) for luminescent studies. AB - A divalent europium complex [(L(Ph))(2)Eu{K(THF)(2)}(2)] (L(Ph) = Ph(2)Si(NAr)(2), Ar = 2,6-(i)Pr(2)C(6)H(3)) (THF = Tetrahydrofuran) (2), which has a sandwich structure with potassium-arene pi interactions, was synthesized in high yield via a one-pot process. This complex has been fully characterized, and luminescent studies showed that the 528 nm emission peak can be attributed to the 4f-5d transition of Eu(2+). PMID- 21594290 TI - Accessing the long-lived near-IR-emissive triplet excited state in naphthalenediimide with light-harvesting diimine platinum(II) bisacetylide complex and its application for upconversion. AB - Room temperature near-IR phosphorescence of naphthalenediimide (NDI) was observed with N^N Pt(II) bisacetylide complex (Pt-NDI) in which the NDI was connected to Pt(II) center via acetylide. Pt-NDI shows intense absorption of visible light and long-lived NDI-localized excited state ((3)IL) (tau(T) = 22.3 MUs). Pt-NDI was used as a triplet sensitizer for upconversion. PMID- 21594291 TI - Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells. AB - Prostate cancer is the second leading cause of cancer-related deaths among US males. Pomegranate juice (PJ), a natural product, was shown in a clinical trial to inhibit progression of this disease. However, the underlying mechanisms involved in the anti-progression effects of PJ on prostate cancer remain unclear. Here we show that, in addition to causing cell death of hormone-refractory prostate cancer cells, PJ also increases cell adhesion and decreases cell migration of the cells that do not die. We hypothesized that PJ does so by stimulating the expression and/or activation of molecules that alter the cytoskeleton and the adhesion machinery of prostate cancer cells, resulting in enhanced cell adhesion and reduced cell migration. We took an integrative approach to these studies by using Affimetrix gene arrays to study gene expression, microRNA arrays to study the non-coding RNAs, molecules known to be disregulated in cancer cells, and Luminex Multiplex array assays to study the level of secreted pro-inflammatory cytokines/chemokines. PJ up-regulates genes involved in cell adhesion such as E-cadherin, intercellular adhesion molecule 1 (ICAM-1) and down-regulates genes involved in cell migration such as hyaluranan mediated motility receptor (HMMR) and type I collagen. In addition, anti-invasive microRNAs such as miR-335, miR-205, miR-200, and miR-126, were up-regulated, whereas pro-invasive microRNA such as miR-21 and miR-373, were down-regulated. Moreover, PJ significantly reduced the level of secreted pro-inflammatory cytokines/chemokines such as IL-6, IL-12p40, IL-1beta and RANTES, thereby having the potential to decrease inflammation and its impact on cancer progression. PJ also inhibits the ability of the chemokine SDF1alpha to chemoattract these cancer cells. SDF1alpha and its receptor CXCR4 are important in metastasis of cancer cells to the bone. Discovery of the mechanisms by which this enhanced adhesion and reduced migration are accomplished can lead to sophisticated and effective prevention of metastasis in prostate and potentially other cancers. PMID- 21594292 TI - Quantitative and sensitive detection of rare mutations using droplet-based microfluidics. AB - Somatic mutations within tumoral DNA can be used as highly specific biomarkers to distinguish cancer cells from their normal counterparts. These DNA biomarkers are potentially useful for the diagnosis, prognosis, treatment and follow-up of patients. In order to have the required sensitivity and specificity to detect rare tumoral DNA in stool, blood, lymph and other patient samples, a simple, sensitive and quantitative procedure to measure the ratio of mutant to wild-type genes is required. However, techniques such as dual probe TaqMan((r)) assays and pyrosequencing, while quantitative, cannot detect less than ~1% mutant genes in a background of non-mutated DNA from normal cells. Here we describe a procedure allowing the highly sensitive detection of mutated DNA in a quantitative manner within complex mixtures of DNA. The method is based on using a droplet-based microfluidic system to perform digital PCR in millions of picolitre droplets. Genomic DNA (gDNA) is compartmentalized in droplets at a concentration of less than one genome equivalent per droplet together with two TaqMan((r)) probes, one specific for the mutant and the other for the wild-type DNA, which generate green and red fluorescent signals, respectively. After thermocycling, the ratio of mutant to wild-type genes is determined by counting the ratio of green to red droplets. We demonstrate the accurate and sensitive quantification of mutated KRAS oncogene in gDNA. The technique enabled the determination of mutant allelic specific imbalance (MASI) in several cancer cell-lines and the precise quantification of a mutated KRAS gene in the presence of a 200,000-fold excess of unmutated KRAS genes. The sensitivity is only limited by the number of droplets analyzed. Furthermore, by one-to-one fusion of drops containing gDNA with any one of seven different types of droplets, each containing a TaqMan((r)) probe specific for a different KRAS mutation, or wild-type KRAS, and an optical code, it was possible to screen the six common mutations in KRAS codon 12 in parallel in a single experiment. PMID- 21594293 TI - Metabonomics study of transgenic Bacillus thuringiensis rice (T2A-1) meal in a 90 day dietary toxicity study in rats. AB - Rice is one of the most important staple foods in the world. The Cry2A gene was inserted into the rice genome to help the plant combat insects. As the unintended effects of the genetically modified (GM) organisms are the most important barriers to the promotion of GM organisms, we have carried out a useful exploration to establish a new in vivo evaluation model for genetically modified foods by metabonomics methods. In this study, the rats were fed for 90 days with the GM and NON-GM rice diets. The changes in metabolites of the urine were detected using (1)H-NMR. The metabonomics were analyzed to see whether the GM rice can induce the metabolite changes in the rats' urine when compared with the NON-GM rice group. The multivariate analysis and ANOVA were used to determine the differences and the significance of differences respectively, and eventually we concluded that these differences did not have a biological significance. The conclusion of the metabonomics was comparable with that from the traditional method. As a non-invasive and dynamic monitoring method, metabonomics will be a new way of assessing the food safety of GM foods. PMID- 21594294 TI - Ultrahigh CO2 adsorption capacity on carbon molecular sieves at room temperature. AB - Although metal-organic framework (MOF) materials have been postulated as superior to any other sorbent for CO(2) adsorption at room temperature, here we prove that the appropriate selection of the raw material and the synthesis conditions allows the preparation of carbon molecular sieves (CMSs) with adsorption capacity, on a volumetric basis, highly exceeding those reported in the literature for MOFs. Furthermore, the excellent sorption properties of CMSs over the whole pressure range (up to 50 bar) are fully reversible after different adsorption/desorption cycles. PMID- 21594295 TI - Oscillations death revisited; coupling of identical chemical oscillators. AB - The coupling of identical reactors containing chemical oscillators is discussed. The coupling is executed by means of transferring chemical species from one cell (reactor) to the other in a diffusion like manner i.e. in proportion to the concentration difference between the cells. The coupling rate constant, however, is the same for all species. The individual, uncoupled, cells may be oscillating or in a stable steady state (the same for all reactors). In both cases, depending on the initial conditions, the symmetry breaks, and the cells may end up-contrary to intuition-in a stable steady state in which the final concentrations are not equal in the various reactors. The Brusselator and Oregonator mechanisms are examined and they behave in the manner described. On the other hand, the Lotka Volterra mechanism, being conservative, keeps, when coupled, only the homogeneous solutions. PMID- 21594296 TI - Comparison of the performance of dispersion-corrected density functional theory for weak hydrogen bonds. AB - Potential energy curves for five complexes with weak to medium strong hydrogen bonds have been computed with dispersion corrected DFT methods. The electronic density based vdW-DF2 and VV10 van der Waals density functionals have been tested, as well as an atom pair-wise correction method (DFT-D3). The short-range exchange-correlation components BLYP and rPW86-PBE together with the extended aug cc-pVQZ basis sets have been employed. Reference data have been computed at the estimated CCSD(T)/CBS(aQ-a5) level of theory. The investigated systems are CH(4).NH(3), Cl(3)CH.NH(3), NH(3).NH(3), CH(3)F.C(2)H(2) and CH(3)F.H(2)O with binding energies ranging from -0.7 kcal mol(-1) to -5.5 kcal mol(-1). We find that all dispersion corrected methods perform reasonably well for these hydrogen bonds, but also observe distinct differences. The BLYP-D3 method provides the best results for three out of five systems. For the fluorinated complexes, the VV10 method gives remarkably good results. The vdW-DF2 method yields good interaction energies similar to the other methods (mean average deviation of 0.2 0.3 kcal mol(-1)), but fails to provide accurate equilibrium separations. Based on these results and previous experience with the computation of non-covalent interactions, for large-scale applications we can recommend DFT-D3 based structure optimizations with subsequent checking of interaction energies by single-point VV10 computations. Comparison of the DFT-D3 and VV10 results leads to the conclusion that the short-range exchange-correlation functional and not the dispersion correction mainly determines the achievable accuracy. PMID- 21594297 TI - Structure-property interplay of proton conducting membranes based on PBI5N, SiO2 Im and H3PO4 for high temperature fuel cells. AB - Polybenzimidazoles (PBIs) are among the polymers of choice to prepare membranes for high temperature polymer fuel cells. Poly-2,2'(2,6-pyridine)-5,5' bibenzimidazole (PBI5N), doped with H(3)PO(4), and acid-doped PBI5N containing 10 wt% of imidazole-functionalized silica membranes were studied with thermogravimetric analysis, differential scanning calorimetry, dynamic-mechanical analysis, infrared spectroscopy, and broadband electric spectroscopy to examine the structure-property relationships. Key results show that: (1) doped PBI5N membranes show thermal decomposition starting at 120 degrees C, while pristine PBI5N is stable up to 300 degrees C; (2) the presence of filler increases the acid uptake and decreases the crystallinity of PBI5N; (3) the addition of phosphoric acid reduces the mechanical properties of the membrane, while the addition of filler has the opposite effect; (4) acid-doped membranes have conductivity values on the order of 10(-2)-10(-3) S cm(-1); and (5) membranes exhibit a Vogel-Tamman-Fulcher (VTF) type proton conduction mechanism, where proton hopping is coupled with the segmental motion of the polymer chain. Infrared spectroscopy combined with DFT quantum mechanical calculations was used to assign the experimental spectrum of PBI5N. PMID- 21594299 TI - Preparation and synthetic applications of alkene complexes of group 9 transition metals in [2+2+2] cycloaddition reactions. AB - The [2+2+2] cycloaddition reaction has become an invaluable tool for the synthetic chemistry in recent years, due to the increase of complexity of the accessed target molecules by this methodology. Over several decades, the members of group 9 of the periodic table have contributed significantly to the development and understanding of this particular cycloaddition reaction. On the other hand, catalyst complexes containing alkenes as ligands are widely used today as either catalysts or as precursor molecules for the facile generation of catalytically active metal species. In this tutorial review we want to describe the catalytically relevant chemistry of group 9 metal-alkene complexes and compile some recent applications in [2+2+2] cycloaddition reactions. PMID- 21594300 TI - Occurrence of selected antibiotics in Jiulongjiang River in various seasons, South China. AB - The concentrations of six sulfonamides (SAs) and three tetracyclines (TCs) were investigated in Jiulongjiang River during the low water season and the high water season. They were monitored in both surface water and sediment. Total concentrations of all these antibiotics varied from 31 to 25,771 ng g(-1) in sediment samples. In water they ranged from 60 to 2607 ng L(-1) during the low water season and from ND (not detected) to 134 ng L(-1) during the high water season. At the sites nearby breeding farms, chlorotetracycline was found to have the highest concentration of 1036 ng L(-1) in water and 14,666 ng g(-1) in sediments. According to the published data, the concentrations of sulfamethazine, sulfameter and TCs at these sites were higher than that in most rivers. The concentrations during the low water season were tens to hundreds of times higher than that in the high water season. The lower concentrations of TCs in the high water season might result from both dilution and photo-degradation, while dilution and bio-degradation might lead to the lower concentrations of SAs. However, further study is needed to clarify the specific reasons. Concerning the relationship between sediment and water samples, the pseudo-partitioning values of TCs were much higher than SAs. It indicates that the TCs are prone to accumulate in the sediment. PMID- 21594301 TI - Donor/acceptor complex of triphenylene and trinitrotoluene on Au(111): a scanning tunneling microscopy study. AB - The co-adsorption of trinitrotoluene (TNT), a typical pi-electron acceptor, and triphenylene (TP), a typical pi-electron donor, on a Au(111) surface was investigated by in situ Electrochemical Scanning Tunneling Microscopy (ECSTM). DFT calculations proved that parallelly stacked and well-overlapped TP and TNT molecules can form Donor-Acceptor dyads through intermolecular pi-pi charge transfer, which agree well with the experimental results in the present work. PMID- 21594298 TI - DNA origami: a quantum leap for self-assembly of complex structures. AB - The spatially controlled positioning of functional materials by self-assembly is one of the fundamental visions of nanotechnology. Major steps towards this goal have been achieved using DNA as a programmable building block. This tutorial review will focus on one of the most promising methods: DNA origami. The basic design principles, organization of a variety of functional materials and recent implementation of DNA robotics are discussed together with future challenges and opportunities. PMID- 21594302 TI - A domino pericyclic route to polysubstituted salicylic acid derivatives: four sequential processes from enynones and ketene silyl acetals. AB - Alkenyl alkynyl ketones and ketene silyl acetals (KSAs) undergo regioselective [2+2]-cycloaddition under thermal conditions, triggering domino pericyclic reactions en route to various poly-substituted salicylic acid derivatives. PMID- 21594303 TI - Anatomical accuracy of abdominal lesion localization. Retrospective automatic rigid image registration between FDG-PET and MRI. AB - Software-based image registration can improve the diagnostic value of imaging procedures and is an alternative to hybrid scanners. The aim of this study was to evaluate the anatomical accuracy of automatic rigid image registration of independently acquired datasets of positron emission tomography with 18F deoxyglucose and abdominal magnetic resonance imaging. PATIENTS, METHODS: Analyses were performed on 28 abdominal lesions from 20 patients. The PET data were obtained using a stand-alone PET camera in 14 cases and a hybrid PET/CT scanner in 9 cases. The abdominal T1- and T2-weighted MRI scans were acquired on 1.5 T MRI scanners. The mean time interval between MRI and PET was 7.3 days (0-28 days). Automatic rigid registration was carried out using a self-developed registration tool integrated into commercial available software (InSpace for Siemens Syngo). Distances between the centres of gravity of 28 manually delineated neoplastic lesions represented in PET and MRI were measured in X-, Y-, and Z-direction. The intra- (intraclass correlation 0.94) and inter- (intraclass correlation 0.86) observer repeatability were high. RESULTS: The average distance in all MRI sequences was 5.2+/-7.6 mm in X-direction, 4.0+/-3.7 mm in Y-direction and 6.1+/-5.1 mm in Z-direction. There was a significantly higher misalignment in Z-direction (p<0.05). The misalignment was not significantly different for the registration of T1- and T2- weighted sequences (p=0.7). CONCLUSION: The misalignment between FDG-PET and abdominal MRI registered using an automated rigid registration tool was comparable to data reported for software-based fusion between PET and CT. Although this imprecision may not affect diagnostic accuracy, it is not sufficient to allow for pixel-wise integration of MRI and PET information. PMID- 21594304 TI - Metabolic tumour volume. Prognostic value in locally advanced squamous cell carcinoma of the head and neck. AB - PURPOSE: Evaluate the predictive and prognostic value of semi-quantitative FDG PET variables derived from pretreatment FDG-PET images in patients suffering from locally advanced squamous cell carcinoma of the head and neck (SCCHN), treated by means of concomitant radiochemotherapy. PATIENTS, METHODS: 40 patients with newly diagnosed SCCHN that were treated with concomitant radiochemotherapy underwent FDG-PET/CT for treatment planning; 18 patients had neck dissection prior to their baseline scan and to receiving radiochemotherapy. FDG-PET images were used to calculate metabolic tumour volumes using region growing and a threshold of 50% (MTV50) of primary lesions and involved lymph nodes as well as the mean and maximum standard uptake value (SUVmean and SUVmax) of the primary tumours. RESULTS: Neither SUVmean nor SUVmax values of the primary tumour were significantly different between responders and non-responders whereas MTV50 values of the primary tumour proved significantly higher in non-responders. SUVmean, SUVmax and MTV50 of the primary tumour were not predictive for overall or disease free survival. Contrariwise, dichotomized summed MTV50 values (cut off>=31 cm3) of the primary tumour and involved lymph nodes in patients that didn't have neck dissection prior to radiochemotherapy were predictive for disease free and overall survival in both univariate and multivariate analysis (p<=0.05). CONCLUSION: Summed MTV50 values of both the primary tumour and involved lymph nodes provided independent prognostic information on disease free and overall survival. PMID- 21594305 TI - Results of research into the frequency of exclusive breastfeeding vary depending on the approach taken in the interview. AB - OBJECTIVE: To compare the frequency of exclusive breastfeeding using two different interview approaches. METHODS: This was a cross-sectional study of 309 mothers of children aged 0 to 6 months, with a median age of 11 days. Mothers were interviewed at the Instituto de Medicina Integral Prof. Fernando Figueira during November and December of 2009. Two approaches to the interview were tested: firstly, the mother was asked if complementary foods had been given during the preceding 24 hours. Secondly, they were asked if at any point during the child's life any other foods had been given. The marginal homogeneity test was applied and the significance level was 5%. RESULTS: According to the 24-hour recall, the frequency of exclusive breastfeeding was 78.0%. According to the wider-ranging recall period, the frequency was 59.2% (p < 0.001). CONCLUSIONS: The frequency of the exclusive breastfeeding is overestimated using the 24-hour recall compared with the whole-life recall. PMID- 21594306 TI - Ras inhibitors. AB - A number of proteins and low-molecular weight compounds have been reported to suppress the activity toward ras-oncogenes and their products. These include anti lias antibody, inhibitors of Ras activation, Ras dominant negative mutants, inhibitors of processing of newly-synthesized Ras, suppressors and inhibitors of downstream effecters and genetic probes such as anti-sense oligonucleotides and ribozymes. There are also other Ras inhibitors whose action mechanisms remain to be proved. Some of these inhibitors might be useful as cancer therapeutic agents. PMID- 21594307 TI - Serum thymidine kinase as a tumor marker of colorectal carcinogenesis induced with 1,2-dimethylhydrazine in rats. AB - Thymidine kinase is the key enzyme in salvage pathway for pyrimidine nucleotide synthesis. High activities of thymidine kinase have been found in rapidly proliferating normal, neoplastic tissues and sera from patients with various diseases including lymphoma, leukemias and small cell lung cancer. We investigated the serum thymidine kinase activities and the colorectal carcinomas in rats treated with 1,2-dimethylhydrazine. The positive correlations between serum thymidine kinase activities and numbers of total and large tumors were observed. These findings suggest the measurement of serum thymidine kinase activity may be clinically valuable in an early stage of the colonic carcinogenesis. PMID- 21594308 TI - Tamoxifen in patients with advanced pancreatic adenocarcinoma. AB - Estrogen and somatostatin receptors have been found in pancreatic carcinoma cells, The growth of pancreatic carcinomas has been shown to be inhibited by various endocrine treatments. In view of these findings, a well known anti estrogen tamoxifen has been used, both as a single agent and in combination with other agents, in clinical trials in patients with unresectable carcinoma of the exocrine pancreas. The impact on survival of tamoxifen in patients with advanced pancreatic adenocarcinoma has been assessed among patients from the previously reported trials of tamoxifen as a single agent, and compared with the survival of patients treated with the synergistic combination of intravenous Onconase plus oral tamoxifen. While a few patients treated with tamoxifen as a single agent may survive for prolonged period of time, the significance of such results remains uncertain in view of the lack of significant survival difference between patients treated with tamoxifen vs. untreated controls in prospectively randomized trials, and vis a vis clearly multifactorial determination of survival. On the other hand, the synergistic combinations of agents that demonstrate favorable toxicity profiles may offer significant survival advantage, at least in some patients with advanced pancreatic cancer. PMID- 21594309 TI - Radiation-induced heart disease. AB - The recent improvement in radiation techniques and the associated significant prolongation of survival have resulted in a widespread utilization of mediastinal irradiation in patients with various neoplasms. However, a large number of experimental and clinical studies have clearly demonstrated that high-dose therapeutic mediastinal irradiation can produce delayed, severe cardiovascular disease. This review presents the data from the Literature regarding the pathogenesis, pathology, prevalence and clinical manifestation of the radiation related heart disease. PMID- 21594310 TI - Transformed cells trigger induction of their own apoptosis in coculture with normal cells. AB - In vitro, transforming growth factor type betal triggers normal cells to induce apoptosis in transformed cells. We show that in the absence of exogenous transforming growth factor type betal, induction of apoptosis of transformed cells in coculture with normal cells is dependent on the number of transformed cells per assay and is abrogated by antibodies against TGF-beta 1. Therefore, transforming growth factor type betal produced by transformed cells seems to be responsible for triggering a mechanism that leads to the induction of their apoptosis. This mechanism may be crucial for the control of carcinogenesis in vivo. PMID- 21594311 TI - Azatyrosine inhibits the activation of c-Raf-1, c-Jun and AP1 but not the activation of Ras during signal transduction triggered by oncogenic c-ErbB-2. AB - Azatyrosine [L-beta-(5-hydroxy-2-pyridyl)alanine] is known to convert ras- or raf transformed NIH3T3 cells to a normal phenotype. We report herein that azatyrosine also inhibits the growth of c-erbB-2-transformed cells and induces normal morphology. We attempted to identify the signal-transduction process triggered by oncogenic c-ErbB-2 that was inhibited by azatyrosine. Azatyrosine neither affected the phosphorylation of the introduced oncogenic c-ErbB-2 nor did it suppress activation of Ras induced by introduction of c-ErbB-2. Thus, azatyrosine did not inhibit the signal transduction from oncogenic c-ErbB-2 to Ras. However, azatyrosine inhibited increases in phosphorylation of c-Raf-1 and c Jun induced by oncogenic c-ErbB-2. Furthermore, azatyrosine inhibited activation of the 12-O-tetradecanoylphorbol-13-acetate (TPA) response element in response to stimulation by oncogenic c-ErbB-2. These results suggest that azatyrosine acts downstream of Ras in signal transduction from oncogenic c-ErbB-2 to nuclear factors. PMID- 21594312 TI - Evaluation of MTX/5-FU sequential chemotherapy utilized MTT assay for gastrointestinal cancer. AB - Fresh human gastrointestinal cancer cells are more resistant to anticancer drugs compared to other cancer cells, and the selection of anticancer drugs for cancer chemotherapy is important. In the present study, it is demonstrated that MTX enhanced the chemosensitivity of 5-FU, especially, in the tumor cells with less than 70% inhibition ratio by the MTT assay. It has been reported that MTX/5-FU sequential chemotherapy was one of the effective chemotherapies against gastric cancer and colon cancer, and it is possible to anticipate the efficacy of MTX/5 FU sequential chemotherapy by the MTT assays. PMID- 21594313 TI - Autologous mixed lymphocyte reaction and postoperative prognosis in patients with gastric carcinoma. AB - The autologous mixed lymphocyte reaction (AMLR) represents a self recognitive response, which is very important in the immunoregulatory network system. We investigated whether the AMLR activity of patients with gastric carcinoma could reflect the postoperative prognosis to clarify the significance of autoreactivity in anti-tumor immune system in cancer patients. The AMLR activity was suppressed both in the peripheral blood and in the spleen of patients with gastric carcinoma. The patients were divided into two groups; high responder and low responder group. The former consisted of patients whose AMLR activity was extremely suppressed, and the latter of patients whose AMLR activity was mildly suppressed. The survival rate and disease-free survival rate were generally higher in the high responder group than in the low responder group, especially in the spleen. Moreover, none of the patients in the high responder group for the AMLR activity in the spleen died within three years. These results indicated that the AMLR activity could reflect the prognosis of patients who received conventional curative operation. Therefore, it was suggested that the AMLR might be a useful parameter of postoperative prognosis in gastric cancer patients and that autoreactive T cells might play a pivotal role in auto-specific immunological control of tumor growth and metastases. PMID- 21594314 TI - Stimulation of the expression of rhoB contributes to the ability of azatyrosine to convert c-erbB-2-transformed cells to a normal morphology. AB - We have reported recently that azatyrosine inhibits the growth of ras-, raf-, or c-erbB-2 transformed NIH3T3 cells and converts the transformed cells to cells with normal morphology. We show in this study that treatment of c-evbB-2 transformed cells with azatyrosine restore the capacity for the formation of actin stress fibers, which is closely associated with the phenotype of normal cells. Azatyrosine also restored the expression of the rhoB gene, the product of which regulates the formation of actin stress fibers. To investigate the roll of expression of rhoB in the morphological reversion, c-erbB-2 transformed cells were transfected with a rhoB expression vector. The cells that overexpressed rhoB were flatter than the parental transformed cells and the formation of actin stress fibers was observed in these flatter cells. Furthermore, the growth rate of these cells was lower than that of parental cells, although the flatter cells were still able to grow anchorage-independently. These results suggest that expression of rhoB is involved in the conversion of c-erbB-2-transformed cells to a normal phenotype that is induced by azatyrosine, but such expression is insufficient by itself for complete reversion. PMID- 21594315 TI - Expression of the retinoblastoma gene product in clinical thyroid tissues. AB - We investigated the expression of the retinoblastoma gene product (pRB) in various clinical thyroid tissues. Follicular cells in the normal thyroid sometimes expressed pRB but their positive cell ratio was always less than 10% as it was in hyperplasia. All of the 57 carcinomas tested expressed pRB immunohistochemically with various positivity and 36 of them (63.2%) showed high immunoreactivity. In contrast, only four of the 15 follicular adenoma samples (26.7%) revealed moderate pRB immunoreactivity and there was a statistically significant difference (p<0.01) in PRE positivity between the carcinomas, including follicular ones, and benign follicular adenomas. These findings indicate that pRB may be closely related to the suppression of tumoral growth, especially of carcinoma growth of the thyroid. Western blot analysis showed pRB immunoreactivity for all tested samples to be a single, sharp band located at 110 kDa, indicating that pRB in thyroid tumors is always unphosphorylated and active. The present study suggests that frequent pRB expression in an active form could be one of the reasons for the slow growth and excellent prognosis of thyroid carcinoma. PMID- 21594316 TI - Neural cell adhesion molecule expression in thyroid cancer. AB - Neural cell adhesion molecule (NCAM) is an integral membrane glycoprotein that participates in cell-cell interactions. We examined the expression of neural cell adhesion molecule (NCAM) by immunohistochemistry in 65 cases of thyroid disease. In the majority of thyroid tumors, NCAM expression was detected in tumor cells. In chronic thyroiditis, Hurthle cells demonstrated expression of NCAM. In normal thyroid gland, neither follicular nor parafollicular cells expressed NCAM at detectable levels. All papillary carcinomas and most poorly differentiated follicular carcinomas and some follicular adenomas demonstrated NCAM expression. In thyroid carcinoma, clinical stage and recurrent laryngeal nerve paralysis did not correlate significantly with expression of NCAM. Papillary carcinomas with strong expression of NCAM were more likely to have extra capsular invasion. It is supposed that immunohistochemical detection of NCAM expression supports histologic diagnosis and offers prognostic information. PMID- 21594317 TI - Serum soluble interleukin-2 receptor and immunohistochemical staining of IL 2R/Tac antigen in gastric cancer. AB - In the present study, we investigated the significance of serum soluble IL-2R as a tumor marker, and examined the existence and localization of positive cells for IL-2R/Tac antigen in gastric cancer tissues and its regional lymph nodes. Eighty two patients with gastric cancer were included. Levels of serum soluble-IL-2R were measured by an enzyme-linked immunosorbent assay. In the tissues obtained from 19 cases, immunohistochemical staining was performed with the use of avidin biotin-peroxidase complex technique, in which mouse anti-human interleukin-2 receptor antibody was used. The preoperative levels of serum soluble IL-2R in patients-with gastric cancer were significantly higher than those of normal controls (p<0.001). The levels of serum soluble IL-2R in cases with metastatic lymph nodes were also significantly higher than those without metastatic lymph nodes (p<0.05). Concerning the tumor markers, there were significant differences of serum soluble IL-2R levels between those who were positive and those negative for CA19-9, CEA, alpha-FTP, and IAP. In the immunohistochemical staining of IL 2R, 13 of 19 cases (68.4%) showed IL-2R positive cells in the gastric cancer tissues. In regard to the metastatic lymph nodes, 3 of 5 cases (60.0%) showed IL 2R positive cells. On the other hand, IL-2R positive cells were not recognized in normal gastric tissues and non-metastatic lymph nodes. These results may suggest that activated T-lymphocytes infiltrating into the cancer tissues play an antitumor role and release a large amount of alpha-chain of IL-2R, resulting in the high levels of serum soluble IL-2R in patients with gastric cancer. PMID- 21594318 TI - Expression of IGF-I, TGF-alpha and p53 protein in imprint smears of bronchial biopsy specimens of lung cancer. AB - The expression of insulin-like growth factor-I (IGF-I), transforming growth factor-alpha (TGF-alpha) and p53 protein was examined in bronchial biopsy imprint smears of patients with primary lung cancer and benign lung disorders, by immunohistochemistry. Of the 44 malignant imprint smears, 26 (59%) were positively stained for IGF-I, 18 (41%) for TGF-alpha and 29 (66%) for p53 protein. In contrast, of the 36 benign imprint smears none was positively stained for IGF-I (p<0.001), whereas 7 were positively stained for TGF-alpha (p>0.05) and 3 for p53 protein (p<0.001). There was no correlation between the expression of the examined markers and the histological type of lung cancer. The most sensitive indicator of malignancy was p53 overexpression (65.9%), the most specific was IGF I (100%) whereas both revealed 77.5% accuracy. The combination of IGF-I and p53 revealed 75% sensitivity, 91.6% specificity and 82.5% accuracy. When one marker was positive the relative possibility of lung cancer was 67.1%. This possibility increased to 77.7% when two markers were positive and to 100% when three markers were positive. These results suggest that the evaluation of IGF-I and p53 in imprint smears could be of value in diagnosis of lung cancer. PMID- 21594319 TI - Lectin bindings in non-neoplastic esophageal epithelium and esophageal carcinomas. AB - Lectin binding was examined histochemically in 22 cases of primary esophageal carcinomas (10 well differentiated, 8 moderately differentiated and 3 poorly differentiated squamous cell carcinomas, and 1 undifferentiated carcinoma) and was compared with the adjacent non-neoplastic epithelium by means of a panel of 10 different lectins (RCA-I, WGA, Con A, LCA, SEA, UEA-I, HPA, PNA, DBA and GS-I) on formalin-fixed paraffin-embedded sections. In the non-neoplastic epithelium, RCA-I and WGA showed basal/parabasal binding, Con A, LCA, SEA, UEA-I, HPA and PNA revealed prickle cell binding, while DBA and GS-I only stained the surface cells of the squamous cell layer. In squamous cell carcinomas, no clear difference was evident regarding the grade of differentiation. However, basal/parabasal specific lectins were expressed in all the cases, the prickle cell-specific lectins were expressed less frequently, whereas lectins expressed at the surface cells of the squamous cell layer were only infrequently expressed. Therefore, basal/parabasal cell specific lectins were widely preserved in squamous cell carcinomas. One case of undifferentiated cancer tested was devoid of all the lectins. PMID- 21594320 TI - Difference in histological activity of non-tumorous liver tissue between hepatitis B virus- and hepatitis C virus-associated hepatocellular carcinoma without cirrhosis. AB - To elucidate the difference in the liver carcinogenetic process during hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, non-tumorous liver tissues obtained from 10 patients who developed HBV-associated hepatocellular carcinoma (HCC) without cirrhosis were compared with those obtained from 26 patients who developed HCV-associated HCC without cirrhosis. The extent of fibrosis was similar in both groups. In contrast, necroinflammatory activities were significantly higher in patients with HCV than in patients with HBV. These results indicate that ongoing liver inflammation mediates the hepatocarcinogenesis more pronouncedly in HCV infection than in HBV infection. PMID- 21594321 TI - The retrospective assessment of surgical resection in the management of small cell carcinoma of the lung. AB - Role of surgical resection for small cell lung carcinoma (SCLC) was retrospectively assessed in 16 patients with pTNM-stage I and 13 with pTNM-stages II and IIIA. The 3-year and 5-year survival rates in patients with stage I were 61% and 45%, respectively, and the median survival time (MST) was 23.5 months. On the other hand, the 3-year survival rate for the 13 surgical patients with stages II and IIIA was 28% (MST=19 m), which showed no statistical difference between that of 21% (MST=10 m) for the 16 non-surgical patients with clinical stages II acid IIIA. These results suggest that resection is desirable for patients with stage I, but is of no benefit for patients with stages II and IIIA. PMID- 21594322 TI - Evaluation of the soluble fragments of cytokeratin 19 (CK19) in non-small cell lung cancer (NSCLC). AB - This study compared the diagnostic efficacy of serum CK19 determination (Cyfra 21 1) with other tumour markers, such as CEA, SCC, NSE, TPA, in patients with resected non-small lung cancer. Tumour marker levels were tested in 90 patients with benign lung disease and at diagnosis in 72 patients with proven NSCLC, 39 squamous cell carcinoma and 33 adenocarcinoma. At presentation baseline levels of all tumor markers were significantly higher (p<0.05) in lung cancer patients than in control subjects, except for NSE. A significant increase (p<0.05) in serum concentrations was observed from stage I to stage IIIb only for Cyfra 21-1 (stage I/II, median=2.7 ng/ml; stage IIIb, median=6.3 ng/ml) and TPA (stage I/II, median=89.8 IU/ml; stage IIIb, median=170.7 IU/ml). Receiver operating characteristic (ROC) analysis was performed to evaluate the best threshold values and the global accuracy of each marker. The highest global sensitivity for NSCLC was reached by TPA (70.8%), whereas that of Cyfra 21-1 was 50%. According to tumour histology, significant difference (p<0.05) in serum levels were found only for CEA (adenocarcinomas, median=5.6 ng/ml; squamous cell carcinoma, median=3.2 ng/ml) and SCC (adenocarcinomas, median=1.0 ng/ml; squamous cell carcinoma, median=1.5 ng/ml). As regards squamous cell carcinoma histotype, the highest sensitivity was obtained by TPA (74.4% at a specificity of 62.2%) and for adenocarcinomas by CEA (78.8% at a specificity of 85.6%). Tumour marker levels were also determined during the follow-up of 10 patients. The best sensitivity in detecting relapses was shown by CEA (90%), followed by TPA (70%), SCC (50%), Cyfra 21-1 (40%) and NSE (10%), even though the CEA test displayed a high percentage of false positive results (98.1%) in patients with no evidence of disease (NED). PMID- 21594323 TI - The riminophenazine agents clofazimine and B669 inhibit the proliferation of intrinsically multidrug resistant carcinoma cell lines. AB - The sensitivity to clofazimine, B669 and eight standard anti-tumour chemotherapeutic agents of four intrinsically multidrug resistant (MDR) cell lines [three human hepatocellular carcinoma cell lines (HepG2, PLC and Mahlavu) and a human colorectal carcinoma cell line (CaCo2)] were compared with that of a human cervix epithelioid carcinoma cell line (HeLa). The MDR cell lines and HeLa cells showed equivalent sensitivity to the riminophenazines, methotrexate and 5 fluorouracil, but exhibited ranging levels of resistance to vinblastine, doxorubicin, mitomycin C, daunorubicin, etoposide and vincristine. Riminophenazines may be useful agents in the chemotherapy of tumours with intrinsic MDR. PMID- 21594324 TI - Treatment results and long-term follow-up in stage I seminoma patients. AB - Between 1979 and 1992 seventy-nine patients with seminoma were treated at our institution, 62 of them with stage I. The mean follow-up time was 6.0 years (range: 36 months to 14 years). Preoperatively, serum beta human chorionic gonadotropin (beta-HCG) was elevated in 12 cases (19%) without prognostic significance. In addition to orchiectomy, 57 patients with stage I seminoma of the testis received adjuvant radiotherapy (mean dose: 33 Gy). Two patients were treated with primary retroperitoneal lymph node dissection (RPLND) and one patient with cisplatin-based chemotherapy. In 2 cases a surveillance strategy was used. Three patients (5%) had a relapse of the seminoma (2 in the retroperitoneum and one suprainguinally). The time interval between orchiectomy and relapse was 5 to 60 months. Salvage treatment consisted of chemotherapy and RPLND in 2 patients and chemotherapy and resection of the suprainguinal recurrent mass in one patient, and was successful in all 3 patients. A total of 60 patients evaluated (100%) are still alive with no evidence of disease. In conclusion, adjuvant radiotherapy is considered the routine treatment in seminomas stage I despite studies with a 'wait and watch' policy or a carboplatin monotherapy. PMID- 21594325 TI - Granulosa cell tumor arising in the ovary irradiated 22 years earlier for endometrial stromal sarcoma. AB - We encountered a rare case of metachronous tumors in a 57-year-old Japanese housewife who presented with an ovarian granulosa cell tumor 22 years after receiving treatment for endometrial stromal sarcoma. Treatment consisted of a total abdominal hysterectomy and left salpingo-oophorectomy followed by 40 Gy whole abdominal irradiation. Since the second tumor occurred in the ovary that had been previously irradiated to treat the first metachtonous neoplasm, the present case can help to improve our understanding of the histogenesis of granulosa cell tumors. PMID- 21594326 TI - Emetic control in breast cancer patients receiving iv CMF. AB - Two consecutive antiemetic studies were performed in a homogeneous population of female breast cancer patients receiving i.v. CMF chemotherapy for six courses. Survival analyses (failure-free survival and emesis-free survival) were used as method of assessment of efficacy in these studies. The first of the two studies was a randomized, single-blind, placebo-controlled trial comparing three different dose levels of i.v. methylprednisolone (80 mg i.v., 250 mg i.v. and 500 mg i.v.) and placebo. 104 consecutive female breast cancer patients entered the study. There were no statistically significant differences in failure-free survival or emesis-free survival among the three methylprednisolone dose levels. Both failure-free survival and emesis-free survival were significantly superior in the three methylprednisolone arms than in the placebo group (p<0.05 to p<0.01). Since the results obtained with methylprednisolone alone in the first study were not completely satisfactory, the second study analyzed the interest of adding oral thyethylperazine (6 mg p.o. every 8 h) to i.v. methylprednisolone (80 mg) in 31 consecutive female patients scheduled to receive 6 courses of i.v. CMF. Sixty-eight percent of patients were free of emesis during the 6 courses of i.v. CMF chemotherapy with i.v. methylprednisolone plus oral thyethylperazine. This figure was significantly better than the emesis-free survival observed in methylprednisnolone-treated patients in the first study (p<0.05). Patients who did not achieve a complete response with methylprednisolone plus thyethylperazine in study 2 were treated with methyl-prednisolone (80 mg i.v.) and ondansetron (8 mg i.v. before chemotherapy and 8 mg per os every 8 h for 3 days) in subsequent courses of chemotherapy. Nearly 3/4 of such patient were rendered emesis-free with subsequent ondansetron treatment. Overall, 90% of patients obtained an excellent control of emesis with first-line methylprednisolone plus thyethylperazine or methylprednisolone-ondansetron rescue. The cost per patient of this antiemetic approach compares favorably with that of ondansetron as primary antiemetic therapy. PMID- 21594327 TI - A case of advanced endometrial cancer with lung metastasis effectively treated with carboplatin and pirarubicin intra-arterial administration. AB - The outcome of advanced endometrial carcinoma is poor, indicating the need for new treatment modalities. We report a case of stage IVb endometrial carcinoma who received neoadjuvant chemotherapy given via intra-arterial infusion with carboplatin and pirarubicin. This treatment reduced the volume of tumors, even those in the lung. Then we succeeded in performing cyto-reduction. The patient is doing well 12 months post-therapy. PMID- 21594328 TI - Inhibitory effect of genistein on a tumor promoter-induced c-fos and c-jun expression in mouse skin. AB - The effects of genistein, a soybean isoflavone, on 12-O-tetradecanoyl phorbol-13 acetate (TPA)-induced expression of c-fos and c-jun in CD-1 mouse skin have been investigated. A promoting dose (8.5 mu mol) of TPA significantly increases transcript levels of c-fos, and 2.7 and 3.2 kb c-jun mRNA in mouse skin by 7.0-, 3.2-, and 1.7-fold, respectively. Topical application of genistein 30 min before TPA treatment inhibits TPA-induced expression of these protooncogenes. Suppression of c-fos was more pronounced than that of c-jun, and at a dose of 10 mu mol genistein, TPA-induced c-fos expression was almost completely diminished. Genistein exhibited only a weak suppressive effect on TPA-induced c-jun mRNA expression. Effect of application time of genistein on TPA-induced c-fos expression was also investigated. The results showed that topical application of 10 mu mol genistein 30 min prior to, simultaneously, and 30 min after tumor promoter treatment can equally suppress TPA-induced c-fos expression. The mechanism by which genistein inhibits TPA-induced proto-oncogene expression is unknown. However, it appears that the inhibition of c-fos expression by genistein is independent of the protein kinase C (PKC) activation pathway because of its weak suppressive effect on PKC activity. It is hypothesized that the inhibitory effect of genistein on TPA-induced c-fos expression may be through the modulation of mitogen-activated protein (MAP) kinase in vivo. PMID- 21594329 TI - Treatment of hepatocellular carcinoma associated with extrahepatic primary cancer. AB - Association of extrahepatic primary cancers (EPC) were studied in 533 consecutive hepatocellular carcinoma (HCC) cases. EPCs were found in 30 cases (5.6%). Three patients had two EPCs. The most frequent sites of EPC were the stomach (n=10, 30.3%), the colon (n=8, 24.2%), otolarynx (n=5, 15.2%), and the lung (n=2, 6.1%). Twenty-nine of 33 EPCs were treated by resection. EPCs did not affect the survival rate, however, the survival of the 20 patients who underwent resection of HCC was better than the 10 patients who did not. Liver cirrhosis was present in 8 of the 30 cases. Advanced stages of HCC were more frequently seen (P<0.05) in cases without cirrhosis. PMID- 21594331 TI - Isolation of a cDNA for the human homolog of MAT-1 oncogene and its expression in human breast cancer cells. AB - Overexpression of mouse MAT-1 oncogene is associated with carcinogensis of mouse mammary epithelial cells. A human cDNA (hMAT) homologous to MAT-1 was isolated from normal human breast tissue. The hMAT cDNA is 1312 bp long and produces a 8.5 kDa peptide in vitro. The hMAT probe hybridized with 2.5 kb RNA in normal human breast epithelial cells from reduction mammoplasty specimens and in human breast cancer cell lines. The extent of hMAT gene expression in human breast cancer cell line was variable, with BT-20, T47-D, and MDA-MB-231 showing about a 10-fold overexpression compared to primary normal human breast epithelial cells, MCF-7, and ZR-75-1. PMID- 21594330 TI - Hyaluronic acid modulates glioma cell proliferation through its interaction with CD44H in vitro. AB - In a recent study we showed that hyaluronic acid (HA) induces cell detachment and promotes migration and invasion of glioma cells in vitro through its interaction with the cell surface molecule CD44H. In this study, the role of HA in proliferation in eight human glioma-derived cell Lines was investigated. We demonstrate that HA exerts a dose dependent proliferative and anti-proliferative effect on glioma cells. This effect was found to be partially counteracted by a CD44H monoclonal antibody, suggesting the involvement of its high affinity receptor, CD44H and other HA receptors in this process. PMID- 21594332 TI - Basic mutant Max reverses a c-Myc block to differentiation. AB - Murine erythroleukemia (MEL) cells overexpressing a transfected c-myc gene are blocked in their ability to undergo inducer-mediated differentiation, whereas overexpression of a transfected max gene mutated within the basic region (bm-max) accelerates differentiation. Based on these findings, we cotransfected MEL cells with plasmids which express human c-Myc constitutively and bm-Max in a zinc inducible manner. Competition of endogenous proteins for binding to bm-Max can be considered negligible in cells expressing such high constitutive levels of c-Myc. Thus, this system provides a cell culture model for studying Myc:Max complex formation and its effect on erythroid differentiation. Clones expressing high levels of c-Myc and low levels of bm-Max are blocked in their ability to undergo N,N'-hexamethylene bisacetamide (HMBA)-mediated differentiation, presumably due to a preponderance of growth-promoting Myc:Max complexes. However, increased expression of bm-Max, in these clones, allows differentiation to occur by decreasing the levels of functional Myc:Max complexes. Although the exogenously expressed c-Myc and bm-Max associate in vivo, the basic region mutation in bm-Max abolishes the binding of Myc:bm-Max complexes to the specific E-box consensus sequence. We demonstrate that this sequestering of c-Myc by bm-Max reverses the c Myc block to differentiation. PMID- 21594333 TI - Collagen markers during anticancer therapy for lung cancer. AB - Recently, many studies have reported that collagen metabolism markers, such as the aminoterminal propeptide of type IIE collagen (PIIIP) and the 7-S domain of type TV collagen (7-S collagen), increased in malignancy and that, they correlate with the clinical behavior of the disease. The objective of the present study was to assess the serum concentration of these collagen markers in relation to the clinical progression of the disease and during chemotherapy in lung cancer patients. This study comprised 48 lung cancer patients. Sixteen patients underwent cisplatin-based chemotherapy. Samples taken from controls were available for comparison. Serum concentrations of PIIIP and 7S-collagen were significantly higher as compared to the control group. While the collagen markes tended to decrease in the responder patients, they increased significantly after chemotherapy in the non-responder group. Collagen markers are suggested to be potentially useful for the early evaluation of the tumor response to chemotherapy in lung cancer. PMID- 21594334 TI - Antitumor effect of the angiogenesis inhibitor TNP-470 and its combination effect with 5-FU and PSK in colon 26 tumors. AB - TNP-470 is known to inhibit angiogenesis. In this study, we investigated the antitumor effect of TNP-470 in colon 26 tumors. A dose dependent growth inhibition of tumor and liver metastasis was observed. An additive administration of PSK enhanced inhibitory effect of the tumor. Combined treatment of TNP-470 and 5-FU significantly prolonged the life span compared to the TNP-470 and 5-FU group. It is suggested that the combination of TNP-470 and 5-FU might be effective for the treatment of colon cancer and PSK might increase the antitumor effect from the viewpoint of immunity and angiogenetic mechanism. PMID- 21594335 TI - ABCVEP (I) treatment for advanced intermediate grade and high grade non-Hodgkin's lymphoma. AB - With the intent to improve the cure rate for non-Hodgkin's lymphoma (NHL), a prospective single-arm trial named ABCVEP (I) was initiated in April 1989. ABCVEP (I) was consisted of 6 drugs: adriamycin (ADM); bleomycin (BLM); cyclophosphamide (CPM); vincristine (VCR); and prednisolone (PDN) with or without granulocyte colony-stimulating factor (G-CSF) to rescue the neutropenia. As of March 1991, 31 patients with intermediate- and high-grade NHL were entered in the trial and all the patients were evaluable with median age of 56 years. Twenty-five out of 31 patients were D. large; 2 were F. large, 2 D. small cleaved; and 2 D. mixed: 9 were in stage II, 6 in stage III and 16 in stage IV. Twenty-five patients achieved complete response and 6 partial response (response rate was 100%). The median follow-up period was 50 months, the actual over all survival rate for the entire group was 59.3%. The relapse-free survival for complete responders was 63.8%. Administration of G-CSF was required for 20 patients. Relative dose intensity (RDI) in patients required G-CSF was maintained at more than 80% of the RDI in patients not requiring G-CSF. Although severe pulmonary toxicity due to bleomycin was found in 4 patients, ABCVEP (I) is a feasible treatment regimen for aggressive NHL. PMID- 21594336 TI - GTP-binding protein and its associated event in membranes from endometrial carcinoma. AB - Endometrial carcinoma expresses gonadotropin-releasing hormone receptor (Gn-RHR) known to be linked by heterotrimeric GTP-binding proteins (G proteins). We have examined endometrial carcinomas for the presence of G protein and its associated membrane event in isolated plasma membranes. Endometrial carcinomas surgically removed had been screened for Gn-RHR expression prior to plasma membrane isolation. G protein level was observed by immunoblotting of membrane extracts with anti-G protein antibodies. G protein-associated membrane event was observed by phosphotyrosine phosphatase (PTP) activity determined with the synthetic substrate p-nitrophenyl in a spectrophotometric assay. Immunoblotting with the specific G alpha 11 and G alpha s antibodies showed significant levels of 42-kDa and 46-kDa proteins in endometrial carcinoma membranes, respectively. The nonhydrolyzable GTP analog GTP-gamma-S stimulated the phosphatase activity in a dose-dependent manner: a half maximal effect occurred with 30 nM. These findings demonstrate the expression of G proteins and the presence G proteins-associated membrane event in endometrial carcinoma. PMID- 21594337 TI - Glycolytic profile in normal brain tissue and gliomas determined by a micro method analysis. AB - High aerobic glycolysis is frequent in cancers. Glucose phosphorylation is under control of hexokinase which is found in the cytosol or bound to mitochondria. Glycolysis parameters (glucose, pyruvate and lactate) and hexokinase were evaluated in extracts of 15 human gliomas and of normal brain tissue. Extracts were run and analysed for glucose lactate and pyruvate content using a centrifugal automatic analyzer, Mitochondria fractions were separated from total extracts and hexokinase enzymatic activities were measured in both, using an original micro-method. Conditions of hexokinase assay were standardized in terms of substrate concentration and linearity. Mean hexokinase activity in gliomas was variable, 3 times lower than in normal tissues and mainly bound to mitochondria, although lactate/pyruvate ratios were found to be 3.5 to 5.4 times higher. Glycolytic profile of tumor tissues can be rapidly assayed and evalated glycolysis in tumors could constitute a basis for therapy using antiglycolytic strategies. PMID- 21594338 TI - Novel mouse repetitive element structures in an embryonal carcinoma mutant cell line. AB - A mutant embryonal carcinoma (EC) cell line, NR1-6, has been isolated subsequent to infection with a retroviral insert containing a neomycin resistance cassette (Neo(r)) (1). This variant cell line has only a single insertion site, but is unique in its morphology, tumorigenicity, and differentiative potential (2). In order to understand the exact nature of the mutational event, we have sequenced the regions immediately flanking the insertion site (encompassing over 18 kb). Searches for homology in GenBank using the GCG and Blast programs have revealed homology to only a few small conserved regions (4 B1 repetitive elements approximately 150 bp long and a CA/GT dinucleotide repeat). Interestingly, B1 repetitive elements have been reported to play a role in germ cell differentiation. One of these elements is immediately 5' upstream of the insertion site and it appears as if the retroviral insertion may be responsible for activating or repressing the expression of this element. The CA/GT repeat has not yet been mapped within the mouse genome. Thus, we have identified a novel mouse locus which apparently regulates a number of cellular phenotypes. PMID- 21594339 TI - Melanoma-specific cytotoxicity of a human MGSA/GRO alpha C-terminal peptide conjugated to daunorubicin. AB - We report the conjugation of the C-terminal alpha-helix of human melanoma growth stimulating activity to daunorubicin using the novel linker polyethylene glycol (3400) dialdehyde. The technique allows us to control the drug:peptide ratio in the conjugate. We also describe the use of capillary zone electrophoresis and HPLC to monitor both the reaction and the stability of the peptide to various pH conditions. We found that the conjugate is about 10-fold more active on human Hs294t and murine B16 melanoma eel lines (which express the MGSA receptor) than the free drug while the same conjugate has little activity on human SKOV-3 and CCL-121 non-melanoma cell lines. PMID- 21594340 TI - A Mr 7 kDa protein is present in both plasma and nuclear membranes in multidrug resistant ovarian cancer cells. AB - We have previously found that a small molecular weight (7 kDa) protein (P7) is overexpressed on the plasma membrane of ovarian cancer cells. Cell fractionation experiments described in the present report show that P7 is present in both microsomal and nuclear fractions of these cells. Indirect immunofluorescence studies confirm the presence of this protein in both plasma and nuclear membranes. The observed involvement of P7 in the proliferation of MDR ovarian cancer cells (1) and its occurrence on the nuclear membrane suggest that this protein may mediate signal transduction in these cells. PMID- 21594341 TI - nm23-H1 protein immunohistochemical expression in human breast cancer. AB - A series of 76 patients undergoing surgery for primary breast carcinoma has been prospectively studied in order to evaluate the relative weight of nm23-H1 protein expression in disease-free survival. Expression of nm23 protein was immunohistochemically assessed. In all, 39% (29/74) of the turners showed positive staining for nm23-H1 protein expression. Negative nm23-H1 expression was found in poorly differentiated, tumors (p<0.02). There was no significant relationship between nm23-H1 and the other clinicopathological and biological features examined. In the univariate statistical analysis, node positivity, G3 histological grade and high flow cytometric S phase fraction (SPF) value proved to be significantly related to risk of relapse. In the multivariate analysis, only histological grade (G3) and high SPF values (>10.6) proved to be independently related to risk of relapse, with a hazard ratio of 9.84 and 7.98 respectively. Our preliminary study suggests that immunohistochemical nm23-H1 expression should not be considered a marker for predicting tumor progression and patient prognosis. PMID- 21594342 TI - Effect of hypoxia on the frequency of bleomycin-induced micronuclei. AB - Normal G(0) pig lymphocytes were maintained in a hypoxic or aerobic environment for one hour and then concurrently exposed to bleomycin at varying concentrations for a second hour. The cytochalasin-block micronucleus assay was used to determine cytotoxicity. Exposure to transient hypoxia significantly decreased the frequency of bleomycin-induced micronuclei per cell as compared to that observed in oxygenated cells. Furthermore, the frequency of micronuclei per hypoxic cell did not correspond to any increase in bleomycin dose as observed in oxygenated cells. These data demonstrate the significance of transient hypoxia in the resistance of G(0) cells to the cytotoxic effects of bleomycin and may explain the observed selectivity of tumor tissue response to bleomycin. PMID- 21594343 TI - Fluorescence polarization changes in the lymphocytic cytoplasm in the various stages of breast cancer. AB - Post-surgical pathological staging and ancillary tests determine the initial treatment of breast cancer. Because change in the structuredness of the cytoplasmic matrix (SCM) of peripheral lymphocytes (as assessed by measurement of fluorescein fluorescence polarization, FFP) has already emerged as diagnostic for breast cancer and an aid to staging in other cancers, testing was carried out in 113 pre-surgical patients to see whether such change could contribute to accurate staging of breast cancer. The FFP test was able to distinguish grouped stages of locoregional disease from metastatic disease but was unable to distinguish between any single locoregional stage and the metastatic stage. Technological improvements now underway may create a role for assessment of SCM changes in breast cancer staging. PMID- 21594344 TI - Stimulatory effects of amphetamine on the development of Walker-256 carcinoma lung metastases in rats. AB - Experiments were performed in order to evaluate the effects of amphetamine (0.4 mg/kg/day) on the development of lung metastases in rats injected i.v. with 10(4) Walker 256 (W-256) carcinosarcoma cells, The number of metastatic nodules on the surface of the lungs, as well as the percentage-area of metastases in the frontal section through pulmonary hilus were increased in rats injected with amphetamine in comparison with those injected with placebo. Survival periods were also assessed and amphetamine was found to increase the lethality of rats. PMID- 21594345 TI - Topical prostaglandin E2 and chemo- and radio-induced oral mucositis. AB - Oral mucositis is a frequent complication of specific antineoplastic treatments. Mouth lesions have a great impact on the quality of life of cancer patients. Current topical and systemic therapies have not yet achieved completely satisfactory results. We studied the effect of topical use of prostaglandin E2 (PGE2) 2.25 mg/day on oral mucositis of 15 chemo- or radio-treated cancer patients. Absolute mean VAS value on mouth pain decreased from 71.2 at TO, to 34.1 at T3 (p<0.001) and to 14.1 at T6 (p<0.001). Objective evaluation according to Miller scale showed significant improvement at day 3 and 6, as well. We suggest that PGE2 could be a useful additional therapeutic agent to palliate oral symptoms. PMID- 21594346 TI - DES-ja vu. AB - Prior to the use of antiestrogens, high dose estrogen therapy was widely used as effective therapy for breast cancer. The introduction of antiestrogens with their reduced toxicity profile greatly minimized subsequent use of estrogen to treat metastatic breast cancer. We administered diethylstilbestrol (DES), a nonsteroidal synthetic estrogen, to eight postmenopausal women with advanced breast cancer who had been heavily pretreated with hormones and cytotoxic chemotherapy. We report on response rates and toxicities related to this form of hormonal therapy. Eight postmenopausal women aged 53 to 79 years with progressive metastatic breast cancer were treated. All had been pretreated with 3 to 6 hormonal agents including an antiestrogen, a progestin and an aromatase inhibitor; 6 of the 8 patients had received treatment with 2 or 3 combinations of cytotoxic agents. All patients received diethylstilbestrol 5 mg orally three times daily until evidence of disease progression or significant toxicity. Four women (50%) showed objective responses, two (25%) had stable disease and two (25%) had progressive disease. Measurable responses included a complete and partial response and two minor responses. The duration of the responses were 12, 11, 6, and 3 months. The hormone was well-tolerated. High-dose estrogen is effective and safe therapy for breast cancer patients even when they are heavily pretreated with prior chemotherapy and hormonal therapy. High dose estrogen could be re-introduced into this clinical setting as effective therapy with an acceptable toxicity profile. PMID- 21594347 TI - Phorbol ester stimulated Cip1 expression in p53-negative leukemic cells. AB - In differentiating leukemic cells, cyclin-dependent kinase interacting protein (Cip1) is induced and stimulates a G(1) arrest. TPA treated U937 monoblastoid cells expressed Cip1, hypophosphorylated retinoblastoma protein (Rb), arrested in G(1) and differentiated. PKC-zeta cells are U937 cells that overexpress the zeta isoform and display alterations in endogenous PKC isoform expression. TPA treated PKC-zeta cells undergo apoptosis without differentiating. TPA treated PKC-zeta cells express Cip1 and display substantial hypophosphorylation of Rb but fail to arrest in G(1). Thus, a novel phorbol ester dependent signalling pathway exists in which Cip1 induction is associated with the absence of a G(1) arrest and induction of apoptosis rather than differentiation. PMID- 21594348 TI - Antimetastatic effects associated with anticoagulant properties of heparin and chemically modified heparin species in a mouse mammary tumor model. AB - Fibrin deposits surrounding circulating tumor cells may protect them from mechanical trauma and destruction by the host immune system, and may facilitate microvascular entrapment required for metastasis. We report that heparin inhibited the clotting of plasma induced by mouse mammary carcinoma cells in a dose-dependent manner and blocked the production of experimental lung metastasis when administered i.p. at the time of intravenous injection of tumor cells. On the other hand, O/N-desulfated N-acetylated heparin did not exhibit anticoagulant properties and had no effects on metastasis formation. Similarly, reduction of metastasis was not seen with N-desulfated N-acetylated heparin, another chemically modified heparin which does not inhibit blood coagulation but has heparanase inhibitory activity. Our data demonstrate the existence of a strong association between antimetastatic and anticoagulant properties of heparin species in the present experimental system. PMID- 21594349 TI - Effect of 5-fluorouracil treatment on IL-2R gene expression in gastric carcinoma patients. AB - Interleukin-2R gene expression was evaluated in peripheral blood T lymphocytes of patients with gastric carcinoma and normal healthy controls. The presence of mRNA for IL-2R alpha evaluated by Northern blot analysis revealed that unstimulated T cells expressed lower levels of IL-2R mRNA than PHA stimulated T cells. Expression of both IL-2R alpha transcripts (3.5 and 1.5 kb) were either not detectable or only weakly detectable on T lymphocytes from patients even after mitogenic stimulation. In contrast, a significant rise in the expression of both IL-2R alpha transcripts was observed on T cells from normal controls followed by mitogenic challenge. Enhanced expression of both IL-2R transcripts was also detected in a follow-up study of the patients, conducted one month following initial trial. of chemotherapy with 5-fluorouracil (5 Fu). Patients post chemotherapy were better responders of PHA stimulation as reflected by enhanced IL-2R gene expression following mitogenic challenge. PMID- 21594350 TI - A common path to tumor growth. AB - Progression of normal cells from the quiescent state into the cell cycle requires passage through the so-called restriction point in the late G1-phase. Here, we summarize evidence suggesting that the regulatory cascade around the product of the retinoblastoma susceptibility gene (pRb) is the regulator of the restriction point. The autoregulatory feedback pathway involves pRb itself, cdk4/6, D-type cyclins and the cdk4/6-specific kinase inhibitors of the p16 family, with D-type cyclins meeting best the criteria for the restriction point regulator. Moreover, most recent data from tumor cell biology suggest that one of the members of this regulatory pathway has to become deregulated to allow for tumor growth. Thus, tumor development requires the loss of certain growth-regulating pathway(s) which is achieved by alternative loss of tumor suppressors (e.g. Rb or p16) or hyperactivity of proto-oncogenic counterparts (like cyclin D1 and cdk4). Deregulation of the Rb pathway probably occurs in every tumor either as an initiating or as a progression-promoting event. PMID- 21594351 TI - Alteration of GTP-binding proteins in ovarian tumors (Review). AB - GTP-binding proteins (G proteins) couple cell surface receptors to generation of a variety of intracellular second messengers. The mutant G protein products may be responsible for trapping the protein in its active and subsequently the abnormal growth of malignant cells and dysfunction. We present recent examples of G protein gene mutations in ovarian tumors and illustrate how such defects might lead to abnormal tumor proliferation. PMID- 21594352 TI - Effects of a new antiulcer agent, ecabet sodium on a cutaneous tumorigenesis induced with 7,12-dimethylbenz(a)anthracene in mice. AB - A new antiulcer agent, ecabet sodium is one of dehydroabietic acid derivatives prepared from pine resin, and is known to have a potent protective effect on gastric hemorrhagic lesions induced with carcinogens by covering a gastric mucosa after oral administration. In the present study, we investigated the effects of synthetic ecabet sodium on cutaneous tumorigenesis and development of skin-tumors induced by 7,12-dimethylbenz(a)anthracene application on mouse back skin. It was tentatively concluded that ecabet sodium reduced the incidence of skin-tumors (squamous cell papillomas) by inhibition of DNA synthesis in de novo pathway, and suppressed the development of papillomas by decrease of DNA synthesis in a salvage pathway. PMID- 21594353 TI - Protein gene product 9.5 (PGP9.5) immunoreactivity in salivary gland tumors. AB - PGP9.5 is a neuron specific protein with a molecular weight of 245 kDa and is expressed in neuronal cytoplasm and neuroendocrine cells, and is a marker of neuronal differentiation in normal and neoplastic tissues. The present study was designed to evaluate expression of PGP 9.5 in salivary gland tumors and its possible correlation with the expression of S-100, NSE and GFAP1 the other markers predominantly present in nerve tissues. Forty cases of pleomorphic adenoma and 10 cases of salivary adenocarcinoma were evaluated by three stage avidin-biotin-immunoperoxidase method using polyclonal antibody raised against PGP9.5. In normal salivary glands (n=6), PGP9.5 was confined to the peripheral nerve fibers. The non-luminal tumor cells in the tubuloductal structures of pleomorphic adenoma (n=40) showed spindle shaped modified myoepithelial cells expressing PGP9.5 with varying intensity of staining as well as S-100 protein, NSE and GFAP. A variant of modified myoepithelial cells, the plasmacytoid cells were intensely positive for PGP9.5, S-100 protein and NSE. One adenocarcinoma (1/10) showed a strong immunostaining for PGP9.5 in neoplastic cells. It is, therefore, suggested that the salivary gland tumors are composed of cells of heterogeneous differentiation: the luminal tumor cells are purely epithelial origin and characteristics, and modified myoepithelial cells express markers of neuronal differentiation and may arise from the cells of neural crest origin. PMID- 21594354 TI - Combination therapy with cisplatin, 5'-deoxy-5-fluorouridine (5'-DFUR) and mitomycin (MMC) in patients with inoperable, advanced gastric cancer. AB - The optimal dose of cisplatin (CDDP) for combination chemotherapy for the treatment of inoperable, advanced gastric cancer has yet to be established. We therefore performed a randomized study to compare the therapeutic usefulness of two dose levels of cisplatin. 5'-deoxy-5-fluorouridine (5'-DFUR 1,400 mg/m(2)/d) was given orally on days 1 to 4 and 15 to 18. Mitomycin C (MMC, 5.75 mg/m(2)/d) was injected intravenously on day 5. In addition, 80 mg/m2/d of CDDP (regimen A) or 60 mg/m(2)/d of CDDP (regimen B) was given by 2-h intravenous drip infusion on day 5. This treatment cycle was repeated every four weeks. Fifty-six patients were enrolled. Clinical response was evaluated in 32 patients (regimen A, 16 patients; regimen B? 16 patients) with measurable lesions. The response rate was significantly higher with regimen A (9 PR/16, 56.3%) than with regimen B (3 PR/16, 18.9%) (p=0.028, chi(2) test). Median survival was slightly but not significantly longer with regimen A (7.4 months) than with regimen B (6.3 months). Drug toxicity included myelosuppression and gastrointestinal symptoms, but there were no serious adverse reactions or differences in safety between the treatment regimens. Regimen A was associated with a high response rate and low toxicity. The optimal dose of CDDP in combination with 5'-DFUR and MMC for the treatment of advanced gastric cancer is regarded to be 80 mg/m(2). PMID- 21594355 TI - Glutathione metabolism during Yoshida ascites sarcoma growth. AB - Glutathione (GSH) metabolism and protein synthesis were observed over a period of about two weeks in Yoshida ascites sarcoma and intracellular concentration relative to days 7, 10 and 13 assumed as 'markers' of different stages of tumor development. During this period the decrease in rate of cell proliferation was followed by decrease in protein synthesis, GSH, oxidized glutathione (GSSG), adenosine triphosphate (ATP), glutathione-S-transferase (GSH-S-transferase) and gamma-glutamyl-cysteine synthatase (gamma-GCS); by increase in glutathione peroxidase (GSH-peroxidase); while glutathione-reductase (GSH-reductase) and glucose-6-phosphate-dehydrogenase (G-6-PD) remained unchanged. In relation to growth curve of the tumor, GSH concentration was very high up to day 7 (logaritmic phase), decreased till quantity similar to that of corresponding normal cells up to day 10 (plateau phase) and on day 13 was significantly smaller. Correlation between high concentration of GSH in tumor cells and their survival and proliferation after intraperitoneal implantation is discussed. PMID- 21594356 TI - T-lymphocyte micronuclei dose response from prostate radiotherapy. AB - Micronuclei (MN) production in the peripheral blood T-lymphocytes of patients receiving pelvic radiotherapy for localized prostate cancer increases with increasing integral radiation dose to the prostate/pelvic area, thereby demonstrating a linear, in vivo, clinical dose response relationship for this biological dosimetry system. Use of this lymphocyte assay system may have practical implications to evaluating and monitoring of treatment planning by encouraging conformal radiation therapy techniques in order to decrease systemic toxicity to the patient's immune system from pelvic radiotherapy. PMID- 21594357 TI - No mutations within conserved domain I of the p53 gene in medullary thyroid cancer. AB - Abnormal mobility shifts in single strand conformational polymorphism (SSCP) analysis of exons 2 and 3 of the p53 gene in 2 out of 5 medullary thyroid cancers (MTC) prompted us to sequence the corresponding genomic region spanning codons 9 32. We found no mutations of the conserved domain I in the two MTCs that had previously shown mobility shifts, nor in a third MTC case indicating wild-type p53 (in this region). However, we detected a polymorphism consisting of a GC to CG transversion in intron 2 in two of the primary MTCs and one associated blood sample. In addition, we report on a deviation of the published sequence of intron 2 affecting positions 11817-8 and 11874, seen in 7/7 samples analyzed. Our findings corroborate the hypothesis, that MTC carcinogenesis does not require p53 mutations (Yana et al, Jpn J Cancer Res 1992). PMID- 21594358 TI - An unusual presentation of Hodgkin's disease. AB - Malignant involvement of the heart and pericardium is uncommon in advanced cancer, and rarely results in cardiac symptoms. Myocardial ischaemia due to metastatic disease is particularly uncommon. We report a case of a young man in whom myocardial ischaemia was diagnosed at presentation of Hodgkin's disease, and which resolved as the underlying lymphoma responded to chemotherapy. PMID- 21594359 TI - Weekly carboplatin in elderly patients with advanced ovarian cancer. AB - Ovarian cancer is frequently diagnosed in patients over 65 years old, but limited data are available on tolerance and effectiveness of chemotherapy in this subset of patients. A total of 21 patients with epithelial ovarian cancer were treated with weekly carboplatin following failure of first-line chemotherapy. Median age was 73 years (range, 66-85). Patients received carboplatin at the dose 100 mg/m(2)/week with discontinuation for severe toxicity or documented progression. A total of 228 cycles were administered (median per patients, 10 cycles). Six partial remissions (29%; 95% confidence interval, 11-52%), 6 stabilizations of disease, and 9 disease progressions were observed. Median time to progression was 6 months. No toxic deaths were observed. Side effects consisted mainly of anemia (grade 3 in 3 cases) and neutropenia. Non-hematologic toxicity was minimal. In conclusion, the schedule has moderate activity with good tolerability in elderly patients with advanced epithelial ovarian cancer. PMID- 21594360 TI - Increased induction of apoptosis of human colorectal cancer cells after preoperative treatment with 5-fluorouracil. AB - We examined whether the administration of 5-fluorouracil (5-FU) could enhance apoptosis of colorectal cancer cells, and we investigated the relationship between apoptosis and the expression of Ki-67, p53, and c-myc. Twenty patients with advanced colorectal cancer were divided into two groups. Ten received continuous intravenous 5-FU at 500 mg/body/day for 7 days preoperatively and 10 did not receive 5-FU and served as controls. Apoptotic cells were stained by so called TUNEL method (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling). Apoptosis of cancer cells increased significantly to 18+/-6% in the 5-FU-treated group as compared to the controls (3+/-1%; p<0.001). Expression of Ki-67, a indicator of cell proliferation, was inversely correlated with the TUNEL staining that was specific for apoptosis and the percentage of cells immunostained for Ki-67 fell significantly to 34+/-14% of the apoptotic area as compared to 72+/-12% in controls (p<0.001). There was no clear correlation between expression of apoptosis and the expression of p53 or c-myc. PMID- 21594361 TI - Precancerous lesions of the uterine cervix. AB - The presence of mucous and non-pathologic elements liable to hamper analysis of the smear is one of the main problems in ploidy assessment of precancerous cervical lesions. For our study, we employed a sampling system guided by microcolpohysteroscopy, which we used to identify the pathologic zone and select the morphologically altered elements only. Fifty-five cervical lesions and 6 negative controls were analyzed. All controls and 24 lesions were diploid, 15 polyploid and 16 aneuploid. All but one aneuploid lesions had a histological diagnosis of GIN. We failed to observe any significant difference in the aneuploid percentage of high and low grade lesions while diploid cases decreased in proportion to the severity of the lesion. The samples obtained had the advantage of being representative, technically valid and at the same time extremely suitable for an automated image analysis of ploidy. Thus this new sampling method could be extensively used. PMID- 21594362 TI - Efficacy of antiestrogen treatment in a benign metastasizing leiomyoma with paraneoplastic estradiol production. AB - Benign metastasizing leiomyoma (BML) is a rare hormone-dependent disease which occurs predominantly in women during their child-bearing years. After our patient had refused ablative hormone therapy (bilateral ovarectomy), evidence of estrogen and progesteron receptors in tumor tissue taken from the lung sites, as well as extremely high estradiol serum levels, led us to conduct high-dosage antiestrogen therapy for 5 years; daily administration of 250 mg of Tamoxpuren(R) resulted in stable disease of the pulmonary sites without any side effects. This also significantly lowered estradiol serum levels, which improved clinical symptoms. Five years later, the patient's vision suddenly deteriorated due to bilateral macula degeneration. This forced us to stop the antiestrogen therapy and commence alternative treatment with LHRH analogue (3.6 mg Goreselin). We observed stable disease of the pulmonary metastases and low estradiol serum levels during the first 6 months of Goserelin treatment. The response to antiestrogen therapy in BML suggests that the muscular component of these disorders is responsive to estrogen ablation. PMID- 21594363 TI - Serum CA125 assay in the early diagnosis of recurrent epithelial ovarian cancer. AB - The present retrospective study included 59 patients who had been treated for epithelial ovarian cancer and who showed an elevation of serum CA125 above 35 U/ml without clinical evidence of disease. Eight patients underwent chemotherapy at the time of serum antigen elevation (group A). The other 51 patients (group B) were periodically checked, and received further chemotherapy only when recurrent disease was detected. Forty-four of the 59 patients relapsed. One patient of group B experienced two different recurrences with two distinct time intervals. The median follow-up of survivors from CA125 elevation was 10 months (range 2-92 months). Of the 8 patients of group A, 3 (37.5%) developed recurrent disease after 14, 17 and 22 months, respectively, from antigen elevation. Of the 51 patients of group B, 41 (80.4%) relapsed. The overall recurrence rate was 82.4% (42/51). The median lead time between CA125 increase and clinical detection of relapse was 3 months (range 2-27 months). The present data confirmed the reliability of serum CA125 assay as predictor of clinical relapse in epithelial ovarian cancer. The recurrence rate seemed to be lower for patients who received chemotherapy at the time of CA125 elevation (37.5% versus 82.4%, p=0.02). However, the small number of patients, the short follow-up, and the non randomized design of the study do not allow to draw any conclusion on the appropriate timing for second-line chemotherapy. PMID- 21594364 TI - The effects of high dietary fat and indomethacin on 7,12 dimethylbenz(a)anthracene-induced mammary carcinomas in rats. AB - The effects of high dietary fat and indomethacin (IND) on tumorigenesis, tumor growth, tumor histology, cell kinetics and receptor contents of 7,12 dimethylbenz(a)anthracene (DMBA)-induced mammary carcinomas were investigated in Sprague-Dawley (S-D) rats. Tumorigenesis was stimulated by high dietary fat and inhibited by IND. However, both high dietary fat and IND stimulated tumor growth. Switching the animals from the high-fat diet with or without IND to the low-fat diet suppressed tumor growth and affected the cell kinetics. Histologically, the tumors showed a dense proliferation of ductal cells in the high-fat alone or IND treated high-fat diet group. Tumors in the low-fat or IND-treated low-fat group, as well as the group switched from a high-fat or IND-treated high-fat diet to a low-fat diet, demonstrated well-developed glandular structures. The estrogen receptor and progesterone receptor contents were not different between the groups either prior to or following switching diets. Therefore, high dietary fat stimulates tumorigenesis and tumor proliferation, while IND has dual effects: a stimulating effect on tumor proliferation, but an inhibiting effect on tumorigenesis. It also appears that hormone-receptor status does not play an important role in the stimulatory effects of high-fat diet or IND on tumor proliferation. PMID- 21594365 TI - Multiple sites of loss of heterozygosity on chromosome arms 3p and 3q in human breast carcinomas. AB - Loss of heterozygosity (LOH) at loci from both arms of chromosome 3 were shown to occur in a high proportion of breast carcinomas. Six regions of consistent loss were identified, and were variably involved in the tumors. This suggests that multiple potential tumor suppressor genes involved in mammary carcinogenesis are present on chromosome 3. PMID- 21594366 TI - Enhancement of chemotherapeutically-induced apoptosis in vivo by biochemical modulation of poly (ADP-ribose) polymerase. AB - An inhibitor of poly (ADP-ribose) polymerase, 1,5-dihydroxyisoquinoline (DHIQ), evaluated in vivo against a murine advanced breast cancer, significantly improved by 20% the PR rate of tumor-regressing chemotherapy. A detailed sequential biochemical cascade is proposed for chemotherapy-induced apoptosis, and the rationale for the utilization of the inhibitor is explained. PMID- 21594367 TI - How many prognostically significant grades of prostate carcinoma are there? AB - Carcinoma of the prostate (CAP) is often graded as well, moderately or poorly differentiated. We identified 74 well differentiated stage A1 CAP, 58 stage D1 CAP with moderately differentiated metastases, 107 moderately differentiated stage D2 CAP, and 53 poorly differentiated stage D2 CAP and divided each group into 3, 4 or 5 histological patterns. We found that each histological pattern within well, moderately and poorly differentiated prostate carcinoma had similar survival rates. These observations suggest that, using Light microscopy, 3 prognostically significant grades of CAP can be identified - well, moderately and poorly differentiated. PMID- 21594368 TI - Selective expansion of circulating CD8+ lymphocytes during cancer immunotherapy with interleukin-2 plus alpha-interferon but not with interleukin-2 alone. AB - The use of interferons in anti-cancer therapy is justified by the experimental evidence that these cytokines are able to enhance in vitro the expression of some surface molecules such as major histocompatibility complex and tumor associated lymphocytes. Furthermore, a synergism of action of interleukin-2 with alpha interferon in the treatment of human malignancies has been described. Nevertheless, whether the in vivo role of interferons associated to interleukin-2 as anti-cancer drugs is actually related to the properties of this cytokine of modulating surface molecule expression on target cells, has never been clearly reported. In this report, we describe an immune system cell resetting, during immunotherapy with interleukin-2 plus alpha-interferon, which seems to support this hypothesis. PMID- 21594369 TI - The Ehrlich ascites carcinoma (EAC) contains 300-500 Da inhibitor(s) suppressing DNA synthesis in cultured EAC cells and EAC cell division in tumor-bearing mice. AB - A protein preparation obtained from the Ehrlich ascites carcinoma (EAC) by acetone precipitation, water extraction and subsequent two-step alcohol fractionation reduced significantly EAC cell proliferation in vivo and in vitro. The preparation was found to contain a low molecular-weight growth-inhibitory activity, suppressing both DNA synthesis in cultured EAC cells and EAC cell division in tumor-bearing mice. The approximate molecular weight of this inhibitory component(s) is about 300-500 Da, corresponding to oligopeptide molecule(s). PMID- 21594370 TI - Comparative virology and AIDS (review). AB - The scientific debate between pros and cons of the HIV criminal theory of AIDS still remains unsettled. The purpose of this review is to promote resolution of the problem by extracting a common principle of the host-virus relation using data resources for each of 4 viruses as follows: a) polyoma virus, b) Marek's disease virus, c) Ebola virus, d) Korean hemorrhagic fever virus. Conclusions drawn from this study are given as follows: i) Environment emerged as the cardinal factor to modify the process of virus infection in all of the 4 viruses studied. Above all, an accelerating effect of environmental stress on the progression of virus infection was noted in vivo in the majority of viral diseases. ii) Evidence is available to indicate that a healthy cell (or a healthy individual) may harbor virus genes of multiple species without manifesting any pathologic sign. iii) Evidence also suggests that the biological property as well as morphological structure of a virus may vary in reponse to a change of the bioenvironment. On the basis of the above information, we propose to renounce 2 assumptions of classical infection model: a) the hereditarily determined virulence of a microorganism (including virus) be the sole determinant of infection to the effect that its invasion into the host should automatically complete the programmed course of infection; b) virus, a quasi-living creature, should reserve its behavioral independence irrespective of a change of the bioenvironment. The new infection model was constructed on the basis of the selfish gene concept that had been invented by Richard Dawkins to explain the altruistic behavior of an individual. That is, the fate of an exogenous or endogenous virus is under the dual control of the host genome (selfish gene) and the outer environment. The progression of virus infection is conditioned by a crosstalk between them. The selfish gene may use virus (a lifeless substance) as a magic bullet to induce a designated host response. In that sense, virus is not allowed to retain behavioral independence in the practice of its task. The above new model of virus infection was tested for its validity in the recent data of AIDS epidemiology. PMID- 21594371 TI - Use of interferon and medroxyprogesterone acetate for the treatment of endometrial cancer. AB - Endometrial cancer is a hormone sensitive tumor. Response rate to progestational therapy is related to steroid receptor expression of the tumor. Interferons have been shown to enhance hormonal receptors. In this study the effect of four different interferons and medroxyprogesterone acetate (MPA), on three human endometrial cancer cell lines (AE-7, HEC-1A and HEC-1B), was studied. The ATP cell viability assay was used to measure the antiproliferative activity of the agents used. Synergistic effect was noted only when interferons and MPA were used in combination for the treatment of AE-7, which is the only cell line with a high baseline level of progesterone receptors. These observations indicate that the use of interferons and MPA may have a role for the treatment of endometrial cancer patients with progesterone receptor positive cells. PMID- 21594372 TI - Detection of herpesvirus-like DNA sequences in Mediterranean Kaposi's sarcoma. AB - The aetiology of Kaposi's sarcoma remains obscure, however, epidemiological studies indicate that the disease possesses an infectious aetiology. Recent data revealed the presence of specific herpesvirus-like DNA sequences (KHSV) in all forms of Kaposi's sarcoma indicating that a novel virus may be the infectious agent which causes the disease. The aim of the present investigation was to assess the incidence of this herpesvirus-like DNA sequence in 28 Mediterranean Kaposi's sarcomas. DNA was extracted from formalin-fixed paraffin-embedded tissues and analysed by a sensitive PCR based assay. The KSHV specific DNA sequences were found in 22 of 28 (79%) cases suggesting a potential important role in the development of the disease. PMID- 21594373 TI - p53-expression and chromosome 17-copy number in colorectal adenomas. AB - To get better insight into the role of numerical chromosome 17-aberrations and functional loss of the tumor suppressor gene TP53 during the early steps of colorectal carcinogenesis we analyzed paraffin-embedded tumor tissue from 58 colorectal adenomas with different histological features for p53-expression by immunohistology (IH; moAb DO1), #17-copy number by interphase-cytogenetics [nonradioactive in situ-hybridization (NISH) with a centromer-specific DNA-probe (D17Z1)], and DNA-ploidy by flow cytometry (FCM) with special emphasis on histopathological correlation. Seven adenomas (12%) showed nuclear p53 immunoreactivity. p53-expression was correlated with villous/tubulo-villous growth pattern (p=0.005) and grade of atypia (p=0.003) or dysplasia (p=0.0018). #17-aneusomy was present in 31% of the cases (29% deletions, 2% gains). In the FCM-analysis, 33% of the adenomas were DNA-non-diploid. p53-immunoreactivity correlated statistically significantly with FCM-non-diploidy (p=0.004) suggesting a role for the TP53-gene in the aneuploidization process. #17-deletions were associated to p53-immunoreactivity (p=0.046) but no correlation was found between FCM-ploidy and #17-copy number. As for loss of a tumor suppressor gene both alleles have to be affected, our data suggest a multistep process of TP53 inactivation. Whether the subgroup of adenomas with p53-expression might progress faster into invasive carcinoma than p53-negative cases remains to be tested. PMID- 21594374 TI - Radiofrequency and testicular cancer (review). AB - Physical agents such as ultraviolet or ionizing radiation, heat, and repetitive trauma have been related to the causation of cancer in humans. Much less clear is the association between exposure to radiofrequency, i.e. radar and microwave radiation, emitted from television screens, antennas and detection equipment, to the development of cancer. Sporadic case reports and small series suggest that this type of radiation might lead to cancer or contribute to its evolution. The association between radiofrequency and testicular damage and cancer is unproved, but clinical and experimental data are suggestive of such possibility. We have recently encountered a case of secondary severe oligospermia, followed by seminoma, most probably induced by exposure to radar and microwave radiation, in an 18-year-old man. The population handling or repairing dangerous radar facilities is too small to be evaluated by epidemiological surveys. Even it were so, this material is handled in secrecy, either military or industrial. Arousing the alertness of the medical team in those facilities and bringing better protection to the employees is the aim of our report. PMID- 21594375 TI - Interferon-gamma enhances TNF sensitivity in A172 human glioblastoma cell line. AB - Although human glioblastoma cell line A172 presents tumor necrosis factor (TNF) high affinity receptors, it is resistant to TNF-mediated cytotoxicity. Preincubation of cells with 10 ng/ml interferon (IFN)-gamma for 6 h causes a great increase in TNF receptor numbers (about 477%). IFN-gamma alone is not cytotoxic in A172 cells. Cells preincubated with 10 ng/ml IFN-gamma for 6 h became more sensitive to the TNF cytotoxicity (about 400%). In A172 cells the enhanced TNF receptor expression may contribute to the enhancement of TNF cytotoxicity. This observation may have importance in designing new more effective therapies for human gliomas. PMID- 21594376 TI - Identification of exons in a novel embryonal carcinoma locus using the GRAIL program. AB - Embryonal carcinoma (EC) cells have proven to be of particular value in studies of both oncogenesis and mammalian development, as well as in evaluating the relationship between these two phenomena. Infection of the EC cell line, NR1-0, with a defective retrovirus containing a neomycin resistance cassette (Neo(r)), produced a mutant cell line: NR1-6. Genetic analysis of this variant cell line indicates that there is only a single insertion site. Interestingly, however, the NR1-6 cell line is unique in its morphology, tumorigenicity, and differentiative potential (1). We have sequenced over 18 kb from the regions flanking the retroviral insertion which we then analyzed using the computer programs GCG and BLAST. Although homology was found to 4 B1 repeat elements (approximately 150 bp long) and a novel CA/GT dinucleotide repeat, no homology was found to any known genes (2). Furthermore, attempts to identify potential exons or transcripts using various molecular techniques and the above mentioned computer programs were all negative. Most recently we employed the GRAIL (Gene Recognition and Analysis Internet Link) computer program which was specifically designed to identify potential exons (3). Analysis with this program identified 5 exon candidates: two characterized as excellent (>90% probability) and three as marginal (>60% probability). Using reverse transcriptase (RT)-PCR we have demonstrated that the two 'excellent' and one of the 'marginal' exon candidates identified by GRAIL are expressed as mRNA in the mutant cells. Sequencing of these PCR products indicates that the mRNA is identical to the genomic DNA sequence. Thus, we have found that GRAIL provides an efficient, reliable means of identifying real exons within long regions of novel genomic DNA. PMID- 21594377 TI - The C-terminal part of human melanoma growth stimulating activity (MGSA/GRO alpha) binds to neutrophils but does not stimulate enzyme release. AB - CXC chemokines are known to bind to their receptors on neutrophils and activate them through the N-terminal ELR box. In this study, we show that the C-terminal alpha helix of human MGSA does bind to neutrophils, but contrary to complete MGSA, is unable to promote enzyme release by neutrophils. These results raise the possibility of MGSA being a multi-functional molecule with various domains of activation. PMID- 21594378 TI - Endoglin (CD105) expression in non-neoplastic and neoplastic human tissues and human cancer cell lines. AB - Endoglin is an integral membrane glycoprotein that binds TGF-beta(1,3) with high affinity and is thought to play an important role in modulating the interaction of TGF-beta with its cell surface receptors. In this study a recently characterized monoclonal antibody (29-G8) recognizing endoglin was used to examine expression in a variety of human tissues and human cancer cell lines. Formalin-fixed, paraffin-embedded sections were examined by light microscopy and cell lines were analyzed by now cytometry. Immunostaining was noted in a variety of non-neoplastic epithelia from different organs; most of the neoplastic tissues surveyed also demonstrated prominent immunoreactivity for 29-G8. Flow cytometric analysis of the cell lines revealed strong 29-G8 immunoreactivity in almost all lines examined. Our results suggest that endoglin expression is much more ubiquitous than was previously thought and that endoglin may play a role in modulating TGF-beta binding activity in a variety of normal and neoplastic human tissues. PMID- 21594379 TI - Molecular analysis of lymphoid malignancies. AB - Although lymphoid malignancies have been widely studied at the molecular level, no group has reported on the simultaneous investigation of t(14;18) chromosomal translocation, B-cell clonality and bcl2 gene expression. We have performed PCR analysis of t(14;18) translocation and B-cell clonality as well as semi quantitation of bcl2 expression by Western blotting on a group of 41 patients treated at our institution for lymphoid malignancies. The t(14;18) translocation was observed in 10 out of 40 cases (25%) with a prevalence in the subgroup of centrofollicular lymphoma (9 out of 19, or 47%, which includes one patient in complete clinical remission). bcl2 was overexpressed in 84% of the patients (21/25) and B monoclonality was observed in 21 out of 37 B-cell neoplasia patients (57%) with or without a t(14;18) translocation. In 4 patients, bcl2 overexpression, which has been implicated in the sensitivity to a variety of cytotoxic drugs, was the only abnormality detected. Studies are currently underway to determine whether semi-quantitation of bcl2 expression provides improved prediction of a patient's response to chemotherapy. PMID- 21594380 TI - A phase I evaluation of chronotropic delivery of floxuridine by hepatic arterial infusion in patients with metastatic colorectal cancer. AB - Hepatic arterial infusion (HAI) of floxuridine is often used for metastatic colorectal cancer, though this is associated with dose-limiting hepatobiliary toxicity. A phase I trial was initiated to determine if circadian-patterned HAI floxuridine would reduce toxicity. Twenty-one patients were enrolled, and they received a continuous 14-day HAI of floxuridine, with 90-95% of the drug delivered over the same six-hour period daily. The therapy was tolerable, but there was no reduction in hepatobiliary toxicity. The response rate of 33% (1 complete and 6 partial responses) was similar to that of regimens that do not utilize circadian timing. HAI floxuridine chronotherapy for metastatic colorectal cancer cannot be recommended. PMID- 21594381 TI - Long-term risk of sarcoma following radiation treatment for breast cancer. AB - At the hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 3,120 patients with breast carcinoma were submitted to radiation between 1976 and 1994. Among them there were three patients (0.06%) in whom malignant neoplasm developed in areas of prior irradiation. Histologically, the three tumors were postirradiation sarcomas (PIS): 2 osteogenic sarcomas and one angiosarcoma. The radiation doses varied between 46 and 50 Gy. One patient additionally received chemotherapy. The median interval that transcurred between the start of radiation therapy and the detection of the new growth was 14.3 years. One patient is still alive and in treatment. The other two patients died of sarcoma, 1 and 12 months after the diagnosis of PIS. Taking into account the unfavourable outcome of these three cases, we want to emphasize that the benefit of postsurgical radiation therapy in breast cancer patients by far exceeds its risk of causing a second malignant growth. PMID- 21594382 TI - Effect of video display terminal irradiation on urethane-induced lung carcinogenesis in mice. AB - Female Swiss-derived SHR mice were exposed intraperitoneally to 4 injections of 1% urethane at the Ist, 8th, 54th and 61st days of the experiment (a single dose was 20 mg per mouse). Groups of mice starting from the Ist day were also exposed 5 days per week to 1 hour irradiation of video display terminal (VDT) or VDT+ screen filter (SF). The distance from VDT screen and bottom of animal cage was 38 cm. The experiment was finalized in 1 year. Longterm exposure of urethane-treated mice to both VDT or VDT+SF was followed by slight decrease in survival time of lung tumor-bearing animals. The tendency to increase of the incidence of lung tumors and the number of lung tumor per mouse was observed in mice exposed to urethane + VDT as compared to those exposed to urethane alone. The incidence of lung tumors and lung tumor multiplicity were significantly decreased in mice treated with urethan and VDT+SF in comparison to mice exposed to urethane + VDT. Thus, a slight promoting effect of VDT-induced irradiation on lung tumorigenesis was observed induced by urethane in mice, and SF alleviated this effect. The dose of urethane in these experiments was rather high to show more clearly the effect of VDT irradiation on lung carcinogenesis. PMID- 21594383 TI - Alterations of CDKN2(p16/MTS1) exon 2 in human hepatocellular carcinoma. AB - To determine the state of CDKN2(p16/MTS1) gene in human hepatocellular carcinoma (HCC), the polymerase chain reaction (PCR), dot blot hybridization, PCR-single strand conformation polymorphism (SSCP) and DNA sequencing techniques were applied to investigate the homozygous deletions and intragenic mutations of CDKN2 exon 2 in tumor and non-tumor liver tissues from 24 patients with HCCs. Alterations of CDKN2 exon 2 were found in 10 (2 homozygous deletions and 8 intragenic mutations) of the 24 tumor samples (41.7%), no alteration was found in any of the non-tumor liver tissues. All of the intragenic mutations were located at codon 81 of CDKN2 with GC bases deletions confirmed by DNA sequencing. A different sequence at codon 53-54 (C-G rather than G-C) was also found in all of the liver and tumor tissues. Our study indicates that alterations of CDKN2 gene is not a rare phenomenon in HCC, however, it might play an important role in the development of HCC and codon 81 might be a mutational hotspot of CDKN2 gene in HCC. PMID- 21594384 TI - Intra-arterial induction chemotherapy. AB - When effective anti-cancer drugs first became available to clinicians they were commonly used by surgeons by intra-arterial infusion to treat difficult regional cancer problems. Because they were most often used to treat poorly vascularised recurrent cancers results were, in general, unsatisfactory. The intra-arterial approach fell into disrepute and continued use of these techniques has often been criticised and results achieved treated with scepticism. Reasons for the original poor results are now well understood and techniques for effective and safe regional chemotherapy have been developed. These techniques of regional chemotherapy, when appropriately used especially as induction treatment, have an important role to play in a comprehensive oncology therapeutic service. However the criticisms and reluctance to accept the use of chemotherapy on a regional basis remain widespread. Some of the objections and difficulties expressed are valid but some are quite invalid and indicate reluctance to review the situation in spite of valuable progress and understanding and in spite of important clinical applications. Outlined in this review are valid objections, including increased facilities and skills needed and their cost, as well as invalid objections based on misconceptions, inexperience and reluctance to review or accept need for change of familiar practices. PMID- 21594385 TI - A splice variant of the c-met proto-oncogene is the predominant population expressed in human gastric mucosa and carcinoma. AB - Difference in the expression of the c-met protooncogene transcription variants in human gastric mucosa and cancer was studied by deoxynucleotide sequencing and cloning-restriction fragment length assay of the PCR products amplified with the specific primer set to membrane proximal extracellular domain of the c-met c-DNA. Fight gastric cancer cell lines, five gastric carcinoma tissues as well as their corresponding non-neoplastic gastric mucosas had the 54 bp- form splice variant of the c-met which encodes mature 190 kDa alpha beta heterodimeric protein as the major transcript population and 54 bp+ form variant which encodes 170 kDa protein, which is distinct from the met precursor protein, could not be detected. These results indicate that 190 kDa alpha beta heterodimeric protein encoded by major 54 bp- form c-met transcript mainly mediates the effect of HGF/SF in the stomach. PMID- 21594386 TI - Tumor suppression by manganese superoxide dismutase. AB - Manganese superoxide dismutase (MnSOD) is a nuclear-encoded primary antioxidant enzyme in the mitochondria. The known function of MnSOD is to remove superoxide radicals generated in the mitochondria. Given the recent explosion of evidence linking the role of MnSOD to the suppression of cancer, it has been proposed that MnSOD might function as a new type of tumor suppressor gene. Considering the role of free radicals in carcinogenesis, the significance of oxidative stress in the mitochondria, and the involvement of MnSOD in tumor suppression, the author proposes a reconciliation of the antioxidant function of MnSOD with its tumor suppression function. The focus of this report is to present some of the evidence supporting this idea. PMID- 21594387 TI - Effects of estrogen receptor expression on growth and transformation of cells overexpressing neu. AB - The mechanism by which breast cancers progress to hormone independence does not always require the loss of estrogen receptor(ER) expression or function. Cellular alterations that disturb the normal pathway of estrogen-regulated growth may contribute to a state of hormone independence. We and others have described an inverse relationship between estrogen stimulation of ER(+) breast cancer cell lines and their expression of neu. Amplification and overexpression of neu are known to enhance cellular transformation and increase the metastatic potential of cancer cells. Clinically, they are also correlated with more aggressive tumor phenotypes. Therefore, expression of neu may represent a key regulatory point in estrogenic control of cellular growth and transformation. In this communication we demonstrate that the presence of E2/ER can repress transformation of NIH/3T3 cells by the neu oncogene. Furthermore, we have investigated the effects of E2/ER on growth and transformation of an ER(+), neu-overexpressing breast cancer cell line. We report that the presence of E2/ER in these cells leads to repression of the transformed phenotype (as measured by anchorage-independent growth) while stimulating cellular proliferation (in monolayer culture) and propose a model for the role of neu in progression to hormone independence based on these results. PMID- 21594388 TI - DNA-protein crosslinks as a biomarker of cis-platinum activity in cancer patients. AB - We have developed a new method to assess the amount of DNA-protein crosslinks (DNA-PC) in peripheral lymphocytes, based on the selective precipitation of the DNA crosslinked to proteins. We assessed the amount of DNA-PC in peripheral lymphocytes of 18 cancer patients who underwent chemotherapy with cis-platinum for the first time. Since the chemotherapy was administered over a two-day period, blood samples were drawn at baseline (before starting the therapy), 4 h after the infusion of the first dose of cis-platinum, the next day (24 h after the first dose, and immediately before the infusion of the second dose), and 2 days later (48 h after the first dose). The mean change of DNA-PC 4 h after therapy was 0.8+/-0.8% (p=0.006), 0.5+/-0.6% after 1 day (p=0.007), and 0.1+/ 0.5% after two days (ns). The correlation between DNA-PC changes and cumulative dose of cis-platinum was -0.22 at 4 h, -0.19 after 1 day, and -0.68 at 2 days (p=0.005). The crosslinking effect of cis-platinum seems to vary among individuals and with dose; the DNA-PC may be used to define sub-populations of patients with various degree of sensitivity to the pharmacologic action of this chemotherapeutic agent, and thus to adjust the dosage on an individual basis. PMID- 21594389 TI - Tissue factor mRNA expression in breast carcinoma cells. AB - Tissue factor (TF) activity has been found in tumor cell homogenates and high TF mRNA expression has been observed in metastatic tumor cell lines. TF is responsible for initiating the extrinsic pathway of coagulation. In the present study, TF cDNA was cloned on the basis of high expression of the corresponding mRNA in metastatic MDA-MB-231 breast carcinoma cells, as opposed to its low expression in non-metastatic MCF-7 cells. However, further analyses revealed that TF mRNA was not uniquely expressed in malignant breast carcinoma cells. Thus, high levels of TF mRNA were observed in nonmalignant, immortalized A1N4, MCF-10 and HBL100 breast epithelial cell lines, whereas low levels were observed in 4 breast carcinoma derived cell lines. TF mRNA was analysed in node-negative breast carcinomas by RT-PCR. Strong expression was observed in 10/24 tumors. We conclude that TF expression did not correlate with the malignant potential of the breast cell lines examined and that TF mRNA can be detected in node-negative breast cancers. PMID- 21594390 TI - Phase I-II study of interferon-gamma and eflornithine (DFMO) in patients with advanced renal cell carcinoma, malignant melanoma and colorectal carcinoma. AB - Eflornithine (DFMO) and interferon-gamma (IFN-gamma) are known to exert synergistic activity on inhibition of ornithinedecarboxylase (ODC) in vitro and in experimental animal tumors thereby inhibiting tumor proliferation. In this study, we prospectively investigated therapeutic effects and side effects of a combination of DFMO and IFN-gamma in 15 patients with renal cell carcinoma (RCC), 9 with malignant melanoma (MM), and 9 with colorectal carcinoma (CRC). DEMO was given orally at a dose of 3x4 g/day during the first 2 weeks of each month; IFN gamma was administered daily subcutaneously during the DFMO administration periods and every other day during the following 2 weeks. The starting dose of IFN-gamma was 30 mu g/m(2) in the first 5 patients and 60 mu g/m(2) in the next 28. IFN-gamma dose was doubled every 4 weeks to a maximum dose of 120 mu g/m(2) and 240 mu g/m(2), respectively. Therapy was applied for three months in cases with stable disease or partial remission. In 15 patients treatment was stopped after 3 to 11 weeks after initiation of therapy because of tumor progression (14 cases) or severe side effects (1 case). In one out of 15 patients with renal cell carcinoma a partial response was observed lasting 7 months, 5 patients showed stable disease, and 9 progressed. In patients with malignant melanoma and colorectal carcinoma, stable disease was observed in one patient and progressive disease in 8 patients per group. The most frequent side effects were fever and gastrointestinal disturbances observed in 26 patients each. The results of this study indicate that DFMO combined with IFN-gamma has no significant therapeutic activity in patients with advanced renal cell carcinoma, malignant melanoma, and colorectal carcinoma. PMID- 21594391 TI - An improved operative technique for placement of brachytherapy catheters in treatment of soft tissue sarcomas. AB - Two patients with malignant soft tissue sarcomas were treated with local excision followed by a combination of brachytherapy and external beam radiation therapy. The involved areas were large resulting in extensive and irregular sites of resection. The individual placement of multiple brachytherapy catheters in such large, irregular contours can be a time-consuming and technically difficult task often resulting in an uneven distribution of the catheters within the sites of resection. We therefore describe a technique of catheter distribution. PMID- 21594392 TI - Cholesteryl 14-methylhexadecanoate as a possible marker of malignant tumours. AB - Concentration of cholesteryl 14-methylhexadecanoate was determined by high performance liquid chromatography in serum of 123 healthy individuals, 83 of patients with other diseases than cancer, and of 394 patients with cancer. A mean level of 22.89 nmol/ml in healthy persons was not significantly different from 23.22 nmol/ml found in other diseases than cancer. With a cut-off value of 40.0 nmol/ml, there were 2 falsely positive results in the former and 4 in the later group. Significantly elevated mean concentrations (60-80 nmol/ml) were demonstrated in most patients with cancer irrespective of the clinical stage. No differences were found in this respect between males and females, and in different age groups. The sensitivity of the test was 81.8% for the whole population tested, if progressive and stable diseases as well as partial remissions were evaluated. Lower sensitivities were found in females and in patients more than 60 years old (down to 70.6%). The test showed a significantly greater sensitivity in less advanced stages of the disease (T1 and T2). Considering the type of cancer, highest sensitivity was observed for testicular cancer (86.2%), lower for prostatic (77.8%), mammary (76.5%), ovarian (75.8%), and colorectal tumors (73.3%) as well as for lymphomas (70%). Follow-up of patients with all these types of cancer revealed that changes in their clinical condition are accompanied with significant alterations in the cholesteryl 14 methylhexadecanoate level. When this ester was determined in 807 sera with a known level of other markers (irrespective of diagnosis), a significant correlation was demonstrated with carcinoembryonic antigen and nearly a significant one with prostatic specific antigen. There was no correlation with CA 15-3, CA 19-9, CA 125, or TPA. Because of its sound theoretical basis, absolutely specific method of determination, high specificity (97.1%), and predictive value (94.7%), the cholesteryl 14-methylhexadecanoate level determination may be useful as an alternate procedure supplementing the spectrum of tumor markers generally used. PMID- 21594394 TI - Association of laminin receptor gene fragments with nuclear matrices in high and low metastatic cancer cell lines. AB - Interactions between tumor cells and laminin play an important role in the complex cascade of events in metastasis. We investigated the association of laminin receptor DNA fragments with nuclear matrix in two carcinoma cell lines with different metastatic potentials. Two fragments of DNA (474 bp and 855 bp) were amplified and detected in the genomic DNA of both cell lines. With the extraction of residual DNA from nuclear matrix, positive association of the 474 bp DNA fragment with nuclear matrix was demonstrated in both cell lines. Nevertheless, the intensity of this amplified product in the high metastatic cell line is much stronger than that in the low metastatic cell line. The long DNA fragment was not detected in both cell lines indicating that part of the laminin receptor gene was hardly intact after sequential extraction with detergent, high salt and enzymes. Our findings show the possibility that the attachment of the 474 bp DNA fragment to nuclear matrix may contribute to the difference in metastatic properties of these two cell lines. PMID- 21594393 TI - Microvessel density and vascular endothelial growth factor expression in human tumors of different localization. AB - In order to study the angiogenic activity of individual human tumors, microvessel density and vascular endothelial growth factor (VEGF) expression were determined in 152 human tumors of different localization (lung, ovary, breast, colon/rectum, kidney) using immunohistochemistry. Considerable variability in vascular density has been noted between different tumors with the same histology as well as between tumors of different localization. Kidney and breast carcinomas exhibited significantly higher vessel counts than carcinomas of other localization (p<0.001). In most tumor types (lung, breast, ovarian, nephroblastoma) about two thirds of the tumors expressed VEGF. In contrast, only 7 out of 20 colorectal carcinomas (35%) and 9 out of 20 kidney carcinomas (45%) and all small cell lung carcinomas (13/13) were positive for VEGF, despite a relatively low vascularity. These results indicate that each single tumor has its own pattern of vascularity and its variable expression of VEGF and that the individual determination of the degree of vascularization together with the assessment of one or more angiogenic peptides may provide valid information on the angiogenic activity of a tumor. This may lead to identification of those patients who are more likely to have benefit from antiangiogenic therapies. PMID- 21594395 TI - Fluoride supplementation status, fractures and osteopenia in children with acute lymphoblastic leukemia. AB - Children with acute lymphoblastic leukemia (ALL) experience fractures on the basis of osteopenia related to chemotherapy administered for the maintenance of remission. It is likely that corticosteroids are the main cause of bone mineral loss in this circumstance. Because fluoride has been used as a therapeutic intervention in osteoporosis, including that induced by corticosteroid therapy, we explored the prospect that children with ALL who received fluoride supplementation (in drinking water or from other sources) may be relatively protected from iatrogenic skeletal morbidity. Children who completed therapy according to the Dana Farber Cancer Institute protocol 87-01 (n=35) were assessed by skeletal radiology and bone densitometry every 6 months from diagnosis. In addition, their families completed a questionnaire relating to fluoride supplementation. There was no correlation between such fluoride supplementation and either the prevalence of fractures or the severity of osteopenia. This outcome may reflect the mainly appendicular location of the fractures in this group of children. These findings, together with a consideration of the risk benefit ratio of fluoride administration to children at large, suggest that such intervention is unlikely to be beneficial in limiting skeletal morbidity during the treatment of ALL in childhood. PMID- 21594396 TI - Clinical investigation of 145 cases of chronic lymphocytic leukemia in Japan. AB - CLL is the most common leukemia in Europe and America, representing 30% of all forms of leukemia. In contrast, in Japan, the incidence is only 3%. This is the largest multicenter study in Japan to evaluate the relationship between outcome in CLL patients and the data obtained during patient's first visits. The data obtained during first visits of 145 patients with chronic lymphocytic leukemia (CLL) that were made between 1982 and 1991 and their outcomes were analyzed and compared with those of patients with CLL diagnosed in terms of Rai and Binet staging in Europe and America. In our patients, the male-to-female ratio was 1.8, and the mean age at onset was 63.2+/-11.7 (+/-SD) years. The crude 5-year survival rate was 42.4% in men and 44.9% in women. Patients with B-CLL with surface IgM phenotype had better outcomes than those with B-CLL with surface IgG (P<0.1); patients with surface IgM/IgD phenotypes and those with T-CLL had the poorest outcomes (B-CLL with surface IgM vs. B-CLL with surface IgM/IgD T-CLL, P<0.05). When these patients were re-evaluated in terms of Binet and Rai staging, generalized Wilcoxon analysis revealed no differences between the survival curves of different stage groups, as seen in patients with CLL in Europe and America. Patients whose CLL developed during their fifties or earlier had the most favorable outcomes (P<0.05); the later the onset of disease, the worse the outcome. CLL was associated with hypogammaglobulinemia (30%) and autoimmune hemolytic anemia (7.6%), and 4 patients (2.8%) died of secondary cancer. Outcomes of our patients were compared with those of patients with CLL in Europe and America. PMID- 21594397 TI - A patient-like human malignant pleural mesothelioma nude-mouse model. AB - Human malignant pleural mesothelioma is an aggressive cancer with no effective treatment. A relevant animal model is required to study the biology and to develop effective treatment. To meet this need we have developed an orthotopic transplant model for malignant mesothelioma in nude mice. Fresh specimens derived from four patients with malignant mesothelioma were implanted on the parietal pleura of nude mice. All xenografted tumors gave rise to locally growing tumors in the mice. The transplanted mice presented with symptoms of malignancy such as decrease in physical activity and signs of tumor-related respiratory distress. These animals were shown to have extensive tumor spread in the ipsilateral and contralateral pleural cavity as well as mediastinal lymph nodes. When the lesions were confined to the ipsilateral parietal pleura, the implanted animals were in good physical condition. The macroscopic features usually found in the patients were also found in the implanted animals such as nodules, masses and pleural thickness. Histologic examination revealed malignant mesothelioma similar to that from which the original tumor specimen was derived. Orthotopic parietal-pleura implantation of fresh histological human malignant mesothelioma thus allows mesothelioma growth in an animal model that mimics the clinical spread of the human disease. This model provides for the first time a useful human model for biological studies of this disease and for developing effective treatment. PMID- 21594398 TI - Microsatellite instability in patients with chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a relatively common disease, affecting mainly males in the western world. Although substantial data are available as regards the clinicopathological characterization of COPD, little is known of the molecular basis of the disease. In the present study we analysed the incidence of microsatellite instability (MI) in cytological specimens from patients with COPD. MI reflects increased mutational rate and is associated with decreased accuracy in the DNA repair, resulting in the accumulation of somatic mutations in cells manifesting this genetic alteration. Among 31 specimens tested, 7 (23%) exhibited MI in at least one among 6 microsatellite markers tested. 5 cases were affected in only one marker while the remaining two cases exhibited evidence of MI in two microsatellite markers. These data suggest that an elevated mutational rate as reflected by the increased incidence of MI is associated with the development of the disease. PMID- 21594399 TI - Usefulness of oral medroxyprogesterone acetate in the management of cancer related cachexia-anorexia syndrome. AB - A study on the activity and tolerability of high-dose medroxyprogesterone acetate in the treatment of ACS in neoplastic patients was carried out in a series of 103 patients with advanced cancer beyond cure with standard chemotherapeutic or radiotherapeutic treatments. The treatment plan was: medroxyprogesterone acetate (MAP) 1,000 mg/day as liquid suspension orally at a single dose, for at least one month. If there was no improvement in body weight, SSA, performance status therapy was interrupted. An increase in body weight greater than or equal to 5%, in SSA score greater than or equal to 2 points, in performance status and then in quality of life were recorded as positive MAP-related events. Therapy-related toxicity was evaluated according to the WHO criteria. A mean body weight increased from 63 kg recorded before therapy to 67 kg recorded after 30 days of MAP. This difference was statistically significant (p<0.001). SSA increased from baseline value of 2.4 to 4.7, and mean performance status from 58.4 to 65. Again, these difference were highly significant (p<0.005 and p<0.001 respectively). The improvement in both mean body weight and SSA were statistically significant independent of performance status. Data presented in the present study confirm the clinical effectiveness of oral medroxy-progesterone acetate in the management of anorexia-cachexia syndrome in patients with advanced cancer resistant to systemic chemotherapy. PMID- 21594400 TI - Socioeconomic status, lactation and breast cancer risk of parous women in Taiwan. AB - The objective of this study was to evaluate effects of socioeconomic status and lactation on breast cancer of parous women in Taiwan. A total of 102 parous incident cases of female breast cancer in Taipei City were recruited from National Cancer Registry. Another 102 community parous controls individually matched with each case on residential area and age (within five years) were randomly selected from household registration profiles. Socioeconomic status including ethnic group, schooling years, family income, and religion, reproductive risk factors, lactation and body size risk factors for breast cancer were collected from a structured questionnaire interview. Conditional logistic regression was used to estimate the multivariate-adjusted odds ratio of each risk factor. Family income was positively and significantly associated with breast cancer, showing a significant dose-response trend. High parity above three showed a significant protective effect. There was a prominent protective effect from breast feeding. The longer the duration, the smaller the risk of breast cancer. The protective effect of breast feeding was significant only in women who had more than three deliveries. PMID- 21594401 TI - Inhibition of DNA synthesis in rat hepatoma and human lymphoma cell lines, by partially purified factors from mouse embryos. AB - Cancer cells express particular genes, part of which are normally active during the embryonic development. On the other hand, young embryos are able to differentiate and regulate the division rate of teratocarcinoma or leukemia cells, likely by producing differentiation factors. A partial purification of these factors, extracted from mouse embryo cell nuclei, was achieved by high performance liquid chromatography on anion exchange column. High ionic strength eluting fractions, constituted with DNA and tightly bound proteins, have a high inhibitory effect on DNA synthesis, in rat hepatoma and human lymphoma cell lines. The possibility of treatment of cancer cells in this way is discussed. PMID- 21594402 TI - Growth suppression of low HER-2/neu-expressing breast cancer cell line MDA-MB-435 by tyrosine kinase inhibitor emodin. AB - The tyrosine kinase inhibitor emodin (3-methyl-1,6,8-tridroxyanthaquinone) is known to preferentially suppress the growth of the HER-2/neu-overexpressing breast cancer cell line. In this study, emodin effectively suppressed growth of MDA-MB-435, a breast cancer cell line with low HER-2/neu expression. Since emodin is a tyrosine kinase inhibitor, we questioned whether another tyrosine kinase might play a role in the tumorigenicity of MDA-MB-435. By Western blotting with anti-phosphotyrosine antibody, we detected a 72-kDa protein which is uniquely phosphorylated on tyrosine in MDA-MB-435. The level of phosphotyrosine in the 72 kDa protein was significantly reduced by treatment with emodin. This suggests that a strong tyrosine kinase may reside in MDA-MB-435 and the 72-kDa protein serves as a substrate for the tyrosine kinase. PMID- 21594403 TI - Cytoreductive surgery and sandwich therapy with chemohyperthermic peritoneal perfusion and intra-aortic chemotherapy for peritoneal dissemination in gastric cancer. AB - Cytoreductive resection (RST), chemohyperthermic peritoneal perfusion (CHPP) and/or intra-aortic chemotherapy (IA-chemo) were performed for peritoneal dissemination in gastric cancer. Ninety-six patients with peritoneal dissemination were grouped into tubercular (TB), 40; nodular (ND), 31; diffuse (DF) type, 19; and others, 6, respectively, by the gross findings. Sixty-three patients underwent RST. Fifty-nine patients received CHPP by 10-liter heated saline. Thirty patients underwent intra-aortic catheterization for the IA-chemo. The 1-year and 2-year survival rate (1-ysr and 2-ysr) of the RST(+) group were 47% and 10% significantly greater than the 9% and 0% of the RST(-) group (p<0.001). The 1-ysr and 2-ysr of the CHPP(+) group were 37% and 11% significantly greater than the 27% and 0% of the CHPP(-) group (p=0.04). In the TB type the 1-ysr and 2-ysr of the former was 43% and 8% significantly greater than the 15% and 0% of the latter (p=0.04). But there was no significant difference in survival time between the CHPP(+) and the CHPP(-) group in the ND type (p=0.22) or in the DF type (p=0.42). The 1-ysr and 2-ysr of the IA-chemo(+) group were 49% and 19% significantly greater than the 27% and 2% of the IA-chemo( ) group (p<0.01). In the DF type the 1-ysr and 2-ysr of the former was 50% and 33% significantly greater than the 8% and 0% of the latter (p=0.02). However, there was no significant difference in survival time between the IA-chemo(+) and the IA-chemo(-) group in the TB type (p=0.06) or in the ND type (p=0.50). Moreover, the effect of the combination therapy of CHPP and IA-chemo (the sandwich therapy, SDW) were examined. The 1-ysr and 2-ysr of the SDW(+) group were 49% and 22% significantly greater than the 24% and 0% of the SDW(-) group (p=0.002). The sandwich therapy should be performed in addition to cytoreductive surgery for improvement of prognosis in the patient with intractable peritoneal dissemination. PMID- 21594404 TI - Treatment of high-risk solid tumors of childhood with myeloablative chemotherapy and autologous stem cell transplantation. AB - Sixteen consecutive stem cell transplantations (SCT) were performed after myeloablative chemotherapy in patients with high-risk solid tumors of childhood. Seven patients received autologous bone marrow transplantation (ABMT), seven received peripheral blood stem cell transplantation (PBSCT) and two received ABMT + PBSCT. The progression-free survival was similar in three types of transplants (57% ABMT, 43% PBSCT vs. 50% ABMT + PBSCT). The rate of relapse in site of distant organs was also similar (57% ABMT, 57% PBSCT vs. 50% ABMT + PBSCT). There was no statistically significant difference in the hematopoietic recovery time between each group. PBSCT group had a significantly fewer days of food intolerance and a lower morbidity than ABMT group. The disease-free survival was 71% for neuroblastoma, 50% for small round cell tumors and 25% for rhabdomyosarcoma. Post-SCT therapy for possible reinfused tumor cells should be mandatory to decrease the frequency of relapse. PMID- 21594405 TI - Tumor stage and postoperative survival in invasive colon cancer. AB - Most of the prognostic factors of invasive colon cancer are controversial, and tumor stage is accepted worldwide in relation to survival. In this study, relationships between the 5-year survival rate and prevailing tumor stages were investigated, and pathological factors relating to nodal involvement which is an important determinant of staging were analyzed. The pTNM system, Borrmann classification and the Japanese microscopic stage were significantly related to the survival rates, as well as the presence or absence of nodal involvement. Accuracy of intraoperative diagnosis of nodal involvement was poor; 11.7% of patients with macroscopic negative-nodes and 36% of those with positive-nodes were microscopically found to be false. Complete resection of primary tumor with adequate nodal-dissection can contribute to better survival of colon cancer patients. PMID- 21594406 TI - Treatment of cervical intraepithelial neoplasia (CIN) with interferon alpha-2a, CO2 laser (vaporization, cone) and 5-fluorouracil. AB - This study was undertaken to assess the effect of CO2 laser (vaporization, conization), 5-FU topical application and interferon alpha-2a parenterally in the therapy of GIN. Three hundred and forty-seven (347) women with CIN were treated with CO2 laser (vaporization, conization), 5-FU topical application and interferon alpha-2a parenterally. The cure rates in the various treatment groups were analysed by the chi(2) test. The most effective treatment used for CIN I was the combination of CO2 laser vaporization plus 5-FU (p<0.05). The most effective treatment used for CIN II was the combination of CO2 laser vaporization plus 5-FU (p<0.001). The treatment modalities used for patients with CIN III achieved the same therapeutic results (p>0.1). The addition of interferon does not achieve better cure rates in patients with CIN. PMID- 21594407 TI - Treatment of flat or accuminata condylomata of female genital tract. AB - This prospective study was undertaken to test the hypothesis that if the male partners of women with condylomata accuminata or flat are treated, the treatment failure rate, of women, decreases. From March 1986 to October 1992, 246 women with condylomata accuminata or flat were presented. The women were assigned into 4 groups. Group A (n=64) women whose partners were submitted to peoscopy and then treated if appropriate; moreover condom use was prescribed for one year. Group B (n=79) women whose partners were not submitted to peoscopy and not treated but they used condoms for one year. Group C (n=40) women whose partners were submitted to peoscopy and then treated if appropriate but without the use of condoms. Group D (n=63) women whose partners were not submitted to peoscopy, not treated and without the use of condoms. The treatment failure rate of women of group A (peoscopy, treatment, condom) was 29.68% and was independent upon the treatment of male sexual partners because of the use of condom (chi(2)=2.32, p>0.1). The treatment failure rate of group B (no peoscopy, no treatment, condom) was 32.91%. The treatment failure rate of group C (peoscopy, treatment, no condom) was 47.5% and was dependent upon the treatment of male sexual partners (chi(2)=14.71, p<0.001). The treatment failure rate of group D (no peoscopy, no treatment, no condom) was 69.84%. The results of this study supports the hypothesis that the treatment failure rate of women with flat or accuminata condylomata decreases if their male sexual partners are also treated. PMID- 21594408 TI - Modulation of cytokine production from TH2-lymphocytes and monocytes by the pineal neurohormone melatonin. AB - Preliminary clinical and experimental studies have suggested that cytokine secretion is not regulated only by immune substances, but also by the neuroendocrine system through the release of immunomodulating neurohormones, such as the pineal hormone melatonin (MLT). The anticancer immune response would also depend on complex interactions between cytokines and neurohormones. IL-2 is one of the most active antitumor cytokines. However, in addition to the generation of cytotoxic antitumor lymphocytes, IL-2 may concomitantly induce suppressive factors, in particular IL-10 by TH2 lymphocytes and IL-6 by both TH2 lymphocytes and monocytes. IL-10 appeared to inhibit IL-2 secretion and activity, whereas IL 6 has been proven to exert both antineoplastic and proneoplastic immune functions. The present experimental study was performed to evaluate the in vitro effects of MLT on IL-10 and IL-6 secretions, either in basal condition or after IL;2 stimulation. Human pure lymphocyte and pure monocyte cultures were obtained from healthy donors and incubated for 3 days with medium alone, MLT (100 pg/ml), IL-2 (100 Cetus U/ml) or IL-2 plus MLT. IL-2 induced a significant increase in mean medium concentrations of both IL-10 and IL-6. MLT alone had no effect on IL 10 levels, but it was able to significantly reduce IL-2-induced IL-10 release. IL 2-induced IL-6 secretion was not abrogated by a concomitant MLT incubation, whereas MLT alone was able to significantly reduce the basal secretion of IL-6 only in the pure monocyte cultures. These results, by showing a modulatory effect of MLT on lymphocyte and monocyte cytokine secretion, would further confirm the rationale of a concomitant administration of cytokines and immunomodulating neurohormones during cancer immunotherapies. PMID- 21594409 TI - Locally advanced breast cancer. AB - In vitro studies suggest p53 and bcl-2 may be important in the apoptotic response to irradiation, and that rapidly proliferating cells are more sensitive to radiotherapy. The clinical relevance of biological factors in predicting radiotherapy response was investigated in 62 patients with locally advanced breast cancer. Immunocytochemical staining for p53 protein, BCL-2 protein and MIB 1 antigen on the primary tumour, showed that none of these factors significantly predicted radiotherapy response (BCL-2 p=0.45, p53 p=1.0, MIB 1 p=0.92) and appear to be of no clinical value. A semi-quantitative assessment of MIB 1 staining showed a reduction in positive cells following radiotherapy (p=0.04), consistent with a reduced proliferation associated with response. PMID- 21594410 TI - An immunocytochemical study of ras and myc oncoproteins and EGFr expression in pleural effusion smears. AB - Pleural effusion smears from 112 patients with either benign or malignant lung disease were investigated for the expression of EGFr and the oncogene proteins myc p64 and ras p21. The streptavidin-biotin peroxidase technique was used. In the studied malignant group of effusions both EGFr and ras have greater sensitivity in the detection of a malignant process than does routine cytological examination though EGFr was less specific. The combination of positive cytology and 3 positive markers is highly specific for a malignant process (90%). Myc and ras had a 100% sensitivity in squamous cell carcinomas but an overall specificity of only 67.3% and 66.6% respectively. The differences in myc and ms positivity, between squamous cell and adenocarcinoma effusion smears were highly significant (p <0.005). All effusion smears associated with undifferentiated carcinomas were ras positive and 2 of them were myc and EGFr positive. PMID- 21594411 TI - Regulation of expression of the hepatocyte growth factor scatter factor receptor, c-met, by cytokines. AB - The c-met proto-oncogene product is a 190 kDa heterodimeric receptor tyrosine kinase activated by the binding of its li,gand, hepatocyte growth factor/scatter factor (HGF/SF), a cytokine known to stimulate cell growth, motility and morphogenesis. Altered expression of c-met receptor levels in tumour cells may therefore play an important role in regulating the metastatic progression of cancers. We have determined the effects of a number of cytokines on c-met expression in the colon cancer cell line HT29. We report that c-met message and protein levels are up-regulated by the cytokines IL-5, IL-10, TGF-beta, PDGF and basic FCF while down-regulation occurred after treatment with IFN-gamma. We conclude that up-regulation of the HGF/SF receptor in vivo by the above cytokines may enhance tumour cell sensitivity to HGF/SF and therefore be an important step in the progression of metastatic spread. PMID- 21594412 TI - Liposarcoma. AB - Using nuclear suspensions, the DNA-content of 7 bone-associated, paraffin embedded liposarcomas and 3 lipomas were examined by means of flow cytometry (FCM) and was compared with the results of image cytophotometric measurements (ICM). Using ICM, 6 of 7 liposarcomas showed an aneuploid DNA content (86%), whereas FCM showed aneuploidy in 3 cases (43%). None of the lipomas had an aneuploid DNA-content using either method. The correspondance of the two methods was 70%. Because aneuploidy is of prognostic importance, ICM could be the method to determine the DNA content of liposarcoma. PMID- 21594413 TI - Single agent vinorelbine in the treatment of unresectable lung metastases from colorectal cancer. AB - Vinorelbine (VNR; 5'-nor-anydro-vinblastine) is a new semisynthetic vinca alkaloid which has demonstrated significant clinical activity against non-small cell lung cancer, bronchial adenocarcinoma, breast cancer, and head/neck squamous cell carcinoma. Moreover, vinorelbine has been widely employed in combination with cisplatinum with or without 5-fluorouracil for the treatment of lung cancer and head/neck carcinomas. Sixteen consecutive patients with lung metastases from colorectal adenocarcinomas were treated with vinorelbine tartrate (Navelbine R) given at the dose of 25 mg/m(2) i.v. bolus every week for eight consecutive times employing metoclopramide as an antiemetic tool. All patients had previous surgery, two had adjuvant chemo-immunotherapy with i.v. 5-fluorouracil and oral levamisole, 5 patients had adjuvant radiotherapy, and 1 patient had chemotherapy with levofolinic acid and 5-fluorouracil for advanced disease. Sites of disease included lung in all cases, liver metastases in 3 patients and nodal tumoral deposits in 2 cases. All patients entered in the study had lung disease as predominant site of disease and showed multiple metastases. One patient was not evaluable for response, toxicity and survival because he was lost to follow-up before completion of therapy. No major objective response was seen. Four patients had stable disease which lasted a mean of 5.2 months, and the remaining 11 patients showed progressive disease. Mean survival was 6.7+ months (range 4.0 12.0+ months). The treatment was quite well tolerated by most patients, granulocytopenia being the most frequent side-effect. Nausea/vomiting was very mild with grade 1 episodes in 5 patients (33%). Grade 1 leukopenia was seen in 5 patients (33%), grade 2 leukopenia in 3 patients (20%), and grade 3 in 2 cases (13%). Grade 1 thrombocytopenia was recorded in 3 cases (20%). No significant neurotoxicity was observed, except mild constipation in 4 cases (26%). The activity of VNR on a weekly schedule against lung metastases from large bowel adenocarcinoma is very low, however it should be noted that the treatment was well tolerated by most patients. PMID- 21594414 TI - Aneuploid polyclonality in image analysis. AB - Solid tumors such as colorectal adenocarcinomas consist of biologically diverse cell subpopulations. Nuclear DNA content of tumor cells in colorectal carcinomas may be studied with different techniques of intranuclear DNA quantification. In the current study, the DNA ploidy of samples obtained from 68 patients with colorectal carcinoma (age ranging from 46 to 86 years, mean age 66 years), treated with radical surgery, between the years 1992 and 1995 was analyzed. DNA ploidy was assessed using a CAS 200 image analyzer and was evaluated on neoplastic tissue and undamaged healthy mucosa obtained from the edges of the surgical resection. Approximately 150-300 cells were analyzed for each sample. The aim of this study was to evaluate the prognostic significance of the polyclonal cases correlated with lymph node infiltration and disease free survival. The pathological stage according to the TNM classification was compared to ploidy: an increase in multiple stemlines was observed in stage III cases, i.e., a progression towards aneuploidy and multiple stemlines was significantly associated with lymphatic metastasis (p<0.0003). Concerning distant metastasis, we found a correlation between stage IV and polyclonality. A significant correlation was observed between disease-free survival and aneuploid and polyclonal cases (p<0.0053). In polyclonal cases a nine fold greater relapse risk compared to the non-polyclonal cases was observed (p<0.0004). In two cases, the adeno-carcinoma of the sigma was polyclonal and its hepatic metastasis contained the predominant aneuploid clone with the same cytometric characteristics (DNA index) of the original lesion. PMID- 21594415 TI - Delay in diagnosis and treatment of breast cancer in northern Norway. AB - The delay in diagnosis and treatment of 173 breast cancer patients admitted for radiotherapy at the University Hospital of Tromso is presented. The median delay from symptom to diagnosis was 2.4 months (0-98.6 months), from histological/cytological diagnosis to operation 7 days (range 0-523 days) and from operation to start of radiotherapy 47 days (range 24-102 days). There were no correlations between delay and age, tumour size, estrogen receptor status, breast involved, relapse or death of disease. A prolonged diagnostic delay (p=0.041) was revealed in the county (Finnmark) having the worsed prognosis. Delay should be minimised to reduce anxiety and unnecessary suffering and improve survival. PMID- 21594416 TI - Spermidine/spermine N-1-acetyltransferase as a marker of dimethylhydrazine induced colonic carcinogenesis in the rat. AB - We investigated whether spermidine/spermine N-1-acetyltransferase (SSAT) might be a useful marker of 1,2-dimethylhydrazine (DMH)-induced colorectal tumors in rats. Male Wistar rats were given DMH weekly for 5 weeks (150 mg/kg/dose), and then sacrificed 5, 10, 15 or 20 weeks after the first dose. Tumors were detected in 2 of 6 rats sacrificed at 10 weeks. Colorectal mucosal SSAT activity was 25.8+/-2.4 pmoles/mg/min before dosing, and only slightly higher at 5 weeks (36.8+/-10.0). From week 5 onward, activity rose sharply and significantly, reaching 87.2+/-29.0 by week 20. These results indicate that SSAT is an excellent marker of DMH induced colonic carcinogenesis. PMID- 21594417 TI - Combination chemotherapy for advanced lung cancer. AB - Lung cancer is now a major public health problem in Thailand. This study was undertaken to gain some preliminary data regarding the potential effectiveness in treating advanced non-small cell lung carcinoma (NSCLC) using an ifosfamide combination therapy IA(E)P. A clinical study was made of all 50 patients (Thais) with histologically proven, advanced NSCLC admitted to the University of Siriraj Hospital between 1985 and 1987 and followed up until February 1992. Survival was calculated for responders and non-responders as distinct groups, and for the different histological tumors among the responders. There were 22 cases of adenocarcinoma, 13 large cell carcinoma, and 15 squamous carcinoma. Twenty-seven out of 50 (54%) responded to treatment. The median survival of the response group was 17 months, compared with 5.5 months in the nonresponse group. The longest survival period was seen in patients with large cell carcinoma. The results suggest that moderate success might be expected in selected patients using the IA(E)P. Further work should be undertaken in developing countries using controlled clinical trials to more fully determine the efficacy of IA(E)P in treating NSCLC. PMID- 21594418 TI - In vitro antiproliferative effects, toxicity profiles in vivo in mice and antitumour activity in tumour-bearing mice of four diorganotin compounds. AB - The in vitro antiproliferative effects, the in vivo toxicity profiles in mice and the antitumour activity in tumour bearing mice were screened for four novel di-n butyltin carboxylates, di-n-butyltin bis(2,4-dihydroxybenzoate) [compound 1 (C1)], di-n-butyltin bis(2,5-dihydroxybenzoate) (C2), di-n-butyltin bis(pentafluorophenylacetate) (C3), and bis[di-n butyl(pentafluorophenylacetato)tin] oxide (C4). All compounds revealed similar in vitro chemosensitivities in two cell lines, C26-10 and C26-A, two murine undifferentiated colon carcinoma cell lines. With all compounds tested, not only was cell growth inhibited in vitro, but also cell kill was achieved. At their maximum tolerated dose (MTD), C1 and C4 were inactive in vivo against colon 26 tumours in Balb/C mice when administered twice with one week interval (qd7x2 schedule). At their MTD, compound 2 (single dose administration and qd7x2 schedule) and compound 3 (qd7x2) showed slight in vivo antitumour activity with a ratio of the relative tumour size of the treated mice to that of control mice (T/C) = ca. 0.6 (T/C less than or equal to 0.6 being the cut-off level for sensitivity). However, the cut-off level for the growth delay factor (GDF) (>1) was not reached. With the exception of C2 administered with a single dose and C3 with the 2 doses protocol, treatment with these compounds did not increase the life span of the mice. Repeated administration of compound 2 did not improve the antitumour activity compared to single dose administration. This was probably due to the higher toxicity when C2 was administered a second time after one week. PMID- 21594419 TI - Breast cancer metastatic to the gastrointestinal tract. AB - The clinical course of patients with breast cancer is often protracted with metastases presenting a considerable time after initial diagnosis and surgical intervention. Whilst specific common patterns of tumour dissemination may be anticipated and readily recognised, more unusual sites may present with confusing symptoms seemingly unconnected to the breast primary. This report documents two cases of primary breast cancer metastatic to the gastrointestinal tract presenting to one surgical unit. PMID- 21594420 TI - Intraoperative measurement of peritumoral regional cortical cerebral blood flow. AB - Peritumoral regional cortical blood flow (rCoBF) was studied intraoperatively using thermal diffusion flowmetry. Histology included glioblastomas (n=5), anaplastic astrocytoma (n=1), pilocytic astrocytomas (n=2), metastatic melanoma (n=1), and trigeminal schwannoma (n=1). Pre-resection rCoBF values were low in all but two tumors where perfusion was in the low normal range. Post-resection rCoBF values were either low or normalized. Seizure activity was documented in a pilocytic astrocytoma with a significant rCoBF increase during resection. Our findings indicate that hypoperfusion in the cortex adjacent to malignant brain tumors is the result of primary metabolic failure and tumor pressure ischemia. PMID- 21594421 TI - Interaction between amphotericin B, carboplatin, and radiation in human osteosarcoma xenografts in nude mice. AB - In order to evaluate and modify the radiosensitizing effect of carboplatin, amphotericin B (AmB) was given as pre-treatment to nude mice with bilateral subcutaneous human osteosarcoma xenografts. One of the two tumours in each animal was irradiated with a single dose of 12 Gy following treatment with AmB (5 mg kg( 1)), or carboplatin (20 mg kg(-1)), or AmB (5 mg kg(-1)) plus carboplatin (20 mg kg(-1)), respectively. Tumour growth was compared with non-treated tumours. A significant reduction of tumour growth was observed after irradiation. Carboplatin in itself reduced tumour growth and also added to the effect of radiation. An unexpected interaction was seen where AmB obviously decreased the effect of either carboplatin or radiation alone or the two given concomitantly. The presented results are contradictory to some earlier in vitro studies and imply that the interactive effect in general and especially with regard to AmB can not be universally applied to all experimental situations. PMID- 21594422 TI - Antitumor effect of trimelamol against human breast carcinoma xenografts in nude mice. AB - The antitumor effect of N-2, N-4, N-6-trihydroxymethyl-N-2, N-4, N-6 trimethylmelamine (trimelamol), a synthetic analogue of hexamethylmelamine, was investigated using human breast carcinoma xenografts in nude mice. Four tumor models, T-61, Br-10, R-27 and MCF-7 were estrogen receptor (ER)-positive and their growth was estradiol-dependent. The MX-1 model was ER-negative and grew estradiol-independently. Sixty mg of trimelamol per kg dissolved in 5% dimethylsulphoxide (DMSO) with 5% glucose was administered intraperitoneally for 5 days weekly for three weeks. Trimelamol showed potent antitumor activity on T 61 and MX-1 in a dose-responsive manner with a marginal effect on Br-10, whilst R 27 and MCF-7 were insensitive to this agent. This antitumor spectrum on human breast carcinoma xenografts was similar to that of hexamethylmelamine previously reported using the same xenograft models. Trimelamol is water-soluble and does not require metabolic activation which is needed for hexamethylmelamine. These advantages allow the paraenteral administration of trimelamol, and warrant the further investigation of this drug for breast carcinomas. PMID- 21594423 TI - Detection of hepatitis B virus genome in hepatocellular carcinoma from both hepatitis B surface antigen- and antibody to hepatitis C virus-negative patients. AB - Twenty-two patients who tested seronegative for both hepatitis B virus (HBV) and hepatitis C virus (HCV) markers and undefined pathogenesis of hepatocellular carcinoma (HCC) were studied using polymerase chain reaction (PCR). Among these patients, 5 (23%) were positive for HBV-DNA in serum by PCR, but no patient was positive for HCV-RNA by reverse transcription PCR. Liver tissue specimens were available for analyzing HBV genome by PCR in 17 patients, and HBV sequences were detected in 10 (59%) patients. These results indicate that HBV is commonly implicated in serologically undefined pathogenesis of HCC in Japan. PMID- 21594424 TI - Azatyrosine is incorporated into proteins instead of tyrosine residues, with the resultant conversion of transformed cells to cells with a normal phenotype. AB - We reported recently that azatyrosine inhibits the growth of c-Ha-ras, c-raf or c erbB-2-transformed NIH3T3 cells and converts the transformed cells to cells with a normal phenotype. To analyze the mode of action of azatyrosine, we examined the effects of azatyrosine on the synthesis of macromolecules. Azatyrosine had no obvious inhibitory effects on the synthesis of DNA, RNA and protein in c-erbB-2 transformed cells. Furthermore, azatyrosine inhibited cell growth but did not interrupt the cell cycle at any specific stage. Thus, the mode of action of azatyrosine appeared to be different from that of typical anticancer drugs. Moreover, we found that azatyrosine was incorporated into proteins instead of tyrosine. The simultaneous presence of a high concentration of tyrosine inhibited the conversion to a normal phenotype of transformed cells by azatyrosine. These results strongly suggest that incorporation of azatyrosine into proteins might convert the transformed cells to cells with a normal phenotype. The analysis of azatyrosine-containing proteins by two-dimensional electrophoresis revealed that the mobilities of some proteins differed from those of the corresponding tyrosine containing proteins. An alteration in molecular structure of the proteins that include azatyrosine residues might be associated with the ability of azatyrosine to convert transformed cells to cells with a normal phenotype. PMID- 21594425 TI - Immunohistochemical study on sebaceous adenoma and sebaceous carcinoma arising in parotid gland. AB - The present study presents two cases of parotid mass diagnosed as sebaceous adenoma and sebaceous carcinoma in which immunohistochemical staining was performed for cytokeratins, vimentin, S-100 proteins, lactoferrin, lysozyme, alpha 1-antichymotrypsin, alpha 1-antitrypsin, and proliferating cell nuclear antigen to evaluate the characteristics of tumor cells and to distinguish these lesions from their counterparts in the skin. Sebaceous adenoma had circumscribed lobules containing sebaceous cell nests with well differentiated sebaceous cells surrounded by basaloid cells and a population of transitional cells. Sebaceous carcinoma had cellular pleomorphism and nuclear atypia and a population of cells resembling neoplastic myoepithelial cells of pleomorphic adenoma. The profile of markers used in the present study when compared with studies on sebaceous tumors of skin and the characteristics of other salivary neoplasms reasonably allowed us to conclude that the sebaceous differentiation and sebaceous tumors in salivary glands may differ from that of their counterparts in skin. The histogenesis of salivary sebaceous neoplasms may be attributable to the process of sebaceous metaplasia in the salivary tissues and based on our finding of similar immunohistochemical profile of sebaceous cells in sebaceous carcinoma with that of neoplastic myoepithelial cells in pleomorphic adenoma as reported earlier, sebaceous neoplasms may have a common histogenetic origin with other salivary neoplasms. However, their origin from the sebaceous glands normally present in the salivary tissues could not be excluded. PMID- 21594426 TI - Preparation and application of anti-HBx/anti-CD3 bispecific monoclonal antibody (BsAb) retargeting effector cells for lysis of human hepatoma xenografts in nude mice. AB - Evidence indicated that the x gene of human HBV can cause cancer in transgenic mice, moreover, HBxAg was so far the most frequent and strong antigen among those HBV markers expressed in hepatocellular carcinoma (HCC) tissues. Aiming to enhance killing of HCC by effector cells, we established an anti-HBx/anti-CD3 hybrid-hybridomas by fusion of anti-HBx hybridoma cells with FITC-labeled anti CD3 HAT sensitive cells, and followed by FACStar sterile cell sorting, HAT selection and eventually verified by ELISA and double bridging assay. Using two color cytometric analysis, we found that bispecific monoclonal antibody (BsAb) remarkably enhanced in vitro effector-target cell conjugates (48.3% vs. 8.5%). In in vivo study, BsAb retargeting effector cells were significantly more effective than that of effector cells alone in shrinkage of LTNM4 HCC xenografts (HBxAg positive) in nude mice, not only in fresh inoculated tumors but also in established tumors (p<0.01, p<0.01, respectively). Besides, pronounced apoptotic cell death and infiltration of lymphocytes in the peripheral of tumor nodules can also be witnessed in the tissues treated by BsAb plus effector cells, but not in the controls. The results demonstrated that antiHBx/anti-CD3 BsAb was able to redirect effector cells for lysis of HBxAg positive HCC cells both in vitro and in vivo and it also indicated that shrinkage of tumors in nude mice with therapy of BsAb retargeting effector cells was partially due to initiation of apoptotic cell death. PMID- 21594427 TI - Increasing incidence of non-Hodgkin's lymphomas in Sweden 1958-1992. AB - In recent years, there have been many reports from Europe and North-America describing non-Hodgkin's-lymphoma (NHL) as one of the most rapidly increasing malignancies. The reasons for this are poorly understood. This study describes the incidence pattern of NHL in Sweden during 1958-1992. A total of 26,925 cases (14,854 males and 12 071 females aged 15 years or older reported to the Swedish Cancer Registry between 1958 and 1992 were analysed. The increase in the age adjusted incidence during this period was 433% among men and 386% among women, a mean yearly increase of 3.6% in men and 2.9% in women. The highest rates were seen during the most recent years and in the oldest age group, although there was a clear trend with increased age-adjusted incidence over time in both the male and the female groups in ages over 35. The incidence was low in the ages below 35 years. Known etiologic factors including viruses, environmental exposures and immunosuppression of different types are discussed. It is concluded that there has been a true increase in the age-adjusted incidence of non-Hodgkin's lymphomas in Sweden during the years 1958-1992. PMID- 21594428 TI - Identification of a rearrangement in the 5' upstream region of the poly(ADP ribose) polymerase pseudogene on chromosome 13 in Ewing's sarcoma cells. AB - We have cloned a 3.0 kb SalI-Sau3AI fragment containing 5' upstream sequences of a human poly(ADP-ribose) polymerase (PARR) pseudogene from the Ewing's sarcoma (ES) cell line A4573. The nucleotide sequence of the entire cloned fragment has been determined. Nucleotide sequence homology and Southern hybridization analysis of a panel of human/hamster somatic cell hybrids allowed us to map the PARP 5' sequences to human chromosome 13. Because it has been reported that the duplication of a 193 bp within the PARP sequences on chromosome 13 results in a 2.7/2.5 kb HindIII restriction fragment length polymorphism (RFLP), defined as A/B allele polymorphism, and that an elevated B allele frequency has been proposed to be associated with predisposition to cancer, we have analyzed ES cell lines for the presence of PARR-linked polymorphisms on chromosome 13. Using a probe from the cloned 5' PARP sequences, we found that ES cells homozygous (A/A) and heterozygous (A/B) for the 2.7/2.5 kb HindIII RFLP also differ in the organization of the genomic region upstream of the PARP pseudogene sequences. HindIII fragments of about 6.3, 10.5 and 22.0 kb were detected in A/B heterozygous cell lines (A4573 and SK-ES-1), whereas the A/A homozygous TC-106 ES cells showed fragments of about 6.6, 11.0 and 24.0 kb. This novel rearrangement on chromosome 13 may provide an additional marker to investigate cancer predisposition in human populations. PMID- 21594429 TI - Could thymostimulin prevent hepatocellular carcinoma occurrence in patients with liver cirrhosis? AB - On the basis of a possible pathogenetic role of immunodepression in the development of hepatocellular carcinoma in patients with chronic hepatitis B/C viral infection and liver cirrhosis, we treated 34 liver cirrhosis patients (M/F 24/10; age: 14 pts less than or equal to 60 years, 20>60; Performance status: 22 0-1, 12 2-3; Childs' grade: 21 A, 13 B; ascites yes/not: 4/30) employing thymostimulin (TST), at the dosage of 50 mg/m(2) i.m. 3 times a week, until death or severe toxicity occurrence. Etiology of cirrhosis was viral in all cases. The patients were followed up every 3 months by means of clinical examination and biochemical analyses; every 6 months by checking viral serum markers, alpha fetoprotein and by means of ultrasounds. To date, 34 patients have been treated, with a median follow-up of 6 (1-8) years. No occurrence of hepatocellular carcinoma has been observed, with a statistically significant difference between observed and expected HCC (p<0.05). Thymostimulin treatment was well tolerated. Our data seem to suggest that the immunomodulating treatment could significantly reduce the risk of HCC occurrence in patients with liver cirrhosis. PMID- 21594430 TI - Expression of GalCer sulfotransferase by human uterine endometrial carcinoma cell lines. AB - We investigated the expression of sulfoglycolipids in several gynecological cancer cell lines by metabolic labeling with S-35-sulfate as well as the activity of GalCer sulfotransferase (ST) and arylsulfatase A (ASA), enzymes which are responsible for the synthesis and degradation of sulfoglycolipids. The endometrial carcinoma cell lines expressed sulfoglycolipids and showed ST activity, indicating that increased synthesis of sulfoglycolipids due to elevated ST activity is a characteristic of endometrial carcinoma that distinguishes it from other carcinomas. These cell lines could provide a useful model for studying the functions of sulfoglycolipids as well as biological properties of ST in cancer cells. PMID- 21594431 TI - Estrogen receptor expression and depressive mood disorders in untreated breast cancer patients. AB - Women newly admitted to hospital for suspect breast lump (99) were blind studied 5+/-3 days before diagnosis. Depression was evaluated by using DSM-III-R diagnostic criteria and MMPI psychometric test; estrogen receptor (ER) by DCC. High prevalence of depressive mood disorders and particularly of dysthymia were observed in patients with ER(-) tumors (p=0.03), that scored low in MMPI 9-Ma scale (p<0.001) and high in TA index (p=0.01) as expression of depressed mood. On the contrary ER(+) patients showed higher mean values in almost all the MMPI scales and indexes (AV p<0.01; AS p<0.03). In conclusion depressive mood have different prevalence in untreated breast cancer patients depending on ER status. PMID- 21594432 TI - Immunocytochemical analysis of MDM2 protein expression and its relevance to tumor angiogenesis in primary breast cancer. AB - MDM2 once-protein is known to be involved in the inactivation of p53 and RE functions. We have investigated the expression of MDM2 protein in breast cancer by immunocytochemical analysis. Out of 103 primary tumors 39 (38%) showed positive nuclear staining of MDM2, although its gene amplification was infrequent. There was no correlation between MDM2 expression and various clinicopathological factors. However, MDM2 expression was significantly associated with expression of angiogenesis factors including vascular endothelial growth factor and platelet-derived endothelial cell growth factor. Anti endothelial immunostaining demonstrated a correlation between MDM2 expression and the increment of intratumoral microvessel density. It is suggested that altered MDM2 protein expression might be involved in the promotion of angiogenesis in human breast cancer. PMID- 21594433 TI - Chemo-radiotherapy versus chemo-surgery in stage IIIA non-small cell lung cancer. AB - Forty patients with non-small cell lung cancer stage IIIA, aged 33-72 years were allocated to two groups in order to get therapy of two different combined modalities. All the patients were staged and considered inoperable. Staging was done by bronchoscopy, CT scan, bone scan and in patients with mediastinal lymph nodes less than 2 cm in size by thoracotomy. Group A patients were programmed to have induction chemotherapy and then radiotherapy while patients of group B to have induction chemotherapy, of the same kind as Group A and then surgery. Chemotherapy included cis-platinum 90 mg/m(2) given once every 3 weeks for 4-6 courses. Radiotherapy of Group A patients was 5000 cGy in the primary tumor site and mediastinum. Toxicity was tolerable. The following results were obtained: a) high response rate (over 70%) after chemotherapy, b) 66% of Group B patients were redered operable and c) the survival rate was significantly higher in patients with chemo-surgery versus those with chemo-radiotherapy. PMID- 21594434 TI - Immunohistochemical profile of phyllodes tumors of the breast. AB - The immunohistochemical profiles of 16 cases of phyllodes tumor of the breast (9 benign and 7 malignant) from 15 patients were examined by the labeled streptavidin biotin method. The expression of Ki-67, p53, bcl-2, alpha-smooth muscle actin (alpha-SMA), desmin, S-100 protein, estrogen receptor (ER), and progesterone receptor (PgR) was analyzed. The number of Ki-67-positive stromal cell nuclei of malignant phyllodes tumor were significantly more prominent than the benign tumors. The p53 expression on the stromal cell nuclei showed a significant difference between malignant and benign cases (86% vs 22%; p<0.05). bcl-2 was regularly seen on the luminal cell cytoplasm and stromal cell labeling showed no significant difference between malignant and benign cases (29% vs 33%). Stromal cells were alpha-SMA positive but refractory among cases, and desmin and S-100 protein were negative. PgR was expressed in all 16 cases and ER in most cases (12/16) the expression of which was restricted to luminal epithelial cell nuclei. These findings indicate that the Ki-67 labeling index and p53 expression in the stroma would be a good diagnostic parameter distinguishing benign tumors from malignant tumors. However, the absence of steroid receptor expression in stromal cells suggests the ineffectiveness of hormonal therapy for phyllodes tumor of the breast. PMID- 21594435 TI - Multiple primary bronchogenic carcinomas. AB - Multiple primary bronchogenic carcinomas (MPBCa) are extremely rare. The differentiation of a MPBCa from a pulmonary metastasis due to an extrathoracic neoplasm is sometimes difficult. We reviewed 324 pathologically proved primary pulmonary carcinomas and found six cases of MPBCa (1.9%). We herewith present the series and discuss the diagnosis of MPBCa. PMID- 21594436 TI - Branched-chain amino acid catabolism and cancer cachexia (review). AB - The present study focuses on the role of branched-chain amino acids (BCAA) (leucine, isoleucine and valine) in cancer cachexia. This is a frequent and devastating complication of cancer occurring in more than two thirds of patients who die with advanced cancer, and in up to 22% of cancer deaths it is the only abnormality found at autopsy. BCAA are essential amino acids often increased in cancer patients and this phenomenon may be related with increased protein degradation in skeletal muscle and consequently, cancer cachexia. The relevance of this association in medical terms is evident, future investigations may focus on therapeutical strategies based on the administration of BCAA to cachectic patients. PMID- 21594437 TI - Nuclear matrix of human nasopharyngeal carcinoma cells in culture. AB - Nuclear matrix is a scaffold-like structure of the nucleus after sequential treatments with detergents, DNase, and high salt buffers. Its involvement in various cellular activities has been emphasised in various studies. In this study, nuclear matrix of two human nasopharyngeal carcinoma cell Lines were compared and analysed in terms of their morphological appearance and electrophoretic patterns of proteins. The stability of nuclear matrices against enzymatic digestion was found to be similar in these two cell lines. However, cell line specific nuclear matrix proteins were detected in each cell line. The significance of these proteins in cellular function and oncogenesis will be investigated in due course. PMID- 21594438 TI - The relation between the aging of the steroid generating system and the geneses of cancers of the stomach, the breast and the uterine cervix. AB - The purpose of the present study is to test the validity of the steroid carcinogenesis hypothesis in humans by investigating the problem whether or not a cancer-specific change of the hormonal milieu emerges at a specified stage of life where the growth rate of cancer risk is at its zenith. A case-control study of 14 urinary steroid excretions was conducted for each of 3 human neoplasias. The identification and the size (in parenthesis) of the population units used in this study were,given as follows: a) the male gastric cancer group (421); b) the male control group (104); c) the female breast cancer group (245); d) the cervical cancer group (345); e) the female control group (127). Two kinds of steroid parameters were employed for the statistical analysis of hormonal data: a) the logarithm of a steroid excretion figure (mu g/day), as expressed by log x; b) the logarithm of a relative weight of a given steroid to tetrahydrocortisol, as expressed by log x/THF. The case-control difference for each parameter was expressed in terms of a t-value of Student's t-test. The steroid deviation profile was prepared for each neoplasia and for each of the log x data set and the log x/THF data set. The results obtained are as follows: a) the 2 steroid parameters (log x and log x/THF) for each of 14 urinary steroids were both subject to change with the progress of host age. The rate of age-dependent change was different for each steroid parameter and for each population unit. b) The above differential age dependency of the steroid parameters gave rise to a continual transition of the steroid deviation profile in the course of aging. c) The hormonal traits of male gastric cancer, female breast cancer and cervical cancer were described each as a complex of androgen depression and glucocorticoid stimulation (male gastric cancer), a sequential emergence of premenopausal progestin depression and postmenopausal predominance of glucocorticoid over androgen (female breast cancer), and a complex of androgen-glucocorticoid depression over progestin (cervical cancer). d) The emergence of the above cancer specific steroid disorders chronologically coincided with the quasiexponential growth phase of cancer risk (and slow growth phase of cancer risk in postmenopausal breast cancer). e) The usefulness of the log x/THF type deviation profile for the assessment of the hormonal milieu of the host was verified by both theoretical approach to the problem and its application to the real data of a case-control study. f) The age dependent decline of androgens was generally much faster in their progressions than that of glucocorticoids - a finding to suggest the possibility that the production of a cancer-specific steroid deviation profile might have taken the form of the stress shift of Hans Selye, since both phenomena share depletion of gonadal steroids relative to glucocorticoid in common. The etiological relevancy of the 3 cancer-specific steroid changes to the geneses of 3 cancers:was discussed in the light of the experimental pathology studies in our laboratory as well as in other laboratories. PMID- 21594439 TI - Enhancing effects of immunization with rectal extract on rectal carcinogenesis by local X-irradiation caused in male A/HeJ mice. AB - The influence of preimmunization with a rectal extract on X-irradiation rectal carcinogenesis in the rectum was investigated in male 4-7-week-old A/HeJ mice. They were given 20 Gy per week for a total 40 Gy in the pelvic region with or without 2 prior injections of rectal extract emulsified with complete Freund's adjuvant. Rectal adenocarcinomas were observed in 21 of 34 (62%) immunized animals and in 4 of 22 (18%) non-immunized mice 32 weeks after the last X irradiation (P<0.01). The total incidences of adenocarcinomas at the 84 week time point were 25/45 (56%) and 12/36 (33%), respectively (P<0.05). PMID- 21594440 TI - Vascular endothelial growth factor-121 mRNA expression and neomicrovessel density in primary lung cancer. AB - The correlation between vascular endothelial growth factor (VEGF)121 mRNA expression and microvessel density was examined in 42 cases of primary lung cancer. Microvessels in tumors were highlighted by staining endothelial cells for factor VIII, CD31, and BNH9. The microvessel density in a high VEGF121 expressing group was significantly greater than that in the low expressing group in the assessment with anti-CD31 antibody. The difference of survival stratified by the vessel density was significant in patients. with stage I disease. The results suggest a relationship between neomicrovessel density and VEGF121. VEGF121 may be a useful marker of the tumor neovascularization in lung cancer. PMID- 21594441 TI - Cystadenoma of the liver treated by hepatic resection. AB - The aim of this study is to report a case of cystadenoma in the liver and to discuss the difficulty of differential diagnosis from malignant tumor and the importance of complete resection of the lesion. The patient had epigastric pain and abdominal distension. Hepatic ultrasonography, abdominal CT, magnetic resonance imaging, and angiography showed the presence of a large cystic tumor occupying the right hepatic lobe indicating malignant cystadenocarcinoma. Needle biopsy of the cyst wall with sampling of the cyst fluid was performed, which revealed no malignant cells. However, CEA and CA19-9 were markedly elevated in the cyst fluid. A right trisegmentectomy via laparotomy was performed successfully. The resected tumor was 11.5x9x9 cm in size and weighed 1,240 g. The cut surface revealed the tumor with multiple cysts, in some parts of which large papillary projections into lumina were seen. Though the gross features were similar to those of cystadenocarcinoma, the final histological diagnosis was benign cystadenoma of the liver. The postoperative course was uneventful, and the patient is in good condition six years postoperatively without evidence of recurrence of the disease. PMID- 21594442 TI - Radiation enhancing effect of pentoxifylline. AB - In order to find radiosensitizers with low toxicity, radiation enhancing effects of the pentoxifylline (PENTO), which is known to bear so little toxicity as to be widely used for clinical purpose to improve peripheral blood circulation for vascular disorders, was compared with the nitroimidazole derivative SR 2508 (SR), which is an effective radiosensitizer but has severe neurotoxicity as do other nitroimidazole derivatives. We used an experimental tumor in mice and calculated an-enhancement ratio (ER) using a growth delay method. ER of PENTO and SR were 1.6 and 1.4, respectively, showing PENTO has stronger radiosensitizing effect than SR. Also combined effects with nicotinamide (NA) were compared between PENTO and SR. When combined with NA, the enhancing effects of PENTO was enhanced especially at lower radiation doses, whereas that of SR was decreased. Together with the fact that both PENTO and NA have very low toxicity, the usefulness of PENTO as a radiosensitizer either alone or combined with NA is suggested. PMID- 21594443 TI - Clinical characteristics and analysis of survival rate of breast cancer patients with a family history in Japan. AB - We compared the clinical characteristics and survival rate of 52 patients of unilateral breast cancer with family history (UFH) with 665 patients with no family history (UNFH). The distribution of clinical stage and histologic type were almost equal between two groups. The estrogen receptor-positive rate was significantly higher in UFH than UNFH. As for a disease-free survival, there was no difference, however, the overall survival seemed to be better in UFH than in UNFH. These results suggest that the survival of the UFH may depend on a higher incidence of estrogen receptor-positive cases because UFH responds well to hormonal treatment after relapse. PMID- 21594444 TI - Maintenance therapy with recombinant interferon alpha-2B (alpha IFN) in prognostically unfavourable aggressive non-Hodgkin's lymphomas (NHL). AB - Fifteen patients from a series of 37 consecutive patients with aggressive NHL who achieved a complete remission (CR) with first line chemotherapy were defined at high or high-intermediate risk of relapse according to International Prognostic Risk Index and were treated with alpha IFN as maintenance therapy for two years. After a median follow-up of 62 months only 3/15 patients (20%) relapsed and 2/15 (13.3%) died in the alpha IFN treated group, favourably comparing with the expected relapse and death rate in that setting; on the other hand 40.9% of 'low risk' patients from the same series, who did not receive alpha IFN, had relapsed. alpha IFN maintenance therapy appears to result in prolonged response duration and survival in patients with aggressive and prognostically unfavourable NHL. PMID- 21594445 TI - Nuclear matrix protein composition of human lung carcinoma cell lines. AB - The nuclear matrix is the RNA-protein skeleton within the nucleus that contributes to the structural and functional organization of DNA. Differences in the nuclear matrix protein composition between cancer and normal cells have been reported in various cell lines and tissues, suggesting altered gene expression. This study examined the nuclear matrix protein composition of various human lung cell lines. Using high resolution two-dimensional electrophoresis, at least ten common proteins, as well as specific differences, were identified in each category of lung cell lines. These protein differences may be responsible, at least in part, for the different phenotypes of human lung cancer. PMID- 21594446 TI - INK4 genes in pancreatic carcinoma. AB - The INK4 family includes the structurally and functionally related p15, p16 and p18 genes. in vitro they arrest the cell in G1 phase, thus far in an apparently similar manner. It is not clear yet how their functions relate in vivo, whether these genes have distinct or redundant functions. The INK4 genes are thought to be candidates for tumor suppressor genes. The p16 gene has been found to be inactivated in many tumor types, usually by homozygous deletion. In most tumors it was noted that the deletions involve the neighboring p15 gene as well, thus it was not clear whether these inactivation events targeted p16, p15, or both genes. p16 was also found to be inactivated by intragenic mutations in 40% of pancreatic carcinomas; these cancers provide a unique opportunity to test whether p16 and p15 must both be inactivated during tumorigenesis. If p15 were a second target at chromosome 9p, it would be predicted to be inactivated in at least some of these tumors. In addition to studies of the p15 gene in these pancreatic cancers, we assayed for mutations in the p18 gene, which offered a third, independent site to infer possible redundant functions of the INK4 proteins. Sequence analysis indicated that p15 and p18 were not targets of inactivation in pancreatic carcinoma. p16, therefore, plays a different role in vivo, since inactivation of only this gene had proven to confer a selective growth advantage to evolving clones of pancreatic tumor cells. The preference for homozygous deletions as a means to inactivate p16 remains unexplained. PMID- 21594447 TI - Adjuvant levamisole and fluorouracil in high risk colorectal cancer patients. AB - Adjuvant chemotherapy in colorectal cancer patients is aimed at decreasing the relapse rate of the disease and increasing the disease-free and the overall survival of the patients. In a prospective study we evaluated the efficacy of 5 FU plus levamisole as an aduvant therapy for 153 patients with Dukes' B-2 or C colon or rectal cancer following a curative-intended surgery. Adjuvant chemotherapy was started within 4 to 6 weeks following the operation. Combination of 5-FU 375 mg/m(2)/day was given intravenously over 15-20 min for 5 consecutive days, every month for 1 year. Levamisole 50 mg t.i.d. was administered orally during the first 3 days of each course of chemotherapy. Rectal cancer patients were also irradiated to the tumor bed and pelvic lymphatics. The dose intensities (DI) of 5-FU and levamisole in our study were 432.6 mg/m(2)/w and 103.8 mg/m(2)/w, respectively. Failure analysis in Dukes' B and C patients showed that the rectum accounted for 47.5% of the relapses, of which only 3 cases were in the vicinity of the resected area. Almost half of the failures were observed within the year of adjuvant treatment. The liver was the most common site for first relapse (50%). The 3-year disease-free survival of Dukes' B-2 patients group was 84%, compared with 64% in Dukes' C. The main toxic manifestations were diarrhea, nausea and vomiting, weakness and mucositis. No dose reduction was needed. Our protocol, using lower DI of levamisole yielded similar results with a lower rate of toxicity than other common protocols. PMID- 21594448 TI - Primary isolated epithelioid hemangioendothelioma of a lumbar vertebra. AB - Epithelioid hemangioendothelioma is a rare vascular tumour which occasionally occurs in bone. It presents predominantly as multifocal lesions in young males and is frequently misdiagnosed as metastatic carcinoma. We describe a case presenting as a solitary vertebral lesion in a 48-year-old female, which was initially misdiagnosed as a carcinoma and which responded well to radiotherapy. PMID- 21594449 TI - Increased expression of insulin-like growth factor 1 (IGF-1) in multinodular non toxic goiter. AB - Thyroid cell growth and function both in vivo and in vitro, are mainly regulated by TSH. Recent studies have shown that growth factors including insulin-like growth factors (IGF-1) have an important role in the control of thyrocyte proliferation and differentiation. The aim of this study was to evaluate the expression of the IGF-1 gene by Northern analysis and the IGF-1 tissue protein by radioimmunoassay in multinodular euthyroid goiters. The study population consisted of 20 patients with multinodular goiter (14 females and 6 males) living in a non endemic geographic area. All patients were euthyroid at the time of surgery and submitted to total or subtotal thyroidectomy. Samples of normal thyroid tissue were obtained from three patients who were operated due to laryngeal carcinomas. The IGF-1 protein content was increased in non toxic multinodular goiter, 22 ng/g vs. 14 in controls (p<0.03), as was IGF-1 gene expression (p<0.05). The increase in the steady state mRNA content correlated with the increase in the protein content (r=0.665; p<0.005). These results suggest that IGF-1 may play a role in proliferation events involved in benign hyperplastic thyroid diseases. PMID- 21594450 TI - pS2 protein detected by immunohistochemistry in archival primary breast cancer. AB - It has been proposed that pS2 protein in breast cancer provides information on the individual prognosis and biological properties of the tumor with respect to response to endocrine treatment. In this retrospective study the pS2 protein expression was detected by immunohistochemistry in formalin-fixed, paraffin embedded breast cancer sections from 219 patients with primary breast cancer. The data were compared with patients' age, disease stage and tumor grading tumor estrogen and progesterone receptor status, disease-free interval and overall survival. Documented follow-up of up to 138 months with a mean of 69 months was analysed. 54% of the tumors were pS2-positive. There was a significant positive correlation with steroid receptor content. There was no correlation of pS2 with patient age, staging or grading pS2 could not contribute more prognostic information beyond steroid receptor status or axillary lymph node involvement. Survival analysis of the pS2-positive and negative. tumor patients failed to show a significant difference. PMID- 21594451 TI - Current trends in the treatment of advanced non-small cell lung cancer (Review). AB - Several advances have been made in the treatment of advanced non-small cell lung cancer in the last few years. Combined modality therapies utilizing chemotherapy have improved survival of patients with locally advanced disease (stage III) when compared to either radiation or surgery alone. New chemotherapeutic agents, used alone or in combination, have also made a strong impact in patients with metastatic disease (stage IV). Ongoing randomized trials will certainly define new treatment standards and hopefully improve the outcome of patients with advanced non-small cell lung cancer. PMID- 21594452 TI - Influence of Schistosoma mansoni infection on carcinogen-metabolizing capacities and in vitro aflatoxin B-1 metabolism in human liver. AB - It is well known that schistosomal infection and food contamination with aflatoxins caused marked histopathological changes in human liver. This study demonstrates the influence of Schistosoma mansoni infection on the capacity of drug-metabolizing enzymes and in vitro aflatoxin B-1 metabolism in human liver. Clinical data showed an increase in alkaline phosphatase, alanine and aspartate aminotransferase by 82, 74 and 100%, respectively. The activity of NADPH cytochrome C reductase and cytochrome P-450 content were significantly decreased in the liver of schistosomal patients by 70 and 52% respectively. The cytochrome b-5 content was also decreased by 61%. Aflatoxin B-1 tris-diol could not be detected using the microsomal fractions of the schistosomal group relative to the control group. The content of aflatoxin Q(1) metabolite produced by microsomal fractions of schistosomal patients increased by 308%. There was no difference in the formation of aflatoxin M(1) between the two groups. These observations indicate that Schistosoma mansoni infection might potentiate the deleterious effects of environmental carcinogens. PMID- 21594453 TI - Severe musculoskeletal pain after cyclosporin A treatment in a patient undergoing allogeneic BMT. AB - Allogeneic BMT was performed in a 33-year-old man because of CML. Donor was his HLA-identical brother. GVHD prophylaxis consisted of short-term MTX and i.v. CsA. On day 17 cutaneous GVHD grade-III developed and high-dose methyl-prednisone was added. Initial daily dose of CsA was 4 mg/kg i.v. CsA dosage was adapted to maintain blood trough levels between 200 and 350 ng/ml. On day 27 the patient developed severe musculoskeletal pain of knees, legs, feet, hands, shoulders and ellbows. Only high-dose opioids and dextropropoxyphen were effective for analgesia. Additional medication besides CsA consisted of parenteral nutrition, steroids and antibiotics for total intestinal decontamination. Clinical and radiological examinantion revealed no causes for musculoskeletal pain. Serum levels for lactate-dehydrogenase, aldolase, alkaline-phosphatase, creatinphosphokinase with isoenzymes, electrolytes including magnesium were within normal ranges. Pain decreased within 4 days after switching, from intravenous to oral application. This case indicates that CsA in high dosage given intravenously combined with steroids can cause severe musculoskeletal pain as side effect in allogeneic BMT. PMID- 21594454 TI - Radiotherapy costs in glioblastoma. AB - This study reveals the cost of radiotherapy (54 Gy or 39 Gy) in glioblastoma in northern Norway 1987-92. 29 patients were registered, 9 patients (group 1) and 10 patients (group 2) received 54 Gy and 39 Gy, respectively. The total treatment costs were registered according to the 1994-prices. The median survival in group 1 and group 2 was 12 months and 7 months, respectively. The cost effective analysis revealed a treatment cost of pound 4.858 per year saved. A cost utility and a sensitivity analysis is included. The prolonged treatment looks cost effective only when performed in an outpatient setting and the survival benefit is >2 months. PMID- 21594455 TI - Prognostic implications of P-glycoprotein, epidermal growth factor receptor and transforming growth factor alpha. AB - The prognostic value of clinical and pathological factors in 97 patients (pts) with non-small cell lung cancer (NSCLC), were analyzed through immunohistochemical methods. The impact on response rate and survival of age, Karnofsky performance status (PS), sex, NSCLC subtype and grade, extent of disease, objective chemotherapy response, LDH values, metastatic sites involved and immunohistochemical study of epidermal growth factor receptor (EGF-r), transforming growth factor alpha (TGF-alpha) and P-glycoprotein (Pgp) employing two monoclonal antibodies: C-219 and JSB-1, were analyzed. Median age was 61 years, seven pts were women. Histologically, 58 had squamous cell carcinoma, 28 adenocarcinoma and 11 large cell undifferentiated carcinoma. One patient had stage II, 35 stage IIIA, 19 stage IIIB and 42 stage IV. Six pts achieved complete response, 18 partial response, 34 stable disease and 39 progressive disease. EGF r was positive in 30 cases, TGF-alpha in 51, C-219 Pgp in 13 and JSB-1 Pgp in 35 cases. The univariate analysis showed that 4 parameters had significant adverse effect on survival: non-responders, poor PS, abnormal LDH value and absence of EGF-r expression. On the other hand, we found no correlation between TOP-alpha and EGF-r immunostaining. But 22 pts expressed both autocrine markers and these pts had a worse median survival time. Multivariate analysis showed that the only independent prognostic factor in predicting survival was Karnofsky performance status. PMID- 21594456 TI - Quality of life (QoL) measurement in economical analysis in cancer. AB - In health economy, the measure of quality of life (QoL) is essential in cost utility analysis. The most common utility measure is the quality-adjusted-life year (QALY) combining the benefits of survival and QoL during the survival period. Health authorities have to take priority decisions. These should not be founded on differences between choices caused by method chosen. A study on 98 cancer patients (42 Hodgkin's disease, 56 colorectal cancer) was performed to clarify the consistency of three QoL-instruments [EuroQol questionnaire, simple QoL-scale, global QoL-measure (EORTC QLQ-C30)]. The three instruments were significantly correlated (p<0.001). Cost-utility analysis employing one of the three instruments are comparable. PMID- 21594457 TI - Dysfunction of the E-cadherin/catenin cell adhesion cascade in epithelial cancers (Review). AB - The E-cadherin/catenin complex is the major adhesion system that maintains the intercellular contacts in all epithelial cells. E-cadherin mediates Ca++ dependent, homotypic cell-cell adhesion and associates with the cytoskeleton through the interaction with three cytoplasmic proteins, called catenins. Dysfunction of the E-cadherin/catenin complex occurs frequently in the epithelial cancers and is correlated with dedifferentiation, advanced stage and poor prognosis. Additionally, loss of E-cadherin and alpha-catenin expression in epithelial cells in vitro, is associated with fibroblastic morphology and increased invasiveness. E-cadherin and alpha-catenin might be regarded as tumor suppressor molecules with potential diagnostic and prognostic value in epithelial cancers. PMID- 21594458 TI - Malignant fibrous histiocytoma of bone - Review of thirteen cases. AB - Malignant fibrous histiocytoma of bone (MFHB) constitutes 0.5-8% of all malignant primary bone tumours. It has a poor prognosis when treated with surgery alone. Chemosensitivity of this tumour entity with increased disease-free survival rates has been reported. We reviewed the treatment of patients with MFHB at Hannover University Medical School since 1982. Thirteen patients were diagnosed with MFHB, nine had localized and four metastatic disease. All patients have been treated with surgery, except two patients who received radiation treatment. Additionally, eleven patients underwent different chemotherapy regimens mainly including anthracyclines in neoadjuvant (n=5) or palliative (n=6) settings. At a median follow up of 35 months (range, 14-134+) six patients (46%) are alive and four of these patients have no evidence of disease (31%). This report confirms the chemosensivity of MFHB and neoadjuvant treatment approaches may be warranted in these patients. PMID- 21594459 TI - Hepatocyte growth factor induces tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin and enhances cell-matrix interactions. AB - This study examined the effects of hepatocyte growth factor/scatter factor (HGF/SF) on the adhesion of HT115 (human colon) and MDA MB 231 (human breast) tumour cells to an extracellular matrix, Matrigel, together with the tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin. Treatment of cells with HGF increased cell adhesion to matrix. Following adhesion to Matrigel, FAK and paxillin were quickly phosphorylated and located to the focal adhesion area. HGF/SF increased both tyrosine phosphorylation of FAK and paxillin and also increased formation of focal adhesion. HGF also induced an increased spreading on matrix. It is concluded therefore that HGF/SF stimulated FAK and paxillin phosphorylation resulting in an increased tumour-matrix adhesion. PMID- 21594460 TI - Different expression of Bcl-2 in diffuse and intestinal type stomach carcinomas. AB - The aim of the present study was to examine immunohistochemically the expression of Bcl-2 in stomach carcinomas in relation to the clinical staging of the patients. Staining with a monoclonal antibody against Bcl-2 was positive in 60% of the 40 investigated carcinomas. A significant difference in staining patterns could be demonstrated, as 87% of the intestinal type tumors and only 44% of tumors of the diffuse type showed positive staining. No specific relation was observed concerning pTNM staging or tumor grading. Four investigated stomach carcinoma cell lines showed strong positive staining. We conclude from our results that the expression of Bcl-2 is a common phenomenon in stomach carcinomas, where it is related to more differentiated tumors, but its detection seems of no direct value for clinical staging of the patients. PMID- 21594461 TI - Improved detection of chromosome 16 rearrangements in acute myeloid leukemias using 16p and 16q specific microdissection DNA libraries. AB - DNA libraries of the human chromosome arms 16p and 16q have been constructed by means of microdissection for the use of fluorescence in situ hybridization (FISH) analysis of rearranged chromosome 16 in acute myeloid leukemia. FISH with differently labeled chromosome 16p and 16q arm-specific libraries on normal metaphase spreads resulted in bright painting signals on both arms of chromosome 16, each stained in a different color. Hybridization on bone marrow samples of acute leukemia patients having a pericentric inversion of chromosome 16 showed on one chromosome 16 the presence of q-arm specific material on the p-arm adjacent to the centromere and vice versa, resulting in an alternating red-green-red-green colored chromosome pattern in the FISH analysis. PMID- 21594462 TI - Diagnostic pitfalls of echography in a case of hepatic cavernous hemangioma. AB - An ecographic study of the liver in a 55-year-old female, with a history of mastectomy for a breast ductal cancer, showed multiple focal lesions. On computer tomography, we interpreted these lesions as metastatic disease. 99m Tc-labeled RBC showed non-homogeneous flow distribution in the right lobe of the liver. Fine needle aspiration biopsy under ecographic guidance showed no metastatic disease, and suggested a vascular lesion. The presence of spindle-shaped cells, reactive for CD 34 and for factor VIII, enabled definitive diagnosis of angiomatous lesion. Cytological confirmation of each hepatic mass is a mandatory prerequisite for any therapy. PMID- 21594463 TI - Accumulation of products of lipid peroxidation in spontaneous liver tumors of C3H/HeN mice. AB - To study the implication of oxidative stress in liver tumors, quantitative analysis of products of lipid peroxidation, which are reactants of 2 thiobarbituric acid (TEA) in the TEA method, was carried out in both neoplastic and intact liver tissues of C3H/HeN mice. All liver tumors were derived spontaneously at the age of 15-18 months. We found that TEA value in neoplastic foci was increased about 10-fold higher than that in intact liver counterparts. Moreover, antioxidant activities such as catalase, glutathione peroxidase and superoxide dismutase were all decreased in neoplastic foci in comparison with those in respective intact liver counterparts. We also established a histochemical method to detect peroxides and applied this method to the liver tumors. Peroxides were stained abundantly in the vacuolated cells of neoplastic foci. Fragments of condensed peroxides were occasionally seen in some vacuolated cells. Therefore, peroxide staining described here should be useful to identify the localization of peroxides in the tissues. PMID- 21594464 TI - Peoscopic diagnosis of flat condyloma and penile intraepithelial neoplasia V scrotal reservoir. AB - The aim of the present study was to evaluate prospectively male sexual partners of women with flat condyloma (FC) or accuminata (CA) or cervical intraepithelial neoplasia (CIN) and to determine the incidence of scrotal involvement by HPV. Of the 218 patients, 20 (9.17%) revealed areas of acetowhite epithelium involving the anterior lateral and superior aspects of the scrotum. Eight patients (40%) also presented concomitant small telangiectatic lesions measuring 1-3 mm of the scrotum in the acetowhite areas, and one patient presented scrotal intraepithelial neoplasia grade I (SIN I). The new combination treatment schedule (cream 5-fluorouracil 5% + Interferon alpha-2 alpha) resulted in a 100% cure rate, with no recurrences for the follow-up period (11.52 months). Concluding, the scrotum appears to be an important and presently overlooked area in the evaluation of male patients, and interferon in combination with 5-FU cream seems to be a promising treatment for HPV infection. PMID- 21594465 TI - p53 as tumor marker for the early detection of reincidence in lung cancer. AB - To examine the p53 expression in cancer development, we studied the case of a 59 year-old male suffering from squamous cell lung cancer. He was submitted to surgery for resection of the tumoral mass. Through immunoblot and immunohistochemical analysis, the tumor fragment was shown to bear p53 and hsp70 accumulation not detected in the normal lung tissue sample. Six months later, immunohistochemical analysis of a biopsy sample taken from the previous tumor site showed p53 accumulation. Considering the high specificity for p53 detection (100%), this result suggests probable tumor reincidence, not detected by the ordinary H&E staining. PMID- 21594466 TI - Fluorescence in situ hybridization (FISH) for evaluating residual disease in Philadelphia chromosome-positive chronic myeloid leukemia during interferon alpha therapy. AB - Fluorescence in situ hybridization (FISH) is a quantitative technique which allows, by means of specific probes, to detect the t(9;22) translocation typical of chronic myeloid leukemia (CML) hematopoietic cells. We have evaluated FISH on interphase nuclei as a method for assessment of residual disease in bone marrow samples from 5 Philadelphia chromosome positive (Ph(+)) CML patients after 12 months therapy with interferon alpha; results were compared with findings obtained by conventional cytogenetics and by polymerase chain reaction (PCR). Our data indicate that FISH is more sensitive than cytogenetics for evaluation of residual disease, being positive in 1 out of 2 cases scored as Ph negative by cytogenetics, but is less sensitive than PCR which turned out to be positive in all patients. As additional advantage over conventional cytogenetics, FISH on interphase nuclei can be performed also on samples lacking metaphases or having poor chromosome spreading or unsatisfactory chromosome banding. PMID- 21594467 TI - How practice patterns in lung cancer patient follow-up are affected by surgeon age. AB - Strategies for the follow-up of lung cancer patients after potentially curative treatment are known to vary widely. The optimal regimen remains unknown. We investigated whether the age of the surgeon affects choice of surveillance strategy. The 3,700 members of the Society of Thoracic Surgeons (STS) were surveyed using a detailed questionnaire to measure how these surgical experts deal with lung cancer patient follow-up. Subjects were asked how they use 10 specific follow-up modalities during years 1-5 following primary treatment for patients with lung cancer (TNM stages I-III). Repeated-measures analysis of variance was used to compare practice patterns by surgeon age, as well as by TNM stage and year post-surgery. Evaluable responses from 768 STS members (21%) were received. Follow-up strategies for most of the ten modalities were highly correlated across TNM stages and years post-surgery, as expected. The pattern of testing varied significantly by surgeon age for only one modality (LFTs). Even in this instance, the absolute differences in surveillance strategies among age groups were small. This analysis indicates that the post-treatment surveillance practice patterns of surgeons caring for patients with lung cancer do not vary substantially with practitioner age. The data provide credible evidence that post graduate education is effective in homogenizing practitioner behavior. PMID- 21594468 TI - Le(b), a novel glycosphingolipid antigen of human distal colorectal cancer. AB - The expression of the glycosphingolipid antigens was investigated in human colorectal carcinomas and adjacent normal tissues obtained by surgical operation from six patients. The glycosphingolipids, including both non-acidic glycolipid and ganglioside, were extracted from the tissue specimens and separated by two dimensional thin-layer chromatography of silica gel. A novel neutral glycolipid antigen migrating lower than Le(a) blood group antigen was detected in the cancerous tissues of all six patients, but not in normal regions in the same patients. The structure of the glycosphingolipid was partially characterized by gas chromatography and gas chromatography/mass spectrometry of alditol acetate and negative ion fast atom bombardment mass spectrometry (FAB/MS) of the intact glycolipid, and TLC-immunostaining with monoclonal anti-Le(a), -Le(b), -sialyl Le(a), and -Le(Y) antibody, respectively. The novel neutral glycosphingolipid in colorectal cancer was identified to be the III(4)IV(2)Fuc(2)Lc(4)Cer, Le(b) antigen of the human Lewis blood system. Direct FAB/MS showed the ceramide was composed mainly of 2-hydroxy tetradecanon and C18 phytosphingosine. In such individuals, the expression of Le(b) antigen in normal tissues is absent or minimal. Based on this study, we suggest that this Le(b) antigen may be a human distal colorectal cancer-associated antigen, which will be helpful for diagnosis and treatment of distal colorectal cancer. PMID- 21594469 TI - Prediction of the effect of 5'-deoxy-5-fluorouridine by the status of angiogenic enzyme thymidine phosphorylase expression in recurrent breast cancer patients. AB - The anti-cancer drug, 5'-deoxy-5-fluorouridine (5'DFUR) is known to have antitumor activity through the conversion to 5FU by thymidine phosphorylase (TP). Recently, TP was demonstrated to be identical to angiogenic molecule platelet derived endothelial cell growth factor (PD-ECGF) by cDNA cloning and subsequent biochemical analyses. We have examined the relationship between the clinical response of 5'DFUR and TP/PD-ECGF expression determined by immunocytochemical analysis in 24 recurrent breast cancer patients. Of 24, 13 were TP/PD-ECGF positive and 11 were TP/PD-ECGF negative. In 13 TP/PD-ECGF positive patients, 4 showed objective response (OR) and 3 showed stable disease (SD) with 5'DFUR treatment, however only one case showed OR and no case showed SD in 11 TP/PD-ECGF negative patients, suggesting that 5'DFUR was likely to be effective for TP/PD ECGF positive patients. In another group of recurrent breast cancer patients treated by adriamycin containing regimen, no significant correlation was observed between the response of 5'DFUR and the status of TP/PD-ECGF expression. It was indicated that an angiogenic enzyme TP/PD-ECGF expression might be a predictor of the effect of 5'DFUR treatment in human breast cancer. PMID- 21594470 TI - Second line chemotherapy for metastatic colorectal carcinoma. AB - 25 patients with metastatic colorectal carcinoma previously treated with 5 fluorouracil and folinic acid for advanced disease, were treated with mitomycin C 8 mg/m(2) i.v. bolus on day 1, adriamycin 40 mg/m(2) i.v. bolus on day 1, and lonidamine 150 mg per os t.i.d. starting one day before chemotherapy and stopping 2 days after the end of chemotherapy. Treatment was repeated every 4 weeks. All patients had previous surgery and systemic chemotherapy with 5-fluorouracil and folinic acid given as first line chemotherapy for metastatic tumor. Sites of disease included liver, lung, nodes, abdomen, and bone. All enrolled patients were evaluable for objective response. Only one patient, affected by rectal carcinoma, showed a partial response (4%) which lasted 5.8+ months. No complete response was seen. Stable disease was recorded in 4 cases (16%) with a mean duration of 4.6+ months. All remaining patients had progressive disease. Median overall survival was 8.7+ months. Toxicity was significant. Grade 3 thrombocytopenia was seen in 8 cases (32%), and grade 3 leukopenia in 5 cases (20%). Grade 3 vomiting was observed in 9 patients (36%). The combination of mitomycin C, adriamycin and lonidamine is not effective in the treatment of metastatic colorectal adenocarcinoma resistant to 5-fluorouracil-based chemotherapy. These data suggest that lonidamine is not able to potentiate antineoplastic activity of chemotherapeutic drugs in humans and its use in colorectal cancer should be avoided since it has no or little impact on response rate and survival. PMID- 21594471 TI - Pleurectomy, intrapleural cisplatin and interferon followed by systemic carboplatin plus interferon in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma has a dismal prognosis and median survival rarely exceeds 12 months. Since multimodality therapy initially showed promising results, we tested the feasibility of a new approach consisting of pleurectomy, immediately followed by intrapleural chemotherapy with cisplatin (100 mg/m(2) day 1) and alpha-interferon (12x10(6) U/m(2) days 1 and 2), followed by 4 cycles of carboplatin, 350 mg/m(2), repeated every 3 weeks and associated to alpha interferon (3x10(6) U/x3/week). Fourteen patients have been submitted to the protocol and are evaluable for side effects. All patients had surgery and intrapleural chemotherapy, and 4 patients also had systemic chemotherapy. No treatment-related deaths have been observed. Major postoperative complications included chest tube air leak >7 days (1 pt). Intracavitary chemo-immunotherapy related toxicity was responsible for 7 cases of grade I nephro-toxicity and 2 cases of grade I fever. Grade I-II toxicity from systemic chemotherapy included asthenia (2 cases), fever (3 cases), anemia (2 cases) and neutropenia (2 cases). Grade III-IV toxicity included asthenia (1 case), anemia (2 cases), neutropenia (2 cases) and fever (1 case). Two cases required interruption of systemic chemotherapy for intolerance. Based on these data, systemic chemotherapy has been stopped. In conclusion, our results indicate that pleurectomy plus intra-cavitary cisplatin and interferon is feasible. Since systemic chemotherapy is correlated with severe side effects, a phase II trial with surgery plus intrapleural treatment alone is ongoing. PMID- 21594472 TI - Good response of glioblastoma in a child with sickle cell anemia supports the therapeutic potential of tumor infarcting agents. AB - A number of anti-angiogenesis and thrombosing agents are in development for the treatment of a range of cancer types. However, there are few clinical data to support this approach. We reviewed our experience with a child with sickle cell anemia and glioblastoma multiforme to look at a possible contribution of sickling and therefore vascular infarction on tumor control. A 3 1/2-year-old girl with sickle cell anemia, developed a cerebral glioblastoma multiforme. She received 5 cycles of ifosfamide and etoposide as well as 54 Gy local irradiation. Follow-up was monitored with serial MR scans. Four and a half years from diagnosis the child is neurologically normal and has no radiographic evidence of tumor. While we cannot say whether this child did well by chance alone, we hypothesize that local sickling with resultant tumor infarction may have been a factor in her unexpectedly good outcome. Her course lends anecdotal support to the notion that small vessel infarction can play a therapeutic role in the management of solid tumors. PMID- 21594473 TI - Feasibility of intra-arterial chemotherapy followed by chemoembolization, every 28 days, in unresectable hepatocellular carcinoma. AB - Encouraging response rates and survival have been reported with intra-arterial (i.a.) chemotherapy and chemoembolization, but limited data are available on the association of the two treatment modalities. We therefore started a feasibility study of i.a. chemotherapy plus chemoembolization, performed every 28 days for 3 cycles, according to the following schedule: L-leucovorin (100 mg/m(2) i.v.), fluorouracil (800 mg/m(2) i.a.), and carboplatin (250 mg/m(2) i.a.). Chemoembolization with mitoxantrone (10 mg/m(2)) plus ethiodized oil was performed immediately after this treatment, followed by gelatin powder. Fourteen patients entered the study and were evaluable for side effects. Main patient characteristics were: males 13, females 1; median age 65 yr (range 45-75); stage TNM II-III 10, IVA 4; Childs' A 8, Childs' B 6; elevated baseline alpha fetoprotein, 11; cirrhosis 14. No drug-related deaths have been observed. Ten patients were able to complete the program. The reasons for discontinuing treatment were worsening of liver functions in 3 cases and grade IV neutropenia in 1 patient. Eight patients had grade I-II pain and 10 patients had grade I-II fever. In conclusion the study demonstrated that chemoembolization plus i.a. chemotherapy is feasible in patients with hepatocellular carcinoma in cirrhosis and deserves further investigation. PMID- 21594474 TI - c-erbB-2 and common prognostic factors in breast cancer patients. AB - We report data on c-erbB-2, hormone receptors, and Ki-67 proliferation associated antigen in ninety-seven unselected breast carcinoma specimens. Immunohistochemical results and clinical data (age, axillary nodal involvement, menopausal status, tumor size) were compared. Positivity for c-erbB-2 staining was detected in the 46% of tumors. There was no correlation among c-erbB-2 status and age, menopausal status, tumor size, lymph nodes involvement or Ki-67 index. An inverse relationship of c-erbB-2 and estrogen and progesterone receptor status was detected, although not statistically significant. Increased levels of c-erbB 2 were observed in 40-50% of all the subsets of patients grouped on the basis of established prognostic factors. These higher levels could lead to the identification of further subsets of patients at higher risk of relapse. However, at present, the role of c-erbB-2 for clinical management of patients with breast cancer remains unclear. PMID- 21594475 TI - The von-Hippel-Lindau (VHL) tumor suppressor gene is not mutated in sporadic ovarian carcinomas. AB - The von Hippel-Lindau (VHL) tumor suppressor gene has been shown to be mutated frequently not only in neoplasms from von Hippel-Lindau disease, but also in sporadic clear cell renal carcinoma. In order to reveal the possible role of the VHL tumor suppressor gene in the development of ovarian carcinoma, a total of 71 primary sporadic ovarian carcinomas were analyzed for the presence of mutations in the exon 2 and 3 of the VHL tumor suppressor gene, using the polymerase chain reaction with single strand conformation polymorphism analysis. No mutations in the VHL gene were found in any of the tumors analyzed. This result shows that the VHL tumor suppressor gene does not play a major role in the tumorigenesis of sporadic ovarian carcinoma. PMID- 21594476 TI - Serum levels of soluble receptors for tumor necrosis factor (p55 and p75 sTNFr) in patients with cervical cancer. AB - The pretreatment serum levels of the soluble receptors for tumor necrosis factor (p55 and p75 sTNFr) were retrospectively measured in 54 patients with cervical cancer and in 55 patients with benign uterine disease as controls. Serum mean (+/ standard deviation) concentrations of both p55 and p75 sTNFr were higher in patients with cervical cancer than in controls (2.6+/-1.3 vs 1.9+/-0.7 ng/ml, p<0.0001, and, respectively, 7.8+/-4.3 vs 5.9+/-3.0 ng/ml, p=0.009). Both receptor levels were significantly higher in patients with stage IIb-IV than in those with stage I-IIa cervical cancer or with cervical intraepithelial neoplasia (CIN) 3. Among the 31 patients with stage I-IIa disease who underwent initial surgery, the preoperative serum p55 and p75 sTNFr values correlated neither with the common prognostic variables nor with the clinical outcome. In conclusion, serum p55 and p75 sTNFr levels are significantly elevated in patients with cervical cancer. However, the serum measurement of these soluble receptors seems to be of limited clinical value for the management of patients with this malignancy. PMID- 21594477 TI - Influence of verapamil on tumour cell growth in vitro following treatment with antiblastic drugs. AB - The effect of antiblastic drugs with different mechanisms of action has been investigated in LoVo cells (on the resistant line LoVo R and the parental LoVo S) for 48 h and for further 24 h in drug-free medium (recovery time) in order to evaluate drug action after its removal. Our results show that the drug effect persists in time, particularly in LoVo R cells. The inhibitory effect on cell growth was enhanced when the drugs were associated with verapamil, while no difference was detected with cisplatin and 4-hydroperoxycyclophosphamide, drugs which are not involved in P-glycoprotein-mediated multidrug resistance. These results demonstrate that verapamil is an effective agent in association with those drugs which are actively transported out of the tumour cells, while it is ineffective on drugs which can induce resistance by different mechanisms. PMID- 21594478 TI - Colonic pseudo-tumor linked to Ogilvie's syndrome. AB - We present a case of a giant colonic pseudolipoma in a patient with colonic dysmotility due to chronic Ogilvie's syndrome. PMID- 21594479 TI - Histogenesis of the gastric differentiated adenocarcinoma-expression of oncogene protein products and mucin histochemistry in minute gastric cancer. AB - Examination of the immuno-overexpression for myc, ras, c-erbB-2 and p53 and the mucin histochemistry of the gastric adenocarcinoma cells at the earlier stages were performed using 12 lesions of the well differentiated tubular adenocarcinomas, less than 1 mm in greatest dimension (G-ade-1), from the pyloric gland or the intermediate area of the surgically resected stomach. The G-ade-1 had a high frequency of expression of oncogene myc (58%) and of the cancer suppressor gene p53 (83%), while almost no expression of ras or c-erbB-2 was observed. All lesions of G-ade-1 were positive for acid mucin staining, and 8/12 lesions (67%) also for sulfomucin, in 4/12 lesions (33%) gastric native mucin was observed. The adjacent mucosa to all G-ade-1 lesions in this study showed chronic gastritis with incomplete intestinal metaplasia. These results suggested that the human gastric differentiated adenocarcinoma developed accompanying the abnormal expression of myc and p53 with reference to intestinal metaplasia, and that these carcinoma cells always had acid mucin, often the colonic native mucin as sulfomucin, and also sometimes gastric native mucin in the earlier stages. PMID- 21594480 TI - Efficacy of adjuvant chemotherapy for endometrial carcinoma with high-risk factor for recurrence. AB - Between April 1989 and December 1992, 38 patients with endometrial cancer who were at high risk for recurrence entered a prospective study designed to evaluate the efficacy of adjuvant platinum (cisplatin), adriamycin (doxorubicin), and cytoxan (cyclophosphamide) (PAC) chemotherapy. Patients received cisplatin (50 mg/m(2)) doxorubicin (30 mg/m(2)) and cyclophosphamide (500 mg/m(2)) at 3-week intervals for 2-3 cycles. All patients completed the treatment, there were no life-threatening adverse events. The median duration of follow-up was 52.9+/-16.9 months. Six patients developed a recurrence, and 4 of them died after a median interval of 45.5 months. Five of the six patients with recurrence had stage IIIc disease. The 3-year progression-free survival was 83.3%, the overall survival rate was 89.2%. Results suggest that adjuvant chemotherapy with PAC may reduce the incidence of recurrence and improve the survival rate of patients with endometrial cancer. PMID- 21594481 TI - Involvement of prostate specific antigen in the stimulation of LNCaP cell growth. AB - Since its identification in 1979, prostatic specific antigen (PSA) has been used extensively as a serum marker for diagnosis and prognosis of prostate cancer. In addition, PSA is an immunohistochemical marker for the identification of prostatic tissues and cells in histological specimens. PSA is found in normal prostate, benign prostatic hypertrophy (BPH) tissue, in cancer of the prostate, and its metastases as well as in other hormone dependent cancers, such as breast and ovarian carcinoma. However, the importance of PSA as a regulator of cell growth generally has not been appreciated. The role of PSA in the development of prostate or other hormone-dependent cancers has remained unclear. We therefore examined the role of PSA in the control of cell growth using both the PSA positive cell line, LNCaP cells and the PSA negative cell line PC-3 and DU145. LNCaP cell growth was stimulated by the conditioned medium (CM) from LNCaP cells, but not by CM from PC-3 or DU145 cells. No such stimulation was observed when PC 3 or DU145 cells were exposed to CM from LNCaP cells nor from CM produced by their own lines. The stimulation of LNCaP cell growth by its own CM could not be attributed to the high level of insulin-like growth factor binding protein-2 (IGFBP-2) present in the CM since even higher level of IGFBP-2 was also found to be present in CM from both PC-3 and DU145 CMs. High level of PSA and 66 kDa epidermal growth factor (EGF) were present in LNCaP CM as measured by Western blotting. The stimulation of LNCaP cell growth by its own CM was eliminated partially by PSA or EGF antibody. Stimulation of DNA biosynthesis in LNCaP cells by LNCaP CM or pure PSA was also observed. These data indicate that PSA and EGF are involved in the growth regulation of PSA positive LNCaP cell line. PMID- 21594482 TI - Ondansetron (OND) vs granisetron (GRA) in the control of chemotherapy induced acute emesis. AB - We enrolled 118 chemonaive cancer patients (pts) to receive OND i.v. dl or GRA i.v. dl. Seventy of the 118 pts received moderately emetogenic (ME) chemotherapy (140 cycles), while 48 received highly emetogenic (HE) chemotherapy (93 cycles). Therapeutic success was obtained in 89% (OND) vs 94% (GRA) cycles of HE and in 96.8% (OND) vs 95.6% (GRA) cycles of ME. The main toxicities were headache (24%, OND; 23%, GRA); light-headedness (13%, OND; 18%, GRA); constipation (11%, OND; 6%, GRA). In conclusion, we think that OND and GRA are effective and the two drugs are equally active and toxic. PMID- 21594483 TI - Overexpression of MDM2 and p53 protein is infrequently but significantly associated with progression of human prostatic adenocarcinoma. AB - In the present immunohistochemical study using anti-p53 (DO-7) and anti-MDM2 (IF2) antibodies, we determined the frequency of p53 and MDM2 protein expression in a series of 115 primary prostatic adenocarcinomas (stage A1 to D2) and evaluated the reliability of p53 and MDM2 immunoreactivity as an indicator for tumor progression. Overall, 13.9% (16/115) of surgically resected tumors were positive for anti-p53 antibody. A significantly higher association of immunoreactivity for p53 was detected in both high-grade (4/16, 25%; p<0.05) and advanced stage tumors (14/73, 19.1%; p<0.05) compared with that of other grade or stage. Positive staining for anti-MDM2 antibody was observed in only 4.3% (5/115) of the tumors examined. However, nuclear MDM2 protein overexpression, detected as focal and markedly heterogeneous staining, was sometimes observed especially in advanced stage tumors (4 stage C and 1 stage D tumors), and was significantly more common in locally advanced cancers (p<0.05) than in those of other stage. Only 2 cases (1.7%) exhibited positive staining with both p53 and MDM2 antibodies. These findings suggest that p53 and MDM2 alterations might play significant roles in the development and progression of some advanced stage or high-grade prostatic cancers, although MDM2 and p53 protein overexpression is infrequent in prostatic adenocarcinoma. PMID- 21594484 TI - Biosynthesis of IL-8 and endothelin-1,2 by immortal simian virus 40 tsA transformed human endothelial cells. AB - Immortal human umbilical cord vein endothelial cells (HUVEC-SV40) established in our laboratory by gene transfection of plasmid pSVts58neo were analyzed for their biological activities. The growth and cellular viability of these immortal cells were temperature dependent. Typical bioactive products of endothelial cells, IL-8 and endothelins, were released into the culture medium as in the case of mortal cells. The production of IL-8 was temperature dependent and significantly increased in cells incubated at 37 degrees C as compared with those incubated at 33 degrees C. Such a temperature dependence was not observed in endothelin production. Stimulation of cells with both TNF-alpha and IFN-gamma increased the biosynthesis of IL-8 or endothelins significantly (p<0.05). From these results, it became clear that immortal HUVEC-SV40 cells also secrete IL-8 or endothelins in the same manner as mortal cells, and that they react to the stimulation by cytokines to promote IL-8 or endothelin production. PMID- 21594485 TI - Tamoxifen inhibits phorbol ester-induced reactive nitrogen intermediate production by U937 cells. AB - Phorbol 12-myristate 13-acetate (PMA) enhanced nitrite production by U937 cells. During a 6-day treatment of U937 cells with PMA (200 nM-1000 nM) there was a significant increase (p<0.001) in NO2- secreted into the culture medium. Treatment of the same cells with tamoxifen (10(-10) M -10(-6) M) had no effect on nitrite production. However, tamoxifen was able to significantly (p<0.05) down regulate PMA-enhanced nitrite production by U937 cells. PMID- 21594486 TI - Unique presentation of Crohn's disease during treatment of Hodgkin's disease. AB - Although Hodgkin's disease and Crohn's disease are associated with abnormalities in cell-mediated immunity, their co-existence in an individual patient is uncommon. To our knowledge, this is the first report of the clinical presentation of Crohn's disease during treatment for Hodgkin's disease. The basic immunologic mechanisms underlying these two pathologic states as well as chemotherapy-related effects are postulated as potential etiologic mechanisms for the codevelopment of these diseases. A brief review of the literature and basic immunologic defects associated with Crohn's disease and Hodgkin's disease are presented. PMID- 21594487 TI - Current status of inherited medullary thyroid carcinoma in Japan. AB - We conducted a large-scale nationwide questionnaire survey to characterize the clinical course of inherited medullary thyroid carcinoma (MTC). Out of a total of 634 MTC patients (M:F ratio 1:2.5), 175 patients had multiple endocrine neoplasia (MEN) 2A, 49 had familial non-MEN medullary thyroid carcinoma (FMTC), 20 had MEN 2B, and 390 had sporadic MTC. Median age at the time of diagnosis was 40.3, 43.0, 26.5 and 48.5 years, respectively. Total thyroidectomy plus modified neck dissection (MND) was the most common operation. The 5-year survival rates were 96.9% in MEN 2A, 100% in FMTC, 73.8% in MEN 2B, 90.8% in sporadic MTC. The outcome in order from best to worst was: FMTC, MEN 2A, sporadic MTC, and MEN 2B, with MEN 2B considered the most aggressive type. PMID- 21594488 TI - Immunotherapy with subcutaneous low dose interleukin-2 plus melatonin as salvage therapy of heavily chemotherapy-pretreated ovarian cancer. AB - Preliminary results showed that IL-2 immunotherapy may be effective in the treatment of recurring advanced ovarian cancer. The pineal neurohormone melatonin (MLT) has been proven to amplify IL-2 efficacy by counteracting macrophage mediated immunosuppression. On this basis, a pilot phase II study of low-dose IL 2 plus MLT was performed in advanced ovarian cancer patients progressing after at least 3 previous polychemotherapeutic lines. The study included 12 evaluable patients. IL-2 was injected subcutaneously at 3 million IU/day for 6 days/week for 4 weeks, by repealing the cycle after a al-day rest period in nonprogressing patients. MLT was given orally at 40 mg/day. No complete response was seen. A partial response was achieved in 2/12 (16%) patients. A stable disease was obtained in 5 other patients, whereas the remaining 5 patients progressed. The treatment was well tolerated. This preliminary study suggests that immunotherapy with low-dose IL-2 plus MLT may represent a well tolerated and promising therapy of advanced ovarian cancer progressing on standard medical treatments. PMID- 21594489 TI - Treatment of flat or accuminata condylomata of the female genital tract with interferon alpha-2 alpha. AB - This study was undertaken to assess the effectiveness of Interferon administered parenterally in the treatment of flat or accuminata condylomata of the female genital tract. One hundred and forty-three women with condylomata were treated with CO2 laser vaporization, 5-FU topical application and interferon alpha-2 alpha (IFN alpha-2 alpha) parenterally. The cure rates in the various treatment groups were analysed by the chi-square test. The cure rates of the treatments used in the patients with condylomata accuminata were similar (p>0.1). The best cure rate for flat condylomata was achieved with the combination of CO2 laser vaporization plus 5-FU plus IFN alpha-2 alpha (high dose) (p<0.01). In conclusion, Interferon can be used as adjuvant treatment in patients with recalcitrant condylomata accuminata and as first line treatment in combination with 5-FU and CO2 laser vaporization in patients with flat condylomata. PMID- 21594490 TI - nm23 and p53 expression. AB - Breast cancer is a common malignancy and the modalities and the aggressiveness of treatment strategies are variable and depend on information regarding the biological characteristics and behavior of an individual tumor. Therefore, to improve overall survival it is important to identify and select lymph node negative patients at high risk who would benefit from adjuvant therapy. Besides prognostic factors such as lymph node status, hormone receptor status and histopathologic parameters, nm23 antimetastatic gene and the p53 protein were studied in 32 breast cancer patients. Positive staining for nm23 was inversely associated with lymph node involvement in 82.4% of the cases. Most of the non diploid lesions (70.8%) showed a high protein expression. Positive immunostaining for p53 was present in 28.1% of the cases and was strongly correlated with prognostic indicators such as necrosis and histologic grading. Tumor grade, DNA ploidy and lymph node metastasis were not significantly correlated with p53 protein expression. In this study, all the prognostic indicators studied, satisfactorily explain the important characteristics of the biologic behaviour of breast cancer, but the detection of lymph node metastasis is still the most accurate prognostic factor utilized for a predictive role in disease recurrence. PMID- 21594491 TI - Expression of epidermal and transforming growth factors in pancreatic cancer. AB - Pancreatic cancer continues to be a major clinical problem and little is known of the various cellular and molecular events associated with this malignancy. Growth factors and their receptors have important functions in the process of tumor progression. We have examined by immunocytochemistry, the expression of epidermal growth factor (EGF), its receptor (EGFR) and the transforming growth factors alpha and beta (TGF alpha and beta) in various grades of pancreatic adenocarcinoma. Expression of the growth factors was compared to their distribution in apparently normal pancreas and chronic pancreatitis. EGF, TGF alpha and TGF beta was expressed in normal pancreatic tissue while the expression of EGFR was slight and restricted. In chronic pancreatitis, this expression of EGFR increased and was found to be moderate in intensity. Expression of EGF, TGF alpha and TGF beta was similar to that seen in normal pancreas. Moderate to intense expression of EGF and TGF alpha was evident in all grades of pancreatic cancer. Expression of EGFR was intense in all these lesions. However, the most significant finding was the absence of TGF beta in all pancreatic cancer lesions. These results may have significant implications for pancreatic tumor progression. EGF and TGF alpha are growth promoters influencing the expression of EGFR. TGF beta, on the other hand exerts an anti-proliferative effect and favours differentiation. It therefore appears that the balance between EGF and TGF alpha on the one hand and TGF beta on the other may be critical in the process of tumor progression, especially if one considers chronic pancreatitis as a pre-malignant condition and the growth factor expression associated with it. PMID- 21594492 TI - Sequential chemo-immunotherapy treatment of metastatic malignant melanoma. AB - Twelve patients with recurring metastatic inoperable malignant melanoma (performance status ECOG 0-1), received the following chemotherapy: tamoxifen p.o., carmustine i.v., dacarbazine i.v., and cisplatin i.v., followed by immunotherapy: interleukin-2 s.c. and interferon-alpha s.c. The treatment cycle was repeated every 6 weeks. Total response rate was 66.6%, with 25% (3 patients) achieving complete cure that has persisted for a period of 17.75 months (mean). In addition, different responses to treatment were observed between the local recurrence lesions and the metastatic lesions. Medium to severe side effects were observed, all but one of them being reversible (neurotoxicity), such as fever, anemia, leukopenia: nephrotoxicity, neurotoxicity, and dyspnea. PMID- 21594493 TI - Clinical course and management of paclitaxel extravasation. AB - Four case reports describing our experience with clinical course and management of paclitaxel extravasation are presented. Local reactions included swelling, mild pain, erythema, induration and hyperpigmentation, but no ulceration. Two patients were treated with cooling only while two further patients received additional hyaluronidase injections subcutaneously. The latter patients suffered longer from symptoms. Local reaction resolved within two weeks and paclitaxel treatment was continued in 3 of 4 patients without further complications. Overall, paclitaxel extravasation induced only mild soft tissue reaction and cooling should be considered standard treatment. PMID- 21594494 TI - High tumor-preventive effects of polyclonal IgG generated against p53 tumor associated protein obtained from benign-tumor bearing rats. AB - We have shown the different effects of rabbit IgG generated against various types of p53 tumor-associated protein on chemically induced colon cancer in rats. p53 protein was isolated in the form of cytoplasmic, soluble, protein from sera obtained from: a) rats with colon cancer and b) rats with benign colon tumors. The isolation was performed using the affinity chromatography columns with,eel fiberglass membranes. Anti-p53 IgG were obtained from rabbits vaccinated with the above mentioned types of p53. Sprague Dawley rats were vaccinated with anti-p53 IgG (100 mu g/rat) at two-week intervals for 2 months and then monthly for 3 months. The induction of colon cancer was caused by weekly injections with 1,2 dimethylhydrazine (20 mg/kg) for 7 weeks and was initiated 8 weeks after the start of the vaccination. Results of experiments were evaluated 6 months after the start of cancer induction. It was found that vaccination of rats with IgG generated against the p53 protein isolated from cancer-bearing rats did not exhibit significant protective effect. Only IgG generated against p53 protein from benign tumor-bearing rats significantly prevented the carcinogenic effect of DMH. The number of tumor-bearing rats in vaccinated group decreased to 44% as compared with 93% in the control group. In vaccinated rats, the number of tumors/rat was 0.8 as compared to 9.3 in controls. The number of malignant tumors in vaccinated rats was half that in controls: 29% and 58%, respectively. In the controls, metastases were found in 6 of 45 rats (13%). Anti-p53 IgG not only has an anti-tumor effect but also prevented benign tumors from becoming malignant. We suggest that the anticancer role of a vaccine generated against p53 protein from benign tumor-bearing rats is related to a wild-type p53 protein. Further studies will be performed to clarify this hypothesis. PMID- 21594495 TI - Liposome DNA delivery and uptake by cells (review). AB - Human gene therapy is a rapidly emerging field; therapeutic genes are engineered into adenovirus, retrovirus, or into plasmid-liposome complexes for their delivery into cells in culture or in vivo. Steps to improve for successful liposome-mediated gene delivery to somatic cells include persistence of the plasmid in blood circulation, port of entry and transport across the cell membrane, release from endosomal compartments into the cytoplasm, nuclear import by docking through the pore complexes of the nuclear envelope, expression driven by the appropriate promoter/enhancer control elements, and persistence of the plasmid in the nucleus for long periods. A number of strategies for enhancing the efficiency of uptake by the cells and release from endosomal compartments of liposome-plasmid or liposome-oligonucleotide complexes are reviewed here; emphasis is given to the direction of liposomes to caveolae vesicles. PMID- 21594496 TI - Percutaneous and endobronchial high dose rate brachytherapy for lung cancer. AB - Endobronchial and percutaneous high dose rate (HDR) brachytherapy was performed with a microSelectron HDR using iridium-192 as a radiation source. As spontaneous pain was uncontrollable by external beam radiation (EBR), chemotherapy, hyperthermia or a combination of these treatment methods, three patients with lung cancer infiltration into the chest wall underwent percutaneous HDR brachytherapy for palliation of severe pain. Selectron needles were inserted under CT guidance and the irradiation dose was set to 10 or 12 Gy at the point 1 cm from the center of the radiation source. A total of 2-4 selectron needles was introduced by means of a template. Irradiation was performed once a week for 1-2 weeks depending on the degree of alleviation of spontaneous pain. In all 3 cases, alleviation of spontaneous pain occured within 7 days after the completion of HDR brachytherapy, and the mean pain score decreased from a value of 2 to 1 within 2 weeks. After discharge from the hospital, the pain score remained between 1-4 in all 3 patients. One problem in percutaneous brachytherapy is the possible hindrance of multiple selectron needle insertion through the template by the ribs depending on the location of the lesion. Six patients aged 51-75 years were subjected to endobronchial HDR brachytherapy. Two of these patients had postoperative recurrence of lung cancer, and 3 patients received concomitant chemotherapy. Brachytherapy was performed 3.4 months (average) after the administartion of 40-70 Gy of EBR. Endobronchial irradiation was performed at a dose of 7 Gy, measured at 1 cm from the center of the radiation source, once a week over a 3 week period for a total of 21 Gy. With the exception of 2 patients who died due to systemic exacerbation, local control of the illness has been good. In endobronchial HDR brachytherapy, it is important to develop a system for altering radiation dose in response to changes in the caliber of the tracheobronchial tree and the degree of the tumor invasion under the bronchial mucosa. PMID- 21594497 TI - Metamorphosis of the steroid deviation profile from the pro-cervical cancer type to the pro-breast cancer type, as detected in the course of aging of cervical cancer patients. AB - The present study is an extension of the latest report from our laboratory, and attempts to investigate the etiological relevancy of the aging of the steroid generating system to the genesis of cervical cancer. The urinary steroid deviation profile of a cervical cancer patient has been known to commit distinct metamorphosis from young age through middle age to old age, and our access to the problem was designed to answer the question whether or not an ex-cervical cancer patient may develop a new primary malignant growth at an advanced age. In the practice of this study, we employed a regression analysis technique for the analysis of the urinary steroid deviation data of cervical cancer on the one hand, and applied the chi square test to the epidemiological data of the double cancer population on the other hand. Results obtained are as follows: i) The steroid deviation profile that was specific to cervical cancer patients chronologically coincided in its emergence with the quasi-exponential growth phase of cancer risk (before age 40); ii) After entry into the stagnation phase of cancer risk, a new change of urinary steroid excretions was progressing with age to the point that the steroid deviation profile of cervical cancer of old age (60 years) assumed an appearance that showed a remarkable resemblance with that of old-age breast cancer; iii) In accordance with the observed changes of the steroid deviation profile of cervical cancer, the breast cancer incidence of an ex-cervical cancer patient was significantly higher than the cervical cancer incidence of an ex-breast cancer patient, and the predominance of the former over the latter was found to be one of the most striking contrasts, as compared in a number of examples of 2 reciprocal cancer pairs of the double cancer population. The observed relationship between the hormonal and epidemiological findings of cancer patients is discussed from the view point of the steroid carcinogenesis hypothesis of human neoplasia. PMID- 21594498 TI - Differential synthesis and binding of hyaluronan by human breast cancer cell lines. AB - In the present study we investigated a panel of human breast cancer cell lines which were sensitive or resistant to the cytotoxic drug doxorubicin, for their abilities to synthesize and bind hyaluronan. We found that MDA-231 and HS-578T cells which express very low amounts of estrogen and progesterone receptors, both synthesized hyaluronan and expressed hyaluronan binding sites on the cell surface as did their doxorubicin-adapted counterparts MDA-231 Dox and HS-578T Dox. The binding was highly specific with a K-d of 0.48x10(-9) M. Most of the hyaluronan binding activity was blocked by mAbs against Hermes-l antigen indicating that the adhesion molecule CD44 is responsible for hyaluronan binding. Only 0.5% of the total amount of labeled hyaluronan added to the cultures was degraded during a period of 16 h. The hormone positive receptor cell lines, MCF-5, Zr-5-1 and Zr-5 1 Dox synthesized only minute amounts of hyaluronan and did not bind hyaluronan or express CD44 receptors. Expression of CD44-related hyaluronan receptors and synthesized hyaluronan may endow hormone receptor negative cells with a highly hydrated environment that facilitates cell motility and invasiveness. The lack of CD44 and thereby the lack of ability to bind hyaluronan in the extracellular matrix may contribute to the non-invasive behavior of hormone positive cell lines. PMID- 21594499 TI - Potential applicability of clinical hyperthermia using a Thermotron-RF8 as assessed from thermal distribution in an agar phantom containing hydroxyapatite. AB - We have already reported the antitumour effect of hydroxyapatite (HAP) containing anticancer drugs. In this study, we found an increased temperature effect around HAP particle(s) in an agar phantom in comparison with other areas when a Thermotron-RF8 (RF generator) was used for heating. Furthermore, it was revealed that the quantity of doxorubicin hydrochloride (DOX) released from HAP containing the drug (DOX-HAP complex) was increased by raising the temperature. These results indicated that the antitumor effect of the DOX-HAP complex + hyperthermia system was greater than that of either the DOX-HAP complex or hyperthermia system alone. PMID- 21594500 TI - Immunolocalization of the components of the plasminogen activating system in breast carcinoma tissue. AB - The plasminogen activating system plays an important role in the progression of carcinomas and the significance of this system in various carcinomas has been thoroughly investigated. To follow up these investigations, we examined the immunolocalization of the components of the plasminogen activating system, namely the urokinase-type plasminogen activator (uPA), its receptor (uPAR), and two inhibitors (PAI-1 and PAI-2), in 72 cases of breast carcinomas. uPA, uPAR and PAI 1 were uniformly expressed in 75.0%, 84.7% and 80.6% of the cases respectively, although their expression was less uniform in T3 or larger carcinomas (p<0.05). Furthermore, the immunoreactivities of these three proteins were often very similar in the lesions. PAI-2 expression was, to the contrary, statistically less extensive (p<0.01)than PAI-1, and only 52.8% of the cases were uniformly positive. The incidence of PAI-2 expression was statistically lower in T3 or larger carcinomas (p<0.01), and in stage III (p<0.01) and grade III carcinomas (p<0.05). Moreover, PAI-1 immunoreactivity was more commonly found in lymph node positive (p<0.05), T3 or larger and stage III carcinomas than PAI-2 immunoreactivity. These findings suggest that uPA, uPAR and PAI-1, whose expression should be regulated by carcinomas once they have grown to a certain degree, work in association with one another, probably promoting carcinoma progression, while PAI-2 might act as the inhibitor in this system. Furthermore, breast carcinomas containing more PAI-I than PAI-2 are more active in respect to both local proliferation and metastasis. PMID- 21594501 TI - Antitumor effect of a novel multifunctional antitumor nucleoside, 3' ethynylcytidine, on human cancers. AB - The antitumor activity of 1-(3-C-ethynyl-beta-D-ribopentofuranosyl) cytosine (ECyd), designed as a potential multifunctional antitumor nucleoside that could be expected to inhibit RNA and DNA syntheses, was examined. ECyd inhibited the growth of 47 kinds of cultured human cells in vitro, and also showed strong antitumor effects on 15 human solid cancers xenografted into nude mice at a dose of 0.25 mg/kg by intravenous administration for 10 consecutive days. The in vitro cytotoxic effect of ECyd was prevented dose dependently by cytidine and uridine, suggesting that ECyd may require phosphorylation by uridine/cytidine kinase for antitumor activity. ECyd strongly inhibited RNA synthesis and also slightly inhibited DNA synthesis. ECyd has shown potent antitumor activity against human experimental solid type tumors with minimal toxic effects in vivo, suggesting that ECyd will be a promising agent with a unique mechanism of action for the treatment of cancer. PMID- 21594502 TI - Carboplatin and vinorelbine in elderly patients with non-small cell lung cancer. AB - Many lung cancers are diagnosed in patients over 70 years of age, but there are little published data on chemotherapy in elderly patients. We therefore activated a phase II study in order to assess the tolerance and activity of carboplatin (80 mg/m(2)) and vinorelbine (25 mg/m(2)) administered weekly in patients aged greater than or equal to 70 with advanced non-small cell lung cancer. Twenty-five patients (22 males, 3 females; performance status ECOG, 0-2; median age, 75 years, range 70-85) were included in the study and are assessable for response and side effects. A total of 162 cycles of therapy have been delivered (median/patient, 6 cycles). Seven partial remissions (28%; 95% confidence interval 5-36%), 8 disease stabilizations, and 10 progressions have been observed. Median time to disease progression was 4 months, and median survival was 5 months (range, 2-25+). Grade III/IV toxicity consisted mainly of leukopenia and neutropenia observed respectively in 5 and 7 patients. In conclusion, the schedule demonstrated activity and good tolerability in this subset of patients. Elderly patients with good performance status and adequate organ function can be safely treated with systemic chemotherapy. PMID- 21594503 TI - Aneusomy and tumor heterogeneity in metastatic breast cancer detected by fluorescence in situ hybridization. AB - Direct interphase cytogenetic analysis was performed on nuclei of metastatic effusions from breast cancer using fluorescence ill situ hybridization (FISH). DNA probes specific for repetitive pericentromeric regions on chromosomes 6, 8, 17, and human midi-satellite probe specific for one locus on the short arm of chromosome 1 were used to determine chromosome copy numbers in interphase tumor cells. The analysis showed cytogenetic heterogeneity in most nuclei examined with multiple subpopulations and a range of 0-6 chromosome signals per cell. The presence of subclones in these fluids, their correlation with highly malignant phenotypes and the diagnostic and prognostic applications of this method is discussed. PMID- 21594504 TI - Local hyperthermia and radiation therapy in the treatment of superficially located lymphomas and recurrent Hodgkin's disease. AB - The combination of radiation therapy CRT) and hyperthermia (HT) has proved to be an effective treatment of a wide variety of superficially located recurrences of different tumors, particularly those arising in previously irradiated areas. Some studies have been reported with the use of this combined approach in the management of cutaneous lymphomas or recurrent previously irradiated sites of Hodgkin's disease (HD). We report a small series of five patients with six located sites of recurrent HD, and four patients with six superficially located sites of non Hodgkin's lymphomas (NHL), all of them being treated with combined HT and RT at our institution. Local control was obtained in each of combined treatment fields, and all patients are alive after a median follow-up of 24 months. All the patients tolerated the HT treatments well, and in all cases average intratumoral temperatures were >42 degrees C, with 8 out of 12 sites achieving the goal of average temperatures >42.5 degrees C. Two patients, one with recurrent HD and one with NHL, are free of disease after 20 and 21 months from the end of combined therapy. Our results thus seem to confirm previous experiences, suggesting a role of HT/RT not only for palliative purposes in cutaneous lymphomas, but also in the management of selected, heavily pretreated patients with superficially located recurrences of HD. PMID- 21594505 TI - Tumor necrosis factor-alpha (TNF alpha) enhances cisplatin cytotoxicity to ovarian carcinoma xenografts. AB - Antitumor effect was compared between administration schedule of once a day dosing of cisplatin (DDP) for 2 consecutive days (q40d) with or without TNF alpha. In two controls, TNF alpha or dilutor alone was administered. Against the ovarian carcinoma 2008 cells, DDP given at dose level of daily x 2 (3.5 mg/kg/day q40d) combined with TNF alpha (50 mu g/kg/day) schedule showed 6.08-fold tumor growth delay (TGD) (17.10+/-1.65; P<0.01), produced 3.17-fold greater cell kill [ratio of tumor volume of treated and control groups (T:C)=0.148; P<0.01] and resulted in longer survival [median survival (MS)=166; P<0.01] than DDP alone. These are superior to even high dose DDP (7.0 mg/kg/day x 2d) without TNF alpha administration schedule showing TGD=11.38 days T:C=0.271 and MS=97 days. High dose DDP (7.0 mg/kg/day q40d) with TNF alpha showed further DDP antitumor potency (TGD=29.74+/-2.08, P<0.01), however, this schedule showed only 2.56-fold TGD extension and no improvement was found in survival because of its severe toxicity. TNF alpha did not alter DDP induced systemic toxicity. These data indicate that optimal antitumor activity, tolerance and survival improvement occured on a schedule of low dose DDP combined with TNF alpha, and this has prompted the clinical evaluation of this administration schedule. PMID- 21594506 TI - Inhibition of fibrinolysis by a synthetic urokinase inhibitor enhances lung colonization of metastatic murine mammary tumor cells. AB - We have investigated the role of coagulation and fibrinolysis during the metastatic lung colonization of F3II mouse mammary carcinoma cells. The selective synthetic urokinase inhibitor B623 significantly enhanced lung colonization and blocked the antimetastatic effect of heparin when administered i.p. during the first stages of metastasis formation. In B623-treated mice the overall activity of the fibrinolytic system was reduced and circulating urokinase was specifically inhibited by this agent. In vitro studies demonstrated that B623 induces the aggregation of F3II cells in the presence of mouse plasma and facilitates the entrapment of tumor cells in a fibrin gel matrix. Our data suggest that imbalances of fibrin deposition and removal may dramatically influence metastatic lung colonization. PMID- 21594507 TI - TNF-alpha and doxorubicin in hyperthermic perfusion for limb sarcomas. AB - Eighteen patients, subdivided into groups of three, were perfused for 90 min with escalating doses of TNF-alpha (0.5-3.3 mg) and standard doses of doxorubicin (bolus 0.7-1.4 mg/kg) at a tumor temperature of at least 41 degrees C, with the aim to ascertain the maximum tolerable dose (MTD) and the activity of TNF-alpha combined with doxorubicin in hyperthermic antiblastic perfusion (HAP) for patients with limb sarcomas, candidates for amputation. Tumor response was assessed both pathologically and radiologically. Severe systemic toxicity (WHO) was observed in only 2 patients. Locoregional toxicity (Wieberdink's) was grade I in 3 patients, grade II or III in 10 and grade IV in 5. A strict correlation between the TNF dosage and the grade of limb reaction was found, grade IV being retrieved only with TNF dose >1 mg and/or muscular temperature >41.5 degrees C. Tumor necrosis was evaluated in 16 patients: in 11 (68.8%) it scored more than 75% while in 5 it was 25 to 75%. Four cases (25%) had 100% tumor histological necrosis. Limb sparing surgery was feasible in 13 (81%). Our findings suggest that this is a well-tolerated and highly active regimen in HAP. PMID- 21594508 TI - Adhesion molecules involved in pleural dissemination of esophageal cancer cells. AB - Pleural dissemination is a common cause of recurrence after surgery of patients with esophageal cancer. Very little is known about the biochemical processes involved in the initial attachment of cancer cells to pleural mesothelial cells. The authors conducted in vitro and in vivo studies to assess the role of adhesion molecules in this process, using 2 cell lines derived from human esophageal cancer. TE-1 cells, which pronouncedly express CD44H, adhered to the monolayers of mesothelial cells more firmly than T.Tn cells. On the other hand, the adhesion of TE-I cells to mesothelial cells was markedly inhibited by antibodies to CD44H or the beta(1) integrin subunit, and more strongly blocked by using a combination of the two antibodies. These antibodies inhibited the dissemination of TE-1 cells in the pleural cavity of nude mice. The findings suggest that CD44 and integrin play important roles in the initial attachment of esophageal cancer cells to mesothelial cells. PMID- 21594509 TI - Chronic myeloid leukemia treated with busulfan. AB - Interferon alpha is presently viewed as the first choice drug for treatment of chronic myeloid leukemia; however patients who are not eligible for this type of therapy are still treated with conventional chemotherapeutic agents as for instance hydroxyurea and/or busulfan. In a series of 23 patients with Philadelphia chromosome positive chronic myeloid leukemia who have been treated solely with busulfan, we have evaluated the relationship between total amount of drug required during the first 12 months of treatment and duration of the chronic phase. A statistically significant (p<0.005) inverse relationship between these two parameters was found, indicating that patients with low busulfan requirement during the first year of therapy have a better prognosis. PMID- 21594510 TI - Can Paneth cell metaplasia in cecum indicate the presence of colorectal epithelial neoplasia? AB - The main purpose of the present study was to investigate the relationship between the incidence of Paneth cells in cecal mucosa and the incidence of colorectal epithelial neoplasias. Using endoscopic biopsy specimens, obtained from cecum of 375 subjects in cases of total colonoscopy, we examined the incidence of Paneth cells in the cecal mucosa. In the present study, Paneth cells were present in the human cecal mucosa (47.7%, 179/375 subjects) regardless of age. Paneth cells were found more frequently in the subjects with colorectal epithelial neoplasia (57.3%, 90/157 subjects) than in the subjects without colorectal epithelial neoplasia (40.8%, 89/218 subjects) (p<0.01, chi(2) test). Our results suggest that the incidence of Paneth cells in cecal mucosa indicate some changes in the environment with tumorigenesis of the colorectal region according to the function of Paneth cells, proposed by other investigators. PMID- 21594511 TI - Is pleomorphic adenoma of the salivary glands a tumor of congenital or very early origin? AB - The cytogenetical observations in a cultured parotid pleomorphic adenoma are presented. The patient had received treatment with X-rays for an infectious disorder in the same region about 50 years earlier. A polyclonal chromosomal pattern was disclosed with predominance of unique structural deviations. We have observed a similar chromosomal picture in a previously reported adenoma. This patient had also been treated with X-rays about 50 years earlier. The findings in these two cases suggest that many, perhaps all, pleomorphic adenomas are either congenital or arise very early in life. Their clinical manifestation at strongly varying time points in adulthood would then depend on accumulated mutational effects of unknown oncogenic agents. PMID- 21594512 TI - A cisplatin-based regimen as a salvage treatment for metastatic breast carcinoma. AB - The role of chemotherapy in refractory metastatic breast cancer is still debated. We employed a schedule of cisplatin, mitomycin and vindesine in twenty-one anthracycline- or anthraquinone-pretreated breast cancer patients. The most relevant characteristics of our group were a good performance status (mean Karnofsky index 84) and a high percentage of bone disease (71%). Out of 20 evaluable patients, 4 (20%) achieved a partial response with a median duration of 3.7 months. Median survival was 12.5 months. Severe gastrointestinal toxicity was reported in 66% of patients and G3 alopecia was seen in 24%. Other side effects, including hematological, were negligible. On the basis of the low response rate and poor tolerability we do not reccommend this combination as salvage treatment in metastatic breast cancer. The use of cisplatin-based regimens in untreated patients waits further investigation. PMID- 21594513 TI - Benign tumors and tumor-like lesions of the lung. AB - We detail an investigation of the diagnosis and operative method for benign tumors and tumor-like lesions of the lung. In benign tumors, the preoperative diagnosis was almost the same as the postoperative one. In tumor-like lesions, the correlation of preoperative and postoperative diagnosis was poor. Since 1986, no patient with benign tumors has undergone invasive methods, but this has been required in some tumor-like lesions. Malignant tumors are easily distinguished from benign tumors but difficult from tumor-like lesions, preoperatively. Therefore, open biopsy is necessary in cases of suspicious malignancy. Then small invasive procedure should be selected due to the possibility of benign tumors. PMID- 21594514 TI - Combined effects of Delta(7)-prostaglandin A(1) and lipo Delta(7)-prostaglandin A(1) to cis-diamminedichloroplatinum(II) on tumor growth in scid mice bearing 2008 and 2008/c13 cells. AB - The aim of this study was to elucidate effects of Delta(7)-prostaglandin A(1) methyl ester (Delta(7)-PGA(1)) alone, and Delta 7-PGA(1) emulsified in lecithin oil (lipo Delta(7)-PGA(1)) alone, and their combinations with cis diamminedichloroplatinum(II) (CDDP) on the tumor growth of an ovarian carcinoma cell line resistant to CDDP (2008/c13) and the parental cell line (2008) in vitro and in scid mice. With regard to concentration of CDDP required for 50% inhibition of cell proliferation in vitro (IC50), 2008/c13 was 5.76-fold higher resistant to CDDP than 2008, while the degree of resistance of 2008/c13 to Delta(7)-PGA(1) was less than a half of that to CDDP. When 2008 cells were heterotransplanted s.c. into the right flank of scid mice, the tumor growth was not inhibited by treatment with CDDP alone, Delta(7)-PGA(1) alone or lipo Delta(7)-PGA(1) alone. However, when CDDP was combined with lipo Delta(7)-PGA(1) (but not Delta(7)-PGA(1)), the tumor growth was significantly (P<0.05) inhibited on days 35 and 42 after tumor inoculation, compared to untreated and all alone treated groups. When CDDP-resistant 2008/c13 cells were inoculated s.c. into the right flank of scid mice, CDDP alone treatment resulted in a significant (P<0.05) inhibition of the tumor growth, suggesting that the sensitivity of this tumor to CDDP is rather higher than 2008-tumor of which growth was not inhibited by CDDP alone. A significant decrease of body weight was observed only when CDDP was combined with lipo Delta(7)-PGA(1) in scid mice bearing 2008 cells, as confirmed by monitoring hematocrit and body weight. However, these mice had no serious weight loss leading to death. These results suggest that combination of CDDP and lipo Delta(7)-PGA(1) may be effective for treatment of patients with ovarian carcinoma clinically resistant or insensitive to CDDP. PMID- 21594515 TI - Primary hepatic carcinoid tumor. AB - We report the case of primary hepatic carcinoid tumor of which diagnosis was made by fine needle biopsy of a liver mass. The patient was treated successfully by left hepatic trisegmentectomy. This patient presented with complaints of generalized fatigue, but denied the presence of flushing, diarrhea, or other endocrine symptoms. Physical examination was unremarkable. A biopsy specimen revealed Grimelius stained cells that were immunoreactive for chromogranin A. Careful pre- and intraoperative examinations revealed no other primary lesions. Argyrophilia of the tumor cells suggested that the tumor was of fore five cases of primary hepatic carcinoid tumors previously reported in the literature are also reviewed. PMID- 21594516 TI - Current results of pelvic perfusion for non-resectable relapsing of pelvic cancer. AB - Twenty-eight patients affected by non-resectable pelvic recurrence of a primary pelvic malignant neoplasm were treated by isolated pelvic perfusion, at mean hyperthermia, with different drugs, chosen taking into account tumor chemosensitivity. All patients had been previously treated. Four complete and six partial responses were observed; nine patients had stable disease and four other patients were non-responders and died due to progression in a few months. Two patients were lost to follow-up, one patients died for other reasons and two recent patients are not yet assessable. PMID- 21594517 TI - Intraperitoneal hyperthermic perfusion (IPHP). AB - Intraperitoneal hyperthermic perfusion (IPHP) with a solution that contains CDDP (25 mg/m(2)/l) and MMC (3.3 mg/m(2)/l) was clinically introduced in the treatment of peritoneal carcinomatosis. Twenty-six patients underwent surgical treatment and IPHP. Peritoneal carcinomatosis was classified at laparotomy using the Japanese classification: P1 (n=3), P2 (n=5), P3 (n=15), unclassifiable (n=3). In this series of patients only the creatinine and amylase values were significant in biological toxicity evaluation. The surgical complication rate (2 duodenal fistulas) does not differ from the general extensive abdominal surgery. PMID- 21594518 TI - Expression of Fas in female reproductive tract tumors. AB - Fas, a cell surface receptor, mediates cell death by means of apoptosis in a variety of cell types. We attempted to detect Fas within plasma membrane isolated from surgically removed female reproductive tract tumors. Eight of 9 endometrial carcinomas and all ovarian carcinoma tested expressed Fas mRNA as assessed by RT PCR using oligonucleotide primers according to published sequences. Immunoblotting of membrane proteins with the specific antibodies detected an immunoreactive Fas in 15 of the 16 tumors tested. In contrast, none of 9 uterine cervical carcinomas demonstrated Fas expression. Fas was expressed in a wide range of the carcinomas originating from the uterine endometrium and ovary, but not in the uterine cervix-derived tumors. Despite a poorly understood processes of apoptosis at present, this may suggest frequent expression of Fas in adenocarcinoma histologic types. PMID- 21594519 TI - Evidence for common signalling pathways of GnRH receptor and Fas in tumors. AB - Fas, a cell surface receptor, mediates cell death by means of apoptosis in a variety of cell types. GnRH receptor-bearing tumors undergo apoptosis with GnRH analogs. To examine whether Fas and GnRH receptor share the same signal transduction pathway, we attempted to detect Fas-linked responses within plasma membrane isolated from GnRH receptor-bearing tumors. Surgically removed gynecological tumors were screened for Fas and GnRH receptor expression prior to analyses. The plasma membranes from these tumors responded to anti-Fas antibody (N-18) exposure with an inhibition in phosphatidylinositol (PtdIns) kinase activity, analogous to response to GnRH analog (buserelin) exposure; the activity was measured as phosphorylation from [gamma-P-32]ATP of exogenous substrate PtdIns by the purified plasma membranes. This inhibition was dependent on the N 18 dose, and a maximal effect occurred at 300 ng/ml with 60% decrease in PtdIns phosphorylation. The maximal inhibitory effects of N-18 and buserelin were not additive on PtdIns kinase inhibition; inhibition by both N-18 and GnRH analog was no greater than with either one alone. These data might suggest that there may be at least some similarity in signal transduction pathway utilized by GnRH analogs and Fas ligands. PMID- 21594520 TI - TGF-beta 1 overexpression in breast cancer. AB - TGF-beta 1 belongs to a family of pluripotent growth factors (TGF beta s) and has been implicated in the development and progression of human breast cancer. There are conflicting data though, suggesting that TGF-beta has the pontency both to promote and inhibit the progression of mammary neoplasia. We examined the expression of TGF-beta 1 mRNA in 24 breast carcinomas using the technique of the reverse transcription polymerase chain reaction (RT-PCR) to obtain quantitative results. Overexpression of TGF-beta 1 gene was found in 75% of the cases. We also correlated the overexpression of the TGF-beta 1 gene with clinicopathological parameters including histological grade, tumour cellularity, oestrogen receptor status (ER), progesterone receptor status (PR) and lymph node involvement. The results led us to the conclusion that the increasing ratio of overexpression related to the stage of cancer in an analogous way (P similar to 1). No significant association was identified between the ratio of overexpression and the grade, ER, PR, or lymph node involvement (r(s) = 0.5, 0.2, 0.1, 0.1 respectively; P < 0.0001) in all categories. PMID- 21594521 TI - Antioxidative levels in two nutritional population groups. AB - Plasma profile of polyunsaturated fatty acids, conjugated dienes of fatty acids (CD) in plasma, levels of vitamins C, E, A and beta-carotene, as well as plasma levels of trace elements (selenium, zinc, copper) were estimated in a group of 162 healthy lacto-vegetarians and lacto-ovo-vegetarians (non-smokers, aged 30-63 years, average period of vegetarianism was 5 years). When compared to omnivores (n = 159, average sample of non-smokers of the same age range from the same geographic region as the vegetarians), a significantly higher content of linoleic acid C 18:2 and linolenic acid C 18:3 was found in vegetarians. Plasma level of the first product of lipoperoxidation (CD) was significantly reduced in vegetarians compared to omnivores. Levels of essential antioxidative vitamins in plasma were significantly higher in vegetarians (vitamin C, beta-carotene, vitamin A, vitamin E/cholesterol-indicating more effective protection of LDL against oxidation, vitamin E/triacylglycerols and 2.27-fold pronounced the positive linear correlation between vitamin E/triacylglycerols and plasma C 18:2 content-indicating higher protective effect against peroxidation of polyunsaturated fatty acids). Beneficial antioxidative values were complemented by elevated level of selenium as well as copper and zinc values equivalent to omnivores. These results support the positive effect of vegetarianism on the regulation of prooxidative processes. This nutritional habit can thus contribute to reduced risk of free radical diseases such as cancer or cardiovascular diseases. PMID- 21594522 TI - Survival of patients with pulmonary metastases in differentiated thyroid cancer. AB - To clarify the factors affecting survival of the patients with differentiated thyroid cancer and pulmonary metastases, 46 patients treated at our hospital during the past 23 years were studied using statistical analysis. Nineteen patients died as a result of their thyroid cancer. The follow-up period ranged from 1 to 31 years with a median of 10.5 years. Age at primary surgery, interval between primary surgery and appearance of pulmonary metastases and RI therapy affected survival from primary surgery and age at pulmonary metastases and RI therapy determined survival after pulmonary metastases, as revealed by the Cox proportional hazard model. These results suggest that prognostic factor of patients with differentiated thyroid cancer and pulmonary metastases is the age at initial surgery and at appearance of pulmonary metastases. But RI therapy could change the course of pulmonary metastases of thyroid cancer. PMID- 21594523 TI - Pelvic inflammatory pseudotumor with predominant macrophagic reaction. AB - We describe the clinical and pathological features of a case of inflammatory pseudotumor of the pelvis, exceptionally reported in the female genital tract. Macroscopically the lesion consisted in several yellowish nodules, one on the uterus fundus, others along the ureteral serosa and the urinary bladder suggesting a multifocal pelvic malignancy during the surgical intervention. The histological examination of the nodules showed a total lack of malignant cell proliferation and a macrophagic reaction, enclosing numerous non birefringent heterogeneous crystal structures. In the patient file no colonic diverticulosis or previous pelvic surgical excision was recorded. The differential diagnosis in particular malignant tumors is discussed. PMID- 21594524 TI - Identification of spontaneous programmed cell death during development of human breast cancer. AB - Breast tumorigenesis proceeds through an accumulation of specific genetic alteration. Breast malignant transformation is dependent not only on the rate of cell production but also on apoptosis, a genetically programmed process of autonomous cell death. We investigated whether breast tumorigenesis involves an altered susceptibility to apoptosis by examining normal breast epithelium and breast cancer samples. We found there is a significant inhibition of spontaneous apoptosis in breast cancer cells compared with normal breast epithelium. The inhibition of apoptosis in breast cancer may contribute to neoplastic transformation. PMID- 21594525 TI - Interleukin-2 and interferon alpha 2 combination. AB - We have studied activity and toxicity of subcutaneous recombinant interleukin-2 and interferon alpha 2b in a series of 14 patients with advanced renal cell carcinoma. No objective response was observed, and the median survival was 16 months (range 3-19); toxicity was acceptable. All the patients had poor prognostic factors and were pretreated with interferon. PMID- 21594526 TI - Potential for anatomic localization in colorectal cancer using the SCM test. AB - We analysed a series of 81 colorectal cancer cases in which the SCM (structuredness of the cytoplasmic matrix) test had already been performed with a diagnostic sensitivity of 92% and a specificity of 92.6%, yielding positive and negative predictive values of 96.3% and 84.7% respectively. We subdivided this group of 81 patients by anatomic location of the malignancy. Although the resultant subgroups were admittedly small, we noted a tendency for the most prominent changes in observed and calculated polarization parameters to be associated with cecal cancers. This finding was of special interest because the cecum is the most inaccessible site for colonoscopy. Ongoing site-specific surveillance in SCM-tested cases of colorectal cancer is necessary to validate this result. PMID- 21594527 TI - p53 overexpression in oral lichen planus. AB - Oral lichen planus (OLP) is considered as a premalignant lesion, but some argue that only lichenoid lesions with dysplasia is precancerous. To address the question whether OLP without dysplasia is premalignant, we investigated the immunohistochemical expression of p53 in OLPs without dysplasia. Half of the OLPs showed p53 positive cells in the basal epithelium. SSCP-PCR analysis of 4 p53 positive OLPs failed to demonstrate mutations. What is the significance of p53 expression in these OLPs? The confinement of p53 positive cells to the basal cells seems to be against false positivity. Since the pathogenesis of OLPs involves cell-mediated cytotoxicity (CMC) which causes marked apoptosis, it is possible that the p53 expression represents wild-type p53 that may be regulating the apoptosis. Alternatively p53 protein may be stabilized by some mechanisms other than gene mutation as a result of cellular insults from CMC. PMID- 21594528 TI - Experimental study of the protective effect of glutathione against cisplatin induced nephrotoxicity. AB - Glutathione (GSH) is the most important intracellular thiol-compound which participates in the detoxification mechanisms of the cell. Its high affinity to react with platinum complexes would give rise to lower or non-toxic metabolites and prevent cisplatin nephrotoxicity. In order to determine if GSH can protect against cisplatin-induced renal toxicity, 120 female Wistar rats received LD-100 or LD-50 of cisplatin with or without GSH, at two different dose levels and by two different routes. Biochemical and histological changes as survival was observed in each group. The administration of GSH did not modify cisplatin LD 100. When cisplatin LD-50 was used, a significant improvement in the survival rate was observed in the group which received GSH as chemoprotector (100% vs 40%). The average values of urea and creatinine were significantly lower in the group treated with GSH (115 vs 370 mg/dl and 1.07 vs 4.02 mg/dl respectively). The degree of the tissue injury was also lower in the GSH group. The administration of GSH prior to cisplatin reduces its nephrotoxicity in this animal model. Further clinical trials are necessary to verify this protective effect when cisplatin is used as a cyclic administration and at different dose levels. PMID- 21594529 TI - Enhanced therapeutic effect of amsalog (CI-921) in combination with cisplatin in vitro and in vivo. AB - CI-921, the 5-methyl-4-carboxamide analog of amsacrine, in combination with cisplatin produced a 6-fold better cell kill in vitro than expected based on additive effects. The combination of CI-921 and cisplatin was subsequently evaluated in three in vivo model systems: intraperitoneally (TP) and intravenously (IV) implanted P388 leukemia, and advanced stage subcutaneously (SC) implanted LC-12 squamous cell carcinoma. All drug treatments were administered IP on an intermittent treatment schedule which was optimal for both agents. Combination therapy was superior to therapy with the best single agent alone, CI-921, in all three model systems. Against IP implanted P388 leukemia, combination therapy produced greater than 8 logs of net tumor cell kill with 60 day survivors (cures). This level of activity was 50-fold greater (1.7 log) than that obtained with CI-921 alone. An IV implant of P388 leukemia was used in a confirmatory study to provide a more rigorous evaluation against disseminated disease. Combination therapy against IV implanted P388 leukemia produced greater than 7.7 logs of net tumor cell kill, which was 630-fold greater (2.8 logs) than that obtained with CI-921 therapy alone. Against advanced stage LC-12 (200-1000 mg tumors at initial treatment), combination therapy improved tumor cell kill by 0.6 log (4-fold) over that obtained with CI-921 therapy alone and also produced greater numbers of 120-day survivors than did single agent therapy with CI-921. The combination of carboplatin and CI-921 was also evaluated against IV implanted P388 leukemia to determine if the enhanced therapeutic effect of CI-921 and cisplatin could be extended to include CI-921 and carboplatin. Combination therapy with CI-921 and carboplatin increased net log tumor cell kill by 0.8 and 1.5 log in two separate tests (6- and 32-fold, respectively) over that obtained with CI-921 therapy alone. The data indicate that combination therapy with CI-921 and platinum containing anticancer agents may have clinical application. PMID- 21594530 TI - Bradykinin stimulation does not induce intracellular Ca2+ elevation in cells from desmoid tumors. AB - The intracellular mechanisms controlling cell proliferation in desmoid tumors (DT) are unknown. Bradykinin stimulated an increase in [Ca2+](i), (monitored by the fura-2 fluorescence) in fibroblasts obtained from both the skin of a normal donor and the mesenter of a familial adenomatous polyposis (FAP) patient. Cells from DT of the same patient as well as those from another FAP patient failed to show the elevation of [Ca2+](i) usually caused by bradykinin stimulation. PMID- 21594531 TI - Analysis of ploidy status in progression of head and neck cancers by DNA image cytometry. AB - Eight cases of leukoplakia, 25 lingual cancers, 15 cancers of the floor of the oral cavity, 11 pharyngeal cancers and 14 lymph nodes with squamous cell cancer metastases were stained using the Feulgen method to evaluate the ploidy status and ploidy related parameters. All leukoplakias were euploid. Percentage of aneuploid cancers correlated with the grade of tumours. Significant differences between tumours with 3 different locations were not found. Metastatic carcinoma cells in lymph nodes had significantly more cells in S-phase as compared to primary tumours. PMID- 21594532 TI - Intermittent continuous infusion of fluorouracil, low-dose oral leucovorin and oral etoposide in advanced gastric cancer. AB - Gastric carcinoma is considered moderately chemosensitive, but a 'standard' chemotherapy regimen has not yet been found. Encouraging results in terms of activity and tolerability have been reported with a combination of i.v. leucovorin, fluorouracil and etoposide. However, etoposide and fluorouracil have demonstrated a schedule-dependency with high activity for the former when administered orally and for the latter when administered as a continuous infusion. In order to improve clinical results, we tested the activity and feasibility of the following combination: oral L-leucovorin, 5 mg/m(2) days 1-14; oral etoposide, 50 mg/m(2) days 1-14; fluorouracil, 200 mg/m(2)/day by continuous infusion days 1-14; cycles repeated every 28 days. A total of 26 patients [male/ female, 17/9; median age, 65 years (range, 42-75); performance status, 0-2] have been enrolled and are evaluable for response and side effects. A total of 78 cycles has been delivered (median/patient, 3 cycles). Two complete remissions (8%), 11 partial remissions (42%), 4 stabilizations of disease, and 9 progressions have been observed, for an overall response rate of 50% (95% confidence interval 30-70%). Median time to disease progression was 4.5 months and median survival 9.5 months. No toxic death or grade III-IV toxicity has been observed. Mild or moderate side effects included mucositis (42%), nausea/vomiting (19%) and leukopenia (8%). In conclusion, our results indicate that the schedule is safe, well tolerated and highly effective in advanced gastric cancer. PMID- 21594533 TI - Activity of cholesterol-esterifying enzymes from rat liver cytosol is affected by malignant growth. AB - Three cholesterol-esterifying enzymes purified recently to apparent homogeneity from rat liver cytosol (Hradec, et al: J Chromatogr B 681: 55-62, 1996) showed in vitro an absolute requirement for natural mixtures of phosphatidylcholines. These phospholipids may be replaced by the addition of minute quantities of serum from cancer patients but not by that of healthy individuals. Individual enzymes showed different sensitivities in this respect. They utilized only phosphatidylcholines containing saturated fatty acids as substrates but not those containing unsaturated fatty acids. As revealed by high-performance liquid chromatography, products of the esterification were esters with saturated C12-C18 fatty acids (including odd-numbered) in comparable proportions. If cancer serum was added as the only source of substrate, enzymes synthesized predominantly cholesteryl 14 methylhexadecanoate. The enzymatic activity and nature of reaction products thus depended on the availability of particular phosphatidylcholines present in the cancer serum but not (or in lower quantities) in the serum of healthy individuals. These results may be of significance for further studies on metabolic changes accompanying the growth of malignant tumours. PMID- 21594534 TI - Tropisetron-dexamethasone combination for carboplatin-induced emesis. AB - Sixty-six patients being given polychemotherapy schedules including carboplatin entered an antiemetic protocol with tropisetron and dexamethasone at the dose of 5 mg and 8 mg respectively. A complete response (no episodes of vomiting) and a major response (less than or equal to 2 episodes of vomiting) were observed in 55 and and 7 patients respectively. It is concluded that the tropisetron dexamethasone combination is highly active in the control of emesis induced by conventional doses of carboplatin in combination. PMID- 21594535 TI - Inhibition of apoptosis in human breast cancer as related to prognosis. AB - Breast tumorigenesis proceeds through an accumulation of specific genetic alterations. Breast malignant transformation is dependent on not only the rate of cell production but also on apoptosis, a genetically programmed process of autonomous cell death. It may also be important in the overall growth dynamics of neoplastic cells, both in the natural history and when they are exposed to chemotherapy or radiation. This study evaluated the biological and clinical implications of spontaneous apoptosis in human breast cancer. Apoptosis was measured in 8 normal breast tissues and 91 human breast cancer samples by Apoptag end labeling method. We found there was a significant inhibition of spontaneous apoptosis in breast cancer cells compared with normal breast epithelium. In 91 breast cancer samples, apoptotic index (AI) was strongly associated with lymph node metastasis; Low apoptosis of tumor cells was more frequent in poorly differentiated tumors and has a poor outcome. PMID- 21594536 TI - Hepatocellular carcinoma in young patients. AB - The study was based on the biopsy material collected in Eastern coastal region of South Africa with high incidence of primary hepatocellular carcinoma (HCC). Forty one patients were between 9 and 25 years old of the total number of 474 cases of HCC available for examination. Liver biopsies were fixed in 10% of neutralised formalin, processed to paraffin blocks, cut and stained with hematoxylin and eosin, silver reticulin, Masson trichrome and Prussian blue stains. Representative biopsies of 21 patients younger than 25 years and 56 older than 35 years were in addition examined immunohistochemically with HBsAg antibody, endothelial marker (F VIII-related antigen) and for oncoproteins c-myc and c-erbB 2 using peroxidase-antiperoxidase method. Cirrhotic liver was evident in 41.5% of all patients and in 28% of younger than 25 years. Hemosiderosis of the liver of patients over 35 years was nearly twice as common as in younger than 25 years and showed the opposite relationship to the presence of HBsAg in liver tissue. Oncoprotein expression was also higher in tumor tissue of younger patients. These results indicate the etiological association of HCC with HBV infection, cirrhosis and possibly siderosis of the liver with HCC. Simultaneous expression of oncoproteins and HBsAg indicate the primary importance of viral infection in etiopathogenesis of HCC. PMID- 21594537 TI - Human recombinant tumor necrosis factor alpha in combined therapy of advanced pancreatic cancer. AB - Preliminary results of a combined therapy consisting of interferon-alpha, human recombinant tumor necrosis factor-alpha and 5-FU in patients with advanced pancreatic cancer are presented. Each patient underwent surgical treatment, except one case in which partial resection was done. In all other patients only palliative operation was performed because of the advanced stage of the disease. The patients have been followed up for 4-19 months and all of them are still alive. Complete remission was observed in one patient; survival time 13 months. In two patients partial remission was achieved, survival time 10 and 6.5 months, respectively. The general condition of other patients was good and stable during the follow up. PMID- 21594538 TI - Proliferating cell nuclear antigen expression and the progression of cervical intraepithelial neoplasia. AB - Cell proliferation is an important biological aspect of a tumor cell population which can affect clinical outcome. In addition to other well established clinical and histopathological prognostic criteria? cell kinetic data have significant predictive value. This study evaluates the proliferative activity of benign, premalignant and malignant cervical tissue by analyzing the expression of the proliferating cell nuclear antigen (PCNA). PCNA is a 36 kD nuclear protein associated with the cell cycle and is directly involved in DNA synthesis during cell proliferation. A total of 122 subjects were included in the study. This included 30 benign tissue samples, 30 low grade lesions (CIN 1), 30 high grade lesions (CIN 2/3) and 32 invasive squamous carcinomas. There was significant difference in PCNA index between benign and high grade lesions as well as benign and invasive cancer. The percentage of PCNA positive cells were significantly higher in invasive carcinoma when compared with non malignant lesions. Moreover, there was also good correlation between increasing histological abnormality and PCNA expression. These results suggest that cell proliferation index as detected by PCNA expression may be useful in the evaluation of alterations in cell kinetics of various grades of cervical lesions. Such data could also possibly help explain the biological behaviour of these lesions and be useful in planning of radiotherapy for invasive cervical cancer. PMID- 21594539 TI - Active gastrointestinal hemorrhage identification by blood pool contrast-enhanced magnetic resonance angiography. AB - Localization of the source of gastrointestinal hemorrhage can be challenging. Currently, this is often accomplished with tagged red blood cell scintigraphy, with attendant ionizing radiation and relatively poor spatial resolution. We describe an analogous method of detecting acute gastrointestinal hemorrhage by enhanced MRI with blood pool contrast agent. Briefly, following precontrast fat suppressed volumetric T1-weighted image acquisition, single-dose gadofosveset trisodium, a blood pool agent, is administered. Then serial post-T1-weighted images are obtained. This technique is a novel method for evaluating gastrointestinal hemorrhage. PMID- 21594540 TI - Common and uncommon vascular rings and slings: a multi-modality review. AB - Vascular rings and pulmonary slings are congenital anomalies of the aortic arch/great vessels and pulmonary arteries, respectively, that commonly present early during infancy and childhood with respiratory and/or feeding difficulties. The diagnosis of these conditions frequently utilizes a multi-modality radiological approach, commonly utilizing some combination of radiography, esophagography, CT angiography and MR angiography. The purpose of this pictorial review is to illustrate the radiological findings of common and uncommon vascular rings and pulmonary slings in children using a state-of-the-art multi-modality imaging approach. PMID- 21594541 TI - Labeling human embryonic stem-cell-derived cardiomyocytes for tracking with MR imaging. AB - BACKGROUND: Human embryonic stem cells (hESC) can generate cardiomyocytes (CM), which offer promising treatments for cardiomyopathies in children. However, challenges for clinical translation result from loss of transplanted cell from target sites and high cell death. An imaging technique that noninvasively and repetitively monitors transplanted hESC-CM could guide improvements in transplantation techniques and advance therapies. OBJECTIVE: To develop a clinically applicable labeling technique for hESC-CM with FDA-approved superparamagnetic iron oxide nanoparticles (SPIO) by examining labeling before and after CM differentiation. MATERIALS AND METHODS: Triplicates of hESC were labeled by simple incubation with 50 MUg/ml of ferumoxides before or after differentiation into CM, then imaged on a 7T MR scanner using a T2-weighted multi echo spin-echo sequence. Viability, iron uptake and T2-relaxation times were compared between groups using t-tests. RESULTS: hESC-CM labeled before differentiation demonstrated significant MR effects, iron uptake and preserved function. hESC-CM labeled after differentiation showed no significant iron uptake or change in MR signal (P < 0.05). Morphology, differentiation and viability were consistent between experimental groups. CONCLUSION: hESC-CM should be labeled prior to CM differentiation to achieve a significant MR signal. This technique permits monitoring delivery and engraftment of hESC-CM for potential advancements of stem cell-based therapies in the reconstitution of damaged myocardium. PMID- 21594542 TI - New knowledge about CT usage and dose optimisation in children, but a major question is still unanswered. PMID- 21594543 TI - MRI of closed spinal dysraphisms. AB - We present a pictorial review of MRI features of various closed spinal dysraphisms based on previously described clinicoradiological classification of spinal dysraphisms proposed. The defining imaging features of each dysraphism type are highlighted and a diagnostic algorithm for closed spinal dysraphisms is suggested. PMID- 21594544 TI - CT appearance of the duodenum and mesenteric vessels in children with normal and abnormal bowel rotation. AB - BACKGROUND: Demonstration of the third duodenal segment (D3) in retroperitoneal location has been recently proposed as a method for excluding malrotation. OBJECTIVE: This study was performed to determine whether a retroperitoneal third duodenal segment can reliably exclude malrotation. MATERIALS AND METHODS: CTs of 38 patients with proven malrotation and 100 patients without malrotation were evaluated for the location of the duodenum/proximal small bowel, and the relationship of the superior mesenteric vein (SMV) to superior mesenteric artery (SMA). RESULTS: The D3 segment was in normal retroperitoneal location in 100% of control patients, compared to 2.5% or (1 of 38) of patients with malrotation. Nine of 11 patients (91%) with malrotation imaged prior to surgery had the proximal bowel in an abnormal location, while all 100 control patients had it in a normal location. The SMV was in normal relationship to the SMA in 11/38 patients (29%) with malrotation, compared to 79% of normal controls. In 10 controls, a branch of the SMV was partially wrapped around the SMA, potentially mimicking partial mesenteric volvulus. CONCLUSION: A retroperitoneal location of the D3 segment makes the diagnosis of malrotation unlikely but not impossible. Additional imaging of the duodenojejunal junction or cecum may be necessary to reliably exclude intestinal malrotation. PMID- 21594545 TI - Normal conus medullaris FDG uptake in children. AB - BACKGROUND: The biodistribution of 18F-FDG has been well described in both adults and children. Many findings are limited to children and warrant understanding prior to interpretation. OBJECTIVE: To determine the normal level of conus medullaris uptake, not previously reported in the literature to date, in a series of consecutive FDG PET/CT scans performed in children. MATERIALS AND METHODS: With IRB approval, we retrospectively reviewed 100 consecutive whole-body pediatric 18F-FDG PET/CT examinations obtained for various clinical indications. Scans that showed visible uptake of FDG at the conus were objectively evaluated, and standardized uptake value (SUV) was determined. Maximum SUV of the conus was compared to background, normal liver and lung, and ratios were recorded. Pathology in the conus was excluded. RESULTS: The scans of 100 patients ages 5 months to 24 years (mean 11.7 years) were reviewed. Three patients were excluded. Seventy percent showed uptake at the conus medullaris. SUVs ranged from 1.33 to 4.2 (mean 2.14). CONCLUSION: Low-level 18F-FDG uptake is common in the conus medullaris, represents normal distribution in children and should not be interpreted as metastatic disease to the CNS. PMID- 21594546 TI - MR enterography of perforated acute Meckel diverticulitis. AB - Meckel diverticulum is the most common congenital anomaly of the small intestine that generally comes to attention due to a variety of complications, such as gastrointestinal tract bleeding, bowel obstruction or acute inflammation. These diverticula frequently are difficult to prospectively diagnose by imaging. Clinically, acute Meckel diverticulitis can be mistaken for acute appendicitis or Crohn disease. We present a 6-year-old boy with perforated acute Meckel diverticulitis that mimicked Crohn disease both clinically and by CT imaging and was definitively diagnosed using MR enterography. PMID- 21594547 TI - Patterns of intravenous contrast material use and corticosteroid premedication in children--a survey of Society of Chairs of Radiology in Children's Hospitals (SCORCH) member institutions. AB - BACKGROUND: There are few data available concerning the use of intravenous contrast materials in children. OBJECTIVE: To assess patterns of intravenous iodinated/gadolinium-based contrast material (ICM/GBCM) use in children. MATERIALS AND METHODS: Society of Chairs of Radiology in Children's Hospitals (SCORCH) members were invited to complete a Web-based survey regarding intravenous contrast material use at their institutions. RESULTS: Sixty-six percent (42/64) of SCORCH member institutions responded, 76% of which are academic hospitals. Ioversol and gadopentetate dimeglumine are the most commonly used ICMs and GBCMs (52% and 81%, respectively). Premedication policies to mitigate risk of allergic-like contrast reactions are more common for ICMs than GBCMs (71% vs. 32%). For both ICMs and GBCMs, most institutions premedicate or avoid contrast material in the setting of a prior allergic-like contrast reaction of any severity. Policies regarding ICM and GBCM use in children with renal insufficiency are in place at 74% and 88% of institutions, respectively, but are variable. CONCLUSION: Policies concerning premedication for prevention of allergic-like contrast agent reactions and administration of contrast materials in children with renal insufficiency are variable and not consistently present at all pediatric institutions. This highlights the need for standardization of practice patterns and pediatric-specific research on these topics. PMID- 21594548 TI - CT scans in young people in Northern England: trends and patterns 1993-2002. AB - BACKGROUND: Although CT can be greatly beneficial, its relatively high radiation doses have caused public health concerns. OBJECTIVE: To assess patterns in CT usage among patients aged less than 22 years in Northern England during the period 1993-2002. MATERIALS AND METHODS: Electronic data were obtained from radiology information systems of all nine National Health Service trusts in the region. RESULTS: A total of 38,681 scans had been performed in 20,483 patients aged less than 22 years. The number of CT examinations rose, with the steepest increase between 1997 and 2000. The number of patients scanned per year increased less dramatically, with 2.24/1,000 population aged less than 22 years having one scan or more in 1993 compared to 3.54/1,000 in 2002. This reflects an increase in the median number of scans per patient, which rose from 1 in 1993 to 2 by 1999. More than 70% of CT examinations were of the head, with the number of head examinations varying with time and patient age. CONCLUSION: The frequency of CT scans in this population more than doubled during the study period. This is partly, but not wholly, explained by an increase in the number of scans per patient. PMID- 21594549 TI - Thoracic vertebral osteomyelitis with paraspinous mass and intraspinal extension: an atypical presentation of cat-scratch disease. AB - Children with cat-scratch disease (CSD) commonly present with fever and tender lymphadenopathy. The disease is mild and manifestations of infection resolve spontaneously within several weeks. However, some children with CSD have unusual features that present diagnostic challenges. Children with atypical CSD may present with prolonged fever, hepatosplenic disease or ocular disease. We performed an MRI on a child who presented with persistent back pain. The MRI demonstrated a paravertebral mass with intraspinous extension and the collapse of T7 vertebral body. A biopsy was reported to show a small round blue cell tumor. An evaluation for malignancy was negative, but Bartonella henselae DNA was detected by polymerase chain reaction on the biopsy specimen. We present this case because it is a rare but important radiological presentation of CSD. PMID- 21594550 TI - Hemangiomas revisited: the useful, the unusual and the new. Part 1: overview and clinical and imaging characteristics. AB - Hemangiomas are common vascular tumors occurring in children. Though most of the lesions present in infants and young children with a typical appearance, it is important to understand that they all do not behave in the same way. Rather, they are a group of vascular lesions with different clinico-pathological subtypes, with their clinical behavior varying with the stage of the tumor as well. As such, they can and do have a varied clinical, imaging and pathological appearance according to the location of the tumor and also the stage at which the patient is seen. In this pictorial essay, the classification, pathogenesis, clinical appearance, natural history and imaging characteristics of hemangiomas are reviewed and illustrated. PMID- 21594551 TI - Reducing abdominal CT radiation dose with the adaptive statistical iterative reconstruction technique in children: a feasibility study. AB - BACKGROUND: The use of the adaptive statistical iterative reconstruction (ASIR) algorithm has been shown to reduce radiation doses in adults undergoing abdominal CT studies while preserving image quality. To our knowledge, no studies have been done to validate the use of ASIR in children. OBJECTIVE: To retrospectively evaluate differences in radiation dose and image quality in pediatric CT abdominal studies utilizing 40% ASIR compared with filtered-back projection (FBP). MATERIALS AND METHODS: Eleven patients (mean age 8.5 years, range 2-17 years) had separate 40% ASIR and FBP enhanced abdominal CT studies on different days between July 2009 and October 2010. The ASIR studies utilized a 38% mA reduction in addition to our pediatric protocol mAs. Study volume CT dose indexes (CTDI(vol)) and dose-length products (DLP) were recorded. A consistent representative image was obtained from each study. The images were independently evaluated by two radiologists in a blinded manner for diagnostic utility, image sharpness and image noise. RESULTS: The average CTDI(vol) and DLP for the 40% ASIR studies were 4.25 mGy and 185.04 mGy-cm, compared with 6.75 mGy and 275.79 mGy-cm for the FBP studies, representing 37% and 33% reductions in both, respectively. The radiologists' assessments of subjective image quality did not demonstrate any significant differences between the ASIR and FBP images. CONCLUSION: In our experience, the use of 40% ASIR with a 38% decrease in mA lowers the radiation dose for children undergoing enhanced abdominal examinations by an average of 33%, while maintaining diagnostically acceptable images. PMID- 21594552 TI - MRI diagnosis of trapped periosteum following incomplete closed reduction of distal tibial Salter-Harris II fracture. AB - Irreducible fracture of the distal tibial physis due to interposed soft tissue including periosteum is well documented in the orthopedic literature but is uncommon. This condition has been associated with subsequent growth disturbance and requires open reduction. There are very few prior reports of MRI depiction of soft tissue interposition and none of periosteal interposition in the distal tibial physis. This is a relatively common location of physeal injury and related growth disturbance. We present a case of periosteum trapped in the distal tibial physis, diagnosed on MRI, in a Salter-Harris II fracture and its management implications. PMID- 21594553 TI - Two cases of leptomeningeal metastases from lung adenocarcinoma which progressed during gefitinib therapy but responded to erlotinib. AB - We present two patients with leptomeningeal metastases (LM) from lung adenocarcinoma that progressed or newly developed, respectively, during gefitinib therapy which had exhibited substantial antitumor effects on widespread lesions. In both cases, a switch to erlotinib therapy brought about long-lasting dramatic symptomatic improvement and markedly prolonged survival. The first patient is a 46-year-old female who presented with progressive headache and vomiting. Multiple pulmonary, hepatic and bone metastases immediately shrank in response to gefitinib. However, 1 month after completion of concurrent whole brain radiation, dizziness and urinary retention newly emerged, worsening the symptoms observed at presentation. Magnetic resonance imaging (MRI) demonstrated enlargement of ventricles and new gadolinium (Gd)-enhanced disseminated nodules on the surface of the cerebral cortex, suggesting the existence of uncontrollable LM. Sequential erlotinib therapy resulted in symptomatic improvement with a finding of regression of Gd-enhancement on MRI. The beneficial effect lasted for 10 months, though a follow-up brain MRI showed further enlarged ventricles. She finally died due to LM after surviving for 11 months under erlotinib treatment. The other patient is a 55-year-old female in whom headache and vomiting occurred while gefitinib therapy had maintained shrinkage of all pre-existing tumors in the thorax and bones. Brain MRI strongly suggested occurrence of LM with a finding of Gd-enhanced sulci. A switch to erlotinib therapy relieved the symptoms with disappearance of Gd-enhancement. However, the symptoms recurred with a finding of further enlargement of ventricles on brain MRI after 11 months. Finally, she died due to LM after surviving for 12 months under erlotinib treatment. PMID- 21594554 TI - Adoptive cell therapy using antigen-specific CD4-CD8-T regulatory cells to prevent autoimmune diabetes and promote islet allograft survival in NOD mice. AB - AIMS/HYPOTHESIS: A new differentiation pathway for CD4(-)CD8(-) (DN) T cells has recently been identified that exhibits the potent function of peripheral converted DN T cells in suppressing immune responses and provides the potential to treat autoimmune diseases. The aim of this study was to determine if the DN T cells converted from CD4(+) T cells of NOD mice retain the antigen-specific regulatory capacity and prevent autoimmune diabetes in vivo. We also sought to determine if the combination of DN T cells with rapamycin promotes islet allograft survival in autoimmune diabetic NOD recipients. METHODS: NOD CD4(+) T cells were converted to DN T cells in an in vitro mixed-lymphocyte reaction, with or without GAD65 peptide, as previously reported. The antigen-specific DN T cells were adoptively transferred to NOD/SCID mice, new-onset diabetic NOD mice or islet-allograft-recipient NOD mice as the part of cell-based therapy. The development of diabetes and allograft survival was assessed by monitoring blood glucose levels. RESULTS: NOD CD4(+) T cells were converted in vitro to DN T cells at a rate of 50% and expressed unique cell features. The DN T cells from NOD donors blocked autoimmunity and prevented diabetes in NOD models, and these effects were even greater for GAD65-peptide-primed DN T cells. DN T cells acted in conjunction with rapamycin to suppress alloantigen-triggered T cell proliferation, promoted apoptosis and prolonged islet allograft survival in NOD recipients. CONCLUSIONS/INTERPRETATION: Administration of the islet beta cell antigen-specific DN T cells can prevent the development of autoimmune diabetes and promote islet allograft survival in NOD mice. PMID- 21594555 TI - Staphylococcus lugdunensis strain with a modified PBP1A/1B expressing resistance to beta-lactams. AB - We describe for the first time the emergence of an mecA-negative Staphylococcus lugdunensis strain with a modified PBP1A/1B that expresses resistance to all beta lactams. A duplication of the tetrapeptide S(569)AYG, which is part of the transpeptidase domain of PBP1A/1B and closely located to the K(583)TG catalytic motif, was associated with this unusual phenotype. PMID- 21594556 TI - Procalcitonin as a potent marker of bacterial infection in febrile Afro-Caribbean patients at the emergency department. AB - Procalcitonin (PCT) has been shown to be of additional value in the work-up of a febrile patient. This study is the first to investigate the additional value of PCT in an Afro-Caribbean febrile population at the emergency department (ED) of a general hospital. Febrile patients were included at the ED. Prospective, blinded PCT measurements were performed in patients with a microbiologically or serologically confirmed diagnosis or a strongly suspected diagnosis on clinical grounds. PCT analysis was performed in 93 patients. PCT levels differentiated well between confirmed bacterial and confirmed viral infection (area under the curve [AUC] of 0.82, sensitivity 85%, specificity 69%, cut-off 0.24 ng/mL), between confirmed bacterial infection and non-infectious fever (AUC of 0.84, sensitivity 90%, specificity 71%, cut-off 0.21 ng/mL) and between all bacterial infections (confirmed and suspected) and non-infectious fever (AUC of 0.80, sensitivity 85%, specificity 71%, cut-off 0.21 ng/mL). C-reactive protein (CRP) levels were shown to be less accurate when comparing the same groups. This is the first study showing that, in a non-Caucasian febrile population at the ED, PCT is a more valuable marker of bacterial infection than CRP. These results may improve diagnostics and eventually decrease antibiotic prescriptions in resource-limited settings. PMID- 21594557 TI - Preoperative identification of intraoperative blood loss of more than 1,500 mL during elective hepatectomy. AB - BACKGROUND: Despite recent advances in surgical techniques, hepatectomies remain one of the most hemorrhagic procedures in abdominal surgery. It is important to identify preoperatively patients who are at high risk of suffering massive intraoperative blood loss. METHODS: The clinical records of 251 patients who underwent an elective hepatectomy for liver tumors between September 2007 and December 2009 were reviewed retrospectively. A multivariate logistic regression analysis of preoperative factors potentially influencing intraoperative blood loss was performed. We set the cut-off value of the amount of blood loss for safe hepatectomy as less than 1,500 mL because no patients with blood loss of less than 1,500 mL received blood transfusion in this study. A scoring system to predict blood loss of more than 1,500 mL was constructed and validated in a cohort of 59 subsequent patients. RESULTS: Intraoperative blood loss of more than 1,500 mL was recognized in 35 of 251 patients (13.9%). Prothrombin activity < 70%, nonperipheral location of the tumor, involvement of hepatic veins, body mass index >= 23.0, and major hepatectomy were independently associated with intraoperative blood loss of more than 1,500 mL. The score was calculated by assigning 1 point for each of the 5 risk factors. The area under the receiver operating characteristic curve (AUC) was 0.814 (95% CI 0.731-0.898). This scoring system was highly predictive in the subsequent validation group of 59 patients (AUC = 0.839, 95% CI 0.710-0.969). CONCLUSION: This predictive scoring system is considered to be useful for identifying before hepatectomy those patients with a high risk of intraoperative blood loss of more than 1,500 mL. PMID- 21594558 TI - The chemotactic interaction between CCL21 and its receptor, CCR7, facilitates the progression of pancreatic cancer via induction of angiogenesis and lymphangiogenesis. AB - BACKGROUND: In this study, we report the influence of CCL21 and its receptor, CCR7, on the progression of pancreatic cancer and illuminates the correlation between the CCL21/CCR7 axis and the angiogenesis and lymphangiogenesis of pancreatic adenocarcinoma (PAC). METHODS: A total of 30 patients with pancreatic cancer was involved in the current study. The expression of CCL21 and CCR7 in cancerous tissues, paracancerous tissues and normal pancreas were investigated using real-time PCR, Western blot and immunohistochemistry, respectively. In addition, we assessed microvessel density (MVD) and microlymphatic vessel density (MLVD) in tumor tissues using immunohistochemistry. RESULTS: Compared to paracancerous tissues and normal pancreas, CCL21 expression in cancerous tissues was detected at a significantly low level. In contrast, the CCR7 expression was considerably higher in cancerous tissues than in normal pancreas and paracancerous tissues. Additionally, a significant correlation between the expression pattern of the CCL21/CCR7 axis and clinicopathological features, such as lymph node metastasis, was identified. Furthermore, we found that CCL21 expression was significantly associated with MVD but not significantly associated with MLVD, while CCR7 expression was significantly associated with MLVD but not significantly associated with MVD. CONCLUSIONS: The chemotactic interaction between CCR7 and its ligand, CCL21, may be a critical event during progression in pancreatic cancer, and its underlying mechanism may be induction of angiogenesis and lymphangiogenesis regulated by this chemotactic interaction. PMID- 21594559 TI - Persisting ratio of total amylase output in drain fluid can predict postoperative clinical pancreatic fistula. AB - BACKGROUND/PURPOSE: A consistent predictor for pancreatic fistula (PF) development in the early period after pancreatic resection is still lacking. PATIENTS AND METHODS: A total of 54 consecutive patients undergoing pancreatic resection were enrolled between June 2007 and April 2010. Pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) were performed in 38 and 16 patients, respectively. For the purpose of finding an early predictor for PF development, we investigated drain amylase levels (d-Amy, IU/mL), drain output volume (d-Vol, mL/day) and drain amylase output (Amy-V, IU/day) on postoperative days (POD) 1 and 3. Amy-V was calculated as the product of d-Amy and d-Vol, and was expressed as the sum of values obtained from all drains. In addition, the ratio of d-Amy or Amy-V on POD3 to that on POD1 was calculated as the persisting ratio in each patient. RESULTS: The overall incidence of clinical PF (International Study Group on Pancreatic Fistula Grade B and C) was 16.7%, occurring in 13.1% after PD and 25% after DP. All PF occurred in cases with a remnant pancreas of soft texture. There was no significant difference in d-Amy, d-Vol, or Amy-V on POD1 and POD3 between patients with and without clinical PF. The persisting ratio of Amy-V was significantly lower in patients without clinical PF compared to those with clinical PF (p = 0.029). Furthermore, the persisting ratio of Amy-V was significantly lower in patients with Grade A PF compared to those with Grade B PF (p = 0.03). CONCLUSION: The persisting ratio of drain amylase output is a new significant predictive factor for clinical PF development. PMID- 21594560 TI - Effect of D-cycloserine and valproic acid on the extinction of reinstated fear conditioned responses and habituation of fear conditioning in healthy humans: a randomized controlled trial. AB - RATIONALE: Although the effects of D: -cycloserine (DCS) and valproic acid (VPA) on the facilitation of the extinction of fear-conditioned memory have been elucidated in animals, these effects have not been clearly confirmed in humans. OBJECTIVE: This study aimed to determine the effect of DCS (100 mg) and VPA (400 mg) on the facilitation of the extinction and acquisition of fear-conditioned memory in humans. METHODS: We performed a randomized, blind, placebo-controlled, four-arm clinical trial in 60 healthy adults. Visual cues and electric shocks were used as the conditioned stimulus (CS) and unconditioned stimulus (US), respectively. RESULTS: The extinction or acquisition effect was not observed in the simple recall after the extinction or acquisition of coupled CS-US; however, the extinction and habituation effects but not the acquisition effects were presented after the unexpected re-exposure of coupled CS-US (reinstatement stimuli). Extinction and habituation effects were facilitated by either a single dose of DCS or VPA or a combination of DCS and VPA. However, we did not observe the expected synergistic effect of the combined treatment on the extinction or habituation of fear conditioning. CONCLUSION: A single dose of DCS or VPA might enhance exposure-based cognitive therapy of anxiety disorders by reducing the vulnerability to reinstatement and preventing relapses of fear-conditioned responses. PMID- 21594561 TI - Motivation to quit smoking and startle modulation in female smokers: context specificity of smoking cue reactivity. AB - RATIONALE: Cue reactivity and startle reflex modulation paradigms have been used in addiction research to determine the affective motivational state of craving induced by viewing drug-related cues. However, recent studies suggest that cue reactivity and startle reflex modulation in people with addictions can be suppressed, or even reversed, depending on context. OBJECTIVE: The present study looked at the contextual specificity of smoking cue startle modulation by examining individuals with low and high motivation to quit smoking. MATERIALS AND METHODS: Emotional modulation of the startle reflex was examined in 32 female smokers exposed to affective stimuli and tobacco cues. The sample was divided into high and low motivation to quit smoking groups using the Processes of Change Questionnaire. RESULTS: The tobacco cues produced a greater startle magnitude in the group with high motivation to quit smoking than the group with low motivation, which was independent of craving level. CONCLUSION: Motivation to be abstinent is a relevant contextual factor accounting for variance in cue reactivity in individual smokers. PMID- 21594562 TI - Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients. AB - BACKGROUND: Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). In order to dissect the genetic basis for the production of these autoantibodies, as well as the development and progression of PBC in Japanese patients, we examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients. METHODS: Four SNPs for both CTLA4 and SLC4A2 were genotyped, using the polymerase chain reaction restriction fragment length polymorphism method and TaqMan assay, in 450 Japanese PBC patients and 371 sex-matched healthy controls. RESULTS: The CTLA4 rs231775, rs3087243, and rs231725 SNPs were significantly associated with PBC susceptibility. The CTLA4 rs231725 SNP was significantly associated with progression to late-stage disease. The CTLA-4 haplotype 1 (rs231775 G, rs231777 C, rs3087243 G, rs231725 A; GCGA) was a risk factor for PBC susceptibility but a protective factor for PBC progression. Conversely, the CTLA-4 haplotype 2 (ACAG) was a protective and risk factor, respectively, for PBC susceptibility and progression. In addition, the CTLA4 rs231777 SNP and haplotype 3 (ATGG) was significantly associated with anti-gp210 antibody production, while SLC4A2 haplotype 4 (rs2069443 A, rs2303933 G, rs2303937 A, rs2303941 T; AGAT) and haplotype 3 (AAGC) were significantly associated with PBC susceptibility and anti centromere antibody production, respectively. CONCLUSIONS: CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients. PMID- 21594563 TI - Development of corpus atrophic gastritis may be associated with Helicobacter pylori-related idiopathic thrombocytopenic purpura. AB - BACKGROUND: A strict correlation between Helicobacter pylori eradication and an increase in platelet count has previously been reported in patients with chronic idiopathic thrombocytopenic purpura (ITP). To clarify the pathogenesis of H. pylori-induced ITP and the factors predicting the platelet response to H. pylori eradication therapy, we evaluated the markers of atrophic gastritis in ITP patients. METHODS: The study population comprised 31 H. pylori-infected patients with chronic ITP. After undergoing upper gastrointestinal endoscopy and gastric biopsy, all patients received H. pylori eradication therapy. The effect of H. pylori eradication on the platelet count was evaluated for up to 6-54 months after the therapy. The degree of endoscopic gastric atrophy, histological parameters in the gastric mucosa, and serum pepsinogen (PG) levels were compared between platelet responders and nonresponders to the therapy. RESULTS: H. pylori was successfully eradicated in all patients and a platelet response was seen in 18 (58%) of these patients. The serum pepsinogen (PG) I/II ratio at pretreatment was significantly lower in responders than in nonresponders. The degree of endoscopic gastric atrophy was significantly more severe in responders than in nonresponders. Furthermore, the levels of histological parameters of activity, inflammation, and atrophy in the gastric corpus, but not in the gastric antrum, were significantly more severe in responders than in nonresponders,. CONCLUSION: The development of corpus atrophic gastritis may be a suitable condition for inducing thrombocytopenia. Evaluation of the serum, endoscopic, and histological markers of atrophic gastritis may assist in selecting patients with ITP who are more likely to respond to H. pylori eradication therapy. PMID- 21594564 TI - A retrospective cohort study of partial splenic embolization for antiviral therapy in chronic hepatitis C with thrombocytopenia. AB - BACKGROUND: Although partial splenic embolization (PSE) is reportedly effective prior to interferon (IFN)-based therapy, the number of subjects in these studies is small, and the appropriate candidates and disease prognosis remain unknown. METHODS: PSE was performed in 30 patients with advanced hepatitis C who could not receive IFN-based therapy because of thrombocytopenia, platelet counts of <=100,000/mm(3), and hypersplenism. Also, we compared 25 PSE-treated patients with 23 PSE-untreated patients with thrombocytopenia receiving pegylated IFN (PEG IFN)-alpha 2b plus ribavirin over the same period. RESULTS: PSE significantly increased platelet and leukocyte counts. PSE was well tolerated with no severe complications. All the patients could receive IFN-based therapy. Discontinuation of therapy in the total cohort of PSE-treated patients was not due to thrombocytopenia. Although PSE did not significantly increase the sustained virological response (SVR) rate, it significantly maintained higher platelet counts throughout the observation period and increased the percentage of patients with 100% adherence to PEG-IFN in the total controlled study population and in subjects with genotype 2. In PSE-treated patients with genotype 2, a trend towards increased SVR was noted. Four patients developed hepatocellular carcinoma (HCC) at a median of 14.5 months after PSE, even though two of these patients had achieved an SVR. CONCLUSIONS: IFN-based therapy following PSE had an advantage in the maintenance of higher platelet counts, and PSE possibly caused an increase in adherence to PEG-IFN. Although patients with genotype 2 might be better candidates for PSE, further evaluation is needed. Careful follow-up of PSE treated patients, even though they may have achieved an SVR, is needed to detect HCC. PMID- 21594567 TI - Immobilization and catheter guidance for breast brachytherapy. AB - PURPOSE: Brachytherapy is an important mode of breast cancer treatment; however, improvements in both treatment planning and delivery are needed. In order to meet these specific needs, integration of pre-operative imaging, supplemented by computerized surgical planning and mathematical optimization were used to develop and test an intra-operative immobilization and catheter guidance system. METHOD: A custom template specific to each patient with optimally placed guide holes for catheter insertion was designed and fabricated. Creation of the template is based on a virtual reality reconstruction of the patient's anatomy from computed tomography imaging. The template fits on the patient's breast, immobilizing the soft tissue, and provides pre-planned catheter insertion holes for guidance to the tumor site. Agar-based phantom and target models were used for quantitative validation of the template by ascertaining the precision and accuracy of the templates. RESULTS: Tests were performed on agar-based tissue models using computed tomography imaging for template planning and validation. Planned catheter tracks were compared to post-insertion image data and distance measurements from target location were used to create an error measure. Initial results yielded an average error of 4.5mm. Once the workflow and template design were improved, an average error of 2.6mm was observed, bringing the error close to a clinically acceptable range. CONCLUSION: Use of a patient-specific template for breast brachytherapy is feasible and may improve the procedure accuracy and outcome. PMID- 21594568 TI - Mandible reconstruction with patient-specific pre-bent reconstruction plates: comparison of a transfer key method to the standard method--results of an in vitro study. AB - PURPOSE: Patient-specific mandible reconstruction plates may be pre-bent to facilitate the surgical procedure. A method using transfer keys (TK) for repositioning pre-bent plates was compared with the standard method on mandibular models to evaluate its feasibility. METHOD: Ten mandible models were used to pre bend reconstruction plates. After plate fixing on the models, TK were fabricated. Plates and TK were removed and segmental resections were performed. The plates were replaced on the models by the standard method of determining the plate position using previous screw holes. Plates were removed and then relocated by use of the TK. To compare the accuracy of both methods, the distances between four corresponding points of the condyles and the mandibular rami were measured. RESULTS: The mean deviation of the absolute values from the initial values for the models between the condyles and the rami was 0.964 mm for the standard method and 0.821 mm for the TK method. To determine whether there was enlargement or shrinkage between the rami or the condyles, we analysed the relative values of the data. For the standard method, the mean deviation from the initial values was +0.178 mm; for the TK method, it was +0.080 mm. In both cases, the differences were not significant. CONCLUSION: Pre-bent reconstruction plates using patient specific 3D models can be useful in mandible reconstruction. The TK method was tested in vitro and shown to be as accurate as the standard method. The TK method may shorten the procedure and may be useful for secondary cases and cases where the pathology involves the outer corte of the mandible. PMID- 21594569 TI - The cytoskeleton and the cellular transduction of mechanical strain in the heart: a special issue. PMID- 21594570 TI - Calcaneo-stop procedure for paediatric flexible flatfoot. AB - BACKGROUND: Flexible flatfoot is a frequent deformity found in children. The aim of this study is to evaluate the pedographic outcome of the percutaneous arthroereisis with the use of a screw through the sinus tarsi into the talus. MATERIALS AND METHODS: 43 calcaneo-stop procedures of 25 patients (18 bilateral, seven unilateral) were evaluated. Mean age at surgery was 10 years (7-14, SD 2.2) (SD: standard deviation), mean follow-up time was 9.7 months (3-19, SD 5.5). Patient satisfaction rate was recorded, the Meary's talus-first metatarsal angle was measured with lateral radiograms, and a dynamic pedographic assessment was also performed. RESULTS: Patient satisfaction rate was excellent for 33 feet of 19 children, good for eight feet of five children, and poor for either feet of one child. We did not observe any complications during or following the surgery.The mean rest heel valgus decreased from 13.4 degrees (10 degrees -17 degrees , SD 1.5) to 2.8 degrees (0 degrees -6 degrees , SD 1.7) post op. The Meary's angle improved from 160.2 degrees (148 degrees -177 degrees , SD 6.8) to 175.9 degrees (167 degrees -179 degrees , SD 3.5). By pedographic analysis, the area and the pressure-time integral (load amount, PTI) values increased on the lateral regions of the sole (except for the lesser toes) and decreased on the medial areas (except for the hallux). The relative contact time in the lateral midfoot increased from 63.8% (39.6-78.4%, SD 10.6) to 75.1% (50-86.1%, SD 9.4), and that in the lateral forefoot region from 81.2% (60.4-89.2%, SD 6.6) to 86.8% (78.1-97.1%, SD 4.8). CONCLUSION: The calcaneo-stop procedure is a simple and reliable method for the correction of severe flexible paediatric flatfoot. Our prospective, short-term results following the anterograde screw implantation into the talus correlate well with the results of similar or different arthroereisis methods. Further investigations are required to evaluate the long-term outcome of the screw calcaneo-stop method, including the conditions following implant removal. PMID- 21594571 TI - Reamed intramedullary nailing versus unreamed intramedullary nailing for shaft fracture of femur: a systematic literature review. AB - INTRODUCTION: Fractures of femoral fracture are among the most common fractures encountered in orthopedic practice. Intramedullary nailing is the treatment choice for femoral shaft fractures in adults. The objective of this article is to determine the effects of reamed intramedullary nailing versus unreamed intramedullary nailing for fracture of femoral shaft in adults. METHODS: Cochrane Central Register of Controlled Trials (October 2010), PubMed (October 2010) and EMBASE (October 2010) were searched. Randomized and quasi-randomized controlled clinical trials were included. After independent study selection by two authors, data were collected and extracted independently. The methodological quality of the studies was assessed. Pooling of data was undertaken where appropriate. RESULTS: Seven trials with 952 patients (965 fractures) were included. Compared with unreamed nailing, reamed nailing was significantly lower reoperation rate (RR 0.25, 95% CI 0.11-0.59, P = 0.002), lower non-union rate (RR 0.20, 95% CI 0.05-0.77, P = 0.02) and lower delay union rate(RR 0.30, 95% CI 0.14-0.64, P = 0.002). There was no significant difference when comparing reamed nailing with unreamed nailing for implant failure (RR 0.51, 95% CI 0.16-1.61, P = 0.25), mortality(RR 0.94, 95% CI 0.19-4.58, P = 0.94) and acute respiratory distress syndrome(RR 1.53, 95% CI 0.37-6.29, P = 0.55). Unreamed nailing was significantly less blood loss (SMD 119.23, 95% CI 59.04-180.43, P = 0.0001). CONCLUSION: Reamed intramedullary nailing has better treatment effects than unreamed intramedullary nailing for shaft fracture of femur in adults. PMID- 21594572 TI - Revitalization of cortical bone allograft by application of vascularized scaffolds seeded with osteogenic induced adipose tissue derived stem cells in a rabbit model. AB - BACKGROUND: Adipogenous tissue derived stem cells (ASC) are available in abundance in the human body and can differentiate in the presence of lineage specific induction factors, for example, in myogenic, adipogenic, chondrogenic and osteogenic cells. The aim of this study was to evaluate the impact of osteogenic induced ASC's (O-ASC) on revascularization and cellular repopulation of avital cortical bone employing a vascularized bovine scaffold. METHODS: An inguinal arterio-venous bundle was dissected in the groin of female white New Zealand rabbits (n = 6) and placed centrally inside an O-ASC seeded scaffold via a central drill hole. In the same surgical session this construct was placed into a segment of avital cortical bone allograft from a donor rabbit. Unseeded scaffolds that were implanted and treated in the same fashion served as controls (n = 6). In order to prevent external revascularization, all constructs were wrapped in silicon foil and finally implanted in the rabbits' groin. Three months later, the constructs were explanted and investigated for vascularization of (a) the scaffold (b) the surrounding bone allograft. Histological stainings to determine cell growth, cellular repopulation of the scaffold and the cortical bone matrix, as well as inflammatory parameters were carried out. RESULTS: O-ASC seeded scaffolds showed a significant increase in new vessel formation in the scaffold as well as in the bone allograft compared to unseeded scaffolds. Furthermore, new vital osteocytes as a sign of cellular repopulation inside the bone allograft were found only in the treatment group. Vital chondrocytes were only found in the O-ASC seeded scaffolds as well. CONCLUSION: The presence of O ASC significantly induce neo-vascularization and osteocytic repopulation of previously avital bone allograft as opposed to unseeded scaffolds in a rabbit model. Hence, this model might be of relevant value for future bone tissue engineering research and for re-vitalizing marginally nourished bone such as in avascular bone necrosis. PMID- 21594573 TI - Polycyclic aromatic hydrocarbons in fish and crayfish from the Calumet region of southwestern Lake Michigan. AB - We identified and quantified polyaromatic hydrocarbons (PAHs) in six aquatic taxa from the Calumet region of southwestern Lake Michigan in order to examine their differential exposure to and health risks from PAH. There was a high degree of variation in PAH concentrations across and within sites. Mean concentrations of total PAH were high in alewife (1,064 ng/g) and minnows (345 ng/g) collected from the Indiana Ship Canal, when compared to other taxa and locations. Concentrations of PAH in sunfish were relatively low (10 to 79 ng/g), even where environmental concentrations were elevated. In sunfish, regardless of location, concentrations of CHR, FLA, FLU, PHE and PYR were high whereas DBA, IPE, BAP, BBF, BGP and BKF concentrations were low. PAH concentrations in crayfish exceeded those of other taxa at three of four locations where they co-occurred. PAH profiles were similar in crayfish, sunfish and minnows from locations where sediment concentrations were low. Profiles for crayfish and minnows from a location where sediment concentrations were elevated displayed lower concentrations of ACY, and higher concentrations of BAA, BBF, and BKF, than those from the other three locations. In contrast, the profiles in sunfish from those three locations were similar. The PHE/ANT and FLA/PYR ratios for crayfish, minnows and sunfish suggested that the primary sources at most locations were pyrogenic, although some sites had strong petrogenic influences. Toxic equivalency factors in biota generally reflected the magnitude of sediment contamination. In three of four locations where they co occurred, TEQs were higher in crayfish than in sunfish and minnows. Sunfish had higher TEQs than minnows at most, though not all, locations; TEQs were notably higher in minnows as compared to sunfish from the Little Calumet River. The selection of aquatic species as sentinels of PAH exposure and risks needs to consider differences in ecologies of taxa as well as the relative magnitude of sediment contamination. PMID- 21594574 TI - Economic burden of neural tube defects and impact of prevention with folic acid: a literature review. AB - Neural tube defects (NTDs) are the second most common group of serious birth defects. Although folic acid has been shown to reduce effectively the risk of NTDs and measures have been taken to increase the awareness, knowledge, and consumption of folic acid, the full potential of folic acid to reduce the risk of NTDs has not been realized in most countries. To understand the economic burden of NTDs and the economic impact of preventing NTDs with folic acid, a systematic review was performed on relevant studies. A total of 14 cost of illness studies and 10 economic evaluations on prevention of NTDs with folic acid were identified. Consistent findings were reported across all of the cost of illness studies. The lifetime direct medical cost for patients with NTDs is significant, with the majority of cost being for inpatient care, for treatment at initial diagnosis in childhood, and for comorbidities in adult life. The lifetime indirect cost for patients with spina bifida is even greater due to increased morbidity and premature mortality. Caregiver time costs are also significant. The results from the economic evaluations demonstrate that folic acid fortification in food and preconception folic acid consumption are cost-effective ways to reduce the incidence and prevalence of NTDs. This review highlights the significant cost burden that NTDs pose to healthcare systems, various healthcare payers, and society and concludes that the benefits of prevention of NTDs with folic acid far outweigh the cost. Further intervention with folic acid is justified in countries where the full potential of folic acid to reduce the risk of NTDs has not been realized. PMID- 21594575 TI - Assessment of brief interventions for nighttime fears in preschool children. AB - Nighttime fears (NF) and sleep problems continue to be major problems in clinical services. The aim was to assess the effects of two brief interventions on NF, and related sleep problems and parental fear-reducing behaviors in children. One hundred and four children aged 4-6 years with significant NF were randomly assigned into two intervention groups: the Huggy-Puppy intervention (HPI), which is based on providing children a puppy doll with a request to take care of the doll, and a revised version (HPI-r) which is based on providing the same doll with a cover story that the doll will serve as a protector. At baseline, the domains of NF, behavior problems, and sleep disruptions were assessed. Data were collected from parents and children using objective and subjective measures. The effects of the interventions were assessed by comparing four time points: baseline, first week of intervention, 1 month, and 6 months after initial intervention time. A waiting list comparison group (WL) was used as spontaneous recovery comparison group. Both interventions significantly reduced NF with similar impact. The improvement after 1 month was significantly higher than in the WL group. Furthermore, both interventions significantly reduced parental fear management behaviors and children's sleep problems. Finally, the reduction in NF and parental fear management strategies were maintained 6 months post-treatment. CONCLUSIONS: Relatively simple and cost-effective doll interventions can reduce NF and their associated sleep problems. Further research is needed to implement these interventions for other anxiety disorders in childhood. PMID- 21594576 TI - The effect of socioeconomic deprivation on efficacy of continuous subcutaneous insulin infusion: a retrospective paediatric case-controlled survey. AB - We aimed to retrospectively evaluate the efficacy of continuous subcutaneous insulin infusion (CSII) therapy in relation to social deprivation in an urban paediatric type 1 diabetic population. Data were compared between 51 children on CSII therapy (mean age 11.2 years and duration of follow-up 1.9 years) and matched controls on multiple daily injection (MDI) therapy. Social deprivation was measured using the UK Office of National Statistics 2007 Index of Multiple Deprivation. Using linear mixed modelling analysis, lower HbA1c levels at 24 months were associated with CSII not MDI therapy (P = 0.02), after adjustment for known variables. Children with the least educated parents showed a rise in HbA1c levels from baseline on MDI therapy (least versus most educated tertile; HbA1c change +0.5% [95% confidence interval -0.1 to 1.1] versus 0% [-0.8 to 0.8]), whereas this was not observed in CSII therapy (least versus most educated tertile; HbA1c change -0.3% [-0.7 to +0.1] versus -0.2% [-0.7 to +0.3], P value for ANCOVA = 0.02, after adjusting for income and employment). CONCLUSION: Parental educational deprivation was associated with a failure of MDI but not CSII therapy. These outcomes need confirmation by larger studies. PMID- 21594577 TI - Quantifying high dependency care: a prospective cohort study in Yorkshire (UK). AB - High dependency care (HDC) is a level of care situated between intensive care and usual ward care with its delivery being independent of location. Inadequate definition makes it problematic to determine the number of children receiving HDC, to identify their care setting and therefore to undertake service planning. We aimed to estimate the volume of hospital inpatient HDC in a geographically defined population using a customised measurement tool in four types of paediatric hospital services (1) tertiary specialist wards, (2) tertiary paediatric intensive care units, (3) district general hospitals (DGHs) general wards and (4) wards at a major acute general hospital. A region-wide prospective cohort study during 2005 collected data to develop a 36-item HDC measurement tool, which then identified children receiving HDC by day and night. The cohort identified 1,763 children as receiving HDC during an admission to 1 of 36 hospital wards in 14 hospitals. HDC was delivered during 9,077 shift periods of 12 h or 4,538 bed days. The volume of care and patient profiles varied by hospital type, within hospital by ward type and by age and season. Tertiary specialist wards and ICUs provided 72% of HDC, with the remainder delivered at the DGHs and the major acute general hospital. The volume of admissions to tertiary specialist wards showed little seasonality and children tended to be older (26% were aged 10-15 years). By comparison, admissions to DGHs were younger with an excess during the winter months. This is the first UK study to quantify HDC from empirical data encompassing all hospital and ward types within a large clinical network. A lack of HDC-designated beds across the region resulted in HDC delivery on all types of hospital wards. The study size and representativeness makes the estimated number of HDC bed days per head of population likely to reflect the wider UK population. PMID- 21594578 TI - Non-cell-autonomous tumor suppression: oncogene-provoked apoptosis promotes tumor cell senescence via stromal crosstalk. AB - Activated oncogenes evoke cellular fail-safe programs such as apoptosis, senescence, or autophagy to protect the organism from the expansion of damaged and potentially harmful cells. Non-cell-autonomous interactions between tumor cells and nonmalignant bystander cells add to cell-autonomous modes of tumor suppression during tumor development and progression. In particular, the role of stroma or host immune cells converting tumor-generated signals into a response that feeds back to the tumor cell population has been experimentally underappreciated. Using the EMU-myc transgenic mouse lymphoma model, we elucidated how constitutive Myc signaling indirectly promotes cellular senescence via cytokines that were released by nonmalignant cells in response to oncogene evoked cell-autonomous effects. Specifically, Myc primarily promotes apoptosis in a subset of the tumor cell population, leading to the attraction of macrophages, which subsequently engulf the apoptotic remainders. Phagocytosis-activated macrophages, in turn, exhibit strongly increased secretion of various cytokines, among them transforming growth factor beta to an extent that is capable of inducing cellular senescence in surrounding malignant cells. Our findings, recapitulated in human aggressive B-cell lymphomas, unveil that apoptosis and senescence are not simply two context-dependent cell-autonomous choices of stress responses, but rather cooperate via extracellular mediators-namely cells of the innate immune system-to profoundly limit tumorigenesis in vivo. A deeper mechanistic understanding of the organismic interconnection between different fail-safe programs will help to identify cellular components of the tumor stroma and their signal mediators that are readily available to impose a second line of host defense against cancer cells. This will open new perspectives for the development of antineoplastic therapies, whose targets not only encompass tumor but also stroma cell populations. PMID- 21594581 TI - Cross-sectional study of bone metabolism with nutrition in adult classical phenylketonuric patients diagnosed by neonatal screening. AB - The mechanism underlying the development of osteopenia or osteoporosis in longstanding phenylketonuria (PKU) remains to be clarified. We investigated the details of bone metabolism in 21 female and 13 male classical PKU patients aged 20-35 years. Vitamin D (VD), parathyroid hormone (PTH), bone turnover markers, and daily nutrient intake were examined. The patients had lower daily energy and protein intake than did the age-matched controls (22 women, 14 men), but their respective fat, VD, and calcium intake did not differ. Serum 1,25-dihydroxy VD and 25-hydroxy VD levels in female and male patient groups were significantly higher and lower than those in respective control groups (females, P < 0.001; males, P < 0.05 and P < 0.01, respectively). Serum intact PTH levels were significantly higher in the female patient group (P < 0.05). Urinary calcium levels in the patient groups were significantly higher than those of the control subjects (females, P < 0.001; males, P < 0.05). Bone resorption markers were significantly higher in patients than in controls, although bone formation markers were not different. Patient serum levels of osteoprotegerin-inhibiting bone resorption were significantly lower (females, P < 0.001; males, P < 0.01). None of the bone parameters correlated significantly with serum phenylalanine or nutrient intake. PKU patients exhibited lower VD status and more rapid bone resorption despite normal calcium-VD intakes. PMID- 21594579 TI - Novel ARF/p53-independent senescence pathways in cancer repression. AB - Cellular senescence, which can be induced by various stimuli, is a stress response that manifests as irreversible cell cycle arrest. Recent studies have revealed that cellular senescence can serve as a critical barrier for cancer development. Induction of cellular senescence by oncogenic insults, such as Ras overexpression or by inactivation of PTEN tumor suppressor, triggers an ARF/p53 dependent tumor-suppressive effect which can significantly restrict cancer progression. Given the important role of the ARF/p53 pathway in cellular senescence and tumor suppression, drugs that stabilize p53 expression have been developed and tested in clinical trials. However, a major hurdle for p53 targeting in cancer treatment arises from the frequent deficiency or mutation of ARF or p53 in human cancers, which, in turn, profoundly compromises their tumor suppressive ability. Recent discoveries of novel regulators involved in ARF/p53 independent cellular senescence not only reveal novel paradigms for cellular senescence but also provide alternative approaches for cancer therapy. PMID- 21594580 TI - Arsenic trioxide induces autophagy and apoptosis in human glioma cells in vitro and in vivo through downregulation of survivin. AB - Gliomas are the most aggressive of all human malignancies. Survivin is overexpressed in gliomas, and overexpression of survivin is associated with the progression of gliomas and the poor prognosis of glioma patients. Arsenic trioxide (ATO) is used in patients with acute promyelocytic leukemia and is active in vitro in several solid tumor cell lines. In the present study, the human glioma cell line U118-MG was used to investigate the anti-cancer effect of ATO in vitro and in vivo. The molecular mechanisms of the relationship between cell death (autophagy and apoptosis) and survivin were analyzed. ATO reduced cell viability through an increase in mitotic cells in a concentration-dependent manner. The mechanisms of ATO-induced autophagy and apoptosis were mediated by the inhibition of PI3K/Akt and the activation of MAPK signaling pathways. The ATO treatment of U118-MG cells pre-treated with specific chemical inhibitors of PI3K/AKT and MAPK significantly changed the cytotoxicity and the expression of survivin, suggesting that survivin plays a pivotal role in ATO-induced cell death. When U118-MG cells were transfected with survivin shRNA, the results demonstrated a significant increase in apoptotic and autophagic cells. In in vivo studies, the ATO treatment of SCID mice showed a significant tumor growth delay time and the decreased expression of survivin in tumor tissue. An important result from the current study is the finding that survivin could suppress both autophagy and apoptosis in glioma cells. This study suggests that ATO treatment or survivin inhibition could be a novel therapeutic strategy in malignant gliomas. PMID- 21594582 TI - Acute-onset hypomagnesemia-induced hypocalcemia caused by the refractoriness of bones and renal tubules to parathyroid hormone. AB - Chronic hypomagnesemia is closely associated with hypocalcemia, which is caused by impaired parathyroid hormone (PTH) secretion or the refractoriness of bone and renal tubules to PTH. The dominant mechanism of acute-onset, hypomagnesemia induced hypocalcemia is currently unclear. An 83-year-old man who had undergone chemotherapy with carboplatin for prostate cancer suffered from acute diarrhea and finger paresthesia. Laboratory data confirmed hypocalcemia as well as hypomagnesemia. Urinary calcium levels were not measured. However, the urinary fractional excretion of Mg (FE(Mg)) was elevated. Despite elevated PTH levels, the renal tubular maximal reabsorption rate of phosphate to GFR (TmP/GFR) was elevated, and bone formation and resorption markers were suppressed. A magnesium loading test revealed a clear magnesium deficiency. After administration of magnesium, bone marker levels were increased, and TmP/GFR was reduced to normal levels, despite the persistent elevation of PTH. Serum calcium levels eventually increased to approximately the reference range. Clinical histories and these observations both suggest that when patients with hypomagnesemia-induced hypocalcemia rapidly lose magnesium through complications such as diarrhea, the primary cause may be the refractoriness of bone and renal tubules to PTH, rather than impaired PTH secretion. PMID- 21594583 TI - Effect of diet and lifestyle factors on bone health in postmenopausal women. AB - Our objective was to examine the effect of nutritional intake and lifestyle factors on bone mass in postmenopausal Saudi women. A total of 122 apparently healthy postmenopausal Saudi women were recruited from the Center of Excellence for Osteoporosis Research in Jeddah. A questionnaire on lifestyle habits and dietary intake was administered to all participants. Anthropometric and bone mineral density (BMD) values were measured. Fasting blood samples were taken to measure concentrations of bone-related parameters and hormones. Most of the sample population was found to be vitamin D deficient with a serum vitamin D level below 50 nmol/l. Those participants with normal BMD values had significantly lower serum vitamin D levels than osteopenic individuals (P < 0.05). Overall, mean total caloric, total fat, and saturated fat intakes were above recommended levels. Almost 60% of the total study population had lower calcium intake than the estimated average requirements whereas the whole population had vitamin D intake level below the estimated average requirements. Only BMD of the femoral neck showed significant correlations with serum vitamin D level and dietary cholesterol intake. After adjustment for confounding variables; serum vitamin D levels were significantly correlated with cholesterol intake. Dietary calcium intake was significantly correlated with intake of protein and fiber whereas dietary vitamin D intake was significantly correlated with intake level of total fat, all fatty acids, cholesterol, and fiber. Our findings reveal the important role of dietary vitamin D and calcium in osteopenic patients and the likely requirement for supplementation of these nutrients in the Saudi population. PMID- 21594584 TI - Unraveling the transcriptional regulatory machinery in chondrogenesis. AB - Since the discovery of SOX9 mutations in the severe human skeletal malformation syndrome campomelic dysplasia in 1994, Sox9 was shown to be both required and sufficient for chondrocyte specification and differentiation. At the same time, its distant relatives Sox5 and Sox6 were shown to act in redundancy with each other to robustly enhance its functions. The Sox trio is currently best known for its ability to activate the genes for cartilage-specific extracellular matrix components. Sox9 and Sox5/6 homodimerize through domains adjacent to their Sry related high-mobility-group DNA-binding domain to increase the efficiency of their cooperative binding to chondrocyte-specific enhancers. Sox9 possesses a potent transactivation domain and thereby recruits diverse transcriptional co activators, histone-modifying enzymes, subunits of the mediator complex, and components of the general transcriptional machinery, such as CBP/p300, Med12, Med25, and Wwp2. This information helps us begin to unravel the mechanisms responsible for Sox9-mediated transcription. We review here the discovery of this master chondrogenic trio and its roles in chondrogenesis in vivo and at the molecular level, and we discuss how these pioneering studies open the way for many additional studies that are needed to further increase our understanding of the transcriptional regulatory machinery operating in chondrogenesis. PMID- 21594585 TI - Correlation between arterial blood volume obtained by arterial spin labelling and cerebral blood volume in intracranial tumours. AB - OBJECTIVE: To compare measurements of the arterial blood volume (aBV), a perfusion parameter calculated from arterial spin labelling (ASL), and cerebral blood volume (CBV), calculated from dynamic susceptibility contrast (DSC) MRI. In the clinic, CBV is used for grading of intracranial tumours. MATERIALS AND METHODS: Estimates of aBV from the model-free ASL technique quantitative STAR labelling of arterial regions (QUASAR) experiment and of DSC-CBV were obtained at 3T in ten patients with eleven tumours (three grade III gliomas, four glioblastomas and four meningiomas, two in one patient). Parametric values of aBV and CBV were determined in the tumour as well as in normal grey matter (GM), and tumour-to-GM aBV and CBV ratios were calculated. RESULTS: In a 4-pixel ROI representing maximal tumour values, the coefficient of determination R (2) was 0.61 for the comparison of ASL-based aBV tumour-to-GM ratios and DSC-MRI-based CBV tumour-to-GM ratios and 0.29 for the comparison of parametric values of ASL aBV and DSC-CBV, under the assumption of proportionality. Both aBV and CBV showed a non-significant tendency to increase when going from grade III gliomas to glioblastomas to meningiomas. CONCLUSION: These results suggest that measurement of aBV is a potential tool for non-invasive assessment of blood volume in intracranial tumours. PMID- 21594586 TI - Personalized antiplatelet therapy: review of the latest clinical evidence. AB - P2Y12-ADP receptor antagonist use has been critical in the development of percutaneous coronary intervention, dramatically reducing the rate of early stent thrombosis. However, it recently was observed that a significant proportion of patients do not achieve optimal platelet reactivity inhibition after clopidogrel loading dose. The large interindividual variability in clopidogrel responsiveness is related to several factors, including the genetic polymorphism of hepatic cytochrome P450 2C19 (CYP2C19*2), which recently has been highlighted by a warning from the U.S. Food and Drug Administration. Of importance, patients exhibiting reduced clopidogrel metabolism and/or low clopidogrel responsiveness (ie, high on-treatment platelet reactivity) have an increased rate of thrombotic events after percutaneous coronary intervention. This review summarizes the current knowledge on this important clinical issue. While the future of genetic testing remains undetermined, several trials are underway to demonstrate the potential utility of platelet reactivity testing with P2Y12-ADP receptor antagonists. PMID- 21594587 TI - A qualitative study of an internet-based support group for women with sexual distress due to gynecologic cancer. AB - Internet-based support groups for cancer patients have been studied extensively; very few have focused on gynecologic cancer. We pilot-tested a web-based support group for gynecologic cancer patients and assessed women's perceptions of the intervention. Twenty-seven gynecologic cancer patients were randomized to an immediate intervention or a waitlist control group. Women participated in a 12 week, web-based support group focusing on sexuality-related topics. Semi structured interviews were conducted to investigate the feasibility and efficacy of the intervention. Women reported benefits to participating in the intervention, including receiving support from group members and moderators, increased emotional well-being, improved feelings of body image and sexuality, and comfort in discussing sexuality online. Web-based support groups are both feasible and accepted by gynecologic cancer patients with psychosexual distress. The online format provided women with easy access to the support group and anonymity in discussing psychosexual concerns. Women with gynecologic cancer may benefit from participating in online support groups which provide an environment of relative anonymity to discuss psychosexual concerns. PMID- 21594588 TI - Urinary pH and renal lithiasis. AB - Formation of calcium oxalate crystals, either as monohydrate or dihydrate, is apparently unrelated to urinary pH because the solubilities of these salts are practically unaltered at physiologic urinary pH values. However, a urinary pH <5.5 or >6.0 may induce uric acid or calcium phosphate crystals formation, respectively, which under appropriate conditions may induce the development of the calcium oxalate calculi. We assessed the relationship between the urinary pH and the formation of different types of calculi. A retrospective study in 1,478 patients was done. We determined the composition, macrostructure, and microstructure of the calculi and the urinary pH, 50.9% of calcium oxalate monohydrate unattached calculi were present in patients with urinary pH <5.5. We found that 34.1 and 41.5% of calcium oxalate dihydrate calculi were present in patients with urinary pH <5.5 and >6.0, respectively. Infectious calculi were found primarily in patients with urinary pH >6.0 (50.7%). Only calcium oxalate monohydrate papillary calculi were associated with urinary pH between 5.5 and 6.0 (43.1%). Urine of pH <5.5 shows an increased capacity to develop uric acid crystals, which can act as a heterogeneous nuclei of calcium oxalate crystals. In contrast, urine of pH >6.0 has an increased capacity to develop calcium phosphate crystals, which can act as a heterogeneous nuclei of calcium oxalate crystals. Oxalate monohydrate papillary calculi were associated to pH between 5.5 and 6.0 because the injured papilla acts as a heterogeneous nucleant. Consequently, measurement of urinary pH may be used to evaluate the lithogen risk of given urine. PMID- 21594589 TI - Pseudoprogression: relevance with respect to treatment of high-grade gliomas. AB - The post-treatment imaging assessment of high-grade gliomas remains challenging notwithstanding the increased utilization of advanced MRI and PET imaging. Several post-treatment imaging entities are recognized including: late-delayed radiation injury, including radionecrosis mimicking tumor progression; early delayed (within 6 months of temozolomide-based chemoradiation) post-treatment radiographic changes, herein referred to as pseudoprogression (the subject of this review); early post-treatment changes following local glioma therapy (i.e. biodegradable BCNU wafer implantation or stereotactic radiotherapy); and pseudoresponse, seen following treatment with angiogenic inhibition based therapy such as bevacizumab. A literature review searched specifically for "pseudoprogression" within the last 5 years (2005-2010). Approximately 24 recent papers were identified and reviewed in detail. Eight small population-based studies demonstrate 26-58% (median 49%) of glioblastoma patients treated with chemoradiotherapy manifest early disease progression at first post-radiotherapy imaging. Patients with early radiographic disease progression continued on planned therapy, and a median of 38% (range 28-66%) showed radiographic improvement or stabilization and were defined retrospectively as manifesting pseudoprogression. In conclusion, pseudoprogression is a frequent early post treatment imaging change that at present is not easily differentiated from tumor progression by anatomic or physiologic brain imaging. Consequently, an operational definition of pseudoprogression has been adopted by the Response Assessment in Neuro-Oncology Working Group wherein either the index (i.e. target) lesion stabilizes or diminishes in size on continued post-radiation (temozolomide) therapy as determined by follow-up radiologic imaging. PMID- 21594590 TI - Quality of drug information database research for clinical decision support. AB - This commentary identifies studies that have compared commercially available DI databases, and discusses improvements in study methodology that might better guide clinicians in selecting resources for their practice setting. We also provide suggestions for future direction of research in this area with an eye towards clinical decision support systems (CDSS). The body of comparative research of commercially available DI databases is small, and provides little value to the average clinician when making purchasing decisions. Transparency of study methodology would allow readers to choose a database that best fits their practice needs. Future research must consider how DI resources are imbedded within CDSS, such that the alerts generated by the CDSS are consistent with the primary DI workhorse of the practice site. Cohesion between CDSS and DI resources needs to be a consideration in future DI resource comparative research. PMID- 21594591 TI - Drug-related problems identified in post-discharge medication reviews for patients taking warfarin. AB - OBJECTIVE: To characterise the nature of the drug-related problems with warfarin therapy identified in pharmacist-conducted medication reviews during a collaborative post-discharge warfarin management service, with a focus on potentially serious drug interactions. SETTING: Australian community pharmacy practice. METHOD: Medication review reports submitted by pharmacists to patients' general practitioners as part of the service were reviewed and the type and clinical significance of the warfarin-associated drug-related problems, and the pharmacists' recommendations were classified. The prevalence of prescribing of 'potentially hazardous' warfarin drug interactions was investigated and compared with the frequency of documentation of these interactions in the medication review reports. MAIN OUTCOME MEASURE: The number and nature of warfarin associated drug-related problems identified and the rate of documentation of 'potentially hazardous' warfarin drug interactions in the reports from pharmacist conducted medication reviews. RESULTS: A total of 157 warfarin-associated drug related problems were documented in 109 medication review reports (mean 1.4 per patient, 95% CI 1.3-1.6, range 0-5). Drug selection and Education or information were the most commonly identified warfarin-associated drug-related problems; most drug-related problems were of moderate clinical significance. Eight of 23 potentially serious warfarin drug interactions (34.8%) were identified in the medication review reports. CONCLUSION: Pharmacists addressing drug selection and warfarin education drug-related problems during medication reviews may have contributed to the positive outcomes of the post-discharge service. Warfarin drug interactions were frequently identified; however, well-recognised potentially hazardous interactions were under-reported. Improved communication along the continuum of care would permit improved targeting of drug-related problem reporting, especially in relation to preventable drug interactions. PMID- 21594592 TI - Study on improvement of extracellular production of recombinant Thermobifida fusca cutinase by Escherichia coli. AB - Escherichia coli is one of the most commonly used host strains for recombinant protein production. More and more research works on the production of recombinant protein indicate that extracellular production throughout a culture medium is more convenient and attractive compared to intracellular production. In present work, inducing temperature and isopropyl beta-D: -1-thiogalactopyranoside (IPTG) concentration were investigated to decrease the formation of inclusion body and increase the amount of soluble recombinant cutinase initially. Enzyme activity in the culture medium reached to 118.9 U/ml at 64 h of culture, and no inclusion body was detected in cytoplasm under the inducement condition of 0.2 mM IPTG and 30 degrees C. In addition, it was found that a large amount of cutinase had been accumulated in periplasm since 16-h cultivation under the same inducement condition. Therefore, glycine and surfactant sodium taurodeoxycholate (TDOC) were further used to promote the leakage of recombinant cutinase from periplasm. Supplied with 100 mM glycine and 1 mM TDOC, the amount of cutinase in periplasm decreased remarkably, and the activity in the culture medium reached to 146.2 and 149.2 U/ml after 54 h of culturing, respectively. PMID- 21594593 TI - Expression and production of therapeutic recombinant human platelet-derived growth factor-BB in Pleurotus eryngii. AB - Recombinant human platelet-derived growth factor-BB (rhPDGF-BB) is widely used in many therapeutic applications. Until now, there has been no report on rhPDGF-BB expressed in fungi. In this study, we tested whether Pleurotus eryngii could support the expression of human therapeutic rhPDGF-BB protein. A binary vector pCAMBIA1304 containing the hPDGF-BB gene was constructed and introduced into P. eryngii via Agrobacterium tumefaciens-mediated transformation. The transformation of hPDGF-BB gene was confirmed by Southern blot and PCR, whereas the expression was confirmed by Western blot analysis. The recombinant hPDGF-BB reached a maximum expression level of 1.98% of total soluble protein in transgenic mycelia and was in dimeric form. A bioassay revealed that hPDGF-BB expressed in P. eryngii increased proliferation of NIH-3T3 cells similarly to standard material. These results suggest that P. eryngii can be a robust system for the production of human therapeutic proteins including the hPDGF-BB. PMID- 21594594 TI - Distribution and selection of poly-3-hydroxybutyrate production capacity in methanotrophic proteobacteria. AB - Methanotrophs are known to produce poly-3-hydroxybutyrate (PHB), but there is conflicting evidence in the literature as to which genera produce the polymer. We screened type I and II proteobacterial methanotrophs that use the ribulose monophosphate and serine pathways for carbon assimilation, respectively, for both phaC, which encodes for PHB synthase, and the ability to produce PHB under nitrogen-limited conditions. Twelve strains from six different genera were evaluated. All type I strains tested negative for phaC and PHB production; all Type II strains tested positive for phaC and PHB production. In order to identify conditions that favor PHB production, we also evaluated a range of selection conditions using a diverse activated sludge inoculum. Use of medium typically recommended for methanotroph enrichment led to enrichments dominated by type I methanotrophs. Conditions that were selected for enrichments dominated by PHB producing Type II methanotrophs were: (1) use of nitrogen gas as the sole nitrogen source in the absence of copper, (2) use of a dilute mineral salts media in the absence of copper, and (3) use of media prepared at pH values of 4-5. PMID- 21594595 TI - Short-term effect of fine particulate matter (PM2.5) and ozone on daily mortality in Lisbon, Portugal. AB - INTRODUCTION: Urban ambient air pollution exposures continue to be a global public health concern. Although air quality targets are often exceeded in Lisbon, the largest city in Portugal, there is currently no study that has assessed the quantitative impact of these pollutants on daily mortality. MATERIALS AND METHOD: In this study, we conduct a time series analysis using generalized additive modeling to determine the exposure-response effect from ambient ozone (O(3)) and fine particulate matter (PM(2.5)) concentrations on daily mortality in Lisbon. The dataset used was limited to the Lisbon municipality and for the period 2004 2006. RESULTS AND CONCLUSION: For PM(2.5) exposures, we found that the relative risk for cardiovascular mortality in the population group >= 65 years is 2.39% (95%C.I. 1.29%, 3.50%) for each 10 MUg/m(3) increase. A statistically significant cause-effect relationship for PM(2.5) and mortality was not observed in other population groups. We also report O(3) exposures to be associated with an increase of 1.11% (95%C.I. (0.58, 1.64)) for all-cause mortality in the population group >= 65 years and an increase of 0.96% (95%C.I. (0.56, 1.35)) for the general population. When analyzing by cause of death, our results showed a stronger association between O(3) exposure and cardiovascular mortality. PMID- 21594596 TI - Detection and follow-up of torque teno midi virus ("small anelloviruses") in nasopharyngeal aspirates and three other human body fluids in children. AB - Torque teno midi virus/small anellovirus (TTMDV/SAV) is a member of the family Anelloviridae. It has a single-stranded, circular, negative-sense DNA genome. Its pathogenic role in human disease remains to be confirmed. In this study, viral shedding, molecular epidemiology and genetic diversity of TTMDV/SAV were studied in human body fluids. Nasopharyngeal aspirates collected from children with acute respiratory disease were tested by PCR/nested PCR for TTMDV/SAV in two seasons (2005/2006, 2006/2007). Two years later, additional urine, stool, and serum samples and nasopharyngeal aspirates were collected from eight symptomless children for follow-up investigation. Forty-three (46.7%) of the 92 nasopharyngeal aspirates collected contained TTMDV/SAV. High genetic diversity was observed; however, identical sequences were also detected in two patients. The mean age of the infected children was 3 years (1 months-8 years), and 58% of them were female. Co-infection with RSV was detected in 23% of the samples. In a follow-up study, nasopharyngeal aspirates and serum of six (75%), stool samples of four (50%) and urine samples of two (25%) of the eight children were anellovirus-positive. None of the anellovirus sequences were identical in the two collection periods, but identical sequences were detected in different body fluids collected at the same time from the same child. TTMDV/SAVs shedding was detected in four human body fluids. As a consequence, it is possible that generalized infection and fecal/uro-oral transmission of TTMDV/SAV occur. TTMDV/SAVs are frequently present in nasopharyngeal aspirates, although the variants may only be transient agents. Further research is needed to investigate the pathogenesis and pathogenic role of TTMDV/SAV. PMID- 21594598 TI - Evaluation of peptide nucleic acid array for the detection of hepatitis B virus mutations associated with antiviral resistance. AB - A major problem of long-term antiviral therapy in chronic hepatitis B patients is the emergence of hepatitis B virus (HBV) mutations associated with drug resistance. Recently, a new array using peptide nucleic acids (PNAs), which are synthetic nucleic acid analogues, was developed for the detection of HBV mutations at six different codon positions associated with lamivudine (LAM) and adefovir (ADV) resistance. We compared the PNA array with direct sequencing and reverse hybridization (INNO-LiPA) in 73 samples obtained from chronic hepatitis B patients. The PNA array detected mutations associated with LAM and/or ADV resistance in 60 (82.2%) of the 73 samples. The overall concordance rate of PNA array and INNO-LiPA compared with direct sequencing was 99.5% and 98.2%, respectively. The rate of complete concordance between PNA array and INNO-LiPA was 92.7%. The PNA array assay results were comparable with INNO-LiPA for detection of HBV mutations associated with antiviral resistance. PMID- 21594597 TI - Identification and characterization of a neutralizing-epitope-containing spike protein fragment in turkey coronavirus. AB - Little is known about the neutralizing epitopes in turkey coronavirus (TCoV). The spike (S) protein gene of TCoV was divided into 10 fragments to identify the antigenic region containing neutralizing epitopes. The expression and antigenicity of S fragments was confirmed by immunofluorescence antibody (IFA) assay using an anti-histidine monoclonal antibody or anti-TCoV serum. Polyclonal antibodies raised against expressed S1 (amino acid position 1 to 573 from start codon of S protein), 4F/4R (482-678), 6F/6R (830-1071), or Mod4F/Epi4R (476-520) S fragment recognized native S1 protein and TCoV in the intestines of TCoV infected turkey embryos. Anti-TCoV serum reacted with recombinant 4F/4R, 6F/6R, and Mod4F/Epi4R in a western blot. The results of a virus neutralization assay indicated that the carboxyl terminal region of the S1 protein (Mod4F/Epi4R) or the combined carboxyl terminal S1 and amino terminal S2 protein (4F/4R) possesses the neutralizing epitopes, while the S2 fragment (6F/6R) contains antigenic epitopes but not neutralizing epitopes. PMID- 21594599 TI - A novel monopartite begomovirus infecting sweet potato in Brazil. AB - The complete genome sequences of two monopartite begomovirus isolates (genus Begomovirus, family Geminiviridae) present in a single sweet potato (Ipomoea batatas) plant collected in Sao Paulo, Brazil, are presented. Based on the current taxonomic criteria for the genus Begomovirus, one of the isolates was shown to represent a novel species, tentatively named Sweet potato leaf curl Sao Paulo virus (SPLCSPV). The other isolate represented a new strain of sweet potato leaf curl virus, named sweet potato leaf curl virus-Sao Paulo (SPLCV-SP). The full genome sequence of the SPLCSPV isolate shared the highest nucleotide identity (87.6%) with isolates of sweet potato leaf curl Spain virus (SPLCESV). Phylogenetic and recombination analyses were used to investigate the relationships of these isolates to other monopartite Ipomoea-infecting begomoviruses. PMID- 21594601 TI - Does laparoscopic ovarian diathermy change clomiphene-resistant PCOS into clomiphene-sensitive? AB - PURPOSE: To test the role of laparoscopic ovarian diathermy (LOD) in improving the ovarian response to clomiphene citrate (CC) in clomiphene-resistant polycystic ovary syndrome (PCOS) patients. METHODS: The study comprised of 234 CC resistant PCOS women who were treated with LOD. Eighty-four patients that remained anovulatory after LOD received 100-150 mg CC for 5 days starting from day 3 of induced menstruation for 1-3 cycles. Outcome measures were; ovulation, pregnancy, miscarriage and live birth rates. RESULTS: Ovulation occurred in 80/162 cycles (49.4%) and in 30/84 patients (35.7%). Pregnancy occurred in 13/84 patients (15.5%) and in 13/80 cycles (16.2%). Miscarriage and live birth rates were 23.1 and 76.9%, respectively. Ovulatory women showed significantly lower baseline BMI (P < 0.001), Ferriman-Gallwey score (P = 0.02), testosterone (P = 0.03), higher sex hormone binding globulin and lower free androgen index (P < 0.001) compared with anovulatory women. The baseline fasting insulin was statistically significantly lower and fasting glucose:insulin ratio was statistically significantly higher (P = 0.003, 0.002) in ovulatory compared with anovulatory patients. CONCLUSIONS: LOD improves the ovarian response to CC in at least one-third of CC-resistant patients who remained anovulatory following LOD especially in women who are less hyperandrogenic and less insulin resistant. PMID- 21594600 TI - Epigenetic profiling of heterochromatic satellite DNA. AB - Sugar beet (Beta vulgaris) chromosomes consist of large heterochromatic blocks in pericentromeric, centromeric, and intercalary regions comprised of two different highly abundant DNA satellite families. To investigate DNA methylation at single base resolution at heterochromatic regions, we applied a method for strand specific bisulfite sequencing of more than 1,000 satellite monomers followed by statistical analyses. As a result, we uncovered diversity in the distribution of different methylation patterns in both satellite families. Heavily methylated CG and CHG (H=A, T, or C) sites occur more frequently in intercalary heterochromatin, while CHH sites, with the exception of CAA, are only sparsely methylated, in both intercalary and pericentromeric/centromeric heterochromatin. We show that the difference in DNA methylation intensity is correlated to unequal distribution of heterochromatic histone H3 methylation marks. While clusters of H3K9me2 were absent from pericentromeric heterochromatin and restricted only to intercalary heterochromatic regions, H3K9me1 and H3K27me1 were observed in all types of heterochromatin. By sequencing of a small RNA library consisting of 6.76 million small RNAs, we identified small interfering RNAs (siRNAs) of 24 nucleotides in size which originated from both strands of the satellite DNAs. We hypothesize an involvement of these siRNAs in the regulation of DNA and histone methylation for maintaining heterochromatin. PMID- 21594602 TI - A singular observation of a giant benign Brenner tumor of the ovary. AB - INTRODUCTION: Brenner tumors are rare transitional cell tumors of the ovary. They are usually benign neoplasms, of solid or solid-cystic structure and small size. We describe the case of a benign, predominantly cystic Brenner tumor measuring 39 cm in diameter. CASE REPORT: A 62-year-old woman presented to the outpatient visit complaining about vague abdominal symptoms such as constipation and meteorism. Ultrasonography and CT scan showed the presence of a voluminous cystic mass, with fluid content, displacing other intra-abdominal organs. The patient underwent elective surgical excision, and there were no complications. Definitive pathological examination showed a metaplastic benign Brenner tumor. CONCLUSION: The largest benign Brenner tumors reported in literature have been up to 30 cm in size, and greater size has been thought to be a predictor of malignancy. We have seen, however, that it is possible for larger lesions of this type to have a completely benign behavior; consequently, a benign nature should not be excluded even in the event of a large ovarian lesion. PMID- 21594603 TI - Clear cell adenocarcinoma of the ovary arising in atypical endometriosis: a report of eight cases. AB - INTRODUCTION: Studies of clear cell adenocarcinoma of the ovary (CCAO) arising from endometriosis are scant. MATERIALS AND METHODS: The author reviewed 13 cases CCAO of our pathology laboratory for the presence of endometriosis within the tumor. Eight (61.5%) of the 13 tumors contained endometriosis within the tumor. Of the eight cases, seven were atypical endometriosis and one was ordinary endometriosis. The age of the eight patients with CCAO ranged from 35 to 82 years with a median of 52 years. RESULTS: Grossly, the ovarian tumors of CCAO were characterized by unilocular cystic lesions containing solitary or multiple nodules in the inner surfaces. The outer surface was smooth and free of tumor. Histologically, the nodules showed typical features of pure CCAO with clear cells, hobnail cells, and hyalinized stroma. The non-nodular flat areas of the tumor were composed of a layer of atypical clear cells and endometriosis consisting of a layer of endometrial epithelium and endometrial stroma. Incipient foci of CCAO were occasionally recognized in the atypical clear cells. Seven cases with endometriosis showed atypia of the endometrial epithelium (atypical endometroiosis), and one case showed no atypia. There was contiguity between the CCAO and atypical clear cells and between atypical clear cells and endometriosis. Contiguity between atypical endometriosis and CCAO was also recognized in a few areas. The outer surface was devoid of tumor cells and endometriosis. CONCLUSIONS: The author speculates as follows. An endometrial cyst develops in the ovary. Its epithelium undergoes initiation, thus giving rise to atypical endometriosis consisting of dysplastic or intraepithelial neoplastic epithelium. The atypical endometriosis further undergoes initiation, leading to the atypical clear cells, and ultimately leads to CCAO showing a unilocular cyst consisting of inner masses of CCAO and flat areas composed of a layer of atypical clear cells with incipient CCAO and atypical endometriosis. PMID- 21594604 TI - Prenatal diagnosis of 45,X/46,XY mosaicism with cleft lip and epispadias. AB - INTRODUCTION: 45,X/46,XY mosaicism is an uncommon chromosomal anomaly with a range of phenotypes from normal males to cases of multiple congenital anomalies. MATERIALS AND METHODS: We report a case with associated cleft lip and epispadias prenatally diagnosed with autopsy evidences. CONCLUSION: Our case, with an uncommon association of congenital anomalies, stresses the difficulty of prenatal counselling regarding 45,X/46,XY mosaicism and discuss the possible role of sex chromosome genes that may be involved in the pathogenesis of both types of midline defect. PMID- 21594605 TI - Economic evaluation of multiplex ligation-dependent probe amplification and karyotyping in prenatal diagnosis: a cost-minimization analysis. AB - PURPOSE: To assess the cost-effectiveness of Multiplex Ligation-dependent Probe Amplification (MLPA, P095 kit) compared to karyotyping. METHODS: A cost minimization analysis alongside a nationwide prospective clinical study of 4,585 women undergoing amniocentesis on behalf of their age (>=36 years), an increased risk following first trimester prenatal screening or parental anxiety. RESULTS: Diagnostic accuracy of MLPA (P095 kit) was comparable to karyotyping (1.0 95% CI 0.999-1.0). Health-related quality of life did not differ between the strategies (summary physical health: mean difference 0.31, p = 0.82; summary mental health: mean difference 1.91, p = 0.22). Short-term costs were lower for MLPA: mean difference 315.68 (bootstrap 95% CI 315.63-315.74; -44.4%). The long term costs were slightly higher for MLPA: mean difference 76.42 (bootstrap 95% CI 71.32-81.52; +8.6%). Total costs were on average 240.13 (bootstrap 95% CI 235.02-245.23; -14.9%) lower in favor of MLPA. Cost differences were sensitive to proportion of terminated pregnancies, sample throughput, individual choice and performance of tests in one laboratory, but not to failure rate or the exclusion of polluted samples. CONCLUSION: From an economic perspective, MLPA is the preferred prenatal diagnostic strategy in women who undergo amniocentesis on behalf of their age, following prenatal screening or parental anxiety. PMID- 21594606 TI - Brain perfusion CT for acute stroke using a 256-slice CT: improvement of diagnostic information by large volume coverage. AB - OBJECTIVES: To compare a 256-slice CT with a simulated standard CT for brain CT perfusion (CTP). METHODS: CTP was obtained in 51 patients using a 256-slice CT (128 detector rows, flying z-focus, 8-cm detector width, 80 kV, 120mAs, 20 measurements, 1 CT image/2.5 s). Signal-to-noise ratios (SNR) were compared in grey and white matter. Perfusion maps were evaluated for cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) in hypoperfused areas and corresponding contralateral regions. Two reconstructed 10-mm slices for simulation of a standard CT (SDCT) were compared with the complete data sets (large-volume CT, LVCT). RESULTS: Adequate image quality was achieved in 50/51 cases. SNR were significantly different in grey and white matter. A perfusion deficit was present in 27 data sets. Differences between the hypoperfusions and the control regions were significant for MTT and CBF, but not for CBV. Three lesions were missed by SDCT but detected by LVCT; 24 lesions were covered incompletely by SDCT, and 6 by LVCT. 21 lesions were detected completely by LVCT, but none by SDCT. CONCLUSIONS: CTP imaging of the brain using an increased detector width can detect additional ischaemic lesions and cover most ischaemic lesions completely. PMID- 21594607 TI - Kinetic properties of Mycobacterium tuberculosis bifunctional GlmU. AB - The UDP-N-acetylglucosamine (UDP-GlcNAc) is present as one of the glycosyl donors for disaccharide linker (D-N-GlcNAc-L-rhamnose) and the precursor of peptidoglycan in mycobacteria. The bifunctional enzyme GlmU involves in the last two sequential steps of UDP-GlcNAc synthetic pathway. Glucosamine-1-phosphate acetyltransferase catalyzes the formation of N-acetylglucosamine-1-phosphate (GlcNAc-1-P) from glucosamine-1-phosphate (GlcN-1-P) and acetyl coenzyme A (Acetyl CoA), and N-acetylglucosamine-1-phosphate uridyltransferase catalyzes the synthesis of UDP-GlcNAc from GlcNAc-1-P and UTP. The previous studies demonstrating the essentiality of GlmU to mycobacterial survival supported GlmU as a novel and potential target for TB drugs. In this work, two accurate and simple colorimetric assays based on 96-well microtiter plate were developed to measure the kinetic properties of bifunctional GlmU including initial velocity, optimal temperature, optimal pH, the effect of Mg2+, and the kinetic parameters. Both of the colorimetric assays for bifunctional GlmU enzyme activities and the kinetic properties will facilitate high-throughput screening of GlmU inhibitors. PMID- 21594608 TI - Evaluation of anthropometric parameters and physical fitness in elderly Japanese. AB - OBJECTIVES: We evaluated anthropometric parameters and physical fitness in elderly Japanese. METHODS: A total of 2,106 elderly Japanese (749 men and 1,357 women), aged 60-79 years, were enrolled in a cross-sectional investigation study. Anthropometric parameters and physical fitness, i.e., muscle strength and flexibility, were measured. Of the 2,106 subjects, 569 subjects (302 men and 267 women) were further evaluated for aerobic exercise level, using the ventilatory threshold (VT). RESULTS: Muscle strength in subjects in their 70s was significantly lower than that in subjects in their 60s in both sexes. Two hundred and twenty-nine men (30.6%) and 540 women (39.8%) were taking no medications. In men, anthropometric parameters were significantly lower and muscle strength, flexibility, and work rate at VT were significantly higher in subjects without medications than these values in subjects with medications. In women, body weight, body mass index (BMI), and abdominal circumference were significantly lower, and muscle strength was significantly higher in subjects without medications than these values in subjects with medications. CONCLUSION: This mean value may provide a useful database for evaluating anthropometric parameters and physical fitness in elderly Japanese subjects. PMID- 21594609 TI - An oat bran meal influences blood insulin levels and related gene sets in peripheral blood mononuclear cells of healthy subjects. AB - The understanding of how fibre-rich meals regulate molecular events at a gene level is limited. This pilot study aimed to investigate changes in gene expression in peripheral blood mononuclear cells (PBMCs) from healthy subjects after consumption of an oat bran-rich meal. Fifteen subjects (8 men and 7 women, aged 20-28 years) ingested meals with oat bran or a control meal after an overnight fast. Blood samples for analysis of postprandial glucose, insulin and triglyceride concentrations were taken during 3 h, while PBMCs for microarray gene expression profiling from five men and five women were taken before and 2 h after the meal. Analysis of transcriptome data was performed with linear mixed models to determine differentially expressed genes in response either to meal intake or meal content, and enrichment analysis was used to identify functional gene sets responding to meal intake and specifically to oat bran intake. Meal intake as such affected gene expression for genes mainly involved in metabolic stress; indicating increased inflammation due to the switch from fasting to fed state. The oat bran meal affected gene sets associated with a lower insulin level, compared with the control meal. The gene sets included genes involved in insulin secretion and beta-cell development, but also protein synthesis and genes related to cancer diseases. The oat bran meal also significantly lowered postprandial blood insulin IAUC compared to control. Further studies are needed to compare these acute effects with the long-term health effects of oat bran. PMID- 21594610 TI - Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8. AB - Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in COL1A1 or COL1A2. We identified a dominant missense mutation, c.3235G>A in COL1A1 exon 45 predicting p.G1079S, in a Japanese family with mild OI. As mutations in exon 45 exhibit mild to lethal phenotypes, we tested if disruption of an exonic splicing cis-element determines the clinical phenotype, but detected no such mutations. In the Japanese family, juvenile-onset hyperuricemia cosegregated with OI, but not in the previously reported Italian and Canadian families with c.3235G>A. After confirming lack of a founder haplotype in three families, we analyzed PRPSAP1 and PRPSAP2 as candidate genes for hyperuricemia on chr 17 where COL1A1 is located, but found no mutation. We next resequenced the whole exomes of two siblings in the Japanese family and identified variable numbers of previously reported hyperuricemia-associated SNPs in ABCG2 and SLC22A12. The same SNPs, however, were also detected in normouricemic individuals in three families. We then identified two missense SNVs in ZPBP2 and GPATCH8 on chromosome 17 that cosegregated with hyperuricemia in the Japanese family. ZPBP2 p.T69I was at the non-conserved region and was predicted to be benign by in silico analysis, whereas GPATCH8 p.A979P was at a highly conserved region and was predicted to be deleterious, which made p.A979P a conceivable candidate for juvenile-onset hyperuricemia. GPATCH8 is only 5.8 Mbp distant from COL1A1 and encodes a protein harboring an RNA-processing domain and a zinc finger domain, but the molecular functions have not been elucidated to date. PMID- 21594612 TI - Bio-medicolegal scientific research in Europe. A country-based analysis. AB - The European mosaic of socio-cultural, economic and legal realities is reflected in forensic and legal medicine, in which a great variety of operational modes of forensic medical services, organisational systems, structures, functional competences and scientific research strategies can be observed. The present work analyses the European bio-medicolegal scientific output of the last 5.5 years (exact time window, January 1, 2005-June 1, 2010), categorising papers by nationality of the corresponding author and forensic sub-discipline in question, in order to identify the peculiarities of national sub-specialised competences and to build up international research projects. This country-based bibliometric analysis, based on the number of articles and the impact factor produced by each European country, also considering its economic profile (gross domestic product and per capita gross domestic product), highlights the prevailing productive role of Western and Southern Europe (Germany, Great Britain, Italy, Switzerland, Spain and France). Categorising scientific output by forensic sub-discipline and branch, significant in terms of impact factor are contributions from Germany (coming first in Pathology, Toxicology, Genetics, Anthropology and Biological Criminalistics), Great Britain (first in Clinical Forensic Medicine, Malpractice and Invalidity-Social Insurance), Switzerland (first in Criminology), Italy (second in Toxicology, Anthropology and Invalidity-Social Insurance), The Netherlands (third in Clinical Forensic Medicine and Medical Law and Ethics), Spain (third in Genetics, Criminalistics and Invalidity-Social Insurance) and France (third in Toxicology and Malpractice). Interestingly, several countries with low gross domestic product, such as Poland, Turkey and other Eastern European nations, show notable scientific production in specific sub-disciplines such as Pathology, Toxicology and Forensic Genetics, suggesting that fruitful international cooperation could be planned and be of interest to funding sources within the European Community, also taking into account funds reserved for depressed areas undergoing development. PMID- 21594611 TI - Genomic medicine and neurological disease. AB - "Genomic medicine" refers to the diagnosis, optimized management, and treatment of disease--as well as screening, counseling, and disease gene identification--in the context of information provided by an individual patient's personal genome. Genomic medicine, to some extent synonymous with "personalized medicine," has been made possible by recent advances in genome technologies. Genomic medicine represents a new approach to health care and disease management that attempts to optimize the care of a patient based upon information gleaned from his or her personal genome sequence. In this review, we describe recent progress in genomic medicine as it relates to neurological disease. Many neurological disorders either segregate as Mendelian phenotypes or occur sporadically in association with a new mutation in a single gene. Heritability also contributes to other neurological conditions that appear to exhibit more complex genetics. In addition to discussing current knowledge in this field, we offer suggestions for maximizing the utility of genomic information in clinical practice as the field of genomic medicine unfolds. PMID- 21594613 TI - Dramatic effect of pop-up satellite tags on eel swimming. AB - The journey of the European eel to the spawning area in the Sargasso Sea is still a mystery. Several trials have been carried out to follow migrating eels with pop up satellite tags (PSATs), without much success. As eels are very efficient swimmers, tags likely interfere with their high swimming efficiency. Here we report a more than twofold increase in swimming cost caused by a regular small satellite tag. The impact was determined at a range of swimming speeds with and without tag in a 2-m swimming tunnel. These results help to explain why the previous use of PSATs to identify spawning sites in the Sargasso Sea was thus far unsuccessful. PMID- 21594614 TI - In the best interests of the deceased: a possible justification for organ removal without consent? AB - Opt-out systems of postmortem organ procurement are often supposed to be justifiable by presumed consent, but this justification turns out to depend on a mistaken mental state conception of consent. A promising alternative justification appeals to the analogical situation that occurs when an emergency decision has to be made about medical treatment for a patient who is unable to give or withhold his consent. In such cases, the decision should be made in the best interests of the patient. The analogous suggestion to be considered, then, is, if the potential donor has not registered either his willingness or his refusal to donate, the probabilities that he would or would not have preferred the removal of his organs need to be weighed. And in some actual cases the probability of the first alternative may be greater. This article considers whether the analogy to which this argument appeals is cogent, and concludes that there are important differences between the emergency and the organ removal cases, both as regards the nature of the interests involved and the nature of the right not to be treated without one's consent. Rather, if opt-out systems are to be justified, the needs of patients with organ failure and/or the possibility of tacit consent should be considered. PMID- 21594615 TI - Urea and atherosclerosis--evidence for a direct link involving apolipoprotein B protein modifications. PMID- 21594616 TI - The level of major urinary proteins is socially regulated in wild Mus musculus musculus. AB - Major urinary proteins (MUPs) are highly polymorphic proteins that have been shown to perform several important functions in the chemical communication of the house mouse, Mus musculus. Production of these proteins in C57Bl/6 females is cyclic, reaching the maximum just before the beginning of estrus. Social environment is an important factor that increases MUP production in both sexes. We examined responsiveness of MUP production to social stimuli in wild mice, Mus musculus musculus. The direction of change of MUP production in males depended on the sex of the stimulus animal. Males up-regulated MUP production when caged with a female, but down-regulated MUP production when caged with a male. Down regulation was more pronounced in males that were defeated in a male-male encounter. Females responded to a male's presence with a decrease in MUP production. We conclude that social modulation of MUP production is specific and, in coordination with other mechanisms, facilitates adjustment of the animal's odor profile to different social contexts. Our results also suggest that in males, MUPs may play an important role in advertizing the male's quality to females. Furthermore, we highlight the importance of analyzing data corrected with creatinine, which show MUP production on the (post)translational level as well as raw data (non-corrected with creatinine), which represent actual concentrations of MUPs in the urine. PMID- 21594617 TI - Reviewer's comment concerning "surgical treatment of thoracic disc herniations via tailored posterior approaches" (doi:10.1007/s00586-011-1821-7 R1 by W. Borm et al.). PMID- 21594618 TI - The chromosomal protein HMGN2 mediates the LPS-induced expression of beta defensins in mice. AB - Human beta-defensin-2 (HBD-2), an antimicrobial peptide produced by epithelial cells, plays an important role in the body's innate and adaptive immunity. High mobility group N2 (HMGN2), a member of the HMG superfamily, binds to chromatin to modulate gene transcription. Previously, we have shown that HMGN2 acts as a positive modulator of the signal transduction cascade in the process of inducible human beta-defensin expression. In our current study, we found that down regulation of HMGN2 reduces the expression level of murine beta-defensin-3 and -4 (mBD-3 and mBD-4), but not mBD-1 upon LPS stimulation in various tissues of pregnant ICR mice, as well as in embryonic and neonatal lungs and livers at different developmental time points. In the control group, murine HMGN2 expression decreased, while mBD-1 and mBD-4 expression increased slightly during development. In the LPS-treated groups, murine HMGN2 and mBD-1 expression did not change significantly, whereas mBD-3 and mBD-4 expression significantly increased in maternal, embryonic, and neonatal tissues, especially the mBD-3 expression. HMGN2 shRNA interference led to decreased mBD-3 and mBD-4 expression, while mBD-1 expression did not significantly change. These results demonstrate that HMGN2 is a component of the LPS-induced mouse beta-defensin response. PMID- 21594619 TI - A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. AB - Selumetinib is a potent, selective MEK inhibitor with efficacy in several tumor models. This study compared selumetinib with capecitabine in patients with advanced or metastatic pancreatic cancer who had been pretreated with a gemcitabine-based regimen. In this randomized, multicenter phase II study (NCT00372944), patients received either 100 mg oral selumetinib twice daily or 1,250 mg/m(2) oral capecitabine twice daily for 2 weeks followed by a 1-week break, given in 3-weekly cycles. The primary endpoint was overall survival. In all 70 patients were randomized. The median survival was 5.4 months in the selumetinib group and 5.0 months in the capecitabine group (hazard ratio 1.03; two-sided 80% confidence interval = 0.68,1.57; P = 0.92). Disease progression events occurred in 84% and 88% of patients in the selumetinib and capecitabine treatment groups, respectively. Gastrointestinal adverse events (nausea, vomiting and diarrhea) were commonly observed in both treatment groups. Other frequently reported adverse events were acneiform dermatitis and peripheral edema with selumetinib, and palmar-plantar erythrodysaesthesia with capecitabine. There was no statistically significant difference in overall survival between selumetinib and capecitabine as second-line treatment in patients with advanced pancreatic cancer. Selumetinib was well tolerated with a manageable safety profile. PMID- 21594620 TI - A right-left aortic arch pattern made up by a bicarotid trunk, a left subclavian, a left vertebral and a right retroesophageal subclavian artery. AB - We present several vascular variations of the aortic arch vessels observed in a 35-year-old man during magnetic resonance angiography (MRA). The arterial branches of the aortic arch are from right to left: a bicarotid trunk, a left vertebral artery, a left subclavian artery, and a right retroesophageal subclavian artery. The right vertebral artery arises from the right carotid artery. Although a right retroesophageal subclavian artery has been reported in association with different anatomic variations of the aortic arch, to our knowledge this is the first MRA description of this particular combination of variations. PMID- 21594621 TI - Musculoskeletal: what is different in children? Running for track; springtime, hip pain. PMID- 21594622 TI - Parasitized snails take the heat: a case of host manipulation? AB - Infection-induced changes in a host's thermal physiology can represent (1) a generalized host response to infection, (2) a pathological side-effect of infection, or (3), provided the parasite's development is temperature-dependent, a subtle case of host manipulation. This study investigates parasite-induced changes in the thermal biology of a first intermediate host infected by two castrating trematodes (genera Maritrema and Philophthalmus) using laboratory experiments and field surveys. The heat tolerance and temperatures selected by the snail, Zeacumantus subcarinatus, displayed alterations upon infection that differed between the two trematodes. Upon heating, snails infected by Maritrema sustained activity for longer durations than uninfected snails, followed by a more rapid recovery, and selected higher temperatures in a thermal gradient. These snails were also relatively abundant in high shore localities in the summer only, corresponding with seasonal elevated microhabitat temperatures. By contrast, Philophthalmus-infected snails fell rapidly into a coma upon heating and did not display altered thermal preferences. The respective heat tolerance of each trematode corresponded with the thermal responses induced in the snail: Maritrema survived exposure to 40 degrees C, while Philophthalmus was less heat tolerant. Although both trematodes infect the same tissues, Philophthalmus leads to a reduction in the host's thermal tolerance, a response consistent with a pathological side effect. By contrast, Maritrema induces heat tolerance in the snail and withstood exposure to high heat. As the developmental rate and infectivity of Maritrema increase with temperature up to 25 degrees C, one adaptive explanation for our findings is that Maritrema manipulates the snail's thermal responses to exploit warm microhabitats. PMID- 21594623 TI - Characterization and developmental expression of genes encoding the early carotenoid biosynthetic enzymes in Citrus paradisi Macf. AB - In the present study, the full-length cDNA sequences of PSY, PDS, and ZDS, encoding the early carotenoid biosynthetic enzymes in the carotenoid pathway of grapefruit (Citrus paradisi), were isolated and characterized for the first time. CpPSY contained a 1311-bp open reading frame (ORF) encoding a polypeptide of 436 amino acids, CpPDS contained a 1659-bp ORF encoding a polypeptide of 552 amino acids, and CpZDS contained a 1713-bp ORF encoding a polypeptide of 570 amino acids. Phylogenetic analysis indicated that CpPSY shares homology with PSYs from Citrus, tomato, pepper, Arabidopsis, and the monocot PSY1 group, while CpPDS and CpZDS are most closely related to orthologs from Citrus and tomato. Expression analysis revealed fluctuations in CpPSY, CpPDS, and CpZDS transcript abundance and a non-coordinated regulation between the former and the two latter genes during fruit development in albedo and juice vesicles of white ('Duncan') and red ('Flame') grapefruits. A 3* higher upregulation of CpPSY expression in juice vesicles of red-fleshed 'Flame' as compared to white-fruited 'Duncan' was observed in the middle stages of fruit development, which correlates with the well documented accumulation pattern of lycopene in red grapefruit. Together with previous data, our results suggest that the primary mechanism controlling lycopene accumulation in red grapefruit involves the transcriptional upregulation of CpPSY, which controls the flux into the carotenoid pathway, and the downregulated expression of CpLCYB2, which controls the step of cyclization of lycopene in chromoplasts during fruit ripening. A correlation between CpPSY expression and fruit color evolution in red grapefruit is demonstrated. PMID- 21594624 TI - The sucrose synthase-1 promoter from Citrus sinensis directs expression of the beta-glucuronidase reporter gene in phloem tissue and in response to wounding in transgenic plants. AB - Interest in phloem-specific promoters for the engineering of transgenic plants has been increasing in recent years. In this study we isolated two similar, but distinct, alleles of the Citrus sinensis sucrose synthase-1 promoter (CsSUS1p) and inserted them upstream of the beta-glucuronidase (GUS) gene to test their ability to drive expression in the phloem of transgenic Arabidopsis thaliana and Nicotiana tabacum. Although both promoter variants were capable of conferring localized GUS expression in the phloem, the CsSUS1p-2 allele also generated a significant level of expression in non-target tissues. Unexpectedly, GUS expression was also instigated in a minority of CsSUS1p::GUS lines in response to wounding in the leaves of transgenic Arabidopsis. Deletion analysis of the CsSUS1p suggested that a fragment comprising nucleotides -410 to -268 relative to the translational start site contained elements required for phloem-specific expression while nucleotides -268 to -103 contained elements necessary for wound specific expression. Interestingly, the main difference between the two CsSUS1p alleles was the presence of a 94-bp insertion in allele 2. Fusion of this indel to a minimal promoter and GUS reporter gene indicated that it contained stamen and carpel-specific enhancer elements. This finding of highly specific and separable regulatory units within the CsSUS1p suggests that this promoter may have a potential application in the generation of constructs for the use in the development of transgenic plants resistant to a wide variety of target pests. PMID- 21594626 TI - A simple broad complex tachycardia? PMID- 21594625 TI - Stress-induced effects on feeding behavior and growth performance of the sea bass (Dicentrarchus labrax): a self-feeding approach. AB - Repetitive aquaculture-related protocols may act as cyclic stressors that induce chronic stress in cultured fish. The sea bass is particularly sensitive to stressful conditions and the mere presence of humans will disturb feeding behavior. In this paper, we study whether chronic stress induced by repetition of acute stress protocols affects long-term feeding behavior and growth performance in sea bass and whether exogenous cortisol may induce stress-like changes in these parameters. We demonstrate that both chronic stress and dietary cortisol decrease food intake and have a negative effect on feed conversion efficiency, severely impairing sea bass performance. Both experimental approaches induced changes in the daily feeding activity by lengthening the active feeding periods. Fish subjected to a cyclic stressor modify their daily feeding pattern in an attempt to avoid interference with the time of the stressor. The delay in feeding when fish are acutely and repeatedly stressed could be of substantial adaptive importance. PMID- 21594627 TI - Asymmetric dimethylarginine concentration and recurrence of atrial tachyarrythmias after catheter ablation in patients with persistent atrial fibrillation. AB - PURPOSE: It has been reported that elevation of asymmetric dimethylarginine (ADMA) concentration is involved in atrial fibrillation (AF) process. The purpose of this study was to determine whether ADMA concentration is related to recurrences of AF after catheter ablation. METHODS: A total of one hundred and thirty-eight patients with persistent AF (49.91 +/- 7.23 years), but without known heart disease, who underwent successful mapping and catheter ablation were included. Serum ADMA levels were measured 1 day before the catheter ablation. RESULTS: After a mean follow-up period of 285 days (range, 98-651 days), 80 (58%) patients underwent the AF recurrence. Comparing with no AF recurrence group, the serum ADMA concentration, left atrial diameter, and persistent duration of AF in patients with AF recurrence group were significantly increased. Left atrial diameter, persistent duration of AF, and the number of non-pulmonary vein ectopy ablation were increased when serum ADMA concentration was elevated. In addition, AF recurrences were significantly increased when serum ADMA concentration was elevated. A multivariable Cox regression analysis demonstrated that the elevated ADMA concentration [hazard ration (95% CI), 4.59 (1.81-11.62); P = 0.001], the left atrial diameter [1.35 (1.18-1.55), P < 0.001], and the number of non pulmonary vein ectopy ablation [1.94 (1.18-3.18), P = 0.009] were independent factors associated with the AF recurrence after catheter ablation. CONCLUSIONS: This study demonstrated that (1) serum ADMA concentrations were associated with non-PV ectopies and (2) increased serum ADMA concentrations were associated with higher rate of AF recurrence after catheter ablation in patients with persistent AF, supporting our hypothesis that ADMA might participate in the process of atrial remodeling. PMID- 21594628 TI - Pulmonary vein electrophysiology during cryoballoon ablation as a predictor for procedural success. AB - BACKGROUND: Cryoballoon technique is an innovative alternative to radiofrequency ablation for atrial fibrillation (AF). However, with current cryoballoon application techniques, the operator has no access to electrical information for 300 s during the freezing cycle. OBJECTIVE: The objective of this study is to investigate the novel approach of real-time monitoring of pulmonary vein (PV) potentials throughout freezing using a circular mapping catheter introduced into the central lumen of the cryoballoon catheter. METHODS: Patients had paroxysmal or persistent AF. Standard balloon catheters (23 or 28 mm diameter, 10.5 F shaft) were used. A coaxial mapping catheter (shaft diameter 0.9 mm; 15 mm loop with six electrodes) was advanced through the lumen of the cryoballoon catheter, replacing the guide wire. The primary procedural end point was successful PV isolation and real-time PV potential recording. Secondary end points were procedural data, complications, and the time to successful PV isolation. RESULTS: In 141 consecutively enrolled patients, balloon positioning and ablation were successful in 439/568 veins (77%). Real-time recording of PV conduction during the freeze cycle was possible in 235/568 PVs (41%). Main reasons for failure to obtain real time PV recordings were a distal position of the circular mapping catheter or insufficient catheter-vessel wall contact during ablation. A cutoff value of 83 s to PV isolation was predictive of stable procedural PV isolation without reconduction. One minor hemoptysis was observed possibly related to the mapping catheter. CONCLUSIONS: This study, the largest to date, showed that real-time monitoring of PV conduction during cryoballoon freezing can be safely performed with a circular mapping catheter. A cutoff time of 83 s to PV isolation was predictive of sustained procedural PV isolation success without reconduction. PMID- 21594629 TI - Cardiac resynchronization therapy in patients with mild heart failure: a systematic review and meta-analysis. AB - PURPOSE: Cardiac resynchronization therapy (CRT) reduces symptoms and improves survival in patients with advanced heart failure (New York Heart Association (NYHA) functional class III-IV), reduced ejection fraction, and wide QRS complex. Whether CRT has the same benefit also in asymptomatic or mildly symptomatic heart failure patients is controversial. Our objective is to summarize the available evidence on the effects of CRT in asymptomatic or mildly symptomatic (NYHA I-II) heart failure patients. METHODS: We searched major web databases for randomized controlled trials of CRT in patients with mild heart failure (NYHA functional class I-II). Data regarding all-cause mortality, heart failure events, left ventricular (LV) volumes and ejection fraction, and worsening of NYHA functional class were extracted. RESULTS: We identified five trials (CONTAK-CD, MIRACLE ICD II, REVERSE, MADIT-CRT, and RAFT) that enrolled 4,213 patients (91% with NYHA II functional class). Primary analysis excluded the CONTAK-CD, which was not specifically conducted on patients with mild heart failure. At pooled analysis, CRT decreased mortality (odds ratio (OR), 0.78 [95% confidence interval (CI)], 0.63 to 0.97; p = 0.024) and heart failure events (OR, 0.63 [95% CI, 0.52 to 0.76], p < 0.001), induced a significant LV reverse remodeling (weighted mean difference (WMD) of LV ejection fraction [Formula: see text], p = 0.015 and WMD of LV end-systolic volume index [Formula: see text], p < 0.001) and prevented the progression of heart failure symptoms (OR for worsening of NYHA functional class = 0.54 [95% CI, 0.31 to 0.93], p = 0.026). Inclusion of the CONTAK-CD did not change the results. CONCLUSIONS: Among patients with mild (NYHA II) heart failure, CRT reduces mortality and the risk of heart failure events, induces a favorable LV reverse remodeling and slows the progression of heart failure symptoms. PMID- 21594630 TI - [Socio-medical aspects of mental disorders : Definition, epidemiology, context and assessment of capacity]. AB - Social medicine is an interdisciplinary field of medicine which analyses and describes the interactions between illness, individual, society, and organisational structures of the health care system, including prevention, treatment and rehabilitation. Part of social medicine is epidemiology, including analytic epidemiology. The goal is to monitor the prevalence and spectrum of illnesses in the general population or subpopulations and to study possible risks of illness. The question is which environmental or contextual factors influence the prevalence and course of illnesses. Another area of social medicine is to evaluate patients and decide who needs social support. Important topics are inability to work, need for early retirement and pension, or disability. In this context it is important to make a distinction between functions, capacities, context and participation. There is a second paper on social medicine which covers modes of care and treatment in social medicine. PMID- 21594631 TI - [The king and the psychiatrist]. PMID- 21594634 TI - Irritable bowel syndrome: what do patients really want? AB - Knowing what patients with irritable bowel syndrome (IBS) want or expect from their medical care is critical in helping them manage the symptoms of this common, chronic gastrointestinal condition. Failure to identify patient expectations can lead to patient dissatisfaction with care, lack of compliance with prescribed treatments, and the inappropriate use of medical resources. Surprisingly little is known about what patients with IBS really want. Several studies suggest that IBS patients value the relational aspects of medical care as highly as technical skills and knowledge. There seems to be a significant communication gap between health care providers and patients regarding IBS care. This article reviews what is known about IBS patients' expectations and needs. PMID- 21594635 TI - Understanding the clinical issues involved with glycemic control in the intensive care unit. PMID- 21594636 TI - Interleukin-6, but not soluble adhesion molecules, predicts a subsequent mortality from cardiovascular disease in patients with acute ST-segment elevation myocardial infarction. AB - Inflammatory responses are an important element in the atherosclerotic process. Therefore, inflammatory markers can potentially serve as predictors of cardiovascular risk. However, the existing data are limited and controversial. We conducted a prospective cohort study with 263 patients with first acute ST segment elevation myocardial infarction (STEMI) who were admitted to our Hospital within 6 h after the symptoms onset. Clinical data were recorded and serum admission levels of interleukin-6 (IL-6), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble P selectin (sP-selectin) were determined. The patients were then followed up for 3 years to document cardiovascular mortality. During the follow-up, 34 patients died from cardiovascular causes. The admission levels of IL-6 were significantly higher in these patients, whereas sICAM-1, sVCAM-1, and sP-selectin were comparable between these and the survived patients. The Kaplan-Meier plots revealed a significant increase in cardiovascular mortality with increasing levels of IL-6 (P = 0.0002, chi(2) test). The logistic regression analysis indicated that IL-6 was an independent predictor for cardiovascular mortality. To conclude, our findings indicate that elevated admission levels of IL-6, but not soluble adhesion molecules, provide valuable information for risk assessment of long-term cardiovascular mortality in patients with STEMI. PMID- 21594637 TI - Strong authentication scheme for telecare medicine information systems. AB - The telecare medicine information system enables or supports health-care delivery services. A secure authentication scheme will thus be needed to safeguard data integrity, confidentiality, and availability. In this paper, we propose a generic construction of smart-card-based password authentication protocol and prove its security. The proposed framework is superior to previous schemes in three following aspects : (1) our scheme is a true two-factor authentication scheme. (2) our scheme can yield a forward secure two-factor authentication scheme with user anonymity when appropriately instantiated. (3) our scheme utilizes each user's unique identity to accomplish the user authentication and does not need to store or verify others's certificates. And yet, our scheme is still reasonably efficient and can yield such a concrete scheme that is even more efficient than previous schemes. Therefore the end result is more practical for the telecare medicine system. PMID- 21594639 TI - Special issue on protein species. PMID- 21594640 TI - Peptides derived from Mycobacterium tuberculosis Rv2301 protein are involved in invasion to human epithelial cells and macrophages. AB - The specific function of putative cut2 protein (or CFP25), encoded by the Rv2301 gene from Mycobacterium tuberculosis H37Rv, has not been identified yet. The aim of this study was to assess some of CFP25 characteristics and its possible biological role in Mycobacterium tuberculosis H37Rv invasion process to target cells. Molecular assays indicated that the gene encoding Rv2301 is present and transcribed in M. tuberculosis complex strains. The presence of Rv2301 protein over the bacilli surface was confirmed by Western blot and immunoelectron microscopy analyses, using goats sera inoculated with synthetic peptides derived from Rv2301 protein. Receptor-ligand binding assays with carcinomic human alveolar basal epithelial cells (A549) and macrophages derived from human histolytic lymphoma monocytes (U937) allowed us to identify five high activity binding peptides (HABPs) in both cell lines, and two additional HABPs only in A549 cells. U937 HABPs binding interactions were characterized by saturation assays, finding dissociation constants (Kd) within the nanomolar range and positive cooperativity (nH>1). Inhibition assays were performed to assess the possible biological role of Rv2301 identified HABPs, finding that some of them were able to inhibit invasion at a 5 MUM concentration, compared with the cytochalasin control. On the other hand, HABPs, and especially HABP 36507 located at the N-terminus of the protein, facilitated the internalization of fluorescent latex beads into A549 cells. These findings are of vital importance for the rational selection of Rv2301 HABPs, to be included as components of an antituberculosis vaccine. PMID- 21594641 TI - Increased apoptosis of CD4 and CD8 T lymphocytes in the airways of horses with recurrent airway obstruction. AB - Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition similar to human asthma caused by exposure of susceptible horses to poorly ventilated stable environments. The disease is characterized by neutrophilic airway inflammation, mucus hypersecretion and reversible bronchoconstriction. This inflammatory process is mediated by several factors, including antibodies, cytokines, resident cells of the airway and inflammatory cellular components that arrive in the respiratory tract. An increasing body of evidence has lent support to the concept that a dysregulation of T cell apoptosis may play a central role in the development of airway inflammation and the associated asthma. Therefore, the aim of this study was to investigate early and late apoptosis of CD4 and CD8 T cell subpopulations obtained from the airways of acute RAO-positive animals after exposure to hay/straw. The percentages of CD4 and CD8 T cells and their associated frequencies of apoptosis were quantified using flow cytometry. Hay/straw exposure induced clinical airway obstruction, airway neutrophilia and increased airway mucus production in RAO-positive horses. In addition, allergen exposure increased the percentage of CD4 T cells in RAO positive horses as well as the frequency of early and late apoptosis in both CD4 and CD8 lymphocyte subpopulations. These results suggest that the higher frequency of lymphocyte apoptosis may play a role in disease progression of horses afflicted with RAO and may partially explain the characteristic remission of this pathological condition once the allergen source is removed. However, further studies are needed to clarify the role of T cell apoptosis in RAO affected horses. PMID- 21594642 TI - The population of a high-virulence strain of Salmonella enterica serovar Enteritidis in subcutaneously infected partridge: a quantitative time-course study using real-time PCR. AB - This research was undertaken to determine the population of a high-virulence strain of Salmonella enterica serovar Enteritidis in partridge by a fluorescent quencher PCR assay and to correlate these findings with the results obtained from the immunohistochemical localization and histopathological examinations of selected Salmonella enterica serovar Enteritidis-infected tissues. To make the results meaningful, a side-by-side bacteriology method (indirect immuno fluorescent antibody staining) was performed too. The results of indirect immuno fluorescent antibody staining and immunohistochemical localization were similar to the fluorescent quencher PCR assay. The time course of the appearance of bacterial antigens and tissue lesions in various tissues was coincident with the levels of the bacterial DNA loads at the infection sites. This suggests that Salmonella enterica serovar Enteritidis loads in internal organs are closely correlated with the progression of the infection. PMID- 21594643 TI - Biogeochemical study of termite mounds: a case study from Tummalapalle area of Andhra Pradesh, India. AB - Termite mounds are abundant components of Tummalapalle area of uranium mineralization of Cuddapah District of Andhra Pradesh, India. The systematic research has been carried out on the application of termite mound sampling to mineral exploration in this region. The distribution of chemical elements Cu, Pb, Zn, Ni, Co, Cr, Li, Rb, Sr, Ba, and U were studied both in termite soils and adjacent surface soils. Uranium accumulations were noticed in seven termite mounds ranging from 10 to 36 ppm. A biogeochemical parameter called "Biological Absorption Coefficient" of the termite mounds indicated the termite affected soils contained huge amounts of chemical elements than the adjacent soils. PMID- 21594644 TI - Distribution of heavy metals in surface sediments from the South China Sea ecosystem, Malaysia. AB - The concentrations of arsenic, cadmium, chromium, copper, mercury, nickel, lead and zinc in surface sediments collected from the east coast of peninsular Malaysia, along the South China Sea, were measured by two methods instrumental neutron activation analysis and inductively coupled plasma mass spectroscopy. The obtained results were use to determine the areal distribution of the metals of in the east coast of peninsular Malaysia and potential sources of these metals to this environment. The geochemical data propose that most of the metals found in the east coast of peninsular Malaysia constitute a redistribution of territorial materials within the ecosystem. Then, the metal concentrations can be considered to be present at natural background levels in surface sediments. PMID- 21594645 TI - Short-term adaptations of the dynamic disparity vergence and phoria systems. AB - The ability to adapt is critical to survival and varies between individuals. Adaptation of one motor system may be related to the ability to adapt another. This study sought to determine whether phoria adaptation was correlated with the ability to modify the dynamics of disparity vergence. Eye movements from ten subjects were recorded during dynamic disparity vergence modification and phoria adaptation experiments. Two different convergent stimuli were presented during the dynamic vergence modification experiment: a test stimulus (4 degrees step) and a conditioning stimulus (4 degrees double step). Dynamic disparity vergence responses were quantified by measuring the peak velocity ( degrees /s). Phoria adaptation experiments measured the changes in phoria over a 5-min period of sustained fixation. The maximum velocity of phoria adaptation was determined from an exponential fit of the phoria data points. Phoria and dynamic disparity vergence peak velocity were both significantly modified (P < 0.001). The maximum velocity of phoria adaptation was significantly correlated with the changes in convergence peak velocity (r > 0.89; P < 0.001). There was a strong correlation between the ability to adaptively adjust two different oculomotor parameters: a tonic and dynamic component. Future studies should investigate additional interactions between these parameters, and the ability to adaptively change other oculomotor systems such as the saccadic or smooth pursuit system. Understanding the ability to modify phoria, dynamic disparity vergence, and other oculomotor parameters can yield insights into the plasticity of short-term adaptation mechanisms. PMID- 21594646 TI - A Monte-Carlo step-by-step simulation code of the non-homogeneous chemistry of the radiolysis of water and aqueous solutions--Part II: calculation of radiolytic yields under different conditions of LET, pH, and temperature. AB - The importance of the radiolysis of water in the initial events following irradiation of biological systems has motivated considerable theoretical and experimental work in the field of radiation chemistry of water and aqueous systems. These studies include Monte-Carlo simulations of the radiation track structure and of the non-homogeneous chemical stage, which have been successfully used to calculate the yields of radiolytic species (H(.), (.)OH, H(2), H(2)O(2), e (aq) (-) , ...). Most techniques used for the simulation of the non-homogeneous chemical stage such as the independent reaction time (IRT) technique and diffusion kinetics methods do not calculate the time evolution of the positions of the radiolytic species. This is a major limitation to their extension to the simulation of the irradiation of radiobiological systems. Step-by-step (SBS) simulation programs provide such information, but they are very demanding in term of computer power and storage capacity. Recent improvements in computer performance now allow the regular use of the SBS method in radiation chemistry simulations. In the first of a series of two papers, the SBS method has been reviewed in details and the implementation of a SBS code has been discussed. In this second paper, the results of several studies are presented: (1) the time evolution of the radiolytic yields from the formation of the radiation track to 10(-6) s; (2) the effect of pH on yields (pH ~ 0.4-7.0); (3) the effect of proton energy (and LET) on yields (300 MeV-0.1 MeV), and iv) the effect of the ion type ((1)H(+), (4)He(2+), (12)C(6+)) on yields. Nonbiological applications, i.e., the study of the temperature on the yields (about 25-300 degrees C) and the simulation of the time evolution of G(Fe(3+)) in the Fricke dosimeter are also discussed. PMID- 21594647 TI - Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis. AB - Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-related malignancy of the thoracic pleura. Although, platinum-based agents are the first line of therapy, there is an urgent need for second-line therapies to treat the drug-resistant MPM. Cell cycle as well as apoptosis pathways are frequently altered in MPM and thus remain attractive targets for intervention strategies. Curcumin, the major component in the spice turmeric, alone or in combination with other chemotherapeutics has been under investigation for a number of cancers. In this study, we investigated the biological and molecular responses of MPM cells to curcumin treatments and the mechanisms involved. Flow-cytometric analyses coupled with western immunoblotting and gene-array analyses were conducted to determine mechanisms of curcumin-dependent growth suppression of human (H2373, H2452, H2461, and H226) and murine (AB12) MPM cells. Curcumin inhibited MPM cell growth in a dose- and time-dependent manner while pretreatment of MPM cells with curcumin enhanced cisplatin efficacy. Curcumin activated the stress-activated p38 kinase, caspases 9 and 3, caused elevated levels of proapoptotic proteins Bax, stimulated PARP cleavage, and apoptosis. In addition, curcumin treatments stimulated expression of novel transducers of cell growth suppression such as CARP-1, XAF1, and SULF1 proteins. Oral administration of curcumin inhibited growth of murine MPM cell-derived tumors in vivo in part by stimulating apoptosis. Thus, curcumin targets cell cycle and promotes apoptosis to suppress MPM growth in vitro and in vivo. Our studies provide a proof-of-principle rationale for further in-depth analysis of MPM growth suppression mechanisms and their future exploitation in effective management of resistant MPM. PMID- 21594648 TI - Overexpression of miR-22 reverses paclitaxel-induced chemoresistance through activation of PTEN signaling in p53-mutated colon cancer cells. AB - Chemoresistance is a key cause of treatment failure in colon cancer. MiR-22 is a tumor-suppressing microRNA. To explore whether miR-22 is an important player in the development of chemoresistance in colon cancer, we overexpressed miR-22 and subsequently tested its role in cell proliferation, apoptosis, survival, and associated signaling in p53-mutated HT-29 and HCT-15 cells, and p53 wild-type HCT 116 cells. We further investigated the role of miR-22 on cytotoxicity of paclitaxel in both the p53-mutated and p53 wild-type colon cancer cells. Results showed that HT-29 and HCT-15 cells were resistant to paclitaxel-induced cytotoxicity, which normally inhibits cell proliferation and survival, and induces apoptosis. Conversely, HCT-116 was relatively sensitive to the cytotoxicity of paclitaxel. Overexpression of miR-22 significantly decreased cell proliferation and survival, and induced cell apoptosis in the p53-mutated colon cancer cells, but played no role in the p53 wild-type cells. Importantly, miR-22 overexpression enhanced the cytotoxic role of paclitaxel in p53-mutated HT-29 and HCT-15 cells, but not in p53 wild-type HCT-116 cell. We further demonstrated that the tumor-suppressive role of miR-22 in p53-mutated colon cancer cells was mediated by upregulating PTEN expression, which negatively regulated Akt phosphorylation at Ser(473) and MTDH expression, and subsequently increased Bax and active caspase-3 levels. Our study is the first to identify the tumor suppressive role of miR-22 and its associated signaling in the p53-mutated colon cancer cells and highlighted the chemosensitive role of miR-22. PMID- 21594649 TI - Does heart rate influence CMR image quality of the coronary vessel wall? PMID- 21594651 TI - Self-enhancement learning: target-creating learning and its application to self organizing maps. AB - In this article, we propose a new learning method called "self-enhancement learning." In this method, targets for learning are not given from the outside, but they can be spontaneously created within a neural network. To realize the method, we consider a neural network with two different states, namely, an enhanced and a relaxed state. The enhanced state is one in which the network responds very selectively to input patterns, while in the relaxed state, the network responds almost equally to input patterns. The gap between the two states can be reduced by minimizing the Kullback-Leibler divergence between the two states with free energy. To demonstrate the effectiveness of this method, we applied self-enhancement learning to the self-organizing maps, or SOM, in which lateral interactions were added to an enhanced state. We applied the method to the well-known Iris, wine, housing and cancer machine learning database problems. In addition, we applied the method to real-life data, a student survey. Experimental results showed that the U-matrices obtained were similar to those produced by the conventional SOM. Class boundaries were made clearer in the housing and cancer data. For all the data, except for the cancer data, better performance could be obtained in terms of quantitative and topological errors. In addition, we could see that the trustworthiness and continuity, referring to the quality of neighborhood preservation, could be improved by the self-enhancement learning. Finally, we used modern dimensionality reduction methods and compared their results with those obtained by the self-enhancement learning. The results obtained by the self-enhancement were not superior to but comparable with those obtained by the modern dimensionality reduction methods. PMID- 21594650 TI - Relationship between cardiovascular risk factors and biomarkers with necrotic core and atheroma size: a serial intravascular ultrasound radiofrequency data analysis. AB - We explored the impact of patient demographics, anthropometric measurements, cardiovascular risk factors, and soluble biomarkers on necrotic core and atheroma size in patients with coronary disease. The IBIS-2 trial enrolled 330 patients. In the multivariate analysis, at baseline, creatinine had a positive, whereas baseline mean lumen diameter and myeloperoxidase had a negative, independent association with percentage of necrotic core (PNC); while age, glomerular filtration rate <60, HbA1c, previous PCI or CABG and baseline % diameter stenosis were positively, and acute coronary syndromes (ACS) were negatively associated with baseline percentage atheroma volume (PAV). The variables associated with a decrease in PNC from baseline were darapladib, ACS and a large content of NC at baseline, while variables associated with an increase in PNC were previous stroke and % diameter stenosis at baseline. Those variables associated with a decrease in PAV from baseline were waist circumference, statin use, CD40L and baseline PAV, while the only variable associated with an increase in PAV was baseline diastolic blood pressure. Treatment with darapladib was associated with a decrease in necrotic core, but was not associated with a decrease in percentage atheroma volume. On the contrary, statin use was only associated with a decrease in percentage atheroma volume. PMID- 21594652 TI - Bacterial metallothioneins: past, present, and questions for the future. AB - Bacterial metallothioneins (MTs) have been known since the mid-1980s. The only family known until recently was the BmtA family, exemplified by the zinc- and cadmium-binding SmtA from the cyanobacterium Synechococcus PCC 7942, for which a structure was determined in 2001. Only in 2008 was a second type of bacterial MT identified in mycobacteria, and the copper-binding gene product was called MymT. Many of the features of SmtA either have been unexpected or are otherwise "unusual", for example the presence of a zinc finger fold and the kinetic inertness of one of the four zinc ions bound to the protein. The unpredictability of molecular properties of this protein exemplified the need for continued biophysical studies of novel proteins. Homologues for SmtA have been identified in a limited number of bacterial genomes from cyanobacteria, pseudomonads, alphaproteobacteria, gammaproteobacteria, and firmicutes. Except for the residues defining the zinc finger fold, these homologous protein sequences display an intriguing variety, especially in terms of metal ligand position and identity. The increased number of homologues has allowed use of hidden Markov models to look for more remote relatives of SmtA, leading to the identification of a novel family of putative hybrid LIM domain MTs. However, database searches based on sequence similarity are of limited use for mining for further "overlooked" bacterial MTs, as so far undiscovered bacterial MTs may be too diverse from any other known MTs, and other approaches are required. PMID- 21594653 TI - Impact of inappropriate empiric antimicrobial therapy on outcome in Pseudomonas aeruginosa bacteraemia: a stratified analysis according to sites of infection. AB - BACKGROUND: The purpose of this study was to evaluate the impact of inappropriate empiric antimicrobial therapy on the outcome of Pseudomonas aeruginosa bacteraemia according to the primary infection site. METHODS: A retrospective cohort study including 202 patients with P. aeruginosa bacteraemia was performed. High-risk sites of infection were defined as the lung, intra-abdominal non hepatobiliary tract or unknown source. RESULTS: Of the 202 patients with P. aeruginosa bacteraemia, 80 (39.6%) had received inappropriate empiric antimicrobial therapy. No significant difference in the 30-day mortality rate was found between the inappropriate therapy group and the appropriate therapy group (19/80 [23.8%] vs. 32/122 [26.2%], P = 0.692). Patients with pneumonia or non hepatobiliary tract intra-abdominal infection showed significant association with high mortality, while those with urinary tract or hepatobiliary tract infection showed negative associations with mortality. In the subgroup analysis including 98 patients with high-risk sites of infection, the mortality rate of the inappropriate therapy group was significantly higher than that of the appropriate therapy group (14/26 [53.8%] vs. 23/72 [31.9%], P = 0.035). Inappropriate empiric antimicrobial therapy was also found to be one of the independent risk factors for mortality in patients with high-risk sites of infection (odds ratio [OR] 8.69; 95% confidence interval [CI] 1.86-40.59), along with renal disease, corticosteroid use, polymicrobial infection and higher Pitt bacteraemia score. CONCLUSION: Inappropriate empiric antimicrobial therapy adversely affected the outcome of P. aeruginosa bacteraemia in patients with high-risk sites of infection. Our data suggest that the impact of inappropriate antimicrobial therapy on the outcome of P. aeruginosa bacteraemia may be dependent on the primary site of infection. PMID- 21594654 TI - Depression, disability and cognitive impairment in multiple sclerosis: a cross sectional Italian study. AB - The disability, cognitive impairment, fatigue and depression are interacting features in multiple sclerosis (MS), whose relation is still unclear. The objective of this study was to evaluate in a sample of MS patients, the frequency of depressive symptoms, its predicting factors and relation with cognitive impairment, fatigue and disability. 255 consecutive MS patients and 166 healthy subjects were assessed for the presence of depressive symptoms with the Beck Depression Inventory-Fast Screen (BDI-FS). Patients with BDI-FS >= 4 were further investigated for the presence of neuropsychological impairment. Depressive symptoms were significantly more frequent and severe in patients than in controls. EDSS score was the only predicting factor of depression (3.5 = threshold EDSS score for depressive symptoms) in patients, whereas neuropsychological impairment was not correlated with BDI-FS and fatigue was found to be significantly correlated with attention, executive function and memory test scores, as well as with BDI-FS score in patients. PMID- 21594655 TI - Free and Cued Selective Reminding Test: an Italian normative study. AB - The presence of episodic memory impairment is required for the diagnosis of Alzheimer's dementia by all current diagnostic criteria. The new research criteria proposed by Dubois et al. (Lancet Neurol 6:734-746, 2007) require that the impairment should not improve significantly with cueing, recognition testing nor after the control of effective encoding. This is considered to be the core deficit of "prodromal Alzheimer's disease". The Free and Cued Selective Reminding Test (FCSRT) is a memory test that allows in assessing these specific features of memory impairment. Here, we report normative data for an Italian version of the FCSRT. The test is based on the 12 pictorial stimuli, 6 belonging to the living domain, and 6 to the non-living domain. Six scores were derived from the performance of 227 healthy Italian adults, with age, sex and education homogenously distributed across subgroups: immediate free recall (IFR), immediate total recall (ITR), delayed-free recall (DFR), delayed total recall (DTR), Index of Sensitivity of Cueing (ISC), number of intrusions. In multiple regression analyses, age emerged as an influencing factor for both IFR and DFR, with older people obtaining lower scores. Education and gender appear to influence only IFR, with better performance by more educated subjects and females. Adjusted scores were used to determine inferential cutoff scores and to compute equivalent scores. PMID- 21594656 TI - A new instrument for assessing the quality of studies on prevalence. AB - There are numerous scientific articles of studies on the prevalence of disorders with non-standardised examination and diagnostic protocols. Because their quality is heterogeneous, a new instrument has been developed for the assessment of such studies. The new instrument is based mainly on statistical criteria. The points assigned for each of the main criteria according to the information gained from each paper are summed up to form a Total Quality Score (TQS). The interrater reliability of the instrument was tested by employing Kappa and Interrater Correlation Coefficient (ICC) statistics. The latter was assessed on the results of three independent investigators. The new quality instrument appeared to be easy to use, and the instructions were comprehensible. The ICC((2,1)) for the TQS ranged between 0.94 and 1.00 indicating almost perfect agreement between the investigators. The reliability of the new instrument enables its use for scientific review purposes. In this way, its validity will also be tested. The instrument could be adopted for assessment of scientific articles of studies on the prevalence of disorders in many, similar, scientific areas. PMID- 21594657 TI - Pouch function and quality of life after successful management of pouch-related septic complications in patients with ulcerative colitis. AB - PURPOSE: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis is associated with pouch-related septic complications (PRSC) in 10% of patients. This study questioned if PRSC have a negative impact on pouch function and quality of life. PATIENTS AND METHODS: One hundred thirty consecutive patients undergoing IPAA for ulcerative colitis between 1997 and 2009 were reviewed. At 1-year follow-up, patients were asked to complete questionnaires including a pouch function score (Oresland score, 0-16 points, 0 optimum) and two quality of life scores [Short Inflammatory Bowel Disease Questionnaire (SIBDQ), 1-7 points, 7 optimum; Gastrointestinal Quality of Life Index (GIQLI), 0-144 points, 144 optimum]. RESULTS: Twelve out of 130 patients (9.2%) undergoing IPAA developed PRSC. These included anastomotic dehiscence (five), pouch leakage (three, one patient had a combined leak), peripouchal abscess (three), pouch-anal fistula (one), and pouch-vaginal fistula (one). Omission of diverting ileostomy was a risk factor for PRSC (OR 4.62, CI 1.17 18.4). PRSC led to four pouch failures (33%), whereas no failure occurred in the control group (p < 0.001). Median 3 (range, 1-10) further operations were necessary until the pouch was salvaged or definitively lost. If the pouch was salvaged, functional Oresland score (8.2 +/- 1.3 vs. 6.6 +/- 0.5; p = 0.127), SIBDQ (5.0 +/- 0.5 vs. 5.5 +/- 0.1; p = 0.203), and GIQLI (95.8 +/- 8.4 vs. 107.3 +/- 2.6; p = 0.119) were not significantly inferior to uncomplicated controls. CONCLUSIONS: In case of PRSC, even multiple surgical approaches are worthwhile as the outcome of salvaged pouches in terms of function and quality of life is not substantially inferior to patients without septic complications. PMID- 21594658 TI - TH-030418: a potent long-acting opioid analgesic with low dependence liability. AB - Numerous efforts have been made on the chemical modification of opioid compounds, with the ultimate goal of developing new opioid analgesics that is highly potent and low/non-addictive. In a search for such compounds, TH-030418 [7alpha-[(R)-1 hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydrooripavine] was synthesized. Here, we evaluated the pharmacological activities of TH-030418, in comparison with morphine, the prototype opioid analgesic. In radioligand binding assays, TH-030418 bound potently and nonselectively to MU-, delta-, kappa-, and ORL1 (opioid receptor-like 1) receptors stably expressed in CHO (Chinese hamster ovary) cells with K (i) values of 0.56, 0.73, 0.60, and 1.55 nM, respectively. When administered subcutaneously, TH-030418 was much more potent than morphine in analgesia, with the ED(50) values of 1.37 MUg/kg and 1.70 MUg/kg in hot plate and acetic acid writhing tests, respectively. The opioid antagonist naloxone blocked the antinociceptive effect of TH-030418, indicating that the action of TH-030418 was mediated by opioid receptors. The antinociceptive effect of s.c. TH-030418 in hot plate test lasted for more than 12 h, which is much longer than those of morphine (2.5 h) and dihydroetorphine (1.5 h). In addition, naloxone did not precipitate withdrawal syndrome in the mice treated with TH-030418 previously. Most importantly, TH-030418 did not induce conditioned place preference in mice after chronic treatment. These results indicate that TH-030418 is a potent long acting opioid analgesic with low dependence liability and may be of some value in the development of new analgesics. PMID- 21594659 TI - [Clonidine for remifentanil-induced hyperalgesia: a double-blind randomized, placebo-controlled study of clonidine under intra-operative use of remifentanil in elective surgery of the shoulder]. AB - BACKGROUND: In the postoperative period, alpha2-adrenergic agonists have an opioid sparing effect. In a previous, experimental study, it was also shown that clonidine attenuates remifentanil-induced hyperalgesia. In this study, we examined under clinical conditions whether early administration of a single dose of clonidine can inhibit remifentanil-induced hyperalgesia in patients undergoing elective surgery of the shoulder and with continuous intraoperative use of remifentanil. PATIENTS AND METHODS: In this study 40 patients received double blind and randomized either 150 ug clonidine or placebo intravenously before skin incision. Anaesthesia was maintained with propofol and remifentanil (0.23 +/- 0.09 ug/kg body weight/min) and morphine (0.1 mg/kg body weight) was administered 20 min before incision closure. Postoperatively, the patients were given a patient-controlled analgesia pump (PCA) with morphine. RESULTS: Overall morphine consumption as well as overall assessment of pain with the visual analogue scale in the first 24 h postoperatively did not differ significantly between the groups. Isolated pain scores at 12 h and 24 h were significantly enhanced in the clonidine group (p<0.05). CONCLUSION: An early single dose of 150 ug of clonidine did not reduce the postoperative morphine consumption and pain scores in patients undergoing elective surgery of the shoulder with remifentanil/propofol-based anaesthesia. After the effect of clonidine has presumably subsided the pain can even increase, therefore further studies with repetitive doses of clonidine should be carried out. PMID- 21594660 TI - [Pain therapy with children and adolescents severely disabled due to chronic pain: long-term outcome after inpatient pain therapy]. AB - BACKGROUND: A prospective study controlled for sex and age was conducted evaluating the success of a 3-week inpatient pain therapy after 3, 6 and 12 months for 200 children and adolescents severely disabled due to chronic pain. METHODS: The following validated German questionnaires were used: pain questionnaire (DSF-K/J/E), pain coping inventory (PPCI-R), anxiety questionnaire (AFS) and depression questionnaire (DIKJ). After an intention-to-treat analysis unifactorial und multifactorial variance analyses were conducted. A significance level of p<0.01 was used. RESULTS: Durable improvements were observed for average pain intensity, pain disability, days absent from school, depression and for passive and interaction-based pain coping strategies 3 months after finishing inpatient pain therapy. On the other hand general anxiety and school aversion were only reduced at 6 and 12 months, respectively. Girls reported more pain in general and during follow-up. Younger children relied in general more on others when dealing with their pain. CONCLUSION: An inpatient pain therapy can help children and adolescents severely disabled due to chronic pain not only in the short term but also in the long term. PMID- 21594661 TI - [Back pain and social status among the working population: what is the association? Results from a German general population survey]. AB - BACKGROUND: Little empirical evidence is available on differential associations between social status indicators and back pain in Germany. This study therefore systematically evaluated associations between different indicators of social status and back pain. METHODS: In total 4,412 employed adults, aged 18 to 65 years participated in a postal survey in 5 regions of Germany. The point prevalence and 1-year prevalence of back pain were assessed as well as the level of disabling back pain. Educational level, professional category and household income served as measures of social status. Associations between social status and back pain have been assessed cross-sectionally using Poisson regression. RESULTS: Educational level was the best predictor for back pain among the assessed social status indicators. Adults with a low educational level had almost a 4-fold risk of reporting disabling back pain compared to subjects with a high educational level. Associations were highest for disabling back pain and attenuated strongly over the point prevalence towards the 1-year prevalence. DISCUSSION: Back pain cannot generally be regarded as a symptom of a low social status. However, social inequality is of major importance regarding the prediction of severe back problems. A better understanding of mediating factors is essential for the prevention and therapy. PMID- 21594662 TI - The relation of the distal femoral physis and the medial patellofemoral ligament. AB - PURPOSE: The purpose of this study was to analyse true lateral radiographs of children and adolescents to determine the relation of the origin of the MPFL and the distal femoral physis considering the complex anatomy of the physis. The hypothesis was that the femoral insertion of the MPFL is distal to the growth plate. METHODS: Antero-posterior and true lateral radiographs from PACS computer records of 27 patients with a history of patellofemoral instability were assessed. To determine the femoral origin of the MPFL, the method by Schottle et al. and the method by Redfern et al. were applied independently. On the anteroposterior radiograph, the distance between the medial most part of the physis and the central part of the physis was measured to quantify the concave curvature of the physis. To cross-reference the femoral insertion of the MPFL onto an ap view, the projected MPFL origin-physis distance was subtracted from the distance between the most medial part of the physis and the central part of the physis. RESULTS: The projected median origin of the MPFL as measured on a lateral radiograph was located 3.2 mm (1.2-5.8 mm) proximal to the physis. The median distance between the most medial part of the physis and the physeal line on the anteroposterior radiograph was 9.9 mm (4.1-12.0 mm). Subtracting the two measured values, the median origin of the MPFL as seen on the ap view was 6.4 mm (2.9-8.5 mm) distal to the femoral physis. CONCLUSION: Considering the concave curvature of the distal femoral physis, it can be assumed that the femoral insertion of the MPFL is distal to the femoral physis. As a too proximal insertion of the graft can cause unintentional tightening of the MPFL in knee flexion, these results have to be considered when performing reconstruction of the MPFL in children and adolescents with open growth plates. PMID- 21594663 TI - Adherence to oral endocrine treatments in women with breast cancer: can it be improved? AB - There is a perception that women on oral endocrine treatments for oestrogen receptor-positive breast cancer will be adherent to these medicines, as they are facing a serious life-threatening disease, and the oral endocrine treatments are effective, easy to use and generally well tolerated. This is not in fact the case, and this is the basis of the first half of this review. The second half is of whether the changes/interventions to 'improve' adherence do actually increase adherence to the oral endocrine medicines. The review shows that better outcomes are achieved with good adherence to endocrine treatments in breast cancer. The rates of adherence to endocrine treatments range between 15 and 50%, and are influenced by a large number of factors (e.g. adverse effects, lack of belief in treatment, psychological problems and poor patient-health care provider relationship). Interventions to minimise the adverse effects have been used in an attempt to improve the adherence to the endocrine treatment therapies, but it is not known whether these do actually improve adherence. Similar, it has been assumed that interventions by health professionals (doctors, nurses and pharmacists) will improve the adherence, but this has not been tested. In conclusion, in women with breast cancer, we know there is a problem with adherence. There are also many approaches and suggestions about how to improve adherence to the oral endocrine treatments, but none of these approaches/suggestions have been scientifically tested, and they need to be. PMID- 21594664 TI - Detection of aberrant promoter methylation of GSTP1, RASSF1A, and RARbeta2 in serum DNA of patients with breast cancer by a newly established one-step methylation-specific PCR assay. AB - Aberrant promoter methylation of genes is a common molecular event in breast cancer. Thus, DNA methylation analysis is expected to be a new tool for cancer diagnosis. In this article, we have established a new, high-performance DNA methylation assay, the one-step methylation-specific polymerase chain reaction (OS-MSP) assay, which is optimized for analyzing gene methylation in serum DNA. The OS-MSP assay is designed to detect aberrant promoter methylation of GSTP1, RASSF1A, and RARbeta2 genes in serum DNA. Moreover, two quality control markers were designed for monitoring the bisulfite conversion efficiency and measuring the DNA content in the serum. Serum samples were collected from patients with primary (n = 101, stages I-III) and metastatic breast cancers (n = 58) as well as from healthy controls (n = 87). If methylation of at least one of the three genes was observed, the OS-MSP assay was considered positive. The sensitivity of this assay was significantly higher than that of the assay involving conventional tumor markers (CEA and/or CA15-3) for stages I (24 vs. 8%) and II (26 vs. 8%) breast cancer and similar to that of the assay involving the conventional tumor markers for stage III (18 vs. 19%) and metastatic breast cancers (55 vs. 59%). The results of the OS-MSP assay and those of the assay involving CEA and/or CA15 3 seemed to compensate for each other because sensitivity of these assays increased to 78% when used in combination for metastatic breast cancer. In conclusion, we have developed a new OS-MSP assay with improved sensitivity and convenience; thus, this assay is more suitable for detecting aberrant promoter methylation in serum DNA. Moreover, the combination of the OS-MSP assay and the assay involving CEA and/or CA15-3 is promising for enhancing the sensitivity of diagnosis of metastatic breast cancer. PMID- 21594665 TI - Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. AB - Trastuzumab (T) is effective in metastatic breast cancer (MBC) with HER2 overexpression and/or amplification, but resistance to T develops in a significant number of HER2-positive patients. Understanding the mechanisms of resistance is critical to the care of these patients. Formalin-fixed paraffin embedded tumor tissue samples were collected from 256 patients with T-treated MBC. Clinical information was collected retrospectively from the patients' medical records. Central review of HER2 status by fluorescent in situ hybridization (FISH) and/or immunohistochemistry (IHC) revealed that of the 227 eligible patients only 139 (61%) were truly HER2-positive. PTEN, ER, PgR, and Ki67 were evaluated by IHC, while PTEN status was evaluated by FISH as well. PIK3CA mutations were identified with single nucleotide polymorphism (SNP) genotyping. Median time to progression (TTP) was 14.4 months for the HER2 positive and 10.3 for the HER2-negative patients (log-rank, P = 0.22). Survival from the initiation of T (survivalT) was 50.4 months for the HER2-positive and 35.3 for the HER2-negative subgroups (P = 0.006). Higher risk of progression was associated with HER2-positive status and the presence of PIK3CA mutations (P = 0.014). PTEN loss, as determined by IHC, was associated with lower survivalT in the whole population (P = 0.029) and in the HER2-positive population (P = 0.017). PIK3CA mutations and/or PTEN loss status were evaluated together as a single parameter, to estimate the impact of activation of the PI3K/AKT molecular pathway, and it was significantly associated with both decreased TTP (P = 0.003 in the total population, P = 0.004 in HER2-positive patients) and survival (survivalT, P = 0.011 in total, P = 0.006 in HER2-positive). In this trastuzumab treated breast cancer population, PIK3CA activating mutations were associated with shorter TTP and PTEN loss with decreased survival. The activation of the PI3K/AKT pathway from either defect was associated with both TTP and survival, indicating the adverse effect of this pathway's status on trastuzumab efficacy. PMID- 21594666 TI - Maternal health care utilization among ever married youths in Kyimyindaing Township, Myanmar. AB - This study aimed to identify maternal care services utilization among ever married female youths (15-24 years) in Kyimyindaing Township, Yangon, Myanmar. A quantitative cross-sectional survey was conducted. A total of 196 ever married females who had delivered at least one child were included. Multistage sampling was employed. Face to face interviews using a structured questionnaire were carried out. Respondents were asked about their maternal care services utilization at the last pregnancy. Bivariate and logistic regression analyses were applied to determine the factors associated with utilization of maternal care services. Overall 96% of respondents received antenatal care (ANC) at least once and 79% had at least 4 ANC visits. The mean number of antenatal visits increased with women's education level. The majority received late ANC regardless of residence, age, education and family income. Nearly 39% delivered at home, especially in rural areas and 79% of home deliveries were attended by traditional birth attendants (TBAs). Only 56.6% of women received at least one postnatal care visit. Inadequate postnatal care (<6 times) was identified (82.6%). Place of residence, women's education and ANC frequency were the key determinants for a delivery place and postnatal care. Despite relatively high antenatal care attendance, most women practiced home deliveries and received inadequate postnatal care. Maternal health services need to be focused on rural women and women with little or no education. Quality ANC should be the entry point of safe delivery and postnatal care. Further intensification of information, education and communication activities on "safe motherhood" is needed. PMID- 21594667 TI - Exploring the relationship between parental concern and the management of childhood obesity. AB - Parental concern about child weight has been identified as a factor in parental monitoring and regulation of child diet. However, little is known about factors that influence parental concern or about how concern may influence parent management of child physical activity. The objectives of the current study were to identify the factors associated with parental concern about child weight and determine if parental concern is associated with specific actions to improve diet and increase physical activity. A stratified random sample of 1,500 parents of children in kindergarten, 2nd, 4th, 5th, 7th, and 9th grade were interviewed. Interviews addressed: (a) child and parent physical activity, (b) child and family nutrition, (c) child and parent BMI weight category, (d) interactions with health care providers, (e) parent obesity knowledge, (f) school assessment of BMI, and (g) parent perception of and concern about child weight. Child gender, weight status, and parent perception of child weight were significant predictors of parental concern. Parents were significantly more likely to report concern if their child was female, they believed their child to be overweight/obese, or their child was overweight/obese as indicated by BMI percentile. Concerned parents were significantly more likely to limit child screen time, take steps to improve child diet, and increase child physical activity than were parents who reported no concern. Treatment and prevention efforts should emphasize parental concern and awareness about child weight by providing accurate feedback on child weight status and education regarding the health risks associated with childhood overweight and obesity. Schools can play an important role in this process through the incorporation of BMI screenings. PMID- 21594668 TI - Anti-TNF-alpha therapies do not increase early postoperative complications in patients with inflammatory bowel disease. An Italian single-center experience. AB - PURPOSE: The impact of preoperative use of TNF-alpha inhibitors on postoperative complications in patients with inflammatory bowel disease (IBD) undergoing abdominal surgery is controversial. The aim of this study was to evaluate the 30 day postoperative outcomes for IBD patients treated with these drugs prior to surgery. METHODS: We analyzed retrospectively the incidence of short-term postoperative complications. Statistical analyses were performed to reveal the independent variables that influenced postoperative complications and the role of preoperative medical therapy with anti-TNF drugs within 12 weeks prior to surgery. RESULTS: One hundred fourteen patients (76 with Crohn's disease (CD) and 38 ulcerative colitis (UC)) underwent abdominal surgery for IBD. Fifty-four patients were treated with anti-TNF-alpha within 12 weeks prior to surgery (anti TNF group). Postoperative mortality and morbidity were 0% and 21%, respectively. The infection rate was 15%. A significantly higher incidence of postoperative complications was found in patients treated with high-dose steroids (58% vs. 17%; p = 0.003) after univariate analysis. The infection rate was significantly higher in patients treated with high-dose corticosteroids (50% vs. 11%; p = 0.002) and concomitant anti-TNF-alpha (60% vs. 13%; p = 0.023). Multivariate analysis revealed that only therapy with high-dose corticosteroids was significantly associated with cumulative (p = 0.017) and infective postoperative complications (p = 0.046). No significant differences were found between the anti-TNF group and the control group. CONCLUSION: High-dose corticosteroids increased the risk of short-term postoperative cumulative and infective complications. Anti-TNF drugs within 12 weeks prior to abdominal surgery in patients with IBD did not appear to increase the rate of postoperative complications. PMID- 21594669 TI - Commentary: proteooxidotoxic process of aggregation. AB - A recent editorial entitled "State of Aggregation" (Nat. Neurosci. 2011; 14:399) described the importance of establishing the structural state of pathogenic protein aggregates (Abeta, alpha-synuclein, huntingtin, etc.) in studies of neurodegenerative disorders. While this is a laudable goal, it is based on the assumption that the neurotoxicity depends upon a specific tertiary structure of the protein aggregates. Here, I describe evidence (not mentioned in the editorial) that suggests that it is not the protein oligomers, per se, that damage neurons. Instead, neurons are damaged by an unseen sequence(s) of chemical reactions that generate reactive oxygen species (ROS), and it is the ROS that cause both protein aggregation and neurotoxicity. The latter "proteooxidotoxicity" mechanism provides an explanation for numerous findings in the field of neurodegenerative disorders, including the inability to identify specific receptors for the pathogenic proteins. PMID- 21594670 TI - Serum 25-hydroxyvitamin D status in hip and spine-fracture patients in Japan. AB - BACKGROUND: Serum 25-hydroxyvitamin D (25(OH)D) is used as an index that reflects the level of vitamin D. We have previously reported, on the basis of a study in Sado in Niigata, that patients with hip fracture have lower serum 25(OH)D levels than non-hip-fracture cases. In this study, the serum 25(OH)D status in hip fracture cases was examined in four regions in Japan. Although most hip-fracture patients have experienced past spine-compression fractures, the relationship of these fractures and 25(OH)D is unknown. Therefore, we also examined the 25(OH)D level in spine-compression fracture patients in the same locations and time periods. METHODS: The levels of 25(OH)D, intact parathyroid hormone (intact PTH), undercarboxylated osteocalcin (ucOC), urine N-terminal crosslinking telopeptide of type I collagen (NTX), and bone mineral density were examined in patients with hip and spine fracture due to osteoporosis in several regions in Japan. RESULTS: There were no significant differences in age, BMI, serum 25(OH)D, serum intact PTH, and serum ucOC among the regions. Levels of serum 25(OH)D were low in patients with hip fracture and spine fracture. The average serum 25(OH)D level was significantly lower in hip-fracture patients than in spine-fracture patients (16.3 vs. 18.1 ng/mL, P < 0.05). High serum ucOC was found in 37% of hip-fracture patients and 44% of spine-fracture patients. CONCLUSIONS: Both hip and spine fracture patients have vitamin D insufficiency, with similar results found in elderly patients in four areas of Japan. The severity of this condition tends to be more serious in hip-fracture patients than in spine-fracture patients. PMID- 21594671 TI - Patella tendon rupture neglected for 55 years. PMID- 21594672 TI - Bioavailability of copper and zinc in mining soils. AB - The soil-contact exposure pathway can be the main driver of ecological risk assessments. There is currently no standard method to measure bioavailability of metals in soil to ecological receptors, yet the influence of metal bioavailability on toxicity has been known for decades and is a major factor influencing risk to ecological receptors. Bioavailability is to a large degree governed by varying soil characteristics within and among sites, yet ecological screening benchmarks are often derived on a total-concentration basis. We compared a calcium chloride (CaCl2) extraction, cyclodextrin extraction, simulated earthworm gut (SEG) test, earthworm kinetic bioaccumulation test, and metal residues in plant tissues with a battery of invertebrate and toxicity tests using mining soils consisting of high organic-matter content cocontaminated with copper (Cu) and zinc (Zn). Earthworm (Eisenia andrei) tissue concentrations of Cu and Zn were regulated and were not predictive of invertebrate toxicity. All chemical measures of bioavailability correlated with several biological responses; however, CaCl2-extractable Cu and SEG-extractable Cu and Zn best predicted effects to E. andrei. Total Cu concentrations in soil best correlated with effects to plants. Overall, a chemical measure was the best predictor of toxicity to each organism compared with biological measures, although the exact measure was dependent on organism and end point. Chemical-extraction techniques provide relatively quick, inexpensive indicators of essential metal bioavailability compared with biological measures; however, no single measure was indicative of all effects to all organisms. PMID- 21594673 TI - Polybrominated diphenyl ethers, polychlorinated biphenyls, and organochlorine pesticides in adipose tissues of Korean women. AB - Studies on residue levels and accumulation profiles of persistent organic pollutants (POPs) in human adipose tissues of Korean populations are scarce. In this study, concentrations and accumulation features of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs) were measured in adipose tissues of Korean women age 40-68 years. The highest concentrations were found for PCBs and DDTs, which were 1-2 orders of magnitude greater than the concentrations of hexachlorocyclohexanes, chlordanes, and PBDEs. The concentrations of PCBs and OCPs were lower than those reported for other countries. However, PBDE concentrations were greater than those reported for other countries, suggesting that ongoing exposure to PBDEs is a concern in Korea. The profiles of PBDEs were characterized by the predominance of BDE 209, followed by nona- and octa-BDEs, which are consistent with the consumption patterns of products containing PBDEs in Korea. The concentrations of PCBs and some OCPs were significantly correlated with each other, whereas PBDEs showed low or moderate correlations with other POPs, suggesting differences in exposure routes and biotransformation potentials of the compounds studied. The concentrations of organochlorines and PBDEs were not correlated with subjects' age and body mass index. The results of this study provide baseline information on POPs in adipose tissues of the general population in Korea. PMID- 21594674 TI - Proteomic analysis of hepatic tissue in adult female zebrafish (Danio rerio) exposed to atrazine. AB - Atrazine (ATZ), the most common herbicide, is a frequently observed contaminant in freshwater ecosystems. In the present study, two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization tandem time-of flight-mass spectrometry, combined with histopathological analysis, were used to detect the hepatic damage in adult female zebrafish (Danio rerio) exposed to ATZ. More than 600 hepatic protein spots were detected in each gel with silver staining, and most of the proteins ranged from 20 to 70 kD and pH 4-9. Through comparison and analysis, 7 proteins were found to be upregulated>2-fold, whereas 6 protein spots were downregulated>2-fold after 10 and 1000 MUg/l ATZ exposures for 14 days, which had caused histological effects in zebrafish livers. We found that these changed proteins were associated with a variety of cellular biological processes, such as response to oxidative stress, oncogenesis, etc. The results demonstrated that ATZ comprehensively influenced a variety of cellular and biological processes in zebrafish. The information presented in this study will be helpful in fully understanding the mechanism of the potential effects induced by ATZ in fish. PMID- 21594675 TI - Cloning and characterization of PR5 gene from Curcuma amada and Zingiber officinale in response to Ralstonia solanacearum infection. AB - Ginger (Zingiber officinale Roscoe), is an important spice crop that is badly affected by Ralstonia solanacearum wilt. Ginger does not set seed and sexual recombination has never been reported. In spite of extensive search in its habitats, no resistance source to Ralstonia induced bacterial wilt, could be located in ginger. Curcuma amada Roxb. is a potential donor for bacterial wilt resistance to Z. officinale, if the exact mechanism of resistance is understood. Pathogenesis-related (PR)-5 proteins are a family of proteins that are induced by different phytopathogens in many plants and share significant sequence similarity with thaumatin. Two putative PR5 genes, CaPR5 and ZoPR5, were amplified from C. amada and ginger, which encode precursor proteins of 227 and 224 amino acid residues, respectively, and share high homology with a number of other PR5 genes. The secondary and three-dimensional structure comparison did not reveal any striking differences between these two proteins. The expression of Ca and ZoPR5s under R. solanacearum inoculation was analyzed at different time points using quantitative real-time PCR (qRT-PCR). Our results reveal that CaPR5 is readily induced by the bacterium in C. amada, while ZoPR5 induction was very weak and slow in ginger. These results suggest that the CaPR5 could play a role in the molecular defense response of C. amada to pathogen attack. This is the first report of the isolation of PR5 gene from the C. amada and Z. officinale. Promoter analysis indicates the presence of a silencing element binding factor in ZoPR5 promoter, but not in CaPR5. Prospective promoter elements, such as GT-1 box and TGTCA, implicated as being positive regulatory elements for expression of PR proteins, occur in the 5'-flanking sequences of the CaPR5. Transient GUS expression study confirms its action with a weaker GUS expression in ginger, indicating that the PR5 expression may be controlled in the promoter. PMID- 21594676 TI - Resistance to Soil-borne cereal mosaic virus in durum wheat is controlled by a major QTL on chromosome arm 2BS and minor loci. AB - Soil-borne cereal mosaic (SBCM) is a viral disease, which seriously affects hexaploid as well as tetraploid wheat crops in Europe. In durum wheat (Triticum durum Desf.), the elite germplasm is characterized by a wide range of responses to SBCMV, from susceptibility to almost complete resistance. In this study, the genetic analysis of SBCMV resistance was carried out using a population of 181 durum wheat recombinant inbred lines (RILs) obtained from Meridiano (resistant) * Claudio (moderately susceptible), which were profiled with SSR and DArT markers. The RILs were characterized for SBCMV response in the field under severe and uniform SBCMV infection during 2007 and 2008. A wide range of disease reactions (as estimated by symptom severity and DAS-ELISA) was observed. A large portion of the variability for SBCMV response was explained by a major QTL (QSbm.ubo-2BS) located in the distal telomeric region of chromosome 2BS near the marker triplet Xbarc35-Xwmc661-Xgwm210, with R(2) values ranging from 51.6 to 91.6%. The favorable allele was contributed by Meridiano. Several QTLs with minor effects on SBCMV response were also detected. Consistently with the observed transgressive segregation, the resistance alleles at minor QTLs were contributed by both parents. The presence and effects of QSbm.ubo-2BS were validated through association mapping in a panel of 111 elite durum wheat accessions. PMID- 21594677 TI - High-frequency sensorineural hearing loss and its underlying genetics (Hfhl1 and Hfhl2) in NIH Swiss mice. AB - Studies using inbred strains of mice have been invaluable for identifying alleles that adversely affect hearing. However, the efficacy of those studies is limited by the phenotypes that these strains express and the alleles that they segregate. Here, by selectively breeding phenotypically and genetically heterogeneous NIH Swiss mice, we generated two lines-the all-frequency hearing loss (AFHL) line and the high-frequency hearing loss (HFHL) line-with differential hearing loss. The AFHL line exhibited characteristics typical of severe, early-onset, sensorineural hearing impairment. In contrast, the HFHL line expressed a novel early-onset, mildly progressive, and frequency-specific sensorineural hearing loss. By quantitative trait loci (QTLs) analyses in these two lines, we identified QTLs on chromosomes 7, 8, and 10 that significantly affected hearing function. The loci on chromosomes 7 and 8 (Hfhl1 and Hfhl2, respectively) are novel and appear to adversely affect only high frequencies (>=30 kHz). Mice homozygous for NIH Swiss alleles at either Hfhl1 or Hfhl2 have 32-kHz auditory-evoked brain stem response thresholds that are 8-14 dB SPL higher than the corresponding heterozygotes. DNA sequence analyses suggest that both the Cdh23(ahl) and Gipc3(ahl5) variants contribute to the chromosome 10 QTL detected in the AFHL line. The frequency specific hearing loss indicates that the Hfhl1 and Hfhl2 alleles may affect tonotopic development. In addition, dissecting the underlying complex genetics of high-frequency hearing loss may prove relevant in identifying less severe and common forms of hearing impairment in the human population. PMID- 21594679 TI - Free-running (non-entrained to 24-h period) circadian sleep disorder in a patient with obstructive sleep apnea, delayed sleep phase tendency, and lack of social interaction. PMID- 21594678 TI - Computational assessment of insulin secretion and insulin sensitivity from 2-h oral glucose tolerance tests for clinical use for type 2 diabetes. AB - In type 2 diabetes mellitus, glucose homeostasis is tightly maintained through insulin secretion and insulin sensitivity. Therefore, finding an accurate method to assess insulin secretion and sensitivity using clinically available data would enhance the quality of diabetic medical care. In an effort to find such a method, we developed a computational approach to derive indices of these factors using a 2-h oral glucose tolerance test (OGTT). To evaluate our method, clinical data from subjects who received an OGTT and a glucose clamp test were examined. Our insulin secretion index was significantly correlated with an analogous index obtained from a hyperglycemic clamp test (r = 0.90, n = 46, p < 0.001). Our insulin sensitivity index sensitivity was also significantly correlated with an analogous index obtained from a hyperinsulinemic-euglycemic clamp test (r = 0.56, n = 79, p < 0.001). These results suggest that our method can potentially provide an accurate and convenient tool toward improving the management of diabetes in clinical practice by assessing insulin secretion and insulin sensitivity. PMID- 21594680 TI - Acute and chronic metal exposure impairs locomotion activity in Drosophila melanogaster: a model to study Parkinsonism. AB - The biometals iron (Fe), manganese (Mn) and copper (Cu) have been associated to Parkinson's disease (PD) and Parkinsonism. In this work, we report for the first time that acute (15 mM for up to 5 days) or chronic (0.5 mM for up to 15 days) Fe, Mn and Cu exposure significantly reduced life span and locomotor activity (i.e. climbing capabilities) in Drosophila melanogaster. It is shown that the concentration of those biometals dramatically increase in Drosophila's brain acutely or chronically fed with metal. We demonstrate that the metal accumulation in the fly's head is associated with the neurodegeneration of several dopaminergic neuronal clusters. Interestingly, it is found that the PPL2ab DAergic neuronal cluster was erode by the three metals in acute and chronic metal exposure and the PPL3 DAergic cluster was also erode by the three metals but in acute metal exposure only. Furthermore, we found that the chelator desferoxamine, ethylenediaminetetraacetic acid, and D: -penicillamine were able to protect but not rescue D. melanogaster against metal intoxication. Taken together these data suggest that iron, manganese and copper are capable to destroy DAergic neurons in the fly's brain, thereby impairing their movement capabilities. This work provides for the first time metal-induced Parkinson-like symptoms in D. melanogaster. Understanding therefore the effects of biometals in the Drosophila model may provide insights into the toxic effect of metal ions and more effective therapeutic approaches to Parkinsonism. PMID- 21594681 TI - Influence of diabetes mellitus on vertebral fractures in men with acromegaly. AB - Acromegaly is frequently complicated by fragility vertebral fractures and diabetes mellitus. Since type 2 diabetes mellitus is a cause of secondary osteoporosis in the general population, in this cross-sectional study we aimed at investigating the association between diabetes mellitus and vertebral fractures in males with acromegaly. Fifty-seven patients (median age 47 years, range: 24 85) with active (21 cases) and controlled (36 cases) acromegaly and 57 control subjects were evaluated for bone mineral density (BMD) by DXA and vertebral fractures by a quantitative morphometric analysis. Diabetes mellitus was found in 18 patients and 18 control subjects. The prevalence of vertebral fractures was higher in acromegalic patients as compared with the control subjects (50.9 vs. 10.5%; chi(2): 21.8; P < 0.001). Acromegalic patients with fractures had serum IGF-I values significantly higher (P = 0.009), longer duration of active disease (P < 0.001) and higher prevalence of active acromegaly (P = 0.007) and diabetes mellitus (P = 0.04) as compared to patients who did not fracture. When acromegaly was active, the prevalence of vertebral fractures was high independently of the coexistent diabetes mellitus. On the contrary, when acromegaly was controlled the prevalence of vertebral fractures was significantly higher in patients with diabetes as compared to patients without diabetes (62.6 vs. 28.0%; P = 0.04). In both diabetic and non diabetic patients, vertebral fractures occurred independently of BMD. In conclusion, this study suggests that diabetes mellitus may be associated with an increased prevalence of vertebral fractures in males with acromegaly. However, this effect seems to be relatively attenuated in the presence of persistent GH hypersecretion. PMID- 21594682 TI - Early and personalized ambulatory follow-up to tailor furosemide and fluid intake according to congestion in post-discharge heart failure. AB - Congestive heart failure (CHF) worsening is a worldwide cause of rehospitalization and mortality, specially during the early period after hospitalization. Fluid accumulation plays a key role in the pathophysiology of both acute heart decompensation and disease progression. The effective use of drugs to maintain restored clinical stabilization in recently discharged patients is a difficult task, and it relies on matching the most appropriately tailored therapy to specific clinical profiles. However, no successful treatment has been shown to reduce post-discharge readmission. We evaluated in a case-control study the effectiveness of an early and personalized congestion-guided ambulatory program on medium-term (6 months) compensation in recently discharged CHF patients. Group A (22 patients) underwent a post-discharge close follow-up consisting of: an early clinic visit within 10 days; a second visit within 10 days after the first; and the other visits at month 1, 2, 3 after discharge. Controls (Group B, 21 patients) underwent a conventional ambulatory follow-up only at month 1, 2, 3 after discharge. The ambulatory approach in both groups was based on the monitoring of signs/symptoms of congestion and body weight, body hydration estimation by using bioelectrical impedance analysis (BIA) and laboratory data. This assessment was finalized to tailor furosemide and daily fluid intake at each visit to eliminate clinical or instrumental evidence of persistent congestion relieving the signs and symptoms. At 6 months, Group A was associated with a better clinical compensation (improved hydration state, lower BNP levels and congestion score), an improved quality of life, and reduced re hospitalizations. We conclude that in CHF the early and personalized ambulatory follow-up based on congestion-guided treatment is effective to optimize management and maintain clinical stability in the post-discharge period. PMID- 21594683 TI - Natural history of idiopathic normal-pressure hydrocephalus. AB - Natural history of idiopathic normal-pressure hydrocephalus (INPH) is not clear. We performed a literature search for studies that looked into the outcome of unshunted INPH patients trying to answer the following questions: Do all INPH patients deteriorate without shunt? If yes, at what rate? Do some NPH patients improve without shunt? If yes, to what extent? Six studies objectively described the outcome of 102 INPH patients. Result shows that without surgery, most INPH patients had measurable deterioration as early as 3 months following initial assessment. A small number of patients might improve without shunt, however the extent of improvement is not clear. The homogeneity of the findings of the cohort studies provided high evidence supporting the rule of shunt surgery in INPH patients. PMID- 21594685 TI - Amycolatopsis endophytica sp. nov., a novel endophytic actinomycete isolated from oil-seed plant Jatropha curcas L. AB - A novel actinomycete, designated KLBMP 1221(T), was isolated from the surface sterilized seeds of an oil-seed plant Jatropha curcas L. collected from Sichuan Province, south-west China and was characterized taxonomically by using a polyphasic approach. Phylogenetic analyses based on 16S rRNA gene sequence showed that this strain formed a distinct phyletic line within the radiation of the genus Amycolatopsis. The 16S rRNA gene sequence similarity indicated that strain KLBMP 1221(T) was most closely related to Amycolatopsis eurytherma NT202(T) (98.9%), Amycolatopsis tucumanensis ABO(T) (98.8%), Amycolatopsis thermoflava N1165(T) (98.6%) and Amycolatopsis methanolica IMSNU 20055(T) (98.5%). Strain KLBMP 1221(T) had morphological and chemotaxonomic properties that were consistent with its classification in the genus Amycolatopsis. However, DNA-DNA relatedness data and phenotypic differences clearly distinguished the isolate from its closest relatives. Based on the combined genotypic and phenotypic evidence, it is proposed that strain KLBMP 1221(T) be classified as representative of a novel species for which the name Amycolatopsis endophytica sp. nov. is proposed. The type strain is KLBMP 1221(T) (= KCTC 19776(T) = CCTCC AA 2010003(T)). PMID- 21594684 TI - Proline-rich antimicrobial peptides: converging to a non-lytic mechanism of action. AB - Proline-rich antimicrobial peptides are a group of cationic host defense peptides of vertebrates and invertebrates characterized by a high content of proline residues, often associated with arginine residues in repeated motifs. Those isolated from some mammalian and insect species, although not evolutionarily related, use a similar mechanism to selectively kill Gram-negative bacteria, with a low toxicity to animals. Unlike other types of antimicrobial peptides, their mode of action does not involve the lysis of bacterial membranes but entails penetration into susceptible cells, where they then act intracellularly. Some aspects of the transport system and cytoplasmic targets have been elucidated. These features make them attractive both as anti-infective lead compounds and as a new class of potential cell-penetrating peptides capable of internalising membrane-impermeant drugs into both bacterial and eukaryotic cells. PMID- 21594686 TI - Fatigue and progression of corpus callosum atrophy in multiple sclerosis. AB - Fatigue is one of the most disabling symptoms in multiple sclerosis (MS) patients. There is no or only weak correlation between conventional magnetic resonance imaging (MRI) parameters and level of fatigue. The aim of this study was to investigate the relationship between progression of corpus callosum (CC) atrophy and fatigue in MS patients. This was a cohort study in 70 patients with relapsing form of MS (RRMS) and serial MRIs over a mean follow-up of 4.8 years [67% female, mean age 42 +/- 11 years, mean disease duration 9.7 +/- 7.6 years, mean Expanded Disability Status Scale (EDSS) 2.8 +/- 1.6]. Fatigue was assessed by the Fatigue Severity Scale (FSS). CC size was measured with the CC index (CCI). In total, 40% of the patients suffered from fatigue (mean FSS score 5.3 +/ 1.1) and 60% patients had no fatigue (mean FSS score of 2.1 +/- 1). Patients with fatigue had higher EDSS scores (p = 0.01) and CC atrophy was more pronounced in patients with fatigue (-21.8 vs. -12.1%, p = 0.005). FSS correlated with CCI change over time (r = -0.33; p = 0.009) and EDSS (p = 0.008; r = 0.361). The association between annualized CCI change and FSS was independent from EDSS, disease duration, gender and age in a multivariate linear regression analysis (p < 0.001). Progression of CC atrophy may play a role in the evolution of MS related fatigue. PMID- 21594688 TI - What's new on ACL surgery horizon? PMID- 21594687 TI - Greenhouse and field cultivations of antigen-expressing potatoes focusing on the variability in plant constituents and antigen expression. AB - The production of plant-derived pharmaceuticals essentially requires stable concentrations of plant constituents, especially recombinant proteins; nonetheless, soil and seasonal variations might drastically interfere with this stability. In addition, variability might depend on the plant organ used for production. Therefore, we investigated the variability in plant constituents and antigen expression in potato plants under greenhouse and field growth conditions and in leaves compared to tubers. Using potatoes expressing VP60, the only structural capsid protein of the rabbit haemorrhagic disease virus (RHDV), CTB, the non-toxic B subunit (CTB) of the cholera toxin (CTA-CTB(5)) and the marker protein NPTII (neomycinphosphotransferase) as a model, we compare greenhouse and field production of potato-derived antigens. The influence of the production organ turned out to be transgene specific. In general, yield, plant quality and transgene expression levels in the field were higher than or similar to those observed in the greenhouse. The variation (CV) of major plant constituents and the amount of transgene-encoded protein was not influenced by the higher variation of soil properties observed in the field. Amazingly, for specific events, the variability in the model protein concentrations was often lower under field than under greenhouse conditions. The changes in gene expression under environmental stress conditions in the field observed in another event do not reduce the positive influence on variability since events like these should excluded from production. Hence, it can be concluded that for specific applications, field production of transgenic plants producing pharmaceuticals is superior to greenhouse production, even concerning the stability of transgene expression over different years. On the basis of our results, we expect equal or even higher expression levels with lower variability of recombinant pharmaceuticals in the field compared to greenhouse production combined with approximately 10 times higher tuber yield in the field. PMID- 21594689 TI - Pediatric anterior cruciate ligament reconstruction. AB - An increasing number of anterior cruciate ligament (ACL) injuries are seen in children now than in the past due to increased sports participation. The natural history of ACL deficient knees in active individuals, particularly in children is poor. Surgical management of ACL deficiency in children is complex due to the potential risk of injury to the physis and growth disturbance. Delaying ACL reconstruction until maturity is possible but risks instability episodes and intra-articular damage. Surgical options include physeal-sparing, partial transphyseal and complete transphyseal procedures. This article reviews the management of ACL injured skeletally immature patients including the functional outcome and complications of contemporary surgical techniques. PMID- 21594690 TI - Mini-invasive technique for bone patellar tendon bone harvesting: its superiority in reducing anterior knee pain following ACL reconstruction. AB - Arthroscopically-assisted ACL-reconstructions are currently reliable, reproducible. Residual anterior knee symptoms however, especially after patellar BTB graft use, are not uncommon occurrences. Contributing factors are numerous and include injury to the saphenous nerve infrapatellar branches and/or histologic changes at the harvest site. The use of mini invasive harvesting technique decreases the risk of injury to the saphenous nerve infrapatellar branches while preserving the peritenon. The double-incision approach significantly reduces the mid-term incidence of anterior knee pain after ACL reconstruction. Additionally, this technique markedly decreases the occurrence of sensory disorders and the extent of hypoesthesia. We thus advocate the use of a double-incision graft harvesting technique in ACL-reconstruction using a patellar bone-tendon-bone transplant. PMID- 21594691 TI - Arthroscopic intra- and extra-articular anterior cruciate ligament reconstruction with gracilis and semitendinosus tendons: a review. AB - The purposes of this paper are to summarize the concepts relating to the use of a combined intra-articular and extra-articular reconstructive procedure in the arthroscopic treatment of a torn ACL and to review several operative techniques utilizing gracilis and semitendinosus tendons that are currently in use to treat this instability. The highly satisfactory results obtained over the time show that a combination of intra- and extra-articular procedures for ACL reconstruction is a valid surgical option. PMID- 21594692 TI - Exposure to phthalates: reproductive outcome and children health. A review of epidemiological studies. AB - Phthalates are a family of industrial chemicals that have been used for a variety of purposes. As the potential consequences of human exposure to phthalates have raised concerns in the general population, they have been studied in susceptible subjects such as pregnant women, infants and children. This article aims at evaluating the impact of exposure to phthalates on reproductive outcomes and children health by reviewing most recent published literature. Epidemiological studies focusing on exposure to phthalates and pregnancy outcome, genital development, semen quality, precocious puberty, thyroid function, respiratory symptoms and neurodevelopment in children for the last ten years were identified by a search of the PubMed, Medline, Ebsco, Agricola and Toxnet literature bases. The results from the presented studies suggest that there are strong and rather consistent indications that phthalates increase the risk of allergy and asthma and have an adverse impact on children's neurodevelopment reflected by quality of alertness among girls, decreased (less masculine) composite score in boys and attention deficit hyperactivity disorder. Results of few studies demonstrate negative associations between phthalate levels commonly experienced by the public and impaired sperm quality (concentration, morphology, motility). Phthalates negatively impact also on gestational age and head circumference; however, the results of the studies were not consistent. In all the reviewed studies, exposure to phthalates adversely affected the level of reproductive hormones (luteinizing hormone, free testosterone, sex hormone-binding globulin), anogenital distance and thyroid function. The urinary levels of phthalates were significantly higher in the pubertal gynecomastia group, in serum in girls with premature thelarche and in girls with precocious puberty. Epidemiological studies, in spite of their limitations, suggest that phthalates may affect reproductive outcome and children health. Considering the suggested health effects, more epidemiologic data is urgently needed and, in the meantime, precautionary policies must be implemented. PMID- 21594694 TI - PSP_MCSVM: brainstorming consensus prediction of protein secondary structures using two-stage multiclass support vector machines. AB - Secondary structure prediction is a crucial task for understanding the variety of protein structures and performed biological functions. Prediction of secondary structures for new proteins using their amino acid sequences is of fundamental importance in bioinformatics. We propose a novel technique to predict protein secondary structures based on position-specific scoring matrices (PSSMs) and physico-chemical properties of amino acids. It is a two stage approach involving multiclass support vector machines (SVMs) as classifiers for three different structural conformations, viz., helix, sheet and coil. In the first stage, PSSMs obtained from PSI-BLAST and five specially selected physicochemical properties of amino acids are fed into SVMs as features for sequence-to-structure prediction. Confidence values for forming helix, sheet and coil that are obtained from the first stage SVM are then used in the second stage SVM for performing structure-to structure prediction. The two-stage cascaded classifiers (PSP_MCSVM) are trained with proteins from RS126 dataset. The classifiers are finally tested on target proteins of critical assessment of protein structure prediction experiment-9 (CASP9). PSP_MCSVM with brainstorming consensus procedure performs better than the prediction servers like Predator, DSC, SIMPA96, for randomly selected proteins from CASP9 targets. The overall performance is found to be comparable with the current state-of-the art. PSP_MCSVM source code, train-test datasets and supplementary files are available freely in public domain at: http://sysbio.icm.edu.pl/secstruct and http://code.google.com/p/cmater-bioinfo/ PMID- 21594693 TI - Identification of new potential Mycobacterium tuberculosis shikimate kinase inhibitors through molecular docking simulations. AB - Tuberculosis (TB) is the major cause of human mortality from a curable infectious disease, attacking mainly in developing countries. Among targets identified in Mycobacterium tuberculosis genome, enzymes of the shikimate pathway deserve special attention, since they are essential to the survival of the microorganism and absent in mammals. The object of our study is shikimate kinase (SK), the fifth enzyme of this pathway. We applied virtual screening methods in order to identify new potential inhibitors for this enzyme. In this work we employed MOLDOCK program in all molecular docking simulations. Accuracy of enzyme-ligand docking was validated on a set of 12 SK-ligand complexes for which crystallographic structures were available, generating root-mean square deviations below 2.0 A. Application of this protocol against a commercially available database allowed identification of new molecules with potential to become drugs against TB. Besides, we have identified the binding cavity residues that are essential to intermolecular interactions of this enzyme. PMID- 21594695 TI - Iron status in elite young athletes: gender-dependent influences of diet and exercise. AB - Iron depletion seems to occur more frequently among athletes than in the general population and may affect performance capacity. Only little information is available about the prevalence of iron status abnormalities in young elite athletes and whether iron depletion is associated with gender, sport, age or nutrition- and exercise-related factors in this group. Hence, diet, exercise and haematological data from 193 elite athletes (96 males, 97 females; 16.2 +/- 2.7 years) from 24 different sports were analyzed retrospectively. Most female athletes failed to meet the recommended daily allowance for iron, even though dietary iron density was higher than in males (5.75 +/- 0.78 vs. 6.17 +/- 0.98 mg/1,000 kcal; P = 0.001). Iron depletion (serum ferritin < 35 MUg/L) occurred in 31% of male and 57% of female athletes (P < 0.001). Low haemoglobin (males: <13 g/dL; females: <12 g/dL) and haematocrit (males: <40%; females: <36%) values were equally prevalent in both genders [haemoglobin: 7.3% (males), 6.2% (females); haematocrit: 13.5% (males); 15.5% (females)]. In females, reduced ferritin levels were associated with a lower dietary iron density (5.9 +/- 0.8 vs. 6.6 +/- 1.1 mg/1,000 kcal; P = 0.002). Males with iron depletion had a significantly higher estimated energy expenditure (48.7 +/- 7.0 vs. 44.4 +/- 7.6 kcal/kg/day; P = 0.009). PMID- 21594697 TI - Cerebrospinal fluid/serum gradient of IgG is associated with disability at acute attacks of neuromyelitis optica. AB - Increased blood-brain barrier (BBB) disruption can be found in patients with neuromyelitis optica (NMO); however, its clinical implication and association with disability at acute attack remains obscure. The purpose of the study was to evaluate the clinical significance of BBB disruption and the subsequent cerebrospinal fluid (CSF)/serum IgG gradient in NMO. Retrospective analysis was made of acute-stage CSF samples from NMO (n = 40) and multiple sclerosis (MS; n = 26) patients. The CSF/serum IgG gradient (QIgG), albumin ratio (Qalb), and IgG index were calculated. Multivariate regression analysis was used to identify clinical and CSF variables associated with disability at acute attacks (extended disability scale score, EDSS) in both groups. The EDSS was significantly associated with the QIgG (p < 0.001), Qalb (p = 0.012), and number of cumulative attacks (p = 0.012) in NMO but not in MS with univariate analysis. Length of spinal cord involvement was also associated with EDSS in NMO (p = 0.030). However, multivariate analysis revealed that the QIgG was only significantly associated with EDSS in NMO (0.580; 95% CI -0.257, 0.961; p = 0.002). The QIgG was also highly associated with the Qalb in NMO (p < 0.001). The QIgG may reflect systemic IgG leakage into the CNS and is strongly associated with disability at acute attacks in NMO, suggesting that BBB disruption can aggravate disease activity by facilitating systemic IgG infiltration into the CNS. PMID- 21594696 TI - Venous gas embolism as a predictive tool for improving CNS decompression safety. AB - A key process in the pathophysiological steps leading to decompression sickness (DCS) is the formation of inert gas bubbles. The adverse effects of decompression are still not fully understood, but it seems reasonable to suggest that the formation of venous gas emboli (VGE) and their effects on the endothelium may be the central mechanism leading to central nervous system (CNS) damage. Hence, VGE might also have impact on the long-term health effects of diving. In the present review, we highlight the findings from our laboratory related to the hypothesis that VGE formation is the main mechanism behind serious decompression injuries. In recent studies, we have determined the impact of VGE on endothelial function in both laboratory animals and in humans. We observed that the damage to the endothelium due to VGE was dose dependent, and that the amount of VGE can be affected both by aerobic exercise and exogenous nitric oxide (NO) intervention prior to a dive. We observed that NO reduced VGE during decompression, and pharmacological blocking of NO production increased VGE formation following a dive. The importance of micro-nuclei for the formation of VGE and how it can be possible to manipulate the formation of VGE are discussed together with the effects of VGE on the organism. In the last part of the review we introduce our thoughts for the future, and how the enigma of DCS should be approached. PMID- 21594698 TI - Evaluation of absorbable and permanent mesh fixation devices: adhesion formation and mechanical strength. AB - PURPOSE: Laparoscopic ventral hernia repair is commonly performed with mesh prostheses; however, there is no standard for fixation devices used to secure mesh to the abdominal wall. This study is a functional comparison of novel, screw type absorbable and permanent fixation devices with a traditional titanium fixation device. METHODS: Fifteen pigs each underwent the laparoscopic placement of two 11 * 14-cm mesh prostheses and were randomized for mesh fixation with either titanium spiral tacks (TS), absorbable screw-type fasteners (SF), or permanent screw-type fasteners (PF) (n = 10 mesh prostheses for each fixation group). Adhesions were assessed laparoscopically at 4 weeks. The fixation devices were also embedded in porcine abdominal rectus muscle for ex vivo mechanical testing along with partial thickness polypropylene suture (PR) as a control group (n = 40 for each group). Maximum pull-off forces were measured. All statistical tests were two-tailed, and a P-value < 0.05 was considered to be significant. RESULTS: The mean tenacity adhesion scores were 1.40 +/- 0.52 (PF), 1.7 +/- 0.82 (SF), and 2.6 +/- 1.07 (TS). Adhesions in the PF group were significantly less tenacious compared with the TS group (P = 0.01). Quantitative adhesion scores were not significantly different among groups. The maximum pull-off forces, measured in Newtons, were 28.61 N +/- 4.89 N (TS), 22.71 N +/- 7.86 N (SF), 16.98 N +/- 7.59 N (PF), and 20.83 N +/- 6.25 N (PR). The pull-off force in the TS group was higher than all of the other groups (P < 0.001). The SF group also had a higher pull-off force compared with the PF group (P < 0.001). CONCLUSIONS: The screw-type absorbable and permanent fixation devices provided adequate fixation and were associated with decreased adhesions in this porcine model. PMID- 21594699 TI - The sex ratio and age of onset features of gastric cancer patients in hereditary diffuse gastric cancer families. AB - An understanding of the clinical features of gastric cancer (GC) in hereditary diffuse gastric cancer (HDGC) families may be helpful in deciding who should receive prophylactic total gastrectomy and when. This study evaluates the sex ratio and age of onset features of these patients. Forty-seven HDGC families were screened from the English (40 families), Chinese (7 families) literature. One family was ascertained in our hospital. A total of 48 HDGC families with 192 GC cases were analyzed. The patients were grouped as Asian and non-Asian cases according the first author corresponding address. The male to female ratio of GC patients in our study was less than general GC population (0.769 vs. 1.826, P < 0.0001). The mean age of male cases was higher than that for females (48.9 vs. 43.1 years; P = 0.012). The mean age for parents of cases was higher than that for the offspring of cases (52.5 vs. 37.4 years; P = 0.0001). There was a significant age correlation between sib-sib GC pairs (P < 0.0001). The male to female ratio of Asian GC patients was higher than that of non-Asian GC cases (1.450 vs. 0.614, P = 0.01). The age for Asian GC patients was higher than that of non-Asian GC patients (52.1 vs. 43.5 years, P = 0.001). The results showed that female GC patients were more frequent and younger than male patients in HDGC families. The parents of cases were older than offspring cases. There was a significant age correlation between sib-sib cases. There was regional disparity in the sex ratio and age features. PMID- 21594700 TI - "Open" esophagectomy. AB - "Open" esophagectomy has been the standard of care for treatment of esophageal carcinoma against which evolving minimally invasive surgical, endoscopic, and non operative therapies must be compared. In experienced hands and with appropriate patient selection, "open" esophagectomy can achieve good rates of cure with low mortality, acceptable morbidity, and good long-term quality of life. PMID- 21594701 TI - SSAT maintenance of certification: literature review on gastroesophageal reflux disease and hiatal hernia. AB - BACKGROUND: This article reviews the current literature pertaining to the diagnosis and management of gastroesophageal reflux disease (GERD) and hiatal hernia. DISCUSSION: GERD is one of the most common gastrointestinal disorders in the USA. For effective management, a conclusive diagnosis must be made. Most patients are effectively managed by acid suppression therapy, whereas others require procedural treatment. Endoluminal treatment of GERD is an option, but long-term results of this therapy are unknown. The "gold standard" surgical treatment of GERD is laparoscopic Nissen fundoplication. Large hiatal hernias are difficult to manage with a relatively high rate of recurrent hiatal hernia. CONCLUSION: Whether or not to use mesh at the hiatus to decrease this occurrence is currently debatable. PMID- 21594702 TI - Staging of papillary thyroid carcinoma with ultrasonography: performance in a large series. AB - BACKGROUND: This study was designed to evaluate the performance of ultrasonography (US) for the preoperative staging of papillary thyroid carcinoma (PTC) in a large series according to the TNM classification. METHODS: Preoperative US was performed for the evaluation of primary tumors and lymph node metastasis in 722 consecutive patients with cytologically proven PTC. Three experienced radiologists prospectively determined T and N categories of PTC. N categorization was based on compartments, including left and right lateral compartments (levels II-V) and central compartment (level VI). All patients underwent surgery and central compartment dissection. Lateral compartment dissection was selectively performed. We assessed the diagnostic performance of preoperative US for staging of PTC on the basis of pathologic findings of surgical specimens. Subgroup analysis according to suspicion of diffuse thyroid disease (DTD) on US was performed to compare US accuracies for N categorization. RESULTS: US predicted 61.7% (142/230) of patients with multifocal PTC and 67.1% (100/149) of patients with bilateral malignancy. Overall accuracy of US for T categorization was 69.7% (503/722) and that of US for N categorization was 59% (426/722). Accuracies of sonographic categorization for N0, N1a, and N1b were 66% (276/418), 33.3% (70/210), and 85.1% (80/94), respectively. Overall US accuracy for prediction of an N category was significantly lower in patients with US indicated DTD (51.1%, 67/131) than it was in patients without DTD (60.7%, 359/591; P = 0.043). CONCLUSIONS: Preoperative US is a feasible technique for the preoperative staging of PTC and is helpful for the detection of lateral compartment metastasis. Presence of DTD can affect the staging of lymph node metastasis. PMID- 21594703 TI - Both BRAF V600E mutation and older age (>= 65 years) are associated with recurrent papillary thyroid cancer. AB - PURPOSE: This study was designed to examine the aggressive features of BRAF positive papillary thyroid cancer (PTC) and association with age. METHODS: We compared the clinicopathologic parameters and BRAF V600E mutation status of 121 elderly (age >=65 years) PTC patients who underwent thyroidectomy from January 2007 to December 2009 to a consecutive cohort of 98 younger (age <65 years) PTC patients. RESULTS: Younger and elderly PTC patients had similar incidences of BRAF-positive tumors (41% vs. 38%; p = 0.67). The elderly cohort was more likely to have smaller tumors (mean 1.6 vs. 2.1 cm; p = 0.001), present with advanced TNM stage (36% vs. 19%; p = 0.008), and have persistent/recurrent disease (10% vs. 1%; p = 0.006). BRAF-positive status was associated with PTC that were tall cell variant (p < 0.001), had extrathyroidal extension (p < 0.001), lymph node involvement (p = 0.008), advanced (III/IV) TNM stage (p < 0.001), and disease recurrence (p < 0.001). Except for lymph node involvement, the association between aggressive histology characteristics at presentation and BRAF-positive PTC also was observed within the age-defined cohorts. In short-term follow-up (mean, 18 months), persistent/recurrent PTC was much more likely to occur in patients who were both BRAF-positive and elderly (22%). CONCLUSIONS: BRAF mutations are equally present in younger and older patients. Aggressive histology characteristics at presentation are associated with BRAF-positive PTC, irrespective of age. However, the well-established association of BRAF with recurrence is limited to older (age >=65 years) patients. PMID- 21594704 TI - Long-term experience in sentinel node biopsy for early oral and oropharyngeal squamous cell carcinoma. AB - OBJECTIVE: Long-term results of sentinel node biopsy (SNB) in early (T1/T2) oral and oropharyngeal squamous cell carcinoma (OSCC) in a single-institution experience. METHODS: Prospective consecutive cohort analysis of 79 patients (67% male, median age 60 years, age range 34-87 years) included between 2000 and 2006. Lymphatic mapping consisted of preoperative lymphoscintigraphy, single photon emission computed tomography (SPECT/CT), and intraoperative use of a handheld gamma probe. Endpoints of the study were neck control rate, overall (OS), disease specific (DSS), and disease-free survival (DFS). RESULTS: Twenty-nine of 79 patients (37%) had positive sentinel nodes (SN). Six of 29 (21%) patients showed isolated tumor cells, 14/29 (48%) micrometastases, and 9/29 (31%) macrometastases. OS, DFS, and DSS at 5 years for the entire cohort were 80, 85, and 87%, for SN-negative patients were 88, 96, and 96%, and for SN-positive patients were 74, 73, and 77%, respectively. Only the difference in DSS achieved statistical significance. The neck control rate after 5 years was 96% in SN negative and 74% in SN-positive patients. This difference was statistically significant. CONCLUSIONS: SNB is a safe and accurate staging modality to select patients with clinically stage I/II OSCC with occult lymph node disease for elective neck dissection (END). The promising reported short-term results have been sustained by long-term follow-up. Patients with negative SN and no END achieve an excellent neck control rate which compares favorably with reports on primary END. The neck control rate in SN-negative patients is superior to that in SN-positive patients, which is reflected in superior DSS. PMID- 21594705 TI - Prognostic value of pathological resection margin distance in squamous cell cancer of the vulva. AB - BACKGROUND: A tumor-free resection margin of at least 8 mm is considered state of the art in vulvar cancer. This standard is based on small and heterogeneous patient cohorts, and its implementation can result in mutilation. METHODS: One hundred two consecutive patients with primary squamous cell vulvar cancer were analyzed. All patients received resection of the primary tumor and the inguinofemoral lymph nodes via three separate incisions, resulting in complete tumor resection. Median follow-up was 31 months. Minimal margin distances were pathologically determined in all dimensions after fixation. RESULTS: Median age of the patients was 62 years; 38.2% had International Federation of Gynecology and Obstetrics (FIGO) stage I, 17.6% stage II, 24.4% stage III, and 8.8% stage IV disease. The median minimal resection margin was 5 mm (range 0.5-25 mm). Sixteen patients (15.6%) developed disease recurrence, of whom 10 (62.5%) at the vulva. Margin distance had no significant impact on disease-free survival when analyzed continuously (p = 0.388). When cases were divided into three subgroups of <3 mm (28.4%), >=3 to <8 mm (42.2%), and >=8 mm (29.4%) resection margin, neither univariate nor multivariate analysis revealed a difference in disease-free survival. There was no significant difference between any of the subgroups regarding tumor stages and adjuvant radiotherapy of the vulva. These results were independent of the direction of the minimal margin distance and consistent when only vulvar recurrences were analyzed. CONCLUSIONS: A tumor-free resection margin is essential for locoregional control in vulvar cancer. However, in this large, single-center study, we could not demonstrate any prognostic impact of pathological margin distance. PMID- 21594706 TI - Quality improvement in multidisciplinary cancer teams: an investigation of teamwork and clinical decision-making and cross-validation of assessments. AB - PURPOSE: Teamworking and clinical decision-making are important in multidisciplinary cancer teams (MDTs). Our objective is to assess the quality of information presentation and MDT members' contribution to decision-making via expert observation and self-report, aiming to cross-validate the two methods and assess the insight of MDT members into their own team performance. MATERIALS AND METHODS: Behaviors were scored using (i) a validated observational tool employing Likert scales with objective anchors, and (ii) a 29-question online self-report tool. Data were collected from observation of 164 cases in five MDTs, and 47 surveys from MDT members (response rate 70%). Presentation of information (case history, radiological, pathological, comorbidities, psychosocial, and patients' views) and quality of contribution to decision-making of MDT members (surgeons, oncologists, radiologists, pathologists, nurses, and MDT coordinators) were analyzed via descriptive statistics and the Jonckheere-Terpstra test. Correlation between observational and self-report assessments was assessed with Spearman's correlations. RESULTS: Quality of information presentation: Case histories and radiology information rated highest; patients' views and comorbidities/psychosocial issues rated lowest (observed: Z = 14.80, P <= 0.001; self-report: Z = 3.70, P < 0.001). Contribution to decision-making: Surgeons and oncologists rated highest, nurses and MDT coordinators rated lowest, and others in between (observed: Z = 20.00, P <= 0.001; self-report: Z = 8.10, P < 0.001). Correlations between observational and self-report assessments: Median Spearman's rho = 0.74 (range = 0.66-0.91; P < 0.05). CONCLUSIONS: The quality of teamworking and clinical decision-making in MDTs can reliably be assessed using observational and self-report metrics. MDT members have good insight into their own team performance. Such robust assessment methods could provide the basis of a toolkit for MDT team evaluation and improvement. PMID- 21594707 TI - Central compartment reoperation for recurrent/persistent differentiated thyroid cancer. PMID- 21594708 TI - Long-term experience with early single mitomycin C instillations in patients with low-risk non-muscle-invasive bladder cancer: prospective, single-centre randomised trial. AB - PURPOSE: To study the benefits of a single, early, intravesical instillation of mitomycin C(MMC) after transurethral bladder resection (TURB) in patients with low-risk non-muscle-invasive bladder cancer (NMIBC). METHODS: In this prospective randomised single-centre trial, 211 patients with primary and low-risk tumours were enrolled between 2000 and 2009. Patients were randomly allocated to receive MMC intravesically within 24 h of TUR or no further treatment. The primary end point was recurrence rate reduction. RESULTS: A total of 202 patients (97 in the MMC group and 105 in the control group) remained for analysis after exclusions. Median age was 61 years (IQR 42-78), and median follow-up was 90 months (IQR 3 112). No significant differences for patients' characteristics were observed between the two groups. During the study period, 10% (10/97) of the patients in the MMC group and 43% (46/105) in the control group experienced a recurrence (P = 0.0001). Four patients in the MMC group and 11 (P = 0.008) in the control group experienced an early recurrence (within 2 years). One patient in the control group presented a tumour progression (T2G3). MMC treatment was associated with a 31% absolute risk reduction of recurrence and a 3.26 numbers needed to treat to prevent one recurrence. CONCLUSIONS: In this single-centre, long-term follow-up, experience a single, early instillation of MMC after TUR for low-risk NMIBC is associated with a significant reduction in risk of early and late recurrences. PMID- 21594709 TI - The predictive value of immunohistochemical markers in untreated Wilms' tumour: are they useful? AB - PURPOSE: This study reevaluates the potential role of different tumour markers as prognostic indicators in untreated nephroblastoma. METHODS: Expression of a broad panel of tumour markers was investigated by means of immunohistochemical analysis in 43 WT patients. Patients were treated by radical nephrectomy and had a mean follow-up of 11.9 years. RESULTS: Generally, all the tumour markers studied were expressed in normal kidney tissue and at variable levels in the three cell types of WT (blastema, epithelium and stroma). Immunoreactive blastemal (Bcl-X, Bcl-2 and CD44s) and epithelial (Bcl-X, Bcl-2 and MIB-1) cells were present in the majority of tumours. No correlation was found between their expression and pathological stages. Univariate analysis showed that blastemal WT-1, TGF-alpha, VEGF, MIB-1 and p27 Kip1 were indicative for clinical progression. In a multivariate analysis, WT-1 protein expression by blastemal cells was an independent prognostic marker for clinical progression. CONCLUSIONS: The blastemal WT-1, TGF-alpha, VEGF, MIB-1 and p27Kip1 expression correlate with clinical progression in untreated nephroblastoma. Therefore, their expression may be of value in identifying patients with a high propensity to develop distant metastases. PMID- 21594710 TI - Gender effect on renal outcome in patients with urothelial carcinoma. AB - PURPOSE: Taiwan is a highly endemic area for urothelial carcinoma (UC) and chronic kidney disease (CKD). We evaluate the gender effect on the relationship between renal outcome and clinical characteristics of CKD patients with UC. METHODS: The clinical and pathologic records of 404 patients were retrospectively analyzed. We calculated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) equation, and staged CKD status according to K/DOQI guideline. RESULTS: The female group had a significantly higher proportion (67.6% vs 29.0%, P < 0.001) of upper urinary tract urothelial carcinoma (UUT-UC). Pathologically, the frequency of high T stage UC (32.4% and 19.1%; P = 0.003), high-grade UC (89.4% and 75.6%; P = 0.001), and larger UC (51.4% and 37.8%; P = 0.009) in the female patients were significantly higher, when compared with the male group. Male gender, diabetes, anemia, poor preoperative renal function, UUT UC, and low-grade tumor were independent risk factors of poor renal outcome by multivariate analysis in these UC patients. Diabetes was a risk factor of poor renal outcome in male UUT-UC patients, but not in the female patients (P = 0.009). CONCLUSION: Female gender had a more aggressive histological urothelial carcinoma pattern than male patients did, but paradoxically had a more favorable renal outcome. PMID- 21594711 TI - Peroxisomal alterations in Alzheimer's disease. AB - In Alzheimer's disease (AD), lipid alterations are present early during disease progression. As some of these alterations point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based, longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages I-II, III-IV, and V-VI, respectively). Lipid analyses of cortical regions from the other hemisphere revealed accumulation of C22:0 and very long-chain fatty acids (VLCFA, C24:0 and C26:0), all substrates for peroxisomal beta-oxidation, in cases with stages V-VI pathology compared with those modestly affected (stages I-II). Conversely, the level of plasmalogens, which need intact peroxisomes for their biosynthesis, was decreased in severely affected tissues, in agreement with a peroxisomal dysfunction. In addition, the peroxisomal volume density was increased in the soma of neurons in gyrus frontalis at advanced AD stages. Confocal laser microscopy demonstrated a loss of peroxisomes in neuronal processes with abnormally phosphorylated tau protein, implicating impaired trafficking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical findings and the amount of neurofibrillary tangles (NFT) and neuritic plaques, quantified in adjacent tissue sections. Interestingly, the decrease in plasmalogens and the increase in VLCFA and peroxisomal volume density in neuronal somata all showed a stronger association with NFT than with neuritic plaques. These results indicate substantial peroxisome-related alterations in AD, which may contribute to the progression of AD pathology. PMID- 21594713 TI - Clinical impact of cycling the administration of antibiotics for febrile neutropenia in Japanese patients with hematological malignancy. AB - Despite the availability of newer classes of antibiotics, infection with multi drug-resistant bacteria is a serious problem. To suppress the appearance of multi drug-resistant bacteria and to avoid severe infection derived from febrile neutropenia (FN), we conducted cycling the administration of antibiotics for FN in patients with hematological malignancy. The treatment protocol consisted of the administration of four antibiotics each for 3 months in 1 year. The above regimen was repeated for 4 years. A total of 193 patients were registered in the protocol. The mean duration of the administration of cycling antibiotics was 5.9 days (range: 1-16 days). The frequency of FN before the study and during the study was unchanged until the third year, but decreased significantly in the fourth year. The frequency of detection of multi-drug-resistant bacteria in the first year was the same as that before the study was started, but dramatically decreased after the second year. Bacteriological treatment success rates were similar in each trimester and each year. The effective rate was not statistically different in each trimester and each year. We conclude that cycling the administration of antibiotics in patients with FN is useful for suppressing the appearance of multi-drug-resistant bacteria and for obtaining excellent clinical efficacy. PMID- 21594714 TI - 4-epi-Pimaric acid: a phytomolecule as a potent antibacterial and anti-biofilm agent for oral cavity pathogens. AB - The present study focused on the antibacterial and biofilm inhibitory potential of 4-epi-pimaric acid isolated from aerial parts (stem and leaves) of Aralia cachemirica L. (Araliaceae) against oral cavity pathogens. 4-epi-Pimaric acid exhibited minimum inhibitory concentration (MIC) in the range of 4-16 MUg/ml and minimum bactericidal concentration (MBC) two- to four-folds higher than MIC. There was significant inhibition in the biofilm formation by Streptococcus mutans on the saliva coated surface (P < 0.05), and confocal microscopy revealed that 4 epi-pimaric acid inhibited the clumping and attachment of S. mutans. At 8 * MIC concentration, it significantly prevented the pH drop and reduced S. mutans biofilms (P < 0.05). Increased propidium iodide staining and leakage of 260- and 280-nm absorbing material by 4-epi-pimaric acid treated cells of S. mutans suggested that it probably causes disruption of the cytoplasmic membrane structure. It also exhibited significant suppression of TNF-alpha expression in human neutrophils, suggestive of its anti-inflammatory activity. Furthermore, the compound was found to be significantly safe (IC(50) >100 MUg/ml) in the MTT assay on AML-12 cell lines. In conclusion, 4-epi-pimaric acid showed promising antibacterial, anti-biofilm and anti-inflammatory potency and this compound can be exploited for therapeutic application in oral microbial infections. PMID- 21594715 TI - PEGylation improves nanoparticle formation and transfection efficiency of messenger RNA. AB - PURPOSE: Cationic polymers have been intensively investigated for plasmid-DNA (pDNA), but few studies addressed their use for messenger-RNA (mRNA) delivery. We analyzed two types of polymers, linear polyethylenimine (l-PEI) and poly-N,N dimethylaminoethylmethacrylate P(DMAEMA), to highlight specific requirements for the design of mRNA delivery reagents. The effect of PEGylation was investigated using P(DMAEMA-co-OEGMA) copolymer. METHODS: The influence of polymer structure on mRNA binding and particle formation was assessed in a side-by-side comparison with pDNA by methods such as agarose-retardation assay and scanning probe microscopy. Transfection studies were performed on bronchial epithelial cells. RESULTS: Binding of cationic polymers inversely correlated with type of nucleic acid. Whereas P(DMAEMA) bound strongly to pDNA, only weak mRNA binding was observed, which was vice versa for l-PEI. Both polymers resulted in self assembled nanoparticles forming pDNA complexes of irregular round shape; mRNA particles were significantly smaller and more distinct. Surprisingly, PEGylation improved mRNA binding and transfection efficiency contrary to observations made with pDNA. Co-transfections with free polymer improved mRNA transfection. CONCLUSIONS: Gene delivery requires tailor-made design for each type of nucleic acid. PEGylation influenced mRNA-polymer binding efficiency and transfection and may provide a method of further improving mRNA delivery. PMID- 21594716 TI - Targeted delivery to neuroblastoma of novel siRNA-anti-GD2-liposomes prepared by dual asymmetric centrifugation and sterol-based post-insertion method. AB - PURPOSE: To optimise and simplify preparation of targeted liposomes for efficient siRNA delivery to neuroblastoma, the most common solid tumour in early childhood. METHODS: Liposomes containing siRNA were prepared by combining the novel dual asymmetric centrifugation (DAC) method and the recently optimised sterol-based post-insertion technique (SPIT) to couple anti-GD2 antibody for selective interaction with neuroblastoma cells. Cultured human neuroblastoma cell lines were used to evaluate the efficiency of siRNA delivery. RESULTS: The size of liposomes prepared by DAC ranged from 190 to 240 nm; siRNA encapsulation efficiency was up to 50%. An average of 70 and 100 molecules of anti-GD2 antibody per particle were coupled. A significant association of liposomes with neuroblastoma cells as well as effective siRNA delivery was observed only when anti-GD2 antibody was coupled. Preliminary data suggest delivery of siRNA using anti-GD2-liposomes occurs via GD2-mediated endocytosis. Vascular endothelial growth factor A (VEGF-A) was down-regulated using siRNA delivered by anti-GD2 liposomes. CONCLUSIONS: DAC and SPIT allow for the straightforward preparation of liposomes for the targeted delivery of siRNA. Anti-GD2-liposomes thus produced can serve as versatile carriers of siRNA to neuroblastoma cells. PMID- 21594712 TI - Gene sequencing and characterization of the light-harvesting complex 2 from thermophilic purple sulfur bacterium Thermochromatium tepidum. AB - In this study, gene sequences coding for the light-harvesting (LH) 2 polypeptides from a thermophilic purple sulfur bacterium Thermochromatium tepidum are reported and characterization of the LH2 complex is described. Three sets of pucBA genes have been identified, and the gene products have been analyzed by electrophoresis and reversed-phase chromatography. The result shows that all of the genes are expressed but the distribution of the expression is not uniform. The gene products undergo post-translational modification, where two of the beta polypeptides appear to be N-terminally methylated. Absorption spectrum of the purified LH2 complex exhibits Q (y) transitions at 800 and 854 nm in dodecyl beta maltopyranoside solution, and the circular dichroism spectrum shows a "molischianum"-like characteristic. No spectral change was observed for the LH2 when the bacterium was cultured under different conditions of light intensity. In lauryl dimethylamine N-oxide (LDAO) solution, significant changes in the absorption spectrum were observed. The B850 peak decreased and blue-shifted with increasing the LDAO concentration, whereas the B800 intensity increased without change in the peak position. The spectral changes can be partially or almost completely reversed by addition of metal ions, and the divalent cations seem to be more effective. The results indicate that ionic interactions may exist between LH2, detergent molecules and metal ions. Possible mechanisms involved in the detergent- and cation-induced spectral changes are discussed. PMID- 21594717 TI - Renal abscess in Papillion-Lefevre syndrome. AB - A 5-year-old female with Papillon-Lefevre syndrome presented with renal mass. A radiological diagnosis of malignancy was made; however, partial nephrectomy revealed granulomatous disease indicative of chronic infection. Although liver abscess is an emerging complication in patient with Papillon-Lefevre syndrome, this case represents the first renal abscess described in such patients. PMID- 21594718 TI - Predictor of mortality in children with typhoid intestinal perforation in a Tertiary Hospital in Nigeria. AB - PURPOSE: Typhoid intestinal perforation (TIP) exerts a great toll both on the patients and the surgeons in resource poor countries. Factors that predict mortality in patients with TIP remain controversial. The study aims to determine factors that predict mortality in a Nigerian tertiary facility and to offer strategies for improvement. MATERIALS AND METHODS: We conducted a retrospective analysis of data of 153 children who underwent surgery for TIP at a Tertiary Hospital in Nigeria over a period of 8 years (January 2002 to December 2009). Data collected included patient demographics, presentation, haemoglobin level (Hgb), presentation-operation interval, type of surgical procedure, nature of peritoneal collection, the number of perforations and duration of surgery. Postoperative complications, duration of hospital stay and outcome were also examined. RESULTS: There were 99 (64.7%) boys and 54 (35.3%) girls aged 3-15 years, mean (SD) = 9.4 (+/-3.6) years. There were 105 single perforations and 46 multiple perforations (range 1-32). The surgical procedure was simple 2-layer closure in 128 (83.7%) and segmental resection in 9 (5.9%) children. The mortality was 16 (10.4%). The mean (SD) age of children who survived and those who died was 9.3 (+/-3.6) years and 10.1 (+/-4.0) years, respectively; p = 0.446, the mean duration of symptom in children who survived and those who died was 10.3 (+/-4.9) days and 12.3 (+/-5.6) days; p = 0.164, and the mean interval between presentation and operation in those who died and those who survived was 29.3 (+/ 25) h and 28.4 (+/-13.4) h; p = 0.896. Temperature >= 38.5 degrees C (p = 0.040), anastomotic leak (p = 0.029) and faecal fistula (p = 0.000) were significantly associated with mortality. Age <5 years (p = 0.675), male gender (p = 0.845), presentation-operation interval >=24 h (p = 0.940), Hgb less than 8 g/dL (p = 0.058), faeculent peritoneal collection (p = 0.757), number of perforations (p = 0.518) and the surgical technique (p = 0.375) were not related to mortality. Logistic regression analysis showed that only postoperative faecal fistula (p = 0.001; OR = 13.7) independently predicted mortality. CONCLUSION: Development of postoperative fecal fistula significantly predicted mortality. Prioritizing the prevention of typhoid fever than its treatment and attention to surgical details may significantly reduce mortality of TIP in children in this setting. PMID- 21594719 TI - Effectiveness of physical activity in reducing pain in patients with fibromyalgia: a blinded randomized clinical trial. AB - The purpose of this study was to evaluate and compare the effectiveness of muscle strengthening exercises (MS) and a walking program (WA) in reducing pain in patients with fibromyalgia. Ninety women, 30-55 years of age, diagnosed with fibromyalgia according to the American College of Rheumatology 1990 criteria, were randomized into 3 groups: WA Group, MS Group, and control group. Pain (visual analog scale) was evaluated as the primary outcome. Physical functioning (Fibromyalgia Impact Questionnaire, FIQ), health-related quality of life (Short Form 36 Health Survey, SF-36), and use of medication were evaluated as secondary outcomes. Assessments were performed at baseline, 8, 16, and 28 weeks. Intention to-treat and efficacy analyses were conducted. Sixty-eight patients completed the treatment protocol. All 3 groups showed improvement after the 16-week treatment compared to baseline. At the 28-week follow-up, pain reduction was similar for the WA and MS groups (P = 0.39), but different from the control group (P = 0.01). At the end of the treatment, 80% of subjects in the control group took pain medication, but only 46.7% in the WA and 41.4% in the MS groups. Mean FIQ total scores were lower for the WA and MS groups (P = 0.96) compared with the control group (P < 0.01). Patients in the WA and MS groups reported higher scores (better health status) than controls in almost all SF-36 subscales. MS was as effective as WA in reducing pain regarding all study variables; however, symptoms management during the follow-up period was more efficient in the WA group. PMID- 21594720 TI - Massive intracerebral hemorrhage associated with Wegener granulomatosis. AB - Wegener granulomatosis (WG) is a necrotizing granulomatous vasculitis that predominantly affects airways and kidneys. But central nervous system involvement (7-11%) is an uncommon. Massive ICH may occur in the course of WG, and this serious condition is related with high risk of mortality. Therefore, the new treatment strategies may be considered in addition to classical practices in serious organ involvement and recurrent attack. Here, we present an adult patient with WG whose disease was complicated by a massive intracerebral hemorrhage (ICH), which subsequently led to death. PMID- 21594721 TI - In vitro assessment of cytochrome P450 inhibition and induction potential of tanespimycin and its major metabolite, 17-amino-17-demethoxygeldanamycin. AB - PURPOSE: To assess the inhibition and induction potential of tanespimycin and its major metabolite, 17-amino-17-demethoxygeldanamycin (17-AG) on cytochrome P450 (CYP) enzymes. METHODS: The inhibitory effect of tanespimycin and 17-AG on various CYP enzymes was determined in human liver microsomes. The inductive effects of tanespimycin and 17-AG on CYP1A2, CYP2B6, and CYP3A4/5 were determined in cultured primary human hepatocytes. RESULTS: Tanespimycin did not inhibit the activities of CYP1A2, 2A6, 2B6, and 2E1 up to a concentration of 60 MUM, while it moderately inhibited CYP3A4/5 and 2C19, and weakly inhibited CYP2C8, 2C9, and 2D6. In addition, its inhibition on CYP3A4/5 was time-dependent. 17-AG moderately inhibited the activities of CYP3A4/5 and CYP2C19, but did not inhibit other CYPs up to a concentration of 30 MUM. The inhibition of CYP3A4/5 by 17-AG was not time dependent. Tanespimycin and 17-AG did not significantly induce the activities of CYP1A2, CYP2B6, or CYP3A4/5 in cultured human hepatocytes at concentrations up to 40 and 20 MUM for tanespimycin and 17-AG, respectively. CONCLUSIONS: Tanespimycin together with its active metabolite, 17-AG are moderate inhibitors of CYP3A4/5 and CYP2C19, but not inducers of CYPs. Therefore, co-administration of tanespimycin has the potential to increase the exposure of substrates of CYP2C19 and CYP3A4/5. PMID- 21594722 TI - PR-104 plus sorafenib in patients with advanced hepatocellular carcinoma. AB - PURPOSE: PR-104 is activated by reductases under hypoxia or by aldo-keto reductase 1C3 (AKR1C3) to form cytotoxic nitrogen mustards. Hepatocellular carcinoma (HCC) displays extensive hypoxia and expresses AKR1C3. This study evaluated the safety and efficacy of PR-104 plus sorafenib in HCC. METHODS: Patients with advanced-stage HCC, Child-Pugh A cirrhosis, and adequate organ function, were assigned to dose escalating cohorts of monthly PR-104 in combination with twice daily sorafenib. The plasma pharmacokinetics (PK) of PR 104 and its metabolites were evaluated. RESULTS: Fourteen (11 men, 3 women) HCC patients: median age 60 years, ECOG 0-1, received PR-104 at two dose levels plus sorafenib. Six patients were treated at starting cohort of 770 mg/m(2). In view of one DLT of febrile neutropenia and prolonged thrombocytopenia, a lower PR-104 dose cohort (550 mg/m(2)) was added and accrued 8 patients. One patient had a partial response and three had stable disease of >=8 weeks in the 770 mg/m(2) cohort. Three patients at the 550 mg/m(2) had stable disease. There were no differences in PK of PR-104 or its metabolites with or without sorafenib, but the PR-104A AUC was twofold higher (P < 0.003) than in previous phase I studies at equivalent dose. CONCLUSIONS: PR-104 plus sorafenib was poorly tolerated in patients with advanced HCC, possibly because of compromised clearance of PR-104A in this patient population. Thrombocytopenia mainly and neutropenia were the most clinically significant toxicities and led to discontinuation of the study. PR-104 plus sorafenib is unlikely to be suitable for development in this setting. PMID- 21594723 TI - Histopathological and ultrastructural effects of cutting radiofrequency energy on palatal soft tissues: a prospective study. AB - Radiofrequency (RF) surgery has gained popularity as a safe and effective method for treating patients with snoring and mild obstructive sleep apnoea (OSA). Both interstitial and cutting radiofrequency energy may be used for multi-segmental management of the upper airway. Little is known about the effect of cutting radiofrequency energy on human soft palate. Excessive collateral injury may have an impact on tissue healing and functional outcomes. A histological analysis of specimens of human soft palate and uvula following resection with cutting RF energy was performed. In addition, ultrastructural analysis using scanning electron microscopy of excision margins was performed and compared with CO(2) LASER. Twelve patients were included. In ten patients, specimens of redundant uvula and faucial pillars were collected and underwent formal histological analysis. The maximum depth of tissue injury was 1 mm in two specimens and overall average depth of injury was 0.15 mm. Injury depth was independent of tissue subtype at the resection margin. Ultrastructural analysis demonstrated accurate incision when compared to CO(2) LASER. Cutting RF energy causes minimal collateral injury to the soft palate during resection for the treatment of snoring and mild OSA. A detailed knowledge of local effects on resection specimens allows accurate inference of in vivo tissue injury at the resection margin and may enable more precise prediction of healing patterns and repair. PMID- 21594724 TI - An open-label, single-dose, crossover study of the pharmacokinetics and metabolism of two oral formulations of 1-octanol in patients with essential tremor. AB - Existing therapeutic options for management of essential tremor are frequently limited by poor efficacy and adverse effects. Likely the most potent tremor suppressant used is ethanol, although its use is prohibitive due to a brief therapeutic window, and the obvious implications of excessive alcohol use. Longer chain alcohols have been shown to suppress tremor in harmaline animal models, and appear to be safe and well tolerated in 2 prior studies in humans. Here we report on the findings of a phase I/II study of 1-octanol designed to explore pharmacokinetics, efficacy, and safety. The most significant finding was the identification of octanoic acid as the product of rapid 1-octanol metabolism. Furthermore, the temporal profile of efficacy closely matches the plasma concentration of octanoic acid. Therefore, these findings identify a novel class of compound (e.g., carboxylic acids) with tremor suppressive properties in ET. Administration of 1-octanol also appears to be safe based on various measures collected. Essential tremor (ET) is the most common tremor disorder, with tremors occurring during static posturing or movement. These tremors are known to briefly improve in many cases after alcohol (ethanol) consumption. Two previous studies of a longer chain alcohol, 1-octanol, have demonstrated longer duration tremor suppressive effects without the occurrence of intoxication. The aim of this study was to characterize the pharmacokinetics of 1-octanol and its primary metabolite octanoic acid using two formulations, along with additional safety and efficacy measures. Participants with proven ethanol-responsive ET were recruited into 1 of 2 parts: (part A) a dose escalation study (1-64 mg/kg; n = 4), and (part B) a fixed dose (64 mg/kg; n = 10) balanced, open-label crossover design. Two participants in part B then completed an exploratory part C evaluating 128 mg/kg.Plasma samples were collected at 10 intervals during a 6-hour period postingestion. Efficacy was assessed using spirography, whereas safety was assessed with electrocardiograms, vital signs, adverse effects surveys, and an intoxication assessment. Plasma concentrations of 1-octanol were detectable at low levels whereas octanoic acid (OA) concentrations were approximately 100-fold higher. The half-life of OA was 87.6 minutes. This was matched by a clinical reduction in tremor severity of 32% at 90 minutes, assessed using spirography. The safety profile was favorable, with the most commonly reported adverse effect being dysgeusia (38%). Early detection and higher plasma concentrations of OA are a product of rapid metabolism of 1-octanol.OA pharmacokinetics mirrored the timing of clinical improvement. These findings provide preliminary evidence for a new class of compound that may be effective in the treatment of ET. PMID- 21594726 TI - Barrett's esophagus after resection of the gastroesophageal junction: effects of concomitant fundoplication. AB - BACKGROUND: Barrett's metaplasia has been known to occur after esophagectomy or gastrectomy in which the gastroesophageal junction with its associated lower esophageal sphincter has been resected. It is thought to be secondary to the refluxogenic nature of the operation. The present study was based on the hypothesis that patients who undergo a fundoplication with the resection would have a lower incidence of the development of postoperative Barrett's metaplasia. METHODS: All patients who underwent any type of esophagectomy or proximal gastrectomy in which the gastroesophageal junction was resected and an esophagogastrostomy performed were eligible for the study. Data gathered included age, gender, preoperative diagnosis, operation, postoperative pathology, occurrence and timing of postoperative upper endoscopy, and presence of Barrett's metaplasia on postoperative endoscopy. Statistical analysis was done with Fisher's exact test. RESULTS: Of the 179 patients who underwent resection, 151 had follow-up endoscopy documenting the presence or absence of Barrett's esophagus. Follow-up ranged from 6 months to 10 years. Of the 53 patients without fundoplications, 8 (18%) had Barrett's esophagus on follow-up upper endoscopy. Of the 98 patients with fundoplications, 5 (6%) had Barrett's esophagus (P = 0.04). CONCLUSIONS: The present study suggests that concomitant fundoplication with resection of the gastroesophageal junction may have some protective effect against the development of Barrett's esophagus. A randomized trial will be required to prove this assertion. Also, it is still unclear as to the consequences of the development of post-resection Barrett's esophagus. PMID- 21594727 TI - Overview of tracheal tissue engineering: clinical need drives the laboratory approach. AB - Breathing is a natural function that most of us do not even think about, but for those who suffer from disease or damage of the trachea, the obstruction of breathing can mean severe restrictions to quality of life or may even be fatal. Replacement and reconstruction of the trachea is one of the most difficult procedures in otolaryngology/head and neck surgery, and also one of the most vital. Previous reviews have focused primarily on clinical perspectives or instead on engineering strategies. However, the current review endeavors to bridge this gap by evaluating engineering approaches in a practical clinical context. For example, although contemporary approaches often include in vitro bioreactor pre-culture, or sub-cutaneous in vivo conditioning, the limitations they present in terms of regulatory approval, cost, additional surgery, and/or risk of infection challenge engineers to develop the next generation of biodegradable/resorbable biomaterials that can be directly implanted in situ. Essentially, the functionality of the replacement is the most important requirement. It must be the correct shape and size, achieve an airtight fit, resist collapse as it is replaced by new tissue, and be non-immunogenic. As we look to the future, there will be no one-size-fits-all solution. PMID- 21594728 TI - Preparation and characterization of nicotine-magnesium aluminum silicate complex loaded sodium alginate matrix tablets for buccal delivery. AB - Nicotine (NCT) buccal tablets consisting of sodium alginate (SA) and nicotine magnesium aluminum silicate (NCT-MAS) complexes acting as drug carriers were prepared using the direct compression method. The effects of the preparation pH levels of the NCT-MAS complexes and the complex/SA ratios on NCT release, permeation across mucosa, and mucoadhesive properties of the tablets were investigated. The NCT-MAS complex-loaded SA tablets had good physical properties and zero-order release kinetics of NCT, which indicate a swelling/erosion controlled release mechanism. Measurement of unidirectional NCT release and permeation across porcine esophageal mucosa using a modified USP dissolution apparatus 2 showed that NCT delivery was controlled by the swollen gel matrix of the tablets. This matrix, which controlled drug diffusion, resulted from the molecular interactions of SA and MAS. Tablets containing the NCT-MAS complexes prepared at pH 9 showed remarkably higher NCT permeation rates than those containing the complexes prepared at acidic and neutral pH levels. Larger amounts of SA in the tablets decreased NCT release and permeation rates. Additionally, the presence of SA could enhance the mucoadhesive properties of the tablets. These findings suggest that SA plays the important role not only in controlling release and permeation of NCT but also for enhancing the mucoadhesive properties of the NCT-MAS complex-loaded SA tablets, and these tablets demonstrate a promising buccal delivery system for NCT. PMID- 21594729 TI - Design and in vitro performance evaluation of purified microparticles of pravastatin sodium for intestinal delivery. AB - The purpose of research was to develop a mucoadhesive multiparticulate sustained drug delivery system of pravastatin sodium, a highly water-soluble and poorly bioavailable drug, unstable at gastric pH. Mucoadhesive microparticles were formulated using eudragit S100 and ethyl cellulose as mucoadhesive polymers. End step modification of w/o/o double emulsion solvent diffusion method was attempted to improve the purity of the product, that can affect the dose calculations of sustained release formulations and hence bioavailability. Microparticles formed were discrete, free flowing, and exhibited good mucoadhesive properties. DSC and DRS showed stable character of drug in microparticles and absence of drug polymer interaction. The drug to polymer ratio and surfactant concentration had significant effect on mean particle size, drug release, and entrapment efficiency. Microparticles made with drug: eudragit S100 ratio of 1:3 (F6) exhibited maximum entrapment efficiency of 72.7% and ex vivo mucoadhesion time of 4.15 h. In vitro permeation studies on goat intestinal mucosa demonstrated a flux rate (1,243 MUg/cm(2)/h) that was 169 times higher than the flux of pure drug. The gastric instability problem was overcome by formulating the optimized microparticles as enteric-coated capsules that provided a sustained delivery of the highly water-soluble drug for 12 h beyond the gastric region. The release mechanism was identified as fickian diffusion (n = 0.4137) for the optimized formulation F6. Conclusively, a drug delivery system was successfully developed that showed delayed and sustained release up to 12 h and could be potentially useful to overcome poor bioavailability problems associated with pravastatin sodium. PMID- 21594730 TI - The restoration of full-thickness cartilage defects with mesenchymal stem cells (MSCs) loaded and cross-linked bilayer collagen scaffolds on rabbit model. AB - Cartilage has a limited self-repair capability and the repair of large cartilage defects remains a challenge in clinic. This study aimed to investigate the effect of mesenchymal stem cells (MSCs) loaded three-dimensional bilayer collagen scaffold for cartilage repair. Cross-linked three-dimensional bilayer collagen scaffolds seeded with or without MSCs were implanted into large cartilage defects (4 mm in diameter; 3 mm in depth) in rabbit knees. The untreated cartilage defects served as control. The tissue response was evaluated at 6 and 12 weeks after implantation by general histology and semi-quantitative histological grading systems. In addition, the repaired tissues were evaluated by mechanical test at 12 weeks after implantation. The MSCs-loaded collagen scaffold group showed the most hyaline cartilage, highest histological scores and compressive modulus. Moreover, it showed a good integration with the subchondral bone and adjacent cartilage. The structure of the novel bilayer collagen scaffolds provided architectural support for the differentiation of MSCs and demonstrated successful induction of in vivo chondrogenesis. These findings suggested that MSCs-loaded bilayer collagen scaffold could be an appealing candidate to be used for cartilage regeneration. PMID- 21594731 TI - Differentially expressed proteins associated with myogenesis and adipogenesis in skeletal muscle and adipose tissue between bulls and steers. AB - The objective of this study was to identify some proteins associated with testosterone-related differences in myogenesis and adipogenesis between bulls and steers. Global proteins were monitored in skeletal muscle and adipose tissue from bulls (n = 20) and steers (n = 20), respectively. We identified four differentially expressed (twofold or more) proteins in skeletal muscle from bulls, myosin light chain 1 (MLC1), ankyrin repeat domain-containing protein 1 (ANKRD1) and heat shock protein beta 1 (HSPB1) that were up-regulated and cofilin 2 (CFL2) that was down-regulated, and also identified two down-regulated proteins in adipose tissue, transaldolase 1 (TALDO1) and L: -lactate dehydrogenase B chain (LDHB). In vitro, after myogenic differentiation of a bovine cell line, the mRNA expression of HSPB1 not only increased approximately tenfold in response to differentiation but threefold in response to testosterone addition, respectively, but that of ANKRD1 and CFL2 did not significantly change in response to myogenic differentiation or testosterone addition. Likewise, after adipogenic differentiation of a bovine cell line, the mRNA expression of TALDO1 and LDHB did not significantly vary in response to adipogenic differentiation or testosterone addition. Therefore, we suggest that HSPB1 could have an important role during testosterone-related myogenesis. PMID- 21594732 TI - Perceptual scale expansion: an efficient angular coding strategy for locomotor space. AB - Whereas most sensory information is coded on a logarithmic scale, linear expansion of a limited range may provide a more efficient coding for the angular variables important to precise motor control. In four experiments, we show that the perceived declination of gaze, like the perceived orientation of surfaces, is coded on a distorted scale. The distortion seems to arise from a nearly linear expansion of the angular range close to horizontal/straight ahead and is evident in explicit verbal and nonverbal measures (Experiments 1 and 2), as well as in implicit measures of perceived gaze direction (Experiment 4). The theory is advanced that this scale expansion (by a factor of about 1.5) may serve a functional goal of coding efficiency for angular perceptual variables. The scale expansion of perceived gaze declination is accompanied by a corresponding expansion of perceived optical slants in the same range (Experiments 3 and 4). These dual distortions can account for the explicit misperception of distance typically obtained by direct report and exocentric matching, while allowing for accurate spatial action to be understood as the result of calibration. PMID- 21594733 TI - Implicit learning increases preference for predictive visual display. AB - We investigated whether implicit learning in a visual search task would influence preferences for visual stimuli. Participants performed a contextual cueing task in which they searched for visual targets, the locations of which were either predicted or not predicted by the positioning of distractors. The speed with which participants located the targets increased across trials more rapidly for predictive displays than for non-predictive displays, consistent with contextual cueing. Participants were subsequently asked to rate the "goodness" of visual displays. The rating results showed that they preferred predictive displays to both non-predictive and novel displays. The participants did not recognize predictive displays any more frequently than they did non-predictive or novel displays. These results suggest that contextual cueing occurred implicitly and that the implicit learning of visual layouts promotes a preference for visual layouts that are predictive of target location. PMID- 21594735 TI - Estimating a dynamic model of sex selection in China. AB - High ratios of males to females in China, which have historically concerned researchers (Sen 1990), have increased in the wake of China's one-child policy, which began in 1979. Chinese policymakers are currently attempting to correct the imbalance in the sex ratio through initiatives that provide financial compensation to parents with daughters. Other scholars have advocated a relaxation of the one-child policy to allow more parents to have a son without engaging in sex selection. In this article, I present a model of fertility choice when parents have access to a sex-selection technology and face a mandated fertility limit. By exploiting variation in fines levied in China for unsanctioned births, I estimate the relative price of a son and daughter for mothers observed in China's census data (1982-2000). I find that a couple's first son is worth 1.42 years of income more than a first daughter, and the premium is highest among less-educated mothers and families engaged in agriculture. Simulations indicate that a subsidy of 1 year of income to families without a son would reduce the number of "missing girls" by 67% but impose an annual cost of 1.8% of Chinese gross domestic product (GDP). Alternatively, a three-child policy would reduce the number of "missing girls" by 56% but increase the fertility rate by 35%. PMID- 21594734 TI - Moderate alcohol consumption and the risk of mortality. AB - There has been a growing consensus that moderate consumption of alcohol is associated with a lower risk of mortality and that this association is probably causal. However, a recent review article has raised a serious challenge to this consensus. In short, it determined that most prior research in this area committed serious misclassification errors; furthermore, among those studies that were free of these misclassification errors, no support for a protective role of alcohol consumption was found. This article reexamines the issue using prospective data for more than 124,000 persons interviewed in the U.S. National Health Interview Surveys of 1997 through 2000 with mortality follow-up through 2002 using the Linked Mortality File. The study involves about 488,000 person years. Controlling for a variety of covariates, this study finds that compared with nondrinkers, those who consume a moderate amount of alcohol have lower all cause and CHD mortality. The fact that the current study has taken care to avoid the pitfalls of some earlier studies and still finds that those who consume a moderate amount of alcohol have lower all-cause mortality and CHD mortality lends credence to the argument that the relationship is causal. PMID- 21594736 TI - Anti-reflux surgery does not remove cancer risk in Barrett's esophagus. PMID- 21594737 TI - Sentinel node biopsy in laparoscopic surgical oncology. PMID- 21594738 TI - Pilot study on objective measurement of abdominal wall strength in patients with ventral incisional hernia. AB - BACKGROUND: Outcomes after ventral incisional hernia (VIH) repair are measured by recurrence rate and subjective measures. No objective metrics evaluate functional outcomes after abdominal wall reconstruction. This study aimed to develop testing of abdominal wall strength (AWS) that could be validated as a useful metric. METHODS: Data were prospectively collected during 9 months from 35 patients. A total of 10 patients were evaluated before and after VIH repair, for a total of 45 encounters. The patients were tested simultaneously or in succession by two of three examiners. Data were collected for three tests: double leg lowering (DLL), trunk raising (TR), and supine reaching (SR). Raw data were compared and tested for validity, and continuous data were transformed to categorical data. Agreement was measured using the intraclass correlation coefficient (ICC) for DLL and using kappa for the ordinal measures. RESULTS: Simultaneous testing yielded the following interobserver reliability: DLL (0.96 and 0.87), TR (1.00 and 0.95), and SR (0.76). Reproducibility was assessed by consecutive tests, with correlation as follows: DLL (0.81), TR (0.81), and RCH (0.21). Due to poor interobserver reliability for the SR test compared with the DLL and TR tests, the SR test was excluded from calculation of an overall score. Based on raw data distribution from the DLL and TR tests, the DLL data were categorized into 10o increments, allowing construction of a 10-point score. The median AWS score was 5 (interquartile range [IQR], 4-7), and there was agreement within 1 point for 42 of the 45 encounters (93%). CONCLUSIONS: The findings from this study demonstrate that the 10-point AWS score may measure AWS in an accurate and reproducible fashion, with potential for objective description of abdominal wall function of VIH patients. This score may help to identify patients suited for abdominal wall reconstruction while measuring progress after VIH repair. Further longitudinal outcomes studies are needed. PMID- 21594739 TI - Residual heat of laparoscopic energy devices: how long must the surgeon wait to touch additional tissue? AB - BACKGROUND: Energy devices are essential laparoscopic tools. Residual heat is defined as the increased instrument temperature after energy activation is completed. This study aimed to determine the length of time a surgeon needs to wait before touching other tissue using four common laparoscopic energy sources. METHODS: Thermal imaging quantified instrument and tissue temperature ex vivo using monopolar coagulation, argon beam coagulation, ultrasonic dissection, and bipolar tissue fusion devices. To simulate realistic operative usage, each instrument was activated for 5 s four consecutive times with 5 s pauses between fires. Thermal conductivity to bovine liver tissue was measured 2.5, 5, 10, and 20 s after final activation. RESULTS: The maximum increase in instrument tip temperature was 172 +/- 63 degrees C for the ultrasonic dissection, 81 +/- 18 degrees C for the monopolar coagulation, 46 +/- 19 degrees C for the bipolar tissue fusion, and 1 +/- 1 degrees C for the argon beam coagulation (P < 0.05 for all comparisons). Touching the instrument tip to tissue at four intervals after the final activation (2.5, 5, 10, and 20 s) found that ultrasonic energy raised the tissue temperature higher (maximum change, 58 degrees C) than the other three energy devices at all four time points (P < 0.05). CONCLUSIONS: Ultrasonic energy instruments have greater residual heat than monopolar electrosurgery, bipolar tissue fusion, and argon beam. The ultrasonic energy instrument tips heated tissue more than 20 degrees C from baseline even 20 s after activation; whereas all the other energy sources raised the tissue temperature less than 20 degrees C by 5 s. These practical findings may alter a surgeon's usage of these common energy devices. PMID- 21594740 TI - Laparoscopic fixation of biologic mesh at the hiatus with fibrin or polyethylene glycol sealant in a porcine model. AB - BACKGROUND: The objective of this study was to determine the acute and chronic fixation strengths achieved by fibrin or polyethylene glycol (PEG) sealants to secure biologic mesh at the esophageal hiatus in a porcine model. METHODS: For this study, 32 female domestic pigs were divided into four groups of 8 each. The four groups respectively received acute fibrin sealant, acute PEG sealant, chronic fibrin sealant, and chronic PEG sealant. Laparoscopically, a 5.5 * 8.5-cm piece of Biodesign Surgisis Hiatal Hernia Graft (porcine small intestine submucosa) was oriented with the U-shaped cutout around the gastroesophageal junction and the short axis in the craniocaudal direction to simulate hiatal reinforcement with a biologic mesh. The mesh then was secured with 2 ml of either fibrin sealant or PEG sealant. The pigs in the acute groups were maintained alive for 2 h to allow for complete polymerization of the sealants, and the pigs in the chronic group were maintained alive for 14 days. After the pigs were euthanized, specimens of the mesh-tissue interface were subjected to lap shear testing to determine fixation strength, and hematoxylin and eosin (H&E) stained slides were evaluated for evidence of remodeling. RESULTS: No significant differences were observed between the acute and chronic fixation strengths or the remodeling characteristics of the two sealants. However, fixation strength increased significantly over time for both types of sealant. Evidence of remodeling also was significantly more pronounced in the chronic specimens than in the acute specimens. CONCLUSIONS: This study demonstrated the feasibility of using fibrin or PEG sealants to secure biologic mesh at the hiatus in a porcine model. PMID- 21594741 TI - Long-term oncologic outcomes of laparoscopic radical nephrectomy for kidney cancer resection: Dundee cohort and metaanalysis of observational studies. AB - BACKGROUND: The long-term oncologic outcome of laparoscopic radical nephrectomy compared with that of open radical nephrectomy remains unclear. A few case series with follow-up periods longer than 5 years are reported in the literature. The existing literature is focused primarily on early and intermediate outcomes of laparoscopic radical nephrectomy. This study aimed to assess the outcome of laparoscopic radical nephrectomy for localized disease compared with open surgery. METHODS: The search strategy was designed to identify observational and experimental studies conducted in any country that investigated the long-term oncologic outcomes of laparoscopic radical nephrectomy compared with open surgical resection, published in any language. We searched the MEDLINE (1996 to May 2010), EMBASE (1996 to May 2010), and Cochrane databases using the OVID interrogation software. The study included 77 men from the Dundee cohort referred for clinically localized renal cell carcinoma who underwent open or laparoscopic radical nephrectomy between January 1998 and 2004, with at least 5 years of follow-up evaluation for each. These men were included in a metaanalysis of observational studies reporting on 438 patients with a mean or median follow-up period of 5 years. The data was analyzed using Minitab statistical software and Cochrane RevMan 5.4 using the random model. RESULTS: The five studies (including the Dundee cohort) investigating the effects of the laparoscopic approach on renal cancer management showed no significant differences in 5 years survival between laparoscopic and open surgical approaches for the resection of kidney cancer. The resulting pooled odds ratio (OR) did not differ markedly between the two groups (pooled OR, 0.82; 95% confidence interval [CI], 0.48-1.39). Similar to overall survival, the laparoscopic and open surgical approaches for renal cancer surgery did not differ significantly (Figs. 4, 5). The pooled ORs for the two outcomes were 0.76 (955 CI, 0.36-1.56) for laparoscopic surgery and 0.73 (95% CI, 0.32-1.69) for open surgery. The quality of the studies was poor. The reported designs of the studies were prone to selection, confounding, and reporting biases. CONCLUSIONS: The current retrospective data (observational studies) comparing long-term oncologic outcomes between laparoscopic and open radical nephrectomy did not demonstrate any significant differences during a follow-up period of 5 years. PMID- 21594742 TI - Generation and identification of rat fetal cerebral radial glia-like cells in vitro. AB - The role of radial glia cells (RGCs) as neural progenitors and as guides for migrating neurons is well established, mouse or human-derived radial glia (RG) like cells in vitro showed some astroglia and stem/progenitor properties like RGCs in vivo, but different species-derived RG-like cells present some different properties. Here we acquired rat-derived RG-like cells on adherent conditions in vitro and then identified their astroglia and stem/progenitor properties. Similarly to the RGCs, the RG-like cells could be double-labeled by brain lipid binding protein, glial fibrillary acidic protein, vimentin with nestin and expressed some astroglia and stem/progenitor genes; these cells also presented tripotent differentiation potentialities, albeit the ability of gliogenesis far exceeded the neurogenesis in vitro. Taken together, we acquired and identified some properties of rat-derived RG-like cells from fetal cerebral cortices in vitro. PMID- 21594743 TI - Diffusion-weighted MRI of exercise-induced acute renal failure (ALPE). AB - Acute renal failure with severe loin pain induced by anaerobic exercise (ALPE) is a rare condition that is accompanied by wedge-shaped contrast enhancement on computed tomography (CT) without evidence of rhabdomyolysis. In two pediatric cases with ALPE, we tried to determine the relationship between findings from CT and magnetic resonance imaging (MRI). Case 1 involved a 13-year-old Japanese girl with a diagnosis of ALPE with normo-uricemia. Contrast-enhanced CT after 24 and 48 h showed a wedge-shaped excretion delay for the contrast media. A clear wedge shaped signal hyperintensity matching the CT images was obtained by diffusion weighted MRI. Case 2 involved a 16-year-old boy who presented with a second attack of ALPE after diagnosis of ALPE with hypouricemia 1 year earlier. Only diffusion-weighted imaging was performed. Clear wedge-shaped signal hyperintensity was apparent, similar to Case 1. MRI is safer than contrast enhanced CT for patients with ALPE. Diffusion-weighted MRI is a very useful examination for diagnosing ALPE, providing noninvasive detection of lesions peculiar to ALPE. PMID- 21594744 TI - Pulse wave velocity, blood pressure and bicycle tyres. PMID- 21594745 TI - Reading, laterality, and the brain: early contributions on reading disabilities by Sara S. Sparrow. AB - Although best known for work with children and adults with intellectual disabilities and autism spectrum disorders, training in speech pathology and a doctorate in clinical psychology and neuropsychology was the foundation for Sara Sparrow's long-term interest in reading disabilities. Her first papers were on dyslexia and laterality, and the maturational lag theory of developmental dyslexia proposed with Paul Satz, her mentor. The research program that emerged from this work had a wide impact on early neuropsychological models of reading disabilities. Although Sara went on to research focused on children with other developmental disabilities after she moved to Yale University, this initial research influenced her career- long interests in assessment, developmental models of disabilities, and early screening methods. PMID- 21594746 TI - Plasma membrane charging of Jurkat cells by nanosecond pulsed electric fields. AB - The initial effect of nanosecond pulsed electric fields (nsPEFs) on cells is a change of charge distributions along membranes. This first response is observed as a sudden shift in the plasma transmembrane potential that is faster than can be attributed to any physiological event. These immediate, yet transient, effects are only measurable if the diagnostic is faster than the exposure, i.e., on a nanosecond time scale. In this study, we monitored changes in the plasma transmembrane potential of Jurkat cells exposed to nsPEFs of 60 ns and amplitudes from 5 to 90 kV/cm with a temporal resolution of 5 ns by means of the fast voltage-sensitive dye Annine-6. The measurements suggest the contribution of both dipole effects and asymmetric conduction currents across opposite sides of the cell to the charging. With the application of higher field strengths the membrane charges until a threshold voltage value of 1.4-1.6 V is attained at the anodic pole. This indicates when the ion exchange rates exceed charging currents, thus providing strong evidence for pore formation. Prior to reaching this threshold, the time for the charging of the membrane by conductive currents is qualitatively in agreement with accepted models of membrane charging, which predict longer charging times for lower field strengths. The comparison of the data with previous studies suggests that the sub-physiological induced ionic imbalances may trigger other intracellular signaling events leading to dramatic outcomes, such as apoptosis. PMID- 21594747 TI - Community characteristics and implementation factors associated with effective systems of care. AB - How are characteristics of communities associated with the implementation of the principles of systems of care (SOC)? This study uses multilevel modeling with a stratified random sample (N = 225) of US counties to explore community-level predictors of the implementation factors of the System of Care Implementation Survey. A model composed of community-level social indicators fits well with 5 of 14 factors identified as relevant for effective SOCs. As hypothesized, community disadvantage was negatively and residential stability positively associated with the implementation of SOC principles. Designation as a mental health professional shortage area was positively related to some implementation scores, as was the percentage of minority residents, while rurality was not significantly associated with any of the factors. Given the limitations of the study, the results should be interpreted with caution, but suggest that further research is merited to clarify these relationships that could inform efforts directed at promoting SOCs. PMID- 21594748 TI - Evolutionary history of the GH3 family of acyl adenylases in rosids. AB - GH3 amino acid conjugases have been identified in many plant and bacterial species. The evolution of GH3 genes in plant species is explored using the sequenced rosids Arabidopsis, papaya, poplar, and grape. Analysis of the sequenced non-rosid eudicots monkey flower and columbine, the monocots maize and rice, as well as spikemoss and moss is included to provide further insight into the origin of GH3 clades. Comparison of co-linear genes in regions surrounding GH3 genes between species helps reconstruct the evolutionary history of the family. Combining analysis of synteny with phylogenetics, gene expression and functional data redefines the Group III GH3 genes, of which AtGH3.12/PBS3, a regulator of stress-induced salicylic acid metabolism and plant defense, is a member. Contrary to previous reports that restrict PBS3 to Arabidopsis and its close relatives, PBS3 syntelogs are identified in poplar, grape, columbine, maize and rice suggesting descent from a common ancestral chromosome dating to before the eudicot/monocot split. In addition, the clade containing PBS3 has undergone a unique expansion in Arabidopsis, with expression patterns for these genes consistent with specialized and evolving stress-responsive functions. PMID- 21594749 TI - Long-term outcome of idiopathic hypertrophic thoracic pachymeningitis. AB - Idiopathic hypertrophic spinal pachymeningitis (IHSP) is a comparatively rare disease characterized by hypertrophic inflammation of the dura mater and clinical symptoms that progress from local pain to myelopathy. We report a case of IHSP followed up for 20 years in a 46-year-old man. Expansive laminoplasty was performed in 1991, and this case has been previously reported by a co-author. After 17 years, the patient's gait disturbance returned. Physical examination and imaging confirmed IHSP that had developed into syringomyelia at the T2-L1 conus level. This case was diagnosed as adhesive spinal arachnoiditis due to pachymeningitis caused by syringomyelia. T1-T4 laminectomy, a syringo subarachnoid shunt (S-S shunt), and L2-L3 laminectomy were performed. The patient again developed dysesthesia and gait disturbance 3 years after the second operation. Most reports of IHSP have limited their focus to short-term follow-up after initial treatment with no long-term results. At present, there are only five reports referring to long-term results of greater than 5 years. All but one case needed additional surgery. To the best of our knowledge, this is the first case in which syringomyelia occurred in a patient with IHSP. It is important to note that syringomyelia may be a cause of symptom recrudescence during long-term follow-up in IHSP patients. PMID- 21594750 TI - Spinal gout tophus: a very rare cause of radiculopathy. AB - Gout is a common metabolic disease characterized by the development of arthritis and nephropathy related to the deposition of monosodium urate crystals within the joints, periarticular tissues, skin and kidneys. Tophus formation seen around the spinal column is very rare, while occurrences of spinal gout tophus without systemic gout disease are much more unique. In our study, we report a spinal gout case that presented with right sciatica without previous history of systemic gout disease. PMID- 21594751 TI - Predicting the peak growth velocity in the individual child: validation of a new growth model. AB - Predicting the peak growth velocity in an individual patient with adolescent idiopathic scoliosis is essential or determining the prognosis of the disorder and timing of the (surgical) treatment. Until the present time, no accurate method has been found to predict the timing and magnitude of the pubertal growth spurt in the individual child. A mathematical model was developed in which the partial individual growth velocity curve was linked to the generic growth velocity curve. The generic curve was shifted and stretched or shrunk, both along the age axis and the height velocity axis. The individual age and magnitude of the PGV were obtained from the new predicted complete growth velocity curve. Predictions were made using 2, 1.5, 1 and 0.5 years of the available longitudinal data of the individual child, starting at different ages. The predicted values of 210 boys and 162 girls were compared to the child's own original values of the PGV. The individual differences were compared to differences obtained when using the generic growth velocity curve as a standard. Using 2 years of data as input for the model, all predictions of the age of the PGV in boys and girls were significantly better in comparison to using the generic values. Using only 0.5 years of data as input, the predictions with a starting age from 13 to 15.5 years in boys and from 9.5 to 14.5 years in girls were significantly better. Similar results were found for the predictions of the magnitude of the PGV. This model showed highly accurate results in predicting the individual age and magnitude of the PGV, which can be used in the treatment of patients with adolescent idiopathic scoliosis. PMID- 21594752 TI - Outcome of spinal decompression in Cauda Equina syndrome presenting late in developing countries: case series of 50 cases. AB - The purpose of this study is to find the clinical outcome of decompression of Cauda Equina presenting late in the course of disease. There were 33 males and 17 females with average age of 48 years, ranging from 25 to 85 years. All patients presented to us with a fully developed Cauda Equina syndrome (CES). All of them presented late with mean delay of 12.2 days. Time interval between bladder and bowel dysfunction and admission to hospital varied from 1 to 35 days. The average follow-up was 34.5 months, ranging from 12 to 60 months. There was no statistically significant difference in time of delay in surgery between the recovered and non-recovered group as tested by Student's t test. But there was a statistically significant positive correlation between duration taken for total recovery and delay in surgery. Anal wink as a predictor of bladder and bowel recovery also showed statistical significance, as patients with an absence had a poorer prognosis for bladder recovery. The result of surgery in CES is not as dramatic and fast as seen after routine disc surgery. Some improvement can be expected with decompression even in those patients presenting late and results are not universally poor as previously thought. The treating physicians of such patients should be aware that the recovery in this group of patients can take an exceptionally long time and hence should involve in constant reassurance and rehabilitation of the patient. Presence of anal wink is a very good predictor of bladder and bowel recovery. PMID- 21594753 TI - The evolving classification of dementia: placing the DSM-V in a meaningful historical and cultural context and pondering the future of "Alzheimer's". AB - Alzheimer's disease is a 100-year-old concept. As a diagnostic label, it has evolved over the 20th and 21st centuries from a rare diagnosis in younger patients to a worldwide epidemic common in the elderly, said to affect over 35 million people worldwide. In this opinion piece, we use a constructivist approach to review the early history of the terms "Alzheimer's disease" and related concepts such as dementia, as well as the more recent nosological changes that have occurred in the four major editions of the Diagnostic and Statistical Manual since 1952. A critical engagement of the history of Alzheimer's disease and dementia, specifically the evolution of those concepts in the DSM over the past 100 years, raises a number of questions about how those labels and emergent diagnoses, such as Neurocognitive Disorders and Mild Cognitive Impairment, might continue to evolve in the DSM-V, due for release in 2013. PMID- 21594754 TI - Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy. AB - Fluorofenidone (FD) is a novel pyridone agent with significant antifibrotic effects in vitro. The purpose of this study is to investigate the effects of FD on renal interstitial fibrosis in rats with obstructive nephropathy caused by unilateral ureteral obstruction (UUO). With pirfenidone (PD, 500 mg/kg/day) and enalapril (10 mg/kg/day) as the positive treatment controls, the rats in different experimental groups were administered with FD (500 mg/kg/day) from day 4 to day 14 after UUO. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and type III collagen, transforming growth factor-beta(1) (TGF-beta(1)), connective tissue growth factor (CTGF), platelet derived growth factor (PDGF), alpha-smooth muscle actin (alpha-SMA), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed. FD treatment significantly attenuated the prominently increased scores of tubulointerstitial injury, interstitial collagen deposition, and protein expression of type I and type III collagen in ureter-obstructed kidneys, respectively. As compared with untreated rats, FD also significantly reduced the expression of alpha-SMA, TGF beta(1), CTGF, PDGF, and inhibitor of TIMP-1 in the obstructed kidneys. Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy through its regulation on fibrogenic growth factors, tubular cell transdifferentiation, and extracellular matrix. PMID- 21594755 TI - Genetic variants in ADIPOQ gene and the risk of type 2 diabetes: a case-control study of Chinese Han population. AB - This study was to evaluate the association between ADIPOQ gene variants and type 2 diabetes mellitus (T2DM). TaqMan((r)) assay was performed to test the genotypes in T2DM patients (n = 1,105) and normal control subjects (n = 1,107). Serum adiponectin concentration was measured by ELISA kit. The variant genotypes rs7649121AT and rs7649121AT/TT, compared with the AA genotype, were associated with a significantly decreased risk of T2DM [Adjusted OR (95% CI) = 0.79(0.66 0.95), 0.80(0.67-0.96), respectively]. In stratified analysis, rs2241767AG genotype increased the risk of T2DM in obesity group [Adjusted OR (95% CI) = 1.32(1.03-1.69)]. Patients with genotype AG/GG of rs2241767 had lower levels of serum adiponectin than those with the genotype AA (P = 0.044). Haplotype analyses were not significant. Crossover analysis of rs7649121 and environmental risk factor (obesity) indicated that the protect effect of rs7649121AT/TT maybe offset by the environmental risk. Those who exposed to environmental risk factor (obesity) had a chance to attack T2DM compared with those who did not expose to the two factors [Adjusted OR (95% CI) = 1.64(1.30-2.06)]. This study suggested that the ADIPOQ gene polymorphisms were associated with the risk of T2DM in a Chinese Han population. PMID- 21594756 TI - Incidence of hip fracture and prevalence of osteoporosis in Turkey: the FRACTURK study. AB - The incidence of hip fractures in Turkey increased markedly from that reported in 1988/1989 so that FRAX(r) models for Turkey should be revised. INTRODUCTION: The MEDOS study in 1988/1989 reported that men and women from Turkey had exceptionally low rates of hip fracture. The aim of the FRACTURK study was to estimate current and future hip fracture risks and the prevalence of osteoporosis in Turkey. METHODS: Hip fracture cases in 2009 were identified from interviews of a population-based sample of 26,424 residents aged 50 years or more in 12 different regions of Turkey and in two hospital surveys. Bone mineral density was evaluated by DXA in an age-stratified sample of 1,965 men and women. RESULTS: Hip fracture incidence in the community-based survey was similar to that in the hospital survey. The age-specific incidence in men and women was substantially higher than that reported for 1988/1989. At the age of 50 years, the remaining lifetime probability of a hip fracture was 3.5% in men and 14.6% in women. In 2009, there were approximately 24,000 hip fractures estimated in Turkey, 73% of which were found in women. Assuming no change in the age- and sex-specific incidence, the number of hip fractures was expected to increase to nearly 64,000 in 2035. The prevalence of osteoporosis at the femoral neck was 7.5% and 33.3% in men and women, respectively, aged 50 years or more. CONCLUSION: Although Turkey is still among the countries with low hip fracture rates in Europe, the incidence has increased markedly in the last 20 years. This finding can be used to recalibrate fracture risk assessment models for Turkey. PMID- 21594758 TI - Theoretical study on chiral recognition mechanism of methyl mandelate enantiomers on permethylated beta-cyclodextrin. AB - Host-guest interactions of permethylated beta-cyclodextrin (PM-beta-CD) with methyl mandelate enantiomers ((R/S)-MMA) were simulated using semiempirical PM3 and ONIOM (B3LYP/6-31G(d):PM3) method. The chiral recognition mechanism of (R/S) MMA enantiomers on PM-beta-CD was investigated. The binding energies for all orientations considered in this research are reported. The most stable geometry structures of the two complexes are different. The benzene ring of (R)-MMA locates horizontally approximately on the wider edge of the PM-beta-CD cavity, but the aromatic ring of (S)-MMA is deeply included into the hydrophobic cavity. Furthermore, the results of NBO analysis show that the main driving forces in the inclusion process of PM-beta-CD with (R/S)-MMA are hydrogen bonding interaction, dipole-dipole interaction, charge-transfer and hydrophobic interaction. The stabilization energy of the (R)-MMA/PM-beta-CD complex is lower than that of the (S)-MMA/PM-beta-CD complex. Moreover, the chiral carbon in MMA of (R/S)-MMA/PM beta-CD complexes are close to the C2 and C3 in the glucose unit. The chiral recognition mechanism is thus closely related to the chiral environment provided by C2 and C3 in the glucose unit and the degree of (R/S)-MMA and PM-beta-CD inclusion. PMID- 21594759 TI - Noncovalent and covalent functionalization of a (5, 0) single-walled carbon nanotube with alanine and alanine radicals. AB - We have systematically investigated the noncovalent and covalent adsorption of alanine and alanine radicals, respectively, onto a (5, 0) single-walled carbon nanotube using first-principles calculation. It was found that XH...pi (X = N, O, C) interactions play a crucial role in the non-ovalent adsorption and that the functional group close to the carbon nanotube exhibits a significant influence on the binding strength. Noncovalent functionalization of the carbon nanotube with alanine enhances the conductivity of the metallic (5, 0) nanotube. In the covalent adsorption of each alanine radical onto a carbon nanotube, the binding energy depends on the adsorption site on CNT and the electronegative atom that binds with the CNT. The strongest complex is formed when the alanine radical interacts with a (5, 0) carbon nanotube through the amine group. In some cases, the covalent interaction of the alanine radical introduces a half-filled band at the Fermi level due to the local sp (3) hybridization, which modifies the conductivity of the tube. PMID- 21594757 TI - How do trypanosomes change gene expression in response to the environment? AB - All organisms are able to modulate gene expression in response to internal and external stimuli. Trypanosomes represent a group that diverged early during the radiation of eukaryotes and do not utilise regulated initiation of transcription by RNA polymerase II. Here, the mechanisms present in trypanosomes to alter gene expression in response to stress and change of host environment are discussed and contrasted with those operating in yeast and cultured mammalian cells. PMID- 21594760 TI - A MP2 and DFT study of the influence of complexation on the aromatic character of phosphole. AB - This work is focused in three topical subjects: intermolecular interactions, metal ions, and aromaticity. A comprehensive MP2/6-31 + G and B3LYP/6-31 + G study of the influence of cation-pi interactions on the aromatic character of phosphole was conducted. For this purpose, the structures of complexes were optimized at both theoretical level and different magnetic properties were evaluated. The main conclusion is the increase of the aromatic character of the phosphole when complexes with Li(+), Be(2+), and Al(3+) are formed. PMID- 21594761 TI - Effect of the methylation of uracil and/or glycine on their mutual interaction. AB - In order to simulate the hydrogen bonding and proton transfer (PT) in protein DNA/RNA interactions, a series of simplified models were employed and investigated in the gas phase. These models included various neutral, anionic and cationic glycine-uracil dimers, and their methylated derivatives generated by the mono- or dimethylation of glycine and/or uracil moieties of the dimer. The results reveal that the only process that can occur in the neutral complexes is a double-PT process leading to proton exchange between the two moieties (i.e., point mutation). The first methyl substitute can reduce the activation energy of the PT process and thus promote the isomerization of the two moieties; further methylation can reduce the isomerization in only some of the cases. In the anionic complexes, only the one-way PT (i.e., amino acid -> nucleic acid base) process is energetically favorable, and this PT process is an interesting barrier free one (BFPT), with the attached electron locating itself at the base moiety. Methylation will disfavor BFPT, but it cannot alter the nature of BFPT. In the cationic complexes, three different PT processes can occur. These processes can transform mutually by adjusting either or both of the methylated sites and methyl number, indicating that the methylation can regulate the dynamics of these PT processes. PMID- 21594762 TI - Density functional theory study of small nickel clusters. AB - The stable geometries and atomization energies for the clusters Ni( n ) (n = 2-5) are predicted with all-electron density functional theory (DFT), using the BMK hybrid functional and a Gaussian basis set. Possible isomers and several spin states of these nickel clusters are considered systematically. The ground spin state and the lowest energy isomers are identified for each cluster size. The results are compared to available experimental and other theoretical data. The molecular orbitals of the largest cluster are plotted for all spin states. The relative stabilities of these states are interpreted in terms of superatom orbitals and no-pair bonding. PMID- 21594763 TI - Lack of non-hematological cross intolerance of dasatinib to imatinib in imatinib intolerant patients with Philadelphia chromosome positive chronic myeloid leukemia or acute lymphatic leukemia: a retrospective safety analysis. AB - The aim of this retrospective study was to evaluate the toxicity profiles of dasatinib in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) or acute lymphatic leukemia (ALL) who were intolerant to imatinib, and who had been enrolled in our previous clinical trials to evaluate efficacy of dasatinib in patients resistant or tolerant to imatinib therapy. Twenty-four patients with CML and four with ALL were enrolled in the clinical studies to evaluate the efficacy according to the eligibility criteria related to intolerance to imatinib therapy. The toxicities reported during imatinib therapy were non-hematological toxicities in 23 patients and hematological toxicities in six patients. Patients were administered dasatinib 50-70 mg BID or 100 mg QD. Cross intolerance was observed in four patients who showed hematological toxicity after dasatinib treatment. However, it was possible to successfully continue therapy with only temporary interruption. No cross intolerance in non hematological toxicity was found with the exception of one patient who showed cross intolerance, which did not result in treatment interruption. Dasatinib can be safely administered to imatinib-intolerant CML or Ph-positive ALL patients. PMID- 21594764 TI - New perspectives in cAMP-signaling modulation. AB - Cyclic adenosine 3',5'-monophosphate (cAMP) mediates the biological effects of various hormones and neurotransmitters. Stimulation of cardiac beta-adrenergic receptors (beta-AR) via catecholamines leads to activation of adenylyl cyclases and increases cAMP production to enhance myocardial function. Because many other receptors signaling through cAMP generation exist in cardiac myocytes, a central question is how different hormones induce distinct cellular responses through the same second messenger. A large body of evidence suggests that the localization and compartmentalization of beta-AR/cAMP signaling affects the net outcome of biological functions. Spatiotemporal dynamics of cAMP action is achieved by various proteins, including protein kinase A (PKA), phosphodiesterases, and scaffolding proteins such as A-kinase-anchoring proteins. In addition, the discovery of the cAMP target Epac (exchange proteins directly activated by cAMP), which functions in a PKA-independent manner, represents a novel mechanism for governing cAMP-signaling specificity. Aberrant cAMP signaling through dysregulation of beta-AR/cAMP compartmentalization may contribute to cardiac remodeling and heart failure. PMID- 21594765 TI - Sleep disorders and fibromyalgia. AB - Disordered sleep is such a prominent symptom in fibromyalgia that the American College of Rheumatology included symptoms such as waking unrefreshed, fatigue, tiredness, and insomnia in the 2010 diagnostic criteria for fibromyalgia. Even though sleep recording is not part of the routine evaluation, polysomnography may disclose primary sleep disorders in patients with fibromyalgia, including obstructive sleep apnea and restless leg syndrome. In addition, genetic background and environmental susceptibility link fibromyalgia and further sleep disorders. Among nonpharmacological treatment proposed for sleep disturbance in fibromyalgia, positive results have been obtained with sleep hygiene and cognitive-behavioral therapy. The effect of exercise is contradictory, but overweight or obese patients with fibromyalgia should be encouraged to lose weight. Regarding the approved antidepressants, amitriptyline proved to be superior to duloxetine and milnacipran for sleep disturbances. New perspectives remain on the narcolepsy drug sodium oxybate, which recently was approved for sleep management in fibromyalgia. PMID- 21594766 TI - Minimal change disease associated with MALT lymphoma. AB - Low-grade Extranodal Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, a subtype of non-Hodgkin's Lymphoma, involving the kidney is a rare clinical entity. Association of Minimal change disease nephrotic range proteinuria with Hodgkin's lymphoma is well described, however is extremely uncommon with non-Hodgkin's lymphoma. We describe a patient who presented with nephrotic syndrome and a kidney biopsy revealed marginal zone lymphoma and diffuse epithelial foot process effacement. He showed dramatic response to a combination therapy with cyclophosphamide, corticosteroids, and Rituximab. PMID- 21594767 TI - Genetic polymorphism at the C-terminal domain (region III) of knob-associated histidine-rich protein (KAHRP) of Plasmodium falciparum in isolates from Iran. AB - The knob-associated histidine-rich protein (KAHRP) plays a major role in the virulence of Plasmodium falciparum and is one of the targets for molecular therapy. The primary structure of KAHRP of P. falciparum consists of three domains (regions I-III), of which the C-terminal domain (region III) is the most polymorphic segment of this protein. One of the main obstacles is genetic diversity in designing and developing of malaria control strategies such as molecular therapy and vaccines. The primary objective of the present study was to investigate and analyze the extent of genetic polymorphism at the region III of KAHRP of P. falciparum in isolates from Iran. A fragment of the kahrp gene spanning the C-terminal domain was amplified by nested PCR from 50 P. falciparum isolates collected from two malaria endemic areas of Iran during 2009 to August 2010 and sequenced. In this study, three allelic types were observed at the C terminal domain of KAHRP on the basis of the molecular weight of nested PCR products and the obtained sequencing data. The presence of multiple alleles of the kahrp gene indicates that several P. falciparum strains exist in the malaria endemic areas of Iran. Our findings will be valuable in the design and the development of the molecular therapeutic reagents for falciparum malaria. PMID- 21594768 TI - Predictive value of remission status after 6 months induction therapy in patients with proliferative lupus nephritis: a retrospective analysis. AB - The objective of this study was to evaluate whether remission status after completion of induction therapy can be used to predict long-term renal outcomes, including renal relapse and chronic renal failure (CRF) in patients with proliferative lupus nephritis (LN). Of 201 patients with biopsy proven LN between 1998 and 2008, 117 were reviewed. Fifty nine (50.4%), 33 (28.2%), and 25 (21.4%) were assigned to the complete remission (CR), partial remission (PR), and non remission (NR) groups, respectively. The 24-h urinary protein level was significantly lower in the CR than in the PR and NR groups. Induction therapy after the first detection of nephritis signs was initiated earlier in the CR than in the PR and NR groups. During follow-up, 36 (39.1%) patients suffered relapse. Multivariate analysis showed that longer latency period and a lack of CR were independent predictors of renal relapse. Seventeen (14.5%) patients experienced CRF. Multivariate analysis showed that higher baseline creatinine concentration and a lack of CR after induction therapy were independent predictors of CRF. We found that renal outcomes were related to remission status after 6 months induction therapy in patients with proliferative LN. Further, poor outcomes were associated with delayed intervention and higher creatinine concentration. PMID- 21594769 TI - Progression from first symptom to diagnosis in childhood brain tumours. AB - This study was undertaken to investigate the evolution of clinical features between onset of symptoms and diagnosis in children with brain tumours and to identify ways of shortening the time to diagnosis. One hundred and thirty-nine children with a brain tumour were recruited from four UK paediatric neuro oncology centres. Children had a median of one symptom or sign at symptom onset and six by diagnosis. The symptoms and/or signs experienced at symptom onset and at diagnosis were as follows: headache in 55 and 81 children, nausea and vomiting in 39 and 88 children, motor system abnormalities in 31 and 93 children, cranial nerve palsies in 24 and 75 children, visual system abnormalities in 23 and 96 children, endocrine or growth abnormalities in 10 and 35 children and behavioural change in 4 and 55 children. The median time between symptom onset and diagnosis (symptom interval) was 3.3 months. A longer symptom interval was associated with head tilt, cranial nerve palsies, endocrine and growth abnormalities and reduced visual acuity. More than half of children with brain tumours developed problems with vision and more than a third developed motor problems, cranial nerve palsies, behavioural change, or nausea and vomiting between symptom onset and diagnosis. PMID- 21594772 TI - Platinum(II) chloride indenyl complexes: electrochemical and biological evaluation. AB - Four platinum(II) complexes of general formula [PtCl(eta(1)-C(9)H(7))L(2)] [where L(2) is 1,2-bis(diphenylphosphino)ethane (dppe) 1 or cycloocta-1,5-diene (cod) 3] and [PtCl(2)L(2)] (where L(2) is dppe 2 or cod 4) were studied. Inhibition growth assays on human tumor cell lines evidenced for 1 and 3 an antiproliferative effect and, interestingly, the cytotoxic effect exerted by 1 is similar to that of cisplatin. Electrochemical and NMR measurements allowed us to determine the structural and redox properties. Investigation of the mechanism of action responsible for the cytotoxicity demonstrated a weak capacity of interacting with DNA. Some experiments performed on rat liver mitochondria indicate that 1 acts as an inducer of the mitochondrial permeability transition, thus leading to the release of proapoptotic factors, such as cytochrome c and apoptosis-inducing factor. PMID- 21594770 TI - Molecular bases of genetic diversity and evolution of the immunoglobulin heavy chain variable region (IGHV) gene locus in leporids. AB - The rabbit has long been a model for studies of the immune system. Work using rabbits contributed both to the battle against infectious diseases such as rabies and syphilis, and to our knowledge, of antibodies' structure, function, and regulated expression. With the description of rabbit Ig allotypes, the discovery of different gene segments encoding immunoglobulins became possible. This challenged the "one gene-one protein" dogma. The observation that rabbit allotypic specificities of the variable regions were present on IgM and IgG molecules also led to the hypothesis of Ig class switching. Rabbit allotypes contributed to the documentation of phenomena such as allelic exclusion and imbalance in production of allelic gene products. During the last 30 years, the rabbit Ig allotypes revealed a number of unique features, setting them apart from mice, humans, and other mammals. Here, we review the most relevant findings concerning the rabbit IGHV. Among these are the preferential usage of one VH gene in VDJ rearrangements, the existence of trans-species polymorphism in the IGHV locus revealed by serology and confirmed by sequencing IGHV genes in Lepus, the unusually large genetic distances between allelic lineages and the fact that the antibody repertoire is diversified in this species only after birth. The whole genome sequence of a rabbit, plus re-sequencing of additional strains and related genera, will allow further evolutionary investigations of antibody variation. Continued research will help define the roles that genetic, allelic, and population diversity at antibody loci may play in host-parasite interactions. PMID- 21594774 TI - Introduction to Section I: the relevance of CF diagnostic tools for measuring restoration of CFTR function after therapeutic interventions in human clinical trials. AB - The pilocarpine sweat test, and in vivo assessment of CFTR function via nasal potential difference or intestinal current measurement are important tools to confirm the diagnosis of CF in subjects with suggestive symptoms. Since these tests reflect CFTR function and thus relate to the basic disease process in CF, changes in these parameters are also being used to assess the pharmacologic effect of compounds aimed at restoring CFTR function. However, longitudinal data proving that changes in these measurements are associated with meaningful clinical improvements in the course of disease in CF patients are needed. Consequently, many CF clinical investigators need to be facile with these existing methods to measure CFTR-related outcomes. This introduction sets the stage for more in-depth discussion of existing strategies to measure changes in CFTR function generated by gene therapy or small molecule modulators of CFTR function such as correctors and potentiators. It is hoped that lessons learned through the use of these measures will inform the future development of other robust methods to assess novel therapeutic strategies uncovered by basic scientists. PMID- 21594775 TI - High-throughput screening of libraries of compounds to identify CFTR modulators. AB - Small molecules acting as selective activators (potentiators), inhibitors, or "correctors" of the CFTR chloride channel represent candidate drugs for various pathological conditions including cystic fibrosis and secretory diarrhea. The identification of CFTR pharmacological modulators may be achieved by screening highly diverse synthetic or natural compound libraries using high-throughput methods. A convenient assay for CFTR function is based on the halide sensitivity of the yellow fluorescent protein (YFP). CFTR activity can be simply assessed by measuring the rate of YFP signal decrease caused by iodide influx. This assay can be automated to test thousands of compounds per day. PMID- 21594776 TI - Repair of CFTR folding defects with correctors that function as pharmacological chaperones. AB - The major cause of cystic fibrosis is the presence of processing mutations in CFTR (such as deletion of Phe-508 (F508del-CFTR)) that disrupt folding of the protein and trafficking to the cell surface. Processing mutations appear to inhibit folding of CFTR so that it accumulates in the endoplasmic reticulum as a partially folded protein. Expressing the proteins in the presence of small molecules called correctors can repair CFTR folding defects. Some correctors appear to function as pharmacological chaperones that specifically bind to the CFTR processing mutants and induce them to complete the folding process. In this chapter, we describe techniques to examine the effects of correctors on folding of CFTR processing mutants. PMID- 21594777 TI - Use of primary cultures of human bronchial epithelial cells isolated from cystic fibrosis patients for the pre-clinical testing of CFTR modulators. AB - The use of human bronchial epithelial (HBE) cell cultures derived from the bronchi of CF patients offers the opportunity to study the effects of CFTR correctors and potentiators on CFTR function and epithelial cell biology in the native pathological environment. Cultured HBE cells derived from CF patients exhibit many of the morphological and functional characteristics believed to be associated with CF airway disease in vivo, including abnormal ion and fluid transport leading to dehydration of the airway surface and the loss of cilia beating. In addition, they can be generated in sufficient quantities to support routine lab testing of compound potency and efficacy and retain reproducible levels of CFTR function over time. Here we describe the development and validation of the CF HBE pharmacology model and its use to characterize, optimize, and select clinical candidates. It is expected that the pre-clinical testing of CFTR potentiators and correctors using epithelial cell cultures derived from CF patients will help to increase their likelihood of clinical efficacy. PMID- 21594778 TI - Design of gene therapy trials in CF patients. AB - The report of the first CF patients to receive CFTR gene therapy appeared in 1993; since then, there have been over 20 clinical trials of both viral and non viral gene transfer agents. These have largely been single dose to either nose or lower airway and have been designed around molecular or bioelectrical outcome measures. Both transgene mRNA and partial correction of chloride secretion have been reported, although sodium hyperabsorption has not been improved. The UK CF Gene Therapy Consortium is focussed on a clinical programme to establish whether these proof-of-principle measures translate into clinical benefit. Here, we discuss the considerations in designing such a programme, focusing in particular on our choice of the optimal, currently available delivery method and established and novel outcome measures. We highlight the logistic and regulatory complexities of such a clinical programme and finally, we look to the future and consider possible alternative strategies. PMID- 21594780 TI - Measurement of ion transport function in rectal biopsies. AB - Cystic fibrosis (CF) is caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as an anion channel and is known to interact with a number of other cellular proteins involved in ion transport. To date more than 1,800 mutations are known, most of which result in various degrees of impaired transport function of the gene product. Due to the high inter-individual variability of disease onset and progression, CF still is a diagnostic challenge. Implemented almost 20 years ago, the measurement of electrolyte transport function of rectal biopsies is a useful ex vivo tool to diagnose CF. In this chapter we will review the different approaches to perform ion transport measurements and try to highlight the advantages and limitations of these techniques. PMID- 21594779 TI - Nasal potential difference measurements to assess CFTR ion channel activity. AB - The Nasal potential difference measurement is used to measure the voltage across the nasal epithelium, which results from transepithelial ion transport and reflects in part CFTR function. The electrophysiologic abnormality in cystic fibrosis was first described 30 years ago and correlates with features of the CF phenotype. NPD measurement is an important in vivo research and diagnostic tool, and is used to assess the efficacy of new treatments such as gene therapy and ion transport modulators. This chapter will elaborate on the electrophysiological principles behind the test, the equipment required, the methods, and the analysis of the data. PMID- 21594781 TI - Introduction to Section II: RNA methods to approach CFTR expression. AB - In this section, we review methods for the analysis of the CFTR gene and its transcript. First, we discuss techniques to accurately measure levels of CFTR mRNA in primary human cells; next, protocols for measuring CFTR transcripts that contain premature termination codons and for evaluating the role of nonsense mediated decay which targets these transcripts; a further chapter considers methodology to investigate pre-mRNA splicing. The penultimate chapter concentrates on methods for evaluating microRNA regulation of gene expression in the context of airway disease. The final chapter considers methods to evaluate the chromatin structure of the active CFTR locus and to analyse the cis-acting regulatory elements that control it. PMID- 21594782 TI - Quantification of CFTR transcripts. AB - Quantification and analysis of CFTR transcripts is of crucial importance not only for cystic fibrosis (CF) diagnosis and prognosis, but also in evaluating the efficiency of various therapeutic approaches to CF, including gene therapy. Reverse transcription (RT) followed by quantitative polymerase chain reaction (qPCR) is at present the most sensitive method for transcript abundance measurement. Classical RNA-based methods require significant expression levels in target samples for appropriate analysis, thus PCR-based methods have evolved towards reliable quantification. In this chapter we describe and discuss several protocols for the quantitative analysis of CFTR transcripts, including those variants that result from alternative splicing. PMID- 21594783 TI - Nonsense-mediated mRNA decay and cystic fibrosis. AB - Approximately one-third of the alleles causing genetic diseases carry premature termination codons (PTCs). Therapeutic approaches for mutations generating in frame PTCs are aimed at promoting translational readthrough of the PTC, to enable the synthesis and expression of full-length functional proteins. Interestingly, readthrough studies in tissue culture cells, mouse models, and clinical trials revealed a wide variability in the response to the readthrough treatments. The molecular basis for this variability includes the identity of the PTC and its sequence context, the chemical composition of the readthrough drug, and, as we showed recently, the level of PTC-bearing transcripts. One post-transcriptional mechanism that specifically regulates the level of PTC-bearing transcripts is nonsense-mediated mRNA decay (NMD). We have previously shown a role for NMD in regulating the response of CF patients carrying CFTR PTCs to readthrough treatment. Here we describe all the protocols for analyzing CFTR nonsense transcript levels and for investigating the role of NMD in the response to readthrough treatment. This includes inhibition of the NMD mechanism, quantification of CFTR nonsense transcripts and physiologic NMD substrates, and analysis of the CFTR function. PMID- 21594784 TI - Approaches to study CFTR pre-mRNA splicing defects. AB - In cystic fibrosis, genomic variants can result in defective processing of the CFTR precursor mRNA. Due to the complexity of the splicing process, the evaluation of their pathological effect is an important aspect both in the diagnostic field and in the study of basic regulatory mechanism. Efficient and correct splicing of CFTR relies on a complex process that includes recognition within the nascent transcripts of a series of different splicing regulatory elements that frequently overlap with the coding sequences. Identification of these elements is essential to determine the pathological impact of splicing affecting genomic variants. In this chapter, to evaluate the effect of CFTR DNA variations on the pre-mRNA splicing process, different tools based on hybrid minigenes will be described. PMID- 21594785 TI - Impact of microRNA in normal and pathological respiratory epithelia. AB - Extensive sequencing efforts, combined with ad hoc bioinformatics developments, have now led to the identification of 1222 distinct miRNAs in human (derived from 1368 distinct genomic loci) and of many miRNAs in other multicellular organisms. The present chapter is aimed at describing a general experimental strategy to identify specific miRNA expression profiles and to highlight the functional networks operating between them and their mRNA targets, including several miRNAs deregulated in cystic fibrosis and during differentiation of airway epithelial cells. PMID- 21594786 TI - Genomic approaches to studying CFTR transcriptional regulation. AB - The CFTR gene was identified over 20 years ago, and yet how the gene is transcriptionally regulated is not fully understood. Completion of the human genome sequence has encouraged a new generation of genomic techniques that can be used to identify and characterize the regulatory elements of the genome, which are often hidden in non-coding regions. In this chapter we describe two techniques that we have used to identify regulatory regions of the CFTR locus: DNase-chip, which utilizes DNase I-digested chromatin hybridized to tiled microarrays in order to locate regions of the CFTR locus that are "open" and thus likely regions of transcription factor binding; and quantitative chromosome conformation capture (q3C), which uses quantitative PCR analysis of digested and ligated, crosslinked chromosomes to measure physical interactions between distal genomic regions. When used together, these methods provide a powerful avenue to discover transcriptional regulatory elements within large genomic regions. PMID- 21594787 TI - Introduction to section III: biochemical methods to study CFTR protein. AB - This section of Cystic Fibrosis: Diagnosis and Protocols is focussed on methods aimed at detecting expression, localization, endocytic sorting and metabolism (biogenesis and turnover), as well as interacting partners of the cystic fibrosis transmembrane conductance regulator (CFTR), the protein product of the gene mutated in cystic fibrosis (CF). An overview of the protocols to be found in subsequent chapters of this book section is provided here, as well as the rationale for utilizing these protocols (also as a workflow) explaining which scientific question(s) each of them helps to address. Protocols included in other sections of this book are also cross-referenced. PMID- 21594788 TI - Analysis of CFTR folding and degradation in transiently transfected cells. AB - Misfolding and premature degradation of F508del-CFTR is the major cause of cystic fibrosis. Components of the ubiquitin-proteasome system function on the surface of the endoplasmic reticulum to select misfolded proteins for degradation. The folding status of F508del-CFTR is monitored by at least two ER quality control checkpoints. The ER-associated Derlin-1/RMA1 E3 complex appears to recognize folding defects in CFTR that involve misassembly of NBD1 into a complex with the R-domain. In contrast, the cytosolic Hsp70/CHIP E3 complex appears to sense folding defects that occur after synthesis of NBD2. Herein we describe methods that allow for the study of how modulation of these ER quality control factors by siRNA impacts CFTR folding and degradation. The experimental system described employs transiently transfected HEK293 cells and is utilized to monitor the biogenesis of CFTR by both Western blot and pulse chase studies. Methods to detect complexes formed between CFTR folding intermediates and ER quality control factors will also be described. PMID- 21594789 TI - In vitro methods for CFTR biogenesis. AB - Cell-free expression systems provide unique tools for understanding CFTR biogenesis because they reconstitute the cellular folding environment and are readily amenable to biochemical and pharmacological manipulation. The most common system for this purpose is rabbit reticulocyte lysate (RRL), supplemented with either canine pancreatic microsomes or semi-permeabilized cells, which has yielded important insights into the folding of CFTR and its individual domains. A common problem in such studies, however, is that biogenesis of large proteins such as CFTR is often inefficient due to low translation processivity, ribosome stalling, and/or premature termination. The first part of this chapter therefore describes parameters that affect in vitro translation of CFTR in RRL. We have found that CFTR expression is uniquely dependent upon 5'- and 3'-untranslated regions (UTRs) of the mRNA. Full-length CFTR expression can be markedly increased using mRNA lacking a 5'-cap analog (G(5')ppp(5')G), whereas the reverse usually holds for smaller proteins and individual CFTR domains. In the context of the full-length mRNA, translation was further stimulated by the presence of a long 3' UTR. The second part of this chapter describes CFTR translation in lysates derived from cultured mammalian cells including human bronchial epithelial cells. Unfortunately, mammalian cell-derived lysates showed limited ability to sustain full-length CFTR synthesis. However, they provide a unique opportunity to examine specific CFTR domains (i.e., nucleotide-binding domain 1 and transmembrane domain 1) under conditions that more closely resemble the native folding environment. PMID- 21594790 TI - Analysis of CFTR interactome in the macromolecular complexes. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel localized primarily at the apical surface of epithelial cells lining the airway, gut, exocrine glands, etc., where it is responsible for transepithelial salt and water transport. A growing number of proteins have been reported to interact directly or indirectly with CFTR chloride channel, suggesting that CFTR might regulate the activities of other ion channels, receptors, and transporters, in addition to its role as a chloride conductor. Most interactions occur primarily between the opposing terminal tails (N or C) of CFTR and its binding partners, either directly or mediated through various PDZ domain-containing proteins. This chapter describes methods we developed to cross-link CFTR into a macromolecular complex to identify and analyze the assembly and regulation of CFTR-containing complexes in the plasma membrane. PMID- 21594791 TI - Methods to monitor cell surface expression and endocytic trafficking of CFTR in polarized epithelial cells. AB - Cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride secretion is critical to maintaining airway surface hydration and efficient mucociliary clearance in the upper airways. Mutations in CFTR in cystic fibrosis lead to reduced expression of functional CFTR channels at the apical plasma membrane of the airway epithelium, leading to dehydration of the airway surface liquid and diminished mucociliary clearance. Cell surface CFTR is modulated by changes in CFTR endocytosis and recycling, effectively altering the cell surface abundance of the channel. This chapter examines current methods employed to measure the cell surface expression of CFTR, as well as methods to monitor CFTR movement through the endocytic pathway. PMID- 21594792 TI - Segmental and subcellular distribution of CFTR in the kidney. AB - Besides its location at the plasma membrane, CFTR is present in intracellular vesicles along both the exocytic and the endocytic pathways. Immunostaining and subcellular fractionation studies of mouse kidney demonstrate that CFTR is located in endosomes of the cells lining the terminal part of the proximal tubule (PT). The PT cells efficiently reabsorb the ultrafiltered low molecular weight (LMW) proteins by apical endocytosis involving the multiligand receptors megalin and cubilin. The progression from early endosomes to lysosomes depends on the integrity of the cytoskeleton, as well as on vesicular acidification. The latter is mediated by the vacuolar H+-ATPase (V-ATPase) and requires an anionic conductance to dissipate the transmembrane potential gradient. CFTR might ensure such chloride conductance, thereby participating to endosomal acidification and protein uptake by PT cells. Immunostaining with well-characterized antibodies shows that CFTR is located in the terminal segment of PT, where it co-distributes with megalin and cubilin. Subcellular fractionation of total mouse kidneys through Percoll gradients demonstrates the co-localization of CFTR with the V ATPase and early endosome markers including the Cl-/H+ exchanger, ClC-5, and the small GTPase, Rab5a. Deglycosylation studies and immunoblotting show a distinct glycosylation pattern for CFTR in mouse kidney and lung. The segmental and subcellular distribution of CFTR in mouse kidney supports a role for CFTR in PT receptor-mediated endocytosis of ultrafiltered LMW proteins. PMID- 21594793 TI - Endocytic sorting of CFTR variants monitored by single-cell fluorescence ratiometric image analysis (FRIA) in living cells. AB - The wild-type CFTR channel undergoes constitutive internalization and recycling at the plasma membrane. This process is initiated by the recognition of the Tyr- and di-Leu-based endocytic motifs of CFTR by the AP-2 adaptor complex, leading to the formation of clathrin-coated vesicles and the channel delivery to sorting/recycling endosomes. Accumulating evidence suggests that conformationally defective mutant CFTRs (e.g. rescued F508del and glycosylation-deficient channel) are unstable at the plasma membrane and undergo augmented ubiquitination in post Golgi compartments. Ubiquitination conceivably accounts for the metabolic instability at cell surface by provoking accelerated internalization, as well as rerouting the channel from recycling towards lysosomal degradation. We developed an in vivo fluorescence ratiometric image analysis (FRIA) that in concert with genetic manipulation can be utilized to establish the post-endocytic fate and sorting determinants of mutant CFTRs. PMID- 21594794 TI - Introduction to section IV: biophysical methods to approach CFTR structure. AB - Inefficient folding of CFTR into a functional three-dimensional structure is the basic pathophysiologic mechanism leading to most cases of cystic fibrosis. Knowledge of the structure of CFTR and placement of these mutations into a structural context would provide information key for developing targeted therapeutic approaches for cystic fibrosis. As a large polytopic membrane protein containing disordered regions, intact CFTR has been refractory to efforts to solve a high-resolution structure using X-ray crystallography. The following chapters summarize current efforts to circumvent these obstacles by utilizing NMR, electron microscopy, and computational methodologies and by development of experimental models of the relevant domains of CFTR. PMID- 21594795 TI - CFTR three-dimensional structure. AB - CFTR is a member of the ATP-binding cassette family of membrane proteins. This is one of the best characterised membrane protein families in terms of structure and function. CFTR operates as an ion channel, unlike nearly all other family members which are active transporters. Here, we discuss methods that have allowed such data to be obtained for CFTR. PMID- 21594796 TI - Molecular modeling tools and approaches for CFTR and cystic fibrosis. AB - Cystic fibrosis is a multi-faceted disease resulting from the dysfunction of the CFTR channel. Understanding the structural basis of channel function and the structural origin of the defect is imperative in the development of therapeutic strategies. Here, we describe molecular modeling tools that, in conjunction with complementary experimental tools, lead to significant findings on CFTR channel function and on the effect of the pathogenic mutant F508del. PMID- 21594797 TI - Biochemical and biophysical approaches to probe CFTR structure. AB - The cystic fibrosis transmembrane regulator (CFTR) is a multi-domain integral membrane protein central to epithelial fluid secretion (see Chapter 21). Its activity is defective in the recessive genetic disease cystic fibrosis (CF). The most common CF-causing mutation is F508del in the first nucleotide binding domain (NBD1) of CFTR. This mutation is found on at least one allele of more than 90% of all CF patients. It is known to interfere with the trafficking/maturation of CFTR through the secretory pathway, leading to a loss-of-function at the plasma membrane. Notably, correction of the trafficking defect by addition of intragenic second-site suppressor mutations, or the alteration of bulk solvent conditions, such as by reducing the temperature or adding osmolytes, leads to appearance of functional channels at the membrane--thus, the rescued F508del-CFTR retains measurable function. High-resolution structural models of NBD1 from X-ray crystallographic data indicate that F508 is exposed on the surface of the domain in a position predicted by homologous ABC transporter structures to lie at the interface with the intracellular loops (ICLs) connecting the transmembrane spans. Determining the relative impact of the F508del mutation directly on NBD1 folding or on steps of domain assembly or both domain folding and assembly requires methods for evaluating the structure and stability of the isolated domain. PMID- 21594798 TI - NMR spectroscopy to study the dynamics and interactions of CFTR. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a multi-domain membrane chloride channel whose activity is regulated by ATP at two nucleotide binding domains (NBD1 and NBD2) and by phosphorylation of the regulatory (R) region. The NBDs and the R region have functionally relevant motions that are critical for channel gating. Nuclear magnetic resonance (NMR) spectroscopy is a highly useful technique for obtaining information on the structure and interactions of CFTR and is extremely powerful for probing dynamics. NMR approaches for studying CFTR are reviewed, using our previous NBD1 and the R region results to provide examples. These NMR data are yielding insights into the dynamic properties and interactions that facilitate normal CFTR regulation as well as pathological effects of mutations, including the most common disease mutant, deletion of F508 in NBD1. PMID- 21594799 TI - Introduction to section V: assessment of CFTR function. AB - This chapter introduces the various techniques to asses the function of CFTR. The numerous functional interactions of CFTR and cellular properties affected by CFTR will be described initially. This will be followed by sections explaining the importance of patch clamping and double electrode voltage clamp experiments in Xenopus oocytes for expression analysis of CFTR, and the Ussing chamber technique to analyze CFTR in polarized epithelia. It is concluded that examining CFTR function should occur at different levels, starting with the intact epithelium and ending with isolated CFTR proteins. PMID- 21594801 TI - Electrophysiological, biochemical, and bioinformatic methods for studying CFTR channel gating and its regulation. AB - CFTR is the only member of the ABC (ATP-binding cassette) protein superfamily known to function as an ion channel. Most other ABC proteins are ATP-driven transporters, in which a cycle of ATP binding and hydrolysis, at intracellular nucleotide binding domains (NBDs), powers uphill substrate translocation across the membrane. In CFTR, this same ATP-driven cycle opens and closes a transmembrane pore through which chloride ions flow rapidly down their electrochemical gradient. Detailed analysis of the pattern of gating of CFTR channels thus offers the opportunity to learn about mechanisms of function not only of CFTR channels but also of their ABC transporter ancestors. In addition, CFTR channel gating is subject to complex regulation by kinase-mediated phosphorylation at multiple consensus sites in a cytoplasmic regulatory domain that is unique to CFTR. Here we offer a practical guide to extract useful information about the mechanisms that control opening and closing of CFTR channels: on how to plan (including information obtained from analysis of multiple sequence alignments), carry out, and analyze electrophysiological and biochemical experiments, as well as on how to circumvent potential pitfalls. PMID- 21594800 TI - Application of high-resolution single-channel recording to functional studies of cystic fibrosis mutants. AB - The patch-clamp technique is a powerful and versatile method to investigate the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel, its malfunction in disease and modulation by small molecules. Here, we discuss how the molecular behaviour of CFTR is investigated using high-resolution single channel recording and kinetic analyses of channel gating. We review methods used to quantify how cystic fibrosis (CF) mutants perturb the biophysical properties and regulation of CFTR. By explaining the relationship between macroscopic and single-channel currents, we demonstrate how single-channel data provide molecular explanations for changes in CFTR-mediated transepithelial ion transport elicited by CF mutants. PMID- 21594802 TI - CFTR regulation by phosphorylation. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is the gene product mutated in cystic fibrosis, a common lethal genetic disease characterized by abnormal electrolyte transport across epithelia. CFTR functions as an ATP gated, phosphorylation-regulated Cl- channel that mediates agonist-stimulated apical membrane epithelial Cl- and bicarbonate secretion and also regulates a variety of other transport proteins and cellular processes. CFTR belongs to the ATP-binding cassette (ABC) transporter superfamily. Its presumed architecture consists of two transmembrane domain regions that form the channel pore, two nucleotide-binding domains that bind and hydrolyze ATP, and a unique regulatory (R) domain that contains numerous protein kinase A (PKA) and protein kinase C (PKC) phosphorylation sites. Other kinases have also been shown more recently to phosphorylate and regulate CFTR activity. This chapter describes strategies and methods for studying the phosphorylation of CFTR both in vitro and whole-cell systems. PMID- 21594803 TI - How to measure CFTR-dependent bicarbonate transport: from single channels to the intact epithelium. AB - Bicarbonate serves many functions in our body. It is the predominant buffer maintaining a physiological pH in the blood and within our cells. It is also essential for proper digestion of nutrients and solubilization of complex protein mixtures, such as digestive enzymes and mucins, in epithelial secretions. Transepithelial HCO3- transport also drives net fluid secretion in many epithelial tissues including those in the gastrointestinal and reproductive tracts as well as the airways. Indeed, defective bicarbonate secretion is a hallmark of the pathophysiology in the pancreas of most patients suffering from cystic fibrosis. Some, but not all, disease-causing mutations in the CF gene lead to impaired bicarbonate transport when expressed in heterologous systems. Recently developed pharmacological modulators of mutant CFTR have demonstrated an ability to activate chloride transport but little is known about whether they also increase the secretion of bicarbonate. It is therefore essential to assay bicarbonate transport when studying the effect of small molecules on CFTR function. However, due to the chaotropic nature of the ion, the measurement of the absolute bicarbonate concentration and its permeability through CFTR is far from trivial. In this chapter we will review some of the techniques available to measure bicarbonate transport through single ion channels, individual cells, and intact epithelial layers. PMID- 21594806 TI - On "Perioperative Antibiotics in the Setting of Microvascular Free Tissue Transfer: Current Practices" (J Reconstr Microsurg 2010;26(6):401-407). PMID- 21594807 TI - Treatment of serious femoral neck fractures with the transposition of vascularized greater trochanter bone flap in young adults. AB - Femoral neck fractures in young adults are not uncommon in clinical work. For fresh fractures or old femoral neck fractures of subcapital type or Garden types III to IV, femoris caput necrosis and nonunion are apt to occur if conventional therapeutic method is adopted and direct joint replacement is attempted. However, this has brought about bitter controversies in medical circles. The authors of this article define such fractures as serious femoral neck fractures. What kind of operational method should be selected, to the maximum extent, to restore the function of hip joints of patients and reduce their complications after operation still remains a problem to be studied. In this article, cases of patients (from 1999 to today) treated with transposition of vascularized greater trochanter bone flap and hollow compression strews are analyzed. Patients were followed for 39 to 84 months, and the results are summarized. PMID- 21594808 TI - An objective evaluation of an injured vessel wall using fluorescein sodium before microvascular anastomosis in an experimental rat model. AB - The aim of this study was to establish an objective evaluation method for intraoperative detection of damaged vascular endothelium in avulsion injuries. Twenty male Fischer rats were randomly assigned to control or experimental groups ( N = 10, each). Crush-avulsion injury was performed on right femoral arteries. Resection of damaged segments was performed according to operative microscopic findings in the control group; fluorescein sodium was applied to the artery lumen before resection in the experimental group to help visualize the damaged endothelium. Microvascular repair was performed in five rats in each group. In the other animals, the whole length of the femoral arteries was resected to assess the actual extent of injury histologically. At the end of the follow-up period, patency of microvascular anastomoses was examined and the lengths of the resected segments were compared with the actual length of the injured segment measured histologically. The difference between these two measurements was statistically significant in the control group ( P < 0.05) but not in the experimental group ( P > 0.05). Anastomosis patency was significantly higher in the experimental group ( P < 0.0001). In conclusion, fluorescein sodium may help to accurately determine the length of the injured vascular segment in avulsion injuries. PMID- 21594810 TI - A case of degloving injury of the whole hand reconstructed by a combination of distant flaps comprising an anterolateral thigh flap and a groin flap. AB - A case of degloving injury of the whole hand reconstructed by a combination of an anterolateral thigh (ALT) flap and a groin flap applied as a pedicled distant flap was reported. Despite complications of congestion of the ALT flap and superficial infection, both flaps were severed at 4 weeks after transplantation, and a useful hand was finally reconstructed. The combination of a pedicled groin flap and an ALT flap is not optimal for reconstruction of a whole-hand degloving injury but is considered to be an available procedure for covering a large skin defect without microsurgical procedures. PMID- 21594809 TI - The Y-V-I principle for salvaging distal digit replantation. AB - The replantation and revascularization of a distal finger following a crush injury or avulsion are difficult because of the shortness of the vessels after debridement. The success rate of the anastomoses may decrease when they are under tension. To address this, many maneuvers have been described, such as shortening the amputated part or proximal finger stump for tensionless closing, interposing a vein graft between the vessel ends, and vessel transfer from a neighboring finger. Regardless of which of these techniques is chosen, it is an additional drawback for the already traumatized hand or amputation stump. Y-V-I pedicle lengthening is a method for providing extra pedicle length. This article presents a pediatric patient with a traumatic partial amputation at the fourth distal interphalangeal joint in whom the finger was salvaged by achieving anastomoses using the Y-V-I pedicle-lengthening principle. PMID- 21594811 TI - Arteriovenous fistula following radial forearm free flap. AB - The authors describe the development of a right facial arteriovenous fistula following debulking of a radial forearm free flap for reconstruction of the neck due to a burn contraction scar. The arteriovenous fistula was immediately excised following interventional embolization, without recurrence on postoperative follow up. The authors report this as being the first arteriovenous fistula following a secondary debulking procedure, likely due to cross-clamping of the vascular pedicle. Thus, the authors recommend that the vascular pedicle be identified and that the artery and vein be selectively ligated during secondary debulking procedure following microvascular free flap reconstruction to avoid communication of the respective vessels potentially predisposing to development of an unintended arteriovenous fistula. PMID- 21594812 TI - [Health consequence of stalking victimization]. AB - Life time prevalence of stalking is about 12-20%, while females are more often affected than male. Stalking is a statutory offense. However, it is not an assault of victims' law. For the purpose of health consequences for stalking victims, research in following database were conducted: EMBASE, CINAHL, MEDLINE, PsycINFO and Social Science Index. English and German published studies of the years 2002-2010 were included. 17 primary studies and 2 meta-analyses were identified. Direct physiological consequences are relatively rare; however stalking victims report a poorer physiological health status. Almost every second stalking victim shows impairments on his/her psychical well-being. Impairments of social well-being are common, too. As a result, there is still a lot of research, especially in long-term studies, required. Socio-legal reassessment of stalking will probably benefit only a few of the affected people. PMID- 21594813 TI - [Continuative approaches of social structure for health inequality research- which perspective opens up the concept of living conditions?]. AB - For the last 30 years the appropriateness of social strata concepts has been discussed controversially in Germany. It was hypothesised that changes in the social structure resulting in a greater heterogeneity of social living conditions has decreased the relevance of social strata concepts. However, socio epidemiological research still revealed a strong social gradient, indicating that health risks are still depending on individual social background. Nevertheless, enhanced models of social stratification could be fruitful for socio epidemiological research, particularly with respect to the objective of reducing health inequality. The 'concept of living conditions' is one of the continuative social strata approaches, which is based on a multidimensional concept of social inequality. First use of this concept provided promising results in obtaining a more precise description of health-related living conditions. In this paper, the concept is presented in more detail, spotlighting on questions about conceptual realisation as well as empirical implementation. The paper aims to encourage a wider discussion about the use of these concepts for socio-epidemiological research and medical sociological theory. PMID- 21594814 TI - [Knowledge transfer methods in German disease prevention and health promotion. A survey of experts in the federal prevention research program]. AB - AIM OF THE STUDY: This expert survey analyzed the application and perceived usefulness of knowledge transfer methods for disease prevention and health promotion research. METHODS: 302 experts from 70 administratively distinct projects sponsored under the German federal prevention research program received a questionnaire on transfer methods used for preparation, dissemination and implementation of their project results and the perceived expediency of these methods. 130 experts (43%) from 59 projects (84.3%) responded. 40% were cooperation partners from health care suppliers or practitioners, and 60% worked in research institutions. Descriptive statistics and ANOVA were used for data analysis. RESULTS: The experts had wide range of transfer methods at their disposal. The main implementation barriers were scarce funding and the complexity of disease prevention and health promotion programs. The predominant channels of dissemination were scientific media (congresses, journals) and the Internet. Manuals and handouts were the most common methods of processing of research results for facilitators. Regarding implementation, two-thirds of the projects conducted user training, integrated experts in program development, and co operated with important institutions. Most of the transfer methods implemented were perceived as useful, but some rated as useful were rarely used, e. g. health economics and quality assurance in wide-scale rollout. There were no substantial rating differences between experts from research and user institutions. CONCLUSIONS: In view of the fundaments for the broad application of knowledge transfer technologies laid by prevention scientists, health care suppliers and decision-makers should support the transfer of prevention research, and precendence should be given to evidence-based programs with quality assurance in the implementation stages. Prevention researchers, in turn, should further develop health economics evidence and quality assurance for effective interventions. The rich skills available for knowledge transfer in disease prevention and health promotion can be systematically developed and disseminated in the future. PMID- 21594816 TI - [Decision criteria for the appropriateness of inpatient treatment in patients with peripheral angiopathy]. AB - In various medical subspecialties like angiology, invasive diagnostic procedures and elective therapy, which under certain conditions may be carried out on outpatients, represent a large proportion of all inpatient medical treatment. As regulations for the statutory health insurance in Germany demand that medical procedures should be preferentially carried out in outpatient facilities, there is a high potential for conflicting views with respect to the question whether hospitalisation of an individual patient is mandatory for medical reasons. Explicit criteria may be useful to prevent conflicting views and to increase truth and fairness in the proceedings of hospitals on one hand and the medical service of the statutory health insurance on the other hand. With respect to this problem we present decision criteria which were compiled by a hospital (Hochrhein Eggberg-Klinik Bad Sackingen) and the medical service of the statutory health insurance in the state of Baden-Wurttemberg (MDK-Baden-Wurttemberg). Our model has proven to be of value in our practical experience. It seems to be transferable to medical subspecialties with similar problems. PMID- 21594817 TI - [Creation of a second enterostomy in patients with Crohn's disease and multiple small bowel lesions]. PMID- 21594818 TI - [Ulnar collateral ligament repair of the thumb with a transosseous suture technique: a retrospective analysis]. AB - BACKGROUND: This study analyses the outcome of a transosseous suture fixation for the ulnar collateral ligament (UCL) of the thumb, which is performed completely internally. METHODS: 60 patients with distal rupture of the UCL of the thumb were surgically treated with a transosseous suture technique. Patients with ligament tears surgically treated within 14 days after injury were included in Group 1 (n = 33); patients with delayed surgical treatment (> 14 days after injury) in Group 2 (n = 13). Group 3 (n = 14) contained patients with avulsion fractures. Subjective, functional, and radiological outcomes were evaluated after at least 24 months, and up to an average of 68 months after surgery. Statistical analysis was performed using the Kruskal-Wallis test, Mann-Whitney test, chi-square test, and Wilcoxon test. RESULTS: No significant differences were seen for the disability of the arm, shoulder and hand (DASH) scores among the groups. The average DASH score was 2.4 +/- 3 points in Group 1, 4.6 +/- 9 points in Group 2 and 5 +/- 8 points in Group 3. The visual and verbal pain analogue scales showed significant differences between Groups 1 and 2 at (p = 0.02) and after exertion (p = 0.03). Significant differences were seen for the flexion of the interphalangeal joint in Group 1 (p = 0.004) and the radial abduction of the thumb in Group 3 (p = 0.001), as compared to the contralateral hand. Furthermore, significant differences were obtained for the pinch strength between the thumb and the ring finger in Group 1 (p = 0.03) and 3 (p = 0.04), as well as pinch (p = 0.02) and key strength (p = 0.03) of the little finger in Group 1, again compared to the contralateral hand. Group 3 (p < 0.001) showed significantly more radiological bony alterations at the distal UCL insertion than the other groups. CONCLUSIONS: This study shows good to very good subjective, functional, and radiological results in all three groups. Therefore, we recommend this transosseous suture fixation as an affordable, practicable technique for the treatment of acute rupture of the UCL of the thumb with and without avulsion fractures. PMID- 21594819 TI - Erdheim-Chester disease in a female cardiac surgery patient. AB - We report a case of Erdheim-Chester disease (ECD) with isolated cardiac involvement in a 74-year-old female patient. The patient initially presented with superior vena cava syndrome and PET-CT imaging demonstrating an obstructing hypermetabolic lesion in the right atrium, and a distinct nonobstructing hypermetabolic lesion in the left atrium, expected to be malignant. There was no evidence of extracardiac disease. At surgical exploration, consistent with malignancy, the right atrial tumor was found to have grown into the pericardium and was resected to address symptoms and for histological diagnosis which revealed ECD on immunohistochemistry. We conclude that isolated cardiac ECD should be included in the surgical strategy for cardiac tumors showing infiltrative growth. PMID- 21594820 TI - [Tanorexia - a new lifestyle disease]. PMID- 21594821 TI - [Exposing and then? We need a rational discussion about dealing appropriately with conflicts of interest]. PMID- 21594822 TI - Expression of genes KCNQ1 and HERG encoding potassium ion channels Ikr, Iks in long QT syndrome. AB - BACKGROUND: The KCNQ1 and HERG genes mutations are responsible for specific types of congenital long QT syndrome (LQT). AIM: To examine the expression of KCNQ1 and HERG genes that encode potassium channels (rapid and slow) responsible for the occurrence of particular types of LQT syndrome. The study also attempted to prove that beta-actin is a good endogenous control when determining the expression of the studied genes. METHODS: The study enrolled six families whose members suffered from either LQT1 or LQT2, or were healthy. Examination of gene expression was achieved with quantitative PCR (QRT-PCR). Expression of the investigated genes was inferred from the analysis of the number of mRNA copies per 1 mg total RNA isolated from whole blood. On the basis of KCNQ1 gene expression profile, the presence of, or absence of, LQT1 could be confirmed. RESULTS AND CONCLUSIONS: The study revealed a statistically significant difference (p = 0.031) between the number of KCNQ1 gene copies in patients and healthy controls. On the basis of HERG (KCNH2) gene expression profile, patients with LQT2 cannot be unequivocally differentiated from healthy subjects (p = 0.37). PMID- 21594823 TI - Counting mRNA in blood of LQTS - new direction? PMID- 21594824 TI - Patent ductus arteriosus at low and high altitudes: anatomical and haemodynamic features and their implications for transcatheter closure. AB - BACKGROUND: Living at high altitude increases the prevalence of patent ductus arteriosus (PDA) and may affect its morphology. AIM: To compare the anatomical and haemodynamic features of isolated PDA in patients living at low and high altitudes (1,500-4,200 metres above sea level - m.a.s.l.). METHODS: We studied retrospectively data from 1,404 consecutive patients - 708 living in lowland areas (group L) and 696 in highland areas (group H), in whom transcatheter closure of PDA was attempted. The mean age of the patients in group L was 9.9 +/- 13.5 years and in group H it was 8.2 +/- 19.7 years. RESULTS: The diameter of PDA in group L was 2.3 +/- 1.3 mm and 4.1 +/- 1.2 mm in group H (p < 0.001), while the mean pulmonary artery pressure was 17.9 +/- 5.9 mm Hg and 25.5 +/- 12.3 mm Hg, respectively (p < 0.001). Angiographic PDA type A was more frequently observed in highland patients. In groups L and H, self expanding nitinol occluders (mostly Amplatzer devices) were used in 25.7% vs 92.2% of patients (p < 0.001), whereas coils were used in 69.2% vs 7.5% (p < 0.001), respectively. Double umbrella systems were used in 4.8% of patients in group L. CONCLUSIONS: In catheterised patients with PDA living at high altitude, larger ductal diameter, anatomic type A and higher pulmonary artery pressure were more frequently observed. This finding has important implications for future strategy regarding transcatheter closure in populations living at different altitudes. Kardiol Pol 2011; 69, 5: 431-436. PMID- 21594825 TI - [Stenting of the patent ductus arteriosus]. PMID- 21594826 TI - Clinical course of unoperated mild chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Pulmonary endarterectomy is the treatment of choice for a majority of patients with chronic thromboembolic pulmonary hypertension (CTEPH), however, haemodynamic criteria for the surgery have not been established. It is still unknown whether patients with mild CTEPH should be operated on and what is the clinical course of unoperated, anticoagulated mild CTEPH. AIM: To determine the clinical course in chronically anticoagulated, unoperated patients with mild CTEPH. METHODS: A single-centre, non-randomised, follow-up study involved 10 anticoagulated, unoperated patients (3 males and 7 females aged 46 to 77 years) with mild CTEPH (mean pulmonary artery pressure [MPAP] L 30 mm Hg and pulmonary vascular resistance L 300 dynes x s x cm(-5), >= 2 METs achieved during symptom limited treadmill exercise test) selected from 73 consecutive patients with CTEPH. The 3-year follow up included yearly echocardiographic evaluation of pulmonary artery systolic pressure (PASP), right ventricular end-diastolic diameter (RVEDD) and acceleration time (AcT) as well as NYHA functional class and symptom-limited treadmill exercise test. RESULTS: All the patients survived the 3 year follow-up. The PASP, RVEDD and AcT (mean +/- SD) at baseline and at the end of follow-up were 43.9 +/- 6.1 mm Hg and 25.6 +/- 8.0 mm Hg, p = 0.0017, 25.4 +/- 4.9 mm and 17.8 +/- 3.82 mm, p = 0.00006, 68.3 +/- 10.0 ms and 104.4 +/- 16.48 ms, p = 0.0004, respectively. The NYHA functional class improved from 2.1 +/- 0.32 to 1.3 +/- 0.48, p = 0.002 and was accompanied by the trend to improve results of exercise test. CONCLUSIONS: The results of the study suggest that patients with mild CTEPH can be treated successfully by anticoagulation alone with excellent 3-year survival rate, improved functional status and with gradual decrease of pulmonary pressure and right ventricular overload. PMID- 21594827 TI - [Things are not as bad as they seen]. PMID- 21594828 TI - Percutaneous transvenous mitral commissurotomy: with or without heparin? A randomised double blind study. AB - BACKGROUND: Percutaneous transvenous mitral commissurotomy (PTMC) is an alternative approach to open heart surgery in patients with symptomatic mitral stenosis (MS). AIM: To compare the outcome of performing PTMC with or without heparin administration. METHODS: In this randomised clinical trial, 480 patients with symptomatic MS were randomly allocated to one of two groups, with or without heparin administration as part of the procedure. Echocardiographic and clinical outcomes of PTMC assessed before the procedure, during hospitalisation, and after the one-month follow-up, were compared between the two groups. RESULTS: Baseline demographic and clinical characteristics were similar in the 240 patients with heparin administration (the Hep [+] group) and the 240 patients without heparin administration (the Hep [-] group) during the procedure. In the whole study group mitral valve area (MVA) was 0.94 +/- 0.03 cm(2) prior to PTMC, and increased to 1.85 +/- 0.06 cm(2) after the procedure (p = 0.0001). The mean increase in MVA was 0.85 +/- 0.27 cm(2) in the Hep (+) group and 0.88 +/- 0.2 cm(2) in the Hep ( ) group (NS). During the procedure, or immediately after PTMC, embolic events were recorded in two (0.83%) Hep (+) patients and one (0.42%) Hep (-) patient (NS). The frequency of haematoma at puncture site (three [1.25%] Hep [+] vs two [0.83%] Hep [-]), and the need for urgent surgery (two [0.83%] Hep [+] vs five [2.1%] Hep [-]), were similar in both groups. There were no embolic events after discharge or during the one month follow-up period. CONCLUSIONS: Our study revealed that in high volume centres and in selected patients without left atrial thrombus, heparin administration during PTMC is not associated with any additional protective effect against embolic events during short-term follow-up. PMID- 21594829 TI - [Percutaneous transvenous mitral commissurotomy-what perspective?]. PMID- 21594830 TI - Predictors of infarct-related artery patency following combined lytic therapy in patients with ST-segment elevation myocardial infarction treated with immediate percutaneous coronary intervention. AB - BACKGROUND AND AIM: Patency of infarct-related artery (IRA) before percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is associated with better outcomes. Little is known of the clinical or angiographic predictors of IRA recanalisation after administration of combined fibrinolytic therapy before PCI. METHODS: A total of 225 STEMI patients, admitted to remote hospitals with anticipated transfer time to cathlab > 90 min were enrolled. All patients received a half dose of alteplase and a full dose of abciximab at the remote hospital and were immediately transferred for angiography. In angiographic analysis, the culprit lesion (CL) was defined as the minimal lumen diameter (MLD) point in IRA (CLMLD) (in group with occluded IRA, measurement was done after the first pass of the guidewire). RESULTS: Occluded IRA (TIMI 0+1) was found in 14.2% of patients (n = 32) and patent IRA (TIMI 2+3) in 85.8% (n = 193) at baseline angiography. Baseline and angiographic characteristics were similar in both groups, except for a higher rate of smoking in the TIMI 2+3 group (73.1% vs 50%; p = 0.009) and longer distance from CLMLD point to the nearest proximal side branch in the TIMI 0+1 group (21.2 +/- 10.3 mm vs 13.8 +/- 11.2 mm; p = 0.002). In multivariate analysis, smoking and distance from CLMLD to the nearest proximal side branch were independent predictors of IRA patency at baseline. CONCLUSIONS: Angiographic (anatomical) IRA parameter as distance from CLMLD point to nearest proximal side branch may influence the efficacy of combined fibrinolytic therapy before PCI despite the similar clinical characteristics and time delay to angiography. Smoking has a paradoxical beneficial effect on combined thrombolytic therapy effectiveness. PMID- 21594831 TI - [Optimal pharmacotherapy of myocardial infraction before percutaneous coronary intervention-current (un)knowledge]. PMID- 21594832 TI - Prospective randomised pilOt study evaLuating the safety and efficacy of hybrid revascularisation in MultI-vessel coronary artery DisEaSe (POLMIDES) - study design. AB - BACKGROUND: Hybrid coronary artery revascularisation (HCR) is a combination of minimally invasive left internal mammary artery bypass grafting to the left anterior descending artery (LAD) and percutaneous coronary interventions (PCI) with drug eluting stent implantation to other coronary arteries. Due to the paucity of data from large, prospective randomised trials comparing HCR to standard surgical revascularisation, the POLMIDES study has been designed to assess the safety and efficacy of HCR in patients with multivessel coronary artery disease (CAD) referred for standard coronary artery bypass grafting (CABG). AIM: The primary objective is evaluating the feasibility and safety of HCR. METHODS: Feasibility has been defined by means of the percentage of patients with a complete hybrid procedure according to the study protocol and a percentage of conversion to standard CABG. Safety has been defined as the occurrence of major adverse cardiac events such as death, myocardial infarction, stroke, repeat revascularisation and major bleeding within the 12 month period after randomisation. All consecutive patients with angiographically confirmed multivessel CAD involving LAD and a critical (> 70%) lesion in at least one major epicardial vessel (except LAD) amenable to both PCI and CABG referred for conventional surgical revascularisation, will be randomised in a 1:1 fashion for HCR or standard surgical revascularisation. CONCLUSIONS: The POLMIDES is a prospective, randomised pilot trial designed to determine whether HCR in patients with multivessel CAD referred for conventional CABG is safe, feasible and efficacious (ClinicalTrials.gov number, NCT01035567). Kardiol Pol 2011; 69, 5: 460-466. PMID- 21594833 TI - [Few words of interventional cardiologist about POLMIDES clinical research protocol]. PMID- 21594834 TI - [Mechanical valve replacement in tricuspid (systemic) position in a patient with corrected transposition of the great arteries]. AB - The authors report a case of a 55 year-old male with corrected transposition of the great arteries and severe tricuspid (systemic) regurgitation treated with anatomical mechanical tricuspid valve replacement. PMID- 21594835 TI - [Arrhythmogenic right ventricular cardiomyopathy with left ventricular involvement mimicking acute coronary syndrome - two case reports]. AB - We describe 2 patients with arrhythmogenic right ventricular cardiomyopathy (ARVD): 58 year-old female and 48 year-old man. Both patients presented with echocardiographic features typical for ARVD and impaired systolic left ventricular function. Both patients had symptoms resembling acute coronary syndrome and received cardioverter-defibrillator due to recurrent sustained ventricular tachycardia. PMID- 21594836 TI - [Recurrent syncope in a male patient with bicuspid aortic valve]. AB - We present a case of a 31 year-old male patient with a congenital heart disease - bicuspid aortic valve with secondary aortic valve insufficiency, in whom recurrent syncope associated with episodes of complete atrioventricular block was observed. After implantation of a pacemaker syncope did not reccur. Due to risk of complications with bicuspid aortic valve it was decided that surgical treatment should be considered in this case. PMID- 21594838 TI - [Delirium in cardiac surgery patients - a multi-disciplinary approach]. AB - We describe a case of a 86 year-old male who underwent urgent cardiac surgery and developed post-operative delirium. The treatment and prevention of this condition are discussed. PMID- 21594839 TI - [Cardiac tamponade as the initial symptom of lung cancer]. AB - We report a case of a 55 year-old woman in whom cardiac tamponade was first symptom of lung cancer. The pericardium is involved in about 12% of patients with malignant disease. Cardiac tamponade is life-threatening situation. In our case diagnosis was made on clinical symptoms and echocardiography. Only urgent pericardiocentesis performed under echocardiograhic guidance can save patient's life. In described case final diagnosis was made on histological examination. We should take into the consideration lung cancer in differentiation causes of cardiac tamponade. PMID- 21594841 TI - Contemporary trans-catheter treatment of severe aortic stenosis. PMID- 21594842 TI - [Amiodarone and thyroid function]. PMID- 21594843 TI - [Electrocardiogram of the patient after Fontan operation]. PMID- 21594845 TI - Diagnosis and treatment of lead-dependent infective endocarditis. AB - We report a typical case of lead-dependent infective endocarditis in an 84 year old patient, occurring two years after pacemaker implantation. Before the correct diagnosis was reached, the patient was repeatedly hospitalised in several centres due to fever of unknown origin. Eventually, the diagnosis was confirmed when the patient was referred for transoesophageal echocardiography by a consulting cardiologist from the pacemaker implantation centre. The successful treatment included the removal of the whole pacing system with endocardial leads and adequate antibiotic therapy. PMID- 21594846 TI - Left main coronary artery arising from right sinus of Valsalva: a rare congenital anomaly associated with distal vasospasm. AB - A 50 year-old female patient was admitted to our outpatient clinic with a two year history of chest pain and dyspnoea on exertion. Echocardiography revealed apical hypokinesia with an ejection fraction of 50% on the left ventricle. Coronary angiography revealed that the left main coronary artery was arising from the right sinus of Valsalva and than coursing posterior to the aorta. There were significant stenoses at the proximal right coronary artery (RCA) and the proximal left anterior descending coronary artery (LAD). The RCA lesion disappeared after intracoronary nitroglycerine administration, and the LAD lesion disappeared the next day when the patient was due to undergo percutaneous intervention. Stress myocardial perfusion scintigraphy revealed anteroseptal ischaemia consistent with reversible ischaemia. PMID- 21594848 TI - Tako-tsubo cardiomyopathy following complete atrioventricular nodal heart block during transcatheter radiofrequency ablation of atrioventricular nodal reentrant tachycardia. AB - We report a case of tako-tsubo cardiomyopathy after an unintentional atrioventricular (AV) block during an ablation procedure in a 77 year-old woman. This intriguing case explores three possible reasons that could have triggered the disease: (1) slow pathway destruction; (2) AV nodal complete heart block; (3) the overall stress the patient had experienced. PMID- 21594849 TI - [Summary of the article: Matchar B, Jacobson DB, Dolor R et al. Effect of home testing of international normalized ratio on clinical events. N Engl J Med, 2010; 363: 1608-1620]. PMID- 21594850 TI - [INR measurement at home-Polish perspective]. PMID- 21594851 TI - [Hybrid ablation of the left atrium on beating-heart - initial experience]. PMID- 21594853 TI - [Effect of sildenafil on haemodynamic parameters of pulmonary circulation and physical capacity in patients with systolic chronic heart failure with secondary severe pulmonary hypertension]. PMID- 21594854 TI - [Recommendations of National Team of Cardiologic and Oncologic Supervision on cardiologic safety of patients with breast cancer. The prevention and treatment of cardiovascular complications in breast cancer. The Task Force of National Consultants in Cardiology and Clinical Oncology for the elaboration of recommendations of cardiologic proceeding with patients with breast cancer]. PMID- 21594855 TI - [Panayiotopoulos syndrome: academic difficulties and behavioural disorders]. AB - INTRODUCTION: Panayiotopoulos syndrome (PS) is one of the benign epilepsies found in childhood. Some papers have shown that patients can present behavioural disorders and learning difficulties. AIMS: To review patients diagnosed with PS in our hospital and to check whether they display evidence of such disorders and if there is any specific feature that allows high-risk patients to be identified. PATIENTS AND METHODS: A retrospective review of the medical records of patients diagnosed with PS was carried out. An electroencephalogram (EEG) or video-EEG polygraph recordings were performed on all patients during sleep. The Weschler Intelligence Scale for Children was used to evaluate intelligence. RESULTS: Data were collected for 33 patients, 17 of whom were children. The mean age at onset was 3.2 years and the follow-up was 4.9 years (range: 1-12 years). Irritative EEG phenomena were detected in the occipital (67.7%), temporal (45.2%) or parietal regions (22.5%) in 31 patients. Furthermore, 72.7% of patients presented more than two seizures. Twenty-three patients required treatment with antiepileptic drugs. Two patients were diagnosed with attention deficit hyperactivity disorder. Additionally, 30.3% reported dispersed attention and 27.3% had an impulsive character. It was found that 51.1% had a good level of academic achievement, in 26.5% it was regular and in 17.6% poor. A total of 39.4% needed assistance in the form of after-school classes. The level of intelligence was evaluated in 11 patients. CONCLUSION: PS is a condition with a good prognosis, but seems to be associated to learning and behavioural disorders. PMID- 21594856 TI - [The use of bibliographic information resources and Web 2.0 by neuropaediatricians]. AB - AIM: To determine the state of knowledge and use of the main sources of bibliographic information and Web 2.0 resources in a sample of pediatricians linked professionally to child neurology. SUBJECTS AND METHODS: Anonymous opinion survey to 44 pediatricians (36 neuropediatric staffs and 8 residents) with two sections: sources of bibliographic information: (25 questions) and Web 2.0 resources (14 questions). RESULTS: The most consulted journals are Revista de Neurologia and Anales de Pediatria. All use PubMed database and less frequently Indice Medico Espanol (40%) and Embase (27%); less than 20% use of other international and national databases. 81% of respondents used the Cochrane Library, and less frequently other sources of evidence-based medicine: Tripdatabase (39%), National Guideline Clearinghouse (37%), Excelencia Clinica (12%) and Sumsearch (3%). 45% regularly receive some e-TOC (electronic table of contents) of biomedical journals, but only 7% reported having used the RSS (really system syndication). The places to start searching for information are PubMed (55%) and Google (23%). The four resources most used of Web 2.0 are YouTube (73%), Facebook (43%), Picasa (27%) and blogs (25%). We don't found differences in response between the group of minus or equal to 34 and major or equal to 35 years. CONCLUSIONS: Knowledge of the patterns of use of information databases and Web 2.0 resources can identify the limitations and opportunities for improvement in the field of pediatric neurology training and information. PMID- 21594857 TI - [Genotype-phenotype discordance in a Duchenne muscular dystrophy patient due to a novel mutation: insights into the shock absorber function of dystrophin]. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) is a genomic disorder characterized by progressive muscle wasting and weakness due to the absence or abnormal function of dystrophin; a protein that protects muscle cells from mechanical induced stress during contraction. Mutations in the DMD gene, may lead to different clinical phenotypes, collectively known as dystrophinopathies, of which DMD has the earliest onset and most severe progression. CASE REPORT: We report a novel deletion of exons 24-41, predicted to maintain the reading frame and expected to result in a mild phenotype. Conversely, the patient has a severe DMD phenotype. CONCLUSIONS: Our report supports the hypothesis that disruption of the gamma-actin-binding site located in the central rod domain plays a crucial role in the shock absorber function of dystrophin in muscle cells. Description of pathogenic variants in the DMD gene and the resulting phenotypes has important implications on the designing of molecular therapeutic approaches for DMD. PMID- 21594858 TI - [Relation between white matter and cognitive functions]. AB - INTRODUCTION: After being largely neglected as a contributor to the organisation of the cognitive operations for many years, the white matter of the brain is now again the object of much research. These advances are complemented with the latest neuroimaging techniques, such as diffusion tensor imaging, which make it possible to obtain a more detailed view of the role played by the pathways of the white matter in the cognitive operations. DEVELOPMENT: The study reviews the relation between lesions in the white matter and different cognitive processes and functions such as language, attention, visuospatial and visual-constructional skills, spatial negligence, processing speed, memory and executive functions. CONCLUSIONS: Focusing attention on the white matter and its disorders promises to further our knowledge of the brain as an extraordinarily complex organ in which the connectivity and processing speed provided by the white matter are key features in cognition, emotion and consciousness itself. The white matter does not appear to be the deposit for cognitive processes and functions, but rather its role would seem to be linked to two properties that are essential for a highly complex system like the brain to be effective: speed and connectivity. Further studies must be conducted to delve deeper into these processes and perhaps begin to clarify the different roles they play in the outcome of cognitive processes. PMID- 21594860 TI - [A new cause of structural vertigo: superior semicircular canal dehiscence]. AB - The medical history of vertigo must be updated to accommodate current knowledge. In 1998 a new cause of vertigo associated with a structural anomaly was reported: superior semicircular canal dehiscence. This condition causes vestibular and auditory disorders, which are frequently associated, and a well-directed medical history allows a suspected diagnosis to be reached: the subject may suffer from vertigo triggered by loud sounds (Tullio's phenomenon) and by changes in pressure within the ear or in the intracranial space, when Valsalva's manoeuvres are performed or on pressing on the tragus (Hennebert's sign). It is not uncommon for subjects to suffer from a chronic imbalance that is exacerbated by the aforementioned precipitating factors. One frequent auditory symptom of superior semicircular canal dehiscence is autophony in the dehiscent ear, associated with hypoacusis of its transmission. This article outlines the questions that must be included in the medical history of vertigo in order to determine whether these dehiscences are present or not. The diagnostic procedures that are best suited to confirming it are also addressed. Superior semicircular canal dehiscence can be resolved satisfactorily by surgery. PMID- 21594859 TI - [Glial stem cells and their relationship with tumour angiogenesis process]. AB - INTRODUCTION: A subpopulation of neoplastic cells with characteristics of stem cells has been described on human multiform glioblastomas. These cells play a pivotal role in tumour angiogenesis and malignancy being involved in infiltration of adjacent normal parenchyma. The named glial stem cells could be responsible for recurrences after surgery. This is due to their survival capacity after quimio/radiotherapy treatments. DEVELOPMENT: In this work we review the role of glial stem cells in relationship with angiogenesis process. We also review some findings related to the appearance of these cells during angiogenesis in a rat endogenous experimental model of gliomas. These cells were characterized by antibodies against the antigens CD133, nestin and the vascular endothelial growth factor (VEGF). Nestin+ cells were found in every stage of tumour development, whereas CD133+ cells were only present since intermediates stages corresponding with VEGF overexpression. This moment is known as start of angiogenesis or 'angiogenic switch'. We also found that some nestin+ cells co-expressed CD133 antigen. Glial stem cells are distributed in the experimental glioma model as well as in human multiform glioblastomas, shaping niches into perivascular or intra-tumoral hypoxic areas. CONCLUSION: Many evidences corroborate the hypothesis that glial stem cells have a close relationship with angiogenic switch, intratumor hypoxia and neoplastic microvascular network. PMID- 21594861 TI - [Change in the pattern of pain in a patient with migraine]. PMID- 21594863 TI - [Syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis associated to papilloedema]. PMID- 21594869 TI - Warmth from skin-to-skin contact with mother is essential for the acquisition of filial huddling preference in preweanling rats. AB - During a single, 2-hr session with a scented foster dam, preweanling rat pups form an affiliative attraction to an odor associated with the maternal caregiver, manifest as a huddling preference. To identify maternal stimuli that induce this filial preference, we quantitatively examined behavioral interactions during odor conditioning. Bout duration of skin-to-skin (STS) contact was positively associated with the preference. In contrast, simple physical contact and anogenital licking were not significantly related to the preference. The frequency of nonanogenital licking was negatively associated with the preference as well as with bout duration of STS contact. When odor conditioning was conducted with a warm cylinder, ambient warmth, or stroking as the unconditioned stimulus, only pups exposed to the warm cylinder exhibited a preference for the conditioned odor. These results suggest a positive, affiliative effect of maternal STS contact on pup filial preference, which may be disrupted by maternal licking. PMID- 21594870 TI - Organizational effects of oxytocin on serotonin innervation. AB - Oxytocin (OT) has an organizational effect within the central nervous system and can have long-lasting effects on the expression of social behavior. OT has recently been implicated in modulating the release of serotonin through activation of receptors in the raphe nuclei. Here we test the hypothesis that OT can have an organizational effect on the serotonergic system. Male prairie voles received an intraperitoneal injection on postnatal day 1 with 3.0 or .3 ug OT, an OT antagonist, or a saline control. Brains were collected on day 21 and immunostained for serotonin. Serotonin axons were quantified in the anterior hypothalamus, cortical amygdala, medial amygdala, paraventricular nucleus of the hypothalamus, and ventromedial hypothalamus. Males treated with 3.0 ug OT displayed significantly higher serotonin axon length densities in the anterior hypothalamus, cortical amygdala, and the ventromedial hypothalamus than control males. These results support the hypothesis that OT has an organizational effect on the serotonin system during the neonatal period, and that these effects are site-specific. PMID- 21594872 TI - Activation and deactivation in response to visual stimulation in the occipital cortex of 6-month-old human infants. AB - In an infant's developing cortex, the explanation for the mechanisms underlying the activations and deactivations in response to visual stimuli remains controversial. While previous near-infrared spectroscopy (NIRS) studies in awake infants have demonstrated cortical activations in response to meaningful/attractive visual stimuli, functional magnetic resonance imaging (fMRI) studies performed on sleeping infants showed negative blood oxygenation level-dependent (BOLD) responses to high-luminance unpatterned stimulations, such as a photic stimulation. To examine the effect of the characteristics of visual stimuli on cortical processing in awake infants, we measured cortical hemodynamic responses in 6-month-old infants during the presentation of a high-luminance unpatterned stimulus by using a NIRS system with 94 measurement channels. Results from 35 infants showed dissociated cortical responses between the occipital region and the other parts of the cortex, including the temporal and prefrontal regions. Although the visual stimulus produced sustained increases in oxygenated hemoglobin (oxy-Hb) signals in the temporal and prefrontal regions, it produced a transient increase in oxy-Hb signals followed by a salient decrease in oxy-Hb signals during a trial in a focal region of the occipital visual region. This suggests that the deactivation of the occipital visual region in response to visual stimulation is not a phenomenon that occurs only in the sleeping state, but that a high-luminance unpatterned stimulus can induce deactivation even in the awake infants. PMID- 21594871 TI - Ethanol-mediated appetitive conditioning in infant rats, but not corticosterone release, is dependent on route of ethanol administration. AB - A recent study found appetitive reinforcement in infant rats given 1.0 but not 2.0 g/kg ethanol and only when ethanol was delivered intragastrically (i.g., but not if intraperitoneally, i.p.; Nizhnikov, Pautassi, Truxell, & Spear [2009] Alcohol 43, 347-358). Corticosterone release could modulate ethanol's motivational effects. The goal of this study was to replicate the differential capability of i.g. vs. i.p. ethanol to induce conditioning and to find hormonal correlates underlying this phenomenon. Experiment 1 confirmed that 1.0 g/kg ethanol induced conditioned preference in infant rats when given i.g. but not i.p. In Experiment 2 corticosterone was assessed at 20, 40, 60, or 120 min after ethanol (0.0, 0.5, 1.0, and 2.0 g/kg, i.g. or i.p.). Route of administration failed to alter corticosterone release. The 2.0 g/kg, but not 0.5 or 1.0 g/kg, ethanol dose evoked heightened corticosterone release. The results confirm the differing motivational effects associated with i.g. and i.p. ethanol. These effects do not seem to be related to differential corticosterone responsiveness. PMID- 21594873 TI - State diagram of salmon (Salmo salar) gelatin films. AB - BACKGROUND: A state diagram presents different physical states of a biomaterial as a function of solid content and temperature. Despite their technological interest, little information is available on protein systems such as gelatin/water mixtures. The objective of this work was to develop state diagrams of salmon gelatin (SG) and bovine gelatin (BG) in order to determine maximal freeze concentration parameters (T'(g) , T'(m) and X(s') ) and to relate possible differences to their biochemical characteristics. RESULTS: Biochemical characterisation of SG showed lower molecular weight and iminoacid concentration compared with BG. Likewise, the glass transition temperature (T(g) ) was lower for SG at X(s) > 0.8, which was associated with its lower molecular weight. Unexpectedly, the depression of freezing temperature (T(f) ) was greater for SG at X(s) > 0.1, which was associated with its higher ash content. Isothermal annealing produced effective values of T'(g) ~ - 52 degrees C, T'(m) ~ - 46 degrees C and X'(s) ~ 0.6 for both gelatins. Interestingly, the enthalpy change associated with T'(m) (DeltaH T m) was significantly higher for SG than for BG after annealing, indicating a higher proportion of ice present at about - 50 degrees C. CONCLUSION: Maximal freeze concentration parameters were similar between the two gelatins, though differences in biochemical properties were evident. The results show that there are likely different ways of interaction of SG and BG with water. PMID- 21594874 TI - Shrimp shell peptide hydrolysates inhibit human cancer cell proliferation. AB - BACKGROUND: Shrimp wastes contain high-quality protein that is underutilized, and particularly peptides derived from shrimp wastes (normally used as animal feed) have not been utilized for bioactive properties. Hence the objective was to utilize shrimp waste proteins in generating peptides and to investigate these for cancer antiproliferative activities. The objectives involved hydrolyzing shrimp proteins (intact in shell) using a food-grade Cryotin enzyme, obtaining gastrointestinal resistant peptides, fractionation to generate < 10, 10-30 and > 30 kDa fractions, and evaluating for colon and liver cancer cell growth inhibitory effects. Three shrimp shells--whole langostino lobster shells from El Salvador (South America), shrimp shells from St Petersburg, FL (USA), and shrimp shell whites from the Gulf of Mexico, LA (USA)--were evaluated for the study. RESULTS: Peptide fractions (<10 and 10-30 kDa) obtained from shrimp shell whites (Gulf of Mexico) as well as from langostino shells (El Salvador) significantly inhibited the growth of both colon and liver cancer cells by 60%, while < 10 kDa fraction from shrimp shells (FL) inhibited growth of liver cancer cells alone by 55%, compared to controls. CONCLUSION: The promising anticancer peptide fractions from shrimp waste proteins has the potential for novel nutraceutical ingredient applications. PMID- 21594875 TI - Manubrial resection and anterior mediastinal tracheostomy: friend or Foe? AB - OBJECTIVES/HYPOTHESIS: To review our experience with manubrial resection and anterior mediastinal tracheostomy and formulate operative guidelines to improve the surgical outcome. STUDY DESIGN: Retrospective study. METHODS: Between January 1980 and June 2010, we performed 38 manubrial resections. The indications of the procedure, reconstructive methods, and operative outcomes were analyzed. RESULTS: Fourteen patients had tumors of the hypopharynx/cervical esophagus, eight had parastomal recurrences of laryngeal tumor, four had recurrent esophageal tumors, four had postirradiation sarcoma, four suffered from subglottic/upper tracheal tumors, three had thyroid malignancy, and the remaining patient had tumor recurrence at the previous tracheostomy site. The hospital mortality rate was 5.3% due to bleeding from major vessel erosion. The mean length of the tracheal stump was 5.4 cm, of which 81.6% required relocation inferior to the innominate artery for construction of the mediastinal tracheostomy. Among the different reconstructive methods for the pharyngoesophageal defects, the anastomotic leakage rate was 17.6%, the majority of which required exteriorization followed by second stage reconstruction. The long-term tracheostomy stenosis rate was 47.4%, the risk of which was significantly increased by anastomotic leakage and necrosis of distal trachea. The use of a pectoralis major flap was shown to protect against this complication. The overall survival was 80.6% at 1 year and 55.6% at 5 years after surgery. CONCLUSIONS: With attention to operative details, manubrial resection and anterior mediastinal tracheostomy is a safe procedure with acceptable outcome. It should be performed when indicated to facilitate tumor resection in the cervicothoracic region. PMID- 21594876 TI - Determination of ipriflavone in human plasma by LC-MS and its application in a pharmacokinetic study. AB - A sensitive liquid chromatography-mass spectrometric method was developed for the quantification of ipriflavone in human plasma. The method utilized liquid-liquid extraction of plasma with ethyl acetate. A gradient elution was performed on a Hedera ODS-2 column (150*2.1 mm i.d., 5 um), using a mobile phase consisting of 0.1% formic acid solution and methanol at a flow rate of 0.5 mL/min. The single quadrupole mass spectrometer was operated in selected-ion monitoring mode via positive electrospray ionization interface detecting m/z 239.1 and 285.1 for ipriflavone and diazepam (the internal standard), respectively. To improve the selectivity and sensitivity, the fragment ion m/z 239.1, which was produced by in source collision-induced dissociation, was chosen as the quantitative ion for ipriflavone. The method was fully validated and applied to a pharmacokinetic study of ipriflavone. After oral administration of a single 200 mg ipriflavone tablet, the C(max,) AUC(0-72 h) , t(1/2) and T(max) were 6.3+/-6.3 ng/mL, 80.0+/ 69.1 ug h/L, 23.0+/-8.6 h and 3.4+/-2.1 h, respectively. PMID- 21594877 TI - Detection and identification of diterpenoid alkaloids, isoflavonoids and saponins in Qifu decoction and rat plasma by liquid chromatography-time-of-flight mass spectrometry. AB - A liquid chromatography-time-of-flight mass spectrometric (LC-TOFMS) method has been developed for analysis of components in Qifu decoction (QFD), a traditional Chinese medical formula consisting of Radix Astragali and Acontium carmichaeli, and in rat plasma after oral administration. Based on accurate mass measurements within 3 ppm error for each molecular ion and subsequent fragment ions of TOFMS, as well as matching of empirical molecular formulae with those of published components in the in-house chemical library, a total of 44 major components including 21 diterpenoid alkaloids, 12 flavonoids and 11 saponins were identified in QFD. After oral administration of QFD, 22 components in rat plasma were detected and identified by comparing and contrasting the constituents measured in QFD with those in the plasma samples. The results provided valuable chemical information for further pharmacology and active mechanism research on QFD. LC TOFMS was also applied for the comparison of relative peak area of major active components between QFD and the single herb extracts. The concentration ratios of major saponins detected in the crude herb Radix Astragali were found to be different from those in QFD. The experimental data indicated that the decocting process could result in differences in the amounts of active components. PMID- 21594878 TI - Determination of memantine in rat plasma by HPLC-fluorescence method and its application to study of the pharmacokinetic interaction between memantine and methazolamide. AB - A sensitive high-performance liquid chromatographic method with fluorescence detection was developed to determine memantine (MT) in rat plasma. The method consists of pre-column labeling of MT with 4-(4,5-diphenyl-1H-imidazol-2 yl)benzoyl chloride (DIB-Cl) and a clean-up step with solid-phase extraction. A good separation of DIB-MT was achieved within 12 min on an octadecylsilica (ODS) column (150 * 4.6 mm i.d.; 5 um) with a mobile phase of acetonitrile-water (70:30, v/v). The calibration curve prepared with fluoxetine as an internal standard showed good linearity in the range of 10-400 ng/mL (r = .999). The limits of detection and quantitation at signal-to-noise ratios of 3 and 10 were 2.0 and 6.6 ng/mL, respectively. The method was shown to be reliable with precisions of <5% for intra-day and <9% for inter-day as relative standard deviation. The fluorescence property and reaction yield of authentic DIB-MT were also examined. The proposed method was successfully applied to study the pharmacokinetic interaction between MT and methazolamide. PMID- 21594879 TI - Determination of daumone in mouse plasma by HPLC/MS-MS. AB - Daumone, a pheromone secreted by Caenorhabditis elegans, is an essential regulator of chemosensory processes in development and aging. A quantification method using HPLC/MS-MS was developed for the determination of daumone in mouse plasma. After simple protein precipitation with acetonitrile including methaqualone (an internal standard), the analytes were chromatographed on a reversed-phase column and detected by liquid chromatography/tandem mass spectrometry with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for validation of bioanalytical methods. This method was applied to measure the plasma daumone concentrations following a 5-week repeated oral administration of daumone in mice. PMID- 21594880 TI - Highly sensitive method for the determination of JI-101, a multi-kinase inhibitor in human plasma and urine by LC-MS/MS-ESI: method validation and application to a clinical pharmacokinetic study. AB - A highly sensitive, rapid assay method has been developed and validated for the estimation of JI-101 in human plasma and urine using LC-MS/MS-ESI in the positive ion mode. The assay procedure involves extraction of JI-101 and alfuzosin (internal standard, IS) from human plasma/urine with a solid-phase extraction process. Chromatographic resolution was achieved on two Zorbax SB-C(18) columns connected in series with a PEEK coupler using an isocratic mobile phase comprising acetonitrile-0.1% formic acid in water (70:30, v/v). The total run time was 2.0 min. The MS/MS ion transitions monitored were 466.20 -> 265.10 for JI-101 and 390.40 -> 156.10 for IS. The method was subjected to rigorous validation procedures to cover the following: selectivity, sensitivity, matrix effect, recovery, precision, accuracy, stability and dilution effect. In both matrices the lower limit of quantitation was 10.0 ng/mL and the linearity range extended from ~10.0 to 1508 ng/mL in plasma or urine. The intra- and inter-day precisions were in the ranges 1.57-14.5 and 6.02-12.4% in plasma and 0.97-15.7 and 8.66-10.2% in urine. This method has been successfully applied for the characterization of JI-101 pharmacokinetics in cancer patients. PMID- 21594881 TI - Construction of a light-emitting diode fluorescence detector for high-performance liquid chromatography and its application to fluorometric determination of L-3 hydroxybutyrate. AB - This study employed a new light source, a light-emitting diode (LED), for fluorescence detection of high-performance liquid chromatography to measure the concentration of trace constituents in biological fluids. Using l-3 hydroxybutyrate ( l-3HB) as a tested trace compound, the function of the new system was compared with that of the current commercially available model. A detailed schematic diagram of the path of the detection rays in the LED detector is given. A voltage-stabilizer for the drive circuit was designed with an input of 10 V and an output of 8 V, and another voltage regulator was used to maintain a constant 8 V. Then the regulator was used to set the output voltage for the LED at 2.8 V by two external resistors. Replacing the xenon lamp with LED, this system provided higher photon density and a narrow spectrum at a wavelength of 491 nm. At room temperature (22.1 degrees C), the average temperature of six places in the chamber of LED detector was 22.1 degrees C compared with 51.1 degrees C in the xenon detector. The spectra of the excitation light sources were measured. Compared with the xenon lamp, approximately 1.32 times higher excitation intensity was obtained by the LED source. The accuracy of detection of l-3HB in 50 MUL of rat serum was 99.85-100.85%, and the intra-day and inter-day precision values were within 8.99 and 13.90%, respectively. The limit of detection of l-3HB was approximately 0.73 uM (signal-to-noise ratio 3). The sensitivity of the proposed LED detector was comparable to that of traditional fluorescence detectors using xenon arc lamps; however, the cost and operating temperature of LED lamps were far lower. This assay system could be further used to detect trace constituents in various samples. PMID- 21594882 TI - Increased high-sensitivity C-reactive protein predicts a high risk of lower urinary tract symptoms in Chinese male: Results from the Fangchenggang Area Male Health and Examination Survey. AB - BACKGROUND: Reports have shown that increased serum C-reactive protein (CRP) suggests a risk of lower urinary tract symptoms (LUTS) in the West population. However, few studies have investigated the role of CRP as regards LUTS in a Chinese male population. METHODS: Data were collected from 1,452 men who participated in the population-based Fangchenggang Area Male Health and Examination Survey (FAMHES), which was carried out in Guangxi, China, from September 2009 to December 2009. In the current study, serum CRP was measured with a high-sensitivity method (hsCRP) and LUTS was assessed by International Prostate Symptom Score (IPSS). Meanwhile, information about potential confounding variables (smoking, hypertension, diabetes, etc.) were included. RESULTS: We observed that statistically significant distinction presented in the distribution of hsCRP levels and age between LUTS group and non-LUTS group (P < 0.001). Comparing with the lowest hsCRP tertile, men with the highest hsCRP tertile were 1.72 times more likely to have overall LUTS and 1.93 times more likely to have irritative symptoms. As for individual symptoms of LUTS, statistically significant correlations were noted between serum hsCRP levels and urgency (OR = 1.74, 95% CI = 1.09-2.78) and nocturia (OR = 1.64, 95% CI = 1.18-2.27), when comparing them from the 1st to 3rd hsCRP tertiles. After multivariate adjusted, the results changed slightly and were still significant. CONCLUSIONS: In a Chinese male population, we firstly confirmed a positive correlation of serum hsCRP with LUTS. It can be inferred that inflammation may be involved in the processes of LUTS. PMID- 21594884 TI - What we are not talking about: an evaluation of prevention messaging in print media reporting on agricultural injuries and fatalities. AB - BACKGROUND: Agricultural injury and fatality pose a significant burden on farmers, families, health care systems, and economies. One way of increasing knowledge of this problem and promoting prevention is the use of printed mass media such as newspapers. METHODS: We conducted a scan of all media reports contained in the Canadian Agricultural Safety Association (CASA) archives for the period January, 2007 to September, 2009, inclusive, for injury and fatality and analyzed newspaper articles for prevention messages. RESULTS: Of the 409 articles in the database, 392 met the inclusion criteria. Ninety-three of the articles (24%) contained a prevention message, and 39 (10%) of these were considered to be strong. Urban papers were two times more likely to have a safety message (OR = 2.03) while adult-related events were less likely to have a safety message included (OR = 0.49). CONCLUSION: Print media reporting of agricultural injury and fatality represents a missed opportunity to provide a prevention message. More can be done to improve linkages between news media outlets and injury prevention specialists to improve prevention content in newsprint. PMID- 21594883 TI - The role of Pax2 in mouse prostate development. AB - BACKGROUND: Loss-of-function of Pax2 results in severe defects of the male reproductive system, and Pax2 expression is detected in mouse prostate lobes and human prostatic cancers. However, the role for Pax2 in prostate development remains poorly understood. METHODS: The expression of Pax2 was examined by in situ hybridization at various developmental stages. Urogenital sinuses were dissected out at E18.5 from mouse Pax2 mutants and controls, cultured in vitro or grafted under the renal capsule of CD1 nude mice. The expression of prostate developmental regulatory factors was analyzed by semi-quantitative real-time PCR or immuohistochemistry. RESULTS: Pax2 is expressed in the epithelial cells of prostate buds. Loss-of-function of Pax2 does not affect the initiation of prostatic buds, but in vitro culture assays show that the prostates of Pax2 mutants are hypomorphic and branching is severely disrupted compared to controls. RT-PCR data from Pax2 mutant prostates demonstrate increased expression levels of dorsolateral prostate marker MSMB and ventral prostate marker SBP and dramatically reduced expression levels of anterior prostate marker TGM4. CONCLUSIONS: Pax2 is essential for mouse prostate development and regulates prostatic ductal growth, branching, and lobe-specific identity. These findings are important for understanding the molecular regulatory mechanisms in prostate development. PMID- 21594885 TI - Infrared imaging for leak detection of N95 filtering facepiece respirators: a pilot study. AB - BACKGROUND: This study was undertaken to determine the utility of an infrared camera (IRC) for assessing leaks around filtering facepiece respirators (FFR) during quantitative respirator fit testing. METHODS: Eight subjects underwent quantitative fit testing on six N95 FFR models (48 total fit tests) while simultaneously being recorded with an IRC. RESULTS: The IRC detected 49 exhalation leaks during 39 tests and no leaks in nine tests. Exhalation leaks were identified in all failed fit tests (13) and a majority (26 of 35) of passed tests. Anatomically, the nasal region and malar (cheekbone) regions accounted for 71% of identified leak sites. Fit factors for fit tests without identified exhalation leaks were significantly higher than fit tests with leaks detected by IRC (P = 0.01). CONCLUSIONS: Thermal imaging using IRC can detect leaks in respiratory protective equipment and has the potential as a screening tool for assessment of the adequacy of post-donning FFR fit. PMID- 21594886 TI - Myelodysplastic syndromes: 2011 update on diagnosis, risk-stratification, and management. AB - DISEASE OVERVIEW: The myelodysplastic (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older male and in individuals with prior exposure to cytotoxic therapy. DIAGNOSIS: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry, or molecular genetics is complementary but not diagnostic. RISK-STRATIFICATION: Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow, and cytogenetic characteristics. The most commonly used system is the International Prognostic Scoring System. This score divides patients into a lower risk subset (low and intermediate-1) and a higher risk subset (int-2 and high). Other more modern systems have been developed that allow more precise risk calculation. RISK-ADAPTED THERAPY: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts and more recently cytogenetic profile. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy, and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia, and a chromosome 5 alteration. 5 azacitidine and decitabine have activity in higher risk MDS. 5-azacitidine has been shown to improve survival in higher risk MDS. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation. MANAGEMENT OF PROGRESSIVE OR REFRACTORY DISEASE: At the present time, there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include cytarabine based therapy, transplantation, and participation on a clinical trial. PMID- 21594887 TI - Laboratory testing for cryoglobulins. AB - Cryoglobulins are immunoglobulins that precipitate below 37 degrees C and can cause multiorgan damage. There are three types of cryoglobulins: Type I (also called simple), which is mostly associated with monoclonal gammopathy and/or other hematologic disorders and Type II and Type III (known as mixed cryoglobulins), which are associated with infectious and systemic diseases. Testing for cryoglobulins is complicated by lack of reference range, standards, and stringency in maintaining testing temperature conditions. Identification of cryoprecipitate can be critical for patient care; therefore, correct testing conditions are crucial for reliable cryoglobulin testing. The patient's blood sample should be kept at 37 degrees C initially to avoid premature precipitation of cryoglobulins and thereby decreasing the yield for subsequent identification. This could cause a false negative result. After warm centrifugation or warm cell precipitation, the clear serum is observed at 4 degrees C for formation of cryoprecipitate. The cryoprecipitate is then washed in cold buffer, and the resulting precipitate is warmed to 37 degrees C and subjected to further analysis by immunodiffusion and immunofixation. In addition to Meltzer's triad of purpura, weakness and arthralgias, cryoglobulinemias have protean manifestations involving skin, joints, kidney, nervous system, as well as the hematopoietic system. The management of cryoglobulinemia especially in patients with organ damage remains difficult. Treatment of cryoglobulinemia focuses on management of the underlying lymphoproliferative disorder or infectious or systemic causes. Medical management may also include corticosteroids and other immunosuppressive agents and plasmapheresis. Rituximab therapy seems to abrogate the aberrant B cell response. PMID- 21594888 TI - Floral variant of follicular lymphoma. PMID- 21594889 TI - Transition from pediatric to adult care for sickle cell disease: results of a survey of pediatric providers. PMID- 21594890 TI - Transient bone marrow lymphoproliferation after umbilical cord blood transplantation: exacerbated reconstitution of B-cell ontogeny in adults. PMID- 21594891 TI - Hammersmith score application identifies chronic myeloid leukemia patients with poor prognosis before treatment with second-generation tyrosine kinase inhibitors. PMID- 21594892 TI - JAK2 V617F mutational frequency in essential thrombocythemia associated with splanchnic or cerebral vein thrombosis. PMID- 21594893 TI - Detecting rare and common variants for complex traits: sibpair and odds ratio weighted sum statistics (SPWSS, ORWSS). AB - It is generally known that risk variants segregate together with a disease within families, but this information has not been used in the existing statistical methods for detecting rare variants. Here we introduce two weighted sum statistics that can apply to either genome-wide association data or resequencing data for identifying rare disease variants: weights calculated based on sibpairs and odd ratios, respectively. We evaluated the two methods via extensive simulations under different disease models. We compared the proposed methods with the weighted sum statistic (WSS) proposed by Madsen and Browning, keeping the same genotyping or resequencing cost. Our methods clearly demonstrate more statistical power than the WSS. In addition, we found that using sibpair information can increase power over using only unrelated samples by more than 40%. We applied our methods to the Framingham Heart Study (FHS) and Wellcome Trust Case Control Consortium (WTCCC) hypertension datasets. Although we did not identify any genes as reaching a genome-wide significance level, we found variants in the candidate gene angiotensinogen significantly associated with hypertension at P = 6.9 * 10(-4), whereas the most significant single SNP association evidence is P = 0.063. We further applied the odds ratio weighted method to the IFIH1 gene for type-1 diabetes in the WTCCC data. Our method yielded a P-value of 4.82 * 10(-4), much more significant than that obtained by haplotype-based methods. We demonstrated that family data are extremely informative in searching for rare variants underlying complex traits, and the odds ratio weighted sum statistic is more efficient than currently existing methods. PMID- 21594895 TI - When is the absence of evidence, evidence of absence? Use of equivalence-based analyses in genetic epidemiology and a conclusion for the KIF1B rs10492972*C allelic association in multiple sclerosis. AB - Statistical equivalence methods have been in development since the late 1980s in order to provide an appropriate statistical methodology to address nondifferences in biological experiments. This is analogous to genetic association studies in which a polymorphism "is not associated" with a trait. We applied the equivalence method to genetic data to confirm that an association between the KIF1B (kinesin family member1B) rs10492972 allele and multiple sclerosis (MS), reported in Nature Genetics in 2008, is present neither in eight data sets of cases and controls nor in three independent data sets of the International Multiple Sclerosis Genetic Consortium. When the data sets are considered together, a nonsuperiority test excludes the rs10492972*C allele as a major "risk" allele for MS with a high degree of confidence (P = 1.18 * 10(-4) ). We propose that equivalence methods are more appropriate for stating that a polymorphism does not contribute to disease susceptibility. If an equivalence test applied to genetic data sets fails to reveal an association based on standard methods, it demonstrates that there is no genetic association-i.e., the absence of evidence is evidence of absence. When reporting genetic association based on a cohort of a limited size, caution is needed regardless of how attractive the underlying biological rationale is. The data gathered for KIF1B in MS also underscore the need for very large sample sizes with the appropriate equivalence statistical methods in order to exclude reported false-positive results. PMID- 21594896 TI - Thyroid hormone receptor beta mediates thyroid hormone effects on bone remodeling and bone mass. AB - Excess thyroid hormone (TH) in adults causes osteoporosis and increases fracture risk. However, the mechanisms by which TH affects bone turnover are not elucidated. In particular, the roles of thyroid hormone receptor (TR) isotypes in the mediation of TH effects on osteoblast-mediated bone formation and osteoclast mediated bone resorption are not established. In this study we have induced experimental hypothyroidism or hyperthyroidism in adult wild-type, TRalpha- or TRbeta-deficient mice and analyzed the effects of TH status on the structure and remodeling parameters of trabecular bone. In wild-type mice, excess TH decreased bone volume and mineralization. High TH concentrations were associated with a high bone-resorption activity, assessed by increased osteoclast surfaces and elevated concentrations of serum bone-resorption markers. Serum markers of bone formation also were higher in TH-treated mice. TRalpha deficiency did not prevent TH action on bone volume, bone mineralization, bone formation, or bone resorption. In contrast, TRbeta deficiency blocked all the early effects of excess TH observed in wild-type mice. However, prolonged exposure to low or high TH concentrations of TRbeta-deficient mice induced mild modifications of bone structure and remodeling parameters. Together our data suggest that TRbeta receptors mediate the acute effects produced by transient changes of TH concentrations on bone remodeling, whereas TRalpha receptors mediate long-term effects of chronic alterations of TH metabolism. These data shed new light on the respective roles of TRs in the control of bone metabolism by TH. PMID- 21594894 TI - The use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery. AB - The field of phenomics has been investigating network structure among large arrays of phenotypes, and genome-wide association studies (GWAS) have been used to investigate the relationship between genetic variation and single diseases/outcomes. A novel approach has emerged combining both the exploration of phenotypic structure and genotypic variation, known as the phenome-wide association study (PheWAS). The Population Architecture using Genomics and Epidemiology (PAGE) network is a National Human Genome Research Institute (NHGRI) supported collaboration of four groups accessing eight extensively characterized epidemiologic studies. The primary focus of PAGE is deep characterization of well replicated GWAS variants and their relationships to various phenotypes and traits in diverse epidemiologic studies that include European Americans, African Americans, Mexican Americans/Hispanics, Asians/Pacific Islanders, and Native Americans. The rich phenotypic resources of PAGE studies provide a unique opportunity for PheWAS as each genotyped variant can be tested for an association with the wide array of phenotypic measurements available within the studies of PAGE, including prevalent and incident status for multiple common clinical conditions and risk factors, as well as clinical parameters and intermediate biomarkers. The results of PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation. The PAGE network has developed infrastructure to support and perform PheWAS in a high-throughput manner. As implementing the PheWAS approach has presented several challenges, the infrastructure and methodology, as well as insights gained in this project, are presented herein to benefit the larger scientific community. PMID- 21594898 TI - Desferrioxamine treatment of aceruloplasminemia: Long-term follow-up. PMID- 21594899 TI - Disaster survivors in their third decade: trajectories of initial stress responses and long-term course of mental health. AB - This study analyzed trajectories of initial stress and long-term mental health after the 1980 North Sea oil rig disaster. A growth-mixture model of the survivors' stress manifestations in the first 8 weeks (Posttraumatic Stress Scale, [PTSS-10]) and general mental health in 1980, 1981, 1985, and 2007 (General Health Questionnaire, [GHQ-20]) was estimated. Survivors' GHQ-scores in 1985 and 2007 were contrasted to those of a comparison group. Four trajectories were identified among survivors. The resilient (n = 43) displayed initially moderate stress that rapidly declined. The recovery (n = 10), chronic (n = 8), and relapse (n = 9) showed initially stable high stress scores, but the long-term mental health differed. Early screening may identify those at long-term risk. PMID- 21594897 TI - Quality of life in patients with treated and clinically stable Wilson's disease. AB - Health-related quality of life (HRQoL) in Wilson's disease (WD) has not been extensively studied. Therefore, the purpose of this cross-sectional study was to identify clinical and demographic factors influencing HRQoL in 60 treated, clinically stable patients with WD using a generic questionnaire, the Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36). The level of disability and grading of WD multisystemic manifestations were assessed by the Global Assessment Scale for WD (GAS for WD). The Mini Mental State Examination (MMSE) and the 21-item Hamilton Depression Rating Scale (HDRS) scoring were also applied by the same trained interviewers. Lower scores on the SF-36 domains were found in patients with neurological compared with those with a predominantly hepatic form of WD. The HRQoL of patients with WD and psychiatric symptoms was also lower than that of those without them. Finally, significant inverse correlations were obtained between the various SF-36 domains and all the following: period of latency from the first symptoms/signs appearance and treatment initiation, MMSE and HDRS scores, and different domains of the GAS for WD. PMID- 21594901 TI - Comparing the diagnosis of PTSD when assessing worst versus multiple traumatic events in a chronically mentally ill sample. AB - Despite interest in the nature of the traumatic event required to meet Criterion A for posttraumatic stress disorder (PTSD) as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994), little attention has been paid to the diagnostic ramifications of linking PTSD symptoms to a single traumatic event in the context of multiple trauma exposures. In this study, 67 dually diagnosed clients with at least 2 potential Criterion A traumatic events completed the Posttraumatic Stress Diagnostic Scale twice, in counterbalanced order: once regarding their worst event and once regarding all events. When responding regarding their worst trauma, 53.7% met probable PTSD criteria. This rose to 67.2% when considering all traumas. Although preliminary, these results suggest that linking PTSD symptoms to a single traumatic event excludes a meaningful number of cases who are otherwise indistinguishable based on symptom profile. PMID- 21594900 TI - A pilot randomized controlled trial assessing secondary prevention of traumatic stress integrated into pediatric trauma care. AB - Medical settings provide opportunities for secondary prevention of traumatic stress and other sequelae of pediatric injury. This pilot randomized trial evaluated the delivery and effectiveness of a targeted preventive intervention based on best practice recommendations and integrated within acute medical care. Hospitalized injured children were screened for risk of developing posttraumatic stress disorder (PTSD). Those at risk (N = 85) were randomized to the intervention (n = 46) or usual care (n = 39). The preventive intervention did not reduce PTSD or depression severity or increase health-related quality of life, compared to usual care. Both groups improved over time, but 6 months postinjury approximately 10% of each group still met criteria for PTSD, suggesting room for improvement in comprehensive pediatric injury care. PMID- 21594902 TI - FPipTB, a benzimidazole derivative, induces chondrosarcoma cell apoptosis via endoplasmic reticulum stress and apoptosis signal-regulating kinase 1. AB - Chondrosarcoma is the second most common primary bone tumor and it responds poorly to both chemotherapy and radiation treatment. In this study, we investigated the anticancer effects of a new benzimidazole derivative, 2 (furanyl)-5-(piperidinyl)- (3,4,5-trimethoxybenzyl) benzimidazole (FPipTB) in human chondrosarcoma cells. FPipTB-induced apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353) but not in primary chondrocytes. Furthermore, it triggered endoplasmic reticulum (ER) stress, which was characterized by changes in cytosolic calcium levels. Treatment of chondrosarcoma cells with FPipTB was associated with increased intracellular levels of ASK1, p38, p53, and Bax, followed by release of cytochrome c from mitochondria and activation of caspases. It is also known that ER stress activates apoptosis signal-regulating kinase 1 (ASK1), which mediates activation of JNK and p38 pathways. We also found that FPipTB-induced p38 and p53 phosphorylation and upregulated Bax expression. To study the mechanism of Bax upregulation, we determined that Bax promoter activity was increased in FPipTB-treated cells, leading to an increase in intracellular levels of Bax. In addition, cell treated with Ca(2+) chelator or p38 inhibitor showed reduced transcriptional activity. The results further suggest that FPipTB triggered ER stress, as indicated by changes in cytosolic calcium levels and activated the ASK1-MKK3/6-p38-p53-Bax pathway, causing chondrosarcoma cell death. Importantly, animal studies revealed a dramatic 40% reduction in tumor volume after 21 d of treatment. Thus, FPipTB may be a novel anticancer agent for the treatment of chondrosarcoma. PMID- 21594903 TI - CCND1 rs9344 polymorphisms are associated with the genetic susceptibility to cervical cancer in Chinese population. AB - Cyclin D1, with a common G/A polymorphism in rs9344, is an essential regulator of the G1 phase in cell cycles and plays an important role in several tumor types, and the homology of cyclin D1 with human papillomavirus (HPV)-16 E7 brought our attention to CCND1 gene in cervical cancer. A total of 738 native Chinese subjects consist of 327 cases and 411 controls were enrolled in this study. CCND1 genotyping was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and partially verified by sequencing of genomic DNA and cDNA. The transcription of cyclin D1 mRNA isoforms was analyzed by quantitative PCR; expression of protein isoforms by immunohistochemistry and Western blotting. We observed that the AA genotype had decreased risk of developing cervical cancer (odds ratio [OR] = 0.332; 95% confidence interval [CI] = 0.113-0.978; P = 0.045). The two mRNA isoforms were both transcripted from A and G allele. Transcript b decreased in squamous cell carcinoma of the uterine cervix (SCCUC) group (P = 0.004), especially poorly differentiated group (P = 0.004), and in G allele group of normal subjects (P = 0.001). In immunohistochemistry analysis, cyclins D1, D1a, and D1b failed to correlate with cervical cancer (P = 0.808, 0.445, and 0.095). However, cyclin D1b was downregulated in SCCUC group analyzed by Western blotting (P = 0.039). This study indicates that CCND1 rs9344 polymorphisms confer host susceptibility to cervical cancer. A allele possesses a relative protective effect probably through the cyclin D1b's inhibition on HPV carcinogenesis. PMID- 21594904 TI - Involvement of the transcription factor twist in phenotype alteration through epithelial-mesenchymal transition in lung cancer cells. AB - Epithelial-mesenchymal transition (EMT), which involves the persistent loss of epithelial markers and expression of mesenchymal markers, is assumed to have a critical role in not only tissue development during embryogenesis but also central mechanisms that enhance the invasive and metastatic ability of cancer cells. Twist has been identified to play an essential role in EMT-mediated tumor invasion and metastasis. Although recent studies suggest that twist expression levels in tissue specimens of lung cancer might be associated with prognosis, the expression of twist in lung cancer cells itself and its effect have not been fully evaluated. Here, we evaluated twist expression and its effect on phenotype alteration in lung cancer cell lines. Twist expression varied among human lung cancer cell lines. The lung cancer cell lines with high twist expression also tended to show a high vimentin/E-cadherin ratio, which was supported by a migration assay, in which high twist expression gave rise to high cell motility. Furthermore, in comparison to control cells, the lung cancer cells with ectopic expression of twist showed a significant phenotype alteration through EMT and an increasing ability to migrate in vitro, in part, due to a tenfold increase in matrix metalloproteinases activity and almost a 60% increase in modulation of focal adhesion kinase activity, although a contribution of microRNA appeared unlikely in our study. Our present analysis of twist expression in lung cancer provide clues to comprehensive understanding of the mechanisms, by which metastasis often develops in lung cancer. PMID- 21594905 TI - A novel structural design of a Pt/C-CeO2 catalyst with improved performance for methanol electro-oxidation by beta-cyclodextrin carbonization. PMID- 21594906 TI - Hybrid colloidal plasmonic-photonic crystals. AB - We review the recently emerged class of hybrid metal-dielectric colloidal photonic crystals. The hybrid approach is understood as the combination of a dielectric photonic crystal with a continuous metal film. It allows to achieve a strong modification of the optical properties of photonic crystals by involving the light scattering at electronic excitations in the metal component into moulding of the light flow in series to the diffraction resonances occurring in the body of the photonic crystal. We consider different realizations of hybrid plasmonic-photonic crystals based on two- and three-dimensional colloidal photonic crystals in association with flat and corrugated metal films. In agreement with model calculations, different resonance phenomena determine the optical response of hybrid crystals leading to a broadly tuneable functionality of these crystals. PMID- 21594907 TI - Patterning graphene with zigzag edges by self-aligned anisotropic etching. PMID- 21594908 TI - Highly photosensitive J-aggregated single-crystalline organic transistors. PMID- 21594909 TI - Room-temperature compression-induced diamondization of few-layer graphene. PMID- 21594910 TI - Largely enhanced efficiency with a PFN/Al bilayer cathode in high efficiency bulk heterojunction photovoltaic cells with a low bandgap polycarbazole donor. PMID- 21594911 TI - How can theory predict the selectivity of palladium-catalyzed cross-coupling of pristine aromatic molecules? AB - The new approach for palladium-catalyzed cross-coupling of two non-activated aromatic compounds (D. R. Stuart, K. Fagnou, Science 2007, 316, 1172) was studied theoretically. The energetic span model (S. Kozuch, S. Shaik, Acc. Chem. Res. 2011, 44, 101, and references therein) was employed to analyze the kinetic behavior of the catalytic cycle. The computed energy profile, combined with the energetic span model, accounts for the experimental selectivity, which favors the hetero-coupling of benzene with indole. This selectivity is driven by a fine balance of the entropic contributions and the high ratio of concentrations used for benzene over indole. This analysis may allow future theoretical predictions of how different aromatic compounds can be effectively coupled. PMID- 21594912 TI - A family of calix[4]arene-supported [Mn(III)2Mn(II)2] clusters. AB - In the cone conformation calix[4]arenes possess lower-rim polyphenolic pockets that are ideal for the complexation of various transition-metal centres. Reaction of these molecules with manganese salts in the presence of an appropriate base (and in some cases co-ligand) results in the formation of a family of calixarene supported [Mn(III)(2)Mn(II)(2)] clusters that behave as single-molecule magnets (SMMs). Variation in the alkyl groups present at the upper-rim of the cone allows for the expression of a degree of control over the self-assembly of these SMM building blocks, whilst retaining the general magnetic properties. The presence of various different ligands around the periphery of the magnetic core has some effect over the extended self-assembly of these SMMs. PMID- 21594913 TI - Magnetic decoupling of surface Fe3+ in magnetite nanoparticles upon nitrocatechol anchored dispersant binding. PMID- 21594914 TI - Understanding catalysis of phosphate-transfer reactions by the large ribozymes. AB - Large ribozymes are unique among catalytic RNA molecules in that their reactions involve intermolecular nucleophilic attack on an RNA phosphodiester linkage. Crystal structures of near-atomic resolution are now available for the group I and group II self-splicing introns and the RNA subunit of RNase P. The structural data agrees well with the earlier models proposed on the basis of biochemical studies and the evidence at hand suggests that all of the large ribozymes utilize a mechanism in which coordination of Mg(II) ions reduces the negative charge on the scissile phosphodiester linkage, as well as assists both the nucleophilic attack and the departure of the leaving group. PMID- 21594915 TI - Design and synthesis of "dumb-bell" and "triangular" inorganic-organic hybrid nanopolyoxometalate clusters and their characterisation through ESI-MS analyses. AB - A series of tris(hydroxymethyl)aminomethane (TRIS)-based linear (bis(TRIS)) and triangular (tris(TRIS)) ligands has been synthesised and were covalently attached to the Wells-Dawson type cluster [P(2)V(3)W(15)O(62)](9-) to generate a series of nanometer-sized inorganic-organic hybrid polyoxometalate clusters. These huge hybrids, with a molecular mass similar to that of small proteins in the range of ~10-16 kDa, were unambiguously characterised by using high-resolution ESI-MS. The ESI-MS spectra of these compounds revealed, in negative ion mode, a characteristic pattern showing distinct groups of peaks corresponding to different anionic charge states ranging from 3(-) to 8(-) for the hybrids. Each peak in these individual groups could be unambiguously assigned to the corresponding hybrid cluster anion with varying combinations of tetrabutylammonium (TBA) and other cations. This study therefore highlights the prowess of the high-resolution ESI-MS for the unambiguous characterisation of large, nanoscale, inorganic-organic hybrid clusters that have huge mass, of the order of 10-16 kDa. Also, the designed synthesis of these compounds points to the fact that we were able to achieve a great deal of structural pre-design in the synthesis of these inorganic-organic hybrid polyoxometalates (POMs) by means of a ligand design route, which is often not possible in traditional "one-pot" POM synthesis. PMID- 21594916 TI - Intramolecularly coordinated [{2,6-(Me2NCH2)2C6H3}Sn(II)]+: a strong sigma donor for Pt(II). PMID- 21594917 TI - BMSS ISO-SIG (27-28 April), SIMSUG 2010 (28-30 April) and SIBAE (28-29 April 2010), University of Exeter, UK. PMID- 21594918 TI - Fully automated software solution for protein quantitation by global metabolic labeling with stable isotopes. AB - Metabolic stable isotope labeling is increasingly employed for accurate protein (and metabolite) quantitation using mass spectrometry (MS). It provides sample specific isotopologues that can be used to facilitate comparative analysis of two or more samples. Stable Isotope Labeling by Amino acids in Cell culture (SILAC) has been used for almost a decade in proteomic research and analytical software solutions have been established that provide an easy and integrated workflow for elucidating sample abundance ratios for most MS data formats. While SILAC is a discrete labeling method using specific amino acids, global metabolic stable isotope labeling using isotopes such as (15)N labels the entire element content of the sample, i.e. for (15)N the entire peptide backbone in addition to all nitrogen-containing side chains. Although global metabolic labeling can deliver advantages with regard to isotope incorporation and costs, the requirements for data analysis are more demanding because, for instance for polypeptides, the mass difference introduced by the label depends on the amino acid composition. Consequently, there has been less progress on the automation of the data processing and mining steps for this type of protein quantitation. Here, we present a new integrated software solution for the quantitative analysis of protein expression in differential samples and show the benefits of high resolution MS data in quantitative proteomic analyses. PMID- 21594919 TI - Gross and net rates of nitrogen mineralisation in soil amended with composted olive mill pomace. AB - Olive mill pomace is the major waste product in the olive oil industry and composting these by-products for the purpose of recycling nutrients and organic matter is a sound environmental strategy. Yet little is known about the quantity and timing of nitrogen (N) release from composted olive mill pomace. This paper assesses both gross (using the (15)N dilution technique) and net (aerobic incubation) nitrogen (N) mineralisation and N(2)O emissions of soil amended with seven commercially available composts of olive mill pomace (COMP). All are currently produced in Andalusia and differ in the proportions of raw materials co composted with the pomace. The absence of significant differences in net N or gross mineralisation and nitrification in COMP-amended soil compared with a control, except for COMP combined with poultry manure, highlighted the recalcitrant nature of the COMP-N. Applications of COMP are hence unlikely to supply available N in available forms, at least in the short-term. Furthermore, N(2)O emissions from COMP-amended soil were negligible and, therefore, applications in the field should not result in increased N loss through denitrification. PMID- 21594920 TI - Differential growth of the fungus Absidia cylindrospora on 13C/15N-labelled media. AB - Many studies utilise enrichment of stable isotopes as tracers to follow the interactions occurring within soil food webs and methods have been developed to enrich bacteria, soil fauna and plant litter, Here for the first time we attempt to enrich a soil fungus to 99 atom% with (13)C and (15)N stable isotopes. In this study our objectives were to (a) assess whether the saprotrophic zygomycete fungus Absidia cylindrospora could grow on a medium enriched to 99 atom% with (13)C-glucose and (15)N-ammonium chloride, (b) to determine the level of enrichment obtained, and (c) to examine the change in growth rate of this fungus while it was growing on the dually enriched medium. To achieve this, the fungus was grown on agar enriched with (13)C and (15)N to 99 atom% and its growth rate monitored. The results showed that A. cylindrospora would grow on the highly labelled growth medium, but that its rate of growth was affected compared with the rate on either natural abundance media or media highly enriched with a single isotope ((13)C or (15)N). The implications of these results is that although the fungus is able to utilise these heavier isotopes, the biochemical processes involved in growth are affected, and consideration should be given to these differences when using stable isotope tracers in, for example, soil food web studies. PMID- 21594921 TI - Organic matter flow in the food web at a temperate heath under multifactorial climate change. AB - The rising atmospheric CO(2) concentration, increasing temperature and changed patterns of precipitation currently expose terrestrial ecosystems to altered environmental conditions. This may affect belowground nutrient cycling through its intimate relationship with the belowground decomposers. Three climate change factors (elevated CO(2), increased temperature and drought) were investigated in a full factorial field experiment at a temperate heathland location. The combined effect of biotic and abiotic factors on nitrogen and carbon flows was traced in plant root -> litter -> microbe -> detritivore/omnivore -> predator food-web for one year after amendment with (15)N(13)C(2)-glycine. Isotope ratio mass spectrometry (IRMS) measurement of (15)N/(14)N and (13)C/(12)C in soil extracts and functional ecosystem compartments revealed that the recovery of (15)N sometimes decreased through the chain of consumption, with the largest amount of bioactive (15)N label pool accumulated in the microbial biomass. The elevated CO(2) concentration at the site for 2 years increased the biomass, the (15)N enrichment and the (15)N recovery in detritivores. This suggests that detritivore consumption was controlled by both the availability of the microbial biomass, a likely major food source, and the climatic factors. Furthermore, the natural abundance delta(13)C of enchytraeids was significantly altered in CO(2)-fumigated plots, showing that even small changes in delta(13)C-CO(2) can be used to detect transfer of carbon from primary producers to detritivores. We conclude that, in the short term, the climate change treatments affected soil organism activity, possibly with labile carbohydrate production controlling the microbial and detritivore biomass, with potential consequences for the decomposition of detritus and nutrient cycling. Hence, there appears to be a strong coupling of responses in carbon and nitrogen cycling at this temperate heath. PMID- 21594922 TI - Stable isotope profiles of nitrogen gas indicate denitrification in oxygen stratified humic lakes. AB - Mid-summer N(2) profiles were analyzed from nine oxygen-stratified, humic-acid rich lakes using a continuous flow isotope ratio mass spectrometer and a Gasbench II device. Sample preparation steps were performed under water to avoid air contamination. The instrument precision for the delta(15)N measurement was high (0.030/00), but for the whole sampling and analysis procedure the mean deviation between replicate samples was 0.130/00 for the delta(15)N measurements and 5.5% for the N(2) gas concentration analysis. The results show that the Gasbench peripheral was suitable for measurement of the (15)N natural abundance of dissolved nitrogen gas, with denitrification indicated by the oversaturation and slightly (<10/00) depleted delta(15)N values of the dissolved N(2) gas in the suboxic zones of some of the study lakes. Calculated values for the denitrified (excess) N(2) varied between -5.3 and 0.70/00. The denitrification potential was determined using the (15)N tracer method, with results showing nitrate-inducible denitrification and no signs of anaerobic ammonium oxidation (anammox). PMID- 21594923 TI - Tracking the flow of bacterially derived 13C and 15N through soil faunal feeding channels. AB - The soil food web has been referred to as a 'black box', a 'poor man's tropical rainforest' and an 'enigma', due to its opacity, diversity and the limited insight into feeding specificity. Here we investigate the flow of C and N through the soil food web as a way to gain understanding of the feeding interactions occurring. A bacterium, Pseudomonas lurida, was introduced to soil cores from two different habitats, a grassland and a woodland with the same soil type, enriched to 99 atom% in (13)C and (15)N, to trace the flow of bacterial C and N through the soil food web. Throughout the experiment the soil remained enriched in (13)C and (15)N. Almost all the invertebrates tested gained C and N enrichment indicative of the labelled bacteria, implying that bacterial feeding is a common mechanism within the soil. Only three groups were significantly enriched in both (13)C and (15)N in both habitats. These were Collembola (Entomobryomorpha), Acari (Oribatida), and Nematoda, indicating that these organisms are consuming the most bacteria within both systems. When the invertebrates were grouped into hypothesised trophic levels, those considered secondary decomposers were gaining the most enrichment across all invertebrates tested. This enrichment was also high in the micro-predators within the soil, implying that their main food source was the secondary decomposers, particularly the Collembola. Using an enriched bacterium to track the trophic transfer between organisms within the soil food web is a novel way of empirically showing that interactions are occurring, which normally cannot be seen. PMID- 21594924 TI - Long-term release of carbon from grassland soil amended with different slurry particle size fractions: a laboratory incubation study. AB - Application of animal manure to agricultural soils enhances both native soil carbon (C) and overall (native soil C and added C) respiration. CO(2) effluxes were measured in a laboratory incubation study for 1465 days after the application of different slurry fractions (>2000, 425-2000, 250-425, 150-250, 45 150 and <45 um) to a grassland soil. The slurry-derived C present in the soil was traced using the natural abundance delta(13)C method. We used two kinetic (single and two pool) models to fit the experimental data and to test the model validity with respect to long-term data sets. Mean residence times (MRTs) of the particle size based slurry-C fractions were estimated using these models and a linear (13)C natural abundance based approach. The results showed that slurry-C degradation in soil over time varied between the different particle size based slurry treatments. The two kinetic soil-C models were successful to predict medium- to long-term carbon release from soil amended with animal slurry. The estimated MRTs did vary between the linear (3.8-5.6 years) and non-linear based (0.8-3.8 years) (model) approaches. Slurry-derived C could still be (isotopically) detected in the soil 4 years after slurry application using the natural abundance delta(13)C method. This suggests that it may take a decadal timescale or longer before the entire amount of C introduced through whole slurry amendments to grassland soils is fully dissipated. PMID- 21594925 TI - High rates of nitrogen cycling in volcanic soils from Chilean grasslands. AB - There are over one million hectares of pasture in Chile, and 80% and 50% of the country's milk and meat comes from 72% of this area, situated in the lake region of southern Chile. The soils are volcanic and a major characteristic is that they have very high organic matter (OM) contents with the potential to support plant growth with only moderate levels of added nitrogen (N). To understand better the potential fertility of these soils in order to maximise production and minimise losses of N, we undertook studies using the stable isotope of N ((15)N) to resolve the rates of the main internal N cycling processes in three soils representing the two main volcanic soil types: Osorno and Chiloe (Andisol) and Cudico (Ultisol). We also assessed the longer-term potential of these soils to sustain N release using anaerobic incubation. Gross rates (ug N g(-1) day(-1)) of mineralisation were 27.9, 27.1 and 15.5 and rates of immobilisation were 5.9, 12.0 and 6.3 for Osorno, Chiloe and Cudico, respectively, implying high rates of net mineralisation in these soils. This was confirmed by anaerobic incubation which gave potential seasonal net mineralisation indices of 1225, 1059 and 450 kg N ha(-1) in the top 10 cm soil layers of the three soils. However, plant production may still benefit from added N, as the release of N from organic sources may not be closely synchronised with crop demand. The low rates of nitrification that we found with these acidic soils suggest that the more mobile N (viz. nitrate-N) would be in limited supply and plants would have to compete for the less mobile ammonium-N with the soil microbial biomass. Nitrogen was mineralised in appreciable amounts even down to 60 cm depth, so that leaching could become significant, particularly if the soils were limed, which could enhance nitrification and N mobility through the soil profile. PMID- 21594926 TI - Effect of elevated CO2 on carbon partitioning in young Quercus ilex L. during resprouting. AB - Stored carbon (C) represents a very important C pool with residence times of years to decades in tree organic matter. With the objective of understanding C assimilation, partitioning and remobilization in 2-year-old Quercus ilex L., those trees were exposed for 7 months to different [CO(2)] (elevated: 700 umol mol(-1) ; and ambient: 350 umol mol(-1) CO(2)). The (13)C-isotopic composition of the ambient CO(2) (ca.-12.80/00) was modified (to ca.-19.20/00) under the elevated CO(2) conditions in order to analyze C allocation and partitioning before aerial biomass excision, and during the following regrowth (resprouting). Although after 7 months of growth under elevated [CO(2)], Q. ilex plants increased dry matter production, the absence of significant differences in photosynthetic activity suggests that such an increase was lower than expected. Nitrogen availability was not involved in photosynthetic acclimation. The removal of aboveground organs did not enable the balance between C availability and C requirements to be achieved. The isotopic characterization revealed that before the cutting, C partitioning to the stem (main C sink) prevented leaf C accumulation. During regrowth the roots were the organ with more of the labelled C. Furthermore, developing leaves had more C sink strength than shoots during this period. After the cutting, the amount of C delivered from the root to the development of aboveground organs exceeded the requirements of leaves, with the consequent carbohydrate accumulation. These findings demonstrate that, despite having a new C sink, the responsiveness of those resprouts under elevated [CO(2)] conditions will be strongly conditioned by the plant's capacity to use the extra C present in leaves through its allocation to other organs (roots) and processes (respiration). PMID- 21594927 TI - Modification of citrulline residues with 2,3-butanedione facilitates their detection by liquid chromatography/mass spectrometry. AB - Citrullination is a post-translational modification (PTM) that results from the deimination of the amino acid arginine into citrulline by Peptidyl Arginine Deiminase enzymes and occurs in a wide range of proteins in health and disease. This modification causes a 1 Da mass shift, which can be used to identify citrullination sites in proteins by the use of mass spectrometry. However, other PTMs, such as deamidation from asparagine to aspartic acid or from glutamine to glutamic acid, can also cause a 1 Da mass shift, making correct interpretation of the data more difficult. We developed a chemical tagging strategy which, combined with an open source search application, allowed us to selectively pinpoint citrullinated peptides in a complex mixture after liquid chromatography/mass spectrometry (LC/MS) analysis. After incubation of a peptide mixture with 2,3 butanedione, citrulline residues were covalently modified which resulted in a 50 Da shift in singly charged mass. By comparison of the peptide mass fingerprint from a modified and an unmodified version of the same sample, our in-house search application was able to identify the citrullinated peptides in the mixture. This strategy was optimized on synthetic peptides and validated on a digest of in vitro citrullinated fibrinogen, where different proteolytic enzymes were used to augment the protein coverage. This new method results in easy detection of citrullinated residues, without the need for complex mass spectrometry equipment. PMID- 21594928 TI - Development of a liquid chromatography/mass spectrometry methodology to separate, detect, characterize and quantify PEG-resveratrol prodrugs and the conjugation reaction precursors and intermediates. AB - A simple and reliable liquid chromatography/mass spectrometry (LC/MS) method to monitor pegylation of resveratrol is described. The developed LC/MS method can separate and quantify unmodified MeO-PEG-OH, carboxylic acid terminated PEG, resveratrol and PEG-resveratrol prodrugs. This methodology was able to monitor and determine the extent of conversion of MeO-PEG-OH into respective acidic functional derivatives such as MeO-PEG succinylester acid (MeO-PEGO-SuccOH), which was found to be complete. The developed method was also utilised to determine the extent of conjugation of resveratrol to carboxylic acid terminated PEG. The conversion of carboxylic acid terminated PEG into a PEG-resveratrol conjugate was found to be 100% and 73%, respectively, for MeO-PEG succinylamide resveratrol (MeO-PEGN-Succ-RSV) and MeO-PEG succinylester resveratrol (MeO-PEGO Succ-RSV). The 100% conjugation of MeO-PEGN-Succ-RSV is consistent with the result obtained from a nuclear magnetic resonance (NMR) study. The average molecular weights determined by LC/MS for MeO-PEG-OH, MeO-PEGO-SuccOH and MeO PEGO-Succ-RSV were found to be 2108, 2321 and 2423 Da, respectively. These data correlate well with the theoretical values. This methodology proved to be simple and effective in determining the extent of functionalisation of PEG and its conjugation to resveratrol. Overall our LC/MS method coupled with NMR permitted complete characterisation of the polymeric prodrug pegylated-resveratrol and the reaction precursors. PMID- 21594929 TI - Surface-activated chemical ionization combined with electrospray ionization and mass spectrometry for the analysis of cannabinoids in biological samples. Part I: analysis of 11-nor-9-carboxytetrahydro-cannabinol. AB - Recently, electrospray ionization mass spectroscopy (ESI-MS) has been widely used for the identification of drugs of abuse and their metabolites in biological samples. However, the sensitivity and selectivity of this technique are commonly inadequate for the analysis of tetrahydrocannabinol (THC) and its metabolites at very low levels, such as those sometimes required in forensic and clinical-legal applications. We coupled electrospray ionization and surface-activated chemical ionization (ESI-SACI) to various types of mass analyzers (ion trap, triple quadrupole and orbitrap) (ESI-SACI-MS) to improve the detection of 11-nor-9 carboxy-tetrahydrocannabinol (THC-COOH), the most common marker of THC abuse. The benefits of this approach in terms of sensitivity and selectivity compared with a common ESI-MS approach are clearly demonstrated. PMID- 21594930 TI - Enhancements in travelling wave ion mobility resolution. AB - The use of ion mobility separation to determine the collision cross-section of a gas-phase ion can provide valuable structural information. The introduction of travelling-wave ion mobility within a quadrupole/time-of-flight mass spectrometer has afforded routine collision cross-section measurements to be performed on a range of ionic species differing in gas-phase size/structure and molecular weight at physiologically relevant concentrations. Herein we discuss the technical advances in the second-generation travelling-wave ion mobility separator, which result in up to a four-fold increase in mobility resolution. This improvement is demonstrated using two reverse peptides (mw 490 Da), small ruthenium-containing anticancer drugs (mw 427 Da), a cisplatin-modified protein (mw 8776 Da) and the noncovalent tetradecameric chaperone complex GroEL (mw 802 kDa). What is also shown are that the collision cross-sections determined using the second generation mobility separator correlate well with the previous generation and theoretically derived values. PMID- 21594931 TI - Developing a methodology for carbon isotope analysis of lacustrine diatoms. AB - Stable isotope analysis of sedimentary carbon in lakes can help reveal changes in terrestrial and aquatic carbon cycles. A method based on a single, photosynthetic organism, where host effects are minimised, should offer more precision than carbon isotope studies of bulk lake sediments. Here we report the development of a systematic method for use on fossil lacustrine diatom frustules, adapted from previous studies in marine environments. A step-wise cleaning experiment on diatomaceous lake sediments from Lake Challa, near Mount Kilimanjaro, was made to demonstrate the necessary treatment stages to remove external sedimentary carbon. Changes in soluble carbon compounds during these cleaning experiments were measured using gas chromatography/mass spectrometry (GC/MS). The mass spectrometry methods were refined to measure the small percentage of carbon in these samples and details of these methods are presented. Samples of cleaned diatoms containing <1% carbon yielded robust results. Carbon isotope analyses of diatom samples containing different species mixtures were performed and suggested that differences existed, although the effects lay within current experimental error and require further work. Unlike what was found in work on oxygen and silicon isotopes from diatom frustules, mineral contamination had no discernible impact on the diatom carbon isotope ratios from these sediments. The range of values found in the lakes investigated thus far can be interpreted with reference to the supply and nature of carbon from the catchment as well as to the demand generated from lake primary productivity. PMID- 21594932 TI - Tandem mass spectrometric fragmentation patterns of known and new steviol glycosides with structure proposals. AB - Stevia rebaudiana contains several steviol glycosides that have a sweet flavor. They are up to 450 times sweeter than sucrose, but some have an undesirable aftertaste. Up to 2010, ten different steviol glycosides have been described from the leaves or purified extracts of S. rebaudiana. In this paper, the tandem mass spectrometric fragmentation patterns of these ten compounds are compiled, along with a scheme for structural elucidation. This scheme is then applied to 12 steviol glycosides that have not yet been described. The proposed structures of five steviol glycosides have been confirmed by other authors. PMID- 21594933 TI - Selected reaction monitoring (SRM) mass spectrometry without isotope labeling can be used for rapid protein quantification. AB - The validation of putative biomarker candidates has become the major bottle-neck in protein biomarker development. Conventional immunoaffinity methods are limited by the availability of antibodies and kits. Here we demonstrate the feasibility of using selected reaction monitoring (SRM) without isotope labeling to achieve fast and reproducible quantification of serum proteins. The SRM/MRM assays for three standard serum proteins, including ceruloplasmin (CP), serum aymloid A (SAA) and sex hormone binding globulin (SHBG), have good linear ranges, generally 10(3) to 10(4) . There are almost perfect correlations between SRM intensities and the loaded peptide amounts (R(2) is usually ~0.99). Our data suggest that SRM/MRM is able to quantify proteins within the range of 0.2-2 fmol, which is comparable to the commercial ELISA/LUMINEX kits for these proteins. Excellent correlations between SRM/MRM and ELISA/LUMINEX assays were observed for SAA and SHBG (R(2)=0.928 and 0.851, respectively). However, the correlation between SRM/MRM and ELISA for CP is less desirable (R(2)=0.565). The reproducibility for SRM/MRM assays is generally very good but may depend on the proteins/peptides being analyzed (R(2)=0.931 and 0.882 for SAA and SHBG, and 0.723 for CP). The SRM/MRM assay without isotope labeling is a rapid and useful method for protein biomarker validation in a modest number of samples and is especially useful when other assays such as ELISA or LUMINEX are not available. PMID- 21594934 TI - Use of soft and hard ionization techniques for elucidation of unknown compounds by gas chromatography/time-of-flight mass spectrometry. AB - Investigation of trace-level non-target compounds by gas chromatography/mass spectrometry (GC/MS) often is a challenging task that requires powerful software tools to detect the unknown components, to obtain the deconvoluted mass spectra, and to interpret the data if no acceptable library match is obtained. In this paper, the complementary use of electron ionization (EI) and chemical ionization (CI) is investigated in combination with GC/time-of-flight (TOF) MS for the elucidation of organic non-target (micro)contaminants in water samples. Based on accurate mass measurement of the molecular and fragment ions from the TOF MS, empirical formulae were calculated. Isotopic patterns, carbon number prediction filter and nitrogen rule were used to reduce the number of possible formulae. The candidate formulae were searched in databases to find possible chemical structures. Selection from possible structure candidates was achieved using information on substructures and observed neutral losses derived from the fragment ions. Four typical examples (bifenazate, boscalid, epoxiconazole, and fenhexamid) are used to illustrate the methodology applied and the various difficulties encountered in this process. Our results indicate that elucidation of unknowns cannot be achieved by following a standardized procedure, as both expertise and creativity are necessary in the process. PMID- 21594935 TI - Distribution of chloroquine in ocular tissue of pigmented rat using matrix assisted laser desorption/ionization imaging quadrupole time-of-flight tandem mass spectrometry. AB - In pharmacology and toxicology, localization of the distribution of a drug molecule in its target tissue provides very important in vivo biological information. Traditionally, this has been examined using autoradiography (ARG). However, there are significant limitations in this application. One is the synthesis and use of radiolabeled compounds, the other is that the image generated expresses an undifferentiated mixture of the parent drug and/or its metabolites. The objective of the study was to define the specific distribution of the parent drug in rat ocular tissue containing melanin (e.g. the retina) using non-labeled chloroquine by MALDI Imaging tandem mass spectrometry (MS/MS). After single oral administration (at 20 mg/kg) of chloroquine, sections (10 um) of rat eye tissue were prepared at 24 h. The MS system used was a quadrupole time of flight (Q-TOF) tandem mass spectrometer (MALDI SynaptTM, Waters, Milford, MA, USA). Tissue sections were sprayed with CHCA (alpha-cyano-4-hydroxycinnamic acid, 5 mg/mL) in 80% acetonitrile (ACN) containing 5% formic acid (FA) using either a manual sprayer (airbrush) or an automated sprayer (TM-SprayerTM, HTX Technologies, Carrboro, NC, USA). Chloroquine was readily detected in the MS/MS mode by monitoring one of its major fragment ions (m/z 247.10) and imaged through the rat eye tissue. The image of the specific distribution within the retina in the rat eye tissue was confirmed, and found to be similar to autoradiograms after oral administration of (14)C-chloroquine reported previously. PMID- 21594936 TI - Two-dimensional Fourier transform ion cyclotron resonance mass spectrometry: reduction of scintillation noise using Cadzow data processing. AB - In two-dimensional Fourier transform ion cyclotron resonance mass spectrometry (2D FTICR-MS), scintillation noise, caused mostly by fluctuations in the number of ions in the ICR cell, is the leading cause for errors in spectrum interpretation. In this study, we adapted an algorithm based on singular value decomposition and first introduced by Cadzow et al. (IEE Proceedings Pt. F 1987, 134, 69) to 2D FTICR-MS and we measured its performance in terms of noise reduction without losing signal information in the 2D mass spectrum. PMID- 21594937 TI - Multi-stage mass spectrometric information obtained by deconvolution of energy resolved spectra acquired by triple-quadrupole mass spectrometry. AB - Triple-quadrupole mass spectrometry (TQ-MS) provides the capability to carry out collision-induced dissociation (CID) and it offers advantages in quantification when connected with high-performance liquid chromatography through an electrospray ionization interface. However, although TQ-MS provides information on partial structures through the analysis of product ions obtained by CID experiments, the method only provides single-stage CID experiments, which limits the detailed structural information that can be obtained. Herein, a method of overcoming this limitation of TQ-MS is described. A spectrum obtained by energy resolved mass spectrometry (ERMS) was used to deconvolute the fragmentation process, with a Galili-antigenic trisaccharide derivative being used as an example. A replot of the ERMS data showing the ratios of the product ions to the precursor ion resulted in a descriptive graph. Analysis of the sum of the ratios of individual product ions to the precursor ion at specific CID energies revealed that the members of a series of product ions were related to each other. The obtained relationships and the m/z values of the product ions provided information on the fragmentation process taking place during the dissociation, indicating that the ERMS spectrum obtained by TQ-MS contained equivalent information to that obtainable by multi-stage MS/MS (MS(n); n>=2). This method may allow users of triple-quadrupole mass spectrometers to obtain MS(n)-type information by performing a single ERMS experiment, which is even advantageous over quadrupole ion trap (QIT)-MS/MS because CID experiments on individual first generation product ions are not required. PMID- 21594938 TI - A strategy for selection of reference materials in stable oxygen isotope analyses of solid materials. AB - The propagation of uncertainties associated with the stable oxygen isotope reference materials through a multi-point normalisation procedure was evaluated in this study using Monte Carlo (MC) simulation. We quantified the normalisation error for a particular selection of reference materials and their number of replicates, when the choice of standards is restricted to either nitrates, sulphates or organic reference materials alone, and in comparison with when this restriction was relaxed. A lower uncertainty in stable oxygen isotope analyses of solid materials performed using High-Temperature Pyrolysis (HTP) can be readily achieved through an optimal selection of reference materials. Among the currently available certified reference materials the best performing pairs minimising the normalisation errors are USGS35 and USGS34 for nitrates; IAEA-SO-6 and IAEA-SO-5 for sulphates; and IAEA-601 and IAEA-602 for organic materials. The normalisation error can be reduced further--by approximately half--if each of these two analysed reference materials is replicated four times. The overall optimal selection among all nine considered reference materials is the IAEA-602 and IAEA SO-6 pair. If each of these two reference materials is replicated four times the maximum predicted normalisation error will equal 0.220/00, the minimum normalisation error 0.120/00, and the mean normalisation error 0.150/00 over the natural range of delta(18)O variability. We argue that the proposed approach provides useful insights into reference material selection and in assessing the propagation of analytical error through normalisation procedures in stable oxygen isotope studies. PMID- 21594939 TI - Classification of protein binders in artist's paints by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry: an evaluation of principal component analysis (PCA) and soft independent modelling of class analogy (SIMCA). AB - Proteomics techniques are increasingly applied for the identification of protein binders in historical paints. The complex nature of paint samples, with different kinds of pigments mixed into, and degradation by long term exposure to light, humidity and temperature variations, requires solid analysis and interpretation methods. In this study matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectra of tryptic-digested paint replicas are subjected to principal component analysis (PCA) and soft independent modelling of class analogy (SIMCA) in order to distinguish proteinaceous binders based on animal glues, egg white, egg yolk and milk casein from each other. The most meaningful peptide peaks for a given protein class will be determined, and if possible, annotated with their corresponding amino acid sequence. The methodology was subsequently applied on egg temperas, as well as on animal glues from different species. In the latter small differences in the MALDI-TOF mass spectra can allow the determination of a mammal or sturgeon origin of the glue. Finally, paint samples from the 16(th) century altarpiece of St Margaret of Antioch (Mlynica, Slovakia) were analysed. Several expected peaks are either present in lower abundance or completely missing in these natural aged paints, due to degradation of the paints. In spite of this mammalian glue was identified in the St Margaret samples. PMID- 21594940 TI - Systematic comparison of delta13C measurements of testosterone and derivative steroids in a freeze-dried urine candidate reference material for sports drug testing by gas chromatography/combustion/isotope ratio mass spectrometry and uncertainty evaluation using four different metrological approaches. AB - An alternative calibration procedure for use when performing carbon isotope ratio measurements by gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) has been developed. This calibration procedure does not rely on the corrections in-built in the instrument software, as the carbon isotope ratios of a sample are calculated from the measured raw peak areas. The method was developed for the certification of a urine reference material for sports drug testing, as the estimation of measurement uncertainty is greatly simplified. To ensure that the method is free from bias arising from the choice of calibration material and instrument, the carbon isotope ratios of steroids in urine extracts were measured using two different instruments in different laboratories, and three different reference materials (CU/USADA steroid standards from Brenna Laboratory, Cornell University; NIST RM8539 mineral oil; methane calibrated against NIST RM8560 natural gas). The measurements were performed at LGC and the Australian National Measurement Institute (NMI). It was found that there was no significant difference in measurement results when different instruments and reference materials were used to measure the carbon isotope ratio of the major testosterone metabolites androsterone and etiocholanolone, or the endogenous reference compounds pregnanediol, 11- ketoetiocholanolone and 11beta hydroxyandrosterone. Expanded measurement uncertainties at the 95% coverage probability ranged from 0.210/00 to 1.40/00, depending on analyte, instrument and reference material. The measurement results of this comparison were used to estimate a measurement uncertainty of delta(13)C for the certification of the urine reference material being performed on a single instrument using a single reference material at NMI. PMID- 21594941 TI - Study of three-dimensional configurations of (gamma-methacryloxypropyl) silsesquioxanes by ultraviolet laser matrix-assisted desorption/ionization time of-flight mass spectrometry and quantum chemical calculation. AB - [(3-Methacryloxy)propyl]silsesquioxanes (MSSO) were prepared from the hydrolytic condensation of [(3-methacryloxy)-propyl]trimethoxysilane (MPMS) in the presence of an acid catalyst (HCOOH). The proposed MSSO structures were characterized with Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) ((1)H, (13)C and (29)Si), and were assigned by ultraviolet laser matrix-assisted desorption/ionization time-of-flight mass spectrometry (UV-MALDI-TOF MS). The large organic group connected to silicon was simplified for the quantum chemical calculation (QCC), and the correlation of the calculated total energies (E(T)) before and after simplification was analyzed by multiple linear regression, verifying no significant influence on the final conclusions of the research of structural formulas by a correlation coefficient (r). The geometric parameters (Si-O bond length and Si-O-Si, O-Si-O bond angles) and E(T) of the simplified MSSO were calculated by QCC to determine the relative stability of various MSSO structures. The structural geometry (silicon ring), the fraction of intramolecular cycles (f) and the number of the silicon rings (F) were also employed to qualitatively determine the relative stability. The results of the calculation showed that almost all of the cage structures had a lower E(T) than the isomeric ladder structures; therefore, most MSSO structures are of the cage type. PMID- 21594942 TI - Identification of multiple components in Guanxinning injection using hydrophilic interaction liquid chromatography/time-of-flight mass spectrometry and reversed phase liquid chromatography/time-of-flight mass spectrometry. AB - An approach for the identification of multiple components in traditional Chinese medicine injections (TCMIs) using a combination of hydrophilic interaction chromatography (HILIC) and reversed-phase liquid chromatography (RPLC) coupled with time-of-flight mass spectrometry (TOFMS) was developed for the quality control of Guanxinning injection (GXNI), a widely used TCMI, composed of Salvia miltiorrhiza and Ligusticum Chuanxiong. A total of 50 compounds from five compound classes, including saccharides, amino acids, organic acids, phenolic acids and phthalides, were identified or tentatively characterized on the basis of accurate mass measurements and subsequent TOFMS product ions. Six groups of isomers of phenolic acids and saccharides were tentatively distinguished. It was observed that the ESI-TOFMS fragmentation behavior of phthalides was different in negative and positive ion mode, and the fragmentation pathways were tentatively elucidated using structurally-relevant product ions. Several highly polar constituents were characterized for the first time from GXNI by HILIC/TOFMS. In addition, all the constituents identified from GXNI were further assigned in the two individual crude drugs. The integrated strategy has provided a powerful approach for the separation and identification of the multiple components in GXNI, and it has also assisted in the establishment of methods for the comprehensive safety and quality evaluation of TCMIs. PMID- 21594943 TI - Evaluation of allergens in propolis by ultra-performance liquid chromatography/tandem mass spectrometry. AB - The purified extract of propolis is used as a traditional remedy for the treatment of several diseases. Its beneficial activities are mainly attributed to the polyphenolic fraction. Nevertheless, propolis can cause allergic dermatitis and the sensitization rate in humans is increasing significantly mainly in younger subjects. The aim of this study was to develop and validate a selective and sensitive ultra-performance liquid chromatography tandem mass spectrometry analysis (UPLC/MS/MS) for the evaluation of the amount of caffeic acid and its esters with allergenic action in raw propolis samples and commercial formulations. The separation was carried out on a 1.7 MUm C(18) BEH Shield column and the detection performed by means of electrospray ionization in negative ion mode with multiple reaction monitoring. The confirmation of formulae of the precursor and product ions was accomplished by injection into a high-resolution system (FTICR-MS) using accurate mass measurements. The error was below 1.4 ppm.The range of the standard curves was 0.5-10 MUg/mL and dihydrocaffeic acid was used as internal standard (IS). The lower limit of detection (LLOD) for 3 methyl-2-butenyl-(3M2B), 3-methyl-3-butenyl-(3M3B), 2-methyl-2-butenyl-(2M2B), benzyl-(CABE), phenylethylcaffeic acid (CAPE) and for caffeic acid (CA) and the IS was 0.1 and 0.3 MUg/mL, respectively. The recoveries were in the range 96-104% and the intra- and inter-day precisions were within 6.2%. In the European (n=8) and Asiatic (n=3) propolis the most abundant allergens were CABE>3M2B>CAPE>3M3B>CA>2M2B. These compounds were not found in the red (n=1) and green (n=1) Brazilian propolis. Hydroalcoholic extracts (n=6) and tablets (n=6) were analyzed by the proposed UPLC/MS/MS method. The results showed that in the commercial products CABE, 3M2B, CAPE and 3M3B were also the most abundant. PMID- 21594944 TI - Long-term performance of the Gasbench isotope ratio mass spectrometry system for the stable isotope analysis of carbonate microsamples. PMID- 21594945 TI - NASCA-HMBC, a new NMR methodology for the resolution of severely overlapping signals: application to the study of agathisflavone. AB - INTRODUCTION: Standard NMR 2D heteronuclear HMBC spectra have a low resolution in the indirect carbon dimension, making it very difficult to assign signals to individual carbons when their chemical shifts are < 0.3 ppm apart. OBJECTIVE: To establish spectral aliasing for HMBC experiments to improve the resolution in the carbon dimension without increasing the total experimental time and avoiding ambiguities in the observed chemical shifts. METHODOLOGY: The NASCA-HMBC (Non ambiguous Assignment by Superposition of Coupled Aliased HMBC) methodology combines a pair of HMBC spectra recorded with slightly different carbon windows to provide typically one order of magnitude increase in the resolution and unambiguous chemical shifts. RESULTS: The application of this methodology to a biflavonoid found in Ouratea gilgiana resulted in spectra with a sufficiently high resolution to make the assignment straightforward and report, for the first time, the full assignment of agathisflavone. CONCLUSION: The methodology should find many applications in dimeric and oligomeric compounds such as peptides, carbohydrates, polyketides and other cases where signal clustering is expected. PMID- 21594946 TI - Allostery turns 50: is the vintage yet attractive? PMID- 21594947 TI - Backdoor opening mechanism in acetylcholinesterase based on X-ray crystallography and molecular dynamics simulations. AB - The transient opening of a backdoor in the active-site wall of acetylcholinesterase, one of nature's most rapid enzymes, has been suggested to contribute to the efficient traffic of substrates and products. A crystal structure of Torpedo californica acetylcholinesterase in complex with the peripheral-site inhibitor aflatoxin is now presented, in which a tyrosine at the bottom of the active-site gorge rotates to create a 3.4-A wide exit channel. Molecular dynamics simulations show that the opening can be further enlarged by movement of Trp84. The crystallographic and molecular dynamics simulation data thus point to the interface between Tyr442 and Trp84 as the key element of a backdoor, whose opening permits rapid clearance of catalysis products from the active site. Furthermore, the crystal structure presented provides a novel template for rational design of inhibitors and reactivators, including anti Alzheimer drugs and antidotes against organophosphate poisoning. PMID- 21594948 TI - Quantification of postsynaptic density proteins: glutamate receptor subunits and scaffolding proteins. AB - The postsynaptic density (PSD) protein complex has long been a major target of proteomics in neuroscience. As the number of glutamate receptors on a synapse is one of the main determinants of synaptic efficacy, determining the absolute numbers of receptors in the PSD is necessary for estimating the amplitude of the excitatory postsynaptic current (EPSC) in individual synapses. Moreover, as the receptor molecules are embedded in a macromolecular complex within the PSD, stoichiometry between the receptors and other PSD proteins could help explain the functional and regional specialization of the synapses and their possible roles in synaptic plasticity. Here, I review various studies concerned with the quantification of PSD proteins. PMID- 21594949 TI - New insights into "GPR40-CREB interaction in adult neurogenesis" specific for primates. AB - Polyunsaturated fatty acids (PUFA), such as docosahexaenoic (DHA) and arachidonic acids (ARA) are known to be closely related to the brain development and also have beneficial effects on adult neurogenesis, learning, and mental disorders. Although PUFA were demonstrated as ligands for G protein-coupled receptor 40 (GPR40), their signaling mechanism in the brain, especially in the neurogenic niche, remains unknown. Using a monkey model of ischemia-enhanced hippocampal neurogenesis, we studied the spatial correlation between GPR40 and the phosphorylated cAMP response element-binding protein (pCREB), a transcription factor involved in adult neurogenesis, learning and memory. Furthermore, the brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB), both being downstream gene transcripts of pCREB, were studied. Similar to the dynamic change of GPR40 as the authors reported previously, pCREB was up-regulated significantly after transient global brain ischemia on Western blots, and this was associated with an enhanced hippocampal neurogenesis. Immunofluorescence microscopic analysis showed that GPR40 and pCREB expression patterns were completely identical, and they were coexpressed in both mature and newborn neurons as well as in the astrocytes residing in the subgranular zone (SGZ). GPR40/pCREB double-positive cells significantly increased in the SGZ on day 15 after ischemia. The mature form of BDNF (mBDNF) and TrkB receptor showed no remarkable changes on Western blots, although proBDNF (precursor of mBDNF) was maximal on day 9. Immunofluorescence microscopy showed that the newborn neurons expressed BDNF, but not TrkB. These results altogether suggest that PUFA, GPR40, pCREB, and BDNF may be engaged in the same signaling pathway to promote neurogenesis in the adult primate hippocampus. PMID- 21594951 TI - Cerebrospinal fluid control of neurogenesis induced by retinoic acid during early brain development. AB - Embryonic-cerebrospinal fluid (E-CSF) plays crucial roles in early brain development including the control of neurogenesis. Although FGF2 and lipoproteins present in the E-CSF have previously been shown to be involved in neurogenesis, the main factor triggering this process remains unknown. E-CSF contains all-trans retinol and retinol-binding protein involved in the synthesis of retinoic acid (RA), a neurogenesis inducer. In early chick embryo brain, only the mesencephalic rombencephalic isthmus (IsO) is able to synthesize RA. Here we show that in chick embryo brain development: (1) E-CSF helps to control RA synthesis in the IsO by means of the RBP and all-trans-retinol it contains; (2) E-CSF has retinoic acid activity, which suggests it may act as a diffusion pathway for RA; and (3) the influence of E-CSF on embryonic brain neurogenesis is to a large extent due to its involvement in RA synthesis. These data help to understand neurogenesis from neural progenitor cells. PMID- 21594950 TI - The identification of transcription factors expressed in the notochord of Ciona intestinalis adds new potential players to the brachyury gene regulatory network. AB - The notochord is the distinctive characteristic of chordates; however, the knowledge of the complement of transcription factors governing the development of this structure is still incomplete. Here we present the expression patterns of seven transcription factor genes detected in the notochord of the ascidian Ciona intestinalis at various stages of embryonic development. Four of these transcription factors, Fos-a, NFAT5, AFF and Klf15, have not been directly associated with the notochord in previous studies, while the others, including Spalt-like-a, Lmx-like, and STAT5/6-b, display evolutionarily conserved expression in this structure as well as in other domains. We examined the hierarchical relationships between these genes and the transcription factor Brachyury, which is necessary for notochord development in all chordates. We found that Ciona Brachyury regulates the expression of most, although not all, of these genes. These results shed light on the genetic regulatory program underlying notochord formation in Ciona and possibly other chordates. PMID- 21594952 TI - Neural crest cells retain their capability for multipotential differentiation even after lineage-restricted stages. AB - Multipotency of neural crest cells (NC cells) is thought to be a transient phase at the early stage of their generation; after NC cells emerge from the neural tube, they are specified into the lineage-restricted precursors. We analyzed the differentiation of early-stage NC-like cells derived from Sox10-IRES-Venus ES cells, where the expression of Sox10 can be visualized with a fluorescent protein. Unexpectedly, both the Sox10+/Kit- cells and the Sox10+/Kit+ cells, which were restricted in vivo to the neuron (N)-glial cell (G) lineage and melanocyte (M) lineage, respectively, generated N, G, and M, showing that they retain multipotency. We generated mice from the Sox10-IRES-Venus ES cells and analyzed the differentiation of their NC cells. Both the Sox10+/Kit- cells and Sox10+/Kit+ cells isolated from these mice formed colonies containing N, G, and M, showing that they are also multipotent. These findings suggest that NC cells retain multipotency even after the initial lineage-restricted stages. PMID- 21594953 TI - Isolation and cytogenetic characterization of zebrafish meiotic prophase I mutants. AB - We describe here the isolation and cytogenetic characterization of three meiotic prophase I mutants, denoted ietsugu (its), iesada (isa), and iemochi (imo), isolated by a novel N-ethyl-N-nitrosourea mutagenesis screen for adult zebrafish gonadogenesis. Histological examination and flow cytometry analysis of testes from these mutants showed that each contained neither spermatids nor sperm. Staining for Sycp3 and cleaved Caspase-3 and TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end-labeling) assay further revealed that its had defects at the onset of meiosis, and that isa and imo spermatocytes failed to progress past the zygotene stage with apoptosis occurring in the testicular somatic cells. Staining for phosphorylated histone H2AX showed that foci formation in leptotene spermatocytes was disrupted in isa and imo. Furthermore, in vitro differentiation experiments revealed the possibility that the defects and sterility associated with mutations were germ line autonomous. Our results thus indicate that each responsible gene is necessary for meiotic progression during spermatogenesis and for male fertility. PMID- 21594954 TI - Assessing risk and prioritizing referral for self-harm: when and why is my judgement different from yours? AB - This study investigated individual differences in the use of risk factors when making risk assessments for self-harm. Clinical judgement analysis using 35 hypothetical case scenarios was used to determine how case characteristics influence risk assessment for self-harm by mental health professionals. Seven practitioners made four risk/priority assessment judgements for each case, and individual models of judgement for risk and priority were constructed by regressing 10 case variables onto these sets of judgements. All but two of the variables (potential risk factors) examined were related to risk and/or priority judgements. Risk assessors applied cues to make assessments consistently-broadly consistent with practice guidelines-although precise cue application varied between professionals. The findings demonstrate the potential for ambiguity in risk assessment (terms such as 'low' or 'high' risk had variable interpretation) and that it can be important to specify whether risk is to be assessed for the initiation, continuation, re-occurrence, or escalation of an event or condition. The study shows the importance of clear practice guidelines (not all risk factors were used as might be anticipated from practice guidelines) and illustrates how clinical judgement analysis can be used to understand and enhance the reliability of professional judgement. KEY PRACTITIONER MESSAGE: The process by which risk assessment is undertaken can be reliably statistically modelled to allow an in depth examination of an individual practitioner or comparisons between practitioners, which can be used to support efforts to improve assessment reliability. Senior practitioners may be more consistent in applying information to clinical judgements of self-harm. Apparent agreement over a categorical judgement of risk may mask an underlying disagreement over numerical probabilities. The term 'low risk' may be particularly subject to variability in its interpretation. The term 'risk' can be ambiguous, reflecting the probability of occurrence for some practitioners and the severity of its occurrence for others, a problem that may be compounded if it is unclear exactly which event is being assessed (e.g., risk of initiating the behaviour versus risk of re occurrence). PMID- 21594955 TI - Colonic duplication mimicking fistulizing Crohn's colitis. PMID- 21594956 TI - Research integrity and misconduct: first-hand experiences of plagiarism and data manufacture. PMID- 21594957 TI - Self-assembly of a bifunctional DNA carrier for drug delivery. PMID- 21594958 TI - A microbiological-chemical strategy to produce chondroitin sulfate A,C. PMID- 21594960 TI - A randomized, controlled study of autologous therapy with bone marrow-derived aldehyde dehydrogenase bright cells in patients with critical limb ischemia. AB - OBJECTIVES: The safety and efficacy of direct intramuscular injections of aldehyde dehydrogenase bright (ALDH(br)) cells isolated from autologous bone marrow mononuclear cells (ABMMNCs) and ABMMNCs were studied in patients with critical limb ischemia (CLI) who were not eligible for percutaneous or surgical revascularization. BACKGROUND: Many CLI patients are not candidates for current revascularization procedures, and amputation rates are high in these patients. Cell therapy may be a viable option for CLI patients. METHODS: Safety was the primary objective and was evaluated by occurrence of adverse events. Efficacy, the secondary objective, was evaluated by assessment of Rutherford category, ankle-brachial index (ABI), transcutaneous partial pressure of oxygen (TcPO(2)), quality of life, and pain. RESULTS: ALDH(br) cells and ABMMNCs were successfully administered to all patients. No therapy-related serious adverse events occurred. Patients treated with ALDH(br) cells (n = 11) showed significant improvements in Rutherford category from baseline to 12 weeks (mean, 4.09 +/- 0.30 to 3.46 +/- 1.04; P = 0.05) and in ABI at 6 (mean, 0.22 +/- 0.19 to 0.30 +/- 0.24; P = 0.02), and 12 weeks (mean, 0.36 +/- 0.18; P = 0.03) compared with baseline. Patients in the ABMMNC group (n = 10) showed no significant improvements at 6 or 12 weeks in Rutherford category but did show improvement in ABI from baseline to 12 weeks (0.38 +/- 0.06 to 0.52 +/- 0.16; P = 0.03). No significant changes from baseline were noted in ischemic ulcer grade or TcPO(2) in either group. CONCLUSIONS: Administration of autologous ALDH(br) cells appears to be safe and warrants further study in patients with CLI. PMID- 21594961 TI - Uptake, translocation and metabolism of aminocyclopyrachlor in prickly lettuce, rush skeletonweed and yellow starthistle. AB - BACKGROUND: Aminocyclopyrachlor is a new herbicide proposed to control broadleaf weeds and shrubs in non-crop and rangeland systems. To gain a better understanding of observed field efficacy, the uptake and translocation of foliar applied aminocyclopyrachlor (DPX-MAT28) and aminocyclopyrachlor methyl ester (DPX KJM44) were evaluated in two annuals, prickly lettuce (Lactuca serriola L.) and yellow starthistle (Centaurea solstitialis L.), and one perennial, rush skeletonweed (Chondrilla juncea L.). RESULTS: Absorption and translocation varied between species. While absorption of DPX-KJM44 was greater than absorption of DPX MAT28, rush skeletonweed absorbed the most, followed by yellow starthistle and prickly lettuce. Overall, the total translocation of either herbicide was highest in yellow starthistle, followed by rush skeletonweed and prickly lettuce. Proportional herbicide movement between species was similar, with the majority translocating to developing shoots. However, in rush skeletonweed, early translocation was directed to root tissue. In rush skeletonweed, no DPX-MAT28 metabolism occurred, while DPX-KJM44 was rapidly de-esterified and translocated as DPX-MAT28. CONCLUSION: Aminocyclopyrachlor absorption and translocation are dependent on active ingredient structure and species sensitivity. Highly sensitive species such as prickly lettuce absorb and translocate less material than relatively less sensitive species such as rush skeletonweed. De esterification of DPX-KJM44 appears to delay translocation of the resulting acid in yellow starthistle and rush skeletonweed. PMID- 21594963 TI - Assessment of resistance risk in Spodoptera exigua (Hubner) (Lepidoptera: Noctuidae) to chlorantraniliprole. AB - BACKGROUND: Beet armyworm, Spodoptera exigua (Hubner) (Lepidoptera: Noctuidae), is a major pest of numerous cultivated crops. Chlorantraniliprole, the first commercialised ryanodine receptor insecticide from the anthranilic diamide class, has exceptional insecticidal activity on a range of lepidopteran pests. The aim of this study was to assess the resistance of S. exigua to chlorantraniliprole in the laboratory. RESULTS: A field-collected population of S. exigua was selected after repeated exposure to chlorantraniliprole to determine the risk of resistance evolution. After 22 generations of selection, there was a 12.0-fold increase in LC(50) . The realised heritability (h(2)) of resistance was estimated as 0.1082 by using threshold trait analysis. The projected rate of resistance evolution indicated that, if h(2) = 0.1082 and 70% of the population was killed at each generation, then a tenfold increase in LC(50) would be expected in 21.7 generations for chlorantraniliprole. CONCLUSION: These results show that the risk of resistance development to chlorantraniliprole exists in S. exigua after continuous application. PMID- 21594962 TI - Isoforms of the heteropteran Nezara viridula ecdysone receptor: protein characterisation, RH5992 insecticide binding and homology modelling. AB - BACKGROUND: Certain bisacylhydrazine compounds such as tebufenozide (RH5992) have been shown to act as order-specific insecticides. Their compatibility with predatory Heteroptera, which are used as biological control agents, has also been demonstrated. However, the molecular mode of action of these ecdysone agonists has not been explored in a heteropteran, much less one that is a significant agricultural pest, such as Nezara viridula. RESULTS: Alternatively spliced ligand binding regions of the N. viridula ecdysone receptor were expressed, purified and characterised by 2D gel analysis, mass spectrometry, homology modelling and competitive binding of a bisacylhydrazine insecticidal compound (RH5992) and various ecdysteroids. Ligand binding by the two splice isoforms was indistinguishable, and relative affinities were found to occur in the order muristerone A > ponasterone A > 20-hydroxyecdysone > inokosterone > RH5992 > alpha-ecdysone. CONCLUSION: The predicted difference in amino acid sequence between the ligand-binding domains of the N. viridula ecdysone receptor splice variants was verified by mass spectrometry. Both splice variant isoforms exhibit a greater affinity for the bisacylhydrazine insecticide RH5992 than do the other hemipteran ecdysone receptors characterised to date. Their affinities for a range of ecdysteroids also distinguish them from the ecdysone receptors of other Hemiptera characterised thus far. Homology models of both N. viridula receptor isoforms provide further insight into the bisacylhydrazine- and ecdysteroid binding properties of these receptors, including their similar affinity for 20 hydroxyecdysone and the postulated pentatomomorphan moulting hormone makisterone A. PMID- 21594964 TI - Studies on the development of a mating disruption system to control the tomato leafminer, Tuta absoluta Povolny (Lepidoptera: Gelechiidae). AB - BACKGROUND: The tomato leafminer (Tuta absoluta Povolny) has rapidly colonised the whole Mediterranean and South-Atlantic coasts of Spain, and it has become a key problem in both outdoor and greenhouse crops. New control methods compatible with biological control are required, and mating disruption appears to be a perfect method in current agriculture, as it is an environmentally friendly and residue-free technique. IPM packages tested have included the use of pheromones to detect populations, but there has not been much previous research on mating disruption of T. absoluta. In this work, pheromone doses varying from 10 to 40 g ha(-1), emitted at a constant rate over 4 months, were tested in greenhouses with different levels of containment in order to evaluate the efficacy of mating disruption on T. absoluta. RESULTS: Trials on containment level revealed that the flight of T. absoluta was satisfactorily disrupted with an initial pheromone dose of 30 g ha(-1), and levels of damage did not significantly differ from those in reference plots with insecticide treatments. Later efficacy trials confirmed previous experiences, and release studies showed that control of damage and flight disruption were taking place when releasing at least 85 mg pheromone per ha per day. CONCLUSION: Effective control using pheromone application against T. absoluta can be achieved, in greenhouses with high containment levels, for 4 months, with initial doses of 30 g ha(-1). Further research must be conducted in order to evaluate the prospect of outdoor application of mating disruption systems. PMID- 21594965 TI - Volumetry-based selection of right posterior sector grafts for adult living donor liver transplantation. AB - To determine the feasibility of volumetric criteria without anatomic exclusion for the selection of right posterior sector (RPS) grafts for adult-to-adult living donor liver transplantation (LDLT), we reviewed and compared our transplant data for RPS grafts and right lobe (RL) grafts. Between January 2008 and September 2010, adult-to-adult LDLT was performed 65 times at our institute; 13 of the procedures (20%) were performed with RPS grafts [the posterior sector (PS) group], and 39 (60%) were performed with RL grafts (the RL group). The volumetry of the 13 RPS donor livers showed that the RPS volume was 39.8% +/- 7.6% of the total liver volume. Ten of the 13 donors had to donate RPS grafts because the left liver volume was inadequate. All donor procedures were performed successfully, and all donors recovered from hepatectomy. However, longer operative times were required for the procurement of RPS grafts versus RL grafts (418 +/- 40 versus 345 +/- 48 minutes, P < 0.001). The postoperative recovery of liver function was smoother for the donors of the PS group versus the donors of the RL group. The RPS grafts had significantly smaller hepatic artery and bile duct openings than the RL grafts. All recipients with RPS grafts survived LDLT. No recipients experienced vascular graft complications or small-for-size graft dysfunction. There were no significant differences in the incidence of posttransplant complications between the donors and recipients of the PS and RL groups. The 3-year graft survival rates were favorable in both groups (100% in the PS group versus 91% in the RL group). In conclusion, the selection of RPS grafts by volume criteria is a feasible strategy for an adult-to-adult LDLT program. PMID- 21594966 TI - Outcomes of orthotopic liver transplantation for hepatic sarcoidosis: an analysis of the United Network for Organ Sharing/Organ Procurement and Transplantation Network data files for a comparative study with cholestatic liver diseases. AB - Hepatic sarcoidosis is a rare indication for liver transplantation. Using the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) database, we evaluated patient and graft survival after orthotopic liver transplantation for sarcoidosis between October 1987 and December 2007. We assessed the potential prognostic value of multiple demographic and clinical variables, and we also compared these patients to a case-matched group of patients with primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC). The 1- and 5-year survival rates for the sarcoidosis group were 78% and 61%, respectively, and these rates were significantly worse than the rates for the PSC/PBC group (P = 0.001). Disease recurrence in the liver is a rare cause of graft loss or patient death. Three deaths occurred in the sarcoidosis group because of recurrent hepatic sarcoidosis, and 1 death was a result of cardiac sarcoidosis. A univariate analysis identified an increasing donor risk index as a significant negative factor for outcomes for the sarcoidosis group [hazard ratio (HR) = 2.06, confidence interval (CI) = 1.04-4.06, P = 0.037], but this finding was not found in a multivariate analysis, in which no independent predictors were found to have a significant impact. A case-matched univariate analysis demonstrated that sarcoidosis and morbid obesity were significant negative factors for outcomes, and in a multivariate analysis, sarcoidosis continued to predict worse outcomes (HR = 2.39, CI = 1.21-4.73, P = 0.012). In conclusion, an analysis of the UNOS/OPTN database indicates that the patient and allograft survival rates for hepatic sarcoidosis are satisfactory, but they are worse in comparison with the rates for other cholestatic liver diseases. PMID- 21594968 TI - Vital significance of addition of "shape similarity" between solutes to shape complementarity for more precise molecular recognition in aqueous binary solvents. AB - Precise and specific molecular recognition is vital to living systems. Discrimination has mainly been studied by using particular host molecules (e.g., crown ethers, cyclodextrin and urea derivatives). Several studies in various fields have pointed out that the famous "lock-and-key theory" (the concept of shape complementarity) is, at present, insufficient for understanding precise discrimination. This seems to come from the fact that various types of intermolecular interactions are decisive in such discrimination. This Review intends to describe the novel concept that "shape similarity" between interacting solutes should be added to "shape complementarity" for more precise discrimination to be achieved. Further, the role of shape similarity between solvent and solute molecules is also described. In relation to precise molecular recognition, weak interactions, which depend on the three-dimensional shape of substituents (shape-specific weak interactions), are described. Possibility of alterations in solvent structures is discussed in aqueous binary solvents. PMID- 21594967 TI - Tissue biomarkers as predictors of outcome and selection of transplant candidates with hepatocellular carcinoma. PMID- 21594969 TI - Nanoscale polyoxometalate-based inorganic/organic hybrids. AB - The latest advances in the area of polyoxometalate (POM)-based inorganic/organic hybrid materials prepared by self-assembly, covalent modification, and supramolecular interactions are presented. This Review is composed of five sections and documents the effect of organic cations on the formation of novel POMs, surfactant encapsulated POM-based hybrids, polymeric POM/organic hybrid materials, POMs-containing ionic crystals, and covalently functionalized POMs. In addition to their role in the charge-balancing, of anionic POMs, the crucial role of organic cations in the formation and functionalization of POM-based hybrid materials is discussed. PMID- 21594970 TI - Expression analysis of some genes regulated by retinoic acid in controls and triadimefon-exposed embryos: is the amphibian Xenopus laevis a suitable model for gene-based comparative teratology? AB - BACKGROUND: The use of nonmammal models in teratological studies is a matter of debate and seems to be justified if the embryotoxic mechanism involves conserved processes. Published data on mammals and Xenopus laevis suggest that azoles are teratogenic by altering the endogenous concentration of retinoic acid (RA). The expression of some genes (Shh, Ptch-1, Gsc, and Msx2) controlled by retinoic acid is downregulated in rat embryos exposed at the phylotypic stage to the triazole triadimefon (FON). In order to propose X. laevis as a model for gene-based comparative teratology, this work evaluates the expression of Shh, Ptch-1, Gsc, and Msx2 in FON-exposed X. laevis embryos. METHODS: Embryos, exposed to a high concentration level (500 uM) of FON from stage 13 till 17, were examined at stages 17, 27, and 47. Stage 17 and 27 embryos were processed to perform quantitative RT-PCR. RESULTS: The developmental rate was never affected by FON at any considered stage. FON-exposed stage 47 larvae showed the typical craniofacial malformations. A significant downregulation of Gsc was observed in FON-exposed stage 17 embryos. Shh, Ptch-1, Msx2 showed a high fluctuation of expression both in control and in FON-exposed samples both at stages 17 and 27. CONCLUSION: The downregulation of Gsc mimics the effects of FON on rat embryos, showing for this gene a common effect of FON in the two vertebrate classes. The high fluctuation observed in the gene expression of the other genes, however, suggests that X. laevis at this stage has limited utility for gene-based comparative teratology. PMID- 21594971 TI - Juvenile toxicity assessment of open-acid lovastatin in rats. AB - BACKGROUND: Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, reduces de novo cholesterol biosynthesis primarily in the liver. Since cholesterol is a major component of brain myelin and peak periods of brain myelination occurs after birth, this study was designed to encompass this period in rats and evaluate the potential neurotoxic effects. METHODS: The pharmacologically active, open-acid form of lovastatin was administered to groups of 50 Sprague-Dawley rats per sex subcutaneously once daily at dose levels of 0 (vehicle), 2.5, 5, or 10 mg/kg/day beginning on postnatal day 4 and continuing until termination on postnatal day 41 to 51. Physical signs and body weights were monitored during the study. Animals were assessed in a battery of behavioral tests, and at termination a set of animals were examined for gross and histological changes. RESULTS: There were no test article-related deaths, physical signs, or effects on preweaning and postweaning body weights during the study. In the behavior tests there were no test article-related effects in the passive avoidance, auditory startle habituation, open-field motor activity, or FOB. No test article-related postmortem findings were observed, including brain weights and histomorphology of brain, spinal cord, eye, optic nerve, or peripheral nerve. CONCLUSION: Based on these results, the no-effect level for general and neurobehavioral toxicity in neonatal rats was >=10 mg/kg/day for open acid lovastatin. PMID- 21594972 TI - Toxicity study in juvenile rats with the alpha4beta2 nicotinic acetylcholine receptor partial agonist CP-601,927. AB - BACKGROUND: CP-601927 is a selective alpha(4) beta(2) nicotinic acetylcholine receptor (nAChR) partial agonist. The objective of this study was to assess the potential effects persisting into adulthood when CP-601,927 was administered to neonatal/juvenile rats. Since the juvenile toxicity study was being performed early in the development program and this study would represent the longest dosing period yet evaluated, the study design incorporated standard endpoints typically evaluated in a general toxicity screening study. METHODS: CP-601,927 was administered to Sprague-Dawley rats from postnatal day (PND) 7-70 by oral gavage at doses of 0.3, 1, or 3 mg/kg. During treatment animals were evaluated for growth, development, and sexual maturation. At the end of the treatment period general toxicity screening endpoints were collected (e.g., organ weights, histology, clinical chemistry). Following a 2-week latency period, animals were evaluated for CNS function in a comprehensive behavioral training battery consisting of a functional observational battery, motor activity, acoustic startle response, and learning and memory evaluations. Reproductive competency was evaluated by mating treated rats and allowing pregnant dams to deliver and rear their litters until PND 10. RESULTS AND CONCLUSIONS: Treatment-related findings included the death of 2 males receiving 3 mg/kg CP-601,927, and transient reductions in body weight for both males and females during the third week of dosing which quickly recovered to control levels. The only treatment related alteration in behavior was decreased motor activity, which occurred only in females at the highest dose tested. CP-601,927 had no effect on acoustic startle response, learning and memory, sexual maturation, reproductive capacity, or general toxicity endpoints. PMID- 21594973 TI - Juvenile animal studies in the development of pediatric medicines: experience from European medicines and pediatric investigation plans. AB - INTRODUCTION: The need for early consideration of pediatric investigation plans (PIP) to support an indication in pediatric population has led to an increased focus on the relevance of nonclinical studies in juvenile animals (JAS). The usefulness of JAS is not yet established and a criterion for request is still a learning process. OBJECTIVE: This article compares data from JAS in all medicines approved by European centralized procedure before Pediatric Regulation (1995 2005) and data from JAS in the nonclinical information on all approved PIP (2007 2009). RESULTS: Of the 226 substances licensed by centralized procedure in 10 years, 31.9% were considered for children and 31 JAS were described in 9.7%. Since 2007, of the 205 PIP decisions, 50 PIP (24.3%) have 87 JAS planned or requested. The mean number of JAS in each medicine or PIP, increased from 1.4 to 1.7 between the two periods and the juvenile rat remained as the prevalent species. CONCLUSIONS: Results demonstrate that JAS planned/performed in EU environment has significantly increased. PMID- 21594974 TI - The value of juvenile animal studies: a Japanese industry perspective. AB - Pharmaceuticals have been used on adults and children; however, they were previously investigated only by adult human clinical studies and adult animal nonclinical studies. The US FDA finalized the guidance of juvenile animal toxicity studies in 2006, and EMEA was finalized in 2008. At that point, juvenile animal toxicity studies were encouraged to investigate the safety of the pediatric population. In Japan, the awareness of the development of pediatric drugs is increasing, and many scientific meetings about juvenile animal studies are being held. A Japanese guideline for juvenile animal toxicity studies has been long awaited by many Japanese pharmaceutical companies because concrete directionality has not been available in Japan thus far. The Ministry of Health, Labour, and Welfare started to prepare the guideline for nonclinical safety studies in juvenile animals since October 2010. After completion of the Japanese guideline, guidelines would exist in the three regions: Japan, US, and Europe. Then, global development of pediatric pharmaceuticals would be accelerated effectively. PMID- 21594975 TI - Juvenile toxicity assessment of anidulafungin in rats: an example of navigating case-by-case study design through scientific and regulatory challenges. AB - BACKGROUND: Anidulafungin, an echinocandin antifungal marketed for adult use, is being considered for use in pediatric populations, including neonates. The evolution of the nonclinical pediatric safety strategy for anidulafungin serves as an example of case-by-case negotiation through the European Medicines Agency pediatric investigation plan process, resulting in an acceptable juvenile rat toxicity study. METHODS: Study design challenges included animal selection, route, dose, age, and duration of dosing in relation to brain maturity, and appropriate study endpoints. The definitive study consisted of subcutaneous dosing at 0, 3, 10, and 30 mg/kg/day from postnatal day 4 to 62 (preterm infant to adulthood) with a 5-week recovery period. Study endpoints evaluated the potential for increased juvenile sensitivity to liver toxicity (seen in adults) and for novel toxicities in the central nervous system. RESULTS: Anidulafungin related effects included slightly reduced body weight, increased liver weight, and a mild decrease in red blood cell mass with increased reticulocyte count. There was no liver pathology and in the posttreatment phase there were no effects on neurological function. Following recovery, effects on body weight, hematology, and liver weight were reversing or reversed. CONCLUSIONS: Therefore, the juvenile rat no-adverse-effect-level was 30 mg/kg/day. Exposures at this dose are similar to those achieved at the adult rat no-adverse-effect-level, suggesting that the juvenile rat is no more sensitive to anidulafungin than the adult rat. In conclusion, dialog and negotiation between the sponsor and the European Medicines Agency allowed for successful execution of a nonclinical safety strategy that enabled further clinical investigation of anidulafungin in pediatric populations. PMID- 21594976 TI - Nonclinical support of pediatric drug development in a global context: an industry perspective. AB - The earlier inclusion of children into clinical trials has challenged toxicologists to develop nonclinical strategies to support these trials early in the drug development process, and the routine practise of global development strategies (i.e., concomitant development and filing in multiple geographical regions) adds another complication. Ideally, one would like to develop a stagey that would meet regulatory requirements from all regions. This presentation illustrated the challenges faced in developing a strategy regarding the need to perform a toxicity study in juvenile animals and the design of any necessary study that will receive global regulatory agreement. PMID- 21594977 TI - Juvenile animal studies and pediatric drug development retrospective review: use in regulatory decisions and labeling. AB - Juvenile animal toxicity studies are conducted to support applications for drugs intended for use in children. They are designed to address specific questions of potential toxicity in the growing animal or provide data about long-term safety effects of drugs that cannot be obtained from clinical trials. Decisions to conduct a juvenile animal study are based on existing data, such as a safety signal already identified in adult studies, or previous knowledge of the drug or chemical class for its potential to impair growth or developmental milestones. In 2006, the FDA issued an industry guidance in which considerations for determining when a juvenile animal study is warranted were outlined. A retrospective study was conducted covering years both before and after the issued guideline to examine the contribution of juvenile animal toxicity studies to the risk/benefit assessment of pediatric drugs at the FDA. The initial findings were presented as part of the May 2010 HESI workshop on the value of juvenile animal studies. The objective of the review was to better understand the value that the juvenile animal study contributes to regulatory decision making for pediatric drug development by looking at when the studies have been included in the product assessment; what, if any, impact the studies had on the regulatory decisions made; and whether the data were incorporated into the label. The data described below represent a first look at impact of the juvenile animal study since the pediatric legislation and the juvenile animal guidance were issued in the US. PMID- 21594978 TI - The value of juvenile animal studies: a pediatric clinical perspective. AB - With the emphasis of US American and European legislators on consideration of children in the drug development process regulatory authorities ask increasingly for additional non-clinical data to elucidate the safety of a given drug in development in future pediatric use. Juvenile animal studies are increasingly requested. These requests should never be tick box requests. Companies, academic toxicologists, clinicians, and regulatory authorities need a dialogue to differentiate between the perceived need to do "something" and the request for studies that have clinically meaningful results. PMID- 21594979 TI - Developmental toxicity of Citrus aurantium in rats. AB - BACKGROUND: Ephedra was commonly used in herbal products marketed for weight loss until safety concerns forced its removal from products. Even before the ban, manufacturers had begun to replace ephedra with other compounds, including Citrus aurantium, or bitter orange. The major component in the bitter orange extract is synephrine which is chemically similar to ephedrine. The purpose of this study was to determine if relatively pure synephrine or synephrine present as a constituent of a bitter orange extract produced developmental toxicity in rats. METHOD: Sprague-Dawley rats were dosed daily by gavage with one of several different doses of synephrine from one of two different extracts. Caffeine was added to some doses. Animals were sacrificed on GD 21, and fetuses were examined for the presence of various developmental toxic endpoints. RESULTS AND CONCLUSION: At doses up to 100 mg synephrine/kg body weight, there were no adverse effects on embryolethality, fetal weight, or incidences of gross, visceral, or skeletal abnormalities. There was a decrease in maternal weight at 50 mg synephrine/kg body weight when given as the 6% synephrine extract with 25 mg caffeine/kg body weight; there was also a decrease in maternal weight in the caffeine only group. This decrease in body weight may have been due to decreased food consumption which was also observed in these two groups. Overall, doses of up to 100 mg synephrine/kg body weight did not produce developmental toxicity in Sprague-Dawley rats. PMID- 21594980 TI - Hospital-based home care for children with cancer. AB - Hospital-based home care (HBHC) is widely applied in Pediatric Oncology. We reviewed the potential effect of HBHC on children's physical health and risk of adverse events, parental and child satisfaction, quality of life of children and their parents, and costs. A search of PubMed, CINAHL, and EMBASE led to identification of five studies that met the inclusion criteria. All sample sizes were small, and both the interventions and the outcome measures were diverse. Although burdened by these limitations, the studies indicate that HBHC is feasible and carries no crucial negative effects for children with cancer. PMID- 21594981 TI - The impact of nutritional status on outcomes: a neglected area of research. PMID- 21594982 TI - Primary mediastinal neuroendocrine carcinoma in a child with Down syndrome. PMID- 21594983 TI - Is it time to SWiTCH to composite primary endpoints? PMID- 21594985 TI - Karyotype result prior to surgery in patients with suspected ovarian germ cell tumors. PMID- 21594986 TI - Achievements of risk-based produced water management on the Norwegian continental shelf (2002-2008). AB - In 1996, the Norwegian government issued a White Paper requiring the Norwegian oil industry to reach the goal of "zero discharge" for the marine environment by 2005. To achieve this goal, the Norwegian oil and gas industry initiated the Zero Discharge Programme for discharges of produced formation water from the hydrocarbon-containing reservoir, in close communication with regulators. The environmental impact factor (EIF), a risk-based management tool, was developed by the industry to quantify and document the environmental risks from produced water discharges. The EIF represents a volume of recipient water containing concentrations of one or more substances to a level exceeding a generic threshold for ecotoxicological effects. In addition, this tool facilitates the identification and selection of cost-effective risk mitigation measures. The EIF tool has been used by all operators on the Norwegian continental shelf since 2002 to report progress toward the goal of "zero discharge," interpreted as "zero harmful discharges," to the regulators. Even though produced water volumes have increased by approximately 30% between 2002 and 2008 on the Norwegian continental shelf, the total environmental risk from produced water discharges expressed by the summed EIF for all installations has been reduced by approximately 55%. The total amount of oil discharged to the sea has been reduced by 18% over the period 2000 to 2006. The experience from the Zero Discharge Programme shows that a risk based approach is an excellent working tool to reduce discharges of potential harmful substances from offshore oil and gas installations. PMID- 21594990 TI - Early pontocerebellar hypoplasia with vanishing testes: A new syndrome? AB - We report on a full-term male infant with hypoplastic male genitalia and bilateral impalpable testes noted at birth, who over the following months developed increasing hypotonia, apneic episodes, and seizures resulting in his death at age 24 weeks. During this period regression of penile corporeal tissue was observed. An endocrinological diagnosis of primary hypogonadism was made and cerebral imaging at 19 weeks showed reduced periventricular white matter with marked pontocerebellar hypoplasia (PCH)/atrophy, but a well-developed posterior fossa. We propose that this condition constitutes a new form of severe PCH/atrophy with testicular regression that has onset in the fetal period. PMID- 21594991 TI - A comparison of the background, needs, and expectations of patients seeking genetic counseling services. AB - Patient background, needs, and expectations (BNE) can be important predictors and modifiers of the process and outcomes of genetic counseling. We describe the assessment of BNE of 216 genetic counseling clients using the BNE Scale. Twenty five percent sought reproductive genetic counseling (RGC), 57% sought adult pediatric genetic counseling (APGC), and 18% sought cancer genetic counseling (CaGC). Analyses of the BNE of these patient groups identified significant differences in general unsureness/uncertainty about their condition (df = 2, F = 3.96, Significance =0.02), beliefs about treatment for the condition (d f= 2, F = 3.352, Significance = 0.04), and interest in support group involvement (df = 2, F =4.6, Significance = 0.01). Respondents who had not had genetic counseling more readily endorsed the desire to address educational issues than those who had previously had genetic counseling (Previous GC: Mean = 4.03, SD = 0.67; No Previous GC: Mean = 4.29, SD = 0.61; t-value; -2.86; P < 0.01). These results suggest that there are significant differences in the BNE of groups of patients seeking genetic counseling. These data support differential genetic counseling goal setting based on practice subspecialty, as well as sustain the requirement of broad based clinical training in genetic counseling. Further, these data provide additional evidence of the reliability and validity of the BNE Scale to characterize groups of individuals eligible for genetic counseling. PMID- 21594992 TI - Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3' end of the FBN1 gene. AB - We report on a 20-year-old man who presented in infancy with severe generalized lipodystrophy with a progeroid appearance and some Marfanoid features. He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years which prompted analysis of the FBN1 gene. This analysis showed him to have a novel heterozygous, de novo, c.8156_8175del, p.Lys2719ThrfsX12, frameshift mutation in exon 64 of his FBN1 gene. His phenotype is similar to a patient described by Graul-Neumann et al. [2010] who was found to have a de novo, heterozygous, c.8155_8156del deletion in exon 64 of FBN1. Both mutations result in a truncated protein with an extremely charged C-terminus, containing two positive and four negative charges in the last eight amino acids. This most likely has a profound impact on protein-protein interactions, which are very important in the extracellular matrix. The similarities in the phenotypes, and overlapping molecular defects, provides further evidence that the phenotype with features of Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy is a distinct clinical entity due to frameshift mutations in exon 64 of the FBN1 gene. PMID- 21594993 TI - Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene. AB - The association of progeroid features and lipodystrophy was very recently described in a female adult with additional manifestations of Marfan syndrome. Mutation analysis of the fibrillin I (FBN1) gene revealed a novel heterozygous frameshift mutation at the 3' end in that patient. Here, we report on a 3.5-year old girl with progeroid facial signs of neonatal onset, lipodystrophy, large head circumference with corresponding hydrocephaly, and tall stature at the end of infancy. Her facial appearance showed convincing clinical similarities to the above-mentioned case. We identified a novel heterozygous de novo splice site mutation c.8226+1G>T affecting the last intron of FBN1. We suggest a specific clinical entity characterized by progeroid facial features, lipodystrophy, and at least some clinical signs of Marfan syndrome is associated with a subset of mutations located at the 3' end of FBN1. This phenotype which is different from that of classical Marfan syndrome could be caused by a truncated FBN1 protein which could escape nonsense-mediated RNA decay. PMID- 21594994 TI - 5q12.1 deletion: delineation of a phenotype including mental retardation and ocular defects. AB - Array-CGH enables the detection of submicroscopic chromosomal deletions and duplications and leads to an accurate delineation of the imbalances, raising the possibility of genotype to phenotype and mapping minimal critical regions associated with particular patterns of clinical features. We report here on four patients sharing common clinical features (psychomotor retardation, coarse facies and ocular anomalies), with proximal 5q deletions identified by oligo array-CGH. The deletions range from 5.75 to 17.26-Mb in size and occurred de novo. A common 2.63-Mb region between the deletions described here can be defined in 5q12.1 (59,390,122-62,021,754 bp from 5pter, hg18) and includes 12 genes. Among them, KIF2A, which encodes a kinesin superfamily protein, is a particularly interesting candidate for the phenotype, as it suppresses the growth of axonal collateral branches and is involved in normal brain development. Ocular defects, albeit unspecific, seem to be common in the 5q12.1 deletion. Identification of additional cases of deletions involving the 5q12.1 region will allow more accurate genotype-phenotype correlations. PMID- 21594995 TI - A new microdeletion syndrome of 5q31.3 characterized by severe developmental delays, distinctive facial features, and delayed myelination. AB - Chromosomal deletion including 5q31 is rare and only a few patients have been reported to date. We report here the first two patients with a submicroscopic deletion of 5q31.3 identified by microarray-based comparative genomic hybridization. The common clinical features of both patients were marked hypotonia,feeding difficulty in infancy, severe developmental delay, and epileptic/nonepileptic encephalopathy associated with delayed myelination. Both patients also shared characteristic facial features,including narrow forehead, low-set and dysmorphic ears, bilateral ptosis, anteverted nares, long philtrum, tented upper vermilion,edematous cheeks, and high arched palate. The deleted region contains clustered PCDHs, including PCDHA [corrected]. and PCDHG, which are highly expressed in the brain where they function to guide neurons during brain development, neuronal differentiation, and synaptogenesis. The common deletion also contains neuregulin 2(NRG2), a major gene for neurodevelopment. We suggest that 5q31.3 deletion is responsible for severe brain developmental delay and distinctive facial features, and that the common findings in these two patients should be recognized as a new microdeletion syndrome. We need further investigations to determine which genes are really responsible for patients' characteristic features PMID- 21594996 TI - Ehlers-Danlos type VIII, periodontitis-type: further delineation of the syndrome in a four-generation pedigree. AB - The periodontitis type of Ehlers-Danlos syndrome (EDS type VIII) is distinguished from other subtypes of EDS by severe periodontitis leading to premature loss of permanent teeth. A limited number of patients and pedigrees with this condition have been described. We report a four-generation EDS VIII kindred with a phenotype of joint hypermobility, normal scar formation but eventual scar atrophy, and severe periodontal disease. Similar to other subtypes of EDS, the age of onset and severity of symptoms were variable amongst affected individuals, confirming the presence of intra-familial variability in this subtype. This pedigree is not linked to the previously reported region, confirming genetic locus heterogeneity in EDS type VIII. PMID- 21594997 TI - An additional patient with mycophenolate mofetil embryopathy: cardiac and facial analyses. AB - We describe an infant male of Cambodian background who has typical craniofacial features of mycophenolate mofetil (MMF) embryopathy and a complex congenital heart defect (CHD) (double outlet right ventricle, mitral atresia, pulmonic stenosis, and total anomalous pulmonary venous return). Together with four case reports and the 20 patients included in two recent reviews, we report 24 (19 affected, five normal) patients with this pattern of anomalies. Eight (33%) have a CHD, most commonly, conotruncal or aortic arch defects (6/8, 75%). This would support the hypothesis that disturbance of cranial neural crest migration occurs in exposed infants, and may predict which additional anomalies will be observed in the future. We also attempted to score the severity of the facial anomalies in each MMF patient using a system created by plastic surgeons for patients with hemifacial microsomia. This classification had modest utility in comparing severity and correlating facial to extracranial defects. The findings are viewed with caution because of the preliminary methodology. Finally, since several exposed infants have been reported to be minimally affected, we remind clinicians to be sensitive to the potential mild expression of the effects of this teratogen. This awareness may influence clinical management of apparently normal MMF-exposed individuals. PMID- 21594998 TI - UPD detection using homozygosity profiling with a SNP genotyping microarray. AB - Single nucleotide polymorphism (SNP) based chromosome microarrays provide both a high-density whole genome analysis of copy number and genotype. In the past 21 months we have analyzed over 13,000 samples primarily referred for developmental delay using the Affymetrix SNP/CN 6.0 version array platform. In addition to copy number, we have focused on the relative distribution of allele homozygosity (HZ) throughout the genome to confirm a strong association of uniparental disomy (UPD) with regions of isoallelism found in most confirmed cases of UPD. We sought to determine whether a long contiguous stretch of HZ (LCSH) greater than a threshold value found only in a single chromosome would correlate with UPD of that chromosome. Nine confirmed UPD cases were retrospectively analyzed with the array in the study, each showing the anticipated LCSH with the smallest 13.5 Mb in length. This length is well above the average longest run of HZ in a set of control patients and was then set as the prospective threshold for reporting possible UPD correlation. Ninety-two cases qualified at that threshold, 46 of those had molecular UPD testing and 29 were positive. Including retrospective cases, 16 showed complete HZ across the chromosome, consistent with total isoUPD. The average size LCSH in the 19 cases that were not completely HZ was 46.3 Mb with a range of 13.5-127.8 Mb. Three patients showed only segmental UPD. Both the size and location of the LCSH are relevant to correlation with UPD. Further studies will continue to delineate an optimal threshold for LCSH/UPD correlation. PMID- 21594999 TI - Pharmaco-genetically guided treatment of recurrent rage outbursts in an adult male with 15q13.3 deletion syndrome. AB - 15q13.3 deletion syndrome (15q13.3DS) is a common recurrent genomic disorder associated with epilepsy, intellectual impairment, aggressive behavior, schizophrenia, and autism. A 39-year-old male presented with 15q13.3DS, epilepsy, intellectual impairment, psychosis, and recurrent episodes of aggressive rage. We hypothesized that the patient's aggressive behavior reflected deficits in alpha7 nicotinic cholinergic receptor (NChR)-mediated neurotransmission, arising from haploinsufficiency of the structural gene CHRNA7 due to the deletion. Treatment with the NChR allosteric modulator and acetylcholinesterase (AChE) inhibitor, galantamine, led to a dramatic decline in the frequency and intensity of rage outbursts, suggesting that enhancement of alpha7 NChR function can ameliorate 15q13.3DS-associated rage outbursts. PMID- 21595000 TI - A deletion 13q34/duplication 14q32.2-14q32.33 syndrome diagnosed 50 years after neonatal presentation as infantile hypercalcemia. AB - During infancy, this 50-year-old man with a previously undiagnosed multiple congenital anomalies/intellectual disability (MCA/MR) syndrome had grossly symptomatic hypercalcemia and was (briefly) thought to have Williams syndrome. Results of studies with the cytogenetic methods of the 1960s and 1970s were apparently normal. He matured late, but is high-functioning and healthy. Over 50 years he remained a diagnostic enigma. Thus, it came as a surprise when recent high-resolution banding methods showed an abnormality of the terminal portion of 13q, determined on array-comparative genomic hybridization to constitute an unbalanced chromosome rearrangement with a 0.35 Mb loss of 13q34-ter and 7.67 Mb gain of 14q32.2q32.33 translocated to 13q34. This apparently de novo genomic abnormality must be presumed as the cause of this previously undescribed MCA/MR syndrome which, however, may remain a private syndrome in this family. Williams syndrome was ruled out, and presently it is not possible to ascribe this patient's severely symptomatic infantile hypercalcemia to any gene on the deleted or duplicated chromosome segments. This "case" does underscore the importance of re-studying previously obscure but evidently genetic conditions, of long-term follow-up and documentation of natural history, and of providing, at last, a causal explanation to the family. PMID- 21595001 TI - Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome. AB - Ablepharon-macrostomia syndrome (AMS) is characterized by absent or short eyelids, macrostomia, ear anomalies, absent lanugo and hair, redundant skin, abnormal genitalia, and developmental delay in two-thirds of the reported patients. Additional anomalies include dry skin, growth retardation, hearing loss, camptodactyly, hypertelorism, absent zygomatic arches, and umbilical abnormalities. We present the second familial case of ablepharon-macrostomia syndrome in a newborn female and her 22-year-old father making autosomal dominant inheritance more likely than the previously proposed autosomal recessive transmission for this disorder. These cases likely represent the 16th and 17th reported cases of AMS and the first case suspected on prenatal ultrasound. Additionally, the child shows more prominent features of the disorder when compared to her father documenting variable expression and possible anticipation. PMID- 21595002 TI - Terminal deletions of the long arm of chromosome X that include the FMR1 gene in female patients: a case series. AB - Terminal deletions on the X chromosome in female patients may be detected as part of a work up for infertility, premature ovarian insufficiency (POI) or in screening for fragile X carrier status. We present the clinical, cytogenetic and molecular features of four patients with terminal deletions of chromosome X that include the FMR1 gene, and discuss biological and genetic implications of this deletion. Providers should be aware of possible identification of Xq27 deletions as a potential outcome of fragile X screening. PMID- 21595003 TI - A microduplication on chromosome 17p13.1p13.3 including the PAFAH1B1 (LIS1) gene. AB - Recently, three children with a microduplication in 17p13 including the PAFAH1B1 gene that encodes LIS1 were reported. LIS1 overexpression has earlier been shown to affect brain development by causing migrational defects and reductions in brain volume [Bi et al., 2009]. Here, we report an additional patient with a microduplication on chromosome 17p13.1p13.3 including the PAFAH1B1 gene, that was inserted into the long arm of chromosome 4. The patient had psychomotor and growth retardation, dysmorphic features, small ventricular septal defect (VSD), and immunoglobulin abnormality. Only subtle abnormalities in brain MRI scan were seen. Interestingly, the facial features of our patient closely resemble those previously reported in 17p trisomy patients. PMID- 21595004 TI - Mutational analysis of PACT gene in Chinese patients with microtia. PMID- 21595005 TI - Ring 21 chromosome presenting with epilepsy and intellectual disability: clinical report and review of the literature. PMID- 21595006 TI - Epiphyseal stippling is not a feature of 7-dehydrocholesterol reductase deficiency (Smith-Lemli-Opitz syndrome). PMID- 21595007 TI - Ethnic disparities in the perception of ethical risks from psychiatric genetic studies. AB - To examine if ethnic differences in concerns about unfavorable consequences from psychiatric genetic studies, existing between non-Hispanic Black and White populations, persist among participants in an actual genetic study of bipolar disorder. Historically, minority subjects have been less willing to participate in such studies. Participants in the US Bipolar Genome Study (BIGS) were assessed on six items of concerns in the Questionnaire on Genetic Risk (QGR). Each item had five response categories, ranging from "not at all" concerned to "very concerned." Responses from Black (N = 188) and White participants (N = 1,065) formed the base for this analysis. Concerns about unfavorable consequences of conducting psychiatric genetic studies were prevalent in the whole sample. Concern for medical insurance was most prevalent (63.4%), followed by job concern (58.8%) and stigma (57.4%). Racial discrimination was less prevalent (28.1%). Blacks endorsed significantly stronger concerns for all consequences except the medical insurance item (P < 0.008). The most significant ethnic disparity in concerns was for racial discrimination (P < 0.0001). Associations between levels of concern and ethnicity remained significant after adjustments for other factors in multivariate models. Ethnic differences (Blacks vs. Whites) in perceived concerns about unfavorable consequences from participation persist among participants in an actual psychiatric genetic study. This suggests that other factors may play a more critical role in the decision not to participate. Future studies should investigate more comprehensive sources of barriers to consenting for ongoing psychiatric genetic studies in representative samples, incorporating assessments from non-participants as well as participants. PMID- 21595008 TI - Exploring DRD4 and its interaction with SLC6A3 as possible risk factors for adult ADHD: a meta-analysis in four European populations. AB - Attention-deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting about 4-8% of children. ADHD persists into adulthood in around 65% of cases, either as the full condition or in partial remission with persistence of symptoms. Pharmacological, animal and molecular genetic studies support a role for genes of the dopaminergic system in ADHD due to its essential role in motor control, cognition, emotion, and reward. Based on these data, we analyzed two functional polymorphisms within the DRD4 gene (120 bp duplication in the promoter and 48 bp VNTR in exon 3) in a clinical sample of 1,608 adult ADHD patients and 2,352 controls of Caucasian origin from four European countries that had been recruited in the context of the International Multicentre persistent ADHD CollaboraTion (IMpACT). Single-marker analysis of the two polymorphisms did not reveal association with ADHD. In contrast, multiple-marker meta-analysis showed a nominal association (P = 0.02) of the L-4R haplotype (dup120bp-48bpVNTR) with adulthood ADHD, especially with the combined clinical subtype. Since we previously described association between adulthood ADHD and the dopamine transporter SLC6A3 9R-6R haplotype (3'UTR VNTR-intron 8 VNTR) in the same dataset, we further tested for gene * gene interaction between DRD4 and SLC6A3. However, we detected no epistatic effects but our results rather suggest additive effects of the DRD4 risk haplotype and the SLC6A3 gene. PMID- 21595009 TI - Converging evidence implicates the dopamine D3 receptor gene in vulnerability to schizophrenia. AB - The dopamine D3 receptor has been implicated in the pathophysiology of schizophrenia (SZ). A glycine-to-serine polymorphism at codon 9 of the dopamine D3 receptor gene (DRD3), rs6280, has been widely studied for its association with SZ, but with conflicting results. Altered levels of DRD3 mRNA have also been reported in SZ compared with normal controls. Moreover, it has been suggested that DRD3 is subject to recent positive selection in European populations. To explore the potential role of DRD3 in SZ from these various aspects, we conducted a threefold study. First, we tested the genetic association of rs6280 with SZ in 685 SZ patients and 768 normal controls. Second, we examined DRD3 mRNA levels in peripheral leukocytes in a subset of 37 patients and 37 controls. Finally, we investigated the possible recent positive selection on DRD3 in an East Asian population. Consequently, we observed that the genotypic distribution of rs6280 was nominally associated with SZ (P = 0.045), with the ancestral CC genotype being significantly over-represented in SZ patients. DRD3 mRNA levels were significantly lower in patients than in controls (P = 5.91E-5). The derived C allele of rs6280 might have been subject to recent positive selection (P < 0.001) in the East Asian population. Taken together, our results suggest that DRD3, a gene possibly under natural selection, might be involved in vulnerability to SZ in the Han Chinese population. These findings may further add to the body of data implicating DRD3 as a schizophrenia risk gene. PMID- 21595012 TI - Importance of stoichiometry in cells science: iPSC, CNS leukocytes, and more. PMID- 21595013 TI - Cytometric assessment of mitochondria using fluorescent probes. AB - Mitochondria are most important organelles in the survival of eukaryotic aerobic cells because they are the primary producers of ATP, regulators of ion homeostasis or redox state, and producers of free radicals. The key role of mitochondria in the generation of primordial ATP for the survival and proliferation of eukaryotic cells has been proven by extensive biochemical studies. In this context, it is crucial to understand the complexity of the mitochondrial compartment and its functionality and to develop experimental tools allowing the assessment of its nature and its function and metabolism. This review covers the role of the mitochondria in the cell, focusing on its structure, the mechanism of the mitochondrial respiratory chain, the maintenance of the transmembrane potential and the production of reactive oxygen species. The main probes used for mitochondrial compartment monitoring are described. In addition, various applications using mitochondrial-specific probes are detailed to illustrate the potential of flow and image cytometry in the study of the mitochondrial compartment. This review contains a panel of tools to explore mitochondria and to help researchers design experiments, determine the approach to be employed, and interpret their results. PMID- 21595014 TI - Cell fixation in zinc salt solution is compatible with DNA damage response detection by phospho-specific antibodies. AB - By virtue of superior preservation of proteins and nucleic acids the zinc salt based fixatives (ZBF) has been proposed as an alternative to precipitants and cross-linking fixatives in histopathology. It was recently reported that ZBF is compatible with analysis of cell surface immunophenotype and detection of intracellular epitopes by flow cytometry. The aim of this study was to explore whether ZBF is also compatible with the detection of DNA damage response assessed by phospho-specific antibodies (Abs) detecting phosphorylation of the key proteins of that pathway. DNA damage in human pulmonary adenocarcinoma A549 cells was induced by treatment with the DNA topoisomerase I inhibitor camptothecin and phosphorylation of histone H2AX on Ser139 (gammaH2AX) and of ATM on Ser1981 was detected with phospho-specific Abs; cellular fluorescence was measured by laser scanning cytometry (LSC). The sensitivity and accuracy of detection of H2AX and ATM phosphorylation concurrent with the detection of DNA replication by EdU incorporation and "click chemistry" was found in ZBF fixed cells to be comparable to that of cell fixed in formaldehyde. The accuracy of DNA content measurement as evident from the resolution of DNA content frequency histograms of cells stained with DAPI was somewhat better in ZBF- than in formaldehyde-fixed cells. The pattern of chromatin condensation revealed by the intensity of maximal pixel of DAPI that allows one to identify mitotic and immediately post-mitotic cells by LSC was preserved after ZBF fixation. ZBF fixation was also compatible with the detection of gammaH2AX foci considered to be the hallmarks of induction of DNA double-strand breaks. Analysis of cells by flow cytometry revealed that ZBF fixation of lymphoblastoid TK6 cells led to about 60 and 33% higher intensity of the side and forward light scatter, respectively, compared to formaldehyde fixed cells. PMID- 21595015 TI - Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) activity decreases estrogenesis in ovarian granulosa cells. PMID- 21595016 TI - Phenethyl isothiocyanate sensitizes human cervical cancer cells to apoptosis induced by cisplatin. AB - SCOPE: Naturally-occurring chemopreventive agent phenethyl isothiocyanate (PEITC), derived primarily from watercress, has been shown to inhibit cell growth and induce apoptosis in cancer cells. In this study, we examined the potential of PEITC in enhancing cisplatin-induced apoptosis in cervical cancer cells and its mechanisms. METHODS AND RESULTS: HeLa cells were exposed to PEITC, cisplatin or both. Pretreatment of cells with PEITC strongly enhanced cisplatin-induced cytotoxicity. PEITC activated the mitogen-activated protein kinases, including c Jun N-terminal kinase (JNK), extracellular signal-related kinase (ERK), and p38. Caspase-3 activity assay demonstrated that the synergistic induction of apoptosis was significantly attenuated by MEK1/2 inhibitor U0126, but not by JNK or p38 inhibitor, suggesting that ERK activation is responsible for the synergistic effect. We found that NF-kappaB signaling pathway is not involved in the synergistic effect. Sulforaphane and benzyl isothiocyanate, two other members of the isothiocyanate family, also sensitize HeLa cells to apoptosis induced by cisplatin. Furthermore, we found that the synergistic effect was also observed in cervical cancer C33A and breast cancer MCF-7 cells but not in normal mammary epithelial MCF-10A cells. Finally, we demonstrated that Noxa induction was associated with apoptosis induced by PEITC plus cisplatin. CONCLUSION: Taken together, this study shows that PEITC can sensitize cancer cells to apoptosis induced by cisplatin and this effect is mediated through ERK activation, suggesting the potential of PEITC to be used as an adjuvant with cisplatin in combination therapeutic treatments. PMID- 21595017 TI - Green tea extract ameliorates reperfusion injury to rat livers after warm ischemia in a dose-dependent manner. AB - SCOPE: Polyphenolic constituents of green tea (Camellia sinensis) have been shown to be potent scavengers of reactive oxygen species (ROS). Thus, this study was designed to assess its effects after liver ischemia-reperfusion. METHODS AND RESULTS: Fasted Sprague-Dawley rats were gavaged with different concentrations of green tea extract (GTE) 2 h before 90 min of warm ischemia of the left lateral liver lobe (30% of liver). Controls were given the same volume of Ringer's solution. A preparation of pentobarbital sodium (intraperitoneal) and ketamine (intramuscular) was used for anesthesia. After reperfusion, transaminases, liver histology, hepatic microcirculation, and both phagocytosis of latex bead particles as well as the expression of tumor necrosis alpha (TNF-alpha) to index cellular activation were investigated. Furthermore, the expression of superoxide dismutase (Mn-SOD) was assessed. After 90 min of warm ischemia aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) increased dramatically to 1946 +/- 272/3244 +/- 757 U/L, 1680 +/- 134/2080 +/- 379 U/L, and 7857 +/- 1851/2036 +/- 1193 U/L at 2/6 h, respectively. GTE (200 mg/kgbody weight) significantly prevented this increase in a dose-dependent manner by 21 51% at 2 h and 29-34% at 6 h, respectively. Histology confirmed the protective effects while both TNF-alpha expression and phagocytosis of latex beads by Kupffer cells (KCs) were significantly reduced. GTE intake significantly increased the expression of manganese superoxide dismutase. In vivo microscopy revealed improved acinar and sinusoidal perfusion after GTE. CONCLUSION: Preconditioning with a single oral dose of GTE ameliorates ischemia-reperfusion injury in liver. Decreased cellular activation and improved microcirculation are the proposed mechanisms. PMID- 21595019 TI - Nanotechnology with soft matter: from structures to functions. PMID- 21595018 TI - Green and black tea in relation to gynecologic cancers. AB - SCOPE: Observational studies have evaluated the relationship between green tea intake and cancers of the ovary and endometrium, but we are not aware of the published studies on green tea intake and risk of human papillomavirus (HPV) related cancers of the cervix, vagina, or vulva. METHODS AND RESULTS: A critical review of the published literature on tea intake and risk of ovarian and endometrial cancers was conducted. In meta-analyses, we report inverse associations for green tea intake and risk of ovarian cancer (odds ratio [OR]=0.66; 95% confidence interval [CI]: 0.54, 0.80), and for green tea and risk of endometrial cancer (OR=0.78, 95% CI: 0.62, 0.98). There was no association for black tea and ovarian cancer risk (OR=0.94, 95% CI: 0.87, 1.02) and a positive association with endometrial cancer risk (OR=1.20, 95% CI: 1.05, 1.38). We summarized the experimental evidence supporting the antiviral and immunomodulatory activities of green tea catechins, and results from randomized clinical trials that demonstrated green tea catechin efficacy on treatment of cervical lesions and external genital warts. CONCLUSION: Observational data support a protective role of green tea on risk of ovarian and endometrial cancers. Observational data are needed to evaluate whether green tea reduces risk of human papillomavirus-related cancers. PMID- 21595024 TI - Synthesis of ionic liquid-bonded organic-silica hybrid monolithic column for capillary electrochromatography. AB - An ionic liquid (IL) was introduced into the organic-silica hybrid monolithic column as the stationary phase for capillary electrochromatography (CEC). The monolithic silica matrix containing chloropropyl functional group was prepared by the in situ co-condensation of tetramethoxysilane and (3-chloropropyl) trimethoxysilane via a sol-gel process and chemical modification with N methylimidazole. The electroosmotic flow of the IL-modified hybrid monolithic column was reversed at acidic pH and the morphology of the column was characterized by scanning electron microscope. Four aromatic hydrocarbons were completely separated with 40% acetonitrile phosphate buffer as the mobile phase and seven inorganic ions were efficiently separated with the phosphate buffer on the column in CEC. Reproducibilities of migration time for four aromatic hydrocarbons (benzene, naphthalene, anthracene, chrysene) were acceptable on IL modified hybrid monolithic columns. Relative standard deviations of run-to-run (n=5), peak area-to-peak area (n=5), day-to-day (n=3) and column-to-column (n=3) were in the range of 0.72-0.88, 1.47-5.40, 2.44-4.99 and 3.01-8.11%, respectively. PMID- 21595023 TI - Synthesis of biomolecule-modified mesoporous silica nanoparticles for targeted hydrophobic drug delivery to cancer cells. AB - Synthetic methodologies integrating hydrophobic drug delivery and biomolecular targeting with mesoporous silica nanoparticles are described. Transferrin and cyclic-RGD peptides are covalently attached to the nanoparticles utilizing different techniques and provide selectivity between primary and metastatic cancer cells. The increase in cellular uptake of the targeted particles is examined using fluorescence microscopy and flow cytometry. Transferrin-modified silica nanoparticles display enhancement in particle uptake by Panc-1 cancer cells over that of normal HFF cells. The endocytotic pathway for these particles is further investigated through plasmid transfection of the transferrin receptor into the normal HFF cell line, which results in an increase in particle endocytosis as compared to unmodified HFF cells. By designing and attaching a synthetic cyclic-RGD, selectivity between primary cancer cells (BT-549) and metastatic cancer cells (MDA-MB 435) is achieved with enhanced particle uptake by the metastatic cancer cell line. Incorporation of the hydrophobic drug Camptothecin into these two types of biomolecular-targeted nanoparticles causes an increase in mortality of the targeted cancer cells compared to that caused by both the free drug and nontargeted particles. These results demonstrate successful biomolecular-targeted hydrophobic drug delivery carriers that selectively target specific cancer cells and result in enhanced drug delivery and cell mortality. PMID- 21595025 TI - A highly sensitive LC-MS/MS method capable of simultaneously quantitating celiprolol and atenolol in human plasma for a cassette cold-microdosing study. AB - A highly sensitive simultaneous quantitative method for a cassette cold microdosing study on celiprolol and atenolol was developed with liquid chromatography-tandem mass spectrometry. The method utilizes a combination of solid-phase extraction (SPE) with strong cation exchange (SCX) cartridge columns and reversed-phase chromatography with an ODS analytical column. SCX-SPE cartridge columns (100 mg sorbent) were used for a selective extraction of celiprolol, atenolol and metoprolol (internal standard) from 500 MUL of human plasma samples. Turbo-ion spray at positive mode was employed for the ionization of the drug compounds. Quantitation was performed on a triple quadrupole mass spectrometer by selected reaction monitoring with the transitions of m/z 380 to m/z 251 for celiprolol and m/z 267 to m/z 145 for atenolol. Separation of analytes was achieved on an ODS column (100 mm length * 2.1 mm id, 3 MUm) by a gradient elution with 10 mM formic acid and methanol by varying their proportion at a flow rate of 0.2 mL/min. The method was validated in the range of 1-250 pg/mL for celiprolol and 2.5-250 pg/mL for atenolol and was successfully applied to the elucidation of pharmacokinetic profiling in a cold cassette microdosing study of the beta-blockers. PMID- 21595026 TI - QuEChERS-based extraction procedure for multifamily analysis of phytohormones in vegetables by UHPLC-MS/MS. AB - A new method has been developed and validated for the simultaneous analysis of different phytohormones (auxins, cytokinins and gibberellins) in vegetables. The compounds were extracted using a QuEChERS-based method (acronym of quick, easy, cheap, effective, rugged and safe). The separation and determination of the selected phytohormones were carried out by ultra high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS), using electrospray ionization source (ESI) in positive and negative ion modes. The method was validated and mean recoveries were evaluated at three concentration levels (50, 100 and 250 MUg/kg), ranging from 75 to 110% at the three levels assayed. Intra- and interday precisions, expressed as relative standard deviations (RSDs), were lower than 20 and 25%, respectively. Limits of quantification (LOQs) were equal or lower than 10 MUg/kg. The developed procedure was applied to seven courgette samples, and naphthylacetic acid, naphthylacetamide and benzyladenine were found in some of the analysed samples. PMID- 21595027 TI - Determination of free cyanide and zinc cyanide complex by capillary electrophoresis. AB - A capillary electrophoretic (CE) protocol was developed for the separation and quantification of free cyanide and zinc cyanide complex, two key species in gold cyanidation of zinc-bearing sulfidic ores. Several common carrier electrolytes were implemented in an indirect UV detection method. The effect of electric field strength, injection volume, concentration of electro-osmotic flow (EOF) modifier and UV-absorbing agent in background electrolyte (BGE) was examined while peak height, peak area and noise were considered for optimization. The best results were obtained using a BGE that contained 35 mM sodium chromate, 12 mM free cyanide and 0.45 mM hexamethonium bromide at pH 10.5. Free cyanide concentration was compared to that measured with the conventional silver nitrate titration method in solutions containing free cyanides and weak cyano-complexes. The developed CE protocol proved very robust in capturing the concentration of free cyanides (4% error) unlike the titration method which exhibited substantial sensitivity to the interfering weak cyano-complexes (38% error). PMID- 21595028 TI - Rapid analysis of aldehydes by simultaneous microextraction and derivatization followed by GC-MS. AB - Ultrasound-assisted dispersive liquid-liquid microextraction (UDLLME) and simultaneous derivatization followed by GC-MS was developed for the analysis of four aldehydes including acetaldehyde (ACE), propionaldehyde (PRO), butyraldehyde (BUT) and valeraldehyde (VAL) in water samples. In the proposed method, the aldehydes were derivatized with O-2,3,4,5,6-(pentafluorobenzyl)hydroxylamine (PFBHA) and extracted by UDLLME in aqueous solution simultaneously; finally, the derivatives were analyzed by GC-MS. The experimental parameters were investigated and the method validations were studied. The optimal conditions were: aqueous sample of 5 mL, PFBHA of 50 MUL, 1.0 mL ethanol (disperser solvent) containing 20 MUL chlorobenzene (extraction solvent), ultrasound time of 2 min and centrifuging time of 3 min at 6000 rpm. The proposed method provided satisfactory precision (RSD 1.8-10.2%), wide linear range (0.8-160 MUg/L), good linearity (R(2) 0.9983 0.9993), good relative recovery (85-105%) and low limit of detection (0.16-0.23 MUg/L). The proposed method was successfully applied for the analysis of aldehydes in water samples. The experimental results showed that the proposed method was a very simple, rapid, low-cost, sensitive and efficient analytical method for the determination of trace amount of aldehydes in water samples. PMID- 21595029 TI - Enthalpy-entropy compensation effect on adsorption of light hydrocarbons on monolithic stationary phases. AB - Enthalpy and entropy of adsorption of light hydrocarbons C1-C4 have been measured for three monoliths of different polarity and for five different carrier gases: helium, hydrogen, nitrogen, carbon dioxide and dinitrogen oxide. Using carrier gas helium the highest values of enthalpy and entropy were observed for monolith based on ethylenedimethacrylate and the lowest values were observed for monolith based on silica, while monolith based on divinylbenzene demonstrated intermediate values. Entropy-enthalpy correlations were observed with carrier gas helium for all thee monoliths and possess similar slope indicating similar adsorption mechanism on all monoliths studied. Comparing different carrier gases entropy enthalpy correlations within a homological series of solutes were observed for light carrier gases (He, H2 and N2) and were not observed for heavy carrier gases (CO2 and N2O). Instead, entropy-enthalpy correlations for heavy carrier gases were observed with pressure as variable and the higher the carrier gas pressure the lower the values of enthalpy and entropy observed. The observed changes in entropy-enthalpy correlations were explained by competitive adsorption of heavy carrier gas on monoliths. PMID- 21595030 TI - A novel RP-HPLC method for simultaneous determination of potassium sorbate and sodium benzoate in soft drinks using C18-bonded monolithic silica column. AB - Potassium sorbate and sodium benzoate are food additives that are generally employed for prevention of food spoilage originating from bacteria, molds or yeasts. Although these compounds were generally recognized as safe due to their low risk of acute and chronic toxicity, they have limitations of usage to protect human health. Development and validation of a novel RP-HPLC method, in which a C18-bonded monolithic silica column was used as stationary phase to assay these compounds, is described for the first time. Aliquots of 10 MUL of samples were injected into chromatograph and eluted using phosphate buffer (0.025 M, pH 2.0) water-acetonitrile (50:45:5, v/v/v) solution, which was pumped at the rate of 3.0 mL/min. To sharpen the peaks, 10 mM octylamine was added to the mobile phase. Potassium sorbate and sodium benzoate were detected at about 12(th) and 14(th) min, respectively, and quantified at 230 nm using photodiode array detector. A total of 41 samples were prepared by simply filtering through 0.45 MUm filters after sonication, and injected into the system without any pre-treatment steps. Applicability of the method was demonstrated by performing total procedure on samples of different brands and types, and their compliance to official regulations was assessed. PMID- 21595031 TI - Effects of functional monomers on retention behavior of small and large molecules in monolithic capillary columns at isocratic and gradient conditions. AB - The polarity of (poly)methacrylate monolithic capillary columns was varied by using alkylmethacrylate monomers with butyl, cyclohexyl, 2-ethylhexyl, lauryl, and stearyl functional groups in the polymerization mixture. The hydrodynamic properties, as well as the retention characteristics in RP-LC of small molecules (alkylbenzenes) and of proteins under gradient elution conditions were studied. The RP selectivity depends on the type of alkyl chain in methacrylate monomer; however, there was no direct correlation between the size of the monomer molecule and methylene or aromatic selectivity of the monlithic column. The lowest selectivity was found for column based on lauryl methacrylate monomer. On the other hand, butyl methacrylate column shows high phenyl selectivity and the column with stearyl methacrylate possesses the highest methylene selectivity for small molecules. The retention increases with longer alkyl chain in methacrylate monomer, especially for high molar mass proteins on all prepared columns and showed gradient elution behavior of proteins in agreement with the linear solvent strength gradient model. The poly(laurylmethacrylate) column showed lowest hydrophobicity but best efficiency for proteins of all columns tested. PMID- 21595032 TI - Determination of ammonium in wastewaters by capillary electrophoresis on a column coupling chip with conductivity detection. AB - Analytical potentialities of a chip-based CE in determination of ammonium in wastewaters were investigated. CZE with the electric field and/or ITP sample stacking was performed on a column-coupling (CC) chip with integrated conductivity detectors. Acetate background electrolytes (pH ~3) including 18 crown-6-ether (18-crown-6) and tartaric acid were developed to reach rapid (in 7 8 min) CZE and ITP-CZE resolutions of ammonium from other cations (sodium, potassium, calcium and magnesium) present in wastewater samples. Under preferred working conditions (suppressed hydrodynamic flow (HDF) and EOF on the column coupling chip), both the employed methods did provide very good repeatabilities of the migration (RSD of 0.2-0.8% for the migration time) and quantitative (RSD of 0.3-4.9% for the peak area) parameters in the model and wastewater samples. Using a 900-nL sample injection volume, LOD for ammonium were obtained at 20 and 40 MUg/L concentrations in CZE and ITP-CZE separations, respectively. Very good agreements of the CZE and ITP-CZE determinations of ammonium in six untreated wastewater samples (only filtration and dilution) with the results obtained by a reference spectrometric method indicate a very good accuracy of both the CE methods presented. PMID- 21595033 TI - Proteomic analysis of urinary exosomes from patients of early IgA nephropathy and thin basement membrane nephropathy. AB - To identify biomarker candidates associated with early IgA nephropathy (IgAN) and thin basement membrane nephropathy (TBMN), the most common causes presenting isolated hematuria in childhood, a proteomic approach of urinary exosomes from early IgAN and TBMN patients was introduced. The proteomic results from the patients were compared with a normal group to understand the pathophysiological processes associated with these diseases at the protein level. The urinary exosomes, which reflect pathophysiological processes, collected from three groups of young adults (early IgAN, TBMN, and normal) were trypsin-digested using a gel assisted protocol, and quantified by label-free LC-MS/MS, using an MS(E) mode. A total of 1877 urinary exosome proteins, including cytoplasmic, membrane, and vesicle trafficking proteins, were identified. Among the differentially expressed proteins, four proteins (aminopeptidase N, vasorin precursor, alpha-1 antitrypsin, and ceruloplasmin) were selected as biomarker candidates to differentiate early IgAN from TBMN. We confirmed the protein levels of the four biomarker candidates by semi-quantitative immunoblot analysis in urinary exosomes independently prepared from other patients, including older adult groups. Further clinical studies are needed to investigate the diagnostic and prognostic value of these urinary markers for early IgAN and TBMN. Taken together, this study showed the possibility of identifying biomarker candidates for human urinary diseases using urinary exosomes and might help to understand the pathophysiology of early IgAN and TBMN at the protein level. PMID- 21595035 TI - Novel clues on abiotic stress tolerance emerge from embryo proteome analyses of rice varieties with contrasting stress adaptation. AB - Cereal embryos sustain severe water deficit at the final stage of seed maturation. The molecular mechanisms underlying the acquisition of desiccation tolerance in seed embryos are similar to those displayed during water deficit in vegetative tissues. The genetic variation among six rice genotypes adapted to diverse environmental conditions was analysed at the proteome level to get further clues on the mechanisms leading to water-stress tolerance. MS analysis allowed the identification of 28 proteins involved in stress tolerance (late embryogenesis abundant proteins), nutrient reservoir activity, among other proteins implicated in diverse cellular processes potentially related to the stress response (e.g., mitochondrial import translocase). Hierarchical clustering and multidimensional scaling analyses revealed a close relationship between the stress-sensitive genotypes, whereas the stress-tolerant varieties were more distantly related. Besides qualitative and significant quantitative changes in embryo proteins across the distinct varieties, we also found differences at post translational level. The results indicated that late embryogenesis abundant Rab21 was more strongly phosphorylated in the embryos of the sensitive varieties than in the embryos of the tolerant ones. We propose that the differences found in the phosphorylation status of Rab21 are related to stress tolerance. PMID- 21595034 TI - Identification and characterization of human leukocyte antigen class I ligands in renal cell carcinoma cells. AB - The presentation of tumor antigen-derived peptides by human leukocyte antigen (HLA) class I surface antigens on tumor cells is a key prerequisite to trigger effective T-cell responses in cancer patients. Multiple complementary strategies like cDNA and serological expression cloning, reverse immunology and different 'ome'-based methods have been employed to identify potential T-cell targets. This report focuses on a ligandomic profiling approach leading to the identification of 49 naturally processed HLA class I peptide ligands presented on the cell surface of renal cell carcinoma (RCC) cells. The source proteins of the defined HLA ligands are classified according to their biological function and subcellular localization. Previously established cDNA microarray data of paired tissue specimen of RCC and renal epithelium assessed the transcriptional regulation for 28 source proteins. In addition, HLA-A2-restricted, peptide-specific T cells directed against a HLA ligand derived from sulfiredoxin-1 (SRXN1) were generated, which were able to recognize and lyse ligand-presenting target cells in a HLA class I-restricted manner. Furthermore, tumor-infiltrating T cells isolated from a RCC patient were also able to kill SRXN1 expressing tumor cells. Thus, this experimental strategy might be suited to define potential candidate biomarkers and novel targets for T-cell-based immunotherapies of this disease. PMID- 21595036 TI - Genomic and proteomic characterization of Staphylococcus aureus mastitis isolates of bovine origin. AB - Staphylococcus aureus colonizes and infects humans as well as animals. In the present study, 17 S. aureus strains isolated from cows suffering from mastitis were characterized. The well-established multilocus sequence typing (MLST) technique and a diagnostic microarray covering 185 S. aureus virulence and resistance genes were used for genetic and epidemiological analyses. Virulence gene expression studies were performed by analyzing the extracellular protein pattern of each isolate on 2-D gels. By this way, a pronounced heterogeneity of the extracellular proteome between the bovine isolates has been observed which was attributed to genome plasticity and variation of gene expression. Merely 12 proteins were expressed in at least 80% of the isolates, i.e. Atl, Aur, GlpQ, Hla, LtaS, Nuc, PdhB, SAB0846, SAB2176, SAB0566, SspA, and SspB forming the core exoproteome. Fifteen extracellular proteins were highly variably expressed and only present in less than 20% of the isolates. This includes the serine proteases SplB, C, and F, and the superantigens SEC-bov, SEL and TSST-1. Compared to human isolates we identified at least six proteins with significantly different expression frequencies. While SAB0846 was expressed more frequently in bovine isolates, LytM, EbpS, Spa, Geh, and LukL1 were seen less frequently in these isolates. PMID- 21595037 TI - Proteome profiling reveals potential toxicity and detoxification pathways following exposure of BEAS-2B cells to engineered nanoparticle titanium dioxide. AB - Oxidative stress is known to play important roles in engineered nanomaterial induced cellular toxicity. However, the proteins and signaling pathways associated with the engineered nanomaterial-mediated oxidative stress and toxicity are largely unknown. To identify these toxicity pathways and networks that are associated with exposure to engineered nanomaterials, an integrated proteomic study was conducted using human bronchial epithelial cells, BEAS-2B and nanoscale titanium dioxide. Utilizing 2-DE and MS, we identified 46 proteins that were altered at protein expression levels. The protein changes detected by 2 DE/MS were verified by functional protein assays. These identified proteins include some key proteins involved in cellular stress response, metabolism, adhesion, cytoskeletal dynamics, cell growth, cell death, and cell signaling. The differentially expressed proteins were mapped using Ingenuity Pathway AnalysesTM canonical pathways and Ingenuity Pathway Analyses tox lists to create protein interacting networks and proteomic pathways. Twenty protein canonical pathways and tox lists were generated, and these pathways were compared to signaling pathways generated from genomic analyses of BEAS-2B cells treated with titanium dioxide. There was a significant overlap in the specific pathways and lists generated from the proteomic and the genomic data. In addition, we also analyzed the phosphorylation profiles of protein kinases in titanium dioxide-treated BEAS 2B cells for a better understanding of upstream signaling pathways in response to the titanium dioxide treatment and the induced oxidative stress. In summary, the present study provides the first protein-interacting network maps and novel insights into the biological responses and potential toxicity and detoxification pathways of titanium dioxide. PMID- 21595038 TI - Small colony variants of Staphylococcus aureus reveal distinct protein profiles. AB - Small-colony variants (SCVs) of Staphylococcus aureus represent a slow-growing subpopulation causing chronic and relapsing infections due to their physiological adaptation on an intracellular lifestyle. In this first proteomic study on physiological changes associated with a natural, clinically derived SCV, its proteomic profile was investigated in comparison to corresponding isogenic strains displaying normal (clinical wild-type strain, complemented hemB mutant and spontaneous revertant of the clinical SCV) and SCV phenotypes (hemB mutant and gentamicin-induced SCV). Applying an ultra-high resolution chromatography and high mass accuracy MS(E) -based label-free relative and absolute protein quantification approach, the whole cytoplasmic proteome of this strain sextet was investigated in a growth phase-controlled manner covering early-exponential, late exponential and stationary phases. Of 1019 cytoplasmic proteins identified, 154 were found to be differently regulated between strains. All SCV phenotypes showed down-regulation of the tricarboxylic acid (TCA) cycle-related proteins and of a protein cluster involved in purine/pyrimidine and folate metabolism. In contrast to hemB mutant and gentamicin-induced SCVs, the clinically derived SCVs showed no prominent up-regulation of glycolytic proteins. The spontaneous switch into the normal phenotype resulted in up-regulation of TCA cycle-related parts, while oxidative stress-related proteins were down-regulated. However, the natural revertant from the clinical SCV retained also dominant protein features of the clinical SCV phenotype. In conclusion, physiological changes between normal and SCV S. aureus phenotypes are more complex than reflected by defined electron transport chain-interrupting mutants and their complemented counterparts. PMID- 21595039 TI - Application of pi-extended ferrocene with varied anchoring groups as photosensitizers in TiO2-based dye-sensitized solar cells (DSSCs). AB - Two new compounds, FcCH=NC(6)H(4)COOH (1) and FcCH=NCH(2)CH(2)OH (2) (Fc=C(5)H(4)FeC(5)H(5)), have been synthesized and characterized by elemental analyses, IR and (1)H NMR spectroscopy, and ESI-MS. Attempt has been made to explain their quasi-reversible redox behavior evidenced by cyclic voltammetry using density functional theory (DFT) calculations. Light-harvesting properties of both the compounds and also the starting material, FcCHO (3), have been studied using these compounds as photosensitizers in TiO(2)-based dye-sensitized solar cells having either a propylene carbonate-based electrolyte or ionic liquid electrolyte, namely, 1-propyl-3-methyl imidazolium iodide (PMII). Long-term stability of the photocurrent output of the cell using compound 1 as photosensitizer has been monitored periodically over 1400 h. PMID- 21595040 TI - Stereoaligned epitaxial growth of single-crystalline platinum nanowires by chemical vapor transport. AB - Epitaxial Pt nanowire (NW) arrays are synthesized for the first time by a chemical vapor transport method by using a metal halide as a precursor. Here we report that the epitaxial growth direction of NWs can be steered by seed crystal morphology. Octahedral seeds grow into inclined NWs possessing six growth directions, whereas half-octahedral seeds grow into vertical and horizontal NWs. Interfacial energies between the seed material and the substrate are critical in determining the morphology of seed crystals. We also demonstrate that non-SERS active Pt NWs can show strong surface-enhanced Raman scattering (SERS) spectra by placing them on Ag films. The active SERS observation would help to elucidate platinum-catalyzed chemical reactions. PMID- 21595041 TI - Synthesis of terpolymers by click reactions. AB - Well-defined polymeric structures were easily generated through living polymerization systems, in particular, living radical polymerizations. The polymeric precursors with orthogonal functionalities were subsequently clicked together with single or double (combinatorial) click reactions, such as the copper-catalyzed azide-alkyne cycloadditions (CuAAC) and Diels-Alder reactions, to create a wide variety of linear and nonlinear terpolymers. PMID- 21595042 TI - How histological features of basal cell carcinomas influence image quality in optical coherence tomography. AB - Optical coherence tomography (OCT) has the potential to diagnose and measure the depth of nonmelanoma skin cancer (NMSC) in skin, but some lesions appear blurred in OCT images. The aim of this study is to identify histological characteristics of basal cell carcinomas (BCC) that correlate with good quality OCT images of the same lesions. A total of 34 patients with BCC were OCT scanned. The influence of histology parameters (e.g. inflammation, sun damage of skin, carcinoma cell size) on OCT image quality was studied by comparing 15 BCC lesions easily identified compared to 19 BCC lesions that produced only blurred in OCT images. Inflammation was more pronounced in blurred OCT images, whereas solar elastosis dominated in easily identified lesions. Hyperkeratosis did not impair imaging significantly. OCT image quality of BCC may depend on specific histology parameters. PMID- 21595043 TI - Can color inhomogeneity of bruises be used to establish their age? AB - Bruises become spatially inhomogeneous during the healing process; a smaller red blue core area, caused by hemoglobin, is surrounded by a larger yellow area, caused by bilirubin, which is enzymatically formed from hemoglobin. These two areas develop at different rates and hence carry information about the age of the bruise. We present a proof of principle demonstration that the age of bruises can be determined via an inverse procedure using a mathematical model and daily measurements of these two areas using a hyperspectral imaging system. The inaccuracy found is 2.3% for fresh bruises and 3 to 24% for bruises up to 3 days old. In conclusion, color inhomogeneity of bruises can be used to determine their age. We expect that future age determination of bruises by the inverse procedure described here, possibly also including the distribution of concentrations in the areas will open up a new phase in clinical bruise classification. PMID- 21595044 TI - Automated classification of healthy and keloidal collagen patterns based on processing of SHG images of human skin. AB - All-optical microspectroscopic and tomographic tools have a great potential for the clinical investigation of human skin and skin diseases. However, automated optical tomography or even microscopy generate immense data sets. Therefore, in order to implement such diagnostic tools into the medical practice in both hospitals and private practice, there is a need for automated data handling and image analysis ideally implementing automized scores to judge the physiological state of a tissue section. In this contribution, the potential of an image processing algorithm for the automated classification of skin into normal or keloid based on second-harmonic generation (SHG) microscopic images is demonstrated. Such SHG data is routinely recorded within a multimodal imaging approach. The classification of the tissue implemented in the algorithm employs the geometrical features of collagen patterns that differ depending on the constitution, i.e., physiological status of the skin. PMID- 21595045 TI - Real-time monitoring of hydrogen peroxide consumption in an oxidation reaction in molecular solvent and ionic liquids by a hydrogen peroxide electrochemical sensor. AB - An efficient electrochemical protocol to monitor hydrogen peroxide consumption during metal-catalyzed oxidation by using screen-printed electrodes modified with Prussian blue is presented. In particular, cyclooctene oxidation to cyclooctene oxide, catalyzed by a vanadium(V)-salophen complex (H(2)salophen=N,N'-o phenylenebis(salicylideneimine)), in molecular and ionic media was tested. Initially, a protocol for batch analysis was developed for a monophasic system in acetonitrile, and subsequently, an in situ protocol was developed for a biphasic system of 1-butyl-3-methylimidazolium hexafluorophosphate/phosphate buffer. Calibration curves were performed in amperometric mode by applying -50 mV versus an Ag pseudo-reference. The calibration curve of hydrogen peroxide showed a linear correlation from 1 * 10(-6) up to 5 * 10(-3) mol L(-1) with satisfactory inter- and intra-electrode reproducibility (relative standard deviation (RSD) values of 5 and 13%, respectively, for the monophasic system and 11 and 13%, respectively, for the biphasic system). Kinetic studies to investigate the oxidation reaction for both the mono- and biphasic systems have been carried out in amperometric mode as well. Firstly, the decomposition of hydrogen peroxide was examined, which showed that, in 1-butyl-3-methylimidazolium hexafluorophosphate(,) it completely decomposed in 300 min, whereas in acetonitrile, in the same time frame, 20% of the initial amount was still active. In the presence of 1% of the catalyst the decomposition rate increased in both solvents. Finally, the complete oxidation of cyclooctene was followed and the effective conversion was determined. The developed protocols showed high reproducibility, with the advantage that the environmentally friendly biphasic system could also be recycled. The good analytical performance obtained, coupled with a short analysis time, the possibility of in-line automation and the use of ionic liquids instead of molecular solvents, made this system a very attractive choice for monitoring oxidative reactions. PMID- 21595046 TI - Structure and catalysis of cellulose-derived amorphous carbon bearing SO3H groups. AB - The correlation between catalytic performance and structure of a cellulose derived and carbon-based solid acid (CCSA), an amorphous carbon bearing SO(3)H, COOH, and phenolic OH groups, was investigated. Sulfonation of partially carbonized cellulose under a N(2) atmosphere resulted in the formation of a CCSA, which was amorphous carbon consisting of small polycyclic aromatic carbon sheets with a high density of SO(3)H groups (ca. 2 mmol g(-1)). CCSAs were prepared from carbon precursors, which were obtained at temperatures <=723 K, and exhibited a high catalytic performance for the esterification of acetic acid with ethanol and for the hydrolysis of cellobiose, although the surface areas were small (<5 m(2) g(-1)). In contrast, CCSAs, which were prepared from carbon precursors obtained at >=823 K, exhibited much lower catalytic activities for both reactions, although the CCSAs had sufficient amounts of SO(3)H groups. Structural analyses, including spectroscopic analysis of CCSAs with adsorbed probe molecules, revealed that cross-linking between the polycyclic aromatic carbon sheets caused the sharp decrease in activity. PMID- 21595047 TI - Adult neurogenesis and brain regeneration in zebrafish. AB - Adult neurogenesis is a widespread trait of vertebrates; however, the degree of this ability and the underlying activity of the adult neural stem cells differ vastly among species. In contrast to mammals that have limited neurogenesis in their adult brains,zebrafish can constitutively produce new neurons along the whole rostrocaudal brain axis throughout its life.This feature of adult zebrafish brain relies on the presence of stem/progenitor cells that continuously proliferate,and the permissive environment of zebrafish brain for neurogenesis. Zebrafish has also an extensive regenerative capacity, which manifests itself in responding to central nervous system injuries by producing new neurons to replenish the lost ones. This ability makes zebrafish a useful model organism for understanding the stem cell activity in the brain, and the molecular programs required for central nervous system regeneration.In this review, we will discuss the current knowledge on the stem cell niches, the characteristics of the stem/progenitor cells, how they are regulated and their involvement in the regeneration response of the adult zebrafish brain. We will also emphasize the open questions that may help guide the future research. PMID- 21595050 TI - Drug delivery through the skin: molecular simulations of barrier lipids to design more effective noninvasive dermal and transdermal delivery systems for small molecules, biologics, and cosmetics. AB - The delivery of drugs through the skin provides a convenient route of administration that is often preferable to injection because it is noninvasive and can typically be self-administered. These two factors alone result in a significant reduction of medical complications and improvement in patient compliance. Unfortunately, a significant obstacle to dermal and transdermal drug delivery alike is the resilient barrier that the epidermal layers of the skin, primarily the stratum corneum, presents for the diffusion of exogenous chemical agents. Further advancement of transdermal drug delivery requires the development of novel delivery systems that are suitable for modern, macromolecular protein and nucleotide therapeutic agents. Significant effort has already been devoted to obtain a functional understanding of the physical barrier properties imparted by the epidermis, specifically the membrane structures of the stratum corneum. However, structural observations of membrane systems are often hindered by low resolutions, making it difficult to resolve the molecular mechanisms related to interactions between lipids found within the stratum corneum. Several models describing the molecular diffusion of drug molecules through the stratum corneum have now been postulated, where chemical permeation enhancers are thought to disrupt the underlying lipid structure, resulting in enhanced permeability. Recent investigations using biphasic vesicles also suggested a possibility for novel mechanisms involving the formation of complex polymorphic lipid phases. In this review, we discuss the advantages and limitations of permeation-enhancing strategies and how computational simulations, at the atomic scale, coupled with physical observations can provide insight into the mechanisms of diffusion through the stratum corneum. PMID- 21595051 TI - An analysis of legal highs: do they contain what it says on the tin? AB - In recent years the availability of so-called legal highs over the Internet has hugely increased. Numerous online legal-high retailers market a broad variety of products which are advertised as research chemicals, bath salts, or plant food although clearly intended for human consumption as recreational drug replacements. No guidelines exist as to what is sold and in what purity. Consumers are led to believe that purchased goods are entirely legal. In this study, several legal-high products were purchased and analyzed for their content. The powdered products were screened with attenuated total reflectance-Fourier Transform Infrared (ATR-FTIR) followed by gas chromatography-mass spectrometry (GC-MS) analysis of methanol extracts. Spectra were compared to reference standards and the NIST library. Results showed that 6 out of 7 products did not contain the advertised active ingredient. Moreover, five samples contained the controlled substances benzylpiperazine and 1-[3 (trifluoromethyl)phenyl]piperazine combined with caffeine. PMID- 21595049 TI - Reserve pool neuron transmitter respecification: Novel neuroplasticity. AB - The identity of the neurotransmitters expressed by neurons has been thought to be fixed and immutable, but recent studies demonstrate that changes in electrical activity can rapidly and reversibly reconfigure the transmitters and corresponding transmitter receptors that neurons express. Induction of transmitter expression can be achieved by selective activation of afferents recruited by a physiological range of sensory input. Strikingly, neurons acquiring an additional transmitter project to appropriate targets prior to transmitter respecification in some cases, indicating the presence of reserve pools of neurons that can boost circuit function. We discuss the evidence for such reserve pools, their likely locations and ways to test for their existence, and the potential clinical value of such circuit-specific neurotransmitter respecification for treatments of neurological disorders. PMID- 21595054 TI - Resident care decisions in assisted living: who is in charge? PMID- 21595048 TI - The visual system of zebrafish and its use to model human ocular diseases. AB - Free swimming zebrafish larvae depend mainly on their sense of vision to evade predation and to catch prey. Hence, there is strong selective pressure on the fast maturation of visual function and indeed the visual system already supports a number of visually driven behaviors in the newly hatched larvae.The ability to exploit the genetic and embryonic accessibility of the zebrafish in combination with a behavioral assessment of visual system function has made the zebrafish a popular model to study vision and its diseases.Here, we review the anatomy, physiology, and development of the zebrafish eye as the basis to relate the contributions of the zebrafish to our understanding of human ocular diseases. PMID- 21595052 TI - Cell culture and gene transcription effects of copper sulfate on Chinese hamster ovary cells. AB - This study reports the effects of varying concentrations of copper sulfate on the metabolic and gene transcriptional profile of a recombinant Chinese hamster ovary (CHO) cell line producing an immunoglobulin G (IgG)-fusion protein (B0). Addition of 50 MUM copper sulfate significantly decreased lactate accumulation in the cultures while increasing viable cell density and protein titer. These changes could be seen from day 6 and became increasingly evident with culture duration. Reducing the copper sulfate concentration to 5 MUM retained all the above beneficial effects, but with the added benefit of reduced levels of the aggregated form of the B0 protein. To profile the cellular changes due to copper sulfate addition at the transcriptional level, Affymetrix(r) CHO microarrays were used to identify differentially expressed genes related to reduced cellular stresses and facilitated cell cycling. Based on the microarray results, down regulation of the transferrin receptor and lactate dehydrogenase, and up regulation of a cytochrome P450 family-2 polypeptide were then confirmed by Western blotting. These results showed that copper played a critical role in cell metabolism and productivity on recombinant CHO cells and highlighted the usefulness of microarray data for better understanding biological responses on medium modification. PMID- 21595055 TI - Cancer: Optimism surrounds new targeted therapies for pancreatic neuroendocrine tumors. PMID- 21595056 TI - Esophagus: Eosinophilic esophagitis may be overestimated. PMID- 21595057 TI - Celiac disease: Retinoic acid and IL-15 jointly implicated in reversal of oral tolerance. PMID- 21595058 TI - IBD: MAdCAM-targeted therapy success. PMID- 21595060 TI - IBD: Modified Lactobacillus acidophilus may regulate intestinal inflammation. PMID- 21595059 TI - Transplantation: Functional ectopic liver tissue in the lymph nodes of mice with lethal liver disease. PMID- 21595061 TI - Quantification of low-level exposure. PMID- 21595064 TI - Biological consequences and health concerns from low-dose and low-dose-rate radiation in mice and humans. PMID- 21595063 TI - Exploring biological effects of low level radiation from the other side of background. PMID- 21595062 TI - Is a dose dose-rate effectiveness factor (DDREF) needed following exposure to low total radiation doses delivered at low dose-rates? PMID- 21595065 TI - What is the use of systems biology approaches in radiation biology? PMID- 21595066 TI - Systems-related facts and consequences in assessing risk from low-level irradiation. PMID- 21595067 TI - Responses to primary effects: from initial events to cellular radiobiological effects. PMID- 21595068 TI - Interaction of low dose radiation and other factors. PMID- 21595069 TI - Individual susceptibility to radiosensitivity and to genomic instability: its impact on low-dose phenomena. PMID- 21595070 TI - Stimulation of the natural anti-tumor cells by single and fractionated irradiations of mice with low doses of x-rays. PMID- 21595071 TI - Health effects from low dose occupational and medical radiation exposure and the role of adaptive response. PMID- 21595073 TI - Metabolic oxidative stress and low dose radiation responses: are mitochondria involved. PMID- 21595072 TI - Oxidative stress-induced tumorigenesis in the small intestines of DNA repair deficient mice. PMID- 21595074 TI - A new method of assessing the dose-carcinogenic effect relationship in patients exposed to ionizing radiation. A concise presentation of preliminary data. PMID- 21595075 TI - Neoplastic transformation in vitro: is it a valid assay or not for assessing the shape of the dose-response curve for radiation-induced cancer in vivo? PMID- 21595076 TI - Radiation-induced non-targeted effects of low doses-what, why and how? PMID- 21595077 TI - Dose rate dependence of radiation cancer risk as measured by non-tumor dose. PMID- 21595078 TI - Implications of radiation epidemiologic data for risk assessment and radiation protection. PMID- 21595079 TI - Non-radiation causes of carcinogenesis in the atomic bomb survivors. PMID- 21595080 TI - Recommendations for assessment of consequences and health risks of low-level exposure to ionizing radiation. PMID- 21595081 TI - Defending the use of medical imaging. PMID- 21595082 TI - Low-dose radiotherapy of disease. PMID- 21595083 TI - Computed tomography-patient dose and dose reduction technologies. PMID- 21595084 TI - Concepts to reduce x-ray radiation in interventional radiology. PMID- 21595085 TI - Science-informed, justified, and optimized radiation safety policies. PMID- 21595086 TI - The anatomy and physiology of cutaneous sensibility: a critical review. By FMR Walshe. Brain 1942: 65; 48-112. PMID- 21595088 TI - Low-dose-radiation activated natural protection and LNT. PMID- 21595087 TI - Incorporating information about low-level exposure to ionizing radiation into regulatory and policy decision-making-challenges and opportunities. PMID- 21595089 TI - Hormetic effects on human cancer mortality are inducible only after long-term irradiation at low dose rates. PMID- 21595090 TI - Expectations of Indian applicants of an educational fellowship. PMID- 21595091 TI - Collagen surfaces to measure thrombus formation under flow: possibilities for standardization. PMID- 21595092 TI - Conquering cancer in the 21st century: leading a movement to save more lives worldwide. AB - This article examines the current state of the global fight against cancer and of noncommunicable disease in general, the progress to date against cancer, and postulates that there has never been a more challenging-nor more ideal-time to succeed in making significant headway against the disease worldwide. Based on progress made particularly in the past two decades, and with proven interventions and scientific knowledge, it is possible to bring cancer as a major health problem worldwide under control in this century.The article also discusses what the American Cancer Society, the nation's largest voluntary health organization dedicated to saving lives from cancer, is doing to lead a global movement in support of achieving this goal. PMID- 21595093 TI - 25 years of wellness. PMID- 21595094 TI - Staffing. Hospitalist movement is finding fertile ground in clinical specialties. PMID- 21595095 TI - Clinical management. Cardiac patients get pumped up, avoid readmissions. PMID- 21595097 TI - Nomenclature of genetic variants in hemostasis. PMID- 21595096 TI - The relationship between post-traumatic ventilator-associated pneumonia outcomes and American College of Surgeons trauma centre designation. AB - INTRODUCTION: The relationship between outcomes following severe trauma and American College of Surgeons (ACS) trauma centre designation has been studied. Little is known, however, about the association between ACS level and outcomes associated with ventilator-associated pneumonia (VAP). METHODS: The National Trauma Databank (NTDB, Version 5.0) was queried to identify adult (age 18)trauma patients who (1) developed VAP and (2) were admitted to either an ACS level I or level II centre.Transfer and burn patients were excluded. Univariate analysis defined differences between patient cohorts. Logistic regression analysis was utilised to identify independent risk factors for mortality. RESULTS: A total of 3465 patients were identified where 65.6% were admitted to a level I facility and 34.4%to a level II centre. Patients admitted to a level I centre were more likely to have an age > 55 (71.5% vs.66.8%, p = 0.004) and to be hypotensive (SBP < 90) on admission (16.2% vs. 13.6%, p = 0.042). They were also more likely to have a longer duration of mechanical ventilation (18.5 days vs. 16.5 days, p = 0.001),longer hospital LOS (34.2 days vs. 29.6 days, p < 0.001) and a higher rate of early (+/-7 days) tracheostomy(33.1% vs. 29.1%, p = 0.017). Level I admission was, however, associated with lower mortality rates (10.8%vs. 14.7%, p = 0.001) and a higher likelihood of achieving discharge to home (20.2% vs. 16.1%, p < 0.001).Logistic regression analysis identified admission to a level II facility as an independent risk factor for mortality (OR 1.34, 95% CI 1.08-1.66; p = 0.008) in patients developing post-traumatic VAP. CONCLUSION: For adults who develop VAP after trauma, admission to a level I facility is associated with improved survival. Further prospective study is needed. PMID- 21595098 TI - Inferior vena cava variation compared to pulse contour analysis as predictors of fluid responsiveness: a prospective cohort study. AB - BACKGROUND: Both occult hypoperfusion and volume overload are associated with increased morbidity and mortality in critically ill patients. Accurately predicting fluid responsiveness (FRes) allows for optimization of cardiac performance while avoiding fluid overload and prolonged mechanical ventilation. OBJECTIVE: To simultaneously assess the ability to predict FRes using the stroke volume variation (SVV) obtained with the Vigileo/Flotrac monitor and inferior vena cava respiratory variation (DeltaIVC) measured by standard echocardiography ([ECHO) during mechanical ventilation. METHODS: We included medical intensive care unit (ICU) patients undergoing mechanical ventilation that required vasopressors, had worsening organ function, and that were well adapted to the ventilator. We excluded patients requiring escalating doses of vasopressors, hemodialysis, with ascites and patients with atrial fibrillation or a heart rate >120/min. Stroke volume index (SVI) and SVV were obtained from the Vigileo monitor whereas DeltaIVC was obtained with ECHO (M-mode). Doppler ECHO was used to measure SVI and used to determine FRes (defined by SVI increase >= 10%). A data set was obtained before and 30 minutes after a 10-minute fluid challenge (FC) with 500 mL of saline. RESULTS: In all, 25 patients were prospectively enrolled over an 8-month period. A total of 12 patients had acute respiratory distress syndrome (ARDS), 3 had a cardiac arrest, and 10 had sepsis. The patients' mean age was 61.36 years (+/-13.7), study enrollment since ICU admission was 3.4 days (+/-3.39), the Sequential Organ Failure Assessment (SOFA) score was 12.44 (+/-2.59), and the tidal volume 8.6 mL/kg (+/-1.68). Of the 25 patients, 8 (32%) were FRes. The correlation coefficient between the baseline DeltaIVC and percentage increase in SVI (by ECHO) after an FC was R(2) = .51 with a receiver operating characteristic (ROC) curve of 0.81 while that for the baseline SVV by Vigileo was R(2) = .12 with an ROC curve of 0.57. The mean SVI bias between ECHO and Vigileo was -2 mL/m(2), the precision was -18 to 14 and the mean error was 46%. CONCLUSIONS: ECHO assessment of the IVC variation during mechanical ventilation may prove to be a useful technique to predict FRes and guide fluid resuscitation in the ICU. The SVV obtained with the Vigileo monitor failed to predict FRes likely due to lack of calibration and the use of a complex algorithm that may be unreliable in patients with sepsis. PMID- 21595140 TI - Rewriting the history of Chinese families in nineteenth-century Australia. AB - The nineteenth-century Chinese population in Australia was made up mostly of men, drawing many commentators to the conclusion these men faced an absence of family life, resulting in prostitution, gambling, opium use and other so-called vices. Recent research has, however, expanded and complicated our knowledge of Chinese families in New South Wales and Victoria, particularly concerning the extent to which Chinese men and white Australian women formed intimate relationships. This article traces the origins of the misconceptions about Chinese families in nineteenth-century Australia, and considers how new directions in scholarship over the past decade are providing methods for enlarging our knowledge. It argues that instead of being oddities or exceptions, Chinese-European families were integral to the story of Australia's early Chinese communities. PMID- 21595141 TI - Factory farms in a consumer society. PMID- 21595142 TI - [Neuromuscular disease--myasthenia gravis]. PMID- 21595143 TI - [Comparison of treatment expenses of naturopathic and orthopedic in-patient treatment]. AB - BACKGROUND: In health services research comparative studies between orthopaedics and naturopathy are necessary. They allow evidence based decisions between individual therapeutical alternatives as well as decisions on health politics, e.g. concerning allocation of resources. PATIENTS AND METHODS: A controlled prospective cohort study is presented. Conservatively treated patients were recruited for the study, if they needed in-patient treatment because of chronic back pain. The conservative orthopaedic treatment including Minimal invasive Therapy (MIT) was compared to in-patient naturopathic "complex"-treatment. The real costs to the public health insurance system are unknown--relating to both the individual patient and the physician. Hence an approximation was attempted on the basis of the billing of the concerned hospitals, the analysis of extensive patient interviews, randomly selected evaluation of in- and out-patient records, validated by an expert panel. RESULTS: Costs for medication decreased in the post stationary phase after orthopedic and naturopathic treatment. Rehabilitation measures and treatments at a health resort increased after orthopedic treatment, whereas the frequency of specialist consultation decreased in both cohorts indicating the efficacy of the in-patient treatment. Incidence of psychotherapy was highest in the naturopathic group before admission to hospital and decreased afterwards. The gathered data point to a reduction of the total outpatient treatment costs in both cohorts. There were treatment-specific differences when regarding single components. CONCLUSION: Naturopathic complex in-patient treatment is a cost-efficient complement of the conventional orthopedic treatment options. PMID- 21595144 TI - [Medical risk assessment in personal life insurance, disability insurance and accident insurance]. PMID- 21595145 TI - [Beta-cell function in the foreground. GLP-1 based therapy of type 2 diabetes]. PMID- 21595147 TI - [Efficacy and safety of a beta2-agonist-combination in patients with bronchial asthma--a clinical practice surveillance study]. PMID- 21595146 TI - [Evaluation of a new disposable insulin pen and injection habits of diabetes patients in everyday clinical practice]. AB - Evaluation of a new disposable insulin pen and injection habits of diabetes patients in everyday clinical practice BACKGROUND: Injection devices (pens) for insulin application play a major role in treatment acceptance and adherence in insulin-treated diabetes patients. The mechanical disposable pen SoloStar containing the insulin analogs glargine or glulisine (each 100 IE/ml) provides modern design with user-friendly handling features. METHODS: In two independent, non-interventional, observational studies conducted nation-wide between April and December 2007 in outpatient practices, patients with diabetes newly instructed on how to use the pen were interviewed by their trainers (physicians, diabetes consultants) after approx. 6-8 weeks of pen use to give feedback on technical deficiencies, handling problems with the pen, injection habits, as well as on pen properties. Trainers were also asked to assess pen properties and particularly to document the time required for pen training. The evaluation applied a grading system similar to that used in German schools (1: very good; 6: very insufficient/failed). Furthermore, trainers were asked to retrospectively record any adverse events occurring during the observational period. RESULTS: A total of 2,412 trainers from 1,626 centres and 8,428 patients (80% type 2) participated in the studies. In each study 0.5% of patients reported 41 and 19 technical problems with the pen, respectively. Similarly 3% of patients from each study reported handling problems. Recommended changes of needles and safety checks of the pen before each injection were performed by 40% and max. 25% of the patients, respectively. The features of the new disposable pen were all rated "very good" to "good" by the majority of patients and trainers. The best rated features were usability, dose adjustment and the low effort for the dose release. Pen training of patients were rated as "very simple" or "simple" by the training staff and average instruction time was reported not to exceed more than 10 minutes for the majority of patients. In 19 patients (0.2%) a total of 34 adverse events were documented. CONCLUSION: The results of these two observational studies showed no relevant technical deficiencies and handling problems associated with the new disposable pen in everyday clinical practice. Ease of use and little time required for pen training may contribute to a high acceptance and satisfaction by the patients and training staff. Injection habits, however, indicated that patients did not well comply with recommendations given for needle changes and safety tests. PMID- 21595148 TI - [Herpes zoster in Germany. A retrospective analyse of SHL data]. AB - The incidence of herpes zoster in the elderly (50 years and older) 2004 in Germany was determined by retrospectively analysing representative treatment data of the statutory health insurance sample of AOK Hesse/KV Hesse. The overall observed incidence rate of herpes zoster was 9.4 cases per 1,000 person-years (PY). 10.1% of herpes-zoster-patients suffered at least 1 month from pain, the so called postherpetic neuralgia (PHN1), 6.9% had at least 3 months pain (PHN3). Incidence rate of herpes zoster rose markedly with age: from 6.8 per 1,000 PY in 50 to 54 year-olds to 12.4 PY in persons 80 years and older. Incidence rate in the immunocompromised was higher (11.6 per 1,000 PY) than in the immunocompetent (9.1 per 1,000 PY). According to a standardized extrapolation of the sample to the German population, about 300,000 persons 50 years and older suffered from acute herpes zoster on the year 2004 in Germany. PMID- 21595149 TI - [Electrocardiographic changes in the context of febrile illness in infancy and childhood]. PMID- 21595150 TI - [Fetal programming of type 2 diabetes--intrauterine growth retardation (IUGR) as risk factor?]. PMID- 21595151 TI - [(No) chance of slowing down the biological clock? In the focus: heart and ageing]. PMID- 21595152 TI - [BOT with insulin glargine versus BOT with insulin detemir: comparison of treatment costs in type 2 diabetes based on the results of the insulin glargine (Lantus) versus insulin detemir (Levemir) Treat-To-Target (L2T3) study from the German Statutory Health Insurance perspective]. PMID- 21595153 TI - [Adjustment of antihypertensive therapy to a generic eprosartan preparation. Results of a non-interventional study]. PMID- 21595154 TI - [Cost effectiveness of BDP/formoterol fixed vs. two single inhalers in the treatment of bronchial asthma]. PMID- 21595155 TI - [Recommendations for the management of chronic pain by intrathecal ziconotide]. PMID- 21595156 TI - [Diabetes and cancer, the significance of multidisciplinary management]. PMID- 21595157 TI - [Obesity, diabetes and cancer risk]. PMID- 21595158 TI - [Cancer plan, living during and after the disease]. AB - Cancer is one of the first cause of mortality in industrialised countries. In France, the national mobilisation plan against cancer is one of the five national strategic plans forming part of the 2004 public healthcare law. The 1st Cancer Plan (2003-2007) was thereby established, followed by the 2nd Cancer Plan (2009 2013), which notably includes a specific measure to support patients during and after the disease. PMID- 21595159 TI - [Interactions between diabetes and cancer]. AB - Diabetes and cancer are two very common pathologies, all the more so as the population ages. There are many interactions between them, both on a physiopathological level as well as in daily clinical practice. Thanks to new therapies, cancer is increasingly being considered as a chronic disease, and oncology teams have a lot to learn in this area from the treatment of diabetic patients. PMID- 21595160 TI - [Managing diabetes in cancer patients]. AB - Cancer is a situation which generates a risk of the onset or destabilisation of diabetes. Glycemic goals and treatments must be adapted to the patient's prognosis and regularly reassessed. Renutrition forms part of the support care and requires adjustments to be made to the hypoglycaemic treatments. PMID- 21595161 TI - [Mobile palliative and supportive care unit]. AB - The mobile palliative and supportive care unit is a model of inter-disciplinary organisation. Its mission consists in facilitating the setting up of the patient's palliative care and the supportive care provided by their carers by collaborating, for example, with a visceral surgery department. PMID- 21595162 TI - [Diet and cancer]. AB - The public is eager for information on health and in particular nutrition and naturally turns towards healthcare professionals. The jobs and specialities of these professionals may differ. However, it is essential that the health message is relatively consistent. Effectively, conflicting messages can cause confusion and even lead to rejection by patients and their family. PMID- 21595163 TI - [Nutritional care with diabetes and ENT cancer]. AB - The food intake of patients suffering from head and neck cancer is frequently affected by dysphagia caused by the tumour and its treatments (surgery, radiotherapy, chemotherapy). Nutritional care has a dual aim of preventing malnutrition, by increasing calorie intake, and adapting the consistency of the food and drink. PMID- 21595164 TI - [An educational tool for diabetic children]. AB - The 2010 Abbott Diabetes Care--Societe Francophone du Diabete (SFD) Paramedical prize was awarded to the nursing team of the paediatric unit of the William Morey hospital in Chalon-sur-Saone (71) for the creation of a new educational tool. The interactive game aims to encourage children with type 1 diabetes to do sport by providing them with the education and knowledge they need to manage their diabetes before, during and after the physical activity. PMID- 21595165 TI - [The role of matrix metalloproteinases in cardiovascular diseases]. AB - Matrix metalloproteinases (MMPs) belong to a large family of multidomain zinc endopeptidases. They are one of the most important proteolytic enzymes which digest components of the extracellular matrix and take part in many physiological processes, such as apoptosis or angiogenesis. It was shown that MMPs are also involved in the pathogenesis of many diseases such as malignant tumors and cardiovascular diseases. The discovery of the mechanisms of MMPs' action can have significant influence on therapeutic strategy, especially in cardiovascular diseases. PMID- 21595166 TI - [Vascular complications in patients with metabolic syndrome]. AB - All risk factors of metabolic syndrome (MS) are responsible for endothelial dysfunction what accelerate the development of atherosclerosis. It causes increased cardiovascular risk and development of cardiovascular complications in these subjects. The aim of the study was to assess the presence of vascular complications in subjects with MS. MATERIAL AND METHODS: The study comprised of 108 patients with metabolic syndrome (36 males and 72 females), aged 46-67 (57+/ 8.5) years. MS was diagnosed according to the International Diabetes Federation criteria from 2005. Ischaemic heart disease was diagnosed according to the coronarography or patient care documentation. The assessment of nephrological complications was conducted with use of glomerular filtration rate (eGFR) calculated by using the simplified Modification of Diet in Renal Disease Study (MDRD) equation. The occurrence of brain strokes and diabetic foot was estimated basing on medical history and documentation. Vascular complications in the bottom of the eye were assessed with ophtalmoscopic examination and fluorescein angiography. RESULTS: The frequency of vascular complications in subjects with MS was: vascular complications in the bottom of the eye - 72.7% (symptoms of vascular angiopathy without retinopathy - 41.2%, retinopathy - 31.5%), ischaemic heart disease - 54.9%, eGFR < 90 m/min. - 38.9%, diabetic foot - 5.55%. brain stroke - 3.7%. Ischaemic heart disease was present in all subjects with MS qualified to the second and higher class of retinopathy. CONCLUSIONS: In patients with MS, ischaemic heart disease was the most common macroangiopathic complication, with increasing in the frequency together with retinopathy intensification. Changes in the bottom of the eye were the most common microangiopathic complications. Early identification and treatment of metabolic syndrome may have important value in prophylaxis and delay of vascular complications. PMID- 21595167 TI - [Tissue inhibitor of metalloproteinases-1 level in patients with metabolic syndrome qualified for cardiac rehabilitation]. AB - Each year in Poland, the number of patients treated by PCI and CABG increases. Many of them have metabolic syndrome. After these procedures patients are qualified for cardiac rehabilitation. It is preceded by risk stratification for cardiac events. Metalloproteinases belong to the enzymes responsible for destabilization of atheroma plaques. The activity of metalloproteinases is tightly regulated by their inhibitors. The aim of the study was to estimate plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) level in patients with metabolic syndrome qualified for cardiac rehabilitation after PCI procedures. MATERIAL AND METHODS: The study comprised of 50 subjects with metabolic syndrome (26 males, 24 females) aged 18-65 (mean 50.9+/-11.8) years, qualified for cardiac rehabilitation after PCI procedures and 25 healthy participants (13 males, 12 females) aged 21-55 (mean 50.2+/-12.8) years. The estimation of plasma TIMP-1 level was determined with use of R&D Systems kit. RESULTS: Plasma level of tissue inhibitor of metalloproteinases-1 in subjects with metabolic syndrome was 119.1+/ 15.3 ng/ml and it was significantly lower than in group of healthy participants (188.5+/-14.7 ng/ml (p<0.001). CONCLUSIONS: Decreased plasma level of tissue inhibitor of metalloproteinases-1 in subjects with metabolic syndrome qualified for cardiac rehabilitation indicates disturbances of metalloproteinases activity control which take part in destabilization of atheroma plaque. In cardiac rehabilitation of subjects with metabolic syndrome we should pay attention to the type, time and intensity of exercise, because of increased risk of cardiovascular events. PMID- 21595168 TI - [Plasma nitric oxide and vascular endothelial growth factor levels in patients with metabolic syndrome and co-existing vascular complications]. AB - Subjects with metabolic syndrome (MS) are especially exposed to co-existing several cardiovascular risk factors. It's aggregated action leads to the endothelial damage. Tissue hipoxaemia increases VEGF synthesis. NO may also play the crucial role in VEGF synthesis The balance between factors increasing and decreasing VEGF synthesis has special importance in development of vascular complications. The aim of the study was to estimate plasma nitric oxide (NO) and vascular endothelial growth factor (VEGF) levels in patients with metabolic syndrome and vascular complications. MATERIAL AND METHODS: The study was conducted in two groups of patients. I Group--54 patients with metabolic syndrome (diagnosed according to the IDF criteria from 2005) and macro- and microvascular complications, aged 46-67 (58 +/- 6.7) years. II Group--20 healthy subjects, aged 40-61 (51 +/- 5.1) years. Plasma levels of NO and VEGF were determined in all participants. RESULTS: Plasma level of nitric oxide in subjects with metabolic syndrome and vascular complications was 6.48 +/- 1.5 micromol/l and in healthy participants 10.08 +/- 1.09 micromol/l (p < 0.05). Plasma level of vascular endothelial growth factor in subjects with metabolic syndrome and vascular complications was 193.45 +/- 131.0 pg/ml and in healthy participants 71.09 +/- 14.49 pg/ml (p < 0.05). CONCLUSIONS: Endothelial dysfunction seems to be the substantial factor responsible for the vascular complications in subjects with metabolic syndrome, which manifests in increased plasma level of VEGF and decreased plasma level of NO. PMID- 21595169 TI - [The cyclin A, B1, D1 and E expression in advanced non-small cell lung cancer- stages IIIB-IV (preliminary report)]. AB - Lung cancer is the leading cause of cancer death in the majority of developed countries. Uncontrolled cell proliferation is the hallmark of malignant tumours. Cyclins play an important role in cell cycle regulation. The aim of this study was to evaluate the expression of cyclins A, B1, D1 and E in advanced non-small cell lung cancer (stages IIIB-IV) with its prognostic significance. MATERIAL AND METHOD: An immunohistochemical assessment of cyclins A, B1, D1 and E expression was performed in the paraffin-embedded tumor tissues of 19 patients (9 men and 10 women). The mean was age 59 +/- 6.64 years. 9 patients were in IIIB and 10 in IV. The 2-years survival rate was evaluated. RESULTS: We showed positive cyclin A expression in 13 tumor tissue specimens (68%), cyclin B1 in 3 (16%), cyclin D1 in 9 (47%) and cyclin E in 7 (37%). We analyzed the prognostic value of examinated cyclins in all NSCLC patients and separately in patients with squamous cell lung cancer and adenocarcinoma and in patients in stage IIIB and IV, but we have no found any correlations. We did not find also any differences in examinated cyclins expression depending on stages nor different histopathological types. CONCLUSION: We did not observe prognostic value of cyclins A, B1, D1 or E expression in advanced non-small cell lung cancer. PMID- 21595170 TI - [Magnetic resonance imaging and hormonal profile of the pituitary gland in patients with primary congenital hypothyroidism]. AB - The aim of our study was an estimation of the size and structure of the pituitary gland using MRI and the estimation of hormonal profile of the pituitary anterior lobe (except for ACTH) in 21 adult patients with congenital primary hypothyroidism. MATERIAL AND METHODS: The studied group was divided into 2 subgroups: A--with normal level of serum TSH and B--with its elevated. The MRI showed pituitary hyperplasia or tumor in 28.5% of patients, partially empty sella in 14.3% and hypoplasia in 9.5%. In subgroup B there were mostly hyperplasia or tumor (35.7%), while in subgroup A there were no domination of any abnormalities. RESULTS: Serum mean TSH level was 49.8+/-86.2 mU/l with an increase in 67%. The mean prolactin was 11.2+/-7.5 mg/ml with an increase in 19%. Serum LH and FSH concentrations were normal in the whole group. The mean alpha subunit level was elevated in 52%. In 42.8% somatotropic hypopituitarism was recognised due to GH stimulation tests. CONCLUSIONS: The TRH hyperstimulation in patients with congenital primary hypothyroidism may lead to pituitary hyperplasia or tumor visible on MRI and to pituitary hormonal abnormalities. PMID- 21595171 TI - [Nonoperative management of spontaneous splenic rupture in infectious mononucleosis]. AB - Spontaneous splenic rupture is a rare complication of infectious mononucleosis observed in 0.1-0.5% of patients with this condition. Mandatory mode of management in hemodynamically stable patients is nonoperative treatment. We report the case of a 19-year old man with splenic rupture, during the course of serological and hematological confirmed infectious mononucleosis, with no history of trauma. Parenchymal and subcapsular splenic hematomas and presence of blood in vesico-rectal recess was demonstrated. Circulatory and respiratory findings and blood cell count were stable. Nonoperative management was instituted which comprised monitoring of valid vital signs, serial USG and tomography scans and vital activity limitation. Imaging radiological investigations demonstrated disappearance of observed abnormalities on post admission day 20. The patient was discharged from the hospital in good general condition. CONCLUSION: Nonoperative management can be a safe alternative to splenectomy in hemodynamically stable patient with spontaneous rupture of the spleen. PMID- 21595172 TI - [Two-stage liver resections with portal branch ligation--a novel treatment strategy for patients with initially irresectable, bilobar colorectal liver metastases]. AB - Liver resection is the only potentially curative treatment option of patients with colorectal cancer metastases. However, at the time of diagnosis, most patients have irresectable tumors. Preoperative chemotherapy and portal vein embolization may lead to downsizing of initially irresectable colorectal cancer metastases, located in one lobe of the liver. Although, in group of patients with bilobar involvement such neoadjuvant therapy does not enable performance of radical operation. Irresectability of these tumors is mainly due to a functionally insufficient amount of future, postoperative remnant liver volume. Hereby, we present a novel treatment strategy of two-stage liver resection with portal branch ligation and inter and postoperative chemotherapy, we discuss the indications for this procedure in view of the presented cases and we review the literature on the treatment of patients with initially irresectable, bilobar liver metastases from colorectal cancer. PMID- 21595173 TI - [Erythema induratum--atypical manifestation of infection Mycobacterium tuberculosis--case report]. AB - The term erythema induratum refers to nodules usually located on the flexion surface of the lower legs, characterized by chronic and recurrent course--usually in women. The lesions are directly related to Mycobacterium tuberculosis infection which may be confirmed by tuberculin skin test, Quantiferon test or PCR. Diagnosis of erythema induratum is a direct indication for antytuberculous therapy extended with vascular drugs. In the presented case all above mentioned skin symptoms were diagnosed and their ethiological connection with Mycobacterium tuberculosis was documented. PMID- 21595174 TI - [Diagnosis, prevention and treatment of sarcopenia]. AB - Mass and power muscle declines with age, and is connected with impairment of their function. Every our proceedings associated with recognizing and curing elderly people should contain the evaluation of mass and muscle power. At the paper is presented causes, recognizing, preventive proceedings in older persons with sarcopenia. Adequate diet, physical exercises, giving the vitamin D has the beneficial influence on mass and strength of muscles, as well as they are improving the functional condition of older persons. PMID- 21595176 TI - [The meaning of biologic therapy in the treatment of rheumatoid arthritis with the focus on clinical remission. Part I. Tumor necrosis factor alpha inhibitors]. AB - Aims of management of rheumatoid arthritis (RA) patients are not only a delay in progression of the disease and improvement of motor function, but also inhibition of progress of joint damage and achievement of remission. Early RA diagnosis is important, allowing introduction of active therapy as early as possible. Immediate treatment with disease modifying anti-rheumatic drugs (DMARDs) is necessary. In case DMARDs fail to evoke an adequate therapeutic response, introduction of biological drugs should be considered. Failure to achieve remission in case of many patients treated with classic DMARDs was a stimulus for intensive research on new drugs. Introduction of tumour necrosis factor alpha (TNF-alpha) inhibitors to therapy of RA 15 years ago caused a significant progress in management of the disease. Five TNF-alpha inhibitors are currently authorised (Infliximab, Etanercept, Adalimumab, Certolizumab and Golimumab) for RA treatment. Numerous clinical trials and observational programs proved higher efficacy of a combination therapy consisting of MTX and a TNF-alpha inhibitor in terms of RA remission. That applies mainly to patients burdened with risk factors of fast progression of the disease. PMID- 21595175 TI - [Diagnostic difficulties in myasthenia gravis]. AB - The aim of this work is to approach the subject of myasthenia gravis (MG). The clinical symptoms of the disease has been described based on own clinical experience and literature review. Particular attention was dedicated to nonstandard beginning of MG. Diagnostic methods were presented with description of their applications and usefulness. Differential clinical view of MG depends of type of antibodies affecting neuromuscular junction. The most accurate test in MG diagnostic is SFEMG and most specific is measuring of AChRAB level in blood serum. The detection of antibodies anti-MuSK calls against execution of thymectomy on patients with MG. PMID- 21595178 TI - [Disturbances of folic acid and homocysteine metabolism in alcohol abuse]. AB - Chronic alcohol abuse leads to malnutrition, and thus to the deficiency of many nutrients, including vitamins and trace elements. Most often comes to the deficiency of all vitamins, however because the clinical implications, the most important is folic acid (vitamin B9) deficiency. Biochemical effect of folate deficiency is elevated homocysteine concentration in the blood, named "cholesterol of XXI. century". In the paper, the folate and homocysteine metabolism in alcohol abuse was discussed. Mechanisms of alcohol action on folate homeostasis in the human body have been indicated. Chronic alcohol consumption leads to deficiency of this vitamin due to their dietary inadequacy, intestinal malabsorption, decreased hepatic uptake and increased body excretion, mainly via urine. The decreased concentration of serum folic acid may occur in 80% of alcoholics. The cause of elevated concentrations of homocysteine in the serum of alcohol abusers is also a deficiency of vitamins involved such as vitamin B12 and pyridoxal phosphate. Disturbance of folic acid and homocysteine metabolism in alcohol abusers can lead to serious clinical consequences. Folic acid deficiency leads inter alia to macrocytic and megaloblastic anemia and neurological disorders. Megaloblastic anemia occurs in about half of alcohol abusers with chronic liver diseases. In turn, high level of homocysteine in blood is associated with an inreased risk of cardiovascular diseases. Hyperhomocysteinemia is an independent risk factor that favors the occurrence of acute coronary syndromes in patients with coronary heart disease. PMID- 21595177 TI - [The meaning of biologic therapy in the treatment of rheumatoid arthritis with the focus on clinical remission. Part II. Tocilizumab, Abatacept, Rituximab- drugs characterised by a different mechanism of action than TNF-alpha inhibitors]. AB - Current aims of management of rheumatoid arthritis (RA) patients are remission of the disease, or at least, achievement of its low activity. Early diagnosis of RA is highly important, allowing immediate start of therapy with classic disease modifying anti-rheumatic drugs (DMARDs). However, that kind of therapy does not guarantee achievement of therapeutic goals in all patients. In case of failure, introduction of biological drugs is necessary Despite a significant progress noted in RA therapy since introduction of tumour necrosis factor alpha (TNF alpha) inhibitors several years ago, also that scheme failed to be effective in all cases of RA. New biological drugs characterised by a different mechanism of action than TNF-alpha inhibitors: Tocilizumab, Rituximab and Abatacept, are hope for non-responders to previous therapies. PMID- 21595179 TI - [The medical biochemistry studies for 50 years (from biochemistry to molecular medicine and regenerative medicine)]. PMID- 21595180 TI - [Non-angiogenic functions of vascular endothelial growth factor]. AB - Vascular endothelial growth factor (VEGF or VEGF-A), also named as vascular permeable factor (VPF), is a multi-functional bio-macromolecule belonging to the family of secreted glycoprotein growth factor. VEGF can induce a variety of cellular responses through two high-affinity tyrosine kinases, VEGFR1 and VEGFR2. VEGF plays a key role in the angiogenesis and development in the embryo phase, promoting the proliferation, migration, tube formation and survival of the vascular endothelial cells. In the adult phase, VEGF mainly participates in maintaining the vascular structure and regulating physiological and pathological angiogenesis. Clinical data showed that VEGF signaling inhibitors significantly induced the degeneration of the tumor vessels and reduced tumor size. Meanwhile, various side-effects also have been observed in some patients, indicating that the non-angiogenesis functions of VEGF should be greatly emphasized, especially when developing anti-cancer drugs. Several studies showed that VEGF plays essential roles in various adult organs, such as small intestine, pancreatic islets, thyroid, kidney and liver. When VEGF level in these organs is lower than normal, the complexity of capillary network will be partially degenerated. Apart from that, VEGF also promotes the bone marrow formation, tissue repair and regeneration, the maturation of ovarian, and participates in some pathological courses such as thrombosis, inflammation and ischemia. This review focuses on the non-angiogenesis functions of VEGF and briefly discusses the molecular mechanisms. PMID- 21595181 TI - [Research progress on mechanism of antimicrobial peptides]. AB - The antimicrobial peptide is a class of small molecule peptide derived from a variety of creatures, able to kill the pathogens efficiently and has the potential of broad-spectrum activity, rapid and strong bactericidal activity, low propensity for resistance development, and many other advantages. As a new generation of anti-infective drug candidates, the mechanism of antimicrobial peptides has not yet entirely clear, but now there are two views have been widely recognized that the destruction of permeation through the membrane structural integrity and through the different intracellular target to affect bacterium growth and metabolic balance. In this paper, the physical and chemical properties, secondary structure, mechanism, and the relationship between the latter two to make a conclusion, in order to better understand the structure activity relationships and to provide a theoretical basis for rational design of antimicrobial peptides. PMID- 21595182 TI - [Advance of research on HLA-B27 and the immunological mechanism of ankylosing spondylitis]. AB - Ankylosing spondylitis (AS) is an autoimmune disease which has a strong association with HLA-B27. Its pathogenesis includes the interaction between microorganism and host, the recognition of MHC class I molecule by immune cells and the imbalance of the cytokine network and so on. Unfolded protein response (UPR) participates in the development of AS. And the activation of the IL-23/IL 17 axis, which is in the downstream of UPR, may make a critical contribution to the pathogenesis. UPR and IL-23/IL-17 axis open new avenues of investigation as well as identifying new therapeutic target in this disease. PMID- 21595183 TI - [Regulation of microglia on neurogenesis in adult mammals]. AB - Adult neurogenesis had been confirmed in rodents and other mammals for decades. The mechanisms underlying neurogenesis have been investigated extensively in recent years. Microglial cells, an immuno-cell in the central nervous system, have been found playing important roles in modulating the process of adult neurogenesis. The inflammatory microenvironment contributed by microglia are harmful to the survival of new born neurons. On the other hand, by interacting with T cells, microglia could act as a trophic factor for neurogenesis, most possibly by releasing growth factors. We reviewed the progress on how microglia regulating adult neurogenesis in variant pathological conditions. To understand the relationship between microglia and neurogenesis will help us to approach for promising therapeutic strategy for neuronal injury. PMID- 21595184 TI - [The capping protein on the slow-growing end of actin filament: erythrocyte tropomodulin]. AB - Erythrocyte tropomodulin (E-Tmod) is first isolated from human erythrocyte membrane as a TM-binding protein. Its N-terminus contains two TM-binding sites and one TM-dependent actin capping domain and C-terminus contains 5 leucine-rich repeats and a TM-independent actin capping domain. As the unique capping protein at the slow-growing end of F-actin, E-Tmod binds to N-terminus of TM and actin and decreases the TM-coated F-actin depolymerization. E-Tmod encoding gene is highly conserved and E-Tmod is distributed widely in erythrocytes and cardiomyocytes, etc. E-Tmod plays a pivotal role in organizing F-actin and cytoskeleton and maintaining the mechanical properties of the cells. PMID- 21595185 TI - [Oxidative stress of platelet and atherosclerosis]. AB - Most platelet-derived oxidants are produced through NAD (P) H-oxidase enzyme system. There are antioxidants such as superoxide dismutase and reduced glutathione in platelet. Oxidative stress alters platelet functions via regulation of platelet aggregation phase, impact on platelet nitric oxide and alpha II bbeta3 integrin, and imbalance between reduced and oxidized glutathione in platelet. Activated platelet by oxidative stress can influence blood vessel endothelium cell function, and worsen atherosclerosis through CD40 ligand. LDL is modified to oxidized LDL by platelets which can trigger foam cell formation. Some drugs with therapeutic intervention to reduce oxidative stress of platelet will be of use for atherosclerosis treatment. PMID- 21595186 TI - [Investigations of Na+ channels in pancreatic beta cells]. PMID- 21595187 TI - [The role of renin-angiotensin-aldosterone system in salty taste and sodium intake regulation]. PMID- 21595188 TI - [Advances in the researches on bacterial RNA polymerase sigma subunit]. PMID- 21595189 TI - [Effects of chronic hypoxia on the plasticity of carotid body and its regulation]. PMID- 21595190 TI - [Role of CaMKII in modulating Ca2+ homeostasis and cardioprotection]. PMID- 21595191 TI - [The role of histone acetyltransferase Tip60 in transcription and DNA damage response]. PMID- 21595192 TI - [Role of cannabinoid receptors in the control of gastrointestinal motility]. PMID- 21595193 TI - [The relationship between pregnane X receptor and multidrug resistance in tumor]. PMID- 21595194 TI - [Midbrain dopamine-ergic neurons and song behavior in songbird]. PMID- 21595195 TI - [Application and prospect of multi-spectral remote sensing in major natural disaster assessment]. AB - After the occurrence of major natural disasters, it is of great significance that disaster states are assessed timely and accurately for decision-making departments to draw up effective response programs. Multi-spectral remote sensing has a great advantage and potential in disaster assessment, with the characteristics of a wide range of data acquisition, high speed, etc. In several major natural disaster assessments in China, multi-spectral remote sensing technology has played an important role. Firstly, the present paper takes earthquake disasters, floods disasters and drought disasters as examples to summarize the specific applications of major natural disaster assessment based on the multi-spectral remote sensing. Secondly, in these specific applications they suffer from both relative shortage of data sources and limited breadth and depth of application; both of these problems are analyzed. Finally, the future development direction of major natural disaster assessment based on the multi spectral remote sensing, such as the expansion of multi-spectral remote sensing data acquisition means, the establishment of major natural disasters assessment index system based on remote sensing, and the improvement of the assessment technology system based on multi-spectral remote sensing are also discussed. PMID- 21595196 TI - [Studies on the remote measurement of the distribution of city gaseous pollutant by mobile passive differential optical absorption spectroscopy]. AB - An optical remote sensing method based on passive differential optical absorption spectroscopy for the measurement of the distribution of city gaseous pollutant was studied. The passive DOAS system, which was installed in a car, successively measures the interested area (such as city, industrial area) and the column density was obtained by DOAS fitting process using the zenith scattered sunlight. The mobile DOAS was applied to measurement in Shenzhen City during the continuous six days and got the distribution of SO2, NO2 in this paper. It showed that the pollution in the west is higher than in the east. The average concentration in the west is 2.0 times higher than the eastern for SO2 and 3.6 times for NO2. And comparison of the values between mobile DOAS and the point instrument was carried out in Baguang site. There was an agreement between the two instruments, the correlation coefficient was 0.86 for SO2, while 0.57 for NO2. The results indicate that this optical remote sensing method based on passive DOAS is an effective means of rapidly determining the distribution of city gaseous pollutant. PMID- 21595197 TI - [Advance of the imaging spectral technique in diagnosis of the information of crop]. AB - Labor intensive, time consuming, high technical requirements in operation and much affected by human factors is the limitation of diagnosing the crop information with conventional method, which could not make diagnosis real-time and rapid. Imaging spectral technique could simultaneously obtain the image and spectral information of crops. It could diagnose the growth and insects information of crop rapidly and non-destructively. In recent years, imaging spectroscopy has been widely used in diagnosis of the information of crop, so it provides technical support for agricultural informatization. In the present study, the principle of imaging spectroscopy was presented. The application progress of imaging spectroscopy technique in crop detection was investigated, including seed component detection, seed variety discrimination, seed disease and insect pest detection, field crop growth monitoring and field crop disease and insects monitoring. Then the paper analyzed difficulty of imaging spectroscopy for crop measurement, and the prospect of this technique was also discussed. PMID- 21595198 TI - [Time-resolved evaluation of self-absorption in laser induced plasma from nickel sample]. AB - Laser induced breakdown spectroscopy (LIBS) has been shown to be a promising technique for element analysis. However, self-absorption effect deeply influences the LIBS measurements. In the present paper, a Q-switched Nd:YAG laser operated at 1 064 nm was used to generate nickel plasmas in air. Four atomic lines Ni I 341.476/351.034/351.505/352.454 nm which belong to the same electronic configuration (3d9 (2D)4p-3d9 (2D)4s) of Ni were chosen for self-absorption investigation. Self-absorption of Ni I 351. 034 nm corresponding to the highest energy level 3D1 of 3d(9) (2D)4s was not observed in the plasma emission investigated. While for the other three lines, a strong self-absorption appeared at the prophase of the plasma and tended to weaken. The self-absorption at Ni I 352.454 nm was the most serious and still visible at the delay of 1100 ns, compared with the lines of Ni I 341.476/351.505 nm whose self-absorption duration is 900 and 500 ns respectively. It was also found that the self-absorption effect had power dependence and decreased with the increase in laser pulse energy. The obtained results suggest that the self-absorption effect could be alleviated by suitable atomic line selection, operating at a higher pulse energy and detecting with a longer delay. The possible reasons for the self-absorption duration difference for different lines were also discussed. PMID- 21595199 TI - [Terahertz time-domain spectroscopy of ractopamine hydrochloride]. AB - The terahertz spectra of Ractopamine hydrochloride in the range of 0.2 to 2.2 THz was obtained by THz time-domain spectroscopy, and the absorption and refraction spectra of Ractopamine hydrochloride was got meanwhile. The structure and vibrational frequencies of Ractopamine molecule in the THz range were simulated by density functional theory. The difference between experimental and theoretical results was analyzed. And assisted by Gaussian View 3.09, the origin of the vibrational frequencies was recognized. The results show that besides the intramolecular vibrations, THz absorption of Ractopamine hydrochloride originated from the intermolecular hydrogen bond network and Van der Waals force between molecules. This study demonstrated the feasibility of time-domain terahertz spectroscopy for the identification of Ractopamine hydrochloride and provided a new way for the detection of Ractopamine hydrochloride. PMID- 21595200 TI - [Study of the energy transfer between excited Rb2 and H2 using the CARS technique]. AB - Using the CARS (coherent anti-Stokes Raman spectroscopy) detection technique, the authors investigated the electronic-to-rovibrational levels energy transfer between electronically excited Rb2 and H2. In this CARS experiment, the S-branch (delta upsilon = 1, delta J = 2) transition of H2 was excited by two laser pulses, the pump and the Stokes, respectively, centered at 532 and 690 nm. The internal state distribution of collisionally populated H2 was probed. The scanned CARS spectra reveal that during energy transfer processes H2 molecules were produced only at the upsilon = 1, J = 1,2 and upsilon = 2, J = 0,1,2 rovibrational levels. From scanned CARS spectral peaks the population ratios were obtained. The n1/n5, n2/n5, n3/n5 and n4/n5 are 3.57 +/- 0.71, 2.65 +/- 0.53, 3.00 +/- 0.60 and 0.93 +/- 0.17, respectively, where n1, n2, n3, n4 and n5 represent the number densities of H2 at the rovibrational levels (2,0), (2,1), (2,2), (1,1) and (1,2), respectively. The population ratios indicate that the H2 molecules produced by the energy transfer process are 83% populated at the upsilon = 2 vibrational level and 17% at upsilon = 1. The relative fractions ( : = of average energy disposal were derived as (0.48, 0.01, 0.51), with major translational and vibrational energy release. Through semilog plot of the time-resolved CARS profiles under a simple kinetic model under the experimental conditions of T = 573 K and P = 5 x 10(3) Pa, the collisional transfer rate coefficients k12 = (3.1 +/- 0.6) x 10(-14) cm(-3) x s( 1) and k2 = (4.9 +/- 1.0) x 10(-15) cm(-3) x s(-1) have been obtained. PMID- 21595201 TI - [Spectroscopic diagnosis of striation in hollow cathode discharge]. AB - The characteristics of striations in cylindrical hollow cathode discharge were investigated experimentally. The emission intensity and spectra of striations were measured, and the spatial characteristics of electron excitation temperature and relative electron density were calculated. It is shown that the emission intensity, the electron excitation temperature and the electron density appear as a periodic structure. The electrons have higher excitation temperature but lower density in the bright regions compared with the dark regions. The electron excitation temperature in the bright regions decreases from the cathode to the anode. It is also shown that the electron excitation temperature increases with increasing current. PMID- 21595202 TI - [Preparation of Y2O3:Er3+ by coprecipitation method and influence of initial pH on the luminescent properties]. AB - Samples of Y2O3:1%Er were prepared by coprecipitation method and the pH value of precipitant ammonium bicarbonate was adjusted by ammonia. Results of Fourier transform infrared spectra (FTIR) and elemental analysis showed that the chemical construction of precursors at pH range of 8.0-9.5 had little change. By X-ray fluorescence spectrometer (XRF) and scanning electron microscope (SEM) analysis, it was found that the pH value of precipitant had a significant impact on the content of erbium in precursor and it can influence particle size as well as its distribution of the products, both of which had important effects on the luminescent properties of the products. PMID- 21595203 TI - [Photoluminescence of green phosphors Gd2Ba3B3O12 doped with Tb3+]. AB - The green emitting phosphor, Gd2Ba3B3O12:Tb3+ was synthesized with the method of high-temperature solid-state reaction. The phase structure and photoluminescence (PL) properties of the samples were characterized by The X-ray diffraction (XRD), vacuum ultraviolet spectrum and ultraviolet spectrum (VUV-UV). The results indicate that Tb3+ ion acting as the luminescent center inhabited the site of Gd3+ ion in the host of Gd2Ba3B3O12. The VUV-UV excitation spectrum consists of the two strong broad bands at about 160-200 and 200-250 nm and sharp lines at about 260-280 and 300-320 nm. The two strong broad bands were assigned to the host absorption and f--d transition of Tb3+. The sharp lines were ascribed to the f--f transition of Tb3+ and Gd3+. All the samples of Gd2Ba3B3O12:Tb3+ exhibit strong green emission corresponding to (5)D4-->(7)F5 transition (543 nm) of Tb3+ under VUV-UV light excitation. Under 172 nm excitation, 15 mol% Tb3+ doped Gd2Ba3B3O12 sample exhibits strong green emission with good color purity (x = 0.3136, y = 0.4843) and a fitted a decay time r around 2.98 ms. It can be concluded that this series of phosphors Gd2Ba3B3O12:Tb3+ is a promising green vacuum ultraviolet (VUV) phosphor for plasma display panels (PDPs) and Hg-free fluorescent tubes application. PMID- 21595204 TI - [Fabrication and luminescent properties of Dy3+ doped Sr(1-x)Ca(x)MoO4]. AB - Dy3+ doped Sr(1-x)CaxMoO4 phosphors were prepared by solid state method in the present paper. The crystal structure, luminescent properties and the effect of x on the luminescent properties were studied by XRD, SEM, excitation, emission and color parameters. The XRD patterns indicated that the samples were single phase of CaMoO4 and SrMoO4 when x=1 and x=0. It can be seen that the crystal size of samples prepared at 750 degrees C for 3 h were 0.2-1.0 microm, which was matched with solid state luminescent device. The excitation spectra monitored at 576 nm were composed of a broad band at 250-340 nm and a series of narrow band at 340 460 nm. The excitation peaks situation of CT transition and the excitation peaks intensity of narrow bands varied with Sr/Ca. The emission spectra excited by 350 nm were composed of two broad bands at 470 and 576 nm, which were attributed to the transition of 4F(9/2)-->(6)H(15/2) and (4)F(9/2)-->(6)H(13/2). The emission intensity of yellow and blue emission varied with the value of Sr/Ca. PMID- 21595205 TI - [Mechanism study on the extraction of nonylphenol by ionic liquids in water through IR spectroscopy and quantum chemical calculation]. AB - The interaction mechanism of the typical ionic liquid (IL) 1-methyl-3-butyl imidazolium hexafluorophosphate ([BMIM][PF6]), imidazolium ionic liquid with hydroxyl group and nonylphenol (NP) was studied through infrared (IR) spectroscopy and quantum chemical calculations for density functional theory. The results indicated the hydrogen bonds could not be found in the IR spectra before and after IL [BMIM][PF6] extracting NP while the absorption peaks of the hydroxyl group of the ILs containing hydroxyl group have red shifts after the ILs extracting NP. It could be seen in the theoretical calculation that the cation [BMIM]+ of [BMIM][PF6] has the C--H...O hydrogen bond interaction with NP. The O- H...O type hydrogen bond could also be formed between the cation [C4H9OHIM]+ of the IL with hydroxyl group and NP. It could be concluded through the two mechanism study methods that the strength of hydrogen bond between the IL with hydroxyl group and NP was bigger than the one between the typical IL [BMIM][PF6] and NP, followed by the bigger extraction efficiency of NP by the former, which coincided with the extraction experiment result. PMID- 21595206 TI - [FTIR spectra study on the film of polyurethane coated urea controlled-release fertilizer]. AB - The polyurethane films were prepared to wrap the urea in order to achieve a desirable release rate by mixing isocyanate, polyols and wax. The effect of wax, urea and isocyanate on the structure and properties of the films was investigated by FTIR. The structural changes were monitored as the polyurethane films together with the wrapped urea were immersed into ammonia water for 28 days, which is used to model soil conditions. The FTIR results showed that the width and intensity of the NH-free band increased remarkably with time, and all kinds of carbonly bands shifted to high wavenumber and their intensity increased obviously. The results suggest that the structure of the polyurethane films was destroyed more heavily in soil than in water, and this explains the relatively fast release rate of urea in soil. It was observed that the increase in the chemical crosslinking density in the polyurethane films can effectively decrease the release rate of the urea nitrogen in soil. PMID- 21595207 TI - [The way to identify the man-made-lime in Neolithic in China]. AB - Archaeological studies indicated that the "Baihuimian" building material has been excavated widely in the Neolithic Age, which was not only hard, but also of beauty and cleanly. Archaeologist concluded that the "Baihuimian" may be the earliest man-made-lime in China. So, the infrared spectroscopy was used to analyze the "Baihuimian" and "Baitiaoshi" from Taosi site. The results indicated that the ratio of upsilon2 to upsilon4 is markedly different between "Baihuimian" and "Baitiaoshi" by infrared spectroscopy which shows that there is a big difference in the disorder parameter of calcium carbonate crystal, suggesting calcined "Baihuimian" is identified depending on infrared spectroscopy. Thereby, it offers a simpler and more efficient method to study the origin of lime. Meanwhile, the temper of "Baihuimian" was also analyzed by microscope and infrared spectroscopy methods, respectively, which proves that the mixed materials (admixture) in "Baihuimian" is cellulose. PMID- 21595208 TI - [Fourier transform infrared spectroscopy and FT-Raman spectrometer study of hyperdispersant on atrazine surface]. AB - The main methods in performing the study of the adsorption properties of hyperdispersant on atrazine surface were fourier transform infrared spectroscopy (FTIR) and FT-Raman spectrometer (FT-Raman), and the results suggested that the hydrogen bond force was the main force combining the surface of atrazine particles and the dispersant. And it also promoted the adsorption of dispersant on atrazine particles. However, the information of what accurate quantity of the dispersant adsorbed on the surface of atrazine should a successful suspension ability of the suspension concentrate acquire is still not available. And researches on this question still need to be done with the help of quantized spectroscopy method. The result of this study provided a theoretical foundation for the development of stable atrazine suspension concentrate and the spectroscopy quantitative analysis of it. This result provided significant information for the application of atrazine suspension concentrate at the same time. PMID- 21595209 TI - [Studies on normal and mildewy Auricularia auricular by Fourier transform infrared spectroscopy]. AB - In order to verify the capability of Fourier transform infrared spectroscopy in food safety, Fourier transform infrared spectroscopy (FTIR) was used to obtain the spectra of normal and mildewy auricularia auricula, The result showed the frequency of hydroxyl and aliphatic absorption band in their spectra had evident differentia, with the dispersion being 23.31 and 13.41 cm(-1) respectively. The curve-fitting analysis was used for the fold peaks of hydroxyl and amido, and it presented that the content of hydroxyl and amido had evident change. The substances in the auricularia auricula generated chemical change, and Fourier transform infrared spectroscopy could show the differentia easily. The results show that Fourier transform infrared spectroscopy can provide valuable information about the auricularia auricula. It could be used as a reference method for identification of the normal and mildewy auricularia auricula. PMID- 21595210 TI - [Estimation of the physical and mechanical properties of Neosinocalamus affinins using near infrared spectroscopy]. AB - Near infrared spectroscopy was applied to rapidly predict density, modulus of rupture and tensile strength parallel to grain of neosinocalamus affinins. Backward interval partial least squares (BiPLS) was used to find the most informative spectrum ranges, and build models based on raw spectra and pretreated spectra, including first derivative spectra, second derivative spectra, Savitzky Golay smoothing spectra and standard normalized variate spectra. And partial least squares (PLS) models were also developed in the whole wavelength range 350 2500 nm. The results show that compared with PLS models, BiPLS could effectively find the optimal spectrum regions and improve the predictive ability of models. The optimal models of density, modulus of rupture and tensile strength parallel to grain were obtained through BiPLS method that separated the whole spectra pretreated by standard normalized variate, second derivative and first derivative respectively into 20, 30 and 20 intervals. And the prediction models of density, modulus of rupture and tensile strength parallel to grain had correlation coefficient (r) 0.85, 0.88 and 0.88, as well as root mean standard error of prediction (RMSEP) 0.0524, 0.0185 and 0.0292, respectively. The relation between NIR predicted values and actual values was good in all cases. Therefore, the experimental results demonstrated that NIR spectroscopy was promising for predicting the physical and mechanical properties of neosinocalamus affinins. PMID- 21595211 TI - [Application of Fourier transform attenuated total reflection infrared spectroscopy in analysis of pulp and paper industry]. AB - As one of the most powerful tools to investigate the compositions of raw materials and the property of pulp and paper, infrared spectroscopy has played an important role in pulp and paper industry. However, the traditional transmission infrared spectroscopy has not met the requirements of the producing processes because of its disadvantages of time consuming and sample destruction. New technique would be needed to be found. Fourier transform attenuated total reflection infrared spectroscopy (ATR-FTIR) is an advanced spectroscopic tool for nondestructive evaluation and could rapidly, accurately estimate the production properties of each process in pulp and paper industry. The present review describes the application of ATR-FTIR in analysis of pulp and paper industry. The analysis processes will include: pulping, papermaking, environmental protecting, special processing and paper identifying. PMID- 21595212 TI - [Analysis and evaluation of taxol contents in different parts between Taxus media and Taxus mairei based on Fourier transform infrared spectroscopy]. AB - In the present study, combined with external standard method, second derivative as well as curve-fitting equation, the infrared spectroscopy techniques were applied to research the discrepancy of paclitaxel content among different parts of them repectively as well as the differences of infrared spectral character between Taxus Media (T. Media) and Taxus Mairei (T. Mairei). The results showed: (1) The band around 1516, 1371, 1 244, 1109 and 773 cm(-1) was markedly enhanced when paclitaxel standard sample was added by more than 0. 004 5 mg to original traditional Chinese materials, in addition, in infrared fingerprint area, the second derivative spectra show that there was good corresponding peak between traditional Chinese materials and standard paclitaxel sample around 1371, 1315, 1244, 1143, 1106, 1070, 1022 and 773 cm(-1), furthermore, the intensity of above character band would increase accompanying with increased standard paclitaxel sample. So, the band character around 1371, 1315, 1244, 1143, 1106, 1070, 1022 and 773 cm(-1) could be used to evaluate paclitaxel content of T. media and T. mairei; (2) Around 1800-700 cm(-1), IR spectral features suggest that two kinds of Chinese yew had quite similar infrared vibration character, but when Gaussian function was applied to decompose the band around 1058 cm(-1), the result demonstrated that the T. media were decomposed with 8 while T. mairei were only decomposed with 7 component bands. (3) Second-derivative and curve-fitting equation analysis demonstrated that there were certain differences of paclitaxel content between T. media and T. mairei as well as different parts of them. Specifically, the paclitaxel content of T. media was higher than T. mairei, while the paclitaxel content in leaf of T. media was highest, on the contrary, the paclitaxel content in root of T. mairei was highest when comparing the content among the different parts of T. media and T. mairei respectively. Therefore, above methods could be quickly analyze and evaluate the differences of paclitaxel content between T. media and T. mairei as well as the different parts of them. PMID- 21595213 TI - [Rapid and nondestructive discrimination of hybrid maize seed purity using near infrared spectroscopy]. AB - Near infrared spectroscopy technology was applied to study rapid and nondestructive discrimination method of hybrid maize seed purity. With NongDa108 hybrid seeds and mother 178 seeds, a discrimination model for the purity of maize single seed was built by near infrared reflectance spectroscopy with distinguished partial least squares (DPLS). A total of 200 seeds including 100 hybrid seeds and 100 mother seeds were divided into two groups: calibration set (150 samples) and validation set (50 samples), and each group had same number of hybrid and mother seeds. To eliminate human errors as much as possible we used two sample cups with transmission hole diameter of 3.0 and 4.5 mm, respectively, at the bottom for spectrum acquisition. The location of sample cups and seeds were fixed during spectrum acquisition process. The result showed that the average identification rate with 3 mm transmission hole diameter was 99.82%, significantly higher than that of 4.5 mm whose average identification rate was just 90.96%. There was no significant difference among the identification rates of one replicate and two replicates spectrum on endosperm face, two replicates spectrum on embryo face and four replicates. The rates of validation set reached about 99%, slightly more than that of one replicate on embryo face. The identification rates of one spectrum and two replicates spectrum on endosperm face in calibration and validation set were 100%, with the spectral region between 4000 and 8000 cm(-1). With 3.0 mm transmission hole diameter and 4000 8000 cm(-1) spectral region, the seed purity identification rates in calibration and validation sets built up by one spectrum on endosperm face were 100%. With the increase in principal components, the identification rates in calibration set and validation set gradually increased, and when principal components reached 9, the rate in both of sets were 100%. The results have important value for rapid and nondestructive testing of hybrid maize seed purity. PMID- 21595214 TI - [Determination of fat, protein and DM in raw milk by portable short-wave near infrared spectrometer]. AB - Near infrared diffuse reflectance spectroscopy calibrations of fat, protein and DM in raw milk were studied with partial least-squares (PLS) regression using portable short-wave near infrared spectrometer. The results indicated that good calibrations of fat and DM were found, the correlation coefficients were all 0.98, the RMSEC were 0.187 and 0.217, RMSEP were 0.187 and 0.296, the RPDs were 5.02 and 3.20 respectively; the calibration of protein needed to be improved but can be used for practice, the correlation coefficient was 0.95, RMSEC was 0.105, RMSEP was 0.120, and RPD was 2.60. Furthermore, the measuring accuracy was improved by analyzing the correction relation of fat and DM in raw milk This study will probably provide a new on-site method for nondestructive and rapid measurement of milk. PMID- 21595215 TI - [Study on discrimination of varieties of corn using near-infrared spectroscopy based on GA and LDA]. AB - A new method for the fast discrimination of varieties of corn based on near infrared spectroscopy using genetic algorithm and linear discriminant analysis (LDA) was proposed. First, data of NIS of 37 varieties of corn was collected, second, genetic algorithm used for choosing the feature band of spectrum, then PCA and LDA were used to extract features, and finally corn seeds were classified. The result showed that GA could remove noise band effectively and improve the generalization ability of LDA. A large number of redundant data was removed to simplify the computing, which resulted in the data dimension reduction from 2075 to 233. For the 300 samples of test set one, the average correct recognition rate and average correct rejection rate attained 99.30% for both, and the average correct recognition rate of 73.33% varieties of corn attained for 100%. For the 175 samples of test set 2 (all of whose varieties had not been trained), the average correct recognition rate attained 99.65%. The run time is shorter and the correct rate is higher compared to the common method of PCA. PMID- 21595216 TI - [An authentication method of bear bile powder based on the near infrared spectroscopy]. AB - A method based on the near infrared (NIR) spectroscopy was established for the authentication of bear bile powder and the quantitative analysis of the proportion in the counterfeits. The NIR spectra of 30 bear bile powder samples from 4 different origins, 6 pig gall powder samples, and 65 mixed samples of bear bile powder and pig gall powder with different proportions range from 0 to 100% were collected. The principal component analysis (PCA) was done and well-marked boundaries were observed between the bear bile and the counterfeits, also the bear bile samples from different origins. Partial least squares discriminant analysis (PLS-DA) was used to differentiate the bear bile and the counterfeits, and the rate of accuracy is 95%. Finally, the PLS calibration model was established for the quantitative analysis of the bear bile proportion in the counterfeits, the coefficient of determination of the prediction set is 0.9759, and the root-mean-square prediction error is 4.25%, which indicated that the result was satisfied. This research contributes to the rapid and undamaged identification of bear bile powder, and also offers reference for the quality identification of other expensive medicinal materials. PMID- 21595217 TI - [Rapid diagnosis of TCM syndrome based on spectrometry]. AB - Tongue color provides important information in traditional Chinese medicine (TCM) diagnosis, but in the process of TCM inspection, the various surrounding environment and subjective effect of doctors will influence the correctness of diagnosis. The present article put forward a brand new thought to study TCM objectivity, that is to research the essence message of tongue from perspective of spectrum, study the continuous spectrum to replace the observation of tongue color. The experiment used near infrared spectrum to collect reflection spectrum data of tongue among 53 exterior cold and interior heat patients, 37 healthy people and 21 wind chill suffers. Used matlab for data pretreatment, minitab for statistics modeling and prediction used partial least squares, the accuracy of prediction is 85.6%, but however, the spectrum of near infrared fail to distinguish exterior cold and interior heat patients from wind chill sufferers. The article provides a brand new way to implement the objectivity of tongue diagnosis in TCM, and also offers data support for the study of TCM syndrome. PMID- 21595218 TI - [Raman spectra and structure analysis of 2,6-pyridine dicarboxylic acid in different states and single Bacillus spore]. AB - The Raman spectra of 2,6-pyridine dicarboxylic acid (DPA) and their calcium salts(Ca-DPA) in different states and the Ca-DPA in a single bacterial spore have been recorded by laser tweezers Raman system (LTRS) and the spectra have been assigned. Raman spectra of different states of DPA and Ca-DPA are different evidently. Analysis leading to differences in the structure of spectrum may be due to that the Raman spectra of DPA crystalline reflected more precise characteristics information compared to DPA powder, in which the laser can penetrate through DPA crystalline and the Raman scatter from the crystalline interior is greater than that from DPA powder. The second reason is that DPA powder and Ca-DPA crystalline contain water molecules, and the intermolecular hydrogen bonding in the crystals of these molecules is extensive. The presence of calcium ions would affect the pyridine ring so that both sides of the carboxyl pyridine ring have a certain geometric deformation and the hydroxy carboxylic was damaged. The DPA2-anion is principal in Ca-DPA and the DPA solution. The calcium ion affects the stability of the pyridine ring structure in the Ca-DPA solution. The result from the spectra also showed that the DPA in single spores present Ca DPA crystal state. PMID- 21595219 TI - [Confocal micro Raman spectroscopy for the identification of the binder used in Chinese painted cultural relics]. AB - For identification of the binder used in Chinese painted cultural relics, the micro-Raman spectroscopy was used to test the pig skin glue, pig bone glue, egg yolk, egg white and peach glue which were commonly used as binder in the relies. The difference between proteinaceous binder and peach glue are distinctly. According to the analysis of their Raman spectrum, the vibrations located at 1463 and 1088 cm(-1) are the features of peach glue. The four kinds of proteinaceous binder also have respective features of their own, although there are many common features in their Raman spectrum. The vibration of 1737 cm(-1) is the feature of pig skin glue, and tie pig bone glue has the feature of vibration located in 962 cm(-1). The vibrations of 1535-1555 and 759 cm(-1) are the features of egg, including egg yolk and egg white. And the egg yolk has another vibration located at 1749 cm(-1) which is different from egg white. It was concluded that the binder can be identified based on the features of Raman spectrum. PMID- 21595220 TI - [Research on the experiment of hydrogen isotope fractionation using diamond anvil cell and Raman spectra]. AB - Hydrothermal diamond-anvil cell and Raman spectroscopy were used to measure the hydrogen isotope fractionation factor between gypsum and liquid water. Hydrogen isotopes of deuterium (D) and hydrogen (H) show the largest relative mass difference in all stable isotope systems. The exchange reaction between D and H would easily take place and the extent of exchange would be larger than others under same condition. So we selected the hydrogen isotopes for the investigation. The concept of fractionation factor is the quotient of ratios of heavy and light isotopes in different minerals, and can be expressed as alpha(A-B) = R(A)/R(B). There is a linear relationship between ratio of Raman peak intensities and ratio of corresponding amount of substances. So the fractionation factor between gypsum and heavy water can be expressed as [formula: see text] The experimental study for the isotope fractionation is based on the dissolution and recrystallization of minerals in aqueous solutions. The process can reach the total isotope fractionation equilibrium and get isotope fractionation factors with different temperatures. Compared with other methods, chemical synthesis one has following advantages: (1) short time for the experiment; (2) no problem about the equilibrium for isotope exchanges. It was proved that the new method would be more convenient and reliable for obtaining the isotopic fractionation factor compared with previous ways. PMID- 21595221 TI - [Raman characterization of high-pressure phase transition in AlN nanowires]. AB - High-pressure phase transition of AlN nanowires was investigated in the range of 0-33.1 GPa by in situ Raman spectrum method in diamond anvil cell (DAC). The A1 (LO) vibration mode exhibits considerably asymmetry and broadening, indicating the occurrence of wurtzite-to-rocksalt phase transition. The Raman signal of high pressure phase can be assigned to the disorder activated Raman scattering of rocksalt AlN. After fully releasing pressure, the Raman characterization of high pressure phase was quenched. According to the pressure dependence of phonon frequency of AlN nanowires, the difference of transiton path between AlN nanowires and bulk materials was discussed and the mode Gruneisen parameters were determined. PMID- 21595222 TI - [Raman spectral investigations on the phase transition behaviors of MgSO4.7H2O crystals in different efflorescence processes]. AB - In the present paper, the in situ confocal Raman spectra of MgSO4.7H2O crystal in different efflorescence processes were obtained through changing relative humidities in differernt ways. Thus, detailed investigation of phase transition of MgSO4.7H2O crystal was achieved. At 3% RH, the phase transition of MgSO4 crystal from MgSO4.7H2O to MgSO4.3H2O both occurred in the fast-efflorescence and slow-efflorescence processes. However, in the deliquescence process, distinct phase transition behaviors were found between the MgSO4.3H2O crystals which formed in different efflorescence processes, the MgSO4. 3H20 crystals formed in fast-efflorescence process transformed to MgSO4.6H2O crystals at 70% RH in the deliquescence process. On the contrary, the MgSO4.3H2O crystals formed in slow efflorescence process deliquesced to supersaturated MgSO4 droplet. The studies indicated that there is a correlation between the phase transition behaviors and ways of changing RH for the different MgSO4 crystal hydrates. PMID- 21595223 TI - [Quantitative determination of PVC concentration by Raman spectrum]. AB - Quantitative determination of polyvinyl chloride (PVC) concentration by Raman spectrum was studied in the present work. According to partial least squares (PLS) analysis, it was found that scores of PLS factor 1 were proportional to the concentrations of the sample solutions. Meanwhile, the loadings of factor 1 could reflect the contents of PVC and cyclohexanone simultaneously. The PLS regression model for PVC concentration prediction was built. The values of r and root mean square error (RMSE) between predictive results and actual values were 0.9963 and 2.775, respectively. The Raman characteristic peaks of PVC and cyclohexanone were found, including the C-Cl bond for PVC (620 and 695 cm(-1)) and the alicyclic ketone for cyclohexanone (1709 cm(-1)). By using internal standard method, another model for PVC concentration prediction was established, and the values of r and RMSE were 0.9941 and 3.151, respectively. The results indicated that it is feasible to use Raman spectrum to detect the PVC concentration, which is of significant importance to PVC recycling. PMID- 21595224 TI - [Measurement of ethylene content in polypropylene by Raman spectrum]. AB - Ethylene content in polypropylene was studied by Raman spectrum, combined with partial least squares (PLS) method. The comparison between Raman spectra for polyethylene and polypropylene was carried out, and the spectra between 50 and 600, 600 and 1600, and 2700 and 3100 cm(-1) were analyzed respectively. The models for ethylene content prediction were built, while the model based on 50 3600 cm(-1) spectra gave the best performance. The experiment indicated that Raman spectrum gave the similar predictive results as the near infrared (NIR) spectrum; the values of correlation coefficient (r), relative average deviation (RAD) and root mean square error (RMSE) between predictive results and actual values were 0.995, 2.65% and 0.319, respectively. According to PLS analysis, the loadings of factor 1 could reflect the relationship between the composition of polypropylene molecular chain and ethylene content, and ethylene content had a positive correlation with CH2 content, but a negative correlation with content of CH3, C-H, and C-C. The results indicated that it was feasible to detect the ethylene content in polypropylene by Raman spectrum. PMID- 21595225 TI - [Impacts of different inoculation methods on fluorescence characteristics of DOM in solid waste composting]. AB - In order to determine the best inoculation methods of compound microorganisms in solid waste composting, dissolved organic matter (DOM) during the process of composting under five different inoculation methods, including inoculation at the start, at the high-temperature phase, after the high-temperature phase, at the maturity phase and without inoculation, was tested through spectral analysis to investigate the time variations of DOM components in solid waste composting. Fluorescence spec-tra analysis of DOM indicated that the spectral characteristics of DOM in the composting piles of the five treatments exhibited a certain trend with composting time increasing, in which macromolecules with complex structures and humic substances gradually increased, and the heap materials became more and more stabilized. According to the comparisons of the fluorescence spectroscopy maps and related parameters, the treatment of inoculating compound microorganisms at the start time or after the high-temperature phase could notably speed up the humification process in solid waste composting. PMID- 21595226 TI - [Study on the microstructure of fluorescent labelling ghee microcapsules by Tomoscan imaging]. AB - In the present paper, fluorescein isothiocyanate was chosen as a fluorescence probe to mark casein protein in alkaline conditions. The interaction of the casein protein marked or not marked and fluorescein isothiocyanate was preliminarily discussed by the spectrum changes of UV-absorption and fluorescence spectrometry. Fluorescent marker was separated from SephadexG-50 chromatography column. With it as an emulsifier, the fluorescently-labeled ghee microcapsules were prepared by spray drying. And using laser scanning confocal microscope by tomoscan imaging to detect the microstructure of ghee microcapsules with the excitation of 488 nm argon-ion laser, the results showed that the casein protein assembled in the membrane surface of oil-water interface and microcapsules. The ghee microcapsules had two forms, namely mononuclear and multinuclear. The microcapsule was spherical. Its surface was smooth with no crack and no hollow. Its wall surface was intact and wall structure was relatively dense. The particle size showed obvious difference. Small particles attached to large particles, forming partial agglomerating powders to contribute to enhancing the solubility of microcapsules. These prove that the ghee microcapsule is an ideal microcapsule product. PMID- 21595227 TI - [Synthesis of SiO2 coated Eu(TTA)3phen and study on its fluorescent property]. AB - New-style fluorescent material of SiO2/Eu(TTA)3 phen was synthesized by the method of dispersing Eu(TTA)3 phen in isopropanol and hydrolyzing TEOS. Fluorescence spectra showed that the emission intensities of SiO2/Eu(TTA)3 phen were much more stronger than that of Eu(TTA)3 phen by more than two times. At the same time, the peak at 617.4 nm became very sharp, which could not be observed for Eu(TTA)3 phen. This indicated that the structure of Eu(TTA)3 phen became more rigid after coated by SiO2. Thus, the emission intensity was enhanced largely. Life-time of SiOz/Eu(TTA)3 phen decreasing just confirmed the rigidity of SiO2/Eu(TTA)3 phen. PMID- 21595228 TI - [Synthesis and characterization of new lanthanide complexes using pipemidic acid (PPA) and dioxane as ligands]. AB - Eu(PPA)3 dioxane and Tb(PPA)3 dioxane were synthesized by firstly adopting dioxane as second ligand and using pipemidic acid (PPA) as first ligand. In contrast with two kinds of binary lanthanide complexes Eu(PPA)3 and Tb(PPA)3, the photoluminescent intensities of Eu (PPA)3 dioxane and Tb (PPA)3 dioxane are much stronger, especially for that of Tb(PPA)3 dioxane. The enhancement of photoluminescent intensities of Eu(PPA)3 dioxane and Tb(PPA)3 dioxane is because of the replacement of dioxane for water bonded to Eu3+ and Tb3+, by which the energy loss through heat oscillation will be inhibited. The as-synthesized lanthanide complexes were characterized by FT-IR, photoluminescence spectra and photoluminescence lifetime. The lifetime of Eu(PPA)3 dioxane and Tb(PPA) dioxane remarkably changed compared with those of Eu(PPA)3 and Tb(PPA)3. However, there is much difference for the lifetime change of as-synthesized lanthanide complexes formed by Eu3+ and Tb3+, which shows that there is different energy transfer process for the lanthanide complexes formed by Eu3+ and Tb3+. The synthesis of lanthanide complexes using dioxane as second ligand will provide a new method to detect the existence of dioxane. PMID- 21595229 TI - [Research on the 3D discrete fluorescence spectrum technique for differentiation of phytoplankton population]. AB - The present research was targeted to develop a fluorescence analyser for phytoplankton population which uses a series of LEDs as the light source. So the 3D discrete fluorescence spectra with 12 excitation wavelengths (400, 430, 450, 460,470, 490, 500, 510, 525, 550, 570 and 590 nm) were determined by fluorescence spectrophotometer for 43 phytoplankton species. Then, the wavelet, Daubechies-7 (Db7), and Bayes Classifier were applied to extract the characteristics for each classes from the 3D discrete fluorescence spectra. Lastly, the fluorescence differentiation method for phytoplankton populations was established by multivariate linear regression and non-negative least squares, which could differentiate phytoplankton populations at the levels of both divisions and genus. This method was tested: for simulatively mixed samples(the dominant species accounted for 70%, 80%, 90% and 100% of the gross biomass, respectively) from 32 red tide algal species, and the correct discrimination rates at the level of genus were 67.5%, 75.8%, 81.4% and 79.4%, respectively. For simulatively mixed samples (the dominant divisions algae accounted for 50%, 75% and 100% of the gross biomass, respectively) from 43 algal species, the discrimination rates at the level of division were 95.2%, 99.7% and 91.9% with average relative content of 38.1%, 63.2% and 90.5%, respectively. PMID- 21595230 TI - [Characterization and identification of spilled oils using synchronous fluorescence spectroscopy of concentrated solutions]. AB - In the present paper, a tentative study was made to identify spilled oils using synchronous fluorescence spectrum (SFS). Seventeen crude oil samples from different areas in China were studied. SFS of oil solutions with three concentrations, which were 5, 500 and 5000 mg x L(-1), were analyzed. The number and position of SFS peaks were different for the different concentrations of oil solutions. Oil solutions of 5, 500 and 5000 mg x L(-1) had characteristic peaks in excitation wavelength 260 -460, 290-550 and 400-850 nm, respectively. In order to study the weathering effect on SFS, four crude oils were also set outdoors for weathering experiment and SFS of weathered oils after 1, 3, 5, 10, 15 and 35 d were determined. All the SFS of original and weathered oils were analyzed using principal component analysis (PCA). The principal component scores charts showed that the SFS of the oil solution of 500 mg x L(-1) had better distinguishing ability than the other two concentrations. Thus SFS of 500 mg x L(-1) between 290 and 600 nm were selected as spectrum feature of crude oils and used to build oil fingerprint data base for identifying crude oils. Taking one oil sample with unknown source among the seventeen crude oils as a case study, SFS were analyzed by PCA to find the origin of the unknown crude oil. The results draw a conclusion that SFS of high concentration solution (500 mg x L(-1)) may become a useful means in spilled oils identification. PMID- 21595231 TI - [Investigation on internal energy transfer and relaxation kinetics of NO2 by photoacoustic and fluorescence emission spectra]. AB - With 532 nm laser as excitation source, the excitation and relaxation process of NO2 molecule was investigated by the technique of photoacoustic and fluorescence emission spectra. The results show that NO2 molecules will be pumped to the first excited electronic state by laser photon. When the sample pressure is lower, some of the excited molecules relax to the ground state by radiation process directly; the other parts are redistributed to a few of the excited rovibronic energy levels by the process of fast internal energy transfer. With the increase in the sample pressure, continual collisions dominate the relaxation process gradually. This makes the excited molecules to be redistributed to many excited rovibronic energy levels. Emission from these excited levels forms a continuous spectrum. Just then, the efficiency of fluorescence emission from laser excited level decreases and the fluorescence intensity on the long wavelength side increases. The intensity of PA signals increases also. These phenomena indicate that besides the relaxation process of radiation, there is a strong relaxation process of continual collision under the condition of higher sample pressure. It converts vibration energy of the excited molecules into translation one. This induces the increase in gas temperature and a sound wave is produced. PMID- 21595232 TI - [Comparison among remotely sensed image fusion methods based on spectral response function]. AB - Remotely sensed image fusion is a critical issue, and many methods have been developed to inject features from a high spatial resolution panchromatic sensor into low spatial resolution multi-spectral images, trying to preserve spectral signatures while improving spatial resolution of multi-spectral images. However, no explicit physical information of the detection system has been taken into account in usual methods, which might lead to undesirable effects such as severe spectral distortion. Benefiting from the proper decomposition of the image fusion problem by a concise image fusion mathematical model, the present paper focuses on comparing reasonable modulation coefficient of spatial details based on analysis of the spectral response function (SRF). According to the classification of former methods, three modulation coefficients based on SRF of sensors were concluded, which lead to three image fusion methods incorporating spatial detail retrieved by Gaussian high-pass filter. All these methods were validated on Ikonos data compared to GS and HPM method. PMID- 21595233 TI - [Remote sensing monitoring and pre-alarming of algal blooms in Taihu Lake]. AB - The explosive growth of algae in inland water bodies is one of the major water environmental problems in China, and it's very important to monitor the dynamic of algae in both temporal and spatial scales. In the present paper, a model, which was used to extract the algae information from the water body of Taihu Lake using MODIS data, was established based on the remote sensing index and image false color composite methods. Using this model, we studied the algae explosive growth formation process between March and May in 2007. Through the analysis of the temporal and spatial distribution features of the algae outbreak between the spring and summer seasons, an early warning method of algal blooms was proposed, that is, when the MODIS green index mainly concentrated in the range between 0. 6 and 0. 8, the water body of Taihu Lake can be considered to have been in the early alarming stage of algal blooms. PMID- 21595234 TI - [Research on predicting modeling for chlorophyll contents of greenhouse tomato leaves based on multi-spectral imaging]. AB - Traditional spectrum analysis technology has low accuracy for forecasting chlorophyll content of plants. Research based on 3CCD camera has the limitations of high cost and the number of sensitive wavelengths not adjustable. The present paper develops a new approach to forecasting the chlorophyll content of tomato leaves by the image gray value of the selected sensitive wavelengths (532, 610 and 700 nm). Three common methods such as multi-linear regression, principal component analysis and partial least square regression were employed in forecast modeling, the good results were obtained, and both Rc2 and Rv2 reached about 0.9. The method has proven effective and feasible for prediction of chlorophyll contents of tomato leaves, which also lays the foundation for the development of testing instruments for the growing of crops. PMID- 21595235 TI - [Studies on the estimation of soil organic matter content based on hyper spectrum]. AB - Hyperspectral remote sensing technology can be extensively applied in soil nutrient research due to its three special advantages, high spectral resolution, strong waveband continuity as well as a great deal of spectral information. Based on analyzing the soil organic matter content using hyper-spectral remote sensing technology, soil nutrients status and its dynamic changes can be fully understood, thus providing the scientific basis for guidance of the agricultural production and protection of agricultural ecological environment. The present paper studies the relationship between soil spectrum and soil organic fraction based on spectrum curves (ranging from 350 to 2500 nm) of 34 soil samples, which were collected in Yujiang and Taihe County, Jiangxi Province. First, soil reflection spectrum was mathematically manipulated into first derivative reflectance spectra (FDR) and inverse-log spectra (log(1/R)); second, the relationship between soil spectrum and soil organic fraction was investigated by step-wise multiple linear regression (SMLR) and partial least square regression (PLSR) on the ground of characteristic absorption; third, corresponding estimation model was built and examined. The result conveys that spectral data are compressed by carrying out arithmetic average operation by 10 nm for intervals. The first derivative of the reflectivity is an effective spectrum indicator, in the stepwise multiple linear regression analysis of soil organic matter, for the first derivative transformation, the regression models' precision of establishment and verification increased. The model built by PLSR method based on the characteristic absorption bands precedes that of SMLR. In the PLSR model of soil reflection spectrum and the inverse-log spectra, the test samples' average of relative error is 16% and 17% respectively, the correlation coefficient between retrieval value and measured value is 0.84 and 0.91 respectively, for it's faster to estimate the soil organic fraction. PMID- 21595236 TI - [Feature extraction of hyperspectral scattering image for apple mealiness based on singular value decomposition]. AB - Apple mealiness is an important sensory parameter for classification of apple quality. Hyperspectral scattering technique was investigated for noninvasive detection of apple mealiness. A singular value decomposition (SVD) method was proposed to extract the feature/ or singular values of the hyperspectral scattering images between 600 and 1000 nm for 20 mm distance including 81 wavelengths. As characteristic parameters of apple mealiness, singular values were applied to develop the classification model coupled with partial least squares discriminant analysis (PLSDA) using the samples from different origin and different storage conditions. The classification accuracies for the two-class ("mealy" and "non-mealy") model were between 76.1% and 80.6% better than mean method (75.3%-76.5%). The results indicated that SVD method was potentially useful for the feature extraction of hyperspectral scattering images and the model developed with these features can detect the mealy and non-mealy apple, but the classification accuracies need to be improved. PMID- 21595237 TI - [A field-based pushbroom imaging spectrometer for estimating chlorophyll content of maize]. AB - As an image-spectrum merging technology, the field-hperspectral imaging technology is a need for dynamic monitoring and real-time management of crop growth information acquiring at field scale in modern digital agriculture, and it is also an effective approach to promoting the development of quantitative remote sensing on agriculture. In the present study, the hyperspectral images of maize in potted trial and in field were acquired by a self-development push broom imaging spectrometer (PIS). The reflectance spectra of maize leaves in different layers were accurately extracted and then used to calculate the spectral vegetation indices, such as TCARI, OSAVI, CARI and NDVI. The spectral vegetation indices were used to construct the prediction model for measuring chlorophyll content. The results showed that the prediction model constructed by spectral index of MCARI/OSAVI had high accuracy. The coefficient of determination for the validation samples was R2 = 0.887, and RMSE was 1.8. The study indicated that PIS had extensive application potentiality on detecting spectral information of crop components in the micro-scale. PMID- 21595238 TI - [Determination of migration level of benzo(a) pyrene from paper cups into food simulants]. AB - This paper quantitatively determined the migration level of benzo(a)pyrene (BaP) from paper cups into aqueous food simulants or fatty stimulants, under different conditions by second derivative constant-energy synchronous fluorescence spectrometry (DCESFS), which proved to be a method with high sensitivity and spectral resolution. The influences of food simulants, time and temperature on the relative migration percent(%) of benzo(a) pyrene were discussed. Results showed that the recoveries of this method ranged from 89.2% to 104.3%. The migration percent(%) of fatty stimulants was higher than that of aqueous simulants. Migration into hot water was also observed, while the migration into cool water was almost negligible. The relative migration percent(%) increased with the increase of time and temperature. PMID- 21595239 TI - [Impact of moss soil crust on vegetation indexes interpretation]. AB - Vegetation indexes were the most common and the most important parameters to characterizing large-scale terrestrial ecosystems. It is vital to get precise vegetation indexes for running land surface process models and computation of NPP change, moisture and heat fluxes over surface. Biological soil crusts (BSC) are widely distributed in arid and semi-arid, polar and sub-polar regions. The spectral characteristics of dry and wet BSCs were quite different, which could produce much higher vegetation indexes value for the wet BSC than for the dry BSC as reported. But no research was reported about whether the BSC would impact on regional vegetation indexes and how much dry and wet BSC had impact on regional vegetation indexes. In the present paper, the most common vegetation index NDVI were used to analyze how the moss soil crusts (MSC) dry and wet changes affect regional NDVI values. It was showed that 100% coverage of the wet MSC have a much higher NDVI value (0.657) than the dry MSC NDVI value (0.320), with increased 0.337. Dry and wet MSC NDVI value reached significant difference between the levels of 0.000. In the study area, MSC, which had the average coverage of 12.25%, would have a great contribution to the composition of vegetation index. Linear mixed model was employed to analyze how the NDVI would change in regional scale as wet MSC become dry MSC inversion. The impact of wet moss crust than the dry moss crust in the study area can make the regional NDVI increasing by 0.04 (14.3%). Due to the MSC existence and rainfall variation in arid and semi-arid zones, it was bound to result in NDVI change instability in a short time in the region. For the wet MSC's spectral reflectance curve is similar to those of the higher plants, misinterpretation of the vegetation dynamics could be more severe due to the "maximum value composite" (MVC) technique used to compose the global vegetation maps in the study of vegetation dynamics. The researches would be useful for detecting and mapping MSC from remote sensing imagery. It also is to the advantage to employing vegetation index wisely. PMID- 21595240 TI - [The qualitative analysis method of the dissolved organic matter (DOM) for ABS wastewater]. AB - The dissolved organic matter (DOM) of acrylonitrile-butadiene-styrene (ABS) resin wastewater was qualitatively analysed by gas chromatography with mass spectrometry(GC-MS), Fourier transform infrared spectrometer(FTIR) and three dimensional excitation-emission matrix (EEM) fluorescence spectroscopy. The detected results shows that the GC-MS qualitatively analysed 21 dissolved organic pollutants, such as acetophenone, styrene, alpha, alpha-dimethyl-benzenemethanol, 3,3'oxybis-propanenitrile, 3, 3'-iminobis-propanenitrile, 3,3'-thiobis propanenitrile, 3-(dimethylamino)-propanenitrile and 2-propenenitrile. The results of Fourier transform infrared spectrometer (FTIR) and three-dimensional excitation-emission matrix (EEM) fluorescence spectroscopy could examine and certify the accuracy and integrity for the qualitative analysis of GC-MS. The results of this study provides an important guiding role for the development of wastewater treatment process. PMID- 21595241 TI - [Atmospheric HCHO gradient monitoring and analysis in Beijing City with a scanning DOAS system]. AB - Scanning differential optical absorption spectroscopy (DOAS) technique combined with meteorological tower was used for monitoring vertical profiles of SO2, NO2, O3, HCHO and HONO along three light paths in Beijing City during July 28, 2009 to August 13, 2009. As a result, the time series of concentrations and vertical gradient of HCHO as well as other gases were acquired. By analyzing the vertical distribution frequency characteristics of HCHO, data of other gases and meteorological data, it was concluded that the main source of HCHO is vehicles emissions around the measurement site. The photochemical reaction as the secondary source accounts for a significant proportion of the source of HCHO at certain times of day (around noon, for a few hours). PMID- 21595242 TI - [Response of chloroplast ultrastructure of ear leaves of spring maize to field managements]. AB - Spring maize was selected as research object, and the characteristics of chloroplast ultrastructure of ear leaves were evaluated with scanning electron microscopy (SEM) as affected by irrigation, organic manure fertilization and nitrogen application. The results showed that with increasing irrigation amount, organic manure fertilization amount and nitrogen application amount, the chloroplast ultrastructure gradually became integrated, the membrane envelope of chloroplast became clear, the stroma lamellae increased and arranged regularly, the grana were clear and stacked increasingly, the starch particles increased and the osmiophilic grains decreased. Compared with other treatments, irrigation, organic manure fertilization and nitrogen application at a rate of 1200 milliliter per pot and per day, 4000 kilogram per mu and 23 kilogram N per mu could make the chloroplast ultrastructure show greater predominance. Compared with one topdressing, two topdressing and one deep application with control fertilizer made chloroplast become a more integrated membrane system. It was indicated that whether the chloroplast ultrastructure was normal was considered as an important index judging activities of plant cells, and reasonable field managements could make chloroplast ultrastructure of spring maize more stable, which was advantaged for high-efficiency production of spring maize. PMID- 21595243 TI - [Application of Landsat ETM+ in monitoring of desertification in agro-pastoral ecotone of northern China]. AB - Agro-pastoral ecotone of northern China is a transitional and interlaced zone of agricultural cultivation region and grazing region The ecotone is a complex containing several ecosystems. Soil desertification has become a serious problem that endangered sustainable development in the ecotone. The area of desertification land has been increasing year after year in agro-pastoral ecotone of northern China. This problem concerns the ecological environment, economic development and living quality of people in northern and central eastern of China. For these reasons, ecotone has recently become a focus of research of restoration ecology and global climate change. Remote sensing monitoring of desertification land is a key technique to collect the status and development of sandy land, providing scientific bases for the national desertification control. Landsat ETM+ is an advanced multispectral remote sensing system for the research of regional scale and has been widely used in many fields, such as geologic surveys, mapping, vegetation monitoring, etc. In the present, the authors introduce that spectral characteristics, desertification information extraction, desertification classification and development analyses in detail, and summarizes the study progresses discusses the problems and trends. PMID- 21595244 TI - [Study of remote sensing the flux of carbon dioxide gas with tunable diode laser absorption spectroscopy]. AB - Tunable diode laser absorption spectroscopy (TDLAS) technique is a new method to detect trace gas qualitatively or quantificationally based on the scan characteristic of the diode laser to obtain the absorption spectra in the characteristic absorption region. TDLAS is a highly sensitive, highly selective and fast time response trace gas detection technique. In the present paper, a DFB laser at room temperature was used as the light source, wavelength modulation method was employed, and the second harmonic signal of one absorption line near 1.578 microm of carbon dioxide molecule was measured. A system was built for online monitoring of carbon dioxide concentration within the optical path of more than 700 meters at different heights. Combined with Alonzo Mourning-Obukhov length and characteristic velocity detected by large aperture scintillometer, the flux of carbon dioxide gas calculated by the experiential formula is within -60 60 mg x m(-2) x s(-1). The comparison of the datea detected by TDLAS system and the eddy covariance showed that the change of the data detected by TDLAS had a similar trend to that detected by the eddy covariance, and the best results can be produced by this method, breaking through the phenomenon of only providing the flux of trace gases near the ground at present, and making the measurement of trace gas fluxes within a large area possible. PMID- 21595245 TI - [The preparation, characterization and ultraviolet photodegradation of LNG-HP beta-CD]. AB - The characteristics of levonorgestrel (LNG), low solubility and the quick degradation under ultraviolet, limited its study and application in rodent contraception. The inclusion complex of hydroxypropyl-beta-cyclodextrin (HP-beta CD) with LNG was investigated in present study. The inclusion complex was prepared by solution method and characterized by ultraviolet absorption spectrum and infrared spectrum spectra. And the stability was evaluated by being exposed to ultraviolet. The authors' results showed that the accurate and simple method of quantitative determination for LNG was established by ultraviolet spectrum, the molar ratio of the complex was 1:1 calculated from the phase solubility diagram, the stability constant was 187.3 L x mol(-1) at 25 degrees C, and the formation of the inclusion complex was validated by UV-Vis and Fourier transform infrared spectroscopy. Moreover, the degradation rate of the inclusion complex was less than 5%, which was slower than the LNG monomer. The present study indicated that HP-beta-CD could be formed inclusion complexes with LNG and the solubility, and stability were obviously enhanced. PMID- 21595246 TI - [Study on arsenic speciation changes in crude and processed traditional Chinese medicines by HPLC-ICP-MS]. AB - A HPLC-ICP-MS method for simultaneous determination of As(III), As(V), MMA and DMA in traditional Chinese medicines (TCMs) was established, and the contents of As(III), As(V), MMA and DMA in a TCM with high total arsenic content (Cordyceps) and 5 crude and processed TCMs (Radix Astragali, Radix et Rhizoma Rhei, Radix Scutellariae, Radix Polygoni Multiflori and Radix Rehmanniae) were determined and analyzed. The method validation indicated that the correlative coefficients (r) for all speciations were bigger than 0.9984; the limits of quantitation (LOQ) were from 0.8 to 1.0 microg x L(-1); the reproducibility and stability were satisfactory with all RSDs less than 10%; the spiked recoveries ranged from 82.40% to 119.5%. The results of samples analysis showed that the inorganic arsenic (As(III) and As(V)) was the dominating speciation in the tested TCMs; MMA and DMA were not found in all plant resourced TCMs, but MMA was found in Cordyceps; all the tested TCMs indicated a content increasing of inorganic arsenic after processing. PMID- 21595247 TI - [Study on five heavy metal elements dissolution characteristics of Fructus Aurantii by ICP-MS]. AB - The method for the determination of 5 kinds of trace heavy metal elements (Cu, As, Hg, Cd and Pb) in Fructus Aurantii by inductively coupled plasma-mass (ICP MS) with HNO3-H2O2 microwave digestion was established. The recoveries of the elements detected were in the range of 85%-109% and the relative standard deviations (RSD) was in the range of 3.6%-5.4%. It indicates that the method is rapid, sensitive and accurate. It was suitable for the determination of the contents of 5 trace heavy metal elements in Fructus Aurantii. The dissolution characteristics of the 5 heavy metal elements in different extraction methods (microwave-assisted extraction, ultrasonic extraction and decocting extraction, respectively) were studied. The results showed that the concentrations of trace elements As and Pb obtained by microwave-assisted extraction were relatively lower than that by ultrasonic extraction and decocting extraction. The dissolving concentrations of the 5 trace heavy metal elements (Cu, As, Hg, Cd and Pb) in Fructus Aurantii in different extracting methods were all lower than the limits of Chinese Pharmacopoeia and Green Trade Standard for Importing and Exporting Medicinal Plant and Preparation. Microwave-assisted extraction for effective constituent was rapid, effective and safe. PMID- 21595248 TI - [Real-time, quantitative analysis of multi-elements in liquid steel by LIBS]. AB - The technique of laser induced breakdown spectroscopy (LIBS) was applied to analyze the composition of liquid steel. The results of research indicated that oxidation of liquid steel on the surface could be avoided because the argon and the plasma signal was enhanced at the same time. The surface of liquid steel was excited by high-energy pulse laser and plasma was formed in argon atmosphere. The spectral signal was collected with a multi-channel CCD spectrometer when the plasma cooled off and relevant information about the composition of samples was obtained. The characteristic spectral lines of analyzed elements were selected according to the selecting principle of line in LIBS and the calibration curves of major alloying elements Mn, Si and Cr were constructed. The degrees of linear fitting were all more than 0. 925 and the limit of detection of Mn, Si and Cr were 75.7, 23.8 and 724.5 microg x g(-1), respectively. PMID- 21595249 TI - [Determination of trace elements in garlic from Xinjiang different groups by AAS]. AB - In the present paper, the contents of Ca, Fe, Zn, Mg, Cu, Mn, Cr, Pb and Cd in garlic which comes from different groups of Xinjiang were measured by wet digestion and flame-atomic absorption spectrometry. And the standard addition recovery experiment was done. The results of recovery experiment show that the atomic absorption spectrometry is a quick and easy method for determining; The correlation coefficient of each standard curve was between 0.9944 and 0.9998, with good linear relationship; The relative standard deviation (RSD) of each result is less than 5.15%, the recovery rate of each sample was between 99.4% and 101.7%, and the determination results are correct and reliable. The results show that the beneficial elements are richer in the garlic of Xinjiang, and the contents of trace elements are different among different places. To some extent, the difference in contents reflects the difference in the topography, climate, soil, hydrology and other environmental factor between the south and the north of Xinjiang. PMID- 21595250 TI - [Simulation of the depth profile of tritium based on X-ray spectrum measurement]. AB - Tritium is very important fusion materials,it has been broad applied both in military area and in civil area. It is very important to study the depth profile and composition of tritium in materials. This thesis establishes the whole simulation method for tritium b-ray induced X-ray spectrometry technique and researches the algorithm of X-ray spectra simulation, and the X-ray spectrum and the depth and composition of tritium based on simulation has been investigated to expose their relationships. The results show that there is a corresponding relationship between depth profile and X-ray spectra, and the results lay a foundation for further research on inverse problem. PMID- 21595251 TI - [A very sensitive CW cavity ring-down spectrometer and its application]. AB - A cavity ring-down spectrometer was built up using a CW tunable Ti: sapphire laser. The experiments show that not only the spectral resolution is up to the 10(-4) cm(-1) level, but the detecting sensitivity also exceeds 10(-10) cm(-1). With the measurements of the absorption spectroscopy of C2H2 near 12,696.4 cm( 1), the quantitative capability of the instrument was demonstrated. Through the spectroscopy of the samples mixed with trace C2H2 in N2 gas, the detection limit of C2H2 was determined to be 0.2 ppm. PMID- 21595252 TI - [Automatic adjustment control system for DC glow discharge plasma source]. AB - There are three important parameters in the DC glow discharge process, the discharge current, discharge voltage and argon pressure in discharge source. These parameters influence each other during glow discharge process. This paper presents an automatic control system for DC glow discharge plasma source. This system collects and controls discharge voltage automatically by adjusting discharge source pressure while the discharge current is constant in the glow discharge process. The design concept, circuit principle and control program of this automatic control system are described. The accuracy is improved by this automatic control system with the method of reducing the complex operations and manual control errors. This system enhances the control accuracy of glow discharge voltage, and reduces the time to reach discharge voltage stability. The glow discharge voltage stability test results with automatic control system are provided as well, the accuracy with automatic control system is better than 1% FS which is improved from 4% FS by manual control. Time to reach discharge voltage stability has been shortened to within 30 s by automatic control from more than 90 s by manual control. Standard samples like middle-low alloy steel and tin bronze have been tested by this automatic control system. The concentration analysis precision has been significantly improved. The RSDs of all the test result are better than 3.5%. In middle-low alloy steel standard sample, the RSD range of concentration test result of Ti, Co and Mn elements is reduced from 3.0% 4.3% by manual control to 1.7%-2.4% by automatic control, and that for S and Mo is also reduced from 5.2%-5.9% to 3.3%-3.5%. In tin bronze standard sample, the RSD range of Sn, Zn and Al elements is reduced from 2.6%-4.4% to 1.0%-2.4%, and that for Si, Ni and Fe is reduced from 6.6%-13.9% to 2.6%-3.5%. The test data is also shown in this paper. PMID- 21595253 TI - [A new optical switch using upconversion nanoparticles conjugated aptamer]. AB - As new class of fluorescent biolabels, upconversion nanoparticles (UCNPs) were very attractive for use as labels, compared with these traditional downconversion materials. It can eliminate problems associated with autofluorescence and scattered excitation light under near infrared light (NIR) excitation. In the present work, water-soluble NaYF4:Yb3+, Er+ UCNPs were successfully prepared by solvothermal synthesis, using branched polyethylenimine as the surfactants, and a generic design strategy for UCNPs conjugated aptamer based optical switch was presented. In the absence of the target thrombin protein, such a duplex structure brings the UCNPs and TAMRA close proximity of each other, leading to luminescence resonance energy transfer from UCNPs to TAMRA upon near-infrared light irradiation. When target is introduced, the quadruplex conformation of the aptamer should be preferentially stabilized, resulting in the displacement of the TAMRA labelled oligonucleotide conjugate and triggering UCNPs fluorescence intensity to increase and the corresponding TAMRA fluorescence intensity to decrease. Since the aptamer responds to its target molecule by switching on its fluorescent properties, the authors named this an "optical switch". PMID- 21595254 TI - [Development of multi-spectral thermometer for explosion flame true temperature measurement]. AB - A kind of multi-target multi-spectral thermometer has been developed to be used in large explosive environment. At the moment of explosion, the thermometer simultaneously collects explosion flame radiation energy under different spectra after the lights go through the prism spectrometer. The second measurement method was used to calculate true temperature and emissivity of the explosion flame. The fiber-optic long-distance transmission technique and fiber coupling technique were used for the first time in optical system design, which largely solves the problems of anti-vibration, anti-explosion and anti-electromagnetic interference for the core of the instrument. The high-speed acquisition system and multi-stage amplification system were used to realize instaneous collection of the rapidly changing explosion flame temperature. The wireless long-distance transmission was used to ensure the staff safety. PMID- 21595255 TI - [Spectral discrimination method information divergence combined with gradient angle]. AB - The present paper proposes a spectral discrimination method combining spectral information divergence with spectral gradient angle (SID x tan(SGA(pi/2)) which overcomes the shortages of the existing methods which can not take the whole spectral shape and local characteristics into account simultaneously. Using the simulation spectra as input data, according to the interferogram acquirement principle and spectrum recovery algorithm of the temporally and spatially modulated Fourier transform imaging spectrometer (TSMFTIS), we simulated the distortion spectra recovery process of the TMSFTIS in different maximum mix ratio and distinguished the difference between the recovered spectra and the true spectrum by different spectral discrimination methods. The experiment results show that the SID x tan(SGA(pi/2)) can not only identify the similarity of the whole spectral shapes, but also distinguish local differences of the spectral characteristics. A comparative study was conducted among the different discrimination methods. The results have validated that the SID x tan(SGA(pi/2)) has a significant improvement in the discriminatory ability. PMID- 21595256 TI - [Development of a simultaneous strain and temperature sensor with small-diameter FBG]. AB - Manufacture of the small diameter FBG was designed. Cross sensitivity of temperature and strain at sensing point was solved. Based on coupled-mode theory, optical properties of the designed FBG were studied. The reflection and transmission spectra of the designed FBG in small diameter were studied A single mode optical fiber, whose cladding diameter is 80 microm, was manufactured to a fiber Bragg grating (phi80FBG). According to spectrum simulation, the grating length and period were chosen as the wavelength was 1528 nm. The connector of the small diameter FBG with demodulation was designed too. In applications, the FBG measures the total deformation including strain due to forces applied to the structures as well as thermal expansion. In order to overcome this inconvenience and to measure both parameters at the same time and location, a novel scheme for simultaneous strain and temperature sensor was presented. Since the uniform strength beam has same deformation at all points, a pair of phi80 FBG was attached on a uniform strength cantilever. One of the FBG was on the upper surface, with the other one on the below. Therefore, the strains at the monitoring points were equal in magnitude but of opposite sign. The strain and temperature in sensing point could be discriminated by matrix equation. The determination of the K is not null and thus matrix inversion is well conditioned, even the values for the K elements are close. Consequently, the cross sensitivity of the FBG with temperature and strain can be experimentally solved. Experiments were carried out to study the strain discriminability of small-diameter FBG sensors. The temperature and strain were calculated and the errors were, respectively, 5% and 6%. PMID- 21595257 TI - [Structure and function of incretin-secreting cells (K cell, L cell)]. PMID- 21595258 TI - [The history of incretin hormones]. AB - 'Incretin' hormones has lately attracted considerable attention as new strategy improving insulin secretion of type 2 diabetes mellitus. Spending many years for study of incretin hormones, GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1), we can use incretin mimetics as new drugs for type 2 diabetes clinically today in Japan. In this section, we describe the concept and the history of incretin hormones. PMID- 21595259 TI - [The concept of incretins and the physiological roles of incretins]. AB - Incretins, exemplified by glucagon-like peptide 1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted in a nutrient-dependent manner and stimulate glucose-dependent insulin secretion. Both GLP-1 and GIP also promote beta cell proliferation and inhibit apoptosis, leading to expansion of beta cell mass. GLP-1, but not GIP, controls glycemia via additional actions on glucose sensors, inhibition of gastric emptying, food intake and glucagon secretion. PMID- 21595260 TI - [The use of new agents enhancing incretin effects for patients with diabetes in Japan]. PMID- 21595261 TI - [Cross-talk among pancreatic alpha, beta and delta cells stimulated by incretin hormones]. AB - Incretin hormones, GLP-1 and GIP, contribute to whole body glucose homeostasis by modulating secretion of islet hormones, insulin, glucagon and somatostatin. Both GLP-1 and GIP stimulate insulin and somatostatin secretion. While glucagon secretion is stimulated by GIP, GLP-1 suppresses glucagon secretion. The mechanism by which GLP-1 suppresses glucagon secretion seems to include direct action of the hormone on alpha cells and indirect one through activation of beta and delta cells. However, molecular details of these actions still remain elusive. PMID- 21595262 TI - [Regulatory mechanism of incretin secretion]. AB - Incretin hormones GIP(glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) improve glycemic control by potentiating glucose induced insulin secretion in pancreatic beta-cells and also have beneficial effects on appetite control and body weight. In response to food ingestion, GIP and GLP-1 are secreted from enteroendocrine K- and L-cells, respectively. In these cells, it is shown that a variety of molecular sensors are involved in the detection of carbohydrates, lipids, and proteins. In view of development of new incretin-related drugs, these sensors are attractive targets to enhance the endogenous pools of incretins. PMID- 21595263 TI - [Molecular mechanism of insulin secretion facilitated by incretin]. AB - Incretins, such as GIP and GLP-1 enhance insulin secretion from pancreatic beta cells in a glucose dependent manner. Incretins potentiate adenylate cyclase activity trough their G-protein coupled receptors and then increase intracellular cAMP level. Intracellular cAMP modulates insulin secretion by both PKA-dependent and PKA-independent pathways. PKA potentiates intracellular Ca2+ influx via phosphorylation of voltage-dependent calcium channel(VDCC), which increases insulin exocytosis. PKA also phosphorylates K(ATP) channel and facilitates insulin release. In contrast, Epac2 potentiates insulin secretion by cAMP in a PKA-independent pathway. The small G-protein Rap1, which is activated specifically through Epac2, contributes the first phase of insulin secretion possibly by control of insulin granules fusion to plasma membrane. PMID- 21595264 TI - [Structure and function of incretin receptor]. AB - G protein-coupled receptor (GPCR) is integral membrane protein with seven alfa helices and most diverse families of protein in mammals. It is located on cell membrane and activated by binding neurotransmit proteins and hormones. It has critical role of functional regulation in central nerve system and peripheral organs. Recently, many orphan GPCRs have been identified from the data of genomic sequence in human genomic project. GIP receptor and GLP-1 receptor belong to glucagon receptor subfamily of class B and are widely expressed in many organs. GIP receptor is expressed in intestine, adipose tissue, brain, adrenal gland, and bone, while GLP-1 receptor is expressed in intestine, CNS, lung, kidney and heart. GIP and GLP-1 have not only pancreatic effect, such as potentiation of insulin secretion but also many extrapancreatic effects. PMID- 21595265 TI - [Effects of incretins on the regulation of beta-cell mass, proliferation and survival]. AB - Incretins including GLP-1 and GIP have pleiotropic effects on islet biology especially on beta-cell function. Not only enhancing glucose-stimulated insulin secretion, but incretins exert beta-cell mass maintaining effects by upregulation of proliferation and prevention of cell death (apoptosis). Recent research data revealed detailed molecular mechanisms underlying these effects of incretin on beta-cell biology. These beneficial effects of incretins on the regulation of beta-cell mass could contribute to future therapeutic approaches to diabetes focusing on preservation and upregulation of beta-cell mass as well as function. PMID- 21595267 TI - [Protective effects of incretin on atherosclerosis]. AB - Type 2 diabetes is a major risk factor for atherosclerotic disease. Thus, the one of the therapeutic goal is to prevent the progression of atherosclerosis in these patients. Recently, exogenous administration of glucagon-like peptide-1 (GLP-1) or GLP-1 receptor agonist has direct beneficial effects on vascular cells such as endothelial cell, monocyte/macrophage and vascular smooth muscle cells independent of their glucose lowering effects. These data highlight the potential protective effects of GLP-1 on the progression of atherosclerosis. However, further experimental study is needed to clarify the mechanism of these effects on vascular cells with GLP-1 and large clinical trial is also required to assess whether GLP-1 could reduce the cardiovascular events in patients with type 2 diabetes. PMID- 21595266 TI - [Food intake-suppressing action of incretin and anti-obesity therapy]. AB - Suppressing food intake is the most well-known central nervous action of glucagon like peptide-1 (GLP-1). Neurons expressing preproglucagon (PPG) in the nucleus tractus solitarius (NTS) are the only source of "central" GLP-1, and they project to the hypothalamus. Recently, properties of these PPG-neurons have been revealed using transgenic mice expressing fluorescent protein under control of the PPG promoter; whereas they are directly responsible to leptin but not to GLP-1, they can be the second-order neurons of vagal afferents. "Peripheral" GLP-1 released from intestinal L-cells may possess central nervous action through the vagal afferent fibers. The question remains whether food intake suppression due to "peripheral" GLP-1 depends on "central" one. The action is being applied to anti obesity therapy. PMID- 21595268 TI - [Effects of incretin on cardiovascular disease and risk factors]. AB - Diabetes is an important poor prognostic factor for ischemic heart disease and other cardiovascular diseases. Various study results have previously shown that new diabetes therapeutic agents including GLP-1 agonists and DPP-4 inhibitors have been suggested to be able to not only improve the pathology of diabetes, but also improve cardiovascular risk and be useful in prognosis. This report describes the effects of incretin on the cardiovascular system and its expected efficacy in reducing cardiovascular risk. PMID- 21595269 TI - [Role of incretins in the regulation of bone metabolism]. AB - Diabetes is associated with increased risk of osteoporosis. Gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide(GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones released upon meal ingestion, and GIP and/or GLP-1 signaling is decreased in diabetic state. We have demonstrated that both GIP receptor knockout mice and GLP-1 receptor knockout mice have osteoporosis. GIP has anabolic effects on bone mainly by stimulating osteoblastic bone formation through intermittent elevation of intracellular cAMP levels. On the other hand, GLP-1 is suggested to regulate bone resorption indirectly through the thyroid C cell. Our studies show that incretins play important roles in bone metabolism by distinct mechanisms. PMID- 21595270 TI - [Incretin analogues as a novel treatment strategy for Alzheimer's disease]. PMID- 21595271 TI - [Attenuation of fatty accumulation in hepatocyte by incretin--expectation of novel medicine for treatment of NASH]. AB - Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been recognized as a metabolic disorder characterized by fatty accumulation of the liver without alcohol consumption. The progression of the diseases has been considered to link to metabolic syndrome, consisting of obesity, diabetes mellitus(DM), dyslipidemia and hypertension. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide(GIP) function as incretin and stimulate glucose-mediated insulin production by pancreatic beta cells. Incretin was also reported to have various kinds of extrapancreatic effects including the regulation of hepatic glucose production, the inhibition of pancreatic exocrine secretion, cardioprotective and cardiotropic effects, the regulation of appetite and satiety, and stimulation of afferent sensory nerves. Therefore, incretins are also expected as therapeutic agents for NFLD and NASH. PMID- 21595272 TI - [Incretin enhancer: sitagliptin]. AB - Recently, incretin-based therapies have become available for patients with type 2 diabetes in Japan. Sitagliptin is one of several DPP-4 inhibitors. After an OGTT, active endogenous GLP-1 concentrations are increased about twofold by sitagliptin. In clinical trials, sitagliptin was shown to be effective in monotherapy and in combination with other oral agents. Hypoglycemic events were not increased in monotherapy. However in Japan, severe hypoglycemic events have been reported especially in older patients with high dose of sulfonylurea. The long-term effectiveness needs to be evaluated in Japanese patients with type 2 diabetes. PMID- 21595273 TI - [Vildagliptin]. PMID- 21595274 TI - [Alogliptin]. AB - Alogliptin, a dipeptidyl peptidase-4(DPP-4) inhibitor, is launched in Japan in advance of other countries in the world. Alogliptin has high-selectivity to inhibit DPP-4 activity compared to other DPP-4 inhibitors due to its unique formula of chemical structure. Clinical studies provided evidences that alogliptin monotherapy with daily doses of 12.5 and 25 mg decreased the HbAlc level approximately 0.4-0.8% accompanied with an elevation of active glucagon like peptide(GLP)-1 level. Neither body weight change nor apparent adverse events was observed. In type 2 diabetic patients who already treated with pioglitazone or voglibose, addition of alogliptin further decreased HbAlc by 0.9% from basal level during 12-week study period. Here, we entirely reviewed pharmacological and clinical profiles of alogliptin by introducing preclinical and clinical studies conducted inside and outside of Japan. PMID- 21595275 TI - [A compounding agent of alogliptin and pioglitazone]. AB - Type 2 diabetes is characterized by insulin resistance and pancreatic beta cell dysfunction, and the latter is known to usually progress during the entire disease history. Thus, monotherapy cannot ameliorate both aspects of these and often fails to achieve the target level of glucose control. Pioglitazone, a thiazolidinedione class agent, is an insulin sensitizer and alogliptin belongs to DPP-4 (dipeptidyl peptidase-4) inhibitor class agents, which promote postprandial insulin secretion and suppress glucagon secretion in a blood glucose dependent fashion. Both agents have been shown to protect beta cell from apoptosis in animal models, which is one of major causes of beta cell dysfunction in human. Therefore, the combination therapy or more ideally a compounding agent of pioglitazone and alogliptin is expected to be effective and beneficial for a large number of people with type 2 diabetes in terms of strict glycemic control. PMID- 21595276 TI - [Liraglutide]. AB - Liraglutide is the first once-daily human GLP-1 analogue developed for the treatment of type 2 diabetes mellitus(T2DM). The half-life of liraglutide is 13 h following subcutaneous injection, making it suitable for once-daily dosing. Clinical data indicates improved beta cell function with liraglutide treatment in patients with T2DM. Liraglutide increases insulin secretion in a glucose dependent manner, and improves first- and second-phase insulin responses. Liraglutide delays the rate of gastric emptying, reduces energy intake and exerts a moderate suppression on hunger as indicates by diverse appetite rating endpoints. Liraglutide dose not impair the counter-regulatory glucagons response to hypoglycaemia in patients with T2DM, which is consistent with the glucose dependent action of liraglutide. Liraglutide was associated with no major or minor hypoglycaemia and was generally well tolerated, with the most common side effect reported as mild, transient nausea. Liraglutide allows significantly more patients to achieve HbAlc targets compared with current treatment. Liraglutide significantly reduces weight in patients. PMID- 21595277 TI - [Clinical application of exenatide in Japanese patients with type 2 diabetes mellitus]. AB - Exenatide belongs to a class of antidiabetic agents called incretin mimetics. In 2005, exenatide was first applied clinical therapy of type 2 diabetes mellitus patients in US, and it has now began to be used in Japanese type 2 diabetes mellitus patients since 2010. Large phase 3 clinical trials in Japan revealed that HbA1c, fasting glucose and postprandial glucose levels were improved with exenatide treatment, which were maintained over 52 weeks. Body weight reduction could be achieved with 10 microg treatment. HDL-C was significantly reduced. Exenatide was generally well tolerated, however incidence of hypoglycemia and gastro-intestinal side effect were elevated. Antibodies to exenatide were observed among approximately half of patients, however had no clinical relevant effects on the efficacy or safety. PMID- 21595278 TI - [Emerging GLP-1 analogues and dipeptidyl peptidase 4(DPP-4) inhibitors]. AB - In recent years new antidiabetic medications utilizing incretin effects came to clinical practice, and enthusiasm surrounding this class of drugs has been mounting for their clinical efficacy as well as expected beneficial effects beyond lowering blood glucose levels. New DPP-4 inhibitors are expected to be available soon in addition to currently available DPP-4 inhibitors, sitagliptin, vildagliptin, and alogliptin. GLP-1 analogues, presently liraglutide and exenatide in clinical use, will also see newer alternatives in coming years. Long acting GLP-1 analogues, which only require weekly or monthly injection, have also been developed, and their favorable clinical results have been reported. In this review, those newly developing DPP-4 inhibitors and GLP-1 analogues and their clinical efficacy are described. PMID- 21595279 TI - [Combination of incretin-related drugs with other anti-hyperglycemic drugs]. AB - Incretin-related drugs(GLP-1 receptor agonists and DPP IV inhibitors) have novel mechanisms for treatment of diabetes and can be combined with other anti hyperglycemic drugs, such as SU, BG, TZD and alpha-GI drugs to achieve the better control of blood glucose levels. Combination of incretin-related drugs with SU is very effective, as incretin-related drugs and SU can stimulate insulin secretion in a synergistic manner. Combination of DPP IV inhibitors with alpha-GI drugs is also very effective, as alpha-GI drugs increase the secretion of GLP-1 and DPP IV inhibitors decrease the degradation of GLP-1. PMID- 21595280 TI - [Severe hypoglycemia by combination therapy with dipeptidyl peptidase-4 (DPP-4) inhibitors and sulfonylureas]. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors were available in Japan since the end of 2009, and incretin-based therapies including glucagon-like peptide-1(GLP-1) mimetics are currently expected to be effective to Japanese patients with type 2 diabetes. Recently, there are a few reports that DPP-4 inhibitors cause severe hypoglycemia when combined with sulfonylureas although no major hypoglycemic episodes were reported in clinical studies. We discuss the mechanism of hypoglycemia by combination therapy, based on our islet studies about ATP sensitive K+ channel inhibition by sulfonylureas and novel effects and mechanism of incretin. PMID- 21595281 TI - [Efficacy of a DPP-4 inhibitor as assessed by continuous glucose monitoring (CGM)]. AB - During the course of treatment with a DPP-4 inhibitor, 24-hour glycemic variations were assessed by continuous glucose monitoring to evaluate the magnitude of postprandial glycemic excursions as well as nighttime/late-night glycemic variations. The DPP-4 inhibitor given alone or in combination with a sulfonylurea (SU) reduced not only the 24-hour mean glucose level as equivalent to the HbAlc value but also the SD of 288 glucose levels for 24 hour and the mean amplitude glucose excursions (MAGE). Particularly, the DPP-4 inhibitor, when given in addition to SU, produces not only additive reductions in mean glucose levels but also reductions in the magnitude of glycemic variations, while at the same time exhibiting the potential to serve as a glucose modulator in low glucose levels. Furthermore, while monotherapy with a DPP-4 inhibitor improves postprandial hyperglycemia, combination therapy with a DPP-4 inhibitor and an alphaglucosidase inhibitor leads to additive improvements in postprandial hyperglycemia, thus exhibiting the potential to flatten the 24-hour glycemic variations. In summary, when assessed for its effects on 24-hour glycemic variations, the DPP-4 inhibitor produces reductions not only in the 24-hour mean glucose level but also in the magnitude of glycemic excursions, thus likely representing a new type of anti-diabetic agent that combines the merits of an SU, which potently lowers HbAlc primarily by reducing fasting glucose levels, and an alpha-glucosidase inhibitor, which reduces the magnitude of glycemic variations primarily by lowering postprandial glucose levels. PMID- 21595282 TI - [Development of the novel delivery system of GLP-1 administration for the treatment of diabetes mellitus]. AB - Glucagon-like peptide 1 (GLP-1) is a peptide produced in the endocrine L cells of the distal intestine. GLP-1(7-36)NH2 is a major molecular form that stimulates insulin release, reduces food intake, and has a potential to promote beta-cell regeneration. We have developed a device for intranasal application of GLP-1(7 36)NH2 and completed a double-blind clinical trial of intranasal administration of GLP-1(7-36)NH2 to 26 type II diabetic patients. Intranasal administration of GLP-1 increased its plasma level, stimulated postprandial insulin release, and suppressed glucagon release. Two-week intranasal administration of GLP-1 just before meals significantly decreased serum glycoalbumin level and significantly increased 1,5-AG (1,5-anhydro-D-glucitol) level. Hypoglycemia was not found through this study. Intranasal GLP-1 administration using the novel device and medication improved glycemic control in type 2 diabetic patients without any adverse effects. PMID- 21595283 TI - [Incretin-based therapy in patients with type 1 diabetes mellitus]. AB - GLP-1 has multiple physiological functions including glucose-dependent insulin secretion and glucagon suppression, delay of gastic emptying, suppression of hepatic glucose production, stimulation of beta cell replication and neogenesis, inhibition of beta cell apoptosis. All of these actions are beneficial for the treatment of diabetes. Therefore, incretin-based therapy may be still worthwhile as evidenced by studies demonstrating that beta cell mass may be preserved or expand in animals and that residual insulin secretion may be elevated to reduce the risk of hypoglycemia in patients treated with intensive insulin therapy, although the effect of GLP-1R agonists and DPP-4 inhibitors(DPP-4is) on beta cells may be small because destruction of beta cells leads to absolute insulin deficiency by cell-mediated autoimmune attack. Recent report also showed that DPP 4i might ameliorate an autoimmune attack against beta cells by restoring or increasing the number of regulatory T lymphocytes. Furthermore, GLP-1R-mediated signals might suppress the expression of chemokine ligand CXCL10 which binds to newly identified receptor TLR4 (Toll-like receptor 4), and impairs beta cell function and viability in diabetes. Taken together, incretin-based therapy may be worth testing in patients with type 1 diabetes. PMID- 21595284 TI - [Association between polymorphisms of TCF7L2 and type 2 diabetes with special reference to incretin action]. AB - TCF7L2 is a Wnt signaling-associated transcription factor and is ubiquitously expressed. Polymorphisms in the TCF7L2 gene exhibit the strongest association with type 2 diabetes among approximately twenty susceptibility gene variants identified to date. Although the mechanisms by which TCF7L2 affects susceptibility to type 2 diabetes remain to be elucidated, several studies have shown that decreased TCF7L2 protein inhibits the insulin secretory response to oral glucose through impaired incretin action(GLP-1, GIP). In this review, we discuss studies that investigate the association between polymorphisms of TCF7L2 and the diabetic phenotype, especially in vitro beta cell function with special reference to incretin action and the response to lifestyle intervention. PMID- 21595285 TI - [Effects of GIP receptor antagonist for treatment of obesity]. AB - Glucose-dependent insulinotropic polypeptide(GIP) has been known as a peptide hormone with the effects not only of the augmentation of glucose induced insulin secretion but of the fat accumulation in adipocytes, of the bone formation and of the modulation of brain function. As indicated in GIP receptor deficient experimental animals, GIP receptor antagonists possess favorable effects such as, decreased body adiposity or improvement of glucose intolerance through change of fat metabolism in high-fat diet induced or genetically induced obese experimental animals. This review principally focused on these preclinical data of GIP receptor antagonism. PMID- 21595286 TI - [Immunoassays for the incretin hormones GIP and GLP-1]. AB - Immunoassays for incretin hormones, GLP-1 and GIP are critical to study their secretion and DPP-4-processing in vivo, as well as to evaluate therapeutic efficacies of current and future incretin-based drugs in patients with diabetes. However, large variability in levels of incretins, especially intact GLP-1, determined by various immunoassays hampers our understanding of the incretin biology. Recent studies have revealed an importance of an ethanol or solid-phase extraction prior to immunoassays for intact GLP-1. The extraction removes interferences with unknown identity from plasma to obtain results less variable among different subjects. The extraction improves correlation across the different immunoassays for intact GLP-1. Here, we summarize current knowledge and potential problems regarding immunoassays for GLP-1 and GIP. PMID- 21595287 TI - [Dementia and lifestyle-related diseases in Japanese aging society]. AB - Recently, the number of elderly patients with dementia has been increasing in Japan because of both the extension of average life expectancy and a considerable rise in the incidence of dementia with age. For these reasons, dementia in Japan has become common, and more than half of all cases are Alzheimer disease. This disease has typically been considered to be a degenerative disorder due to genetic abnormalities, but recent epidemiological studies have indicated that lifestyle-related diseases such as hypertension, diabetes, dyslipidemia, and obesity in midlife could accelerate the dementing process, via either vascular changes in cerebral infarction or Alzheimer-related pathological changes with plaque and tangle formations which result in dementia in later life. Furthermore, several studies have suggested that a high intake of vegetables and fish, an active daily life, and lifelong education might positively influence cognitive function as neuroprotective factors. Therefore, we should try to prevent dementia based on the clinical and hygienic management of the lifestyles and lifestyle related diseases, even in the youth. PMID- 21595288 TI - [Evaluation of sub-maximal aerobic capacity level determined by double product break point (DPBP) among Japanese adults]. AB - OBJECTIVES: The purpose of this study was to determine sub-maximal aerobic capacity levels evaluated by metabolic equivalents (unit is METs) at the double product break point (DPBP) and elucidate the safe and effective average exercise intensity among Japanese adults. A total of 438 subjects (123 males and 315 females) who participated in the exercise prescription course with measurement of the DPBP during a continuous incremental exercise test with a bicycle METHODS: ergometer were enrolled in this study. The DP (heart rate-systolic blood pressure product) featured rapid increase with increasing exercise load during the continuous incremental exercise test. RESULTS: The metabolic equivalents at the DPBP level for males and females were 5.3+/-0.9 METs and 4.9+/-0.7 METs, respectively. Interestingly, the metabolic equivalent at the DPBP level in 87.2% of the study subjects was less than 6 METs. CONCLUSIONS: This study indicated that some physical activities above moderate intensity, such as the stair climbing (8 METs), might be inappropriate as health promotion exercises. Thus, the upper limit of exercise intensity for health promotion was 6 METs, especially if the subject was at cardiovascular risk. In addition, it was found necessary to make synthetic judgments in consideration of heart rate and rating of perceived exertion (RPE) during exercise. PMID- 21595289 TI - [Community-based care service needs and related factors among the elderly in a Chinese farming village]. PMID- 21595290 TI - [The association between standardized incidence ratio of fall accidents with ambulance responses of elderly people and socio-economic status]. PMID- 21595291 TI - [Longitudinal change in awareness levels of Japanese exercise guidelines and physical activity]. AB - OBJECTIVES: According to the interim report "National Health Promotion in the 21st Century (Healthy Japan 21)", the Exercise and Physical Activity Guide for Health Promotion 2006 (EPAGH2006) is an im-portant resource in the field of physical activity in Japan. A previous study (Higo & Nakamura, 2008) showed that although the awareness level of EPAGH2006 was lower than for other health pro motion policies (e.g., Healthy Japan 21), the proportion of people who walked regularly was higher in the EPAGH2006 awareness group than in the no-awareness group. This result indicates that pro-motion of EPAGH2006 would contribute to increase in the number of physically active people. The purpose of the present study was to identify longitudinal change in awareness of EPAGH2006, and to examine the relationship with levels of physical activity. METHODS: The subjects were 1,100 Japanese adults (mean [SD], 39.8 [10.1 years) recruited from among the registrants of a Japanese social research company. This longitudinal study was conducted using online questionnaires in surveys in November 2007 (T1) and December 2008 (T2). The awareness level of EPAGH2006 was assessed with 3 choices, i.e., good understanding, awareness and no-awareness. The International Physical Activity Questionnaire short Version (Craig et al., 2003; Murase et al., 2002) was used to estimate the amount of physical activity that the subjects engaged in. The Mann-Whitney test was utilized to assess inter-group differences in changes in the amount of physical activity between the understanding and no awareness groups. RESULTS: The proportion of those who fully understood EPAGH2006 was 1.4% at T1 and 2.2%0 at T2 and did not significantly increase. The physical activity level in the understanding group at T2 was significantly decreased compared with the no-awareness groups at both T1 and T2 (p=0.013). CONCLUSION: The lack of increase in the awareness level between the two time points suggests that dissemination of EPAGH2006 has not been effective. A more strategic approach would appear to be required. However, the results also did not indicate that the awareness level of EPAGH2006 had a positive in-fluence on physical activity. Further studies, conducted when the awareness levels improve, may elucidate the relationship between the levels of EPAGH2006 awareness and physical activity. PMID- 21595292 TI - [Hypertrophic pachymeningitis: three adult cases and a review of the literature]. AB - Hypertrophic pachymeningitis (HP) is thought to have an autoimmune etiology but its precise cause and treatment remains to be elucidated. Here, we report the clinical details and therapeutic responses of 3 patients with HP and reviewed 66 previously reported cases in the literature. Among these patients, headache was the most frequent complaint. Cranial nerve involvement was also frequently observed, with the optic nerve being the most frequently impaired followed by the oculomotor, trochlear, and abducens nerves in frequency. Elevated C-reactive protein levels and erythrocyte sedimentation rates were found in approximately 97% of the patients. Steroids were the most commonly prescribed therapy, but no definite protocols for the standard dose and duration in HP have been proposed thus far. The average initial dose of prednisolone (PSL) was 42.7 mg/day, and the average maintenance dose was 12.4 mg/day in the chronic stage. Recurrence occurred in many patients when the dose of PSL was reduced to under 20 mg/day. Therefore, steroids should be tapered extremely slowly. PMID- 21595293 TI - [Clinical features of predominantly sensory stroke due to brainstem infarction]. AB - We report 13 patients presenting with predominantly sensory strokes due to brainstem infarction, without any other brainstem symptoms such as hemiparesis, dysarthria or vertigo. All of them had lacunar infarctions localized at the medial lemniscus and/or spinothalamic tract, at the pontine (12 patients) or midbrain (1 patient) tegmentum. The presenting symptom was dysesthesia with a variety of distributions for all cases, and a thalamic-pain-like unpleasant dysesthesia persisted in 4 patients. The lesion on brain MRI was usually very small, and was sometimes overlooked by radiological evaluation, which led to a long delay in the correct diagnosis of a stroke in two cases. Median nerve somatosensory evoked potentials showed a depressed N20 amplitude or a loss of the P15 potential unilaterally with preserved P13/14 potential in 7 out of 10 cases examined, and was useful in localizing the lesion intracranially. During the 4 year study period, 10 patients with brainstem infarctions were admitted to our department as acute sensory stroke cases (2.1% of all acute strokes), whereas 11 patients with thalamic infarctions (2.3%) were admitted due to similar symptoms. Cases with brainstem infarctions had sensory symptoms localized below the neck more frequently (5/10) than cases with thalamic infarctions (1/11), thus would be more likely to be confused with cervical or peripheral nerve disorders. The relative frequency of brainstem infarction as compared to thalamic infarction was higher than that in previous reports, implying that some cases with brainstem infarction might have been overlooked due to difficulty in obtaining the correct diagnosis. One should always keep this syndrome in mind when assessing patients with acute-onset sensory symptoms. PMID- 21595294 TI - [Anti-aquaporin-4 antibody autoimmune syndrome with disturbance of consciousness, respiratory failure, and ophthalmoplegia associated with extensive brain stem involvement with intractable hiccup and nausea as an initial manifestation. A case report]. AB - A 45-year-old female was positive for anti-aquaporin-4 antibody with disturbance of consciousness, respiratory failure, and ophthalmoplegia associated with extensive brain stem involvement with intractable hiccup and nausea as an initial manifestation. Her level of consciousness and state of respiration worsened approximately one month later. There was no abnormality in the cerebrospinal fluid examination. A lesion was found in the medullary tegmentum on brain MRI. The patient received steroid pulse therapy and her level of consciousness improved the next day. However, her state of respiration worsened, and she had extensively clinical involvement of the brain stem. Her symptoms gradually improved with intravenous administration of prednisolone and intravenous immunoglobulin therapy (IVIg). The patient had almost completely recovered, but she relapsed with cervical myelitis extending over 3 vertebral segments approximately 10 months later. She underwent steroid pulse therapy, oral prednisolone, and IVIg again and improved. PMID- 21595295 TI - [Infliximab treatment trial in a patient with neuro-Behcet's disease unresponsive to other treatments]. AB - A 22-year-old man with a previous uveitis episode was admitted to our hospital because of persistent hiccup. On admission, he presented right-upper quadrantanopia, mydriasis and lack of the light reflex in the left eye, left sided hemiplegia, and bilateral pathologic hyperreflexia. The MR fluid attenuated inversion recovery images showed left side dominant, high intensity lesions on the brainstem and the diencephalon. The HLA-B51 was positive. The CSF IL-6 was extremely elevated (998 pg/ml: reference value < = 6.0 pg/ml). Based on these, we concluded he had the neuro-Behcet's disease and treated him by high dose intravenous corticosteroids. This treatment improved his symptoms and MRI lesions, and decreased the CSF IL-6 levels initially. On 13th day after the first his discharge, however, dysarthria appeared and the CSF IL-6 levels elevated again. In addition to the high dose intravenous corticosteroids therapy for acute attack, 15 mg/week of methotrexate was started to prevent the recurrence. Even with this prevention, meningitis related to neuro-Behcet's disease occurred within six weeks. We administered 5 mg/kg of infliximab intravenously at 0, 2, 6, and 14 weeks. After the infliximab treatment, his symptoms improved and the IL-6 levels decreased, and no recurrence has occurred. This case supports that infliximab, anti-TNF-alpha agent, is a good candidate for neuro-Behcet's disease treatment when it is resistant to conventional immunosuppressive agents such as corticosteroids or methotrexate. PMID- 21595296 TI - [Tuberculous cranial pachymeningitis presenting with long-standing diffuse brain dysfunction]. AB - We report a 59-year-old immunocompetent man presenting with slowly progressive gait unsteadiness, dysarthria, and clumsiness in writing over 6 months. There were bilateral pyramidal signs, pseudobulbar palsy, and attention deficits. Cerebrospinal fluid examination showed mild mononuclear pleocytosis, and magnetic resonance imaging revealed pachymeningeal pattern of contrast enhancement beneath the calvarium and the posterior cranial fossa. Interferon-gamma release assay in whole blood after stimulation by specific tuberculosis antigens was positive and repeat polymerase chain reaction assay detected Mycobacterium tuberculosis genome in the cerebrospinal fluid. After combination therapy with anti-tuberculous agents and corticosteroids, the patient's pachymeningitis regressed. Tuberculous cranial pachymeningitis may present with chronic diffuse brain dysfunction without headache, fever, or cranial nerve dysfunction. PMID- 21595297 TI - [Degeneration of ponto-cerebellar tract visualized by diffusion tensor imaging in multiple system atrophy]. AB - We visualized ponto-cerebellar tracts projecting through the middle cerebellar peduncle of 3 patients with early stage multiple system atrophy (MSA), 3 patients with advanced stage MSA, and a healthy control using diffusion tensor imaging (DTI) on 1.5T magnetic resonance imaging (MRI). We also examined whether the location of the degenerated ponto-cerebellar tracts coincided with that of the transverse part of the so-called "hot cross bun sign (HCB)" on MRI. DTI successfully demonstrated the degeneration of ponto-cerebellar tracts in MSA patients. The tracts in advanced stage MSA patients appeared more sparse than those in patients of the early stage. High apparent diffusion coefficient (ADC) values and low fractional anisotropy (FA) values also indicated the degeneration of the ponto-cerebellar tracts in MSA patients. The tracts in the ventral pons were more sparse than those in the central pons. The location of the degenerated ponto-cerebellar tracts of the central pons appeared to coincide with that of the transverse part of HCB. Visualization of degenerated ponto-cerebellar tracts that cross the ventral pons using DTI might be useful for the early diagnosis. PMID- 21595298 TI - [Japanese SUNCT patient responsive to gabapentin]. AB - We report a Japanese patient with short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUCNT) responsive to gabapentin. A 29-year-old man presented with sudden-onset intermittent left-sided orbital headache, which was not accompanied by lacrimation and conjunctival injection. We diagnosed trigeminal neuralgia at first and administered carbamazepine and loxoprofen. However, these medications were entirely ineffective at all and 6 days later, autonomic symptoms including conjunctival injection and tearing appeared. Diagnosis of SUNCT was made and gabapentin was started at up to 800 mg per day. Soon after, the headache and autonomic symptoms disappeared. Gabapantin at 800 mg per day was continued for 3 months and then reduced to 400 mg per day. Soon he had only a slight headache without tearing and conjunctival injection. He has continued to take gabapenin at 400 mg per day until now. This case indicated that headache and autonomic symptoms in SUNCT did not always emerge simultaneously, but they sometimes appear with time lag. Furthermore, the long term clinical course and therapeutic outcome in SUNCT remain unknown. A therapeutic strategy and optimal dosage of medications including gabapentin should be established for the treatment of SUNCT. PMID- 21595299 TI - [Disseminated metastatic tumor at dorsal surface of medulla oblongata presenting intractable hiccups. A case report]. AB - We report the case of disseminated metastatic tumor at dorsal surface of medulla oblongata presenting intractable hiccups. A 73-year-old man has a history of for metastatic lung tumor of the left tempral lobe. Although 3 surgeries and 4 radiotherapies were performed in the last 8 years, residual tumor grew slowly. He presented with intractable hiccups. His hiccups continued for 30 minutes, sometimes for 3 hours with obstruction of eating. Contrast-enhanced Magnetic resonance (MR) imaging demonstrated the dissemination of metastatic lung tumor at dorsal surface of medulla oblongata and ventral surface of midbrain. Some literatures reported the patients with intractable hiccups caused by dorsal medullary lesions. Therefore, we thought that the small disseminated tumor at dorsal surface of medulla oblongata caused the hiccups. Evaluation of dorsal medullay area by MR imaging is important to reveal the cause of intractable hiccups. PMID- 21595300 TI - [Case of multiple sclerosis with "yes-yes" type head tremor]. AB - A 32-year-old woman, who had developed head tremor and paresthesia of the right upper limb for several months, was admitted to our hospital The diagnosis of multiple sclerosis was made because the serial MRI showed multiple lesions in both the cerebral white matter and the cervical cord. Oligoclonal IgG band was positive. Her symptoms were improved by intravenous methylprednisolone and an antiepileptic drug (MEPM 1 g/day and CZP 1 mg/day). The head tremor was the so called "yes-yes" type which shakes back and forth. Although this type of tremor has been considered to be developed by the lesions in the cerebellum, our patient seemed to develop the tremor by cervical cord lesion. Further investigation is needed to confirm the association of the head tremor and the cervical lesions in MS. PMID- 21595301 TI - [Plant extracts in drug discovery: traditional considerations, novel possibilities]. AB - Natural product based drug discovery, especially for strategies, based on plant extracts has several and almost traditional arguments. In practice, however, keeping in mind the interest of cost, the chemical diversity and the biological potential provided by secondary plant metabolites could be reached only by rational and harmonized adoption and application of related disciplines and technologies. New and relevant approaches and solutions are presented in this review regarding the accessible way, starting with the collection and extraction of plant material, via the robust high throughput biological screening (HTS) of extracts, reaching isolation, structure elucidation and development phase of the active principle. Special emphasis was made on applications, achieving HTS compatible extracts and on on-line analytical technics, speeding up the complete isolation process. In addition, beside reviewing international trends and case studies, the results of the examination of the plant extract library of Gedeon Richter Plc. are published as well. PMID- 21595302 TI - [Good laboratory practice of equilibrium solubility measurement]. AB - The biggest part of my PhD work was the standardization of the classical saturation shake-flask solubility method. During the experiments we examined systematically which parameters have significant influence on the solubility value and how large experimental error (standard deviation) is caused by them in the solubility method. Hydrochlorothiazide was used as model compound. Modification in temperature, sedimentation time, composition of aqueous buffer and the technique of separation of solid and liquid phases were found to influence the equilibrium solubility results strongly. However, variations in the amount of solid excess and stirring time were found to have less influence. Based on this standardization study, we developed a new shorter (36 hours) protocol for measurements of equilibrium solubility of drug molecules. The new protocol was validated with the aid of 6 structurally different compounds. The equilibrium solubility was measured by both (standard and new) protocols. The results were in good agreement, so the shorter protocol can be applied to measure the equilibrium solubility of drug compounds. PMID- 21595303 TI - [Importance of particle size decrease in the preformulation]. AB - Present work provides a short review concerning the importance of particle size decreasing in the drug formulation. The presented theoretical introduction collects the must important factors which influence the dezintegration and integration mechanisms. Modification of particle size and morphology could overcome the formulation problems, resulted improved drug release. Wet milling and solvent diffusion, as a novel methods to complete with drying will be presented applying the poorly water-soluble niflumic acid. Differences in particle sizes were found according to the used processing. The specific surface area of the drug was increased following particle size reduction and the dissolution rate was therefore significantly improved. During structural characterizations (DSC and XRPD), strong interactions were detected between the drug and stabilizer. PMID- 21595304 TI - [Amorphous form in pharmaceutical technological research]. AB - Detecting and analysing of the amorphous phase are increasingly important in pharmaceutical technology. The amorphous or glassy state has a several advantages and disadvantages. The amorphous form can be applied in deliberate amorphization, when active pharmaceutical ingredient (API) is formulated in glassy state, or this form can appear accidentally during formulation or storage. The aim of this study was to characterize glass-forming properties of 13 different materials. Differential Scanning Calorimetry (DSC) was used as an analytical technique and T(g) and T(m) values were determined. The equation of T(g)/T(m) (K/K) was applied to determine the glass-forming tendencies. We made 2 groups of investigated substances. The first group was that we could not amorphized: tenoxicam, mannitol, niflumic acid, theophyllin and lidocain. The second group contains materials, which could be prepared in glassy form. This group can be divided into 2 sub-groups: poor-glass formers and good-glass formers. Poor-glass formers are following: meloxicam, ibuprofen and piroxicam. Good-glass formers are lacidipine, gemfibrosil, sorbitol, loratadine, chlorhexidine and clopidogrel hydrogensulfate. PMID- 21595305 TI - [The applicability of sucrose laurate in hot-melt technology]. AB - Nowadays, one of the most important task of the pharmaceutical technology is to optimize the dissolution of active ingredients, because most of the drug candidates have a poorly water solubility and hence a slow absorption. According to the latest examinations, the bioavailability of poorly water soluble drugs can be increased significantly by using surfactants or the mixture of surfactants and polymers. Nowadays, surfactants (like polysorbates) are generally used in the production of solid dispersions, so the use of surface-active sucrose esters can be resulted an innovative solution in the pharmaceutical technology. The aim of our investigation was to examine the applicability of sucrose laurate in hot-melt technology in order to influence the crystalline structure and dissolution rate of a poorly water soluble drug (gemfibrosil) having low-melting point. The results of the X-ray powder diffractometry have showed that the sucrose laurate had no significant effect on the crystallization degree of the drug which is important in case of the stability. On the bases of the results of in-vitro dissolution studies, it can be concluded that the sucrose laurate (using minimum 5%) can be well applied in hot-melt technology with carriers having characteristic melting point (e.g. Macrogol) to increase the dissolution rate of poorly soluble drugs. PMID- 21595306 TI - [Talc pleurodesis by thoracoscopy: a minimally invasive technique finally legal]. PMID- 21595307 TI - [Endobronchic palliative brachytherapy]. AB - Brachytherapy, the placement of an encapsuled radioactive source (Iridium) in or near a tumor, is a palliative therapeutic modality available for patients suffering of a bronchogenic cancer, especially if they present invalidating symptoms such an incoercible cough, haemoptysis, dyspnea. The treatment modality is indicated if chemotherapy or external irradiation are not possible. It is typically a team work. PMID- 21595308 TI - [Medical thoracoscopy]. AB - Medical thoracoscopy (MT) remains a mini-invasive and very efficient technique to diagnose pleural diseases. In case of pleural effusion of unknown etiology its diagnostic yield is higher than 90%. MT also allows to perform cheap and successful pleurodesis by simple talc insufflation in case of recurring pneumothorax and invalidating malignant pleural effusion with very poor quality of life despite repeated thoracocentes. PMID- 21595309 TI - [Foreign bodies and hemoptysis: about danger of ingesting blister-wrapped tablets]. AB - A case of hemoptysis may be challenging for clinicians because of the many etiologies involved in this differential diagnosis. Sometimes the cause of this symptom may be very surprising. We present a case of hemoptysis due to ingestion of a blister. This case illustrates the difficulties of identifying rare causes of hemoptysis, especially blister ingestion frequently occurring in old and neurological or cognitive impaired patients. PMID- 21595311 TI - [Pulmonary fibrosis and emphysema]. AB - We report a case of combined pulmonary fibrosis and emphysema. This syndrome, including upper-lobe emphysema and pulmonary fibrosis of the lower lung was recently described in smokers or ex-smokers (mean age: 65 years). Exertional dyspnea is always present. Pulmonary functions are subnormal while carbon monoxyde transfer is reduced and exercise hypoxemia is present. High resolution CT-scan is key of diagnosis with upper lobes emphysema with diffuse infiltrating fibrosing disease at the bases. Pulmonary hypertension is present is almost 50% of patients, representing the principal negative pronostic factor. Five years survival is 54.6% (median survival 6, 1 years). PMID- 21595310 TI - [Cystic fibrosis, a paradigm for modern medicine]. AB - Cystic fibrosis is the most frequent and severe genetic disorder in caucasian children. It is a multisystemic disease progressively involving many organs. Patients' survival was poor most of them dying as children. There has been now however an important improvement of prognosis. The median survival is 38 years today. Such a progress is related to comprehensive care based not only on scientific research but multidisciplinary clinical approach implying physicians and paramedics. Moreover pediatricians stimulated already in the 1960s patient autonomy by supporting national and international patients organisations. This approach has greatly contributed to increase the visibility of this disease and its support in our society. Cystic fibrosis is a paradigm for improving care of chronic diseases in medicine. PMID- 21595312 TI - [A rare etiology of massive haemoptysis: a case description]. AB - We present here a case of severe haemoptysis occurring 2 times in a man having some anomaly of lung development, i.e. a right pulmonary artery agenesis. We ought to keep in mind these anomalies of lung development which are quite rare. Moreover in absence of pulmonary artery, the ipsilateral lung parenchyma is vascularized by systemic circulation and exposed to very high systemic pressure responsible for very severe haemoptysis requiring sometimes a pneumonectomy to be controlled. Finally we make a short review on etiology of lung haemoptysis. PMID- 21595313 TI - [Rationale and clinical evidence for the use of rituximab in glomerular diseases]. AB - Autoimmune glomerulopathies are an important cause of chronic kidney disease. Conventional treatments based on steroids, antiproliferative and cytotoxic agents are efficacious, but highly toxic. Because of their central role in the pathogenesis of autoimmunity, B cells have become an attractive therapeutic target. Rituximab is a monoclonal antibody directed against CD20 expressed on the surface of B cells, inducing profound depletion of B cells in the peripheral blood. In spite of encouraging results regarding the off-label use of Rituximab in membranous nephropathy, systemic lupus erythematosus and small vessel vasculitis, controlled, long-term data, and data with specific renal endpoints are currently lacking. PMID- 21595314 TI - [Tuberculosis: is the UN objective credible?]. PMID- 21595315 TI - [Ethical miscellany]. PMID- 21595317 TI - [Politics: go there, pull the cord]. PMID- 21595316 TI - [Pregnant, me? Never!]. PMID- 21595318 TI - Coincidences: a tale of two genes, ami-1 and upr-1. PMID- 21595319 TI - [Q & A on diagnostic imaging. A history of pneumothorax and stubborn inflammatory adhesion due to an infectious cyst (found later to be aspergillosis)]. PMID- 21595320 TI - [Current problems of diagnostics and treatment of pyoinflammatory ENT diseases in patients with diabetes mellitus]. AB - The present review is devoted to the problem of diagnostics and treatment of pyoinflammatory ENT diseases in patients with diabetes mellitus (DM). Modern concepts of pathological changes in the immune system and specific features of the pyogenic process in ears, nose, and throat are discussed with special reference to the difficulty of the choice of rational and efficacious antibacterial therapy posed by diabetic complications. PMID- 21595321 TI - [Surgical interventions for the treatment of median paralytic laryngeal stenosis]. PMID- 21595322 TI - Selection in insurance markets: theory and empirics in pictures. AB - Government intervention in insurance markets is ubiquitous and the theoretical basis for such intervention, based on classic work from the 1970s, has been the problem of adverse selection. Over the last decade, empirical work on selection in insurance markets has gained considerable momentum. This research finds that adverse selection exists in some insurance markets but not in others. And it has uncovered examples of markets that exhibit "advantageous selection"-a phenomenon not considered by the original theory, and one that has different consequences for equilibrium insurance allocation and optimal public policy than the classical case of adverse selection. Advantageous selection arises when the individuals who are willing to pay the most for insurance are those who are the most risk averse (and so have the lowest expected cost). Indeed, it is natural to think that in many instances individuals who value insurance more may also take action to lower their expected costs: drive more carefully, invest in preventive health care, and so on. Researchers have taken steps toward estimating the welfare consequences of detected selection and of potential public policy interventions. In this essay, we present a graphical framework for analyzing both theoretical and empirical work on selection in insurance markets. This graphical approach provides both a useful and intuitive depiction of the basic theory of selection and its implications for welfare and public policy, as well as a lens through which one can understand the ideas and limitations of existing empirical work on this topic. PMID- 21595323 TI - The (paper) work of medicine: understanding international medical costs. AB - This paper draws on international evidence on medical spending to examine what the United States can learn about making its healthcare system more efficient. We focus primarily on understanding contemporaneous differences in the level of spending, generally from the 2000s. Medical spending differs across countries either because the price of services differs (for example, a coronary bypass surgery operation may cost more in the United States than in other countries) or because people receive more services in some countries than in others (for example, more bypass surgery operations). Within the price category, there are two further issues: whether factors earn different returns across countries and whether more clinical or administrative personnel are required to deliver the same care in different countries. We first present the results of a decomposition of healthcare spending along these lines in the United States and in Canada. We then delve into each component in more detail-administrative costs, factor prices, and the provision of care received-bringing in a broader range of international evidence when possible. Finally, we touch upon the organization of primary and chronic disease care and discuss possible gains in that area. PMID- 21595324 TI - The pragmatist's guide to comparative effectiveness research. AB - Following an acrimonious health care reform debate involving charges of "death panels," in 2010, Congress explicitly forbade the use of cost-effectiveness analysis in government programs of the Patient Protection and Affordable Care Act. In this context, comparative effectiveness research emerged as an alternative strategy to understand better what works in health care. Put simply, comparative effectiveness research compares the efficacy of two or more diagnostic tests, treatments, or health care delivery methods without any explicit consideration of costs. To economists, the omission of costs from an assessment might seem nonsensical, but we argue that comparative effectiveness research still holds promise. First, it sidesteps one problem facing cost effectiveness analysis--the widespread political resistance to the idea of using prices in health care. Second, there is little or no evidence on comparative effectiveness for a vast array of treatments: for example, we don't know whether proton-beam therapy, a very expensive treatment for prostate cancer (which requires building a cyclotron and a facility the size of a football field) offers any advantage over conventional approaches. Most drug studies compare new drugs to placebos, rather than "head-to-head" with other drugs on the market, leaving a vacuum as to which drug works best. Finally, the comparative effectiveness research can prove a useful first step even in the absence of cost information if it provides key estimates of treatment effects. After all, such effects are typically expensive to determine and require years or even decades of data. Costs are much easier to measure, and can be appended at a later date as financial Armageddon draws closer. PMID- 21595325 TI - Patient cost-sharing and healthcare spending growth. AB - In this paper, we explore the role patient incentives play in slowing healthcare spending growth. Evidence suggests that while patients do indeed respond to financial incentives, cost-sharing does not uniformly improve value; rather, cost sharing provisions must be deliberately structured and targeted to reduce care of low marginal value. Other mechanisms may be helpful in targeting particular populations or types of utilization. The spillover effects between privately insured and publicly insured populations as well as market imperfections suggest a potential role for public policy in promoting insurance design that slows spending growth while increasing the health that each dollar buys. PMID- 21595326 TI - Reforming payments to healthcare providers: the key to slowing healthcare cost growth while improving quality? AB - This paper focuses on a broad movement toward a fundamentally different way of paying healthcare providers. The approach reaches beyond the old dichotomies about whether healthcare providers are reimbursed on a fee-for-service or a "capitated" or per-person payment. Instead, these reforms seek to create direct linkages between payments to healthcare providers and measures of the quality and efficiency of care. After an overview of payment reforms for healthcare providers and their welfare implications, this paper discusses a range of empirical studies. These often small-scale studies suggest that provider payment reforms in conjunction with greater attention to improving measurements of care quality and outcomes can have a significant impact on quality of care and, in some cases, resource use and costs of care. PMID- 21595327 TI - Evaluating the medical malpractice system and options for reform. AB - The U.S. medical malpractice liability system has two principal objectives: to compensate patients who are injured through the negligence of healthcare providers and to deter providers from practicing negligently. In practice, however, the system is slow and costly to administer. It both fails to compensate patients who have suffered from bad medical care and compensates those who haven't. According to opinion surveys of physicians, the system creates incentives to undertake cost-ineffective treatments based on fear of legal liability--to practice "defensive medicine." The failures of the liability system and the high cost of health care in the United States have led to an important debate over tort policy. How well does malpractice law achieve its intended goals? How large of a problem is defensive medicine and can reforms to malpractice law reduce its impact on healthcare spending? The flaws of the existing system have led a number of states to change their laws in a way that would reduce malpractice liability--to adopt "tort reforms." Evidence from several studies suggests that wisely chosen reforms have the potential to reduce healthcare spending significantly with no adverse impact on patient health outcomes. PMID- 21595328 TI - The minimum legal drinking age and public health. AB - The Amethyst Initiative, signed by more than 100 college presidents and other higher education officials calls for a reexamination of the minimum legal drinking age in the United States. A central argument of the initiative is that the U.S. minimum legal drinking age policy results in more dangerous drinking than would occur if the legal drinking age were lower. A companion organization called Choose Responsibility explicitly proposes "a series of changes that will allow 18-20 year-olds to purchase, possess and consume alcoholic beverages." Does the age-21 drinking limit in the United States reduce alcohol consumption by young adults and its harms, or as the signatories of the Amethyst Initiative contend, is it "not working"? In this paper, we summarize a large and compelling body of empirical evidence which shows that one of the central claims of the signatories of the Amethyst Initiative is incorrect: setting the minimum legal drinking age at 21 clearly reduces alcohol consumption and its major harms. We use a panel fixed effects approach and a regression discontinuity approach to estimate the effects of the minimum legal drinking age on mortality, and we also discuss what is known about the relationship between the minimum legal drinking age and other adverse outcomes such as nonfatal injury and crime. We document the effect of the minimum legal drinking age on alcohol consumption and estimate the costs of adverse alcohol-related events on a per-drink basis. Finally we consider implications for the correct choice of a minimum legal drinking age. PMID- 21595329 TI - Managing in a union environment. PMID- 21595330 TI - Succession planning: a different leadership yardstick. PMID- 21595331 TI - Recruitment tools utilized in the healthcare industry. PMID- 21595332 TI - Encounters of stress. PMID- 21595333 TI - What do HR and coding have to do with each other? PMID- 21595334 TI - Turnover among healthcare professionals. AB - Turnover among healthcare professionals is a costly consequence. The existing body of knowledge on healthcare professional turnover is correlated with job satisfaction levels. A landmark study differentiated 2 areas of job satisfaction categories: satisfiers and dissatisfiers (intrinsic and extrinsic motivators). The aim of this article is to examine existing research on precursors of turnover, such as burnout behaviors experienced by healthcare professionals, job satisfaction levels, employee organizational commitment, health complications which precede turnover, some current strategies to reduce turnover, and some effects CEO turnover has on employee turnover intentions. PMID- 21595335 TI - The journey from entitlement to performance. PMID- 21595336 TI - Mentoring for the next generation of new managers. AB - Mentoring programs can be key to the continued success of an organization. With anticipated increasing turnover of employees and senior management getting closer to retirement, it has never been more important to train and mentor the next generation of new managers. This article identifies personality traits that may contribute to a successful mentor/mentee relationship and discusses new schemes and approaches designed to mentor new managers.Old and new ideas can be melded together through generational mentoring. This article highlights issues regarding both the advantages and disadvantages to mentoring. PMID- 21595337 TI - Basic training: new challenges and old issues. PMID- 21595338 TI - Orientation: the key to successful, engaged staff. AB - Orientation programs are an important component of employee retention and engagement, yet the importance of orientation is often overlooked by many organizations. A lack of an adequate orientation program can result in new employees finding it difficult to adapt to the organization's culture,and may lead to high turnover rates. This article relates the story of Banner Baywood Medical Center's quest to cultivate an effective orientation program and increase retention of quality, engaged employees. PMID- 21595339 TI - Preparing for an aging workforce. AB - A mini-study was conducted to determine how hospitals in the United States are preparing for the aging workforce phenomenon. Human resource managers within the healthcare field, specifically from hospital settings, participated in a survey designed to reveal how the healthcare industry is focusing their retention efforts in terms of aging workers. Furthermore, the study sought to determine the methods by which the human resource managers are using to retain aging employees. PMID- 21595340 TI - Saving budgets with recruitment and retention practices. PMID- 21595341 TI - HR rocks (and Whitney too!). PMID- 21595342 TI - Taking care of hospitalized patients also means taking care of business. AB - To be an advocate for their patients and keep their hospital's best interest in mind, case managers should be informed about the financial aspects of patient care. Clinical decisions should always guide patient care, but payer requirements and coverage limits are also important. Know how the hospital is paid, and understand payer requirements for reimbursement. Keep patients' benefits and lifetime limits in mind when developing a discharge plan. Ensure that patients get the care they need to avoid unnecessary time in the hospital. Keep up with Medicare's and other payers changes in terms of what they will and won't approve. PMID- 21595343 TI - Work closely with the business office. AB - At the University of Pittsburgh Medical Center, members of the case management department work closely with the contracting and business department by pointing out payer issues and keeping the chief financial officer informed about payer requirements that could affect reimbursement. Case managers track payer issues on a dayto-day basis and report trends to the contracting department. Contracting staff obtain input from members of the case management department when negotiating or renegotiating contracts. Changes in payer contracts are communicated to the case management staff. PMID- 21595344 TI - Revenue integrity team follows the patient stay. AB - At DCH Regional Medical Center and DCH Northport Medical Center, both in Tuscaloosa, AL, nurses and financial service experts comprise the revenue integrity team in the case management department. The team reviews the patient record through the entire stay to make sure everything is in place for the hospital to be paid appropriately. Members of the team analyze underpayments and denials to determine if an appeal is in order. They look for patterns of denials and decide what action to take to correct them. The team audits every case manager and social worker each month to determine whether he or she is documenting correctly and completely. PMID- 21595345 TI - Follow these sure-fire tips to sort through data and measure outcomes in your department. PMID- 21595346 TI - Rule for conditions acquired at hospital. AB - The Centers for Medicare and Medicaid Services (CMS) has issued a proposed rule that would stop payments for hospital-acquired conditions for Medicaid beneficiaries. State Medicaid agencies would be required to use the Medicare list of hospital-acquired conditions and would have the option to add additional conditions for non-payment. Hospitals must carefully and completely document all conditions on the list that are present on admission. Case managers should work with admitting physicians to ensure that the documentation is in the chart. Documentation for all patients must have the same scrutiny as for Medicare patients. PMID- 21595347 TI - Home monitoring cuts cardiac readmissions. AB - A collaboration between Ocean Medical Center and Meridian At Home care agency in Brick, NJ, to provide remote monitoring for heart failure patients has resulted in a drop in readmissions from 14.93% before the program began to 4.84% in the first eight months of the pilot program. Program aims to get patients accustomed to monitoring weight gain and other symptoms. Hospital case managers screen patients for appropriateness for the program. Eligible patients receive a daily automated phone call, answer questions and record their weight on a remote monitoring device connected to the remote monitoring nurse. Nurses work with patients to reinforce hospital teaching and determine the causes of exacerbation. PMID- 21595348 TI - Surge in underinsured, self-pay? Use these tips. PMID- 21595349 TI - How can careproviders most help patients during a disaster? AB - This article reviews careproviders' most difficult emotional challenges during disasters and provides approaches for responding optimally to them. It describes key approaches that careproviders may pursue to best help patients and others during a catastrophe. It raises unanswered questions regarding when, if ever, careproviders should provide active euthanasia to patients who are incompetent, and when, if ever, careproviders should give their own food and water to patients or others who may otherwise soon die without them. PMID- 21595350 TI - Imagining the unthinkable, illuminating the present. AB - During a catastrophe that disables the health system, ethically charged situations will undoubtedly emerge that will challenge patients, relatives, clinicians, and others involved in health delivery. This second of two special sections of The Journal of Clinical Ethics includes discussions of the implications of a system collapse on particularly vulnerable member of society, children, pregnant women, and those who are socio-economically, culturally, and linguistically disempowered. Additionally, it offers insights into the processes used by committees to plan for catastrophic care. PMID- 21595351 TI - An ethical framework for the responsible management of pregnant patients in a medical disaster. AB - The ethics of managing obstetric patients in medical disasters poses ethical challenges that are unique in comparison to other disaster patients, because the medical needs of two patients--the pregnant patient and the fetal patient--must be considered. We provide an ethical framework for doing so. We base the framework on the justice-based prevention of exploitation of populations of patients, both obstetric and non-obstetric, in medical disasters. We use the concept of exploitation to identify a spectrum from ethically acceptable, to ethically challenging, to ethically unacceptable, management of obstetric patients in medical disasters. We also address the ethics of the care of obstetric and neonatal patients when the resources of a hospital are completely overwhelmed in a large-scale medical disaster. PMID- 21595352 TI - Non-pharmaceutical interventions to limit the transmission of a pandemic virus: the need for complementary programs to address children's diverse needs. AB - Non-pharmaceutical interventions, including social distancing, quarantine, and isolation, are a potentially attractive means to limit the transmission of a pandemic virus. Many of these interventions are directed at children given children's disproportionate role in amplifying epidemics. The ethics of non pharmaceutical interventions can be analyzed using Nancy Kass' ethics framework for public health. Such an analysis highlights the limited data supporting these interventions' effectiveness. It also suggests the framework itself needs to be expanded to consider harms other than constraints on liberty and to consider affirmative programs to mitigate these broader harms. PMID- 21595353 TI - Unaltered ethical standards for individual physicians in the face of drastically reduced resources resulting from an improvised nuclear device event. AB - When disaster disrupts healthcare and other systems, the ethical allocation of resources should follow principles of justice, defined as fairness, established for normal clinical practice. Standards of clinical practice may be altered during disaster, but ethical standards must remain centered on prioritizing the treatment of patients according to need and the effectiveness of treatment. Should resources become extremely limited, it is fair to restrict their use to patients who have the highest needs, provided that the intervention is effective. When resources become more available, patients with lower priority can be increasingly accommodated. PMID- 21595354 TI - Attending to social vulnerability when rationing pandemic resources. AB - Pandemic plans are increasingly attending to groups experiencing health disparities and other social vulnerabilities. Although some pandemic guidance is silent on the issue, guidance that attends to socially vulnerable groups ranges widely, some procedural (often calling for public engagement), and some substantive. Public engagement objectives vary from merely educational to seeking reflective input into the ethical commitments that should guide pandemic planning and response. Some plans that concern rationing during a severe pandemic recommend ways to protect socially vulnerable groups without prioritizing access to scarce resources based on social vulnerability per se. The Minnesota Pandemic Ethics Project (MPEP), a public engagement project on rationing scarce health resources during a severe influenza pandemic, agrees and recommends an integrated set of ways to attend to the needs of socially vulnerable people and avoid exacerbation of health disparities during a severe influenza pandemic. Among other things, MPEP recommends: 1. Engaging socially vulnerable populations to clarify unique needs and effective strategies; 2. Engaging socially vulnerable populations to elicit ethical values and perspectives on rationing; 3. Rejecting rationing based on race, socioeconomic class, citizenship, quality of life, length of life-extension and first-come, first-served; 4. Prioritizing those in the general population for access to resources based on combinations of risk (of death or severe complications from influenza, exposure to influenza, transmitting influenza to vulnerable groups) and the likelihood of responding well to the resource in question. 5. Protecting critical infrastructures on which vulnerable populations and the general public rely; 6. Identifying and removing access barriers during pandemic planning and response; and 7. Collecting and promptly analyzing data during the pandemic to identify groups at disproportionate risk of influenza-related mortality and serious morbidity and to optimize the distribution of resources. PMID- 21595355 TI - Ethical care for infants with conditions not curable with intensive care. AB - Offering intensive care to neonates who have conditions that carry extremely poor prognoses is a source of great contention amongst neonatologists. The concept of best interests is commonly used as a rationale for refusing such care, despite the fact that parents of these infants often have a different view of what best interests means. This article takes up the question of what best interests should incorporate for infants with lethal conditions not curable with intensive care, and how and who should decide which treatment options should be implemented. Based on our recommendation that parents be apprised of the basis upon which physicians are evaluating treatment options, we offer a framework that allows all relevant parties to approach the issue of what is appropriate treatment from a similar place. We maintain that this approach will increase transparency, dialogue, understanding, and trust, which, in turn, may result in greater consensus. PMID- 21595357 TI - "Evidence-debased medicine" and the integrity of the medical profession. AB - Patients trust physicians to prescribe based on their fiduciary duty to act in the best interests of their patients, and physicians prescribe based on confidence in research data and clinical guidelines. Recent reports erode confidence in evidence-based medicine. Through self-regulation and a willingness to change, the medical profession can assert its status as a profession distinct from outside influence, serving one interest: the healthcare of patients and the public. PMID- 21595356 TI - Priority setting up close. AB - Published accounts of specific priority-setting projects in healthcare are relatively few. This article chronicles the collaborative efforts of a professional practice lead and a bioethicist to strengthen the priority-setting process for a specific home care service. The project included two features not often reported in other priority-setting projects: the entire "frontline team" was involved for the project's duration, and a group of parents was canvassed for their views. Informed by both Daniels's "accountability for reasonableness" approach and challenges levied against it, the article explains the evolution of an assessment procedure, eligibility and priority criteria, and guiding substantive principles and concludes with the "lessons learned" by the project leads. PMID- 21595358 TI - Legal briefing: Healthcare ethics committees. AB - This issue's "Legal Briefing" column covers recent legal developments involving institutional healthcare ethics committees. This topic has been the subject of recent articles in JCE. Healthcare ethics committees have also recently been the subject of significant public policy attention. Disturbingly, Bobby Schindler and others have described ethics committees as "death panels." But most of the recent attention has been positive. Over the past several months, legislatures and courts have expanded the use of ethics committees and clarified their roles concerning both end-of-life treatment and other issues. These developments are usefully grouped into the following eight categories: 1. Existence and availability. 2. Membership and composition. 3. Operating procedures. 4. Advisory roles. 5. Decision-making and gate-keeping roles. 6. Confidentiality. 7. Immunity. 8. Litigation and court cases. PMID- 21595359 TI - Ethical issues related to direct nursing care time, compared to time spent charting in intensive care units. PMID- 21595360 TI - Esprit de corps. PMID- 21595361 TI - The biological precedents for medieval impetus theory and its Aristotelian character. AB - While the impetus theory is often regarded as a non-Aristotelian theory that could not have emerged within the development of Aristotelianism, I argue that it is essentially Aristotelian. Given the state of the theories of body, movement and sexual reproduction and the development of the theory of the four elements in the Latin West at the end of the thirteenth century, the impetus theory was probably developed as an application to projectiles of Aristotle's theories of the male semen and of family resemblance. In addition, the impetus theory was even a convenient expedient to simplify the Aristotelian theory of movement and prevent it from drifting into non-Aristotelian territory. PMID- 21595362 TI - The AMS/Paterson Lecture: becoming alternative? Modern transformations of Chinese medicine in China and in the United States. AB - "Becoming Alternative" offers an overview of the transformations of Chinese medicine at home and abroad since the mid-19th century. After coming into contact with biomedicine, China's indigenous medicine was redefined in terms of national culture and history on the one hand, and a competitive alternative science on the other. Reimagined in terms of scientific syncretism in the PRC, and embraced as a counter-cultural alternative to bio-medicine in the United States, the medicine we call "Chinese" today emerges as a pluralistic system with global reach involving complex accommodations with local medical cultures and institutions both at home and abroad. PMID- 21595363 TI - Menopause and historical constructions of cancer risk. AB - This paper explores the association between menopause and cancer over the past 250 years in relation to the disease model of menopause. Relying primarily upon medical literature produced in Great Britain, the United States, and Canada, it shows how this association evolved from traditional humoral theory; how it was sustained during the 19th century as part of a larger vision of female vulnerability at midlife countered, partially and temporarily, by a more optimistic outlook at the beginning of the 20th century; and how, over the past 80 years, the debate over cancer risk at menopause was intertwined with the vacillating fortunes of the disease model and its normalization of hormone replacement therapy. PMID- 21595364 TI - What is a "health" professional? The changing relationship of occupational therapists and social workers to therapy and healthcare in Quebec, 1940-1985. AB - Studies regarding the medicalization process generally focus on the way various physical and psychological conditions have been identified as "health" problems, within specific historical contexts. Less well known is how the therapeutic roles of certain "health" professionals were also a result of the confluence of particular historical events. By comparing the professional trajectories of Quebec's occupational therapists and hospital social workers from 1940 to 1985, this article demonstrates how professionals originally outside of the world of health care created new therapeutic roles for themselves within the constantly expanding institutional health care system. PMID- 21595365 TI - The role of the Irish Division of the Royal Medico-Psychological Association in the development of intellectual disability nursing in Ireland. AB - The development of a specialist intellectual disability workforce in independent Ireland by the Royal Medico-Psychological Association was influenced by nursing regulatory bodies and Catholic religious orders, the latter of which provided lay residential education to people with intellectual disabilities. Although the RMPA shaped curriculum and examinations, practice scope, clinical assessment and practical skills were weighted more heavily towards bedside nursing, psychology and education due to the input of the religious orders and nursing board. PMID- 21595366 TI - Questioning medicine in seventeenth-century Rome: the consultations of Paolo Zacchia. AB - This paper surveys the life and contributions of Paolo Zacchia (1584-1659) before analyzing 85 Latin consilia (or consultations) in his Quaestiones medico-legales. Topics include death, paternity, sexuality, disease, and miracles. Because the consilia cite the rest of his treatise, they open the entire work, elucidating applications of theory. This research relied on the construction of a database, built on subject, date, and citations. The paper closes with historiographic suggestions for why this prominent author has been ignored in North America. PMID- 21595367 TI - An illness in the family: Dr. Maude Abbott and her sister, Alice Abbott. AB - This paper explores Maude Abbott's internationally significant career in medicine and her parallel commitment to caring for her sister, Alice Abbott. An examination of Abbott's life reveals the difficulties faced by an ambitious Canadian woman in medicine from the 1890s to the 1920s; difficulties compounded by caring for a sister with a mental illness. The Abbott archive suggests that it was far more difficult for a woman doctor to make the kind of sharp distinction between public and private life that might be expected of professional men. PMID- 21595368 TI - Introducing Darwinism to Toronto's post-1887 reconstituted medical school. AB - Charles Darwin's scientific paradigm was largely welcomed in Canadian academic biology and medicine, while reaction among other faculty and laypeople ranged from interest to outrage. In 1874, Ramsay Wright, a Darwinian-era biologist from Edinburgh, was appointed to the University of Toronto's Chair of Natural History. Over his 38-year career Wright integrated the evolutionary perspective into medical and biology teaching without accentuating its controversial source. He also applied the emerging German experimental research model and laboratory technology. This study identifies five categories of scientific and personal influences upon Wright through archival research on biographical sources and his writings. PMID- 21595369 TI - Counter-memory activism in the aftermath of tragedy: a case study of the Westray Families Group. AB - Narratives are critical to how people understand themselves and the significant events of their lives. Drawing upon social memory theory and the social constructionist approach to social problems, this study provides a narrative analysis of the counter-memory activism of the Westray Families Group (WFG), which formed after 26 men died in the 1992 Westray mine explosion (Plymouth, NS). Against alternative explanations promoted by more powerful stakeholders, the WFG adopted and weaved a corporate negligence narrative into their commemorative activism. This study illustrates how a small families group can draw reflexively upon and reshape cultural scripts to narrate how others should remember and respond to key events. PMID- 21595370 TI - Rising to the challenge: addressing the concerns of people working in the sex industry. AB - In September 2010, three Canadian Criminal Code provisions related to prostitution were ruled unconstitutional because they increase the risk of harm to people working in the sex industry (PWSI). Using data from studies with PWSI and key informants conducted in several Canadian cities, we examine three domains related to worker health and safety: occupational health and safety, perceptions of and behaviors toward workers, and access to essential services. Addressing these issues necessitates moving beyond decriminalization. We conclude that using a harm reduction/labor rights framework would enhance our ability to address issues related to the physical, social, and mental well-being as well as rights of PWSI. PMID- 21595371 TI - When formal laws and informal norms collide: lineage networks versus birth control policy in China. AB - Ancestor worship and bloodline continuation are the core norms of lineage in China. Beginning in the late 1970s, these cultural norms came into direct confrontation with the state birth control policy. Pitched against each other are the antinatalist laws backed by the powerful and unyielding state apparatus on the one side and the ancient pronatalist norms backed by revived lineage networks on the other. Even though the draconian state policies did succeed in dramatically reducing the overall birthrates, data analyses show that villages with strong kinship networks tend to have higher birthrates. The findings demonstrate the normative capacity of social networks to bend the iron bars of formal institutions. A general framework is developed for analyzing the roles of social networks in four ideal-typical juxtapositions of formal and informal institutions: normativism, legalism, congruence, and conflict. PMID- 21595372 TI - Long-term change and short-term results. PMID- 21595373 TI - How to survive and thrive in today's medical practice. AB - The healthcare environment is changing so rapidly that everyone needs to dedicate time to read and research the multitude of changes that are being mandated. Keep in mind if you are doing the same thing today that you did six months ago, it's probably wrong. Every practice is going to have to reexamine its policies and procedures and become flexible. This article outlines some of the major changes that you will be facing in 2011 and beyond. PMID- 21595374 TI - Culture of transition: from the way we've always done it! PMID- 21595375 TI - Contract litigation: prepare for war to ensure peace. AB - Contract litigation can prove devastating for all but the deepest of pockets. Physicians need to prepare for war to ensure the most favorable outcome. This includes identifying your risks, negotiating from strength, and hedging your bets. Negotiate and read your contracts carefully. Beware of critical loser pays provisions in your contracts that will require you to pay your adversary's fees in the event of an adverse ruling at trial or summary judgment. Keep your insurance portfolio up to date, including the latest risk management tools, such as contract litigation insurance. Protect yourself and your practice by planning ahead. PMID- 21595376 TI - A perspective on communicating with the female patient. AB - Most doctors' medical school training does not differentiate history taking between men and women. As a result, many physicians communicate with both sexes exactly the same. However, there are unique aspects of care, making it important to understand the differences between men and women and to take these differences into consideration when taking a medical history from a woman. This article will review those unique differences and provide you with suggestions for enhancing your communication with women. PMID- 21595377 TI - Needed meetings meet needs. PMID- 21595378 TI - A case study in success: the expansion of Salem Cardiovascular Associates. AB - With current or anticipated shortages in nearly all clinical specialties, physician practices and hospitals across the country must be committed to the recruitment and retention of their doctors. This case study of Salem CardioVascular Associates will detail how the practice faced and overcame challenges related to physician recruitment and retention in the larger context of rebuilding and expanding their services scope to include the booming specialties of vascular and electrophysiology. As part of the expansion, the Salem team worked to make the practice even stronger as a component of the rebuilding process. This was achieved through a commitment to a recruitment process that would find the right fit, while also giving much needed attention to elements of retention, such as work/life balance, that would keep hired physicians happy. The Salem story will help other practices in the midst of any expansion, rebuilding, or recruitment effort understand the implications of such initiatives and give examples of successes and lessons learned. PMID- 21595379 TI - Staffing snafus driving surgeons over the edge. AB - Staff expenses range from 23% to 34% of a practice's total revenue according to recent Medical Group Management Association surveys, making salaries one of the biggest expense categories. As a result, physicians and senior practice managers must assess the competency of employees, implement stepped-up training programs to meet the technology and reimbursement training needs of today, and institute more sophisticated hiring assessments and background checks before hiring new or replacement staff. PMID- 21595380 TI - How can physicians break through job boredom? AB - Physicians are not immune to job boredom, which may be brought on by lack of a stimulating job; a job that provides little opportunity for personal growth, development, or advancement; and work settings that are poorly matched to physicians' skills, interests, and capabilities. Common remedies include switching specialties, practicing concierge medicine, and taking locum tenens assignments. Some physicians counter boredom by leaving practice for jobs in the pharmaceutical and managed care industries, as well as other types of medical organizations. A small percentage of exceptional physicians pursue unique opportunities based on individual talents and interests that may or may not be related to their medical training and background. PMID- 21595381 TI - New GINA regulations from EEOC. PMID- 21595382 TI - Survival of solo practitioners and small group practices in today's challenging marketplace: setting the ground work now--Part II. AB - In Part I of this article, in the January/February 2011 issue, we discussed how the delivery of healthcare of the future will be dramatically different from the past for physicians in private practice. As the debate continues to swirl around the Patient Protection and Affordable Care Act, physicians in private practice continue to face the biggest challenges of their careers: how to maintain profitability and survive in this recession that appears to have no end in sight. This article provides guidelines to empower physicians and their staff with proven practice management tools and techniques that have stood the test of time. PMID- 21595383 TI - The ten commandments of recruiting: best practices for hiring the best employees. AB - Good hiring choices will enable your office to run efficiently and confront challenges with confidence and will increase your peace of mind. A more structured and rigorous recruiting process is recommended and described. The process is embodied in 10 distinct best practices that, if implemented, can lead to attracting, selecting, and retaining excellent staff. PMID- 21595384 TI - eDiscovery is here to stay: is your medical practice prepared for its risks and costs? AB - The adoption of electronic medical records technology in medical practices is helping to improve quality and decrease costs. While electronic records can increase practice efficiencies, this stored digital information is also playing an increasingly central role in the discovery phase of lawsuits. The sheer volume of electronic files that may be subject to a search and review during the electronic discovery phase (eDiscovery or e-discovery) can be overwhelming to produce. This phase of litigation is costly, too--the average eDiscovery project can run into the hundreds of thousands of dollars. A medical practice can reduce the number of procedural headaches and unnecessary legal costs by designing and implementing an eDiscovery strategy and process to reduce their legal and financial risk. PMID- 21595385 TI - Small things, done consistently, create major impact. PMID- 21595386 TI - Developing the excellence habit: 25 rules to live by. AB - Most medical practice employees agree pretty readily that they want to achieve a high level of excellence both in their work and in their lives. But defining and achieving excellence can be a challenge. This article explores specifically what it means to be excellent both inside and outside the medical practice. It suggests that the small things we do and the company we keep definitely matter and that excellence can become habitual if it is repeated again and again. Specifically, this article provides 25 clearly defined rules medical practice employees can learn and live by to develop and increase their personal excellence. It describes three hallmarks common to all excellent medical practice employees and five benefits of excellence. Finally, this article provides 10 daily affirmations the medical practice employee can use to develop and cement his or her own habit of excellence. PMID- 21595387 TI - Legal considerations for protecting the physician's assets. AB - Most states require that as a consideration of obtaining and maintaining a medical license, all applicants must demonstrate "financial responsibility." Usually this includes: (1) establishing an escrow account of cash and/or readily marketable securities; (2) an irrevocable, non-transferable letter of credit; or (3) in most cases, medical malpractice insurance coverage. In recent years, some states have passed legislation that provides that under certain circumstances, a physician may qualify to forego any of the financial requirements, commonly referred to as "going bare." In this regard, much of the impetus for the recently enacted Obama healthcare plan was the rising cost of healthcare in the United States arising from the extensive, and, to some, unnecessary and extraneous testing and retesting to confirm medical diagnosis and treatment-for the patient's benefit but, as importantly, to forestall a potential medical malpractice claim. As the political challenge to what is commonly referred to as "Obamacare" proceeds, and in the absence of any legislative support for "tort reform" and limitations on frivolous malpractice claims, it is abundantly clear that an integral part of any professional's "estate planning" should include and incorporate the asset protection and exempt property statutes available under the laws of the jurisdiction where the physician resides. PMID- 21595388 TI - Information overload in medical practice. AB - Most practices are inundated with an excess of information. This information overload, or "infoglut," results in distractions and a loss of productivity. This article will discuss the concept of infoglut and what every practice can do to manage the tsunami of information that threatens to consume our practices. PMID- 21595389 TI - Introduction of an electronic medical record system into physician practice offices: why is it so #%!&-ing hard for everybody?-Part I. AB - U.S. physician offices are experiencing a revolutionay change in the micro processes that have been the norm for documenting and communicating patient care over past decades. While this revolution is welcome for dozens of reasons, migration of data storage from the paper-based record to electronic form has effects on physician work that go well beyond what is immediately evident. Creation and implementation of these new systems is a huge challenge to all involved, particularly physicians and information technology professionals. This three-part series looks at underlying organizational and sociological aspects of the paper-to-digital transition causing implementation delays and considerable stress. These aspects often go unappreciated during electronic medical record implementations. PMID- 21595390 TI - Computer briefs: tagging the EMR. PMID- 21595393 TI - Warning: flooding ahead. PMID- 21595391 TI - Dr. no money. PMID- 21595394 TI - Coral in love. PMID- 21595392 TI - Trust me, i'm a scientist. PMID- 21595395 TI - Cancer testing? There's an app for that. PMID- 21595396 TI - Bracing for the big one. PMID- 21595397 TI - Steel rainbow. PMID- 21595398 TI - Beating back the bugs. PMID- 21595399 TI - HIV vs. measles. PMID- 21595400 TI - Beyond mammograms. PMID- 21595401 TI - Gadgets are garbage. PMID- 21595402 TI - Radical energy solutions. PMID- 21595403 TI - The lost galaxies. PMID- 21595404 TI - The hidden organ in your eyes. PMID- 21595405 TI - The strangest numbers in string theory. PMID- 21595406 TI - Fast track to vaccines. PMID- 21595407 TI - The space station's crown jewel. PMID- 21595408 TI - The growing menace from superweeds. PMID- 21595409 TI - Masters of disguise. PMID- 21595410 TI - Inner sparks. Interview by Alicia Anstead. PMID- 21595411 TI - Extrasensory pornception. PMID- 21595412 TI - Exposed. Medical imaging delivers big doses of radiation. PMID- 21595413 TI - Proceedings of the Sixth Northern Region Paediatric Colloquium. AB - It is apparent that the practice of medicine in today's society can often raise difficult legal and ethical dilemmas. With this in mind, senior figures from the medical, legal and theological professions have met on a biennial basis in order to discuss anonymised case material of such a nature. This provides a valuable forum in which to discuss such dilemmas, enabling the sharing of knowledge and experience from which we all can learn. To this end, we report the proceedings of the 'Sixth Northern Region Paediatric Colloquium', which are now the third set of proceedings to be published. PMID- 21595414 TI - Detentions of older adults under the Mental Health (Care and Treatment) (Scotland) Act 2003. AB - This study prospectively examined all initial emergency and short-term detention orders of older adults under the Mental Health (Care and Treatment) (Scotland) Act 2003 in a Scottish health region in 2008 to determine differences in characteristics and outcomes by patients' age, gender and those detained by consultant compared with non-consultant clinicians. Detention order papers were scrutinized, the detaining practitioners were interviewed and case records were examined. Appropriate statistical analyses were performed. For the 87 detentions, subjects were Caucasian, male (54%) and 45% were aged 80 years or older. Ninety four percent of detentions occurred on a weekday, during working hours (87%), in hospital (67%) with consultants initiating 74% of orders. Detention rates ranged from 66 to 171 per 100,000 over-65s. Seventy-five percent of patients had an organic disorder, 46% exhibiting psychotic symptoms. The older group had higher rates of confusion, organic diagnoses, but lower levels of previous psychiatric admissions. Consultants were more likely to detain patients with a wider variety of disorders, with more admissions to and detentions in psychiatric hospital care. Final detention outcomes were significantly different between the consultant and non-consultant groups. The results indicated few differences between the genders, but differences were more significant between the age cohorts and were further influenced by the grade of the detaining clinician. Further research is required to examine the influence that community mental health teams, advance statements and the use of guardianship and incapacity legislation have on the increasing rates of mental health detentions in the aging population. PMID- 21595415 TI - Evaluation of semen presumptive tests for use at crime scenes. AB - The SERATEC PSA Semiquant and RSID-Semen tests are immunoassay kits that identify semen by detecting prostate-specific antigen (PSA) and semenogelin (Sg), respectively. Both kits were tested with semen, urine, blood, saliva, vaginal secretions and breast milk in order to determine their sensitivity and specificity. These results demonstrate that the SERATEC PSA kit is more sensitive than the RSID-Semen kit with a limit of detection of 200 ng/mL as opposed to 8.0 x 10(3) ng/mL. The RSID-Semen kit gave no false-positives or -negatives compared with 2.9% false-negatives with the SERATEC PSA kit. Results from postcoital samples show the RSID-Semen kit to be more effective, indicating that this kit is more suitable for semen identification in the Haven Suites. As a more robust and cost-effective kit, the SERATEC PSA test is recommended for use at crime scenes. The ability to obtain DNA profiles from the buffer of both kits demonstrates the potential benefit of these kits in a rape investigation. The use of these kits at crime scenes would provide an invaluable contribution by prioritizing samples for subsequent analysis, thereby allowing greater efficiency with investigation times. PMID- 21595416 TI - Estimation of total length of humerus from its segments. AB - The aim of the present study was to calculate the total length of the humerus from its segments using linear, transverse and sagittal measures. One hundred and fifty dry adult unpaired humeri of both sides and of unknown sex from South India were studied. The humeri were divided into eight segments using salient bony points and muscular markings. The length of each segment was compared with the total length. These were subjected to statistical analysis. A high degree of correlation was found between segment length and total length and hence regression equations were calculated to estimate total length of humerus from each segment. The difference in measurements of the right and left sides was insignificant; hence single equations were calculated for all 150 bones. The length of the humerus and finally the stature of the individual could be calculated fairly accurately with an error of less than 2 cm. The results were compared with similar studies on other Indian populations. Calculation of total length from longer segments is comparable with other Indian populations, but if only shorter segments are available, new equations are needed for each population. PMID- 21595417 TI - Hyoid-laryngeal fractures in hanging: where was the knot in the noose? AB - The aims of this study were to determine the frequency of hyoid-laryngeal fractures in hanging in relation to the position of the ligature knot, to reconstruct the location of the ligature knot in cases of hanging when the furrow is not detectable on the skin, and to identify the possible mechanism of neck structure injuries. We report a retrospective autopsy study which included 557 cases of suicidal hanging: 413 men and 144 women, with an average age of 52.4 +/- 17.8 years. In 57.3% of them, hyoid-laryngeal fractures were found (average age was 54.3 +/- 16.5 years): 15.1% had only hyoid bone fracture, 26% had only thyroid cartilage fracture and 16.2% had both types of injury at the same time. Hyoid-laryngeal fractures were found more often in persons aged over 30 years. Hyoid bone fracture was a weak predictor of ligature knot position in our sample. Fracture frequencies of the thyroid cartilage show a statistically significant difference in relation to the ligature knot position among persons older than 30 years, which indicated the ipsilateral and posterior position of the knot. Absence or presence of any form of hyoid-laryngeal fracture indicated that knot position was anterior or posterior, respectively. The derived data would be useful for cases where the ligature has been removed from the body of the deceased shortly after hanging, where the noose is unavailable, and in cases where the ligature mark has faded such as with soft ligatures removed promptly or in decomposed bodies. PMID- 21595418 TI - Improved capillary electrophoresis determination of carbohydrate-deficient transferrin including on-line immunosubtraction. AB - The instrumental analysis of carbohydrate-deficient transferrin (CDT), a recognized marker of chronic alcohol abuse, is most commonly carried out by high performance liquid chromatography (HPLC) or capillary zone electrophoresis (CZE). Between these two techniques, CZE shows higher efficiency and productivity, but is often reported to be inferior to HPLC in terms of selectivity, because of a less specific ultraviolet detection wavelength than HPLC. On these grounds, the present work was aimed at the development of an improved CZE method for CDT determination, including an on-line immunosubtraction step specifically aimed at enhancing the analytical specificity of CZE determination. The analytical conditions were as follows: uncoated fused silica capillary, 30 microm x 60 cm (L = 50 cm to detector); running buffer, 100 mmol/L borate and 6 mmol/L DAB (1,4 diaminobutane), pH 8.3; voltage, 30 kV; temperature, 25 degrees C; detection, 200 nm. Under the described CZE conditions, a baseline separation between all the CDT related peaks was achieved with good analytical performances in terms of both precision and accuracy. In order to achieve unequivocal recognition of the CDT peaks, an in-capillary immunosubtraction step was included by loading a plug of anti-human transferrin antibody solution after the sample plug. This analytical approach was applied successfully to recognize CDT peaks in the presence of potential interferences. PMID- 21595419 TI - Report on suicidal trends in persons aged 60 or over in Japan: the need for effective prevention measures. AB - In Japan, the suicide rate has remained high since 1998, and effective suicide prevention measures that can bring about an immediate decrease in suicides are needed now. Specific suicide prevention measures must be based on the results of detailed research into the trends and causative factors of suicide. In the present study, we investigated the number of suicides and the proportion of causative factors in persons aged 60 or over compared with the total number of suicides in Japan from 1999 to 2005. We also discussed the causative factors of suicide among men and women aged 60 or over in detail. During the period from 1999 to 2005, the proportion of the number of suicides in persons aged 60 or over to the total number of suicides changed from 28.9% to 31.1% among men and from 42.5% to 45.9% among women. The most common causative factor was 'health problems' among both men and women, and the second most common cause was 'economic and life problems' among men. 'Family problems' was one of the major causative factors among both men and women. Therefore, more attention needs to be paid to persons aged 60 or over with regard to these factors in particular. Professionals and organizations involved in suicide prevention must work cooperatively to prevent suicide. PMID- 21595420 TI - The responses of professional groups to the use of Section 136 of the Mental Health Act (1983, as amended by the 2007 Act) in Gloucestershire. AB - BACKGROUND: Section 136 (S136) of the Mental Health Act (1983, as amended by the 2007 Act) empowers the police to detain those suspected of being mentally disordered in a public place and to convey them to a place of safety (POS) for further assessment. Gloucestershire has not had a specialist facility for S136 detentions and individuals were taken to the police cells or occasionally A&E departments for assessment. AIMS: This paper forms one part of three aspects under investigation. Two companion papers by the authors describe the use of S136 using anonymised audit data and the experiences of detainees. The objectives of this paper have been to assess the responses of the different professional groups involved in the process of S136. METHOD: An anonymous postal questionnaire was distributed to eight groups of professionals who were identified as having the potential to be involved in part of the process of a S136 detention. Results were collated and analysed, and formed the basis for a series of follow-up focus groups within groups to explore themes that warranted further investigation. RESULTS: An overall response rate of 59% was achieved. Seventy-four per cent of participants thought that there should be an alternative POS to the police station. A&E was thought to be an unsuitable alternative POS, with a psychiatric hospital being the first choice for 58%. CONCLUSIONS: There is a gap in the expectations of the different agencies involved in the S136 process, which have the potential to be divisive if interagency pathways and agreements are not in place. PMID- 21595421 TI - Pattern of homicide coroner's autopsies at University College Hospital, Ibadan, Nigeria: 1997-2006. AB - There is relatively little information regarding the pattern of homicides in developing countries such as Nigeria. This study is aimed at determining the pattern and demographic factors associated with homicide cases seen in a Nigerian Teaching Hospital. It is a descriptive autopsy study of homicide cases seen at the University College Hospital (UCH), Ibadan over a 10-year period from January 1997 to December 2006. All the coroner's autopsies for the period, of homicides or suspected homicides, were reviewed with emphasis on the following: gender, age, occupation, circumstances surrounding event, likely motive, type of weapon used, site(s) of injury and mechanism of death. Homicides accounted for 153 (3.1%) of the 4928 coroner's cases at the UCH within the study period. One hundred and thirty-seven of the 152 cases were men, and the overall age range was 4-83 years. The mechanism of death was haemorrhagic shock in 91 cases (59.9%); severe raised intracranial pressure in 58 cases (38.2%); septicaemic shock in two cases (1.3%); and asphyxia in one case (0.7%). Gunshot injuries accounted for 64.5% of the fatalities, sharp objects 21.1% and blunt force 14.5%. Most were victims of armed robbery attacks. The head, abdomen, chest and lower limbs were single sites of injuries in descending order of frequency and most of the cases sustained multiple injuries involving two or more of these sites. Gunshot deaths were the commonest form of homicides in the period under review. Young males and victims of armed robbery attacks were most susceptible. PMID- 21595422 TI - Medication misuse and abuse: duties and responsibilities of dispensing pharmacists. AB - Misuse of medications can have major consequences for the consumer or patient's health. In the case of a drug delivered only on medical prescription, the misuse usually results from an error or negligence on the part of the prescribing doctor and/or the pharmacist dispensing the medication. But whereas, under French Law, doctors are regularly prosecuted for their irresponsibility, pharmacists frequently avoid any legal charges. This is even more surprising in view of the fact that French Legislation controls the practice of pharmacy very strictly. The authors discuss four cases that illustrate this issue and present a study of comparative pharmaceutical law requirements. PMID- 21595423 TI - Air embolism: an unusual cause of delayed death following gunshot wound to the chest. AB - A 29-year-old man was shot in the chest twice sustaining extensive contusion of the right lung. He was, however, clinically stable with no major vessel injury or significant blood loss. Unexpected cardiac arrest occurred hours after hospital admission due to left coronary artery air embolism. Lung parenchymal damage from the passage of two projectiles within the chest wall close to the pleural cavity had occurred, with disruption of the capillary-alveolar interface and passage of air into the pulmonary venous circulation. While tangential gunshot wounds to the chest wall may rarely cause air embolism, symptoms are usually immediate. The present case demonstrates, however, that death may occur unexpectedly some time after the initial trauma in an individual who is considered clinically stable. PMID- 21595424 TI - Bloodstain pattern in the form of gushing in a case of fatal exsanguination due to ruptured varicose vein. PMID- 21595425 TI - Catalytic asymmetric vinylogous Mannich-type (AVM) reaction of nonactivated alpha angelica lactone. AB - A direct highly diastereo- and enantioselective asymmetric vinylogous Mannich type (AVM) reaction of aldimines with nonactivated natural alpha-angelica lactone has been successfully developed. It was demonstrated that the nonactivated natural alpha-angelica lactone is a useful vinylogous nucleophile to give the chiral delta-amino gamma,gamma-disubstituted butenolide carbonyl derivatives. The N,N'-dioxide L2-Sc(III) complex is efficient toward the obtention of a range of corresponding products with adjacent quaternary and tertiary stereocenters in excellent dr and ee values. PMID- 21595426 TI - Wall-selective probing of double-walled carbon nanotubes using covalent functionalization. AB - Double-walled carbon nanotubes (DWNTs) present an original coaxial geometry in which the inner wall is naturally protected from the environment by the outer wall. Covalent functionalization is introduced here as an effective approach to investigate DWNT devices. Performed using an aryldiazonium salt, the functionalization is reversible upon thermal annealing and occurs strictly at the surface of the outer wall, leaving the inner wall essentially unaltered by the chemical bonding. Measurements on functionalized DWNT transistors show that the electrical current is carried by the inner wall and provide unambiguous identification of the metallic or semiconducting character of both walls. New insights about current saturation at high bias in DWNTs are also presented as an illustration of new experiments unlocked by the method. The wall-selectivity of the functionalization not only enables selective optical and electrical probing of the DWNTs, but it also paves the way to designing novel electronic devices in which the inner wall is used for electrical transport while the outer wall chemically interacts with the environment. PMID- 21595427 TI - Importance of polar solvation for cross-reactivity of antibody and its variants with steroids. AB - Understanding the factors determining the binding of ligands to receptors in detail is essential for rational drug design. Here, the free energies of binding of the steroids progesterone (PRG) and 5beta-androstane-3,17-dione (5AD) to the Diels-Alderase antibody 1E9, as well as the Leu(H47)Trp/Arg(H100)Trp 1E9 double mutant (1E9dm) and the corresponding single mutants, have been estimated and decomposed using the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method. Also the difference in binding free energies between the PRG-1E9dm complex and the complex of PRG with the antiprogesterone antibody DB3 have been evaluated and decomposed. The steroids bind less strongly to 1E9 than to DB3, but the mutations tend to improve the steroid affinity, in quantitative agreement with experimental data. Although the complexes formed by PRG or 5AD with 1E9dm and by PRG with DB3 have similar affinity, the binding mechanisms are different. Reduced van der Waals interactions as observed for 5AD-1E9dm versus PRG-1E9dm or for PRG-1E9dm versus PRG-DB3 are energetically compensated by an increased solvation of polar groups, partly contrasting previous conclusions based on structural inspection. Our study illustrates that deducing binding mechanisms from structural models alone can be misleading. Therefore, taking into account solvation effects as in MM-PBSA calculations is essential to elucidate molecular recognition. PMID- 21595428 TI - Site selective and single complex laser-based spectroscopies: a window on excited state electronic structure, excitation energy transfer, and electron-phonon coupling of selected photosynthetic complexes. PMID- 21595429 TI - Probing the metal-ion-binding strength of the hydroxyl group. PMID- 21595430 TI - Abiotic reductive dechlorination of cis-dichloroethylene by Fe species formed during iron- or sulfate-reduction. AB - This study investigated reductive dechlorination of cis-dichloroethylene (cis DCE) by the reduced Fe phases obtained from in situ precipitation, which involved mixing of Fe(II), Fe(III), and S(-II) solutions. A range of redox conditions were simulated by varying the ratio of initial Fe(II) concentration ([Fe(II)](o)) to initial Fe(III) concentration ([Fe(III)](o)) for iron-reducing conditions (IRC) and the ratio of [Fe(II)](o) to initial sulfide concentration ([S(-II)](o)) for sulfate-reducing conditions (SRC). Significant dechlorination of cis-DCE occurred under highly reducing IRC and iron-rich SRC, suggesting that Fe (oxyhydr)oxides including green rusts are highly reactive with cis-DCE but that Fe sulfide as mackinawite (FeS) is nonreactive. Relative concentrations of sulfate to chloride were also varied to examine the anion impact on cis-DCE dechlorination. Generally, slower dechlorination occurred in the batches with higher sulfate concentrations. As indicated by higher dissolved Fe concentration, the slower dechlorination in the presence of sulfate was probably due to the decreased surface-complexed Fe(II). This study demonstrates that the chemical form of reduced Fe(II) is critical in determining the fate of cis-DCE under anoxic conditions. PMID- 21595431 TI - Dissipation and sequestration of the veterinary antibiotic sulfadiazine and its metabolites under field conditions. AB - Veterinary antibiotics introduced into the environment may change the composition and functioning of soil microbial communities and promote the spreading of antibiotic resistance. Actual risks depend on the antibiotic's persistence and (bio)accessibility, which may differ between laboratory and field conditions. We examined the dissipation and sequestration of sulfadiazine (SDZ) and its main metabolites in soil under field conditions and how it was influenced by temperature, soil moisture, plant roots, and soil aggregation compared to controlled laboratory experiments. A sequential extraction accounted for easily extractable (CaCl2-extractable) and sequestered (microwave-extractable, residual) SDZ fractions. Dissipation from both fractions was largely temperature-dependent and could be well predicted from laboratory data recorded at different temperatures. Soil moisture additionally seemed to control sequestration, being accelerated in dry soil. Sequestration, as indicated by increasing apparent distribution coefficients and decreasing rates of kinetic release into CaCl2, governed the antibiotic's long-term fate in soil. Besides, we observed spatial gradients of antibiotic concentrations across soil aggregates and in the vicinity of roots. The former were short-lived and equilibrated due to aggregate reorganization, while dissipation of the easily extractable fraction was accelerated near roots throughout the growth period. There was little if any impact of the plants on residual SDZ concentrations. PMID- 21595432 TI - Separating and recovering Pb from copper-rich particles of crushed waste printed circuit boards by evaporation and condensation. AB - Waste printed circuit boards (WPCBs) are treated by crushing and electrostatic separation to obtain the copper-rich particles. However, the copper-rich particles contain a certain content of solder, which may cause Pb contamination if improperly treated. The separation behaviors of Pb from single solder and solder mixed with Cu particles under vacuum are studied in this work. Due to the presence of Cu particles in the copper-rich particles, it becomes much easier to separate Pb from mixed particles than from single solder. On the basis of the experiments, the rules and phenomena different from previous studies are concluded, including the multilayer evaporation effect, the formation of Cu-Sn intermetallic compound and so on. Mechanisms of these phenomena are also explored. Pb is separated and recovered from copper-rich particles of crushed WPCBs at 1123 K for 90 min under 0.1-1 Pa. The metals including Cu, Pb, Sn in WPCBs are all efficiently recovered. This work enriches separating rules for recovering Pb by evaporation and condensation, and also points out an efficient and promising method for recovering toxic heavy metals from WPCBs. PMID- 21595433 TI - Oxygen-dependent auto-oscillations of water luminescence triggered by the 1264 nm radiation. AB - A 5-min exposure of air-saturated bidistilled water to low-intensity laser infrared radiation at the wavelength of the electronic transition of dissolved oxygen to the singlet state ((3)?(g)(-)-> (1)Delta(g)) induces, after a long latent period, auto-oscillations of water luminescence in the blue-green region, which last many hours. Laser irradiation causes the accumulation of hydrogen peroxide, which depends on the concentration of dissolved oxygen. The auto oscillations do not arise if water is irradiated beyond the oxygen absorption band and if the oxygen is removed from water. The wavelet transform analysis of luminescence records indicates that there are two characteristic periods of pulsations of about 300 and 1150 s. The results obtained suggest that auto oscillations are triggered by photoinduced singlet oxygen (1)Delta(g), and this phenomenon is closely related to formation of hydrogen peroxide. PMID- 21595434 TI - Synthesis of Z-alkenyl phosphorus compounds through hydroalumination and carbocupration of alkynyl precursors. AB - The stereocontrolled synthesis of Z-alkenylphosphine-borane complexes is easily accomplished via the hydroalumination or carbocupration of alkynyl precursors. Z/E ratios are generally higher than 95/5. These reactions are stereocomplementary to our olefination approach. PMID- 21595435 TI - Preparation of polyfunctional zinc organometallics using an Fe- or Co-catalyzed Cl/Zn-exchange. AB - A new Fe- or Co-catalyzed Cl/Zn-exchange reaction allows the direct transformation of aryl, heteroaryl, and also alkyl chlorides into the corresponding zinc reagents. The method tolerates functional groups such as a nitrile or an ester. Remarkably, secondary and tertiary alkyl chlorides are suitable substrates for the Cl/Zn exchange. PMID- 21595436 TI - Complex nanoscale cage clusters built from uranyl polyhedra and phosphate tetrahedra. AB - Five cage clusters that self-assemble in alkaline aqueous solution have been isolated and characterized. Each is built from uranyl hexagonal bipyramids with two or three equatorial edges occupied by peroxide, and three also contain phosphate tetrahedra. These clusters contain 30 uranyl polyhedra; 30 uranyl polyhedra and six pyrophosphate groups; 30 uranyl polyhedra, 12 pyrophosphate groups, and one phosphate tetrahedron; 42 uranyl polyhedra; and 40 uranyl polyhedra and three pyrophosphate groups. These clusters present complex topologies as well as a range of compositions, sizes, and charges. Two adopt fullerene topologies, and the others contain combinations of topological squares, pentagons, and hexagons. An analysis of possible topologies further indicates that higher-symmetry topologies are favored. PMID- 21595437 TI - Well-defined DNA-mimic brush polymers bearing adenine moieties: synthesis, layer by-layer self-assembly, and biocompatibility. AB - Two new DNA-mimicking brush polymers were synthesized: poly[oxy(11-(3-(9 adeninyl)propionato)-undecanyl-1-thiomethyl)ethylene] (PECH-AP) and poly[oxy(11 (5-(9-adenylethyloxy)-4-oxopentanoato)undecanyl-1-thiomethyl)ethylene] (PECH-AS). These polymers were found to be thermally stable up to 220 degrees C and could be applied easily by conventional coating processes to produce good quality films. Interestingly, both brush polymers formed molecular multibilayer structures to provide an adenine-rich surface. Despite the structural similarities, PECH-AS surprisingly exhibited higher hydrophilicity and better water sorption properties than PECH-AP. These differences were attributed to the chemical structures in the bristles of the polymers. The adenine-rich surfaces of the polymer films demonstrated selective protein adsorption, suppressed bacterial adherence, facilitated HEp-2 cell adhesion, and exhibited good biocompatibility in mice. However, the high hydrophilicity and good water sorption characteristics of the PECH-AS film suggest that this brush polymer is better suited to applications requiring good biocompatibility and reduced chance of bacterial infection compared with the PECH-AP film. PMID- 21595438 TI - Flavoprotein hydroxylase PgaE catalyzes two consecutive oxygen-dependent tailoring reactions in angucycline biosynthesis. AB - A simplified model system composed of a NADPH-dependent flavoprotein hydroxylase PgaE and a short-chain alcohol dehydrogenase/reductase (SDR) CabV was used to dissect a multistep angucycline modification redox cascade into several subreactions in vitro. We demonstrate that the two enzymes are sufficient for the conversion of angucycline substrate 2,3-dehydro-UWM6 to gaudimycin C. The flavoenzyme PgaE is shown to be responsible for two consecutive NADPH- and O(2) dependent reactions, consistent with the enzyme-catalyzed incorporation of oxygen atoms at C-12 and C-12b in gaudimycin C. The two reactions do not significantly overlap, and the second catalytic cycle is initiated only after the original substrate 2,3-dehydro-UWM6 is nearly depleted. This allowed us to isolate the product of the first reaction at limiting NADPH concentrations and allowed the study of the qualitative and kinetic properties of the separated reactions. Dissection of the reaction cascade also allowed us to establish that the SDR reductase CabV catalyzes the final biosynthetic step, which is closely coupled to the second PgaE reaction. In the absence of CabV, the complete PgaE reaction leads invariably to product degradation, whereas in its presence, the reaction yields the final product, gaudimycin C. The result implies that the C-6 ketoreduction step catalyzed by CabV is required for stabilization of a reactive intermediate. The close relationship between PgaE and CabV would explain previous in vivo observations: why the absence of a reductase gene may result in the lack of C-12b-oxygenated species and, vice versa, why all C-12b-oxygenated angucyclines appear to have undergone reduction at position C-6. PMID- 21595440 TI - Aromatic character of polycyclic pi systems formed by fusion of two or more rings of the same size. AB - The sequential line plot of topological resonance energy (TRE) against the number of pi electrons (N(pi)) for any polycyclic aromatic hydrocarbon (PAH) is very similar with the same number of extrema to that for benzene. Thus, global aromaticity of a PAH molecular ion strongly reflects that of a benzene molecular ion. Likewise, the N(pi) dependence of TRE for any polycyclic pi system formed by fusion of two or more rings of the same size reflects that for a monocyclic species of the same ring size. In general, TREs for such polycyclic pi systems and their molecular ions can be interpreted consistently by reference to those for neutral and charged monocyclic species of the same ring size. PMID- 21595439 TI - Mechanistic studies of reactions of peroxodiiron(III) intermediates in T201 variants of toluene/o-xylene monooxygenase hydroxylase. AB - Site-directed mutagenesis studies of a strictly conserved T201 residue in the active site of toluene/o-xylene monooxygenase hydroxylase (ToMOH) revealed that a single mutation can facilitate kinetic isolation of two distinctive peroxodiiron(III) species, designated T201(peroxo) and ToMOH(peroxo), during dioxygen activation. Previously, we characterized both oxygenated intermediates by UV-vis and Mossbauer spectroscopy, proposed structures from DFT and QM/MM computational studies, and elucidated chemical steps involved in dioxygen activation through the kinetic studies of T201(peroxo) formation. In this study, we investigate the kinetics of T201(peroxo) decay to explore the reaction mechanism of the oxygenated intermediates following O(2) activation. The decay rates of T201(peroxo) were monitored in the absence and presence of external (phenol) or internal (tryptophan residue in an I100W variant) substrates under pre-steady-state conditions. Three possible reaction models for the formation and decay of T201(peroxo) were evaluated, and the results demonstrate that this species is on the pathway of arene oxidation and appears to be in equilibrium with ToMOH(peroxo). PMID- 21595441 TI - IR and UV photodissociation as analytical tools for characterizing lipid A structures. AB - The utility of 193-nm ultraviolet photodissociation (UVPD) and 10.6-MUm infrared multiphoton dissociation (IRMPD) for the characterization of lipid A structures was assessed in an ion trap mass spectrometer. The fragmentation behavior of lipid A species was also evaluated by activated-electron photodetachment (a-EPD), which uses 193-nm photons to create charge reduced radicals that are subsequently dissociated by collisional activation. In contrast to collision-induced dissociation (CID), IRMPD offered the ability to selectively differentiate product ions with varying degrees of phosphorylation because of the increased photoabsorption cross sections and thus dissociation of phosphate-containing species. Both 193-nm UVPD and a-EPD yielded higher abundances and a larger array of product ions arising from C-C cleavages, as well as cross-ring and inter-ring glucosamine cleavages, compared to CID and IRMPD, because of high energy, single photon absorption, and/or radical-directed dissociation. UVPD at 193 nm also exhibited enhanced cleavage between the amine and carbonyl groups on the 2- and 2'-linked primary acyl chains. Lastly, UVPD of phosphorylethanolamine-modified lipid A species resulted in preferential cleavage of the C-O bond between ethanolamine and phosphate, enabling the selective identification of this modification. PMID- 21595442 TI - Analysis of Streptomyces coelicolor phosphopantetheinyl transferase, AcpS, reveals the basis for relaxed substrate specificity. AB - The transfer of the phosphopantetheine chain from coenzyme A (CoA) to the acyl carrier protein (ACP), a key protein in both fatty acid and polyketide synthesis, is catalyzed by ACP synthase (AcpS). Streptomyces coelicolor AcpS is a doubly promiscuous enzyme capable of activation of ACPs from both fatty acid and polyketide synthesis and catalyzes the transfer of modified CoA substrates. Five crystal structures have been determined, including those of ligand-free AcpS, complexes with CoA and acetyl-CoA, and two of the active site mutants, His110Ala and Asp111Ala. All five structures are trimeric and provide further insight into the mechanism of catalysis, revealing the first detailed structure of a group I active site with the essential magnesium in place. Modeling of ACP binding supported by mutational analysis suggests an explanation for the promiscuity in terms of both ACP partner and modified CoA substrates. PMID- 21595443 TI - Computational investigation of the role of counterions and reorganization energy in a switchable bistable [2]rotaxane. AB - Switchable bistable [2]rotaxanes, such as those of the Stoddart-Heath-type, show promise for the development of molecular electronic devices and functional prototypes have been demonstrated. Herein, one such switchable rotaxane system is studied computationally at the AM1-FS1 and DFT levels of theory. The results show that the computationally efficient AM1-FS1 method, (efficient relative to DFT) is capable of reliably predicting properties such as binding site preference and coconformational relative stabilities as well as the barrier to isomerization between the different coconformational states. These properties play important roles in the functionality of rotaxane-based molecular electronic devices. In addition, the role of the counterions is assessed from a computational standpoint. The results reveal that inclusion of counterions is not as significant as has been previously suggested. Finally, the reorganization energy associated with oxidation/reduction of the complex is studied. This provides a possible link to the origin of the observed conductivity difference between the two coconformational states, the property upon which device functionality is based. PMID- 21595444 TI - Encapsulation and enzyme-mediated release of molecular cargo in polysulfide nanoparticles. AB - Poly(propylene sulfide) nanoparticles (<150 nm) have been synthesized by an anionic, ring-opening emulsion polymerization. Upon exposure to parts per million (ppm) levels of oxidizing agent (NaOCl), hydrophobic polysulfide particles are oxidized to hydrophilic polysulfoxides and polysulfones. Utilizing this mechanism, the encapsulation of hydrophobic molecular cargo, including Nile red and Reichardt's dye, within polysulfide nanoparticles has been characterized by a variety of microscopic and spectroscopic methods and its release demonstrated via chemical oxidation. Moreover, release of cargo has been enzymatically driven by oxidoreductase enzymes such as chloroperoxidase and myeloperoxidase in the presence of low concentrations of sodium chloride (200 mM) and hydrogen peroxide (500 MUM). This oxidation-driven mechanism holds promise for controlled encapsulation and release of a variety of hydrophobic cargos. PMID- 21595445 TI - Role of packing defects in the evolution of allostery and induced fit in human UDP-glucose dehydrogenase. AB - Allosteric feedback inhibition is the mechanism by which metabolic end products regulate their own biosynthesis by binding to an upstream enzyme. Despite its importance in controlling metabolism, there are relatively few allosteric mechanisms understood in detail. This is because allostery does not have an identifiable structural motif, making the discovery of new allosteric enzymes a difficult process. The lack of a conserved motif implies that the evolution of each allosteric mechanism is unique. Here we describe an atypical allosteric mechanism in human UDP-alpha-d-glucose 6-dehydrogenase (hUGDH) based on an easily acquired and identifiable structural attribute: packing defects in the protein core. In contrast to classic allostery, the active and allosteric sites in hUGDH are present as a single, bifunctional site. Using two new crystal structures, we show that binding of the feedback inhibitor, UDP-alpha-d-xylose, elicits a distinct induced-fit response; a buried loop translates ~4 A along and rotates ~180 degrees about the main chain axis, requiring surrounding side chains to repack. This allosteric transition is facilitated by packing defects, which negate the steric conformational restraints normally imposed by the protein core. Sedimentation velocity studies show that this repacking favors the formation of an inactive hexameric complex with unusual symmetry. We present evidence that hUGDH and the unrelated enzyme dCTP deaminase have converged to very similar atypical allosteric mechanisms using the same adaptive strategy, the selection for packing defects. Thus, the selection for packing defects is a robust mechanism for the evolution of allostery and induced fit. PMID- 21595446 TI - Temperature dependence of multilayering at the free surface of ionic liquids probed by X-ray reflectivity measurements. AB - The effect of the temperature on the surface layering of ionic liquids has been studied for two ionic liquids, trioctylmethylammonium bis(nonafluorobutanesulfonyl)amide([TOMA(+)][C(4)C(4)N(-)]) and trihexyltetradecylphosphonium bis(nonafluorobutanesulfonyl)amide ([THTDP(+)][C(4)C(4)N(-)]), using X-ray reflectivity measurements at 285, 300, and 315 K. Both [TOMA(+)][C(4)C(4)N(-)] and [THTDP(+)][C(4)C(4)N(-)] develop multilayers at the surface. The structure of the multilayers at the [TOMA(+)][C(4)C(4)N(-)] surface shows little temperature-dependent change, whereas that at the [THTDP(+)][C(4)C(4)N(-)] surface clearly becomes diffused with increasing temperature. The different temperature dependence seems to be related to the difference in the recently reported ultraslow dynamics of the interfacial structure of [TOMA(+)][C(4)C(4)N(-)] and [THTDP(+)][C(4)C(4)N(-)] at the ionic liquid|water interface. PMID- 21595447 TI - Detection of interfacial phenomena with osteoblast-like cell adhesion on hydroxyapatite and oxidized polystyrene by the quartz crystal microbalance with dissipation. AB - The adhesion process of osteoblast-like cells on hydroxyapatite (HAp) and oxidized polystyrene (PSox) was investigated using a quartz crystal microbalance with dissipation (QCM-D), confocal laser scanning microscope (CLSM), and atomic force microscope (AFM) techniques in order to clarify the interfacial phenomena between the surfaces and cells. The interfacial viscoelastic properties (shear viscosity (eta(ad)), elastic shear modulus (MU(ad)), and tan delta) of the preadsorbed protein layer and the interface layer between the surfaces and cells were estimated using a Voigt-based viscoelastic model from the measured frequency (Deltaf) and dissipation shift (DeltaD) curves. In the DeltaD-Deltaf plots, the cell adhesion process on HAp was classified as (1) a mass increase only, (2) increases in both mass and DeltaD, and (3) slight decreases in mass and DeltaD. On PSox, only DeltaD increases were observed, indicating that the adhesion behavior depended on the surface properties. The interfacial MU(ad) value between the material surfaces and cells increased with the number of adherent cells, whereas eta(ad) and tandelta decreased slightly, irrespective of the surface. Thus, the interfacial layer changed the elasticity to viscosity with an increase in the number. The tan delta values on HAp were higher than those on PSox and exceeded 1.0. Furthermore, the pseudopod-like structures of the cells on HAp had periodic stripe patterns stained with a type I collagen antibody, whereas those on PSox had cell-membrane-like structures unstained with type I collagen. These results indicate that the interfacial layers on PSox and HAp exhibit elasticity and viscosity, respectively, indicating that the rearrangements of the extracellular matrix and cytoskeleton changes cause different cell-surface interactions. Therefore, the different cell adhesion process, interfacial viscoelasticity, and morphology depending on the surfaces were successfully monitored in situ and evaluated by the QCM-D technique combined with other techniques. PMID- 21595448 TI - Self-assembly of mixed anionic and nonionic surfactants in aqueous solution. AB - We present the phase diagram and the microstructure of the binary surfactant mixture of AOT and C(12)E(4) in D(2)O as characterized by surface tension and small angle neutron scattering. The micellar region is considerably extended in composition and concentration compared to that observed for the pure surfactant systems, and two types of aggregates are formed. Spherical micelles are present for AOT-rich composition, whereas cylindrical micelles with a mean length between 80 and 300 A are present in the nonionic-rich region. The size of the micelles depends on both concentration and molar ratio of the surfactant mixtures. At higher concentration, a swollen lamellar phase is formed, where electrostatic repulsions dominate over the Helfrich interaction in the mixed bilayers. At intermediate concentrations, a mixed micellar/lamellar phase exists. PMID- 21595449 TI - On the secondary droplets of self-running gallium droplets on GaAs surface. AB - Self-running droplets by thermal evaporation GaAs (001) surface are studied and analyzed using a scanning electron microscope. The sample is prepared under high temperature annealing in an ultrahigh vacuum molecular beam epitaxy system. Particularly, secondary droplets which formed along primary droplet running trails are investigated. The secondary droplets are found to initially move along the [1 10] instead of [110] direction, but these droplets tend to turn into [110] direction as they grow bigger. The scanning electron microscope also captures nanoscale footprints of secondary droplets different from the main droplets. PMID- 21595450 TI - Spatially indirect emission in a luminescent nanocrystal molecule. AB - Recent advances in the synthesis of multicomponent nanocrystals have enabled the design of nanocrystal molecules with unique photophysical behavior and functionality. Here we demonstrate a highly luminescent nanocrystal molecule, the CdSe/CdS core/shell tetrapod, which is designed to have weak vibronic coupling between excited states and thereby violates Kasha's rule via emission from multiple excited levels. Using single particle photoluminescence spectroscopy, we show that in addition to the expected LUMO to HOMO radiative transition, a higher energy transition is allowed via spatially indirect recombination. The oscillator strength of this transition can be experimentally controlled, enabling control over carrier behavior and localization at the nanoscale. PMID- 21595451 TI - Nanoparticle dispersion and aggregation in polymer nanocomposites: insights from molecular dynamics simulation. AB - It is a great challenge to fully understand the microscopic dispersion and aggregation of nanoparticles (NPs) in polymer nanocomposites (PNCs) through experimental techniques. Here, coarse-grained molecular dynamics is adopted to study the dispersion and aggregation mechanisms of spherical NPs in polymer melts. By tuning the polymer-filler interaction in a wide range at both low and high filler loadings, we qualitatively sketch the phase behavior of the PNCs and structural spatial organization of the fillers mediated by the polymers, which emphasize that a homogeneous filler dispersion exists just at the intermediate interfacial interaction, in contrast with traditional viewpoints. The conclusion is in good agreement with the theoretically predicted results from Schweizer et al. Besides, to mimick the experimental coarsening process of NPs in polymer matrixes (ACS Nano 2008, 2, 1305), by grafting polymer chains on the filler surface, we obtain a good filler dispersion with a large interparticle distance. Considering the PNC system without the presence of chemical bonding between the NPs and the grafted polymer chains, the resulting good dispersion state is further used to investigate the effects of the temperature, polymer-filler interaction, and filler size on the filler aggregation process. It is found that the coarsening or aggregation process of the NPs is sensitive to the temperature, and the aggregation extent reaches the minimum in the case of moderate polymer filler interaction, because in this case a good dispersion is obtained. That is to say, once the filler achieves a good dispersion in a polymer matrix, the properties of the PNCs will be improved significantly, because the coarsening process of the NPs will be delayed and the aging of the PNCs will be slowed. PMID- 21595452 TI - Nitrogen-doped graphene for high-performance ultracapacitors and the importance of nitrogen-doped sites at basal planes. AB - Although various carbon nanomaterials including activated carbon, carbon nanotubes, and graphene have been successfully demonstrated for high-performance ultracapacitors, their capacitances need to be improved further for wider and more challenging applications. Herein, using nitrogen-doped graphene produced by a simple plasma process, we developed ultracapacitors whose capacitances (~280 F/g(electrode)) are about 4 times larger than those of pristine graphene based counterparts without sacrificing other essential and useful properties for ultracapacitor operations including excellent cycle life (>200,000), high power capability, and compatibility with flexible substrates. While we were trying to understand the improved capacitance using scanning photoemission microscopy with a capability of probing local nitrogen-carbon bonding configurations within a single sheet of graphene, we observed interesting microscopic features of N configurations: N-doped sites even at basal planes, distinctive distributions of N-configurations between edges and basal planes, and their distinctive evolutions with plasma duration. The local N-configuration mappings during plasma treatment, alongside binding energy calculated by density functional theory, revealed that the origin of the improved capacitance is a certain N-configuration at basal planes. PMID- 21595454 TI - In situ STM evidence for the adsorption geometry of three N-heteroaromatic thiols on Au(111). AB - The electrochemical behavior of three heteroaromatic thiols (MBs) (2 mercaptobenzimidazole (MBI), 2-mercaptobenzothiazole (MBT), and 2 mercaptobenzoxazole (MBO)) on a Au(111) surface has been investigated by electrochemical scanning tunneling microscopy (ECSTM) and cyclic voltammetry (CV) in 0.1 M HClO(4) solution. All three thiols form oriented molecular cluster lines along the reconstruction line direction at 0.55 V. With the electrode potential shifting negatively, the molecules undergo a disordered-ordered structural transition. Molecularly resolved STM images show that all three molecules form striped adlayers in the desorption region on the Au(111) surface. The different heteroatoms in the heteroaromatic rings result in different electrochemical behavior of the MB self-assembled monolayers (SAMs). MBI, MBT, and MBO are proposed to interact with the substrate via the S-Au bonds from thiol group and the coordination interaction of N, S, and O with the substrate from the heteroaromatic ring, respectively. These results provide direct evidence of the electrochemical behavior and the adlayer structures of MB SAMs on the Au electrode. PMID- 21595455 TI - Dielectron attachment and hydrogen evolution reaction in water clusters. AB - Binding of excess electrons to nanosize water droplets, with a focus on the hitherto largely unexplored properties of doubly-charged clusters, were investigated experimentally using mass spectrometry and theoretically with large scale first-principles simulations based on spin-density-functional theory, with all the valence electrons (that is, 8e per water molecule) and excess electrons treated quantum mechanically. Singly-charged clusters (H(2)O)(n)(-1) were detected for n = 6-250, and our calculated vertical detachment energies agree with previously measured values in the entire range 15 <= n <= 105, giving a consistent interpretation in terms of internal, surface and diffuse states of the excess electron. Doubly-charged clusters were measured in the range of 83 <= n <= 123, with (H(2)O)(n)(-2) clusters found for 83 <= n < 105, and mass-shifted peaks corresponding to (H(2)O)(n-2)(OH(-))(2) detected for n >= 105. The simulations revealed surface and internal dielectron, e(-)(2), localization modes and elucidated the mechanism of the reaction (H(2)O)(n)(-2) -> (H(2)O)(n-2) (OH( ))(2) + H(2) (for n >= 105), which was found to occur via concerted approach of a pair of protons belonging to two water molecules located in the first shell of the dielectron internal hydration cavity, culminating in formation of a hydrogen molecule 2H(+) + e(-)(2) -> H(2). Instability of the dielectron internal localization impedes the reaction for smaller (n < 105) doubly-charged clusters. PMID- 21595453 TI - Membrane orientation of MSI-78 measured by sum frequency generation vibrational spectroscopy. AB - Antimicrobial peptides (AMPs) selectively disrupt bacterial cell membranes to kill bacteria whereas they either do not or weakly interact with mammalian cells. The orientations of AMPs in lipid bilayers mimicking bacterial and mammalian cell membranes are related to their antimicrobial activity and selectivity. To understand the role of AMP-lipid interactions in the functional properties of AMPs better, we determined the membrane orientation of an AMP (MSI-78 or pexiganan) in various model membranes using sum frequency generation (SFG) vibrational spectroscopy. A solid-supported single 1,2-dipalmitoyl-an-glycero-3 [phospho-rac-(1-glycerol)] (DPPG) bilayer or 1-palmitoyl-2-oleoyl-sn-glycero-3 [phospho-rac-(1-glycerol)] (POPG) bilayer was used as a model bacterial cell membrane. A supported 1,2-dipalmitoyl-an-glycero-3-phosphocholine (DPPC) bilayer or a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer was used as a model mammalian cell membrane. Our SFG results indicate that the helical MSI-78 molecules are associated with the bilayer surface with ~70 degrees deviation from the bilayer normal in the negatively charged gel-phase DPPG bilayer at 400 nM peptide concentration. However, when the concentration was increased to 600 nM, MSI-78 molecules changed their orientation to make a 25 degrees tilt from the lipid bilayer normal whereas multiple orientations were observed for an even higher peptide concentration in agreement with toroidal-type pore formation as reported in a previous solid-state NMR study. In contrary, no interaction between MSI-78 and a zwitterionic DPPC bilayer was observed even at a much higher peptide concentration (~12,000 nM). These results demonstrate that SFG can provide insights into the antibacterial activity and selectivity of MSI-78. Interestingly, the peptide exhibits a concentration-dependent membrane orientation in the lamellar-phase POPG bilayer and was also found to induce toroidal-type pore formation. The deduced lipid flip-flop from SFG signals observed from lipids also supports MSI-78-induced toroidal-type pore formation. PMID- 21595456 TI - Real-time quantification of microscale bioadhesion events in situ using imaging surface plasmon resonance (iSPR). AB - From macro- to nanoscales, adhesion phenomena are all-pervasive in nature yet remain poorly understood. In recent years, studies of biological adhesion mechanisms, terrestrial and marine, have provided inspiration for "biomimetic" adhesion strategies and important insights for the development of fouling resistant materials. Although the focus of most contemporary bioadhesion research is on large organisms such as marine mussels, insects and geckos, adhesion events on the micro/nanoscale are critical to our understanding of important underlying mechanisms. Observing and quantifying adhesion at this scale is particularly relevant for the development of biomedical implants and in the prevention of marine biofouling. However, such characterization has so far been restricted by insufficient quantities of material for biochemical analysis and the limitations of contemporary imaging techniques. Here, we introduce a recently developed optical method that allows precise determination of adhesive deposition by microscale organisms in situ and in real time; a capability not before demonstrated. In this extended study we used the cypris larvae of barnacles and a combination of conventional and imaging surface plasmon resonance techniques to observe and quantify adhesive deposition onto a range of model surfaces (CH(3)-, COOH-, NH(3)-, and mPEG-terminated SAMs and a PEGMA/HEMA hydrogel). We then correlated this deposition to passive adsorption of a putatively adhesive protein from barnacles. In this way, we were able to rank surfaces in order of effectiveness for preventing barnacle cyprid exploration and demonstrate the importance of observing the natural process of adhesion, rather than predicting surface effects from a model system. As well as contributing fundamentally to the knowledge on the adhesion and adhesives of barnacle larvae, a potential target for future biomimetic glues, this method also provides a versatile technique for laboratory testing of fouling-resistant chemistries. PMID- 21595457 TI - Competition between Li+ and Mg2+ in metalloproteins. Implications for lithium therapy. AB - Lithium is used (in the form of soluble salts) to treat bipolar disorder and has been considered as a possible drug in treating chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. One of the proposed mechanisms of Li(+) action involves a competition between the alien Li(+) and native Mg(2+) for metal-binding sites and subsequent inhibition of key enzymes involved in specific neurotransmission pathways, but not vital Mg(2+) proteins in the cell. This raises the following intriguing questions: Why does Li(+) replace Mg(2+) only in enzymes involved in bipolar disorder, but not in Mg(2+) proteins essential to cells? In general, what factors allow monovalent Li(+) to displace divalent Mg(2+) in proteins? Specifically, how do the composition, overall charge, and solvent exposure of the metal-binding site as well as a metal-bound phosphate affect the selectivity of Li(+) over Mg(2+)? Among the many possible factors, we show that the competition between Mg(2+) and Li(+) depends on the net charge of the metal complex, which is determined by the numbers of metal cations and negatively charged ligands, as well as the relative solvent exposure of the metal cavity. The protein itself is found to select Mg(2+) over the monovalent Li(+) by providing a solvent-inaccessible Mg(2+)-binding site lined by negatively charged Asp/Glu, whereas the cell machinery was found to select Mg(2+) among other competing divalent cations in the cellular fluids such as Ca(2+) and Zn(2+) by maintaining a high concentration ratio of Mg(2+) to its biogenic competitor in various biological compartments. The calculations reveal why Li(+) replaces Mg(2+) only in enzymes that are known targets of Li(+) therapy, but not in Mg(2+) enzymes essential to cells, and also reveal features common to the former that differ from those in the latter proteins. PMID- 21595458 TI - Kinetics and mechanism for the sonophotocatalytic degradation of p-chlorobenzoic acid. AB - The advanced oxidation processes of sonolysis (213 kHz), photocatalysis, and a hybrid combination of both (sonophotocatalysis) have been used in the degradation of a representative aromatic carboxylic acid, p-chlorobenzoic acid (PCBA), in ambient air saturated aqueous solutions. The formation of degradation products were monitored quantitatively and qualitatively using HPLC and MS/MS. A kinetic model was used to account for the degradation of the PCBA in the presence of intermediate degradation products and also their formation and subsequent degradation. Under certain experimental conditions a small (20% enhancement) synergistic effect in the degradation rate was evident in the combined process compared with the sum of the individual processes. PMID- 21595459 TI - Triphenylamine/tetracyanobutadiene-based D-A-D pi-conjugated systems as molecular donors for organic solar cells. AB - Thiophene-based D-A-D pi-conjugated systems containing triphenylamine end groups connected to a 1,1,4,4-tetracyanobuta-1,3-diene acceptor by oligothiophene chains of variable length have been synthesized. These compounds show interesting light harvesting properties and low-lying HOMO levels. Preliminary results on bilayer heterojunction solar cells with C(60) as acceptor show power conversion efficiency higher than 1.0%. PMID- 21595460 TI - Size selective supramolecular cages from aryl-bisimidazolium derivatives and cucurbit[8]uril. AB - A series of bisimidazolium salts were synthesized as novel guests for the macrocyclic host molecule cucurbit[8]uril (CB[8]). These bisimidazolium-CB[8] binary complexes exhibited a unique cage structure with the imidazolium rings acting as lids, leading to a size-dependent binding selectivity by altering the hydrophobic linker between the two imidazolium moieties. This new class of CB[8] complexes was also capable of binding small solvent molecules, including acetone, acetonitrile, diethyl ether, and tetrahydrofuran (THF) in an aqueous environment. PMID- 21595461 TI - Magnetic properties of a manganese(III) Chain with monoatomic bridges: catena MnF(salen). AB - In the solid state, MnF(salen) forms chains wherein fairly linear fluoride bridges between high-spin Mn(III) centers are observed. We interpret the magnetic properties of these chains by use of the classical Fisher model and by use of the high-temperature expansion approach, as well as by exact matrix diagonalization of the spin Hamiltonian, of model rings. In solution, electron paramagnetic resonance shows the chains to be symmetrically cleaved to monomeric MnF(salen). PMID- 21595462 TI - Predicting pore water EPA-34 PAH concentrations and toxicity in pyrogenic impacted sediments using pyrene content. AB - Sediment and freely dissolved pore water concentrations of the U.S. Environmental Protection Agency's list of 34 alkyl and parent PAHs (EPA-34) were measured in 335 sediment samples from 19 different sites impacted by manufactured gas plants, aluminum smelters and other pyrogenic sources. The total EPA-34 freely dissolved pore water concentration, C(pw,EPA-34), expressed as toxic units (TU) is currently considered one of the most accurate measures to assess risk at such sites; however, it is very seldom measured. With this data set, we address how accurately C(pw,EPA-34) can be estimated using limited 16 parent PAH data (EPA 16) commonly available for such sites. An exhaustive statistical analysis of the obtained data validated earlier observations that PAHs with more than 3 rings are present in similar relative abundances and their partitioning behavior typically follows Raoult's law and models developed for coal tar. As a result, sediment and freely dissolved pore water concentrations of pyrene and other 3- and 4-ring PAHs exhibit good log-log correlations (r2 > 0.8) to most individual EPA-34 PAHs and also to C(pw,EPA-34). Correlations improve further by including the ratio of high to low molecular weight PAHs, as 2-ring PAHs exhibit the most variability in terms of their relative abundance. The most practical result of the current work is that log C(pw,EPA-34) estimated by the recommended pyrene-based estimation techniques was similarly well correlated to % survival of the benthic amphipods Hyalella azteca and Leptocheirus plumulosus as directly measured log C(pw,EPA-34) values (n = 211). Incorporation of the presented C(pw,EPA-34) estimation techniques could substantially improve risk assessments and guidelines for sediments impacted by pyrogenic residues, especially when limited data are available, without requiring any extra data or measurement costs. PMID- 21595463 TI - Temperature dependence of 1HN-1HN distances in ubiquitin as studied by exact measurements of NOEs. AB - Although NMR relaxation phenomena provide a great deal of insight into local molecular dynamics, the dynamic picture of biomacromolecules is still largely incomplete, as no method is available to detect motions between atoms that are far apart in the sequence. Our recent investigations (Vogeli et al. J. Am. Chem. Soc. 2009, 131 (47), 17215-17225) indicate that extraction of exact effective distances from NOE rates might allow the determination of such motions. Using this approach, we measured exact effective distances between amide protons in (15)N,(13)C,(2)H-labeled ubiquitin at three temperatures (284, 307, and 326 K). Comparisons among the three data sets reveal that, whereas the correlation-time corrected cross-relaxation rates increase by 18% from 284 to 307 K, those at 326 K increase by 32% as compared to those at 284 K. Because theoretical considerations indicate that the NOE is largely insensitive to fast motion, as long as the local order parameter (e.g., S(NH)(2)) is larger than 0.5, the effective distance can be calculated from the NOE using its [linear span]r( 6)[linear span] dependency. Doing so, the average NOE increases translate into effective distance changes of 2.4% and 4.0% in the temperature ranges measured. The data presented demonstrate that the determination of quantitative NOEs is a powerful tool for extracting small structural and dynamical changes in a biomolecule. PMID- 21595464 TI - Structure of the [M + H - H2O]+ ion from tetraglycine: a revisit by means of density functional theory and isotope labeling. AB - Collision-induced dissociations of protonated (18)O-labeled tetraglycines labeled separately at either the first or the second amide bond established that water loss from the backbone occurs from the N-terminal residue. Density functional theory at B3LYP/6-311++G(d,p) predicted that the low-energy [G(4) + H - H(2)O](+) product ion is an N(1)-protonated 3,5-dihydro-4H-imidazol-4-one. The ion at the lowest energy, III, is 24.8 kcal mol(-1) lower than the protonated oxazole structure, II, proposed by Bythell et al. (J. Phys. Chem A2010, 114, 5076-5082). In addition, structure III has a predicted IR spectrum that provides a better match with the published experimental IRMPD spectrum than that of structure II. PMID- 21595465 TI - Electron spin multiplicities of transition-metal aromatic radicals and ions: M[C6(CH3)6] and M(+)[(C6(CH3)6] (M = Ti, V, and Co). AB - Determination of electron spin multiplicities of transition-metal radicals and ions challenges both experimentalists and theoreticians. In this work, we report preferred electron spin states of M[C(6)(CH(3))(6)] and M(+)(C(6)(CH(3))(6)], where M = Ti, V, and Co. The neutral radicals were formed in a supersonic metal cluster beam source, and their masses were measured with time-of-flight mass spectrometry. Precise ionization energies of the radicals and metal-ligand stretching frequencies of the ions were measured by pulsed field ionization zero electron kinetic energy spectroscopy. C-H stretching frequencies of the methyl group in the radicals were obtained by infrared-ultraviolet two-photon ionization. Electron spin multiplicities of the radicals and ions were investigated by combining the spectroscopic measurements, density functional theory, and Franck-Condon factor calculations. The preferred spin states are quintet, sextet, and quartet for the neutral Ti, V, and Co radicals, respectively; for the corresponding singly charged cations, they are quartet, quintet, and triplet. In these high-spin states, the aromatic ring remains nearly planar. This finding contrasts to the previous study of Sc(hmbz), for which low spin states are favored, and the aromatic ring is severely bent. PMID- 21595466 TI - pH-Operated mechanized porous silicon nanoparticles. AB - Porous silicon nanoparticles (PSiNPs) were synthesized by silver-assisted electroless chemical etching of silicon nanowires generated on a silicon wafer. The rod-shaped particles (200-400 nm long and 100-200 nm in diameter) were derivatized with a cyclodextrin-based nanovalve that was closed at the physiological pH of 7.4 but open at pH <6. Release profiles in water and tissue culture media showed that no cargo leaked when the valves were closed and that release occurred immediately after acidification. In vitro studies using human pancreatic carcinoma PANC-1 cells proved that these PSiNPs were endocytosed and carried cargo molecules into the cells and released them in response to lysosomal acidity. These studies show that PSiNPs can serve as an autonomously functioning delivery platform in biological systems and open new possibilities for drug delivery. PMID- 21595467 TI - Regioselective synthesis of 1,2- vs 1,3-squaraines. AB - Squaraines have been known for many decades as very stable and versatile vis-NIR absorbing dyes. They have found applications for example as sensitizers in organic photovoltaics and photodetectors. The most common squaraine structure is the 1,3-regioisomer. Their 1,2-regioisomers are seldom mentioned and unanimously regarded as side products. A facile direct synthesis of 1,2-squaraines, highlighting the role played by reaction conditions and electronic factors, is described. The first electrochemical characterization of these dyes is also shown. PMID- 21595468 TI - Size-dependent reactivity in hydrosilylation of silicon nanocrystals. AB - We present an investigation into the influence of nanocrystal size on the reactivity of silicon nanocrystals (Si-NCs) in near-UV photochemical hydrosilylation. The size-dependent reactivity of Si-NCs with photoluminescence (PL) in the visible and near-infrared regions was evaluated using PL and Fourier transform infrared (FTIR) spectroscopy, and small-angle X-ray scattering (SAXS). Under near-UV excitation, Si-NCs with PL in the visible spectral region react faster than Si-NCs with near-IR PL, allowing partial separation of a mixture of Si-NC sizes through hydrosilylation. This is attributed to quantum size effects in the exciton-mediated mechanisms proposed for this reaction. PMID- 21595469 TI - Phase selection and site-selective distribution by tin and sulfur in supertetrahedral zinc gallium selenides. AB - Doping is among the most important methods to tune the properties of semiconductors. For dense phase semiconductors, the distribution of dopant atoms in crystal lattices is often random. However, when the size of semiconductors becomes increasingly smaller and reaches the extreme situation as is the case in chalcogenide supertetrahedral clusters, different chemically distinct sites (e.g., corner, edge, face, and core) occur, which can dramatically affect the doping chemistry at different sites and also spatial assembly of such clusters into covalent superlattices. In this work, we use the Zn-Ga-Se supertetrahedral clusters and their frameworks as the model system to examine the doping chemistry of Sn(4+) and S(2-) in the Zn-Ga-Se clusters. A series of selenide clusters (undoped supertetrahedral T4-ZnGaSe, S-doped T4-ZnGaSeS, Sn-doped T4-ZnGaSnSe, and dual S- and Sn-doped T4-ZnGaSnSeS) have been prepared with various levels of Sn- and S-doping and with different superlattice structures (OCF-1, -5, -40, and 42). The complex compositional and structural features of these materials are dictated by the convoluted interplay of three key factors: (1) the overall charge density and size/shape matching between clusters/frameworks and protonated guest amines determine the framework topology and the doping levels of Sn(4+) and S(2 ); (2) the site selectivity of Sn(4+) is dictated by the local charge balance surrounding anionic Se/S sites as required by the electrostatic valence sum rule; and (3) the site selectivity and doping levels of sulfur is dictated by the location and amount of Sn based on hard soft acid base (HSAB) principle. The cooperative effect of amine-templating and doping by Sn and/or S leads to a rich chemical system with tunable framework compositions, topologies, and electronic properties. PMID- 21595470 TI - Temperature dependence of charge separation and recombination in porphyrin oligomer-fullerene donor-acceptor systems. AB - Electron-transfer reactions are fundamental to many practical devices, but because of their complexity, it is often very difficult to interpret measurements done on the complete device. Therefore, studies of model systems are crucial. Here the rates of charge separation and recombination in donor-acceptor systems consisting of a series of butadiyne-linked porphyrin oligomers (n = 1-4, 6) appended to C(60) were investigated. At room temperature, excitation of the porphyrin oligomer led to fast (5-25 ps) electron transfer to C(60) followed by slower (200-650 ps) recombination. The temperature dependence of the charge separation reaction revealed a complex process for the longer oligomers, in which a combination of (i) direct charge separation and (ii) migration of excitation energy along the oligomer followed by charge separation explained the observed fluorescence decay kinetics. The energy migration is controlled by the temperature-dependent conformational dynamics of the longer oligomers and thereby limits the quantum yield for charge separation. Charge recombination was also studied as a function of temperature through measurements of femtosecond transient absorption. The temperature dependence of the electron-transfer reactions could be successfully modeled using the Marcus equation through optimization of the electronic coupling (V) and the reorganization energy (lambda). For the charge-separation rate, all of the donor-acceptor systems could be successfully described by a common electronic coupling, supporting a model in which energy migration is followed by charge separation. In this respect, the C(60)-appended porphyrin oligomers are suitable model systems for practical charge-separation devices such as bulk-heterojunction solar cells, where conformational disorder strongly influences the electron-transfer reactions and performance of the device. PMID- 21595471 TI - Watershed sulfur biogeochemistry: shift from atmospheric deposition dominance to climatic regulation. AB - North American atmospheric S emissions peaked in the early 1970s followed by a dramatic decrease that resulted in marked declines in sulfate (SO42-)) concentrations in precipitation and many surface waters. These changes in S biogeochemistry have important implications with respect to the mobilization of toxic (Al(n+), H+) and nutrient (Ca2+, Mg2+, K+) cations and the acidification of watersheds. We used the continuous long-term record for watersheds 1, 3, 5, and 6 (37-44 years from 1965 through 2008) of SO42- concentrations and fluxes at Hubbard Brook Experimental Forest in New Hampshire (U.S.) for evaluating S budgets. Analysis revealed that the annual discrepancies in the watershed S budgets (SO42- flux in drainage waters minus total atmospheric S deposition) have become significantly (p < 0.001) more negative, indicating the increasing importance of the release of S from internal sources with time. Watershed wetness, as a function of log10 annual water flux, was highly significant (p < 0.001) and explained 57% (n = 157) of the annual variation for the combined results from watersheds 1, 3, 5, and 6. The biogeochemical control of annual SO42 export in streamwater of forested watersheds has shifted from atmospheric S deposition to climatic factors by affecting soil moisture. PMID- 21595472 TI - Stoichiometric photoisomerization of mononuclear ruthenium(II) monoaquo complexes controlling redox properties and water oxidation catalysis. AB - Although various reactions involved in photoexcited states of polypyridyl ruthenium(II) complexes have been extensively studied, photoisomerization of the complexes is very rare. We report the first illustration of stoichiometric photoisomerization of trans-[Ru(tpy)(pynp)OH(2)](2+) (1a) [tpy = 2,2':6',2'' terpyridine; pynp = 2-(2-pyridyl)-1,8-naphthyridine] to cis [Ru(tpy)(pynp)OH(2)](2+) (1a') and the isolation of 1a and 1a' for X-ray crystallographic analysis. Polypyridyl ruthenium(II) aquo complexes are attracting much attention related to proton-coupled electron transfer and water oxidation catalysis. We demonstrate that the photoisomerization significantly controls the redox reactions and water oxidation catalyses involving the ruthenium(II) aquo complexes 1a and 1a'. PMID- 21595473 TI - Field validation of anaerobic degradation pathways for dichlorodiphenyltrichloroethane (DDT) and 13 metabolites in marine sediment cores from China. AB - Although the production and use of dichlorodiphenyltrichloroethane (DDT), a legacy component of persistent organic pollutants, have been highly restricted worldwide, the environmental fate of DDT has remained a great concern as it is not only ubiquitous and bioaccumulative but can also be degraded to a series of metabolites that may be more hazardous ecologically. The present study, taking advantage of the abundant levels of DDT and its metabolites in a subtropical coastal region of China, investigated into the degradation pathways of DDT in natural coastal sediment. Sediment profiles indicated that degradation of 1,1,1 trichloro-2,2-bis-(p-chlorophenyl)ethane (p,p'-DDT) to 1,1-dichloro-2,2-bis-(p chlorophenyl)ethane (p,p'-DDD) mainly occurred in sediment of the top 20 cm layer. 1,1-dichloro-2,2-bis-(p-chlorophenyl)ethylene (p,p'-DDE), aerobically transformed from p,p'-DDT prior to sedimentation, was likely to degrade to 1 chloro-2,2-bis-(p-chlorophenyl)ethylene (p,p'-DDMU) which was further converted to 2,2-bis(p-chlorophenyl)ethylene (p,p'-DDNU). In addition, p,p'-DDNU could be transformed to 2,2-bis(p-chlorophenyl)ethane (p,p'-DDNS) and other high-order metabolites. On the other hand, the conversions of p,p'-DDD to p,p'-DDMU and 1 chloro-2,2-bis-(p-chlorophenyl)ethane (p,p'-DDMS) to p,p'-DDNU were deemed slow in anaerobic sediment. Therefore, the present study confirmed all the degradation pathways involving reductive dechlorination and p,p'-DDE being a more important precursor for p,p'-DDMU than p,p'-DDD in anaerobic sediment, as proposed previously. On the other hand, the present study suggested that p,p'-DDMU instead of p,p'-DDMS was more likely the precursor for formation of high-order metabolites. Based on the current assessments, use of (DDD+DDE)/DDTs to indicate whether there is fresh DDT input may lead to large uncertainties if the concentrations of high-order metabolites are not negligible. Similarly, ecological risk assessment associated with DDT should be conducted with consideration of high-order DDT metabolites. PMID- 21595474 TI - All-optical high-resolution nanopatterning and 3D suspending of graphene. AB - We introduce a laser-based technique capable of both imaging and patterning graphene with high spatial resolution. Both tasks are performed in situ using the same confocal microscope. Imaging graphene is based on the recombination of a laser-created electron-hole plasma yielding to a broadband up- and down-converted fluorescence. Patterning is due to burning graphene by local heating causing oxidation and conversion into CO(2). By shaping the laser beam profile using 1D phase-shifting plates and 2D vortex plates we can produce graphene dots below 100 nm in diameter and graphene nanoribbons down to 20 nm in width. Additionally, we demonstrate that this technique can also be applied to freely suspended graphene resulting in freely suspended graphene nanoribbons. We further present a way of freely hanging graphene vertically and imaging it in 3D. Taking advantage of having vertically hanging graphene for the first time, we measure the out-of plane anisotropy of the upconversion fluorescence. PMID- 21595475 TI - Stereoselective Pd-catalyzed synthesis of quaternary alpha-D-C-mannosyl-(S)-amino acids. AB - In this paper, we report the stereoselective synthesis of alpha-D-C-mannosyl-(S) amino acids exploiting, as a key step, an allylic alkylation of glycal-derived pi allyl Pd(II) intermediates, prepared by oxidative addition of Pd(0) species to 2,3-unsaturated pyranosides (pseudoglycals). The reaction of 4,6-di-O-acetyl alpha-pseudoglucal carbonate 10a with racemic alanine-, valine-, and phenylalanine-derived azlactones gave the corresponding (4S)-4-alpha-D-C-mannosyl 2-phenyloxazol-5(4H)-ones as the major diastereoisomers in high yields. The final alpha-D-C-mannosyl-(S)-amino acids were obtained in a few steps comprising highly diastereoselective dihydroxylation of the glucal derivative double bond followed by the one-pot hydrolysis of the benzamido and acetate protecting groups. Main features of this method are the conciseness of the synthetic sequence, the high diastereoselection of the allylic alkylation step, the use of racemic alpha-amino acids as starting material, and the good overall yields. PMID- 21595476 TI - Redox-switchable surface for controlling peptide structure. AB - A general surface chemistry strategy is described for the development of a new switchable material. The method modulates a surface-immobilized-molecules structure by using two orthogonal "click" reactions based on Huisgen cycloaddition and oxime chemistry, where the oxime linkage is redox active and switchable. We demonstrate this strategy by developing a noninvasive, biocompatible, in situ surface chemistry that is able to modulate the affinity of a cell-adhesive peptide to cell integrin receptors to study dynamic cell adhesion and cell migration in real time and as a new hide-and-reveal strategy for application in new types of smart biofouling biomaterials. PMID- 21595478 TI - Moving protons with pendant amines: proton mobility in a nickel catalyst for oxidation of hydrogen. AB - Proton transport is ubiquitous in chemical and biological processes, including the reduction of dioxygen to water, the reduction of CO(2) to formate, and the production/oxidation of hydrogen. In this work we describe intramolecular proton transfer between Ni and positioned pendant amines for the hydrogen oxidation electrocatalyst [Ni(P(Cy)(2)N(Bn)(2)H)(2)](2+) (P(Cy)(2)N(Bn)(2) = 1,5-dibenzyl 3,7-dicyclohexyl-1,5-diaza-3,7-diphosphacyclooctane). Rate constants are determined by variable-temperature one-dimensional NMR techniques and two dimensional EXSY experiments. Computational studies provide insight into the details of the proton movement and energetics of these complexes. Intramolecular proton exchange processes are observed for two of the three experimentally observable isomers of the doubly protonated Ni(0) complex, [Ni(P(Cy)(2)N(Bn)(2)H)(2)](2+), which have N-H bonds but no Ni-H bonds. For these two isomers, with pendant amines positioned endo to the Ni, the rate constants for proton exchange range from 10(4) to 10(5) s(-1) at 25 degrees C, depending on isomer and solvent. No exchange is observed for protons on pendant amines positioned exo to the Ni. Analysis of the exchange as a function of temperature provides a barrier for proton exchange of DeltaG(?) = 11-12 kcal/mol for both isomers, with little dependence on solvent. Density functional theory calculations and molecular dynamics simulations support the experimental observations, suggesting metal-mediated intramolecular proton transfers between nitrogen atoms, with chair-to-boat isomerizations as the rate-limiting steps. Because of the fast rate of proton movement, this catalyst may be considered a metal center surrounded by a cloud of exchanging protons. The high intramolecular proton mobility provides information directly pertinent to the ability of pendant amines to accelerate proton transfers during catalysis of hydrogen oxidation. These results may also have broader implications for proton movement in homogeneous catalysts and enzymes in general, with specific implications for the proton channel in the Ni-Fe hydrogenase enzyme. PMID- 21595477 TI - Etoposide quinone is a redox-dependent topoisomerase II poison. AB - Etoposide is a topoisomerase II poison that is used to treat a variety of human cancers. Unfortunately, 2-3% of patients treated with etoposide develop treatment related leukemias characterized by 11q23 chromosomal rearrangements. The molecular basis for etoposide-induced leukemogenesis is not understood but is associated with enzyme-mediated DNA cleavage. Etoposide is metabolized by CYP3A4 to etoposide catechol, which can be further oxidized to etoposide quinone. A CYP3A4 variant is associated with a lower risk of etoposide-related leukemias, suggesting that etoposide metabolites may be involved in leukemogenesis. Although etoposide acts at the enzyme-DNA interface, several quinones poison topoisomerase II via redox-dependent protein adduction. The effects of etoposide quinone on topoisomerase IIalpha-mediated DNA cleavage have been examined previously. Although findings suggest that the activity of the quinone is slightly greater than that of etoposide, these studies were carried out in the presence of significant levels of reducing agents (which should reduce etoposide quinone to the catechol). Therefore, we examined the ability of etoposide quinone to poison human topoisomerase IIalpha in the absence of reducing agents. Under these conditions, etoposide quinone was ~5-fold more active than etoposide at inducing enzyme-mediated DNA cleavage. Consistent with other redox-dependent poisons, etoposide quinone inactivated topoisomerase IIalpha when incubated with the protein prior to DNA and lost activity in the presence of dithiothreitol. Unlike etoposide, the quinone metabolite did not require ATP for maximal activity and induced a high ratio of double-stranded DNA breaks. Our results support the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis. PMID- 21595479 TI - Cleavage of carbene-stabilized disilicon. AB - Reaction of carbene-stabilized disilicon L:Si?Si:L (L: = :C{N(2,6 Pr(i)(2)C(6)H(3))CH}(2), 1) with BH(3).THF results in facile cleavage of the silicon-silicon double bond and the formation of two quite different "push-pull" stabilized products with borane- and carbene-coordinated silylene moieties: 2, containing a parent silylene (:SiH(2)); and 3, containing a unique three-membered cyclosilylene. PMID- 21595482 TI - Electrostatic induction of lipid asymmetry. AB - The asymmetric arrangement of phospholipids between the two leaflets of the plasma membrane of eukaryotic cells is an integral part of cellular function. ATP dependent translocases capable of selective lipid transport across the membrane are believed to play a role in this lipid asymmetry, but our understanding of this process is incomplete. Here we show the first direct and quantitative experiments demonstrating the induction of phosphatidylserine asymmetry in a membrane by electrostatic association of poly-l-lysine in an attempt to elucidate the complex factors which govern the establishment and maintenance of lipid compositional asymmetry in the plasma membrane on a fundamental level. The attractive electrostatic interactions between the charged surface-associated polylysine and phosphatidylserine are sufficient to both induce and maintain an asymmetric arrangement of phosphatidylserine in a planar supported membrane, as measured by sum-frequency vibrational spectroscopy. These studies provide a glimpse of the physical and chemical underpinnings of lipid asymmetry in the eukaryotic plasma membrane. PMID- 21595480 TI - Steering carbon nanotubes to scavenger receptor recognition by nanotube surface chemistry modification partially alleviates NFkappaB activation and reduces its immunotoxicity. AB - Carbon nanotubes (CNTs) cause perturbations in immune systems and limit the application of CNTs in biomedicine. Here we demonstrate that a surface chemistry modification on multiwalled CNTs (MWCNTs) reduces their immune perturbations in mice and in macrophages. The modified MWCNTs change their preferred binding pattern from mannose receptor to scavenger receptor. This switch significantly alleviates NFkappaB activation and reduces immunotoxicity of MWCNTs. PMID- 21595483 TI - Electron mobility and injection dynamics in mesoporous ZnO, SnO2, and TiO2 films used in dye-sensitized solar cells. AB - High-performance dye-sensitized solar cells are usually fabricated using nanostructured TiO(2) as a thin-film electron-collecting material. However, alternative metal-oxides are currently being explored that may offer advantages through ease of processing, higher electron mobility, or interface band energetics. We present here a comparative study of electron mobility and injection dynamics in thin films of TiO(2), ZnO, and SnO(2) nanoparticles sensitized with Z907 ruthenium dye. Using time-resolved terahertz photoconductivity measurements, we show that, for ZnO and SnO(2) nanoporous films, electron injection from the sensitizer has substantial slow components lasting over tens to hundreds of picoseconds, while for TiO(2), the process is predominantly concluded within a few picoseconds. These results correlate well with the overall electron injection efficiencies we determine from photovoltaic cells fabricated from identical nanoporous films, suggesting that such slow components limit the overall photocurrent generated by the solar cell. We conclude that these injection dynamics are not substantially influenced by bulk energy level offsets but rather by the local environment of the dye-nanoparticle interface that is governed by dye binding modes and densities of states available for injection, both of which may vary from site to site. In addition, we have extracted the electron mobility in the three nanoporous metal-oxide films at early time after excitation from terahertz conductivity measurements and compared these with the time-averaged, long-range mobility determined for devices based on identical films. Comparison with established values for single-crystal Hall mobilities of the three materials shows that, while electron mobility values for nanoporous TiO(2) films are approaching theoretical maximum values, both early time, short distance and interparticle electron mobility in nanoporous ZnO or SnO(2) films offer considerable scope for improvement. PMID- 21595481 TI - The effects of redox-inactive metal ions on the activation of dioxygen: isolation and characterization of a heterobimetallic complex containing a Mn(III)-(MU-OH) Ca(II) core. AB - Rate enhancements for the reduction of dioxygen by a Mn(II) complex were observed in the presence of redox-inactive group 2 metal ions. The rate changes were correlated with an increase in the Lewis acidity of the group 2 metal ions. These studies led to the isolation of heterobimetallic complexes containing Mn(III)-(MU OH)-M(II) cores (M(II) = Ca(II), Ba(II)) in which the hydroxo oxygen atom is derived from O(2). This type of core structure has relevance to the oxygen evolving complex within photosystem II. PMID- 21595484 TI - Diffusion-controlled protein adsorption in mesoporous silica. AB - In this work, the pore size-dependent PPL diffusion and protein distribution in SBA-15 support have been investigated in detail by confocal laser scanning microscopy (CLSM) and X-ray diffraction (XRD) observations in combination with hindered diffusion simulation, intraparticle diffusion analysis, and apparent kinetics calculation. The CLSM observations indicate porcine pancreatic lipase (PPL) diffuses partly into the pores with a diameter of 5.6 nm and much deeper into the pores with a diameter of 8.0 or 9.7 nm. PPL distribution along the pore length has been simulated by hindered diffusion model and the result coincides well with CLSM observations. Besides pore diffusion, boundary resistance is revealed by the intraparticle diffusion analysis of adsorption data. The populations of PPL adsorbed inside the pores or on the external surface are estimated. A higher PPL uptake is found in the 8.0 nm than 9.7 nm pores, indicative of the existence of an optimal pore size to match the protein dimension for maximum adsorption capacity. The so-called "confinement" of PPL in the mesoporous supports, revealed by the XRD observation and intraparticle diffusion analysis above, is further confirmed by apparent kinetics calculation. PMID- 21595485 TI - Confined growth of poly(butylene succinate) in its miscible blends with poly(vinylidene fluoride): morphology and growth kinetics. AB - The morphology and confined crystallization behavior of poly(butylene succinate) (PBS) in miscible poly(vinylidene fluoride) (PVDF)/PBS blends has been studied using differential scanning calorimetry (DSC) and optical and atomic force microscopy (OM and AFM). It was found that PBS crystal lamellae nucleated and grew confined inside the matrix of PVDF spherulites. Crystallized PBS domains grow with an ellipsoidal outline within PVDF spherulites formed at a relatively high PVDF crystallization temperature (T(c,PVDF)), while circular domains, engulfing several PVDF spherulites, are seen when growing in the PVDF spherulites created at lower T(c,PVDF). The growth kinetics of PBS confined in the PVDF matrix was investigated under various conditions. The growth rate of PBS (G(PBS)) increases with decreasing crystallization temperature and increasing PBS content under a given PVDF crystallization temperature (T(c,VDF)). For T(c,PVDF) above 145 degrees C, G(PBS) decreases with T(c,PVDF) for both 50:50 and 30:70 PVDF/PBS blends. However, for T(c,PVDF) below 145 degrees C, 50:50 and 30:70 PVDF/PBS blends exhibit the opposite G(PBS) trend; that is, G(PBS) for the 50:50 blend decreases with decreasing T(c,PVDF), while for the 30:70 PVDF/PBS blend G(PBS) increases with decreasing T(c,PVDF). It is shown that this behavior cannot be associated with the effect of crossing the boundary of smaller PVDF spherulites formed at a lower temperature. Rather, the behavior appears to be related to the interleaving growth of PBS lamellae among PVDF lamellae or between bundles of PVDF lamellae (fibrils), as in situ AFM observation shows. It is found that the interconnectedness of the molten pockets within the PVDF spherulites, which depends on the PVDF crystallization temperature, is an important factor determining the growth kinetics of PBS confined within the PVDF scaffold. PMID- 21595487 TI - Activation energy distributions predicted by dispersive kinetic models for nucleation and denucleation: anomalous diffusion resulting from quantization. AB - The activation energy distributions underpinning the two complementary dispersive kinetic models described by the author in a recent work (Skrdla, P. J. J. Phys. Chem. A 2009, 113, 9329) are derived and investigated. In the case of nucleation rate-limited conversions, which exhibit "acceleratory" sigmoidal transients (a kind of S-shaped stretched exponential conversion profile), an activation energy distribution visually similar to the Maxwell-Boltzmann (M-B) distribution is recovered, consistent with the original derivation of that model. In the case of predominantly "deceleratory" conversions, the activation energy distribution is skewed from normal in the opposite direction. While the "M-B-like" activation energy distribution supports the empirical observation of a rate enhancement as a function of the conversion time in nucleation rate-limited processes, the complementary distribution, with its pronounced low-energy tail, reflects a slow down in the specific rate as the conversion progresses, consistent with experimentally observed denucleation rate-limited conversions. Activation energy distributions were also plotted for real-world data (Qu, H.; Louhi-Kultanen, M.; Kallas, J. Cryst. Growth Des. 2007, 7, 724), depicting the impact of various additives on the nucleation rate-limited kinetics of the solvent-mediated phase transformation of the crystalline drug carbamazepine. Last, by coupling the author's dispersive kinetic description of the time-dependent activation energy for nucleation to the classical description of the critical nucleus energy provided by the Kelvin equation, an accelerated hopping mechanism for the diffusion of monomers to the growing embryo surface was observed. That hopping mechanism was rationalized by modifying the Einstein-Smoluchowski (E-S) equation to allow it to describe the "supra-brownian" molecular motion thought to lie at the heart of nucleation kinetics. PMID- 21595486 TI - Reconstitution of functional mycobacterial arabinosyltransferase AftC proteoliposome and assessment of decaprenylphosphorylarabinose analogues as arabinofuranosyl donors. AB - Arabinosyltransferases are a family of membrane-bound glycosyltransferases involved in the biosynthesis of the arabinan segment of two key glycoconjugates, arabinogalactan and lipoarabinomannan, in the mycobacterial cell wall. All arabinosyltransferases identified have been found to be essential for the growth of Mycobcterium tuberculosis and are potential targets for developing new antituberculosis drugs. Technical bottlenecks in designing enzyme assays for screening for inhibitors of these enzymes are (1) the enzymes are membrane proteins and refractory to isolation; and (2) the sole arabinose donor, decaprenylphosphoryl-d-arabinofuranose is sparingly produced and difficult to isolate, and commercial substrates are not available. In this study, we have synthesized several analogues of decaprenylphosphoryl-d-arabinofuranose by varying the chain length and investigated their arabinofuranose (Araf) donating capacity. In parallel, an essential arabinosyltransferase (AftC), an enzyme that introduces alpha-(1->3) branch points in the internal arabinan domain in both arabinogalactan and lipoarabinomannan synthesis, has been expressed, solubilized, and purified for the first time. More importantly, it has been shown that the AftC is active only when reconstituted in a proteoliposome using mycobacterial phospholipids and has a preference for diacylated phosphatidylinositoldimannoside (Ac(2)PIM(2)), a major cell wall associated glycolipid. alpha-(1->3) branched arabinans were generated when AftC-liposome complex was used in assays with the (Z,Z)-farnesylphosphoryl d-arabinose and linear alpha-d-Araf-(1->5)(3-5) oligosaccharide acceptors and not with the acceptor that had a alpha-(1->3) branch point preintroduced. PMID- 21595488 TI - Honoring Stuart Schreiber. PMID- 21595492 TI - Biophysics at the cutting edge: a report from the 55th Annual Meeting of the Biophysical Society. PMID- 21595493 TI - Synthesis and antityrosinase activities of alkyl 3,4-dihydroxybenzoates. AB - In insects, tyrosinase plays important roles in normal developmental processes, such as cuticular tanning, scleration, wound healing, production of opsonins, encapsulation and nodule formation for defense against foreign pathogens. Thus, tyrosinase may be regarded as a potential candidate for novel bioinsecticide development. A family of alkyl 3,4-dihydroxybenzoates (C6-C9), new tyrosinsase inhibitors, were synthesized. Their inhibitory effects on the activity of tyrosinase have been investigated. The results showed all of them could inhibit the activity of tyrosianse effectively. The order of potency was nonyl 3,4 dihydroxybenzoate (C9DB) > octyl 3,4-dihydroxybenzoate(C8DB) > heptyl 3,4 dihydroxybenzoate(C7DB) > hexyl 3,4-dihydroxybenzoate (C6DB). The kinetic analysis of these four compounds on tyrosinase was taken to expound their inhibitory mechanism. The research of the control of insects in agriculture was taken as C6DB for example. C6DB could inhibit the development and molting of Plutella xylostella effectively. To clarify its insecticidal mechanism, we researched the expression of tyrosinase in the P. xylostella treated with C6DB by real-time quantitative PCR. The results showed C6DB could inhibit the expression of tyrosinase in the P. xylostella as expected. PMID- 21595494 TI - Antifungal properties of wheat histones (H1-H4) and purified wheat histone H1. AB - Wheat ( Triticum spp.) histones H1, H2, H3, and H4 were extracted, and H1 was further purified. The effect of these histones on specific fungi that may or may not be pathogenic to wheat was determined. These fungi included Aspergillus flavus , Aspergillus fumigatus , Aspergillus niger , Fusarium oxysporum , Fusarium verticillioides , Fusarium solani , Fusarium graminearum , Penicillium digitatum , Penicillium italicum , and Greeneria uvicola . Non-germinated and germinating conidia of these fungi were bioassayed separately. The non-germinated and germinating conidia of all Fusarium species were highly susceptible to the mixture (H1-H4) as well as pure H1, with viability losses of 99-100% found to be significant (p < 0.001) at <=10 MUM or less for the histone mixture and pure H1. F. graminearum was the most sensitive to histone activity. The histones were inactive against all of the non-germinated Penicillium spp. conidia. However, they significantly reduced the viability of the germinating conidia of the Penicillium spp. conidia, with 95% loss at 2.5 MUM. Non-germinated and germinating conidia viability of the Aspergillus spp. and G. uvicola were unaffected when exposed to histones up to 10 MUM. Results indicate that Fusarium spp. pathogenic to wheat are susceptible to wheat histones, indicating that these proteins may be a resistance mechanism in wheat against fungal infection. PMID- 21595495 TI - Comparative studies on the interaction of genistein, 8-chlorogenistein, and 3',8 dichlorogenistein with bovine serum albumin. AB - Chlorination can significantly enhance the antioxidant and antitumor activity of genistein. In this paper, genistein, 8-chlorogenistein, and 3',8 dichlorogenistein were selected to investigate the binding to bovine serum albumin (BSA) using fluorescence spectroscopy and circular dichroism (CD). The results showed that chlorination, especially at position 3', had significant effects on the binding constant value of chlorinated genistein derivatives to BSA; however, the binding site and the binding number were slightly affected. The thermodynamic parameters indicated that hydrophobic and electrostatic forces played important roles in the binding process and the enhanced binding affinity mainly associated with the increase of the hydrophobicity caused by the chlorine atom substitution. Furthermore, the CD data demonstrated that the conformation of BSA was slightly altered in the presence of genistein, 8-chlorogenistein, and 3',8-dichlorogenistein, with different reduced alpha-helix contents. The results obtained herein will be of biological significance in toxicology investigation and genistein derivative drug design. PMID- 21595496 TI - Synthesis, characterization, self-assembly, and physical properties of 11 methylbenzo[d]pyreno[4,5-b]furan. AB - Synthesis, structure, and physical properties of a novel 11 methylbenzo[d]pyreno[4,5-b]furan (BPF) and its self-assembly in water have been reported. The performance of nanowire-based films in organic light-emitting diodes is much better than that of the thin film deposited by directly drop coating BPF molecules in THF solution. SEM study indicates that the well organized structure (nanowires) is an important factor in enhancing the performance of OLED devices. PMID- 21595498 TI - Global health education for medical undergraduates. AB - CONTEXT: The Rural Undergraduate Support and Coordination (RUSC) program has stimulated teaching in remote indigenous health, primary health care and international health for Australian students prior to their placements. Medical students have traditionally taken electives in the developing world, although these electives are of variable use to the communities hosting them and to the students. Calls for development of a curriculum in international or global health have resulted in some attempts to define a curriculum. An International Health (IH) course at the University of Adelaide Medical School, South Australia, has evolved since 1999. ISSUES: The IH course has functioned both as an introduction to the social determinants of health and as a pre-departure course for student electives. The sequence progresses from general information to disease specific information and service provision for refugees and returning travellers. Experienced presenters deliver the content; student assessment is via a group development program proposal. LESSONS LEARNT: The current course aligns with international thinking on 3 structural themes for global health: the burden of global disease, travellers' medicine and immigrant/refugee health. Student opinion expressed in qualitative evaluation has been largely positive and consistent with the debate about whether this content should be a core unit or an elective part of the curriculum. From 2011 the course will be known as 'Global Health' and ongoing content development is expected. PMID- 21595499 TI - Lentiviral-mediated gene transfer to the sheep brain: implications for gene therapy in Batten disease. AB - The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are inherited neurodegenerative lysosomal storage diseases with common clinical features of blindness and seizures culminating in premature death. Gene-therapy strategies for these diseases depend on whether the missing activity is a secreted lysosomal protein taken up by neighboring cells, or an intramembrane protein that requires careful targeting. Therapies are best developed in animal models with large complex human-like brains. Lentiviral-mediated gene delivery to neural cell cultures from normal sheep and sheep affected with an NCL resulted in green fluorescent protein (GFP) expression in neurons and neuroblasts, more efficiently than in astrocytes. Similar transgene expression was obtained from two constitutive promoters, the viral MND promoter and the human EF1alpha promoter. In vivo studies showed stable and persistent GFP expression throughout the cell bodies, axons, and dendrites from intracortical injections and indicated ependymal and subependymal transduction. The sheep showed no ill effects from the injections. These data support continuing gene-therapy trials in the sheep models of Batten disease. PMID- 21595497 TI - Clinical utility of maraviroc. AB - Maraviroc belongs to the family of chemokine (C-C motif) receptor 5 (CCR5) antagonists that prevent the entry of human immunodeficiency virus (HIV) into host CD4+ T cells by blocking the CCR5 co-receptor R5. Maraviroc is currently the only CC5R co-receptor inhibitor that has been approved for clinical use in HIV-1 infected patients carrying the CCR5 tropism who are antiretroviral-naive or have experienced therapeutic failure following traditional antiretroviral therapies. This article is a review of the main characteristics of maraviroc and the latest data regarding its clinical application. Maraviroc is effective and well tolerated in pre-treated and antiretroviral-naive patients with HIV-1 infections carrying the CCR5 tropism. Data from the phase III programme of maraviroc, which includes the MOTIVATE 1 and 2 studies and the MERIT study, indicate that maraviroc significantly (p < 0.001) increases CD4+ cell counts compared with placebo in pre-treated patients and to a similar extent as efavirenz in antiretroviral-naive patients. Even in cases where viral load is not completely suppressed, maraviroc improves immunological response compared with placebo. In addition, promising research suggests that maraviroc has favourable pharmacokinetic and safety profiles in patients with high cardiovascular risk or those co-infected with tuberculosis or hepatitis and could be considered an option for treatment of HIV-infected patients with these co-morbidities. Resistance to maraviroc is low and mainly related to the presence of chemokine (C X-C motif) receptor 4 (CXCR4) tropism HIV-1-infections or to mutations in the V3 region of glycoprotein (gp) 120; however, the exact mechanisms by which resistance is acquired and their genotypic and phenotypic pattern have not yet been established. It is recommended that a tropism test should be performed when considering maraviroc as an alternate drug in HIV-1-infected patients. Current tropism assays have increased sensitivity to reliably detect CXCR4 HIV with rapid turn-around and at a low cost. Improved detection together with positive data on the drug's efficacy and safety profiles should help physicians to identify more accurately the appropriate candidates for commencement of treatment with maraviroc. In summary, maraviroc improves immunological response and has shown favourable pharmacokinetic and safety profiles in patients with high cardiovascular risk or in those co-infected with tuberculosis or hepatitis. Long term studies are needed to confirm whether therapeutic expectations resulting from clinical trials with maraviroc translate into a real benefit for HIV-1 infected patients for whom traditional antiretroviral therapies have failed or are not suitable. PMID- 21595500 TI - Recent advances in herbal medicine for treatment of liver diseases. AB - CONTEXT: Liver disease is a serious ailment and the scenario is worsened by the lack of precise therapeutic regimens. Currently available therapies for liver ailments are not apposite and systemic toxicity inhibits their long term use. Medicinal plants have been traditionally used for treating liver diseases since centuries as the toxicity factor appears to be on the lower side. OBJECTIVE: Several phytochemials have been identified which have significant hepatoprotective activity with minimal systemic adverse effects which could limit their long term use. The scenario calls for extensive investigations which can lead to development of lead molecules for hepatoprotective molecules of future. This review deals with the biological activity, mode of action and toxicity and forthcoming application of some of these leads. METHODS: These generally have strong antioxidative potential and cause induction of antioxidant enzymes like superoxide dismutase, reduced glutathione and catalase. Additional mechanisms of hepatoprotection include stimulation of heme oxygenase-1 activity, inhibition of nitric oxide production, hepatocyte apoptosis and nuclear factor-kappaB activation. RESULTS AND CONCLUSION: Out of the several leads obtained from plant sources as potential hepatoprotective agents, silymarin, andrographolide, neoandrographolide, curcumin, picroside, kutkoside, phyllanthin, hypophyllanthin, and glycyrrhizin have been established as potent hepatoprotective agents. The hepatoprotective potential of several herbal medicines has been clinically evaluated. Significant efficacy has been seen with silymarin, glycyrrhizin and Liv-52 in treatment of hepatitis, alcoholic liver disease and liver cirrhosis. PMID- 21595501 TI - Silver linings of oversimplification. PMID- 21595503 TI - Master switch of mitochondrial biogenesis: a clinical target for health span enhancement? PMID- 21595502 TI - Effect of obesity, serum lipoproteins, and apolipoprotein E genotypes on mortality in hospitalized elderly patients. AB - BACKGROUND: The aim of this study was to investigate the relationship among apolipoprotein E (APOE) polymorphism, body mass index (BMI), and dyslipidemia and how these factors modify overall mortality in a cohort of hospitalized elderly patients. METHODS: Plasma concentrations of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), BMI, and APOE genotype were evaluated in 1,012 hospitalized elderly patients, who were stratified into three groups according to their baseline BMI and APOE allele status. Multivariate logistic regression analysis was used to assess whether APOE genotype, BMI, and dyslipidemia are associated with mortality, adjusting for potential confounders. Interaction analysis was also performed. RESULTS: Obese patients have significantly higher levels of TC and LDL-C compared to normal-weight and overweight subjects, for both sexes. APOE epsilon4 carriers have significantly higher levels of TC and LDL-C compared with epsilon2 and epsilon3 carrier both in males and females. Interaction analysis showed that women with TC < 180 mg/dL, LDL-C < 100 mg/dL, normal weight, and epsilon3 carrier (odds ratio [OR] = 3.42, 95% confidence interval [CI] 1.36-8.60) and men with LDL-C < 100 mg/dL, HDL-C < 40 mg/dL, and epsilon3 carrier (OR = 1.97, 95% CI 1.04-3.74) were at highest risk of mortality. CONCLUSIONS: In elderly hospitalized patients, obesity and APOE genotype influence the lipid profile and mortality risk. A significant interaction among BMI, dyslipidemia, and APOE genotype was observed that could identify elderly patients with different risks of mortality. PMID- 21595505 TI - Interview with Judith Campisi, Ph.D. Interview by Vicki Glaser. PMID- 21595507 TI - Effect of treatment at different time intervals for traumatic tympanic membrane perforation on the closure. AB - CONCLUSION: Treatment of traumatic tympanic membrane (TM) perforation with everted or involute edge flaps at different time intervals within 1 week after the injury did not affect the perforation closure rate and mean closure time. OBJECTIVE: To retrospectively analyze the effect of treatment at different time intervals for traumatic tympanic membrane perforation with gelatin sponge patch and edge approximation plus gelfoam patching. METHODS: Patients with traumatic TM perforation visited at different days since the injury for medical treatment (1, 2, 3, 4, and 5-7 days post trauma). These patients were treated with the following prominent methods of treatment: gelatin sponge patch treatment and edge approximation plus gelfoam patching. Measurement indicators were perforation closure rate and mean closure time at 3 months. RESULTS: In the group treated with the gelatin sponge patch technique, the patients sought medical treatment at different time intervals since the injury. Accordingly, the outcome of the treatment varied in terms of the perforation closure rates achieved in different patients in this group. The respective perforation closure rates were 100%, 100%, 96%, 94%, and 89% in accordance with the time interval at which the patients were treated since the injury. The results were not significantly different when compared by statistical analysis (p > 0.05); the mean closure times in each of the different sets of cases in this group were calculated and the following values were reported: 7.1 +/- 2.3, 8.2 +/- 1.6, 8.7 +/- 1.2, 9.2 +/- 3.1, and 10.7 +/- 3.9 days. On the other hand, in the edge approximation plus gelfoam patching group, the perforation closure rates were 100%, 97%, 96%, 97%, and 94%, respectively. This was in accordance with the time elapsed since the injury for the patients who visited the hospital on different days. Statistical analysis confirmed that the perforation closure rates for the different cases of this group did not have any significant difference (p > 0.05); the mean closure times were 7.6 +/- 1.9, 7.9 +/- 2.2, 9.2 +/- 2.8, 8.5 +/- 3.6, and 11.2 +/- 4.1 days, respectively, indicating that differences were not significant even in terms of mean closure rates for the different cases of this group (p > 0.05). PMID- 21595508 TI - Effects of smell loss on daily life and adopted coping strategies in patients with nasal polyposis with asthma. AB - CONCLUSIONS: Results from prior studies of quality of life (QoL) in heterogeneous patient groups (regarding disorder type and etiology) with olfactory disorders may be useful also for understanding QoL in homogeneous patient groups. Diagnosis and treatment of smell loss should be given high priority in polyposis with asthma, and coping strategies can be suggested to these patients. OBJECTIVES: To investigate the effects of smell loss on daily life and coping strategies in patients with smell loss without dysosmia and with nasal polyposis with asthma as the only primary etiology, and to compare these results with those from a prior study of a patient group with heterogeneous olfactory disorders and etiology. METHODS: Fifty patients with smell loss and with nasal polyposis and asthma responded to questions about consequences of smell loss, QoL, psychological well being and distress, and coping strategies. RESULTS: Negative consequences of smell loss, associated risks, and diminished food enjoyment were commonly reported, and various aspects of QoL were rated as being deteriorated. Psychological well-being was found to be poorer than normal, and use of both problem- and emotion-focused strategies was common. The results from this homogeneous patient group are very similar to those previously obtained from a heterogeneous group. PMID- 21595510 TI - Phentermine (Duromine) precipitated psychosis. PMID- 21595509 TI - Rhodotorula fungemia: two cases and a brief review. AB - Rhodotorula is emerging as an important cause of nosocomial and opportunistic infections. We present two cases of Rhodotorula mucilaginosa fungemia diagnosed over a period of 3 months at our hospital. The first case was of a pre-term neonate in the neonatal ICU who presented with respiratory failure and sepsis. The second involved an adult female who had been injured in a road traffic accident requiring an operation for a hematoma and was later shifted to the medical ICU. For a new hospital like ours, finding two cases of Rhodotorula fungemia within a span of 3 months prompted us to describe them in this report. These cases emphasize the emerging importance of Rhodotorula mucilaginosa as a pathogen and the importance of identification and MIC testing for all fungal isolates recovered from the blood stream. PMID- 21595511 TI - Planning a genome-wide association study: points to consider. AB - It is well established that genetic diversity combined with specific environmental exposures contributes to disease susceptibility. However, it has turned out to be challenging to isolate the genes underlying the genetic component conferring susceptibility to most complex disorders. Traditional candidate gene and family-based linkage studies, which dominated gene discovery efforts for many years, were largely unsuccessful in unraveling the genetics of these traits due to the relatively limited information gained. Within the last 5 years, new advances in high-throughput methods have allowed for large volumes of single nucleotide polymorphisms (SNPs) throughout the genome to be genotyped across large and comprehensively phenotyped patient cohorts. Unlike previous approaches, these 'genome-wide association studies' (GWAS) have extensively delivered on the promise of uncovering genetic determinants of complex diseases, with hundreds of novel disease-associated variants being largely replicated by independent groups. This review provides an overview of these recent breakthroughs in the context of the pitfalls and challenges related to designing and carrying out a successful GWAS. PMID- 21595513 TI - Age-related increase of airway neutrophils in older healthy nonsmoking subjects. AB - BACKGROUND: Although an influence of advancing age on lung cellularity in healthy subjects has already been described, induced sputum reference values for cell counts in older healthy adults are not available. The aim of the present study was to evaluate the influence of age on the variation of sputum cell distribution in a considerable number of healthy subjects. A total of 70 nonatopic, nonsmoker healthy subjects aged >=50 years underwent sputum induction and blood cell count. Sputum samples were processed and then were analyzed by optical microscopy. Differential cell counts were reported as percentages and amount of cells/mg. RESULTS: Sputum cell distribution of healthy subjects aged >=50 years was mainly composed of neutrophils. Both the percentage and the amount of sputum neutrophils correlated with the subjects' age, r=0.5, p=0.00001 and r=0.32, p=0.007, respectively. This correlation was more evident in women (n=35) than in men (n=35). No correlation was found between blood neutrophils and age. The increase in sputum neutrophils was not secondary to an increase in blood neutrophils. CONCLUSIONS: In the studied subjects, aging was associated, particularly in women, with an increase in sputum neutrophils not related to an increase of blood neutrophils. These results could be useful in clinical and experimental settings as reference values to compare with data from subjects aged over 50 years. These data showed that sputum neutrophila can be dissociated from airway symptoms and could create a favorable background for the development of age-related lung diseases. PMID- 21595512 TI - Neuropeptide y and neuropeptide y y5 receptor interaction restores impaired growth potential of aging bone marrow stromal cells. AB - Abstract improved growth characteristics of the aging bone marrow cells subsequent to neuropeptide Y (NPY)/neuropeptide Y Y5 receptor (NPY Y5R) ligand receptor interaction. Bone marrow cells were isolated from neonatal (2-3 weeks), young (8-12 weeks), and old (24-28 months) rats on the basis of their preferential adherence to plastic surface. After culturing the cells at initial seeding density of 1*10(4) cells/cm(2), we found that the proliferation potential of bone marrow cells declined with age. Real-time polymerase chain reaction (PCR) and Western blotting showed that bone marrow cells in different age groups constitutively expressed NPY and NPY receptor subtypes (Y1R, Y2R, and Y5R). However, NPY and Y5R expression increased by more than 130-fold and decreased by 28-fold, respectively, in old bone marrow cells as compared to young bone marrow cells. NPY (10 nM) stimulated the proliferation of all bone marrow cells age groups, and their proliferation was blocked by Y5R antagonist. However, the pro proliferative effect of NPY on old bone marrow cells was weaker than other cell groups due to lower Y5R expression. Y5R gene transfection of old bone marrow cells with subsequent NPY(3-36) (10 nM) treatment significantly increased proliferation of old bone marrow cells (>56%) as compared to green fluorescence protein-transfected control old bone marrow cells. Stimulation of old bone marrow cells by NPY treatment rejuvenated the growth characteristics of aging bone marrow cells as a result of Y5R overexpression. PMID- 21595514 TI - Platinum-based compounds and risk for cardiovascular toxicity in the elderly: role of the antioxidants in chemoprevention. AB - Cancer in elderly patients is an increasingly common problem. Older patients have more co-morbidity, therefore the toxic effects of chemotherapy treatment are less tolerable compared to younger patients. Platinum-based compounds (PBCs) are commonly used cytotoxic agents in the treatment of several solid tumors; however, their application is still limited in elderly patients, due to the risks in cardiovascular toxicity. The increased risk for myocardial ischemia, stroke, and vascular thrombosis linked with PBCs treatment is mainly due to reactive oxygen species (ROS) production and the subsequent induction of oxidative stress and switch to a prothrombotic condition. Recently, studies have shown a different genetic susceptibility in cardiovascular toxicity induced by therapy with PBCs. Antioxidants, such as vitamin E, selenium, lycopene, melatonin, and resveratrol, have been implicated in cancer treatment by their property to suppress the oxidant injury. Resveratrol, especially, has been shown to increase the antineoplastic activity of cisplatin. In addition, resveratrol's ability to activate the sirtuin1 (SIRT1) pathway has been heavily implicated in the mechanisms controlling longevity and quality of life in the aged population. This article reviews the current state of treatment with PBCs and their associated risk for cardiovascular disease. It discusses the most powerful antioxidant supplementation options as a possible strategy to reduce the cardiovascular toxicity effects of chemotherapy in the elderly. PMID- 21595515 TI - Thyroid and the heart: the intimacy is strained. PMID- 21595516 TI - Absorption of levothyroxine when coadministered with various calcium formulations. AB - BACKGROUND: Calcium carbonate is a commonly used dietary supplement and has been shown to interfere with levothyroxine absorption. However, calcium citrate, which is also used for supplementation purposes, has not been studied previously and calcium acetate, which is used to treat hyperphosphatemia in renal failure, has been reported to show little or no interference with levothyroxine absorption in a retrospective pharmacoepidemiologic study. We aimed to compare the effect of these three calcium formulations on levothyroxine absorption. MATERIALS AND METHODS: The study was conducted in eight healthy, euthyroid adults. We performed single-dose pharmacokinetic studies in which we measured levothyroxine absorption when given alone or when coadministered with calcium carbonate, calcium citrate, or calcium acetate in doses containing 500 mg elemental calcium. Serum thyroxine was measured at intervals over a 6-hour period after ingestion of the study drugs. RESULTS: Coadministration of each of the three calcium preparations significantly reduced levothyroxine absorption by about 20%-25% compared with levothyroxine given alone. CONCLUSIONS: Contrary to a prior report, our data suggest that calcium acetate interferes with levothyroxine absorption in a manner similar to that seen with calcium carbonate and calcium citrate. Although the effect of calcium is modest compared with some other medications previously studied, hypothyroid patients should be cautioned to take their levothyroxine well-separated from all of these calcium formulations. PMID- 21595517 TI - Dichotomous responses to thyroid hormone treatment in a patient with primary hypothyroidism and thyroid hormone resistance. AB - BACKGROUND: Resistance to thyroid hormone (RTH) is a rare syndrome of reduced TH sensitivity most often due to mutations affecting the beta-isoform of the thyroid hormone receptor (TRbeta). Patients with RTH may develop hypothyroidism as a result of surgery, mistreatment with radioiodine, or autoimmune thyroid disease. PATIENT FINDINGS: We describe a patient who underwent partial thyroid lobectomy for benign goiter at age 17 and remained healthy through five uncomplicated pregnancies before abnormal laboratory results were noted. She was followed by multiple consecutive specialists after age 40, intermittently treated with levothyroxine, and referred to our clinic at age 66 because of severe progressive fatigue and abnormal thyroid function tests. Initial workup revealed elevated TH levels and inappropriately elevated thyroid-stimulating hormone. TH levels progressively declined into the normal range, accompanied by marked thyroid stimulating hormone elevation. Antibody testing and thyroid biopsy confirmed Hashimoto's thyroiditis, and genetic testing revealed a TRbeta mutation. Patient response to TH therapy has been good although limited by palpitations. CONCLUSIONS: Patients with RTH may develop significant hypothyroidism with normal TH levels in the setting of Hashimoto's thyroiditis. RTH presents a unique challenge in both the diagnosis and management of autoimmune hypothyroidism. PMID- 21595518 TI - Treating Hashimoto's thyroiditis with selenium: no risks, just benefits? PMID- 21595522 TI - Stability of infliximab dosing in inflammatory bowel disease: results from a multicenter US chart review. AB - OBJECTIVE: Infliximab dosing for inflammatory bowel disease (IBD) is based on patient weight and treatment response. Understanding dosing patterns may provide insight into treatment response and predictability of treatment cost. The purpose of this medical record review was to assess dose and dose frequency of infliximab maintenance treatment in patients with IBD using patient chart data. METHODS: A retrospective chart review was conducted at 14 community gastroenterology clinics (GI clinics). Patients were aged >=18 years, diagnosed with Crohn's disease (CD) or ulcerative colitis (UC), and had a first infliximab administration (index date) between January 1, 2005 and September 30, 2007. At least 24 months of continuous data availability were required with dosing data collected for 12 months after initiation of infliximab therapy. Patients with biologic use and/or participation in an IBD clinical trial within 12 months before the index date were excluded. RESULTS: Charts from 182 CD patients and 86 UC patients were analyzed. About half of the patients were female. Over 90% of patients initiated treatment with infliximab 5 mg/kg. Among CD patients and UC patients, respectively, 79% and 61% continued receiving this dose for maintenance therapy at stable intervals. LIMITATIONS: This retrospective descriptive study is limited by the type and quantity of information available in patient charts from 14 GI clinics during the first year of infliximab treatment. Further, non-anti-tumor necrosis factor medication data were intermittently collected in some charts and, therefore, did not allow for analysis. CONCLUSIONS: Weight-based dosing and, presumably, patient response enabled providers to find the effective infliximab dose for IBD patients. The maintenance dose and administration frequency remained stable during the initial year. PMID- 21595523 TI - Double repression of soluble starch synthase genes SSIIa and SSIIIa in rice (Oryza sativa L.) uncovers interactive effects on the physicochemical properties of starch. AB - Soluble starch synthases (SSs) are major enzymes involved in starch biosynthesis in developing rice (Oryza sativa L.) endosperm. Despite extensive studies of SSs in various plant species including rice, the functional modes of action among multiple SS genes are still not clear. Here, we generated transgenic RNA interference (RNAi) repressed lines for seven of the eight members of the rice SS gene family and studied their effects on starch synthesis and grain formation. Consistent with their expression domains, RNAi repression of genes that encode isozymes SSI, SSIIa, and SSIIIa had strong effects on grain development, whereas no obvious phenotypic changes were observed in transgenic plants with the other SS genes being RNAi repressed, indicating functional redundancies among the genes. To study the potential functional interactions of SS genes, we generated SSIIa/SSIIIa double repression lines whose kernels displayed a chalky kernel appearance and had increased amylose levels, increased pasting temperatures, and decreased viscosities. The double mutation also reduced short (degree of polymerization (DP) 5-6) and long (DP 12-23) amylopectin chain contents in the grain and increased the medium long types (DP 7-11). The nonadditive nature of the double mutation line suggests that SSIIa and SSIIIa interact with each other during starch synthesis. Such interaction may be physical via starch phophorylase as indicated by our pair-wise yeast two-hybrid assays on major starch synthesis enzymes. Collectively, the data showed that SSIIa and SSIIIa play distinctive, but partially overlapping, roles during rice grain starch synthesis. The possibility of extensive redundancy or complementarity among SS isozymes is discussed. PMID- 21595524 TI - Comparison of problematic internet and alcohol use and attachment styles among industrial workers in Korea. AB - The objective of this article is to fully understand Internet addiction, we aimed to compare the attachment styles and psychopathologies associated with problematic Internet use with those related to alcohol use. Through the participation of 141 male participants, the present study assessed problematic Internet and alcohol use, attachment, psychopathology, and demographic data via the use of self-rating questionnaires. We explored the significant predictors among avoidant and anxious attachments, depression, anxiety, and phobia to explain problematic Internet and alcohol use. The results showed that anxious attachment, depression, and anxiety could explain problematic alcohol use. In contrast, both anxious and avoidant attachment as well as depression and phobia explained problematic Internet use. Additionally, depression moderated the effects of avoidant attachment on problematic Internet use. We demonstrated that the interaction of attachment and psychopathology predicts problematic Internet use originating from an earlier stage of life than that associated with problematic alcohol use. PMID- 21595525 TI - Sensory gating deficit is associated with catechol-O-methyltransferase polymorphisms in bipolar disorder. AB - OBJECTIVES. Recent studies have evidenced that bipolar patients show a sensory gating deficit (P50). Among the neural systems that could be influencing this electrophysiological phenotype, dopamine seems to play an important role. We hypothesize that catechol-O-methyltransferase (COMT), the main metabolizer of dopamine in prefrontal cortex, is related to this deficit. METHODS. We selected three polymorphisms in COMT gene: rs2075507 (Promoter 2 region), Val158Met (rs4680) and rs165599 (3' region). A case-control study was performed in 784 controls and 238 bipolar patients. Besides, 122 euthymic bipolar subjects and 95 healthy subjects carried out a sensory gating task (P50). RESULTS. Polymorphism rs165599 in the COMT gene was associated with susceptibility to bipolar disorder (BD), mainly in women (AG: OR = 1.46; GG: OR = 1.84; P = 0.03). In the female group, haplotype AAG was associated with an OR = 7.6. Subjects who carried Val158 allele evidenced a deficit in suppression (P = 0.046) and rs165599 allele G carriers (mainly in homozygosis) had a bigger S2 amplitude and a higher S2/S1 ratio (1.6(e-5) < P < 0.01). Not a single association was proven in the control group. CONCLUSIONS. Our results support the association of the COMT gene with BD and with one of its potential endophenotypes, auditory sensory gating deficit, measured by the P50 paradigm. PMID- 21595526 TI - A model to incorporate genetic testing (5-HTTLPR) in pharmacological treatment of major depressive disorders. AB - OBJECTIVE: To evaluate the benefit of pharmacogenetics in antidepressant treatment. METHODS: In a simulated trial 100,000 subjects in a current episode of major depressive disorder (MDD) received citalopram or bupropion based on the clinician's decision (algorithm A) or following indications from 5-HTTLPR genetic testing (algorithm B), which effect size of was estimated from a meta-analysis of pharmacogenetic trials. A and B were compared in a cost-utility analysis (12 weeks). Costs (international $, 2010) were drawn from official sources. Treatment effects were expressed as quality-adjusted life weeks (QALWs). Outcome was incremental cost-effectiveness ratio (ICER). RESULTS: Under base-case conditions, genetic test use was associated with increases in antidepressant response (0.062 QALWs) and tolerability (0.016 QALWs) but cost benefit was not acceptable (ICER = $2,890; $1,800-$4,091). However, when the joint effect on antidepressant response and tolerability was analyzed in two recurrent episodes, ICER dropped to $1,392 ($837-$1,982). Cost-effectiveness acceptability curve (CEAC) showed a >80% probability that ICER value fell below the commonly accepted 3 times Gross Domestic Product (GDP) threshold (World Health Organization) and therefore suggesting cost-effectiveness. CONCLUSION: Notwithstanding some caveats (exclusion of gene-gene and gene-environment interactions; simple 5-HTTLPR architecture), this simulation is favourable to incorporate pharmacogenetic test in antidepressant treatment. PMID- 21595527 TI - Open ear hearing aids in tinnitus therapy: An efficacy comparison with sound generators. AB - OBJECTIVE: This study aimed to compare the effectiveness of tinnitus retraining therapy (TRT) with sound generators or with open ear hearing aids in the rehabilitation of tinnitus for a group of subjects who, according to Jastreboff categories, can be treated with both approaches to sound therapy (borderline of Category 1 and 2). DESIGN: This study was a prospective data collection with a parallel-group design which entailed that each subject was randomly assigned to one of the two treatments group: half of the subjects were fitted binaurally with sound generators, and the other half with open ear hearing aids. Both groups received the same educational counselling sessions. STUDY SAMPLE: Ninety-one subjects passed the screening criteria and were enrolled into the study. Structured interviews, with a variety of measures evaluated through the use of visual-analog scales and the tinnitus handicap inventory self-administered questionnaire, were performed before the therapy and at 3, 6, and 12 months during the therapy. RESULTS: Data showed a highly significant improvement in both tinnitus treatments starting from the first three months and up to one year of therapy, with a progressive and statistically significant decrease in the disability every three months. CONCLUSIONS: TRT was equally effective with sound generator or open ear hearing aids: they gave basically identical, statistically indistinguishable results. PMID- 21595528 TI - The perceptions of physicians in southeast Nigeria on truth-telling for cancer diagnosis and prognosis. AB - BACKGROUND: The perceptions of Nigerian physicians on truth-telling for cancer diagnosis and prognosis have not been widely studied. There is a need to know the perception of the doctors on truth telling so as to inform appropriate professional education on the subject. OBJECTIVES: To ascertain the perceptions of the physicians on truth-telling for cancer diagnosis and prognosis. METHODS: A cross-sectional study was done with a self-administered questionnaire to 228 physicians available in the clinics and seminars at the hospital between January and April 2010. RESULTS: A total of 173 questionnaires were returned. Eighty-one (46.8%) always, 54 (31.2%) generally, and 38 (22%) rarely disclose cancer diagnosis and favorable prognosis to patients. Only 7.5% would disclose the truth of the prognosis to patients when the cancer is advanced. Physicians' age, specialty, training in palliative care, and doctors' views on truth disclosure if he/she had cancer significantly influenced the doctors' practice of truth-telling for cancer diagnosis. CONCLUSION: The physicians who treat cancer patients in southeast Nigeria tend to practice truth-telling for cancer diagnosis but not for a poor prognosis. Most of the physicians need training in physician-patient communication. PMID- 21595529 TI - Corneal astigmatism in unilateral Fuchs heterochromic iridocyclitis. AB - PURPOSE: To analyze the results of scanning slit topography in both eyes of patients with unilateral Fuchs heterochromic iridocyclitis (FHI). METHODS: A noninterventional, case-controlled study was conducted with 30 patients with unilateral FHI. Corneal topographic parameters, obtained with the Orbscan II (Bausch & Lomb), were compared between the two eyes and analyzed statistically. The same number of age-matched normals was enrolled as a control group. RESULTS: Thirty patients were enrolled in this study. The mean age was 33.3 years +/- 10.6 (SD). The mean Sim K astigmatism was 1.65 +/- 1.27 diopter in the FHI eyes and 0.88 +/- 0.52 diopter in the normal eyes (p = .001). CONCLUSION: Corneal astigmatism is a common finding in patients with FHI and disparity of corneal astigmatism between the two eyes can be considered a sign of the unilateral form of this disease. PMID- 21595530 TI - Rubella-related intermediate uveitis in pregnancy--a rare presentation. AB - PURPOSE: To report a rare case of intermediate uveitis following rubella infection in pregnancy. DESIGN: Case report. METHODS: A 35-year-old pregnant woman, at 24 weeks of gestation, presented with sudden floaters and blurring of vision of the left eye. Ocular examination revealed vitritis 1-2+ with no retinal involvement. Rubella serology showed a high IgG titr eof 268 IU/mL. Treatment with periocular steroids (posterior subtenon triamcinalone) injection into the left eye was initiated. RESULTS: Improvement of vision with resolution of the vitritis was seen after 3 weeks. Repeat rubella IgG titer dropped to 20.4 IU/mL. Obstetrics evaluation of the fetus remained normal. CONCLUSIONS: Rubella-related intermediate uveitis is a very rare presentation during pregnancy. It is worthwhile to investigate for rubella infections in pregnant patients complaining of recent onset of visual disturbances. This type of intermediate uveitis can be treated successfully with minimal ocular complications if recognized early. PMID- 21595531 TI - Pigment dispersion syndrome masquerading as acute anterior uveitis. AB - INTRODUCTION: Signs and symptoms of pigment dispersion may be confused with those of acute anterior uveitis. This case series is intended to aid the ophthalmologist in the clinical differentiation between these two disorders. CASE SERIES: The authors present a series of 6 patients with pigment dispersion who were initially diagnosed as having acute anterior uveitis and treated with anti inflammatory medication, including corticosteroids. The patients were referred for a second opinion due to poor or no response to therapy and were found to have pigment dispersion instead of uveitis. DISCUSSION: Symptoms of pigment dispersion may consist of blurred vision, redness, ocular pain, and photophobia, all of which are also symptoms of acute anterior uveitis. These symptoms, plus the fact that pigment floating in the aqueous humor can be mistaken for inflammation, make diagnosis challenging. Moreover, the possible co-existence of true anterior uveitis and pigment dispersion makes the diagnosis and treatment more difficult. PMID- 21595532 TI - Optic nerve involvement with panuveitis in Sweet syndrome. AB - PURPOSE: To report a case of a patient with optic nerve involvement in neuro Sweet syndrome and review the literature on this systemic disease. METHODS: Interventional case report and review of the literature. RESULTS: A 49-year-old man developed an acute exacerbation of bilateral panuveitis and optic disc edema together with symptoms of a papular rash on his forearms, fevers, malaise, and arthalgias. Laboratory findings revealed an aseptic meningitis and neutrophilic leukocytosis. Biopsy of the skin rash demonstrated an intense neutrophilic infiltrate in the dermis consistent with the diagnosis of neuro-Sweet syndrome. The patient continued to require corticosteroids for inflammation control in spite of immunomodulatory therapies, including tumor necrosis factor-alpha inhibitor infliximab. CONCLUSIONS: Sweet syndrome can present with optic nerve involvement. Screening for underlying etiologies, including autoimmune disease, malignancy, and offending drugs, is important for targeted therapy. PMID- 21595533 TI - Review for disease of the year: differential diagnosis of ocular toxoplasmosis. AB - The diagnosis of ocular toxoplasmosis is mainly clinical, based in the presence of focal necrotizing retinochoroiditis often associated with a preexistent chorioretinal scar, and variable involvement of the vitreous, retinal blood vessels, optic nerve, and anterior segment of the eye. Recognition of this clinical spectrum of toxoplasmic retinochoroiditis is crucial, but other infectious, noninfectious, and neoplastic entities should also be considered in the differential diagnosis. Investigations such as serological tests, polymerase chain reaction of ocular fluids, and assessment of intraocular antibody synthesis are helpful in uncertain cases. This article provides an overview of the differential diagnosis of ocular toxoplasmosis, focusing on the most important entities to be considered and emphasizing distinctive features of each one of them in the clinical setting. Ocular toxoplasmosis has multiple clinical manifestations, which partially overlap with those of other entities and these should be carefully considered when making the differential diagnosis, particularly in less typical cases. PMID- 21595534 TI - The role of perivascular melanophage infiltrates in the conjunctiva in sympathetic ophthalmia. AB - PURPOSE: To report pathologic changes in the conjunctiva from the exciting eye in a case of sympathetic ophthalmia (SO). METHODS: Report of clinical findings and conjunctival histopathology in a patient with SO. RESULTS: A 50-year-old male developed SO, with unusual peribulbar conjunctival pigmentation in the inciting eye. Histological examination of the conjunctival biopsy revealed perivascular distribution of CD68(+) melanophages that also expressed HLA-DR, suggesting that these macrophages may act as antigen-presenting cells. In addition, increased CD4(+) and CD3(+) lymphocytes were noted in the subconjunctival space when compared to specimens of normal conjunctiva and traumatic uveal prolapse without SO, suggesting T-cell recruitment. CONCLUSIONS: These pathologic findings suggest a possible mechanism by which local antigen processing by subconjunctival melanophages may play a role in the initiation of the complex cell-mediated response seen in SO. PMID- 21595535 TI - Killer immunoglobulin-like receptor genes in uveitis. AB - PURPOSE: to review the function and genetics of killer immunoglobulin-like receptors (KIRs) and studies of KIR genetic associations with uveitis. METHODS: Review of published studies. RESULTS: KIRs are receptors on NK and some T cells. They may inhibit or activate cellular function, such as cytotoxicity and cytokine production. Studies have been published examining KIR gene associations with birdshot chorioretinopathy (BCR), Vogt-Koyanagi-Harada (VKH) disease, and HLA-B27 associated acute anterior uveitis (AAU) and axial spondyloarthropathy. Evidence for increased activating and/or less inhibitory KIR and HLA gene combinations was found for BCR and VKH disease. In HLA-B27-associated disease, a trend toward decreased activation and stronger inhibition was found, except for the weakly inhibitory 3DL1 and Bw4(T80) combination. This latter combination was also found to confer risk in BCR. CONCLUSIONS: KIR genetics are complex, as are the functions of KIR-bearing cells. Nonetheless, evidence for KIRs in the pathogenesis of uveitis has been found. PMID- 21595536 TI - Investigation of association between TLR9 gene polymorphisms and VKH in Japanese patients. AB - PURPOSE: Vogt-Koyanagi-Harada (VKH) disease is an autoimmune disorder affecting melanocytes in the skin, eyes, inner ear, and meninges. The Epstein-Barr virus and cytomegalovirus (CMV) antigen have been hypothesized as possible triggering factors for the disease. Toll-like receptors (TLRs) play an important role in the induction of defense mechanisms of the innate and adaptive immune responses to microbial pathogens. Among TLRs, TLR9 recognizes unmethylated 2'-deoxyribo (cytidine-phosphate guanosine)(CpG) DNA motifs that are frequently present in viruses and plays a central role in the host defense against viral infection. The aim of this study was to investigate whether TLR9 polymorphisms were associated with VKH in a Japanese population. METHODS: Ninety-four Japanese patients diagnosed with VKH and 125 healthy control subjects were recruited. Five single nucleotide polymorphisms (SNPs: rs187084, rs5743836, rs352139, rs352140, rs5743845) in the TLR9 gene were genotyped, and allelic and phenotypic diversity was assessed between cases and control subjects. RESULTS: Strong linkage disequilibrium was observed among three SNPs (D' > 0.99), which were located in one haplotype block. Two SNPs (rs5743836 and rs5743845) were monopolymorphic in both cases and controls. No statistically significant association was observed for any of the SNPs between cases and controls. CONCLUSION: Three SNPs in the TLR9 gene were not significantly associated with susceptibility to VKH. PMID- 21595537 TI - Fluocinolone acetonide implant (Retisert) for chronic cystoid macular edema in two patients with AIDS and a history of cytomegalovirus retinitis. AB - PURPOSE: To report the authors' experience using fluocinolone acetonide (Retisert) to treat cystoid macular edema (CME) resulting from immune recovery uveitis (IRU) in 2 acquired immunodeficiency syndrome (AIDS) patients with a history of cytomegalovirus (CMV) retinitis. DESIGN: Interventional case series. METHODS: Medical records were reviewed of 2 patients who received Retisert implantation in 3 eyes for IRU-associated inflammation and CME. Suppression of CMV disease was achieved with oral medication in one patient and with simultaneous implantation of a ganciclovir implant in the other patient. RESULTS: After Retisert implantation in 3 eyes in AIDS patients on HAART, improvement in CME was seen in 2 eyes. No CMV reactivation was detected during the several-month follow-up period. CONCLUSIONS: Retisert may be an effective treatment for CME in AIDS patients with IRU reactivation and a history of CMV retinitis. PMID- 21595538 TI - A functional, nonfunctioning Retisert implant. AB - The fluocinolone acetonide (RetisertTM) implant is an approved therapy for chronic, posterior, non-infectious uveitis. Continued episodes of inflammation can occur in patients after device implantation and suspected RetisertTM malfunction has been previously reported. We report a case of a patient who continued to have inflammation after RetisertTM implantation, which subsided after device exchange with a normally functioning explant after detailed manufacturer analysis. PMID- 21595539 TI - Intravitreal foscarnet for the treatment of acyclovir-resistant acute retinal necrosis caused by varicella zoster virus. AB - PURPOSE: To report of a case of acute retinal necrosis (ARN), successfully treated with intravitreal foscarnet. METHODS: Case report. RESULTS: A 40-year-old man diagnosed with varicella zoster virus (VZV)-induced ARN failed standard acyclovir treatment. He was treated subsequently with intravenous foscarnet, but developed acute renal failure after 1 day of treatment. All systemic anti-viral agents were discontinued, and intravitreal foscarnet was administered weekly. After 5 injections, the retinitis was dramatically improved. CONCLUSIONS: Intravitreal foscarnet was efficacious in the treatment of acyclovir-resistant ARN caused by VZV. It may be used as the sole treatment in patients with intolerance to systemic administration. PMID- 21595540 TI - Use of a high infusion rate to prevent posterior dislocation of fluocinolone acetonide implant during surgical removal. AB - PURPOSE: To describe a strategy for reducing the risk of posterior dislocation of a fluocinolone implant during exchange or removal. DESIGN: Case report and in vitro model. METHODS: Description of a surgical case and an in vitro experiment evaluating the role of infusion pressure in maintaining implant stability in surgery. RESULTS: Use of an elevated infusion pressure allowed safe removal of a fluocinolone implant that spontaneously dissociated into two pieces during removal. An in vitro model using the implant's drug reservoir in a cadaver eye demonstrated that the implant remained in a stable location at the scleral incision if the infusion pressure was high, whereas with a lower infusion pressure the implant spontaneously fell onto the posterior pole of the eye. CONCLUSIONS: During exchange or removal of a fluocinolone implant, an elevated infusion pressure may reduce the risk of posterior dislocation of the device. PMID- 21595541 TI - Successful treatment of chronic pseudophakic macular edema (Irvine-Gass syndrome) with interferon alpha: a report of three cases. AB - PURPOSE: To describe treatment of chronic Irvine-Gass syndrome (CME) with interferon (IFN) alpha. METHODS: Interventional retrospective case series. IFN alpha-2a was administered at a dose of 3 million IU/day subcutaneously for 4 weeks, and was tapered thereafter. Treatment efficacy was assessed by best corrected visual acuity (BCVA) and by optical coherence tomography (OCT). RESULTS: Three patients (4 eyes) with chronic Irvine-Gass syndrome were treated. Ineffective pretreatment included local and systemic corticosteroids. Within 4 weeks, IFN alpha led to resolution of CME in all eyes. BCVA improved in 3 eyes and remained unchanged in 1 eye. During follow-up of 3-11 months no relapse of CME occurred. No systemic or local side effects were noted. CONCLUSIONS: IFN alpha has been demonstrated to be a successful and well-tolerated treatment option for resistant chronic pseudophakic CME. Further studies are necessary to evaluate the role of IFN alpha in Irvine-Gass syndrome. PMID- 21595542 TI - Incisional hernia after robot-assisted radical prostatectomy-predisposing factors in a prospective cohort of 250 cases. AB - BACKGROUND AND PURPOSE: The incidence of incisional hernia after robot-assisted radical prostatectomy (RARP) has not been described previously. We report our prospective data in an attempt to identify factors that may predispose to this important complication. PATIENTS AND METHODS: The information contained in our prospectively collected RARP database was used to assess the incidence and predisposing factors for incisional hernia post-RARP in a single surgeon series of 250 patients. RESULTS: The incidence of incisional hernia in our series was 4.8% (12 of 250 patients). Statistical analysis demonstrated a higher rate of incisional hernias in patients for whom the supraumbilical incision for specimen retrieval was closed with a continuous, rather than interrupted suture. Incisional hernia is associated with a significantly longer length of hospital stay. CONCLUSION: Urologists should be aware that incisional hernia is an important postoperative complication after RARP. Closure of linea alba with a nonabsorbable suture using an interrupted technique may help to minimize the incidence of this morbid complication. PMID- 21595543 TI - Effects of traditional Japanese massage therapy on gene expression: preliminary study. AB - OBJECTIVES: Changes in gene expression after traditional Japanese massage therapy were investigated to clarify the mechanisms of the clinical effects of traditional Japanese massage therapy. DESIGN: This was a pilot experimental study. SETTINGS/LOCATION: The study was conducted in a laboratory at Tsukuba University of Technology. SUBJECTS: The subjects were 2 healthy female volunteers (58-year-old Participant A, 55-year-old Participant B). INTERVENTIONS: The intervention consisted of a 40-minute full-body massage using standard traditional Japanese massage techniques through the clothing and a 40-minute rest as a control, in which participants lie on the massage table without being massaged. OUTCOME MEASURES: Before and after an intervention, blood was taken and analyzed by microarray: (1) The number of genes whose expression was more than double after the intervention than before was examined; (2) For those genes, gene ontology analysis identified statistically significant gene ontology terms. RESULTS: The gene expression count in the total of 41,000 genes was 1256 genes for Participant A and 1778 for Participant B after traditional Japanese massage, and was 157 and 82 after the control, respectively. The significant gene ontology terms selected by both Participants A and B after massage were "immune response" and "immune system," whereas no gene ontology terms were selected by them in the control. CONCLUSIONS: It is implied that traditional Japanese massage therapy may affect the immune function. Further studies with more samples are necessary. PMID- 21595544 TI - Organ-specific scaffolds for in vitro expansion, differentiation, and organization of primary lung cells. AB - In light of the increasing need for differentiated primary cells for cell therapy and the rapid dedifferentiation occurring during standard in vitro cultivation techniques, there is an urgent need for developing three-dimensional in vitro systems in which expanded cells display in vivo-like differentiated phenotypes. It is becoming clear that the natural microenvironment provides the optimal conditions for achieving this aim. To this end, we prepared natural decellularized scaffolds of microscopic dimensions that would allow appropriate diffusion of gases and nutrients to all seeded cells. Scaffolds from either the lung or the liver were analyzed for their ability to support growth and differentiation of progenitor alveolar cells and hepatocytes. We observed that progenitor alveolar cells that have been expanded on plastic culture and thus dedifferentiated grew within the lung-derived scaffolds into highly organized structures and regained differentiation markers classical for type I and type II alveolar cells. The cells generated proper alveolar structures, and only 15%-30% of them secreted surfactant proteins in a localized manner for extended periods. Vice versa, liver-derived scaffolds supported the differentiation state of primary hepatocytes. We further demonstrate that the natural scaffolds are organ specific, that is, only cells derived from the same organ become properly differentiated. A proteomic analysis shows significant different composition of lung and liver scaffolds, for example, decorin, thrombospondin 1, vimentin, and various laminin isoforms are especially enriched in the lung. Altogether, our data demonstrate that complex interactions between the seeded cells and a highly organized, organ-specific stroma are required for proper localized cell differentiation. Thus, our novel in vitro culture system can be used for ex vivo differentiation and organization of expanded primary cells. PMID- 21595545 TI - Expansion of the human adipose-derived stromal vascular cell fraction yields a population of smooth muscle-like cells with markedly distinct phenotypic and functional properties relative to mesenchymal stem cells. AB - Adipose tissue contains a heterogeneous cell population composed of endothelial cells, adipocytes, smooth muscle cells (SMC), and mesenchymal progenitors and stromal cells that meet the criteria put forth by the International Society for Cellular Therapy as defining mesenchymal stem cells (MSC). In this study, we expanded the stromal vascular fraction (SVF) of human adipose tissue and characterized the resulting adherent primary cell cultures by quantitative reverse transcription-polymerase chain reaction, antigen expression, protein fingerprinting, growth kinetics, in vitro tri-lineage differentiation bioactivity, and functional responses to small molecules modulating SMC-related developmental pathways and compared the results to those obtained with functionally validated MSC cultures. SVF-derived initial cultures (P0) were expanded in a defined medium that was not optimized for MSC growth conditions, neither were recombinant cytokines or growth factors added to the media to direct differentiation. The adherent cell cultures derived from SVF expansion under these conditions had markedly distinct phenotypic and biological properties relative to functionally validated MSC cultures. SVF-derived adherent cell cultures retained characteristics consistent with the SMC subpopulation within adipose tissue--phenotype, gene, and protein expression--that were independent of passage number and source of SVF (n=4 independent donors). SVF-derived cells presented significantly less robust in vitro tri-lineage differentiation bioactivity relative to validated MSC. Expanded SVF cells and MSC had opposite responses to the thromboxane A2 mimetic U46619, demonstrating an unambiguous functional distinction between the two cell types. Taken together, these data support the conclusions that SVF cells expanded under the conditions described in these studies are accurately described as adipose-derived SMC and represent a cellular subpopulation of adipose SVF that is separate and distinct from other classes of adipose-derived cells. PMID- 21595546 TI - Management of patients with malignant bowel obstruction and stage IV colorectal cancer. AB - BACKGROUND: Malignant bowel obstruction (MBO), a serious problem in stage IV colorectal cancer (CRC) patients, remains poorly understood. Optimal management requires realistic assessment of treatment goals. This study's purpose is to characterize outcomes following palliative intervention for MBO in the setting of metastatic CRC. STUDY DESIGN: Retrospective review of a prospective palliative database identified 141 patients undergoing surgical (OR; n = 96) or endoscopic (GI; n = 45) procedures for symptoms of MBO. RESULTS: Median patient age was 58 years, median follow-up 7 months. Most (63%) had multiple sites of metastases. Computed tomography (CT) scan findings of carcinomatosis (p = 0.002), ascites (p = 0.05), and multifocal obstruction with carcinomatosis and ascites (p = 0.03) significantly predicted the need for percutaneous or open gastrostomy tube, or stoma. Procedure-associated morbidity for 81 patients with small bowel obstruction (SBO) was 37%; 7% developed an enterocutaneous fistula/anastomotic leak. Thirty-day mortality was 6%. Most (84%) patients were palliated successfully; some received additional chemotherapy (38%) or surgery (12%). Procedure-associated morbidity for 60 patients with large bowel obstruction (LBO) was 25%; 11 patients (18%) required other procedures for stent failure, with one death at 30 days. Symptom resolution was >97%. Patients with LBO had improved symptom resolution, shorter length of stay (LOS), and longer median survival than patients with SBO. CONCLUSIONS: Patients with MBO and stage IV CRC were successfully palliated with GI or OR procedures. Patients with CT-identified ascites, carcinomatosis, or multifocal obstruction were least likely to benefit from OR procedures. CT plays an important role in preoperative planning. Sound clinical judgment and improved understanding are required for optimal management of MBO. PMID- 21595547 TI - What will it take to get IRB reform? PMID- 21595550 TI - Intense pulsed light protects fibroblasts against the senescence induced by 8 methoxypsoralen plus ultraviolet-A irradiation. AB - OBJECTIVE: The purpose of this study was to evaluate the influence of intense pulsed light (IPL) irradiation on 8-methoxypsoralen plus ultraviolet-A irradiation (PUVA)-induced senescence of fibroblasts in vitro. BACKGROUND DATA: Exposure to PUVA may result in stress-induced senescence in fibroblasts. IPL has been widely used to treat photo-aged skin, but the mechanism is not clear. METHODS: The expression of senescence-associated beta-galactosidase (SA-beta-gal) was determined by histochemical staining, cell viability was assessed via an MTT assay, telomere length was determined by real-time polymerase chain reaction (PCR), and changes in the generation of reactive oxygen species (ROS) were determined by flow cytometry (FCM). RESULTS: In comparison with the control cells, cells irradiated with PUVA and PUVA+IPL showed a general elevation in SA beta-gal activity (p<0.05). The number of SA-beta-gal-positive fibroblasts in the PUVA+IPL group was clearly lower than that in the PUVA group (p<0.05). Cell viability showed a time-dependent decrease in both the PUVA and PUVA+IPL groups, in comparison with the viability in the control group, and there was no difference in viability between the PUVA and PUVA+IPL groups. PUVA treatment shortened telomere length and increased the level of ROS, in comparison with the corresponding findings for the control cells (p<0.05), whereas irradiation with IPL after PUVA exposure prevented telomere shortening and decreased the ROS level, in comparison with PUVA treatment only (p<0.05). CONCLUSIONS: PUVA treatment induced fibroblast senescence, and irradiation with IPL after PUVA exposure partially rejuvenated the cells, demonstrating a protective effect against PUVA-induced fibroblast senescence. PMID- 21595551 TI - Effect of a single application of TiF4 and NaF varnishes and solutions combined with Nd:YAG laser irradiation on enamel erosion in vitro. AB - OBJECTIVE: This in vitro study aimed to analyze the influence of neodymium-doped yttrium aluminum garnet (Nd:YAG) laser irradiation on the efficacy of titanium tetrafluoride (TiF(4)) and sodium fluoride (NaF) varnishes and solutions to protect enamel against erosion. BACKGROUND DATA: The effect of Nd:YAG laser irradiation on NaF and AmF was analyzed; however, there is no available data on the interaction between Nd:YAG laser irradiation and TiF(4). METHODS: Bovine enamel specimens were pre-treated with NaF varnish, TiF(4) varnish, NaF solution, TiF(4) solution, placebo varnish, Nd:YAG (84.9 J/cm(2)), Nd:YAG prior to or through NaF varnish, Nd:YAG prior to or through TiF(4) varnish, Nd:YAG prior to or through NaF solution, Nd:YAG prior to or through TiF(4) solution, and Nd:YAG prior to or through placebo varnish. Controls remained untreated. Ten specimens in each group were then subjected to an erosive demineralization (Sprite Zero, 4 * 90 s/day) and remineralization (artificial saliva, between the erosive cycles) cycling for 5 days. Enamel loss was measured profilometrically (MUm). Additionally, treated but non-eroded specimens were additionally analyzed by scanning electron microscope (SEM) (each group n = 2). The data were statistically analyzed by ANOVA and Tukey's post-hoc test (p < 0.05). RESULTS: Only TiF(4) varnish (1.8 +/- 0.6 MUm), laser prior to TiF(4) varnish (1.7 +/- 0.3 MUm) and laser prior to TiF(4) solution (1.4 +/- 0.3 MUm) significantly reduced enamel erosion compared to the control (4.1 +/- 0.6 MUm). SEM pictures showed that specimens treated with TiF(4) varnish presented a surface coating. CONCLUSIONS: Nd:YAG laser irradiation was not effective against enamel erosion and it did not have any influence on the efficacy of F, except for TiF(4) solution. On the other hand, TiF(4) varnish protected against enamel erosion, without the influence of laser irradiation. PMID- 21595552 TI - Effect of LED phototherapy (lambda700 +/- 20 nm) on TGF-beta expression during wound healing: an immunohistochemical study in a rodent model. AB - OBJECTIVE: The aim of the present investigation was to evaluate transforming growth factor beta (TGF-beta) expression on cutaneous wounds in rodents treated or not treated with LED light. BACKGROUND: TGF-beta is a multifunctional cytokine that presents a central action during tissue repair. Although several studies both in vitro and in vivo have shown that LED phototherapy influences tissue repair, a full understanding of the mechanisms involved in its usage, such as in the modulation of some growth factors, remains unclear. MATERIALS AND METHODS: Under general anesthesia, 24 young adult male Wistar rats weighing 200-250 g had one excisional wound created on the dorsum of each, and were randomly distributed into two groups: G0 (Control) and G1 (LED, lambda700 +/- 20 nm, 16 mW, SAEF = 5 J/cm(2), Illuminated Area = 2 cm(2), 8 mWcm(2), 626 s) Each group was subdivided into three subgroups according to the animal death timing (2, 4, and 6 days). LED phototherapy started immediately after surgery and was repeated every other day during the experimental time. Following animal death, specimens were removed, routinely processed to wax, cut and immunomarked with polyclonal anti-TGF-beta, and underwent histological analysis by light microscopy. The mean area of expression of each group was calculated. The data were statistically analyzed using ANOVA and Tukey's test. RESULTS: The area of the expression of TGF-beta on LED-irradiated animals was significantly smaller than on controls at day 2 (p = 0.013). No significant difference was found at later times. It is concluded that the use of LED light, at these specific parameters, caused an inhibition of the expression of TGF-beta at an early stage of the healing process. PMID- 21595553 TI - Single instrument for hemostatic control in laparoscopic partial nephrectomy in a porcine model without renal vascular clamping. AB - PURPOSE: To test the viability of a new device to obtain hemostasis during laparoscopic partial nephrectomy (LPN) without vascular clamping. MATERIALS AND METHODS: We performed a comparative experimental study between a new radiofrequency (RF)-assisted device consisting of a handheld instrument that simultaneously conducts coagulation and cutting tasks without hilar clamping vs a standard technique with hilar clamping. A porcine model was used (10 animals per group) with survival of 17 days. RESULTS: The estimated blood loss with the new device was significantly lower than with the standard technique (15.5+/-23.7 vs 79.4+/-76.3 mL). Although transection time was longer with the new device (10.7+/-13.7 vs 2.1+/-1.2 min), the total operative time was significantly shorter (35.3+/-13.7 vs 60.2+/-10.5 min). Evidence of localized urinary extravasation (urinoma) was identical in both groups (five cases). The group subjected to the new device, however, showed a significantly higher number of cases of leakage after conducting the methylene-blue test: eight (80%) cases vs only one (11%) with the standard technique. Necrosis depth was significantly greater with the new device (6.6+/-0.9 vs <1 mm). CONCLUSIONS: The experimental results suggest that the proposed RF-assisted device provides adequate hemostatic control during transection of the renal parenchyma without additional instruments or surgical maneuvers and could therefore be a valuable adjunct for LPN without vascular clamping. The device was unsuccessful in effectively sealing the collecting system. PMID- 21595554 TI - Environmental mycobacteria: a threat to human health? AB - In many cases, bacterial pathogens are close relatives to nonpathogens. Pathogens seem to be limited lineages within nonpathogenic bacteria. Nonpathogenic isolates are generally more diverse and widespread in the environment and it is generally considered that environmental bacteria do not pose a risk to human health as clinical isolates do; this may not be the case with mycobacteria, but environmental mycobacteria have not been well studied. It is documented that several environmental mycobacteria constitute a source for human infections. Diverse mycobacterial environmental isolates are rarely involved in human disease. Environmental mycobacteria may have a role in degradation of different compounds. Environmental mycobacteria have had a long interaction with humans, maybe as long as the human species, and may have contributed to human evolution. PMID- 21595557 TI - Serum thyrotropin levels and blood pressure response to exercise in a population based study. AB - BACKGROUND: Studies on the relation between thyroid function and exercise blood pressure (EBP) are rare and not population-based, and have yielded inconsistent results. The aim of this study was to investigate whether serum thyrotropin (TSH) levels are related to increased EBP. METHODS: Cross-sectional data from 1438 subjects (711 women) aged 25-83 years without histories of cardiovascular diseases from the 5-year follow-up of the population-based Study of Health in Pomerania (SHIP-1) were analyzed. Blood pressure was measured at the 100 W stage of a symptom-limited bicycle ergometry test. Increased EBP was defined as a value above the sex- and age-specific 80th percentile of participants with serum TSH levels within the reference range (0.25-2.12 mIU/L). RESULTS: There was no association between serum TSH levels and EBP after adjusting for sex, age, waist circumference, diabetes mellitus, smoking status, and antihypertensive medication. The odds for increased systolic EBP (odds ratio 1.24, 95% confidence interval 0.88; 1.76) and diastolic EBP (odds ratios 0.98, 95% confidence interval 0.70; 1.39) as well as for exercise-induced increase of systolic and diastolic blood pressure were not significantly different between subjects with high and low serum TSH levels within the reference range. Similar findings were found for both subjects with TSH levels below and above the reference range, respectively. CONCLUSIONS: We conclude that serum TSH levels are not associated with exercise related blood pressure response. PMID- 21595556 TI - Ultrasound-guided laser ablation of incidental papillary thyroid microcarcinoma: a potential therapeutic approach in patients at surgical risk. AB - BACKGROUND: Incidental papillary thyroid microcarcinoma (PTMC), a frequent clinical problem, is usually associated with a favorable outcome. During long term follow-up, only a minority of cases show aggressive behavior with either lymph node or distant metastases. Recently, we had an opportunity to evaluate the efficacy of nonsurgical, ultrasound (US)-guided percutaneous laser ablation (PLA) for local treatment of PTMC in an otherwise inoperable patient. PATIENT AND METHODS: Neck US examination revealed an incidental, solitary, 8 * 7 * 7 mm hypoechoic nodule with microcalcifications of the right thyroid lobe. The patient suffered from decompensated liver cirrhosis, renal failure, and recent surgery followed by external beam radiation therapy for breast cancer. Cytologic diagnosis showed papillary thyroid carcinoma, but the patient declined surgery because of high risk of thyroid surgery. After local anesthesia with 2% xylocaine, PLA was performed according to the previously reported procedure with an Nd:YAG laser. SUMMARY: The procedure was well tolerated, without side effects, and the patient required no analgesics. US-guided fine-needle aspiration biopsy and core-needle biopsy were performed at 1 and 12 months after PLA, which demonstrated necrotic material and inflammatory cells with no viable neoplastic cell. At the 24 months US follow-up examination, the area of necrosis further decreased, demonstrating a 4 * 4 mm hypoechoic zone and a small hyperechoic area due to fibrotic changes. A fine-needle aspiration biopsy confirmed the absence of malignant cells. CONCLUSIONS: Laser-induced thermal ablation was a safe and effective ablative treatment for a patient with PTMC confined to the thyroid gland who was at high surgical risk. This approach should be considered only in elderly patients and/or in those with comorbidities that might expose the patients to an undue high surgical risk and only after the evaluation by neck US, computed tomography, magnetic resonance imaging, or positron emission tomography/computed tomography rules out lymph-node involvement or metastatic disease. PMID- 21595558 TI - Follicular thyroid carcinoma with metastases to the pituitary causing pituitary insufficiency. AB - BACKGROUND: Pituitary metastases are found in about 1% of all pituitary resections. They often derive from breast, lung, and gastroenteric tract adenocarcinomas, very rarely from thyroid carcinoma. Presenting symptoms of thyroid carcinoma metastatic to the pituitary gland are usually chiasmatic with central neurological impairment due to space-occupying expansion in the parasellar region. Hypopituitarism is more often associated with papillary and medullary rather than follicular thyroid carcinoma (FTC). Here we describe a patient with pituitary metastasis from FTC who had hypopituitarism with thyrotropin (TSH) deficiency. SUMMARY: A 61-year-old woman, who presented with visual deficits and pain to the right orbit, was found on magnetic resonance imaging to have a large mass involving the pituitary gland. She was found to have pituitary insufficiency based on corticotropin-releasing hormone and TSH releasing hormone testing. Transnasopharyngeal biopsy of the mass revealed metastases from FTC. After total thyroidectomy, which confirmed widely invasive FTC, the patient underwent external beam radiation therapy of the metastases for progressive neurological symptoms and an increase in orbit pain. Since endogenous TSH production was insufficient, we used recombinant human TSH (rhTSH) as preparation for a series of radioiodine treatments. rhTSH administration, followed by 7.4 GBq of (131)I, was repeated seven times over a 10-year period. This was associated with a marked decrease in serum thyroglobulin levels accompanied by substantial clinical improvement, but after 7 years disease progression occurred. CONCLUSIONS: Seven patients with pituitary metastases from FTC have been reported. In all cases, some neurological signs and symptoms related to mass effect were reported, but no pituitary insufficiency was described. This may be the first case of FTC with metastases to the pituitary causing hypopituitarism. It seems likely that management of such cases could be limited to biopsy to confirm thyroid carcinoma, rather than more extensive surgery, and that this could be followed by multiple treatments with rhTSH followed by (131)I. PMID- 21595559 TI - Cervical thymic cysts in adults. AB - BACKGROUND: Three types of cervical thymic anomalies have been described: ectopia, thymic cyst, and thymoma. Thymic cysts are very rare causes of benign neck masses in adults and are usually not diagnosed before surgery. Their prevalence is less than 1% of all cervical masses, and they are usually noted in childhood. We systematically reviewed the literature concerning cervical thymic cysts (CTCs) in adults. SUMMARY: We identified 36 adult patients with a CTC. Our analysis included age, gender, cyst size, location, type, symptoms, time from cyst appearance, treatment, pathology, and follow-up. The male/female ratio was 4/5, the mean age was 36 years. Most of the cysts were asymptomatic masses diagnosed by pathology. In only one case did the differential diagnosis include a thymic cyst. Surgery should be considered the treatment of choice, but the size and location of the lesion and its relationship to nearby vital structures should be defined as clearly as possible preoperatively. Excision can be made via a transverse cervical incision. It may be a demanding procedure because of the close anatomical relationship of the CTCs with the carotid sheath and major nerves of the neck (recurrent laryngeal nerve, glossopharyngeal nerve, hypoglossic nerve, and phrenic nerve), particularly if there is adherence of the CTC with those structures. CONCLUSIONS: CTCs are uncommon lesions causing neck swelling and are often misdiagnosed preoperatively. Surgical excision and histological examination of the specimen usually makes the diagnosis. The existence of normal thymus gland in the mediastinum should be confirmed intraoperatively, but this is not critical in adult patients. A CTC should be included in the differential diagnosis of cervical cystic masses. PMID- 21595560 TI - Effects of acupuncture therapy on abdominal fat and hepatic fat content in obese children: a magnetic resonance imaging and proton magnetic resonance spectroscopy study. AB - OBJECTIVES: The aim of this study was to use magnetic resonance imaging (MRI) together with proton magnetic resonance spectroscopy ((1)H-MRS) to study the influence of acupuncture therapy on abdominal fat and hepatic fat content in obese children. DESIGN: The design was a longitudinal, clinical intervention study of acupuncture therapy. SUBJECTS: SUBJECTS were 10 healthy, obese children (age: 11.4 +/- 1.65 years, body-mass index [BMI]: 29.03 +/- 4.81 kg/m(2)). MEASUREMENTS: Measurements included various anthropometric parameters, abdominal fat (assessed by MRI) and hepatic fat content (assessed by (1)H-MRS) at baseline and after 1 month of acupuncture therapy. RESULTS: One (1) month of acupuncture therapy significantly reduced the subjects' BMI by 3.5% (p = 0.005), abdominal visceral adipose tissue (VAT) volume by 16.04% (p < 0.0001), abdominal total adipose tissue volume by 10.45% (p = 0.001), and abdominal visceral to subcutaneous fat ratio by 10.59% (p = 0.007). Decreases in body weight (-2.13%), waist circumference (-1.44%), hip circumference (-0.33%), waist-to-hip ratio (WHR) (-0.99%), abdominal subcutaneous adipose tissue (SAT) volume (-5.63%), and intrahepatic triglyceride (IHTG) content (-9.03%) were also observed, although these were not significant (p > 0.05). There was a significant correlation between the level of abdominal fat (SAT, VAT) and anthropometric parameters (weight, BMI, waist circumferences, hip circumferences). There was no statistically significant correlation between IHTG and anthropometric parameters or abdominal fat content. CONCLUSIONS: The first direct experimental evidence is provided demonstrating that acupuncture therapy significantly reduces BMI and abdominal adipose tissue by reducing abdominal VAT content without significant changes in body weight, waist circumference, hip circumference, WHR, abdominal SAT, or IHTG content. Thus, the use of acupuncture therapy to selectively target a reduction in abdominal VAT content should become more important and more popular in the future. PMID- 21595562 TI - Stem cell standardization. AB - Stem cell research promises, despite the uncertainty that still affects many of its technological aspects, to significantly impact a broad range of life science domains (from drug discovery to innovative cell treatments). A decade of intensive research has produced only fragmented knowledge and unsubstantiated options for innovative treatments to be delivered in the clinical setting. Therapeutic applicability can only be realized or, indeed discarded, based on investigations that adopt more rigorous procedures and strategies. PMID- 21595564 TI - Sprouty1 regulates neural and endothelial differentiation of mouse embryonic stem cells. AB - Fibroblast growth factor (FGF) signaling is implicated in the control of pluripotency and lineage differentiation of both human and mouse embryonic stem cells (mESCs). FGF4 dependent stimulation of ERK1/2 signaling triggers transition of pluripotent ESCs from self-renewal and lineage commitment. In this study, Sprouty 1 (Spry1) expression was observed in undifferentiated mESCs, where it modulated ERK1/2 activity. Spry1 was confirmed as dispensable for the maintenance of self-renewal. However, suppression of Spry1 expression and subsequent activation of ERK1/2 signaling promoted neural differentiation and inhibited endothelial differentiation of mESCs. Moreover, evidence is presented which indicates that SHP2, a major determinant of balance between mESC self-renewal and differentiation, directly regulates Spry1 activity to modulate ERK1/2 signaling and lineage-specific differentiation in mESCs. Our results show that Spry1 has an essential role in the lineage specific differentiation of mESCs. PMID- 21595566 TI - The effect of polymorphisms in candidate genes on the long-term risk of lipodystrophy and dyslipidemia in HIV-infected white patients starting antiretroviral therapy. AB - We investigated whether polymorphisms in human candidate genes could be associated with a different risk of developing lipodystrophy and dyslipidemia in HIV-infected patients starting combination antiretroviral therapy (cART). Genomic DNA samples from white HIV-1-infected patients were analyzed for seven polymorphisms located in the MDR1, TNF-alpha, APM1, APOE, and LPL genes. Lipid data were retrospectively collected beginning with the initiation of cART. Lipodystrophy was assessed cross-sectionally and then prospectively. The association with lipodystrophy and National Cholesterol Evaluation Program Adult Treatment Panel III-defined lipid thresholds was analyzed using survival analysis and logistic regression. One-hundred and seventy-four patients were genotyped. In 151 patients assessed for lipodystrophy, MDR1 3435 T homozygosis was associated with a higher hazard (adjusted hazard ratio, aHR, versus CT 0.25; p=0.02) and tumor necrosis factor (TNF)-alpha 308 G homozygosis with a lower hazard (vs. AA aHR 2.14; p=0.04) of developing trunk fat accumulation after adjusting for gender and initial cART type. The TNF 238 GG genotype was associated with a higher risk of developing low HDL-cholesterol levels (adjusted odd ratio, aOR, 5.91; p=0.01) while patients carrying the LPL S477X mutation were at lower risk of reaching high non-HDL-cholesterol levels (aOR 0.39; p=0.05). The APOEe3/3 genotype patients were at lower risk (aOR 0.26, p=0.015), whereas the adiponectin 276 GT carriers were at higher risk of developing hypertriglyceremia (vs. GG aOR 3.10; p=0.04). Knowledge of the effect of genetic determinants on dyslipidemia and lipodystrophy may prompt the investigation of potential pathogenetic mechanisms and might eventually be used for guiding individualized treatment decisions. PMID- 21595565 TI - Protein S-glutathionylation in malaria parasites. AB - AIMS: Protein S-glutathionylation is a widely distributed post-translational modification of thiol groups with glutathione that can function as a redox sensitive switch to mediate redox regulation and signal transduction. The malaria parasite Plasmodium falciparum is exposed to intense oxidative stress and possesses the enzymatic system required to regulate protein S-glutathionylation, but despite its potential importance, protein S-glutathionylation has not yet been studied in malaria parasites. In this work we applied a method based on enzymatic deglutathionylation, affinity purification of biotin-maleimide-tagged proteins, and proteomic analyses to characterize the Plasmodium glutathionylome. RESULTS: We identified 493 targets of protein S-glutathionylation in Plasmodium. Functional profiles revealed that the targets are components of central metabolic pathways, such as nitrogen compound metabolism and protein metabolism. Fifteen identified proteins with important functions in metabolic pathways (thioredoxin reductase, thioredoxin, thioredoxin peroxidase 1, glutathione reductase, glutathione S-transferase, plasmoredoxin, mitochondrial dihydrolipoamide dehydrogenase, glutamate dehydrogenase 1, glyoxalase I and II, ornithine delta aminotransferase, lactate dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase [GAPDH], pyruvate kinase [PK], and phosphoglycerate mutase) were further analyzed to study their ability to form mixed disulfides with glutathione. We demonstrate that P. falciparum GAPDH, PK, and ornithine delta-aminotransferase are reversibly inhibited by S-glutathionylation. Further, we provide evidence that not only P. falciparum glutaredoxin 1, but also thioredoxin 1 and plasmoredoxin are able to efficiently catalyze protein deglutathionylation. INNOVATION: We used an affinity purification based proteomic approach to characterize the Plasmodium glutathionylome. CONCLUSION: Our results indicate a wide regulative use of S glutathionylation in the malaria parasite and contribute to our understanding of redox-regulatory processes in this pathogen. PMID- 21595567 TI - Connective tissue growth factor (CTGF/CCN2) ELISA: a novel tool for monitoring fibrosis. AB - BACKGROUND: Connective tissue growth factor (CTGF) has been identified as a key factor in the pathogenesis of diseases with significant fibrosis-related complications such as hepatitis, diabetes and renal transplantation. Increasing evidence shows that CTGF levels in plasma, serum and urine have promising biomarker applicability in these disorders. OBJECTIVE: To present an overview of current knowledge on CTGF in various patient populations and the technical aspects of CTGF measurement by enzyme-linked immunosorbent assay (ELISA). METHOD: We performed a comprehensive literature search by using electronic bibliographic databases. CONCLUSION: CTGF is associated with disease severity parameters and outcome in fibrotic disease and may have diagnostic and prognostic values. However, CTGF ELISA needs standardization. PMID- 21595568 TI - Neuroendocrine differentiation as an indicator of chemosensitivity and prognosis in nonsmall cell lung cancer. AB - CONTEXT: Nonsmall cell lung cancers with neuroendocrine differentiation (NSCLC ND) may demonstrate biologic behavior intermediate between NSCLC and small cell lung cancer (SCLC) with impact on prognosis. METHODS: We analyzed 116 consecutive patients with Stage III and IV NSCLC who were diagnosed and treated between 2001 and 2006. Using immuno-histochemical staining for neuron-specific enolase (NSE), chromogranin A (ChrA), and synaptophysin (Syn), 29 (25%) NSCLC-ND were identified. RESULTS: Expression of NSE was present in 22.4%, ChrA in 15.5% and Syn in 14.8% of patients with NSCLC. Therapeutic response was significantly better in the NSCLC-ND group and specimens with > 30% neuroendocrine (NE) differentiated tumor cells showed favourable therapeutic response (P < 0.05). Multivariate binary logistic regression showed that percentage of NE positive tumor cells was a significant independent prognostic factor associated with a favourable outcome. Receiver operating characteristic (ROC) curves and areas under ROC curves confirmed that percentage of NE-differentiated tumor cells could be useful prediction factor of therapeutic response. Moreover, according to percentage of NE-differentiated tumor cells, optimal cutoffs and related sensitivities and specificities were determined for each markers. CONCLUSION: Advanced-stage NSCLC with NE tumor cells are clinically less aggressive tumors. Percentage of NE-differentiated tumor cells identifies patients with favourable therapy response to paclitaxel-cisplatin. PMID- 21595569 TI - Is mid-regional pro-atrial natriuretic peptide (MRproANP) an accurate marker of bacteremia in pyelonephritis? AB - INTRODUCTION: Mid-regional pro-atrial natriuretic peptide (MRproANP) increases during systemic infections and could possibly correlate with bacteremia. METHODS: We determined the characteristics of MRproANP for accuracy to detect positive blood culture. RESULTS: Bacteremia was positive in 58 (15%) of 347 patients. MRproANP levels increased in patients with bacteremia (98.4 pmol/L [interquartile range (IQR) 68.2-153.1] vs. 66.4 pmol/L [IQR 51.0-90.3], p <0.01). Performance of MRproANP to predict bacteremia [AUC = 0.69, 95%CI: 0.61-0.77] was equivalent to C reactive protein (0.66 [95%CI: 0.59-0.74], p = 0.53) but less accurate than procalcitonin (0.78 [95%CI: 0.72-0.84], p <0.001). CONCLUSION: Although MRproANP increased in bacteremic patients with acute pyelonephritis, results of likelihood ratios discarded its use at bedside to predict bacteremia. PMID- 21595570 TI - Serum pneumoproteins in firefighters. AB - Serum Clara cell protein (CC16) and surfactant-associated protein A (SP-A) were measured in a cross-sectional study in 402 firefighters. For the population as a whole, no associations were detected between serum pneumoproteins and smoke exposure. SP-A levels were increased in symptomatic subjects exposed to fire smoke within 2 days before testing. SP-A levels were higher after an inhalation incident ever. CC16 was negatively associated with the number of fires fought in the last 12 months in current nonsmokers. These associations between pneumoprotein levels reiterate the importance of adequate use of self-contained breathing apparatus by firefighters. PMID- 21595571 TI - Iridoid content and biological activities of Veronica cuneifolia subsp. cuneifolia and V. cymbalaria. AB - CONTEXT: The genus Veronica L. (Plantaginaceae) is represented by 79 species, 26 of which are endemic in Turkey. Some Veronica species are used for the treatment of different inflammatory diseases and cancer in traditional medicine. In addition, chemotaxonomy of the genus is important for the reclassification of the family Plantaginaceae after different phylogenetic studies. OBJECTIVE: Veronica cuneifolia subsp. cuneifolia D. Don and V. cymbalaria Bodard were studied from the view point of iridoid glucosides which are known as chemotaxonomical markers for this genus. Radical scavenging and cytotoxic activities of the extracts were also determined in this study. MATERIAL AND METHODS: Major compounds, isolated from iridoid fractions of V. cuneifolia subsp. cuneifolia were used as the standard compounds for HPLC after determination of their structures, and investigated for their presence in iridoid fractions of V. cymbalaria. Additionally, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and SO radical scavenging and cytotoxic activities against three cancer and a noncancerous cell lines of both extract were also tested using the MTT method. RESULTS: While aucubin, catalpol, verproside, amphicoside, verminoside, and veronicoside were obtained from V. cuneifolia subsp. cuneifolia, two more iridoid glucosides, 6-O veratroylcatalposide and 6-O-isovanilloylcatalpol, were isolated from V. cymbalaria. Comparing both species, V. cuneifolia subsp. cuneifolia showed stronger radical scavenging and cytotoxic activities than V. cymbalaria. DISCUSSION: Our results demonstrated that the iridoid contents of both species were very close to each other confirming to the chemotaxonomic studies on Veronica species and their different bioactivity range make the plants interesting from the view point of natural drug discovery research. PMID- 21595572 TI - Enhancement of in vitro and in vivo anticancer activities of polysaccharide peptide from Grifola frondosa by chemical modifications. AB - CONTEXT: Grifola frondosa (Polyporaceae), maitake, is a widely consumed edible mushroom in some Asian countries. The fruit bodies and mycelia of maitake have shown different bioactive compounds with anticancer and other therapeutic properties. OBJECTIVE: This study evaluated three chemically modified maitake polysaccharide-peptides' (MPSP) adjuvant effect (in vivo) and anticancer activity (in vitro growth inhibitory effect) compared with crude MPSP from G. frondosa. MATERIALS AND METHODS: We investigated the possibility of enhancing the adjuvant effect and anticancer effect of crude MPSP by using simple chemical modification methods to convert crude MPSP to phosphorylated, acetylated or esterified MPSPs. The adjuvant effect and growth inhibitory effect were evaluated by C6 cell inoculated rat model with cyclophosphamide (CPA) treatment and in vitro cell viability assay, respectively. RESULTS: All four tested MPSPs showed significant adjuvant effect to CPA treatment on rats inoculated with C6 cancer cells. In addition, an obvious growth inhibitory effect was observed in C6 cancer cells but not in normal brain cells treated with various forms of MPSPs. Only phosphorylation could significantly (p < 0.05) improve the adjuvant effect (in vivo) and growth inhibitory effect. A same rank order (phosphorylated MPSP > esterified MPSP >= acetylated MPSP >= crude MPSP) of efficacy was observed in both the in vivo and in vitro assays. DISCUSSION AND CONCLUSION: This study showed chemical phosphorylation could markedly enhance both adjuvant effects and growth inhibitory effects. This study demonstrated the feasibility of enhancing the efficacy of MPSP by using a simple chemical modification method, and this provides a foundation for future study in this area. PMID- 21595573 TI - Antioxidant and cytotoxic activity of polyphenolic compounds isolated from the leaves of Leucenia leucocephala. AB - CONTEXT: Cancer is a serious clinical problem to the health care system. Anticancer drugs have been extracted from plants containing phenolic compounds. Leucenia species (Fabaceae) contain a variety of bioactive components of numerous biological and pharmacological properties. OBJECTIVE: This study explored the constitutive polyphenols of Leucenia leucocephala Lam. growing in Egypt and evaluated the antioxidant and cytotoxic activity. MATERIALS AND METHODS: Chemical structures of the isolated compounds from the leaves of L. leucocephala were established by spectral techniques (UV, (1)H, and (13)C NMR, MS). RESULTS: Chromatographic separation of 80% MeOH extract of the leaves of L. leucocephala have resulted in a novel flavonoid-galloyl glycoside [myricetin 3-O-(2',3'4'-tri O-galloyl)-alpha-L-rhamnopyranoside] with three known polyphenolic compounds isolated for the first time from this species (apigenin 7-O-beta-D glucuronopyranoside methyl ester, luteolin 7-O-beta-D-glucuronopyranoside methyl ester, and 1,3,6-tri-O-galloyl-beta-D-glucopyranose) and seven known previously isolated compounds. Also, 80% methanol extract exhibited high antioxidant activity (SC(50) = 3.94 ug/ml), which is correlated with its phenolic content. The extract also showed cytotoxic activity against Hep G2 (IC(50) value 1.41 ug/ml) confirming its anticancer activity against hepatocellular carcinoma. Among the tested compounds (4-8) for antioxidant property, compound 7 was the most active compound (SC(50) = 2.49 ug/ml). Also compounds 7 and 8 exhibited high cytotoxic activity (IC(50) = 2.41 and 2.81 ug/ml, respectively). DISCUSSION AND CONCLUSION: These findings demonstrate that the leaves of L. leucocephala contain a considerable amount of polyphenolic compounds with high antioxidant properties, thus it has great potential as a source for natural health products. PMID- 21595574 TI - Stimulative effects of Polygonum amplexicaule var. sinense on osteoblastic MC3T3 E1 cells. AB - CONTEXT: Polygonum amplexicaule D. Don var. sinense Forb. (Polygonaceae) (PAF) is a well known traditional herb used to treat some diseases, such as fractures, rheumatoid arthritis, muscle injury, and pain. However, its pharmacological mechanism of promoting the healing of fractures is still unknown. OBJECTIVE: The present study was designed to investigate the effects of PAF ethanol extracts on the proliferation and differentiation of osteoblastic MC3T3-E1 cell in vitro, thereby to illuminate the pharmacological mechanism to promote the healing of fractures. MATERIALS AND METHODS: The effects of PAF ethanol extracts on MC3T3-E1 cell proliferation and differentiation were detected by using CCK-8, cell cycle, alkaline phosphatase (ALP), and prostaglandin E(2) (PGE(2)) assays in vitro. RESULTS: The results showed that PAF ethanol extracts significantly stimulated cell proliferation at 0.1-100 MUg/mL and the proportion of cells in S-phase increased from 16.33 to 27.29% in osteoblastic MC3T3-E1 cells. Moreover, PAF ethanol extracts increased ALP expression in MC3T3-E1 cells at the concentration from 0.1 to 100 MUg/mL and inhibited PGE(2) production induced by TNF-alpha in osteoblasts at the concentrations ranging from 10 to 100 MUg/mL in MC3T3-E1 osteoblasts. DISCUSSION AND CONCLUSION: These results indicated that PAF directly stimulates cell proliferation and differentiation of osteoblasts; therefore, this study preliminarily explored the pharmacological mechanism of PAF to promote the healing of bone rheumatism and various fractures. PMID- 21595575 TI - Effect of Da-Cheng-Qi decoction on pancreatitis-associated lung injury in patients and anti-inflammatory responses in rat models. AB - BACKGROUND: The traditional herbal medicinal formula Da-Cheng-Qi decoction (DCQD) has long been used to treat pancreatitis in China; however, the underlying mechanisms remain unclear. AIM: To investigate whether DCQD is beneficial to the patients with lung injury in severe acute pancreatitis (SAP); if it is, then to explore the lung protective effect of DCQD and the mechanism involved in rats. METHODS: DCQD was enema administered to 70 patients for 7 days. Mortality, (multi)organ failure during admission were observed, blood samples for laboratory analysis were drawn on admission, on Days 3, 7, and 14 of the treatment. We also experimentally examined the function of two doses of DCQD in SAP rat models. IL 1beta, IL-6, and IL-10 mRNA expression in rat lungs was measured quantitatively by the RT-PCR method and confirmed by morphometric studies of the lungs. RESULTS: It was demonstrated that the administration of DCQD did shorten the average time that patients suffered acute respiratory distress syndrome (ARDS). Compared with untreated rats, the lungs of rats treated with DCQD showed significantly lower levels of proinflammatory cytokine IL-1beta and IL-6 mRNA. Rats treated with DCQD had lower mean pathological lung lesion scores than those in SAP rats. CONCLUSION: DCQD has good prospects in the treatment for SAP because it did shorten the average time that patients suffered ARDS in the clinic. It exerts therapeutic effects on this disease through inhibiting the production of inflammatory mediators, decreasing the anti-inflammatory factors, and mitigating the pathological damage of the lung injury in SAP model. PMID- 21595586 TI - An evaluation of the RNase H inhibitory effects of Vietnamese medicinal plant extracts and natural compounds. AB - CONTEXT: Acquired immune deficiency syndrome (AIDS) is a severe pandemic disease especially prevalent in poor and developing countries. Thus, developing specific, potent antiviral drugs that restrain infection by human immunodeficiency virus type 1 (HIV-1), a major cause of AIDS, remains an urgent priority. OBJECTIVE: This study evaluated 32 extracts and 23 compounds from Vietnamese medicinal plants for their inhibitory effects against HIV-1 ribonuclease H (RNase H) and their role in reversing the cytopathic effects of HIV. MATERIALS AND METHODS: The plants were air-dried and extracted in different solvent systems to produce plant extracts. Natural compounds were obtained as previously published. Samples were screened for RNase H inhibition followed by a cytopathic assay. Data were analyzed using the Microsoft Excel. RESULTS AND DISCUSSION: At 50 MUg/mL, 11 plant extracts and five compounds inhibited over 90% of RNase H enzymatic activity. Methanol extracts from Phyllanthus reticulatus and Aglaia aphanamixis leaves inhibited RNase H activity by 99 and 98%, respectively, whereas four extracts showed modest protection against the cytopathic effects of HIV. CONCLUSION: The screening results demonstrated that the butanol (BuOH) extract of Celastrus orbiculata leaves, methanol (MeOH) extracts of Glycosmis stenocarpa stems, Eurya ciliata leaves, and especially P. reticulatus leaves showed potential RNase H inhibition and protection against the viral cytopathic effects of HIV-1. Further chemical investigations should be carried out to find the active components of these extracts and compounds as potential anti-HIV drug candidates. PMID- 21595588 TI - Anti-inflammatory activities, triterpenoids, and diarylheptanoids of Alnus acuminata ssp. arguta. AB - CONTEXT: The main use of stem bark infusions of Alnus acuminata ssp. arguta (Schlecht.) Furlow (Betulaceae) includes treatments for acute inflammation in Mexican traditional medicine. OBJECTIVE: n-Hexane (CHE), chloroform (CCE), and methanol (CME) extracts of the stem bark were investigated for anti-inflammatory activity and its safety. MATERIALS AND METHODS: The anti-inflammatory effects of the orally administered CME, CCE, and CHE extracts, using carrageenan-induced rat hind paw edema model, and acute oral toxicity in mice, using Lorke's method, were determined. RESULTS AND DISCUSSION: The column chromatographic fraction (CME-3) showed a higher anti-inflammatory activity (92.2%) (IC(50): 60.8 mg/mL) as compared with CME (76.9%); both were in the same order of magnitude as that of indomethacin, the positive control drug. Safety parameters for acute oral toxicity test showed that CME was not toxic (LD(50): >5000). Several triterpenoids (1-7) from hexane extracts and diarylheptanoids (10-14) from methanol extracts of A. acuminata ssp. arguta were isolated and characterized. CONCLUSIONS: These results confirm the traditional uses of A. acuminata in acute inflammatory conditions and its safety for consumption. PMID- 21595589 TI - Could combating vitamin D deficiency reduce the incidence of autoimmune disease? PMID- 21595590 TI - Symptom-adjusted therapy in asthma: it is time to listen to our patients. PMID- 21595592 TI - Icatibant in hereditary angioedema: news and challenges. AB - Hereditary angioedema (HAE) is a rare condition. Its prognosis depends on whether there is laryngeal involvement with a risk of asphyxia, which is present in 25% of such cases. Improved understanding of the pathophysiology of this disease has resulted in the development of targeted therapies including icatibant, which acts as an antagonist at bradykinin B2 receptors. This agent has been shown to be effective in the treatment of attacks of HAE in three Phase III randomized double blind published studies. Efficacy data have been collected in all types of attack: cutaneous, abdominal and laryngeal. Safety data are also encouraging. Icatibant is administered subcutaneously, with the potential for patients to self administer. In the future, this therapy may offer increased independence for HAE patients. PMID- 21595593 TI - Leflunomide in renal transplantation. AB - Leflunomide is a synthetic isoxazole-derivative drug that possesses both immunosuppressive and antiviral properties. Although its only US FDA-approved indication is for the treatment of rheumatoid arthritis, accumulating clinical experience in addition to animal study data makes it an appealing option for patients who are in need of reduction of immunosuppression in the setting of resistant cytomegalovirus infection or BK virus nephropathy, or in renal transplant recipients with chronic allograft dysfunction. While concern over adverse effects such as hepatotoxicity and hemolytic anemia cannot be ignored and there has yet to be a prospective randomized trial for its use in transplantation, its careful usage under close monitoring may provide the best chance for patients who risk allograft rejection during the time of immunosuppressive reduction as they attempt to eradicate BK virus or cytomegalovirus. At the present time, its use as a first-line agent in lieu of mycophenolate mofetil or sirolimus cannot be recommended. PMID- 21595594 TI - Th17 cells generated in the absence of TGF-beta induce experimental allergic encephalitis upon adoptive transfer. AB - The discovery of IL-17-producing helper T cells (Th17) has led to new concepts of T-cell differentiation and immunity. Importantly, Th17 cells are thought to be important drivers of autoimmunity. TGF-beta and IL-6 in combination were shown to induce differentiation of murine naive CD4 T cells into IL-17-producing cells in vitro. By contrast, human Th17 differentiation was shown to be independent of TGF beta and could be induced by IL-6 in conjunction with IL-21 or with IL-1. Ghoreschi et al. have elegantly demonstrated that mouse Th17 cell differentiation can also occur in the absence of TGF-beta. A combination of IL-23, IL-1 and IL-6 can give rise to IL-17-producing cells, which are characterized by the expression of T-bet. Intriguingly, the adoptive transfer of such in vitro differentiated Th17 cells into lymphocyte-deficient mice resulted in the induction of experimental allergic encephalitis, which was more severe than in mice receiving Th17 cells differentiated in the presence of TGF-beta. Collectively, the results suggest that a subpopulation of Th17 cells differentiated in the absence of TGF beta, expressing T-bet and RORgammat, occur in vivo and may be responsible for autoimmunity. PMID- 21595595 TI - Obesity and susceptibility to autoimmune diseases. AB - For decades, obesity has been considered to be the result of the complex interaction between genes and the environment and its pathogenesis is still unresolved. The discovery of hormones and neural mediators responsible for the control of food intake and metabolism at the hypothalamic level has provided fundamental insights into the complicated pathways that control food intake. However, the molecular basis for the association between obesity and low-degree chronic inflammation is still unknown. More recently, the discovery of leptin, one of the most abundant adipocyte-derived hormones, has suggested that nutritional status, through leptin secretion, can control immune self-tolerance modulating Treg suppressive function and responsiveness. Furthermore, recent experimental evidence has shown the presence of an abundant adipose tissue resident Treg population responsible for the control of metabolic parameters and glucose homeostasis. Better knowledge of the intricate network of interactions among leptin-related energy regulation, Treg activities and obesity could lead to valuable strategies for therapeutic intervention in obesity and obesity associated insulin resistance. PMID- 21595596 TI - Ofatumumab in the treatment of low-grade non-Hodgkin's lymphomas and chronic lymphocytic leukemia. AB - Ofatumumab is a novel anti-CD20 monoclonal antibody recently approved for the treatment of chronic lymphocytic leukemia refractory to alemtuzumab and fludarabine. Ofatumumab has also demonstrated activity in other low-grade non Hodgkin's lymphomas. However, the optimal time to use ofatumumab and in what patient population is debatable. This article will review some of the key clinical studies that led to the drug's approval, current recommended usage of the drug and significant future directions. PMID- 21595597 TI - Indications and safety of intravenous and subcutaneous immunoglobulin therapy. AB - Immunoglobulin (Ig) therapy is an important method of treatment for a number of immunological, hematological, neurological and dermatological disorders. Over the years, the range of indications in which Ig therapy, either replacement or immunomodulatory, is effective has substantially increased. Although Ig therapy was originally limited to intramuscular injection, intravenous infusion has became the most frequent route of administration, followed by subcutaneous injection. This article presents current information on indications, mechanisms of action, efficacy and practical aspects of intravenous and subcutaneous Ig replacement/immunomodulatory therapy as well as associated adverse reactions. PMID- 21595598 TI - Current understanding of the immune mechanisms of food protein-induced enterocolitis syndrome. AB - Food protein-induced enterocolitis syndrome (FPIES) is an under-recognized and frequently misdiagnosed non-IgE-mediated food hypersensitivity disorder, characterized by severe vomiting and/or diarrhea. Despite the potential severity of acute reactions, FPIES can be considered self-limiting as avoidance of the incriminating allergen(s) leads to resolution of symptoms. Symptoms typically begin in the first month of life in association with failure to thrive and may progress to acidemia and shock. Although FPIES is well established as a distinct clinical entity, its pathophysiology has not yet been clearly defined and requires further characterization. Several immunologic alterations have been reported in FPIES, suggesting the involvement of antigen-specific T cells and their production of proinflammatory cytokines that regulate the permeability of the intestinal barrier. Humoral immune responses may also be involved in the pathomechanism of FPIES. The aim of this article is to delineate the immunological characteristics of this disorder based on the existing reports and to review the possible pathophysiologic basis of this disease. PMID- 21595599 TI - The risk of tuberculosis in patients treated with TNF antagonists. AB - Over the last 12 years, TNF antagonists have been successfully used for the treatment of numerous patients afflicted by chronic inflammatory disorders. However, data from clinical trials and registries have shown that patients treated with these biologics have an increased risk of reactivating latent TB. The fact that TNF plays a role in the immune cell response and, more specifically, in maintenance of granuloma integrity is the accepted grounds for reactivation of TB following inhibition of TNF. Appropriate screening of latent TB and proper management of cases substantially reduces the incidence of active TB. Nevertheless, debate still remains regarding the value of the tuberculin skin test and IFN-gamma-release assays as diagnostic tools, and treatment across guidelines and recommendations. This largely reflects differences in background population. PMID- 21595600 TI - Regulation of immunity and inflammation by intravenous immunoglobulin: relevance to solid organ transplantation. AB - Intravenous immunoglobulin (IVIg) products are derived from pooled human plasma from thousands of donors and have been used for the treatment of primary immunodeficiency disorders for more than 30 years. IVIg products are also effective in the treatment of autoimmune and inflammatory disorders, however, the precise mechanism(s) of action are not known. Recent data suggest that IVIg has a much broader ability to regulate cellular immunity, including innate and adaptive components. IVIg-induced upregulation of Fcgamma receptor IIB on B cells appears to be an important mode of action in suppression of antigen-presenting cell activity and antibody production. IVIg is also a recently recognized modifier of complement activation and injury. Analysis of clinical studies examining the use of IVIg in desensitization protocols and for treatment of antibody-mediated rejection in transplant recipients are supportive. Here, we discuss these important advancements and their relevance to transplant medicine. PMID- 21595601 TI - The basophil activation test in the diagnosis of immediate drug hypersensitivity. AB - Hypersensitivity reactions to drugs account for 15% of all adverse drug reactions and represent an important health problem with significant morbidity and mortality. This article describes the current applications and perspectives of the basophil activation test by flow cytometry in the diagnosis of immediate-type drug allergy, with particular focus on its diagnostic performance in allergy to neuromuscular blocking agents, antibiotics and NSAIDs and on future applications. PMID- 21595602 TI - Group B coxsackieviruses and autoimmunity: focus on Type 1 diabetes. AB - Group B coxsackieviruses (CVB) and/or their components have been found in the blood and pancreas of patients with Type 1 diabetes (T1D). CVB infections lead to the activation of the innate and adaptive immune systems, which can result in the induction or aggravation of autoimmune processes. Persistent and/or repeated infections of pancreas islet beta cells with CVB and the resulting production of IFN-alpha and inflammatory mediators, combined with a predisposed genetic background, may induce bystander activation of autoimmune effector T cells and an autoreactive response to islet self-antigens through molecular mimicry. Moreover, the antibody-dependent enhancement of CVB infection of monocytes, as well as infection of the thymus can intervene in the pathogenesis of T1D. In contrast with the deleterious effect of CVB, it has been shown that these viruses can protect against the development of T1D under certain experimental conditions. The role of CVB in autoimmunity is complex, and therefore a better understanding of the inducer versus protective effects of these viruses in T1D will help to design new strategies to treat and prevent the disease. PMID- 21595603 TI - Stimulating natural killer cells to protect against cancer: recent developments. AB - Current cancer immunotherapies have begun to target cell types involved in innate immunity, such as natural killer (NK) cells that recognize and kill tumor cells. Recent advances in the study of NK cell biology have generated interest in manipulating these cells to generate anti-tumor responses. A rise in the number of activated NK cells has been shown to prevent and treat cancer in many preclinical models and is a positive clinical factor in human tumors. This article will focus on recent research on the ability of IL-15 and Toll-like receptor ligands to stimulate NK cell activity against cancer. The potential of these therapies, both alone and in conjunction with traditional and other vaccine platforms, will be reviewed. The current status of these therapies in clinical trials will also be discussed. Targeting these cell types in the context of human cancers may be an essential factor in future cancer treatments. PMID- 21595605 TI - Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) can cause progressive walking impairment that contributes to disability, loss of independence, and reduced quality of life. Dalfampridine (4-aminopyridine), a voltage-dependent potassium channel blocker, has been shown to improve walking in patients with MS, as demonstrated by an increase in walking speed. OBJECTIVE: To summarize knowledge about the mechanism of action of dalfampridine in the context of clinical evidence of walking improvement in MS patients. METHODS: Although this was not a systematic review, which is the primary limitation of this study, searches of PubMed were performed using relevant search terms to identify studies that examined the mechanism of action related to MS and its effects in patients with MS in clinical trials. RESULTS: Voltage-gated potassium channels represent a family of related proteins that span cell membranes, open and close in response to changes in the transmembrane potential, and help regulate ionic potassium currents. Action potential conduction deficits in demyelinated axons result in part from the exposure after demyelination of the paranodal and internodal potassium channels that are distributed in the axonal membrane. This exposure leads to abnormal currents across the axonal membrane that can slow action potential conduction, result in conduction failure, or affect the axon's capacity for repetitive discharge. While dalfampridine is a broad-spectrum blocker of voltage-dependent potassium channels at millimolar concentrations, studies have shown improvement in action potential conduction in demyelinated axons at concentrations as low as 1 MUM, and therapeutic plasma concentrations (associated with improved walking) are in the range of 0.25 uM. However, no specific potassium channel subtype has yet been characterized with significant sensitivity to dalfampridine in this range, and the effects of the drug at this low concentration appear to be quite selective. Improved conduction translates into clinical benefit as measured by objectively and subjectively assessed walking relative to placebo. Such improvements were observed in approximately one third of patients treated with an extended-release formulation of dalfampridine in clinical trials. These patients who responded to dalfampridine had an average increase in walking speed of approximately 25%, and greater improvements than nonresponders on a self-reported subjective measure of walking. CONCLUSIONS: The extended-release formulation of dalfampridine has been shown in clinical trials to improve walking speed in approximately one third of MS patients with ambulatory impairment. The putative mechanism of action of dalfampridine is restoration of action potential conduction via blockade of an as yet uncharacterized subset of potassium channels in demyelinated axons. PMID- 21595607 TI - HPLC/MS/MS methodology for sensitive quantitation of monic acid A, the metabolic product of the antibiotic mupirocin. AB - Patients who are treated by self-medication with intranasal mupiricin (BactrobanTM) for controlling meticillin-resistant Staphylococcus aureus may, or may not, adhere to their regimen. Herein, we describe a potential methodology for assessing adherence by measuring the gastric degradation product, monic acid A (MA), as a biomarker in urine. MA was isolated (~80% recovery) through a Waters Oasis HLB cartridge and detected (e.g. 25 pg on the column) by HPLC/MS/MS (API4000). Within a calculated 10(6)-fold margin, this analytical sensitivity should facilitate urinary MA quantitation if, for example, 1% of intranasal mupirocin is swallowed and degraded characteristically to MA by gastric acidity. PMID- 21595606 TI - Evaluating the effects of genetic variants of DNA repair genes using cytogenetic mutagen sensitivity approaches. AB - Mutagen sensitivity, measured in short-term cultures of peripheral blood lymphocytes by cytogenetic endpoints, is an indirect measure for DNA repair capacity and has been used for many years as a biomarker for intrinsic susceptibility for cancer. In this article, we briefly give an overview of the different cytogenetic mutagen sensitivity approaches that have been used successfully to evaluate the biological effects of polymorphisms in DNA repair genes based on a current review of the literature and based on the need for biomarkers that would allow the characterization of the biological and functional significance of such polymorphisms. We also address some of the future challenges facing this emerging area of research. PMID- 21595608 TI - Hospitalizations for asthma in children are linked to undertreatment and insufficient asthma education. AB - BACKGROUND: Most hospital admissions for asthma exacerbation are avoidable with adequate disease management. OBJECTIVES: The objective of this study was to describe the characteristics of children hospitalized with an asthma exacerbation to identify modifiable factors leading to hospitalization. METHODS: The study was conducted in 14 pediatric units and included children 3-17 years of age who were hospitalized for an asthma exacerbation. The present analysis covers 498 children with known asthma. Staff physicians used a standardized questionnaire to collect data. Asthma history came from a parental interview and included usual asthma care, frequency of symptoms and quick-relief medication use in the previous month, frequency of exacerbations and number of unscheduled healthcare visits during the past year, and prior asthma-related hospitalizations. RESULTS: More than half the children had previously been hospitalized for an exacerbation, 42% used continuous inhaled corticosteroids, and 57% had a regular follow-up for asthma. Asthma had been well controlled over the past year for 11%, 12% had experienced exacerbations during the past year but that had been optimally controlled during the previous month, and 11% had recently become poorly controlled (infrequent exacerbations in the previous year and non-optimal control in the previous month). The remaining 327 children (66%) were consistently poorly controlled (non-optimal asthma control in the previous month and frequent exacerbations over the previous year). Among this group, 69% had at least one of the following preventable risk factors for hospitalization: no regular controller therapy (49%), no asthma action plan (40%), or no follow-up for asthma (35%). CONCLUSIONS: Two-thirds of the children with asthma hospitalized for an exacerbation had been consistently poorly controlled during the previous year. They were frequently undertreated and insufficiently educated about asthma. Further efforts are needed to improve asthma treatment and education in France. PMID- 21595609 TI - International conference on physical activity and obesity in children: summary statement and recommendations. AB - The increasing prevalence of obesity among the world's children and youth was the impetus for an international conference convened in Toronto, Canada to examine issues related to physical activity and obesity in children (June 24-27, 2007). The goal of the conference was to assimilate, interpret and share scientific evidence with key stakeholders to develop recommendations concerning effective physical activity policies and programs to address obesity in children. The conference was attended by approximately 1000 delegates from 33 countries who gathered to listen to the invited speakers and to share information on promising practices related to the promotion of physical activity with the aim to reduce the burden of obesity in children. The major topics addressed at the conference included the biological and behavioural causes of obesity, current and past levels of physical activity and sedentarism in children, the role of the social, family and built environment in addressing the physical activity deficit, and the role of legislation and industry in promoting physical activity. Promising physical activity interventions among children were presented, and important research, policy and practice recommendations to address the issue of physical inactivity and obesity were provided. PMID- 21595610 TI - A comparison of lower genital tract glycogen and lactic acid levels in women and macaques: implications for HIV and SIV susceptibility. AB - Understanding factors that affect heterosexual transmission of HIV in women is of great importance. Lactobacilli in the lower genital tract of women utilize glycogen in vaginal epithelial cells as an energy source and produce lactic acid. The resultant vaginal acidity is believed to provide protection against HIV infection. Conversely, bacterial vaginosis (BV) is characterized by less lactic acid and a higher pH, and is associated with increased susceptibility to HIV infection. Because vaginal infection of macaques with simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) is used as a model to study HIV sexual transmission, and because previous studies have shown a paucity of lactobacilli in rhesus macaques' lower genital tract, we compared lactic acid and glycogen levels in the genital fluid of rhesus and pigtail macaques with levels found in humans. The levels of lactic acid were lower in both rhesus (median=1.2 mol lactate/mg protein) and pigtail macaques (median=0.7 mol/mg) compared to women with healthy genital microbiota (median=4.2 mol/mg). Glycogen levels were significantly lower in both rhesus (median=0.004 MUg glycogen/MUg protein) and pigtail macaques (median=0 MUg/MUg) than in women (median=0.2 MUg/MUg). No significant differences in glycogen or lactate levels were observed comparing longitudinally collected samples from cycling pigtail macaques. These data show that the previously reported scarcity of lactobacilli in macaques correlates with low glycogen and lactic acid levels. These findings have important implications for studies of vaginal infection of macaques with SIV or SHIV and further our understanding of how the bacterial microbiota influences HIV infection. PMID- 21595611 TI - Description of anaphylactic reactions to paclitaxel and docetaxel reported to the FDA, with a focus on the role of premedication. AB - PURPOSE: Anaphylactic reactions (ARs) have been frequently reported with taxanes. The authors' purpose was to summarize published case reports and describe ARs from taxanes reported to the Food and Drug Administration (FDA) with a focus on use of package insert-specified prophylactic premedications (PPMs). METHODS: The authors searched PubMed for the relevant literature. The authors obtained cases of ARs reported to the FDA through 31 December 2009 using the drug names and preferred terms for ARs. The authors used chi2 and Student's t-tests to compare ARs from paclitaxel and docetaxel. The authors compared mortality based on presence/absence of PPMs. For signal detection, the authors calculated empirical Bayes geometric mean (EBGM) values. RESULTS: There was one docetaxel and eight paclitaxel case report articles describing ARs. The authors found 290 and 683 FDA reports of ARs from docetaxel and paclitaxel, respectively. More docetaxel cases were associated with mortality (54 vs 29%, p < 0.001). When PPMs were administered, mortality occurred in more docetaxel cases (52 vs 18%, p < 0.001). EBGM signals were 1.74 for docetaxel and 2.50 for paclitaxel. CONCLUSIONS: Mortality was reported in more docetaxel ARs than paclitaxel. Documented use of PPMs did not significantly impact mortality from ARs with docetaxel, but was associated with significantly lower mortality from ARs with paclitaxel. PMID- 21595612 TI - Nanomaterials and hydrogel scaffolds for articular cartilage regeneration. AB - Osteoarthritis (OA) is a major clinical and scientific challenge. The degradation of articular cartilage in the joints is a common manifestation of painful arthritis. The regeneration of articular cartilage in OA is an unmet clinical need. The assembly of articular cartilage by tissue engineering toward complete regeneration is the goal of most scientists and surgeons. The key ingredients for regeneration are signals, stem cells, and scaffolds. This brief review focuses on the scaffold, with special emphasis on hydrogels and nanomaterials for the assembly of tissue-engineered cartilage, and ultimately leading to the total regeneration of articular cartilage in the joints. PMID- 21595613 TI - Genotoxic effects of anesthetic agents: an update. AB - INTRODUCTION: Exposure to anesthetics in the health environment may entail a health risk for patients and operating room personnel. Knowing the effects of anesthetic agents on genetic material could be a valuable basic support for anesthesia care providers to improve treatment performance, increase patient safety and reduce the risks for patients and staff in the operating room. AREAS COVERED: Relevant literature was identified using MEDLINE, CINAHL(r) and Cochrane Library databases. Over 200 abstracts for articles published from 1980 to 2010 were examined. Original articles were reviewed and relevant citations from these articles were also considered. EXPERT OPINION: Despite some conflicting results, the current available data indicate that exposure to anesthetics, especially nitrous oxide and halogenated agents, is associated with general and genotoxic risks, whereas intravenous agents, such as propofol and its metabolites are not associated with genotoxic effects. Moreover, given that different anesthetic drugs are used in combination it is, thus, very difficult to understand whether the observed effects or absence of effects are due to an individual agent action or linked to a synergy action of different anesthetics involved. Further clinical and experimental evidence is warranted. PMID- 21595614 TI - [Hearing aid use and patient satisfaction]. AB - OBJECTIVES: In this study, we assessed the hearing aid usage ratios and durations, patient satisfaction and the probable causes of disuse if they are not used. PATIENTS AND METHODS: A questionnaire with 16 questions was applied to the patients who were prescribed hearing aids in our clinic between January 2007 and December 2009. A total of 517 patients were called by phone. Hundred and seventy nine of the patients (75 females, 104 males; mean age 60+/-23 years; range 17 to 94 years) participated in the trial. Hearing aid usage ratios and patients' satisfaction were determined and the factors influencing usage were statistically investigated. RESULTS: Hundred and forty-two of the patients used their hearing aids regularly and 37 of the patients either used their aids rarely or never used them. The most common cause reported for disuse was the frequent noise coming from the hearing aid. CONCLUSION: Failure to explain the usage of the hearing aids to the patients and age over 70 years have a statistically significant negative effect on the duration of hearing aid use and patient satisfaction. PMID- 21595615 TI - [Effect of the levels of vascular endothelial growth factor-A and C on the prognosis of patients with laryngeal carcinoma]. AB - OBJECTIVES: In this study, we determined the prognostic importance of vascular endothelial growth factor (VEGF)-A and C values and their relationship with tumor stages and neck lymp node involvement and also, the relationship between microvessel density and tumor stage in the pathologic specimens. PATIENTS AND METHODS: Thirty-three male patients (mean age 57.8+/-7.2 years; range 49 to 69 years) who underwent surgical treatment for laryngeal squamous cell carcinoma and a control group of 13 healthy male subjects (mean age 54.2+/-6.1 years; range 41 to 62 years) were included in the study. Patients were divided into two groups: the early-stage group consisting of patients with T1 and T2 stage tumors and the advanced stage group including patients with T3 and T4 stage tumors. Patients are evaluated in terms of plasma VEGF-A and C levels before and six months after the surgery. In the pathologic specimens, CD 31 was used for immunohistochemical staining. For each patient the number of microvessels per millimeter square (microvessel density) was determined. RESULTS: The preoperative plasma VEBF-A levels of the patients with early-stage tumors were significantly lower compared to those of the control group, while there was no significant difference between the preoperative levels of the patients with advanced stage tumors and the levels of the control group. There was no significant difference between the preoperative and postoperative 6th month VEGF-A levels of the patients both in the early-stage and the advanced stage groups. The preoperative plasma VEGF-C values of the patients with lymph node involvement were significantly lower than those of the patients with early-stage tumors. There was no significant difference between the VEGF-C levels in pre- and postoperatively at six months after the operation of patients with lymph node involvement. There was no significant difference between the preoperative VEGF-C levels of the patients with lymph node involvement and those without lymph node involvement. No significant difference was found in microvessel density between the cases with early and advanced stage tumors. CONCLUSION: It was seen that the plasma VEGF-A value did not increase in patients with laryngeal cancer and rather it is low in patients with early-stage disease. No relationship was found between the plasma VEGF-C values and cervical lymph node involvement. PMID- 21595616 TI - Does nasal obstruction affect the articulation of plosive consonants? AB - OBJECTIVES: In this study, we investigated the impact of chronic nasal obstruction on articulation of the Turkish voiceless plosive (stop) consonants and examined the effect of the nose- and mouth-breathing on the articulatory characteristics of the specific speech sounds. PATIENTS AND METHODS: Twenty-one controls with nose-breathing and 20 patients with mouth breathing were included in this study. The nasal obstruction history of the patients was 10 to 22 years. In the mouth-breather group, intranasal pathologies except septal deviation and turbinate hypertrophy were excluded. The nose-breather subjects without nasal pathologies served as the control group. The subjects graded nasal obstruction through visual analog scale (VAS) from 0 to 10. The minimal cross-sectional area (MCA) and minimal cross-sectional volume (MCV) at the level of septal tubercle and the head of inferior turbinate were established to be 1 and 2 by acoustic rhinometry. Minimal cross-sectional volume was defined as the volume below the curve. The syllables [pa], [ta], [ka] uttered by the subjects were recorded for the spectrographic analysis. Voice onset time (VOT) was measured on wide-band spectrogram. RESULTS: The VOT value of /p/ was found lower and the VOT values for /t/ and /k/ were found higher in mouth-breathers compared to nose-breathers, while the difference was not statistically significant. The right and left-sided VAS values of the nasal obstruction group were significantly higher compared to controls (p=0.001). The right and left-sided MCA1, MCA2, MCV1 and MCV2 were found statistically different between the two groups. CONCLUSION: It was concluded that the articulation features of plosive consonants were not significantly affected by nasal obstruction. PMID- 21595617 TI - Quantifying the expression of VEGF using qRT-PCR, evaluation of MVD and their correlation with clinicopathological factors in laryngeal squamous cell carcinoma. AB - OBJECTIVES: In this study we quantified the expression of vascular endothelial growth factor (VEGF) using quantitative real-time polymerase chain reaction in laryngeal squamous cell carcinoma (LSCC) tissues and evaluated the correlation between the level of VEGF and microvessel density (MVD), and clinicopathological factors. PATIENTS AND METHODS: Twenty-seven patients with LSCC undergoing total or partial laryngectomy at the Ear, Nose, and Throat and Head and Neck Surgery Department of the Izmir Tepecik Training and Research Hospital between September 2006 and July 2008. There was no VEGF expression in two patients that were excluded from the study. Twenty-five patients (24 males, 1 female; mean age 61 years; range 43 to 82 years) were included in this study, but MVD levels of 10 patients could not be determined. RESULTS: As defined by the 2003 American Joint Committee on Cancer (AJCC) TNM classification, seven patients (28%) were stage 1, six patients (24%) were stage 2, four patients (16%) were stage 3, and eight patients (32%) were stage 4. Thirteen patients (52%) had well-differentiated (G1) tumors, and twelve had moderately differentiated tumors. Among the 15 patients for whom the MVD was determined, the median value was 48, with a (range 13-78; vessels / 3.76 mm2). Among the 25 patients for whom the VEGF level was determined, the median value was 0.035 vessels / 3.76 mm2 (range 0.010-0.127). CONCLUSION: We could not find a statistical correlation between clinicopathological factors and either VEGF or MVD. Our study demonstrates that VEGF is expressed by LSCC. PMID- 21595618 TI - Comparison of efficacy of different treatment methods in the treatment of idiopathic tinnitus. AB - OBJECTIVES: This study aims to detect whether any differences were present between betahistine dihydrochloride, transcutaneal electrical nerve stimulation and pure tone masking-tinnitus retraining therapy (TRT) methods in the effects on quality of life and treatment of the symptoms of the patients. PATIENTS AND METHODS: A total of 91 patients (42 females, 49 males; mean age 49.3+/-8.3 years; range 30 to 70 years) who admitted to the Otorhinolaryngology Clinic of the Ufuk University between June 2009 and June 2010 with a complaint of subjective tinnitus and who had no hearing loss were included in the study. In this study, the effects of these three treatment methods on healing and quality of life in patients suffering from bilateral subjective tinnitus were comparatively evaluated using Tinnitus Handicap Inventory Score (THIS), visual analog scale (VAS) and audiological parameters. The evaluations were made immediately before the treatment, immediately after the treatment and three weeks after the treatment. Kolmogorov-Smirnov analysis was used to test the normal distribution of the data and Wilcoxon signed rank test was used to show the differences between the different treatment methods before the treatment, immediately after the treatment and three weeks after the treatment. Mann-Whitney U and Kruskal Wallis H tests were used to show the inter-group differences. RESULTS: In the inter-group analyzes, success rate of the pure tone masking-TRT was much higher when compared to the other treatment methods. In the evaluations performed at the end of the three-month period, it was seen that the efficacy of the treatment was continuing. CONCLUSION: According to these results, pure tone masking-TRT was found to be the best treatment method when compared to other methods and it was concluded that this treatment may be considered as the first choice in patients with idiopathic tinnitus. PMID- 21595619 TI - Does mitomycin-C increase collagen turnover as a modulator of wound healing in tracheostomyzed rats? AB - OBJECTIVES: This study aims to investigate the effect of mitomycin-C in the wound healing process on collagen synthesis in tracheostomyzed rats. MATERIALS AND METHODS: Fourteen healthy, in both sexes, mean weight of 270 g (range 250-300 g), Wistar-Albino type rats underwent tracheotomy and tracheal mucosa was damaged with micro-scissors on both sides of tracheostomyzed area. The rats were divided into two groups: The experimental group (group 1) received immediate topical application of mitomycin-C 0.2 mg/ml; the control group (group 2) received saline solution. The rats were sacrificed after a period of one month. Subsequently, the tracheostomyzed region was excised and vertically divided into the two parts. The level of hydroxyproline in the dry tissue was measured in one part of the tissue. Fibroblast count was performed in the other part of the tracheostomyzed region using the stereological method. RESULTS: The hydroxyproline level was much higher in the mitomycin-C group when compared to the control group (p<0.05). In contrary, the number of fibroblasts was lower in the mitomycin-C group than control group (p<0.05). CONCLUSION: When used in wound healing, mitomycin-C may increase collagen synthesis or quicken the wound healing process after one month. PMID- 21595620 TI - Supraclavicular thoracic duct cyst. AB - The thoracic duct cysts located in the supraclavicular region are very rare masses, the etiology of which is not completely known. This article presents the clinical follow-up of a 35-year-old male patient diagnosed with throracic duct cyst situated in the left supraclavicular region and the patient's condition is discussed in line with literature. The patient admitted to our clinic with a complaint of a mass in the left supraclavicular region that had appeared six months ago and that had been increasingly growing. A cyst excision under general anesthesia was performed to the patient who was pre-diagnosed with thoracic duct cyst following the radiological evaluation and the needle aspiration biopsy. There were no complications or a recurrence during the six months of postoperative follow-up. PMID- 21595621 TI - Ossifying fibroma of the inferior turbinate. AB - Hypertrophy of inferior turbinate is a common condition, especially with nasal septum deviation. Sometimes, the cause of hypertrophy of inferior turbinate can be fibro-osseous lesions. Benign, rare, and non-aggressive fibro-osseous neoplasms such as ossifying fibroma can affect paranasal sinuses. Isolated inferior turbinate involvement is extremely rare in ossifying fibroma. In this article, we present a 28-year-old female suffering from nasal obstruction due to septal deviation and hypertrophy of inferior turbinate. Preoperative and postoperative investigation show that cause of hypertrophy of inferior turbinate is ossifying fibroma. To our knowledge, that this is the second case of ossifying fibroma reported in the English-language literature due to its isolated localization. However, if the patients with inferior turbinate hypertrophy are examined carefully, we can prevent unnecessary medical treatment and surgery for inferior turbinate hypertrophy. PMID- 21595622 TI - Pre-auricular and ascending helical free composite flap in reconstructing an alar defect resulting from a human bite: a case report. AB - Full-thickness defects of the nose result in severe aesthetic and functional problems. Nasal alar defects are frequently caused by trauma, surgical resection or congenital deformities, yet an alar defect due to a human bite is quite rarely seen. For a successful alar reconstruction, selected tissue must be similar to nasal structures in texture, color and thickness. The structural similarities between the nasal alae and auricular helices have allowed the use of free helical composite flaps for the repair of nasal defects. In this article, we report a 36 year-old male patient who had a right alar defect caused by a human bite. The defect was successfully reconstructed with a reverse flow superficial temporal vessel based pre-auricular and ascending helical free composite flap. Since the color and the texture of the flap was compatible with the nose integuments, this flap enjoyed of an optimal integration in the central facial area. PMID- 21595623 TI - A rare anatomic variation of the chorda tympani. AB - The chorda tympani is an important anatomical structure in the tympanic cavity. It may have some anatomic variations. Its anatomic variations are of interest in certain otologic surgical procedures. There are limited reports in the literature about the variations of the chorda tympani. A 49-year-old female patient was refered to our clinic because of conductive hearing loss and tympanic membran perforation in the right ear. During the tympanoplasty surgery, when the tympanomastoid flap was elevated, the chorda tympani was seen between flap and bone as a non-described anatomic variation. This article present a non-described anatomic variation of the chorda tympani. PMID- 21595624 TI - [Congenital cholesteatoma frequently mistaken for temporal bone dermoid cyst: a case report]. AB - Dermoid cysts of the middle ear are very rare and can develop behind an intact tympanic membrane, just like congenital cholesteatoma. The visual and clinical symptoms of congenital cholesteatomas and dermoid cysts are difficult to distinguish from each other. Their treatments are similar, however the correct diagnosis can be obtained histopathologically after removing the lesion. In this article a case of a twenty-seven-year-old male patient, whose diagnosis was presumed to be dermoid cyst in the middle ear according to the preoperative radiologic examination but reported to be congenital cholesteatoma as a result of the postoperative histopathologic examination, was reported. PMID- 21595625 TI - Doxycycline inhibition of abdominal aortic aneurysm growth: a systematic review of the literature. AB - Abdominal aortic aneurysm (AAA) is a common disease and a major cause of death through rupture, the risk of which increases with aneurysm size. There is approximately a 5 year interval from when aneurysmal dilatation develops until it reaches a size where surgery is indicated. Slowing, or arresting, aneurysm growth during this period would be beneficial. Aneurysmal aortic wall degeneration is a multifactorial, chronic inflammatory process resulting via activation of matrix metalloproteinases (MMPs), in destruction of mural connective tissue. Doxycycline, a tetracycline antibiotic, is a known inhibitor of MMPs. Animal studies of doxcycline for AAA provide significant evidence of a beneficial effect. However, the human studies, comprising 6 controlled trials and 2 cohort studies, provide conflicting evidence. They are generally of poor methodological quality with small numbers (just 255 subjects analyzed), lack of adjustment for confounding variables, short term doxycycline exposure and a lack of long term follow up. Standardization of dose (per unit weight) and confirmation of compliance remain other systemic failings. The safety of long-term doxycycline use is yet to be proved. The evidence for any beneficial effect of doxycycline as a treatment for AAA, therefore, remains weak. Further studies are required and will ideally be multicentre, involve large subject numbers and be of high quality randomization and blinding with longer periods of doxycycline exposure, confirmation of compliance, standardization of confounding variables and prolonged follow up. PMID- 21595626 TI - Medical treatment of critical limb ischemia: current state and future directions. AB - Atherosclerotic critical limb ischemia (CLI) is manifested by ischemic rest pain, non-healing ulcers or gangrene. The incidence of CLI is estimated to be approximately 500-1000 new cases per year per million people and is expected to grow in developed countries as the population ages with an increasing prevalence of diabetes. Patients diagnosed with CLI are at very high risk of major amputation and cardiovascular morbidity and mortality and experience poor physical function and quality of life. The goals of treatment for CLI are relieving ischemic pain, healing ulcers, preventing limb loss, improving patient function and quality of life, and prolonging survival. Prompt surgical or endovascular revascularization is currently recommended for limb salvage in CLI. All patients with CLI should receive cardiovascular risk reduction therapies, focused on optimizing antiplatelet therapy and risk factor management, to reduce cardiovascular event rates. Adjunctive pharmacotherapy with antithrombotic drugs, statins, and beta-blockers is critical to decrease perioperative cardiovascular complications in patients undergoing surgical vascular reconstruction and enhance postrevascularization arterial and graft patency. In non-reconstructable patients with stable pain and tissue loss, evidence suggests that prostanoids, dedicated wound care programs, and several mechanical devices, such as spinal cord stimulation, intermittent pneumatic compression, and hyperbaric oxygen therapy, can alleviate ischemic symptoms and improve limb salvage. Current medical armamentarium used in treating ischemic wounds also includes ultrasound and negative pressure wound therapy. Therapeutic neovascularization, including gene- and cell-based approaches, is a novel promising tool in the management of CLI under ongoing investigation. PMID- 21595627 TI - XDR-TB, what is it; how is it treated; and why is therapeutic failure so high? AB - Drug resistance is a major hurdle in the global battle against tuberculosis (TB). In tackling this problem it is important to understand both how resistance emerges as well as the ways in which multi-drug and extensively drug-resistant TB (M/XDR-TB) may be successfully treated. The biggest problem with treatment is the lack of effective drugs. Exciting developments have been made in this area over recent years with useful drugs being found from older agents as well as new discoveries. Patent applications are being made for novel agents and are also possible as new use for older agents such as thioridazine. A flourishing drug pipeline is critical if we are to make progress in the management of M/XDR-TB. PMID- 21595628 TI - "European panel on low density lipoprotein (LDL) subclasses": a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses. AB - Aim of the present Consensus Statement is to provide a comprehensive and up to date document on the pathophysiology, atherogenicity and clinical significance of low density liproproteins (LDL) subclasses. We sub-divided our statement in 2 sections. section I discusses the pathophysiology, atherogenicity and measurement issues, while section II is focused on the effects of drug and lifestyle modifications. Suggestions for future research in the field are highlighted at the end of section II. Each section includes Conclusions. PMID- 21595629 TI - "European panel on low density lipoprotein (LDL) subclasses": a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses: executive summary. PMID- 21595630 TI - Therapeutic interventions to renin-angiotensin-aldosterone system, and vascular redox state. AB - It is well established that RAS plays a key role in the development of hypertension, cardiovascular and renal disease. On the other hand oxidative stress is a key feature in vascular homeostasis. Many of the cellular effects of Ang II appear to be mediated by ROS generated by NAD(P)H oxidase. In this review, we provide an overview of ROS physiology in human vessels especially in relation with RAS. We also discuss how therapeutic interventions on RAS affect redox signaling in the vascular wall at a clinical level with the discussion of recent patents. PMID- 21595631 TI - Computer-aided drug design for AMP-activated protein kinase activators. AB - AMP-activated protein kinase (AMPK) is an important therapeutic target for the potential treatment of metabolic disorders, cardiovascular disease and cancer. Recently, various classes of compounds that activate AMPK by direct or indirect interactions have been reported. The importance of computer-aided drug design approaches in the search for potent activators of AMPK is now established, including structure-based design, ligand-based design, fragment-based design, as well as structural analysis. This review article highlights the computer-aided drug design approaches utilized to discover of activators targeting AMPK. The principles, advantages or limitation of the different methods are also being discussed together with examples of applications taken from the literatures. PMID- 21595632 TI - Redox properties of the tissue factor Cys186-Cys209 disulfide bond. AB - TF (tissue factor) is a transmembrane cofactor that initiates blood coagulation in mammals by binding Factor VIIa to activate Factors X and IX. The cofactor can reside in a cryptic configuration on primary cells and de-encryption may involve a redox change in the C-terminal domain Cys(186)-Cys(209) disulfide bond. The redox potential of the bond, the spacing of the reduced cysteine thiols and their oxidation by TF activators was investigated to test the involvement of the dithiol/disulfide in TF activation. A standard redox potential of -278 mV was determined for the Cys(186)-Cys(209) disulfide of recombinant soluble TF. Notably, ablating the N-terminal domain Cys(49)-Cys(57) disulfide markedly increased the redox potential of the Cys(186)-Cys(209) bond, suggesting that the N-terminal bond may be involved in the regulation of redox activity at the C terminal bond. Using As(III) and dibromobimane as molecular rulers for closely spaced sulfur atoms, the reduced Cys(186) and Cys(209) sulfurs were found to be within 3-6 A (1 A=0.1 nm) of each other, which is close enough to reform the disulfide bond. HgCl2 is a very efficient activator of cellular TF and activating concentrations of HgCl2-mediated oxidation of the reduced Cys(186) and Cys(209) thiols of soluble TF. Moreover, PAO (phenylarsonous acid), which cross-links two cysteine thiols that are in close proximity, and MMTS (methyl methanethiolsulfonate), at concentrations where it oxidizes closely spaced cysteine residues to a cystine residue, were efficient activators of cellular TF. These findings further support a role for Cys(186) and Cys(209) in TF activation. PMID- 21595633 TI - Dissection of carotid sinus hypersensitivity: the timing of vagal and vasodepressor effects and the effect of body position. AB - We assessed the timing of vagal and sympathetic factors that mediate hypotension during CSM (carotid sinus massage) in patients with carotid sinus hypersensitivity. We hypothesized that a fall in cardiac output would precede vasodepression, and that vasodepression would be exaggerated by head-up tilt. We performed pulse contour analyses on blood pressure recordings during CSM in syncope patients during supine rest and head-up tilt. In a subset we simultaneously recorded muscle sympathetic nerve activity supine. During supine rest, systolic blood pressure decreased from 150+/-7 to 107+/-7 mmHg (P<0.001) and heart rate from 64+/-2 to 39+/-3 beats/min (P<0.01). Cardiac output decreased with heart rate to nadir (66+/-6% of baseline), 3.1+/-0.4 s after onset of bradycardia. In contrast, total peripheral resistance reached nadir (77+/-3% of baseline) after 11+/-1 s. During head-up-tilt, systolic blood pressure fell from 149+/-10 to 90+/-11 mmHg and heart rate decreased from 73+/-4 to 60+/-7 beats/min. Compared with supine rest, cardiac output nadir was lower (60+/-8 compared with 83+/-4%, P<0.05), whereas total peripheral resistance nadir was similar (81+/-6 compared with 80+/-3%). The time to nadir from the onset of bradycardia did not differ from supine rest. At the onset of bradycardia there was an immediate withdrawal of muscle-sympathetic nerve activity while total peripheral resistance decay occurred much later (6-8 s). The haemodynamic changes following CSM have a distinct temporal pattern that is characterized by an initial fall in cardiac output (driven by heart rate), followed by a later fall in total peripheral resistance, even though sympathetic withdrawal is immediate. This pattern is independent of body position. PMID- 21595634 TI - First description of posterior reversible encephalopathy syndrome as a complication of glycerolnitrate patch following open cardiac surgery. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) affects predominantly the parietal and occipital lobes. Frequent clinical features are epileptic seizure, altered mental status and visual disturbances. CLINICAL PRESENTATION: We present the first case of a patient with pericarditis and mitral valve insufficiency, who developed PRES after application of a glycerolnitrate patch day three post-operatively and whose neurological deficits improved within 2 days after withdrawal of patch therapy. CONCLUSION: The precise pathomechanism of PRES is unknown. The lower sympathetic innervation of the posterior circulation may be one explanation for its particular vulnerability to vasodilatation caused by glycerolnitrate. PMID- 21595635 TI - Longitudinal measurement of cytokines in pre-eclamptic and normotensive pregnancies. AB - OBJECTIVE: To evaluate differences in plasma cytokine levels longitudinally in pre-eclamptic and normotensive pregnancies. An increased inflammatory response has long been associated with pre-eclampsia, both early and late in the pre eclamptic pregnancy. DESIGN: Blood samples were collected longitudinally during pregnancy from a cohort of 1 631 pregnant women. Thirty-two women with pre eclampsia and 67 normotensive pregnant women were identified from the cohort. SETTING: A Danish regional hospital. SAMPLES: Samples were collected from the 18th week of pregnancy until delivery and divided into the following four gestational intervals: <25th week, 26th-29th week, 30th-35th week and >36th week. METHODS: Simultaneous measurement of all nine cytokines was done using a capture bead system. MAIN OUTCOME MEASURES: Plasma levels of interleukin (IL)-1beta, IL 2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-alpha, interferon-gamma and granulocyte macrophage colony-stimulating factor during pre-eclamptic and normotensive pregnancies. RESULTS: Pre-eclampsia was associated with increased tumor necrosis factor-alpha between the 26th and 29th week (p=0.0421) and increased IL-6 after the 36th week (p=0.0044). The other cytokines measured were comparable in the two groups. CONCLUSIONS: This large prospective collection of blood samples was undertaken to determine inflammatory status during pre eclamptic and normotensive pregnancies. Our results support a tendency towards increased inflammation in pre-eclampsia, but the measured cytokines are not eligible for prediction, monitoring or diagnosing pre-eclampsia. PMID- 21595636 TI - Massive subchorionic thrombohematoma: termination should not be discouraged by antenatal diagnosis. PMID- 21595639 TI - A multi-species model to assess the effect of refugia on worm control and anthelmintic resistance in sheep grazing systems. AB - OBJECTIVE: Develop a computer simulation model that uses daily meteorological data and farm management practices to predict populations of Trichostrongylus colubriformis, Haemonchus contortus and Teladorsagia (Ostertagia) circumcincta and the evolution of anthelmintic resistance within a sheep flock. Use the model to explore if increased refugia, provided by leaving some adult sheep untreated, would delay development of anthelmintic resistance without compromising nematode control. PROCEDURES: Compare model predictions with field observations from a breeding flock in Armidale, NSW. Simulate the impact of leaving 1-10% of adult sheep untreated in diverse sheep-grazing systems. RESULTS: Predicted populations of Tr. colubriformis and T. circumcincta were less than those observed in the field, attributed to nutritional stress experienced by the sheep during drought and not accounted for by the model. Observed variation in faecal egg counts explained by the model (R(2) ) for these species was 40-50%. The H. contortus populations and R(2) were both low. Leaving some sheep untreated worked best in situations where animals were already grazing or were moved onto pastures with low populations of infective larvae. In those cases, anthelmintic resistance was delayed and nematode control was maintained when 1-4% of adult stock remained untreated. CONCLUSIONS: In general, the model predicted that leaving more than 4% of adults untreated did not sufficiently delay the development of anthelmintic resistance to justify the increased production risk from such a strategy. The choice of a drug rotation strategy had an equal or larger effect on nematode control, and selection for resistance, than leaving 1-10% of adults untreated. PMID- 21595640 TI - An outbreak of granulomatous peritonitis caused by injectable selenium in a flock of Merino sheep. AB - During meat inspection, unusual pigmented lesions were found in the abdomens of 411 sheep from a flock raised in the Northern Tablelands of New South Wales. In each affected sheep there were multiple discrete, soft, yellow homogeneous plaques beneath the parietal peritoneum and extending into marginating facial planes of the diaphragm and body wall. Microscopically, the lesions consisted of focal granulomatous peritonitis with intracellular acicular refractile golden brown crystals. Energy dispersive X-ray spectroscopy revealed intralesional barium and selenium, two components of an injectable selenium compound administered to the sheep 6-8 months prior, which contains the yellow pigment, iron oxide. The mechanism of subperitoneal deposition of the compound could not be confirmed, but is presumed to have involved intraperitoneal injection of barium selenate. Meat inspectors and diagnosticians should consider barium selenate injection-site granulomas as a possible explanation for yellow pigmented lesions, especially in livestock from selenium-deficient areas. Animal care providers should be aware that incorrect administration of barium selenate can result in losses from condemnation or downgrading of meat product. PMID- 21595641 TI - Traumatic elbow luxation in 14 dogs and 11 cats. AB - OBJECTIVE: To report the presentation and treatment of traumatic elbow luxation and to evaluate success following closed or open reduction. DESIGN: Retrospective case series conducted between April 1999 and April 2009. METHODS: Records of 14 dogs and 11 cats were reviewed for signalment, history, radiographic findings and treatment; 14 owners were contacted via phone questionnaire to assess for limb function following treatment. Fisher's two-tailed P test was used to evaluate potential risk factors for lameness. RESULTS: The majority of luxations were caused by car accident and 96% of the cases luxated in a lateral direction. Closed reduction was successful in all cats and 11 dogs; 3 dogs required open reduction. Owners rated the animals' limb function as excellent (71%), good (7%), fair (22%) or poor (0%). All cats were rated excellent. An excellent result following closed reduction was achieved in 67% of canine cases. All cases of open reduction achieved fair results. All owners were satisfied with the outcome. No risk factors were significantly associated with post-reduction lameness. CONCLUSIONS: Elbow joints with good stability following closed reduction have a favourable outcome. Poor stability following closed reduction is an indication for surgery. Results suggest that cats tolerate elbow luxation better than dogs. PMID- 21595642 TI - Omentalisation of a caudal mediastinal abscess in a dog. AB - A caudal mediastinal abscess was diagnosed in a 2-year-old German Short-haired Pointer with acute onset of lethargy, pyrexia and tachypnoea. The abscess was managed surgically by median sternotomy, abscess content evacuation and omentalisation of the abscess cavity via the diaphragm. Although surgical management of mediastinal abscesses has been reported previously, this is the first report to describe successful management of the condition in a dog by omentalisation. PMID- 21595643 TI - Methicillin-resistant Staphylococcus aureus in a population of horses in Australia. AB - OBJECTIVE: To evaluate if methicillin-resistant Staphylococcus aureus (MRSA) is present in the horse population in Australia. DESIGN: A two-part retrospective study of laboratory submissions of microbial culture results from horses. METHODS: Part A: medical records of 216 horses that had MRSA screening performed on nasal swabs collected over a 30-day period at admission to the Scone Equine Hospital Clovelly Intensive Care Unit were retrieved. Part B: laboratory records from 2004 to 2009 of culture submissions to the Scone Veterinary Laboratory were reviewed and cultures that grew MRSA were identified. The MRSA isolates from Parts A and B were genotyped over an 18-month period. RESULTS: MRSA screening of 216 horses identified eight (3.7%) positive samples. MRSA was isolated from cultures of 80 (0.002%) clinical bacteriology samples over a 6-year period. Genotypic analysis was performed on 36 isolates. All MRSA characterised had the same pulse field gel electrophoresis pattern (type 1), with eight closely related subtypes identified (subtypes A-F and H) and 66% of isolates classified as subtype D, which multilocus sequence and staphylococcal cassette chromosome mec typing analysis identified as ST612-MRSA-IVa, a clonal complex (CC) 8 S. aureus strain. Antimicrobial resistance to more than two classes of antimicrobials was common. CONCLUSIONS: MRSA was present in a population of horses in Australia. Genotypic analysis of the isolates identified the MRSA strain as CC8 S. aureus. Further research needs to be undertaken to evaluate MRSA infection and colonisation of horses and personnel in Australia. PMID- 21595644 TI - Retrospective investigation of prognostic indicators for adult horses with infection of a synovial structure. AB - OBJECTIVE: To investigate predictors of survival and athletic function in adult horses with infection of a synovial structure. HYPOTHESES: Increasing duration from contamination to referral, bone or tendon involvement and positive microbial culture decreases short-term survival. Synovitis and/or sepsis at 5 days post admission and involvement of Staphylococcus spp. decreases long-term athletic function. DESIGN: Retrospective study. METHODS: Records over 4 years of adult horses with synovial sepsis were reviewed. A two-tailed Fisher's exact test, Mann Whitney U test or t-test was used to examine whether variables were predictive of short-term survival and long-term athletic function. RESULTS: During the study period 75 horses underwent treatment for infection of 93 synovial structures. Short-term survival was 84% (63/75) and 54% (30/56) of horses returned to athletic function. Of the variables measured at admission, duration from contamination to referral did not affect survival, whereas evidence of bone or tendon involvement decreased survival and athletic function. Of the variables available during treatment, abnormal synovial fluid at 4-6 days post-admission and positive microbial culture reduced athletic function. Staphylococcal infection was associated with persistent sepsis. CONCLUSIONS: Of the variables available at presentation, only evidence of bone or tendon involvement negatively affected survival and athletic function. During treatment of synovial sepsis, analysis of synovial fluid at 4-6 days and bacterial culture results have prognostic value. PMID- 21595645 TI - Molecular detection of two adenoviruses associated with disease in Australian lizards. AB - We give the first published description of the pathology and molecular findings associated with adenovirus infection in lizards in Australia. A central netted dragon (Ctenophorus nuchalis) exhibited severe necrotising hepatitis with abundant intranuclear inclusion bodies within hepatocytes and rarely within intestinal epithelial cells. Polymerase chain reaction (PCR) using pooled tissues yielded an amplicon that shared strong nucleotide identity with an agamid adenovirus (EU914203). PCR on the liver of a bearded dragon (Pogona minor minor) with illthrift, coccidiosis, nematodiasis and hepatic lipidosis yielded an amplicon with strong nucleotide identity to a helodermatid adenovirus (EU914207). PMID- 21595646 TI - Guideline on the investigation, management and prevention of venous thrombosis in children. AB - Venous thrombo-embolism (VTE) is increasingly recognized in paediatric practice. Few clinical trials have been performed in this area in children and management is largely extrapolated from adult practice where there is a considerable evidence base. This is likely to be unsatisfactory for a number of reasons. Firstly, there are significant differences in epidemiology and potential differences in the mechanisms for VTE in this age group. Secondly, many aspects of haemostasis are age-dependant, which has implications for the use of anticoagulants in the paediatric population. Thirdly, there are very limited data available on the safety and efficacy of anticoagulants to manage specific indications in paediatric practice, often with limited paediatric formulations available. In addition, children may survive for a prolonged period following these events so that long-term consequences may be highly significant in this age group. The aim of this guideline is to provide a rational basis for the investigation and management of children aged 1 month-16 years with VTE, including cerebral venous thrombosis (CVT). The guideline is targeted at healthcare professionals involved in the management of children and adolescents with VTE, particularly paediatric haematologists. PMID- 21595647 TI - Resolution of bone lysis in Langerhans cell histiocytosis by bisphosphonate therapy. PMID- 21595648 TI - Global arginine bioavailability in Tanzanian sickle cell anaemia patients at steady-state: a nested case control study of deaths versus survivors. PMID- 21595650 TI - At last, a truly selective EP2 receptor antagonist. AB - Ever since the discovery of prostaglandin E(2)(PGE(2)), this lipid mediator has been the focus of intense research. The diverse biological effects of PGE(2) are due, at least in part, to the existence of four distinct receptors (EP(1-4)). This can complicate the analysis of the biological effects produced by PGE2. While there are currently selective pharmacological tools to explore the roles of the EP(1,3,4) receptors in cellular and tissue responses, analysis of EP(2) receptor-induced responses has been hampered by the lack of a selective EP(2) receptor antagonist. The recent publication in this journal by af Forselles et al. suggests that such a tool compound is now available. In their manuscript, the authors describe a series of experiments that show PF-04418948 to be a potent and selective EP(2) receptor antagonist. The discovery of this tool compound will interest many scientists and through collaborations with Pfizer they may have access to PF-04418948 to facilitate further investigation of the biology of this fascinating lipid mediator. PMID- 21595649 TI - Methaemalbumin formation in sickle cell disease: effect on oxidative protein modification and HO-1 induction. AB - Normally, cell free haemoglobin is bound by haptoglobin and efficiently cleared. However, the chronic haemolysis in sickle cell disease (SCD) overwhelms haptoglobin binding capacity and protein turnover, resulting in elevated cell free haemoglobin. Cell free haemoglobin acts as both a scavenger of vasoactive nitric oxide and a pro-oxidant. In addition, methaemoglobin (metHb) releases the haem moiety, which can bind to albumin to form methaemalbumin (metHSA). This study used electron paramagnetic resonance to detect metHSA in SCD plasma and demonstrated that haptoglobin prevents haem transfer from metHb to HSA. MetHSA may either provide a second line of defence against haemoglobin/haem-mediated oxidation or contribute to the pro-oxidant environment of SCD plasma. We demonstrated that HSA inhibited oxidative protein modification induced by metHb. Additionally, we showed that while metHb induced haem oxygenase 1 (HO-1), an indicator of oxidative stress, HSA attenuated metHb induction of this enzyme, thereby limiting the potential benefits of HO-1. Furthermore, HO-1 induction by metHSA was less than HO-1 induction by equimolar metHb not bound to albumin. Our findings confirm the presence of metHSA in SCD and suggest that haem transfer from metHb to HSA reduces the oxidative effects of free haemoglobin/haem on endothelium with both beneficial (reduced protein oxidation) and potentially harmful (reduced HO-1 induction) outcomes. PMID- 21595651 TI - In vitro and in vivo characterization of PF-04418948, a novel, potent and selective prostaglandin EP2 receptor antagonist. AB - BACKGROUND AND PURPOSE: Studies of the role of the prostaglandin EP(2) receptor) have been limited by the availability of potent and selective antagonist tools. Here we describe the in vitro/in vivo pharmacological characterization of a novel EP(2) receptor antagonist, PF-04418948 (1-(4-fluorobenzoyl)-3-{[(6-methoxy-2 naphthyl)oxy]methyl} azetidine-3-carboxylic acid). EXPERIMENTAL APPROACH: Functional antagonist potency was assessed in cell-based systems expressing human EP(2) receptors and native tissue preparations from human, dog and mouse. The selectivity of PF-04418948 was assessed against related receptors and a panel of GPCRs, ion channels and enzymes. The ability of PF-04418948 to pharmacologically block EP(2) receptor function in vivo was tested in rats. KEY RESULTS: PF 04418948 inhibited prostaglandin E(2)(PGE(2))-induced increase in cAMP in cells expressing EP(2) receptors with a functional K(B) value of 1.8 nM. In human myometrium, PF-04418948 produced a parallel, rightward shift of the butaprost induced inhibition of the contractions induced by electrical field stimulation with an apparent K(B) of 5.4 nM. In dog bronchiole and mouse trachea, PF-04418948 produced parallel rightward shifts of the PGE(2)-induced relaxation curve with a K(B) of 2.5 nM and an apparent K(B) of 1.3 nM respectively. Reversal of the PGE(2)-induced relaxation in the mouse trachea by PF-04418948 produced an IC(50) value of 2.7 nM. Given orally, PF-04418948 attenuated the butaprost-induced cutaneous blood flow response in rats. PF-04418948 was selective for EP(2) receptors over homologous and unrelated receptors, enzymes and channels. CONCLUSIONS AND IMPLICATIONS: PF-04418948 is an orally active, potent and selective surmountable EP(2) receptor antagonist that should aid further elaboration of EP(2) receptor function. PMID- 21595652 TI - Antibodies against the cardiac sodium/bicarbonate co-transporter (NBCe1) as pharmacological tools. AB - BACKGROUND AND PURPOSE: Na(+) /HCO(3) (-) co-transport (NBC) regulates intracellular pH (pH(i) ) in the heart. We have studied the electrogenic NBC isoform NBCe1 by examining the effect of functional antibodies to this protein. EXPERIMENTAL APPROACH: We generated two antibodies against putative extracellular loop domains 3 (a-L3) and 4 (a-L4) of NBCe1 which recognized NBCe1 on immunoblots and immunostaining experiments. pH(i) was monitored using epi-fluorescence measurements in cat ventricular myocytes. Transport activity of total NBC and of NBCe1 in isolation were evaluated after an ammonium ion-induced acidosis (expressed as H(+) flux, J(H) , in mmol.L(-1) min(-1) at pH(i) 6.8) and during membrane depolarization with high extracellular potassium (potassium pulse, expressed as DeltapH(i) ) respectively. KEY RESULTS: The potassium pulse produced a pH(i) increase of 0.18 +/- 0.006 (n= 5), which was reduced by the a-L3 antibody (0.016 +/- 0.019). The a-L-3 also decreased J(H) by 50%. Surprisingly, during the potassium pulse, a-L4 induced a higher pH(i) increase than control,(0.25 +/- 0.018) whereas the recovery of pH(i) from acidosis was faster (J(H) was almost double the control value). In perforated-patch experiments, a-L3 prolonged and a L4 shortened action potential duration, consistent with blockade and stimulation of NBCe1-carried anionic current respectively. CONCLUSIONS AND IMPLICATIONS: Both antibodies recognized NBCe1, but they had opposing effects on the function of this transporter, as the a-L3 was inhibitory and the a-L4 was excitatory. These antibodies could be valuable in studies on the pathophysiology of NBCe1 in cardiac tissue, opening a path for their potential clinical use. PMID- 21595653 TI - Delta(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. AB - BACKGROUND AND PURPOSE: Endometriosis is a disorder in which the endometrium forms growths outside the uterus and is associated with chronic pain. Recent evidence suggests that endometrial motility plays a role in the aetiology of endometriosis. The endocannabinoid system regulates cellular migration. Given the growing involvement of the endocannabinoids in reproduction, we investigated the role of the endocannabinoid system in migration of endometrial cells. EXPERIMENTAL APPROACH: Migration of the human endometrial HEC-1B cells was assayed. Standard PCR techniques were used to determine the presence of the GPCR, GPR18, in HEC-1B cells, and p44/42 MAPK was assayed in stably transfected HEK293 GPR18 cells to determine receptor specificity for known cannabinoid agonists and antagonists. N-arachidonoyl ethanolamine (AEA) metabolism was measured, using HPLC/MS/MS for lipid analysis. KEY RESULTS: AEA, Delta(9) -tetrahydrocannabinol (Delta(9) -THC) and N-arachidonoyl glycine (NAGly) induce migration of HEC-1B cells through cannabinoid CB(1) receptor-independent mechanisms. MAPK activation in HEK293-GPR18 cells revealed novel pharmacology for known CB(1) and CB(2) receptor ligands at GPR18 receptors, including Delta(9) -THC, which activates MAPK at nanomolar concentrations, whereas WIN 55212-2, CP55940, JWH-133 and JWH 015, and arachidonyl-1-hydroxy-2-propylamide (R1-methanandamide) had no effect. Moreover, HEC-1B migration and MAPK activation by NAGly and Delta(9) -THC were antagonized by Pertussis toxin, AM251 and cannabidiol. CONCLUSIONS AND IMPLICATIONS: An understanding of the function and regulation of GPR18 and its molecular interactions with endogenous ligands, and how phytocannabinoids play a role with GPR18 signalling is vital if we are to comprehensively assess the function of the cannabinoid signalling system in human health and disease. LINKED ARTICLES: This article is commented on by Alexander, pp. 2411-2413 of this issue and is part of a themed section on Cannabinoids in Biology and Medicine. To view Alexander visit http://dx.doi.org/10.1111/j.1476-5381.2011.01731.x. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue 8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. PMID- 21595654 TI - Massively parallel sequencing and identification of genes for primary lymphoedema: a perfect fit. AB - Primary lymphoedema is a clinically and genetically heterogeneous group of disorders characterized by disruption of the lymphatic system. To date, the majority of the causative genes in primary lymphoedema have been identified through linkage analysis in large families with multiple affected subjects. Studies aimed at isolating additional genes responsible for primary lymphoedema have been hampered by cohorts comprised primarily of sporadic cases and small affected kindreds. In the absence of genetic heterogeneity, recent development of massively parallel DNA sequencing technology, specifically exome sequencing, has provided novel paradigms for disease gene identification in such cohorts. In this review, we summarize the novel approaches to disease gene discovery with massively parallel sequencing also known as Next Generation Sequencing (NGS), and show how the selection of unrelated affected cases from clinically homogenous phenotypic subclassifications is proving to be a successful approach for disease gene discovery in primary lymphoedema. PMID- 21595655 TI - Celiac disease: moving from genetic associations to causal variants. AB - Genome-wide association studies are providing insight into the genetic basis of common complex diseases: more than 1150 genetic loci [2165 unique single nucleotide polymorphisms (SNPs)] have recently been associated to 159 complex diseases. The hunt for genes contributing to immune-related diseases has been particularly successful in celiac disease, for example, with 27 genome-wide significantly associated loci identified so far. One of the current challenges is how to move from a genetic association with a disease to finding disease associated genes and causal variants, as a step towards understanding the underlying disease process. About 50% of disease-associated SNPs affect the expression of nearby genes (so-called expression quantitative traits loci or eQTLs) and these can provide clues for finding causal variants. Although eQTLs can be useful, fine mapping and sequencing are required to refine the association signal. Ultimately, sophisticated study designs will be needed to find the causal variants involved in complex diseases. In this review, we use celiac disease as an example to describe the different aspects that need to be considered on the path from genetic association to disease-causing variants. PMID- 21595656 TI - Basal cell carcinoma: evidence-based medicine and review of treatment modalities. AB - Non-melanoma skin cancers (NMSCs) are the most common type of human cancer, with basal cell carcinomas representing the majority of these cancers. The following article will focus on a review of the current knowledge regarding incidence, risk factors, and pathogenesis, including genetics, clinical features, and treatment options of basal cell carcinomas. PMID- 21595657 TI - Update on nephrogenic systemic fibrosis: are we making progress? AB - Nephrogenic systemic fibrosis is a rare fibrosing disorder associated with the use of gadolinium-based contrast agents in patients with renal dysfunction. However, only a small proportion of at-risk patients develops the disorder, and the exact determinants of disease are still not completely clear. Here, we present an update on emerging evidence for the role of gadolinium-based contrast agents, renal dysfunction, and background inflammation in disease expression, with a focus on current experimental models. Based on these findings, significant progress has been made in our understanding of the pathophysiology of this disorder over the last few years. This review provides a summary of these developments with discussion of the implications for clinical practice and directions for additional study. PMID- 21595658 TI - An unidentified ulcer on the dorsum of the hand. Cutaneous leishmaniasis. PMID- 21595659 TI - A boy with an unusual scalp birthmark. Nevus Comedonicus. PMID- 21595660 TI - A multicenter epidemiological study of acne vulgaris in Korea. AB - BACKGROUND: Acne is a common skin disorder that affects both adolescents and adults. However, few epidemiological studies on this condition have been conducted in Asia. OBJECTIVES: The purpose of this study was to analyze the incidence of acne and to identify its demographic and clinical features and aggravating factors. In addition, we examined the relationships between these factors. METHODS: Epidemiological and clinical data were obtained, using a self administered questionnaire, from patients who visited 17 general hospitals and from the consulting dermatologists. RESULTS: A total of 1236 patients were involved in this study. Acne first developed and presented most commonly on the forehead and cheeks, although the cheeks were more severely affected. Significant associations were found between the clinical, epidemiological, and behavioral characteristics of acne patients according to several factors, such as sex, age at onset, previous treatment history, and family history. The present study indicates that stress, lack of sleep, smoking, alcohol consumption, and menstruation aggravate acne. CONCLUSIONS: This study presents the demographic features and clinical characteristics of acne sufferers in Korea. This large scale analysis provides a useful overview of acne in Korea. PMID- 21595661 TI - Colonization with community-acquired methicillin-resistant Staphylococcus aureus in children with atopic dermatitis: a cross-sectional study. AB - BACKGROUND: Bacterial infection with Staphylococcus aureus is a common complication of atopic dermatitis (AD). The incidence of community-acquired methicillin-resistant S. aureus infection (MRSA) in the AD population is unknown. OBJECTIVES: This study aimed to assess the prevalence of S. aureus and MRSA in pediatric patients with AD, to compare disease severity, and to characterize the clonal diversity of the isolates. METHODS: We carried out a prospective, cross sectional study of 200 patients with AD. The severity of AD was defined as mild, moderate, or severe depending on a composite AD severity score. A swab was taken from the nares of each patient and another from affected skin or folds. Genotyping of all S. aureus isolates was conducted by polymerase chain reaction (PCR) amplification of the S. aureus protein A (spa) gene. RESULTS: According to the severity score, 66.5% of subjects were ranked as having mild AD, 29.5% as having moderate and 4% as having severe AD. Staphylococcus aureus colonization was seen in 61.5% of all patients, represented by 43.7% of skin swabs and 48% of nares swabs. Only one of the isolations represented MRSA. Older age and higher AD severity scores were associated with S. aureus colonization (P = 0.03 and P < 0.001, respectively). No significant associations were noted for attendance at day care, family members with frequent skin infections, or family members working in healthcare. Isolates from spa CC015 were cultured in 19.2% of patient samples. The single MRSA culture showed a new spa type that belonged to CC127. CONCLUSIONS: The results of this study confirm a high rate of S. aureus colonization of pediatric patients with AD. The low rate of MRSA requires further proof from larger prospective studies. PMID- 21595662 TI - Parental attitudes towards head lice infestation in Greece. AB - BACKGROUND: Pediculosis capitis constitutes a growing problem worldwide and is usually considered as an inconvenience. Parents often handle this infestation on their own initiative. OBJECTIVE: We conducted a survey in order to depict the parental attitudes towards head lice infestation in Greece. METHODS: Parents of children aged 3-14 years, attending a dermatology outpatient clinic at a children's hospital, were given a questionnaire regarding head lice. Demographic data, management, and prevention strategies were included in the questionnaire. RESULTS: Three-hundred and seventy-two complete questionnaires were analyzed (response rate: 89%). Pediculosis capitis was more prevalent in the age groups 3 5 years and 6-8 years. The percentage of parents of infested children who sought advice on treatment from the pharmacist was 73%, and only 15% consulted their doctor. Chemical agents to treat head lice were used by 59% of them, products containing natural oils by 38%, and wet combing in parallel was employed by 79% of them. Preventive measures were employed by 66% of the respondents, and 54% applied botanical and synthetic products commercially available for this purpose. CONCLUSION: There is a trend towards the use of natural oils for either prevention or treatment. More needs to be done to promote public education and rational use of either pediculicides or non-pharmacological agents for pediculosis capitis infestation. PMID- 21595663 TI - Prolactin level is significantly elevated in lesional skin of patients with psoriasis. AB - BACKGROUND: Accumulating data point to a potential role of prolactin in the pathogenesis of psoriasis. METHODS: We initiated a study including psoriasis patients (n = 15) and healthy volunteers (n = 15) as controls. Psoriasis area and severity index (PASI) score was evaluated, and prolactin levels in serum and blister fluid were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Prolactin levels were significantly (P < 0.01) elevated in blister fluid of psoriatic lesional skin. Correlations between PASI score and different serum prolactin levels in lesional and non-lesional skin were insignificant. Significant positive correlations of prolactin level were observed between lesional and non-lesional skin in psoriasis (P < 0.05) and between serum and clinically normal skin in both psoriasis and control subjects (P < 0.05). CONCLUSIONS: Locally produced prolactin may be involved in the pathogenesis of psoriatic lesions. PMID- 21595664 TI - Analysis of associations between the patterns of global DNA hypomethylation and expression of DNA methyltransferase in patients with systemic lupus erythematosus. AB - OBJECTIVES: To analyze associations between the patterns of global DNA hypomethylation and expression of DNA methyltransferase (DNMT1, DNMT3A, and DNMT3B) in patients with systemic lupus erythematosus (SLE) and to obtain a deeper understanding of the role that epigenetic mechanism may have on SLE. METHODS: The global DNA methylation profile in T cells from 34 patients with SLE and 23 healthy controls was assessed by the specific monoclonal antibodies to 5 methylcytosine and was analyzed quantitatively by flow cytometry. Real-time reverse transcription-polymerase chain reaction was applied to analyze DNMTs (DNMT1, DNMT3A, and DNMT3B) mRNA levels in T cells from patients and controls. RESULTS: Patients with SLE had significantly global DNA hypomethylation than that in controls (P = 0.004), and the global DNA methylation was inverse correlated with the SLE Disease Activity Index (P < 0.0005). Patients with SLE had significantly lower levels of DNMT1 mRNA than that in controls (P < 0.0005), and there was no correlation between the level of DNMT1 mRNA and SLE Disease Activity Index, neither the correlation between the levels of DNMT1 mRNA and global DNA methylation. There was no statistical difference in levels of DNMT3A mRNA between the patients with SLE and normal controls. The levels of DNMT3B mRNA were very low, and there was no difference in patients with SLE and normal controls. CONCLUSIONS: Global DNA hypomethylation plays an important role in the pathogenesis of SLE. Lower expression of DNMT1 mRNA may play a role in the pathogenesis of SLE, which is not the exclusive regulation factor of global DNA methylation of SLE. The mechanism of global DNA hypomethylation in patients with SLE was complicated. Enzymes that participate in DNA methylation and demethylation events should be studied further. PMID- 21595665 TI - Transmission of Panton-Valentine leukocidin-producing Staphylococcus aureus from returning travelers to household contacts. PMID- 21595666 TI - Prevalence and risk factors for herpes simplex infection among patients at high risk for HIV infection in Brazil. AB - BACKGROUND: Herpes simplex infection is responsible for substantial morbidity in patients with HIV infection. Data from less-developed countries analyzing risk factors within this population are largely unavailable. AIMS: Investigate the incidence and seroprevalence of HSV-1 and HSV-2 infection in populations at high and low risk for HIV infection. MATERIALS AND METHODS: A prospective cohort study was performed in a population at high risk for STDs composed of 170 HIV seronegative male homosexuals and bisexuals (group A). The population at low risk for STDs was composed of 155 volunteer male blood donors (group B). All blood samples were screened using a type specific ELISA to HSV-1 and HSV-2 glycoprotein G (gG). RESULTS: The prevalence of HSV-1 and HSV-2 infection among all the 325 patients was 83.5% and 63.4%, respectively. Annual incidence of HSV-1 and 2 among group A were 0.053% and 0.08%, respectively. Among group B, the incidence for HSV 1 was 0.04% and for HSV-2 was 0.02%. Educational parameters (P<0.001), irregular use of condoms (P<0.001), and percentage of previous receptive anal intercourse (P<0,012) were significantly associated with seropositivity to HSV-2. About 8.4% of the HSV-1 seronegative subjects presented recurrence episodes of herpes labialis as well as 7.6% of the HSV-2 seronegative patients had genital herpes in the past. DISCUSSION: The high seroprevalence detected suggests that routine screening for HSV should be performed in populations at high risk for STDs, especially in HIV-infected patients. CONCLUSION: Educational campaigns, with particular focus on the transmission of HSV, and the regular use of condoms are important measures to reduce the HSV dissemination among patients with less advanced educations and at high risk for STDs. PMID- 21595667 TI - Isolation of both Pseudozyma aphidis and Nocardia otitidiscaviarum from a mycetoma on the leg. AB - We describe a case of mycetoma which typified the classic presentation of the disease: a male farmer with affection of the lower limbs and a history of trauma. The patient presented with a swollen right lower limb showing multiple discharging sinuses for 25 years. Histopathologically, grains were found by HE stain, and clustered yeast-like cells were observed by PAS stain. The distinctive 'dot-in-circle' sign was found through MRI. Besides Nocardia otitidiscaviarum, Pseudozyma aphidis was isolated from deep tissue culture, and the identification of the etiologic species was ascertained by DNA sequencing. Generally speaking, Nocardia otitidiscaviarum is an infrequent cause of mycetoma, and Pseudozyma species are usually isolated from plant material rather than clinical specimens. This is the first case of mycetoma from which both Nocardia otitidiscaviarum and Pseudozyma aphidis were isolated. PMID- 21595668 TI - Lichen planus mimicking seborrheic keratoses. PMID- 21595669 TI - Prolactinoma presenting as unilateral galactorrhea in a man exposed to radioactivity from the Chernobyl accident: radiation-induced pituitary tumor? PMID- 21595670 TI - A man with generalized small white skin lesions and abdominal pain. PMID- 21595671 TI - Precursor B-lymphoblastic lymphoma in a 3-month-old baby. PMID- 21595672 TI - Aplasia cutis congenita of the trunk and scalp associated with fetus papyraceus. PMID- 21595673 TI - Epidural needle for recipient site preparation in hair restoration surgery. AB - BACKGROUND: The mini- and micro-grafting method is still one of the most current treatment methods for male pattern baldness and female androgenic alopecia. The preparation of the recipient area with 16G needle has been reported in the literature. However, during the insertion of grafts, the neighboring grafts tend to 'pop out'. The study presents our experience in the hair implantation for recipient site preparation with 16G epidural needle. METHODS: The 16G epidural needle was used during preparation of the recipient field in eight patients. Approximately 500 micrografts were grafted in each patient to reconstruct the anterior hairline. RESULTS: During insertion of the micrografts, almost none of the previously inserted grafts tended to 'pop out'. The anterior hairline of the patients was natural without obvious scarring. The mean follow-up period of these patients was 1.5 years. The amount of graft survival was found to be satisfactory. CONCLUSION: According to the surgeon's clinical observations, application of this technique was found to be easier than standard needle techniques. It can be used by inexperienced surgeons. Use of epidural needle for recipient hole preparation works well in reducing the popping out, and the curved fashion of the holes reduced the angle of the hair follicle. PMID- 21595674 TI - In vivo reflectance confocal microscopy for the differential diagnosis between vitiligo and nevus depigmentosus. AB - BACKGROUND: Nevus depigmentosus (ND) is frequently confused with vitiligo. Differential diagnosis can be difficult. In vivo reflectance confocal microscopy (RCM) is a noninvasive technique for real-time en face imaging of the superficial layers of the skin down to the superficial dermis with cellular level resolution close to conventional histopathology. In this study, we tried to use this new technology to study the features of the distribution of pigment cells of these two hypopigmentation disorders and then concluded the differential features. METHODS: Sixty vitiligo patients and 62 ND patients were enrolled in the study. Three points in each patient (lesional, margin of the lesions and adjacent non- lesional points) were examined with RCM. The gray value of image was quantified using software, and we calculated the relative gray value. RESULTS: The RCM image feature was different between vitiligo and ND patients. The differential diagnosis was made based on the following four RCM features: complete absence of pigment cells; the distribution of pigment cells; the margins; and the relative gray value. CONCLUSION: RCM can be used as an auxiliary diagnostic tool for the differential diagnosis between vitiligo and ND. PMID- 21595675 TI - Cryoanalgesia for post-herpetic neuralgia: a new treatment. AB - The existent therapeutic options for post-herpetic neuralgia (PHN) are varied, albeit not sufficiently effective. The aim of this study was to try a new treatment modality for PHN. A spray of liquid nitrogen (LN) was used in 47 patients suffering from PHN as a stimulator of a mechanism not yet completely understood. The LN spray was carefully applied (so as not to freeze the skin surface) along the diseased sensory nerve dermatome, at weekly sessions lasting for 30 seconds each, with a mean of three applications per patient. The area corresponding to the dermatomes affected by the herpes zoster satisfactorily attenuated the herpetic neuralgia in all patients. Before the sixth treatment session, good or excellent improvement was obtained in 94% of the study patients. Pain was eliminated with one session in nine patients (19%), and with two sessions in eight patients (17%). We conclude that this non-freezing technique is absolutely safe and injury-free, and is very efficient in calming PHN. PMID- 21595676 TI - Successful treatment of argyria using a low-fluence Q-switched 1064-nm Nd:YAG laser. AB - BACKGROUND: Argyria is a rare skin disease caused by cutaneous deposits of silver granules as a result of exposure to silver substrates or ingestion of silver salt. This pigmentation change causes cosmetic problems, and there was previously no recognized effective treatments for argyria. OBJECTIVE: To evaluate the treatment effect of a low-fluence Q-switched 1064-nm Nd:YAG laser on argyria. SUBJECTS AND METHODS: Case report of a 49-year-old with a history of ingestion of a colloidal silver solution daily for approximately one year as a traditional remedy. RESULTS: After seven sessions of treatment, the patient's skin color returned to normal. CONCLUSION: A low-fluence Q-switched 1064-nm Nd:YAG laser provided safe and effective treatment for the skin discoloration associated with argyria. PMID- 21595677 TI - Carcinoma erysipeloides deriving from a primary cutaneous squamous cell carcinoma. PMID- 21595678 TI - Few comments on the treatment of Old World cutaneous leishmaniasis. PMID- 21595679 TI - Simulation of cutaneous Bowen's disease by freeze artifact in tissue briefly fixed in formalin. PMID- 21595680 TI - Cryotherapy using melamine foam of warts - an easy and rapid new trial method instead of cotton-tipped applicator: a case series of 13 patients. PMID- 21595681 TI - Trichophyton violaceum infection in an adult black patient in Europe. PMID- 21595682 TI - Acute generalized exanthematous pustulosis induced by docetaxel. PMID- 21595686 TI - Impact of unintentional selective harvesting on the population dynamics of red grouse. AB - 1. The effect of selective exploitation of certain age, stage or sex classes (e.g., trophy hunting) on population dynamics is relatively well studied in fisheries and sexually dimorphic mammals. 2. Harvesting of terrestrial species with no morphological differences visible between the different age and sex classes (monomorphic species) is usually assumed to be nonselective because monomorphicity makes intentionally selective harvesting pointless and impractical. But harvesting of the red grouse (Lagopus lagopus scoticus), a monomorphic species, was recently shown to be unintentionally selective. This study uses a sex- and age-specific model to explore the previously unresearched effects of unintentional harvesting selectivity. 3. We examine the effects of selectivity on red grouse dynamics by considering models with and without selectivity. Our models include territoriality and parasitism, two mechanisms known to be important for grouse dynamics. 4. We show that the unintentional selectivity of harvesting that occurs in red grouse decreases population yield compared with unselective harvesting at high harvest rates. Selectivity also dramatically increases extinction risk at high harvest rates. 5. Selective harvesting strengthens the 3- to 13-year red grouse population cycle, suggesting that the selectivity of harvesting is a previously unappreciated factor contributing to the cycle. 6. The additional extinction risk introduced by harvesting selectivity provides a quantitative justification for typically implemented 20-40% harvest rates, which are below the maximum sustainable yield that could be taken, given the observed population growth rates of red grouse. 7. This study shows the possible broad importance of investigating in future research whether unintentionally selective harvesting occurs on other species. PMID- 21595685 TI - C-type lectins on macrophages participate in the immunomodulatory response to Fasciola hepatica products. AB - Fasciola hepatica releases excretory-secretory products (FhESP), and immunomodulatory properties have been described for the carbohydrates present in these parasite products. The interaction of FhESP with the innate immune cells, such as macrophages, is crucial in the early stage of infection. In this work we observed that peritoneal macrophages from naive BALB/c mice stimulated in vitro with FhESP presented: an increased arginase activity as well as Arginase I expression, and high levels of transforming growth factor-beta and interleukin 10. A similar macrophage population was also observed in the peritoneum of infected mice. A partial inhibition of the immunomodulatory effects described above was observed when macrophages were pre-incubated with Mannan, anti-mannose receptor, Laminarin or anti-Dectin-1, and then stimulated with FhESP. In addition, we observed a partial inhibition of these effects in macrophages obtained from mice that were intraperitoneally injected with Mannan or Laminarin before being infected. Taken together, these results suggest the participation of at least two C-type lectin receptors, mannose receptor and Dectin-1, in the interaction of FhESP with macrophages, which allows this parasite to induce immunoregulatory effects on these important innate immune cells and may constitute a crucial event for extending its survival in the host. PMID- 21595687 TI - Signature of ecological partitioning in the maintenance of damselfly diversity. AB - 1. Ecological differences among co-occurring taxa are often invoked as an explanation for the maintenance of biodiversity. Whether these differences facilitate coexistence, which allows unequal competitors to remain in systems and thus maintain biodiversity, is still unclear. 2. Here, we used observational and experimental studies to test for ecological partitioning in ways that would promote coexistence among three co-occurring damselfly genera. We evaluated two necessary conditions for coexistence: (i) that the damselfly genera differ in their abilities to engage in interactions with other damselfly genera and environmental conditions such that their relative abundances covary differently along environmental gradients and (ii) that an increase in intrageneric abundance is more detrimental to performance-related demographic features of each genus than increases in intergeneric abundances. 3. Observational studies across 40 lakes showed that relative abundances of each genus covaried differently along an environmental gradient of lake abiotic and biotic features consistent with ecological partitioning. Field experiments in which we manipulated both intra- and intergeneric densities demonstrated that per capita growth rates of each genus are negatively density-dependent and are only limited by increases in intra not intergeneric densities. 4. Collectively, these results show a clear signature of ecological partitioning among each genus, which should prevent competitive exclusion and maintain each genus in this system. The results do not guarantee local coexistence among the three genera but are consistent with criteria that should promote their coexistence. Our results also suggest that a food web model coupling keystone predation and apparent competition is likely necessary to explain the ecological dynamics of persistence among these genera. PMID- 21595688 TI - Developmental validation of the SPERM HY-LITERTM kit for the identification of human spermatozoa in forensic samples. AB - With sexual assault evidence, the visualization of spermatozoa confirms that ejaculation has occurred. However, microscopic examination of spermatozoa is a laborious process and can sometimes result in sperm cells being overlooked. Here, we present the developmental validation of the SPERM HY-LITERTM kit, which contains a human sperm-specific mouse monoclonal antibody coupled to a fluorescent Alexa 488 dye. The kit was tested using samples of human semen, saliva, blood, and urine, various animal semen extracts, sexual lubricants, and a commercially available spermicidal film. Postcoital vaginal swabs, degraded semen samples, and samples prepared with sample fixation techniques that deviated from the kit-provided protocol were also tested. In each case, the SPERM HY-LITERTM kit was demonstrated to bind only to human sperm cell heads. Limitations to this fluorescent staining procedure include nonspecific staining and increased background fluorescence with extreme heat fixation in some samples. PMID- 21595689 TI - Application of superimposition-based personal identification using skull computed tomography images. AB - Superimposition has been applied to skulls of unidentified skeletonized corpses as a personal identification method. The current method involves layering of a skull and a facial image of a suspected person and thus requires a real skeletonized skull. In this study, we scanned skulls of skeletonized corpses by computed tomography (CT), reconstructed three-dimensional (3D) images of skulls from the CT images, and superimposed the 3D images with facial images of the corresponding persons taken in their lives. Superimposition using 3D reconstructed skull images demonstrated, as did superimposition using real skulls, an adequate degree of morphological consistency between the 3D reconstructed skulls and persons in the facial images. Three-dimensional skull images reconstructed from CT images can be saved as data files and the use of these images in superimposition is effective for personal identification of unidentified bodies. PMID- 21595690 TI - Virtual determination of sex: metric and nonmetric traits of the adult pelvis from 3D computed tomography models. AB - Examination of the adult os coxae and sacrum is one of the most common methods of sex estimation from bone. Medical imaging, such as computed tomography (CT), provides the opportunity for three-dimensional (3D) imaging of the skeleton from clinical scans of known individuals in situ. In this study, a randomly selected subset of abdominopelvic CT-derived models were used to evaluate simple, repeatable metric methods of sex estimation based on a combination of obstetric measurements and the traditionally nonmetric Phenice-derived traits. A four variable discriminant function for sex estimation was developed based on statistical analyses. Overall, the cross-validated accuracy of this method was 100%, with inter-observer error showing an average of only 2.2%. Comparative analysis was run on the data set using FORDISC 3.0. This study shows that current sex determination standards from the pelvis should be updated to include more in vivo data to increase the accuracy of identification. PMID- 21595691 TI - Increased adrenaline to noradrenaline ratio is a superior indicator of antemortem hypothermia compared with separate catecholamine concentrations. AB - The significance of urinary catecholamines and small gastric mucosal bleedings, Wischnewsky's spots, in postmortem diagnosis of hypothermia deaths was evaluated. Autopsy cases (n=358) were divided into hypothermia, suspected hypothermia, and control groups. The catecholamine levels did not correlate with the length of the postmortem period. The adrenaline to noradrenaline ratio was most effective in detecting hypothermia (68.9% sensitivity, 78.1% specificity). The median adrenaline concentrations were significantly higher in hypothermia than in control groups. The control group containing mostly sudden cardiac deaths with no cold exposure had a noradrenaline level comparable to the hypothermia groups. The sensitivity and specificity of determining Wischnewsky's spots in hypothermia deaths were 63.9% and 88.3%, respectively. The adrenaline to noradrenaline ratio is more suitable in proving antemortem cold stress than either of these independently, and its diagnostic value is comparable to that of Wischnewsky's spots. PMID- 21595692 TI - Sulfuric, hydrochloric, and nitric acid-catalyzed triacetone triperoxide (TATP) reaction mixtures: an aging study. AB - The organic peroxide explosive triacetone triperoxide (TATP) is regularly encountered by law enforcement agents in various stages of its production. This study utilizes solid-phase microextraction (SPME) and gas chromatography/mass spectrometry (GC/MS) to examine sulfuric acid-, hydrochloric acid-, and nitric acid-catalyzed TATP syntheses during the initial 24 h of these reactions at low temperatures (5-9 degrees C). Additionally, aging of the reaction mixtures was examined at both low and ambient temperatures (19-21 degrees C) for a further 9 days. For each experiment, TATP could be readily identified in the headspace above the reaction mixture 1 h subsequent to the combination of reagents; at 24 h, TATP and diacetone diperoxide (DADP) were prominent. TATP degraded more rapidly than DADP. Additionally, chlorinated acetones chloroacetone and 1,1, dichloroacetone were identified in the headspace above the hydrochloric acid catalyzed TATP reaction mixture. These were not present when the catalyst was sulfuric acid or nitric acid. PMID- 21595693 TI - Effect of temperature on rectifying Schottky barriers formed from fingerprint sweat corrosion of brass. AB - Corrosive electrochemical processes of brass, including those resulting from fingerprint sweat, continue to be studied because of the widespread industrial use of brass. Here, we examine how increased temperature affects the relative abundance of fingerprint sweat corrosion products and the rectifying Schottky barrier formed between p-type copper (I) oxide corrosion and brass. X-ray photoelectron spectroscopy confirms increasing dezincification with increasing temperature. This leads to n-type zinc oxide replacing copper (I) oxide as the dominant corrosion product, which then forms a rectifying Schottky barrier with the brass, instead of copper oxide, when the temperature reaches c. 600 degrees C. Using X-ray diffraction, resulting diodes show polycrystalline oxides embedded in amorphous oxidation products that have a lower relative abundance than the diode forming oxide. Conventional current/voltage (I/V) characteristics of these diodes show good rectifying qualities. At temperatures between c. 100 and c. 600 degrees C, when neither oxide dominates, the semiconductor/brass contact displays an absence of rectification. PMID- 21595694 TI - Synthesis and identification of urinary metabolites of 4-iodo-2,5 dimethoxyphenethylamine. AB - This article describes the synthesis and identification of urinary metabolites of 4-iodo-2,5-dimethoxyphenethylamine (2C-I), a new psychoactive drug. 2C-I hydrochloride was administered orally to male Sprague-Dawley rats, and the urinary extracts were analyzed by gas chromatography/mass spectrometry (GC/MS), then five putative 2C-I metabolites were synthesized in our laboratory. In the synthetic process of the 2C-I metabolites, iodination of the aromatic ring was successfully carried out using iodine and orthoperiodic acid as the iodination reagent, and selective debenzylation of aryl benzyl ether was accomplished by the acid hydrolysis method using trifluoroacetic acid and thioanisole. The synthesized metabolites were well separated and detected by GC/MS after valeryl derivatization. The results showed that 2C-I underwent O-demethylation, N acetylation, and deamination, followed by oxidation to the corresponding carboxylic acid in rats. The data presented in this study will be very useful for the analysis of 2C-I and its metabolites in forensic samples. PMID- 21595695 TI - Exploiting expressed sequence tag databases for the development and characterization of gene-derived simple sequence repeat markers in the opium poppy (Papaver somniferum L.) for forensic applications. AB - Simple sequence repeat (SSR) markers in the opium poppy (Papaver somniferum L.) were identified from an expressed sequence tag (EST) database comprised of 20,340 sequences. In total, 2780 SSR-containing sequences were identified. The most frequent microsatellite had an AT/TA motif (37%). Twenty-two opium poppy EST-SSR markers were presently developed and polymorphisms of six markers (psom 2, 4, 12, 13, 17, and 22) were utilized in 135 individuals under narcotic control investigation. An average of three alleles per locus (range: 2-5 alleles) with a mean heterozygosity of 0.167 was detected. Six loci identified 29 unique profiles in 135 individuals. The EST-SSR markers exhibited small degrees of genetic differentiation (fixation index = 0.727, p < 0.001). Other variable markers will be needed to facilitate the forensic identification of the opium poppy for future cases. To determine the potential for cross-species amplification, six markers were tested in five Papaver genera species and two Eschscholzia genera. The psom 4 and psom 17 primer pair was transferable. This is the first study to report SSR markers of the opium poppy. PMID- 21595696 TI - Validation of a multiplex PCR assay for the forensic identification of Indian crocodiles. AB - A dependable and efficient wildlife species identification system is essential for swift dispensation of the justice linking wildlife crimes. Development of molecular techniques is befitting the need of the time. The forensic laboratories often receive highly ill-treated samples for identification purposes, and thus, validation of any novel methodology is necessary for forensic usage. We validate a novel multiplex polymerase chain reaction assay, developed at this laboratory for the forensic identification of three Indian crocodiles, Crocodylus palustris, Crocodylus porosus, and Gavialis gangeticus, following the guidelines of Scientific Working Group on DNA Analysis Methods. The multiplex PCR was tested for its specificity, reproducibility, sensitivity, and stability. This study also includes the samples treated with various chemical substances and exposed to various environmental regimes. The result of this validation study promises this technique to be an efficient identification tool for Indian crocodiles and therefore is recommended for forensic purposes. PMID- 21595697 TI - Sleep deprivation does not mimic alcohol intoxication on field sobriety testing. AB - Previous research shows that sleep deprivation (SD) produces cognitive impairment similar to that caused by alcohol intoxication. Individual studies suggest that SD also causes deficits in motor skills that could be mistaken for intoxication. Consequently, SD often is used as a defense when an impaired driver is charged with driving while intoxicated. Twenty-nine adult subjects participated in two test sessions each, one after a full night's rest and the other after wakefulness of at least 24 h. Subjects consumed prescribed amounts of alcohol during each session. Law enforcement officers conducted field sobriety tests identical to those with which a driver would be assessed at roadside. Researchers also measured clinical responses of visual function and vital signs. The presence and number of validated impairment clues increase with increasing blood alcohol concentration but not with SD. Thus, SD does not affect motor skills in a manner that would lead an officer to conclude that the suspect is intoxicated, unless intoxication also is present. PMID- 21595698 TI - Axonal injury in young pediatric head trauma: a comparison study of beta-amyloid precursor protein (beta-APP) immunohistochemical staining in traumatic and nontraumatic deaths. AB - We tested the independent utility of beta-amyloid precursor protein (beta-APP) immunohistochemical staining as evidence of brain trauma in the deaths of young children. Blinded reviewers retrospectively reviewed immunostained brain tissues from homicidal deaths, age-matched control cases without evidence of trauma, as well as cases of sudden infant death syndrome (SIDS). The reviewers correctly identified five of the seven cases with documented inflicted head trauma. However, one of seven age-matched control cases and one of 10 SIDS/sudden unexplained death in infancy (SUDI) cases demonstrated staining patterns similar to those seen in cases of inflicted trauma. We discuss these cases and the circumstances surrounding them with the intent to explain the difficulties associated with immunohistological interpretation of axonal injury. Although the utility of beta-APP is quite powerful if not confounded by global hypoxic ischemic injury, ultimately, beta-APP studies should be only one piece of information in the determination of cause and manner of death. PMID- 21595699 TI - The effect of electrostatic fingerprint visualization on integrated ballistic identification systems. AB - Visualization of fingerprint corrosion on spent brass cartridge cases by the application of a high electrical potential and conducting carbon powder is becoming an accepted method of fingerprint enhancement. However, to date, no examination has been made of any effect this technique has on ballistic identification. To resolve this, images of the breech face and firing pin marks were captured on six plated nickel and six brass primer cup spent cartridge cases. Three nickel and three brass cases were then subjected to the application of a potential of +2500 V for a period of 1 min. The remaining cases were additionally subjected to the application of carbon powder. These latter cases were then washed to remove all traces of powder. Each case was recaptured with the same ballistic identification apparatus and imaging procedure. None of the twelve cases showed any visual difference after the application of the potential or conducting powder. PMID- 21595700 TI - Multicentre patch testing with a resol resin based on phenol and formaldehyde. AB - BACKGROUND: Contact allergy to phenol-formaldehyde resins (PFRs) based on phenol and formaldehyde is not detected by a p-tertiary-butylphenol-formaldehyde resin (PTBP-FR) included in most baseline patch test series. OBJECTIVES: To investigate the rate of contact allergy to PFR-2 (a mixture of monomers and dimers from a resol resin based on phenol and formaldehyde) in a Swedish population, and to investigate associated simultaneous allergic reactions. METHODS: Five centres representing the Swedish Contact Dermatitis Research Group included PFR-2 in their patch test baseline series for a period of 1.5 years. RESULTS: Of 2504 patients tested, 27 (1.1%) reacted to PFR-2. Of those 27 individuals, 2 had a positive reaction to formaldehyde and 2 to PTBP-FR. Simultaneous allergic reactions were noted to colophonium in 6, to Myroxylon pereirae in 14, and to fragrance mix I in 15. CONCLUSIONS: The contact allergy frequency in the tested population (1.1%) merits its inclusion in the Swedish baseline series and possibly also in other baseline series. Simultaneous allergic reactions were noted to colophonium, M. pereirae, and fragrance mix I. PMID- 21595701 TI - Extreme patch test reactivity to p-phenylenediamine but not to other allergens in children. AB - BACKGROUND: According to clinical impression, extreme patch test reactions (+++) to p-phenylenediamine (PPD) are not uncommon in children. OBJECTIVES: To investigate the patch test reactivity in children (aged 1-14 years) in comparison with other age groups and other allergens. METHODS: A retrospective analysis was performed of data from the German Information Network of Departments of Dermatology, including all patients consecutively patch tested between 1994 and 2004 with PPD, and, for comparison, nickel, fragrance mix I, and methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI). The distribution of +, ++ and +++ grades of positive reactions among those with a positive reaction were analysed in five age strata. RESULTS: We found a strikingly higher proportion of +++ reactions to PPD in children than in all other age groups (p < 0.001). No such difference was observed for the other allergens. The main suspected exposures associated with extreme reactions to PPD in children were hair dyes and 'henna tattoos'. CONCLUSIONS: The high proportion of extreme patch test reactions to PPD, but not to other important allergens, in children reflects intense sensitization, probably because of a high induction dose from PPD containing 'henna tattoos'. In children with a history of contact allergy to 'henna tattoos' or hair dyes, the standard patch test concentration of PPD 1% should be drastically reduced. PMID- 21595702 TI - Genomics and population biology of Cryptosporidium species. AB - We describe recent advances in the genomics and population biology of Cryptosporidium parvum and C. hominis, the causative agents of cryptosporidiosis in humans and animals. Many basic aspects of the biology of Cryptosporidium species remain to be investigated and effective drugs to control cryptosporidiosis are not available. Sequencing and annotation of the genome of C. parvum and C. hominis has uncovered unique features of the metabolism of these species. The recently sequenced genome of the gastric species C. muris is providing new insights into the evolution of the genus. Cryptosporidian sequence information has facilitated the identification of polymorphic genetic markers. Genotyping of oocysts excreted by human and animal hosts using such markers has revealed many new species and genotypes, and is leading to a better understanding of the epidemiology of cryptosporidiosis. PMID- 21595703 TI - Hypothalamic actions and interactions of alcohol and IGF-1 on the expression of glial receptor protein tyrosine phosphatase-beta during female pubertal development. AB - BACKGROUND: Hypothalamic glial-neuronal communications are important for the activation of luteinizing hormone releasing hormone (LHRH) secretion at the time of puberty. As we have shown that alcohol (ALC) diminishes prepubertal LHRH secretion and delays puberty, we first assessed the effects of short-term ALC administration on the basal expression of a specific gene family involved in glial-neuronal communications. Second, as insulin-like growth factor-1 (IGF-1) is a critical regulator of LHRH secretion and the pubertal process, we then assessed whether IGF-1 could induce the expression of these signaling genes and determine whether ALC can block this affect. METHODS: Immature female rats were fed a liquid diet containing ALC for 6 days beginning when 27 days old. Control animals received either the companion isocaloric liquid diet or rat chow and water. Animals were decapitated on day 33, in the late juvenile stage of development. Medial basal hypothalamic (MBH) tissues were obtained for gene and protein analyses of glial receptor protein tyrosine phosphatase-beta (RPTPbeta) and the 2 neuronal components, contactin and contactin-associated protein 1 (Caspr1). In the second experiment, IGF-1 was administered into the third ventricle (3V) and the MBH removed 6 hours after peptide delivery, and the above-mentioned 3 genes were analyzed by real-time PCR. To determine whether this action was affected by ALC, immature female rats were administered either ALC (3 g/kg) or water via gastric gavage at 0900 hours. At 1030 hours, the ALC and control groups were subdivided such that half of the animals were injected into the 3V with IGF-1 and the other half with an equal volume of saline. Rats were killed 6 hours after the IGF-1 injection and MBHs collected. RESULTS: Real-time PCR showed that when compared with control animals, ALC caused a marked decrease (p < 0.001) in the basal expression of the RPTPbeta gene, but did not affect the expression of either contactin or Caspr1. Likewise, analysis by Western blotting demonstrated that ALC caused suppressed (p < 0.001) levels of the RPTPbeta protein, with the expressions of both contactin and Caspr1 proteins being unaltered. In the second experiment, results showed that only the RPTPbeta gene was stimulated (p < 0.05) by IGF-1 in the MBH 6 hours after peptide delivery. Assessments revealed that the IGF-1 induced increase (p < 0.01) in the expression of the RPTPbeta gene was blocked by the presence of ALC. CONCLUSIONS: Prepubertal ALC exposure is capable of interfering with hypothalamic glial-neuronal communications by suppressing the synthesis of the glial product, RPTPbeta, which is required for binding to the contactin-Caspr1 complex on LHRH neuronal terminals, thus suggesting that this action of ALC contributes to its detrimental effects on the pubertal process. PMID- 21595704 TI - Activity of secretory sphingomyelinase is increased in plasma of alcohol dependent patients. AB - BACKGROUND: Acid sphingomyelinase (ASM, EC 3.1.4.12) hydrolyzes sphingomyelin to ceramide and represents a major regulator of sphingolipid metabolism. Increased activity of ASM has been observed in a variety of human diseases, and a critical contribution of ASM to medical conditions was demonstrated in several mouse models. In agreement with increased ASM activity in cell lines treated with ethanol, we have recently found higher levels of ASM activity in peripheral blood cells of active drinkers. However, the influence of ethanol on secretory ASM (S ASM) has not been investigated so far. METHODS: ASM activity and routine blood parameters were determined in plasma samples of 27 patients with alcohol dependence during physical withdrawal and compared to a group of 36 healthy volunteers. RESULTS: Compared to the control group, patients with alcohol dependence had S-ASM activity increased by about 3-fold (141 +/- 69 vs. 428 +/- 220 pmol/ml/h; p < 0.001) at the beginning of physical withdrawal. During withdrawal, S-ASM activity decreased by about 50% (p < 0.001; day 0 vs. day 7 to 10) and finally approximated nearly normal values. On the day of admission, S-ASM activity correlated positively with levels of carbohydrate-deficient transferrin (r = 0.410, p = 0.034) and high-density lipoprotein cholesterol (r = 0.440, p = 0.022) and inversely with body mass index (r = -0.509; p = 0.007), glucose (r = 0.480; p = 0.011), triglycerides (r = -0.592; p = 0.001), and large unstained cells (r = -0.526; p = 0.017). CONCLUSIONS: Activity of S-ASM is increased in alcohol-dependent patients and correlates with established biomarkers of excessive drinking. The increased S-ASM activity is implicated in alcohol-induced lipid alterations and might be relevant for the occurrence of alcohol-related disorders. PMID- 21595706 TI - Wrestling uremia in war and peace. PMID- 21595708 TI - Implantable centrifugal blood pump with dual impeller and double pivot bearing system: electromechanical actuator, prototyping, and anatomical studies. AB - An implantable centrifugal blood pump has been developed with original features for a left ventricular assist device. This pump is part of a multicenter and international study with the objective to offer simple, affordable, and reliable devices to developing countries. Previous computational fluid dynamics investigations and wear evaluation in bearing system were performed followed by prototyping and in vitro tests. In addition, previous blood tests for assessment of normalized index of hemolysis show results of 0.0054+/-2.46 * 10-3 mg/100 L. An electromechanical actuator was tested in order to define the best motor topology and controller configuration. Three different topologies of brushless direct current motor (BLDCM) were analyzed. An electronic driver was tested in different situations, and the BLDCM had its mechanical properties tested in a dynamometer. Prior to evaluation of performance during in vivo animal studies, anatomical studies were necessary to achieve the best configuration and cannulation for left ventricular assistance. The results were considered satisfactory, and the next step is to test the performance of the device in vivo. PMID- 21595709 TI - A new model of centrifugal blood pump for cardiopulmonary bypass: design improvement, performance, and hemolysis tests. AB - A new model of blood pump for cardiopulmonary bypass (CPB) application has been developed and evaluated in our laboratories. Inside the pump housing is a spiral impeller that is conically shaped and has threads on its surface. Worm gears provide an axial motion of the blood column. Rotational motion of the conical shape generates a centrifugal pumping effect and improves pumping performance. One annular magnet with six poles is inside the impeller, providing magnetic coupling to a brushless direct current motor. In order to study the pumping performance, a mock loop system was assembled. Mock loop was composed of Tygon tubes (Saint-Gobain Corporation, Courbevoie, France), oxygenator, digital flowmeter, pressure monitor, electronic driver, and adjustable clamp for flow control. Experiments were performed on six prototypes with small differences in their design. Each prototype was tested and flow and pressure data were obtained for rotational speed of 1000, 1500, 2000, 2500, and 3000 rpm. Hemolysis was studied using pumps with different internal gap sizes (1.35, 1.45, 1.55, and 1.7 mm). Hemolysis tests simulated CPB application with flow rate of 5 L/min against total pressure head of 350 mm Hg. The results from six prototypes were satisfactory, compared to the results from the literature. However, prototype #6 showed the best results. Best hemolysis results were observed with a gap of 1.45 mm, and showed a normalized index of hemolysis of 0.013 g/100 L. When combined, axial and centrifugal pumping principles produce better hydrodynamic performance without increasing hemolysis. PMID- 21595710 TI - Single axis controlled hybrid magnetic bearing for left ventricular assist device: hybrid core and closed magnetic circuit. AB - In previous studies, we presented main strategies for suspending the rotor of a mixed-flow type (centrifugal and axial) ventricular assist device (VAD), originally presented by the Institute Dante Pazzanese of Cardiology (IDPC), Brazil. Magnetic suspension is achieved by the use of a magnetic bearing architecture in which the active control is executed in only one degree of freedom, in the axial direction of the rotor. Remaining degrees of freedom, excepting the rotation, are restricted only by the attraction force between pairs of permanent magnets. This study is part of a joint project in development by IDPC and Escola Politecnica of Sao Paulo University, Brazil. This article shows advances in that project, presenting two promising solutions for magnetic bearings. One solution uses hybrid cores as electromagnetic actuators, that is, cores that combine iron and permanent magnets. The other solution uses actuators, also of hybrid type, but with the magnetic circuit closed by an iron core. After preliminary analysis, a pump prototype has been developed for each solution and has been tested. For each prototype, a brushless DC motor has been developed as the rotor driver. Each solution was evaluated by in vitro experiments and guidelines are extracted for future improvements. Tests have shown good results and demonstrated that one solution is not isolated from the other. One complements the other for the development of a single-axis-controlled, hybrid type magnetic bearing for a mixed-flow type VAD. PMID- 21595711 TI - Cardiovascular simulator improvement: pressure versus volume loop assessment. AB - This article presents improvement on a physical cardiovascular simulator (PCS) system. Intraventricular pressure versus intraventricular volume (PxV) loop was obtained to evaluate performance of a pulsatile chamber mimicking the human left ventricle. PxV loop shows heart contractility and is normally used to evaluate heart performance. In many heart diseases, the stroke volume decreases because of low heart contractility. This pathological situation must be simulated by the PCS in order to evaluate the assistance provided by a ventricular assist device (VAD). The PCS system is automatically controlled by a computer and is an auxiliary tool for VAD control strategies development. This PCS system is according to a Windkessel model where lumped parameters are used for cardiovascular system analysis. Peripheral resistance, arteries compliance, and fluid inertance are simulated. The simulator has an actuator with a roller screw and brushless direct current motor, and the stroke volume is regulated by the actuator displacement. Internal pressure and volume measurements are monitored to obtain the PxV loop. Left chamber internal pressure is directly obtained by pressure transducer; however, internal volume has been obtained indirectly by using a linear variable differential transformer, which senses the diaphragm displacement. Correlations between the internal volume and diaphragm position are made. LabVIEW integrates these signals and shows the pressure versus internal volume loop. The results that have been obtained from the PCS system show PxV loops at different ventricle elastances, making possible the simulation of pathological situations. A preliminary test with a pulsatile VAD attached to PCS system was made. PMID- 21595712 TI - Development of a voxel model of the heart for dosimetry. AB - This article investigates the dosimetry of a radioactive stent and radioactive liquid balloon placed into the heart vasculature to prevent restenosis after atherosclerosis treatment. The research aims to know the dosages to establish a suitable activity which achieves restenosis control and thereafter minimize radiation effects in the cardiac muscle. In order to accomplish the dosimetric analysis, a heart voxel model was assembled based on tomographic images. The computational model consists of a three-dimensional matrix taken from 60 tomographic images representing the major heart tissues. A radioactive 153Sm liquid balloon is simulated as well as a 32P radioactive stent, inserted in an arbitrary heart artery. After simulation processing, the absorbed dose rate was evaluated in the heart musculature. The models are presented in two- and three dimensional previews and the dosage profiles are shown by isodose curves superimposed onto the heart model. PMID- 21595713 TI - Specification of supervisory control systems for ventricular assist devices. AB - One of the most important recent improvements in cardiology is the use of ventricular assist devices (VADs) to help patients with severe heart diseases, especially when they are indicated to heart transplantation. The Institute Dante Pazzanese of Cardiology has been developing an implantable centrifugal blood pump that will be able to help a sick human heart to keep blood flow and pressure at physiological levels. This device will be used as a totally or partially implantable VAD. Therefore, an improvement on device performance is important for the betterment of the level of interaction with patient's behavior or conditions. But some failures may occur if the device's pumping control does not follow the changes in patient's behavior or conditions. The VAD control system must consider tolerance to faults and have a dynamic adaptation according to patient's cardiovascular system changes, and also must attend to changes in patient conditions, behavior, or comportments. This work proposes an application of the mechatronic approach to this class of devices based on advanced techniques for control, instrumentation, and automation to define a method for developing a hierarchical supervisory control system that is able to perform VAD control dynamically, automatically, and securely. For this methodology, we used concepts based on Bayesian network for patients' diagnoses, Petri nets to generate a VAD control algorithm, and Safety Instrumented Systems to ensure VAD system security. Applying these concepts, a VAD control system is being built for method effectiveness confirmation. PMID- 21595714 TI - Dendronized polyaniline nanotubes for cardiac tissue engineering. AB - Today, nanobiomaterials represent a very important class of biomaterials because they differ dramatically in their bulk precursors. The properties of these materials are determined by the size and morphology, thus creating a fascinating line in their physicochemical properties. Polyaniline nanotubes (PANINTs) are one of the most promising nanobiomaterials for cardiac tissue engineering applications due to their electroactive properties. The biocompatibility and low hydrophilic properties of PANINTs can be improved by their functionalization with the highly hydrophilic polyglycerol dendrimers (PGLDs). Hydrophilicity plays a fundamental role in tissue regeneration and fundamental forces that govern the process of cell adhesion and proliferation. In this work, the biocompatible properties and cardiomyocyte proliferation onto PANINTs modified by PGLD are described. PGLDs were immobilized onto PANINTs via surface-initiated anionic ring opening polymerization of glycidol. The microstructure and morphology of PGLD PANINTs was determined by X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM), respectively. The cardiac cell growth on the PGLD PANINTs was investigated. The PGLD-coated PANINTs showed noncytotoxic effects to Chinese hamster ovary cells. It was observed that the application of microcurrent stimulates the differentiation of cardiac cells cultured on PGLD-PANINTs scaffolds. The electroactive and biocompatible results of PGLD-PANINTs observed in this work demonstrate the potential of this nanobiomaterial for the culture of cardiac cells and open the possibility of using this material as a biocompatible electroactive three-dimensional matrix in cardiac tissue engineering. PMID- 21595715 TI - Development of artificial muscles based on electroactive ionomeric polymer-metal composites. AB - This work contextualizes the research of materials that can be applied as artificial muscles. The main motivation of this research is the importance of the development of mechatronic systems for the replacement of traditional devices of actuation and motion based on rotational electrical motors by other devices that reproduce biological muscle movements. Electroactive polymers (EAPs) are materials that respond to electric stimuli with shape and/or dimension changes, and accomplish movements that are smooth enough to mimic biological muscles. Among EAPs, the ionomeric polymer-metal composites (IPMCs) are an interesting alternative to biomimetic devices due to large displacements when submitted to low applied voltage. This article presents a brief review of IPMCs, a sample preparation procedure, and some electromechanical experimental results. We also discuss the applicability of this technology in medical devices and as artificial muscles. PMID- 21595716 TI - Preparation and characterization of an acellular bovine pericardium intended for manufacture of valve bioprostheses. AB - Major problems with biological heart valves post-implantation are associated with progressive structural deterioration and calcification attributed to glutaraldehyde processing, dead cells, and cell fragments present in the native tissue. In spite of these problems, glutaraldehyde still is the reagent of choice. The results with acellular matrix xenograft usually prepared by detergent treatment in association with enzymes are rather conflicting because while preserving mechanical properties, tissue morphology and collagen structure are process dependent. This work describes a chemical approach for the preparation of an acellular bovine pericardium matrix intended for the manufacture of heart valve bioprostheses. Cell removal was performed by an alkaline extraction in the presence of calcium salts for periods ranging from 6 to 48 h. The results showed that cell removal was achieved after 12 h, with swelling and negative charge increasing with processing time. Nevertheless, collagen fibril structure, ability to form fibrils, and stability to collagenase were progressive after 24-h processing. There was no denaturation of the collagen matrix. A process is described for the preparation of acellular bovine pericardium matrices with preserved fibril structure and morphology for the manufacture of cardiac valve bioprostheses and may be used in other applications for tissue reconstruction. PMID- 21595717 TI - In vitro and in vivo evaluation of lyophilized bioprosthetic valve. AB - Freeze-drying of biological tissues allows for dry storage and gamma ray sterilization, which may improve their use as a medical prosthesis. The objective of this study was to evaluate the rehydration characteristics and hydrodynamic performance of prosthetic valves before and after lyophilization. Two size 23 bovine pericardium aortic valve prostheses from different manufacturers were evaluated in a Shelhigh (Union, NJ, USA) pulse duplicator (80 ppm, 5 L/min) before and after lyophilization. Flow and transvalvular pressure gradient were registered in vitro and in vivo, and images of opening and closing of the prosthesis were obtained in the pulse duplicator in a digital camera. Rehydration was evaluated by comparison of dry valve weight with valve weight after 15 min, and 1, 24, 48, and 72 h in saline solution, inside the pulse duplicator. In vivo performance was assessed by surgical implantation in Santa Ines young male sheep in the pulmonary position after 30 min rehydration with 0.9% saline. Transvalvular pressure gradient and flow measurements were obtained immediately after implantation and 3 months after surgery when valves were explanted. Captured images showed a change in the profile opening and closing of valve prosthesis after lyophilization. The gradient measured (in vitro) in two valves was 17.08 +/- 0.57 and 18.76 +/- 0.70 mm Hg before lyophilization, and 34.24 +/- 0.59 and 30.40 +/- 0.97 mm Hg after lyophilization. Rehydration of both lyophilized valves was approximately 82%. Drying changed the profile of the opening and closing of valve prostheses, and increased on average by 83% the gradient in vitro tests. The result of the in vivo tests suggests maintaining pressure levels of the animal with the lyophilized prostheses within acceptable levels. PMID- 21595718 TI - In vitro properties and performance of glutaraldehyde-crosslinked bovine pericardial bioprostheses treated with glutamic acid. AB - Calcification is one of the major causes of failure of heart valve bioprostheses (HVBs) derived from glutaraldehyde (GA)-processed bovine pericardium (BP) or porcine aortic valves. New crosslinking reagent procedures are still far from giving satisfactory results, and this is the main reason why GA is still the reagent of choice for the fixation of native tissue intended for HVB manufacture. Nevertheless, two new findings with respect to GA processing may significantly improve HVB performance postimplantation: the finding that increasing concentrations of GA result in a decrease in calcification; the blocking of free aldehyde usually by nucleophyles or the treatment of processed material at low pH. This work investigates the in vitro properties of BP fixed with GA followed by the treatment with glutamic acid under alkaline conditions in order to prepare BP materials with lower calcification potential postimplantation. In comparison to conventional processing, except for the tensile strength that was slightly lower, elongation and toughness were higher than the accepted values. No significant differences were observed in the performance indexes (mean pressure gradient, mean effective area, regurgitant fraction, performance and efficiency indexes) with wear resistance over 150 * 106 cycles. These results indicate that the processing of BP described in this work may be of potential use in the manufacture of HVBs. PMID- 21595719 TI - Cytotoxicity and endothelial cell adhesion of lyophilized and irradiated bovine pericardium modified with silk fibroin and chitosan. AB - Grafts of biological tissues have been used since the 1960s as an alternative to the mechanical heart prostheses. Nowadays, the most consolidated treatment to bovine pericardial (BP) bioprostheses is the crosslinking with glutaraldehyde (GA), although GA may induce calcification in vivo. In previous work, our group demonstrated that electron beam irradiation applied to lyophilized BP in the absence of oxygen promoted crosslinks among collagen fibers of BP tissue. In this work, the incorporation of silk fibroin (SF) and chitosan (CHIT) in the BP not treated with GA was studied. The samples were irradiated and then analyzed for their cytotoxicity and the ability of adhesion and growth of endothelial cells. Initially, all samples showed cytotoxicity. However, after a few washing cycles, the cytotoxicity due to acetic acid and ethanol residues was removed from the biomaterial making it suitable for the biofunctional test. The samples modified with SF/CHIT and electron beam irradiated favored the adhesion and growth of endothelial cells throughout the tissue. PMID- 21595720 TI - Delivery of the bioactive gas hydrogen sulfide during cold preservation of rat liver: effects on hepatic function in an ex vivo model. AB - The insults sustained by transplanted livers (hepatectomy, hypothermic preservation, and normothermic reperfusion) could compromise hepatic function. Hydrogen sulfide (H2S) is a physiologic gaseous signaling molecule, like nitric oxide (NO) and carbon monoxide (CO). We examined the effect of diallyl disulfide as a H2S donor during hypothermic preservation and reperfusion on intrahepatic resistance (IVR), lactate dehydrogenase (LDH) release, bile production, oxygen consumption, bromosulfophthalein (BSP) depuration and histology in an isolated perfused rat liver model (IPRL), after 48 h of hypothermic storage (4 degrees C) in University of Wisconsin solution (UW, Viaspan). Livers were retrieved from male Wistar rats. Three experimental groups were analyzed: Control group (CON): IPRL was performed after surgery; UW: IPRL was performed in livers preserved (48 h-4 degrees C) in UW; and UWS: IPRL was performed in livers preserved (48 h-4 degrees C) in UW in the presence of 3.4 mM diallyl disulfide. Hypothermic preservation injuries were manifested at reperfusion by a slight increment in IHR and LDH release compared with the control group. Also, bile production for the control group (1.32 uL/min/g of liver) seemed to be diminished after preservation by 73% in UW and 69% in UW H2S group at the end of normothermic reperfusion. Liver samples analyzed by hematoxylin/eosin clearly showed the deleterious effect of cold storage process, partially reversed (dilated sinusoids and vacuolization attenuation) by the addition of a H2S delivery compound to the preservation solution. Hepatic clearance (HC) of BSP was affected by cold storage of livers, but there were no noticeable differences between livers preserved with or without diallyl disulfide. Meanwhile, livers preserved in the presence of H2S donor showed an enhanced capacity for BSP uptake (k(A) CON = 0.29 min-1; k(A) UW = 0.29 min-1 ; k(A) UWS = 0.36 min -1). In summary, our animal model suggests that hepatic hypothermic preservation for transplantation affects liver function and hepatic depuration of BSP, and implies that the inclusion of an H2S donor during hypothermic preservation could improve standard methods of preparing livers for transplant. PMID- 21595721 TI - Influence of heat treatment and oxygen doping on the mechanical properties and biocompatibility of titanium-niobium binary alloys. AB - The most commonly used titanium (Ti)-based alloy for biological applications is Ti-6Al-4V, but some studies associate the vanadium (V) with the cytotoxic effects and adverse reactions in tissues, while aluminum (Al) has been associated with neurological disorders. Ti-Nb alloys belong to a new class of Ti-based alloys with no presence of Al and V and with elasticity modulus values that are very attractive for use as a biomaterial. It is well known that the presence of interstitial elements (such as oxygen, for example) changes the mechanical properties of alloys significantly, particularly the elastic properties, the same way that heat treatments can change the microstructure of these alloys. This article presents the effect of heat treatment and oxygen doping in some mechanical properties and the biocompatibility of three alloys of the Ti-Nb system, characterized by density measurements, X-ray diffraction, optical microscopy, Vickers microhardness, in vitro cytotoxicity, and mechanical spectroscopy. PMID- 21595722 TI - Computational fluid dynamics design and analysis of a passively suspended Tesla pump left ventricular assist device. AB - This article summarizes the use of computational fluid dynamics (CFD) to design a novel suspended Tesla left ventricular assist device. Several design variants were analyzed to study the parameters affecting device performance. CFD was performed at pump speeds of 6500, 6750, and 7000 rpm and at flow rates varying from 3 to 7 liters per minute (LPM). The CFD showed that shortening the plates nearest the pump inlet reduced the separations formed beneath the upper plate leading edges and provided a more uniform flow distribution through the rotor gaps, both of which positively affected the device hydrodynamic performance. The final pump design was found to produce a head rise of 77 mm Hg with a hydraulic efficiency of 16% at the design conditions of 6 LPM through flow and a 6750 rpm rotation rate. To assess the device hemodynamics the strain rate fields were evaluated. The wall shear stresses demonstrated that the pump wall shear stresses were likely adequate to inhibit thrombus deposition. Finally, an integrated field hemolysis model was applied to the CFD results to assess the effects of design variation and operating conditions on the device hemolytic performance. PMID- 21595723 TI - In vivo evaluation of the "TinyPump" as a pediatric left ventricular assist device. AB - Pediatric patients with end-stage heart failure require mechanical circulatory support (MCS) just as adults do. In order to meet the special requirements for neonates' and infants' MCS, pediatric circulatory support devices must be compact with low priming volume, easily controllable with low flow, less traumatic for blood cells and tissues, and biocompatible with minimum anticoagulation. We have designed and developed a miniature rotary centrifugal blood pump, "TinyPump," with a priming volume of 5 mL, which has already demonstrated its controllable performance for low flow and durability in vitro. To evaluate the feasibility of the TinyPump as a left ventricular assist device (LVAD) suitable for neonates and infants, we have examined the biocompatibility and hemodynamic performance of the TinyPump in a pediatric animal model using Shiba goats. The TinyPump is a miniaturized centrifugal pump weighing 150 g comprising a disposable pump head with a 30-mm diameter impeller having six straight-vanes and a reusable motor driver. The impeller in the pump head is supported by a hydrodynamic bearing at its center and is driven by radial magnetic force coupled to the motor driver. TinyPump implantations were performed in 22 Shiba goats (17 female and 5 male), with body weights ranging from 8.4 to 27.2 kg. Under gas anesthesia, via left lateral thoracotomy, a 22 Fr inflow cannula was inserted through the left ventricular apex, while a 6-mm outflow graft was anastomosed to the descending aorta, which were then connected to a TinyPump mounted on the animal's back. Postoperative hemodynamic monitoring included heart rate, arterial and central venous pressure, pump flow, and rotation speed. Target pump flow in all animals was maintained at 0.9 +/- 0.1 L/min, which is approximately half the normal pulmonary artery flow measured in control animals. Blood samples were collected to evaluate peripheral organ functions, hemolysis, and thrombosis. Goats were divided into three groups-acute phase (6 h; n = 4), subchronic phase (6 h 2 postoperative days [POD]; n = 11), and chronic phase (3 POD-16 POD; n = 8)-based on their survival duration. In the early experiments, hemolysis and thrombi formation at the impeller bearing resulted in termination of the study. Subsequent modifications of the bearing design, pump housing design, and magnetic coupling force helped to minimize the hemolysis and thrombi formation, prolonging the survival duration of the Shiba goats to 2 weeks with minimum adverse effects on the blood components and organ functions. With further experiments and improvements in pump durability and hemocompatibility, the TinyPump can serve as a suitable circulatory support device for neonates and infants bridging to heart transplantation as well as to heart recovery. PMID- 21595724 TI - Microbubble formation during minimized cardiopulmonary bypass. PMID- 21595727 TI - Diversity and biogeochemical structuring of bacterial communities across the Porangahau ridge accretionary prism, New Zealand. AB - Sediments from the Porangahau ridge, located off the northeastern coast of New Zealand, were studied to describe bacterial community structure in conjunction with differing biogeochemical regimes across the ridge. Low diversity was observed in sediments from an eroded basin seaward of the ridge and the community was dominated by uncultured members of the Burkholderiales. Chloroflexi/GNS and Deltaproteobacteria were abundant in sediments from a methane seep located landward of the ridge. Gas-charged and organic-rich sediments further landward had the highest overall diversity. Surface sediments, with the exception of those from the basin, were dominated by Rhodobacterales sequences associated with organic matter deposition. Taxa related to the Desulfosarcina/Desulfococcus and the JS1 candidates were highly abundant at the sulfate-methane transition zone (SMTZ) at three sites. To determine how community structure was influenced by terrestrial, pelagic and in situ substrates, sequence data were statistically analyzed against geochemical data (e.g. sulfate, chloride, nitrogen, phosphorous, methane, bulk inorganic and organic carbon pools) using the Biota-Environmental matching procedure. Landward of the ridge, sulfate was among the most significant structuring factors. Seaward of the ridge, silica and ammonium were important structuring factors. Regardless of the transect location, methane was the principal structuring factor on SMTZ communities. PMID- 21595729 TI - Experiences of living with increased risk of developing colorectal and gynaecological cancer in individuals with no identified gene mutation. AB - BACKGROUND: In most families with familial cancers, mutations have not been demonstrated; thus, healthy individuals cannot be tested for mutation status. As a consequence, many persons at risk of familial cancer live with an unknown, but presumably high, risk of developing cancer. AIM: The aim of this study was to describe individuals' perceptions of living with an increased risk of colorectal and gynaecologic cancer where the gene mutation is unknown. METHODS: Interviews were conducted with 30 individuals with familial colorectal cancer. These persons have no known mutation and therefore should be considered presumptive carriers. In connection with the interviews, all participants were offered to take part in a surveillance programme consisting of a colonoscopy and gynaecological examinations. The interview transcriptions were analysed by the use of qualitative content analysis. RESULTS: Two themes emerged from the analyses: first, living under a threat with two subthemes, threat awareness and distancing oneself from the threat. The second theme, living with uncertainty, was divided into four subthemes: influencing one's family, being on the safe side, facing emotions evoked by examinations and trust and disappointment to the medical services. CONCLUSION: These persons live with a lifelong uncertainty with a varying intensity depending on what happens throughout the life trajectory. They have no diagnosis or patient group to relate to; therefore, the entire situation is often perceived as abstract. Thus, providing information and counselling needs to be more deeply elucidated, and we need to address both situational and existential ways of uncertainty. This will, however, require professionals of all disciplines to understand the meaning of uncertainty and help ensure that its adverse effects are decreased with adequate nursing interventions. PMID- 21595730 TI - Reduced levels of E-cadherin correlate with progression of corticotroph pituitary tumours. AB - OBJECTIVES: Loss of E-cadherin is an important marker of epithelial tumour progression. The aims of this study were to explore whether E-cadherin expression and localization correlate to corticotroph tumour progression, relate the expression of the E-cadherin gene (CDH1) to immunohistochemical E-cadherin staining pattern, and study whether the E-cadherin levels were correlated to methylation status of the CDH1 promoter region. DESIGN: Immunohistochemical analyses of E-cadherin protein were performed, as was RT-qPCR of the CDH1 and the POMC genes. Methylation pattern of the promoter region of CDH1 was measured using pyrosequencing of bisulfite-treated DNA. PATIENTS: Forty-five patients operated at a tertiary referral centre in Oslo, Norway. Adenoma tissue sections and RNA samples from patients with verified Cushing's disease or Nelson's syndrome were collected. MEASUREMENTS: Expression of E-cadherin mRNA and protein in pituitary corticotroph adenomas and average percentage of methylated cytosines in a cytosine-phosphate-guanosine island of the CDH1 promoter. RESULTS: Correlations were observed between tumour progression and both nuclear expression of E cadherin and reduced CDH1 mRNA. The E-cadherin expression was not determined by the methylation pattern of the CDH1 promoter. CONCLUSIONS: Corticotroph tumour progression was associated with reduced expression of the epithelial marker E cadherin. PMID- 21595731 TI - Serum 25-hydroxyvitamin D levels and the metabolic syndrome in older persons: a population-based study. AB - BACKGROUND: Recent evidence indicates that a lower plasma level of 25 hydroxyvitamin D (25 OHD) is associated with a higher risk of the metabolic syndrome. It has not been studied in older people with a high prevalence of vitamin D insufficiency. OBJECTIVE: This study investigates the association between vitamin D status and the metabolic syndrome in community-dwelling older persons in the Netherlands. DESIGN AND PATIENTS: The study is part of the Longitudinal Aging Study Amsterdam, an ongoing cohort study in a representative sample of Dutch older persons. A total of 1286 subjects (629 men and 657 women) between the ages of 65 and 88 years participated in the study. MEASUREMENTS: Metabolic syndrome (U.S. National Cholesterol Education Program definition) and its individual components were assessed as well as serum 25 OHD levels. RESULTS: Among the participants, the prevalence of the metabolic syndrome was 37.0%. The mean 25 OHD level was 53.3 nM; 47.8% had 25 OHD levels below 50 nM. There was a significantly increased risk of the metabolic syndrome in the subjects with serum 25 OHD levels below 50 nM, compared with that of subjects with levels over 50 nM [odds ratio (OR) = 1.54; 95% confidence interval (CI) 1.23-1.94]. After adjustment for confounders, age, sex, season, years of education, alcohol use, total activity, smoking and PTH, the OR was 1.29 (95% CI 1.00-1.68). The association between vitamin D deficiency and the metabolic syndrome was mainly determined by the components low HDL and (high) waist circumference. CONCLUSIONS: Vitamin D deficiency is common in the older population in the Netherlands, and subjects with serum 25 OHD below 50 nM have a higher risk of the metabolic syndrome. PMID- 21595732 TI - Clinical and molecular characteristics of immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in China. AB - Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare X-linked recessive disorder causing life-threatening systemic autoimmunity because of immunodysregulation. The FOXP3 gene had been reported as the responsible gene, which was critical for the functions of CD4(+) CD25(+) FOXP3(+) regulatory T cells (Tregs) and maintenance of peripheral immunologic tolerance. So far, no IPEX patients with definite mutations in the FOXP3 gene had been reported in China. In this study, the genotypes and phenotypes were investigated in three IPEX infants from three unrelated Chinese families. Patient 1 (P1) presented with a classical clinical phenotype, whose mutation was a novel frameshift insertion in exon 11, led to the complete abrogation of Tregs. Patient 2 (P2) showed incomplete IPEX phenotype. He carried a missense mutation in exon 11 with slightly increased frequency of Tregs, whereas Patient 3 (P3) presented with a relatively mild classical phenotype and had a previously reported missense mutation in exon 10 with decreased frequency of Tregs. We firstly report three Chinese IPEX patients with definite mutations of FOXP3 gene. Our study indicated the potential correlation between the genotype and the phenotype of IPEX, which was different from the previous reports. PMID- 21595728 TI - Identification of microbial communities involved in the methane cycle of a freshwater meromictic lake. AB - Lake Pavin is a meromictic crater lake located in the French Massif Central area. In this ecosystem, most methane (CH(4)) produced in high quantity in the anoxic bottom layers, and especially in sediments, is consumed in the water column, with only a small fraction of annual production reaching the atmosphere. This study assessed the diversity of methanogenic and methanotrophic populations along the water column and in sediments using PCR and reverse transcription-PCR-based approaches targeting functional genes, i.e. pmoA (alpha-subunit of the particulate methane monooxygenase) for methanotrophy and mcrA (alpha-subunit of the methyl-coenzyme M reductase) for methanogenesis as well as the phylogenetic 16S rRNA genes. Although methanogenesis rates were much higher in sediments, our results confirm that CH(4) production also occurs in the water column where methanogens were almost exclusively composed of hydrogenotrophic methanogens, whereas both hydrogenotrophs and acetotrophs were almost equivalent in the sediments. Sequence analysis of markers, pmoA and the 16S rRNA gene, suggested that Methylobacter may be an important group actively involved in CH(4) oxidation in the water column. Two main phylotypes were characterized, one of which could consume CH(4) under conditions where the oxygen amount is undetectable. PMID- 21595733 TI - Glatiramer acetate treatment directly targets CD11b(+)Ly6G(-) monocytes and enhances the suppression of autoreactive T cells in experimental autoimmune encephalomyelitis. AB - Glatiramer acetate (GA) is used for the treatment of relapsing-remitting multiple sclerosis (MS) and can suppress experimental autoimmune encephalomyelitis in animals. Effective GA treatment is associated with the induction of anti inflammatory T(H)2 responses and antigen-specific expansion of CD25(+)/Foxp3(+) Tregs through the modulation of antigen-presenting cells. Here, we show that intravenous injection of fluorochrome-labelled GA resulted in rapid and specific binding of GA to CD11b(+) F4/80(lo) Ly6G(-) blood monocytes via an MHC class II independent mechanism. Intravenous GA treatment enhanced the intrinsic capability of these monocytes to directly suppress T cell proliferation in vitro. The suppressive function correlated with reduced proliferation of myelin-specific T cells in vivo after intravenous GA treatment. In contrast, subcutaneous treatment with GA inhibited the pro-inflammatory IFNgamma-producing T cell phenotype rather than suppressing T cell proliferation. These data indicate that (1) GA engages directly with circulating monocytes to induce type II monocyte suppressor function; and (2) the therapeutic efficacy of GA may be expanded by employing different routes of GA administration to engage alternative mechanisms of suppression of autoreactive T cells in MS. PMID- 21595734 TI - Ex vivo expansion of CD56+ NK and NKT-like lymphocytes from peripheral blood mononuclear cells of patients with ovarian neoplasia. AB - Methods for ex vivo expansion of natural killer (NK) cells have allowed obtaining enough numbers of human NK cells for clinical trials. However, the evaluation of these methods has been mostly limited to haematological malignancies. This study aimed at evaluating a method for selective expansion of NK cells when applied in peripheral blood mononuclear cells (PBMC) of patients with ovarian neoplasia. PBMC from 13 volunteer patients with ovarian neoplasia, seven benign and six malignant tumours, were cultured in CellGro medium supplemented with anti-CD3 (9 10 initial days), IL-2 and foetal bovine serum for 21 days. The resulting effector cells were evaluated for their phenotype, cytotoxicity and cytokine secretion. PBMC cultures resulted in multiple populations (NK, NKT and T) of effector cells, enriched with CD56(+) lymphocytes. NK cells from patients with benign and malignant ovarian neoplasia were expanded 139.6 +/- 63.4 and 82.7 +/- 25.3-fold, respectively, being the largest lymphocyte subtype among CD56(+) population. Effector cells expanded from patients with malignant ovarian neoplasia had higher proportion of T lymphocytes and altered cytokine production patterns, characterized by lower INF-gamma, TNF-alpha and higher IL-4, compared with patients with benign ovarian neoplasia. Effector cells were cytotoxic against K562 and OVCAR3 cell lines. Cytotoxicity was significantly higher (P < 0.05) using magnetically separated CD56(+) effector cell fractions compared with CD56-deprived ones. The present study demonstrates the feasibility of the culture system employed to generate effector cells, enriched with CD56(+) lymphocytes, from PBMC of patients with ovarian neoplasia. NK cells were the largest lymphocyte subtype among the CD56(+) population and the main variable among the final effector cell preparation affecting target cell killing. PMID- 21595735 TI - Differential binding and internalization of Clostridium difficile toxin A by human peripheral blood monocytes, neutrophils and lymphocytes. AB - Colitis due to Clostridium difficile infection is mediated by secreted toxins A and B and is characterized by infiltration by cells from the systemic circulation. The aim of our study was to investigate interactions between fluorescently labelled toxin A and peripheral blood monocytes, neutrophils and lymphocytes. Purified toxin A was labelled with Alexa Fluor(r) 488 (toxin A(488)) and incubated with isolated human peripheral blood mononuclear cells or washed whole blood cells for varying time intervals at either 37 or 4 degrees C/ice. The ability of trypan blue to quench cell surface-associated (but not cytoplasmic) fluorescence was also investigated. At 37 degrees C, toxin A(488) associated fluorescence in monocytes peaked at 1 h (majority internalized), with subsequent loss associated with cell death. In contrast to monocytes, binding of toxin A(488) in neutrophils was greater on ice than at 37 degrees C. Studies using trypan blue suggested that over 3 h at 37 degrees C, most of the toxin A(488)-associated fluorescence in neutrophils remained at the cell surface. Over 48 h (37 degrees C and ice/4 degrees C), there was minimal toxin A(488) associated fluorescence in lymphocytes. These studies suggest major differences in interactions between toxin A and circulating cells that infiltrate the mucosa during colonic inflammation in C. difficile infection. PMID- 21595736 TI - Evaluation of the microbicidal activity and cytokines/chemokines profile released by neutrophils from HTLV-1-infected individuals. AB - Human T cell lymphotropic virus type-1 (HTLV-1) induces activation and spontaneous proliferation of T cells with production of type-1 pro-inflammatory cytokines. It modifies the immune response to other antigens and increases susceptibility to infectious diseases. However, little is known about innate immunity in HTLV-1 infection. HTLV-1-infected individuals have higher spontaneous neutrophil activation than HTLV-1-seronegative individuals, as shown by the nitroblue tetrazolium (NBT) assay. This study was conducted to evaluate neutrophil function in HTLV-1-infected individuals. Participants in the study included 18 HTLV-1-infected individuals and 14 HTLV-1-seronegative controls. We evaluated the ability of neutrophils (PMNs) to control a parasite infection, to produce peroxynitrite, cytokines and chemokines and to express activation markers in cultures when stimulated with LPS or infected with Leishmania. When compared with the control group, there was no difference in the percentage of PMNs infected with Leishmania or in the number of amastigotes/100 PMNs in HTLV-1 infected individuals. The microbicidal activity of the PMNs and the levels of CXCL8 and CCL4 released by these cells did not show a difference between HTLV-1 infected individuals and the control group. In both the HTLV-1 group and the control group, infection with Leishmania or stimulation of PMNs led to cellular activation. These observations suggest that neutrophils from HTLV-1-infected individuals have preserved their ability to become activated and to produce chemokines and peroxynitrite after stimulation and that the susceptibility to infection by intracellular Leishmania amazonensis in HTLV-1-infected individuals does not depend on impairment of neutrophil function. PMID- 21595737 TI - Tumour-loaded alpha-type 1-polarized dendritic cells from patients with chronic lymphocytic leukaemia produce a superior NK-, NKT- and CD8+ T cell-attracting chemokine profile. AB - Tumour-loaded dendritic cells (DCs) from patients with chronic lymphocytic leukaemia (CLL) matured using an alpha-type 1-polarized DC cocktail (IL-1beta/TNF alpha/IFN-alpha/IFN-gamma/poly-I:C;alphaDC1) were recently shown to induce more functional CD8(+) T cells against autologous tumour cells in vitro than DCs matured with the 'standard' cocktail (IL-1beta/TNF-alpha/IL-6/PGE(2) ;PGE(2) DCs). However, the ability of vaccine DCs to induce a type 1-polarized immune response in vivo probably relies on additional features, including their ability to induce a CXCR3-dependent recruitment of NK cells into vaccine-draining lymph nodes. Moreover, their guiding of rare tumour-specific CD8(+) T cells to sites of DC-CD4(+) T cell interactions by secretion of CCL3 and CCL4 is needed. We therefore analysed the chemokine profile and the lymphocyte-attracting ability in vitro of monocyte-derived PGE(2) DCs and alphaDC1s from patients with CLL. alphaDC1s produced much higher levels of CXCR3 ligands (CXCL9/CXCL10/CXCL11) than PGE(2) DCs. Functional studies further demonstrated that alphaDC1s were superior recruiters of both NK and NKT cells. Moreover, alphaDC1s produced higher levels of CCL3/CCL4 upon CD40 ligation. These findings suggest that functional alphaDC1s, derived from patients with CLL, produce a desirable NK-, NKT- and CD8(+) T cell-attracting chemokine profile which may favour a guided and Th1 deviated priming of CD8(+) T cells, supporting the idea that alphaDC1-based vaccines have a higher immunotherapeutic potential than PGE(2) DCs. PMID- 21595738 TI - Quality of life and psychosocial outcomes after fixed orthodontic treatment: a 17 year observational cohort study. AB - BACKGROUND: There is little evidence to suggest that orthodontic treatment can prevent or reduce the likelihood of dental caries or of periodontal disease or dental trauma and temporomandibular disorders, but there is a modest association between the presence of malocclusion/orthodontic treatment need and quality of life. However, little is known of the long-term outcomes of orthodontic treatment. This study reports on the longitudinal follow-up of quality of life and psychosocial outcomes of orthodontic treatment among a cohort of adults who were examined as adolescents in 1988/1989. MATERIALS AND METHODS: Children who were examined in 1988/1989 were invited to a follow-up in 2005/2006. Respondents completed a questionnaire, which collected information on quality of life, receipt of orthodontic treatment and psychosocial factors, and were invited for a clinical examination. Oral health conditions including occlusal status using the Dental Aesthetic Index were recorded. Analysis of variance and multiple linear regression were used to examine the relationship between the measured factors. RESULTS: There was no statistically significant association between occlusal status at adolescence and quality of life at adulthood. Those individuals who had orthodontic treatment but did not need orthodontic treatment had higher self esteem (23.1, SD 5.2) and were more satisfied with life (18.5, SD 3.7) than other treatment groups (self-esteem range, 20.0-22.7; life satisfaction range, 16.4 18.1), anovaP < 0.01 and P < 0.05, respectively. Occlusal status at adulthood was significantly associated with quality of life, P < 0.01. Multivariate analyses showed a statistically significant association between occlusal status at adolescence ('Desirable treatment'beta = 0.70, P = 0.04) and adulthood ('Desirable treatment'beta = 1.66, P < 0.01) with quality of life. Orthodontic treatment was negatively associated with psychosocial factors (life satisfaction; fixed orthodontic treatment (FOT) beta = -0.91, P = 0.02 and self-esteem; FOT beta = -1.39, P < 0.01). CONCLUSIONS: Occlusal status appears to have limited association with quality of life and psychosocial factors. Receipt of fixed orthodontic treatment does not appear to be associated with oral health-related quality of life but appears to be negatively associated with self-esteem and satisfaction with life. PMID- 21595739 TI - Prevalence of self-reported symptoms related to temporomandibular disorders in an Italian population. AB - The aim of this study was to estimate the prevalence of temporomandibular disorders (TMD) symptoms in an Italian population sample, focusing on gender and age differences. We selected 2005 individuals by telephone survey and asked them about TMD symptoms like difficulty in jaw movement, jaw pain and joint sounds. Also, tooth-clenching and/or tooth-grinding habits were investigated. Of the study population, 8.1% reported limitations in jaw movements, 5.1% reported jaw pain and 33.3% reported joint sounds. Furthermore, 37.3% reported tooth clenching/tooth-grinding. Confidence intervals of proportions were calculated. Significant gender differences were found for jaw limitation and pain (chi-square test; P < 0.05). Symptoms reduced with increasing age. The prevalence of TMD symptoms in the Italian population was consistent with data reported from similar studies. Gender and age differences were found for jaw pain and limitation in jaw movements. PMID- 21595740 TI - Octreotide inhibits capsaicin-induced activation of C and Adelta afferent fibres in rat hairy skin in vivo. AB - 1. The present study investigated whether the somatostatin receptor (SSTR) agonist, octreotide, could inhibit the activation of dorsal skin afferent fibres induced by local injection of capsaicin in the rat. 2. Single unit activity from Adelta mechano-heat sensitive (AMH; n = 41) and C mechano-heat sensitive (CMH; n = 30) afferents was recorded after their isolation in thin filaments from the dorsal cutaneous nerve branches. The effect of subcutaneous octreotide injection on the change in discharge rate and mechanical threshold induced by capsaicin was determined. 3. Capsaicin (0.05%) injection into the edge of the receptive field of both AMH and CMH units increased their discharge rate and decreased their mechanical threshold. Pre-injection of octreotide inhibited these responses, and co-application of SSTR antagonist, cyclosomatostatin, reversed the inhibitory effect of octreotide. 4. The present study provides electrophysiological evidence that the signal evoked by the somatostatin receptor inhibits the activation and mechanical sensitization evoked by capsaicin in the terminals in small-diameter sensory neurons. PMID- 21595742 TI - Sustained remission of nodular inflammatory acne after treatment with infliximab. PMID- 21595741 TI - Cardiac effects of muscarinic receptor antagonists used for voiding dysfunction. AB - Antimuscarinic agents are the main drugs used to treat patients with the overactive bladder (OAB) syndrome, defined as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia. Since the treatment is not curative and since OAB is a chronic disease, treatment may be life-long. Antimuscarinics are generally considered to be 'safe' drugs, but among the more serious concerns related to their use is the risk of cardiac adverse effects, particularly increases in heart rate (HR) and QT prolongation and induction of polymorphic ventricular tachycardia (torsade de pointes). An elevated resting HR has been linked to overall increased morbidity and mortality, particularly in patients with cardiovascular diseases. QT prolongation and its consequences are not related to blockade of muscarinic receptors, but rather linked to inhibition of the hERG potassium channel in the heart. However, experience with terodiline, an antimuscarinic drug causing torsade de pointes in patients, has placed the whole drug class under scrutiny. The potential of the different antimuscarinic agents to increase HR and/or prolong the QT time has not been extensively explored for all agents in clinical use. Differences between drugs cannot be excluded, but risk assessments based on available evidence are not possible. PMID- 21595743 TI - Validation of the cantharidin-induced skin blister as an in vivo model of inflammation. AB - AIM: Pharmacological profiling techniques, such as the cantharidin-induced skin blister, may be used to assess the anti-inflammatory properties of novel drugs. However, no data are available on the reproducibility of this technique or on the blocking effect of anti-inflammatory drugs, such as anti-TNF and corticosteroids. METHODS: A group of 30 healthy subjects were randomized into three parallel groups treated with placebo, oral methylprednisolone 20 mg day(-1) for 7 days or anti-tumour necrosis factor (TNF) (adalimumab, Humira(r), Abbott) 40 mg s.c. single dose. A first blister was induced at baseline and collected, immediately before the start of treatment and a second blister was obtained 7 days after the start of treatment. The total number of cells, the cell viability and the differential cell count were evaluated by two independent observers, who were blind to treatment. anova was used to compare change from baseline among the three groups before pairwise comparisons. RESULTS: Among the placebo group, there was no significant difference in the total cell count, neutrophils, eosinophils and monocytes between day 1 and day 7. Methylprednisolone inhibited the eosinophil influx in mean % (95% CI) (-1.0 (-1.7, -0.3); P < 0.02) and absolute (P < 0.02) values, while anti-TNF inhibited the neutrophil influx in mean % (95% CI) (-19.3 (-29.5, -9.1); P < 0.01) and absolute (P < 0.05) values. CONCLUSIONS: The cantharidin-induced skin blister is a safe, well tolerated and reproducible procedure. Pre-treatment with anti-TNF or methylprednisolone inhibited the neutrophilic or eosinophilic trafficking, respectively. It could be useful in profiling anti-inflammatory drugs regarding their effects on the cellular inflammatory response. PMID- 21595745 TI - Biofilms and infectious diseases: biology to mathematics and back again. AB - There has been tremendous growth in biofilm research in the past three decades. This growth has been reflected in development of a wide variety of experimental, clinical, and theoretical techniques fostered by our increased knowledge. Keeping the theoretical developments abreast of the experimental advancements and ensuring that the theoretical results are disseminated to the experimental and clinical community is a major challenge. This manuscript provides an overview of recent developments in each scientific domain. More importantly, this manuscript aims to identify areas where the theory lags behind the experimental understanding (and vice versa). The major themes of the manuscript derive from discussions and presentations at a recent interdisciplinary workshop that brought together a variety of scientists whose underlying studies focus on biofilm processes. PMID- 21595744 TI - Growth phase-dependent gene regulation in vivo in Sulfolobus solfataricus. AB - Ribosomal genes are strongly regulated dependent on growth phase in all organisms, but this regulation is poorly understood in Archaea. Moreover, very little is known about growth phase-dependent gene regulation in Archaea. SSV1 based lacS reporter gene constructs containing the Sulfolobus 16S/23S rRNA gene core promoter, the TF55alpha core promoter, or the native lacS promoter were tested in Sulfolobus solfataricus cells lacking the lacS gene. The 42-bp 16S/23S rRNA gene and 39-bp TF55alpha core promoters are sufficient for gene expression in S. solfataricus. However, only gene expression driven by the 16S/23S rRNA gene core promoter is dependent on the culture growth phase. This is the smallest known regulated promoter in Sulfolobus. To our knowledge, this is the first study to show growth phase-dependent rRNA gene regulation in Archaea. PMID- 21595746 TI - Partial exchange transfusion results in increased cerebral oxygenation and faster peripheral microcirculation in newborns with polycythemia. AB - AIM: The aim of this study was to assess cerebral and peripheral oxygenation, by using near infrared spectroscopy (NIRS) and microcirculation by using side stream dark field (SDF) imaging in newborns with polycythemia before and after partial exchange transfusion (PET) therapy to investigate treatment effect on tissue oxygenation and microcirculation. METHODS: Polycythemic newborns with venous haematocrit (Htc) >70% or >=65% with symptoms were included. NIRS measurements for cerebral and peripheral oxygenation and SDF recordings for microcirculatory flow assessment were obtained before and after PET. Fractional tissue oxygen extraction (FTOE) was calculated based on tissue oxygenation index and oxygen saturation. Wilcoxon test was used for statistical analysis. RESULTS: Fifteen newborns were included. Cerebral tissue oxygenation index, microvascular flow index and % of vessels with hyperdynamic flow increased after PET; median (range): 61.27 (51.36-61.87) versus 64.54 (54.1-74.38), 2.74 (2.46-3) versus 3.22 (2.64-3.75) and 0 (0-2.8) versus 3 (0-99.3), respectively. Whereas cerebral fractional tissue oxygen extraction (CFTOE), % of vessels with sluggish flow decreased after treatment; 0.36 (0.22-0.44) versus 0.31 (0.17-0.46), 1.4 (0-69) versus 0 (0-0.9), respectively. Peripheral oxygenation was unchanged. CONCLUSION: Partial exchange transfusion improves microcirculation in polycythemic newborns. Cerebral oxygenation increases and cFTOE decreases suggesting increased blood flow. Microvascular flow increases possibly representing reactive hyperperfusion after hemodilution. Whether these effects are beneficial require further research. PMID- 21595747 TI - The clinical benefit of evaluating health-related quality-of-life in children with problematic severe asthma. AB - AIM: To evaluate health-related quality-of-life (HR-QoL) and the asthma control test (ACT) in children with problematic severe asthma and those with controlled asthma and to identify whether clinical characteristics show correlations with these measurements. METHODS: This multicentre cross-sectional study included 93 children in total, 54 with problematic severe asthma and 39 age-matched with controlled asthma. Subjects completed the Paediatric Asthma Quality-of-Life Questionnaire as well as a standardized health questionnaire and the ACT. Objective measurements of exhaled nitric oxide, specific sensitization, pulmonary function and bronchial hyper-responsiveness to methacholine were also taken. RESULTS: HR-QoL was reduced in children with problematic severe asthma (5.4 vs. 6.7, p < 0.001), particularly for girls (5.1 vs. 5.6 for boys, p = 0.02), and their ACT scores were also lower (17 vs. 23, p < 0.001) compared with those of subjects with controlled asthma. A HR-QoL score <6.2 discriminated problematic severe asthma from controlled asthma with 85% sensitivity and 97% specificity, as did the ACT score <20 (79% sensitivity and 94% specificity). Objective measures and other clinical characteristics were weakly associated with HR-QoL or ACT score. CONCLUSION: Subjective measurements of HR-QoL and asthma control are both equally useful in differentiating children with problematic severe asthma from those with controlled asthma. PMID- 21595748 TI - Intestinal transplantation: current status and future directions. AB - Three decades after the first intestinal transplant was performed in humans, this life-saving procedure has come of age and now offers hope of long-term survival in a small group of patients with life-threatening complications of intestinal failure and parenteral nutrition. Success rates have greatly improved, largely through advances in immunosuppression protocols, improved surgical technique and postoperative care, and accumulated experience. Management of the intestinal transplant recipient entails careful surveillance, prevention, and treatment of rejection and infection, as well as optimization of feeding and nutrition. With this approach, survival and quality of life are demonstrably improved, such that intestinal transplantation is now an established and accepted procedure for this very select group of highly-complex patients. PMID- 21595749 TI - A proliferation-inducing ligand (APRIL) serum levels predict time to first treatment in patients affected by B-cell chronic lymphocytic leukemia. AB - PURPOSE: A proliferation-inducing ligand (APRIL), a tumor necrosis factor superfamily member involved in B-lymphocytes differentiation and survival, plays a role in protecting B-Cell Chronic lymphocytic leukemia (B-CLL) cells from apoptosis. Having observed that APRIL serum (sAPRIL) levels were higher in B-CLL patients with CLL at diagnosis as compared to healthy donors (14.61+/-32.65 vs. 4.19+/-3.42 ng/mL; P<0.001), we tested the correlation existing in these patients between sAPRIL, clinical-biological parameters and disease progression. EXPERIMENTAL DESIGN: sAPRIL levels were measured by ELISA in 130 patients with B CLL at diagnosis and in 25 healthy donors. RESULTS: sAPRIL levels did not correlate with gender, age, clinical stage, blood cell counts, beta2 microglobulin (beta2M) levels, ZAP-70 and CD38 expression. Using median sAPRIL natural logarithm (ln) as cutoff, we distinguished two groups of patients (APRIL(LOW) and APRIL(HIGH) ) who were comparable with regard to clinical biological parameters and overall survival, but different with regard to time to the first treatment (TTFT; P=0.035). According to univariate analysis, high lymphocyte count, high beta2M, Binet stage B-C, ZAP-70 expression and ln(sAPRIL) above median were associated with earlier TTFT. Advanced clinical stage, high beta2M, ZAP-70 expression and ln(sAPRIL) above median remained independently predictive of shorter TTFT at multivariate analysis. Moreover, sAPRIL increased its prognostic significance when patients were stratified according to independent favorable clinical-biological characteristics (low beta2M, stage A and lack of ZAP-70 expression). CONCLUSIONS: sAPRIL is a novel indicator of shorter TTFT in B-CLL and a predictor of progression especially in patients otherwise considered at low risk according to validated prognostic factors. PMID- 21595750 TI - Role of human papillomavirus infection in carcinogenesis of oral squamous cell carcinoma with evidences of prognostic association. AB - BACKGROUND: Betel nut chewing, cigarette smoking and alcohol drinking are thought to be major environmental risk factors responsible for the development of oral squamous cell carcinomas. Oncogenic human papillomavirus infections have a well established association with uterine cervical carcinoma. However, little is known about the exact role of human papillomavirus infections in oral squamous cell carcinomas. This study is designed to elucidate the role of human papillomavirus infections in cancer development and prognosis of oral squamous cell carcinomas. METHODS: Molecular techniques including in situ hybridization and immunohistochemistry of p16(INK4A) and p53 for evidences of human papillomavirus in tissue micro-arrays were investigated. RESULTS: Twenty-four of 65 cases of oral squamous cell carcinomas were found positive for in situ hybridization and 14 were found positive for p16(INK4A). The majority of cases without the evidence of human papillomavirus were related to p53 over-expression. There were statistically significant correlations between the results of human papillomavirus test and size or extent of the tumor (P = 0.003) or the stage of oral squamous cell carcinomas (P = 0.015). Kaplan-Meier plot analysis demonstrated a tendency of longer survival in cases of oral squamous cell carcinomas with the evidence of human papillomavirus or positive p16 (INK4A). CONCLUSIONS: Human papillomavirus infections may play a unique role in oral carcinogenesis. Our data strongly suggest that human papillomavirus-positive oral squamous cell carcinomas comprise a distinct clinical and pathological disease entity that appears related to a better outcome with longer survival and bears a causally associated relationship different from other carcinogenic mechanisms. PMID- 21595751 TI - Midkine expression in oral squamous cell carcinoma and leukoplakia. AB - BACKGROUND: Midkine (MK), a 13-kDa heparin-binding growth factor, is overexpressed in various human cancers. However, its role in the development and progression of oral cavity squamous cell carcinoma (OCSCC) is still unclear. Thus, the aim of this study was to evaluate the expression of MK in samples of OCSCC, leukoplakia, and healthy oral mucosa (control). METHODS: Surgically excised specimens from patients with primary OCSCC (n = 28) were immunostained for MK, Ki-67, PCNA, p53, bcl-2, Bax, and CD31. Besides this, MK expression was also investigated in leukoplakia and normal oral mucosa. The relationship of MK(+) cells with clinical parameters (tumor location, tumor size, lymph node metastasis, and survival) and microscopic parameters (WHO histological grading, intensity of inflammation, proliferation index, apoptosis, and angiogenesis) was also evaluated. RESULTS: The results showed that MK expression was increased in OCSCC in relation to leukoplakia and normal mucosa. Furthermore, MK expression was increased in late-stage tumors (T3/T4) compared with early-stage lesions (T1/T2). MK-positive lesions also showed increased expression of the anti apoptotic protein bcl-2. CONCLUSION: OCSCC, particularly late-stage tumors, exhibits increased MK expression, which may be involved in tumor progression via upregulation of anti-apoptotic genes, as shown by the augmented bcl-2 positivity in MK-positive tumors. PMID- 21595752 TI - Effects of melanocortins on fetal development. AB - Melanocortins, adrenocorticotropic hormone (ACTH) and alpha-, beta-, and gamma melanocyte-stimulating hormone (MSH) are produced in the placenta and secreted into embryos/fetuses. ACTH concentrations are higher in fetal plasma than in maternal plasma and peak at mid-gestation in rats, whereas ACTH production starts in the anterior lobe of the fetal pituitary at later stages. Melanocortin receptors (MC1-5R), receptors for ACTH and alpha-, beta- and gamma-MSH, are expressed in various adult organs. The specific function of these receptors has been well examined in the hypothalamic-pituitary-adrenocortical (HPA) axis and the HPA axis-like network in the skin, and anti-inflammatory effects for white blood cells have also been investigated. MC2R and/or MC5R are also expressed in the testis, lung, kidney, adrenal, liver, pancreas, brain and blood cells at different stages in mouse and rat embryos/fetuses. Melanocortins in embryos and fetuses promote maturation of the HPA axis and also contribute to the development of lung, testis, brain and blood cells. Recently, a unique ACTH function was revealed in fetuses: placental ACTH, which is secreted by the maternal leukemia inhibitory factor (LIF), and induces LIF secretion from fetal nucleated red blood cells. Finally, the maternal LIF-placental ACTH-fetal LIF signal relay regulates the LIF level and promotes neurogenesis in fetuses, which suggests that ACTH acts as a signal transducer or effector for fetal development in the maternal-fetal signal pathway. PMID- 21595753 TI - Hypothyroidism caused by phenobarbital affects patterns of estrous cyclicity in rats. AB - We found that repeated treatment with phenobarbital (PB), a thyroid modulator, resulted in a persistent estrous stage in the present study. Although the effects of PB in blocking the surge release of luteinizing hormone (LH), inducing anovulation and prolonging the diestrous period has been well established, there is still no research describing the appearance of persistent estrous states in normal cycling rats dosed with PB. To further study this phenomenon, female rats exhibiting regular estrous cycle were administered an oral dose of PB for 14 consecutive days. Consecutively, vaginal smears were observed and rats from all the groups were sacrificed and serum hormone levels for prolactin, progesterone, estradiol, triiodothyronin (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) were measured. Pituitary, thyroid, liver, uteri and ovaries were excised, weighed and further subjected to histological observations. We found that PB induced irregular estrous cycles, especially persistent estrus in rats. Histopathologically, the persistent estrous stages are characterized by persistent vaginal cornification in the vagina, cystic follicles and anovulation in the ovaries. Endocrinologically, serum T3 and T4 levels were significantly lower, and TSH was higher in treated-female rats compared to control females. The serum estradiol level and the estradiol/progesterone ratio tend to increase in treated-females. Furthermore, PB-treated animals with irregular estrous cycle were reduced by T4 replacement. Our data indicate that treatment with PB resulted in hypothyroidism and irregular estrous cycle, particularly a persistent estrous stage in normal cycling female rats. PMID- 21595754 TI - Pattern differentiation in co-culture biofilms formed by Staphylococcus aureus and Pseudomonas aeruginosa. AB - Biofilm infections may not simply be the result of colonization by one bacterium, but rather the consequence of pathogenic contributions from several bacteria. Interspecies interactions of different organisms in mixed-species biofilms remain largely unexplained, but knowledge of these is very important for understanding of biofilm physiology and the treatment of biofilm-related infectious diseases. Here, we have investigated interactions of two of the major bacterial species of cystic fibrosis lung microbial communities -Pseudomonas aeruginosa and Staphylococcus aureus- when grown in co-culture biofilms. By growing co-culture biofilms of S. aureus with P. aeruginosa mutants in a flow-chamber system and observing them using confocal laser scanning microscopy, we show that wild-type P. aeruginosa PAO1 facilitates S. aureus microcolony formation. In contrast, P. aeruginosa mucA and rpoN mutants do not facilitate S. aureus microcolony formation and tend to outcompete S. aureus in co-culture biofilms. Further investigations reveal that extracellular DNA (eDNA) plays an important role in S. aureus microcolony formation and that P. aeruginosa type IV pili are required for this process, probably through their ability to bind to eDNA. Furthermore, P. aeruginosa is able to protect S. aureus against Dictyostelium discoideum phagocytosis in co-culture biofilms. PMID- 21595755 TI - Quantitative analysis of biofilm formation of methicillin-resistant Staphylococcus aureus (MRSA) strains from patients with orthopaedic device related infections. AB - Biofilms play a pivotal role in medical device-related infections. However, epidemiological analysis of biofilm formation and genotyping among clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients with orthopaedic infections has rarely been reported. A total of 168 MRSA strains were examined: 23 strains from patients with device-related infection (the device group); 55 from patients with device-non-related infection (the nondevice group); and 90 from asymptomatic nasal carriers (the colonization group). Pulsed-field gel electrophoresis analysis and five genotyping methods including agr typing were performed. Biofilm formation was quantified using a microtitre plate assay. The device group had a significantly higher incidence of agr-2 than the colonization group (78.3% vs. 34.4%, P=0.001). The biofilm index of the agr-2 (0.523 +/- 0.572) strains was significantly higher than those of agr-1 (0.260 +/- 0.418, P<0.0001) and agr-3 (0.379 +/- 0.557, P=0.045). The prevalence of strong biofilm formers in the device group (43.5%) was significantly higher than that in the nondevice group (12.7%, P=0.003) and the colonization group (20.0%, P=0.020). agr-2 MRSA strains may be more likely to cause orthopaedic device infection because of their strong biofilm formation ability. PMID- 21595756 TI - Nutrient profile and availability of co-products from bioethanol processing. AB - Bioethanol production in North America has led to the production of considerable quantities of different co-products. Variation in nutrient profiles as well as nutrient availability among these co-products may lead to the formulation of imbalanced diets that may adversely affect animal performance. This study aimed to compare three types of dried distiller's grains with solubles [100% wheat DDGS (WDDGS); DDGS blend1 (BDDGS1, corn to wheat ratio 30:70); DDGS blend2 (BDDGS2, corn to wheat ratio 50:50)] and their different batches within DDGS type with regard to: (i) protein and carbohydrate sub-fractions based on Cornell Net Carbohydrate and Protein System (CNCPS); (ii) calculated energy values; and (iii) rumen degradation of dry matter (DDM), organic matter (DOM), crude protein (DCP), neutral detergent fibre (DNDF) and starch (Dstarch) at 36 and 72 h of ruminal incubations. Wheat DDGS had a lower intermediately (PB2, 136.4 vs. 187.4 g/kg DM) and a higher slowly degradable true protein (PB3, 142.2 vs.105.3 g/kg DM) than BDDGS1, but similar to those of BDDGS2. Sugar (CA4) was higher, whereas starch (PB1) and digestible fibre (PB3) were lower in WDDGS than in BDDGS1 and BDDGS2. All carbohydrate sub-fractions determined differed significantly between the two batches of BDDGS2. The BDDGS2 had the highest calculated energy values (TDN, DE(3*) , ME(3*) , NEL(3*) , NE(m) and NE(g) ) among the three DDGS types. The energy values were slightly different between the batches of the three DDGS types. At all incubation times, wheat DDGS had a significantly higher (p < 0.05) DDM, DOM, DCP and DNDF than both DDGS blends. Differences were observed between different batches within DDGS types with regard to in situ rumen degradation of DM, OM, CP, NDF and starch. In conclusion, differences were observed in protein and carbohydrate sub-fractions and in situ ruminal degradation of DM, OM, CP, NDF and starch among the three DDGS types and different batches within DDGS type. This indicates that the nutrients supplied to ruminants may not only differ among different types of DDGS but it may also differ among different batches within DDGS type. PMID- 21595757 TI - Effects of feeding roasted safflower seeds (variety IL-111) and fish oil on dry matter intake, performance and milk fatty acid profiles in dairy cattle. AB - Safflower seed has the highest concentration of linoleic acid among 80 oilseeds but little information exists on the effective use of SS for lactation cows. It was hypothesised that a diet supplemented with an Iranian SS variety (IL-111) in combination with fish oil (FO) would result in higher concentrations of trans 18:1 (including vaccenic acid) and conjugated linoleic acids in milk fat than feeding an unsupplemented control diet. Our objective was to determine the effects of feeding diets containing: (i) CONTROL: (C); (ii) 25 g of roasted SS IL 111 (RSS); (iii) 20 g FO and (iv) 25 g RSS + 10 g FO (RSS + FO) per kilogram of dietary DM on feed intake, ruminal fermentation, milk production and fatty acid profile. Eight multiparous Holstein cows were used in a replicated 4 * 4 Latin square design study. The experiment had four periods of 21 days. Milk Fat percentage was lower (p < 0.01) with FO supplementation and averaged 19.0 and 21.5 g/kg milk with FO and RSS + FO compared with 30.3 and 32.5 g/kg with C and RSS. Feed intake also was lower (p < 0.01) with FO vs. C (23.1 vs. 24.5 kg/day) but feeding RSS resulted in greater feed intake compared with other treatments (26 kg/day). Despite lower feed intake with FO, milk production did not change from controls but feeding RSS + FO resulted in greater milk yield than controls (42.6 vs. 39.3 kg/day). Ruminal pH was greater (p < 0.01) in cows fed FO than other treatments. Supplemental FO alone or in combination with RSS resulted in dramatic increases (p < 0.01) in c9,t11-18:2 in milk fat (12.7 and 13.2 g/day vs. 5.8 and 7.02 with C and RSS). It was surprising to note that 25 g/kg RSS can improve feed intake. PMID- 21595758 TI - Central injection of exogenous IL-1beta in the control activities of hypothalamic pituitary-gonadal axis in anestrous ewes. AB - This study was performed to determine the effect of intracerebroventricular (icv) injection of interleukin (IL)-1beta on the gene expression, translation and release of gonadotropin-releasing hormone (GnRH) and the GnRH receptor (GnRHR) gene expression in the hypothalamus of anestrous ewes. In the anterior pituitary gland (AP), the expression of genes encoding: GnRHR, beta subunits of luteinizing hormone (LH) and folliculotropic hormone (FSH) was determined as well as the effect of IL-1beta on pituitary gonadotropins release. The relative mRNA level was determined by real-time PCR, GnRH concentration in the cerebrospinal fluid (CSF) was assayed by ELISA and the plasma concentration of LH and FSH were determined by radioimmunoassay. Our results showed that icv injection of IL-1beta (10 or 50 MUg/animal) decreased the GnRH mRNA level in the pre-optic area (POA) (35% and 40% respectively; p <= 0.01) and median eminence (ME) (75% and 70% respectively; p <= 0.01) and GnRHR gene expression in ME (55% and 50% respectively; p <= 0.01). A significant decrease in GnRHR mRNA level in the AP in the group treated with the 50 MUg (60%; p <= 0.01) but not with the 10 MUg dose was observed. The centrally administrated IL-1beta lowered also GnRH concentration in the CSF (60%; p <= 0.01) and reduced the intensity of GnRH translation in the POA (p <= 0.01). It was not found any effect of icv IL-1beta injection upon the release of LH and FSH. However, the central injection of IL 1beta strongly decreased the LHbeta mRNA level (41% and 50%; p <= 0.01; respectively) and FSHbeta mRNA in the case of the 50 MUg dose (49%; p <= 0.01) in the pituitary of anestrous ewes. These results demonstrate that the central IL 1beta is an important modulator of the GnRH biosynthesis and release during immune/inflammatory challenge. PMID- 21595759 TI - Cell division blockage: but this time by a surprisingly conserved protein. AB - Activation of DNA repair proteins is often accompanied by an arrest in cell division. Several proteins have been identified that regulate the division blockage associated with the SOS response. When Bacillus subtilis cells become genetically competent they also activate DNA repair proteins and stop dividing. In this issue of Molecular Microbiology, Briley et al., 2011 describe a new protein involved in this process. This protein, Maf, does not prevent FtsZ polymerization, but it inhibits synthesis of the division septum. What is fascinating about Maf is that it is conserved and can be found in all kingdoms of life. PMID- 21595760 TI - Lotus japonicus symRK-14 uncouples the cortical and epidermal symbiotic program. AB - SYMRK is a leucine-rich-repeat (LRR)-receptor kinase that mediates intracellular symbioses of legumes with rhizobia and arbuscular mycorrhizal fungi. It participates in signalling events that lead to epidermal calcium spiking, an early cellular response that is typically considered as central for intracellular accommodation and nodule organogenesis. Here, we describe the Lotus japonicus symRK-14 mutation that alters a conserved GDPC amino-acid sequence in the SYMRK extracellular domain. Normal infection of the epidermis by fungal or bacterial symbionts was aborted in symRK-14. Likewise, epidermal responses of symRK-14 to bacterial signalling, including calcium spiking, NIN gene expression and infection thread formation, were significantly reduced. In contrast, no major negative effects on the formation of nodule primordia and cortical infection were detected. Cumulatively, our data show that the symRK-14 mutation uncouples the epidermal and cortical symbiotic program, while indicating that the SYMRK extracellular domain participates in transduction of non-equivalent signalling events. The GDPC sequence was found to be highly conserved in LRR-receptor kinases in legumes and non-legumes, including the evolutionarily distant bryophytes. Conservation of the GDPC sequence in nearly one-fourth of LRR receptor-like kinases in the genome of Arabidopsis thaliana suggests, however, that this sequence might also play an important non-symbiotic function in this plant. PMID- 21595761 TI - Using spontaneous photon emission to image lipid oxidation patterns in plant tissues. AB - Plants, like almost all living organisms, spontaneously emit photons of visible light. We used a highly sensitive, low-noise cooled charge coupled device camera to image spontaneous photon emission (autoluminescence) of plants. Oxidative stress and wounding induced a long-lasting enhancement of plant autoluminescence, the origin of which is investigated here. This long-lived phenomenon can be distinguished from the short-lived chlorophyll luminescence resulting from charge recombinations within the photosystems by pre-adapting the plant to darkness for about 2 h. Lipids in solvent were found to emit a persistent luminescence after oxidation in vitro, which exhibited the same time and temperature dependence as plant autoluminescence. Other biological molecules, such as DNA or proteins, either did not produce measurable light upon oxidation or they did produce a chemiluminescence that decayed rapidly, which excludes their significant contribution to the in vivo light emission signal. Selective manipulation of the lipid oxidation levels in Arabidopsis mutants affected in lipid hydroperoxide metabolism revealed a causal link between leaf autoluminescence and lipid oxidation. Addition of chlorophyll to oxidized lipids enhanced light emission. Both oxidized lipids and plants predominantly emit light at wavelengths higher than 600 nm; the emission spectrum of plant autoluminescence was shifted towards even higher wavelengths, a phenomenon ascribable to chlorophyll molecules acting as luminescence enhancers in vivo. Taken together, the presented results show that spontaneous photon emission imaged in plants mainly emanates from oxidized lipids. Imaging of this signal thus provides a simple and sensitive non-invasive method to selectively visualize and map patterns of lipid oxidation in plants. PMID- 21595768 TI - Wolbachia-mediated persistence of mtDNA from a potentially extinct species. AB - Drosophila quinaria is polymorphic for infection with Wolbachia, a maternally transmitted endosymbiont. Wolbachia-infected individuals carry mtDNA that is only distantly related to the mtDNA of uninfected individuals, and the clade encompassing all mtDNA haplotypes within D. quinaria also includes the mtDNA of several other species of Drosophila. Nuclear gene variation reveals no difference between the Wolbachia-infected and uninfected individuals of D. quinaria, indicating that they all belong to the same interbreeding biological species. We suggest that the Wolbachia and the mtDNA with which it is associated were derived via interspecific hybridization and introgression. The sequences in the Wolbachia and the associated mtDNA are >=6% divergent from those of any known Drosophila species. Thus, in spite of nearly complete species sampling, the sequences from which these mitochondria were derived remain unknown, raising the possibility that the donor species is extinct. The association between Wolbachia infection and mtDNA type within D. quinaria suggests that Wolbachia may be required for the continued persistence of the mtDNA from an otherwise extinct Drosophila species. We hypothesize that pathogen-protective effects conferred by Wolbachia operate in a negative frequency-dependent manner, thus bringing about a stable polymorphism for Wolbachia infection. PMID- 21595769 TI - Testing for causality in covarying traits: genes and latitude in a molecular world. AB - Many traits are assumed to have a causal (necessary) relationship with one another because of their common covariation with a physiological, ecological or geographical factor. Herein, we demonstrate a straightforward test for inferring causality using residuals from regression of the traits with the common factor. We illustrate this test using the covariation with latitude of a proxy for the circadian clock and a proxy for the photoperiodic timer in Drosophila and salmon. A negative result of this test means that further discussion of the adaptive significance of a causal connection between the covarying traits is unwarranted. A positive result of this test provides a point of departure that can then be used as a platform from which to determine experimentally the underlying functional connections and only then to discuss their adaptive significance. PMID- 21595770 TI - Breast cancer and screening information needs and preferred communication medium among Iranian immigrant women in Toronto. AB - Few studies have investigated what information women from minority immigrant groups need about breast cancer and screening. Nor has much research been conducted about how such women would prefer to receive this information. Mere translation of breast cancer and screening information from generic materials, without considering and respecting women's unique historical, political, and cultural experiences, is insufficient. This study explored breast cancer and screening information needs and preferred methods of communication among Iranian immigrant women. A convenience sample of 50 women was recruited and interviewed over a 4-month period (June-September 2008); all resided in Toronto Canada, and had no history of breast cancer. Tape-recorded interviews were transcribed and analysed using a thematic analysis technique. While generic breast health communication focusing on physiological risk information meets some of the needs of Iranian immigrant women, results showed that the needs of this group go beyond this basic information. This group is influenced by historical, sociopolitical, and cultural experiences pre- and post-immigration. Their experiences with chemical war, unsafe physical environment (air and water pollution), and their sociopolitical situation appear to have limited their access to accurate and reliable breast cancer and screening information in their homeland. Moreover, the behavioural and psychosocial changes they face after immigration appear to have a strong influence on their breast cancer and screening information needs. Considering their limited time due to their multiple demands post-migration, multi-media methods were highly preferred as a communication means by this group. The results of this study can be used to guide the design and implementation of culturally sensitive breast health information. For instance, video presentations conducted by a trusted Iranian healthcare professional focusing on socioculturally relevant breast cancer risk factors, symptoms, and screening methods, as well as a list of available breast health resources, could improve Iranian women's knowledge and uptake of breast health practices. PMID- 21595772 TI - The importance of addressing social determinants of health at the local level: the case for social capital. AB - Social determinants are gaining momentum in public health practice. Many proposed solutions for tackling social determinants are outside the scope of local public health professionals. This article reviews the literature to find possible moderating variables which may buffer the effects of the social determinants of health at the local level, and allow social determinants to be addressed within the purview of local health departments. The systematic approach employed for this article entailed searches of electronic academic databases (PubMed, EBSCO and Medline) and additional searches using Internet search engines and relevant websites for articles published between 1,975 and May 2010. The search revealed 2,554 articles, and 36 were determined appropriate for inclusion. The purpose of the search was to identify published articles relating to social determinants of health, social capital and effective approaches for addressing both at the level of the local health department. The search was then expanded to include unpublished material, to include the perspectives of local health departments. This process resulted in the inclusion of content from five sources. In this article, the case is made for focusing on social capital interventions to mitigate health problems associated with social determinants. Examples of successful interventions are provided to aid public health professionals in developing locale-specific solutions for addressing social determinants. PMID- 21595771 TI - Partner or perish? Exploring inter-organisational partnerships in the multicultural community aged care sector. AB - Given an Australian national and state policy agenda that continues to promote collaborative work, many community organisations are attempting to engage in partnerships with mixed results. This paper reports on a qualitative study conducted to explore the experiences of existing partnerships between organisations and small community groups who deliver community based support services to older people from culturally diverse backgrounds. In particular, this study sought to identify the key factors that facilitate and hinder the formation, maintenance and effectiveness of partnerships within the ethnic and multicultural community aged care (EMCAC) sector. Fourteen participants representing nine community and health service organisations located in the Melbourne metropolitan area took part in semi-structured interviews. Participants reported that partnerships between organisations are necessary and beneficial within the EMCAC sector. Organisational capacity, access to information and guidelines, and the inequality experienced by smaller organisations were key issues identified by participants. Increasing organisational capacity and reducing the inequalities experienced in partnerships may be addressed via training and education about the nature of partnerships, as well as by advocating for increased resources to smaller ethno-specific organisations. Further investigation is required to examine whether not engaging in partnerships will deem an organisation unsustainable in the longer term. PMID- 21595773 TI - Phorbol 12,13 dibutyrate behaves in a tumor-inhibitory manner in esophageal adenocarcinoma cell lines. AB - Esophageal cancer is an extremely lethal human disease. Relatively little is known about the molecular mechanisms leading to esophageal cancers, nor the signaling pathways activated to maintain and augment the tumor growth. Esophageal cancer cell lines were evaluated to assess the effect of phorbol 12,13 dibutyrate on protein kinase C activity, indirectly using protein kinase D (formerly known as protein kinase C-MU), Akt activity, and cell proliferation. Treatment of esophageal cancer cell lines with the phorbol ester phorbol 12,13 dibutyrate led to a rapid and dramatic increase in the activation of protein kinase D. In addition, administration of phorbol 12,13 dibutyrate also decreased the phosphorylation of Akt. Interestingly, in the OE19 esophageal adenocarcinoma cell line, treatment with phorbol 12,13 dibutyrate also led to inhibition of cell growth. All the phorbol ester effects observed were reversible by combined treatment with a protein kinase C inhibitor, implicating protein kinase C in the cells' response to the phorbol ester. Overall, these studies suggest that protein kinase D (e.g. protein kinase C-MU) may behave as a tumor suppressor in some esophageal cancer samples, serving to inhibit Akt activity and block cell growth. PMID- 21595774 TI - Esophageal symptoms questionnaire for the assessment of dysphagia, globus, and reflux symptoms: initial development and validation. AB - Esophageal symptoms often co-occur. A validated self-report measure encompassing multiple esophageal symptoms is necessary to determine their frequency and severity both independently and in association with each other. Such a questionnaire could streamline the diagnostic process and guide patient management. We aimed to develop an integrative measure that provides a clinical 'snapshot' of common esophageal symptoms. Internal reliability and content validity of a 38-item self-report Esophageal Symptoms Questionnaire (ESQ), measuring the frequency and severity of typical esophageal symptoms using Likert rating scales were assessed in 211 patients presenting to gastroenterology and ENT outpatient tertiary care clinics. Reproducibility, concurrent and predictive validity were evaluated using the reduced-item ESQ. The 38-item ESQ had high internal reliability. Principal component analyses and item reduction methods identified three components, to which 30 of 38 items contributed significantly, providing 59% of total variance. The test-retest correlations were moderate-to strong for 24 of 30 new items (r(s) >= 0.44, P < 0.05). The resultant subscales measuring dysphagia (ESQ-D), globus (ESQ-G), and reflux (ESQ-R) compared well against concurrent physician's 'working' diagnosis (odds ratio 1.04-1.09). The receiver operating characteristics were adequate-to-good for ESQ-D (area under the curve [AUC]= 0.87) and ESQ-G (AUC = 0.74), but poor for ESQ-R (AUC = 0.61) although it matched the content of the validated Reflux Disease Questionnaire. The brief 30-item ESQ shows good internal reliability and content validity as a summary of the extent of dysphagia, globus and reflux symptoms. As a tool measuring more than one esophageal symptom, ESQ could guide patient management by indicating which of the coexisting symptoms needs to be addressed first. PMID- 21595775 TI - p53 codon 72 polymorphism and the risk of esophageal cancer: a Korean case control study. AB - The aim of this study was to assess whether p53 codon 72 polymorphism is associated with an increased risk of esophageal cancer (EC) in South Korea. We conducted a case-control study including 340 patients with EC, and 1700 controls. P53 codon 72 polymorphism was determined by real-time polymerase chain reaction. The frequencies of p53 codon 72 polymorphisms (Arg/Arg, Arg/Pro, and Pro/Pro) in EC were 39.4%, 45.6%, and 15.0%, respectively; frequencies in the controls were 43.2%, 45.6%, and 11.2%, respectively. Compared with the Arg/Arg genotype, the OR of the Arg/Pro genotype was 1.09 (95% CI = 0.85-1.41) and that of the Pro/Pro genotype was 1.47 (95% CI = 1.02-2.11) for EC overall. When adjusted by age, gender, and smoking status, the OR of the Arg/Pro genotype was 1.24 (95% CI = 0.92-1.67) and that of the Pro/Pro genotype was 1.77 (95% CI = 1.15-2.74) for EC overall. In never-smokers and ever-smokers, the OR of the Arg/Pro genotype was 0.59 (95% CI = 0.37-0.95) and 1.39 (95% CI = 1.00-1.91), respectively, and there was a significant difference in the homogeneity test (P= 0.011). We observed that the p53 codon 72 polymorphism was associated with an increased risk of EC in this Korean case-control study, and smoking status modified the association between the p53 codon 72 polymorphism and the risk of EC. PMID- 21595776 TI - Comparative study between endoscopic ultrasonography and positron emission tomography-computed tomography in staging patients with esophageal squamous cell carcinoma. AB - Treatment strategy of esophageal cancer mainly depends on accurate staging. At present, no single ideal staging modality is superior to another in preoperative tumor-node-metastasis (TNM) staging of patients with esophageal cancer. We aimed to investigate the efficacy of endoscopic ultrasonography (EUS) and positron emission tomography-computed tomography (PET-CT) for staging of esophageal cancer. We retrospectively studied 118 consecutive patients with esophageal squamous cell carcinoma who underwent esophagectomy with or without neoadjuvant chemoradiotherapy (CRT) over a near 3-year period between January 2005 and November 2008 at a tertiary hospital in Taiwan. Patients were separated into two groups: without neoadjuvant CRT (group 1, n= 28) and with CRT (group 2, n= 90). Medical records of demographic data and reports of EUS and PET-CT of patients before surgery were reviewed. A database of clinical staging by EUS and PET-CT was compared with one of pathological staging. The accuracies of T staging by EUS in groups 1 and 2 were 85.2% and 34.9%. The accuracies of N staging by EUS in groups 1 and 2 were 55.6% and 39.8%. The accuracies of T and N staging by means of PET-CT scan were 100% and 54.5% in group 1, and were 69.4% and 86.1% in group 2, respectively. In group 2, 38 of 90 patients (42.2%) achieved pathologic complete remission. Among them, two of 34 (5.9%) and 12 of 17 (70.6%) patients were identified as tumor-free by post-CRT EUS and PET-CT, respectively. EUS is useful for initial staging of esophageal cancer. PET-CT is a more reliable modality for monitoring treatment response and restaging. Furthermore, the accuracy of PET-CT with regard to N staging is higher in patients who have undergone CRT than those who have not. PMID- 21595777 TI - Prevalence of gastroesophageal reflux in a Tunisian primary care population determined by patient interview. AB - Although gastresophageal reflux disease (GERD) is highly prevalent in Western countries, we have very little data about it in African countries. The aim of the study is to determine the prevalence and severity of GERD symptoms among Tunisian subjects and report its characteristics, consultation rate, management modes, as well as patients' satisfaction. Five hundred subjects living in Tunisia were interviewed face to face. The study was conducted at seven centers of primary care at Monastir's department by six interviewer doctors. The questionnaire consisted of 30 questions relating to subject attributes, lifestyle factors, medical history, reflux-related symptom characteristics, consultation behavior, previous treatments for GERD, and description of the last episode. Symptoms were defined as 'frequent' if they occurred at least weekly and 'occasional' if they occurred less frequently during the last year. The mean age was 42.3 +/- 17.3 years and 75.6% were females. Over the previous year, 60% of the respondents reported suffering any GERD symptom. The prevalence of frequent GERD is 24%. Female gender (odds ratio [OR]: 1.97[1.15-3.37]) and body mass index >= 25 (OR: 1.54[1.042-2.29]) were associated with increased risk of GERD symptom. Only 22.3%, sought medical advice about GERD symptoms in the last year. In the univariate and multivariate analysis, work status, frequency and intensity of symptoms, duration of symptom, and association of atypical symptoms were associated with a higher frequency of medical consultation for GERD symptoms. Among the subjects complaining about heartburn, 34% took medications. GERD symptoms are common among Tunisian subjects. Few heartburn sufferers seek medical attention, and most do not take medications for symptomatic control. PMID- 21595779 TI - The Kagoshima consensus on esophageal achalasia. AB - Esophageal achalasia is a primary esophageal motility disorder characterized by lack of peristalsis and a lower esophageal sphincter that fails to relax appropriately in response to swallowing. This article summarizes the most salient issues in the diagnosis and management of achalasia as discussed in a symposium that took place in Kagoshima, Japan, in September 2010 under the auspices of the International Society for Diseases of the Esophagus. PMID- 21595778 TI - Safety and efficacy of self-expanding removable metal esophageal stents during neoadjuvant chemotherapy for resectable esophageal cancer. AB - Patients with esophageal cancer may present with dysphagia and weight loss. Resectable lesions require consideration of neoadjuvant chemotherapy, which improves survival but have side effects, which compound already poor intake. Prevention of malnutrition has historically required interventions such as surgical jejunostomy or percutaneous endoscopic gastrostomy, which carry associated morbidity. With established roles in palliation, self-expanding removable metal stents (SERMS) may provide an alternative intervention in resectable disease. We sought to evaluate outcomes from our unit's introduction of SERMS in dysphagic patients prior to esophagectomy. All dysphagic patients presenting with esophageal cancer and considered for curative surgery between April 2006 and November 2008 were offered preoperative treatment of dysphagia with SERMS during neoadjuvant chemotherapy. Baseline and preoperative outcomes assessed included dysphagia score and nutritional markers. Sixteen patients underwent esophageal stenting during neoadjuvant therapy of whom 7/16 (44%) were female with mean age 63 (53-76). In 12/16 (75%), tumors were located in the lower one third of the esophagus. There was a significant fall in mean dysphagia score from 2.5 (range 1-4) to 1.1 (range 0-3) immediately preoperatively. There was no significant change in serum albumin, weight, or body mass index. Stent-related morbidity occurred in 4/16 (25%) patients and stomach migration occurred in 7/16 (43.8%). All were resolved endoscopically and there was no stent-related mortality. Of 10/16 (62.5%) patients ultimately progressing to esophagectomy, 30 day mortality was 6.3%. Anastomotic leak occurred in one patient (10%) and R1 resection rate was 20%. SERMS are a safe and effective intervention in dysphagic patients undergoing neoadjuvant chemotherapy for esophageal cancer. Complications are minor and readily treatable with endoscopy. Objective parameters suggest nutritional status is maintained and symptoms are improved. SERMS do not appear to compromise resection. PMID- 21595780 TI - Morphology of the developing muscularis externa in the mouse esophagus. AB - Muscularis externa of mouse esophagus is composed of two skeletal muscle layers in the adult. But less attention is paid to the histogenesis of the muscularis externa of the esophagus, and controversies still exist about the developmental process and the spatio-temporal expression characteristics of muscle-specific proteins during the development of esophageal muscularis externa. To further probe into the developmental pattern of muscularis externa of the mouse esophagus and the expression characteristics of different muscle-specific proteins, immunohistochemical and terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP)-digoxigenin nick-end labeling apoptotic staining methods are used to investigate the expression patterns of different muscle specific proteins and to elucidate the relationship of these protein expressions with the development of muscularis externa of the mouse esophagus. Thus, an understanding of the developing esophageal muscularis externa may be important for developing therapeutic strategies for the treatment of human esophagus diseases. Serial sections of mouse embryos from embryonic day (ED) 12 to ED18, and full-length esophagi from postnatal first to 5th day were stained with monoclonal antibodies against alpha-smooth muscle actin (alpha-SMA), alpha sarcomerical actin (alpha-SCA), desmin, and monoclonal anti-skeletal myosin (MHC), while apoptosis was determined using the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling assay. The expression of alpha-SMA was started at ED12. During the development of ED14-ED15, alpha-SMA positive cells were seen extending from the walls of left three, four, and six arch arteries toward the dorsal wall of esophagus. Stronger expression of alpha SCA and desmin could be detected at ED14 and ED15, expression intensity in caudal segment and inner layer was stained stronger than that of cranial segment and outer layer, but after ED16, strong expression of alpha-SCA and desmin was found in the outer layer of muscularis externa. Expression of MHC was first detected in the outer layer of cranial segment of muscularis externa at ED17. At ED18, MHC had extended to the level of thyroid gland, staining intensity in the outer layer and cranial segment was stronger than that of inner layer and caudal segment. One to five days after birth, the thickness of the esophageal muscle layer was obviously increased. Most of the muscle cells in the cranial segment of esophagus showed strong expression of alpha-SCA and clear cross striations at higher magnification. With progression toward the caudal segment, expression intensity of alpha-SCA became weaker, but the expression intensity of desmin was the same at different levels of esophagus. The muscle fibers were arranged densely with high expression of MHC in the cranial segment. During the development of esophageal muscularis externa, few apoptotic cells were observed. alpha-SMA, alpha-SCA, desmin, and MHC show different expression patterns. The differentiation of outer layer of esophageal muscularis externa is quicker than that of inner layer, and the caudal segment is quicker than that of the cranial segment. Besides, apoptosis may not participate in the development of esophageal muscularis externa. The smooth muscle cells from arch arteries may participate in the development of esophageal muscularis externa. PMID- 21595781 TI - Measuring tumor hypoxia with 18F-FETNIM PET in esophageal squamous cell carcinoma: a pilot clinical study. AB - The purpose of this study was to evaluate hypoxia in esophageal squamous cell carcinoma (SCC) with (18)F-fluoroerythronitroimidazole positron emission tomography/computed tomography ((18)F-FETNIM PET/CT). We determined an imaging threshold for hypoxia, quantified the spatiotemporal variability of hypoxia in untreated tumor, and evaluated the ability of (18)F-FETNIM PET to predict clinical response following concurrent chemoradiotherapy (CCRT). Twenty-eight consecutive patients with inoperable SCC of the esophagus were consecutively accrued between April 2007 and June 2010. The first 10 patients received two pretreatment (18)F-FETNIM PET/CT scans on separate days. The remaining 18 patients only underwent (18)F-FETNIM PET/CT once before CCRT. The ratio of the maximum standardized uptake value (SUV(max) ) of 336 normal tissue regions (i.e. heart, lung, brain, or muscle) to the mean standardized uptake value (SUV(mean)) of the respective patient's spleen was calculated, and the imaging threshold for hypoxia defined as the level of uptake demonstrated by less than 5% of tissue regions. Among the patients with two pretreatment scans, each pair of scans was compared with respect to location and intensity of uptake to assess for baseline spatiotemporal variability. Logistic regression analysis was used to determine whether pretreatment imaging characteristics are predictive of clinical response. The mean and median ratios of the SUV(max) of tissue : SUV(mean) of spleen were nearly identical, and 95% of the ratios fell below 1.3. The mean Dice similarity coefficient for the hypoxic volumes on pretreatment PET scans acquired in the same patient on different days was 0.12 (range, 0.05-0.21). Individuals' tumor SUV(max) and SUV(mean) did not vary significantly, but on average, the geometric centers of hypoxic regions shifted 15 mm (range, 8-20 mm) from the first pretreatment scan to the second. SUV(max) was the imaging characteristic most predictive of treatment response (P= 0.041), with high SUVmax associated with poor clinical response. (18)F-FETNIM PET/CT can depict hypoxia in esophageal SCC. Prior to CCRT, tumor hypoxia demonstrates spatial variability on different days, although overall (18)F-FETNIM uptake remains similar. Baseline SUV(max) may be predictive of treatment response. PMID- 21595782 TI - Oropharyngeal dysphagia: pathophysiology and diagnosis for the anniversary issue of Diseases of the Esophagus. AB - The oropharyngeal swallow involves a rapid, highly coordinated set of neuromuscular actions beginning with lip closure and terminating with opening of the upper esophageal sphincter. Evaluation of the oropharyngeal swallow usually involves the use of a modified barium swallow radiographic study with the goals of (i) defining the patient's swallow anatomy and physiology causing the dysphagia; and (ii) evaluating the immediate effectiveness of treatment procedures including selected postures, sensory enhancement, swallow maneuvers, and diet changes. Exercise programs may be helpful, but their immediate effects cannot be examined during the initial modified barium swallow. Exercise programs can be evaluated on a second radiographic study 3-4 weeks later. The resultant report should include all of this information. The speech-language pathologist is usually the professional most involved in the evaluation and treatment. Medications and surgery have a very limited role in the treatment of oropharyngeal dysphagia. PMID- 21595783 TI - Perioperative management of children undergoing craniofacial reconstruction surgery: a practice survey. AB - OBJECTIVE/AIMS: To assess current practices in the management of children undergoing craniofacial surgery and identify areas of significant practice variability with the intent to direct future research. BACKGROUND: The perioperative management of infants and children undergoing craniofacial reconstruction surgery can be challenging because of the routine occurrence of significant blood loss with associated morbidity. A variety of techniques have been described to improve the care for these children. It is presently unknown to what extent these practices are currently employed. METHODS: A web-based survey was sent to representatives from 102 institutions. One individual per institution was surveyed to prevent larger institutions from being over-represented in the results. RESULTS: Requests to complete the survey were sent to 102 institutions; 48 surveys were completed. The survey was composed of two parts: management of infants undergoing strip craniectomies, and management of children undergoing major craniofacial reconstruction. CONCLUSIONS: Significant variability exists in the management of children undergoing these procedures; further study is required to determine the optimal management strategies. Clinical trials assessing the utility of central venous pressure and other hemodynamic monitoring modalities would enable evidence-based decision-making for monitoring in these children. The development of institutional transfusion thresholds should be encouraged, as there exists a body of evidence supporting their efficacy and safety. PMID- 21595784 TI - Secular trends in antibiotic consumption in the adult population in Emilia Romagna, Italy, 2003-2009. AB - Antibiotic resistance is closely related to antibiotic use and Italy is a country with high levels of both antibiotic use and antimicrobial resistance. We analysed the trend in antibiotic use in the community among adults (>=15 years) and elderly, in the period 2003-2009, in Emilia-Romagna, Italy, a region with over 4 000 000 inhabitants. Data regarding antibiotic use were obtained from the regional public health system databases. Between 2003 and 2009 the antibiotic consumption increased from 15.4 to 18.7 defined daily doses/1000 inhabitants per day (DID) (+21.4%, p <0.0001). The prescription rate in 2009 was 2.19 prescriptions/1000 inhabitants per day, an increase of 13.8% compared with 2003. The highest increase in antibiotic use was observed among persons aged 20-59 years (+24.7%). The proportion of inhabitants receiving at least one antibiotic treatment was 36.4% in 2003 and 39.7% in 2009, and the proportions receiving at least three antibiotic treatments were 3.5% and 4.2%, respectively. The H1N1 pandemic was associated, in October and November 2009, with a 37-90% increase in antibiotic use among the 15-19-year and 20-59-year age groups compared with 2007 and 2008. No other difference was observed in any other age group. The analysis per antibiotic class showed increases for penicillin + beta-lactamase inhibitor (from 3.6 to 6.3 DID), quinolones (from 2.6 to 3.0 DID) and macrolides (from 3.1 to 3.7 DID), whereas cephalosporin use was stable (1.4 DID). A steady increase in antibiotic use in the adult population has been observed in the Emilia-Romagna: public health interventions are mandatory to counteract this trend. PMID- 21595785 TI - Healthcare workers and influenza vaccination: an ERS-ESCMID Web-based survey. AB - We performed a Web-based survey on attitudes and uptake of H1N1 influenza vaccination among members of two European societies, namely the European Respiratory Society and the European Society of Clinical Microbiology and Infectious Diseases. A multidisciplinary panel developed a questionnaire that examined physicians' and members' knowledge, attitudes and practice about seasonal and pandemic (H1N1) influenza vaccination. In all, 1334 healthcare workers from 83 countries (785 men and 549 women, mean age 45 +/- 7 years) accessed and completed the survey. Safety concerns about vaccines was the main reason reported by 451/1285 respondents for not being vaccinated. More than 30% of 1282 respondents considered the management of communication on the flu pandemic by health authorities to be insufficient. The results of this survey should help health authorities to better design future steps for the successful vaccination of healthcare workers. PMID- 21595786 TI - Rapid diagnostic testing of methicillin-resistant Staphylococcus aureus carriage at different anatomical sites: costs and benefits of less extensive screening regimens. AB - Multiple body site screening and pre-emptive isolation of patients at risk for methicillin-resistant Staphylococcus aureus (MRSA) carriage are considered essential for control of nosocomial spread. The relative importance of extranasal screening when using rapid diagnostic testing (RDT) is unknown. Using data from a multicentre study evaluating BD GeneOhmTM MRSA PCR (IDI), Xpert MRSA (GeneXpert) and chromogenic agar, added to conventional cultures, we determined cost effectiveness assuming isolation measures would have been based on RDT results of different hypothetical screening regimes. Costs per isolation day avoided were calculated for regimes with single or less extensive multiple site RDT, regimes without conventional back-up cultures and when PCR would have been performed with pooling of swabs. Among 1764 patients at risk, MRSA prevalence was 3.3% (n = 59). In all scenarios the negative predictive value is above 98.4%. With back-up cultures of all sites as a reference, the costs per isolation day avoided were ?15.19, ?30.83 and ?45.37 with 'nares only' screening using chromogenic agar, IDI and GeneXpert, respectively, as compared with ?19.95, ?95.77 and ?125.43 per isolation day avoided when all body sites had been screened. Without back-up cultures costs per isolation day avoided using chromogenic agar would range from ?9.24 to ?76.18 when costs per false-negative RDT range from ?5000 up to ?50 000; costs for molecular screening methods would be higher in all scenarios evaluated. In conclusion, in a low endemic setting chromogenic agar screening added to multiple site conventional cultures is the most cost-effective MRSA screening strategy. PMID- 21595787 TI - Predictors of catheter-related gram-negative bacilli bacteraemia among cancer patients. AB - Gram-negative bacillary bacteraemia (GNB) is associated with high morbidity and mortality among cancer patients. We conducted this study to determine the risk factors that may predict the catheter as the source of GNB in cancer patients. From July 2005 to December 2006 all 266 cancer patients with GNB and central venous catheters (CVCs) at The University of Texas M. D. Anderson Cancer Centre in Houston, were classified as catheter-related bloodstream infection (CRBSI) according to Infectious Diseases Society of America criteria. We compared clinical and microbiological features of CRBSIs and non-CRBSIs. We identified 78 CRBSIs and 126 non-CRBSIs. On univariate analysis, polymicrobial bacteraemia, Stenotrophomonas maltophilia bacteraemia, and more than 1000 CFUs in CVC blood cultures, were more common among CRBSI cases. Escherichia coli bacteraemia, haematologic cancer, neutropenia and prior antibiotic use were more common among non-CRBSI cases. On multivariate analysis, S. maltophilia bacteraemia (odds ratio (OR), 5.78; 95% confidence interval (CI), 1.47-22.78; p 0.045), polymicrobial bacteraemia (OR, 4.04; 95% CI, 1.56-10.44; p 0.042), and more than 1000 CFUs from CVC blood cultures (OR, 4.39; 95% CI, 2.02-9.27; p <0.01), were associated with CRBSI. Neutropenia was associated with non-CRBSI (OR, 0.26; 95% CI, 0.13-0.53; p <0.01). Several factors such as S. maltophilia bacteraemia, polymicrobial bacteraemia and more than 1000 CFUs from a blood culture drawn through the CVC may assist the clinicians in assessing whether an indwelling catheter is the source of a GNB and hence CVC removal may be considered. PMID- 21595788 TI - Molecular epidemiology of HPV infection using a clinical array methodology in 2952 women in Greece. AB - The molecular epidemiology of human papillomavirus (HPV) infection in a sample of Greek women (n = 2952, mean age 42.2 +/- 13.3 years) was examined. HPV prevalence was 50.7% (95% confidence interval, 48.8-52.6). The most frequent HPV types were HPV 53, 51 and 66 (10.2%, 9.4% and 9.3%, respectively). HPV positivity was associated with age, age of sexual debut, number of sexual partners and duration of sexual relationship, while marriage or multiparity protected against infection (all p <0.001). Follow-up of this cohort will assist in predicting the effect of vaccination with the new HPV vaccines on future screening with HPV-based tests for cervical cancer. PMID- 21595789 TI - Improved performance with saliva and urine as alternative DNA sources for malaria diagnosis by mitochondrial DNA-based PCR assays. AB - Saliva and urine from malaria-infected individuals contain trace amounts of Plasmodium DNA, and therefore, could be used as alternative specimens for diagnosis. A nested PCR targeting the mitochondrial cytochrome b gene (Cytb-PCR) of four human malaria species and Plasmodium knowlesi was developed and tested with 693 blood samples from febrile patients living in diverse malaria-endemic areas of Thailand, and compared with microscopy and nested PCR targeting small subunit rRNA (18S-PCR). Cytb-PCR was 16% and 39.8% more sensitive than 18S-PCR and microscopy, respectively, in detecting all of these malarial species in blood samples. Importantly, 34% and 17% of Plasmodium falciparum and Plasmodium vivax mono-infections, respectively, detected by microscopy were, in fact, mixed P. falciparum and P. non-falciparum infections. Analysis of matched blood, saliva and urine from 157 individuals showed that microscopy and Cytb-PCR of saliva yielded no significant difference in detecting P. falciparum and P. vivax. However, Cytb-PCR of saliva was more sensitive than microscopy for diagnosis of mixed-species infections. A combination of Cytb-PCR of saliva and of urine significantly outperformed microscopy (p 0.0098 for P. falciparum, p 0.006 for P. vivax, and p 0.0002 for mixed infections). Furthermore, Plasmodium malariae and P. knowlesi could also be identified in saliva and urine with this method. Therefore, the Cytb-PCR developed herein offers a high potential for the use of both saliva and urine for malaria diagnosis, with a sensitivity comparable with or superior to that of microscopy. PMID- 21595790 TI - Evaluation of the microscopic observation drug susceptibility assay for detection of Mycobacterium tuberculosis resistance to pyrazinamide. AB - The microscopic observation drug susceptibility assay (MODS) was evaluated to determine susceptibility to pyrazinamide in Mycobacterium tuberculosis, and compared with the broth microdilution method (BMM), absolute concentration method (ACM), and pyrazinamidase (PZase) determination. We tested 34 M. tuberculosis clinical isolates (24 sensitive and eight resistant to pyrazinamide) and the control strains M. tuberculosis H37Rv (ATCC 27294) and Mycobacterium bovis AN5. The MODS, BMM, ACM and PZase determination provided results in average times of 6, 18, 28 and 7 days, respectively. All methods showed excellent sensitivity and specificity (p <0.05). Of the methods studied, the MODS proved to be faster, efficient, inexpensive, and easy to perform. However, additional studies evaluating the MODS in differentiating pyrazinamide-resistant and pyrazinamide susceptible M. tuberculosis must be conducted with a larger number of clinical isolates. PMID- 21595791 TI - Low seroprevalence of sandfly fever Sicilian virus antibodies in humans, Marseille, France. AB - A seroprevalence study was carried out in the region of Marseille (south-eastern France) to address the public health importance of sandfly fever Sicilian virus (SFSV) and SFSV-like viruses, as recently recognized vectors of those viruses are present in this area. The low seroprevalence rate observed in this study suggests that SFSV is not likely to be of major medical importance in the Marseille area. PMID- 21595792 TI - Clinical comparison between exogenous and haematogenous periprosthetic joint infections caused by Staphylococcus aureus. AB - Patient-related risk factors for invasive Staphylococcus aureus infection overlap with those for periprosthetic joint infections (PJIs). We compared these factors and clinical characteristics between 17 exogenous and 40 haematogenous PJIs caused by S. aureus. Exogenous cases presented significantly more often with damaged periprosthetic soft tissue, whereas haematogenous cases more often had systemic signs of infection, such as fever, chills, and sepsis syndrome. However, comorbid conditions associated with S. aureus infection and/or PJIs did not differ between the two groups. These findings imply that patient-related risk factors for S. aureus infection do not help to predict the mode of infection acquisition in prosthetic joints. PMID- 21595793 TI - Predictors of mortality in patients with bloodstream infections caused by KPC producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. AB - Bloodstream infections (BSIs) caused by Klebsiella pneumoniae carbapenemases (KPC)-producing K. pneumoniae (KPC-KP) are associated with high mortality rates. We investigated outcomes, risk factors for mortality and impact of appropriate antimicrobial treatment in patients with BSIs caused by molecularly confirmed KPC KP. All consecutive patients with KPC-KP BSIs between May 2008 and May 2010 were included in the study and followed-up until their discharge or death. Potential risk factors for infection mortality were examined by a case-control study. Case patients were those who died from the BSI and control-patients those who survived. Appropriate antimicrobial therapy was defined as treatment with in vitro active antimicrobials for at least 48 h. A total of 53 patients were identified. Overall mortality was 52.8% and infection mortality was 34%. Appropriate antimicrobial therapy was administered to 35 patients; mortality due to infection occurred in 20%. All 20 patients that received combination schemes had favourable infection outcome; in contrast, seven of 15 patients given appropriate monotherapy died (p 0.001). In univariate analysis, risk factors for mortality were age (p <0.001), APACHE II score at admission and infection onset (p <0.001) and severe sepsis (p <0.001), while appropriate antimicrobial treatment (p 0.003), combinations of active antimicrobials (p 0.001), catheter related bacteraemia (p 0.04), prior surgery (p 0.014) and other therapeutic interventions (p 0.015) were significantly associated with survival. Independent predictors of mortality were age, APACHE II score at infection onset and inappropriate antimicrobial treatment. Among them, appropriate treatment is the only modifiable independent predictor of infection outcome. PMID- 21595794 TI - Multiple ST clonal complexes, with a predominance of ST131, of Escherichia coli harbouring blaCTX-M-15 in a tertiary hospital in Tanzania. AB - The molecular epidemiology of 32 non-duplicate, CTX-M-15 extended-spectrum beta lactamase (ESBL)-producing Escherichia coli strains, isolated from clinical samples, was investigated. Multilocus sequence typing revealed multiple sequence type clonal complexes: ST131 (12), ST405 (4), ST638 (3), ST38 (2), ST827 (2), ST224 (1), ST648 (1), ST46 (1) and two new sequence type clonal complexes (1845 and 1848) in 22 pulsed field gel electrophoresis clusters. The bla(CTX-M-15) gene was located on conjugative IncF plasmids. This is the first report of the worldwide emerging clonal complex ST131 linked to bla(CTX-M-15) in Tanzania and demonstrates the need for constant surveillance in developing countries to prevent the spread of these multiresistant isolates. PMID- 21595795 TI - Comparison of a multiplexed MassARRAY system with real-time allele-specific PCR technology for genotyping of methicillin-resistant Staphylococcus aureus. AB - The Sequenom MassARRAY iPLEX single-nucleotide polymorphism (SNP) typing platform uses matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) coupled with single-base extension PCR for high-throughput multiplex SNP detection. In this study, we investigated the use of iPLEX MassARRAY technology for methicillin-resistant Staphylococcus aureus (MRSA) genotyping. A 16-plex MassARRAY iPLEX GOLD assay (MRSA-iPLEX) was developed that targets a set of informative SNPs and binary genes for MRSA characterization. The method was evaluated with 147 MRSA isolates, and the results were compared with those of an established SYBR Green-based real-time PCR system utilizing the same SNP-binary markers. A total of 2352 markers belonging to 44 SNP-binary profiles were analysed by both real-time PCR and MRSA-iPLEX. With real-time PCR as the reference standard, MRSA-iPLEX correctly assigned 2298 of the 2352 (97.7%) markers. Sequence variation in the MRSA-iPLEX primer targets accounted for the majority of MRSA-iPLEX erroneous results, highlighting the importance of primer target selection. MRSA-iPLEX provided optimal throughput for MRSA genotyping, and was, on a reagent basis, more cost-effective than the real-time PCR methods. The 16-plex MRSA-iPLEX is a suitable alternative to SYBR Green-based real-time PCR typing of major sequence types and clonal complexes of MRSA. PMID- 21595796 TI - The economic value of screening haemodialysis patients for methicillin-resistant Staphylococcus aureus in the USA. AB - Methicillin-resistant Staphylococcus aureus (MRSA) can cause severe infections in patients undergoing haemodialysis. Routine periodic testing of haemodialysis patients and attempting to decolonize those who test positive may be a strategy to prevent MRSA infections. The economic value of such a strategy has not yet been estimated. We constructed a Markov computer simulation model to evaluate the economic value of employing routine testing (agar-based or PCR) at different MRSA prevalence, spontaneous clearance, costs of decolonization and decolonization success rates, performed every 3, 6 or 12 months. The model showed periodic MRSA surveillance with either test to be cost-effective (incremental cost effectiveness ratio <=$50 000/quality-adjusted life-year) for all conditions tested. Agar surveillance was dominant (i.e. less costly and more effective) at an MRSA prevalence >=10% and a decolonization success rate >=25% for all decolonization treatment costs tested with no spontaneous clearance. PCR surveillance was dominant when the MRSA prevalence was >=20% and decolonization success rate was >=75% with no spontaneous clearance. Routine periodic testing and decolonization of haemodialysis patients for MRSA may be a cost-effective strategy over a wide range of MRSA prevalences, decolonization success rates, and testing intervals. PMID- 21595797 TI - Molecular characterization of VIM-producing Klebsiella pneumoniae from Scandinavia reveals genetic relatedness with international clonal complexes encoding transferable multidrug resistance. AB - VIM-producing Klebsiella pneumoniae (VPKP) has been identified as a source of hospital outbreaks and is prevalent particularly in the Mediterranean region. In this study we have characterized eight VPKP isolates identified in Scandinavia during 2005-2008. With the exception of one isolate, all were from patients with recent history of hospitalization abroad (Greece, n = 6; Turkey, n = 1). Multilocus sequence typing (MLST) resulted in five sequence types (STs), ST36 (n = 1), ST147 (n = 4), ST272 (n = 1), ST273 (n = 1) and ST383 (n = 1), which except for ST272 were part of putative international clonal complexes. All were multidrug resistant due to the presence of other resistance determinants, including extended-spectrum beta-lactamases (CTX-M-3, SHV-5 and SHV-12), 16S rRNA methylases (ArmA) and plasmid-mediated quinolone resistance determinants (QnrS). One isolate harboured a novel VIM-variant (VIM-26) while VIM-1 and VIM-19 were detected in six and one isolate, respectively. Two different genetic structures surrounding the bla(VIM) gene were identified in four isolates. In two isolates bla(VIM-1) and bla(VIM-26) were located in an integron similar to In-e541 (intI1;bla(VIM-1/-26);aacA7; dhfrI;aadA1;3'CS) while in the other two isolates bla(VIM-1) was located in an integron lacking 3'CS but with an IS26 element in the 3'end (intI1;bla(VIM-1);aac(6')-Ib;IS26), as identified in the IncN plasmid pKOX105. The bla(VIM) -genes were located on transferable plasmids ranging from ~40 to ~240 kb and associated with Tn21 in four isolates. PCR-based replicon typing indicated association of bla(VIM) with IncN (n = 3) and A/C (n = 1) broad host-range plasmids but also with unknown replicons (n = 4). In conclusion, Scandinavian VPKP is associated with importation and genetically related to international clones encoding transferable plasmid-mediated multidrug resistance. PMID- 21595798 TI - Virulence factors and genotypes of Staphylococcus aureus from infection and carriage in Gabon. AB - Staphylococcus aureus isolates from developed countries have been extensively analyzed with respect to their virulence patterns and clonal relatedness but there is only sparse information on the molecular diversity of S. aureus isolates from Africa. In particular, little is known about S. aureus isolates from asymptomatic carriers compared with isolates causing infections. From 2008 to 2010, we prospectively collected S. aureus isolates from asymptomatic carriers and infections in Lambarene, Gabon, Central Africa. For these isolates, we determined major virulence factors, and performed multilocus sequence typing (MLST) and spa typing. Among 163 S. aureus isolates from asymptomatic carriers, we found the MLST clonal complexes (CCs) 5, 6, 7, 8, 9, 15, 25, 30, 45, 88, 101, 121 and 152; 3.7% were methicillin-resistant (MRSA). The clinical isolates were associated with CCs 5, 8, 9, 15, 88, 121 and 152; 11% were MRSA. Sequence types 1 and 88 were significantly associated with infection and sequence type 508 was associated with carriage. Remarkably, there was a high prevalence of Panton Valentine leukocidin (PVL) -encoding genes both in disease-related isolates (57.4%) and in carrier isolates (40.5%). We found differences in the clonal structure and virulence pattern of Gabonese S. aureus isolates from asymptomatic carriers and infections. Of note, S. aureus isolates from Gabon show a very high prevalence of PVL-encoding genes, which exceeds the rates observed for developed countries. PMID- 21595800 TI - Molecular mechanisms of transforming growth factor-beta signaling and disease: The 59th Fujihara International Seminar, 2010. AB - The Fujihara International Seminar series is supported by the Fujihara Foundation for Science, for the purpose of organizing seminars for basic and applied science, including medical science, physics, chemistry, engineering, mathematics, geology, and biology. The 59th Fujihara International Seminar was held on July 14 17, 2010 at Tomakomai, Hokkaido, Japan, focusing on molecular mechanisms of transforming growth factor (TGF)-beta signaling and disease. Recent findings on mechanisms of TGF-beta signaling, the roles of TGF-beta signaling in carcinogenesis and progression of tumors, and possible strategies of TGF-beta based treatment of cancer were discussed at the seminar. In particular, novel mechanisms of regulation of Smad signaling, the differential roles of Smad proteins in carcinogenesis, function of Smads in regulation of microRNA biogenesis, and treatment of cancer stem cells by targeting the TGF-beta signaling pathways were discussed. PMID- 21595801 TI - Identification of promiscuous HLA-DR-restricted CD4+ T-cell epitopes on the cancer-testis antigen HCA587. AB - The cancer testis antigen HCA587 is an attractive candidate for T cell-based immunotherapy because it is overexpressed in a wide spectrum of malignant tumors but not normal tissues, except testis. Several CTL epitopes derived from HCA587 have been described. Our aim was to identify helper T lymphocyte epitopes of HCA587 for the optimization of T cell-based immunotherapies against HCA587 expressing tumors. Candidate helper T lymphocyte epitopes for HCA587 were predicted using the SYFPEITHI algorithm and were tested for their ability to induce helper T lymphocyte responses by in vitro peptide vaccination of CD4(+) T lymphocytes from healthy individuals and hepatocellular carcinoma patients. Four CD4(+) T-cell epitopes for HCA587 (p43-57, p145-159, p186-200 and p249-263) were identified. Among them, the p43-57 epitope was shown to be naturally processed and presented by HCA587-expressing tumor cells as well as autologous dendritic cells pulsed with whole-protein HCA587. Notably, this epitope behaved as a promiscuous T-cell epitope as it stimulated T cells in the context of more than one HLA class II allele. Thus, p43-57 is the first HCA587-derived major histocompatibility complex class II-restricted epitope to fulfil all prerequisites for use as a peptide vaccine in patients with HCA587-expressing tumors. PMID- 21595802 TI - Measurement of acid exposure of proximal esophagus: a better tool for diagnosing non-erosive reflux disease. AB - BACKGROUND: The sensitivity of 24-h pH monitoring is poor in non-erosive reflux disease (NERD). In NERD patients, the proximal extent of acid reflux is one of the main determinants of reflux perception. The present study was aimed to compare the diagnostic accuracy of acid exposure time (AET), at 5 cm above the lower esophageal sphincter, with those at 10 cm and at 3 cm below the upper esophageal sphincter as well as the reproducibility of these parameters. METHODS: A total of 93 consecutive NERD patients, with typical symptoms responsive to proton pump inhibitor treatment, and 40 controls underwent esophageal manometry and multi-channel 24-h pH-test; 13 patients underwent the same study on two occasions. Symptom association probability (SAP) values were evaluated at each esophageal level. KEY RESULTS: The ROC curve indicates that the area under the curve was 0.79 at distal (SE=0.039), 0.87 (SE=0.032) at proximal (P=0.029 vs distal), and 0.85 (SE=0.033) at very proximal esophagus (P =0.148). AET showed a reproducibility of 61% (Kappa 0.22) at distal esophagus, 77% (Kappa 0.45) at proximal and 53% (Kappa 0.05) at very proximal esophagus. The percentage of patients with a positive SAP was not significantly different when assessed at the distal compared with the proximal esophagus. CONCLUSIONS & INFERENCES: In NERD patients, the diagnostic yield of the pH test is significantly improved by the assessment of AET at the proximal esophagus. As this variable seems to be less affected by the day to day variability, it could be considered a reliable and useful diagnostic tool in NERD patients. PMID- 21595804 TI - Acute presentation of autoimmune hepatitis: Does it exist? A published work review. AB - Autoimmune hepatitis (AIH), initially called chronic aggressive hepatitis, is conceptually classified as a primary chronic disease; periportal fibrous expansion and periportal infiltration of mononuclear cells, including plasma cells, have also been considered to be histologically important diagnostic signs of AIH. However, several manuscripts which reported the acute presentation of AIH have been published recently and the reported cases of acute presentation in these manuscripts contained two different clinical entities. One is acute exacerbation of chronic AIH (acute exacerbation form) and the other is genuine acute AIH without chronic histological changes (acute form). It is clinically important to distinguish the acute form from the acute exacerbation form. The reports of the acute form revealed that the existence of centrilobular necrosis without chronic changes was the most important histological finding related to the acute form. Because the elevation of serum levels of immunoglobulin G and antinuclear antibody are not observed in some acute presentation AIH patients, the physician may not consider AIH when they encounter such patients. Therefore, it is very important to bear in mind a possibility of acute presentation AIH when the physician encounters patients with hepatic dysfunction of unknown cause because it became clear that delay of the diagnosis and start of therapy lead to the poor prognosis of AIH. In this review, we outline the current state of acute presentation of AIH including the genuine acute form based on the published clinical studies and case reports. PMID- 21595803 TI - 3D-high resolution manometry of the esophagogastric junction. AB - BACKGROUND: The esophagogastric junction (EGJ) is a complex structure that challenges accurate manometric recording. This study aimed to define EGJ pressure morphology relative to the squamocolumnar junction (SCJ) during respiration with 3D-high resolution manometry (3D-HRM). METHODS: A 7.5-cm long 3D-HRM array with 96 independent solid-state pressure sensors (axial spacing 0.75 cm, radial spacing 45 degrees ) was used to record EGJ pressure in 15 normal subjects. Concurrent videofluoroscopy was used to localize the SCJ marked with an endoclip. Ex vivo experiments were done on the effect of bending the probe to match that seen fluoroscopically. KEY RESULTS: 3D-high resolution manometry EGJ pressure recordings were dominated by an asymmetric pressure peak superimposed on the lower esophageal sphincter (LES) attributable to the crural diaphragm (CD). Median peak CD pressure at expiration and inspiration (51 and 119 mmHg, respectively) was much greater in 3D-HRM than evident in HRM with circumferential pressure averaging. Esophagogastric junction length, defined as the zone of circumferential pressure exceeding that of adjacent esophagus or stomach was also substantially shorter (2.4 cm) than evident in conventional HRM. No consistent circumferential EGJ pressure was evident distal to the SCJ in 3D-HRM recordings and ex vivo experiments suggested that the intra-gastric pressure peak seen contralateral to the CD related to bending the assembly rather than the sphincter per se. CONCLUSIONS & INFERENCES: 3D-high resolution manometry demonstrated a profoundly asymmetric and vigorous CD component to EGJ pressure superimposed on the LES. Esophagogastric junction length was shorter than evident with conventional HRM and the distal margin of the EGJ sphincteric zone closely correlated with the SCJ. PMID- 21595805 TI - The concerns of school staff in caring for children with diabetes in primary school. AB - OBJECTIVES: Primary school children spend 25% of their waking hours in school. Education authorities have a duty of care to support children with chronic illnesses within schools, but this is very variable. This study has examined the concerns of primary school staff working with children with Type 1 diabetes and their parents, and related these concerns to the views of health-care professionals (HCP) working with school personnel. METHODS: We undertook in depth, semi-structured face-to-face interviews with 22 primary school staff and 5 multidisciplinary HCP from the local healthcare team. Interview transcripts were analysed using a structured, iterative approach grouping together key themes and issues to create a coding scheme. RESULTS: Primary school staff expressed a range of concerns about injecting and blood glucose testing, the ability of children to mishandle their condition, and corresponding reactions of parents to school decisions on health-based matters. These fears had some convergence with the perspectives of HCP who also highlighted the institutional nature of primary schools and dynamics of home/family life as factors impacting upon care of children with diabetes at school. CONCLUSIONS: Increased training for teachers having direct and current responsibility for children with diabetes was thought to lessen anxiety. Greater and more accessible knowledge about diabetes for all staff was requested. A range of practical management strategies were highlighted, including fostering good communication and teamwork between child, parent, school, and HCP. Professionals felt that support services would improve by using community-based dieticians and including psychological input into the diabetes team. PMID- 21595806 TI - The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus. AB - Solid-organ transplantation is the optimal long-term treatment for most patients with end-stage organ failure. After solid-organ transplantation, short-term graft survival significantly improved (1). However, due to chronic allograft nephropathy and death with functioning graft, long-term survival has not prolonged remarkably (2). Posttransplant immunosuppressive medications consist of one of the calcineurin inhibitors in combination with mycophenolate mofetil (MMF) or azathioprine (Aza) and steroids. All of them have different adverse effects, among which posttransplant diabetes mellitus (PTDM) is an independent risk factor for cardiovascular (CV) events and infections causing the death of many transplant patients and it may directly contribute to graft failure (3). According to the criteria of the American Diabetes Association (4), diabetes mellitus (DM) is defined by symptoms of diabetes (polyuria and polydipsia and weight loss) plus casual plasma glucose concentration >= 11.1 mmol/L or fasting plasma glucose (FPG) >= 7.0 mmol/L or 2-h plasma glucose level >= 11.1 mmol/L following oral glucose tolerance test (OGTT). This metabolic disorder occurring as a complication of organ transplantation has been recognized for many years. PTDM, which is a combination of decreased insulin secretion and increased insulin resistance, develops in 4.9/15.9% of liver transplant patients, in 4.7/11.5% of kidney recipients, and in 15/17.5% of heart and lung transplants [cyclosporine A (CyA)/tacrolimus (Tac)-based regimen, respectively] (5). Risk factors of PTDM can be divided into non-modifiable and modifiable ones (6), among which the most prominent is the immunosuppressive therapy being responsible for 74% of PTDM development (7). Emphasizing the importance of the PTDM, numerous studies have determined the long-term outcome. On the basis of these studies, graft and patient survival is tendentiously (8) or significantly (9, 10) decreased for those developing PTDM. PMID- 21595808 TI - Predicting health-related quality of life by using a health promotion model among Iranian adolescent girls: a structural equation modeling approach. AB - Predicting the significant determinants of health-related quality of life through the application of structural equation modeling in adolescents has received little attention in the health education and health promotion literature. The purpose of this study was to investigate the relationships between self-efficacy, barriers, social support, health-promoting lifestyle, and health-related quality of life among Iranian adolescent girls. Pender's health promotion model guided this study. This was a cross-sectional survey of 500 students who were recruited in Kashan, Iran. Their health-related quality of life was measured by using the Short Form Health Survey. A path analysis was conducted to predict the health related quality of life determinants. The results indicated that 71% of the variance in health-related quality of life could be predicted by the variables. The results affirmed that self-efficacy was the most significant predictor of the students' health-related quality of life. It was concluded that interventions that are aimed at improving self-efficacy can lead to the enhancement of health related quality of life among adolescent girls in the developing country of Iran. PMID- 21595807 TI - Prevalence and characteristics of diabetes among Somali children and adolescents living in Helsinki, Finland. AB - OBJECTIVE: We compared the prevalence and characteristics of diabetes between Somali and Finnish children in the City of Helsinki. SUBJECTS AND METHODS: Ten Somali and 310 non-Somali children <16 yr of age were treated for diabetes in Helsinki at the end of 2007. We analyzed autoantibodies, HLA alleles, and serum 25-hydroxy-vitamin D [S25(OH)D] concentrations. RESULTS: The prevalence of diabetes was 40/10,000 (95% CI 19-73/10,000) for the Somali children and 37/10,000 (95% CI 33-41/10,000) for the background population. At least one autoantibody was detected in all seven Somali patients sampled within 18 months after the diagnosis. Most Somalis (75%) carried HLA-conferred susceptibility to type 1 diabetes (T1D), DR3-DQ2 being the dominating HLA haplotype. Low S25(OH)D levels (<40 nmol/L) were seen in 83% of the Somali patients and in 60% of their siblings. CONCLUSIONS: These data show that (i) Somali children have autoimmune diabetes, (ii) the prevalence of T1D is similar among Somali and Finnish children, and (iii) both affected and unaffected Somali children have low concentrations of S25(OH)D. PMID- 21595809 TI - Quality of life reporting by parent-child dyads in Japan, as grouped by depressive status. AB - When children are unable to assess their own health-related quality of life (HRQOL), their parents can provide useful proxy information; however, minimal agreement between the two groups on this issue has been reported in some situations. In order to clarify the degree of accordance between the self-reports of children and the proxy reports of their parents on the former's HRQOL, 679 parent-child dyads, as grouped by their depressive status, were assessed by the Pediatric Quality of Life Inventory (PedsQL). It was found that the self reporting of the children differed significantly between those who were healthy and those who had depressive symptoms, whereas the proxy-reporting of the parents did not vary with their child's mental condition. However, the latter's reports did reveal notable dissimilarities between the healthy parents and those with depressive symptoms. The results indicated that the parents' perception of their child's HRQOL differed with their child's own perception and that the parents' perceptions were affected by their mental condition. Medical providers should assess both the child's and the parents' evaluations of the child's HRQOL, as the views of the parents could determine the use of health services and the making of decisions in clinical settings. PMID- 21595810 TI - Turnover intention among Italian nurses: the moderating roles of supervisor support and organizational support. AB - The purpose of this study was to examine the variables that are related to person environment fit in Italian nurses, highlighting the role of supervisor support and organizational support in the relationship between nurses' perceptions of care adequacy, job satisfaction, and turnover intention. Therefore, 1240 nurses from three hospitals completed a self-administered questionnaire. The results showed that supervisor support and organizational support act differently as moderators of the care adequacy-job satisfaction-turnover intention relationship. Finally, job satisfaction was a mediating variable between care adequacy and turnover intention. These findings have important implications for hospitals because they help to promote effective work environments and to reduce turnover intention. PMID- 21595811 TI - Workplace injury and nurses: Insights from focus groups with Australian return-to work coordinators. AB - Few studies have examined the return-to-work process for nurses who are injured at work. The purpose of this study was to identify the factors that facilitate or impede the successful return to work of nurses who have sustained a workplace injury from the perspective of return-to-work coordinators. A qualitative, descriptive study was conducted and 25 return-to-work coordinators from 14 different organizations participated in focus group discussions. The participants were recruited from healthcare settings in metropolitan and rural areas of New South Wales, Australia. These included aged-care, residential, and community disability support services, public and private hospitals, and the community health sector. Workforce shortages, individual life circumstances and nurses' work, and nurses' qualifications, specialization, experience, and job tenure were identified as the factors that influence the timely, safe, and sustainable return to work of injured nurses. This study provides insight into how workforce shortages have driven innovative practice in accommodating a nurse's life circumstances when developing the return-to-work plan. Barriers to nurses' return to work included a lack of qualifications, specialization, and the casualization of the workforce. PMID- 21595812 TI - Palliative day care: a qualitative study of service users' experiences in the United Kingdom. AB - In many countries, specialist palliative day care for patients with life-limiting conditions is provided by specific teams of professionals from a range of relevant disciplines. During 2006 to 2007, the day care services at a hospice in the U.K. were redesigned so that specialist palliative care sessions replaced the existing long-established, traditional day care model. The purpose of this study was to enhance the understanding of those aspects of the service that the users valued most (the "X-factor"). Qualitative data were collected via semistructured interviews with 29 patients and eight carers. These data were subjected to a framework analysis. The users of the service used poignant and powerful words to describe the special qualities that they valued, some phrasing it as the X factor. The data are presented under three themes: the quality of the staff; the sense of community; and relationships. Of these, the relationships between and within the staff and patient groups held the greatest significance for the patients. Service providers need to recognize that opportunities for the formation of relationships between the patients, staff, and carers are of utmost importance when designing palliative day care services. PMID- 21595813 TI - Internet-based approach to population screening for common hemoglobinopathies in United Arab Emirates. AB - This article reports on efforts to overcome common hurdles that were faced during population-based screening for common hemoglobinopathies in the United Arab Emirates. An Internet-based approach was designed and implemented to increase the acceptance of the screening program. The process involved: an awareness campaign, a simple bilingual (Arabic/English) online consent form and registration process, the use of a barcode for sample labeling, an equipment upgrade, electronic communication of a successful registration process, test results, and a counseling process. Before the implementation of the Internet-based system, great concern was noted among the clients in terms of the availability of accurate and timely test results, the need for pretest and post-test counseling, and the way that their personal health information was handled. Lapses in information exchange between the clients who participated in the screening program for the carrier state of inherited disorders and the screening laboratory posed significant challenges. The emphasis on confidentiality and the ease of access to services was instrumental in increasing the level of acceptance of these services in our community. Based on an analysis of > 10,000 samples, we conclude that Internet-based reporting holds much promise for improving the quality of care that clients receive. PMID- 21595814 TI - Realistic evaluation of an emergency department-based mental health nurse practitioner outpatient service in Australia. AB - Evaluation of new models of care requires consideration of the complexity inherent within health care programs and their sensitivity to local contextual factors as well as broader community, social and political influences. Evaluation frameworks that are flexible and responsive while maintaining research rigor are therefore required. Realistic evaluation was adopted as the methodology for the implementation and evaluation of an emergency department-based mental health nurse practitioner outpatient service in Sydney, Australia. The aim of realistic evaluation is to generate, test and refine theories of how programs work within a given context. This paper represents the final methodological step from the completed evaluation. A summary of quantitative and qualitative findings from the mixed-methods evaluation is presented, which is transformed into a set of overarching statements or "middle range theories". Middle range theory statements seek to explain the success of a program and provide transferable lessons for practitioners wishing to implement similar programs elsewhere. For example, the research team consider that early consultation with key local stakeholders and emergency department ownership of the project was pivotal to the implementation process. PMID- 21595815 TI - Barriers to and facilitators of coping with spinal cord injury for Iranian patients: a qualitative study. AB - The purpose of the present study was to explore the perspectives and experiences of Iranian patients regarding barriers and facilitators to their ability to cope with spinal cord injury (SCI). A qualitative design, based on the content analysis approach, was used to collect and analyze the experiences of 18 patients with spinal cord injury in two centers in Tehran, Iran. After using purposeful sampling for selection of the participants, semi-structured interviews were held for data collection. Lack of "knowledge", "financial resources", "employment opportunities", "suitable facilities and accessibility" as well as "societal acceptance and support" emerged as barriers; and having "self-confidence", "religious beliefs", "support networks" and "positive thinking" emerged as facilitators in coping with spinal cord injury. Participants believed that with these hindering factors in place, adapting to their new condition had been difficult, therefore they can only manage to adapt partially to their situation. Additional multidisciplinary endeavors are needed to help this group cope adequately and further research is required to influence policy making and legislation processes efficiently. PMID- 21595816 TI - Effect of evidence-based education on Iranian nursing students' knowledge and attitude. AB - To adopt an evidence-based approach to education there is a need for research based evidence to support its effectiveness. This study investigated the impact of evidence-based education on the knowledge and attitude of nursing students. In this quasi-experimental study, all nursing students (n = 41) studying the courses of musculoskeletal and gastrointestinal systems were chosen and assigned randomly to intervention and control groups. The groups were taught through an evidence based or traditional approach. Students' knowledge and attitude were then evaluated. Data were gathered by three knowledge and two attitude questionnaires with multiple choice and Likert scales and then analyzed. It was shown that there was a significant difference between the average scores for attitude of the groups, but there was no statistically significant difference between the average scores of knowledge. The results suggest the evidence-based approach might be used as a complementary approach to nursing education. It was not only as effective as the usual method but also led to the acquisition of particular skills by students. The results can be used to formulate programs to design and implement evidence-based nursing education. PMID- 21595817 TI - Views of Iranian patients on life with cancer: a phenomenological study. AB - Cancer is one of the major causes of death worldwide. The diagnosis of this disease can cause significant stress, which destroys the patient's hopes, dreams and expectations. The aim of this qualitative phenomenological study was to explore the perceptions of 23 Iranian patients about life with cancer using in depth and semi-structured interviews as the method of data collection. The data were analyzed using Benner's interpretive thematic analysis method. Four main themes were clarified by studying the patients' experiences of life with cancer: (i) cancer as a kind of divine test; (ii) a very bitter and debilitating experience; (iii) chemotherapy as the most difficult experience of cancer; and (iv) a continuous struggle. Life with cancer is full of suffering, stress and bitterness. Fear and hope are intertwined; this phase can be successfully endured by patience, tolerance and stability. It is also helpful if close relatives can raise the patient's morale. Certainly, in this process, religious beliefs, faith and culture-oriented interventions can significantly help patients deal with cancer. PMID- 21595818 TI - Correlation between a self-administered walk test and a standardised Six Minute Walk Test in adults. AB - This study was undertaken to assess the correlation between a self-administered, adapted Six Minute Walk Test (the Home-Heart-Walk) and the standard Six Minute Walk Test based on the American Thoracic Society guideline. A correlational study was conducted at a university campus in Sydney, Australia. Thirteen healthy volunteers underwent the Home-Heart-Walk and the standard Six Minute Walk Test on a single occasion. The distance that participants walked during the two tests was assessed using Pearson's correlation. The correlation between the Home-Heart-Walk and the Six Minute Walk Test distance was 0.81. The Home-Heart-Walk distance was highly correlated to the standard Six Minute Walk Test distance in this study. This relationship provides confidence for further research in populations to facilitate monitoring and evaluation. PMID- 21595819 TI - Isolation and lack of access in multiple chemical sensitivity: A qualitative study. AB - This paper describes a qualitative interview study of 26 persons with multiple chemical sensitivity (MCS), also referred to as chemical intolerance. We used a phenomenological perspective and planned to focus on the impact of MCS on relationships, but found that difficulty with accessing safe spaces at times prevented relationships by limiting access to personal interactions. Thus, persons with MCS either lost or were unable to cultivate new relationships as a result of lack of spatial access. Others' lack of understanding and refusal to make accommodations at times denied spatial access to those with MCS. In this way, relationships (relationality) and spatial access (spatiality) interacted with one another to keep persons isolated. In this paper, we describe informants' detailed experience of living with chemical intolerance in a culture where chemical exposures are commonplace. PMID- 21595820 TI - Age at surgery, educational level and long-term urinary incontinence after radical prostatectomy. AB - OBJECTIVE: To identify predictors for long-term urinary leakage after radical prostatectomy. PATIENTS AND METHODS: A consecutive series of 1411 patients who underwent radical prostatectomy (open surgery or robot-assisted laparoscopic surgery) at Karolinska University Hospital between 2002 and 2006 were invited to complete a study-specific questionnaire. Urinary leakage was defined as use of two or more pads per day. RESULTS: Questionnaires were received from 1288 (91%) patients with a median follow-up of 2.2 years. Age at surgery predicts in an exponential manner long-term urinary incontinence at follow-up with an estimated relative increase of 6% per year. Among the oldest patients, 19% had urinary incontinence compared with 6% in the youngest age group, translating to a prevalence ratio of 2.4 (95% confidence interval [CI], 1.5-8.1). Low educational level, as compared with high, yielded an increased age-adjusted prevalence ratio of 2.5 (95% CI, 1.7-3.9). Patients who had undergone salvage radiation therapy had an increased prevalence of urinary incontinence (2.5; 95% CI, 1.6-3.8), as did those with respiratory disease (2.4; 95% CI, 1.3-4.4). Body mass index, prostate weight, presence of diabetes or previous transurethral resection did not appear to influence the prevalence of urinary incontinence. CONCLUSIONS: In this series, a patient's age at radical prostatectomy influenced, in an exponential manner, his risk of long-term urinary incontinence. Other predictors are low educational level, salvage radiation therapy and respiratory disease. Intervention studies are needed to understand if these data are relevant to the prevalence of urinary leakage if a radical prostatectomy is postponed in an active monitoring programme. PMID- 21595821 TI - The effect of hypertension and diabetes on the degree of renal function deterioration after unilateral nephrectomy. AB - OBJECTIVE: * To quantify the effect of hypertension and diabetes - which have been identified as both initiating and progressing factors in chronic kidney disease (CKD), as well as predictors of long-term renal impairment in patients undergoing nephrectomy - on renal function after unilateral nephrectomy for malignancy. PATIENTS AND METHODS: * A retrospective analysis was carried out of 80 unilateral nephrectomies performed at the Wagga Wagga Base Hospital, Calvary Private Hospital and Austin Hospital from January 2007 to December 2009. * Prognostic variables were patient age, sex and the presence of hypertension or diabetes. * The percentage reduction in glomerular filtration rate (GFR) after nephrectomy was measured and compared between variables using a two-sample Student's t-test. RESULTS: * All patients who had diabetes also had hypertension. * Of the 80 patients, 22 (27.5%) fulfilled the criteria for CKD with a preoperative GFR < 60 mL/min. * Patients with hypertension and diabetes had a significantly greater percentage reduction in postoperative GFR (36 +/- 2%) than those who had neither risk factor (23 +/- 2%, P < 0.003). A similar finding was observed for patients with hypertension alone (32 +/- 1%, P < 0.009). * The difference in postoperative GFR reduction between diabetics and those with hypertension alone was not statistically significant (P= 0.205). * The differential reduction in GFR in patients with CKD risk factors persisted at 3-12 months follow-up. CONCLUSIONS: * An increased percentage reduction in GFR is seen in patients with hypertension and diabetes undergoing unilateral nephrectomy for malignancy. * These data could be used to identify those patients who would benefit from early referral and subsequent intervention to delay the progression of CKD, as well as those for whom nephron-sparing surgery might be a more appropriate surgical option. PMID- 21595822 TI - NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. AB - Treatment of high-risk neuroblastoma (NB) represents a major challenge in paediatric oncology. Alternative therapeutic strategies include antibodies targeting the disialoganglioside GD(2) , which is expressed at high levels on NB cells, and infusion of donor-derived natural killer (NK) cells. To combine specific antibody-mediated recognition of NB cells with the potent cytotoxic activity of NK cells, here we generated clonal derivatives of the clinically applicable human NK cell line NK-92 that stably express a GD(2) -specific chimeric antigen receptor (CAR) comprising an anti-GD(2) ch14.18 single chain Fv antibody fusion protein with CD3-zeta chain as a signalling moiety. CAR expression by gene-modified NK cells facilitated effective recognition and elimination of established GD(2) expressing NB cells, which were resistant to parental NK-92. In the case of intrinsically NK-sensitive NB cell lines, we observed markedly increased cell killing activity of retargeted NK-92 cells. Enhanced cell killing was strictly dependent on specific recognition of the target antigen and could be blocked by GD(2) -specific antibody or anti-idiotypic antibody occupying the CAR's cell recognition domain. Importantly, strongly enhanced cytotoxicity of the GD(2) -specific NK cells was also found against primary NB cells and GD(2) expressing tumour cells of other origins, demonstrating the potential clinical utility of the retargeted effector cells. PMID- 21595823 TI - Near-infrared tissue oximetry and digital image analysis: quantification of renal ischaemia in real time during partial nephrectomy. AB - OBJECTIVE: To determine the feasibility of using near-infrared tissue oximetry (TO) and digital image analysis for assessing renal function and to quantify local renal ischaemia in a porcine model. MATERIALS AND METHODS: Tissue oximetry was performed and red/blue (R/B) colour ratios were determined on renal units of Yorkshire swine. Interval measurements were taken before clamping the renal hilum, during warm ischaemia, and after unclamping using a ViOptix T.OxTM Tissue Oximeter and Matlab((r)) digital image analysis. Matlab software analysed images from the laparoscopic camera and determined an R/B ratio to track renal ischaemia. The tissue oximeter used direct infrared light and was placed adjacent to the kidney parenchymal surface. The data were divided into preclamp, clamp and post-clamp, and compared between methodologies. RESULTS: The R/B ratio showed a higher rate of change compared with TO during clamp time in both the 15-min experiment (R/B = 96.0 vs. TO = 52.1 unit/reference) and the 30-min experiment (R/B = 97.6 vs. TO = 45.9). The R/B ratio showed a higher rate of change compared with TO at 1 min after clamping in the 15-min experiment (R/B = 80.1 vs. TO = 12.4). Both detection devices showed similar changes in pre- and post-clamp measurements in the 15- min experiment (R/B = 1.6 vs. TO = 3.8) and the 30-min experiment (R/B = 4.7 vs. TO =-4.5). In the 30-min experiment the R/B ratio showed a significant difference between preclamp, clamp, and post-clamp states (P= 0.026). CONCLUSIONS: Both TO and digital image analysis were able to calculate an ischaemic drop in tissue oxygen saturation during periods of acute renal ischaemia. The findings suggest that the R/B ratio observed during histogram analysis shows a greater sensitivity compared with TO in quantifying renal ischaemia. PMID- 21595825 TI - Molecular profiling indicates orthotopic xenograft of glioma cell lines simulate a subclass of human glioblastoma. AB - Cell line models have been widely used to investigate glioblastoma multiforme (GBM) pathobiology and in the development of targeted therapies. However, GBM tumours are molecularly heterogeneous and how cell lines can best model that diversity is unknown. In this report, we investigated gene expression profiles of three preclinical growth models of glioma cell lines, in vitro and in vivo as subcutaneous and intracerebral xenografts to examine which cell line model most resembles the clinical samples. Whole genome DNA microarrays were used to profile gene expression in a collection of 25 high-grade glioblastomas, and comparisons were made to profiles of cell lines under three different growth models. Hierarchical clustering revealed three molecular subtypes of the glioblastoma patient samples. Supervised learning algorithm, trained on glioma subtypes predicted the intracerebral cell line model with one glioma subtype (r = 0.68; 95% bootstrap CI -0.41, 0.46). Survival analysis of enriched gene sets (P < 0.05) revealed 19 biological categories (146 genes) belonging to neuronal, signal transduction, apoptosis- and glutamate-mediated neurotransmitter activation signals that are associated with poor prognosis in this glioma subclass. We validated the expression profiles of these gene categories in an independent cohort of patients from 'The Cancer Genome Atlas' project (r = 0.62, 95% bootstrap CI: -0.42, 0.43). We then used these data to select and inhibit a novel target (glutamate receptor) and showed that LY341595, a glutamate receptor specific antagonist, could prolong survival in intracerebral tumour-implanted mice in combination with irradiation, providing an in vivo cell line system of preclinical studies. PMID- 21595824 TI - Extracellular matrix remodelling properties of human fibrocytes. AB - The fibrocytes are thought to serve as a source of newly deposited collagens I and III during reparative processes and in certain fibrotic disorders, but their matrix remodelling properties are incompletely understood. We evaluated their ability to produce several extracellular matrix (ECM) components, in comparison with fibroblasts, and to participate in collagen turnover. The collagen gene expression profile of fibrocytes differed from that of fibroblasts because fibrocytes constitutively expressed relatively high levels of the mRNA encoding collagen VI and significantly lower levels of the mRNA encoding collagens I, III and V. The proteoglycan (PG) gene expression profile was also different in fibrocytes and fibroblasts because fibrocytes constitutively expressed the mRNA encoding perlecan and versican at relatively high levels and the mRNA encoding biglycan and decorin at low and very low levels, respectively. Moreover, fibrocytes expressed the mRNA for hyaluronan synthase 2 at higher level than fibroblasts. Significant differences between the two cell populations were also demonstrated by metabolic labelling and analysis of the secreted collagenous proteins, PGs and hyaluronan. Fibrocytes constitutively expressed the scavenger receptors CD163 and CD204 as well as the mannose receptors CD206 and Endo180, and internalized and degraded collagen fragments through an Endo180-mediated mechanism. The results of this study demonstrate that human fibrocytes exhibit ECM remodelling properties previously unexplored, including the ability to participate in collagen turnover. The observed differences in collagen and PG expression profile between fibrocytes and fibroblasts suggest that fibrocytes may predominantly have a matrix-stabilizing function. PMID- 21595826 TI - Association of upregulated Ras/Raf/ERK1/2 signaling with autism. AB - Autism is a neurodevelopmental disorder characterized by impairments in social interaction, verbal communication and repetitive behaviors. BTBR mouse is currently used as a model for understanding mechanisms that may be responsible for the pathogenesis of autism. Growing evidence suggests that Ras/Raf/ERK1/2 signaling plays death-promoting apoptotic roles in neural cells. Recent studies showed a possible association between neural cell death and autism. In addition, two studies reported that a deletion of a locus on chromosome 16, which includes the MAPK3 gene that encodes ERK1, is associated with autism. We thus hypothesized that Ras/Raf/ERK1/2 signaling could be abnormally regulated in the brain of BTBR mice that models autism. In this study, we show that expression of Ras protein was significantly elevated in frontal cortex and cerebellum of BTBR mice as compared with B6 mice. The phosphorylations of A-Raf, B-Raf and C-Raf were all significantly increased in frontal cortex of BTBR mice. However, only C-Raf phosphorylation was increased in the cerebellum of BTBR mice. In addition, we further detected that the activities of both MEK1/2 and ERK1/2, which are the downstream kinases of Ras/Raf signaling, were significantly enhanced in the frontal cortex. We also detected that ERK1/2 is significantly over-expressed in frontal cortex of autistic subjects. Our results indicate that Ras/Raf/ERK1/2 signaling is upregulated in the frontal cortex of BTBR mice that model autism. These findings, together with the enhanced ERK1/2 expression in autistic frontal cortex, imply that Ras/Raf/ERK1/2 signaling activities could be increased in autistic brain and involved in the pathogenesis of autism. PMID- 21595828 TI - Insight into the phosphodiesterase mechanism from combined QM/MM free energy simulations. AB - Molecular dynamics simulations employing a combined quantum mechanical and molecular mechanical potential have been carried out to elucidate the reaction mechanism of the hydrolysis of a cyclic nucleotide cAMP substrate by phosphodiesterase 4B (PDE4B). PDE4B is a member of the PDE superfamily of enzymes that play crucial roles in cellular signal transduction. We have determined a two dimensional potential of mean force (PMF) for the coupled phosphoryl bond cleavage and proton transfer through a general acid catalysis mechanism in PDE4B. The results indicate that the ring-opening process takes place through an S(N)2 reaction mechanism, followed by a proton transfer to stabilize the leaving group. The computed free energy of activation for the PDE4B-catalyzed cAMP hydrolysis is about 13 kcal.mol(-1) and an overall reaction free energy is about -17 kcal.mol( 1), both in accord with experimental results. In comparison with the uncatalyzed reaction in water, the enzyme PDE4B provides a strong stabilization of the transition state, lowering the free energy barrier by 14 kcal.mol(-1). We found that the proton transfer from the general acid residue His234 to the O3' oxyanion of the ribosyl leaving group lags behind the nucleophilic attack, resulting in a shallow minimum on the free energy surface. A key contributing factor to transition state stabilization is the elongation of the distance between the divalent metal ions Zn(2+) and Mg(2+) in the active site as the reaction proceeds from the Michaelis complex to the transition state. PMID- 21595827 TI - Understanding the complex mechanisms of beta2-microglobulin amyloid assembly. AB - Several protein misfolding diseases are associated with the conversion of native proteins into ordered protein aggregates known as amyloid. Studies of amyloid assemblies have indicated that non-native proteins are responsible for initiating aggregation in vitro and in vivo. Despite the importance of these species for understanding amyloid disease, the structural and dynamic features of amyloidogenic intermediates and the molecular details of how they aggregate remain elusive. This review focuses on recent advances in developing a molecular description of the folding and aggregation mechanisms of the human amyloidogenic protein beta(2)-microglobulin under physiologically relevant conditions. In particular, the structural and dynamic properties of the non-native folding intermediate I(T) and its role in the initiation of fibrillation and the development of dialysis-related amyloidosis are discussed. PMID- 21595829 TI - Regulation of translational efficiency by different splice variants of the Disc large 1 oncosuppressor 5'-UTR. AB - Human Disc large (DLG1) has been demonstrated to be involved in the control of cell polarity and maintenance of tissue architecture, and is frequently lost in human tumours. However, the mechanisms controlling DLG1 expression are poorly understood. To further examine the regulation of DLG1 expression, we analysed the 5' ends of DLG1 transcripts by rapid amplification of cDNA ends polymerase chain reaction. We identified an alternative splicing event in the 5' region of DLG1 mRNA that generates transcripts with two different 5' untranslated regions (5' UTRs). We show by reporter assays that the DLG1 5'-UTR containing an alternatively spliced exon interferes with the translation of a downstream open reading frame (ORF). However, no significant differences in mRNA stability among the DLG1 5'-UTR variants were observed. Sequence analysis of the additional exon present in the larger DLG1 5'-UTR showed the presence of an upstream short ORF which is lost in the short version of the 5'-UTR DLG1. By mutagenesis and luciferase assays, we analysed the contribution of this upstream short ORF in reducing translation efficiency, and showed that its disruption can revert, to some extent, the negative regulation of large 5'-UTR. Using computational modelling we also show that the large DLG1 5'-UTR isoform forms a more stable structure than the short version, and this may contribute to its ability to repress translation. This represents the first analysis of the 5' region of the DLG1 transcripts and shows that differential expression of alternatively spliced 5'-UTRs with different translational properties could result in changes in DLG1 abundance. PMID- 21595830 TI - Negative pressure wound therapy: an adjuvant to surgical reconstruction of large or difficult skin and soft tissue defects. AB - Wide and deep wound defects are a challenge to surgeons, particularly when aggressive or more radical operations are unavailable. This article introduces refined techniques, indications and the clinical experience of the application of negative pressure wound therapy (NPWT) as an easy ancillary wound dressing method for the reconstruction of large or difficult skin and soft tissue defects. The authors used NPWT on 88 patients as an adjuvant therapy before reconstructive surgery since 2006. NPWT was applied for two different treatment strategies: as an adjuvant therapy to facilitate the formation of a healthy wound bed and to reduce the size and depth of a defect. NPWT was used as an alternative dressing method for skin grafting for infants or mobile skin surfaces such as the neck, penis, dorsum of the hand, knee joint, abdomen, etc. There were no typical wound complications. NPWT application, if used appropriately, produces successful surgical reconstructions for large, deep skin and soft tissue defects without extensive or radical flap surgery or loss of skin graft. PMID- 21595831 TI - The accordion gracilis muscle flap: a new design for coverage of recurrent and complicated ischeal pressure sores. AB - Management of patients with large or recurrent pressure ulcerations can be complicated by the lack of available local flap, whether already used or because adjacent lesions make such flap insufficient for complete coverage. In this article, the gracilis muscle was modified to cover large defects without help from its cutaneous territory. Twelve ischeal pressure sores were treated between August 2007 and 2009 with the modified gracilis muscle flap in a single-staged procedure. Five ulcers were recurrent and seven patients have associated pressure ulcers. All reconstructions were successful. Mean patient age was 35 years and nearly all patients had multiple significant comorbidities, including associated ulcers, diabetes and urethrocutaneous fistula. All flaps and donor sites healed uneventfully. There was one complication presented as cellulites at the donor site. Follow-up in some cases extend up to 1.5 years. No recurrence was observed. The accordion gracilis muscle flap is a handy, safe and fast flap for reconstruction of recurrent, difficult ischeal pressure sores. PMID- 21595832 TI - Erectile dysfunction after plaque incision and grafting: short-term assessment of incidence and predictors. AB - INTRODUCTION: Plaque incision and grafting (PIG) surgery for Peyronie's disease (PD) is a recognized management strategy. One of the recognized complications of PIG surgery is the development of postoperative erectile dysfunction (ED). AIM: To determine the incidence of ED after PIG surgery and attempt to define predictors of ED development. METHODS: All patients underwent preoperative cavernosometry. Grafting was performed with either cadaveric pericardium (Tutoplast) or intestinal submucosa (Surgisis). Prior to 2006, the procedure used an H-type incision, whereas after this date, the Egydio approach has been used. MAIN OUTCOME MEASURES: Men undergoing PIG completed preoperative and 6-month postoperative International Index of Erectile Function (IIEF) questionnaires. RESULTS: 56 patients were analyzed. Mean patient and partner ages were 57 +/- 22 and 54 +/- 18 years, respectively. Mean duration of PD at the time of PIG was 22 +/- 9 months. Seventy-five percent had curvature alone, 11% had hourglass/indentation deformity, and the remainder had combined curvature/indentation. Mean preoperative curvature was 52 +/- 23 degrees . Fifty two had grafting with Tutoplast, while four had grafting with Surgisis. All men at baseline were capable of generating a penetration rigidity erection. Preoperatively, 50% of men had cavernosal insufficiency and 21% had venous leak (baseline and postoperative erectile function [EF] domain scores were 23 +/- 4 and 17 +/- 9, respectively [P < 0.01]). Forty-six percent of men experienced a >=6-point decrease in EF domain score after PIG. The predictors of a >=6-point reduction in IIEF-EF domain score on multivariable analysis were degree of preoperative curvature, type of plaque incision, patient age, and baseline venous leak. Conclusions. Almost one-half of men had significant reduction in their erectile rigidity after PIG. Reduction was predicted by larger baseline curvature, the Egydio plaque incision technique, older patient age, and the presence of venous leak at baseline. Based on these data, we discourage older men, those with venous leak, and those with profound curvature from considering PIG surgery. PMID- 21595833 TI - Moderate alcohol intake, genital vascularization, and sexuality in young, healthy, eumenorrheic women. A pilot study. AB - INTRODUCTION: The relationship between alcohol and sexual function is complex and not completely understood. AIM: To evaluate (in the early follicular phase and independently from sexual stimulation) in young, eumenorrheic, healthy, lean women the genital vascular effects of the light and moderate use of alcohol. METHODS: Eighty-four women undertook, in the early follicular phase of the menstrual cycle (days 3-5), the administration of the two-factor Italian McCoy Female Sexuality (MFSQ) and the Beck Depression Inventory (BDI) questionnaires; ultrasonographic measurement of the carotid intima-media thickness (IMT); and color Doppler evaluation of the carotid, clitoral, and labia minora arteries. Hormonal (estradiol, androstenedione, and testosterone) and biochemical (lipids, glucose, and insulin) parameters were tested. MAIN OUTCOME MEASURES: The MFSQ and BDI questionnaires; the carotid IMT; the Pulsatility Index of internal carotid, clitoral, and labia minora arteries; blood pressure measurement; and hormonal and biochemical assays. RESULTS: The subjects were divided in: nondrinkers (group I); current (>1 year) light drinkers--1-10 drinks/month (group II); and current moderate drinkers--11-20 drinks/month (group III). The majority of the studied parameters did not vary among the different groups. The mean BDI was normal in the studied women. However, the lowest values were observed in the moderate drinkers group. The MFSQ did not show any difference among all the studied women. However, the number of intercourses/week and the incidence of vaginal orgasm were significantly higher in group III (moderate drinkers). The relationship between the drinking habits and different parameters showed an inverse relationship with the BDI. Furthermore, the BDI inversely correlated with orgasm frequency and with orgasm intensity. CONCLUSIONS: Chronic slight/moderate alcohol consumption has no effects on genital vessels and vaginal lubrication. However, a moderate consumption of alcohol, through psychological and social disinhibiting effects, may favor sexual activities. PMID- 21595834 TI - Cross-sex hormone therapy alters the serum lipid profile: a retrospective cohort study in 169 transsexuals. AB - INTRODUCTION: Cross-sex hormone therapy (CSHT) is known to lead to alterations in the serum lipid profile. However, the available reports in the literature are problematic, because of methodological limitations. AIMS: To assess changes in the fasting serum lipid profile during CSHT, including long-term follow-up. METHODS: Retrospective chart analysis of all 89 male-to-female (MtF) and 80 female-to-male (FtM) transsexuals who underwent standard CSHT at the Department of Gynecologic Endocrinology of the Medical University of Vienna (university hospital, tertiary care center), from 1995 to 2009. MAIN OUTCOME MEASURES: The results of the lipid profile were analyzed, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and the TC-to-HDL ratio, at the time of treatment initiation (time point "0") and at 3, 12, 24, and 60 months after the start of CSHT. RESULTS: The mean age of patients about to commence CSHT was 35.7 +/- 11.4 years (MtF) and 26.0 +/- 6.3 years (FtM). For MtF transsexuals, consistent follow-up for 24 and 60 months was available in 83 (93.3%) and 58 (65.2%) patients, respectively; for FtM transsexuals, follow-up was available in 57 (71.3%) and 39 (48.8%) patients, respectively. When testing for an association between the lipid parameters and the time after treatment initiation, significant increases for TG (P < 0.001), TC (P = 0.021), and HDL (P = 0.001) were found for MtF transsexuals, whereas TG, TC, and LDL (P < 0.001) increased and HDL (P < 0.001) decreased in FtM patients. CONCLUSION: Both MtF and FtM transsexuals experience alterations in the serum lipid profile because of CSHT, with the changes in FtM patients possibly more relevant in terms of atherogenesis. PMID- 21595835 TI - Risk factors for low sexual function among urban Chinese women: a hospital-based investigation. AB - INTRODUCTION: Sexual dysfunction is a common problem affecting women's quality of life. However, reports on sexual dysfunction and its risk factors in Chinese women are scarce in the literature. AIM: To identify the potential risk factors for low sexual function in urban Chinese women. METHODS: A cross-sectional hospital-based survey was conducted in Nanjing, China. Data on sexual function and related variables of 1,457 women from the urban district of Nanjing city were obtained. Potential risk factors for low sexual function were determined using multiple logistic regression analysis. MAIN OUTCOME MEASURE: The Female Sexual Function Index (FSFI) was used to evaluate sexual function, and the median of the FSFI score was used as a cutoff to define women with low sexual function. RESULTS: The mean FSFI total score was 23.25 +/- 4.00 (median = 22.8). Multivariate analysis showed that age (odds ratio [OR] 1.840 for 40-49 years; 5.006 for 50-60 years), depression (OR 1.896), low education level (primary or secondary school only, OR 1.450), alcohol use (OR 2.671), menopause or postmenopause (OR 3.157), chronic medical disease (OR 1.605), poor health status of partner (OR 3.358), presence of sexual dysfunction in partner (OR 4.604), dystocia (OR 3.109), and living apart from the partner (OR 1.316) were independent risk factors for low sexual function of women in urban China. By contrast, better communication with the partner regarding sex (OR 0.531) was a protective factor. CONCLUSION: Low sexual function for urban Chinese women was associated with multiple variables. Women who communicated more frequently with their partner were less likely to have low sexual function. PMID- 21595836 TI - Content validity of the Female Sexual Function Index (FSFI) in pre- and postmenopausal women with hypoactive sexual desire disorder. AB - INTRODUCTION: The Female Sexual Function Index (FSFI) has consistently been shown to have discriminant validity, test-retest reliability, and internal consistency as a measure of female sexual function. However, the content validity (relevance, clarity, comprehensiveness) of the instrument in women with hypoactive sexual desire disorder (HSDD) must also be established. AIM: The aim of this study were to assess the content validity of the FSFI, specifically the FSFI desire domain, in pre- and postmenopausal women with HSDD. METHODS: Two single-visit content validation studies were conducted in the United States. Eligible premenopausal (both studies) and postmenopausal (second study only) women with HSDD completed the FSFI followed by one-on-one, face-to-face cognitive debriefing interviews including open-ended questions to capture information on their perceptions of the instrument. Information on women's experiences of decreased sexual desire was also captured. MAIN OUTCOME MEASURES: The main outcome measures of this study were the women's ratings of the clarity, ease of understanding, comprehensiveness, and relevance of the 19 items of the FSFI. RESULTS: Interviews with 15 premenopausal women (first study), and 30 pre- and 31 postmenopausal women (second study), were analyzed. Across the whole sample, most women (80 100%) found every item of the FSFI clear and easy to understand. The majority (53 70%) felt that the FSFI captured all their feelings about decreased sexual desire and other sexual problems, and most (84-90%) indicated that additional questions were unnecessary. Most women in both studies (93-100%) reported that the two items comprising the FSFI desire domain were clear, easy to understand, and were relevant to them. The majority of women thought that a recall period of >=7 days is most relevant for recall of their sexual desire. CONCLUSIONS: These studies establish the content validity of the FSFI in pre- and postmenopausal women with HSDD, supporting the use of this instrument as a measure of sexual function in women with this condition. PMID- 21595837 TI - A surprising finding related to executive control in a patient sample of hypersexual men. AB - INTRODUCTION: Patients seeking help for hypersexual behavior often exhibit features of impulsivity, cognitive rigidity, and poor judgment as well as deficits in emotion regulation and excessive preoccupation with sex. Some of these characteristics are also common among patients presenting with neurological pathology associated with executive dysfunction. Exploring relationships between dysregulated sexual behavior and executive deficits will enhance our understanding of hypersexuality. AIM: This study sought to assess whether patients seeking help for hypersexual behavior exhibit executive deficits as measured by standardized neuropsychological tests of executive functioning when compared with healthy controls. METHODS: Executive deficits were assessed in a sample of male patients (N = 30) seeking help for hypersexual behavior compared with a nonhypersexual community sample of men (N = 30) using neuropsychological tests of executive functioning. Using multivariate statistics, differences between the groups were examined. MAIN OUTCOME MEASURES: Sexual activity measured by the Hypersexual Behavior Inventory and the Compulsive Sexual Behavior Inventory. Executive functions measured through neuropsychological testing using several subtests of Delis-Kaplan Executive Function System: Color-Word Interference Test, the Tower Test, the Trail Making Test, the Verbal Fluency Test, as well as the Wisconsin Card Sorting Test. Psychopathology was assessed using the Mini International Neuropsychiatric Interview, and cognitive ability was assessed using the Wechsler Adult Intelligence Scale. RESULTS: Significant differences on measures of hypersexuality were observed. However, the groups failed to exhibit significant differences across neuropsychological tests of executive functioning even after controlling for cognitive ability. CONCLUSIONS: These results contradict a previous finding of executive deficits among hypersexual men measured by self-report. The lack of executive deficits suggests that this population may exhibit domain-specific aspects of impulsivity, poor judgment, and risky behavior that are not generalizable to other domains of life. Furthermore, our findings fail to support a conceptualization of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, proposed hypersexual disorder based on models of executive dysfunction. . PMID- 21595839 TI - Higher expression of mRNA and protein of insulin-like growth factor binding protein-3 in old rat penile tissues: implications for erectile dysfunction. AB - INTRODUCTION: Previous studies have confirmed the gene transfer of insulin-like growth factor-1 (IGF-1) and the IGF-1 protein can improve the erectile function in aging rats. IGF binding protein (BP)-3 can regulates the availability of IGF I. The higher expression of IGFBP-3 may play an important role in erectile dysfunction (ED). AIM: The study aimed to investigate the mRNA and protein expression of IGFBP-3 in young and old rat penile tissues and assess the alteration of the penile structure and the NO-guanosine 3',5'-cyclic monophosphate (cGMP) signaling pathways-related marker in ED associated with aging. MAIN OUTCOME MEASURES: The main outcome measures for this study were the expression of IGFBP-3, morphological changes, NO-cGMP signaling pathways-related marker, erectile responses were determined. METHODS: Traditional reverse transcriptase polymerase chain reaction (RT-PCR) and real-time PCR were performed to examine the mRNA expression of the IGFBP-3. The Western blot was used to confirm the protein expression. Immunohistochemistry was also performed to identify the cellular localization of the encoded protein. The percentage of smooth muscle in corpus cavernosum tissue, the activity of nitric oxide synthase (NOS), and concentration of cGMP in penile tissue were also analyzed. RESULTS: The expression levels of IGFBP-3 of mRNA and protein were greatly increased in aging rats compared with young control rats, which is confirmed by traditional RT PCR, real-time PCR, and Western blot (P < 0.01, respectively). Increased IGFBP-3 protein was localized to the epithelium of the urethra, penile endothelium, and smooth muscle in the corpus cavernosum. Significant depletion of the smooth muscle density relative to the connective tissue was also observed in the penis of the aged rats, and the lower activity of NOS and lower concentration of cGMP was also demonstrated accompanied with a significant reduction in the intracavernous pressure. CONCLUSIONS: Our data suggest that the increased mRNA and protein expression of IGFBP-3 in old rats may play a role in ED. PMID- 21595838 TI - Impaired erectile function in CD73-deficient mice with reduced endogenous penile adenosine production. AB - INTRODUCTION: Adenosine has been implicated in normal and abnormal penile erection. However, a direct role of endogenous adenosine in erectile physiology and pathology has not been established. AIM: To determine the functional role of endogenous adenosine production in erectile function. METHODS: CD73-deficient mice (CD73(-/-)) and age-matched wild-type (WT) mice were used. Some WT mice were treated with alpha, beta-methylene adenosine diphosphate (ADP) (APCP), a CD73 specific inhibitor. High-performance liquid chromatography was used to measure adenosine levels in mouse penile tissues. In vivo assessment of intracorporal pressure (ICP) normalized to mean arterial pressure (MAP) in response to electrical stimulation (ES) of the cavernous nerve was used. MAIN OUTCOME MEASUREMENT: The main outcome measures of this study were the in vivo assessment of initiation and maintenance of penile erection in WT mice and mice with deficiency in CD73 (ecto-5'-nucleotidase), a key cell-surface enzyme to produce extracellular adenosine. RESULTS: Endogenous adenosine levels were elevated in the erected state induced by ES of cavernous nerve compared to the flaccid state in WT mice but not in CD73(-/-) mice. At cellular levels, we identified that CD73 was highly expressed in the neuronal, endothelial cells, and vascular smooth muscle cells in mouse penis. Functionally, we found that the ratio of ES-induced ICP to MAP in CD73(-/-) mice was reduced from 0.48 +/- 0.03 to 0.33 +/- 0.05 and ES-induced slope was reduced from 0.30 +/- 0.13 mm Hg/s to 0.15 +/- 0.05 mm Hg/s (both P < 0.05). The ratio of ES-induced ICP to MAP in APCP-treated WT mice was reduced from 0.49 +/- 0.03 to 0.38 +/- 0.06 and ES-induced slope was reduced from 0.29 +/- 0.11 mm Hg/s to 0.19 +/- 0.04 mm Hg/s (both P < 0.05). CONCLUSION: Overall, our findings demonstrate that CD73-dependent production of endogenous adenosine plays a direct role in initiation and maintenance of penile erection. PMID- 21595840 TI - The Subjective Sexual Arousal Scale for Men (SSASM): preliminary development and psychometric validation of a multidimensional measure of subjective male sexual arousal. AB - INTRODUCTION: Sexual arousal is a multifaceted process that involves both mental and physical components. No instrument has been developed and validated to assess subjective aspects of male sexual arousal. AIM: To develop and psychometrically validate a self-administered scale for assessing subjective male sexual arousal. METHODS: Using recommendations of the Food and Drug Administration (FDA) guidance on patient-reported outcome instruments, important aspects of male sexual arousal were identified via qualitative research (focus groups and interviews) of U.S. men with erectile dysfunction (ED) and healthy controls. After a preliminary questionnaire was developed by a panel of experts, a quantitative study of men with ED and controls was conducted to psychometrically validate the Subjective Sexual Arousal Scale for Men (SSASM). MAIN OUTCOME MEASURES: To develop a male sexual arousal scale and determine its factor structure, reliability, and construct validity. RESULTS: Five aspects of male sexual arousal were identified from the qualitative focus groups and cognitive interviews. Men's preferred language for describing sexual arousal and preferred response formats were incorporated into the questions. Factor analysis of data from the quantitative study of 304 men aged 21 to 70 years identified five domains with eigenvalues >1: sexual performance (six items), mental satisfaction (five items), sexual assertiveness (three items), partner communication (three items), and partner relationship (three items). The five domains had a high degree of internal consistency (Cronbach's alpha values 0.88-0.94). Test-retest reliability over a 2 to 4-week period was high-moderately high (r values 0.75-0.88) for the five domain scores. Correlations between SSASM domain scores and standardized scale scores for social desirability, general health, life satisfaction, and sexual function demonstrated the construct validity of the scale. CONCLUSIONS: Preliminary validation data suggest that the 20-item SSASM scale may be useful as a multidimensional, reliable, self-administered instrument for assessing subjective sexual arousal in men of different ages. PMID- 21595841 TI - Effects of hypoxia on nocturnal erection quality: a case report from the Manaslu expedition. AB - INTRODUCTION: High altitude environment represents a fine model to study physiological and pathophysiological effects of oxygen availability on sleep related erections (SREs). AIM: To describe altitude-dependent effects on quality of SREs in order to estimate the role of hypoxia in erection physiology. METHODS: A healthy 37-year-old male mountain climber underwent a chronic high altitude related hypoxia experience during the 43 days of the Manaslu expedition (Nepal). SREs were recorded by RigiScan (Timm Medical Technologies, Inc., Eden Prairie, MN, USA) at altitudes ranging from 0 to 5,800 m above sea level. The erection related parameters assessed were: number, duration, event duration (% of session), event rigidity %, time rigidity %, tumescence and rigidity activated unit, and event tum % > bline (%). MAIN OUTCOMES MEASURES: SREs were recorded by RigiScan at altitudes ranging from 0 to 5,800 m above sea level. RESULTS: Erectile parameters showed an altitude-related reduction during the hypoxic exposure, although all functional alterations were reverted by the return to sea level. CONCLUSIONS: Our case report supports the hypothesis that oxygen availability and delivery could play an important role in the regulation of local penile erection-related mechanisms and that low oxygen levels might be considered an etiological cofactor in erectile dysfunction. PMID- 21595842 TI - No (wo)man is an island--the influence of physicians' personal predisposition to labia minora appearance on their clinical decision making: a cross-sectional survey. AB - INTRODUCTION: Physicians are increasingly presented with women requesting a labia minora reduction procedure. AIM: To assess the influencing factor of personal predisposition in general practitioners, gynecologists, and plastic surgeons to labia minora appearance in relation to their willingness to refer for, or perform, a surgical labia minora reduction. METHODS: Cross-sectional self administered questionnaire survey. Between May 2009 and August 2009, 210 physicians were surveyed. Primary care: general practitioners working in the north of the Netherlands. Secondary care: gynecologists and plastic surgeons working in five hospitals in the north of the Netherlands. MAIN OUTCOME MEASURES: A five-point Likert scale appraisal of four pictures showing a vulva, each displaying different sizes of labia minora, indicating a physician's personal predisposition, manifesting as willingness to refer for, or perform, a labia minora reduction. RESULTS: A total of 164/210 (78.1%) physicians completed the questionnaire, consisting of 80 general practitioners, 41 gynecologists, and 43 plastic surgeons (96 males, 68 females). Ninety percent of all physicians believe, to a certain extent, that a vulva with very small labia minora represents society's ideal (2-5 on the Likert scale). More plastic surgeons regarded the picture with the largest labia minora as distasteful and unnatural, compared with general practitioners and gynecologists (P < 0.01), and regarded such a woman as a candidate for a labia minora reduction procedure (P < 0.001). Irrespective of the woman's labia minora size and the absence of physical complaints, plastic surgeons were significantly more open to performing a labia minora reduction procedure than gynecologists (P < 0.001). Male physicians were more inclined to opt for a surgical reduction procedure than their female colleagues (P < 0.01). CONCLUSIONS: The personal predisposition of physicians (taking account of their specific gender and specialty) concerning labia minora size and appearance influences their clinical decision making regarding a labia minora reduction procedure. Heightened awareness of one's personal predisposition vis-a-vis referral and willingness to operate is needed. PMID- 21595843 TI - Recent advances in CKD-MBD research. PMID- 21595844 TI - Guideline-practice gap in the management of predialysis chronic kidney disease mineral bone disorder in Japan. AB - No study has reported the current status of the management of chronic kidney disease mineral bone disorder (CKD-MBD) in Japan. Using the Osaka Vitamin D Study in CKD (OVIDS-CKD), we examined the prevalence of patients with serum calcium, phosphate, parathyroid hormone (PTH), or 25-hydroxyvitamin D levels outside the target of KDOQI guidelines. Eighty-four percent of the patients had 25 hydroxyvitamin D <30 ng/mL. Significant determinants of poor vitamin D status were female gender, diabetes, high PTH, and high urinary protein (2+ or greater). The percentage of patients with intact PTH higher than the target was 8% in CKD stage 3a, while between 20-22% in stages 3b to 5. The patients indicated for ergocalciferol were 7, 18, and 19% in stages 3a, 3b, and 4, respectively, and those indicated for active vitamin D were 21% in stage 5. Since neither ergocalciferol nor cholecalciferol is available in 2011 in Japan, we have no choice but to prescribe alfacalcidol or calcitriol; however, the percent of patients receiving these drugs was only 1, 4, 8, and 14% in stages 3a, 3b, 4, and 5, respectively, indicating that PTH and vitamin D status are not well controlled in Japan. In contrast, more than 80% of the patients met the target of serum calcium and phosphate. Contrary to expectations, nearly 20% of the patients had hypophosphatemia in stage 3 and 5, possibly because of strict protein restriction. Given these results, nephrologists should consider prescribing active vitamin D, especially for females and patients with diabetes, massive proteinuria, or secondary hyperparathyroidism. PMID- 21595845 TI - Nuclear chromatin-concentrated osteoblasts in renal bone diseases. AB - The morphological appearance of an osteoblast largely alters with its differentiation and maturation, along with the change of cell function. We quantitatively observed the osteoblast morphology and compared it with bone metabolism. Biopsied iliac bone samples obtained from 77 dialysis patients (14 mild change, 37 osteitis fibrosa, 2 osteomalacia, 8 mixed, and 16 adynamic bone) were included in the study. Osteoblast appearances were classified into three groups: (i) type II and III osteoblasts, namely, active osteoblasts characterized by cuboidal or columnar shapes with or without a nuclear clear zone; (ii) type IV osteoblasts, lining osteoblasts characterized by extremely thin cytoplasm; and (iii) type V osteoblasts, apoptotic osteoblasts characterized by nuclear chromatin concentration. The results were quantitatively expressed as the length of bone surface covered by each type of osteoblasts. The type II and III osteoblasts were predominant in osteitis fibrosa, mixed, and mild change. The type IV osteoblasts were overwhelmingly predominant in adynamic bone. The type V osteoblasts appeared most frequently in osteitis fibrosa, followed by mixed and mild change. Both absolute and relative lengths of bone surface covered by the type V osteoblasts were significantly higher in the high-turnover bone group (osteitis fibrosa and mixed) than the low-turnover bone group (adynamic bone and osteomalacia). The type V osteoblasts were slightly correlated with serum intact parathyroid hormone levels. In conclusion, a high bone-turnover condition seems to be associated with the promotion of osteoblastic apoptosis in dialysis patients. This finding may explain the fact that osteopenia develops faster in CKD patients with high turnover of bone. PMID- 21595846 TI - Role of megalin and cubilin in the metabolism of vitamin D(3). AB - Vitamin D deficiency is associated with various medical conditions including musculoskeletal disorders, infection, metabolic diseases, and cardiovascular disease. Megalin and cubilin, endocytic receptors in proximal tubule cells, are involved in the reabsorption of vitamin D binding protein from glomerular filtrates and the subsequent intracellular conversion of 25-hydroxyvitamin D(3) to biologically active 1alpha,25-dihydroxyvitamin D(3). Dysfunction of these receptors, which is commonly found in patients with diabetic nephropathy, even at early stages, may explain why vitamin D deficiency is often complicated in these patients. Therapeutic strategies to protect the functions of these receptors from injury could be used to prevent vitamin D deficiency and its related disorders. PMID- 21595847 TI - Involvement of matrix metalloproteinase-2 in the development of medial layer vascular calcification in uremic rats. AB - Vascular calcification is the most important cause of cardiovascular disease in patients with chronic kidney disease (CKD). Medial layer vascular calcification, which is recognized to be an active process (i.e. the transformation of vascular smooth muscle cells into osteoblast-like cells), is common in CKD patients. We have recently reported the possibility of an interaction between elastin degradation and medial layer vascular calcification. Matrix metalloproteinase-2 (MMP-2), which induces the degradation of elastin, has been implicated in the elastic calcification in arteries of dialysis patients; however, the precise mechanisms by which elastin degradation interacts with the development of vascular calcification remain to be studied. To clarify the mechanisms by which elastin degradation is involved in the development of medial layer vascular calcification in the uremic milieu, we induced aortic medial layer calcification in 5/6 nephrectomized uremic rats (male Sprague-Dawley rats) fed a diet containing high phosphate (1.2%) and lactate (20%). After 10 weeks, the rats were euthanized for the measurement of serum chemistry profiles and histological analyses. The uremic rats showed significant increases in blood pressure, serum creatinine, phosphate, and parathyroid hormone levels compared with normal rats. Von Kossa staining showed medial layer aortic calcification in the uremic rats. In calcified lesions, thin elastic lamellae were observed by elastin staining, indicating that elastin degradation could occur in the area. Furthermore, MMP-2 expression determined by immunohistochemistry was also observed in the same area. Elastin degradation accompanied by MMP-2 expression might be involved in the development of medial layer vascular calcification in uremic rats. PMID- 21595848 TI - Bone histology in chronic kidney disease-related mineral and bone disorder. AB - A quantitative histological analysis of biopsied bone samples is currently regarded as the gold standard for a diagnosing procedure for bone diseases associated with chronic kidney disease-related mineral and bone disorder. Conventionally, "bone cell activities" and "bone mineralization" are applied as two independent assessment axes, and the histology results are classified into five categories according to these axes. Recently, a new bone histology classification system called the Turnover-Mineralization-Volume system, which applied "cancellous bone volume" as another major assessing axis, was advocated; however, both classification systems have many unsolved problems. Clinicians must realize the limitations in evaluating bone metabolism by bone histology. We will need to establish a new classification method for renal bone diseases independent of histological findings. PMID- 21595849 TI - Role of multifunctional cell cycle modulators in advanced secondary hyperparathyroidism. AB - Long-term dialysis for patients with end stage renal disease leads to an unavoidable common complication, which is secondary hyperparathyroidism. Two histological patterns (nodular and diffuse hyperplasia) are detected, indicating that continuous uremia-related stimulation promotes parathyroid cell proliferation from diffuse to nodular growth. However, the key molecular mechanism is not fully understood, which narrows the range of therapeutic options for advanced secondary hyperparathyroidism. To address this issue, we utilized surgically resected normal and hyperplastic parathyroid glands to perform immunohistochemical analysis of a multifunctional cell cycle modulator, CCAAT enhancer binding protein (C/EBP)beta. In contrast to normal parathyroid tissue and diffuse hyperplasia, the intensity of C/EBPbeta staining was homogeneously increased in the parathyroid cells from nodules, along with a higher cyclin D1 labeling index (108.0 +/- 19.5, mean +/- SEM) and Ki-67 labeling index (31.70 +/- 0.49). Normal and diffuse hyperplastic parathyroid glands had far fewer cyclin D1 and Ki-67-positive cells (P < 0.001). Immunofluorescent double staining showed abundant coexpression of Th235 (mitogen-activated protein kinase [MAPK] phosphorylation site) C/EBPbeta, along with upregulation of cytoplasmic Ras in nodular hyperplasia. In conclusion, hyperplastic parathyroid cells in nodules have an autonomous proliferation mechanism similar to that of cancer, in which C/EBPbeta is upregulated and phosphorylated to interact with the oncogenic Ras/MAPK pathway. C/EBPbeta may be a novel target molecule for blocking the growth circuit that underlies parathyroid tumorigenesis in secondary hyperparathyroidism. PMID- 21595850 TI - Tertiary hyperparathyroidism resistant to cinacalcet treatment. AB - Cinacalcet hydrochloride (cinacalcet) has been reported to be efficacious for patients with tertiary hyperparathyroidism (THPT). We experienced five patients with THPT requiring parathyroidectomy (PTx) because of resistance to cinacalcet treatment and investigated their clinical characteristics and clinical course. The maximum diameter of the parathyroid gland estimated by ultrasonography before renal transplantation was evaluated. Serum total calcium, phosphorus, intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), and creatinine (Cr) levels were investigated every three months after the administration of cinacalcet and at PTx. After surgery, the Cr levels were followed. In all five patients, at least one parathyroid gland had a largest diameter of more than 1 cm, and the mean diameter was 18.7 mm (range 14.9-24.1 mm). Intact PTH and ALP levels gradually increased after the initiation of cinacalcet and the Cr levels transiently increased after PTx. These findings suggest that the existence of a severely enlarged nodular hyperplastic gland is a main factor involved in resistance to cinacalcet. PMID- 21595851 TI - Parathyroidectomy markedly reduces oxidative stress in a patient with primary hyperparathyroidism. AB - Parathyroidectomy for hyperparathyroidism has been associated with a survival benefit, but the mechanisms remain unclear. We are reporting on an 88-year-old female patient who had high serum calcium and intact parathyroid hormone levels associated with an enlarged parathyroid gland. A parathyroidectomy was performed due to a diagnosis of primary hyperparathyroidism. After the surgery, there was a marked decrease in the oxidative stress markers, such as the ratios of oxidized to unoxidized albumin and advanced oxidation protein products. These results suggest that parathyroidectomy reduces oxidative stress in patients with primary hyperparathyroidism, which may in part explain the reduced risk for cardiovascular and all-cause mortality after parathyroidectomy. PMID- 21595853 TI - Parathyroid hormone control survey to determine inter-method and inter-lab variations in Japan. AB - For uremic patients, Kidney Disease: Improving Global Outcomes suggest that parathyroid hormone (PTH) levels should be maintained within approximately 2-9 times the upper normal limit for the assay. One of reasons for the lack of definite approximate PTH values is the inability to use the Allegro Intact PTH assay from Nicols. We aimed to evaluate whether other parathyroid hormone assays were suitable for these assessments. We compared the parathyroid hormone concentrations measured with five commercial immunoassays by using three serum pools and seven artificially spiked samples of parathyroid hormone; the Total Intact parathyroid hormone assay was used as the reference assay. Although the results of parathyroid hormone assays showed high correlation, the concentrations differed from Yamasa's assay to another. And the third/second-generation assay ratio was approximately 60%. Further, the Immulite assay overestimated the levels of 1-84 PTH. We showed important inter-method variations in the parathyroid hormone assays used in Japan. PMID- 21595852 TI - Comparison between whole and intact parathyroid hormone assays. AB - The standard measurement of parathyroid hormone (PTH) is the intact PTH (iPTH) assay, which is used for approximately 90% of Japanese dialysis patients. The iPTH assay reacts not only with 1-84 PTH, but also with large truncated fragments of non-1-84 PTH, including 7-84 PTH. On the other hand, the whole PTH assay is specific for 1-84 PTH. The aim of the current study was to define the validity of both whole and intact PTH assays. A total of 738 hemodialysis patients were enrolled from twelve dialysis services. The serum PTH level was evaluated by both intact and whole PTH assays simultaneously. Non-1-84 PTH was determined by subtracting the whole PTH value from that of the intact PTH assay. The median level of whole PTH was 121 pg/mL, and that of iPTH was 210 pg/mL. The whole PTH assay had a very high correlation with the iPTH assay (r = 0.870, P < 0.001). For 43 out of 738 patients (5.8%) the value for intact PTH-whole PTH was <0. Both assays significantly correlated with non-1-84 PTH (P < 0.001), while the iPTH assay, particularly, had a very high correlation with non-1-84 PTH (r = 0.791). As a whole, 18% of the total population was misclassified into a different Japanese guideline category. Stratified by Japanese guideline classifications, 28% of patients within an iPTH target range were misclassified. Using Bland Altman plot analysis, as the serum PTH level increased, there was a large difference between two assays. Both PTH assays correlate strongly, although the whole PTH assay may be more useful for precise evaluation of PTH function than the iPTH assay. PMID- 21595854 TI - Novel electrochemiluminescence immunoassay exclusively for full-length parathyroid hormone during treatment with cinacalcet for secondary hyperparathyroidism. AB - A novel, electrochemiluminescence immunoassay that exclusively measures full length parathyroid hormone (PTH), called Elecsys PTH (1-84) assay, is currently under development for clinical use. We measured serum PTH levels using this novel assay, as well as the Elecsys Intact PTH assay and the Whole PTH immunoradiometric assay, in 53 hemodialysis patients who participated in a 52 week clinical trial of cinacalcet. At baseline, serum PTH (1-84) levels measured with the Elecsys PTH (1-84) assay and those with the Whole PTH assay were comparable, and both values were significantly lower than Elecsys Intact PTH levels. After 52 weeks of cinacalcet treatment, Elecsys PTH (1-84) levels and Whole PTH levels decreased significantly by 56% and 60% from baseline, respectively. These results indicate that the Elecsys PTH (1-84) assay provides comparable data to the Whole PTH assay for monitoring parathyroid function in patients receiving hemodialysis. Introduction of this novel automated immunoassay would provide more widespread measurements of full-length PTH (1-84) in clinical practice. PMID- 21595855 TI - Effects of raloxifene on bone mineral metabolism in postmenopausal Japanese women on hemodialysis. AB - In addition to renal osteodystrophy, postmenopausal women on hemodialysis are at high risk for osteoporosis. Recent studies reported the effects of raloxifene, a selective estrogen receptor modulator for osteoporosis, in postmenopausal women. The present study evaluated the efficacy of raloxifene and its effects on bone mineral metabolism in postmenopausal Japanese patients on dialysis. In a prospective, multicentre study, 17 postmenopausal women on chronic hemodialysis with severe osteoporosis (bone mineral density [BMD]<=2 SD by bone densitometry) were treated with 60 mg/day raloxifene hydrochloride for 12 months. The study also included 10 age-matched control women. Vitamin D and calcium salts were not changed during the study. Intact parathyroid hormone (iPTH), serum calcium and phosphorus, and bone resorption marker (NTx) were measured, and BMD were determined by DEXA, at 0, 6, and 12 months after administration of raloxifene. The mean lumbar spine BMD at baseline was similar in the two groups. Raloxifene therapy (for 12 months) improved lumbar spine BMD (by 2.6%) in 53% of the patients, while 70% of the control group showed a reduction in BMD (by 4.0%). Raloxifene significantly decreased serum calcium and increased iPTH. Our results suggested that raloxifene improved trabecular BMD in postmenopausal Japanese women on hemodialysis. The effects of raloxifene on serum calcium and serum iPTH level suggest it improves bone resorption. Vitamin D and/or calcium salts should be added to raloxifene treatment to avoid secondary hyperparathyroidism. PMID- 21595856 TI - Genetic polymorphisms in antioxidative enzymes are associated to forced expiratory volume in 1 s (FEV1) in smokers independently of asthma. AB - INTRODUCTION: In this study, we hypothesised that the genotypes coding for low antioxidative enzyme activity are associated with asthma and reduced lung function. METHODS: Using the European Community Respiratory Health Survey protocol, we enlisted 1091 Danish subjects in this cross-sectional study. Asthma phenotypes were defined as asthma symptoms in combination with steroid usage, bronchial hyperresponsiveness and atopy. These phenotypes and lung function were analysed with respect to glutathione peroxidase, GPX1 (Pro198Leu, rs1050450), manganese superoxide dismutase, SOD2 (Ala16Val, rs4880) and three glutathione S transferases; GSTP1 (Ile105Val, rs1695), GSTT1 (gene copy number) and GSTM1 (gene copy number). RESULTS: We found no associations between these genotypes and the asthma phenotypes. For the 201 subjects identified as current smokers and recruited via random sampling, an association was seen between increasing number of genotypes coding for high antioxidative enzyme activity (GPX1 Pro/Pro, SOD2 Val/Val, GSTP1 Ile/Ile, GSTT1 two copies, GSTM1 two copies) and forced expiratory volume in 1 s (FEV1%) predicted. The increase in FEV1% predicted was 2.0% (95% confidence interval 0.3-3.8) per genotype. There was no identified significance for the inverse association between FEV1% predicted and number of genotypes coding for low antioxidative enzyme activity. CONCLUSION: The present study does not support the hypothesis that asthma is associated with genotypes of these major antioxidative enzymes. However, we speculate that since we see an impact of these genotypes on lung function in young adult smokers, polymorphisms in antioxidative enzymes may contribute to the range of susceptibility of smokers have to Chronic obstructive lung disease. PMID- 21595857 TI - Oral antimicrobial use in outpatient cystic fibrosis pulmonary exacerbation management: a single-center experience. AB - INTRODUCTION: Cystic fibrosis (CF) pulmonary disease is characterized by intermittent episodes of acute lung symptoms known as 'pulmonary exacerbations'. While exacerbations are classically treated with parenteral antimicrobials, oral antibiotics are often used in 'mild' cases. OBJECTIVES: We determined how often management progressed to intravenous (IV) therapy. We also examined multiple courses of oral antimicrobials within one exacerbation, and identified patient factors associated with unsuccessful treatment. METHODS: We performed a retrospective chart audit of oral antibiotic use in CF patients, from March 2009 through March 2010, for 'mild' CF exacerbations. RESULTS: Administration of a single vs multiple courses of oral antibiotics for treatment of 'mild' CF exacerbation avoided progression to IV therapy 79.8% and 50.0% of the time, respectively. Overall, oral antibiotics circumvented the need for IV therapy 73.8% of the time. Using multi-variant analysis, we found multiple patient characteristics to be independent risk factors for oral antibiotic failure including a history of pseudomonas infection [odds ratio (OR) 2.13, confidence interval (CI) 1.29-3.54], CF-related diabetes (OR 1.85, CI 1.00-3.41), allergic Bronchopulmonary aspergillosis (OR 3.81, CI 1.38-10.56), low socioeconomic status (OR 1.67, CI 1.04-2.67), and calculated baseline forced expiratory volume in 1 s (FEV1) < 75% of predicted prior to an acute exacerbation (OR 1.93, CI 1.20-3.08). Decline in FEV1 > 10%, weight for age, body mass index, distance from the CF center and gender were not significant. CONCLUSION: Our observations suggest that one course of oral antimicrobials is frequently effective in outpatient CF pulmonary exacerbations but exacerbations requiring more than one course of oral antibiotics are likely to require IV therapy. PMID- 21595858 TI - The phosphatidyl inositol 3-kinase pathway is central to the pathogenesis of Kit activated melanoma. AB - Mouse Kit L575P, the ortholog of human KIT L576P, a common KIT mutation found in human melanoma was expressed in an immortalized but non-transformed mouse Ink4a Arf-deficient melanocyte cell line. The resultant Ink4a-Arf-deficient Kit L575P expressing melanocytes exhibited increased proliferation, the ability to grow in soft agar, and increased migration. When these cells were injected subcutaneously into NOD/SCID/gamma(c) mice, melanomas arose in 5 of 7 (71%) mice. One of seven mice (14%) injected with these cells developed metastatic disease. Evaluation of signal transduction pathways downstream of constitutively activated Kit L575P revealed striking activation of the phosphatidyl inositol 3-kinase (PI3K) pathway. Inhibition of the PI3K pathway pharmacologically or genetically abolished the transformation phenotypes gained by the L575P single mutant. These studies validate this Kit L575P-activated model of melanoma and establish the PI3K pathway as a dominant signaling pathway downstream of Kit in melanoma. PMID- 21595859 TI - The role of visual evoked potential and electroretinography in the preoperative assessment of osteo-keratoprosthesis or osteo-odonto-keratoprosthesis surgery. AB - PURPOSE: To determine the value of electroretinography (ERG) and visual evoked potential (VEP) in predicting visual outcome in patients undergoing osteo keratoprosthesis (OKP) or osteo-odonto-keratoprosthesis (OOKP) surgery. METHODS: We performed a retrospective cohort study of 143 eyes in 101 patients who underwent OKP or OOKP surgery. The subjects underwent ERG, VEP testing or both up to 6 months prior to surgery. The ERG and VEP results were classified into four categories based on wave amplitude, latency and configuration. The main outcome was the maximum best-corrected visual acuity (maxBCVA) reached at any time postoperatively. RESULTS: One hundred thirty-four cases had undergone preoperative ERG, 82 VEP and 73 both examinations. The sensitivities of ERG and VEP to detect maxBCVA>=0.05 were 68.5% and 87%, respectively, while the specificity was 63.2% for ERG and 47.4% for VEP. The maxBCVA was significantly better in patients with normal ERG (p=0.033) and those with normal VEP (p=0.048), once having defined appropriate normal and abnormal cut-off levels. When comparing fellow eyes in patients who underwent surgery in both eyes, maxBCVA was better in the eyes that had better VEP results (p=0.013). CONCLUSION: Eyes demonstrating normal ERG or VEP achieved better visual outcome than those with abnormal results. In addition, VEP proved instrumental in determining the eye with the best prognosis when comparing both eyes of a given patient. PMID- 21595860 TI - Recurrence of a limbal conjunctival melanoma 30 years after lamellar corneo sclero-conjunctival excision. PMID- 21595861 TI - Evaluation of limbal and pars plana silicone oil removal in aphakic eyes. AB - PURPOSE: To compare limbal and pars plana silicone oil removal (SOR) in aphakic eyes and to evaluate the acute effect of silicone oil flow to the corneal endothelium. METHODS: Sixteen aphakic patients with silicone oil endotamponade requiring SOR were recruited for this prospective study and randomly scheduled for limbal or pars plana SOR. The central corneal thickness (CCT), visual acuity (VA) and intraocular pressure were measured preoperatively, on the first postoperative day and 4 months after surgery. Endothelial cell density (ECD) was measured preoperatively and at the end of follow-up. The in vitro study was performed on ten enucleated porcine eyes. Corneoscleral discs were prepared and fixed on artificial anterior chamber followed by 2.5-mm limbal incision and 5-ml silicone oil injection in six cases and 5 ml balanced salt solution (BSS) in four cases. RESULTS: The ECD decreased by 239.2 +/- 86.7 (13.9%) and 86.7 +/- 22.4 cells/mm(2) (5%) after limbal (n = 8) and pars plana SOR (n = 8), respectively (p < 0.001 for both). The difference between the groups was significant (p < 0.001). A significant increase in CCT and corresponding decrease in VA was noted on the first postoperative day using both procedures. At the end of follow-up, the CCT and VA were comparable to initial values. Postoperative hypotony (<=6 mmHg) was observed more frequently after limbal SOR. In the experiment, lamellar abrasions of corneal endothelium were observed after silicone oil injection, whereas no changes were observed after BSS injection. CONCLUSION: Limbal SOR causes more considerable damage to the corneal endothelium than the pars plana approach because of mechanical abrasion. PMID- 21595862 TI - Transretinal uveal melanoma biopsy with 25-gauge vitrectomy system. AB - PURPOSE: To evaluate the efficacy and the safety of uveal melanoma transretinal biopsy using 25-gauge vitrectomy system. METHODS: At the patient's request of a tissue diagnosis, nine posterior uveal melanomas treated by proton-beam therapy were biopsied during the insertion of tantalium markers. RESULTS: The diagnosis was uveal melanoma, confirmed in all cases using cytological (7 of 9) and histological analysis (2 of 9). Immunocytochemistry was performed on all samples (9 of 9). In eight of nine patients, minor postoperative vitreous haemorrhages were seen, which resolved in 1 day. No other ocular complications were noticed. CONCLUSION: Uveal melanoma biopsy using 25-gauge vitrectomy system is a valuable procedure to confirm the diagnosis, with adequate sample and low ocular morbidity. PMID- 21595863 TI - Quality of image of grating target placed in vitreous of isolated pig eyes photographed through different implanted multifocal intraocular lenses. AB - PURPOSE: To determine the quality of the image of a grating target placed in the vitreous of isolated pig eyes and photographed through implanted refractive and diffractive multifocal intraocular lenses (IOL). METHODS: Refractive multifocal (NXG1, PY60MV), diffractive multifocal (ZM900, SA60D3) and monofocal (SA60AT, ZA9003) IOL were implanted in the capsular bag of isolated pig eyes. A grating target was placed in the vitreous and photographed through a flat or a wide-field viewing contact lens. The contrast of the grating targets of different spatial frequencies was measured. RESULTS: With the flat corneal contact lens, the gratings appeared clear and not distorted when viewed through the optics of the NXG1 and PY60MV for far vision but were distorted with reduced contrast when viewed through the optical zone for near vision. The images through the diffractive zone of the ZM900 and SA60D3 were more defocused than with the monofocal IOL (p < 0.005). Ghost images oriented centrifugally of the original image were seen with the ZM900 resulting in lower contrast at higher spatial frequencies than with the SA60D3 with less defocused images only in the central area. With the wide-field viewing contact lens, the images were less defocused and the contrast was comparable to both refractive and diffractive multifocal IOL. CONCLUSION: Both refractive and diffractive multifocal IOL reduced the contrast of the retinal image when viewed through a flat corneal contact lens but less defocused when viewed through a wide-field viewing contact lens. PMID- 21595864 TI - The frequency of other autoimmune disorders in patients with ocular cicatricial pemphigoid. PMID- 21595866 TI - Diffusion of hydrophobin proteins in solution and interactions with a graphite surface. AB - BACKGROUND: Hydrophobins are small proteins produced by filamentous fungi that have a variety of biological functions including coating of spores and surface adhesion. To accomplish these functions, they rely on unique interface-binding properties. Using atomic-detail implicit solvent rigid-body Brownian dynamics simulations, we studied the diffusion of HFBI, a class II hydrophobin from Trichoderma reesei, in aqueous solution in the presence and absence of a graphite surface. RESULTS: In the simulations, HFBI exists in solution as a mixture of monomers in equilibrium with different types of oligomers. The oligomerization state depends on the conformation of HFBI. When a Highly Ordered Pyrolytic Graphite (HOPG) layer is present in the simulated system, HFBI tends to interact with the HOPG layer through a hydrophobic patch on the protein. CONCLUSIONS: From the simulations of HFBI solutions, we identify a tetrameric encounter complex stabilized by non-polar interactions between the aliphatic residues in the hydrophobic patch on HFBI. After the formation of the encounter complex, a local structural rearrangement at the protein interfaces is required to obtain the tetrameric arrangement seen in HFBI crystals. Simulations performed with the graphite surface show that, due to a combination of a geometric hindrance and the interaction of the aliphatic sidechains with the graphite layer, HFBI proteins tend to accumulate close to the hydrophobic surface. PMID- 21595865 TI - Hierarchies in eukaryotic genome organization: Insights from polymer theory and simulations. AB - Eukaryotic genomes possess an elaborate and dynamic higher-order structure within the limiting confines of the cell nucleus. Knowledge of the physical principles and the molecular machinery that govern the 3D organization of this structure and its regulation are key to understanding the relationship between genome structure and function. Elegant microscopy and chromosome conformation capture techniques supported by analysis based on polymer models are important steps in this direction. Here, we review results from these efforts and provide some additional insights that elucidate the relationship between structure and function at different hierarchical levels of genome organization. PMID- 21595867 TI - A Bayesian method for inferring quantitative information from FRET data. AB - BACKGROUND: Understanding biological networks requires identifying their elementary protein interactions and establishing the timing and strength of those interactions. Fluorescence microscopy and Forster resonance energy transfer (FRET) have the potential to reveal such information because they allow molecular interactions to be monitored in living cells, but it is unclear how best to analyze FRET data. Existing techniques differ in assumptions, manipulations of data and the quantities they derive. To address this variation, we have developed a versatile Bayesian analysis based on clear assumptions and systematic statistics. RESULTS: Our algorithm infers values of the FRET efficiency and dissociation constant, Kd, between a pair of fluorescently tagged proteins. It gives a posterior probability distribution for these parameters, conveying more extensive information than single-value estimates can. The width and shape of the distribution reflects the reliability of the estimate and we used simulated data to determine how measurement noise, data quantity and fluorophore concentrations affect the inference. We are able to show why varying concentrations of donors and acceptors is necessary for estimating Kd. We further demonstrate that the inference improves if additional knowledge is available, for example of the FRET efficiency, which could be obtained from separate fluorescence lifetime measurements. CONCLUSIONS: We present a general, systematic approach for extracting quantitative information on molecular interactions from FRET data. Our method yields both an estimate of the dissociation constant and the uncertainty associated with that estimate. The information produced by our algorithm can help design optimal experiments and is fundamental for developing mathematical models of biochemical networks. PMID- 21595868 TI - Thermotropic phase behavior and headgroup interactions of the nonbilayer lipids phosphatidylethanolamine and monogalactosyldiacylglycerol in the dry state. AB - BACKGROUND: Although biological membranes are organized as lipid bilayers, they contain a substantial fraction of lipids that have a strong tendency to adopt a nonlamellar, most often inverted hexagonal (HII) phase. The polymorphic phase behavior of such nonbilayer lipids has been studied previously with a variety of methods in the fully hydrated state or at different degrees of dehydration. Here, we present a study of the thermotropic phase behavior of the nonbilayer lipids egg phosphatidylethanolamine (EPE) and monogalactosyldiacylglycerol (MGDG) with a focus on interactions between the lipid molecules in the interfacial and headgroup regions. RESULTS: Liposomes were investigated in the dry state by Fourier-transform Infrared (FTIR) spectroscopy and Differential Scanning Calorimetry (DSC). Dry EPE showed a gel to liquid-crystalline phase transition below 0 degrees C and a liquid-crystalline to HII transition at 100 degrees C. MGDG, on the other hand, was in the liquid-crystalline phase down to -30 degrees C and showed a nonbilayer transition at about 85 degrees C. Mixtures (1:1 by mass) with two different phosphatidylcholines (PC) formed bilayers with no evidence for nonbilayer transitions up to 120 degrees C. FTIR spectroscopy revealed complex interactions between the nonbilayer lipids and PC. Strong H bonding interactions occurred between the sugar headgroup of MGDG and the phosphate, carbonyl and choline groups of PC. Similarly, the ethanolamine moiety of EPE was H-bonded to the carbonyl and choline groups of PC and probably interacted through charge pairing with the phosphate group. CONCLUSIONS: This study provides a comprehensive characterization of dry membranes containing the two most important nonbilayer lipids (PE and MGDG) in living cells. These data will be of particular relevance for the analysis of interactions between membranes and low molecular weight solutes or soluble proteins that are presumably involved in cellular protection during anhydrobiosis. PMID- 21595869 TI - Human bocavirus (HBoV) in children with respiratory tract infection by enzyme linked immunosorbent assay (ELISA) and qualitative polymerase chain reaction (PCR). AB - BACKGROUND: Human bocavirus (HBoV) is a recently discovered parvovirus associated with mild to severe lower respiratory tract infections in children, the aim of the work was determination of human bocavirus in nasopharyngeal aspirate (NPA) of infants by qualitative PCR and determination of acute human bocavirus infection by estimation of immunoglobulin M (IgM) antibodies in serum by enzyme linked immunosorbent assay. RESULTS: Twenty two (22%) out of the 100 NPA specimens of the patients with respiratory manifestations were positive for HBoV by qualitative PCR, while ELISA revealed positive HBoV IgM antibodies in 18 (18%) patients who were also positive by PCR. Non of the controls were positive by both techniques. The correlation study between ELISA and PCR revealed high significant association, (p < 0.001, X2 = 36 and agreement = 96%). Also PCR detected 4 (18.1%) NPA samples as HBoV positive cases among the patients that were not identified by ELISA. This could be due to high sensitivity and efficacy of PCR. ELISA being less sensitive than RT-PCR, sensitivity was (81.8% vs 100%), the efficacy was 97.7% in ELISA versus 99.7% for RT-PCR. CONCLUSION: HBoV infections could be diagnosed in NPA of children by conventional PCR as a rapid and sensitive technique. While ELISA was a reliable serologic analysis for diagnosis of acute HBoV infection by estimation IgM antibodies in serum. PMID- 21595871 TI - Brucella spp. infection in large ruminants in an endemic area of Egypt: cross sectional study investigating seroprevalence, risk factors and livestock owner's knowledge, attitudes and practices (KAPs). AB - BACKGROUND: Brucellosis is regarded as one of the major zoonotic infections worldwide. It was first reported in Egypt in 1939 and is now endemic, the predominate species of Brucella in cattle and buffalo in Egypt is B. melitensis. The aim of the study was to estimate seroprevalence of Brucella spp. in cattle and buffalo reared in households in an Egyptian village, identify risk factors for animals testing seropositive and to assess the knowledge, attitudes and practices (KAPs) of livestock owners with regards to brucellosis. METHODS: A cross-sectional study was carried out in a village in Menufiya Governorate of Egypt. In June and July 2009, 107 households were selected using systematic sample and all lactating cattle and buffalo present in the household were sampled and tested for antibodies against Brucella spp. In addition, a questionnaire collecting information on potential risk factors for Brucella spp. infection in cattle and buffalo was administered to the household member responsible for rearing the livestock. Between December 2009 and February 2010 households were revisited and a second questionnaire regarding KAPs associated with brucellosis was administered. RESULTS: True individual and household seroprevalence were estimated to be 11.0% (95% CI: 3.06% to 18.4%) and 15.5% (95% CI: 6.61% to 24.7%), respectively. Cattle and buffalo kept in a household with sheep and goats had 6.32 (95% CI: 1.44 to 27.9) times the odds of testing seropositive for Brucella spp., compared to cattle and buffalo that were not. Most participants in the study stated that livestock owners assist in the parturition of ruminants without wearing gloves and that some farmers sell animals which they suspect are Brucella infected to butchers or at market. Many participants made their livestock's milk into cheese and other dairy products without pasteurising it. CONCLUSIONS: Brucellosis was endemic at high levels, in the current study. Although livestock owners had good general knowledge of brucellosis, they still appeared to participate in high-risk behaviours, which may contribute to the high seroprevalence in the area. Veterinarians, public health authorities and other community leaders need to collaborate to control the disease in animals and to manage the risk of human exposure. PMID- 21595870 TI - BAC library resources for map-based cloning and physical map construction in barley (Hordeum vulgare L.). AB - BACKGROUND: Although second generation sequencing (2GS) technologies allow re sequencing of previously gold-standard-sequenced genomes, whole genome shotgun sequencing and de novo assembly of large and complex eukaryotic genomes is still difficult. Availability of a genome-wide physical map is therefore still a prerequisite for whole genome sequencing for genomes like barley. To start such an endeavor, large insert genomic libraries, i.e. Bacterial Artificial Chromosome (BAC) libraries, which are unbiased and representing deep haploid genome coverage, need to be ready in place. RESULT: Five new BAC libraries were constructed for barley (Hordeum vulgare L.) cultivar Morex. These libraries were constructed in different cloning sites (HindIII, EcoRI, MboI and BstXI) of the respective vectors. In order to enhance unbiased genome representation and to minimize the number of gaps between BAC contigs, which are often due to uneven distribution of restriction sites, a mechanically sheared library was also generated. The new BAC libraries were fully characterized in depth by scrutinizing the major quality parameters such as average insert size, degree of contamination (plate wide, neighboring, and chloroplast), empty wells and off scale clones (clones with <30 or >250 fragments). Additionally a set of gene based probes were hybridized to high density BAC filters and showed that genome coverage of each library is between 2.4 and 6.6 X. CONCLUSION: BAC libraries representing >20 haploid genomes are available as a new resource to the barley research community. Systematic utilization of these libraries in high-throughput BAC fingerprinting should allow developing a genome-wide physical map for the barley genome, which will be instrumental for map-based gene isolation and genome sequencing. PMID- 21595872 TI - A review of health system infection control measures in developing countries: what can be learned to reduce maternal mortality. AB - A functional health system is a necessary part of efforts to achieve maternal mortality reduction in developing countries. Puerperal sepsis is an infection contracted during childbirth and one of the commonest causes of maternal mortality in developing countries, despite the discovery of antibiotics over eighty years ago. Infections can be contracted during childbirth either in the community or in health facilities. Some developing countries have recently experienced increased use of health facilities for labour and delivery care and there is a possibility that this trend could lead to rising rates of puerperal sepsis. Drug and technological developments need to be combined with effective health system interventions to reduce infections, including puerperal sepsis. This article reviews health system infection control measures pertinent to labour and delivery units in developing country health facilities. Organisational improvements, training, surveillance and continuous quality improvement initiatives, used alone or in combination have been shown to decrease infection rates in some clinical settings. There is limited evidence available on effective infection control measures during labour and delivery and from low resource settings. A health systems approach is necessary to reduce maternal mortality and the occurrence of infections resulting from childbirth. Organisational and behavioural change underpins the success of infection control interventions. A global, targeted initiative could raise awareness of the need for improved infection control measures during childbirth. PMID- 21595873 TI - Prospecting for genes involved in transcriptional regulation of plant defenses, a bioinformatics approach. AB - BACKGROUND: In order to comprehend the mechanisms of induced plant defense, knowledge of the biosynthesis and signaling pathways mediated by salicylic acid (SA), jasmonic acid (JA) and ethylene (ET) is essential. Potentially, many transcription factors could be involved in the regulation of these pathways, although finding them is a difficult endeavor. Here we report the use of publicly available Arabidopsis microarray datasets to generate gene co-expression networks. RESULTS: Using 372 publicly available microarray data sets, a network was constructed in which Arabidopsis genes for known components of SA, JA and ET pathways together with the genes of over 1400 transcription factors were assayed for co-expression. After determining the Pearson Correlation Coefficient cutoff to obtain the most probable biologically relevant co-expressed genes, the resulting network confirmed the presence of many genes previously reported in literature to be relevant for stress responses and connections that fit current models of stress gene regulation, indicating the potential of our approach. In addition, the derived network suggested new candidate genes and associations that are potentially interesting for future research to further unravel their involvement in responses to stress. CONCLUSIONS: In this study large sets of stress related microarrays were used to reveal co-expression networks of transcription factors and signaling pathway components. These networks will benefit further characterization of the signal transduction pathways involved in plant defense. PMID- 21595874 TI - IP-10 response to RD1 antigens might be a useful biomarker for monitoring tuberculosis therapy. AB - BACKGROUND: There is an urgent need of prognosis markers for tuberculosis (TB) to improve treatment strategies. The results of several studies show that the Interferon (IFN)-gamma-specific response to the TB antigens of the QuantiFERON TB Gold (QFT-IT antigens) decreases after successful TB therapy. The objective of this study was to evaluate whether there are factors other than IFN-gamma [such as IFN-gamma inducible protein (IP)-10 which has also been associated with TB] in response to QFT-IT antigens that can be used as biomarkers for monitoring TB treatment. METHODS: In this exploratory study we assessed the changes in IP-10 secretion in response to QFT-IT antigens and RD1 peptides selected by computational analysis in 17 patients with active TB at the time of diagnosis and after 6 months of treatment. The IFN-gamma response to QFT-IT antigens and RD1 selected peptides was evaluated as a control. A non-parametric Wilcoxon signed rank test for paired comparisons was used to compare the continuous variables at the time of diagnosis and at therapy completion. A Chi-square test was used to compare proportions. RESULTS: We did not observe significant IP-10 changes in whole blood from either NIL or QFT-IT antigen tubes, after 1-day stimulation, between baseline and therapy completion (p = 0.08 and p = 0.7 respectively). Conversely, the level of IP-10 release to RD1 selected peptides was significantly different (p = 0.006). Similar results were obtained when we detected the IFN gamma in response to the QFT-IT antigens (p = 0.06) and RD1 selected peptides (p = 0.0003). The proportion of the IP-10 responders to the QFT-IT antigens did not significantly change between baseline and therapy completion (p = 0.6), whereas it significantly changed in response to RD1 selected peptides (p = 0.002). The proportion of IFN-gamma responders between baseline and therapy completion was not significant for QFT-IT antigens (p = 0.2), whereas it was significant for the RD1 selected peptides (p = 0.002), confirming previous observations. CONCLUSIONS: Our preliminary study provides an interesting hypothesis: IP-10 response to RD1 selected peptides (similar to IFN-gamma) might be a useful biomarker for monitoring therapy efficacy in patients with active TB. However, further studies in larger cohorts are needed to confirm the consistency of these study results. PMID- 21595875 TI - WRKY transcription factors involved in activation of SA biosynthesis genes. AB - BACKGROUND: Increased defense against a variety of pathogens in plants is achieved through activation of a mechanism known as systemic acquired resistance (SAR). The broad-spectrum resistance brought about by SAR is mediated through salicylic acid (SA). An important step in SA biosynthesis in Arabidopsis is the conversion of chorismate to isochorismate through the action of isochorismate synthase, encoded by the ICS1 gene. Also AVRPPHB SUSCEPTIBLE 3 (PBS3) plays an important role in SA metabolism, as pbs3 mutants accumulate drastically reduced levels of SA-glucoside, a putative storage form of SA. Bioinformatics analysis previously performed by us identified WRKY28 and WRKY46 as possible regulators of ICS1 and PBS3. RESULTS: Expression studies with ICS1 promoter::beta-glucuronidase (GUS) genes in Arabidopsis thaliana protoplasts cotransfected with 35S::WRKY28 showed that over expression of WRKY28 resulted in a strong increase in GUS expression. Moreover, qRT-PCR analyses indicated that the endogenous ICS1 and PBS3 genes were highly expressed in protoplasts overexpressing WRKY28 or WRKY46, respectively. Electrophoretic mobility shift assays indentified potential WRKY28 binding sites in the ICS1 promoter, positioned -445 and -460 base pairs upstream of the transcription start site. Mutation of these sites in protoplast transactivation assays showed that these binding sites are functionally important for activation of the ICS1 promoter. Chromatin immunoprecipitation assays with haemagglutinin-epitope-tagged WRKY28 showed that the region of the ICS1 promoter containing the binding sites at -445 and -460 was highly enriched in the immunoprecipitated DNA. CONCLUSIONS: The results obtained here confirm results from our multiple microarray co-expression analyses indicating that WRKY28 and WRKY46 are transcriptional activators of ICS1 and PBS3, respectively, and support this in silico screening as a powerful tool for identifying new components of stress signaling pathways. PMID- 21595877 TI - How to develop a program to increase influenza vaccine uptake among workers in health care settings? AB - BACKGROUND: Apart from direct protection and reduced productivity loss during epidemics, the main reason to immunize healthcare workers (HCWs) against influenza is to provide indirect protection of frail patients through reduced transmission in healthcare settings. Because the vaccine uptake among HCWs remains far below the health objectives, systematic programs are needed to take full advantage of such vaccination. In an earlier report, we showed a mean 9% increase of vaccine uptake among HCWs in nursing homes that implemented a systematic program compared with control homes, with higher rates in those homes that implemented more program elements. Here, we report in detail the process of the development of the implementation program to enable researchers and practitioners to develop intervention programs tailored to their setting. METHODS: We applied the intervention mapping (IM) method to develop a theory- and evidence-based intervention program to change vaccination behaviour among HCWs in nursing homes. RESULTS: After a comprehensive needs assessment, we were able to specify proximal program objectives and selected methods and strategies for inducing behavioural change. By consensus, we decided on planning of three main program components, i.e., an outreach visit to all nursing homes, plenary information meetings, and the appointment of a program coordinator -- preferably a physician -- in each home. Finally, we planned program adoption, implementation, and evaluation. CONCLUSION: The IM methodology resulted in a systematic, comprehensive, and transparent procedure of program development. A potentially effective intervention program to change influenza vaccination behaviour among HCWs was developed, and its impact was assessed in a clustered randomised controlled trial. PMID- 21595876 TI - EMIRGE: reconstruction of full-length ribosomal genes from microbial community short read sequencing data. AB - Recovery of ribosomal small subunit genes by assembly of short read community DNA sequence data generally fails, making taxonomic characterization difficult. Here, we solve this problem with a novel iterative method, based on the expectation maximization algorithm, that reconstructs full-length small subunit gene sequences and provides estimates of relative taxon abundances. We apply the method to natural and simulated microbial communities, and correctly recover community structure from known and previously unreported rRNA gene sequences. An implementation of the method is freely available at https://github.com/csmiller/EMIRGE. PMID- 21595878 TI - Effect of human activated NRAS on replication of delNS1 H5N1 influenza virus in MDCK cells. AB - BACKGROUND: RAS, coded by ras proto-oncogenes, played an important role in signal transmission to regulate cell growth and differentiation. Host activation of RAS was significant for IFN-sensitive vaccinia virus (delE3L) or attenuate influenza virus in unallowable cells. RESULTS: Huamn NRAS gene was activated by mutating in codon 61. Then the activation of NRAS was detected by western blot in MDCK cells. The delNS1 H5N1 influenza virus with deletion of NS1 eIF4GI binding domain was weak multiplication in MDCK cells. And the replication of delNS1 virus and expression of IFN-beta and IRF-3 were detected by Real-time PCR in MDCK cells infected with delNS1 virus. It was found that the delNS1 virus had a significant increase in MDCK cells when the NRAS was activated, and yet, expression of IRF-3 and IFN-beta were restrained. CONCLUSIONS: The study demonstrated that activated NRAS played an important part for delNS1 virus replication in MDCK cells. Activated NRAS might be down-regulating the expression of antiviral cellular factors in delNS1 virus infected cells. PMID- 21595879 TI - A rice calcium-dependent protein kinase is expressed in cortical root cells during the presymbiotic phase of the arbuscular mycorrhizal symbiosis. AB - BACKGROUND: The arbuscular mycorrhizal (AM) symbiosis consists of a mutualistic relationship between soil fungi and roots of most plant species. This association provides the arbuscular mycorrhizal fungus with sugars while the fungus improves the uptake of water and mineral nutrients in the host plant. Then, the establishment of the arbuscular mycorrhizal (AM) symbiosis requires the fine tuning of host gene expression for recognition and accommodation of the fungal symbiont. In plants, calcium plays a key role as second messenger during developmental processes and responses to environmental stimuli. Even though calcium transients are known to occur in host cells during the AM symbiosis, the decoding of the calcium signal and the molecular events downstream are only poorly understood. RESULTS: The expression of seventeen Calcium-dependent Protein Kinase (CPK) genes representative of the four distinct phylogenetic groups of rice CPKs was monitored during the presymbiotic phase of the AM symbiosis. Among them, OsCPK18 and OsCPK4, were found to be transcriptionally activated in response to inoculation with the AM fungus Glomus intraradices. OsCPK18 and OsCPK4 gene expression was also up-regulated by fungal-produced diffusible molecules. Laser microdissection revealed expression of OsCPK18 in cortical cells, and not in epidermal cells of G. intraradices-inoculated rice roots, suggesting a preferential role of this gene in the root cortex. Moreover, a plasma membrane localization of OsCPK18 was observed by transient expression assays of green fluorescent protein-tagged OsCPK18 in onion epidermal cells. We also show that the myristoylation site of the OsCPK18 N-terminus is required for plasma membrane targeting. CONCLUSION: The rapid activation of OsCPK18 expression in response to AM inoculation, its expression being also induced by fungal secreted signals, together with the observed plasma membrane localization of OsCPK18, points to a role for OsCPK18 in perception of the AM fungus. The OsCPK18 gene might be considered as a marker for the presymbiotic phase of the symbiotic process. These findings provide a better understanding of the signaling mechanisms operating during the AM symbiosis and will greatly facilitate their molecular dissection. PMID- 21595880 TI - Genotype calling in tetraploid species from bi-allelic marker data using mixture models. AB - BACKGROUND: Automated genotype calling in tetraploid species was until recently not possible, which hampered genetic analysis. Modern genotyping assays often produce two signals, one for each allele of a bi-allelic marker. While ample software is available to obtain genotypes (homozygous for either allele, or heterozygous) for diploid species from these signals, such software is not available for tetraploid species which may be scored as five alternative genotypes (aaaa, baaa, bbaa, bbba and bbbb; nulliplex to quadruplex). RESULTS: We present a novel algorithm, implemented in the R package fitTetra, to assign genotypes for bi-allelic markers to tetraploid samples from genotyping assays that produce intensity signals for both alleles. The algorithm is based on the fitting of several mixture models with five components, one for each of the five possible genotypes. The models have different numbers of parameters specifying the relation between the five component means, and some of them impose a constraint on the mixing proportions to conform to Hardy-Weinberg equilibrium (HWE) ratios. The software rejects markers that do not allow a reliable genotyping for the majority of the samples, and it assigns a missing score to samples that cannot be scored into one of the five possible genotypes with sufficient confidence. CONCLUSIONS: We have validated the software with data of a collection of 224 potato varieties assayed with an Illumina GoldenGateTM 384 SNP array and shown that all SNPs with informative ratio distributions are fitted. Almost all fitted models appear to be correct based on visual inspection and comparison with diploid samples. When the collection of potato varieties is analyzed as if it were a population, almost all markers seem to be in Hardy Weinberg equilibrium. The R package fitTetra is freely available under the GNU Public License from http://www.plantbreeding.wur.nl/UK/software_fitTetra.html and as Additional files with this article. PMID- 21595881 TI - Chemical Entity Semantic Specification: Knowledge representation for efficient semantic cheminformatics and facile data integration. AB - BACKGROUND: Over the past several centuries, chemistry has permeated virtually every facet of human lifestyle, enriching fields as diverse as medicine, agriculture, manufacturing, warfare, and electronics, among numerous others. Unfortunately, application-specific, incompatible chemical information formats and representation strategies have emerged as a result of such diverse adoption of chemistry. Although a number of efforts have been dedicated to unifying the computational representation of chemical information, disparities between the various chemical databases still persist and stand in the way of cross-domain, interdisciplinary investigations. Through a common syntax and formal semantics, Semantic Web technology offers the ability to accurately represent, integrate, reason about and query across diverse chemical information. RESULTS: Here we specify and implement the Chemical Entity Semantic Specification (CHESS) for the representation of polyatomic chemical entities, their substructures, bonds, atoms, and reactions using Semantic Web technologies. CHESS provides means to capture aspects of their corresponding chemical descriptors, connectivity, functional composition, and geometric structure while specifying mechanisms for data provenance. We demonstrate that using our readily extensible specification, it is possible to efficiently integrate multiple disparate chemical data sources, while retaining appropriate correspondence of chemical descriptors, with very little additional effort. We demonstrate the impact of some of our representational decisions on the performance of chemically-aware knowledgebase searching and rudimentary reaction candidate selection. Finally, we provide access to the tools necessary to carry out chemical entity encoding in CHESS, along with a sample knowledgebase. CONCLUSIONS: By harnessing the power of Semantic Web technologies with CHESS, it is possible to provide a means of facile cross-domain chemical knowledge integration with full preservation of data correspondence and provenance. Our representation builds on existing cheminformatics technologies and, by the virtue of RDF specification, remains flexible and amenable to application- and domain-specific annotations without compromising chemical data integration. We conclude that the adoption of a consistent and semantically-enabled chemical specification is imperative for surviving the coming chemical data deluge and supporting systems science research. PMID- 21595882 TI - Extracranial propagation of glioblastoma with extension to pterygomaxillar fossa. AB - BACKGROUND: Glioblastoma multiforme is a highly malignant primary brain tumor that shows marked local aggressiveness, but extracranial spread is not a common occurrence. We present an unusual case of recurrent glioblastoma in 54-year old male that spread through the scull base to the ethmoid and sphenoid sinuses, to the orbita, pterygomaxillar fossa, and to the neck. METHODS: A 54-year old male underwent left temporal resection because of brain tumor of his left temporal lobe. Operation was followed by external beam radiation combined with temozolomide. The tumor recurred eight months after first surgery. The patient developed swelling of left temporal region, difficult swallowing and headache. MRI of head showed recurrent tumor, which invaded orbita, ethmoid and sphenoid sinuses, nasal cavity, pterygomaxillar fossa. RESULTS: The patient died ten months after initial diagnosis of glioblastoma multiforme, and two months after his second operation. CONCLUSIONS: The aggressive surgical operation helped to downsize the tumor mass as much as possible, but did not prolonged significantly the life or improved the life quality of the patient. The current literature is reviewed, and the diagnostic approaches as well as therapeutic options are discussed. PMID- 21595883 TI - Analysis and design of randomised clinical trials involving competing risks endpoints. AB - BACKGROUND: In randomised clinical trials involving time-to-event outcomes, the failures concerned may be events of an entirely different nature and as such define a classical competing risks framework. In designing and analysing clinical trials involving such endpoints, it is important to account for the competing events, and evaluate how each contributes to the overall failure. An appropriate choice of statistical model is important for adequate determination of sample size. METHODS: We describe how competing events may be summarised in such trials using cumulative incidence functions and Gray's test. The statistical modelling of competing events using proportional cause-specific and subdistribution hazard functions, and the corresponding procedures for sample size estimation are outlined. These are illustrated using data from a randomised clinical trial (SQNP01) of patients with advanced (non-metastatic) nasopharyngeal cancer. RESULTS: In this trial, treatment has no effect on the competing event of loco regional recurrence. Thus the effects of treatment on the hazard of distant metastasis were similar via both the cause-specific (unadjusted csHR = 0.43, 95% CI 0.25 - 0.72) and subdistribution (unadjusted subHR 0.43; 95% CI 0.25 - 0.76) hazard analyses, in favour of concurrent chemo-radiotherapy followed by adjuvant chemotherapy. Adjusting for nodal status and tumour size did not alter the results. The results of the logrank test (p = 0.002) comparing the cause-specific hazards and the Gray's test (p = 0.003) comparing the cumulative incidences also led to the same conclusion. However, the subdistribution hazard analysis requires many more subjects than the cause-specific hazard analysis to detect the same magnitude of effect. CONCLUSIONS: The cause-specific hazard analysis is appropriate for analysing competing risks outcomes when treatment has no effect on the cause-specific hazard of the competing event. It requires fewer subjects than the subdistribution hazard analysis for a similar effect size. However, if the main and competing events are influenced in opposing directions by an intervention, a subdistribution hazard analysis may be warranted. PMID- 21595884 TI - ShRNA-mediated gene silencing of MTA1 influenced on protein expression of ER alpha, MMP-9, CyclinD1 and invasiveness, proliferation in breast cancer cell lines MDA-MB-231 and MCF-7 in vitro. AB - BACKGROUND: MTA1(metastasis associated-1) is a tumor metastasis associated candidate gene and overexpression in many human tumors, including breast cancer. In this study, we investigated depressive effect on MTA1 by MTA1-specific short hairpin RNA(shRNA) expression plasmids in human breast cancer cell lines MDA-MB 231 and MCF-7, and effect on protein levels of ER alpha, MMP-9, cyclinD1, and tumor cell invasion, proliferation. METHODS: ShRNA expression vectors targeting MTA1 was constructed and transfected into human breast cancer cell lines MDA-MB 231 and MCF-7. The transfection efficiency was evaluated by fluorescence microscopy, mRNA levels of MTA1 were detected by reverse transcription-polymerase chain reaction (RT-PCR), protein levels of ER alpha, MMP-9 and cyclinD1 were detected by Western blotting, respectively. Tumor cells invasive ability were evaluated by Boyden chamber assay, the cells proliferation were evaluated using cell growth curve and MTT analysis, the cell cycle analysis was performed using flow cytometry. RESULTS: Down-regulation of MTA1 by RNAi approach led to re expression of ER alpha in ER-negative breast cancer cell lines MDA-MB-231, and reduced protein levels of MMP-9 and CyclinD1, as well as decreased tumor cell invasion and proliferation, more cells were blocked in G0/G1 stage(P < 0.05). However, after inhibiting mRNA levels of MTA1, protein expression of ER alpha, MMP-9, cyclinD1 and the changes of cancer cells invasiveness, proliferation, cells cycle were no statistical difference in ER-positive human breast cancer cell lines MCF-7 (P > 0.05). CONCLUSIONS: ShRNA targeted against MTA1 could specifically mediate the MTA1 gene silencing and consequentially recover the protein expression of ER alpha, resulting in increase sensitivity of antiestrogens, as well as suppress the protein levels of MMP-9 and cyclinD1 in ER negative human breast cancer cell lines MDA-MB-231. Silencing effect of MTA1 could efficiently inhibit the invasion and proliferation in MDA-MB-231 cells. The shRNA interference targeted against MTA1 may have potential therapeutic utility in human breast cancer. PMID- 21595887 TI - The EVIDEM framework and its usefulness for priority setting across a broad range of health interventions. PMID- 21595886 TI - IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. AB - BACKGROUND: Although the cellular mechanisms responsible for the pathogenesis of autism are not understood, a growing number of studies have suggested that localized inflammation of the central nervous system (CNS) may contribute to the development of autism. Recent evidence shows that IL-6 has a crucial role in the development and plasticity of CNS. METHODS: Immunohistochemistry studies were employed to detect the IL-6 expression in the cerebellum of study subjects. In vitro adenoviral gene delivery approach was used to over-express IL-6 in cultured cerebellar granule cells. Cell adhesion and migration assays, DiI labeling, TO PRO-3 staining and immunofluorescence were used to examine cell adhesion and migration, dendritic spine morphology, cell apoptosis and synaptic protein expression respectively. RESULTS: In this study, we found that IL-6 was significantly increased in the cerebellum of autistic subjects. We investigated how IL-6 affects neural cell development and function by transfecting cultured mouse cerebellar granule cells with an IL-6 viral expression vector. We demonstrated that IL-6 over-expression in granule cells caused impairments in granule cell adhesion and migration but had little effect on the formation of dendritic spines or granule cell apoptosis. However, IL-6 over-expression stimulated the formation of granule cell excitatory synapses, without affecting inhibitory synapses. CONCLUSIONS: Our results provide further evidence that aberrant IL-6 may be associated with autism. In addition, our results suggest that the elevated IL-6 in the autistic brain could alter neural cell adhesion, migration and also cause an imbalance of excitatory and inhibitory circuits. Thus, increased IL-6 expression may be partially responsible for the pathogenesis of autism. PMID- 21595888 TI - Validation of the conceptual research utilization scale: an application of the standards for educational and psychological testing in healthcare. AB - BACKGROUND: There is a lack of acceptable, reliable, and valid survey instruments to measure conceptual research utilization (CRU). In this study, we investigated the psychometric properties of a newly developed scale (the CRU Scale). METHODS: We used the Standards for Educational and Psychological Testing as a validation framework to assess four sources of validity evidence: content, response processes, internal structure, and relations to other variables. A panel of nine international research utilization experts performed a formal content validity assessment. To determine response process validity, we conducted a series of one on-one scale administration sessions with 10 healthcare aides. Internal structure and relations to other variables validity was examined using CRU Scale response data from a sample of 707 healthcare aides working in 30 urban Canadian nursing homes. Principal components analysis and confirmatory factor analyses were conducted to determine internal structure. Relations to other variables were examined using: (1) bivariate correlations; (2) change in mean values of CRU with increasing levels of other kinds of research utilization; and (3) multivariate linear regression. RESULTS: Content validity index scores for the five items ranged from 0.55 to 1.00. The principal components analysis predicted a 5-item 1 factor model. This was inconsistent with the findings from the confirmatory factor analysis, which showed best fit for a 4-item 1-factor model. Bivariate associations between CRU and other kinds of research utilization were statistically significant (p < 0.01) for the latent CRU scale score and all five CRU items. The CRU scale score was also shown to be significant predictor of overall research utilization in multivariate linear regression. CONCLUSIONS: The CRU scale showed acceptable initial psychometric properties with respect to responses from healthcare aides in nursing homes. Based on our validity, reliability, and acceptability analyses, we recommend using a reduced (four-item) version of the CRU scale to yield sound assessments of CRU by healthcare aides. Refinement to the wording of one item is also needed. Planned future research will include: latent scale scoring, identification of variables that predict and are outcomes to conceptual research use, and longitudinal work to determine CRU Scale sensitivity to change. PMID- 21595889 TI - Mesozoic fossils (>145 Mya) suggest the antiquity of the subgenera of Daphnia and their coevolution with chaoborid predators. AB - BACKGROUND: The timescale of the origins of Daphnia O. F. Mueller (Crustacea: Cladocera) remains controversial. The origin of the two main subgenera has been associated with the breakup of the supercontinent Pangaea. This vicariance hypothesis is supported by reciprocal monophyly, present day associations with the former Gondwanaland and Laurasia regions, and mitochondrial DNA divergence estimates. However, previous multilocus nuclear DNA sequence divergence estimates at < 10 Million years are inconsistent with the breakup of Pangaea. We examined new and existing cladoceran fossils from a Mesozoic Mongolian site, in hopes of gaining insights into the timescale of the evolution of Daphnia. RESULTS: We describe new fossils of ephippia from the Khotont site in Mongolia associated with the Jurassic-Cretaceous boundary (about 145 MYA) that are morphologically similar to several modern genera of the family Daphniidae, including the two major subgenera of Daphnia, i.e., Daphnia s. str. and Ctenodaphnia. The daphniid fossils co-occurred with fossils of the predaceous phantom midge (Chaoboridae). CONCLUSIONS: Our findings indicate that the main subgenera of Daphnia are likely much older than previously known from fossils (at least 100 MY older) or from nuclear DNA estimates of divergence. The results showing co-occurrence of the main subgenera far from the presumed Laurasia/Gondwanaland dispersal barrier shortly after formation suggests that vicariance from the breakup of Pangaea is an unlikely explanation for the origin of the main subgenera. The fossil impressions also reveal that the coevolution of a dipteran predator (Chaoboridae) with the subgenus Daphnia is much older than previously known -- since the Mesozoic. PMID- 21595885 TI - Congenital neutropenia: diagnosis, molecular bases and patient management. AB - The term congenital neutropenia encompasses a family of neutropenic disorders, both permanent and intermittent, severe (<0.5 G/l) or mild (between 0.5-1.5 G/l), which may also affect other organ systems such as the pancreas, central nervous system, heart, muscle and skin. Neutropenia can lead to life-threatening pyogenic infections, acute gingivostomatitis and chronic parodontal disease, and each successive infection may leave permanent sequelae. The risk of infection is roughly inversely proportional to the circulating polymorphonuclear neutrophil count and is particularly high at counts below 0.2 G/l.When neutropenia is detected, an attempt should be made to establish the etiology, distinguishing between acquired forms (the most frequent, including post viral neutropenia and auto immune neutropenia) and congenital forms that may either be isolated or part of a complex genetic disease.Except for ethnic neutropenia, which is a frequent but mild congenital form, probably with polygenic inheritance, all other forms of congenital neutropenia are extremely rare and have monogenic inheritance, which may be X-linked or autosomal, recessive or dominant.About half the forms of congenital neutropenia with no extra-hematopoietic manifestations and normal adaptive immunity are due to neutrophil elastase (ELANE) mutations. Some patients have severe permanent neutropenia and frequent infections early in life, while others have mild intermittent neutropenia.Congenital neutropenia may also be associated with a wide range of organ dysfunctions, as for example in Shwachman Diamond syndrome (associated with pancreatic insufficiency) and glycogen storage disease type Ib (associated with a glycogen storage syndrome). So far, the molecular bases of 12 neutropenic disorders have been identified.Treatment of severe chronic neutropenia should focus on prevention of infections. It includes antimicrobial prophylaxis, generally with trimethoprim-sulfamethoxazole, and also granulocyte-colony-stimulating factor (G-CSF). G-CSF has considerably improved these patients' outlook. It is usually well tolerated, but potential adverse effects include thrombocytopenia, glomerulonephritis, vasculitis and osteoporosis. Long-term treatment with G-CSF, especially at high doses, augments the spontaneous risk of leukemia in patients with congenital neutropenia. PMID- 21595890 TI - Modification of stool's water content in constipated infants: management with an adapted infant formula. AB - BACKGROUND: Constipation is a common occurrence in formula-fed infants. The aim of this preliminary study was to evaluate the impact of a formula with high levels of lactose and magnesium, in compliance with the official regulations, on stool water content, as well as a parental assessment of constipation. MATERIALS AND METHODS: Thirty healthy term-born, formula-fed infants, aged 4-10 weeks, with functional constipation were included. All infants were full-term and fed standard formula. Exclusion criteria were preterm and/or low birth weight, organic constipation, being breast fed or fed a formula specially designed to treat constipation. Stool composition was measured by near-infrared reflectance analysis (NIRA) and parents answered questions about crying associated with defecation and stool consistency at baseline and after two weeks of the adapted formula. RESULTS: After 2 weeks of the adapted formula, stool water content increased from 71 +/- 8.1% to 84 +/- 5.9%, (p < 0.02). There was no significant change in the stool's fat, protein or carbohydrate content. Parental impressions of constipation were improved with the decrease in stool hardness (100% with hard stools at baseline, 10% after 2 weeks), pain with defecation (90% at baseline, 10% after 2 weeks), and the requirement for rectal stimulation to achieve defecation (70% at baseline, 30% after 2 weeks, p < 0.001 for all three indicators). CONCLUSIONS: This preliminary study suggests that an adapted formula with high levels of lactose and magnesium increases stool water content and improves symptoms of constipation in term-born, formula-fed infants. A larger randomized placebo-controlled trial is indicated. PMID- 21595891 TI - Composition of fatty acids in plasma and erythrocytes and eicosanoids level in patients with metabolic syndrome. AB - BACKGROUND: Disturbances of the fatty acids composition in plasma and red blood cells and eicosanoid synthesis play an important role in the metabolic syndrome (MS) formation. METHODS: The observation group included 61 people with metabolic syndrome (30 patients with MS and normal levels of insulin, 31 people with MS and insulin resistance--IR). The parameters of carbohydrate and lipid metabolism in blood serum were examined. The composition of nonesterified fatty acids (NEFA), fatty acid (FA) of red blood cells lipids was analyzed by gas-liquid chromatography. Eicosanoids level in MS patients blood serum was studied by enzyme immunoassay. RESULTS: In MS patients in the absence of glucose-insulin homeostasis disturbances and in patients with IR the accumulation of polyunsaturated fatty acids (18:2 n6, 18:3 n3, 22:4 n6) and lower pool of saturated FA (12:0, 14:0, 16: 0, 17:0) in plasma were discovered. A deficit of polyunsaturated FA (18:3 n3, 20:4 n6) with a predominance of on-saturated FA (14:0, 18:0) in erythrocyte membranes was revealed. In MS patients regardless of the carbohydrate metabolism status high levels of leukotriene B4 and 6-keto prostaglandin-F1alpha in serum were found. The development of IR in MS patients leads to increased synthesis of thromboxane A2. CONCLUSION: The results revealed a disturbance in nonesterified fatty acids of plasma lipids and red blood cells, eicosanoid synthesis in MS patients. The breach of the plasma and cell membranes fatty acids compositions, synthesis of vasoactive and proinflammatory eicosanoids is an important pathogenetic part of the MS development. PMID- 21595892 TI - Low doses of 3-aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, stimulate angiogenesis by regulating expression of urokinase type plasminogen activator and matrix metalloprotease 2. AB - BACKGROUND: Poly(ADP-Ribose) polymerase (PARP) activity has been demonstrated fundamental in many cellular processes, including DNA repair, cell proliferation and differentiation. In particular, PARP activity has been recently found to affect proliferation, migration, and tube formation of human umbilical vein endothelial cells. In recent times, PARP inhibitors have entered in clinical trials to potentiate cancer treatments by preventing DNA repair, but little is known about the effects performed by different drug concentrations on neoangiogenesis, an essential step in tumor growth. METHODS: Human umbilical vein endothelial cells were treated with 3 aminobenzamide (3ABA), a PARP inhibitor, and tested for several different cellular parameters. RESULTS: Here we present in vitro evidence that a low concentration of 3ABA (50 MUM), stimulates angiogenesis by decreasing fibrinolytic activity, carried out by urokinase-type plasminogen activator (uPA), and by enhancing matrix metalloprotease-2 (MMP-2) gelatinolytic activity, in fibroblast growth factor-2-stimulated endothelial cells. These unbalanced pathways modify in vitro angiogenic steps, inhibiting chemoinvasion and stimulating tubulogenic activity. CONCLUSIONS: Our results suggest that the proangiogenic effect of low concentrations of 3ABA alerts on the efficacy of PARP inhibitors to potentiate anticancer therapy. Moreover, they indicate that endothelial chemoinvasion and tubulogenesis depend on distinct proteolytic pathways. PMID- 21595893 TI - A multiple antibiotic and serum resistant oligotrophic strain, Klebsiella pneumoniae MB45 having novel dfrA30, is sensitive to ZnO QDs. AB - BACKGROUND: The aim of this study was to describe a novel trimethoprim resistance gene cassette, designated dfrA30, within a class 1 integron in a facultatively oligotrophic, multiple antibiotic and human serum resistant test strain, MB45, in a population of oligotrophic bacteria isolated from the river Mahananda; and to test the efficiency of surface bound acetate on zinc oxide quantum dots (ZnO QDs) as bactericidal agent on MB45. METHODS: Diluted Luria broth/Agar (10-3) media was used to cultivate the oligotrophic bacteria from water sample. Multiple antibiotic resistant bacteria were selected by employing replica plate method. A rapid assay was performed to determine the sensitivity/resistance of the test strain to human serum. Variable region of class 1 integron was cloned, sequenced and the expression of gene coding for antibiotic resistance was done in Escherichia coli JM 109. Identity of culture was determined by biochemical phenotyping and 16S rRNA gene sequence analyses. A phylogenetic tree was constructed based on representative trimethoprim resistance-mediating DfrA proteins retrieved from GenBank. Growth kinetic studies for the strain MB45 were performed in presence of varied concentrations of ZnO QDs. RESULTS AND CONCLUSIONS: The facultatively oligotrophic strain, MB45, resistant to human serum and ten antibiotics trimethoprim, cotrimoxazole, ampicillin, gentamycin, netilmicin, tobramycin, chloramphenicol, cefotaxime, kanamycin and streptomycin, has been identified as a new strain of Klebsiella pneumoniae. A novel dfr gene, designated as dfrA30, found integrated in class 1 integron was responsible for resistance to trimethoprim in Klebsiella pneumoniae strain MB45. The growth of wild strain MB45 was 100% arrested at 500 mg/L concentration of ZnO QDs. To our knowledge this is the first report on application of ZnO quantum dots to kill multiple antibiotics and serum resistant K. pneumoniae strain. PMID- 21595894 TI - Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes. AB - INTRODUCTION: Insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) is phosphorylated in all breast cancer subtypes. Past findings have shown that IGF 1R mediates antiestrogen resistance through cross-talk with estrogen receptor (ER) signaling and via its action upstream of the epidermal growth factor receptor and human epidermal growth factor receptor 2. Yet, the direct role of IGF-1R signaling itself in antiestrogen resistance remains obscure. In the present study, we sought to elucidate whether antiestrogen resistance is induced directly by IGF-1R signaling in response to its ligand IGF-1 stimulation. METHODS: A breast cancer cell line ectopically expressing human wild-type IGF-1R, MCF7/IGF-1R, was established by retroviral transduction and colony selection. Cellular antiestrogen sensitivity was evaluated under estrogen-depleted two dimensional (2D) and 3D culture conditions. Functional activities of the key IGF 1R signaling components in antiestrogen resistance were assessed by specific kinase inhibitor compounds and small interfering RNA. RESULTS: Ectopic expression of IGF-1R in ER-positive MCF7 human breast cancer cells enhanced IGF-1R tyrosine kinase signaling in response to IGF-1 ligand stimulation. The elevated IGF-1R signaling rendered MCF7/IGF-1R cells highly resistant to the antiestrogens tamoxifen and fulvestrant. This antiestrogen-resistant phenotype involved mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase/protein kinase B pathways downstream of the IGF-1R signaling hub and was independent of ER signaling. Intriguingly, a MAPK/ERK dependent agonistic behavior of tamoxifen at low doses was triggered in the presence of IGF-1, showing a mild promitogenic effect and increasing ER transcriptional activity. CONCLUSIONS: Our data provide evidence that the IGF 1/IGF-1R signaling axis may play a causal role in antiestrogen resistance of breast cancer cells, despite continuous suppression of ER transcriptional function by antiestrogens. PMID- 21595895 TI - If the data contradict the theory, throw out the data: Nicotine addiction in the 2010 report of the Surgeon General. AB - The reports of US Surgeon General on smoking are considered the authoritative statement on the scientific state of the art in this field. The previous report on nicotine addiction published in 1988 is one of the most cited references in scientific articles on smoking and often the only citation provided for specific statements of facts regarding nicotine addiction. In this commentary we review the chapter on nicotine addiction presented in the recent report of the Surgeon General. We show that the nicotine addiction model presented in this chapter, which closely resembles its 22 years old predecessor, could only be sustained by systematically ignoring all contradictory evidence. As a result, the present SG's chapter on nicotine addiction, which purportedly "documents how nicotine compares with heroin and cocaine in its hold on users and its effects on the brain," is remarkably biased and misleading. PMID- 21595896 TI - Protein kinase A-dependent neuronal nitric oxide synthase activation mediates the enhancement of baroreflex response by adrenomedullin in the nucleus tractus solitarii of rats. AB - BACKGROUND: Adrenomedullin (ADM) exerts its biological functions through the receptor-mediated enzymatic mechanisms that involve protein kinase A (PKA), or neuronal nitric oxide synthase (nNOS). We previously demonstrated that the receptor-mediated cAMP/PKA pathway involves in ADM-enhanced baroreceptor reflex (BRR) response. It remains unclear whether ADM may enhance BRR response via activation of nNOS-dependent mechanism in the nucleus tractus solitarii (NTS). METHODS: Intravenous injection of phenylephrine was administered to evoke the BRR before and at 10, 30, and 60 min after microinjection of the test agents into NTS of Sprague-Dawley rats. Western blotting analysis was used to measure the level and phosphorylation of proteins that involved in BRR-enhancing effects of ADM (0.2 pmol) in NTS. The colocalization of PKA and nNOS was examined by immunohistochemical staining and observed with a laser confocal microscope. RESULTS: We found that ADM-induced enhancement of BRR response was blunted by microinjection of NPLA or Rp-8-Br-cGMP, a selective inhibitor of nNOS or protein kinase G (PKG) respectively, into NTS. Western blot analysis further revealed that ADM induced an increase in the protein level of PKG-I which could be attenuated by co-microinjection with the ADM receptor antagonist ADM22-52 or NPLA. Moreover, we observed an increase in phosphorylation at Ser1416 of nNOS at 10, 30, and 60 min after intra-NTS administration of ADM. As such, nNOS/PKG signaling may also account for the enhancing effect of ADM on BRR response. Interestingly, biochemical evidence further showed that ADM-induced increase of nNOS phosphorylation was prevented by co-microinjection with Rp-8-Br-cAMP, a PKA inhibitor. The possibility of PKA-dependent nNOS activation was substantiated by immunohistochemical demonstration of co-localization of PKA and nNOS in putative NTS neurons. CONCLUSIONS: The novel finding of this study is that the signal transduction cascade that underlies the enhancement of BRR response by ADM in NTS is composed sequentially of cAMP/PKA and nNOS/PKG pathways. PMID- 21595897 TI - Married women's decision making power on modern contraceptive use in urban and rural southern Ethiopia. AB - BACKGROUND: Women in developing countries are either under collective decision making with their partners or completely rely on the male partner's decision on issues that affect their reproductive live. Identifying the major barriers of married women's decision making power on contraceptive use has significant relevance for planning contextually appropriate family planning interventions. The objective of this study was to determine current modern contraceptive practices and decision making power among married women in Tercha Town and surrounding rural areas of Dawro zone, Southern Ethiopia. METHODS: Community based comparative cross-sectional design with both quantitative and Qualitative study has been employed in March and April 2010. The respondents were 699 married women of child bearing age from urban and rural parts of Dawro zone. After conducting census, we took the sample using simple random sampling technique. RESULTS: Current modern contraceptive use among married women in the urban was 293 (87.5%) and 243 (72.8%) in rural. Married women who reside in urban area were more likely to decide on the use of modern contraceptive method than rural women. Having better knowledge about modern contraceptive methods, gender equitable attitude, better involvement in decisions related to children, socio-cultural and family relations were statistically significant factors for decision making power of women on the use of modern contraceptive methods in the urban setting. Better knowledge, fear of partner's opposition or negligence, involvement in decisions about child and economic affairs were statistically significant factors for better decision making power of women on the use of modern contraceptive methods in the rural part. CONCLUSIONS: High level of current modern contraceptive practice with reduced urban-rural difference was found as compared to regional and national figures. Urban women had better power to make decisions on modern contraceptive than rural women. Modern family planning interventions in the area should be promoted by considering empowering of women on modern contraceptive use decision making. PMID- 21595898 TI - Identification of malaria transmission and epidemic hotspots in the western Kenya highlands: its application to malaria epidemic prediction. AB - BACKGROUND: Malaria in the western Kenya highlands is characterized by unstable and high transmission variability which results in epidemics during periods of suitable climatic conditions. The sensitivity of a site to malaria epidemics depends on the level of immunity of the human population. This study examined how terrain in the highlands affects exposure and sensitivity of a site to malaria. METHODS: The study was conducted in five sites in the western Kenya highlands, two U-shaped valleys (Iguhu, Emutete), two V-shaped valleys (Marani, Fort-Ternan) and one plateau (Shikondi) for 16 months among 6-15 years old children. Exposure to malaria was tested using circum-sporozoite protein (CSP) and merozoite surface protein (MSP) immunochromatographic antibody tests; malaria infections were tested by microscopic examination of thick and thin smears, the children's homes were georeferenced using a global positioning system. Paired t-test was used to compare the mean prevalence rates of the sites, K-function was use to determine if the clustering of malaria infections was significant. RESULTS AND DISCUSSION: The mean antibody prevalence was 22.6% in Iguhu, 24% in Emutete, 11.5% in Shikondi, 8.3% in Fort-Ternan and 9.3% in Marani. The mean malaria infection prevalence was 23.3% in Iguhu, 21.9% in Emutete, 4.7% in Shikondi, 2.9% in Fort Ternan and 2.4% in Marani. There was a significant difference in the antibodies and malaria infection prevalence between the two valley systems, and between the two valley systems and the plateau (P < 0.05). There was no significant difference in the antibodies and malaria infection prevalence in the two U-shaped valleys (Iguhu and Emutete) and in the V-shaped valleys (Marani and Fort Ternan) (P > 0.05). There was 8.5- fold and a 2-fold greater parasite and antibody prevalence respectively, in the U-shaped compared to the V-shaped valleys. The plateau antibody and parasite prevalence was similar to that of the V-shaped valleys. There was clustering of malaria antibodies and infections around flat areas in the U-shaped valleys, the infections were randomly distributed in the V shaped valleys and less clustered at the plateau. CONCLUSION: This study showed that the V-shaped ecosystems have very low malaria prevalence and few individuals with an immune response to two major malaria antigens and they can be considered as epidemic hotspots. These populations are at higher risk of severe forms of malaria during hyper-transmission seasons. The plateau ecosystem has a similar infection and immune response to the V-shaped ecosystems. The U-shaped ecosystems are transmission hotspots. PMID- 21595899 TI - Body weight, weight perceptions and food intake patterns. A cross-sectional study among male recruits in the Norwegian National Guard. AB - BACKGROUND: Young men tend to have a low intake of vegetables and fruit. Unfortunately, this group is difficult to reach with health information. Furthermore, knowledge about weight perceptions and the relationship to food behaviour among young men is scant. The purpose of this study was to explore the relationship between BMI, health and weight perceptions and food intake patterns among young men in the military. METHODS: Data were collected with a 4-day food diary among 578 male recruits (age 18-26, mean 19.7) in the Norwegian National Guard (response rate 78%), in addition to a questionnaire, including questions about health and weight perceptions, and food frequency when still living at home. Weight and height were objectively measured. Food patterns were explored with principal component analysis, based on the diary data. A multivariate linear regression analysis determined the association between BMI and food patterns, and attitudes to health and slenderness, adjusting for smoking, physical activity and phase of data collection. RESULTS: Twenty eight percent of the recruits were overweight/obese (BMI > 25 kg/m(2)). Two-thirds meant that it is important for them to be slender, and these recruits reported more of both light (p = 0.025) and hard (p = 0.016) physical activity than the others. It was a positive association between the recruits' food frequency at home, and the amount of intake in the military camp for several food items. A principal component analysis identified three distinct food patterns, loading on 1) plant foods, 2) fast food/soft drinks, 3) milk/cereals. Those who stated that it is important for them to be slender, or to have good health, did not have significantly different food intake patterns than the others. BMI was inversely related to scores on the plant food pattern, and positive attitudes to slenderness. CONCLUSION: The majority of the recruits find it important to be slender. This orientation had a bearing on their physical activity pattern, but less on the food intake pattern. The data also indicate that subjects with high intakes of plant foods were less likely to have a high BMI than others. It is important to raise awareness of healthy eating in young men. PMID- 21595900 TI - Massive right hemothorax as the source of hemorrhagic shock after laparoscopic cholecystectomy - case report of a rare intraoperative complication. AB - A 62-year old man was referred to our institution in hemorrhagic shock after a laparoscopic cholecystectomy for acute cholecystitis, performed at an outside hospital. A chest X-ray revealed a right-sided massive pleural effusion. Urgent surgical exploration was performed through a video-assisted mini-thoracotomy which revealed active bleeding from a pleural adherence. Successful hemostasis was achieved intraoperatively and the patient had an uneventful recovery. In absence of intra-abdominal hemorrhage, a hemothorax should be considered as a potential source of major bleeding in patients who develop symptoms of hypovolemia after laparoscopic surgery. PMID- 21595901 TI - Mechanistic indicators of childhood asthma (MICA) study: piloting an integrative design for evaluating environmental health. AB - BACKGROUND: Asthma is a common complex disease responsible for considerable morbidity and mortality, particularly in urban minority populations. The Mechanistic Indicators of Childhood Asthma study was designed to pilot an integrative approach in children's health research. The study incorporates exposure metrics, internal dose measures, and clinical indicators to decipher the biological complexity inherent in diseases such as asthma and cardiovascular disease with etiology related to gene-environment interactions. METHODS/DESIGN: 205 non-asthmatic and asthmatic children, (9-12 years of age) from Detroit, Michigan were recruited. The study includes environmental measures (indoor and outdoor air, vacuum dust), biomarkers of exposure (cotinine, metals, total and allergen specific Immunoglobulin E, polycyclic aromatic hydrocarbons, volatile organic carbon metabolites) and clinical indicators of health outcome (immunological, cardiovascular and respiratory). In addition, blood gene expression and candidate SNP analyses were conducted. DISCUSSION: Based on an integrative design, the MICA study provides an opportunity to evaluate complex relationships between environmental factors, physiological biomarkers, genetic susceptibility and health outcomes. PROJECT APPROVAL: IRB Number 05-EPA-2637: The human subjects' research protocol was reviewed by the Institutional Review Board (IRB) of the University of North Carolina; the IRB of Westat, Inc., the IRB of the Henry Ford Health System; and EPA's Human Subjects' Research Review Official. PMID- 21595902 TI - Community mobilisation and health management committee strengthening to increase birth attendance by trained health workers in rural Makwanpur, Nepal: study protocol for a cluster randomised controlled trial. AB - BACKGROUND: Birth attendance by trained health workers is low in rural Nepal. Local participation in improving health services and increased interaction between health systems and communities may stimulate demand for health services. Significant increases in birth attendance by trained health workers may be affected through community mobilisation by local women's groups and health management committee strengthening. We will test the effect of community mobilisation through women's groups, and health management committee strengthening, on institutional deliveries and home deliveries attended by trained health workers in Makwanpur District. DESIGN: Cluster randomised controlled trial involving 43 village development committee clusters. 21 clusters will receive the intervention and 22 clusters will serve as control areas. In intervention areas, Female Community Health Volunteers are supported in convening monthly women's groups. The groups work through an action research cycle in which they consider barriers to institutional delivery, plan and implement strategies to address these barriers with their communities, and evaluate their progress. Health management committees participate in three-day workshops that use appreciative inquiry methods to explore and plan ways to improve maternal and newborn health services. Follow-up meetings are conducted every three months to review progress. Primary outcomes are institutional deliveries and home deliveries conducted by trained health workers. Secondary outcome measures include uptake of antenatal and postnatal care, neonatal mortality and stillbirth rates, and maternal morbidity. TRIAL REGISTRATION NUMBER: ISRCTN99834806. PMID- 21595903 TI - The evolution of plasmid-carried antibiotic resistance. AB - BACKGROUND: Antibiotic resistance represents a significant public health problem. When resistance genes are mobile, being carried on plasmids or phages, their spread can be greatly accelerated. Plasmids in particular have been implicated in the spread of antibiotic resistance genes. However, the selective pressures which favour plasmid-carried resistance genes have not been fully established. Here we address this issue with mathematical models of plasmid dynamics in response to different antibiotic treatment regimes. RESULTS: We show that transmission of plasmids is a key factor influencing plasmid-borne antibiotic resistance, but the dosage and interval between treatments is also important. Our results also hold when plasmids carrying the resistance gene are in competition with other plasmids that do not carry the resistance gene. By altering the interval between antibiotic treatments, and the dosage of antibiotic, we show that different treatment regimes can select for either plasmid-carried, or chromosome-carried, resistance. CONCLUSIONS: Our research addresses the effect of environmental variation on the evolution of plasmid-carried antibiotic resistance. PMID- 21595905 TI - Harmonisation of variables names prior to conducting statistical analyses with multiple datasets: an automated approach. AB - BACKGROUND: Data requirements by governments, donors and the international community to measure health and development achievements have increased in the last decade. Datasets produced in surveys conducted in several countries and years are often combined to analyse time trends and geographical patterns of demographic and health related indicators. However, since not all datasets have the same structure, variables definitions and codes, they have to be harmonised prior to submitting them to the statistical analyses. Manually searching, renaming and recoding variables are extremely tedious and prone to errors tasks, overall when the number of datasets and variables are large. This article presents an automated approach to harmonise variables names across several datasets, which optimises the search of variables, minimises manual inputs and reduces the risk of error. RESULTS: Three consecutive algorithms are applied iteratively to search for each variable of interest for the analyses in all datasets. The first search (A) captures particular cases that could not be solved in an automated way in the search iterations; the second search (B) is run if search A produced no hits and identifies variables the labels of which contain certain key terms defined by the user. If this search produces no hits, a third one (C) is run to retrieve variables which have been identified in other surveys, as an illustration. For each variable of interest, the outputs of these engines can be (O1) a single best matching variable is found, (O2) more than one matching variable is found or (O3) not matching variables are found. Output O2 is solved by user judgement. Examples using four variables are presented showing that the searches have a 100% sensitivity and specificity after a second iteration. CONCLUSION: Efficient and tested automated algorithms should be used to support the harmonisation process needed to analyse multiple datasets. This is especially relevant when the numbers of datasets or variables to be included are large. PMID- 21595904 TI - The mode and tempo of hepatitis C virus evolution within and among hosts. AB - BACKGROUND: Hepatitis C virus (HCV) is a rapidly-evolving RNA virus that establishes chronic infections in humans. Despite the virus' public health importance and a wealth of sequence data, basic aspects of HCV molecular evolution remain poorly understood. Here we investigate three sets of whole HCV genomes in order to directly compare the evolution of whole HCV genomes at different biological levels: within- and among-hosts. We use a powerful Bayesian inference framework that incorporates both among-lineage rate heterogeneity and phylogenetic uncertainty into estimates of evolutionary parameters. RESULTS: Most of the HCV genome evolves at ~0.001 substitutions/site/year, a rate typical of RNA viruses. The antigenically-important E1/E2 genome region evolves particularly quickly, with correspondingly high rates of positive selection, as inferred using two related measures. Crucially, in this region an exceptionally higher rate was observed for within-host evolution compared to among-host evolution. Conversely, higher rates of evolution were seen among-hosts for functionally relevant parts of the NS5A gene. There was also evidence for slightly higher evolutionary rate for HCV subtype 1a compared to subtype 1b. CONCLUSIONS: Using new statistical methods and comparable whole genome datasets we have quantified, for the first time, the variation in HCV evolutionary dynamics at different scales of organisation. This confirms that differences in molecular evolution between biological scales are not restricted to HIV and may represent a common feature of chronic RNA viral infection. We conclude that the elevated rate observed in the E1/E2 region during within-host evolution more likely results from the reversion of host-specific adaptations (resulting in slower long-term among-host evolution) than from the preferential transmission of slowly-evolving lineages. PMID- 21595906 TI - Successful recruitment to trials: a phased approach to opening gates and building bridges. AB - BACKGROUND: The pragmatic randomised controlled trial is widely regarded as the gold standard method for evaluating the effectiveness of health care interventions. Successful conduct of trials and generalisation of findings depends upon efficient recruitment of representative samples, which often requires the collaboration of 'gatekeepers' who mediate access to potential participants. Effective negotiation of gatekeeping is thus vital to process and outcomes of trials and the quality of evidence. Whilst relevant literature contains discussion of the problems of recruitment and gatekeeping, little is known about how recruitment can be optimised and factors leading to successful recruitment. DISCUSSION: As practised researchers with first-hand experience of gatekeeping, we were aware that some researchers recruit more effectively than others and curious about the ingredients of success. With the goal of developing practical guidance, we conducted a series of workshops with 19 expert researchers to investigate and map successful recruitment. Workshops were digitally recorded and transcribed. Analysis of discussion supported modelling of effective recruitment as a process involving three phases, each comprising two key tasks. Successful negotiation of set-up, alliance, and exchange require judicious deployment of interpersonal skills in an appropriately assertive manner. Researcher flexibility and credibility are vital for success, such that a foundation for rapprochement between the worlds of research and practice is established.Our model provides a framework to support design and implementation of recruitment activities and will enable trouble shooting and support recruitment, supervision and training of effective researchers. This, in turn will support delivery of trials on time and on budget, maximising return on investment in the production of evidence. SUMMARY: Pragmatic trials are central to development of evidence based health care but often failure to recruit the necessary sample in a timely manner means many fail or require costly extensions. Gatekeeping is implicated in this. Drawing on the knowledge of 19 expert researchers, we argue that successful researchers are resourceful and personable, judiciously deploying interpersonal skills and expertise to engage with gatekeepers and establish a shared objective. We propose that understanding recruitment as a phased process can enhance design and conduct of trials, supporting completion on time, on budget. PMID- 21595907 TI - The paratransgenic sand fly: a platform for control of Leishmania transmission. AB - BACKGROUND: Leishmania donovani is transmitted by the bite of the sand fly, Phlebotomus argentipes. This parasite is the agent of visceral leishmaniasis (VL), an endemic disease in Bihar, India, where prevention has relied mainly on DDT spraying. Pesticide resistance in sand fly populations, environmental toxicity, and limited resources confound this approach. A novel paratransgenic strategy aimed at control of vectorial transmission of L. donovani is presented using Bacillus subtilis, a commensal bacterium isolated from the sand fly gut. In this work, B. subtilis expressing Green Fluorescent Protein (GFP) was added to sterilized larval chow. Control pots contained larval chow spiked either with untransformed B. subtilis or phosphate-buffered saline. Fourth-instar P. argentipes larvae were transferred into the media and allowed to mature. The number of bacterial colony forming units, relative abundance and the mean microbial load were determined per developmental stage. RESULTS: Addition of B. subtilis to larval chow did not affect sand fly emergence rates. B. cereus and Lys fusiformis were identified at each developmental stage, revealing transstadial passage of endogenous microbes. Larvae exposed to an exogenous bolus of B. subtilis harbored significantly larger numbers of bacteria. Bacterial load decreased to a range comparable to sand flies from control pots, suggesting an upper limit to the number of bacteria harbored. Emerging flies reared in larval chow containing transformed B. subtilis carried large numbers of these bacteria in their gut lumens. Strong GFP expression was detected in these paratransgenic flies with no spread of transformed bacteria to other compartments of the insects. This is the first demonstration of paratransgenic manipulation of P. argentipes. CONCLUSIONS: Paratransgenic manipulation of P. argentipes appears feasible. Expression of leishmanicidal molecules via commensal bacteria commonly found at breeding sites of P. argentipes could render adult sand flies refractory to L. donovani infection. PMID- 21595908 TI - An analysis of single amino acid repeats as use case for application specific background models. AB - BACKGROUND: Sequence analysis aims to identify biologically relevant signals against a backdrop of functionally meaningless variation. Increasingly, it is recognized that the quality of the background model directly affects the performance of analyses. State-of-the-art approaches rely on classical sequence models that are adapted to the studied dataset. Although performing well in the analysis of globular protein domains, these models break down in regions of stronger compositional bias or low complexity. While these regions are typically filtered, there is increasing anecdotal evidence of functional roles. This motivates an exploration of more complex sequence models and application-specific approaches for the investigation of biased regions. RESULTS: Traditional Markov chains and application-specific regression models are compared using the example of predicting runs of single amino acids, a particularly simple class of biased regions. Cross-fold validation experiments reveal that the alternative regression models capture the multi-variate trends well, despite their low dimensionality and in contrast even to higher-order Markov-predictors. We show how the significance of unusual observations can be computed for such empirical models. The power of a dedicated model in the detection of biologically interesting signals is then demonstrated in an analysis identifying the unexpected enrichment of contiguous leucine-repeats in signal-peptides. Considering different reference sets, we show how the question examined actually defines what constitutes the 'background'. Results can thus be highly sensitive to the choice of appropriate model training sets. Conversely, the choice of reference data determines the questions that can be investigated in an analysis. CONCLUSIONS: Using a specific case of studying biased regions as an example, we have demonstrated that the construction of application-specific background models is both necessary and feasible in a challenging sequence analysis situation. PMID- 21595909 TI - Overexpression of human virus surface glycoprotein precursors induces cytosolic unfolded protein response in Saccharomyces cerevisiae. AB - BACKGROUND: The expression of human virus surface proteins, as well as other mammalian glycoproteins, is much more efficient in cells of higher eukaryotes rather than yeasts. The limitations to high-level expression of active viral surface glycoproteins in yeast are not well understood. To identify possible bottlenecks we performed a detailed study on overexpression of recombinant mumps hemagglutinin-neuraminidase (MuHN) and measles hemagglutinin (MeH) in yeast Saccharomyces cerevisiae, combining the analysis of recombinant proteins with a proteomic approach. RESULTS: Overexpressed recombinant MuHN and MeH proteins were present in large aggregates, were inactive and totally insoluble under native conditions. Moreover, the majority of recombinant protein was found in immature form of non-glycosylated precursors. Fractionation of yeast lysates revealed that the core of viral surface protein aggregates consists of MuHN or MeH disulfide linked multimers involving eukaryotic translation elongation factor 1A (eEF1A) and is closely associated with small heat shock proteins (sHsps) that can be removed only under denaturing conditions. Complexes of large Hsps seem to be bound to aggregate core peripherally as they can be easily removed at high salt concentrations. Proteomic analysis revealed that the accumulation of unglycosylated viral protein precursors results in specific cytosolic unfolded protein response (UPR-Cyto) in yeast cells, characterized by different action and regulation of small Hsps versus large chaperones of Hsp70, Hsp90 and Hsp110 families. In contrast to most environmental stresses, in the response to synthesis of recombinant MuHN and MeH, only the large Hsps were upregulated whereas sHsps were not. Interestingly, the amount of eEF1A was also increased during this stress response. CONCLUSIONS: Inefficient translocation of MuHN and MeH precursors through ER membrane is a bottleneck for high-level expression in yeast. Overexpression of these recombinant proteins induces the UPR's cytosolic counterpart, the UPR-Cyto, which represent a subset of proteins involved in the heat-shock response. The involvement of eEF1A may explain the mechanism by which only large chaperones, but not small Hsps are upregulated during this stress response. Our study highlights important differences between viral surface protein expression in yeast and mammalian cells at the first stage of secretory pathway. PMID- 21595910 TI - Low bone mass in microscopic colitis. AB - BACKGROUND: Microscopic colitis presents with similar symptoms to classic inflammatory bowel diseases. Osteoporosis is a common complication of Crohn's disease but there are no data concerning bone metabolism in microscopic colitis. AIMS: The aim of the present study was to evaluate bone density and metabolism in patients with microscopic colitis. METHODS: Fourteen patients microscopic colitis were included in the study, and 28 healthy persons and 28 age and gender matched Crohn's disease patients were enrolled as controls. Bone mineral density was measured using dual x-ray absorptiometry at the lumbar spine, femoral neck and the radius. Serum bone formation and bone resorption markers (osteocalcin and beta-crosslaps, respectively) were measured using immunoassays. RESULTS: Low bone mass was measured in 57.14% patients with microscopic colitis. Bone mineral density at the femoral neck in patients suffering from microscopic colitis and Crohn's disease was lower than in healthy controls (0.852 +/- 0.165 and 0.807 +/- 0.136 vs. 1.056 +/- 0.126 g/cm2; p < 0.01). Bone mineral density at the non dominant radius was decreased in microscopic colitis patients (0.565 +/- 0.093 vs. 0.667 +/- 0.072 g/cm2; p < 0.05) but unaffected in Crohn's disease patients (0.672 +/- 0.056 g/cm2). Mean beta-crosslaps concentration was higher in microscopic colitis and Crohn's disease patients than controls (417.714 +/- 250.37 and 466.071 +/- 249.96 vs. 264.75 +/- 138.65 pg/ml; p < 0.05). A negative correlation between beta-crosslaps concentration and the femoral and radius t scores was evident in microscopic colitis patients. CONCLUSIONS: Low bone mass is frequent in microscopic colitis, and alterations to bone metabolism are similar to those present in Crohn's disease. Therefore, microscopic colitis-associated osteopenia could be a significant problem in such patients. PMID- 21595911 TI - Childhood meat eating and inflammatory markers: the Guangzhou Biobank Cohort Study. AB - BACKGROUND: We hypothesized that socio-economic development could, via nutritionally driven levels of pubertal sex-steroids, promote a pro-inflammatory state among men but not women in developing countries. We tested this hypothesis, using recalled childhood meat eating as a proxy for childhood nutrition, in southern China. METHODS: We used multivariable linear regression in the Guangzhou Biobank Cohort Study phase 3 (2006-8) to examine the adjusted associations of recalled childhood meat eating, <1/week (n = 5,023), about once per week (n = 3,592) and almost daily (n = 1,252), with white blood cell count and its differentials among older (>= 50 years) men (n = 2,498) and women (n = 7,369). RESULTS: Adjusted for age, childhood socio-economic position, education and smoking, childhood meat eating had sex-specific associations with white blood cell count and lymphocyte count, but not granulocyte count. Men with childhood meat eating almost daily compared to <1/week had higher white blood cell count (0.33 109/L, 95% confidence interval (CI) 0.10 to 0.56) and higher lymphocyte count (0.16 109/L, 95% CI 0.07 to 0.25). Adjustment for obesity slightly attenuated these associations. CONCLUSION: If confirmed, this hypothesis implies that economic development and the associated improvements in nutrition at puberty may be less beneficial among men than women; consistent with the widening sex differentials in life expectancy with economic development. PMID- 21595913 TI - Bone mineral density of the proximal femur after hip resurfacing arthroplasty: 1 year follow-up study. AB - BACKGROUND: Hip resurfacing arthroplasty (HRA) is considered a bone-preserving procedure and may eliminate proximal femoral stress shielding and osteolysis. However, in addition to implant-related stress-shielding factors, various patient related factors may also have an effect on bone mineral density (BMD) of the proximal femur in patients with HRA. Thus, we studied the effects of stem-neck angle, demographic variables, and physical functioning on the BMD of the proximal femur in a one-year follow-up. METHODS: Thirty three patients (9 females and 24 males) with a mean (SD) age of 55 (9) years were included in the study. BMD was measured two days and 3, 6, and 12 months postoperatively and 10 regions of interest (ROI) were used. Stem-neck angle was analyzed from anteroposterior radiographs. RESULTS: Three months postoperatively, BMD decreased in six out of 10 regions of interest (ROI) on the side operated on and in one ROI on the control side (p<0.05) compared to the second postoperative day. At 12 months, BMD had increased in 7 ROIs on the operated side and one ROI on the control side (all p<0.001). Correlation was found between the stem-neck angle and BMD in ROIs 2, 3, 7, and 9 (r=0.36-0.61). In multiple regression analysis, stem-neck angle, age, sex, body mass index, and walking distance did not explain the BMD changes. CONCLUSIONS: After an early drop, the BMD of the upper femur was restored and even exceeded the preoperative level at one year follow-up. From a clinical standpoint, the changes in BMD in these HRA patients could not be explained by stem-neck angle or patient related factors. PMID- 21595912 TI - High rates of albuminuria but not of low eGFR in urban indigenous Australians: the DRUID study. AB - BACKGROUND: Indigenous Australians have an incidence of end stage kidney disease 8-10 times higher than non-Indigenous Australians. The majority of research studies concerning Indigenous Australians have been performed in rural or remote regions, whilst the majority of Indigenous Australians actually live in urban settings. We studied prevalence and factors associated with markers of kidney disease in an urban Indigenous Australian cohort, and compared results with those for the general Australian population. METHODS: 860 Indigenous adult participants of the Darwin Region Urban Indigenous Diabetes (DRUID) Study were assessed for albuminuria (urine albumin-creatinine ratio>=2.5 mg/mmol males, >=3.5 mg/mmol females) and low eGFR (estimated glomular filtration rate < 60 mls/min/1.73 m(2)). Associations between risk factors and kidney disease markers were explored. Comparison was made with the AusDiab cohort (n = 8,936 aged 25-64 years), representative of the general Australian adult population. RESULTS: A high prevalence of albuminuria (14.8%) was found in DRUID, whilst prevalence of low eGFR was 2.4%. Older age, higher HbA1c, hypertension, higher C-reactive protein and current smoking were independently associated with albuminuria on multiple regression. Low eGFR was independently associated with older age, hypertension, albuminuria and higher triglycerides. Compared to AusDiab participants, DRUID participants had a 3-fold higher adjusted risk of albuminuria but not of low eGFR. CONCLUSIONS: Given the significant excess of ESKD observed in Indigenous versus non-Indigenous Australians, these findings could suggest either: albuminuria may be a better prognostic marker of kidney disease than low eGFR; that eGFR equations may be inaccurate in the Indigenous population; a less marked differential between Indigenous and non-Indigenous Australians for ESKD rates in urban compared to remote regions; or that differences in the pathophysiology of chronic kidney disease exist between Indigenous and non Indigenous populations. PMID- 21595914 TI - Negative enrichment by immunomagnetic nanobeads for unbiased characterization of circulating tumor cells from peripheral blood of cancer patients. AB - BACKGROUND: A limitation of positive selection strategies to enrich for circulating tumor cells (CTCs) is that there might be CTCs with insufficient expression of the surface target marker which may be missed by the procedure. We optimized a method for enrichment, subsequent detection and characterization of CTCs based on depletion of the leukocyte fraction. METHODS: The 2-step protocol was developed for processing 20 mL blood and based on red blood cell lysis followed by leukocyte depletion. The remaining material was stained with the epithelial markers EpCAM and cytokeratin (CK) 7/8 or for the melanoma marker HMW MAA/MCSP. CTCs were detected by flow cytometry. CTCs enriched from blood of patients with carcinoma were defined as EpCAM+CK+CD45-. CTCs enriched from blood of patients with melanoma were defined as MCSP+CD45-. One-hundred-sixteen consecutive blood samples from 70 patients with metastatic carcinomas (n = 48) or metastatic melanoma (n = 22) were analyzed. RESULTS: CTCs were detected in 47 of 84 blood samples (56%) drawn from carcinoma patients, and in 17 of 32 samples (53%) from melanoma patients. CD45-EpCAM-CK+ was detected in pleural effusion specimens, as well as in peripheral blood samples of patients with NSCLC. EpCAM CK+ cells have been successfully cultured and passaged longer than six months suggesting their neoplastic origin. This was confirmed by CGH. By defining CTCs in carcinoma patients as CD45-CK+ and/or EpCAM+, the detection rate increased to 73% (61/84). CONCLUSION: Enriching CTCs using CD45 depletion allowed for detection of epithelial cancer cells not displaying the classical phenotype. This potentially leads to a more accurate estimation of the number of CTCs. If detection of CTCs without a classical epithelial phenotype has clinical relevance need to be determined. PMID- 21595915 TI - Regulation of hypoxia inducible factor-1alpha expression by the alteration of redox status in HepG2 cells. AB - Hypoxia inducible factor-1 (HIF-1) has been considered as a critical transcriptional factor in response to hypoxia. It can increase P-glycoprotein (P Gp) thus generating the resistant effect to chemotherapy. At present, the mechanism regulating HIF-1alpha is still not fully clear in hypoxic tumor cells. Intracellular redox status is closely correlated with hypoxic micro-environment, so we investigate whether alterations in the cellular redox status lead to the changes of HIF-1alpha expression. HepG2 cells were exposed to Buthionine sulphoximine (BSO) for 12 h prior to hypoxia treatment. The level of HIF-1alpha expression was measured by Western blot and immunocytochemistry assays. Reduce glutathione (GSH) concentrations in hypoxic cells were determined using glutathione reductase/5,5'-dithiobis-(2-nitrob-enzoic acid) (DTNB) recycling assay. To further confirm the effect of intracellular redox status on HIF-1alpha expression, N-acetylcysteine (NAC) was added to culture cells for 8 h before the hypoxia treatment. The levels of multidrug resistance gene-1 (MDR-1) and erythropoietin (EPO) mRNA targeted by HIF-1alpha in hypoxic cells were further determined with RT-PCR, and then the expression of P-Gp protein was observed by Western blotting. The results showed that BSO pretreatment down-regulated HIF 1alpha and the effect was concentration-dependent, on the other hand, the increases of intracellular GSH contents by NAC could partly elevate the levels of HIF-1alpha expression. The levels of P-Gp (MDR-1) and EPO were concomitant with the trend of HIF-1alpha expression. Therefore, our data indicate that the changes of redox status in hypoxic cells may regulate HIF-1alpha expression and provide valuable information on tumor chemotherapy. PMID- 21595916 TI - Horizontal gene transfer in silkworm, Bombyx mori. AB - BACKGROUND: The domesticated silkworm, Bombyx mori, is the model insect for the order Lepidoptera, has economically important values, and has gained some representative behavioral characteristics compared to its wild ancestor. The genome of B. mori has been fully sequenced while function analysis of BmChi-h and BmSuc1 genes revealed that horizontal gene transfer (HGT) maybe bestow a clear selective advantage to B. mori. However, the role of HGT in the evolutionary history of B. mori is largely unexplored. In this study, we compare the whole genome of B. mori with those of 382 prokaryotic and eukaryotic species to investigate the potential HGTs. RESULTS: Ten candidate HGT events were defined in B. mori by comprehensive sequence analysis using Maximum Likelihood and Bayesian method combining with EST checking. Phylogenetic analysis of the candidate HGT genes suggested that one HGT was plant-to- B. mori transfer while nine were bacteria-to- B. mori transfer. Furthermore, functional analysis based on expression, coexpression and related literature searching revealed that several HGT candidate genes have added important characters, such as resistance to pathogen, to B. mori. CONCLUSIONS: Results from this study clearly demonstrated that HGTs play an important role in the evolution of B. mori although the number of HGT events in B. mori is in general smaller than those of microbes and other insects. In particular, interdomain HGTs in B. mori may give rise to functional, persistent, and possibly evolutionarily significant new genes. PMID- 21595917 TI - Pandemic influenza A (H1N1v) infection in pediatric population: a multicenter study in a north-east area of Italy. AB - BACKGROUND: Data on clinical presentation, morbidity and mortality of 2009 pandemic influenza virus (H1N1v) in paediatric population are still emerging; most of the data so far available came from selected cohorts of children admitted to tertiary care paediatric hospitals. METHODS: An observational study involving all the 19 Divisions of Paediatrics of the Veneto Region was conducted with the aim of investigating into the demographic and clinical characteristics, the treatment, the outcome and the risk factors for disease severity of H1N1v infection occurring in children. RESULTS: Two hundred children, median age of 4.15 years (range 0-15) were enrolled from the last week of October till the first week of January 2010 for an overall hospitalization rate of 23/100,000. At least one underlying medical condition was found in 44% of patients. Fever and cough were the most frequent symptoms (93% and 65% respectively). 11 patients (6%) were admitted to a PICU and 5 (2.5%) required mechanical ventilation. Antiviral therapy was administered in 103 patients (51.5%) Death occurred in 2 patients (1%); both had severe prior medical conditions. Pre-existing neurologic diseases (OR 7.82; 95%CI: 1.15-53.34), the presence of hypoxemia (OR 10.47; 95%CI: 2.12-51.70) and anemia (Haemoglobin < 10 g/dL) (OR 14.15; 95%CI: 2.36 84.64) were risk factor for Intensive Care Unit admission. CONCLUSIONS: This observational study in a given area of North-East Italy confirms the rather favourable prognosis of children with influenza A H1N1 (2009). Pre-existing conditions, and which is new, significant anemia, are risk factors for a complicated course. PMID- 21595918 TI - Expression and characterization of duck enteritis virus gI gene. AB - BACKGROUND: At present, alphaherpesviruses gI gene and its encoding protein have been extensively studied. It is likely that gI protein and its homolog play similar roles in virions direct cell-to-cell spread of alphaherpesviruses. But, little is known about the characteristics of DEV gI gene. In this study, we expressed and presented the basic properties of the DEV gI protein. RESULTS: The special 1221-bp fragment containing complete open reading frame(ORF) of duck enteritis virus(DEV) gI gene was extracted from plasmid pMD18-T-gI, and then cloned into prokaryotic expression vector pET-32a(+), resulting in pET-32a(+)-gI. After being confirmed by PCR, restriction endonuclease digestion and sequencing, pET-32a(+)-gI was transformed into E.coli BL21(DE3) competent cells for overexpression. DEV gI gene was successfully expressed by the addition of isopropyl-beta-D-thiogalactopyranoside(IPTG). SDS-PAGE showed that the recombinant protein His6-tagged gI molecular weight was about 61 kDa. Subsequently, the expressed product was applied to generate specific antibody against gI protein. The specificity of the rabbit immuneserum was confirmed by its ability to react with the recombinant protein His6-tagged gI. In addition, real time-PCR was used to determine the the levels of the mRNA transcripts of gI gene, the results showed that the DEV gI gene was transcribed most abundantly during the late phase of infection. Furthermore, indirect immunofluorescence(IIF) was established to study the gI protein expression and localization in DEV infected duck embryo fibroblasts (DEFs), the results confirmed that the protein was expressed and located in the cytoplasm of the infected cells, intensively. CONCLUSIONS: The recombinant prokaryotic expression vector of DEV gI gene was constructed successfully. The gI protein was successfully expressed by E.coli BL21(DE3) and maintained its antigenicity very well. The basic information of the transcription and intracellular localization of gI gene were presented, that would be helpful to assess the possible role of DEV gI gene. The research will provide useful clues for further functional analysis of DEV gI gene. PMID- 21595919 TI - Expanding a dynamic flux balance model of yeast fermentation to genome-scale. AB - BACKGROUND: Yeast is considered to be a workhorse of the biotechnology industry for the production of many value-added chemicals, alcoholic beverages and biofuels. Optimization of the fermentation is a challenging task that greatly benefits from dynamic models able to accurately describe and predict the fermentation profile and resulting products under different genetic and environmental conditions. In this article, we developed and validated a genome scale dynamic flux balance model, using experimentally determined kinetic constraints. RESULTS: Appropriate equations for maintenance, biomass composition, anaerobic metabolism and nutrient uptake are key to improve model performance, especially for predicting glycerol and ethanol synthesis. Prediction profiles of synthesis and consumption of the main metabolites involved in alcoholic fermentation closely agreed with experimental data obtained from numerous lab and industrial fermentations under different environmental conditions. Finally, fermentation simulations of genetically engineered yeasts closely reproduced previously reported experimental results regarding final concentrations of the main fermentation products such as ethanol and glycerol. CONCLUSION: A useful tool to describe, understand and predict metabolite production in batch yeast cultures was developed. The resulting model, if used wisely, could help to search for new metabolic engineering strategies to manage ethanol content in batch fermentations. PMID- 21595921 TI - 'A major lobbying effort to change and unify the excise structure in six Central American countries': How British American Tobacco influenced tax and tariff rates in the Central American Common Market. AB - BACKGROUND: Transnational tobacco companies (TTCs) may respond to processes of regional trade integration both by acting politically to influence policy and by reorganising their own operations. The Central American Common Market (CACM) was reinvigorated in the 1990s, reflecting processes of regional trade liberalisation in Latin America and globally. This study aimed to ascertain how British American Tobacco (BAT), which dominated the markets of the CACM, sought to influence policy towards it by member country governments and how the CACM process impacted upon BAT's operations. METHODS: The study analysed internal tobacco industry documents released as a result of litigation in the US and available from the online Legacy Tobacco Documents Library at http://legacy.library.ucsf.edu/. Documents were retrieved by searching the BAT collection using key terms in an iterative process. Analysis was based on an interpretive approach involving a process of attempting to understand the meanings of individual documents and relating these to other documents in the set, identifying the central themes of documents and clusters of documents, contextualising the documentary data, and choosing representative material in order to present findings. RESULTS: Utilising its multinational character, BAT was able to act in a coordinated way across the member countries of the CACM to influence tariffs and taxes to its advantage. Documents demonstrate a high degree of access to governments and officials. The company conducted a coordinated, and largely successful, attempt to keep external tariff rates for cigarettes high and to reduce external tariffs for key inputs, whilst also influencing the harmonisation of excise taxes between countries. Protected by these high external tariffs, it reorganised its own operations to take advantage of regional economies of scale. In direct contradiction to arguments presented to CACM governments that affording the tobacco industry protection via high cigarette tariffs would safeguard employment, the company's regional reorganisation involved the loss of hundreds of jobs. CONCLUSIONS: Regional integration organisations and their member states should be aware of the capacity of TTCs to act in a coordinated transnational manner to influence policy in their own interests, and coordinate their own public health and tax policies in a similarly effective way. PMID- 21595922 TI - Prevalence of metabolic syndrome in bus and truck drivers in Kashan, Iran. AB - BACKGROUND: Bus and truck drivers are apparently more involved in metabolic syndrome and its complications due to their working conditions. The related impacts are not only harmful for driver's health, but also may endanger others. The present research was carried out to determine the prevalence of metabolic syndrome among bus and truck drivers in Kashan, a city in Iran. MATERIALS: In 2007, 429 bus and truck male drivers were enrolled to this cross sectional study to examine the metabolic syndrome using ATPIII criteria. Statistical tests including Chi-Square test, T-student test and Pearson's correlation coefficient were used to analyze the data. RESULTS: Prevalence of metabolic syndrome in subjects was 35.9%. Hypertension and diabetes were seen in 42.9% and 7% of the drivers respectively. Body mass index (BMI) in 41% of the drivers within the range of 25-30 was considered overweight and 23% of them were found to be obese. High triglyceride (53.4%) and low HDL-C levels (48.7%) were more common than other components of metabolic syndrome. A significant positive correlation was seen between BMI, diabetes, high blood pressure and metabolic syndrome (p < 0.001); but there was no positive correlation between metabolic syndrome and smoking (p < 0.06). CONCLUSION: High prevalence of metabolic syndrome and other relevant risk factors for coronary heart diseases (CHD) were detected among the drivers. Based on these findings, it is recommended to consider training programs, establish pertinent health regulations, and focus on the metabolic syndrome complications in high risk group to improve and maintain their quality of life and to promote their public health. PMID- 21595920 TI - Curcumin reduces expression of Bcl-2, leading to apoptosis in daunorubicin insensitive CD34+ acute myeloid leukemia cell lines and primary sorted CD34+ acute myeloid leukemia cells. AB - BACKGROUND: Acute myeloid leukemia (AML) is an immunophenotypically heterogeneous malignant disease, in which CD34 positivity is associated with poor prognosis. CD34+ AML cells are 10-15-fold more resistant to daunorubicin (DNR) than CD34- AML cells. Curcumin is a major component of turmeric that has shown cytotoxic activity in multiple cancers; however, its anti-cancer activity has not been well studied in DNR-insensitive CD34+ AML cells. The aim of this study was to therefore to explore curcumin-induced cytotoxicity in DNR-insensitive CD34+ AML cell lines (KG1a, Kasumi-1), DNR-sensitive U937 AML cells, and primary CD34+ AML bone-marrow-derived cells. METHODS: Primary human CD34+ cells were isolated from peripheral blood mononuclear cells or bone marrow mononuclear cells using a CD34 MicroBead kit. The growth inhibitory effects of curcumin were evaluated by MTT and colony-formation assays. Cell cycle distribution was examined by propidium iodide (PI) assay. Apoptosis was analyzed by Wright-Giemsa, Hoechst 33342 and Annexin-V/PI staining assays. The change in mitochondrial membrane potential (MMP) was examined by JC-1 staining and flow cytometry. Expression of apoptosis related proteins was determined by reverse transcription-polymerase chain reaction and Western blotting. Short interfering RNA (siRNA) against Bcl-2 was used in CD34+ KG1a and Kasumi-1 cells incubated with/without DNR. RESULTS: Curcumin inhibited proliferation and induced apoptosis and G1/S arrest in both DNR-insensitive KG1a, Kasumi-1 and DNR-sensitive U937 cells. Curcumin-induced apoptosis was associated with reduced expression of both Bcl-2 mRNA and protein, subsequent loss of MMP, and activation of caspase-3 followed by PARP degradation. Curcumin synergistically enhanced the cytotoxic effect of DNR in DNR-insensitive KG1a and Kasumi-1 cells, consistent with decreased Bcl-2 expression. Accordingly, siRNA against Bcl-2 increased the susceptibility of KG1a and Kasumi-1 cells to DNR-induced apoptosis. More importantly, curcumin suppressed Bcl-2 expression, selectively inhibited proliferation and synergistically enhanced the cytotoxicity of DNR in primary CD34+ AML cells, while showing limited lethality in normal CD34+ hematopoietic progenitors. CONCLUSION: Curcumin down-regulates Bcl-2 and induces apoptosis in DNR-insensitive CD34+ AML cell lines and primary CD34+ AML cells. PMID- 21595923 TI - Changes in interleukin-1 signal modulators induced by 3,4 methylenedioxymethamphetamine (MDMA): regulation by CB2 receptors and implications for neurotoxicity. AB - BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA) produces a neuroinflammatory reaction in rat brain characterized by an increase in interleukin-1 beta (IL 1beta) and microglial activation. The CB2 receptor agonist JWH-015 reduces both these changes and partially protects against MDMA-induced neurotoxicity. We have examined MDMA-induced changes in IL-1 receptor antagonist (IL-1ra) levels and IL 1 receptor type I (IL-1RI) expression and the effects of JWH-015. The cellular location of IL-1beta and IL-1RI was also examined. MDMA-treated animals were given the soluble form of IL-1RI (sIL-1RI) and neurotoxic effects examined. METHODS: Dark Agouti rats received MDMA (12.5 mg/kg, i.p.) and levels of IL-1ra and expression of IL-1RI measured 1 h, 3 h or 6 h later. JWH-015 (2.4 mg/kg, i.p.) was injected 48 h, 24 h and 0.5 h before MDMA and IL-1ra and IL-1RI measured. For localization studies, animals were sacrificed 1 h or 3 h following MDMA and stained for IL-1beta or IL-1RI in combination with neuronal and microglial markers. sIL-1RI (3 MUg/animal; i.c.v.) was administered 5 min before MDMA and 3 h later. 5-HT transporter density was determined 7 days after MDMA injection. RESULTS: MDMA produced an increase in IL-ra levels and a decrease in IL-1RI expression in hypothalamus which was prevented by CB2 receptor activation. IL-1RI expression was localized on neuronal cell bodies while IL-1beta expression was observed in microglial cells following MDMA. sIL-1RI potentiated MDMA-induced neurotoxicity. MDMA also increased IgG immunostaining indicating that blood brain barrier permeability was compromised. CONCLUSIONS: In summary, MDMA produces changes in IL-1 signal modulators which are modified by CB2 receptor activation. These results indicate that IL-1beta may play a partial role in MDMA-induced neurotoxicity. PMID- 21595924 TI - Transcriptomic and proteomic profiling of maize embryos exposed to camptothecin. AB - BACKGROUND: Camptothecin is a plant alkaloid that specifically binds topoisomerase I, inhibiting its activity and inducing double stranded breaks in DNA, activating the cell responses to DNA damage and, in response to severe treatments, triggering cell death. RESULTS: Comparative transcriptomic and proteomic analyses of maize embryos that had been exposed to camptothecin were conducted. Under the conditions used in this study, camptothecin did not induce extensive degradation in the genomic DNA but induced the transcription of genes involved in DNA repair and repressed genes involved in cell division. Camptothecin also affected the accumulation of several proteins involved in the stress response and induced the activity of certain calcium-dependent nucleases. We also detected changes in the expression and accumulation of different genes and proteins involved in post-translational regulatory processes. CONCLUSIONS: This study identified several genes and proteins that participate in DNA damage responses in plants. Some of them may be involved in general responses to stress, but others are candidate genes for specific involvement in DNA repair. Our results open a number of new avenues for researching and improving plant resistance to DNA injury. PMID- 21595925 TI - High quality RNA isolation from Aedes aegypti midguts using laser microdissection microscopy. AB - BACKGROUND: Laser microdissection microscopy (LMM) has potential as a research tool because it allows precise excision of target tissues or cells from a complex biological specimen, and facilitates tissue-specific sample preparation. However, this method has not been used in mosquito vectors to date. To this end, we have developed an LMM method to isolate midgut RNA using Aedes aegypti. RESULTS: Total RNA was isolated from Ae. aegypti midguts that were either fresh-frozen or fixed with histological fixatives. Generally, fresh-frozen tissue sections are a common source of quality LMM-derived RNA; however, our aim was to develop an LMM protocol that could inactivate pathogenic viruses by fixation, while simultaneously preserving RNA from arbovirus-infected mosquitoes. Three groups (10 - 15 mosquitoes per group) of female Ae. aegypti at 24 or 48-hours post-blood meal were intrathoracically injected with one of seven common fixatives (Bouin's, Carnoy's, Formoy's, Cal-Rite, 4% formalin, 10% neutral buffered formalin, or zinc formalin) to evaluate their effect on RNA quality. Total RNA was isolated from the fixed abdomens using a Trizol(r) method. The results indicated that RNA from Carnoy's and Bouin's fixative samples was comparable to that of fresh frozen midguts (control) in duplicate experiments. When Carnoy's and Bouin's were used to fix the midguts for the LMM procedure, however, Carnoy's-fixed RNA clearly showed much less degradation than Bouin's-fixed RNA. In addition, a sample of 5 randomly chosen transcripts were amplified more efficiently using the Carnoy's treated LMM RNA than Bouin's-fixed RNA in quantitative real-time PCR (qRT-PCR) assays, suggesting there were more intact target mRNAs in the Carnoy's fixed RNA. The yields of total RNA ranged from 0.3 to 19.0 ng per ~3.0 * 10(6) MUm2 in the LMM procedure. CONCLUSIONS: Carnoy's fixative was found to be highly compatible with LMM, producing high quality RNA from Ae. aegypti midguts while inactivating viral pathogens. Our findings suggest that LMM in conjunction with Carnoy's fixation can be applied to studies in Ae. aegypti infected with arboviruses without compromising biosafety and RNA quality. This LMM method should be applicable to other mosquito vector studies. PMID- 21595926 TI - Rebooting the human mitochondrial phylogeny: an automated and scalable methodology with expert knowledge. AB - BACKGROUND: Mitochondrial DNA is an ideal source of information to conduct evolutionary and phylogenetic studies due to its extraordinary properties and abundance. Many insights can be gained from these, including but not limited to screening genetic variation to identify potentially deleterious mutations. However, such advances require efficient solutions to very difficult computational problems, a need that is hampered by the very plenty of data that confers strength to the analysis. RESULTS: We develop a systematic, automated methodology to overcome these difficulties, building from readily available, public sequence databases to high-quality alignments and phylogenetic trees. Within each stage in an autonomous workflow, outputs are carefully evaluated and outlier detection rules defined to integrate expert knowledge and automated curation, hence avoiding the manual bottleneck found in past approaches to the problem. Using these techniques, we have performed exhaustive updates to the human mitochondrial phylogeny, illustrating the power and computational scalability of our approach, and we have conducted some initial analyses on the resulting phylogenies. CONCLUSIONS: The problem at hand demands careful definition of inputs and adequate algorithmic treatment for its solutions to be realistic and useful. It is possible to define formal rules to address the former requirement by refining inputs directly and through their combination as outputs, and the latter are also of help to ascertain the performance of chosen algorithms. Rules can exploit known or inferred properties of datasets to simplify inputs through partitioning, therefore cutting computational costs and affording work on rapidly growing, otherwise intractable datasets. Although expert guidance may be necessary to assist the learning process, low-risk results can be fully automated and have proved themselves convenient and valuable. PMID- 21595927 TI - HGF/c-met/Stat3 signaling during skin tumor cell invasion: indications for a positive feedback loop. AB - BACKGROUND: Stat3 is a cytokine- and growth factor-inducible transcription factor that regulates cell motility, migration, and invasion under normal and pathological situations, making it a promising target for cancer therapeutics. The hepatocyte growth factor (HGF)/c-met receptor tyrosine kinase signaling pathway is responsible for stimulation of cell motility and invasion, and Stat3 is responsible for at least part of the c-met signal. METHODS: We have stably transfected a human squamous cell carcinoma (SCC) cell line (SRB12-p9) to force the expression of a dominant negative form of Stat3 (S3DN), which we have previously shown to suppress Stat3 activity. The in vitro and in vivo malignant behavior of the S3DN cells was compared to parental and vector transfected controls. RESULTS: Suppression of Stat3 activity impaired the ability of the S3DN cells to scatter upon stimulation with HGF (c-met ligand), enhanced their adhesion, and diminished their capacity to invade in vitro and in vivo. Surprisingly, S3DN cells also showed suppressed HGF-induced activation of c-met, and had nearly undetectable basal c-met activity, as revealed by a phospho specific c-met antibody. In addition, we showed that there is a strong membrane specific localization of phospho-Stat3 in the wild type (WT) and vector transfected control (NEO4) SRB12-p9 cells, which is lost in the S3DN cells. Finally, co-immunoprecipitation experiments revealed that S3DN interfered with Stat3/c-met interaction. CONCLUSION: These studies are the first confirm that interference with the HGF/c-met/Stat3 signaling pathway can block tumor cell invasion in an in vivo model. We also provide novel evidence for a possible positive feedback loop whereby Stat3 can activate c-met, and we correlate membrane localization of phospho-Stat3 with invasion in vivo. PMID- 21595928 TI - Asthma in an urban population in Portugal: a prevalence study. AB - BACKGROUND: The prevalence and incidence of asthma are believed to be increasing but research on the true incidence, prevalence and mortality from asthma has met methodological obstacles since it has been difficult to define and diagnose asthma in epidemiological terms. New and widely accepted diagnostic criteria for asthma present opportunities for progress in this field. Studies conducted in Portugal have estimated the disease prevalence between 3% and 15%. Available epidemiological data present a significant variability due to methodological obstacles. AIM: To estimate the true prevalence of asthma by gender and age groups in the population of the area covered by one urban Health Centre in Portugal. METHOD: An observational study was conducted between February and July 2009 at the Horizonte Family Health Unit in Matosinhos, Portugal. A random sample of 590 patients, stratified by age and gender was obtained from the practice database of registered patients. Data was collected using a patient questionnaire based on respiratory symptoms and the physician's best knowledge of the patient's asthma status. The prevalence of asthma was calculated by age and gender. RESULTS: Data were obtained from 576 patients (97.6% response rate). The mean age for patients with asthma was 27.0 years (95% CI: 20.95 to 33.16). This was lower than the mean age for non-asthmatics but the difference was not statistically significant. Asthma was diagnosed in 59 persons giving a prevalence of 10.24% (95% CI: 8.16 to 12.32). There was no statistically significant difference in the prevalence of asthma by gender. CONCLUSION: The prevalence of asthma found in the present study was higher than that found in some studies, though lower than that found in other studies. Further studies in other regions of Portugal are required to confirm these findings. PMID- 21595929 TI - Integration of Solexa sequences on an ultradense genetic map in Brassica rapa L. AB - BACKGROUND: Sequence related amplified polymorphism (SRAP) is commonly used to construct high density genetic maps, map genes and QTL of important agronomic traits in crops and perform genetic diversity analysis without knowing sequence information. To combine next generation sequencing technology with SRAP, Illumina's Solexa sequencing was used to sequence tagged SRAP PCR products. RESULTS: Three sets of SRAP primers and three sets of tagging primers were used in 77,568 SRAP PCR reactions and the same number of tagging PCR reactions respectively to produce a pooled sample for Illumina's Solexa sequencing. After sequencing, 1.28 GB of sequence with over 13 million paired-end sequences was obtained and used to match Solexa sequences with their corresponding SRAP markers and to integrate Solexa sequences on an ultradense genetic map. The ultradense genetic bin map with 465 bins was constructed using a recombinant inbred (RI) line mapping population in B. rapa. For this ultradense genetic bin map, 9,177 SRAP markers, 1,737 integrated unique Solexa paired-end sequences and 46 SSR markers representing 10,960 independent genetic loci were assembled and 141 unique Solexa paired-end sequences were matched with their corresponding SRAP markers. The genetic map in B. rapa was aligned with the previous ultradense genetic map in B. napus through common SRAP markers in these two species. Additionally, SSR markers were used to perform alignment of the current genetic map with other five genetic maps in B. rapa and B. napus. CONCLUSION: We used SRAP to construct an ultradense genetic map with 10,960 independent genetic loci in B. rapa that is the most saturated genetic map ever constructed in this species. Using next generation sequencing, we integrated 1,878 Solexa sequences on the genetic map. These integrated sequences will be used to assemble the scaffolds in the B. rapa genome. Additionally, this genetic map may be used for gene cloning and marker development in B. rapa and B. napus. PMID- 21595930 TI - Homer1a signaling in the amygdala counteracts pain-related synaptic plasticity, mGluR1 function and pain behaviors. AB - BACKGROUND: Group I metabotropic glutamate receptor (mGluR1/5) signaling is an important mechanism of pain-related plasticity in the amygdala that plays a key role in the emotional-affective dimension of pain. Homer1a, the short form of the Homer1 family of scaffolding proteins, disrupts the mGluR-signaling complex and negatively regulates nociceptive plasticity at spinal synapses. Using transgenic mice overexpressing Homer1a in the forebrain (H1a-mice), we analyzed synaptic plasticity, pain behavior and mGluR1 function in the basolateral amygdala (BLA) in a model of arthritis pain. FINDINGS: In contrast to wild-type mice, H1a-mice mice did not develop increased pain behaviors (spinal reflexes and audible and ultrasonic vocalizations) after induction of arthritis in the knee joint. Whole cell patch-clamp recordings in brain slices showed that excitatory synaptic transmission from the BLA to the central nucleus (CeA) did not change in arthritic H1a-mice but increased in arthritic wild-type mice. A selective mGluR1 antagonist (CPCCOEt) had no effect on enhanced synaptic transmission in slices from H1a-BLA mice with arthritis but inhibited transmission in wild-type mice with arthritis as in our previous studies in rats. CONCLUSIONS: The results show that Homer1a expressed in forebrain neurons, prevents the development of pain hypersensitivity in arthritis and disrupts pain-related plasticity at synapses in amygdaloid nuclei. Furthermore, Homer1a eliminates the effect of an mGluR1 antagonist, which is consistent with the well-documented disruption of mGluR1 signaling by Homer1a. These findings emphasize the important role of mGluR1 in pain-related amygdala plasticity and provide evidence for the involvement of Homer1 proteins in the forebrain in the modulation of pain hypersensitivity. PMID- 21595931 TI - Fostering accurate HIV/AIDS knowledge among unmarried youths in Cameroon: do family environment and peers matter? AB - BACKGROUND: The last three decades have seen a series of HIV interventions in sub Saharan Africa. However, youths still have a mixture of correct and incorrect HIV/AIDS knowledge of transmission routes and prevention strategies. Previous studies have identified parents and peers as the most important socializing agents for youths. This paper assesses the relationships between family structure, family/peer communication about sexuality and accurate knowledge of transmission routes and prevention strategies. METHODS: Data were drawn from the Cameroon Family Life and Health Survey (CFHS) conducted in 2002. The CFHS collected information on a representative sample of 4950 people aged 10 years and over nested within 1765 selected households from the 75 localities forming the administrative prefecture of Bandjoun, using detailed questionnaires about family, HIV/AIDS/STDs knowledge, sexual behaviors, contraception, health, media exposure, household assets and neighborhood characteristics. The survey cooperation rates were high (97%). For the purpose of this study, a sub-sample of 2028 unmarried youths aged 12-29 years was utilized. RESULTS: Overall, 42% of respondents reported accurate knowledge of documented HIV transmission routes whereas 21% of them had inaccurate knowledge such as AIDS can be transmitted through mosquito bites or casual contact with an infected person. Only 9% of respondents were knowledgeable about all HIV prevention strategies. Multivariate analyses showed that family structure, communication with parents/guardians and peers about sexual topics were significantly associated with accurate HIV knowledge. Additionally, age, education, sexual experience and migration had significant effects on accurate knowledge. Finally, living in poor households and disadvantaged neighborhoods significantly increased inaccurate knowledge of HIV transmission modes and prevention strategies. CONCLUSIONS: This paper evidenced the limited effects of HIV interventions/programmes in sub-Saharan Africa. Indeed, few respondents reported accurate knowledge about HIV transmission routes and prevention strategies. Findings showed that the role of family environment as source of accurate HIV knowledge transmission routes and prevention strategies is of paramount significance; however, families have been poorly integrated in the design and implementation of the first generation of HIV interventions. There is an urgent need that policymakers work together with families to improve the efficiency of these interventions. Peer influences is likely controversial because of the double positive effect of peer-to-peer communication on both accurate and inaccurate knowledge of HIV transmission routes. PMID- 21595932 TI - C-reactive protein in critically ill cancer patients with sepsis: influence of neutropenia. AB - INTRODUCTION: Several biomarkers have been studied in febrile neutropenia. Our aim was to assess C-reactive protein (CRP) concentration in septic critically ill cancer patients and to compare those with and without neutropenia. METHODS: A secondary analysis of a matched case-control study conducted at an oncologic medical-surgical intensive care unit (ICU) was performed, segregating patients with severe sepsis/septic shock. The impact of neutropenia on CRP concentrations at admission and during the first week of ICU stay was assessed. RESULTS: A total of 154 critically ill septic cancer patients, 86 with neutropenia and 68 without, were included in the present study. At ICU admission, the CRP concentration of neutropenic patients was significantly higher than in non-neutropenic patients, 25.9 +/- 11.2 mg/dL vs. 19.7 +/- 11.4 mg/dL (P = 0.009). Among neutropenic patients, CRP concentrations at ICU admission were not influenced by the severity of neutropenia (< 100/mm3 vs. >= 100/mm3 neutrophils), 25.1 +/- 11.6 mg/dL vs. 26.9 +/- 10.9 mg/dL (P = 0.527). Time dependent analysis of CRP from Day 1 to Day 7 of antibiotic therapy showed an almost parallel decrease in both groups (P = 0.335), though CRP of neutropenic patients was, on average, always higher in comparison to that of non-neutropenic patients. CONCLUSIONS: In septic critically ill cancer patients CRP concentrations are more elevated in those with neutropenia. However, the CRP course seems to be independent from the presence or absence of neutropenia. PMID- 21595933 TI - PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease. AB - BACKGROUND: Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO. RESULTS: In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively. CONCLUSIONS: These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD. PMID- 21595934 TI - A Shigella boydii bacteriophage which resembles Salmonella phage ViI. AB - BACKGROUND: Lytic bacteriophages have been applied successfully to control the growth of various foodborne pathogens. Sequencing of their genomes is considered as an important preliminary step to ensure their safety prior to food applications. RESULTS: The lytic bacteriophage, PhiSboM-AG3, targets the important foodborne pathogen, Shigella. It is morphologically similar to phage ViI of Salmonella enterica serovar Typhi and a series of phages of Acinetobacter calcoaceticus and Rhizobium meliloti. The complete genome of PhiSboM-AG3 was determined to be 158 kb and was terminally redundant and circularly permuted. Two hundred and sixteen open reading frames (ORFs) were identified and annotated, most of which displayed homology to proteins of Salmonella phage ViI. The genome also included four genes specifying tRNAs. CONCLUSIONS: This is the first time that a Vi-specific phage for Shigella has been described. There is no evidence for the presence of virulence and lysogeny-associated genes. In conclusion, the genome analysis of PhiSboM-AG3 indicates that this phage can be safely used for biocontrol purposes. PMID- 21595936 TI - The effect of education on the assessment of optic nerve head photographs for the glaucoma diagnosis. AB - BACKGROUND: To evaluate the effect of one lesson of continuing medical education (CME) of subjective assessment of optic nerve head appearance on sensitivity and specificity for the diagnosis of glaucoma. METHODS: Ophthalmologists and residents in ophthalmology attending an international glaucoma meeting arranged at Malmo University Hospital, Malmo, Sweden, were asked to grade optic nerve head (ONH) photographs of healthy and glaucomatous subjects at two sessions separated by a lecture on glaucoma diagnosis by ONH assessment. Each grader had access to an individual portfolio of 50 ONH photographs randomly selected from a web-based data bank including ONH photographs of 73 glaucoma patients and 123 healthy subjects. The individual portfolio of photographs was graded before and after the lecture, but in different randomized order. RESULTS: Ninety-six doctors, 91% of all attending the meeting, completed both assessment sessions. The number of correct classifications increased from 69 to 72% on the average. Diagnostic sensitivity increased significantly (p < 0.0001) from 70% to 80%, and the number of photographs classified as uncertain decreased significantly (p < 0.0001) from 22% to 13%. Specificity remained at 68%, and intra-grader agreement decreased. CONCLUSION: CME had only a small effect on the assessment of ONH for the glaucoma diagnosis. Sensitivity increased and the amount of uncertain classifications decreased, while specificity was unchanged. PMID- 21595935 TI - AMP-activated protein kinase deficiency reduces ozone-induced lung injury and oxidative stress in mice. AB - BACKGROUND: Acute ozone exposure causes lung oxidative stress and inflammation leading to lung injury. At least one mechanism underlying the lung toxicity of ozone involves excessive production of reactive oxygen and nitrogen intermediates such as peroxynitrite. In addition and beyond its major prooxidant properties, peroxynitrite may nitrate tyrosine residues altering phosphorylation of many protein kinases involved in cell signalling. It was recently proposed that peroxynitrite activates 5'-AMP-activated kinase (AMPK), which regulates metabolic pathways and the response to cell stress. AMPK activation as a consequence of ozone exposure has not been previously evaluated. First, we tested whether acute ozone exposure in mice would impair alveolar fluid clearance, increase lung tissue peroxynitrite production and activate AMPK. Second, we tested whether loss of AMP-activated protein kinase alpha1 subunit in mouse would prevent enhanced oxidative stress and lung injury induced by ozone exposure. METHODS: Control and AMPKalpha1 deficient mice were exposed to ozone at a concentration of 2.0 ppm for 3 h in glass cages. Evaluation was performed 24 h after ozone exposure. Alveolar fluid clearance (AFC) was evaluated using fluorescein isothiocyanate tagged albumin. Differential cell counts, total protein levels, cytokine concentrations, myeloperoxidase activity and markers of oxidative stress, i.e. malondialdehyde and peroxynitrite, were determined in bronchoalveolar lavage (BAL) and lung homogenates (LH). Levels of AMPK-Thr172 phosphorylation and basolateral membrane Na(+)-K(+)-ATPase abundance were determined by Western blot. RESULTS: In control mice, ozone exposure induced lung inflammation as evidence by increased leukocyte count, protein concentration in BAL and myeloperoxidase activity, pro inflammatory cytokine levels in LH. Increases in peroxynitrite levels (3 vs 4.4 nM, p = 0.02) and malondialdehyde concentrations (110 vs 230 MUmole/g wet tissue) were detected in LH obtained from ozone-exposed control mice. Ozone exposure consistently increased phosphorylated AMPK-Thr172 to total AMPK ratio by 80% in control mice. Ozone exposure causes increases in AFC and basolateral membrane Na(+)-K(+)-ATPase abundance in control mice which did not occur in AMPKalpha1 deficient mice. CONCLUSIONS: Our results collectively suggest that AMPK activation participates in ozone-induced increases in AFC, inflammation and oxidative stress. Further studies are needed to understand how the AMPK pathway may provide a novel approach for the prevention of ozone-induced lung injury. PMID- 21595937 TI - A late origin of the extant eukaryotic diversity: divergence time estimates using rare genomic changes. AB - BACKGROUND: Accurate estimation of the divergence time of the extant eukaryotes is a fundamentally important but extremely difficult problem owing primarily to gross violations of the molecular clock at long evolutionary distances and the lack of appropriate calibration points close to the date of interest. These difficulties are intrinsic to the dating of ancient divergence events and are reflected in the large discrepancies between estimates obtained with different approaches. Estimates of the age of Last Eukaryotic Common Ancestor (LECA) vary approximately twofold, from ~1,100 million years ago (Mya) to ~2,300 Mya. RESULTS: We applied the genome-wide analysis of rare genomic changes associated with conserved amino acids (RGC_CAs) and used several independent techniques to obtain date estimates for the divergence of the major lineages of eukaryotes with calibration intervals for insects, land plants and vertebrates. The results suggest an early divergence of monocot and dicot plants, approximately 340 Mya, raising the possibility of plant-insect coevolution. The divergence of bilaterian animal phyla is estimated at ~400-700 Mya, a range of dates that is consistent with cladogenesis immediately preceding the Cambrian explosion. The origin of opisthokonts (the supergroup of eukaryotes that includes metazoa and fungi) is estimated at ~700-1,000 Mya, and the age of LECA at ~1,000-1,300 Mya. We separately analyzed the red algal calibration interval which is based on single fossil. This analysis produced time estimates that were systematically older compared to the other estimates. Nevertheless, the majority of the estimates for the age of the LECA using the red algal data fell within the 1,200-1,400 Mya interval. CONCLUSION: The inference of a "young LECA" is compatible with the latest of previously estimated dates and has substantial biological implications. If these estimates are valid, the approximately 1 to 1.4 billion years of evolution of eukaryotes that is open to comparative-genomic study probably was preceded by hundreds of millions years of evolution that might have included extinct diversity inaccessible to comparative approaches. REVIEWERS: This article was reviewed by William Martin, Herve Philippe (nominated by I. King Jordan), and Romain Derelle. PMID- 21595938 TI - Rheumatoid arthritis-associated polymorphisms are not protective against Alzheimer's disease. AB - BACKGROUND: Rheumatoid arthritis (RA) and Alzheimer's disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors recently identified in genome-wide association studies (GWAS) for their association with AD in a two-stage, case-control analysis. RESULTS: In our Stage 1 analysis of ~800 AD and ~1,200 non-AD individuals, three of seventeen RA associated SNPs were nominally associated with AD (p < 0.05) with one SNP, rs2837960, retaining significance after correction for multiple testing (p = 0.03). The rs2837960_G (minor) allele, which is associated with increased RA risk, was associated with increased AD risk. Analysis of these three SNPs in a Stage 2 population, consisting of ~1,100 AD and ~2,600 non-AD individuals, did not confirm their association with AD. Analysis of Stage 1 and 2 combined suggested that rs2837960 shows a trend for association with AD. When the Stage 2 population was age-matched for the Stage 1 population, rs2837960 exhibited a non significant trend with AD. Combined analysis of Stage 1 and the age-matched Stage 2 subset showed a significant association of rs2837960 with AD (p = 0.002, OR 1.24) that retained significance following correction for age, sex and APOE (p = 0.02, OR = 1.20). Rs2837960 is near BACE2, which encodes an aspartic protease capable of processing the AD-associated amyloid precursor protein. Testing for an association between rs2837960 and the expression of BACE2 isoforms in human brain, we observed a trend between rs2837960 and the total expression of BACE2 and the expression of a BACE2 transcript lacking exon 7 (p = 0.07 and 0.10, respectively). CONCLUSIONS: RA-associated SNPs are generally not associated with AD. Moreover, rs2837960_G is associated with increased risk of both RA and, in individuals less than 80 years of age, with AD. Overall, these results contest the hypothesis that genetic variants associated with RA confer protection against AD. Further investigation of rs2837960 is necessary to elucidate the mechanism by which rs2837960 contributes to both AD and RA risk, likely via modulation of BACE2 expression. PMID- 21595940 TI - The Health Systems Funding Platform: Is this where we thought we were going? AB - BACKGROUND: In March 2009, the Task Force for Innovative International Financing for Health Systems recommended "a health systems funding platform for the Global Fund, GAVI Alliance, the World Bank and others to coordinate, mobilize, streamline and channel the flow of existing and new international resources to support national health strategies." Momentum to establish the Health Systems Funding Platform was swift, with the World Bank convening a Technical Workshop on Health Systems Strengthening (HSS), and serial meetings organized to progress the agenda. Despite its potential significance, there has been little comment in peer reviewed literature, though some disquiet in the international development community around the scope of the Platform and the capacity of the partners, which appears disproportionate to the available information. METHODS: This case study uses documentary analysis, participant observation and 24 in-depth interviews to examine the processes of development and key issues raised by the Platform. RESULTS: The findings show a fluid and volatile process, with debate over whether ongoing engagement in HSS by Global Fund and GAVI represents a dilution of organizational focus, risking ongoing support, or a paradigm shift that facilitates the achievement of targeted objectives, builds systems capacity, and will attract additional resources. Uncertainty in the development of the Platform reflects the flexibility of the recently formed global health initiatives, and the instability of donor commitments, particularly in the current financial climate. But implicit in the conflict is tension between key global stakeholders over defining and ownership of the health systems agenda. CONCLUSIONS: The tensions appear to have been resolved through a focus on national planning, applying International Health Partnership principles, though the global financial crisis and key personnel changes may yet alter outcomes. Despite its dynamic evolution, the Platform may offer an incremental path towards increasing integration around health systems, that has not been previously possible. PMID- 21595941 TI - Network-based scoring system for genome-scale metabolic reconstructions. AB - BACKGROUND: Network reconstructions at the cell level are a major development in Systems Biology. However, we are far from fully exploiting its potentialities. Often, the incremental complexity of the pursued systems overrides experimental capabilities, or increasingly sophisticated protocols are underutilized to merely refine confidence levels of already established interactions. For metabolic networks, the currently employed confidence scoring system rates reactions discretely according to nested categories of experimental evidence or model-based likelihood. RESULTS: Here, we propose a complementary network-based scoring system that exploits the statistical regularities of a metabolic network as a bipartite graph. As an illustration, we apply it to the metabolism of Escherichia coli. The model is adjusted to the observations to derive connection probabilities between individual metabolite-reaction pairs and, after validation, to assess the reliability of each reaction in probabilistic terms. This network based scoring system uncovers very specific reactions that could be functionally or evolutionary important, identifies prominent experimental targets, and enables further confirmation of modeling results. CONCLUSIONS: We foresee a wide range of potential applications at different sub-cellular or supra-cellular levels of biological interactions given the natural bipartivity of many biological networks. PMID- 21595939 TI - Geminin overexpression prevents the completion of topoisomerase IIalpha chromosome decatenation, leading to aneuploidy in human mammary epithelial cells. AB - INTRODUCTION: The nuclear enzyme topoisomerase IIalpha (TopoIIalpha) is able to cleave DNA in a reversible manner, making it a valuable target for agents such as etoposide that trap the enzyme in a covalent bond with the 5' DNA end to which it cleaves. This prevents DNA religation and triggers cell death in cancer cells. However, development of resistance to these agents limits their therapeutic use. In this study, we examined the therapeutic targeting of geminin for improving the therapeutic potential of TopoIIalpha agents. METHODS: Human mammary epithelial (HME) cells and several breast cancer cell lines were used in this study. Geminin, TopoIIalpha and cell division cycle 7 (Cdc7) silencing were done using specific small interfering RNA. Transit or stable inducible overexpression of these proteins and casein kinase Iepsilon (CKIepsilon) were also used, as well as several pharmacological inhibitors that target TopoIIalpha, Cdc7 or CKIepsilon. We manipulated HME cells that expressed H2B-GFP, or did not, to detect chromosome bridges. Immunoprecipitation and direct Western blot analysis were used to detect interactions between these proteins and their total expression, respectively, whereas interactions on chromosomal arms were detected using a trapped in agarose DNA immunostaining assay. TopoIIalpha phosphorylation by Cdc7 or CKIepsilon was done using an in vitro kinase assay. The TopoGen decatenation kit was used to measure TopoIIalpha decatenation activity. Finally, a comet assay and metaphase chromosome spread were used to detect chromosome breakage and changes in chromosome condensation or numbers, respectively. RESULTS: We found that geminin and TopoIIalpha interact primarily in G2/M/early G1 cells on chromosomes, that geminin recruits TopoIIalpha to chromosomal decatenation sites or vice versa and that geminin silencing in HME cells triggers the formation of chromosome bridges by suppressing TopoIIalpha access to chromosomal arms. CKIepsilon kinase phosphorylates and positively regulates TopoIIalpha chromosome localization and function. CKIepsilon kinase overexpression or Cdc7 kinase silencing, which we show phosphorylates TopoIIalpha in vitro, restored DNA decatenation and chromosome segregation in geminin-silenced cells before triggering cell death. In vivo, at normal concentration, geminin recruits the deSUMOylating sentrin specific proteases SENP1 and SENP2 enzymes to deSUMOylate chromosome-bound TopoIIalpha and promote its release from chromosomes following completion of DNA decatenation. In cells overexpressing geminin, premature departure of TopoIIalpha from chromosomes is thought to be due to the fact that geminin recruits more of these deSUMOylating enzymes, or recruits them earlier, to bound TopoIIalpha. This triggers premature release of TopoIIalpha from chromosomes, which we propose induces aneuploidy in HME cells, since chromosome breakage generated through this mechanism were not sensed and/or repaired and the cell cycle was not arrested. Expression of mitosis-inducing proteins such as cyclin A and cell division kinase 1 was also increased in these cells because of the overexpression of geminin. CONCLUSIONS: TopoIIalpha recruitment and its chromosome decatenation function require a normal level of geminin. Geminin silencing induces a cytokinetic checkpoint in which Cdc7 phosphorylates TopoIIalpha and inhibits its chromosomal recruitment and decatenation and/or segregation function. Geminin overexpression prematurely deSUMOylates TopoIIalpha, triggering its premature departure from chromosomes and leading to chromosomal abnormalities and the formation of aneuploid, drug-resistant cancer cells. On the basis of our findings, we propose that therapeutic targeting of geminin is essential for improving the therapeutic potential of TopoIIalpha agents. PMID- 21595943 TI - The evolutionary history of the stearoyl-CoA desaturase gene family in vertebrates. AB - BACKGROUND: Stearoyl-CoA desaturases (SCDs) are key enzymes involved in de novo monounsaturated fatty acid synthesis. They catalyze the desaturation of saturated fatty acyl-CoA substrates at the delta-9 position, generating essential components of phospholipids, triglycerides, cholesterol esters and wax esters. Despite being crucial for interpreting SCDs roles across species, the evolutionary history of the SCD gene family in vertebrates has yet to be elucidated, in particular their isoform diversity, origin and function. This work aims to contribute to this fundamental effort. RESULTS: We show here, through comparative genomics and phylogenetics that the SCD gene family underwent an unexpectedly complex history of duplication and loss events. Paralogy analysis hints that SCD1 and SCD5 genes emerged as part of the whole genome duplications (2R) that occurred at the stem of the vertebrate lineage. The SCD1 gene family expanded in rodents with the parallel loss of SCD5 in the Muridae family. The SCD1 gene expansion is also observed in the Lagomorpha although without the SCD5 loss. In the amphibian Xenopus tropicalis we find a single SCD1 gene but not SCD5, though this could be due to genome incompleteness. In the analysed teleost species no SCD5 is found, while the surrounding SCD5-less locus is conserved in comparison to tetrapods. In addition, the teleost SCD1 gene repertoire expanded to two copies as a result of the teleost specific genome duplication (3R). Finally, we describe clear orthologues of SCD1 and SCD5 in the chondrichthian, Scyliorhinus canicula, a representative of the oldest extant jawed vertebrate clade. Expression analysis in S. canicula shows that whilst SCD1 is ubiquitous, SCD5 is mainly expressed in the brain, a pattern which might indicate an evolutionary conserved function. CONCLUSION: We conclude that the SCD1 and SCD5 genes emerged as part of the 2R genome duplications. We propose that the evolutionary conserved gene expression between distinct lineages underpins the importance of SCD activity in the brain (and probably the pancreas), in a yet to be defined role. We argue that an expression independent of an external stimulus, such as diet induced activity, emerged as a novel function in vertebrate ancestry allocated to the SCD5 isoform in various tissues (e.g. brain and pancreas), and it was selectively maintained throughout vertebrate evolution. PMID- 21595942 TI - Novel viral vectors utilizing intron splice-switching to activate genome rescue, expression and replication in targeted cells. AB - BACKGROUND: The outcome of virus infection depends from the precise coordination of viral gene expression and genome replication. The ability to control and regulate these processes is therefore important for analysis of infection process. Viruses are also useful tools in bio- and gene technology; they can efficiently kill cancer cells and trigger immune responses to tumors. However, the methods for constructing tissue- or cell-type specific viruses typically suffer from low target-cell specificity and a high risk of reversion. Therefore novel and universal methods of regulation of viral infection are also important for therapeutic application of virus-based systems. METHODS: Aberrantly spliced introns were introduced into crucial gene-expression units of adenovirus vector and alphavirus DNA/RNA layered vectors and their effects on the viral gene expression, replication and/or the release of infectious genomes were studied in cell culture. Transfection of the cells with splice-switching oligonucleotides was used to correct the introduced functional defect(s). RESULTS: It was demonstrated that viral gene expression, replication and/or the release of infectious genomes can be blocked by the introduction of aberrantly spliced introns. The insertion of such an intron into an adenovirus vector reduced the expression of the targeted gene more than fifty-fold. A similar insertion into an alphavirus DNA/RNA layered vector had a less dramatic effect; here, only the release of the infectious transcript was suppressed but not the subsequent replication and spread of the virus. However the insertion of two aberrantly spliced introns resulted in an over one hundred-fold reduction in the infectivity of the DNA/RNA layered vector. Furthermore, in both systems the observed effects could be reverted by the delivery of splice-switching oligonucleotide(s), which corrected the splicing defects. CONCLUSIONS: Splice-switch technology, originally developed for genetic disease therapy, can also be used to control gene expression of viral vectors. This approach represents a novel, universal and powerful method for controlling gene expression, replication, viral spread and, by extension, virus-induced cytotoxic effects and can be used both for basic studies of virus infection and in virus-based gene- and anti-cancer therapy. PMID- 21595944 TI - Persistent neutrophilic meningitis in an immunocompetent patient after basilar skull fracture: case report. AB - BACKGROUND: Persistent neutrophilic meningitis is an unusual form of chronic meningitis that is defined as clinical meningitis with a neutrophilic pleocytosis that persists for greater than 7 days despite empiric antimicrobial therapy. Although numerous disease processes can cause this syndrome, the majority of cases are due to opportunistic pathogens infecting immunocompromised hosts. CASE PRESENTATION: A 47 year-old female presented after basilar skull fracture with persistent neutrophilic meningitis unresponsive to empiric broad-spectrum antibiotics. After more than weeks of intensive therapy, 4 hospitalizations and 3 relapses, Nocardia cyriacigeorgica was identified from cerebral spinal fluid. Induction therapy was begun with Ceftriaxone and trimethoprim-sulfamethoxazole (TMP-SMX) for 6 weeks followed by therapy with TMP-SMX and doxycycline for one year. The patient made a complete recovery without sequelae. CONCLUSIONS: Due to the difficulty in obtaining a microbiologic diagnosis, appropriate treatment in cases of persistent neutrophilic meningitis is often delayed leading to morbidity, This case highlights a number of the unique features of Nocardia meningitis and the importance of considering Nocardia infection as a cause of persistent neutrophilic meningitis even in immunocompetent patients. PMID- 21595945 TI - Benzodiazepine use and misuse among patients in a methadone program. AB - BACKGROUND: Benzodiazepines (BZD) misuse is a serious public health problem, especially among opiate-dependent patients with anxiety enrolled in methadone program because it puts patients at higher risk of life-threatening multiple drug overdoses. Both elevated anxiety and BZD misuse increase the risk for ex-addicts to relapse. However, there is no recent study to assess how serious the problem is and what factors are associated with BZD misuse. This study estimates the prevalence of BZD misuse in a methadone program, and provides information on the characteristics of BZD users compared to non-users. METHODS: An anonymous survey was carried out at a methadone program in Baltimore, MD, and all patients were invited to participate through group meetings and fliers around the clinic on a voluntary basis. Of the 205 returned questionnaires, 194 were complete and entered into final data analysis. Those who completed the questionnaire were offered a $5 gift card as an appreciation. RESULTS: 47% of the respondents had a history of BZD use, and 39.8% used BZD without a prescription. Half of the BZD users (54%) started using BZD after entering the methadone program, and 61% of previous BZD users reported increased or resumed use after entering methadone program. Compared to the non-users, BZD users were more likely to be White, have prescribed medication for mental problems, have preexistent anxiety problems before opiate use, and had anxiety problems before entering methadone program. They reported more mental health problems in the past month, and had higher scores in anxiety state, depression and perceived stress (p < .05). CONCLUSIONS: Important information on epidemiology of BZD misuse among methadone-maintenance patients suggests that most methadone programs do not address co-occurring anxiety problems, and methadone treatment may trigger onset or worsening of BZD misuse. Further study is needed to explore how to curb misuse and abuse of BZD in the addiction population, and provide effective treatments targeting simultaneously addiction symptoms, anxiety disorders and BZD misuse. PMID- 21595946 TI - Development of modelling method selection tool for health services management: from problem structuring methods to modelling and simulation methods. AB - BACKGROUND: There is an increasing recognition that modelling and simulation can assist in the process of designing health care policies, strategies and operations. However, the current use is limited and answers to questions such as what methods to use and when remain somewhat underdeveloped. AIM: The aim of this study is to provide a mechanism for decision makers in health services planning and management to compare a broad range of modelling and simulation methods so that they can better select and use them or better commission relevant modelling and simulation work. METHODS: This paper proposes a modelling and simulation method comparison and selection tool developed from a comprehensive literature review, the research team's extensive expertise and inputs from potential users. Twenty-eight different methods were identified, characterised by their relevance to different application areas, project life cycle stages, types of output and levels of insight, and four input resources required (time, money, knowledge and data). RESULTS: The characterisation is presented in matrix forms to allow quick comparison and selection. This paper also highlights significant knowledge gaps in the existing literature when assessing the applicability of particular approaches to health services management, where modelling and simulation skills are scarce let alone money and time. CONCLUSIONS: A modelling and simulation method comparison and selection tool is developed to assist with the selection of methods appropriate to supporting specific decision making processes. In particular it addresses the issue of which method is most appropriate to which specific health services management problem, what the user might expect to be obtained from the method, and what is required to use the method. In summary, we believe the tool adds value to the scarce existing literature on methods comparison and selection. PMID- 21595947 TI - Expression of neuroimmune semaphorins 4A and 4D and their receptors in the lung is enhanced by allergen and vascular endothelial growth factor. AB - BACKGROUND: Semaphorins were originally identified as molecules regulating a functional activity of axons in the nervous system. Sema4A and Sema4D were the first semaphorins found to be expressed on immune cells and were termed "immune semaphorins". It is known that Sema4A and Sema4D bind Tim-2 and CD72 expressed on leukocytes and PlexinD1 and B1 present on non-immune cells. These neuroimmune semaphorins and their receptors have been shown to play critical roles in many physiological and pathological processes including neuronal development, immune response regulation, cancer, autoimmune, cardiovascular, renal, and infectious diseases. However, the expression and regulation of Sema4A, Sema4D, and their receptors in normal and allergic lungs is undefined. RESULTS: Allergen treatment and lung-specific vascular endothelial growth factor (VEGF) expression induced asthma-like pathologies in the murine lungs. These experimental models of allergic airway inflammation were used for the expression analysis of immune semaphorins and their receptors employing immunohistochemistry and flow cytometry techniques. We found that besides accessory-like cells, Sema4A was also detected on bronchial epithelial and smooth muscle cells, whereas Sema4D expression was high on immune cells such as T and B lymphocytes. Surprisingly, under inflammation various cell types including macrophages, lymphocytes, and granulocytes in the lung expressed Tim-2, a previously defined marker for Th2 cells. CD72 was found on lung immune, inflammatory, and epithelial cells. Bronchial epithelial cells were positive for both plexins, whereas some endothelial cells selectively expressed Plexin D1. Plexin B1 expression was also detected on lung DC. Both allergen and VEGF upregulated the expression of neuroimmune semaphorins and their receptors in the lung tissue. However, the lung tissue Sema4A-Tim2 expression was rather weak, whereas Sema4D-CD72 ligand receptor pair was vastly upregulated by allergen. Soluble Sema4D protein was present in the lung lysates and a whole Sema4A protein plus its dimer were readily detected in the bronchoalveolar (BAL) fluids under inflammation. CONCLUSIONS: This study clearly shows that neuroimmune semaphorins Sema4A and Sema4D and their receptors might serve as potential markers for the allergic airway inflammatory diseases. Our current findings pave the way for further investigations of the role of immune semaphorins in inflammation and their use as potential therapeutic targets for the inflammatory lung conditions. PMID- 21595948 TI - Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation. AB - BACKGROUND: Accumulation of aberrant proteins to form Lewy bodies (LBs) is a hallmark of Parkinson's disease (PD). Ubiquitination-mediated degradation of aberrant, misfolded proteins is critical for maintaining normal cell function. Emerging evidence suggests that oxidative/nitrosative stress compromises the precisely-regulated network of ubiquitination in PD, particularly affecting parkin E3 ligase activity, and contributes to the accumulation of toxic proteins and neuronal cell death. RESULTS: To gain insight into the mechanism whereby cell stress alters parkin-mediated ubiquitination and LB formation, we investigated the effect of oxidative stress. We found significant increases in oxidation (sulfonation) and subsequent aggregation of parkin in SH-SY5Y cells exposed to the mitochondrial complex I inhibitor 1-methyl-4-phenlypyridinium (MPP+), representing an in vitro cell-based PD model. Exposure of these cells to direct oxidation via pathological doses of H2O2 induced a vicious cycle of increased followed by decreased parkin E3 ligase activity, similar to that previously reported following S-nitrosylation of parkin. Pre-incubation with catalase attenuated H2O2 accumulation, parkin sulfonation, and parkin aggregation. Mass spectrometry (MS) analysis revealed that H2O2 reacted with specific cysteine residues of parkin, resulting in sulfination/sulfonation in regions of the protein similar to those affected by parkin mutations in hereditary forms of PD. Immunohistochemistry or gel electrophoresis revealed an increase in aggregated parkin in rats and primates exposed to mitochondrial complex I inhibitors, as well as in postmortem human brain from patients with PD with LBs. CONCLUSION: These findings show that oxidative stress alters parkin E3 ligase activity, leading to dysfunction of the ubiquitin-proteasome system and potentially contributing to LB formation. PMID- 21595949 TI - Multi-source analysis reveals latitudinal and altitudinal shifts in range of Ixodes ricinus at its northern distribution limit. AB - BACKGROUND: There is increasing evidence for a latitudinal and altitudinal shift in the distribution range of Ixodes ricinus. The reported incidence of tick-borne disease in humans is on the rise in many European countries and has raised political concern and attracted media attention. It is disputed which factors are responsible for these trends, though many ascribe shifts in distribution range to climate changes. Any possible climate effect would be most easily noticeable close to the tick's geographical distribution limits. In Norway- being the northern limit of this species in Europe- no documentation of changes in range has been published. The objectives of this study were to describe the distribution of I. ricinus in Norway and to evaluate if any range shifts have occurred relative to historical descriptions. METHODS: Multiple data sources - such as tick-sighting reports from veterinarians, hunters, and the general public - and surveillance of human and animal tick-borne diseases were compared to describe the present distribution of I. ricinus in Norway. Correlation between data sources and visual comparison of maps revealed spatial consistency. In order to identify the main spatial pattern of tick abundance, a principal component analysis (PCA) was used to obtain a weighted mean of four data sources. The weighted mean explained 67% of the variation of the data sources covering Norway's 430 municipalities and was used to depict the present distribution of I. ricinus. To evaluate if any geographical range shift has occurred in recent decades, the present distribution was compared to historical data from 1943 and 1983. RESULTS: Tick-borne disease and/or observations of I. ricinus was reported in municipalities up to an altitude of 583 metres above sea level (MASL) and is now present in coastal municipalities north to approximately 69 degrees N. CONCLUSION: I. ricinus is currently found further north and at higher altitudes than described in historical records. The approach used in this study, a multi source analysis, proved useful to assess alterations in tick distribution. PMID- 21595950 TI - Infraglenoidal scapular notching in reverse total shoulder replacement: a prospective series of 60 cases and systematic review of the literature. AB - BACKGROUND: The impact of infraglenoidal scapular notching in reversed total shoulder arthroplasty (RTSA) is still controversially discussed. Our goal was to evaluate its potential influence on subjective shoulder stability and clinical outcome. We hypothesized that subjective instability and clinical outcome after implantation of RTSA correlates with objective scapular notching. METHODS: Sixty shoulders were assessed preoperatively and at minimum 2-year follow-up for active range of motion and by use of the Oxford instability score, Rowe score for instability, Constant score for pain, Constant shoulder score, DASH score. All shoulders were evaluated on anterior-posterior and axillary lateral radiographic views. These X-ray scans were classified twice by two orthopaedic surgeons with respect to infraglenoidal scapular notching according to the classification of Nerot. Notching was tested for correlation with clinical outcome scores to the evaluated notching. RESULTS: We found no significant correlation between infraglenoidal scapular notching and clinical outcomes after a mid-term follow-up from 24 to 60 months, but at the final follow-up of 60 months and more, we did see statistically significant, positive correlations between infraglenoidal scapular notching and the Constant pain score as well as active range of motion. At mean follow-up of 42 months (range from 24 to 96 months) we found no significant correlation between subjective instability and infraglenoidal scapular notching. CONCLUSIONS: We conclude that patients' subjective impression on their shoulders' stability is not correlating with radiological signs of infraglenoidal scapular notching. Nevertheless clinical parameters are affected by infraglenoidal scapular notching, at least in the long term. PMID- 21595951 TI - Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. AB - BACKGROUND: This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed. METHODS: This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan Meier curves and treatment comparisons made with the log-rank test. RESULTS: There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms. CONCLUSIONS: Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC. PMID- 21595952 TI - A transcriptional analysis of carotenoid, chlorophyll and plastidial isoprenoid biosynthesis genes during development and osmotic stress responses in Arabidopsis thaliana. AB - BACKGROUND: The carotenoids are pure isoprenoids that are essential components of the photosynthetic apparatus and are coordinately synthesized with chlorophylls in chloroplasts. However, little is known about the mechanisms that regulate carotenoid biosynthesis or the mechanisms that coordinate this synthesis with that of chlorophylls and other plastidial synthesized isoprenoid-derived compounds, including quinones, gibberellic acid and abscisic acid. Here, a comprehensive transcriptional analysis of individual carotenoid and isoprenoid related biosynthesis pathway genes was performed in order to elucidate the role of transcriptional regulation in the coordinated synthesis of these compounds and to identify regulatory components that may mediate this process in Arabidopsis thaliana. RESULTS: A global microarray expression correlation analysis revealed that the phytoene synthase gene, which encodes the first dedicated and rate limiting enzyme of carotenogenesis, is highly co-expressed with many photosynthesis-related genes including many isoprenoid-related biosynthesis pathway genes. Chemical and mutant analysis revealed that induction of the co expressed genes following germination was dependent on gibberellic acid and brassinosteroids (BR) but was inhibited by abscisic acid (ABA). Mutant analyses further revealed that expression of many of the genes is suppressed in dark grown plants by Phytochrome Interacting transcription Factors (PIFs) and activated by photoactivated phytochromes, which in turn degrade PIFs and mediate a coordinated induction of the genes. The promoters of PSY and the co-expressed genes were found to contain an enrichment in putative BR-auxin response elements and G boxes, which bind PIFs, further supporting a role for BRs and PIFs in regulating expression of the genes. In osmotically stressed root tissue, transcription of Calvin cycle, methylerythritol 4-phosphate pathway and carotenoid biosynthesis genes is induced and uncoupled from that of chlorophyll biosynthesis genes in a manner that is consistent with the increased synthesis of carotenoid precursors for ABA biosynthesis. In all tissues examined, induction of beta-carotene hydroxylase transcript levels are linked to an increased demand for ABA. CONCLUSIONS: This analysis provides compelling evidence to suggest that coordinated transcriptional regulation of isoprenoid-related biosynthesis pathway genes plays a major role in coordinating the synthesis of functionally related chloroplast localized isoprenoid-derived compounds. PMID- 21595953 TI - Regional chemotherapy in locally advanced pancreatic cancer: RECLAP trial. AB - BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death in the United States. Surgery offers the only chance for cure. However, less than twenty percent of patients are considered operative candidates at the time of diagnosis. A common reason for being classified as unresectable is advanced loco-regional disease.A review of the literature indicates that almost nine hundred patients with pancreatic cancer have received regional chemotherapy in the last 15 years. Phase I studies have shown regional administration of chemotherapy to be safe. The average reported response rate was approximately 26%. The average 1-year survival was 39%, with an average median survival of 9 months. Of the patients that experienced a radiographic response to therapy, 78 (78/277, 28%) patients underwent exploratory surgery following regional chemotherapy administration; thirty-two (41%) of those patients were amenable to pancreatectomy. None of the studies performed analyses to identify factors predicting response to regional chemotherapy.Progressive surgical techniques combined with current neoadjuvant chemoradiotherapy strategies have already yielded emerging support for a multimodality approach to treatment of advanced pancreatic cancer.Intravenous gemcitabine is the current standard treatment of pancreatic cancer. However, >90% of the drug is secreted unchanged affecting toxicity but not the cancer per se. Gemcitabine is converted inside the cell into its active drug form in a rate limiting reaction. We hypothesize that neoadjuvant regional chemotherapy with continuous infusion of gemcitabine will be well tolerated and may improve resectability rates in cases of locally advanced pancreatic cancer. DESIGN: This is a phase I study designed to evaluate the feasibility and toxicity of super selective intra-arterial administration of gemcitabine in patients with locally advanced, unresectable pancreatic adenocarcinoma. Patients considered unresectable due to locally advanced pancreatic cancer will receive super selective arterial infusion of gemcitabine over 24 hours via subcutaneous indwelling port. Three to six patients will be enrolled per dose cohort, with seven cohorts, plus an additional six patients at the maximum tolerated dose; accrual is expected to last 36 months. Secondary objectives will include the determination of progression free and overall survival, as well as the conversion rate from unresectable to potentially resectable pancreatic cancer. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01294358. PMID- 21595954 TI - Association of PGC-1alpha polymorphisms with age of onset and risk of Parkinson's disease. AB - BACKGROUND: Peroxisome proliferator-activated receptor-gamma co-activator (PGC) 1alpha is a transcriptional co-activator of antioxidant genes and a master regulator of mitochondrial biogenesis. Parkinson's disease (PD) is associated with oxidative stress and mitochondrial dysfunction and recent work suggests a role for PGC-1alpha. We hypothesized that the rs8192678 PGC-1alpha single nucleotide polymorphism (SNP) may influence risk or age of onset of PD. The A10398G mitochondrial SNP has been inversely associated with risk of PD in some studies. In the current study we analyzed whether rs8192678 or other PGC-1alpha SNPs affect PD risk or age of onset, singularly or in association with the A10398G SNP. METHODS: Genomic DNA samples from 378 PD patients and 173 age matched controls were analyzed by multiplexed probe sequencing, followed by statistical analyses of the association of each SNP, alone or in combination, with risk or age of onset of PD. Adjustments were made for age of onset being less than the age of sampling, and for the observed dependence between these two ages. The PD samples were obtained as two separate cohorts, therefore statistical methods accounted for different sampling methods between the two cohorts, and data were analyzed using Cox regression adjusted for sampling in the risk set definition and in the model. RESULTS: The rs8192678 PGC-1alpha SNP was not associated with the risk of PD. However, an association of the PGC-1alpha rs8192678 GG variant with longevity was seen in control subjects (p=0.019). Exploratory studies indicated that the CC variant of rs6821591 was associated with risk of early onset PD (p=0.029), with PD age of onset (p=0.047), and with longevity (p=0.022). The rs2970848 GG allele was associated with risk of late onset PD (p=0.027). CONCLUSIONS: These data reveal possible associations of the PGC-1alpha SNPs rs6821591 and rs2970848 with risk or age of onset of PD, and of the PGC-1alpha rs8192678 GG and the rs6821591 CC variants with longevity. If replicated in other datasets, these findings may have important implications regarding the role of PGC-1alpha in PD and longevity. PMID- 21595955 TI - Population-level effects of the national diabetes prevention programme (FIN-D2D) on the body weight, the waist circumference, and the prevalence of obesity. AB - BACKGROUND: The implementation project of the national diabetes prevention programme in Finland, FIN-D2D, was carried out in primary health care in the area of five hospital districts during 2003-2007. METHODS: The population strategy of FIN-D2D was primarily aimed at increasing the awareness of type 2 diabetes and preventing obesity. To investigate the effects of this strategy, we studied the changes in the prevalence of obesity, overweight, and central obesity among a random independent sample of individuals aged 45-74 years in the FIN-D2D area; and assessed whether they differed from a sample of individuals in the control area, which consisted of four geographical areas not participating in FIN-D2D (FINRISK study). Data was obtained for 5850/ 6406 (in the beginning/ in the end) individuals. The duration of the observation period varied from three to five years. RESULTS: The mean body weight decreased from 78.7 to 78.1 kg (p = 0.041) in the FIN-D2D area, and from 78.7 to 78.0 kg (p = NS) in the control area. The prevalence of obesity (BMI >=30 kg/m(2)) decreased in the FIN-D2D area (26.5% vs. 24.4%, p = 0.015), and in the control area (28.4% vs. 25.2%, p = 0.005). The prevalence of morbid obesity (BMI >=40 kg/m(2)) remained unchanged in the FIN-D2D area, but increased in the control area (1.2% vs. 2.3%, p = 0.007). The mean waist circumference remained unchanged in the FIN-D2D area, but increased in the control area (92.8 vs. 94.0 cm, p = 0.005). CONCLUSIONS: The prevalence of obesity may be decreasing among 45-74 year old Finns. We still need a longer time perspective and future studies to see whether this favourable trend can be sustained in Finland. The actions of this implementation project can at least partly explain the differences in the mean waist circumference and the prevalence of morbid obesity between the intervention and control areas. PMID- 21595956 TI - Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced sickness behavior. AB - BACKGROUND: Interleukin (IL)-6 is produced in the brain during peripheral infection and plays an important but poorly understood role in sickness behavior. Therefore, this study investigated the capacity of soluble gp130 (sgp130), a natural inhibitor of the IL-6 trans-signaling pathway to regulate IL-6 production in microglia and neurons in vitro and its effects on lipopolysaccharide (LPS) induced sickness behavior in vivo. METHODS: A murine microglia (BV.2) and neuronal cell line (Neuro.2A) were used to study the effects of stimulating and inhibiting the IL-6 signaling pathway in vitro. In vivo, adult (3-6 mo) BALB/c mice received an intracerebroventricular (ICV) injection of sgp130 followed by an intraperitoneal (i.p.) injection of LPS, and sickness behavior and markers of neuroinflammation were measured. RESULTS: Soluble gp130 attenuated IL-6- and LPS stimulated IL-6 receptor (IL-6R) activation along with IL-6 protein release in both microglial (BV.2) and neuronal (Neuro.2A) cell types in vitro. Moreover, in vivo experiments showed that sgp130 facilitated recovery from LPS-induced sickness, and this sgp130-associated recovery was paralleled by reduced IL-6 receptor signaling, mRNA, and protein levels of IL-6 in the hippocampus. CONCLUSIONS: Taken together, the results show that sgp130 may exert an anti inflammatory effect on microglia and neurons by inhibiting IL-6 binding. These data indicate that sgp130 inhibits the LPS-induced IL-6 trans-signal and show IL 6 and its receptor are involved in maintaining sickness behavior. PMID- 21595957 TI - HIV and incarceration: prisons and detention. AB - The high prevalence of HIV infection among prisoners and pre-trial detainees, combined with overcrowding and sub-standard living conditions sometimes amounting to inhuman or degrading treatment in violation of international law, make prisons and other detention centres a high risk environment for the transmission of HIV. Ultimately, this contributes to HIV epidemics in the communities to which prisoners return upon their release. We reviewed the evidence regarding HIV prevalence, risk behaviours and transmission in prisons. We also reviewed evidence of the effectiveness of interventions and approaches to reduce the risk behaviours and, consequently, HIV transmission in prisons. A large number of studies report high levels of risk behaviour in prisons, and HIV transmission has been documented. There is a large body of evidence from countries around the world of what prison systems can do to prevent HIV transmission. In particular, condom distribution programmes, accompanied by measures to prevent the occurrence of rape and other forms of non-consensual sex, needle and syringe programmes and opioid substitution therapies, have proven effective at reducing HIV risk behaviours in a wide range of prison environments without resulting in negative consequences for the health of prison staff or prisoners.The introduction of these programmes in prisons is therefore warranted as part of comprehensive programmes to address HIV in prisons, including HIV education, voluntary HIV testing and counselling, and provision of antiretroviral treatment for HIV positive prisoners. In addition, however, action to reduce overcrowding and improve conditions in detention is urgently needed. PMID- 21595958 TI - Modeling microRNA-mRNA interactions using PLS regression in human colon cancer. AB - BACKGROUND: Changes in microRNA (miRNA) expression patterns have been extensively characterized in several cancers, including human colon cancer. However, how these miRNAs and their putative mRNA targets contribute to the etiology of cancer is poorly understood. In this work, a bioinformatics computational approach with miRNA and mRNA expression data was used to identify the putative targets of miRNAs and to construct association networks between miRNAs and mRNAs to gain some insights into the underlined molecular mechanisms of human colon cancer. METHOD: The miRNA and mRNA microarray expression profiles from the same tissues including 7 human colon tumor tissues and 4 normal tissues, collected by the Broad Institute, were used to identify significant associations between miRNA and mRNA. We applied the partial least square (PLS) regression method and bootstrap based statistical tests to the joint expression profiles of differentially expressed miRNAs and mRNAs. From this analysis, we predicted putative miRNA targets and association networks between miRNAs and mRNAs. Pathway analysis was employed to identify biological processes related to these miRNAs and their associated predicted mRNA targets. RESULTS: Most significantly associated up regulated mRNAs with a down-regulated miRNA identified by the proposed methodology were considered to be the miRNA targets. On average, approximately 16.5% and 11.0% of targets predicted by this approach were also predicted as targets by the common prediction algorithms TargetScan and miRanda, respectively. We demonstrated that our method detects more targets than a simple correlation based association. Integrative mRNA:miRNA predictive networks from our analysis were constructed with the aid of Cytoscape software. Pathway analysis validated the miRNAs through their predicted targets that may be involved in cancer associated biological networks. CONCLUSION: We have identified an alternative bioinformatics approach for predicting miRNA targets in human colon cancer and for reverse engineering the miRNA:mRNA network using inversely related mRNA and miRNA joint expression profiles. We demonstrated the superiority of our predictive method compared to the correlation based target prediction algorithm through a simulation study. We anticipate that the unique miRNA targets predicted by the proposed method will advance the understanding of the molecular mechanism of colon cancer and will suggest novel therapeutic targets after further experimental validations. PMID- 21595959 TI - Factors influencing cancer risk perception in high risk populations: a systematic review. AB - BACKGROUND: Patients at higher than average risk of heritable cancer may process risk information differently than the general population. However, little is known about clinical, demographic, or psychosocial predictors that may impact risk perception in these groups. The objective of this study was to characterize factors associated with perceived risk of developing cancer in groups at high risk for cancer based on genetics or family history. METHODS: We searched Ovid MEDLINE, Ovid Embase, Ovid PsycInfo, and Scopus from inception through April 2009 for English-language, original investigations in humans using core concepts of "risk" and "cancer." We abstracted key information and then further restricted articles dealing with perceived risk of developing cancer due to inherited risk. RESULTS: Of 1028 titles identified, 53 articles met our criteria. Most (92%) used an observational design and focused on women (70%) with a family history of or contemplating genetic testing for breast cancer. Of the 53 studies, 36 focused on patients who had not had genetic testing for cancer risk, 17 included studies of patients who had undergone genetic testing for cancer risk. Family history of cancer, previous prophylactic tests and treatments, and younger age were associated with cancer risk perception. In addition, beliefs about the preventability and severity of cancer, personality factors such as "monitoring" personality, the ability to process numerical information, as well as distress/worry also were associated with cancer risk perception. Few studies addressed non-breast cancer or risk perception in specific demographic groups (e.g. elderly or minority groups) and few employed theory-driven analytic strategies to decipher interrelationships of factors. CONCLUSIONS: Several factors influence cancer risk perception in patients at elevated risk for cancer. The science of characterizing and improving risk perception in cancer for high risk groups, although evolving, is still relatively undeveloped in several key topic areas including cancers other than breast and in specific populations. Future rigorous risk perception research using experimental designs and focused on cancers other than breast would advance the field. PMID- 21595960 TI - Toward an interactive article: integrating journals and biological databases. AB - BACKGROUND: Journal articles and databases are two major modes of communication in the biological sciences, and thus integrating these critical resources is of urgent importance to increase the pace of discovery. Projects focused on bridging the gap between journals and databases have been on the rise over the last five years and have resulted in the development of automated tools that can recognize entities within a document and link those entities to a relevant database. Unfortunately, automated tools cannot resolve ambiguities that arise from one term being used to signify entities that are quite distinct from one another. Instead, resolving these ambiguities requires some manual oversight. Finding the right balance between the speed and portability of automation and the accuracy and flexibility of manual effort is a crucial goal to making text markup a successful venture. RESULTS: We have established a journal article mark-up pipeline that links GENETICS journal articles and the model organism database (MOD) WormBase. This pipeline uses a lexicon built with entities from the database as a first step. The entity markup pipeline results in links from over nine classes of objects including genes, proteins, alleles, phenotypes and anatomical terms. New entities and ambiguities are discovered and resolved by a database curator through a manual quality control (QC) step, along with help from authors via a web form that is provided to them by the journal. New entities discovered through this pipeline are immediately sent to an appropriate curator at the database. Ambiguous entities that do not automatically resolve to one link are resolved by hand ensuring an accurate link. This pipeline has been extended to other databases, namely Saccharomyces Genome Database (SGD) and FlyBase, and has been implemented in marking up a paper with links to multiple databases. CONCLUSIONS: Our semi-automated pipeline hyperlinks articles published in GENETICS to model organism databases such as WormBase. Our pipeline results in interactive articles that are data rich with high accuracy. The use of a manual quality control step sets this pipeline apart from other hyperlinking tools and results in benefits to authors, journals, readers and databases. PMID- 21595961 TI - Food and macronutrient intake of elite Ethiopian distance runners. AB - BACKGROUND: Explanations for the phenomenal success of East African distance runners include unique dietary practices. The aim of the present study was to assess the food and macronutrient intake of elite Ethiopian distance runners during a period of high intensity exercise training at altitude and prior to major competition. METHODS: The dietary intake of 10 highly-trained Ethiopian long distance runners, living and training at high altitude (approximately 2400 m above sea level) was assessed during a 7 day period of intense training prior to competition using the standard weighed intake method. Training was also assessed using an activity/training diary. RESULTS: Body mass was stable (i.e., was well maintained) over the assessment period (pre: 56.7 +/- 4.3 kg vs. post: 56.6 +/- 4.2 kg, P = 0.54; mean +/- SD). The diet comprised of 13375 +/- 1378 kJ and was high in carbohydrate (64.3 +/- 2.6%, 545 +/- 49 g, 9.7 +/- 0.9 g/kg). Fat and protein intake was 23.3 +/- 2.1% (83 +/- 14 g) and 12.4 +/- 0.6% (99 +/- 13 g, 1.8 +/- 0.2 g/kg), respectively. Fluid intake comprised mainly of water (1751 +/- 583 mL), while no fluids were consumed before or during training with only modest amounts being consumed following training. CONCLUSIONS: Similar to previous studies in elite Kenyan distance runners, the diet of these elite Ethiopian distance runners met most recommendations of endurance athletes for macronutrient intake but not for fluid intake. PMID- 21595962 TI - A general life history theory for effects of caloric restriction on health maintenance. AB - BACKGROUND: Caloric restriction (CR) has been shown to keep organisms in a relatively youthful and healthy state compared to ad libitum fed counterparts, as well as to extend the lifespan of a diverse set of organisms. Several attempts have been made to understand the underlying mechanisms from the viewpoint of energy tradeoffs in organisms' life histories. However, most models are based on assumptions which are difficult to justify, or are endowed with free-adjusting parameters whose biological relevancy is unclear. RESULTS: In this paper, we derive a general quantitative, predictive model based on physiological data for endotherms. We test the hypothesis that an animal's state of health is correlated with biological mechanisms responsible for the maintenance of that animal's functional integrities. Such mechanisms require energy. By suppressing animals' caloric energy supply and biomass synthesis, CR alters animals' energy allocation strategies and channels additional energy to those maintenance mechanisms, therefore enhancing their performance. Our model corroborates the observation that CR's effects on health maintenance are positively correlated with the degree and duration of CR. Furthermore, our model shows that CR's effects on health maintenance are negatively correlated to the temperature drop observed in endothermic animals, and is positively correlated to animals' body masses. These predictions can be tested by further experimental research. CONCLUSION: Our model reveals how animals will alter their energy budget when food availability is low, and offers better understanding of the tradeoffs between growth and somatic maintenance; therefore shedding new light on aging research from an energetic viewpoint. PMID- 21595963 TI - Community acquired bacteremia in young children from central Nigeria--a pilot study. AB - BACKGROUND: Reports of the etiology of bacteremia in children from Nigeria are sparse and have been confounded by wide spread non-prescription antibiotic use and suboptimal laboratory culture techniques. We aimed to determine causative agents and underlying predisposing conditions of bacteremia in Nigerian children using data arising during the introduction of an automated blood culture system accessed by 7 hospitals and clinics in the Abuja area. METHODS: Between September 2008 and November 2009, we enrolled children with clinically suspected bacteremia at rural and urban clinical facilities in Abuja or within the Federal Capital Territory of Nigeria. Blood was cultured using an automated system with antibiotic removing device. We documented clinical features in all children and tested for prior antibiotic use in a random sample of sera from children from each site. RESULTS: 969 children aged 2 months-5 years were evaluated. Mean age was 21+/-15.2 months. All children were not systematically screened but there were 59 (6%) children with established diagnosis of sickle cell disease and 42 (4.3%) with HIV infection. Overall, 212 (20.7%) had a positive blood culture but in only 105 (10.8%) were these considered to be clinically significant. Three agents, Staphylococcus aureus (20.9%), Salmonella typhi (20.9%) and Acinetobacter (12.3%) accounted for over half of the positive cultures. Streptococcus pneumoniae and non-typhi Salmonellae each accounted for 7.6%. Although not the leading cause of bacteremia, Streptococcus pneumoniae was the single leading cause of all deaths that occurred during hospitalization and after hospital discharge. CONCLUSION: S. typhi is a significant cause of vaccine-preventable morbidity while S. pneumoniae may be a leading cause of mortality in this setting. This observation contrasts with reports from most other African countries where non-typhi Salmonellae are predominant in young children. Expanded surveillance is required to confirm the preliminary observations from this pilot study to inform implementation of appropriate public health control measures. PMID- 21595964 TI - Agrobacterium-mediated genetic transformation of Coffea arabica (L.) is greatly enhanced by using established embryogenic callus cultures. AB - BACKGROUND: Following genome sequencing of crop plants, one of the main challenges today is determining the function of all the predicted genes. When gene validation approaches are used for woody species, the main obstacle is the low recovery rate of transgenic plants from elite or commercial cultivars. Embryogenic calli have frequently been the target tissue for transformation, but the difficulty in producing or maintaining embryogenic tissues is one of the main problems encountered in genetic transformation of many woody plants, including Coffea arabica. RESULTS: We identified the conditions required for successful long-term proliferation of embryogenic cultures in C. arabica and designed a highly efficient and reliable Agrobacterium tumefaciens-mediated transformation method based on these conditions. The transformation protocol with LBA1119 harboring pBin 35S GFP was established by evaluating the effect of different parameters on transformation efficiency by GFP detection. Using embryogenic callus cultures, co-cultivation with LBA1119 OD600 = 0.6 for five days at 20 degrees C enabled reproducible transformation. The maintenance conditions for the embryogenic callus cultures, particularly a high auxin to cytokinin ratio, the age of the culture (optimum for 7-10 months of proliferation) and the use of a yellow callus phenotype, were the most important factors for achieving highly efficient transformation (> 90%). At the histological level, successful transformation was related to the number of proembryogenic masses present. All the selected plants were proved to be transformed by PCR and Southern blot hybridization. CONCLUSION: Most progress in increasing transformation efficiency in coffee has been achieved by optimizing the production conditions of embryogenic cultures used as target tissues for transformation. This is the first time that a strong positive effect of the age of the culture on transformation efficiency was demonstrated. Our results make Agrobacterium-mediated transformation of embryogenic cultures a viable and useful tool both for coffee breeding and for the functional analysis of agronomically important genes. PMID- 21595965 TI - Web-based metabolic network visualization with a zooming user interface. AB - BACKGROUND: Displaying complex metabolic-map diagrams, for Web browsers, and allowing users to interact with them for querying and overlaying expression data over them is challenging. DESCRIPTION: We present a Web-based metabolic-map diagram, which can be interactively explored by the user, called the Cellular Overview. The main characteristic of this application is the zooming user interface enabling the user to focus on appropriate granularities of the network at will. Various searching commands are available to visually highlight sets of reactions, pathways, enzymes, metabolites, and so on. Expression data from single or multiple experiments can be overlaid on the diagram, which we call the Omics Viewer capability. The application provides Web services to highlight the diagram and to invoke the Omics Viewer. This application is entirely written in JavaScript for the client browsers and connect to a Pathway Tools Web server to retrieve data and diagrams. It uses the OpenLayers library to display tiled diagrams. CONCLUSIONS: This new online tool is capable of displaying large and complex metabolic-map diagrams in a very interactive manner. This application is available as part of the Pathway Tools software that powers multiple metabolic databases including Biocyc.org: The Cellular Overview is accessible under the Tools menu. PMID- 21595967 TI - The impact of personality factors on delay in seeking treatment of acute myocardial infarction. AB - BACKGROUND: Early hospital arrival and rapid intervention for acute myocardial infarction is essential for a successful outcome. Several studies have been unable to identify explanatory factors that slowed decision time. The present study examines whether personality, psychosocial factors, and coping strategies might explain differences in time delay from onset of symptoms of acute myocardial infarction to arrival at a hospital emergency room. METHODS: Questionnaires on coping strategies, personality dimensions, and depression were completed by 323 patients ages 26 to 70 who had suffered an acute myocardial infarction. Tests measuring stress adaptation were completed by 180 of them. The patients were then categorised into three groups, based on time from onset of symptoms until arrival at hospital, and compared using logistic regression analysis and general linear models. RESULTS: No correlation could be established between personality factors (i.e., extraversion, neuroticism, openness, agreeableness, conscientiousness) or depressive symptoms and time between onset of symptoms and arrival at hospital. Nor was there any significant relationship between self-reported patient coping strategies and time delay. CONCLUSIONS: We found no significant relationship between personality factors, coping strategies, or depression and time delays in seeking hospital after an acute myocardial infraction. PMID- 21595966 TI - Alterations of lipid metabolism in Wilson disease. AB - INTRODUCTION: Wilson disease (WD) is an inherited disorder of human copper metabolism, characterised by accumulation of copper predominantly in the liver and brain, leading to severe hepatic and neurological disease. Interesting findings in animal models of WD (Atp7b-/- and LEC rats) showed altered lipid metabolism with a decrease in the amount of triglycerides and cholesterol in the serum. However, serum lipid profile has not been investigated in large human WD patient cohorts to date. PATIENTS AND METHODS: This cohort study involved 251 patients examined at the Heidelberg and Dresden (Germany) University Hospitals. Patients were analysed on routine follow-up examinations for serum lipid profile, including triglycerides, cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL). Data on these parameters at time of diagnosis were retrieved by chart review where available. For statistical testing, patients were subgrouped by sex, manifestation (hepatic, neurological, mixed and asymptomatic) and treatment (D-penicillamine, trientine, zinc or combination). RESULTS: A significant difference in total serum cholesterol was found in patients with hepatic symptoms, which diminished under therapy. No alterations were observed for HDL, LDL and triglycerides. CONCLUSION: Contradictory to previous reports using WD animal models (Atp7b-/- and LEC rats), the most obvious alteration in our cohort was a lower serum cholesterol level in hepatic-affected patients, which might be related to liver injury. Our data suggested unimpaired cholesterol metabolism in Wilson disease under therapy, independent of the applied medical treatment. PMID- 21595968 TI - Decompressive cervical laminectomy and lateral mass screw-rod arthrodesis. Surgical analysis and outcome. AB - BACKGROUND: This study evaluates the outcome and complications of decompressive cervical Laminectomy and lateral mass screw fixation in 110 cases treated for variable cervical spine pathologies that included; degenerative disease, trauma, neoplasms, metabolic-inflammatory disorders and congenital anomalies. METHODS: A retrospective review of total 785 lateral mass screws were placed in patients ages 16-68 years (40 females and 70 males). All cases were performed with a polyaxial screw-rod construct and screws were placed by using Anderson-Sekhon trajectory. Most patients had 12-14-mm length and 3.5 mm diameter screws placed for subaxial and 28-30 for C1 lateral mass. Screw location was assessed by post operative plain x-ray and computed tomography can (CT), besides that; the facet joint, nerve root foramen and foramen transversarium violation were also appraised. RESULTS: No patients experienced neural or vascular injury as a result of screw position. Only one patient needed screw repositioning. Six patients experienced superficial wound infection. Fifteen patients had pain around the shoulder of C5 distribution that subsided over the time. No patients developed screw pullouts or symptomatic adjacent segment disease within the period of follow up. CONCLUSION: decompressive cervical spine laminectomy and Lateral mass screw stabilization is a technique that can be used for a variety of cervical spine pathologies with safety and efficiency. PMID- 21595969 TI - A hepatitis A, B, C and HIV prevalence and risk factor study in ever injecting and non-injecting drug users in Luxembourg associated with HAV and HBV immunisations. AB - BACKGROUND: In Luxembourg, viral hepatitis and HIV infection data in problem drug users (PDUs) are primarily based on self-reporting. Our study aimed to determine the prevalence of HAV, HBV, HCV and HIV infections in ever injecting (IDUs) and non-injecting drug users (nIDUs) including inherent risk factors analysis for IDUs. Secondary objectives were immunisation against HAV and HBV, referral to care and treatment facilities as well as reduction in risk behaviour. METHODS: A nationwide, cross-sectional multi-site survey, involving 5 in-, 8 out-treatment and 2 prison centres, included both an assisted questionnaire (n = 368) and serological detection of HIV and Hepatitis A, B, C (n = 334). A response rate of 31% resulted in the participation of 310 IDUs and 58 nIDUs. Risk factors such as drug use, sexual behaviour, imprisonment, protection and health knowledge (HAV, HBV status and immunisations, HCV, HIV), piercing/tattoo and use of social and medical services were studied by means of chi2 and logistic models. RESULTS: Seroprevalence results for IDUs were 81.3% (218/268, 95%CI=[76.6; 86.0]) for HCV, 29.1% (74/254, 95%CI=[25.5;34.7 ]) for HBV (acute/chronic infection or past cured infection), 2.5% (5/202, 95%CI=[0.3; 4.6]) for HIV-1 and 57.1% (108/189, 95%CI=[50.0; 64.1]) for HAV (cured infections or past vaccinations). Seroprevalence results for nIDUs were 19.1% (9/47, 95%CI=[7.9;30.3]) for HCV, 8.9% (4/45, 95%CI=[0.6;17.2]) for HBV (acute/chronic infection or past cured infection), 4.8% (2/42, 95%CI=[-1.7;11.3]) for HIV-1 and 65.9% (27/41, 95%CI=[51.4;80.4]) for HAV. Prisoners showed the highest rates for all infections. Age, imprisonment and setting of recruitment were statistically associated with HCV seropositivity. Age, speedball career and nationality were significantly associated with HBV seropositivity. Only 56% of the participants in outpatient centres collected their serology results and 43 doses of vaccine against HAV and/or HBV were administered. CONCLUSIONS: Despite the existing national risk-reduction strategies implemented since 1993, high prevalence of HCV and HBV infections in injecting drug users is observed. Our study showed that implementing risk-prevention strategies, including immunisation remains difficult with PDUs. Improvement should be looked for by the provision of field healthcare structures providing tests with immediate results, advice, immunisation or treatment if appropriate. PMID- 21595970 TI - Phase II study of induction chemotherapy with TPF followed by radioimmunotherapy with Cetuximab and intensity-modulated radiotherapy (IMRT) in combination with a carbon ion boost for locally advanced tumours of the oro-, hypopharynx and larynx -TPF-C-HIT. AB - BACKGROUND: Long-term locoregional control in locally advanced squamous cell carcinoma of the head and neck (SCCHN) remains challenging. While recent years have seen various approaches to improve outcome by intensification of treatment schedules through introduction of novel induction and combination chemotherapy regimen and altered fractionation regimen, patient tolerance to higher treatment intensities is limited by accompanying side-effects. Combined radioimmunotherapy with cetuximab as well as modern radiotherapy techniques such as intensity modulated radiotherapy (IMRT) and carbon ion therapy (C12) are able to limit toxicity while maintaining treatment effects. In order to achieve maximum efficacy with yet acceptable toxicity, this sequential phase II trial combines induction chemotherapy with docetaxel, cisplatin, and 5-FU (TPF) followed by radioimmunotherapy with cetuximab as IMRT plus carbon ion boost. We expect this approach to result in increased cure rates with yet manageable accompanying toxicity. METHODS/DESIGN: The TPF-C-HIT trial is a prospective, mono-centric, open-label, non-randomized phase II trial evaluating efficacy and toxicity of the combined treatment with IMRT/carbon ion boost and weekly cetuximab in 50 patients with histologically proven locally advanced SCCHN following TPF induction chemotherapy. Patients receive 24 GyE carbon ions (8 fractions) and 50 Gy IMRT (2.0 Gy/fraction) in combination with weekly cetuximab throughout radiotherapy. Primary endpoint is locoregional control at 12 months, secondary endpoints are disease-free survival, progression-free survival, overall survival, acute and late radiation effects as well as any adverse events of the treatment as well as quality of life (QoL) analyses. DISCUSSION: The primary objective of TPF-C-HIT is to evaluate efficacy and toxicity of cetuximab in combination with combined IMRT/carbon ion therapy following TPF induction in locally advanced SCCHN. PMID- 21595971 TI - Construction of high quality GatewayTM entry libraries and their application to yeast two-hybrid for the monocot model plant Brachypodium distachyon. AB - BACKGROUND: Monocots, especially the temperate grasses, represent some of the most agriculturally important crops for both current food needs and future biofuel development. Because most of the agriculturally important grass species are difficult to study (e.g., they often have large, repetitive genomes and can be difficult to grow in laboratory settings), developing genetically tractable model systems is essential. Brachypodium distachyon (hereafter Brachypodium) is an emerging model system for the temperate grasses. To fully realize the potential of this model system, publicly accessible discovery tools are essential. High quality cDNA libraries that can be readily adapted for multiple downstream purposes are a needed resource. Additionally, yeast two-hybrid (Y2H) libraries are an important discovery tool for protein-protein interactions and are not currently available for Brachypodium. RESULTS: We describe the creation of two high quality, publicly available GatewayTM cDNA entry libraries and their derived Y2H libraries for Brachypodium. The first entry library represents cloned cDNA populations from both short day (SD, 8/16-h light/dark) and long day (LD, 20/4-h light/dark) grown plants, while the second library was generated from hormone treated tissues. Both libraries have extensive genome coverage (~5 * 107 primary clones each) and average clone lengths of ~1.5 Kb. These entry libraries were then used to create two recombination-derived Y2H libraries. Initial proof of-concept screens demonstrated that a protein with known interaction partners could readily re-isolate those partners, as well as novel interactors. CONCLUSIONS: Accessible community resources are a hallmark of successful biological model systems. Brachypodium has the potential to be a broadly useful model system for the grasses, but still requires many of these resources. The GatewayTM compatible entry libraries created here will facilitate studies for multiple user-defined purposes and the derived Y2H libraries can be immediately applied to large scale screening and discovery of novel protein-protein interactions. All libraries are freely available for distribution to the research community. PMID- 21595972 TI - Copeptin concentration in cord blood in infants with early-onset sepsis, chorioamnionitis and perinatal asphyxia. AB - BACKGROUND: Vasopressin is one of the most important physiological stress and shock hormones. Copeptin, a stable vasopressin precursor, is a promising sepsis marker in adults. In contrast, its involvement in neonatal diseases remains unknown. The aim of this study was to establish copeptin concentrations in neonates of different stress states such as sepsis, chorioamnionitis and asphyxia. METHODS: Copeptin cord blood concentration was determined using the BRAHMS kryptor assay. Neonates with early-onset sepsis (EOS, n = 30), chorioamnionitis (n = 33) and asphyxia (n = 25) were compared to a control group of preterm and term (n = 155) neonates. RESULTS: Median copeptin concentration in cord blood was 36 pmol/l ranging from undetectable to 5498 pmol/l (IQR 7 - 419). Copeptin cord blood concentrations were non-normally distributed and increased with gestational age (p < 0.0001). Neonates born after vaginal compared to cesarean delivery had elevated copeptin levels (p < 0.0001). Copeptin correlated strongly with umbilical artery pH (Spearman's Rho -0.50, p < 0.0001), umbilical artery base excess (Rho -0.67, p < 0.0001) and with lactate at NICU admission (Rho 0.54, p < 0.0001). No difference was found when comparing copeptin cord blood concentrations between neonates with EOS and controls (multivariate p = 0.30). The highest copeptin concentrations were found in neonates with asphyxia (median 993 pmol/l). Receiver-operating-characteristic curve analysis showed that copeptin cord blood concentrations were strongly associated with asphyxia: the area under the curve resulted at 0.91 (95%-CI 0.87-0.96, p < 0.0001). A cut-off of 400 pmol/l had a sensitivity of 92% and a specifity of 82% for asphyxia as defined in this study. CONCLUSIONS: Copeptin concentrations were strongly related to factors associated with perinatal stress such as birth acidosis, asphyxia and vaginal delivery. In contrast, copeptin appears to be unsuitable for the diagnosis of EOS. PMID- 21595973 TI - Sero-survey of rubella IgM antibodies among children in Jos, Nigeria. AB - Sero-survey of rubella IgM antibodies was carried out among children aged 0-10 years in Jos, Nigeria. Blood samples were collected from the subjects and sera extracted. Of the 93(100%) assayed for the rubella IgM antibody, 42(45.2%) were seropositive for rubella IgM antibody while 51(54.8%) were seronegative. A breakdown of the seropositive subjects reveals that 14(15.1%) of the infected children were males while 28(30.1%) were females. Those subjects within the age groups of 1-2, 3-4 and 5-6 years had the highest prevalence of 8(8.6%) followed by those within the age groups of 7-8, 9-10 years with 7(7.5%). Blood transfusion as a risk factor did not show any significant influence on the status of the subjects. The demographic data of the mothers of the subjects were also linked with the seropositivity of the children. PMID- 21595974 TI - Relationships between stress, coping and depressive symptoms among overseas university preparatory Chinese students: a cross-sectional study. AB - BACKGROUND: Mental health problems in young people are an important public health issue. Students leaving their hometown and family at a young age to pursue better educational opportunities overseas are confronted with life adjustment stress, which in turn affects their mental health and academic performance. This study aimed to examine the relationships among stress, coping strategies, and depressive symptoms using the stress coping framework in overseas Chinese university preparatory students in Taiwan. METHODS: A cross-sectional study was conducted at an overseas Chinese university preparatory institute in Taiwan. Of enrolled overseas Chinese university preparatory students at 2009, 756 completed a structured questionnaire measuring stress, strategies for coping with it, and the Center for Epidemiologic Studies Depression Scale. RESULTS: High levels of stress significantly predicted the adoption of active, problem-focused coping strategies (R(2) = 0.13, p < .01) and passive, emotion-focused coping strategies (R(2) = 0.24, p < .01). Acceptable CFI, SRMR, and RMSEA values from the structural equation modeling analysis demonstrated that the model satisfactorily fits the stress coping framework, after active coping strategies were eliminated from the model. Results from the Sobel test revealed that passive coping strategies mediated the relation between stress and depressive symptoms (z = 8.06, p < .001). CONCLUSION: Our study results suggested that stress is associated with coping strategies and depressive symptoms and passive strategies mediate the relation between stress and depressive symptoms in overseas Chinese university preparatory students. PMID- 21595976 TI - Small invasive colon cancer with systemic metastasis: a case report. AB - BACKGROUND: Recently, especially in Japan, several researchers have suggested that colorectal cancer can develop not only through an adenoma-carcinoma sequence but also from normal mucosa via a de novo pathway, and that these de novo cancers have more aggressive malignant potential. We report a case of aggressive colon cancer resulting in systemic metastasis despite small tumour size. CASE PRESENTATION: A 35-year-old woman presented at the referring hospital with swelling of the left cervical lymph node. Biopsy of the lymph node revealed metastatic adenocarcinoma; however, CT scan and mammography were unable to identify the site of the primary lesion. She was diagnosed with unknown primary cancer and referred to our hospital for further examination. Immunohistochemical reevaluation showed the cervical lymph node biopsy specimen to be positive for CDX2 and CK20 and negative for CK7 expression, leading us to suspect the presence of a primary colorectal cancer. We performed a total colonoscopy, and detected a small protruding lesion in the transverse colon. The tumour was only 12 mm in diameter, with a central depressed component and a severely thickened stalk, which suggested direct cancer invasion of the deep submucosa. We concluded that this lesion was the site of origin of the metastasis despite the small tumour size, and performed diagnostic endoscopic mucosal resection. The lesion was found to have an intramucosal cancer component, demonstrating that this lesion represented primary colon cancer. The patient was referred to the gastrointestinal oncology division for systemic chemotherapy. CONCLUSIONS: In this case, immunohistochemical findings strongly suggested the existence of a colorectal cancer. The non-polypoid gross appearance of the tumour suggested that it can originate de novo , thus providing a valuable case in support of the aggressive malignant potential of a de novo colorectal cancer pathway. PMID- 21595975 TI - Association of dialysis facility-level hemoglobin measurement and erythropoiesis stimulating agent dose adjustment frequencies with dialysis facility-level hemoglobin variation: a retrospective analysis. AB - BACKGROUND: A key goal of anemia management in dialysis patients is to maintain patients' hemoglobin (Hb) levels consistently within a target range. Our aim in this study was to assess the association of facility-level practice patterns representing Hb measurement and erythropoiesis-stimulating agent (ESA) dose adjustment frequencies with facility-level Hb variation. METHODS: This was a retrospective observational database analysis of patients in dialysis facilities affiliated with large dialysis organizations as of July 01, 2006, covering a follow-up period from July 01, 2006 to June 30, 2009. A total of 2,763 facilities representing 436,442 unique patients were included. The predictors evaluated were facility-level Hb measurement and ESA dose adjustment frequencies, and the outcome measured was facility-level Hb variation. RESULTS: First to 99th percentile ranges for facility-level Hb measurement and ESA dose adjustment frequencies were approximately once per month to once per week and approximately once per 3 months to once per 3 weeks, respectively. Facility-level Hb measurement and ESA dose adjustment frequencies were inversely associated with Hb variation. Modeling results suggested that a more frequent Hb measurement (once per week rather than once per month) was associated with approximately 7% to 9% and 6% to 8% gains in the proportion of patients with Hb levels within a +/-1 and +/-2 g/dL range around the mean, respectively. Similarly, more frequent ESA dose adjustment (once per 2 weeks rather than once per 3 months) was associated with approximately 6% to 9% and 5% to 7% gains in the proportion of patients in these respective Hb ranges. CONCLUSIONS: Frequent Hb measurements and timely ESA dose adjustments in dialysis patients are associated with lower facility-level Hb variation and an increase in proportion of patients within +/-1 and +/-2 g/dL ranges around the facility-level Hb mean. PMID- 21595977 TI - beta-Elemene-induced autophagy protects human gastric cancer cells from undergoing apoptosis. AB - BACKGROUND: beta-Elemene, a compound found in an herb used in traditional Chinese medicine, has shown promising anti-cancer effects against a broad spectrum of tumors. The mechanism by which beta-elemene kills cells remains unclear. The aim of the present study is to investigate the anti-tumor effect of beta-elemene on human gastric cancer cells and the molecular mechanism involved. RESULTS: beta Elemene inhibited the viability of human gastric cancer MGC803 and SGC7901 cells in a dose-dependent manner. The suppression of cell viability was due to the induction of apoptosis. A robust autophagy was observed in the cells treated with beta-elemene; it was characterized by the increase of punctate LC3 dots, the cellular morphology, and the increased levels of LC3-II protein. Further study showed that beta-elemene treatment up-regulated Atg5-Atg12 conjugated protein but had little effect on other autophagy-related proteins. PI3K/Akt/mTOR/p70S6K1 activity was inhibited by beta-elemene. Knockdown of Beclin 1 with small interfering RNA, or co-treatment with the autophagy inhibitor, 3-methyladenine or chlorochine enhanced significantly the antitumor effects of beta-elemene. CONCLUSIONS: Our data provides the first evidence that beta-elemene induces protective autophagy and prevents human gastric cancer cells from undergoing apoptosis. A combination of beta-elemene with autophagy inhibitor might thus be a useful therapeutic option for advanced gastric cancer. PMID- 21595978 TI - Tailored, iterative, printed dietary feedback is as effective as group education in improving dietary behaviours: results from a randomised control trial in middle-aged adults with cardiovascular risk factors. AB - BACKGROUND: Tailored nutrition interventions have been shown to be more effective than non-tailored materials in changing dietary behaviours, particularly fat intake and fruit and vegetable intake. But further research examining efficacy of tailored nutrition education in comparison to other nutrition education methods and across a wider range of dietary behaviours is needed. The Stages to Healthy Eating Patterns Study (STEPs) was an intervention study, in middle-aged adults with cardiovascular risk factors, to examine the effectiveness of printed, tailored, iterative dietary feedback delivered by mail in improving short-term dietary behaviour in the areas of saturated fat, fruit, vegetable and grain and cereal intake. METHODS: STEPs was a 3-month randomised controlled trial with a pre and post-test design. There were three experimental conditions: 1) tailored, iterative, printed dietary feedback (TF) with three instalments mail-delivered over a 3-month period that were re-tailored to most recent assessment of dietary intake, intention to change and assessment of self-adequacy of dietary intake. Tailoring for dietary intake was performed on data from a validated 63-item combination FFQ designed for the purpose 2) small group nutrition education sessions (GE): consisting of two 90-minute dietitian-led small group nutrition education sessions and 3) and a wait-listed control (C) group who completed the dietary measures and socio-demographic questionnaires at baseline and 3-months later. Dietary outcome measures in the areas of saturated fat intake (g), and the intake of fruit (serves), vegetables (serves), grain and cereals as total and wholegrain (serves) were collected using 7-day estimated dietary records. Descriptive statistics, paired t-tests and general linear models adjusted for baseline dietary intake, age and gender were used to examine the effectiveness of different nutrition interventions. RESULTS: The TF group reported a significantly greater increase in fruit intake (0.3 serves/d P = 0.031) in comparison to GE and the C group. All three intervention groups showed a reduction in total saturated fat intake. GE also had a within-group increase in mean vegetable intake after 3 months, but this increase was not different from changes in the other groups. CONCLUSIONS: In this study, printed, tailored, iterative dietary feedback was more effective than small group nutrition education in improving the short-term fruit intake behaviour, and as effective in improving saturated fat intake of middle-aged adults with cardiovascular risk factors. This showed that a low-level dietary intervention could achieve modest dietary behaviour changes that are of public health significance. PMID- 21595979 TI - Clinical and molecular characterization of a transmitted reciprocal translocation t(1;12)(p32.1;q21.3) in a family co-segregating with mental retardation, language delay, and microcephaly. AB - BACKGROUND: Chromosome translocation associated with neurodevelopmental disorders provides an opportunity to identify new disease-associated genes and gain new insight into their function. During chromosome analysis, we identified a reciprocal translocation between chromosomes 1p and 12q, t(1; 12)(p32.1; q21.3), co-segregating with microcephaly, language delay, and severe psychomotor retardation in a mother and her two affected boys. METHODS: Fluorescence in situ hybridization (FISH), long-range PCR, and direct sequencing were used to map the breakpoints on chromosomes 1p and 12q. A reporter gene assay was conducted in human neuroblastoma (SKNSH) and Chinese hamster ovary (CHO) cell lines to assess the functional implication of the fusion sequences between chromosomes 12 and 1. RESULTS: We determined both breakpoints at the nucleotide level. Neither breakpoint disrupted any known gene directly. The breakpoint on chromosome 1p was located amid a gene-poor region of ~ 1.1 Mb, while the breakpoint on chromosome 12q was located ~ 3.4 kb downstream of the ALX1 gene, a homeobox gene. In the reporter gene assay, we discovered that the fusion sequences construct between chromosomes 12 and 1 had a ~ 1.5 to 2-fold increased reporter gene activity compared with the corresponding normal chromosome 12 sequences construct. CONCLUSION: Our findings imply that the translocation may enhance the expression of the ALX1 gene via the position effect and result in the clinical symptoms of this family. Our findings may also expand the clinical phenotype spectrum of ALX1 related human diseases as loss of the ALX1 function was recently reported to result in abnormal craniofacial development. PMID- 21595980 TI - Clinical outcomes of chemoradiotherapy for locally recurrent rectal cancer. AB - BACKGROUND: To assess the clinical outcome of chemoradiotherapy with or without surgery for locally recurrent rectal cancer (LRRC) and to find useful and significant prognostic factors for a clinical situation. METHODS: Between January 2001 and February 2009, 67 LRRC patients, who entered into concurrent chemoradiotherapy with or without surgery, were reviewed retrospectively. Of the 67 patients, 45 were treated with chemoradiotherapy plus surgery, and the remaining 22 were treated with chemoradiotherapy alone. The mean radiation doses (biologically equivalent dose in 2-Gy fractions) were 54.6 Gy and 66.5 Gy for the chemoradiotherapy with and without surgery groups, respectively. RESULTS: The median survival duration of all patients was 59 months. Five-year overall (OS), relapse-free (RFS), locoregional relapse-free (LRFS), and distant metastasis-free survival (DMFS) were 48.9%, 31.6%, 66.4%, and 40.6%, respectively. A multivariate analysis demonstrated that the presence of symptoms was an independent prognostic factor influencing OS, RFS, LRFS, and DMFS. No statistically significant difference was found in OS (p = 0.181), RFS (p = 0.113), LRFS (p = 0.379), or DMFS (p = 0.335) when comparing clinical outcomes between the chemoradiotherapy with and without surgery groups. CONCLUSIONS: Chemoradiotherapy with or without surgery could be a potential option for an LRRC cure, and the symptoms related to LRRC were a significant prognostic factor predicting poor clinical outcome. The chemoradiotherapy scheme for LRRC patients should be adjusted to the possibility of resectability and risk of local failure to focus on local control. PMID- 21595981 TI - Evidence for the additions of clustered interacting nodes during the evolution of protein interaction networks from network motifs. AB - BACKGROUND: High-throughput screens have revealed large-scale protein interaction networks defining most cellular functions. How the proteins were added to the protein interaction network during its growth is a basic and important issue. Network motifs represent the simplest building blocks of cellular machines and are of biological significance. RESULTS: Here we study the evolution of protein interaction networks from the perspective of network motifs. We find that in current protein interaction networks, proteins of the same age class tend to form motifs and such co-origins of motif constituents are affected by their topologies and biological functions. Further, we find that the proteins within motifs whose constituents are of the same age class tend to be densely interconnected, co evolve and share the same biological functions, and these motifs tend to be within protein complexes. CONCLUSIONS: Our findings provide novel evidence for the hypothesis of the additions of clustered interacting nodes and point out network motifs, especially the motifs with the dense topology and specific function may play important roles during this process. Our results suggest functional constraints may be the underlying driving force for such additions of clustered interacting nodes. PMID- 21595982 TI - Measurement invariance of the Center for Epidemiological Studies Depression Scale (CES-D) among Chinese and Dutch elderly. AB - BACKGROUND: Although previous studies using non- elderly groups have assessed the factorial invariance of the Center for Epidemiological Studies Depression Scale (CES-D) across different groups with the same social-cultural backgrounds, few studies have tested the factorial invariance of the CES-D across two elderly groups from countries with different social cultures. The purposes of this study were to examine the factorial structure of the CES-D, and test its measurement invariance across two different national elderly populations. METHODS: A total of 6806 elderly adults from China (n = 4903) and the Netherlands (n = 1903) were included in the final sample. The CES-D was assessed in both samples. Three strategies were used in the data analysis procedure. First, a confirmatory factor analysis (CFA) was carried out to determine the factor structures of the CES-D that best fitted the two samples. Second, the best fitting model was incorporated into a multi-group CFA model to test measurement invariance of the CES-D across the two population groups. Third, latent mean differences between the two groups were tested. RESULTS: The results of confirmatory factor analysis (CFA) showed: 1) in both samples, Radloff's four-factor model resulted in a significantly better fit and the four dimensions (somatic complaints, depressed affect, positive affect, and interpersonal problems) of the CES-D seem to be the most informative in assessing depressive symptoms compared to the single-, three-, and the second-order factor models; and 2) the factorial structure was invariant across the populations under study. However, only partial scalar and uniqueness invariance of the CES-D items was supported. Latent means in the partial invariant model were lower for the Dutch sample, compared to the Chinese sample. CONCLUSIONS: Our findings provide evidence of a valid factorial structure of the CES-D that could be applied to elderly populations from both China and the Netherlands, producing a meaningful comparison of total scores between the two elderly groups. However, for some specific factors and items, caution is required when comparing the depressive symptoms between Chinese and Dutch elderly groups. PMID- 21595983 TI - ConReg-R: Extrapolative recalibration of the empirical distribution of p-values to improve false discovery rate estimates. AB - BACKGROUND: False discovery rate (FDR) control is commonly accepted as the most appropriate error control in multiple hypothesis testing problems. The accuracy of FDR estimation depends on the accuracy of the estimation of p-values from each test and validity of the underlying assumptions of the distribution. However, in many practical testing problems such as in genomics, the p-values could be under estimated or over-estimated for many known or unknown reasons. Consequently, FDR estimation would then be influenced and lose its veracity. RESULTS: We propose a new extrapolative method called Constrained Regression Recalibration (ConReg-R) to recalibrate the empirical p-values by modeling their distribution to improve the FDR estimates. Our ConReg-R method is based on the observation that accurately estimated p-values from true null hypotheses follow uniform distribution and the observed distribution of p-values is indeed a mixture of distributions of p-values from true null hypotheses and true alternative hypotheses. Hence, ConReg-R recalibrates the observed p-values so that they exhibit the properties of an ideal empirical p-value distribution. The proportion of true null hypotheses (pi0) and FDR are estimated after the recalibration. CONCLUSIONS: ConReg-R provides an efficient way to improve the FDR estimates. It only requires the p-values from the tests and avoids permutation of the original test data. We demonstrate that the proposed method significantly improves FDR estimation on several gene expression datasets obtained from microarray and RNA seq experiments. PMID- 21595985 TI - Natural radionuclide of Po210 in the edible seafood affected by coal-fired power plant industry in Kapar coastal area of Malaysia. AB - BACKGROUND: Po210 can be accumulated in various environmental materials, including marine organisms, and contributes to the dose of natural radiation in seafood. The concentration of this radionuclide in the marine environment can be influenced by the operation of a coal burning power plant but existing studies regarding this issue are not well documented. Therefore, the aim of this study was to estimate the Po210 concentration level in marine organisms from the coastal area of Kapar, Malaysia which is very near to a coal burning power plant station and to assess its impact on seafood consumers. METHODS: Concentration of Po210 was determined in the edible muscle of seafood and water from the coastal area of Kapar, Malaysia using radiochemical separation and the Alpha Spectrometry technique. RESULTS: The activities of Po210 in the dissolved phase of water samples ranged between 0.51 +/- 0.21 and 0.71 +/- 0.24 mBql-1 whereas the particulate phase registered a range of 50.34 +/- 11.40 to 72.07 +/- 21.20 Bqkg 1. The ranges of Po210 activities in the organism samples were 4.4 +/- 0.12 to 6.4 +/- 0.95 Bqkg-1 dry wt in fish (Arius maculatus), 45.7 +/- 0.86 to 54.4 +/- 1.58 Bqkg-1 dry wt in shrimp (Penaeus merguiensis) and 104.3 +/- 3.44 to 293.8 +/ 10.04 Bqkg-1 dry wt in cockle (Anadara granosa). The variation of Po210 in organisms is dependent on the mode of their life style, ambient water concentration and seasonal changes. The concentration factors calculated for fish and molluscs were higher than the recommended values by the IAEA. An assessment of daily intake and received dose due to the consumption of seafood was also carried out and found to be 2083.85 mBqday-1person-1 and 249.30 MUSvyr-1 respectively. These values are comparatively higher than reported values in other countries. Moreover, the transformation of Po210 in the human body was calculated and revealed that a considerable amount of Po210 can be absorbed in the internal organs. The calculated values of life time mortality and morbidity cancer risks were 24.8 * 10-4 and 34 * 10-4 respectively which also exceeded the recommended limits set by the ICRP. CONCLUSIONS: The findings of this present study can be used to evaluate the safety dose uptake level of seafood as well as to monitor environmental health. However, as the calculated dose and cancer risks were found to cross the limit of safety, finding a realistic way to moderate the risk is imperative. PMID- 21595984 TI - STAT6 expression in glioblastoma promotes invasive growth. AB - BACKGROUND: Glioblastoma (GBM) is a highly aggressive malignant primary brain tumor, characterized by rapid growth, diffuse infiltration of cells into both adjacent and remote brain regions, and a generalized resistance to currently available treatment modalities. Recent reports in the literature suggest that Signal Transducers and Activators of Transcription (STATs) play important roles in the regulation of GBM pathophysiology. METHODS: STAT6 protein expression was analyzed by Western blotting in GBM cell lines and by immunohistochemistry in a tissue microarray (TMA) of glioma patient tissues. We utilized shRNA against STAT6 to investigate the effects of prolonged STAT6 depletion on the growth and invasion of two STAT6-positive GBM cell lines. Cell proliferation was assessed by measuring (3)H-Thymidine uptake over time. Invasion was measured using an in vitro transwell assay in which cells invade through a type IV collagen matrix toward a chemoattractant (Fetal Bovine Serum). Cells were then stained and counted. Kaplan-Meyer survival curves were generated to show the correlation between STAT6 gene expression and patient survival in 343 glioma patients and in a subset of patients with only GBM. Gene expression microarray and clinical data were acquired from the Rembrandt 1 public data depository (https://caintegrator.nci.nih.gov/rembrandt/). Lastly, a genome-wide expression microarray analysis was performed to compare gene expression in wild-type GBM cells to expression in stable STAT6 knockdown clones. RESULTS: STAT6 was expressed in 2 GBM cell lines, U-1242MG and U-87MG, and in normal astrocytes (NHA) but not in the U-251MG GBM cell line. In our TMA study, STAT6 immunostaining was visible in the majority of astrocytomas of all grades (I-IV) but not in normal brain tissue. In positive cells, STAT6 was localized exclusively in the nuclei over 95% of the time. STAT6-deficient GBM cells showed a reduction in (3)H-Thymidine uptake compared to the wild-type. There was some variation among the different shRNA- silenced clones, but all had a reduction in (3)H-Thymidine uptake ranging from 35%- 70% in U-1242MG and 40- 50% in U-87MG cells. Additionally, STAT6- depleted cells were less invasive than controls in our in vitro transmembrane invasion assay. Invasiveness was decreased by 25-40% and 30-75% in U-1242MG and U-87MG cells, respectively. The microarray analysis identified matrix metalloproteinase 1 (MMP-1) and urokinase Plasminogen activator (uPA) as potential STA6 target genes involved in the promotion of GBM cell invasion. In a Kaplan-Meier survival curve based on Rembrandt 1 gene expression microarray and clinical data, there was a significant difference in survival (P < 0.05) between glioma patients with up- and down-regulated STAT6. Decreased STAT6 expression correlated with longer survival times. In two subsets of patients with either grade IV tumors (GBM) or Grade II/III astrocytomas, there was a similar trend that however did not reach statistical significance. CONCLUSIONS: Taken together, these findings suggest a role for STAT6 in enhancing cell proliferation and invasion in GBM, which may explain why up-regulation of STAT6 correlates with shorter survival times in glioma patients. This report thus identifies STAT6 as a new and potentially promising therapeutic target. PMID- 21595986 TI - Agrobacterium-mediated transformation of safflower and the efficient recovery of transgenic plants via grafting. AB - BACKGROUND: Safflower (Carthamus tinctorius L.) is a difficult crop to genetically transform being susceptible to hyperhydration and poor in vitro root formation. In addition to traditional uses safflower has recently emerged as a broadacre platform for the production of transgenic products including modified oils and pharmaceutically active proteins. Despite commercial activities based on the genetic modification of safflower, there is no method available in the public domain describing the transformation of safflower that generates transformed T1 progeny. RESULTS: An efficient and reproducible protocol has been developed with a transformation efficiency of 4.8% and 3.1% for S-317 (high oleic acid content) and WT (high linoleic acid content) genotypes respectively. An improved safflower transformation T-DNA vector was developed, including a secreted GFP to allow non destructive assessment of transgenic shoots. Hyperhydration and necrosis of Agrobacterium-infected cotyledons was effectively controlled by using iota carrageenan, L-cysteine and ascorbic acid. To overcome poor in vitro root formation for the first time a grafting method was developed for safflower in which ~50% of transgenic shoots develop into mature plants bearing viable transgenic T1 seed. The integration and expression of secreted GFP and hygromycin genes were confirmed by PCR, Southern and Western blot analysis. Southern blot analysis in nine independent lines indicated that 1-7 transgenes were inserted per line and T1 progeny displayed Mendelian inheritance. CONCLUSIONS: This protocol demonstrates significant improvements in both the efficiency and ease of use over existing safflower transformation protocols. This is the first complete method of genetic transformation of safflower that generates stably-transformed plants and progeny, allowing this crop to benefit from modern molecular applications. PMID- 21595987 TI - Y-box protein-1/p18 fragment identifies malignancies in patients with chronic liver disease. AB - BACKGROUND: Immunohistochemical detection of cold shock proteins is predictive for deleterious outcome in various malignant diseases. We recently described active secretion of a family member, denoted Y-box (YB) protein-1. We tested the clinical and diagnostic value of YB-1 protein fragment p18 (YB-1/p18) detection in blood for malignant diseases. METHODS: We used a novel monoclonal anti-YB-1 antibody to detect YB-1/p18 by immunoblotting in plasma samples of healthy volunteers (n=33), patients with non-cancerous, mostly inflammatory diseases (n=60), hepatocellular carcinoma (HCC; n=25) and advanced solid tumors (n=20). YB 1/p18 was then tested in 111 patients with chronic liver diseases, alongside established tumor markers and various diagnostic measures, during evaluation for potential liver transplantation. RESULTS: We developed a novel immunoblot to detect the 18 kD fragment of secreted YB-1 in human plasma (YB-1/p18) that contains the cold-shock domains (CSD) 1-3 of the full-length protein. YB-1/p18 was detected in 11/25 HCC and 16/20 advanced carcinomas compared to 0/33 healthy volunteers and 10/60 patients with non-cancerous diseases. In 111 patients with chronic liver disease, YB-1/p18 was detected in 20 samples. Its occurrence was not associated with advanced Child stages of liver cirrhosis or liver function. In this cohort, YB-1/p18 was not a good marker for HCC, but proved most powerful in detecting malignancies other than HCC (60% positive) with a lower rate of false-positive results compared to established tumor markers. Alpha-fetoprotein (AFP) was most sensitive in detecting HCC, but simultaneous assessment of AFP, CA19-9 and YB-1/p18 improved overall identification of HCC patients. CONCLUSIONS: Plasma YB-1/p18 can identify patients with malignancies, independent of acute inflammation, renal impairment or liver dysfunction. The detection of YB-1/p18 in human plasma may have potential as a tumor marker for screening of high-risk populations, e.g. before organ transplantation, and should therefore be evaluated in larger prospective studies. PMID- 21595988 TI - Laboratory selection for an accelerated mosquito sexual development rate. AB - BACKGROUND: Separating males and females at the early adult stage did not ensure the virginity of females of Anopheles arabiensis (Dongola laboratory strain), whereas two years earlier this method had been successful. In most mosquito species, newly emerged males and females are not able to mate successfully. For anopheline species, a period of 24 h post-emergence is generally required for the completion of sexual maturation, which in males includes a 180 degrees rotation of the genitalia. In this study, the possibility of an unusually shortened sexual maturity period in the laboratory-reared colony was investigated. METHODS: The effect of two different sex-separation methods on the virginity of females was tested: females separated as pupae or less than 16 h post-emergence were mated with males subjected to various doses of radiation. T-tests were performed to compare the two sex-separation methods. The rate of genitalia rotation was compared for laboratory-reared and wild males collected as pupae in Dongola, Sudan, and analysed by Z-tests. Spermatheca dissections were performed on females mated with laboratory-reared males to determine their insemination status. RESULTS: When the sex-separation was performed when adults were less than 16 h post-emergence, expected sterility was never reached for females mated with radio sterilized males. Expected sterility was accomplished only when sexes were separated at the pupal stage. Observation of genitalia rotation showed that some males from the laboratory strain Dongola were able to successfully mate only 11 h after emergence and 42% of the males had already completed rotation. A small proportion of the same age females were inseminated. Wild males showed a much slower genitalia rotation rate. At 17 h post-emergence, 96% of the laboratory reared males had completed genitalia rotation whereas none of the wild males had. CONCLUSION: This colony has been cultured in the laboratory for over one hundred generations, and now has accelerated sexual maturation when compared with the wild strain. This outcome demonstrates the kinds of selection that can be expected during insect colonization and maintenance, particularly when generations are non-overlapping and similar-age males must compete for mates. PMID- 21595989 TI - An application of kernel methods to variety identification based on SSR markers genetic fingerprinting. AB - BACKGROUND: In crop production systems, genetic markers are increasingly used to distinguish individuals within a larger population based on their genetic make up. Supervised approaches cannot be applied directly to genotyping data due to the specific nature of those data which are neither continuous, nor nominal, nor ordinal but only partially ordered. Therefore, a strategy is needed to encode the polymorphism between samples such that known supervised approaches can be applied. Moreover, finding a minimal set of molecular markers that have optimal ability to discriminate, for example, between given groups of varieties, is important as the genotyping process can be costly in terms of laboratory consumables, labor, and time. This feature selection problem also needs special care due to the specific nature of the data used. RESULTS: An approach encoding SSR polymorphisms in a positive definite kernel is presented, which then allows the usage of any kernel supervised method. The polymorphism between the samples is encoded through the Nei-Li genetic distance, which is shown to define a positive definite kernel between the genotyped samples. Additionally, a greedy feature selection algorithm for selecting SSR marker kits is presented to build economical and efficient prediction models for discrimination. The algorithm is a filter method and outperforms other filter methods adapted to this setting. When combined with kernel linear discriminant analysis or kernel principal component analysis followed by linear discriminant analysis, the approach leads to very satisfactory prediction models. CONCLUSIONS: The main advantage of the approach is to benefit from a flexible way to encode polymorphisms in a kernel and when combined with a feature selection algorithm resulting in a few specific markers, it leads to accurate and economical identification models based on SSR genotyping. PMID- 21595991 TI - Lack of processing of the expressed ORF1 gene product of hepatitis E virus. AB - BACKGROUND: Proteolytic processing is a common mechanism among plus strand RNA viruses and the replicases of all plus strand RNA viruses of animals thus far characterized undergo such processing. The replicase proteins of hepatitis E virus (HEV) are encoded by ORF1. A previous report published by our group 1 provided data that processing potentially occurred when ORF1 (Burma strain; genotype 1) was expressed using a vaccinia virus-based expression system. FINDINGS: To further test for processing and to rule out artifacts associated with the expression system, ORF1 was re-expressed using a plasmid-based expression vector with the result that the previous processing profile could not be confirmed. When ORF1 from an HEV infectious cDNA clone (US swine strain; genotype 3) was expressed using the plasmid-based system, the only species detected was the 185 kDa precursor of ORF1. A putative papain-like cysteine protease 2 had been predicted within ORF1 using the original HEV genomic sequence. However, analysis of subsequent ORF1 sequences from a large number of HEV isolates reveals that this protease motif is not conserved. CONCLUSIONS: The expressed HEV ORF1 gene product does not undergo proteolytic processing, indicating that the replicase precursor of HEV is potentially unique in this regard. PMID- 21595990 TI - Live in vivo imaging of Egr-1 promoter activity during neonatal development, liver regeneration and wound healing. AB - BACKGROUND: The zinc finger transcription factor Egr-1 (Early growth response 1) is central to several growth factors and represents an important activator of target genes not only involved in physiological processes like embryogenesis and neonatal development, but also in a variety of pathophysiological processes, for example atherosclerosis or cancer. Current options to investigate its transcription and activation in vivo are end-point measurements that do not provide insights into dynamic changes in the living organism. RESULTS: We developed a transgenic mouse (Egr-1-luc) in which the luciferase reporter gene is under the control of the murine Egr-1 promoter providing a versatile tool to study the time course of Egr-1 activation in vivo. In neonatal mice, bioluminescence imaging revealed a high Egr-1 promoter activity reaching basal levels three weeks after birth with activity at snout, ears and paws. Using a model of partial hepatectomy we could show that Egr-1 promoter activity and Egr-1 mRNA levels were increased in the regenerating liver. In a model of wound healing, we demonstrated that Egr-1 promoter activity was upregulated at the site of injury. CONCLUSION: Taken together, we have developed a transgenic mouse model that allows real time in vivo imaging of the Egr-1 promoter activity. The ability to monitor and quantify Egr-1 activity in the living organism may facilitate a better understanding of Egr-1 function in vivo. PMID- 21595992 TI - A high-resolution method for the localization of proanthocyanidins in plant tissues. AB - BACKGROUND: Histochemical staining of plant tissues with 4 dimethylaminocinnamaldehyde (DMACA) or vanillin-HCl is widely used to characterize spatial patterns of proanthocyanidin accumulation in plant tissues. These methods are limited in their ability to allow high-resolution imaging of proanthocyanidin deposits. RESULTS: Tissue embedding techniques were used in combination with DMACA staining to analyze the accumulation of proanthocyanidins in Lotus corniculatus (L.) and Trifolium repens (L.) tissues. Embedding of plant tissues in LR White or paraffin matrices, with or without DMACA staining, preserved the physical integrity of the plant tissues, allowing high-resolution imaging that facilitated cell-specific localization of proanthocyanidins. A brown coloration was seen in proanthocyanidin-producing cells when plant tissues were embedded without DMACA staining and this was likely to have been due to non enzymatic oxidation of proanthocyanidins and the formation of colored semiquinones and quinones. CONCLUSIONS: This paper presents a simple, high resolution method for analysis of proanthocyanidin accumulation in organs, tissues and cells of two plant species with different patterns of proanthocyanidin accumulation, namely Lotus corniculatus (birdsfoot trefoil) and Trifolium repens (white clover). This technique was used to characterize cell type-specific patterns of proanthocyanidin accumulation in white clover flowers at different stages of development. PMID- 21595993 TI - Detection of four novel polymorphisms in PrP gene of Pakistani sheep (Damani and Hashtnagri) and goats (Kamori and Local Hairy) breeds. AB - Scrapie is a fatal neurodegenerative disorder of sheep and goats caused by post translational conformational change in the host-encoded prion protein (PrPC). Susceptibility or resistance to scrapie has been associated with the presence of polymorphisms in the prion protein (PrP) gene. In the present study, we analyzed the PrP gene sequence to determine the frequency of polymorphisms in 56 sheep (28 each from Damani and Hashtnagri breeds) and 56 goats (28 each from Kamori and Local Hairy breeds). A total of 7 amino acid polymorphisms were detected in the PrP gene for sheep and 4 for goats. These amino acid polymorphisms were combined in 13 alleles and 15 genotypes in sheep and 5 alleles and 6 genotypes in goats. The overall frequency of the most sheep scrapie-resistant polymorphism (Q171R) was calculated to be 0.107. The most scrapie-susceptible polymorphism (A136V) was not detected in any of the studied sheep. The overall frequency of scrapie associated polymorphism (H143R) in goats was found to be 0.152. Along with already known amino acid polymorphisms, two novel polymorphisms were also detected for each of sheep (Q171N and T191I) and goats (G22C and P63L). However, the overall frequency of these polymorphisms was extremely low. PMID- 21595994 TI - Design of an efficient medium for heterologous protein production in Yarrowia lipolytica: case of human interferon alpha 2b. AB - BACKGROUND: The non conventional yeast Yarrowia lipolytica has aroused a strong industrial interest for heterologous protein production. However most of the studies describing recombinant protein production by this yeast rely on the use of complex media, such media are not convenient for large scale production particularly for products intended for pharmaceutical applications. In addition medium composition can also affect the production yield. Hence it is necessary to design an efficient medium for therapeutic protein expression by this host. RESULTS: Five different media, including four minimal media and a complex medium, were assessed in shake flasks for the production of human interferon alpha 2b (hIFN alpha2b) by Y. lipolytica under the control of POX2 promoter inducible with oleic acid. The chemically defined medium SM4 formulated by Invitrogen for Pichia pastoris growth was the most suitable. Using statistical experimental design this medium was further optimized. The selected minimal medium consisting in SM4 supplemented with 10 mg/l FeCl3, 1 g/l glutamate, 5 ml/l PTM1 (Pichia Trace Metals) solution and a vitamin solution composed of myo-inositol, thiamin and biotin was called GNY medium. Compared to shake flask, bioreactor culture in GNY medium resulted in 416-fold increase of hIFN alpha2b production and 2-fold increase of the biological activity. Furthermore, SM4 enrichment with 5 ml/l PTM1 solution contributed to protect hIFN alpha2b against the degradation by the 28 kDa protease identified by zymography gel in culture supernatant. The screening of the inhibitory effect of the trace elements present in PTM1 solution on the activity of this protease was achieved using a Box-Behnken design. Statistical data analysis showed that FeCl3 and MnSO4 had the most inhibitory effect. CONCLUSION: We have designed an efficient medium for large scale production of heterologous proteins by Y. lipolytica. The optimized medium GNY is suitable for the production of hIFN alpha2b with the advantage that no complex nitrogen sources with non-defined composition were required. PMID- 21595995 TI - Increased IL-10 mRNA expression in tumor-associated macrophage correlated with late stage of lung cancer. AB - BACKGROUND: Monocyte recruited into the tumor and maturation to tumor-associated macrophage (TAM). Interleukin-10(IL-10) is a potent immunosuppressive cytokine, which can be secreted from both primary tumor and stromal cells. However, there are controversies regarding its role in the progression of cancer. So it is important to isolate TAM from tumor cells to study the role of IL-10 in the progress of cancer. The aim of our study was to determine whether IL-10 expressed by TAM correlated with clinicopathological factors in NSCLC. METHODS: TAM in NSCLC was isolated by short-term culture in serum free medium with the modification to literature reports. The mRNA expression levels of IL-10, cathepsin B, cathepsin S, which were closely related with TAM according to the literatures, were evaluated by Quantitative real-time RT-PCR in 63 NSCLC. The relationships between their expression levels and clinicopathological features were investigated. RESULTS: We successfully achieved up to 95% purity of TAM, derived from 63 primary lung cancer tissues. TAM expressed high levels of IL-10, cathepsin B in NSCLC. High levels of IL-10 in TAM significantly correlated with stage, tumor size, lymph node metastasis, lymphovascular invasion or histologic poor differentiation. CONCLUSIONS: Our results revealed that TAM with high levels of IL-10 expression may play an important role in the progression of non-small cell lung cancer. The data also suggested that TAMs may involve in tumor immunosuppression through overexpressed IL-10. Additionally, the phenotype of isolated TAM can be potentially used to predict clinicopathological features as well. PMID- 21595996 TI - New horizons in Biophysics. AB - This editorial celebrates the re-launch of PMC Biophysics previously published by PhysMath Central, in its new format as BMC Biophysics published by BioMed Central with an expanded scope and Editorial Board. BMC Biophysics will fill its own niche in the BMC series alongside complementary companion journals including BMC Bioinformatics, BMC Medical Physics, BMC Structural Biology and BMC Systems Biology. PMID- 21595997 TI - Diffusion and association processes in biological systems: theory, computation and experiment. AB - Macromolecular diffusion plays a fundamental role in biological processes. Here, we give an overview of recent methodological advances and some of the challenges for understanding how molecular diffusional properties influence biological function that were highlighted at a recent workshop, BDBDB2, the second Biological Diffusion and Brownian Dynamics Brainstorm. PMID- 21595998 TI - Diffusion in crowded biological environments: applications of Brownian dynamics. AB - Biochemical reactions in living systems occur in complex, heterogeneous media with total concentrations of macromolecules in the range of 50 - 400 mgml. Molecular species occupy a significant fraction of the immersing medium, up to 40% of volume. Such complex and volume-occupied environments are generally termed 'crowded' and/or 'confined'. In crowded conditions non-specific interactions between macromolecules may hinder diffusion - a major process determining metabolism, transport, and signaling. Also, the crowded media can alter, both qualitatively and quantitatively, the reactions in vivo in comparison with their in vitro counterparts. This review focuses on recent developments in particle based Brownian dynamics algorithms, their applications to model diffusive transport in crowded systems, and their abilities to reproduce and predict the behavior of macromolecules under in vivo conditions. PMID- 21596000 TI - A solvable model for the diffusion and reaction of neurotransmitters in a synaptic junction. AB - BACKGROUND: The diffusion and reaction of the transmitter acetylcholine in neuromuscular junctions and the diffusion and binding of Ca2+ in the dyadic clefts of ventricular myocytes have been extensively modeled by Monte Carlo simulations and by finite-difference and finite-element solutions. However, an analytical solution that can serve as a benchmark for testing these numerical methods has been lacking. RESULT: Here we present an analytical solution to a model for the diffusion and reaction of acetylcholine in a neuromuscular junction and for the diffusion and binding of Ca2+ in a dyadic cleft. Our model is similar to those previously solved numerically and our results are also qualitatively similar. CONCLUSION: The analytical solution provides a unique benchmark for testing numerical methods and potentially provides a new avenue for modeling biochemical transport. PMID- 21595999 TI - Gated Diffusion-controlled Reactions. AB - The binding and active sites of proteins are often dynamically occluded by motion of the nearby polypeptide. A variety of theoretical and computational methods have been developed to predict rates of ligand binding and reactivity in such cases. Two general approaches exist, "protein centric" approaches that explicitly treat only the protein target, and more detailed dynamical simulation approaches in which target and ligand are both treated explicitly. This mini review describes recent work in this area and some of the biological implications. PMID- 21596001 TI - Brownian dynamics simulation of analytical ultracentrifugation experiments. AB - BACKGROUND: We have devised a protocol for the Brownian dynamics simulation of an analytical ultracentrifugation experiment that allows for an accurate and efficient prediction of the time-dependent concentration profiles, c(r, t) in the ultracentrifuge cell. The procedure accounts for the back-diffusion, described as a Brownian motion that superimposes to the centrifugal drift, and considers the sector-shaped geometry of the cell and the boundaries imposed by the meniscus and bottom. RESULTS: Simulations are carried out for four molecules covering a wide range of the ratio of sedimentation and diffusion coefficients. The evaluation is done by extracting the molecular parameters that were initially employed in the simulation by analyzing the profiles with an independent tool, the well-proved SEDFIT software. The code of simulation algorithm has been parallelized in order to take advantage of current multi-core computers. CONCLUSIONS: Our Brownian dynamics simulation procedure may be considered as an alternative to other predictors based in numerical solutions of the Lamm equation, and its efficiency could make it useful in the most relevant, inverse problem, which is that of extracting the molecular parameters from experimentally determined concentration profiles. PMID- 21596002 TI - Many-particle Brownian and Langevin Dynamics Simulations with the Brownmove package. AB - BACKGROUND: Brownian Dynamics (BD) is a coarse-grained implicit-solvent simulation method that is routinely used to investigate binary protein association dynamics, but due to its efficiency in handling large simulation volumes and particle numbers it is well suited to also describe many-protein scenarios as they often occur in biological cells. RESULTS: Here we introduce our "brownmove" simulation package which was designed to handle many-particle problems with varying particle numbers and allows for a very flexible definition of rigid and flexible protein and polymer models. Both a Brownian and a Langevin dynamics (LD) propagation scheme can be used and hydrodynamic interactions are treated efficiently with our recently introduced TEA-HI ansatz [Geyer, Winter, JCP 130 (2009) 114905]. With simulations of constrained polymers and flexible models of spherical proteins we demonstrate that it is crucial to include hydrodynamics when multi-bead models are used in BD or LD simulations. Only then both the translational and the rotational diffusion coefficients and the timescales of the internal dynamics can be reproduced correctly. In the third example project we show how constant density boundary conditions [Geyer et al, JCP 120 (2004) 4573] can be used to set up a non-equilibrium simulation of diffusional transport across an array of fixed obstacles. Finally, we demonstrate how the agglomeration dynamics of multiple particles with attractive patches can be analysed conveniently with the help of a dynamic interaction network. CONCLUSIONS: Combining BD and LD propagation, fast hydrodynamics, a flexible protein model, and interfaces for "open" simulation settings, our freely available "brownmove" simulation package constitutes a new platform for coarse grained many-particle simulations of biologically relevant diffusion and transport processes. PMID- 21596004 TI - Youth is wasted on the young. AB - Amphibians and zebrafish are able to regenerate lost myocardial tissue without loss of cardiac function; whereas mammals, in response to myocardial injury, develop scar and lose cardiac function. This dichotomy of response has been thought to be due to the fact that adult mammalian cardiac myocytes are multinucleated and have limited proliferative capacity. Neonatal mammalian cardiac myocytes do have a limited capacity to proliferate. What has been unknown is whether this limited proliferative capacity is associated with the ability to regenerate myocardial tissue soon after birth. Recently, it has been demonstrated that 1-day-old neonatal mice do have the ability to regenerate resected cardiac tissue, and that the capacity to regenerate cardiac tissue is lost by 7 days after birth. The present commentary reviews these results and attempts to offer perspective as to how these important findings relate to current and future strategies to prevent and treat cardiac dysfunction in clinical populations. PMID- 21596003 TI - Amnion-derived stem cells: in quest of clinical applications. AB - In the promising field of regenerative medicine, human perinatal stem cells are of great interest as potential stem cells with clinical applications. Perinatal stem cells could be isolated from normally discarded human placentae, which are an ideal cell source in terms of availability, the fewer number of ethical concerns, less DNA damage, and so on. Numerous studies have demonstrated that some of the placenta-derived cells possess stem cell characteristics like pluripotent differentiation ability, particularly in amniotic epithelial (AE) cells. Term human amniotic epithelium contains a relatively large number of stem cell marker-positive cells as an adult stem cell source. In this review, we introduce a model theory of why so many AE cells possess stem cell characteristics. We also describe previous work concerning the therapeutic applications and discuss the pluripotency of the AE cells and potential pitfalls for amnion-derived stem cell research. PMID- 21596006 TI - An outbreak of Salmonella Typhimurium traced back to salami, Denmark, April to June 2010. AB - Between April and June 2010, a small national outbreak of Salmonella Typhimurium with a particular multilocus variable-number tandem repeat analysis (MLVA) type was identified in Denmark through laboratory-based surveillance. The outbreak involved twenty cases, primarily living within the greater Copenhagen area. Half of the cases were children aged ten years or younger and 12 were male; three cases were hospitalised.A matched case-control study showed a strong link between illness and eating a particular salami product containing pork and venison, matched odds ratio(mOR):150, confidence interval (CI): 19-1,600. The salami had been produced in Germany. Microbiological confirmation in food samples was sought but not obtained. Danish consumers were notified that they should return or dispose of any packages from the suspected salami batch. Because the salami product had potentially been sold in other European countries, the European Centre for Disease Prevention and Control urgent enquiry and Rapid Alert System for Food and Feed systems were used to highlight the possibility of outbreaks in these countries. Case-control studies area strong tool in some outbreak investigations and evidence from such studies may give sufficient information to recall a food product. PMID- 21596007 TI - Yersinia enterocolitica O:9 infections associated with bagged salad mix in Norway, February to April 2011. AB - In March 2011, the Norwegian Institute of Public Health identified a possible outbreak involving 21 cases of Yersinia enterocolitica O:9 infection with similar MLVA-profiles. Preliminary results of epidemiological and microbiological investigations indicate bagged salad mix containing radicchio rosso (also known as Italian chicory) as a possible source. As a result of the investigation, bagged salad mixes of a specific brand were voluntarily withdrawn from the market by the producer. PMID- 21596008 TI - Diphtheria in the south of France, March 2011. AB - In March 2011, a 40 year-old French man was diagnosed with diphtheria caused by toxigenic Corynebacterium diphtheriae. Fifty-three close contacts were identified from whom throat samples were analysed. C. diphtheriae was found only in the asymptomatic partner of the index case. The two cases had travelled in Spain during the incubation period of the index case. Investigation around the second case identified 13 new close contacts.None of them was found to be infected. PMID- 21596009 TI - Increased incidence of Mycoplasma pneumoniae infection in England and Wales in 2010: multiocus variable number tandem repeat analysis typing and macrolide susceptibility. PMID- 21596010 TI - Differences and similarities between obsessive and ruminative thoughts in obsessive-compulsive and depressed patients: a comparative study. AB - Repetitive, intrusive cognitive phenomena are central both to obsessive compulsive patients - typically as obsessive thoughts - and to depressed patients - typically as ruminative thoughts. The objective of the present study is to compare obsessive and ruminative thoughts in non-depressed obsessive-compulsive and depressed patients. Thirty-four patients diagnosed with obsessive-compulsive disorder and 34 patients diagnosed with major depression disorder were asked to identify both a personally relevant obsessive and a personally relevant ruminative thought and to subsequently evaluate these thoughts on a modified version of the Cognitive Intrusions Questionnaire (CIQ) developed by Freeston, Ladouceur, Thibodeau, and Gagnon (1991). The CIQ assesses general descriptors, emotional reactions, appraisal and coping strategies on a nine-point Likert scale. A mixed-model ANOVA demonstrated that obsessive and ruminative thoughts are distinct cognitive processes, clearly distinguishable in form, appraisal and temporal orientation across disorders. In obsessive-compulsive patients, ruminative thoughts were more common and more emotionally distressing than predicted. In depressed patients, obsessive thoughts occurred infrequently and were not associated with high negative emotions. Clarifying similarities and differences between ruminative and obsessive thoughts and understanding their interaction might ultimately help to expand on the role of cognitive vulnerability factors in obsessive-compulsive and major depression disorder. PMID- 21596011 TI - Speeches, strangers, and alcohol use: the role of context in social stress response dampening. AB - According to the Stress Response Dampening model, problem drinking develops after learning that alcohol limits the stress response in anxiety-provoking situations. However, laboratory-based studies testing alcohol's effects on social anxiety have yielded mixed results. The current study was the first to examine stress response dampening across two contexts: a performance-based (a speech) and an interaction-based (a conversation) social situation. Undergraduates (N = 62; M(age) = 22.85; 31% women; 81% Caucasian) were randomly assigned to consume an alcoholic (target BAC = .08%; n = 22), placebo (n = 20), or nonalcoholic control (n = 20) beverage followed by the anxiety-inducing social tasks. Results revealed a 3 (alcohol condition) * 2 (social task condition) * 4 (measurement point) interaction, controlling for baseline subjective state anxiety and trait social anxiety. The pattern of scores over the course of the task varied across alcohol conditions for the speech, but not the conversation. Specifically, participants in the alcohol and placebo conditions evidenced increased subjective anxiety following the first measurement point prior to the speech and their anxiety remained elevated at all subsequent measurements. Participants in the nonalcoholic control condition evidenced stable subjective anxiety ratings for all speech measurement points. Results did not support stress response dampening for either type of social situation. Instead, the only between-group difference found was that the placebo group reported greater subjective anxiety than the nonalcoholic control group after the speech. Concerns about alcohol's negative effects on one's performance might have led to increased anxiety. Findings shed light on previous inconsistent findings and highlight the need to consider context and timing in understanding drinking to cope with social anxiety. PMID- 21596013 TI - Equilibration of (2)H labeling between body water and free amino acids: enabling studies of proteome synthesis. AB - Protein synthesis can be estimated by measuring the incorporation of a labeled amino acid into a proteolytic peptide. Although prelabeled amino acids are typically administered, recent studies have tested (2)H(2)O; the assumption is that there is rapid equilibration of (2)H (in body water) with the carbon-bound hydrogens of amino acids before those amino acids are incorporated into a protein(s). We have determined the temporal changes in (2)H labeling of body water and amino acids which should build confidence in (2)H(2)O-based studies of protein synthesis when one aims to measure the (2)H labeling of proteolytic peptides. PMID- 21596014 TI - Fast analysis of recombinant monoclonal antibodies using IdeS proteolytic digestion and electrospray mass spectrometry. AB - We describe a fast and informative method to investigate the posttranslational modifications of monoclonal antibodies (MAbs). The MAb is first digested by a specific enzyme that cleaves heavy chains under the hinge domain. After reduction of disulfide bridges, three polypeptide chains of approximately 25 kDa are released and analyzed by liquid chromatography-mass spectrometry (LC-MS). By bisecting the heavy chains prior to MS analysis, this method provides a better MS resolution and facilitates the study of the N-linked glycans as well as of other modifications (loss of C-terminal lysine, pyroglutamination, and oxidation). The sample preparation and analysis can be performed within few hours. PMID- 21596015 TI - Immunodetection of caspase-3 by Western blot using glutaraldehyde. AB - Cell death by apoptosis triggers the engagement of a conserved intracellular machinery of execution, involving mainly the activation of the caspase family of cysteine proteases. Caspase-3 is a common effector of most of the apoptotic pathways and is able to cleave several target proteins whose degradation will contribute to the execution phase of the cell demise program. Here we present a modification of the Western blot protocol to improve sensitivity of caspase-3 detection, providing a valuable tool to access its activation in biological specimens. PMID- 21596012 TI - Trauma exposure and posttraumatic stress disorder in adults with severe mental illness: a critical review. AB - There is a great deal of research on the prevalence, correlates, and treatment of PTSD in the general population. However, we know very little about the manifestation and consequences of PTSD in more complicated patient populations. The purpose of the current paper is to provide a comprehensive review of PTSD within the context of severe mental illness (SMI; i.e., schizophrenia spectrum disorders, mood disorders). Extant data suggest that trauma and PTSD are highly prevalent among individuals with SMI relative to the general population, and both are associated with adverse clinical functioning and increased healthcare burden. However, trauma and PTSD remain overlooked in this population, with low recognition rates in public-sector settings. Additionally, there are few data on the clinical course and treatment of PTSD among individuals with SMI. Particularly lacking are longitudinal studies, randomized controlled treatment trials, and studies using ethno-racially diverse samples. Furthermore, there is a need to better understand the interplay between trauma, PTSD, and severe forms of mental illness and to further develop and disseminate evidence-based PTSD treatments in this population. The current state of the literature and future directions for practice are discussed. PMID- 21596016 TI - Nrdp1 governs differentiation of the melanocyte lineage via Erbb3b signaling in the zebrafish embryogenesis. AB - NRDP1/FLRP1 is an E3-ubiquitin ligase with RBCC (RING, B-box, coiled-coil) motifs. NRDP1 is involved in versatile cellular signaling mechanisms in various species. Nonetheless, their functional roles in embryogenesis are largely unknown. We thus identified, isolated, and analyzed spatiotemporal expression and functional roles of zebrafish nrdp1 in the zebrafish embryogenesis. nrdp1 transcripts are prevalent in the neural crest cells, nervous system and skeletal muscle throughout the embryogenesis. Morpholino based knockdown of nrdp1 hinders pigmentation process. Based on further analysis of the nrdp1 morphants with markers for pigmentation process, we propose that Nrdp1 is associated with differentiation process of the melanocyte lineage by regulating Erbb3b, an Erbb signaling molecule along zebrafish embryogenesis. PMID- 21596017 TI - Sialyl Lewisx-dependent binding of human monocyte-derived dendritic cells to selectins. AB - The limited efficacy of monocyte-derived dendritic cell (mo-DC)-based vaccines is primarily attributed to the reduced mo-DC migratory capacity. One undefined aspect is the initial binding of mo-DCs to endothelial cells and vascular selectins. In this study, we investigated the role and modulation of the selectin binding determinant sialyl Lewis(x) (sLe(x)) in selectin-dependent mo-DC binding. Our data reveal that sLe(x) is required for maximal binding of mo-DCs to tumor necrosis factor (TNF)-alpha-activated endothelial cells under static conditions, as evidenced by the use of sialidase. Sialidase treatment also abrogated mo-DC cell tethering to immobilized, purified P-, L-, or E-selectin under flow. The requirement of sLe(x)-dependent binding of mo-DC to selectins was further substantiated by using sLe(x) free sugar and anti-sLe(x) antibody, which significantly suppressed mo-DC-selectin binding. P-selectin glycoprotein ligand-1 is required for mo-DC binding to both P- and L-selectin, but it is dispensable for E-selectin recognition. Interestingly, the extent of mo-DC tethering was maximal on P-selectin, followed by E- and L- selectin. Accordingly, L-selectin mediated faster mo-DC rolling than E- or P-selectin. Interferon (IFN)-gamma induces a significant increase in mo-DC surface sLe(x) expression, which is probably due to the enhanced synthesis of C2GnT-I. These findings may contribute to improving mo-DC-based vaccination protocols. PMID- 21596018 TI - Aliphatic acetogenin constituents of avocado fruits inhibit human oral cancer cell proliferation by targeting the EGFR/RAS/RAF/MEK/ERK1/2 pathway. AB - Avocado (Persea americana) fruits are consumed as part of the human diet and extracts have shown growth inhibitory effects in various types of human cancer cells, although the effectiveness of individual components and their underlying mechanism are poorly understood. Using activity-guided fractionation of the flesh of avocado fruits, a chloroform-soluble extract (D003) was identified that exhibited high efficacy towards premalignant and malignant human oral cancer cell lines. From this extract, two aliphatic acetogenins of previously known structure were isolated, compounds 1 [(2S,4S)-2,4-dihydroxyheptadec-16-enyl acetate] and 2 [(2S,4S)-2,4-dihydroxyheptadec-16-ynyl acetate]. In this study, we show for the first time that the growth inhibitory efficacy of this chloroform extract is due to blocking the phosphorylation of EGFR (Tyr1173), c-RAF (Ser338), and ERK1/2 (Thr202/Tyr204) in the EGFR/RAS/RAF/MEK/ERK1/2 cancer pathway. Compounds 1 and 2 both inhibited phosphorylation of c-RAF (Ser338) and ERK1/2 (Thr202/Tyr204). Compound 2, but not compound 1, prevented EGF-induced activation of the EGFR (Tyr1173). When compounds 1 and 2 were combined they synergistically inhibited c RAF (Ser338) and ERK1/2 (Thr202/Tyr204) phosphorylation, and human oral cancer cell proliferation. The present data suggest that the potential anticancer activity of avocado fruits is due to a combination of specific aliphatic acetogenins that target two key components of the EGFR/RAS/RAF/MEK/ERK1/2 cancer pathway. PMID- 21596019 TI - A novel Fbxo25 acts as an E3 ligase for destructing cardiac specific transcription factors. AB - Alterations in ubiquitin-proteasome system (UPS) have been implicated in the etiology of human cardiovascular diseases. Skp1/Cul1/F-box (SCF) ubiquitin E3 ligase complex plays a pivotal role in ubiquitination of cardiac proteins. However, a specific ubiquitin E3 ligase responsible for the destruction of cardiac transcription factors such as Nkx2-5, Isl1, Mef2C, and Tbx5 remains elusive to date. Here, we show that a novel F-box containing Fbxo25 is cardiac specific and acts as an ubiquitin E3 ligase for cardiac transcription factors. Fbxo25 expression was nuclei-specific in vitro and cardiomyocytes. Expression level of Fbxo25 was higher in a fetal heart than an adult. Moreover, Fbxo25 expression was increased along with those of cardiac-specific genes during cardiomyocyte development from ESCs. Fbxo25 expression facilitated protein degradation of Nkx2-5, Isl1, Hand1, and Mef2C. Especially, Fbxo25 ubiquitinated Nkx2-5, Isl1, and Hand1. Altogether, Fbxo25 acts as an ubiquitin E3 ligase to target cardiac transcription factors including Nkx2-5, Isl1, and Hand1, indicating that cardiac protein homeostasis through Fbxo25 has a pivotal impact on cardiac development. PMID- 21596020 TI - Hydrogen-rich medium protects human skin fibroblasts from high glucose or mannitol induced oxidative damage. AB - Reactive oxygen species (ROS) are an important factor in the development of skin lesions in diabetes. A new antioxidant, hydrogen, can selectively neutralize hydroxyl radicals (()OH) and peroxynitrite (ONOO(-)) in cell-free systems, whereas it seldom reacts with other ROS. Fibroblasts are a key component of skin. In the present study, we investigated the protective effects of hydrogen-rich medium on human skin fibroblasts (HSFs) under oxidative stress. Confocal microscopy was used to assay both the intracellular superoxide anion (O(2)(-)) concentration and the mitochondrial membrane potential (DeltaPsi). Cell viability was determined using the Cell Counting Kit-8 (CCK-8). The concentrations of cellular malonaldehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), 8 hydroxy-2'-deoxyguanosine (8-OHdG) and 3-nitrotyrosine (3-NT) were also measured. The results revealed that both mannitol and high glucose could cause oxidative stress in HSFs. Interestingly, the use of a hydrogen-rich medium significantly reduced the level of intracellular O(2)(-), stabilized the DeltaPsi and attenuated production of MDA, 8-OHdG and 3-NT which efficiently enhanced the antioxidative defense system and protected the HSFs from subsequent oxidative stress damage. In other words, hydrogen decreased the excessive generation of intracellular O(2)(-) and elevated the cellular antioxidative defense. Based on our results, hydrogen may have applications in the treatment of skin diseases caused by diabetes. PMID- 21596022 TI - Epigenetic activation of human kallikrein 13 enhances malignancy of lung adenocarcinoma by promoting N-cadherin expression and laminin degradation. AB - The tissue kallikrein (KLK) family contains 15 genes (KLK1-KLK15) tandemly arranged on chromosome 19q13.4 that forms the largest cluster of contiguous protease genes in the human genome. Here, we provide mechanistic evidence showing that the expression of KLK13, one of the most recently identified family members, is significantly up-regulated in metastatic lung adenocarcinoma. Whilst overexpression of KLK13 resulted in an increase in malignant cell behavior, knockdown of its endogenous gene expression caused a significant decrease in cell migratory and invasive properties. Functional studies further demonstrated that KLK13 is activated via demethylation of its upstream region. The elevated KLK13 protein then enhances the ability of tumor cells to degrade extracellular laminin that, subsequently, facilitates cell metastatic potential in the in vivo SCID mouse xenograft model. KLK13 was also found to induce the expression of N cadherin to help promote tumor cell motility. Together, these results reveal the enhancing effects of KLK13 on tumor cell invasion and migration, and that it may serve as a diagnostic/prognostic marker and a potential therapeutic target for lung cancer. PMID- 21596021 TI - TNFalpha enhances the motility and invasiveness of prostatic cancer cells by stimulating the expression of selective glycosyl- and sulfotransferase genes involved in the synthesis of selectin ligands. AB - Sialyl Lewis x (sLe(x)) plays an important role in cancer metastasis. But, the mechanism for its production in metastatic cancers remains unclear. The objective of current study was to examine the effects of a proinflammatory cytokine on the expression of glycosyltransferase and sulfotransferase genes involved in the synthesis of selectin ligands in a prostate cancer cell line. Androgen independent human lymph node-derived metastatic prostate cancer cells (C-81 LNCaP), which express functional androgen receptor and mimic the castration resistant advanced prostate cancer, were used. TNFalpha treatment of these cells increased their binding to P-, E- and L-selectins, anti-sLe(x) antibody, and anti 6-sulfo-sialyl Lewis x antibody by 12%, 240%, 43%, 248% and 21%, respectively. Also, the expression of C2GnT-1, B4GalT1, GlcNAc6ST3, and ST3Gal3 genes was significantly upregulated. Further treatment of TNFalpha-treated cells with either anti-sLe(x) antibody or E-selectin significantly suppressed their in vitro migration (81% and 52%, respectively) and invasion (45% and 56%, respectively). Our data indicate that TNFalpha treatment enhances the motility and invasion properties of LNCaP C-81 cells by increasing the formation of selectin ligands through stimulation of the expression of selective glycosyl- and sulfotransferase genes. These results support the hypothesis that inflammation contributes to cancer metastasis. PMID- 21596023 TI - Inhibition of hepatitis B virus (HBV) by LNA-mediated nuclear interference with HBV DNA transcription. AB - Silencing target genes with small regulatory RNAs is widely used to investigate gene function and therapeutic drug development. Recently, triplex-based approaches have provided another attractive means to achieve targeted gene regulation and gene manipulation at the molecular and cellular levels. Nuclear entry of oligonucleotides and enhancement of their affinity to the DNA targets are key points of such approaches. In this study, we developed lipid-based transport of a locked-nucleic-acid (LNA)-modified oligonucleotide for hepatitis B virus (HBV) DNA interference in human hepatocytes expressing HBV genomic DNA. In these cells, the LNA-modified oligonucleotides passed efficiently across the cell membrane, and lipid-coating facilitated translocation from the cytoplasm to the nucleus. The oligonucleotide specifically targeting HBV DNA clearly interfered with HBV DNA transcription as shown by a block in pregenomic RNA (pgRNA) production. The HBV DNA-targeted oligonucleotide suppressed HBV DNA replication and HBV protein production more efficiently than small interfering RNAs directed to the pgRNA. These results demonstrate that fusion with lipid can carry LNA modified oligonucleotides to the nucleus where they regulate gene expression. Interfering with HBV DNA transcription by LNA-modified oligonucleotides has strong potential as a new strategy for HBV inhibition. PMID- 21596024 TI - Effects of highly active novel artemisinin-chloroquinoline hybrid compounds on beta-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum. AB - 4-Aminoquinolines were hybridized with artemisinin and 1,4-naphthoquinone derivatives via the Ugi-four-component condensation reaction, and their biological activities investigated. The artemisinin-containing compounds 6a-c and its salt 6c-citrate were the most active target compounds in the antiplasmodial assays. However, despite the potent in vitro activities, they also displayed cytotoxicity against a mammalian cell-line, and had lower therapeutic indices than chloroquine. Morphological changes in parasites treated with these artemisinin-containing hybrid compounds were similar to those observed after addition of artemisinin. These hybrid compounds appeared to share mechanism(s) of action with both chloroquine and artemisinin: they exhibited potent beta-hematin inhibitory activities; they caused an increase in accumulation of hemoglobin within the parasites that was intermediate between the increase observed with artesunate and chloroquine; and they also appeared to inhibit endocytosis as suggested by the decrease in the number of transport vesicles in the parasites. No cross-resistance with chloroquine was observed for these hybrid compounds, despite the fact that they contained the chloroquinoline moiety. The hybridization strategy therefore appeared to be borrowing the best from both classes of antimalarials. PMID- 21596026 TI - Circulating tenascin-C levels in patients with dilated cardiomyopathy in the course of Emery-Dreifuss muscular dystrophy. AB - BACKGROUND: Tenascin-C (TN-C), an extracellular matrix glycoprotein, is of diagnostic and prognostic value in different heart diseases. One such dilated cardiomyopathy (DCM) with conduction disturbances is one of the most serious manifestations in Emery-Dreifuss muscular dystrophy (EDMD). Herein we therefore detail work to evaluate the potential significance of circulating TN-C in patients with EDMD, speculating that it may define the cardiac dysfunction, especially in patients who may be cardiac asymptomatic, but still be at risk of sudden death. MATERIAL AND METHOD: Serum levels of TN-C were quantified by sandwich immunoassay ELISA in 25 EDMD patients (10 with laminopathy-AD-EDMD and 15 with emerinopathy-X-EDMD), 8 X-EDMD carriers, 9 disease controls (patients with dystrophinopathy), and 15 age-matched healthy controls. Fourteen of the EDMD patients had repeated TN-C examinations after 3 to 7 years. RESULTS: The levels of circulating TN-C were elevated in AD-EDMD and X-EDMD patients, as well as in some X-EDMD carriers, and patients with dystrophinopathy. The correlation between the TN-C level and left end-systolic ventricle diameter (LVDD) was significant in X-EDMD, while those with left atrium diameter (LAD) and the ejection fraction (EF) were not. In "follow-up" studies TN-C levels were not found to change over time in AD-EDMD, while rising in X-EDMD. CONCLUSIONS: The presented results indicate that assessments of circulating TN-C levels may help to identify EDMD patients at risk of dilated cardiomyopathy. TN-C might therefore be considered a candidate for a new biomarker, useful in detecting of cardiomyopathy and in further monitoring of the DCM therapy in patients with EDMD. PMID- 21596025 TI - Allosteric modulators of the alpha4beta2 subtype of neuronal nicotinic acetylcholine receptors. AB - Nicotinic acetylcholine receptors are ligand-gated ion conducting transmembrane channels from the Cys-loop receptor super-family. The alpha4beta2 subtype is the predominant heteromeric subtype of nicotinic receptors found in the brain. Allosteric modulators for alpha4beta2 receptors interact at a site other than the orthosteric site where acetylcholine binds. Many compounds which act as allosteric modulators of the alpha4beta2 receptors have been identified, with both positive and negative effects. Such allosteric modulators either increase or decrease the response induced by agonist on the alpha4beta2 receptors. Here we discuss the concept of allosterism as it pertains to the alpha4beta2 receptors and summarize the important features of allosteric modulators for this nicotinic receptor subtype. PMID- 21596028 TI - Prostanoid DP receptor antagonists suppress symptomatic asthma-like manifestation by distinct actions from a glucocorticoid in rats. AB - While inhaled glucocorticoids are the best treatment for the majority of chronic asthmatics, there is a small group who do not respond to these drugs or whose disease can only be controlled by high doses of oral glucocorticoids with risks of severe side effects. Therefore, a safe novel anti-asthmatic agent which has a different mechanism from that of glucocorticoids is needed for the management of asthma. We have previously shown that an orally active prostanoid DP receptor antagonist, S-5751, had potent anti-inflammatory effects in guinea pig and sheep asthma models. In this study, using a rat asthma like model, we found that lung neutrophilia and proinflammatory cytokine secretion as well as bronchial hyperresponsiveness and lung eosinophilia were induced by repeated antigen inhalations after antigen-sensitization. These symptoms are similar to the pathogenesis of symptomatic asthma. Orally-administered prostanoid DP receptor antagonists S-5751 and pinagladin significantly suppressed not only bronchial hyperresponsiveness and lung eosinophilia but also neutrophilia and mucus secretion in the lung, while oral prednisolone inhibited only bronchial hyperresponsiveness and eosinophil infiltration. In addition, prostanoid DP receptor antagonists significantly suppressed interleukin (IL)-1beta, IL-6 and CXCL1 mRNA in contrast to suppression of IL-4 and CCL11 mRNA by prednisolone. The majority of prostanoid DP receptor-expressing cells in both rat and human asthmatic lungs are infiltrative macrophages and/or monocytes. These results suggest that prostanoid DP receptor antagonists utilize different mechanisms from glucocorticoids, and that they would be a novel alternative and/or combination drug for asthma therapy. PMID- 21596029 TI - The effects of jatrorrhizine on contractile responses of rat ileum. AB - This study was designed to evaluate the effect of jatrorrhizine on smooth muscle contractions isolated from rat ileum longitudinal muscles. Jatrorrhizine increased the amplitude of spontaneous contractions of ileum longitudinal muscles in concentration-dependent manner with an EC(50) of 30.0+/-8.4MUM. Preincubation of ileum strips with atropine (1MUM), 4-diphenyllacetoxy-N (2-chloriethyl) piperidine (4-DAMP, 1MUM) or darifenacin (1MUM) significantly inhibited acetylcholine (0.1MUM)- and jatrorrhizine (100MUM)-induced ileum longitudinal muscle contractions, whereas they were not affected by AF-DX116 (1MUM) or hexamethonium (100MUM). Pretreatment with SB204070 (1MUM) rather than 3-tropanyl indole-3-carboxyleat (tropisetron, 1MUM) significantly inhibited 5-HT (10MUM) induced ileum longitudinal muscle contractions. In contrast, jatrorrhizine induced ileum longitudinal muscle contractions were not inhibited by tropisetron or SB204070. Furthermore, jatrorrhizine-induced ileum longitudinal muscle contractions were strongly inhibited by nifedipine (1MUM), and also attenuated by removal of extracellular Ca(2+), U73122 (1MUM), ruthenium red (50MUM) or 2 aminoethoxydiphenylborate (2-APB, 10MUM). Taken together, jatrorrhizine-elicited spontaneous contractions in rat ileum longitudinal muscles are mediated by activation of acetylcholine receptors, mostly the M(3) receptor. Ca(2+) influx through L-type Ca(2+) channel is significantly contributed to jatrorrhizine elicited spontaneous contractions, and Ca(2+) release via IP(3) and ryanodine pathways are also involved. PMID- 21596027 TI - Fragile X mental retardation protein is required for programmed cell death and clearance of developmentally-transient peptidergic neurons. AB - Fragile X syndrome (FXS), caused by loss of fragile X mental retardation 1 (FMR1) gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 product (FMRP) is an RNA-binding protein best established to function in activity-dependent modulation of synaptic connections. In the Drosophila FXS disease model, loss of functionally-conserved dFMRP causes synaptic overgrowth and overelaboration in pigment dispersing factor (PDF) peptidergic neurons in the adult brain. Here, we identify a very different component of PDF neuron misregulation in dfmr1 mutants: the aberrant retention of normally developmentally-transient PDF tritocerebral (PDF-TRI) neurons. In wild type animals, PDF-TRI neurons in the central brain undergo programmed cell death and complete, processive clearance within days of eclosion. In the absence of dFMRP, a defective apoptotic program leads to constitutive maintenance of these peptidergic neurons. We tested whether this apoptotic defect is circuit-specific by examining crustacean cardioactive peptide (CCAP) and bursicon circuits, which are similarly developmentally-transient and normally eliminated immediately post eclosion. In dfmr1 null mutants, CCAP/bursicon neurons also exhibit significantly delayed clearance dynamics, but are subsequently eliminated from the nervous system, in contrast to the fully persistent PDF-TRI neurons. Thus, the requirement of dFMRP for the retention of transitory peptidergic neurons shows evident circuit specificity. The novel defect of impaired apoptosis and aberrant neuron persistence in the Drosophila FXS model suggests an entirely new level of "pruning" dysfunction may contribute to the FXS disease state. PMID- 21596030 TI - Repeated citalopram administration counteracts kainic acid-induced spreading of PSA-NCAM-immunoreactive cells and loss of reelin in the adult mouse hippocampus. AB - Systemic or intracerebral administration of kainic acid in rodents induces neuronal death followed by a cascade of neuroplastic changes in the hippocampus. Kainic acid-induced neuroplasticity is evidenced by alterations in hippocampal neurogenesis, dispersion of the granule cell layer and re-organisation of mossy fibres. Similar abnormalities are observed in patients with temporal lobe epilepsy and, therefore, kainic acid-induced hippocampal neuroplasticity might mimic pathological mechanisms leading to the formation of 'epileptic brain' in patients with temporal lobe epilepsy. Previous studies have demonstrated that selective serotonin re-uptake inhibitor antidepressants might reduce the severity of seizures in epileptic patients and reduce neuronal death in laboratory animal models of kainic acid-induced neurotoxicity. In the present study, we investigated whether kainic acid-induced neuroplasticity in mice is modulated by the repeated administration of citalopram, a selective serotonin reuptake inhibitor. We found that at the histopathological level, repeated citalopram treatment counteracted the kainic acid-induced neuronal loss and dispersion of young granule neurons expressing the polysialylated neural cell adhesion molecule within the granule cell layer of the hippocampus. Citalopram also counteracted the downregulation of reelin on both mRNA and protein levels induced by kainic acid administration. Our findings indicate that repeated administration of citalopram is able to prevent kainic acid-induced abnormal brain plasticity and thereby prevent the formation of an epileptic phenotype. PMID- 21596031 TI - Dehydrocostus lactone prevents mitochondrial dysfunction in osteoblastic MC3T3-E1 cells. AB - The dried root of Saussurea lappa Clarke (Compositae) has been used as a traditional medicine. Dehydrocostus lactone is one of the main bioactive constituents of this medicinal plant. In the present study, the protective effect of dehydrocostus lactone against antimycin A (an inhibitor of mitochondrial complex III)-induced cytotoxicity was investigated in osteoblastic MC3T3-E1 cells. Pre-treatment with dehydrocostus lactone prior to antimycin A exposure significantly prevented mitochondrial membrane potential dissipation, complex IV inactivation, ATP loss, cytochrome c release, intracellular calcium elevation and potassium loss, and reactive oxygen species production induced by antimycin A. These results suggest that dehydrocostus lactone protects osteoblastic MC3T3-E1 cells from antimycin A-induced cell damage through the improved mitochondrial function. PMID- 21596032 TI - The effect of topiramate on tumor-related angiogenesis and on the serum proteome of mice bearing Lewis lung carcinoma. AB - Topiramate has been used in patients with brain tumors who develop epilepsy. In our previous research we found topiramate could inhibit tumor metastases of Lewis lung carcinoma in C57BL/6 mice. In this study we aimed to assess the antimetastatic activity of topiramate and determine its mechanism of action. After confirming the effects of topiramate on Lewis lung carcinoma in C57BL/6 mice, we assessed the mRNA expression of carbonic anhydrases II and IX, and the vascular endothelial growth factor (VEGF) distribution in tumor tissue. We studied the role of topiramate on primary angiogenesis using a chicken embryo chorioallantoic membrane angiogenesis model, and analyzed the protein profile of serum from mice treated with or without topiramate by two-dimensional electrophoresis. We found that topiramate significantly reduced the primary tumor growth (P<0.05) and the degree of damage to the lung alveoli caused by metastatic tumor deposits. The two-dimensional electrophoresis revealed changes that occurred with topiramate treatment and four down-regulated protein spots were clearly identified as tropomyosin, osteopontin, transthyretin, and serum amyloid A-1. The mRNA and protein expression of serum amyloid A-1, osteopontin and its receptor, integrin alpha(v)beta(3) in tumor tissue were reconfirmed. The results suggest that topiramate has antitumor and antimetastatic effects on Lewis lung carcinoma. Its mechanism of action may be related to its inhibition of angiogenesis by down-regulation of osteopontin, VEGF and carbonic anhydrase II. PMID- 21596033 TI - Relationship between angiotensin II receptor expression and cardiovascular risk factors in Mexican patients with coronary occlusive disease. AB - The density of Angiotensin II (Ang) receptors on tissue surfaces is regulated by multiple hormones, cytokines and metabolic factors and is profoundly affected by various pathological conditions, such as age, diet and environmental conditions. The participation of several cardiovascular risk factors in the regulation of Angiotensin II receptor expression has been incompletely studied. We performed an ex-vivo study with human aortic postsurgical specimens to test the hypothesis that Ang AT1 and AT2 receptor expression in human aortic arteries is associated with the presence of cardiovascular risk factors. We included 31 Mexican patients with coronary artery disease. We evaluated Angiotensin II receptor expression by immunostaining and angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphisms by polymerase chain reaction. AT1 and AT2 receptor expression was increased in the aortic segments from the cardiovascular patients compared with control arteries and in patients with the DD genotype. There was a correlation between increased AT1 receptor expression and the number of cardiovascular risk factors present in the patient. Furthermore, reduction of AT1 expression correlated with the number of drug combinations used in the patients. These correlations were not present with respect to AT2 receptor expression. We suggest that increased AT1 receptor expression is associated with the DD genotype. Thus the presence of several cardiovascular risk factors as well as DD genotype, induce AT1 expression increasing the probability to develop coronary occlusive disease. PMID- 21596034 TI - Significance of DC-LAMP and DC-SIGN expression in psoriasis vulgaris lesions. AB - OBJECTIVE: To detect and compare the expression levels of two dendritic cell proteins, namely Dendritic Cell Lysosome-Associated Membrane Protein (DC-LAMP) and Dendritic Cell-Specific ICAM-3 Grabbing Non-integrin (DC-SIGN) in psoriasis vulgaris lesions and normal skin tissues. METHODS: We used Reverse Transcription Polymerase Chain Reaction (RT-PCR) and immunohistochemical analysis to detect the expression of DC-LAMP and DC-SIGN in 33 samples representing plaque lesions of psoriasis vulgaris and 11 normal skin samples from healthy volunteers. RESULTS: RT-PCR The expression levels of DC-LAMP and DC-SIGN were higher in samples of psoriasis vulgaris lesions than in that of normal skin, based on RT-PCR results.Whereas DC-LAMP staining was mostly cytoplasmic in keratinocytes of basal and spinous epidermis and dermal dendritic cells, DC-SIGN staining was both cytoplasmic and nuclear in keratinocytes of spinous epidermis and dermal dendritic cells. The expression levels of DC-LAMP and DC-SIGN proteins were significantly higher in psoriasis vulgaris lesions when compared with normal skin tissues (P<0.01). Furthermore, we found a positive correlation between high DC LAMP and high DC-SIGN expression levels in psoriasis vulgaris lesions (P<0.05, r=0.368). CONCLUSION: Compared with normal tissues, the levels of DC-LAMP and DC SIGN were higher in psoriasis vulgaris lesions. Both DC-LAMP and DC-SIGN proteins may be involved in the pathogenesis of psoriasis vulgaris. The high expression of DC-LAMP may be associated with the altered differentiation of keratynocytes in psoriasis. PMID- 21596035 TI - Neuroprotective potential of erythropoietin and its derivative carbamylated erythropoietin in periventricular leukomalacia. AB - Periventricular leukomalacia (PVL) is the predominant pathology in premature infants, characterized by prominent cerebral white matter injury, and commonly caused by hypoxia-ischemia and inflammation. Activated microglia trigger white matter damage and play a major role in the development of PVL. Erythropoietin (EPO) and its derivative carbamylated erythropoietin (CEPO) have been shown to be neuroprotective in several brain disease models. Here we investigated whether EPO and CEPO could provide protection in mouse models of PVL induced by hypoxia ischemia or hypoxia-ischemia-inflammation. We administered EPO or CEPO to mice with PVL, and found that both EPO and CEPO treatments decreased microglia activation, oligodendrocyte damage and myelin depletion. We also noted improved performance in neurological function assays. Inhibited disease progression in PVL mice by EPO or CEPO treatment was associated with decreased poly-(ADP-ribose) polymerase-1 (PARP-1) activity. PARP-1 activity was increased dramatically in activated microglia in untreated mice with PVL. Furthermore, we demonstrated that the neuroprotective properties of EPO and CEPO were diminished after PARP-1 gene depletion. The therapeutic doses of EPO and CEPO used in this study did not interfere with normal oligodendrocyte maturation and myelination. Together, our data demonstrate that EPO and CEPO are neuroprotective in cerebral white matter injury via a novel microglial PARP-1 dependent mechanism, and hold promise as a future treatment for PVL and other hypoxic-ischemic/inflammatory white matter diseases. PMID- 21596037 TI - Chondroitinase treatment following spinal contusion injury increases migration of oligodendrocyte progenitor cells. AB - Following spinal cord injury (SCI), the demyelination of spared intact axons near the lesion site likely contributes to the loss of motor function. This demyelination occurs when oligodendrocytes, the myelinating cells of the central nervous system (CNS), are either destroyed during the initial trauma or die as a result of secondary pathology. In an attempt to remyelinate the affected axons, endogenous oligodendrocyte progenitor cells (OPCs) begin to accumulate at the border of demyelination. However, the differentiation of OPCs into fully myelinating cells is limited. While the reasons for this are unknown, it is well known that the injured spinal cord is rich in inhibitory molecules that block repair. One such family of molecules is the chondroitin sulfate proteoglycans (CSPGs), which are known to be highly inhibitory to the process of axonal elongation. Recent in vitro findings have demonstrated that CSPGs are also highly inhibitory to OPCs, affecting both their migration and differentiation. Treatment with the enzyme chondroitinase ABC (cABC), which removes the glycosaminoglycan side chains of CSPGs, reverses the inhibitory effects of CSPGs on these cells. In the present study, we examined the effects of cABC on the migratory behavior of endogenous OPCs in vivo following a moderate spinal contusion injury. The total number of OPCs surrounding the lesion site was significantly increased after cABC treatment as compared to controls. cABC treatment also enhanced axonal sprouting, but OPC migration occurs along a different time course and appears independent of new process outgrowth. These data suggest that CSPGs in the post-injury environment inhibit the migration of OPCs, as well as axonal regeneration. Therefore, cABC treatment may not only enhance regenerative axonal sprouting, but may also enhance remyelination after SCI. PMID- 21596036 TI - Some lumbar sympathetic neurons develop a glutamatergic phenotype after peripheral axotomy with a note on VGLUT2-positive perineuronal baskets. AB - Glutamate is the main excitatory neurotransmitter in the nervous system, including in primary afferent neurons. However, to date a glutamatergic phenotype of autonomic neurons has not been described. Therefore, we explored the expression of vesicular glutamate transporter (VGLUT) types 1, 2 and 3 in lumbar sympathetic chain (LSC) and major pelvic ganglion (MPG) of naive BALB/C mice, as well as after pelvic nerve axotomy (PNA), using immunohistochemistry and in situ hybridization. Colocalization with activating transcription factor-3 (ATF-3), tyrosine hydroxylase (TH), vesicular acetylcholine transporter (VAChT) and calcitonin gene-related peptide was also examined. Sham-PNA, sciatic nerve axotomy (SNA) or naive mice were included. In naive mice, VGLUT(2)-like immunoreactivity (LI) was only detected in fibers and varicosities in LSC and MPG; no ATF-3-immunoreactive (IR) neurons were visible. In contrast, PNA induced upregulation of VGLUT(2) protein and transcript, as well as of ATF-3-LI in subpopulations of LSC neurons. Interestingly, VGLUT(2)-IR LSC neurons coexpressed ATF-3, and often lacked the noradrenergic marker TH. SNA only increased VGLUT(2) protein and transcript in scattered LSC neurons. Neither PNA nor SNA upregulated VGLUT(2) in MPG neurons. We also found perineuronal baskets immunoreactive either for VGLUT(2) or the acetylcholinergic marker VAChT in non-PNA MPGs, usually around TH-IR neurons. VGLUT(1)-LI was restricted to some varicosities in MPGs, was absent in LSCs, and remained largely unaffected by PNA or SNA. This was confirmed by the lack of expression of VGLUT(1) or VGLUT(3) mRNAs in LSCs, even after PNA or SNA. Taken together, axotomy of visceral and non-visceral nerves results in a glutamatergic phenotype of some LSC neurons. In addition, we show previously non-described MPG perineuronal glutamatergic baskets. PMID- 21596040 TI - The intricate dance between repair and inflammation: introduction to special issue. PMID- 21596038 TI - Plasticity in reflex pathways to the lower urinary tract following spinal cord injury. AB - The lower urinary tract has two main functions, storage and periodic expulsion of urine, that are regulated by a complex neural control system in the brain and lumbosacral spinal cord. This neural system coordinates the activity of two functional units in the lower urinary tract: (1) a reservoir (the urinary bladder) and (2) an outlet (consisting of bladder neck, urethra and striated muscles of the external urethra sphincter). During urine storage the outlet is closed and the bladder is quiescent to maintain a low intravesical pressure. During micturition the outlet relaxes and the bladder contracts to promote efficient release of urine. This reciprocal relationship between bladder and outlet is generated by reflex circuits some of which are under voluntary control. Experimental studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through a coordination center (the pontine micturition center) located in the rostral brainstem. This reflex pathway is in turn modulated by higher centers in the cerebral cortex that are involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter function. Following spinal cord injury the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. However the bladder does not empty efficiently because coordination between the bladder and urethral outlet is lost. Studies in animals indicate that dysfunction of the lower urinary tract after spinal cord injury is dependent in part on plasticity of bladder afferent pathways as well as reorganization of synaptic connections in the spinal cord. Reflex plasticity is associated with changes in the properties of ion channels and electrical excitability of afferent neurons and appears to be mediated in part by neurotrophic factors released in the spinal cord and/or the peripheral target organs. PMID- 21596041 TI - Unravelling the different functions of protein kinase C isoforms in platelets. AB - Platelets tightly regulate haemostasis and arterial thrombosis. Protein kinase C (PKC) is involved in most platelet responses implicated in thrombus formation. Recent pharmacological and mouse gene knockout approaches show that the conventional PKC isoforms and the novel PKC isoforms contribute in distinct ways to these platelet responses. We hypothesize that, in platelets and other cells, the characteristic functions of PKC isoforms are established through unique activation mechanisms and unique interacting protein partners, which result in isoform-specific patterns of substrate phosphorylation. For identifying the substrate proteins in a living cell, new methodology is available and discussed. PMID- 21596039 TI - Role of myelin-associated inhibitors in axonal repair after spinal cord injury. AB - Myelin-associated inhibitors of axon growth, including Nogo, MAG and OMgp, have been the subject of intense research. A myriad of experimental approaches have been applied to investigate the potential of targeting these molecules to promote axonal repair after spinal cord injury. However, there are still conflicting results on their role in axon regeneration and therefore a lack of a cohesive mechanism on how these molecules can be targeted to promote axon repair. One major reason may be the lack of a clear definition of axon regeneration in the first place. Nevertheless, recent data from genetic studies in mice indicate that the roles of these molecules in CNS axon repair may be more intricate than previously envisioned. PMID- 21596043 TI - California gull chicks raised near colony edges have elevated stress levels. AB - Coloniality in nesting birds represents an important life history strategy for maximizing reproductive success. Birds nesting near the edge of colonies tend to have lower reproductive success than individuals nesting near colony centers, and offspring of edge-nesting parents may be impaired relative to those of central nesting parents. We used fecal corticosterone metabolites in California gull chicks (Larus californicus) to examine whether colony size or location within the colony influenced a chick's physiological condition. We found that chicks being raised near colony edges had higher fecal corticosterone metabolite concentrations than chicks raised near colony centers, but that colony size (ranging from 150 to 11,554 nests) had no influence on fecal corticosterone levels. Fecal corticosterone metabolite concentrations also increased with chick age. Our results suggest that similarly aged California gull chicks raised near colony edges may be more physiologically stressed, as indicated by corticosterone metabolites, than chicks raised near colony centers. PMID- 21596042 TI - MyD88 and retinoic acid signaling pathways interact to modulate gastrointestinal activities of dendritic cells. AB - BACKGROUND & AIMS: Gut-associated dendritic cells (DC) metabolize vitamin A into all-trans retinoic acid (RA), which is required to induce lymphocytes to localize to the gastrointestinal tract and promotes the differentiation of Foxp3+ regulatory T cells and IgA antibody-secreting cells. We investigated whether RA functions in a positive-feedback loop in DC to induce its own synthesis. METHODS: We measured levels of retinoids in intestinal tissues from mice and assessed the role of RA in the functional specialization of gut-associated DC in cell cultures and mice. We used pharmacologic antagonists to determine the signaling pathways involved in regulation of DC and used MyD88-/- mice to determine the contribution of Toll-like receptor signaling in RA-mediated effects on DC. RESULTS: The concentration of retinoids decreased in a proximal-to-distal gradient along the intestine, which correlated with the activity of gut-specific DC. Importantly, RA regulated the ability of gut-associated DC to produce RA, induce T cells to localize to the gastrointestinal tract, and generate regulatory T cells and IgA secreting cells. RA was sufficient to induce its own production by extraintestinal DC in vitro and in vivo. RA-mediated regulation of DC required signaling through the mitogen-activated protein kinase signaling pathway and unexpectedly required MyD88, which is conventionally associated with Toll-like receptor, interleukin-1, and interleukin-18 signaling. CONCLUSIONS: RA is necessary and sufficient to induce DC to regulate T-cell localization to the gastrointestinal tract and IgA secretion. Our findings also indicate crosstalk between the RA receptor and MyD88-dependent Toll-like receptor signaling pathways. PMID- 21596044 TI - Cloning of an insulin-like androgenic gland factor (IAG) from the blue crab, Callinectes sapidus: implications for eyestalk regulation of IAG expression. AB - In malacostracan crustaceans, sex differentiation is uniquely regulated by a hormone secreted by the male-specific androgenic gland (AG). An isopod AG hormone was the first to be structurally elucidated and was found to belong to the insulin superfamily of proteins. Recently, it has been found that the AGs of several decapod crustaceans express insulin-like androgenic gland factors (IAGs), whose function is believed to be similar to that of the isopod AG hormone. Here we report the isolation from the blue crab Callinectes sapidus of the full-length cDNA encoding a candidate insulin-like AG hormone, termed Cas-IAG. The predicted protein Cas-IAG was encoded as a precursor consisting of a signal peptide, the B chain, the C peptide, and the A chain in that order. While the AG was the main source of Cas-IAG expression, as found in other decapod species, the hepatopancreas of male Callinectes sapidus crabs displayed minor Cas-IAG expression. Eyestalk ablation confirmed the presence of a possible endocrine axis between the eyestalk ganglia and the AG, implying that Cas-IAG expression is negatively regulated by (a) substance(s) present in the eyestalk ganglia. PMID- 21596045 TI - Expression of insulin-like growth factor I receptors at mRNA and protein levels during metamorphosis of Japanese flounder (Paralichthys olivaceus). AB - Insulin-like growth factor I (IGF-I) is an important regulator of fish growth and development, and its biological actions are initiated by binding to IGF-I receptor (IGF-IR). Our previous study has revealed that IGF-I could play an important role during metamorphosis of Japanese flounder, Paralichthys olivaceus. The analysis of IGF-IR expression thus helps further elucidate the IGF-I regulation of metamorphic processes. In this study, the spatial-temporal expression of two distinct IGF-IR mRNAs was investigated by real-time RT-PCR. The spatial distribution of two IGF-IR mRNAs in adult tissues is largely overlapped, but they exhibit distinct temporal expression patterns during larval development. A remarkable decrease in IGF-IR-2 mRNA was detected during metamorphosis. In contrast, a significant increase in IGF-IR-1 mRNA was determined from pre metamorphosis to metamorphic completion. These indicate that they may play different function roles during the flounder metamorphosis. The levels and localization of IGF-IR proteins during larval development were further studied by Western blotting and immunohistochemistry. Immunoreactive IGF-IRs were detected throughout larval development, and the IGF-IR proteins displayed a relatively abundant expression during metamorphosis. Moreover, the IGF-IR proteins appeared in key tissues, such as thickened skin beneath the migrating eye, developing intestine, gills and kidney during metamorphosis. These results further suggest that the IGF-I system may be involved in metamorphic development of Japanese flounder. PMID- 21596046 TI - Oxytocin infusion increases charitable donations regardless of monetary resources. AB - This study examined if the prosocial effects of oxytocin (OT) extend from individuals to a generalized other who is in need. Participants played a series of economic games to earn money and were presented with an opportunity to donate a portion of their earnings to charity. OT did not significantly increase the decision to donate, but among the 36% of participants who did donate, people infused with OT were found to donate 48% more to charity than those given a placebo. The amount of money earned in the experiment had no effect on whether or not a donation was made or the size of a donation. This is the first study showing that OT increases generosity in unilateral exchanges directed toward philanthropic social institutions, as opposed to immediate benefits directed at individuals or groups. PMID- 21596048 TI - Conformational plasticity and dynamics in the generic protein folding catalyst SlyD unraveled by single-molecule FRET. AB - The relation between conformational dynamics and chemistry in enzyme catalysis recently has received increasing attention. While, in the past, the mechanochemical coupling was mainly attributed to molecular motors, nowadays, it seems that this linkage is far more general. Single-molecule fluorescence methods are perfectly suited to directly evidence conformational flexibility and dynamics. By labeling the enzyme SlyD, a member of peptidyl-prolyl cis-trans isomerases of the FK506 binding protein type with an inserted chaperone domain, with donor and acceptor fluorophores for single-molecule fluorescence resonance energy transfer, we directly monitor conformational flexibility and conformational dynamics between the chaperone domain and the FK506 binding protein domain. We find a broad distribution of distances between the labels with two main maxima, which we attribute to an open conformation and to a closed conformation of the enzyme. Correlation analysis demonstrates that the conformations exchange on a rate in the 100 Hz range. With the aid from Monte Carlo simulations, we show that there must be conformational flexibility beyond the two main conformational states. Interestingly, neither the conformational distribution nor the dynamics is significantly altered upon binding of substrates or other known binding partners. Based on these experimental findings, we propose a model where the conformational dynamics is used to search the conformation enabling the chemical step, which also explains the remarkable substrate promiscuity connected with a high efficiency of this class of peptidyl-prolyl cis trans isomerases. PMID- 21596047 TI - Testosterone and 11-ketotestosterone have different regulatory effects on electric communication signals of male Brachyhypopomus gauderio. AB - The communication signals of electric fish can be dynamic, varying between the sexes on a circadian rhythm and in response to social and environmental cues. In the gymnotiform fish Brachyhypopomus gauderio waveform shape of the electric organ discharge (EOD) is regulated by steroid and peptide hormones. Furthermore, EOD amplitude and duration change on different timescales and in response to different social stimuli, suggesting that they are regulated by different mechanisms. Little is known about how androgen and peptide hormone systems interact to regulate signal waveform. We investigated the relationship between the androgens testosterone (T) and 11-ketotestosterone (11-KT), the melanocortin peptide hormone alpha-MSH, and their roles in regulating EOD waveform of male B. gauderio. Males were implanted with androgen (T, 11-KT, or blank), and injected with alpha-MSH before and at the peak of androgen effect. We compared the effects of androgen implants and social interactions by giving males a size-matched male stimulus with which they could interact electrically. Social stimuli and both androgens increased EOD duration, but only social stimuli and 11-KT elevated amplitude. However, no androgen enhanced EOD amplitude to the extent of a social stimulus, suggesting that a yet unidentified hormonal pathway regulates this signal parameter. Additionally, both androgens increased response of EOD duration to alpha-MSH, but only 11-KT increased response of EOD amplitude to alpha-MSH. Social stimuli had no effect on EOD response to alpha-MSH. The finding that EOD amplitude is preferentially regulated by 11-KT in B. gauderio may provide the basis for independent control of amplitude and duration. PMID- 21596049 TI - Multiple POT1-TPP1 proteins coat and compact long telomeric single-stranded DNA. AB - Telomeres are nucleoprotein complexes that cap and protect the ends of linear chromosomes. In humans, telomeres end in 50-300 nt of G-rich single-stranded DNA (ssDNA) overhangs. Protection of telomeres 1 (POT1) binds with nanomolar affinity to the ssDNA overhangs and forms a dimer with another telomere-end binding protein called TPP1. Whereas most previous studies utilized telomeric oligonucleotides comprising single POT1-TPP1 binding sites, here, we examined 72- to 144-nt tracts of telomeric DNA containing 6-12 POT1-TPP1 binding sites. Using electrophoretic mobility gel shift assays, size-exclusion chromatography, and electron microscopy, we analyzed telomeric nucleoprotein complexes containing POT1 alone, POT1-TPP1, and a truncated version of POT1 (POT1-N) that maintains its DNA-binding domain. The results revealed that POT1-N and POT1-TPP1 can completely coat long telomeric ssDNA substrates. Furthermore, we show that ssDNA coated with human POT1-TPP1 heterodimers forms compact, potentially ordered structures. PMID- 21596051 TI - Effects of dietary fat on appetite and energy intake in health and obesity--oral and gastrointestinal sensory contributions. AB - While epidemiological studies have revealed a strong positive relationship between the intake of dietary fat with total energy intake and body weight, laboratory-based studies investigating physiological effects of fat have demonstrated that the direct exposure of receptors in the oral cavity and small intestine to fat, specifically fatty acids (FAs), induces potent effects on gastrointestinal (GI) motility and gut peptide secretion that favor the suppression of appetite and energy intake. Recent studies in humans have demonstrated an association between a decreased ability to detect the presence of FAs in the oral cavity with increased energy intake and body mass index suggesting that impairment of oral fat sensing mechanisms may contribute to overeating and obesity. Furthermore, while sensing of the presence of FAs in the small intestine results in the modulation of GI motility, stimulation of GI hormone release, including cholecystokinin (CCK) and peptide YY (PYY), and suppression of subsequent energy intake, recent data indicate that these effects of fat are attenuated in individuals with reduced oral sensitivity to fat, and following consumption of a high-fat diet. This review will focus on emerging knowledge about the physiological mechanisms that sense the presence of fat in both the oral cavity and the small intestine, and environmental factors, such as high-fat diet exposure and energy restriction, that may modulate sensitivity to nutrients, and thereby contribute to the regulation of appetite and body weight. PMID- 21596050 TI - Hippocampal dysfunction effects on context memory: possible etiology for posttraumatic stress disorder. AB - Hippocampal volume reductions and functional impairments are reliable findings in posttraumatic stress disorder (PTSD) imaging studies. However, it is not clear if and how hippocampal dysfunction contributes to the etiology and maintenance of PTSD. Individuals with PTSD are often described as showing fear responses to trauma reminders outside of contexts in which these cues would reasonably predict danger. Animal studies suggest that the hippocampus is required to form and recall associations between contextual stimuli and aversive events. For example, the hippocampus is critical for encoding memories in which a complex configuration of multiple cues is associated with the aversive event. Conversely, the hippocampus is not required for associations with discrete cues. In animal studies, if configural memory is disrupted, learning strategies using discrete cue associations predominate. These data suggest poor hippocampal function could bias the organism toward forming multiple simple cue associations during trauma, thus increasing the chances of fear responses in multiple environments (or contexts) in which these cues may be present. Here we will examine clinical and preclinical literature to support a theory of hippocampal dysfunction as a primary contributory factor to the etiology of PTSD, and discuss future research required to test these hypotheses. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. PMID- 21596052 TI - Hemostatic and toxinological diversities in venom of Micrurus tener tener, Micrurus fulvius fulvius and Micrurus isozonus coral snakes. AB - The coral snake Micrurus tener tener (Mtt) from the Elapidae family inhabits the southwestern United States and produces severe cases of envenomations. Although the majority of Mtt venom components are neurotoxins and phospholipase A2s, this study demonstrated, by SDS-PAGE and molecular exclusion chromatography (MEC), that these venoms also contain high-molecular-weight proteins between 50 and 150 kDa that target the hemostatic system. The biological aspects of other Micrurus venoms were also studied, such as the LD50s of Micrurus isozonus (from 0.52 to 0.61 mg/kg). A pool from these venoms presented a LD50 of 0.57 mg/kg, Micrurus f. fulvius (Mff) and Mtt had LD50s of 0.32 and 0.78 mg/kg, respectively. These venoms contained fibrino(geno)lytic activity, they inhibited platelet aggregation, as well as factor Xa and/or plasmin-like activities. M. isozonus venoms from different Venezuelan geographical regions inhibited ADP-induced platelet aggregation (from 50 to 68%). Micrurus tener tener venom from the United States was the most active with a 95.2% inhibitory effect. This venom showed thrombin-like activity on fibrinogen and human plasma. Fractions of Mtt showed fibrino(geno)lytic activity and inhibition on plasmin amidolytic activity. Several fractions degraded the fibrinogen Aalpha chains, and fractions F2 and F7 completely degraded both fibrinogen Aalpha and Bbeta chains. To our knowledge, this is the first report on thrombin-like and fibrino(geno)lytic activity and plasmin or factor Xa inhibitors described in Micrurus venoms. Further purification and characterization of these Micrurus venom components could be of therapeutic use in the treatment of hemostatic disorders. PMID- 21596053 TI - Imaging single cells in the living retina. AB - A quarter century ago, we were limited to a macroscopic view of the retina inside the living eye. Since then, new imaging technologies, including confocal scanning laser ophthalmoscopy, optical coherence tomography, and adaptive optics fundus imaging, transformed the eye into a microscope in which individual cells can now be resolved noninvasively. These technologies have enabled a wide range of studies of the retina that were previously impossible. PMID- 21596054 TI - Premature aging-related peripheral neuropathy in a mouse model of progeria. AB - Peripheral neuropathy is a common aging-related degenerative disorder that interferes with daily activities and leads to increased risk of falls and injury in the elderly. The etiology of most aging-related peripheral neuropathy is unknown. Inherited defects in several genome maintenance mechanisms cause tissue specific accelerated aging, including neurodegeneration. We tested the hypothesis that a murine model of XFE progeroid syndrome, caused by reduced expression of ERCC1-XPF DNA repair endonuclease, develops peripheral neuropathy. Nerve conduction studies revealed normal nerve function in young adult (8 week) Ercc1( /Delta) mice, but significant abnormalities in 20 week-old animals. Morphologic and ultrastructural analysis of the sciatic nerve from mutant mice revealed significant alterations at 20 but not 8 weeks of age. We conclude that Ercc1( /Delta) mice have accelerated spontaneous peripheral neurodegeneration that mimics aging-related disease. This provides strong evidence that DNA damage can drive peripheral neuropathy and offers a rapid and novel model to test therapies. PMID- 21596056 TI - Lower utilization of cervical cancer screening by nurses in Taiwan: a nationwide population-based study. AB - OBJECTIVE: Using a nationwide population-based database in Taiwan, this study compares use of Pap smear testing by nurses and the general population. METHOD: We compared 1093 practicing female nurses and 5465 randomly selected female patients from the 2006 National Health Insurance (NHI) database to evaluate the likelihood of receiving at least one Pap smear during a three-year period. RESULTS: We found that 48.9% of the nurses and 56.2% of comparison subjects received a Pap test from 2004 to 2006 in Taiwan. Regression analysis showed that practicing female nurses were less likely to receive a Pap smear compared with the general population (OR=0.42, 95% CI=0.35-0.50, p<0.001), after adjusting for monthly incomes, number of ob/gyn ambulatory care visits, urbanization level and the geographic location of the communities where subjects resided. CONCLUSION: Nurses were less likely to undergo cervical screening than the general population, despite ease of access and a national health insurance system providing universal coverage to residents of Taiwan. Efforts to raise the Pap screening rate among nurses may require addressing unique cultural and occupational concerns. PMID- 21596057 TI - The role of clinical breast examination and breast self-examination. AB - The efficacy of screening by clinical breast examination (CBE) and/or breast self examination (BSE) is reviewed using indirect evidence from randomized breast screening trials and that from observational studies. In countries where breast cancer is diagnosed at an advanced stage, screening by CBE with the teaching of BSE as an integral component will probably be effective in reducing breast cancer mortality. However, in technically advanced countries where adequate treatment is given, no screening modality is likely to be sufficiently beneficial to outweigh the harms of screening, especially false positives and over-diagnosis. PMID- 21596058 TI - Prospective of guar gum and its derivatives as controlled drug delivery systems. AB - Guar gum is a non-ionic polysaccharide that is found abundantly in nature and has many properties desirable for drug delivery applications. However, due to its high swelling characteristics in aqueous solution, the use of guar gum as delivery carriers is limited. Guar gum can be modified by derivatization, grafting and network formation to improve its property profile for a wide spectrum of biomedical applications. This review article is aimed at focusing the recent efforts and developments on guar gum and its derivatives as colon specific, antihypertensive, protein and transdermal drug delivery systems. Based on the literatures reviewed, it is concluded that guar gum and its derivatives in the various forms such as coatings, matrix tablets, hydrogels and nano/microparticles can be exploited as potential carriers for targeted drug delivery. PMID- 21596055 TI - Cognitive enhancers for the treatment of ADHD. AB - Attention-deficit hyperactivity disorder (ADHD) is associated with multiple cognition-related phenotypic features in both children and adults. This review aims to clarify the role of cognition in ADHD and how prevailing treatments, which are often highly effective at reducing the clinical symptoms of the disorder, fare in modulating ADHD-related cognitive processes. First, we consider how the broad construct of cognition can be conceptualized in the context of ADHD. Second, we review the available evidence for how a range of both pharmacological and non-pharmacological interventions have fared with respect to enhancing cognition in individuals affected by this pervasive disorder. Findings from the literature suggest that the effects across a broad range of pharmacological and non-pharmacological interventions on the characteristic symptoms of ADHD can be distinguished from their effects on cognitive impairments. As such the direct clinical relevance of cognition enhancing effects of different interventions is somewhat limited. Recommendations for future research are discussed, including the identification of cognition-related endophenotypes, the refinement of the ADHD clinical phenotype, and studying the difference between acute and chronic treatment regimens. PMID- 21596059 TI - Antimicrobial textile treated with chitosan from Aspergillus niger mycelial waste. AB - The waste biomass of Aspergillus niger, following citric acid production, was used as a source for fungal chitosan extraction. The produced chitosan was characterized with deacetylation degree of 89.6%, a molecular weight of 25,000 dalton, 97% solubility in 1% acetic acid solution and comparable FT-IR spectra to standard shrimp chitosan. Fungal chitosan was applied as a cotton fabric finishing agent using pad-dry-cure method. The topographical structure of chitosan-treated fabrics (CTF) was much improved compared with control fabrics. CTF, after durability tests, exhibited a powerful antimicrobial activity against both E. coli and Candida albicans, the captured micrographs for E. coli cells contacted with CTF showed a complete lysis of cell walls with the prolonging contact time. The produced antimicrobial CTF could be proposed as a suitable material for many medical and hygienic applications. PMID- 21596060 TI - Human brain EEG indices of emotions: delineating responses to affective vocalizations by measuring frontal theta event-related synchronization. AB - At present there is no direct brain measure of basic emotional dynamics from the human brain. EEG provides non-invasive approaches for monitoring brain electrical activity to emotional stimuli. Event-related desynchronization/synchronization (ERD/ERS) analysis, based on power shifts in specific frequency bands, has some potential as a method for differentiating responses to basic emotions as measured during brief presentations of affective stimuli. Although there appears to be fairly consistent theta ERS in frontal regions of the brain during the earliest phases of processing affective auditory stimuli, the patterns do not readily distinguish between specific emotions. To date it has not been possible to consistently differentiate brain responses to emotion-specific affective states or stimuli, and some evidence to suggests the theta ERS more likely measures general arousal processes rather than yielding veridical indices of specific emotional states. Perhaps cortical EEG patterns will never be able to be used to distinguish discrete emotional states from the surface of the brain. The implications and limitations of such approaches for understanding human emotions are discussed. PMID- 21596061 TI - A comparison of methods for separation of transient and oscillatory signals in EEG. AB - Brain oscillations constitute a prominent feature of electroencephalography (EEG), in both physiological and pathological states. An efficient separation of oscillation from transient signals in EEG is important not only for detection of oscillations, but also for advanced signal processing such as source localization. A major difficulty lies in the fact that filtering transient phenomena can lead to spurious oscillatory activity. Therefore, in the presence of a mixture of transient and oscillatory events, it is not clear to which extent filtering methods are able to separate them efficiently. The objective of this study was to evaluate methods for separating oscillations from transients. We compared three methods: finite impulse response (FIR) filtering, wavelet analysis with stationary wavelet transform (SWT), time-frequency sparse decomposition with Matching Pursuit (MP). We evaluated the quality of reconstruction and the results of automatic detection of oscillations intermingled with transients. The emphasis of our study was on epileptic signals and single channel processing. In both simulations and on real data, FIR performed generally worse than the time frequency methods. Both SWT and MP showed good results in separation and detection, each method having its advantages and its limitations. The SWT had good results in separation and detection of transients due to the time invariance property, but still did not completely resolve the frequency overlap for the oscillation during the time-frequency thresholding. The MP provides a sparse representation, and gave good results for simulated data. However, in the real data, we observed distortions introduced by the subtractive approach, and departure from dictionary waveforms. Future directions are proposed for overcoming these limitations. PMID- 21596062 TI - The ITFR, impulsive tail flick reflex by short duration nociceptive stimuli. AB - A new method for evoking the tail flick reflex is introduced, using short duration or "impulsive" nociceptive stimuli, which allow synchronization and recording of electrophysiological responses. Ten adult rats were studied, by means of thermal (CO(2) laser infrared pulse with 30 ms duration, 7.5 or 10W), electric (a 25 ms train of five 0.2 ms pulses, with 5 or 10 mA intensity) or mechanical (pin pressed with 5 g force) stimuli. Both electromyographic and strain gauge mechanical responses were recorded from the tail. All three types of stimulation gave rise to three components, named early, late and ultralate, respectively occurring in the range of 19-97 ms, 190-519 ms, 1,523-2,765 ms. Conduction velocities of the underlying afferent fibres were calculated by moving the stimulation site. The early component could be linked to Adelta afferents, while late and ultralate components were due to unmyelinated C afferents. Experiments with Fentanyl (20 MUg/kg) showed that only the C linked components were depressed, with the ultralate component the most affected, possibly because supraspinally originated. Tail flick reflex evoked by impulsive stimuli is believed to be an important electrophysiological complement to behavioural procedures, useful in identifying the site of action of analgesics and other drugs upon the spinal and supraspinal centres involved in nociception. PMID- 21596063 TI - Long-term survivors after immunotherapy for metastatic melanoma. PMID- 21596064 TI - Differences in capabilities of different enzyme immunoassays to detect anti hepatitis E virus immunoglobulin G in pigs infected experimentally with hepatitis E virus genotype 3 or 4 and in pigs with unknown exposure. AB - Hepatitis E virus (HEV), a major cause of acute viral hepatitis in humans in many developing countries, is highly prevalent in the pig population worldwide. The objective of this study was to assess the capability of three porcine prototypes of a human enzyme-linked immunosorbent assay (ELISA), an in-house ELISA and a line-immunoassay (LIA) to detect anti-HEV antibodies in pigs infected experimentally with HEV (n = 57), known to be negative for HEV infection (n = 27), or with unknown exposure to HEV infection (field samples, n = 90). All 27 samples from non-infected pigs were negative with all five assays. The earliest detection of anti-HEV antibodies occurred at 14 days post-inoculation (dpi) with four of five assays. From 42 dpi, all samples from infected pigs were detected correctly as anti-HEV positive. Kappa analysis demonstrated substantial agreement among tests (0.62-1.00) at 14 dpi and complete agreement (1.00) at 56 dpi. The overall area under the curve for all quantitative tests as determined by receiver operator characteristic analysis ranged from 0.794 to 0.831 indicating moderate accuracy. The results showed that all five assays can detect anti-HEV IgG antibodies accurately in pigs infected experimentally with HEV. In field samples, a higher prevalence of anti-HEV IgG was found in breeding herds than in growing pigs (100% versus 66.7-93.9%). These serological assays should be very useful in veterinary diagnostic labs for HEV diagnosis in swine. PMID- 21596065 TI - Posttrial d-cycloserine enhances the emotional memory of an incentive downshift event. AB - The present research was designed to determine whether an incentive downshift event induces an emotional memory that can be modulated by d-cycloserine (DCS), a partial agonist at the glycine site of N-methyl-d-aspartate receptor (NMDAR). DCS has been reported to have memory-enhancing properties in other training situations. Experiments 1 and 2 involved a consummatory successive negative contrast (cSNC) situation in which animals are exposed to an incentive downshift involving sucrose solutions of different concentrations. DCS administration (30 mg/kg, ip) immediately after the first 32-to-4% sucrose downshift trial (Experiment 1) retarded recovery of consummatory behavior, but immediately after the first 32-to-6% sucrose downshift trial (Experiment 2) did not affect recovery. There was no evidence that DCS affected consummatory behavior in the absence of an incentive downshift in a manner analogous to a conditioned taste aversion (Experiment 3). These results suggest that activation of NMDARs via the glycine modulatory site enhances the emotional memory triggered by exposure to an incentive downshift event. PMID- 21596066 TI - Age-related differences in the anticipation of future rewards. AB - The present study examined the anticipation of future reward in 7-mo- and 26-mo old Fischer 344/Brown Norway rats. Young and old rats were divided randomly and assigned into one of two conditions. In the Contrast Condition, subjects were given a water solution containing 2% sucrose for 3 min followed immediately by a water solution containing 32% sucrose for 3 min. In the No-Contrast Condition, subjects were given a water solution containing 2% sucrose for 3 min followed immediately by a water solution containing 2% sucrose for 3 min. Across 10 days of testing in the Contrast Condition, young rats showed significantly less intake of the less preferred 2% sucrose solution, whereas old rats showed increased intake of the 2% sucrose solution. Young rats showed a significant increase in intake of the preferred 32% sucrose solution compared to aged rats across the 10 day testing period with the exception of days 8-10 where intake did not differ between groups. In the No-Contrast Condition, there were no significant differences between young and old rats, with both groups consuming significantly more of the first 2% solution than the second 2% solution. Therefore, these data suggest that age-related changes may impair the ability to anticipate future rewards. PMID- 21596067 TI - Stress-induced depressive behaviors are correlated with Par-4 and DRD2 expression in rat striatum. AB - Depression is a common mental disorder; however, its molecular mechanism has not been fully elucidated. In this study, we investigated the role of maternal deprivation (MD) and chronic mild stress (CMS) in the pathogenesis of depression in rat models. The mRNA levels of prostate apoptosis response-4 (Par-4) and dopamine receptor D2 (DRD2) genes in the striatum were measured by real-time PCR. Methylation level in the promoter of Par-4 gene was detected by bisulfite sequencing. Correlation between gene expression and depression-like behaviors were analyzed. Our results demonstrated that MD and CMS alone or their combination (dual stresses: DS) caused depression-like behaviors in rats. The mRNA levels of Par-4 and DRD2 genes in the striatum were significantly lower in MD-, CMS-, and DS-treated rats than in control rats. Importantly, Par-4 and DRD2 mRNA levels significantly correlated with depression-like behaviors. However, no significant differences in total methylation levels in the promoter of Par-4 gene were found between four groups. Our study suggested that either maternal deprivation or chronic mild stress plays a crucial role in the development of depression-like behaviors in rats. This process is associated with down-regulated Par-4 and DRD2 gene expression in the striatum through a non-methylation mechanism. PMID- 21596069 TI - Extracellular ATP induces spikes in cytosolic free Ca(2+) but not in NADPH oxidase activity in neutrophils. AB - In order to establish whether non-mitochondrial oxidase activity in human neutrophils is tightly related to cytosolic Ca(2+) concentration, we simultaneously measured Ca(2+) oscillations induced by ATP and oxidant production in single adherent neutrophils using confocal microscopy. ATP induced fast damped Ca(2+) spikes with a period of 15s and slower irregular spikes with a period greater than 50s. Spikes in Ca(2+) occurred in the absence of Ca(2+) influx, but the amplitude was damped by inhibition of Ca(2+) influx. Using the oxidation of hydroethidine as a cytosolic marker of oxidant production, we show that the generation of reactive oxygen species by neutrophils adherent to glass was accelerated by ATP. The step-up in NADPH oxidase activity followed the first elevation of cytosolic Ca(2+) but, despite subsequent spikes in Ca(2+) concentration, no oscillations in oxidase activity could be detected. ATP induced spikes in Ca(2+) in a very reproducible way and we propose that the Ca(2+) signal is an on-switch for oxidase activity, but the activity is apparently not directly correlated with spiking activity in cytosolic Ca(2+). PMID- 21596068 TI - Baicalein, a component of Scutellaria baicalensis, induces apoptosis by Mcl-1 down-regulation in human pancreatic cancer cells. AB - Scutellaria baicalensis (SB) and SB-derived polyphenols possess anti proliferative activities in several cancers, including pancreatic cancer (PaCa). However, the precise molecular mechanisms have not been fully defined. SB extract and SB-derived polyphenols (wogonin, baicalin, and baicalein) were used to determine their anti-proliferative mechanisms. Baicalein significantly inhibited the proliferation of PaCa cell lines in a dose-dependent manner, whereas wogonin and baicalin exhibited a much less robust effect. Treatment with baicalein induced apoptosis with release of cytochrome c from mitochondria, and activation of caspase-3 and -7 and PARP. The general caspase inhibitor zVAD-fmk reversed baicalein-induced apoptosis, indicating a caspase-dependent mechanism. Baicalein decreased expression of Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, presumably through a transcriptional mechanism. Genetic knockdown of Mcl 1 resulted in marked induction of apoptosis. The effect of baicalein on apoptosis was significantly attenuated by Mcl-1 over-expression, suggesting a critical role of Mcl-1 in this process. Our results provide evidence that baicalein induces apoptosis in pancreatic cancer cells through down-regulation of the anti apoptotic Mcl-1 protein. PMID- 21596070 TI - Evaluation of FT-IR spectroscopy as a tool to quantify bacteria in binary mixed cultures. AB - Fourier-transform infrared (FT-IR) spectroscopy is known as a high-resolution method for the rapid identification of pure cultures of microorganisms. Here, we evaluated FT-IR as a method for the quantification of bacterial populations in binary mixed cultures consisting of Pseudomonas putida and Rhodococcus ruber. A calibration procedure based on Principal Component Regression was developed for estimating the ratio of the bacterial species. Data for method calibration were gained from pure cultures and artificially assembled communities of known ratios of the two member populations. Moreover, to account for physiological variability, FT-IR measurements were performed with organisms sampled at different growth phases. Measurements and data analyses were subsequently applied to growing mixed cultures revealing that growth of R. ruber was almost completely suppressed in co-culture with P. putida. Population ratios obtained by fatty acid analysis as an independent reference method were in high agreement with the FT-IR derived ratios. PMID- 21596071 TI - Immunomagnetic bead-based recovery and real time quantitative PCR (RT iq-PCR) for sensitive quantification of aflatoxin B(1). AB - Aflatoxin B(1) is an unavoidable natural mycotoxin that enters the food chain by contamination of food grains and feedstuffs, potentially posing carcinogenic risks to animal and human health. Immuno-PCR methods have the potential to address the need of meeting the regulatory limits by detecting trace levels of toxins present in food and animal feeds. This paper describes a real-time immuno quantitative PCR (RT-iqPCR) assay for quantification of aflatoxin B(1) suspended in methanol:water solution that can also serve as an extraction solvent. Immuno PCR approaches were examined including direct vs. indirect sandwich assays using monoclonal vs. polyclonal antibodies. Our best approach was obtained using monoclonal antibodies to capture aflatoxin in solution prior to immobilizing the F(c) portion of the capture antibodies onto to protein G magnetic beads. This was followed by the addition of a polyclonal 'signal antibody' tethered with an oligonucleotide template for a subsequent PCR assay. The RT-iqPCR assay described herein leads to the sensitive detection and quantification of aflatoxin B(1) from 10ppb down to 0.1ppb with high correlation (r(2)=0.97) and efficiency (99.5%). The approach also detected the high-dose 'hook effect' phenomenon (excess antigen) which was overcome by the use of dilution protocols to eliminate false negatives that may occur at levels above quantification limits of the assay. The RT-iqPCR approach discussed here is presented as a model system that could easily be adapted for aflatoxin detection in a variety of food or animal feed samples using a simple methanol:water solution as an extraction solvent. PMID- 21596072 TI - Microsecond thermal ablation of skin for transdermal drug delivery. AB - Thermal ablation is a promising mechanism to increase permeability of the skin's outer barrier layer of stratum corneum while sparing deeper living tissues. In this study, finite element modeling predicted that the skin surface should only be heated on the microsecond timescale in order to avoid significant temperature rises in living cells and nerve endings in deeper tissue. To achieve such short thermal pulses, we developed a microdevice that rapidly heats a few microliters of water by an electrical discharge and ejects the resulting superheated steam at the skin surface on a timescale on the order of 100 MUs. According to its design, we showed that this microdevice selectively removed stratum corneum of cadaver skin without significantly removing deeper tissue. This one-dimensional depth control was supplemented through the use of a masking film containing 100 MUm diameter holes placed on the skin surface during ablation to define the ablated skin area and thereby provide three-dimensional control over tissue removal. Using this approach, thermal ablation increased skin permeability to sulforhodamine B and bovine serum albumin by at least 1000-fold in vitro. We conclude that microsecond thermal ablation of skin can selectively remove stratum corneum and thereby dramatically increase skin permeability for transdermal drug delivery. PMID- 21596073 TI - Serving large portions of vegetable soup at the start of a meal affected children's energy and vegetable intake. AB - This study tested whether varying the portion of low-energy-dense vegetable soup served at the start of a meal affects meal energy and vegetable intakes in children. Subjects were 3- to 5-year-olds (31 boys and 41 girls) in daycare facilities. Using a crossover design, children were served lunch once a week for four weeks. On three occasions, different portions of tomato soup (150, 225, and 300 g) were served at the start of the meal, and on one occasion no soup was served. Children had 10 min to consume the soup before being served the main course. All foods were consumed ad libitum. The primary outcomes were soup intake as well as energy and vegetable intake at the main course. A mixed linear model tested the effect of soup portion size on intake. Serving any portion of soup reduced entree energy intake compared with serving no soup, but total meal energy intake was only reduced when 150 g of soup was served. Increasing the portion size increased soup and vegetable intake. Serving low-energy-dense, vegetable soup as a first course is an effective strategy to reduce children's intake of a more energy-dense main entree and increase vegetable consumption at the meal. PMID- 21596074 TI - Generation of HIV-1 Virus-Like Particles expressing different HIV-1 glycoproteins. AB - Elicitation of a potent and broadly neutralizing antibody response is the main goal of an effective preventive HIV-1 vaccine. It has been shown by us and others that the expression of Env glycoproteins on the surface of particulate structures, such as Virus-Like Particles (VLPs), could be a more efficient strategy to deliver conformational epitopes to the immune system. To this aim, VLPs expressing native HIV Env gp140 or gp41 glycoproteins have been produced in insect cells using a baculovirus expression system and characterized for appropriate protein expression. VLP-bound HIV gp140 glycoprotein showed the appropriate expression and trimeric conformation. Immunogenicity studies have been performed in BALB/C mice by intra-peritoneal administration and sera from immunized mice have been tested in ELISA assays, for their reactivity with HIV specific antigens, as well as in ex vivo neutralization assay. Sera from immunized animals showed a high reactivity with individual HIV proteins expressed in VLPs. Results of TZM-bl based neutralization assay show that combined sera from animals independently immunized with gp140- or full-length-gp41-expressing VLPs have an additive/synergistic effect in the neutralization activity of HIV pseudoviruses. In conclusion, novel VLPs expressing different HIV Env glycoproteins with native trimeric conformation have been generated, showing the induction of effective antibody response with neutralization activity in TZM-bl neutralization assay. These results confirm the effectiveness of VLPs as presentation and delivery system for conformational proteins and show the improved neutralization activity upon the combination of anti-sera elicited by different HIV envelope antigens, suggesting the possibility of broadening the spectrum of viral epitopes targeted by immune response. PMID- 21596075 TI - A DNA vaccine encoding the E protein of West Nile virus is protective and can be boosted by recombinant domain DIII. AB - West Nile Virus (WNV) is an emerging pathogenic flavivirus with increasing distribution worldwide. Birds are the natural host of the virus, but also mammals, including humans, can be infected. In some cases, a WNV infection can be associated with severe neurological symptoms. All currently available WNV vaccines are in the veterinary sector, and there is a need to develop safe and effective immunization technologies, which can also be used in humans. An alternative to current vaccination methods is DNA immunization. Most current DNA vaccine candidates against flaviviruses simultaneously express the viral envelope (E) and membrane (prM) proteins, which leads to the formation of virus-like particles. Here we generated a DNA plasmid, which expresses only the E-protein ectodomain. Vaccination of mice stimulated anti-WNV T-cell responses and neutralizing antibodies that were higher than those obtained after immunizing with a recombinant protein previously shown to be a protective WNV vaccine. A single dose of the plasmid was sufficient to protect animals from a lethal challenge with the virus. Moreover, immunogenicity could be boosted when DNA injection was followed by immunization with recombinant domain DIII of the E protein. This resulted in significantly enhanced neutralizing antibody titers and a more prominent cellular immune response. The results suggest that the WNV E protein is sufficient as a protective antigen in DNA vaccines and that protection can be significantly improved by adding a recombinant protein boost to the DNA prime. PMID- 21596076 TI - Protection from persistent infection with a bovine viral diarrhea virus (BVDV) type 1b strain by a modified-live vaccine containing BVDV types 1a and 2, infectious bovine rhinotracheitis virus, parainfluenza 3 virus and bovine respiratory syncytial virus. AB - Recent studies showed that BVDV-1b subgenotype is dominant in North and South American field BVDV isolates. However, nearly all commercially available BVDV-1 vaccines contain BVDV-1a strains. In order to study the efficacy of BVDV-1a vaccine against BVDV-1b infection, this study was designed to evaluate a modified live vaccine (MLV) containing BVDV-1a and BVDV-2 strains for its efficacy in prevention of persistent infection of fetuses against BVDV-1b strain, when the heifers were vaccinated prior to breeding. Heifers were vaccinated subcutaneously with a single dose of the MLV and bred four weeks after vaccination. The pregnant heifers were challenged with a non-cytopathic BVDV-1b strain at approximately 80 days of gestation. Vaccinated heifers were protected from clinical disease and viremia caused by the BVDV-1b virus. At approximately 155 days of gestation, the fetuses were harvested and tissue samples of thymus, lungs, spleen, kidney and intestines were collected for virus isolation. BVDV was isolated from 100% of the fetuses in the non-vaccinated control group, and from only one fetus (4.3%) from the vaccinated group. Results demonstrated that the MLV containing BVDV-1a and BVDV-2 strains provided 96% protection from fetal persistent infection caused by the BVDV-1b strain. PMID- 21596077 TI - Dose-ranging study of a single injection of pneumococcal conjugate vaccine (1 *, 2 *, or 4 *) in healthy subjects aged 70 years or older. AB - Healthy adults aged >= 70 years (N=443) with no history of pneumococcal vaccination received 7- or 9-valent pneumococcal conjugate vaccine (PCV7 or PCV9) at 1 * (PCV7 only), 2 * (PCV7+PCV9), or 4 * (2 * PCV7+2 * PCV9) dosage in a randomised, open-label study evaluating pneumococcal protein conjugate vaccine (PnC). Controls received 23-valent pneumococcal polysaccharide vaccine (PPV). Both geometric mean concentration enzyme-linked immunosorbent assay and opsonophagocytic activity antibody titres assessed 1 month after vaccination were significantly increased over baseline titres for all PCV7 serotypes, with a trend toward a dose-dependent immune response. Local reactions for the 4 * dose, but not the 2 * dose, were statistically significantly higher than for the 1 * dose. No treatment-related serious adverse events occurred. PMID- 21596079 TI - Evidence for the inhibition of fertilization in vitro by anti-ZP3 antisera derived from DNA vaccine. AB - Previously we have found that DNA vaccine, pCMV4-rZPC' can generate specific antibodies against rabbit ZPC (amino acid 263-415, rZPC'), which binds to ovarian ZP and leads to a significant reduction of fertility in vivo. The purpose of this study was to evaluate the effect of antisera from pCMV4-rZPC(')-immunized mice on sperm-oocyte interaction in vitro. The effect of antisera from DNA vaccine immunized mice on fertilization and early embryonic development was studied using an in vitro fertilization system. The results showed that the antisera supplemented in fertilization medium (10%, v/v) significantly decreased the rate of fertilization compared to that of control groups (P<0.05); whereas the antisera showed no significant effect on the rate of fertilization when ZP-free eggs were used. Moreover, the antisera pre-neutralized with mouse soluble zona pellucida lost the capacity to inhibit fertilization when compared with that of control groups. In addition, the antisera showed no detrimental effect on early developmental potential of mouse embryos in vitro. Taken together, our study provided herein direct evidence showing that antisera generated by DNA vaccine can block sperm-egg recognition during fertilization via targeting the oocyte ZP proteins. PMID- 21596080 TI - Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split virion H1N1 (2009) pandemic influenza vaccine during pregnancy: a prospective cohort study. AB - Infection with influenza virus during pregnancy poses a significant risk of complications for both mother and fetus. During the H1N1 2009 pandemic, pregnant women constituted one of the priority groups for vaccination in many countries, creating a need for close monitoring of the safety of the vaccine in pregnant women. We present findings from an analysis of a cohort of pregnant women (N=267) from a prospective, observational, post-authorization safety study of the AS03 adjuvanted split virion H1N1 (2009) pandemic vaccine. There were 265 known pregnancy outcomes with 261 live births, four spontaneous abortions with no congenital anomalies, and no stillbirths. There were six live births with congenital anomalies, of which one was diagnosed before vaccination. A total of 247 women (94.6%), of whom four had twin pregnancies, delivered at term, and 14 women (5.4%), of whom two had twin pregnancies, delivered preterm (between Weeks 24 and 36 of gestation), with three of them (1.1%) occurring before 32 weeks (very preterm). Twenty-one neonates (8.1%) had a low birth weight (<2.5 kg), of whom nine (3.5%) were term neonates. The prevalence of all outcomes was in line with the expected rates. The adverse events reported were consistent with the events anticipated to be reported by this study population. No adverse events of special interest were reported. The results of this analysis suggest that exposure to the AS03 adjuvanted H1N1 (2009) vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes including spontaneous abortion, congenital anomalies, preterm delivery, low birth weight neonates, or maternal complications. Although limited in size, the fully prospective nature of the safety follow-up of these women vaccinated during pregnancy is unique and offers an important degree of reassurance for the use of the AS03 adjuvanted H1N1 (2009) vaccine in this high risk group for H1N1 infection. PMID- 21596078 TI - Immune evaluation and vaccine responses in Down syndrome: evidence of immunodeficiency? AB - BACKGROUND: Patients with Down syndrome (DS) appear to be at a greater risk for serious infections, but it is unclear whether this is due to anatomic variations or intrinsic immune defects. OBJECTIVE: We assessed a cohort of pediatric subjects with DS to determine if immunological abnormalities indeed account for the excess infections. METHODS: We performed quantitative assessment of T independent (type 2 - pneumococcal polysaccharide vaccine) and T-dependent Ab responses (with inactivated seasonal influenza vaccine) along with numerical quantitation of lymphocyte subpopulations and thymic output in a random population sample of children with DS (cases) along with family-matched sibling or community controls. RESULTS: Median serum IgG levels were significantly higher in cases (1090 mg/dL) as compared with controls (808 mg/dL, P=0.02). Cases had significantly lower median CD4 T cell counts than the controls (636 cells/MUL, P=0.01). Cases had reduced CD19 B cell counts and CD19% than the controls (P=0.009 and 0.006 respectively). Cases also showed decreased total memory (CD19+CD27+, P=0.002) and class-switched memory (CD19+CD27+IgM-IgD-, P=0.004) B cells. The median CD4 recent thymic emigrant (RTE) in females and males cases was lower than controls (P=0.007 and 0.07 respectively). Cases had a lower median T cell receptor excision circle (TREC) count of 2556 as compared to the controls count of 5216, P<0.006 although both the cases and controls were within the established reference range. There were no differences in the percentage of cases and controls who responded to inactivated influenza vaccine, but the response to polysaccharide pneumococcal vaccine was suboptimal in cases. CONCLUSIONS: Our study suggests that there are subtle abnormalities in both humoral and cellular arms of the immune response in children with DS as compared to the control subjects. PMID- 21596081 TI - Bacterial etiology and serotypes of acute otitis media in Mexican children. AB - Streptococcus pneumoniae and Haemophilus influenzae have been consistently reported to be the two major bacterial pathogens responsible for acute otitis media (AOM), mainly from studies in the US and Europe. However, data on bacterial pathogens causing AOM in Latin America are limited. Understanding the relative importance of these pathogens in a specific setting, the serotype distribution, and their antibiotic susceptibility levels is important to provide local vaccine and treatment recommendations. We therefore conducted a prospective, multi center, tympanocentesis-based epidemiological study of Mexican children three months to less than five years of age. Fifty percent of episodes were in children who had received at least one dose of PCV7. Overall, 64% of samples were culture positive for bacterial pathogens. H. influenzae and S. pneumoniae were the leading causes of bacterial AOM, detected in 34% and 29% of AOM episodes, respectively. The most commonly isolated S. pneumoniae serotypes were 19A, 19F and 23F. All H. influenzae isolates were identified as non-typeable. Seventy-four percent of S. pneumoniae were susceptible to penicillin, while 97% were susceptible to amoxicillin/clavulanate. All H. influenzae samples were susceptible to amoxicillin/clavulanate and cefotaxime, 95% to cefuroxime and 75% to ampicillin. Both S. pneumoniae and non-typable H. influenzae represent important targets for vaccination strategies to reduce AOM in Mexican children. PMID- 21596082 TI - Autoimmune hepatitis type 2 following anti-papillomavirus vaccination in a 11 year-old girl. AB - In the last years numerous reports describing a possible association between administration of vaccines and development of autoimmune phenomena and overt autoimmune disease were published. Possible mechanisms of induction of autoimmune phenomena by vaccines and their excipients are probably similar to those implicated in induction by infectious agents. Here we report the case of an 11 year-old girl who developed autoimmune hepatitis type II after four weeks from vaccination against human papillomavirus. The possible relationships between the use of adjuvated vaccine against papillomavirus and autoimmune hepatitis are discussed. Although we do not provide evidence for a causal link, we suggest that the occurrence of the autoimmune hepatitis may be related to the stimulation of immune system by adjuvated-vaccine, that could have triggered the disease in a genetically predisposed individual. Therefore a monitoring of liver function test following administration of vaccine against papillomavirus may be useful in adolescent girl with signs of hepatopathy, as jaundice, dark urine or hepatomegaly, to early identify and to promptly treat autoimmune liver disorders. PMID- 21596083 TI - Multistrain genome analysis identifies candidate vaccine antigens of Anaplasma marginale. AB - Anaplasmosis in domestic livestock is an impediment to animal health and production worldwide, especially in developing countries in Africa, Asia, and South America. Vaccines have been developed and marketed against the causative organism, Anaplasma marginale; however, these have not been widely used because of breakthrough infections caused by heterologous strains and because of the risk of disease induced by live vaccine strains themselves. Recently, molecular studies have enabled progress to be made in understanding the causes for breakthrough infections and in defining new vaccine targets. A. marginale has a system for antigenic variation of the MSP2 and MSP3 outer membrane proteins which are members of the pfam01617 gene superfamily. In this study, we used high throughput genome sequencing to define conservation of different superfamily members in ten U.S. strains of A. marginale and also in the related live vaccine strain A. marginale subspecies centrale. The comparisons included the pseudogenes that contribute to antigenic variation and other superfamily-encoded outer membrane proteins. Additionally, we examined conservation of other proteins proposed previously as vaccine candidates. These data showed significantly increased numbers of SNPs in A. marginale subspecies centrale when compared to all U.S. A. marginale strains. We defined a catalog of 19 conserved candidate vaccine antigens that may be suitable for development of a multi-component recombinant vaccine. The methods described are rapid and may be suitable for other prokaryotes where repeats comprise a substantial portion of their genomes. PMID- 21596084 TI - Induction of a potent immune response in the elderly using the TLR-5 agonist, flagellin, with a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125, STF2.HA1 SI). AB - BACKGROUND: Influenza vaccines perform poorly in the elderly with reduced serological response and vaccine efficacy. We evaluated a novel influenza vaccine consisting of the globular head of the HA1 domain of the A/Solomon Islands/3/2006 (H1N1) influenza virus (VAX125) genetically fused to the TLR5 ligand, flagellin, and produced in Escherichia coli. METHODS: 120 subjects >= 65 years old were enrolled at three clinical centers. VAX125 vaccine was administered at doses of 0.5, 1, 2, 3, 5 or 8 MUg delivered i.m. as a single dose vaccination on Day 0 using a dose-escalation with 20 subjects in each dose level. Subjects were followed for adverse events and sera were tested by hemagglutination-inhibition (HAI) against egg-grown virus on days 0, 7, 14, and 28. Serum C-reactive protein (CRP) and anti-flagellin antibody were also assessed. RESULTS: The mean age was 71 years. The vaccine was well tolerated at all dose levels, with no more than mild to moderate local or systemic symptoms. The geometric mean titers (GMT) increased in all dose groups. In the 5 MUg group the day 14 post-vaccination HAI titer was 1:226 showing a 12-fold increase over baseline. The 8 MUg group showed a similar post-vaccination GMT increase (~ 8-fold). In the combined 5 and 8 MUg groups, the seroconversion rate was 75% and the seroprotection rate was 98%. CONCLUSIONS: A 5 MUg dose of VAX125 was safe and able to induce a greater than 10 fold increase HAI antibody levels and nearly complete seroprotection in subjects over 65 years old. The use of flagellin to adjuvant influenza vaccines via the TLR5 innate immune pathway appears to be a useful approach to overcome poor immune responses in the elderly. VAX125 is a promising new candidate for prevention of influenza A disease in both young adults and the elderly. PMID- 21596085 TI - HIV-Gag VLPs presenting trimeric HIV-1 gp140 spikes constitutively expressed in stable double transfected insect cell line. AB - We have previously described the establishment and characterization of a stably transfected insect cell line for the constitutive and efficient expression of Pr55 HIV Gag proteins, which auto-assemble into enveloped Virus-Like Particles (VLPs) released into the cell culture supernatant. Such HIV-Gag VLPs have been shown to elicit a specific systemic humoral response in vivo, proving the appropriate antigenic presentation of the HIV Gag protein to the immune system. Here we describe the establishment of a stable double transfected insect cell line for the constitutive and reproducible production of Pr55Gag-VLPs expressing on their surface trimeric forms of HIV-1 envelope glycoproteins. The persistence of HIV coding genes has been verified in clonal resistant insect cells, the protein expression and conformation has been verified by Western blot analysis. The resulting HIV-VLPs have been visualized by standard transmission electron microscopy and their immunogenicity has been evaluated in vivo. This represents, to our knowledge, the first example of stable double transfected insect cell line for the constitutive production of enveloped HIV-Gag VLPs presenting trimeric HIV gp140 on their surface. PMID- 21596086 TI - Shigella sonnei vaccine candidates WRSs2 and WRSs3 are as immunogenic as WRSS1, a clinically tested vaccine candidate, in a primate model of infection. AB - Shigella causes diarrhea and dysentery through contaminated food and water. Shigella sonnei live vaccine candidates WRSs2 and WRSs3 are attenuated principally by the loss of VirG(IcsA) that prevents bacterial spread within the colonic epithelium. In this respect they are similar to the clinically tested vaccine candidate WRSS1. However, WRSs2 and WRSs3 are further attenuated by loss of senA, senB and WRSs3 also lacks msbB2. As previously shown in cell culture assays and in small animal models, these additional gene deletions reduced the levels of enterotoxicity and endotoxicity of WRSs2 and WRSs3, potentially making them safer than WRSS1. However the behavior of these second-generation VirG(IcsA) based vaccine candidates in eliciting an immune response in a gastrointestinal model of infection has not been evaluated. In this study, WRSs2 and WRSs3 were nasogastrically administered to rhesus monkeys that were evaluated for colonization, as well as for systemic and mucosal immune responses. Both vaccine candidates were safe in rhesus monkeys and behaved comparably to WRSS1 in bacterial excretion rates that demonstrated robust intestinal colonization. Furthermore, humoral and mucosal immune responses elicited against bacterial antigens appeared similar in all categories across all three strains indicating that the additional gene deletions did not compromise the immunogenicity of these vaccine candidates. Based on data from previous clinical trials with WRSS1, it is likely that, WRSs2 and WRSs3 will not only be safer in human volunteers but will generate comparable levels of systemic and mucosal immune responses that were achieved with WRSS1. PMID- 21596087 TI - A postmarketing evaluation of the frequency of use and safety of live attenuated influenza vaccine use in nonrecommended children younger than 5 years. AB - The 2007 US approval for use of live attenuated influenza vaccine (LAIV) in children aged 24-59 months included precautions against use in (1) children <24 months and children aged 24-59 months with (2) asthma, (3) recurrent wheezing, and (4) altered immunocompetence. A postmarketing commitment was initiated to monitor LAIV use and the frequency of select safety outcomes in these cohorts. Vaccination rates and the frequency of hospitalizations or emergency department visits within 42 days after LAIV and trivalent inactivated influenza vaccine (TIV) administration were estimated from 2007 to 2009 claims data from a health insurance database. Rates of LAIV use per 10,000 child-days among cohorts 1, 2, and 4 were low relative to rates among the LAIV-recommended population (2007 2008; 0.03-0.78 vs. 1.32, 2008-2009; 0.08-3.26 vs. 5.94). However, rates of LAIV use per 10,000 child-days in cohort 3 were similar to rates among the LAIV recommended population (2007-2008; 1.55 vs. 1.32, 2008-2009; 5.01 vs. 5.94). The rate of emergency department visits/hospitalizations within 42 days of vaccination with LAIV was the same as or less than the rate within 42 days of vaccination with TIV. Less restricted LAIV use in children with past wheezing may be related to the broad definition of recurrent wheezing used in national guidelines and the current study. In the small number of nonrecommended children receiving LAIV, no safety signals were identified. PMID- 21596088 TI - Monitoring vaccine safety using the Vaccine Safety Datalink: utilizing immunization registries for pandemic influenza. AB - Mass vaccination campaigns during which new vaccines may be administered to many millions of people in a short period of time call for timely and accurate post licensure surveillance to monitor vaccine safety. To address the need for timely H1N1 influenza vaccine safety information during the 2009-2010 H1N1 influenza pandemic, the Vaccine Safety Datalink (VSD) project assessed the feasibility and potential mechanisms for utilizing data from state and local immunization registries to capture vaccinations that would not otherwise be captured by the data systems of the participating VSD managed care organizations (MCOs). Three of the eight VSD sites were able to capture H1N1 immunization data electronically from the state and local registries, and one site was able to capture the immunizations through a paper-based system; however, the remaining four sites encountered various obstacles that prevented capture of such data. Additional work will be required at these sites to overcome the barriers, which included privacy and confidentiality laws, time constraints brought on by the pandemic, as well as data quality concerns. PMID- 21596089 TI - The potential for human exposure, direct and indirect, to the suspected carcinogenic triphenylmethane dye Brilliant Green from green paper towels. AB - Triphenylmethanes - Malachite Green (MG), Crystal Violet (CV) and Brilliant Green (BG) are dyes with known genotoxic and carcinogenic properties. Apart from being illegally used in aquaculture for treatment of fish diseases they are also applied in industry such as paper production to colour paper towels widely used in hospitals, factories and other locations for hand drying after washing. The present study provides evidence that the triphenylmethane dye (BG) present in green paper towels can migrate through the skin even when the exposure time is short (30-300 s). The transfer of the dye from the towel to food (fish) was also studied and a high amount of colour was found to migrate during overnight exposure. The risk to humans associated with these two dye transfer studies was assessed using a 'margin of exposure approach' on the basis of the toxicological data available for the closely related dye MG and its metabolite Leucomalachite Green. The data indicated that the risk associated with the use of triphenylmethane containing paper towels is of a similar proportion to the risk associated with consumption of fish contaminated with these dyes due to the illegal application in aquaculture. PMID- 21596090 TI - Identification and characterization of a novel spermidine/spermine acetyltransferase encoded by gene ste26 from Streptomyces sp. 139. AB - Streptomyces sp. 139 produces a novel exopolysaccharide (EPS) designated Ebosin which can bind IL-1R specifically and exhibits anti-rheumatic arthritis activity in vivo. With the Ebosin biosynthesis gene cluster (ste) consisting of 27 ORFs identified previously the focus of this study was to characterize the protein encoded by ste26 gene. After cloning and expressing ste26 in Escherichia coli BL21, we purified the recombinant Ste26 protein and revealed its ability of transferring the acetyl group from AcCoA to spermidine and spermine, with spermine being the preferred substrate. Therefore Ste26 has been determined to be a spermidine/spermine acetyltransferase which can use spermine (Km of 72.1 +/- 7.4 MUM), spermidine (Km of 147.2 +/- 11 MUM), AcCoA (Km of 45.7 +/- 2.5 MUM) and poly-l-lysine (Km of 99.7 +/- 11 MUM) as substrates. The optimum pH, temperature and time for the activity have been shown to be 7.5, 37 degrees C and 10 min, respectively. This is the first spermidine/spermine acetyltransferase characterized in Streptomyces and its function in Ebosin biosynthesis is discussed. PMID- 21596091 TI - A novel method for preparation of HAMLET-like protein complexes. AB - Some natural proteins induce tumor-selective apoptosis. alpha-Lactalbumin (alpha LA), a milk calcium-binding protein, is converted into an antitumor form, called HAMLET/BAMLET, via partial unfolding and association with oleic acid (OA). Besides triggering multiple cell death mechanisms in tumor cells, HAMLET exhibits bactericidal activity against Streptococcus pneumoniae. The existing methods for preparation of active complexes of alpha-LA with OA employ neutral pH solutions, which greatly limit water solubility of OA. Therefore these methods suffer from low scalability and/or heterogeneity of the resulting alpha-LA - OA samples. In this study we present a novel method for preparation of alpha-LA - OA complexes using alkaline conditions that favor aqueous solubility of OA. The unbound OA is removed by precipitation under acidic conditions. The resulting sample, bLA-OA 45, bears 11 OA molecules and exhibits physico-chemical properties similar to those of BAMLET. Cytotoxic activities of bLA-OA-45 against human epidermoid larynx carcinoma and S. pneumoniae D39 cells are close to those of HAMLET. Treatment of S. pneumoniae with bLA-OA-45 or HAMLET induces depolarization and rupture of the membrane. The cells are markedly rescued from death upon pretreatment with an inhibitor of Ca(2+) transport. Hence, the activation mechanisms of S. pneumoniae death are analogous for these two complexes. The developed express method for preparation of active alpha-LA - OA complex is high throughput and suited for development of other protein complexes with low molecular-weight amphiphilic substances possessing valuable cytotoxic properties. PMID- 21596092 TI - Perceived transgressor agreeableness decreases cortisol response and increases forgiveness following recent interpersonal transgressions. AB - Stress associated with interpersonal conflict can adversely impact mental and physical health-especially when it causes activation of the hypothalamic pituitary-adrenal axis. Among victims of interpersonal transgressions, certain personality characteristics (viz., neuroticism and agreeableness) have been associated in some studies with successful conflict resolution and decreased physiological activity. How victims' perceptions of their transgressors' personalities affect conflict resolution and physiological reactivity, however, has not been examined. Here, we examined the relationships of (a) victims' agreeableness and neuroticism, and (b) victims' perceptions of their transgressors' agreeableness and neuroticism with plasma cortisol responses in women and (in a larger sample of men and women) forgiveness over time. Victims who perceived their transgressors as highly agreeable had (a) lower cortisol responses following a simulated speech to the transgressor, and (b) higher self reported forgiveness, even after controlling for initial levels of forgiveness. Participants' own agreeableness and neuroticism had negligible associations with cortisol response and forgiveness over time. PMID- 21596093 TI - Foreword. PMID- 21596095 TI - Electrophysiological analysis of the perception of passive movement. AB - The goal of the present study was to determine the electrophysiological correlate of the threshold of perception of passive motion (TPPM) in a group of healthy individuals. We expect a different pattern of activation over the frontoparietal network produced by the conscious perception of the passive movement. Ten right handed male volunteers, between 20 and 30 years of age, were submitted to the threshold of perception of passive motion (TPPM) task in a proprioception testing device (PTD). The device was designed to passively move the arm in internal and external rotations about the shoulder joint. Participants were instructed to press a hand-held switch every time movement of the shoulder was detected. Electromyographic (EMG) and electroencephalographic (EEG) activities were acquired during the task. Passive movement of the shoulder joint was followed by a clear and prolonged decrease in the signal magnitude of the electroencephalogram. The electrophysiological correlate of the TPPM was characterized by the establishment of a frontoparietal network, during the processing of somatosensory information. PMID- 21596094 TI - The role of orexin-1 receptors in physiologic responses evoked by microinjection of PgE2 or muscimol into the medial preoptic area. AB - The medial preoptic area (mPOA) of the hypothalamus has long been thought to play an important role in both fever production and thermoregulation. Microinjections of prostaglandin E2 (PgE2) or the GABA(A) agonist muscimol into the mPOA cause similar increases in body temperature, heart rate, and blood pressure. Microinjections of these compounds however evoke different behavioral responses with muscimol increasing and PgE2 having no effect on locomotion. The purpose of this study was to determine the role of orexin-1 receptors in mediating these dissimilar responses. Systemic injections of the orexin-1 receptor antagonist SB 334867 reduced temperature and cardiovascular responses produced by microinjections of muscimol, but had no effect on either response produced by PgE2. SB-334867 did not significantly decrease locomotion evoked by microinjections of muscimol into the mPOA. These data suggest that there are two central nervous system circuits involved in increasing body temperature, heart rate and blood pressure: one circuit activated by muscimol, involving orexin neurons, and a separate orexin-independent circuit activated by PgE2. PMID- 21596096 TI - An inhibitor of cAMP-dependent protein kinase induces behavioural and neurological antidepressant-like effects in rats. AB - Although it is well established that cyclic adenosine monophosphate (cAMP) signalling via cAMP-dependent protein kinase (PKA)within neurons plays an important role in depression and antidepressant treatment, the importance of several newly discovered targets that function independently from PKA, such as exchange protein activated by cAMP (Epac), remains unexplored in this regard. In this study we used a cAMP analogue that inhibits PKA but not Epac (Rp-8-Br-cAMP), to explore the modifying actions of these two targets on immobility in the forced swim test (FST) and cerebellar cAMP response element binding protein (CREB) phosphorylation in rats. In addition, we assessed central cAMP and cGMP levels and investigated the involvement of cGMP-dependent protein kinase (PKG) on any observed effects by using a selective PKG inhibitor (Rp-8-Br-PET cGMPS).Interestingly, Rp-8-Br-cAMPS strongly reduced immobility in the FST and induced an increase in the phosphorylation of CREB in the cerebellum, effects that were unaltered by the co-administration of Rp-8-Br-PET-cGMPS. Furthermore, Rp-8-Br-cAMPS increased the accumulation of cAMP and cGMP in the hippocampus, frontal cortex and cerebellum of these rats. Together, these results suggest that in addition to activating PKA, elevated cAMP may also stimulate other targets that mediate antidepressant activity. According to the pharmacodynamic profile of Rp-8-Br-cAMPS and taking into consideration what has recently been discovered regarding the cAMP signalling system, a likely candidate is the guanine nucleotide exchange factor, Epac. PMID- 21596097 TI - Nicotinamide attenuates the ischemic brain injury-induced decrease of Akt activation and Bad phosphorylation. AB - Nicotinamide protects cortical neuronal cells against cerebral ischemic injury through activation of various cytoprotective mechanisms. Here, this study confirmed the neuroprotective effects of nicotinamide in focal cerebral ischemic injury and investigated whether nicotinamide modulates a crucial survival pathway, Akt and its downstream targets. Adult male rats were treated with vehicle or nicotinamide (500 mg/kg) 2h after the onset of middle cerebral artery occlusion (MCAO). Brains were collected 24h after MCAO and infarct volumes were analyzed. Nicotinamide significantly reduced the infarct volume in the cerebral cortex. Potential activation was measured by phosphorylation of PDK1 at Ser(241), Akt at Ser(473), and Bad at Ser(136) using Western blot analysis. Nicotinamide prevented the injury-induced decrease of pPDK1, pAkt, and pBad levels. 14-3-3 levels were not different between vehicle- and nicotinamide-treated animals. However, pBad and 14-3-3 interaction levels decreased during MCAO, but were maintained in the presence of nicotinamide, compared to levels in control animals. These findings suggest that nicotinamide attenuates cell death due to focal cerebral ischemic injury and that neuroprotective effects are mediated through the Akt signaling pathway, thus enhancing neuronal survival. PMID- 21596098 TI - Activation of JAK2/STAT pathway in cerebral cortex after experimental traumatic brain injury of rats. AB - The janus kinase/signal transducer and activator of transcription (JAK/STAT) is one of the main pathways downstream of cytokine receptors and growth factor receptors by transducing signals from cell surface to the nucleus. In this study, we aimed to survey the role of JAK2/STAT pathway in the progress of TBI. Right parietal cortical contusion in rats was induced by the Feeney free falling model. The activation of JAK2, STAT1 and STAT3 in pericontusional cortex was determined by Western blotting, electrophoretic mobility shift assay (EMSA), immunohistochemistry and immunofluorescence. Moreover, we assessed the neurological recovery (using Neurological Severity Scores (NSS)) of rats under the pretreatment of a JAK2 inhibitor, AG490. Western blotting revealed that expression of p-JAK2, p-STAT1 and p-STAT3 increased immediately, peaked at 3h after TBI and decreased thereafter, and the activation could be inhibited by AG490. Immunohistochemical study showed that JAK2/STAT pathway was activated in both neurons and astrocytes at 3h after TBI. STAT3-specific binding activity was obviously enhanced after TBI and down-regulated after AG490 administration. The higher NSS of TBI+AG490 group revealed a worse behavior recovery when compared with TBI+DMSO group. Our results suggest that the JAK2/STAT pathway is activated in pericontusional cortex of rats, and may be involved in the neurological function recovery after TBI. PMID- 21596099 TI - Emerging pathways in asthma: innate and adaptive interactions. AB - BACKGROUND: Allergic asthma is a complex and chronic airway inflammatory disorder, and the prevalence of asthma has increased. Adaptive antigen-dependent immunity is a classical pathway of asthmatic pathology. Recent studies have focused on innate antigen-independent immunity in asthma. SCOPE OF REVIEW: This review discusses updated research associating innate immunity with allergic asthma. We focus on innate molecules (Toll-like receptors and nucleotide-binding oligomerization domain-like receptors) and review studies regarding innate and adaptive interactions in allergic responses (surfactant protein D, lipopolysaccharide, and early life immune responses). We also highlight new emerging concepts in the field applicable to innate immunity and asthma. MAJOR CONCLUSIONS: Innate immunity plays a key role in asthma. Understanding innate and adaptive interactions provide significant information in asthmatic research. Innate molecules not only contribute to classical pulmonary defense, but also modulate inflammatory responses. Emerging concepts in the analysis of the microbiome, microRNA and autophagy may provide new insights in searching therapeutic targets. GENERAL SIGNIFICANCE: Finding specific mechanisms of innate and/or adaptive immunity in asthma are timely goals for further research. Integration of bioinformatics and systems biology tools, particularly in relation to microbiome analysis, may be helpful in providing an understanding to allergic immune responses. This article is part of a Special Issue entitled Biochemistry of Asthma. PMID- 21596101 TI - C-jun phosphorylation contributes to down regulation of neuronal nitric oxide synthase protein and motoneurons death in injured spinal cords following root avulsion of the brachial plexus. AB - Previous studies have shown that c-jun and neuronal nitric oxide synthase (nNOS) are both induced in injured motoneurons, but their roles in motoneuron death remain unclear. We hypothesized that nNOS might be the downstream effector of c jun N-terminal kinase (JNK)/c-jun in avulsion-induced motoneuron death. Here, we found that brachial root-avulsion induced a temporary increase in JNK activity and three- and four-fold increases in phospho-c-jun and c-jun, respectively; however, brachial root-avulsion caused a decrease in nNOS protein expression from 4 h to 14 days post-injury. At 14 days post-injury, almost all nNOS-positive motoneurons were co-localized with phospho-c-jun-positive motoneurons in ipsilateral ventral horns. The JNK inhibitor SP600125, applied immediately post injury, resulted in an upregulation of nNOS protein both in injured spinal cords and motoneurons and caused a slight alleviation of motoneuron death by inhibiting c-jun phosphorylation at 14 days post-injury. Our results demonstrated that the JNK/c-jun signal transduction pathway is involved in root-avulsion. The inhibition of c-jun phosphorylation prevents nNOS levels from dropping below baseline levels in the spinal cord and partially alleviates motoneuron death following root-avulsion. Therefore, inhibiting c-jun phosphorylation or up regulating the nNOS protein in injured spinal cords at the early stage might be used in the future as the molecular-target strategies to prevent the motoneurons degeneration in root-avulsion. PMID- 21596100 TI - Isoprostanes and asthma. AB - Isoprostanes are prostaglandin (PG)-like compounds generated in vivo following oxidative stress by non-enzymatic peroxidation of polyunsaturated fatty acids, including arachidonic acid. They are named based on their prostane ring structure and by the localization of hydroxyl groups on the carbon side chain; these structural differences result in a broad array of isoprostane molecules with varying biological properties. Generation of specific isoprostanes is also regulated by host cell redox conditions; reducing conditions favor F2-isoprostane production while under conditions with deficient antioxidant capacity, D2- and E2 isoprostanes are formed. F2-isoprostanes (F2-isoP) are considered reliable markers of oxidative stress in pulmonary diseases including asthma. Importantly, F2-isoP and other isoprostanes function as ligands for PG receptors, and potentially other receptors that have not yet been identified. They have been reported to have important biological properties in many organs. In the lung, isoprostanes regulate cellular processes affecting airway smooth muscle tone, neural secretion, epithelial ion flux, endothelial cell adhesion and permeability, and macrophage adhesion and function. In this review, we will summarize the evidence that F2-isoP functions as a marker of oxidative stress in asthma, and that F2-isoP and other isoprostanes exert biological effects that contribute to the pathogenesis of asthma. This article is part of a Special Issue entitled Biochemistry of Asthma. PMID- 21596102 TI - Changes in calcineurin message, enzyme activity and protein content in the spinal dorsal horn are associated with chronic constriction injury of the rat sciatic nerve. AB - Plasticity in the spinal dorsal horn is thought to underlie the development of neuropathic pain. Calcineurin (protein phosphatase 3) plays an important role in plasticity in the brain. Here we examined whether chronic constriction injury (CCI) of the sciatic nerve modifies calcineurin expression in the spinal dorsal horn. Male rats were assigned to control (uninjured), sham-operated or CCI groups. CCI animals exhibited both a shift in weight bearing and a reduction in paw withdrawal latencies as signs of pain behavior. At 3 days (3D) the pain behavior was associated with a significant increase in calcineurin gene expression, enzyme activity and content of its Aalpha isoform in the ipsilateral spinal dorsal horn. In contrast, while the pain behavior persisted at 7 days (7D) calcineurin gene expression returned to control levels and activity and protein content decreased. A single intrathecal injection of MK-801 15 min before the ligation attenuated both signs of pain behavior in 3D but not 7D CCI animals. The same pre-treatment also prevented the CCI-associated increases in calcineurin in these animals. These data suggested an involvement of calcineurin in CCI-elicited neuropathic pain. The time-dependent divergent changes in calcineurin expression may underlie the different phases of neuropathic pain development. PMID- 21596103 TI - Multimodal and multispatial deficits of verticality perception in hemispatial neglect. AB - Recent evidence suggests that patients with left-sided visuospatial neglect often show deviations in their visual and haptic perception of verticality in the frontal and sagittal plane. However, little is known about the multimodality of these impairments and the relationship between deviations in the frontal and the sagittal plane. Moreover, no previous study has combined investigations of verticality judgments in both modalities and both spatial planes within the same sample of subjects using the same apparatus. Thus, the aim of the present study was to investigate both subjective visual vertical (SVV) and subjective haptic vertical (SHV) judgments in the frontal and the sagittal plane in right-brain damaged patients with visuospatial neglect (n=16), right-brain-damaged patients without neglect (n=18) and age-matched healthy individuals (n=16) using the same testing device for all tasks. This allowed for direct comparisons of visual vs. haptic and frontal vs. sagittal verticality judgments. Neglect patients showed significant counterclockwise tilts in their SVV and SHV judgments in the frontal plane as well as marked backward (upper end of the rod towards the observer) tilts in the sagittal plane. In contrast, right-brain-damaged patients without neglect and healthy individuals showed no marked deviations in the frontal plane, but small forward (upper end of the rod away from the observer) tilts in the sagittal plane. Moreover, neglect patients showed significantly higher unsigned errors in all tasks. These results demonstrate multimodal and multispatial deficits in the judgment of verticality in patients with visuospatial neglect which are most likely due to an altered representation of verticality caused by lesions of brain areas related to multisensory integration and space representation in the right temporo-parietal cortex. PMID- 21596104 TI - Ventrolateral prefrontal cortex is required for fear extinction in a modified delay conditioning paradigm in rats. AB - Recent evidence has demonstrated that the ventromedial prefrontal cortex (vmPFC) is a critical site of the neural circuits underlying fear extinction memory. The ventrolateral prefrontal cortex (vlPFC) is not directly involved in extinction processes within the aversive domain. However, most of the current cumulated data on extinction is based on a classical delay fear conditioning paradigm in which the interval between the onset of the conditioned stimulus (CS) and the unconditioned stimulus (US) is consistent in a given protocol. In the present study, we developed a modified delay fear conditioning paradigm in which the temporal distribution of the footshock US during the duration of the tone CS is programmed to be pseudorandom. Here, we examined the effects of electrolytic vmPFC and vlPFC lesions made before training on conditioned fear response in the modified paradigm. The behavioral procedure involved four sessions with a 24-h interval: habituation, fear conditioning, extinction training, and extinction test. Percent freezing to tone was assessed as a measure of conditioned fear response. The results show that neither vmPFC nor vlPFC lesions affect acquisition or extinction of conditioned fear response during the fear conditioning and extinction training sessions, respectively. During the extinction test session, both vmPFC- and vlPFC-lesioned rats showed deficits in the recall of the between-session extinction memory. The deficits could not be attributed to altered nonspecific responses (footshock sensitivity, locomotor activity, and nonspecific freezing response). Furthermore, vlPFC lesions made before training had no effect on conditioned fear response in the classical fear conditioning paradigm. These data suggest a preserved role of the vmPFC in fear extinction and a selective involvement of the vlPFC in extinction process in certain fear conditioning tasks. PMID- 21596105 TI - Gestational nicotine exposure regulates expression of AMPA and NMDA receptors and their signaling apparatus in developing and adult rat hippocampus. AB - Untimely activation of nicotinic acetylcholine receptors (nAChRs) by nicotine results in short- and long-term consequences on learning and behavior. In this study, the aim was to determine how prenatal nicotine exposure affects components of glutamatergic signaling in the hippocampus during postnatal development. We investigated regulation of both nAChRs and glutamate receptors for AMPA and N methyl-D-aspartate (NMDA), from postnatal day 1 (P1) to P63 after a temporally restricted exposure to saline or nicotine for 14 days in utero. We analyzed postsynaptic density components associated with AMPA receptor (AMPAR) and NMDA receptor (NMDAR) signaling: calmodulin (CaM), CaM Kinase II alpha (CaMKIIalpha), and postsynaptic density-95 (PSD95), as well as presynaptically localized synaptosomal-associated protein 25 (SNAP25). At P1, there was significantly heightened expression of AMPAR subunit GluR1 but not GluR2, and of NMDAR subunits NR1, NR2a, and NR2d but not NR2b. NR2c was not detectable. CaM, CaMKIIalpha, and PSD95 were also significantly upregulated at P1, together with presynaptic SNAP25. This enhanced expression of glutamate receptors and signaling proteins was concomitant with elevated levels of [3H]epibatidine (3H]EB) binding in prenatal nicotine-exposed hippocampus, indicating that alpha4beta2 nAChR may influence glutamatergic function in the hippocampus at P1. By P14, neither [3H]EB binding nor the expression levels of subunits GluR1, GluR2, NR1, NR2a, NR2b, NR2c, or NR2d seemed changed with prenatal nicotine. However, CaMKIIalpha was significantly upregulated with nicotine treatment while CaM showed downregulation at P14. The effects of nicotine persisted in P63 young adult brains which exhibited significantly downregulated GluR2, NR1, and NR2c expression levels in hippocampal homogenates and a considerably muted overall distribution of [3H]AMPA binding in areas CA1, CA2 and CA3, and the dentate gyrus. Our results suggest that prenatal nicotine exposure can regulate the glutamatergic signaling system throughout postnatal development by enhancing or inhibiting availability of AMPAR and NMDAR or their signaling components. The persistent depression, in adults, of the requisite NR1 subunit for NMDAR assembly, and of GluR2, important for assembly, trafficking, and biophysical properties of AMPAR, indicates that nicotine may alter ionotropic glutamate receptor stoichiometry and functional properties in adults after prenatally restricted nicotine exposure. PMID- 21596106 TI - Inhibition of T-type calcium channels and hydrogen sulfide-forming enzyme reverses paclitaxel-evoked neuropathic hyperalgesia in rats. AB - Hydrogen sulfide (H2S), a gasotransmitter, facilitates pain sensation by targeting Ca(v)3.2 T-type calcium channels. The H2S/Ca(v)3.2 pathway appears to play a role in the maintenance of surgically evoked neuropathic pain. Given evidence that chemotherapy-induced neuropathic pain is blocked by ethosuximide, known to block T-type calcium channels, we examined if more selective T-type calcium channel blockers and also inhibitors of cystathionine-gamma-lyase (CSE), a major H2S-forming enzyme in the peripheral tissue, are capable of reversing the neuropathic pain evoked by paclitaxel, an anti-cancer drug. It was first demonstrated that T-type calcium channel blockers, NNC 55-0396, known to inhibit Ca(v)3.1, and mibefradil inhibited T-type currents in Ca(v)3.2-transfected HEK293 cells. Repeated systemic administration of paclitaxel caused delayed development of mechanical hyperalgesia, which was reversed by single intraplantar administration of NNC 55-0396 or mibefradil, and by silencing of Ca(v)3.2 by antisense oligodeoxynucleotides. Systemic administration of dl-propargylglycine and beta-cyanoalanine, irreversible and reversible inhibitors of CSE, respectively, also abolished the established neuropathic hyperalgesia. In the paclitaxel-treated rats, upregulation of Ca(v)3.2 and CSE at protein levels was not detected in the dorsal root ganglia (DRG), spinal cord or peripheral tissues including the hindpaws, whereas H(2)S content in hindpaw tissues was significantly elevated. Together, our study demonstrates the effectiveness of NNC 55-0396 in inhibiting Ca(v)3.2, and then suggests that paclitaxel-evoked neuropathic pain might involve the enhanced activity of T-type calcium channels and/or CSE in rats, but not upregulation of Ca(v)3.2 and CSE at protein levels, differing from the previous evidence for the neuropathic pain model induced by spinal nerve cutting in which Ca(v)3.2 was dramatically upregulated in DRG. PMID- 21596107 TI - Hepatoprotective effects of polyprenols from Ginkgo biloba L. leaves on CCl4 induced hepatotoxicity in rats. AB - The hepatoprotective effects of polyprenols from Ginkgo biloba L. leaves were evaluated against carbon tetrachloride induced hepatic damage in Sprague-Dawley rats. The elevated levels of serum ALT, AST, ALP, ALB, TP, HA, LN, TG, and CHO were restored towards normalization significantly by GBP in a dose dependent manner. The biochemical observations were supplemented with histopathological examination of rat liver sections. Meanwhile, GBP also produced a significant and dose-dependent reversal of CCl(4)-diminished activity of the antioxidant enzymes and reduced CCl(4)-elevated level of MDA. In general, the effects of GBP were not significantly different from those of the standard drug Essentiale. PMID- 21596109 TI - Neuroprotective bakkenolides from the roots of Valeriana jatamansi. AB - Two new bakkenolides, valerilactones A (1), and B (2), and two known analogues, bakkenolide-H (3) and bakkenolide-B (4), were isolated from the roots of Valeriana jatamansi. Their structures and relative configurations were elucidated by spectroscopic methods (IR, ESIMS, HRESIMS, 1D and 2D NMR) and by comparison of their NMR data with those of related compounds. Compounds 1, 2, and 3 exhibited potent neuroprotective effects against MPP(+)-induced neuronal cell death in human dopaminergic neuroblastoma SH-SY5Y cells. PMID- 21596108 TI - Anticoagulant effect of polyphenols-rich extracts from black chokeberry and grape seeds. AB - Blood coagulation consists of a series of zymogens that can be converted by limited proteolysis to active enzymes leading to the generation of thrombin. Fresh plasma and human thrombin was incubated with extracts from berries of Aronia melanocarpa or seeds of Vitis vinifera (0.5; 5; 50 MUg/ml). The in vitro experiments showed that both extracts prolonged clotting time and decreased the maximal velocity of fibrin polymerization in human plasma. Moreover thrombin incubation with both extracts results in the inhibition of amidolytic activity of this enzyme. It gives hopes for development of diet supplements, which may be preventing thrombosis in pathological states. PMID- 21596110 TI - The potent anti-inflammatory agent escin does not increase corticosterone secretion and immune cell apoptosis in mice. AB - Escin exerts potent glucocorticoid-like anti-inflammatory effects. The aim of this study was to investigate whether the anti-inflammatory effect of escin is through the up-regulation of glucocorticoids and if escin induces pathological changes in immune organs. Mice were administrated with escin intravenously for 7 days before observing the relevant parameters. The results showed that escin exhibits a potent anti-inflammatory effect, but does not increase corticosterone secretion in mice, and does not increase immune cell apoptosis in the spleen and thymus of mice. These findings suggest that the anti-inflammatory effect of escin is not dependent on the release of corticosterone. PMID- 21596111 TI - Four new fluorenone alkaloids and one new dihydroazafluoranthene alkaloid from Caulophyllum robustum Maxim. AB - Four new fluorenone alkaloids, caulophylline A-D (1-4), and one new dihydroazafluoranthene alkaloid, caulophylline E (5) were isolated from the roots of Caulophyllum robustum Maxim. Their structures were elucidated by spectroscopic analysis. Among the isolated alkaloids, Caulophylline E showed good scavenging effects against DPPH radical with IC(50) of 39 MUM. PMID- 21596112 TI - Antioxidant flavonoids from the seed of Oroxylum indicum. AB - Three new flavonoid glycosides (1-3) and nineteen known compounds (4-22) were isolated from the aqueous ethanolic extract of the seed of Oroxylum indicum. The structures of 1-3 were elucidated on the basis of spectroscopic analysis. Antioxidant activities of all the isolated compounds were evaluated using a DPPH and an ORAC assay. Compounds 3, 5-7, 9 and 12 exhibited potent antioxidant activity in the DPPH assay, while compounds 3-15 showed potent antioxidant capacity in the ORAC assay, and seven antioxidant flavonoids (4-6, 8, 9, 11, 12) were detected as the main ingredients in the methanolic extract of seed of O. indicum using an HPLC analysis. PMID- 21596114 TI - Knockout of hepatic P450 reductase aggravates triptolide-induced toxicity. AB - Triptolide, the primary active component of Tripterygium wilfordii Hook F, has various pharmacological activities but also a narrow therapeutic window. Cytochrome P450s are proposed to be responsible for the hydroxylation of triptolide in vitro and CYP3A induction by dexamethasone can increase the metabolism of triptolide and decrease the hepatotoxicity in rat. However, triptolide-induced toxicity has not been investigated in an animal model having a suppression of P450 activities. Here we compared the toxicological effects and toxicokinetics of triptolide between liver-specific cytochrome P450 reductase (CPR) knockout (KO) mice (abolished hepatic P450 activities) and wild-type (WT) control mice after a single oral gavage of triptolide at 0.5mg/kg or 1.0mg/kg. A low toxic dose of triptolide at 0.5mg/kg for WT mice resulted in severe toxicities including death in KO mice. Changes in serum biochemistry, hematology and histopathology further indicated much more severe toxicities in multiple organs in KO mice compared to WT mice after triptolide administration. The mono hydroxylated metabolites of triptolide detected in the blood of WT mice were undetectable in KO mice, accompanied by much higher triptolide levels in the blood and tissues including the liver, kidney, and spleen determined by LC-MS/MS. Taken together, our results confirmed that inactivation of hepatic P450s abolishes the ability in metabolism of triptolide in the liver, subsequently resulting in an increase in bioavailability and toxicity of triptolide in vivo. It is suggested that P450 inhibition/inactivation might pose a significant health risk in the clinic use of triptolide. PMID- 21596113 TI - A snapshot of the Ixodes scapularis degradome. AB - Parasitic encoded proteases are essential to regulating interactions between parasites and their hosts and thus they represent attractive anti-parasitic druggable and/or vaccine target. We have utilized annotations of Ixodes scapularis proteases in gene bank and version 9.3 MEROPS database to compile an index of at least 233 putatively active and 150 putatively inactive protease enzymes that are encoded by the I. scapularis genome. The 233 putatively active protease homologs hereafter referred to as the degradome (the full repertoire of proteases encoded by the I. scapularis genome) represent ~1.14% of the 20485 putative I. scapularis protein content. Consistent with observations in other animals, the content of the I. scapularis degradome is ~6.0% (14/233) aspartic, ~19% (44/233) cysteine, ~40% (93/233) metallo, ~28.3% (66/233) serine and ~6.4% (15/233) threonine proteases. When scanned against other tick sequences, ~11% (25/233) of I. scapularis putatively active proteases are conserved in other tick species with >= 60% amino acid identity levels. The I. scapularis genome does not apparently encode for putatively inactive aspartic proteases. Of the 150 putative inactive protease homologs none are from the aspartic protease class, ~8% (12/150) are cysteine, ~58.7% (88/150) metallo, 30% (45/150) serine and ~3.3% (5/150) are threonine proteases. The I. scapularis tick genome appears to have evolutionarily lost proteolytic activity of at least 6 protease families, C56 and C64 (cysteine), M20 and M23 (metallo), S24 and S28 (serine) as revealed by a lack of the putatively active proteases in these families. The overall protease content is comparable to other organisms. However, the paucity of the S1 chymotrypsin/trypsin-like serine protease family in the I. scapularis genome where it is ~12.7% (28/233) of the degradome as opposed to ~22-48% content in other blood feeding arthropods, Pediculus humanus humanus, Anopheles gambiae, Aedes Aegypti and Culex pipiens quinquefasciatus is notable. The data is presented as a one-stop index of proteases encoded by the I. scapularis genome. PMID- 21596115 TI - Microglial activation, recruitment and phagocytosis as linked phenomena in ferric oxide nanoparticle exposure. AB - Microglia as the resident macrophage-like cells in the central nervous system (CNS) play a pivotal role in the innate immune responses of CNS. Understanding the reactions of microglia cells to nanoparticle exposure is important in the exploration of neurobiology of nanoparticles. Here we provide a systemic mapping of microglia and the corresponding pathological changes in olfactory-transport related brain areas of mice with Fe(2)O(3)-nanoparticle intranasal treatment. We showed that intranasal exposure of Fe(2)O(3) nanoparticle could lead to pathological alteration in olfactory bulb, hippocampus and striatum, and caused microglial proliferation, activation and recruitment in these areas, especially in olfactory bulb. Further experiments with BV2 microglial cells showed the exposure to Fe(2)O(3) nanoparticles could induce cells proliferation, phagocytosis and generation of ROS and NO, but did not cause significant release of inflammatory factors, including IL-1beta, IL-6 and TNF-alpha. Our results indicate that microglial activation may act as an alarm and defense system in the processes of the exogenous nanoparticles invading and storage in brain. PMID- 21596116 TI - The down-regulation of galectin-1 expression is a specific biomarker of arsenic toxicity. AB - Galectin-1 (GAL1) is known as a beta-galactoside-binding protein that also can bind with arsenic to regulate cell functions. Using RNA interference technique, we investigated the possible mechanism involved in GAL1 modulation of arsenite inhibited cell survival in 3T3 fibroblast and KB oral cancer cells. GAL1 gene knockdown significantly attenuated sodium arsenite (NaAsO(2)) and arsenic trioxide (As(2)O(3)) inhibition of cell survival. However, GAL1 gene knockdown did not alter the inhibition of cell survival by antimony chloride, cadmium chloride or nickel sulfate. These results suggested the GAL1 selectively affects particular types of heavy metal elements. Flow cytometric analysis indicated GAL1 gene knockdown also suppressed As(III)-stimulated levels of sub-G1 and G2/M growth arrest in both cells. Moreover, atomic absorption spectrophotometric results showed that GAL1 gene knockdown reduced the total arsenic accumulation of both cells after the NaAsO(2) and As(2)O(3) treatment. These results suggested that GAL1 gene knockdown mediates the apoptotic effects of arsenic in 3T3 and KB cells via regulation of the cellular arsenic levels. We propose that down regulation of GAL1 expression may be a useful and specific biomarker in assessing the toxicity of arsenic exposure. PMID- 21596117 TI - Investigation of the riddle of sulfathiazole polymorphism. AB - Since the discovery of sulfathiazole as an antimicrobial agent in 1939, numerous works in the screening for its different polymorphic forms, which is an essential part of drug development, have been conducted and published. These works consequently result in the availability of various methods for generating a particular polymorph. By following these methods, however, one cannot be guaranteed to obtain the intended pure polymorph because most of the methods do not clearly and adequately describe the crystallisation conditions, such as cooling rates and initial solute concentrations. In this paper, the available methods for generating all the known polymorphs of sulfathiazole are reviewed and selected methods for generating certain polymorphs, performed with their processes monitored using process analytical technology tools, i.e. focussed beam reflectance measurement and attenuated total reflectance ultraviolet spectroscopy, are presented. The properties of the obtained crystals, examined using various characterisation methods, are also presented and whenever possible, are compared with those of other workers. PMID- 21596118 TI - Scale-up of in vitro permeation assay data to human intestinal permeability using pore theory. AB - The aim of this study is to establish a theoretical method for the prediction of human intestinal permeability from in vitro permeation assay. Pore radius and porosity/length and ion selectivity of the paracellular pathway were calculated using the Renkin function using permeabilities of mannitol and urea and potential difference study to evaluate paracellular permeability in Caco-2 cell monolayer; they were calculated to be 5.91 A, 7.51 cm(-1) and 2.75, respectively. These values in the human epithelium were calculated from the reported intestinal permeability. The area factor, which can correct the difference in the transcellular permeability between Caco-2 cell monolayer and human epithelium, was obtained using the ratio of permeability of high lipophilicity compounds (human/Caco-2) and was calculated to be 13.3. Paracellular and transcellular permeabilities of 9 compounds in human epithelium were estimated on the basis of the characteristics of the paracellular pathway using physicochemical properties of compounds and the area factor, respectively. Human intestinal permeabilities were predicted by the sum of estimated transcellular and paracellular permeabilities. A linear correlation whose slope and intercept were nearly 1 and 0, respectively, was observed between predicted and reported human intestinal permeabilities. We successfully predicted human intestinal permeability from in vitro data. PMID- 21596119 TI - The conflict between in vitro release studies in human biorelevant media and the in vivo exposure in rats of the lipophilic compound fenofibrate. AB - The performance of four different lipid-based (Tween 80-Captex 200P, Tween 80 Capmul MCM, Tween 80-Caprol 3GO and Tween 80-soybean oil) and one commercially available micronized formulation (Lipanthyl Micronized((r))) of the lipophilic compound fenofibrate was compared in vitro in various biorelevant media and in vivo in rats. In simulated gastric fluid without pepsin (SGF(sp)) and fasted state simulated intestinal fluid (FaSSIF), only Tween 80-Captex 200P system resulted in a stable fenofibrate concentration, but no supersaturation was obtained. The other three lipid based systems created fenofibrate supersaturation; however they did not maintain it. In fed state simulated intestinal fluid (FeSSIF), all lipid-based formulations resulted in complete dissolution of fenofibrate during the experiment, which represented a supersaturated state for Tween 80-Capmul MCM and Tween 80-Caprol 3GO systems. In both FaSSIF and FeSSIF, all lipid-based formulations yielded a higher fenofibrate concentration than the micronized formulation. Contrary to the in vitro results, no significant difference in the in vivo performance was observed among the four tested lipid-based formulations both in the fasted and the fed states. The in vivo performance of all lipid-based formulations was better than that of Lipanthyl Micronized((r)), in the fasted as well as in the fed state. The fact that for the lipid based systems the in vitro differences in pharmaceutical performance were not translated into in vivo differences can be attributed to the continuous excretion of bile in the gastrointestinal tract of rats, causing enhanced solubilizing capacity for lipophilic drugs. This study clearly points to the conflicting situation that might arise during the preclinical phase of the development of lipid based formulations of lipophilic drugs as the performance of such systems is very often evaluated by both in vitro release studies in human biorelevant media as well as in vivo studies in rats. Care must be taken to select a relevant animal model. PMID- 21596120 TI - A theoretical approach to evaluate the release rate of acetaminophen from erosive wax matrix dosage forms. AB - To predict drug dissolution and understand the mechanisms of drug release from wax matrix dosage forms containing glyceryl monostearate (GM; a wax base), aminoalkyl methacrylate copolymer E (AMCE; a pH-dependent functional polymer), and acetaminophen (APAP; a model drug), we tried to derive a novel mathematical model with respect to erosion and diffusion theory. Our model exhibited good agreement with the whole set of experimentally obtained values pertaining to APAP release at pH 4.0 and pH 6.5. In addition, this model revealed that the eroding speed of wax matrices was strongly influenced by the loading content of AMCE, but not that of APAP, and that the diffusion coefficient increased as APAP loading decreased and AMCE loading increased, thus directly defining the physicochemical properties of erosion and diffusion. Therefore, this model might prove a useful equation for the precise prediction of dissolution and for understanding the mechanisms of drug release from wax matrix dosage forms. PMID- 21596121 TI - Biocompatible hydrogels based on hyaluronic acid cross-linked with a polyaspartamide derivative as delivery systems for epithelial limbal cells. AB - The aim of this work was to evaluate the potential use of hydrogels based on hyaluronic acid (HA) chemically cross-linked with alpha,beta-poly(N-2 hydroxyethyl) (2-aminoethylcarbamate)-D,L-aspartamide (PHEA-EDA) as substitutes for the amniotic membrane able to release limbal cells for corneal regeneration. Hydrogels, shaped as films, with three different molar ratios (X) between PHEA EDA and HA (X = 0.5, 1.0 and 1.5) have been investigated. First, it has been evaluated their swelling ability, hydrolytic resistance in simulated physiological fluid and cell compatibility by using human dermal fibroblasts chosen as a model cell line. Then adhesion studies in comparison with collagen gel, have been performed by using immortalized cells, such as human corneal epithelial cells (HCEC) or primary cells, such as rabbit limbal epithelial cells (RLEC) and/or rabbit limbal fibroblasts (RLF). HA/PHEA-EDA hydrogels allow a moderate/poor adhesion of all investigated cells thus suggesting their potential ability to act as cell delivery systems. Finally, commercial contact lenses have been coated, in their inner surface, with each HA/PHEA-EDA film and it has been found that in these conditions, a greater cell adhesion occurs, particularly when RLEC are in co-culture with RLF. However, this adhesion is only transitory, in fact after three days, viable cells are released in the culture medium thus suggesting a potential application of HA/PHEA-EDA hydrogels, for delivering limbal cells in the treatment of corneal damage. PMID- 21596122 TI - Lipid nanocarriers for dermal delivery of lutein: preparation, characterization, stability and performance. AB - Topical application of lutein as an innovative antioxidant, anti-stress and blue light filter, which is able to protect skin from photo damage, has got a special cosmetic and pharmaceutical interest in the last decade. Lutein is poorly soluble, and was therefore incorporated into nanocarriers for dermal delivery: solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and a nanoemulsion (NE). Nanocarriers were produced by high pressure homogenization. The mean particle size was in the range of about 150 nm to maximum 350 nm, it decreased with increasing oil content of the carriers. The zeta potential in water was in the range -40 to -63 mV, being in agreement with the good short term stability at room temperature monitored for one month. In vitro release was studied using a membrane free model. Highest release in 24h was observed for the nanoemulsion (19.5%), lowest release (0.4%) for the SLN. Release profiles were biphasic (lipid nanoparticles) or triphasic (NE). In vitro penetration study with a cellulose membrane showed in agreement highest values for the NE (60% in 24h), distinctly lower values for the solid nanocarriers SLN and NLC (8-19%), lowest values for lutein powder (5%). Permeation studies with fresh pig ear skin showed that no (SLN, NLC) or very little lutein (0.4% after 24h) permeated, that means the active remains in the skin and is not systemically absorbed. The nanocarriers were able to protect lutein against UV degradation. In SLN, only 0.06% degradation was observed after irradiation with 10 MED (Minimal Erythema Dose), in NLC 6-8%, compared to 14% in the NE, and to 50% as lutein powder suspended in corn oil. Based on size, stability and release/permeation data, and considering the chemical protection of the lutein prior to its absorption into the skin, the lipid nanoparticles are potential dermal nanocarriers for lutein. PMID- 21596123 TI - Formulation and in vitro characterization of inhalable rifampicin-loaded PLGA microspheres for sustained lung delivery. AB - The solvent evaporation method with premix membrane homogenization was applied, with class-3 ethyl acetate as organic solvent, to produce narrowly size distributed rifampicin (RIF)-loaded poly(lactide-co-glycolide) (PLGA) microspheres for sustained lung delivery as aerosol. Microsphere formulations (simple or multiple emulsions, different PLGA and RIF concentrations) and process parameters (transmembrane pressure, SPG membrane pore diameter) were investigated as their effects on RIF content, microsphere size, aerodynamic properties of the freeze-dried powder and in vitro release profiles. Narrowly size distributed microspheres with diameters from 2 to 8 MUm, satisfactory RIF contents (from 4.9 to 16.5%), 80% RIF release from 12h to 4 days, and adequate aerodynamic properties were prepared from a multiple emulsion and using SPG membrane pore diameter of 19.9 MUm. The premix membrane homogenization appeared to be a rapid and efficient method to prepare monodisperse drug-loaded microspheres suitable for lung delivery as sustained-release microsphere aerosol. PMID- 21596124 TI - Characterization, pharmacokinetics and disposition of novel nanoscale preparations of paclitaxel. AB - Polymeric nanoparticles (NPs) have great potential application in achieving targeted delivery of anticancer drugs. Paclitaxel (PTX) loaded NPs were developed using biodegradable methoxy poly (ethylene glycol)-poly (epsilon-caprolactone) (MPEG-PCL) diblock copolymer by solid dispersion technique without toxic organic solvent. The lyophilized powder has been stored at room temperature for more than six months and still unchanged. PTX-loaded MPEG-PCL nanoparticles (PTX-NPs) displayed that the highest drug loading of PTX was about 25.6% and entrapment efficiency was over 98%, and the optimized average diameter and polydispersity index (PDI) were about 27.6 +/- 0.1 nm and 0.05, respectively. Moreover, experimental results shown PTX-NPs had sustained-release effects and its curve fitting followed the Higuchi model. The maximum tolerated dose (MTD) of PTX-NPs after single dose in Balb/c mice was above 80 mg PTX/kg body weight (b.w), which was 2.6-fold higher than that of Taxol((r)) (30 mg PTX/kg b.w). The levels of PTX administrated PTX-NPs had obvious distinction to Taxol((r)) in plasma, liver, spleen, kidneys, lungs, heart and tumor. Especially, the concentration of PTX in tumor administrated PTX-NPs was higher than administration of Taxol((r)). All results suggested that we had contrived a simple, biodegradable, effective and controllable drug delivery system for paclitaxel. PMID- 21596125 TI - A new nanomedicine based on didanosine glycerolipidic prodrug enhances the long term accumulation of drug in a HIV sanctuary. AB - New nanomedicines could improve drug accumulation in HIV sanctuaries and ameliorate their antiretroviral efficiency. In this view, we propose herein a combined strategy based on a biomimetic prodrug of ddI and its formulation in well-characterized lipid nanoobjects. The glycerolipidic prodrug of ddI (ProddINP) has been synthesized and its bulk structure was characterized. An appropriate formulation of this prodrug has been designed using a rational approach combining different physicochemical techniques. The high incorporation ratio of the prodrug into dipalmitoylphosphatidylcholine (DPPC) bilayers was determined by DSC. Then two liposome preparation methods were compared, with respect to size, incorporation yield and molecular/supramolecular organization of vesicles. The best liposomal formulation of ProddINP has been checked to keep intact the anti-HIV activity of ddI. This formulation was finally compared to ddI after oral route in rat. The animal experiments evidenced the increase of ddI blood half life (3-fold) and its enhanced accumulation as prodrug form at 24h in numerous organs and especially intestine after administration of ProddINP in comparison with free drug. Finally, the tested liposomal formulation of ProddINP seems to be a promising approach to eradicate HIV infection from intestinal sanctuaries where the virus can concentrate. PMID- 21596126 TI - Preparation of polymeric nanoparticles of cyclosporin A using infrared pulsed laser. AB - Nanoparticle formation of poorly water-soluble drugs is a means of providing much benefit for improving solubility and bioavailability. We showed that laser irradiation of drugs can be a novel tool for dispersing drug nanoparticles in water. Using our method, we were able to produce nanoparticles containing immunosuppressant drug, cyclosporin A, which shows poor solubility toward water, with high levels of the drug using polyvinyl pyrrolidone and sodium dodecyl sulfate as stabilizing agents. The absence of degradation products was confirmed and the loss of pharmaceutical activity with an inhibitory effect on the interleukin-2 production of Jurkat T cells did not occur. Cyclosporin A nanoparticles showed a spherical shape and their particle size was distributed uniformly around 200 nm. Powder X-ray diffraction analysis suggested that cyclosporin A in the nanoparticles was in an amorphous state. In the measurement of solubility rate, the nanoparticle formulation showed a higher rate than that which had not been processed. At present, although this laser irradiation technology has low productivity, it is expected as a new technology for drug nanoparticle manufacturing together with the development of a new laser device. PMID- 21596127 TI - Absorption of the novel artemisinin derivatives artemisone and artemiside: potential application of PheroidTM technology. AB - Artemisinins have low aqueous solubility that results in poor and erratic absorption upon oral administration. The poor solubility and erratic absorption usually translate to low bioavailability. Artemisinin-based monotherapy and combination therapies are essential for the management and treatment of uncomplicated as well as cerebral malaria. Artemisone and artemiside are novel artemisinin derivatives that have very good antimalarial activities. PheroidTM technology is a patented drug delivery system which has the ability to entrap, transport and deliver pharmacologically active compounds. Pharmacokinetic models were constructed for artemisone and artemiside in PheroidTM vesicle formulations. The compounds were administered at a dose of 50.0mg/kg bodyweight to C57 BL/6 mice via an oral gavage tube and blood samples were collected by means of tail bleeding. Drug concentrations in the samples were determined using an LC/MS/MS method. There was 4.57 times more artemisone in the blood when the drug was entrapped in PheroidTM vesicles in comparison to the drug only formulation (p < 0.0001). The absorption of artemiside was not dramatically enhanced by the PheroidTM delivery system. PMID- 21596128 TI - Development and characteristics of temperature-sensitive liposomes for vinorelbine bitartrate. AB - A novel liposome with temperature-sensitivity for vinorelbine bitartrate (VB) was designed to enhance VB targeted delivery and antitumor effect. Liposomes without drugs were prepared by thin film hydration, and then VB was entrapped into liposomes by pH gradient loading method. The mean particle size of the liposomes was about 100 nm, and the drug entrapment efficiency was more than 90%. Stability data indicated that the liposome was physically and chemically stable for at least 6 months at 4 degrees C. In vitro drug release study showed that drugs hardly released at 37 degrees C; while at 42 degrees C, drugs released quickly. For in vivo experiments, the lung tumor model was established by subcutaneous inoculation of cell suspension on mice, liposomes and free VB were injected i.v. in mice, followed by exposure the tumors to hyperthermia (HT) for 30 min after administration. The ratio of inhibition tumor of temperature-sensitive liposomes group was significantly higher than the normal injection group. Combining temperature-sensitive liposomes with HT enhanced the delivery of VB and, consequently, its antitumor effects. This liposome could potentially produce viable clinical strategies for improved targeting and delivery of VB for treatment of cancer. PMID- 21596130 TI - Pyocyanin-induced toxicity in A549 respiratory cells is causally linked to oxidative stress. AB - Pyocyanin, a virulence factor produced by Pseudomonas aeruginosa, has many damaging effects on mammalian cells. Several lines of evidence suggest that this damage is primarily mediated by its ability to generate ROS and deplete host antioxidant defence mechanisms. However, a causal role for oxidative stress has not yet been demonstrated conclusively. Parallel measures of ROS production, antioxidant levels and cytotoxicity provide convincing evidence that pyocyanin induced cytotoxicity in A549 respiratory cells is mediated by acute ROS production and subsequent oxidative stress. Pyocyanin increased ROS levels in A549 cells as measured by the fluorescent H(2)O(2) probes Amplex Red and DCFH-DA. These effects were attenuated by the antioxidant N-acetylcysteine. Furthermore, pyocyanin-induced depletion of intracellular GSH levels 24h after exposure was also prevented by pre-treatment of cells with NAC. Under these conditions, NAC protected cells against pyocyanin-induced cytotoxicity as measured by resazurin reduction to resorufin and viable cell counts, strongly supporting a causal role for oxidative stress. Finally, we also show that pyocyanin-induced activation of the immune and inflammatory transcription factor NF-kappaB in A549 cells is likely mediated by increased ROS. This increased understanding of mechanisms underlying pyocyanin-induced cytotoxicity may ultimately lead to better strategies for reducing the virulence associated with chronic P. aeruginosa infection. PMID- 21596131 TI - Identification of new Gbetagamma interaction sites in adenylyl cyclase 2. AB - The role of Gbetagamma in adenylyl cyclase (AC) signaling is complicated due to its role as a conditional activator (AC2, AC4 and AC7) and an inhibitor (AC1, AC3 and AC8). AC2 is stimulated by Galpha(s) and if Gbetagamma is present the stimulation is synergistic. The precise mechanism of this synergistic activation is still not known. In order to further elucidate the role of Gbetagamma in AC2 activation by Galpha(s), peptides derived from the C1 domains of AC2 were synthesized and the ability of the various peptides to regulate AC2 function was tested. Our results identify two new Gbetagamma-binding sites in the AC2 C1 domain, AC2 C1a 339-360 and AC2 C1b 578-602 that are involved with stimulation of AC2 by Gbetagamma. These two regions are different from the previously described QEHA motif in the C2 domain of AC2. Further, the recently discovered PFAHL motif was confirmed to bind and to be involved with stimulation of AC2 by Gbetagamma. These functional studies indicate that multiple regions of AC2 are involved in the interaction with Gbetagamma. PMID- 21596132 TI - ROS/Epac1-mediated Rap1/NF-kappaB activation is required for the expression of BAFF in Raw264.7 murine macrophages. AB - B-cell activating factor (BAFF) plays a role for the maturation and the maintenance of B cells. Lipopolysaccharide (LPS) activates toll-like receptor 4 (TLR4)-dependent signal transduction, which resulted in BAFF expression through nuclear factor kappa B (NF-kappaB) activation. Here, we investigated whether BAFF expression could be regulated by p65 phosphorylation through the production of reactive oxygen species (ROS) or cyclic AMP (cAMP) in Raw264.7 murine macrophages. mBAFF expression was reduced by ROS scavengers and it was increased by dibutyl-cAMP, a cAMP analogue. mBAFF expression and mBAFF promoter activity were increased by co-transfection of p65 but they were reduced by p65-small interference (si) RNA. Serine (Ser) 276 phosphorylation of p65 was increased by LPS-mediated PKA activation or by the treatment with forskolin, adenylate cyclase activator and dibutyl-cAMP. In contrast, p65 phosphorylation at Ser276 was decreased by ROS scavengers. H(2)O(2) increased intracellular cAMP concentration, significantly. While no increase in p65 phosphorylation at Ser276 was detected by the treatment with H(2)O(2), CREB and p65 phosphorylation at Ser133 and Ser536 was observed, respectively. It implicates that p65 phosphorylation at Ser276 is independent of ROS-induced cAMP production. As another cAMP effector protein was cAMP-responsive guanine nucleotide exchange factor (Epac), a Rap GDP exchange factor, NF-kappaB was activated by the treatment with 8-(4-chloro-phenylthio)-2' O-methyladenosine-3',5'-cyclic monophosphate (CPT) that is an activator to Epac. Epac1-mediated Rap1 was activated by the treatment with H(2)O(2) but it was inhibited by ROS scavengers. CPT induced p65 phosphorylation at both Ser276 and Ser536. CPT also increased not only mBAFF expression but mBAFF promoter activity. Data demonstrate that TLR4-mediated mBAFF expression was resulted from the crosstalk of p65 phosphorylation at Ser536 and Ser276 through ROS- and/or cAMP mediated signal transduction. It suggests for the first time that ROS/Epac1 mediated Rap1/NF-kappaB pathway could be required for BAFF expression. PMID- 21596129 TI - Nerve maintenance and regeneration in the damaged cochlea. AB - Following the onset of sensorineural hearing loss, degeneration of mechanosensitive hair cells and spiral ganglion cells (SGCs) in humans and animals occurs to variable degrees, with a trend for greater neural degeneration with greater duration of deafness. Emergence of the cochlear implant prosthesis has provided much needed aid to many hearing impaired patients and has become a well-recognized therapy worldwide. However, ongoing peripheral nerve fiber regression and subsequent degeneration of SGC bodies can reduce the neural targets of cochlear implant stimulation and diminish its function. There is increasing interest in bio-engineering approaches that aim to enhance cochlear implant efficacy by preventing SGC body degeneration and/or regenerating peripheral nerve fibers into the deaf sensory epithelium. We review the advancements in maintaining and regenerating nerves in damaged animal cochleae, with an emphasis on the therapeutic capacity of neurotrophic factors delivered to the inner ear after an insult. Additionally, we summarize the histological process of neuronal degeneration in the inner ear and describe different animal models that have been employed to study this mechanism. Research on enhancing the biological infrastructure of the deafened cochlea in order to improve cochlear implant efficacy is of immediate clinical importance. PMID- 21596133 TI - Protein kinase C epsilon affects mitochondrial function through estrogen-related receptor alpha. AB - Members of the protein kinase C (PKC) family have been implicated in controlling cell proliferation, differentiation, and motility. Many of these processes are energy demanding. How PKCs affect mitochondrial function to regulate energy production is not well defined. Using an inhibitor Go6983 with broad specificity, we found that inhibiting PKCs reduced mitochondrial mass and altered mitochondrial function characterized by elevations in mitochondrial membrane potential (Deltapsim) and reactive oxygen species (ROS) levels. These alterations indicated that Go6983 suppressed the activities of mitochondrial regulators such as estrogen-related receptor alpha (ERRalpha). Indeed, Go6983 dose-dependently suppressed the expression levels of ERRalpha-target genes peroxisome proliferator activated receptor alpha (PPARalpha) and medium-chain acyl-CoA dehydrogenase (MCAD). Conversely, PKC activator phorbol ester (PMA) enhanced the expression level of another ERRalpha-target gene pyruvate dehydrogenase kinase 4 (PDK4). This PMA-mediated induction of PDK4 was blunted by an ERRalpha inverse agonist XCT-790, suggesting that ERRalpha plays a role in mediating the effects of PKCs on mitochondrial function. By over-expressing constitutively active forms of PKCs, we found that PKCepsilon preferentially stimulated the transcription activity of ERRalpha. Through mutating residues on ERRalpha, we established that this PKCepsilon-induced ERRalpha activity involves threonine 106, serine 110, and threonine 124 of ERRalpha. Collectively, these pieces of evidence suggest that ERRalpha plays an important role down-stream of PKCepsilon to regulate mitochondrial homeostasis. PMID- 21596135 TI - PEG-OCL micelles for quercetin solubilization and inhibition of cancer cell growth. AB - In this study, quercetin (QCT), a flavonoid with high anticancer potential, was loaded into polymeric micelles of PEG-OCL (poly(ethylene glycol)-b-oligo(epsilon caprolactone)) with naphthyl or benzyl end groups in order to increase its aqueous solubility. The cytostatic activity of the QCT-loaded micelles toward different human cancer cell lines and normal cells was investigated. The results showed that the solubility of QCT entrapped in mPEG750-b-OCL micelles was substantially increased up to 1 mg/ml, which is approximately 110 times higher than that of its solubility in water (9 MUg/ml). The average particle size of QCT loaded micelles ranged from 14 to 19 nm. The QCT loading capacity of the polymeric micelles with naphthyl groups was higher than that with benzyl groups (10% and 6%, respectively). QCT-loaded, benzyl- and naphthyl-modified micelles effectively inhibited the growth of both sensitive and resistance cancer cells (human erythromyelogenous leukemia cells (K562) and small lung carcinoma cells (GLC4)). However, the benzyl-modified micelles have a good cytocompatibility (in the concentration range investigated (up to 100 MUg/ml), they are well tolerated by living cells), whereas their naphthyl counterparts showed some cytotoxicity at higher concentrations (60-100 MUg/ml). Flow cytometry demonstrated that the mechanism underlying the growth inhibitory effect of QCT in its free form was inducing cell cycle arrest at the G2/M phase. Benzyl-modified micelles loaded with QCT also exhibited this cycle arresting the effect of cancer cells. In conclusion, this paper shows the enhancement of solubility and cell cycle arrest of QCT loaded into micelles composed of mPEG750-b-OCL modified with benzyl end groups. These micelles are therefore considered to be an attractive vehicle for the (targeted) delivery of QCT to tumors. PMID- 21596134 TI - Mitochondrial RNA processing in trypanosomes. AB - The mitochondrial genome of trypanosomes is composed of ~50 maxicircles and thousands of minicircles. Maxi-(~25 kb) and mini-(~1 kb)circles are catenated and packed into a dense structure called a kinetoplast. Both types of circular DNA are transcribed by a phage-like RNA polymerase: maxicircles yield multicistronic rRNA and mRNA precursors, while guide RNA (gRNA) precursors are produced from minicircles. To function in mitochondrial translation, pre-mRNAs must undergo a nucleolytic processing and 3' modifications, and often uridine insertion/deletion editing. gRNAs, which represent short (50-60 nt) RNAs directing editing reactions, are produced by 3' nucleolytic processing of a much longer precursor followed by 3' uridylation. Ribosomal RNAs are excised from precursors and their 3' ends are also trimmed and uridylated. All tRNAs are imported from the cytoplasm and some are further modified and edited in the mitochondrial matrix. Historically, the fascinating phenomenon of RNA editing has been extensively studied as an isolated pathway in which nuclear-encoded proteins mediate interactions of maxi- and minicircle transcripts to create open reading frames. However, recent studies unraveled a highly integrated network of mitochondrial genome expression including critical pre- and post-editing 3' mRNA processing, and gRNA and rRNA maturation steps. Here we focus on RNA 3' adenylation and uridylation as processes essential for biogenesis, stability and functioning of mitochondrial RNAs. PMID- 21596136 TI - Tailor-made release triggering from hot-melt extruded complexes of basic polyelectrolyte and poorly water-soluble drugs. AB - The aim of the study was the formulation of polyelectrolyte complexes composed of poorly water-soluble acid drugs and basic polymethacrylates by hot-melt extrusion enabling a tailor-made release pattern by the addition of inorganic salts. The influence of different electrolytes was analyzed at varying conditions in order to control drug delivery from the complexes. Poorly water-soluble model drugs naproxen and furosemide were applied in their non-ionic form. After hot-melt extrusion of the naproxen-polymethacrylate powder blend, XRPD and DSC measurements indicated the formation of a single-phase amorphous system. Milled extrudates were stable under storage at long-term and intermediate conditions. Polyelectrolyte complex formation by an acid-base reaction during hot-melt extrusion could be proven by the lack of vibrations of dimethylamino and carboxylic groups by FT-IR and Raman spectroscopy. The complexes did not dissolve in demineralized water. Drug release could be immediately induced by addition of neutral electrolytes. Tailor-made dissolution profiles were realized by controlled electrolyte triggering. Maximal effects were achieved by concentrations of 0.05-0.15 M NaCl. Different anions of alkali halogenides revealed variant magnitudes of the effect depending on the anion radius. Polyelectrolyte complex formation and dissolution principles were also confirmed for furosemide. PMID- 21596137 TI - Rapamycin-conditioned, alloantigen-pulsed myeloid dendritic cells present donor MHC class I/peptide via the semi-direct pathway and inhibit survival of antigen specific CD8(+) T cells in vitro and in vivo. AB - Dendritic cells (DC) are "professional" bone marrow-derived antigen (Ag) presenting cells of interest both as therapeutic targets and potential cellular vaccines due to their ability to regulate innate and adaptive immunity. Harnessing the inherent tolerogenicity of DC is a promising and incompletely explored approach to the prevention of allograft rejection. Previously, we and others have reported the ability of pharmacologically-modified DC, that resist maturation, to inhibit CD4(+) T cell responses and prolong allograft survival. Here we evaluated the ability of murine myeloid DC conditioned with the immunosuppressive pro-drug rapamycin (RAPA) to acquire and directly present alloAg to syngeneic CD8(+) T cells. RAPA-conditioned DC (RAPA-DC) pulsed with allogeneic splenocyte lysate acquired and expressed donor MHC class I and enhanced the apoptotic death of directly-reactive donor Ag-specific CD8(+) T cells in vitro. Moreover, following their adoptive transfer, they reduced the survival of these T cells in vivo. The ability of RAPA-DC to inhibit the survival of alloAg-specific CD8(+) T cells provides a potential mechanism by which host derived DC may act as negative regulators of T cell alloreactivity and support donor-specific unresponsiveness. Adoptive cell therapy with alloAg-pulsed RAPA-DC may offer an effective approach to suppression of alloimmunity, with reduced dependence on systemic immunosuppression. PMID- 21596138 TI - Nmnat exerts neuroprotective effects in dendrites and axons. AB - Dendrites can be maintained for extended periods of time after they initially establish coverage of their receptive field. The long-term maintenance of dendrites underlies synaptic connectivity, but how neurons establish and then maintain their dendritic arborization patterns throughout development is not well understood. Here, we show that the NAD synthase Nicotinamide mononucleotide adenylyltransferase (Nmnat) is cell-autonomously required for maintaining type specific dendritic coverage of Drosophila dendritic arborization (da) sensory neurons. In nmnat heterozygous mutants, dendritic arborization patterns of class IV da neurons are properly established before increased retraction and decreased growth of terminal branches lead to progressive defects in dendritic coverage during later stages of development. Although sensory axons are largely intact in nmnat heterozygotes, complete loss of nmnat function causes severe axonal degeneration, demonstrating differential requirements for nmnat dosage in the maintenance of dendritic arborization patterns and axonal integrity. Overexpression of Nmnat suppresses dendrite maintenance defects associated with loss of the tumor suppressor kinase Warts (Wts), providing evidence that Nmnat, in addition to its neuroprotective role in axons, can function as a protective factor against progressive dendritic loss. Moreover, motor neurons deficient for nmnat show progressive defects in both dendrites and axons. Our studies reveal an essential role for endogenous Nmnat function in the maintenance of both axonal and dendritic integrity and present evidence of a broad neuroprotective role for Nmnat in the central nervous system. PMID- 21596139 TI - Quantitative comparison and analysis of sulcal patterns using sulcal graph matching: a twin study. AB - The global pattern of cortical sulci provides important information on brain development and functional compartmentalization. Sulcal patterns are routinely used to determine fetal brain health and detect cerebral malformations. We present a quantitative method for automatically comparing and analyzing the sulcal pattern between individuals using a graph matching approach. White matter surfaces were reconstructed from volumetric T1 MRI data and sulcal pits, the deepest points in local sulci, were identified on this surface. The sulcal pattern was then represented as a graph structure with sulcal pits as nodes. The similarity between graphs was computed with a spectral-based matching algorithm by using the geometric features of nodes (3D position, depth and area) and their relationship. In particular, we exploited the feature of graph topology (the number of edges and the paths between nodes) to highlight the interrelated arrangement and patterning of sulcal folds. We applied this methodology to 48 monozygotic twins and showed that the similarity of the sulcal graphs in twin pairs was significantly higher than in unrelated pairs for all hemispheres and lobar regions, consistent with a genetic influence on sulcal patterning. This novel approach has the potential to provide a quantitative and reliable means to compare sulcal patterns. PMID- 21596140 TI - Wallerian degeneration after spinal cord lesions in cats detected with diffusion tensor imaging. AB - One goal of in vivo neuroimaging is the detection of neurodegenerative processes and anatomical reorganizations after spinal cord (SC) injury. Non-invasive examination of white matter fibers in the living SC can be conducted using magnetic resonance diffusion-weighted imaging. However, this technique is challenging at the spinal level due to the small cross-sectional size of the cord and the presence of physiological motion and susceptibility artifacts. In this study, we acquired in vivo high angular resolution diffusion imaging (HARDI) data at 3T in cats submitted to partial SC injury. Cats were imaged before, 3 and 21 days after injury. Spatial resolution was enhanced to 1.5 * 1.5 * 1 mm(3) using super-resolution technique and distortions were corrected using the reversed gradient method. Tractography-derived regions of interest were generated in the dorsal, ventral, right and left quadrants, to evaluate diffusion tensor imaging (DTI) and Q-Ball imaging metrics with regards to their sensitivity in detecting primary and secondary lesions. A three-way ANOVA tested the effect of session (intact, D3, D21), cross-sectional region (left, right, dorsal and ventral) and rostrocaudal location. Significant effect of session was found for FA (P<0.001), GFA (P<0.05) and radial diffusivity (P<0.001). Post-hoc paired T-test corrected for multiple comparisons showed significant changes at the lesion epicenter (P<0.005). More interestingly, significant changes were also found several centimeters from the lesion epicenter at both 3 and 21 days. This decrease was specific to the type of fibers, i.e., rostrally to the lesion on the dorsal aspect of the cord and caudally to the lesion ipsilaterally, suggesting the detection of Wallerian degeneration. PMID- 21596141 TI - Non-Gaussian diffusion in human brain tissue at high b-factors as examined by a combined diffusion kurtosis and biexponential diffusion tensor analysis. AB - Diffusion tensor imaging (DTI) permits non-invasive probing of tissue microstructure and provides invaluable information in brain diagnostics. Our aim was to examine approaches capable of capturing more detailed information on the propagation mechanisms and underlying tissue microstructure in comparison to the conventional methods. In this work, we report a detailed in vivo diffusion study of the human brain in an extended range of the b-factors (up to 7000 s mm(-2)) performed on a group of 14 healthy volunteers at 3T. Combined diffusion kurtosis imaging (DKI) and biexponential diffusion tensor analysis (BEDTA) were applied to quantify the attenuation curves. New quantitative indices are suggested as map parameters and are shown to improve the underlying structure contrast in comparison to conventional DTI. In particular, fractional anisotropy maps related to the slow diffusion tensor are shown to attain significantly higher values and to substantially improve white matter mapping. This is demonstrated for the specified regions of the frontal and occipital lobes and for the anterior cingulate. The findings of this work are substantiated by the statistical analysis of the whole slice histograms averaged over 14 subjects. Colour-coded directional maps related to the fast and slow diffusion tensors in human brain tissue are constructed for the first time and these demonstrate a high degree of axial co-alignment of the two tensors in the white matter regions. It is concluded that a combined DKI and BEDTA offers a promising framework for monitoring tissue alteration during development and degeneration or as a consequence of the neurological disease. PMID- 21596142 TI - Selective updating of working memory content modulates meso-cortico-striatal activity. AB - Accumulating evidence from non-human primates and computational modeling suggests that dopaminergic signals arising from the midbrain (substantia nigra/ventral tegmental area) mediate striatal gating of the prefrontal cortex during the selective updating of working memory. Using event-related functional magnetic resonance imaging, we explored the neural mechanisms underlying the selective updating of information stored in working memory. Participants were scanned during a novel working memory task that parses the neurophysiology underlying working memory maintenance, overwriting, and selective updating. Analyses revealed a functionally coupled network consisting of a midbrain region encompassing the substantia nigra/ventral tegmental area, caudate, and dorsolateral prefrontal cortex that was selectively engaged during working memory updating compared to the overwriting and maintenance of working memory content. Further analysis revealed differential midbrain-dorsolateral prefrontal interactions during selective updating between low-performing and high-performing individuals. These findings highlight the role of this meso-cortico-striatal circuitry during the selective updating of working memory in humans, which complements previous research in behavioral neuroscience and computational modeling. PMID- 21596143 TI - Neural responses to perceived pain in others predict real-life monetary donations in different socioeconomic contexts. AB - Empathy has been proposed to be a proximate mechanism underlying altruistic behavior. However, both empathy and altruistic behavior differ between human individuals with low and high socioeconomic status. Here we investigated whether subjective socioeconomic status (SSS) modulates the relationship between neural activity to perceived pain in others and human altruistic behaviors in a real life situation. After being scanned using functional MRI while observing videos of others in pain, participants were invited to make an anonymous monetary donation to a charitable organization. Painful stimuli increased activity in the inferior frontal, insula and somatosensory cortices compared to non-painful stimuli. A hierarchical regression analysis revealed that neural responses to perceived pain predicted the amount of monetary donations with different patterns in high and low SSS individuals. Stronger neural responses to perceived pain were associated with greater monetary donations in high SSS individuals, whereas a reverse pattern was observed in low SSS individuals. Our results suggest that SSS moderates the functional role of empathy-related neural activity in predicting altruistic behavior. Empathy may follow different mechanisms involved in altruistic behaviors (e.g., donation) depending on the social environment. PMID- 21596144 TI - Linear and nonlinear prefrontal and parietal activity during multiple-item working memory. AB - Most parts of the prefrontal and posterior parietal cortices show sustained activity during short-term maintenance of visual information and their activity increases with increasing memory set size. To investigate the interplay of feature selectivity, memory load and inter-item interaction (or interference) on sustained activity, we compared and contrasted fMRI signal during the retention of two items from the same or different visual feature categories (e.g., two line orientations versus a line and a color) relative to the retention of single items. Data from 16 young adults revealed three types of activation patterns in the prefrontal and posterior parietal cortices. First, among the prefrontal and posterior parietal areas that showed preferential responses to line orientations, some exhibited linear increases in sustained activity whereas others exhibited nonlinear increases in correspondence to the number of lines in the memory set. Second, the right lateral prefrontal and ventral posterior parietal areas, albeit not showing differential sustained activity relative to lines or colors, were disproportionately more active during holding two lines in comparison to holding a line and a color. Third, the left posterior intraparietal sulcus showed a weak effect of memory set size regardless of the items' visual features. These observations suggest that rather than number of items, a combination of factors such as visual feature and memory-set homogeneity may have the greater influence on prefrontal and parietal activity during multiple-item working memory. This is consistent with the view that working memory capacity is influenced by the level of interaction or interference between visual stimuli, which is stronger between items from the same feature category. PMID- 21596145 TI - Molecular phylogenetics, vocalizations, and species limits in Celeus woodpeckers (Aves: Picidae). AB - Species limits and the evolutionary mechanisms that have shaped diversification of woodpeckers and allies (Picidae) remain obscure, as inter and intraspecific phylogenetic relationships have yet to be comprehensively resolved for most genera. Herein, we analyzed 5020 base pairs of nucleotide sequence data from the mitochondrial and nuclear genomes to reconstruct the evolutionary history of Celeus woodpeckers. Broad geographic sampling was employed to assess species limits in phenotypically variable lineages and provide a first look at the evolution of song and plumage traits in this poorly known Neotropical genus. Our results strongly support the monophyly of Celeus and reveal several novel relationships across a shallow phylogenetic topology. We confirm the close sister relationship between Celeus spectabilis and the enigmatic Celeus obrieni, both of which form a clade with Celeus flavus. The Mesoamerican Celeus castaneus was placed as sister to a Celeus undatus-grammicus lineage, with the species status of the latter drawn into question given the lack of substantial genetic, morphological, and vocal variation in these taxa. We recovered paraphyly in Celeus elegans; however, this result appears to be the consequence of mitochondrial introgression from Celeus lugubris considering the monophyly of elegans at the beta-FIBI7 locus. A second instance of paraphyly was observed in Celeus flavescens with deep genetic splits and substantial phenotypic variation indicating the presence of two distinct species in this broadly distributed lineage. As such, we advocate elevation of Celeus flavescens ochraceus to species status. Our analysis of Celeus vocalizations and plumage characters demonstrates a pattern of lability consistent with a relatively recent origin of the genus and potentially rapid speciation history. PMID- 21596146 TI - Using pharmacokinetic modeling to determine the effect of drug and food on gastrointestinal transit in dogs. AB - INTRODUCTION: The gastrointestinal (GI) tract is one of the target organs of adverse drug effects in different phases of drug development. This study aimed to investigate the feasibility of population pharmacokinetic modeling to quantify the rate of gastric emptying (GE) and small intestinal transit time (SITT) in response to drugs that affect GI motility in fed and fasted dogs. Paracetamol and sulfapyridine (sulfasalazine metabolite) pharmacokinetics were used as markers for GE and SITT, respectively. METHODS: In two separate studies, under fed and fasted conditions, six male beagle dogs received a 15min intravenous infusion of vehicle, atropine (0.06mg/kg) or erythromycin (1mg/kg) followed by an intragastric administration of a mixture of paracetamol (24mg/kg) and sulfasalazine (20mg/kg). Food was given just before or at 6h after drug administration in the fed and fasted study, respectively. Blood samples were collected for analysis of paracetamol and sulfapyridine in plasma. Population pharmacokinetic analysis of paracetamol and sulfapyridine in plasma was used to determine the rate of GE and SITT. RESULTS: The quantitative parameter estimates demonstrated a detailed and significant influence of atropine, erythromycin and food on GE and SITT. Compared to fasted conditions food intake delayed GE in pharmacologically treated dogs and SITT was shortened after treatment with vehicle or erythromycin. Atropine substantially delayed GE in fed and fasted conditions but the effect on SITT was evident only under fed condition. Erythromycin, in contrast, increased GE only in fasted conditions, and generally delayed SITT. DISCUSSION: Population pharmacokinetic modeling of paracetamol and sulfapyridine provides a suitable preclinical non-invasive experimental method for quantification of drug- and food-induced changes in the rate of GE and SITT in conscious beagle dogs for use in safety evaluations to predict changes in GI transit and/or to explain the pharmacokinetic profile of drugs under development. PMID- 21596147 TI - Differential role of the hippocampus in response-outcome and context-outcome learning: evidence from selective satiation procedures. AB - Instrumental performance in rats with hippocampal lesions is insensitive to the degradation of action-outcome contingencies, but sensitive to the effects of selective devaluation by satiation. One interpretation of this dissociation is that damage to the hippocampus impairs the formation of context-outcome associations upon which the effect of contingency degradation, but not selective satiation, relies. Here, we provide a direct assessment of this interpretation, and showed that conditioned responding to contexts did not show sensitivity to selective satiation (Experiment 1), and confirmed that instrumental performance was sensitive to selective satiation (Experiment 2) following hippocampal cell loss. PMID- 21596148 TI - Examining the sex- and circadian dependency of a learning phenotype in mice with glycine transporter 1 deletion in two Pavlovian conditioning paradigms. AB - Behavioural characterisation of transgenic mice has been instrumental in search of therapeutic targets for the modulation of cognitive function. However, little effort has been devoted to phenotypic characterisation across environmental conditions and genomic differences such as sex and strain, which is essential to translational research. The present study is an effort in this direction. It scrutinised the stability and robustness of the phenotype of enhanced Pavlovian conditioning reported in mice with forebrain neuronal deletion of glycine transporter 1 by evaluating the possible presence of sex and circadian dependency, and its consistency across aversive and appetitive conditioning paradigms. The Pavlovian phenotype was essentially unaffected by the time of testing between the two circadian phases, but it was modified by sex in both conditioning paradigms. We observed that the effect size of the phenotype was strongest in female mice tested during the dark phase in the aversive paradigm. Critically, the presence of the phenotype in female mutants was accompanied by an increase in resistance to extinction. Similarly, enhanced conditioned responding once again emerged solely in female mutants in the appetitive conditioning experiment, which was again associated with an increased resistance to extinction across days, but male mutants exhibited an opposite trend towards facilitation of extinction. The present study has thus added hitherto unknown qualifications and specifications of a previously reported memory enhancing phenotype in this mouse line by identifying the determinants of the magnitude and direction of the expressed phenotype. This in-depth comparative approach is of value to the interpretation of behavioural findings in general. PMID- 21596149 TI - Associative learning performance is impaired in zebrafish (Danio rerio) by the NMDA-R antagonist MK-801. AB - The zebrafish is gaining popularity in behavioral neuroscience perhaps because of a promise of efficient large scale mutagenesis and drug screens that could identify a substantial number of yet undiscovered molecular players involved in complex traits. Learning and memory are complex functions of the brain and the analysis of their mechanisms may benefit from such large scale zebrafish screens. One bottleneck in this research is the paucity of appropriate behavioral screening paradigms, which may be due to the relatively uncharacterized nature of the behavior of this species. Here we show that zebrafish exhibit good learning performance in a task adapted from the mammalian literature, a plus maze in which zebrafish are required to associate a neutral visual stimulus with the presence of conspecifics, the rewarding unconditioned stimulus. Furthermore, we show that MK-801, a non-competitive NMDA-R antagonist, impairs memory performance in this maze when administered right after training or just before recall but not when given before training at a dose that does not impair motor function, perception or motivation. These results suggest that the plus maze associative learning paradigm has face and construct validity and that zebrafish may become an appropriate and translationally relevant study species for the analysis of the mechanisms of vertebrate, including mammalian, learning and memory. PMID- 21596151 TI - Characterisation of AnBEST1, a functional anion channel in the plasma membrane of the filamentous fungus, Aspergillus nidulans. AB - Two distant homologues of the bestrophin gene family have been identified in the filamentous fungus, Aspergillus nidulans (anbest1 and anbest2). AnBEST1 was functionally characterised using the patch clamp technique and was shown to be an anion selective channel permeable to citrate. Furthermore, AnBEST1 restored the growth of the pdr12Delta yeast mutant on inhibitory concentrations of extracellular propionate, benzoate and sorbate, also consistent with carboxylated organic anion permeation of AnBEST1. Similar to its animal counterparts, AnBEST1 currents were activated by elevated cytosolic Ca(2+) with a K(d) of 1.60MUM. Single channel currents showed long (>10s) open and closed times with a unitary conductance of 16.3pS. Transformation of A. nidulans with GFP-tagged AnBEST1 revealed that AnBEST1 localised to the plasma membrane. An anbest1 null mutant was generated to investigate the possibility that AnBEST1 mediated organic anion efflux across the plasma membrane. Although organic anion efflux was reduced from anbest1 null mutants, this phenotype was linked to the restoration of uracil/uridine-requiring A. nidulans strains to uracil/uridine prototrophy. In conclusion, this study identifies a new family of organic anion-permeable channels in filamentous fungi. We also reveal that uracil/uridine-requiring Aspergillus strains exhibit altered organic anion metabolism which could have implications for the interpretation of physiological studies using auxotrophic Aspergillus strains. PMID- 21596150 TI - Expression of activating KIR2DS2 and KIR2DS4 genes after hematopoietic cell transplantation: relevance to cytomegalovirus infection. AB - The important role of activating killer immunoglobulin-like receptors (KIRs) in protecting against cytomegalovirus (CMV) reactivation has been described previously in patients undergoing hematopoietic cell transplantation (HCT). More specifically, the presence of multiple activating KIRs and the presence of at least KIR2DS2 and KIR2DS4 in the donor genotype identified a group of HCT patients at low risk for CMV reactivation. However, CMV infection still occurs in patients with the KIR protective genotype, and the question has been raised as to whether this is related to the lack of KIR expression. In this report, expression of the KIR2DS2 and KIR2DS4 genes, as measured by mRNA-based quantitative polymerase chain reaction in both the donor cells and the HCT recipient cells, was studied relative to CMV reactivation. In the control samples from healthy donors, the median range for KIR2DS2 and KIR2DS4 expression was low, with 35% of donors considered null-expressers. Interestingly, KIR2DS2 and KIR2DS4 expression was elevated after HCT compared with donor expression before HCT, and was significantly elevated in CMV viremic compared with CMV nonviremic HCT recipients. The CMV seropositivity of donors was not associated with activating KIR expression, and donor null expression in those with the KIR2DS2 or KIR2DS4 genotype was not predictive for CMV reactivation in the recipient. After controlling for other transplant factors, including donor type (sibling or unrelated), transplant source (bone marrow or peripheral blood stem cells), and acute GVHD grade, regression analysis of elevated KIR gene expression found an association for both KIR2DS2 and KIR2DS4, with a 7-fold increase in risk for CMV reactivation. We speculate that the elevated activating KIR expression in CMV viremic HCT recipients is either coincidental with factors that activate CMV or is initiated by CMV or cellular processes responsive to such CMV infection reactivation. PMID- 21596152 TI - Frontiers in nitric oxide and redox signaling. PMID- 21596153 TI - Disruption of ATP homeostasis during chronic cold stress and recovery in the chill susceptible beetle (Alphitobius diaperinus). AB - This study examined the impact of fluctuating thermal regimes (FTRs) on cold tolerance of the polyphagous beetle Alphitobius diaperinus. Daily pulses of elevated temperatures can provide breaks in chronic cold stress, potentially allowing for physiological recovery and improving survival. Perturbations in central metabolism appear to be a common physiological response in insects exposed to low temperatures. It has been suggested that energy supplies, which may be depleted during cold exposure, can be regenerated during the warming pulses of FTRs. This study tested the assumption that chronic cold stress may induce ATP depletion and that recovery during FTR warming pulses may allow re establishment of ATP supplies. In this study, A. diaperinus were exposed to cold stress under different thermal regimes (constant or fluctuating). The results did not confirm the aforementioned assumption. No cold-induced ATP depletion was observed. The lowest ATP levels were repeatedly detected in the untreated controls. The data show that homoeostasis of ATP is lost when adults A. diaperinus are exposed to cold stress, whatever thermal regime (constant or fluctuating). ATP accumulation may be viewed as a symptom of a production/consumption imbalance under cold stress conditions. Periodic short (2 h) warming pulses clearly improved cold survival. Cellular homeostasis, however, probably requires a longer recovery period to be fully restored. PMID- 21596154 TI - Seasonal modulation in the secondary stress response of a carcharhinid shark, Rhizoprionodon terraenovae. AB - Some animals have the ability to modulate their stress response depending on the type and duration of the stressor. Modulations can initiate behavioral changes that increase fitness during the stressful period. The goal of this study was to determine if Atlantic sharpnose sharks, Rhizoprionodon terraenovae, exhibit seasonal modulations in their secondary stress parameters. Mature, male Atlantic sharpnose sharks were acutely stressed and serially sampled for one-hour, during spring, summer, and fall. An elevated stress response was observed for plasma glucose, lactate and osmolality during summer compared to spring and fall. Glucose also exhibited elevated initial concentrations, followed by a linear response during summer; varying from the asymptotic response during spring and fall. Hematocrit did not show differences over time or season; however, the power of the analysis was low due to the small sample size. When an additional 120 samples were included in the analysis, significantly higher initial hematocrit values were found during summer. Based on these results we suggest that summer is a demanding time for Atlantic sharpnose sharks. PMID- 21596155 TI - High-density lipoprotein remains elevated despite reductions in total cholesterol in fasting adult male elephant seals (Mirounga angustirostris). AB - We examined changes in lipid profiles of 40 adult northern elephant seal bulls over the 3-month breeding fast and the 1-month molting fast to investigate impacts of fasting on serum total cholesterol (TC), triglycerides (TG) and lipoproteins. Total cholesterol and low-density lipoprotein (LDL) levels were initially high (3930 +/- 190mgL(-1)and 1610 +/- 170mgL(-1), respectively) and decreased significantly over the breeding season. Total cholesterol and LDL declined significantly with adipose tissue reserves (p<0.001), and LDL levels as low as 43 mgL(-1) were measured in seals late in the breeding fast. Less dramatic but similar changes in lipid metabolism were observed across the molting fast. High-density lipoproteins (HDL) remained consistently elevated (>1750 mgL(-1)) suggesting that elephant seals defend HDL concentrations, despite significant depletion of TC and LDL across the breeding fast. Triglyceride levels were significantly higher during the molt, consistent with lower rates of lipid oxidation needed to meet metabolic energy demands during this period. The maintenance of HDL during breeding is consistent with its role in delivering cholesterol from adipose tissue for steroidogenesis and spermatogenesis and potentially mitigates oxidative stress associated with fasting. PMID- 21596157 TI - Mucinous cystic neoplasm of the pancreas. PMID- 21596156 TI - Zinc transporter expression in zebrafish (Danio rerio) during development. AB - Zinc is a micronutrient important in several biological processes including growth and development. We have limited knowledge on the impact of maternal zinc deficiency on zinc and zinc regulatory mechanisms in the developing embryo due to a lack of in vivo experimental models that allow us to directly study the effects of maternal zinc on embryonic development following implantation. To overcome this barrier, we have proposed to use zebrafish as a model organism to study the impact of zinc during development. The goal of the current study was to profile the mRNA expression of all the known zinc transporter genes in the zebrafish across embryonic and larval development and to quantify the embryonic zinc concentrations at these corresponding developmental time points. The SLC30A zinc transporter family (ZnT) and SLC39A family, Zir-,Irt-like protein (ZIP) zinc transporter proteins were profiled in zebrafish embryos at 0, 2, 6, 12, 24, 48 and 120 h post fertilization to capture expression patterns from a single cell through full development. We observed consistent embryonic zinc levels, but differential expression of several zinc transporters across development. These results suggest that zebrafish is an effective model organism to study the effects of zinc deficiency and further investigation is underway to identify possible molecular pathways that are dysregulated with maternal zinc deficiency. PMID- 21596158 TI - Long-standing intestinal lymphangiectasia detected by double-balloon enteroscopy. PMID- 21596159 TI - Developmental changes in the magnitude and activation characteristics of Na(+) currents of petrosal neurons projecting to the carotid body. AB - Carotid bodies mediate hypoxia sensing for the respiratory system and increase their sensitivity in the post-natal period. The present study examined the characteristics and developmental change of fast Na(+) currents of chemoreceptor afferent neurons. Rat carotid bodies (P2-P19) were harvested intact with the petrosal ganglia and whole-cell recordings obtained from petrosal somas whose axons projected to the carotid body. The magnitude of Na(+) current increased in the post-natal period in parallel with increased conduction velocity and somal size. Voltage-dependence of activation significantly shifted towards negative potentials but no significant change occurred in the voltage dependence of inactivation or the slope factors for activation or inactivation. The leftward shift in activation increased slowly or non-inactivating currents around resting potential which increases afferent neuron excitability, a result confirmed in current clamp recordings. These results suggest that a developmental shift in Na(+) current activation plays a role in chemoreceptor maturation by enhancing excitability of the afferent neuron. PMID- 21596160 TI - Developmental trajectories, critical windows and phenotypic alteration during cardio-respiratory development. AB - Embryo-environment interactions affecting cardio-respiratory development in vertebrates have been extensively studied, but an equally extensive conceptual framework for interpreting and interrelating these developmental events has lagged behind. In this review, we consider the conceptual constructs of "developmental plasticity", "critical windows", "developmental trajectory" and related concepts as they apply to both vertebrate and invertebrate development. Developmental plasticity and the related phenomenon of "heterokairy" are considered as a subset of phenotypic plasticity, and examples of cardiovascular, respiratory and metabolic plasticity illustrate the variable outcomes of embryo environment interactions. The concept of the critical window is revealed to be overarching in cardio-respiratory development, and events originating within a critical window, potentially mitigated by "self-repair" capabilities of the embryo, are shown to result in modified developmental trajectories and, ultimately, modified adult phenotype. Finally, epigenetics, fetal programming and related phenomena are considered in the context of potentially life-long cardio respiratory phenotypic modification resulting from embryo-environment interactions. PMID- 21596161 TI - Homozygous deletion of chromosome 15q13.3 including CHRNA7 causes severe mental retardation, seizures, muscular hypotonia, and the loss of KLF13 and TRPM1 potentially cause macrocytosis and congenital retinal dysfunction in siblings. AB - The heterozygous 15q13.3 microdeletion syndrome (MIM #612001) was first described by Sharp et al. in 2008. So far four patients with 15q13.3 homozygous or compound heterozygous microdeletions have been identified. Here we report a non consanguineous family with two affected siblings carrying a homozygous microdeletion of ~1.5 Mb at the 15q13.3 locus. They presented with congenital retinal dysfunction, refractory epilepsy, encephalopathy, mental retardation, repetitive hand movements, severe muscular hypotonia and macrocytosis. Dysmorphic facial features are synophrys and bilateral proptosis. The siblings carry a homozygous microdeletion at 15q13.3 of ~1.5 Mb including the genes ARHGAP11B, MTMR15, MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7. The absence of CHRNA7 has been suggested as a cause of refractory seizures. According to knock-out experiments the deletion of KLF13 could be an explanation for macrocytosis. The homozygous loss of TRPM1 could be a possible explanation for congenital retinal dysfunction. PMID- 21596162 TI - Characterization of mitochondrial proteome in a severe case of ETF-QO deficiency. AB - Multiple acyl-CoA dehydrogenase deficiency (MADD) is a mitochondrial fatty acid oxidation disorder caused by mutations that affect electron transfer flavoprotein (ETF) or ETF:ubiquinone oxidoreductase (ETF-QO) or even due to unidentified disturbances of riboflavin metabolism. Besides all the available data on the molecular basis of FAO disorders, including MADD, the pathophysiological mechanisms underlying clinical phenotype development, namely at the mitochondrial level, are poorly understood. In order to contribute to the elucidation of these mechanisms, we isolated mitochondria from cultured fibroblasts, from a patient with a severe MADD presentation due to ETF-QO deficiency, characterize its mitochondrial proteome and compare it with normal controls. The used approach (2 DE-MS/MS) allowed the positive identification of 287 proteins in both patient and controls, presenting 35 of the significant differences in their relative abundance. Among the differentially expressed are proteins associated to binding/folding functions, mitochondrial antioxidant enzymes as well as proteins associated to apoptotic events. The overexpression of chaperones like Hsp60 or mitochondrial Grp75, antioxidant enzymes and apoptotic proteins reflects the mitochondrial response to a complete absence of ETF-QO. Our study provides a global perspective of the mitochondrial proteome plasticity in a severe case of MADD and highlights the main molecular pathways involved in its pathogenesis. PMID- 21596163 TI - Comprehensive proteomic profiling of adult Angiostrongylus costaricensis, a human parasitic nematode. AB - Angiostrongylus costaricensis is a nematode helminth that causes an intestinal acute inflammatory process known as abdominal angiostrongyliasis, which is a poorly understood human disease occurring in Latin America. Our aim was to study the proteomic profiles of adult parasites focusing on immunogenic proteins. Total cellular extracts from both genders showed similar 2-DE profiles, with 60% of all protein spots focused between pH 5-7 and presenting molecular masses from 20.1 to 66 kDa. A total of 53 different dominant proteins were identified in our dataset and were mainly associated with the following over-represented Gene Ontology Biological Process terms: "macromolecule metabolic process", "developmental process", "response to stress", and "biological regulation". Female and male immunoblots showed similar patterns of reactive proteins. Immunoreactive spots identified by MALDI-PSD were found to represent heat shock proteins, a putative abnormal DAuer Formation family member, and galectins. To date, very few biochemical analyses have focused on the nematode Angiostrongylus costaricensis. As such, our results contribute to a better understanding of its biology and the mechanisms underlying the host-parasite relationship associated with this species. Moreover, our findings represent a first step in the search for candidate proteins for diagnostic assays and the treatment of this parasitic infection. PMID- 21596164 TI - Emerging nanoproteomics approaches for disease biomarker detection: a current perspective. AB - Availability of genome sequence of human and different pathogens has advanced proteomics research for various clinical applications. One of the prime goals of proteomics is identification and characterization of biomarkers for cancer and other fatal human diseases to aid an early diagnosis and monitor disease progression. However, rapid detection of low abundance biomarkers from the complex biological samples under clinically relevant conditions is extremely difficult, and it requires the development of ultrasensitive, robust and high throughput technological platform. In order to overcome several technical limitations associated with sensitivity, dynamic range, detection time and multiplexing, proteomics has started integrating several emerging disciplines such as nanotechnology, which has led to the development of a novel analytical platform known as 'nanoproteomics'. Among the diverse classes of nanomaterials, the quantum dots, gold nanoparticles, carbon nanotubes and silicon nanowires are the most promising candidates for diagnostic applications. Nanoproteomics offers several advantages such as ultralow detection, short assay time, high-throughput capability and low sample consumption. In this article, we have discussed the application of nanoproteomics for biomarker discovery in various diseases with special emphasis on various types of cancer. Furthermore, we have discussed the prospects, merits and limitations of nanoproteomics. PMID- 21596165 TI - Activity-based proteomics: identification of ABHD11 and ESD activities as potential biomarkers for human lung adenocarcinoma. AB - Lung cancer is the leading cause of all cancer related deaths with a worldwide mortality of 1.2 million each year. The 5-year survival rate ranges from 80% in early stages to a dismal 5% in advanced disease. Prognosis is currently mostly determined based on the extension of disease at diagnosis. Thereby it has become evident that predicted and real outcomes can vary significantly, even for patients with the same stage of disease. Novel biomarkers with a reliable predictive significance are therefore clearly needed. In this study we implemented an activity-based, solely mass spectrometry dependent biomarker discovery platform. We investigated the role of serine hydrolase activities as potential biomarkers for human lung adenocarcinoma, the most common lung cancer subtype. Forty pairs of fresh frozen malignant and matching non-neoplastic lung tissues were analyzed and enzymatic activities linked to clinical follow-up data. We found that the activities of Abhydrolase domain-containing protein 11 and Esterase D predict the development of distant metastases and the presence of aggressive lung adenocarcinomas, respectively, in a statistically significant model. We conclude that serine hydrolase activities bear a predictive potential for human lung adenocarcinoma and that activity-based proteomics represents a powerful methodology in the search for novel disease biomarkers. PMID- 21596166 TI - Charge state-selective separation of peptides by reversible modification of amino groups and strong cation-exchange chromatography: evaluation in proteomic studies using peptide-centric database searches. AB - Here we describe an integrated approach for the selective separation of peptides from complex mixtures using strong cation-exchange chromatography. The procedure exploits the charge differences produced by reversible modification of primary amino groups in peptides, enabling their separation into three major fractions: 1) neutral peptides 2) peptides with one positive charge and 3) peptides with 2 or more positive charges. The procedure demonstrated an excellent selectivity which allowed restricted MS/MS ion searches with peptide-centric databases. PMID- 21596167 TI - [Introduction]. PMID- 21596168 TI - [Impact of exacerbations on the clinical course of chronic obstructive pulmonary disease]. AB - The clinical course of chronic obstructive pulmonary disease (COPD) is marked by frequent exacerbations. Not all patients suffer exacerbations and not all decompensations have the same consequences; however, in the last few years, these episodes of clinical instability - especially if recurrent - have come to be viewed as a major element in the natural history of the disease insofar as they generate heavy workload and high costs, sintonegatively affect patients' quality of life, contribute to the multidimensional progression of the disease and, finally, affect its prognosis. The present article reviews the current scientific evidence on the impact of exacerbations on the clinical course of COPD and analyzes this impact from a multidimensional perspective. The need to base the management of COPD on clinical phenotypes is discussed, emphasizing the importance of the exacerbation phenotype, a clinical phenotype characterized by frequent exacerbations. This phenotype is often associated with the presence of cough and chronic expectoration, latent bronchial infection and bronchiectasis and leads to higher morbidity and mortality. PMID- 21596169 TI - [Complexity in chronic obstructive pulmonary disease. Individualized treatment, new approaches, phenotypes and comorbidities]. AB - The current definition and severity stages of chronic obstructive pulmonary disease (COPD) focus excessively on spirometric criteria alone. Measurement of chronic airflow obstruction and its degree of reversibility is complex. The etiology of this disease cannot be fully explained in relation to smoking and the heterogeneity of this systemic disease that affects mainly the lung cannot be expressed through forced expiratory volume in 1 second (FEV(1)) alone. This simplification was useful for a period but the loss of clinical subtlety in large studies hampers interpretation of their results and their conclusions lose external validity. Accepting the complexity of COPD requires substituting the analytic focus centered on FEV(1) for a multifaceted approach that integrates other aspects in the analysis of real COPD patients. Identifying and classifying clinically significant subgroups or "COPD phenotypes" may help to guide treatment more efficiently. In patients with COPD, mortality due to cardiovascular diseases or malignancies occurs earlier than that due to respiratory causes; that is, deaths from COPD occur in patients not succumbing to cardiovascular diseases or cancer. To prolong survival in these patients, comorbidity should be evaluated and treated. COPD treatment based on severity measured by lung function can no longer be recommended. The various therapeutic options should be individualized according to the patient's other characteristics. PMID- 21596170 TI - [Phosphodiesterase-4 inhibitors: roflumilast]. AB - Chronic obstructive pulmonary disease (COPD) encompasses a group of diseases characterized by chronic airway obstruction. This broad diagnostic umbrella includes several clinical phenotypes that overlap and respond differently to each type of therapeutic intervention. Roflumilast is a drug belonging to the new therapeutic class of phosphyldiesterase-4 (PDE4) inhibitors and can be considered the first drug to be developed for a specific COPD phenotype (COPD associated with chronic bronchitis). In preclinical models, roflumilast has shown potent antiinflammatory action against a wide variety of cells and inflammatory mediators, as well as against the etiopathogenic mechanisms of COPD. The present article reviews the evidence generated during the clinical development of roflumilast, with special emphasis on studies evaluating the drug in a context similar to that of routine clinical practice. PMID- 21596171 TI - Beginning of percutaneous coronary interventions: Zurich 1976-1977. PMID- 21596172 TI - Historical perspectives of The American Association for Thoracic Surgery: Adrian V. S. Lambert (1872-1952). PMID- 21596173 TI - Impact of pulmonary hypertension on outcomes after aortic valve replacement for aortic valve stenosis. AB - OBJECTIVE: The presence of pulmonary hypertension historically has been considered a significant risk factor affecting early and late outcomes after valve replacement. Given the number of recent advances in the management of pulmonary hypertension after cardiac surgery, a better understanding of its impact on outcomes may assist in the clinical management of these patients. The purpose of this study was to determine whether pulmonary hypertension remains a risk factor in the modern era for adverse outcomes after aortic valve replacement for aortic valve stenosis. METHODS: From January 1996 to June 2009, a total of 1080 patients underwent aortic valve replacement for primary aortic valve stenosis, of whom 574 (53%) had normal systolic pulmonary artery pressures (sPAP) and 506 (47%) had pulmonary hypertension. Pulmonary hypertension was defined as mild (sPAP 35-44 mm Hg), moderate (45-59 mm Hg), or severe (>= 60 mm Hg). In the group of patients with pulmonary hypertension, 204 had postoperative echocardiograms. RESULTS: Operative mortality was significantly higher in patients with pulmonary hypertension (47/506, 9%, vs 31/574, 5%, P = .02). The incidence of postoperative stroke was similar (P = .14), but patients with pulmonary hypertension had an increased median hospital length of stay (8 vs 7 days, P = .001) and an increased incidence of prolonged ventilation (26% vs 17%, P < .001). Preoperative pulmonary hypertension was an independent risk factor for decreased long-term survival (relative risk 1.7, P = .02). Those with persistent pulmonary hypertension postoperatively had decreased survival. Five-year survival (Kaplan-Meier) was 78% +/- 6% with normal sPAP and 77% +/- 7% with mild pulmonary hypertension postoperatively, compared with 64% +/- 8% with moderate and 45% +/- 12% with severe pulmonary hypertension (P < .001). CONCLUSIONS: In patients undergoing aortic valve replacement, preoperative pulmonary hypertension increased operative mortality and decreased long-term survival. Patients with persistent moderate or severe pulmonary hypertension after aortic valve replacement had decreased long-term survival. These data suggest that pulmonary hypertension had a significant impact on outcomes in patients undergoing aortic valve replacement and should be considered in preoperative risk assessment. PMID- 21596175 TI - Impact of surgical ventricular restoration on stroke volume: surgical fine-tuning of the relationship between end-diastolic volume and stroke volume. PMID- 21596177 TI - Ralph Lewis, MD: a pioneer in thoracic surgery. PMID- 21596178 TI - Gentle giant: Wilford Neptune, MD. PMID- 21596179 TI - [Cryopyrin-associated periodic syndromes (CAPS)]. PMID- 21596180 TI - [Autoinflammatory syndromes]. AB - Autoinflammatory syndromes are characterised by recurrent or persistent inflammation with no increase in the antibody titers or antigen-specific T lymphocytes, and absence of infection. Initially, they included the hereditary periodic fever syndromes, a group of innate immune system monogenic diseases characterised by recurrent febrile episodes, with different characteristics, duration and interval, accompanied by other symptoms. Secondary amyloidosis is a complication in this group. The advances in the last few years has led to the identification of susceptible genes, new proteins, and characterising mechanisms and pathogenic routes that have led to an improvement in the diagnosis and establishing more effective treatments. Among these routes, are the changes in the inflammasome components, a group of cytoplasmic proteins that regulate the production of several inflammatory response mediators. The initial group of monogenic autoinflammatory diseases have increased in the last few years, due to including several polygenic hereditary diseases. PMID- 21596181 TI - [Syndrome CINCA/NOMID]. AB - CINCA/NOMID syndrome was first reported in 1981, identified as a new disease in 1987 and the main cause discovered in 2001, when mutations in the CIAS1 gene modifying the structure of the protein cryopirin were found in those patients (although other factors seem to play a role). Together with the major symptoms that characterized the syndrome, neurological, cutaneous and articular manifestations, others have been added which seem to be quite constant among CINCA/NOMID diagnosed patients: pre and perinatal symptoms, morfological changes, outbreaks of fever and biological abnormalities which reveal a persistent inflammatory background. The radiological studies have been able to identify the physis as the origin of the osteoarticular malformations seen in this syndrome. Diferential diagnosis includes diseases with similar onset at the neonatal period or infancy: systemic onset juvenile idiopathic athritis, periodic fever associated with mevalonate kinase deficiency, deficiency of IL-1 receptor antagonist (DIRA) and Muckle-Wells syndrome. PMID- 21596182 TI - [Syndrome of Muckle-Wells and autoinflammatory familiar syndrome induced by cold]. AB - Familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS) belong to the cryopyrin-associated periodic syndromes (CAPS) with CIAS1 gene mutations as a common molecular basis. Patients with FCAS have the least severe clinical phenotype but are characterized by the development of symptoms induced by a generalized exposure to cold appearing during the first months of childhood. It is important to make differential diagnosis between FCAS and acquired cold urticaria (ACU) and familial atypical cold urticaria (FACU). Muckle-Wells syndrome is characterized by recurrent fever and urticarial rash, progressive sensorineural deafness and the development of secondary amyloidosis, but it is not considered the most severe disease of this group. Sensorineural deafness and amyloidosis are the two major complications of MWS and determine poor prognosis of the disease. PMID- 21596183 TI - [Pathophysiological mechanisms underlying cryopyrin-associated periodic syndromes: genetic and molecular basis and the inflammasome]. AB - NLRP3 gene (formerly known as CIAS1) encodes for cryopyrin (Nalp3) protein, which belongs to the Nod-like family of innate immune receptors. Cryopyrin recruits different adaptor and effectors proteins into a cytosolic macromolecular complex termed Nalp3-inflammasome, which senses both several pathogen-associated and damage-associated molecular patterns as well as inorganic particles (asbestos, silica), and triggers innate immune and inflammatory responses. Gain-of-function NLRP3 mutations are the common molecular basis of cryopyrin-associated periodic syndromes (CAPS), which encompasses three clinical entities along a spectrum of disease severity (familial cold autoinflammatory syndrome, Muckle-Wells syndrome and CINCA-NOMID syndrome). This hypermorphic cryopyrin provokes an increased, unregulated secretion of different inflammatory cytokines (IL-1beta, IL-18, IL 33) in patients with CAPS, and in vivo administration of IL-1 blocking agents results in excellent therapeutic responses in these patients. PMID- 21596184 TI - [CAPS treatment]. AB - Non-steroidal anti-inflammatories, corticoids and antihistamines, as well as a great many other molecules, have classically been used to control the symptoms of cryopyrin-associated periodic syndromes (CAPS), with very few encouraging results. Knowledge of its genetic character, and its aetiopathogenesis associated with inflammasome and the production of interleukin-1 (IL-1) has led to the development of new therapeutic weapons that have not just obtained improvements of the symptoms and quality of life of the patients, but also managed to control the underlying inflammation. Results show that anakinra, an IL-1 receptor antagonist molecule, improved the clinical symptoms and the inflammatory markers of patients with CAPS has motivated research with other molecules directed against IL-1: rilonacept and canakinumab. It is likely that the use of these molecules could prevent the development of the late complications associated with chronic inflammation. PMID- 21596185 TI - [Canakinumab, a monoclonal antibody against IL-1beta, with potential utility in different inflammatory processes]. AB - Canakinumab is a fully human monoclonal antibody targeted at IL-1beta which has shown to be effective in the control the symptoms of patients affected by CAPS and other autoinflammatory diseases. Its effect is rapid and sustained. In clinical trials conducted up until now, the most common adverse effects reported with the use of this drug have been different types of infections, migraines and vertigo. PMID- 21596186 TI - [Science beyond calculations]. PMID- 21596187 TI - [Evaluation of cytokine levels and pulmonary function in patients undergoing coronary artery bypass graft]. AB - BACKGROUND AND OBJECTIVES: Systemic inflammatory response syndrome is commonly observed in coronary artery bypass grafts (CABG) with cardiopulmonary bypass (CB). The objective of this study was to evaluate the systemic and pulmonary levels of cytokines and their correlation with lung function in patients undergoing myocardial revascularization (MR) with CB. METHODS: This study was approved by the Institutional Ethics Committee, and 13 patients undergoing MR with CB were evaluated. After anesthetic induction and at the end of CB, plasma and bronchoalveolar lavage levels of IL-1beta, IL-6, IL-8, IL-10, and TNF-alpha were determined. The duration of CB and surgery, PaO(2)/FiO(2) ratio, alveolar arterial oxygen gradient (A-a gradient), shunt, and lung compliance were evaluated. Results were submitted to analysis of variance for repeated measurements (*p < 0.05) and Spearman's correlation coefficient. RESULTS: We observed increased levels of cytokines in plasma and bronchoalveolar lavage after CB and a direct relationship between the increase in IL-1beta and decrease in lung compliance (p = 0.0439), as well as the inverse relationship between the increase in IL-10 and a decrease in compliance (p = 0.0325). The increase in IL-6 was directly related to the duration of CB (p = 0.012), while the increase in IL 8 was directly related to the duration of surgery (p < 0.0001). Levels of interleukin-1beta, IL-8, and TNF-alpha in bronchoalveolar lavage were higher than in plasma. CONCLUSIONS: There is an increase in cytokine levels in plasma and bronchoalveolar lavage after CB, as well as a correlation between increased cytokine levels and CB duration and surgery and changes in lung compliance. PMID- 21596188 TI - [Association between the use of blood components and the five-year mortality after liver transplant]. AB - BACKGROUND AND OBJECTIVES: Liver transplant (LT) surgery is associated with significant bleeding in 20% of cases, and several authors have demonstrated the risks related to blood components. The objective of the present study was to evaluate the impact of using blood components during hospitalization in five-year survival of patients undergoing LT. METHODS: One hundred and thirteen patients were evaluated retrospectively. Several variables, including the use of blood components intraoperatively and throughout hospitalization, were categorized and evaluated by univariate analysis using Fisher's test. A level of significance of 5% was adopted. Results with p < 0.2 underwent multivariate analysis using multinomial logistic regression. RESULTS: Parenchymal diseases, preoperative renal dysfunction, and longer stay in hospital and ICU are associated with greater five-year mortality after LT (p < 0.05). Unlike the intraoperative use of blood components, the accumulated transfusion of packed red blood cell, frozen fresh plasma, and platelets during the entire hospitalization was associated with greater five-year mortality after liver transplantation (p < 0.01). CONCLUSIONS: This study emphasizes the relationship between the use of blood components during hospitalization and increased mortality in five years after LT. PMID- 21596189 TI - [Postoperative analgesia: comparing continuous epidural catheter infusion of local anesthetic and opioid and continuous wound catheter infusion of local anesthetic]. AB - BACKGROUND AND OBJECTIVES: Continuous wound infusion has been investigated as a method of postoperative pain control and its efficacy has been demonstrated when compared to saline infusion. The objective of this study was to compare the quality of postoperative analgesia, the use of opioids as rescue analgesia, patient satisfaction, and the incidence of complications between epidural catheter infusion of local anesthetic and opioids and continuous wound infusion of local anesthetic. METHODS: Thirty-eight patients undergoing elective laparotomy under general anesthesia, randomly divided into two groups, participated in this study. Group I (GI) received postoperative patient controlled epidural analgesia (PCEA) with continuous infusion of ropivacaine and fentanyl, while Group II (GII) receive postoperative patient-controlled continuous wound catheter infusion of ropivacaine. In the postoperative period, the following parameters were assessed: quality of analgesia through the Visual Analogue Scale; use of rescue opioids; and adverse effects driving patient satisfaction. RESULTS: Decreased pain at rest and with movements (p < 0.05) and lower consumption of rescue opioids (p < 0.05) were observed in GI in all intervals evaluated, as well as greater patient satisfaction in the post anesthesia care unit (PACU). The incidence of complications was similar in both groups except for pruritus which prevailed in GI between 6 (p < 0.05) and 24 (p < 0.001) postoperative hours. CONCLUSIONS: Postoperative analgesia with opioids and local anesthetics via PCEA was superior to the patient-controlled local anesthetic infusion into surgical wound. The incidence of side effects was similar in both groups. PMID- 21596190 TI - [Effects of sedation produced by the association of midazolam and ketamine s(+) on encephalographic variables]. AB - BACKGROUND AND OBJECTIVES: Ketamine S(+) is important in pain modulation in surgical patients. The objective of the present study was to evaluate the relationship between the levels of sedation produced by low doses of ketamine S(+), as well as encephalographic variables: BIS, SEF 95%, pEMG, suppression rate, and presence of burst-suppression. METHODS: Thirty patients of both sexes, aged 25-50 years, were randomized into three groups. Group G1 (10) received intravenous ketamine S(+) 0.050 mg,kg(-1); group G2 (10) intravenous ketamine S(+) 0.125 mg.kg(-1); and group G3 (10) intravenous ketamine S(+) 0.250 mg.kg( 1). All patients received 0.08 mg.kg(-1) of intravenous midazolam 10 minutes before administration of ketamine S(+). In each group, two moments were evaluated: M1, before ketamine S(+) administration; and M2, after ketamine S(+) administration. Sedation levels and encephalographic variables: BIS, SEF 95%, pEMG, suppression rate, and the presence of burst-suppression were evaluated in all patients before and after ketamine S(+) administration. ANOVA was used for repeated measurements and the p-value was adjusted for multiple comparisons by Tukey's test. RESULTS: A decrease in alertness-sedation scale scores was observed in all three groups in moment M2. Electroencephalographic variables showed significant variation in all three groups when moments M1 and M2 were compared, both in pEMG and BIS (p < 0.05). CONCLUSIONS: Sedation levels showed significant correlation with the increase in ketamine S(+) dosage. However, increased BIS levels may have reflected increased pEMG induced by ketamine S(+). PMID- 21596191 TI - [Atraumatic endotracheal tube for mechanical ventilation]. AB - BACKGROUND AND OBJECTIVES: Patients who need to stay under endotracheal intubation for long periods or when undergoing general anesthesia may develop tracheal lumen injuries due to pressure from distal cuff. In some cases, these injuries may evolve to stenosis or, occasionally, necrosis. The objective of this study was to present a modified endotracheal tube (METT) in which the cuff pressure is variable according to the cycle of mechanical ventilation (MV), which was tested on a lung simulator and animal model. METHODS: Two models of endotracheal tubes, a modified (METT) and a conventional (CETT), number 7.5 mm and 8.0 mm, were connected to a lung simulator in a mechanical ventilator adjusted with two tidal volumes (TV) of 10 and 15 mL.kg(-1) and a compliance of 60 mL.cmH(2)O to evaluate the ventilatory efficiency of METT. Both models were also compared in Large-White pigs under general anesthesia and MV for 48 consecutive hours. Subsequently, animals were sacrificed for histopathological analysis of their tracheas. RESULTS: Both METTs (#7.5 and 8.0) presented air leaks in lung simulator. The smallest air leak (13%) was observed in METT #7.5 with TV = 15 mL.kg(-1), while the largest air leak (32%) was observed in METT #8.0 with TV = 10 mL.kg(-1). Nevertheless, both METTs showed good efficiency on the lung simulator. In animals, on histopathological analysis of their tracheas, it was found that METT caused less trauma to the epithelium when compared to CETT. CONCLUSION: The use of a new model of ETT may decrease the risks of tracheal injury without hindering respiratory mechanics. PMID- 21596192 TI - [Non-invasive monitoring based on bioreactance reveals significant hemodynamic instability during elective cesarean delivery under spinal anesthesia]. AB - BACKGROUND AND OBJECTIVES: Blood pressure monitoring offers a limited understanding of the hemodynamic consequences of spinal anesthesia for cesarean delivery. The purpose of this study was to assess, with the aid of a non-invasive cardiac output monitor based on bioreactance, the hemodynamic changes during elective cesarean delivery under spinal anesthesia in which intermittent boluses of phenylephrine were used to prevent and treat hypotension. METHODS: This observational study was conducted with the Research Ethics Board approval, and all participants provided written informed consent. Healthy patients undergoing elective cesarean delivery under spinal anesthesia were enrolled. Intermittent boluses of phenylephrine were administered in an attempt to maintain systolic blood pressure at baseline levels, and patients were assessed with a non-invasive cardiac output monitor based on bioreactance. Hemodynamic data was collected continuously at baseline, and during the postspinal and postdelivery periods. Data was analyzed using a mixed model ANOVA, and a p < 0.05 was considered significant. RESULTS: Systolic blood pressure was maintained within 79.2 +/- 14.2 and 105.8 +/- 10.0 percent of baseline during the postspinal period, and 78.4 +/- 11.3 and 100.9 +/- 10.7 percent of baseline in the postdelivery period (mean +/- SD) There were significant fluctuations in systolic blood pressure, heart rate, and cardiac output during the postspinal period, and significant fluctuations in systolic blood pressure and cardiac output in the postdelivery period. CONCLUSIONS: A new non-invasive monitor based on bioreactance reveals significant hemodynamic fluctuations during cesarean delivery under spinal anesthesia, despite attempts to maintain blood pressure at baseline levels with intermittent boluses of phenylephrine. PMID- 21596193 TI - [Influence of work-related variables on quality of life of anesthesiologists in the city of Joao Pessoa]. AB - BACKGROUND AND OBJECTIVES: Anesthesiologists work under great pressure because they are dealing with disease, pain, suffering, and death. Exposure of these professionals to the effects of fatigue and physical, chemical, and biological factors can cause physical and psychological disorders. The objective of the present study was to understand the influences of work-related variables on anesthesiologists' quality of life in the city of Joao Pessoa. METHODS: This is a descriptive, transversal study with a quantitative approach, with 83 physicians who answered a generic questionnaire proposed by the World Health Organization to evaluate quality of life (QOL). Data was analyzed by descriptive statistics and mean comparison tests. The level of significance adopted for analyses was 5%. RESULTS: Analysis demonstrated that work-related variables, i.e., the total hours of the weekly on-call schedule, working hours, sleep patterns after shifts and at shift intervals, and physical activity are all correlated with QOL. A statistically significant difference was seen between the domains of QOL scale and the number of working hours. On the other hand, monthly income influences QOL (p < 0.05) only in the environmental domain. CONCLUSIONS: It was observed that work-related variables had a significant correlation with QOL. In addition to expressive statistical difference between the domains of QOL scale and the number of working hours, the same divergence was also observed regarding the environmental domain and monthly income. PMID- 21596194 TI - [Transesophageal echocardiography in Ross procedure]. AB - BACKGROUND AND OBJECTIVES: Ross procedure is one of the surgical procedures for correction of severe congenital aortic insufficiency. Intraoperative transesophageal echocardiography is essential for optimal surgical evaluation. Furthermore, it is able to assess the blood volume profile and the need for administration of vasoactive drugs during surgery. CASE REPORT: This is a 15-year old teenager with severe congenital aortic insufficiency scheduled for corrective surgery with the Ross procedure. In the operating room, the patient was monitored with electrocardiography and pulse oximeter, and he was premedicated with midazolam. After the administration of premedication, the left radial artery and right subclavian vein were punctured. Anesthetic induction was accomplished with etomidate, cisatracurium, and fentanyl while maintenance was achieved with sevoflurane. The probe of the transesophageal echocardiography equipment was introduced immediately after tracheal intubation, showing increased left ventricle; severe aortic insufficiency due to coaptation failure of the three leaflets; and competent pulmonary valve without anatomical and physiological changes. Intercurrences were not observed during surgery, with 120 minutes of extracorporeal circulation (ECC) and 8 hours of surgery. Immediately after removal from ECC the transesophageal echocardiography showed good function of both the auto- and homograft; however, the right ventricle presented hypocontractility, which was corrected with a bolus of milrinone followed by continuous infusion. The patient was transferred to the postanesthetic recovery unit intubated and hemodynamically stable with infusion of milrinone and sodium nitroprusside. CONCLUSIONS: Ross procedure is one of the techniques for correction of congenital aortic insufficiency in which transesophageal echocardiography guides the surgeon precisely on the physiological and anatomical status of vascular grafts. PMID- 21596195 TI - [Failure of self-inflating manual resuscitator due to the presence of dried pulmonary secretions]. AB - BACKGROUND AND OBJECTIVES: Self-inflating manual resuscitators (SIMR) are devices used to ventilate patients with ventilatory needs. These devices consist of a set of valves that work sequentially, and changes in their function may be harmful to patients. CASE REPORT: During the use of SIMR, it was observed that the valve remained fixed due to the presence of dried pulmonary secretion, which made it impossible to ventilate the patient, but not manipulate the compressible unit. CONCLUSIONS: This situation reaffirms that the resuscitator is a device that should be used by trained professionals because, although changes in functioning are rare, they can be potentially fatal. PMID- 21596196 TI - [Post-dural headache with seven months duration: case report]. AB - BACKGROUND AND OBJECTIVES: Post-dural puncture headache is a possible and expected complication in a small percentage of cases after spinal anesthesia. The objective of the current report was to describe the therapeutic conduct in a case of post-dural puncture headache with seven months of evolution. CASE REPORT: A 40 year-old healthy female who complained of headache for seven months, which began after spinal anesthesia. She reported that some analgesics and decubitus position provided partial pain relief. An epidural blood patch was performed, with complete resolution of pain. She was discharged without complaints. CONCLUSIONS: This case demonstrated that the epidural blood patch was effective in the treatment of chronic post-dural puncture headache in a case with seven-month evolution. PMID- 21596197 TI - [Latex-induced anaphylactic reaction in a patient undergoing open appendectomy. Case report]. AB - BACKGROUND AND OBJECTIVE: Despite the increase of latex allergy in general population, severe anaphylactic events during some surgical procedures are still rare; however, they are associated with increased morbidity and mortality. Prevention, diagnosis, treatment, and follow-up of patients affected by this event represent a challenge for anesthesiologists. The objective of this report was to describe a case of severe latex induced anaphylactic reaction and discuss its diagnosis and treatment. CASE REPORT: This is a 39-year-old Caucasian female patient, with a diagnostic suspicion of appendicitis, who underwent an emergency surgery under spinal anesthesia. Approximately 30 minutes after beginning the surgery, the patient developed an anaphylactic reaction with cardiorespiratory arrest, which was reversed after treatment. Possible causative agents were isolated and, posteriorly, the patient was transferred to the intensive care unit, evolving without sequelae. Latex-specific IgE-RAST (Radioallergosorbent Test) was positive. The patient was referred to an allergist for follow-up. CONCLUSIONS: Anesthesiologists should focus on patient's history, even in urgent procedures, being aware of the limitations arising on these situations. The prognosis of anaphylaxis depends on prompt initiation of adequate treatment; diagnosis is not limited to the event occasion, but to the determination of the causative factor. Creating the means of following-up these patients, similar to other international centers, seems to be the example to be followed. PMID- 21596198 TI - [Anesthesia and rheumatoid arthritis]. AB - BACKGROUND AND OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology. It is known that RA patients have a reduced life expectancy when compared with the general population. Rheumatic diseases are numerous and occur with high variability; some of them develop very rapidly while others occur chronically provoking disability throughout life. Anesthetic risks in osteoarticular disorders involve not only the mechanical deformations caused by the disease, but also the cardiovascular, respiratory, renal, and digestive systems. CONTENTS: The purpose of this review was to stress the importance of stages in disease process that may affect anesthesia control before, during, and after surgery, highlighting the authors' experience in a retrospective review of patients with juvenile rheumatoid arthritis (JRA) undergoing placement of orthopedic prosthesis with emphasis on intubation techniques. CONCLUSIONS: Rheumatoid arthritis patients can present a number of complex problems for the anesthesiologist. This requires careful preoperative evaluation; anesthesia requires experience with the technique; and postoperative care should be judiciously chosen to meet the specific needs of the patient. The procedure requires effective communication among surgeon, rheumatologist and anesthesiologist so each member of the multidisciplinary team can contribute with his/her expertise in order to better benefit the patient. PMID- 21596199 TI - [Pain and the protagonism of women in parturition]. AB - BACKGROUND AND OBJECTIVES: To understand through the theory of social representations the sociocultural dimensions of pain and its impact on the protagonism of women in parturition. METHODS: In this investigation, we used a qualitative methodology with the theoretical reference of phenomenology and the theory of social representation. Forty-five semi-structured interviews were conducted with gravidas in public and private health services of Joinville, SC, Brazil, who had at least four prenatal visits and were in the third trimester of pregnancy. RESULTS: From analysis of content reported in interviews, three empirical categories were formed: fears and concerns, experience, and sociocultural influence, which allowed the building of three interpretative categories: biomedical model, lack of information, and the role of women in the decision regarding the mode of delivery. The findings reported here indicate pain as one of the elements that form female social representations in parturition. It was observed that pain influences the behavior of gravidas from fear and becomes the genesis of other aversive feelings and concerns that involve parturition. CONCLUSIONS: In this context, pain represented one of the main building blocks of female social representations on parturition, contributing to the ascending curve of cesarean section indices in Brazil. PMID- 21596200 TI - Racial differences in the prevalence of antenatal depression. AB - OBJECTIVE: This study examined whether there were racial/ethnic differences in the prevalence of antenatal depression based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnostic criteria in a community-based sample of pregnant women. METHOD: Data were drawn from an ongoing registry of pregnant women receiving prenatal care at a university obstetric clinic from January 2004 through March 2010 (N =1997). Logistic regression models adjusting for sociodemographic, psychiatric, behavioral and clinical characteristics were used to examine racial/ethnic differences in antenatal depression as measured by the Patient Health Questionnaire. RESULTS: Overall, 5.1% of the sample reported antenatal depression. Blacks and Asian/Pacific Islanders were at increased risk for antenatal depression compared to non-Hispanic White women. This increased risk of antenatal depression among Blacks and Asian/Pacific Islanders remained after adjustment for a variety of risk factors. CONCLUSION: Results suggest the importance of race/ethnicity as a risk factor for antenatal depression. Prevention and treatment strategies geared toward the mental health needs of Black and Asian/Pacific Islander women are needed to reduce the racial/ethnic disparities in antenatal depression. PMID- 21596201 TI - The long-term trajectory of depression among Latinos in primary care and its relationship to depression care disparities. AB - OBJECTIVE: Lower use of medication treatment, poorer doctor-patient communication (DPC) and depression stigma are key contributors to mental healthcare disparities among Latinos with depression. The current study investigated the relationship between these key variables and the long-term trajectory of depression in primary care among Latinos. METHOD: Participants (N=220) were Latinos presenting to primary care who screened positive for depression. A repeated measures design was used to assess participants at baseline and 6, 25 and 30 months. Repeated measures included depression (Patient Health Questionnaire-9), self-reported quality of DPC and stigma pertaining to antidepressants. Using growth curve modeling, participants' depressive symptom trajectories were examined for a 30 month period. Self-reported utilization of antidepressants, DPC and antidepressant stigma were examined as predictors of the depressive symptom trajectory. In addition, rates of depression improvement/remission and recurrence/relapse were examined. RESULTS: Improvement/remission was experienced by 69.4% of participants during a 30-month period. Among those who improved/remitted at 6 or 25 months, 63.4% maintained that improvement/remission by 30 months. The long-term trajectory of depressive symptoms demonstrated a significant positive association with antidepressant stigma and significant negative associations with use of antidepressant treatment and quality DPC. CONCLUSIONS: While relapse/recurrence is common, most Latinos in this study experienced improvement in depression over 30 months. For many, there is a considerable time to reach improvement/remission. Also, these findings confirm the significance of antidepressant underutilization, DPC and stigma in the long term outcome of depression among Latinos in primary care. PMID- 21596202 TI - The prevalence of restless legs syndrome in adult Saudis attending primary health care. AB - OBJECTIVE: This study assessed the prevalence and severity of restless leg syndrome (RLS) among patients attending primary health care (PHC) facilities. METHODS: We interviewed 1303 consecutive patients attending PHC face-to-face using the International Restless Legs Syndrome Study Group (IRLSSG) criteria. We assessed the severity of RLS using the IRLSSG severity scale for RLS. RESULTS: The prevalence of RLS in our sample was 5.2% and was highest among participants between 45 and 60 years of age. The overall prevalence was roughly equal between males and females; however, RLS was more prevalent in females older than 45 years compared to males in the same age group. Eight participants (11.8%) reported mild symptoms, 29 (42.6%) moderate, 29 (42.6%) severe, and 2 (2.9%) very severe. None of the participants had been diagnosed or treated for RLS. CONCLUSION: Restless leg syndrome is common among Saudis (Arabs). Our study supports the findings of reports in other countries demonstrating that primary care physicians do not often recognize RLS. PMID- 21596203 TI - Racial and ethnic differences in diabetes mellitus among people with and without psychiatric disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - OBJECTIVE: This study examined racial/ethnic differences in the prevalence of diabetes mellitus in a nationally representative sample of adults with and without common psychiatric disorders. METHOD: Data were drawn from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (N=34,653). Logistic regression models adjusting for sociodemographic variables and diabetes risk factors were used to examine racial/ethnic differences in 12-month prevalence rates of diabetes by psychiatric status. RESULTS: Among people without psychiatric disorders, African Americans, Hispanics and American Indians/Alaska Natives, but not Asians/Pacific Islanders, had significantly higher rates of diabetes than non-Hispanic whites even after adjusting for sociodemographic variables and diabetes risk factors. In the presence of psychiatric disorders, these health disparities persisted for African Americans and Hispanics, but not for American Indians/Alaska Natives. No significant interactions between race/ethnicity and psychiatric disorders in the odds of diabetes were found across any group. CONCLUSION: Policies and services that support culturally appropriate prevention and treatment strategies are needed to reduce racial/ethnic disparities in diabetes among people with and without psychiatric disabilities. PMID- 21596204 TI - Associations between posttraumatic stress disorder and hemoglobin A1(C) in low income minority patients with diabetes. AB - OBJECTIVE: Posttraumatic Stress Disorder (PTSD) is prevalent among low-income minorities and is associated with poorer health. However, the association between PTSD and hemoglobin A1(C) (A1(C)) among patients with diabetes has not been fully described. The objective of this cross-sectional study was to evaluate associations between PTSD and A1(C) among low-income minorities with diabetes. METHOD: Adults with diabetes were recruited from a network of primary care clinics. Data were obtained from surveys and electronic medical records. Lifetime PTSD symptoms were assessed using the Structured Clinical Interview-DSM-IV and depressive symptoms with the Patient Health Questionnaire-9. A1(C) was obtained from chart review. RESULTS: Of 103 adults analyzed, 12% had lifetime full PTSD and 12% had subthreshold PTSD. On backward stepwise logistic regression, patients with any PTSD symptoms were significantly more likely to have an A1(C) >7% compared to patients without symptoms (OR(adj) 2.98, 95% CI 1.04-8.52, P=.04). An A1(C) >7% also was associated with an interaction between PTSD symptoms and longer diabetes duration (P<.05). CONCLUSION: In this cohort of low-income minorities with diabetes, lifetime PTSD symptoms were significantly associated with an A1(C) >7%. PMID- 21596205 TI - Enhancing the population impact of collaborative care interventions: mixed method development and implementation of stepped care targeting posttraumatic stress disorder and related comorbidities after acute trauma. AB - OBJECTIVE: The objective of the study was to develop and implement a stepped collaborative care intervention targeting posttraumatic stress disorder (PTSD) and related comorbidities to enhance the population impact of early trauma focused interventions. METHOD: We describe the design and implementation of the Trauma Survivors Outcomes and Support study. An interdisciplinary treatment development team was composed of trauma surgical, clinical psychiatric and mental health services "change agents" who spanned the boundaries between frontline trauma center clinical care and acute care policy. Mixed method clinical epidemiologic and clinical ethnographic studies informed the development of PTSD screening and intervention procedures. RESULTS: Two hundred seven acutely injured trauma survivors with high early PTSD symptom levels were randomized into the study. The stepped collaborative care model integrated care management (i.e., posttraumatic concern elicitation and amelioration, motivational interviewing and behavioral activation) with cognitive behavioral therapy and pharmacotherapy targeting PTSD. The model was feasibly implemented by frontline acute care masters in social work and nurse practioner providers. CONCLUSIONS: Stepped care protocols targeting PTSD may enhance the population impact of early interventions developed for survivors of individual and mass trauma by extending the reach of collaborative care interventions to acute care medical settings and other nonspecialty posttraumatic contexts. PMID- 21596206 TI - Posttraumatic stress disorder is a risk factor for metabolic syndrome in an impoverished urban population. AB - OBJECTIVE: Metabolic syndrome is associated with elevated risk for cardiovascular disease and diabetes and has increased prevalence in low-income African Americans, which constitutes a significant health disparity. The mechanisms responsible for this disparity remain unclear; the current study investigated the relationship between posttraumatic stress disorder (PTSD) and metabolic syndrome. METHOD: We assessed childhood and adult trauma history, major depressive disorder, PTSD and the components of metabolic syndrome in an urban population. We recruited 245 low-socioeconomic-status, primarily African American subjects from general medical clinics in an inner-city hospital. RESULTS: Trauma exposure was extremely prevalent, with 90.6% of subjects reporting at least one significant trauma and 18.8% of subjects meeting criteria for current PTSD. Metabolic syndrome was also prevalent in this population (33.2%), with significantly higher rates among patients with current PTSD (47.8%, P<.05). After controlling for demographics, smoking history, antipsychotic use, depression and exercise, current PTSD remained the only significant predictor of metabolic syndrome (P=.006). CONCLUSIONS: PTSD is associated with increased rates of metabolic syndrome within a traumatized, impoverished urban population. Further studies should investigate if PTSD treatment may reduce the rates of metabolic syndrome, improve overall health outcomes and decrease health care disparities in minority populations. PMID- 21596208 TI - Catastrophizing, depression and pain-related disability. AB - OBJECTIVE: The objective of the study was to examine catastrophizing, depression and their interactive effects in predicting disability in patients with chronic pain. METHOD: A battery of questionnaires was mailed to primary care patients in a large integrated health care delivery system. The Patient Health Questionnaire was used to assess major depression, the Coping Strategies Questionnaire assessed catastrophizing and the Graded Chronic Pain Scale was used to assess pain intensity and two measures of disability, including self-report of pain interference and days missed from usual activities. Patient medical records were used to assess severe medical illness. Of the 5808 respondents, 2618 met criteria for chronic pain. Multiple regression analyses, covarying for age, gender, severe medical illness and pain intensity, estimated the main and interactive effects of catastrophic thinking and depression on two measures of pain-related disability. RESULTS: Both catastrophic thinking and depression were statistically significant predictors of both measures of pain-related disability, with larger effect sizes observed for catastrophic thinking. CONCLUSIONS: Routine assessment of both catastrophic thinking and depression is important in the treatment of chronic pain patients, and modification of these factors may reduce disability and increase the ability of chronic pain patients to participate in daily life activity. PMID- 21596207 TI - Depressive disorders and panic attacks in women with bladder pain syndrome/interstitial cystitis: a population-based sample. AB - OBJECTIVE: We report the population prevalence of probable depressive disorders and current panic attacks in women with bladder pain syndrome/interstitial cystitis (BPS/IC) symptoms and describe their characteristics and access care. METHOD: We conducted a telephone screening of 146,231 households and telephone interviews with women with BPS/IC symptoms. A weighted probability sample of 1469 women who met the criteria for BPS/IC was identified. Measures of BPS/IC severity, depressive symptoms, panic attacks and treatment utilization were administered. T and chi(2) tests were used to examine differences between groups. RESULTS: Over one third of the sample (n=536) had a probable diagnosis of depression, and 52% (n=776) reported recent panic attacks. Women with a probable diagnosis of depression or current panic attacks reported worse functioning and increased pain and were less likely to work because of bladder pain. CONCLUSIONS: In this community-based sample, rates of probable current depression and panic attacks are high, and there is considerable unmet need for treatment. These findings suggest that clinicians should be alert to complaints of bladder pain in patients seeking treatment for depressive or anxiety disorders and to complaints of emotional or personal problems in patients seeking treatment for painful bladder symptoms. PMID- 21596210 TI - "Well it's like someone at the other end cares about you." A qualitative study exploring the views of users and providers of care of contact-based interventions following self-harm. AB - OBJECTIVE: We investigated the views of service users and staff regarding contact based interventions (e.g., letters, telephone calls or crisis cards) following self-harm. METHOD: Self-harm patients recently discharged from an emergency department were selected using purposive sampling (n=11). Clinical staff from relevant service areas and voluntary staff took part in a focus group and individual interviews (n=10). Interviews were transcribed and thematic analyses were conducted using methods of constant comparison to ensure that emergent themes remained grounded in the data. RESULTS: Most service users and staff participants identified the period of time directly after discharge as the time of greatest need. A contact-based intervention was viewed by service users as a gesture of caring, which counteracted feelings of loneliness. Delivery by mental health specialists was preferred, initially by phone, but letters were considered helpful later. The intervention should be both genuine in delivery and linked to current services. Potential barriers included means of accessing the service and threats to privacy. CONCLUSION: The findings suggest that an appropriate design for an intervention might be the provision of an information leaflet, telephone calls (soon after discharge), then letters (offering continuity of contact). Aspects of value and concern expressed by service users should be helpful to clinicians and service providers. PMID- 21596209 TI - Association between the Malnutrition-Inflammation Score and depressive symptoms in kidney transplanted patients. AB - OBJECTIVE: Depressive symptoms and the Malnutrition-Inflammation Complex Syndrome (MICS) are prevalent in patients with chronic kidney disease. The complex relationship between MICS and depression has never been studied in kidney transplanted (Tx) patients. Here we evaluate the association between the Malnutrition-Inflammation Score (MIS) (Kalantar score) and depressive symptoms in Tx patients. METHODS: Cross-sectional data of 973 prevalent Tx patients were analyzed. Sociodemographic and anthropometric characteristics and clinical and laboratory data were collected, and serum levels of inflammatory markers [C reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF alpha)] were measured. The Center for Epidemiologic Studies-Depression (CES-D) scale, the MIS and the Charlson Comorbidity Index (CCI) were computed. We used linear regression analysis to examine whether the relationship between MIS and CES-D score is independent from sociodemographic and laboratory parameters. RESULTS: The CES-D score, corrected for age, gender and estimated glomerular filtration rate weakly but significantly correlated with serum IL-6 and the CCI (0.124 and 0.103, respectively; P<.05 for both) and marginally significantly with CRP (0.06; P=.06). We found a moderate correlation between CES-D score and MIS (0.262; P<.001). In a multivariable linear regression model, the MIS was independently associated with the CES-D score (B=0.110; P<.001). CONCLUSIONS: The MIS was significantly associated with depressive symptoms after adjusting for important covariables in patients after renal transplantation. PMID- 21596211 TI - The association of traumatic experiences and posttraumatic stress disorder with health care utilization in the elderly - a German population based study. AB - OBJECTIVE: Traumatic experiences (TE) and posttraumatic stress disorder (PTSD) are related to impaired mental and physical health and to increased health care utilization (HCU). However, general population studies simultaneously investigating the association of TE and PTSD with HCU in the elderly are lacking to date. METHODS: A representative sample of 1456 people aged 60-85 years from the German general population was examined using self-rating instruments for TE, PTSD, HCU and physical health (PH). RESULTS: In regression analyses including age and gender, TE are significantly associated with increased probability of visits to specialists and to mental health professionals, and of hospitalization, but not with the frequency of HCU. Current PTSD is significantly associated with increased probability of visits to mental health professionals and of hospitalization, and with increased frequency of general practitioner visits, of specialist visits, and of visits to mental health professionals. In two mediation models, the relationships between TE and PTSD, respectively, with HCU were weakened but remained significant after including PTSD and physical morbidity, respectively. CONCLUSION: These results indicate that both trauma and PTSD are positively associated to some indicators of HCU. Posttraumatic stress disorder has a weak mediating role in the association of TE and HCU. Physical health has a weak mediating role in the association of PTSD and HCU. PMID- 21596213 TI - The base rates and factors associated with reported access to firearms in psychiatric inpatients. AB - OBJECTIVE: The aim of this study was to define whether specific patient demographic groups, diagnoses or other factors are associated with psychiatric inpatients reporting firearms access. METHODS: A retrospective medical records review study was conducted using information on access to firearms from electronic medical records for all patients 16 years and older admitted between July 2007 and May 2008 at the Mayo Clinic Psychiatric Hospital in Rochester, MN. Data were obtained only on patients providing authorization for record review. Data were analyzed using univariate and multivariate logistic regression analyses accounting for gender, diagnostic groups, comorbid substance use, history of suicide attempts and family history of suicide/suicide attempts. RESULTS: Seventy four percent (1169/1580) of patients provided research authorization. The ratio of men to women was identical in both research and nonresearch authorization groups. There were 14.6% of inpatients who reported firearms access. In univariate analysis, men were more likely (P<.0001) to report access than women, and a history of previous suicide attempt(s) was associated with decreased access (P=.02). Multiple logistic regression analyses controlling for other factors found females and patients with history of previous suicide attempt(s) less likely to report access, while patients with a family history of suicide or suicide attempts reported increased firearms access. Diagnostic groups were not associated with access on univariate or multiple logistic regression analyses. CONCLUSIONS: Men and inpatients with a family history of suicide/suicide attempts were more likely to report firearms access. Clinicians should develop standardized systems of identification of firearms access and provide guidance on removal. PMID- 21596212 TI - Is it possible to assess subjective well-being among bipolar inpatients? An 18 week follow-up study. AB - OBJECTIVE: The study evaluates the association between subjective well-being and psychopathology in bipolar inpatients at the time of hospitalization and during a follow-up period. METHOD: One hundred twenty consecutive inpatients with a diagnosis of bipolar affective disorder were studied on admission (T0), at discharge (T1) and every 6 weeks for 18 weeks after hospitalization. The Young's Mania Rating Scale (YMRS) and the Hamilton Rating Scale for Depression (HAM-D) were used to determine affective symptoms, while subjective well-being was assessed by subjective well-being under neuroleptic (SWN). Associations between SWN and HAM-D or YMRS scores and between their changes were analyzed across the different time points by using Pearson correlation coefficients. Linear regression models were constructed using SWN as the dependent variable and demographic and clinical characteristics as possible predictors. RESULTS: At baseline, depression explained 24% and mania explained an additional 16% of baseline SWN variance. Changes in SWN and HAM-D total score displayed an inverse correlation during hospitalization and follow-up. End point severity of depression was associated with the end point SWN total score explaining additional 26% of SWN total score variance, whereas severity of mania was inversely associated with SWN total score. CONCLUSION: Data of this study provide further support for the need to consider the subjective well-being as a personal variable associated to psychopathological state in bipolar patients. However, results seem to be in line with authors who suggest to use other subjective quality of life scales in acute mania. PMID- 21596214 TI - Clinical correlates of worsening in obsessive-compulsive symptoms during pregnancy. AB - This study examined clinical factors related to worsening of obsessive-compulsive disorder (OCD) in pregnant women. For comorbid diagnoses at the onset of pregnancy and frequency of several obsessive-compulsive symptoms, there was a significant difference between women whose OCD worsened during the pregnancy and those in whom the OCD did not worsen. PMID- 21596215 TI - New-age patient communications through social networks. AB - Suicide prevention continues to be a significant clinical challenge in the care of psychiatric patients, particularly among youth. New patterns of interactions and communications using online social networks create opportunities for persons to indicate their mood, their opinions, and also to express ideation and plans about suicide. We report a case of a suicide attempt and how communications through online social networks initiated treatment and affected its outcome. We discuss advantages and challenges to clinicians regarding use social networks and electronic communication in patient care. PMID- 21596216 TI - Decreased thyroid function in Korean women with bipolar disorder receiving valproic acid. AB - We report here two adult female patients with bipolar disorder who developed abnormal thyroid function after short-or long-term administration of valproic acid (VPA). The first patient developed sick euthyroid syndrome (relative to her pretreatment thyroid levels) after only 2 months of treatment with VPA and quetiapine. The second patient, who had no pretreatment medical history including thyroid disease, developed hypothyroidism after several years of treatment with VPA and quetiapine. PMID- 21596217 TI - Paralytic ileus requiring hospitalization secondary to high-dose antipsychotic polypharmacy and benztropine. AB - Ileus can result from the combined activity of antipsychotic and anticholinergic medications. Despite frequent use, case reports in the literature are sparse. We present a patient who developed a paralytic ileus requiring extended hospitalization. Providers should minimize antipsychotic and concurrent anticholinergic medications, consider prophylactic bowel regimens and monitor for constipation. PMID- 21596218 TI - A manic episode in a 64-year-old man: an adverse effect of varenicline. AB - Varenicline is a novel treatment for smoking cessation. However, it has not been well studied in patients with medical and psychiatric comorbidity. We report a case of an acute manic episode in a 64-year-old man with a history of bipolar disorder post stroke, who was started on varenicline. This case demonstrates the importance of monitoring neuropsychiatric adverse drug reactions after the start of varenicline therapy in patients with a current or past history of mental illness. PMID- 21596219 TI - Rapid identification of community-associated methicillin-resistant Staphylococcus aureus by Fourier transform infrared spectroscopy. AB - The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) carrying Panton-Valentine leukocidin is a worldwide problem. Their identification is based currently on costly and complicated molecular methods. This article describes a simple method for differentiating CA-MRSA from hospital associated (HA) epidemic MRSA pulsed-field gel electrophoresis types using Fourier transform infrared (FTIR) spectroscopy. The 47 CA-MRSA isolates included 3 Southwest Pacific (resembling USA1100), 24 CMRSA7 (resembling USA400/MW2), 19 CMRSA10 (resembling USA300), and 1 European ST80, while HA-MRSA were represented by 27, 16, 11, 15, 7, and 8 Canadian epidemic isolates CMRSA1 through CMRSA6 respectively, plus 25 nontyped Canadian HA-MRSA. Principal component analysis (PCA), self-organized maps (SOMs), and the K-nearest neighbor (KNN) method were used to cluster the isolates based on chemometric analysis of FTIR spectra of dried films of stationary-phase cells grown on Que-Bact(r) Universal Medium No. 2 (Quelab Laboratories, Montreal, QC, Canada). First-derivative normalized data from a single narrow spectral region (1361-1236 cm(-1), suggesting differences in protein amide III and nucleic acid phosphodiester contents) allowed 98% correct classification by KNN, 93% by SOMs, and 92% by PCA. FTIR spectroscopic analysis of cells grown on Que-Bact(r) Universal Medium No. 2 offers a rapid and simple alternative to molecular methods for routine identification of CA-MRSA epidemic isolates. PMID- 21596220 TI - Characteristics and outcomes of Fusobacterium nucleatum bacteremia--a 6-year experience at a tertiary care hospital in northern Taiwan. AB - Fusobacterium nucleatum bacteremia is critical and not well defined. To identify the clinical characteristics and outcomes, we conducted a retrospective review of hospitalized patients from January 2004 to December 2009 at a tertiary center in northern Taiwan. Fifty-seven patients were enrolled. The mean age was 58.1 years, and the mean Pitt bacteremia score was 4.7. Males predominated (59.6%), and the overall 30-day mortality rate was up to 47.4%. Malignancy was the major comorbidity (26/57, 45.6%), especially oropharyngeal and gastrointestinal cancers (19/26, 73.1%). Pneumonia (17/57, 29.8%) was the most common presentation with high rates of respiratory failure (15/17, 88.2%) and mortality (11/17, 64.7%), followed by intra-abdominal infections (7/57, 12.3%). In multivariate analysis, higher Pitt bacteremia score, nosocomial infection, anemia, and intensive care unit stay were the independent factors for 30-day mortality. Nosocomial F. nucleatum bacteremia was a significant mortality predictor independent to other parameters of disease severities. PMID- 21596221 TI - First identification of methicillin-resistant Staphylococcus aureus MLST types ST5 and ST45 and SCCmec types IV and Vt by multiplex PCR during an outbreak in a respiratory care ward in central Taiwan. AB - We used molecular typing methods to investigate an outbreak of methicillin resistant Staphylococcus aureus (MRSA) infections in a respiratory care ward in Taiwan. From March to June 2006, the incidence of MRSA infection increased 3.75 fold. The overall carrier rates among the health care workers (HCWs) were 31.3% (total S. aureus), 16.4% (MRSA), and 14.9% (methicillin-sensitive SA, MSSA). Pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), antibiograms derived from susceptibility testing of MRSA isolates, and multiplex polymerase chain reaction (PCR) provided strong epidemiologic and microbiologic evidence that the outbreak of MRSA infections at our hospital was linked to the same PFGE pulsotype A SCCmec type II, pvl-negative, MLST ST5 strain of MRSA isolated from seven HCWs and five patients. The outbreak was controlled by application of topical fucidin ointment to the anterior nares in all colonized HCWs. Multiplex PCR combined with PFGE and MLST is a feasible method for outbreak investigations in routine clinical laboratories. PMID- 21596222 TI - Evaluation of automated repetitive-sequence-based PCR (DiversiLab) compared to PCR ribotyping for rapid molecular typing of community- and nosocomial-acquired Clostridium difficile. AB - Automated repetitive PCR (rep-PCR; DiversiLab) was compared to PCR ribotyping of the 16S-23S RNA intergenic spacer of Clostridium difficile (CD) as the "gold standard" method for CD typing. PCR products were separated on DiversiLab LabChips (bioMerieux, St. Laurent, Quebec, Canada) utilizing a 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA) operating the DiversiLab v1.4 assay. Bioanalyzer data were exported to a secure DiversiLab website and analyzed with DiversiLab v3.4 software. Replicability of each method was verified by confirming that the 5 CD reference strains (RS) formed distinct clusters (CD4, CD6, VL0047, VL0013 [ribotype 027], VL0018 [ribotype 001]) by both typing methods. Ninety randomly selected clinical isolates (CS) were analyzed by both methods: 49 from community-acquired and 41 from hospital-acquired cases. A similarity index (SI) of >=90% was used to define clusters when comparing the known RS cluster to the PCR ribotyping and rep-PCR patterns of CS. Fourteen different PCR-ribotype clusters were identified, but most CS formed 4 major clusters (i.e., CD4 [15/90; 17%], CD6 [17%], 027 [12%], and 001 [9%]). A total of 7 rep-PCR types were identified, but most CS formed 2 major rep-PCR clusters (i.e., CD4 [29/90; 32%] and CD6 [23%]); several PCR ribotypes occurred within a single rep-PCR cluster. Rep-PCR did not distinguish 027 or 001 isolates; i) 027 RS strain did not cluster, ii) eleven 027 CS strains clustered as CD4, iii) no 027 CS strains clustered with the 027 RS, and iv) only 2 001 CS clustered with the RS. Agreement between the PCR-ribotype and rep-PCR clusters only occurred for 35/90 (39%) of the CS using a rep-PCR SI of >=90%. Rep-PCR time to results was similar, but the annual costs of routinely using this method are 32% higher than PCR ribotyping. Routine use of rep-PCR for CD typing is limited by its lack of definitive separation of the hypertoxigenic 027 or 001 outbreak CD strains. PMID- 21596223 TI - Recovery of Legionella species from water samples using an internal method based on ISO 11731: suggestions for revision and implementation. AB - The study aim was to determine retrospectively whether the parallel use of 2 media [buffered charcoal yeast extract (BCYE) and medium of Wadowsky and Yee (MWY)] to isolate Legionella spp. from water samples taken from hospital water supply systems increased the sensitivity of the culture method as compared with methods/protocols in which only seeding on a selective medium is used. We analyzed the results obtained from 931 positive water samples. In 484 of the 931 positive water samples, Legionella spp. was isolated in the presence of other microorganisms; in 83% (400/484), we used MWY to count suspected colonies, which gave a lower number of unreadable plates. In the 447 samples containing only Legionella spp., the highest frequency of positive samples (93%, 418/447) was obtained with BCYE, whereas seeding on MWY yielded 78% (348/447) (P < 0.001). Evaluation of the influence of the media on the Legionella spp. counts obtained by the 2 media showed that BCYE agar produced significantly higher counts than MWY (P < 0.001). The major conclusions that may be drawn from our data are as follows: 1) BCYE gives a high recovery rate of positive samples (93%) and a much greater yield of Legionella spp. than MWY; 2) BCYE was necessary for the detection of non-L. pneumophila spp. which grew poorly on selective media; 3) selective media [MWY or GVPC (glycine, vancomycin, polymyxin B, and cycloheximide)] were necessary for the recovery of Legionella spp. when the non selective medium (BCYE) was difficult to interpret because of contaminating background flora. The use of different media is recommended for routine water tests in hospitals. PMID- 21596224 TI - Pneumonia risk factors and clinical features of hospitalized patients older than 15 years with pandemic influenza A (H1N1) in South Korea: a multicenter study. AB - While most patients with pandemic influenza A (H1N1) virus had a self-limited disease, some patients had severe pneumonia requiring hospitalization. We conducted a retrospective review to characterize demographically the patients older than 15 years with H1N1 infection requiring hospitalization and assess the risk factors for pneumonia development. The most common underlying medical condition was a respiratory disorder such as asthma or chronic bronchitis (11.4%). The symptoms most common at presentation included fever and cough (91.9% and 71.2%, respectively). Of the 210 patients studied, 55 (26.2%) had viral pneumonia. The independent risk factors for pneumonia were asthma [odds ratio (OR) 4.006], male gender (OR 3.507), and age >=50 years (OR 2.653). There were insufficient numbers of pregnant, obese, and diabetic patients to allow statistical analyses. Early treatment with antiviral agents was associated with reduced risk of pneumonia (OR 0.822). Our results suggest that asthma, old age, and male gender may be related to pneumonia and that early antiviral treatment may reduce pneumonia risk. PMID- 21596225 TI - Rapid detection of qnr and qepA plasmid-mediated quinolone resistance genes using real-time PCR. AB - Plasmid-mediated quinolone resistance genes in clinical strains cannot be detected by phenotypic traits but require gene detection. We developed a multiplex real-time polymerase chain reaction (PCR) assay using high-resolution melting master mix with ResoLight dye to detect qnr genes and a simplex real-time PCR assay using SYBR Green I to detect qepA genes. Using qnr-positive and qepA1 positive control strains, the ResoLight method was able to rapidly identify qnrA, qnrB, qnrS, qnrC, and qnrD genes; the SYBR Green I method identified qepA genes. Among 118 extended spectrum beta-lactamase-producing Enterobacteriaceae isolates, the 2 new assays efficiently detected and identified qnr in 9 strains, but no qepA gene. To our knowledge, this is the first study describing the detection of all 5 qnr and qepA genes using real-time PCR. The 2 tests constitute a significant step forward for screening for plasmid quinolone resistance genes in clinical strains. PMID- 21596227 TI - The etiology of atrial myxoma tumor plop. PMID- 21596226 TI - In vitro activity of tigecycline against extended-spectrum beta-lactamase producing Enterobacteriaceae and MRSA clinical isolates from Mexico: a multicentric study. AB - Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and methicillin resistant Staphylococcus aureus (MRSA) are important nosocomial pathogens. This study reports the in vitro activity of tigecycline against 573 and 482 ESBL-producing Enterobacteriaceae and MRSA isolates, respectively. More than 94% of all tested isolates were susceptible to tigecycline; MIC(90) found was 0.25 to 2 mg/L for ESBL-producing Enterobacteriaceae and was 0.125 mg/L for MRSA. Tigecycline demonstrated excellent in vitro activity against a wide spectrum of nosocomial pathogens. PMID- 21596228 TI - Heart failure and chronic obstructive pulmonary disease the quandary of Beta blockers and Beta-agonists. AB - The combination of heart failure and chronic obstructive pulmonary disease presents many therapeutic challenges. The cornerstones of therapy are beta blockers and beta-agonists, respectively. Their pharmacological effects are diametrically opposed, and each is purported to adversely affect the alternative condition. The tolerability of beta-blockade in patients with mild and fixed airflow obstruction likely extends to those with more severe disease. However, the evidence is rudimentary. The long-term influence of beta-blockade on pulmonary function, symptoms, and quality of life is unclear. Low-dose initiation and gradual up-titration of cardioselective beta-blockers is currently recommended. Robust clinical trials are needed to provide the answers that may finally allay physicians' mistrust of beta-blockers in patients with chronic obstructive pulmonary disease. Beta-agonists are associated with incident heart failure in patients with pulmonary disease and with increased mortality and hospitalization in those with existing heart failure. These purported adverse effects require further investigation. In the meantime, clinicians should consider carefully the etiology of dyspnea and obtain objective evidence of airflow obstruction before prescribing beta-agonists to patients with heart failure. PMID- 21596229 TI - Long-term comparison of everolimus-eluting and sirolimus-eluting stents for coronary revascularization. AB - OBJECTIVES: This study sought to compare the unrestricted use of everolimus eluting stents (EES) with sirolimus-eluting stents (SES) in patients undergoing percutaneous coronary intervention. BACKGROUND: It is unclear whether there are differences in safety and efficacy between EES and SES during long-term follow up. METHODS: Using propensity score matching, clinical outcome was compared among 1,342 propensity score-matched pairs of patients treated with EES and SES. The primary outcome was a composite of death, MI, and target vessel revascularization. RESULTS: The median follow-up was 1.5 years with a maximum of 3 years. The primary outcome occurred in 14.9% of EES- and 18.0% of SES-treated patients up to 3 years (hazard ratio [HR]: 0.83, 95% confidence interval [CI]: 0.68 to 1.00, p = 0.056). All-cause mortality (6.0% vs. 6.5%, HR: 0.92, 95% CI: 0.68 to 1.25, p = 0.59) was similar, risks of myocardial infarction (MI) (3.3% vs. 5.0%, HR: 0.62, 95% CI: 0.42 to 0.92, p = 0.017), and target vessel revascularization (7.0% vs. 9.6%, HR: 0.75, 95% CI: 0.57 to 0.99, p = 0.039) were lower with EES than SES. Definite stent thrombosis (ST) (HR: 0.30, 95% CI: 0.12 to 0.75, p = 0.01) was less frequent among patients treated with EES. The reduced rate of MI with EES was explained in part by the lower risk of definite ST and the corresponding decrease in events associated with ST (HR: 0.25, 95% CI: 0.08 to 0.75, p = 0.013). CONCLUSIONS: The unrestricted use of EES appears to be associated with improved clinical long-term outcome compared with SES. Differences in favor of EES are driven in part by a lower risk of MI associated with ST. PMID- 21596230 TI - Complexity of atherosclerotic coronary artery disease and long-term outcomes in patients with unprotected left main disease treated with drug-eluting stents or coronary artery bypass grafting. AB - OBJECTIVES: The aim of this study was to compare treatment effects of drug eluting stents (DES) or coronary artery bypass grafting (CABG) for left main coronary artery (LMCA) disease according to the complexity of atherosclerotic disease burden. BACKGROUND: Limited information is available on the relationships between the extent of coronary atherosclerosis and very long-term outcomes of surgical or percutaneous LMCA revascularization. METHODS: A total of 1,146 patients with unprotected LMCA disease who received DES (n = 645) or underwent CABG (n = 501) were evaluated. The extent of atherosclerotic disease burden was measured using the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score; a low-risk score was defined as <= 22, an intermediate-risk score as 23 to 32, and a high-risk score as >= 33. RESULTS: After multivariate adjustment with the inverse-probability-of-treatment weighting method, the 5-year risks for death (6.1% for DES vs. 16.2% for CABG; hazard ratio [HR]: 0.52; 95% confidence interval [CI]: 0.21 to 1.28; p = 0.15) and the composite of death, Q-wave myocardial infarction, or stroke (6.4% vs. 16.2%; HR: 0.54; 95% CI: 0.22 to 1.34; p = 0.18) favored DES in patients with low-risk SYNTAX scores; in contrast, the 5 year risks for death (26.9% vs. 17.8%; HR: 1.46; 95% CI: 0.92 to 2.30; p = 0.11) and the composite outcome (27.6% vs. 19.5%; HR: 1.36; 95% CI: 0.87 to 2.12; p = 0.18) favored CABG in patients with high-risk SYNTAX scores (interaction p = 0.047 for death, interaction p = 0.08 for composite outcome). Patients undergoing CABG consistently had lower rates of target vessel revascularization. CONCLUSIONS: According to the complexity of concomitant coronary disease, there were differential treatment effects on long-term mortality in patients with unprotected LMCA disease who received DES or underwent CABG. PMID- 21596231 TI - SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism. AB - OBJECTIVES: The aim of this study was to discern the role of the cardiac voltage gated sodium ion channel SCN5A in the etiology of dilated cardiomyopathy (DCM). BACKGROUND: Dilated cardiomyopathy associates with mutations in the SCN5A gene, but the frequency, phenotype, and causative nature of these associations remain the focus of ongoing investigation. METHODS: Since 1991, DCM probands and family members have been enrolled in the Familial Cardiomyopathy Registry and extensively evaluated by clinical phenotype. Genomic deoxyribonucleic acid samples from 338 individuals among 289 DCM families were obtained and screened for SCN5A mutations by denaturing high-performance liquid chromatography and sequence analysis. RESULTS: We identified 5 missense SCN5A mutations among our DCM families, including novel mutations E446K, F1520L, and V1279I, as well as previously reported mutations D1275N and R222Q. Of 15 SCN5A mutation carriers in our study, 14 (93%) manifested arrhythmia: supraventricular arrhythmia (13 of 15), including sick sinus syndrome (5 of 15) and atrial fibrillation (9 of 15), ventricular tachycardia (5 of 15), and conduction disease (9 of 15). CONCLUSIONS: Mutations in SCN5A were detected in 1.7% of DCM families. Two-thirds (6 of 9) of all reported DCM mutations in SCN5A localize to the highly conserved homologous S3 and S4 transmembrane segments, suggesting a shared mechanism of disruption of the voltage-sensing mechanism of this channel leading to DCM. Not surprisingly, SCN5A mutation carriers show a strong arrhythmic pattern that has clinical and diagnostic implications. PMID- 21596232 TI - Arrhythmias and dilated cardiomyopathy common pathogenetic pathways? PMID- 21596233 TI - Association of annular calcification and aortic valve sclerosis with brain findings on magnetic resonance imaging in community dwelling older adults: the cardiovascular health study. AB - OBJECTIVES: The objective of this study was to investigate the associations of mitral annular calcification, aortic annular calcification, and aortic valve sclerosis with covert magnetic resonance imaging (MRI)-defined brain infarcts. BACKGROUND: Clinically silent brain infarcts defined by MRI are associated with increased risk for cognitive decline, dementia, and future overt stroke. Left sided cardiac valvular and annular calcifications are suspected as risk factors for clinical ischemic stroke. METHODS: A total of 2,680 CHS (Cardiovascular Health Study) participants without clinical histories of stroke or transient ischemic attack underwent brain MRI in 1992 and 1993, 1 to 2 years before echocardiographic exams (1994 to 1995). RESULTS: The mean age of the participants was 74.5 +/- 4.8 years, and 39.3% were men. The presence of any annular or valvular calcification (mitral annular calcification, aortic annular calcification, or aortic valve sclerosis), mitral annular calcification alone, or aortic annular calcification alone was significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular or valve calcification remained associated with covert brain infarcts (risk ratio: 1.24; 95% confidence interval: 1.05 to 1.47). The degree of annular or valvular calcification severity showed a direct relation with the presence of covert MRI findings. CONCLUSIONS: Left-sided cardiac annular and valvular calcifications are associated with covert MRI defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening in the progression of annular and valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk for cognitive impairment and future stroke. PMID- 21596235 TI - Inorganic nitrate therapy improves Doxorubicin-induced cardiomyopathy a new window for an affordable cardiovascular therapy for everyone? PMID- 21596234 TI - Dietary nitrate supplementation protects against Doxorubicin-induced cardiomyopathy by improving mitochondrial function. AB - OBJECTIVES: The aim of this study was to test the hypothesis that long-term dietary nitrate supplementation protects against doxorubicin-induced cardiomyopathy by improving ventricular function and reducing mitochondrial respiratory chain damage. BACKGROUND: Doxorubicin is a powerful anthracycline antibiotic used to treat divergent human neoplasms. Its clinical use is limited because of severe cardiotoxic side effects. Dietary nitrate and nitrite are essential nutrients for maintenance of steady-state tissue levels of nitric oxide and may play a therapeutic role in diseases associated with nitric oxide insufficiency or dysregulation. Dietary nitrate and nitrite supplementation alleviates myocardial injury caused by ischemia-reperfusion and cardiac arrest resuscitation. METHODS: Adult male CF-1 mice were given a single dose of doxorubicin (15 mg/kg intraperitoneally), and left ventricular contractile function was assessed 5 days later using both echocardiography and pressure volume Millar catheterization. A nitrate supplementation regimen (1 g/l sodium nitrate in drinking water) was started 7 days before doxorubicin injection and continued thereafter. Cardiomyocyte necrosis and apoptosis, tissue lipid peroxidation, and plasma nitrate and nitrite levels were assessed. In addition, mitochondrial complex I activity, oxidative phosphorylation capacity, and hydrogen peroxide generation were determined in parallel experiments. RESULTS: Doxorubicin caused impairment of ventricular contractility and cell death, which were significantly reduced by nitrate supplementation (p < 0.05). These cardioprotective effects were associated with a significant decrease in tissue lipid peroxidation. Nitrate supplementation significantly preserved mitochondrial complex I activity and oxidative phosphorylation and attenuated hydrogen peroxide generation after doxorubicin treatment. CONCLUSIONS: Long-term oral intake of inorganic nitrate attenuates doxorubicin-induced ventricular dysfunction, cell death, oxidative stress, and mitochondrial respiratory chain damage. Nitrate could be a promising therapeutic agent against doxorubicin-induced cardiotoxicity. PMID- 21596236 TI - Mycophenolate mofetil decreases atherosclerotic lesion size by depression of aortic T-lymphocyte and interleukin-17-mediated macrophage accumulation. AB - OBJECTIVES: This study tested whether immunosuppression with mycophenolate mofetil (MMF) inhibits atherosclerosis development in apolipoprotein-E-deficient (Apoe(-/-)) mice and investigated the mechanism. BACKGROUND: Chronic vascular inflammation involving both innate and adaptive immunity is central in the development of atherosclerosis, but immunosuppressive treatment is not uniformly beneficial. The immunosuppressive MMF targets lymphocyte proliferation by inhibiting inosine-monophosphate dehydrogenase. METHODS: Young and aged Apoe(-/-) mice were treated with 30 mg/kg daily MMF during 12 and 3 weeks of a high-fat diet, respectively. Aortic lesion size and composition was investigated by histology and flow cytometry; soluble inflammatory mediators were investigated by enzyme-linked immunosorbent assay. RESULTS: Macroscopic and histologic aortic atherosclerotic lesions were significantly decreased in both MMF-treated groups. While systemic immunoglobulin G directed against low-density lipoproteins was not significantly altered, the T-cell cytokine interleukin (IL)-17 was significantly reduced in plasma of MMF-treated mice and supernatants from their aortas after T cell stimulation. The MMF treatment decreased aortic alphabeta T-cell receptor(+) lymphocyte proliferation and cell numbers. Also, aortic contents of CD11b(+)CD11c(+) cells and their proliferation were reduced in MMF-treated Apoe( /-) mice. The IL-17 supplementation restored the number of proliferating aortic CD11b(+)CD11c(+) cells in MMF-treated mice. The IL-17 receptor A was highly expressed on circulating monocytes that are macrophage progenitors. Genetic deletion of IL-17 receptor A or IL-17A reduced inflammatory peritoneal CD11b(+)CD11c(+) macrophage accumulation. CONCLUSIONS: The lymphocyte-directed immunosuppressant MMF that curbs IL-17 production was a successful antiatherosclerotic treatment. Our data delineate a role for IL-17 in CD11b(+)CD11c(+) cell accumulation. PMID- 21596237 TI - A giant "twin" aneurysm of the thoracic aorta. PMID- 21596239 TI - Importance of local hemodynamic conditions in the atherosclerotic effect of increased heart rate. PMID- 21596240 TI - Five minutes, 1 day, 1 week, 1 month? PMID- 21596241 TI - Anterior capsule staining using micronized triamcinolone in the absence of red reflex. AB - We describe a technique to stain the anterior lens capsule with micronized triamcinolone to perform a continuous curvilinear capsulorhexis (CCC) during phacoemulsification in the absence of a red reflex due to vitreous hemorrhage. After a self-sealing clear corneal tunnel incision is performed using a 2.75 mm blade, a dispersive ophthalmic viscosurgical device (OVD) is injected to protect the iridocorneal angle. An air bubble as large as possible is injected into the center of the anterior chamber, and a small amount of micronized triamcinolone is then injected as needed to stain the anterior lens capsule. The OVD injection permits the removal of excessive triamcinolone and protects the corneal endothelium from damage during phacoemulsification. A capsulorhexis forceps is used to perform the CCC. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596242 TI - Sheep practice eye for ophthalmic surgery training in skills laboratory. AB - Pig eyes are not available for surgical practice in the Middle East and Central Asia. We reviewed the literature to select an alternative animal practice eye based on biometry, availability, expense, and the ethical issue of animal sacrifice. Twenty enucleated sheep eyes were studied with an ultrasonography immersion technique, and a variety of techniques for globe harvesting were tested and compared. The sheep eye was judged to be the best practical choice for ophthalmic surgery practice and the "bone shattering" exenteration maneuver, the most efficient harvesting method. Several anterior segment procedures were performed in the sheep eyes. Introduction of this sheep model would be instrumental in the development of ophthalmology skills laboratories and surgical training in Middle Eastern and Central Asian regions. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596243 TI - Simultaneous bilateral cataract surgery: economic analysis; Helsinki Simultaneous Bilateral Cataract Surgery Study Report 2. AB - PURPOSE: To present an economic-analysis comparison of simultaneous and sequential bilateral cataract surgery. SETTING: Helsinki University Eye Hospital, Helsinki, Finland. DESIGN: Economic analysis. METHODS: Effects were estimated from data in a study in which patients were randomized to have bilateral cataract surgery on the same day (study group) or sequentially (control group). The main clinical outcomes were corrected distance visual acuity, refraction, complications, Visual Function Index-7 (VF-7) scores, and patient-rated satisfaction with vision. Health-care costs of surgeries and preoperative and postoperative visits were estimated, including the cost of staff, equipment, material, floor space, overhead, and complications. The data were obtained from staff measurements, questionnaires, internal hospital records, and accountancy. Non-health-care costs of travel, home care, and time were estimated based on questionnaires from a random subset of patients. The main economic outcome measures were cost per VF-7 score unit change and cost per patient in simultaneous versus sequential surgery. RESULTS: The study comprised 520 patients (241 patients included non-health-care and time cost analyses). Surgical outcomes and patient satisfaction were similar in both groups. Simultaneous cataract surgery saved 449 Euros (?) per patient in health-care costs and ?739 when travel and paid home-care costs were included. The savings added up to ?849 per patient when the cost of lost working time was included. CONCLUSION: Compared with sequential bilateral cataract surgery, simultaneous bilateral cataract surgery provided comparable clinical outcomes with substantial savings in health-care and non-health-care-related costs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596244 TI - Pain perception in sequential cataract surgery: comparison of first and second procedures. AB - PURPOSE: To compare pain and anxiety between first and second cataract extractions under topical anesthesia with monitored anesthesia care. SETTING: University ophthalmology clinic. DESIGN: Cohort study. METHODS: Consecutive adults having bilateral sequential clear corneal cataract extraction using phacoemulsification under topical anesthesia with monitored anesthesia care were recruited. Exclusion criteria included baseline eye pain, poor comprehension, and complicated cataract extraction. Patients completed 4 short perioperative surveys with each cataract extraction as follows: the Amsterdam Preoperative Anxiety and Information Scale (APAIS) and the State-Trait Anxiety Scale (STAI) preoperatively and a 0-to-10 visual analog scale pain survey twice after surgery. Pain and difference in pain were the primary outcomes. RESULTS: Of the 65 patients who completed the study, 26 (40%) reported higher visual analog scale pain scores for the second cataract extraction. Overall, the median pain score was 0 (range 0 to 6) for the first cataract extraction and 1 (range 0 to 9) for the second (P = .004). By 1 day postoperatively, the pain scores were similar (median 0; range 0 to 9; P = .58). Both APAIS and STAI anxiety scores decreased between surgeries (P = .003 and P < .001, respectively). CONCLUSIONS: Although cataract extraction remained relatively painless under topical anesthesia with monitored anesthesia care, there was a subtle increase in pain in the second surgery relative to the first. This appears to be associated with decreased preoperative anxiety and may be related to the amnestic effects of intravenous sedation. These data may explain a common operative observation. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596245 TI - Spherotoric bag-in-the-lens intraocular lens: power calculation and predictive misalignment nomogram. AB - PURPOSE: To propose a method of calculating the power of the 1-sided posterior chamber toric bag-in-the-lens (BIL) intraocular lens (IOL) and propose a misalignment nomogram to calculate the postoperative rotational misalignment or predict the effect of preoperative existing irregular corneal astigmatism. SETTING: Antwerp University Hospital, Department of Ophthalmology, Antwerp, Belgium. DESIGN: Cohort study. METHODS: The new IOL calculation formula uses the steepest corneal meridian and flattest corneal meridian separately (regular spherical IOL formula) followed by a customized A-constant approach based on the changes in the IOL principal plane depending on the spherical and cylindrical powers (thickness) of the IOL. The calculation of the remaining astigmatism (power and axis) in cases of postoperative rotational misalignment resulted in a nomogram that can also be used to predict the degree of tolerance for irregular corneal astigmatism correction at the lenticular plane. The calculation is performed using a worksheet. RESULTS: Because 10 degrees of misalignment would result in 35% refractive inaccuracy, it is the maximum acceptable corneal astigmatic irregularity for correction at the lenticular plane. CONCLUSIONS: Calculation of spherocylindrical power is specific to each toric IOL. Because the surgeon must fully understand the optical properties of the toric IOL that is going to be implanted, a comprehensive outline of a new calculation method specific to the toric BIL IOL is proposed. Primary rotational misalignment of the toric BIL IOL can be fine tuned postoperatively. FINANCIAL DISCLOSURE: Drs. Gobin and Mathysen have no financial or proprietary interest in any material or method mentioned. Additional disclosures are found in the footnotes. PMID- 21596246 TI - Vector analysis of astigmatic changes after cataract surgery with toric intraocular lens implantation. AB - PURPOSE: To analyze the astigmatic changes after cataract surgery with toric intraocular lens (IOL) implantation and determine the relationship between these changes and the final visual outcomes. SETTING: Vissum-Instituto de Oftalmologico de Alicante, Alicante, Spain. DESIGN: Prospective case series. METHODS: This study comprised eyes with visually significant cataract that had surgery with Acrysof toric IOL implantation. Refractive, corneal topography, internal astigmatism, and contrast sensitivity outcomes were evaluated over 6 months. The Alpins vectorial method was used to analyze the target (TIA) and surgically (SIA) induced astigmatism, difference vector, magnitude of error, flattening effect, and torque. RESULTS: The study enrolled 27 eyes (21 patients). Postoperatively, there was a significant reduction in refractive cylinder (P < .01) with an associated visual improvement (P < .01). The magnitude of the SIA vector was significantly lower than the TIA 1 month and 6 months after surgery (P < .01). The mean magnitude of the difference vector was 0.91 diopter (D) +/- 0.45 (SD) at 6 months, with no significant differences between postoperative visits (p > 0.19). The mean magnitude of torque vector was 0.59 +/- 0.42 D at 6 months. There was a significant negative correlation between refractive cylinder and the magnitude of torque (r <= -0.54, P < .01) and the difference vector (r = -0.98, P < .01). CONCLUSION: The toric IOL restored distance visual function in eyes with cataract and significant corneal astigmatism, although there was a small trend toward undercorrection related to misalignment of treatment. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596247 TI - Comparison of posterior capsule opacification with hydrophobic acrylic and hydrophilic acrylic intraocular lenses. AB - PURPOSE: To compare posterior capsule opacification (PCO) 3 years postoperatively in contralateral eyes with a single-piece hydrophobic acrylic and 1 of 2 single piece hydrophilic acrylic intraocular lenses (IOLs) with different configurations. SETTING: Iladevi Cataract and IOL Research Institute, Ahmedabad, India. DESIGN: Prospective randomized clinical trial. METHODS: A hydrophobic Acrysof (hydrophobic group) or a hydrophilic C-flex (hydrophilic group C) or Akreos Adapt IOL (hydrophilic group A) was randomized for implantation in the fellow eye or vice versa of each patient. The Evaluation of Posterior Capsule Opacification (EPCO) area, EPCO score, and neodymium:YAG (Nd:YAG) capsulotomy rates were compared using digital photographs. RESULTS: The study enrolled 68 patients. Although there was no significant difference at 1 month, the median EPCO score was statistically significantly lower in the hydrophobic group than in hydrophilic group C (P = .00) and hydrophilic group A (P = .000) at 3 years. There were no significant differences in the median EPCO area at 1 month; however, the area was statistically significantly less in the hydrophobic group than in hydrophilic group C and hydrophilic group A at 3 years (both P = .000). Four (12.9%) of 31 eyes in hydrophilic group C and 5 (16%) of 31 eyes in hydrophilic group A required an Nd:YAG capsulotomy; no eye in the hydrophobic group required a capsulotomy (P = .04 and P = .02, respectively). CONCLUSION: Posterior capsule opacification was significantly less with the Acrysof hydrophobic acrylic IOL at 3 years. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596248 TI - Hydrophobic versus double-square-edged hydrophilic foldable acrylic intraocular lens: effect on posterior capsule opacification. AB - PURPOSE: To evaluate posterior capsule opacification (PCO) 2 years after cataract surgery with implantation of a hydrophobic acrylic or single-piece sharp-edged hydrophilic acrylic intraocular lens (IOL). SETTING: Toyama Prefectural Central Hospital, Toyama, Japan. DESIGN: Case-control study. METHODS: Patients with bilateral senile cataract were prospectively randomized to receive a hydrophobic IOL (Acrysof SA60AT) in 1 eye and a hydrophilic IOL (Meridian HP60M) in the other eye. The PCO density value, degree of IOL decentration and tilt, and anterior chamber depth (ACD) were measured using Scheimpflug videophotography 1, 6, 12, 18, and 24 months after surgery. Visual acuity and the number of eyes requiring neodymium:YAG laser capsulotomy were also assessed. RESULTS: The study evaluated 16 eyes (63 patients). The PCO value in the hydrophilic group increased significantly with time and was statistically significantly greater than in the hydrophobic group 18 and 24 months postoperatively (both P < .001). The capsulotomy rate was statistically significantly higher in the hydrophilic group than in the hydrophobic group (P < .01). Visual acuity in the hydrophilic group worsened significantly with time and was statistically significantly worse than in the hydrophobic group at 18 and 24 months (both P < .001). Intraocular lens decentration, IOL tilt, and the ACD did not change significantly during the follow-up in either group (P > .05), and there were no statistically significant postoperative differences in these parameters between the 2 IOL groups (P > .05). CONCLUSION: Two years after surgery, the hydrophobic IOL group had less PCO, a lower capsulotomy rate, and better visual acuity than the hydrophilic IOL group. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596249 TI - Characterizing the learning curve in phacoemulsification. AB - PURPOSE: To characterize how residents learn phacoemulsification and determine which steps of the procedure are most difficult to master. SETTING: University of Colorado Hospital, Aurora, Colorado, USA. DESIGN: Comparative case series. METHODS: Cataract cases were divided into 3 levels of difficulty for comparison. Residents were given a grade for each step of the procedure by the attending surgeon. Main outcome measures were total case time and a proficiency grade. Independent variables were level of resident experience and degree of difficulty. Case times of attending cases were collected for comparison. RESULTS: Nine residents were evaluated by 4 attending surgeons while performing 324 cases of phacoemulsification. Case times of 319 attending cases were used for comparison. The easiest-to-learn steps (highest scores versus level of experience) included intraocular lens insertion, ophthalmic viscosurgical device removal, hydrodissection, and nucleus sculpting. Wound integrity, nucleus disassembly and removal, cortex removal, and capsulorhexis had the lowest scores versus level of experience. Resident case times decreased significantly with experience, approaching average case times for attendings. CONCLUSIONS: For this study, competency was defined as the ability of the resident to perform a case in a reasonable time without intervention or complication. Using this definition, competency was achieved when case experience exceeded 75 cataract surgeries. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596250 TI - Effect of residual ocular spherical aberration on objective and subjective quality of vision in pseudophakic eyes. AB - PURPOSE: To determine the level of residual spherical aberration that gives the best objective and subjective quality of image after cataract surgery with intraocular lens (IOL) implantation. SETTING: Department of Ophthalmology, CHU Bretonneau, Tours, France. DESIGN: Cohort study. METHODS: Six months after microincision (1.8 mm) cataract surgery with aspheric IOL implantation, total aberrations were computed using a Wavescan aberrometer. The modulation transfer function (MTF), Strehl ratio, and objective index of scattering were measured using the Objective Quality Analysis System. Objective depth of focus was computed as the focus range at which the Strehl ratio did not fall below 50% of maximum. Subjective depth of focus was calculated as the difference between the vergence of the punctum remotum and that of the punctum proximum. RESULTS: Thirty patients (54 eyes) were evaluated. The MTF cutoff values were higher with decreasing total ocular spherical aberration (r = 0.56; P < .05). Objective and subjective depth of focus were positively correlated with total spherical aberration (r = 0.26 and r = 0.46, respectively; P < .05). CONCLUSIONS: A final spherical aberration of zero obtained by compensation of IOL asphericity gave the greatest improvement in objective quality of vision and better MTF contrast. However, a final target ocular spherical aberration between 0.07 MUm and 0.10 MUm should be considered to be the best compromise between subjective depth of focus and objective contrast sensitivity. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596251 TI - Human aqueous humor concentrations of besifloxacin, moxifloxacin, and gatifloxacin after topical ocular application. AB - PURPOSE: To determine the concentrations of besifloxacin, moxifloxacin, and gatifloxacin in human aqueous humor after topical instillation of commercially available besifloxacin ophthalmic suspension 0.6%, moxifloxacin ophthalmic solution 0.5%, and gatifloxacin ophthalmic solution 0.3%, and to assess these concentrations relative to the minimum inhibitory concentration for 90% of strains (MIC(90)) for each drug against bacterial pathogens identified in recent cases of postoperative endophthalmitis. SETTING: Six clinical sites, United States. DESIGN: Randomized open-label controlled clinical trial. METHODS: The aqueous humor drug concentrations were compared 60 minutes +/- 5 minutes after instillation of 1 topical drop to patients aged 18 years or older having uncomplicated cataract surgery. Concentrations of besifloxacin, moxifloxacin, and gatifloxacin were determined using a validated liquid chromatography with tandem mass spectrometry method. RESULTS: A total of 105 patients were randomized, and aqueous humor samples were analyzed for 103 patients. Mean aqueous humor concentrations were 0.13 MUg/mL +/- 0.58 (SD), 0.67 +/- 0.50 MUg/mL, and 0.13 +/- 0.08 MUg/mL for besifloxacin, moxifloxacin, and gatifloxacin, respectively. Both besifloxacin and moxifloxacin achieved aqueous humor concentrations equal to or slightly higher than their respective MIC(90) for methicillin-resistant and methicillin-susceptible Staphylococcus aureus and Staphylococcus epidermidis; none of the fluoroquinolones achieved concentrations above their MIC(90) for ciprofloxacin-resistant strains of S aureus and S epidermidis. CONCLUSIONS: Based on the aqueous humor drug concentrations measured in this study, it is unlikely that any of the fluoroquinolones tested would be therapeutically effective in the aqueous humor against the most frequently identified drug-resistant staphylococcal isolates from recent cases of postoperative endophthalmitis. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. Additional disclosures are found in the footnotes. PMID- 21596252 TI - Visual quality after diffractive intraocular lens implantation in eyes with previous hyperopic laser in situ keratomileusis. AB - PURPOSE: To evaluate distance, intermediate, and near visual quality in eyes with diffractive intraocular lens (IOL) implantation after previous hyperopic laser in situ keratomileusis (LASIK). SETTING: Fernandez-Vega Ophthalmological Institute, Oviedo, Spain. DESIGN: Cohort study. METHODS: Corrected distance visual acuity (CDVA) at 12.5%, 25.0%, and 100% contrast levels under photopic and mesopic conditions; uncorrected (UNVA) and distance-corrected (DCNVA) near visual acuity, defocus curves, and corneal higher-order aberrations (HOAs) were measured in eyes that had AcrySof Restor SN60D3 spherical IOL implantation (study group) and in phakic eyes (control group) after hyperopic LASIK. RESULTS: Under photopic conditions at 100% contrast, there were no statistically significant differences between the 2 groups (P > .01) and the CDVA was 0.1 logMAR or better (approximately 20/25) in both groups. At 25.0% and 12.5% contrast, there were no statistically significant differences between the 2 groups (P > .01). Under mesopic conditions, the control group had better CDVA than the study group without glare at all contrasts (P < .01). In the study group, the mean UNVA was 0.017 logMAR +/- 0.030 (SD) (approximately 20/20) and the mean DCNVA, 0.009 +/- 0.030 logMAR. There was statistically significant worsening of visual acuity as a function of the distance to the test (P < .01). There were no statistically significant differences in HOAs between the 2 groups (P > .01). CONCLUSIONS: In eyes with previous hyperopic LASIK, the diffractive IOL provided good visual quality at distance, comparable to that obtained in phakic eyes under photopic conditions, although visual performance was slightly poorer under mesopic conditions. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596253 TI - Photorefractive keratectomy in posterior polymorphous dystrophy with vesicular and band subtypes. AB - PURPOSE: To evaluate the safety and efficacy of photorefractive keratectomy (PRK) in patients with posterior polymorphous dystrophy (PPMD) with vesicular and band subtypes. SETTING: Walter Reed Center for Refractive Surgery, Washington, DC, USA. DESIGN: Case series. METHODS: The records of patients with PPMD who had PRK between January 2002 and May 2009 were reviewed. Data for analysis included sex, age, ablation depth, residual stromal bed thickness, manifest spherical equivalent, uncorrected (UDVA) and corrected (CDVA) distance visual acuities, central corneal thickness (CCT), endothelial cell density (ECD), intraocular pressure (IOP), and complications. Preoperative and postoperative results were compared using the Wilcoxon signed-rank test, with P < .05 considered significant. RESULTS: Fourteen eyes of 7 men (mean age 29.1 years +/- 9.1 [SD]; range 21 to 42 years) with at least a 6-month follow-up were reviewed. At the final follow-up (mean 19.5 months; range 6.3 to 58.3 months), all eyes had a UDVA of 20/15 and all eyes were within +/- 0.50 diopter of emmetropia. The CDVA was unchanged from preoperatively in 71.4% of eyes and improved by 1 line in 28.6%. There were no significant complications. The IOP did not change significantly over the follow-up (P = .272). At the final visit, the mean ECD (2795.3 +/- 366.0 cells/mm(2)) was unchanged from baseline (2809.1 +/- 338.3 cells/mm(2)) (P = .114). CONCLUSIONS: Photorefractive keratectomy in PPMD patients with vesicular and band subtypes resulted in excellent visual outcomes and a low incidence of adverse effects. Endothelial cell densities did not change significantly in the early postoperative period. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596254 TI - Corneal asphericity and spherical aberration after refractive surgery. AB - PURPOSE: To evaluate changes in corneal asphericity (Q) and spherical aberrations after refractive surgery using Scheimpflug imaging. SETTING: University of California, San Diego, Shiley Eye Center, La Jolla, California, USA. DESIGN: Cohort study. METHODS: After wavefront-guided laser in situ keratomileusis, patients within +/- 0.50 diopter of plano and with an uncorrected distance visual acuity of at least 20/20 were evaluated. The Q values and corneal spherical aberration Zernike values were obtained using Scheimpflug imaging preoperatively and 1 to 3 months postoperatively. RESULTS: The study enrolled 177 myopic eyes and 32 hyperopic eyes. The mean Q value was -0.28 +/- 0.11 (SD) and -0.22 +/- 0.15, respectively, preoperatively and +0.35 +/- 0.44 and -0.64 +/- 0.31, respectively, postoperatively. The asphericity change was highly correlated with preoperative spherical equivalent (r(2) = 0.81; P <= .001). The mean corneal spherical aberration was +0.21 +/- 0.08 MUm in myopic eyes and +0.36 +/- 0.11 MUm in hyperopic eyes preoperatively and +0.36 +/- 0.17 MUm and 0.00 +/- 0.29 MUm, respectively, postoperatively. The corneal spherical aberration changes were correlated with the amount of preoperative refractive error (r(2) = 0.34; P < .001). There was a tendency for Q values and spherical aberrations to become more positive after myopic ablation and more negative after hyperopic ablation. CONCLUSIONS: Myopic and hyperopic corrections induced changes in the Q value and spherical aberrations in opposite directions (ie, positive and negative, respectively). The changes depended on the magnitude of the refractive correction. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596255 TI - Evaluation of Scheimpflug imaging parameters in subclinical keratoconus, keratoconus, and normal eyes. AB - PURPOSE: To determine the efficacy of different Scheimpflug-imaging parameters in discriminating between subclinical keratoconus, keratoconus eyes, and normal eyes. SETTING: Department of Ophthalmology, Ankara University Faculty of Medicine, Ankara, Turkey. DESIGN: Comparative case series. METHODS: Pentacam Scheimpflug measurements were taken in eyes with mild to moderate keratoconus, subclinical keratoconus, or with myopic astigmatism (normal eyes). Several parameters provided by the software or derived from the elevation maps were evaluated and compared between the groups. The Mann-Whitney test, receiver operating-characteristic (ROC) curves, and logistic regression analysis were used to compare the mean measurements and to evaluate the sensitivity and specificity of the parameters or constructed models. RESULTS: The corneal power and elevation measurements were statistically significantly higher and the cornea was significantly thinner in eyes with subclinical or clinical keratoconus than in normal eyes (P < .05). The ROC curve analysis showed high overall predictive accuracy of various elevation and thickness indices in discriminating ectatic corneas from normal corneas. Logistic regression analysis showed that the goodness of fit of a model using a combination of corneal power, thickness, and anterior elevation parameters was best in discriminating keratoconus eyes from normal eyes, whereas that of a model using a combination of corneal power, thickness, and posterior elevation was best in discriminating subclinical keratoconus eyes from normal eyes. CONCLUSION: Combined analysis of anterior and posterior corneal power, elevation, and thickness data provided by the Scheimpflug device effectively discriminated between ectatic corneas and normal corneas. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596256 TI - Preliminary results of intrastromal corneal ring segment implantation to treat moderate to severe keratoconus. AB - PURPOSE: To present our preliminary experience with implantation of Ferrara intrastromal corneal ring segments (ICRS) in keratoconus patients. SETTING: Magrabi Eye and Ear Center, Jeddah, Saudi Arabia. DESIGN: Case series. METHODS: This study comprised patients diagnosed with primary keratoconus who had ICRS implantation. Uncorrected (UDVA) and corrected (CDVA) distance visual acuities were recorded. The change in manifest refraction spherical equivalent (MRSE), mean refractive cylinder, average simulated keratometry (K), and topographic cylinder from preoperatively to 6 months postoperatively was analyzed, and complications were noted. The t test was used to compare 2 independent means and the Wilcoxon signed-rank test, to compare nonparametric data. RESULTS: By 6 months postoperatively, the CDVA was unchanged in 27% of cases and had improved between 1 line and 6 lines in 64% of cases; 9% of cases lost 1 or 2 lines. There was a decrease in the following mean values: MRSE (-3.60 diopters [D] +/- 3.10 [SD] to -2.52 +/- 3.10 D; P = .209); refractive cylinder (5.18 +/- 2.10 D to 2.90 +/- 2.50 D; P = .000); simulated K (51.16 +/- 5.60 D to 48.11 +/- 3.60 D; P = .000); topographic cylinder (5.30 +/- 2.80 D to 3.80 +/- 3.20 D; P = .000). For cases with a 24-month follow-up, stability was similar for all parameters. Intraoperative or postoperative complications occurred in 13% of cases; all were managed without clinically significant visual loss. CONCLUSION: Implantation of ICRS resulted in reasonable refractive and visual outcomes in a wide spectrum of keratoconus cases. FINANCIAL DISCLOSURE: The author has no financial or proprietary interest in any material or method mentioned. Additional disclosure is found in the footnotes. PMID- 21596257 TI - Wavefront-guided epithelial laser in situ keratomileusis with mitomycin-C for myopia and myopic astigmatism: flap-on versus flap-off technique. AB - PURPOSE: To compare the postoperative pain, visual recovery, and outcomes of flap on and flap-off epithelial laser in situ keratomileusis (epi-LASIK) with mitomycin-C (MMC). SETTING: Asian Eye Institute, Makati, Philippines. DESIGN: Case-control study. METHODS: Patients with myopia up to 9.00 diopters had wavefront-guided epi-LASIK with MMC. After randomization, the epithelium was removed in 1 eye (flap off) and repositioned in the other eye (flap on). Questionnaires were used to evaluate postoperative pain and visual recovery in each eye during the first postoperative week. Visual results, refractive outcomes, contrast sensitivity, and higher-order aberrations (HOAs) were compared and analyzed. RESULTS: The study evaluated 48 eyes. The mean pain scores were lower and better vision was perceived in the flap-off group during the first postoperative week. One year postoperatively, the mean uncorrected distance visual acuity was -0.088 logMAR in the flap-on group and -0.036 logMAR in the flap-off group (P = .918). The spherical equivalent was within +/- 0.50 D in 92% of eyes in both groups (P > .05). Forty-six percent in the flap-on group and 38% in the flap-off group gained 1 line of corrected distance visual acuity (P = .915). Contrast sensitivity tests under daytime and nighttime conditions were comparable. There was no statistically significant difference in the mean change in HOAs between groups. CONCLUSIONS: Wavefront-guided epi-LASIK with MMC was effective, safe, and predictable in treating myopia and myopic astigmatism. Eyes that had flap-off epi-LASIK had less pain and faster visual recovery. Visual results, refractive outcomes, contrast sensitivity, and HOAs were comparable between groups. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596258 TI - Methyl blue and aniline blue versus patent blue and trypan blue as vital dyes in cataract surgery: capsule staining properties and cytotoxicity to human cultured corneal endothelial cells. AB - PURPOSE: To evaluate capsule-staining properties and biocompatibility of the triarylmethane dyes methyl blue and aniline blue compared with patent blue and trypan blue on cultured human corneal endothelial cells. SETTING: Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany. DESIGN: Experimental study. METHODS: Human corneal endothelial cell cultures were harvested from human donor cells and exposed to various concentrations (0.025 to 5.0 mg/mL) of methyl blue, aniline blue, patent blue, and trypan blue. Cytotoxicity was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test after 24 hours of incubation. Calcein live cell staining was performed at the same time point. The dyes were also used to stain pig lens capsules in vitro by incubating the lenses for 1 minute with 3 concentrations (0.5, 1.5, and 2.5 mg/mL) of dye, after which the staining properties were evaluated. RESULTS: No significant cytotoxicity was detected for patent blue and methyl blue at any tested concentration. However, aniline blue exerted significant cytotoxicity at concentrations of 1.5 mg/mL or higher and trypan blue at 2.5 mg/mL or higher. Capsule staining of the tested triarylmethane dyes was suitable for performing capsulorhexis, but only at higher concentrations than with trypan blue. CONCLUSIONS: High concentrations and long incubation times of trypan blue and aniline blue showed significant cytotoxicity to human cultured endothelial cells in contrast to patent blue and methyl blue. All tested dyes were able to stain lens capsules sufficiently for capsulorhexis creation. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21596259 TI - Determining the local origin of hydroxyl radical generation during phacoemulsification. AB - PURPOSE: To determine the local origin of hydroxyl radicals during phacoemulsification using an ultrasonic phacoemulsification device that includes longitudinal and torsional modalities. SETTING: Chemistry and Biochemistry Department, Utah State University, Logan, Utah, USA. DESIGN: Experimental study. METHODS: Experiments were conducted using the Infiniti Vision System and Ozil handpiece. Hydroxyl radical concentrations during longitudinal and torsional phacoemulsification were quantitated as malondialdehyde (MDA) determined spectrophotometrically using the deoxyribose assay. The difference between the total concentration found in the aspirated solution at steady-state concentrations and the pre-aspirate levels deductively determined the concentration of MDA formed along the interior of the sonicating tip. The time to reach 50% of steady state as a function of reaction vessel volume was determined. RESULTS: The mean maximum for torsional ultrasound at 100% amplitude was 7.70 nM +/- 0.38 (SD), 91.1% of which was generated outside the tip. During longitudinal ultrasound at 100% power, MDA concentration in the aspirated solution was 29.5 +/ 0.3 nM, 71.6% of which was generated outside the tip. The time (seconds) to reach 50% of maximum for longitudinal ultrasound using 5 mL, 10 mL, and 20 mL reaction vessels was 12.6 +/- 1.5, 21.0 +/- 1.5, and 25.3 +/- 3.4, respectively. CONCLUSION: Although a significantly greater proportion of the hydroxyl radicals generated during ultrasound modality were formed outside the phaco tip (91.1% torsional; 71.6% longitudinal), torsional ultrasound generated only about one fourth the amount of MDA as longitudinal ultrasound in total and about one-third that generated outside the tip (7.02 nM versus 21.1 nM). FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. Additional disclosures are found in the footnotes. PMID- 21596260 TI - Bilateral corneal opacities in a LASIK patient after the use of titanium eye shields. AB - We report a case of bilateral corneal opacities in a laser in situ keratomileusis (LASIK) patient who subsequently had carbon dioxide (CO(2)) laser skin resurfacing. The presumed etiology of the visually significant corneal opacities was late-onset diffuse lamellar keratitis (DLK), secondary to traumatic corneal abrasions from the use of metal eye shields. The DLK went untreated for 1 month, resulting in permanent interface scarring and a corrected distance visual acuity of 20/30 in the patient's right eye and 20/20 in the left eye. We think patients who have had LASIK and are planning to have CO(2) laser skin resurfacing or any procedure that uses protective metal eye shields should be counseled about the risk for late-onset DLK as a potential complication. This warning is particularly germane now as an increasing number of patients who have had LASIK are entering the decades of life when cosmetic surgery is most likely to be sought. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 21596261 TI - Sudden corneal edema due to retained lens nuclear fragment presenting 8.5 years after cataract surgery. AB - A 79-year-old woman presented with a 1-week history of sudden onset of decreased vision, pain, and redness in the right eye. Ocular history included uneventful cataract surgery in both eyes more than 8 years prior to presentation. Slitlamp examination revealed significant corneal edema and mild iritis. Gonioscopy revealed a retained lens nuclear fragment in the inferior angle. Surgical removal of the fragment improved the patient's condition. The retained nuclear fragment presumably lodged behind the iris at the time of the initial surgery and spontaneously moved forward more than 8 years later. To our knowledge, this is the longest reported delay between phacoemulsification and presentation of a retained nuclear fragment. Before this case, retained nuclear fragments had been associated with complications within a year of surgery only. We recommend gonioscopy in cases of sudden-onset corneal edema extending to the inferior limbus in patients with a history of phacoemulsification. PMID- 21596262 TI - Macular infarction after inadvertent intracameral cefuroxime. AB - We present the case of a 70-year-old patient who had uneventful cataract surgery. Because of a procedural mishap, the patient received an excess dose of intracameral cefuroxime of approximately 62.5 mg. Two weeks postoperatively, evidence of macular infarction with cystoid macular edema was seen on fundus fluorescein angiography. The patient was treated with 4.0 mg of intravitreal triamcinolone, but the visual acuity failed to improve; the final pinhole acuity was 3/60. Based on the postoperative progress, we speculate that a delayed mechanism of vascular toxicity is implicated. The importance of systematic procedures to reduce the risk for mistakes is emphasized, especially for a procedure such as cataract surgery where efficiency is increasingly important. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 21596263 TI - Consultation section: Cataract surgical problem: June consultation. PMID- 21596272 TI - Letter from the guest editor: congenital/developmental brain abnormalities, part I. PMID- 21596273 TI - Embryology of the brain and molecular genetics of central nervous system malformation. PMID- 21596274 TI - Prenatal imaging of congenital malformations of the brain. AB - This article represents an overview of ultrasound (US) and magnetic resonance imaging (MRI) of the normal fetal brain during the second and third trimesters, followed by the description of congenital pathologic conditions. Fetal imaging of the brain requires an understanding of embryology that defines the normal anatomy of the brain at each gestational age. Without knowledge of the normal developmental milestones, it is impossible to accurately diagnose prenatal central nervous system (CNS) disorders. In the first section, a brief review of the normal anatomy and milestones by using US and fetal MRI will be described. The second part will provide a summary of congenital malformations with respect to embryologic event and their typical imaging patterns on prenatal US and MRI. PMID- 21596275 TI - Malformations of dorsal induction. AB - Dorsal induction includes the formation and closure of neural tube, occurs during 3-5 weeks of gestation. Neurulation occurs in two phases, primary neurulation (formation of the neural plate and subsequently neural tube) and secondary neurulation (formation of distal cord and sacral and coccygeal segments). Failure of dorsal induction leads to anencephaly, exencephaly, cephaloceles, Chiari malformation and spinal dysraphism. In this article we discuss the relevant embryology, etiopathology and detail imaging appearances of these malformations. PMID- 21596276 TI - Malformations of ventral induction. PMID- 21596277 TI - Malformations of cortical development. AB - The advent of high resolution MRI techniques has revolutionized the imaging of cortical malformations. Today, specific gene defects have been identified to be responsible for several of the developmental cortical malformations. In this article we have discussed the developmental cortical malformations under stages of proliferation, migration and organization. The relevant molecular genetics and its relationship to the cortical defects are also outlined. Neuroimaging features and relevant etio-pathogenesis of various cortical malformations are discussed in detail. PMID- 21596278 TI - Posterior fossa malformations. AB - Understanding embryologic development of the cerebellum and the 4th ventricle is essential for understanding posterior fossa malformations. Posterior fossa malformations can be conveniently classified into those that have a large posterior fossa and those with normal or small posterior fossa. Disorders associated with a large posterior fossa include classic Dandy-Walker malformation, Blake's pouch cyst, mega cisterna magna, and posterior fossa arachnoid cyst. Disorders associated with normal or small posterior fossa include Dandy-Walker variant, Joubert syndrome, tecto-cerebellar dysraphia, rhombencephalosynapsis, the neocerebellar hypoplasias, and cerebellar atrophy. Neuro-imaging features should enable the imager to provide the referring physician a logical approach to these complex posterior fossa malformations. PMID- 21596279 TI - Normal cerebral arterial development and variations. AB - The cerebral vascular architecture is both unique and heterogeneous in its structure, organization, and function. For many years, it was believed that brain vasculature was dominated by nonanastomosing terminal or "end-arteries." This was primarily based upon the observation of discrete distribution of brain infarcts after embolic occlusion of particular vessels. It was not until the detailed anatomy work of Pfeiffer in 1928 that the new concept of an almost-uninterrupted vascular network of brain vasculature was proposed. Since then, the cerebral vascular anatomy and embryology has been studied in great detail. Its full description is beyond the scope of this article, and our aim is to provide a brief overview of the development of cranial arterial anatomy, with special emphasis on commonly encountered anatomical variations that may have clinical implications. The failure to recognize these can lead to misdiagnosis as well as otherwise-preventable iatrogenic injuries and complications. We describe the proposed underlying embryologic processes, pathology and clinical implications of these variations, including aberrant internal carotid arteries, carotid agenesis and hypoplasia, azygous anterior cerebral arteries, arterial fenestrations, and persistent embryonic vessels. PMID- 21596280 TI - Cerebral venous development in relation to developmental venous anomalies and Vein of Galen aneurysmal malformations. AB - Cerebrovascular venous development and intracranial vascular malformations are extensive topics for which volumes of text may be devoted. However, a basic knowledge of the embryology of cerebral venous system and venous architecture is essential for understanding of cerebral vascular malformations. The aim of this work is to provide the reader with a brief overview of the development of the cranial venous anatomy. We will highlight the superficial and deep venous systems with special attention to developmental venous anomalies and vein of Galen aneurysmal malformations. PMID- 21596281 TI - [Management of invasive fungal infections in children]. PMID- 21596282 TI - [Fungal infections in cystic fibrosis]. AB - Fungal colonization in cystic fibrosis patient is frequent and dominated by Aspergillus fumigatus (A. fumigatus). Mycological analysis on specific media showed other filamentous species Scedosporium, Geosmithia argillacea. Prospective studies are necessary to appreciate prevalence and pathogenicity in this pathology. A. fumigatus causes the most frequently allergic bronchopulmonary aspergillosis (ABPA). Invasive infection is exceptional in this context. An early diagnosis is important to avoid bronchial deterioration but is very difficult despite international consensus. New more specific biological markers are evaluated. Oral corticotherapy is the cornerstone of therapy but adverse effects are more frequent in cystic fibrosis. Antifungal therapy has a corticosteroid sparing effect. New therapeutic strategies have to be evaluated. PMID- 21596283 TI - [Invasive candidiasis in neonatal intensive care units]. AB - In the USA, the incidence of invasive candidiasis in neonates is respectively 0.3% of infants over 2500 g and up to 20% of infants less than 1000 g. Their incidence is increasing. Two populations of newborn infants are particularly vulnerable: the premature infants and newborn infants with severe neonatal digestive diseases. Fifty percent of infants hospitalized in NICU are colonized with Candida at the end of the first week of hospitalization; a direct relationship exists between the importance of colonization and the invasive infection risk. C. albicans is the species most often responsible for invasive candidiasis in the newborn. These infections represent the third cause of related catheter infection in the USA. Mortality rate in neonates linked to this disease is 20 to 50%; morbidity primarily concerns brain and lungs. Neonatal invasive candidiasis risk factors are known and a primary prevention is possible. The diagnosis of neonatal invasive candidiasis is difficult and often delayed because of a polymorphic clinical expression. Empiric and preemptive treatment are based on the use of amphotericin B. Prophylactic treatment using fluconazole of newborns with birth weight <= 1000 grams and/or gestational age <= 27 weeks gestation is recommended by the American Academy of Paediatrics and the Infectious Diseases Society of America. A better knowledge of French epidemiological data in this area would improve both the diagnosis and therapeutic management of this disease. PMID- 21596284 TI - [Fungal infections in children with malignant disease]. AB - Intensified chemotherapy and hematopoietic stem cell transplantation result in severe and prolonged granulocytopenia with an increased risk of invasive fungal infections. The major fungal species that cause serious infections in cancer patients are Candida species and Aspergillus species. The main features of Candida infection in this context are oropharyngeal candidiasis and Candida esophagitis, chronic disseminated candidiasis, also known as hepatosplenic candidiasis, and candidemia. Aspergillus can cause severe lung infection but also sinusal or CNS infection. Because invasive fungal infections are severe and often life-threatening, preventive and empirical managements have become standard practice. An increasing number of antifungal drugs is now available, notably lipid formulations of amphotericin B (liposomal amphotericin B), new azoles with broad spectrum of activity and echinocandin. PMID- 21596285 TI - [Echinocandins in children]. AB - Echinocandins are a new class of antifungal agents with a specific mechanism of action. These drugs inhibit the enzyme 1,3beta-D-glucan synthetase which is responsible for the formation of 1,3beta-D-glucan, an essential fungal cell wall component. They have a good activity against Candida species and Aspergillus. Three agents are available at the present time or under development : caspofungin, micafungin and anidulafungin. These drugs require intravenous administration. Efficacy, safety, rare drugs interactions and specificity of action are advantages for therapy of invasive fungal infections. In France, micafungin and caspofungin are approved for a pediatric use. PMID- 21596286 TI - [Pharmacokinetics and pharmacodynamics of antifungal drugs in children]. AB - The pharmacokinetics and pharmacodynamics of the main antifungal drugs used for invasive fungal infections (amphotericin B, flucytosine, triazole compounds, echinocandins) have been more or less completely investigated in the paediatric population. This article reviews the pharmacokinetic profiles of these drugs in children, with a focus on the age-related changes. The concentration/efficacy relationships that were evidenced in children are also described. PMID- 21596287 TI - [Fungal infections and congenital immune deficiencies]. AB - Different types of hereditary immune deficiencies are at risk of severe fungal infections. Such infections can reveal the deficit. The type of micro-organisms involved, the clinical presentation, the immune reaction observed around the germ can then guide the etiological diagnosis. As often in the field of immunodeficiencies, advances in the pathophysiology provide crucial informations on the natural defense mechanisms against these organisms. Therapeutic advances have dramatically improved the prognosis of these potentially serious and disabling infections. PMID- 21596288 TI - Case reports, reviews, and changes to the Journal of AAPOS. PMID- 21596289 TI - Learning disabilities, dyslexia, and vision: The role of the pediatric ophthalmologist. PMID- 21596290 TI - Treatment of symptomatic convergence insufficiency in children with a home-based computer orthoptic exercise program. PMID- 21596291 TI - The future of diagnostic imaging in retinoblastoma. PMID- 21596292 TI - Globe perforation during strabismus surgery in an animal model: Treatment versus observation. AB - PURPOSE: To evaluate the role of cryopexy or laser therapy versus observation for management of accidental globe perforation during strabismus surgery in an experimental animal model. METHODS: An S-24 needle was passed through the sclera and into the vitreous cavity in both eyes of 42 rabbits. Cryopexy was performed in 22 eyes, and laser therapy was applied in 20 other eyes; the 42 untreated fellow eyes served as controls. The incidence of complications was compared between treated and untreated eyes. RESULTS: Cataracts were observed in 7 eyes (8.3%) and corneal opacity in 1 eye (1.2%) vitreous hemorrhage occurred in 28 eyes (33.3%), leading to vitreous opacity in 1 eye (1.2%). Transient localized subretinal fluid accumulation around the retinal break developed in 1 eye (1.2%). There were no cases of endophthalmitis or retinal detachment. There was no significant difference in the rate of complications among the 3 groups. CONCLUSIONS: Vision-threatening consequences of globe perforation during strabismus surgery were uncommon in this rabbit model. Simple observation without intervention may have similar results as prophylactic cryopexy or laser therapy. PMID- 21596293 TI - Long-term outcome of primary congenital glaucoma. AB - PURPOSE: To evaluate the long-term outcome of primary congenital glaucoma in patients followed for more than 20 years. METHODS: All patients with a diagnosis of congenital glaucoma who were examined in the pediatric glaucoma clinic at Moorfields Eye Hospital from 2005 to 2006 were included. The follow-up period was a minimum of 20 years; patients with pediatric glaucoma secondary to other etiologies were excluded. Data collected included visual acuity, optic disk cupping, intraocular pressure (IOP), corneal diameter, pachymetry, visual fields, refraction, strabismus, glaucoma management, and ocular comorbidity. Progressive congenital glaucoma, defined as an increase of the cup/disk ratio of >0.2 secondary to elevated IOP, was evaluated with the use of Kaplan-Meier survival curves. Patients were divided into 1 of 3 groups: (1) stable glaucoma with no visual impairment; (2) glaucoma progression with sight-threatening consequences; and (3) poor visual acuity as a result of ocular comorbidity. RESULTS: A total of 30 eyes of 16 patients were identified. Mean follow-up was 34 +/- 10 years (range, 22-59 years). At the final clinical assessment, mean IOP was 13.6 +/- 4.3 mm Hg and mean cup/disk ratio was 0.7 +/- 0.3 (p < 0.05). Survival analysis demonstrated lack of progression in 90.3% at 1 year, 83.1% at 5 years, 70.8% at 10 years, 58.3% at 34 years, and 48.6% at 40 years. CONCLUSIONS: Apparently stable congenital glaucoma may progress with sight-threatening complications after many years of IOP stability. Monitoring of these patients is indicated throughout life. PMID- 21596294 TI - Ophthalmic findings in Angelman syndrome. AB - PURPOSE: To provide detailed information about opthalmological findings in a group of patients with Angelman syndrome (AS). METHODS: Consecutive patients with a genetically confirmed diagnosis of AS were submitted to ophthalmic and orthoptic examinations. Strabismus, visual acuity, cycloplegic refraction, and iris and fundus pigmentation were evaluated. Parents were also examined to compare the extent of fundus pigmentation. RESULTS: A total of 34 patients were identified, representing 3 genetic classes: deletion, uniparental disomy, and mutation. Ametropia >1 D was present in 97% of cases: myopia in 9%, hyperopia in 76%, and astigmatism in 94%. Myopia and anisometropia were found only in the genetic deletion group. Strabismus, most frequently exotropia, was found in 24 patients (75%). Ocular hypopigmentation was observed in 18 subjects (53%), with choroidal involvement in 3 cases and isolated iris involvement in 4. Hypopigmentation was observed in all of the 3 genetic classes. CONCLUSIONS: Ophthalmic alterations in AS were observed more frequently than has been previously reported, except for ocular hypopigmentation, which was observed less frequently. PMID- 21596295 TI - Autofluorescence of treated retinoblastoma. AB - PURPOSE: To describe the autofluorescent features of retinoblastomas after treatment. METHODS: Standard fundus photography and autofluorescence (AF) photography (580 nm excitation, 695 nm barrier filter) were performed on 88 tumors of 61 patients. Clinical features were correlated with autofluorescent features. RESULTS: The mean patient age at AF was 10.3 years. Of the 88 tumors, 5 (6%) were untreated, and 83 (94%) were treated. The untreated retinoblastomas showed hyperautofluorescence (hyperAF) at the site of calcification in all 5 cases (100%). The treated retinoblastomas showed intrinsic calcification in 54 cases (65%) and bright hyperAF at the site of calcification was detected in all cases. Of the 60 tumors with noncalcified remnant, the noncalcified portion was mildly hyperAF in 20 (33%), isoautofluorescence in 31 (52%), and mildly hypoautofluorescence (hypoAF) in 9 (15%). Surrounding retinal pigment epithelium hyperplasia appeared moderately hypoAF in 58 of 58 eyes (100%). Retinal pigment epithelium atrophy appeared mildly hyperAF in 29 (37%), isoautofluorescence in 33 (42%), and mildly hypoAF in 16 (21%). CONCLUSIONS: AF of retinoblastoma generally shows bright hyperAF of the calcified portion and variable AF of the noncalcified portion. The AF of calcification in retinoblastoma was confirmed by fluorescent microscopy of unstained sections of retinoblastoma after enucleation. PMID- 21596296 TI - Pediatric orbital floor fractures. AB - PURPOSE: To summarize the unique aspects of orbital floor fractures in children with regard to clinical presentation, management, and outcomes. METHODS: MEDLINE was searched using PubMed for English-language articles on orbital floor fractures in children. All 154 indexed articles pertaining to floor fractures in patients under 18 years of age in PubMed were reviewed. Studies looking at primarily complex fractures and case reports and studies that included pediatric patients but did not analyze them separately were excluded. Overall, 25 studies were included for the review. RESULTS: Inferior trapdoor fractures with muscle and soft tissue incarceration are the most common type of orbital fracture in children (27.8%-93%). They often present uniquely with severely restricted extraocular motility and diplopia (44%-100%), nausea and vomiting (14.7-55.6%), and minimal signs of external trauma. The majority of studies (83%) that analyzed time to surgery in relation to outcomes found that children who present early after initial injury and undergo prompt surgical repair appear to recover faster and have better postoperative motility than those receiving delayed treatment. CONCLUSIONS: Our understanding of pediatric orbital floor fractures continues to evolve. For young patients with symptomatic diplopia with positive forced ductions, soft tissue entrapment confirmed by computed axial tomography, and/or trapdoor fracture plus restricted ocular movement, having surgery within 2-5 days has been shown to result in better postoperative outcomes. It is recommended that surgery be considered within 48 hours of diagnosis. Long-term prospective studies are still needed to further characterize orbital floor fractures in children. PMID- 21596298 TI - Fiber-optic microcatheter trabeculotomy combined with anterior segment surgery in children: report of three cases. AB - Pediatric glaucoma may coexist with other anterior segment disorders, and when 2 surgeries are indicated in children, they are generally performed on separate days. We present 3 cases, documented with video, that illustrate the combination of anterior segment surgery (including cataract extraction and papillary membrane removal) with fiber-optic microcatheter trabeculotomy in infants. In one case, the microcatheter procedure could not be completed, and a trabeculotome was used to complete the trabeculotomy. One patient developed a mild hyphema after microcatheter trabeculotomy, which resolved. All cases were performed without other complications and with satisfactory results. PMID- 21596297 TI - An evidence-based update on myopia and interventions to retard its progression. AB - Myopia is the most common human eye disorder. With its increasing prevalence and earlier age-of-onset in recent birth cohorts, myopia now affects almost 33% of adults in the United States, and epidemic proportions of 85% to 90% adults in Asian cities. Unlike children in Western populations, where the prevalence of myopia is very low (less than 5%), Asian children have prevalences as high as 29% in 7-year-olds. In addition to the direct economic and social burdens of myopia, associated ocular complications may lead to substantial vision loss. This workshop summarizes the current literature regarding myopia epidemiology, genetics, animal model studies, risk factors, and clinical treatments. Published treatment strategies to retard the progression of myopia in children, such as pharmacologic agents, progressive addition lenses, and neural adaptation programs, are outlined. PMID- 21596299 TI - Familial juvenile glaucoma with underlying homozygous p.G61E CYP1B1 mutations. AB - We describe siblings with familial primary juvenile glaucoma from a consanguineous Saudi Arabian family. The phenotype segregated with homozygous p.G61E CYP1B1 mutations while MYOC mutation was not detected, illustrating that mutations in CYP1B1 rather than mutation in MYOC can underlie familial primary juvenile glaucoma in certain populations. PMID- 21596300 TI - Unilateral congenital glaucoma in a child with optic nerve aplasia. AB - Unilateral optic nerve aplasia is a rare, nonhereditary defect associated with anterior chamber malformations and other ocular malformations. We report the case of an 81/2-week-old boy with unilateral optic nerve aplasia who was diagnosed with glaucoma on presentation with corneal edema and an intraocular pressure of 36 mm Hg. The cornea edema cleared after a trabeculotomy, and subsequent fundus examination revealed optic nerve aplasia that was confirmed with magnetic resonance imaging. Intraocular pressure remained well-controlled with 71/2 months of follow-up. To our knowledge, this is the first documented case of optic nerve aplasia associated with glaucoma at presentation. PMID- 21596301 TI - Uveitis in Blau syndrome from a de novo mutation of the NOD2/CARD15 gene. AB - Blau syndrome (MIM 186580) is a rare autoinflammatory, familial granulomatous condition that occurs secondary to a single amino acid mutation of the NOD2/CARD15 gene on chromosome 16p12-q21. We report the case of a 2.5-year-old girl who presented for ophthalmic examination in the setting of rash and synovitis. Initially, small, evanescent, ovoid corneal subepithelial opacities unique to Blau syndrome were observed. She later developed a fulminant panuveitis that responded to immunomodulatory therapy. Subsequent genetic testing confirmed the diagnosis of Blau syndrome. Despite immunosuppression, at almost 7 years of age, she continues to have persistent panuveitis with vision of 20/20. PMID- 21596302 TI - Primary orbital mycosis in immunocompetent infants. AB - Fungal orbital infections are rare among children, especially in immunocompetent infants. Two infants presented to us with unilateral proptosis and swelling of the eyelids and periorbital area. Imaging showed an intraorbital mass causing proptosis and bony orbital expansion. There was no sinus, nasal, or intracranial involvement. Systemic evaluation did not reveal any evidence of a compromised immune system. A biopsy from the mass showed the presence of fungal infection. Both infants responded well to medical therapy with intravenous amphotericin B. PMID- 21596303 TI - Crystalline retinopathy in primary hyperoxaluria. AB - We present the case of a 2.5-month-old boy with type 1 primary hyperoxaluria and severe systemic oxalosis resulting in massive retinal crystalline deposition. Maculopathy was demonstrated by optical coherence tomography, and nystagmus was present. Electroretinography demonstrated retinal dysfunction, unusual in oxalosis. PMID- 21596304 TI - Mixed messages: how bacteria resolve conflicting signals. AB - An elegant new study by Bollenbach and Kishony (2011) in this issue of Molecular Cell shows how bacteria resolve the apparent conflicts created when they face two signals with opposite effects on gene expression. PMID- 21596305 TI - Stay tuned: miRNA expression and nonsense-mediated decay in brain development. AB - In this issue of Molecular Cell (Bruno et al., 2011), regulation of the key nonsense-mediated RNA decay (NMD) proteins UPF1 and MNL51 (BTZ) by miRNA 128 is discovered to fine-tune gene expression in brain differentiation, thus documenting a novel cooperation of two posttranscriptional mechanisms of gene regulation in developmental decision making. PMID- 21596306 TI - Tango between ubiquitin ligase and deubiquitinase keeps cyclin A tag free. AB - Ubiquitin ligases (E3s) and ubiquitin-specific proteases (USPs) dynamically oppose each other during ubiquitination. In this issue of Molecular Cell, Huang et al. (2011) provide a counterintuitive example of a USP residing in an E3 complex, and establish Usp37 as a gatekeeper of APC/C-mediated ubiquitination of cyclin A. PMID- 21596307 TI - "Competence" progress. AB - Zwang et al. (2011) have identified outputs of two EGF pulses that commit cells to cycle. The first induces components for lipid biosynthesis and sets up an inhibitory latch through p53. The second works through ERK to EGR1 and releases the latch to promote restriction point traverse. PMID- 21596308 TI - Resolution of gene regulatory conflicts caused by combinations of antibiotics. AB - Regulatory conflicts occur when two signals that individually trigger opposite cellular responses are present simultaneously. Here, we investigate regulatory conflicts in the bacterial response to antibiotic combinations. We use an Escherichia coli promoter-GFP library to study the transcriptional response of many promoters to either additive or antagonistic drug pairs at fine two dimensional (2D) resolution of drug concentration. Surprisingly, we find that this data set can be characterized as a linear sum of only two principal components. Component one, accounting for over 70% of the response, represents the response to growth inhibition by the drugs. Component two describes how regulatory conflicts are resolved. For the additive drug pair, conflicts are resolved by linearly interpolating the single drug responses, while for the antagonistic drug pair, the growth-limiting drug dominates the response. Importantly, for a given drug pair, the same conflict resolution strategy applies to almost all genes. These results provide a recipe for predicting gene expression responses to antibiotic combinations. PMID- 21596309 TI - Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. AB - The decision by a cell to enter a round of growth and division must be intimately coordinated with nutrient availability and its metabolic state. These metabolic and nutritional requirements, and the mechanisms by which they induce cell growth and proliferation, remain poorly understood. Herein, we report that acetyl-CoA is the downstream metabolite of carbon sources that represents a critical metabolic signal for growth and proliferation. Upon entry into growth, intracellular acetyl CoA levels increase substantially and consequently induce the Gcn5p/SAGA catalyzed acetylation of histones at genes important for growth, thereby enabling their rapid transcription and commitment to growth. Thus, acetyl-CoA functions as a carbon-source rheostat that signals the initiation of the cellular growth program by promoting the acetylation of histones specifically at growth genes. PMID- 21596310 TI - L3MBTL2 protein acts in concert with PcG protein-mediated monoubiquitination of H2A to establish a repressive chromatin structure. AB - We have identified human MBT domain-containing protein L3MBTL2 as an integral component of a protein complex that we termed Polycomb repressive complex 1 (PRC1)-like 4 (PRC1L4), given the copresence of PcG proteins RING1, RING2, and PCGF6/MBLR. PRC1L4 also contained E2F6 and CBX3/HP1gamma, known to function in transcriptional repression. PRC1L4-mediated repression necessitated L3MBTL2 that compacted chromatin in a histone modification-independent manner. Genome-wide location analyses identified several hundred genes simultaneously bound by L3MBTL2 and E2F6, preferentially around transcriptional start sites that exhibited little overlap with those targeted by other E2Fs or by L3MBTL1, another MBT domain-containing protein that interacts with RB1. L3MBTL2-specific RNAi resulted in increased expression of target genes that exhibited a significant reduction in H2A lysine 119 monoubiquitination. Our findings highlight a PcG/MBT collaboration that attains repressive chromatin without entailing histone lysine methylation marks. PMID- 21596311 TI - Multiple sequence-specific factors generate the nucleosome-depleted region on CLN2 promoter. AB - Nucleosome-depleted regions (NDRs) are ubiquitous on eukaryotic promoters. The formation of many NDRs cannot be readily explained by previously proposed mechanisms. Here, we carry out a focused study on a physiologically important NDR in the yeast CLN2 promoter (CLN2pr). We show that this NDR does not result from intrinsically unfavorable histone-DNA interaction. Instead, we identified eight conserved factor binding sites, including that of Reb1, Mcm1, and Rsc3, that cause the local nucleosome depletion. These nucleosome-depleting factors (NDFs) work redundantly, and simultaneously mutating all their binding sites eliminates CLN2pr NDR. The loss of the NDR induces unreliable "on/off" expression in individual cell cycles, but in the presence of the NDR, NDFs have little direct effect on transcription. We present bioinformatic evidence that the formation of many NDRs across the genome involves multiple NDFs. Our findings also provide significant insight into the composition and spatial organization of functional promoters. PMID- 21596312 TI - RNF20 inhibits TFIIS-facilitated transcriptional elongation to suppress pro oncogenic gene expression. AB - hBRE1/RNF20 is the major E3 ubiquitin ligase for histone H2B. RNF20 depletion causes a global reduction of monoubiquitylated H2B (H2Bub) levels and augments the expression of growth-promoting, pro-oncogenic genes. Those genes reside preferentially in compact chromatin and are inefficiently transcribed under basal conditions. We now report that RNF20, presumably via H2Bub, selectively represses those genes by interfering with chromatin recruitment of TFIIS, a factor capable of relieving stalled RNA polymerase II. RNF20 inhibits the interaction between TFIIS and the PAF1 complex and hinders transcriptional elongation. TFIIS ablation selectively abolishes the upregulation of those genes upon RNF20 depletion and attenuates the cellular response to EGF. Consistent with its positive role in transcription of pro-oncogenic genes, TFIIS expression is elevated in various human tumors. Our findings provide a molecular mechanism for selective gene repression by RNF20 and position TFIIS as a key target of RNF20's tumor suppressor activity. PMID- 21596313 TI - Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. AB - Poly(ADP-ribose) is a major regulatory macromolecule in the nucleus, where it regulates transcription, chromosome structure, and DNA damage repair. Functions in the interphase cytoplasm are less understood. Here, we identify a requirement for poly(ADP-ribose) in the assembly of cytoplasmic stress granules, which accumulate RNA-binding proteins that regulate the translation and stability of mRNAs upon stress. We show that poly(ADP-ribose), six specific poly(ADP-ribose) polymerases, and two poly(ADP-ribose) glycohydrolase isoforms are stress granule components. A subset of stress granule proteins, including microRNA-binding Argonaute family members Ago1-4, are modified by poly(ADP-ribose), and such modification increases upon stress, a condition when both microRNA-mediated translational repression and microRNA-directed mRNA cleavage are relieved. Similar relief of repression is also observed upon overexpression of specific poly(ADP-ribose) polymerases or, conversely, upon knockdown of glycohydrolase. We conclude that poly(ADP-ribose) is a key regulator of posttranscriptional gene expression in the cytoplasm. PMID- 21596314 TI - Identification of a microRNA that activates gene expression by repressing nonsense-mediated RNA decay. AB - Nonsense-mediated decay (NMD) degrades both normal and aberrant transcripts harboring stop codons in particular contexts. Mutations that perturb NMD cause neurological disorders in humans, suggesting that NMD has roles in the brain. Here, we identify a brain-specific microRNA-miR-128-that represses NMD and thereby controls batteries of transcripts in neural cells. miR-128 represses NMD by targeting the RNA helicase UPF1 and the exon-junction complex core component MLN51. The ability of miR-128 to regulate NMD is a conserved response occurring in frogs, chickens, and mammals. miR-128 levels are dramatically increased in differentiating neuronal cells and during brain development, leading to repressed NMD and upregulation of mRNAs normally targeted for decay by NMD; overrepresented are those encoding proteins controlling neuron development and function. Together, these results suggest the existence of a conserved RNA circuit linking the microRNA and NMD pathways that induces cell type-specific transcripts during development. PMID- 21596315 TI - Deubiquitinase USP37 is activated by CDK2 to antagonize APC(CDH1) and promote S phase entry. AB - Cell cycle progression requires the E3 ubiquitin ligase anaphase-promoting complex (APC/C), which uses the substrate adaptors CDC20 and CDH1 to target proteins for proteasomal degradation. The APC(CDH1) substrate cyclin A is critical for the G1/S transition and, paradoxically, accumulates even when APC(CDH1) is active. We show that the deubiquitinase USP37 binds CDH1 and removes degradative polyubiquitin from cyclin A. USP37 was induced by E2F transcription factors in G1, peaked at G1/S, and was degraded in late mitosis. Phosphorylation of USP37 by CDK2 stimulated its full activity. USP37 overexpression caused premature cyclin A accumulation in G1 and accelerated S phase entry, whereas USP37 knockdown delayed these events. USP37 was inactive in mitosis because it was no longer phosphorylated by CDK2. Indeed, it switched from an antagonist to a substrate of APC(CDH1) and was modified with degradative K11-linked polyubiquitin. PMID- 21596316 TI - Two phases of mitogenic signaling unveil roles for p53 and EGR1 in elimination of inconsistent growth signals. AB - Normal cells require continuous exposure to growth factors in order to cross a restriction point and commit to cell-cycle progression. This can be replaced by two short, appropriately spaced pulses of growth factors, where the first pulse primes a process, which is completed by the second pulse, and enables restriction point crossing. Through integration of comprehensive proteomic and transcriptomic analyses of each pulse, we identified three processes that regulate restriction point crossing: (1) The first pulse induces essential metabolic enzymes and activates p53-dependent restraining processes. (2) The second pulse eliminates, via the PI3K/AKT pathway, the suppressive action of p53, as well as (3) sets an ERK-EGR1 threshold mechanism, which digitizes graded external signals into an all or-none decision obligatory for S phase entry. Together, our findings uncover two gating mechanisms, which ensure that cells ignore fortuitous growth factors and undergo proliferation only in response to consistent mitogenic signals. PMID- 21596317 TI - The specificity and topology of chromatin interaction pathways in yeast. AB - Packaging of DNA into chromatin has a profound impact on gene expression. To understand how changes in chromatin influence transcription, we analyzed 165 mutants of chromatin machinery components in Saccharomyces cerevisiae. mRNA expression patterns change in 80% of mutants, always with specific effects, even for loss of widespread histone marks. The data are assembled into a network of chromatin interaction pathways. The network is function based, has a branched, interconnected topology, and lacks strict one-to-one relationships between complexes. Chromatin pathways are not separate entities for different gene sets, but share many components. The study evaluates which interactions are important for which genes and predicts additional interactions, for example between Paf1C and Set3C, as well as a role for Mediator in subtelomeric silencing. The results indicate the presence of gene-dependent effects that go beyond context-dependent binding of chromatin factors and provide a framework for understanding how specificity is achieved through regulating chromatin. PMID- 21596319 TI - Assessment of echo-attenuated plaque by optical coherence tomography and its impact on post-procedural creatine kinase-myocardial band elevation in elective stent implantation. AB - OBJECTIVES: This study examined morphological characteristics of echo-attenuated plaques by optical coherence tomography (OCT) and evaluated their influence on creatine kinase-myocardial band (CK-MB) elevation after percutaneous coronary intervention (PCI) in patients with elective stent implantation. BACKGROUND: Recent intravascular ultrasound studies have described atherosclerotic plaques with echo attenuation (EA) without associated bright echoes that are correlated with no-reflow phenomenon after PCI. METHODS: We studied 135 native de novo culprit coronary lesions in 135 patients with normal pre-PCI CK-MB levels (28 with unstable angina; 107 with stable angina) who underwent intravascular ultrasound and OCT examinations before elective stent implantation. The lesions were divided into 2 groups based on the presence or absence of EA, and OCT findings were compared. We then determined predictors of post-PCI CK-MB elevation. RESULTS: EA was found in 47 (34.8%) lesions and was associated with the presence of OCT-derived thin-capped fibroatheroma, ruptured plaques, greater lipid content, intravascular ultrasound-derived large reference and plaque area, lesion eccentricity, and microcalcification. Elevated CK-MB levels were observed in 36 (26.7%) lesions, and significantly more frequently in lesions with EA than without. In multivariable analysis, EA (odds ratio [OR]: 3.49; 95% confidence interval [CI]: 1.53 to 7.93; p = 0.003) and OCT-derived ruptured plaque (OR: 2.92; 95% CI: 1.21 to 7.06; p = 0.017) were independent predictors of post-PCI CK MB elevation. CONCLUSIONS: Atherosclerotic plaques with EA were associated with characteristics considered to be high risk or unstable. OCT examination showed an additive predictive value to the presence of EA for post-PCI CK-MB elevation. PMID- 21596320 TI - Optical coherence tomography or intravascular ultrasound? PMID- 21596318 TI - Emerging genomic applications in coronary artery disease. AB - Over the last 4 years, an unprecedented number of studies illuminating the genomic underpinnings of common "polygenic" diseases including coronary artery disease have been published. Notably, these studies have established numerous deoxyribonucleic acid (DNA) variants within or near chromosome 9p21.3, the LPA, CXADR, and APOE genes, to name a few, as key coronary artery disease and sudden cardiac death susceptibility markers. Most importantly, many of these DNA variants confer over a 2-fold increase in risk for coronary artery disease, myocardial infarction, and ventricular fibrillation. Additionally, loss-of function variants in the hepatic cytochrome 2C19 system have now been found to be the predominant genetic mediators of clopidogrel antiplatelet response, with variant carriers having a >3-fold increase in risk for stent thrombosis. In the near future, many additional rare polymorphisms, structural variants, and tissue specific epigenetic features of the human genome including DNA methylation, histone modifications, and chromatin state will emerge as significant contributors to disease pathogenesis and drug response. In aggregate, these findings will have the potential to radically change the practice of cardiovascular medicine. However, only the individual clinician can ultimately enable the translation of these important discoveries to systematic implementation in clinical practice. PMID- 21596321 TI - The relationship between attenuated plaque identified by intravascular ultrasound and no-reflow after stenting in acute myocardial infarction: the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial. AB - OBJECTIVES: The aim of this study was to understand the impact of attenuated plaque on distal embolization during stent implantation in patients with acute myocardial infarction (AMI). BACKGROUND: Attenuated plaques identified by grayscale intravascular ultrasound (IVUS) might predict transient deterioration in coronary flow and/or no-reflow during percutaneous coronary intervention (PCI). METHODS: We analyzed clinical, angiographic, and IVUS data from 364 patients (n = 364 infarct-related arteries) enrolled in the randomized HORIZONS AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial. No-reflow was final Thrombolysis In Myocardial Infarction (TIMI) flow grade <=2 in the absence of mechanical obstruction. Attenuated plaque was hypoechoic or mixed atheroma with ultrasound attenuation without calcification. A mean attenuation score was created by measuring the angle of attenuation each 1 mm, scoring the angle as 1 to 4 (corresponding to <90 degrees , 90 degrees to 180 degrees , 180 degrees to 270 degrees , or 270 degrees to 360 degrees , respectively), summing the scores, and normalizing for analysis length. RESULTS: Overall, 284 (78.0%) patients had attenuated plaques; no-reflow occurred in 37 (10.2%). Patients with no-reflow had a higher mean attenuation score (median [interquartile range] 2.2 [0.0 to 2.8] vs. 1.3 [0.7 to 1.8], p < 0.001), lower baseline left ventricular ejection fraction (52.8% [43.2% to 61.5%] vs. 61.4% [52.2% to 68.1%], p = 0.002), and more baseline angiographic thrombus (89.2% vs. 74.1%, p = 0.043) with no differences in post-PCI stent expansion versus patients without no-reflow. Multivariate analysis indicated that mean attenuation score was the strongest predictor of no-reflow. The mean attenuation score that best predicted no-reflow was >=2 points (90 degrees to 180 degrees , sensitivity of 81.5%, and specificity of 80.5%). CONCLUSIONS: Attenuated plaque was present in three-quarters of patients with AMI. The amount of attenuated plaque strongly correlated with no-reflow; the larger the attenuated plaque, the greater the likelihood of no-reflow. (Dual Arm Factorial Randomized Trial in Patients w/ST Segment Elevation AMI to Compare the Results of Using Anticoagulation With Either Unfractionated Heparin + Routine GP IIb/IIIa Inhibition or Bivalirudin + Bail-out GP IIb/IIIa Inhibition; and Primary Angioplasty with stent implantation with Either a Slow Rate-release Paclitaxel eluting Stent [TAXUSTM] or Uncoated Bare Metal Stent [EXPRESS2TM]; NCT00433966). PMID- 21596323 TI - Insights from a virtual world. PMID- 21596322 TI - The relationship between volumetric plaque components and classical cardiovascular risk factors and the metabolic syndrome a 3-vessel coronary artery virtual histology-intravascular ultrasound analysis. AB - OBJECTIVES: The aim of this study was to analyze volumetric plaque composition of the coronary arterial tree according to the classical cardiovascular risk factors and metabolic syndrome (MS) using virtual histology-intravascular ultrasound (VH IVUS). BACKGROUND: It remains unclear how the cardiovascular risk factors correlate with the histological components of coronary plaques. METHODS: "Whole vessel" VH-IVUS analysis was performed in 189 vessels of 63 patients. The components of atherosclerotic plaques were classified as fibrous, fibrofatty, necrotic core (NC), and dense calcium. Quantitative assessment of these plaque components and the presence of VH-IVUS-derived thin-cap fibroatheroma in the coronary arterial trees were compared with cardiovascular risk factors. RESULTS: There was a significantly larger mean plaque-plus-media burden in patients with diabetes mellitus (DM) (47 +/- 5% vs. 39 +/- 7% in non-DM patients, p < 0.001) and MS (47 +/- 4% vs. 39 +/- 7% in non-MS patients, p < 0.001). DM patients had a significantly larger %NC (17.8 +/- 5.6% vs. 12.5 +/- 6.1%, p = 0.003) compared with non-DM patients; and MS patients had a significantly larger %NC (17.3 +/- 5.8% vs. 12.8 +/- 6.2%, p = 0.016) as compared to non-MS patients. Finally, VH IVUS-derived thin-cap fibroatheromas were more frequent in DM patients (3.4 +/- 2.0 vs. 2.1 +/- 1.7 in non-DM patients, p = 0.016) and in MS patients (4.1 +/- 2.1 vs. 1.9 +/- 1.4 in non-MS patients, p = 0.001). CONCLUSIONS: Three-vessel VH IVUS analysis showed that DM and MS patients, compared to patients without DM or MS, had a larger plaque-plus-media burden, larger amount of NC, and more frequent VH-IVUS-derived thin-cap fibroatheromas in coronary arterial trees, implying greater plaque vulnerability in DM and MS patients. PMID- 21596324 TI - The impact of pravastatin pre-treatment on periprocedural microcirculatory damage in patients undergoing percutaneous coronary intervention. AB - OBJECTIVES: This study evaluated the effect of pravastatin pre-treatment on post procedural index of microcirculatory resistance (IMR) values that are introduced for assessing the status of the microcirculation independently of the epicardial area. BACKGROUND: Pre-treatment with statins decreased the incidence of cardiac enzyme increase after percutaneous coronary intervention (PCI). However, 2 different etiologies, distal embolization of atheroma or ischemia caused by side branch occlusion, cannot be differentiated by measuring cardiac enzyme levels. METHODS: Eighty patients with stable angina were randomly assigned to either pravastatin treatment (20 mg/day, n = 40) or no treatment (n = 40) 4 weeks before elective PCI. An intracoronary pressure/temperature sensor-tipped guidewire was used. Thermodilution curves were obtained during maximal hyperemia. The IMR was calculated from the ratio of the mean distal coronary pressure at maximal hyperemia to the inverse of mean hyperemic transit time. Creatine kinase myocardial band and troponin I values were measured at baseline and at 8 and 24 h after PCI. RESULTS: Post-PCI troponin I levels tended to be lower in patients with pravastatin treatment (median: 0.13 [interquartile range (IQR): 0.10 to 0.31] vs. 0.22 [IQR: 0.10 to 0.74] ng/ml, p = 0.1). However, patients with pravastatin treatment had significantly lower IMR than did patients without pravastatin treatment (median: 12.6 [IQR: 8.8 to 18.0] vs. 17.6 [IQR: 9.7 to 33.9], p = 0.007). Multivariate analysis revealed that the lack of pravastatin pre-treatment was the only independent predictor of post-PCI impaired IMR (p = 0.03). CONCLUSIONS: Post-PCI measurement of the IMR confirmed that pre-treatment with pravastatin was associated with reduced microvascular dysfunction induced by PCI regardless of side branch occlusions. These data suggest that pre-treatment with statin is desired in patients undergoing elective PCI. (The Impact of Pravastatin Pretreatment on Periprocedural Microcirculatory Damage After Percutaneous Coronary Intervention; UMIN000002885). PMID- 21596325 TI - The impact of circulating cholesterol crystals on vasomotor function: implications for no-reflow phenomenon. AB - OBJECTIVES: The purpose of this study was to determine if cholesterol crystals can injure the endothelial surface by their jagged edges altering vasoreactivity and contributing to no-reflow after intervention. BACKGROUND: After plaque rupture, cholesterol crystals are released into the circulation and flow downstream contacting the arterial wall. METHODS: Both carotid arteries from 22 rabbits were placed in a dual perfusion chamber and challenged with norepinephrine followed by acetylcholine and nitroprusside. Arterial diameters were measured before and after exposure to cholesterol crystals or microspheres and compared with diameters of normal control arteries. Arteries were examined by light, confocal, atomic force and scanning electron microscopy. RESULTS: Pre exposure mean arterial diameter was 2.33 +/- 0.27 mm. With baseline norepinephrine there was vasoconstriction of 0.82 +/- 0.19 mm, 0.79 +/- 0.18 mm, and 0.83 +/- 0.16 mm in lumen diameter in the crystal, microsphere, and control groups, respectively. After cholesterol crystals or microspheres, vasoconstriction was significantly less for cholesterol crystals but not for microspheres (0.71 +/- 0.28 mm and 0.81 +/- 0.15 mm; p < 0.02 and p = 0.68). After acetylcholine in the same artery, there was significantly less dilation before versus after crystals (0.49 +/- 0.24 mm vs. 0.38 +/- 0.22 mm, p = 0.04) but not with microspheres or in the control group. There was no significant difference after nitroprusside in any group, suggesting endothelial injury. By scanning electron microscopy, cholesterol crystals were found embedded in the intima with endothelial cell tears whereas the microsphere treatment and control groups had minimal or no injury (93% vs. 31% vs. 14%; p < 0.01). By atomic force microscopy, surface roughness was significantly greater with cholesterol crystals compared with microspheres or in control arteries (p < 0.05). CONCLUSIONS: Cholesterol crystals damaged the endothelium and reduced vasodilator response, potentially aggravating myocardial ischemia after interventions. PMID- 21596326 TI - Long-term safety and efficacy of paclitaxel-eluting stents final 5-year analysis from the TAXUS Clinical Trial Program. AB - OBJECTIVES: These studies sought to evaluate the clinical outcomes of the slow release Taxus paclitaxel-eluting stent (PES) versus an otherwise identical bare metal stent (BMS). BACKGROUND: Prior studies were not individually powered to generate reliable estimates of low-frequency safety endpoints or to characterize the long-term safety and efficacy profile of PES. METHODS: The completed 5-year databases from the prospective, randomized, double-blind TAXUS I, II, IV, and V trials were pooled for a patient-level analysis. RESULTS: The study population comprised 2,797 randomized patients (1,400 PES and 1,397 BMS). At the end of the 5-year study period, PES compared with BMS significantly reduced the rate of ischemia-driven target lesion revascularization (12.3% vs. 21.0%, p < 0.0001), with consistent reductions across high-risk subgroups and in patients with and without routine angiographic follow-up. There were no significant differences between the stent types in the 1-year or cumulative 5-year rates of death or myocardial infarction (MI). However, cardiac death or MI between 1 and 5 years was increased with PES (6.7% vs. 4.5%, p = 0.01), as was stent thrombosis (protocol definition: 0.9% vs. 0.2%, p = 0.007; ARC definition: 1.4% vs. 0.9%, p = 0.18). CONCLUSIONS: In this pooled patient-level analysis from the prospective, randomized, double-blind TAXUS trials, PES compared with BMS resulted in a durable 47% reduction in the 5-year rate of ischemia-driven target lesion revascularization in simple and complex lesions, with nonsignificant differences in the cumulative 5-year rates of death or MI. Between 1 and 5 years, however, the rates of cardiac death or MI and protocol-defined stent thrombosis were increased with PES. PMID- 21596327 TI - Late-term clinical outcomes with zotarolimus- and sirolimus-eluting stents. 5 year follow-up of the ENDEAVOR III (A Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions). AB - OBJECTIVES: This study sought to compare late safety and efficacy outcomes following percutaneous coronary revascularization with zotarolimus-eluting stents (ZES) and sirolimus-eluting stents (SES). BACKGROUND: Despite higher late lumen loss and binary restenosis with ZES compared with SES, it is uncertain whether differences in early angiographic measures translate into more disparate late clinical events. METHODS: Clinical outcomes were prospectively evaluated through 5 years in the ENDEAVOR III (A Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) that randomized 436 patients of relatively low anatomic and clinical risk to treatment with ZES (n = 323) or SES (n = 113) and evaluated a primary endpoint of 8-month angiographic late lumen loss. RESULTS: At 5 years (completeness of follow-up: 95.2%), pre-specified endpoints of all-cause mortality (5.2% vs. 13.0%, p = 0.02), myocardial infarction (1.0% vs. 4.6%, p = 0.03), and the composite event rates of cardiac death/myocardial infarction (1.3% vs. 6.5%, p = 0.009) and major adverse cardiac events (14.0% vs. 22.2%, p = 0.05) were significantly lower among patients treated with ZES. Rates of target lesion (8.1% ZES vs. 6.5% SES, p = 0.68) and target vessel revascularization were similar between treatment groups. Stent thrombosis was infrequent and similar in both groups (0.7% ZES vs. 0.9% SES, p = 1.0). Between 9 months and 5 years, progression of major adverse cardiac events was significantly more common with SES than with ZES (16.7% vs. 7.8%, p = 0.015). CONCLUSIONS: Despite initially higher angiographic late lumen loss, rates of clinical restenosis beyond the protocol-specified angiographic follow-up period remain stable with ZES compared with the rates for SES, resulting in similar late-term efficacy. Over 5 years, significant differences in death, myocardial infarction, and composite endpoints favored treatment with ZES. (The Medtronic Endeavor III Drug Eluting Coronary Stent System Clinical Trial [ENDEAVOR III]; NCT00217256). PMID- 21596328 TI - My stent is better than your stent...Or is it? PMID- 21596329 TI - Autopsy validation study of the academic research consortium stent thrombosis definition. AB - OBJECTIVES: This study sought to validate the sensitivity and specificity of the Academic Research Consortium's (ARC) classification of stent thrombosis. BACKGROUND: Classification of stent thrombosis according to ARC criteria has become widely accepted. The criteria have not been validated against an autopsy standard. METHODS: An autopsy registry of 139 subjects with prior coronary stenting underwent detailed histopathological analysis to assess for stent thrombosis. Based on clinical data only, cases were adjudicated according to ARC stent thrombosis criteria, including a proposed modification of the possible classification to include death beyond 30 days due only to sudden death or acute ischemia. RESULTS: Autopsy results confirmed 51 cases as positive and 88 as negative for stent thrombosis. Clinical adjudication classified 105 cases as definite (10), probable (31), or possible (64) ARC stent thrombosis. Specificity was high for definite (99%) and definite plus probable (83%) criteria, but sensitivity was poor at 18% and 51%, respectively. Including the possible cases improved sensitivity to 92% but reduced specificity to 34% (58 false positives). The modified possible criteria eliminated 13 false positive cases (specificity = 49%) and was the best approximation of a hypothetical gold standard in a sensitivity analysis if late death represented at least 20% of all stent thrombosis cases. CONCLUSIONS: In a selected autopsy sample, restricting ARC stent thrombosis to definite or definite plus probable criteria results in substantial under-reporting of confirmed cases. Inclusion of a modified possible classification may provide the best estimate of late and very late stent thrombosis rates. PMID- 21596330 TI - Early and long-term outcomes after combined percutaneous revascularization in patients with carotid and coronary artery stenoses. AB - OBJECTIVES: This study sought to evaluate the 30-day and long-term clinical outcomes of patients with carotid obstructive disease (COD) and concomitant coronary artery disease (CAD) undergoing a combined percutaneous revascularization, in 4 high-volume centers skilled for the treatment of multilevel vascular disease. BACKGROUND: The optimal management of patients with COD and concomitant CAD remains controversial. A variety of therapeutic strategies, including coronary artery bypass grafting, alone or in combination with carotid artery revascularization, have been reported. METHODS: Between January 2006 and April 2010, 239 consecutive patients with COD (symptomatic carotid stenosis in 20.5%) and concomitant CAD were treated with staged or simultaneous carotid artery stenting and percutaneous coronary intervention, and enrolled in this prospective registry. The primary endpoint was the incidence of major cardiac and cerebrovascular events, including any death, myocardial infarction, or stroke occurring between the first revascularization procedure and 30 days after treatment of the second vascular territory affected. RESULTS: The incidence of the primary endpoint at 30 days was 4.2% (95% confidence interval [CI]: 2.02 to 7.56). The rate of death, myocardial infarction, and stroke at long term follow-up (median 520 days) was 4.2%, 2.1%, and 3.8%, respectively. At long term follow-up, patients with previous cardiovascular disease had significantly higher rates of major cardiac and cerebrovascular events than did patients with a first clinical episode (17% vs. 6%, hazard ratio: 3.34; 95% CI: 1.46 to 7.63; p = 0.004). CONCLUSIONS: In patients with COD and concomitant CAD, a combined percutaneous treatment compares favorably with previous surgical or hybrid experiences. Such strategy may be particularly suited to complex patients at high surgical risk. PMID- 21596331 TI - 30-day readmissions after coronary artery bypass graft surgery in New York State. AB - OBJECTIVES: The aim of this study was to identify reasons for and predictors of readmission. BACKGROUND: Short-term readmissions have been identified as an important cause of escalating health care costs, and coronary artery bypass graft (CABG) surgery is 1 of the most expensive procedures. METHODS: We retrospectively analyzed 30-day readmissions for 33,936 New York State patients who underwent CABG surgery between January 1, 2005, and November 30, 2007. The main reasons for readmission (principal diagnoses) and the significant independent predictors of readmission were identified. The hospital-level relationship between risk adjusted mortality rate and risk-adjusted readmission rate was explored to determine the value of readmission rate as a complementary measure of quality. RESULTS: The most common reasons for readmission were post-operative infection (16.9%), heart failure (12.8%), and "other complications of surgical and medical care" (9.8%). Increasing age, female sex, African-American race, higher body mass index, numerous comorbidities, 2 post-operative complications (renal failure and unplanned cardiac reoperation), Medicare or Medicaid status, discharges to a skilled nursing facility, saphenous vein grafts, and longer lengths of stay were all associated with higher rates of readmission. The correlation between the risk adjusted 30-day readmission rate of hospitals and risk-adjusted in-hospital/30 day mortality rate was 0.32 (p = 0.047). The range across hospitals in the readmission rate was from 8.3% to 21.1%. CONCLUSIONS: The 30-day readmission rate for CABG surgery remains high, despite decreases in short-term mortality. Patients with any of the numerous risk factors for readmission should be closely monitored. Hospital readmission rates are not highly correlated with mortality rates and might serve as an independent quality measure. PMID- 21596332 TI - Reducing readmission rates: Does coronary artery bypass graft surgery provide clarity? PMID- 21596333 TI - Explantation of patent foramen ovale closure devices: a multicenter survey. AB - OBJECTIVES: The aim of this study was to examine the frequency and causes of surgical explantation of patent foramen ovale (PFO) closure devices. BACKGROUND: PFO has been linked with cryptogenic strokes, recurrent transient neurologic deficits, sleep apnea, decompression illness, and migraines. Several randomized trials are in progress to determine whether PFO closure is preferable to medical management in the treatment of patients with cryptogenic strokes or migraine. The majority of PFO closures are performed off-label, because there is no U.S. Food and Drug Administration approval for use of any device to close a PFO. As data are accumulating on the benefits of implanting PFO closure devices, it is also important to examine complications that might occur. METHODS: We performed a database review to identify the frequency and causes of PFO device explantation, examining 18 PFO closure centers in Europe and the United States. RESULTS: Of the 13,736 percutaneous PFO device implantations performed over the past 9 years at these 18 institutions, 38 devices (0.28% [95% confidence interval: 0.20% to 0.37%]) required surgical removal. There were a wide range of causes cited for these removals. The most common cause for explantation was chest pain (n = 14), often determined to be secondary to nickel allergy to the PFO device. Other causes for explantation included persistence of a residual shunt (n = 12), the presence of thrombus on the device (n = 4), pericardial effusion (n = 2), perforation of the atrium or aortic root (n = 2), recurrent strokes (n = 1), the development of endocarditis (n = 1), and undocumented reasons (n = 2). CONCLUSIONS: The vast majority of PFO closure procedures are performed safely with minimal complications. However, there is a small (0.28%) incidence of severe long-term problems associated with PFO closure that might require surgical removal of the device. In addition, the frequency of surgical explantation was found to be device-dependent; some of these devices seem to be safer than others. PMID- 21596334 TI - Radial artery graft string sign due to lumen obliteration by neointima: insight from optical coherence tomography. PMID- 21596335 TI - Usefulness of rotational atherectomy in preventing polymer damage of everolimus eluting stent in calcified coronary artery. PMID- 21596336 TI - Drug-eluting stents for saphenous vein graft lesions. PMID- 21596337 TI - Drug-eluting stents versus bare-metal stents in saphenous vein graft interventions. PMID- 21596340 TI - Use of cardiac computed tomography prior to percutaneous coronary sinus device placement for the treatment of mitral regurgitation. PMID- 21596341 TI - The academic research consortium governance charter. PMID- 21596342 TI - Interventional cardiology, alive and well at ACC.11 and i2 Summit 2011. PMID- 21596343 TI - Introduction: Clinical pathology and hematology. PMID- 21596344 TI - When normal is abnormal: keys to laboratory diagnosis of hidden endocrine disease. AB - Although veterinary clinicians commonly rely on panels of laboratory tests with individual results flagged when abnormal, care should be taken in interpreting normal test results as well. There are several examples of this in evaluating patients with endocrine disease. The finding of a normal leukogram (absence of a stress leukogram) can be indicative of adrenal insufficiency in dogs, and this disorder can be especially elusive when there are no overt indicators of mineralocorticoid deficiency. Cats with hyperthyroidism can have normal serum thyroid hormone concentrations, normal hematocrits, and normal serum concentrations of creatinine despite the presence of disease that affects these parameters. A normal serum phosphorus concentration, in the face of azotemia, isosthenuria, and hypertension can point a clinician toward a diagnosis of primary hyperaldosteronism rather than primary renal disease. A normal serum parathyroid hormone concentration in the face of hypercalcemia is inappropriate and can indicate the presence of primary hyperparathyroidism. Similarly, hypoglycemia accompanied by a normal serum insulin concentration can be found in cases of hyperinsulinism. These normal findings in abnormal patients, and their mechanisms, are reviewed. PMID- 21596345 TI - Advances in hematology analyzers. AB - The complete blood count is one of the basic building blocks of the minimum database in veterinary medicine. Over the past 20 years, there has been a tremendous advancement in the technology of hematology analyzers and their availability to the general practitioner. There are 4 basic methodologies that can be used to generate data for a complete blood count: manual methods, quantitative buffy coat analysis, automated impedance analysis, and flow cytometric analysis. This article will review the principles of these methodologies, discuss some of their advantages and disadvantages, and describe some of the hematology analyzers that are available for the in-house veterinary laboratory. PMID- 21596346 TI - Cytology of canine and feline cutaneous and subcutaneous lesions and lymph nodes. AB - Fine-needle aspirates and impression smears of cutaneous and subcutaneous lesions and lymph nodes are the most commonly submitted cytology samples from veterinary patients. Diagnostic cytology samples of these lesions are easily collected in patients without anesthesia or analgesia. Cytology can yield immediate results and may prevent the need for additional tests that use more invasive methods of sample collection. This article offers a brief review of how to collect and submit cytology samples and describes cytologic lesions that often are diagnosed in dogs and cats. When applicable, differences between disease progression in dogs and cats are described. PMID- 21596347 TI - Getting to the point: indications for fine-needle aspiration of internal organs and bone. AB - The technique of fine-needle biopsy (fine-needle aspiration or fine-needle fenestration) for cytologic evaluation can be extended to many sites beyond the traditional lymph node and skin. Intra-abdominal, intrathoracic, and bone lesions can be easily and rapidly evaluated cytologically. Percutaneous fine-needle aspiration and fine-needle fenestration are useful, accurate, and inexpensive techniques with a rapid turnaround time, and outpatient applicability. For most pets, these minimally invasive techniques do not require anesthesia or analgesia. Although risks are inherent with any invasive procedure, complications are uncommon even with visceral and intrathoracic fine-needle biopsy. Attention to appropriate technique and close patient monitoring minimize the morbidity and improve the diagnostic utility. The low cost, low risk, minimal invasiveness, and high diagnostic yield make fine-needle biopsy particularly attractive to clients. In combination with ultrasound guidance and newer staining techniques, these diagnostic procedures are invaluable to the veterinary clinician. PMID- 21596348 TI - Laboratory tests for diagnosis of gastrointestinal and pancreatic diseases. AB - The panel of laboratory tests available for diagnosis of gastrointestinal (GI) diseases in dogs and cats is wide, and, recently, several new tests have been developed. This article will focus on advances in laboratory tests that are available for the general practitioner for diagnosis of GI diseases. Laboratory tests for diagnosis of gastric and intestinal infectious diseases include fecal parasite screening tests, enzyme-linked immunosorbent assays for parvoviral enteritis, and some specific bacterial tests like fluorescent in situ hybridization for identification of specific bacteria attached to the intestinal epithelial cells. Serum concentrations of folate and cobalamin are markers of intestinal absorption, but are also changed in exocrine pancreatic insufficiency and intestinal bacterial overgrowth. Hypocobalaminemia is common in GI and pancreatic disease. Decreased serum trypsin-like immunoreactivity is a very sensitive and specific test for the diagnosis of exocrine pancreatic insufficiency in dogs and cats. Serum pancreatic lipase is currently the most sensitive and specific test to identify pancreatic cell damage and acute pancreatitis. However, serum canine pancreas-specific lipase is less sensitive in canine chronic pancreatitis. Increased serum trypsin-like immunoreactivity is also specific for pancreatic damage but is less sensitive. It is very likely that further studies will help to better specify the role of these new tests in the diagnosis of canine and feline pancreatic diseases. PMID- 21596349 TI - Interpretation of laboratory tests for canine Cushing's syndrome. AB - Hypercortisolism (HC) is a common disease in dogs. This article will review the laboratory tests that are available for diagnosis of HC and laboratory tests for differentiating between causes of HC. An emphasis will be made on the clinical process that leads to the decision to perform those tests and common misconceptions and issues that arise when performing them. To choose between the adrenocorticotropic hormone (ACTH)-stimulation test and the low-dose dexamethasone suppression test (LDDST), the advantages and disadvantages of both tests should be considered, as well as the clinical presentation. If the index of suspicion of HC is high and other diseases have been appropriately ruled out, the specificity of the ACTH stimulation test is reasonably high with an expected high positive predictive value. Because of the low sensitivity, a negative result in the ACTH stimulation test should not be used to rule out the diagnosis of HC. The LDDST is more sensitive but also less specific and affected more by stress. A positive result on the urine cortisol:creatinine ratio does not help to differentiate HC from other diseases. A negative result on the urine cortisol:creatinine ratio indicates that the diagnosis of HC is very unlikely. The LDDST is useful in differentiating pituitary-dependent HC from an adrenal tumor in about two thirds of all dogs with HC. Differentiation of HC from diabetes mellitus, liver diseases, and hypothyroidism cannot be based solely on endocrine tests. Clinical signs, imaging studies, histopathology, and response to treatment should all be considered. PMID- 21596350 TI - Common laboratory artifacts caused by inappropriate sample collection and transport: how to get the most out of a sample. AB - Clinicians are frequently presented with laboratory test results that are not consistent with preconceived expectations for a given case. One important reason for such results is the occurrence of preanalytical errors. In this article preanalytical errors are discussed in 2 parts. The first part covers the steps of sample collection, preparation, and transportation, in which preanalytical errors often occur. This part would be most useful if read in full before collecting a sample. The second part of this article includes a systematic review of preanalytical errors divided according to individual analytes or parameters or, when appropriate, groups of analytes and parameters that represent the same biological system. This part will hopefully serve the clinician as a quick and user friendly guide for identification of possible pitfalls when presented with unexpected laboratory test results for a given case. This article is limited to errors that can affect the complete blood count, chemistry, and coagulation panels. PMID- 21596351 TI - The myth of the fillers and extenders: let us clarify the role of nurse practitioners. PMID- 21596352 TI - Cultural competencies for graduate nursing education. AB - Nursing is challenged to meet the health needs of ethnic and socioculturally diverse populations. To this end, American Association of Colleges of Nursing (AACN) charged an expert nursing faculty advisory group to formulate competencies for graduate nursing education, expanding them to integrate leadership and scholarship. The Cultural Competency in Baccalaureate Nursing Education served as the springboard for the initiative. In formulating the graduate cultural competencies and the toolkit, the advisory group reviewed all AACN Essentials documents and the cultural competency literature, drew upon their collective experiences with cultural diversity, and used cultural humility as the supporting framework. Six core competencies were formulated and endorsed by the AACN board of directors and key professional nursing organizations. A companion toolkit was compiled to provide resources for the implementation of the competencies. A 1-day conference was held in California to launch the cultural competencies and toolkit. Dissemination to graduate nursing programs is in process, with emphasis on faculty readiness to undertake this graduate educational transformation. The AACN Cultural Competencies for Graduate Nursing Education set national standards to prepare culturally competent nurses at the graduate level who will contribute to the elimination of health disparities through education, clinical practice, research, scholarship, and policy. PMID- 21596353 TI - West Texas nursing education portal project: developing a regional centralized application system. AB - Because of the nursing shortage and a demand for maximum enrollment, a group of five baccalaureate and seven associate degree nursing programs in West Texas first met in 2007 to form the West Texas Nursing Education Consortium (WTNEC). To emphasize the importance of scale and distance, the West Texas region is larger than all of the northeastern states combined. The founding group agreed that the first mission of WTNEC should be to pool resources in order to increase admission and graduation rates for WTNEC schools. Two years later, this mission is being accomplished by the implementation of a plan designed to increase participating schools' admissions, retention, and graduation rates. A grant proposal was written and funded to develop a central regionalization of the application process for entry into WTNEC generic programs (associates degree in nursing and bachelor of science in nursing), with the goal of decreasing and possibly eliminating student vacancy rates in member schools and perhaps reducing the resources needed by each school for the admission process. The implemented centralized application system allowed prospective students to apply online to the centralized admission portal. Students maintained the freedom to choose the nursing program(s) they wanted to attend, but they were also made aware of possible openings in other participating schools. The admission portal also saved potential students time and money by submitting one centralized application, resulting in consolidation of the nursing school application process. Eleven of the 12 consortium schools participated in the centralized application system. PMID- 21596354 TI - Clinical experiences for doctor of nursing practice students-a survey of postmaster's programs. AB - The American Association of Colleges of Nursing has recommended that doctor of nursing practice (DNP) graduates complete 1,000 hours of practice at the postbaccalaureate level during a supervised academic program. Information is lacking about specific DNP program clinical requirements in existing postmaster's programs. The purpose of this research study was to investigate the number of clinical hours required in postmaster's programs and the types of clinical experiences provided. Forty-three DNP program directors completed an electronic survey in a prospective, descriptive cross-sectional study. Results indicated that the majority of schools (68%) required the same number of clinical hours regardless of specialty or previous hours. Respondents described a range of clinical experiences that integrated DNP competencies. Programs differed in their clinical hour requirements, ranging from 0 to 1,000. In comparison with schools with only DNP programs, those that had both DNP and PhD programs were more likely to require additional clinical hours if applicants had less than 1,000 hours previous to admission. PMID- 21596355 TI - Lessons learned in research, collaboration, and dissemination in a national institute of nursing research-funded research center. AB - This article provides the key findings of interviews and focus groups with researchers and administrators throughout a P30 Center on the issues of collaboration among researchers, multidisciplinary research, center support, and dissemination. The most notable findings confirmed throughout this process include methods of collaboration and shared strategies for subject recruitment. Specifically, the researchers participating in the P30 Center recommended that a research-intensive environment facilitate the ability of investigators to discuss their methods, struggles, and findings in ways that unite investigators toward a common goal to advance the science and improve health care. Researchers become isolated easily, thus running the risk of losing valuable time by duplicating others' work, falling short in fulfilling their commitments to scientific research, and losing opportunities to learn from each others' experiences. Especially in the realm of subject recruitment and study design, researchers often have similar problems and can benefit from both informal conversations and structured forums. Based on these findings, the authors provide recommendations for future collaborative research in schools of nursing. These include establishing certain key institutional structures and mechanisms by which established researchers can interact with junior investigators to train and mentor them. PMID- 21596356 TI - Transitioning into the nurse practitioner role through mentorship. AB - Transitioning into the nurse practitioner (NP) role is stressful. The stress arises from both internal or personal and external or organizational and professional sources. The novice NP may have a sense of inadequacy and lack of confidence in the ability to provide optimal patient care. The organizational expectations to be clinically competent and able to meet the demands of a complex health care system can be overwhelming. Most NP programs excel in their ability to provide the didactic information and clinical exposure necessary for the beginning-level practitioner; however, additional guidance and support are essential for the novice NP to evolve into an expert clinical practitioner. To this end, mentorship is an effective transition strategy for novice NPs. An awareness of the many stressors facing the novice NP, the benefits of mentorship, and how an effective mentoring relationship can ease the transition establishes sound rationale for mentoring as a strategy for optimal transitioning into the NP role. PMID- 21596357 TI - Conceptual debates and empirical evidence about the peer review process for scholarly journals. AB - Until recently, nursing scholars have seldom questioned the underlying premises of peer review, nor have they engaged in the conceptual debates about the peer review process. In this article, literature from a wide range of nursing and nonnursing journals was examined to provide an overview of (a) the conceptual debates and (b) the empirical evidence about the peer review process in scholarly journals. A multiplicity of questions for future research are proposed. PMID- 21596358 TI - Evaluation of a team-building retreat to promote nursing faculty cohesion and job satisfaction. AB - With the growing global shortage of nursing faculty, there is increased need to develop and evaluate strategies to promote nursing faculty job satisfaction. Using quantitative and qualitative research methods, a team-building faculty retreat including challenge course activities was evaluated to determine its effects on group cohesion and job satisfaction. Mean Job in General scores for the sample (n = 29) at the start of the study were comparable with national norms for employees with graduate degrees. There were statistically significant increases in Job in General scores and group cohesion scores from pretest to posttest on the day of the retreat. However, the positive changes were not maintained at the end of the semester when follow-up data were gathered. Content analysis of the retreat day reflections revealed the following themes: getting to know each other better, seeing commonalities and differences, spending time together, developing trust, and working as a group. Several themes were identified in the end of the semester reflections: getting to know each other, feeling closer as a group, setting a friendlier tone for the semester, and that the retreat was a positive experience. Based on these findings, we recommend the use of a faculty retreat with challenge course activities to promote nursing faculty cohesion and job satisfaction. However, follow-up activities are recommended to maintain positive results over time. PMID- 21596359 TI - Establishing the outcome indicators for the essential nursing competencies and curricula guidelines for genetics and genomics. AB - The translation of genetics/genomics to clinical care has implications for nurses. The Essential Nursing Competencies and Curricula Guidelines for Genetics and Genomics, established by consensus, apply to all registered nurses. Learning outcomes and clinical practice indicators have been developed to provide additional guidance. The Essentials Advisory Group (EAG) established a team to establish the Outcome Indicators. A draft was developed based on published peer reviewed documents and syllabi. The draft underwent three layers of review: (a) critique by the EAG; (b) review by representatives at a Genetics/Genomics Toolkit for Faculty meeting; and (c) review by workshop attendees of the American Association of Colleges of Nursing's baccalaureate and master's education conferences, followed by EAG's final approval. Outcome Indicators clarify specific knowledge areas and suggest clinical performance indicators for each competency. They provide the foundation to establish a competency-based education repository with outcome indicator mapping matrixes for genetic/genomic education resources. A gap analysis of education resources identified resource deficits, and online unfolding case studies were developed. Outcome Indicators assist the academic and continuing education nurse community to prepare the nursing workforce in genetics/genomics and provide a platform from which to build tools needed to achieve this goal. PMID- 21596360 TI - Domain general mechanisms account for imagined transformations of whole body perspective. AB - Three experiments investigated the contribution of domain general processes to imagined transformations of whole body perspective. In a task where participants make left-right judgements about a schematic human figure, reaction times made from the point of view of the figure are longer when the figure does not share the same spatial orientation as the participant and are substantially longer than those made from the participant's own point of view. These phenomena have been attributed to a specialised mechanism for imagined perspective transformations. In the present experiments, the effect of orientation on performance was influenced by factors that affect spatial stimulus-response (S-R) compatibility; it was attenuated with reduced dimensional overlap and reversed by crossed S-R mappings. Performance in a control experiment in which no figure was present suggests that processes moderating S-R mappings may account for the effect of adopting another's point of view. Our findings demonstrate a role for domain general processes in imagined transformations of whole body perspective, imply that egocentric codes for spatial relationships within visually presented bodies are automatically generated, and undermine evidence for a specialised mechanism for imagined perspective transformations. PMID- 21596361 TI - [Skin bioengineering: preclinical and clinical applications]. AB - Regenerative Medicine is an emerging field that combines basic research and clinical observations in order to identify the elements required to replace damaged tissues and organs in vivo and to stimulate the body's intrinsic regenerative capacity. Great benefits are expected in this field as researchers take advantage of the potential regenerative properties of both embryonic and adult stem cells, and more recently, of induced pluripotent stem cells. Bioengineered skin emerged mainly in response to a critical need for early permanent coverage of extensive burns. Later this technology was also applied to the treatment of chronic ulcers. Our group has established a humanized mouse model of skin grafting that involves the use of bioengineered human skin in immunodeficient mice. This model is suitable for the study of physiologic and pathologic cutaneous processes and the evaluation of treatment strategies for skin diseases, including protocols for gene and cell therapy and tissue engineering. PMID- 21596362 TI - [Treatment of mucosal vascular malformations with variable-pulse neodymium:yttrium-aluminum-garnet laser]. AB - BACKGROUND AND OBJECTIVES: Treatment of mucosal vascular lesions is a challenge for dermatologists, although various approaches have proven efficacy, including surgery, sclerotherapy, intralesional injection of corticosteroids, transfixion, and laser therapy. The aim of this study was to describe the results of treatment with neodymium:yttrium-aluminum-garnet (Nd:YAG) laser in 11 patients with venous malformations and varicosities. PATIENTS AND METHODS: We describe the use of variable-pulse Nd:YAG to treat venous malformations or varicosities in the oral or genital mucosa of 8 women and 3 men seen in our hospital over a 1-year period. RESULTS: The following laser parameters were used: wavelength, 1064 nm; fluence, 100 to 200J/cm(2); spot diameter, 3 to 5mm; and pulse duration, 30 to 65 ms. The size of the lesions ranged from 5 to 30 mm. In all cases, a clearance of 75% to 100% was achieved in a single session with excellent healing and no significant side effects. CONCLUSIONS: Given its efficacy and ease of use, Nd:YAG may become a treatment of choice for mucosal vascular lesions. Comparative studies are now required to assess its potential superiority over other treatment options. PMID- 21596363 TI - Asymmetric gas mixture transport in composite membranes. AB - The asymmetry effects in gas and electrolyte transport through composite membranes are considered. The interrelation between the kinetic theory and non equilibrium thermodynamics description of gas mixture transport in channels is discussed. The kinetic expressions for transport and slip coefficients are given. The effect of surface forces on gas transport is discussed. A set of general equations related to gas mixture flows in capillaries and porous media is deduced. The nano-size effects in gas flows are outlined. The theoretical analysis of one-way flow effect and asymmetric separation properties of a two layer porous membrane is given. PMID- 21596364 TI - Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up titration of rosuvastatin in patients with hypercholesterolemia (the ACTE Study). AB - The present multicenter, 6-week, randomized, double-blind, parallel-group, clinical trial evaluated the safety and efficacy of ezetimibe (10 mg) added to stable rosuvastatin therapy versus up-titration of rosuvastatin from 5 to 10 mg or from 10 to 20 mg. The study population included 440 subjects at moderately high/high risk of coronary heart disease with low-density lipoprotein (LDL) cholesterol levels higher than the National Cholesterol Education Program Adult Treatment Panel III recommendations (<100 mg/dl for moderately high/high-risk subjects without atherosclerotic vascular disease or <70 mg/dl for high-risk subjects with atherosclerotic vascular disease). Pooled data demonstrated that ezetimibe added to stable rosuvastatin 5 mg or 10 mg reduced LDL cholesterol by 21%. In contrast, doubling rosuvastatin to 10 mg or 20 mg reduced LDL cholesterol by 5.7% (between-group difference of 15.2%, p <0.001). Individually, ezetimibe plus rosuvastatin 5 mg reduced LDL cholesterol more than did rosuvastatin 10 mg (12.3% difference, p <0.001), and ezetimibe plus rosuvastatin 10 mg reduced LDL cholesterol more than did rosuvastatin 20 mg (17.5% difference, p <0.001). Compared to rosuvastatin up-titration, ezetimibe add-on achieved significantly greater attainment of LDL cholesterol levels of <70 or <100 mg/dl (59.4% vs 30.9%, p <0.001), and <70 mg/dl in all subjects (43.8% vs 17.5%, p <0.001); produced significantly greater reductions in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B (p <0.001); and resulted in similar effects on other lipid parameters. Adverse experiences were generally comparable among the groups. In conclusion, compared to up-titration doubling of the rosuvastatin dose, ezetimibe 10 mg added to stable rosuvastatin 5 mg or 10 mg produced greater improvements in many lipid parameters and achieved greater attainment of the National Cholesterol Education Program Adult Treatment Panel III recommended LDL cholesterol targets in subjects with elevated LDL cholesterol and at moderately high/high coronary heart disease risk. PMID- 21596365 TI - Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. AB - Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is mainly characterized by recurrent, often fatal, respiratory and gastrointestinal infections. About 50% of patients carry mutations in the DNA methyltransferase 3B gene (DNMT3B) (ICF1). The remaining patients carry unknown genetic defects (ICF2) but share with ICF1 patients the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences. We performed homozygosity mapping in five unrelated ICF2 patients with consanguineous parents and then performed whole exome sequencing in one of these patients and Sanger sequencing in all to identify mutations in the zinc-finger- and BTB (bric-a-bric, tramtrack, broad complex)-domain-containing 24 (ZBTB24) gene in four consanguineously descended ICF2 patients. Additionally, we found ZBTB24 mutations in an affected sibling pair and in one patient for whom it was not known whether his parents were consanguineous. ZBTB24 belongs to a large family of transcriptional repressors that include members, such as BCL6 and PATZ1, with prominent regulatory roles in hematopoietic development and malignancy. These data thus indicate that ZBTB24 is involved in DNA methylation of juxtacentromeric DNA and in B cell development and/or B and T cell interactions. Because ZBTB24 is a putative DNA-binding protein highly expressed in the lymphoid lineage, we predict that by studying the molecular function of ZBTB24, we will improve our understanding of the molecular pathophysiology of ICF syndrome and of lymphocyte biology in general. PMID- 21596366 TI - Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya. AB - Moyamoya is a cerebrovascular angiopathy characterized by a progressive stenosis of the terminal part of the intracranial carotid arteries and the compensatory development of abnormal and fragile collateral vessels, also called moyamoya vessels, leading to ischemic and hemorrhagic stroke. Moyamoya angiopathy can either be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions, including neurofibromatosis, Down syndrome, TAAD (autosomal-dominant thoracic aortic aneurysm), and radiotherapy of head tumors (moyamoya syndromes). Its prevalence is ten times higher in Japan than in Europe, and an estimated 6%-12% of moyamoya disease is familial in Japan. The pathophysiological mechanisms of this condition remain obscure. Here, we report on three unrelated families affected with an X-linked moyamoya syndrome characterized by the association of a moyamoya angiopathy, short stature, and a stereotyped facial dysmorphism. Other symptoms include an hypergonadotropic hypogonadism, hypertension, dilated cardiomyopathy, premature coronary heart disease, premature hair graying, and early bilateral acquired cataract. We show that this syndromic moyamoya is caused by Xq28 deletions removing MTCP1/MTCP1NB and BRCC3. We also show that brcc3 morphant zebrafish display angiogenesis defects that are rescued by endothelium-specific expression of brcc3. Altogether, these data strongly suggest that BRCC3, a deubiquitinating enzyme that is part of the cellular BRCA1 and BRISC complexes, is an important player in angiogenesis and that BRCC3 loss-of-function mutations are associated with moyamoya angiopathy. PMID- 21596367 TI - Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. AB - BACKGROUND: There is limited information about the safety of chronic nonsteroidal anti-inflammatory drugs (NSAIDs) in hypertensive patients with coronary artery disease. METHODS: This was a post hoc analysis from the INternational VErapamil Trandolapril STudy (INVEST), which enrolled patients with hypertension and coronary artery disease. At each visit, patients were asked by the local site investigator if they were currently taking NSAIDs. Patients who reported NSAID use at every visit were defined as chronic NSAID users, while all others (occasional or never users) were defined as nonchronic NSAID users. The primary composite outcome was all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Cox regression was used to construct a multivariate analysis for the primary outcome. RESULTS: There were 882 chronic NSAID users and 21,694 nonchronic NSAID users (n = 14,408 for never users and n=7286 for intermittent users). At a mean follow-up of 2.7 years, the primary outcome occurred at a rate of 4.4 events per 100 patient-years in the chronic NSAID group, versus 3.7 events per 100 patient-years in the nonchronic NSAID group (adjusted hazard ratio [HR] 1.47; 95% confidence interval [CI], 1.19-1.82; P=.0003). This was due to an increase in cardiovascular mortality (adjusted HR 2.26; 95% CI, 1.70-3.01; P<.0001). CONCLUSION: Among hypertensive patients with coronary artery disease, chronic self-reported use of NSAIDs was associated with an increased risk of adverse events during long-term follow-up. PMID- 21596369 TI - Bariatric surgery in a national cohort of women: sociodemographics and obstetric outcomes. AB - OBJECTIVE: In a large, prospective Swedish national cohort, we investigated individual birth characteristics for women who had undergone bariatric surgery and their obstetric outcome and made comparisons with all other women during the same period. STUDY DESIGN: The cohort consisted of 494,692 women born 1973-1983 of which 681 women who had undergone bariatric surgery constituted the index group. RESULTS: The index women more often have parents with lower sociodemographic status and are more often born large for gestational age. The women surgically treated before their first child had a shorter gestational length, their children had lower birthweight, and were more often born small for gestational age compared with the children born to the reference mothers. Women whose child was born before their bariatric surgery more often had a cesarean section, and their children were more often large for gestational age. CONCLUSION: Preconception bariatric surgery in obese women may be associated with improved obstetric outcomes. PMID- 21596368 TI - Placental protein 13 (PP13/galectin-13) undergoes lipid raft-associated subcellular redistribution in the syncytiotrophoblast in preterm preeclampsia and HELLP syndrome. AB - OBJECTIVE: To investigate placental protein 13 (PP13) localization in relation to cytoskeleton and lipid rafts in preeclampsia and HELLP syndrome. STUDY DESIGN: Placental cryosections from patients with preeclampsia and HELLP, and controls were stained for PP13, actin, PLAP (lipid raft marker), and CD71 (nonraft marker). BeWo cells exposed to stress conditions were stained for PP13 and actin. Protein localizations were investigated by confocal microscopy, PP13 concentrations by ELISA. RESULTS: PP13-actin colocalization was increased in syncytiotrophoblast juxtamembrane regions in term/preterm preeclampsia and HELLP. PP13-CD71 colocalization was decreased and PP13-PLAP proximity was increased in preterm but not term preeclampsia and HELLP. PP13-release from BeWo cells was inhibited by cytoskeleton disruption, and augmented by Ca2+-influx and ischemic stress. CONCLUSION: The actin cytoskeleton, probably in connection with lipid rafts, controls trophoblastic "nonclassical" PP13 export. PP13 is released from the syncytiotrophoblast in preterm preeclampsia and HELLP, mimicked in BeWo cells by ischemic stress, suggesting PP13 is a placental alarmin. PMID- 21596370 TI - Predictive factor for photodynamic therapy effects on oral squamous cell carcinoma and oral epithelial dysplasia. AB - OBJECTIVE: The aim of this study was to investigate the correlation between the immunohistochemical expression of proliferating cell nuclear antigen (PCNA), factor VIII, and CD34 (markers of endothelial cells), and vascular endothelial growth factor (VEGF) and the recurrence of oral squamous cell carcinoma (OSCC) and oral epithelial dysplasia (OED) subjected to photodynamic therapy (PDT). DESIGN: Twenty-one biopsy specimens (14 cases of OSCC and 7 cases of OED) before PDT were immunohistochemically investigated in terms of their expressions of PCNA, factor VIII, CD34 and VEGF. The percentages of the total sample area that were immunopositive for factor VIII (percentage factor VIII immunopositive area: PFIA) CD34 (PCIA) and VEGF (PVIA) were calculated using computer-assisted image analysis for quantitative assessment of endothelial cells or VEGF expression in the lesions. The PCNA labelling index (LI) was evaluated as a proliferation marker. RESULTS: Five cases of OSCC and one case of OED recurred 4 to 30 months after PDT. We found that the average PVIA was 14.5% in the no-recurrence group and 1.7% in the recurrence group. The difference between these values was statistically significant (P=0.0483). On the other hand, the average PCNA LI was 30.3% in the no-recurrence group and 24.3% in the recurrence group; the average PFIA was 3.7% in the no-recurrence group and 1.6% in the recurrence group; and the average PCIA was 2.0% in the no-recurrence group and 1.4% in the recurrence group. There were no significant differences between the two groups for any of these markers (P=0.3379, P=0.1195, P=0.4835, respectively). CONCLUSIONS: These results provide clinical data indicating that VEGF expression may be a useful predictive marker for the effects of PDT in OSCC and OED. PMID- 21596371 TI - The tripartite model of fear in children with specific phobias: assessing concordance and discordance using the behavioral approach test. AB - Lang's tripartite model posits that three main components characterize a fear response: physiological arousal, cognitive (subjective) distress, and behavioral avoidance. These components may occur in tandem with one another (concordance) or they may vary independently (discordance). The behavioral approach test (BAT) has been used to simultaneously examine the three components of the fear response. In the present study, 73 clinic-referred children and adolescents with a specific phobia participated in a phobia-specific BAT. Results revealed an overall pattern of concordance: correlation analyses revealed the three indices were significantly related to one another in the predicted directions. However, considerable variation was noted such that some children were concordant across the response components while others were not. More specifically, based on levels of physiological arousal and subjective distress, two concordant groups (high arousal-high distress, low arousal-low distress) and one discordant (high arousal low distress or low arousal-high distress) group of youth were identified. These concordant and discordant groups were then compared on the percentage of behavioral steps completed on the BAT. Analyses revealed that the low arousal-low distress group completed a significantly greater percentage of steps than the high arousal-high distress group, and a marginally greater percentage of steps than the discordant group. Potential group differences associated with age, gender, phobia severity, and phobia type were also explored and no significant differences were detected. Implications for theory and treatment are discussed. PMID- 21596372 TI - Acupuncture-like stimulation at auricular point Heart evokes cardiovascular inhibition via activating the cardiac-related neurons in the nucleus tractus solitarius. AB - Fifty-eight male Sprague-Dawley rats used in the present study to investigate the role of baroreceptor sensitive neurons of the nucleus tractus solitarius (NTS) in the regulation of cardiovascular inhibition during acupuncture at the auricular point Heart, single unit recording was made in anesthetized Sprague-Dawley rats. A neuron was considered to be excited or inhibited by acupuncture stimulation if it displayed 15% more or less spikes s(-1), respectively. NTS neurons were classified into cardiac-related (CR) neurons and non-cardiac-related neurons based on whether their rhythmic discharges were synchronized with the R-waves and responding to sodium nitroprusside (NP; 20 MUg/kg, i.v.) administration. Manual acupuncture was applied at the auricular point Heart and somatic acupuncture points ST36 and PC6. Acupuncture at auricular point Heart showed a more significant inhibitory effect on arterial pressure (-22.1+/-2.4mm Hg; P<0.001) and heart rate (-12.7+/-1.7 bpm; P<0.001) than that at ST36 and PC6. Acupuncture at auricular point Heart also increased the level of response of CR neurons in the NTS (93.8%+/-26.0% increase in discharge rate; P<0.01). Systemic or local administration of atropine attenuated the cardiovascular inhibition and activation of CR neurons evoked by auricular acupuncture, but had no effect on the same responses evoked by somatic acupuncture. Inactivation of the NTS with local anesthetics also decreased the cardiovascular inhibitory responses evoked by auricular acupuncture. Our results show that acupuncture at the auricular point Heart regulates cardiovascular function by activating baroreceptor sensitive neurons in the NTS in a similar manner as the baroreceptor reflex in cardiovascular inhibition. PMID- 21596373 TI - Bilingualism as a contributor to cognitive reserve: evidence from brain atrophy in Alzheimer's disease. AB - Much of the research on delaying the onset of symptoms of Alzheimer's disease (AD) has focused on pharmacotherapy, but environmental factors have also been acknowledged to play a significant role. Bilingualism may be one factor contributing to 'cognitive reserve' (CR) and therefore to a delay in symptom onset. If bilingualism is protective, then the brains of bilinguals should show greater atrophy in relevant areas, since their enhanced CR enables them to function at a higher level than would be predicted from their level of disease. We analyzed a number of linear measurements of brain atrophy from the computed tomography (CT) scans of monolingual and bilingual patients diagnosed with probable AD who were matched on level of cognitive performance and years of education. Bilingual patients with AD exhibited substantially greater amounts of brain atrophy than monolingual patients in areas traditionally used to distinguish AD patients from healthy controls, specifically, the radial width of the temporal horn and the temporal horn ratio. Other measures of brain atrophy were comparable for the two groups. Bilingualism appears to contribute to increased CR, thereby delaying the onset of AD and requiring the presence of greater amounts of neuropathology before the disease is manifest. PMID- 21596374 TI - [Increase of PTH in post-menopausal osteoporosis]. AB - AIMS: Increased parathyroid values (PTH) serum values can be observed in postmenopausal women. However, the clinical repercussion and causes of this finding are poorly understood. This study has aimed to analyze the prevalence and conditions associated to the increased serum PTH levels in postmenopausal women with osteoporosis as well as their clinical characteristics. METHODS: Post menopausal women with osteoporosis were included in the study. PTH, 25 hydroxyvitamin D (25OHD), 24-h urinary calcium, glomerular filtration rate (GFR) and calcium intake were evaluated. The prevalence of increased PTH serum values and its relationship with vitamin D deficiency and insufficiency, kidney failure, hypercalciuria and calcium intake deficiency were evaluated, these being conditions that may increase PTH secretion. RESULTS: A total of 204 postmenopausal women with osteoporosis with a mean age of 64 years were included. Increase PTH levels (>65 pg/ml) were observed in 35% and 5 women had primary hyperparathyroidism. Women with increased serum PTH levels were older (67 +/- 9 years) were old than those with normal PTH levels (63 +/- 11 years) (P=0.03). PTH elevation was associated to calcium intake deficiency (<800 mg/d) in 81% of the women, to a vitamin D deficiency and insufficiency in 55% and 86%, respectively, renal insufficiency in 35% and hypercalciuria in 17% of the patients. These values, however, did not differ when compared with patients with normal PTH serum levels. Serum PTH levels were related to age (r=0.19, P=0.01) but not to 25OHD or GFR values. CONCLUSIONS: One third of the post-menopausal women with osteoporosis had elevated PTH levels. This was due to primary hyperparathyroidism in 10%. The prevalence of conditions associated to the increase in PTH (reduced calcium intake, 25-hydroxyvitamin D, renal failure and hypercalciuria) is similar to that observed in women with normal PTH values. PMID- 21596375 TI - Detection of unbalanced chromosome segregations in preimplantation genetic diagnosis of translocations by short comparative genomic hibridization. AB - OBJECTIVE: To apply a comprehensive chromosomal screening through short comparative genomic hybridization (CGH) in the preimplantation genetic diagnosis (PGD) of translocations. DESIGN: Clinical research study. SETTING: A PGD laboratory and two IVF clinics. PATIENT(S): Three Robertsonian translocation carriers, two reciprocal translocation carriers, and a double-translocation carrier. INTERVENTION(S): After using the short-CGH approach in the reanalysis of two unbalanced embryos, discarded from a PGD for a reciprocal translocation carrier, the same method was applied in the PGD of day-3 embryos of translocation carriers. MAIN OUTCOME MEASURE(S): Ability of short CGH to detect partial chromosomal abnormalities in unbalanced embryos, translocation segregation proportions, and proportion of embryos carrying chromosomal abnormalities not related to the translocations. RESULT(S): The short-CGH technique detected errors resulting from the meiotic segregation of the chromosomes involved in the translocations and other abnormalities affecting the remaining chromosomes. Alternate segregation was detected most frequently among Robertsonian translocation cases, whereas unbalanced chromosome segregations were found predominantly in reciprocal ones. Aneuploidy and structural chromosome errors were found more frequently in Robertsonian than in reciprocal translocation carriers. Application of short-CGH PGD achieved pregnancy in two cases. CONCLUSION(S): Short CGH is a reliable approach for PGD of translocations, as it is capable of detecting partial chromosome errors caused by unbalanced segregations simultaneously to the screening of all chromosomes, and it may improve the results after PGD for translocation carriers. PMID- 21596376 TI - Enhancement of fracture healing with the diamond concept: the role of the biological chamber. AB - Bone regeneration presents a unique challenge to both clinicians and scientists. Recently, a vast amount of knowledge has been attained with regard to the molecular mediators, cell populations and the overall cascade of events participating in the bone repair processes. For the treatment of bone non-unions or bone defects, the 'diamond concept' for biological enhancement supports the implantation of mesenchymal stem cells, a scaffold and a growth factor. Prior to the implantation of any or all of these materials however, the surgeon must develop the ideal biological environment (non-union bed) where molecular and physiological processes will evolve facilitating an early and successful osteogenesis leading to bone continuity and functional restoration of the affected limb. At the end of the surgical procedure the non-union bed should have been transformed to a 'biological chamber' active enough to support efficiently all the necessary physiological processes for a successful outcome. The notion of creating the optimum 'biological chamber' represents the centre of the highest biological activity and in a sense the heart of the diamond concept. PMID- 21596377 TI - Obstetric quality assurance to reduce maternal and fetal mortality in Kano and Kaduna State hospitals in Nigeria. AB - OBJECTIVE: To achieve Millennium Development Goals 4 and 5 in Nigeria, a quality assurance project in obstetrics in 10 hospitals in northern Nigeria was established to improve maternal and fetal outcome. METHODS: The project commenced in January 2008 with assessment and improvement of the structure of the 10 hospitals. Continuous maternal and fetal data collection and analysis were conducted from 2008 to 2009 by means of a maternity record book and structured monthly summary form. The quality of hospital infrastructure and equipment was also assessed. RESULTS: The mean maternal mortality ratio (MMR) was reduced from 1790 per 100000 births in the first half of 2008 to 940 per 100000 births in the second half of 2009. The average fetal mortality ratio (FMR) decreased slightly from 84.9 to 83.5 per 1000 births. There was an inversely proportional relationship between the total number of deliveries in a hospital and MMR and FMR. There was a close correlation between the MMR and the equipment status and hygiene conditions of the hospitals. CONCLUSION: Continuous monitoring of quality assurance in maternity units raised the awareness of the quality of obstetric performance and improved the quality of care provided, thereby improving MMR. PMID- 21596378 TI - Patient demographic characteristics and facial expressions influence nurses' assessment of mood in the context of pain: a virtual human and lens model investigation. AB - BACKGROUND: Sex, race, and age disparities in pain assessment and treatment have been reported in the literature. However, less is known about how these demographic characteristics influence nurses' assessment of the emotional experiences of patients who are in pain. OBJECTIVES: To investigate the influence of patient demographic characteristics and facial expressions on nurses' assessment of patient mood in the context of pain. DESIGN: A cross-sectional study employing Virtual Human (VH) technology and lens model methodology. SETTINGS: The current study was delivered via the internet. PARTICIPANTS: Participants consisted of 54 registered nurses currently engaged in clinical practice. Nurses were recruited from healthcare settings across the United States. METHODS: Nurses viewed 32 patient vignettes consisting of a video clip of the VH patient and text-based clinical summary information describing a post surgical context. Patient sex, race, age, and facial expression of pain were systematically manipulated across vignettes. Participants made positive and negative mood assessment ratings on computerized visual analogue scales. Idiographic multiple regression analyses were used to examine the patient characteristics that were significant predictors of nurses' assessment ratings. Nomothetic paired samples t-tests were used to compare ratings within cue for the entire sample. RESULTS: The results of idiographic and nomothetic analyses indicated that VH sex, race, age, and facial expression cues were significant predictors of the mood assessment ratings of many nurses. The age cue had the largest impact among the demographic variables. CONCLUSIONS: The results of the current study suggest that patient demographic characteristics and facial expressions may influence how nurses assess patient emotional status in the clinical pain context. These findings may lead to greater awareness by individual nurses and nursing administrators about the influence of patient demographic characteristics on clinical decision-making. Future research is needed to better understand these relationships, with the ultimate goal of improving patient care. PMID- 21596380 TI - Clinical aspects of PCSK9. AB - Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulating protein that impairs LDL clearance by promoting the LDL receptor (LDLR) degradation. PCSK9 has emerged as a new pharmacological target for hypercholesterolemia, and different PCSK9 inhibitors are now evaluated in clinical trials. Here, we propose an overview of the clinical perspectives of PCSK9. First, we describe the clinical features of patients with PCSK9 mutations, and how these variations impact the cardiovascular risk. Then, we extensively discuss the potential role of circulating PCSK9 as a new biomarker of lipid metabolism. Indeed, many studies conducted in healthy and type 2 diabetic patients have tested the association of circulating PCSK9 with LDL-cholesterol as well as with multiple metabolic parameters. The overall picture of the clinical relevance of circulating PCSK9 is complicated by the effect of nutritional status and hypolipidemic drugs such as statins, fibrates, ezetimibe on plasma PCSK9 concentrations. Finally, we present a brief overview of the available therapeutic strategies to inhibit PCSK9. PMID- 21596379 TI - Current status of medical management for abdominal aortic aneurysm. AB - Previous trials indicate that surgical management of small abdominal aortic aneurysms (AAA) does not reduce mortality. The medical management of AAA, however, has to a large degree been ignored until recently. Medical management is not only needed to limit the expansion of small AAAs but also to reduce the high incidence of other cardiovascular events in these patients. In this review current evidence regarding medical therapy for patients with small AAAs is discussed. Four current randomised controlled trials are examining the efficacy of exercise, doxycycline and angiotensin converting enzyme inhibition in limiting AAA progression. A further trial using a mast cell stabilisation agent is expected to start soon. It is anticipated that a range of novel therapies for small AAAs will be identified within the next decade. PMID- 21596381 TI - Identification of factors associated with risk of fall using a force platform and power spectrum analysis technique. AB - The purpose of this retrospective study was to investigate some parameters of neuromuscular performance of the lower limbs in a population cross-section and their relationship to the risk of falls, using a force platform (FP). Individuals from the Lower Franconia population were invited by public advertisement. Out of a total of 1720 invited subjects 50-90 years of age, the successful completion of all tests were achieved by 807 women, age 66.4+/-9.3, and 442 men, age 64.0+/ 9.2. A novel FP measured the time series of vertical forces over 10 s during 3 kinds of tests: tandem stand with eyes closed, knee bends, and chair rise. Proprietary software captured the peak force and calculated the power density distribution (PSD), intended to characterize balance and power through the FP. Grip strength as a common geriatric force test was dynamometrically measured for comparison. The parameters were related to the number of falls in the past 12 months in both genders. Mean PSD showed little age dependency and was not related to falls in tandem stance. Peak forces and power over 10 s knee bends showed a larger age-related decrease in men than in women and these parameters were related to falls (p<0.001), whereas they were not related to falls in the chair rise test. Chair rise time and grip strength was related to falls in women (p<0.01). The PSD obtained from the tandem test with eyes closed did not provide a sensitive parameter associated with falls. Knee bends may be a meaningful FP screening test that justifies further studies of physical performance related to the risk of falls, whereas chair rise and grip measurements provided inferior information in this study. PMID- 21596382 TI - Modelling tendon excursions and moment arms of the finger flexors: anatomic fidelity versus function. AB - A detailed musculoskeletal model of the human hand is needed to investigate the pathomechanics of tendon disorders and carpal tunnel syndrome. The purpose of this study was to develop a biomechanical model with realistic flexor tendon excursions and moment arms. An existing upper extremity model served as a starting point, which included programmed movement of the index finger. Movement capabilities were added for the other fingers. Metacarpophalangeal articulations were modelled as universal joints to simulate flexion/extension and abduction/adduction while interphalangeal articulations used hinges to represent flexion. Flexor tendon paths were modelled using two approaches. The first method constrained tendons with control points, representing annular pulleys. The second technique used wrap objects at the joints as tendon constraints. Both control point and joint wrap models were iteratively adjusted to coincide with tendon excursions and moment arms from a anthropometric regression model using inputs for a 50th percentile male. Tendon excursions from the joint wrap method best matched the regression model even though anatomic features of the tendon paths were not preserved (absolute differences: mean<0.33 mm, peak<0.74 mm). The joint wrap model also produced similar moment arms to the regression (absolute differences: mean<0.63 mm, peak<1.58 mm). When a scaling algorithm was used to test anthropometrics, the scaled joint wrap models better matched the regression than the scaled control point models. Detailed patient-specific anatomical data will improve model outcomes for clinical use; however, population studies may benefit from simplified geometry, especially with anthropometric scaling. PMID- 21596383 TI - Optimization of startup and shutdown operation of simulated moving bed chromatographic processes. AB - This paper presents new multistage optimal startup and shutdown strategies for simulated moving bed (SMB) chromatographic processes. The proposed concept allows to adjust transient operating conditions stage-wise, and provides capability to improve transient performance and to fulfill product quality specifications simultaneously. A specially tailored decomposition algorithm is developed to ensure computational tractability of the resulting dynamic optimization problems. By examining the transient operation of a literature separation example characterized by nonlinear competitive isotherm, the feasibility of the solution approach is demonstrated, and the performance of the conventional and multistage optimal transient regimes is evaluated systematically. The quantitative results clearly show that the optimal operating policies not only allow to significantly reduce both duration of the transient phase and desorbent consumption, but also enable on-spec production even during startup and shutdown periods. With the aid of the developed transient procedures, short-term separation campaigns with small batch sizes can be performed more flexibly and efficiently by SMB chromatography. PMID- 21596384 TI - Avidin/PSS membrane microcapsules with biotin-binding activity. AB - Polyelectrolyte microcapsules with avidin-poly(styrene sulfonate) (PSS) membrane were prepared by a layer-by-layer deposition technique. The uptake and release of biotin-labeled fluorescein (b-FITC) as well as immobilization of biotin-labeled glucose oxidase (b-GOx) to the microcapsule were studied. The polyelectrolyte microcapsules were prepared by coating the surface of calcium carbonate (CaCO(3)) microparticles with an avidin/PSS multilayer membrane, followed by dissolution of CaCO(3) core in an ethylenediaminetetraacetic acid solution. Inner and outer poly(allylamine)/PSS films were required to isolate the microcapsules, whereas microcapsules could not be formed without the support. The uptake of b-FITC into the microcapsule was highly enhanced through a strong binding of b-FITC to avidin as compared with the uptake of biotin-free FITC. Release of b-FITC from the microcapsule was accelerated upon addition of biotin due to a competitive binding of the added biotin to the binding site of avidin. Similarly, the surface of microcapsule was modified with b-GOx with retaining its catalytic activity. PMID- 21596385 TI - Preparation and characterization of highly stable lipid nanoparticles with amorphous core of tuneable viscosity. AB - Lipid nanoparticles (LNP) have been designed based on low cost and human-use approved excipients, and manufactured by an easy, robust, and up-scalable process. Fluid colloidal dispersions or gel viscous formulations of highly stable nanoparticles (more than 12 month stability is achieved for some formulations) can be obtained. Their physicochemical properties are studied by Dynamic Light Scattering, Differential Scanning Calorimetry, and NMR. The results picture nanoparticles with a non-crystalline core, which viscosity can be finely tuned by the lipid composition and the temperature. A design of experiments has been used to investigate the limits of the system colloidal stability. The impact of core and surfactant weight fractions have been explored both experimentally and using the design of experiments. The versatility of this physicochemical system could open the way to a wide range of future pharmaceutical applications. PMID- 21596386 TI - A controlled approach to iron oxide nanoparticles functionalization for magnetic polymer brushes. AB - In this article, we report a detailed study of surface modification of magnetite nanoparticles by means of three different grafting agents, functional for the preparation of magnetic polymer brushes. 3-Aminopropyltriethoxysilane (APTES), 3 chloropropyltriethoxysilane (CPTES), and 2-(4 chlorosulfonylphenyl)ethyltrichlorosilane (CTCS) were chosen as grafting models through which a wide range of polymer brushes can be obtained. By means of accurate thermogravimetric analysis a good control over the amount of immobilized molecules is achieved, and optimal operating conditions for each grafting agent are consequently determined. Graft densities ranging from approximately 4 to 7 molecules per nm(2) are obtained, depending on the conditions used. In addition, the surface-initiated atom transfer radical polymerization (ATRP) of methyl methacrylate (MMA) carried out with CTCS-coated nanoparticles is presented as an example of polymer brushes, leading to a well-defined and dense polymeric coating of around 0.6 PMMA chains per nm(2). PMID- 21596387 TI - Facile fabrication of amphiphilic gold nanoparticles with V-shaped brushes from block copolymers with a trithiocarbonate group as the junction. AB - Amphiphilic gold nanoparticles grafted with V-shaped brushes (Au-V-brushes) were prepared by grafting a polystyrene-b-poly(ethylene oxide) (PS-b-PEO) block copolymer with a trithiocarbonate group as the junction to the Au surface. The obtained Au-V-brushes were subjected to solubility test and UV-vis, FT-IR, TEM and DLS characterizations. It is found that the Au-V-brushes are soluble in both water and organic solvents. In the common solvent DMF, the size of the Au-V brushes is about 17 nm, whereas in selective solvents (toluene and water) aggregates of 70-90 nm are formed. Phase transfer of the Au-V-brushes from the water phase into the toluene phase occurs upon addition of Na(2)SO(4) into water and the Au-V-brushes can also transfer from the toluene phase to the interface of toluene and water phases after addition of citric acid in the water phase. PMID- 21596388 TI - Creative applications and innovations to emotion assessment in children and adolescents: an introduction to the special section. PMID- 21596389 TI - The relationship between clinically identifiable intrapartum sentinel events and short-term outcome after therapeutic hypothermia. AB - OBJECTIVE: To determine the impact of intrapartum sentinel events on short-term outcome post-hypothermia. STUDY DESIGN: Records of 77 infants of 36 weeks' gestation or more, who received therapeutic hypothermia, were reviewed. Some were delivered after a clinically identifiable intrapartum sentinel event (IISE). All survivors had brain magnetic resonance imaging (MRI) at 7 to 10 days of life. The primary outcome of neonatal death related to hypoxic-ischemic encephalopathy was compared in infants born with (n = 39) or without an IISE (n = 38). MRI abnormalities were also compared. Logistic regression analysis was used to determine the variables predicting the primary outcome. RESULTS: The two groups had similar Apgar scores, initial blood pHs, and early neurologic examinations. Base deficit was more severe in the IISE group. Neonatal death and hypoxic ischemic injury was shown on brain MRI with basal nuclei, cortical, and subcortical white matter lesions extending beyond the watershed areas in infants surviving beyond the neonatal period were more common in the IISE group (P = .014; OR 11.1; 95% CI 1.3-92.6; and P = .034; OR 4.1; 95% CI 1.1-14.9, respectively). Multivariate analysis identified IISE (P = .023; OR 12.2; 95% CI 1.4-105.8) to be independently associated with neonatal death. CONCLUSIONS: IISEs are associated with neonatal death and severe injury as shown in brain MRI, even after hypothermia. PMID- 21596390 TI - Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study. AB - OBJECTIVE: To assess the incidence rate (IR), changes in IR over time, risk factors, treatment, and outcomes of pediatric noncerebral thromboembolism (TE). STUDY DESIGN: The study included all patients aged 0 to 18 years diagnosed with first-ever noncerebral venous thromboembolism (VTE) and/or arterial TE in Denmark between 1994 and 2006. Patients were identified in national registries, followed by validation of diagnoses by medical records review. RESULTS: We confirmed 331 cases of VTE and 46 cases of arterial TE during 15.8 million person-years of observation, with corresponding IRs of 2.09 and 0.29 per 100 000 person-years. The IR peaked in infancy (age <1 year) for both VTE and arterial TE, with an additional peak among adolescents (age 15 to 18 years) for VTE. Boys predominated in IR of VTE in infancy, whereas girls did so in adolescence (P < .01). The IRs of VTE and arterial TE remained stable during the study period, but with an trend toward increasing VTE in 2001 to 2006 (P = .064). Underlying diseases/external triggers were present in 86.6% of the patients, and thrombophilia was present in 47.9% of the VTE cases. All-cause and TE-related 30-day case fatalities were 4.0% and 1.6%, respectively. CONCLUSIONS: We found age- and sex-related disparities in the IRs of pediatric VTE and arterial TE, but insignificant changes in IR from 1994 to 2006. PMID- 21596392 TI - Transapical transcatheter aortic valve implantation and off-pump left internal thoracic artery-left anterior descending anastomosis: back to the future? PMID- 21596391 TI - Increased pulsatile cerebral blood flow, cerebral vasodilation, and postsyncopal headache in adolescents. AB - OBJECTIVE: We hypothesize that, after a sudden decrease in cerebral blood flow velocity (CBFV) in adolescents, a faint, rapid hyperemic pulsatile CBFV occurs upon the patient's return to the supine position and is associated with postsyncopal headache. STUDY DESIGN: This case-control study involved 16 adolescent subjects with a history of fainting and headaches. We induced fainting during 70 degrees tilt-table testing and measured mean arterial pressure, heart rate, end-tidal CO(2), and CBFV. Fifteen control subjects were similarly evaluated with a tilt but did not faint, and comparisons with fainters were made at equivalent defined time points. RESULTS: Baseline values were similar between the groups. Upon fainting, mean arterial pressure decreased 49% in the patients who fainted vs 6% in controls (P < .001). The heart rate decreased 15% in fainters and increased 35% in controls (P < .001). In patients who fainted, cerebrovascular critical closing pressure increased markedly, which resulted in reduced diastolic (-66%) and mean CBFV (-46%) at faint; systolic CBFV was similar to controls. Pulsatile CBFV (systolic-diastolic CBFV) increased 38% in fainters, which caused flow-mediated dilatation of cerebral vessels. When the fainters returned to the supine position, CBFV exhibited increased systolic and decreased diastolic flows compared with controls (P < .02). CONCLUSION: Increased pulsatile CBFV during and after faint may cause postsyncopal cerebral vasodilation and headache. PMID- 21596393 TI - Complete resection of asymptomatic solitary right atrial metastasis from renal cell carcinoma without inferior vena cava involvement. PMID- 21596394 TI - Early warning indicators for river nutrient and sediment loads in tropical seagrass beds: a benchmark from a near-pristine archipelago in Indonesia. AB - In remote, tropical areas human influences increase, potentially threatening pristine seagrass systems. We aim (i) to provide a bench-mark for a near-pristine seagrass system in an archipelago in East Kalimantan, by quantifying a large spectrum of abiotic and biotic properties in seagrass meadows and (ii) to identify early warning indicators for river sediment and nutrient loading, by comparing the seagrass meadow properties over a gradient with varying river influence. Abiotic properties of water column, pore water and sediment were less suitable indicators for increased sediment and nutrient loading than seagrass properties. Seagrass meadows strongly responded to higher sediment and nutrient loads and proximity to the coast by decreasing seagrass cover, standing stock, number of seagrass species, changing species composition and shifts in tissue contents. Our study confirms that nutrient loads are more important than water nutrient concentrations. We identify seagrass system variables that are suitable indicators for sediment and nutrient loading, also in rapid survey scenarios with once-only measurements. PMID- 21596395 TI - Application of artificial mussels (AMs) under South African marine conditions: a validation study. AB - Over the last three decades there has been a significant decline in the number of marine pollution monitoring-related studies in South Africa. Thus, the current study was conducted to assess the current state of metal contamination within the South African marine environment through the validation of the artificial mussel (AM). Indigenous reference mussels (Perna perna) were deployed alongside the passive device within the South African marine environment for a 6 week exposure period. Analysis of metal uptake (Cd, Cr, Cu, Pb and Zn) was determined by filtration and elution of the AM chelex resins, microwave digestion of the transplanted mussels, and determination of their metal concentrations by ICP-MS and ICP-OES analysis. Uptake patterns between the AM and transplanted mussels showed significant temporal and spatial correlation for the majority of the elements analysed. While the AM provided relevant and complementary information on the dissolved metal concentrations, limitations were also observed. PMID- 21596396 TI - [Intrahospitalary stroke: hidden side of acute cerebrovascular disease]. PMID- 21596397 TI - [Emergencies in cannabis users]. PMID- 21596398 TI - [Lymphocytopenia following radiation therapy: probably common but unknown]. PMID- 21596399 TI - [Follow-up of cancer survivors: a shared responsibility]. PMID- 21596400 TI - [Khat, mephedrone and chest pain]. PMID- 21596401 TI - [Neurological complications of Wilson's disease]. PMID- 21596402 TI - [Clinical features and prognosis of patients with scleroderma renal crisis]. AB - BACKGROUND AND OBJECTIVE: Scleroderma renal crisis is a severe complication of systemic sclerosis, which causes arterial hypertension and acute renal failure. Early treatment of these patients with ACE inhibitors may improve prognosis. We aimed to analyze the frequency, clinical and epidemiological characteristics, morbidity and mortality and prognosis of scleroderma renal crisis. PATIENTS AND METHODS: Retrospective study of a cohort of 328 patients with SSc, of whom 194 had the limited form, 64 the diffuse form, 49 the sine scleroderma and 21 preescleroderma. We considered different subtypes of disease: limited (188), diffuse (63), scleroderma sine scleroderma (46) and preescleroderma (21). The data were obtained from a review of medical records. The differences in the prevalence of variables were analyzed by the Fisher's test. RESULTS: A renal crisis was observed in 14 patients (4.26%), 3 men and 11 women, 64% had the diffuse form of the disease, 28% had the limited form, and 7.69% had the scleroderma sine scleroderma. The average time was 48 months. All received ACE inhibitors. The mortality was 85% (18 months) and 85% required dialysis. CONCLUSIONS: Renal crisis is a rare manifestation of scleroderma which mainly affects patients with diffuse involvement of the disease in the early stages. These patients have a poor prognosis despite treatment with ACE inhibitors. PMID- 21596403 TI - Perception of plant volatile blends by herbivorous insects--finding the right mix. AB - Volatile plant secondary metabolites are detected by the highly sensitive olfactory system employed by insects to locate suitable plants as hosts and to avoid unsuitable hosts. Perception of these compounds depends on olfactory receptor neurones (ORNs) in sensillae, mostly on the insect antennae, which can recognise individual molecular structures. Perception of blends of plant volatiles plays a pivotal role in host recognition, non-host avoidance and ensuing behavioural responses as different responses can occur to a whole blend compared to individual components. There are emergent properties of blend perception because components of the host blend may not be recognised as host when perceived outside the context of that blend. Often there is redundancy in the composition of blends recognised as host because certain compounds can be substituted by others. Fine spatio-temporal resolution of the synchronous firing of ORNs tuned to specific compounds enables insects to pick out relevant host odour cues against high background noise and with ephemeral exposure to the volatiles at varying concentrations. This task is challenging as they usually rely on ubiquitous plant volatiles and not those taxonomically characteristic of host plants. However, such an odour coding system has the advantage of providing flexibility; it allows for adaptation to changing environments by alterations in signal processing while maintaining the same peripheral olfactory receptors. PMID- 21596404 TI - Evaluation of recombinant proteins of Haemophilus parasuis strain SH0165 as vaccine candidates in a mouse model. AB - The recently completed genome sequence of Haemophilus parasuis strain SH0165 allowed us to screen putative OMPs for the development of recombinant vaccines. The objective of this study was to evaluate the immunogenicity and protective efficacy of three OMPs of H. parasuis. Three putative OMPs (SmpA, YgiW and FOG) were cloned, expressed and purified by Ni affinity chromatography using nitriloacetic acid resin. Mice were immunized either individually (individual protein, IP) or synergistically (synergistic protein, SP) with the recombinant proteins. A significant increase in IgG titer was detected in all protein immunized mice. Isotyping studies revealed that the antibodies produced were predominantly IgG2a-type, indicating a predominant Th1 response. A significant increase was observed in IL-2, IL-4 and IFN-gamma levels in the culture supernatants of splenocytes isolated from immunized mice. Furthermore, mice were challenged intraperitoneally with 6*10(9)CFU (5*LD(50)) of highly virulent homologous serovar 5 strain (SH0165) or 7.0*10(9) CFU (5*LD(50)) of the heterologous serovar 4 strain (MD0322) at fourteen days after the last immunization. All of the recombinant proteins enhanced survival and reduced histopathological lesions. Our results indicated that the three OMPs showed protection both individually and synergistically against infection with the highly virulent H. parasuis in mice. PMID- 21596405 TI - Angiogenic markers in canine lymphoma tissues do not predict survival times in chemotherapy treated dogs. AB - Angiogenesis, which is essential for malignancies to progress, depends on various signalling proteins including vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors 1 and 2 (VEGFR-1 and VEGFR-2). Microvessel density (MVD) is frequently used to evaluate angiogenesis. This study assessed the relationship between expression of VEGF, VEGFR-1 and VEGFR-2, MVD and the survival time in dogs with lymphoma. VEGF, VEGFR-1 and VEGFR-2 expression was evaluated immunohistochemically and microvessel profiles were counted in 34 lymphoma samples. Seventy-nine percent of the samples showed high VEGF expression and 62% were highly positive for VEGFR-1; VEGFR-2 immunoreactivity was mostly negative. Dogs treated with chemotherapy had a median survival time of 266days, but no significant relationships were found between overall survival time, MVD and expression of VEGF, VEGFR-1 or VEGFR-2. In this study, VEGF its receptors and the MVD were no prognostic factors in dogs with lymphoma. PMID- 21596406 TI - [Editorial. The James Barrett Brown Award]. PMID- 21596407 TI - [Papillomavirus and head and neck cancer]. AB - Tobacco and alcohol consumption are the main risk factors for head and neck cancers. Papillomavirus (HPV) infection was recently associated with the development of malignant tumors of the oropharynx, according to molecular and biological arguments. We describe the oncogenic mechanisms of HPV infections, the epidemiological and clinical aspects of associated head and neck cancers, their prognosis, and issues of specific therapeutic strategies. PMID- 21596408 TI - [Left mesiotemporal lesions and anterograde memory impairement: a case of neurosyphilis]. AB - INTRODUCTION: Neurosyphilis has become uncommun in the developed countries. OBSERVATION: We report a case of neurosyphilis with limbic presentation, left mesiotemporal lesions on MRI and severe anterograde amnesia. DISCUSSION: Pathogeneses of MRI findings are unknown. We suggest the implication of arteritis wich affects small vessels, parenchymatous and excitotoxic lesions. The absence of mesiotemporal lesion in immunodeficient patients, the limbic systematization of pathology underlines the involvement of probably auto-immune process. Neurosyphilis should always be considered in the differential diagnosis of limbic encephalitis in order to initiate treatment and to prevent cognitives sequelaes. At last, partial status epilepticus should be diagnosed and excitotoxicity lesions prevents with antiepileptic treatment. PMID- 21596409 TI - [Demyelinating disease affecting both central and peripheral nervous system]. AB - INTRODUCTION: Demyelinating disease affecting both the central and the peripheral nervous systems has rarely been reported. CASE REPORT: A 30-year-old man, presented with ataxia and diffuse areflexia due to polyneuropathy fullfilling demyelination criteria. His medical history was notable for central nervous system demyelination compatible with multiple sclerosis. He improved transiently with intravenous immunoglobulin and then stabilized with methotrexate. CONCLUSION: This case report distinguishes a new kind of inflammatory disease affecting both central and peripheral nervous system. It seems to be different from multiple sclerosis and chronic immune demyelinating polyneuropathy, because of high hyperproteinorachia and absence of oligoclonal bands in the cerebrospinal fluid. PMID- 21596410 TI - Impulse control disorders and dopaminergic treatments in Parkinson's disease. AB - A group of disorders sharing a failure to resist an impulse to perform a typically pleasurable activity that is finally harmful to the person or to others are known under the common denomination of impulse control disorders (ICDs). These behaviors, possibly previously neglected by lack of awareness, are increasingly reported among PD patients. Compelling evidence has stressed the relation between dopaminergic replacement and development of ICDs in PD, especially but not exclusively, with dopamine agonist therapy. Besides dopaminergic replacement, younger age, smoking habit, presence of familiar gambling problems and alcohol abuse can increase the risk. ICDs in PD may greatly affect patients and caregivers quality of life, stressing the importance of their screening. Management strategies include a careful use of dopaminergic therapy using the lowest effective doses. PMID- 21596411 TI - Detection of microsporidia in local HIV-positive population in Malaysia. AB - The HIV-positive population, due to their immuno-compromised nature, is considered more susceptible to parasitic infections than other populations. However despite the reports of other opportunistic pathogens such as Cryptosporidium and tuberculosis reported in vulnerable communities, microsporidia have not been highlighted in the local HIV-positive population in Malaysia. This study aimed to provide preliminary information on the prevalence of microsporidia in the local HIV-population. Microsporidia were detected in 21/247 (8.5%) stool samples from the HIV-infected individuals, a significantly higher (P-value <0.05) prevalence than in the control group, in which 5/173 (2.9%) were positive. HIV patients were 3x more at risk for acquiring microspordium (OR: 3.12; 95% CI 1.15-8.44). Spores were ellipsoid in shape with outlines that stained dark pink with the interior a lighter shade. Approximately 21% of the positive specimens were from individuals in the 40-49 years age group. Ten individuals who were positive for microsporidia were also positive for other enteric parasites such as Blastocystis hominis and Giardia lamblia. We detected Encephalitozoon intestinalis DNA following nested PCR from three of 10 samples analysed, as demonstrated by an amplicon of 370bp. From the findings reported, it appears that microsporidial infection in humans may actually be more common than reported. We strongly advocate greater emphasis on personal hygiene through public education on personal hygiene and the consumption of boiled or filtered water. PMID- 21596412 TI - The caspase inhibitor IDN-6556 (PF3491390) improves marginal mass engraftment after islet transplantation in mice. AB - BACKGROUND: Islet transplantation has become a viable option for selected type 1 diabetic patients; however, a significant portion need to return to exogenous insulin. The predominant factors include impaired islet engraftment and early islet loss. Caspase inhibition is a potent way to improve islet engraftment, but all tested compounds so far have not been clinically relevant. IDN-6556 (PF3491390) has already been used clinically and can be delivered orally with high portal vein concentrations. METHODS: Mice were given a marginal mass islet graft of either mouse or human islets and treated with either IDN-6556 (10 or 20 mg/kg ip bid) or vehicle and followed for diabetes reversal. At 1 month post transplant, mice were subjected to a glucose tolerance test and an assessment of graft mass. In separate experiments, human islets were cultured with IDN-6556 or vehicle to assess for islet survival and viability. RESULTS: In both syngeneic mouse islets and human islets transplanted into immunodeficient mice, IDN-6556 (20 mg/kg) given for 7 days post-transplant led to a significantly enhanced rate of diabetes reversal as compared to vehicle. In addition, mice receiving caspase inhibitor displayed improved glucose tolerance and graft survival at the 1-month point. We also found protective effects in vitro for islet viability and marked reduction in apoptosis in vivo. CONCLUSION: Taken together, these results demonstrate the effectiveness of caspase inhibition with IDN-6556 on islet transplantation and in particular islet engraftment and survival. PMID- 21596413 TI - Can a tailored knowledge translation strategy improve short term outcomes? A pilot study to increase compliance with bowel preparation recommendations in general surgery. AB - BACKGROUND: Previous studies have shown that practices supported by level I evidence may take up to 20 years before they are adopted. Although mechanical bowel preparation (MBP) has been a routine practice in colorectal surgery, there is strong evidence dating back to the early 1990s suggesting that in most patients MBP before elective colorectal surgery is not required. The objective of this study was to determine if surgical practices pertaining to bowel preparation could be altered using a tailored knowledge translation strategy. METHODS: A multi-faceted strategy including guideline development, consensus, education by opinion leaders, audit and feedback, and reminder cards was used in this before after study. The primary outcome was compliance with the recommendations presented in the guideline regarding MBP, normal diet on the day prior to surgery, and enemas. RESULTS: Two-hundred eighty-two patients were enrolled in the study with 111 enrolled before the intervention and 171 enrolled after the intervention. Demographic and clinical characteristics between the 2 groups were similar. Overall, there was a 7.8% increase in compliance with MBP recommendations (81.1% vs 88.4%, P = .038), a 10.2% increase in compliance with diet recommendations (45.6% vs 55.8%, P = .080), and a 5.6% increase in compliance with enema recommendations (88.5% vs 94.2%, P < .001). CONCLUSION: The results of this study reveal that a tailored, multi-faceted knowledge translation strategy is effective in changing surgeon behavior. PMID- 21596414 TI - Renoprotective effect of erythropoietin in rats subjected to ischemia/reperfusion injury: gender differences. AB - BACKGROUND: Renal ischemia reperfusion injury induces gender-dependent heat-shock protein 72 expression, which maintains membrane localization of renal Na(+)/K(+)ATPase-alpha1. The erythropoietin has a protecting effect against ischemia reperfusion injury in various organs. In this study, we investigated whether erythropoietin exerts a beneficial effect against post-ischemic renal injury. Furthermore, we studied the erythropoietin signaling on heat-shock protein 72 and Na(+)/K(+)ATPase-alpha1 expression and localization. METHODS: In male and female Wistar rats, rHuEPO (1000 IU/bwkg intraperitoneal) or vehicle was administered 24 hours prior to unilateral left renal ischemia reperfusion (50 minutes). Kidneys were subsequently removed at hours 2 or 24 of the reperfusion; sham-operated rats served as controls (C) (n = 8/group). We measured serum erythropoietin, renal function, evaluated histological injury, and observed heat shock protein 72 as well as Na(+)/K(+)ATPase-alpha1 protein level and localization. Additional groups were followed for 7-day survival. RESULTS: Erythropoietin treatment was associated with better post-ischemic survival and less impaired renal function in males while diminishing the renal structural damage in both sexes. Endogenous erythropoietin was higher in males and increased in both genders after erythropoietin treatment. The erythropoietin treatment elevated protein levels of heat-shock protein 72 and Na(+)/K(+)ATPase-alpha1 in 24 hours in males, whereas in females, the already higher expression of heat shock protein 72 and Na(+)/K(+)ATPase-alpha1 was not increased. Moreover, erythropoietin prevented ischemia reperfusion induced Na(+)/K(+)ATPase-alpha1 translocation from the basolaterale membrane in males. CONCLUSION: Erythropoietin diminishes gender difference in the susceptibility to renal post-ischemic injury and reduces post-ischemic structural damage while preserving kidney function, particularly in males. This additional protection may be associated with a heat shock protein 72-mediated effect on Na(+)/K(+)ATPase-alpha1 expression and translocation. PMID- 21596415 TI - Minimally invasive thyroidectomy: a comprehensive appraisal of existing techniques. PMID- 21596416 TI - The protease-sensitive loop of the vesicular stomatitis virus matrix protein is involved in virus assembly and protein translation. AB - To study the contribution of the protease-sensitive loop of the VSV M protein in virus assembly we recovered recombinant VSV (rVSV) with mutations in this region and examined virus replication. Mutations in the highly conserved LXD motif (aa 123-125) resulted in reduced virion budding, reduced virus titers and enhanced M protein exchange with M-ribonucleocapsid complexes (M-RNPs), suggesting that the mutant M proteins were less tightly associated with RNP skeletons. In addition, viral protein synthesis began to decrease at 4h post-infection (hpi) and was reduced by ~80% at 8 hpi for the mutant rVSV-D125A. The reduced protein synthesis was not due to decreased VSV replication or transcription; however, translation of a reporter gene with an EMCV IRES was not reduced, suggesting that cap dependent, but not cap-independent translation initiation was affected in rVSV D125A infected cells. These results indicate that the LXD motif is involved in both virus assembly and VSV protein translation. PMID- 21596417 TI - River health assessment in peri-urban landscapes: an application of multivariate analysis to identify the key variables. AB - An array of river health assessment approaches and water quality variables have been suggested in the past for assessing the level of river health. However, the selection of suitable variables to be monitored for the assessment remains ambiguous and often it is not practical to monitor all the suggested variables. In this study, we employ a multivariate data reduction technique, called Factor Analysis (FA), to identify the key river health variables for a peri-urban river system, viz., the Hawkesbury-Nepean River system in New South Wales, Australia. Out of 40 water quality variables included in the analysis, the FA identified nine key variables, under three varifactors (VFs), explaining 50% of the variance in the river water quality. Variables in the first, second and third VFs revealed anaerobic conditions, microbial quality and effects of eutrophication in the Hawkesbury-Nepean River. Thus, the present work shows a notable reduction in the number of variables and the application of FA for identification of key variables was found promising. The finding of this study has potential application in designing a cost-effective river health monitoring program by reducing the number of variables to be monitored in a peri-urban situation. It can also assist in partitioning variables according to their unique contribution to the total variance. PMID- 21596418 TI - Simultaneous removal of phosphorus and potassium from synthetic urine through the precipitation of magnesium potassium phosphate hexahydrate. AB - This study investigated the simultaneous removal of P and K from synthetic urine through the precipitation of magnesium potassium phosphate hexahydrate (MPP, MgKPO(4).6H(2)O) in bench-scale experiments. Results show that the removal efficiencies of P and K are mainly determined by the solution pH and the molar ratio of Mg:K:P. Co-precipitation of struvite-type compounds, i.e., magnesium ammonium phosphate hexahydrate (MAP, MgNH(4)PO(4).6H(2)O), magnesium sodium phosphate heptahydrate (MSP, MgNaPO(4).7H(2)O), and MPP, was confirmed by analysis of the solid precipitates using a Scanning Electron Microscope/Energy Dispersive X-ray Apparatus and an X-ray Diffractometer. The co-precipitation significantly influenced the removal of K. As much ammonium as possible should be removed prior to MPP precipitation because MAP had higher tendency to form than MPP. The inevitable co-precipitation of MPP and MSP resulted in the addition of more MgCl(2).6H(2)O and Na(2)HPO(4).12H(2)O to obtain the high removal of K. In total, the removal efficiencies of P and K were 77% and 98%, respectively, in the absence of ammonium when pH was 10 and the molar ratio of Mg:K:P was 2:1:2. The results indicate that the MPP precipitation is an efficient method for the simultaneous removal of P and K to yield multi-nutrient products. PMID- 21596419 TI - Dietary intake of hexabromocyclododecane diastereoisomers (alpha-, beta-, and gamma-HBCD) in the Belgian adult population. AB - A study was performed to assess exposure of the Belgian population to HBCD diastereoisomers. Measurements of HBCD were performed by UPLC-MS/MS, on 45 composite samples from 5 major food groups: dairy (products), meat (products), eggs, fish (products) and a group of "other" products. The medium bound estimated average daily intake (EDI) of SigmaHBCD in the Belgian population was 0.99 ng kg( 1)bw d(-1). The diastereoisomer contribution to the mean EDI showed a predominance of gamma-HBCD at 67%, followed by alpha-HBCD at 25% and 8% for beta HBCD. These results are consistent with the pattern found in the two food groups contributing the most to the EDI: meat (products) and the group of "other" products. Anyway, it has to be noted that diastereomeric distribution of HBCD can change due to bioisomerisation in biological material. Levels of HBCD diastereoisomers found in Belgian food samples of animal origin were low in comparison with those found in other EU countries and the resulting EDI was substantially below the proposed thresholds. PMID- 21596421 TI - Residual behaviour and risk assessment of flubendiamide on chickpea (Cicer arietinum L.). AB - The study was undertaken to determine the disappearance trends of flubendiamide residues on chickpea under field conditions and thereby, ensure consumer safety. Average initial deposits of flubendiamide on chickpea pods were found to be 0.68 and 1.17 mg kg(-1), respectively, following three applications of flubendiamide 480SC @ 48 and 96 g a.i. ha(-1) at 7d intervals. Half-life of flubendiamide on chickpea pods was observed to be 1.39 and 1.44 d, respectively, at single and double dosages whereas with respect to chickpea leaves, these values were found to be 0.77 and 0.86 d. Desiodo flubendiamide was not detected at 0.05 mg kg(-1) level on chickpea samples collected at different intervals. Theoretical maximum residue contribution (TMRC) for flubendiamide was calculated and found to be well below the maximum permissible intake (MPI) on chickpea pods and leaves at 0-day (1 h after spraying) for the both dosages. Thus, the application of flubendiamide at the recommended dose on chickpea presents no human health risks and is safe to the consumers. PMID- 21596420 TI - Assessing the potential for rhizoremediation of PCB contaminated soils in northern regions using native tree species. AB - Rhizosphere bioremediation of polychlorinated biphenyls (PCBs) offers a potentially inexpensive approach to remediating contaminated soils that is particularly attractive in remote regions including the Arctic. We assessed the abilities of two tree species native to Alaska, Salix alaxensis (felt-leaf willow) and Picea glauca (white spruce), to promote microbial biodegradation of PCBs via the release of phytochemicals upon fine root death. Crushed fine roots, biphenyl (PCB analogue) or salicylate (willow secondary compound) were added to microcosms containing soil spiked with PCBs and resultant PCB disappearance, soil toxicity and microbial community changes were examined. After 180d, soil treated with willow root crushates showed a significantly greater PCB loss than untreated soils for some PCB congeners, including the toxic congeners, PCB 77, 105 and 169, and showed a similar PCB loss pattern (in both extent of degradation and congeners degraded) to biphenyl-treated microcosms. Neither P. glauca (white spruce) roots nor salicylate enhanced PCB loss, indicating that biostimulation is plant species specific and was not mediated by salicylate. Soil toxicity assessed using the Microtox bioassay indicated that the willow treatment resulted in a less toxic soil environment. Molecular microbial community analyses indicated that biphenyl and salicylate promoted shifts in microbial community structure and composition that differed distinctly from each other and from the crushed root treatments. The biphenyl utilizing bacterium, Cupriavidus spp. was isolated from the soil. The findings suggest that S. alaxensis may be an effective plant for rhizoremediation by altering microbial community structure, enhancing the loss of some PCB congeners and reducing the toxicity of the soil environment. PMID- 21596422 TI - Retesting in children with beta-lactam allergy. PMID- 21596423 TI - TNF-alpha blockade in chronic granulomatous disease-induced hyperinflammation: patient analysis and murine model. PMID- 21596425 TI - Characterization of drug-specific lymphocyte responses in a patient with drug induced liver injury. PMID- 21596427 TI - TEM interfacial characterization of an experimental self-adhesive filling material bonded to enamel/dentin. AB - A great challenge regarding the ease-of-use of composites involves the development of 'self-adhesive' composites that no longer require a separate adhesive to bond to tooth enamel/dentin. OBJECTIVES: To characterize the interfacial ultra-structure of an experimental self-adhesive filling material bonded to enamel and dentin using transmission electron microscopy (TEM). METHODS: The experimental self-adhesive material was bonded to bur-cut human enamel and dentin, and to fractured (smear-free) dentin, strictly according to the manufacturers' instructions. The specimens were stored for 1 day in distilled water (37 degrees C) prior to further common specimen processing for TEM. RESULTS: The experimental self-adhesive filling material revealed a typical micro hybrid filler distribution. At bur-cut enamel, a tight interface was formed, mostly exhibiting only tiny micro-tags without distinct surface demineralization. At bur-cut dentin, the experimental self-adhesive filling material interacted superficially, with the surface structure being more irregular because of the bur preparation. No clear resin tags were formed due to the obstruction of dentin tubules with smear plugs. At fractured dentin, the formation of a relatively thin hybrid layer of maximum a few hundreds of nanometer was disclosed without clear surface demineralization. Distinct resin tags were formed due to the absence of smear plugs. Silver-nitrate infiltration showed a pattern of spot-like appearance of nano-leakage. Ag deposition was observed more along the dentin-adhesive interface of bur-cut dentin, as compared to that of fractured dentin. SIGNIFICANCE: The obtained tight interface at both enamel and dentin demonstrates the self-adhesive capacity of the experimental self-adhesive filling material. PMID- 21596426 TI - Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. AB - Little is known about how combinations of histone marks are interpreted at the level of nucleosomes. The second PHD finger of human BPTF is known to specifically recognize histone H3 when methylated on lysine 4 (H3K4me2/3). Here, we examine how additional heterotypic modifications influence BPTF binding. Using peptide surrogates, three acetyllysine ligands are indentified for a PHD-adjacent bromodomain in BPTF via systematic screening and biophysical characterization. Although the bromodomain displays limited discrimination among the three possible acetyllysines at the peptide level, marked selectivity is observed for only one of these sites, H4K16ac, in combination with H3K4me3 at the mononucleosome level. In support, these two histone marks constitute a unique trans-histone modification pattern that unambiguously resides within a single nucleosomal unit in human cells, and this module colocalizes with these marks in the genome. Together, our data call attention to nucleosomal patterning of covalent marks in dictating critical chromatin associations. PMID- 21596428 TI - Metabolic phenotyping for monitoring surgical patients. PMID- 21596429 TI - Novel melatonin-based therapies: potential advances in the treatment of major depression. AB - Major depression is one of the leading causes of premature death and disability. Although available drugs are effective, they also have substantial limitations. Recent advances in our understanding of the fundamental links between chronobiology and major mood disorders, as well as the development of new drugs that target the circadian system, have led to a renewed focus on this area. In this review, we summarise the associations between disrupted chronobiology and major depression and outline new antidepressant treatment strategies that target the circadian system. In particular, we highlight agomelatine, a melatonin receptor agonist and selective serotonergic receptor subtype (ie, 5-HT(2C)) antagonist that has chronobiotic, antidepressant, and anxiolytic effects. In the short-term, agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline and, in the longer term, fewer patients on agomelatine relapse (23.9%) than do those receiving placebo (50.0%). Patients with depression treated with agomelatine report improved sleep quality and reduced waking after sleep onset. As agomelatine does not raise serotonin levels, it has less potential for the common gastrointestinal, sexual, or metabolic side-effects that characterise many other antidepressant compounds. PMID- 21596430 TI - Nanofiber-mediated controlled release of siRNA complexes for long term gene silencing applications. AB - Nanofiber scaffold-mediated delivery of small-interfering RNA (siRNA) holds great potential in regenerative medicine by providing biomimicking topographical signals and enhanced gene silencing effects to seeded cells. While the delivery of naked siRNA was demonstrated previously using poly (epsilon-caprolactone) (PCL) nanofibers, the resulting siRNA release kinetics and gene knockdown efficiencies were sub-optimal. In this study, we investigated the feasibility of encapsulating siRNA and transfection reagent (TKO) complexes within nanofibers comprising of a copolymer of caprolactone and ethyl ethylene phosphate (PCLEEP, diameter ~ 400 nm). Sustained release of bioactive naked siRNA and siRNA/TKO complexes were obtained for at least 28 days. By copolymerizing EEP with caprolactone, siRNA release was significantly enhanced (total siRNA that was released by day 49 was ~ 89.3-97.2% as compared to previously reported 3% by plain PCL nanofiber delivery). Using GAPDH as the model protein, bioactivity analyses by supernatant transfection revealed the partial retention of bioactivity of naked siRNA and siRNA/TKO complexes for at least 30 days. In particular, GAPDH siRNA/TKO supernatant alone induced significant gene silencing (~40%), indicating the feasibility of co-encapsulating siRNA and transfection reagent within a single scaffold construct for sustained delivery. Direct culture of cells on siRNA incorporated scaffolds for scaffold-mediated gene transfection revealed significant gene knockdown even in the absence of transfection reagent (21.3% knockdown efficiency by scaffolds incorporating naked siRNA only). By encapsulating siRNA/TKO complexes, more significant gene knockdown was obtained (30.9% knockdown efficiency as compared to previously reported 18% by plain PCL scaffold-mediated transfection). Taken together, the results demonstrated the feasibility of co-encapsulating siRNA-transfection reagent complexes within a single nanofiber construct for sustained siRNA delivery and enhanced gene knockdown efficiency. The study also highlights the potential of PCLEEP as a platform for tailoring siRNA release kinetics for long-term gene silencing applications. PMID- 21596431 TI - Enhanced gene expression in tumors after intravenous administration of arginine-, lysine- and leucine-bearing polypropylenimine polyplex. AB - The possibility of using non-viral gene delivery systems for the treatment of cancer is currently limited by their lower transfection efficacy compared to viral systems. On the basis that amino acids such as arginine, lysine and leucine were involved in enhancing DNA transportation into cells, we hypothesized that the grafting of these amino acids to the highly promising generation 3 diaminobutyric polypropylenimine (DAB) dendrimer would improve its transfection efficacy in cancer cells. In this work we demonstrated that the conjugation of arginine, lysine and leucine to the dendrimer led to an enhanced anti proliferative activity of the polyplexes, by up to 47-fold for DAB-Lys in T98G cancer cells compared to the unmodified polyplex in vitro. In vivo, the intravenous administration of amino acid-bearing DAB polyplexes resulted in a significantly improved tumor gene expression, with the highest gene expression level observed after treatment with DAB-Lys polyplex. Arginine, lysine and leucine-bearing generation 3 polypropylenimine polymers are therefore highly promising gene delivery systems for gene transfection in tumors. PMID- 21596432 TI - The potential of Pluronic polymeric micelles encapsulated with paclitaxel for the treatment of melanoma using subcutaneous and pulmonary metastatic mice models. AB - The increasing global incidence of malignant melanoma combined with the poor prognosis and low survival rates of patients necessitates the development of new chemotherapeutic strategies. Thus, the objective of this present study was to investigate the therapeutic efficacy of Pluronic polymeric micelles encapsulating paclitaxel (PTX) in both B16F10 melanoma subcutaneous mice model and pulmonary metastatic mice model. Herein, we developed a PTX-loaded polymeric micelles (PF PTX) consisting of Pluronic P 123 and F127 block copolymers with small particle size (~25 nm), high encapsulation efficiency (>90%), good stability in lyophilized form and pH-dependent in vitro release. Furthermore, influence of PF PTX on in vitro cytotoxicity was determined by MTT assay using B16F10 melanoma cell line, while cellular distribution of PF-PTX was detected by confocal microscopy. Additionally, C57BL/6 mice bearing subcutaneous or pulmonary B16F10 melanoma tumors were treated with Taxol or PF-PTX, and antitumor effect was compared. It was found that antitumor efficacy of PF-PTX in both tumor models showed significant tumor growth delay and increased survival. In summary, the simple Pluronic-based nanocarrier could be harnessed for the delivery of anticancer drug to melanoma, with increased therapeutic index. PMID- 21596433 TI - Characterisation of the nuclear receptors FXR, PXR and CAR in normal and cholestatic placenta. AB - Bile acids are the toxic end products of hepatic cholesterol metabolism. They are synthesised from early in gestation and excreted via the placenta. The mechanism for transplacental excretion of bile acids is not known. The gene and protein expression of the nuclear receptors responsible for hepatic bile acid metabolism and transport was studied in eight normal and fourteen cholestatic placentas, and in an ex vivo model. The expression of the nuclear receptor FXR and several of it's target genes and of PXR and CAR was found to be very low in both normal and cholestatic placenta. PMID- 21596434 TI - Role of IP3 receptor in development. AB - IP3 receptor is a Ca(2+) release channel localized on the endoplasmic reticulum. IP(3) receptor is composed of three isoforms, which are expressed in various cells and tissues, and play variety of roles throughout development. I here describe the role of IP3 receptor from oogenesis, meiotic maturation and fertilization. I also describe the Ca(2+) signaling at meiosis and mitosis, and especially the role in early embryogenesis to determine dorso-ventral axis formation. Loss of function mutation of type 1 IP3 receptor in mouse, both by gene targeting and spontaneous mutations shows severe ataxia and other phenotypes. Interestingly, double knockouts of type 1 and type 2 exhibit cardiogenesis arrest and that of type 2 and type 3 results in exocrine secretion deficit. IP3R of Drosophila or Caenorhabditis elegans is single gene and mutation results severe phenotype of behavior. All the data described here show that IP3Rs are essential for life and abnormality of IP(3)Rs results in severe abnormality in its structure and function of organism. PMID- 21596435 TI - Transient/reversible ring sideroblasts in bone marrow of patients post cytotoxic therapies for primary malignancies. AB - The diagnosis of therapy-related myelodysplastic syndrome (t-MDS) in the absence of increased myeloblasts or cytogenetic abnormalities is challenging. The presence of ring sideroblasts (RS) in this setting is often used to support the diagnosis of t-MDS. In this study, we reviewed 843 patients initially classified as therapy-related myeloid neoplasm in our hospital over 10 years. Nineteen (2.3%) patients had a normal karyotype, <5% bone marrow (BM) blasts, and >=15% RS (17-70%), forming this study group. After reviewing clinical charts and follow-up BM specimens, we confirmed the diagnosis of MDS in 13 patients, but in 6 patients the blood counts returned to normal and RS and associated dyserythropoiesis disappeared in the follow-up BM biopsy. With a median follow-up of 21 months, none of these 6 patients died of BM causes. Compared with t-MDS cases, the 6 patients with transient/reversible RS showed comparable numbers of RS and BM blasts, but infrequent dysplasia involving non-erythroid lineages. We conclude that the presence of >=15% RS in the post-therapy setting is not necessarily indicative of a clonal stem cell neoplasm. Four patients with transient/reversible RS received alpha-interferon therapy which may contribute to RS formation in this setting. PMID- 21596436 TI - Prognostic value of MRD-dynamics in childhood acute lymphoblastic leukemia treated according to the MB-2002/2008 protocols. AB - Detection of minimal residual disease (MRD) during the treatment of acute lymphoblastic leukemia (ALL) by RQ-PCR analysis of clonal Ig/TCR rearrangements is used for risk group stratification in European treatment protocols. In Belarus patients with childhood ALL are treated according to ALL-MB protocols, which do not use MRD-based risk stratification. To evaluate the prognostic significance of MRD for ALL-MB-2002/2008 protocols, MRD was quantified by RQ-PCR in 68 ALL patients at four time points: on day 15, on day 36, before and after maintenance therapy (MT). MRD positivity, as well as quantitative level of MRD were analyzed and compared between patients who stayed in remission and relapsed. Relapse-free survival revealed to be significantly associated with MRD levels at different time points. Unfavorable prognosis was shown for MRD>=10(-3) on day 36 (p<0.001), and any positive MRD before (p<0.001) and after (p=0.001) MT. Multivariate Cox regression analysis proved MRD as independent significant prognosis factor at day 36 (p=0.005) and before MT (p=0.001). We conclude, that MRD quantified by RQ-PCR in children with ALL treated with ALL-MB protocols is feasible and independently associated with outcome. MRD may be a suitable parameter for treatment stratification in MB protocols in future. PMID- 21596437 TI - Effects of Prochloraz fungicide on soil enzymatic activities and bacterial communities. AB - We studied in the laboratory the effect of Prochloraz fungicide on the biological properties (soil enzymatic activities and soil bacterial communities) of a Plaggic Anthrosol. Five hundred grams of soil (<2mm) was mixed with three dosages of Prochloraz (1, 2, and 4 l ha(-1)) for 83 days. A non-Prochloraz polluted soil was used as control. Following commercial recommendations, fungicide was applied four times during the incubation experiment. For all treatments, the soil ergosterol and levels of dehydrogenase, urease, beta-glucosidase, and phosphatase activity were measured at nine different times (0, 1, 21, 22, 41, 42, 62, 63, and 83 days). The 16S rDNA-DGGE profiles in all treatments were determined at the beginning and end of the incubation period. At the end of the experiment, a significant decrease in ergosterol by 72.3%, 80.8%, and 83.1%, compared with control soil, was observed when 1, 2, and 4 l ha(-1), respectively, was added. Soil enzymatic activities increased when the Prochloraz applied to the soil increased, possibly because the fungicide is used by bacterial communities as a source of energy and nutrients. The 16S rDNA-DGGE profiles indicated that the fungicide did not negatively affect soil bacterial biodiversity. These results suggested that the fungicide Prochloraz has a very interesting agronomic effect, possibly due to the negative effect on soil fungal population stimulating the growth of soil bacterial activity. PMID- 21596438 TI - Inevitable recidivism--the origin and centrality of an urban legend. AB - This paper examines the pervasive conviction that sex offenders - particularly child molesters - will continue to re-offend. This belief in inevitable recidivism turns out to be absolutely essential to both the justification for, and the structure of, the sexually violent predator laws. When actual evidence of sex offender recidivism is examined, however, a huge gap exists between what is assumed and what the data actually show because most sex offenders do not in fact re-offend. Thus there is a galaxy of sexually violent predator laws and an entire branch of Supreme Court jurisprudence that is founded upon a demonstrable urban legend. PMID- 21596439 TI - Bisphenol A (BPA) in China: a review of sources, environmental levels, and potential human health impacts. AB - Bisphenol A (BPA), identified as an endocrine disruptor, is an industrially important chemical that is used as a raw material in the manufacture of many products such as engineering plastics (e.g., epoxy resins/polycarbonate plastics), food cans (i.e., lacquer coatings), and dental composites/sealants. The demand and production capacity of BPA in China have grown rapidly. This trend will lead to much more BPA contamination in the environmental media and in the general population in China. This paper reviews the current literature concerning the pollution status of BPA in China (the mainland, Hong Kong, and Taiwan) and its potential impact on human health. Due to potential human health risks from long-term exposure to BPA, body burden of the contaminant should be monitored. PMID- 21596440 TI - Clinical outcome and microbiological findings using antibiotic-loaded spacers in two-stage revision of prosthetic joint infections. AB - OBJECTIVES: Antibiotic-loaded spacers may improve antimicrobial efficacy in two stage revision of prosthetic joint infections, but they may also interfere in the course of infection. This prospective study of prosthetic joint infections managed with two-stage revision and antibiotic-loaded spacers (2004-09) analyzes case outcomes and proposes a second-stage culture interpretation scheme. METHODS: Second-stage infection was diagnosed upon second-stage cultures (synovial membranes, joint fluid, spacers), as either superinfection (>=2 samples, new organism) or persistence (>=1 samples, previously isolated organism). Isolated positive antibiotic-loaded spacers cultures were considered as colonizations. RESULTS: Of 42 patients, two had two prosthetic infections (n = 44): 25 knees, 19 hips. Spacers contained gentamicin (33), vancomycin (10) and aztreonam (1). Three patients (7%) with wound healing impairment required debridement and spacer exchange. The remainder underwent second-stage surgery as planned: 34 (77%) new arthroplasties, five arthrodeses, one resection arthroplasty and one permanent spacer. Of 18 cases (44%) with >=1 positive sample, only four (10%) were second stage infections. Fourteen antibiotic-loaded spacers cultures (34%) were positive. Four new prostheses (9%) supervened further infections: one by the organism isolated in the spacer, three by new bacteria. CONCLUSIONS: The findings of second-stage cultures show that the surgical site is frequently non-sterile at reimplantation. Isolated positive antibiotic-loaded spacer cultures usually have no clinical consequences, but together with tissue cultures they help to diagnose second-stage infections when clinical signs are absent. PMID- 21596441 TI - Enquiring about traumatic experiences in bipolar disorder: a case note and self- report comparison. AB - OBJECTIVES: This study examined: (i) the prevalence of lifetime trauma, childhood trauma and trauma related to civil unrest in a Bipolar Disorder sample, and (ii) the agreement between rates of disclosure of trauma in case notes and self-report questionnaires. METHODS: The case notes of sixty participants, recruited from a geographically well-defined mental health service in Northern Ireland, were examined for reports of experiences of lifetime, childhood and traumatic events related to civil conflict. The participants also completed self-report measures of trauma. RESULTS: Considerable differences were found between the prevalence of trauma as measured by self-report questionnaires and case notes reports. The prevalence of lifetime trauma as measured by the Trauma History Questionnaire was 61.7% (compared to case notes prevalence of 33.3%). The prevalence of moderate and severe levels of childhood trauma as measured by the Childhood Trauma Questionnaire was 65% (case notes 21.7%). Rates of trauma related to civil unrest were 35% (case notes 3.3%). Poor levels of agreement were found between all self report trauma measures and case notes reports. Agreement on two categories of trauma (childhood emotional neglect and childhood physical neglect) reached statistical significance but kappa scores suggest this agreement was poor (kappa=.14, p<.05; kappa=.127, p<.05). CONCLUSIONS: It is probable that the increased rate of trauma disclosed in the self-report questionnaire arises because clinicians during initial assessment and subsequent treatment do not consistently enquire about trauma. The need for staff training is discussed. PMID- 21596442 TI - Time to rehospitalization in patients with schizophrenia discharged on first generation antipsychotics, non-clozapine second generation antipsychotics, or clozapine. AB - Rehospitalization is an important outcome of drug effectiveness in schizophrenia. In this study, the hypothesis that clozapine and some second generation antipsychotics (SGA) were superior to first generation antipsychotics (FGA) in preventing rehospitalization of patients with schizophrenia discharged from a university hospital in Brazil was tested. A retrospective observational study was conducted designed to evaluate time to rehospitalization of patients with schizophrenia discharged on a regimen of oral FGA, depot FGA, risperidone, olanzapine and amisulpride, other SGA, or clozapine, during a three-year follow up period. Risk factors associated with rehospitalization were examined. Of the 464 patients with schizophrenia discharged from hospital, 242 met criteria for study entry. Higher rehospitalization rates were observed in patients treated with depot FGA (30%), risperidone (30%) and other SGA groups (28.5%), respectively. Clozapine was significantly associated with lower rehospitalization risk compared with risperidone. The risk of rehospitalization in patients on olanzapine and amisulpride, and oral FGA, was similar to that of patients in use of clozapine. These results however, are limited by the heterogeneity of illness severity across the groups. PMID- 21596443 TI - Theory of Mind and psychometric schizotypy. AB - The extent to which Theory of Mind impairments are a trait associated with schizotypy is unclear. To date, findings have been mixed. We compared two groups of psychometrically identified schizotypes, namely, those characterized by positive schizotypy (perceptual aberrations and magical ideation; n=36) and those characterized by negative schizotypy (social anhedonia; n=30) to a low schizotypy comparison group (n=68) in terms of their Theory of Mind performance. Theory of Mind was assessed in two ways: a composite Hinting Task and the Reading the Mind in the Eyes Test. The groups were also compared in terms of their self-reported levels of referential thinking. Our results indicate that individuals characterized by positive schizotypy show Theory of Mind deficits, as measured by the Hinting Task. The three groups did not differ in terms of the Eyes Test. Referential thinking was significantly associated with the Eyes Test but not the Hinting Task. Overall these findings suggest that different aspects of schizotypy are associated differentially with Theory of Mind deficits. The results also provide further rationale for the inclusion of multiple tasks when attempting to study multifaceted constructs such as Theory of Mind. PMID- 21596444 TI - Sub-cellular localisation of alkaline phosphatase activity in the cytoplasm of tammar wallaby (Macropus eugenii) neutrophils and eosinophils. AB - Alkaline phosphatase (ALP) has been used in studies of neutrophil morphology and function as a marker for identifying different granule populations. In human neutrophils, ALP is found within secretory vesicles, a rapidly mobilisable vesicle population important for upregulating membrane receptors during early activation. Intra-cellular ALP activity in the heterophils of rabbits and guinea pigs, in contrast, is found only in secondary granules. The neutrophils and eosinophils of tammar wallabies (Macropus eugenii) have previously been reported to contain large amounts of ALP activity when stained using routine cytochemical techniques. To define the subcellular location of ALP in this species, cell suspensions were examined using cerium chloride cytochemistry and transmission electron microscopy (TEM). ALP was found in 2 distinct cytoplasmic compartments. One compartment displayed morphology consistent with a subpopulation of secondary granules while a second tubulo-vesicular population appeared similar to the secretory vesicles of human neutrophils. Thin tubular vesicles containing ALP were also identified within the cytoplasm of tammar wallaby eosinophils. Large numbers of ALP-containing vesicles have not been recognised previously in eosinophils and this may represent a novel cytoplasmic compartment. In both cell types, ALP-containing structures showed alteration in morphology following stimulation with N-formyl-Met-Leu-Phe (fMLP) and PMA. PMID- 21596445 TI - Novel B regs down-regulate TLR9-induced cytokine responses in sheep Peyer's patches. AB - Regulation of TLR responses is required in the intestine to prevent unnecessary responses to commensal microorganisms and maintain tissue homeostasis. Several mechanisms have been proposed for the regulation of TLR responses in intestinal epithelial and lamina propria cells. However, whether this regulation occurs in Peyer's patches (PP) is not known. While investigating cellular responses to the TLR9 agonist CpG ODN, we observed that PP cells responded poorly to CpG ODN stimulation despite expressing TLR9. We hypothesized that PP cells produced the immunoregulatory cytokine IL-10 which suppressed TLR-induced cytokine responses. In vitro neutralization of IL-10 or depletion of CD21+ B cells from PP resulted in significant increases in IL-12, IFNgamma and IFNalpha responses in PP cells stimulated with CpG ODN. Essentially, our investigation have identified a novel population of IL-10-secreting B cells in PP with regulatory functions (B(regs)). These B(regs) may play an important role in the maintenance of intestinal homeostasis. PMID- 21596446 TI - Auditory neuropathy/dyssynchrony as a cause of failed neonatal hearing screening. AB - The prevalence of auditory neuropathy/dyssynchrony (AN/AD) is not exactly known. We retrospectively analysed the prevalence of this condition among 135 infants who failed a neonatal screening. Hearing screening was performed by automated auditory brainstem responses (AABR). Unilateral presence of click-evoked oto acoustic emissions with absent auditory brainstem responses was found in 4 infants. Magnetic resonance imaging of the posterior fossa showed an aplasia/hypoplasia of the ipsilateral cochlear nerve in these 4 cases. The prevalence of AN/AD was 19% in infants with confirmed hearing loss. Our findings underscore the role of AABR in neonatal hearing screening. PMID- 21596447 TI - Are randomised controlled trials involving adenotonsillectomy well reported? AB - INTRODUCTION: Evidence-based medicine guides clinical practice. Currently, the evidence base on adenotonsillectomy is under scrutiny to establish clinical guidelines. It is therefore important that reports of clinical trials are of high quality. Guidance on reporting of randomised controlled trials (RCTs) are available in the Consolidated Standards for Reporting Trials (CONSORT) statement first published in 1996 and revised in 2001 and 2010. METHODS: A review of randomised controlled trials on adenotonsillectomy published after 2001 was undertaken. Each report was systematically assessed using the checklist of items from the CONSORT statement. RESULTS: Twenty-five trials were identified. All trials, except one, were identified as a randomised controlled trial by title or abstract. Twenty percent of trials reported a sample size calculation. A third of trials reported their method of generating a random allocation sequence. Similarly, a third stated the method of implementing the random allocation. A fifth of trials reported a clear flow of trial participants, with only a single trial reporting this with the aid of a diagram. CONCLUSION: This review shows the quality of reporting needs to be improved. Critical appraisal of poorly reported trials may result in erroneous conclusions, even though these trials may have been carried out with rigorous adherence to a protocol of high standard. Authors of clinical trial reports should be encouraged to consult the CONSORT statement. PMID- 21596448 TI - Presynaptic function in health and disease. AB - Neurons communicate with one another at specialized contact sites called synapses, composed of pre- and postsynaptic compartments. Presynaptic compartments, or 'boutons', signal to the postsynaptic compartment by releasing chemical neurotransmitter in response to incoming electrical impulses. Recent studies link defects in the function of presynaptic boutons to the etiology of several neurodevelopmental and neurodegenerative diseases, including autism, schizophrenia and Alzheimer's disease. In this review, we describe five core functions of presynaptic boutons and the molecules that mediate these functions, focusing on a subset that are linked to human disease. We also discuss potential mechanisms through which the loss or alteration of these specific molecules could lead to defects in synaptic communication, neural circuit function and, ultimately, cognition and behavior. PMID- 21596449 TI - A post-hoc analysis of the CUSTOMIZE Registry on the differential impact of EuroSCORE and SYNTAX score in left main patients with intermediate Global Risk. PMID- 21596450 TI - Clinical outcomes of adult survivors of pulmonary atresia with intact ventricular septum. AB - BACKGROUND: There are no studies on the long term clinical outcomes and complications in the adult patient with pulmonary atresia with intact ventricular septum (PA/IVS). This study reviews our experience with a limited group of adult survivors of PA/IVS seen in our adult congenital clinics. METHODS: Twenty adult patients with PA/IVS (1998 to 2009) were identified from Mayo Clinic adult congenital heart disease databases. Surgical history and clinical outcomes were reviewed. RESULTS: Mean age at last evaluation was 29 years (19-39 years). There were five deaths within the study period (1998-2009). Median age at death was 32 years (30-37 years). Seven patients underwent the Fontan operation, eight patients had a biventricular repair, and five patients remained with palliative shunts. All patients required re-interventions in adulthood. Tricuspid valve (TV) (n=5), pulmonary valve (PV)/conduit (n=6), and mitral valve (n=2) replacements were the most frequent re-intervention in the biventricular repair subset. Atrial arrhythmias were present in 80% of the total cohort, the highest rate among Fontan repairs (n=7) and biventricular repairs (n=7). Ventricular arrhythmias occurred in 15% of the cohort. CONCLUSIONS: Although limited in number, the adult PA/IVS patients in this series continue to have high rates of morbidity and mortality, with arrhythmias and need for re-operations as the major causes. Patients with biventricular repairs had the highest re-intervention rate in adulthood. While this subset of patients might not be representative of all adult PA/IVS survivors, continued follow-up at centers with expertise in adult congenital cardiology is recommended for all patients. PMID- 21596451 TI - The negative inotropic effects of homocysteine were prevented by matrine via the regulating intracellular calcium level. PMID- 21596452 TI - New index alpha improves detection of pulmonary hypertension in comparison with other cardiac magnetic resonance indices. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) has been proposed for the evaluation of patients with pulmonary hypertension (PH). However, there is no consensus on the optimal method for PH diagnosis using CMR. OBJECTIVE: To compare the diagnostic ability of multiple CMR-derived indices for the detection of PH as determined by right heart catheterization (RHC). METHODS: A total of 185 patients with known or suspected chronic PH who underwent cardiac CMR and RHC in <=15 days were included. PH was defined as a mean pulmonary artery (PA) pressure >=25 mmHg. Right ventricular (RV) volumes, RV ejection fraction (RVEF), PA areas, and PA average blood flow velocity were quantified with CMR. A novel index alpha was defined as the ratio between minimal PA area and RVEF. RESULTS: According to the RHC, PH was present in 152 patients. All CMR-derived parameters correlated with the degree of mean PA pressure, with alpha having the highest correlation coefficient (r=0.61, p<0.001). Correlations were also highest for alpha in the patients with pulmonary arterial hypertension (PAH; r=0.55, p<0.001) and non-PAH subgroup (r=0.61, p<0.001). Diagnostic accuracy for the detection of PH, based on receiver operating curve analysis, was best for alpha (area under the curve=0.95). A cutoff value of 7.2 demonstrated a sensitivity of 90% and a specificity of 88%. CONCLUSIONS: An easily-obtainable and novel CMR index alpha that combines geometrical and functional information of the PA and the RV allows for the noninvasive diagnosis of PH with high accuracy, above other common CMR derived parameters. PMID- 21596453 TI - Serum FGF21 levels are increased in newly diagnosed type 2 diabetes with nonalcoholic fatty liver disease and associated with hsCRP levels independently. AB - OBJECTIVE: Fibroblast growth factor (FGF21) has beneficial effects on lipolysis. Highly sensitive C-reactive protein (hs-CRP) is a predictor of type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). This study aimed to determine the levels of serum FGF21 and hs-CRP in newly diagnosed type 2 diabetes patients with and without NAFLD, and further explored the correlation between FGF21 with hs-CRP in newly diagnosed type 2 DM. RESEARCH DESIGN AND METHODS: 69 patients with newly diagnosed type 2 DM and 30 normal subjects were included in the study. FGF21 and hs-CRP were measured by ELISA kits. The severity of NAFLD was measured by ultrasound. RESULTS: Serum FGF21 in newly diagnosed type 2 DM with NAFLD group were significantly increased (p<0.01). There was no difference for the FGF21 level in normal control group and newly diagnosed type 2 DM without NFALD group. In type 2 DM group, the FGF21 level was positively correlated with hsCRP (r=0.417, p<0.001). In multiple stepwise regression models, only hsCRP was a significantly independent determinant for serum FGF21. CONCLUSIONS: Serum levels of FGF21 are closely related to liver steatosis in newly diagnosed type 2 DM patients. PMID- 21596454 TI - VEGF gene polymorphism association with diabetic foot ulcer. AB - OBJECTIVE: Functional polymorphisms within vascular endothelial growth factor (VEGF) gene have shown association with various conditions including diabetic neuropathy and retinopathy. In this study we have performed a candidate gene association study in order to examine VEGF gene polymorphism association with diabetic foot ulcer (DFU). METHODS: The study group comprised of type 2 diabetes patients with (N=247) and without (N=241) DFU. Healthy control subjects (N=98) were also recruited from the same area. The ARMS-PCR technique was applied for genotyping of VEGF gene SNPs at positions -7*C/T and -2578*C/A. RESULTS: The frequency of genotype AA was significantly decreased in patients with DFU compared with diabetic subjects without DFU (AA vs CA+CC, p=0.003, OR=0.44, CI=0.24-0.80). Also there was a significant decrease in frequency of A allele in patients with DFU compared to the controls (p=0.02, OR=0.68, CI=0.48-0.96). CONCLUSION: It seems that lower frequency of A allele in patients with DFU is conferring a protective effect which might be as a result of increased angiogenesis in patients carrying this allele. PMID- 21596456 TI - Papular and annular fixed urticarial eruption: a characteristic skin manifestation in patients with relapsing polychondritis. AB - BACKGROUND: Skin manifestations of relapsing polychondritis (RP) are usually nonspecific. OBJECTIVE: We report a series of patients with RP who presented with annular skin lesions. METHODS: The clinical and histologic features and follow-up data of patients with RP and an annular urticarial eruption were retrospectively reviewed. RESULTS: Ten patients (9 male, 1 female) (mean age 63.7 years) were included. All patients had tense, fixed, urticarial papules with an annular configuration predominantly located on the upper part of the trunk. Skin lesions occurred before the chondritis in 7 of 10 cases with a mean delay of 23 +/- 13 months. Histologic examination consistently showed a lymphocytic vasculitis with no leukocytoclastic vasculitis, even when biopsies were repeated during the evolution (n = 7). Hematologic abnormalities were found in all cases. A myelodysplastic syndrome was found in 4 patients. Oral corticosteroids were effective in all cases, although skin lesions recurred during the decrease of corticosteroid doses in 4 cases. Five patients died during the evolution. LIMITATION: Retrospective case series design is a limitation. CONCLUSION: Annular and papular fixed urticarial eruption may represent a characteristic skin manifestation of RP. It is frequently associated with hematologic abnormalities and may auger a poor prognosis. PMID- 21596455 TI - Positive patch test reactions in older individuals: retrospective analysis from the North American Contact Dermatitis Group, 1994-2008. AB - BACKGROUND: Relatively little is known about the epidemiology of allergic contact dermatitis in older individuals. OBJECTIVES: We sought to determine the frequency of positive and clinically relevant patch test reactions in older individuals (>= 65 years old) referred for patch testing, and to compare these results with those of adults (<= 64-19 years) and children (<18 years). DESIGN: This was a retrospective cross-sectional analysis of North American Contact Dermatitis Group data from 1994 to 2008. RESULTS: A total of 31,942 patients (older n = 5306; adults n = 25,028; children n = 1608) were patch tested. The overall frequency of at least one allergic reaction in older individuals was 67.3% as compared with 66.9% for adults (P = .5938) and 47% for children (P = .0011). Reaction rates that were statistically higher in older individuals as compared with both adults and children included: Myroxylon pereirae, fragrance mix I, quaternium-15, formaldehyde, imidazolidinyl urea, diazolidinyl urea, neomycin, bacitracin, methyldibromo glutaronitrile, methyldibromo glutaronitrile/phenoxyethanol, ethyleneurea melamine formaldehyde mix, and carba mix (P values < .0004). Patch test reaction rates that were significantly lower in older individuals than both comparison groups included: nickel, thimerosal, and cobalt (P values < .0001). LIMITATIONS: Referral population was a limitation. CONCLUSIONS: Older individuals were more likely to have at least one positive patch test reaction as compared with children, but had similar rates to adults. The frequency of positive reactions to specific allergens differed by age group, most likely as a result of exposures. PMID- 21596459 TI - [Results of carotid endarterectomy in elderly patients]. AB - INTRODUCTION: Forty-five per cent of stoke patients have a surgically accessible stenosis. The objective of our study is to describe the response to carotid endarterectomy (EA) in patients of advanced age compared to younger ones. MATERIAL AND METHOD: Retrospective evaluation of the clinical history of all patients who underwent an endarterectomy in a tertiary hospital between January 1995 and December 2006. The patients were grouped into those 75 years or older and those less than this age. The incidence of peri-operative complications in the first month after surgery, and the long-term mortality was evaluated using a survival analysis. RESULTS: Data were collected on 147 EA in 134 patients of 75 years or more, and on 201 EA in 177 patients less than 75 years-old. The incidence of peri-operative complications was similar in both groups, with a mortality of 2% in the older age group and a stroke incidence of 2.6% (half transient ischaemic accidents). The older patients had a mean follow-up of 4.1 years, with a survival of 86% at one year and 54% at 5 years and with the main cause of death being heart disease. CONCLUSIONS: Carotid EA is a safe and effective technique for the treatment of extracranial carotid stenosis in the elderly, having the same peri-operative morbidity and mortality as younger ones. Age must not affect our therapeutic attitude, although an exhaustive cardiology study must be made in the elderly prior to the operation. PMID- 21596458 TI - Posterior cerebral atrophy in the absence of medial temporal lobe atrophy in pathologically-confirmed Alzheimer's disease. AB - Medial temporal lobe atrophy (MTA) is a recognized marker of Alzheimer's disease (AD), however, it can be prominent in frontotemporal lobar degeneration (FTLD). There is an increasing awareness that posterior atrophy (PA) is important in AD and may aid the differentiation of AD from FTLD. Visual rating scales are a convenient way of assessing atrophy in a clinical setting. In this study, 2 visual rating scales measuring MTA and PA were used to compare atrophy patterns in 62 pathologically-confirmed AD and 40 FTLD patients. Anatomical correspondence of MTA and PA was assessed using manually-delineated regions of the hippocampus and posterior cingulate gyrus, respectively. Both MTA and PA scales showed good inter- and intrarater reliabilities (kappa > 0.8). MTA scores showed a good correspondence with manual hippocampal volumes. Thirty percent of the AD patients showed PA in the absence of MTA. Adding the PA to the MTA scale improved discrimination of AD from FTLD, and early-onset AD from normal aging. These results underline the importance of considering PA in AD diagnosis, particularly in younger patients where medial temporal atrophy may be less conspicuous. PMID- 21596460 TI - Predominant copper deficiency during prolonged enteral nutrition through a jejunostomy tube compared to that through a gastrostomy tube. AB - BACKGROUND & AIMS: Trace element deficiencies are known to occur during long-term enteral nutrition feeding. We compared the serum concentrations of trace elements between patients treated with gastrostomy and those treated with jejunostomy. METHODS: Our subjects were 36 patients who underwent percutaneous endoscopic gastrostomy (PEG group) and 23 patients who underwent percutaneous endoscopic jejunostomy (PEJ group) and were maintained with enteral tube feeding for more than one year. The serum concentrations of copper, zinc, selenium, and iron were measured in the two groups. Clinical manifestations and the effectiveness of supplementation therapy against copper deficiency were also investigated. RESULTS: From 6 months after the onset of enteral feeding, the copper concentration of the PEJ group was significantly decreased compared with that of the PEG group (p<0.001). There were no significant differences in the concentrations of zinc, selenium, or iron between the two groups. Severe copper deficiency was observed in 6 patients of the PEJ group and was accompanied with neutropenia and anemia. The copper deficiency was successfully treated in all of these patients by supplementation with 10-40 g of cocoa powder a day which was equivalent to a total daily dose of 1.36-2.56 mg of copper. CONCLUSIONS: Prolonged PEJ tube nutrition tends to result in copper deficiency, and cocoa supplementation is effective for treating such copper deficiency. PMID- 21596461 TI - Investigation of perfusion in osseous vessels in close vicinity to piezo-electric bone cutting. AB - Cutting bones by piezosurgery leads to failure of perfusion at the site of the osteotomy, the cause of which cannot be identified immediately. Among other things the formation of vascular thrombi by the transmission of oscillations from the piezoelectric unit to the bone may be responsible. We used three output levels of oscillation that were predefined by the system. The outer cortical bone of the calvaria of rats (n=24) was removed horizontally and the intraosseous vessels exposed at the surface of the osteotomy. The blood flow was then examined repeatedly using intravital fluorescence microscopy. To calculate the transmission of oscillations to the bone, the spatial oscillation frequency of each calvarium and the contact pressure during removal of bone in vitro (n=18) were also examined. After removal of the bone there was constant blood flow at all three levels of oscillation output. In no case did an individual vessel seem to be occluded. The excitation oscillation of the bone was established at 2000 Hz in all spatial directions, irrespective of the predefined oscillation output. The application of piezosurgery does not cause the formation of vascular thrombi in the bone. This probably results from the oscillation damping properties of bone. PMID- 21596462 TI - Internet use among head and neck cancer survivors in the North West of England. AB - In general, use of the internet by patients in their healthcare is increasing. However, its use specifically among those with head and neck cancer in the UK has not been reported. The aims of this study were to report access to the internet by survivors of head and neck cancer, to indicate where it fits within their information sources, how they have used it, and how they might use it in future. A question on its use has been included in annual surveys of patients since 2006. Patient-reported access to the internet increased from 32% in 2006 to 54% in 2010. There were considerable differences in access by age; currently (2010) 83% of those under 55 years, and 40% of those aged 65-84 years. Binary logistic regression modelling involving age at survey (p<0.001), age leaving education (p<0.001), and sex (p=0.01), gave all three as independent predictors of access. In the 2010 survey 49% (234/473) never used the internet, 10% (49/473) used it rarely, 15% (70/473) used it occasionally, and 25% (120/473) used it often. The main reasons for its use for head and neck cancer were to find information, learn about treatment, side effects, and medication, and obtain advice from members of multidisciplinary teams. The findings of this study show that the internet has an important role for patients in providing information and support about their cancer, although other sources are still very important. Data from the study will help inform those promoting e-health about the type of resource that is wanted by patients. PMID- 21596463 TI - Postural dependence of passive tension in the supraspinatus following rotator cuff repair: a simulation analysis. AB - BACKGROUND: Despite surgical advances, repair of rotator cuff tears is associated with 20-70% incidence of recurrent tearing. The tension required to repair the torn tendon influences surgical outcomes and may be dependent on the gap length from torn tendon that must be spanned by the repair. Detailed understanding of forces throughout the range of motion (ROM) may allow surgeons to make evidence based recommendations for post-operative care. METHODS: We used a computational shoulder model to assess passive tension and total moment-generating capacity in supraspinatus for repairs of gaps up to 3 cm throughout the shoulder (ROM). FINDINGS: In 60 degrees abduction, increased gap length from 0.5 cm to 3 cm caused increases in passive force from 3N to 58 N, consistent with those seen during clinical repair. For reduced abduction, passive forces increased substantially. For a 0.5 cm gap, tension throughout the ROM (elevation, plane of elevation, and rotation) is within reasonable limits, but larger gaps are associated with tensions that markedly exceed reported pull-out strength of sutures and anchors. Peak moment for a large 3 cm gap length was 5.09 Nm, a 53% reduction in moment-generating capacity compared to uninjured supraspinatus. INTERPRETATION: We conclude that shoulder posture is an important determinant of passive forces during rotator cuff repair surgery. Choosing postures that reduce forces intraoperatively to permit repair of larger gaps may lead to failure postoperatively when the shoulder is mobilized. For larger defects, loss of strength in supraspinatus may be substantial following repair even if retear is prevented. PMID- 21596464 TI - Haemoglobinopathy diagnosis: algorithms, lessons and pitfalls. AB - Diagnosis of haemoglobinopathies, including thalassaemias, can result from either a clinical suspicion of a disorder of globin chain synthesis or from follow-up of an abnormality detected during screening. Screening may be carried out as part of a well defined screening programme or be an ad hoc or opportunistic test. Screening may be preoperative, neonatal, antenatal, preconceptual, premarriage or targeted at specific groups perceived to be at risk. Screening in the setting of haemoglobinopathies may be directed at optimising management of a disorder by early diagnosis, permitting informed reproductive choice or preventing a serious disorder by offering termination of pregnancy. Diagnostic methods and algorithms will differ according to the setting. As the primary test, high performance liquid chromatography is increasingly used and haemoglobin electrophoresis less so with isoelectric focussing being largely confined to screening programmes and referral centres, particularly in newborns. Capillary electrophoresis is being increasingly used. All these methods permit only a presumptive diagnosis with definitive diagnosis requiring either DNA analysis or protein analysis, for example by tandem mass spectrometry. PMID- 21596465 TI - Trends in atmospheric reactive nitrogen for the Eastern United States. AB - Reactive nitrogen can travel far from emission sources and impact sensitive ecosystems. From 2002 to 2006, policy actions have led to decreases in NO(x) emissions from power plants and motor vehicles. In this study, atmospheric chemical transport modeling demonstrates that these emissions reductions have led to a downward trend in ambient measurements of transported reactive nitrogen, especially atmospheric concentrations and wet deposition of nitrate. The trend in reduced nitrogen, namely ammonium, is ambiguous. As reduced nitrogen becomes a larger fraction of the reactive nitrogen budget, wide-spread NH(3) measurements and improved NH(3) emissions assessments are a critical need. PMID- 21596466 TI - Connecting food environments and health through the relational nature of aesthetics: gaining insight through the community gardening experience. AB - Current environmental and health challenges require us to identify ways to better align aesthetics, ecology, and health. At the local level, community gardens are increasingly praised for their therapeutic qualities. They also provide a lens through which we can explore relational processes that connect people, ecology and health. Using key-informant interview data, this research explores gardeners' tactile, emotional, and value-driven responses to the gardening experience and how these responses influence health at various ecological levels (n = 67 participants, 28 urban gardens). Our findings demonstrate that gardeners' aesthetic experiences generate meaning that encourages further engagement with activities that may lead to positive health outcomes. Gardeners directly experience nearby nature by 'getting their hands dirty' and growing food. They enjoy the way vegetables taste and form emotional connections with the garden. The physical and social qualities of garden participation awaken the senses and stimulate a range of responses that influence interpersonal processes (learning, affirming, expressive experiences) and social relationships that are supportive of positive health-related behaviors and overall health. This research suggests that the relational nature of aesthetics, defined as the most fundamental connection between people and place, can help guide community designers and health planners when designing environment and policy approaches to improve health behaviors. PMID- 21596467 TI - [Median inferior cervicomandibular cleft: a case report, etiologic and therapeutic aspects]. AB - INTRODUCTION: The orofacial clefts include 30 variant according to Tessier classification: the number 30 contain mandibular arc damage isolated or associated with damage of surrounding soft tissue. CASE REPORT: Our patient was a newborn with median mandibular cleft associated with ankyloglossia, bifid tongue and a top cervical fistula. We have not found polymalformative syndrome. The early surgical management included one time and after-effect were simple within 11 months. DISCUSSION: We point out difficulties for antenatal diagnosis and controversy about appropriate time for surgical management of the bone defect. The last physiopathologic hypotheses were explicated. PMID- 21596468 TI - [Improving physical fitness in adolescents through a school-based intervention: the EDUFIT study]. AB - INTRODUCTION AND OBJECTIVES: Physical fitness level is a marker of cardiovascular health in young people. The aim of this study was to analyze the effects of a school-based intervention program, focused on increasing the volume and intensity of physical education (PE) sessions, on adolescents' physical fitness. METHODS: Sixty-seven adolescents (12-14 years old) from three secondary school classes participated in a 16-week intervention. The classes were randomly allocated to the control group, experimental group 1 (EG1) or experimental group 2 (EG2). The control group received standard PE (2 sessions/week), the EG1 received 4 standard PE sessions/week and the EG2 received four high-intensity PE sessions/week. Aerobic fitness, muscle strength, speed-agility and flexibility were assessed using previously validated field-based tests before and after the intervention. RESULTS: Doubling the number of PE sessions/week resulted in improvements in aerobic fitness and flexibility (P=.008 and P=.04, respectively). Further increases in the intensity of the sessions were related to improvements in speed agility (P<.001). The maximal oxygen consumption increased by 3 and 5 mL/kg/min in the EG1 and EG2, respectively. No differences were observed for muscle strength. CONCLUSIONS: The results suggest that doubling the frequency of PE sessions is a sufficient stimulus to improve physical fitness, particularly aerobic fitness, which has been shown to be a powerful indicator of cardiovascular health in children and adolescents. Future studies involving larger sample sizes should confirm or refute these findings. PMID- 21596469 TI - [AMI secondary to coronary compression by a periaortic hematoma]. PMID- 21596470 TI - [Intramyocardial fat infiltration: magnetic resonance imaging or multidetector CT?]. PMID- 21596471 TI - Increasing AED use by lay responders: implementation challenges and opportunities for knowledge translation. PMID- 21596472 TI - The risk of caesarean section in obese women analysed by parity. AB - OBJECTIVE: This study looked at the association between caesarean section (CS) and Body Mass Index (BMI) in primigravidas compared with multigravidas. STUDY DESIGN: We enrolled women at their convenience, in the first trimester after an ultrasound examination confirmed an ongoing pregnancy. Weight and height were measured digitally and BMI calculated. After delivery, clinical details were again collected from the Hospital's computerised database. RESULTS: Of the 2000 women enrolled, there were 50.4% (n=1008) primigravidas and 49.6% (n=992) multigravidas. Of the 2000 8.5% were delivered by elective CS and 13.4% were delivered by emergency CS giving an overall rate of 21.9%. The overall CS rate was 30.1% in obese women compared with 19.2% in the normal BMI category (p<0.001). In primigravidas the increase in CS rate in obese women was due to an increase in emergency CS (p<0.005) and in multigravidas the increase was due to an increase in elective CS (p<0.01). In obese primigravidas 20.6% had an emergency section for fetal distress. In obese multigravidas 17.2% had a repeat elective CS. CONCLUSION: The influence of maternal obesity on the increase in CS rates is different in primigravidas compared with multigravidas. PMID- 21596473 TI - Epithelial to mesenchymal transition (EMT) induced by bleomycin or TFG(b1)/EGF in murine induced pluripotent stem cell-derived alveolar Type II-like cells. AB - Induced pluripotent stem (iPS) cells are derived from reprogrammed somatic cells and are similar to embryonic stem (ES) cells in morphology, gene/protein expression, and pluripotency. In this study, we explored the potential of iPS cells to differentiate into alveolar Type II (ATII)-like epithelial cells. Analysis using quantitative real time polymerase chain reaction and immunofluorescence staining showed that pulmonary surfactant proteins commonly expressed by ATII cells such as surfactant protein A (SPA), surfactant protein B (SPB), and surfactant protein C (SPC) were upregulated in the differentiated cells. Microphilopodia characteristics and lamellar bodies were observed by transmission electron microscopy and lipid deposits were verified by Nile Red and Periodic Acid Schiff staining. C3 complement protein, a specific feature of ATII cells, was present at high levels in culture supernatants demonstrating functionality of these cells in culture. These data show that the differentiated cells generated from iPS cells using a culture method developed previously (Rippon et al., 2006) are ATII-like cells. To further characterize these ATII like cells, we tested whether they could undergo epithelial to mesenchymal transition (EMT) by exposure to drugs that induce lung fibrosis in mice, such as bleomycin, and the combination of transforming growth factor beta1 (TGF(b1)) and epidermal growth factor (EGF). When the ATII-like cells were exposed to either bleomycin or a TGF(b1)-EGF cocktail, they underwent phenotypic changes including acquisition of a mesenchymal/fibroblastic morphology, upregulation of mesenchymal markers (Col1, Vim, a-Sma, and S100A4), and downregulation of surfactant proteins and E-cadherin. We have shown that ATII-like cells can be derived from skin fibroblasts and that they respond to fibrotic stimuli. These cells provide a valuable tool for screening of agents that can potentially ameliorate or prevent diseases involving lung fibrosis. PMID- 21596474 TI - Physico-chemical and biological studies on water from Aries River (Romania). AB - Our work was focused on physico-chemical and biological characteristics of Aries River, one of the largest rivers from Romania. Water samples were collected from 11 sites along Aries River course. We have measured de (18)O and D isotopic composition of Aries River water in these locations and correlated these data with the isotopic composition of aquatic plants and with the pollution degree. Some ions from Aries River water were also analyzed: NO(3)(-), NO(2)(-), PO(4)(3 ) Cu(2+), Fe(3+). Analysis of diatom communities has been performed in order to quantify the level of water pollution of Aries River. All physico-chemical analyses revealed that the most polluted site is Abrud; the source of pollution is most probably the mining enterprise from Rosia Montana. Water isotope content increases from upstream to downstream of the locations analyzed. The structure of diatom communities is strongly influenced by the different pollution sources from this area: mine waters, industrial waters, waste products, land cleaning, tourism etc. The water eutrophication increases from upstream of Campeni to downstream of Campia Turzii. PMID- 21596475 TI - Photocatalytic activity of tungsten-doped TiO2 with hydrothermal treatment under blue light irradiation. AB - Tungsten doping and hydrothermal treatment were found to significantly improve the visible-light photoactivity of TiO(2) synthesized by the sol-gel method. It was observed that TiO(2) doped with a 0.5% W:Ti mole ratio and treated with 4 h of hydrothermal curing showed photoactivity under blue light irradiation equal to 74% of the commercial Degussa P-25 under UV irradiation, i.e., 0.01 mM 2 chlorophenol was completely removed in 120 and 90 min, respectively. Light absorptivity and photocatalytic activity under blue light irradiation were not dependent on the crystallite structure of the TiO(2). The oxidation kinetics under blue light irradiation can be effectively explained by the Langmuir Hinshelwood model with an apparent reaction rate constant and a Langmuir constant of 3.60 * 10(-4) mM min(-1) and 206.53 mM(-1), respectively. PMID- 21596476 TI - Enhancing atrazine biodegradation by Pseudomonas sp. strain ADP adsorption to Layered Double Hydroxide bionanocomposites. AB - To mimic the role of hydroxide minerals and their humic complex derivatives on the biodegradability of pesticides in soils, synthetic Mg(R)Al Layered Double Hydroxides (LDH) and Mg(R)Al modified by Humic substances (LDH-HA) were prepared for various R values (2, 3 and 4) and fully characterized. Adsorption properties of LDH and LDH-HA toward Pseudomonas sp. strain ADP were evaluated. The adsorption kinetics were very fast (<5 min to reach equilibrium). The adsorption capacities were greater than previously reported (13.5*10(11), 41*10(11) and 45.5*10(11) cells/gLDH for Mg(2)Al, Mg(3)Al and Mg(4)Al, respectively) and varied with both surface charge and textural properties. Surface modification by HA reduced the adsorption capacities of cells by 2-6-fold. Biodegradation kinetics of atrazine by Pseudomonas sp. adsorbed on both LDHs and LDH-HA complexes were measured for various solid/liquid ratios and adsorbed cell amounts. Biodegradation activity of bacterial cells was strongly boosted after adsorption on LDHs, the effect depending on the quantity and properties of the LDH matrix. The maximum biodegradation rate was obtained in the case of a 100 mg/mL Mg(2)Al LDH suspension (26 times higher than that obtained with cells alone). PMID- 21596477 TI - Measurement of itching: validation of the Leuven Itch Scale. AB - OBJECTIVE: To develop the Leuven Itch Scale (LIS), which measures itching through evaluation of the dimensions of the itch experience; and to provide evidence of the validity, reliability, and responsiveness of the LIS. MATERIALS AND METHODS: A clinimetric study using a longitudinal design. Patients with burns (n=46), atopic dermatitis (n=63), or chronic urticaria (n=41) were included. Evidence for validity (based on test content, relations with other variables and internal structure), reliability and responsiveness of the LIS was evaluated. RESULTS: Validity evidence based on test content was demonstrated by very low percentages of invalid scores for most items. Validity evidence based on relations with other variables was found, because all hypotheses that were put forward could be accepted. With respect to validity evidence on internal structure, a significant moderate positive correlation was found between itch frequency and itch distress, and between itch frequency and severity. As hypothesized, itch severity and distress were strongly correlated. Test-retest reliability showed a moderate to almost perfect agreement for about half of the items. However, the remaining items could be subject to changes in the itch, rather than reflecting instability of the Leuven Itch Scale. In terms of responsiveness, the Leuven Itch Scale did not suffer from floor or ceiling effects and could detect changes in itch frequency in patients with burns. CONCLUSION: The Leuven Itch Scale is a useful and clinimetrically sound instrument to measure pruritus in different patient populations affected by itching. PMID- 21596478 TI - Early depth assessment of local burns by videomicroscopy: 24 h after injury is a critical time point. AB - PURPOSE: Videomicroscopy has simple and prompt operability, and useful in the burn depth assessment in its early phase. A burn wound is, however, a dynamic environment in the first few days and the critical time to assess a burn wound by videomicroscopy has not been investigated. The aim of this study is to investigate the critical time point to assess the burn depth by videomicroscopy. METHODS: Forty one patients with 44 intermediate depth burns admitted within 7 days after injury were included. Accuracies were assessed by comparison with clinical outcome: healing within 21 days after injury or not with conservative treatment. We prospectively evaluated and compared the accuracy of the videomicroscopy measurements with the clinical assessments. All findings were serialized in order of time after injury and divided into three groups, and we compared the appreciation of burn depth by videomicroscopy findings among groups. RESULTS: The videomicroscopy measurements is significantly accurate compared with clinical assessments (p=0.001). The accuracy of videomicroscopy measurements was significantly lower in the post-injury <24 h group compared with post-injury >=24 h group (p=0.004). CONCLUSION: Videomicroscopy is effective tool in assessment of early burn depth and the critical time point to assess the burn depth by videomicroscopy is 24 h after injury. PMID- 21596479 TI - A cost model case comparison of current versus modern management of burns at a regional hospital in South Africa. AB - INTRODUCTION: Institutional data shows a high burden of burn injury, which is managed by a conservative delayed approach. This is daily dressing until spontaneous eschar separation occurs followed by delayed skin grafting. Early excision and grafting is considered active management and is shown to be more cost effective in first world situations. We developed a costing model for both approaches to analyse financial costs in a developing country burns unit. METHODS: Utilising previous audit data of burn care at our institution, a costing model was developed. Individual cost drivers such as dressing, analgesia, theatre costs, and hospital stay were identified. Cost for each driver was multiplied by number of patients and or number of days in hospital. Total cost was a summation of these individual drivers. The costs derived from this model were compared to the cost of care of a single patient in which the burn wound was actively managed. RESULTS: The total cost of care for patients admitted with a burn injury was 29,549,750 ZAR. The estimated total cost of the single patient with a 20% body surface area deep dermal thickness burn treated conservatively at our institution was estimated at 154,000 ZAR, compared with a single patient with equivalent injury treated with an active approach costing 103,000 ZAR. The potential cost saving was ten million rand. CONCLUSION: This simple cost model suggests considerable savings could be made with active burn wound management implementation. Accurate costing of a larger cohort should define these savings more accurately. PMID- 21596480 TI - A modification of the Hynes procedure--a surgical innovation in the treatment of mature hypertrophic scars in children. AB - In 1957, Hynes first described the shaving and grafting procedure for the treatment of mature hypertrophic scars (HTSs). This procedure involved excision of mature HTS using a scalpel blade followed by split-skin grafting (SSG). We have modified this technique through the novel application of VersajetTM (Smith & Nephew, Hull, UK) for the sub-total excision of mature HTS with SSG. To date, this modified technique has shown excellent cosmetic results. A review of cases and an example of the technique is provided. PMID- 21596481 TI - BDNF Val66Met polymorphism is associated with higher anticipatory cortisol stress response, anxiety, and alcohol consumption in healthy adults. AB - BACKGROUND: The brain-derived neurotrophic factor (BDNF) is a key protein in maintaining neuronal integrity. The BDNF gene is thought to play an important role in the pathophysiology of mood and anxiety disorders. The aim of this study was to investigate, for the first time in a single study, the association between BDNF Val(66)Met polymorphism, anxiety, alcohol consumption, and cortisol stress response. METHOD: 98 healthy university students (54 females and 44 males), genotyped for the Val(66)Met polymorphism, participated in a physical-stress procedure (cold pressure test, CPT) after having been informed that they would undergo a painful experience. Indices of anxiety and of stress were collected from repeated measurement of salivary cortisol, blood pressure, and heart rate. RESULTS: BDNF Met carriers, were more anxious during the CPT (p<0.001), drank more alcohol per week, (p<0.05), and showed significantly higher anticipatory cortisol response (p<0.05), but not in response to the CPT, than Val/Val homozygotes. The association of BDNF Val(66)Met polymorphism with HPA axis reactivity to stress was not modulated by gender. These results suggest that Met carriers are particularly sensitive in anticipating stressful events, which extends previous findings on the moderating role of the BDNF Val(66)Met polymorphism in the face of stressful life events. PMID- 21596482 TI - Fetopathological investigations after induced abortions performed in mid-term gemini pregnancies. AB - Multiple pregnancies present a special obstetric condition whose importance has increased due to the spread of assisted reproductive techniques. We have processed the fetopathological data of 43 abortions induced in mid-term gemini pregnancies, owing to malformations affecting one or both fetuses. 67.4% of the gemini pregnancies were conceived naturally and 32.6% by assisted reproduction techniques. The most commonly occurring malformations affected the fetuses' cardiovascular and central nervous systems. Positive histories could be detected in 23% of the cases. The male-to-female ratio was found to be 1.14. In the majority of the cases with central nervous system malformation, fetus "A" was affected (85.7%). In 29.4% of the cases, monochorionic placentation was established. Ultrasonography and fetopatological findings yielded perfectly matching results in 78.9% of the cases. The incidence of fetal malformations is probably not higher among fetuses conceived by assisted reproduction techniques compared to the ones conceived naturally. Fetal central nervous system malformations usually affect fetus "A". Based on the results of the fetopathological examinations, ultrasonography is a reliable method in the diagnostics of malformations affecting twin fetuses. Fetal echocardiography is indicated simply because of the pregnancy being a multiple one. PMID- 21596483 TI - Predictors of IMRT and conformal radiotherapy use in head and neck squamous cell carcinoma: a SEER-Medicare analysis. AB - PURPOSE: The extent to which new techniques for the delivery of radiotherapy for head and neck squamous cell carcinoma (HNSCC) have diffused into clinical practice is unclear, including the use of 3-dimensional conformal RT (3D-RT) and intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we identified 2,495 Medicare patients with Stage I-IVB HNSCC diagnosed at age 65 years or older between 2000 and 2005 and treated with either definitive (80%) or adjuvant (20%) radiotherapy. Our primary aim was to analyze the trends and predictors of IMRT use over this time, and the secondary aim was a similar description of the trends and predictors of conformal radiotherapy (CRT) use, defined as treatment with either 3D-RT or IMRT. RESULTS: Three hundred sixty-four (15%) patients were treated with IMRT, and 1,190 patients (48%) were treated with 3D-RT. Claims for IMRT and CRT rose from 0% to 33% and 39% to 86%, respectively, between 2000 and 2005. On multivariable analysis, IMRT use was associated with SEER region (West 18%; Northeast 11%; South 12%; Midwest 13%), advanced stage (advanced, 21%; early, 9%), non-larynx site (non-larynx, 23%; larynx, 7%), higher median census tract income (highest vs. lowest quartile, 18% vs. 10%), treatment year (2003-2005, 31%; 2000-2002, 6%), use of chemotherapy (26% with; 9% without), and higher radiation oncologist treatment volume (highest vs. lowest tertile, 23% vs. 8%). With CRT as the outcome, only SEER region, treatment year, use of chemotherapy, and increasing radiation oncologist HNSCC volume were significant on multivariable analysis. CONCLUSIONS: The use of IMRT and CRT by Medicare beneficiaries with HNSCC rose significantly between 2000 and 2005 and was associated with both clinical and non-clinical factors, with treatment era and radiation oncologist HNSCC treatment volume serving as the strongest predictors of IMRT use. PMID- 21596484 TI - Evaluation of the role of radiation therapy in the management of malignant thymoma. AB - PURPOSE: The management of patients diagnosed with thymoma remains unclear. This report attempts to identify the impact of adjuvant radiotherapy on overall survival (OS) and cause-specific survival (CSS) in patients diagnosed with thymoma. METHODS AND MATERIALS: Patients diagnosed with thymic malignancy between 1973 and 2003 were retrospectively identified from centers participating in the Surveillance, Epidemiology, and End Results (SEER) program. Those patients classified as having thymic carcinoma were excluded from this analysis. OS and CSS were estimated by the Kaplan-Meier method. Outcomes for patients treated with and without radiation therapy were compared using the log-rank test. Multivariate analysis was performed with the Cox proportional hazards model to analyze factors predictive of OS and CSS. RESULTS: A total of 1,464 patients were identified as having thymic malignancy, and of these, 1,254 patients were identified as having malignant thymoma. The median follow-up time was 41 months (range, 4-337 months). Among patients who did not receive radiotherapy (RT), the 10-year rate of OS was 41% compared to 42% for those who did receive RT (p = 0.06). The median OS for the patients who did not receive RT was 80 months compared to 97 months for those who did receive RT. In patients with Masaoka stage II-III malignancy, OS was significantly improved with RT (p = 0.002), and a trend in improved CSS was observed (p = 0.1). Patients were also analyzed based on resection status. For those patients who had an incomplete excision, the 10-year OS was 63% with RT and 46% without RT (p = 0.38). On multivariate analysis, factors predictive of OS included age, extent of surgery, stage, and number of lymph nodes examined. CONCLUSIONS: This study reports treatment results of a large cohort of patients who were diagnosed with malignant thymoma. This study demonstrates that the use of RT following resection for thymoma significantly improves OS for those with regional disease and marginally improves CSS. PMID- 21596485 TI - Low or high fractionation dose beta-radiotherapy for pterygium? A randomized clinical trial. AB - PURPOSE: Postoperative adjuvant treatment using beta-radiotherapy (RT) is a proven technique for reducing the recurrence of pterygium. A randomized trial was conducted to determine whether a low fractionation dose of 2 Gy within 10 fractions would provide local control similar to that after a high fractionation dose of 5 Gy within 7 fractions for surgically resected pterygium. METHODS: A randomized trial was conducted in 200 patients (216 pterygia) between February 2006 and July 2007. Only patients with fresh pterygium resected using a bare sclera method and given RT within 3 days were included. Postoperative RT was delivered using a strontium-90 eye applicator. The pterygia were randomly treated using either 5 Gy within 7 fractions (Group 1) or 2 Gy within 10 fractions (Group 2). The local control rate was calculated from the date of surgery. RESULTS: Of the 216 pterygia included, 112 were allocated to Group 1 and 104 to Group 2. The 3-year local control rate for Groups 1 and 2 was 93.8% and 92.3%, respectively (p = .616). A statistically significant difference for cosmetic effect (p = .034), photophobia (p = .02), irritation (p = .001), and scleromalacia (p = .017) was noted in favor of Group 2. CONCLUSIONS: No better local control rate for postoperative pterygium was obtained using high-dose fractionation vs. low-dose fractionation. However, a low-dose fractionation schedule produced better cosmetic effects and resulted in fewer symptoms than high-dose fractionation. Moreover, pterygia can be safely treated in terms of local recurrence using RT schedules with a biologic effective dose of 24-52.5 Gy(10.). PMID- 21596486 TI - Prognostic significance of neuroendocrine differentiation in patients with Gleason score 8-10 prostate cancer treated with primary radiotherapy. AB - PURPOSE: To determine the prognostic significance of neuroendocrine differentiation (NED) in Gleason score 8-10 prostate cancer treated with primary radiotherapy (RT). METHODS AND MATERIALS: Chromogranin A (CgA) staining was performed and overseen by a single pathologist on core biopsies from 176 patients from the William Beaumont prostate cancer database. A total of 143 had evaluable biopsy material. Staining was quantified as 0%, <1%, 1-10%, or >10% of tumor cells. Patients received external beam RT alone or together with high-dose-rate brachytherapy. Cox regression and Kaplan-Meier estimates determined if the presence/frequency of neuroendocrine cells correlated with clinical endpoints. RESULTS: Median follow-up was 5.5 years. Forty patients (28%) had at least focal positive CgA staining (<1% n = 21, 1-10% n = 11, >10% n = 8). No significant differences existed between patients with or without staining in terms of age, pretreatment prostate-specific antigen, tumor stage, hormone therapy administration, % biopsy core involvement, mean Gleason score, or RT dose/modality. CgA staining concentration independently predicted for biochemical and clinical failure, distant metastases (DM), and cause-specific survival (CSS). For patients with <1% vs. >1% staining, 10-year DM rates were 13.4% vs. 55.3%, respectively (p = 0.001), and CSS was 91.7% vs. 58.9% (p < 0.001). As a continuous variable, increasing CgA staining concentration predicted for inferior rates of DM, CSS, biochemical control, and any clinical failure. No differences in outcomes were appreciated for patients with 0% vs. <1% NED. CONCLUSIONS: For Gleason score 8-10 prostate cancer, >1% NED is associated with inferior clinical outcomes for patients treated with radiotherapy. This relates most directly to an increase in distant disease failure. PMID- 21596487 TI - New breast cancer recursive partitioning analysis prognostic index in patients with newly diagnosed brain metastases. AB - PURPOSE: The aim of the study was to present a new breast cancer recursive partitioning analysis (RPA) prognostic index for patients with newly diagnosed brain metastases as a guide in clinical decision making. METHODS AND MATERIALS: A prospectively collected group of 441 consecutive patients with breast cancer and brain metastases treated between the years 2003 and 2009 was assessed. Prognostic factors significant for univariate analysis were included into RPA. RESULTS: Three prognostic classes of a new breast cancer RPA prognostic index were selected. The median survival of patients within prognostic Classes I, II, and III was 29, 9, and 2.4 months, respectively (p < 0.0001). Class I included patients with one or two brain metastases, without extracranial disease or with controlled extracranial disease, and with Karnofsky performance status (KPS) of 100. Class III included patients with multiple brain metastases with KPS of <=60. Class II included all other cases. CONCLUSIONS: The breast cancer RPA prognostic index is an easy and valuable tool for use in clinical practice. It can select patients who require aggressive treatment and those in whom whole-brain radiotherapy or symptomatic therapy is the most reasonable option. An individual approach is required for patients from prognostic Class II. PMID- 21596488 TI - Use of germline polymorphisms in predicting concurrent chemoradiotherapy response in esophageal cancer. AB - PURPOSE: To identify germline polymorphisms to predict concurrent chemoradiation therapy (CCRT) response in esophageal cancer patients. MATERIALS AND METHODS: A total of 139 esophageal cancer patients treated with CCRT (cisplatin-based chemotherapy combined with 40 Gy of irradiation) and subsequent esophagectomy were recruited at the National Taiwan University Hospital between 1997 and 2008. After excluding confounding factors (i.e., females and patients aged >=70 years), 116 patients were enrolled to identify single nucleotide polymorphisms (SNPs) associated with specific CCRT responses. Genotyping arrays and mass spectrometry were used sequentially to determine germline polymorphisms from blood samples. These polymorphisms remain stable throughout disease progression, unlike somatic mutations from tumor tissues. Two-stage design and additive genetic models were adopted in this study. RESULTS: From the 26 SNPs identified in the first stage, 2 SNPs were found to be significantly associated with CCRT response in the second stage. Single nucleotide polymorphism rs16863886, located between SGPP2 and FARSB on chromosome 2q36.1, was significantly associated with a 3.93-fold increase in pathologic complete response to CCRT (95% confidence interval 1.62-10.30) under additive models. Single nucleotide polymorphism rs4954256, located in ZRANB3 on chromosome 2q21.3, was associated with a 3.93-fold increase in pathologic complete response to CCRT (95% confidence interval 1.57-10.87). The predictive accuracy for CCRT response was 71.59% with these two SNPs combined. CONCLUSIONS: This is the first study to identify germline polymorphisms with a high accuracy for predicting CCRT response in the treatment of esophageal cancer. PMID- 21596489 TI - Tumor control outcomes after hypofractionated and single-dose stereotactic image guided intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma. AB - PURPOSE: To report tumor local progression-free outcomes after treatment with single-dose, image-guided, intensity-modulated radiotherapy and hypofractionated regimens for extracranial metastases from renal cell primary tumors. PATIENTS AND METHODS: Between 2004 and 2010, 105 lesions from renal cell carcinoma were treated with either single-dose, image-guided, intensity-modulated radiotherapy to a prescription dose of 18-24 Gy (median, 24) or hypofractionation (three or five fractions) with a prescription dose of 20-30 Gy. The median follow-up was 12 months (range, 1-48). RESULTS: The overall 3-year actuarial local progression free survival for all lesions was 44%. The 3-year local progression-free survival for those who received a high single-dose (24 Gy; n = 45), a low single-dose (<24 Gy; n = 14), or hypofractionation regimens (n = 46) was 88%, 21%, and 17%, respectively (high single dose vs. low single dose, p = .001; high single dose vs. hypofractionation, p < .001). Multivariate analysis revealed the following variables were significant predictors of improved local progression-free survival: 24 Gy dose compared with a lower dose (p = .009) and a single dose vs. hypofractionation (p = .008). CONCLUSION: High single-dose, image-guided, intensity-modulated radiotherapy is a noninvasive procedure resulting in high probability of local tumor control for metastatic renal cell cancer generally considered radioresistant according to the classic radiobiologic ranking. PMID- 21596490 TI - [Pregnancy in chronic hemodialysis patients]. AB - INTRODUCTION: Pregnancy in hemodialysis patients is a rare event, with a high risk of maternal and fetal morbidity. The aim of our study is to report our experience in management of pregnancies occurred in hemodialysis patients, and clarify the factors of good prognosis. PATIENTS AND METHODS: We identified all pregnancies occurred in patients on hemodialysis between January 2000 and July 2010, and analysed their clinical and biological characteristics. The adjustment parameters of hemodialysis sessions, and treatment adjustments have been specified. The maternal and fetal complications and pregnancy outcome have been reported. RESULTS: Over a period of 10 years and 6 months, among 23 patients of childbearing age, 14 patients were married. We observed 11 pregnancies in eight patients, with an incidence of 7,14% year, and a prevalence of 71,4%. The evolution was marked by intrauterine fetal death in one case, medical pregnancy termination in a second one and four spontaneous abortions. Only five pregnancies were completed. The average age of conception was 34 years. The average duration of dialysis prior to conception was 76 months. Pregnancy diagnosis was made on average after 10,4 weeks. The mean gestational age at delivery was 33,6 weeks, and the mean newborn weight was 2070g. Apgar score was of 10/10 in the first minute in all newborns. No maternal complication was found. One case of intrauterine growth restriction and another case of pyelo-caliceal dilatation with resolving renal insufficiency were reported. In the long term, the fetal psychomotor development was normal. DISCUSSION: The fertility chronic hemodialysis patients in childbearing age have improved together with the quality of dialysis, with an increased incidence of pregnancy and the proportion of viable children. However, treatment modalities are not clearly established, because of the absence of randomized studies and the small number of pregnancies during the playoffs. Treatment of anemia with erythropoietin and blood transfusions, and the improvement in blood urea by extensive dialysis in women on hemodialysis, may improve outcomes by reducing the incidence of prematurity and increasing gestational age. CONCLUSION: Pregnancy in hemodilalysis patient is a rare event, but desired and valuable. Its completion requires a multidisciplinary management involving the nephrologist to ensure adequate dialysis and the gynecologist to ensure good obstetrical monitoring. PMID- 21596493 TI - Effects of group exposure on single injection-induced behavioral sensitization to drugs of abuse in mice. AB - BACKGROUND: Behavioral sensitization in rodents is hypothesized to reflect neuronal adaptations that are related to drug addiction in humans. We evaluated the effects of group exposure on the acute hyperlocomotion and behavioral sensitization induced by four drugs of abuse in C57BL/6 mice: methylenedioxymethamphetamine (MDMA), d-amphetamine, morphine and ethanol. METHODS: In the priming session, animals received an ip injection of one of the drugs of abuse and were exposed to an open field either individually or in groups of four. Seven days later, we assessed behavioral sensitization in the challenge session. All animals received an ip injection of the same drug and were exposed to the open field in the same social conditions described for the priming session. Locomotion and social interaction were quantified during each session. RESULTS: Acute MDMA, morphine and ethanol, but not d-amphetamine, increased social interaction. However, group exposure only potentiated MDMA-induced hyperlocomotion. After a challenge injection of each drug, there was no sensitization to the facilitating effect of MDMA, morphine or ethanol on social interaction, but locomotion sensitization developed to all drugs of abuse except ethanol. This sensitization was potentiated by group exposure in MDMA-treated animals, attenuated in morphine-treated animals and not modified in d-amphetamine treated animals. Acute MDMA enhanced body contact and peaceful following, while acute morphine and ethanol increased social sniffing. CONCLUSIONS: These results provide preclinical evidence showing that while different drugs of abuse affect different components of social interaction, the neuronal adaptations related to drug dependence can be critically and specifically influenced by group exposure. PMID- 21596492 TI - Rifampin, but not rifabutin, may produce opiate withdrawal in buprenorphine maintained patients. AB - BACKGROUND: This series of studies examines the pharmacokinetic/pharmacodynamic interactions between buprenorphine, an opioid partial agonist increasingly used in treatment of opioid dependence, and rifampin, a medication used as a first line treatment for tuberculosis; or rifabutin, an alternative antituberculosis medication. METHODS: Opioid-dependent individuals on stable doses of buprenorphine/naloxone underwent two, 24-h blood sampling studies: (1) for buprenorphine pharmacokinetics and (2) following 15 days of rifampin 600 mg daily or rifabutin 300 mg daily for buprenorphine and rifampin or rifabutin pharmacokinetics. RESULTS: Rifampin administration produced significant reduction in plasma buprenorphine concentrations (70% reduction in mean area under the curve (AUC); p=<0.001) and onset of opiate withdrawal symptoms in 50% of participants (p=0.02). While rifabutin administration to buprenorphine-maintained subjects resulted in a significant decrease in buprenorphine plasma concentrations (35% decrease in AUC; p<0.001) no opiate withdrawal was seen. Compared with historical control data, buprenorphine had no significant effect on rifampin pharmacokinetics, but was associated with 22% lower rifabutin mean AUC (p=0.009), although rifabutin and its active metabolite concentrations remained in the therapeutic range. CONCLUSIONS: Rifampin is a more potent inducer of buprenorphine metabolism than rifabutin with pharmacokinetic and pharmacodynamic adverse consequences. Those patients requiring rifampin treatment for tuberculosis and receiving buprenorphine therapy are likely to require an increase in buprenorphine dose to prevent withdrawal symptoms. Rifabutin administration was associated with decreases in buprenorphine plasma concentrations, but no clinically significant adverse events were observed. PMID- 21596494 TI - 5th International Conference on Mycobacterium bovis. Preface. PMID- 21596491 TI - Shorter interpuff interval is associated with higher nicotine intake in smokers with schizophrenia. AB - BACKGROUND: People with schizophrenia are frequent and heavy smokers. METHODS: The objective of this study was to measure serum nicotine levels and ad libitum smoking behavior for 24+2h using the CReSS micro topography device in 75 smokers with schizophrenia (SCZ) and compare these to 86 control smokers (CON) without mental illness. Mean values of repeatedly measured topography variables were compared using three-level nested linear models to adjust for between subject differences and the double nested data. RESULTS: Smokers with SCZ smoked more cigarettes in the 24h period and took an average of 2.8 more puffs per cigarette than CON (p<0.001). The time between puffs, or interpuff interval (IPI), was shorter in SCZ by an average of 6.5s (p<0.001). The peak flow rate was higher in SCZ by an average of 4.9 ml/s (p<0.05). Smokers with SCZ spent an average of 1.0 min less time smoking a single cigarette vs. CON (p<0.001). Smokers with SCZ also had shorter IPI and more puffs per cigarette in an analysis of first cigarette of the day. For all subjects, a decrease in IPI by 1s was associated with an increase in serum nicotine of 0.19 ng/ml and in cotinine of 5.01 ng/ml (both p<0.05). After controlling for diagnosis group, higher craving scores on QSU Factor 2 (urgent desire to smoke) were associated with shorter IPI. DISCUSSION: Smokers with schizophrenia demonstrate more intense cigarette puffing that is associated with greater nicotine intake. This pattern may provide insight into other heavily dependent smokers. PMID- 21596495 TI - Reassortant H1N1 influenza virus vaccines protect pigs against pandemic H1N1 influenza virus and H1N2 swine influenza virus challenge. AB - Influenza A (H1N1) virus has caused human influenza outbreaks in a worldwide pandemic since April 2009. Pigs have been found to be susceptible to this influenza virus under experimental and natural conditions, raising concern about their potential role in the pandemic spread of the virus. In this study, we generated a high-growth reassortant virus (SC/PR8) that contains the hemagglutinin (HA) and neuraminidase (NA) genes from a novel H1N1 isolate, A/Sichuan/1/2009 (SC/09), and six internal genes from A/Puerto Rico/8/34 (PR8) virus, by genetic reassortment. The immunogenicity and protective efficacy of this reassortant virus were evaluated at different doses in a challenge model using a homologous SC/09 or heterologous A/Swine/Guangdong/1/06(H1N2) virus (GD/06). Two doses of SC/PR8 virus vaccine elicited high-titer serum hemagglutination inhibiting (HI) antibodies specific for the 2009 H1N1 virus and conferred complete protection against challenge with either SC/09 or GD/06 virus, with reduced lung lesions and viral shedding in vaccine-inoculated animals compared with non-vaccinated control animals. These results indicated for the first time that a high-growth SC/PR8 reassortant H1N1 virus exhibits properties that are desirable to be a promising vaccine candidate for use in swine in the event of a pandemic H1N1 influenza. PMID- 21596496 TI - The pathogenesis of ovine footrot. AB - Ovine footrot is a contagious and debilitating disease that is of major economic significance to the sheep meat and wool industries. The causative bacterium is the gram negative anaerobe Dichelobacter nodosus. Research that has used a classical molecular genetics approach has led to major advances in our understanding of the role of the key virulence factors of D. nodosus in the disease process. D. nodosus strains produce polar type IV fimbriae and extracellular serine proteases. Mutagenesis of the fimbrial subunit gene fimA and the pilT gene, which is required for fimbrial retraction, and subsequent testing of these mutants in sheep virulence trials has shown that type IV fimbriae mediated twitching motility is essential for virulence. The extracellular protease genes aprV2, aprV5 and bprV have also been mutated. Analysis of these mutants has shown that ArpV5 is the major extracellular protease and that AprV2 is the thermostable protease that is responsible for the extracellular elastase activity. Structural analysis of AprV2 has revealed that it contains several novel loops, one of which appears to act as an exosite that may modulate substrate accessibility. Finally, virulence experiments in sheep have shown that the AprV2 protease is required for virulence. PMID- 21596497 TI - Physical performance characteristics related to disability in older persons: a systematic review. AB - BACKGROUND: Progressive disability develops with older age in association with underlying disease, comorbidity and frailty. Physical performance characteristics are important to improve the physical condition of older persons and therefore may be able to prevent or delay the onset of (progressive) disability. However lack of understanding of the physiology and etiology of functional decline leading to disability causes a problem in the development of effective preventive interventions. The aim of the present review is to determine which physical performance characteristics are determinants of disability in the older general population. METHODS: We searched systematically the electronic databases of PubMed (MEDLINE), CINAHL, Cochrane Library, Psychlit and Embase for cohort studies and randomized controlled trials assessing disability in the older general population. Outcomes of interest were handgrip strength, upper and lower extremity function, balance gait and physical activity. The searching strategy resulted in 22 studies included in the present systematic review. RESULTS: Although heterogeneity was present in the measurements of disability, consistent findings were shown for physical performance characteristics and disability. In general, a lower score of the physical performance characteristics was associated with a higher probability of (the development of) disability. The association for other aspects of gait (e.g. gait-step continuity, gait-step symmetry, path deviation and turning) and disability seems to be present, though the number of studies is limited. CONCLUSION: In the present systematic review, associations were found for hand grip strength, upper and lower body strength, gait speed, physical activity and the probability of disability. PMID- 21596498 TI - Ovarian cysts on prenatal MRI. AB - OBJECTIVE: Ovarian cysts are the most frequently encountered intra-abdominal masses in females in utero. They may, at times, require perinatal intervention. Using magnetic resonance imaging (MRI) as an adjunct to ultrasonography (US) in prenatal diagnosis, we sought to demonstrate the ability to visualize ovarian cysts on prenatal MRI. MATERIALS AND METHODS: This retrospective study included 17 fetal MRI scans from 16 female fetuses (23-37 gestational weeks) with an MRI diagnosis of ovarian cysts after suspicious US findings. A multiplanar MRI protocol was applied to image and to characterize the cysts. The US and MRI findings were compared, and the prenatal findings were compared with postnatal imaging findings or histopathology. RESULTS: Simple ovarian cysts were found in 10/16 cases and complex cysts in 7/16 cases, including one case with both. In 11/16 (69%) cases, US and MRI diagnoses were in agreement, and, in 5/16 (31%) cases, MRI specified or expanded the US diagnosis. In 6/16 cases, postnatal US showed that the cysts spontaneously resolved or decreased in size, and in 1/16 cases, postnatal imaging confirmed a hemorrhagic cyst. In 4/16 cases, the prenatal diagnoses were confirmed by surgery/histopathology, and for the rest, postnatal correlation was not available. CONCLUSION: Our results illustrate the MRI visualization of ovarian cysts in utero. In most cases, MRI will confirm the US diagnosis. In certain cases, MRI may provide further diagnostic information, additional to US, which is the standard technique for diagnosis, monitoring, and treatment planning. PMID- 21596499 TI - Imaging of the nerves of the knee region. AB - Peripheral neuropathies are a frequent, but often underdiagnosed, cause of pain and functional impairment. The clinical symptoms can be subtle, and other neurologic or non neurologic clinical entities are often evoked. MRI and ultrasonography are the imaging modalities of choice for depicting nerves and assessing neuropathies. Common neuropathies in the knee area involve the saphenous, the tibial, the common peroneal and the sural nerves. The most frequent mechanisms of nerve injury in this area are nerve entrapment and nerve stretching. A perfect knowledge of the normal imaging anatomy is essential for accurate assessment of neuropathies. In this article, we will review the anatomy of the nerves around the knee, and their normal and pathological appearance. PMID- 21596500 TI - Fecal-tagging CT colonography with structure-analysis electronic cleansing for detection of colorectal flat lesions. AB - PURPOSE: To evaluate the feasibility and sensitivity of the 3D-reading of fecal tagging CT colonography (CTC) with a novel structure-analysis electronic cleansing (SAEC) in detecting colorectal flat lesions in comparison with a cleansed 3D reading with Viatronix V3D Colon system (V3D) and primary uncleansed 2D reading (2D). MATERIALS AND METHODS: Forty CTC cases with flat lesions were retrospectively observed. The Subjects from a multicenter clinical trial underwent cathartic bowel preparation with orally administrated barium-based fecal-tagging. Sixty-nine flat lesions were confirmed using colonoscopy and histopathology as a reference standard. The results from SAEC reading were compared with those of prospective V3D and 2D readings. RESULTS: Overall detection sensitivity with SAEC was 52% (36/69), which was statistically higher than that of 32% (22/69) and 29% (20/69) with V3D and 2D readings, respectively (p<0.05). The sensitivities in detecting not-on-fold flat lesions were 63% (24/38), 45% (17/38), and 42% (16/38) with SAEC, V3D, and 2D readings, respectively; whereas those of on-fold flat lesions were 39% (12/31), 16% (5/31), and 13% (4/31), respectively. None of the eight flat lesions (2-9mm) at cecum was detected by any of the three reading methods. Excluding the flat lesions at cecum, the sensitivity with SAEC for detecting flat lesion >=4mm increased to 84% (31/37). CONCLUSIONS: The fecal-tagging CTC with structure-analysis electronic cleansing could yield a high sensitivity for detecting flat lesions >=4mm. The not-on-fold flat lesions were detected with higher sensitivity than on-fold flat lesions. PMID- 21596501 TI - No correlation between glucose metabolism and apparent diffusion coefficient in diffuse large B-cell lymphoma: a PET/CT and DW-MRI study. AB - PURPOSE: Both positron emission tomography/computed tomography (PET/CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) are oncologic feasible techniques for evaluating the malignancy of tumors. Standardized uptake value (SUV) is a marker of tumor glucose metabolism detected by PET/CT. Apparent diffusion coefficient (ADC) measured by DWI can provide information about tissue cellularity. The aim of the study was to evaluate the correlation between SUV and ADC in untreated diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: Fifteen pre-therapy patients with histologically proven DLBCL underwent PET/CT and DWI examinations within two days. Tumor glucose metabolism was evaluated by the maximum and mean SUV (SUV(max) and SUV(mean)) on the PET/CT images. The mean ADC value was measured directly on the parametric ADC maps. RESULTS: In total, 28 lymphoma lesions with best match PET/CT and DWI were identified and evaluated. The mean SUV(max) and SUV(mean) were 16.8 and 11.1, respectively; the mean ADC was 0.74 * 10(-3)mm(2)/s. There was no correlation between the mean ADC and the SUV(max) or SUV(mean). CONCLUSION: SUV determined from PET/CT and ADC value measured from DWI are different indices for the diagnosis of tumor malignancy, they may provide complimentary functional information of tumor tissue. PMID- 21596502 TI - Effectiveness of percutaneous metal stent placement in cholangiocarcinoma patients with midterm follow-up: Single center experience. AB - PURPOSE: Patients with advanced cholangiocarcinoma present with high rate of local complications. The primary aim of this study is to report clinical course of advanced cholangiocarcinoma patients those who were presented with biliary obstruction and treated with percutaneous biliary stenting. MATERIAL AND METHODS: Patients with unresectable locally advanced or metastatic cholangiocarcinoma followed by our center for a period of 4 years were analyzed. For statistical analysis demographic and clinical characteristics of patients, primary biliary drainage method, metal stent occlusion rate, time to stent occlusion, and overall survival rates were recorded. RESULTS: A total of 34 eligible patients were analyzed. 27 patients had metal stent placement. These 27 patients formed the basis of this study. Median overall survival (OS) was 6.0 months. After metal stent deployment bilurubin levels were normalized within a mean of 10 days. During the follow-up period, 13 patients were experienced metal stent occlusion. Median TtSO was 10 weeks. Cytotoxic chemotherapy was administered to 14 (52%) patients. Patients without stent dysfunction had significantly higher rate of chemotherapy exposure rate (p=0.021). Statistical analysis, however, failed to exhibit significant effect of stent dysfunction on OS. CONCLUSION: In advanced cholangiocarcinoma, relief of bile duct obstruction is an important part of the initial patient management. This study therefore described the clinical value of percutaneous metal stent in cholangiocarcinoma patients and raises the question about patency of metal stent in cholangiocarcinoma whether we can expect success similar to the success achieved in pancreas carcinoma. PMID- 21596503 TI - Anatomical study of spinal accessory nerve using ultrasonography. AB - OBJECTIVE: The purpose of our study was to demonstrate that ultrasonography may allow a precise assessment of the course and relationships of the spinal accessory nerve (SAN). MATERIAL AND METHODS: This study, initially undertaken in 7 cadavers, was followed by high-resolution ultrasonographic study in 15 volunteers (30 nerves) by two radiologists in consensus. The location, course and relations to the adjacent anatomic structures of the SAN were analyzed. RESULTS: The precise course of the SAN between the lateroposterior border of the sternocleidomastoid muscle and the anterior border of the trapezius muscle could be identified by high-resolution ultrasonography. In contrast, clinical bone landmarks were not found helpful for the identification of the nerve. CONCLUSION: The SAN can be clearly depicted by means of ultrasonography. Knowledge of the nerve's precise location, which may evidence individual variations, may have useful clinical applications. PMID- 21596504 TI - Dose-length product of scanners correlates with DNA damage in patients undergoing contrast CT. AB - OBJECTIVES: Computed tomography (CT) exams contribute for a large part to the population's radiation burden. This study addresses the question if dose settings of scanners expressed by dose-length product (DLP) are correlated with directly measurable biological effects in patients. METHODS: DLP, blood dose, effective dose and DNA damage were analyzed for patients undergoing a thoracic or abdominal contrast CT scan on two CT scanners with different dose settings. The DNA damage was assessed by scoring gamma-H2AX foci representing DNA double-strand breaks (DSBs) in patient's lymphocytes. Blood dose was calculated using the ImPACT software. RESULTS: The CT system operating at higher dose settings represented by higher DLP values, resulted in a significantly higher number of radiation-induced gamma-H2AX foci in patient's lymphocytes (DLP: 2.1 times higher; gamma-H2AX foci: 2.3 times higher; p<0.05). Plotting gamma-H2AX foci versus blood dose showed a systematic increase of DNA damage with dose. In vitro experiments ruled out a possible X-ray enhancement of DNA damage effect by contrast agent. CONCLUSIONS: Present study demonstrates that optimization of DLP setting of scanners results in a reduction of X-ray effects in patients. PMID- 21596505 TI - Detection, selective isolation and characterisation of Dactylosporangium strains from diverse environmental samples. AB - A culture-independent, nested PCR procedure based on genus-specific oligonucleotide primers detected the presence of members of the genus Dactylosporangium in 14 out of 21 diverse environmental samples. Clones generated from the 14 positive environmental samples formed distinct phyletic lines in the dactylosporangial 16S rRNA gene tree. Presumptive dactylosporangiae were isolated from 7 of these samples using a medium designed to be selective for members of the genus Dactylosporangium, namely Streptomyces Isolation Medium supplemented with gentamicin and antifungal antibiotics. One hundred and two out of 219 representative presumptive dactylosporangiae were considered as authentic members of the genus Dactylosporangium as they gave PCR amplification products using the genus-specific primers and had chemical features typical of dactylosporangiae. Representative of the Dactylosporangium isolates formed distinctive phyletic lines in the dactylosporangial 16S rRNA gene tree, contained the non-ribosomal peptide and type-I polyketide synthase genes and inhibited the growth of Bacillus subtilis, Kocuria rhizophila and Staphylococcus aureus strains. It is evident from these results that the genus Dactylosporangium is underspeciated, widely distributed in natural habitats and is a potentially rich source of novel secondary metabolites. PMID- 21596506 TI - Phylogenetic characterisation of picoplanktonic populations with high and low nucleic acid content in the North Atlantic Ocean. AB - In flow cytometric analyses of marine prokaryotic picoplankton often two populations with distinct differences in their apparent nucleic acid content are discernable, one with a high and one with a low nucleic acid content (HNA and LNA, respectively). In this study we determined the phylogenetic composition of flow cytometrically sorted HNA and LNA populations, collected at six stations along a transect across three oceanic provinces from Iceland to the Azores. Catalysed reporter deposition fluorescence in situ hybridisation (CARD-FISH) analysis of sorted cells revealed distinct differences in phylogenetic composition between the LNA and HNA populations with only little overlap. At all stations the LNA population was dominated by the alphaproteobacterial clade SAR11 (45-74%). Also, Betaproteobacteria were always present at 2-4%. While the LNA composition was rather stable, the HNA populations were composed of distinct phylogenetic clades in the different oceanic provinces of Arctic and Tropics. For example Cyanobacteria dominated the North Atlantic Gyre HNA population (29-44%) with Prochlorococcus as the major clade (34-44%), but were low in Arctic and Polar waters (1% and 5%, respectively). In contrast, Bacteroidetes accounted for the majority of HNA cells in the Polar and Arctic province (26% and 32%, respectively), but were low in the Gyre region (3-10%). The DNA content of the HNA population was about 3.5 times higher than that of the LNA populations. This reflects differences in the genome sizes of closely related cultured representatives of HNA clades (3-6Mbp) and LNA clades (1.3-1.5Mbp). PMID- 21596508 TI - Nocardia rhamnosiphila sp. nov., isolated from soil. AB - In this study two actinomycete strains were isolated in Cape Town (South Africa), one from a compost heap (strain 202GMO(T)) and the other from within the fynbos rich area surrounded by the horseracing track at Kenilworth Racecourse (strain C2). Based on 16S rRNA gene sequence BLAST analysis, the strains were identified as members of the genus Nocardia. Phylogenetic analysis showed that the strains clustered together and are most closely related to Nocardia flavorosea NRRL B 16176(T), Nocardia testacea JCM 12235(T), Nocardia sienata IFM 10088(T) and Nocardia carnea DSM 43397(T). This association was also supported by gyrB based phylogenetic analysis. The results of DNA-DNA hybridization and physiological tests allowed genotypic and phenotypic differentiation of both strains 202GMO(T) and C2 from related species. However, their high DNA relatedness showed that they belong to the same species. Strain 202GMO(T) was selected as the type strain to represent this novel species, for which the name Nocardia rhamnosiphila is proposed (=DSM 45147(T)=NRRL B-24637(T)). PMID- 21596507 TI - Salimicrobium salexigens sp. nov., a moderately halophilic bacterium from salted hides. AB - Two Gram-positive, moderately halophilic bacteria, designated strains 29CMI(T) and 53CMI, were isolated from salted hides. Both strains were non-motile, strictly aerobic cocci, growing in the presence of 3-25% (w/v) NaCl (optimal growth at 7.5-12.5% [w/v] NaCl), between pH 5.0 and 10.0 (optimal growth at pH 7.5) and at temperatures between 15 and 40 degrees C (optimal growth at 37 degrees C). Phylogenetic analysis based on 16S rRNA gene sequence comparison showed that both strains showed a similarity of 98.7% and were closely related to species of the genus Salimicrobium, within the phylum Firmicutes. Strains 29CMI(T) and 53CMI exhibited 16S rRNA gene sequence similarity values of 97.9 97.6% with Salimicrobium album DSM 20748(T), Salimicrobium halophilum DSM 4771(T), Salimicrobium flavidum ISL-25(T) and Salimicrobium luteum BY-5(T). The DNA G+C content was 50.7mol% and 51.5mol% for strains 29CMI(T) and 53CMI, respectively. The DNA-DNA hybridization between both strains was 98%, whereas the values between strain 29CMI(T) and the species S. album CCM 3517(T), S. luteum BY 5(T), S. flavidum ISL-25(T) and S. halophilum CCM 4074(T) were 45%, 28%, 15% and 10%, respectively, showing unequivocally that strains 29CMI(T) and 53CMI constitute a new genospecies. The major cellular fatty acids were anteiso C(15:0), anteiso-C(17:0), iso-C(15:0) and iso-C(14:0). The main respiratory isoprenoid quinone was MK-7, although small amounts of MK-6 were also found. The polar lipids of the type strain consist of diphosphatidylglycerol, phosphatidylglycerol, one unidentified phospholipid and one glycolipid. The peptidoglycan type is A1gamma, with meso-diaminopimelic acid as the diagnostic diamino acid. On the basis of the phylogenetic analysis, and phenotypic, genotypic and chemotaxonomic characteristics, we propose strains 29CMI(T) and 53CMI as a novel species of the genus Salimicrobium, with the name Salimicrobium salexigens sp. nov. The type strain is 29CMI(T) (=CECT 7568(T)=JCM 16414(T)=LMG 25386(T)). PMID- 21596510 TI - Cultivation of the first mesophilic representative ("mesotoga") within the order Thermotogales. AB - Cultivated members of the order Thermotogales comprise only thermophilic to hyperthermophilic anaerobic microorganisms. However, based on molecular studies, the existence of mesophilic members ("mesotoga") within this order has been postulated but has not been demonstrated by cultural approaches so far. A "mesotoga" (strain PhosAc3) that belonged to an uncultivated lineage distantly related to the thermophilic Kosmotoga genus has now been cultivated in axenic culture. It grew between 30 degrees C and 50 degrees C (optimum 40 degrees C) and oxidized lactate using elemental sulphur as a terminal electron acceptor. Further genomic and physiological characterization of strain PhosAc3 will be important not only for understanding bacterial adaptation to high and moderate temperatures at small evolutionary scales, but also because "mesotoga" might play a crucial ecological role in ecosystems polluted by aromatic compounds. PMID- 21596509 TI - Vibrio plantisponsor sp. nov., a diazotrophic bacterium isolated from a mangrove associated wild rice (Porteresia coarctata Tateoka). AB - Two Gram negative, facultatively anaerobic, halophilic, motile, slightly curved rod-shaped bacterial strains MSSRF60(T) and MSSRF64 were isolated from the roots of a mangrove-associated wild rice collected in the Pichavaram mangroves, India. These strains possess the key functional nitrogenase gene nifH. Phylogenetic analysis based on the 16S rRNA, recA, gapA, mreB, gyrB and pyrH, gene sequences revealed that strains MSSRF60(T) and MSSRF64 belong to the genus Vibrio, and had the highest sequence similarity with the type strains of Vibrio diazotrophicus LMG 7893(T) (99.7, 94.8, 98.5, 97.9, 94.0 and 90.7%, respectively), Vibrio areninigrae J74(T) (98.2, 87.5, 91.5, 88.9, 86.5 and 84.6% respectively) and Vibrio hispanicus LMG 13240(T) (97.8, 87.1, 91.7, 89.8, 84.1 and 81.9%, respectively). The fatty acid composition too confirmed the affiliation of strains MSSRF60(T) and MSSRF64 to the genus Vibrio. These strains can be differentiated from the most closely related Vibrio species by several phenotypic traits. The DNA G+C content of strain MSSRF60(T) was 41.8mol%. Based on phenotypic, chemotaxonomic, genotypic (multilocus sequence analysis using five genes and genomic fingerprinting using BOX-PCR) and DNA-DNA hybridization analyses, strains MSSRF60(T) and MSSRF64 represent a novel species of the genus Vibrio, for which the name Vibrio plantipsonsor sp. nov. is proposed. The type strain is MSSRF60(T) (=DSM 21026(T)=LMG 24470(T)=CAIM 1392(T)). PMID- 21596511 TI - Development and validation of an ultra performance liquid chromatography-tandem mass spectrometry method for the quantification of daptomycin in human plasma. AB - A rapid, simple and accurate analytical method based on ultra performance liquid chromatography (UPLC) combined with electrospray ionization (ESI) tandem mass spectrometry (MS/MS) on a hybrid q TOF instrument has been developed and fully validated for the quantification of daptomycin (DPT) in human plasma. The samples were analyzed after simple pretreatment involving protein precipitation, while chromatographic separation of DPT and the internal standard (reserpine) was achieved on an Acquity BEH C18 column (100 mm * 2.1 mm, 1.7 MUm) using gradient elution with 0.1% aqueous formic acid (FA) and acetonitrile with 0.1% FA (with DPT eluting at 2.60 min). The method presented good fit (r>0.999) over the quantification range of 0.01-10 MUg mL-1 with the lower limit of quantitation (LLOQ) being 0.01 MUg mL-1 of human plasma for DPT. The intra- and inter-day precision, measured as % relative standard deviation, was less than 11% for DPT. The validation results showed that the developed method demonstrated adequate selectivity, sensitivity, precision and accuracy and therefore was successfully applied to the analysis of clinical samples following intravenous (iv) administration of 5.4 mg kg-1 DPT to patients suffering from post-traumatic osteomyelitis induced by methicillin-resistant Staphylococcus aureus (MRSA). The developed methodology is the first report of an accurate mass tandem MS method for the analysis of this potent antibiotic in human plasma and can be used to further study pharmacokinetic, bioequivalence and even metabolic aspects related to this drug. PMID- 21596512 TI - HPLC-FLD methods to quantify chloroaluminum phthalocyanine in nanoparticles, plasma and tissue: application in pharmacokinetic and biodistribution studies. AB - Analytical and bioanalytical methods of high-performance liquid chromatography with fluorescence detection (HPLC-FLD) were developed and validated for the determination of chloroaluminum phthalocyanine in different formulations of polymeric nanocapsules, plasma and livers of mice. Plasma and homogenized liver samples were extracted with ethyl acetate, and zinc phthalocyanine was used as internal standard. The results indicated that the methods were linear and selective for all matrices studied. Analysis of accuracy and precision showed adequate values, with variations lower than 10% in biological samples and lower than 2% in analytical samples. The recoveries were as high as 96% and 99% in the plasma and livers, respectively. The quantification limit of the analytical method was 1.12 ng/ml, and the limits of quantification of the bioanalytical method were 15 ng/ml and 75 ng/g for plasma and liver samples, respectively. The bioanalytical method developed was sensitive in the ranges of 15-100 ng/ml in plasma and 75-500 ng/g in liver samples and was applied to studies of biodistribution and pharmacokinetics of AlClPc. PMID- 21596513 TI - Information about medicines to cardiac in-patients: patient satisfaction alongside the role perceptions and practices of doctors, nurses and pharmacists. AB - OBJECTIVE: To explore the satisfaction of cardiac in-patients regarding the information they received about their medicines, and the role perceptions and practices of practitioners whose responsibility it was to provide such information. METHOD: A questionnaire was constructed by selecting medicine information topics from a validated instrument, the Satisfaction with Information about Medicines Scale. Patients and practitioners were recruited from cardiac wards at a London teaching hospital providing tertiary care. RESULTS: Questionnaires were returned by 140 patients and 52 doctors, 53 nurses and 4 pharmacists. Patients were satisfied with information about the action and usage of medicines but were significantly less satisfied with information about potential problems with their medicines. In parallel, practitioners provided more information about the action and usage of medicines than its potential problems. CONCLUSIONS: Information gaps existed largely around potential problems with medicines which reflected the general lack of focus on these issues by the healthcare professionals studied. There was no consensus between doctors, nurses and pharmacists on perceptions of role responsibility of information provision. PRACTICE IMPLICATIONS: Patients may become non-adherent to their medicines if insufficient information is provided. Role responsibilities should be co ordinated when information about medicines is provided by a range of practitioners. PMID- 21596514 TI - Prognostic significance of molecular subtype in T1N0M0 breast cancer: Korean experience. AB - PURPOSE: Gene expression profiling studies have identified several breast cancer subtypes associated with markedly different clinical outcomes. In general, patients with stage I breast cancer have excellent outcomes. We assessed the clinicopathological characteristics and outcomes of patients with T1N0M0 breast cancer according to molecular subtype. METHODS: Seven hundred and sixty-two T1N0M0 breast cancer patients undergoing curative surgery between January 1990 and December 2007 were analyzed. Subtypes were classified according to hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status as follows: HR+/HER2-, HR+/HER2+, HR-/HER2- (triple-negative, TN), and HR-/HER2+. RESULTS: The distribution of subtypes was HR+/HER2-, 56.6%; HR+/HER2+, 10.1%; TN, 20.1%; and HR-/HER2+, 13.3%. Marked differences were observed among subtypes in multifocality/multicentricity, histological grade, extensive intraductal components, p53 expression and the Ki-67 index. There were differences in recurrence-free survival and overall survival among patients with different molecular subtypes (log-rank p < 0.001 and 0.024, respectively). By multivariate analysis, lymphovascular invasion and classification of molecular subtype were independent predictors of recurrence (p = 0.003 and 0.043, respectively). The TN subtype showed significantly worse recurrence-free survival compared to the HR+/HER2- subtype (hazard ratio, 4.54; 95% confidence interval, 1.60-12.86; p = 0.004). CONCLUSION: Patients with T1N0M0 breast cancer, a group with generally favorable clinical outcomes, had prognoses that were associated with the molecular subtype. The TN subtype was an independent predictor for recurrence in patients with T1N0M0 breast cancer. PMID- 21596515 TI - To explore the conditions of dying infants in NICU in Taiwan. AB - PURPOSES: Research purposes were to document the symptoms characteristic of neonates during their last week of life and to describe the activities undertaken in nursing care of dying neonates in neonatal intensive care unit (NICU). METHODS: A retrospective chart review was used in this research. All charts of neonatal inpatients who died in the NICU between 2002 and 2008 and who met entry criteria were included the research review. RESULTS: Sixty-one charts were evaluated in this research. The major underlying disease was the complications of prematurity (33%). Major physiological distress signs in the last week of life included respiratory distress (67.2%), cyanosis (54.1%), bradycardia (36.1%), oliguria (31.1%), and generalized edema (37.7%). All infants were intubated and received artificial ventilation in the last week of life. Physicians prescribed an analgesic medicine for 7 infants, and 7 infants received comfort interventions to manage their distress signs. Forty-one infants had preexisting do-not resuscitate order at the time of death. CONCLUSIONS: Research findings suggest that the application of palliative care paradigm and more aggressive comfort care to manage signs in NICU might be beneficial to dying infants. PMID- 21596516 TI - Ventilator-associated pneumonia is an important risk factor for mortality after major cardiac surgery. AB - PURPOSE: Ventilator-associated pneumonia (VAP) is the main infectious complication in cardiac surgery patients and is associated with an important increase in morbidity and mortality. The aim of our study was to analyze the impact of VAP on mortality excluding other comorbidities and to study its etiology and the risk factors for its development. MATERIALS AND METHODS: This prospective cohort study included 1610 postoperative cardiac surgery patients' status post cardiopulmonary bypass (CPB) between July 2004 and January 2008. The primary outcome measures were the development of VAP and in-hospital mortality. RESULTS: Ventilator-associated pneumonia was observed in 124 patients (7.7%). Patients with VAP had a longer length of hospitalization (40.7 +/- 35.1 vs 16.1 +/- 30.1 days, P < .0001) and greater in-hospital mortality (49.2% [61/124] vs 2.0% [30/1486], P = .0001) in comparison with patients without VAP. After performing the Cox multivariant analysis adjustment, VAP was identified as the most important independent mortality risk factor (adjusted hazard ratio [HR], 8.53; 95% confidence interval, 4.21-17.30; P = .0001). Other independent risk factors of in-hospital mortality were chronic renal failure (HR, 2.56), diabetes mellitus (HR, 1.90), CPB time (HR, 1.51), respiratory failure (HR, 2.13), acute renal failure (HR, 2.39), and mediastinal bleeding of at least 1000 mL (HR, 1.81). CONCLUSIONS: The development of VAP after CPB is the most important independent risk factor for in-hospital mortality. Identification of effective strategies for the prevention of VAP is needed. PMID- 21596517 TI - Association between out-of-hospital emergency department transfer and poor hospital outcome in critically ill stroke patients. AB - INTRODUCTION: Transfer of critically ill patients from outside emergency department has the potential for delaying the admission to the intensive care unit. We sought to determine the effect of outside emergency department transfer on hospital outcomes in critically ill patients with stroke. METHODS: We designed a retrospective cohort analysis using a prospectively compiled and maintained registry (Cerner Project IMPACT). Patients with acute ischemic stroke and intracerebral hemorrhage admitted to our intensive care unit from our emergency department and transfers from outside emergency department within 24 hours of stroke between January 1, 2003, and December 31, 2008, were selected for the analysis. Data collected included demographics, admission physiologic variables, Glasgow Coma Scale, Acute Physiology and Chronic Health Evaluation II score, and total intensive care unit and hospital length of stay. Primary (poor) outcome was a composite of death or fully dependent status at hospital discharge, and secondary outcomes were intensive care unit and hospital length of stay. To assess for the impact of outside emergency department transfer on primary and secondary outcomes, demographic and admission clinical variables were used to construct logistic regression models using the outcome measure as a dependent variable. RESULTS: A total of 448 patients were selected for analysis. The mean age was 65 +/- 14 years, of which 214 (48%) were male and 282 (65%) white, 152 (34%) were patients with acute ischemic stroke, and 296 (66%) were patients with intracerebral hemorrhage. The median hospital length of stay was 7 days (interquartile range, 4-11 days) and median intensive care unit length of stay was 2 days (interquartile range, 1-3 days). Overall hospital mortality was 30%, and outside emergency department transfer increased the odds of poor outcome by 2 fold (65% vs 34%; P = .05). Multivariate regression analysis showed that age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.01-1.1), Acute Physiology and Chronic Health Evaluation II score >14 (OR, 1.9; 95% CI, 1.3-2.7), Glasgow Coma Scale <12 (OR, 2.0; 95% CI, 1.4-2.8), do-not-resuscitate status (OR, 3.5; 95% CI, 2.2-5.9), and outside emergency department transfers (OR, 1.4; 95% CI, 1.02-1.8) were independently associated with poor outcome. Outside emergency department transfer was not significantly associated with secondary outcomes. CONCLUSION: These data suggest that in critically ill patients with stroke, transfer from outside emergency department is independently associated with poor outcome at hospital discharge. Further research is needed as to identify the potential causes for this effect. PMID- 21596518 TI - Clinical implications of risk aversion: an online study of risk-avoidance and treatment utilization in pathological anxiety. AB - Previous research suggests that the pervasive tendency to avoid perceived risks (i.e., the safety bias) may be implicated in the maintenance of pathological anxiety. These studies have not explored, however, the potential clinical implications of such a bias, such as the influence of risk aversion on treatment seeking. The aim of this study was to investigate how risk-avoidance is related to willingness to seek treatment in an online sample of clinically anxious individuals with social phobia (SP), obsessive-compulsive disorder (OCD) and generalized anxiety disorder (GAD). Healthy control participants (n=117) and those endorsing criteria for one or more anxiety disorder(s) (n=92; SP, n=33; OCD, n=19; GAD, n=40) were recruited from various online sources. Respondents completed an online survey comprised of a validated diagnostic interview, self report measures assessing for symptom severity, risk-taking across various domains, a generalized index of risk-taking and treatment utilization. Consistent with hypotheses, SP and GAD individuals reported significantly more risk avoidance when compared to non-clinical controls. Furthermore, willingness to seek treatment was found to be positively associated with social risk-taking and generalized risk-taking orientation in clinically anxious individuals who had never sought treatment. These results suggest that certain individual cognitive factors may contribute to the decision to seek treatment and may provide an interesting avenue of future investigation for increasing service utilization and treatment seeking in anxious populations. PMID- 21596519 TI - Reliability and validity of DSM-IV generalized anxiety disorder features. AB - The reliability of generalized anxiety disorder (GAD) features has been shown to be moderate, based on research utilizing the Anxiety Disorders Interview Schedule for DSM-IV (ADIS-IV), a semi-structured diagnostic interview. This may be a function of the criteria for the diagnosis of GAD, which have undergone much revision since its first inclusion in the Diagnostic and Statistical Manual of Mental Disorders. The reliability and validity of disorder feature ratings were examined in a diverse sample of patients who presented for assessment and treatment of excessive worry, generalized anxiety, or tension at an anxiety specialty clinic and who met criteria for a principal diagnosis of GAD (N=129). Internal consistency of the ratings of excessiveness of worry, uncontrollability of worry, and the associated symptom cluster was moderate to low and varied by disorder feature. Inter-rater reliability for all features of GAD and severity of the disorder varied between good and poor. Additional findings showed that the GAD features, as measured using the ADIS-IV module, have modest to strong convergent validity, varying by feature, and poor discriminant validity when tested against measures of social anxiety. Potential reasons for rater disagreement are discussed. Results are also considered in terms of how they may inform the evolving criteria for GAD in DSM-V. PMID- 21596521 TI - Laryngeal muscle activity and vocal fold adduction during chest, chestmix, headmix, and head registers in females. AB - HYPOTHESIS: Commercial singers produce chestmix register by maintaining or increasing adduction of the vocal processes (VPs) and by engaging the thyroarytenoid (TA) muscle to a greater degree than they would to produce head register. STUDY DESIGN: Prospective cohort study. METHODS: Simultaneous recordings of TA and cricothyroid (CT) muscle activity, videonasendoscopy, and audio were obtained from seven female singers during production of a variety of midrange pitches in chest, chestmix, headmix, and head registers. Fast Fourier transforms were performed to measure the energy in the fundamental frequency and in mid and upper frequency harmonics to determine if the productions that were judged as perceptually distinct registers also showed distinctive acoustic characteristics. Then, measures of TA and CT muscle activity and vocal fold adduction ratings were obtained to determine how these varied as a function of pitch and register. RESULTS: Spectral tilt increased as subjects shifted from chest to chestmix to headmix and finally into head register. For same pitch phonation, subjects increased TA muscle activity and vocal fold adduction as they shifted register from head to headmix to chestmix to chest, particularly during production of higher frequencies. CT activity appeared to be more related to pitch rather than register control. CONCLUSION: Nonclassically trained singers were able to produce pitches at the high end of the midrange in chestmix register by increasing TA muscle activity and adduction of the VPs. PMID- 21596520 TI - The impact of obesity on developmental coordination disorder in adolescence. AB - Developmental coordination disorder (DCD) as well as overweight and obesity are of increasing importance in the study of human development. Data on the relation between DCD and obesity in adolescence are of particular interest because both phenomena are unlikely to disappear with age. The objective of this study was to determine the impact of obesity on severe DCD in adolescence. A total of 99 obese adolescents aged between 11 and 16 years and 99 normal-weight controls matched for age and gender were included in this cross-sectional study. The Movement Assessment Battery for Children 2 (age band 3) was used to determine subjects' stage of motor development. Results made clear that (i) obese show a higher severe DCD-risk in comparison to normal-weight adolescents (p<.01) which is (ii) most pronounced in balance (p<.01), and (iii) thereby rather appears in boys (p<=.10). Thus, our results at least do not exclude the possibility that obesity might have a detrimental effect on the etiopathology of DCD beyond childhood. Therefore, primary obesity prevention measures may additionally contribute to the prevention of a possible consolidation of severe DCD. PMID- 21596522 TI - On pubescent voice change in males. AB - This review of adolescent voice change (AVC) in males is introduced by a brief historical overview of the area. That effort is followed by a summarization of those core studies which describe the AVC process in the normal boy. Although no new experiments are presented, a number of related investigations are organized into a cohesive base-one that permits development of an AVC model The model, then, can be employed to establish a reasonable description of the process by providing information about its initiation, duration, and completion. It also assists in establishing perspectives about pubescent voice change and a baseline for future research. PMID- 21596523 TI - How does the brain rapidly learn and reorganize view-invariant and position invariant object representations in the inferotemporal cortex? AB - All primates depend for their survival on being able to rapidly learn about and recognize objects. Objects may be visually detected at multiple positions, sizes, and viewpoints. How does the brain rapidly learn and recognize objects while scanning a scene with eye movements, without causing a combinatorial explosion in the number of cells that are needed? How does the brain avoid the problem of erroneously classifying parts of different objects together at the same or different positions in a visual scene? In monkeys and humans, a key area for such invariant object category learning and recognition is the inferotemporal cortex (IT). A neural model is proposed to explain how spatial and object attention coordinate the ability of IT to learn invariant category representations of objects that are seen at multiple positions, sizes, and viewpoints. The model clarifies how interactions within a hierarchy of processing stages in the visual brain accomplish this. These stages include the retina, lateral geniculate nucleus, and cortical areas V1, V2, V4, and IT in the brain's What cortical stream, as they interact with spatial attention processes within the parietal cortex of the Where cortical stream. The model builds upon the ARTSCAN model, which proposed how view-invariant object representations are generated. The positional ARTSCAN (pARTSCAN) model proposes how the following additional processes in the What cortical processing stream also enable position-invariant object representations to be learned: IT cells with persistent activity, and a combination of normalizing object category competition and a view-to-object learning law which together ensure that unambiguous views have a larger effect on object recognition than ambiguous views. The model explains how such invariant learning can be fooled when monkeys, or other primates, are presented with an object that is swapped with another object during eye movements to foveate the original object. The swapping procedure is predicted to prevent the reset of spatial attention, which would otherwise keep the representations of multiple objects from being combined by learning. Li and DiCarlo (2008) have presented neurophysiological data from monkeys showing how unsupervised natural experience in a target swapping experiment can rapidly alter object representations in IT. The model quantitatively simulates the swapping data by showing how the swapping procedure fools the spatial attention mechanism. More generally, the model provides a unifying framework, and testable predictions in both monkeys and humans, for understanding object learning data using neurophysiological methods in monkeys, and spatial attention, episodic learning, and memory retrieval data using functional imaging methods in humans. PMID- 21596524 TI - Influence of platelet-rich plasma on ectopic bone formation of bone marrow stromal cells in porous coral. AB - This study evaluated the effect of platelet-rich plasma (PRP) on the bone formation of marrow stromal cells (MSCs) in porous coral. MSCs in 50 MUl of PRP were seeded into natural coral disks (diameter 8.0 mm; thickness 2.0 mm). The composites were clotted and cultured in vitro or implanted subcutaneously into nude mice. Coral scaffolds loading MSCs or PRP alone acted as control. Alkaline phosphatase (ALP) activity of the specimens cultured in vitro for 7 and 14 days was measured, and the level of ectopic bone formation was investigated 4 and 8 weeks after operation. The samples from the coral/PRP/MSC group exhibited significantly higher ALP activity, compared with that from the coral/MSC group or the coral/PRP group (p<0.05). New bone and/or cartilage formation could be observed in specimens from both coral/PRP/MSC and coral/MSC groups in ectopic sites, and osteogenesis followed the pattern of endochondral bone formation. Histomorphometric analyses showed enhanced cartilage and/or bone formation in the coral/PRP/MSC group, 4 and 8 weeks after implantation. No bone or cartilage formation could be observed in the coral/PRP group. The authors concluded that PRP could improve the ALP activity of MSCs on coral and increase ectopic bone formation. PMID- 21596525 TI - Implants placed simultaneously with maxillary sinus floor augmentations in the presence of antral pseudocysts: a case report. AB - An antral pseudocyst on the maxillary sinus has previously been a contraindication for sinus augmentation. The authors report the case of a patient with an antral pseudocyst (16.7 mm * 27.6 mm) in his left sinus, who was referred for dental implant treatment. The surgical plan was to perform the sinus augmentation after removing the cyst whilest simultaneously placing implants. During the operation the cyst could not be found in the left sinus. The sinus augmentation was carried out successfully without sinus membrane perforation and the implants were placed according to plan. Three mouths later, the cyst was still present and good osseointegration of the implants was achieved. After the implants had been in place for a year, a CT scan showed that the cyst had decreased in size. The authors conclude that it is may not be necessary to remove a sinus cyst before sinus augmentation or during the sinus augmentation operation if the patient does not have any symptoms and the cyst is not large. In cases with large lesions or an unclear diagnosis, further evaluation is needed before surgical intervention. PMID- 21596526 TI - Activity of finafloxacin, a novel fluoroquinolone with increased activity at acid pH, towards extracellular and intracellular Staphylococcus aureus, Listeria monocytogenes and Legionella pneumophila. AB - Finafloxacin, an 8-cyano-substituted fluoroquinolone, expresses enhanced activity at acidic pH and is less susceptible to several fluoroquinolone resistance determinants. In this study, we compared finafloxacin and ciprofloxacin for (i) activity against ciprofloxacin-susceptible and -resistant Staphylococcus aureus as well as wild-type and Lde efflux-positive (Lde+) Listeria monocytogenes, (ii) accumulation in THP-1 macrophages and (iii) intracellular activity towards phagocytised S. aureus, L. monocytogenes and Legionella pneumophila (developing in acidic, neutral and mildly acidic environments, respectively), using a pharmacological approach assessing drug potencies and maximal relative efficacies (E(max)). Finafloxacin minimum inhibitory concentrations (MICs) were two-fold lower than those of ciprofloxacin against meticillin-susceptible S. aureus ATCC 25923, were only modestly increased in an isogenic strain overexpressing NorA and were <=0.25 mg/L for community-acquired meticillin-resistant S. aureus. No loss of activity was seen in Lde+ L. monocytogenes. An acidic pH decreased the MIC of finafloxacin and increased that of ciprofloxacin both for S. aureus and L. monocytogenes, in parallel with corresponding changes in drug accumulation (tested with S. aureus ATCC 25923 only). Finafloxacin accumulated less than ciprofloxacin in THP-1 cells, but the situation was reversed by exposure of cells to acid pH. In S. aureus-infected cells, acid pH increased the potency of finafloxacin without change of E(max), whilst decreasing the potency and the maximal relative efficacy of ciprofloxacin (less negative E(max)). Finafloxacin was more potent and showed larger E(max) than ciprofloxacin against phagocytised L. pneumophila, but was less potent against phagocytised L. monocytogenes. Finafloxacin appears to be an acid-pH-favoured antibiotic that may find useful applications in infections where the local pH is low. PMID- 21596527 TI - Role of a novel copper chelate in modulation of resistance by time and dose dependent potential on the growth of tetracycline-resistant Vibrio cholerae O1. PMID- 21596529 TI - A rapid, high-resolution melting (HRM) multiplex PCR assay to detect macrolide resistance determinants in group A streptococcus. PMID- 21596528 TI - In vitro activity of BAL30072 against Burkholderia pseudomallei. AB - Burkholderia pseudomallei is an intrinsically antibiotic-resistant Category B priority pathogen and the aetiological agent of melioidosis. Treatment of B. pseudomallei infection is biphasic and lengthy in order to combat the acute and chronic phases of the disease. Acute-phase treatment preferably involves an intravenous cephalosporin (ceftazidime) or a carbapenem (imipenem or meropenem). In this study, the anti-B. pseudomallei efficacy of a new monosulfactam, BAL30072, was tested against laboratory strains 1026b and 1710b and several isogenic mutant derivatives as well as a collection of clinical and environmental B. pseudomallei strains from Thailand. More than 93% of the isolates had minimal inhibitory concentrations (MICs) in the range 0.004-0.016 MUg/mL. For the laboratory strain 1026b, the MIC of BAL30072 was 0.008 MUg/mL, comparable with the MICs of 1.5 MUg/mL for ceftazidime, 0.5 MUg/mL for imipenem and 1 MUg/mL for meropenem. Time-kill curves revealed that BAL30072 was rapidly bactericidal, killing >99% of bacteria in 2 h. BAL30072 activity was not significantly affected by efflux, it was only a marginal substrate of PenA beta-lactamase, and activity was independent of malleobactin production and transport and the ability to transport pyochelin. In summary, BAL30072 has superior in vitro activity against B. pseudomallei compared with ceftazidime, meropenem or imipenem and it is rapidly bactericidal. PMID- 21596530 TI - Phenomenology of the social self in the prodrome of psychosis: from perceived negative attitude of others to heightened interpersonal sensitivity. PMID- 21596531 TI - Abnormality of VTA local field potential in an animal model of depression was restored by patterned DBS treatment. AB - Depressive disorders affect approximately 5% of the population in any given year. Deep brain stimulation (DBS) was previously shown to have a long-lasting normalizing effect on the ventral tegmental area (VTA) firing pattern in Flinders Sensitive-Line (FSL) rats, an animal model for depression. In the current study, we aimed to find a possible electrophysiological mechanism that underlies this adaptation. Local-field-potential (LFP) time-series were recorded in the VTA of conscious, freely-moving FSL (depressive-like) and control Sprague-Dawley (SD) rats. We found that 42% of recordings both from FSL and SD rats showed clear peaks between 1-8Hz. Within these recordings, SD rats mostly demonstrated a single, uniform peak at frequencies of 1-3Hz. However, FSL rats demonstrated a significantly higher amount of recordings with double or triple peaks, at frequencies of 1-8Hz. In addition to the power spectrum, autocorrelation calculation of LFP recordings also showed significant differences between groups. We examined acute DBS of the VTA as a novel method for ameliorating these electrophysiological aberrations, in addition to attenuation of depressive-like behavior. The pattern of stimulation was fashioned to mimic the firing pattern of VTA neurons in control rats, as shown in previous work. The results suggest that treatment with programmed acute electrical stimulation of the VTA substantially restores VTA LFP in FSL rats to normal activity levels, parallel to alleviation of depressive-like behavior, for an extended period of time. PMID- 21596532 TI - Reduction of dorsolateral prefrontal cortex gray matter in late-life depression. AB - Postmortem studies have documented abnormalities in the dorsolateral prefrontal cortex (dlPFC) in depressed subjects. In this study we used magnetic resonance imaging to test for dlPFC volume differences between older depressed and non depressed individuals. Eighty-eight subjects meeting DSM IV criteria for major depressive disorder and thirty-five control subjects completed clinical evaluations and cranial 3T magnetic resonance imaging. After tissue types were identified using an automated segmentation process, the dlPFC was measured in both hemispheres using manual delineation based on anatomical landmarks. Depressed subjects had significantly lower gray matter in the left and right dorsolateral prefrontal cortex (standardized to cerebral parenchyma) after controlling for age and sex. Our study confirmed the reduction of dorsolateral prefrontal cortex in elderly depressed subjects, especially in the gray matter. These regional abnormalities may be associated with psychopathological changes in late-life depression. PMID- 21596535 TI - [Bronchopulmonary squamous cell carcinoma associated with HPV 11 in a 15-year-old girl with a history of severe recurrent respiratory papillomatosis: a case report]. AB - Malignant transformation of juvenile-onset recurrent respiratory papillomatosis (RRP) is a rare event and the cases reported have been mainly observed in adults. We report the case of a 15-year-old girl with a history of severe RRP who died of a HPV 11-associated bronchopulmonary squamous cell carcinoma with pericardial invasion. HPV 11 was identified in nasopharyngeal and tracheal papillomas, as well as in the pericardial fluid. HPV 11 isolate was further analyzed by amplification and sequencing of the E1, E2, E4, E6, and E7 genes. Only one amino acid substitution in E4 due to natural polymorphism was observed. Exons 5-9 of the patient's tumor protein 53 (TP53) gene were sequenced and no mutations were identified. This observation confirms that malignant conversion of juvenile-onset RRP associated with HPV 11 to squamous cell carcinoma may arise in children. HPV 11-induced carcinogenesis needs to be further investigated. PMID- 21596536 TI - [Thymoma in children: a report of one case]. AB - BACKGROUND: Thymoma is an uncommon tumor of childhood. It is an anterior mediastinal tumor with few symptoms. The pleura is the most frequent metastatic site. Surgery is the treatment of choice and the most important prognostic factors are the stage at initial presentation and whether complete resection can be performed. CASE REPORT: A 6-year-old girl with no pathological antecedent presented with a history of prolonged fever. Frontal chest radiography showed a large mediastinal soft tissue mass with sharp lateral and inferior margins. Computed tomography showed a large anterosuperior and medium mediastinal mass measuring 83 mm * 70 mm, associated with variable size mediastinal adenopathy, suggesting the diagnosis of lymphoma. Histological examination of bone marrow biopsy found no haematological malignant diseases such as lymphoma. The histological examination of computed tomography (CT)-guided transthoracic biopsy demonstrated proliferation of polyclonal lymphocyte T cells, confirming the diagnosis of thymoma. The patient benefited from induction chemotherapy (cisplatin and VP16) followed by surgery with complete resection. The patient is doing well 24 months after resection and has no signs of recurrence; CT follow-up showed a stable size of residual thymus. CONCLUSION: Thymoma is a benign tumor but the significant risk of recurrence warrants long follow-up. PMID- 21596533 TI - Relationship of DAT1 and adult ADHD to task-positive and task-negative working memory networks. AB - Alterations in working memory, default-mode network (DMN), and dopamine transporter have all been proposed as endophenotypes for attention deficit/hyperactivity disorder (ADHD). Despite evidence that these systems are interrelated, their relationship to each other has never been studied in the context of ADHD. In order to understand the potential mediating effects of task positive and task-negative networks between DAT1 and diagnosis, we tested effects of genotype and diagnosis on regions of positive and negative BOLD signal change (as measured with fMRI) in 53 adults with ADHD and 38 control subjects during a working memory task. We also examined the relationship of these responses to ADHD symptoms. Our results yielded four principal findings: 1) association of the DAT1 9R allele with adult ADHD, 2) marginal DAT1 association with task-related suppression in left medial PFC, 3) marginal genotype*diagnosis interaction in the dorsal anterior cingulate cortex, and 4) correlation of DMN suppression to ADHD symptoms. These findings replicate the association of the 9R allele with adult ADHD. Further, we show that DMN suppression is likely linked to DAT1 and to severity of inattention in ADHD. DMN may therefore be a target of DAT1 effects, and lie on the path between the gene and inattention in ADHD. PMID- 21596537 TI - Moa's Ark or volant ghosts of Gondwana? Insights from nineteen years of ancient DNA research on the extinct moa (Aves: Dinornithiformes) of New Zealand. AB - The moa (Aves: Dinornithiformes) of New Zealand represent one of the extinct iconic taxa that define the field of ancient DNA (aDNA), and after almost two decades of genetic scrutiny of bones, feathers, coprolites, mummified tissue, eggshell, and sediments, our knowledge of these prehistoric giants has increased significantly. Thanks to molecular and morphological-based research, the insights that have been obtained into moa phylogenetics, phylogeography, and palaeobiology exceeds that of any other extinct taxon. This review documents the strengths of applying a multidisciplinary approach when studying extinct taxa but also shows that cross-disciplinary controversies still remain at the most fundamental levels, with highly conflicting interpretations derived from aDNA and morphology. Moa species diversity, for example, is still heavily debated, as well as their relationship with other ratites and the mode of radiation. In addition to increasing our knowledge on a lineage of extinct birds, further insights into these aspects can clarify some of the basal splits in avian evolution, and the evolutionary implications of the breakup of the prehistoric supercontinent Gondwana. Did a flightless moa ancestor drift away on proto New Zealand (Moa's Ark) or did a volant ancestor arrive by flight? Here we provide an overview of 19 years of aDNA research on moa, critically assess the attempts and controversies in placing the moa lineage among palaeognath birds, and discuss the factors that facilitated the extensive radiation of moa. Finally, we identify the most obvious gaps in the current knowledge to address the future potential research areas in moa genetics. PMID- 21596538 TI - Finding the founder of Stockholm - a kinship study based on Y-chromosomal, autosomal and mitochondrial DNA. AB - Historical records claim that Birger Magnusson (died 1266), famous regent of Sweden and the founder of Stockholm, was buried in Varnhem Abbey in Vastergotland. After being lost for centuries, his putative grave was rediscovered during restoration work in the 1920s. Morphological analyses of the three individuals in the grave concluded that the older male, the female and the younger male found in the grave were likely to be Birger, his second wife Mechtild of Holstein and his son Erik from a previous marriage. More recent evaluations of the data from the 1920s seriously questioned these conclusions, ultimately leading to the reopening and reexamination of the grave in 2002. Ancient DNA-analyses were performed to investigate if the relationship between the three individuals matched what we would expect if the individuals were Birger, Erik and Mechtild. We used pyrosequencing of Y-chromosomal and autosomal SNPs and compared the results with haplogroup frequencies of modern Swedes to investigate paternal relations. Possible maternal kinship was investigated by deep FLX-sequencing of overlapping mtDNA amplicons. The authenticity of the sequences was examined using data from independent extractions, massive clonal data, the c-statistics, and real-time quantitative data. We show that the males carry the same Y-chromosomal haplogroup and thus we cannot reject a father-son type of relation. Further, as shown by the mtDNA analyses, none of the individuals are maternally related. We conclude that the graves indeed belong to Birger, Erik and Mechtild, or to three individuals with the exact same kind of biological relatedness. PMID- 21596539 TI - Characterization and crop production efficiency of diazotrophic bacterial isolates from coastal saline soils. AB - Use of eco-friendly area specific salt tolerant bioinoculants is better alternatives to chemical fertilizer for sustainable agriculture in coastal saline soils. We isolated diverse groups of diazotrophic bacteria from coastal saline soils of different forest and agricultural lands in the Sundarbans, West Bengal, India, to study their effect on crop productivity in saline soils. Phenotypic, biochemical and molecular identifications of the isolates were performed. The isolates produced indole acetic acid, phosphatase, and solubilized insoluble phosphates. Sequence analysis of 16S rDNA identified the SUND_BDU1 strain as Agrobacterium and the strains SUND_LM2, Can4 and Can6 belonging to the genus Bacillus. The ARA activity, dinitrogen fixation and presence of nifH genes indicated they were diazotrophs. Field trials with these strains as bioinoculants were carried out during 2007-2009, with rice during August-December followed by Lady's finger during April-June. Microplots, amended with FYM inoculated with four bioinoculants individually were compared against sole FYM (5 t ha(-1)) and a sole chemical fertilizer (60:30:30 kg ha(-1) NPK) treated plot. The strain Can6 was by far the best performer in respect of yield attributes and productivity of studied crops. PMID- 21596540 TI - Isolation, selection and characterization of root-associated growth promoting bacteria in Brazil Pine (Araucaria angustifolia). AB - Araucaria angustifolia, a unique species of this genus that occurs naturally in Brazil, has a high socio-economic and environmental value and is critically endangered of extinction, since it has been submitted to intense predatory exploitation during the last century. Root-associated bacteria from A. angustifolia were isolated, selected and characterized for their biotechnological potential of growth promotion and biocontrol of plant pathogenic fungi. Ninety seven strains were isolated and subjected to chemical tests. All isolates presented at least one positive feature, characterizing them as potential PGPR. Eighteen isolates produced indole-3-acetic acid (IAA), 27 were able to solubilize inorganic phosphate, 21 isolates were presumable diazotrophs, with pellicle formation in nitrogen-free culture medium, 83 were phosphatases producers, 37 were positive for siderophores and 45 endospore-forming isolates were antagonistic to Fusarium oxysporum, a pathogen of conifers. We also observed the presence of bacterial strains with multiple beneficial mechanisms of action. Analyzing the fatty acid methyl ester (FAME) and partial sequencing of the 16S rRNA gene of these isolates, it was possible to characterize the most effective isolates as belonging to Bacillaceae (9 isolates), Enterobacteriaceae (11) and Pseudomonadaceae (1). As far as we know, this is the first study to include the species Ewingella americana as a PGPR. PMID- 21596541 TI - Molecular evidence of anti-leukemia activity of gypenosides on human myeloid leukemia HL-60 cells in vitro and in vivo using a HL-60 cells murine xenograft model. AB - We have shown that gypenosides (Gyp) induced cell cycle arrest and apoptosis in many human cancer cell lines. However, there are no reports showing that show Gyp acts on human leukemia HL-60 cells in vitro and in a murine xenograft model in vivo. In the present study effects of Gyp on cell morphological changes and viability, cell cycle arrest and induction of apoptosis in vitro and effects on Gyp in an in vivo murine xenograft model. Results indicated that Gyp induced morphological changes, decreased cell viability, induced G0/G1 arrest, DNA fragmentation and apoptosis (sub-G1 phase) in HL-60 cells. Gyp increased reactive oxygen species production and Ca(2+) levels but reduced mitochondrial membrane potential in a dose- and time-dependent manner. Gyp also changed one of the primary indicators of endoplasmic reticulum (ER) stress due to the promotion of ATF6-alpha and ATF4-alpha associated with Ca(2+) release. Gyp reduced the ratio of Bcl-2 to Bax due to an increase in the pro-apoptotic protein Bax and inhibited levels of the anti-apoptotic protein Bcl-2. Oral consumption of Gyp reduced tumor size of HL-60 cell xenograft mode mice in vivo. These results provide new information on understanding mechanisms by which Gyp induces cell cycle arrest and apoptosis in vitro and in vivo. PMID- 21596542 TI - Terpenoids inhibit Candida albicans growth by affecting membrane integrity and arrest of cell cycle. AB - Anti-Candida potential of six terpenoids were evaluated in this study against various isolates of Candida albicans (n=39) and non-C. albicans (n=9) that are differentially susceptible to fluconazole. All the six terpenoids tested, showed excellent activity and were equally effective against isolates of Candida sps., tested in this study. Linalool and citral were the most effective ones, inhibiting all the isolates at <=0.064% (v/v). Five among the six terpenoids tested were fungicidal. Time dependent kill curve assay showed that MFCs of linalool and eugenol were highly toxic to C. albicans, killing 99.9% inoculum within seven min of exposure, while that of citronellal, linalyl acetate and citral required 15min, 1h and 2h, respectively. FIC index values (Linalool - 0.140, benzyl benzoate - 0.156, eugenol - 0.265, citral - 0.281 and 0.312 for linalyl acetate and citronellal) and isobologram obtained by checker board assay showed that all the six terpenoids tested exhibit excellent synergistic activity with fluconazole against a fluconazole resistant strain of C. albicans. Terpenoids tested arrested C. albicans cells at different phases of the cell cycle i.e. linalool and LA at G1, citral and citronellal at S phase and benzyl benzoate at G2-M phase and induced apoptosis. Linalool, citral, citronellal and benzyl benzoate caused more than 50% inhibition of germ tube induction at 0.008%, while eugenol and LA required 0.032 and 0.016% (v/v) concentrations, respectively. MICs of all the terpenoids for the C. albicans growth were non toxic to HeLa cells. Terpenoids tested exhibited excellent activity against C. albicans yeast and hyphal form growth at the concentrations that are non toxic to HeLa cells. Terpenoids tested in this study may find use in antifungal chemotherapy, not only as antifungal agents but also as synergistic agents along with conventional drugs like fluconazole. PMID- 21596544 TI - Plant derived therapeutics for the treatment of Leishmaniasis. AB - Diseases caused by insect borne trypanosomatid parasites are significant, yet remain a neglected public health problem. Leishmania, a unicellular protozoan parasite is the causative organism of Leishmaniasis and is transmitted by female phlebotamine sandflies affecting millions of people worldwide. In the wake of resistance to pentavalent antimonial drugs, new therapeutic alternatives are desirable. The plant kingdom has in the past provided several affordable compounds and this review aims to provide an overview of the current status of available leishmanicidal plant derived compounds that are effective singly or in combination with conventional anti-leishmanial drugs, yet are non toxic to mammalian host cells. Furthermore, delineation of the contributory biochemical mechanisms involved in mediating their effect would help develop new chemotherapeutic approaches. PMID- 21596543 TI - Synergistic anti-bacterial and proteomic effects of epigallocatechin gallate on clinical isolates of imipenem-resistant Klebsiella pneumoniae. AB - Imipenem-resistant Klebsiella pneumoniae (IRKP) were used to explore the synergistic anti-bacterial and proteomic effects of imipenem alone or in combination with epigallocatechin gallate (EGCg). The minimal inhibitory concentrations (MICs) of EGCG for 12 clinically isolated IRKP strains ranged from 300 to 650 MUg/ml. Each of the 12 IRKP strains experienced a 4- to 64-fold reduction in the MIC of imipenem upon co-incubation with 0.25 * MIC level of EGCg. The time-kill method was used on the 12 IRKP clinical isolates to evaluate the bactericidal activities of imipenem alone or with EGCg. Compared to imipenem alone, EGCg with imipenem demonstrated enhanced bactericidal activity. Two dimensional polyacrylamide gel electrophoresis identified eight down-regulated and four up-regulated proteins in the IRKP strain upon exposure to 1 * MIC of EGCg. Analysis of the outer membrane protein profiles of IRKP cultures treated with EGCg revealed unique changes in outer membrane proteins. In addition, scanning electron microscopic analysis demonstrated the presence of cells with wrinkled surfaces containing perforations and irregular rod-shaped forms after treatment with EGCg or imipenem. These studies demonstrate that EGCg can synergize the bacterial activity of imipenem and differentially stimulate the expression of various proteins in IRKP. PMID- 21596545 TI - Reversal effect of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone on multi drug resistance in resistant human hepatocellular carcinoma cell line BEL-7402/5 FU. AB - Multi drug resistance (MDR) is a major obstacle in the chemotherapeutic treatment of many human cancers. 2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC), a chalcone, isolated from the buds of Cleistocalyx operculatus, has been shown to have antitumor effects on human carcinoma SMMC-7721 cells in vitro and in vivo. In this paper, we studied the reversal effect and the mechanism of DMC on human hepatocellular carcinoma drug-resistant cells BEL-7402/5-FU in vitro. Administration of DMC reversed the multi-drug resistance of human hepatocellular carcinoma BEL-7402/5-FU cells significantly. DMC enhanced the sensitivity of BEL 7402/5-FU cells to 5-fluorouracil (5-FU) and doxorubicin (DOX). Staining with Hoechst 33258 and flow cytometric analysis showed that DMC has apoptosis-inducing effect on BEL-7402/5-FU cells. It could also increase the concentration of 5-FU in the resistant multi-drug-resistant cells. We also observed that over expression of the multi-drug resistance-associated protein (MRP1) and of the glutathione S-transferase pi (GST-pi) contributed to MDR in BEL-7402/5-FU cells. The mRNA expressions of MRP1 and GST-pi and the protein expression of MRP1 were decreased by DMC. These data demonstrated that DMC could effectively reverse MDR in BEL-7402/5-FU cells. PMID- 21596546 TI - Ganoderol B: a potent alpha-glucosidase inhibitor isolated from the fruiting body of Ganoderma lucidum. AB - alpha-Glucosidase inhibitor has considerable potential as a diabetes mellitus type 2 drug because it prevents the digestion of carbohydrates. The search for the constituents reducing alpha-glucosidase activity led to the finding of active compounds in the fruiting body of Ganoderma lucidum. The CHCl(3) extract of the fruiting body of G. lucidum was found to show inhibitory activity on alpha glucosidase in vitro. The neutral fraction, with an IC(50) of 88.7 MUg/ml, had stronger inhibition than a positive control, acarbose, with an IC(50) of 336.7 MUg/ml (521.5 MUM). The neutral fraction was subjected to silica gel column chromatography and repeated p-HPLC to provide an active compound, (3beta,24E) lanosta-7,9(11),24-trien-3,26-diol (ganoderol B). It was found to have high alpha glucosidase inhibition, with an IC(50) of 48.5 MUg/ml (119.8 MUM). PMID- 21596547 TI - The formation of lipid droplets: possible role in the development of insulin resistance/type 2 diabetes. AB - Neutral lipids are stored in so-called lipid droplets, which are formed as small primordial droplets at microsomal membranes and increase in size by a fusion process. The fusion is catalyzed by the SNARE proteins SNAP23, syntaxin-5 and VAMP4. SNAP23 is involved in the insulin dependent translocation of GLUT4 to the plasma membrane, and has an important role in the development of insulin resistance. Thus fatty acids relocalize SNAP23 from the plasma membrane (and the translocation of GLUT 4) to the interior of the cell giving rise to insulin resistance. Moreover this relocalization is seen in skeletal muscles biopsies from patients with type 2 diabetes compared to matched control. Thus a missorting of SNAP23 is essential for the development of insulin resistance. PMID- 21596548 TI - Leukotriene receptors are differently expressed in fibroblast from peripheral versus central airways in asthmatics and healthy controls. AB - Leukotrienes are involved in airway inflammation, and are believed to stimulate airway remodeling in asthma. The aim of the project was to investigate the expression of leukotriene receptors in peripheral and central airway fibroblasts. Peripheral and central airway fibroblasts, from asthmatics and healthy controls, were investigated for the amount of cysteinyl-leukotriene receptors (CysLT(1) and CysLT(2)), leukotriene B(4) receptors (BLT(1) and BLT(2)), IL-13 receptor alpha(1) (IL-13Ralpha(1)) and the IL-4 receptor (IL-4R). The mRNA expression of CysLT(1) in fibroblasts from peripheral airways was higher compared to central airways. There was no difference in CysLT(2) between peripheral and central airways. On the contrary, BLT(1) and BLT(2) were lower in fibroblasts from peripheral airways compared to central. The expression of CysLT(1) was higher than CysLT(2) in fibroblasts from peripheral airways, and the expression of BLT(1) was higher than BLT(2) in both peripheral and central airways. Both BLT(1) and BLT(2) were higher in asthmatics compared to healthy controls, while CysLT(1) and CysLT(2) did not differ. The expression of IL-13Ralpha(1) was higher in asthmatics compared to controls, and correlated to the BLTs. All fibroblasts stained for the different receptor proteins. Leukotriene receptors are differently expressed in fibroblasts from peripheral compared to central airways, which may explain a suggested cysteinyl-leukotriene driven remodeling mainly in the peripheral airways. PMID- 21596549 TI - Transgenic oilseed crops as an alternative to fish oils. AB - Growing evidence suggests that omega-3 long chain polyunsaturated fatty acids (VLC-PUFAs), especially eicosapentaenoic acid (EPA; 20:5Delta5,8,11,14,17) and docosahexaenoic acid (DHA; 22:6Delta4,7,10,13,16,19) play critical roles in human health and development. VLC-PUFAs are mainly found in fish, some fungi, marine bacteria and microalgae. Currently, the predominant dietary sources of VLC-PUFAs are marine fish and seafood. However, the increasing demand for fish and fish oils is putting enormous pressure on marine ecosystems leading to a depletion of fish stocks while commercial cultivation of marine microorganisms and aquaculture are not sustainable and cannot compensate for the shortage in fish supply. Therefore, there is an obvious requirement for an alternative and sustainable source for VLC-PUFAs. Over the last decade, many genes encoding the primary VLC PUFAs biosynthetic activities became available providing a toolkit for the "reverse-engineering" of transgenic plants to produce fish oils. In this review, we will describe the recent advances in this field and the insights they give us into the complexities of metabolic engineering of oil-seed crops producing VLC PUFAs. PMID- 21596550 TI - Effects of biotin deficiency on pancreatic islet morphology, insulin sensitivity and glucose homeostasis. AB - Several studies have revealed that physiological concentrations of biotin are required for the normal expression of critical carbohydrate metabolism genes and for glucose homeostasis. However, the different experimental models used in these studies make it difficult to integrate the effects of biotin deficiency on glucose metabolism. To further investigate the effects of biotin deficiency on glucose metabolism, we presently analyzed the effect of biotin deprivation on glucose homeostasis and on pancreatic islet morphology. Three-week-old male BALB/cAnN Hsd mice were fed a biotin-deficient or a biotin-control diet (0 or 7.2 MUmol of free biotin/kg diet, respectively) over a period of 8 weeks. We found that biotin deprivation caused reduced concentrations of blood glucose and serum insulin concentrations, but increased plasma glucagon levels. Biotin-deficient mice also presented impaired glucose and insulin tolerance tests, indicating defects in insulin sensitivity. Altered insulin signaling was linked to a decrease in phosphorylated Akt/PKB but induced no change in insulin receptor abundance. Islet morphology studies revealed disruption of islet architecture due to biotin deficiency, and an increase in the number of alpha-cells in the islet core. Morphometric analyses found increased islet size, number of islets and glucagon-positive area, but a decreased insulin-positive area, in the biotin deficient group. Glucagon secretion and gene expression increased in islets isolated from biotin-deficient mice. Our results suggest that biotin deficiency promotes hyperglycemic mechanisms such as increased glucagon concentration and decreased insulin secretion and sensitivity to compensate for reduced blood glucose concentrations. Variations in glucose homeostasis may participate in the changes observed in pancreatic islets. PMID- 21596551 TI - Feasibility of producing ethanol from food waste. AB - Food waste generated in Korea is rich in carbohydrate as high as 65% of total solids. Using the food waste, the feasibility of ethanol production was investigated in a lab-scale fermentor. Pretreatment with hydrolyzing enzymes including carbohydrase, glucoamylase, cellulase and protease were tested for hydrolysis of food waste. The carbohydrase was able to hydrolyze and produce glucose with a glucose yield of 0.63 g glucose/g total solid. Enzymatic hydrolysis and ethanol fermentation by using carbohydrase and Saccharomyces cerevisiae were conducted in the batch mode. For separated hydrolysis and fermentation (SHF), ethanol concentration reached at the level corresponding to an ethanol yield of 0.43 g ethanol/g total solids. For simultaneous saccharification and fermentation (SSF), the ethanol yield was 0.31 g ethanol/g total solids. During the continuous operation of SHF, the volumetric ethanol production rate was 1.18 g/lh with an ethanol yield of 0.3g ethanol/g total solids. For SSF process, the volumetric ethanol production rate was 0.8 g/lh with an ethanol yield of 0.2g ethanol/g total solids. PMID- 21596552 TI - Electrochemical impedance spectroscopy sensor for ascorbic acid based on copper(I) catalyzed click chemistry. AB - Copper(I) species can be acquired from the reduction of copper(II) by ascorbic acid (AA) in situ, and which in turn quantitative catalyze the azides and alkynes cycloaddition reaction. In this study, propargyl-functionalized ferrocene (propargyl-functionalized Fc) has been modified on the electrode through reacting with azide terminal modified Au electrode via copper(I) catalyzed azides and alkynes cycloaddition (CuAAC) reaction. The electrochemical impedance spectroscopy (EIS) measurement has been applied to test the electron transfer resistance of the Au electrode before and after click reaction. The changes of the fractional surface coverage (theta) with different AA concentrations are characterized. It is found that the theta value has a linear response to the logarithm of AA concentration in the range of 5.0 pmol/L to 1.0 nmol/L with the detection limits of 2.6 pmol/L. The sensor shows a good stability and selectivity. And it has been successfully applied to the AA detection in the real samples (urine) with satisfactory results. PMID- 21596553 TI - Design, development and application of a bioelectrochemical detection system for meat tenderness prediction. AB - The analytical method described, based on antibody-antigen bio-recognition and the measuring system for amperometric detection, was designed for accurate, easy to use and cost effective quantification of calpastatin, a meat tenderness biomarker. The novel assay for calpastatin quantification was integrated in a portable electrochemical device known as the Tendercheck system and was used to analyze meat samples collected from animals of different breeds and ages. The data obtained were correlated (R2 = 0.62) with Warner Bratzler Shear Force (WBSF) measurements, a routinely used method for meat tenderness determination. PMID- 21596555 TI - Polymorphisms in MUC1, MUC2, MUC5B and MUC6 genes are not associated with the risk of chronic atrophic gastritis. AB - Mucins represent major components of the mucous layer in the stomach, protecting the underlying epithelium from acid, mechanical trauma, proteases and pathogenic bacteria. Previous studies have shown an association of neoplastic transformation in the stomach with aberrant mucin levels, suggesting a potential role of genetic variation in mucin genes in the development of gastric cancer (GC). We assessed the association of genetic variation in candidate single nucleotide polymorphisms (SNPs) in mucin genes with the risk of chronic atrophic gastritis (CAG), a well established precursor of GC in the German population-based ESTHER study. We genotyped MUC1 T31T, MUC2 L58P, MUC2 V116M, MUC5B E34G, MUC5B R51W, MUC5B rs2014486 (intronic) and MUC6 V619M for 533 serologically defined CAG cases and 1054 age- and sex-matched controls. None of the analysed SNPs was associated with CAG. However, large studies are needed to disclose or exclude potential weak associations of these SNPs with CAG risk. PMID- 21596556 TI - Sulfamethoxazole biodegradation and biotransformation in the water-sediment system of a natural river. AB - In this study, the biodegradation of sulfamethoxazole (SMX) as affected by temperature, humic acid (HA) and SMX concentrations was investigated by HPLC MS/MS analysis based on water-sediment batch experiments. The first order decay model (C=C(0) * exp (-kt)) was best fitted for SMX biodegradation. SMX degradation significantly increased with elevated temperature (degradation rate was 82.9% at 25 degrees C vs. 40.5% at 4 degrees C in sediment), HA contents (30 mg/L of HA facilitated SMX degradation rate at 90.1% vs. 82.9% by 5mg/L of HA). However, SMX degradation is not readily dependent on its initial concentrations (1, 2, 20, 50 and 100mg/L), which suggests a co-metabolism mechanism may involove in SMX biodegradation. The prevalence of Bacillus firmus and Bacillus cereus among the strains isolated and identified on the basis of 16s rDNA gene sequence implicates their potential efficiency at degrading SMX. Only less than 1% of the SMX was transformed into its metabolite N(4)-acetyl-sulfamethoxazole, suggesting the need to pay more attention to the parent SMX. Overall, the ubiquitous occurrence of SMX underscores the need to explore better solutions for its removal and to mitigate this risk to public health. PMID- 21596554 TI - Drosophila modeling of heritable neurodevelopmental disorders. AB - Heritable neurodevelopmental disorders are multifaceted disease conditions encompassing a wide range of symptoms including intellectual disability, cognitive dysfunction, autism and myriad other behavioral impairments. In cases where single, causative genetic defects have been identified, such as Angelman syndrome, Rett syndrome, Neurofibromatosis Type 1 and Fragile X syndrome, the classical Drosophila genetic system has provided fruitful disease models. Recent Drosophila studies have advanced our understanding of UBE3A, MECP2, NF1 and FMR1 function, respectively, in genetic, biochemical, anatomical, physiological and behavioral contexts. Investigations in Drosophila continue to provide the essential mechanistic understanding required to facilitate the conception of rational therapeutic treatments. PMID- 21596557 TI - Effect of layers composition on leachate property from functional layer embedded landfill. AB - Two functional layers embedded landfills (FLELs), namely LR1 (with Layers 1 and 2) and LR2 (with double Layer 1), were conducted to evaluate their efficiency on the reduction of leachate strength at source and the acceleration of waste biodegradation process. It was found that the cumulative COD, NH(3)-N, leachate quantity and landfill settlement in LR1 was 63.0%, 34.6%, 94.8% and 80.4% of that in LR2 in the entire test periods, while the leachate effluents from these two reactors presented almost the same concentration at the end of the operation period. It could be concluded that leachate pollutants was removed immediately in Layer 2 through the physical-chemical reaction, while double Layer 1s contributed to the pollutant removal in a long run through the improvement of the micro organism activities in landfill. The layer composition should be applied according to the landfill types, i.e. plain landfill using Layer 2 and valley landfill using Layer 1. PMID- 21596558 TI - Investigating the influence of extractives on the oil yield and alkane production obtained from three kinds of biomass via deoxy-liquefaction. AB - The aim of this study is to investigate the influence of extractives on the yield and composition of oil obtained from biomass samples (Artemisia ordosica, corn stalk and wheat straw). Direct deoxy-liquefaction experiments of original and extracted biomass were performed at certain temperature in a stainless steel tubular reactor. Benzene-alcohol solvent extraction had significant effect on the product distribution of biomass, especially on the yield and composition of the product oils. The oil yield of original biomass and alkane content in the oil were in the range of 5.44-9.27% and 8.23-23.64%, while decreased to 3.83-4.45% and 1.07-6.03% for the extracted biomass. This study concludes that most of alkanes in the oil mainly derive from the decomposition of triglyceride and hydrocarbon existed in the extractives of biomass. The results might be helpful to study the origin of alkanes and benzene derivatives in the oil obtained from biomass via direct deoxy-liquefaction. PMID- 21596559 TI - Application of cellulase and hemicellulase to pure xylan, pure cellulose, and switchgrass solids from leading pretreatments. AB - Accellerase 1000 cellulase, Spezyme CP cellulase, beta-glucosidase, Multifect xylanase, and beta-xylosidase were evaluated for hydrolysis of pure cellulose, pure xylan, and switchgrass solids from leading pretreatments of dilute sulfuric acid, sulfur dioxide, liquid hot water, lime, soaking in aqueous ammonia, and ammonia fiber expansion. Distinctive sugar release patterns were observed from Avicel, phosphoric acid swollen cellulose (PASC), xylan, and pretreated switchgrass solids, with accumulation of significant amounts of xylooligomers during xylan hydrolysis. The strong inhibition of cellulose hydrolysis by xylooligomers could be partially attributed to the negative impact of xylooligomers on cellulase adsorption. The digestibility of pretreated switchgrass varied with pretreatment but could not be consistently correlated to xylan, lignin, or acetyl removal. Initial hydrolysis rates did correlate well with cellulase adsorption capacities for all pretreatments except lime, but more investigation is needed to relate this behavior to physical and compositional properties of pretreated switchgrass. PMID- 21596560 TI - The direct electrocatalysis of phenazine-1-carboxylic acid excreted by Pseudomonas alcaliphila under alkaline condition in microbial fuel cells. AB - In this paper, we reported a kind of exoelectrogens, Pseudomonas alcaliphila (P. alcaliphila) strain MBR, which could excrete phenazine-1-carboxylic acid (PCA) to transfer electron under alkaline condition in microbial fuel cells (MFCs). The electrochemical activity of strain MBR and the extracellular electron transfer mechanism in MFCs were evaluated by cyclic voltammetry (CV) and electricity generation curve measurement. The results indicated a soluble mediator was the key factor for extracellular electron transfer of strain MBR under alkaline condition. The soluble mediator was PCA detected by gas chromatography-mass (GC MS) analyses. PMID- 21596561 TI - Enhancement of photo-hydrogen production in a biofilm photobioreactor using optical fiber with additional rough surface. AB - In this study, a biofilm photobioreactor with optical fibers that have additional rough surface (OFBP-R) was developed and it was shown that additional rough surface greatly enhanced the biofilm formation and thus increased the cell concentration, leading to an improvement in the hydrogen production performance. The effects of operational conditions, including the influent substrate concentration, flow rate, temperature and influent medium pH, on the performance of OFBP-R were also investigated. The experimental results showed that the optimum operational conditions for hydrogen production were: the influent substrate concentration 60 mM, flow rate 30 mL/h, temperature 30 degrees C and influent medium pH 7. Under the optimal operation conditions discovered in this work, the OFBP-R yielded fairly good and stable long-term performance with hydrogen production rate of 1.75 mmol/L/h, light conversion efficiency of 9.3% and substrate degradation efficiency of 75%. PMID- 21596562 TI - Design and synthesis of protein kinase Calpha activators based on 'out of pocket' interactions. AB - Novel types of PKCalpha activators based on isobenzofuranone bearing a myo inositol moiety were designed and synthesized. The derivatives with bulky substituents on the myo-inositol moiety significantly activated PKCalpha, but their binding sites were not the same as that of phorbol ester. PMID- 21596563 TI - Synthesis and SAR studies of novel 2-(6-aminomethylaryl-2-aryl-4-oxo-quinazolin 3(4H)-yl)acetamide vasopressin V1b receptor antagonists. AB - Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction. PMID- 21596564 TI - The prognostic significance of computerised tomography findings in women with liver metastases from breast cancer. AB - AIMS: While computerised tomography (CT) is used for diagnosis and assessing response to treatment little work has been performed on the prognostic significance of the CT findings in women with liver metastases. The aim of this study was to assess if the CT findings in women diagnosed with liver metastases at the time of first presentation with metastatic breast cancer have any prognostic significance. MATERIALS AND METHODS: The staging CT scans of 78 consecutive women diagnosed with liver metastases at the time of first presentation of metastatic breast cancer were reviewed independently by two radiologists who were blinded to survival and the histological features of the tumour. The number and enhancement characteristics of liver metastases, whether metastases were solitary, multiple or diffuse, the diameter of the largest and the sum of the diameter of the five largest lesions, an estimate of % involvement (<10%, 10-50%, >50%), and the presence of metastases at other sites were assessed. HER-2 and ER status and histological grade of the patient's primary breast cancer were also recorded. Survival was ascertained from hospital records. The prognostic significance of these factors was assessed in a univariate and multivariate fashion. RESULTS: At univariate analysis, number of liver metastases, sum of the diameter of the five largest lesions, percentage estimated involvement, presence of ascites, chest metastases and HER-2 status were significantly associated with reduced survival. Liver metastasis pattern (i.e. whether discrete or multiple), enhancement characteristics, ER status and histological grade were not associated with a significant outcome. At multivariate analysis estimated percentage liver involvement and the presence of chest metastases retained prognostic significance. Estimated percentage involvement was reproducible with 90% concordance between the two observers. CONCLUSIONS: The CT appearances of patients with liver metastases at first presentation with metastatic breast cancer provide prognostic information which may be clinically useful. PMID- 21596565 TI - Renin angiotensin system-regulating aminopeptidase activities in serum of pre- and postmenopausal women with breast cancer. AB - Angiotensin peptides regulate vascular tone and natriohydric balance through the renin angiotensin system (RAS) and are related with the angiogenesis which plays an important role in the metastatic pathway. Estrogen influences the aminopeptidases (APs) involved in the metabolism of bioactive peptides of RAS through several pathways. We analyze RAS-regulating AP activities in serum of pre and postmenopausal women with breast cancer to evaluate the putative value of these activities as biological markers of the development of breast cancer. We observed an increase in aminopeptidase N (APN) and aminopeptidase B (APB) activities in women with breast cancer; however, a decrease in aspartyl aminopeptidase (AspAP) activity in premenopausal women. These results suggest a slow metabolism of angiotensin II (Ang II) to angiotensin III (Ang III) in premenopausal women and a rapid metabolism of Ang III to angiotensin IV (Ang IV) in pre- and postmenopausal women with breast cancer. An imbalance in the signals activated by Ang II may produce abnormal vascular growth with different response between pre- and postmenopausal women depending on the hormonal profile and the development of the disease. PMID- 21596566 TI - Rab6, Rab8, and MICAL3 cooperate in controlling docking and fusion of exocytotic carriers. AB - Rab6 is a conserved small GTPase that localizes to the Golgi apparatus and cytoplasmic vesicles and controls transport and fusion of secretory carriers [1]. Another Rab implicated in trafficking from the trans-Golgi to the plasma membrane is Rab8 [2-5]. Here we show that Rab8A stably associates with exocytotic vesicles in a Rab6-dependent manner. Rab8A function is not needed for budding or motility of exocytotic carriers but is required for their docking and fusion. These processes also depend on the Rab6-interacting cortical factor ELKS [1], suggesting that Rab8A and ELKS act in the same pathway. We show that Rab8A and ELKS can be linked by MICAL3, a member of the MICAL family of flavoprotein monooxygenases [6]. Expression of a MICAL3 mutant with an inactive monooxygenase domain resulted in a strong accumulation of secretory vesicles that were docked at the cell cortex but failed to fuse with the plasma membrane, an effect that correlated with the strongly reduced mobility of MICAL3. We propose that the monooxygenase activity of MICAL3 is required to regulate its own turnover and the concomitant remodeling of vesicle-docking protein complexes in which it is engaged. Taken together, the results of our study illustrate cooperation of two Rab proteins in constitutive exocytosis and implicates a redox enzyme in this process. PMID- 21596567 TI - The Arf GAP CNT-2 regulates the apoptotic fate in C. elegans asymmetric neuroblast divisions. AB - During development, all cells make the decision to live or die. Although the molecular mechanisms that execute the apoptotic program are well defined, less is known about how cells decide whether to live or die. In C. elegans, this decision is linked to how cells divide asymmetrically [1, 2]. Several classes of molecules are known to regulate asymmetric cell divisions in metazoans, yet these molecules do not appear to control C. elegans divisions that produce apoptotic cells [3]. We identified CNT-2, an Arf GTPase-activating protein (GAP) of the AGAP family, as a novel regulator of this type of neuroblast division. Loss of CNT-2 alters daughter cell size and causes the apoptotic cell to adopt the fate of its sister cell, resulting in extra neurons. CNT-2's Arf GAP activity is essential for its function in these divisions. The N terminus of CNT-2, which contains a GTPase like domain that defines the AGAP class of Arf GAPs, negatively regulates CNT-2's function. We provide evidence that CNT-2 regulates receptor-mediated endocytosis and consider the implications of its role in asymmetric cell divisions. PMID- 21596568 TI - Visual short-term memory compared in rhesus monkeys and humans. AB - Change detection is a popular task to study visual short-term memory (STM) in humans [1-4]. Much of this work suggests that STM has a fixed capacity of 4 +/- 1 items [1-6]. Here we report the first comparison of change-detection memory between humans and a species closely related to humans, the rhesus monkey. Monkeys and humans were tested in nearly identical procedures with overlapping display sizes. Although the monkeys' STM was well fit by a one-item fixed capacity memory model, other monkey memory tests with four-item lists have shown performance impossible to obtain with a one-item capacity [7]. We suggest that this contradiction can be resolved using a continuous-resource approach more closely tied to the neural basis of memory [8, 9]. In this view, items have a noisy memory representation whose noise level depends on display size as a result of the distributed allocation of a continuous resource. In accord with this theory, we show that performance depends on the perceptual distance between items before and after the change, and d' depends on display size in an approximately power-law fashion. Our results open the door to combining the power of psychophysics, computation, and physiology to better understand the neural basis of STM. PMID- 21596570 TI - Patellofemoral osteoarthritis treated by partial lateral facetectomy: results at long-term follow up. AB - Excision of the eroded lateral patellar facet has been suggested as an acceptable treatment for short-term pain reduction in patients with isolated patellofemoral osteoarthritis. The outcome of this procedure at long-term is however not known. We therefore reviewed the results of 155 consecutive patients (168 knees) treated at our institution with lateral facetectomy at an average follow up of 10.9 years (+/- 6.9 years SD). During follow up 62 knees (36.9%) had failed and were revised to either TKA (60 knees), patellofemoral arthroplasty (one case) or total patellectomy (one case). Average time to reoperation in the failure group was 8.0 years (+/- 6.2 years SD). Kaplan-Meier survival rates with reoperation as endpoint were 85% at 5 years, 67.2% at 10 years, and 46.7% at 20 years respectively. At final follow up 79 (74.5%) of the knees that had not been re operated were rated as either good or fair, which corresponds to 47% of the original group. Our study therefore demonstrates that a satisfactory outcome after lateral patellar facetectomy for isolated patellofemoral osteoarthritis can be expected in approximately half of the cases at 10 year follow up. PMID- 21596569 TI - Degrade, move, regroup: signaling control of splicing proteins. AB - With recent advances in microarrays and sequencing it is now relatively straightforward to compare pre-mRNA splicing patterns in different cellular conditions on a genome-wide scale. Such studies have revealed extensive changes in cellular splicing programs in response to stimuli such as neuronal depolarization, DNA damage, immune signaling and cellular metabolic changes. However, for many years our understanding of the signaling pathways responsible for such splicing changes was greatly lacking. Excitingly, over the past few years this gap has begun to close. Recent studies now suggest notable trends in the mechanisms that link cellular stimuli to downstream alternative splicing events. These include regulated synthesis or degradation of splicing factors, differential protein-protein interactions, altered nuclear translocation and changes in transcription elongation. PMID- 21596571 TI - Tunnel position following posterior cruciate ligament reconstruction: an in vivo computed tomography analysis. AB - The success of posterior cruciate ligament (PCL) reconstruction is dependent on appropriate tunnel placement. Computed tomography (CT) provides detailed images of intra-articular osseous anatomy. The objective of this study was to analyze by CT the position of femoral and tibial tunnels relative to intra-operative goals following arthroscopic-assisted PCL reconstruction. Nineteen patients who underwent single-bundle PCL reconstruction were evaluated 16 months post operatively. Each underwent a CT scan and tunnel locations were identified in the coronal, sagittal, and axial planes. The coronal plane tibial tunnel location was within 5mm of the intra-operative goal (48% of the total tibial plateau width from the medial border of the plateau) in 16 patients (84%). The sagittal plane tibial tunnel location was within 5mm of the intra-operative goal (the middle of the posterior half of the retrospinal surface) in 14 patients (74%). In the sagittal plane, the femoral tunnel location was within 5mm of the intra-operative goal (10mm from in the distal articular margin of the medial femoral condyle) in 15 patients (79%). In the notch, the femoral tunnel was between 10:30 and 11:30 for left knees or between 12:30 and 1:30 for right knees (the intra-operative goal was 11 o'clock for left knees and 1 o'clock for right knees) in 18 patients (95%). Arthroscopic PCL reconstruction results in tunnel positions near intra operative goals. Further work is necessary to define CT-specific criteria for the assessment of PCL tunnel position. PMID- 21596572 TI - Biological activity of water-soluble inclusion complexes of 1'-acetoxychavicol acetate with cyclodextrins. AB - 1'-Acetoxychavicol acetate (ACA), isolated from the rhizomes and the seeds of the Zingiberaceae plant, has a variety of biological activities such as antitumor, antiallergic and repellent effects. However, ACA seems to have some disadvantages which may limit for future possible clinical applications, for example, its poor water solubility. Furthermore, ACA is not stable in aqueous solutions and undergoes hydrolysis and/or isomerization. To improve the solubility and stability of ACA in water, we prepared the inclusion complexes with various beta cyclodextrins (beta-CDs).In aqueous solution, the association constants of ACA with various CDs were estimated at 662+/-95 (beta-CD), 336+/-70 (methyl-beta-CD, Mebeta-CD), and 322+/-44M(-1) (hydroxypropyl-beta-CD, HPbeta-CD), respectively, by a spectrofluorometric displacement method based on competition between a guest and a fluorescent probe for CDs. It was revealed that almost all ACAs existed as a free molecule in the CD-containing aqueous solution. However, in the case of preparing the inclusion complexes of CDs with ACA by a solid phase 'high-speed vibration milling' technique, the average inclusion rates of the obtained water soluble complexes were calculated as 88+/-13% (beta-CD), 70+/-1% (Mebeta-CD), and 63+/-2% (HPbeta-CD), respectively, by (1)H NMR analysis. To characterize the structures of the CD.ACA complexes, 2,3,6-trimethyl-beta-CD (TMebeta-CD).ACA complex was prepared as a model compound (inclusion rate: 40%). As a result of 2D ROESY experiments, it was considered that the aromatic ring of ACA is located in the narrow side of the hydrophobic cavity of the TMebeta-CD and both 1'- and 4 acetoxy groups of ACA positioned in the vicinity of the secondary and primary methoxy groups of TMebeta-CD, respectively. Furthermore, we examined the apoptogenic activity of CD.ACA complexes to evaluate whether or not the bioactivities of ACA were affected by their inclusion. Although the cytotoxicity of all CD.ACA complexes in human epithelial carcinoma HeLa cells and murine adenocarcinoma colon26 cells were diminished as compared with the ACA alone, only HPbeta-CD.ACA maintained high levels of activity. In addition, HPbeta-CD.ACA, and Mebeta-CD.ACA showed suppressive effect for the transcription factor NF-kappaB activation on LPS-activated murine macrophage RAW264.7 cells and the former was more active complex. Furthermore, HPbeta-CD.ACA inhibited the in vivo tumor growth of tumor-bearing mice, although the activity was slightly weak compared with that of free ACA. These results indicate that HPbeta-CD is the best host molecule for ACA to form a water-soluble complex with the similar biological activity of free ACA. PMID- 21596573 TI - Inhibitors of histone demethylases. AB - Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the inhibitors are either previously reported inhibitors of related enzymes or compounds derived from these. Development in terms of selectivity and potency is still pertinent. Several reports on the development of functional assays have been published. PMID- 21596574 TI - Estimation of indoor radon concentration based on radon flux from soil and groundwater. AB - The indoor radon concentration was estimated based on the radon flux in soil and groundwater. The indoor radon concentration in Budhakedar area of Garhwal Himalaya, India is estimated to be 3.0-131.4 Bq/m(3) in summer and 4.6-92.4 Bq/m(3) in winter. Based on the available data from study area, the calculated value of diffusion coefficient for the soil ranges from 0.1*10(-2) to 3.0*10( 2)cm(2) s(-1) in the summer season and 0.1*10(-2) to 0.4*10(-2)cm(2) s(-1) in the winter season. The calculated value of diffusion flux in the study area is found to vary from 0.1*10(-2) to 16.1*10(-2)Bq m(-2) s(-1) in summer season and 0.1*10( 2)-12.2*10(-2)Bq m(-2) s(-1) in winter season. The formulation was tested by comparing the results of radon values from two different seasons of a year. PMID- 21596575 TI - Development of a thick CdTe detector for BNCT-SPECT. AB - As well known, it is difficult to know the exact treatment effect of boron neutron capture therapy (BNCT). It depends on the irradiation time, which is changed rather flexibly. At present, it is once fixed before BNCT. Then the actual stopping time is adjusted during BNCT by some means like activation foils. The author's group hence started development of a single-photon emission computed tomography (SPECT) system for BNCT to know the effect of BNCT in real time. By adopting a side surface (1*2 mm(2)) of a CdTe detector (1*2*20 mm(3)) as radiation entrance window, acceptable spatial resolution and high detection efficiency were simultaneously achieved. Also in about 30 min acceptable number of counts for 478 keV gamma-rays could be expected. In addition, employing a Schottky type detector the energy resolution could be improved. Discrimination of 478 keV and annihilation gamma-rays would thus be successfully made. In the next phase, it is planned to design and develop an array type detector to be implemented in the BNCT-SPECT system. PMID- 21596576 TI - Biochemical and molecular changes in response to aluminium-stress in highbush blueberry (Vaccinium corymbosum L.). AB - Aluminium (Al) stress is an important factor limiting crop yields in acid soils. Despite this, very little is known about the mechanisms of resistance to this stress in woody plants. To understand the mechanisms of Al-toxicity and response in blueberries, we compared the impact of Al-stress in Al-resistant and Al sensitive genotypes using Vaccinium corymbosum L. (Ericaceae) as a plant model. We investigated the effect of Al-stress on the physiological performance, oxidative metabolism and expression of genes that encode antioxidant enzymes in two V. corymbosum cultivars maintained hydroponically with AlCl(3) (0 and 100 MUM). Microscopic analyses of Al-treated root tips suggested a higher degree of Al-induced morphological injury in Bluegold (sensitive genotype) compared to Brigitta (resistant genotype). Furthermore, the results indicated that Brigitta had a greater ability to control oxidative stress under Al-toxicity, as reflected by enhancement of several antioxidative and physiological properties (radical scavenging activity: RSA, superoxide dismutase: SOD and catalase: CAT; maximum quantum yield: Fv/Fm, effective quantum yield: FPSII, electron transport rate: ETR and non-photochemical quenching: NPQ). Finally, we analyzed the expression of genes homologous to GST and ALDH, which were identified in a global expression analysis. In the resistant genotype, the expression of these genes in response to Al-stress was greater in leaves than in roots. PMID- 21596577 TI - Trans-apical beating-heart implantation of neo-chordae to mitral valve leaflets: results of an acute animal study. AB - OBJECTIVE: Trans-apical beating-heart implantation of neo-chordae is yet an experimental procedure for mitral valve (MV) repair. We aimed to assess the performance of a new device in an acute animal study. METHODS: A total of four domestic adolescent pigs were used as an acute model. The MV was assessed on the beating heart through a conventional trans-apical access. The NeoChord DS1000 device was used to implant polytetrafluoroethylene (PTFE) sutures to the MV leaflets. Procedural performance of the device was assessed and completed with surgical workflow analysis. RESULTS: Overall 57 implantations using epicardial echocardiography guidance were performed (mean 14.3 implantations per animal). The MV leaflets were successfully grasped every second attempt (mean 2.3+/-1.9) with no difference between the anterior and the posterior leaflet. A significant difference between an 'expert' surgeon (n>20 implantations) and beginner surgeon was detected with regard to the duration for successful leaflet grasping (65+/-73 vs 127+/-105 s; p=0.02) and the overall duration for implantation (130+/-86 vs 230+/-119 s; p=0.002). Gross anatomy did not show major tear of leaflets. There were no device-related technical problems. CONCLUSION: The NeoChord DS1000 device for trans-apical beating-heart implantation of neo-chordae to the MV valve showed a high procedural success. A significant difference between an expert and beginner surgeon was detected, which emphasizes the importance of training before introduction of this new technique into clinical practice. Surgical workflow analysis proved to be a valuable tool to assess the performance of this new technique. PMID- 21596578 TI - Comparison between intermittent intravenous analgesia and intermittent paravertebral subpleural analgesia for pain relief after thoracotomy. AB - OBJECTIVE: In the present prospective double-blind randomized trial, the effects of intermittent paravertebral subpleural bupivacaine and morphine on pain management in patients undergoing thoracotomy were evaluated and compared with intermittent systemic analgesia. METHODS: Forty-five patients undergoing elective lobectomy were included in the present study. Three randomized groups consisting of 15 patients each were compared. Those in the control group were administered intravenously with tramadol 100 mg plus metamizol 1000 mg every 4 h for 3 days. We placed the catheter just below the parietal pleura along the paravertebral sulcus at the level of T5-T7. At the end of the operation and every 4 h thereafter, the patients received either 1.5 mg kg(-1) bupivacaine (bupivacaine group) or 0.2 mg kg(-1) morphine sulfate (morphine group) with paravertebral subpleural catheter for 3 days. Data regarding demographics, visual analog pain scores, need for supplementary intravenous analgesia, pulmonary function tests, and postoperative pulmonary complications were recorded for each patient. RESULTS: Visual analog pain scores (visual analog scale (VAS)) were lower in the morphine and bupivacaine groups compared with control group at all postoperative time points. The mean postoperative VAS was significantly different between the control and bupivacaine groups at postoperative hour 12, the control and morphine groups at postoperative hours 6, 12, 48, and 72, and the bupivacaine and morphine groups at postoperative hours 6 and 24 (p<0.05). In the control group, additional analgesic requirement was significantly higher than in the bupivacaine and morphine groups (p<0.05). Postoperative pulmonary complications occurred in three patients (20%) in the control group, in two patients (13%) in the bupivacaine group, and in one (6%) in the morphine group. CONCLUSIONS: The patients undergoing lung resection through a thoracotomy were observed with reduced postoperative pain and better surgical outcomes with respect to the length of hospital stay, postoperative forced expiratory volume in the first second, pulmonary complications, and need for bronchoscopic management, when paravertebral subpleural analgesia was induced by morphine. PMID- 21596579 TI - Glutathione preconditioning ameliorates mitochondria dysfunction during warm pulmonary ischemia-reperfusion injury. AB - OBJECTIVES: Reduced glutathione (GSH) has been shown to improve pulmonary graft preservation. Mitochondrial dysfunction is regarded to be the motor of ischemia reperfusion injury (IR) in solid organs. We have shown previously that IR induces pulmonary mitochondrial damage. This study elucidates the impact of GSH preconditioning on the integrity and function of pulmonary mitochondria in the setting of warm pulmonary IR. METHODS: Wistar rats were subjected to control, sham, and to two-study-group conditions (IR30/60 and GSH-IR30/60) receiving IR with or without GSH preconditioning. Rats were anesthetized and received mechanical ventilation. Pulmonary in situ clamping followed by reperfusion generated IR. Mitochondria were isolated from pulmonary tissue. Respiratory chain complexes activities (I-IV) were analyzed by polarography. Mitochondrial viability (Ca2+-induced swelling) and membrane integrity (citrate synthase assay) were determined. Subcellular-fractional cytochrome C-content (Cyt C) was quantified by enzyme-linked immunosorbent assay (ELISA). Mitochondrial membrane potential (DeltaPsim) was analyzed by fluorescence-activated cell sorting (FACS) after energizing and uncoupling. Inflammatory activation was determined by myeloperoxidase activity (MPO), matrix-metalloproteinase 9 (MMP-9) activity by gel zymography. RESULTS: Pulmonary IR significantly reduced mitochondrial viability in combination with DeltaPsim hyper-polarization. GSH preconditioning improved mitochondrial viability and normalized DeltaPsim. Cyt C was reduced after IR; GSH protected from Cyt C liberation. Respiratory chain complex activities (I, II, III) declined during IR; GSH protected complex II function. GSH also protected from MMP-9 and neutrophil sequestration (P>.05). CONCLUSIONS: GSH preconditioning is effective to prevent mitochondrial death and improves complex II function during IR, but not mitochondrial membrane stability. GSH mediated amelioration of DeltaPsim hyper-polarization appears to be the key factor of mitochondrial protection. PMID- 21596580 TI - Results of mechanical circulatory support in France. AB - OBJECTIVE: To present the analyzed results on mechanical circulatory support (MCS) collected over a 7-year period, from 2000 to 2006, in France. METHODS: A cohort of 520 patients was analyzed. Mean age was 43.7 +/- 13.6 years. The main causes of cardiac failure were ischemic cardiomyopathy (39%), idiopathic dilated cardiomyopathy (41.3%), or myocarditis (6.4%). Bridge to transplantation was indicated in 87.8% of patients, bridge to recovery in 9%, while destination therapy was proposed in 3.2% of patients. RESULTS: For patients in cardiogenic shock or advanced heart failure undergoing device implantation as bridge to transplantation or recovery (n=458), overall mortality was 39% (n=179). The main causes of mortality under MCS were multi-organ failure (MOF) (57.4%), neurological events (14.1%), or infections (11.9%). Heart transplantation was performed in 249 (54.3%) patients. The main causes of death following heart transplantation were primary graft failure (22.4%), MOF (14.3%), neurological event (14.3%), or infection (10.2%). Long-term survival in transplanted patients was 75 +/- 2.8% at 1 year and 66 +/- 3.4% at 5 years. CONCLUSIONS: MCS is an essential therapeutic tool to save the life of young patients with cardiogenic shock or advanced cardiac failure. Early MCS implantation and the availability of a device that is adapted to the patient's clinical status are prerequisites for reducing overall mortality rates. PMID- 21596581 TI - Investigation of the interaction between chlorophenols and lysozyme in solution. AB - The binding interactions of lysozyme with 2-chlorophenol, 2,4-dichlorophenol, 2,4,6-trichlorophenol and pentachlorophenol were investigated by UV-vis absorption, CD, fluorescence, synchronous fluorescence, and three-dimensional fluorescence spectra techniques under physiological pH 7.40. The binding constants, quenching mechanism, and the number of binding sites were determined by the quenching of lysozyme fluorescence in presence of chlorophenols. H-bonds and hydrophobic interactions played major roles in stabilizing the chlorophenols lysozyme complex. The distances r between chlorophenols and lysozyme were calculated to be 1.94nm, 2.75nm, 3.54nm, and 3.76nm for 2-CP, 2,4-DCP, 2,4,6-TCP, and PCP, respectively. The effects of chlorophenols on the conformation of lysozyme were analyzed using CD, synchronous fluorescence and three-dimensional fluorescence spectra. PMID- 21596582 TI - Coexistent extra- and intracranial stenosis, cervical atherosclerosis, and abnormal ankle brachial index in acute ischemic stroke. AB - BACKGROUND: There are limited data regarding abnormal ankle brachial index (ABI) with coexistent extracranial carotid stenosis (ECS), intracranial stenosis (ICS), and nonstenotic cervical atherosclerosis (CAS) in stroke, especially in Asia. METHODS: We studied the prevalence of ECS, ICS, CAS, and combined ECS and ICS in 756 Thai patients with acute ischemic stroke and correlated sites of atherosclerosis with stroke risk factors and abnormal ABI. RESULTS: The prevalence of ECS was 8.8%, ICS 52.6%, CAS 36.0%, abnormal ABI 18.8%, combined ECS and ICS 4.6%, combined ECS and abnormal ABI 2.8%, combined ICS and abnormal ABI 10.6%, and combined ECS, ICS, and abnormal ABI 1.6%. The prevalence of ECS, CAS, and combined ECS and ICS was higher in abnormal ABI compared to normal ABI (14.8% v 7.5% [P = .006]; 46.5% v 33.5% [P = .004], and 8.4% v 3.7% [P = .016], respectively). ECS was significantly correlated with history of coronary artery disease (CAD) and abnormal ABI; ICS with male gender, no alcohol use, and no atrial fibrillation; CAS with age >= 60 years, history of CAD and abnormal ABI; and combined ECS and ICS with history of CAD. CONCLUSIONS: The frequency of atherosclerosis, especially ICS, was high. Cervicocerebral atherosclerosis was higher in abnormal ABI. This suggests that ischemic stroke patients should be screened for ECS, CAS, ICS, and abnormal ABI, especially in specific subsets (age >= 60 years, male gender, and history of CAD). The improved identification of vascular lesions could allow for a more optimal choice of antithrombotics, neurointervention, and more aggressive control of risk factors, potentially improving prevention of disease progression and a decrease in recurrent vascular events. PMID- 21596583 TI - Factors related to quality of life of stroke survivors. AB - BACKGROUND: Stroke survivors may be dependent and need additional attention. We aimed to determine factors that related to quality of life of stroke survivors. METHODS: A hospital-based analytical study was performed between January 1 and March 31, 2008 at Srinagarind Hospital in the Khon Kaen province of Thailand. Factors related to quality of life using the Thai 36-item Short Form (SF-36) rating scale were studied. RESULTS: There were 237 stroke survivors in the study. The age range of participants was between 20 and 91 years of age (mean = 63.7 +/- 12.8, median = 65.0). For physical health summary scale, factor related with better scale were male gender (P < .001; 95% confidence interval [CI] 6.3-21.9), aged under 50 (P < .001; 95% CI 6.3-21.9), educational level higher than bachelor degree (P < .001; 95% CI 8.1-22.3), and unemployed status (P < .001; 95% CI 6.4 19.8). For mental health summary scale, the education level (P < .001; 95% CI 7.3 20.1), employment status (P = .007; 95% CI 2.3-14.5), household income (P < .001), and disease severity (P < .001; 95% CI 15.5-27.7) had statistically significant difference. Overall, the age, level of education, employment status, monthly household income and the modified Rankin scale score related to the quality of life. CONCLUSIONS: The factors related to quality of life were age, educational level, occupation, monthly household income, and modified Rankin scale score. PMID- 21596584 TI - A modified method for constraint-induced movement therapy: a supervised self training protocol. AB - BACKGROUND: Constraint-induced movement therapy (CI therapy) is a rehabilitation treatment that is effective for improving upper extremity function in patients with stroke hemiparesis. In standard protocols, the burdens are great on the patient, therapist, and in terms of health care costs, preventing the wider application of CI therapy. To address this, we developed a protocol based on self training and examined its effects. METHODS: Patients with chronic hemiparesis caused by a stroke (intracerebral hemorrhage or cerebral infarct) 180 days after disease onset were included in this study. We performed before and after comparisons after intervention. We assessed motor impairment in the shoulder, elbow, forearm, wrist, and hand with the Fugl-Meyer Assessment (FMA) and determined training tasks, taking into consideration the patient's primary complaint. We established direct supervision by the therapist and self-training to occupy 40% and 60% of the training period, respectively. With this protocol, training was conducted 5 hours per day for 10 consecutive weekdays. We assessed upper extremity function using the FMA, Wolf Motor Function Test (WMFT), and Motricity Index (MI) before and after intervention. RESULTS: There were 40 subjects. Before and after intervention, scores for the FMA upper extremity items, WMFT functional ability scale, WMFT performance times, and MI showed significant improvements, from 49.35 +/- 10.1 (mean +/- SD) to 52.88 +/- 8.0 points, 3.48 +/- 0.65 to 3.72 +/- 0.67 points, 14.37 +/- 13.22 to 10.58 +/- 11.97 seconds, and 75.0 +/- 12.0 to 77.7 +/- 12.0 points, respectively. CONCLUSIONS: Our self-training-based CI therapy protocol is likely to be as effective for improving upper extremity function as the standard CI therapy. The method may contribute to the wider use of CI therapy. PMID- 21596585 TI - Recombinant activated factor VII increases stroke in cardiac surgery: a meta analysis. AB - OBJECTIVES: Recombinant activated factor VII (rFVIIa) is used in various surgical procedures to reduce the incidence of major blood loss and the need for re exploration. Few clinical trials have investigated rFVIIa in cardiac surgery. The authors performed a meta-analysis focusing on the rate of stroke and surgical re exploration. DESIGN: Meta-analysis. SETTING: Hospitals. PARTICIPANTS: A total of 470 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four investigators independently searched PubMed and conference proceedings including backward snowballing (ie, scanning of reference of retrieved articles and pertinent reviews) and contacted international experts. A total of 470 patients (254 receiving rFVIIa and 216 controls) from 6 clinical trials (2 randomized, 3 propensity matched, and 1 case matched) were included in the analysis. The use of rFVIIa was associated with an increased rate of stroke (12/254 [4.7%] in the rFVIIa group v 2/216 [0.9%] in the control arm, odds ratio [OR] = 3.69 [1.1 12.38], p = 0.03) with a nonsignificant reduction in rate of surgical re exploration (13% v 42% [OR = 0.27 (0.04-1.9), p = 0.19]). The authors observed a trend toward an increase of overall perioperative thromboembolic events (19/254 [7.5%] in the rFVIIa group v 10/216 [5.6%] in the control arm [OR = 1.84 (0.82 4.09), p = 0.14]). No difference in the rate of death was observed. CONCLUSIONS: The administration of rFVIIa in cardiac surgery patients could result in a significant increase of stroke with a trend toward a reduction of the need for surgical re-exploration. The authors do not recommend routine use in cardiac surgery patients. rFVIIa may be considered with caution in patients with refractory life-threatening bleeding. PMID- 21596586 TI - Persistent bias in expert judgments about free will and moral responsibility: a test of the expertise defense. AB - Many philosophers appeal to intuitions to support some philosophical views. However, there is reason to be concerned about this practice as scientific evidence has documented systematic bias in philosophically relevant intuitions as a function of seemingly irrelevant features (e.g., personality). One popular defense used to insulate philosophers from these concerns holds that philosophical expertise eliminates the influence of these extraneous factors. Here, we test this assumption. We present data suggesting that verifiable philosophical expertise in the free will debate-as measured by a reliable and validated test of expert knowledge-does not eliminate the influence of one important extraneous feature (i.e., the heritable personality trait extraversion) on judgments concerning freedom and moral responsibility. These results suggest that, in at least some important cases, the expertise defense fails. Implications for the practice of philosophy, experimental philosophy, and applied ethics are discussed. PMID- 21596587 TI - Arthroscopic suture bridge transosseus equivalent fixation of rotator cuff tendon preserves intratendinous blood flow at the time of initial fixation. AB - BACKGROUND: Current etiologic theories concerning healing rates in rotator cuff repair have focused on the blood supply in the tendinous portion of the cuff. We currently have little information regarding the effect of our repair techniques on this critical variable. We hypothesize that intratendinous blood flow is changed during transosseus equivalent tendon fixation. METHODS: Eighteen consecutive patients with rotator cuff tears amenable to double row fixation were included in the study. Each patient underwent a standard arthroscopic transosseous equivalent double row fixation procedure using the Arthrex SutureBridge technique (Arthrex, Naples, FL, USA). After tying down of the medial row, a first set of recordings was taken using a custom laser doppler flowmetry probe (Perimed, Inc., Ohio, USA). A second recording was made following securing of the lateral PushLock anchors. The data were compared to determine the overall effect on blood flow associated with this technique. RESULTS: Summated averages for the 2 groups show a significant (44.67%) decline in the blood flow present after the second row of implants are placed (P < .01). Individual calculations for regions of the cuff tear indicate significant differences in anterior third (P = .01), middle third (P < .01), and posterior third (P = .02) of the tear after transosseous equivalent fixation. CONCLUSION: Completion of the construct with lateral anchors in the transosseous equivalent technique results in reduced but preserved blood flow in the tendon repair site. Further study is required to determine the implications for tendon healing. CLINICAL RELEVANCE: Intratendinous blood flow is a variable that should be considered when evaluating repair methods in rotator cuff surgery. PMID- 21596588 TI - Timing of antibiotic prophylaxis in tourniquet surgery. AB - It is customary to administer prophylactic antibiotics before exsanguination of the limb and inflation of a tourniquet in extremity surgery. To compare the clinical outcome in lower limb operations when prophylactic antibiotics were administered before versus after limb exsanguination and tourniquet inflation, we randomized patients to the administration of prophylactic antibiotics 5 minutes before exsanguination and inflation of the tourniquet (ABT) and administration of prophylactic antibiotics 1 minute after inflation of the tourniquet (AAT). A total of 106 patients completed the study, including 76 males (71.7%) and 30 females (28.3%). Of the 106 patients, 54 (50.9%) received antibiotics before tourniquet inflation (ABT) and 52 (49.1%) after tourniquet inflation (AAT). Most of the operations (71.7%) involved open reduction and internal fixation of fractures. In the ABT group, 8 wounds (14.8%) developed postoperative infection. In the AAT group, 2 (3.9%) developed wound infection (P = .031). The mean period to wound healing in the ABT group was 4.0 +/- 2.3 weeks and was 3.0 +/- 0.5 weeks in the AAT group (P = .002). Overall, 100% of the patients in the AAT group were satisfied compared with 85.2% in the ABT group. The difference was statistically significant (P = .005). The results of our study suggest that administration of prophylactic antibiotics before exsanguination and inflation of a lower extremity tourniquet does not give better results than administration of the antibiotic shortly after inflation of the tourniquet. PMID- 21596589 TI - Lapidus arthrodesis with a single lag screw and a locking H-plate. AB - The aim of this pilot study was to assess if using an interfragmental lag screw and a Darco((r)) locking H-plate for the modified Lapidus arthrodesis in the treatment of hallux abducto valgus deformity (1) would allow for earlier weight bearing than previously described and (2) would indicate whether any changes would occur radiographically with the earlier weight bearing. Twenty-one metatarsocuneiform arthrodeses, in 18 patients, were retrospectively evaluated through chart review and postoperative radiographs. Original diagnoses included painful hallux abducto valgus and osteoarthritis of the first metatarsocuneiform joint. The mean age of the patients was 48 (range, 16 to 70) years. The mean follow-up duration was 38.5 (range, 29 to 60) months. The overall radiographic osseous union rate was 90.5% (19/21 feet), although there were 2 asymptomatic nonunions. There were no cases of fixation failure, and the surgical correction was preserved on follow-up radiographs. Overall, the mean time to full weight bearing was 4.7 (range, 3 to 7.5) weeks, and it was a mean of 8 (range, 7 to 10) weeks before the patient was back to wearing comfortable shoes. The authors concluded that metatarsocuneiform arthrodesis fixated with 1 interfragmentary lag screw and a Darco((r)) locking H-plate provides sufficient stability to allow earlier weight bearing than has been previously described with other internal fixation constructs. PMID- 21596590 TI - The radiographic fate of the syndesmosis after trans-syndesmotic screw removal in displaced ankle fractures. AB - The purpose of this study was to evaluate the radiographic changes of the tibiofibular position and the ankle mortise after removal of trans-syndesmotic fixation to determine if there is loss or maintenance of correction. In addition, the effect of the type of rotational injury, early weight bearing, and the number of trans-syndesmotic screws used on the integrity of the inferior tibiofibular articulation or ankle mortise after screw removal were evaluated. An analysis was conducted of 86 patients, with an unstable rotational ankle fracture requiring open reduction with syndesmosis screw stabilization. Routine radiographic parameters were measured just after open reduction and just before syndesmotic screw removal. There was a high correlation of loss of the integrity of the syndesmotic parameters after screw removal. However, the medial clear space of the ankle changed an insignificant amount, suggesting that although there appears to be some loss of maintenance, the talus did not shift laterally at the expense of a mobile syndesmosis. Ankle injuries requiring stabilization of syndesmotic instability with use of temporary trans-syndesmotic fixation achieve a stable ankle mortise after removal. Tibiofibular diastasis is commonplace upon removal of the syndesmotic hardware, but the ankle mortise remains unchanged. Based on the radiographic criteria described in this study, the postoperative change in medial clear space or tibiofibular diastasis has no bearing on fracture type, deltoid injury, or the use of 1 or 2 cortical screws. As such, other unknown mechanisms affecting the integrity of the syndesmosis after screw removal are in place. PMID- 21596591 TI - Intestinal bacterial colonization induces mutualistic regulatory T cell responses. AB - Mammals harbor a dense commensal microbiota in the colon. Regulatory T (Treg) cells are known to limit microbe-triggered intestinal inflammation and the CD4+ T cell compartment is shaped by the presence of particular microbes or bacterial compounds. It is, however, difficult to distinguish whether these effects reflect true mutualistic immune adaptation to intestinal colonization or rather idiosyncratic immune responses. To investigate truly mutualistic CD4+ T cell adaptation, we used the altered Schaedler flora (ASF). Intestinal colonization resulted in activation and de novo generation of colonic Treg cells. Failure to activate Treg cells resulted in the induction of T helper 17 (Th17) and Th1 cell responses, which was reversed by wild-type Treg cells. Efficient Treg cell induction was also required to maintain intestinal homeostasis upon dextran sulfate sodium-mediated damage in the colon. Thus, microbiota colonization induced Treg cell responses are a fundamental intrinsic mechanism to induce and maintain host-intestinal microbial T cell mutualism. PMID- 21596592 TI - Intravital imaging reveals limited antigen presentation and T cell effector function in mycobacterial granulomas. AB - Cell-mediated adaptive immunity is critical for host defense, but little is known about T cell behavior during delivery of effector function. Here we investigate relationships among antigen presentation, T cell motility, and local production of effector cytokines by CD4+ T cells within hepatic granulomas triggered by Bacille Calmette-Guerin or Mycobacterium tuberculosis. At steady-state, only small fractions of mycobacteria-specific T cells showed antigen-induced migration arrest within granulomas, resulting in low-level, polarized secretion of cytokines. However, exogenous antigen elicited rapid arrest and robust cytokine production by the vast majority of effector T cells. These findings suggest that limited antigen presentation and/or recognition within granulomas evoke a muted T cell response drawing on only a fraction of the host's potential effector capacity. Our results provide new insights into the regulation of host-protective functions, especially how antigen availability influences T cell dynamics and, in turn, effector T cell function during chronic infection. PMID- 21596593 TI - Quantification of regional interstitial lung disease from CT-derived fractional tissue volume: a lung tissue research consortium study. AB - RATIONALE AND OBJECTIVES: Evaluation of chest computed tomography (CT) is usually qualitative or semiquantitative, resulting in subjective descriptions often by different observers over time and imprecise determinations of disease severity within distorted lobes. There is a need for standardized imaging biomarkers to quantify regional disease, maximize diagnostic yield, and facilitate multicenter comparisons. We applied lobe-based voxelwise image analysis to derive regional air (Vair) and tissue (Vtissue) volumes and fractional tissue volume (FTV = tissue/[tissue+air] volume) as internally standardized parameter for assessing interstitial lung disease (ILD). MATERIALS AND METHODS: High-resolution CT was obtained at supine and prone end-inspiration and supine end-expiration in 29 patients with ILD and 20 normal subjects. Lobar Vair, Vtissue, and FTV were expressed along standard coordinate axes. RESULTS: In normal subjects from end inspiration to end-expiration, total Vair declined ~43%, FTV increased ~80%, but Vtissue remained unchanged. With increasing ILD, Vair declined and Vtissue rose in all lobes; FTV increased with a peripheral-to-central progression inversely correlated to spirometry and lung diffusing capacity (r(2) = 0.57-0.75, prone end inspiration). Inter- and intralobar coefficients of variation of FTV increased 84 148% in mild-to-moderate ILD, indicating greater spatial heterogeneity, then normalized in severe ILD. Analysis of discontinuous images incurs <3% error compared to consecutive images. CONCLUSIONS: These regional attenuation-based biomarkers could quantify heterogeneous parenchymal disease in distorted lobes, detect mild ILD involvement in all lobes and describe the pattern of disease progression. The next step would be to study a larger series, examine reproducibility and follow longitudinal changes in correlation with clinical and functional indices. PMID- 21596594 TI - Part Three: Open repair is the best option for type IV thoracoabdominal aortic aneurysms. PMID- 21596595 TI - Multilocular radiolucency of the mandibular condyle in a 19-year-old woman. PMID- 21596596 TI - Acute insomnia: current conceptualizations and future directions. AB - Despite significant contributions made in the area of persistent/chronic insomnia, especially with regard to the underlying mechanisms driving its maintenance, the area of acute insomnia has received comparatively little attention. The aim of this paper is to review the literature with regard to understanding the situational and personaological circumstances that surround the development of acute insomnia. The review begins by examining how the existing diagnostic systems conceptualise acute insomnia. Theoretical models that explain, or inferentially explain, the transition between normal sleep and acute insomnia are then explored and evaluated. The review then examines the current evidence base in terms of the pathogenesis of acute insomnia from naturalistic and experimental studies. Overall, the findings from the review confirm the paucity of evidence available but perhaps more importantly highlight the need for a structured diagnosis of acute insomnia as the first step in a research and treatment strategy. To this end a diagnostic system, drawing on the existing literature on stress and the systems used to diagnose depression, is forwarded and justified and a research agenda advanced. PMID- 21596597 TI - Serum antibody responses in horses and mice following immunization with Actinobacillus equuli outer membrane proteins and recombinant Aqx toxin. AB - The immune responsiveness of mice (without prior natural exposure) and mares (with naturally acquired antibodies) was determined following vaccination with Actinobacillus equuli outer membrane proteins (OMPs) and/or recombinant A. equuli toxin (rAqx). Mice were vaccinated subcutaneously on days 0 and 21 with one of three doses (5, 25 or 50MUg) of A. equuli OMPs, rAqx or both, together with Freund's incomplete adjuvant (FIA). Antibodies against formalin-killed whole bacterial cells (WBCs), OMPs and Aqx were determined on days 0, 21 and 42. Mares were vaccinated subcutaneously on days 0 and 21 with 100MUg OMPs, 100MUg rAqx or a combination of 50MUg of each antigen, together with FIA. Antibodies against WBCs, OMPs and Aqx were determined at 7day intervals for the first 42days, as well as on days 56, 70, 154 and 238. Vaccination of mice stimulated an apparent dose response to OMPs and Aqx. Antibodies against OMPs and Aqx were enhanced following vaccination of mares that had naturally acquired pre-existing antibodies. There was no evidence of interference with antibody responses to the individual antigens when OMPs and rAqx were combined prior to vaccination. PMID- 21596598 TI - Humoral and cellular immune responses in dogs with inapparent natural Leishmania infantum infection. AB - Molecular analysis, serology and immunophenotyping for T lymphocytes and their subsets, B lymphocytes and monocytes were performed on dogs naturally infected with Leishmania infantum. Animals were categorised as asymptomatic dogs I (AD-I), with negative serology and positive molecular results, and asymptomatic dogs II (AD-II), with positive serology and positive molecular results, and these were compared to symptomatic dogs (SD) and control dogs (CD). AD-I exhibited immunophenotypic features similar to those of CD, including isotype profiles and concentrations of monocytes. Similar biomarkers were found in AD-II and SD, such as, higher levels of immunoglobulins IgG, IgG2, IgM and IgA and higher concentrations of eosinophils. High frequencies of T lymphocytes and CD4(+) T cells were observed in both AD-I and AD-II compared to SD, whereas CD8(+) T cells were higher only in AD-II compared with SD. Analysis of B lymphocytes revealed an increased frequency of this cell type only in AD-II animals compared with SD. Asymptomatic dogs appear to have a dichotomous infection spectrum that can influence the humoral and cellular immunological status during canine visceral leishmaniasis. PMID- 21596599 TI - Antinociceptive effect of paeoniflorin via spinal alpha2-adrenoceptor activation in diabetic mice. AB - BACKGROUND: Shakuyakukanzoto (SKT) has been shown to modulate nociception in streptozotocin-induced diabetic mice via selective activation of the descending noradrenergic systems. However, the active components of SKT that exert the analgesic effect remain unknown. Here, we administered Glycyrrhizae radix (G. radix), Paeoniae radix (P. radix), and the two active constituents of P. radix, paeoniflorin and albiflorin, to determine the components that stimulate spinal alpha2-adrenoceptors by promoting noradrenaline release. METHODS: The two SKT components were separately administered to diabetic and non-diabetic mice. A tail pressure test was used to determine the nociceptive threshold between 0 and 3h after oral dosing. The time-course profiles of the nociceptive threshold (g) and the area under the time response curve (AUC) were evaluated. Yohimbine, an alpha2 adrenoceptor antagonist, was intrathecally injected 15 min after paeoniflorin administration. RESULTS: P. radix and G. radix did not induce significant antinociception in non-diabetic mice. However, P. radix (250, 500 mg/kg) dose dependently and significantly increased the nociceptive threshold in diabetic mice between 0.5 and 2 h after administration, whereas all the tested doses of G. radix did not increase the nociceptive threshold. Both paeoniflorin (30 mg/kg) and albiflorin (10 mg/kg) significantly elevated the nociceptive threshold between 0.5 and 3h and between 0.5 and 1h after administration, respectively. The antinociceptive effect of paeoniflorin (30 mg/kg) was completely abolished by yohimbine. CONCLUSION: Our findings suggest that paeoniflorin is the key antinociceptive component in SKT that increases noradrenaline release and activates alpha2-adrenoceptors to modulate spinal nociceptive transmission in diabetic neuropathy. PMID- 21596600 TI - Reporting outcomes of back pain trials: a modified Delphi study. AB - BACKGROUND: Low back pain is a common and expensive health complaint. Many low back pain trials have been conducted, but these are reported in a variety of ways and are often difficult to interpret. AIM: To facilitate consensus on a statement recommending reporting methods for future low back pain trials. METHODS: We presented experts with clinicians' views on different reporting methods and asked them to rate and comment on the suitability reporting methods for inclusion in a standardized set. Panellists developed a statement of recommendation over three online rounds. We used a modified Delphi process and the RAND/UCLA appropriateness method as a formal framework for establishing appropriateness and quantifying panel disagreement. RESULTS: A group of 63 experts from 14 countries participated. Consensus was reached on a statement recommending that the continuous patient-reported outcomes commonly used in back pain trials, are reported using between-group mean differences (accompanied by minimally important difference (between-group/population-level) thresholds where these exist), the proportion of participants improving and deteriorating according to established and relevant minimally important change thresholds, and the number needed to treat; all with 95% confidence intervals. Outcomes may additionally be reported using alternative approaches (e.g. relative risks, odds ratios, or standardized mean difference) according to the needs of a particular trial. CONCLUSIONS: A group of back pain experts reached a high level of consensus on a statement recommending reporting methods for patient-reported outcomes in future low back pain trials. The statement has the potential to increase interpretability and improve patient care. PMID- 21596601 TI - Multi-band frequency encoding method for metabolic imaging with hyperpolarized [1 (13)C]pyruvate. AB - A new method was developed for simultaneous spatial localization and spectral separation of multiple compounds based on a single echo, by designing the acquisition to place individual compounds in separate frequency encoding bands. This method was specially designed for rapid and robust metabolic imaging of hyperpolarized (13)C substrates and their metabolic products, and was investigated in phantom studies and studies in normal mice and transgenic models of prostate cancer to provide rapid metabolic imaging of hyperpolarized [1 (13)C]pyruvate and its metabolic products [1-(13)C]lactate and [1-(13)C]alanine at spatial resolutions up to 3mm in-plane. Elevated pyruvate and lactate signals in the vicinity of prostatic tissues were observed in transgenic tumor mice. The multi-band frequency encoding technique enabled rapid metabolic imaging of hyperpolarized (13)C compounds with important advantages over prior approaches, including less complicated acquisition and reconstruction methods. PMID- 21596602 TI - Heterozygous mutation in the X chromosomal NDUFA1 gene in a girl with complex I deficiency. AB - Respiratory chain enzymes consist of multiple subunits encoded either by the mitochondrial or by the nuclear genome. Recently the first X-chromosomal mutations in complex I deficient males have been described. Heterozygous female carriers did not seem to be affected. Here, we describe a girl initially presenting with mild muscular hypotonia, a moderate lactic acidosis and an increased beta-hydroxybutyrate/acetoacetate ratio. Biochemical investigations of a muscle biopsy revealed a deficiency in the amount and activity of complex I. Mutation screening of all structural subunits of complex I identified a heterozygous mutation c.94G>C, p.Gly32Arg in the X-chromosomal NDUFA1 gene. Analysis of the cDNA showed that 72% of the expressed mRNA was mutated in the muscle biopsy sample. Investigation of the X-inactivation pattern demonstrated that 74% of the paternally inherited allele was active in the muscle. This is the first report of an X-chromosomally inherited respiratory chain defect in a heterozygous female. PMID- 21596604 TI - Use of alternative or adjuvant pharmacologic treatment strategies in the prevention and treatment of Clostridium difficile infection. AB - Infection with Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients, and recent surveillance data indicate that C. difficile has surpassed methicillin-resistant Staphylococcus aureus as the number one cause of hospital-acquired infections in some areas of the USA. In addition, concern over C. difficile has increased over the past decade due to the appearance of new hypervirulent strains. Metronidazole and vancomycin have remained the treatments of choice for initial therapy of primary infection with C. difficile for the past 25 years, but the persistence of spores leads to a recurrence of infection in an estimated 20-25% of patients. Patients who have one recurrent episode have up to a 65% chance of having additional recurrence. While the judicious use of antimicrobials in accordance with antibiotic stewardship guidelines remains the most effective method for the control of C. difficile, the high recurrence rate, increasing incidence, and changing epidemiology of C. difficile has led to an increased interest in the study of alternative strategies for the prevention and treatment of C. difficile disease. These alternative strategies attempt to eliminate C. difficile spores, replenish the normal gut flora, reduce the C. difficile toxin load in the bowel, or bolster the patient's own immune response to the C. difficile toxins. To evaluate the available evidence on these alternative strategies, we conducted a literature search of MEDLINE (1966-March 2011) and International Pharmaceutical Abstracts (1970-March 2011). Available citations from these articles were also utilized. The aim of this review is to summarize the available evidence for alternative treatment strategies for C. difficile disease and to make recommendations for their place in therapy. PMID- 21596605 TI - Poor self-rated health is not associated with a high total allostatic load in type 2 diabetic patients--but high blood pressure is. AB - OBJECTIVE: Allostatic load has been linked to self-rated health (SRH), cardiovascular disease and mortality in non-diabetic individuals. The aim of this study was to construct an allostatic load score and to find any correlations with SRH. METHODS: The subjects included in the study came from a randomized, controlled trial of type 2 diabetes. Blood samples were drawn, urine was collected for 24h, and questionnaires, including SRH, were filled out on three occasions: at baseline; after the 10-week intervention; and at a follow-up 3 months after the intervention. Allostatic load was estimated using a wide range of variables, including systolic and diastolic blood pressure, pulse pressure, cortisol, catecholamines, HbA(1c), insulin, plasma glucose and waist circumference. RESULTS: There was no association between SRH and allostatic load. However, three other components were significantly correlated with allostatic load at the baseline investigation and the two follow-up investigations - namely, systolic blood pressure, diastolic blood pressure and HbA(1c). CONCLUSION: The absence of an association between allostatic load and SRH in diabetic individuals contrasts with previous findings in non-diabetic women, and shows that it is hazardous to apply findings in one population to another, especially diabetic and non-diabetic populations. PMID- 21596603 TI - A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development. AB - Epigenetic regulation of gene expression by histone-modifying corepressor complexes is central to normal animal development. The NAD(+)-dependent deacetylase and gene repressor SIRT1 removes histone H4K16 acetylation marks and facilitates heterochromatin formation. However, the mechanistic contribution of SIRT1 to epigenetic regulation at euchromatic loci and whether it acts in concert with other chromatin-modifying activities to control developmental gene expression programs remain unclear. We describe here a SIRT1 corepressor complex containing the histone H3K4 demethylase LSD1/KDM1A and several other LSD1 associated proteins. SIRT1 and LSD1 interact directly and play conserved and concerted roles in H4K16 deacetylation and H3K4 demethylation to repress genes regulated by the Notch signaling pathway. Mutations in Drosophila SIRT1 and LSD1 orthologs result in similar developmental phenotypes and genetically interact with the Notch pathway in Drosophila. These findings offer new insights into conserved mechanisms of epigenetic gene repression and regulation of development by SIRT1 in metazoans. PMID- 21596606 TI - [Pharmacological modulation of late radio-induced side effects]. AB - After normal tissue exposure to radiation therapy, late side effects can occur and may reduce patients' quality of life due to their progressive nature. Late toxicities occurrence is the main limiting factor of radiotherapy. Various biological disorders related to irradiation are involved in the development of late toxicities including fibrosis. The present review will focus on the recent physiopathological and molecular mechanisms described to be involved in the development of late radio-induced toxicities, that provide therapeutic perspective for pharmacomodulation. PMID- 21596607 TI - [Amniopatch to treat iatrogenic rupture of the fetal membranes]. AB - OBJECTIVE: With the increased use of invasive fetal procedures, the number of patients facing postprocedure membrane rupture is increasing. We aimed to describe the use of platelets and fresh frozen plasma for sealing iatrogenic fetal membrane defects. PATIENTS AND METHODS: We describe the mechanisms of action of the amniopatch procedure as well as published experience. RESULTS: Amniopatch effectively sealed the fetal membranes in over two thirds of published cases (n=44). There is a risk of 17% of in utero fetal death, which may occur remotely from the procedure and is often unexplained. DISCUSSION AND CONCLUSION: In case of early onset but persistent amniotic fluid leakage following an invasive fetal procedure, amniopatch may be offered. PMID- 21596609 TI - [Systematic section of uterine septum before any pregnancy: pros]. PMID- 21596608 TI - [Computed tomography-based virtual colonoscopy: an examination useful for the choice of the surgical management of colorectal endometriosis]. AB - OBJECTIVE: To evaluate the use of computed tomography-based virtual colonoscopy in the preoperative assessment of colorectal endometriosis. PATIENTS AND METHODS: We included in the study consecutive women undergoing surgical management of deep infiltrating endometriosis from August 2009 to April 2010, whose colorectal involvement had been assessed by magnetic resonance imaging (MRI) and rectal endoscopic sonography (RES). Prior to surgical procedure, a computed tomography based virtual coloscopy was performed. Computed tomography was performed by insufflating air into the distal rectum, along with an intravenous injection of contrast agent. Then, 3D reconstruction of pictures was carried out, to allow visualization of the lumen of the rectum and the colon. Data provided by virtual colonoscopy were compared to those given by other imaging techniques and surgical exploration. RESULTS: Twenty-seven patients were included in the study: 7 women underwent colorectal segmental resection, 2 full thickness excision, 15 shaving, while in 3 of them no digestive surgical step was performed. Virtual colonoscopy provided the measurement of the length and the diameter of colorectal stenosis due to infiltrating nodule through rectal and sigmoid wall, which was presenting as an endoluminal indentation. The number of patients presenting with endometriotic nodules arising on the rectum, sigmoid colon, or both of them, were respectively 13, 7 and 7. Ovarian endometriomas were responsible for extrinsic compression leading to digestive tract stenosis in nine cases. The number of lesions and their height reported to the anus were accurately assessed in 24 women out of 27 (sensitivity of 88%). The origin of the digestive tract stenosis, i.e. either infiltrating endometriotic nodules or extrinsic compression due to ovarian endometriomas, was accurately assessed in all cases, by combining information provided by virtual colonoscopy, IRM, RES and transvaginal ultrasonography. CONCLUSION: Computed tomography-based virtual colonoscopy provides useful information about the degree and the height of digestive tract stenosis due to colorectal endometriosis. In our opinion, this information is of major interest to argue the choice of shaving or full thickness excision of nodules in a majority of women presenting with colorectal endometriosis. PMID- 21596611 TI - Methylation analysis of circadian clock gene promoters in forensic autopsy specimens. AB - DNA methylation in gene promoter regions influences gene expression. Circadian clock genes play an important role in the formation of a biological clock and aberrant methylation of these genes contributes to several disorders. In this study, we examined forensic autopsy specimens to determine whether DNA methylation status in the promoter regions of nine circadian clock genes (Per1, Per2, Per3, Cry1, Cry2, Bmal1, Clock, Tim, and Ck1e) is related to a change in acquired diathesis and/or causes of death. Methylation-specific PCR and direct sequencing methods revealed that the promoters of Per1, Cry2, Bmal1, Clock, and Ck1e were unmethylated in all the forensic autopsy specimens, while the promoters of Per2, Per3, Cry1, and Tim were partially methylated. Methylation status varied between individuals and between tissues in the same patient. A detailed analysis of methylation patterns in the Cry1 promoter region revealed that the patterns also varied between individuals and the Cry1 promoter had highly methylated patterns in two cases that had been exposed to methamphetamine. These results suggest that the methylation status of clock gene promoters varies between individuals. Methamphetamine use may influence methylation in the Cry1 gene promoter region and disturb circadian rhythmicity. PMID- 21596610 TI - [Implications of retinoid pathway in human fetal membranes: study of target genes]. AB - Retinoids (active derivatives of vitamin A) were already demonstrated to be important morphogenes and their implication at the placental and fetal level was already established. A new field of research is now developed in order to show their role on fetal membranes constituted by amnion and chorion. To describe the role of retinoids on these membranes, our studies were focused on target gene research. Firstly, all metabolism enzymes needed to vitamin A pathways were demonstrated to be present and active in signal transduction. Secondly, a bioinformatic analysis was performed to assess a list of potential target genes that could be classified in different biological pathways (inflammation, retinoids, hormones, vascularization, extracellular matrix and water homeostasis). Then, it was demonstrated that the gene coding for PLAT, implied in the degradation of extracellular matrix during programmed or premature rupture of membranes, is regulated by retinoids in a two steps mechanism. Finally, preliminary data showed that some aquaporins, which control water transport across membranes, are expressed and regulated by retinoids in the fetal membranes. A disregulation in pathologies like oligo or poly-hydramnios can be anticipated. Improvement of our knowledge about the retinoid implications is a key point in order to obtain a precise and complete documented cartography of the vitamin A (regulating) in amniotic membranes (regulated) that will permit the development of new diagnostic and therapeutic strategies. PMID- 21596612 TI - Studies on intermolecular interaction on binary mixtures of methyl orange-water system: excess molar functions of ultrasonic parameters at different concentrations and at different temperatures. AB - Density (rho), viscosity (eta) and ultrasonic velocity (u) of binary mixtures of methyl orange and water were measured at different concentrations and at different temperatures; several useful parameters such as excess volume, excess velocity, and excess adiabatic compressibility have been calculated. These parameters are used to explain the nature of intermolecular interactions taking place in the binary mixture. The above study is helpful in understanding the dye/solvent interaction at different concentration and temperatures. PMID- 21596613 TI - Relationships between neighborhood walkability and adults' physical activity: How important is residential self-selection? AB - The study's aims were to examine whether residential self-selection differed according to socio-demographic characteristics and objectively assessed neighborhood walkability; and, whether objectively assessed walkability was a significant correlate of physical activity (PA) beyond residential self selection. In total, 412 adults (aged 20-65 years) completed a socio-demographic questionnaire, the long IPAQ, a neighborhood selection questionnaire and wore an accelerometer for seven days. Walkability characteristics were an important reason for selecting the current neighborhood and were more important for women, older and less-educated adults, but not for high-walkable neighborhood residents. Both in the total sample and in participants with high residential self-selection scores, walkability was positively related to active transportation and objectively measured moderate-to-vigorous PA. Designing walkable neighborhoods may help to increase adults' PA, even in those for whom walkability is an important criterion when choosing their neighborhood. However, findings from studies with longitudinal and controlled designs are required to provide more strongly causal evidence. PMID- 21596614 TI - Addressing the problem of rural community engagement in healthcare service design. AB - Policy suggests that health service providers should plan services with communities. In remote and rural areas this is sometimes ineffective, resulting in resistance to change. An action research project investigated best practise in rural community engagement. As a result a planning 'game' was developed that uses a number of types and levels of cards and allows community members, as part of a process of engagement, to express their priorities and designs in a form that is directly usable by health service managers. The game is a unique community engagement resource in that it combines the priorities of the community (including their experiences of using services) with existing service data. It allows community members and service managers to apply their priorities for services to a healthcare budget to identify appropriate and affordable ways of providing safe local services. PMID- 21596615 TI - Crosstalk between cartilage and bone: when bone cytokines matter. AB - The cartilage damage which characterizes osteoarthritis is often accompanied by bone lesions. Joint integrity results from the balance in the physiological interactions between bone and cartilage. Several local factors regulate the physiological remodeling of cartilage, the disequilibrium of these leading to a higher cartilage catabolism. Several cytokines secreted by bone cells can induce chondrocyte differentiation, which suggests their role in the dialogue between both cells. Accumulative in vivo evidence shows that increased bone resorption occurs at an early stage in the development of osteoarthritis and that blocking bone-resorbing cytokines prevents cartilage damage, confirming the role of bone factors in the crosstalk of both tissues. Recently, molecules of the Wnt pathway have emerged as key regulators of bone and cartilage. Activation of Wnt/betacatenin induces an imbalance in cartilage homeostasis, and agonists/antagonists of Wnt are potential candidates for this interaction. This review will summarize what is known about the contribution of bone cytokines to the physiological remodeling of cartilage and in the pathophysiology of osteoarthritis. PMID- 21596616 TI - Induction chemotherapy with docetaxel and cisplatin is highly effective for locally advanced nasopharyngeal carcinoma. AB - Radiotherapy (RT) with concomitant chemotherapy (CT) has improved the therapeutic outcome of patients with locally advanced nasopharyngeal carcinoma (LANC). However, the importance of induction CT before definitive therapy is still undefined. Patients (n=59) who had LANC were included in this retrospective study. They received induction CT consisting of cisplatin and docetaxel followed by definitive RT with cisplatin. The median age was 49 years (18-68). All patients were of stages II (15%), III (63%) and IV (22%). Fifty eight patients could receive 3 cycles of CT. Except one patient, there was no grade 3 or 4 toxicity during induction CT. Chemoradiotherapy could be given to 49 patients (83%). Twelve percent of patients had complete response after induction CT and this number had increased to 95% after the completion of the therapy. Objective responses (complete and partial) were 100% after the completion of the therapy. Median follow up time was 29 months. Nine patients had relapse (2 had local only, 4 distant, 3 local and distant). Three patients who had both local and distant relapse died during follow-up. Three year overall and progression free survival rates were 94.9% and 84.7%, respectively. Induction CT with docetaxel and cisplatin is a feasible and tolerable treatment for patients with LANC. PMID- 21596617 TI - Recent advances in the understanding of archaeal transcription. AB - RNA polymerases (RNAPs) make repeatedly use of their templates by cycling through initiation, elongation and termination phases of transcription; during each step RNAP is interacting with and regulated by distinct transcription factors. The dynamic interplay between nucleic acid sequences, transcription factors and RNAP affects the activity and distribution of transcription complexes across the genome, and ultimately executes the genetic programme of the organism. This review covers recent discoveries about the mechanisms of archaeal transcription obtained by a combination of in vivo and in vitro approaches, from the molecular to the global level. PMID- 21596618 TI - Enhancive effects of D-glucose and its analogs on expression of d-glucose unrelated transgenes in mammalian cells. AB - We studied the effects of d-glucose on transgene expression in mammalian cells by a reporter gene assay using CV-1 cells and a CMV promoter-controlled EGFP gene. Treatment of CV-1 cells with 5% D-glucose unchanged the number of fluorescent cells in fluorescence microscopic observation but significantly intensified fluorescence in the fluorometric assay. Furthermore, EGFP itself and mRNA became more abundant in Western blot and quantitative RT-PCR analyses of 5% D-glucose treated cells, respectively. These results indicate that elevated D-glucose can activate transgene expression via transcriptional stimulation, at least in part. The same concentrations of L-glucose led to only negligible increases in transgene expression, indicating that D-glucose's effect is different from its osmotic effect. The D-glucose-induced augmentation of fluorescence was observed not only in the experiment using the CMV promoter-controlled EGFP gene but also in experiments using the SV40 and RSV promoter-controlled ones, suggesting that elevated D-glucose can enhance transgene expression regulated by various promoters commonly used in transgene expression. The assessment of D-glucose analogs for their enhancive effects on transgene expression revealed that 1,6 anhydro-D-glucose and beta-methyl-D-glucoside had stronger effects than D glucose. From this result, we can expect to find more effective carbohydrates to enhance transgene expression. The alpha- and beta-M-D-glucosides, which are slightly different from each other in three-dimensional structure, exerted largely distinct stimulative effects on transgene expression, suggesting that fundamental rules determine the enhancive effects of saccharides and that the modification of the saccharide by applying such rules will enable us to develop more powerful substances for transgene expression. PMID- 21596619 TI - Identification of Gallibacterium species by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry evaluated by multilocus sequence analysis. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) whole-cell fingerprinting was used for characterization of 66 reference strains of Gallibacterium. The 4 recognised Gallibacterium species and Gallibacterium genomospecies 1 yielded reproducible and unique mass spectrum profiles, which were confirmed with Bruker Biotyper reference database version 3. The reproducibility of MALDI-TOF MS results were evaluated varying the age and storage of the cultures investigated. Reliable species identification was possible for up to 8 days of storage at 4 degrees C and less reliable if the bacteria were stored at room temperature (20 degrees C). However, if the strains were grown longer than 48h at 37 degrees C under microaerobic atmosphere, poor identification results were obtained, due to changes in protein profile. The MALDI-TOF MS results of all 66 strains demonstrated 87.9% concordance with results based upon biochemical/physiological characterization. In addition, diversities outlined by MALDI-TOF MS were verified by sequencing the rpoB (n=43), 16S rRNA (n=28), infB (n=14), and recN (n=14) genes (multilocus sequence analysis, MLSA). In addition, discrepancies were observed between some of the genes sequenced. Results obtained demonstrated that MALDI-TOF MS fingerprinting represents a fast and reliable method for identification and differentiation of the 4 recognised Gallibacterium species and possible a fifth species Gallibacterium genomospecies 1, with applications in clinical diagnostics. PMID- 21596620 TI - ...and a two-edged sword in their hands. PMID- 21596621 TI - Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. AB - BACKGROUND: The TME trial investigated the value of preoperative short-term radiotherapy in combination with total mesorectal excision (TME). Long-term results are reported after a median follow-up of 12 years. METHODS: Between Jan 12, 1996, and Dec 31, 1999, 1861 patients with resectable rectal cancer without evidence of distant disease were randomly assigned to TME preceded by 5 * 5 Gy radiotherapy or TME alone (ratio 1:1). Randomisation was based on permuted blocks of six with stratification according to centre and expected type of surgery. The primary endpoint was local recurrence, analysed for all eligible patients who underwent a macroscopically complete local resection. FINDINGS: 10-year cumulative incidence of local recurrence was 5% in the group assigned to radiotherapy and surgery and 11% in the surgery-alone group (p<0.0001). The effect of radiotherapy became stronger as the distance from the anal verge increased. However, when patients with a positive circumferential resection margin were excluded, the relation between distance from the anal verge and the effect of radiotherapy disappeared. Patients assigned to radiotherapy had a lower overall recurrence and when operated with a negative circumferential resection margin, cancer-specific survival was higher. Overall survival did not differ between groups. For patients with TNM stage III cancer with a negative circumferential resection margin, 10-year survival was 50% in the preoperative radiotherapy group versus 40% in the surgery-alone group (p=0.032). INTERPRETATION: For all eligible patients, preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone without an overall survival benefit. For patients with a negative resection margin, the effect of radiotherapy was irrespective of the distance from the anal verge and led to an improved cancer-specific survival, which was nullified by an increase in other causes of death, resulting in an equal overall survival. Nevertheless, preoperative short-term radiotherapy significantly improved 10-year survival in patients with a negative circumferential margin and TNM stage III. Future staging techniques should offer possibilities to select patient groups for which the balance between benefits and side-effects will result in sufficiently large gains. FUNDING: The Dutch Cancer Society, the Dutch National Health Council, and the Swedish Cancer Society. PMID- 21596622 TI - Urban parasitology: visceral leishmaniasis in Brazil. AB - Since the early 1980s, visceral leishmaniasis (VL) which is, in general, a rural zoonotic disease, has spread to the urban centers of the north, and now the south and west of Brazil. The principal drivers differ between cities, though human migration, large urban canid populations (animal reservoir), and a decidedly peripatetic and adaptable sand fly vector are the primary forces. The exact number of urban cases remains unclear as a result of challenges with surveillance. However, the number of urban cases registered continues to increase annually. Most control initiatives (e.g. culling infected dogs and household spraying to kill the sand fly) could be effective, but have proven hard to maintain at large scales due to logistical, financial and other reasons. In this article, the urbanization of VL in Brazil is reviewed, touching on these and other topics related to controlling VL within and outside Brazil. PMID- 21596623 TI - Surgical technique for antegrade dissection of the preputial vascular pedicle during hypospadias repair. AB - OBJECTIVE: Both layers of the prepuce can be used as vascularized flaps in hypospadias repair. The aim of this communication is to describe an antegrade approach to the harvesting of the vascular pedicle. SURGICAL TECHNIQUE: The vascular pedicle is isolated at the level of the penopubic junction where it is most robust. Dissection then proceeds distally towards the prepuce fanning laterally. RESULTS: Of 306 boys presenting for hypospadias repair in 2002-2008, this approach was utilized in 235 (77%). The vascularized flap was used as 1) a classic single or double faced onlay flap in 95, 2) a vascularized layer to cover a tubularized incised plate urethroplasty in 68, 3) a tube-onlay in 39, 4) a tubularized urethroplasty in 23, 5) for ventral skin coverage alone in 7, and 6) for a planned first stage repair in 3. Age at repair averaged 12 months (range 2 160) and follow up 36 months (range 2-68). CONCLUSIONS: Antegrade dissection of the vascular pedicle is a simple, expeditious and reliable way of isolating the prepuce on its blood supply. The versatility of the resulting flaps allows the repair to be adapted to the individual anatomic conditions as opposed to one type of repair being used for all variants. PMID- 21596624 TI - Geriatric epilepsy: research and clinical directions for the future. AB - There is a growing awareness of the need for improved treatment and care of older adults with epilepsy. The present review article highlights key clinical and research issues in the emerging field of geriatric epilepsy. Drs. Martin and Schmidt explore the scope of the problems in the field, outline topic areas including cognitive health/dementia, and diagnostic challenges, and also present important research questions that should be considered for the future. As part of this presentation, we will highlight the work of two promising young investigators whose work holds great promise for the field of geriatric epilepsy. Dr. Roberson will discuss his work focusing on the relationship of epilepsy and cognitive impairment, particularly as it relates to Alzheimer's disease pathology including tau and its role in epileptiform activity. Dr. Hope will outline key issues, as well as her work, relating to defining and measuring quality care in geriatric epilepsy. PMID- 21596625 TI - Pain in HIV: an evolving epidemic. PMID- 21596626 TI - Antipsychotic use and the risk of diabetes in nursing home residents with dementia. AB - BACKGROUND: Growing evidence suggests an association between antipsychotic use and diabetes onset in schizophrenia, but little is known about this association among patients with dementia. OBJECTIVE: The aim of this study was to quantify the association between antipsychotic use and the risk of diabetes onset among nursing home residents with dementia. METHODS: We conducted a nested case-control study in 29,203 long-stay Medicaid-eligible residents living in nursing homes in California, Florida, Illinois, New York, and Ohio between January 2001 and December 2002 who were at least 65 years old with a dementia diagnosis and no record of diabetes within 90 days of nursing home admission. We identified 762 incident cases of diabetes and randomly selected up to 5 controls, matched on nursing home and quarter of minimum data set (MDS) assessment (N = 2646). Cases of incident diabetes were identified from MDS assessments and Medicaid claims, medication use was ascertained from Medicaid pharmacy files, and resident characteristics were obtained from MDS assessments. RESULTS: Relative to non users of antipsychotics, use of atypical antipsychotics was not associated with diabetes onset (adjusted odds ratio [AOR] = 1.03; 95% CI, 0.84-1.27) and risk of diabetes did not increase with length of time on treatment. Conventional antipsychotic treatment was associated with diabetes onset, particularly when treatment duration was <30 days (AOR = 2.70; 95% CI, 1.57-4.65). CONCLUSIONS: Among nursing home residents with dementia, conventional antipsychotic therapy, particularly short-term therapy, increased their risk of developing diabetes. Atypical antipsychotic use was not associated with an increased risk of diabetes onset. PMID- 21596627 TI - Gastric band erosion presenting as fibrinous exudative idiopathic pleuritis. PMID- 21596628 TI - Early-life environment, height and BMI of young men in Italy. AB - This paper explores the relationship between the two main dimensions of early life environment, namely disease burden (measured by infant mortality) and economic conditions (measured by income or consumption per capita), and height and body-mass index (BMI) for six annual cohorts of young Italian men born between 1973 and 1978. By combining micro-level data on height and weight with regional- and province-level information, we are able to link individual height and BMI at age 18 to regional and provincial averages of environmental variables in the year of birth. Our results are consistent with the hypothesis that, in rich low-mortality settings, the negative effects of childhood disease dominate the positive selection effects of mortality. We find that both income and disease matter, although income matters more than disease for height, while the opposite is true for BMI. PMID- 21596630 TI - Correlation between FIB4, liver stiffness and metabolic parameters in patients with HIV and hepatitis C virus co-infection. AB - BACKGROUND/AIMS: Assessment of liver fibrosis is crucial in HIV/HCV coinfected patients, in whom metabolic disturbances are frequent. Aims of this study were to analyse the association of two non-invasive liver fibrosis evaluation methods, liver stiffness measurement and FIB4, and their correlation with metabolic parameters. METHODS: This was a single centre cross-sectional study. All patients underwent biochemical and virological assessment, FIB4 score, HOMA and transient elastography. RESULTS: Seventy-five patients were evaluated. Liver stiffness values positively correlated with FIB4 (R = 0.62; p < 0.0001). By ROC curve analysis the optimal cut-off for liver stiffness to identify high FIB4 was calculated as 10.1 kPa. The area under the ROC curve was 0.78 (95% CI 0.78-0.94, sensitivity 83.3%, specificity 80.7%). Liver stiffness values positively correlated with HOMA score (R = 0.31; p = 0.006). CONCLUSIONS: The combination of two non invasive tools provide a useful system for the assessment of fibrosis evolution in patients with HIV-HCV coinfection. PMID- 21596631 TI - Non-invasive methods can predict oesophageal varices in patients with biliary atresia after a Kasai procedure. AB - BACKGROUND: After a Kasai procedure, 70% of patients with biliary atresia develop chronic liver disease with portal hypertension and oesophageal varices. AIMS: To investigate the role of new non-invasive parameters in predicting the presence of varices in patients with biliary atresia after a Kasai procedure and to identify the cut-off values of these parameters in predicting the presence of varices. METHODS: 31 patients with biliary atresia who had undergone a Kasai portoenterostomy were studied. Clinical, biochemical and abdominal ultrasound examination, liver stiffness measurement (LSM), LSM-spleen diameter to platelet ratio score (LSPS) and upper digestive endoscopy were performed. RESULTS: 15 (47%) patients had oesophageal varices (Group A) and 16 had no varices (Group B). Median values of LSM (kPa) and LSPS were significantly higher in Group A than in Group B (LSM: 17.0 vs. 7.5, respectively; p=0.0001; LSPS: 19.62 vs. 2.94, respectively; p=0.0001). The optimal cut-offs for predicting oesophageal varices were: LSM>10.6 kPa (sensitivity: 87%, specificity: 87.5%, PPV: 87%, NPV: 87.5%, and AUC: 0.92) and LSPS >=9.2 (sensitivity: 91%, specificity: 92%, PPV: 91%, NPV: 92%, and AUC: 0.96). CONCLUSIONS: Non-invasive methods can predict the presence of oesophageal varices in patients with biliary atresia; the sequential use of two non-invasive methods improves accuracy. PMID- 21596632 TI - Rescue endoscopy to identify site of gastric dysplasia or carcinoma found at random biopsies. AB - BACKGROUND: Incidental findings of high-grade dysplasia or gastric cancer at random biopsies with endoscopic diagnosis of chronic gastritis constitute a serious problem to clinical management of patients and sometimes requires blind gastrectomy. AIM: To evaluate diagnostic value of second-look endoscopy, called "rescue endoscopy", in order to identify focal lesions containing neoplastic changes. METHODS: Over a three-year period, 20 patients underwent rescue endoscopy using advanced endoscopy and mapping technique. All mucosal irregularities were identified and the locations of these areas were mapped onto a schematic diagram of gastric anatomy. Each area was biopsied and samples included in individually marked specimen containers, to evaluate the correlation between macroscopic and microscopic diagnosis. RESULTS: Rescue endoscopy identified a total of 68 focal lesions, 18 of which were focal areas of high grade dysplasia (13 patients) or gastric cancer (5 patients). Two patients had no dysplastic change identified by our targeted biopsies. A second pathologist's opinion confirmed absence of dysplasia on random and targeted biopsies. All patients underwent a median follow-up of 15.2 months (2.6-43.5), and no residual or metachronous lesions were identified. CONCLUSIONS: In our experience, rescue endoscopy is highly effective in localizing undetermined areas of high-grade dysplasia or carcinoma. PMID- 21596633 TI - Pharmacological exposure to ribavirin: a key player in the complex network of factors implicated in virological response and anaemia in hepatitis C treatment. AB - Ribavirin remains today a pivotal drug in the treatment of hepatitis C; in standard double therapy, as well as in triple combination with direct antiviral agents, ribavirin reduces relapse and can double the sustained virological response obtained with peginterferon alone or in association with direct antiviral agents. In the complex network of interacting factors determining sustained virological response independently of known predictive factors related to host and virus, two modern tools are emerging: polymorphisms in the IL28B gene and very early exposure to ribavirin. The use of a pharmacokinetic pharmacodynamic model of early ribavirin exposure to adjust the dose individually would help promote a safer ribavirin use and improve sustained virological response. The variability of the influence of ribavirin exposure on anaemia is probably genetically determined; however, the low prevalence of the implicated protective alleles of the inosine triphosphate pyrophosphatase gene could explain their lack of influence on sustained virological response. PMID- 21596634 TI - [Caustic ingestion: current situation and review of updated recommendations]. AB - BACKGROUND: Household product ingestion is the second cause of visiting an Emergency Department for poisoning in children. Among these products, caustics are of great interest because of their potential toxicity and risk of sequelae. OBJECTIVES: To describe the epidemiological and clinical features of patients admitted to our hospital due to possible caustic ingestion. To analyse the risk factors associated with oesophageal or gastric injury. To review the latest treatment recommendations. MATERIALS AND METHODS: Retrospective review of all patients admitted with suspicion of caustic ingestion between January 2005 and April 2010. Epidemiological, clinical and therapeutic aspects were recorded. RESULTS: A total of 78 patients were admitted, 45 (57.7%) were male, with a median age of 2.2 years (range: 1-17.3 years). In 13 cases the product was kept in a container different than the original. In 36 children, the family had induced vomiting or had given a liquid to dilute the product. Fifty two patients were symptomatic, and 46 of them had some sign on physical examination. Thirty nine oesophagoscopies were performed, and 7 oesophageal or gastric lesions were observed. When patients with normal and abnormal endoscopic findings were compared, the factors associated with an increased risk of mucosal injury were vomiting (P=0.01), and two or more symptoms at admission (P=0.03). No complication was described in patients without endoscopy. CONCLUSIONS: Family education about preventive and initial measures after caustic ingestion must be improved in an attempt to prevent wrong actions which can be harmful. Some patients might benefit from clinical observation without aggressive therapeutic measures. PMID- 21596635 TI - Downward spirals of body surveillance and weight/shape concern among African American and Caucasian college women. AB - Within dominant American culture, females often learn to view themselves from an observer's perspective and to treat themselves as objects to be looked at (i.e., self-objectification), which can result in negative outcomes. Body surveillance (the indicator of self-objectification) has been found to predict concern with weight/shape in predominantly Caucasian samples, but research has not yet examined the potential reciprocal relations between body surveillance and weight/shape concern. Participants were 226 women attending a Midwestern university (70 self-identified as African American and 156 as Caucasian) who provided data at two time points, spaced about 5 months apart. Results revealed that downward spirals of body surveillance and weight/shape concern were apparent for the Caucasian but not the African American women. However, there was evidence that body surveillance helped account for change in weight/shape concern for the African American women. PMID- 21596637 TI - A simple modification of the Bakhach's eponychial flap for nail lengthening after fingertip amputation. PMID- 21596636 TI - Neonatal muscular manifestations in mitochondrial disorders. AB - During the last decade rapid development has occurred in defining nuclear gene mutations causing mitochondrial disease. Some of these newly defined gene mutations cause neonatal or early infantile onset of disease, often associated with severe progressive encephalomyopathy combined with other multi-organ involvement such as cardiomyopathy or hepatopathy and with early death. Findings suggesting myopathy in neonates are hypotonia, muscle weakness and wasting, and arthrogryposis. We aim to describe the clinical findings of patients with mitochondrial disease presenting with muscular manifestations in the neonatal period or in early infancy and in whom the genetic defect has been characterized. The majority of patients with neonatal onset of mitochondrial disease have mutations in nuclear genes causing dysfunction of the mitochondrial respiratory chain, leading to defective oxidative phosphorylation. PMID- 21596638 TI - [Experiment of self blood pressure measurement at home in haemodialysis patients in a hospital unit]. AB - We analyzed, by home blood pressure (BP) self-measurement and conventional predialytic measurement of BP, a cohort of haemodialysis patients in two hospital units between 2008 and 2010. All patients who already own a BP self-measurement device were included in this study. BP was recorded by the two methods for one week. The number of patients with a validated self-measurement device was 69 of 350 (21%) and 60 patients were included in analyses. These patients were divided into 23 (38%) permanent uncontrolled hypertensive (elevated BP at home and in hospital), 13 (22%) masked hypertensive (normal BP in hospital and elevated at home), eight (13%) white coat hypertensive (elevated BP in hospital and normal at home), and 16 (27%) permanent controlled normotensive (normal BP in hospital and at home). Patient compliance with all the self BP measurements was 95%. We did not find in this cohort the factors associated with masked hypertension in the general population such as being male, smoking and high body mass index. These results obtained in an in-hospital dialysis unit should be extrapolated with caution to all haemodialysis patients. However it is, to our knowledge, the first study on home BP self-measurement published in patients undergoing haemodialysis in France. A significant proportion of patients have masked hypertension. This should alert clinicians because of the poor cardiovascular prognosis associated with masked hypertension. PMID- 21596639 TI - [Cytopenias following kidney transplantation]. AB - Cytopenias frequently occur during the first months after solid organ transplantation. Many mechanisms are involved but drugs toxicity and infections are the major causes of cytopenias. Anemia is also related with chronic kidney graft dysfunction. Several drugs are pointed out but antithymocyte globulin, antiproliferative drugs and antiviral drugs are mainly responsible for cytopenias. Infectious causes are mainly viral and can rarely induce macrophage activation syndromes. Passenger lymphocyte syndrome is only described after ABO incompatible transplantations. Thrombotic microangiopathies are frequent and multifactorial (antibody mediated rejection, calcineurine inhibitors toxicity, infections, initial nephropathy recurrence). Cytopenias following transplantation increase the risk of infectious disease by neutropenia and generally lead to an immunosuppressive therapy reduction. It seems to increase the risk of rejection when the baseline immunosuppressive level is not further restored. PMID- 21596640 TI - Chronic patellar tendon rupture reconstruction with a semitendinosus autograft. AB - Chronic patellar tendon ruptures are somewhat rare, thus little work has been done in this area and their true incidence is not known. The management of a neglected, chronic patellar tendon rupture must address three difficulties: the proximally retracted patella, the reconstruction of the patellar tendon, finally, the temporary protection of this repair. By presenting a case of a chronic patellar tendon rupture, the advantages of reconstruction with an isolated semitendinosus tendon autograft, especially from an early rehabilitation perspective, are described. PMID- 21596641 TI - Comments on: "osteochondral lesions of the talus: current concept" by O. Laffenetre published in Orthop Traumatol Surg Res 2010;96: 554-66. PMID- 21596642 TI - Aggressive behavior after traumatic brain injury. AB - INTRODUCTION: In cases of agitation and aggressive behavior after severe traumatic brain injury (TBI), the benefits/risks ratio of pharmacological treatments remains unclear. A qualitative analysis of clinical situations could highlight the relevance of psychotherapy care. CASE REPORT: In January 2005, this 24-year-old patient sustained severe traumatic brain injury (Glasgow at 4/15), with bilateral frontotemporal injury and temporal extradural hematoma. On the third day, a temporal lobectomy was performed. The patient's evolution showed severe neurobehavioral disorders, with agitation and aggressive behavior towards family members and medical caregivers. Maximum doses of antipsychotic drugs brought no improvement. Antidepressant medication improved social contact. Several stays in the psychiatric unit, where institutionalized and psychotherapy care were implemented, showed systematically a real improvement of the behavioral disorders, increased participation in group activities and the ability to walk around alone in a closed environment. DISCUSSION/CONCLUSION: Aggressive behavior can unveil organic brain injuries, depressive syndrome as well as iatrogenic nature of the environment. This clinical case is based on the fact that antipsychotic drugs, aside from their sedative effect, are not the proper treatment for agitation following traumatic brain injury. This case also highlights how management of behavioral disorders following TBI should not be based on pharmacological treatments only but instead should focus on multidisciplinary strategies of care. PMID- 21596643 TI - Juvenile ossifying fibroma of the maxilla. AB - INTRODUCTION: Juvenile ossifying fibroma is a rare, benign fibro-osseous tumour. In the light of a clinical case, the authors review the diagnosis, treatment and histological classification of these tumours. CASE REPORT: A seven-year-old child presented with a naso-orbito-ethmoidal trabecular juvenile ossifying fibroma. Complete surgical resection via a transfacial approach was performed after a preoperative work-up comprising head and neck CT and MRI. DISCUSSION: A review of the literature reveals that treatment of this aggressive tumour must comprise complete surgical resection via an incision determined by local tumour extension. CONCLUSION: Patients with juvenile ossifying fibroma tumour require long-term follow-up due to the high recurrence rate. PMID- 21596644 TI - Congenital internal jugular phlebectasia. AB - INTRODUCTION: Congenital internal jugular phlebectasia corresponds to congenital dilatation of the vein without tortuosity. More than one hundred cases of phlebectasia involving the neck veins have been reported in the literature. The authors describe the clinical features, treatment and outcome of this anomaly. CASE REPORT: A six-year-old child with no particular past medical history presented with a two-year history of progressively enlarging mass on the right side of the neck. Physical examination revealed a non-pulsatile mass that was increased in size by all manoeuvres increasing intrathoracic pressure. Neck computed tomography confirmed the diagnosis of internal jugular vein phlebectasia. In the absence of complications, simple surveillance was advised with a follow-up of 20 months with no complications. DISCUSSION/CONCLUSION: Congenital internal jugular phlebectasia is a rare condition. Management must include imaging to confirm the diagnosis. Long-term surveillance is recommended and surgery is only required in the presence of complications. PMID- 21596645 TI - Nasal infection due to Mycobacterium fortuitum. AB - INTRODUCTION: Mycobacterium fortuitum, a rapidly growing non-tuberculous atypical mycobacterium, is commonly found in soil and water. This organism generally causes skin, bone, and soft tissue infections following local trauma or surgical procedures, and in immunodeficient patients. The case reported here is, to our knowledge, the first published report of M. fortuitum nasal infection. CASE REPORT: The authors report the case of a 3-year-old girl with intranasal tumour like swelling associated with cervical lymph nodes due to M. fortuitum infection. DISCUSSION/CONCLUSION: A combination of radical surgical debridement and prolonged therapy with several antimicrobial agents was required to completely eradicate the infection. This case report indicates that non-tuberculous mycobacterial infections should be considered after failure of conventional antibiotic therapy or when classical microbiological tests fail to identify the pathogen responsible for sinonasal and cervical infections. PMID- 21596646 TI - Should older head and neck patients be treated differently? AB - OBJECTIVES: Growing life expectancy is resulting in an increasing number of elderly patients with upper aero digestive tract tumor. The objective of this study was to assess the appropriateness of aggressive curative treatment for these older patients. PATIENTS AND METHODS: Patients over the age of 70 years, with head and neck squamous cell carcinoma (HNSCC) of the oral cavity, pharynx or larynx, primarily treated in our department between 2005 and 2007, were assessed retrospectively at 36 months' follow-up. Demographics, comorbidity and treatment strategies and their associated morbidity and mortality were reviewed. RESULTS: Thirty-two males and 12 females with a median age of 77 years (range, 70-88 yrs) were given curative treatment. The majority presented with a least one comorbidity. Seven had a history of myocardial ischemia, 15 of chronic obstructive bronchopathy, and 10 of type-2 diabetes; 17 were under treatment for arterial hypertension, four had chronic renal insufficiency, and two had cirrhosis. Nine patients received radiation therapy alone; 18, concomitant chemoradiotherapy; 14, surgery with adjuvant chemoradiotherapy; three were treated by salvage surgery after failure of radiation therapy. In the 44 patients, there were 12 deaths: seven from recurrence, two from treatment complications, one from MI, one from peritonitis and one from pneumonia. At 36 months' follow-up, 32 of the 44 patients were alive. CONCLUSION: HNSCC is a serious disease that often necessitates aggressive treatment. All patients who are medically eligible should receive curative treatment, without age being an exclusion criterion. Taking comorbidity into account, on the other hand, enables treatment options to be optimized. PMID- 21596647 TI - Laryngeal chondrosarcoma: report of two cases. AB - OBJECTIVE: The present study describes the clinical, radiological and histological features of laryngeal chondrosarcoma, on the basis of two clinical cases, and discusses management. CASE STUDIES: Two male patients, aged 63 and 51 years, presented with low-grade chondrosarcoma revealed respectively by a mass in the lateral neck and by laryngeal dyspnea. CT showed a tumoral process with calcification, developed from the thyroid and cricoid cartilage, respectively. The first patient underwent partial and the second total laryngectomy. DISCUSSION: Chondrosarcoma is diagnosed on the basis of combined clinical, radiological and histological signs. Differential diagnosis with chondroma may be difficult, especially in grade-1 chondrosarcoma. CONCLUSION: Laryngeal chondrosarcoma is a rare tumor. Management is basically surgical. Prognosis is generally good, depending essentially on histologic grade. PMID- 21596648 TI - Bruxism and prosthetic treatment: a critical review. AB - PURPOSE: Based on the findings from available research on bruxism and prosthetic treatment published in the dental literature, an attempt was made to draw conclusions about the existence of a possible relationship between the two, and its clinical relevance. STUDY SELECTION: MEDLINE/PubMed searches were conducted using the terms 'bruxism' and 'prosthetic treatment', as well as combinations of these and related terms. The few studies judged to be relevant were critically reviewed, in addition to papers found during an additional manual search of reference lists within selected articles. RESULTS: Bruxism is a common parafunctional habit, occurring both during sleep and wakefulness. Usually it causes few serious effects, but can do so in some patients. The etiology is multifactorial. There is no known treatment to stop bruxism, including prosthetic treatment. The role of bruxism in the process of tooth wear is unclear, but it is not considered a major cause. As informed by the present critical review, the relationship between bruxism and prosthetic treatment is one that relates mainly to the effect of the former on the latter. CONCLUSIONS: Bruxism may be included among the risk factors, and is associated with increased mechanical and/or technical complications in prosthodontic rehabilitation, although it seems not to affect implant survival. When prosthetic intervention is indicated in a patient with bruxism, efforts should be made to reduce the effects of likely heavy occlusal loading on all the components that contribute to prosthetic structural integrity. Failure to do so may indicate earlier failure than is the norm. PMID- 21596649 TI - Effect of storage time on the viscoelastic properties of elastomeric impression materials. AB - PURPOSE: The aim of this study was to evaluate creep and viscoelastic properties of dental impression materials after different storage times. METHODS: Six commercially available impression materials (one polyether and five silicones) were tested after being stored for 30 min to 2 weeks under both static and dynamic testing. Shear and Young's moduli, dynamic viscosity, loss tangent and other viscoelastic parameters were calculated. Four of the materials were tested 1 h after setting under creep for three hours and recovery was recorder for 50 h. RESULTS: The tested materials showed differences among them, while storage time had significant influence on their properties. Young's modulus E ranged from 1.81 to 12.99 MPa with the polyether material being the stiffest. All of the materials showed linear viscoelastic behavior exhibiting permanent deformation after 50h of creep recovery. CONCLUSION: As storage time affects the materials' properties, pouring time should be limited in the first 48 h after impression. PMID- 21596650 TI - Targeted gene correction of laminopathy-associated LMNA mutations in patient specific iPSCs. AB - Combination of stem cell-based approaches with gene-editing technologies represents an attractive strategy for studying human disease and developing therapies. However, gene-editing methodologies described to date for human cells suffer from technical limitations including limited target gene size, low targeting efficiency at transcriptionally inactive loci, and off-target genetic effects that could hamper broad clinical application. To address these limitations, and as a proof of principle, we focused on homologous recombination based gene correction of multiple mutations on lamin A (LMNA), which are associated with various degenerative diseases. We show that helper-dependent adenoviral vectors (HDAdVs) provide a highly efficient and safe method for correcting mutations in large genomic regions in human induced pluripotent stem cells and can also be effective in adult human mesenchymal stem cells. This type of approach could be used to generate genotype-matched cell lines for disease modeling and drug discovery and potentially also in therapeutics. PMID- 21596651 TI - Could the health decline of prehistoric California indians be related to exposure to polycyclic aromatic hydrocarbons (PAHs) from natural bitumen? AB - BACKGROUND: The negative health effects of polycyclic aromatic hydrocarbons (PAHs) are well established for modern human populations but have so far not been studied in prehistoric contexts. PAHs are the main component of fossil bitumen, a naturally occurring material used by past societies such as the Chumash Indians in California as an adhesive, as a waterproofing agent, and for medicinal purposes. The rich archaeological and ethnohistoric record of the coastal Chumash suggests that they were exposed to multiple uptake pathways of bituminous PAHs, including direct contact, fume inhalation, and oral uptake from contaminated water and seafood. OBJECTIVES: We investigated the possibility that PAHs from natural bitumen compromised the health of the prehistoric Chumash Indians in California. CONCLUSIONS: Exposure of the ancient Chumash Indians to toxic PAHs appears to have gradually increased across a period of 7,500 years because of an increased use of bitumen in the Chumash technology, together with a dietary shift toward PAH-contaminated marine food. Skeletal analysis indicates a concurrent population health decline that may be related to PAH uptake. However, establishing such a connection is virtually impossible without knowing the actual exposure levels experienced by these populations. Future methodological research may provide techniques for determining PAH levels in ancient skeletal material, which would open new avenues for research on the health of prehistoric populations and on the long-term effects of human PAH exposure. PMID- 21596652 TI - [Indications and current development of new targeted therapies in pediatric oncology]. AB - Progresses performed in pediatric oncology during the last 30 years allowed to obtain about 70 to 80% healing rates. These progresses are the result of the optimization of the cytotoxic chemotherapies protocols used at standard and high doses, as well as the improvement of the local treatment. Most of the new anticancer treatments currently in developmental stage are based on targeted therapies, acting against numerous tumor cell abnormalities, like growth factors et their receptors, cell proliferation-inducing factors, molecules involved in DNA repair, cell death inducers, tumor invasion and angiogenesis. They are widely used in adult patients since 10 years and they are being more and more employed in children with cancer. The aim of this article is to review the main indications of these new targeted drugs in pediatric oncology and the new developments of these drugs. PMID- 21596654 TI - Erythropoiesis-stimulating agents: the present situation. PMID- 21596653 TI - [Management of adrenocortical carcinomas in children]. AB - Adrenocortical carcinomas are rare in children and sometimes occur in patients with predisposing syndrome like Li-Fraumeni or Beckwith-Wiedemann syndromes. The diagnosis is often based on clinical, biological and radiological findings completed by histological examination. The gold standard of treatment remains radical surgery sometimes completed by a cytotoxic chemotherapy based on platinum derived drugs, etoposide and doxorubicin, in association with mitotane in case of high risk of relapse. The role of radiation therapy is discussed because of the relatively frequent involvement of p53 mutations. The rarity of this type of disease and the poor prognosis of the locally advanced and metastatic forms must lead to the systematic registration of these patients and to the harmonization of the management in a national or even European level. PMID- 21596655 TI - A role for cancer stem cells in drug resistance and metastasis in non-small-cell lung cancer. AB - The cancer stem cell (CSC) theory is currently a very important field in cancer research. This theory states that tumours are organised in a hierarchical manner with a subpopulation of limited number called CSCs with the ability to self-renew and undergo asymmetrical divisions, giving rise to a differentiated progeny that represents most of the tumour populations. CSCs are metastatic and chemoresistant, two features that very likely contribute to the poor response of locally advanced lung cancer. CSCs have been identified in non-small-cell lung cancer cell lines as well as those from patient primary samples. A correlation has been found in terms of chemoresistance and bad prognosis in patient-derived samples enriched with CSCs, indicating that these cells are an important target for future therapy combinations. Therefore, understanding the biology and exploring cell markers and signalling pathways specific for CSCs of lung cancer may help in achieving progress in the treatment of the disease. PMID- 21596657 TI - New DNA sequencing technologies open a promising era for cancer research and treatment. AB - DNA sequencing techniques have evolved rapidly in the last 5 years by the introduction of new sequencing machines, denominated second-generation sequencers, next-generation sequencers or massive parallel sequencers. These technologies make it possible to determine the complete sequence of the human genome, or selected regions of it, at accessible prices and in a short period of time. Therefore, it is now possible to determine the nucleotide sequence of the DNA from cancer cells and to compare it to that of normal cells to identify the genetic changes involved in cancer generation. Actually, the genome of more than 15 tumour types has been determined in the last 3 years. The results obtained have allowed the identification of new cancer driving genes, new susceptibility genes and the detailed identification of genome structural reorganisations. In this review a brief description of the new sequencing technologies will be presented. Recent findings on cancer genome and exome sequencing will be summarised. Finally, the potential applications of these new technologies to cancer prognosis, diagnosis and therapeutics will be discussed. PMID- 21596656 TI - Anti-angiogenic therapy in glioma. AB - There has been great interest in developing anti-angiogenic therapies for the treatment of patients with high-grade gliomas. In fact, some anti-angiogenic agents are now routinely used for the treatment of patients with glioblastoma. However, the use of these agents is largely based on trials which indicate an initial radiographic response, while it remains unclear whether any anti angiogenic therapies tested to date have improved the overall survival of patients with malignant glial tumours. This manuscript reviews the landscape of anti-angiogenic therapy in glioma, with a focus on GBM, and demonstrates that further innovation is needed to determine the true utility of anti-angiogenic therapy. PMID- 21596658 TI - Current management of uterine sarcomas. AB - Uterine sarcomas comprise a heterogeneous group of diseases with different pathology appearance, clinical course and natural history. They account for only 3% of all uterine malignancies. The rarity of this entity has precluded the development of large and well designed randomised clinical trials, and for this reason the current management of some aspects of this disease is based on trials or retrospective studies with a low level of evidence. For this reason, it is mandatory to develop international cooperation to carry out clinically relevant clinical trials in this field. Accordingly, based on the relative rarity of these tumours, management of these patients should be centralised and must be performed by a multidisciplinary team including gynaecologic oncologist, pathologist, medical oncologist and radiation oncologist. This review focuses on the most accepted evidence about the management of uterine sarcomas. Although carcinosarcoma has been recently excluded from the sarcoma classification, some aspects of its treatment have also been included in this review. PMID- 21596659 TI - Therapeutic interventions targeting organ preservation in muscle-invasive bladder cancer: a review. AB - Nowadays in modern oncology there is a tendency towards therapies that target organ preservation. Organ preservation protocols have become standard in the treatment of laryngeal carcinoma, oesophageal cancer, breast carcinoma and soft tissue sarcomas. The three-combined therapy consisting of a transurethral resection of the bladder tumour followed by concomitant chemoradiotherapy has been shown to be an attractive alternative for bladder preservation in selected patients with muscle-invasive bladder cancer. In order to evaluate the organ preservation approaches in muscle-invasive bladder cancer we have conducted a comprehensive literature review. Data reported from the studies have shown that bladder preservation therapy with a trimodality approach is safe and effective. Moreover, such an approach provides patients with the opportunity to maintain an intact and functional bladder with a survival rate similar to that of radical cystectomy. PMID- 21596660 TI - PITASOR epidemiological study: prevalence, incidence and treatment of anaemia in radiation therapy oncology departments in Spain. AB - INTRODUCTION: Anemia is the most common haematological complication in cancer patients. OBJECTIVE: Analysis of the incidence, prevalence and treatment of anemia in oncologic patients treated in Radiation Oncology Departments in Spain (ROD) and monitoring of the existing recommendations for the treatment of anemia. MATERIAL AND METHODS: Observational, prospective, multicenter study which involved 19 Spanish ROD. The study was approved by the CEIC Central Defense Hospital. 477 patients with solid tumors, subsidiary of RT with radical intent referred to such centers within a period of one month (5/5/09 to 5/6/09) and gave their consent to participate in the study. We gathered the main characteristics of patients and their oncologic disease. All patients underwent a determination of Hb levels before RT, upon reaching 25-35 Gy and at the end treatment. In patients with anemia we assessed the existence of related symptoms and its treatment. RESULTS: Basal situation: The prevalence of anemia was 34.8% (166 patients). Mean Hb in patients with anemia was 11.17 +/- 1.07 g/dl. Anemia related symptoms were present in 34% of the patients. Anemia predisposing factors were: stage of the disease, previously received chemotherapy, and hormonal therapy. 39% (66 patients) received anemia treatment, with a mean Hb of 10.43 +/- 1.04 g/dl. During RT: The prevalence of anemia was 38.9% (182 patients) with a mean Hb of 11.24 +/- 1.21 g/dl. Predisposing factors for anemia during RT treatment were: age, male sex, chemotherapy prior to RT, basal anemia and chemotherapy during RT. 36.3% (66 patients) had anemia-related symptoms. 34.6% (63 patients) with a mean Hb of 10.5 +/- 1.37 g/dl received treatment for anemia. The prevalence of anemia at the end of the RT was 38.1% (177 patients) with a mean Hb of 11.19 +/- 1.18 g/dl. The predisposing factors for the appearance of anemia at the end of RT were: male sex, anemia at basal situation and during treatment and chemotherapy during RT. 34% (61 patients) had anemia-related symptoms and 73 patients (41.2%) with a mean Hb of 10.5 +/- 1.22 g/dl received treatment for anemia. The presence of anemia-related symptoms was significantly correlated with the beginning of treatment for anemia. The incidence of anemia (new cases) during radiotherapy was 17.5%. CONCLUSION: The prevalence of anemia in basal situation, during RT and at the end of RT is 34.8%, 38.9% and 38.1%. During RT the incidence of anemia is 17.5%. 39.8%-41.2% of patients with anemia and 64.2%-68% of patients with anemia-related symptoms received treatment. Treatment of anemia starts with Hb<11 g/dl and the goal is to achieve Hb 12 g/dl. In our Radiotherapy Oncology Departments, the treatment of anemia complies with the current recommendations and guidelines in use. PMID- 21596661 TI - Management of lung cancer-associated anaemia: the Spanish Lung Cancer Anaemia Survey (SLCAS). AB - BACKGROUND: The purpose of the Spanish Lung Cancer Anaemia Survey (SLCAS) was to thoroughly investigate lung cancer-associated anaemia management, and describe the profile of lung cancer patients in relation to anaemia incidence and tumour type in Spain. PATIENTS AND METHODS: This survey collected data from 1089 randomly recruited patients gathered by 50 Spanish physicians at 38 sites. In addition, a qualitative assay was performed through 16 one-to-one and 2 one-to two interviews, and a discussion group of 4 cancer specialists participating in the survey. RESULTS: Lung cancer patients undergoing chemotherapy treatment had haemoglobin (Hb) levels <12.0 g/dl in 58.0% of the cases, in contrast to 39.0% of patients receiving no chemotherapy. Anaemia was treated in 53.0% of patients with Hb<12 g/dl (45.0% epoetin, 3.9% transfusion, 4.1% iron). Mean Hb level trigger was 9.7 g/dl for administration of epoetin and 8.2 g/dl for blood transfusion. CONCLUSIONS: SLCAS reveals a significant change in the management of anaemia and clinical practice pattern in the use of erythropoiesis-stimulating agents (45.0% vs. 18.0%) and much less use of blood transfusions (3.9% vs. 15.0%) since the European Cancer Anaemia Survey performed five years ago. PMID- 21596662 TI - HER2 status in breast cancer: experience of a Spanish National Reference Centre. AB - BACKGROUND: Accurate HER2 testing is of great clinical value for the identification of breast cancer patients who are eligible for trastuzumab therapy. The aim of this study is to review breast carcinomas diagnosed from 2001 to 2007 at a Spanish National Reference Centre for HER2 testing, evaluating the agreement between HER2 immunohistochemical (IHC) tests and fluorescence in situ hybridisation (FISH) tests. METHODS: Demographic and clinical information was obtained from 2751 breast carcinoma patients. HER2 IHC and FISH tests were performed both in a local laboratory and in the reference centre. The HER2 IHC0/1+, IHC2+, IHC3+ and FISH-positive patients comprised 64%, 20%, 16% and 24% of the available population, respectively (results from the reference centre). Using statistical approaches, we evaluated the agreement between: (1) HER2 IHC and FISH tests, and (2) results provided by the local and the reference laboratories. RESULTS: The data confirmed a statistically significant relation between HER2 overexpression and amplification. We also found that instances of polysomy 17 and heterogeneous patterns of HER2 expression (heterogeneous staining distribution in different areas of the same tumour) are more frequently observed in HER2-positive tumours. Finally, since the diagnoses were made from 2001 to 2007, we could also observe a rising agreement rate between laboratories/pathologists with time. CONCLUSIONS: HER2 testing is most accurate when performed by experienced pathologists and at a high-volume reference laboratory. Polysomy 17 and HER2 heterogeneous staining patterns should also be considered for a better understanding of the variation in the anti-HER2 therapeutic response. PMID- 21596663 TI - Effectiveness of darbepoetin alfa in a cohort of oncology patients with chemotherapy-induced anaemia. Relationship between variation in three fatigue specific quality of life questionnaire scores and change in haemoglobin level. AB - BACKGROUND: Cancer patients with chemotherapy-induced anaemia (CIA) often experience cancer-related fatigue (CRF). Darbepoetin alfa (DA) once every 3 weeks (q3w) is an effective and well tolerated erythropoiesis-stimulating agent. This study evaluated DA effectiveness and psychometric properties of the Functional Assessment of Cancer Therapy Fatigue-Subscale (FACT-F) and the Fatigue Symptom Inventory (FSI) in CIA patients. METHODS: This was a single-centre, prospective study in 100 patients with solid tumour and moderate to severe CRF (visual analogue scale [VAS-F] >= 30 mm) who received DA 500 MUg q3w during chemotherapy (CT). Clinical data, VAS-F, FACT-F and FSI scores were collected at the beginning and at the end of CT (EOCT). RESULTS: Mean age was 62.7 years (SD: 12.1), 53.0% were women, 92.0% had ECOG 0-1 and 64% had stage IV tumours. Mean haemoglobin (Hb) significantly increased from baseline 10.2 g/dl to 11.3 g/dl at EOCT. Sixty five percent of patients showed haematopoietic response at any study point (Hb >= 12 g/dl or an increase of >= 2 g/dl from baseline), 77% achieved Hb >= 11 g/dl and 7% required blood transfusions from week 5 to EOCT. CRF improvement was demonstrated by significant changes in VAS-F, FACT-F and FSI scores (decreases of 21.54, 3.56 and 12.97 points, respectively). FACT-F and FSI questionnaires showed high internal consistency (Cronbach's alpha of 0.98 and 0.98 for FACT-F and FSI, respectively, at the end of study) and satisfactory intra-class coefficients (FACT-F, r=0.73; FSI, r=0.83). There were significant correlations between scores and Hb changes (FACT-F, r=-0.44; FSI, r=-0.54). CONCLUSIONS: DA 500 MUg q3w showed effectiveness in improving Hb and inducing a clinically significant decrease in CRF of patients with solid tumours undergoing CT. The three instruments, VAS-F, FACT-F and FSI, could be suitable for assessing CRF. PMID- 21596664 TI - Evaluation of ototoxicity in children treated for retinoblastoma: preliminary results of a systematic audiological evaluation. AB - BACKGROUND: The objective of this study was to identify the ocurrence of hearing loss in children treated for retinoblastoma using a multidisciplinary approach. PATIENTS AND METHODS: Thirty-two children were evaluated pre- and post-treatment. Eleven children were treated exclusively with enucleation, fifteen with carboplatin and six with cisplatin. Otoacoustic emissions were performed with the ILO 88, before and after the treatment. RESULTS: In our study we found 5 children (24%) with hearing loss among the 21 evaluated. However in the group of children treated with carboplatin (N=15), 1 case (6.6%) presented hearing loss, while among those treated with cisplatin (N=6) we found 4 cases (66.6%) with hearing loss (p=0.0114). CONCLUSION: We concluded that patients who are treated with cisplatin are at risk for developing hearing loss. PMID- 21596665 TI - Antifertility effect of calcium channel blockers on male rats: association with oxidative stress. AB - PURPOSE: Calcium ions are vital in many biologic processes including a variety of enzymatic reactions, activation of excitable cells, coupling of electrical activation to cellular secretion, haemostasis, bone metabolism and sperm functions. Calcium channel blockers (CCB) appear to have a reversible anti fertility effect on male rats which does not occur through inhibition of the pituitary-gonadal axis. While the effects of CCB on male reproductive function have been investigated, less information is available regarding other reproductive indices and the underlying mechanism in the pathogenesis of male reproductive dysfunction. Therefore, the involvement of oxidative mechanisms in the adverse manifestation induced by CCB on male reproductive functions is investigated in this study. METHODS: For this purpose, lipid peroxidation; enzymatic antioxidants such as superoxide dismutase, catalase and glutathione reduced; epididymal sperm count, motility; histopathology of the testes, epididymis, seminal vesicle, prostate glands; and reproductive performance were determined. RESULTS: CCB administration in rats causes significant oxidative stress in the male reproductive milieu in term of increase in malondialdehyde (MDA) level and a concomitant decrease in catalase, superoxide dismutase and reduced glutathione enzyme activities in the testes. In addition, CCB treatment significantly decreased the sperm count, sperm motility, fertility index, implantation count, and litter size in this study. CONCLUSION: There is substantial evidence that CCB induces significant oxidative stress in the testes, which appears to be responsible for the adverse effects of decreased sperm count and motility ultimately leading to reduced fertility in rats. PMID- 21596671 TI - Reduction of inappropriate urinary catheter use at a Veterans Affairs hospital through a multifaceted quality improvement project. AB - BACKGROUND: Foley catheter (FC) use is a modifiable risk factor for hospital acquired urinary tract infection, the most common type of nosocomial infection. It is unknown whether sustained, hospital-wide reductions in FC use are achievable by combining interventions with demonstrated short-term effectiveness in selected units. METHODS: A multifaceted quality improvement project to decrease unnecessary FC use and increase order documentation was instituted throughout the Minneapolis Veterans Affairs Medical Center in March 2005, after a >2-year baseline period. Bundled interventions included multiple types of education, system redesign, rewards, and feedback (phases I and II), plus, in phase III, involvement of a dedicated FC nurse. RESULTS: The daily prevalence of FC use dropped steeply during intervention phase I (5.5 months), from a 15.2% baseline mean to a 9.3% nadir, but rebounded quickly during the subsequent hiatus phase (1.2 months). It dropped again (mean, 13.6%) during intervention phase II (27.3 months) and even further (mean, 12.0%) during intervention phase III (22.8 months) (P <= .001, phase II or III vs baseline). Compared with baseline, during phase III (with the dedicated FC nurse) the mean daily percentages of nonordered and nonindicated FCs dropped from 17% to 5.1% and from 15% to 1.2%, respectively. During phases II and III combined, an estimated total of 6691 FC days were avoided. CONCLUSIONS: Significant hospital-wide reductions in total and inappropriate FC use and improved FC order documentation were achieved through a multicomponent campaign. The greatest and most sustained improvements accompanied the involvement of a dedicated FC nurse. PMID- 21596672 TI - Disrupting the life cycle of the urinary catheter. PMID- 21596673 TI - Kinetics of immune responses to nasal challenge with meningococcal polysaccharide one year after serogroup-C glycoconjugate vaccination. AB - BACKGROUND: Recipients of serogroup-C glycoconjugate meningococcal vaccine (MCC) exhibit waning of serum bactericidal antibody (SBA) titers, but the rate of decline and the speed of their immunological memory in response to new meningococcal nasopharyngeal colonization are unknown. METHODS: In a prospective challenge study, we measured persistence of SBA and anti-Neisseria meningitidis serogroup-C (MenC) immunoglobulin (Ig) G and IgA in adults aged 18-39, 28 days and 12 months after receiving MCC. Volunteers were then challenged intranasally with 50 MUg MenC polysaccharide to mimic meningococcal colonization, and systemic and mucosal antibody responses were measured. RESULTS: All subjects had protective SBA titers (>=8) 28 days after MCC vaccination, but 12.3% and 20.2% had unprotective (<8) or low (<128) levels, respectively, after 12 months. Following rechallenge (12 months postvaccination) and measurement of antibody responses after 4, 7, and 10 days, rises in SBA titers were only observed in subjects with low (<128) or nonprotective (<8) prerechallenge SBA titers. In subjects with pre rechallenge SBA titers <8, the majority did not reach a protective SBA titer until 7 days post-rechallenge. MenC-specific IgG levels rose in both serum and saliva in correlation with SBA titers. No detectable rise in salivary IgA was observed. CONCLUSIONS: In those individuals who fail to retain protective SBA 12 months after MCC, immunological memory fails to generate protective systemic and mucosal antibodies until 7 days post intranasal challenge with cognate meningococcal polysaccharide. This is likely too slow to protect from natural meningococcal infection. MCC vaccinees rely on persistence of antibody levels rather than immunological memory for sustained protection. PMID- 21596675 TI - Slowly progressive annular skin lesions in an elderly patient. PMID- 21596674 TI - Single nucleotide polymorphisms in the promoter of the gene encoding the lipopolysaccharide receptor CD14 are associated with bacterial diarrhea in US and Canadian travelers to Mexico. AB - BACKGROUND: Under normal conditions, the expression of CD14, which is the principal receptor for bacterial lipopolysaccharide, is down-regulated in the intestinal mucosa but increases in response to inflammatory stimuli. The aim of the present study was to investigate whether fecal CD14 levels increased in response to infection with diarrheagenic Escherichia coli and whether single nucleotide polymorphisms (SNPs) in the CD14 gene were associated with an increased susceptibility to traveler's diarrhea (TD) in US visitors to Mexico. METHODS: Six SNPs located at the promoter, exon, and untranslated regions of CD14 were typed in a prospective cohort study of 1360 visitors to Mexico at risk for TD. Stools from visitors with TD were studied for enteric pathogens by culture, colony hybridization, and polymerase chain reaction. Fecal soluble CD14 (sCD14) was measured in a subgroup of 203 adults with diarrhea and 66 healthy controls by enzyme-linked immunosorbent assay. RESULTS: The minor allele frequencies for CD14 SNPs were significantly different among the various racial and ethnic groups studied. Two SNPs in the promoter region of CD14 (-159 C > T; rs2569190 and -4191 C > T; rs5744441) were found to be associated with TD in White visitors. The -159 TT genotype was associated with a higher risk for TD (Relative risk [RR], 1.21; 95% confidence interval [CI], 1.05-1.38; P = .008), whereas individuals with the 4191 TT genotype were protected from infection (RR, 0.82; 95% CI, 0.71-0.92; P = .006). Subjects with TD excreted higher levels of fecal CD14 than did healthy controls (33,480 pg/mL vs 6178 pg/mL; P < .02). Fecal sCD14 levels were higher in stool samples from visitors with TD and the -159 TT genotype than they were in visitors with the CC/CT genotypes (P = .02), and stool samples from subjects with the -4191 CC genotype had higher fecal sCD14 levels than did stool samples from visitors with the CT/TT (P = .005) genotype. In a multivariate analysis with haplotypes constructed with the 6 SNPs studied, subjects with the haplotype containing the -159 C and the -4191 T allele were less likely to acquire TD (P = .015). CONCLUSIONS: Our study suggests that CD14 levels increase in response to bacterial diarrhea and that polymorphisms in the CD14 gene influence susceptibility to TD. Intestinal CD14 plays an important role in the innate immune response to enteric pathogens. PMID- 21596676 TI - Recent advances in the laboratory detection of Mycobacterium tuberculosis complex and drug resistance. AB - The global control of tuberculosis remains a challenge from the standpoint of diagnosis, detection of drug resistance, and treatment. Because treatment can only be initiated when infection is detected and is based on the results of antimicrobial susceptibility testing, there recently has been a marked increase in the development and testing of novel assays designed to detect Mycobacterium tuberculosis complex, with or without simultaneous detection of resistance to isoniazid and/or rifampin. Both nonmolecular and molecular assays have been developed. To a large extent, the nonmolecular methods are refinements or modifications of conventional methods, with the primary goal of providing more rapid test results. Evaluations of molecular assays have generally shown that these assays have variable sensitivity for detecting the presence of M. tuberculosis complex and, in particular, are insensitive when used with smear negative specimens; high sensitivity for detecting resistance to rifampin; and variable sensitivity for detecting resistance to isoniazid. PMID- 21596677 TI - Review of cases with the emerging fifth human malaria parasite, Plasmodium knowlesi. AB - Human malaria has been known to be caused by 4 Plasmodium species, with Plasmodium falciparum causing the most-severe disease. Recently, numerous reports have described human malaria caused by a fifth Plasmodium species, Plasmodium knowlesi, which usually infects macaque monkeys. Hundreds of human cases have been reported from Malaysia, several cases have been reported in other Southeast Asian countries, and a few cases have been reported in travelers visiting these areas. Similarly to P. falciparum, P. knowlesi can cause severe and even fatal cases of disease that are more severe than those caused by the other Plasmodium species. Polymerase chain reaction is of value for diagnosis because P. knowlesi infection is easily misdiagnosed as less dangerous Plasmodium malariae infection with conventional microscopy. P. knowlesi infection should be suspected in patients who are infected with malaria in Southeast Asia. If human-mosquito-human transmission were to occur, the disease could spread to new areas where the mosquito vectors live, such as the popular tourist areas in western India. PMID- 21596678 TI - Men who have sex with men, risk behavior, and HIV infection: integrative analysis of clinical, epidemiological, and laboratory databases. AB - BACKGROUND: Centralized data collection and analytic tools facilitate tracing HIV transmission trends at the patient-population level with increasing resolution, complementing behavioral studies while avoiding sampling biases. By several measures, the rate of HIV infection among men who have sex with men (MSM) in Israel increased in the past several years more rapidly than was expected. We describe features of the data that connect this increase to behavioral changes. METHODS: We retrospectively analyzed data from the national HIV reference laboratory and the national HIV and sexually transmitted infections registries. We examined changes in selected epidemiologic and clinical parameters and in the pattern of drug-resistant virus transmission among MSM in Israel. In particular, virus isolates from 296 MSM (23.8% of all MSM who received a diagnosis) were genotyped, drug-resistance conferring mutations were characterized, and phylogenetic trees were constructed. RESULTS: Compared with earlier years, during 2007-2009 MSM were more often infected with drug-resistant virus before treatment initiation, were coinfected with syphilis, and received a diagnosis during acute retroviral syndrome. Phylogenetic analysis suggested frequent transmission of drug-resistant HIV by drug-treated individuals to >1 partner. Secondary transmission of resistant virus by drug-naive patients is also consistent with the phylogenetic patterns. In addition, non-B HIV subtypes began to appear among MSM. CONCLUSIONS: Together, our findings suggest that the sexual behavior of MSM, both HIV-infected and uninfected, has become riskier, contributing to the number of those seeking early clarification of status, to syphilis comorbidity, and to the spread of drug resistance. These findings call for action by public health planners and community-based organizations aimed at increasing awareness of the risks, bringing a change in attitude and establishing safe sex norms. PMID- 21596679 TI - Past as prologue: the refractory and evolving HIV epidemic among men who have sex with men. PMID- 21596680 TI - Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)--associated tuberculous meningitis. AB - BACKGROUND: The optimal time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-associated tuberculous meningitis is unknown. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of immediate versus deferred ART in patients with HIV-associated tuberculous meningitis to determine whether immediate ART reduced the risk of death. Antiretroviral drugs (zidovudine, lamivudine, and efavirenz) were started either at study entry or 2 months after randomization. All patients were treated with standard antituberculosis treatment, adjunctive dexamethasone, and prophylactic co-trimoxazole and were followed up for 12 months. We conducted intention-to treat, per-protocol, and prespecified subgroup analyses. RESULTS: A total of 253 patients were randomized, 127 in the immediate ART group and 126 in the deferred ART group; 76 and 70 patients died within 9 months in the immediate and deferred ART groups, respectively. Immediate ART was not significantly associated with 9 month mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], .81-1.55; P = .50) or the time to new AIDS events or death (HR, 1.16; 95% CI, .87-1.55; P = .31). The percentage of patients with severe (grade 3 or 4) adverse events was high in both arms (90% in the immediate ART group and 89% in the deferred ART group; P = .84), but there were significantly more grade 4 adverse events in the immediate ART arm (102 in the immediate ART group vs 87 in the deferred ART group; P = .04). CONCLUSIONS: Immediate ART initiation does not improve outcome in patients presenting with HIV-associated tuberculous meningitis. There were significantly more grade 4 adverse events in the immediate ART arm, supporting delayed initiation of ART in HIV-associated tuberculous meningitis. Clinical Trials Registration. ISRCTN63659091. PMID- 21596683 TI - On a different level: telavancin versus vancomycin for hospital-acquired pneumonia. PMID- 21596681 TI - Poor prognosis of HIV-associated tuberculous meningitis regardless of the timing of antiretroviral therapy. PMID- 21596684 TI - Regarding "raw (unpasteurized) milk: are health-conscious consumers making an unhealthy choice?". PMID- 21596685 TI - Daily cranberry prophylaxis to prevent recurrent urinary tract infections may be beneficial in some populations of women. PMID- 21596686 TI - A variant human IgG1-Fc mediates improved ADCC. AB - Ribosome display was applied to the Fc region of human immunoglobulin G (IgG1) to select for improved binding to human FcgammaRIIIa, the receptor expressed on human natural killer cells that mediates antibody-dependent cellular cytotoxicity (ADCC). A library of human Fcgamma1 variants was generated using error-prone polymerase chain reaction, and subjected to multiple rounds of ribosome display selection against progressively decreasing concentrations of soluble human FcgammaRIIIa, to enrich for improved binders. Radioimmunoassay and alphascreen analyses of the aglycosylated IgG-Fc output revealed variants with improved binding to FcgammaRIIIa relative to wild-type IgG-Fc. Subsequent expression in human (HEK-EBNA) cells generated glycosylated IgGs with modified activity in ADCC assays. One particular variant, 125_B01 triggered enhanced ADCC (EC(50) up to four-fold reduced with increased maximal lysis) relative to wild-type antibody, having more equal levels of ADCC for each allotype (V158/F158) of FcgammaRIIIa. Deconvolution of individual replacements within the variant showed that improved function arose from the Phe243Leu replacement within the CH2 domain, rather than the CH3 domain replacements Thr393Ala or His433Pro. Surprisingly, the oligosaccharide profiles of 125_B01 indicated more oligosaccharide chains lacking fucose, or with bisecting N-acetylglucosamine relative to wild-type IgG1, which correlates with improved function and the replacement Phe243Leu that is a carbohydrate contact residue within the C(H)2 domain. PMID- 21596687 TI - The cyclophilin AtCYP71 interacts with CAF-1 and LHP1 and functions in multiple chromatin remodeling processes. AB - Chromatin is the primary carrier of epigenetic information in higher eukaryotes. AtCYP71 contains both cyclophilin domain and WD40 repeats. Loss of AtCYP71 function causes drastic pleiotropic phenotypic defects. Here, we show that AtCYP71 physically interacts with FAS1 and LHP1, respectively, to modulate their distribution on chromatin. The lhp1 cyp71 double mutant showed more severe phenotypes than the single mutants, suggesting that AtCYP71 and LHP1 synergistically control plant development. Such synergism was in part illustrated by the observation that LHP1 association with its specific target loci requires AtCYP71 function. We also demonstrate that AtCYP71 physically interacts with FAS1 and is indispensable for FAS1 targeting to the KNAT1 locus. Together, our data suggest that AtCYP71 is involved in fundamental processes of chromatin assembly and histone modification in plants. PMID- 21596688 TI - Molecular dissection of xylan biosynthesis during wood formation in poplar. AB - Xylan, being the second most abundant polysaccharide in dicot wood, is considered to be one of the factors contributing to wood biomass recalcitrance for biofuel production. To better utilize wood as biofuel feedstock, it is crucial to functionally characterize all the genes involved in xylan biosynthesis during wood formation. In this report, we investigated roles of poplar families GT43 and GT8 glycosyltransferases in xylan biosynthesis during wood formation. There exist seven GT43 genes in the genome of poplar (Populus trichocarpa), five of which, namely PtrGT43A, PtrGT43B, PtrGT43C, PtrGT43D, and PtrGT43E, were shown to be highly expressed in the developing wood and their encoded proteins were localized in the Golgi. Comprehensive genetic complementation coupled with chemical analyses demonstrated that overexpression of PtrGT43A/B/E but not PtrGT43C/D was able to rescue the xylan defects conferred by the Arabidopsis irx9 mutant, whereas overexpression of PtrGT43C/D but not PtrGT43A/B/E led to a complementation of the xylan defects in the Arabidopsis irx14 mutant. The essential roles of poplar GT43 members in xylan biosynthesis was further substantiated by RNAi down-regulation of GT43B in the hybrid poplar (Populus alba x tremula) leading to reductions in wall thickness and xylan content in wood, and an elevation in the abundance of the xylan reducing end sequence. Wood digestibility analysis revealed that cellulase digestion released more glucose from the wood of poplar GT43B RNAi lines than the control wood, indicating a decrease in wood biomass recalcitrance. Furthermore, RNAi down-regulation of another poplar wood-associated glycosyltransferase, PoGT8D, was shown to cause decreases in wall thickness and xylan content as well as in the abundance of the xylan reducing end sequence. Together, these findings demonstrate that the poplar GT43 members form two functionally non-redundant groups, namely PtrGT43A/B/E as functional orthologs of Arabidopsis IRX9 and PtrGT43C/D as functional orthologs of Arabidopsis IRX14, all of which are involved in the biosynthesis of xylan backbones, and that the poplar GT8D is essential for the biosynthesis of the xylan reducing end sequence. PMID- 21596689 TI - Cytosolic HSP90 cochaperones HOP and FKBP interact with freshly synthesized chloroplast preproteins of Arabidopsis. AB - Most chloroplast and mitochondrial proteins are synthesized in the cytosol of the plant cell and have to be imported into the organelles post-translationally. Molecular chaperones play an important role in preventing protein aggregation of freshly translated preproteins and assist in maintaining the preproteins in an import competent state. Preproteins can associate with HSP70, HSP90, and 14-3-3 proteins in the cytosol. In this study, we analyzed a large set of wheat germ translated chloroplast preproteins with respect to their chaperone binding. Our results demonstrate that the formation of distinct 14-3-3 or HSP90 containing preprotein complexes is a common feature in post-translational protein transport in addition to preproteins that seem to interact solely with HSP70. We were able to identify a diverse and extensive class of preproteins as HSP90 substrates, thus providing a tool for the investigation of HSP90 client protein association. The analyses of chimeric HSP90 and 14-3-3 binding preproteins with exchanged transit peptides indicate an involvement of both the transit peptide and the mature part of the proteins, in HSP90 binding. We identified two partner components of the HSP90 cycle, which were present in the preprotein containing high-molecular-weight complexes, the HSP70/HSP90 organizing protein HOP, as well as the immunophilin FKBP73. The results establish chloroplast preproteins as a general class of HSP90 client proteins in plants using HOP and FKBP as novel cochaperones. PMID- 21596690 TI - Mechanistic analysis of AKT1 regulation by the CBL-CIPK-PP2CA interactions. AB - Arabidopsis K+ transporter 1 (AKT1) participates in K+ uptake in roots, especially under low-K conditions. We recently identified a Ca2+ signaling pathway consisting of multiple calcineurin B-like calcium sensors (CBLs) and multiple target kinases (CBL-interacting protein kinases or CIPKs) that phosphorylate and activate AKT1, whereas a specific PP2C-type phosphatase inactivates CIPK-dependent AKT1 activity. In this study, we analyzed the interactions between PP2Cs and the CBL-CIPK pathway and found previously unsuspected mechanisms underlying the CBL-CIPK-PP2C signaling processes. The interaction between the CIPKs and PP2Cs involves the kinase domain of the CIPK component, in addition to the protein phosphatase interacting motif (PPI) in the regulatory domain. Furthermore, specific CBLs physically interact with and inactivate PP2C phosphatases to recover the CIPK-dependent AKT1 channel activity. These findings provide further insights into the signaling network consisting of CBL-CIPK-PP2C interactions in the activation of the AKT1 channel. PMID- 21596691 TI - Treatment of 5413 hypertensive patients: a cross-sectional study. AB - BACKGROUND: Most hypertensive patients are managed in primary care in Denmark, but previous studies have shown that only 21-43% of hypertensive patients achieve optimal blood pressure (BP) control. Antihypertensive drug treatment, risk factors and cardiovascular disease (CVD) are some of the important factors to consider when optimizing the individual treatment strategy in hypertensive patients. OBJECTIVE: To examine treatment of BP according to Danish guidelines (BP < 140/90 mmHg generally and <130/80 mmHg for diabetics) in a population from general practice in relation to risk factors, CVD and diagnosis of diabetes. METHODS: A cross-sectional study comprising 184 practices and 5413 hypertensive patients was carried out in Denmark. The general practitioners filled in information on each patient's risk factors, CVD and antihypertensive drug treatment. Patients filled in a questionnaire on risk factors. The outcome measures were optimal BP control according to Danish guidelines and antihypertensive drug treatment. RESULTS: Mean patient age was 65.9 years [95% confidence interval (CI): 65.6-66.1]. Optimal BP control was achieved in 29.1% (95% CI: 27.9-30.3) of the study population. Among 842 diabetics with or without CVD, optimal BP control was achieved in 10.9% (95% CI: 8.8-10.3), while 38.7% (35.5-41.9) of patients with CVD achieved optimal BP control. The majority of all patients were treated with 1 (32.5%, 95% CI: 32.5 (31.3-33.8)) or two antihypertensive drugs (39.0%, 95% CI: 38.2-40.8). In hypertensive diabetics, 17.7% were not treated with an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker. CONCLUSION: In general practice, the proportion of hypertensive patients achieving optimal BP control is inadequate. The majority of hypertensive patients are treated with only one or two antihypertensive drugs. PMID- 21596692 TI - Management of out-of-hours calls by a general practice cooperative: a geographical analysis of telephone access and consultation. AB - BACKGROUND: Centralization of urgent care services may reduce access for patients living further away from primary care centres (PCCs). Telephone-based access is often proposed to remedy this. OBJECTIVE: To examine the effect of distance and rurality on the doctor's decision to manage the call by telephone or face-to face. METHODS: Geographical analysis of routine data on calls to an out-of-hours cooperative, including logistic regression to examine the effects of distance and rurality on triage decisions. RESULTS: For distances >6 km, the likelihood of receiving telephone advice only increased progressively with increasing distance from the PCC (Model 1). However, for those patients seen face-to-face, overall, there was increased likelihood of receiving a home visit (compared with PCC attendance) with increasing distance (Model 2). CONCLUSIONS: Patients experience differences in how their call to out-of-hours services is managed depending on where they live. Telephone access and consultation can be used to overcome geographical barriers but do not necessarily make access geographically equitable. Those who live furthest away are more likely to receive telephone advice rather than being seen face-to-face, but paradoxically, those who do get a home visit are more likely to live at a greater distance from the PCC. These findings present important challenges to proposals to integrate urgent care services and increase telephone-based provision and suggest that attention should be given to configuring services to ensure geographical equity of access, regardless of how far away people live from health services. PMID- 21596693 TI - Pre-arrest predictors of failure to survive after in-hospital cardiopulmonary resuscitation: a meta-analysis. AB - PURPOSE: Our objective was to perform a systematic review of pre-arrest predictors of the outcome of in-hospital cardiopulmonary resuscitation (CPR) in adults. METHODS: We searched PubMed for studies published since 1985 and bibliographies of previous meta-analyses. We included studies with predominantly adult patients, limited to in-hospital arrest, using an explicit definition of cardiopulmonary arrest and CPR and reporting survival to discharge by at least one pre-arrest variable. A total of 35 studies were included in the final analysis. Inclusion criteria, design elements and results were abstracted in parallel by both investigators. Discrepancies were resolved by consensus. RESULTS: The rate of survival to discharge was 17.5%; we found a trend towards increasing survival in more recent studies. Metastatic malignancy [odds ratio (OR) 3.9] or haematologic malignancy (OR 3.9), age over 70, 75 or 80 years (OR 1.5, 2.8 and 2.7, respectively), black race (OR 2.1), altered mental status (OR 2.2), dependency for activities of daily living (range OR 3.2-7.0 depending on specific activity), impaired renal function (OR 1.9), hypotension on admission (OR 1.8) and admission for pneumonia (OR 1.7), trauma (OR 1.7) or medical non cardiac diagnosis (OR 2.2) were significantly associated with failure to survive to discharge; cardiovascular diagnoses and co-morbidities were associated with improved survival (range OR 0.23-0.53). Elevated CPR risk scores predicted failure to survive but have not been validated consistently in different populations. CONCLUSIONS: We identified several pre-arrest variables associated with failure to survive to discharge. This information should be shared with patients as part of a shared decision-making process regarding the use of do not resuscitate orders. PMID- 21596694 TI - Immune responses associated with perioperative exposure and reexposure to topical bovine thrombin do not impair hemostasis. AB - Topical bovine thrombin has been associated with immune responses and anecdotal reports of coagulopathy. This open-label study assessed the impact on clinical hemostasis of human antibodies to bovine thrombin (aBT) or factor V/Va (aBV/Va) in response to topical bovine thrombin (THROMBIN-JMI) in patients both with and without preexisting anti-bovine antibodies. Noninferiority analysis assessed primary endpoint for mean shift from baseline activated partial thromboplastin time (aPTT) at 48 hours postsurgery; secondary endpoints included changes from baseline antibodies/titers and coagulation parameters through 8 weeks postsurgery. A total of 550 patients underwent surgery with THROMBIN-JMI utilized at investigator's discretion. Adjusted mean aPTT change in (+)aBT/(+)THROMBIN-JMI cohort was greater than (-)aBT/(-)THROMBIN-JMI cohort; 4.67-second upper confidence bound exceeded 4.5-second margin (based on assumed mean aPTT of 30 seconds) and noninferiority was not met. Post hoc analysis indicated noninferiority would have been met had noninferiority margin been set prior at relative 15% of actual baseline aPTT. Antibodies/titers were unchanged by THROMBIN-JMI exposure 48 hours postsurgery and unrelated to postsurgical changes in coagulation. Thus, THROMBIN-JMI exposure in patients with/without preexisting aBT or aBV/Va does not alter hemostasis. PMID- 21596695 TI - Retinal circulation after carotid artery revascularization. AB - Doubts still exist concerning the mechanisms involved in ocular ischemic syndrome (OIS) and its dependence on carotid disease. We report findings from 14 surgical patients undergoing carotid artery reconstruction for symptomatic cerebrovascular disease. All of them had fluorescein angiography (FA) of the eye ipsilateral to the carotid operation before surgery and 3 months after to provide information regarding retinal circulation time. Before the surgical procedure, the mean circulation time was 29.4 +/- 9.4 seconds (CI 95%: 24.5-34.3). After 3 months, a significant (P < .001) decrease in the circulation time was observed: 18.9 +/- 8.4 seconds (CI 95%: 14.5-23.4). The present series demonstrates that carotid revascularization surgery improved retinal flow in approximately 80% of the patients. PMID- 21596696 TI - Effect of carotid artery stenting on the release of S-100B and neurone-specific enolase. AB - Serum levels of S-100B and neurone-specific enolase (NSE) reflect cerebral injury in a variety of neurological conditions such as stroke, traumatic brain injury, and cardiac arrest. There are limited data on the release of S-100B and NSE following carotid artery stenting (CAS). In 22 patients undergoing CAS, serial blood samples for S-100B and NSE were collected before and 2, 4, and 6 to 8 hours after the procedure. A group of 20 patients with significant CAS undergoing purely diagnostic angiography served as controls. A significant increase in S 100B levels was observed 2 hours after the procedure in patients with CAS (P = .001) with a gradual decline over the next hours. In contrast, patients who underwent purely diagnostic angiography did not show significant changes in S 100B levels up to 8 hours after the procedure. Neither patients with CAS nor those undergoing diagnostic angiography displayed any significant changes in serial NSE levels. PMID- 21596697 TI - Prevalence, characteristics, and in-hospital outcomes of metabolic syndrome among acute coronary syndrome patients from Oman. AB - We evaluated in-hospital outcomes of acute coronary syndrome (ACS) patients with metabolic syndrome (MetS) in Oman. We analyzed the records of 1392 patients admitted with a diagnosis of ACS as part of the Gulf Registry of Acute Coronary Events. The prevalence of MetS among patients with ACS was 66%, with female preponderance (80% vs 57%; P < .001). MetS was associated with several characteristics including diabetes (45% vs 19%; P < .001), hyperlipidemia (40% vs 23%; P < .001), hypertension (62% vs 34%; P < .001), renal impairment (9.3% vs 3.4%; P < .001), Killip score > II (13% vs 8%; P = .004), and non-ST segment elevation myocardial infarction (78% vs 68%; P < .001). After multivariate adjustment, MetS was associated with higher risk of in-hospital heart failure (odds ratio [OR], 1.37; 95% CI: 1.03-1.81; P = .028) and mortality (OR, 4.42; 95% CI: 1.25-15.5; P = .020). Prevalence of MetS among patients with ACS in Oman is high. MetS was associated with higher in-hospital heart failure and mortality. PMID- 21596698 TI - Comparison of hyperemic changes in carotid-radial pulse wave velocity by upper and lower arm cuff occlusion. AB - Carotid-radial pulse wave velocity (PWV) normally decreases following release of upper arm cuff occlusion (hyperemia). Lower arm (LA) elicits less brachial artery dilation than upper arm (UA) occlusion but more closely reflects endothelial function. Using applanation tonometry, we compared changes (Delta) in PWV induced by UA and LA hyperemia in 65 healthy participants. Pulse wave velocity was measured serially. Both techniques decreased PWV maximally at 1 minute with gradual return to baseline by 9 minutes. DeltaPWV(1min) was greater for UA than LA occlusion (-11.5% vs -6.8%, P = .02). Multivariate analysis showed arm location independently related to DeltaPWV (P = .036). In participants with variable cardiovascular risk, PWV decline lessened with increasing Framingham risk for both techniques. IN CONCLUSION: UA and LA occlusion decrease PWV maximally at 1 minute after release of arterial occlusion. PWV(1min) decline are more marked after UA than LA occlusion and progressively lessens with increasing Framingham risk. PMID- 21596699 TI - Novel FDG-PET findings in anti-NMDA receptor encephalitis: a case based report. AB - The clinical manifestation and nuclear imaging findings in a 15-year-old boy with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis are described in this case report. The previously healthy patient presented with new onset hallucinations, seizure, and within a week, his mental status rapidly deteriorated to nonverbal with oro-lingual-facial dyskinesias. An extensive laboratory work-up for encephalopathy was negative. Repeated brain magnetic resonance imaging (MRI) studies were normal. On day 26 of admission, nuclear imaging using fluorodeoxyglucose positron emission tomography (FDG-PET) showed global hypometobolism with a prominent focally intense hypermetabolic lesion in the right cerebellar cortex. Diagnosis of anti-NMDAR encephalitis was confirmed with quantitative serology. The patient showed clinical signs of improvement after 2 courses of intravenous immunoglobulin therapy over 4 weeks. On day 46, repeat brain FDG-PET showed overall improvement but in contrast to the previous, the right cerebellar cortex showed focal hypometabolism. This is the first reported case of such findings using FDG-PET in anti-NMDAR encephalitis. PMID- 21596700 TI - Brain diffusivity in infants with hypoxic-ischemic encephalopathy following whole body hypothermia: preliminary results. AB - Hypoxic-ischemic encephalopathy is an important cause of neuropsychological deficits. Little is known about brain diffusivity in these infants following cooling and its potential in predicting outcome. Diffusion tensor imaging was applied to 3 groups: (1) three infants with hypoxic-ischemic encephalopathy: cooled; (2) three infants with hypoxic-ischemic encephalopathy: noncooled; and (3) four controls. Diffusivity values at the corticospinal tract, thalamus, and putamen were correlated with Apgar scores and early neurodevelopmental outcome. While cooled infants exhibited lower Apgar scores than noncooled infants, their developmental scores at a mean age of 8 months were higher. All groups differed in their diffusivity values with the cooled infants showing better values compared with the noncooled, correlating with early neurodevelopmental outcome. These preliminary results indicate that diffusion tensor imaging performed at an early age in infants with hypoxic-ischemic encephalopathy may forecast clinical outcome and support the neuroprotective effect of hypothermia treatment. PMID- 21596701 TI - Precocious puberty in two girls with PEHO syndrome: a clinical feature not previously described. AB - The authors present 2 girls with progressive encephalopathy, hypsarrhythmia, and optic atrophy syndrome. They describe a novel finding, precocious puberty, a feature not previously reported in this syndrome. The authors also present their clinical features and the results of investigations, including radiological findings, and compare the patients of this report to previously reported cases. PMID- 21596702 TI - Effects of ethyl loflazepate on refractory epilepsy in children. AB - We evaluated the safety and efficacy of ethyl loflazepate in children with epilepsy. The study group comprised 21 outpatients (4 by generalized, 17 by localization-related) aged between 9 months and 17 years. Ethyl loflazepate was administered at a dose of 0.015 mg/kg/day twice daily. The final mean dose was 1.35 mg/day. The mean number of prior antiepileptic drugs was 5.7. The entire treatment period was more than 24 months after ethyl loflazepate administration. Six children (28.6%) became seizure-free for the entire study 6 months after administration, 11 (52.4%) had a seizure reduction of more than 50% for over entire 24 months. The mean number of co-medications was 2.4. Adverse events occurred in only 1 patient. Responders, defined as reduction of >=50% in seizure frequency, included 2/2 of patients with West syndrome and 15/17 (88.2%) with localization-related epilepsy. Ethyl loflazepate represents an important addition to the treatments available for refractory epilepsies in children. PMID- 21596703 TI - Selective mutism and abnormal electroencephalography (EEG) tracings. AB - Epileptic discharges are not considered a part of the clinical picture of selective mutism, and electroencephalography is generally not recommended in its work-up. This report describes 6 children with selective mutism who were found to have a history of epilepsy and abnormal interictal or subclinical electroencephalography recordings. Two of them had benign epilepsy of childhood with centro-temporal spikes. The mutism was not related in time to the presence of active seizures. While seizures could be controlled in all children by medications, the mutism resolved only in 1. Although the discharges could be coincidental, they might represent a co-morbidity of selective mutism or even play a role in its pathogenesis. Selective mutism should be listed among the psychiatric disorders that may be associated with electroencephalographic abnormalities. It can probably be regarded as a symptom of a more complicated organic brain disorder. PMID- 21596704 TI - Bilateral ptosis in a child following massive attack by a swarm of wasps. AB - Neurological manifestations of wasp sting are rare and the etiopathogenesis is not completely understood. We report a 2-year-old girl who developed bilateral ptosis after multiple wasp stings, which responded partially to pyridostigmine. This is the first reported case of wasp venom-induced ptosis in a child. We discuss the possible pathogenetic mechanisms behind this phenomenon. PMID- 21596705 TI - Impaired mandibular function in spinal muscular atrophy type II: need for early recognition. AB - The aim of the study is to assess mandibular function in young patients with spinal muscular atrophy type II. A total of 12 children and young adults with spinal muscular atrophy type II and 12 healthy matched controls participated. The mandibular function impairment was moderate to severe in 50% of patients. A limited mouth opening (<=30 mm) was observed in 75% of the patients. In patients with a severe reduction of the mandibular range of motion the temporomandibular joint mainly rotated during mouth opening instead of the usual combination of rotation and sliding. The severity of the limited active mouth opening correlated with the severity of the disease (motor function measure scores). This study shows that mandibular dysfunction is common among young patients with spinal muscular atrophy type II. Early recognition of mandibular dysfunction may help to prevent complications such as aspiration as a result of chewing problems. PMID- 21596706 TI - Differences in methylphenidate use between immigrants and spaniards in the child population of aragon, Spain: a retrospective study. AB - The aim of this research is to study the differences in methylphenidate use in children from different ethnic groups in the region of Aragon, Spain. Differences in the use of methylphenidate between both groups of children, immigrants and Spanish nationals, were assessed based on the total number of methylphenidate prescriptions made out for all children in Aragon in 2008 (N = 98 837). We have used defined daily doses and the defined daily doses per 1000 inhabitants per day. Defined daily doses per 1000 inhabitants per day of methylphenidate use was 18.49 in Spanish boys compared with 2.70 in immigrant boys, and 5.48 in Spanish girls versus 0.83 in immigrant girls. All differences between groups were statistically significant (P < .001). This study confirms that methylphenidate use is higher in a local population than in an immigrant population. Western European and North American children show the highest use, followed by Latin Americans and Eastern Europeans. PMID- 21596707 TI - Manganese toxicity in a child with iron deficiency and polycythemia. AB - A previously healthy 5-year-old girl presented with pica, emotional lability, and marked gait abnormalities. She had concurrent severe iron deficiency and polycythemia. Her magnetic resonance imaging (MRI) scan showed increased signal in the basal ganglia on T1-weighted images consistent with manganese neurotoxicity. Manganism was subsequently confirmed as her blood manganese levels were extremely elevated. Chelation therapy resulted in improvement in her mobility but she continues to have significant gait impairment. An epidemiological investigation identified well water as the potential source of manganese exposure for our patient, but to date, we have been unable to identify the nature of her neurotoxic susceptibility. PMID- 21596708 TI - Establishment and characterization of a spontaneously immortalized trophoblast cell line (HPT-8) and its hepatitis B virus-expressing clone. AB - BACKGROUND: Most trophoblast cell lines currently available to study vertical transmission of hepatitis B virus (HBV) are immortalized by viral transformation. Our goal was to establish and characterize a spontaneously immortalized human first-trimester trophoblast cell line and its HBV-expressing clone. METHODS: Chorionic villi of Asian human first-trimester placentae were digested with trypsin and collagenase I to obtain the primary trophoblast cell culture. A spontaneously immortalized trophoblast cell line (HPT-8) was analyzed by scanning and transmission electron microscopy, cell cycle analysis, immunohistochemistry and immunofluorescence. HPT-8 cells were stably transfected with the adr subtype of HBV (HPT-8-HBV) and characterized by PCR and enzyme-linked immunosorbent assay. RESULTS: We obtained a clonal derivative of a spontaneously immortalized primary cell clone (HPT-8). HPT-8 cells were epithelioid and polygonal, and formed multinucleate, giant cells. They exhibited microvilli, distinct desmosomes between adjacent cells, abundant endoplasm, lipid inclusions and glycogen granules, which are all characteristic of cytotrophoblasts. HPT-8 cells expressed cytokeratin 7, cytokeratin 18, vimentin, cluster of differentiation antigen 9, epidermal growth factor receptor, stromal cell-derived factor 1 and placental alkaline phosphatase. They secreted prolactin, estradiol, progesterone and hCG, and were positive for HLA-G, a marker of extravillous trophoblasts. HPT-8-HBV cells were positive for HBV relaxed-circular, covalently closed circular DNA and pre-S sequence. HPT-8-HBV cells also produced and secreted HBV surface antigen and HBV e antigen. CONCLUSIONS: We established a trophoblast cell line, HPT-8 and its HBV-expressing clone which could be valuable in exploring the mechanism of HBV viral integration in human trophoblasts during intrauterine infection. PMID- 21596709 TI - Direct and indirect effects of perceived social support on women's infertility related stress. AB - BACKGROUND: Social support can be a critical component of how a woman adjusts to infertility, yet few studies have investigated its impact on infertility-related coping and stress. We examined relationships between social support contexts and infertility stress domains, and tested if they were mediated by infertility related coping strategies in a sample of infertile women. METHODS: The Multidimensional Scale of Perceived Social Support, the Copenhagen Multi-centre Psychosocial Infertility coping scales and the Fertility Problem Inventory were completed by 252 women seeking treatment. Structural equation modeling analysis was used to test the hypothesized multiple mediation model. RESULTS: The final model revealed negative effects from perceived partner support to relationship concern (beta = -0.47), sexual concern (beta = -0.20) and rejection of childfree lifestyle through meaning-based coping (beta = -0.04). Perceived friend support had a negative effect on social concern through active-confronting coping (beta = -0.04). Finally, besides a direct negative association with social concern (beta = -0.30), perceived family support was indirectly and negatively related with all infertility stress domains (beta from -0.04 to -0.13) through a positive effect of active-avoidance coping. The model explained between 12 and 66% of the variance of outcomes. CONCLUSIONS: Despite being limited by a convenience sampling and cross-sectional design, results highlight the importance of social support contexts in helping women deal with infertility treatment. Health professionals should explore the quality of social networks and encourage seeking positive support from family and partners. Findings suggest it might prove useful for counselors to use coping skills training interventions, by retraining active avoidance coping into meaning-based and active-confronting strategies. PMID- 21596711 TI - Detection of falls using accelerometers and mobile phone technology. AB - OBJECTIVES: to study the sensitivity and specificity of fall detection using mobile phone technology. DESIGN: an experimental investigation using motion signals detected by the mobile phone. SETTING AND PARTICIPANTS: the research was conducted in a laboratory setting, and 18 healthy adults (12 males and 6 females; age = 29 +/- 8.7 years) were recruited. MEASUREMENT: each participant was requested to perform three trials of four different types of simulated falls (forwards, backwards, lateral left and lateral right) and eight other everyday activities (sit-to-stand, stand-to-sit, level walking, walking up- and downstairs, answering the phone, picking up an object and getting up from supine). Acceleration was measured using two devices, a mobile phone and an independent accelerometer attached to the waist of the participants. RESULTS: Bland-Altman analysis shows a higher degree of agreement between the data recorded by the two devices. Using individual upper and lower detection thresholds, the specificity and sensitivity for mobile phone were 0.81 and 0.77, respectively, and for external accelerometer they were 0.82 and 0.96, respectively. CONCLUSION: fall detection using a mobile phone is a feasible and highly attractive technology for older adults, especially those living alone. It may be best achieved with an accelerometer attached to the waist, which transmits signals wirelessly to a phone. PMID- 21596712 TI - Non-medical sex-selective abortion in China: ethical and public policy issues in the context of 40 million missing females. AB - INTRODUCTION: The rapidly growing imbalance of the sex ratio at birth (SRB) in China since the late 1980s demonstrates that, despite an extensive official prohibition, sex-selective abortion has been widely practised there in the past two or three decades. Given the reality of 30-40 million missing females, China has a more challenging set of ethical and social policy issues to be addressed regarding sex-selective abortion than is the case in Western and many other countries. SOURCES OF DATA: This article is based on a search and review of Chinese and English-language literature, including several very recent books in Chinese on the imbalance of the sex ratio at birth in China. It also draws on first-hand information gathered from the author's extensive fieldwork on Chinese views and experiences of abortion. AREAS OF AGREEMENT: The current female deficit is a real and serious problem in China-not a 'false alarm' as earlier alleged. It is a direct consequence of the widespread practice of sex-selective abortion and is chiefly caused by the strong socio-cultural preference for sons in China. Chinese academics-demographers and medical ethicists-in general agree with the official position that sex-selective abortion is morally wrong and should be legally prohibited. AREAS OF CONTROVERSY: Some critical voices, mainly in the English-language literature, have asked whether coercive state intervention in this area is ethically justifiable. Another controversial question is whether and to what degree China's ambitious and rigorous population control programme, widely known as the 'one child' policy, is a contributing factor to the phenomenon of millions of missing females. AREAS TIMELY FOR DEVELOPING RESEARCH: Much further research on the ethical and social policy issues surrounding sex selective abortion in the Chinese context needs to be done. Systematic quantitative and in-depth qualitative sociological investigations into Chinese people's attitudes toward the subject, and the role of medical professionals, are long overdue. PMID- 21596710 TI - A translational continuum of model systems for evaluating treatment strategies in Alzheimer's disease: isradipine as a candidate drug. AB - A growing body of evidence supports the 'calcium hypothesis' of Alzheimer's disease (AD), which postulates that a variety of insults might disrupt the homeostatic regulation of neuronal calcium (Ca(2+)) in the brain, resulting in the progressive symptoms that typify the disease. However, despite ongoing efforts to develop new methods for testing therapeutic compounds that might be beneficial in AD, no single bioassay permits both rapid screening and in vivo validation of candidate drugs that target specific components of the Ca(2+) regulatory machinery. To address this issue, we have integrated four distinct model systems that provide complementary information about a trial compound: the human neuroblastoma MC65 line, which provides an in vitro model of amyloid toxicity; a transgenic Drosophila model, which develops age-dependent pathologies associated with AD; the 3*TgAD transgenic mouse, which recapitulates many of the neuropathological features that typify AD; and the embryonic nervous system of Manduca, which provides a novel in vivo assay for the acute effects of amyloid peptides on neuronal motility. To demonstrate the value of this 'translational suite' of bioassays, we focused on a set of clinically approved dihydropyridines (DHPs), a class of well-defined inhibitors of L-type calcium channels that have been suggested to be neuroprotective in AD. Among the DHPs tested in this study, we found that isradipine reduced the neurotoxic consequences of beta-amyloid accumulation in all four model systems without inducing deleterious side effects. Our results provide new evidence in support of the Ca(2+) hypothesis of AD, and indicate that isradipine represents a promising drug for translation into clinical trials. In addition, these studies also demonstrate that this continuum of bioassays (representing different levels of complexity) provides an effective means of evaluating other candidate compounds that target specific components of the Ca(2+) regulatory machinery and that therefore might be beneficial in the treatment of AD. PMID- 21596713 TI - Stem cell therapy for heart diseases. AB - BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Despite the advances in medical and catheter-based therapy for acute myocardial infarction the 1-year mortality remains as high as 13% and the 5-year prognosis for patients with heart failure remains as high as 50%. Left ventricular systolic dysfunction, a major determinant of prognosis, is associated with significant loss of cardiomyocytes which was previously thought to be irreversible as the heart was considered a post-mitotic organ. SOURCES OF DATA: Review of literature published in peer reviewed journals and ClinicalTrials.Gov website. AREAS OF AGREEMENT: There is now growing evidence that the human heart is capable of undergoing repair and in recent years there has been an increase in basic and clinical research with the aim of harnessing the regenerative properties of stem cells in order to facilitate restoration of myocardial function. AREAS OF CONTROVERSY: The mechanisms of action of cell therapy with regards to cardiac repair remain unsatisfactorily understood and the magnitude of benefit demonstrated in animal models is yet to be fully translated in humans. GROWING POINTS: The number of clinical trials continues to increase and include treating patients with acute myocardial infarction and chronic heart failure secondary to ischaemic heart disease or dilated cardiomyopathy. AREAS TIMELY FOR DEVELOPING RESEARCH: The future of this field of research will require closer collaboration between scientists and clinicians to understand how cell therapy works and to define the ideal cell type and method of delivery to be able to derive maximum benefit. PMID- 21596714 TI - Guidance for withdrawal and withholding of intensive care as part of neonatal end of-life care. AB - INTRODUCTION: Advances in foetal medicine and neonatology have enabled increased antenatal diagnosis of life-limiting conditions and improved preterm survival, escalating the debate surrounding the ethics of neonatal end-of-life care and withholding or withdrawing intensive care. SOURCES OF DATA: Literature search of MEDLINE and the Cochrane library databases using the search terms [neonatal palliative care] AND [neonatal AND withdrawal of intensive care and treatment]. Review of consensus statements and guidelines. AREAS OF AGREEMENT: UK practice is aided by Grade 3-4 evidence, consensus statements and practice frameworks. There is limited systematic evidence. AREAS OF CONTROVERSY: We illustrate UK practice with clinical cases and describe worldwide variations. GROWING POINTS: Neonatal end-of-life care incorporating withholding and withdrawing intensive care is not uncommon. The child's 'best interests' take precedent and clinical guidance has been published to support the joint decision-making partnership of clinicians and families. Withholding and withdrawing intensive care should be part of an overall end-of-life care plan incorporating the principles and standards of palliative care. AREAS TIMELY FOR DEVELOPING RESEARCH: Further guidance on standards and staff training with regard to communicating and delivering neonatal end-of-life care is required to ensure consistent practice of staff and choices for families. The recommended establishment of neonatal outcome databases should aid UK preterm decision-making (NHS and Department of Health Neonatal Taskforce, Toolkit for high-quality neonatal services, London, Department of Health 2009). PMID- 21596715 TI - Exercise, appetite and weight management: understanding the compensatory responses in eating behaviour and how they contribute to variability in exercise induced weight loss. AB - Does exercise promote weight loss? One of the key problems with studies assessing the efficacy of exercise as a method of weight management and obesity is that mean data are presented and the individual variability in response is overlooked. Recent data have highlighted the need to demonstrate and characterise the individual variability in response to exercise. Do people who exercise compensate for the increase in energy expenditure via compensatory increases in hunger and food intake? The authors address the physiological, psychological and behavioural factors potentially involved in the relationship between exercise and appetite, and identify the research questions that remain unanswered. A negative consequence of the phenomena of individual variability and compensatory responses has been the focus on those who lose little weight in response to exercise; this has been used unreasonably as evidence to suggest that exercise is a futile method of controlling weight and managing obesity. Most of the evidence suggests that exercise is useful for improving body composition and health. For example, when exercise-induced mean weight loss is <1.0 kg, significant improvements in aerobic capacity (+6.3 ml/kg/min), systolic (-6.00 mm Hg) and diastolic (-3.9 mm Hg) blood pressure, waist circumference (-3.7 cm) and positive mood still occur. However, people will vary in their responses to exercise; understanding and characterising this variability will help tailor weight loss strategies to suit individuals. PMID- 21596716 TI - Five-year changes in school recess and lunchtime and the contribution to children's daily physical activity. AB - OBJECTIVE: To investigate the longitudinal changes in children's recess and lunchtime physical activity levels and in the contribution of recess and lunchtime to daily physical activity levels over 5 years among 5-6- and 10-12 year olds. METHODS: Data were drawn from two longitudinal studies that were conducted in metropolitan Melbourne, Australia. Boys and girls (n=2782) aged 5-6 years and 10-12 years participated in baseline (T0) measures. Physical activity (n=2490) was measured every 60 s for eight consecutive days using hip-mounted accelerometry. Subsequent measurements were taken at 3-year (T1; n=773) and 5 year (T2; n=634) follow-up. Physical activity intensities were derived using age adjusted cut-points. Sedentary time was defined as 100 counts/min. Longitudinal data were analysed using three-level (time, child, school) multilevel analyses, stratified by sex and cohort, and adjusted for potential confounding variables. RESULTS: Significant decreases in recess and lunchtime moderate and vigorous physical activity were observed (p<0.001), with larger decreases occurring in the older cohort. Associated increases were observed in sedentary time over time (p<0.01). Although the contribution of recess to daily moderate intensity physical activity increased in the younger cohort over time (p<0.001), significant decreases were observed in the older cohort (p<0.001). CONCLUSION: Physical activity levels during recess and lunchtime decreased in both cohorts over time. Decreases in the contribution of recess and lunchtime to older children's daily physical activity were also observed. Interventions are needed in both primary and secondary schools to promote physical activity levels during recess and lunchtime, particularly during the early years of secondary school. PMID- 21596717 TI - Prevalence of electrocardiographic abnormalities in West-Asian and African male athletes. AB - OBJECTIVES: To evaluate the electrocardiographic (ECG) characteristics of West Asian, black and Caucasian male athletes competing in Qatar using the 2010 recommendations for 12-lead ECG interpretation by the European Society of Cardiology (ESC). DESIGN: Cardiovascular screening with resting 12-lead ECG analysis of 1220 national level athletes (800 West-Asian, 300 black and 120 Caucasian) and 135 West-Asian controls was performed. RESULTS: Ten per cent of athletes presented with 'uncommon' ECG findings. Black African descent was an independent predictor of 'uncommon' ECG changes when compared with West-Asian and Caucasian athletes (p<0.001). Black athletes also demonstrated a significantly greater prevalence of lateral T-wave inversions than both West-Asian and Caucasian athletes (6.1% vs 1.6% and 0%, p<0.05). The rate of 'uncommon' ECG changes between West-Asian and Caucasian athletes was comparable (7.9% vs 5.8%, p>0.05). Seven athletes (0.6%) were identified with a disease associated with sudden death; this prevalence was two times higher in black athletes than in West Asian athletes (1% vs 0.5%), and no cases were reported in Caucasian athletes and West-Asian controls. Eighteen West-Asian and black athletes were identified with repolarisation abnormalities suggestive of a cardiomyopathy, but ultimately, none were diagnosed with a cardiac disease. CONCLUSION: West-Asian and Caucasian athletes demonstrate comparable rates of ECG findings. Black African ethnicity is positively associated with increased frequencies of 'uncommon' ECG traits. Future work should examine the genetic mechanisms behind ECG and myocardial adaptations in athletes of diverse ethnicity, aiding in the clinical differentiation between physiological remodelling and potential cardiomyopathy or ion channel disorders. PMID- 21596718 TI - Defining asymptomatic status following sports concussion: fact or fallacy? AB - The current management of sports concussion involves a return to the baseline 'asymptomatic' status prior to returning to play and training. Unfortunately, although the term 'asymptomatic' is widely used it has not been operationally defined. This review identifies the need to formally define the term 'asymptomatic' as used in sports concussion, discusses some of the challenges associated with its definition and offers some possible solutions for further debate. The operational definition of the term 'asymptomatic' may provide the stimulus for further informed discussion at a future meeting of the international Concussion in Sport group, and by other peak sports medicine bodies involved in management guideline development. PMID- 21596719 TI - Adjusting the timing of left-ventricular pacing using electrocardiogram and device electrograms. AB - AIMS: Left-ventricular (LV) pacing with optimized atrio-ventricular (AV) timing may provide similar or greater benefit in comparison with bi-ventricular (BiV) pacing in a subset of cardiac resynchronization therapy (CRT) patients with sinus rhythm and preserved AV conduction. We hypothesized that the optimal device AV delays during LV pacing can be predicted using electrocardiogram (ECG) and device electrograms. METHODS AND RESULTS PATIENTS: (n= 55) with sinus rhythm and PR interval < 300 ms had their CRT devices programmed to atrial and LV pacing with a range of AVs as well as to echocardiographically optimized BiV and no ventricular pacing. At each setting, LV function was evaluated using echocardiography and AVs corresponding to the highest LV ejection fraction (LVEF), lowest LV end-systolic volume (LVESV), and the average of the two (by EF and ESV) were determined. Correlation between the optimal AVs and the following intervals was investigated: intrinsic QRS duration (QRSs), intervals from atrial pacing (Ap) to right ventricular (RV) sensing (Ap-RVs), from RV sensing to LV activation (RVs-LVs), and from LV pacing to RV sensing (LVp-RVs). Optimal AVs moderately correlated with intrinsic Ap-RVs interval, whereas other parameters showed weak or no correlation. The best correlation (R = 0.66, P< 0.0001) was between the optimal AV delay according to EF and ESV, and Ap-RVs interval. Programming of AVs during LV pacing to the shortest of 70% of the intrinsic Ap-RVs interval, or Ap-RVs--40 ms resulted in significant improvement in LV function similar to that in case of BiV. CONCLUSION: Optimal AV during LV pacing can be approximated from the intrinsic AV conduction time. PMID- 21596720 TI - An unusual atrial tachycardia in a patient with Friedreich ataxia. AB - We present the unusual association of an atrial tachycardia with Friedreich ataxia. The arrhythmia was initially suspected to be focal in origin; however, use of a three-dimensional mapping system demonstrated that the tachycardia was macro-reentrant. This was subsequently treated successfully by linear ablation. PMID- 21596721 TI - Dissemination of the New Delhi metallo-beta-lactamase-1 (NDM-1) among Enterobacteriaceae in a tertiary referral hospital in north India. PMID- 21596723 TI - Scientific research and corporate influence: smoking, mental illness, and the tobacco industry. AB - Mentally ill individuals have always smoked at high rates and continue to do so, despite public health efforts to encourage smoking cessation. In the last half century, the tobacco industry became interested in this connection, and conducted and supported psychiatric and basic science research on the mental health implications of smoking, long before most mental health professionals outside the industry investigated this issue. Initially, representatives of tobacco industry research organizations supported genetics and psychosomatic research to try to disprove findings that smoking causes lung cancer. Tobacco industry research leaders engaged with investigators because of shared priorities and interests in the brain effects of nicotine. By the 1980s, collaborative funding programs and individual company research and development teams engaged in intramural and extramural basic science studies on the neuropharmacology of nicotine. When mental health researchers outside the industry became interested in the issue of the mentally ill and smoking in the mid-1990s, they increasingly explained it in terms of a disease of nicotine addiction. Both the idea that smoking/nicotine does something positive for the mentally ill and the conclusion that it is the result of nicotine dependence have the potential to support corporate agendas (tobacco or pharmaceutical). PMID- 21596722 TI - Antimicrobial prescribing in European nursing homes. AB - OBJECTIVES: The aim of this study was to investigate antimicrobial prescribing in nursing homes in countries across Europe. METHODS: Point prevalence studies were completed in April and November 2009 in 85 nursing homes in 15 European countries and two UK administrations. RESULTS: A total of 10,388 and 9430 residents participated in April and November 2009, respectively. The mean prevalence of antimicrobial prescribing in the nursing homes was 6.5% in April and 5.0% in November. The most commonly prescribed antimicrobials were methenamine (17.5%), trimethoprim (11.4%) and co-amoxiclav (11.1%) in April and co-amoxiclav (12.2%), nitrofurantoin (12.2%) and methenamine (11.5%) in November. There was large variation in the overall mean antimicrobial prescribing in the selected nursing homes from each of the contributing countries, ranging from 1.4% in Germany and Latvia to 19.4% in Northern Ireland in April and 1.2% in Latvia to 13.4% in Finland in November. Furthermore, differences in prescribing were apparent within countries with the largest variation evident in nursing homes in Northern Ireland (21.5%) in April and Finland in November (30.1%). CONCLUSIONS: This is the first study to investigate antimicrobial prescribing in nursing homes in a large number of European countries. The findings suggest that there is considerable variation in antimicrobial prescribing in nursing homes across and within European countries. Nursing homes provide a significant service to the European community and must be supported in order to optimize antimicrobial use and limit the development of antimicrobial resistance. PMID- 21596724 TI - War neuroses and Arthur Hurst: a pioneering medical film about the treatment of psychiatric battle casualties. AB - From 1917 to 1918, Major Arthur Hurst filmed shell-shocked patients home from the war in France. Funded by the Medical Research Committee, and using Pathe cameramen, he recorded soldiers who suffered from intractable movement disorders as they underwent treatment at the Royal Victoria Hospital in Netley and undertook programs of occupational therapy at Seale Hayne in Devon. As one of the earliest UK medical films, Hurst's efforts may have drawn inspiration from the official documentary of the Battle of the Somme and films made in 1916 by French Army neurologists. Although initially motivated to make use of a novel medium to illustrate lectures, Hurst was alert to the wider appeal of the motion picture and saw an opportunity to position himself in the postwar medical hierarchy. Some "before treatment" shots were reenacted for the camera. Hurst, like some other shell shock doctors, openly used deception as a therapeutic measure. On the basis that the ends justified the means, they defended this procedure as ethical. Clinicians also took advantage of changes in military regulations to address functional symptoms. Claims made of "cures" in the film and associated publications by Hurst were challenged by other doctors treating shell shock. The absence of follow-up data and evidence from war pension files suggested that Hurst may have overstated the effectiveness of his methods. Nevertheless, the message conveyed in the film that chronic cases could be treated in a single session had a powerful resonance for ambitious or charismatic doctors and was revived in World War II. PMID- 21596725 TI - Grading recommendations in clinical practice guidelines: randomised experimental evaluation of four different systems. AB - OBJECTIVE: To evaluate the effect of presenting a recommendation in a clinical practice guideline using different grading systems to determine to what extent the system used changes the clinician's eventual response to a particular clinical question. DESIGN: Randomised experimental study. SETTING: Clinician offices and academic settings. PARTICIPANTS: Paediatricians and paediatric residents in private and public practice in Mexico. INTERVENTION: Case notes of a child with diarrhoea and a question about clinician preference for using racecadotril. The same evidence was provided in a clinical recommendation but with different presentations according to the following grading systems: NICE (National Institute for Health and Clinical Excellence), SIGN (Scottish Intercollegiate Guideline Network), GRADE (Grading of Recommendations Assessment, Development and Evaluation) and CEBM (Centre for Evidence-Based Medicine, Oxford). MAIN OUTCOME MEASURE: Mean change in direction from baseline response (measured on a 10 cm visual scale and a Likert scale) and among groups. RESULTS: 216 subjects agreed to participate. Most participants changed their decision after reading the clinical recommendations (mean difference 0.7 cm, 95% CI 0.29 to 1.0; p<0.001). By groups, mean change (95% CI) from baseline was 0.04 (-0.68 to 0.77) for NICE, 0.31 (-0.41 to 1.05) for SIGN, 2.18 (1.48 to 2.88) for GRADE and 0.08 (-0.52 to 0.69) for CEBM (p=0.007 between groups). In a final survey, a small difference was noted regarding the clarity of the results presented with the GRADE system. CONCLUSION: The clinician's decision to use a therapy was influenced most by the GRADE system. TRIAL REGISTRATION NUMBER: NCT00940290. PMID- 21596726 TI - Serum phenytoin concentrations in paediatric patients following intravenous loading. AB - Phenytoin is used to treat acute tonic-clonic seizures in children who have not responded to a benzodiazepine. In the UK, the loading dose of phenytoin is 18 mg/kg. There is limited evidence on whether this loading dose will achieve the desired levels in paediatric patients. Intravenous loading doses of phenytoin were retrospectively and prospectively audited over 19 months. Doses were normalised for weight and compared with the serum phenytoin concentrations. Errors in dose calculations and adverse events were recorded. Serum phenytoin concentrations were measured on 31 occasions in 27 children (24 retrospective and 10 prospective) between 60 and 180 (median, 153) min after completion of the loading dose. Serum phenytoin concentrations were within the therapeutic range (10-20 MUg/ml) on 24 occasions. No errors in dose calculations or adverse effects were identified. A phenytoin loading dose of 18 mg/kg gave serum concentrations within the recommended therapeutic range in most children. PMID- 21596727 TI - Antibody persistence following MeNZB vaccination of adults and children and response to a fourth dose in toddlers. AB - BACKGROUND: A New Zealand serogroup B meningococcal epidemic prompted trials of a strain-specific (B:4:P1.7-2,4) outer membrane vesicle vaccine (MeNZB). METHODS: Adults, school children, and infants provided serum after three MeNZB doses to evaluate antibody persistence via serum bactericidal assay. Toddler (16-24 months) non-responders and responders received a fourth MeNZB dose 11 and 17 months after dose three respectively. Response was a >=4-fold rise in bactericidal titre to a titre of >=8. RESULTS: Geometric mean bactericidal titres (GMTs), with 95% CI, after dose 3: adults: 27 (14-52), 5 (3-11), and 7 (3-15) at 1, 10, and 22 months; school children: 18 (13-25) and 4 (3-6) at 1 and 4 months; infants: 27 (19-39) and 2 (2-3) at 1 and 7 months. The titre achieved after priming significantly influenced persistence. Toddler non-responder GMTs were 4 (3-5) and 1 (1-1) at 1 and 11 months after dose 3 and 69 (46-106) 1 month after dose 4. Responder GMTs were 24 (19-30) and 3 (2-4) at 1 and 17 months after dose 3 and 259 (184-363) 1 month after dose 4. Dose 4 had no safety concerns. CONCLUSIONS: Immune response to MeNZB was most sustained in adults. In infants, bactericidal titres decayed almost to baseline by 7 months after dose 3. Toddlers showed marked immune response following a fourth dose suggesting memory. Persisting antibody is likely to be necessary for ongoing protection, as seen with serogroup C meningococci. PMID- 21596728 TI - Changes in primary care prescribing patterns for paediatric asthma: a prescribing database analysis. AB - BACKGROUND: Little is known about the impact of British asthma management guideline revisions. Concerns about the use of high dose inhaled corticosteroids (ICS) in children have resulted in the promotion of add-on therapy. AIMS: To assess prescribing patterns of asthma medication in children in the primary care setting. METHODS: Retrospective observational study of asthma prescribing in children aged 0-18 years using primary care database from 2001 to 2006. RESULTS: The proportion of children prescribed oral corticosteroids increased significantly (from 6% in 2001-2002 to 16% in 2005-2006, p<0.001), while the proportion of children prescribed an ICS dose of >400 mcg decreased from 16.2% to 11.7% (P<0.001). The proportion of children prescribed an add-on therapy and an ICS dose >400 ug, increased from 38.8 % in 2001-2002 to 61.2% in 2005-2006 (p<0.001). CONCLUSIONS: Although adherence with asthma management guidelines is not optimal, this study has identified improved adherence in primary care. PMID- 21596729 TI - Recursive partitioning of resistant mutations for longitudinal markers based on a U-type score. AB - Development of human immunodeficiency virus resistance mutations is a major cause of failure of antiretroviral treatment. We develop a recursive partitioning method to correlate high-dimensional viral sequences with repeatedly measured outcomes. The splitting criterion of this procedure is based on a class of U-type score statistics. The proposed method is flexible enough to apply to a broad range of problems involving longitudinal outcomes. Simulation studies are performed to explore the finite-sample properties of the proposed method, which is also illustrated through analysis of data collected in 3 phase II clinical trials testing the antiretroviral drug efavirenz. PMID- 21596730 TI - Social acknowledgement as a predictor of post-traumatic stress and complicated grief after witnessing assisted suicide. AB - BACKGROUND: In Switzerland, right-to-die organizations such as Exit Deutsche Schweiz offer suicide assistance to their members. However, there is limited knowledge of the impact that witnessing assisted suicide has on the post traumatic stress severity or the grief process of family members. Low perceived social acknowledgement may affect mental health. METHODS: A cross-sectional survey of 85 family members who were present at an assisted suicide was conducted in December 2007. The Inventory of Complicated Grief and the Impact of Event Scale were used to assess symptoms of post-traumatic stress disorder (PTSD) and complicated grief (CG) at 14 to 24 months post-loss. Further, the Social Acknowledgement Questionnaire was used to examine the impact that the social environment's acknowledgement of the end-of-life decision had on respondents' mental health. RESULTS: As expected, social acknowledgement as a survivor was related to PTSD symptoms and CG. In particular, perceived general disapproval was strongly correlated with all outcome measures, whereas recognition was not significantly related to PTSD or CG (intrusion and avoidance). CONCLUSION: Family members of patients who use assisted suicide may hesitate to disclose the manner of death, and the community and societal environment may express strong views concerning the end-of-life decision. This can lead to increased levels of PTSD and CG. PMID- 21596731 TI - Revascularization of complete and incomplete distal finger amputations in children below 2 years of age: a report of three cases. AB - Three cases of fingertip amputation at the level between the distal phalanx and the nail base in children below 2 years of age were treated by replantation or revascularization. The injury was complete in two, and incomplete in one. All three fingerstips survived with artery anastomosis without the need for a blood transfusion. In two venous anastomosis failed and venous drainage was achieved by 3-hourly pinprick. Survival of an amputated finger can be expected in cases where venous reconstruction is not possible, provided that there is adequate venous drainage. PMID- 21596732 TI - Anticipatory grief among close relatives of patients in hospice and palliative wards. AB - A Swedish widowhood study revealed that four out of ten widows regarded the pre loss period more stressful than the post-loss. The present investigation of close relatives to patients dying from cancer (using interviews and the Anticipatory Grief Scale) found that preparatory grief involves much emotional stress, as intense preoccupation with the dying, longing for his/her former personality, loneliness, tearfulness, cognitive dysfunction, irritability, anger and social withdrawal, and a need to talk. Psychological status was bad one by every fifth. However, the relatives mostly stated adjustment and ability to mobilize strength to cope with the situation. The results suggest development of support and guiding programs also for the anticipatory period. PMID- 21596733 TI - Getting better. PMID- 21596734 TI - Can a dietary supplement prevent pre-eclampsia? PMID- 21596737 TI - Don't weaken the role of Monitor, spokesman for private and charity providers says. PMID- 21596735 TI - Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medical food on pre-eclampsia in high risk population: randomised controlled trial. AB - OBJECTIVE: To test the hypothesis that a relative deficiency in L-arginine, the substrate for synthesis of the vasodilatory gas nitric oxide, may be associated with the development of pre-eclampsia in a population at high risk. DESIGN: Randomised, blinded, placebo controlled clinical trial. SETTING: Tertiary public hospital in Mexico City. PARTICIPANTS: Pregnant women with a history of a previous pregnancy complicated by pre-eclampsia, or pre-eclampsia in a first degree relative, and deemed to be at increased risk of recurrence of the disease were studied from week 14-32 of gestation and followed until delivery. INTERVENTIONS: Supplementation with a medical food-bars containing L-arginine plus antioxidant vitamins, antioxidant vitamins alone, or placebo-during pregnancy. MAIN OUTCOME MEASURE: Development of pre-eclampsia/eclampsia. RESULTS: 222 women were allocated to the placebo group, 228 received L-arginine plus antioxidant vitamins, and 222 received antioxidant vitamins alone. Women had 4-8 prenatal visits while receiving the bars. The incidence of pre-eclampsia was reduced significantly (chi(2) = 19.41; P < 0.001) in women randomised to L arginine plus antioxidant vitamins compared with placebo (absolute risk reduction 0.17 (95% confidence interval 0.12 to 0.21). Antioxidant vitamins alone showed an observed benefit, but this effect was not statistically significant compared with placebo (chi(2) = 3.76; P = 0.052; absolute risk reduction 0.07, 0.005 to 0.15). L-arginine plus antioxidant vitamins compared with antioxidant vitamins alone resulted in a significant effect (P = 0.004; absolute risk reduction 0.09, 0.05 to 0.14). CONCLUSIONS: Supplementation during pregnancy with a medical food containing L-arginine and antioxidant vitamins reduced the incidence of pre eclampsia in a population at high risk of the condition. Antioxidant vitamins alone did not have a protective effect for prevention of pre-eclampsia. Supplementation with L-arginine plus antioxidant vitamins needs to be evaluated in a low risk population to determine the generalisability of the protective effect, and the relative contributions of L-arginine and antioxidant vitamins to the observed effects of the combined treatment need to be determined. Trial registration Clinical trials NCT00469846. PMID- 21596739 TI - Total disc replacement for chronic low back pain. PMID- 21596741 TI - DH plans over public health are "confused," say experts. PMID- 21596740 TI - Surgery with disc prosthesis versus rehabilitation in patients with low back pain and degenerative disc: two year follow-up of randomised study. AB - OBJECTIVE: To compare the efficacy of surgery with disc prosthesis versus non surgical treatment for patients with chronic low back pain. DESIGN: A prospective randomised multicentre study. SETTING: Five university hospitals in Norway. PARTICIPANTS: 173 patients with a history of low back pain for at least one year, Oswestry disability index of at least 30 points, and degenerative changes in one or two lower lumbar spine levels (86 patients randomised to surgery). Patients were treated from April 2004 to September 2007. INTERVENTIONS: Surgery with disc prosthesis or outpatient multidisciplinary rehabilitation for 12-15 days. MAIN OUTCOME MEASURES: The primary outcome measure was the score on the Oswestry disability index after two years. Secondary outcome measures were low back pain, satisfaction with life (SF-36 and EuroQol EQ-5D), Hopkins symptom check list (HSCL-25), fear avoidance beliefs (FABQ), self efficacy beliefs for pain, work status, and patients' satisfaction and drug use. A blinded independent observer evaluated scores on the back performance scale and Prolo scale at two year follow up. RESULTS: The study was powered to detect a difference of 10 points on the Oswestry disability index between the groups at two years. At two years there was a mean difference of -8.4 points (95% confidence interval -13.2 to -3.6) in favour of surgery. In the analysis of prespecified secondary outcomes, there were significant differences in favour of surgery for low back pain (mean difference 12.2, -21.3 to -3.1), patients' satisfaction (63% (n = 46) v 39% (n = 26)), SF-36 physical component score (mean difference 5.8, 2.5 to 9.1), self efficacy for pain (mean difference 1.0, 0.2 to 1.9), and the Prolo scale (mean difference 0.9, 0.1 to 1.6). There were no significant differences in return to work, SF-36 mental component score, EQ-5D, fear avoidance beliefs, Hopkins symptom check list, drug use, and the back performance scale. One serious complication of leg amputation occurred during surgical revision of a polyethylene dislodgement. The drop-out rate was 20% (34) and the crossover rate was 6% (5). CONCLUSIONS: Surgical intervention with disc prosthesis for chronic low back pain resulted in a significantly greater improvement in the Oswestry score compared with rehabilitation, but this improvement did not clearly exceed the prespecified minimally important clinical difference between groups of 10 points, and the data are consistent with a wide range of differences between the groups, including values well below 10 points. The potential risks of surgery and the substantial amount of improvement experienced by a sizeable proportion of the rehabilitation group also have to be incorporated into overall decision making. Trial registration NCT 00394732. PMID- 21596742 TI - Structural analysis and involvement in plant innate immunity of Xanthomonas axonopodis pv. citri lipopolysaccharide. AB - Xanthomonas axonopodis pv. citri (Xac) causes citrus canker, provoking defoliation and premature fruit drop with concomitant economical damage. In plant pathogenic bacteria, lipopolysaccharides are important virulence factors, and they are being increasingly recognized as major pathogen-associated molecular patterns for plants. In general, three domains are recognized in a lipopolysaccharide: the hydrophobic lipid A, the hydrophilic O-antigen polysaccharide, and the core oligosaccharide, connecting lipid A and O-antigen. In this work, we have determined the structure of purified lipopolysaccharides obtained from Xanthomonas axonopodis pv. citri wild type and a mutant of the O antigen ABC transporter encoded by the wzt gene. High pH anion exchange chromatography and matrix-assisted laser desorption/ionization mass spectrum analysis were performed, enabling determination of the structure not only of the released oligosaccharides and lipid A moieties but also the intact lipopolysaccharides. The results demonstrate that Xac wild type and Xacwzt LPSs are composed mainly of a penta- or tetra-acylated diglucosamine backbone attached to either two pyrophosphorylethanolamine groups or to one pyrophosphorylethanolamine group and one phosphorylethanolamine group. The core region consists of a branched oligosaccharide formed by Kdo2Hex6GalA3Fuc3NAcRha4 and two phosphate groups. As expected, the presence of a rhamnose homo oligosaccharide as O-antigen was determined only in the Xac wild type lipopolysaccharide. In addition, we have examined how lipopolysaccharides from Xac function in the pathogenesis process. We analyzed the response of the different lipopolysaccharides during the stomata aperture closure cycle, the callose deposition, the expression of defense-related genes, and reactive oxygen species production in citrus leaves, suggesting a functional role of the O antigen from Xac lipopolysaccharides in the basal response. PMID- 21596743 TI - BabA-mediated adherence is a potentiator of the Helicobacter pylori type IV secretion system activity. AB - Chronic infection of Helicobacter pylori in the stomach mucosa with translocation of the bacterial cytotoxin-associated gene A (CagA) effector protein via the cag Type IV secretion system (TFSS) into host epithelial cells are major risk factors for gastritis, gastric ulcers, and cancer. The blood group antigen-binding adhesin BabA mediates the adherence of H. pylori to ABO/Lewis b (Le(b)) blood group antigens in the gastric pit region of the human stomach mucosa. Here, we show both in vitro and in vivo that BabA-mediated binding of H. pylori to Le(b) on the epithelial surface augments TFSS-dependent H. pylori pathogenicity by triggering the production of proinflammatory cytokines and precancer-related factors. We successfully generated Le(b)-positive cell lineages by transfecting Le(b)-negative cells with several glycosyltransferase genes. Using these established cell lines, we found increased mRNA levels of proinflammatory cytokines (CCL5 and IL-8) as well as precancer-related factors (CDX2 and MUC2) after the infection of Le(b)-positive cells with WT H. pylori but not with babA or TFSS deletion mutants. This increased mRNA expression was abrogated when Le(b) negative cells were infected with WT H. pylori. Thus, H. pylori can exploit BabA Le(b) binding to trigger TFSS-dependent host cell signaling to induce the transcription of genes that enhance inflammation, development of intestinal metaplasia, and associated precancerous transformations. PMID- 21596744 TI - Proteomics, ultrastructure, and physiology of hippocampal synapses in a fragile X syndrome mouse model reveal presynaptic phenotype. AB - Fragile X syndrome (FXS), the most common form of hereditary mental retardation, is caused by a loss-of-function mutation of the Fmr1 gene, which encodes fragile X mental retardation protein (FMRP). FMRP affects dendritic protein synthesis, thereby causing synaptic abnormalities. Here, we used a quantitative proteomics approach in an FXS mouse model to reveal changes in levels of hippocampal synapse proteins. Sixteen independent pools of Fmr1 knock-out mice and wild type mice were analyzed using two sets of 8-plex iTRAQ experiments. Of 205 proteins quantified with at least three distinct peptides in both iTRAQ series, the abundance of 23 proteins differed between Fmr1 knock-out and wild type synapses with a false discovery rate (q-value) <5%. Significant differences were confirmed by quantitative immunoblotting. A group of proteins that are known to be involved in cell differentiation and neurite outgrowth was regulated; they included Basp1 and Gap43, known PKC substrates, and Cend1. Basp1 and Gap43 are predominantly expressed in growth cones and presynaptic terminals. In line with this, ultrastructural analysis in developing hippocampal FXS synapses revealed smaller active zones with corresponding postsynaptic densities and smaller pools of clustered vesicles, indicative of immature presynaptic maturation. A second group of proteins involved in synaptic vesicle release was up-regulated in the FXS mouse model. In accordance, paired-pulse and short-term facilitation were significantly affected in these hippocampal synapses. Together, the altered regulation of presynaptically expressed proteins, immature synaptic ultrastructure, and compromised short-term plasticity points to presynaptic changes underlying glutamatergic transmission in FXS at this stage of development. PMID- 21596745 TI - Kinetic modeling of hyperpolarized 13C label exchange between pyruvate and lactate in tumor cells. AB - Measurements of the kinetics of hyperpolarized (13)C label exchange between [1 (13)C]pyruvate and lactate in suspensions of intact and lysed murine lymphoma cells, and in cells in which lactate dehydrogenase expression had been modulated by inhibition of the PI3K pathway, were used to determine quantitatively the role of enzyme activity and membrane transport in controlling isotope flux. Both steps were shown to share in the control of isotope flux in these cells. The kinetics of label exchange were well described by a kinetic model that employed rate constants for the lactate dehydrogenase reaction that had been determined previously from steady state kinetic studies. The enzyme showed pyruvate inhibition in steady state kinetic measurements, which the kinetic model predicted should also be observed in the isotope exchange measurements. However, no such pyruvate inhibition was observed in either intact cells or cell lysates and this could be explained by the much higher enzyme concentrations present in the isotope exchange experiments. The kinetic analysis presented here shows how lactate dehydrogenase activity can be determined from the isotope exchange measurements. The kinetic model should be useful for modeling the exchange reaction in vivo, particularly as this technique progresses to the clinic. PMID- 21596746 TI - Characterization of a dipartite iron uptake system from uropathogenic Escherichia coli strain F11. AB - In the uropathogenic Escherichia coli strain F11, in silico genome analysis revealed the dicistronic iron uptake operon fetMP, which is under iron-regulated control mediated by the Fur regulator. The expression of fetMP in a mutant strain lacking known iron uptake systems improved growth under iron depletion and increased cellular iron accumulation. FetM is a member of the iron/lead transporter superfamily and is essential for iron uptake by the Fet system. FetP is a periplasmic protein that enhanced iron uptake by FetM. Recombinant FetP bound Cu(II) and the iron analog Mn(II) at distinct sites. The crystal structure of the FetP dimer reveals a copper site in each FetP subunit that adopts two conformations: CuA with a tetrahedral geometry composed of His(44), Met(90), His(97), and His(127), and CuB, a second degenerate octahedral geometry with the addition of Glu(46). The copper ions of each site occupy distinct positions and are separated by ~1.3 A. Nearby, a putative additional Cu(I) binding site is proposed as an electron source that may function with CuA/CuB displacement to reduce Fe(III) for transport by FetM. Together, these data indicate that FetMP is an additional iron uptake system composed of a putative iron permease and an iron scavenging and potentially iron-reducing periplasmic protein. PMID- 21596747 TI - Differential effects of murine and human factor X on adenovirus transduction via cell-surface heparan sulfate. AB - Serum coagulation factor X (FX) is proposed to play a major role in adenovirus tropism, promoting transduction by bridging the virus to cell-surface heparan sulfate proteoglycans (HSPGs). Both murine FX and human FX increased transduction by Ad.CMVfLuc, an adenovirus vector, in murine hepatocyte-like cells and human hepatocarcinoma cells. In contrast, only hFX increased transduction of several non-hepatic cancer cell lines and Chinese hamster ovary (CHO) cells. Not only was mFX unable to promote transduction in these cells, it competitively blocked hFX enhanced transduction. Competition and HSPG digestion experiments suggested mFX- and hFX-enhanced transduction in hepatocyte-derived cells, and hFX-enhanced transduction in epithelial cancer cells were dependent on HSPGs. Ad.hFX-mediated transduction of CHO mutants unable to produce HSPGs was also curtailed. Hepatocyte-derived cells expressed substantially more HSPGs than the cancer cell lines. Dose-response curves and heparin-Sepharose binding suggested Ad.hFX has greater affinity for HSPGs than does Ad.mFX. In coagulation factor-depleted mice hFX also had enhanced ability, compared with mFX, to reconstitute hepatic adenovirus transduction. The results suggest that differences in Ad.hFX and Ad.mFX affinity to HSPGs may result in differences in their ability to enhance adenovirus transduction of many cells. These findings may have implications for murine models of adenovirus vector targeting. PMID- 21596748 TI - The inflammation-associated protein TSG-6 cross-links hyaluronan via hyaluronan induced TSG-6 oligomers. AB - Tumor necrosis factor-stimulated gene-6 (TSG-6) is a hyaluronan (HA)-binding protein that plays important roles in inflammation and ovulation. TSG-6-mediated cross-linking of HA has been proposed as a functional mechanism (e.g. for regulating leukocyte adhesion), but direct evidence for cross-linking is lacking, and we know very little about its impact on HA ultrastructure. Here we used films of polymeric and oligomeric HA chains, end-grafted to a solid support, and a combination of surface-sensitive biophysical techniques to quantify the binding of TSG-6 into HA films and to correlate binding to morphological changes. We find that full-length TSG-6 binds with pronounced positive cooperativity and demonstrate that it can cross-link HA at physiologically relevant concentrations. Our data indicate that cooperative binding of full-length TSG-6 arises from HA induced protein oligomerization and that the TSG-6 oligomers act as cross linkers. In contrast, the HA-binding domain of TSG-6 (the Link module) alone binds without positive cooperativity and weaker than the full-length protein. Both the Link module and full-length TSG-6 condensed and rigidified HA films, and the degree of condensation scaled with the affinity between the TSG-6 constructs and HA. We propose that condensation is the result of protein-mediated HA cross linking. Our findings firmly establish that TSG-6 is a potent HA cross-linking agent and might hence have important implications for the mechanistic understanding of the biological function of TSG-6 (e.g. in inflammation). PMID- 21596749 TI - Anti-heparan sulfate peptides that block herpes simplex virus infection in vivo. AB - Heparan sulfate (HS) and its highly modified form, 3-O-sulfated heparan sulfate (3-OS HS), contribute strongly to herpes simplex virus type-1 (HSV-1) infection in vitro. Here we report results from a random M13-phage display library screening to isolate 12-mer peptides that bind specifically to HS, 3-OS HS, and block HSV-1 entry. The screening identified representative candidates from two different groups of anti-HS peptides with high positive charge densities. Group 1, represented by G1 peptide (LRSRTKIIRIRH), belongs to a class with alternating charges (XRXRXKXXRXRX), and group 2, represented by G2 peptide (MPRRRRIRRRQK), shows repetitive charges (XXRRRRXRRRXK). Viral entry and glycoprotein D binding assays together with fluorescent microscopy data indicated that both G1 and G2 were potent in blocking HSV-1 entry into primary cultures of human corneal fibroblasts and CHO-K1 cells transiently expressing different glycoprotein D receptors. Interestingly, G2 peptide isolated against 3-OS HS displayed wider ability to inhibit entry of clinically relevant strains of HSV-1 and some divergent members of herpesvirus family including cytomegalovirus and human herpesvirus-8. To identify functional residues within G1 and G2, we performed point mutations and alanine-scanning mutagenesis. Several arginine and a lysine residues were needed for anti-HSV-1 activity, suggesting the importance of the positively charged residues in virus-cell binding and virus-induced membrane fusion. In vivo administration of G1 or G2 peptide as a prophylactic eye drop completely blocked HSV-1 spread in the mouse cornea as evident by immunohistochemistry. This result also highlights an in vivo significance of HS and 3-OS HS during ocular herpes infection. PMID- 21596750 TI - The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination. AB - Human bone marrow-derived mesenchymal stromal cells (hMSCs) have the capacity to differentiate into several cell types including osteoblasts and are therefore an important cell source for bone tissue regeneration. A crucial issue is to identify mechanisms that trigger hMSC osteoblast differentiation to promote osteogenic potential. Casitas B lineage lymphoma (Cbl) is an E3 ubiquitin ligase that ubiquitinates and targets several molecules for degradation. We hypothesized that attenuation of Cbl-mediated degradation of receptor tyrosine kinases (RTKs) may promote osteogenic differentiation in hMSCs. We show here that specific inhibition of Cbl interaction with RTKs using a Cbl mutant (G306E) promotes expression of osteoblast markers (Runx2, alkaline phosphatase, type 1 collagen, osteocalcin) and increases osteogenic differentiation in clonal bone marrow derived hMSCs and primary hMSCs. Analysis of molecular mechanisms revealed that the Cbl mutant increased PDGF receptor alpha and FGF receptor 2 but not EGF receptor expression in hMSCs, resulting in increased ERK1/2 and PI3K signaling. Pharmacological inhibition of FGFR or PDGFR abrogated in vitro osteogenesis induced by the Cbl mutant. The data reveal that specific inhibition of Cbl interaction with RTKs promotes the osteogenic differentiation program in hMSCs in part by decreased Cbl-mediated PDGFRalpha and FGFR2 ubiquitination, providing a novel mechanistic approach targeting Cbl to promote the osteogenic capacity of hMSCs. PMID- 21596752 TI - Discovery and characterization of novel cyclotides originated from chimeric precursors consisting of albumin-1 chain a and cyclotide domains in the Fabaceae family. AB - The tropical plant Clitoria ternatea is a member of the Fabaceae family well known for its medicinal values. Heat extraction of C. ternatea revealed that the bioactive fractions contained heat-stable cysteine-rich peptides (CRPs). The CRP family of A1b (Albumin-1 chain b/leginsulins), which is a linear cystine knot CRP, has been shown to present abundantly in the Fabaceae. In contrast, the cyclotide family, which also belongs to the cystine knot CRPs but with a cyclic structure, is commonly found in the Rubiaceae, Violaceae, and Cucurbitaceae families. In this study, we report the discovery of a panel of 15 heat-stable CRPs, of which 12 sequences (cliotide T1-T12) are novel. We show unambiguously that the cliotides are cyclotides and not A1bs, as determined by their sequence homology, disulfide connectivity, and membrane active properties indicated by their antimicrobial activities against Escherichia coli and cytotoxicities to HeLa cells. We also show that cliotides are prevalent in C. ternatea and are found in every plant tissue examined, including flowers, seeds, and nodules. In addition, we demonstrate that their precursors are chimeras, half from cyclotide and the other half from Albumin-1, with the cyclotide domain displacing the A1b domain in the precursor. Their chimeric structures likely originate from either horizontal gene transfer or convergent evolution in plant nuclear genomes, which are exceedingly rare events. Such atypical genetic arrangement also implies a different mechanism of biosynthetic processing of cyclotides in the Fabaceae and provides new understanding of their evolution in plants. PMID- 21596751 TI - Endorepellin, the angiostatic module of perlecan, interacts with both the alpha2beta1 integrin and vascular endothelial growth factor receptor 2 (VEGFR2): a dual receptor antagonism. AB - Endorepellin, the C-terminal module of perlecan, negatively regulates angiogenesis counter to its proangiogenic parental molecule. Endorepellin (the C terminal domain V of perlecan) binds the alpha2beta1 integrin on endothelial cells and triggers a signaling cascade that leads to disruption of the actin cytoskeleton. Here, we show that both perlecan and endorepellin bind directly and with high affinity to both VEGF receptors 1 and 2, in a region that differs from VEGFA-binding site. In both human and porcine endothelial cells, this interaction evokes a physical down-regulation of both the alpha2beta1 integrin and VEGFR2, with concurrent activation of the tyrosine phosphatase SHP-1 and downstream attenuation of VEGFA transcription. We demonstrate that endorepellin requires both the alpha2beta1 integrin and VEGFR2 for its angiostatic activity. Endothelial cells that express alpha2beta1 integrin but lack VEGFR2, do not respond to endorepellin treatment. Thus, we provide a new paradigm for the activity of an antiangiogenic protein and mechanistically explain the specificity of endorepellin for endothelial cells, the only cells that simultaneously express both receptors. We hypothesize that a mechanism such as dual receptor antagonism could operate for other angiostatic fragments. PMID- 21596753 TI - miR-200a regulates SIRT1 expression and epithelial to mesenchymal transition (EMT)-like transformation in mammary epithelial cells. AB - Evidence supports a critical role for microRNAs (miRNAs) in regulation of tissue specific differentiation and development. Signifying a disruption of these programs, expression profiling has revealed extensive miRNA dysregulation in tumors compared with healthy tissue. The miR-200 family has been established as a key regulator of epithelial phenotype and, as such, is deeply involved in epithelial to mesenchymal transition (EMT) processes in breast cancer. However, the effects of the miR-200 family on transformation of normal mammary epithelial cells have yet to be fully characterized. By examining a TGF-beta driven model of transformation of normal mammary epithelium, we demonstrate that the class III histone deacetylase silent information regulator 1 (SIRT1), a proposed oncogene in breast cancer, is overexpressed upon EMT-like transformation and that epigenetic silencing of miR-200a contributes at least in part to the overexpression of SIRT1. We have established the SIRT1 transcript as subject to regulation by miR-200a, through miR-200a targeting of SIRT1 3'-UTR. We also observed SIRT1 and miR-200a participation in a negative feedback regulatory loop. Restoration of miR-200a or the knockdown of SIRT1 prevented transformation of normal mammary epithelial cells evidenced by decreased anchorage-independent growth and decreased cell migration. Finally, we observed SIRT1 overexpression in association with decreased miR-200a in breast cancer patient samples. These observations provide further evidence for a critical tumor suppressive role of the miR-200 family in breast epithelium in addition to identifying a novel regulatory mechanism, which may contribute to SIRT1 up-regulation in breast cancer. PMID- 21596754 TI - Structure of the PilM-PilN inner membrane type IV pilus biogenesis complex from Thermus thermophilus. AB - Type IV pili are surface-exposed filaments, which extend from a variety of bacterial pathogens and play a major role in pathogenesis, motility, and DNA uptake. Here, we present the crystal structure of a complex between a cytoplasmic component of the type IV pilus biogenesis system from Thermus thermophilus, PilM, in complex with a peptide derived from the cytoplasmic portion of the inner membrane protein PilN. PilM also binds ATP, and its structure is most similar to the actin-like protein FtsA. PilN binds in a narrow channel between the 1A and 1C subdomains in PilM; the binding site is well conserved in other gram-negative bacteria, notably Neisseria meningitidis, Pseudomonas aeruginosa, and Vibrio cholerae. We find no evidence for the catalysis of ATP hydrolysis by PilM; fluorescence data indicate that the protein is likely to be saturated by ATP at physiological concentrations. In addition, binding of the PilN peptide appears to influence the environment of the ATP binding site. This is the first reported structure of a complex between two type IV pilus biogenesis proteins. We propose a model in which PilM binds ATP and then PilN as one of the first steps in the formation of the inner membrane platform of the type IV pilus biogenesis complex. PMID- 21596755 TI - Intracellular storage and regulated secretion of von Willebrand factor in quantitative von Willebrand disease. AB - Several missense mutations in the von Willebrand Factor (VWF) gene of von Willebrand disease (VWD) patients have been shown to cause impaired constitutive secretion and intracellular retention of VWF. However, the effects of those mutations on the intracellular storage in Weibel-Palade bodies (WPBs) of endothelial cells and regulated secretion of VWF remain unknown. We demonstrate, by expression of quantitative VWF mutants in HEK293 cells, that four missense mutations in the D3 and CK-domain of VWF diminished the storage in pseudo-WPBs, and led to retention of VWF within the endoplasmic reticulum (ER). Immunofluorescence and electron microscopy data showed that the pseudo-WPBs formed by missense mutant C1060Y are indistinguishable from those formed by normal VWF. C1149R, C2739Y, and C2754W formed relatively few pseudo-WPBs, which were often short and sometimes round rather than cigar-shaped. The regulated secretion of VWF was impaired slightly for C1060Y but severely for C1149R, C2739Y, and C2754W. Upon co-transfection with wild-type VWF, both intracellular storage and regulated secretion of all mutants were (partly) corrected. In conclusion, defects in the intracellular storage and regulated secretion of VWF following ER retention may be a common mechanism underlying VWD with a quantitative deficiency of VWF. PMID- 21596757 TI - Partnering urban academic medical centers and rural primary care clinicians to provide complex chronic disease care. AB - Many of the estimated thirty-two million Americans expected to gain coverage under the Affordable Care Act are likely to have high levels of unmet need because of various chronic illnesses and to live in areas that are already underserved. In New Mexico an innovative new model of health care education and delivery known as Project ECHO (Extension for Community Healthcare Outcomes) provides high-quality primary and specialty care to a comparable population. Using state-of-the-art telehealth technology and case-based learning, Project ECHO enables specialists at the University of New Mexico Health Sciences Center to partner with primary care clinicians in underserved areas to deliver complex specialty care to patients with hepatitis C, asthma, diabetes, HIV/AIDS, pediatric obesity, chronic pain, substance use disorders, rheumatoid arthritis, cardiovascular conditions, and mental illness. As of March 2011, 298 Project ECHO teams across New Mexico have collaborated on more than 10,000 specialty care consultations for hepatitis C and other chronic diseases. PMID- 21596759 TI - Intramyocardial hydatid cyst: a mistaken identity and its successful removal on a beating heart. AB - Hydatid cyst of the heart is a rare but potentially fatal disease. There have been reports of the occurrence of such cysts, but we present here a unique experience of mistaken identity of a right ventricular intramyocardial hydatid cyst for a mediastinal hydatid cyst, leading to a dangerous intraoperative procedure. PMID- 21596758 TI - How Intermountain trimmed health care costs through robust quality improvement efforts. AB - It has been estimated that full implementation of the Affordable Care Act will extend coverage to thirty-two million previously uninsured Americans. However, rapidly rising health care costs could thwart that effort. Since 1988 Intermountain Healthcare has applied to health care delivery the insights of W. Edwards Deming's process management theory, which says that the best way to reduce costs is to improve quality. Intermountain achieved such quality-based savings through measuring, understanding, and managing variation among clinicians in providing care. Intermountain created data systems and management structures that increased accountability, drove improvement, and produced savings. For example, a new delivery protocol helped reduce rates of elective induced labor, unplanned cesarean sections, and admissions to newborn intensive care units. That one protocol saves an estimated $50 million in Utah each year. If applied nationally, it would save about $3.5 billion. "Organized care" along these lines may be central to the long-term success of health reform. PMID- 21596756 TI - Increased lipogenesis and stearate accelerate vascular calcification in calcifying vascular cells. AB - Vascular calcification is recognized as an independent predictor of cardiovascular mortality, particularly in subjects with chronic kidney disease. However, the pathways by which dysregulation of lipid and mineral metabolism simultaneously occur in this particular population remain unclear. We have shown that activation of the farnesoid X receptor (FXR) blocks mineralization of bovine calcifying vascular cells (CVCs) and in ApoE knock-out mice with 5/6 nephrectomy. In contrast to FXR, this study showed that liver X receptor (LXR) activation by LXR agonists and adenovirus-mediated LXR overexpression by VP16-LXRalpha and VP16 LXRbeta accelerated mineralization of CVCs. Conversely, LXR inhibition by dominant negative (DN) forms of LXRalpha and LXRbeta reduced calcium content in CVCs. The regulation of mineralization by FXR and LXR agonists was highly correlated with changes in lipid accumulation, fatty acid synthesis, and the expression of sterol regulatory element binding protein-1 (SREBP-1). The rate of lipogenesis in CVCs through the SREBP-1c dependent pathway was reduced by FXR activation, but increased by LXR activation. SREBP-1c overexpression augmented mineralization in CVCs, whereas SREBP-1c DN inhibited alkaline phosphatase activity and mineralization induced by LXR agonists. LXR and SREBP-1c activations increased, whereas FXR activation decreased, saturated and monounsaturated fatty acids derived from lipogenesis. In addition, we found that stearate markedly promoted mineralization of CVCs as compared with other fatty acids. Furthermore, inhibition of either acetyl-CoA carboxylase or acyl-CoA synthetase reduced mineralization of CVCs, whereas inhibition of stearoyl-CoA desaturase induced mineralization. Therefore, a stearate metabolite derived from lipogenesis might be a risk factor for the development of vascular calcification. PMID- 21596760 TI - Neurocognitive determinants of novelty and sensation-seeking in individuals with alcoholism. AB - AIM: Sober alcoholic abusers exhibit personality traits such as novelty-seeking (NS) and sensation-seeking, which overlap to a limited extent. In parallel, they also show impaired executive and decision-making processes. However, little is known about the specific and common cognitive processes associated with NS and sensation-seeking personality traits in detoxified sober alcoholic abusers. METHODS: In these present studies, we have investigated the relationships between executive functioning/central executive of working memory (pre-potent response inhibition, manipulation stored in working memory), and decision-making under uncertainty and NS/sensation-seeking traits in such alcoholics. RESULTS: Compared with healthy controls (n = 30, mean age = 40.2), and in agreement with previous studies, alcoholics (n = 30, mean age = 40.4) showed higher levels of both NS and sensation-seeking traits. Alcoholics were also disadvantaged with respect to (a) gambling tasks, as reported previously, and (b) a poor ability to manipulate information stored in working memory and inhibit pre-potent responses. Most importantly, regression analyses and mediation analyses measures showed that poor response inhibition and decision-making were associated with high NS behaviour. In addition, impaired decision-making and manipulation of stored information in working memory were associated with a high sensation-seeking trait. CONCLUSIONS: Overall, these results support the existence of specific links between cognitive executive functioning, decision-making under uncertainty and NS/sensation-seeking personality traits in individuals with alcoholism. PMID- 21596761 TI - Is it my job? Alcohol brief interventions: knowledge and attitudes among future health-care professionals in Scotland. AB - AIMS: To document knowledge and perceptions relating to the professional role in the area of alcohol misuse within a sample of first year (n = 278) and final year (n = 527) medical, nursing and allied health professional (NAHP) students in Scotland. METHODS: A cross sectional survey design involving self-completed questionnaires administered in autumn 2008 (first year students) and spring 2009 (final year students) through course websites and lectures. RESULTS: Gaps in the knowledge relating to current UK health guidelines were identified but more so among NAHP students than medical students. Exploration of the perceived role in this area of practice identified three broad groups of students: those clear about their role (medical and nursing students), those advocating a role but not identified by fellow students (occupational therapy and pharmacy) and those uncertain of their role (radiographers, speech and language therapists/audiologists and physiotherapy). CONCLUSIONS: Higher education institutions should address the gaps in the knowledge around guidance for alcohol consumption. The effectiveness of brief interventions may depend on it. Additionally, through inter-professional teaching and in collaboration with the relevant professional bodies, more could be done to promote the contribution of practitioners other than those traditionally linked (i.e. medical and nursing) to this important clinical role. PMID- 21596762 TI - Robinson's Ecological Correlations and the Behavior of Individuals: methodological corrections. PMID- 21596763 TI - Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography. PMID- 21596764 TI - Neural contributions to flow experience during video game playing. AB - Video games are an exciting part of new media. Although game play has been intensively studied, the underlying neurobiology is still poorly understood. Flow theory is a well-established model developed to describe subjective game experience. In 13 healthy male subjects, we acquired fMRI data during free play of a video game and analyzed brain activity based on the game content. In accordance with flow theory, we extracted the following factors from the game content: (i) balance between ability and challenge; (ii) concentration and focus; (iii) direct feedback of action results; (iv) clear goals; and (v) control over the situation/activity. We suggest that flow is characterized by specific neural activation patterns and that the latter can be assessed-at least partially-by content factors contributing to the emergence of flow. Each of the content factors was characterized by specific and distinguishable brain activation patterns, encompassing reward-related midbrain structures, as well as cognitive and sensorimotor networks. The activation of sensory and motor networks in the conjunction analyses underpinned the central role of simulation for flow experience. Flow factors can be validated with functional brain imaging which can improve the understanding of human emotions and motivational processes during media entertainment. PMID- 21596765 TI - Brain. Editorial. PMID- 21596766 TI - Tight squeeze, slow burn: inflammation and the aetiology of cervical myelopathy. PMID- 21596767 TI - Germinal matrix haemorrhage: destroying the brain's building blocks. PMID- 21596769 TI - NG2 expressed by macrophages and oligodendrocyte precursor cells is dispensable in experimental autoimmune encephalomyelitis. AB - Increased expression of the chondroitin proteoglycan NG2 is a prominent feature in central nervous system injury with unknown cellular source and biological relevance. Here, we describe the first detailed analysis of experimental autoimmune encephalomyelitis in NG2 knockout mice and NG2 knockout bone marrow chimeras. We show that both macrophages and oligodendrocyte progenitor cells express and secrete NG2 in response to transforming growth factor-beta. A subpopulation of macrophages expresses NG2 within leucocyte infiltrates in the central nervous system, but only oligodendrocyte progenitor cells contribute to NG2 accumulation. Notably, NG2 plays no role in experimental autoimmune encephalomyelitis initiation, progression or recuperation. In concurrence, the immune response is unaltered in NG2-deficient mice as are the extent of central nervous system damage and degree of remyelination. PMID- 21596768 TI - Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis is a relentless and devastating adult-onset neurodegenerative disease with no known cure. In mice with amyotrophic lateral sclerosis, CD4+ T lymphocytes and wild-type microglia potentiate protective inflammatory responses and play a principal role in disease pathoprogression. Using this model, we demonstrate that endogenous T lymphocytes, and more specifically regulatory T lymphocytes, are increased at early slowly progressing stages, augmenting interleukin-4 expression and protective M2 microglia, and are decreased when the disease rapidly accelerates, possibly through the loss of FoxP3 expression in the regulatory T lymphocytes. Without ex vivo activation, the passive transfer of wild-type CD4+ T lymphocytes into amyotrophic lateral sclerosis mice lacking functional T lymphocytes lengthened disease duration and prolonged survival. The passive transfer of endogenous regulatory T lymphocytes from early disease stage mutant Cu2+/Zn2+ superoxide dismutase mice into these amyotrophic lateral sclerosis mice, again without ex vivo activation, were substantially more immunotherapeutic sustaining interleukin-4 levels and M2 microglia, and resulting in lengthened disease duration and prolonged survival; the stable disease phase was extended by 88% using mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes. A potential mechanism for this enhanced life expectancy may be mediated by the augmented secretion of interleukin-4 from mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes that directly suppressed the toxic properties of microglia; flow cytometric analyses determined that CD4+/CD25+/FoxP3+ T lymphocytes co-expressed interleukin-4 in the same cell. These observations were extended into the amyotrophic lateral sclerosis patient population where patients with more rapidly progressing disease had decreased numbers of regulatory T lymphocytes; the numbers of regulatory T lymphocytes were inversely correlated with disease progression rates. These data suggest a cellular mechanism whereby endogenous regulatory T lymphocytes are immunocompetent and actively contribute to neuroprotection through their interactions with microglia. Furthermore, these data suggest that immunotherapeutic interventions must begin early in the pathogenic process since immune dysfunction occurs at later stages. Thus, the cumulative mouse and human amyotrophic lateral sclerosis data suggest that increasing the levels of regulatory T lymphocytes in patients with amyotrophic lateral sclerosis at early stages in the disease process may be of therapeutic value, and slow the rate of disease progression and stabilize patients for longer periods of time. PMID- 21596770 TI - Relationship between the brain radiation dose for the treatment of childhood cancer and the risk of long-term cerebrovascular mortality. AB - To date, very little is known about the long-term risk of death from cerebrovascular sequelae following childhood cancer treatment. The purpose of this study was to assess the role of treatment in very long-term cerebrovascular mortality following childhood cancer. We studied 4227 5-year survivors of a childhood cancer. Information on chemotherapy was collected and the radiation dose delivered to 11 anatomical sites in the brain was estimated. The main outcome that was considered was death due to cerebrovascular disease occurring before 1 January 2008. After a median follow-up of 29 years, 23 deaths due to cerebrovascular diseases had occurred. In the brain, the radiation dose delivered to the prepontine cistern seemed to play a greater role than the average radiation dose received throughout the brain or the dose to any other specific anatomical site in the brain. The risk of death from cerebrovascular disease increased linearly with the local radiation dose to the prepontine cistern. Each unit of absorbed radiation (Gray) delivered to this area increased the risk by 22% (95% confidence interval: 1-44%). Compared with patients who had not received radiotherapy or who had received <0.1 Gray in the prepontine cistern area, those who had received >50 Gray had a 17.8-fold (4.4-73.0) higher hazard ratio of death from cerebrovascular disease. In conclusion, among 5-year survivors of childhood cancer, the radiation dose to the brain during radiotherapy was significantly associated with long-term cerebrovascular mortality. PMID- 21596771 TI - Dopamine agonists and risk: impulse control disorders in Parkinson's disease. AB - Impulse control disorders are common in Parkinson's disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a 'Sure' choice and a 'Gamble' choice of moderate risk. To commence each trial, in the 'Gain' condition, individuals started at $0 and in the 'Loss' condition individuals started at -$50 below the 'Sure' amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk ('Gamble Risk'). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the 'Gain' relative to the 'Loss' condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals. PMID- 21596772 TI - The effect of dopamine therapy on ventral and dorsal striatum-mediated cognition in Parkinson's disease: support from functional MRI. AB - The central aim of our study was to elucidate functions mediated by the ventral and dorsal striatum, respectively, to better understand the cognitive effects of dopamine replacement in Parkinson's disease. We proposed that the ventral striatum underlies general learning of stimulus associations, whereas the dorsal striatum promotes integration of various influences on selecting. In Parkinson's disease, dopamine depletion is substantially less notable in the ventral relative to the dorsal striatum, and therefore greater improvements are expected for dorsal striatum-mediated functions with dopamine replacement. Using a simple selection task, we found that dopamine replacement impaired encoding and facilitation of consistent stimulus-stimulus relations across trials. This finding was in line with our contention that ventral striatum mediates learning stimulus associations, even when explicit feedback or reward is not provided. In contrast, dopamine replacement enhanced interference related to assimilating conflicting influences on selection across trials, consistent with our hypothesis that the dorsal striatum supports deciding in ambiguous contexts. We further confirmed these separable roles for the ventral and dorsal striatum in our selection task with healthy young volunteers using functional magnetic resonance imaging. In summary, we present a within-subject, double dissociation of the effects of dopamine replacement in patients with Parkinson's disease for ventral striatum-mediated facilitation and dorsal striatum-mediated interference, confirmed in a separate functional magnetic resonance imaging experiment. Defining the distinct functions of the ventral and dorsal striatum will have direct clinical implications. Titration of therapy in Parkinson's disease is generally geared towards optimizing dorsal striatum-mediated motor symptoms, possibly at the expense of ventral striatum operations, a consequence that is only beginning to be recognized. Enhanced awareness of these different processes will translate into medication strategies that take into account those symptoms that dopamine replacement might hinder, as well as improve. Here, we show impairments in learning new stimulus associations compared with improvements in integrating varied influences related to selection. Ultimately, this knowledge will lead clinicians to survey a broader range of symptoms in determining optimal therapy based on individual patient priorities. PMID- 21596773 TI - Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important? AB - The relative importance of Lewy- and Alzheimer-type pathologies to dementia in Parkinson's disease remains unclear. We have examined the combined associations of alpha-synuclein, tau and amyloid-beta accumulation in 56 pathologically confirmed Parkinson's disease cases, 29 of whom had developed dementia. Cortical and subcortical amyloid-beta scores were obtained, while tau and alpha-synuclein pathologies were rated according to the respective Braak stages. Additionally, cortical Lewy body and Lewy neurite scores were determined and Lewy body densities were generated using morphometry. Non-parametric statistics, together with regression models, receiver-operating characteristic curves and survival analyses were applied. Cortical and striatal amyloid-beta scores, Braak tau stages, cortical Lewy body, Lewy neurite scores and Lewy body densities, but not Braak alpha-synuclein stages, were all significantly greater in the Parkinson's disease-dementia group (P<0.05), with all the pathologies showing a significant positive correlation to each other (P<0.05). A combination of pathologies [area under the receiver-operating characteristic curve=0.95 (0.88-1.00); P<0.0001] was a better predictor of dementia than the severity of any single pathology. Additionally, cortical amyloid-beta scores (r=-0.62; P=0.043) and Braak tau stages (r=-0.52; P=0.028), but not Lewy body scores (r=-0.25; P=0.41) or Braak alpha-synuclein stages (r=-0.44; P=0.13), significantly correlated with mini mental state examination scores in the subset of cases with this information available within the last year of life (n=15). High cortical amyloid-beta score (P=0.017) along with an older age at onset (P=0.001) were associated with a shorter time-to-dementia period. A combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson's disease, with quantitative and semi-quantitative assessment of Lewy pathology being more informative than Braak alpha-synuclein stages. Cortical amyloid-beta and age at disease onset seem to determine the rate to dementia. PMID- 21596774 TI - Hippocampal sclerosis in advanced age: clinical and pathological features. AB - Hippocampal sclerosis is a relatively common neuropathological finding (~10% of individuals over the age of 85 years) characterized by cell loss and gliosis in the hippocampus that is not explained by Alzheimer's disease. Hippocampal sclerosis pathology can be associated with different underlying causes, and we refer to hippocampal sclerosis in the aged brain as hippocampal sclerosis associated with ageing. Much remains unknown about hippocampal sclerosis associated with ageing. We combined three different large autopsy cohorts: University of Kentucky Alzheimer's Disease Centre, the Nun Study and the Georgia Centenarian Study to obtain a pool of 1110 patients, all of whom were evaluated neuropathologically at the University of Kentucky. We focused on the subset of cases with neuropathology-confirmed hippocampal sclerosis (n=106). For individuals aged>=95 years at death (n=179 in our sample), each year of life beyond the age of 95 years correlated with increased prevalence of hippocampal sclerosis pathology and decreased prevalence of 'definite' Alzheimer's disease pathology. Aberrant TAR DNA protein 43 immunohistochemistry was seen in 89.9% of hippocampal sclerosis positive patients compared with 9.7% of hippocampal sclerosis negative patients. TAR DNA protein 43 immunohistochemistry can be used to demonstrate that the disease is usually bilateral even when hippocampal sclerosis pathology is not obvious by haematoxylin and eosin stains. TAR DNA protein 43 immunohistochemistry was negative on brain sections from younger individuals (n=10) after hippocampectomy due to seizures, who had pathologically confirmed hippocampal sclerosis. There was no association between cases with hippocampal sclerosis associated with ageing and apolipoprotein E genotype. Age of death and clinical features of hippocampal sclerosis associated with ageing (with or without aberrant TAR DNA protein 43) were distinct from previously published cases of frontotemporal lobar degeneration TAR DNA protein 43. To help sharpen our ability to discriminate patients with hippocampal sclerosis associated with ageing clinically, the longitudinal cognitive profile of 43 patients with hippocampal sclerosis associated with ageing was compared with the profiles of 75 controls matched for age, gender, education level and apolipoprotein E genotype. These individuals were followed from intake assessment, with 8.2 (average) longitudinal cognitive assessments. A neuropsychological profile with relatively high-verbal fluency but low word list recall distinguished the hippocampal sclerosis associated with ageing group at intake (P<0.015) and also 5.5-6.5 years before death (P<0.005). This may provide a first step in clinical differentiation of hippocampal sclerosis associated with ageing versus pure Alzheimer's disease in their earliest stages. In summary, in the largest series of autopsy-verified patients with hippocampal sclerosis to date, we characterized the clinical and pathological features associated with hippocampal sclerosis associated with ageing. PMID- 21596775 TI - ESPRIT-Tree: hierarchical clustering analysis of millions of 16S rRNA pyrosequences in quasilinear computational time. AB - Taxonomy-independent analysis plays an essential role in microbial community analysis. Hierarchical clustering is one of the most widely employed approaches to finding operational taxonomic units, the basis for many downstream analyses. Most existing algorithms have quadratic space and computational complexities, and thus can be used only for small or medium-scale problems. We propose a new online learning-based algorithm that simultaneously addresses the space and computational issues of prior work. The basic idea is to partition a sequence space into a set of subspaces using a partition tree constructed using a pseudometric, then recursively refine a clustering structure in these subspaces. The technique relies on new methods for fast closest-pair searching and efficient dynamic insertion and deletion of tree nodes. To avoid exhaustive computation of pairwise distances between clusters, we represent each cluster of sequences as a probabilistic sequence, and define a set of operations to align these probabilistic sequences and compute genetic distances between them. We present analyses of space and computational complexity, and demonstrate the effectiveness of our new algorithm using a human gut microbiota data set with over one million sequences. The new algorithm exhibits a quasilinear time and space complexity comparable to greedy heuristic clustering algorithms, while achieving a similar accuracy to the standard hierarchical clustering algorithm. PMID- 21596776 TI - Cross-linking of DNA through HMGA1 suggests a DNA scaffold. AB - Binding of proteins to DNA is usually considered 1D with one protein bound to one DNA molecule. In principle, proteins with multiple DNA binding domains could also bind to and thereby cross-link different DNA molecules. We have investigated this possibility using high-mobility group A1 (HMGA1) proteins, which are architectural elements of chromatin and are involved in the regulation of multiple DNA-dependent processes. Using direct stochastic optical reconstruction microscopy (dSTORM), we could show that overexpression of HMGA1a-eGFP in Cos-7 cells leads to chromatin aggregation. To investigate if HMGA1a is directly responsible for this chromatin compaction we developed a DNA cross-linking assay. We were able to show for the first time that HMGA1a can cross-link DNA directly. Detailed analysis using point mutated proteins revealed a novel DNA cross-linking domain. Electron microscopy indicates that HMGA1 proteins are able to create DNA loops and supercoils in linearized DNA confirming the cross-linking ability of HMGA1a. This capacity has profound implications for the spatial organization of DNA in the cell nucleus and suggests cross-linking activities for additional nuclear proteins. PMID- 21596777 TI - Analysis of genomic variation in non-coding elements using population-scale sequencing data from the 1000 Genomes Project. AB - In the human genome, it has been estimated that considerably more sequence is under natural selection in non-coding regions [such as transcription-factor binding sites (TF-binding sites) and non-coding RNAs (ncRNAs)] compared to protein-coding ones. However, less attention has been paid to them. To study selective pressure on non-coding elements, we use next-generation sequencing data from the recently completed pilot phase of the 1000 Genomes Project, which, compared to traditional methods, allows for the characterization of a full spectrum of genomic variations, including single-nucleotide polymorphisms (SNPs), short insertions and deletions (indels) and structural variations (SVs). We develop a framework for combining these variation data with non-coding elements, calculating various population-based metrics to compare classes and subclasses of elements, and developing element-aware aggregation procedures to probe the internal structure of an element. Overall, we find that TF-binding sites and ncRNAs are less selectively constrained for SNPs than coding sequences (CDSs), but more constrained than a neutral reference. We also determine that the relative amounts of constraint for the three types of variations are, in general, correlated, but there are some differences: counter-intuitively, TF-binding sites and ncRNAs are more selectively constrained for indels than for SNPs, compared to CDSs. After inspecting the overall properties of a class of elements, we analyze selective pressure on subclasses within an element class, and show that the extent of selection is associated with the genomic properties of each subclass. We find, for instance, that ncRNAs with higher expression levels tend to be under stronger purifying selection, and the actual regions of TF-binding motifs are under stronger selective pressure than the corresponding peak regions. Further, we develop element-aware aggregation plots to analyze selective pressure across the linear structure of an element, with the confidence intervals evaluated using both simple bootstrapping and block bootstrapping techniques. We find, for example, that both micro-RNAs (particularly the seed regions) and their binding targets are under stronger selective pressure for SNPs than their immediate genomic surroundings. In addition, we demonstrate that substitutions in TF binding motifs inversely correlate with site conservation, and SNPs unfavorable for motifs are under more selective constraints than favorable SNPs. Finally, to further investigate intra-element differences, we show that SVs have the tendency to use distinctive modes and mechanisms when they interact with genomic elements, such as enveloping whole gene(s) rather than disrupting them partially, as well as duplicating TF motifs in tandem. PMID- 21596778 TI - corRna: a web server for predicting multiple-point deleterious mutations in structural RNAs. AB - RNA molecules can achieve a broad range of regulatory functions through specific structures that are in turn determined by their sequence. The prediction of mutations changing the structural properties of RNA sequences (a.k.a. deleterious mutations) is therefore useful for conducting mutagenesis experiments and synthetic biology applications. While brute force approaches can be used to analyze single-point mutations, this strategy does not scale well to multiple mutations. In this article, we present corRna a web server for predicting the multiple-point deleterious mutations in structural RNAs. corRna uses our RNAmutants framework to efficiently explore the RNA mutational landscape. It also enables users to apply search heuristics to improve the quality of the predictions. We show that corRna predictions correlate with mutagenesis experiments on the hepatitis C virus cis-acting replication element as well as match the accuracy of previous approaches on a large test-set in a much lower execution time. We illustrate these new perspectives offered by corRna by predicting five-point deleterious mutations--an insight that could not be achieved by previous methods. corRna is available at: http://corrna.cs.mcgill.ca. PMID- 21596779 TI - A protein shuttle system to target RNA into mitochondria. AB - Mitochondria play a key role in essential cellular functions. A deeper understanding of mitochondrial molecular processes is hampered by the difficulty of incorporating foreign nucleic acids into organelles. Mitochondria of most eukaryotic species import cytosolic tRNAs. Based on this natural process, we describe here a powerful shuttle system to internalize several types of RNAs into isolated mitochondria. We demonstrate that this tool is useful to investigate tRNA processing or mRNA editing in plant mitochondria. Furthermore, we show that the same strategy can be used to address both tRNA and mRNA to isolated mammalian mitochondria. We anticipate our novel approach to be the starting point for various studies on mitochondrial processes. Finally, our study provides new insights into the mechanism of RNA import into mitochondria. PMID- 21596780 TI - Structures of apo IRF-3 and IRF-7 DNA binding domains: effect of loop L1 on DNA binding. AB - Interferon regulatory factors IRF-3 and IRF-7 are transcription factors essential in the activation of interferon-beta (IFN-beta) gene in response to viral infections. Although, both proteins recognize the same consensus IRF binding site AANNGAAA, they have distinct DNA binding preferences for sites in vivo. The X-ray structures of IRF-3 and IRF-7 DNA binding domains (DBDs) bound to IFN-beta promoter elements revealed flexibility in the loops (L1-L3) and the residues that make contacts with the target sequence. To characterize the conformational changes that occur on DNA binding and how they differ between IRF family members, we have solved the X-ray structures of IRF-3 and IRF-7 DBDs in the absence of DNA. We found that loop L1, carrying the conserved histidine that interacts with the DNA minor groove, is disordered in apo IRF-3 but is ordered in apo IRF-7. This is reflected in differences in DNA binding affinities when the conserved histidine in loop L1 is mutated to alanine in the two proteins. The stability of loop L1 in IRF-7 derives from a unique combination of hydrophobic residues that pack against the protein core. Together, our data show that differences in flexibility of loop L1 are an important determinant of differential IRF-DNA binding. PMID- 21596781 TI - Crystal structures of CGG RNA repeats with implications for fragile X-associated tremor ataxia syndrome. AB - The CGG repeats are present in the 5'-untranslated region (5'-UTR) of the fragile X mental retardation gene FMR1 and are associated with two diseases: fragile X associated tremor ataxia syndrome (FXTAS) and fragile X syndrome (FXS). FXTAS occurs when the number of repeats is 55-200 and FXS develops when the number exceeds 200. FXTAS is an RNA-mediated disease in which the expanded CGG tracts form stable structures and sequester important RNA binding proteins. We obtained and analysed three crystal structures of double-helical CGG repeats involving unmodified and 8-Br modified guanosine residues. Despite the presence of the non canonical base pairs, the helices retain an A-form. In the G-G pairs one guanosine is always in the syn conformation, the other is anti. There are two hydrogen bonds between the Watson-Crick edge of G(anti) and the Hoogsteen edge of G(syn): O6.N1H and N7.N2H. The G(syn)-G(anti) pair shows affinity for binding ions in the major groove. G(syn) causes local unwinding of the helix, compensated elsewhere along the duplex. CGG helical structures appear relatively stable compared with CAG and CUG tracts. This could be an important factor in the RNA's ligand binding affinity and specificity. PMID- 21596782 TI - Reciprocal roles of DBC1 and SIRT1 in regulating estrogen receptor alpha activity and co-activator synergy. AB - Estrogen receptor alpha (ERalpha) plays critical roles in development and progression of breast cancer. Because ERalpha activity is strictly dependent upon the interaction with coregulators, coregulators are also believed to contribute to breast tumorigenesis. Cell Cycle and Apoptosis Regulator 1 (CCAR1) is an important co-activator for estrogen-induced gene expression and estrogen dependent growth of breast cancer cells. Here, we identified Deleted in Breast Cancer 1 (DBC1) as a CCAR1 binding protein. DBC1 was recently shown to function as a negative regulator of the NAD-dependent protein deacetylase SIRT1. DBC1 associates directly with ERalpha and cooperates synergistically with CCAR1 to enhance ERalpha function. DBC1 is required for estrogen-induced expression of a subset of ERalpha target genes as well as breast cancer cell proliferation and for estrogen-induced recruitment of ERalpha to the target promoters in a gene specific manner. The mechanism of DBC1 action involves inhibition of SIRT1 interaction with ERalpha and of SIRT1-mediated deacetylation of ERalpha. SIRT1 also represses the co-activator synergy between DBC1 and CCAR1 by binding to DBC1 and disrupting its interaction with CCAR1. Our results indicate that DBC1 and SIRT1 play reciprocal roles as major regulators of ERalpha activity, by regulating DNA binding by ERalpha and by regulating co-activator synergy. PMID- 21596783 TI - AnnotQTL: a new tool to gather functional and comparative information on a genomic region. AB - AnnotQTL is a web tool designed to aggregate functional annotations from different prominent web sites by minimizing the redundancy of information. Although thousands of QTL regions have been identified in livestock species, most of them are large and contain many genes. This tool was therefore designed to assist the characterization of genes in a QTL interval region as a step towards selecting the best candidate genes. It localizes the gene to a specific region (using NCBI and Ensembl data) and adds the functional annotations available from other databases (Gene Ontology, Mammalian Phenotype, HGNC and Pubmed). Both human genome and mouse genome can be aligned with the studied region to detect synteny and segment conservation, which is useful for running inter-species comparisons of QTL locations. Finally, custom marker lists can be included in the results display to select the genes that are closest to your most significant markers. We use examples to demonstrate that in just a couple of hours, AnnotQTL is able to identify all the genes located in regions identified by a full genome scan, with some highlighted based on both location and function, thus considerably increasing the chances of finding good candidate genes. AnnotQTL is available at http://annotqtl.genouest.org. PMID- 21596784 TI - Phosphorylation of Mcm2 modulates Mcm2-7 activity and affects the cell's response to DNA damage. AB - The S-phase kinase, DDK controls DNA replication through phosphorylation of the replicative helicase, Mcm2-7. We show that phosphorylation of Mcm2 at S164 and S170 is not essential for viability. However, the relevance of Mcm2 phosphorylation is demonstrated by the sensitivity of a strain containing alanine at these positions (mcm2(AA)) to methyl methanesulfonate (MMS) and caffeine. Consistent with a role for Mcm2 phosphorylation in response to DNA damage, the mcm2(AA) strain accumulates more RPA foci than wild type. An allele with the phosphomimetic mutations S164E and S170E (mcm2(EE)) suppresses the MMS and caffeine sensitivity caused by deficiencies in DDK function. In vitro, phosphorylation of Mcm2 or Mcm2(EE) reduces the helicase activity of Mcm2-7 while increasing DNA binding. The reduced helicase activity likely results from the increased DNA binding since relaxing DNA binding with salt restores helicase activity. The finding that the ATP site mutant mcm2(K549R) has higher DNA binding and less ATPase than mcm2(EE), but like mcm2(AA) results in drug sensitivity, supports a model whereby a specific range of Mcm2-7 activity is required in response to MMS and caffeine. We propose that phosphorylation of Mcm2 fine-tunes the activity of Mcm2-7, which in turn modulates DNA replication in response to DNA damage. PMID- 21596785 TI - mirAct: a web tool for evaluating microRNA activity based on gene expression data. AB - MicroRNAs (miRNAs) are critical regulators in the complex cellular networks. The mirAct web server (http://sysbio.ustc.edu.cn/software/mirAct) is a tool designed to investigate miRNA activity based on gene-expression data by using the negative regulation relationship between miRNAs and their target genes. mirAct supports multiple-class data and enables clustering analysis based on computationally determined miRNA activity. Here, we describe the framework of mirAct, demonstrate its performance by comparing with other similar programs and exemplify its applications using case studies. PMID- 21596786 TI - Biological insights from topology independent comparison of protein 3D structures. AB - Comparing and classifying the three-dimensional (3D) structures of proteins is of crucial importance to molecular biology, from helping to determine the function of a protein to determining its evolutionary relationships. Traditionally, 3D structures are classified into groups of families that closely resemble the grouping according to their primary sequence. However, significant structural similarities exist at multiple levels between proteins that belong to these different structural families. In this study, we propose a new algorithm, CLICK, to capture such similarities. The method optimally superimposes a pair of protein structures independent of topology. Amino acid residues are represented by the Cartesian coordinates of a representative point (usually the C(alpha) atom), side chain solvent accessibility, and secondary structure. Structural comparison is effected by matching cliques of points. CLICK was extensively benchmarked for alignment accuracy on four different sets: (i) 9537 pair-wise alignments between two structures with the same topology; (ii) 64 alignments from set (i) that were considered to constitute difficult alignment cases; (iii) 199 pair-wise alignments between proteins with similar structure but different topology; and (iv) 1275 pair-wise alignments of RNA structures. The accuracy of CLICK alignments was measured by the average structure overlap score and compared with other alignment methods, including HOMSTRAD, MUSTANG, Geometric Hashing, SALIGN, DALI, GANGSTA(+), FATCAT, ARTS and SARA. On average, CLICK produces pair-wise alignments that are either comparable or statistically significantly more accurate than all of these other methods. We have used CLICK to uncover relationships between (previously) unrelated proteins. These new biological insights include: (i) detecting hinge regions in proteins where domain or sub domains show flexibility; (ii) discovering similar small molecule binding sites from proteins of different folds and (iii) discovering topological variants of known structural/sequence motifs. Our method can generally be applied to compare any pair of molecular structures represented in Cartesian coordinates as exemplified by the RNA structure superimposition benchmark. PMID- 21596787 TI - PROMoter uPstream Transcripts share characteristics with mRNAs and are produced upstream of all three major types of mammalian promoters. AB - PROMoter uPstream Transcripts (PROMPTs) were identified as a new class of human RNAs, which are heterologous in length and produced only upstream of the promoters of active protein-coding genes. Here, we show that PROMPTs carry 3' adenosine tails and 5'-cap structures. However, unlike mRNAs, PROMPTs are largely nuclear and rapidly turned over by the RNA exosome. PROMPT-transcribing DNA is occupied by RNA polymerase II (RNAPII) complexes with serine 2 phosphorylated C terminal domains (CTDs), mimicking that of the associated genic region. Thus, the inefficient elongation capacity of PROMPT transcription cannot solely be assigned to poor CTD phosphorylation. Conditions that reduce gene transcription increase RNAPII occupancy of the upstream PROMPT region, suggesting that they reside in a common transcription compartment. Surprisingly, gene promoters that are actively transcribed by RNAPI or RNAPIII also produce PROMPTs that are targeted by the exosome. RNAPIII PROMPTs bear hallmarks of RNAPII promoter-associated RNAs, explaining the physical presence of RNAPII upstream of many RNAPIII-transcribed genes. We propose that RNAPII activity upstream gene promoters are wide-spread and integral to the act of gene transcription. PMID- 21596788 TI - Endogenously induced DNA double strand breaks arise in heterochromatic DNA regions and require ataxia telangiectasia mutated and Artemis for their repair. AB - Ataxia telangiectasia (ATM) mutated and Artemis, the proteins defective in ataxia telangiectasia and a class of Radiosensitive-Severe Combined Immunodeficiency (RS SCID), respectively, function in the repair of DNA double strand breaks (DSBs), which arise in heterochromatic DNA (HC-DSBs) following exposure to ionizing radiation (IR). Here, we examine whether they have protective roles against oxidative damage induced and/or endogenously induced DSBs. We show that DSBs generated following acute exposure of G0/G1 cells to the oxidative damaging agent, tert-butyl hydroperoxide (TBH), are repaired with fast and slow components of similar magnitude to IR-induced DSBs and have a similar requirement for ATM and Artemis. Strikingly, DSBs accumulate in ATM(-/-) mouse embryo fibroblasts (MEFs) and in ATM or Artemis-defective human primary fibroblasts maintained for prolonged periods under confluence arrest. The accumulated DSBs localize to HC DNA regions. Collectively, the results provide strong evidence that oxidatively induced DSBs arise in HC as well as euchromatic DNA and that Artemis and ATM function in their repair. Additionally, we show that Artemis functions downstream of ATM and is dispensable for HC-relaxation and for pKAP-1 foci formation. These findings are important for evaluating the impact of endogenously arising DNA DSBs in ATM and Artemis-deficient patients. PMID- 21596789 TI - GenPlay, a multipurpose genome analyzer and browser. AB - MOTIVATION: Rapidly decreasing sequencing cost due to the emergence and improvement of massively parallel sequencing technologies has resulted in a dramatic increase in the quantity of data that needs to be analyzed. Therefore, software tools to process, visualize, analyze and integrate data produced on multiple platforms and using multiple methods are needed. RESULTS: GenPlay is a fast, easy to use and stable tool for rapid analysis and data processing. It is written in Java and runs on all major operating systems. GenPlay recognizes a wide variety of common genomic data formats from microarray- or sequencing-based platforms and offers a library of operations (normalization, binning, smoothing) to process raw data into visualizable tracks. GenPlay displays tracks adapted to summarize gene structure, gene expression, repeat families, CPG islands, etc. as well as custom tracks to show the results of RNA-Seq, ChIP-Seq, TimEX-Seq and single nucleotide polymorphism (SNP) analysis. GenPlay can generate statistics (minimum, maximum, SD, correlation, etc.). The tools provided include Gaussian filter, peak finders, signal saturation, island finders. The software also offers graphical features such as scatter plots and bar charts to depict signal repartition. The library of operations is continuously growing based on the emerging needs. AVAILABILITY: GenPlay is an open-source project available from http://www.genplay.net. The code source of the software is available at https://genplay.einstein.yu.edu/svn/GenPlay. PMID- 21596791 TI - rBioNet: A COBRA toolbox extension for reconstructing high-quality biochemical networks. AB - MOTIVATION: Genome-scale metabolic networks are widely used in systems biology. However, to date no freely available tool exists that ensures quality control during the reconstruction process. RESULTS: Here, we present a COBRA toolbox extension, rBioNet, enabling the construction of publication-level biochemical networks while enforcing necessary quality control measures. rBioNet has an intuitive user interface facilitating the reconstruction process for novices and experts. AVAILABILITY: The rBioNet is freely available from http://opencobra.sourceforge.net. PMID- 21596792 TI - linkcomm: an R package for the generation, visualization, and analysis of link communities in networks of arbitrary size and type. AB - SUMMARY: An essential element when analysing the structure, function, and dynamics of biological networks is the identification of communities of related nodes. An algorithm proposed recently enhances this process by clustering the links between nodes, rather than the nodes themselves, thereby allowing each node to belong to multiple overlapping or nested communities. The R package 'linkcomm' implements this algorithm and extends it in several aspects: (i) the clustering algorithm handles networks that are weighted, directed, or both weighted and directed; (ii) several visualization methods are implemented that facilitate the representation of the link communities and their relationships; (iii) a suite of functions are included for the downstream analysis of the link communities including novel community-based measures of node centrality; (iv) the main algorithm is written in C++ and designed to handle networks of any size; and (v) several clustering methods are available for networks that can be handled in memory, and the number of communities can be adjusted by the user. AVAILABILITY: The program is freely available from the Comprehensive R Archive Network (http://cran.r-project.org/) under the terms of the GNU General Public License (version 2 or later). PMID- 21596790 TI - Bioinformatics challenges for personalized medicine. AB - MOTIVATION: Widespread availability of low-cost, full genome sequencing will introduce new challenges for bioinformatics. RESULTS: This review outlines recent developments in sequencing technologies and genome analysis methods for application in personalized medicine. New methods are needed in four areas to realize the potential of personalized medicine: (i) processing large-scale robust genomic data; (ii) interpreting the functional effect and the impact of genomic variation; (iii) integrating systems data to relate complex genetic interactions with phenotypes; and (iv) translating these discoveries into medical practice. CONTACT: russ.altman@stanford.edu PMID- 21596793 TI - Positional integratomic approach in identification of genomic candidate regions for Parkinson's disease. AB - MOTIVATION: Recent abundance of data from studies employing high-throughput technologies to reveal alterations in human disease on genomic, transcriptomic, proteomic and other levels, offer the possibility to integrate this information into a comprehensive picture of molecular events occurring in human disease. Diversity of data originating from these studies presents a methodological obstacle in the integration process, also due to difficulties in choosing the optimal unified denominator that would allow inclusion of variables from various types of studies. We present a novel approach for integration of such multi origin data based on positions of genetic alterations occurring in human diseases. Parkinson's disease (PD) was chosen as a model for evaluation of our methodology. METHODS: Datasets from various types of studies in PD (linkage, genome-wide association, transcriptomic and proteomic studies) were obtained from online repositories or were extracted from available research papers. Subsequently, human genome assembly was subdivided into 10 kb regions, and significant signals from aforementioned studies were arranged into their corresponding regions according to their genomic position. For each region, rank product values were calculated and significance values were estimated by permuting the original dataset. RESULTS: Altogether, 179 regions (representing 33 contiguous genomic regions) had significant accumulation of signals when P-value cut-off was set at 0.0001. Identified regions with significant accumulation of signals contained 29 plausible candidate genes for PD. In conclusion, we present a novel approach for identification of candidate regions and genes for various human disorders, based on the positional integration of data across various types of omic studies. PMID- 21596794 TI - Diagnostic accuracy of the Berlin Questionnaire in detecting sleep-disordered breathing in patients with a recent myocardial infarction. AB - BACKGROUND: The Berlin Questionnaire (BQ) has been used to identify patients at high risk for sleep-disordered breathing (SDB) in a variety of populations. However, there are no data regarding the validity of the BQ in detecting the presence of SDB in patients after myocardial infarction (MI). The aim of this study was to determine the performance of the BQ in patients after MI. METHODS: We conducted a cross-sectional study of 99 patients who had an MI 1 to 3 months previously. The BQ was administered, scored using the published methods, and followed by completed overnight polysomnography as the "gold standard." SDB was defined as an apnea-hypopnea index of >= 5 events/h. The sensitivity, specificity, and positive and negative predictive values of the BQ were calculated. RESULTS: Of the 99 patients, the BQ identified 64 (65%) as being at high-risk for having SDB. Overnight polysomnography showed that 73 (73%) had SDB. The BQ sensitivity and specificity was 0.68 and 0.34, respectively, with a positive predictive value of 0.68 and a negative predictive value of 0.50. Positive and negative likelihood ratios were 1.27 and 0.68, respectively, and the BQ overall diagnostic accuracy was 63%. Using different apnea-hypopnea index cutoff values did not meaningfully alter these results. CONCLUSION: The BQ performed with modest sensitivity, but the specificity was poor, suggesting that the BQ is not ideal in identifying SDB in patients with a recent MI. PMID- 21596795 TI - Nrf2 regulates NGF mRNA induction by carnosic acid in T98G glioblastoma cells and normal human astrocytes. AB - Nerve growth factor (NGF) is a neurotrophic factor that plays an important role in neuronal cell development and survival. Carnosic acid (CA), a hydrophobic constituent of the herb rosemary, induces NGF production in human T98G glioblastoma cells, but the mechanism through which it works remains unknown. In the present study, we found a redox-sensitive transcription factor, Nrf2, which coordinates the expression of cytoprotective phase 2 genes, also participates in CA-inducible NGF expression. In T98G cells, CA caused NGF gene induction in a dose- and time-dependent manner without altering NGF mRNA stability. Simultaneously, CA increased Nrf2 nuclear accumulation and activated expression of prototypical Nrf2 target genes such as haem oxygenase 1 (HO-1) and thioredoxin reductase 1 (TXNRD1). Knockdown of endogenous Nrf2 by Nrf2-specific siRNA significantly reduced constitutive and CA-inducible NGF gene expression. In addition, NGF gene expression was enhanced by knockdown of Keap1, an Nrf2 inhibitor, in the absence of CA. Furthermore, CA induced NGF expression in normal human astrocytes in an Nrf2-dependent manner. These results highlight a role of Nrf2 in NGF gene expression in astroglial cells. PMID- 21596796 TI - Pulmonary aspergillosis in immunocompetent patients without air-meniscus sign and underlying lung disease: CT findings and histopathologic features. AB - BACKGROUND: Pulmonary aspergillosis in immunocompetent patients has been described as a saprophytic infection with pre-existing lung lesions showing an air-meniscus sign on chest radiograph or CT scans. There have been rare articles dealing with pulmonary aspergillosis in immunocompetent patients without pre existing lung lesions. PURPOSE: To evaluate the CT findings of pulmonary aspergillosis in immunocompetent patients without air-meniscus and underlying lung disease and to correlate the CT findings and pathologic features of pulmonary aspergillosis in these patients. MATERIAL AND METHODS: A total of seven surgically proven pulmonary aspergillosis found in immunocompetent patients without an air-meniscus and underlying lung disease (M:F = 1:6; mean age 63.4 years) were included. On CT, the lesion shape, margin, type, location, diameter, presence of satellite nodules, presence of CT halo sign or hypodense sign, and interval growth were evaluated. Histopathologic features of each lesion were classified as one of the following; primary aspergilloma, chronic necrotizing pulmonary aspergillosis, or invasive pulmonary aspergillosis. Correlation between CT findings and pathological features was performed. RESULTS: All lesions presented as a nodule or mass unable to differentiate from malignancy. Most lesions had well-defined margins (n = 4), appeared as solid lesions (n = 7), and were located in the upper lobe (n = 5). Mean diameter of lesions was 2.3 cm. Satellite nodules (n = 2), CT halo sign (n = 1), and hypodense sign (n = 4) were found. Only one lesion increased in size during follow-up. Lesions were pathologically classified as primary aspergilloma (n = 3) and chronic necrotizing pulmonary aspergillosis (n = 4). The hypodense sign on CT was pathologically proved as dense fungal hyphae filled in bronchus and CT halo sign as parenchymal hemorrhage. CONCLUSION: Pulmonary aspergillosis predominantly presented as a nodule or mass mimicking malignancy in the upper lobes on CT scan in elderly without underlying lung disease and immunosuppressive conditions except for age, and was histopathologically revealed to be either primary aspergilloma or chronic necrotizing pulmonary aspergillosis. PMID- 21596797 TI - Variations of the aortic arch - a study on the most common branching patterns. AB - BACKGROUND: Anatomical variants of the aortic arch and its branching patterns often appear as an incidental finding during routine computed tomography (CT) scanning. These variations can be of relevance when performing angiography or endovascular interventions and may cause symptoms such as dysphagia. PURPOSE: To analyze common anatomical variations found within the arteries originating from the aortic arch in patients using contrast CT imaging techniques. MATERIAL AND METHODS: A total of 2033 contrast CT scans were analyzed. To obtain a truly representative sample, cases were chosen from different hospital departments without previous knowledge of the patient history. RESULTS: The total percentage of variations within the analyzed patients was 13.3%. In 8.0% a truncus bicaroticus was found. 4.2% of the patients showed a left vertebral artery originating directly from the aortic arch, mostly proximal, and in 1 case distal to the left subclavian artery. In 1.0% we found an aberrant right subclavian artery. We also found a single case of a right descending aortic arch. CONCLUSION: Variations of the aortic arch and its branching are frequently found, mostly as an incidental finding during routine diagnostic scanning. A contrast enhanced CT scan is a good method with which to study the aortic arch and its associated branching pattern. PMID- 21596798 TI - Does power Doppler ultrasonography improve the BI-RADS category assessment and diagnostic accuracy of solid breast lesions? AB - BACKGROUND: Power Doppler ultrasonography (US) is used in addition to B-mode US as a tool for the differential diagnosis between benign and malignant lesions. However, there are few data showing how useful power Doppler US is for BI-RADS category assessment. PURPOSE: To assess how much power Doppler US contributed to increasing the category diagnosis from Breast Imaging Reporting and Data System (ACR BI-RADS((r))-US) category 3 to category 4. MATERIAL AND METHODS: A total of 2426 patients (age range 16-91 years, mean 52 years) who underwent B-mode and power Doppler breast US using a linear 10-MHz transducer were analyzed. We devised integrated US category classification (BI-RADS-Integral) based on BI-RADS descriptors and vascularity. Masses with a circumscribed margin, parallel orientation, and negative vascularity on power Doppler US were defined as category 3. Irregular-shaped masses with a spiculated margin or echogenic halo were defined as category 5. Masses with one of the four suspicious findings (no circumscribed margin, no parallel orientation, microcalcifications, and positive vascularity) were defined as category 4a, and masses with two or more suspicious findings were defined as category 4b. RESULTS: There were 98 breast cancer cases, and the average sizes of invasive and non-invasive cancers were 15 mm and 18 mm, respectively. The frequency of breast cancer according to category was: 0.4% (3/714) of the category 3 cases, 2.7% (7/256) in category 4a, 64% (47/73) in category 4b, and 100% (41/41) in category 5. Among the cases with a category 4a mass lesion, there were 183 lesions whose category diagnosis had been raised from category 3 to category 4a based on the Doppler blood flow findings alone, and 3 (1.6%) of those lesions were breast cancer. All three of them were ductal carcinoma in situ (DCIS) cases. When the cut-off point was placed between category 3 and category 4, BI-RADS-Integral and BI-RADS-US without power Doppler had a sensitivity of 96.9% and 93.9%, respectively, specificity of 72.1% and 90.4%, respectively, and accuracy of 74.4% and 90.7%, respectively. CONCLUSION: The presence of Doppler blood flow increases the malignancy pick-up rate, but at the expense of a significant decrease in specificity and diagnostic accuracy and an increase in biopsy rate. PMID- 21596799 TI - Induced pluripotent stem cell (iPSC)-derived Flk-1 progenitor cells engraft, differentiate, and improve heart function in a mouse model of acute myocardial infarction. AB - AIMS: Induced pluripotent stem cell (iPSC)-derived cardiovascular progenitor cells represent a suitable autologous cell source for myocardial regeneration as they have the capability to form myocardial cells and to contribute to revascularization. As a first proof of concept we evaluated the potential of a murine iPSC-derived cardiovascular progenitor population, which expresses the surface marker foetal liver kinase-1 (Flk-1), to restore myocardial tissue and improve cardiac function after acute myocardial infarction (MI) in mice. METHODS AND RESULTS: iPSC-derived Flk-1(pos) vs. Flk-1(neg) cells were selected by fluorescence activated cell sorting (FACS) and injected into the ischaemic myocardium of left anterior descending coronary artery (LAD)-ligated mice. Addressing safety aspects we used an octamer binding factor 4 (Oct4)-enhanced green fluorescent protein (eGFP) expressing iPSC clone from the transgenic Oct4 eGFP reporter mouse strain OG2 to enable FACS-based depletion of undifferentiated cells prior to transplantation. Infarcted animals were treated with placebo (phosphate-buffered saline, n = 13), Flk-1(neg) cells (n = 14), or Flk-1(pos) cells (n = 11; 5 * 10(5) cells each). Heart function was evaluated by magnetic resonance imaging and conductance catheter analysis 2 weeks postoperatively. Cardiovascular in vitro and in vivo differentiations were investigated by immunofluorescence staining. Treatment with Flk-1(pos) and Flk-1(neg) cells resulted in a favourable myocardial remodelling and improved left ventricular function. Engraftment and functional benefits were superior after transplantation of Flk-1(pos) compared with Flk-1(neg) cells. Furthermore, Flk-1(pos) grafts contained considerably more vascular structures in relation to Flk-1(neg) grafts. CONCLUSION: iPSC-derived Flk-1(pos) progenitor cells differentiate into cardiovascular lineages in vitro and in vivo and improve cardiac function after acute MI. This proof of concept study paves the way for an autologous iPSC-based therapy of MI. PMID- 21596800 TI - Young age at first intercourse and risk-taking behaviours--a study of nearly 65 000 women in four Nordic countries. AB - BACKGROUND: Risk-taking behaviours such as early initiation of smoking, alcohol drinking and sexual activity often cluster within individuals and could be characteristics of adolescents who in general are risk takers. In the present study, using a large population-based sample of 64 659 women aged 18-45 years in four Nordic countries, we investigate whether young age at first sexual intercourse is associated with subsequent risk-taking behaviours. METHODS: We examined the association between young age at first sexual intercourse (age <=14 years) and subsequent risk-taking behaviours by using multivariate logistic regression by which odds ratios (ORs) and the corresponding 95% confidence intervals (95% CIs) were estimated. RESULTS: The OR of reporting more than 10 lifetime sexual partners was almost four times higher among women who reported a young age at first intercourse (OR = 3.79; 95% CI: 3.60-4.00) in comparison with women >14 years at first intercourse. Furthermore, women who were young at first intercourse were more likely to report two or more recent partners (OR = 1.67; 95% CI: 1.54-1.82) and to have a history of STIs (OR = 2.03; 95% CI: 1.93-2.13). In addition, young age at first intercourse was associated with current smoking (OR = 2.31; 95% CI: 2.20-2.43) and binge drinking (OR = 1.36; 95% CI: 1.28-1.44). All ORs were adjusted for age, years of education and country of residence. CONCLUSION: Young age at first intercourse is associated with subsequent risk taking behaviours. Our study emphasizes the importance of targeting prevention efforts towards the complexity of risk-taking behaviours. PMID- 21596801 TI - RNAi-induced off-target effects in Drosophila melanogaster: frequencies and solutions. AB - Genes can be silenced with short-interfering RNA molecules (siRNA). siRNAs are widely used to identify gene functions and have high potential for therapeutic treatments. It is critical that the siRNA specifically targets the expression of the gene of interest but has no off-target effects on other genes. Although siRNAs were initially considered to be exclusively active on mature mRNAs in the cytoplasm, additional studies have shown that siRNAs are present in the nucleus as well, suggesting that pre-mRNA sequences containing introns and other untranslated regions can also be targeted. In this study, we investigated the extent to which off-targets may occur in Drosophila melanogaster by looking at mature mRNA sequences and pre-mature RNA sequences separately. First, an in silico approach revealed that, based on sequence similarity, numerous off-targets are predicted to occur in RNAi experiments. Second, existing microarray data were used to investigate a possible effect of the predicted off-targets based on analysis of in vitro data. We found that the occurrence of off-targets in both mature and pre-mature RNA sequences in RNAi experiments can be extensive and significant. Possibilities are discussed how to minimize off-target effects. PMID- 21596802 TI - The Diagnostic, Prognostic, and differential value of enhanced MR imaging in Guillain-Barre syndrome. PMID- 21596803 TI - 3D quantitative evaluation of atherosclerotic plaque based on rotational angiography. AB - BACKGROUND AND PURPOSE: Atherosclerosis is a systemic disease that has been shown to cause various cardiovascular diseases and stroke. However, technologies to evaluate the volume of atherosclerotic plaque are limited. We present a method for determination of 3D plaque volume based on RA. MATERIALS AND METHODS: 3DRA images obtained from patients were used to evaluate the plaque. Six patients who were diagnosed with atherosclerotic lesions were included. The PR model developed for 3DRA was applied to analyze the geometry of the vessel and calculate the plaque volume. To validate the present method, we tested computer-generated phantoms with different degrees of stenosis. RESULTS: Application of PR to clinical cases allowed the estimation of plaque morphology and quantification of plaque volume. Technique validation showed that on average, PR can rebuild 92% of the plaque and provide satisfactory determination of plaque volume. CONCLUSIONS: A new approach to obtain plaque volume based on 3DRA is presented. The initial tests in 6 clinical cases and validation with different phantoms showed that this method is feasible. Further validation in a larger clinical series is required to assess the ultimate value of the present technique. PMID- 21596804 TI - Mechanical characterization of thromboemboli in acute ischemic stroke and laboratory embolus analogs. AB - BACKGROUND AND PURPOSE: Mechanical behavior of the thromboembolus is one of the key factors that determine the efficacy of thrombectomy devices for revascularization in AIS. We characterized the mechanical properties and composition of thromboemboli from clinical cases and compared them with commonly used EAs. MATERIALS AND METHODS: Thromboemboli were obtained from patients with AIS by using aspiration devices and from carotid atherosclerotic plaques harvested during endarterectomy. In the laboratory, common EAs were created by varying blood donor species (human, porcine, and bovine), thrombin concentration, and presence of barium sulfate. Stiffness and elasticity of the specimens were measured with DMA. Scanning electron microscopy and histology were used to investigate the ultrastructure and composition of all specimens. RESULTS: Red thromboemboli from patients composed mainly of fibrin and erythrocytes were much softer than the calcified and cholesterol-rich material. Of the EAs created in the laboratory, those made from bovine blood presented the highest stiffness that was independent of thrombin concentration. Addition of thrombin increased the stiffness and elasticity of human and porcine EAs (P < .05). The presence of barium sulfate significantly reduced the elasticity of all EAs (P < .05). CONCLUSIONS: Endovascular device testing and development requires realistic EAs. The stiffness and elasticity of the cerebral thromboemboli analyzed in this study were closely matched by recalcified porcine EAs and thrombin-induced human EAs. Stiffness of the thrombus extracted from carotid endarterectomy specimens was similar with that of the thrombin-induced bovine and porcine EAs. PMID- 21596805 TI - Isolated diffusion restriction precedes the development of enhancing tumor in a subset of patients with glioblastoma. AB - BACKGROUND AND PURPOSE: Most response criteria for patients with glioblastoma rely on increases in the contrast enhancing abnormality to determine tumor progression. Our aim was to determine retrospectively in patients with glioblastoma whether diffusion restriction can predict the development of new enhancing mass lesions. MATERIALS AND METHODS: We reviewed the brain MR imaging scans (including DWI and ADC maps) of 208 patients with glioblastoma. Patients with restricted diffusion in or adjacent to the tumor were identified, with further analysis only performed on those patients with low-ADC lesions without enhancement. These patients were followed to determine if new concordant enhancement developed at the site of the low-ADC lesion. A Wilcoxon signed rank test, competing risk analysis, and Kaplan-Meier curves were used to compare the mean drop in ADC values, assess enhancement-free survival, and determine overall survival, respectively. RESULTS: In 67 of the 208 patients (32.2%), visibly detectable restricted diffusion was seen during treatment. The study cohort was formed by the 27 patients with low-ADC lesions and no corresponding enhancement. Twenty-three (85.2%) patients developed gadolinium-enhancing tumor at the site of restricted diffusion a median of 3.0 months later (95% CI, 2.6-4.1 months). The mean decrease in ADC was 22.9% from baseline (P < .001). The 3-month enhancement free survival probability was 0.481 (95% CI, 0.288-0.675). The 12-month overall survival probability was 0.521 (95% CI, 0.345-0.788). Restricted diffusion predicted enhancement regardless of antiangiogenic therapy with bevacizumab. CONCLUSIONS: In a subset of patients with glioblastoma, development of a new focus of restricted diffusion during treatment may precede the development of new enhancing tumor. PMID- 21596806 TI - Effect of tonsillar herniation on cyclic CSF flow studied with computational flow analysis. AB - BACKGROUND AND PURPOSE: The Chiari I malformation, characterized by tonsils extending below the foramen magnum, has increased CSF velocities compared with those in healthy subjects. Measuring the effect of tonsillar herniation on CSF flow in humans is confounded by interindividual variation. The goal of this study was to determine the effect of herniated tonsils on flow velocity and pressure dynamics by using 3D computational models. MATERIALS AND METHODS: A previously described 3D mathematic model of the normal subarachnoid space was modified by extending the tonsils inferiorly. The chamber created was compared with the anatomy of the subarachnoid space. Pressures and velocities were calculated by CFA methods for sinusoidal flow of a Newtonian fluid. Results were displayed as 2D color-coded plots and 3D animations. Pressure gradients and flow velocities were compared with those in the normal model. Velocity distributions were also compared with those in clinical images of CSF flow. RESULTS: The model represented grossly the subarachnoid space of a patient with Chiari I malformation. Fluid flow patterns in the Chiari model were complex, with jets in some locations and stagnant flow in others. Flow jets, synchronous bidirectional flow, and pressure gradients were greater in the Chiari model than in the normal model. The distribution of flow velocities in the model corresponded well with those observed in clinical images of CSF flow in patients with Chiari I. CONCLUSIONS: Tonsillar herniation per se increases the pressure gradients and the complexity of flow patterns associated with oscillatory CSF flow. PMID- 21596807 TI - Probabilistic somatotopy of the spinothalamic pathway at the ventroposterolateral nucleus of the thalamus in the human brain. AB - BACKGROUND AND PURPOSE: The STP has been regarded as the most plausible neural tract responsible for pathogenesis of central poststroke pain. The VPL nucleus has been a target for neurosurgical procedures for control of central poststroke pain. However, to our knowledge, no DTI studies have been conducted to investigate the somatotopic location of the STP at the VPL nucleus of the thalamus. In the current study, we attempted to investigate this location in the human brain by using a probabilistic tractography technique of DTI. MATERIALS AND METHODS: DTI was performed at 1.5T by using a Synergy-L SENSE head coil. STPs for both the hand and leg were obtained by selection of fibers passing through 2 regions of interest (the area of the spinothalamic tract in the posterolateral medulla and the postcentral gyrus) for 41 healthy volunteers. Somatotopic mapping was obtained from the highest probabilistic location at the ACPC level. RESULTS: The highest probabilistic locations for the hand and leg were an average of 16.86 and 16.37 mm lateral to the ACPC line and 7.53 and 8.71 mm posterior to the midpoint of the ACPC line, respectively. Somatotopic locations for the hand and leg were different in the anteroposterior direction (P < .05); however, no difference was observed in the mediolateral direction (P > .05). CONCLUSIONS: We found the somatotopic locations for hand and leg of the STP at the VPL nucleus; these somatotopies were arranged in the anteroposterior direction. PMID- 21596808 TI - Assessing the chronic neuropsychologic sequelae of human immunodeficiency virus negative cryptococcal meningitis by using diffusion tensor imaging. AB - BACKGROUND AND PURPOSE: The high rate of neuropsychologic sequelae in CM survivors indicates that initial antifungal therapy is far from being satisfactory. This prospective cross-sectional study applied DTI on HIV-negative CM patients to determine whether microstructural changes in brain tissue are associated with subsequent cognitive symptoms. MATERIALS AND METHODS: Fifteen patients with HIV-negative CM and 15 sex- and age-matched healthy volunteers were evaluated and compared. All underwent complete medical and neurologic examinations and neuropsychologic testing. Brain DTI was obtained to derive the FA and ADC of several brain regions. Correlations among DTI parameters, neuropsychologic rating scores, and cryptococcal-antigen titer in CSF were analyzed. RESULTS: Significant ADC values increased and FA values decreased in HIV-negative CM patients in multiple selected regions of interest, including the genus of the corpus callosum and the frontal, parietal, orbito-frontal, and periventricular white matter and lentiform nucleus. Higher CSF cryptococcal antigen titer on admission was associated with poorer DTI parameters (r = -0.666, P = .018), which were linearly related to worse cognitive performance during follow-up. CONCLUSIONS: The decline in brain DTI parameters in the associated brain areas indicates an HIV-negative CM microstructural pathology that is related to neuropsychologic consequences. PMID- 21596810 TI - Pediatric sensorineural hearing loss, part 2: syndromic and acquired causes. AB - This article is the second in a 2-part series reviewing neuroimaging in childhood SNHL. Previously, we discussed the clinical work-up of children with hearing impairment, the classification of inner ear malformations, and congenital nonsyndromic causes of hearing loss. Here, we review and illustrate the most common syndromic hereditary and acquired causes of childhood SNHL, with an emphasis on entities that demonstrate inner ear abnormalities on cross-sectional imaging. Syndromes discussed include BOR syndrome, CHARGE syndrome, Pendred syndrome, Waardenburg syndrome, and X-linked hearing loss with stapes gusher. We conclude the article with a review of acquired causes of childhood SNHL, including infections, trauma, and neoplasms. PMID- 21596809 TI - Clinical application of readout-segmented- echo-planar imaging for diffusion weighted imaging in pediatric brain. AB - BACKGROUND AND PURPOSE: RS-EPI has been suggested as an alternative approach to EPI for high-resolution DWI with reduced distortions. To determine whether RS-EPI is a useful approach for routine clinical use, we implemented GRAPPA-accelerated RS-EPI DWI at our pediatric hospital and graded the images alongside standard accelerated (ASSET) EPI DWI used routinely for clinical studies. MATERIALS AND METHODS: GRAPPA-accelerated RS-EPI DWIs and ASSET EPI DWIs were acquired on 35 pediatric patients using a 3T system in 35 pediatric patients. The images were graded alongside each other by using a 7-point Likert scale as follows: 1, nondiagnostic; 2, poor; 3, acceptable; 4, standard; 5, above average; 6, good; and 7, outstanding. RESULTS: The following were the average scores for EPI and RS EPI, respectively: resolution, 3.5/5.2; distortion level, 2.9/6.0; SNR, 3.4/4.1; lesion conspicuity, 3.3/5.9; and diagnostic confidence, 3.2/6.0. Overall, the RS EPI had significantly improved diagnostic confidence and more reliably defined the extent and structure of several lesions. Although ASSET EPI scans had better SNR per scanning time, the higher spatial resolution as well as reduced blurring and distortions on RS-EPI scans helped to better reveal important anatomic details at the cortical-subcortical levels, brain stem, temporal and inferior frontal lobes, skull base, sinonasal cavity, cranial nerves, and orbits. CONCLUSIONS: This work shows the importance of both resolution and decreased distortions in the clinics, which can be accomplished by a combination of parallel imaging and alternative k-space trajectories such as RS-EPI. PMID- 21596811 TI - Size and shape of the corpus callosum in adult Niemann-Pick type C reflects state and trait illness variables. AB - BACKGROUND AND PURPOSE: Variable alterations to the structure of the corpus callosum have been described in adults with NPC, a neurometabolic disorder known to result in both white and gray matter pathology. This study sought to examine the structure of the callosum in a group of adult patients with NPC and compared callosal structure with a group of matched controls, and to relate callosal structure with state and trait illness variables. MATERIALS AND METHODS: Nine adult patients with NPC were matched to control subjects (n = 26) on age and sex. The corpus callosum was segmented from the midsagittal section of T1-weighted images on all subjects, and total area, length, bending angle, and mean thickness were calculated. In addition, 39 regional thickness measures were derived by using a previously published method. All measures were compared between groups, and analyzed alongside symptom measures, biochemical parameters, and ocular-motor measures. RESULTS: The callosal area and mean thickness were significantly reduced in the patient group, and regional thickness differences were greatest in the genu, posterior body, isthmus, and anterior splenium. Global callosal measures correlated significantly with duration of illness and symptom score, and at trend level with degree of filipin staining. Measures of reflexive saccadic peak velocity and gain, and self-paced saccades, correlated strongly with total callosal area. CONCLUSIONS: Callosal structure and size reflect both state and trait markers in adult NPC, and they may be useful biomarkers to index both white and gray matter changes that reflect illness severity and progression. PMID- 21596812 TI - Stent placement for flow restoration in acute ischemic stroke: a single-center experience with the Solitaire stent system. AB - BACKGROUND AND PURPOSE: In acute thromboembolic stroke, mechanical recanalization with stents may result in immediate flow restoration. The Solitaire stent can be used both for flow restoration and thrombectomy. In this single-center experience, we report safety and efficacy data on the application of the Solitaire stent. MATERIALS AND METHODS: Between March 2009 and July 2010, 18 patients were treated with the Solitaire stent. To evaluate perfusion of the occluded vessel segment before and after the intervention, the TICI score was used (0-3). Clinical outcome was assessed by using the mRS at discharge. RESULTS: Overall, recanalization was successful in 16 of 18 patients (88.8%). There were no procedure-related complications. Mean TICI score after the intervention was 2.3 +/- 0.8. In 5 patients, reocclusion of the treated vessel occurred immediately after retrieval of the temporarily opened stent, and permanent stent deployment was performed to maintain stable perfusion. In 3 patients, hemorrhage occurred after successful recanalization. Five patients died (infarction, n = 3; hemorrhage, n = 1; organ failure, n = 1). A good clinical outcome (mRS <=2) was achieved in 33.3% of the patients, 5.5% had a moderate outcome (mRS, 3/4), and 61.2% had a poor outcome or died (mRS, 5/6). CONCLUSIONS: Application of the Solitaire stent in acute stroke results in a high recanalization rate (88.8%) without procedural complications and with a good outcome in one-third of patients. These results encourage further evaluation of the stent in larger patient populations. PMID- 21596813 TI - Editor-in-chief, midterm report. PMID- 21596816 TI - Physician payment reform: getting what we pay for. PMID- 21596814 TI - Reversible changes in brain glucose metabolism following thyroid function normalization in hyperthyroidism. AB - BACKGROUND AND PURPOSE: Patients with hyperthyroidism frequently present with regional cerebral metabolic changes, but the consequences of endocrine-induced brain changes after thyroid function normalization are unclear. We hypothesized that the changes of regional cerebral glucose metabolism are related to thyroid hormone levels in patients with hyperthyroid, and some of these changes can be reversed with antithyroid therapy. MATERIALS AND METHODS: Relative regional cerebral glucose metabolism was compared between 10 new-onset untreated patients with hyperthyroidism and 20 healthy control participants by using brain FDG-PET scans. Levels of emotional distress were evaluated by using the SAS and SDS. Patients were treated with methimazole. A follow-up PET scan was performed to assess metabolic changes of the brain when thyroid functions normalized. RESULTS: Compared with controls, patients exhibited lower activity in the limbic system, frontal lobes, and temporal lobes before antithyroid treatment. There were positive correlations between scores of depression and regional metabolism in the cingulate and paracentral lobule. The severity of depression and anxiety covaried negatively with pretreatment activity in the inferior temporal and inferior parietal gyri respectively. Compared with the hyperthyroid status, patients with normalized thyroid functions showed an increased metabolism in the left parahippocampal, fusiform, and right superior frontal gyri. The decrease in both FT3 and FT4 was associated with increased activity in the left parahippocampal and right superior frontal gyri. CONCLUSIONS: The changes of regional cerebral glucose metabolism are related to thyroid hormone levels in patients with hyperthyroidism, and some cerebral hypometabolism can be improved after antithyroid therapy. PMID- 21596817 TI - Panitumumab (vectibix). AB - Panitumumab (Vectibix), is a human monoclonal antibody EGFR antagonist indicated as a single agent for the treatment of metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy regimens. This article will present the mechanism of action as well as the clinical role for this monoclonal antibody. PMID- 21596818 TI - Endovascular treatment for unruptured intracranial aneurysms in elderly patients: single-center report. AB - BACKGROUND AND PURPOSE: The optimal management of patients with unruptured intracranial aneurysms remains controversial in elderly populations. The aim of this study was to evaluate technical results and clinical outcomes in a single center of consecutive elderly patients with unruptured intracranial aneurysms treated with endovascular embolization. MATERIALS AND METHODS: Between May 2003 and February 2010, 96 patients older than 70 years (men, 16 patients; women, 80 patients; mean age, 73 years) with 122 saccular unruptured intracranial aneurysms were treated in our hospital with an endovascular approach. The endovascular procedures and technique, angiographic follow-up, and complications were evaluated. RESULTS: Successful embolizations without complications were completed in 95.9%. Five patients had procedure-related events, including thromboembolism in 1 patient, aneurysm perforation during the procedure in 1, and 3 postoperative transient minor symptoms (headache, otalgia, and trigeminal pain) in 3. The degree of occlusion of the treated aneurysm was complete in 46.7%; there was a small neck remnant in 40.9% and residual filling in 12.2%. Imaging (MR angiography) follow-up was performed in 68.7% of the patients. The mean follow-up duration was 19.4 months (range, 5-57 months). Fifty-five patients (93.9%) showed no interval change of the residual neck. Four (6%) demonstrated recanalizations, all of which were successfully recoiled. CONCLUSIONS: Endovascular treatment of unruptured intracranial aneurysms in patients older than 70 years of age appears to be safe. Favorable outcomes with low morbidities may replace surgery or conservative treatment as an active management alternative. PMID- 21596819 TI - Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. AB - Thyroid cancer is the most common endocrine cancer, and targeted approaches to treat it pose considerable interest. In this study, we report the discovery of ALK gene mutations in thyroid cancer that may rationalize clinical evaluation of anaplastic lymphoma kinase (ALK) inhibitors in this setting. In undifferentiated anaplastic thyroid cancer (ATC), we identified two novel point mutations, C3592T and G3602A, in exon 23 of the ALK gene, with a prevalence of 11.11%, but found no mutations in the matched normal tissues or in well-differentiated thyroid cancers. These two mutations, resulting in L1198F and G1201E amino acid changes, respectively, both reside within the ALK tyrosine kinase domain where they dramatically increased tyrosine kinase activities. Similarly, these mutations heightened the ability of ALK to activate the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein (MAP) kinase pathways in established mouse cells. Further investigations showed that these two ALK mutants strongly promoted cell focus formation, anchorage-independent growth, and cell invasion. Similar oncogenic properties were observed in the neuroblastoma-associated ALK mutants K1062M and F1174L but not in wild-type ALK. Overall, our results reveal two novel gain-of-function mutations of ALK in certain ATCs, and they suggest efforts to clinically evaluate the use of ALK kinase inhibitors to treat patients who harbor ATCs with these mutations. PMID- 21596820 TI - Unamplified cap analysis of gene expression on a single-molecule sequencer. AB - We report the development of a simplified cap analysis of gene expression (CAGE) protocol adapted for single-molecule sequencers that avoids second strand synthesis, ligation, digestion, and PCR. HeliScopeCAGE directly sequences the 3' end of cap trapped first-strand cDNAs. As with previous versions of CAGE, we better define transcription start sites (TSS) than known models, identify novel regions of transcription and alternative promoters, and find two major classes of TSS signal, sharp peaks and broad regions. However, using this protocol, we observe reproducible evidence of regulation at the much finer level of individual TSS positions. The libraries are quantitative over 5 orders of magnitude and highly reproducible (Pearson's correlation coefficient of 0.987). We have also scaled down the sample requirement to 5 MUg of total RNA for a standard HeliScopeCAGE library and 100 ng for a low-quantity version. When the same RNA was run as 5-MUg and 100-ng versions, the 100 ng was still able to detect expression for ~60% of the 13,468 loci detected by a 5-MUg library using the same threshold, allowing comparative analysis of even rare cell populations. Testing the protocol for differential gene expression measurements on triplicate HeLa and THP-1 samples, we find that the log fold change compared to Illumina microarray measurements is highly correlated (0.871). In addition, HeliScopeCAGE finds differential expression for thousands more loci including those with probes on the array. Finally, although the majority of tags are 5' associated, we also observe a low level of signal on exons that is useful for defining gene structures. PMID- 21596822 TI - Assessment of reading behavior with an infrared eye tracker after 360 degrees macular translocation for age-related macular degeneration. AB - PURPOSE. Macular translocation (MT360) is complex surgery used to restore reading in exudative age-related macular degeneration (AMD). MT360 involves retinal rotation and subsequent oculomotor globe counterrotation and is not without significant surgical risk. This study attempts to gauge the optimal potential of MT360 in restoring reading ability and describe the quality and extent of recovery. METHODS. The six best outcomes were examined from a consecutive series of 23 MT360 cases. Reading behavior and fixation characteristics were examined with an infrared eye tracker. Results were compared to age-matched normal subjects and patients with untreated exudative and nonexudative AMD. Retinal sensitivity was examined with microperimetry to establish threshold visual function. RESULTS. MT360 produced significant improvements in visual function over untreated disease and approximated normal function for reading speed and fixation quality. Relative to the comparative groups, eye tracking revealed the MT360 cohort generated a greater number of horizontal and vertical saccades, of longer latency and reduced velocity. In contrast, saccadic behavior when reading (forward and regressive saccades) closely matched normal function. Microperimetry revealed a reduction in the central scotoma with three patients recovering normal foveal sensitivity. CONCLUSIONS. Near normal reading function is recovered despite profound surgical disruption to the anatomy (retinal/oculomotor). MT360 restores foveal function sufficient to produce a single stable locus of fixation, with marked reduction of the central scotoma. Despite the limitations on saccadic function, the quality of reading saccadic behavior is maintained with good reading ability. Oculomotor surgery appears not to limit reading ability, and the results of retinal surgery approximate normal macular function. PMID- 21596821 TI - Initial in vitro investigation of the human immune response to corneal cells from genetically engineered pigs. AB - PURPOSE: To compare the in vitro human humoral and cellular immune responses to wild-type (WT) pig corneal endothelial cells (pCECs) with those to pig aortic endothelial cells (pAECs). These responses were further compared with CECs from genetically engineered pigs (alpha1,3-galactosyltransferase gene-knockout [GTKO] pigs and pigs expressing a human complement-regulatory protein [CD46]) and human donors. METHODS: The expression of Galalpha1,3Gal (Gal), swine leukocyte antigen (SLA) class I and class II on pCECs and pAECs, with or without activation by porcine IFN-gamma, was tested by flow cytometry. Pooled human serum was used to measure IgM/IgG binding to and complement-dependent cytotoxicity (CDC) to cells from WT, GTKO, and GTKO/CD46 pigs. The human CD4(+) T-cell response to cells from WT, GTKO, GTKO/CD46 pigs and human was tested by mixed lymphocyte reaction (MLR). RESULTS: There was a lower level of expression of the Gal antigen and of SLA class I and II on the WT pCECs than on the WT pAECs, resulting in less antibody binding and reduced human CD4(+) T-cell proliferation. However, lysis of the WT pCECs was equivalent to that of the pAECs, suggesting more susceptibility to injury. There were significantly weaker humoral and cellular responses to the pCECs from GTKO/CD46 pigs compared with the WT pCECs, although the cellular response to the GTKO/CD46 pCECs was greater than to the human CECs. CONCLUSIONS: These data provide the first report of in vitro investigations of CECs from genetically engineered pigs and suggest that pig corneas may provide an acceptable alternative to human corneas for clinical transplantation. PMID- 21596825 TI - Opportunities in pulmonary research: not a time to step back. PMID- 21596824 TI - Synthesis, biological studies of linear and branched arabinofuranoside-containing glycolipids and their interaction with surfactant protein A. AB - Oligoarabinofuranoside-containing glycolipids relevant to mycobacterial cell wall components were synthesized in order to understand the functional roles of such glycolipids. A series of linear tetra-, hexa-, octa- and a branched heptasaccharide oligoarabinofuranosides, with 1 -> 2 and 1 -> 5 alpha-linkages between the furanoside residues, were synthesized by chemical methods from readily available monomer building blocks. Upon the synthesis of glycolipids, constituted with a double alkyl chain-substituted sn-glycerol core and oligosaccharide fragments, biological studies were performed to identify the effect of synthetic glycolipids on the biofilm formation and sliding motilities of Mycobacterium smegmatis. Synthetic glycolipids and arabinofuranosides displayed an inhibitory effect on the growth profile, but mostly on the biofilm formation and maturation. Similarly, synthetic compounds also influenced the sliding motility of the bacteria. Further, biophysical studies were undertaken, so as to identify the interactions of the glycolipids with a pulmonary surfactant protein, namely surfactant protein A (SP-A), with the aid of the surface plasmon resonance technique. Specificities of each glycolipid interacting with SP-A were thus evaluated. From this study, glycolipids were found to exhibit higher apparent association constants than the corresponding oligosaccharide portion alone, without the double alkyl group-substituted glycerol core. PMID- 21596823 TI - Segmental versican expression in the trabecular meshwork and involvement in outflow facility. AB - PURPOSE: Versican is a large proteoglycan with numerous chondroitin sulfate (CS) glycosaminoglycan (GAG) side chains attached. To assess versican's potential contributions to aqueous humor outflow resistance, its segmental distribution in the trabecular meshwork (TM) and the effect on outflow facility of silencing the versican gene were evaluated. METHODS: Fluorescent quantum dots (Qdots) were perfused to label outflow pathways of anterior segments. Immunofluorescence with confocal microscopy and quantitative RT-PCR were used to determine versican protein and mRNA distribution relative to Qdot-labeled regions. Lentiviral delivery of shRNA-silencing cassettes to TM cells in perfused anterior segment cultures was used to evaluate the involvement of versican and CS GAG chains in outflow facility. RESULTS: Qdot uptake by TM cells showed considerable segmental variability in both human and porcine outflow pathways. Regional levels of Qdot labeling were inversely related to versican protein and mRNA levels; versican levels were relatively high in sparsely Qdot-labeled regions and low in densely labeled regions. Versican silencing decreased outflow facility in human and increased facility in porcine anterior segments. However, RNAi silencing of ChGn, an enzyme unique to CS GAG biosynthesis, increased outflow facility in both species. The fibrillar pattern of versican immunostaining in the TM juxtacanalicular region was disrupted after versican silencing in perfusion culture. CONCLUSIONS: Versican appears to be a central component of the outflow resistance, where it may organize GAGs and other ECM components to facilitate and control open flow channels in the TM. However, the exact molecular organization of this resistance appears to differ between human and porcine eyes. PMID- 21596826 TI - Controversies in the treatment of the acutely wheezing infant. PMID- 21596827 TI - The in utero effects of maternal vitamin D deficiency: how it results in asthma and other chronic diseases. PMID- 21596828 TI - Focusing on the flood: targeting functional polymorphisms in ALI permeability pathways. PMID- 21596829 TI - Straining to make mechanical ventilation safe and simple. PMID- 21596830 TI - Nitrogen balance in the ecosystem of the cystic fibrosis lung. PMID- 21596831 TI - The brain in sleep-disordered breathing: a vote for the chicken? PMID- 21596832 TI - Epigenetic control of gene expression in the lung. AB - Epigenetics is traditionally defined as the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence. There are three main classes of epigenetic marks--DNA methylation, modifications of histone tails, and noncoding RNAs--each of which may be influenced by the environment, diet, diseases, and ageing. Importantly, epigenetic marks have been shown to influence immune cell maturation and are associated with the risk of developing various forms of cancer, including lung cancer. Moreover, there is emerging evidence that these epigenetic marks affect gene expression in the lung and are associated with benign lung diseases, such as asthma, chronic obstructive pulmonary disease, and interstitial lung disease. Technological advances have made it feasible to study epigenetic marks in the lung, and it is anticipated that this knowledge will enhance our understanding of the dynamic biology in the lung and lead to the development of novel diagnostic and therapeutic approaches for our patients with lung disease. PMID- 21596833 TI - Update in chronic obstructive pulmonary disease in 2010. PMID- 21596834 TI - Update in diffuse parenchymal lung disease 2010. PMID- 21596835 TI - van Leeuwenhoek's disease. PMID- 21596836 TI - Intermittent subglottic secretion drainage and ventilator-associated pneumonia. PMID- 21596837 TI - Intermittent subglottic secretion drainage and ventilator-associated pneumonia. PMID- 21596838 TI - Generator diesel exhaust: a major hazard to health and the environment in Nigeria. PMID- 21596840 TI - Nephrocystin-4 is required for pronephric duct-dependent cloaca formation in zebrafish. AB - NPHP4 mutations cause nephronophthisis, an autosomal recessive cystic kidney disease associated with renal fibrosis and kidney failure. The NPHP4 gene product nephrocystin-4 interacts with other nephrocystins, cytoskeletal and ciliary proteins; however, the molecular and cellular functions of nephrocystin-4 have remained elusive. Here we demonstrate that nephrocystin-4 is required for normal cloaca formation during zebrafish embryogenesis. Time-lapse imaging of the developing zebrafish pronephros revealed that tubular epithelial cells at the distal pronephros actively migrate between the yolk sac extension and the blood island towards the ventral fin fold to join the proctodeum and to form the cloaca. Nphp4-deficient pronephric duct cells failed to connect with their ectodermal counterparts, and instead formed a vesicle at the obstructed end of the pronephric duct. Nephrocystin-4 interacts with nephrocystin-1 and Par6. Depletion of zebrafish NPHP1 (nphp1) increased the incidence of cyst formation and randomization of the normal body axis, but did not augment cloaca malformation in nphp4-deficient zebrafish embryos. However, simultaneous depletion of zebrafish Par6 (pard6) aggravated cloaca formation defects in nphp4 depleted embryos, suggesting that nphp4 orchestrates directed cell migration and cloaca formation through interaction with the Par protein complex. PMID- 21596839 TI - Reproductive dysfunction and decreased GnRH neurogenesis in a mouse model of CHARGE syndrome. AB - CHARGE is a multiple congenital anomaly disorder and a common cause of pubertal defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders and congenital heart malformations. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome. Mutations in CHD7 have also been reported in the Kallmann syndrome (olfactory dysfunction, delayed puberty and hypogonadotropic hypogonadism). CHD7 is a positive regulator of neural stem cell proliferation and olfactory sensory neuron formation in the olfactory epithelium, suggesting that the loss of CHD7 might also disrupt development of other neural populations. Here we report that female Chd7(Gt/+) mice have delays in vaginal opening and estrus onset, and erratic estrus cycles. Chd7(Gt/+) mice also have decreased circulating levels of luteinizing hormone and follicle-stimulating hormone but apparently normal responsiveness to gonadotropin-releasing hormone (GnRH) agonist and antagonist treatment. GnRH neurons in the adult Chd7(Gt/+) hypothalamus and embryonic nasal region are diminished, and there is decreased cellular proliferation in the embryonic olfactory placode. Expression levels of GnRH1 and Otx2 in the hypothalamus and GnRHR in the pituitary are significantly reduced in adult Chd7(Gt/+) mice. Additionally, Chd7 mutant embryos have CHD7 dosage dependent reductions in expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode. Together, these data suggest that CHD7 has critical roles in the development and maintenance of GnRH neurons for regulating puberty and reproduction. PMID- 21596843 TI - Oxidative stress and mitochondrial dysfunction in sepsis. AB - Sepsis-related organ dysfunction remains the most common cause of death in the intensive care unit (ICU), despite advances in healthcare and science. Marked oxidative stress as a result of the inflammatory responses inherent with sepsis initiates changes in mitochondrial function which may result in organ damage. Normally, a complex system of interacting antioxidant defences is able to combat oxidative stress and prevents damage to mitochondria. Despite the accepted role that oxidative stress-mediated injury plays in the development of organ failure, there is still little conclusive evidence of any beneficial effect of systemic antioxidant supplementation in patients with sepsis and organ dysfunction. It has been suggested, however, that antioxidant therapy delivered specifically to mitochondria may be useful. PMID- 21596842 TI - Conditional deletion of Ccm2 causes hemorrhage in the adult brain: a mouse model of human cerebral cavernous malformations. AB - Cerebral cavernous malformations (CCM) are irregularly shaped and enlarged capillaries in the brain that are prone to hemorrhage, resulting in headaches, seizures, strokes and even death in patients. The disease affects up to 0.5% of the population and the inherited form has been linked to mutations in one of three genetic loci, CCM1, CCM2 and CCM3. To understand the pathophysiology underlying the vascular lesions in CCM, it is critical to develop a reproducible mouse genetic model of this disease. Here, we report that limited conditional ablation of Ccm2 in young adult mice induces observable neurological dysfunction and reproducibly results in brain hemorrhages whose appearance is highly reminiscent of the lesions observed in human CCM patients. We first demonstrate that conventional or endothelial-specific deletion of Ccm2 leads to fatal cardiovascular defects during embryogenesis, including insufficient vascular lumen formation as well as defective arteriogenesis and heart malformation. These findings confirm and extend prior studies. We then demonstrate that the inducible deletion of Ccm2 in adult mice recapitulates the CCM-like brain lesions in humans; the lesions display disrupted vascular lumens, enlarged capillary cavities, loss of proper neuro-vascular associations and an inflammatory reaction. The CCM lesions also exhibit damaged neuronal architecture, the likely cause of neurologic defects, such as ataxia and seizure. These mice represent the first CCM2 animal model for CCM and should provide the means to elucidate disease mechanisms and evaluate therapeutic strategies for human CCM. PMID- 21596844 TI - Ultrasound evaluation of abdominal masses in Ethiopian child patients. AB - The aim of this study was to assess the pattern of abdominal masses and evaluate the value of ultrasound in paediatric abdominal masses. We used a cross-sectional study of abdominal masses in children attending a university teaching hospital. The common abdominal masses were: Wilms' tumour, 12 (14.8%); lymphoma, 11 (13.6%); appendiceal mass/abscess, 11 (13.6%); neuroblastoma, 7 (8.6%); TB, 6 (7.4%); hydronephrosis, 5 (6.2%); abdominal wall abscess, 6 (7.4%); hydatidcyst, 4 (4.9%); mesenteric cyst, 3 (3.7%); and intussusceptions, 3 (3.7%). Identification of a purely cystic mass was suggestive of benign lesion (odds ratio [OR] = 118, P = 0.0001) and masses found in the <5 years age group tend to be malignant (OR = 2.77). The most common sites of origin were kidneys, retroperitoneal extra renal and gastrointestinal tract. The overall diagnostic accuracy of ultrasound was 88.9%. PMID- 21596845 TI - Rapid diagnosis of Mycoplasma pneumoniae by polymerase chain reaction in community-acquired lower respiratory tract infections. AB - Two hundred children hospitalized for community-acquired lower respiratory tract infections (LRTIs) were investigated for Mycoplasma pneumoniae employing serological tests and a P1 adhesin gene-based polymerase chain reaction assay (PCR) on nasopharyngeal aspirates. Serological evidence of M. pneumoniae infection was observed in 68 (34%) patients and PCR was positive in 20 (10%) children. Together PCR and/or enzyme immuno assay detected M. pneumoniae in 71(35.5%) children. Our data underline the role of M. pneumoniae in Indian children with community-acquired LRTIs even in children aged < 24 months. PMID- 21596841 TI - Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. AB - Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P heterogeneity = 6.1 * 10(-18)), rs3803662 (16q12) (P = 3.7 * 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 * 10(-6) and P = 4.1 * 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P <= 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P <= 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment. PMID- 21596846 TI - SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis. AB - Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in loss-of-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genome wide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Scl-mutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation. PMID- 21596847 TI - Secondary autoimmune diseases occurring after HSCT for an autoimmune disease: a retrospective study of the EBMT Autoimmune Disease Working Party. AB - To specify the incidence and risk factors for secondary autoimmune diseases (ADs) after HSCT for a primary AD, we retrospectively analyzed AD patients treated by HSCT reported to EBMT from 1995 to 2009 with at least 1 secondary AD (cases) and those without (controls). After autologous HSCT, 29 of 347 patients developed at least 1 secondary AD within 21.9 (0.6-49) months and after allogeneic HSCT, 3 of 16 patients. The observed secondary ADs included: autoimmune hemolytic anemia (n = 3), acquired hemophilia (n = 3), autoimmune thrombocytopenia (n = 3), antiphospholipid syndrome (n = 2), thyroiditis (n = 12), blocking thyroid stimulating hormone receptor antibody (n = 1), Graves disease (n = 2), myasthenia gravis (n = 1), rheumatoid arthritis (n = 2), sarcoidosis (n = 2), vasculitis (n = 1), psoriasis (n = 1), and psoriatic arthritis (n = 1). After autologous HSCT for primary AD, the cumulative incidence of secondary AD was 9.8% +/- 2% at 5 years. Lupus erythematosus as primary AD, and antithymocyte globulin use plus CD34(+) graft selection were important risk factors for secondary AD by multivariate analysis. With a median follow-up of 6.2 (0.54-11) years after autologous HSCT, 26 of 29 patients with secondary AD were alive, 2 died during their secondary AD (antiphospholipid syndrome, hemophilia), and 1 death was HSCT related. This European multicenter study underlines the need for careful management and follow-up for secondary AD after HSCT. PMID- 21596848 TI - Risk stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and gene expression markers. AB - Numerous molecular markers have been recently discovered as potential prognostic factors in acute myeloid leukemia (AML). It has become of critical importance to thoroughly evaluate their interrelationships and relative prognostic importance. Gene expression profiling was conducted in a well-characterized cohort of 439 AML patients (age < 60 years) to determine expression levels of EVI1, WT1, BCL2, ABCB1, BAALC, FLT3, CD34, INDO, ERG and MN1. A variety of AML-specific mutations were evaluated, that is, FLT3, NPM1, N-RAS, K-RAS, IDH1, IDH2, and CEBPA(DM/SM) (double/single). Univariable survival analysis shows that (1) patients with FLT3(ITD) mutations have inferior overall survival (OS) and event-free survival (EFS), whereas CEBPA(DM) and NPM1 mutations indicate favorable OS and EFS in intermediate-risk AML, and (2) high transcript levels of BAALC, CD34, MN1, EVl1, and ERG predict inferior OS and EFS. In multivariable survival analysis, CD34, ERG, and CEBPA(DM) remain significant. Using survival tree and regression methodologies, we show that CEBPA(DM), CD34, and IDH2 mutations are capable of separating the intermediate group into 2 AML subgroups with highly distinctive survival characteristics (OS at 60 months: 51.9% vs 14.9%). The integrated statistical approach demonstrates that from the multitude of biomarkers a greatly condensed subset can be selected for improved stratification of intermediate-risk AML. PMID- 21596850 TI - Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. AB - Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenging diagnosis after hematopoietic stem cell transplantation. Although endothelial injury represents the final common pathway of disease, the exact pathophysiology of TA-TMA remains unclear. Potential causes include infections, chemotherapy, radiation, and calcineurin inhibitors. Recent literature addresses the roles of cytokines, graft-versus-host disease, the coagulation cascade, and complement in the pathogenesis of TA-TMA. Current diagnostic criteria are unsatisfactory, because patients who have received a transplant can have multiple other reasons for the laboratory abnormalities currently used to diagnose TA-TMA. Moreover, our lack of understanding of the exact mechanism of disease limits the development and evaluation of potential treatments. Short- and long-term renal complications contribute to TA-TMA's overall poor prognosis. In light of these challenges, future research must validate novel markers of disease to aid in early diagnosis, guide current and future treatments, prevent long-term morbidity, and improve outcomes. We focus on TA-TMA as a distinct complication of hematopoietic stem cell transplantation, emphasizing the central role of the kidney in this disease. PMID- 21596849 TI - Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes. AB - Inbred mice are a useful tool for studying the in vivo functions of platelets. Nonetheless, the mRNA signature of mouse platelets is not known. Here, we use paired-end next-generation RNA sequencing (RNA-seq) to characterize the polyadenylated transcriptomes of human and mouse platelets. We report that RNA seq provides unprecedented resolution of mRNAs that are expressed across the entire human and mouse genomes. Transcript expression and abundance are often conserved between the 2 species. Several mRNAs, however, are differentially expressed in human and mouse platelets. Moreover, previously described functional disparities between mouse and human platelets are reflected in differences at the transcript level, including protease activated receptor-1, protease activated receptor-3, platelet activating factor receptor, and factor V. This suggests that RNA-seq is a useful tool for predicting differences in platelet function between mice and humans. Our next-generation sequencing analysis provides new insights into the human and murine platelet transcriptomes. The sequencing dataset will be useful in the design of mouse models of hemostasis and a catalyst for discovery of new functions of platelets. Access to the dataset is found in the "Introduction." PMID- 21596851 TI - Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner. AB - Chemokines and adhesion molecules up-regulated in lymphatic endothelial cells (LECs) during tissue inflammation are thought to enhance dendritic cell (DC) migration to draining lymph nodes, but the in vivo control of this process is not well understood. We performed a transcriptional profiling analysis of LECs isolated from murine skin and found that inflammation induced by a contact hypersensitivity (CHS) response up-regulated the adhesion molecules ICAM-1 and VCAM-1 and inflammatory chemokines. Importantly, the lymphatic markers Prox-1, VEGFR3, and LYVE-1 were significantly down-regulated during CHS. By contrast, skin inflammation induced by complete Freund adjuvant induced a different pattern of chemokine and lymphatic marker gene expression and almost no ICAM-1 up regulation in LECs. Fluorescein isothiocyanate painting experiments revealed that DC migration to draining lymph nodes was more strongly increased in complete Freund adjuvant-induced than in CHS-induced inflammation. Surprisingly, DC migration did not correlate with the induction of CCL21 and ICAM-1 protein in LECs. Although the requirement for CCR7 signaling became further pronounced during inflammation, CCR7-independent signals had an additional, albeit moderate, impact on enhancing DC migration. Collectively, these findings indicate that DC migration in response to inflammation is stimulus-specific, mainly CCR7 dependent, and overall only moderately enhanced by LEC-induced genes other than CCL21. PMID- 21596852 TI - Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 Multiple Myeloma Research Consortium trial. AB - This phase 1/2 trial evaluated combination lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (RVDD) in newly diagnosed multiple myeloma (MM) patients. Patients received RVDD at 4 dose levels, including the maximum tolerated dose (MTD). Patients with a very good partial response or better (>= VGPR) after cycle 4 proceeded to autologous stem cell transplantation or continued treatment. The primary objectives were MTD evaluation and response to RVDD after 4 and 8 cycles. Seventy-two patients received a median of 4.5 cycles. The MTDs were lenalidomide 25 mg, bortezomib 1.3 mg/m(2), pegylated liposomal doxorubicin 30 mg/m(2), and dexamethasone 20/10 mg, as established with 3-week cycles. The most common adverse events were fatigue, constipation, sensory neuropathy, and infection; there was no treatment-related mortality. Response rates after 4 and 8 cycles were 96% and 95% partial response or better, 57% and 65% >= VGPR, and 29% and 35% complete or near-complete response, respectively. After a median follow-up of 15.5 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. RVDD was generally well tolerated and highly active, warranting further study in newly diagnosed MM patients. This trial was registered at www.clinicaltrials.gov as NCT00724568. PMID- 21596853 TI - The anti-fibrinolytic SERPIN, plasminogen activator inhibitor 1 (PAI-1), is targeted to and released from catecholamine storage vesicles. AB - Recent studies suggest a crucial role for plasminogen activator inhibitor-1 (PAI 1) in mediating stress-induced hypercoagulability and thrombosis. However, the mechanisms by which PAI-1 is released by stress are not well-delineated. Here, we examined catecholaminergic neurosecretory cells for expression, trafficking, and release of PAI-1. PAI-1 was prominently expressed in PC12 pheochromocytoma cells and bovine adrenomedullary chromaffin cells as detected by Northern blotting, Western blotting, and specific PAI-1 ELISA. Sucrose gradient fractionation studies and immunoelectron microscopy demonstrated localization of PAI-1 to catecholamine storage vesicles. Secretogogue stimulation resulted in corelease of PAI-1 with catecholamines. Parallel increases in plasma PAI-1 and catecholamines were observed in response to acute sympathoadrenal activation by restraint stress in mice in vivo. Reverse fibrin zymography demonstrated free PAI-1 in cellular releasates. Detection of high molecular weight complexes by Western blotting, consistent with PAI-1 complexed with t-PA, as well as bands consistent with cleaved PAI-1, suggested that active PAI-1 was present. Modulation of PAI-1 levels by incubating PC12 cells with anti-PAI-1 IgG caused a marked decrease in nicotine-mediated catecholamine release. In summary, PAI-1 is expressed in chromaffin cells, sorted into the regulated pathway of secretion (into catecholamine storage vesicles), and coreleased, by exocytosis, with catecholamines in response to secretogogues. PMID- 21596855 TI - The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. AB - We have investigated the prognostic significance of isocitrate dehydrogenase 2 (IDH2) mutations in 1473 younger adult acute myeloid leukemia patients treated in 2 United Kingdom Medical Research Council trials. An IDH2 mutation was present in 148 cases (10%), 80% at R140 and 20% at R172. Patient characteristics and outcome differed markedly between the 2 mutations. IDH2(R140) significantly correlated with nucleophosmin mutations (NPM1(MUT)), whereas IDH2(R172) cases generally lacked other molecular mutations. An IDH2(R140) mutation was an independent favorable prognostic factor for relapse (P = .004) and overall survival (P = .008), and there was no significant heterogeneity with regard to NPM1 or FLT3 internal tandem duplication (FLT3/ITD) genotype. Relapse in FLT3/ITD(WT)NPM1(MUT)IDH2(R140) patients was lower than in favorable-risk cytogenetics patients in the same cohort (20% and 38% at 5 years, respectively). The presence of an IDH2(R172) mutation was associated with a significantly worse outcome than IDH2(R140), and relapse in FLT3/ITD(WT)NPM1(WT)IDH2(R172) patients was comparable with adverse-risk cytogenetics patients (76% and 72%, respectively). PMID- 21596856 TI - Sumoylation of CCAAT/enhancer-binding protein alpha promotes the biased primitive hematopoiesis of zebrafish. AB - Hematopoiesis is evolutionarily conserved from zebrafish to mammals, and this includes both primitive and definitive waves during embryogenesis. Primitive hematopoiesis is dominated by erythropoiesis with limited myelopoiesis. Protein sumoylation, a ubiquitination-like posttranslational protein modification, is implicated in a variety of biochemical processes, most notably in transcriptional repression. We show here that the loss of 6 small ubiquitin-related modifier (SUMO) paralogs triggers a sharp up-regulation of the myeloid-specific marker mpo and down-regulation of the erythroid-specific marker gata1 in myelo-erythroid progenitor cells (MPCs) in the intermediate cell mass (ICM) during primitive hematopoiesis. Accordingly, in transgenic zebrafish lines, hyposumoylation expands myelopoiesis at the expense of erythropoiesis. A SUMO-CCAAT/enhancer binding protein alpha (SUMO-C/ebpalpha) fusion restores the normal myelopoiesis/erythropoiesis balance, suggesting that sumoylation status of C/ebpalpha contributes to myelo-erythroid lineage determination. Our results therefore implicate sumoylation in early lineage determination and reveal the possible molecular mechanism underlying the puzzling biased primitive hematopoiesis in vertebrates. PMID- 21596854 TI - Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL. AB - IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastrointestinal GVHD in recipients of a transplant. This reduction in GVHD was associated with expansion of transplanted donor regulatory T cells and with tissue-specific modulation of Th-cell function. IL-21R KO and wild-type donor T cells showed equivalent alloactivation, but IL-21R KO T cells showed decreased infiltration and inflammatory cytokine production within the mesenteric lymph nodes. However, Th cell cytokine production was maintained peripherally, and IL-21R KO T cells mediated equivalent immunity against A20 and P815 hematopoietic tumors. In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T-cell function and GVL capacity are retained. IL-21 is thus an exciting target for therapeutic intervention and improvement of clinical transplantation outcomes. PMID- 21596857 TI - Bone mineral density in adult survivors of childhood acute leukemia: impact of hematopoietic stem cell transplantation and other treatment modalities. AB - Femoral and lumbar bone mineral densities (BMDs) were measured in 159 adults enrolled in the Leucemies de l'Enfant et de l'Adolescent program, a French prospective multicentric cohort of childhood leukemia survivors. BMDs were expressed as Z-scores, and multivariate linear regression analyses were used to construct association models with potential risk factors. Mean age at evaluation and follow-up was 23 and 14.7 years, respectively. In the whole cohort, mean femoral Z-score was -0.19 +/- 0.08. Two factors were associated with lower femoral BMD transplantation (-0.49 +/- 0.15 vs -0.04 +/- 0.10 in the chemotherapy group; P = .006) and female sex (-0.34 +/- 0.10 vs -0.03 +/- 0.13; P = .03). Among patients who received a transplant, the only significant risk factor was hypogonadism (-0.88 +/- 0.16 vs -0.10 +/- 0.23; P = .04). A slight reduction in lumbar BMD (mean Z-score, -0.37 +/- 0.08) was detected in the whole cohort without difference between the transplantation and chemotherapy groups. Among patients who received a transplant, younger age at transplantation was correlated with a low lumbar BMD (P = .03). We conclude that adults who had received only chemotherapy for childhood leukemia have a slight reduction in their lumbar BMD and a normal femoral BMD. Patients who received a transplant with gonadal deficiency have a reduced femoral BMD which might increase the fracture risk later in life. PMID- 21596858 TI - Multiple Hodgkin lymphoma-associated loci within the HLA region at chromosome 6p21.3. AB - Since an association between the human leukocyte antigen (HLA) region and Hodgkin lymphoma (HL) was first reported in 1967, many studies have reported associations between HL risk and both single nucleotide polymorphism (SNP) and classic HLA allele variation in the major histocompatibility complex. However, population stratification and the extent and complexity of linkage disequilibrium within the major histocompatibility complex have hindered efforts to fine-map causal signals. Using SNP data to impute alleles at classic HLA loci, we have conducted an integrated analysis of HL risk within the HLA region in 582 early-onset HL cases and 4736 controls. We confirm that the strongest signal of association comes from an SNP located in the class II region, rs6903608 (odds ratio [OR] = 1.79, P = 6.63 * 10(-19)), which is unlikely to be driven by association to HLA DRB, DQA, or DQB alleles. In addition, we identify independent signals at rs2281389 (OR = 1.73, P = 6.31 * 10(-13)), a SNP that maps closely to HLA-DPB1, and the class II HLA allele DQA1*02:01 (OR = 0.56, P = 1.51 * 10(-7)). These data suggest that multiple independent loci within the HLA class II region contribute to the risk of developing early-onset HL. PMID- 21596860 TI - Two-faced T cells in CLL. AB - In this issue of Blood, Bagnara et al describe the development of a reliable and convincing xenograft model of CLL that recapitulates aspects of the leukemic microenvironment and gives intriguing insights into disease biology. PMID- 21596859 TI - A tumor suppressor function of the Msr1 gene in leukemia stem cells of chronic myeloid leukemia. AB - We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to dissect this pathway by comparing the gene expression profiles of wild type and Alox5(-/-) LSCs. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was upregulated in Alox5(-/-) LSCs, suggesting that Msr1 suppresses the proliferation of LSCs. Using CML mouse model, we show that Msr1 is downregulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and beta-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of the tumor suppressor function of Msr1 may be of significance in the development of novel therapeutic strategies for CML. PMID- 21596861 TI - Hodgkin lymphoma: answers take time! AB - In this issue of Blood, Straus and colleagues on behalf of the Cancer and Leukemia Group B (CALGB) present the outcome of a phase 2 trial of doxorubicin, vinblastine,and gemcitabine for patients with early-stage, non-bulky, Hodgkin lymphoma.The complete response rate and progression-free survival were inferior to comparable series, emphasizing the challenges of improving outcome in this highly curable population. PMID- 21596862 TI - Two antioxidants are better than one. AB - New evidence suggests that the cellular oxygen-sensing hypoxia-inducible factor(HIF) pathway may be protected by a double buffer of cellular antioxidant defense. Key players in the oxygen-dependent regulation of this pathway are the prolyl hydroxylase domain-containing enzymes (PHDs) that catalyze the prolyl-4 hydroxylation of HIFalpha, dependent on the presence of oxygen, 2-oxoglutarate, and iron in the ferrous (Fe(2+)) form. Vitamin C is also required as a cofactor, possibly to maintain the catalytic iron center in its functional Fe(2+)) state, although both the mechanism and the in vivo requirement are not absolutely clear. PMID- 21596863 TI - Curbing an inhibitor for hemostasis. AB - Antibodies against factor VIII cause severe bleeding, requiring therapy that circumvents the normal coagulation pathway. In this issue of Blood, Waters and colleagues report that a novel RNA polymer can block an inhibitor of tissue factor,unleashing native procoagulant activity that stops the bleeding. PMID- 21596865 TI - Airway collapse with an anterior mediastinal mass despite spontaneous ventilation in an adult. AB - Patients with anterior mediastinal masses are at increased risk for perioperative complications. Our case demonstrates that airway collapse and inability to ventilate may occur in the asymptomatic adult despite spontaneous ventilation with inhaled anesthesia and an endotracheal tube. Given the sudden and profound presentation of cardiopulmonary collapse, rigid bronchoscopy should be immediately available to facilitate life-saving ventilation. Though repositioning the pediatric patient lateral or prone has been reported to reestablish airway patency, this maneuver may be of limited benefit in the adult population because of a more ossified and developed chest wall. Lastly, if a high-risk patient requires a general anesthetic, strong consideration should be given to preinduction placement of femoral cardiopulmonary bypass cannulae and the availability to immediately initiate cardiopulmonary bypass. PMID- 21596866 TI - National incidence of use of monitored anesthesia care. AB - BACKGROUND: Sedation or monitored anesthesia care (MAC), alone or after peripheral regional nerve block, is currently administered by anesthesiologists and/or certified registered nurse anesthetists. Some of this care may be at risk for substitution by other providers or by reductions in reimbursement. METHODS: Data from the 2006 United States of America National Survey of Ambulatory Surgery were analyzed to determine national rates for the percentage of total ambulatory anesthesia operating room (OR) time that was either (1) sedation and/or MAC, or (2) peripheral regional nerve block with/without sedation or MAC. RESULTS: MAC cases alone comprised 29%+/- 2% of OR time with an anesthesiologist and/or certified registered nurse anesthetist. MAC and/or peripheral block comprised 34% +/- 2% of OR time. Percentages by cases were larger than by OR time (P < 0.0001). Among cases with anesthesia, 42% +/- 3% were MAC and 47% +/- 2% were MAC with/without peripheral block. Percentages of American Society of Anesthesiologists' Relative Value Guide units for MAC would be intermediate between the 29% and 42%, and for MAC and/or peripheral block between the 34% and 47%. CONCLUSIONS: MAC alone or after peripheral nerve block accounts for a relatively high percentage of ambulatory anesthetics nationwide. PMID- 21596867 TI - The volume of blood for epidural blood patch in obstetrics: a randomized, blinded clinical trial. AB - BACKGROUND: Our aim in this multinational, multicenter, randomized, blinded trial was to determine the optimum of 3 volumes of autologous blood for an epidural blood patch. METHODS: Obstetric patients requiring epidural blood patch after unintentional dural puncture during epidural catheter insertion were allocated to receive 15, 20, or 30 mL of blood, stratified for the timing of epidural blood patch and center. Participants were followed for 5 days. The primary study end point was a composite of permanent or partial relief of headache, and secondary end points included permanent relief, partial relief, persisting headache severity, and low back pain during or after the procedure. RESULTS: One hundred twenty-one women completed the study. The median (interquartile range) volume administered was 15 (15-15), 20 (20-20), and 30 (22-30) mL, with 98%, 81%, and 54% of groups 15, 20, and 30 receiving the allocated volume. Among groups 15, 20, and 30, respectively, the incidence of permanent or partial relief of headache was 61%, 73%, and 67% and that of complete relief of headache was 10%, 32%, and 26%. The 0- to 48-hour area under the curve of headache score versus time was highest in group 15. The incidence of low back pain during or after the epidural blood patch was similar among groups and was of low intensity, although group 15 had the highest postprocedural back pain scores. Serious morbidity was not reported. CONCLUSIONS: Although the optimum volume of blood remains to be determined, we believe these findings support an attempt to administer 20 mL of autologous blood when treating postdural puncture headache in obstetric patients after unintentional dural puncture. PMID- 21596868 TI - A comparison of different dosages of a continuous preperitoneal infusion and systemic administration of ropivacaine after laparotomy in rats. AB - INTRODUCTION: To further explain the mechanisms of action involved in the analgesic effect of a local anesthetic wound infusion, we evaluated parietal and visceral sensitivity as well as indices of inflammation after laparotomy and administration of a local anesthetic. Ropivacaine was administered at different dosages by a continuous infusion using a multiholed catheter in the preperitoneal position or systemically in rats. METHODS: Nine groups of rats received 2 injections after laparotomy or sham surgery: (1) a bolus injection (ropivacaine or saline) via a preperitoneal catheter and (2) an IM injection (IM) (ropivacaine or saline). These injections were followed by a continuous infusion (ropivacaine or saline) in the preperitoneal catheter for 24 hours and 1 IM injection every 8 hours. Mechanical and visceral thresholds after stimulation were evaluated 3 times during the 48 hours after surgery. Stimulated production of tumor necrosis factor alpha, and interleukin 1beta in whole-blood cultures were measured by enzyme-linked immunosorbent assay. The ropivacaine plasma concentration was measured by gas chromatography. RESULTS: Preperitoneal infusion of high doses of ropivacaine and systemic ropivacaine similarly prevented mechanical and visceral sensitivity alterations and led to a better functional recovery. The analgesic effect of systemic administration was associated with an anti-inflammatory effect. CONCLUSION: In the current study, high-dose ropivacaine administered via a preperitoneal infusion or systemic boluses had the same effect on mechanical and visceral sensitivity after laparotomy. Moreover, systemic administration was associated with an anti-inflammatory effect. The merits of the comparable benefit of systemic and high-dose preperitoneal infusion of ropivacaine need to be confirmed with further studies. PMID- 21596869 TI - Application of pulsed radiofrequency currents to rat dorsal root ganglia modulates nerve injury-induced tactile allodynia. AB - BACKGROUND: Application of pulsed radiofrequency (PRF) currents to the dorsal root ganglia (DRG) has been reported to produce relief from certain pain states without causing thermal ablation. In this study, we examined the direct correlation between PRF application to DRG associated with spinal nerve injury and reversal of injury-induced behavioral hypersensitivity in a rat neuropathic pain model. METHODS: Neuropathic lesioning was performed via left L5 spinal nerve ligation on male adult Sprague-Dawley rats. Once the injured rats had developed tactile allodynia, one group was then assigned to PRF treatment of the L5 DRG and another group was assigned to the sham treatment to the DRG. Behavioral testing was performed on both the control and treated paws using the von Frey filament test before the surgery and at indicated days. The resulting data were analyzed using a linear mixed model to assess the overall difference between the treatment groups and the overall difference among the study days. Cohen's d statistic was computed from paired difference-from-baseline scores for each of the 14 study days after treatment and these measures of effect size were then used to descriptively compare the recovery patterns over time for each study group. RESULTS: Spinal nerve injury resulted in the development of behavioral hypersensitivity to von Frey filament stimulation (allodynia) in the hindpaw of the left (injury) side. Mixed linear modeling showed a significant difference between the treatment groups (P = 0.0079) and a significant change of paw withdrawal threshold means over time (P = 0.0006) for all 12 animals. Evaluation of Cohen's d (effect size) revealed that the PRF-treated animals exhibited better recovery and recorded larger effect sizes than the sham-treated animals on 10 of the 14 post-PRF treatment days and exhibited moderate-to-strong effects posttreatment at days 8 to 10 and at and beyond day 32. CONCLUSIONS: Findings from this study support that PRF of the DRG causes reversal of nerve injury (spinal nerve ligation)-induced tactile allodynia in rats. This allodynia reversal indicates that nonablative PRF acting via modulation of the DRG can speed recovery in nerve injury-induced pain. PMID- 21596870 TI - Achalasia-induced left atrial compression diagnosed by transesophageal echocardiography. PMID- 21596871 TI - Head and neck position for direct laryngoscopy. AB - The sniffing position (SP) has traditionally been considered the optimal head position for direct laryngoscopy (DL). Its superiority over other head positions, however, has been questioned during the last decade. We reviewed the scarce literature on the subject to examine the evidence either in favor or against the routine use of the SP. A standard definition for the position should be used (e.g., 35 degrees neck flexion and 15 degrees head extension) to avoid confusion about what constitutes a proper SP and to compare the results from different studies. Although several theories were proposed to explain the superiority of the SP, the three axes alignment theory is still considered a valid anatomical explanation. Although head elevation is needed to achieve the desired neck flexion, the elevation height may vary from one patient to another depending on head and neck anatomy and size of the chest. In infants and small children, for example, no head elevation is needed because the size and shape of the head allow axes approximation in the head-flat position. Horizontal alignment of the external auditory meatus with the sternum, in both obese and non-obese patients, indicates, and can be used as a marker for, proper positioning. Analysis of the available literature supports the use of the SP for DL. To achieve a proper SP in obese patients, the "ramped" (or the back-up) position should be used. The SP does not guarantee adequate exposure in all patients, because many other anatomical factors control the final degree of visualization. However, it should be the starting head position for DL because it provides the best chance at adequate exposure. Attention to details during positioning and avoidance of minor technical errors are essential to achieve the proper position. DL should be a dynamic procedure and position adjustment should be instituted in case poor visualization is encountered in the SP. PMID- 21596872 TI - Subaortic stenosis after atrioventricular septal defect repair. PMID- 21596873 TI - Artifactual increase in journal self-citation. AB - INTRODUCTION: After submission of a manuscript to a peer-reviewed anesthesia journal, several authors were asked to cite additional references from the journal to which they submitted. We hypothesized that there were differences among the anesthesiology journals in both the total number of self-citations and the proportion of self-citations to the total number of references in each manuscript for the years 2005 and 2010. METHODS: We conducted a review of a sample of manuscripts from 2005 and 2010 to examine the number and rate of self citations. As a secondary analysis, we reviewed impact factor (IF), rate of self referencing, and contribution of self-citations to IF in the population of manuscripts published in 8 anesthesia journals between 2000 and 2009 using the ISI Journal Citation Reports. RESULTS: The number (P < 0.0001) and rate (P < 0.0001) of self-citations among the different journals were significantly different in 2005, with similar results for 2010 in the number (P < 0.0001) and rate (P = 0.0002) of self-citations. The mean range of number of self-citations ranged from 0.45 (95% confidence interval [CI], 0.06 to 0.84) to 3.95 (95% CI, 2.2 to 5.7) in 2005 and from 0.25 (95% CI, -0.05 to 0.55) to 4.5 (95% CI, 2.2 to 6.9) in 2010. On a per-journal basis, no difference in the number of self citations was noted between 2005 and 2010. Analysis of the ISI Journal Citation Reports from 2000 to 2009 suggested a general decline in the contribution of self cites to the IF over time for the aggregate journals (Spearman correlation coefficient (Rs) -0.25 (95% CI, -0.45 to -0.03), P = 0.02), with the exception of the journal in question (Rs = 0.59 (95% CI, -0.1 to 0.88), P = 0.05). Positive correlations were found between self-cited rate and IF (Rs 0.52, 95% CI, 0.34 to 0.66, P < 0.0001), percentage of self-cites to years used in IF calculation and IF (Rs 0.41, 95% CI, 0.21 to 0.58, P < 0.0001), and delta-IF and IF (Rs 0.89, 95% CI, 0.84 to 0.93, P < 0.0001). CONCLUSION: Although the number and rate of self citations differed among anesthesia journals, the contribution of self-citation to IF has declined over time for most anesthesia journals. These results suggest periodic reassessment may be important to ensure that the publication process remains transparent and impartial to bias. PMID- 21596874 TI - CYP2D6- and CYP3A-dependent enantioselective plasma concentrations of ondansetron in postanesthesia care. AB - BACKGROUND: An influence of polymorphic cytochromes P450 (CYP) 2D6 genetic variants on antiemetic efficacy of ondansetron has been suggested. However, the role of CYP3A in ondansetron metabolism and efficacy has been unclear. In this study, we evaluated the hypothesis that genotype-dependent CYP2D6 and CYP3A activity selectively influences plasma concentrations of ondansetron enantiomers. Additionally, the effects of doubling the ondansetron dose on genotype-dependent plasma concentrations were investigated. METHODS: Patients received IV ondansetron 4 or 8 mg for emesis prophylaxis before emergence from anesthesia. The CYP2D6-dependent activity score representing no, decreased, normal, or increased CYP2D6 enzyme activity as well as CYP3A low (CYP3A5*3/*3) and high expressor status (CYP3A5 wt/wt or wt/*3) were determined. Plasma concentrations of R- and S-ondansetron enantiomers were measured by liquid chromatography-tandem mass spectrometry. Area under the plasma concentration-time curves (AUCs) of R- and S-ondansetron were associated with CYP2D6 and CYP3A5 genotype-dependent enzyme activity. RESULTS: Complete data of 141 subjects were analyzed. Concentrations of S-ondansetron differed between CYP2D6 activity groups (P = 0.01) with highest values in patients with no CYP2D6 activity (mean [95% confidence interval]: 362.5 [238.3/486.7] h . ng/mL) and lowest values in those with increased activity (149.6 [114.5/184.8] h . ng/mL) compared with subjects displaying genotypes resulting in reduced or normal CYP2D6 activity (263.6 [228.8/298.8], 255.4 [228.2/282.7] h . ng/mL). AUC of R-ondansetron was 2 times higher in CYP3A5 low expressors compared with high expressors (281.5 [248.6/314.3] vs 142.5 [92.4/192.7] h . ng/mL; P = 0.003). Doubling the ondansetron dose increased plasma concentrations only in individuals with low CYP3A activity, but not in individuals with high enzyme activity (P < 0.001). CONCLUSIONS: The metabolism of ondansetron seems to be enantioselective. In this postoperative setting, CYP2D6 activity scores correlated with concentrations of S ondansetron, whereas CYP3A5 expressor status mainly influenced concentrations of R-ondansetron. Genetically and environmentally determined CYP2D6 and CYP3A enzyme activity might have implications for antiemetic efficacy. PMID- 21596875 TI - Hyperbaric oxygenation therapy alleviates chronic constrictive injury-induced neuropathic pain and reduces tumor necrosis factor-alpha production. AB - BACKGROUND: The development of hyperalgesia and allodynia after chronic constrictive injury (CCI) is associated with significantly increased tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Theoretically, if the production of TNF-alpha and/or IL-1beta could be reduced, neuropathic pain syndrome may be alleviated. Recently, a beneficial effect of hyperbaric oxygenation therapy (HBOT) in the treatment of pain disorders has been suggested. Our present study was designed to examine the hypotheses that (1) CCI-induced neuropathic pain may be associated with increased production of TNF-alpha and IL 1beta, (2) HBOT may alleviate CCI-induced neuropathic pain, and (3) the alleviated neuropathic pain may be associated with reduced production of TNF alpha and/or IL-1beta. METHODS: Male rats (weighing 250-300 g) were anesthetized with ketamine and xylazine. The common sciatic nerve was exposed through the biceps femoris. Proximal to the sciatic's trifurcation, 4 ligatures were loosely tied around the nerve. In the sham group, an identical dissection was performed without ligation of the sciatic nerve. Mechanical allodynia and cold allodynia were tested by von Frey filament stimulation and the spread of acetone, respectively. HBO rats (n =18) were exposed to pure oxygen for 1 hour at 2.4 atm once a day. Non-HBO (n =18) and sham rats (n =6) were placed in the HBOT chamber breathing air. TNF-alpha and IL-1beta in the sciatic nerve were assayed with ELISA. The presence of TNF-alpha protein in homogenates was verified by Western blot analysis. RESULTS: CCI induced significant cold and mechanical allodynia as measured after CCI on days 4 and 7. The cold allodynia response frequency was significantly lower in HBO rats than in non-HBO rats. The values were 20% +/- 1.6% vs 50% +/- 4.5% on day 4 and 40% +/- 4.6% vs 70% +/- 4.5% on day 7 (F =87.42, confidence interval [for the difference between HBO and non-HBO]=29.612 +/- 8.781, P < 0.05 for day 4 and day 7). The threshold of mechanical allodynia significantly increased in HBO rats compared with non-HBO rats. The values were 6.20 +/- 0.9 vs 4.1 +/- 1.0 g on day 4 and 3.8.2 +/- 0.5 vs 2.3 +/- 0.4 g on day 7 (F =18.8, confidence interval [for the difference between HBO and non HBO]=1.806 +/- 1.171, P < 0.05 for day 4 and day 7). TNF-alpha content was significantly higher in non-HBO rats than in sham rats on day 4 (17.89 +/- 0.83 vs 10.66 +/- 1.1 pg/mg protein, P < 0.05) and day 7 (18.97 +/- 1.57 vs 9.09 +/- 1.5 pg/mg protein, P < 0.05). HBOT significantly reduced TNF-alpha content to near the level in sham rats, which was 10.94 +/- 2.78 and 11.32 +/- 2.98 pg/mg protein on day 4 (P < 0.05 versus non-HBO) and 7 (P < 0.05 versus non-HBO), respectively. Western blot analysis confirmed the presence of proteins with molecular weights of 51 kDa in the rat sciatic nerve homogenates. IL-1beta content was also significantly higher in non-HBO rats than in sham rats on day 4 (636 +/- 74 vs 256 +/- 31 pg/mg protein, P < 0.05) and on day 7 (687 +/- 89 vs 288 +/- 35 pg/mg protein, P < 0.05). HBOT had no effect on IL-1beta content, which was 671 +/- 85 pg/mg protein on day 4 and 672 +/- 75 pg/mg protein on day 7 in HBO rats (P =not significant versus non-HBO rats). CONCLUSION: These data show that HBOT alleviates CCI-induced neuropathic pain and inhibits endoneuronal TNF alpha production, but not IL-1beta in CCI-induced neuropathic pain. Reduced TNF alpha production may, at least in part, contribute to the beneficial effect of HBOT. PMID- 21596876 TI - Magnesium sulfate prevents remifentanil-induced postoperative hyperalgesia in patients undergoing thyroidectomy. AB - BACKGROUND: In a randomized, double-blind, prospective study, we investigated whether an intraoperative high versus low dose of remifentanil increased postoperative hyperalgesia and whether magnesium can prevent remifentanil-induced hyperalgesia. METHODS: Ninety patients undergoing thyroidectomy were randomly assigned to 1 of 3 groups. Remifentanil was intraoperatively infused at 0.05 MUg/kg/min (group LO) or 0.2 MUg/kg/min (groups HI and HM). Patients in group HM received MgSO(4) 30 mg/kg at induction followed by an intraoperative infusion of 10 mg/kg/h. Mechanical pain thresholds on the forearm and periincisional area were assessed by von Frey filament the evening before surgery and postoperatively at 24 and 48 hours. Pain measured on a verbal numerical rating scale (VNRS) (0 10) and additional analgesics were recorded in the postanesthesia care unit postoperatively at 6, 24, and 48 hours. RESULTS: There was a significantly greater decrease in pain threshold on the periincisional area at 24 and 48 hours postoperatively in group HI, as compared with the other 2 groups. The 95% confidence intervals for the mean difference in pain thresholds on the periincisional area at 24 and 48 hours postoperatively were 0.31 to 1.11 and 0.36 to 1.14 for group HI versus group LO, 0.45 to 1.26 and 0.54 to 1.32 for group HI versus group HM (values are log(10) of force in milligrams). The change in pain threshold on the forearm was similar among the groups. Group HI had significantly higher VNRS scores (median [interquartile range], 3 [2-4]) than group LO (2 [1-3] and group HM (2 [1-3]) at 48 hours postoperatively. The 95% confidence intervals for median difference in VNRS score at 48 hours postoperatively were 1 to 2 for group HI versus group LO and 0 to 2 for group HI versus group HM. There were no significant differences in the number of patients who requested rescue analgesics in the postoperative anesthesia care unit and general ward during 48 hours postoperatively among the 3 groups. CONCLUSIONS: A relatively high dose of intraoperative remifentanil enhances periincisional hyperalgesia. Intraoperative MgSO(4) prevents remifentanil-induced hyperalgesia. However, hyperalgesia did not reach clinical relevance in terms of postoperative pain or analgesic consumption in patients undergoing thyroidectomy. PMID- 21596877 TI - Obesity does not influence the onset and offset of sevoflurane effect as measured by the hysteresis between sevoflurane concentration and bispectral index. AB - BACKGROUND: The onset and offset of action of anesthetic gases might be delayed by respiratory changes and gas exchange alterations present in obese patients. In this study, we assessed the influence of obesity on the hysteresis between sevoflurane and its effect as measured by the bispectral index (BIS). Because the use of positive end-expiratory pressure (PEEP) in obese patients has improved gas exchange, we also assessed the influence of PEEP on hysteresis. METHODS: Fifteen obese and 15 normal-weight patients, ASA physical status I and II, 20 to 50 years old, scheduled to undergo general anesthesia for elective laparoscopic surgery, were prospectively studied. Anesthesia was induced with propofol and maintained with sevoflurane and fentanyl. At the end of surgery and after stable BIS values of 60 to 65, the inspired concentration of sevoflurane was increased to 5 vol% for 5 minutes or until BIS was <40 and then decreased. Sevoflurane transitions were performed once in normal-weight subjects (without PEEP) and twice in obese patients (one without PEEP and one with a PEEP of 8 cm H(2)O). The hysteresis between sevoflurane end-tidal concentrations and BIS during these transition periods was modeled with an inhibitory Emax model using a population pharmacokinetic/ pharmacodynamic (PK/PD) approach with NONMEM VI. A descriptive analysis of sevoflurane inspired and expired concentrations, BIS values, and time to reach different BIS end points was also used to compare the PK and PD characteristics. RESULTS: All patients completed the study. The data were adequately fit with the PK/PD model. The hysteresis expressed as the effect-site elimination rate constant was not influenced by body mass index or PEEP (P > 0.05). Neither obesity nor PEEP showed any influence on the PK/PD descriptors. CONCLUSIONS: Our results do not support the hypothesis that obesity prolongs induction or recovery times when sevoflurane, a poorly soluble anesthetic, is used to maintain anesthesia from 90 to 120 minutes. PMID- 21596878 TI - Malignant disease within 5 years after surgery in relation to duration of sevoflurane anesthesia and time with bispectral index under 45. AB - BACKGROUND: Surgery, general anesthesia, and related events have been implicated to promote cancer proliferation. We investigated the incidence of cancer within 5 years after surgery in relation to duration of anesthesia (T(ANESTH)) and also by time with bispectral index (BIS) under 45 (T(BIS<45)) serving as a proxy for more profound anesthesia exposure. METHODS: New malignant diagnoses after surgery under sevoflurane anesthesia were obtained in a prospective cohort of 2972 BIS monitored patients without any clinically diagnosed malignant disease at the time of index surgery. The risk of cancer during follow-up in relation to T(ANESTH) and T(BIS<45) was assessed by Cox regression. The cancer incidence in this surgical population was compared with the incidence in a standardized general population by calculation of standard incidence ratio. RESULTS: One hundred twenty-nine patients (4.3%) were assigned 136 new malignant diagnoses within 5 years after surgery. No relation between T(ANESTH) or T(BIS<45) and new malignant disease was found, nor were any significant relations obtained when other thresholds for BIS (i.e., <30, <40, and <50, respectively) were used in the calculations. The standard incidence ratio for new malignant disease was 1.37 (confidence interval, 1.15-1.62). CONCLUSION: Neither duration of anesthesia nor increased cumulative time with profound sevoflurane anesthesia was associated with an increased risk for new malignant disease within 5 years after surgery in previously cancer-free patients. PMID- 21596880 TI - Transesophageal echocardiography detection of undiagnosed multiple muscular ventricular septal defects with alteration of shunt flow by right ventricular pacing after an arterial switch operation in a neonate. PMID- 21596879 TI - A randomized, open-label study of the safety and tolerability of fospropofol for patients requiring intubation and mechanical ventilation in the intensive care unit. AB - BACKGROUND: Current drugs for induction and maintenance of sedation in mechanically ventilated patients in the intensive care unit have limitations. Fospropofol, a prodrug of propofol, has not been studied as a sedative in the ICU setting. METHODS: In this randomized, open-label pilot study, patients received 1 of 3 regimens with a goal of maintaining a Ramsay Sedation Score of 2 to 5: (1) fospropofol IV infusion with a bolus and increased infusion rate for agitation events (infusion/bolus); (2) fospropofol IV infusion with an increased infusion rate for agitation events (infusion only); or (3) propofol IV infusion with an increased infusion rate for agitation events. RESULTS: Sixty patients received study drug and were included in the safety and efficacy analyses. Because incidence rates for adverse events were similar between fospropofol groups, and because the study was not powered to determine significant differences between treatment groups for safety variables, adverse events for both fospropofol groups were combined. In the fospropofol groups, 28 out of 38 patients (74%) experienced treatment-emergent adverse events in comparison with 14 out of 22 patients (64%) in the propofol group. The most common treatment-emergent adverse events with fospropofol were procedural pain (21.1%) and nausea (13.2%). Two patients (1 each in the fospropofol infusion/bolus and the propofol groups) experienced hypotension during the study as a potential sedation-related adverse event. Mean plasma formate levels were not significantly different among groups. Patients in all 3 treatment groups maintained Ramsay Sedation Scores of 2 to 5 for >90% of the time they were sedated. CONCLUSION: This pilot study suggests that fospropofol, administered in either an infusion/bolus or infusion-only regimen, is tolerable and effective for short-term induction and maintenance of sedation in mechanically ventilated intensive care unit patients. PMID- 21596881 TI - Isoflurane posttreatment reduces brain injury after an intracerebral hemorrhagic stroke in mice. AB - BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating stroke subtype affecting 120,000 Americans annually. Of those affected, 40%to 50% will die within the first 30 days, whereas the survivors are left with a lifetime of neurobehavioral disabilities. Recently, it has been shown that volatile anesthetics such as isoflurane can reduce brain injury after an ischemic stroke. As a result, in this study, we investigated the effects of isoflurane as a posttreatment therapeutic modality in ICH-injured mice. Specifically, we investigated whether isoflurane posttreatment can preserve the structural integrity of the brain by reducing apoptotic damage and, in turn, improve functional outcome by amelioration of brain edema and neurobehavioral deficits. METHODS: Male CD1 mice (n = 53) were divided into the following groups: sham (n = 14), ICH (n = 14), ICH treated with 1.5% isoflurane posttreatment for 1 hour (n = 15), and ICH treated with 1.5% isoflurane posttreatment for 2 hours (n = 10). The blood injection ICH model was adapted; this involved extracting autologous blood from the mouse tail and injecting it directly into the right basal ganglia. One hour after surgery, treated mice were placed in a glass chamber maintained at 37 degrees C and infused with 1.5% isoflurane for 1 or 2 hours. At 24 hours postinjury, mice were assessed for neurobehavioral deficits using the Modified Garcia Score and then killed and assessed for brain water content. Double immunofluorescent staining was performed using neuronal marker MAP-2 and TUNEL under a fluorescent microscope to assess for apoptosis. RESULTS: Our results indicated that after 1-hour 1.5% isoflurane posttreatment, there was a significant reduction in brain edema, a decrease in apoptotic cell death, and a significant improvement in neurobehavioral deficits. CONCLUSIONS: Our results suggest that isoflurane may be an effective posttreatment therapeutic option for ICH because of its ability to reduce structural damage and subsequently preserve functional integrity. PMID- 21596882 TI - A case series of the anesthetic management of parturients with surgically repaired tetralogy of Fallot. AB - BACKGROUND: Most case reports of pregnancies after surgical repair of tetralogy of Fallot have focused on cardiovascular and obstetric concerns, with relatively few authors focusing on specific intrapartum and postpartum anesthetic management strategies. METHODS: The Mayo Clinic Congenital Heart Disease Clinic and the Boston Adult Congenital Heart Disease Service databases were cross-referenced with the Mayo Clinic and the Brigham and Women's Hospital Department of Anesthesiology databases to identify patients with tetralogy of Fallot who delivered at their respective hospital from January 1, 1994, to January 1, 2008. We reviewed each medical record to evaluate parturient care during pregnancy, labor, and delivery with a focus on anesthetic management. RESULTS: During the 14 year study period, a total of 27 deliveries in 20 patients with repaired tetralogy of Fallot were identified. Twenty-one deliveries (78%) among 15 parturients (75%) involved a trial of labor; all parturients received neuraxial analgesia for labor and delivery, including 18 (86%) epidural, 2 (10%) combined spinal-epidural, and 1 (5%) continuous spinal anesthetic after an unintended dural puncture. Of the 21 patients undergoing labor, 3 (14%) received invasive arterial blood pressure monitoring; 5 (24%) received continuous telemetry; 3 (14%) experienced congestive heart failure that required diuresis; 4 (19%) had obstetric or neonatal complications; and 3 (14%) had anesthesia complications. Cesarean delivery was required in 4 patients (19%) because of labor complications. Concurrent cardiovascular, obstetric, and anesthetic complications in 1 patient resulted in neonatal death. Six (22%) parturients underwent elective cesarean delivery; 4 received epidural and 2 received spinal anesthesia; no anesthetic or immediate obstetric complications occurred. Among all parturients, 5 deliveries in 5 separate parturients (19% of deliveries) reported symptoms of congestive heart failure at the time of delivery. CONCLUSIONS: Pregnancy outcomes for patients with repaired tetralogy of Fallot were found to be generally favorable. All patients undergoing a trial of labor or cesarean delivery had neuraxial analgesia or anesthesia. Recognition and management of congestive heart failure was necessary in 19% of deliveries. PMID- 21596884 TI - The effects of dexmedetomidine on regional cerebral blood flow and oxygen consumption during severe hemorrhagic hypotension in rats. AB - BACKGROUND: We performed this study to determine how dexmedetomidine would affect regional cerebral blood flow (rCBF) and microregional O(2) consumption during nonhemorrhagic normovolemia and during severe hemorrhagic hypotension in rats. METHODS: Forty-eight male rats were anesthetized with isoflurane and their lungs were mechanically ventilated. Half of the rats were bled to reach a mean arterial blood pressure of 40 to 45 mm Hg and were maintained at this level for at least 30 minutes before rCBF or microregional arterial oxygen saturation (Sao(2)) and venous oxygen saturation (Svo(2)) were determined. The other half were not bled and served as nonhemorrhagic controls. Half of each group was given dexmedetomidine 1 MUg/kg/min IV for 45 minutes and the other half was given the same amount of normal saline infusion. The infusion started 10 minutes before blood withdrawal for the hemorrhagic groups. The rCBF was determined using (14)C iodoantipyrine, and the microregional Sao(2) and Svo(2) were determined using cryomicrospectrophotometry at 45 minutes of infusion. RESULTS: Dexmedetomidine decreased heart rate by 25%, but the decrease of mean arterial blood pressure was not significant. The total amount of blood withdrawn and hemoglobin were similar between the normal saline-treated and the dexmedetomidine-treated groups. In normovolemia, dexmedetomidine significantly decreased rCBF (-58%) in the lateral cortex with a similar percentage decrease (-57%) of calculated O(2) consumption. Microregional Svo(2) was similar between the normal saline-treated group (62.8% +/- 1.3% [mean +/- SD]) and the dexmedetomidine-treated group (60.7% +/- 1.8%) despite a large difference in rCBF. Hemorrhage significantly decreased rCBF ( 44%) in the lateral cortex in the normal saline-treated rats with no significant change in regional cerebrovascular resistance. In contrast, in the lateral cortex of the dexmedetomidine-treated rats, the decrease of rCBF was not significant but there was a significant decrease in regional cerebrovascular resistance. A decrease (-25%) in the O(2) consumption was observed in the lateral cortex of the normal saline-treated rats with hemorrhage, but hemorrhage did not decrease O(2) consumption in the dexmedetomidine-treated rats. Despite significantly lower rCBF (-34%) in the dexmedetomidine-treated rats, the Svo(2) was similar between the normal saline-treated (42.8% +/- 2.5%) and the dexmedetomidine-treated rats (43.2% +/- 2.7%). CONCLUSIONS: Our data showed that in normovolemia, dexmedetomidine produced a proportionate decrease of rCBF and O(2) consumption. Hemorrhage decreased rCBF more than O(2) consumption. Dexmedetomidine prevented rCBF and O(2) consumption from decreasing after hemorrhage. Our data suggest that dexmedetomidine may help provide optimal O(2) supply and consumption balance during hemorrhage. PMID- 21596883 TI - Neuropeptides contribute to peripheral nociceptive sensitization by regulating interleukin-1beta production in keratinocytes. AB - BACKGROUND: It is increasingly evident that there is a close connection between the generation of cutaneous inflammatory cytokines and elevated neuropeptide signaling in complex regional pain syndrome (CRPS) patients. Previously, we observed in the rat tibia fracture model of CRPS that activation of caspase-1 containing NALP1 inflammasomes was required for interleukin (IL)-1beta production in keratinocytes, and that administration of an IL-1 receptor antagonist (anakinra) reduced the fracture-induced hindpaw mechanical allodynia. We therefore hypothesized that neuropeptides lead to nociceptive sensitization through activation of the skin's innate immune system by enhancing inflammasome expression and caspase-1 activity. METHODS: We determined whether the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) require IL-1beta to support nociceptive sensitization when injected into mouse hindpaw skin by testing mechanical allodynia. We then investigated whether these neuropeptides could stimulate production of IL-1beta in a keratinocyte cell line (REKs), and could increase the expression of inflammasome component proteins including NALP1 and caspase-1. Finally, we determined whether neuropeptide stimulated IL-1beta production required activation of caspase-1 and cathepsin B. RESULTS: Intraplantar injections of SP and CGRP lead to allodynia in mouse hindpaws but CGRP was approximately 10-fold less potent in causing this response. Moreover, systemic administration of the IL-1 receptor (IL-1R) antagonist anakinra prevented sensitization after neuropeptide injection. Also, mouse skin keratinocytes express IL-1R, which is up-regulated after local neuropeptide application. In vitro data demonstrated that both SP and CGRP increased IL-1beta gene and protein expression in REKs in a dose-dependent manner. Furthermore, SP time- and dose-dependently up-regulated NALP1 and caspase-1 mRNA and protein levels in REKs. In contrast, CGRP time- and dose-dependently enhanced NALP1 and caspase-1 mRNA levels without causing a significant change in NALP1 or caspase-1 protein expression in REKs. Inhibition of caspase-1 activity using the selective inhibitor Ac-YVAD-CHO reduced SP and, less effectively, CGRP induced increases in IL-1beta production in REK cells. The selective cathepsin B inhibitor CA-74Me inhibited neuropeptide induced IL-1beta production in REKs as well. CONCLUSIONS: Collectively, these results demonstrate that neuropeptides induce nociceptive sensitization by enhancing IL-1 beta production in keratinocytes. Neuropeptides rely on both caspase-1 and cathepsin B for this enhanced production. Neurocutaneous signaling involving neuropeptide activation of the innate immunity may contribute to pain in CRPS patients. PMID- 21596885 TI - Gastric sonography in the fasted surgical patient: a prospective descriptive study. AB - BACKGROUND: Aspiration pneumonia remains a serious anesthetic-related complication. A reliable diagnostic tool to assess gastric volume is currently lacking. We recently demonstrated that gastric sonography can provide reliable qualitative and quantitative information about gastric content and volume in healthy volunteers. In the current study, we performed a prospective qualitative and quantitative analysis of the gastric antrum in 200 fasted patients undergoing elective surgery. METHODS: A standardized gastric scanning protocol was applied before anesthetic induction. Patients were classified following a 3-point grading system based solely on qualitative sonographic assessment of the antrum in the supine and right lateral decubitus positions. RESULTS: Eighty-six patients were classified as grade 0 (empty antrum); 107 patients as grade 1 (minimal fluid volume detected only in the right lateral decubitus position); and 7 patients were classified as grade 2 (antrum clearly distended with fluid visible in both supine and lateral positions). The 3-point grading system correlated with total gastric fluid volume as predicted by a previously reported mathematical model. Essentially grade 0 corresponds to a completely empty stomach, grade 1 corresponds to negligible fluid volumes (16 +/- 36 mL) within normal ranges expected for fasted patients, and grade 2 correlates with significantly higher predicted gastric fluid volumes (180 +/- 83 mL) beyond previously reported "safe" limits. One patient with a grade 2 antrum had an episode of significant regurgitation of gastric contents on emergence from anesthesia. CONCLUSION: We propose a 3-point grading system based exclusively on qualitative sonographic assessment of the gastric antrum that correlates well with predicted gastric volume. This grading system could be a promising "biomarker" to assess perioperative aspiration risk. Before it can be applied widely to clinical practice, this diagnostic tool needs to be further validated and characterized. PMID- 21596886 TI - The interaction between emulsified isoflurane and lidocaine is synergism in intravenous regional anesthesia in rats. AB - BACKGROUND: Our previous studies have demonstrated that emulsified isoflurane (EI) produced epidural anesthesia and blockade of nerve conduction. We designed this study to observe whether EI could produce an anesthetic effect in IV regional anesthesia (IVRA) and to investigate the underlying interaction between EI and lidocaine when they were combined in IVRA. METHODS: IVRA was evaluated using tail-flick and tail-clamping tests in a rat model. In experiment 1, Sprague Dawley rats were assigned to 4 groups (n = 10 per group), receiving 0.5 mL of 8%EI, 0.5% lidocaine, 30% Intralipid, or normal saline to observe whether EI could produce an anesthetic effect in IVRA. In experiment 2, for tail IVRA, EC(50) (median effective concentration) of EI alone and EC(50) of lidocaine alone, as well as EC(50) of lidocaine with the addition of Intralipid (0.0% EI) or with the addition of EI at different concentrations (0.4%, 0.8%, and 1.6%) were determined using an up-and-down method. Isobolographic analysis was used to evaluate the interaction between EI and lidocaine. RESULTS: For experiment 1, successful IVRA was observed in 8 of 10 rats with 8% EI, 10 of 10 rats with 0.5% lidocaine, and 0 of 10 rats with 30% Intralipid or normal saline. The anesthetic effect was not different in onset time (1.5 +/- 0.9 vs 1.0 +/- 0.0 minutes, P = 0.104) or recovery time (15 +/- 9 vs 18 +/- 12 minutes, P = 0.394) between 8% EI and 0.5% lidocaine. For experiment 2, EC(50) of EI was 4.467% +/- 0.375% and EC(50) of lidocaine was 0.183% +/- 0.072%; EC(50) of lidocaine was 0.173% +/- 0.036% with the addition of Intralipid, and 0.064% +/- 0.008%, 0.035% +/- 0.005%, and 0.028% +/- 0.006% with the addition of 0.4%, 0.8%, and 1.6% EI, respectively. With the addition of EI, the requirement for lidocaine was reduced in a synergistic manner. CONCLUSIONS: EI produced IVRA, and a synergistic interaction was found between EI and lidocaine for IVRA in a rat tail model. PMID- 21596887 TI - Shortage of perioperative drugs: implications for anesthesia practice and patient safety. AB - Several medications used in clinical perioperative medicine are currently cited on the national shortage list. Medication shortages may be attributed to lack of raw materials, manufacturing issues, and discontinuation of production. Medication shortage has a substantial impact on patient care, and is responsible for creating an environment conducive to an increase in medication errors. Anesthesiologists should be taking an active role with the pharmacy and hospital management to alert caregivers and help to prevent adverse effects on patient care and safety. PMID- 21596888 TI - Hyperglycemia during craniotomy for adult traumatic brain injury. AB - BACKGROUND: Hyperglycemia after traumatic brain injury (TBI) is associated with poor outcome, but previous studies have not addressed intraoperative hyperglycemia in adult TBI. In this study, we examined glucose value variability and risk factors for hyperglycemia during craniotomy in adults with TBI. METHODS: A retrospective cohort study of patients >=18 years who underwent urgent or emergent craniotomy for TBI at Harborview Medical Center (level 1 adult and pediatric trauma center) between October 2007 and May 2010 was performed. Preoperative (within 24 hours of anesthesia start) and intraoperative (during anesthesia) glucose values for each patient were retrieved. The prevalence of intraoperative hyperglycemia (glucose >=200 mg/dL), hypoglycemia (glucose <60 mg/dL), and glycemic trends was determined. Generalized Estimating Equations was used to determine the independent predictors of intraoperative hyperglycemia. Data are presented as adjusted odds ratio (AOR) (95% confidence interval [CI]), and P < 0.05 reflects significance. RESULTS: Intraoperative hyperglycemia was common (26 [15%]) and intraoperative hypoglycemia was not observed. Independent risk factors of intraoperative hyperglycemia were age >=65 years (AOR 3.9 [95% CI: 1.4-10.3]; P = 0.007), Glasgow Coma Scale score <9 (AOR 4.9 [95% CI: 1.6 15.1]; P = 0.006), preoperative hyperglycemia (AOR 4.4 [95% CI: 1.7-11.6]; P = 0.003), and subdural hematoma (AOR 5.6 [95% CI: 1.4-22.2]; P = 0.02). Mean intraoperative glucose was highest in severe TBI patients (P = 0.02). There was both between-patient (79.5% variance; P < 0.001) and within-patient (20.5% variance; P < 0.001) intraoperative glucose value variability. Patients with intraoperative hyperglycemia had higher in-hospital mortality (8 [31%] vs 20 [13%]; P < 0.02). CONCLUSION: Intraoperative hyperglycemia was common in adults undergoing urgent/emergent craniotomy for TBI and was predicted by severe TBI, the presence of subdural hematoma, preoperative hyperglycemia, and age >=65 years. However, there was significant variability in intraoperative glucose values. PMID- 21596889 TI - Silencing IL-13Ralpha2 promotes glioblastoma cell death via endogenous signaling. AB - Glioblastoma multiforme (GBM) is one of the most lethal forms of cancer, with a survival rate of only 13% to 27% within 2 years of diagnosis despite optimal medical treatment. We hypothesize that the presence of a unique IL-13Ralpha2 decoy receptor prevents GBM apoptosis. This receptor has a high affinity for interleukin-13 (IL-13), binds the cytokine, and competitively inhibits the intracellular signaling cascade initiated by IL-13. In cells lacking the IL 13Ralpha2 decoy receptor, IL-13 initiates the production of 15-lipoxygenase-1 (15 LOX-1), which has been implicated in cellular apoptosis. Our group and others have shown that induction of 15-LOX-1 correlates with tumor cell death in colorectal, pancreatic, and prostate cancer. How 15-LOX-1 induces apoptosis remains unclear. Preliminary evidence in GBM cells implicates an apoptotic process mediated by PPARgamma. 15-LOX-1 metabolites can modulate PPARgamma and activation of PPARgamma can suppress tumor growth. We hypothesize that in GBM, IL 13 can induce 15-LOX-1, which regulates cell apoptosis via signaling through PPARgamma and that expression of IL-13Ralpha2 prevents apoptosis and contributes to tumor growth. Our in vitro and in vivo data support this. Knocking down IL 13Ralpha2 with short interfering RNA dramatically induces 15-LOX-1 expression, promotes apoptosis, and reduces GBM tumor growth in vivo. These findings identify a mechanism for eliminating the blockade of endogenous IL-13 signaling and for promotion of apoptosis, and characterize a role for 15-LOX-1 in GBM apoptosis. Identifying a mechanistic pathway that can be targeted for pharmacologic intervention will have applied implications to developing novel and effective treatments of GBM. PMID- 21596890 TI - Farnesoid X receptor activation by chenodeoxycholic acid induces detoxifying enzymes through AMP-activated protein kinase and extracellular signal-regulated kinase 1/2-mediated phosphorylation of CCAAT/enhancer binding protein beta. AB - Farnesoid X receptor (FXR) regulates redox homeostasis and elicits a cytoprotective effect. CCAAT/enhancer binding protein-beta (C/EBPbeta) plays a role in regulating the expression of hepatocyte-specific genes and contributes to hepatocyte protection and liver regeneration. In view of the role of FXR in xenobiotic metabolism and hepatocyte survival, this study investigated the potential of FXR to activate C/EBPbeta for the induction of detoxifying enzymes and the responsible regulatory pathway. Chenodeoxycholic acid (CDCA), a major component in bile acids, activates FXR. In HepG2 cells, CDCA treatment activated C/EBPbeta, as shown by increases in its phosphorylation, nuclear accumulation, and expression. 3-(2,6-Dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl )oxymethyl-5-isopropyl-isoxazole (GW4064), a synthetic FXR ligand, had similar effects. In addition, CDCA enhanced luciferase gene transcription from the construct containing -1.65-kb GSTA2 promoter, which contained C/EBP response element (pGL-1651). Moreover, CDCA treatment activated AMP-activated protein kinase (AMPK), which led to extracellular signal-regulated kinase 1/2 (ERK1/2) activation, as evidenced by the results of experiments using a dominant-negative mutant of AMPKalpha and chemical inhibitor. The activation of ERK1/2 was responsible for the activating phosphorylation of C/EBPbeta. FXR knockdown attenuated the ability of CDCA to activate AMPK and ERK1/2 and phosphorylate C/EBPbeta. Consistently, enforced expression of FXR promoted the phosphorylation of AMPKalpha, ERK1/2, and C/EBPbeta, verifying that C/EBPbeta phosphorylation elicited by CDCA results from the activation of AMPK and ERK1/2 by FXR. In mice, CDCA treatment activated C/EBPbeta with the induction of detoxifying enzymes in the liver. Our results demonstrate that CDCA induces antioxidant and xenobiotic metabolizing enzymes by activating C/EBPbeta through AMPK-dependent ERK1/2 pathway downstream of FXR. PMID- 21596891 TI - The challenge of increasing uptake of pulmonary rehabilitation: what can we do to maximise the chances of success? PMID- 21596892 TI - What prevents people with chronic obstructive pulmonary disease from attending pulmonary rehabilitation? A systematic review. AB - Pulmonary rehabilitation is an essential component of care for people with chronic obstructive pulmonary disease (COPD) and is supported by strong scientific evidence. Despite this, many people with COPD do not complete their program or choose not to attend at all. The aim of this study was to determine the factors associated with uptake and completion of pulmonary rehabilitation for people with COPD. Seven electronic databases were searched for qualitative or quantitative studies that documented factors associated with uptake and completion of pulmonary rehabilitation in people with COPD. Two reviewers independently extracted data, which was synthesized to provide overall themes. Travel and transport were consistently identified as barriers to both uptake and completion. A lack of perceived benefit of pulmonary rehabilitation also influenced both uptake and completion. The only demographic features that consistently predicted non-completion were being a current smoker (pooled odds ratio 0.17, 95% confidence interval 0.10 to 0.32) and depression. The limited data available regarding barriers to uptake indicated that disruption to usual routine, influence of the referring doctor and program timing were important. In conclusion poor access to transport and lack of perceived benefit affect uptake of pulmonary rehabilitation. Current smokers and patients who are depressed are at increased risk of non-completion. Enhancing attendance in pulmonary rehabilitation will require more attention to transportation, support for those at risk of non-completion and greater involvement of patients in informed decisions about their care. PMID- 21596894 TI - The size of current and future problems. PMID- 21596893 TI - Optimal duration of pulmonary rehabilitation for individuals with chronic obstructive pulmonary disease - a systematic review. AB - The purpose of this review was to determine the impact of duration of pulmonary rehabilitation on measures of health-related quality of life and exercise tolerance in individuals with chronic obstructive pulmonary disease (COPD). Randomized controlled trials (RCTs) comparing different lengths of pulmonary rehabilitation in patients with COPD were identified after searches of six electronic databases (MEDLINE, PubMed, CINAHL, EMBASE, Physiotherapy Evidence Database [PEDro] and the Cochrane Library of clinical trials) and reference lists of pertinent articles. Two reviewers performed the searches and assessed trial quality using PEDro and Jadad scales. Five RCTs met inclusion criteria. The mean PEDro score was 6 (range 3-8) and mean Jadad was 2 (range 1-3). Three trials reported a difference in health-related quality of life in favour of the longer duration program; two trials reported a benefit in exercise capacity in favour of longer programs. A meta-analysis of results was not possible due to considerable heterogeneity in program duration and outcomes. Longer duration pulmonary rehabilitation programs appear to have a more favourable effect on health-related quality of life in individuals with COPD; results for exercise capacity are less clear. The limited literature prevents a more definitive conclusion on optimal duration of rehabilitation. PMID- 21596895 TI - Chronic obstructive pulmonary disease (COPD) and old age? AB - Chronic obstructive pulmonary disease (COPD) in old age is an increasing problem. Understanding the features of COPD in older patients is important in order to introduce effective interventions and to inform efforts for health resource allocation. Features of importance to old age include increased prevalence of COPD in non-smokers and rise in the rate of systemic comorbidities. In addition, acute exacerbations in older patients have poorer outcome, manifesting by increase in the rate of hospitalisation, greater length of stay, increase of the rate of re-hospitalisation and in mortality rate. Impaired cognitive functions as well as problems affecting hand joints make using inhaled medications less reliable which leads to further deterioration of outcome of care. Even for those who are competent in using inhalers, the evidence for their efficacy in older patients is not certain. PMID- 21596896 TI - Inference of site frequency spectra from high-throughput sequence data: quantification of selection on nonsynonymous and synonymous sites in humans. AB - Sequencing errors and random sampling of nucleotide types among sequencing reads at heterozygous sites present challenges for accurate, unbiased inference of single-nucleotide polymorphism genotypes from high-throughput sequence data. Here, we develop a maximum-likelihood approach to estimate the frequency distribution of the number of alleles in a sample of individuals (the site frequency spectrum), using high-throughput sequence data. Our method assumes binomial sampling of nucleotide types in heterozygotes and random sequencing error. By simulations, we show that close to unbiased estimates of the site frequency spectrum can be obtained if the error rate per base read does not exceed the population nucleotide diversity. We also show that these estimates are reasonably robust if errors are nonrandom. We then apply the method to infer site frequency spectra for zerofold degenerate, fourfold degenerate, and intronic sites of protein-coding genes using the low coverage human sequence data produced by the 1000 Genomes Project phase-one pilot. By fitting a model to the inferred site frequency spectra that estimates parameters of the distribution of fitness effects of new mutations, we find evidence for significant natural selection operating on fourfold sites. We also find that a model with variable effects of mutations at synonymous sites fits the data significantly better than a model with equal mutational effects. Under the variable effects model, we infer that 11% of synonymous mutations are subject to strong purifying selection. PMID- 21596897 TI - Spatial regulation of lag-2 transcription during vulval precursor cell fate patterning in Caenorhabditis elegans. AB - lag-2 encodes a ligand for LIN-12/Notch and is a component of the lateral signal that activates LIN-12/Notch during Caenorhabditis elegans vulval precursor cell (VPC) fate patterning. lag-2 is specifically transcribed in one VPC, named P6.p, in response to activation of EGFR/Ras/MAPK by the inductive signal that initiates vulval development. Here, we show that a critical molecular event linking inductive and lateral signaling is the relief of VPC-wide lag-2 repression in P6.p. We find that the lag-2 promoter contains an element, VPCrep, which mediates repression in all VPCs when the inductive signal is absent, and another promoter element, VPCact, which is required for activation when repression is relieved by the inductive signal. We show that repression through VPCrep is mediated by the Elk1 ortholog LIN-1, and that the level and subcellular accumulation of a functional LIN-1::GFP protein is similar in all six VPCs before and after vulval induction, suggesting that relief of LIN-1-mediated repression in P6.p is likely due to the known MAPK-dependent phosphorylation of LIN-1. We also provide evidence that the factor(s) acting through VPCact is present in all VPCs but is not modulated by the inductive signal, and that transcription of lag-2 requires the Hth/Meis ortholog UNC-62 and the Mediator complex component SUR-2. Relief of repression of lag-2 in P6.p offers a plausible mechanistic basis for spatial restriction of lag-2 in generating the precise spatial pattern of VPC fates. PMID- 21596898 TI - Inhibition of RNA interference and modulation of transposable element expression by cell death in Drosophila. AB - RNA interference (RNAi) regulates gene expression by sequence-specific destruction of RNA. It acts as a defense mechanism against viruses and represses the expression of transposable elements (TEs) and some endogenous genes. We report that mutations and transgene constructs that condition cell death suppress RNA interference in adjacent cells in Drosophila melanogaster. The reversal of RNAi is effective for both the white (w) eye color gene and green fluorescent protein (GFP), indicating the generality of the inhibition. Antiapoptotic transgenes that reverse cell death will also reverse the inhibition of RNAi. Using GFP and a low level of cell death produced by a heat shock-head involution defective (hs-hid) transgene, the inhibition appears to occur by blocking the conversion of double-stranded RNA (dsRNA) to short interfering RNA (siRNA). We also demonstrate that the mus308 gene and endogenous transposable elements, which are both regularly silenced by RNAi, are increased in expression and accompanied by a reduced level of siRNA, when cell death occurs. The finding that chronic ectopic cell death affects RNAi is critical for an understanding of the application of the technique in basic and applied studies. These results also suggest that developmental perturbations, disease states, or environmental insults that cause ectopic cell death would alter transposon and gene expression patterns in the organism by the inhibition of small RNA silencing processes. PMID- 21596899 TI - Hox and a newly identified E2F co-repress cell death in Caenorhabditis elegans. AB - The development of an organism depends on individual cells receiving and executing their specific fates, although how this process is regulated remains largely unknown. Here, we identify a mechanism by which a specific cell fate, apoptosis, is determined through the cooperative efforts of Hox and E2F proteins. E2F transcription factors are critical, conserved regulators of the cell cycle and apoptosis. However, little is known about the two most recently discovered mammalian E2Fs-E2F7 and E2F8. In the nematode Caenorhabditis elegans, we identify a novel E2F7/8 homolog, EFL-3, and show that EFL-3 functions cooperatively with LIN-39, providing the first example in which these two major developmental pathways-E2F and Hox-are able to directly regulate the same target gene. Our studies demonstrate that LIN-39 and EFL-3 function in a cell type-specific context to regulate transcription of the egl-1 BH3-only cell death gene and to determine cell fate during development. PMID- 21596900 TI - Genome-wide epigenetic perturbation jump-starts patterns of heritable variation found in nature. AB - We extensively phenotyped 6000 Arabidopsis plants with experimentally perturbed DNA methylomes as well as a diverse panel of natural accessions in a common garden. We found that alterations in DNA methylation not only caused heritable phenotypic diversity but also produced heritability patterns closely resembling those of the natural accessions. Our findings indicate that epigenetically induced and naturally occurring variation in complex traits share part of their polygenic architecture and may offer complementary adaptation routes in ecological settings. PMID- 21596901 TI - Second-generation autologous chondrocyte implantation: results in patients older than 40 years. AB - BACKGROUND: Aging is responsible for degenerative changes in all cartilage elements, thus impairing its properties and healing potential. Most studies on surgical procedures for cartilage focus on young patients because these procedures are generally not considered suitable for older patients. PURPOSE: To analyze the clinical outcome of cartilage lesion treatment using second generation autologous chondrocyte implantation (ACI) techniques in patients more than 40 years old with no clear signs of osteoarthritis, to understand their real potential in relation to aging, the failure rate, and complications in older patients. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Sixty-one patients with grade III to IV cartilaginous lesions of the condyles with no clear signs of osteoarthritis and a minimum age of 40 years were treated with second generation ACI and prospectively evaluated at 5 years' follow-up. Twenty-two patients were treated with arthroscopic Hyalograft C implantation, and 39 underwent the open Chondro-Gide MACI procedure. RESULTS: A significant improvement in both subjective and objective evaluations was observed. The International Knee Documentation Committee (IKDC) subjective score improved from 36.8 +/- 8.4 to 68.1 +/- 21.8 at the final evaluation. The failure rate was 20%. A faster improvement was observed in the group treated with the arthroscopic Hyalograft C technique, whereas similar scores were found at the 24-month follow up and final evaluation. CONCLUSION: A clinical improvement was found in patients more than 40 years old, who in most cases benefited from second-generation ACI with good results lasting at medium-term follow-up. However, the results were inferior with respect to those previously found for younger populations, and the failure rate at medium-term follow-up was also higher. These findings were consistent in the 2 treatment groups. The only difference was the faster recovery when the arthroscopic approach was used. PMID- 21596902 TI - Anatomic single- and double-bundle anterior cruciate ligament reconstruction, part 1: Basic science. AB - Anterior cruciate ligament reconstruction is a frequently performed orthopaedic procedure. Although short-term results are generally good, long-term outcomes are less favorable. Thus, there is renewed interest in improving surgical techniques. Recent studies of anterior cruciate ligament anatomy and function have characterized the 2-bundle structure of the native ligament. During non weightbearing conditions, the anteromedial (AM) and posterolateral (PL) bundles display reciprocal tension patterns. However, during weightbearing, both the AM and PL bundles are maximally elongated at low flexion angles and shorten significantly with increasing knee flexion. Conventional single-bundle reconstruction techniques often result in nonanatomic tunnel placement, with a tibial PL to a femoral "high AM" tunnel position. In vitro studies have demonstrated that these nonanatomic single-bundle reconstructions cannot completely restore normal anterior-posterior or rotatory laxity. Cadaveric studies suggest that anatomic single-bundle and anatomic double-bundle reconstruction may better restore knee stability. Although many cadaver studies suggest that double-bundle reconstruction techniques result in superior stability when compared with single-bundle techniques, others failed to demonstrate a clear benefit of this more complex procedure. Cadaver studies generally do not apply physiologically relevant loads and provide only a "time-zero" assessment that ignores effects of healing and remodeling after anterior cruciate ligament reconstruction. In vivo, dynamic studies offer the most comprehensive assessment of knee function after injury or reconstruction, as they can evaluate dynamic stability during functional joint loading. Studies of knee kinematics during activities such as gait and running suggest that nonanatomic single-bundle anterior cruciate ligament reconstruction fails to restore preinjury knee function under functional loading conditions. Similar studies of more anatomic single- and double-bundle surgical approaches are in progress, and preliminary results suggest that these anatomic techniques may be more effective for restoring preinjury knee function. However, more extensive, well-designed studies of both kinematics and long-term outcomes are warranted to characterize the potential benefits of more anatomic reconstruction techniques for improving long term outcomes after anterior cruciate ligament reconstruction. PMID- 21596903 TI - Direct and mediated effects of two theoretically based interventions to increase consumption of fruits and vegetables in the Healthy Body Healthy Spirit trial. AB - This study tested the effects of two theory-based interventions to increase fruit and vegetable intake. Hypothesized intervention mediators included self-efficacy (SE), social support (SS), autonomous motivation (AM), and controlled motivation (CM). At baseline, 1,021 African American adults were recruited from 16 churches randomized to one comparison and two intervention groups: Group 1 (standard educational materials), Group 2 (culturally targeted materials), and Group 3 (culturally targeted materials and telephone-based motivational interviewing). A well-fitted model based on structural equation modeling-chi(2)(df = 541, N = 353, 325) = 864.28, p < .001, normed fit index = .96, nonnormed fit index = .98, comparative fit index = .98, root mean square error of approximation = .042 demonstrated that AM was both a significant mediator and moderator. In the subgroup with low baseline AM, AM mediated 17% of the effect of the Group 3 intervention on fruit and vegetable intake. Conversely, SS, SE, and CM were not significant mediators. Implications related to theory and intervention development are discussed. PMID- 21596904 TI - A murine model for catheter-associated candiduria. AB - Candiduria is a common finding in hospitalized patients with indwelling urine draining devices. Animal models for candiduria are not well-developed and, despite its prevalence and associated mortality, candiduria is understudied. The presence of Candida in urine does not imply disease because it is also a commensal. Biofilm formation on catheters and the host-pathogen interaction are likely to be important factors that contribute to the pathogenesis. The objective of this study was to establish a candiduria model in mice with indwelling catheters. Our data demonstrate that biofilm formation on indwelling catheters and persistent candiduria can be established in mice. The study supports the concept that biofilm formation contributes to persistence. It also outlines differences between catheter-related candiduria in mice and humans. Specifically, mice exhibit higher levels of leukocyturia. In addition, mean daily fungal burden in urine in the murine model is 10- to 100-fold lower than that in humans. These important findings must be taken into consideration when using this model to study host-pathogen interaction in the setting of candiduria. PMID- 21596905 TI - Molecular typing and epidemiology of enteroviruses in Cyprus, 2003-2007. AB - Human enteroviruses (HEVs) are responsible for a wide spectrum of clinical diseases. Even though usually associated with non-specific febrile illness, they are the most common cause of viral meningitis and pose a serious public-health problem, especially during outbreaks. Rapid detection and identification of HEV serotypes in clinical specimens are important in appropriate patient management and epidemiological investigation. A 5 year study (2003-2007) of clinical specimens from patients with viral meningitis and/or symptoms of enteroviral infection was carried out in Cyprus to determine the underlying enteroviral aetiology. Reverse transcription, followed by a sequential PCR strategy targeting the 5' non-coding region and VP1 region, was used for typing the isolated enteroviruses. The serotype of each isolate was determined by blast search of the VP1 amplicon sequence against GenBank. Clinical specimens from a total of 146 patients were diagnosed as enterovirus-positive. Twenty-two different serotypes were identified. The main strains identified were echovirus 18 and echovirus 30, followed by coxsackievirus B5, echovirus 9, echovirus 6, coxsackievirus A10 and coxsackievirus B2. However, rapid changes in serotype frequency and diversity were observed over time. Serotype distribution corresponded essentially with observations reported from other European countries in the same period. The present report demonstrates the epidemiology of enteroviruses in Cyprus from 2003 to 2007. PMID- 21596906 TI - Weissella confusa: a rare cause of vancomycin-resistant Gram-positive bacteraemia. AB - We describe a case of bacteraemia caused by Weissella confusa in a 48-year-old male who was operated on for adenocarcinoma of the gastro-oesophageal junction and maintained on total parenteral nutrition. Blood cultures were positive for a vancomycin-resistant streptococcus-like organism which was identified as W. confusa by 16S rRNA gene sequencing. PMID- 21596907 TI - Genotyping of Mycobacterium leprae from Brazilian leprosy patients suggests the occurrence of reinfection or of bacterial population shift during disease relapse. AB - We performed genotyping of Mycobacterium leprae present in skin biopsy samples that were collected during the first and the second disease occurrences from eight leprosy patients, seven of whom were diagnosed as suffering from disease relapse. Sequence analysis of part of the M. leprae rpoB, folP1, gyrB and gyrA genes did not show genetic change that supported the presence of drug-resistant bacilli. However, we observed a synonymous nucleotide change at position 297 of gyrA among five of these patients, one presenting C to T (CgyrAT) and four presenting T to C (TgyrAC) at this position. Additional genotyping by analysis of the four short tandem repeats GAA, GTA9, AT17 and TA18 showed that the gyrA single nucleotide polymorphism change was accompanied by a change in short tandem repeat genotype. Our data suggest that leprosy relapse in these patients, living in an area endemic for leprosy, could be caused by M. leprae with a genotype different from the one that caused initial disease. PMID- 21596908 TI - A rare, fatal case of invasive spinal aspergillosis in an antiretroviral-naive, HIV-infected man with pre-existing lung colonization. AB - Infection of the central nervous system (CNS) is a rare but devastating complication of invasive aspergillosis. We report a case of invasive aspergillosis with spinal involvement in a human immunodeficiency virus (HIV) infected patient without neutropenia. A 42-year-old, antiretroviral-naive, HIV infected man presented with progressive weakness in the lower limbs and urinary and faecal incontinence for 2 weeks. The patient had been prescribed broad spectrum antibiotics and prednisone. He had upper motor neuron signs and a sensory level at T1, with accompanying neck stiffness on flexion. Magnetic resonance imaging revealed diffuse abnormal signals of the vertebral bodies in the lower cervical and thoracic areas, with cord compression in the C2 and C3 region and signal distortions of the T2 and T3 vertebral bodies. Chest X-ray and computerized tomography demonstrated post-tuberculous apical cavities with suspected fungal colonization. Histopathology of an extradural spinal lesion at T1/T2 suggested invasive aspergillosis. The patient was started on fluconazole in response to the histopathological evidence of Aspergillus infection, but died within 3 weeks. Post-mortem analysis of the biopsy sample by PCR identified the infectious agent as Aspergillus fumigatus. Atypically, his CD4(+) T-cell count was 239 cells mm(-3) and he had no evidence of neutropenia. Invasive aspergillosis should be considered as part of the differential diagnosis among HIV-infected patients with non-specific, focal CNS symptoms, even among those without classical risk factors such as neutropenia, and aggressive antifungal therapy should be instituted as early as possible. PMID- 21596909 TI - Candida parapsilosis meningitis as the first manifestation of AIDS: case report. AB - Candida meningitis is a rare condition that occurs more frequently in premature infants, immunocompromised patients or patients after neurosurgery. We describe a case of a previously healthy 41-year-old man with Candida parapsilosis meningitis associated with oropharyngeal candidiasis as the first manifestation of AIDS. PMID- 21596910 TI - Improved rapid molecular diagnosis of multidrug-resistant tuberculosis using a new reverse hybridization assay, REBA MTB-MDR. AB - Rapid diagnosis of multidrug-resistant tuberculosis (MDR-TB) is essential for the prompt initiation of effective second-line therapy to improve treatment outcome and limit transmission of this obstinate disease. A variety of molecular methods that enable the rapid detection of mutations implicated in MDR-TB have been developed. The sensitivity of the methods is dependent, in principle, on the repertoire of mutations being detected, which is typically limited to mutations in the genes rpoB, katG and the promoter region of inhA. In this study, a new reverse hybridization assay, REBA MTB-MDR (M&D), that probes mutations in the oxyR-ahpC intergenic region, in addition to those in rpoB, katG and the inhA promoter region, was evaluated. A set of 240 Mycobacterium tuberculosis clinical isolates from patients receiving retreatment regimens was subjected to conventional phenotypic drug-susceptibility testing (DST) and the REBA MTB-MDR assay. The nucleotide sequences of the loci known to be involved in drug resistance were determined for comparison. In brief, the results showed that the REBA MTB-MDR assay efficiently recognized nucleotide changes in the oxyR-ahpC intergenic region as well as those in rpoB, katG and the inhA promoter region with higher sensitivity, resulting in an 81.0 % detection rate for isoniazid resistance. Inclusion of the oxyR-ahpC intergenic region in the REBA MTB-MDR assay improved the overall sensitivity of molecular DST for MDR-TB from 73.1 to 79.9 %. PMID- 21596911 TI - Osteoarticular infection by Candida albicans in an infant with cystic fibrosis. AB - Invasive candidiasis is rare in children after the neonatal period, but can occur in children with (secondary) immunodeficiency with a damaged gastrointestinal or skin barrier, or when receiving antibiotics. A 10-month-old girl was diagnosed as suffering from cystic fibrosis (CF) when showing failure to thrive, pulmonary symptoms and hypoproteinaemia. At that time, Candida albicans was identified from blood culture and treated intravenously with liposomal amphotericin B for 13 days. Six weeks later, the girl presented with osteoarticular infection of the left knee caused by C. albicans. The infection showed insufficient response to therapy with liposomal amphotericin B, but the patient recovered after therapy with fluconazole and flucytosine. Follow-up over 4 years revealed no sequelae. In conclusion, invasive Candida infections may occur in patients with CF, and preventive measures might be considered in patients at risk. In the case of an invasive infection, prolonged treatment with a combination of antifungal drugs may be required. PMID- 21596912 TI - Mutant-prevention concentration and mechanism of resistance in clinical isolates and enrofloxacin/marbofloxacin-selected mutants of Escherichia coli of canine origin. AB - The antibacterial activity and selection of resistant bacteria, along with mechanisms of fluoroquinolone resistance, were investigated by integrating the static [MIC or mutant-prevention concentration (MPC)] and in vitro dynamic model approaches using Escherichia coli isolates from diseased dogs. Using the dynamic models, selected E. coli strains and enrofloxacin and marbofloxacin at a range of simulated area under concentration-time curve over a 24 h interval (AUC(24 h))/MIC ratios were investigated. Our results indicated increasing losses in susceptibility of E. coli upon continuous exposure to enrofloxacin and marbofloxacin in vitro. This effect was transferable to other fluoroquinolones, as well as to structurally unrelated drugs. Our results also confirmed an AUC(24 h)/MIC (AUC(24 h)/MPC)-dependent antibacterial activity and selection of resistant E. coli mutants, in which maximum losses in fluoroquinolone susceptibility occurred at simulated AUC(24 h)/MIC ratios of 40-60. AUC(24 h)/MPC ratios of 39 (enrofloxacin) and 32 (marbofloxacin) were considered protective against the selection of resistant mutants of E. coli. Integrating our MIC and MPC data with published pharmacokinetic information in dogs revealed a better effect of the conventional dosing regimen of marbofloxacin than that of enrofloxacin in restricting the selection of resistant mutants of E. coli. Target mutations, especially at codon 83 (serine to leucine) of gyrA, and overexpression of efflux pumps contributed to resistance development in both clinically resistant and in vitro-selected mutants of E. coli. We also report here a previously undescribed mutation at codon 116 of parC in two laboratory-derived resistant mutants of E. coli. Additional studies would determine the exact role of this mutation in fluoroquinolone susceptibility, as well as establish the importance of our findings in the clinical setting. PMID- 21596913 TI - Investigation of carbapenem heteroresistance among different sequence types of Pseudomonas aeruginosa clinical isolates reveals further diversity. PMID- 21596914 TI - A mathematical modeling approach to risk assessment for normal and anemic women chronically exposed to carbon monoxide from biomass-fueled cookstoves. AB - In developing countries, the chronic exposure to carbon monoxide (CO) from biomass-fueled cookstoves may pose a significant health risk for women who use these stoves, especially for those with underlying clinical conditions that impair tissue oxygenation, e.g., anemia and coronary artery disease. CO concentrations measured in the vicinity of these cookstoves often exceed World Health Organization (WHO) indoor air guidelines for an 8-h average (9 ppm) and a 1-h maximum (26 ppm). Carboxyhemoglobin levels, reported infrequently because they are difficult to obtain, often exceed the WHO threshold of 2.5%. Despite this evidence, specific adverse effects have not yet been linked with chronic CO exposures in these women. Furthermore, anemia, which is prevalent in populations that use biomass fuels, could exacerbate the adverse effects of chronic CO exposure. Because of the difficulties inherent in conducting prospective studies to address this issue, we used a mathematical model to calculate the effects of reported CO levels and exercise on carboxyhemoglobin for women living in 1) Guatemalan villages at altitudes of 4,429-4,593 ft, and 2) coastal villages in Pakistan. In addition, we used the model to calculate the effects of CO exposures in women with moderate to severe anemia on specific physiological parameters (carboxyhemoglobin, carboxymyoglobin, cardiac output, and tissue Po(2)) at exercise levels representing the activities in which these women would be engaged. Our results demonstrate the efficacy of using a mathematical model to predict the physiologic responses to CO and also demonstrate that chronic anemia is a critically important determinant of CO toxicity in these women. PMID- 21596915 TI - Neuromuscular adjustments that constrain submaximal EMG amplitude at task failure of sustained isometric contractions. AB - The amplitude of the surface EMG does not reach the level achieved during a maximal voluntary contraction force at the end of a sustained, submaximal contraction, despite near-maximal levels of voluntary effort. The depression of EMG amplitude may be explained by several neural and muscular adjustments during fatiguing contractions, including decreased net neural drive to the muscle, changes in the shape of the motor unit action potentials, and EMG amplitude cancellation. The changes in these parameters for the entire motor unit pool, however, cannot be measured experimentally. The present study used a computational model to simulate the adjustments during sustained isometric contractions and thereby determine the relative importance of these factors in explaining the submaximal levels of EMG amplitude at task failure. The simulation results indicated that the amount of amplitude cancellation in the simulated EMG (~ 40%) exhibited a negligible change during the fatiguing contractions. Instead, the main determinant of the submaximal EMG amplitude at task failure was a decrease in muscle activation (number of muscle fiber action potentials), due to a reduction in the net synaptic input to motor neurons, with a lesser contribution from changes in the shape of the motor unit action potentials. Despite the association between the submaximal EMG amplitude and reduced muscle activation, the deficit in EMG amplitude at task failure was not consistently associated with the decrease in neural drive (number of motor unit action potentials) to the muscle. This indicates that the EMG amplitude cannot be used as an index of neural drive. PMID- 21596916 TI - Acute hemorrhagic shock decreases airway resistance in anesthetized rat. AB - We studied the relation between changes in pulmonary and systemic hemodynamics to those in the airway resistance, respiratory tissue mechanics, and thoracic gas volume (TGV) following acute hemorrhage and blood reinfusion in rats. Forced oscillation technique was used to measure airway resistance (Raw), respiratory tissue damping, and elastance at baseline and after stepwise 1-ml blood withdrawals up to 5 ml total, followed by stepwise reinfusion up to full restoration. Mean systemic (Pam) and pulmonary arterial pressures and suprarenal aortic blood flow were measured at each step. In supplemental animals, plethysmographic TGV, Pam, and respiratory mechanics measurements were performed. Blood volume loss (BVL) led to proportional decreases in Raw (66.5 +/- 8.8 vs. 44.8 +/- 9.0 cmH(2)O.s.l(-1) with 5 ml, P < 0.001), Pam, and aortic blood flow. In contrast, tissue damping increased significantly (1,070 +/- 91 vs. 1,235 +/- 105 cmH(2)O/l, P = 0.009 with 5 ml BVL), whereas tissue elastance did not change significantly. TGV significantly increased with acute BVL (3.7 +/- 0.2 vs. 4.2 +/ 0.2 ml, P = 0.01). Stepwise reinfusions produced opposite changes in the above parameters, with Raw reaching a higher value than baseline (P = 0.001) upon full volume restoration. Both adrenalin (P = 0.015) and noradrenalin levels were elevated (P = 0.010) after 5-ml blood withdrawal. Our data suggest that the decreases in Raw following BVL may be attributed to the following: 1) an increased TGV enhancing airway parenchymal tethering forces; and 2) an increase in circulating catecholamines. The apparent beneficial effect of a reduction in Raw in acute hemorrhagic shock is counteracted by an increase in dead space and the appearance of peripheral mechanical heterogeneities due to de-recruitment of the pulmonary vasculature. PMID- 21596917 TI - High sodium chloride intake exacerbates immobilization-induced bone resorption and protein losses. AB - We examined, in immobilization, the effect of a diet high in sodium chloride (NaCl) on bone markers, nitrogen balance, and acid-base status. Eight healthy male test subjects participated in a 14-day head-down-tilt bed rest (HDBR) study. During the bed rest period they received, in a randomized crossover design, a high (7.7 meq Na(+)/kg body wt per day) and a low (0.7 meq Na(+)/kg body wt per day) NaCl diet. As expected, 24-h excretion of urinary calcium was significantly greater in the high-NaCl-intake HDBR phase than in the low-NaCl-intake HDBR phase (P < 0.001). High NaCl intake caused a 43-50% greater excretion of the bone resorption markers COOH- (CTX) and NH(2)- (NTX) terminal telopeptide of type I collagen in HDBR than low NaCl in HDBR (CTX/NTX: P < 0.001). Serum concentrations of the bone formation markers bone-specific alkaline phosphatase (bAP) and NH(2) terminal propeptide of type I procollagen (PINP) were identical in both NaCl intake phases. High NaCl intake led to a more negative nitrogen balance in HDBR (P < 0.001). Changes were accompanied by increased serum chloride concentration (P = 0.008), reduced blood bicarbonate (P = 0.017), and base excess (P = 0.009) whereas net acid excretion was lower during high than during low NaCl intake in immobilization (P < 0.001). High NaCl intake during immobilization exacerbates disuse-induced bone and muscle loss by causing further protein wasting and an increase in bone resorption. Changes in the acid-base status, mainly caused by disturbances in electrolyte metabolism, seem to determine NaCl-induced degradation processes. PMID- 21596918 TI - The relationship between human skeletal muscle pyruvate dehydrogenase phosphatase activity and muscle aerobic capacity. AB - Pyruvate dehydrogenase (PDH) is a mitochondrial enzyme responsible for regulating the conversion of pyruvate to acetyl-CoA for use in the tricarboxylic acid cycle. PDH is regulated through phosphorylation and inactivation by PDH kinase (PDK) and dephosphorylation and activation by PDH phosphatase (PDP). The effect of endurance training on PDK in humans has been investigated; however, to date no study has examined the effect of endurance training on PDP in humans. Therefore, the purpose of this study was to examine differences in PDP activity and PDP1 protein content in human skeletal muscle across a range of muscle aerobic capacities. This association is important as higher PDP activity and protein content will allow for increased activation of PDH, and carbohydrate oxidation. The main findings of this study were that 1) PDP activity (r(2) = 0.399, P = 0.001) and PDP1 protein expression (r(2) = 0.153, P = 0.039) were positively correlated with citrate synthase (CS) activity as a marker for muscle aerobic capacity; 2) E1alpha (r(2) = 0.310, P = 0.002) and PDK2 protein (r(2) = 0.229, P =0.012) are positively correlated with muscle CS activity; and 3) although it is the most abundant isoform, PDP1 protein content only explained ~ 18% of the variance in PDP activity (r(2) = 0.184, P = 0.033). In addition, PDP1 in combination with E1alpha explained ~ 38% of the variance in PDP activity (r(2) = 0.383, P = 0.005), suggesting that there may be alternative regulatory mechanisms of this enzyme other than protein content. These data suggest that with higher muscle aerobic capacity (CS activity) there is a greater capacity for carbohydrate oxidation (E1alpha), in concert with higher potential for PDH activation (PDP activity). PMID- 21596919 TI - Gene profiling of the rat medial collateral ligament during early healing using microarray analysis. AB - Ligament heals in a synchronized and complex series of events. The remodeling process may last months or years. Experimental evidence suggests the damaged ligament does not recover its normal functional properties. Specific mechanisms to prevent scar formation and to regenerate the original mechanical function remain elusive but likely involve regulation of creeping substitution. Creeping substitution creates a larger hypercellular, hypervascular, and disorganized granulation tissue mass that results in an inefficient and nonregenerative wound healing process for the ligament. Control of creeping substitution may limit the extent of this tissue compromise and reduce the time necessary for healing. The objective of this study is to better understand the mechanism behind scar formation by identifying the extracellular matrix factors and other unique genes of interest differentially expressed during rat ligament healing via microarray. For this study, rat medial collateral ligaments were either surgically transected or left intact. Ligaments were collected at day 3 or 7 postinjury and used for microarray, quantitative PCR, and/or immunohistochemistry. Results were compared with the normal intact ligament. We demonstrate that early ligament healing is characterized by the modulation of several inflammatory and extracellular matrix factors during the first week of injury. Specifically, a number of matrix metalloproteinases and collagens are differentially and significantly expressed during early ligament healing. Additionally, we demonstrate the modulation of three novel genes, periostin, collagen-triple helix repeat containing-1, and serine protease 35 in our ligament healing model. Together, control of granulation tissue creeping substitution and subsequent downstream scar formation is likely to involve these factors. PMID- 21596920 TI - Changes of calf muscle-tendon biomechanical properties induced by passive stretching and active-movement training in children with cerebral palsy. AB - Biomechanical properties of calf muscles and Achilles tendon may be altered considerably in children with cerebral palsy (CP), contributing to childhood disability. It is unclear how muscle fascicles and tendon respond to rehabilitation and contribute to improvement of ankle-joint properties. Biomechanical properties of the calf muscle fascicles of both gastrocnemius medialis (GM) and soleus (SOL), including the fascicle length and pennation angle in seven children with CP, were evaluated using ultrasonography combined with biomechanical measurements before and after a 6-wk treatment of passive stretching and active-movement training. The passive force contributions from the GM and SOL muscles were separated using flexed and extended knee positions, and fascicular stiffness was calculated based on the fascicular force-length relation. Biomechanical properties of the Achilles tendon, including resting length, cross-sectional area, and stiffness, were also evaluated. The 6-wk training induced elongation of muscle fascicles (SOL: 8%, P = 0.018; GM: 3%, P = 0.018), reduced pennation angle (SOL: 10%, P = 0.028; GM: 5%, P = 0.028), reduced fascicular stiffness (SOL: 17%, P = 0.128; GM: 21%, P = 0.018), decreased tendon length (6%, P = 0.018), increased Achilles tendon stiffness (32%, P = 0.018), and increased Young's modulus (20%, P = 0.018). In vivo characterizations of calf muscles and Achilles tendon mechanical properties help us better understand treatment-induced changes of calf muscle-tendon and facilitate development of more effective treatments. PMID- 21596921 TI - Influence of juvenile housing conditions on the ventilatory, thermoregulatory, and endocrine responses to hypoxia of adult male rats. AB - "Extreme" housing conditions, such as isolation (single housing) or crowding, are stressful for rats, and their deleterious impact on behavior is well documented. To determine whether more subtle variations in housing can affect animal physiology, the present study tested the hypothesis that the hypoxic ventilatory response (HVR) of adult male rats housed in pairs during the juvenile period (postnatal day 21 to adulthood) does not differ from that of animals housed in triads. Because neonatal stress augments the neuroendocrine responsiveness to stress and HVR, experiments were performed both on "control" (undisturbed) animals and rats subjected to neonatal maternal separation (NMS; 3 h/day, postnatal days 3-12). At adulthood, ventilatory activity was measured by whole body plethysmography under normoxic and hypoxic conditions (inspired fraction of O(2) = 0.12; 20 min). The ventilatory and body temperature responses to hypoxia of rats raised in triads were less than those of rats housed in pairs. For the HVR, however, the attenuation induced by triad housing was more important in NMS rats. Triad housing decreased "basal" plasma corticosterone, but increased estradiol and testosterone levels. Much like the HVR, housing-related decrease in corticosterone level was greater in NMS than control rats. We conclude that modest changes in housing conditions (pairs vs. triads) during the juvenile period can influence basic homeostatic functions, such as temperature, endocrine, and respiratory regulation. Housing conditions can influence (even eliminate) the manifestations of respiratory plasticity subsequent to deleterious neonatal treatments. Differences in neuroendocrine function likely contribute to these effects. PMID- 21596922 TI - Silencing of sodium/hydrogen exchanger in the heart by direct injection of naked siRNA. AB - Cardiac Na(+)/H(+) exchanger (NHE1) hyperactivity is a central factor in cardiac remodeling following hypertension, myocardial infarction, ischemia-reperfusion injury, and heart failure. Treatment of these pathologies by inhibiting NHE1 is challenging because specific drugs that have been beneficial in experimental models were associated with undesired side effects in clinical practice. In the present work, small interference RNA (siRNA) produced in vitro to specifically silence NHE1 (siRNA(NHE1)) was injected once in vivo into the apex of the left ventricular wall of mouse myocardium. After 48 h, left ventricular NHE1 protein expression was reduced in siRNA(NHE1)-injected mice compared with scrambled siRNA by 33.2 +/- 3.4% (n = 5; P < 0.05). Similarly, NHE1 mRNA levels were reduced by 20 +/- 2.0% (n = 4). At 72 h, siRNA(NHE1) spreading was evident from the decrease in NHE1 expression in three portions of the myocardium (apex, medium, base). NHE1 function was assessed based on maximal velocity of intracellular pH (pH(i)) recovery (dpH(i)/dt) after an ammonium prepulse-induced acidic load. Maximal dpH(i)/dt was reduced to 14% in siRNA(NHE1)-isolated left ventricular papillary muscles compared with scrambled siRNA. In conclusion, only one injection of naked siRNA(NHE1) successfully reduced NHE1 expression and activity in the left ventricle. As has been previously suggested, extensive NHE1 expression reduction may indicate myocardial spread of siRNA molecules from the injection site through gap junctions, providing a valid technique not only for further research into NHE1 function, but also for consideration as a potential therapeutic strategy. PMID- 21596924 TI - Na v1.4 and Na v1.5 are modulated differently during muscle immobilization and contractile phenotype conversion. AB - Muscle immobilization leads to modification in its fast/slow contractile phenotype. Since the properties of voltage-gated sodium channels (Na(v)) are different between "fast" and "slow" muscles, we studied the effects of immobilization on the contractile properties and the Na(v) of rat peroneus longus (PL). The distal tendon of PL was cut and fixed to the adjacent bone at neutral muscle length. After 4 or 8 wk of immobilization, the contractile and the Na(v) properties were studied and compared with muscles from control animals (Student's t-test). After 4 wk of immobilization, PL showed a faster phenotype with a rightward shift of the force-frequency curve and a decrease in both the Burke's index of fatigability and the tetanus-to-twitch ratio. These parameters showed opposite changes between 4 and 8 wk of immobilization. The maximal sodium current in 4-wk immobilized fibers was higher compared with that of control fibers (11.5 +/- 1.2 vs. 7.8 +/- 0.8 nA, P = 0.008), with partial recovery to the control values in 8-wk immobilized fibers (8.6 +/- 0.7 nA, P = 0.48). In the presence of tetrodotoxin, the maximal residual sodium current decreased continuously throughout immobilization. Using the Western blot analysis, Na(v)1.4 expression showed a transient increase in 4-wk muscle, whereas Na(v)1.5 expression decreased during immobilization. Our results indicate that a muscle immobilized at optimal functional length with the preservation of neural inputs exhibits a transient fast phenotype conversion. Na(v)1.4 expression and current are related to the contractile phenotype variation. PMID- 21596923 TI - Ca2+ regulatory mechanisms of exercise protection against coronary artery disease in metabolic syndrome and diabetes. AB - Chronic exercise attenuates coronary artery disease (CAD) in humans largely independent of reductions in risk factors; thus major protective mechanisms of exercise are directly within the coronary vasculature. Further, tight control of diabetes, e.g., blood glucose, can be detrimental. Accordingly, knowledge of mechanisms by which exercise attenuates diabetic CAD could catalyze development of molecular therapies. Exercise attenuates CAD (atherosclerosis) and restenosis in miniature swine models, which enable precise control of exercise parameters (intensity, duration, and frequency) and characterization of the metabolic syndrome (MetS) and diabetic milieu. Intracellular Ca(2+) is a pivotal second messenger for coronary smooth muscle (CSM) excitation-contraction and excitation transcription coupling that modulates CSM proliferation, migration, and calcification. CSM of diabetic dyslipidemic Yucatan swine have impaired Ca(2+) extrusion via the plasmalemma Ca(2+) ATPase (PMCA), downregulation of L-type voltage-gated Ca(2+) channels (VGCC), increased Ca(2+) sequestration by the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA), increased nuclear Ca(2+) localization, and greater activation of K channels by Ca(2+) release from the SR. Endurance exercise training prevents Ca(2+) transport changes with virtually no effect on the diabetic milieu (glucose, lipids). In MetS Ossabaw swine transient receptor potential canonical (TRPC) channels are upregulated and exercise training reverses expression and TRPC-mediated Ca(2+) influx with almost no change in the MetS milieu. Overall, exercise effects on Ca(2+) signaling modulate CSM phenotype. Future studies should 1) selectively target key Ca(2+) transporters to determine definitively their causal role in atherosclerosis and 2) combine mechanistic studies with clinical outcomes, e.g., reduction of myocardial infarction. PMID- 21596925 TI - Influence of acetaminophen and ibuprofen on in vivo patellar tendon adaptations to knee extensor resistance exercise in older adults. AB - Millions of older individuals consume acetaminophen or ibuprofen daily and these same individuals are encouraged to participate in resistance training. Several in vitro studies suggest that cyclooxygenase-inhibiting drugs can alter tendon metabolism and may influence adaptations to resistance training. Thirty-six individuals were randomly assigned to a placebo (67 +/- 2 yr old), acetaminophen (64 +/- 1 yr old; 4,000 mg/day), or ibuprofen (64 +/- 1 yr old; 1,200 mg/day) group in a double-blind manner and completed 12 wk of knee extensor resistance training. Before and after training in vivo patellar tendon properties were assessed with MRI [cross-sectional area (CSA) and signal intensity] and ultrasonography of patellar tendon deformation coupled with force measurements to obtain stiffness, modulus, stress, and strain. Mean patellar tendon CSA was unchanged (P > 0.05) with training in the placebo group, and this response was not influenced with ibuprofen consumption. Mean tendon CSA increased with training in the acetaminophen group (3%, P < 0.05), primarily due to increases in the mid (7%, P < 0.05) and distal (8%, P < 0.05) tendon regions. Correspondingly, tendon signal intensity increased with training in the acetaminophen group at the mid (13%, P < 0.05) and distal (15%, P = 0.07) regions. When normalized to pretraining force levels, patellar tendon deformation and strain decreased 11% (P < 0.05) and stiffness, modulus, and stress were unchanged (P > 0.05) with training in the placebo group. These responses were generally uninfluenced by ibuprofen consumption. In the acetaminophen group, tendon deformation and strain increased 20% (P < 0.05) and stiffness (-17%, P < 0.05) and modulus (-20%, P < 0.05) decreased with training. These data suggest that 3 mo of knee extensor resistance training in older adults induces modest changes in the mechanical properties of the patellar tendon. Over-the-counter doses of acetaminophen, but not ibuprofen, have a strong influence on tendon mechanical and material property adaptations to resistance training. These findings add to a growing body of evidence that acetaminophen has profound effects on peripheral tissues in humans. PMID- 21596926 TI - Thrombosis, physical activity, and acute coronary syndromes. AB - Acute coronary syndromes (ACS) are common, life-threatening cardiac disorders that typically are triggered by rupture or erosion of an atherosclerotic plaque. Platelet deposition and activation of the blood coagulation cascade in response to plaque disruption lead to the formation of a platelet-fibrin thrombus, which can grow rapidly, obstruct coronary blood flow, and cause myocardial ischemia and/or infarction. Several clinical studies have examined the relationship between physical activity and ACS, and numerous preclinical and clinical studies have examined specific effects of sustained physical training and acute physical activity on atherosclerotic plaque rupture, platelet function, and formation and clearance of intravascular fibrin. This article reviews the available literature regarding the role of physical activity in determining the incidence of atherosclerotic plaque rupture and the pace and extent of thrombus formation after plaque rupture. PMID- 21596927 TI - Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitors. AB - G protein-coupled receptors (GPCRs) are key regulators of cell physiology and control processes ranging from glucose homeostasis to contractility of the heart. A major mechanism for the desensitization of activated GPCRs is their phosphorylation by GPCR kinases (GRKs). Overexpression of GRK2 is strongly linked to heart failure, and GRK2 has long been considered a pharmaceutical target for the treatment of cardiovascular disease. Several lead compounds developed by Takeda Pharmaceuticals show high selectivity for GRK2 and therapeutic potential for the treatment of heart failure. To understand how these drugs achieve their selectivity, we determined crystal structures of the bovine GRK2-Gbetagamma complex in the presence of two of these inhibitors. Comparison with the apoGRK2 Gbetagamma structure demonstrates that the compounds bind in the kinase active site in a manner similar to that of the AGC kinase inhibitor balanol. Both balanol and the Takeda compounds induce a slight closure of the kinase domain, the degree of which correlates with the potencies of the inhibitors. Based on our crystal structures and homology modeling, we identified five amino acids surrounding the inhibitor binding site that we hypothesized could contribute to inhibitor selectivity. However, our results indicate that these residues are not major determinants of selectivity among GRK subfamilies. Rather, selectivity is achieved by the stabilization of a unique inactive conformation of the GRK2 kinase domain. PMID- 21596928 TI - Regulation of human vascular protease-activated receptor-3 through mRNA stabilization and the transcription factor nuclear factor of activated T cells (NFAT). AB - Thrombin promotes vascular smooth muscle cell (SMC) proliferation and inflammation via protease-activated receptor (PAR)-1. A further thrombin receptor, PAR-3, acts as a PAR-1 cofactor in some cell-types. Unlike PAR-1, PAR-3 is dynamically regulated at the mRNA level in thrombin-stimulated SMC. This study investigated the mechanisms controlling PAR-3 expression. In human vascular SMC, PAR-3 siRNA attenuated thrombin-stimulated interleukin-6 expression and extracellular signal-regulated kinases 1/2 phosphorylation, indicating PAR-3 contributes to net thrombin responses in these cells. Thrombin slowed the decay of PAR-3 but not PAR-1 mRNA in the presence of actinomycin D and induced cytosolic shuttling and PAR-3 mRNA binding of the mRNA-stabilizing protein human antigen R (HuR). HuR siRNA prevented thrombin-induced PAR-3 expression. By contrast, forskolin inhibited HuR shuttling and destabilized PAR-3 mRNA, thus reducing PAR-3 mRNA and protein expression. Other cAMP-elevating agents, including the prostacyclin-mimetic iloprost, also down-regulated PAR-3, accompanied by decreased HuR/PAR-3 mRNA binding. Iloprost-induced suppression of PAR-3 was reversed with a myristoylated inhibitor of protein kinase A and mimicked by phorbol ester, an inducer of cyclooxygenase-2. In separate studies, iloprost attenuated PAR-3 promoter activity and prevented binding of nuclear factor of activated T cells (NFAT2) to the human PAR-3 promoter in a chromatin immunoprecipitation assay. Accordingly, PAR-3 expression was suppressed by the NFAT inhibitor cyclosporine A or NFAT2 siRNA. Thus human PAR-3, unlike PAR-1, is regulated post-transcriptionally via the mRNA-stabilizing factor HuR, whereas transcriptional control involves NFAT2. Through modulation of PAR-3 expression, prostacyclin and NFAT inhibitors may limit proliferative and inflammatory responses to thrombin after vessel injury. PMID- 21596929 TI - Plasma lecithin:cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk. AB - Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for cholesterol esterification in plasma. LCAT is a major factor in HDL remodeling and metabolism, and it has long been believed to play a critical role in macrophage reverse cholesterol transport (RCT). The effect of LCAT on human atherogenesis is still controversial. In the present study, the plasma LCAT concentration was measured in all subjects (n = 540) not on drug treatment at the time of enrollment in the multicenter, longitudinal, observational IMPROVE study. Mean and maximum intima-media thickness (IMT) of the whole carotid tree was measured by B-mode ultrasonography in all subjects. In the entire cohort, LCAT quartiles were not associated with carotid mean and maximum IMT (P for trend 0.95 and 0.18, respectively), also after adjustment for age, gender, HDL-cholesterol (HDL-C), and triglycerides. No association between carotid IMT and LCAT quartiles was observed in men (P=0.30 and P=0.99 for mean and maximum IMT, respectively), whereas carotid IMT increased with LCAT quartiles in women (P for trend 0.14 and 0.019 for mean and maximum IMT, respectively). The present findings support the concept that LCAT is not required for an efficient reverse cholesterol transport and that a low plasma LCAT concentration and activity is not associated with increased atherosclerosis. PMID- 21596935 TI - Between crossfire...: graduate degree level, policy on higher education and training in health promotion. PMID- 21596930 TI - Serum angiopoietin-like 4 protein levels and expression in adipose tissue are inversely correlated with obesity in monozygotic twins. AB - Animal studies have suggested that angiopoietin-like 4 (Angptl4) regulates adiposity through central and peripheral mechanisms. The aim of this study was to investigate whether serum concentration and adipose tissue expression of Angptl4 are associated with obesity-related parameters in humans. Altogether, 75 dizygotic (DZ) and 46 monozygotic (MZ) twin pairs were studied, from the FinnTwin12 and FinnTwin16 cohorts. Among the MZ pairs, 21 were discordant for body mass index (BMI) (intra-pair BMI-difference >2.5 kg/m2, age 23-33 years). Serum Angptl4 (s-Angptl4) levels were measured by ELISA, and adipose tissue gene expression was analyzed by genome-wide transcript profiling. In MZ twin pairs discordant for BMI, s-Angptl4 and adipose tissue ANGPTL4 mRNA (at-ANGPTL4) levels were significantly decreased (P = 0.04 and P = 0.03, respectively) in obese twins as compared with their nonobese cotwins. In all twins, intra-pair differences in s-Angptl4 levels were inversely correlated with intra-pair differences in BMI (r = -0.27, P = 0.003). In individual MZ twins, at-ANGPTL4 expression was inversely correlated with BMI (r = -0.44, P = 0.001) and positively correlated with at-LIPE (r = 0.24, P = 0.01) and at-ABHD5 (r = 0.41, P = 0.005) expression. Our results demonstrated that variation in Angptl4 concentration was only modestly accounted for by genetic factors and suggest a role for Angptl4 in acquired obesity in humans. PMID- 21596936 TI - The use of conversation analysis to study social accessibility of an online support group on eating disorders. AB - We conducted a conversation analysis of 21 threads initiated by newcomers of an online support group (OSG) on eating disorders, to examine the discursive process of entering such a group. The analysis revealed three important issues. First, many newcomers articulate that the step to join the group is extremely difficult. Second, a presentation of the self in terms of a diagnosis works as a legitimization for joining the forum. The data suggest that participants who do not fulfil the conditions for such a legitimization do not join the forum. Third, the option of acquiring a serious symptom as a solution to the legitimization problem is offered by one of the regular members. Hence, the newcomers' discourse reveals issues relevant to the accessibility for undiagnosed sufferers. We discuss these findings theoretically as a phenomenon of self-presentation in relation to community norms. The analysis generates the hypothesis that newcomers are confronted with implicit norms regarding membership legitimacy that they should obey in their self-presentation, although they may not be ready yet to actually do so. OSGs should find strategies to facilitate various possibilities for newcomers to present themselves to the group while becoming a member. PMID- 21596937 TI - Research capacity building: a US-South African partnership. AB - Research capacity building engenders assets that allow communities (and, in this case, student fellows) to respond adequately to health issues and problems that are contextual, cultural and historical in nature. In this paper, we present a US South African partnership that led to research training for 30 postgraduate students at two South African universities. We begin by exploring the nature of research capacity building in a partnership research project designed to promote HIV and AIDS-related stigma reduction. We examine methodological issues and their relevance to training of postgraduate students in South Africa. We conclude with recommendations for a successful model of partnership for building capacity of health researchers in Africa with the goal of developing research that informs policies and helps to bridge the health inequity gap globally. PMID- 21596938 TI - Developing a scale to measure synergy in health promotion partnerships. AB - Synergy is the degree to which a partnership combines the assets of all the partners in the search for better solutions and is generally regarded as the product of a partnership including vertical integration, shared know-how and shared resources. There has been very little research on the determinants and measurement of synergy in health promotion partnerships. This study was designed to describe how synergy is conceptualized in health promotion partnerships and to develop a synergy measurement tool. Five focus groups were organized with 36 health promotion partners in order to explore how synergy is conceptualized in their partnerships. Participants represented health, community, education, arts, sports and youth sectors. Focus groups were recorded and transcribed verbatim. A content analysis was carried out on the transcripts using counting and data reduction techniques. An item pool was generated from these findings and an eight item five-point scale was developed called the Jones synergy scale. This scale was incorporated into an overall questionnaire on partnership functioning which was posted to 469 partners in 40 health promotion partnerships. A response rate of 72% was achieved for the postal survey (n = 337). The Jones synergy scale was subjected to reliability and validity tests. Cronbach's alpha was 0.91. Corrected item-total correlations ranged from 0.6 to 0.7 with a Cronbach's alpha if item deleted of 0.9 for all items. Principal components analysis (PCA) was the chosen factor analysis method. One component was extracted explaining 62% of the variance. Coefficients ranged from 0.83 to 0.70 with an initial eigenvalue of 4.94. The scale was subjected to item-convergent, item-discriminant and concurrent validity tests. All items correlated more strongly with their own scale than with any other scales used in the questionnaire. The Jones synergy scale was highly correlated (0.73, P < 0.01) with an existing synergy scale. PMID- 21596941 TI - Comments to Emaus et al. ''Does a variation in self-reported physical activity reflect variation in objectively measured physical activity, resting heart rate, and physical fitness? Results from the Tromso study''. PMID- 21596946 TI - Abnormal chronotropic reserve and heart rate recovery in patients with SLE: a case-control study. AB - Abnormal heart-rate (HR) response during or after a graded exercise test has been recognized as a strong and an independent predictor of all-cause mortality in healthy and diseased subjects. The purpose of the present study was to evaluate the HR response during exercise in women with systemic lupus erythematosus (SLE). In this case-control study, 22 women with SLE (age 29.5 +/- 1.1 years) were compared with 20 gender-, BMI-, and age-matched healthy subjects (age 26.5 +/- 1.4 years). A treadmill cardiorespiratory test was performed and HR response during exercise was evaluated by the chronotropic reserve (CR). HR recovery (DeltaHRR) was defined as the difference between HR at peak exercise and at both first (DeltaHRR1) and second (DeltaHRR2) minutes after exercising. SLE patients presented lower peak VO(2) when compared with healthy subjects (27.6 +/- 0.9 vs. 36.7 +/- 1.1 ml/kg/min, p = 0.001, respectively). Additionally, SLE patients demonstrated lower CR (71.8 +/- 2.4 vs. 98.2 +/- 2.6%, p = 0.001), DeltaHRR1 (22.1 +/- 2.5 vs. 32.4 +/- 2.2%, p = 0.004) and DeltaHRR2 (39.1 +/- 2.9 vs. 50.8 +/- 2.5%, p = 0.001) than their healthy peers. In conclusion, SLE patients presented abnormal HR response to exercise, characterized by chronotropic incompetence and delayed DeltaHRR. PMID- 21596947 TI - The athlete biological passport. AB - BACKGROUND: In elite sports, the growing availability of doping substances identical to those naturally produced by the human body seriously limits the ability of drug-testing regimes to ensure fairness and protection of health. CONTENT: The Athlete Biological Passport (ABP), the new paradigm in testing based on the personalized monitoring of biomarkers of doping, offers the enormous advantage of being independent of this endless pharmaceutical race. Doping triggers physiological changes that provide physiological enhancements. In the same way that disease-related biomarkers are invaluable tools that assist physicians in the diagnosis of pathology, specifically selected biomarkers can be used to detect doping. SUMMARY: The ABP is a new testing paradigm with immense potential value in the current climate of rapid advancement in biomarker discovery. In addition to its original aim of providing proof of a doping offense, the ABP can also serve as a platform for a Rule of Sport, with the presentation before competition of the ABP to objectively demonstrate that the athlete will participate in a healthy physiological condition that is unaltered by performance-enhancing drugs. Finally, the decision-support system used today for the biological monitoring of world top-level athletes can also be advantageously transferred to other areas of clinical practice to reach the goal of personalized medicine. PMID- 21596948 TI - Development of cellulosic secondary walls in flax fibers requires beta galactosidase. AB - Bast (phloem) fibers, tension wood fibers, and other cells with gelatinous-type secondary walls are rich in crystalline cellulose. In developing bast fibers of flax (Linum usitatissimum), a galactan-enriched matrix (Gn-layer) is gradually modified into a mature cellulosic gelatinous-layer (G-layer), which ultimately comprises most of the secondary cell wall. Previous studies have correlated this maturation process with expression of a putative beta-galactosidase. Here, we demonstrate that beta-galactosidase activity is in fact necessary for the dynamic remodeling of polysaccharides that occurs during normal secondary wall development in flax fibers. We found that developing stems of transgenic (LuBGAL RNAi) flax with reduced beta-galactosidase activity had lower concentrations of free Gal and had significant reductions in the thickness of mature cellulosic G layers compared with controls. Conversely, Gn-layers, labeled intensively by the galactan-specific LM5 antibody, were greatly expanded in LuBGAL-RNAi transgenic plants. Gross morphology and stem anatomy, including the thickness of bast fiber walls, were otherwise unaffected by silencing of beta-galactosidase transcripts. These results demonstrate a specific requirement for beta-galactosidase in hydrolysis of galactans during formation of cellulosic G-layers. Transgenic lines with reduced beta-galactosidase activity also had biochemical and spectroscopic properties consistent with a reduction in cellulose crystallinity. We further demonstrated that the tensile strength of normal flax stems is dependent on beta galactosidase-mediated development of the phloem fiber G-layer. Thus, the mechanical strength that typifies flax stems is dependent on a thick, cellulosic G-layer, which itself depends on beta-galactosidase activity within the precursor Gn-layer. These observations demonstrate a novel role for matrix polysaccharides in cellulose deposition; the relevance of these observations to the development of cell walls in other species is also discussed. PMID- 21596949 TI - Leaf rolling controlled by the homeodomain leucine zipper class IV gene Roc5 in rice. AB - Leaf rolling is considered an important agronomic trait in rice (Oryza sativa) breeding. To understand the molecular mechanism controlling leaf rolling, we screened a rice T-DNA insertion population and isolated the outcurved leaf1 (oul1) mutant showing abaxial leaf rolling. The phenotypes were caused by knockout of Rice outermost cell-specific gene5 (Roc5), an ortholog of the Arabidopsis (Arabidopsis thaliana) homeodomain leucine zipper class IV gene GLABRA2. Interestingly, overexpression of Roc5 led to adaxially rolled leaves, whereas cosuppression of Roc5 resulted in abaxial leaf rolling. Bulliform cell number and size increased in oul1 and Roc5 cosuppression plants but were reduced in Roc5-overexpressing lines. The data indicate that Roc5 negatively regulates bulliform cell fate and development. Gene expression profiling, quantitative polymerase chain reaction, and RNA interference (RNAi) analyses revealed that Protodermal Factor Like (PFL) was probably down-regulated in oul1. The mRNA level of PFL was increased in Roc5-overexpressing lines, and PFL-RNAi transgenic plants exhibit reversely rolling leaves by reason of increases of bulliform cell number and size, indicating that Roc5 may have a conserved function. These are, to our knowledge, the first functional data for a gene encoding a homeodomain leucine zipper class IV transcriptional factor in rice that modulates leaf rolling. PMID- 21596950 TI - Displacement above the hypocenter of the 2011 Tohoku-Oki earthquake. AB - The moment magnitude (M(w)) = 9.0 2011 Tohoku-Oki mega-thrust earthquake occurred off the coast of northeastern Japan. Combining Global Positioning System (GPS) and acoustic data, we detected very large sea-floor movements associated with this event directly above the focal region. An area with more than 20 meters of horizontal displacement, that is, four times larger than those detected on land, stretches several tens of kilometers long along the trench; the largest amount reaches about 24 meters toward east-southeast just above the hypocenter. Furthermore, nearly 3 meters of vertical uplift occurred, contrary to observed terrestrial subsidence. PMID- 21596951 TI - Endotoxin-induced structural transformations in liquid crystalline droplets. AB - The ordering of liquid crystals (LCs) is known to be influenced by surfaces and contaminants. Here, we report that picogram per milliliter concentrations of endotoxin in water trigger ordering transitions in micrometer-size LC droplets. The ordering transitions, which occur at surface concentrations of endotoxin that are less than 10(-5) Langmuir, are not due to adsorbate-induced changes in the interfacial energy of the LC. The sensitivity of the LC to endotoxin was measured to change by six orders of magnitude with the geometry of the LC (droplet versus slab), supporting the hypothesis that interactions of endotoxin with topological defects in the LC mediate the response of the droplets. The LC ordering transitions depend strongly on glycophospholipid structure and provide new designs for responsive soft matter. PMID- 21596952 TI - Widespread RNA and DNA sequence differences in the human transcriptome. AB - The transmission of information from DNA to RNA is a critical process. We compared RNA sequences from human B cells of 27 individuals to the corresponding DNA sequences from the same individuals and uncovered more than 10,000 exonic sites where the RNA sequences do not match that of the DNA. All 12 possible categories of discordances were observed. These differences were nonrandom as many sites were found in multiple individuals and in different cell types, including primary skin cells and brain tissues. Using mass spectrometry, we detected peptides that are translated from the discordant RNA sequences and thus do not correspond exactly to the DNA sequences. These widespread RNA-DNA differences in the human transcriptome provide a yet unexplored aspect of genome variation. PMID- 21596953 TI - The 2011 magnitude 9.0 Tohoku-Oki earthquake: mosaicking the megathrust from seconds to centuries. AB - Geophysical observations from the 2011 moment magnitude (M(w)) 9.0 Tohoku-Oki, Japan earthquake allow exploration of a rare large event along a subduction megathrust. Models for this event indicate that the distribution of coseismic fault slip exceeded 50 meters in places. Sources of high-frequency seismic waves delineate the edges of the deepest portions of coseismic slip and do not simply correlate with the locations of peak slip. Relative to the M(w) 8.8 2010 Maule, Chile earthquake, the Tohoku-Oki earthquake was deficient in high-frequency seismic radiation--a difference that we attribute to its relatively shallow depth. Estimates of total fault slip and surface secular strain accumulation on millennial time scales suggest the need to consider the potential for a future large earthquake just south of this event. PMID- 21596955 TI - Thermal structure and dynamics of Saturn's northern springtime disturbance. AB - Saturn's slow seasonal evolution was disrupted in 2010-2011 by the eruption of a bright storm in its northern spring hemisphere. Thermal infrared spectroscopy showed that within a month, the resulting planetary-scale disturbance had generated intense perturbations of atmospheric temperatures, winds, and composition between 20 degrees and 50 degrees N over an entire hemisphere (140,000 kilometers). The tropospheric storm cell produced effects that penetrated hundreds of kilometers into Saturn's stratosphere (to the 1-millibar region). Stratospheric subsidence at the edges of the disturbance produced "beacons" of infrared emission and longitudinal temperature contrasts of 16 kelvin. The disturbance substantially altered atmospheric circulation, transporting material vertically over great distances, modifying stratospheric zonal jets, exciting wave activity and turbulence, and generating a new cold anticyclonic oval in the center of the disturbance at 41 degrees N. PMID- 21596954 TI - Predicting a human gut microbiota's response to diet in gnotobiotic mice. AB - The interrelationships between our diets and the structure and operations of our gut microbial communities are poorly understood. A model community of 10 sequenced human gut bacteria was introduced into gnotobiotic mice, and changes in species abundance and microbial gene expression were measured in response to randomized perturbations of four defined ingredients in the host diet. From the responses, we developed a statistical model that predicted over 60% of the variation in species abundance evoked by diet perturbations, and we were able to identify which factors in the diet best explained changes seen for each community member. The approach is generally applicable, as shown by a follow-up study involving diets containing various mixtures of pureed human baby foods. PMID- 21596957 TI - Shallow dynamic overshoot and energetic deep rupture in the 2011 Mw 9.0 Tohoku Oki earthquake. AB - Strong spatial variation of rupture characteristics in the moment magnitude (M(w)) 9.0 Tohoku-Oki megathrust earthquake controlled both the strength of shaking and the size of the tsunami that followed. Finite-source imaging reveals that the rupture consisted of a small initial phase, deep rupture for up to 40 seconds, extensive shallow rupture at 60 to 70 seconds, and continuing deep rupture lasting more than 100 seconds. A combination of a shallow dipping fault and a compliant hanging wall may have enabled large shallow slip near the trench. Normal faulting aftershocks in the area of high slip suggest dynamic overshoot on the fault. Despite prodigious total slip, shallower parts of the rupture weakly radiated at high frequencies, whereas deeper parts of the rupture radiated strongly at high frequencies. PMID- 21596956 TI - The visual impact of gossip. AB - Gossip is a form of affective information about who is friend and who is foe. We show that gossip does not influence only how a face is evaluated--it affects whether a face is seen in the first place. In two experiments, neutral faces were paired with negative, positive, or neutral gossip and were then presented alone in a binocular rivalry paradigm (faces were presented to one eye, houses to the other). In both studies, faces previously paired with negative (but not positive or neutral) gossip dominated longer in visual consciousness. These findings demonstrate that gossip, as a potent form of social affective learning, can influence vision in a completely top-down manner, independent of the basic structural features of a face. PMID- 21596958 TI - Use of the Functional Independence Measure in people for whom weaning from mechanical ventilation is difficult. AB - BACKGROUND: The Functional Independence Measure (FIM) has been proposed as an outcome measure for people receiving pulmonary rehabilitation after an acute exacerbation of chronic obstructive pulmonary disease. Objective The purpose of this study was to examine the clinical utility of the FIM after a weaning program in people for whom weaning from mechanical ventilation is difficult. Design This was a retrospective observational study. METHODS: People who had had a tracheostomy, for whom weaning from mechanical ventilation was difficult, and who were participating in a weaning program (WP group) were retrospectively evaluated. People receiving pulmonary rehabilitation after an acute exacerbation of chronic obstructive pulmonary disease (PR group) were included as a validated control group. The scores on the FIM questionnaire and the Medical Research Council dyspnea scores were assessed at admission to and at discharge from the programs. RESULTS: Admission and discharge data from 56 participants in the WP group and 63 participants in the PR group were compared. At admission, according to the FIM, 5 participants in the WP group (7.7%) were defined as functionally independent, 34 (52.3%) were defined as partially dependent, and 26 (40.0%) were defined as completely dependent. At discharge, the mean FIM global score was significantly improved, from 47.9 (SD=22.8) to 62.6 (SD=30.0). For participants in the WP group, changes in the FIM score were significantly inversely related to the admission Acute Physiology and Chronic Health Evaluation (R=-.286) and Simplified Acute Physiology (R=-.293) scores and directly related to the admission FIM score (R=.355). At admission, 46 participants in the PR group (67.7%) were defined as functionally independent, 19 (27.9%) were defined as partially dependent, and 3 (4.4%) were defined as completely dependent. After pulmonary rehabilitation, the mean FIM global score was significantly improved, from 97.4 (SD=27.5) to 102.5 (SD=25.7). Limitations The study was not randomized and involved a relatively small sample size. CONCLUSIONS: The FIM can be used as a functional status outcome measure in people for whom weaning from mechanical ventilation is difficult. PMID- 21596959 TI - The pelvic girdle questionnaire: a condition-specific instrument for assessing activity limitations and symptoms in people with pelvic girdle pain. AB - BACKGROUND: No appropriate measures have been specifically developed for pelvic girdle pain (PGP). There is a need for suitable outcome measures that are reliable and valid for people with PGP for use in research and clinical practice. OBJECTIVE: The objective of this study was to develop a condition-specific measure, the Pelvic Girdle Questionnaire (PGQ), for use during pregnancy and postpartum. DESIGN: This was a methodology study. METHODS: Items were developed from a literature review and information from a focus group of people who consulted physical therapists for PGP. Face validity and content validity were assessed by classifying the items according to the World Health Organization's International Classification of Functioning, Disability and Health. After a pilot study, the PGQ was administered to participants with clinically verified PGP by means of a postal questionnaire in 2 surveys. The first survey included 94 participants (52 pregnant), and the second survey included 87 participants (43 pregnant). Rasch analysis was used for item reduction, and the PGQ was assessed for unidimensionality, item fit, redundancy, and differential item functioning. Test-retest reliability was assessed with a random sample of 42 participants. RESULTS: The analysis resulted in a questionnaire consisting of 20 activity items and 5 symptom items on a 4-point response scale. The items in both subscales showed a good fit to the Rasch model, with acceptable internal consistency, satisfactory fit residuals, and no disordered threshold. Test-retest reliability showed high intraclass correlation coefficient estimates: .93 (95% confidence interval=0.86-0.96) for the PGQ activity subscale and .91 (95% confidence interval=0.84-0.95) for the PGQ symptom subscale. Limitations The PGQ should be compared with low back pain questionnaires as part of a concurrent evaluation of measurement properties, including validity and responsiveness to change. CONCLUSIONS: The PGQ is the first condition-specific measure developed for people with PGP. The PGQ had acceptably high reliability and validity in people with PGP both during pregnancy and postpartum, it is simple to administer, and it is feasible for use in clinical practice. PMID- 21596960 TI - Construct validation of a knee-specific functional status measure: a comparative study between the United States and Israel. AB - BACKGROUND: Comparative effectiveness research (CER) requires valid outcome measures that discriminate patients by risk factors in similar ways across settings. Standardized functional status (FS) measures in physical therapy are used routinely in multiple countries, creating the potential for CER among countries. OBJECTIVE: The purpose of this study was to assess known-groups construct validity of a knee-specific FS measure within and between 2 countries for patients receiving outpatient physical therapy due to knee impairments. DESIGN: This was a longitudinal, observational cohort study. METHODS: The participants were 4,972 and 2,964 adult (age >=18 years) patients with knee impairments from Israel and the United States, respectively. Differences in patient characteristics between the 2 countries were assessed using chi-square statistics and 2-sample t tests, as appropriate. Known-groups validity within and between the countries was assessed using 2-way analysis of covariance predicting FS at discharge, with sex, age, symptom acuity, surgical and exercise history, intake medication use, and country as risk-adjustment factors. Intake FS was the covariate. To compare how FS discriminated patient groups between countries, each factor was tested separately with models including an interaction term between the factor and country. RESULTS: Patients were different between countries but had similar discharge FS trends, including: higher outcomes in patients who were male, were younger, had acute conditions, had one surgical procedure related to their knee impairment, were more physically active, and did not use related medication at admission. Interactions were not significant for sex, symptom acuity, and exercise history but were significant for age, surgical history, and medication use. Limitations Although strict patient selection criteria were set, some patient selection bias still might have existed. CONCLUSIONS: The results demonstrated the knee FS measures would be valid for use in CER between Hebrew speaking patients (Israel) and English-speaking patients (United States). PMID- 21596961 TI - Measuring student development. PMID- 21596965 TI - Space science. Chinese Academy takes space under its wing. PMID- 21596966 TI - Ecology. Pioneering center ponders future as NSF pulls out. PMID- 21596967 TI - Cancer research. Spain's 'lonely fighter' steps down amid a highly public spat. PMID- 21596968 TI - Tohoku-Oki earthquake. Fukushima revives the low-dose debate. PMID- 21596969 TI - Tohoku-Oki earthquake. Schoolyard radiation policy brings a backlash. PMID- 21596970 TI - Tohoku-Oki earthquake. Crippled reactors to get cooled and wrapped. PMID- 21596971 TI - Seismology. New work reinforces megaquake's harsh lessons in geoscience. PMID- 21596972 TI - Seismology. Seismic crystal ball proving mostly cloudy around the world. PMID- 21596973 TI - History of science. The alchemical revolution. PMID- 21596974 TI - Primary prevention of cancer. PMID- 21596975 TI - Unexamined bodies of evidence. PMID- 21596976 TI - Rights for sentient animals. PMID- 21596977 TI - Comment on "Positive selection of tyrosine loss in metazoan evolution". AB - Tan et al. (Reports, 25 September 2009, p. 1686) argued that loss of tyrosine residues from proteins in metazoans was driven by positive selection to remove potentially deleterious phosphorylation sites. We challenge this hypothesis, providing evidence that the high guanine-cytosine (GC) content of metazoan genomes was the primary driver in the loss of tyrosine residues. PMID- 21596978 TI - Science education. Inquiry-based writing in the laboratory course. PMID- 21596979 TI - Physics. High-power fiber lasers. PMID- 21596980 TI - Physics. Shedding light on oxide interfaces. PMID- 21596982 TI - Atmospheric science. Subtropical rainfall and the Antarctic ozone hole. PMID- 21596981 TI - Cell biology. The TASCC of secretion. PMID- 21596983 TI - Paleontology. Evolving large and complex brains. PMID- 21596984 TI - Retrospective. Lewis R. Binford (1931-2011). PMID- 21596986 TI - Dimensionality control of electronic phase transitions in nickel-oxide superlattices. AB - The competition between collective quantum phases in materials with strongly correlated electrons depends sensitively on the dimensionality of the electron system, which is difficult to control by standard solid-state chemistry. We have fabricated superlattices of the paramagnetic metal lanthanum nickelate (LaNiO(3)) and the wide-gap insulator lanthanum aluminate (LaAlO(3)) with atomically precise layer sequences. We used optical ellipsometry and low-energy muon spin rotation to show that superlattices with LaNiO(3) as thin as two unit cells undergo a sequence of collective metal-insulator and antiferromagnetic transitions as a function of decreasing temperature, whereas samples with thicker LaNiO(3) layers remain metallic and paramagnetic at all temperatures. Metal-oxide superlattices thus allow control of the dimensionality and collective phase behavior of correlated-electron systems. PMID- 21596985 TI - A diiron protein autogenerates a valine-phenylalanine cross-link. AB - All known internal covalent cross-links in proteins involve functionalized groups having oxygen, nitrogen, or sulfur atoms present to facilitate their formation. Here, we report a carbon-carbon cross-link between two unfunctionalized side chains. This valine-phenyalanine cross-link, produced in an oxygen-dependent reaction, is generated by its own carboxylate-bridged diiron center and serves to stabilize the metallocenter. This finding opens the door to new types of posttranslational modifications, and it demonstrates new catalytic potential of diiron centers. PMID- 21596987 TI - Competition of superconducting phenomena and Kondo screening at the nanoscale. AB - Magnetic and superconducting interactions couple electrons together to form complex states of matter. We show that, at the atomic scale, both types of interactions can coexist and compete to influence the ground state of a localized magnetic moment. Local spectroscopy at 4.5 kelvin shows that the spin-1 system formed by manganese-phthalocyanine (MnPc) adsorbed on Pb(111) can lie in two different magnetic ground states. These are determined by the balance between Kondo screening and superconducting pair-breaking interactions. Both ground states alternate at nanometer length scales to form a Moire-like superstructure. The quantum phase transition connecting the two (singlet and doublet) ground states is thus tuned by small changes in the molecule-lead interaction. PMID- 21596988 TI - Fossil evidence on origin of the mammalian brain. AB - Many hypotheses have been postulated regarding the early evolution of the mammalian brain. Here, x-ray tomography of the Early Jurassic mammaliaforms Morganucodon and Hadrocodium sheds light on this history. We found that relative brain size expanded to mammalian levels, with enlarged olfactory bulbs, neocortex, olfactory (pyriform) cortex, and cerebellum, in two evolutionary pulses. The initial pulse was probably driven by increased resolution in olfaction and improvements in tactile sensitivity (from body hair) and neuromuscular coordination. A second pulse of olfactory enhancement then enlarged the brain to mammalian levels. The origin of crown Mammalia saw a third pulse of olfactory enhancement, with ossified ethmoid turbinals supporting an expansive olfactory epithelium in the nasal cavity, allowing full expression of a huge odorant receptor genome. PMID- 21596989 TI - Chromatin "prepattern" and histone modifiers in a fate choice for liver and pancreas. AB - Transcriptionally silent genes can be marked by histone modifications and regulatory proteins that indicate the genes' potential to be activated. Such marks have been identified in pluripotent cells, but it is unknown how such marks occur in descendant, multipotent embryonic cells that have restricted cell fate choices. We isolated mouse embryonic endoderm cells and assessed histone modifications at regulatory elements of silent genes that are activated upon liver or pancreas fate choices. We found that the liver and pancreas elements have distinct chromatin patterns. Furthermore, the histone acetyltransferase P300, recruited via bone morphogenetic protein signaling, and the histone methyltransferase Ezh2 have modulatory roles in the fate choice. These studies reveal a functional "prepattern" of chromatin states within multipotent progenitors and potential targets to modulate cell fate induction. PMID- 21596990 TI - Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. AB - Coevolution of mammals and their gut microbiota has profoundly affected their radiation into myriad habitats. We used shotgun sequencing of microbial community DNA and targeted sequencing of bacterial 16S ribosomal RNA genes to gain an understanding of how microbial communities adapt to extremes of diet. We sampled fecal DNA from 33 mammalian species and 18 humans who kept detailed diet records, and we found that the adaptation of the microbiota to diet is similar across different mammalian lineages. Functional repertoires of microbiome genes, such as those encoding carbohydrate-active enzymes and proteases, can be predicted from bacterial species assemblages. These results illustrate the value of characterizing vertebrate gut microbiomes to understand host evolutionary histories at a supraorganismal level. PMID- 21596991 TI - A packing mechanism for nucleosome organization reconstituted across a eukaryotic genome. AB - Near the 5' end of most eukaryotic genes, nucleosomes form highly regular arrays that begin at canonical distances from the transcriptional start site. Determinants of this and other aspects of genomic nucleosome organization have been ascribed to statistical positioning, intrinsically DNA-encoded positioning, or some aspect of transcription initiation. Here, we provide evidence for a different explanation. Biochemical reconstitution of proper nucleosome positioning, spacing, and occupancy levels was achieved across the 5' ends of most yeast genes by adenosine triphosphate-dependent trans-acting factors. These transcription-independent activities override DNA-intrinsic positioning and maintain uniform spacing at the 5' ends of genes even at low nucleosome densities. Thus, an active, nonstatistical nucleosome packing mechanism creates chromatin organizing centers at the 5' ends of genes where important regulatory elements reside. PMID- 21596993 TI - Knockout of the neurokinin-1 receptor reduces cholangiocyte proliferation in bile duct-ligated mice. AB - In bile duct-ligated (BDL) rats, cholangiocyte proliferation is regulated by neuroendocrine factors such as alpha-calcitonin gene-related peptide (alpha CGRP). There is no evidence that the sensory neuropeptide substance P (SP) regulates cholangiocyte hyperplasia. Wild-type (WT, (+/+)) and NK-1 receptor (NK 1R) knockout (NK-1R(-/-)) mice underwent sham or BDL for 1 wk. Then we evaluated 1) NK-1R expression, transaminases, and bilirubin serum levels; 2) necrosis, hepatocyte apoptosis and steatosis, and the number of cholangiocytes positive by CK-19 and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling in liver sections; 3) mRNA expression for collagen 1alpha and alpha-smooth muscle (alpha-SMA) actin in total liver samples; and 4) PCNA expression and PKA phosphorylation in cholangiocytes. In cholangiocyte lines, we determined the effects of SP on cAMP and D-myo-inositol 1,4,5-trisphosphate levels, proliferation, and PKA phosphorylation. Cholangiocytes express NK-1R with expression being upregulated following BDL. In normal NK-1R(-/-) mice, there was higher hepatocyte apoptosis and scattered hepatocyte steatosis compared with controls. In NK-1R (-)/(-) BDL mice, there was a decrease in serum transaminases and bilirubin levels and the number of CK-19-positive cholangiocytes and enhanced biliary apoptosis compared with controls. In total liver samples, the expression of collagen 1alpha and alpha-SMA increased in BDL compared with normal mice and decreased in BDL NK-1R(-/-) compared with BDL mice. In cholangiocytes from BDL NK 1R (-)/(-) mice there was decreased PCNA expression and PKA phosphorylation. In vitro, SP increased cAMP levels, proliferation, and PKA phosphorylation of cholangiocytes. Targeting of NK-1R may be important in the inhibition of biliary hyperplasia in cholangiopathies. PMID- 21596994 TI - Effect of the alpha2delta ligand, pregabalin, on colonic sensory and motor functions in healthy adults. AB - Pregabalin, an alpha2delta ligand, is used clinically to treat somatic pain. A prior study suggested that pregabalin reduces distension-induced pain while increasing rectal compliance. We aimed to quantify effects of pregabalin on colonic sensory and motor functions and assess relationships between sensory effects and colonic compliance. We conducted a randomized, double-blind, placebo controlled, parallel-group study of a single oral administration of 75 or 200 mg of pregabalin in 62 healthy adults (aged 18-75 yr). Subjects underwent left colon intubation. We assessed "stress-arousal symptoms", compliance, sensation thresholds, sensation ratings averaged over four levels of distension, fasting and postprandial colonic tone, and phasic motility index (MI). Analysis of covariance (adjusted for age, sex, body mass index, and corresponding predrug response) and proportional hazard models were used. There were no clinically important differences among treatment groups for demographics, predrug compliance, tone, MI, and sensation. Treatment was associated with reduced energy and increased drowsiness but no change in tension or relaxation. Sensation ratings averaged over the four distension levels were lower for gas sensation [overall effect P = 0.14, P = 0.05 (pregabalin 200 mg vs. placebo)] and for pain sensation [overall effect P = 0.12, P = 0.04 (pregabalin 200 mg vs. placebo)]. The magnitude of the effect of 200 mg of pregabalin relative to placebo is on average a 25% reduction of both gas and pain sensation ratings. Pregabalin did not significantly affect colonic compliance, sensation thresholds, colonic fasting tone, and MI. Thus 200 mg of pregabalin reduces gas and pain sensation and should be tested in patients with colonic pain. PMID- 21596992 TI - Structures of the bacterial ribosome in classical and hybrid states of tRNA binding. AB - During protein synthesis, the ribosome controls the movement of tRNA and mRNA by means of large-scale structural rearrangements. We describe structures of the intact bacterial ribosome from Escherichia coli that reveal how the ribosome binds tRNA in two functionally distinct states, determined to a resolution of ~3.2 angstroms by means of x-ray crystallography. One state positions tRNA in the peptidyl-tRNA binding site. The second, a fully rotated state, is stabilized by ribosome recycling factor and binds tRNA in a highly bent conformation in a hybrid peptidyl/exit site. The structures help to explain how the ratchet-like motion of the two ribosomal subunits contributes to the mechanisms of translocation, termination, and ribosome recycling. PMID- 21596995 TI - B-vitamin deficiency is protective against DSS-induced colitis in mice. AB - Vitamin deficiencies are common in patients with inflammatory bowel disease (IBD). Homocysteine (Hcys) is a thrombogenic amino acid produced from methionine (Met), and its increase in patients with IBD indicates a disruption of Met metabolism; however, the role of Hcys and Met metabolism in IBD is not well understood. We hypothesized that disrupted Met metabolism from a B-vitamin deficient diet would exacerbate experimental colitis. Mice were fed a B(6)-B(12) deficient or control diet for 2 wk and then treated with dextran sodium sulfate (DSS) to induce colitis. We monitored disease activity during DSS treatment and collected plasma and tissue for analysis of inflammatory tissue injury and Met metabolites. We also quantified Met cycle activity by measurements of in vivo Met kinetics using [1-(13)C-methyl-(2)H(3)]methionine infusion in similarly treated mice. Unexpectedly, we found that mice given the B-vitamin-deficient diet had improved clinical outcomes, including increased survival, weight maintenance, and reduced disease scores. We also found lower histological disease activity and proinflammatory gene expression (TNF-alpha and inducible nitric oxide synthase) in the colon in deficient-diet mice. Metabolomic analysis showed evidence that these effects were associated with deficient B(6), as markers of B(12) function were only mildly altered. In vivo methionine kinetics corroborated these results, showing that the deficient diet suppressed transsulfuration but increased remethylation. Our findings suggest that disrupted Met metabolism attributable to B(6) deficiency reduces the inflammatory response and disease activity in DSS challenged mice. These results warrant further human clinical studies to determine whether B(6) deficiency and elevated Hcys in patients with IBD contribute to disease pathobiology. PMID- 21596997 TI - Dual sensory impairment in older age. AB - OBJECTIVE: Hearing and visual impairments are commonly viewed separately in research and service provision, but they often occur together as dual sensory impairment or DSI in older populations. This article examines the frequency and effects of DSI in older age and notes limitations in the evidence. METHODS: Search of electronic databases of published papers. RESULTS: DSI diminishes communication and well-being and can cause social isolation, depression, reduced independence, mortality, and cognitive impairment. DISCUSSION: Although intuitively DSI may be expected to have additional impacts over single sensory impairment, research findings are inconclusive. Services and supports required by people with DSI are simply a combination of those required by people with single vision and hearing loss, taking account of the unique communication difficulties posed by DSI. PMID- 21596996 TI - Schlafen-3 decreases cancer stem cell marker expression and autocrine/juxtacrine signaling in FOLFOX-resistant colon cancer cells. AB - We have previously demonstrated that expression of the novel gene schlafen-3 (Slfn-3) correlates with intestinal epithelial cell differentiation (Patel VB, Yu Y, Das JK, Patel BB, Majumdar AP. Biochem Biophys Res Commun 388: 752-756, 2009). The present investigation was undertaken to examine whether Slfn-3 plays a role in regulating differentiation of FOLFOX-resistant (5-fluorouracil + oxaliplatin) colon cancer cells that are highly enriched in cancer stem cells (CSCs). Transfection of Slfn-3 in FOLFOX-resistant colon cancer HCT-116 cells resulted in increase of alkaline phosphatase activity, a marker of intestinal differentiation. Additionally, Slfn-3 transfection resulted in reduction of mRNA and protein levels of the CSC markers CD44, CD133, CD166, and aldehyde dehydrogenase 1 in both FOLFOX-resistant HCT-116 and HT-29 cells. This was accompanied by decreased formation of tumorosphere/colonosphere (an in vitro model of tumor growth) in stem cell medium and inhibition of expression of the chemotherapeutic drug transporter protein ABCG2. Additionally, Slfn-3 transfection of FOLFOX-resistant HCT-116 and HT-29 cells reduced Hoechst 33342 dye exclusion. Finally, Slfn-3 transfection inhibited the expression of transforming growth factor-alpha in both FOLFOX-resistant colon cancer cells, but stimulated apoptosis in response to additional FOLFOX treatment. In summary, our data demonstrate that Slfn-3 expression inhibits multiple characteristics of CSC enriched, FOLFOX-resistant colon cancer cells, including induction of differentiation and reduction in tumorosphere/colonosphere formation, drug transporter activity, and autocrine stimulation of proliferation. Thus Slfn-3 expression may render colon CSCs more susceptible to cancer chemotherapeutics. PMID- 21596998 TI - Solution structure of the ESCRT-I complex by small-angle X-ray scattering, EPR, and FRET spectroscopy. AB - ESCRT-I is required for the sorting of integral membrane proteins to the lysosome, or vacuole in yeast, for cytokinesis in animal cells, and for the budding of HIV-1 from human macrophages and T lymphocytes. ESCRT-I is a heterotetramer of Vps23, Vps28, Vps37, and Mvb12. The crystal structures of the core complex and the ubiquitin E2 variant and Vps28 C-terminal domains have been determined, but internal flexibility has prevented crystallization of intact ESCRT-I. Here we have characterized the structure of ESCRT-I in solution by simultaneous structural refinement against small-angle X-ray scattering and double electron-electron resonance spectroscopy of spin-labeled complexes. An ensemble of at least six structures, comprising an equally populated mixture of closed and open conformations, was necessary to fit all of the data. This structural ensemble was cross-validated against single-molecule FRET spectroscopy, which suggested the presence of a continuum of open states. ESCRT-I in solution thus appears to consist of an approximately 50% population of one or a few related closed conformations, with the other 50% populating a continuum of open conformations. These conformations provide reference points for the structural pathway by which ESCRT-I induces membrane buds. PMID- 21596999 TI - Using silver nanowire antennas to enhance the conversion efficiency of photoresponsive DNA nanomotors. AB - Plasmonic near-field coupling can induce the enhancement of photoresponsive processes by metal nanoparticles. Advances in nanostructured metal synthesis and theoretical modeling have kept surface plasmons in the spotlight. Previous efforts have resulted in significant intensity enhancement of organic dyes and quantum dots and increased absorption efficiency of optical materials used in solar cells. Here, we report that silver nanostructures can enhance the conversion efficiency of an interesting type of photosensitive DNA nanomotor through coupling with incorporated azobenzene moieties. Spectral overlap between the azobenzene absorption band and plasmonic resonances of silver nanowires increases light absorption of photon-sensitive DNA motor molecules, leading to 85% close-open conversion efficiency. The experimental results are consistent with our theoretical calculations of the electric field distribution. This enhanced conversion of DNA nanomotors holds promise for the development of new types of molecular nanodevices for light manipulative processes and solar energy harvesting. PMID- 21597000 TI - Phonons of the anomalous element cerium. AB - Many physical and chemical properties of the light rare-earths and actinides are governed by the active role of f electrons, and despite intensive efforts the details of the mechanisms of phase stability and transformation are not fully understood. A prominent example which has attracted a lot of interest, both experimentally and theoretically over the years is the isostructural gamma - alpha transition in cerium. We have determined by inelastic X-ray scattering, the complete phonon dispersion scheme of elemental cerium across the gamma -> alpha transition, and compared it with theoretical results using ab initio lattice dynamics. Several phonon branches show strong changes in the dispersion shape, indicating large modifications in the interactions between phonons and conduction electrons. This is reflected as well by the lattice Gruneisen parameters, particularly around the X point. We derive a vibrational entropy change DeltaS(gamma-alpha)(vib) ~ (0.33+/-0.03)k(B), illustrating the importance of the lattice contribution to the transition. Additionally, we compare first principles calculations with the experiments to shed light on the mechanism underlying the isostructural volume collapse in cerium under pressure. PMID- 21597001 TI - Canonical hedgehog signaling augments tumor angiogenesis by induction of VEGF-A in stromal perivascular cells. AB - Hedgehog (Hh) signaling is critical to the patterning and development of a variety of organ systems, and both ligand-dependent and ligand-independent Hh pathway activation are known to promote tumorigenesis. Recent studies have shown that in tumors promoted by Hh ligands, activation occurs within the stromal microenvironment. Testing whether ligand-driven Hh signaling promotes tumor angiogenesis, we found that Hh antagonism reduced the vascular density of Hh producing LS180 and SW480 xenografts. In addition, ectopic expression of sonic hedgehog in low-Hh-expressing DLD-1 xenografts increased tumor vascular density, augmented angiogenesis, and was associated with canonical Hh signaling within perivascular tumor stromal cells. To better understand the molecular mechanisms underlying Hh-mediated tumor angiogenesis, we established an Hh-sensitive angiogenesis coculture assay and found that fibroblast cell lines derived from a variety of human tissues were Hh responsive and promoted angiogenesis in vitro through a secreted paracrine signal(s). Affymetrix array analyses of cultured fibroblasts identified VEGF-A, hepatocyte growth factor, and PDGF-C as candidate secreted proangiogenic factors induced by Hh stimulation. Expression studies of xenografts and angiogenesis assays using combinations of Hh and VEGF-A inhibitors showed that it is primarily Hh-induced VEGF-A that promotes angiogenesis in vitro and augments tumor-derived VEGF to promote angiogenesis in vivo. PMID- 21597003 TI - Inhibitors of gamma-secretase stabilize the complex and differentially affect processing of amyloid precursor protein and other substrates. AB - gamma-Secretase inhibitors (GSIs) are drugs used in research to inhibit production of Abeta and in clinical trials to treat Alzheimer's disease (AD). They inhibit proteolytic activities of gamma-secretase noncompetitively by unknown mechanisms. Here, we used cortical neuronal cultures expressing endogenous levels of enzymes and substrates to study the effects of GSIs on the structure and function of gamma-secretase. We show that GSIs stabilize the interactions between the C-terminal fragment of presenilin (PS-CTF), the central component of the gamma-secretase complex, and its partners the APH-1/nicastrin and PS1-NTF/PEN-2 subcomplexes. This stabilization dose-dependently correlates with inhibition of N-cadherin cleavage, a process limited by enzyme availability. In contrast, production of amyloid precursor protein (APP) intracellular domain (AICD) is insensitive to low concentrations of GSIs and is limited by substrate availability. Interestingly, APP is processed by both PS1- and PS2-containing gamma-secretase complexes, while N-cadherin and ephrinB1 are processed only by PS1-containing complexes. Paradoxically, low concentrations of GSIs specifically increased the levels of Abeta without affecting its catabolism, indicating increased Abeta production. Our data reveal a mechanism of gamma-secretase inhibition by GSIs and provide evidence that distinct gamma-secretase complexes process specific substrates. Furthermore, our observations have implications for GSIs as therapeutics because processing of functionally important substrates may be inhibited at lower concentrations than Abeta. PMID- 21597002 TI - Intrinsic apoptosis in mechanically ventilated human diaphragm: linkage to a novel Fos/FoxO1/Stat3-Bim axis. AB - Mechanical ventilation (MV) is a life-saving measure in many critically ill patients. However, prolonged MV results in diaphragm dysfunction that contributes to the frequent difficulty in weaning patients from the ventilator. The molecular mechanisms underlying ventilator-induced diaphragm dysfunction (VIDD) remain poorly understood. We report here that MV induces myonuclear DNA fragmentation (3 fold increase; P<0.01) and selective activation of caspase 9 (P<0.05) and Bcl2 interacting mediator of cell death (Bim; 2- to 7-fold increase; P<0.05) in human diaphragm. MV also statistically significantly down-regulates mitochondrial gene expression and induces oxidative stress. In cultured muscle cells, we show that oxidative stress activates each of the catabolic pathways thought to underlie VIDD: apoptotic (P<0.05), proteasomal (P<0.05), and autophagic (P<0.01). Further, silencing Bim expression blocks (P<0.05) oxidative stress-induced apoptosis. Overlapping the gene expression profiles of MV human diaphragm and H2O2-treated muscle cells, we identify Fos, FoxO1, and Stat3 as regulators of Bim expression as well as of expression of the catabolic markers atrogin and LC3. We thus identify a novel Fos/FoxO1/Stat3-Bim intrinsic apoptotic pathway and establish the centrality of oxidative stress in the development of VIDD. This information may help in the design of specific drugs to prevent this condition. PMID- 21597004 TI - Endothelial microparticle formation by angiotensin II is mediated via Ang II receptor type I/NADPH oxidase/ Rho kinase pathways targeted to lipid rafts. AB - OBJECTIVE: Circulating microparticles are increased in cardiovascular disease and may themselves promote oxidative stress and inflammation. Molecular mechanisms underlying their formation and signaling are unclear. We investigated the role of reactive oxygen species (ROS), Rho kinase, and lipid rafts in microparticle formation and examined their functional significance in endothelial cells (ECs). METHODS AND RESULTS: Microparticle formation from angiotensin II (Ang II) stimulated ECs and apolipoprotein E(-/-) mice was assessed by annexin V or by CD144 staining and electron microscopy. Ang II promoted microparticle formation and increased EC O(2)(-) generation and Rho kinase activity. Ang II-stimulated effects were inhibited by irbesartan (Ang II receptor type I blocker) and fasudil (Rho kinase inhibitor). Methyl-beta-cyclodextrin and nystatin, which disrupt lipid rafts/caveolae, blocked microparticle release. Functional responses, assessed in microparticle-stimulated ECs, revealed increased O(2)(-) production, enhanced vascular cell adhesion molecule/platelet-EC adhesion molecule expression, and augmented macrophage adhesion. Inhibition of epidermal growth factor receptor blocked the prooxidative and proinflammatory effects of microparticles. In vitro observations were confirmed in apolipoprotein E(-/-) mice, which displayed vascular inflammation and high levels of circulating endothelial microparticles, effects that were reduced by apocynin. CONCLUSIONS: We demonstrated direct actions of Ang II on endothelial microparticle release, mediated through NADPH oxidase, ROS, and Rho kinase targeted to lipid rafts. Microparticles themselves stimulated endothelial ROS formation and inflammatory responses. Our findings suggest a feedforward system whereby Ang II promotes EC injury through its own endothelial-derived microparticles. PMID- 21597005 TI - An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia. AB - OBJECTIVE: Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity. METHODS AND RESULTS: First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes. CONCLUSIONS: HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG associated variants. PMID- 21597006 TI - Impaired expression of uncoupling protein 2 causes defective postischemic angiogenesis in mice deficient in AMP-activated protein kinase alpha subunits. AB - OBJECTIVE: The aim of the present study was to determine whether mitochondrial uncoupling protein (UCP) 2 is required for AMPK-dependent angiogenesis in ischemia in vivo. METHODS AND RESULTS: Angiogenesis was assayed by monitoring endothelial tube formation (a surrogate for angiogenesis) in human umbilical vein endothelial cells (ECs), isolated mouse aortic endothelial cells (MAECs), and pulmonary microvascular endothelial cells or in ischemic thigh adductor muscles from wild-type (WT) mice or mice deficient in either AMPKalpha1 or AMPKalpha2. AMPK inhibition with pharmacological inhibitor (compound C) or genetic means (transfection of AMPKalpha-specific small interfering RNA) significantly lowered the tube formation in human umbilical vein ECs. Consistently, compared with WT mice, tube formation in MAECs isolated from either AMPKalpha1(-/-) or AMPKalpha2( /-) mice, which exhibited oxidative stress and reduced expression of UCP2, was significantly impaired. In addition, adenoviral overexpression of UCP2, but not adenoviruses encoding green fluorescent protein, normalized tube formation in MAECs from either AMPKalpha1(-/-) or AMPKalpha2(-/-) mice. Similarly, supplementation with sodium nitroprusside, a nitric oxide (NO) donor, restored tube formation. Furthermore, ischemia significantly increased angiogenesis, serine 1177 phosphorylation of endothelial NO synthase, and UCP2 in ischemic thigh adductor muscles from WT mice but not in those from either AMPKalpha1(-/-) or AMPKalpha2(-/-) mice. CONCLUSIONS: We conclude that AMPK-dependent UCP2 expression in ECs promotes angiogenesis in vivo. PMID- 21597007 TI - Vascular calcification and aortic fibrosis: a bifunctional role for osteopontin in diabetic arteriosclerosis. AB - OBJECTIVE: Calcification and fibrosis reduce vascular compliance in arteriosclerosis. To better understand the role of osteopontin (OPN), a multifunctional protein upregulated in diabetic arteries, we evaluated contributions of OPN in male low-density lipoprotein receptor (LDLR)-/- mice fed a high-fat diet. METHODS AND RESULTS: OPN had no impact on high-fat diet-induced hyperglycemia, dyslipidemia, or body composition. However, OPN-/-;LDLR-/- mice exhibited an altered time-course of aortic calcium accrual-reduced during initiation but increased with progression-versus OPN+/+;LDLR-/- controls. Collagen accumulation, chondroid metaplasia, and mural thickness were increased in aortas of OPN-/-;LDLR-/- mice. Aortic compliance was concomitantly reduced. Vascular reexpression of OPN (SM22-OPN transgene) reduced aortic Col2A1 and medial chondroid metaplasia but did not affect atherosclerotic calcification, Col1A1 expression, collagen accumulation, or arterial stiffness. Dosing with the proinflammatory OPN fragment SVVYGLR upregulated aortic Wnt and osteogenic gene expression, increased aortic beta-catenin, and restored early-phase aortic calcification in OPN-/-;LDLR-/- mice. CONCLUSIONS: OPN exerts stage-specific roles in arteriosclerosis in LDLR-/- mice. Actions phenocopied by the OPN metabolite SVVYGLR promote osteogenic calcification processes with disease initiation. OPN limits vascular chondroid metaplasia, endochondral mineralization, and collagen accumulation with progression. Complete deficiency yields a net increase in arteriosclerotic disease, reducing aortic compliance and conduit vessel function in LDLR-/- mice. PMID- 21597008 TI - Apolipoprotein E mediates enhanced plasma high-density lipoprotein cholesterol clearance by low-dose streptococcal serum opacity factor via hepatic low-density lipoprotein receptors in vivo. AB - OBJECTIVE: Recombinant streptococcal serum opacity factor (rSOF) mediates the in vitro disassembly of human plasma high-density lipoprotein (HDL) into lipid-free apolipoprotein (apo) A-I, a neo-HDL that is cholesterol poor, and a cholesteryl ester-rich microemulsion (CERM) containing apoE. Given the occurrence of apoE on the CERM, we tested the hypothesis that rSOF injection into mice would reduce total plasma cholesterol clearance via apoE-dependent hepatic low-density lipoprotein receptors (LDLR). METHODS AND RESULTS: rSOF (4 MUg) injection into wild-type C57BL/6J mice formed neo-HDL, CERM, and lipid-free apoA-I, as observed in vitro, and reduced plasma total cholesterol (-43%, t(1/2)=44+/-18 minutes) whereas control saline injections had a negligible effect. Similar experiments with apoE(-/-) and LDLR(-/-) mice reduced plasma total cholesterol ~0% and 20%, respectively. rSOF was potent; injection of 0.18 MUg of rSOF produced 50% of maximum reduction of plasma cholesterol 3 hours postinjection, corresponding to a ~0.5-mg human dose. Most cholesterol was cleared hepatically (>99%), with rSOF treatment increasing clearance by 65%. CONCLUSIONS: rSOF injection into mice formed a CERM that was cleared via hepatic LDLR that recognize apoE. This reaction could provide an alternative mechanism for reverse cholesterol transport. PMID- 21597009 TI - Growth of engineered human myocardium with mechanical loading and vascular coculture. AB - RATIONALE: The developing heart requires both mechanical load and vascularization to reach its proper size, yet the regulation of human heart growth by these processes is poorly understood. OBJECTIVE: We seek to elucidate the responses of immature human myocardium to mechanical load and vascularization using tissue engineering approaches. METHODS AND RESULTS: Using human embryonic stem cell and human induced pluripotent stem cell-derived cardiomyocytes in a 3-dimensional collagen matrix, we show that uniaxial mechanical stress conditioning promotes 2 fold increases in cardiomyocyte and matrix fiber alignment and enhances myofibrillogenesis and sarcomeric banding. Furthermore, cyclic stress conditioning markedly increases cardiomyocyte hypertrophy (2.2-fold) and proliferation rates (21%) versus unconditioned constructs. Addition of endothelial cells enhances cardiomyocyte proliferation under all stress conditions (14% to 19%), and addition of stromal supporting cells enhances formation of vessel-like structures by ~10-fold. Furthermore, these optimized human cardiac tissue constructs generate Starling curves, increasing their active force in response to increased resting length. When transplanted onto hearts of athymic rats, the human myocardium survives and forms grafts closely apposed to host myocardium. The grafts contain human microvessels that are perfused by the host coronary circulation. CONCLUSIONS: Our results indicate that both mechanical load and vascular cell coculture control cardiomyocyte proliferation, and that mechanical load further controls the hypertrophy and architecture of engineered human myocardium. Such constructs may be useful for studying human cardiac development as well as for regenerative therapy. PMID- 21597010 TI - A critical function for Ser-282 in cardiac Myosin binding protein-C phosphorylation and cardiac function. AB - RATIONALE: Cardiac myosin-binding protein-C (cMyBP-C) phosphorylation at Ser-273, Ser-282, and Ser-302 regulates myocardial contractility. In vitro and in vivo experiments suggest the nonequivalence of these sites and the potential importance of Ser-282 phosphorylation in modulating the protein's overall phosphorylation and myocardial function. OBJECTIVE: To determine whether complete cMyBP-C phosphorylation is dependent on Ser-282 phosphorylation and to define its role in myocardial function. We hypothesized that Ser-282 regulates Ser-302 phosphorylation and cardiac function during beta-adrenergic stimulation. METHODS AND RESULTS: Using recombinant human C1-M-C2 peptides in vitro, we determined that protein kinase A can phosphorylate Ser-273, Ser-282, and Ser-302. Protein kinase C can also phosphorylate Ser-273 and Ser-302. In contrast, Ca(2+) calmodulin-activated kinase II targets Ser-302 but can also target Ser-282 at nonphysiological calcium concentrations. Strikingly, Ser-302 phosphorylation by Ca(2+)-calmodulin-activated kinase II was abolished by ablating the ability of Ser-282 to be phosphorylated via alanine substitution. To determine the functional roles of the sites in vivo, three transgenic lines, which expressed cMyBP-C containing either Ser-273-Ala-282-Ser-302 (cMyBP-C(SAS)), Ala-273-Asp-282 Ala-302 (cMyBP-C(ADA)), or Asp-273-Ala-282-Asp-302 (cMyBP-C(DAD)), were generated. Mutant protein was completely substituted for endogenous cMyBP-C by breeding each mouse line into a cMyBP-C null (t/t) background. Serine-to-alanine substitutions were used to ablate the abilities of the residues to be phosphorylated, whereas serine-to-aspartate substitutions were used to mimic the charged state conferred by phosphorylation. Compared to control nontransgenic mice, as well as transgenic mice expressing wild-type cMyBP-C, the transgenic cMyBP-C(SAS(t/t)), cMyBP-C(ADA(t/t)), and cMyBP-C(DAD(t/t)) mice showed no increases in morbidity and mortality and partially rescued the cMyBP-C((t/t)) phenotype. The loss of cMyBP-C phosphorylation at Ser-282 led to an altered beta adrenergic response. In vivo hemodynamic studies revealed that contractility was unaffected but that cMyBP-C(SAS(t/t)) hearts showed decreased diastolic function at baseline. However, the normal increases in cardiac function (increased contractility/relaxation) as a result of infusion of beta-agonist was significantly decreased in all of the mutants, suggesting that competency for phosphorylation at multiple sites in cMyBP-C is a prerequisite for normal beta adrenergic responsiveness. CONCLUSIONS: Ser-282 has a unique regulatory role in that its phosphorylation is critical for the subsequent phosphorylation of Ser 302. However, each residue plays a role in regulating the contractile response to beta-agonist stimulation. PMID- 21597011 TI - Role of the cholinergic antiinflammatory pathway in murine autoimmune myocarditis. AB - RATIONALE: This study was performed to gain insights into novel therapeutic approaches for the treatment of autoimmune myocarditis. OBJECTIVE: Chemical stimulation of the efferent arm of the vagus nerve through activation of nicotinic acetylcholine receptor subtype-7alpha (alpha7-nAChR) has been shown to be protective in several models of inflammatory diseases. In the present study, we investigated the potentially protective effect of vagus nerve stimulation on myocarditis. METHODS AND RESULTS: A/J mice were immunized with cardiac troponin I (TnI) to induce autoimmune myocarditis. Mice were exposed to drinking water that contained nicotine in different concentrations and for different time periods (for 3 days at 12.5 mg/L; 3 days at 125 mg/L; 21 days at 12.5 mg/L; and 21 days at 125 mg/L after first immunization). TnI-immunized mice with no pharmacological treatment showed extensive myocardial inflammation and fibrosis and significantly elevated levels of interleukin-6 and tumor necrosis factor-alpha. Furthermore, elevated levels of mRNA transcripts of proinflammatory chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta, and RANTES) and chemokine receptors (CCR1, CCR2, and CCR5) were found. Oral nicotine administration reduced inflammation within the myocardium, decreased the production of interleukin-6 and tumor necrosis factor-alpha, and downregulated the expression of monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta, RANTES, CCR1, CCR2, and CCR5. In addition, nicotine treatment resulted in decreased expression of matrix metalloproteinase-14, natriuretic peptide precursor B, tissue inhibitor of metalloproteinase-1, and osteopontin, proteins that are commonly involved in heart failure. Finally, we found that nicotine reduced levels of pSTAT3 (phosphorylated signal transducer and activator of transcription 3) protein expression within the myocardium. Neostigmine treatment did not affect the progression of myocarditis. CONCLUSIONS: We showed that activation of the cholinergic antiinflammatory pathway with nicotine reduces inflammation in autoimmune myocarditis. Our results may open new possibilities in the therapeutic management of autoimmune myocarditis. PMID- 21597012 TI - Nfatc1 coordinates valve endocardial cell lineage development required for heart valve formation. AB - RATIONALE: Formation of heart valves requires early endocardial to mesenchymal transformation (EMT) to generate valve mesenchyme and subsequent endocardial cell proliferation to elongate valve leaflets. Nfatc1 (nuclear factor of activated T cells, cytoplasmic 1) is highly expressed in valve endocardial cells and is required for normal valve formation, but its role in the fate of valve endocardial cells during valve development is unknown. OBJECTIVE: Our aim was to investigate the function of Nfatc1 in cell-fate decision making by valve endocardial cells during EMT and early valve elongation. METHODS AND RESULTS: Nfatc1 transcription enhancer was used to generate a novel valve endocardial cell specific Cre mouse line for fate-mapping analyses of valve endocardial cells. The results demonstrate that a subpopulation of valve endocardial cells marked by the Nfatc1 enhancer do not undergo EMT. Instead, these cells remain within the endocardium as a proliferative population to support valve leaflet extension. In contrast, loss of Nfatc1 function leads to enhanced EMT and decreased proliferation of valve endocardium and mesenchyme. The results of blastocyst complementation assays show that Nfatc1 inhibits EMT in a cell-autonomous manner. We further reveal by gene expression studies that Nfatc1 suppresses transcription of Snail1 and Snail2, the key transcriptional factors for initiation of EMT. CONCLUSIONS: These results show that Nfatc1 regulates the cell-fate decision making of valve endocardial cells during valve development and coordinates EMT and valve elongation by allocating endocardial cells to the 2 morphological events essential for valve development. PMID- 21597013 TI - Germinal matrix hemorrhage: intraventricular hemorrhage in very-low-birth-weight infants: the independent role of inherited thrombophilia. AB - BACKGROUND AND PURPOSE: The etiology of germinal matrix hemorrhage intraventricular hemorrhage (GMH-IVH) is multifactorial and the role of genetic polymorphisms is unclear. The aim of this prospective study was to evaluate prothrombotic genetic mutations as independent risk factors for the development of all grades of GMH-IVH in very-low-birth-weight infants. METHODS: The presence of both factor V Leiden and prothrombin gain-of-function gene mutations were prospectively assessed in 106 very-low-birth-weight infants. Infants with GMH-IVH were compared to those without GMH-IVH according to genetic and clinical characteristics. RESULTS: Twenty-two out of 106 infants had GMH-IVH develop (20.7%). Infants with GMH-IVH had significantly lower gestational ages and birth weights. In the multivariate Poisson regression model, the prevalence of GMH-IVH appeared to be inversely related to gestational age, with a risk ratio of 0.83 (95% CI, 0.72-0.97; P=0.02) per week. Risk ratio of GMH-IVH for carriers of either prothrombotic mutation was 2.65 (95% CI, 1.23-5.72; P=0.01), similar to the risk ratio associated with need for resuscitation at birth (2.30; 95% CI, 1.02-5.18; P=0.04). CONCLUSIONS: Very-low-birth-weight infants who are carriers for either prothrombotic mutations are at increased risk for development of GMH IVH. Genetic factors act as independent risk factors of the same magnitude as other known risk factors. PMID- 21597014 TI - Intravenous thrombolysis in nonagenarians with ischemic stroke. AB - BACKGROUND AND PURPOSE: Demographic changes will result in a rapid increase of patients age >=90 years (nonagenarians), but little is known about outcomes in these patients after intravenous thrombolysis (IVT) for acute ischemic stroke. We aimed to assess safety and functional outcome in nonagenarians treated with IVT and to compare the outcomes with those of patients age 80 to 89 years (octogenarians). METHODS: We analyzed prospectively collected data of 284 consecutive stroke patients age >=80 years treated with IVT in 7 Swiss stroke units. Presenting characteristics, favorable outcome (modified Rankin scale [mRS] 0 or 1), mortality at 3 months, and symptomatic intracranial hemorrhage (SICH) using the National Institute of Neurological Disorders and Stroke (NINDS) and Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria were compared between nonagenarians and octogenarians. RESULTS: As compared with octogenarians (n=238; mean age, 83 years), nonagenarians (n=46; mean age, 92 years) were more often women (70% versus 54%; P=0.046) and had lower systolic blood pressure (161 mm Hg versus 172 mm Hg; P=0.035). Patients age >=90 years less often had a favorable outcome and had a higher incidence of mortality than did patients age 80 to 89 years (14.3% versus 30.2%; P=0.034; and 45.2% versus 22.1%; P=0.002; respectively), while more nonagenarians than octogenarians experienced a SICH (SICH(NINDS), 13.3% versus 5.9%; P=0.106; SICH(SITS-MOST), 13.3% versus 4.7%; P=0.037). Multivariate adjustment identified age >=90 years as an independent predictor of mortality (P=0.017). CONCLUSIONS: Our study suggests less favorable outcomes in nonagenarians as compared with octogenarians after IVT for ischemic stroke, and it demands a careful selection for treatment, unless randomized controlled trials yield more evidence for IVT in very old stroke patients. PMID- 21597015 TI - Microbleeds are associated with subsequent hemorrhagic and ischemic stroke in healthy elderly individuals. AB - BACKGROUND AND PURPOSE: Cerebral microbleeds (MBs) are frequently detected in patients with stroke, especially those who experience intracerebral hemorrhage. However, the clinical significance of MBs in subjects without cerebrovascular disease is still unclear. We performed a prospective study to determine whether the presence of MBs provides useful prognostic information in healthy elderly individuals. METHODS: We tracked 2102 subjects (mean age, 62.1 years) over a mean interval of 3.6 years after they voluntarily participated in the brain checkup system at the Shimane Institute of Health Science. An initial assessment was performed to document the presence of MBs and silent ischemic brain lesions and to map the location of the MBs. During the follow-up period, we obtained information about stroke events that occurred in each subject. RESULTS: MBs were detected in 93 of the 2102 subjects (4.4%). Strokes occurred in 44 subjects (2.1%) during the follow-up period. They were significantly more common among subjects with MBs. Age and hypertension were independent risk factors for MBs. The presence of MBs was more strongly associated with a deep brain hemorrhage (hazard ratio, 50.2; 95% CI, 16.7 to 150.9) than ischemic stroke (hazard ratio, 4.48; 95% CI, 2.20 to 12.2). All hemorrhagic strokes occurred in deep brain regions, and they were associated with MBs located in the deep brain region. CONCLUSIONS: This longitudinal study demonstrated that the presence of MBs can be used to predict hemorrhagic and ischemic stroke, even in healthy elderly individuals. PMID- 21597016 TI - Increased brain injury and worsened neurological outcome in interleukin-4 knockout mice after transient focal cerebral ischemia. AB - BACKGROUND AND PURPOSE: Stroke causes brain injury with activation of an inflammatory response that can contribute to injury. We tested the hypothesis that the anti-inflammatory cytokine interleukin-4 (IL-4) reduces injury after stroke using IL-4 knockout (KO) adult male mice. METHODS: IL-4 KO and wild-type mice were subjected to transient middle cerebral artery occlusion. Outcome was assessed by triphenyltetrazolium chloride staining for infarct volume, neuroscore and spontaneous activity for behavioral outcome, and immunostaining and stereological counting for cellular response. RESULTS: Infarction volume at 24 hours was significantly larger in IL-4 KO mice, neurological score was significantly worse, and spontaneous activity was reduced compared with wild-type mice. Increased macrophage/microglial infiltration, increased numbers of myeloperoxidase-positive cells, and increased Th1/Th2 ratio were observed in the infarct core in IL-4 KO mice. Reduced astrocyte activation was observed in the cortical penumbra in IL-4 KO mice. Recombinant IL-4 administered intracerebroventricularly before middle cerebral artery occlusion significantly reduced infarct volume, improved neurological score, reduced macrophages/microglia, and lowered the Th1/Th2 ratio in IL-4 KO mice, but not in wild-type. CONCLUSIONS: Loss of IL-4 signaling in KO mice was associated with worse outcome, and this was reversed by giving exogenous IL-4. Worsened outcome was associated with increased inflammation in the core, which was reversed in IL 4 KO but not significantly changed in wild-type mice by exogenous IL-4. This is consistent with IL-4 signaling leading to reduced inflammation in the core and a possible beneficial role for activated astrocytes in the penumbra. PMID- 21597017 TI - Letter by Simard et al regarding article, "Sulfonylurea use before stroke does not influence outcome". PMID- 21597018 TI - Consequences of stroke in community-dwelling elderly: the health and retirement study, 1998 to 2008. AB - BACKGROUND AND PURPOSE: Stroke survivors are at risk of developing comorbidities that further reduce their quality of life. The purpose of this study was to determine the risk of developing a secondary health problem after stroke. METHODS: We performed a case-control analysis using 6 biennial interview waves (1998 to 2008) of the Health and Retirement Study. We compared 631 noninstitutionalized individuals who had a single stroke with 631 control subjects matched for age, gender, and interview wave. We studied sleep problems, urinary incontinence, motor impairment, falls, and memory deficits among the 2 groups. RESULTS: Stroke survivors frequently developed new or worsened motor impairment (33%), sleep problems (up to 33%), falls (30%), urinary incontinence (19%), and memory deficits (9%). As compared with control subjects, the risk of developing a secondary health problem was highest for memory deficits (OR, 2.45; 95% CI, 1.34 to 4.46) followed by urinary incontinence (OR, 1.86; 95% CI, 1.31 to 2.66), motor impairment (OR, 1.61; 95% CI, 1.16 to 2.24), falls (OR, 1.5; 95% CI, 1.12 to 2.0), and sleep disturbances (OR, 1.49; 95% CI, 1.09 to 2.03). In contrast, stroke survivors were not more likely to injure themselves during a fall (OR, 1.14; 95% CI, 0.72 to 1.79). After adjusting for cardiovascular risk factors, social status, psychiatric symptoms, and pain, the risks of falling or developing sleep problems were not different from the control subjects. CONCLUSIONS: The risk of developing a secondary health problem that can impact daily life is markedly increased after stroke. A better understanding of frequencies and risks for secondary health problems after stroke is necessary for designing better preventive and rehabilitation strategies. PMID- 21597019 TI - Rescue, combined, and stand-alone thrombectomy in the management of large vessel occlusion stroke using the solitaire device: a prospective 50-patient single center study: timing, safety, and efficacy. AB - BACKGROUND AND PURPOSE: Large vessel occlusion in ischemic stroke is associated with a high degree of morbidity. When intravenous thrombolysis fails, mechanical thrombectomy can provide an alternative and synergistic method for flow restoration. In this study we evaluate the safety and efficacy of our stroke management protocol (RECOST study). METHODS: Fifty consecutive ischemic stroke patients with large vessel occlusion were included. After clinical and MRI imaging assessment, 3 treatment strategies were selected according to time of symptom onset and location of vessel occlusion: rescue therapy; combined therapy; and stand-alone thrombectomy (RECOST study). MRI ASPECT score <5 was the main exclusion criterion. Mechanical thrombectomy was performed exclusively with the Solitaire flow restoration device. Clinical outcome was assessed after treatment, on day 1, and at discharge. RESULTS: Mean patient age was 67.6 years, mean NIHSS score was 14.7, and mean ASPECT score was 6 on presentation. Vessel occlusions were in the middle cerebral artery (40%), the internal carotid artery (28%), and the basilar artery (32%). Rescue treatment represented 24%, combined therapy represented 56%, and stand-alone thrombectomy represented 20%. Mean recanalization time from symptoms onset was 377 minutes, with overall recanalization rate TICI 3 of 84%. NIHSS score at discharge was 6.5, with 60% of patients demonstrating NIHSS score 0 to 1 or an improvement of >9 points. Symptomatic complication rate was 10%. At 3 months, 54% of patients had a modififed Rankin scale score of 0 to 2, with an overall mortality rate of 12%. CONCLUSIONS: The present integrated stroke management protocol (RECOST study) demonstrated rapid, safe, and effective recanalization. We postulate that the Solitaire device contributed to high recanalization and patient selection using MRI ASPECT score to low and complication rates, therefore avoiding futile and dangerous interventions. PMID- 21597020 TI - Letter by Kovacs regarding article, "Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association". PMID- 21597021 TI - Letter by Calvet et al regarding article, "Prevalence of coronary atherosclerosis in patients with cerebral infarction". PMID- 21597023 TI - Microsatellite instability, prognosis and drug sensitivity of stage II and III colorectal cancer: more complexity to the puzzle. PMID- 21597022 TI - DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. AB - BACKGROUND: Approximately 15% of colorectal cancers develop because of defective function of the DNA mismatch repair (MMR) system. We determined the association of MMR status with colon cancer recurrence and examined the impact of 5 fluorouracil (FU)-based adjuvant therapy on recurrence variables. METHODS: We included stage II and III colon carcinoma patients (n = 2141) who were treated in randomized trials of 5-FU-based adjuvant therapy. Tumors were analyzed for microsatellite instability by polymerase chain reaction and/or for MMR protein expression by immunohistochemistry to determine deficient MMR (dMMR) or proficient MMR (pMMR) status. Associations of MMR status and/or 5-FU-based treatment with clinicopathologic and recurrence covariates were determined using chi(2) or Fisher Exact or Wilcoxon rank-sum tests. Time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) were analyzed using univariate and multivariable Cox models, with the latter adjusted for covariates. Tumors showing dMMR were categorized by presumed germline vs sporadic origin and were assessed for their prognostic and predictive impact. All statistical tests were two-sided. RESULTS: In this study population, dMMR was detected in 344 of 2141 (16.1%) tumors. Compared with pMMR tumors, dMMR was associated with reduced 5-year recurrence rates (33% vs 22%; P < .001), delayed TTR (P < .001), and fewer distant recurrences (22% vs 12%; P < .001). In multivariable models, dMMR was independently associated with delayed TTR (hazard ratio = 0.72, 95% confidence interval = 0.56 to 0.91, P = .005) and improved DFS (P = .035) and OS (P = .031). In stage III cancers, 5-FU-based treatment vs surgery alone or no 5-FU was associated with reduced distant recurrence for dMMR tumors (11% vs 29%; P = .011) and reduced recurrence to all sites for pMMR tumors (P < .001). The dMMR tumors with suspected germline mutations were associated with improved DFS after 5-FU based treatment compared with sporadic tumors where no benefit was observed (P = .006). CONCLUSIONS: Patients with dMMR colon cancers have reduced rates of tumor recurrence, delayed TTR, and improved survival rates, compared with pMMR colon cancers. Distant recurrences were reduced by 5-FU-based adjuvant treatment in dMMR stage III tumors, and a subset analysis suggested that any treatment benefit was restricted to suspected germline vs sporadic tumors. PMID- 21597024 TI - Glycated albumin and risk of death and hospitalizations in diabetic dialysis patients. AB - BACKGROUND AND OBJECTIVES: Relative to hemoglobin (Hb) A(1c), glycated albumin (GA) more accurately reflects glycemic control in patients with diabetes mellitus and ESRD. We determined the association between GA, HbA(1c), and glucose levels with survival and hospitalizations in diabetic dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Quarterly GA levels were measured for up to 2.33 years in 444 prevalent patients with diabetes and ESRD. Proportional hazard time-dependent covariate models were computed with adjustment for demographic characteristics, comorbidities, and laboratory variables. Similar analyses were performed for available HbA(1c) and monthly random serum glucose determinations. RESULTS: The participants were 53% male, 54% African American, 43% Caucasian, 90% on hemodialysis, with a mean (SD) age of 62 (12) years and median follow-up duration of 2.25 years. GA and HbA(1c) mean +/- SD 21.5% +/- 6.0%, median 20.4% and mean +/- SD 6.9% +/- 6.6%, median 1.6%, respectively. There were 156 deaths during the observation period. In best-fit models, predictors of death included increasing GA, increasing age, presence of peripheral vascular disease, decreasing serum albumin, and decreasing hemoglobin concentrations. HbA(1c) and random serum glucose concentrations were not predictive of survival. Increasing GA levels were associated with hospitalization in the 17 days after measurement, whereas HbA(1c) was not. CONCLUSIONS: In contrast to the HbA(1c) and random serum glucose values, GA accurately predicts the risk of death and hospitalizations in patients with diabetes mellitus and ESRD. The GA assay should be considered by clinicians who care for patients with diabetes on dialysis. PMID- 21597025 TI - Nocturnal hemodialysis is associated with restoration of early-outgrowth endothelial progenitor-like cell function. AB - BACKGROUND AND OBJECTIVES: Angiogenesis is a key response to tissue ischemia that may be impaired by uremia. Although early-outgrowth endothelial progenitor-like cells promote angiogenesis in the setting of normal renal function, cells from uremic patients are dysfunctional. When compared with conventional hemodialysis, it was hypothesized that nocturnal hemodialysis would improve the in vivo angiogenic activity of these cells in a well described model of ischemic vascular disease. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Early-outgrowth endothelial progenitor-like cells were cultured from healthy controls (n = 5) and age- and gender-matched conventional hemodialysis (12 h/wk, n = 10) and nocturnal hemodialysis (30 to 50 h/wk, n = 9) patients. Cells (5 * 10(5)) or saline were injected into the ischemic hindlimb of athymic nude rats 1 day after left common iliac artery ligation. RESULTS: Although conventional dialysis cell injection had no effect versus saline, nocturnal hemodialysis and healthy control cell injection significantly improved ischemic hindlimb perfusion and capillary density. Nocturnal hemodialysis cell injection was also associated with significant increases in endogenous angiopoietin 1 expression in the ischemic hindlimb compared with saline and conventional dialysis cell injection. CONCLUSIONS: In contrast to a conventional dialytic regimen, nocturnal hemodialysis is associated with a significantly improved ability of early outgrowth endothelial progenitor-like cells to promote angiogenesis and thus restore perfusion in a model of ischemic vascular disease. PMID- 21597026 TI - Making measures count. AB - An abundance of available laboratory information has led in part to the establishment of quantitative performance goals that use serum albumin, hemoglobin, Kt/V, and bone mineral indices to track quality of medical care and even physician reimbursement. As we look to the future, the next generation of measures should should more specifically reflect efforts to improve more fundamental outcomes, such as mortality, hospitalization, and quality of life. In this essay we address the important question of how clinicians can translate rich sources of quantitative data into a service that makes a difference in our patients' lives; a way to distinguish exemplary from ordinary care; a means to support continuous improvement in our care patterns individually and as part of larger, integrated health care systems all while avoiding prematurely advocating flawed quality measures. We also offer a pathway for how future quality measures can be developed. Our ultimate goal is to individualize quantitative assessments and by doing so encourage more meaningful, patient-oriented care that will lead to improved outcomes, greater physician job satisfaction, and wiser allocation of scarce resources. PMID- 21597027 TI - Albuminuria and cardiovascular risk: time for a new direction? PMID- 21597028 TI - Frequent hemodialysis schedules are associated with reduced levels of dialysis induced cardiac injury (myocardial stunning). AB - BACKGROUND AND OBJECTIVES: Recurrent hemodialysis (HD)-induced ischemic cardiac injury (myocardial stunning) is common and associated with high ultrafiltration (UF) requirements, intradialytic hypotension, long-term loss of systolic function, increased likelihood of cardiovascular events, and death. More frequent HD regimens are associated with lower UF requirements and improved hemodynamic tolerability, improved cardiovascular outcomes, and reduced mortality compared with conventional thrice-weekly HD. This study investigated the hypothesis that modification of UF volume and rate with more frequent HD therapies would abrogate dialysis-induced myocardial stunning. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: A cross-sectional study of 46 patients established on hemodialysis >3 months compared four groups receiving the current range of quotidian therapies: conventional thrice-weekly HD (CHD3); more-frequent HD five to six times/week in a center (CSD) and at home (HSD); and home nocturnal HD (HN). Serial echocardiography quantitatively assessed regional systolic function to identify intradialytic left ventricular regional wall motion abnormalities (RWMAs). Cardiac troponin T (cTnT), N-terminal prohormone brain natriuretic peptide (NT-proBNP), and inflammatory markers were quantified. RESULTS: More frequent HD regimens were associated with lower UF volumes and rates compared with CHD3. Intradialytic fall in systolic BP was reduced in CSD and HSD groups and abolished in HN group. Mean RWMAs per patient reduced with increasing dialysis intensity (CHD3 > CSD > HSD > HN). Home-based groups demonstrated lower high-sensitivity C-reative protein levels, with trends to lower cTnT and NT proBNP levels in the more frequent groups. CONCLUSIONS: Frequent HD regimes are associated with less dialysis-induced myocardial stunning compared with conventional HD. This may contribute to improved outcomes associated with frequent HD therapies. PMID- 21597029 TI - Bone alkaline phosphatase and mortality in dialysis patients. AB - BACKGROUND AND OBJECTIVES: Serum alkaline phosphatase (AP) is associated with vascular calcification and mortality in hemodialysis patients, but AP derives from various tissues of origin. The aim of this study was to assess the effect of bone-specific AP (BAP) on morbidity and mortality in dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From a prospective cohort study of incident dialysis patients in The Netherlands, all patients with measured BAP at 12 months after the start of dialysis (baseline) were included in the analysis (n = 800; mean age, 59 +/- 15 years; mean BAP = 18 +/- 13 U/L). By Cox regression analyses, we assessed the impact of BAP levels on short-term mortality (6 months) and longer-term mortality (4-year follow-up). RESULTS: High levels of BAP strongly affected short-term mortality. After adjustment for confounders, patients in the highest BAP tertile had a 5.7-fold increased risk of death within 6 months compared with patients in the lowest tertile. The effect applied to both cardiovascular and noncardiovascular mortality. Furthermore, high levels of BAP were associated with increased cardiovascular mortality in the longer term. In comparison with total AP, the effect sizes related to clinical outcomes were much higher for BAP. CONCLUSIONS: High levels of BAP were strongly associated with short-term mortality in dialysis patients, pointing out the important impact of bone turnover. Longitudinal assessments of BAP may be useful for the treatment monitoring in clinical practice in dialysis patients. PMID- 21597030 TI - Barriers to evaluation and wait listing for kidney transplantation. AB - BACKGROUND AND OBJECTIVES: Many factors have been shown to be associated with ESRD patient placement on the waiting list and receipt of kidney transplantation. Our study aim was to evaluate factors and assess the interplay of patient characteristics associated with progression to transplantation in a large cohort of referred patients from a single institution. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined 3029 consecutive adult patients referred for transplantation from 2003 to 2008. Uni- and multivariable logistic models were used to assess factors associated with progress to transplantation including receipt of evaluations, waiting list placement, and receipt of a transplant. RESULTS: A total of 56%, 27%, and 17% of referred patients were evaluated, were placed on the waiting list, and received a transplant over the study period, respectively. Older age, lower median income, and noncommercial insurance were associated with decreased likelihood to ascend steps to receive a transplant. There was no difference in the proportion of evaluations between African Americans (57%) and Caucasians (56%). Age-adjusted differences in waiting list placement by race were attenuated with further adjustment for income and insurance. There was no difference in the likelihood of waiting list placement between African Americans and Caucasians with commercial insurance. CONCLUSIONS: Race/ethnicity, age, insurance status, and income are predominant factors associated with patient progress to transplantation. Disparities by race/ethnicity may be largely explained by insurance status and income, potentially suggesting that variable insurance coverage exacerbates disparities in access to transplantation in the ESRD population, despite Medicare entitlement. PMID- 21597031 TI - Major depressive disorder, anxiety disorders, and cardiac biomarkers in subjects at high risk of obstructive sleep apnea. AB - OBJECTIVE: Cardiac biomarkers may be valuable when exploring potential mechanisms for the association between cardiovascular disease and psychiatric disorders. In subjects at increased risk for obstructive sleep apnea, we examined whether major depressive disorder (MDD), anxiety disorders, or the combination of these was associated with circulating C-reactive protein (CRP), cardiac troponin T (cTnT), or heart rate variability (HRV). METHODS: From the Akershus Sleep Apnea Project, 290 participants were assessed for MDD or any anxiety disorder by a physician using the Structured Clinical Interview for DSM-IV. Fasting blood samples were analyzed with high-sensitivity assays for CRP, cTnT, and HRV calculated from a Holter recording. Age, sex, hypertension, diabetes, hyperlipidemia, obesity, smoking, apnea-hypopnea index, and previous cardiovascular disease were adjusted for. RESULTS: The CRP levels (median [interquartile range], mg/L) were higher in depressive (2.7 [1.1-5.8]) versus nondepressive (1.3 [0.7-3.1], p = .02) and in anxious (2.8 [0.9-5.2]) versus nonanxious (1.3 [0.7-3.1], p = .01). MDD was independently associated with CRP (unstandardized beta = 0.387, p = .04), but anxiety was not (unstandardized beta = 0.298, p = .09). The CRP level was highest in subjects with comorbid MDD and anxiety (3.4 [1.1-7.8]). The unadjusted and adjusted odds ratios (95% confidence interval) for having measurable cTnT (> 3 ng/L) were 0.49 (0.24-1.07) and 0.92 (0.31-2.67) for MDD versus nondepressive and 0.38 (0.18-0.80) and 0.61 (0.30-2.05) for anxiety versus nonanxiety, respectively. HRV did not vary between groups. CONCLUSIONS: Although CRP was increased both in MDD and anxiety disorders, patients with comorbid MDD and anxiety may be particularly prone to increased systemic inflammation. Neither MDD nor anxiety disorders were associated with low-level myocardial damage or HRV. PMID- 21597032 TI - Leptin as a neuroactive agent. AB - OBJECTIVE: To review the literature regarding the role of leptin in psychiatric disorders. METHODS: A PubMed search was undertaken using the following keywords: leptin, psychosis, affective disorders, alcohol, psychiatry, depression, dementia, and eating disorders. The articles were restricted to the English language. RESULTS: The role of leptin in psychiatric populations has been the subject of increasing investigation. Basic science and clinical observations support a role for leptin in mediating cognition and reward processes. The role of leptin in psychiatric illnesses characterized by cognitive deficits has gained increased attention in recent years. Leptin deficiency and resistance have also been associated with eating disorders as well as affective, alcohol dependence, and psychotic disorders. The mechanisms underlining these associations remain to be determined. CONCLUSIONS: Clinical research suggests an important role of leptin in psychiatric illnesses. Given the morbidity associated with mental illness, clinical research on the role of leptin and related novel therapeutic modalities is needed. PMID- 21597033 TI - Operant conditioning of facial displays of pain. AB - OBJECTIVE: The operant model of chronic pain posits that nonverbal pain behavior, such as facial expressions, is sensitive to reinforcement, but experimental evidence supporting this assumption is sparse. The aim of the present study was to investigate in a healthy population a) whether facial pain behavior can indeed be operantly conditioned using a discriminative reinforcement schedule to increase and decrease facial pain behavior and b) to what extent these changes affect pain experience indexed by self-ratings. METHODS: In the experimental group (n = 29), the participants were reinforced every time that they showed pain indicative facial behavior (up-conditioning) or a neutral expression (down conditioning) in response to painful heat stimulation. Once facial pain behavior was successfully up- or down-conditioned, respectively (which occurred in 72% of participants), facial pain displays and self-report ratings were assessed. In addition, a control group (n = 11) was used that was yoked to the reinforcement plans of the experimental group. RESULTS: During the conditioning phases, reinforcement led to significant changes in facial pain behavior in the majority of the experimental group (p < .001) but not in the yoked control group (p > .136). Fine-grained analyses of facial muscle movements revealed a similar picture. Furthermore, the decline in facial pain displays (as observed during down-conditioning) strongly predicted changes in pain ratings (R(2) = 0.329). CONCLUSIONS: These results suggest that a) facial pain displays are sensitive to reinforcement and b) that changes in facial pain displays can affect self-report ratings. PMID- 21597034 TI - The folate hydrolase 1561C>T polymorphism is associated with depressive symptoms in Puerto Rican adults. AB - OBJECTIVE: To examine the associations between variants of genes involved in the uptake, retention, and metabolism of folate and depressive symptoms and to analyze whether such associations are direct or through mediation by folate or homocysteine. METHODS: We performed a cross-sectional analysis of data from 976 Puerto Rican adults, aged 45 to 75 years, residing in the greater Boston area, Massachusetts. Twelve single nucleotide polymorphisms (SNPs) in genes involved in folate uptake, retention, and metabolism were investigated. These include FOLH1 (folate hydrolase), FPGS (folate polyglutamate synthase), GGH (gamma-glutamyl hydrolase), MTHFR (methylenetetrahydrofolate reductase), MTR (methionine synthase), PCFT (proton-coupled folate transporter), and RFC1 (reduced folate carrier 1). The Center for Epidemiologic Studies Depression Scale (CES-D) was used to measure depressive symptoms. RESULTS: The FOLH1 rs61886492 C>T (or 1561C>T) polymorphism was significantly associated with lower CES-D score (p = .0025) after adjusting for age, sex, population admixture, smoking, and educational attainment. Individuals with the TT and TC genotypes were 49% less likely (odds ratio = 0.51, 95% confidence interval = 0.29-0.89) to report mild depressive symptoms (CES-D score >=16 and <=26) and 64% less likely (odds ratio = 0.36, 95% confidence interval = 0.18-0.69) to report moderate to severe depressive symptoms (CES-D score >26), compared with those with the CC genotype. No significant mediation effects by plasma folate or homocysteine on the associations between this single nucleotide polymorphism and CES-D score were observed. CONCLUSIONS: The FOLH1 1561C>T polymorphism may be associated with the risk of depressive symptoms. PMID- 21597035 TI - Depression and leukocyte telomere length in patients with coronary heart disease: data from the Heart and Soul Study. AB - OBJECTIVE: Shortened telomere length has been associated with mortality in patients with coronary heart disease (CHD) and is considered as an emerging marker of biologic age. Whether depression is associated with telomere length or trajectory has not been evaluated in patients with CHD. METHODS: In a prospective cohort study, we measured leukocyte telomere length in 952 participants with stable CHD at baseline and in 608 of these participants after 5 years of follow up. The presence of major depressive disorder in the past month was assessed using the computerized diagnostic interview schedule at baseline. We used linear and logistic regression models to evaluate the association of depression with baseline and 5-year change in leukocyte telomere length. RESULTS: Of the 952 participants, 206 (22%) had major depression at baseline. After the adjustment for age and sex, the patients with current major depressive disorder had shorter baseline telomere length than those without depression (mean [standard error] = 0.86 [0.02] versus 0.90 [0.01]; p = .02). This association was similar (but no longer statistically significant) after adjustment for body mass index, smoking, diabetes, left ventricular ejection fraction, statin use, antidepressant use, physical inactivity, and anxiety (0.85 [0.02] versus 0.89 [0.01], p = .06). Depression was not predictive of 5-year change in telomere length after adjustment for the mentioned covariates and baseline telomere length. CONCLUSIONS: Depression is associated with reduced leukocyte telomere length in patients with CHD but does not predict 5-year change in telomere length. Future research is necessary to elucidate the potential mechanisms underlying the association between depression and telomere length. PMID- 21597036 TI - The connexin 40 A96S mutation causes renin-dependent hypertension. AB - Deletion of the gap-junction-forming protein connexin40 leads to renin-dependent hypertension in mice, but whether observed human variants in connexin40, such as A96S, promote hypertension is unknown. Here, we generated mice with the A96S variant in the mouse connexin40 gene. Although mice homozygous for the A96S mutations had normal expression patterns of connexin40 in the kidney, they were hypertensive, had sixfold higher plasma renin concentrations, and had 40% higher levels of renin mRNA than controls. Renin-expressing cells were aberrantly located outside the media layer of afferent arterioles, and increased renal perfusion pressure did not inhibit renin secretion from kidneys isolated from homozygous A96S mice. Treatment with a low-salt diet in combination with an ACE inhibitor increased renin mRNA levels, plasma renin concentrations, and the number of aberrantly localized renin-producing cells. Taken together, these findings suggest that the A96S mutation in connexin40 leads to renin-dependent hypertension in mice. Modulation of renin secretion by BP critically depends on functional connexin40; with the A96S mutation, the aberrant extravascular localization of renin-secreting cells in the kidney likely impairs the pressure mediated inhibition of renin secretion. PMID- 21597038 TI - Comment on "Cutting edge: CD8+ T cell priming in the absence of NK cells leads to enhanced memory responses". PMID- 21597039 TI - Fusing HIV and chemokine receptors. PMID- 21597037 TI - Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells. AB - Epithelial-mesenchymal transition (EMT) contributes to the progression of renal tubulointerstitial fibrosis. The N-methyl-d-aspartate receptor (NMDAR), which is present in proximal tubular epithelium, is a glutamate receptor that acts as a calcium channel. Activation of NMDAR induces actin rearrangement in cells of the central nervous system, but whether it helps maintain the epithelial phenotype of the proximal tubule is unknown. Here, knockdown of NMDAR1 in a proximal tubule cell line (HK-2) induced changes in cell morphology, reduced E-cadherin expression, and increased alpha-SMA expression. Induction of EMT with TGF-beta1 led to downregulation of both E-cadherin and membrane-associated beta-catenin, reorganization of F-actin, expression of mesenchymal markers de novo, upregulation of Snail1, and increased cell migration; co-treatment with NMDA attenuated all of these changes. Furthermore, NMDA reduced TGF-beta1-induced phosphorylation of Erk1/2 and Akt and the activation of Ras, suggesting that NMDA antagonizes TGF-beta1-induced EMT by inhibiting the Ras-MEK pathway. In the unilateral ureteral obstruction model, treatment with NMDA blunted obstruction induced upregulation of alpha-SMA, FSP1, and collagen I and downregulation of E cadherin. Taken together, these results suggest that NMDAR plays a critical role in preserving the normal epithelial phenotype and modulating tubular EMT. PMID- 21597040 TI - Pillars article: HIV-1 entry cofactor: functional cDNA cloning of a seven transmembrane, G protein-coupled receptor. Science. 1996. 272: 872-877. PMID- 21597042 TI - Principles of electrospray ionization. AB - Electrospray ionization is today the most widely used ionization technique in chemical and bio-chemical analysis. Interfaced with a mass spectrometer it allows to investigate the molecular composition of liquid samples. With electrospray a large variety of chemical substances can be ionized. There is no limitation in mass which enables even the investigation of large non-covalent protein complexes. Its high ionization efficiency profoundly changed bio-molecular sciences because proteins can be identified and quantified on trace amounts in a high throughput fashion. This review article focusses mainly on the exploration of the underlying ionization mechanism. Some ionization characteristics are discussed which are related to this mechanism. Typical spectra of peptides, proteins and non-covalent complexes are shown and the quantitative character of spectra is highlighted. Finally the possibilities and limitations in measuring the association constant of bivalent non-covalent complexes are described. PMID- 21597041 TI - Basophils, IgE, and autoantibody-mediated kidney disease. AB - Basophils are of interest in immunology due to their ability to produce a Th2 signature cytokine, IL-4, following activation. A new understanding of the role of basophils in immunity shows novel functions at a cellular level through which basophils influence adaptive immunity. This review summarizes new advances in basophil biology and discusses new roles for basophils in human disease, especially in the mediation of the pathogenesis of lupus nephritis. Recently, basophils have been shown to contribute to self-reactive Ab production in systemic lupus erythematosus and may enhance pre-existing loss of B cell tolerance, suggesting that basophils, IL-4, and IgE mediate the pathogenesis of lupus nephritis by promoting the Th2 environment and activating autoreactive B cells. In addition to envisaging exciting therapeutic prospects, these novel findings open the way for the study of basophils in other autoimmune and renal diseases. PMID- 21597043 TI - Insulin receptor substrate 2 is a negative regulator of memory formation. AB - Insulin has been shown to impact on learning and memory in both humans and animals, but the downstream signaling mechanisms involved are poorly characterized. Insulin receptor substrate-2 (Irs2) is an adaptor protein that couples activation of insulin- and insulin-like growth factor-1 receptors to downstream signaling pathways. Here, we have deleted Irs2, either in the whole brain or selectively in the forebrain, using the nestin Cre- or D6 Cre-deleter mouse lines, respectively. We show that brain- and forebrain-specific Irs2 knockout mice have enhanced hippocampal spatial reference memory. Furthermore, NesCreIrs2KO mice have enhanced spatial working memory and contextual- and cued fear memory. Deletion of Irs2 in the brain also increases PSD-95 expression and the density of dendritic spines in hippocampal area CA1, possibly reflecting an increase in the number of excitatory synapses per neuron in the hippocampus that can become activated during memory formation. This increase in activated excitatory synapses might underlie the improved hippocampal memory formation observed in NesCreIrs2KO mice. Overall, these results suggest that Irs2 acts as a negative regulator on memory formation by restricting dendritic spine generation. PMID- 21597045 TI - The role of serum basic fibroblast growth factor, estradiol and urine basic fibroblast growth factor in differentiating infantile haemangiomas from vascular malformations. AB - OBJECTIVE: To investigate the role of serum basic fibroblast growth factor (bFGF), estradiol (E2) and urine bFGF in differentiating infantile haemangiomas from vascular malformations. METHOD: Between October 2007 and January 2009, 97 patients with haemangiomas and 25 patients with vascular malformations who had not been treated previously were included in this prospective study. Forty-eight patients with cleft lip and/or palate were selected as controls. The age of all subjects ranged from 1 to 30 months. The serum and urine levels of bFGF were determined by enzyme-linked immunosorbent assay (ELISA). The serum levels of E2 were examined via radioimmunoassay. All data were analysed with SPSS 11.5 software package. RESULTS: The concentration of serum and urine bFGF was significantly different among the three groups (haemangiomas, vascular malformations and controls) (P = 0.027, P = 0.001). Significantly different urine bFGF levels were found in patients with proliferating and involuting haemangiomas (P = 0.04). The serum E2 levels were significantly higher in patients with haemangiomas than vascular malformations (P = 0.001) and controls (P = 0.001). CONCLUSION: Serum bFGF and E2 as well as urine bFGF can be used to supplement the clinical diagnosis of congenital vascular anomalies. Urine bFGF combined with serum E2 may be the most potential markers for diagnosing haemangiomas and determining the proliferating stage of haemangiomas. PMID- 21597044 TI - Unraveling the contributions of the diencephalon to recognition memory: a review. AB - Both clinical investigations and studies with animals reveal nuclei within the diencephalon that are vital for recognition memory (the judgment of prior occurrence). This review seeks to identify these nuclei and to consider why they might be important for recognition memory. Despite the lack of clinical cases with circumscribed pathology within the diencephalon and apparent species differences, convergent evidence from a variety of sources implicates a subgroup of medial diencephalic nuclei. It is supposed that the key functional interactions of this subgroup of diencephalic nuclei are with the medial temporal lobe, the prefrontal cortex, and with cingulate regions. In addition, some of the clinical evidence most readily supports dual-process models of recognition, which assume two independent cognitive processes (recollective-based and familiarity based) that combine to direct recognition judgments. From this array of information a "multi-effect multi-nuclei" model is proposed, in which the mammillary bodies and the anterior thalamic nuclei are of preeminent importance for recollective-based recognition. The medial dorsal thalamic nucleus is thought to contribute to familiarity-based recognition, but this nucleus, along with various midline and intralaminar thalamic nuclei, is also assumed to have broader, indirect effects upon both recollective-based and familiarity-based recognition. PMID- 21597047 TI - The impact of insurance company mandated compression stocking trial on rate of intervention in patients with symptomatic venous reflux disease. AB - OBJECTIVE: Insurance companies have criteria for a venous intervention to be a covered procedure, including symptoms, vein size, and a trial of conservative therapy with compression stockings. The goal of this study was to see the impact of such mandated stocking use on ultimate intervention. METHOD: A retrospective review was done of prospectively gathered data entered in the electronic medical record. Two-hundred consecutive new patients evaluated at our vein center were included. RESULTS: Forty-four of the 200 patients did not require any procedures and 39 patients had procedures scheduled for small or asymptomatic venous changes that did not meet insurance criteria. This left 117 patients with venous symptoms in whom evaluation concluded that a corrective procedure could be performed. These interventions included largely radiofrequency ablation and phlebectomy. Of these 117 patients, 48 had previously used compression stockings. In the remaining 69 patients, stockings were provided on the day of initial consultation and these 69 patients served as the subjects for this review. At three month follow up, one patient reported the stockings help enough that she did not want to pursue correction. Two patients had continued pain and were planning correction once other unrelated issues resolved. Three patients said they never wore the stockings. Sixty-one patients had procedures performed. The average length of stocking use in patients who chose corrective procedures was 103 days. One patient could not be reached. CONCLUSION: Of the patients that reported they used the stockings as prescribed, one chose chronic stocking therapy and 63 patients either had procedures or were planning procedures. Use of prescription stockings was effective in avoiding intervention in one of 64 cases (2%), despite an average trial of 103 days. These results cast doubt on the merits of the use of an insurance company mandated stocking trial. PMID- 21597046 TI - Lymphoscintigraphic findings: delayed oedema after great saphenous vein harvesting. AB - OBJECTIVE: The aim of this study was to identify lymphoscintigraphic changes associated with lower-extremity oedema after the harvesting of the saphenous vein using a series of short Q2 incisions for coronary bypass. METHOD: Forty-four patients (32 males and 12 females) with a mean age of 62.7 +/- 7.8 (47-75 years old) were evaluated in a retrospective, quantitative, cross-sectional study from June 2007 to January 2008, three to 188 months (mean: 46 months) after the surgical procedure. Assessment was by water displacement volumetry and lymphoscintigraphy of the lower limbs. Results expressed as means with standard deviations were compared employing the Student's t-test and the chi-square or Fisher's exact tests were used to compare data expressed as frequencies. An alpha error of 5% was considered acceptable (P <= 0.05). RESULTS: The presence of dermal backflow, as identified by lymphoscintigraphy with an accumulation of radiotracer in the thoracic duct and popliteal lymph nodes was significantly greater on the operated side. CONCLUSION: There was a significant association between dermal backflow and delayed oedema. PMID- 21597048 TI - Assessment of dermal exposure to bitumen condensate among road paving and mastic crews with an observational method. AB - OBJECTIVE: To assess dermal exposure to bitumen condensate among road pavers and indoor mastic workers in multiple crews using a semi-quantitative observational method [DeRmal Exposure Assessment Method (DREAM)]. METHODS: Two skilled observers assessed dermal exposure to bitumen condensate among 85 asphalt workers from 12 crews from nine companies active within four European countries using the DREAM methodology, which produces an estimate of exposure expressed in dimensionless DREAM units. Both observers independently evaluated each crew member's job (N = 14 jobs) for road paving and mastic applications. Potential and actual dermal exposures were estimated for hands and for the rest of the body separately, taking into account the effect of protective clothing. To evaluate the reproducibility of the observational method intra-class correlation coefficients (ICCs) were estimated. The exposures in DREAM units were modelled using linear mixed models to estimate average relative scores for each job. Correlations between dermal exposure parameters were evaluated by estimating Pearson correlation coefficients. RESULTS: A total of 170 observations were completed by two observers independently (n = 118 and n = 52 for 59 road pavers and 26 mastic workers, respectively) in 11 days. The mean ICCs (for potential and actual exposure in DREAM units) varied between 0.74 and 0.80 with values for actual units being slightly higher. Geometric mean potential dermal exposure units of mastic workers were higher than for road pavers (factor 3 for hands and factor 4 for rest of the body). Differences for actual dermal exposure units were smaller for hands (factor 2) and larger for actual exposure units of rest of the body (factor 5). Differences in dermal exposure at the hands between jobs within a paving crew were much larger than between jobs within a mastic crew. Within paving crews, a consistent pattern for all exposure units emerged with 'screed man' and 'raker' as the two highest exposed jobs. Within mastic crews, 'driver dumper truck' and 'spreader of mastic' were scored as the two jobs with the highest exposure units. Potential and actual exposure units were highly correlated. Hands were more profoundly exposed than the rest of the body, with transfer from contaminated surface to the hands as the most important route. CONCLUSIONS: DREAM observations were reproducible and showed a consistent dermal exposure pattern among the observed crews. The study provided a clear picture of dermal exposure among road pavers and indoor mastic workers, with the mastic workers being considerably more highly exposed. The most important route of exposure appeared to be transferred from contaminated surfaces to the hands. PMID- 21597049 TI - Occupational exposures to styrene vapor in a manufacturing plant for fiber reinforced composite wind turbine blades. AB - OBJECTIVES: A utility-scale wind turbine blade manufacturing plant requested assistance from the National Institute for Occupational Safety and Health (NIOSH) in controlling worker exposures to styrene at a plant that produced 37 and 42 m long fiber-reinforced wind turbine blades. The plant requested NIOSH assistance because previous air sampling conducted by the company indicated concerns about peak styrene concentrations when workers entered the confined space inside of the wind turbine blade. NIOSH researchers conducted two site visits and collected personal breathing zone and area air samples while workers performed the wind turbine blade manufacturing tasks of vacuum-assisted resin transfer molding (VARTM), gelcoating, glue wiping, and installing the safety platform. METHODS: All samples were collected during the course of normal employee work activities and analyzed for styrene using NIOSH Method 1501. All sampling was task based since full-shift sampling from a prior Occupational Safety and Health Administration (OSHA) compliance inspection did not show any exposures to styrene above the OSHA permissible exposure limit. During the initial NIOSH site visit, 67 personal breathing zone and 18 area air samples were collected while workers performed tasks of VARTM, gelcoating, glue wipe, and installation of a safety platform. After the initial site visit, the company made changes to the glue wipe task that eliminated the need for workers to enter the confined space inside of the wind turbine blade. During the follow-up site visit, 12 personal breathing zone and 8 area air samples were collected from workers performing the modified glue wipe task. RESULTS: During the initial site visit, the geometric means of the personal breathing zone styrene air samples were 1.8 p.p.m. (n = 21) for workers performing the VARTM task, 68 p.p.m. (n = 5) for workers installing a safety platform, and 340 p.p.m. (n = 14) for workers performing the glue wipe task, where n is the number of workers sampled for a given mean result. Gelcoating workers included job categories of millers, gelcoat machine operators, and gelcoaters. Geometric mean personal breathing zone styrene air samples were 150 p.p.m. (n = 6) for millers, 87 p.p.m. (n = 2) for the gelcoat machine operators, and 66 p.p.m. (n = 19) for gelcoaters. The geometric mean of the personal breathing zone styrene air samples from the glue wipe task measured during the follow-up site visit was 31 p.p.m. (n = 12). CONCLUSIONS: The closed molding VARTM process was very effective at controlling worker exposures to styrene. Personal breathing zone styrene air samples were reduced by an order of magnitude after changes were made to the glue wipe task. The company used chemical substitution to eliminate styrene exposure during the installation of the safety platform. Recommendations were provided to reduce styrene concentrations during gelcoating. PMID- 21597050 TI - Primary HIV Infection Associated with Acute Urinary Retention. PMID- 21597051 TI - International conference on viral hepatitis 2011. PMID- 21597052 TI - Feather pecking behavior in laying hens: hypothalamic gene expression in birds performing and receiving pecks. AB - Feather pecking (FP) is a welfare and economic problem in the egg production sector. Beak trimming, the current method used to reduce FP, is also criticized. The present study used gene expression to explore the biological mechanisms underlying this behavior, which could lead to a greater understanding of the cause and a tool to mitigate the problem. White Leghorn hens performing and receiving FP, as well as neutral control birds, were identified on a commercial farm. Hypothalamic RNA from 11 peckers, 10 victims, and 10 controls was hybridized onto GeneChip Chicken Genome Arrays (Affymetrix Inc., Santa Clara, CA) to compare gene expression profiles in the different groups. Eleven transcripts corresponding to 10 genes differed significantly between the 3 groups (adjusted P < 0.05). Eight of these transcripts differed in the peckers compared with the controls, 1 was upregulated in the victims compared with the controls, and 6 differed significantly in the peckers compared with the victims. Additionally, 5 transcripts showed a trend (adjusted P < 0.1) to differ in the pecker-victim comparison. Some of the products of the differently expressed genes are involved in disorders, such as intestinal inflammation and insulin resistance, which fit well with the previously proposed hypothesis that FP is an abnormal foraging behavior. Other findings may also support the proposal that FP is linked to immune mechanisms and may serve as an animal model for obsessive compulsive disorder in humans. In conclusion, this study provides a gene list that may be useful in further research on the mechanisms behind FP. PMID- 21597053 TI - Effect of amino acid formulation and supplementation on nutrient mass balance in turkeys. AB - Nutrient mass balances were determined for turkeys fed 4 diets in a 2 * 2 factorial design to investigate the effects of diets with 100 or 110% of NRC (1994)-recommended amino acid (AA) formulation and diets containing 2 (Lys and Met) or 3 (Lys, Met, and Thr) supplemental AA. Hybrid tom turkeys were raised and monitored in 12 rooms (3 replicates/diet; 20 toms/room at hatch, culled to 16 at 21 d and then to 12 at 28 d of age). All feed and litter entering and leaving the rooms were quantified and analyzed for nutrient content. Air emissions were measured throughout the 20-wk study. The 100% NRC diets resulted in lower cumulative loss of NH(3) (by 14%) and H(2)S (by 21%) as compared with the 110% NRC diets. Reductions corresponded to lower N and S intake. Feeding the 3 supplemental AA diets resulted in lower N excretion (by 12%) and lower cumulative loss of NH(3) (by 23%) as compared with the 2 supplemental AA diets. The NH(3) emission as a percentage of N output was not significantly influenced by dietary CP (100 vs. 110% of NRC); however, the 3 supplemental AA diets resulted in less NH(3) emitted as a percentage of N output as compared with the 2 supplemental AA diets (9.9 vs. 11.8%). Across all 4 diets, N partitioning averaged 31.4, 56.9, and11.4% for retention, excretion, and air emission, respectively. The N loss estimated from the mass balance approach (9.6%) was comparable with the measured N loss as air emission (11.9%). Partitioning of P averaged 31.9 and 68.1% for retention and excretion, respectively. Partitioning of S averaged 27.5, 72.1, and 0.5% for retention, excretion, and air emission, respectively. The results illustrated the fate of N, P, and S in a turkey production system and demonstrated the potential for reducing nutrient excretion and air emissions from turkeys through diet modification of AA. PMID- 21597054 TI - Litter ammonia generation: moisture content and organic versus inorganic bedding materials. AB - Negative impacts on the environment, bird well-being, and farm worker health indicate the need for abatement strategies for poultry litter NH(3) generation. Type of bedding affects many parameters related to poultry production including NH(3) losses. In a randomized complete block design, 3 trials compared the cumulative NH(3) volatilization for laboratory-prepared litter (4 bedding types mixed with excreta) and commercial litter (sampled from a broiler house during the second flock on reused pine wood chips). Litters were assessed at the original moisture content and 2 higher moisture contents. Broiler excrement was mixed with pine wood shavings, rice hulls, sand, and vermiculite to create litter samples. Volumetrically uniform litter samples were placed in chambers receiving humidified air where the exhaust passed through H(3)BO(3) solution, trapping litter-emitted NH(3). At the original moisture content, sand and vermiculite litters generated the most NH(3) (5.3 and 9.1 mg of N, respectively) whereas wood shavings, commercial, and rice hull litters emitted the least NH(3) (0.9-2.6 mg of N). For reducing NH(3) emissions, the results support recommendations for using wood shavings and rice hulls, already popular bedding choices in the United States and worldwide. In this research, the organic bedding materials generated the least NH(3) at the original moisture content when compared with the inorganic materials. For each bedding type, incremental increases in litter moisture content increased NH(3) volatilization. However, the effects of bedding material on NH(3) volatilization at the increased moisture levels were not clearly differentiated across the treatments. Vermiculite generated the most NH(3) (26.3 mg of N) at the highest moisture content. Vermiculite was a novel bedding choice that has a high water absorption capacity, but because of high NH(3) generation, it is not recommended for further study as broiler bedding material. Controlling unnecessary moisture inputs to broiler litter is a key to controlling NH(3) emissions. PMID- 21597055 TI - Turkeys are equally susceptible to foot pad dermatitis from 1 to 10 weeks of age and foot pad scores were minimized when litter moisture was less than 30%. AB - Two randomized block experiments were conducted to determine the effects of litter moisture and age on the development of foot pad dermatitis (FPD) in female growing turkeys. Pens were littered with fresh wood shavings at the start of the experiments and excreta and soiled litter were replaced twice daily to maintain clean litter. In experiment 1 the birds (n = 5/pen) were subjected to increasing quantities of water to produce different litter moisture contents for 6 d. In experiment 2 the effects on FPD of high litter moisture for 6 d at 7, 21, 42, and 70 d were assessed. Scores for FPD, food intake, BW gain, litter moisture, litter pH, and behavior were assessed after 6 d on wet compared with dry, clean wood shavings litter. A linear effect was found of increasing litter moisture on mean foot score. Mean foot score increased with age on transfer to wet litter but the effect of age was relatively small. Body weight gains were similar in wet and dry treatments whereas feed intake was higher in turkeys kept on wet litter compared with dry litter. The results are consistent with the conclusion that high litter moisture is the primary cause of FPD and that turkeys are similarly susceptible from 7 to 70 d of age. PMID- 21597056 TI - Floor laying by Pekin ducks: effects of nest box ratio and design. AB - The laying of eggs outside nest boxes is a common problem in poultry production systems. Factors potentially contributing to floor laying by Pekin ducks were investigated. In a 2 * 2 factorial design, 16 groups of 18-wk-old ducks (8/group) were provided access to either 2 (4 ducks/box) or 8 (1 duck/box) closed-topped or open-topped nest boxes. Egg locations were recorded daily for 16 wk. Video analyses were used to determine the time of day eggs were laid on the floor when the ducks were 18 to 22, 26, 30, and 34 wk of age. An analysis of nontoxic dye deposition in the egg yolk was conducted on wk 30, 32, and 36 to determine the contribution of each duck to floor laying. The proportion of floor eggs was especially high early in the laying cycle, reaching 84 and 44% of eggs laid in pens offering ratios of 4 ducks/box and 1 duck/box, respectively, when ducks were 22 wk of age. Repeated measures ANOVA revealed that although the proportion of floor eggs decreased over time (F(3,9) = 29.29, P < 0.0001), it remained greater in the groups housed with 4 ducks/box vs. 1 duck/box (F(1,11) = 24.09, P = 0.0005). The proportion of floor eggs was not affected by box design (F(1,11) = 0.08, P = 0.8). Not all available nest boxes contained eggs on a given day, and the distribution of eggs within the pen was clumped. However, it was unlikely that this reflected nest box location preferences because the locations of the eggs laid within the nest boxes changed over time. Taken together, these results suggest that floor laying by Pekin ducks may be caused in part by insufficient nest box availability. However, the clumped distribution of eggs suggests that other social factors, such as conspecific attraction, may also be important. PMID- 21597057 TI - Sensitivity to disinfection of bacterial indicator organisms for monitoring the Salmonella Enteritidis status of layer farms after cleaning and disinfection. AB - The present study evaluated Escherichia coli, Enterococcus faecalis, and Enterococcus hirae as potential indicator organisms for the possible Salmonella Enteritidis (SE) presence in layer farms after cleaning and disinfection by comparing their susceptibility to disinfection. A quantitative suspension disinfection test according to European Standard EN1656 was performed using disinfection products CID20 and Virocid (both from CID Lines, Ieper, Belgium). In a preliminary test, the sensitivity to both disinfection products was compared between ATCC strains of SE, E. coli, En. faecalis, and En. hirae. The sensitivity of SE to disinfection was most comparable to that of E. coli. A second disinfection test compared the elimination of E. coli to SE ATCC strains as well as field strains. Results showed no significant effect regarding the strain (P > 0.05 for CID20 and Virocid), meaning that no difference was detected in sensitivity toward disinfection. When comparing the sensitivity in general at species level for all concentrations of disinfectant used, no significant difference was found between E. coli and SE in sensitivity to Virocid (P > 0.05). In conclusion, because of its similar response to disinfection in a suspension disinfection test, E. coli could be used as an indicator for possible Salmonella presence after cleaning and disinfection. PMID- 21597058 TI - Use of implantable temperature transponders for the determination of air cell temperature, eggshell water vapor conductance, and their functional relationships in embryonated broiler hatching eggs. AB - Broiler hatching eggs obtained from a 29-wk-old Ross 308 breeder flock were weighed and set on 8 tray levels (60 eggs/level) of a single incubator. On d 10.5 of incubation, the eggs were weighed, and temperature transponders were implanted in the air cells of 4 randomly selected embryonated eggs per tray level for determination of internal egg temperature (IT). Two water-filled vials per tray level containing transponders were also placed within 5 cm of the implanted eggs for determination of external egg temperature (ET). Between 10.5 and 18.5 d of incubation, ET and IT were recorded every 12 h. Egg weights and embryo survival were determined on 10.5 and 18.5 d of incubation and were used for the calculation of average daily incubational weight loss of embryonated eggs (EWL) and average daily percentage of EWL. Approximately 75% (24 out of 32) of the embryos in the implanted eggs survived through d 18.5 of incubation. Mean ET and IT were used to calculate the water vapor pressure gradient across the eggshell, which was subsequently used with EWL to calculate eggshell water vapor conductance (G(H2O)) and specific G(H2O) (g(H2O); G(H2O) adjusted to a 100-g set egg weight basis). Mean percentage of EWL, ET, IT, G(H2O), and g(H2O) for the 10.5- to 18.5-d incubation period were 0.546 +/- 0.02%, 37.1 +/- 0.03 degrees C, 37.8 +/- 0.09 degrees C, 13.9 +/- 0.47 mg of H(2)O/d per Torr, and 24.5 +/- 0.75 mg of H(2)O/d per Torr per 100 g, respectively. It was concluded that temperature transponders may be successfully implanted in the air cells of broiler hatching eggs to determine ET, IT, G(H2O), and g(H2O) in Ross * Ross 308 broiler hatching eggs. Nevertheless, increased embryo survivability by further improving the implantation procedure may increase the practicality of temperature transponder use in commercial settings. PMID- 21597059 TI - Genetic parameters of feeding behavior traits and their relationship with live performance traits in modern broiler lines. AB - Current selection goals in broiler breeding focus on the improvement of live performance traits, such as feed intake, BW, and feed conversion ratio (FCR). The use of electronic feeders allows measurement of feed intake of individuals housed in groups as well as the identification of different feeding behaviors. Feed intake can thus be split into underlying feeding behavior traits, allowing the estimation of genetic correlations and assessment of the genetic consequences of selecting for performance traits on feeding behavior traits. To investigate the genetic relationships between performance traits and feeding behavior, data of visits to feeders by birds from 4 lines of broilers that differed in selection focus on growth and FCR were analyzed. Visits were recorded electronically and grouped into meals using an existing model for estimating meal criteria. Mean individual feeding behavior traits were then calculated across the entire test period (2 to 5 wk of age). Records were available for between 14,000 and 18,000 birds/line. Analyzed feeding behavior traits were meals per day, meal size, visits per meal, meal duration, nonfeeding time in meal, time feeding per day, proportion of meal spent feeding, feeding rate, and ADFI. Analyzed performance traits were 35-d BW, total feed intake over the entire test period, and FCR. All feeding behavior traits showed moderate to high heritabilities (0.24 to 0.57) but low genetic correlations with performance traits (-0.20 to 0.18), except for ADFI, which was moderately correlated with total intake on test (0.57) and highly correlated with FCR (0.91). The low genetic correlations indicate that the difference in selection intensity among lines for these performance traits has had limited effect on feeding behavior. Different feeding strategies that would result in favorable breeding values for FCR were identified, adding opportunities for further improvements in feed efficiency within and across environments. PMID- 21597060 TI - Allele-specific expression analysis reveals CD79B has a cis-acting regulatory element that responds to Marek's disease virus infection in chickens. AB - Marek's disease (MD) is a T cell lymphoma disease of domestic chickens induced by the Marek's disease virus (MDV), a highly infectious and naturally oncogenic alphaherpesvirus. Enhancing genetic resistance to MD in poultry is an attractive method to augment MD vaccines, which protect against MD but do not prevent MDV replication and horizontal spread. Previous work integrating QTL scans, transcript profiling, and MDV-chicken protein-protein interaction screens revealed 3 MD resistance genes; however, a major challenge continues to be the identification of the other contributing genes. To aid in this search, we screened for allele-specific expression (ASE) in response to MDV infection, a simple and novel method for identifying polymorphic cis-acting regulatory elements, which may contain strong candidate genes with specific alleles that confer MD genetic resistance. In this initial study, we focused on immunoglobulin beta (CD79B) because it plays a critical role in the immune response and, more important, is transcriptionally coupled with growth hormone (GH1), one of the previously identified MD resistance genes. Using a coding SNP in CD79B and pyrosequencing to track the relative expression of each allele, we monitored ASE in uninfected and MDV-infected F(1) progeny from reciprocal intermatings of highly inbred chicken lines 6(3) (MD resistant) and 7(2) (MD susceptible). Upon screening 3 tissues (bursa, thymus, and spleen) at 5 time points (1, 4, 7, 11, and 15 d postinfection), we observed that MDV infection alters the CD79B allelic ratios in bursa and thymus tissues at 4 and 15 d postinfection in both mating directions. Our results suggest that CD79B has a cis-acting regulatory element that responds to MDV infection and probably cooperates with GH1 in conferring genetic resistance to MD. This result helps validates the use of ASE screens to identify specific candidate genes for complex traits such as genetic resistance to MD. PMID- 21597061 TI - An antimicrobial peptide is downregulated in the small intestine of Eimeria maxima-infected chickens. AB - Avian coccidiosis is a major disease of poultry caused by the intestinal protozoa Eimeria. Infection leads to reduced feed efficiency and BW gain, resulting in severe economic losses for the poultry industry. Aviagen line A and line B birds show a differential response to Eimeria infection, with line B birds exhibiting higher lesion scores and mortality. The objective of this study was to examine differential intestinal gene expression between 2-wk-old line A and B chicks in response to a challenge with Eimeria maxima. After challenge with 1 * 10(4) oocysts/chick, more than 40% of line A chicks had lesion scores of 0 to 1 (scale of 0 to 4), similar to control chicks. In contrast, all line B chicks challenged at this same dose had lesion scores of 2 to 4. Total RNA was extracted from the jejunum of control and challenged chicks from both lines A and B. Microarray analysis revealed that liver-expressed antimicrobial peptide 2 (LEAP-2), a component of the innate immune system, was downregulated 20-fold in line A challenged chicks with lesion scores of 2 to 4 compared with line A control chicks, and was downregulated 11- to 71-fold in line B challenged chicks with lesion scores of 2 to 4 compared with line B control chicks. Liver-expressed antimicrobial peptide 2 was downregulated less than 2-fold in line A challenged chicks with lesion scores of 1 compared with line A control chicks, indicating that these chicks were similar to control chicks in their expression level of LEAP-2. Other genes (cytochrome P450, heat shock protein 25, keratin 19, and amino acid transporter ASCT1) showed different patterns of over- or underexpression. The expression of LEAP-2 was verified using real-time PCR, revealing a correlation between lesion score and magnitude of LEAP-2 downregulation for both line A and line B chicks. Thus, LEAP-2 may serve as a useful marker for identification of chickens resistant to E. maxima infection and potentially other Eimeria spp. PMID- 21597062 TI - Influence of organic zinc supplementation on the antioxidant status and immune responses of broilers challenged with Eimeria tenella. AB - An experiment was conducted to investigate the influence of Zn supplementation on the performance, antioxidant status, and immune responses of broilers challenged with Eimeria tenella. A total of 384 male broilers (1 d old) were assigned to 8 treatments consisting of 8 replicates of 6 chicks each. A basal corn-soybean meal diet (29.6 mg of Zn/kg) was supplemented with methionine hydroxyl analog-Zn chelate at 0, 20, 40, and 60 mg/kg of diet. At 21 d of age, birds were orally gavaged with 1.5 * 10(4) sporulated E. tenella oocysts. Dietary Zn supplementation had no effect on growth performance of either the challenged or nonchallenged birds. Activities of Cu-Zn superoxide dismutase and glutathione peroxidase were increased (P < 0.001) with increasing Zn levels in both the challenged and nonchallenged groups. Lipid peroxidation tended to be reduced (P = 0.08) at Zn inclusion of 20 and 40 mg/kg. In vitro lymphocyte proliferation responses to mitogen concanavalin A and LPS were not influenced by dietary Zn or challenge. The main effects of Zn level and challenge were significant for secretory IgA on d 28 (P < 0.01) and 35 (P < 0.001). During both periods, secretory IgA of birds receiving dietary Zn supplementation was higher (P < 0.05) than that of those receiving no Zn supplementation. Birds fed Zn supplementation excreted fewer oocysts in the excreta than those receiving no Zn supplement (P < 0.001). Results indicated that organic Zn supplementation reduced oxidative stress and improved some immune responses irrespective of whether birds were healthy or challenged with E. tenella. PMID- 21597063 TI - The effects of propolis on antibody production by laying hens. AB - Propolis is a honeybee product showing several biological properties that enhance the immune response, depending on the concentration and intake period. Because propolis possesses an immunomodulatory action on mammals, the objective of our study was to investigate the effects of propolis on the humoral immune response of laying hens by evaluating antibody production. Laying hens (ISA Brown) were divided into 5 groups with 7 birds each. Group 1 was a nonimmunized control, whereas birds in group 2 were immunized intravenously with SRBC, and those in groups 3, 4, and 5 were treated intraperitoneally with propolis (2, 10, and 50 mg/kg, respectively) on 3 consecutive days and then inoculated intravenously with SRBC. Hematological and serological analyses were carried out on d 0, 3, and 38. Natural and specific antibody levels were determined by hemagglutination with rabbit red blood cells and SRBC, respectively. Propolis-treated birds (50 mg/kg) showed a significant decline in heterophils and in the heterophil:lymphocyte ratio. After SRBC immunization, significant increases in levels of IgG were observed in groups 4 and 5. Furthermore, higher levels of natural antibodies were observed in propolis-treated laying hens. The administration of propolis to laying hens increased the production of IgG specific to SRBC and natural antibodies, and could be used to increase antigen-specific antibody responses to vaccines. PMID- 21597064 TI - Body temperature responses of Pekin ducks (Anas platyrhynchos domesticus) exposed to different pathogens. AB - Poultry, like mammals and other birds, develop fever when exposed to compounds from gram-negative bacteria. Mammals also develop fever when exposed to the constituents of viruses or gram-positive bacteria, and the fevers stimulated by these different pathogenic classes have discrete characteristics. It is not known whether birds develop fever when infected by viruses or gram-positive bacteria. Therefore, we injected Pekin ducks with muramyl dipeptide, the cell walls of heat killed Staphylococcus aureus, or the viral mimic polyinosinic:polycytidylic acid and monitored their body temperature (T(b)). For comparative purposes we also injected a group of ducks with lipopolysaccharide, the only known pyrogen in birds. We then compared the T(b) invoked by each injection with the T(b) after an injection of saline. Muramyl dipeptide did not affect T(b). The cell walls of heat-killed S. aureus invoked long-lasting, dose-dependent fevers with relatively low magnitudes. Polyinosinic:polycytidylic acid invoked dose-dependent fevers with high febrile peaks. Fever is a well-known clinical sign of infection in mammals, and the results of this study indicate that the pattern of increase in T(b) could serve as an indicator for diverse pathogenic diseases in birds. PMID- 21597065 TI - Nutritive value of false yam (Icacina oliviformis) tuber meal for broiler chickens. AB - False yam (Icacina oliviformis syn. Icacina senegalensis) is a drought-resistant plant in West and Central Africa that produces a large tuber with a high starch content, but it contains antinutritive factors (terpenes). The objective was to evaluate its feed value for broilers when the tuber was sun-dried (SFYTM) or boiled (BFYTM). In experiment 1, the tubers were peeled, diced, sun-dried (5 d), and milled. In experiment 2, the diced tubers were boiled (2 h), dried (8 d), and milled. Each meal was substituted for corn (Zea mays, wt/wt basis) at levels of 0, 3, 6, and 9% in a basal broiler grower diet (21% CP; 2,967 kcal/kg of ME) and fed to broiler chicks from 21 to 56 d of age, using a completely randomized design (4 treatments, 3 replicates). Each replicate had 10 chicks. Nutrient concentrations (% of DM) of SFYTM were CP (5.41), ether extract (1.60), NDF (28.61), starch (48.63), ash (2.19), and gross energy (4,067 kcal/kg of DM), and those of BFYTM were CP (6.46), ether extract (0.98), NDF (32.37), starch (43.12), ash (2.76), and gross energy (4,139 kcal/kg of DM). The contents of total resins in the meals ranged from 2.28% (BFYTM) to 3.75% (SFYTM). In experiment 1, increasing the dietary level of SFYTM linearly (P < 0.001) decreased feed intake (P < 0.001), BW gain (P = 0.004), G:F (P = 0.041), and dressed carcass yield (P = 0.011). However, in experiment 2, no differences were observed in growth performance (P > 0.05) between any of the dietary treatments. In both experiments, mortality was 2.00% or less (P > 0.05). Inclusion of each meal in the diets did not affect the health of the birds, and no adverse changes in blood hemoglobin, hematocrit, and white blood cells were observed. PMID- 21597066 TI - Levels of endogenous beta-glucanase activity in barley affect the efficacy of exogenous enzymes used to supplement barley-based diets for poultry. AB - To improve the nutritive value of barley-based diet for broilers, 2 experiments using 2 different barley lots were performed to evaluate the capacity of a mesophilic cellulase when fused to a beta-glucan specific family 11 carbohydrate binding module. The data revealed that the recombinant beta-glucanase derivatives were not appropriate for feed supplementation because of a lack of stability at acidic pH levels. However, under the same experimental conditions, a commercial enzyme mixture improved the nutritive value of 1 of the cereal lots used. Analysis of the nutritive value of the 2 barleys revealed intrinsic differences in the levels of endogenous beta-glucanase activity. These differences were extensively evident when the studies were expanded to a range of 64 barley lots. Thus, to clarify the effect of endogenous cellulases on the efficacy of exogenous beta-glucanases used to supplement barley-based diets for poultry, 2 barley lots presenting low and high levels of endogenous plant cell wall-degrading enzymes were selected. These lots were used to prepare 2 barley-based diets, which were supplemented with or without a commercial enzyme product and fed to broiler chicks. The data revealed that the exogenous enzymes were effective when the basal diet presented low levels of endogenous beta-glucanases but were unable to improve the nutritive value of the barley lot displaying higher beta-glucanase activity. Thus, these studies suggest that levels of endogenous beta-glucanases may affect the efficacy of exogenous enzymes used to improve the nutritive value of barley-based diets for broilers. The development of a quick beta-glucanase assay that could be applied for cereal-based feeds may help identify those barley based diets that are more responsive to the action of feed enzymes. PMID- 21597067 TI - Effect of eggshell temperature and oxygen concentration during incubation on the developmental and physiological status of broiler hatchlings in the perinatal period. AB - This study evaluated the influence of incubation conditions on the developmental and physiological status of birds in the perinatal period, which spans the end of incubation until the early posthatch period. Embryos were incubated at a normal (37.8 degrees C) or high (38.9 degrees C) eggshell temperature (EST) and a low (17%), normal (21%), or high (25%) O(2) concentration from d 7 until 19 of incubation. After d 19 of incubation, EST was maintained, but O(2) concentrations were 21% for all embryos. Body and organ weights, and hepatic glycogen levels were measured at d 18 of incubation and at 12 and 48 h after emergence from the eggshell. In addition, blood metabolites were measured at 12 and 48 h after emergence from the eggshell. Embryos incubated at a high EST and low O(2) concentration had the highest mortality in the last week of incubation, which may be related to their low yolk-free body mass (YFBM) or a reduced nutrient availability for hatching (i.e., hepatic glycogen). High EST, compared with normal EST, decreased YFBM. This may be due to the shorter incubation duration of 8 h, the lower weight of supply organs (i.e., heart and lung), or a lack of glucose precursors. Because of this lack of glucose precursors, embryos incubated at high EST may have used proteins for energy production instead of for body development at the end of incubation. The YFBM at d 18 of incubation increased with an increase in O(2) concentration. However, differences between the normal and high O(2) concentration disappeared at 12 and 48 h after emergence, possibly because the high O(2) concentration had difficulties adapting to lower O(2) concentrations in the perinatal period. Blood metabolites and hepatic glycogen were comparable among O(2) concentrations, indicating that the physiological status at hatch may be related to the environment that the embryo experienced during the hatching process. In conclusion, EST and O(2) concentration differentially influence the developmental and physiological status of broilers during the perinatal period. PMID- 21597068 TI - Hatching system and time effects on broiler physiology and posthatch growth. AB - A multilevel housing system for broilers was developed, named Patio (Vencomatic BV, Eersel, the Netherlands), in which the hatching and brooding phase are combined. In a Patio system, climate conditions differ from those provided in the hatchers currently in use. We compared the physiology of broilers hatched in a hatcher or in a Patio system, and included the effects of hatching time. Eggs from 1 breeder flock were incubated until embryonic d 18 in a setter and subsequently placed in a hatcher or the Patio until the end of incubation. From each hatching system, 154 chicks were collected per hatching time, at 465 h (early), 480 h (midterm), and 493 h (late) of incubation, from which 24 chicks/group were decapitated for analyses of blood plasma and organ weights. The remaining 130 chicks in each group from both systems were individually labeled and placed together in the Patio system. All chicks were given access to feed and water directly after hatch and were housed up to d 45 to monitor growth. From embryonic d 18 until the end of incubation, average ambient temperature and RH were 38.1 degrees C and 50.8% in the hatcher and 35.2 degrees C and 29.7% in the Patio system. Glucose and corticosterone were slightly higher in hatcher chicks, whereas organ weights were not affected by the hatching system. Although hatchling weights were lower in hatchery chicks, growth from d 0 to 45 was not affected by the hatching system. In both systems, glucose increased with hatching time, whereas lactate and triiodothyronine levels decreased. Yolk weights decreased with hatching time, whereas absolute and relative weights of the yolk free body, intestines, stomach, lungs, and heart increased, indicating more advanced maturation of organs. Growth up to d 21 was depressed in chicks in the late group, which was possibly related to lower thyroid hormone levels at hatching. We conclude that the hatching system had minor effects on hatchling physiology and that posthatch growth and livability were not affected. Because hatching time affected broiler physiology, it seems important to take hatching time into account in future studies related to hatchling physiology. PMID- 21597069 TI - Characterization of chicken Sertoli cells in vitro. AB - In the testis, Sertoli cells play a key physiological role in that they support, nourish, and protect germ cells. Because of the importance of Sertoli cells, several laboratories have established a culture system of Sertoli cells. These cultures have been well developed in mammalian species, but to our knowledge no purified avian Sertoli cells culture has been described. The aim of this study was to isolate avian Sertoli cells and to investigate their function using a chicken model in an in vitro test system. Immature chicken Sertoli cells in culture present morphology similar to that of mammalian cells and conserve expression of the specific Sertoli marker, anti-Mullerian hormone. Furthermore, in contrast to mammals, they express the 3beta-hydroxysteroid dehydrogenase enzyme. Stimulation of Sertoli cells with ovine follicle-stimulating hormone rapidly activates the 3 main downstream signaling pathways of the follicle stimulating hormone receptor: cyclic( )adenosine monophosphate/protein kinase A, phosphatidylinositol 3-kinase/Akt, and mitogen-activated protein kinase pathways. In vitro, Sertoli cells are able to secrete lactate and inhibin and have conserved the phagocytosis property. Finally, avian Sertoli cells present 3 interesting characteristics: they actively proliferate in vitro, can be passaged several times, and are suitable for freezing in nitrogen. A direct consequence of these properties is to use this cell culture test system as an alternative method to bird reprotoxicity studies. PMID- 21597070 TI - Methylglyoxal and pulmonary hypertension in broiler chickens. AB - Methylglyoxal (MG) is a dicarbonyl molecule that forms during glycolysis and normally is detoxified via the glyoxalase system. Methylglyoxal is highly reactive with various amino acid residues in proteins, leading to oxidative stress and irreversible protein damage. Increased levels of MG have been associated with endothelial damage and vascular remodeling contributing to the development of systemic arterial hypertension in mammals. This study was conducted to determine whether administering exogenous MG can trigger pulmonary hypertension (increased pulmonary arterial pressure) in broilers. Hematological assays and preliminary mass spectrometric analyses also were conducted using blood samples from broilers that had been injected intramuscularly with either saline or MG to determine whether MG triggers either a toxic response or oxidative posttranslational modification of hemoglobin within 24 h postinjection. Clinically healthy male broilers received 100-uL intravenous injections of saline and then MG, followed by a 500-uL intramuscular injection. Neither intravenous nor intramuscular injections of saline altered the pulmonary arterial pressure, whereas both intravenous and intramuscular MG injections triggered pulmonary hypertension attributable to increased pulmonary vascular resistance. The precise mode of action by which MG triggers pulmonary vasoconstriction remains to be determined. Pulse oximetry, hematology, and matrix-assisted laser desorption ionization-time-of-flight spectra data did not provide evidence of an overt toxic response to MG, nor was modification of hemoglobin detected, although increased heterophil:lymphocyte ratios did demonstrate that MG caused a stress response. To the best of our knowledge the present results constitute the first demonstration in any vertebrate species that exogenously administered MG rapidly initiates pulmonary hypertension attributable to pulmonary vasoconstriction. PMID- 21597071 TI - Effects of commercial in ovo injection of carbohydrates on broiler embryogenesis. AB - The effects of in ovo injection of different carbohydrate solutions on hatchability of fertilized eggs (HF), rate of hatch, BW, body moisture, yolk sac weight, and yolk sac moisture of Ross * 708 broiler chicks, hatched from eggs laid by a 34-wk-old breeder flock, were investigated. Eggs containing live embryos were injected, using an automated multiple-egg injector, in the amnion on d 18.5 of incubation with 0.1, 0.4, 0.7, or 1.0 mL of commercial diluent or a carbohydrate dissolved in diluent. The commercial diluent containing 0.25 g/mL of one of the following carbohydrates was injected into eggs: glucose, fructose, sucrose, maltose, or dextrin. The results showed that no carbohydrate type or solution volume affected rate of hatch. Absolute and proportional BW on day of hatch were positively related to injection volume (P < 0.001). However, HF was negatively related to injection volume (P < 0.001). To realize an HF of 90%, the injection volume could not exceed 0.4 mL for fructose or sucrose and could not exceed 0.7 mL for glucose, maltose, or dextrin. Yolk-free BW was negatively related to injection volume of fructose and sucrose (P < 0.004), but was not related to injection volume of diluent, glucose, maltose, and dextrin. Conversely, absolute and proportional yolk sac weights were positively related to injection volume of fructose, sucrose, and dextrin (P < 0.01), but were also not significantly related to injection volume of diluent, glucose, and maltose. Yolk sac moisture was positively related to injection volume for all injectables, including the diluent (P < 0.03). However, body moisture and yolk-free body moisture were not related to injection type or volume. In conclusion, the use of carbohydrates added to a commercial diluent for the in ovo injection of broiler hatching eggs requires the use of appropriate volumes to promote growth and nutrient utilization without adversely affecting HF. PMID- 21597072 TI - Intermittent thermal manipulations of broiler embryos during late incubation and their immediate effect on the embryonic development and hatching process. AB - Intermittent high (+3 degrees C) and low (-3 degrees C) temperature treatments for 4 h on embryonic day (E) 16, E17, and E18 showed differential effects on embryonic metabolism, without influencing embryonic growth or hatchability. Embryos in the high-temperature group shifted to a more anaerobic metabolism, as indicated by a lower partial pressure of O(2) and a higher partial pressure of CO(2) in the air cell, lower blood pH, and higher lactic acid production. Three hours after the end of the high-temperature treatment, a decrease in metabolism was observed, as indicated by the lower partial pressure of CO(2) and higher partial pressure of O(2) in the air cell and increased plasma triglyceride levels. The embryos in the low-temperature group responded by temporarily slowing down their metabolism, especially the metabolism of carbohydrates and lipids, as indicated by altered air cell gases, a higher relative yolk weight, higher plasma triglyceride level, and higher liver glycogen level. Three hours after the end of the temperature treatment, the metabolism of embryos in the low-temperature treatment had increased to the level of the control temperature group. However, for both temperature treatments, during the hatching process, all the shortages and excesses created were restored to control levels, which would explain the lack of change in embryo growth and hatchability and the slight delay in the hatching process. These mild consequences of the intermittent temperature treatment indicate that the different metabolic shifts made by the embryos seem to be efficient in overcoming the challenges of the intermittent high- or low temperature treatment during late incubation. PMID- 21597073 TI - Evaluation of meat quality from 3 turkey genotypes reared with or without outdoor access. AB - To evaluate color [lightness (L*), redness (a*), and yellowness (b*)], water holding capacity (WHC), and pH values, and for proximate analysis of breast and thigh meats from slow-growing (Bronze; B), fast-growing (Hybrid; H), and medium growing (crosses; H * B) turkey genotypes raised with or without outdoor access, 36 turkeys (2 females and 2 males from each replicate) per housing system or 12, 16, and 8 turkeys per B, H, and H * B genotype, slaughtered at 17 and 21 wk of age, respectively, were used. Therefore, data were analyzed as a factorial arrangement (2 * 3 * 2 * 2) of treatments. All birds were provided with the same starter, grower, and finisher feeds. Muscle samples were collected at 12 h postmortem for evaluation of meat quality and proximate analysis. Outdoor access increased the a* value and protein content of the breast muscle (P < 0.05) and the b* value of the thigh muscle (P < 0.01). The B and H genotypes had higher (P < 0.01) L* values for the breast meat than did the H * B genotype, whereas the B genotype had lower a* (P < 0.01) and pH (P < 0.01) values for the breast meat or a higher (P < 0.05) pH value for the thigh muscle compared with the H genotype. The breast meat of the B genotype was more yellow (P < 0.01) than that of the H and H * B genotype. Thigh meat from the H genotype had a higher L* value and a lower a* value than did thigh meat from the other genotypes (P < 0.01). Thigh meat from the H * B genotype was higher in protein and lower in fat than was thigh meat from the B and H genotypes, respectively (P < 0.05). No interaction effect of housing system and genotype was observed on the parameters studied (P > 0.05). These results show that housing system did not affect the main quality parameters (pH, water-holding capacity, and L* values) of either muscle, and that genotype created more differences in terms of these parameters. PMID- 21597074 TI - Effect of selected modified atmosphere packaging on Campylobacter survival in raw poultry. AB - Most current research on Campylobacter has focused on preharvest or processing plant cross-contamination. Little is known about the effect of storage environment on the survival of Campylobacter on raw poultry. We evaluated the effects of modified storage atmosphere and freezing on the survival of naturally occurring Campylobacter on raw poultry. Broiler carcasses (n = 560) were collected as they exited the chiller in 2 commercial processing plants and were sampled for the detection of Campylobacter, Escherichia coli, psychrophiles, and total aerobes at 0 and 14 d of refrigerated (2 degrees C) storage. Gases evaluated were air, 100% O(2), 100% CO(2), and a standard poultry modified atmosphere packaging mixture (5% O(2) + 10% CO(2) + 85% N). Freezing was included as a control group. All carcasses were sampled by the whole-carcass rinse method. The rinse fluid was recovered and pooled from 5 individual rinses, and serial dilutions were made for examination of Campylobacter (42 degrees C, 48 h), E. coli (37 degrees C, 24 h), psychrophiles (plate count agar, 4 degrees C, 7 d), and total aerobic bacterial populations (plate count agar, 37 degrees C, 24 h). Campylobacter counts for all treatments were reduced during the 14-d storage period but the 100% O(2) treatment caused a significantly (P < 0.05) greater reduction than the other gas treatments. For the psychrophiles, storage in air resulted in the greatest growth after 14 d, with reduced psychrophilic growth allowed by either O(2) or the modified atmosphere packaging mixture (not different from each other). Of the treatments evaluated, CO(2) allowed the least growth of psychrophiles. Proliferation of E. coli and aerobes was the greatest when packaged in air after 14 d, whereas CO(2) packaging resulted in the least growth. These data suggest that storage under O(2) may reduce Campylobacter recovery and slow psychrophile and aerobe recovery following storage. PMID- 21597075 TI - Color and fatty acid profile of abdominal fat pads from broiler chickens fed lobster meal. AB - Consumer demands for food products enriched with healthful n-3 fatty acids are steadily increasing. Feeding marine byproducts may provide an economical means of increasing the long-chain n-3 content of broiler tissues. A study was conducted to evaluate the effect of dietary lobster meal (LM) on the color and fatty acid profile of broiler chicken fatty tissue. Broilers were fed increasing levels (0, 2, 4, 6, 8, and 10%) of LM for 35 d. Fat pad samples were collected at slaughter and color and fatty acid concentrations were determined. A linear effect was found of LM on red coloration (P < 0.05) as dietary LM increased. Fat pad eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels also increased (P < 0.0001) in a linear fashion. The essential long-chain fatty acids were lower for the 10% LM diet (0.37 mg of EPA/g; 0.16 mg of DHA/g) compared with the 8% LM diet (0.51 mg of EPA/g; 0.27 mg of DHA/g). Using lobster meal as a feed ingredient resulted in broiler abdominal fat pads with a favorable increase in n 3 fatty acids. PMID- 21597076 TI - Effect of fat level on physicochemical and sensory properties of dry-cured duck sausages. AB - The effect of fat content (20, 30, and 40%) on chemical composition, color, texture parameters, and sensory properties of dry-cured duck sausages was studied. Protein content showed significant differences (P < 0.001) among batches (19.3, 22.1, and 27.5% for high, medium, and low fat, respectively). Fat level affected the lightness (P < 0.05), redness, and yellowness (P < 0.001) of dry cured duck sausages. Shear force increased with decreased fat content (1.45, 2.37, and 3.81 kg/cm(2) for high, medium, and low fat, respectively). The sensory properties of fat level, cohesiveness, fat odor, hardness, and juiciness were significantly different with respect to fat level. Duck sausages with 20% fat content obtained higher scores for sensory traits compared with sausages of 30 and 40% fat content. PMID- 21597077 TI - Dietary combination effects of conjugated linoleic acid and flaxseed or fish oil on the concentration of linoleic and arachidonic acid in poultry meat. AB - This study was conducted to determine the effects of the combination of dietary conjugated linoleic acid (CLA) and n-3 fatty acids on the linoleic acid (C18:2n 6) and arachidonic acid (C20:4n-6) concentrations of broiler chicken breast and thigh muscles. One hundred and twenty broilers were raised to 6 wk of age. All chicks were fed a basal corn-soybean meal diet containing 5 different fat sources at an inclusion level of 2% total fat: 1) CLA, 2) flaxseed oil, 3) menhaden fish oil, 4) CLA and flaxseed oil, and 5) CLA and menhaden fish oil. Eight broilers from each treatment were processed at 4 and 6 wk of age. Breast and thigh muscle samples were collected and analyzed for total fat content and fatty acid composition. The results showed that broilers from the CLA and fish oil treatment had lower arachidonic acid concentrations in both breast and thigh muscles than those fed the flaxseed oil diet or the CLA and flaxseed oil diet (P < 0.05). The arachidonic acid concentration and n-6:n-3 ratio of breast and thigh samples from the menhaden fish oil diet were similar to those of the CLA and fish oil diet (P > 0.05), but the inclusion of linoleic acid into chicken thigh muscles of broilers fed the CLA and menhaden fish oil diet improved significantly when compared with that of the diet containing menhaden fish oil only. Thus, the combination of CLA and menhaden fish oil is recommended to reduce the concentrations of linoleic and arachidonic acids in broiler chicken breast and thigh muscles. PMID- 21597078 TI - Effects of diet, packaging, and irradiation on protein oxidation, lipid oxidation, and color of raw broiler thigh meat during refrigerated storage. AB - This study was designed to evaluate the effects of dietary treatment, packaging, and irradiation singly or in combination on the oxidative stability of broiler chicken thigh meat. A total of 120 four-week-old chickens were divided into 12 pens (10 birds/pen), and 4 pens of broilers were randomly assigned to a control oxidized diet (5% oxidized oil) or an antioxidant-added diet [500 IU of vitamin E + 200 mg/kg of butylated hydroxyanisole (BHA)] and fed for 2 wk. After slaughter, thigh meats were separated, ground, packaged in either oxygen-permeable or oxygen impermeable vacuum bags, and irradiated at 0 or 3 kGy. Lipid oxidation (TBA reactive substances), protein oxidation (carbonyl), and color of the meat were measured at 1, 4, and 7 d of refrigerated storage. The lipid and protein oxidation of thigh meats from birds fed the diet supplemented with antioxidants (vitamin E + BHA) was significantly lower than the lipid and protein oxidation of birds fed the control diet, whereas the lipid and protein oxidation of broilers fed the oxidized oil diet was higher than that of birds fed the control diet. Vacuum packaging slowed, but irradiation accelerated, the lipid and protein oxidation of thigh meat during storage. Dietary antioxidants (vitamin E + BHA) and irradiation treatments showed a stronger effect on lipid oxidation than on protein oxidation. A significant correlation between lipid and protein oxidation in meat was found during storage. Dietary supplementation of vitamin E + BHA and the irradiation treatment increased the lightness and redness of thigh meat, respectively. It is suggested that appropriate use of dietary antioxidants in combination with packaging could be effective in minimizing oxidative changes in irradiated raw chicken thigh meat. PMID- 21597079 TI - Transfer of melamine in some poultry products. AB - This study deals with the transfer of melamine from poultry feed to certain poultry products, such as eggs and meat destined for human consumption. The tested amounts were, respectively, 50 and 500 mg of melamine/kg of feed. The addition of melamine had no significant effect on feed consumption and egg production. However, melamine appeared in the eggs as early as the first day of exposure. The average concentration was reached after the third day at both levels of contamination. The amounts of melamine found in eggs and tissues were almost directly proportional to the quantities ingested. However, melamine did not appear to accumulate in the organs and tissues that were studied. PMID- 21597080 TI - Broiler performance, hatching egg, and age relationships of progeny from standard and dwarf broiler dams. AB - The relationship of egg and chick weights to the performance of broiler chickens from two 42-wk-old flocks (standard and dwarf dams) having male parents from the same genetic stock was investigated in this study. Fertility (91.7 vs. 94.7%) and hatchability (95.2 vs. 96.3%) were not significantly (P > 0.10) different for eggs from standard and dwarf dams, respectively. Egg weight contributed significantly to the variation in BW [BW = beta(0) + beta(i) (egg weight) + beta(i) (dam) + beta(i) (sex)]. Body weight as a function of chick weight was not significant. However, chick weight was significant when included in a model with egg weight, suggesting that significant differences in BW at 50 d could be attributed to both egg and chick weights. The negative coefficient for chick weight indicated that between the 2 broilers of the same egg weight, the one with the greater chick weight would have the smaller 50-d BW. Chick weight was a linear function of egg weight. Similarly, the effect of egg or chick weight on broiler BW at 35 or 50 d was best represented by a single linear function. Dam genotype did not contribute significantly to variation in 50-d BW after variation attributable to egg weight was removed from the model. Differences in BW attributable to egg weight increased with broiler age. The coefficients of egg weight and chick weight showed that the differences in BW per gram of egg were 1.43, 3.06, 6.24, and 7.61 g and those per gram of chick were 1.87, 3.99, 8.14, and 9.93 g, respectively, at 7, 21, 35, and 50 d. Body weight increased by 0.1563 times egg weight (and 0.2092 times chick weight) with each additional day of age for both sexes and genotypes. Clearly, both egg and chick weights are important for modeling or predicting market-age broiler BW and economic returns. The relatively small relationship between BW and egg weight demonstrates that genetic selection over the past 3 decades has decreased the influence of egg weight on broiler growth. The present dwarf broiler breeder dams may produce progeny comparable in performance with standard dams. PMID- 21597081 TI - Effect of floor density on growth performance of Pearl Grey guinea fowl replacement pullets. AB - Little is known of the optimal floor density for the Pearl Grey (PG) guinea fowl pullet. Hence, the objective of this study was to determine the effect of varying floor density on the growth performance of PG guinea fowl pullets. In 3 replicates, 1-d-old guinea keets (n = 786) were weighed individually and randomly assigned to floor pens covered with pine wood shavings at 80, 69, 60, and 53 birds/pen, equivalent to densities of 18, 15.6, 13.6, and 12 birds/m(2), respectively. The birds were allowed feeder space of 2.3, 2.7, 3.1, and 3.5 cm/bird, respectively, and water space of 1.2, 1.4, 1.6, and 1.8 cm/bird, respectively. The photoperiod was 23 h at 0 to 11 wk of age (WOA) and 8 h at 12 to 16 WOA. Birds were fed diets comprising 3,000 and 3,100 kcal of ME/kg of diet at 0 to 4 and 5 to 8 WOA, respectively, and 24% CP. At 9 to 16 WOA, the diets comprised 3,100 kcal of ME/kg and 18% CP. Feed and water were provided for ad libitum consumption. Body weight and feed consumption were measured weekly. Overall, BW gains were higher (P < 0.05) and feed conversion ratios (FCR) were significantly lower in birds reared at a floor density of 18 birds/m(2) than in birds reared on other treatments at 0 to 8 WOA. However, at 9 to 16 WOA, birds at floor densities of 12 birds/m(2)exhibited higher BW gain and feed consumption and lower FCR (P < 0.05) than those at floor densities of 13.6, 15.6, and 18 birds/m(2). Therefore, this study suggests an optimum floor density of 18 and 12 birds/m(2) at 0 to 8 and 9 to 16 WOA, respectively, to achieve the highest possible FCR for the PG guinea fowl replacement pullets. PMID- 21597083 TI - Abortion, metaphysics and morality: a review of Francis Beckwith's defending life: a moral and legal case against abortion choice. AB - In Defending Life: A Moral and Legal Case Against Abortion Choice (2007) and an earlier article in this journal, "Defending Abortion Philosophically"(2006), Francis Beckwith argues that fetuses are, from conception, prima facie wrong to kill. His arguments are based on what he calls a "metaphysics of the human person" known as "The Substance View." I argue that Beckwith's metaphysics does not support his abortion ethic: Moral, not metaphysical, claims that are part of this Substance View are the foundation of the argument, and Beckwith inadequately defends these moral claims. Thus, Beckwith's arguments do not provide strong support for what he calls the "pro-life" view of abortion. PMID- 21597084 TI - Parental wisdom, empirical blindness, and normative evaluation of prenatal genetic enhancement. AB - The purpose of this paper is to unveil one problem that surrounds the debate over the moral standing of prenatal genetic enhancement (PGE) and to outline a solution to it. The problem is that we have no way to test our speculations about the consequences of prenatal enhancement without begging the question about the moral permissibility of enhancing unborn children. The only way to empirically support our speculations about the consequences of prenatal enhancement is to resort to ethically worrisome (and radical) experimental genetic research. The suggested solution to this problem is to focus on the character of good parents. The virtue of parental wisdom is introduced and used as a basis for evaluating PGE. It is argued that good parents have good reason not to condone PGE for their children (in very many cases), especially as part of the first wave of genetically altered humans. PMID- 21597085 TI - Embryonic stem cells and property rights. AB - This article contributes to the current debate on human embryonic stem cell researchers' possible complicity in the destruction of human embryos and the relevance of such complicity for the issue of commodification of human embryos. I will discuss if, and to what extent, researchers who destroy human embryos, and researchers who merely use human embryos destroyed by others, have moral use rights, and/or moral property rights, in these embryos. I argue that the moral status of the human embryo, however justified, places few restrictions on the latter researchers' use of it, and property rights in it, once it is destroyed. I argue that the former researchers have no property rights in the destroyed embryo but use rights in it to the extent allowed by the legitimate owners of the destroyed embryo. I discuss the implications of this account for previous and current US federal law regulating human embryonic stem cell research. PMID- 21597086 TI - Euthanasia and common sense: a reply to Garcia. AB - J. L. A. Garcia holds that my defense of voluntary euthanasia in an earlier paper amounts to an "assault on traditional common sense" about what medical ethics permits physicians to do, particularly insofar as I hold that a physician's duty to abstain from intentionally killing is only a defeasible duty, not an unconditional one. But I argue here that it is Garcia's views that are more at odds with common sense, and that voluntary euthanasia is in fact a humane alternative that respects patient autonomy and is consistent with the most fundamental moral duties of physicians. Among these is a duty to relieve suffering, which can sometimes outweigh the fundamental duty to conserve life. PMID- 21597087 TI - Ethnic variation in allele distribution of the androgen receptor (AR) (CAG)n repeat. AB - The androgen receptor (AR) is important in reproductive organ development, as well as tissue homeostasis of the pancreas, liver, and skeletal muscle in adulthood. The trinucleotide (CAG)(n) repeat polymorphism in exon 1 of the AR gene is thought to regulate AR activity, with longer alleles conferring reduced receptor activity. Therefore, the evaluation of the allelic distribution of the AR (CAG)(n) repeat in various ethnic groups is crucial in understanding the interindividual variability in AR activity. We evaluated ethnic variation of this AR polymorphism by genotyping individuals from the multiethnic Hyperglycemia and Adverse Pregnancy Outcome study cohort. We genotyped 4421 Caucasian mothers and 3365 offspring of European ancestry; 1494 Thai mothers and 1742 offspring; 1119 Afro-Caribbean mothers and 1142 offspring; and 780 Hispanic mothers and 770 offspring of Mexican ancestry from Bellflower, California. The distributions of (CAG)(n) alleles among all 4 ethnic groups are significantly different (P < .0001). Pairwise tests confirmed significant differences between each pair of ethnicities tested (P < 10(-28)). The relative AR (CAG)(n) repeat length in the different groups was as follows: Afro-Caribbean (shortest repeat lengths and greatest predicted AR activity) < Caucasian < Hispanic < Thai (longest repeat length and lowest predicted AR activity). Significant interethnic differences in the allele frequencies of the AR exon 1 (CAG)(n) polymorphism exist. Our results suggest that there may be potential ethnic differences in androgenic pathway activity and androgen sensitivity. PMID- 21597088 TI - The role of over-the-counter supplements for the treatment of male infertility- fact or fiction? AB - Many over-the-counter (OTC) vitamins and supplements have been used to improve male fertility. The purpose of this study is to review the effects of these OTC supplements on male fertility. A Pub Med and Medline review of the randomized controlled studies utilizing OTC vitamins and supplements readily available in the United States over the last 3 decades was performed. Many studies demonstrate the positive effects of OTC supplementation on semen parameters and pregnancy outcomes. Conversely, many studies also demonstrate a lack of improvement and potential complications with supplementation. Confounding factors include lack of standard dosing regimens, duration of treatment, and control for dietary intake. No standard exists for which OTC supplement and vitamin studies have been conducted or the medications dosed. Definitive conclusions as to their true effects on male subfertility and dosing regimen could not be identified. PMID- 21597089 TI - Physical activity and erectile dysfunction in middle-aged men. AB - The prevalence of erectile dysfunction is high in men of all ages and increases greatly in the elderly. In particular, severity and prevalence both increase with aging. Because erectile dysfunction is a symptom, physicians should diagnose underlying pathologies that might lead to it instead of focusing only on finding a viable treatment. Physical inactivity negatively impacts on erectile function; experimental and clinical exercise interventions have been shown to improve sexual responses and overall cardiovascular health. Several studies have confirmed that combining 2 interventions (Mediterranean diet and physical activity) provides additional benefit to erectile function, likely via reduced metabolic disturbances (eg, inflammatory markers, insulin resistance), decreased visceral adipose tissue, and improvement in vascular function (eg, increased endothelial function). This brief review shows the main clinical evidence of benefits induced by physical activity on erectile and endothelial dysfunction. The literature shows that erectile dysfunction in middle-aged men is often an early event in endothelial damage, and physical activity is able to improve both erectile and endothelial dysfunction. There are conflicting data regarding the effects of exercise on androgen status. In clinical practice it would be recommended to add regular physical activity to balanced diet and drugs to achieve better therapeutic results. PMID- 21597090 TI - Urinary concentrations of di(2-ethylhexyl) phthalate metabolites and serum reproductive hormones: pooled analysis of fertile and infertile men. AB - Urinary concentrations of metabolites of the anti-androgenic xenobiotic di-(2 ethylhexyl) phthalate (DEHP) were previously shown to be weakly associated with serum levels of several hormones in 2 disparate US populations: partners of pregnant women participating in the Study for Future Families and partners in infertile couples from Massachusetts General Hospital infertility clinic. The observed associations between phthalate metabolites and reproductive hormones were robust and insensitive to the characteristics of the subpopulation or the laboratory in which the hormones were measured, despite the fact that these 2 populations span a range of fertility, urinary phthalate metabolites, and reproductive hormone levels. We therefore examined associations between urinary metabolites of DEHP and reproductive hormones-follicle-stimulating hormone, luteinizing hormone, testosterone (T), inhibin B, and estradiol (E(2))-and sex hormone-binding globulin (SHBG) in the pooled population. The magnitude of the associations seen were similar to those reported for each population separately, but effect estimates were more precise because of the increased sample size and the greater range of phthalate metabolite concentrations and hormone levels. Urinary concentrations of 3 metabolites of DEHP [mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5 oxohexyl) phthalate (MEOHP)] were inversely associated with the free androgen index (FAI = T/SHBG) and calculated free testosterone. Urinary concentrations of MEHHP and MEOHP were positively associated with SHBG, and MEHP was inversely associated with E(2). No other phthalate metabolites were associated with serum hormones, consistent with results in each population. Our results in this diverse population suggest that DEHP exposure is robustly associated with some male sex steroid hormones. PMID- 21597091 TI - Germ cell transplantation in felids: a potential approach to preserving endangered species. AB - With the exception of the domestic cat, all members of the family Felidae are considered either endangered or threatened. Although not yet used for this purpose, spermatogonial stem cell (SSC) transplantation has a high potential to preserve the genetic stock of endangered species. However, this technique has not previously been established in felids. Therefore, we developed the necessary procedures to perform syngeneic and xenogeneic SSC transplants (eg, germ cell [GC] depletion in the recipient domestic cats, enrichment and labeling of donor cell suspension, and the transplantation method) in order to investigate the feasibility of the domestic cat as a recipient for the preservation and propagation of male germ plasm from wild felids. In comparison with busulfan treatment, local x-ray fractionated radiation was a more effective approach to depleting endogenous spermatogenesis. The results of both syngeneic and xenogeneic transplants revealed that SSCs were able to successfully colonize and differentiate in the recipient testis, generating elongated spermatids several weeks posttransplantation. Specifically, ocelot spermatozoa were observed in the cat epididymis 13 weeks following transplantation. As donor GCs from domestic cats and ocelots were able to develop and form mature GCs in the recipient environment seminiferous tubules, these findings indicate that the domestic cat is a suitable recipient for SSC transplantation. Moreover, as modern cats descended from a medium-size cat that existed approximately 10 to 11 million years ago, these results strongly suggest that the domestic cat could be potentially used as a recipient for generating and propagating the genome of wild felids. PMID- 21597095 TI - Routine screening for chronic human immunodeficiency virus infection: why don't the guidelines agree? AB - Infection with human immunodeficiency virus remains a major public health problem in the United States. Prominent guidelines from the U.S. Preventive Services Task Force and the Centers for Disease Control and Prevention differ in their recommendations on whether and how to screen adults and adolescents not known to be at higher risk. These discrepancies have led to controversy and debate as well as confusion among clinicians. This article reviews principles of screening, explains specific issues related to screening for human immunodeficiency virus, reviews the discrepancies between the US Preventive Services Task Force and the Centers for Disease Control and Prevention guidelines and the methods used in each guideline, and describes potential reasons for the discrepancies. The case of screening for human immunodeficiency virus illustrates how discrepancies between guidelines may be related to different guideline development methods as well as the different perspectives of the guideline development groups. PMID- 21597096 TI - Survival from common and rare cancers in Germany in the early 21st century. AB - BACKGROUND: Until recently, population-based data of cancer survival in Germany mostly relied on one registry covering ~1 million people (1.3% of the German population). Here, we provide up-to-date cancer survival estimates for Germany based on data from 11 population-based cancer registries, covering 33 million people and compare them to survival estimates from the United States. PATIENTS AND METHODS: Cancer patients diagnosed in 1997-2006 were included. Period analysis was employed to calculate 5-year relative survival for 38 cancers for 2002-2006. German and USA survival rates were compared utilizing the Surveillance, Epidemiology and End Results 13 database. RESULTS: Five-year relative survival >80% was observed for testicular cancer (93.5%), skin melanoma (89.4%), cancers of the prostate (89.1%) and thyroid (87.8%), Hodgkin's lymphoma (84.5%) and cancers of the breast (83.7%) and endometrium (81.0%), which together account for almost 40% of cases. For the majority of cancers, German survival estimates were close to or below those in the United States. Exceptions with higher survival in Germany were cancers of the stomach, pancreas and kidney and Hodgkin's lymphoma. CONCLUSIONS: German cancer survival estimates are mostly higher than the 2000-2002 pan-European estimates. Further research is needed to investigate causes responsible for differences between German and USA cancer survival rates. PMID- 21597097 TI - Association between body mass index and the colorectal cancer risk in Japan: pooled analysis of population-based cohort studies in Japan. AB - BACKGROUND: Obesity has been recognized as important risk factors for colorectal cancer. However, limited evidence is available on colorectal cancer and body mass index (BMI) in Asian population. METHODS: We conducted a pooled analysis of eight population-based prospective cohorts studies in Japan with more than 300,000 subjects to evaluate an impact of obesity in terms of BMI on colorectal cancer risk with unified categories. We estimated summary hazard ratio (HR) by pooling of study-specific HR for BMI categories with random effect model. RESULTS: We found a significant positive association between BMI and colorectal cancer risk in male and female. Adjusted HRs for 1 kg/m(2) increase were 1.03 [95% confidence interval (CI) 1.02-1.04] for males and 1.02 (95% CI 1.00-1.03) for females. The association was stronger in colon, especially in proximal colon, relative to rectum. Males showed a stronger association than females. Population attributable fraction for colorectal cancer by BMI >= 25 kg/m(2) was 3.62% (95% CI 1.91-5.30) for males and 2.62% (95% CI 0.74-4.47) for females. CONCLUSIONS: We found significant association between BMI and colorectal cancer risk by pooling of data from cohort studies with considerable number of subjects among Japanese population. This information is important in cancer control planning, especially in Asian population. PMID- 21597098 TI - Short-term association between ambient air pollution and risk of hospitalization for acute myocardial infarction: results of the cardiovascular risk and air pollution in Tuscany (RISCAT) study. AB - Air pollutant levels have been widely associated with increased hospitalizations and mortality from cardiovascular disease. In this study, the authors focused on pollutant levels and triggering of acute myocardial infarction (AMI). Data on AMI hospitalizations, air quality, and meteorologic conditions were collected in 6 urban areas of Tuscany (central Italy) during 2002-2005. Levels of particulate matter with an aerodynamic diameter <=10 MUm (PM(10)) (range of 4-year mean values, 28.15-40.68 MUg/m(3)), nitrogen dioxide (range, 28.52-39.72 MUg/m(3)), and carbon monoxide (range, 0.86-1.28 mg/m(3)) were considered, and increases of 10 MUg/m(3) (0.1 mg/m(3) for carbon monoxide) were analyzed. A time-stratified case-crossover approach was applied. Area-specific conditional regression models were fitted, adjusting for time-dependent variables. Stratified analyses and analyses in bipollutant models were performed. Pooled estimates were derived from random-effects meta-analyses. Among 11,450 AMI hospitalizations, the meta analytical odds ratio at lag(2) (2-day lag) was 1.013 (95% confidence interval (CI): 1.000, 1.026) for PM(10), 1.022 (95% CI: 1.004, 1.041) for nitrogen dioxide, and 1.007 (95% CI: 1.002, 1.013) for carbon monoxide. More susceptible subgroups were elderly persons (age >=75 years), females, and older patients with hypertension and chronic obstructive pulmonary disease. This study adds to evidence for a short-term association between air pollutants and AMI onset, also evident at low pollutant levels, suggesting a need to focus on more vulnerable subjects. PMID- 21597099 TI - A comparison of subgroup analyses in grant applications and publications. AB - In this paper, the authors compare subgroup analyses as outlined in grant applications and their related publications. Grants awarded by the Netherlands Organization for Health Research and Development (ZonMw) from 2001 onward that were finalized before March 1, 2010, were studied. Of the 79 grant proposals, 50 (63%) were intervention studies, 18 (23%) were diagnostic studies, and 6 (8%) were prognostic studies. Subgroups were mentioned in 49 (62%) grant applications and in 53 (67%) publications. In 20 of the 79 projects (25%), the publications were completely in agreement with the grant proposal; that is, subgroups that were prespecified in the grant proposal were reported and no new subgroup analyses were introduced in the publications. Of the 149 prespecified subgroups, 46 (31%) were reported in the final report or scientific publications, and 143 of the 189 (76%) reported subgroups were based on post-hoc findings. For 77% of the subgroup analyses in the publications, there was no mention of whether these were prespecified or post hoc. Justification for subgroup analysis and methods to study subgroups were rarely reported. The authors conclude that there is a large discrepancy between grant applications and final publications regarding subgroup analyses. Both nonreporting prespecified subgroup analyses and reporting post-hoc subgroup analyses are common. More guidance is clearly needed. PMID- 21597100 TI - Exploring the feasibility of a physical activity intervention for midlife African American men. AB - BACKGROUND: This study tested the initial efficacy of implementing a physical activity (PA) behavior change intervention for midlife African American (AA) men. METHODS: Intervention components were based on information gathered during formative research preceding the intervention. Eligible participants were underactive AA men ages 45-66 years. In a quasi-experimental pre-post design, participants attended 90-min program sessions twice weekly for 8 weeks. Session topics specific to PA included overcoming barriers, gaining social support, setting goals, tracking progress and integrating into one's lifestyle. Participants were assigned to teams to facilitate group discussion, problem solving, accountability and camaraderie. RESULTS: 25 AA men (mean age = 54.7 +/- 4.8 years) completed the intervention. After 8 weeks, significant (P < 0.05) positive changes were observed for moderate to vigorous-intensity PA (+7.3 hour week(-1)) and overall PA (+9.4 hour week(-1)), self-efficacy for PA (+12%), social support for PA from family (+28%) and friends (+53%), self-regulation for planning (+33%) and goal setting (+48%) and each fitness component (+9 to +144%). Based on a post-intervention satisfaction survey, participants rated the program very positively. CONCLUSION: These positive results attest to the feasibility of successfully engaging midlife AA men in a tailored PA behavior change program. PMID- 21597101 TI - Examining primary and secondary school canteens and their place within the school system: a South Australian study. AB - In Australia, school canteens are an integral part of the school environment and an ideal site to encourage healthy eating. However, when the canteen is not supported within the school system, healthy menus may be difficult to implement. The aim of this study was to investigate school canteens and their place within the school system in primary and secondary schools in South Australia. Using a systems approach, 14 schools and their canteens located throughout metropolitan and rural South Australia are discussed. A range of qualitative interviews was conducted with school principals (n = 14), canteen managers (n = 14), parents (n = 50), teachers (n = 10) and focus group interviews were held with students (n = 450). This study showed that although school canteens were located on school grounds and should be supported as an integral part of the school system, in many cases they were not. A range of influences such as: maintaining profit, reduced volunteer support and student choice negatively impacted what was sold on the canteen menu. This study indicated that offering a sustainable healthy school canteen menu largely depended on the support and resources provided to the canteen by the school system in which it belonged. PMID- 21597102 TI - Visual perception of thick transparent materials. AB - Under typical viewing conditions, human observers readily distinguish between materials such as silk, marmalade, or granite, an achievement of the visual system that is poorly understood. Recognizing transparent materials is especially challenging. Previous work on the perception of transparency has focused on objects composed of flat, infinitely thin filters. In the experiments reported here, we considered thick transparent objects, such as ice cubes, which are irregular in shape and can vary in refractive index. An important part of the visual evidence signaling the presence of such objects is distortions in the perceived shape of other objects in the scene. We propose a new class of visual cues derived from the distortion field induced by thick transparent objects, and we provide experimental evidence that cues arising from the distortion field predict both the successes and the failures of human perception in judging refractive indices. PMID- 21597103 TI - Birth cohort patterns of gastric cancer and peptic ulcer among non-whites in the USA. AB - BACKGROUND: The aim of this study was to follow the long-term trends of mortality from gastric cancer, gastric ulcer and duodenal ulcer in the USA. It was hypothesised that the time trends among different ethnic groups would be shaped by similar birth cohort patterns. METHODS: The US ulcer and cancer data were available from 1923 to 2006 and 1930 to 2006, respectively. Age-specific death rates were calculated for consecutive 10-year periods and 10-year age groups, stratified by sex and race. They were plotted against the period of death as period-age contours and against the period of birth as cohort-age contours. The time trends were also summarised as standardised cohort mortality ratios. RESULTS: The occurrence of birth cohort patterns with an initial rise and a subsequent decline was observed in gastric cancer and both ulcer types. It occurred similarly in white and non-white population, as well as men and women. In all ethnic groups alike, the initial rise in mortality from gastric cancer and gastric ulcer preceded the rise of duodenal ulcer by 10-20 years. The two time lags between gastric cancer and gastric ulcer and between gastric and duodenal ulcer were most pronounced in white patients. In non-white patients, the rise of gastric cancer occurred later than in white patients and coincided with that of gastric ulcer. The initial rise in mortality from gastric cancer was more evident in non-white than in white patients. CONCLUSION: The birth cohort pattern has shaped the time trends of Helicobacter pylori-related disease similarly among different ethnic and socioeconomic groups. Its cause remains unknown and warrants further investigation. PMID- 21597104 TI - Mapping clinical phenotype data elements to standardized metadata repositories and controlled terminologies: the eMERGE Network experience. AB - BACKGROUND: Systematic study of clinical phenotypes is important for a better understanding of the genetic basis of human diseases and more effective gene based disease management. A key aspect in facilitating such studies requires standardized representation of the phenotype data using common data elements (CDEs) and controlled biomedical vocabularies. In this study, the authors analyzed how a limited subset of phenotypic data is amenable to common definition and standardized collection, as well as how their adoption in large-scale epidemiological and genome-wide studies can significantly facilitate cross-study analysis. METHODS: The authors mapped phenotype data dictionaries from five different eMERGE (Electronic Medical Records and Genomics) Network sites studying multiple diseases such as peripheral arterial disease and type 2 diabetes. For mapping, standardized terminological and metadata repository resources, such as the caDSR (Cancer Data Standards Registry and Repository) and SNOMED CT (Systematized Nomenclature of Medicine), were used. The mapping process comprised both lexical (via searching for relevant pre-coordinated concepts and data elements) and semantic (via post-coordination) techniques. Where feasible, new data elements were curated to enhance the coverage during mapping. A web-based application was also developed to uniformly represent and query the mapped data elements from different eMERGE studies. RESULTS: Approximately 60% of the target data elements (95 out of 157) could be mapped using simple lexical analysis techniques on pre-coordinated terms and concepts before any additional curation of terminology and metadata resources was initiated by eMERGE investigators. After curation of 54 new caDSR CDEs and nine new NCI thesaurus concepts and using post-coordination, the authors were able to map the remaining 40% of data elements to caDSR and SNOMED CT. A web-based tool was also implemented to assist in semi-automatic mapping of data elements. CONCLUSION: This study emphasizes the requirement for standardized representation of clinical research data using existing metadata and terminology resources and provides simple techniques and software for data element mapping using experiences from the eMERGE Network. PMID- 21597105 TI - Hybrid methods for improving information access in clinical documents: concept, assertion, and relation identification. AB - OBJECTIVE: This paper describes the approaches the authors developed while participating in the i2b2/VA 2010 challenge to automatically extract medical concepts and annotate assertions on concepts and relations between concepts. DESIGN: The authors'approaches rely on both rule-based and machine-learning methods. Natural language processing is used to extract features from the input texts; these features are then used in the authors' machine-learning approaches. The authors used Conditional Random Fields for concept extraction, and Support Vector Machines for assertion and relation annotation. Depending on the task, the authors tested various combinations of rule-based and machine-learning methods. RESULTS: The authors'assertion annotation system obtained an F-measure of 0.931, ranking fifth out of 21 participants at the i2b2/VA 2010 challenge. The authors' relation annotation system ranked third out of 16 participants with a 0.709 F measure. The 0.773 F-measure the authors obtained on concept extraction did not make it to the top 10. CONCLUSION: On the one hand, the authors confirm that the use of only machine-learning methods is highly dependent on the annotated training data, and thus obtained better results for well-represented classes. On the other hand, the use of only a rule-based method was not sufficient to deal with new types of data. Finally, the use of hybrid approaches combining machine learning and rule-based approaches yielded higher scores. PMID- 21597106 TI - Patient safety factors in children dying in a paediatric intensive care unit (PICU): a case notes review study. AB - OBJECTIVE: To identify patient safety factors in pre-hospital and hospital management of critically ill children dying in a paediatric intensive care unit (PICU). DESIGN: Retrospective case notes review. SETTING: Single tertiary regional PICU in London. PARTICIPANTS: 47 patients (7%) who died from a total of 679 children admitted during 2007 and 2008. Median age was 1.1 years and median predicted mortality from the Paediatric Index of Mortality 2 score was 39%. MAIN OUTCOME MEASURES: Adverse events contributing to death (AEds) and critical incidents (CIs). AEd was defined as an unintended injury or complication caused by health care management, contributing to death. CI was defined as an undesirable event in healthcare management, which could have led to harm or did lead to harm of the patient but did not contribute to the patient's death. RESULTS: 22 AEds occurred in 17 of 47 (36%) cases. Two AEds occurred in primary care, 20 in pre-PICU hospital care, and none in PICU. AEds were mainly problems in diagnosis and management of critical illness. 37 CIs occurred in 28 of 47 (60%) cases. Two CIs occurred prior to hospital admission, 17 occurred in pre PICU hospital care, 1 during inter-hospital transport and 17 in PICU. CIs were predominantly medical management and procedure related. Individual, team and organisational factors caused the majority of AEds and CIs. CONCLUSION: Adverse events in pre-PICU hospital care were common in children who subsequently died in PICU. CIs occurred throughout the patient journey. Interventional studies of healthcare organisation and delivery are necessary to identify appropriate strategies to improve patient safety. PMID- 21597107 TI - Coal workers' pneumoconiosis in the United States: regional differences 40 years after implementation of the 1969 Federal Coal Mine Health and Safety Act. AB - OBJECTIVE: To assess whether the recent increases in the prevalence of coal workers' pneumoconiosis (CWP) in the USA reflect increased measured exposures over recent decades, and to identify other potential causative factors. METHODS: The observed CWP prevalence was calculated for 12,408 underground coal miner participants in the Coal Workers' Health Surveillance Program for the period 2005 2009, stratified by the Mine Safety and Health Administration (MSHA) geographical districts. The predicted prevalence was estimated using a published exposure response model from a large epidemiological study among U.S. coal miners using dust exposure, tenure, miner's age and coal rank as predictors. chi2 Testing was performed to compare the observed versus predicted CWP prevalence. RESULTS: Observed prevalence was significantly higher than predicted prevalence in MSHA districts 4-7 (central Appalachian region) (10.1% vs. 4.2%; prevalence ratio (PR) 2.4; p<0.001) and significantly lower than predicted in other regions (1.6% vs. 3.6%; PR 0.4; p<0.001). The central Appalachian region had a significantly older workforce with greater mining tenure, a lower proportion of mines with 200 or more employees, and lower seam heights. Significant lower average compliance dust concentrations were reported for this region. CONCLUSION: The observed CWP prevalence substantially exceeded predicted levels in central Appalachia. However, the increased prevalence was not explained by the measured levels of dust exposures. Likely contributing factors include mine size and low seam mining, which may be associated with higher exposure to silica. Further study is needed to characterise the responsible factors for the elevated CWP rates in central Appalachia. PMID- 21597108 TI - Counselling low-back-pain patients in secondary healthcare: a randomised trial addressing experienced workplace barriers and physical activity. AB - OBJECTIVE: To assess if counselling by an occupational physician (OP) addressing experienced workplace barriers and physical activity integrated as a part of low back pain (LBP) outpatient treatment influences pain, function and sick leave. METHODS: Randomised controlled trial in the secondary healthcare sector with 3 months' follow-up. The participants were LBP patients who, independently of sick leave status, expressed concerns about the ability to maintain their current job. Patients referred for surgery were excluded. The intervention consisted of two counselling sessions conducted by an OP addressing both workplace barriers and leisure-time physical activity. A workplace visit was performed if required. Pain, function and duration of sick leave due to LBP were primary outcomes. RESULTS: A reduction in bodily pain and improvement in physical function both measured by the 36-item short-form health survey questionnaire in favour of the intervention group was found. The change in pain score was found to be clinically relevant. The risk of sick leave for at least 8 weeks due to LBP was significantly reduced in the intervention group. Two secondary outcomes, Fear Avoidance Beliefs about physical activity and maximum oxygen uptake, supported compliance and adherence to the part of the intervention focusing on enhanced physical activity. CONCLUSION: Two short counselling sessions by an OP combining advice on meeting workplace barriers and enhancing physical activity had a substantial effect on important prognostic factors for LBP patients with moderate to severe symptoms diagnosed in outpatient rheumatological clinics. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13071157. PMID- 21597109 TI - The Gettier Problem in informed consent. AB - The duty to procure informed consent (IC) from patients before any significant intervention is among the pillars of medical and research ethics. The provision by the doctor of relevant information about treatment and free decision-making by the patient are essential elements of IC. The paper presents cases of IC where the free decision about treatment is not causally related to the information provided, and claims that such cases pose a difficulty parallel to that presented by the Gettier Problem in epistemology. In analogy to the original problem with the concept of knowledge, these Gettier-type cases show an indeterminacy in the concept of IC: we either need to add some explicit additional condition of causal connection between information and consent, or else we should understand the concept in a new way-specifically, since the practice of autonomy necessarily involves some consideration of the relevant information, we must understand free consent in a way that no longer refers to patient autonomy. PMID- 21597110 TI - Futile treatment, junior doctors and role virtues. AB - Futile treatment is one ethically challenging situation commonly encountered by junior doctors. By analysing an intern's story using a role virtues framework, I propose a set of three steps for junior doctors facing this problem. I claim that junior doctors ought always to investigate the rationale underlying decisions to proceed with apparently futile treatment and discuss their concerns with their seniors, even if such discussion will be difficult. I also suggest that junior doctors facing this ethical challenge ought always to be willing to initiate and engage in ethical dialogue, and that in some situations further action (such as taking concerns outside the team or refusing to participate in treatment) may be morally appropriate. PMID- 21597111 TI - Randomised controlled trial of high concentration versus titrated oxygen therapy in severe exacerbations of asthma. AB - BACKGROUND: The effect on Paco2 of high concentration oxygen therapy when administered to patients with severe exacerbations of asthma is uncertain. METHODS: 106 patients with severe exacerbations of asthma presenting to the Emergency Department were randomised to high concentration oxygen (8 l/min via medium concentration mask) or titrated oxygen (to achieve oxygen saturations between 93% and 95%) for 60 min. Patients with chronic obstructive pulmonary disease or disorders associated with hypercapnic respiratory failure were excluded. The transcutaneous partial pressure of carbon dioxide (Ptco2) was measured at 0, 20, 40 and 60 min. The primary outcome variable was the proportion of patients with a rise in Ptco2 >=4 mm Hg at 60 min. RESULTS: The proportion of patients with a rise in Ptco2 >=4 mm Hg at 60 min was significantly higher in the high concentration oxygen group, 22/50 (44%) vs. 10/53 (19%), RR 2.3 (95% CI 1.2 to 4.4, p<0.006). The high concentration group had a higher proportion of patients with a rise in Ptco2 >=8 mm Hg, 11/50 (22%) vs. 3/53 (6%), RR 3.9 (95% CI 1.2 to 13.1, p=0.016). All 10 patients with a final Ptco2 >=45 mm Hg received high concentration oxygen therapy, and in five there was an increase in Ptco2 >=10 mm Hg. CONCLUSION: High concentration oxygen therapy causes a clinically significant increase in Ptco2 in patients presenting with severe exacerbations of asthma. A titrated oxygen regime is recommended in the treatment of severe asthma, in which oxygen is administered only to patients with hypoxaemia, in a dose that relieves hypoxaemia without causing hyperoxaemia. Clinical trial number ACTRN12607000131459. PMID- 21597112 TI - Neural respiratory drive as a physiological biomarker to monitor change during acute exacerbations of COPD. AB - BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease have a significant negative impact on both patients and healthcare systems. Currently, there are no physiological biomarkers that effectively monitor clinical change or predict respiratory readmission. Acute exacerbations impose a change in the respiratory muscle load-capacity-drive relationship. It was hypothesised that lack of a fall in neural respiratory drive would identify patients at risk of treatment failure and early hospital readmission. METHODS: An observational study was performed at two UK teaching hospitals. Routine clinical physiological parameters and neural respiratory drive index (NRDI), calculated as the product of second intercostal space parasternal electromyography (EMG) activity normalised to the peak EMG activity during a maximum inspiratory sniff manoeuvre and respiratory rate, were recorded daily from admission to discharge. RESULTS: 30 acutely unwell patients of mean (SD) age 72 (10) years, forced expiratory volume in 1 s 0.60 (1.65) l, NRDI 455 (263) AU and median length of stay 6 days were studied. Changes in NRDI correlated with changes in Borg score (r=+0.60; p<0.001), discriminated between patients deemed to have clinically improved rather than deteriorated (mean difference 339 AU; 95% CI 234 to 444; p<0.001) and identified those patients readmitted within 14 days (mean difference 203 AU; 95% CI 39 to 366; p=0.017). CONCLUSIONS: NRDI is a feasible clinical physiological parameter in patients with an acute exacerbation of chronic obstructive pulmonary disease and can provide useful information on treatment response and risk of readmission. PMID- 21597114 TI - Self-concept and coping skills of female early adolescents in South Korea. AB - The purpose of the present study was to investigate the coping strategies and self-concept of Korean female early adolescents. These adolescents (n = 351) were enrolled in a middle school in Seoul. The subjects completed the Multidimensional Self-Concept Scale and Coping Responses Inventory questionnaires. The subjects exhibited the greatest positivity with regard to family self-concept and the greatest negativity with regard to academic self-concept. The subjects most frequently used the seeking guidance strategy of approach coping and the seeking alternative rewards strategy of avoidance coping. Self-concept was positively or negatively related with various coping skills. Using content analysis, seven categories including discord in family relationships were identified. The results of this study provide information that will aid school nurses working with adolescents with regard to helping the adolescents develop a positive self concept and more effective coping strategies. PMID- 21597113 TI - Coral broncholith associated with cystic bronchiectasis. PMID- 21597115 TI - Force spectroscopy reveals multiple "closed states" of the muscle thin filament. AB - Tropomyosin (Tm) plays a critical role in regulating the contraction of striated muscle. The three-state model of activation posits that Tm exists in three positions on the thin filament: "blocked" in the absence of calcium when myosin cannot bind, "closed" when calcium binds troponin and Tm partially covers the myosin binding site, and "open" after myosin binding forces Tm completely off neighboring sites. However, we recently showed that actin filaments decorated with phosphorylated Tm are driven by myosin with greater force than bare actin filaments. This result cannot be explained by simple steric hindrance and suggests that Tm may have additional effects on actin-myosin interactions. We therefore tested the hypothesis that Tm and its phosphorylation state affect the rate at which single actin-myosin bonds form and rupture. Using a laser trap, we measured the time necessary for the first bond to form between actin and rigor heavy meromyosin and the load-dependent durations of those bonds. Measurements were repeated in the presence of subsaturating myosin-S1 to force Tm from the closed to the open state. Maximum bond lifetimes increased in the open state, but only when Tm was phosphorylated. While the frequency with which bonds formed was extremely low in the closed state, when a bond did form it took significantly less time to do so than with bare actin. These data suggest there are at least two closed states of the thin filament, and that Tm provides additional points of contact for myosin. PMID- 21597116 TI - Structure of QnrB1, a plasmid-mediated fluoroquinolone resistance factor. AB - QnrB1 is a plasmid-encoded pentapeptide repeat protein (PRP) that confers a moderate degree of resistance to fluoroquinolones. Its gene was cloned into an expression vector with an N-terminal polyhistidine tag, and the protein was purified by nickel affinity chromatography. The structure of QnrB1 was determined by a combination of trypsinolysis, surface mutagenesis, and single anomalous dispersion phasing. QnrB1 folds as a right-handed quadrilateral beta-helix with a highly asymmetric dimeric structure typical of PRP-topoisomerase poison resistance factors. The threading of pentapeptides into the beta-helical fold is interrupted by two noncanonical PRP sequences that produce outward projecting loops that interrupt the regularity of the PRP surface. Deletion of the larger upper loop eliminated the protective effect of QnrB1 on DNA gyrase toward inhibition by quinolones, whereas deletion of the smaller lower loop drastically reduced the protective effect. These loops are conserved among all plasmid-based Qnr variants (QnrA, QnrC, QnrD, and QnrS) and some chromosomally encoded Qnr varieties. A mechanism in which PRP-topoisomerase poison resistance factors bind to and disrupt the quinolone-DNA-gyrase interaction is proposed. PMID- 21597118 TI - Cross-sectional and longitudinal associations between physical activity and blood pressure in adolescence: birth cohort study. AB - OBJECTIVES: To explore cross-sectional and longitudinal associations between self reported and accelerometry-based physical activity (PA) and blood pressure (BP) between 11 and 14 years of age. METHODS: Prospective birth cohort study in Pelotas, Brazil. Participants were 427 cohort members who were followed up with at 11, 12, and 14 years of age, and had questionnaire data on PA and BP at 11 and 14 years, as well as accelerometry and questionnaire data on PA at 12 years. Outcome measures were continuous systolic and diastolic BP at 14 years, and change in BP from 11 to 14 years. RESULTS: PA was unrelated to systolic BP in any analyses. PA measured by accelerometry at 12 years, but not questionnaire-derived PA, was inversely associated with diastolic BP at 14 years of age in fully adjusted models. Those who exceeded the 300-minutes PA threshold at all 3 visits had a 2.6 mmHg lower mean increase in DBP from 11 to 14 years compared with those classified below the threshold in all visits. CONCLUSIONS: Accelerometry-based PA was longitudinally inversely associated with diastolic BP. This finding was not evident when analyzing self-reported PA at a given age, suggesting a possible underestimation of the association when using subjective data. PMID- 21597119 TI - Physical activity level and ischemic heart disease prevalence among individuals aged 45 years and older with normal weight, BRFSS, 2007. AB - BACKGROUND: Most ischemic heart disease (IHD) prevention programs that promote physical activity (PA) have focused on overweight/obese populations. Persons with normal body mass index (BMI) may mistakenly think that they are not at risk for IHD and remain physically inactive. Studies exploring the risk of IHD and PA level among adults aged 45 years and older with normal weight are limited. METHODS: Cross-sectional study to examine the prevalence of IHD and PA level among 94455 respondents aged 45 years and older with normal BMI using the 2007 Behavioral Risk Factor Surveillance System data. RESULTS: Approximately 50% of respondents reported low/inactive PA. The prevalence of IHD among persons with inactive, low, medium, and high PA was 16.6% (95% CI=15.1-18.1%), 9.6% (8.9 10.3%), 8.9% (8.3-9.6%), and 5.4% (4.9-5.9%). The adjusted odds ratios of IHD among persons with low, medium, and high PA compared with those with inactive PA was 0.68 (95% CI=0.59-0.79), 0.63 (0.54-0.73), and 0.49 (0.42-0.57). CONCLUSIONS: The percentage of respondents with low or inactive PA among populations aged 45 years and older with BMI 18 to <25 was alarmingly high and independently associated with higher IHD prevalence. Persons who are not overweight/obese still need to have adequate PA to reduce the risk of IHD. PMID- 21597117 TI - Physical activity and sedentary activity patterns among children and adolescents: a latent class analysis approach. AB - BACKGROUND: While much is known about the overall levels of physical activity and sedentary activity among youth, few studies have attempted to define clusters of such behaviors. The purpose of this study was to identify and describe unique classes of youth based on their participation in a variety of physical activity and sedentary behaviors. METHODS: Latent class analysis was used to characterize segments of youth based on patterns of self-reported and accelerometer-measured participation in 12 behaviors. Children and adolescents (N=720) from 6th-11th grade were included in the analysis. Differences in class membership were examined using multinomial logistic regression. RESULTS: Three distinct classes emerged for boys and girls. Among boys, the 3 classes were characterized as "Active" (42.1%), "Sedentary" (24.9%), and "Low Media/Moderate Activity" (33.0%). For girls, classes were "Active" (18.7%), "Sedentary" (47.6%), and "Low Media/Functional Activity" (33.7%). Significant differences were found between the classes for a number of demographic indicators including the proportion in each class who were classified as overweight or obese. CONCLUSIONS: The behavioral profiles of the classes identified in this study can be used to suggest possible audience segments for intervention and to tailor strategies appropriately. PMID- 21597120 TI - Physical activity and C-reactive protein levels: the confounding role of body fat. AB - BACKGROUND: This study investigated the relationship between objectively-measured total physical activity (PA), and intensity of PA and high-sensitivity C-reactive protein (CRP) in 211 healthy, middle-age women (43.1+/-3.0 y). In addition, this study examined the extent to which age, BMI, abdominal circumference, and body fat percentage operated as confounders in these associations. METHODS: PA was objectively measured for 7 continuous days using accelerometry. Fasting blood samples were taken, from which CRP was measured using a solid phase ELISA. Body mass index (BMI) (kg/m2), abdominal circumference measured at the umbilicus, and body fat percentage using air displacement plethysmography, were assessed. RESULTS: Total PA (activity counts) was significantly and inversely related to CRP concentrations (F=7.76, P=.006) as was vigorous-intensity PA. After adjusting for differences in body fat percentage, total PA and vigorous-intensity PA were no longer significant predictors of CRP. Abdominal circumference and BMI also tended to weaken the relationship between total or vigorous-intensity PA and CRP but not to the same extent as body fat percentage. CONCLUSIONS: These findings suggest that higher total and vigorous-intensity PA levels are significantly related to lower CRP levels in healthy, middle-age women; however, this relationship is largely a function of differences in body fat percentage. PMID- 21597122 TI - Association between ambulatory physical activity and injuries during United States Army Basic Combat Training. AB - BACKGROUND: Associations between physical activity and injuries have been previously examined using self-reports. The present investigation examined this association using objective measures of activity and injury. METHODS: To quantify ambulatory activity, pedometers were worn daily by recruits in 10 Army Basic Combat Training companies during the 9-week training cycle. Injuries were obtained from a medical surveillance system, defined as traumatic or overuse events resulting in a medical care provider visit. A daily questionnaire documented whether or not recruits wore the pedometers and trained with their companies for the entire day. RESULTS: Training companies were categorized by activity level into 3 groups with higher activity (HA, 17,948+/-550 steps/day), 4 with moderate activity (MA, 16,346+/-768 steps/day) and 3 with lower activity (LA, 14,772+/-400 steps/day). Among men, the MA and HA groups were at 1.52 (95% confidence interval [95% CI]=1.15-2.01) and 1.94 (95% CI=1.46-2.61) times higher injury risk, respectively, compared with the LA group. Among women, the MA and HA groups were at 1.36 (95% CI=1.07-1.73) and 1.53 (95% CI=1.24-1.89) times higher injury risk, respectively, compared with low LA group. The relationships remained significant after considering physical characteristics and physical fitness. CONCLUSIONS: In consonance with previous self-report studies, higher physical activity was associated with higher injury risk. PMID- 21597121 TI - Active commuting to school and association with physical activity and adiposity among US youth. AB - BACKGROUND: Walking or bicycling to school (ie, active commuting) has shown promise for improving physical activity and preventing obesity in youth. Our objectives were to examine, among US youth, whether active commuting was inversely associated with adiposity and positively associated with moderate-to vigorous physical activity (MVPA). We also examined whether MVPA mediated the relationships between active commuting and adiposity. METHODS: Using data of participants aged 12 to 19 years from the US National Health and Nutrition Examination Survey 2003 to 2004 (n=789 unweighted), we constructed multiple linear regression models that controlled for dietary energy intake and sociodemographics. The main exposure variable was active commuting. The outcomes were BMI z-score, waist circumference, skinfolds and objectively measured MVPA. The product-of-coefficients method was used to test for mediation. RESULTS: Active commuting was inversely associated with BMI z-score (beta=-0.07, P=.046) and skinfolds (beta=-0.06, P=.029), and positively associated with overall daily (beta=0.12, P=.024) and before- and after-school (beta=0.20, P<.001) MVPA. Greater before- and after-school MVPA explained part of the relationship between active commuting and waist circumference (Sobel z=-1.98, P=.048). CONCLUSIONS: Active commuting was associated with greater MVPA and lower measures of adiposity among US youth. Before- and after-school MVPA mediated the relationships between active commuting and waist circumference. PMID- 21597123 TI - Assessing cost-effectiveness in obesity: active transport program for primary school children--TravelSMART Schools Curriculum program. AB - BACKGROUND: To assess from a societal perspective the cost-effectiveness of a school program to increase active transport in 10- to 11-year-old Australian children as an obesity prevention measure. METHODS: The TravelSMART Schools Curriculum program was modeled nationally for 2001 in terms of its impact on Body Mass Index (BMI) and Disability-Adjusted Life Years (DALYs) measured against current practice. Cost offsets and DALY benefits were modeled until the eligible cohort reached age 100 or died. The intervention was qualitatively assessed against second stage filter criteria ('equity,' 'strength of evidence,' 'acceptability to stakeholders,' 'feasibility of implementation,' 'sustainability,' and 'side-effects') given their potential impact on funding decisions. RESULTS: The modeled intervention reached 267,700 children and cost $AUD13.3M (95% uncertainty interval [UI] $6.9M; $22.8M) per year. It resulted in an incremental saving of 890 (95%UI -540; 2,900) BMI units, which translated to 95 (95% UI -40; 230) DALYs and a net cost per DALY saved of $AUD117,000 (95% UI dominated; $1.06M). CONCLUSIONS: The intervention was not cost-effective as an obesity prevention measure under base-run modeling assumptions. The attribution of some costs to nonobesity objectives would be justified given the program's multiple benefits. Cost-effectiveness would be further improved by considering the wider school community impacts. PMID- 21597124 TI - A pilot study of acceptance and commitment therapy for promotion of physical activity. AB - BACKGROUND: Acceptance and commitment therapy (ACT) appears to have some promise as a method of promoting physical activity. METHOD: This pilot study evaluated the short-term effectiveness of a brief, physical-activity-focused ACT intervention. Young adult, female participants were randomly assigned to an Education (n=19) or ACT (n=35) intervention. Both interventions consisted of 2, 2 hour group sessions. ACT sessions taught skills for mindfulness, values clarification, and willingness to experience distress in the service of behavior change. RESULTS: Of the intervention completers, ACT participants increased their level of physical activity significantly more than Education participants. CONCLUSIONS: The results indicate that ACT approaches have the potential to promote short-term increases in physical activity. PMID- 21597125 TI - A tale of two trails: exploring different paths to success. AB - BACKGROUND: This comparative case study investigates 2 successful community trail initiatives, using the Active Living By Design (ALBD) Community Action Model as an analytical framework. The model includes 5 strategies: preparation, promotion, programs, policy, and physical projects. METHODS: Key stakeholders at 2 sites participated in in-depth interviews (N=14). Data were analyzed for content using Atlas Ti and grouped according to the 5 strategies. RESULTS: PREPARATION: Securing trail resources was challenging, but shared responsibilities facilitated trail development. PROMOTIONS: The initiatives demonstrated minimal physical activity encouragement strategies. PROGRAMS: Community stakeholders did not coordinate programmatic opportunities for routine physical activity. POLICY: Trails' inclusion in regional greenway master plans contributed to trail funding and development. Policies that were formally institutionalized and enforced led to more consistent trail construction and safer conditions for users. PHYSICAL PROJECTS: Consistent standards for wayfinding signage and design safety features enhanced trail usability and safety. CONCLUSIONS: Communities with different levels of government support contributed unique lessons to inform best practices of trail initiatives. This study revealed a disparity between trail development and use-encouragement strategies, which may limit trails' impact on physical activity. The ALBD Community Action Model provided a viable framework to structure cross-disciplinary community trail initiatives. PMID- 21597126 TI - User demographics and physical activity behaviors on a newly constructed urban rail/trail conversion. AB - BACKGROUND: To examine demographic characteristics and physical activity (PA) behaviors of trail users on a newly constructed 2-mile urban rail/trail (ie, abandoned rail line converted to a recreational trail). METHODS: A systematic evaluation process was initiated to monitor PA behaviors using the System for Observing Play and Recreation in Communities (SOPARC). RESULTS: Slightly more males (n=2578, 54%) than females (n=2198, 46%) were observed using the rail/trail since its inception. A significant age group difference (F=16.68, P<.001) was observed among users with the vast majority being adults (n=3317, 69%). Women were 2.2 times more likely than men (95% CI 1.7-3.0) to be sedentary rather than vigorously active adjusted for age and race. Whites were 2.8 times more likely than nonwhites (95% CI 2.4-3.2) to engage in vigorous activity rather than walking, adjusted for age and gender. Rail/trail users resided on average 2.89 miles from the trail. DISCUSSION: The most frequent users of the rail/trail were male, white adults, and observed PA varied for gender and age. More research is needed to better understand differences in patterns of trail use by various population groups. PMID- 21597127 TI - Stability of habitual physical activity and sedentary behavior monitoring by accelerometry in 6- to 8-year-olds. AB - BACKGROUND: Accelerometry is rapidly becoming the instrument of choice for measuring physical activity in children. However, as limited data exist on the minimum number of days accelerometry required to provide a reliable estimate of habitual physical activity, we aimed to quantify the number of days of recording required to estimate both habitual physical activity and habitual sedentary behavior in primary school children. METHODS: We measured physical activity and sedentary behavior over 7 days in 291 6- to 8-year-olds using Actigraph accelerometers. Between-day intraclass reliability coefficients were calculated and averaged across all combinations of days. RESULTS: Although reliability increased with time, 3 days of recording provided reliabilities for volume of activity, moderate-vigorous intensity activity, and sedentary behavior of 68%, 71%, and 73%, respectively. CONCLUSIONS: For our sample and setting, 3 days accelerometry provided reliable estimates of the main constructs of physical activity and sedentary behavior. PMID- 21597128 TI - The place of physical activity in the time budgets of 10- to 13-year-old Australian children. AB - BACKGROUND: Low physical activity has been associated with increased fatness and deceased fitness. This observational study aimed to describe the magnitude, composition, and time-distribution of moderate-to-vigorous physical activity (MVPA) in Australian children. METHODS: A total of 1132 10 to 13 year old schoolchildren completed a 24-h activity recall diary on 2 to 4 occasions. MVPA was defined as any activity requiring >=3METs, including sport, play, active transport, chores, and other activities. RESULTS: MVPA was higher in boys than girls (173 vs 140 min/day; P<.0001), higher on nonschool days than school days (166 vs 143 min/day; P<.0001), and decreased with age (9 min/day per year of age). MVPA consisted of structured sport (37%), active transport (26%), unstructured play (24%), and chores/miscellaneous activities (13%). Every hour of MVPA was associated with a reduction in screen time (26.5 min), non-screen-based sedentary pastimes (8 min), and sleep (5.5 min). The least active quartile of children were more likely to be girls (OR=3.4), have higher screen time, and sleep more. From 4:00-6:30 PM on school days there were large differences in participation between high-active and low-active children. CONCLUSION: Findings suggest MVPA interventions should target girls, screen time and focus on the after-school period. PMID- 21597129 TI - A statistical summary of mall-based stair-climbing interventions. AB - BACKGROUND: Stair climbing is an accessible activity with proven health benefits. This article summarizes the effectiveness of mall-based stair-climbing interventions, while controlling for, and examining, potential moderators of stair/escalator choice. METHODS: Six comparable studies were identified, which used poster/ banner prompts to promote stair choice. Original data were combined and analyzed using logistic regression. Pedestrians' stair/escalator choices (N=127,221) provided the dichotomous outcome variable. Demographics (eg, gender), condition (baseline vs. intervention), and 'pedestrian traffic volume' were entered as potential moderators. To examine durability of effects, the rate of stair climbing in each half of the intervention period was compared. RESULTS: Overall, stair choice was more common in men (odds ratio [OR]=1.72), under-60s (OR=1.91), Whites (OR=1.38), those without accompanying children (OR=1.53), and periods of high traffic (OR=1.55). The rate of stair climbing increased in the intervention phase relative to baseline (OR=2.09), with greater effects among women (OR=1.99) versus men (OR=1.86), and under-60s (OR=2.62) versus over-60s (OR=1.93). Intervention effects fell slightly during the second half of the intervention period (OR=0.92). CONCLUSIONS: Conventional mass media campaigns engage an extra 5.0% of people in physical activity. The current calculations indicate that comparatively simple poster/banner prompts can increase stair climbing in mall settings by 6.0%. PMID- 21597131 TI - Assigning metabolic equivalent values to the 2002 census occupational classification system. AB - BACKGROUND: The Current Population Survey (CPS) and the American Time Use Survey (ATUS) use the 2002 census occupation system to classify workers into 509 separate occupations arranged into 22 major occupational categories. METHODS: We describe the methods and rationale for assigning detailed Metabolic Equivalent (MET) estimates to occupations and present population estimates (comparing outputs generated by analysis of previously published summary MET estimates to the detailed MET estimates) of intensities of occupational activity using the 2003 ATUS data comprised of 20,720 respondents, 5323 (2917 males and 2406 females) of whom reported working 6+ hours at their primary occupation on their assigned reporting day. RESULTS: Analysis using the summary MET estimates resulted in 4% more workers in sedentary occupations, 6% more in light, 7% less in moderate, and 3% less in vigorous compared with using the detailed MET estimates. The detailed estimates are more sensitive to identifying individuals who do any occupational activity that is moderate or vigorous in intensity resulting in fewer workers in sedentary and light intensity occupations. CONCLUSIONS: Since CPS/ATUS regularly captures occupation data it will be possible to track prevalence of the different intensity levels of occupations. Updates will be required with inevitable adjustments to future occupational classification systems. PMID- 21597130 TI - Determining activity monitor wear time: an influential decision rule. AB - BACKGROUND: Accurately measuring physical activity (PA) with activity monitors requires sufficient monitor wear time which can be difficult to assess. Monitor sensitivity to movement and population characteristics (eg, children vs. adults) may dictate the duration of monitor inactivity indicative of nonwear. A standardized method for determining appropriate decision rules to identify wear time is needed. METHODS: Several decision rules based on minimum durations of monitor inactivity (ie, 60, 90, 120, 150 minutes) to identify nonwear were applied to Stepwatch Activity Monitor data from 1064 adult bariatric surgical candidates. The frequency, pattern, and duration of resulting nonwear and wear periods were examined. Generalized Estimating Equations tested the effect of these decision rules on PA measures. RESULTS: A 60-minute duration resulted in unreasonably large percentages of subjects with unlikely wear patterns [eg, >=3 nonwear periods in a day (29.9%); >=2 wear periods of less than an hour in a day (28.7%)]; 120 minutes appeared most reasonable. Wear time decision rules impacted PA measures. CONCLUSIONS: The methods described in this paper can be used to determine appropriate instrument and population specific wear time decision rules. Recognizing monitor wear time is estimated, PA measures least affected by wear time are preferable. PMID- 21597132 TI - Actical accelerometer sedentary activity thresholds for adults. AB - BACKGROUND: Actical accelerometer thresholds have been derived to enable objective measurement of time spent performing sedentary activity in children and adolescents, but not adults. Thus, the purpose of this study was to determine Actical accelerometer sedentary activity thresholds for adults. METHODS: Data were available from 3187 participants aged 6 to 79 years from a preliminary partial dataset of the Canadian Health Measures Survey, who wore an Actical for 7 days. Step count data were used to evaluate the use of 50, 100, and 800 counts per min (cpm) as sedentary activity thresholds. Minutes when no steps were recorded were considered minutes of sedentary activity. RESULTS: The use of higher cpm thresholds resulted in a greater percentage of sedentary minutes being correctly classified as sedentary. The percentage of minutes that were incorrectly classified as sedentary was substantially higher when using a threshold of 800 cpm compared with 50 or 100 cpm. Results were similar for children, adolescents, and adults. CONCLUSIONS: These findings suggest that a threshold of 100 cpm is appropriate for classifying sedentary activity of adults when using the Actical. As such, wear periods with minutes registering less than 100 cpm would be classified as time spent performing sedentary activity. PMID- 21597133 TI - Efficient dual mode multicolor luminescence in a lanthanide doped hybrid nanostructure: a multifunctional material. AB - The present work deals with inorganic-organic hybrid nanostructures capable of producing intense visible emission via upconversion (UC), downconversion (DC), and energy transfer (ET) processes which show the potential of the material as a luminescent solar collector (LSC), particularly to improve the efficiency of silicon solar cells. To achieve this, Gd2O3:Yb3+/Er3+ phosphor (average particle size~35 nm) and a Eu(DBM)3Phen organic complex have been synthesized separately and then the hybrid structure has been developed using a simple mixing procedure. Intense UC emission (in the red, green, and blue regions) due to Er3+ is observed on near infrared (976 nm) excitation which shows color tunability with input pump power. In contrast, intense red emission of Eu3+ is observed on ultaviolet (UV) (355 nm) excitation. The feasibility of energy transfer from Er3+ ions to Eu3+ ions has also been noted. These excellent optical properties are retained even if the particles of the hybrid nanostructure are dispersed in liquid medium, which also makes it suitable for security ink purposes. PMID- 21597134 TI - Controlled fabrication of TiO2 rutile nanorod/anatase nanoparticle composite photoanodes for dye-sensitized solar cell application. AB - We present a straightforward procedure to prepare composite photoanodes which consisted of TiO2 rutile nanorods/anatase nanoparticles synthesized under hydrothermal conditions, with the ratio of rutile to anatase controlled simply by adjusting the volume of nitric acid. The as-prepared TiO2 composites exhibited high specific surface area, light-scattering effect, and good crystallinity. The dye-sensitized solar cells (DSCs) using the TiO2 composites showed higher short circuit photocurrent and overall conversion efficiency than the DSC from pure anatase nanoparticles. The highest conversion efficiency was achieved from the DSC based on TiO2 nanocomposites with 24 wt% rutile nanorods, which was attributed to improved light harvesting caused by the enhancement of specific surface area and scattering effect from rutile nanorods. PMID- 21597135 TI - Charge transfer and partial pinning at the contacts as the origin of a double dip in the transfer characteristics of graphene-based field-effect transistors. AB - We discuss the origin of an additional dip other than the charge neutrality point observed in the transfer characteristics of graphene-based field-effect transistors with a Si/SiO2 substrate used as the back-gate. The double dip is proved to arise from charge transfer between the graphene and the metal electrodes, while charge storage at the graphene/SiO2 interface can make it more evident. Considering a different Fermi energy from the neutrality point along the channel and partial charge pinning at the contacts, we propose a model which explains all the features observed in the gate voltage loops. We finally show that the double dip enhanced hysteresis in the transfer characteristics can be exploited to realize graphene-based memory devices. PMID- 21597136 TI - Bioassisted capture and release of nanoparticles on nanolithographed ZnO films. AB - Using an artificial peptide library, we have identified a peptide that has strict selective affinity for ZnO surfaces. The binding affinity of the peptide on the ZnO surface can be controlled simply through changes in phosphate concentration at constant pH and temperature. In this study, we functionalized inorganic nanoparticles by orderly conjugating ZnO-binding peptides (ZnOBPs) on the surface of cadmium selenide (CdSe) nanoparticles and performed spontaneous and reversible nanopatterning of ZnOBP-displayed nanoparticles on lithographed ZnO films. Conjugation of ZnOBPs on CdSe nanoparticles caused spontaneous adsorption of the nanoparticles on a ZnO film, and fluorescence and cathodoluminescence images clearly showed specific adsorption of nanoparticles on the ZnO films lithographed on nano- and micrometer scales. The selectively bound nanoparticles on ZnO films were completely released by changing the phosphate concentration in solution; such release did not require heat or mechanical applications. Repeated capture and release of nanoparticles were achieved on the micrometer scale. Our results show the potential of material-binding peptides for nanopatterning and dynamic microarrays. PMID- 21597137 TI - Infrared spectroscopic and electron microscopic characterization of gold nanogap structure fabricated by focused ion beam. AB - Using infrared spectroscopy of plasmonic resonances and mapping of elemental composition and structure, we investigated the correlation between optical and structural properties of nanometre-scale gaps in gold nanorod dimers fabricated by electron beam lithography (EBL) and focused ion beam (FIB) milling. In spite of their very similar scanning electron microscopy (SEM) images, a fully cut nanogap and a shallower cut with slight imperfection near the gap region were clearly distinguished by their strongly different infrared plasmonic resonance behaviour. The differences in the infrared spectra are related to different structural and chemical results from elaborated cross-sectional transmission electron micrographs and energy dispersive x-ray spectrometry (EDX) mapping of the gap region. PMID- 21597138 TI - Patterning of various silicon structures via polymer lithography and catalytic chemical etching. AB - We demonstrate a facile fabrication of a rich variety of silicon patterns with different length scales by combining polymer lithography and a metal-assisted chemical etching method. Several types of polymer patterns were fabricated on silicon substrates, and silver layers were deposited on the patterned silicon surfaces and used to etch the silicon beneath. Various silicon patterns including topographic lines, concentric rings, and square arrays were created at a micro- and nanoscale after etching the silicon and subsequent removal of the patterned polymer masks. Alternatively, the arrays of sub-30 nm silicon nanowires were produced by a chemical etching of the silicon wafer which was covered with highly ordered polystyrene-block-polyvinylpyridine (PS-b-PVP) micellar films. In addition, silicon nanohole arrays were also generated by etching with hexagonally packed silver nanoparticles that were prepared using PS-b-PVP block copolymer templates. PMID- 21597139 TI - Fabrication method of high-quality Ge nanocrystals on patterned Si substrates by local melting point control. AB - The local melting point of a Ge thin film can be controlled by a hole-array pattern on the host Si substrate due to the variations in the stress distribution and the surface morphology induced by the pattern. A simple annealing process is developed from this effect to produce Ge NCs with a single-domain-crystal size over 20 nm, confirmed by transmission electron microscopy and Raman spectroscopy, from an electron-gun-evaporated Ge thin film on the patterned Si substrate. The effect of the dimensions of the hole array is also investigated. Photoluminescence observed around 1157 nm from some of the samples shows the possibility of improving the infrared emission capability by this proposed method. PMID- 21597140 TI - Stability studies of CdSe nanocrystals in an aqueous environment. AB - In this paper, CdSe nanocrystal dissolution in an aqueous solution was studied. It was found that light is a key factor affecting the dissolution of nanocrystals. In the presence of light, the electrons generated from CdSe nanocrystals reduce water to hydrogen and hydroxide ions (OH-) while photo generated holes oxidize CdSe to Cd2+ and elemental Se. The dissolution was accelerated in an acidic medium while moderate alkalinity (pH=10.3) can slow down the dissolution possibly due to precipitation of nanocrystals. This study has strong implications for the use of these crystals in aqueous environments (bioimaging and dye-sensitized solar cells). PMID- 21597141 TI - Tuned longitudinal surface plasmon resonance and third-order nonlinear optical properties of gold nanorods. AB - In order to elucidate the relationship for third-order nonlinear optical properties of anisotropic metal nanoparticles between the incident laser wavelength and surface plasmon resonance (SPR) wavelength, gold nanorods (GNRs) with a tuned longitudinal SPR mode in frequency were prepared by seed-mediated methods with two different surfactants, cetyltrimethylammonium bromide (CTAB) and benzyldimethylammonium chloride (BDAC). The real and imaginary parts of the third order nonlinear optical susceptibilities chi(3) were examined by near-infrared (800 nm) femtosecond Z-scan and I-scan techniques for various gold sols with SPR wavelengths of 530 nm (spheres), 800 nm (nanorods) and 1000 nm (nanorods), named as 530GNSs, 800GNRs and 1000GNRs, respectively. All the samples showed intrinsically third-order nonlinear optical refractive responses. However, as for the real part of chi(3) for one particle, 800GNRs whose plasmon peak was tuned to the incident laser wavelength exhibited a Rechi(3) value 45 times stronger than 530GNSs. More interestingly, the imaginary part of chi(3) was more greatly influenced at the tuned SPR wavelength. Here we first demonstrate that 800GNRs showed plasmon-enhanced saturable absorption (SA) due to a longitudinal SPR tuned to the incident laser wavelength. PMID- 21597142 TI - Electrochemical protection of thin film electrodes in solid state nanopores. AB - Solid state nanopores are a core element of next-generation single molecule tools in the field of nano-biotechnology. Thin film electrodes integrated into a pore can interact with charges and fields within the pore. In order to keep the nanopore open and thus functional electrochemically induced surface alteration of electrode surfaces and bubble formation inside the pore have to be eliminated. This paper provides electrochemical analyses of nanopores drilled into TiN membranes which in turn were employed as thin film electrodes. We studied physical pore integrity and the occurrence of water decomposition yielding bubble formation inside pores by applying voltages between -4.5 and +4.5 V to membranes in various protection stages continuously for up to 24 h. During potential application pores were exposed to selected electrolyte-solvent systems. We have investigated and successfully eliminated electrochemical pore oxidation and reduction as well as water decomposition inside nanopores of various diameters ranging from 3.5 to 25 nm in 50 nm thick TiN membranes by passivating the nanopores with a plasma-oxidized layer and using a 90% solution of glycerol in water as KCl solvent. Nanopore ionic conductances were measured before and after voltage application in order to test for changes in pore diameter due to electrochemical oxidation or reduction. TEM imaging was used to confirm these observations. While non-passivated pores were electrochemically oxidized, neither electrochemical oxidation nor reduction was observed for passivated pores. Bubble formation through water decomposition could be detected in non-passivated pores in KCl/water solutions but was not observed in 90% glycerol solutions. The use of a protective self-assembled monolayer of hexadecylphosphonic acid (HDPA) was also investigated. PMID- 21597143 TI - Size effects on silver nanoparticles' properties. AB - In this work a systematic study of the dependence of the structural, electronic, and vibrational properties on nanoparticle size is performed. Based on our total energy calculations we identified three characteristic regimes associated with the nanoparticle's dimensions: (i) below 1.5 nm (100 atoms) where remarkable molecular aspects are observed; (ii) between 1.5 and 2.0 nm (100 and 300 atoms) where the molecular behavior is influenced by the inner core crystal properties; and (iii) above 2.0 nm (more than 300 atoms) where the crystal properties are preponderant. In all considered regimes the nanoparticle's surface modulates its properties. This modulation decreases with the increasing of the nanoparticle's size. PMID- 21597144 TI - The morphology and evolution of bipyramidal gold nanoparticles. AB - We examine the growth and evolution with time of bipyramidal gold nanoparticles grown by a seed-mediated process. The nanoparticles are characterized both by their physical dimensions determined by transmission electron microscopy and by the wavelength position of their localized surface plasmon resonance. Each growth's physical dimensions correspond to particular initial conditions, and we observe two distinct modes of temporal evolution during growth. The effects of varying silver nitrate concentration and growth time are also explored. We observe a linear relationship between the tip radius of curvature and the wavelength of the longitudinal localized surface plasmon resonance (LSPR) peak. Critical parameters for synthesizing bipyramidal nanoparticles with sharp tips and correct length to width ratio are determined. PMID- 21597145 TI - DNA origami-based nanoribbons: assembly, length distribution, and twist. AB - A variety of polymerization methods for the assembly of elongated nanoribbons from rectangular DNA origami structures are investigated. The most efficient method utilizes single-stranded DNA oligonucleotides to bridge an intermolecular scaffold seam between origami monomers. This approach allows the fabrication of origami ribbons with lengths of several micrometers, which can be used for long range ordered arrangement of proteins. It is quantitatively shown that the length distribution of origami ribbons obtained with this technique follows the theoretical prediction for a simple linear polymerization reaction. The design of flat single layer origami structures with constant crossover spacing inevitably results in local underwinding of the DNA helix, which leads to a global twist of the origami structures that also translates to the nanoribbons. PMID- 21597146 TI - Fluorescent magnetic hybrid nanoprobe for multimodal bioimaging. AB - A fluorescent magnetic hybrid imaging nanoprobe (HINP) was fabricated by the conjugation of superparamagnetic Fe3O4 nanoparticles and visible light emitting (~600 nm) fluorescent CdTe/CdS quantum dots (QDs). The assembly strategy used the covalent linking of the oxidized dextran shell of magnetic particles to the glutathione ligands of QDs. The synthesized HINP formed stable water-soluble colloidal dispersions. The structure and properties of the particles were characterized by transmission electron and atomic force microscopy, energy dispersive x-ray analysis and inductively coupled plasma optical emission spectroscopy, dynamic light scattering analysis, optical absorption and photoluminescence spectroscopy, and fluorescent imaging. The luminescence imaging region of the nanoprobe was extended to the near-infrared (NIR) (~800 nm) by conjugation of the superparamagnetic nanoparticles with synthesized CdHgTe/CdS QDs. Cadmium, mercury based QDs in HINP can be easily replaced by novel water soluble glutathione stabilized AgInS2/ZnS QDs to present a new class of cadmium free multimodal imaging agents. The observed NIR photoluminescence of fluorescent magnetic nanocomposites supports their use for bioimaging. The developed HINP provides dual-imaging channels for simultaneous optical and magnetic resonance imaging. PMID- 21597147 TI - Achieving chiral resolution in self-assembled supramolecular structures through kinetic pathways. AB - Chiral phase transitions were studied in a self-assembled 2,6 dibromoanthraquinones supramolecular system prepared on Au(111) using scanning tunneling microscopy. As the molecules were deposited at about 150 K, they formed heterochiral chevron structures (a racemate) consisting of two alternating prochiral molecular rows. When the as-deposited sample was warmed to 300 K followed by cooling to 80 K, phase-separated homochiral structures (a conglomerate), as well as the chevron structures, were observed. We propose molecular models for the structures that are in good agreement with ab initio studies and can be explained by hydrogen bonds and halogen bonds. We found that heterochiral chevron structures were more stable than homochiral structures due to two additional [Formula: see text] halogen bonds per molecule. We considered kinetic pathways for the phase transitions that were made possible via a disordered liquid phase entropically stabilized at 300 K. We show how chiral resolution can be achieved by exploiting kinetic paths allowed in supramolecular systems. PMID- 21597148 TI - Non-chemical approach toward 2D self-assemblies of Ag nanoparticles via cold plasma treatment of substrates. AB - The nano-modification of selected substrates by means of atmospheric cold plasma treatment was exploited for the two-dimensional (2D) self-assembling of silver nanoparticles (Ag NPs). Such a useful combination of the cold plasma treatment of substrate surface and an immediate easy deposition of Ag NPs creating the 2D self assemblies on the substrates is published for the first time, to the best of our knowledge. Except for the cold plasma treatment, mainly the following parameters influenced the resulting NP assemblies: the choice of solvent mixture, concentration of Ag NP dispersions, and the deposition technique. The 2D self assemblies of Ag NPs, providing the same work function as a Ag electrode, were formed on the cold plasma-treated substrates when a drop-casting technique was employed. The possibility of an easy preparation of the Ag NP 2D self-assemblies on substrates without using any chemical agents and/or evaporating chamber could be exploited, e.g. in photovoltaic and light-emitting diode devices. PMID- 21597149 TI - Depth-sensing nano-indentation on a myelinated axon at various stages. AB - A nano-mechanical characterization of a multi-layered myelin sheath structure, which enfolds an axon and plays a critical role in the transmission of nerve impulses, is conducted. Schwann cells co-cultured in vitro with PC12 cells for various co-culture times are differentiated to form a myelinated axon, which is then observed using a transmission electron microscope. Three major myelination stages, with distinct structural characteristics and thicknesses around the axon, can be produced by varying the co-culture time. A dynamic contact module and continuous depth-sensing nano-indentation are used on the myelinated structure to obtain the load-on-sample versus measured displacement curve of a multi-layered myelin sheath, which is used to determine the work required for the nano indentation tip to penetrate the myelin sheath. By analyzing the harmonic contact stiffness versus the measured displacement profile, the results can be used to estimate the three stages of the multi-layered structure on a myelinated axon. The method can also be used to evaluate the development stages of myelination or demyelination during nerve regeneration. PMID- 21597150 TI - Aqueous synthesis of internally doped Cu:ZnSe/ZnS core-shell nanocrystals with good stability. AB - To prepare biologically available Zn-based NCs in aqueous solution, we herein reported the synthesis of aqueous Cu:ZnSe/ZnS NCs with internally doped aqueous Cu:ZnSe NCs as the core template. Due to the dual protection of Cu impurities by the ZnSe core and ZnS shells, the as-prepared Cu:ZnSe/ZnS NCs show excellent stability in the open air, which overcomes the intrinsic instability of traditional aqueous Cu:ZnSe NCs. The as-prepared Cu:ZnSe/ZnS NCs possess extremely good stability, good biocompatibility and lower cytotoxicity, and thus can be used as a promising candidate for fluorescent NC-based biological applications. PMID- 21597151 TI - Electronic structures of an epitaxial graphene monolayer on SiC(0001) after gold intercalation: a first-principles study. AB - The atomic and electronic structures of an Au-intercalated graphene monolayer on the SiC(0001) surface were investigated using first-principles calculations. The unique Dirac cone of graphene near the K point reappeared as the monolayer was intercalated by Au atoms. Coherent interfaces were used to study the mismatch and the strain at the boundaries. Our calculations showed that the strain at the graphene/Au and Au/SiC(0001) interfaces also played a key role in the electronic structures. Furthermore, we found that at an Au coverage of 3/8 ML, Au intercalation leads to a strong n-type doping of graphene. At 9/8 ML, it exhibited a weak p-type doping, indicative that graphene was not fully decoupled from the substrate. The shift in the Dirac point resulting from the electronic doping was not only due to the different electronegativities but also due to the strain at the interfaces. Our calculated positions of the Dirac points are consistent with those observed in the ARPES experiment (Gierz et al 2010 Phys. Rev. B 81 235408). PMID- 21597152 TI - Analysis of single quantum-dot mobility inside 1D nanochannel devices. AB - We visualized individual quantum dots using a combination of a confining nanochannel and an ultra-sensitive microscope system, equipped with a high numerical aperture lens and a highly sensitive camera. The diffusion coefficients of the confined quantum dots were determined from the experimentally recorded trajectories according to the classical diffusion theory for Brownian motion in two dimensions. The calculated diffusion coefficients were three times smaller than those in bulk solution. These observations confirm and extend the results of Eichmann et al (2008 Langmuir 24 714-21) to smaller particle diameters and more narrow confinement. A detailed analysis shows that the observed reduction in mobility cannot be explained by conventional hydrodynamic theory. PMID- 21597153 TI - A simple and cost-effective sensing strategy of mercury (II) based on analyte inhibited aggregation of gold nanoparticles. AB - A simple, cheap and ultrasensitive colorimetric Hg2+ sensing strategy has been developed in this paper. It was based on a special 'Hg2+-inhibited aggregation' mechanism, in which the pyridine-induced aggregation of unmodified gold nanoparticles (AuNPs) could be inhibited upon addition of Hg2+. Compared with the previous Hg2+-induced aggregation mechanism, the new design just employed a cheap and facile chemical reagent, pyridine, as an inducer of aggregation of AuNPs and elimination of the modifying or labeling step. The effects of pyridine concentration and size of AuNPs were investigated. The calibration curve showed that the extinction ratio value at 525 and 700 nm increased linearly over the Hg2+ concentration range of 0.15-3.00 uM with a detection limit of 55 nM. The specificity of this sensor is remarkably high over that of the other metal ions without adding any masking agent. PMID- 21597154 TI - Growth and optical properties of Ag clusters deposited on poly(ethylene terephthalate). AB - The growth and concomitant evolution of the optical properties of Ag nano clusters deposited on biaxially extruded poly(ethylene terephthalate) films is studied by reflectance difference spectroscopy. It is demonstrated by low energy ion scattering and simulated optical spectra that the clusters form a two dimensional layer buried beneath the surface of the substrate. The experimental spectra are described by simulations in which different configurations of the host such as anisotropy, amorphization, and dilution are considered in an effective medium approach. The contribution of the anisotropic substrate is used to explain the resulting line shapes. We also discuss the role of the rate of change of the filling fraction with Ag coverage in the evolution of the spectra and the detection of the onset of coalescence by optical means. PMID- 21597155 TI - Enhancement of UV emission in ZnO nanorods by growing additional ZnO layers on the surface. AB - Ultraviolet (UV) photoluminescence emission from ZnO nanorod arrays was greatly enhanced by growing additional thin ZnO layers on the surface after thermal reduction of the nanorods. Appropriate selection of additives based on the shape of the original ZnO samples was found to be an important factor in designing the solution composition for growing the additional ZnO layers. This is because the additives modify the growth rates with respect to crystallographic planes. Adding ethylene glycol to the solution was effective for rod-shaped ZnO nanorods in enhancing the UV emission, whereas adding polyethylenimine was better for plate like particles. These results can be explained by the presence of non-luminescent regions near the surface, where UV emission is thought to be suppressed by non radiative surface centers. Growing additional layers on side planes increases the volume of the optically active region of ZnO nanorods, with a lower transmittance loss; thus, it effectively enhances the UV emission intensity. PMID- 21597156 TI - Lead (II) ion detection in surface water with pM sensitivity using aza-crown ether-modified silver nanoparticles via dynamic light scattering. AB - In this paper, we reported ultrasensitive lead ion detection in environmental water with pM sensitivity using aza-crown-ether-modified silver nanoparticles (ACE-Ag NPs) through dynamic light scattering (DLS). The colorimetric method based on ACE-Ag NPs is not capable of detecting Pb2+ ions over other metal ions (Fe3+, Co2+, Cu2+, Hg2+, Cd2+, Ag+, Li+, Na+, K+ and Cs+) with high sensitivity. But DLS has improved the selectivity and sensitivity of the Pb2+ detection system (50-fold or more) over colorimetric method, and its detection limit is 0.25 pM (1.03 ppt). The Pb2+ DLS assay can be applied to detect Pb2+ in the environmental water, such as in Yangtze and East Lake water samples with a detection limit of 0.20 and 0.22 pM, which is much lower than the maximum contamination level of 4.8*10(-8) M for lead in surface water defined by the national environmental quality standards of China (GB 3838-2002). Also, this method has a good performance in the determination of Pb2+ in drinking water, which is much lower than the maximum contamination level (MCL) of 72 nM for lead as defined by the US Environmental Protection Agency (EPA). PMID- 21597157 TI - The sol-gel template synthesis of porous TiO2 for a high performance humidity sensor. AB - This research develops a simple template assisted sol-gel process for preparing porous TiO2 for a high performance humidity sensor. Tetraethyl orthosilicate (TEOS) as a template was directly introduced into TiO2 sol formed by the hydrolysis and condensation of titanium alkoxide; the following calcination led to the formation of TiO2-SiO2 composite, and the selective removal of SiO2 by dilute HF solution led to the formation of porous structure in TiO2. The resulting porous TiO2-based sensor exhibits high sensitivity and linear response in the wide relative humidity (RH) range of 11%-95%, with an impedance variation of four orders of magnitude to humidity change. Moreover, it exhibits a rapid and highly reversible response characterized by a very small hysteresis of <1% RH and a short response-recovery time (5 s for adsorption and 8 s for desorption), and a 30-day stability test also confirms its long-term stability. Compared with pure TiO2 prepared by the conventional sol-gel method, our product shows remarkably improved performance and good prospect for a high performance humidity sensor. The complex impedance spectra were used to elucidate its humidity sensing mechanism in detail. PMID- 21597158 TI - Macroporous conductive polymer films fabricated by electrospun nanofiber templates and their electromechanical properties. AB - We demonstrate a facile method to fabricate macroporous poly (3,4 ethylenedioxythiophene)/poly (4-styrene sulfonate) (PEDOT/PSS) films with empty channels by using electrospun nanofiber as a sacrificial template. The channels within the PEDOT/PSS films were prepared by depositing PEDOT/PSS aqueous dispersion onto poly (vinyl pyrrolidone)/poly(methyl methacrylate) (PVP/PMMA) nanofiber template, and then the nanofibers were removed by solvent extraction. The average diameter of the channels is 313+/-45 nm, which is almost the same as the parent PVP/PMMA nanofibers. The macroporous PEDOT/PSS film with the empty channels showed an enhancement of electromechanical properties compared to the nonporous PEDOT/PSS film. PMID- 21597159 TI - Theoretical and experimental study of nanopore drilling by a focused electron beam in transmission electron microscopy. AB - Sub-10 nm nanopores drilled by a focused electron beam in a transmission electron microscope are widely used in solid-state nanopore devices for DNA translocation. However, there still remains much controversy surrounding the drilling mechanism. In order to explain the drilling of nanopores by electrons, we undertook a theoretical consideration of the energy transfer from the fast electrons to the solid through such mechanisms as elastic and inelastic scattering. According to the calculations based on the scattering cross-section, the direct atomic displacement cross-section induced by elastic scattering increases with increasing incident electron energy, while the ionization cross-section and temperature increment decrease. We performed nanopore drilling in a Si3N4 membrane using two different electron energies, 200 and 300 kV, to identify the drilling mechanism. The dependence of the nanopore drilling on the incident electron energy was well matched with the direct atomic displacement. PMID- 21597160 TI - Optical properties and luminescence dynamics of Eu3+-doped terbium orthophosphate nanophosphors. AB - The development of luminescent inorganic nanocrystals (NCs) doped with rare-earth (RE) ions has attracted increasing interest owing to their distinct optical properties and versatile applications in time-resolved bioassays, multiplex biodetection, DNA hybridization and bioimaging. Hexagonal TbPO4:Eu3+ NCs (10-30 nm) were synthesized via a facile hydrothermal method assisted with oleic acid (OA) surfactants, which exhibit tunable emissions from green to red by varying the concentration of Eu3+. The Tb3+-to-Eu3+ energy transfer efficiency observed reaches up to 94%. Different from their bulk counterparts, a new interface-state band (316 nm) in addition to the commonly observed spin-forbidden 4f-5d transition band (265 nm) of Tb3+ was found to be dominant in the excitation spectrum of NCs due presumably to the formation of surface TbPO4/OA complexes, which provides an additional excitation antenna in practical utilization. Two kinds of luminescence sites of Eu3+ in TbPO4 NCs, with the site symmetry of C2 or C1, were identified based on the emission spectra at 10 K and room temperature. Furthermore, the photoluminescence (PL) dynamics of Tb3+ ions in pure TbPO4 NCs have been revealed. Compared to the exponential PL decay in bulk counterparts induced by very fast energy migration, the non-exponential decay from 5D4 of Tb3+ in TbPO4 NCs is mainly attributed to the diffusion-limited energy migration due to more rapid energy transfer from Tb3+ to defects than the energy migration among Tb3+. PMID- 21597161 TI - A multi-scaled hybrid orthopedic implant: bone ECM-shaped Sr-HA nanofibers on the microporous walls of a macroporous titanium scaffold. AB - We report here, for the first time, a novel multi-scaled hybrid orthopedic implant material consisting of a macroporous Ti scaffold, whose macropores' walls have a microporous titania layer which is fully covered with nanofibers of Sr doped hydroxyapatite (Sr-HA). The microporous titania layer is formed on and within the Ti scaffold by micro-arc oxidation, which firmly binds to the Ti substrate and contains Ca2+, Sr2+ and PO4(3-) ions. It is then hydrothermally treated to form Sr-HA nanofibers. During the hydrothermal treatment, Sr-HA nanoprisms nucleate from Ca0.5Sr0.5TiO3 pre-formed on the TiO2 and grow in length to nanofibers at the expense of Ca2+, Sr2+ and PO4(3-) ions that migrate from the TiO2. These Sr-HA nanofibers construct a network structure similar to the hierarchical organization of bone extracellular matrix (ECM), and the resulting nanofibrous surface displays a firm adhesion to substrate, superhydrophilicity and apatite-inducing ability. The induced apatite prefers to nucleate on the basal-faceted surfaces of Sr-HA nanofibers. The nanofiber-walled scaffold has a great potential for load-bearing orthotopic use. PMID- 21597162 TI - High yield of self-catalyzed GaAs nanowire arrays grown on silicon via gallium droplet positioning. AB - We report and detail a method to achieve growth of vertical self-catalyzed GaAs nanowires directly on Si(111) with a near-perfect vertical yield, using electron beam-defined arrays of holes in a dielectric layer and molecular beam epitaxy. In our conditions, GaAs nanowires are grown along a vapor-liquid-solid mechanism, using in situ self-forming Ga droplets. The focus of this paper is to understand the role of the substrate preparation and of the pre-growth conditioning. Without changing temperature or the V/III ratio, the yield of vertical nanowires is increased incrementally up to 95%. The possibility to achieve very dense arrays, with center-to-center inter-wire distances less than 100 nm, is demonstrated. PMID- 21597163 TI - Bioprinting of hybrid tissue constructs with tailorable mechanical properties. AB - Tissue/organ printing aims to recapitulate the intrinsic complexity of native tissues. For a number of tissues, in particular those of musculoskeletal origin, adequate mechanical characteristics are an important prerequisite for their initial handling and stability, as well as long-lasting functioning. Hence, organized implants, possessing mechanical characteristics similar to the native tissue, may result in improved clinical outcomes of regenerative approaches. Using a bioprinter, grafts were constructed by alternate deposition of thermoplastic fibers and (cell-laden) hydrogels. Constructs of different shapes and sizes were manufactured and mechanical properties, as well as cell viability, were assessed. This approach yields novel organized viable hybrid constructs, which possess favorable mechanical characteristics, within the same range as those of native tissues. Moreover, the approach allows the use of multiple hydrogels and can thus produce constructs containing multiple cell types or bioactive factors. Furthermore, since the hydrogel is supported by the thermoplastic material, a broader range of hydrogel types can be used compared to bioprinting of hydrogels alone. In conclusion, we present an innovative and versatile approach for bioprinting, yielding constructs of which the mechanical stiffness provided by thermoplastic polymers can potentially be tailored, and combined specific cell placement patterns of multiple cell types embedded in a wide range of hydrogels. PMID- 21597164 TI - Double-knockout of putative endo-beta-N-acetylglucosaminidase (ENGase) genes in Arabidopsis thaliana: loss of ENGase activity induced accumulation of high mannose type free N-glycans bearing N,N'-acetylchitobiosyl unit. AB - Endo-beta-N-acetylglucosaminidase (ENGase) is involved in the production of high mannose type free N-glycans during plant development and fruit maturation. In a previous study (K. Nakamura et al. Biosci. Biotechnol. Biochem., 73, 461-464 (2009)), we identified the tomato ENGase gene and found that gene expression remained relatively constant. In the present study, we constructed an Arabidopsis thaliana mutant in which the expression of two putative ENGase genes was suppressed. The mutant showed no ENGase activity, but produced high-mannose type free N-glycans carrying the N,N'-acetylchitobiosyl unit that is produced by peptide:N-glycanase, indicating that both these genes encode Arabidopsis ENGase. PMID- 21597165 TI - Establishment of a novel method of screening anti-allergic lactic acid bacteria. AB - In this study, we attempted to establish a novel method of screening anti allergic lactic acid bacteria (LAB). We cloned the human histidine decarboxylase (HDC) promoter into the promoter-less pPhi-Yellow-RPL-dest1 vector and established KU812F cells transduced with this vector (pHDCp-Phi-Yellow/KU812F). After adding LAB to these cells, the change in fluorescence intensity was monitored by flow cytometry. After screening, we identified several LAB strains that downregulated HDC promoter activity. Functional analysis of these LAB strains indicated that two LAB strains inhibited histamine release from KU812F cells, indicating that this assay system can be used to screen for anti-allergic LAB in a high-throughput manner. PMID- 21597166 TI - Inhibitory effect of dietary carotenoids on dinitrofluorobenzene-induced contact hypersensitivity in mice. AB - We evaluated the effect of carotenoids on the dinitrofluorobenzene (DNFB)-induced contact hypersensitivity in mice. Dietary carotenoids significantly inhibited ear swelling and reduced the contents of TNF-alpha and histamine in the DNFB-treated mice. Our results suggest that dietary carotenoids exerted an anti-inflammatory effect by suppressing mast cell degranulation in vivo. PMID- 21597167 TI - Disruption of ion homeostasis by verrucosin and a related compound. AB - We have found that (-)-virgatusin and related compounds have antimicrobial and antifungal activity. To identify further biological activities of these compounds, we tested the activity of acridine orange efflux, which shows ionophore-like disruption of cellular ion homeostasis activity. After testing 31 compounds, we found that verrucosin and a related compound had disruption activity. PMID- 21597168 TI - Citronellol and geraniol, components of rose oil, activate peroxisome proliferator-activated receptor alpha and gamma and suppress cyclooxygenase-2 expression. AB - We evaluated the effects of rose oil on the peroxisome proliferator-activated receptor (PPAR) and cyclooxygenase-2 (COX-2). Citronellol and geraniol, the major components of rose oil, activated PPARalpha and gamma, and suppressed LPS-induced COX-2 expression in cell culture assays, although the PPARgamma-dependent suppression of COX-2 promoter activity was evident only with citronellol, indicating that citronellol and geraniol were the active components of rose oil. PMID- 21597169 TI - Characterization of Mesorhizobium loti L-rhamnose isomerase and its application to L-talose production. AB - The L-rhamnose isomerase gene (rhi) of Mesorhizobium loti was cloned and expressed in Escherichia coli, and then characterized. The enzyme exhibited activity with respect to various aldoses, including D-allose and L-talose. Application of it in L-talose production from galactitol was achieved by a two step reaction, indicating that it can be utilized in the large-scale production of L-talose. PMID- 21597170 TI - Reduction of plant-specific arabinogalactan-type O-glycosylation by treating tobacco plants with ferrous chelator 2,2'-dipyridyl. AB - Plant specific O-glycosylation of proteins includes the attachment of arabinogalactan to hydroxyproline (Hyp) residues. These Hyp residues are generated from peptidyl proline residues by the action of prolyl 4-hydroxylase which requires the ferrous ion. We investigated the effect of the ferrous chelator, 2,2'-dipyridyl on tobacco plants, and found that such treatment reduced the arabinogalactosylation of proteins. PMID- 21597171 TI - Exopolysaccharide production is influenced by sugars, N-acylhomoserine lactone, and transcriptional regulators RcsA and RcsB, but does not affect pathogenicity in the plant pathogen Pantoea ananatis. AB - Pantoea ananatis SK-1 produced EPS by AHL-mediated quorum sensing on an LB agar plate containing glucose, fructose, and sucrose. rcsA and rcsB mutants did not produce EPS with or without AHLs and with or without sugars, but they induced necrotic symptoms in onion leaves. These results indicate that EPS production does not relate to the pathogenicity of SK-1. PMID- 21597172 TI - Hydroxynitrile lyases from prunus seeds in the preparation of cyanohydrins. AB - The hydroxynitrile lyase (HNL) activity of nine defatted Prunus seeds was compared for catalyzing the addition of HCN to aromatic, heteroaromatic and alpha,beta-unsaturated aldehydes. Although the conversion and enantiomeric excess (ee) of the corresponding cyanohydrins were both influenced by the HNL source and the chemical structure of the aldehyde, Prunus HNLs were all suitable for the enantioselective preparation of cyanohydrins. PMID- 21597173 TI - Pinctada fucata mantle gene 5 (PFMG5) from pearl oyster mantle inhibits osteoblast differentiation. AB - PFMG5 (Pinctada fucata mantle gene 5) was identified from mantle tissue of the pearl oyster, Pinctada fucada (P. fucada). Here we report that PFMG5 decreased osteoblast differentiation marker alkaline phosphatase (ALP) activity and the transcript levels of osteoblast differentiation specific marker genes in MC3T3-E1 cells. PFMG5 was identified as a new molecule inhibiting osteoblast differentiation. PMID- 21597174 TI - A tolerance gene for prenylated flavonoid encodes a 26S proteasome regulatory subunit in Sophora flavescens. AB - Yeast functional screening with a Sophora flavescens cDNA library was performed to identify the genes involved in the tolerant mechanism to the self-producing prenylated flavonoid sophoraflavanone G (SFG). One cDNA, which conferred SFG tolerance, encoded a regulatory particle triple-A ATPase 2 (SfRPT2), a member of the 26S proteasome subunit. The yeast transformant of SfRPT2 showed reduced SFG accumulation in the cells. PMID- 21597175 TI - Sterol composition in larvae of the silkworm, Bombyx mori. AB - Sterols in silkworm larvae were analyzed. Cholesterol was predominantly detected in all tissues examined. Dietary phytosterols and desmosterol, a putative biosynthetic intermediate from phytosterols to cholesterol, were also detected, indicating that imperfect intestinal conversion from phytosterols to cholesterol influences the sterol composition in larval tissues. PMID- 21597176 TI - The mucin box and signal/anchor sequence of rat neutral ceramidase recruit bacterial sphingomyelinase to the plasma membrane. AB - Sphingolipid metabolites act as lipid mediators in various cellular events. We found that the mucin box and signal/anchor sequence of a rat neutral ceramidase recruit bacterial sphingomyelinase to the plasma membranes of mammalian cells. The mucin box-fused sphingomyelinase hydrolyzed cellular sphingomyelin efficiently to generate ceramide. PMID- 21597177 TI - Adsorption of lecithin liposomes to acid clay. AB - The interaction between lecithin liposomes and acid clay was investigated to clarify the mechanism for liposome adsorption to the clay. It was found that the multilamellar vesicular structure of the liposomes was broken as a result of primary adsorption. The acid clay particles aggregated and were eventually covered by the lecithin layer structure. In the case of kaolin, on the other hand, the liposomes were weakly adsorbed to the clay and maintained the vesicular structure. The amount of primary adsorption to the clay surface, which was estimated from the adsorption isotherm, was more for acid clay than for kaolin, and the total amount adsorbed to the acid clay was also more than to kaolin. This result can be explained by the much higher density of the negative charge on the acid clay surface than that for kaolin. The liposomes are therefore considered to be adsorbed to the acid clay mainly by the choline positive charge residing at the end of the lecithin molecule, although this is of no net charge as a whole. PMID- 21597178 TI - Syntheses of secocyclolignanes and comparative antioxidative activity between secocyclolignane and the dibenzyl type of lignan. AB - The antioxidative activity of secocyclolignanes was compared with that of the corresponding dibenzyl lignans for the first time. The radical scavenging activity of the secocyclolignanes was weaker than that of the corresponding dibenzyl lignans, the butane diol type showing the highest activity. The butane type of secocyclolignane exhibited the highest antioxidant activity of the unsaturated fatty acid. PMID- 21597179 TI - Immunomodulatory effect of (--)-matairesinol in vivo and ex vivo. AB - Matairesinol is one of the lignan compounds found in a variety of plant foodstuffs. We investigated the immunomodulatory effects of (-)-matairesinol in vivo and ex vivo by using mice. Although we found no significant differences in the IgG, IgA and IgM levels in the serum, the IgE level was strongly suppressed by the uptake of (-)-matairesinol in both intact and ovalbumin-immunized mice. The immunoglobulin produced by lymphocytes from the spleen was not activated by the intake of (-)-matairesinol. However, lymphocytes in such gut-associated lymphatic tissues as Peyer's patches and mesenteric lymph nodes were activated by the administration of (-)-matairesinol. PMID- 21597180 TI - Characterization of glucosylceramides in the Polygonaceae, Rumex obtusifolius L. injurious weed. AB - Rumex obtusifolius L., a member of Polygonaceae, is one of the world's worst weeds. We characterized the glucosylceramide molecular species in leaves of R. obtusifolius by liquid chromatography/tandem mass spectrometry. 4,8 Sphingadienines were principally paired with 2-hydroxy palmitic acids. In contrast, 4-hydroxy-8-sphingenines were chiefly attached to 2-hydroxy fatty acids with 22 to 26 carbon-chain length. A unique characteristic of the 2-hydroxy fatty acid composition of R. obtusifolius was the high content of n-9 monoenoic 2 hydroxy fatty acids with 22 and 24 carbon-chain length. The levels of the Z and E stereoisomers of the 8-unsaturated long-chain bases were reliably distinguished from those in other plant families in ten species of Polygonaceae. PMID- 21597181 TI - Alleviation of OVA-induced airway inflammation by flowers of Inula japonica in a murine model of asthma. AB - The flowers of Inula japonica (Inulae Flos) have long been used in traditional medicine for treating inflammatory diseases. The effects on OVA-induced asthmatic mice of an Inulae Flos extract (IFE) were evaluated in this study. The anti asthmatic effects of IFE were determined by observing eosinophil recruitment, airway hyper-responsiveness (AHR), Th2 cytokine and IgE levels, and lung histopathology. The IFE treatment effectively reduced the percentage of eosinophils and Th2 cytokines in the bronchoalveolar lavage fluid (BALF) when compared to the levels in OVA-induced mice. IFE also suppressed AHR induced by aerosolized methacholine in OVA-induced mice. The results of the histopathological studies indicate that inflammatory cell infiltration and mucus hypersecretion were both inhibited by the IFE administration when compared to the effect on OVA-induced mice. The IFE treatment also suppressed the serum IgE levels and decreased Th2 cytokines in the supernatant of cultured splenocytes. These results suggest that IFE may have therapeutic potential against asthma. PMID- 21597182 TI - Isolation of a mutant auxotrophic for L-alanine and identification of three major aminotransferases that synthesize L-alanine in Escherichia coli. AB - For Escherichia coli, it has been assumed that L-alanine is synthesized by alanine-valine transaminase (AvtA) in conjunction with an unknown alanine aminotransferase(s). We isolated alanine auxotrophs from a prototrophic double mutant deficient in AvtA and YfbQ, a novel alanine aminotransferase, by chemical mutagenesis. A shotgun cloning experiment identified two genes, uncharacterized yfdZ and serC, that complemented the alanine auxotrophy. When the yfdZ- or serC mutation was introduced into the double mutant, one triple mutant (avtA yfbQ yfdZ) showed alanine auxotrophy, and another (avtA yfbQ serC), prototrophy. In addition, we found that four independent alanine auxotrophs possessed a point mutation in yfdZ but not in serC. We also found that yfdZ expression was induced in minimal medium. Furthermore, yfbQ-bearing plasmid conferred the ability to excrete alanine on the mutant lacking D-amino acid dehydrogenase-encoding gene, dadA. From these results, we concluded that E. coli synthesizes L-alanine by means of three aminotransferases, YfbQ, YfdZ, and AvtA. PMID- 21597183 TI - Suppression by fucoidan of liver fibrogenesis via the TGF-beta/Smad pathway in protecting against oxidative stress. AB - Fucoidan, a sulfated polysaccharide extracted from various types of brown seaweed, possesses a wide range of pharmacological properties. We investigated the protective effect of fucoidan on dimethylnitrosamine-induced liver fibrogenesis in rats and its mechanism. Liver fibrosis was induced by injecting DMN (10 mg/kg, 3 times per week, I.P.) for 4 weeks, and fucoidan was simultaneously administered (100 mg/kg, 3 times per week, P.O.). The anti oxidative and anti-inflammatory effects of fucoidan were observed by relative mediators. Fucoidan improved liver fibrosis by inhibiting the expression of transforming growth factor beta 1 (TGF-beta(1))/Smad3 and the tissue inhibitor of metalloproteinase 1 (TIMP-1), and increasing the expression of metalloproteinase 9 (MMP-9). Fucoidan also significantly decreased the accumulation of the extracellular matrix (ECM) and collagen. These results suggest that fucoidan had an anti-fibrotic effect, which was exerted by inhibiting the TGF-beta/Smad pathway, as well as anti-oxidative and anti-inflammatory effects. PMID- 21597184 TI - A highly N-glycosylated chitin deacetylase derived from a novel strain of Mortierella sp. DY-52. AB - Chitin deacetylase (CDA), the enzyme that catalyzes the hydrolysis of acetamido groups of GlcNAc in chitin, was purified from culture filtrate of the fungus Mortierella sp. DY-52 and characterized. The extracellular enzyme is likely to be a highly N-glycosylated protein with a pI of 4.2-4.8. Its apparent molecular weight was determined to be about 52 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and 67 kDa by size-exclusion chromatography. The enzyme had an optimum pH of 6.0 and an optimum temperature of 60 degrees C. Enzyme activity was slightly inhibited by 1-10 mM Co(2+) and strongly inhibited by 10 mM Cu(2+). It required at least two GlcNAc residues for catalysis. When (GlcNAc)(6) was used as substrate, K(m) and V(max) were determined to be 1.1 mM and 54.6 umol min(-1) respectively. PMID- 21597185 TI - Establishment of intestinal epithelial cell lines from adult mouse small and large intestinal crypts. AB - Small and large intestinal epithelial cell (IEC) lines were established from adult murine intestinal crypts. Both established small and large IECs line (named aMoS7 and aMoC1 respectively) expressed epithelial markers. Similarly to IECs isolated from adult mouse intestines, the expression of major histocompatibility complex (MHC) class II molecules was induced by interferon-gamma-treatment in both established cell lines. This expression of MHC class II molecules was higher in small intestinal aMoS7 cells than in large intestinal aMoC1 cells. Treatment with lipopolysaccharide and with ligands of Toll-like receptors 1, 2, 3, and 7 induced secretion of interleukin-6 from both adult IEC lines. These results suggest that the aMoS7 and aMoC1 cell lines can serve as useful tools in analyzing the immunological functions of IECs, especially in studying the IEC response to microbial components and its antigen presenting ability. PMID- 21597187 TI - The genome of Bacillus subtilis phage SP10: a comparative analysis with phage SPO1. AB - A nucleotide sequence of the whole genome of Bacillus subtilis phage SP10 was determined. It was composed of 143,986 bp with 236 putative open reading frames (ORFs). Sixty-five of 236 predicted ORFs showed high similarity to that of SPO1, and the genome organizations of the two phages were similar to each other. SP10 belongs to the Myoviridae family, for which the well-studied phage SPO1 is the representative phage. Hence, we compared SP10 to SPO1. The SP10 genome DNA showed different sensitivity to restriction enzymes than SPO1, due to differences in base modification. According to transcriptional analysis, the gene expression of regulatory network of SP10 was similar to SPO1. It was observed that RNA polymerase containing sigma-A was inactive in directing the host genes but active in directing the phage genes. It appeared that the association of sigma-A with the core enzyme complex of RNA polymerase was strengthened during development. PMID- 21597186 TI - TRPV1 agonist monoacylglycerol increases UCP1 content in brown adipose tissue and suppresses accumulation of visceral fat in mice fed a high-fat and high-sucrose diet. AB - The administration of such a transient receptor potential vanilloid 1 (TRPV1) agonist as capsaicin, which is a pungent ingredient of red pepper, promotes energy metabolism and suppresses visceral fat accumulation. We have recently identified monoacylglycerols (MGs) having an unsaturated long-chain fatty acid as the novel TRPV1 agonist in foods. We investigated in this present study the effects of dietary MGs on uncoupling protein 1 (UCP1) expression in interscapular brown adipose tissue (IBAT) and on fat accumulation in mice fed with a high-fat, high-sucrose diet. The MG30 diet that substituted 30% of all lipids for MGs (a mixture of 1-oleoylglycerol, 1-linoleoylglycerol and 1-linolenoylglycerol) significantly increased the UCP1 content of IBAT and decreased the weight of epididymal white adipose tissue, and the serum glucose, total cholesterol and free fatty acid levels. The diet containing only 1-oleoylglycerol as MG also increased UCP1 expression in IBAT. MGs that activated TRPV1 also therefore induced the expression of UCP 1 and prevented visceral fat accumulation as well as capsaicin. PMID- 21597188 TI - Soybean beta-conglycinin bromelain hydrolysate stimulates cholecystokinin secretion by enteroendocrine STC-1 cells to suppress the appetite of rats under meal-feeding conditions. AB - A peptic digest of soybean beta-conglycinin (BconP) suppresses the appetite in rats through cholecystokinin (CCK) secretion by enteroendocrine cells. We investigate in this study more appetite-suppressing hydrolysates. beta Conglycinin hydrolyzed with food-processing proteases thermolysin (BconT), bromelain (BconB), chymotrypsin, protease S, and protease M was examined for CCK secreting activity in a CCK-producing cell line for comparison with BconP. The potent CCK-releasing hydrolysates were then tested for their suppression of the food intake by rats. BconB, BconT, and BconP stimulated high CCK secretion, with the highest by BconB. Orogastric preloading by BconB, but not by BconT, suppressed the 60-min food intake. A meal-feeding trial twice a day in the morning (a.m.) and evening (p.m.) for 10 d showed that BconB preloading before every meal attenuated the p.m. meal size, but not that a.m., resulting in an overall reduction of the daily meal size. These results demonstrate that the bromelain hydrolysate of beta-conglycinin having potent CCK-releasing activity suppressed the appetite of rats under meal-feeding conditions. PMID- 21597189 TI - Protective group-free syntheses of (+/-)-frontalin, (+/-)-endo-brevicomin, (+/-) exo-brevicomin, and (+/-)-3,4-dehydro-exo-brevicomin: racemic pheromones with a 6,8-dioxabicyclo[3.2.1]octane ring. AB - Protective group-free syntheses of four racemic pheromones with a 6,8 dioxabicyclo[3.2.1]octane ring were achieved in five or six steps from commercially available (+/-)-3-butyn-2-ol (6) and 2-alkenyl halides or 2-alken-1 ol by employing Lewis acid-catalyzed acetalization of delta, epsilon-epoxy ketones as the key reaction. (+/-)-Frontalin (1) was prepared in a 25% overall yield in five steps from methallyl chloride (5a), (+/-)-endo-brevicomin (2) was prepared in a 23% overall yield in five steps from (E)-2-pentenyl bromide (5b), and (+/-)-exo-brevicomin (3) and (+/-)-3,4-dehydro-exo-brevicomin (4) were both prepared in a 4% overall yield in six steps based on (Z)-2-penten-1-ol (12). PMID- 21597190 TI - Piezotolerance of the respiratory terminal oxidase activity of the piezophilic Shewanella violacea DSS12 as compared with non-piezophilic Shewanella species. AB - The facultative piezophile Shewanella violacea DSS12 is known to alter its respiratory components under the influence of hydrostatic pressure during growth, suggesting that it has a respiratory system that functions in adaptation to high pressure. We investigated the pressure- and temperature-dependencies of the respiratory terminal oxidase activity of the membrane of S. violacea relative to non-piezophilic Shewanella species. We observed that the activity in the membrane of S. violacea was more resistant to high pressure than those of non-piezophilic Shewanella even though DSS12 was cultured under atmospheric pressure. On the other hand, the temperature dependency of this activity was almost the same for all of the tested strain regardless of optimal growth temperature. Both high pressure and low temperature are expected to lower protein flexibility, causing a decrease in enzyme activity, but the results of this study suggest that the mechanism maintaining enzyme activity under high hydrostatic pressure is different from that at low temperature. Additionally, the responses of the activity to the pressure- and temperature-changes were independent of membrane lipid composition. Therefore, the piezotolerance of the respiratory terminal oxidases of S. violacea is perhaps dependent on the properties of the protein itself and not on the lipid composition of the membrane. Our observations suggest that S. violacea constitutively express piezotolerant respiratory terminal oxidases that serve adaptation to the deep-sea environment. PMID- 21597191 TI - Heterologous expression of the Oceanobacillus iheyensis SigW and its anti-protein RsiW in Bacillus subtilis. AB - Pairs of the ECF sigma factor and its anti-sigma factor, SigW and RsiW, of Bacillus-related species that inhabit extreme environments were heterologously expressed in B. subtilis. All the RsiWs, membrane proteins, failed to fill their function of repressing cognate SigW activity, despite their close structural similarities. Particularly, uncontrolled expression of Oceanobacillus iheyensis OISigW due to abortive OIRsiW was harmful to B. subtilis. Analysis of revertants of this growth defect and site-directed mutagenesis indicated that the insertion of six and a minimum of three hydrophobic amino acid residues occurring in the transmembrane region allowed OIRsiW to function as anti-OISigW. Subcellular localization of OIRsiW was detected by immunoblot analysis, suggesting that both the wild-type and the mutant form of OIRsiW were localized to the membrane. An appropriate length of a transmembrane region required for proper integration into the membrane after translocation might vary among these Bacillus-related species. PMID- 21597192 TI - The development of transgenic crops to improve human health by advanced utilization of seed storage proteins. AB - Seed storage proteins are a major component of mature seeds. They are utilized as protein sources in foods. We designed seed storage proteins containing bioactive peptides based on their three-dimensional structures. Furthermore, to create crops with enhanced food qualities, we developed transgenic crops producing seed storage proteins with bioactive peptides. This strategy promises to prevent lifestyle-related diseases by simple daily food consumption. In this review, we discuss a strategy to develop transgenic crops to improve human health by advanced utilization of seed storage proteins. PMID- 21597193 TI - Molecular cloning and partial characterization of a peroxidase gene expressed in the roots of Portulaca oleracea cv., one potentially useful in the remediation of phenolic pollutants. AB - Portulaca (Portulaca oleracea cv.) efficiently removes phenolic pollutants from hydroponic solution. In plant roots, peroxidase (PRX) is thought to be involved in the removal of phenolic pollutants by the cross-linking them to cell wall polysaccharides or proteins at the expense of reduction of hydrogen peroxide (H(2)O(2)). In this study, we found that portulaca roots secreted an acidic PRX isozyme that had relatively high H(2)O(2) affinity. We isolated five PRX genes, and the recombinant PRX proteins produced in cultured tobacco cells were partially characterized. Among these genes, PoPRX2 probably encoded the acidic PRX isozyme. PoPRX2 had an extra N-terminal region which has not been reported for other PRX proteins. We found that PoPRX2 oxidized phenolic pollutants, including bisphenol A, octylphenol, nonylphenol, and 17beta-estradiol. In addition, we found that the Cys261 residue of PoPRX2 played an important role in the determination of affinity for H(2)O(2) and stability toward H(2)O(2). PMID- 21597194 TI - Role of chlorogenic acid quinone and interaction of chlorogenic acid quinone and catechins in the enzymatic browning of apple. AB - Chlorogenic acid (CQA) is one of the major polyphenols in apple and a good substrate for the polyphenol oxidase (PPO) in apple. Apple contains catechins as well as CQA, and the role of CQA quinone and its interaction with catechins in the enzymatic browning of apple were examined. Browning was repressed and 2 cysteinyl-CQA was formed when cysteine was added to apple juice. CQA quinone was essential for browning to occur. Although catechins and CQA were oxidized by PPO, some catechins seemed to be non-enzymatically oxidized by CQA quinone. PMID- 21597195 TI - Anti-aging effects of phloridzin, an apple polyphenol, on yeast via the SOD and Sir2 genes. AB - The anti-aging effects of phloridzin on the yeast Saccharomyces cerevisiae were investigated by employing a replicative lifespan assay of the K6001 yeast strain. After administrating phloridzin at doses of 3, 10, and 30 uM, the lifespan of the yeast was significantly prolonged in comparison with the untreated group (p<0.01, p<0.001). To determine the mechanism of action, anti-oxidative experiments and ROS assay were performed. Phloridzin improved the viability of the yeast dose dependently under oxidative stress by 7.5 mM H(2)O(2), and a low dose of phloridzin inhibited ROS of the yeast. Further, SOD1, SOD2, and Sir2 gene expression was examined by reverse transcription-polymerase chain reaction (RT PCR), and was found to be significantly increased. Finally, superoxide dismutase (SOD) and SIRT1 activity assays showed that phloridzin notably increased the activity of SOD and SIRT1. These results suggest that SOD and Sir2 have important roles in phloridzin-regulated lifespan extension of yeast, and potentially anti aging effects for mammalian cells via SIRT1. PMID- 21597196 TI - In vitro and in vivo melanogenesis inhibition by biochanin A from Trifolium pratense. AB - Our previous study showed that a methanol extract from Trifolium pratense exerted potent inhibitory activity on melanogenesis in mouse B16 melanoma cells. In the present study, the active compound in this Chinese herb extract was isolated and identified as biochanin A by mass spectrum, (1)H-NMR, and (13)C-NMR analysis. The inhibitory effects of biochanin A on melanogenesis were investigated in vitro in cultured melanoma cells and in vivo in zebrafish and mice. Biochanin A dose dependently inhibited both melanogenesis and cellular tyrosinase activity in B16 cells and in zebrafish embryos. Application of a cream containing 2% biochanin A twice daily to the skin of mice also increased the skin-whitening index value after 1 week of treatment, and the increase continued for another 2 weeks. Biochanin A was confirmed as a good candidate for use as a skin-whitening agent in the treatment of skin hyperpigmentation disorders. PMID- 21597197 TI - Molecular characteristics of water-soluble extracts from Hypsizigus marmoreus and their in vitro growth inhibition of various cancer cell lines and immunomodulatory function in Raw 264.7 cells. AB - Water-soluble extracts isolated from Hypsizigus marmoreus and fractionated by ion exchange chromatography were investigated to determine their molecular characteristics and biological activities. The crude and fractionated water soluble extracts (F(1), F(2) and F(3)) consisted mostly of carbohydrates (55.8 98.9%) with varied protein contents (1.1-23.0%). Their monosaccharide levels were significantly different, including the glucose content (67.0-100%) and galactose content (0-33.0%). The backbone of each fraction was mainly glucose molecules connected with 1,4-glycosidic linkages which contained considerable amounts of glucose and/or galactose connected through 1,6-glycosidic linkages. The average molecular weight (M(w)) of the extracts varied considerably, ranging from 1,665*10(4) to 19*10(4) g/mol. Little cytotoxicity was apparent in cancer cell lines from the addition of these extracts; however, they significantly stimulated Raw 264.7 cells to release nitric oxide (NO) and prostaglandin E(2) (PGE(2)), suggesting their potential immunomodulating activities. PMID- 21597198 TI - S-adenosyl-L-methionine activates actinorhodin biosynthesis by increasing autophosphorylation of the Ser/Thr protein kinase AfsK in Streptomyces coelicolor A3(2). AB - S-Adenosyl-L-methionine (SAM) is one of the major methyl donors in all living organisms. The exogenous treatment with SAM leads to increased actinorhodin production in Streptomyces coelicolor A3(2). In this study, mutants from different stages of the AfsK-AfsR signal transduction cascade were used to test the possible target of SAM. SAM had no significant effect on actinorhodin production in afsK, afsR, afsS, or actII-open reading frame 4 (ORF4) mutant. This confirms that afsK plays a critical role in delivering the signal generated by exogenous SAM. The afsK-pHJL-KN mutant did not respond to SAM, suggesting the involvement of the C-terminal of AfsK in binding with SAM. SAM increased the in vitro autophosphorylation of kinase AfsK in a dose-dependent manner, and also abolished the effect of decreased actinorhodin production by a Ser/Thr kinase inhibitor, K252a. In sum, our results suggest that SAM activates actinorhodin biosynthesis in S. coelicolor M130 by increasing the phosphorylation of protein kinase AfsK. PMID- 21597199 TI - Fermented Viola mandshurica inhibits melanogenesis in B16 melanoma cells. AB - We assessed the effects of chloroform extract of fermented Viola mandshurica (CEFV) on melanogenesis B16 melanoma cells. CEFV treatment significantly decreased melanin content and tyrosinase activity in dose-dependent manners. To elucidate the mechanism of the inhibitory effects of CEFV on melanogenesis, we performed RT-PCR and Western blotting for melanogenesis-related genes such as tyrosinase, tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia associated transcription factor (MITF). CEFV strongly inhibited mRNA as well as the protein expression of tyrosinase and MITF, but had no significant effect on TRP-1 or TRP-2 expressions. It markedly decreased the phosphorylation of cAMP responsive element binding protein (CREB), and induced the duration of extracellular signal-regulated kinase (ERK) activation, leading to reduction of MITF expression and subsequently that of tyrosinase. Therefore, we suggest that CEFV induces downregulation of melanogenesis through decreased CREB phosphorylation and ERK activation. PMID- 21597200 TI - Xylose triggers reversible phosphorylation of XlnR, the fungal transcriptional activator of xylanolytic and cellulolytic genes in Aspergillus oryzae. AB - XlnR is a transcription factor that mediates D-xylose-triggered induction of xylanolytic and cellulolytic genes in Aspergillus. In order to clarify the molecular mechanisms underlying XlnR-mediated induction, Aspergillus oryzae XlnR was fused with the c-myc tag and examined by Western blotting. Phosphate-affinity SDS-PAGE revealed that XlnR was present as a mixture of variously phosphorylated forms in the absence of D-xylose, and that D-xylose triggered additional phosphorylation of the protein. D-Xylose-triggered phosphorylation was a rapid process occurring within 5 min prior to the accumulation of xynG2 mRNA, and removal of D-xylose caused slow dephosphorylation, leading to less-phosphorylated forms. At 30 min after removal, the phosphorylation status was almost identical to that in the absence of D-xylose, and the level of xynG2 mRNA started to decrease. These results indicate that XlnR is highly phosphorylated when it is active in transactivation, implying that D-xylose-triggered reversible phosphorylation controls XlnR activity. PMID- 21597201 TI - A [Lys49]phospholipase A2 from Protobothrops flavoviridis venom induces caspase independent apoptotic cell death accompanied by rapid plasma-membrane rupture in human leukemia cells. AB - Protobothrops flavoviridis venom contains plural phospholipase A(2) (PLA(2)) isozymes. A [Lys(49)]PLA(2) called BPII induced cell death in human leukemia cells. PLA2, an [Asp(49)]PLA(2) that has much stronger lipolytic activity than BPII, failed to induce cell death. BPII-treated cells showed morphological changes, DNA fragmentation, and nuclear condensation. This BPII-induced apoptotic cell death was neither inhibited by inhibitors of caspases 3 and 6 nor accompanied by activation of procaspase 3, indicating that BPII-induced cell death is caspase independent. Since inactive p-bromophenacylated BPII induced cell death, BPII-induced apoptotic cell death is independent of PLA(2) lipolytic activity. Rapid externalization of phosphatidylserine in BPII-treated cells was observed for fluorescein isothiocyanate (FITC)-labeled annexin V. In the cells treated with BPII, this spread over the cell membranes, implying that the cell toxicity of BPII is mediated via its cell-surface receptor. PMID- 21597202 TI - What can we tell by the fast pathway effective refractory period? PMID- 21597203 TI - Gender differences in idiopathic ventricular arrhythmias. PMID- 21597204 TI - Right ventricular septal pacing preserves global left ventricular longitudinal function in comparison with apical pacing: analysis of speckle tracking echocardiography. AB - BACKGROUND: Right ventricular (RV) pacing alters left ventricular (LV) mechanical activation, resulting in adverse impacts on LV function. This study was aimed to investigate the acute effect of RV apical (RVA) and septal pacing (RVS) on LV dyssynchrony and function using speckle tracking echocardiography. METHODS AND RESULTS: The 103 patients (749 years) with symptomatic bradyarrhythmia and preserved LV ejection fraction, and 50 age-matched control subjects were studied. All patients received a permanent pacemaker and were randomly assigned into 2 groups (RVA: n = 51, RVS: n = 52). After insertion, patients underwent an echocardiographic study during RV pacing. LV dyssynchrony and global strain parameters were analyzed using speckle tracking echocardiography. The QRS width and dyssynchrony indices by longitudinal and radial strain were significantly greater in RVA than in both the control and RVS. The LV longitudinal dyssynchrony index was significantly related to global longitudinal strain (GLS) among 103 patients receiving RV pacing (R2 = 0.25, P < 0.0001). The GLS in RVA were the lowest among the 3 groups (GLS: CONTROL: -18.22.4%, RVA: -14.33.1%, P < 0.001 vs. control, RVS: -16.82.7%, P<0.01 vs. RVA). CONCLUSIONS: RVA created heterogeneous LV contraction, which resulted in deteriorated LV longitudinal contraction. RVS could be a better pacing alternative in terms of less LV dyssynchrony and better longitudinal function compared to RVA. PMID- 21597205 TI - Early results of rheolytic thrombectomy in patients with proximal deep vein thrombosis. AB - BACKGROUND: The utility of rheolytic thrombectomy as a treatment for proximal deep vein thrombosis (DVT) is not well understood. METHODS AND RESULTS: Patients with proximal DVT were treated with rheolytic thrombectomy, and the safety and efficacy of the procedure were evaluated. The improvement of venous thrombi was assessed using the venographic segment (VS) score. The rheolytic rate was defined as the percentage thrombus aspiration achieved. We also evaluated whether there were differences in age, aspiration time, D-dimer concentration, or the duration from onset to therapy between the high and low rheolytic rate groups. The mean VS score before thrombectomy was 28.8 +/- 7.9 points, and the mean VS score after thrombectomy was 10.4 +/- 7.1 points (ie, the VS score was significantly decreased after thrombectomy). There were no major treatment-related adverse complications. The mean duration from onset to rheolytic therapy in the 4 patients with a low rheolytic rate was 13.5 +/- 13.2 days, which was much longer than for the 9 patients with a high rheolytic rate (mean duration: 4.0 +/- 2.2 days: P = 0.045). CONCLUSIONS: Rheolytic thrombectomy is safe and effective for treating proximal DVT. The duration from onset to therapy was the only factor that was significantly predictive of the outcome of rheolytic thrombectomy. Rheolytic thrombectomy was especially effective when performed within 1 week of onset. PMID- 21597206 TI - Factors associated with the longevity of resin composite restorations. AB - This study investigated factors associated with the longevity of resin composite restorations, which were placed in 97 patients (mean age of 58 years) by 24 dentists in Nagasaki University Hospital between 1995 and 2005. All patients were under the charge of the principal investigator (SK) and most of them had been regularly checked up for up to 11 years. A total of 503 resin composite restorations (433 by SK and 70 by the other dentists) were analyzed by the Kaplan Meier and the Cox proportional hazards model. Ten-year survival rates were 84.2% for SK and 71.8% for the others, showing a significant difference. Although the retreatment risk had a great influence on the survival time, gender and age at placement did not have. There were no significant differences in survival between conventional 2-step etch-and-rinse, 2-step self-etch adhesives with and without prior enamel etching. Cavity type had a significant influence, whereas tooth type had no effect. PMID- 21597207 TI - Novel fabrication method for zirconia restorations: bonding strength of machinable ceramic to zirconia with resin cements. AB - A novel method was developed to fabricate all-ceramic restorations which comprised CAD/CAM-fabricated machinable ceramic bonded to CAD/CAM-fabricated zirconia framework using resin cement. The feasibility of this fabrication method was assessed in this study by investigating the bonding strength of a machinable ceramic to zirconia. A machinable ceramic was bonded to a zirconia plate using three kinds of resin cements: ResiCem (RE), Panavia (PA), and Multilink (ML). Conventional porcelain-fused-to-zirconia specimens were also prepared to serve as control. Shear bond strength test (SBT) and Schwickerath crack initiation test (SCT) were carried out. SBT revealed that PA (40.42 MPa) yielded a significantly higher bonding strength than RE (28.01 MPa) and ML (18.89 MPa). SCT revealed that the bonding strengths of test groups using resin cement were significantly higher than those of Control. Notably, the bonding strengths of RE and ML were above 25 MPa even after 10,000 times of thermal cycling -adequately meeting the ISO 9693 standard for metal-ceramic restorations. These results affirmed the feasibility of the novel fabrication method, in that a CAD/CAM-fabricated machinable ceramic is bonded to a CAD/CAM-fabricated zirconia framework using a resin cement. PMID- 21597208 TI - An eighteen-month clinical evaluation of posterior restorations with fluoride releasing adhesive and composite systems. AB - This study evaluated the clinical performance of a fluoride releasing restorative system (FL-Bond II & Beautifil II) in posterior restorations after 18-month placement. IRB forms were submitted with each patient approving by signing their acceptance. Seven Class I and 46 Class II restorations were placed by three clinicians in 38-patients. Each FL-Bond II & Beautifil II restoration was placed under rubber dam isolation according to manufacture's instruction. Clinical evaluation was assessed at baseline, 6 and 18-months using modified USPHS criteria. No post-operative sensitivity was reported in any restored tooth at each patient assessment. Only slight color change with some surface staining was noted. Slight marginal changes were observed in 12 of 53-restorations -seen as step irregularities when a sharp explorer was drawn across the tooth from the enamel toward the restoration interface. Utilizing USPHS evaluation criteria, the clinical performance of each (FL-Bond II & Beautifil II) posterior fluoride releasing system was clinically acceptable at 18-month. PMID- 21597209 TI - Roughness and pH changes of enamel surface induced by soft drinks in vitro applications of stylus profilometry, focus variation 3D scanning microscopy and micro pH sensor. AB - This study aimed to evaluate enamel surface roughness (Ra) and pH before and after erosion by soft drinks. Enamel was exposed to a soft drink (cola, orange juice or green tea) for 1, 5 or 60 min; Ra was measured using contact-stylus surface profilometry (SSP) and non-contact focus variation 3D microscope (FVM). Surface pH was measured using a micro pH sensor. Data were analyzed at significance level of alpha=0.05. There was a significant correlation in Ra between SSP and FVM. FVM images showed no changes in the surface morphology after various periods of exposure to green tea. Unlike cola and orange juice, exposure to green tea did not significantly affect Ra or pH. A significant correlation was observed between surface pH and Ra change after exposure to the drinks. Optical surface analysis and micro pH sensor may be useful tools for non-damaging, quantitative assessment of soft drinks erosion on enamel. PMID- 21597210 TI - Transformation behavior of nickel-titanium orthodontic wires under tensile load. AB - This study investigated transformations of nickel-titanium wires using differential scanning calorimetry (DSC) and thermomechanical analysis (TMA) under tensile load (100 gf or 500 gf). Two nickel-titanium wires, 35 degrees C Copper Ni-Ti and Nitinol SE, were selected. DSC analyses were performed between -90 degrees and 100 degrees C. Specimens prepared for TMA were approximately 150 um thick and 12 mm long. TMA analyses were performed between -120 degrees and 100 degrees C. With TMA, all transformation temperatures for a tensile load of 500 gf, obtained from both the heating and cooling curves, were higher than those for a tensile load of 100 gf. While mean A(s) and A(f) temperatures for Copper Ni-Ti obtained by TMA were much higher than those obtained by DSC analysis, mean M(s) and M(f) temperatures obtained by TMA were much lower than those obtained by DSC analysis. The transformation behavior of nickel-titanium wires with change in temperature was affected by application of tensile load. PMID- 21597211 TI - Microbicidal activities of low frequency atmospheric pressure plasma jets on oral pathogens. AB - Research using low frequency atmospheric pressure plasma jets (LF jet) is becoming increasingly more common. We carried out experiments to evaluate the sterilizing effects of this technology on oral pathogenic microorganisms (S.mutans, C.albicans and E. faecalis) and to determine its potential for clinical application. We performed the direct exposure test on a solid surface, indirect exposure test on a liquid phase, and ROS (reactive oxygen species) inhibitory test. The results showed the LF jet had microbicidal effects on oral pathogens, and that the ROS influenced this sterilization effect. The experiments of this study revealed that LF jet had a sterilizing effect on oral pathogenic microorganisms present in both the solid and liquid phases. The sterilizing mechanism was considered to be related to the effect of superoxide anion radicals. These results indicate that LF jets may represent a novel technology that can be applied to the field of clinical dentistry. PMID- 21597212 TI - Influence of the volumes of bis-acryl and poly(methyl methacrylate) resins on their exothermic behavior during polymerization. AB - This study aimed to evaluate the influence of the volumes of a bis-acryl resin (Luxatemp) and a poly(methyl methacrylate) resin (Jet) on their exothermic behaviors during polymerization based on vinyl group conversion. The number of vinyl groups reacted and exotherm were determined based on weight percent of methacrylate groups using FTIR spectroscopy. Temperature changes during polymerization at 23 degrees C were recorded for 20 minutes using a multiple cavity mold overlying a thermocouple. The number of vinyl groups reacted and exotherm of Luxatemp were consistently lower than those of Jet at each resin volume. Mean peak temperature rises of Luxatemp and Jet were in the range of 2.0 6.6 degrees C and 4.2-11.6 degrees C respectively, with Luxatemp and Jet taking 2 and 10 minutes respectively to reach their peak temperatures. As their resin volumes increased, their peak temperatures and total peak areas were also observed to increase significantly (p<0.01). PMID- 21597213 TI - Viscoelastic properties of low-shrinking composite resins compared to packable composite resins. AB - The aim of this study was to evaluate the viscoelastic properties of novel low shrinking composites and compare them to those of packable composites. Six materials were tested: Clearfil Majesty Posterior (CM), ELS Extra Low Shrinkage (EL), Filtek P60 (FP), Filtek Silorane (FS), Prodigy (PR) and Surefil (SU). Static and dynamic testing was performed and materials were tested dry and wet at different temperatures (21 degrees C to 50 degrees C). Shear and flexural modulus, loss tangent, dynamic viscosity, Poisson's ratio and creep recovery were calculated among others. Significant differences were found both between the two groups and between materials belonging to the same group. CM presented the highest shear and flexural modulus and EL the lowest. All materials were softened by an increase of temperature, while FS was the least affected by water and PR showed to be the most susceptible. Different approaches used to overcome polymerization shrinkage lead to materials with different properties. PMID- 21597214 TI - Characteristics of novel di-alpha-fluoroacrylate derivatives with polyfluoroalkyl aromatic backbone as a binder resin of direct filling materials. AB - To realize good mechanical properties and water resistance of a dental resin, novel di-alpha-fluoroacrylates with polyfluoroalkyl aromatic backbone were studied. The monomers were 2,2-bis(4-alpha-fluoroacryloxy phenyl)propane, 2,2 bis(4-alpha-fluoroacryloxy phenyl) hexafluoropropane, and 1,3-bis(2-alpha fluoroacryloxy-2-hexafluoropropyl)benzene. The copolymers of the monomers and methyl methacrylate (MMA) were excellent in hardness, Izod impact strength, abrasion resistance, and water resistance, and showed similar values of compressive, diametral tensile, tensile, and bending strength compared with copolymers prepared from the corresponding dimethacrylate derivatives and MMA. PMID- 21597215 TI - Phase transformation of zirconia ceramics by hydrothermal degradation. AB - Zirconia has found wide application in dentistry because of its high mechanical strength and superior esthetic properties. However, zirconia degradation caused by phase transformation occurring in a hydrothermal environment is of concern. In the present study, phase transformation and microstructure of tetragonal zirconia polycrystal partially stabilized with yttrium oxide (Y-TZP) and alumina-toughened zirconia (ATZ) sintered at different temperatures were estimated. On grazing angle X-ray diffraction analysis, ATZ showed less phase transformation to the monoclinic phase during hydrothermal treatment and this transformation appeared to occur within a few micrometers below the surface. At a higher sintering temperature the monoclinic phase content of ATZ was found to be lesser than that of Y-TZP, indicating that the alumina in ATZ was effective in suppressing hydrothermal degradation. Examination by transmission electron microscopy and studying of electron backscatter diffraction patterns indicated that grain growth in ATZ was slightly suppressed compared with that in Y-TZP at higher sintering temperatures. The present study demonstrated the effect of adding alumina to zirconia for suppressing hydrothermal degradation and studied the effect of this addition on grain growth in zirconia. PMID- 21597216 TI - Design of a metal primer containing a dithiooctanoate monomer and a phosphonic acid monomer for bonding of prosthetic light-curing resin composite to gold, dental precious and non-precious metal alloys. AB - The effect of metal primers on adhesion of a resin composite to dental metal alloys was investigated. Experimental primers containing a dithiooctanoate monomer [10-methacryloyloxydecyl 6,8-dithiooctanoate (10-MDDT) or 6 methacryloyloxyhexyl 6,8-dithiooctanoate (6-MHDT)] and a phosphonic acid monomer [6-methacryloyloxyhexyl phosphonoacetate (6-MHPA) or 6-methacryloyloxyhexyl 3 phosphonopropionate (6-MHPP)] were prepared. After treating Au, Au alloy, Ag alloy, Au-Ag-Pd alloy, and Ni-Cr alloy with the experimental primers, their shear bond strengths (SBSs) with a prosthetic light-curing resin composite (Solidex, Shofu Inc., Japan) were measured after 1-day storage followed by 5,000 thermal cycles. The SBSs between Solidex and the primer-treated metals which were incubated in air at 50 degrees C for 2 months were further measured. Results showed that the SBSs [mean (SD)] of all metal adherends treated with primer DT-PA 1 (5.0 wt% 10-MDDT, 1.0 wt% 6-MHPA) ranged between 31.2 (5.2) and 34.5 (5.8) MPa. The SBSs of the primer-treated metals did not degrade after 2-month incubation at 50 degrees C. Therefore, a combined primer application consisting of a dithiooctanoate monomer and a phosphonic acid monomer provided efficacious bonding to Au as well as precious and non-precious metal alloys. PMID- 21597217 TI - The influence of light intensities irradiated directly and indirectly through resin composite to self-etch adhesives on dentin bonding. AB - This study was designed to evaluate effects of light-irradiated intensities directly and indirectly through resin composites to one- and two-step self-etch adhesives on dentin bonding. One-step (Clearfil S(3) Bond; TS, Bond Force; BF) or two-step (Clearfil SE Bond; SE) self-etch adhesives was applied to dentin surface. The adhesive agent was light-cured with light-intensity of 350 or 600 mW/cm(2), and then resin composite with different colors (translucent or opaque shade) was filled and light-cured with the same light-intensity as the bonding procedure. After 24 h water storage, bond strengths to dentin were determined using uTBS test. For the 600 and 350 mW/cm(2) groups, translucent shade resin obtained higher uTBS than opaque shade resin. Using SE and BF, the 350 mW/cm(2) group in translucent shade resin was higher uTBS than the 600 mW/cm(2) group in opaque shade resin, while TS showed no different uTBS between them. PMID- 21597218 TI - Machinable glass-ceramics forming as a restorative dental material. AB - MgO, SiO(2), Al(2)O(3), MgF(2), CaF(2), CaCO(3), SrCO(3), and P(2)O(5) were used to prepare glass-ceramics for restorative dental materials. Thermal properties, phases, microstructures and hardness were characterized by DTA, XRD, SEM and Vickers microhardness. Three-point bending strength and fracture toughness were applied by UTM according to ISO 6872: 1997(E). XRD showed that the glass crystallized at 892 degrees C (second crystallization temperature+20 degrees C) for 3 hrs consisted mainly of calcium-mica and fluorapatite crystalline phases. Average hardness (3.70 GPa) closely matched human enamel (3.20 GPa). The higher fracture toughness (2.04 MPa?m) combined with the hardness to give a lower brittleness index (1.81 um(-1/2)) which indicates that they have exceptional machinability. Bending strength results (176.61 MPa) were analyzed by Weibull analysis to determine modulus value (m=17.80). Machinability of the calcium mica fluorapatite glass-ceramic was demonstrated by fabricating with CAD/CAM. PMID- 21597219 TI - The effect of adding silica to zirconia to counteract zirconia's tendency to degrade at low temperatures. AB - Yttria-based zirconia material (Y-TZP) widely used in dentistry, may degrade in a humid, low-temperature environment such as that in the oral cavity. The aim of this study was to compare the degradation of a new silica doped Y-TZP material with that of conventional Y-TZP by using accelerated aging tests at 200 degrees C. The results of the accelerated tests revealed that after 50 hours of aging, the conventional Y-TZP samples had damaged surfaces that were weakened by 50 to 60%, while the silica-doped Y-TZP samples were only weakened by less than 20%. The monoclinic content of the conventional Y-TZP samples increased substantially to 62.7%, however, that of silica-doped Y-TZP samples was 18.9% after 5 hours of aging. It was concluded that a new type of silica-doped Y-TZP, created by adding a small amount of silica to Y-TZP, will be more resistant to low temperature degradation than conventional Y-TZP. PMID- 21597220 TI - Influence of silane heat treatment on bond strength of resin cement to a feldspathic ceramic. AB - This study evaluated the influence of heat treatment (HT) of the silane on the microtensile bond strength of resin cement to a feldspathic ceramic. Ceramic (VITA VM7) and composite blocks (N=32) were divided into four groups (n=6 for bond test, n=2 for SEM) at random and subject to following sequence of conditioning: G1: HF 9.6%+Silane+Panavia F2.0, G2: HF 9.6%+Silane+HT+Panavia F2.0, G3: Silane+HT+Panavia F2.0, and G4: Silane+Panavia F2.0. HT was performed in an oven (100 degrees C, 2 minutes). G1 (17.6+/-2.3 MPa) and G2 (19+/-3.2 MPa) showed significantly higher mean bond strength than those of G3 (9.1+/-2.8 MPa) and G4 (10.9+/-1.8 MPa). SEM analysis showed exclusively mixed failures. Silane HT did not increase the bond strength. PMID- 21597221 TI - Surface characterization and bond strengths between Ti-20Cr-1X alloys and low fusing porcelain. AB - This study evaluated the bond strengths between experimental Ti-20Cr-1X (X=Nb, Mo, Fe, Zr) alloys and porcelain (Duceratin). The results of this bond strength testing indicated that all the Ti-20Cr-1X alloys exceeded the lower limit value in the ISO 9693 standard for the 3-point bending test (25 MPa), and were all higher than that of commercially pure titanium (c.p. Ti). The coefficient of thermal expansion (CTE) values of all Ti-20Cr-1X alloys were higher than that of c.p. Ti, and this result of a closer match between CTEs shows the fact that the Ti-20Cr-1Mo alloy had a significantly higher bond strength than both the other Ti 20Cr-1X alloys and c.p. Ti. PMID- 21597222 TI - The influence of zirconia coping designs on the fracture load of all-ceramic molar crowns. AB - This study investigated the influence of zirconia coping designs on the fracture load of all-ceramic crown. Four kinds of zirconia copings were designed (a: Conventional zirconia coping with flat occlusal surface: thickness of the each coping is 0.6 mm evenly, and at the cervical margin area, the coping is adjusted sharply so as to fit preparation margin, b: Conventional zirconia coping with shoulder collar of 1 mm: thickness of the each coping is 0.6 mm evenly, and there is a collar of 0.6 mm from the margin, c: Zirconia coping with following original cuspal configuration (concave): two inclined cusp planes, and at the cervical margin area, the coping is adjusted sharply so as to fit preparation margin, and d: Zirconia coping with supporting configuration on the occlusal area: supporting configuration against the occlusal force, and at the cervical margin area, the coping is adjusted sharply so as to fit preparation margin) and porcelain was fired. Vertical and lateral load were conducted until fracture. Coping design affected the fracture load; conventional uniform thickness coping design showed the lowest load (a), whereas cuspal configuration to perform even thickness of porcelain showed the highest fracture load both load directions (c). PMID- 21597223 TI - Strength of a feldspar ceramic according to the thickness and polymerization mode of the resin cement coating. AB - The aim of this study was to evaluate, in vitro, the biaxial flexural strength (ISO 6872) of a feldspathic ceramic (VM7, Vita Zahnfabrik) coated with a resin cement with different thicknesses and polymerization mode. Control groups consisted in VM7 with and without acid etching with 10% hydrofluoric acid for 1 min. Experimental groups comprised VM7 etched, silanated and coated with Variolink II (Ivoclar Vivadent) cement, that was polymerized through the porcelain in light-cure and dual-cure modes, with thickness <=150 um or >150 um. The specimens (n=15) were subjected to the biaxial flexural strength essay and analyzed fractographically. Parametric (Dunnet, Anova 2-way, Tukey) and non parametric tests (Weibull) were used to evaluate results. Ceramic disks coated with resin cements of either activation modes and thicknesses exhibited higher flexural strength while the Weibull moduli did not present significant differences for a confidence interval of 95%. PMID- 21597224 TI - Cracks formed by Vickers indentation adjacent to the interface in bonded dental ceramics with various marginal angles. AB - The objective of this study was to assess the influence of the ceramic marginal angle on the length and nature of indentation cracks in ceramics near the ceramic/resin bonded interface. Disks of a leucite-reinforced ceramic or a diopside-based glass-ceramic bonded to a resin composite were sectioned so that the ceramic marginal angles were 45, 60, and 90 degrees . Vickers indentations were placed in the ceramic at various distances from the bonded interface. The lengths of the indentation cracks running near parallel to the interface were measured and the orientation of crack propagation was characterized. The crack length and orientation were significantly affected by the distance from the interface and by the marginal angle, respectively. The crack length extended as the distance from the interface was shortened. Smaller marginal angles resulted in more oblique cracks. The toughness of the ceramic affected the indentation crack length, shape, and direction. PMID- 21597225 TI - Shear bond strengths of veneering porcelain to cast, machined and laser-sintered titanium. AB - The aim of this study was to compare the shear bond strengths (SBS) of cast, machined, and laser-sintered titanium to dental porcelain. Two kinds of dental porcelains (Titankeramik and Triceram) were applied on cast (Tritan), machined (DC-Titan), and laser-sintered (EOSINT) titanium specimens (n=10). SBS test was conducted, and fracture surface analysis was also performed to determine the failure modes. Two-way ANOVA, Student's t-test, and post hoc test were used to analyze the data (p<0.05). Among the titanium specimens, the SBS values of laser sintered titanium specimens were significantly higher than the machined and cast titanium specimens (p<0.01). Comparison of Triceram and Titankeramik veneering porcelains showed no statistically significant differences in SBS when they were applied on laser-sintered and cast titanium specimens (p>0.05). Specimens in all the test groups exhibited adhesive or combined failure, with the Titankeramik machined titanium group exhibiting the highest adhesive failure rate (40%). Results showed that porcelain-titanium bond strengths could be improved by using the new laser sintering technique to produce titanium for prosthodontic applications. PMID- 21597226 TI - Gatifloxacine-loaded PLGA and beta-tricalcium phosphate composite for treating osteomyelitis. AB - Gatifloxacine (GFLX)-containing poly(lactide-co-glycolide) (PLGA) was introduced to the pores and surfaces of porous beta-tricalcium phosphate (betaTCP) granules by melt compounding whereby no toxic solvent was used. The granular composite of GFLX-loaded PLGA and betaTCP released GFLX for 42 days in Hanks' balanced solution and exhibited sufficient in vitro bactericidal activity against Streptococcus milleri and Bacteroides fragilis for at least 21 days. For in vivo evaluation, the granular composite was implanted in the dead space created by the debridement of osteomyelitis lesion induced by S. milleri and B. fragilis in rabbit mandible. After a 4-week implantation, the inflammation area within the debrided area was markedly reduced accompanied with osteoconduction and vascularization in half of the rabbits, and even disappeared in one of the six rabbits without any systemic administration of antibiotics. Outside the debrided area, inflammation and sequestrum were observed but the largest of such affected areas amounted to only 0.125 times of the originally infected and debrided area. These findings showed that the granular composite was effective for the local treatment of osteomyelitis as well as an osteoconductive scaffold which supported and encouraged vascularization. PMID- 21597227 TI - Proteome analyses of human macrophages exposed to low cytotoxic IC90 copper (2+) ions. AB - Dental noble alloys often contain copper (Cu). Eluted metal ions sometimes irritate oral tissues. The most eluted ions are Cu ions. The purpose of this study was to investigate the effects of low cytotoxic (IC90, 100 umol/L) Cu ions on macrophages by proteome analyses consisting of two-dimensional (2D) electrophoresis and matrix-assisted laser desorption/ionization -time of flight (MALDI-TOF) mass spectrometry. The analyses revealed that stimulation with IC90 Cu ions for 1 day caused the macrophage to significantly increase five specific protein spots. Mascot peptide mass finger-print matching suggested that four of them were attributed to 70 kDa heat shock protein 1A/1B (HSP70). HSP70 expression was verified by expressions of corresponding HSPA1A and HSPA1B mRNAs of the macrophage in quantitative real-time PCR analyses. It was concluded that by producing abundant HSP70, the macrophage protected itself against intracellularly intruding cytotoxic Cu ions that might un-fold and crosslink cellular proteins. PMID- 21597228 TI - Toxicity evaluations of various carbon nanomaterials. AB - After the discovery of fullerene and carbon nanotubes, various carbon nanomaterials were discovered or synthesized. The carbon nanomaterials have remarkable properties, different from bulk materials with the same chemical composition, and are therefore useful for industrial applications. However, the toxicity of nanomaterials may also differ from that of the bulk materials; this difference poses a concern. The physical similarity of nanomaterials to asbestos has led to evaluations for toxicity by many researchers using various methods. In this review, we compile and compare the toxicity evaluations of each carbon nanomaterial. PMID- 21597229 TI - High iFGF23 level despite hypophosphatemia is one of the clinical indicators to make diagnosis of XLH. AB - X-linked hypophosphatemic rickets (XLH) is caused by inactivating mutations in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene. Deletion of Phex leads to increased serum fibroblast growth factor23 (FGF23) levels in mouse. The aim is to assure the clinical usefulness of FGF23 determination in the diagnosis of XLH. Participants were 21 patients with XLH having abnormalities in PHEX from 13 kindred (PtPHEX: 1 to 42 years old; 10 males, 11 females) and 55 healthy controls (1 month to 18 years old; 27 males, 28 females). Temporal changes in FGF23 were determined by a single oral phosphate administration in PtPHEX and an ad lib diet in controls. Reference ranges of intact FGF23 (iFGF23) for children were determined. iFGF23 level which distinguish between controls and PtPHEX were validated. Correlations between iFGF23 and the severity of XLH (gender, age of onset, bone deformity, The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmPO(4)/GFR), inorganic phosphate (IP), Alkaline Phosphatase (ALP), therapeutic dose) were investigated. Increasing tendency after phosphate administration and no general tendency after breakfast in iFGF23 were observed. Reference range (5(th) and 95(th) percentiles) of iFGF23 for children (12.9 and 51.2 pg/mL) was similar to that for adults. iFGF23 were above the reference range in 19 of 21 PtPHEX (40 to 4710 pg/mL). iFGF23 did not correlate with any index of severity of XLH. Relatively high iFGF23 despite hypophosphatemia is one of the clinical indicators to diagnose XLH. PMID- 21597231 TI - Flow-mediated dilation is associated with microalbuminuria independent of cardiovascular risk factors in type 2 diabetes - interrelations with arterial thickness and stiffness. AB - AIMS: To investigate whether endothelial dysfunction assessed by brachial artery flow-mediated dilation (FMD) is associated with urinary albumin excretion (UAE) and is interrelated with carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) in type 2 diabetes. METHODS: We measured FMD, IMT and PWV in 158 subjects with type 2 diabetes (normo- 49, micro- 64, macroalbuminuria 45), explored the determinants of FMD, and analyzed the relationship of FMD with traditional cardiovascular risk factors according to IMT and PWV levels. RESULTS: Microalbuminuria was significantly associated with lower FMD, higher IMT and higher PWV compared to normoalbuminuria (p < 0.001 for all). FMD was significantly correlated with IMT and PWV, and also with traditional risk factors, UAE, glomerular filtration rate, diabetic retinopathy, and neuropathy. Multivariate regression analysis revealed that UAE remained a significant determinant of FMD independent of traditional risk factors, metabolic control, and renal function. The relationship of FMD with IMT and PWV was less pronounced in subjects with increased IMT and PWV. CONCLUSIONS: In individuals with type 2 diabetes, FMD is impaired in subjects with microalbuminuria and is associated with IMT and PWV only when these values are not increased, i.e., at an early stage of atherosclerosis. PMID- 21597230 TI - Molecular analysis of a novel LCAT mutation (Gly179 -> Arg) found in a patient with complete LCAT deficiency. AB - Lecithin-cholesterol acyltransferase (LCAT) is an important enzyme involved in the esterification of cholesterol. Here, we report a novel point mutation in the LCAT gene of a 63-year-old female with characteristics of classic familial LCAT deficiency. The patient's clinical manifestations included corneal opacity, mild anemia, mild proteinuria and normal renal function. She had no sign of coronary heart disease. Her LCAT activity was extremely low. DNA sequencing revealed a point mutation in exon 5 of the LCAT gene: a G to C substitution converting Gly(179) to an Arg, located in one of the catalytic triads of the enzyme. In vitro expression of recombinant LCAT proteins in HEK293 cells showed that the mutant G179R protein was present in the cell lysate, but not the culture medium. LCAT activity was barely detectable in the cell lysate or medium of the cells expressing the G179R mutant. This novel missense mutation seems to cause a complete loss of catalytic activity of LCAT, which is also defective in secretion. PMID- 21597232 TI - Brief morning exposure to bright light improves subjective symptoms and performance in nurses with rapidly rotating shifts. AB - OBJECTIVE: To investigate whether or not brief bright light (BL) exposure on workday mornings can improve health, performance and safety in nurses with rapidly rotating shifts. METHODS: We conducted a randomized crossover study involving registered nurses at a teaching hospital working a two-shift system including the night shift. Participants were instructed to expose themselves to BL for 10 min on workday mornings. RESULTS: A total of 61 participants were enrolled in the present study. Thirty-one participants received BL exposure in the first month, and the other 30 received it in the second month. Significant improvements were noted in the BL periods compared with the non-BL periods for self-assessed sleepiness at 10:00 on day-shift days evaluated using the Karolinska Sleepiness Scale, self-assessment of night sleep for day-shift days using the Visual Analogue Scale and for fatigue assessed using the Checklist Individual Strength Questionnaire. The estimated mean difference for each scale (95% confidence interval) was -0.55 (-0.91, -0.20), 0.37 (0.04, 0.70) and -2.13 ( 3.78, -0.48), respectively. Mean response time evaluated using the psychomotor vigilance task test (PVT) showed significant improvement in the BL periods compared with the non-BL periods. No statistically significant differences were observed for sleepiness at 14:00, depression, number of PVT lapses or frequency of perceived adverse events and near misses. CONCLUSION: Our findings suggest that brief BL exposure on mornings preceding a day shift is effective in improving sleepiness and performance during day-shift work, subjective nighttime sleep on day-shift days, and perceived fatigue for the preceding two weeks in rapidly rotating shift nurses. PMID- 21597233 TI - Pulmonary toxicity following an intratracheal instillation of nickel oxide nanoparticle agglomerates. AB - OBJECTIVE: We examined the pulmonary toxicity of nickel oxide nanoparticle agglomerates in the rat lung following an intratracheal instillation. METHODS: The weighted average surface primary diameter of nickel oxide nanoparticles was 8.41 nm, and the count median diameter of nickel oxide nanoparticle agglomerates suspended in saline was 1.34 um. Male Wistar rats were exposed to 1 mg (3.3 mg/kg) of nickel oxide nanoparticles intratracheally. The control group received intratracheal instillation of saline. Rats were dissected 3 days, 1 wk, 1 mo, 3 mo, and 6 mo after the instillation. Cytokine-induced neutrophil chemoattractant (CINC)-2alphabeta in the lung tissue was determined by quantitative measurement of protein by ELISA. RESULTS: The total cell count in bronchoalveolar lavage fluid (BALF) was increased persistently from 3 days to 6 mo. The neutrophil counts in BALF were also increased at 3 days, 1 wk, 3 mo, and 6 mo. In the lung tissue, infiltration of mainly neutrophils and alveolar macrophages was observed in alveoli from 3 days to 6 mo. The CINC-2alphabeta concentration was elevated from 3 days to 6 mo in the lung tissue. CONCLUSIONS: These results showed that micron-sized nickel oxide nanoparticle agglomerates also induced a persistent inflammatory response. PMID- 21597234 TI - Review of different quantification methods for the diagnosis of digital vascular abnormalities in hand-arm vibration syndrome. AB - OBJECTIVE: This study was undertaken to review the diagnostic ability of different quantification methods in the assessment of vibration-induced white finger (VWF), the typical clinical manifestation of vascular injuries in Hand-arm Vibration Syndrome (HAVS). METHODS: A literature search of original and major review articles related to the quantification techniques for diagnosing vascular injuries in HAVS was performed. Relevant data from the publications were extracted and included in this study for reporting and discussion. RESULTS: Few studies were available to substantiate the diagnostic techniques using the nail press test and nailfold capillaroscopy. Also, few studies were found to conclusively demonstrate the diagnostic ability using thermometry and thermography incorporated with cold provocation. Some recent reports raised the question regarding the diagnostic ability of finger plethysmography; but by virtue of its comparable assessment parameters and better diagnostic performance, plethysmography appears to be a suitable diagnostic method. In noninvasive quantification of vascular injuries, diagnostic techniques like laser Doppler perfusion imaging and nailfold capillaroscopy require further evaluation in future studies. CONCLUSIONS: For a reliable objective diagnosis of VWF at present, quantification of vascular responses using a test battery including established methods like thermometry or thermography and strain gauge plethysmography appears to be useful. PMID- 21597235 TI - An effective quarantine measure reduced the total incidence of influenza A H1N1 in the workplace: another way to control the H1N1 flu pandemic. AB - OBJECTIVES: To evaluate the effectiveness of a non-vaccine quarantine measure against pandemic influenza A H1N1 in workplaces. METHODS: Design was quasi cluster randomized controlled trial in two sibling companies (Cohort 1 n=6,634, Cohort 2 n=8,500). The follow-up period was from July 1st, 2009 to February 19th, 2010 (233 days). Intervention was voluntary waiting at home on full pay if the family became Influenza like Illness (ILI). The incidences of influenza A H1N1 and those of the subgroups whose families got ILI in both cohorts were compared by a Cox regression model and log-rank test. RESULTS: There were 189 and 270 workers who got H1N1 infection during the follow-up period in each cohort. In this period 317 workers in Cohort 1 were asked to wait at home for several days (100% obeyed). The intervention group (Cohort 1) showed a statistically significant lower risk (p for log-rank test=0.033) compared with the control (Cohort 2), and the hazard ratio of the intervention was 0.799 [0.658-0.970] after adjusting for age, sex, BMI and smoking status. The workers who were asked to wait at home showed H1N1 infection more frequently (49 out of 317) compared with the workers whose family got ILI but were not asked to wait and work regularly (77 out of 990, RR=2.17 [1.48-3.18]). CONCLUSIONS: The waiting on full pay policy in the workplace reduced the overall risk of influenza A H1N1 by about 20% in one flu season in Japan. This kind of non-vaccine measure will be a promising option in workplaces to control the next flu pandemic. PMID- 21597236 TI - Impairment by hypoxia or hypoxia/reoxygenation of nitric oxide-mediated relaxation in isolated monkey coronary artery: the role of intracellular superoxide. AB - To investigate the effect of hypoxia or hypoxia/reoxygenation on vascular smooth muscle function, mechanical response of monkey coronary artery without endothelium was studied under normoxia, hypoxia, and hypoxia/reoxygenation. Hypoxia or hypoxia/reoxygenation impaired the relaxation by nitroglycerin or isosorbide dinitrate but not that by 8-bromoguanosine-3',5'-cyclic monophosphate or isoproterenol. Tempol restored the impaired relaxation by nitroglycerin or isosorbide dinitrate, but superoxide dismutase had no effect. Apocynin, an NADPH oxidase inhibitor, improved the nitroglycerin-induced relaxation under hypoxia, but not under reoxygenation. Under combined treatment of apocynin with oxypurinol (xanthine oxidase inhibitor), rotenone (mitochondria electron transport inhibitor), or both, hypoxic impairment of vasorelaxation was restored more effectively. Similarly, impairment of the nitroglycerin-induced vasorelaxation under hypoxia/reoxygenation was restored by combined treatment with three inhibitors, apocynin, oxypurinol, and rotenone. Increase in superoxide production under hypoxia tended to be inhibited by apocynin and that under hypoxia/reoxygenation was abolished by combined treatment with three inhibitors. These findings suggest that increased intracellular superoxide production under hypoxia or hypoxia/reoxygenation attenuates vasodilation mediated with a nitric oxide/soluble guanylyl cyclase, but not adenylyl cyclase, signaling pathway. The main source of superoxide production under hypoxia seems to be different from that under reoxygenation: superoxide is produced by NADPH oxidase during hypoxia, whereas it is produced by xanthine oxidase, mitochondria, or both during reoxygenation.[Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.11031FP]. PMID- 21597237 TI - Big mitogen-activated protein kinase 1 protects cultured rat aortic smooth muscle cells from oxidative damage. AB - Oxidative stress is considered a major mediator of arteriosclerosis. In vascular smooth muscle cells, oxidative stress-induced cell death (including apoptosis) is probably related to arterial calcification in arteriosclerosis. Big mitogen activated protein kinase-1 / extracellular signal-regulated kinase 5 (BMK1/ERK5) is a newly identified member of the mitogen-activated protein kinases family. Like Src tyrosine kinase, BMK1/ERK5 is known to be sensitive to oxidative stress; however, its pathophysiological significance is poorly understood. In this study, we investigated the involvement of BMK1 and Src in H(2)O(2)-induced cell death using cultured rat aortic smooth muscle cells (RASMCs). Cell apoptosis was evaluated by using the TdT-mediated dUTP nick end labeling (TUNEL) method, and BMK1 and Src activities were determined by Western blotting. The main results are as follows: 1) BMK1 and Src were activated by H(2)O(2) in a time- and concentration-dependent manner in RASMCs; 2) BMK1 activation by H(2)O(2) was attenuated both in Src-knockdown RASMCs and in RASMCs pretreated with 4-amino-5 (4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), a Src family kinases inhibitor; and 3) H(2)O(2)-induced cell death was increased in BMK1- and Src-knockdown RASMCs as well as in PP2-treated RASMCs. These findings suggested that Src and BMK1 may play defensive and resistive roles against oxidative stress induced death in RASMCs. PMID- 21597238 TI - Comparative effects of azelnidipine and amlodipine on myocardial function and mortality after ischemia/reperfusion in dogs. AB - Effects of azelnidipine were examined and compared with those of amlodipine on stunned myocardium in dogs. The left anterior descending (LAD) coronary artery was ligated for 20 min and subsequently released for 60 min. A vehicle, azelnidipine (0.3 mg/kg), or amlodipine (0.3 or 1 mg/kg) was injected intravenously 20 min before LAD ligation. The heart rate increased after a depressor response in the presence of amlodipine, while it decreased despite a decrease in arterial pressures in the presence of azelnidipine. After reperfusion, the coronary flow (CF) significantly increased in the presence of azelnidipine, but did not change with amlodipine after reperfusion. A positive inotropic effect was observed after treatment with both calcium antagonists. Ischemia significantly decreased the percentage of segment shortening (%SS) in all groups. Treatment with both calcium antagonists significantly increased %SS after reperfusion, although high-energy phosphate levels did not improve in the presence of calcium antagonists 60 min after reperfusion. Mortality with azelnidipine was significantly lower than that with 0.3 mg/kg amlodipine immediately after reperfusion. In conclusion, improvement in myocardial stunning after pretreatment with azelnidipine is associated with an increase in CF after reperfusion. The negative chronotropic action may have contributed to decreased mortality due to reperfusion arrhythmias. Azelnidipine is more beneficial than amlodipine and may provide an additional advantage to patients with angina and hypertension. PMID- 21597239 TI - Developmental ability of somatic cell nuclear transferred embryos aggregated at the 8-cell stage or 16- to 32-cell stage in cattle. AB - Aggregation of somatic cell nuclear transfer (SCNT) embryos in mice is reported to improve full-term development. In the present study, we attempted to improve the development of SCNT embryos by aggregation in cattle. In Experiment 1, to examine the effect of the timing of aggregation on in vitro development of cumulus-cell NT embryos, we aggregated two or three SCNT embryos (2X or 3X embryos) at the 1-cell, 8-cell and 16- to 32-cell stages. Irrespective of the timing of aggregation, 3X embryos developed to the blastocyst stage at a high rate. However, aggregation did not improve the total blastocyst formation rate of the embryos used. The cell numbers of 3X embryos aggregated at the 1-cell stage and 2X embryos tended to be higher than that of single NT embryos (1X embryos). Furthermore, a significant increase in cell number was observed in 3X embryos aggregated at the 8-cell stage and 16- to 32-cell stage. In Experiment 2, we used fibroblast cells as nuclear donors and examined in vitro development of 3X embryos aggregated at the 8-cell stage and 16- to 32-cell stage. As a result, 3X embryos had high blastocyst formation rates and higher cell numbers than 1X embryos, which was consistent with the results of Experiment 1. In Experiment 3, we examined the full-term developmental ability of 3X embryos aggregated at the 8 cell stage and 16- to 32-cell stage. After transfer of fibroblast-derived NT embryos into recipient animals, a significantly higher pregnancy rate was obtained on Day 60 in 3X embryos than in 1X embryos. Two embryos aggregated at 8 cell stage and one embryo aggregated at the 16- to 32-cell stage developed to term, while no pregnancies derived from 1X embryos that lasted to Day 60. However, two of the cloned calves were stillborn. These results suggest that aggregation of the 8-cell stage or 16- to 32-cell stage SCNT embryos may improve the pregnancy rate, but that it cannot reduce the high incidence of fetal loss and stillbirth, which is often observed in bovine SCNT. PMID- 21597241 TI - Treatment of canine otitis externa using video otoscopy. AB - Otitis externa in 27 toy poodles and 40 miniature dachshunds was treated using a video otoscope. A distinct concavity (external tympanic concavity) was observed at the junction between the ventral part of the external surface of the tympanum and the ear canal to which a considerable amount of hair and debris had adhered. All hair and debris adhering to the external tympanic concavity were removed, and systemic antibiotic and antifungal agents were administered, after which all of the dogs recovered. The pattern of hair growth observed in the external tympanic concavity could be characterized according to the breed of dog. All of the toy poodles presented with curly hairs, while the miniature dachshunds had upright or flat-lying hairs. PMID- 21597242 TI - Protective effects of anisodamine on renal function in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - ST-segment elevation myocardial infarction (STEMI) is the most severe type of heart attack, and primary percutaneous coronary intervention (PCI) is the first line treatment for STEMI. However, these patients are at higher risk of contrast induced nephropathy (CIN), which increases the length of hospital stay and mortality rate. Anisodamine, an alkaloid extracted from a Chinese herb, has been shown to exert protective effects on the renal function. The aim of this study was to investigate the protective effect of anisodamine on CIN in STEMI patients undergoing primary PCI. A total of 126 consecutive STEMI patients were randomly assigned to receive anisodamine (n=60) or placebo (control, n=66) from admission to 24 hours after PCI. The serum creatinine (SCr) concentrations, estimated glomerular filtration rate (eGFR) and incidence of CIN were measured on admission, and 24, 48 and 72 hours after PCI between the two groups. We found that the renal function of all patients after PCI underwent a course from injury to recovery. The incidence of CIN was 5.0%, 8.3%, and 6.7% at 24, 48 and 72 hours, respectively, after primary PCI in anisodamine group, while in control group it was 16.7%, 22.7%, and 19.7%, respectively. The incidence of CIN in anisodamine group was lower than that in control group during 72 hours after PCI (all P<0.05). In conclusion, intravenous infusion of anisodamine before and after primary PCI may reduce the occurrence of CIN in STEMI patients undergoing primary PCI, without serious side effects. PMID- 21597240 TI - Molecular characterization of fungal communities in non-tilled, cover-cropped upland rice field soils. AB - This study aimed to characterize soil fungal communities in upland rice fields managed with tillage/non-tillage and winter cover-cropping (hairy vetch and cereal rye) practices, using PCR-based molecular methods. The study plots were maintained as upland fields for 5 years and the soils sampled in the second and fifth years were analyzed using T-RFLP (terminal restriction fragment length polymorphism) profiling and clone libraries with the internal transcribed spacer (ITS) region and domain 1 (D1) of the fungal large-subunit (fLSU) rRNA (D1(fLSU)) as the target DNA sequence. From the 2nd-year-sample, 372 cloned sequences of fungal ITS-D1(fLSU) were obtained and clustered into 80 nonredundant fungal OTUs (operational taxonomic units) in 4 fungal phyla. The T-RFLP profiling was performed with the 2nd- and 5th-year-samples and the major T-RFs (terminal restriction fragments) were identified using a theoretical fragment analysis of the ITS-D1(fLSU) clones. These molecular analyses showed that the fungal community was influenced more strongly by the cover-cropping than tillage practices. Moreover, the non-tilled, cover-cropped soil was characterized by a predominance of Cryptococcus sp. in the phylum Basidiomycota. We provided a genetic database of the fungal ITS-D1(fLSU)s in the differently managed soils of upland rice fields. PMID- 21597243 TI - Amplification of the telomerase RNA component gene in the process of human esophageal carcinogenesis. AB - Amplification of the human telomerase RNA component (hTERC) gene occurs early in cervical cancer development. Telomerase, the product of the hTERC gene, plays an important role in tumor cell apoptosis and genomic stability. Given the numerous similarities between esophageal and cervical cancers, we hypothesized that hTERC gene amplification may also be related with esophageal cancer development. We therefore examined 189 tissue sections from 63 cases of esophageal cancer and preneoplastic lesions. hTERC gene amplification in the lesions was detected by interphase fluorescence in situ hybridization. Of the 189 tissue sections, 149 were successfully evaluated (40 samples were excluded because of inappropriately preparation) and were classified as normal (n=45), atypical hyperplasia I (n=27), atypical hyperplasia II/III (n=22), and squamous cell carcinomas (SCCs; the most common type of esophageal cancer) (n=55). hTERC gene expression was not detected in normal esophageal tissue, whereas its expression was detected in atypical hyperplasias I (25.9%), atypical hyperplasia II/III (54.5%), and SCCs (90.9%) (p<0.05). The average copy numbers of hTERC in atypical hyperplasias I and II/III, as well as SCCs were 2.19, 2.35, and 2.64, respectively. In particular, the numbers of abnormal nuclei in atypical hyperplasias II/III were significantly higher than those of in atypical hyperplasia I (p<0.05). The hTERC gene amplification was not related with patient gender, histological stage, lymph nodes metastasis, and SCC differentiation grade (p>0.05). All these findings suggest that hTERC gene amplification is associated with SCC development. PMID- 21597244 TI - Suitability of tartrate-resistant acid phosphatase type 5b as a screening marker for bone mineral density in community-dwelling elderly individuals. AB - Osteoporosis is a common disorder in aging populations that imposes considerable health problems. Tartrate-resistant acid phosphatase type 5b (TRAP-5b) is derived from osteoclasts, and is involved in normal bone homeostasis. Recently, a novel assay system for TRAP-5b, the fragments absorbed immunocapture enzymatic assay method, has been developed. To evaluate the suitability of TRAP-5b as a screening marker for bone mineral density (BMD), we explored the correlations between serum TRAP-5b concentrations and laboratory findings, body mass index, or BMD in 462 community-dwelling elderly individuals (249 men and 213 women, age 73.4+/-6.5 years) who participated in a regular medical screening program. By multivariate linear regression analysis adjusted for confounding factors, TRAP-5b was significantly correlated with body mass index (beta=-0.005, p=0.043), alkaline phosphatase, a marker for osteoid formation and calcification (beta=0.001, p<0.001), and triglyceride (beta=-0.097, p=0.016) in men, and with body mass index (beta=-0.009, p=0.025), alkaline phosphatase (beta=0.001, p<0.001), calcium (beta=-0.059, p=0.039), and bone trabecular area ratio (beta=-0.47, p=0.025) in women. In conclusion, the elevated serum level of TRAP-5b is independently correlated with the decreased BMD in women, but not in men. Because measurement of TRAP-5b is not affected by food intake, and blood samples can be collected at any time of the day, we suggest the suitability of serum TRAP-5b as a simple marker for the evaluation of BMD in women. PMID- 21597245 TI - Human t-complex protein 11 (TCP11), a testis-specific gene product, is a potential determinant of the sperm morphology. AB - Fertilization promoting peptid (FPP) is essential for capacitation and acrosome reaction. The mouse t-complex protein 11 (Tcp11) gene, which encodes the receptor of FPP, plays an important role in fertilization. We had identified three alternative splicing products of its human homologous gene, TCP11, nominated as TCP11a, TCP11b and TCP11c. Their testis-specific expression had been noted, suggesting that TCP11 may play an important role in spermatogenesis and sperm function. In order to explore the function of TCP11, we investigated its expression, subcellular location and binding protein in the sperm. RT-PCR assay shows that all isoforms of TCP11 are present in both human testis and sperm. However, we could only detect the expression of 56-kDa protein, representing TCP11a and TCP11c, but not TCP11b, by western blot analysis. Furthermore, the expression level of 56-kDa TCP11 protein was lower by about threefold in sperm samples containing over 15% of coiled sperms than the level in sperm samples with normal morphology. The coiled sperm, which shows a coiling or bending back of the tail on itself, is associated with infertility. In addition, several TCP11a binding proteins were isolated using full-length TCP11a as bait. Among them, we focused on outer dense fiber 1 (ODF1), a component of sperm tail outer dense fibers, because outer dense fibers contribute to the distinct morphology and the function of sperm tail. Co-immunoprecipitation assays of sperm cell extracts confirmed that TCP11 protein interacted with ODF1. These results suggest that TCP11 may be responsible for the sperm tail morphology and motility. PMID- 21597246 TI - Slowing down in spatially patterned ecosystems at the brink of collapse. AB - Predicting the risk of critical transitions, such as the collapse of a population, is important in order to direct management efforts. In any system that is close to a critical transition, recovery upon small perturbations becomes slow, a phenomenon known as critical slowing down. It has been suggested that such slowing down may be detected indirectly through an increase in spatial and temporal correlation and variance. Here, we tested this idea in arid ecosystems, where vegetation may collapse to desert as a result of increasing water limitation. We used three models that describe desertification but differ in the spatial vegetation patterns they produce. In all models, recovery rate upon perturbation decreased before vegetation collapsed. However, in one of the models, slowing down failed to translate into rising variance and correlation. This is caused by the regular self-organized vegetation patterns produced by this model. This finding implies an important limitation of variance and correlation as indicators of critical transitions. However, changes in such self-organized patterns themselves are a reliable indicator of an upcoming transition. Our results illustrate that while critical slowing down may be a universal phenomenon at critical transitions, its detection through indirect indicators may have limitations in particular systems. PMID- 21597247 TI - Biodiversity conservation in metacommunity networks: linking pattern and persistence. AB - A central goal of conservation science is to identify the most important habitat patches for maintaining biodiversity on a landscape. Spatial biodiversity patterns are often used for such assessments, and patches that harbor unique diversity are generally prioritized over those with high community similarity to other areas. This places an emphasis on biodiversity representation, but removing a patch can have cascading effects on biodiversity persistence in the remaining ecological communities. Metacommunity theory provides a mechanistic route to the linking of biodiversity patterns on a landscape with the subsequent dynamics of diversity loss after habitat is degraded. Using spatially explicit neutral theory, I focus on the situation where spatial patterns of diversity and similarity are generated by the structure of dispersal networks and not environmental gradients. I find that gains in biodiversity representation are nullified by losses in persistence, and as a result the effects of removing a patch on metacommunity diversity are essentially independent of complementarity or other biodiversity patterns. In this scenario, maximizing protected area and not biodiversity representation is the key to maintaining diversity in the long term. These results highlight the need for a broader understanding of how conservation paradigms perform under different models of metacommunity dynamics. PMID- 21597249 TI - Seeing the forest for the trees: the limitations of phylogenies in comparative biology. (American Society of Naturalists Address). AB - The past 30 years have seen a revolution in comparative biology. Before that time, systematics was not at the forefront of the biological sciences, and few scientists considered phylogenetic relationships when investigating evolutionary questions. By contrast, systematic biology is now one of the most vigorous disciplines in biology, and the use of phylogenies not only is requisite in macroevolutionary studies but also has been applied to a wide range of topics and fields that no one could possibly have envisioned 30 years ago. My message is simple: phylogenies are fundamental to comparative biology, but they are not the be-all and end-all. Phylogenies are powerful tools for understanding the past, but like any tool, they have their limitations. In addition, phylogenies are much more informative about pattern than they are about process. The best way to fully understand the past-both pattern and process-is to integrate phylogenies with other types of historical data as well as with direct studies of evolutionary process. PMID- 21597250 TI - Evolution of specialization: a phylogenetic study of host range in the red milkweed beetle (Tetraopes tetraophthalmus). AB - Specialization is common in most lineages of insect herbivores, one of the most diverse groups of organisms on earth. To address how and why specialization is maintained over evolutionary time, we hypothesized that plant defense and other ecological attributes of potential host plants would predict the performance of a specialist root-feeding herbivore (the red milkweed beetle, Tetraopes tetraophthalmus). Using a comparative phylogenetic and functional trait approach, we assessed the determinants of insect host range across 18 species of Asclepias. Larval survivorship decreased with increasing phylogenetic distance from the true host, Asclepias syriaca, suggesting that adaptation to plant traits drives specialization. Among several root traits measured, only cardenolides (toxic defense chemicals) correlated with larval survival, and cardenolides also explained the phylogenetic distance effect in phylogenetically controlled multiple regression analyses. Additionally, milkweed species having a known association with other Tetraopes beetles were better hosts than species lacking Tetraopes herbivores, and milkweeds with specific leaf area values (a trait related to leaf function and habitat affiliation) similar to those of A. syriaca were better hosts than species having divergent values. We thus conclude that phylogenetic distance is an integrated measure of phenotypic and ecological attributes of Asclepias species, especially defensive cardenolides, which can be used to explain specialization and constraints on host shifts over evolutionary time. PMID- 21597251 TI - Climatic predictors of temperature performance curve parameters in ectotherms imply complex responses to climate change. AB - Determining organismal responses to climate change is one of biology's greatest challenges. Recent forecasts for future climates emphasize altered temperature variation and precipitation, but most studies of animals have largely focused on forecasting the outcome of changes in mean temperature. Theory suggests that extreme thermal variation and precipitation will influence species performance and hence affect their response to changes in climate. Using an information theoretic approach, we show that in squamate ectotherms (mostly lizards and snakes), two fitness-influencing components of performance, the critical thermal maximum and the thermal optimum, are more closely related to temperature variation and to precipitation, respectively, than they are to mean thermal conditions. By contrast, critical thermal minimum is related to mean annual temperature. Our results suggest that temperature variation and precipitation regimes have had a strong influence on the evolution of ectotherm performance, so that forecasts for animal responses to climate change will have to incorporate these factors and not only changes in average temperature. PMID- 21597252 TI - Predicting predation through prey ontogeny using size-dependent functional response models. AB - The functional response is a critical link between consumer and resource dynamics, describing how a consumer's feeding rate varies with prey density. Functional response models often assume homogenous prey size and size-independent feeding rates. However, variation in prey size due to ontogeny and competition is ubiquitous, and predation rates are often size dependent. Thus, functional responses that ignore prey size may not effectively predict predation rates through ontogeny or in heterogeneous populations. Here, we use short-term response-surface experiments and statistical modeling to develop and test prey size-dependent functional responses for water bugs and dragonfly larvae feeding on red-eyed treefrog tadpoles. We then extend these models through simulations to predict mortality through time for growing prey. Both conventional and size dependent functional response models predicted average overall mortality in short term mixed-cohort experiments, but only the size-dependent models accurately captured how mortality was spread across sizes. As a result, simulations that extrapolated these results through prey ontogeny showed that differences in size specific mortality are compounded as prey grow, causing predictions from conventional and size-dependent functional response models to diverge dramatically through time. Our results highlight the importance of incorporating prey size when modeling consumer-prey dynamics in size-structured, growing prey populations. PMID- 21597253 TI - Range size heritability in Carnivora is driven by geographic constraints. AB - Range size heritability refers to an intriguing pattern where closely related species occupy geographic ranges of similar extent. Its existence may indicate selection on traits emergent only at the species level, with interesting consequences for evolutionary processes. We explore whether range size heritability may be attributable to the fact that range size is largely driven by the size of geographic domains (i.e., continents, biomes, areas given by species' climatic tolerance) that tend to be similar in phylogenetically related species. Using a well-resolved phylogeny of Carnivora, we show that range sizes are indeed constrained by geographic domains and that the phylogenetic signal in range sizes diminishes if the domain sizes are accounted for. Moreover, more detailed delimitation of species' geographic domain leads to a weaker signal in range size heritability, indicating the importance of definition of the null model against which the pattern is tested. Our findings do not reject the hypothesis of range size heritability but rather unravel its underlying mechanisms. Additional analyses imply that evolutionary conservatism in niche breadth delimits the species' geographic domain, which in turn shapes the species' range size. Range size heritability patterns thus emerge as a consequence of this interplay between evolutionary and geographic constraints. PMID- 21597254 TI - Sexual conflict and the tragedy of the commons. AB - It is widely understood that the costs and benefits of mating can affect the fecundity and survival of individuals. Sexual conflict may have profound consequences for populations as a result of the negative effects it causes males and females to have on one another's fitness. Here we present a model describing the evolution of sexual conflict, in which males inflict a direct cost on female fitness. We show that these costs can drive the entire population to extinction. To males, females are an essential but finite resource over which they have to compete. Population extinction owing to sexual conflict can therefore be seen as an evolutionary tragedy of the commons. Our model shows that a positive feedback between harassment and the operational sex ratio is responsible for the demise of females and, thus, for population extinction. We further show that the evolution of female resistance to counter harassment can prevent a tragedy of the commons. Our findings not only demonstrate that sexual conflict can drive a population to extinction but also highlight how simple mechanisms, such as harassment costs to males and females and the coevolution between harassment and resistance, can help avert a tragedy of the commons caused by sexual conflict. PMID- 21597255 TI - A metapopulation paradox: partial improvement of habitat may reduce metapopulation persistence. AB - The adverse influence of habitat degradation on the survival of populations may sometimes be amplified by rapid evolution over ecological timescales. This phenomenon of "evolutionary suicide" has been described in theoretical as well as empirical studies. However, no studies have suggested that habitat improvement could possibly also trigger an evolutionary response that would result in a decline in population size. We use individual-based simulations to demonstrate the potential for such a paradoxical response. An increase in the quality, size, or stability of only a fraction of the habitat patches in a metapopulation may result in an evolutionary decline in the dispersal propensity of individuals, followed by a decrease in recolonization, a reduction in the number of patches occupied, a decline in overall population size, and even extinction. Thus, well intended conservation efforts that ignore potential evolutionary consequences of habitat management may increase the extinction risk of populations. PMID- 21597256 TI - What makes a leaf tough? Patterns of correlated evolution between leaf toughness traits and demographic rates among 197 shade-tolerant woody species in a neotropical forest. AB - Slow-growing juveniles of shade-tolerant plant species are predicted to have tough leaves because of the high cost of leaf replacement in shade relative to potential carbon gain. We assessed the degree of correlated evolution among eight traits associated with leaf toughness and the relationships of those traits with the growth and mortality rates of 197 tree and shrub species from the understory of the 50-ha forest dynamics plot on Barro Colorado Island, Panama. Path analysis with phylogenetically independent contrasts revealed that leaves attained material toughness (resistance to fracture per unit fracture area) through increases in tissue density, percent cellulose per unit dry mass, and vein fracture toughness. Lamina density and cellulose content evolved independently and thus represent different paths to material toughness. Structural toughness (resistance to fracture per unit fracture length) depended on material toughness and lamina thickness. Mortality rates of individuals 1-10 cm in stem diameter were negatively correlated with material toughness and lamina density but were independent of structural toughness and cell wall fiber contents. Leaf toughness traits were uncorrelated with relative growth rates. Results imply that material toughness enhances resistance to natural enemies, which increases survival and offsets the biomass allocation cost of producing tough leaves in the shaded understory. PMID- 21597257 TI - Condition dependence of a multicomponent sexual display trait in Drosophila serrata. AB - Theory predicts that costly sexual displays should evolve condition dependence if the marginal fitness gain from trait exaggeration is greater for high- than for low-condition individuals and that the strength of condition dependence should increase with the strength of directional selection. While there is substantial support for the first prediction, evidence for the latter is much weaker. We undertook a quantitative test of this prediction for a multivariate sexual display consisting of a suite of contact pheromones termed "cuticular hydrocarbons" (CHCs) in Drosophila serrata. We performed a dietary manipulation of condition (i.e., the pool of metabolic resources available for allocation to fitness-enhancing traits) within a half-sibling breeding design, thereby also providing insight into the genetic basis of condition dependence. As predicted, the linear combination of CHCs under the strongest sexual selection from female mate preferences was unusually condition dependent relative to other CHC combinations within the population ([Formula: see text]). A significant positive correlation also existed between the strengths of condition dependence and sexual selection among different CHC blends ([Formula: see text], [Formula: see text]). Finally, sires varied in their response to the dietary manipulation, demonstrating significant genetic variance in condition dependence. Our results are consistent with the evolution of heightened condition dependence of sexual displays in response to persistent sexual selection. PMID- 21597258 TI - Experimental evidence for genetic heritability of maternal hormone transfer to offspring. AB - In many animal species, embryos are exposed to maternal hormones that affect their development. Maternal hormone transfer varies with environmental conditions of the mother and is often interpreted as being shaped by natural selection to adjust the offspring to prevailing environmental conditions. Such hormone transfer requires genetic variability, which has not yet been experimentally demonstrated. Our study reports direct evidence for additive genetic variance of maternal androgens through a bidirectional selection on yolk testosterone (T) levels in Japanese quail. Lines selected for high egg T (HET) and low egg T (LET) concentration differed in yolk levels of this androgen, resulting in high realized heritability (h2 = 0.42)Correlated responses to selection on other gonadal hormones indicated that selection specifically targeted biologically active androgens. Eggs of HET quail contained higher androstenedione and lower estradiol concentrations than did those of LET quail, with no line differences in yolk progesterone concentration. Plasma T concentrations in adult females were not affected by selection, seriously challenging the hypothesis that transfer of maternal hormones to offspring is constrained by hormone levels in a mother's circulation. Our results suggest that transfer of maternal T represents an indirect genetic effect that has important consequences for the evolution of traits in offspring. PMID- 21597259 TI - Between-year variation in population sex ratio increases with complexity of the breeding system in Hymenoptera. AB - While adaptive adjustment of sex ratio in the function of colony kin structure and food availability commonly occurs in social Hymenoptera, long-term studies have revealed substantial unexplained between-year variation in sex ratio at the population level. In order to identify factors that contribute to increased between-year variation in population sex ratio, we conducted a comparative analysis across 47 Hymenoptera species differing in their breeding system. We found that between-year variation in population sex ratio steadily increased as one moved from solitary species, to primitively eusocial species, to single-queen eusocial species, to multiple-queen eusocial species. Specifically, between-year variation in population sex ratio was low (6.6% of total possible variation) in solitary species, which is consistent with the view that in solitary species, sex ratio can vary only in response to fluctuations in ecological factors such as food availability. In contrast, we found significantly higher (19.5%) between year variation in population sex ratio in multiple-queen eusocial species, which supports the view that in these species, sex ratio can also fluctuate in response to temporal changes in social factors such as queen number and queen-worker control over sex ratio, as well as factors influencing caste determination. The simultaneous adjustment of sex ratio in response to temporal fluctuations in ecological and social factors seems to preclude the existence of a single sex ratio optimum. The absence of such an optimum may reflect an additional cost associated with the evolution of complex breeding systems in Hymenoptera societies. PMID- 21597260 TI - Phosphatidylinositol 3-kinase inhibitor LY294002 suppresses proliferation and sensitizes doxorubicin chemotherapy in bladder cancer cells. AB - BACKGROUND: Phosphatidylinositol 3-kinase (PI3K)-AKT signaling is a well characterized pathway involved in the control of cell proliferation, apoptosis and oncogenesis. LY294002 is a commonly used pharmacologic inhibitor which acts at the ATP-binding site of the PI3K enzyme, thus selectively inhibiting the PI3K AKT nexus. The purpose of the present study was to examine whether PI3K inhibited by LY294002 had an effect on human bladder cancer cells. METHODS: After treatment with LY294002, MTT assay, chemosensitivity test, colony formation assay, apoptosis assay and Western blot analysis were conducted in EJ cells. RESULT: EJ cells treated with LY294002 showed significant AKT phosphorylation suppression in a dose-response manner. Also, PI3K/AKT signaling inhibitor LY294002 suppressed cell proliferation and enhanced the chemosensitivity of doxorubicin in human bladder cancer EJ cells. Furthermore, LY294002 increased cell apoptosis to doxorubicin. CONCLUSION: The augmentation of doxorubicin with PI3K inhibitor LY294002 may resolve the multidrug resistance of bladder cancer, and this may be a new strategy for achieving tolerance for chemotherapeutic agents in bladder cancer therapy. PMID- 21597261 TI - Effect of terazosin on lower urinary tract symptoms and pain due to double-J stent: a double-blind placebo-controlled randomized clinical trial. AB - OBJECTIVE: We evaluated the effect of terazosin in the improvement of lower urinary tract symptoms and flank pain in patients with internal ureteral stents. METHODS: In this double-blind randomized clinical trial, 73 patients with unilateral ureteral stone and hydroureteronephrosis who underwent insertion of an internal ureteral stent after transureteral lithotripsy (TUL) were randomized into two groups. 37 patients received terazosin 2 mg (once nightly) for 4 weeks and 36 patients received placebo for the same time duration. After 4 weeks, all patients were asked about the incidence of frequency, nocturia and urgency by an International Prostate Symptom Score (IPSS) questionnaire, flank pain and pain during urination by a visual analog scale (VAS) score, and hematuria. RESULTS: The mean VAS score was 2.21 in the terazosin group compared with 4.93 in the control group (p < 0.001). Nearly all the patients in the placebo group reported flank pain during urination but this was only reported in 54.5% of the patients in the terazosin group (p < 0.001). All criteria measured by the IPSS in the terazosin group were significantly lower than those in the placebo group (p = 0.0001). CONCLUSIONS: Administration of terazosin for patients with an internal ureteral stent relieved some stent-related symptoms such as flank pain, pain during voiding, frequency, nocturia and urgency, but had no effect on hematuria. PMID- 21597262 TI - Fourier transform infrared imaging analysis of cancellous bone in alendronate- and raloxifene-treated osteopenic sheep. AB - Fourier transform infrared imaging spectroscopy (FTIRI)-assessed bone composition parameters (mineral content, collagen maturity, crystal size and perfection, and carbonate content) describe bone quality and correlate to bone fracture risk. The challenge with studying bone quality in patients treated with antiresorptive drugs such as bisphosphonates (e.g., alendronate) and selective estrogen receptor modulators (SERMs) (e.g. raloxifene) is being able to test bone mechanical performance and material properties pre- and posttreatment. The purpose of this study was to evaluate the FTIRI changes in a large animal model of osteoporosis (female sheep with dietary induced metabolic acidosis; MA). Previous studies have investigated the relationship between bone material properties and bone strength in humans and smaller animals and have shown that changes in compositional properties influence fracture risk. Here we characterize the MA model at 6 and 12 months, demonstrate the loss of bone and changes in compositional properties, and show that 6 months of treatment with both antiresorptives ameliorate the bone loss as assessed by bone mineral density and FTIRI. This preliminary data suggest that the MA sheep model allows investigation of whether drug treatments preserve bone properties that exist at the time of treatment or if they induce further beneficial changes. PMID- 21597263 TI - Cryogenic transmission electron microscopy study of amelogenin self-assembly at different pH. AB - Cryogenic transmission electron microscopy (cryo-EM) was used to explore the self assembly of recombinant murine amelogenin (rM179) in vitro. Our cryo-EM data showed that amelogenin self-assembly is a strongly pH-dependent process. At pH 4.4 the main fraction of the protein exists in a monomeric form, although some peculiar structures consisting of chains of monomers were also observed. At pH 5.8 large nanospheres comprising ring-like structures ~50 nm in diameter were the most abundant particle class. Similarly, at pH 8.0 amelogenins self-assembled into ring-like oligomers of different sizes, which subsequently assembled into nanospheres 15-20 nm in diameter. Furthermore, at pH 7.2, which is close to a physiological pH, branched chains of nanospheres were observed. Our results show that amelogenin assembly is a multistep hierarchical process and provides new insight into the control of enamel mineralization. PMID- 21597264 TI - Robot-assisted partial cystectomy of a bladder pheochromocytoma. AB - Pheochromocytoma of the urinary bladder is an unusual tumor that typically presents with hypertensive crises related to micturition. We report here an unusual case of bladder pheochromocytoma that was treated by robotic-assisted laparoscopic partial cystectomy. A 35-year-old male patient presented with headache and hypertension related to micturition. The patient, who had a 3.5 * 4 cm solitary bladder tumor in the bladder dome, underwent robot-assisted partial cystectomy. The whole procedure was successfully performed using the robot without conversion to open surgery. The total operative time was 120 min and the estimated blood loss was 30 ml. PMID- 21597265 TI - Amelogenesis imperfecta: genotype-phenotype studies in 71 families. AB - Amelogenesis imperfecta (AI) represents hereditary conditions affecting the quality and quantity of enamel. Six genes are known to cause AI (AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72). Our aim was to determine the distribution of different gene mutations in a large AI population and evaluate phenotype-genotype relationships. Affected and unaffected family members were evaluated clinically and radiographically by one examiner. Genotyping was completed using genomic DNA obtained from blood or saliva. A total of 494 individuals were enrolled, with 430 (224 affected, 202 unaffected, and 4 not definitive) belonging to 71 families with conditions consistent with the diagnosis of AI. Diverse clinical phenotypes were observed (i.e. hypoplastic, hypocalcified, and hypomaturation). Genotyping revealed mutations in all 6 candidate genes. A molecular diagnosis was made in 132 affected individuals (59%) and in 26 of the families (37%). Mutations involved 12 families with FAM83H (46%), 6 families with AMELX (23%), 3 families with ENAM (11%), 2 families with KLK4 and MMP20 (8% for each gene), and 1 family with a WDR72 mutation (4%). Phenotypic variants were associated with allelic FAM83H and AMELX mutations. Two seemingly unrelated families had the same KLK4 mutation. Families affected with AI where candidate gene mutations were not identified could have mutations not identifiable by traditional gene sequencing (e.g. exon deletion) or they could have promoter sequence mutations not evaluated in this study. However, the results suggest that there remain new AI causative genes to be identified. PMID- 21597266 TI - Differential effects of fibromodulin deficiency on mouse mandibular bones and teeth: a micro-CT time course study. AB - Fibromodulin (Fmod) is a keratan sulfate small leucine-rich proteoglycan which is enriched in bones and teeth. In order to determine its functions on bone and tooth mineralization we characterized the phenotype of Fmod-deficient (Fmod-KO) mice using a new-generation microfocus computerized tomography system (micro-CT) and software allowing advanced visualization of 3-D data. Three-week-old and 10- week-old Fmod-KO mandibles and teeth were compared with those of age-matched wild type (WT) mice. In both young and mature mice the Fmod-KO mandibles were hypomineralized, especially the posterior (proximal) part of the mandible as it appeared to be the main target of the molecule deficiency whereas less extensive alterations were found in the alveolar bone. In transverse sections, larger marrow spaces were observed in the Fmod-KO mice compared with age-matched young or mature WT mice. Quantitative evaluation of the pulp volume of the first molar and 3-D reconstructions suggested that dentinogenesis was diminished in 3-week old Fmod-KO teeth. In contrast, increased dentin formation was found in 10-week old Fmod-KO mice and it was accompanied by a reduced pulp volume. Thus, the differential effects of Fmod deficiency on bones and teeth appear to diverge in adult mice. This may result from the previously reported differences in the molecular weight of Fmod in the 2 tissues or from compensatory mechanisms due to the overexpression of DSP and DMP-1 in the dental pulp of Fmod-KO. It is also possible that a single molecule plays diverging roles in a tissue-specific or region-specific manner. PMID- 21597267 TI - Poorly ordered bone as an endogenous scaffold for the deposition of highly oriented lamellar tissue in rapidly growing ovine bone. AB - The mechanical properties of bone are known to depend on its structure at all length scales. In large animals, such as sheep, cortical bone grows very quickly and it is known that this occurs in 2 stages whereby a poorly ordered (mostly woven) bone structure is initially deposited and later augmented and partially replaced by parallel fibered and lamellar bone with much improved mechanical properties, often called primary osteons. Most interestingly, a similar sequence of events has also recently been observed during callus formation in a sheep osteotomy model. This has prompted the idea that fast intramembranous bone formation requires an intermediate step where bone with a lower degree of collagen orientation is deposited first as a substrate for osteoblasts to coordinate the synthesis of lamellar tissue. Since some osteoblasts become embedded in the mineralizing collagen matrix which they synthesize, the resulting osteocyte network is a direct image of the location of osteoblasts during bone formation. Using 3-dimensional imaging of osteocyte networks as well as tissue characterization by polarized light microscopy and backscattered electron imaging, we revisit the structure of growing plexiform (fibrolamellar) bone and callus in sheep. We show that bone deposited initially is based on osteocytes without spatial correlation and encased in poorly ordered matrix. Bone deposited on top of this has lamellar collagen orientation as well as a layered arrangement of osteocytes, both parallel to the surfaces of the initial tissue. This supports the hypothesis that the initial bone constitutes an endogenous scaffold for the subsequent deposition of parallel fibered and lamellar bone. PMID- 21597268 TI - Cost-effectiveness analysis of ureteroscopic laser lithotripsy and shock wave lithotripsy in the management of ureteral calculi in eastern China. AB - INTRODUCTION: It was the aim of this study to compare the efficiency and safety between shock wave lithotripsy (SWL) and ureteroscopic holmium laser lithotripsy (URL) methods for ureteral calculi while also determining which option is more cost-effective. PATIENTS AND METHODS: During January 2008 to September 2009, a prospective randomized study was conducted to compare both modalities for the management of solitary radiopaque ureteral stones. Patient and stone characteristics, treatment outcome and charges were documented. Both options were compared using univariate statistical tests to identify the efficiency quotient and cost-effectiveness for ureteral calculi according to the stone location. RESULTS: A total of 257 patients were in the SWL group, while 269 were in the URL group. The efficiency quotients for SWL and URL were 0.81 and 0.88, respectively. The initial stone-free rate of URL for lower ureteral calculi was higher (p = 0.002), while the complication rate of SWL for upper ureteral calculi was lower (p = 0.027). The SWL group required lower hospitalization charges (USD 440 vs. 1,221; p < 0.001), lower total charges (USD 454 vs. 1,284; p < 0.001) and a shorter period of hospitalization (5.4 vs. 6.6 days; p < 0.001) compared with the URL group for all ureteral locations. For mid and lower ureteral calculi, the postoperative office visits of the URL group were fewer (1.03 vs. 1.1 times; p = 0.001). CONCLUSIONS: Primary in situ SWL for upper and middle ureteral calculi showed lower complication rates compared to URL and was more cost-effective in Eastern China. However, primary URL was a better option for treating lower ureteral stones with a higher stone-free rate but was more expensive. PMID- 21597269 TI - The nature and role of periosteum in bone and cartilage regeneration. AB - This study was undertaken to determine whether periosteum from different bone sources in a donor results in the same formation of bone and cartilage. In this case, periosteum obtained from the cranium and mandible (examples of tissue supporting intramembranous ossification) and the radius and ilium (examples of tissues supporting endochondral ossification) of individual calves was used to produce tissue-engineered constructs that were implanted in nude mice and then retrieved after 10 and 20 weeks. Specimens were compared in terms of their osteogenic and chondrogenic potential by radiography, histology, and gene expression levels. By 10 weeks of implantation and more so by 20 weeks, constructs with cranial periosteum had developed to the greatest extent, followed in order by ilium, radius, and mandible periosteum. All constructs, particularly with cranial tissue although minimally with mandibular periosteum, had mineralized by 10 weeks on radiography and stained for proteoglycans with safranin-O red (cranial tissue most intensely and mandibular tissue least intensely). Gene expression of type I collagen, type II collagen, runx2, and bone sialoprotein (BSP) was detectable on QRT-PCR for all specimens at 10 and 20 weeks. By 20 weeks, the relative gene levels were: type I collagen, ilium >> radial >= cranial >= mandibular; type II collagen, radial > ilium > cranial >= mandibular; runx2, cranial >>> radial > mandibular >= ilium; and BSP, ilium >= radial > cranial > mandibular. These data demonstrate that the osteogenic and chondrogenic capacity of the various constructs is not identical and depends on the periosteal source regardless of intramembranous or endochondral ossification. Based on these results, cranial and mandibular periosteal tissues appear to enhance bone formation most and least prominently, respectively. The appropriate periosteal choice for bone and cartilage tissue engineering and regeneration should be a function of its immediate application as well as other factors besides growth rate. PMID- 21597270 TI - Abnormalities in the enamel in bmp2-deficient mice. AB - Tooth development is regulated by epithelial-mesenchymal interactions and their reciprocal molecular signaling. Bone morphogenetic protein 2 (Bmp2) is essential for tooth formation. However, the role of Bmp2 during enamel formation remains unknown in vivo. In this study, the role of Bmp2 in the regulation of postnatal enamel formation was investigated via the conditional ablation of Bmp2 in enamel using the (Osx-Cre) mouse. Bmp2 gene ablation was confirmed by PCR analysis in Osx-Cre, Bmp2(flox/flox) mice. Bmp2-null mice displayed a severe and profound tooth phenotype with asymmetric and open forked incisors. Microradiographs revealed broken incisor tips and dental pulp chamber exposure. The enamel layer of incisors and molars was thin with hypomineralization. Scanning electron microscopy analysis showed that the enamel surface was rough with chipping and the enamel lacked a typical prismatic architecture. These results demonstrate that Bmp2 is essential for enamel formation. PMID- 21597271 TI - Bone cell autophagy is regulated by environmental factors. AB - The goal of this investigation was to ascertain whether bone cells undergo autophagy and to determine if this process is regulated by environmental factors. We showed that osteocytes in both murine and human cortical bone display a punctuate distribution of microtubule-associated protein light chain 3, indicative of autophagy. In addition, we noted a basal level of autophagy in preosteocyte-like murine long bone-derived osteocytic (MLO)-A5 cells. Autophagy was upregulated following nutrient deprivation and hypoxic culture, stress conditions that osteocytes encounter in vivo. Furthermore, in response to calcium stress, the transcription factor hypoxia inducible factor 1 regulated MLO-A5 autophagy. Finally, we showed that the more differentiated MLO-Y4 osteocyte-like cells exhibited a significant basal autophagic flux. Based on these findings, we suggest that raising the level of autophagic flux is a mechanism by which differentiated bone cells survive in a stressful environment. PMID- 21597272 TI - Theoretical study of bone sialoprotein in bone biomineralization. AB - Bone sialoprotein (BSP) is an acidic, non-collagenous protein specific to bone proposed previously to promote hydroxyapatite (HAP) nucleation and modulate HAP nanocrystal growth. Specifically, two phosphorylated acidic amino acid sequences in BSP, highly conserved across several vertebrates, are the proposed active sites. We selected one of these sites, i.e. (Sp)(2)E(8), where Sp represents a phosphoserine as a model peptide to study the role of BSP. We used molecular dynamics simulations to determine whether an alpha-helix or a random coil peptide conformation promotes templated HAP nucleation. A bioinformatics method helps infer preferential crystal growth directions by predicting the likely peptide conformations adsorbed on the (001), (100), and (110) crystal faces of HAP. Results suggest that, independent of conformation, no stable nucleating template is formed and, thus, the ion distributions in the vicinity of the peptide that eventually lead to a stable nucleus start out with disordered arrangements of ions. When adsorbed on all three faces, the Sp residues bind strongly regardless of the peptide conformation, and the Glu residues show different propensities to form helical conformations. The lack of geometrical templating between the peptide residues and all HAP surface sites indicates that adsorption and subsequent crystal growth modulation may be structurally nonspecific. PMID- 21597274 TI - Differential enamel and osteogenic gene expression profiles in odontogenic tumors. AB - Odontogenic tumors occur within the jaw bones and may be derived from odontogenic epithelium or ectomesenchyme or contain active components of both tissue types. We investigated the gene expression profile of enamel matrix proteins (EMPs), genes related to osteogenesis, and the mineralization process in odontogenic tumor cell populations focusing on an ameloblastoma (AB-1), a keratocystic odontogenic tumor (KCOT-1), and a calcifying epithelial odontogenic tumor (CEOT 1). All cell populations were shown to be epithelial in origin by CK14 expression. All tested EMPs were expressed by all odontogenic tumor cell types, with higher transcript levels seen in the AB-1 population especially for AMEL, AMBN, and ODAM. CEOT-1 cell populations showed a greater content of ALP-positive cells as well as higher ALP mRNA levels. Using qRT-PCR, we found a higher expression of 8 genes in the CEOT-1 compared to the AB-1 and KCOT-1. In this study we demonstrated the establishment of AB-1, KCOT-1 and CEOT-1 cell populations. The unique gene expression profiles of AB-1, KCOT-1, and CEOT-1 cells and their interactions with the surrounding microenvironment may support their unique tumor development, progression, and survival. PMID- 21597273 TI - Chondrocyte-specific regulatory activity of Runx2 is essential for survival and skeletal development. AB - Coordinated activities of multiple mesenchymal cell types contribute to the development of the mammalian skeleton formed through endochondral ossification. Synthesis of a cartilage template by chondrocytes is an obligatory step for the generation of skeletal elements during endochondral ossification. Gene ablation studies have established that Runx2 is an essential transcription factor for bone formation and the differentiation of skeletal cells. However, global gene deletion has failed to discern the tissue- and cell type-specific roles of Runx2. We generated floxed mice to elucidate the Runx2 regulatory control distinctive to cartilage tissue during bone development. Exon 8 of the Runx2 gene was selectively deleted in developing chondrocytes by utilizing Col2a-Cre mice. Cell- and tissue-specific gene recombination was confirmed by beta-gal activity in R26R mice. The chondrocyte-specific loss of Runx2 caused failure of endochondral ossification, impaired craniofacial development, dwarfism, and perinatal lethality. Radiographic imaging and histochemical approaches were used to characterize the skeletal phenotype. We conclude that regulatory control of Runx2 in chondrocytes is essential for endochondral ossification, and it is independent of the role of Runx2 in osteoblasts. PMID- 21597275 TI - Runx2 regulates the gene network associated with insulin signaling and energy homeostasis. AB - Glucose intolerance seen in metabolic disorders, such as type II diabetes, is commonly associated with improper execution of the insulin signaling pathway, as well as an imbalance of bone and fat tissues, such that a gain in adipose tissue occurs at the expense of bone loss. Fat-producing adipocytes and bone-forming osteoblasts stem from a common mesenchymal progenitor cell. Runx2 positively regulates the commitment of the mesenchymal cell toward osteogenesis, but its effects on energy homeostasis and the insulin signaling pathway are unknown. To investigate the connection, focused microarray profiling of genes associated with the insulin signaling pathway was performed on calvarial cells from Runx2-null embryonic mice and 3T3-L1 preadipocytes treated with control and insulin containing media. The microarray showed that addition of insulin resulted in a robust induction of genes (>95%) in 3T3-L1 cells. Surprisingly, Runx2-null cells cultured in control media were at an elevated state of energy metabolism and addition of insulin resulted in a marked suppression of genes required for insulin signaling. Clustering analysis revealed that the suppression occurred at all stages of the insulin pathway, from the receptors and transducers to nuclear effectors and target genes. Taken together, these results demonstrate that Runx2 is central for transduction and execution of the insulin regulatory signal. In conclusion, Runx2 actively regulates the gene network required for glucose metabolism and energy homeostasis in mesenchymal cells. PMID- 21597276 TI - Epigenetic regulation of early osteogenesis and mineralized tissue formation by a HOXA10-PBX1-associated complex. AB - Homeodomain-containing (HOX) factors such as the abdominal class homeodomain protein HOXA10 and the TALE-family protein PBX1 form coregulatory complexes and are potent transcriptional and epigenetic regulators of tissue morphogenesis. We have identified that HOXA10 and PBX1 are expressed in osteoprogenitors; however, their role in osteogenesis has not been established. To determine the mechanism of HOXA10-PBX-mediated regulation of osteoblast commitment and the related gene expression, PBX1 or HOX10 were depleted (shRNA or genetic deletion, respectively) or exogenously expressed in C3H10T1/2, bone marrow stromal progenitors, and MC3T3 E1 (preosteoblast) cells. Overexpression of HOXA10 increased the expression of osteoblast-related genes, osteoblast differentiation and mineralization; expression of PBX1 impaired osteogenic commitment of pluripotent cells and the differentiation of osteoblasts. In contrast, the targeted depletion of PBX1 by shRNA increased the expression of bone marker genes (osterix, alkaline phosphatase, BSP, and osteocalcin). Chromatin-associated PBX1 and HOXA10 were present at osteoblast-related gene promoters preceding gene expression, but PBX1 was absent from promoters during the transcription of bone-related genes, including osterix (Osx). Further, PBX1 complexes were associated with histone deacetylases normally linked with chromatin inactivation. Loss of PBX1 but not of HOXA10 from the Osx promoter was associated with increases in the recruitment of histone acetylases (p300), as well as decreased H3K9 methylation, reflecting transcriptional activation. We propose PBX1 plays a central role in attenuating the activity of HOXA10 as an activator of osteoblast-related genes and functions to establish the proper timing of gene expression during osteogenesis, resulting in proper matrix maturation and mineral deposition in differentiated osteoblasts. PMID- 21597277 TI - U.K. National COPD Resources and Outcomes Project 2008: patients with chronic obstructive pulmonary disease exacerbations who present with radiological pneumonia have worse outcome compared to those with non-pneumonic chronic obstructive pulmonary disease exacerbations. AB - BACKGROUND: Limited comparative data exist on the outcomes of patients presenting with chronic obstructive pulmonary disease (COPD) exacerbations with or without radiological pneumonia. OBJECTIVE: To examine the outcome differences amongst these patients. METHODS: We analysed 2008 U.K. National COPD audit data to examine the characteristics, management and outcomes, inpatient- and 90-day mortality and length of stay of patients admitted with COPD exacerbations. RESULTS: Of 9,338 admissions, 16% (1,505) had changes consistent with pneumonia indicated on the admission chest X-ray. They tended to be older (mean ages 75 vs. 72 years), male (53 vs. 50%), more likely to come from care homes, with more disability, higher BMI and co-morbidity, lower albumin but higher urea levels, and less likely to be current smokers. COPD exacerbations with pneumonia were associated with worse outcomes: inpatient mortality was 11 and 7% and 90-day mortality was 17 and 13% for pneumonia and non-pneumonia patients, respectively (p < 0.001). After adjusting for factors that are significantly different between the 2 groups, including age, sex, place of residence, level of disability, co morbidity, albumin and urea levels, estimated risk ratios for inpatient and 90 day mortality for pneumonia compared to non-pneumonia cases in this series were 1.19 (1.01,1.42) and 1.09 (0.96,1.23), respectively. The adjusted risk ratio of a prolonged acute hospital stay of more than 7 days was 1.15 (1.07, 1.23). CONCLUSIONS: Patients who present with radiological pneumonia have worse outcomes compared to those admitted without pneumonia in exacerbation of COPD. PMID- 21597278 TI - Health care professionals underestimate the mean life expectancy of older people. AB - BACKGROUND: The estimated life expectancy of older persons is an important component of medical decision-making. To date, no data are available on the accuracy of health care professionals in estimating the remaining life expectancy of older subjects. METHODS: A survey estimating the mean remaining life expectancy of Germans of both sexes at the ages of 0, 70, 80 and 90 years was performed from September to November 2010. RESULTS: Two hundred and six health care professionals underestimated the mean remaining life expectancy of older persons by 10%, on average, and with great variance (SD = 34%). Medical doctors, especially those not specialized in geriatrics, estimated worst. CONCLUSIONS: Underestimation of the remaining life expectancy of older people is prevalent in health care professionals and may lead to patients being managed inappropriately. This underscores the need for further studies and better training on this issue in health care education. PMID- 21597279 TI - Transcriptional response of MxA, PKR and SOCS3 to interferon-based therapy in HCV genotype 4-infected patients and contribution of p53 to host antiviral response. AB - AIMS: To investigate the myxovirus-resistance protein A (MxA) and double-stranded RNA-activated protein kinase (PKR) genetic response to interferon (IFN) therapy in hepatitis C virus (HCV) genotype 4-infected patients. Moreover, we studied the association between suppressor of cytokine signaling 3 (SOCS3) gene expression and therapy resistance in genotype 4. Finally, we investigated the novel link between p53 and IFN-stimulated genes (ISGs) in humans. METHODS: Gene expression analyses were performed in peripheral blood using TaqMan real-time PCR. Virologic response was assessed with a branched-DNA assay. Genotyping was confirmed. RESULTS: Early virologic responders (EVRs, n = 23) but not non-EVRs (n = 7) showed strong upregulation of PKR at week 12 of therapy compared to baseline. Both EVRs and non-EVRs showed MxA upregulation at week 12 compared to baseline. Baseline SOCS3 expression did not distinguish EVRs from non-EVRs in genotype 4. An association was found between p53 and MxA and PKR gene expression. CONCLUSION: Measurement of MxA and PKR transcriptional induction during treatment may distinguish EVRs from non-EVRs in genotype 4. SOCS3 gene does not seem to be implicated in therapy resistance in genotype 4. An association between p53 and ISGs expression was shown for the first time in HCV-infected patients, further supporting the contribution of p53 to host antiviral response. PMID- 21597281 TI - Editorial. Thoracoscopy 1910-2010: serendipity. PMID- 21597280 TI - Health problems in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. AB - Following the introduction of life-saving glucocorticoid replacement 60 years ago, congenital adrenal hyperplasia (CAH) has evolved from being perceived as a paediatric disorder to being recognized as a lifelong, chronic condition affecting patients of all age groups. Increasing evidence suggests that patients with CAH have an increased risk to develop health problems during adult life, with signs and symptoms of forerunner conditions of adult disease already emerging during the time of paediatric care. Transition of paediatric CAH patients to medical care in the adult setting is an important step to ensure optimal lifelong treatment, aiming to achieve good health and normal life expectancy and quality of life. Thus, primary and secondary prevention of health problems has to become a task of increasing importance for those involved in the care of CAH patients throughout their life. PMID- 21597282 TI - The concept of 'smokers' boils' is suggestive of a new hypothesis on the pathogenesis of hidradenitis suppurativa. PMID- 21597284 TI - 16th Meeting of the European Society of Neurosonology and Cerebral Hemodynamics. Munich, Germany, May 20-23, 2011. PMID- 21597283 TI - Paroxysmal nocturnal hemoglobinuria after autologous stem cell transplantation: extinction of the clone during treatment with eculizumab - pathophysiological implications of a unique clinical case. AB - The clinical and biological spectrum of paroxysmal nocturnal hemoglobinuria (PNH) is variable, ranging from classical hemolytic forms to PNH associated with aplastic anemia or other bone marrow (BM) failure syndromes. We report a previously undescribed case of PNH occurring after autologous stem cell transplantation (ASCT) in a patient affected by relapsing non-Hodgkin's lymphoma. The intensive chemotherapy and the ASCT resulted in a contraction of the effective hematopoietic stem cell (HSC) pool and a derangement of the immune system. The delayed engraftment and the BM hypoplasia represented a favorable environment for the expansion of the pathological clone. This case is paradigmatic even for the unexpected trend of the PNH clone during treatment with the terminal complement inhibitor eculizumab; in fact, the clone reduced until undergoing unexpected extinction, i.e. the recovery of normal hematopoiesis. Eculizumab seems not to play a direct role in HSC kinetics; the clinical remission probably occurred because the environmental conditions that led to the expansion of the PNH clone were transient and disappeared. PMID- 21597285 TI - Optimizing clinical care in patients with advanced soft tissue sarcoma: a phase II study of a new schedule of high-dose continuous infusion ifosfamide and doxorubicin combination. AB - BACKGROUND: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. PATIENTS AND METHODS: Thirty four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m(2)/12 days as continuous infusion) and doxorubicin (75 mg/m(2) on day 8) every 28 days with granulocyte colony-stimulating factor. RESULTS: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. CONCLUSIONS: Our study confirms that the ifosfamide and doxorubicin combination has a very low non hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted. PMID- 21597286 TI - Suspicion of drug-drug interaction between high-dose methotrexate and proton pump inhibitors: a case report - should the practice be changed? AB - We report a case of a potential drug-drug interaction in a woman treated by a first injection of high-dose methotrexate for a T-lymphoblastic lymphoma. Valaciclovir, fluoxetine and pantoprazole were given concomitantly. A methotrexate overdosage was shown at 36 h after infusion associated with a severe renal failure. Alkaline hyperhydration, folinic acid and carboxypeptidase G2 were given. Prescription analyses by pharmacists and literature research have permitted us to suggest that a drug-drug interaction between methotrexate and proton pump inhibitors (PPI) was responsible for this renal failure. Several mechanisms of interaction were suggested and might be related to the inhibition of renal methotrexate transporters by PPI, an increase in the methotrexate efflux to the blood by an upregulation of multidrug resistance protein 3 by PPI or genetic polymorphisms. This case shows that pharmacists can help physicians to optimize patient treatment: they consensually decided on the systematic discontinuation of PPI or a switch to ranitidine when patients were treated by high-dose methotrexate. PMID- 21597287 TI - Comparison of cisplatin-5-fluorouracil-folinic acid versus modified docetaxel cisplatin-5-fluorouracil regimens in the first-line treatment of metastatic gastric cancer. AB - OBJECTIVE: Prognosis of metastatic gastric cancer is poor and median survival is between 3 and 5 months. Response rates of combination chemotherapy with 5 fluorouracil (5-FU) and cisplatin in first-line treatment have been found to be 20-25% in the English literature. It has been demonstrated that adding docetaxel to combination chemotherapy improved time to progression and overall survival. However, the toxicity rates of the docetaxel-cisplatin-5-FU protocol were high. In our study we compared efficacy and toxicity of cisplatin-5-FU-folinic acid (CFF) and modified docetaxel-cisplatin-5-FU (mDCF) regimens in the first-line treatment of metastatic gastric cancer. PATIENTS AND METHODS: Between June 2004 and October 2008, 70 patients with previously untreated metastatic gastric cancer treated with CFF (n = 30) and mDCF (n = 40) were retrospectively evaluated in the study. Survival and toxicity data were compared. RESULTS: Median age of the patients was 53 years (range 23-69). Forty-eight percent of the patients were male and 75.7% had an ECOG performance status of 0-1. Prognostic factors including age, ECOG performance status, histopathological grade, and number and sites of metastases were similar between the groups. Objective response rates (complete and partial response) were higher in the mDCF group (30.0 vs. 13.3%, p = 0.19). While toxicity was acceptable in both groups, the most common grade 3-4 toxicities were anemia in 3.3 and 5.0%, neutropenia in 20 and 7.5%, febrile neutropenia in 6.7 and 5.0%, and diarrhea in 3.3 and 5.0% in the CFF and mDCF groups, respectively. Median follow-up was 10.3 (1.5-59.6) months. During that period 90 and 97.5% of the patients were dead in the CFF and mDCF groups, respectively. Median time to progression was 4.4 (95% CI 1.8-7.0) and 6.2 months (95% CI 5.6-6.8) (p = 0.85), median overall survival was 6.5 (95% CI 1.8-11.2) and 8.7 months (95% CI 6.7-10.7) (p = 0.88) in the CFF and mDCF groups, respectively. CONCLUSION: The mDCF regimen has been found to be more favorable than the CFF regimen with an acceptable toxicity profile in the first-line treatment of metastatic gastric cancer. PMID- 21597288 TI - Prospective phase II trial of gemcitabine in combination with irinotecan as first line chemotherapy in patients with advanced biliary tract cancer. AB - BACKGROUND: Chemotherapy is a critical treatment option in advanced biliary tract cancer (BTC), which is often diagnosed at advanced stage and is therefore inoperable. The aim of this phase II trial was to evaluate the efficacy and safety of a combination therapy with gemcitabine and irinotecan as the first-line chemotherapy in patients with previously untreated advanced BTC. PATIENTS AND METHODS: Patients with pathologically confirmed advanced BTC received gemcitabine (1,000 mg/m(2) over 30 min) and irinotecan (100 mg/m(2) over 2 h) on days 1 and 8 every 3 weeks. RESULTS: Of 39 patients eligible for this trial, 6 had intrahepatic bile duct cancer, 2 had extrahepatic bile duct cancer and 31 had gallbladder cancer. A total of 193 cycles of chemotherapy were administered, with a median of 4 cycles per patient (range 1-18). The objective response rate was 20.5%, and the disease control rate was 66.7% in intention-to-treat analysis. The median progression-free survival was 4.3 months (95% CI 2.70-5.90), and overall survival was 7.6 months (95% CI 4.56-10.64). Grade 3 and 4 toxicities included anemia (20.5% of patients), thrombocytopenia (2.3%), neutropenia (10.3%), aspartate transaminase increase (10.3%), alanine transaminase increase (5.1%) and emesis (5.1%). CONCLUSION: Combination therapy of gemcitabine and irinotecan had an efficacy comparable to historic control and can be a viable treatment option. It was well tolerated by patients with advanced BTC. PMID- 21597289 TI - Beyond antiangiogenesis: intratumorally injected bevacizumab plays a cisplatin sensitizing role in squamous cell carcinomas in mice. AB - BACKGROUND: The anticancer mechanism of bevacizumab beyond antiangiogenesis remains unclear. Here, we investigated whether intratumorally injected bevacizumab could serve as an effective cisplatin sensitizer in squamous cell carcinoma (SCC) in vivo. METHODS: Hela and SCC-VII experimental SCC models were established to investigate the anticancer effect of bevacizumab plus cisplatin and the underlying mechanism using immunostaining, TUNEL, and Western blot assays. RESULTS: Bevacizumab-cisplatin therapy markedly inhibited tumor growth and significantly increased survival in both Hela- and SCC-VII-bearing mice compared with single-agent treatments and the untreated control, respectively. Immunostaining of CD34 showed that intratumorally injected bevacizumab significantly reduced microvessel density in bevacizumab-cisplatin and bevacizumab-alone groups of Hela xenografts. TUNEL assay showed that bevacizumab cisplatin significantly promoted tumor cell apoptosis compared with single-agent treatments and untreated controls in these 2 models. Western blot showed that upregulation of cleaved caspase-3 and downregulation of Bcl-2 and p-Erk expressions are part of the molecular mechanisms beyond angiogenesis which contribute to the cooperative effect of bevacizumab plus cisplatin in the 2 SCC models. CONCLUSIONS: Bevacizumab functions not only as an angiogenesis inhibitor but also as a chemosensitizer which enhances the cytotoxicity of cisplatin and promotes apoptosis of SCC cells. PMID- 21597290 TI - Population pharmacokinetics of a novel histone deacetylase inhibitor, cyclo{(2S) 2-amino-8-[(aminocarbonyl)hydrazono] decanoyl-1-L-tryptophyl-L-isoleucyl-(2R)-2 piperidinecarbonyl} (SD-2007), and its metabolic conversion to apicidin after intravenous injection and oral administration in rats. AB - BACKGROUND: This study assessed the population pharmacokinetics and metabolic conversion of a novel histone deacetylase (HDAC) inhibitor, SD-2007, into its active metabolite, apicidin, in rats. METHODS: SD-2007 was given to rats by intravenous injection (4 mg/kg) and oral administration (40 mg/kg). Serum concentrations of SD-2007 and apicidin were determined by LC-MS/MS. All concentrations were analyzed using a population pharmacokinetic model with 9 compartments in S-ADAPT. RESULTS: The area under the curve for apicidin was 96 +/ 16 mg.h/ml after 4 mg/kg administered intravenously and 2,455 +/- 1,211 mg.h/ml after 40 mg/kg given orally. The population pharmacokinetic model described all profiles well. After oral administration of SD-2007, the median absolute bioavailability of SD-2007 was 6.67% (range 3.83-9.89) and the median apparent bioavailability was 22.3% (range 15.7-35.8) for apicidin, whereas only a median of 8.85% (range 7.57-9.34) of an intravenous SD-2007 dose was converted to apicidin. CONCLUSIONS: Oral SD-2007 displayed a substantial presystemic metabolism to active apicidin. The high serum concentrations of apicidin after oral administration of SD-2007 may cause significant HDAC inhibition. PMID- 21597291 TI - Assessment of statistical heterogeneity in the PLATO trial. PMID- 21597294 TI - 58th Annual ORCA Congress. PMID- 21597293 TI - Hypoadiponectinemia is associated with valvular inflammation and faster disease progression in patients with aortic stenosis. AB - OBJECTIVES: Adiponectin is a protein secreted by adipocytes which has anti inflammatory properties. The objective of this study was to examine the relationship between adiponectinemia and the hemodynamic progression of aortic stenosis (AS) as well as the degree of inflammation in the valve explanted at the time of aortic valve replacement (AVR). METHODS: The plasma level of adiponectin was measured in 122 patients undergoing AVR. The explanted aortic valves were analyzed and the density of leukocytes (CD45+), T cells (CD3+) and blood vessels (von Willebrand factor positive; vWF+) was documented. Also, a subset of patients (n = 67) had >=2 echocardiographic studies separated by at least 6 months, thereby allowing assessment of the rate of progression of stenosis during the preoperative period. RESULTS: Patients with lower plasma levels of adiponectin (<5.4 MUg/ml) had a faster progression rate of the mean transvalvular gradient before surgery than those with higher levels (9 +/- 1 vs. 4 +/- 1 mm Hg/year; p = 0.008). Moreover, these patients with hypoadiponectinemia had significantly more leukocytes (CD45+), T cells and blood vessels (vWF+) in their explanted valves compared to those with higher adiponectin levels. CONCLUSION: These findings support the concept that adiponectin may play a protective role against the inflammatory process and progression of calcific AS. PMID- 21597295 TI - Elevated plasma homocysteine is associated with increased brain atrophy rates in older subjects with mild hypertension. AB - We determined using serial MR imaging whether raised plasma homocysteine levels are associated with increased brain atrophy, white matter lesion (WML) progression or incidence of silent brain infarcts (SBIs) in older hypertensive subjects. Brain atrophy rates (0.58 +/- 0.48% per year, mean +/- SD) were significantly correlated with homocysteine (beta = 0.46, p = 0.001 homocysteine; beta = 0.44, p = 0.007 homocysteine/folate/B12 models) but not with folate or B12 levels. Progression of WML (0.08 +/- 0.16%) was not associated with homocysteine level (B = 0.01, p = 0.29). New SBIs were uncommon. In older hypertensive individuals, plasma homocysteine levels are associated with increased rates of whole-brain atrophy but not WML progression. PMID- 21597296 TI - Hemodynamic impact of fetal-variant Willisian circle on cerebral circulation: a duplex ultrasonography study. AB - BACKGROUND/AIMS: The Willisian circle can redistribute the vertebrobasilar flow and the reduction of flow is attributable to orthrostatic presyncope. To evaluate this hemodynamic aspect, we investigated anterior and posterior cerebral blood flow (CBF) volume distributions according to the variation of the Willisian circle, and compared those between controls and patients with presyncope. METHODS: Subjects underwent cerebral CT angiography and color-coded duplex sonography measuring flow volumes of the internal carotid artery (ICAs) and vertebral artery (VAs). According to clinical manifestations and Willisian configurations, CBF volume patterns were analyzed. RESULTS: Between the presyncope (n = 25) and control groups (n = 76), the prevalence of fetal-variant Willisian configuration (48% vs. 21%, p = 0.004) and posterior CBF volume (126 +/ 85 vs. 165 +/- 64 ml/min, p = 0.015) was significantly different, but A1 morphology, anterior CBF, and total CBF volumes were not. Total CBF volume was 769 +/- 176 ml/min (80% ICAs and 20% VAs). The posterior CBF volume lowered significantly (172 +/- 70 vs. 122 +/- 62 vs. 92 +/- 44 ml/min; p < 0.001) toward the two-sided fetal type variation, although total CBF volume is similar among the three groups (p = 0.742). CONCLUSIONS: The present study suggests that Willisian configuration contributes to orthostatic presyncope and flow distribution of the cerebral circulation. PMID- 21597297 TI - Rapamycin-induced impaired wound healing is associated with compromised tissue lactate accumulation and extracellular matrix remodeling. AB - INTRODUCTION: Extracellular matrix (ECM) remodeling involving matrix metalloproteinases (MMPs) and wound lactate accumulation are essential elements of tissue repair. The aim of this study was to investigate whether rapamycin induced impaired healing is associated with compromised wound fluid lactate accumulation and altered ECM remodeling. METHODS: Polyvinyl alcohol sponges were subcutaneously implanted in male C57/BL6 mice. Animals were randomized to daily intraperitoneal treatment with either vehicle or 1.5 mg/kg rapamycin. After 7 or 14 days, sponges were harvested to collect wound fluid for subsequent analyses. Wounds were excised for assessment of tensile strength. RESULTS: After 7 days, wound hydroxyproline content was significantly decreased due to rapamycin therapy, whereas the observed difference in tensile strength marginally failed to show statistical significance. In addition, rapamycin reduced wound lactate accumulation and enhanced MMP-2 protein expression, and both MMP-2 and MMP-9 activity. At day 14, wound tensile strength and hydroxyproline content were significantly lower along with an increase in MMP-2 and MMP-9 activity in rapamycin-treated mice. Similarly, wound fluid lactate concentration and MMP-2 protein expression were found to be persistently decreased and increased, respectively. CONCLUSIONS: Rapamycin affects tissue repair by interfering with fundamental mechanisms involved in healing, namely lactate accumulation and ECM remodeling. PMID- 21597298 TI - Azithromycin inhibits IL-5 production of T helper type 2 cells from asthmatic children. AB - BACKGROUND: Childhood asthma is a type 2 helper T (Th2) cell-driven inflammatory airway disease characterized by recurrent episodes of airway obstruction. Azithromycin (AZM), a macrolide antibiotic exhibiting anti-inflammatory activity aside from its antibacterial effect, may prove beneficial for asthmatic children. This study aimed to determine the effect of AZM on Th2 cells from atopic asthmatic children and non-atopic controls. METHODS: CD4+ cells were isolated from peripheral blood mononuclear cells of 9 patients with asthma and 9 non atopic individuals. Cells were activated as Th0 and differentiated into Th2 cells. The effect of AZM on activated CD4+ cells was evaluated with respective cell proliferation and cytokine production. RESULTS: Th0 and Th2 CD4+ T cells from atopic asthmatic children produced greater interleukin (IL)-5 (Th2 cytokine) but lower interferon (IFN)-gamma (Th1 cytokine) compared to the non-atopic controls, respectively. AZM inhibited IL-5 production of Th0 and Th2 cells from atopic asthmatics in a dose-dependent fashion, without significantly affecting their IL-13 and IFN-gamma production. A similar effect was observed in non-atopic controls except that AZM did inhibit IFN-gamma production of their Th0 cells. AZM at a higher dose decreased cell viability by inhibiting CD4+ T cell proliferation and enhanced their apoptosis, an effect similarly observed in Th0 and Th2 cells, and did not differ between asthmatic children and controls. CONCLUSION: Our finding that AZM preferentially downregulates IL-5 production suggests its therapeutic potentials in controlling childhood asthma. PMID- 21597299 TI - Immune regulation by CD4+CD25+ regulatory T cells in patients with Japanese cedar pollinosis. AB - BACKGROUND: Evidence indicating that CD4+CD25+ regulatory T (Treg) cells play a crucial role in the maintenance of peripheral T cell tolerance to allergens has been accumulated. To explore the functional role of Treg cells in patients with Japanese cedar pollinosis, we performed an in vitro investigation of the regulation of immune responses to allergens by Treg cells. METHODS: CD4+ and CD4+CD25- T cells obtained from 12 patients with Japanese cedar pollinosis were stimulated with Cry j 1 protein and Cry j 1-derived peptide. On day 6, T cells were tested for allergen-specific reactivity using a CFSE-based proliferation assay and cytokine ELISA assays. The frequency of Cry j 1-specific interleukin (IL)-10-producing Treg cells was assessed by ELISPOT assays. RESULTS: The proportion of proliferated cells induced by allergen stimulation was similar in both CD4+ and CD4+CD25- cell cultures. The production of interferon (IFN)-gamma, but not that of IL-5 was significantly enhanced in CD4+CD25- cell cultures compared to that in CD4+ cell cultures. Interestingly, the production of IL-10 was decreased in CD4+CD25- cell cultures. Moreover, Cry j 1-specific IL-10 producing Treg cells were detected in pollen-allergic patients. CONCLUSION: Our findings suggest that in pollen-allergic patients, Treg cells predominantly suppresses Th1 responses rather than Th2 responses, where allergen-specific IL-10 producing Treg cells may also be responsible for the downregulation of allergen specific immune responses. PMID- 21597300 TI - Oral administration of bacterial lysates attenuates experimental food allergy. AB - BACKGROUND: Modulating early immune response by application of bacteria and their by-products has been suggested as a preventive strategy against the development of allergic diseases. In light of this, the aim of the study was to test the effects of oral administration of bacterial lysates (BL) in a rat model of food allergy. METHODS: BL or PBS were administered orally to neonatal Brown Norway rats up to an age of 42 days. Additionally, animals were sensitized 3 times (days 35, 40 and 45) intraperitoneally with ovalbumin (OVA). On days 60 and 61, rats were locally challenged with OVA by gavage feeding. RESULTS: Detection of increased allergen-specific Ig serum levels and proliferative responses of spleen mononuclear cells confirmed systemic sensitization. In serum of animals that received BL in addition to OVA sensitization, the levels of allergen-specific IgE and IgG were significantly reduced compared to animals which were not exposed to BL. Allergen-stimulated lymphocytes from spleen and mesenteric lymph nodes of BL treated animals showed a significantly elevated cytokine production of IL-10. To assess local functional changes of the intestinal barrier we measured the intestinal permeability, which was increased in OVA-sensitized and challenged animals compared to nonsensitized controls, yet significantly reduced in sensitized animals which received BL. CONCLUSION: These data suggest that local administration of BL (pathogen-associated molecular patterns) in the intestine exhibits immuno-modulating effects. Furthermore, pathophysiological features of food allergy, such as the loss of gut mucosal integrity, might be reduced by the treatment with BL. PMID- 21597301 TI - Hyaluronidase and hyaluronan in insect venom allergy. AB - BACKGROUND: Insect venoms contain an allergen hyaluronidase that catalyzes the hydrolysis of hyaluronan (HA), a polymer of disaccharide GlcUA-GlcNAc in skin. HAs depending on their size have variable function in inflammation and immunity. This paper reports on whether hyaluronidase, HA polymers and oligomers can promote antibody response in mice. METHODS: HA oligomers (8- to 50-mer; 3-20 kDa) were obtained by bee venom hyaluronidase digestion of HA polymers (750- to 5,000 mer; 300-2,000 kDa). Antibody responses in mice were compared following 3 biweekly subcutaneous injection of ovalbumin (OVA) with or without test adjuvant. RESULTS: OVA-specific IgG1 levels were approximately 2 times higher in BALB/c and C3H/HeJ mice receiving OVA and HA oligomer or polymer than those treated with OVA alone, and no increase in total IgE level was observed. In C57Bl/6 mice, observed increases in IgG1 and IgE were 3.5- and 1.7-fold, respectively, for the oligomer and 16- and 5-fold (p < 0.05), respectively, for the polymer. CONCLUSION: Hyaluronidase by its action on HA in skin can function indirectly as adjuvant to promote IgE and IgG1 response in mice. Insect venoms also have cytolytic peptides and phospholipases with inflammatory roles. These activities found in mice may contribute to venom allergenicity in susceptible people. PMID- 21597302 TI - Incidence of anaphylaxis in hospitalized patients. AB - BACKGROUND: Only two studies have analyzed the incidence of anaphylaxis during admission to hospital. We have analyzed the incidence of anaphylaxis among hospitalized patients and determined the timing of and risk factors for episodes of anaphylaxis. METHODS: Our study was performed between 1999 and 2005. We used the definition of anaphylaxis of the NIAID-FAAN symposium. Cases of anaphylaxis were extracted from an official database of discharge diagnoses coded according to the International Classification of Diseases, Clinical Modification, Ninth Revision (ICD-9-CM), Sixth Edition. Specific and generic codes related to anaphylaxis were chosen. This strategy revealed 83.3% (95% confidence interval, CI, 47-99%) of all episodes of anaphylaxis in a pilot study. The incidence of episodes of anaphylaxis and the hazard ratios were calculated for the different variables. RESULTS: We observed a crude cumulative incidence of 1.5 episodes of anaphylaxis (95% CI, 0.9-1.9) in 5,000 admissions. The cumulative incidence according to the Standardized European Population was 1.6 cases in 5,000 admissions (95% CI, 0.8-2.3). Cox regression analysis showed that anaphylaxis occurs mainly in young people (0.97; 95% CI, 0.95-0.99) and its incidence differs according to the clinical unit. The Vascular Surgery Unit had the highest incidence rate (hazard ratio 7.7; 95% CI, 2.1-28.6). Males had a lower risk of suffering from anaphylaxis than females (0.5; 95% CI, 0.2-0.9). CONCLUSIONS: Anaphylaxis is a very rare event among hospitalized patients. Female gender, young age and admission to the Vascular Surgery Unit favored the occurrence of episodes of anaphylaxis among hospitalized patients. PMID- 21597303 TI - Safety of parecoxib in asthmatic patients with aspirin-exacerbated respiratory disease. AB - BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) affects a subset of patients with asthma. Cyclooxygenase 2 inhibitors are a safe alternative in patients with AERD. Parecoxib is the first cyclooxygenase 2 selective drug for parenteral administration, especially useful after surgery thanks to its analgesic power. The aim of the study is to assess the tolerance of parecoxib (Dynastat; Pfizer) given by intramuscular route in patients with AERD. METHODS: Patients evaluated were referred to the Pneumology and Respiratory Allergy Department of the Hospital Clinic (Barcelona, Spain) for asthma exacerbations precipitated by 2 or more different non-steroidal anti-inflammatory drugs (NSAIDs). AERD was confirmed by a nasal challenge test with aspirin. Patients were challenged with parecoxib, and urine samples were collected to measure the leukotriene E(4) concentration. RESULTS: Ten patients were challenged with parecoxib. No symptoms were reported with any of the administered doses, and there were no signs of immediate or delayed hypersensitivity. There were no alterations in the forced expiratory volume in 1 s or in acoustic rhinometry measurements. No significant differences between leukotriene E(4) levels were detected. CONCLUSION: The drug was well tolerated by all patients, with no adverse reactions. This lack of reactions found in our study supports the fact that parecoxib could be a safe alternative in postsurgery analgesia in NSAID intolerant asthma patients. PMID- 21597304 TI - Chronic urticaria: etiology and natural course in children. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) in childhood is infrequent, and information about the disease in children is limited. We attempted to investigate its etiologic factors, natural course, and predictors of prognosis. METHODS: All children aged <= 18 years followed for CSU during an 8-year period were analyzed retrospectively, and the final outcomes were queried via a telephone interview. RESULTS: One hundred patients (male/female ratio 1.27) with a median age of 9.2 years (range 0.7-17.2) at symptoms onset were evaluated. The median follow-up was 2.5 years (range 0.2-18.1). An autologous serum skin test was positive in 46.7% of the subjects (n = 45), with a female predominance (71.4%) (p = 0.023). In 13.8% of the children, ANA titers were over 1/100. Food allergy (n = 1), thyroid autoantibodies (n = 3), possible collagen disease (n = 1), and drug usage (deferoxamine) (n = 1) were found to be associated factors. Infections could not be confirmed as the cause of CSU. Recovery was seen in 16.5, 38.8, and 50.0% of the children after 12, 36, and 60 months, respectively. Though in multivariate analysis none of the factors, including age, gender, autologous serum skin test positivity, the presence of angioedema, or other allergic diseases, appeared to predict the prognosis, in univariate analysis being female and being older than 10 years of age predicted an unfavorable prognosis. CONCLUSION: The etiology of CSU in children is mainly related to an autoreactive background, as in adults. CSU has a favorable prognosis, and resolution is seen in half of the children within 5 years. Girls older than 10 years may have an unfavorable prognosis. PMID- 21597305 TI - Physical activity and self-reported cardiovascular comorbidities in persons with multiple sclerosis: evidence from a cross-sectional analysis. AB - BACKGROUND: This study examined the possibility of a linear, inverse association between physical activity and the number of self-reported cardiovascular comorbidities in persons with multiple sclerosis (MS). METHODS: The sample included 561 persons with MS who completed demographic, cardiovascular comorbidity, disability status, and physical activity self-report assessments, and then wore an accelerometer for 7 days. The data were analyzed using bivariate correlation and multiple linear regression analyses. RESULTS: Bivariate correlation analysis indicated that there were statistically significant, inverse associations between the number of self-reported cardiovascular comorbidities and objectively measured (r = -0.192, p = 0.0001) and self-reported (r = -0.151, p = 0.0001) physical activity. The first multiple linear regression indicated that objectively measured physical activity was significantly associated with the number of self-reported cardiovascular comorbidities (B = -0.003, SE B = 0.001, beta = -0.128), even after controlling for confounding variables. The second multiple linear regression indicated that self-reported physical activity, too, was significantly associated with the number of self-reported cardiovascular comorbidities (B = -0.011, SE B = 0.004, beta = -0.114), even after controlling for confounding variables. CONCLUSION: Physical activity was associated with the number of self-reported cardiovascular comorbidities, independent of disability status and other possible confounding variables, in persons with MS. PMID- 21597306 TI - Physical activity in multiple sclerosis: the missing prescription. PMID- 21597307 TI - Taut internal limiting membrane causing diffuse diabetic macular edema after vitrectomy: clinicopathological correlation. AB - AIMS: To describe 2 cases of diffuse diabetic macular edema (DME) after diabetic vitrectomy caused by a taut internal limiting membrane (ILM), with clinicopathological correlation. METHODS: Interventional case series with immunohistochemical analysis. RESULTS: Two patients were referred for unresponsive diffuse DME after pars plana vitrectomy with removal of the posterior hyaloid. Clinically, a taut ILM was noted over the fovea, and its removal resulted in rapid and long-term resolution of the edema, confirmed by optical coherence tomography with visual acuity improvement. Histopathology with immunostaining revealed a segment of ILM with an inner monolayer of cytokeratin positive (retinal pigment epithelial cells) and/or glial fibrillary acidic protein-positive cells with smooth muscle actin immunoreactivity. CONCLUSIONS: A taut ILM can cause diffuse DME after vitrectomy, and its removal can restore the normal foveal contour and improve visual acuity. Tangential tractional forces from contractile cells propagated across the fovea via the ILM appear to be the etiology. PMID- 21597308 TI - Intraoperative image fusion to ascertain adequate lead placement. AB - BACKGROUND: In order to view the position of the deep brain stimulator (DBS) lead in relation to the stereotactic target on 3-tesla magnetic resonance (3T-MR) images prior to the conclusion of the procedure, intraoperative postimplantation computed tomography (CT) images were fused with preoperative 3T-MR images. The method to do this is described and discussed in this paper. METHODS: Over the last year, this method was used for 8 procedures: 6 for subthalamic nucleus and 2 for ventral-intermediate nucleus of the thalamus. The procedures were done on the CT table in a stereotactic frame. CT and MR images plus coordinates from the Schaltenbrand atlas were used to plan the target. After the lead had been placed at the target, intraoperative CT images were obtained and fused with preoperative 3T-MR images prior to the conclusion of the procedure. If error was detected in the lead position, it was corrected. RESULTS: Errors in the x-coordinate were detected in 2 patients. These errors were corrected prior to the conclusion of the procedures. CONCLUSION: This is a simple method to intraoperatively visualize DBS lead position on high-quality 3T-MR images. It gives the surgeon the capability to detect errors and correct them prior to the conclusion of the procedure. PMID- 21597309 TI - Cerebral ischemia related to globus pallidus internus stimulation for cervical dystonia. AB - BACKGROUND: Deep brain stimulation (DBS) is generally a safe and effective method to treat intractable movement disorders. However, complications of surgery have been reported, such as hemorrhage, infection and hardware failure. OBJECTIVES AND METHODS: We describe an unusual complication associated with DBS of the globus pallidus internus (GPi). The patient was a 34-year-old man with a 5-year history of progressive cervical dystonia that was unresponsive to medical treatment. He underwent bilateral DBS of the posteroventral GPi. After test stimulation, the patient developed left facial weakness, as well as dysarthria and hemiparesis of the left side. Magnetic resonance imaging showed a small infarct in the right posterior internal capsule. There was no misplacement of the microelectrode. RESULTS AND CONCLUSION: The authors present this unique case of cerebral infarction as a complication of DBS. The mechanism of ischemia is unclear. However, in this case, we had performed microstimulation with high amplitude in order to determine the adverse effects. This magnitude of electrical stimulation may have led to small-vessel vasospasm, which may have induced ischemia. Although ischemia after DBS surgery is seldom reported, cerebral ischemia may be a surgical complication after DBS implantation. PMID- 21597310 TI - Bilateral globus pallidus internus deep brain stimulation for DYT1+ generalized dystonia with previously received bilateral thalamotomy and unilateral pallidotomy. AB - Ablation of the globus pallidus internus (GPi) and thalamotomy have been extensively used in the past. Posteroventral GPi deep brain stimulation has been considered as a treatment for dystonia. However, to date, there is no report in the literature of any dystonia patient who underwent GPi deep brain stimulation who had previously undergone staged bilateral thalamotomy and unilateral pallidotomy. The authors of the present study have acquired relatively good clinical results, even in patients who previously received bilateral thalamotomy and unilateral pallidotomy for DYT1+ primary generalized dystonia. PMID- 21597311 TI - Treatment of homocystinuria-related dystonia with deep brain stimulation: a case report. AB - A 23-year-old woman with the medical history of homocystinuria that had been diagnosed at the age of 14 has been non-responsive to treatment. The patient presented with the symptoms of dysphonia, dysarthria and severe dystonia of the neck and left extremities. Blood and urine biochemistry revealed high levels of homocystine. Brain magnetic resonance imaging was normal with no detectable pathologies. Medical treatment strategies were used and repeated injections of botulinum toxin A were administered, but the symptoms showed no significant improvement. The patient was then operated, and deep brain stimulators targeting the bilateral globus pallidus internus were implanted. After the activation of the electrodes, dystonia symptoms showed a remarkable improvement. Good outcome was documented during the follow-up period of 7 months. To our best knowledge, this is the first reported case of homocystinuria-related dystonia symptoms that were successfully treated with deep brain stimulation. PMID- 21597312 TI - Deep brain stimulation of the pedunculopontine nucleus in a patient with freezing of gait. AB - CASE PRESENTATION: A 54-year-old male patient presenting probable multiple system atrophy with predominant parkinsonism who underwent bilateral deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) is presented. The patient had dominant freezing of gait (FOG), levodopa-resistant bradykinesia, and autonomic disturbances, but with a good cognitive condition. METHODS: The patient underwent bilateral DBS of the PPN, which ended with modest benefits. RESULTS AND CONCLUSION: Although he had a short postoperative follow-up (6 months), his neurological status remained stable and PPN DBS provided modest improvements in the gait disorder and freezing episodes. This unusual case suggests that the mesencephalic pedunculopontine region may have a role in locomotor symptoms and the potential to provide a limited improvement in FOG. PMID- 21597313 TI - Acute and chronic hypothyroidism are associated with similar left ventricular diastolic dysfunction relative to the euthyroid state: results of doppler echocardiographic comparisons. AB - BACKGROUND: How the duration of hypothyroidism affects left ventricular diastolic function is not well-characterized. AIM: We sought to compare left ventricular diastolic function in acutely vs chronically hypothyroid patients vs euthyroid controls, and within individuals while on vs off T4. SUBJECTS AND METHODS: We prospectively performed such comparisons measuring pulsed-wave and color M-mode Doppler echocardiographic variables: early or late mitral peak velocities (E wave or A wave, respectively), E wave/A wave ratio, E wave deceleration time, isovolumic relaxation time (IVRT), mitral flow propagation velocity (Vp), E wave/Vp ratio. Subjects comprised the acute HYPO group, 10 patients undergoing T4 withdrawal >= 6 months post-primary treatment for differentiated thyroid cancer (DTC); the chronic HYPO group, 23 treatment-naive Hashimoto thyroiditis patients; and 21 healthy euthyroid controls. Subjects were adults aged <= 60 yr, predominantly female, with sinus rhythm; exclusion criteria were cardiovascular or thyroid disorder besides DTC (Hashimoto thyroiditis) in acute (chronic) HYPO patients or medication (besides thyroid hormone) affecting cardiac or thyroid function. RESULTS: Mean IVRT was significantly delayed and mean Vp, significantly slowed in both HYPO groups vs controls (p<0.0005), but did not differ between HYPO groups. These variables also were significantly impaired (p<0.05) within individuals when off vs on T4 (no.=8 acute, 10 chronic HYPO patients). Both HYPO groups had elevated mean E wave/Vp ratios vs controls, but the elevation reached significance (p<0.05) only in the larger chronic HYPO group. CONCLUSIONS: Left ventricular diastolic dysfunction is largely similar in acutely or chronically hypothyroid patients off T4 vs healthy controls or the same patients on T4. PMID- 21597314 TI - Deletion of thyrotropin receptor residue Asp403 in a hyperfunctioning thyroid nodule provides insight into the role of the ectodomain in ligand-induced receptor activation. AB - Somatic mutations of the TSH receptor (TSHR) gene are the main cause of autonomously functioning thyroid nodules. Except for mutations in ectodomain residue S281, all of the numerous reported activating mutations are in the TSHR membrane-spanning region. Here, we describe a patient with a toxic adenoma with a novel heterozygous somatic mutation caused by deletion of ectodomain residue Asp403 (Del-D403). Subsequent in vitro functional studies of the Del-D403 TSHR mutation demonstrated greatly increased ligand-independent constitutive activity, 8-fold above that of the wild-type TSHR. TSH stimulation had little further effect, indicating that the mutation produced near maximal activation of the receptor. In summary, we report only the second TSHR ectodomain activating mutation (and the first ectodomain deletion mutation) responsible for development of a thyroid toxic adenoma. Because Del-D403 causes near maximal activation, our finding provides novel insight into TSHR structure and function; residue D403 is more likely to be involved in the ligand-mediated activating pathway than in the ectodomain inverse agonist property. PMID- 21597315 TI - Differential expression of estrogen receptor alpha and beta transcripts in tissues and in primary culture cells from pubertal gynecomastia. AB - BACKGROUND: Pubertal gynecomastia is a common problem occurring in up to 65% of adolescent boys. Gynecomastia comes at a time when self-image awareness is at its greatest and psychologically could be a psychologically disabling condition. Surgery is considered the mainstay of treatment for severe or persistent cases. A medical management aimed at altering the effective androgen/estrogen ratio has been suggested with inconstant results. Some promising results have been obtained by using anti-estrogens. Surprisingly there are no data on the estrogen receptor (ER) alpha and beta RNA expression in gynecomastia. AIM: We studied ER RNA subtypes in pubertal gynecomastia. METHODS: ERalpha and beta RNA were determined by real time RT-PCR in 50 mammary samples from pubertal boys with idiopathic gynecomastia subjected to reductive mammoplasty. To study ERalpha and beta pattern of expression, epithelial and stromal primary cell cultures were set up from fresh tissues. RESULTS: These analyses indicated that in all stromal cells ERbeta was expressed at higher level than ERalpha and in epithelial cells both ERalpha and ERbeta were barely detectable. CONCLUSIONS: Our data suggest that also stromal cells are involved in the pathophysiology of pubertal gynecomastia. The high level of expression of ERbeta seen in pubertal gynecomastia adds new insight on validation of ERbeta as a target for candidate diseases and exploration of ERbeta as a marker for clinical decision-making and treatment in pubertal gynecomastia. This could drive to search for new and selective anti estrogen drugs for medical treatment of pubertal gynecomastia with a particular attention to the ERbeta-selective ligand. PMID- 21597316 TI - Androgens and estrogens prevent rosiglitazone-induced adipogenesis in human mesenchymal stem cells. AB - Thiazolidinediones (TZD), a class of anti-diabetic drugs, determine bone loss and increase fractures particularly in post-menopausal women, thus suggesting a protective role of sex steroids. We have previously demonstrated that the TZD rosiglitazone (RGZ) negatively affects bone mass by inhibiting osteoblastogenesis, yet inducing adipogenesis, in bone marrow-derived human mesenchymal stem cells (hMSC). The aim of this study was to determine whether estrogens and androgens are able to revert the effects of RGZ on bone. hMSC express estrogen receptor alpha and beta and the androgen receptor. We found that 17beta-estradiol (10 nM), the phytoestrogen genistein (10 nM), testosterone (10 nM) and the non-aromatizable androgens dihydrotestosterone (10 nM) and methyltrienolone (10 nM) effectively counteracted the adipogenic effect of RGZ (1 MUM) in hMSC induced to differentiate into adipocytes, as determined by evaluating the expression of the adipogenic marker peroxisome proliferator activated receptor gamma and the percentage of fat cells. Furthermore, when hMSC were induced to differentiate into osteoblasts, all the above-mentioned molecules and also quercetin, another phytoestrogen, significantly reverted the inhibitory effect of RGZ on the expression of the osteogenic marker osteocalcin and decreased the number of fat cells observed after RGZ exposure. Our study represents, to our knowledge, the first demonstration in hMSC that androgens, independently of their aromatization, and estrogens are able to counteract the negative effects of RGZ on bone. Our data, yet preliminary, suggest the possibility to try to prevent the negative effects of TZD on bone, using steroid receptor modulators, such as plant-derived phytoestrogens, which lack evident adverse effects. PMID- 21597317 TI - The role of programmed cell death in streptozotocin-induced early diabetic nephropathy. AB - The mechanism of autophagy in diabetic nephropathy (DN) is still unclear. The study was performed on streptozotocin (STZ) rats to investigate whether programmed cell death contribute to the pathogenesis and progression of DN. STZ rats were induced by an single intravenous injection of STZ dissolved in citrate buffer, early DN (E-DN) for STZ rats was defined as the stage from modeling to the end of the 8th week according to previous studies. A total of 36 male Sprague Dawley rats were randomly divided into two groups: an E-DN group and a control group. After the 1st, 4th, and 8th week, the rats were sacrificed. Beclin1 and microtubule associated protein 1 light chain 3 (LC3) were examined, apoptosis level in renal tissue was detected by Tunnel assay detected as the apoptotic index. An electron microscopic examination of kidney tissues was performed at end of the 4th and 8th week. Compared with the control group, Beclin1 expression increased since the 1st week after modeling in STZ rats kidney and peaked at the end of the 8th week in western blotting and immunohistochemical stain. Meanwhile the level of LC3-II in DN group was significantly lower from the end of the 1st to the 8th week. A small amount of autophagosomes were observed in both E-DN group and control group under electron microscopic examination, and there was no significant difference between the groups. These findings indicate that an abnormality on autophagy may play an important role in the pathogenesis of E-DN. PMID- 21597319 TI - GABARAPL1 (GEC1): original or copycat? AB - The GABARAPL1 (GABARAP-LIKE 1) gene was first described as an early estrogen regulated gene that shares a high sequence homology with GABARAP and is thus a part of the GABARAP family. GABARAPL1, like GABARAP, interacts with the GABAA receptor and tubulin and promotes tubulin polymerization. The GABARAP family members (GABARAP, GABARAPL1 and GABARAPL2) and their close homologs (LC3 and Atg8) are not only involved in the transport of proteins or vesicles but are also implicated in various mechanisms such as autophagy, cell death, cell proliferation and tumor progression. However, despite these similarities, GABARAPL1 displays a complex regulation that is different from that of other GABARAP family members. Moreover, it presents a regulated tissue expression and is the most highly expressed gene among the family in the central nervous system. In this review article, we will outline the specific functions of this protein and also hypothesize about the roles that GABARAPL1 might have in several important biological processes such as cancer or neurodegenerative diseases. PMID- 21597318 TI - Mammalian prions: tracking the infectious entities. AB - Protein misfolding is central to the pathogenesis of several neurodegenerative disorders. Among these disorders, prion diseases are unique because they are transmissible. The conversion of the host-encoded GPI-anchored PrP protein into a structurally altered form is crucially associated with the infectious and neurotoxic properties of the resulting abnormal PrP. Many lines of evidence indicate that distinct aggregated forms with different size and protease resistance are produced during prion multiplication. The recent isolation of various subsets of abnormal PrP, along with the improved biochemical tools and infectivity detection assays have shed light on the diversity of abnormal PrP protein and may give insights into the features of the more infectious subsets of abnormal PrP. PMID- 21597320 TI - A possible role of Atg8 homologs as a scaffold for signal transduction. AB - Atg8 and its homologs are essential for autophagosome formation in various species. In animal cells, Atg8 homologs have an additional function in clearance of damaged organelles and bacteria, acting as a landmark for selective autophagy. We have recently shown that OATL1, a Rab-GTPase-activating protein (Rab-GAP), is a novel binding partner of Atg8 homologs in mammalian cells, but to our surprise, it is not a substrate of autophagy. Further analysis indicates that OATL1 is involved in the fusion between autophagosomes and lysosomes through its GAP activity and its Atg8 homolog binding activity. Our findings suggest a novel function of Atg8 homologs as a scaffold for signal transduction that regulates autophagosomal maturation. PMID- 21597321 TI - Coping with a stressful host. PMID- 21597322 TI - The complex roles of histone demethylases in vivo. PMID- 21597323 TI - Cellular studies reveal mechanistic differences between taccalonolide A and paclitaxel. AB - Taccalonolide A is a microtubule stabilizer that has cellular effects almost identical to paclitaxel. However, biochemical studies show that, unlike paclitaxel, taccalonolide A does not enhance purified tubulin polymerization or bind tubulin/microtubules. Mechanistic studies aimed at understanding the nature of the differences between taccalonolide A and paclitaxel were conducted. Our results show that taccalonolide A causes bundling of interphase microtubules at concentrations that cause antiproliferative effects. In contrast, the concentration of paclitaxel that initiates microtubule bundling is 31-fold higher than its IC 50. Taccalonolide A's effects are further differentiated from paclitaxel in that it is unable to enhance the polymerization of tubulin in cellular extracts. This finding extends previous biochemical results with purified brain tubulin to demonstrate that taccalonolide A requires more than tubulin and a full complement of cytosolic proteins to cause microtubule stabilization. Reversibility studies were conducted and show that the cellular effects of taccalonolide A persist after drug washout. In contrast, other microtubule stabilizers, including paclitaxel and laulimalide, demonstrate a much higher degree of cellular reversibility in both short-term proliferation and long term clonogenic assays. The propensity of taccalonolide A to alter interphase microtubules at antiproliferative concentrations as well as its high degree of cellular persistence may explain why taccalonolide A is more potent in vivo than would be expected from cellular studies. The close linkage between the microtubule bundling and antiproliferative effects of taccalonolide A is of interest given the recent hypothesis that the effects of microtubule targeting agents on interphase microtubules might play a prominent role in their clinical anticancer efficacy. PMID- 21597324 TI - MiRNA-27a controls FBW7/hCDC4-dependent cyclin E degradation and cell cycle progression. AB - The F-box protein FBW7/hCDC4 is a tumor suppressor that acts as the substrate recognition component of an SCF ubiquitin ligase that targets numerous oncoproteins for proteasomal degradation. In this study, we investigated whether FBW7 is regulated by microRNAs, using a screen combining bioinformatic analysis, luciferase reporters and microRNA libraries. The ubiquitous miR-27a was identified as a major suppressor of FBW7 and in line with this, miR-27a prohibited ubiquitylation and turnover of the key FBW7 substrate cyclin E. Notably, we found that miR-27a only suppresses FBW7 during specific cell cycle phases, relieving its negative impact at the G1 to S-phase transition, prior to cyclin E protein degradation. We also demonstrate that attenuation of FBW7 by miR 27a overexpression leads to improper cell cycle progression and DNA replication stress, consistent with dysregulation of cyclin E expression. Finally, in the context of human cancer, miR-27a was discovered to be generally overexpressed in pediatric B-ALL and its expression to be inversely correlated with that of FBW7 in hyperdiploid cases of B-ALL. These data provide evidence for microRNA-mediated regulation of FBW7, and highlight the role of miR-27a as a novel factor fine tuning the periodic events regulating cell cycle progression. PMID- 21597326 TI - Starch-related carbon fluxes in roots and leaves of Arabidopsis thaliana. AB - Both photoautotrophic and heterotrophic tissues from plants are capable of synthesizing and degrading starch. To analyse starch metabolism in the two types of tissue from the same plant, several starch-related mutants from Arabidopsis thaliana were grown hydroponically together with the respective wild type control. Starch contents, patterns of starch-related enzymes, and the monomer patterns of the cytosolic starch-related heteroglycans were determined. Based on the phenotypical data obtained, three comparisons were made: First, data from leaves and roots of the mutants were compared with the respective wild type controls. Secondly, data from leaves and roots from the same plant were compared. Third, we included data obtained from soil-grown plants and compared them with those from hydroponically grown plants. Thus, phenotypical features reflecting altered gene expression can be distinguished from those that are due to the specific growth conditions. Implications on the carbon fluxes in photoautotrophic and heterotrophic cells are discussed. PMID- 21597325 TI - Urinary tract infection drives genome instability in uropathogenic Escherichia coli and necessitates translesion synthesis DNA polymerase IV for virulence. AB - Uropathogenic Escherichia coli (UPEC) produces ~80% of community-acquired UTI, the second most common infection in humans. During UTI, UPEC has a complex life cycle, replicating and persisting in intracellular and extracellular niches. Host and environmental stresses may affect the integrity of the UPEC genome and threaten its viability. We determined how the host inflammatory response during UTI drives UPEC genome instability and evaluated the role of multiple factors of genome replication and repair for their roles in the maintenance of genome integrity and thus virulence during UTI. The urinary tract environment enhanced the mutation frequency of UPEC ~100-fold relative to in vitro levels. Abrogation of inflammation through a host TLR4-signaling defect significantly reduced the mutation frequency, demonstrating in the importance of the host response as a driver of UPEC genome instability. Inflammation induces the bacterial SOS response, leading to the hypothesis that the UPEC SOS-inducible translesion synthesis (TLS) DNA polymerases would be key factors in UPEC genome instability during UTI. However, while the TLS DNA polymerases enhanced in vitro, they did not increase in vivo mutagenesis. Although it is not a source of enhanced mutagenesis in vivo, the TLS DNA polymerase IV was critical for the survival of UPEC during UTI during an active inflammatory assault. Overall, this study provides the first evidence of a TLS DNA polymerase being critical for UPEC survival during urinary tract infection and points to independent mechanisms for genome instability and the maintenance of genome replication of UPEC under host inflammatory stress. PMID- 21597327 TI - Molecular functions of the PP2A regulatory subunit Tap46 in plants. AB - Tap42/alpha4 is a regulatory subunit of the protein phosphatase 2A (PP2A) family of phosphatases and plays a role in the target of rapamycin (TOR) pathway that regulates cell growth, ribosome biogenesis, translation and cell cycle progression in both yeast and mammals. We determined the cellular functions of Tap46, the plant homolog of Tap42/alpha4, in both Arabidopsis thaliana and Nicotiana benthamiana. Tap46 associated with the catalytic subunits of PP2A and the PP2A-like phosphatases PP4 and PP6 in vivo. Tap46 was phosphorylated by TOR in vitro, indicating that Tap46 is a direct substrate of TOR kinase. Tap46 deficiency caused cellular phenotypes that are similar to TOR-depletion phenotypes, including repression of global translation and activation of both autophagy and nitrogen recycling. Furthermore, Tap46 depletion regulated total PP2A activity in a time-dependent manner similar to TOR deficiency. These results suggest that Tap46 acts as a positive effector of the TOR signaling pathway in controlling diverse metabolic processes in plants. However, Tap46 silencing caused acute cell death, while TOR silencing only hastened senescence. Furthermore, mitotic cells with reduced Tap46 levels exhibited chromatin bridges at anaphase, while TOR depletion did not cause a similar defect. These findings suggest that Tap46 may have TOR-independent functions as well as functions related to TOR signaling in plants. PMID- 21597328 TI - Cohesin complexes get more complex: the novel kleisin RAD21L. PMID- 21597329 TI - Rae1: a new clue for nucleoporin leukemias. PMID- 21597330 TI - Vitamin K does not prevent soft tissue mineralization in a mouse model of pseudoxanthoma elasticum. AB - Pseudoxanthoma elasticum (PXE) is a heritable disease characterized by calcified elastic fibers in cutaneous, ocular, and vascular tissues. PXE is caused by mutations in ABCC6, which encodes a protein of the ATP-driven organic anion transporter family. The inability of this transporter to secrete its substrate into the circulation is the likely cause of PXE. Vitamin K plays a role in the regulation of mineralization processes as a co-factor in the carboxylation of calcification inhibitors such as Matrix Gla Protein (MGP). Vitamin K precursor or a conjugated form has been proposed as potential substrate(s) for ABCC6. We investigated whether an enriched diet of vitamin K1 or vitamin K2 (MK4) could stop or slow the disease progression in Abcc6 (-/-) mice. Abcc6 (-/-) mice were placed on a diet of either vitamin K1 or MK4 at 5 or 100 mg/kg at prenatal, 3 weeks or 3 months of age. Disease progression was quantified by measuring the calcium content of one side of the mouse muzzle skin and histological staining for calcium of the opposing side. Raising the vitamin K1 or MK4 content of the diet increased the concentration of circulating MK4 in the serum. However, this increase did not significantly affect the MGP carboxylation status or reduce its abnormal abundance, the total calcium content or the pathologic calcification in the whiskers of the 3 treatment groups compared to controls. Our findings showed that raising the dietary intake of vitamin K1 or MK4 was not beneficial in the treatment of PXE and suggested that the availability of vitamin K may not be a limiting factor in this pathology. PMID- 21597331 TI - p53: Guardian of pancreatic epithelial identity. PMID- 21597333 TI - Remote control of mRNA cleavage by a small RNA. PMID- 21597332 TI - The insulin receptor substrate (IRS) proteins: at the intersection of metabolism and cancer. AB - Increasing evidence supports a connection between cancer and metabolism and emphasizes the need to understand how tumors respond to the metabolic microenvironment and how tumor cell metabolism is regulated. The insulin receptor (IR) and its close family member the insulin-like growth factor-1 receptor (IGF 1R) mediate the cellular response to insulin in normal cells and their function is tightly regulated to maintain metabolic homeostasis. These receptors are also expressed on tumor cells and their expression correlates with tumor progression and poor prognosis. Understanding how the IR/IGF-1R pathway functions in tumors is increasing in importance as the efficacy of drugs that target metabolic pathways, such as metformin, are investigated in prospective clinical trials. This review will focus on key signaling intermediates of the IR and IGF-1R, the Insulin Receptor Substrate (IRS) proteins, with an emphasis on IRS-2, and discuss how these adaptor proteins play a pivotal role at the intersection of metabolism and cancer. PMID- 21597334 TI - Characterization of Syrian hamster adapted prions derived from L-type and C-type bovine spongiform encephalopathies. AB - Atypical forms of bovine spongiform encephalopathy (BSE) may be caused by different prions from classical BSE (C-BSE). In this study, we examined the susceptibility of mice overexpressing mouse and hamster chimeric prion protein (PrP) to L-type atypical BSE (L-BSE). None of the transgenic mice showed susceptibility to L-BSE, except mice overexpressing hamster PrP. We also examined the transmission properties of L-BSE in hamsters. The incubation period of hamsters intracerebrally inoculated with L-BSE was 576.8 days, and that of the subsequent passage was decreased to 208 days. Although the lesion and glycoform profiles and relative proteinase K resistant core fragment of the abnormal isoform of PrP (PrPcore) of L-BSE were similar to that of C-BSE, the deposition of the abnormal isoform of PrP (PrPSc) and the molecular weight of PrPcore of L BSE was different from than that of C-BSE. In hamster models, some prion strain characteristics of L-BSE were indistinguishable from those of C-BSE. PMID- 21597335 TI - A Chinese Creutzfeldt-Jakob disease patient with E196K mutation in PRNP. AB - Genetic Creutzfeldt-Jakob disease (gCJD) is caused by a range of mutations in the prion protein gene (PRNP) and account for approximately 10-15% of overall human prion diseases worldwide. They are different with disease onset, disease duration, clinical signs and diagnostic findings. Here we reported a 71 year-old female with an E196K mutation in one PRNP allele, while the codon 129 was a methionine homozygous genotype. The patient started with non-specific symptoms, but displayed rapidly progressive disturbances of speech, memory, cognitive and physical movement. No periodic activity was recorded at electroencephalography (EEG) during the entire disease course. Retrospective investigation of her family members did not reveal similar neurological disorders. Total clinical course was about seven months. PMID- 21597337 TI - Maternal dietary protein affects transcriptional regulation of myostatin gene distinctively at weaning and finishing stages in skeletal muscle of Meishan pigs. AB - Myostatin (MSTN) is suggested to mediate the effect of maternal nutrition on offspring phenotype, yet the mechanisms underlying such adaptive gene regulation is elusive. In this study, we determined the effects of maternal dietary protein on transcriptional regulation of MSTN in skeletal muscle of pig offspring. Fourteen Meishan sows were fed either low-protein (LP) or standard-protein (SP) diets throughout gestation and lactation. MSTN expression in the longissimus dorsi muscle was determined both at weaning and finishing stages. Myostatin mRNA abundance was downregulated at weaning, but upregulated at finishing in LP pigs, indicating stage-specific transcriptional regulation. At weaning, CCAAT/enhancer binding protein beta (C/EBPbeta) in muscle nuclear lysate was decreased in LP piglets, associated with diminished binding of C/EBPbeta to all the 3 putative binding sites in MSTN promoter. None of the four histone modification marks investigated showed differences between SP and LP piglets. Among 12 microRNAs predicted to target MSTN, none was differently expressed. At finishing stage, C/EBPbeta content remained unchanged, but the binding of C/EBPbeta to two of the 3 putative binding sites increased in LP pigs. Histone H3 acetylation and histone H3 lysine 27 trimethylation on MSTN promoter were increased, while histone H3 lysine 9 monomethylation was decreased in LP pigs. Moreover, expression of ssc miR-136 and ssc-miR-500 was significantly reduced. These results indicate that maternal dietary protein affects MSTN expression through distinct regulatory mechanisms at different stages. The immediate effect at weaning is mediated by C/EBPbeta binding without epigenetic modifications, whereas the long-term effect at finishing stage involves both C/EBPbeta binding and epigenetic regulations, including histone modification and microRNA expression. PMID- 21597339 TI - Envision...energize...engage! PMID- 21597336 TI - Tracking protein aggregate interactions. AB - Amyloid fibrils share a structural motif consisting of highly ordered beta-sheets aligned perpendicular to the fibril axis ( 1, 2) . At each fibril end, beta sheets provide a template for recruiting and converting monomers ( 3) . Various amyloid fibrils often occur in the same individual, yet whether distinct protein aggregates aid or inhibit the assembly of heterologous proteins is unclear. In prion disease, different amyloid-like prion aggregate structures, or strains, are thought to be the basis of disparate disease phenotypes in the same species expressing identical prion protein sequences ( 4-7) . Here we focus on the interactions reported to occur when two pre-existing amyloids or two distinct prion strains occur together in the central nervous system. PMID- 21597338 TI - Biological memories of past environments: epigenetic pathways to health disparities. AB - Human health tends to mirror gradients in social standing related to class, ethnicity and race. Past research in the social sciences suggests that environmental experiences related to social status contribute to these disparities, but the underlying biological mechanisms are only partially understood. Here, we review research related to three domains of environmental exposure that point to epigenetic contributions to health disparities: nutrition, psychosocial stress, and environmental toxicant exposure. Each exposure has effects that may persist across the life course and in some instances may be transmitted to offspring via epigenetic inheritance. Since epigenetic markings provide a "memory" of past experiences, minimizing future disparities in health will be partially contingent upon our ability to address inequality in the current environment. We suggest that future research in environmental epigenetics focus on establishing the reversibility of stress-induced epigenetic modifications, and also on identifying positive epigenetic effects of environmental enrichment. PMID- 21597340 TI - Changing nursing to change America's health. PMID- 21597341 TI - Lower extremity orthoses in children with spastic quadriplegic cerebral palsy: implications for nurses, parents, and caregivers. AB - Understanding trends in the prevalence of children with cerebral palsy is vital to evaluating and estimating supportive services for children, families, and caregivers. The majority of children with cerebral palsy require lower extremity orthoses to stabilize their muscles. The pediatric nurse needs a special body of knowledge to accurately assess, apply, manage, teach, and evaluate the use of lower extremity orthoses typically prescribed for this vulnerable population. Inherent in caring for these children is the need to teach the child, the family, and significant others the proper application and care of the orthoses used in hospital and community settings. Nursing literature review does not provide a basis for evidence in designing and teaching orthopaedic care for children with orthoses. A protocol for orthoses management has been developed to assist caregivers to accurately care for children with lower extremity orthotic devices. PMID- 21597343 TI - The silent thief: diagnosis and management of osteoporosis. AB - Osteoporosis causes approximately 1.5 million fractures every year in the United States. Not only can these fractures be painful and disfiguring but they may reduce a person's ability to lead an active life as well. Osteoporosis affects every bone in the body, but the most common places where fractures occur are the back, hips, and wrists. Because osteoporosis thins bones, weakening them and making them more susceptible to fractures, practitioners must understand the risk factors and the diagnosis and management of this very common problem. This article, geared toward advanced practice nurses, presents a summary of the latest diagnostic tests and medication treatments available and approved by the Food and Drug Administration for the management of osteoporosis. PMID- 21597345 TI - Improving follow-up after fragility fractures: an evidence-based initiative. AB - BACKGROUND: Patients with fragility fractures are at risk for recurrent fractures and are at risk for inadequate follow up. Prevention of future fractures through appropriate follow-up can decrease annual healthcare expenditures and patient morbidity and mortality. PURPOSE: The purpose of this quality improvement project was to delineate an evidence-based practice initiative at a university health center to improve patient follow-up care after fragility fractures. METHODS: A review of the literature revealed significant evidence calling for notification of the patients' primary care provider, ordering a bone density scan within 3 months, and a referral to osteoporosis. A plan for improving patient outcomes was developed utilizing the iowa Model of Evidence-Based Practice to Promote Quality Care. The evidence-based initiative was implemented, and the outcomes were assessed. OUTCOME: The results were that 100% of patients received adequate follow-up after fragility fractures. PMID- 21597347 TI - Venous thromboembolism after fibula fracture: a patient's perspective. AB - Venous Thromboembolism (VTE) is a significant healthcare issue in the United States. This article presents information on the scope of the problem of VTE through a case study demonstrating the physical and psychosocial experiences of a 24-year-old woman with a fibula fracture treated in a short leg cast who developed a deep vein thrombosis that went on to become a pulmonary embolism. The patient experience is evaluated and supported by literature review in terms of risk factors as well as diagnostic, prophylaxis, medical treatment, and nursing implications. Analysis of a patient experience with VTE is valuable to add to the nursing body of knowledge for improvement of evidence-based practice. PMID- 21597349 TI - Category I pressure ulcers: how reliable is clinical assessment? AB - INTRODUCTION: Pressure ulcer prevention is an indicator of quality of care. Reliable identification of Category I pressure ulcers is essential in prevalence studies and to prevent further tissue damage. PURPOSE: The primary purpose of this study was to establish interrater reliability between blanching and nonblanching erythema assessed by 2 independent assessors. The secondary purpose was to investigate potential correlations between risk factors and pressure ulcers. METHOD: Ninety-seven patients 65 years or older with hip fractures were consecutively recruited for this prospective, comparative observation study. Seventy-eight patients completed the study. The sacral area of each patient was visually assessed and a finger-press test was administered to each patient by 2 independent assessors. Kappa statistics were used for analysis. FINDINGS: finger press tests and visual observation alone were not reliable methods to discriminate between blanching and nonblanching erythema. Forty-seven percent of the patients had a risk score 20 or fewer (high risk for pressure ulcers). Forty four patients (56%) had pressure ulcers at discharge. PMID- 21597351 TI - Hope floats: an orthopaedic tip sheet for float pool nurses. AB - A common method to address staffing shortages is the use of float nurses. This short-term resolution is not without its issues. When float nurses are unfamiliar with the assigned patient population or when there is little time for unit orientation, unnecessary anxiety and undue stress can affect the staff, healthcare providers, and, most importantly, the patients. Developing creative and informative tools to guide the float nurse during their shift can be beneficial to all involved. PMID- 21597352 TI - Lisfranc fracture-dislocation. PMID- 21597357 TI - Subcutaneous nodule on the left hand: challenge. PMID- 21597358 TI - Dysthymia and depression increase risk of dementia and mortality among older veterans. AB - OBJECTIVE: To determine whether less severe depression spectrum diagnoses such as dysthymia, as well as depression, are associated with risk of developing dementia and mortality in a "real-world" setting. DESIGN: Retrospective cohort study conducted using the Department of Veterans Affairs (VA) National Patient Care Database (1997-2007). SETTING: VA medical centers in the United States. PARTICIPANTS: A total of 281,540 veterans aged 55 years and older without dementia at study baseline (1997-2000). MEASUREMENTS: Depression status and incident dementia were ascertained from International Classification of Diseases, Ninth Revision codes during study baseline (1997-2000) and follow-up (2001-2007), respectively. Mortality was ascertained by time of death dates in the VA Vital Status File. RESULTS: Ten percent of veterans had baseline diagnosis of depression and nearly 1% had dysthymia. The unadjusted incidence of dementia was 11.2% in veterans with depression, 10.2% with dysthymia and 6.4% with neither. After adjusting for demographics and comorbidities, patients diagnosed with dysthymia or depression were twice as likely to develop incident dementia compared with those with no dysthymia/depression (adjusted dysthymia hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.71-2.25; and depression HR: 2.18, 95% CI: 2.08-2.28). Dysthymia and depression also were associated with increased risk of death (31.6% dysthymia and 32.9% depression versus 28.5% neither; adjusted dysthymia HR: 1.41, 95% CI: 1.31-1.53; and depression HR: 1.47, 95% CI: 1.43 1.51). CONCLUSIONS: Findings suggest that older adults with dysthymia or depression need to be monitored closely for adverse outcomes. Future studies should determine whether treatment of depression spectrum disorders may reduce risk of these outcomes. PMID- 21597359 TI - Preoperative ultrasound-guided needle biopsy of axillary nodes in invasive breast cancer: meta-analysis of its accuracy and utility in staging the axilla. AB - OBJECTIVE: Systematic evidence synthesis of ultrasound-guided needle biopsy (UNB) of axillary nodes in breast cancer. SUMMARY BACKGROUND DATA: Women affected by invasive breast cancer undergo initial staging with sentinel node biopsy, generally progressing to axillary node dissection (AND) if metastases are found. Preoperative UNB can potentially identify and triage women with node metastases directly to AND. METHODS: Review and meta-analysis of studies reporting UNB accuracy: we estimated sensitivity, specificity, and PPV, using bivariate random effects models and examined the effect of covariates; we calculated UNB utility (effect on axillary surgery). RESULTS: Thirty-one studies provided 2874 UNB data from 6166 subjects (median proportion with metastatic nodes 47.2%; IQR 39.5%, 61.2%). Modeled estimates for UNB were: sensitivity 79.6% (95% confidence intervals [CI] 74.1-84.2), specificity 98.3% (95%CI 97.2-99.0), PPV 97.1% (95%CI 95.2-98.3); median UNB insufficiency was 4.1% (IQR0%-10.9%). UNB sensitivity increased with increasing ultrasound sensitivity, and was higher in studies performing UNB for "suspicious" than for "visible" nodes. Specificity was higher in studies of consecutive (vs. selected) subjects, in studies reporting ultrasound data, and in more recent studies. Median proportion of women triaged directly to AND (attributed to UNB) was 19.8% (IQR11.6%-28.1%) or 17.7% (IQR11.6% 27.1%) if restricted to clinically node-negative series. Median proportion of women with metastatic axillary nodes potentially triaged to AND was 55.2% (IQR41.8%-68.2%) and was higher (65.6%; IQR48.9%-69.7%) in the subgroup of studies with median tumor size >=21 mm. CONCLUSIONS: Preoperative UNB of the axilla is accurate for initial staging of women with invasive breast cancer. Meta analysis indicates that UNB provides better utility in women with average or higher underlying risk of node metastases. PMID- 21597360 TI - Laparoscopy in combination with fast track multimodal management is the best perioperative strategy in patients undergoing colonic surgery: a randomized clinical trial (LAFA-study). AB - OBJECTIVE: To investigate which perioperative treatment, ie, laparoscopic or open surgery combined with fast track (FT) or standard care, is the optimal approach for patients undergoing segmental resection for colon cancer. SUMMARY BACKGROUND DATA: Important developments in elective colorectal surgery are the introduction of laparoscopy and implementation of FT care, both focusing on faster recovery. METHODS: In a 9-center trial, patients eligible for segmental colectomy were randomized to laparoscopic or open colectomy, and to FT or standard care, resulting in 4 treatment groups. Primary outcome was total postoperative hospital stay (THS). Secondary outcomes were postoperative hospital stay (PHS), morbidity, reoperation rate, readmission rate, in-hospital mortality, quality of life at 2 and 4 weeks, patient satisfaction and in-hospital costs. Four hundred patients were required to find a minimum difference of 1 day in hospital stay. RESULTS: Median THS in the laparoscopic/FT group was 5 (interquar-tile range: 4-8) days; open/FT 7 (5-11) days; laparoscopic/standard 6 (4.5-9.5) days, and open/standard 7 (6-13) days (P < 0.001). Median PHS in the laparoscopic/FT group was 5 (4-7) days; open/FT 6 (4.5-10) days; laparoscopic/standard 6 (4-8.5) days and open/standard 7 (6-10.5) days (P < 0.001). Secondary outcomes did not differ significantly among the groups. Regression analysis showed that laparoscopy was the only independent predictive factor to reduce hospital stay and morbidity. CONCLUSIONS: Optimal perioperative treatment for patients requiring segmental colectomy for colon cancer is laparoscopic resection embedded in a FT program. If open surgery is applied, it is preferentially done in FT care. This study was registered under NTR222 (www.trialregister.nl). PMID- 21597362 TI - Activation of metabotropic glutamate receptor 7 in spinal cord inhibits pain and hyperalgesia in a novel formalin model in sheep. AB - This study set out to characterize the contribution of group III metabotropic glutamate receptor 7 activation to nociceptive behaviour and mechanical hypersensitivity in a novel formalin test in sheep. The mGlu receptor 7 allosteric agonist, N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082; 2-20 mM), the nonselective group III mGlu receptor agonist L-(+)-2-amino-4 phosphonobutyric acid (0.2-20 mM) and drug vehicle were injected intrathecally into naive subjects (n=7 per group), or 5 min preformalin (3%; 0.2 ml)/saline injection (intradermal), into the lower forelimb of adult female sheep (n=5-7 per group). Forelimb withdrawal thresholds to noxious mechanical stimulation and pain behaviours (time spent nonweight bearing or flinching) were assessed for up to 180 min. Formalin induced a characteristic biphasic pain-behaviour response and mechanical hyperalgesia between 1-5 and 30-120 min postinjection. Treatment with AMN082, but not L-(+)-2-amino-4-phosphonobutyric acid significantly inhibited both early and late phase formalin-induced hyperalgesia and pain behaviours. AMN082 also induced a rapid but short lasting analgesia in naive subjects. These data suggest that enhancing endogenous metabotropic glutamate receptor 7 activity in spinal cord, using the novel allosteric modulator, AMN082, blocks pain and hyperalgesia, and may be of therapeutic benefit for the treatment of inflammatory pain. PMID- 21597363 TI - A comparison of economic demand and conditioned-cued reinstatement of methamphetamine-seeking or food-seeking in rats. AB - This study examined whether continued access to methamphetamine or food reinforcement changed economic demand for both. The relationship between demand elasticity and cue-induced reinstatement was also determined. Male Long-Evans rats were lever pressed under increasing fixed-ratio requirements for either food pellets or methamphetamine (20 MUg/50 MUl infusion). For two groups, demand curves were obtained before and after continued access (12 days, 2-h sessions) to the reinforcer under a fixed-ratio 3 schedule. A third group was given continued access to methamphetamine between determinations of food demand and a fourth group abstained from methamphetamine between determinations. All groups underwent extinction sessions, followed by a cue-induced reinstatement test. Although food demand was less elastic than methamphetamine demand, continued access to methamphetamine shifted the methamphetamine demand curve upward and the food demand curve downward. In some rats, methamphetamine demand also became less elastic. Continued access to food had no effect on food demand. Reinstatement was higher after continued access to methamphetamine relative to food. For methamphetamine, elasticity and reinstatement measures were correlated. Continued access to methamphetamine, but not food, alters demand in ways suggestive of methamphetamine accruing reinforcing strength. Demand elasticity thus provides a useful measure of abuse liability that may predict future relapse to renewed drug seeking and drug use. PMID- 21597364 TI - The role of PTPN22 gene polymorphism in childhood immune thrombocytopenic purpura. AB - Immune thrombocytopenia is an autoimmune disorder characterized by antibody mediated platelet destruction. A protein tyrosine phosphatase (PTPN22) present in lymphocytes is an important negative regulator of signal transduction for the T cell receptor-MHC complex and has been associated with autoimmune disorders that produce autoantibodies. The present study investigated the frequency of the 1858C>T single-nucleotide polymorphism (SNP) in the PTPN22 gene in idiopathic thrombocytopenic purpura (ITP) patients. This case series study included 50 children with ITP, 24 acute and 26 chronic cases, and 50 normal children as a control group. All were subjected to clinical history and laboratory investigations including complete blood count, genotyping of PTPN22 1858C/T SNP by polymerase chain reaction-restriction fragment length polymorphism and platelet antibodies using platelets suspension immunofluorescence test for the cases. Thirteen patients (26%) were positive for the PTPN22 1858C>T SNP. Three patients were homozygous for the mutation and 10 were heterozygous. Comparison of the 26% of the ITP patients who were positive for the PTPN22 1858C>T mutation with the 6% positive in the control group yielded a P value of 0.006. Antiplatelet antibodies were detected in five patients (20.8%) with acute ITP and in three patients (11.5%) with chronic ITP; no significant association between the presence of PTPN22 1858C>T mutation and the presence of antiplatelet antibodies was detected. The prevalence of PTPN22 gene mutation was higher in ITP patients, thus it may be considered as a genetic risk factor in the development of ITP in Egyptian children. PMID- 21597365 TI - The role of tissue factor in systemic inflammatory response syndrome. AB - Tissue factor (TF) is a major initiator of extrinsic pathway of blood coagulation. A dual role of TF in the extensive crosstalk between blood coagulation and inflammation has recently become apparent. The majority of the cases of systemic inflammatory response syndrome, disseminated intravascular coagulation, and sepsis are accompanied by hyperactivation of TF in circulating monocytes and damaged tissue. Systemic Gram-negative infection induces expression of TF by vascular cells. In addition to extrinsic coagulation pathway, TF induces proinflammatory signaling cascade originating from activation of protease activated receptors. Because TF-activated proteolytic cascade is placed in a nexus between coagulation and inflammation, early modulation of TF activity presently becomes a tempting experimental therapeutic strategy in systemic inflammatory response syndrome patients. PMID- 21597366 TI - Sex difference in long-term clinical outcome after sirolimus-eluting stent implantation. AB - BACKGROUND: Coronary stenting in women has been associated with worse results in terms of morbidity, mortality, and restenosis rate in the bare-metal stent era, possibly due to higher risk profile and smaller coronary vessels. Although drug eluting stents have equalized clinical results, no data are available on long term outcomes between sexes. OBJECTIVES: To evaluate the role of sex in acute, mid-term, and long-term clinical outcome after sirolimus-eluting stent (SES) implantation. METHODS: We retrospectively evaluated 1186 patients, 970 (81.8%) male and 216 (18.2%) female, treated with SES implantation between April 2002 and December 2005. RESULTS: Women were older (P=0.049), more likely to have hypertension (43.5 vs. 33.7%, P=0.006), single-vessel disease (63.9 vs. 42.5%, P=0.03), and unstable angina (16.6% vs. 9.2%, P=0.001) and more frequently received small (<= 2.75 mm) vessel stenting (39.3 vs. 28.2%, P=0.001). The two groups were similar for lesion and procedural characteristics. Overall, the stent thrombosis rate was 0.4% (0.5% in women vs. 0.3% in men, P=not significant). At 6 month follow-up, no significant difference in major adverse cardiac event was observed. Long-term follow-up (median time 33.2 months), available in 180 (83.3%) women and 720 (75%) men, showed higher angina recurrence rate (17.7 vs. 11%, P=0.013), percutaneous coronary re-intervention (16.1 vs. 8.7%, P=0.001) and target vessel revascularization (3.9 vs. 0.9%, P=0.001) in women compared with men. Late stent thrombosis, need for coronary artery bypass grafting, and mortality were similar in both groups. CONCLUSION: No sex difference was observed in acute and 6-month outcome after SES implantation despite older age, more unstable clinical presentation, and more frequent small vessel stenting in women. However, long-term clinical follow-up (up to 5 years) in women showed higher symptom recurrence and target vessel revascularization rate but no difference in overall major adverse cardiac events. PMID- 21597367 TI - What should be the blood pressure target for diabetic patients? AB - PURPOSE OF REVIEW: To summarize the pros and cons of a lower-than-usual blood pressure goal (e.g., <130/80 mmHg) for diabetic patients. RECENT FINDINGS: Aside from general socioeconomic and preventive medicine principles that either support or reject potential benefits associated with a lower blood pressure goal, clinical trial data from the last millennium have been challenged by the results of the prospective, randomized, National Institutes of Health-sponsored Action to Control Cardiovascular Risk in Diabetes trial, which found no significant benefit for a systolic goal of less than 120 mmHg, compared with less than 140 mmHg. Updated meta-analyses of five clinical trials are presented that show a significant (P < 0.05) reduction in the risk of stroke or major cardiovascular events. SUMMARY: Although a major clinical trial has shown that it is possible to lower blood pressure to a very low goal in a large number of diabetic patients, it remains to be seen whether those who are preparing the Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure will agree with the American Diabetes Association and continue to recommend the less than 130/80 mmHg target for all diabetic patients. PMID- 21597369 TI - Is blood pressure control to less than 140/less than 90 mmHg in 50% of all hypertensive patients as good as we can do in the USA: or is this as good as it gets? AB - PURPOSE OF REVIEW: This review assesses whether controlling hypertension in 50% of all patients is the best we can do. RECENT FINDINGS: NHANES 2007-2008 data show that blood pressure was controlled to less than 140/less than 90 mmHg in 50% of all hypertensive patients, an increase from 27% in 1988-1994. The 50% control rate reflects the product of 72.5% of all patients treated and 69% of all treated patients controlled. However, there are opportunities for improvement, as 27.5% of all hypertensives, or 55% of uncontrolled patients, were untreated in 2007 2008. These individuals are disproportionately younger, men, and Hispanic. Moreover, 31% of all treated hypertensives, or 45% of uncontrolled patients, have blood pressure of at least 140/at least 90 mmHg. They are disproportionately older, women, and black. SUMMARY: Initiatives to raise hypertension treatment from 72.5% in 2007-2008 to 87.5% in the future are conceivable by targeting unaware and untreated patient groups and engaging them in ongoing healthcare. This could improve hypertension control by an absolute 10% of all patients. Reducing therapeutic inertia and increasing therapeutic efficiency could raise the proportion of patients on treatment who are controlled from 69 to 80% and could increase hypertension control by 8%. Combining these approaches could raise hypertension control to 70% of all hypertensive adults in the USA. PMID- 21597368 TI - Medication adherence: emerging use of technology. AB - PURPOSE OF REVIEW: Adherence to proven, effective medications remains low, resulting in high rates of clinical complications, hospital readmissions, and death. The use of technology to identify patients at risk and to target interventions for poor adherence has increased. This review focuses on research that tests these emerging technologies and evaluates the effect of technology based adherence interventions on cardiovascular outcomes. RECENT FINDINGS: Recent studies have evaluated technology-based interventions to improve medication adherence by using pharmaceutical databases, tailoring educational information to individual patient needs, delivering technology-driven reminders to patients and providers, and integrating in-person interventions with electronic alerts. Cellular phone reminders and in-home electronic technology used to communicate reminder messages have shown mixed results. Only one study has shown improvement in both adherence and clinical outcome. Current trials suggest that increasing automated reminders will complement but not replace the benefits seen with in person communication for medication taking. SUMMARY: Integration of in-person contacts with technology-driven medication adherence reminders, electronic medication reconciliation, and pharmaceutical databases may improve medication adherence and have a positive effect on cardiovascular clinical outcomes. Opportunities for providers to monitor the quality of care based on new adherence research are evolving and may be useful as standards for quality improvement emerge. PMID- 21597370 TI - Cryotherapy for Barrett's esophagus and esophageal cancer. AB - PURPOSE OF REVIEW: To summarize the recent literature on endoscopic spray cryotherapy for the treatment of Barrett's esophagus and esophageal cancer. RECENT FINDINGS: Endoscopic spray cryotherapy is a relatively new ablative modality for the treatment of gastrointestinal diseases. Spray cryotherapy rapidly cools tissues by spraying them with either liquid nitrogen or rapidly expanding carbon dioxide gas. Initial, nonrandomized and uncontrolled studies show success rates comparable to other ablative modalities for the treatment of Barrett's esophagus with high-grade dysplasia, with complete eradication of dysplasia seen in 87-96% and complete eradication of intestinal metaplasia in 57 96% of treated patients. In early-stage esophageal cancer, spray cryotherapy appears to have a unique role, eliminating mucosal cancer in 75% of patients, including those who have failed other modalities. Patient tolerance of the procedure is very good. Limitations of current studies include small sample sizes and short durations of follow-up, and further studies are needed to validate the promising early results. SUMMARY: Endoscopic spray cryotherapy is a promising ablative modality for treatment of Barrett's esophagus and esophageal cancer. PMID- 21597371 TI - Endomicroscopy in the evaluation of Barrett's esophagus. AB - PURPOSE OF REVIEW: Confocal laser endomicroscopy (CLE) can provide real-time, microscopic visualization of the gastrointestinal mucosa, allowing an endoscopic approach to the histologic evaluation of Barrett's esophagus and Barrett's esophagus-associated neoplasia. RECENT FINDINGS: Both endoscope-based (eCLE) and probe-based (pCLE) CLE systems have been used to evaluate Barrett's esophagus and Barrett's esophagus-associated neoplasia. Criteria for distinguishing Barrett's esophagus with neoplasia from nondysplastic Barrett's esophagus have been developed and validated for both eCLE and pCLE. Several studies have shown excellent detection of Barrett's esophagus neoplasia by CLE, and the technique may be used to guide endoscopic therapy. Advanced endomicroscopy systems and peptides and antibodies that target neoplasia are in development. SUMMARY: CLE has provided a new way of evaluating Barrett's esophagus and Barrett's esophagus associated neoplasia and is being used to improve detection and management of neoplasia in Barrett's esophagus. PMID- 21597372 TI - The pediatric corneal infiltrate. AB - PURPOSE OF REVIEW: To highlight the most important causes of acquired corneal scarring and infiltrates in children. The lack of recognition of these disorders can lead to long-term visual loss in children. RECENT FINDINGS: There have been few articles on this topic in the recent ophthalmic literature, but all have stressed the need for early diagnosis and treatment of these diseases. SUMMARY: The most important causes of corneal scarring or infiltrates in children are keratoconus, phlyctenulosis, and herpes simplex keratitis. PMID- 21597373 TI - Models for joint ophthalmology-optometry patient management. AB - PURPOSE OF REVIEW: American Academy of Ophthalmology (AAO) and American Society of Cataract and Refractive Surgery (ASCRS) presented a joint position paper in February 2000 declaring that they do not support routine comanagement of patients with the optometrists. American Optometric Association and American Academy of Optometry quickly responded in support of AAO and ASCRS. All four entities did not preclude legitimate and proper comanagement arrangements. RECENT FINDINGS: Since that time, the pattern of practice has changed, requiring us to rethink our positions. SUMMARY: This paper is written to provide a possible model for the ophthalmology-optometry practice management in ophthalmic surgeries including refractive surgery. Since the publication of the Joint Position Paper, the concept of comanagement has faded and a new model of integrated management has evolved. This has occurred as the changes in the employment pattern of the ophthalmic practice have incorporated optometrists into its fold. This evolution allowed ophthalmic and optometric community to co-exist and thrive to provide better patient care. PMID- 21597374 TI - Nutritional supplements for dry eye syndrome. AB - PURPOSE OF REVIEW: Essential fatty acids have been of interest in the treatment of systemic and ocular diseases, and is most recently of interest in the area of dry eye disease. RECENT FINDINGS: Systemic and topical omega-3 fatty acids and omega-6 fatty acids have been used recently as an adjunctive treatment for patients with dry eye disease. They appear to have efficacy against the symptoms of dry eye that many patients experience. This symptom is postulated to be secondary to the anti-inflammatory effects that have been previously described. Although this effect is promising, more investigation is warranted in order to standardize indication for use, and composition and dosing for treatment. SUMMARY: The use of essential fatty acids as a nutritional supplement is a novel treatment for patients with dry eye syndrome. PMID- 21597375 TI - Biological treatments and connective tissue disease associated interstitial lung disease. AB - PURPOSE OF REVIEW: There is no specific therapy for interstitial lung disease associated with connective tissue diseases (CTDs-ILD), a potentially fatal condition for some of these patients. This article reviews currently available information on the effects on CTDs-ILD of biological treatments that are increasingly used with considerable success in various systemic diseases. RECENT FINDINGS: A beneficial effect of antitumor necrosis factor (TNF) agents on CTDs ILD has been described in sporadic patients with rheumatoid arthritis (RA), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). However, and despite the fact that there was no clear evidence of pulmonary toxicity of these agents in randomized-controlled trials comprising thousands of patients with RA and spondylarthropathies, new onset or exacerbation of preexisting ILD with high mortality rates has so far been observed in 144 RA patients following anti-TNF treatment in clinical practice. Likewise, administration of the B-cell depleting anti-CD20 antibody rituximab was beneficial for ILD in SSc patients but associated with new-onset ILD in isolated patients with RA and SLE. Pertinent information on other biological treatments is currently lacking. SUMMARY: Data on the therapeutic role of biological agents in CTDs-ILD is preliminary and controversial. Although preexisting ILD is not a contraindication for these agents, until more information is available their administration should be stopped when new pulmonary symptoms occur. PMID- 21597376 TI - Newer modes of treating interstitial lung disease. AB - PURPOSE OF REVIEW: This review critically discusses recent advances in the treatment of idiopathic pulmonary fibrosis (IPF). Moreover, it also focuses on the practical approach of a patient diagnosed with IPF and uncovers challenges for the future. RECENT FINDINGS: Treatment can be divided into three major parts. Firstly, many new agents have been tested, but only the combination of N acetylcysteine with corticosteroids, azathioprine and pirfenidone was able to show some significant effects. In the mean time, many second-generation agents are under development. Lung transplantation has made some major progress by introducing an appropriate allocation system. Finally, as part of best supportive care, several studies show that pulmonary rehabilitation might induce some important effects on quality of life. SUMMARY: So, it is clear that major progress has been made in the treatment of IPF, but we are convinced that an orchestrated effort will lead to a better understanding and treatment of this devastating condition. PMID- 21597377 TI - Molecular imaging in sarcoidosis. AB - PURPOSE OF REVIEW: In recent years molecular imaging techniques have made important advances as regards the study of sarcoidosis. This paper reviews new developments in these techniques as well as their present role and limitations in the assessment of patients with sarcoidosis. RECENT FINDINGS: PET with (18)F fluorodeoxyglucose ((18)F-FDG PET) has proved to be more sensitive than (67)gallium ((67)Ga) scan for assessing the inflammatory activity of sarcoidosis. Integrated (18)F-FDG PET/computed tomography (CT) scanners have improved diagnostic accuracy, and an emerging role for (18)F-FDG PET/CT in monitoring therapy has been described. The use of MRI is well established in neurosarcoidosis and musculoskeletal sarcoidosis. MRI is also the test of choice in suspected cardiac sarcoidosis. It provides anatomical information and quantification of ventricular function, and reveals very early changes in the signal of the myocardium in delayed enhancement. SUMMARY: (18)F-FDG PET/CT is useful in the detection of occult granuloma sites and residual activity in patients with fibrotic pulmonary sarcoidosis. It has an emerging role in the therapeutic management of patients with multisystemic sarcoidosis. MRI is indicated when neurosarcoidosis or cardiac or musculoskeletal involvement is suspected. Although most lesions detected are nonspecific in appearance, some patterns may be present in the early stages. PMID- 21597378 TI - Radiological evaluation of interstitial lung disease. AB - PURPOSE OF REVIEW: Chest radiograph, computed tomography and high-resolution computed tomography (HRCT) are an integral part in the diagnosis and evaluation of diffuse interstitial lung disease (DILD) and are reviewed briefly. This review then delves into the burgeoning interest associated with enhanced imaging and computational capabilities of multidetector HRCT in the automated evaluation of computer-aided recognition of different patterns associated with DILD, automated regional and global distribution and quantitation of DILD, and automated longitudinal comparison of HRCT scans to estimate progression of DILD. RECENT FINDINGS: Problems associated with automatic segmentation of lung in DILD because of high-attenuation lesions in subpleural locations have been overcome to a large extent. Use of two-dimensional HRCT has made it possible to automate identification and quantification of patterns associated with DILD with an overall accuracy of 89%. Significant progress has been made with automated image registration and noise reduction, which are essential for sequential comparison of HRCT in DILD. Early experience with automated determination of progression or regression of DILD on two-dimensional HRCT, using the dissimilarity-based feature strategy, compared favorably with radiologist assessment and approached a concordance rate of 80%. SUMMARY: The combination of multidetector HRCT, the support vector machine classifier and various computational algorithms have made it possible to fully automate isolation of lungs in DILD, recognize radiographic patterns associated with DILD and sequentially estimate progression of DILD. It is hoped there will be further improvement when these are extended to three dimensional HRCT. PMID- 21597379 TI - Chemopreventive effects of synthetic C-substituted diindolylmethanes originating from cruciferous vegetables in human oral cancer cells. AB - Diindolylmethane (DIM), an isothiocyanate found in cruciferous vegetables, has been shown to have cancer chemopreventive effects. A series of synthetic C substituted DIMs (C-DIMs) analogs was developed, including DIM-C-pPhtBu and DIM-C pPhC6H5, which exhibited better inhibitory activity in cancer cells than DIM. This study examined the effects of C-DIMs on the growth of human oral cancer cells. DIM-C-pPhtBu and DIM-C-pPhC6H5 decreased the number of viable KB cells and induced caspase-dependent apoptosis. The apoptotic cell death was accompanied by a change in Bax/Bcl-2 ratio and damage to mitochondrial membrane potential through the induction of death receptor 5 and the cleavage of Bid and caspase 8. Studies on the mechanism of action showed that the apoptotic cell death induced by DIM-C-pPhtBu and DIM-C-pPhC6H5 was mediated by endoplasmic reticulum stress. In addition, C-DIMs inhibited cell proliferation and induced PARP cleavage through death receptor 5 and CHOP in HEp-2 and HN22 cells. This provides the first evidence that synthetic C-DIMs originating from cruciferous vegetables induce apoptosis in human oral cancer cells through the endoplasmic reticulum stress pathway. PMID- 21597381 TI - A review of atypical antipsychotic medications for posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) can be a chronic and disabling illness with a limited response to antidepressant treatment, particularly in the case of combat-induced PTSD. The purpose of this study is to review randomized controlled and open-label trials of atypical antipsychotics for the treatment of PTSD. We conducted PUBMED and PILOTS database searches for clinical trials of atypical antipsychotic medications for PTSD in May 2010. Eighteen clinical trials (10 double-blind placebo-controlled, eight open-label) of atypical antipsychotics for PTSD were found and reviewed. Effect sizes of double-blind placebo-controlled trials were small, but were positive for risperidone and quetiapine. Intrusive and hypervigilance symptom subscales showed the most improvement. We concluded that atypical antipsychotic medications have a modest benefit for the treatment of PTSD. Larger randomized controlled trials are needed to clarify the potential utility of these medications in the treatment of PTSD and more rigorous examination of metabolic side effects is warranted. PMID- 21597380 TI - Predictors and risk model development for menopausal age in fragile X premutation carriers. AB - PURPOSE: Women who carry a fragile X mental retardation 1 premutation are at risk for fragile X-associated primary ovarian insufficiency and should be counseled for a potentially reduced fertility. Multiple factors can affect the age of onset and severity of fragile X-associated primary ovarian insufficiency. In this study, we assessed the predictive power of several factors with menopausal age, a surrogate measure of onset of fragile X-associated primary ovarian insufficiency. METHODS: Genetic, environmental, and reproductive factors were analyzed by Cox proportional hazard models in 1068 women, 385 of fragile X families ascertained through the Nijmegen study and 683 of fragile X families or general population families ascertained through the Atlanta study. RESULTS: The highest association with menopausal age among fragile X mental retardation 1 premutation carriers was found for risk index by CGG repeat size (hazard ratio, 1.43) and smoking (hazard ratio, 1.34). Women from the Nijmegen cohort showed an overall lower age at menopause onset, for which a correction was made. A prediction model based on these two parameters, mean menopausal age of first-degree relatives with the same mutation status and the correction for ascertainment site, estimated the probability of becoming postmenopausal for premutation carriers, with a margin of 7-10%. CONCLUSION: We conclude that this model serves as a first step toward clinical application of fragile X-associated primary ovarian insufficiency prediction. PMID- 21597382 TI - Mechanism of a reproducible accordion phenomenon: insights by optical coherence tomography visualization. AB - Pseudostenosis or 'accordion phenomenon' is a transient angiographic multifocal filling defect observed mostly during percutaneous coronary intervention, mainly in tortuous vessels. We describe a case of a reproducible accordion effect in the right coronary artery accompanied by only a mild clinical syndrome. Optical coherence tomography evaluation of this strange and fortunately completely reversible phenomenon is discussed. PMID- 21597383 TI - A new view on congenital heart disease: clinical burden prevision of changing patients. AB - The introduction and diffusion of cross-sectional echocardiography at the end of 1970s significantly improved case ascertainment and allowed the identification of congenital heart defects with a significant increase of mild forms. However, the prevalence of severe congenital heart disease (CHD), which represented 11.7% of overall cardiovascular malformations, remained quite stable (less than 1 per 1000 live births). In past decades, a new population of adults with CHD emerged who need specialized care in centres with trained and experienced professional staff with a different level of expertise. Clinical implications of this new scenario are discussed in this article. PMID- 21597384 TI - "Tonic" but not "Adie" pupils. AB - Tonic pupils react poorly to light but constrict during viewing of a near stimulus. Adie's name is typically used in association with tonic pupils, but a review of Adie's articles reveals that he described the syndrome of tonic pupils and absent reflexes and not the pupillary abnormality per se. Therefore, it would be more appropriate to refer to a tonic pupil as simply a "tonic pupil" and leave Adie's name for the syndrome. PMID- 21597385 TI - Measuring quality: one hospice's process. AB - This article describes the recent modifications to the Medicare Conditions of Participation as they relate to hospice programs' quality requirements. The process used by one hospice program in the Washington Metropolitan Area to implement the National Hospice and Palliative Care Organizations Quality Partners Self-Assessment Surveys is explained. Baseline survey results were used to identify and prioritize areas for improvement related to the standards of hospice care. PMID- 21597386 TI - Spontaneous correction of partial physeal arrest: report of a case and review of the literature. AB - This study describes the rare phenomenon of partial physeal arrest spontaneous correction. It concerns a case of a 3.5-year-old girl who suffered from a Salter Harris IV fracture of the distal tibial epiphysis, which was managed conservatively. After fracture healing an osseous bridge was formed at the medial part of the physis, leading to a varus deformity. The parents refused the operation, but 6 years later, both the ankle's deformity and the shortening of the extremity had been spontaneously corrected. It seems that the growth potential of the physis healthy portion is able to break the already transformed osseous bridge. PMID- 21597388 TI - Non-small cell lung cancer induces an immunosuppressive phenotype of dendritic cells in tumor microenvironment by upregulating B7-H3. AB - INTRODUCTION: Tumors may shift the phenotype and function of dendritic cells (DC) toward the induction of tolerance. In the status of full maturity, DC express a multitude of T cell costimulatory molecules enabling them to induce immune reactions, whereas nonactivated resident DC lack these T cell stimulating capacities. Therefore, we investigated the changes in DC phenotype and expression of B7-H molecules induced by non-small cell lung cancer (NSCLC). METHODS: The expression of T cell coinhibitory B7 molecules (B7-DC, B7-1, B7-2, B7-H1, B7-H3) on DC isolated from malignant and nonmalignant lung and lymph node tissue from patients attending curative surgery for NSCLC (n = 12) was analyzed. T cell stimulatory functions of DC isolated from malignant and nonmalignant lung and lymph node tissue samples were measured by allogeneic mixed lymphocyte reactions. Furthermore, the secretion of IL-10 and IL-12p40 by DC was analyzed (enzyme linked immunosorbent assay). RESULTS: : B7-H3 was significantly upregulated in tumor-residing DC, whereas the expression of other B7 molecules, such as B7-DC, B7-1, B7-2, B7-H1, remained unchanged. Significantly reduced levels of T cell proliferation in mixed lymphocyte reactions with tumor-derived DC were recorded. Moreover, elevated concentrations of IL-10 were measured in tumor-derived DC, whereas IL-12 levels were reduced. CONCLUSION: Our data indicate that (1) DC derived from NSCLC are immunosuppressive, and (2) under tumor conditions the coinhibitory molecule B7-H3 plays a crucial role in mediating the T cell suppressive effects of DC. PMID- 21597387 TI - Phase 2 trial of Linifanib (ABT-869) in patients with advanced non-small cell lung cancer. AB - INTRODUCTION: This study assessed activity and safety of linifanib (ABT-869), a selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, in patients with locally advanced or metastatic non small cell lung cancer. METHODS: In this open-label trial (NCT00517790), patients who received one to two prior lines of systemic therapy were randomized to oral linifanib 0.10 mg/kg (low dose) or 0.25 mg/kg (high dose) once daily. Tumor responses were assessed by independent central imaging review every 8 weeks. The primary end point was progression-free rate at 16 weeks. Secondary end points included objective response rate, time to progression, progression-free survival, and overall survival. Safety was also assessed. RESULTS: Between August 2007 and October 2008, 139 patients were enrolled; 60% had two or more prior regimens, and 88% had nonsquamous cell carcinoma. The objective response rate (low dose and high dose) was 5.0% (3.1 and 6.8%), progression-free rate at 16 weeks was 33.1% (32.3 and 33.8%), median time to progression was 3.6 months (3.6 and 3.7 months), median progression-free survival was 3.6 months (3.5 and 3.6 months), and median overall survival was 9.0 months (10.0 and 8.3 months). The most common linifanib related adverse events were fatigue (42%), decreased appetite (38%), hypertension (37%), diarrhea (32%), nausea (27%), palmar-plantar erythrodysesthesia (24%), and proteinuria (22%). These events were more common in the high-dose group. The most common linifanib-related grade 3 or 4 adverse event was hypertension (14%). CONCLUSIONS: Linifanib is active in advanced non-small cell lung cancer as second or third-line therapy. Increased adverse event rates were observed at the high dose of linifanib. PMID- 21597389 TI - Loss of special AT-rich binding protein 1 expression is a marker of poor survival in lung cancer. AB - INTRODUCTION: Lung cancer is the leading cause of cancer-related mortality and requires more effective molecular markers of prognosis and therapeutic responsiveness. Special AT-rich binding protein 1 (SATB1) is a global genome organizer that recruits chromatin remodeling proteins to epigenetically regulate hundreds of genes in a tissue-specific manner. Initial studies suggest that SATB1 overexpression is a predictor of poor prognosis in breast cancer, but the prognostic significance of SATB1 expression has not been evaluated in lung cancer. METHODS: A cohort of 257 lung cancers was evaluated by immunohistochemistry. Epigenetic silencing of SATB1 was examined in cell lines by 5-Aza 2-deoxycytidine and trichostatin A treatment, and chromatin immunoprecipitation. RESULTS: Significant loss of SATB1 expression was found in squamous preinvasive lesions (p < 0.04) and in non-small cell lung cancers (p < 0.001) compared with matched normal bronchial epithelium. Loss of SATB1 independently predicted poor cancer-specific survival in squamous cell carcinomas (SCCs; hazard ratio: 2.06, 95% confidence interval: 1.2-3.7, p = 0.016). Treatment of lung cancer cell lines with the histone deacetylase inhibitor trichostatin A resulted in up-regulation of SATB1. SATB1 was associated with a decrease in the active chromatin mark acetylated histone H3K9 and an increase in the repressive polycomb mark trimethylated H3K27 in a SCC cell line relative to a normal bronchial epithelial cell line. CONCLUSIONS: This is the first study showing that SATB1 expression is lost in early preinvasive squamous lesions and that loss of SATB1 is associated with poor prognosis in lung SCC. We hypothesize that the SATB1 gene is epigenetically silenced through histone modifications. PMID- 21597390 TI - Epithelial to mesenchymal transition in an epidermal growth factor receptor mutant lung cancer cell line with acquired resistance to erlotinib. AB - INTRODUCTION: Mesenchymal status is related to "inherent resistance" to gefitinib or erlotinib in non-small cell lung cancer without epidermal growth factor receptor(EGFR) mutations. In addition, a recent report showed that the epithelial to mesenchymal transition (EMT) plays a role in acquired resistance to gefitinib in A549 cells, which harbor a KRAS mutation. However, recent clinical studies revealed that gefitinib or erlotinib are highly effective in the treatment of non small cell lung cancer with EGFR mutations. METHODS: We developed resistant cells (HCC4006ER) from erlotinib-sensitive HCC4006 cells harboring an EGFR deletion mutation by chronic exposure to increasing concentrations of erlotinib. Acquired resistance mechanisms of HCC4006ER cells were analyzed. RESULTS: Neither known resistance mechanisms nor novel molecules that may confer erlotinib resistance were identified using candidate or comprehensive analyses. In addition, HCC4006ER cells lost dependency for EGFR. However, we found that HCC4006ER cells acquired a mesenchymal phenotype and exhibited down-regulation of E-cadherin expression (2.7 * 10 times compared with parental cells). We also found that the histone deacetylase inhibitor, MS-275, restored E-cadherin expression and moderate sensitivity to erlotinib in HCC4006ER cells, on the other hand, transforming growth factor beta, an inducer of EMT, led to moderate erlotinib resistance in HCC4006 parental cells. CONCLUSIONS: This is the first report of a relationship between EMT and erlotinib acquired resistance in an erlotinib sensitive EGFR mutant lung cancer cell line. Our results indicate that it would be important to consider the influence of EMT in the development of treatments against acquired resistance to gefitinib or erlotinib. PMID- 21597392 TI - Spectral-temporal analysis of cortical oscillations during lexical processing. AB - We investigated the oscillatory neural correlates of auditory lexical processing in healthy adults. Synthetic aperture magnetometry was used to characterize the timing of event-related desynchronization (ERD)/event-related synchronization (ERS) in superior temporal gyri following low-frequency and high-frequency words in contrast to nonwords. ERS and ERD responses were found with both word and nonword stimuli. Analysis of power revealed significantly elevated theta-alpha range (6-14 Hz) ERD in response to words compared with nonwords (left hemisphere: 390-945 ms poststimulus). Furthermore, a burst of ERS in the gamma band (40-50 Hz, centered at 410 ms poststimulus) distinguished high-frequency and low frequency words, and also displayed left-hemispheric enhancement following words. Results demonstrate a clear neural correlate of lexical access and provide a basis for further study of spectral-temporal brain activity during language processing. PMID- 21597391 TI - Changes in oligosaccharide chains of autoantibodies to GRP78 expressed during progression of malignant melanoma stimulate melanoma cell growth and survival. AB - A correlation between expression of the glucose-regulated protein of 78 kDa (GRP78) in malignant melanoma tumors and poor patient survival is well established. In this study, in addition to demonstrating the expression of GRP78 in tumor tissue, we investigated the immune response against GRP78 in a group of patients with different progression stages of malignant melanoma. Furthermore, we analyzed the glycosylation status of GRP78 immunoglobulin (Ig) G autoantibodies at these stages and evaluated their capacities to affect the protein B-dependent protein kinase signaling pathway and unfolded protein response signaling mechanisms, all known to promote malignant melanoma cell proliferation and survival. We found that progression of disease correlates not only with enhanced expression of GRP78 in the tumor but also with an increase in GRP78 autoantibody serum titers in these patients. We also found that the glycosylation status of anti-GRP78 IgG changes as the disease progresses. The anti-GRP78 IgG is abnormally glycosylated in the Fc region and asymmetrically glycosylated in the Fab region. We demonstrate that hyperglycosylated anti-GRP78 IgGs stimulate cell proliferation through protein B-dependent protein kinase signaling pathways. They also mimic the effects of alpha2-macroglobulin on the upregulation of GRP78 and X box binding protein 1, activating transcription factor 6 alpha, and serine/threonine-protein kinase/endoribonuclease precursor alpha as endoplasmic reticulum stress biomarkers and show no effect on expression or activation of caspases 3, 9, or 12. In conclusion, the anti-GRP78 IgG autoantibodies downregulate apoptosis and activate unfolded protein response mechanisms, which are essential to promote melanoma cell growth and survival. PMID- 21597393 TI - Ga-67 scintigraphic imaging: role of combined optimized energy photopeaks and scatter correction in improving lesion detectability. AB - BACKGROUND: The detection of lymphoma in gallium imaging is largely affected by image quality as Ga-67 emits three different energies with the highest contributing to septal penetration and image noise. Therefore, determining an optimal imaging protocol is crucial in the diagnosis and staging of lymphoma. The aim of this study was to further investigate the effect of using two energy windows rather than three (in improving signal-to-noise ratio, contrast, and resolution). In addition, application of the triple-energy-window (TEW) scatter correction method and its influence on lesion detectability have also been studied with emphasis placed on minimum detectable lesion and contrast. METHODS: An anthropomorphic torso phantom with chest lesion of different sizes and locations was used. Static planar and single-photon emission computed tomographic images for various lesion sizes and contrasts were acquired using the two different acquisition protocols. Contrast, resolution, and image noise were determined by the lesion-to-background ratio, full width at half maximum, and uniformity measurements, respectively. The TEW scatter compensation method was applied on two peaks-acquired images using two subwindows. RESULTS: Significant improvement (32%) in contrast was found in images acquired with two photopeaks in both planar and single-photon emission computed tomography (P<0.05). Observers' performance was significantly in favor of two photopeaks (P=0.003). The minimum detectable lesion was found to be 7 mm with an object ratio of 5 : 1 in two peaks images. This lesion, however, was not detectable in three photopeaks. Lesion detectability was significantly improved with the TEW scatter compensation method (P<0.01). CONCLUSION: Images acquired using two peaks were found to be superior to those normally used in clinical practice (i.e. three energies). The TEW scatter compensation method was found to be useful in improving Ga-67 image quality and lesion detectability. Thus, it is advised to reconsider using two photopeaks in gallium imaging with TEW scatter correction. PMID- 21597394 TI - Effect of 99Tc on the radiochemical purity of 99mTc radiopharmaceuticals. AB - OBJECTIVE: The longer the time between elutions of a technetium-99m (Tc) generator, the greater the Tc : Tc ratio in the eluate. Information is limited on how this affects the radiochemical purity (RCP) of Tc radiopharmaceuticals. The aim was to determine whether the RCPs of Tc radiopharmaceuticals are affected when prepared using Tc-pertechnetate from a generator that remained uneluted for 7 days. METHODS: Eight Tc radiopharmaceuticals were investigated: albumin nanocolloid, macrosalb, medronate, mertiatide, pentetate, sestamibi, succimer and tetrofosmin. Five samples of each were prepared with eluate from a generator that had been previously eluted within 24 h (control). These were compared with five samples adulterated with Tc to replicate the Tc : Tc ratio present in eluate from a generator that has remained uneluted for 7 days (test). The RCP of each sample was measured 1 h after preparation and at the product's expiry. RESULTS: Significant differences (P<0.05) were found between the RCPs of control and test samples of albumin nanocolloid, mertiatide and sestamibi 1 h after preparation. In each, the test sample had lower RCP, but was satisfactory. Similar results were found for macrosalb with added Tc, but the RCPs of the test samples were unsatisfactory at 83.9+/-4.2%. The RCPs of all control and test samples were satisfactory at expiry. CONCLUSION: Seven of the eight radiopharmaceuticals tested can safely be prepared using eluate from a generator that has remained uneluted for 7 days. Under these conditions, care must be taken when preparing Tc macrosalb, as its RCP remains unsatisfactory up to 2 h after preparation. PMID- 21597395 TI - Left ventricular myocardial ischemia in collagen disease associated with pulmonary hypertension: an evaluation by rest-stress gated SPECT and coronary angiography. AB - OBJECTIVE: To detect coronary artery disease in asymptomatic patients with systemic lupus erythematosus and scleroderma associated with pulmonary hypertension, and to determine whether it is focal or diffuse ischemia. METHODS: Twenty patients with systemic lupus erythematosus (10 with pulmonary hypertension and 10 without), and 20 patients with scleroderma (10 with pulmonary hypertension and 10 without) were included in this study. Resting ECG, echocardiography, and stress-rest 99mTc sestamibi gated myocardial perfusion imaging were performed for all patients. Patients with ischemia were subjected to coronary angiography to exclude/confirm coronary artery lesions. RESULTS: Myocardial perfusion SPECT showed that seven patients had myocardial ischemia, including three (30%) of 10 with systemic lupus erythematosus and pulmonary hypertension, three (30%) of 10 with scleroderma and pulmonary hypertension, and one (10%) of 10 with systemic lupus erythematosus without pulmonary hypertension. There was a high incidence of positive myocardial perfusion defects among patients with pulmonary hypertension than those without. Normal coronary angiography was found in all patients with ischemia, except for only one patient with scleroderma who had coronary artery stenosis. Significant correlation was found between pulmonary artery diameter obtained by echocardiography and severity of LV myocardial ischemia detected by SPECT (r=0.83). Significant correlation was found between SPECT-detected myocardial ischemia and ECG ST-T segment changes (r=0.82). CONCLUSION: Coronary artery disease is a common association in patients with systemic lupus erythematosus and scleroderma, especially in those with pulmonary hypertension. This may reflect anatomical compression by distended pulmonary artery rather than diffuse ischemia or small vessel disease. It is important to determine the presence of coronary artery disease in these patients, which may be amenable to coronary stenting. PMID- 21597396 TI - Mefloquine for uncomplicated Plasmodium falciparum malaria in children. AB - BACKGROUND: Children with uncomplicated Plasmodium falciparum imported malaria are treated with various antimalarial regimens including mefloquine depending on national guidelines. Little is known regarding mefloquine treatment efficacy in this setting. METHODS: In this prospective study, children 3 months to 16 years of age admitted in a tertiary hospital emergency ward in France with uncomplicated P. falciparum malaria were treated with oral mefloquine. Each dose was given with an antiemetic. RESULTS: Between 2004 and 2009, 95 children were evaluated. In all, 94% had traveled in the Indian Ocean region (Comoros and Madagascar); 79% used a malaria chemoprophylaxis, but none was fully compliant with World Health Organization recommended regimens. Main clinical features at admission were fever (91%), vomiting (44%), and headaches (44%). Hemoglobin < 80 g/L and platelets <100 G/L were observed in 16% and 17%, respectively. All children were initially cured by mefloquine, and no relapse was noted within 45 days after admission. One Plasmodium vivax relapse occurred 6 months later. Vomiting within 1 hour after dosing occurred in 20% of children. Significant features associated with early vomiting by univariate analysis were a weight <= 15 kg, C-reactive protein >= 50 mg/L, and parasitemia >= 1%, but only low weight was significant by multivariate analysis. CONCLUSION: Mefloquine is an effective treatment for uncomplicated imported P. falciparum malaria in children returning from countries with low mefloquine resistance. Early vomiting after mefloquine dosing is frequent, especially in children < 15 kg of weight, but a second dose can be given successfully. PMID- 21597397 TI - Genetic and environmental determinants of plasma total homocysteine levels: impact of population-wide folate fortification. AB - OBJECTIVES: Folate metabolism is an important target for drug therapy. Drug induced inhibition of folate metabolism often causes an elevation of plasma total homocysteine (tHcy). Plasma tHcy levels are influenced by several nongenetic (e.g. folate intake, age, smoking) as well as genetic factors. Over the last decade, several countries have implemented a nationwide folate fortification program of all grain products. This investigation sought to determine the impact of folate fortification on the relative contribution of environmental and genetic factors to the variability of plasma tHcy. METHODS: Two cohorts were compared in this study, one from the United States (with folate fortification, n=281) and one from Austria (without folate fortification, n=139). Several environmental factors as well as previously identified gene variants important for tHcy levels (MTHFR C677T, MTHFR A1298C, MTRR A66G) were examined for their ability to predict plasma tHcy in a multiple linear regression model. RESULTS: Nongenetic, environmental factors had a comparable influence on plasma tHcy between the two cohorts (R: approximately 0.19). However, after adjusting for other covariates, the tested gene variants had a substantially smaller impact among patients from the folate fortified cohort (R=0.021) compared with the nonfolate-fortified cohort (R=0.095). The MTHFR C677T polymorphism was the single most important genetic factor. Male sex, smoking, and folate levels were important predictors for nonfolate-fortified patients; age was for folate-fortified patients. CONCLUSION: Population wide folate fortification had a significant effect on the variability of plasma tHcy and reduced the influence of genetic factors, most importantly the MTHFR 677TT genotype, and may be an important confounder for a personalized drug therapy. PMID- 21597398 TI - Using a genetic, observational study as a strategy to estimate the potential cost effectiveness of pharmacological CCR5 blockade in dialysis patients. AB - BACKGROUND AND OBJECTIVE: Randomized clinical trials are expensive and time consuming. Therefore, strategies are needed to prioritise tracks for drug development. Genetic association studies may provide such a strategy by considering the differences between genotypes as a proxy for a natural, lifelong, randomized at conception, clinical trial. Previously an association with better survival was found in dialysis patients with systemic inflammation carrying a deletion variant of the CC-chemokine receptor 5 (CCR5). We hypothesized that in an analogous manner, pharmacological CCR5 blockade could protect against inflammation-driven mortality and estimated if such a treatment would be cost effective. METHODS: A genetic screen and treat strategy was modelled using a decision-analytic Markov model, in which patients were screened for the CCR5 deletion 32 polymorphism and those with the wild type and systemic inflammation were treated with pharmacological CCR5 blockers. Kidney transplantation and mortality rates were calculated using patient level data. Extensive sensitivity analyses were performed. RESULTS: The cost-effectiveness of the genetic screen and treat strategy was &OV0556;18 557 per life year gained and &OV0556;21 896 per quality-adjusted life years gained. Concordance between the genetic association and pharmacological effectiveness was a main driver of cost-effectiveness. Sensitivity analyses showed that even a modest effectiveness of pharmacological CCR5 blockade would result in a treatment strategy that is good value for money. CONCLUSION: Pharmacological blockade of the CCR5 receptor in inflamed dialysis patients can be incorporated in a potentially cost-effective screen and treat programme. These findings provide formal rationale for clinical studies. This study illustrates the potential of genetic association studies for drug development, as a source of Mendelian randomized evidence from an observational setting. PMID- 21597400 TI - Influence of CYP2C9 genetic variants on gastrointestinal bleeding associated with nonsteroidal anti-inflammatory drugs: a systematic critical review. AB - The existence of genetic polymorphisms in metabolizing enzymes can be regarded as one of the principal causes of interindividual variation in response to drugs and adverse reactions. In the case of enzyme CYP2C9, the presence of genetic coding variants could be considered a risk factor for suffering from gastrointestinal haemorrhages associated with the use of nonsteroidal anti-inflammatory drugs, due to a reduction in the enzyme's rate of metabolism. The aim of this study was to conduct a systematic critical review aimed at assessing whether the presence of CYP2C9*2 and CYP2C9*3 could increase the risk of suffering from gastrointestinal haemorrhages due to nonsteroidal anti-inflammatory drug use. Using MEDLINE as the data source, the search was limited to scientific studies published in English. Six studies met the inclusion criteria, whereas three reported no results because there were no homozygous mutant genotypes for CYP2C9*2 and *3 in their samples, risk of bleeding was associated by one with the presence of CYP2C9*2 and by two with the CYP2C9*3 coding variant. Some of the studies included in this review contained methodological limitations, which prevented the increased risk of suffering gastrointestinal haemorrhages due to nonsteroidal anti-inflammatory drug use from being satisfactorily linked to the presence of CYP2C9 coding variants. PMID- 21597399 TI - The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans. AB - OBJECTIVE: To study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism. METHODS: The conversion of deuterated (D2)-nicotine to D2-cotinine was quantified in 189 European-Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, (i) single time point measures of D2-cotinine/(D2-cotinine+D2-nicotine) after oral administration were used as a metric of CYP2A6 activity; (ii) the impact of CYP2A6 haplotype was treated as acting multiplicatively; (iii) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and (iv) a minimum number of predictive polymorphisms were justified to be included in the model based on statistical evidence of differences between haplotypes. RESULTS: The final model includes seven polymorphisms and fits the phenotype, 30-min after D2 nicotine oral administration, with R=0.719. The predictive power of the model is robust: parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R=0.758 and vice versa with R=0.617; estimates calculated in current smokers (n=102) predict the phenotype in former-smokers (n=86) with R=0.690 and vice versa with R=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss-of-function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5'-untranslated region conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype, modest associations were found between increased metabolism and both female sex (P=4.8*10) and current smoking (P=0.02). CONCLUSION: Among European-Americans, seven polymorphisms in the CYP2A6 gene explain the majority of variability in the metabolism of nicotine to cotinine after oral administration. Parameters determined from this in-vivo experiment can be used to predict nicotine metabolism based on CYP2A6 genotype. PMID- 21597401 TI - Prophylactic peritoneal fenestration to prevent morbidity after kidney transplantation: a randomized study. AB - BACKGROUND: Formation of lymphocele (accumulation of lymphatic fluid) is a common surgical complication following kidney transplantation. This open randomized trial evaluated the effect of prophylactic fenestration on lymphocele formation. METHODS: Adult recipients of kidney grafts from deceased donors were randomized to undergo peritoneal fenestration during the transplantation or to standard surgical procedure without fenestration. The incidence of symptomatic lymphocele in the two groups was compared at 1 year after transplantation. A protocol-based ultrasound examination was performed in the 1st, 5th, and 10th postoperative week. Any hypoechoic perirenal collection was registered. RESULTS: One hundred thirty recipients were randomized to peritoneal fenestration (n = 69) or standard therapy (n = 61). Six patients were excluded. Nine of 58 (15.5%) patients in the standard group developed symptomatic lymphoceles requiring treatment during the first postoperative year, versus 2 of 66 (3.0%) in the fenestration group (relative risk = 0.20, 95% confidence interval: 0.04-0.82, P = 0.015). Seven major surgical procedures and five percutaneous drainages due to lymphoceles were performed in the standard group, compared with two percutaneous drainages in the fenestration group. The prevalence of fluid collections in the fifth postoperative week was significantly higher in the standard group (66% vs. 37%; relative risk = 0.57, 95% confidence interval: 0.37-0.71, P = 0.005). CONCLUSION: Prophylactic fenestration reduced the risk of lymphoceles and the need for invasive procedures to treat this condition. The results need to be confirmed in a population of transplant recipients on lower steroids and with the use of wound drains. PMID- 21597402 TI - Bitemporal visual field defects in ethambutol-induced optic neuropathy. AB - BACKGROUND: Ethambutol-induced optic neuropathy is well documented and most frequently associated with central or cecocentral scotomas. We designed a study to characterize the subset of patients who exhibit bitemporal visual field defects. METHODS: A computer search was performed for patients evaluated in a university academic neuro-ophthalmology consultative practice to identify those with the diagnosis of ethambutol-induced optic neuropathy. Clinical features were tabulated, including dose and duration of ethambutol use, time to onset of visual loss, initial and follow-up visual acuities, automated perimetry, optic disc appearance, and MRI features. Assessments for bitemporal visual field defect with alignment on vertical midline and for visual improvement after discontinuing ethambutol were performed. RESULTS: Nineteen cases of ethambutol-induced optic neuropathy were identified; All but 2 eyes demonstrated visual field defects worse in the temporal fields, most with margination along the vertical midline with superimposed central or cecocentral scotomas. Six cases (12 eyes) showed bitemporal defects with such margination without superimposed scotomas. Median time to onset of visual loss was 6.0 months. Visual improvement occurred (of 17 cases with data available) by at least 3 Snellen lines in 17 of 34 eyes (50%); mean visual acuity improvement was 3.74 lines (median, 3.0). Visual improvement by at least 3.0 decibels (dB) mean deviation (MD) on automated perimetry occurred in 27 of 34 eyes (79%); mean improvement in MD was 7.82 dB (median, 7.86). Median follow-up was 8.0 months. None had MRI abnormality in the chiasmal region. CONCLUSION: Bitemporal visual field defects are common in ethambutol-induced optic neuropathy. The pattern may mimic chiasmal compression, and neuroimaging is required. It may reflect susceptibility to toxicity of chiasmal crossing fibers. PMID- 21597403 TI - Gastroesophageal reflux in young children treated for esophageal atresia: evaluation with pH-multichannel intraluminal impedance. AB - OBJECTIVES: Gastroesophageal reflux (GER) and dismotility occur frequently after repair of esophageal atresia (EA). GER-associated complications can manifest either early or later; then precocious diagnosis and treatment are essential. The aim of the study was to evaluate characteristics of GER and esophageal clearance in children treated for EA with distal tracheoesophageal fistula, using pH multichannel intraluminal impedance (pH-MII). PATIENTS AND METHODS: Twenty-two children (ages 3-40 months) treated for EA at birth, and 20 normal children of similar age with suspected GER disease were included in the study. Impedance parameters were analyzed according to age and symptoms. RESULTS: Reflux events were mainly nonacidic. About bolus exposure index, mean acid clearing time (MACT), and mean bolus clearing time (MBCT), a significant difference was found between 2 groups: the median MACT and MBCT were longer, with values of 281 and 39 seconds, respectively, in the EA group and 110 and 15 seconds in the control group (P < 0.0005). CONCLUSIONS: Our data show that in young patients the majority of refluxes are not acid. This implies that the incidence of GER may be underestimated if pH-metry is used. The pH-MII is an ideal test in children because it studies both GER with its characteristics and motility pattern. The quality of reflux does not seem to influence the onset of symptoms that are related to an impaired esophageal clearance. Hence, this technique could be useful to study patients treated for EA, avoiding the onset of complications. PMID- 21597404 TI - Another new era for cardiac surgeons? Induction of TAVI procedure to Japan. PMID- 21597405 TI - Esophageal reconstruction using a pedicled jejunum with microvascular augmentation. AB - The pedicled colon segment is widely accepted as a substitute to the gastric tube in esophageal reconstruction of cases where the stomach is not available. The usefulness of reconstruction with a pedicled jejunum has also been reported in recent years. In order to make a long jejunal graft, at least the second and third jejunal vessels have to be severed. However, this leads to a decrease of circulation in the pedicled jejunum. This poor circulation was primarily responsible for the high rates of gangrene and mortality (22.2% and 46.5%, respectively) in the beginnings of jejunal reconstruction. Advances in microsurgery have now enabled surgeons to overcome these disadvantages, as a result, both the rates of gangrene and mortality have decreased to almost zero since the addition of microvascular anastomosis with the jejunal vessels and the internal thoracic vessels. At present, the reconstruction using a pedicled jejunum is a safe operation that provides such advantages as a low incidence of intrinsic disease, more active transport of food, and a lower rate of regurgitation by peristalsis, compared with the reconstruction using the pedicled colon. The disadvantage of the procedure is the relatively high rate of anastomotic leakage (11.1% to 19.2%). Improvements in the surgical procedures to overcome this disadvantage are, therefore, needed before it can be recommended without any reservations. PMID- 21597406 TI - Prognostic significance of ERCC1 expression in resected non small cell lung carcinoma. AB - BACKGROUND AND AIM: The effects of DNA repair pathway on survival were assessed by measuring the tumoral excision repair cross complementation 1 (ERCC1) expression in patients with resected non-small cell lung carcinoma (NSCLC). We aimed to determine the prognostic and predictive significance of ERCC1 in patients with completely resected NSCLC. METHODS: Immunohistochemistry (IHC) was used to assess the expression of ERCC1 in resected lung tumor samples obtained from 98 patients untreated without pre- or post-operative chemotherapy and/or radiotherapy. The median H score was used as a cut-off for ERCC1 IHC. Univariate and multivariate analyses were performed for factors influencing patient survival. RESULTS: The 5-year survival rates of patients for ERCC1 positive expression and ERCC1 negative expression were 76% and 49%, respectively; this difference was statistically significant (p = 0.004). Subsequent multivariate analysis suggested that ERCC1 expression (adjusted hazard ratio for death, 0.38; 95% CI, 0.18 to 0.78; p = 0.008) and pathological stage (2.2; 95% CI, 1.09 to 4.5; p = 0.027) were both independent prognostic factors. CONCLUSION: The level of ERCC1 expression in tumors a strong predictor of survival in resected NSCLC patients untreated without pre- or post-operative chemotherapy and/or radiotherapy. PMID- 21597407 TI - Coil embolization for pulmonary arteriovenous malformation as an organ-sparing therapy: outcome of long-term follow-up. AB - PURPOSE: Pulmonary artery coil embolization (PACE) is increasingly utilized to treat pulmonary arteriovenous malformations (PAVMs), but the long-term outcome of this treatment modality remains unclear. By evaluating the long-term outcome of patients at St. Marianna University Hospital treated with PACE, we wanted to see if PACE could effectively replace the surgical resection of PAVMs. PATIENTS AND METHODS: We retrospectively evaluated 9 consecutive patients (4 males, 5 females; age range, 16-67 years; mean +/- SD, 43.6 +/- 18.7 years) who underwent PACE for PAVMs. Selective pulmonary artery angiography using Seldinger's method was initially performed to identify the feeding arteries. This was followed by embolization using interlocking detachable coils and microcoils. RESULTS: The procedure resulted in no severe complications. All treated patients were free from PAVM symptoms. A recurrence did not occur after PACE in 8 of 9 (88%) patients for 31 to 173 months (86 +/- 51). Recanalization of the embolized malformation occurred after 3 months in one patient. This patient underwent an additional successful PACE without any further recurrences for 73 months. CONCLUSIONS: PACE is an organ-sparing therapy with satisfactory long-term results. It can safely replace the surgical resection of PAVMs. PMID- 21597408 TI - Long-term survival after complete mediastinal lymph node resection and lobectomy in patients with bulky N2 non-small cell lung cancer. AB - BACKGROUND: At Juntendo University Hospital, Japan, two patients with complete resection of bulky N2 non-small cell lung cancer (NSCLC) has survived over the long term. Therefore, we decided to retrospectively study patients who also had a complete resection of the tumor including the "bulky" superior mediastinal node for the purpose of reviewing covariates that might be related to the favorable outcome. METHODS: We retrospectively analyzed the relation between covariates and survival after complete lobectomy and mediastinal lymph node resection (from April 1997 to August 2007) in 15 patients with bulky N2 NSCLC, lymph nodes greater than 2 cm in short-axis diameter (bulky nodal disease) measured on preoperative chest computer tomography. RESULTS: Of 15 patients, 5 with bulky N2 single station had survival after the resection. Univariate analysis revealed that the postoperative stage significantly affected overall survival (p = 0.0101). Single-station node involvement in bulky N2 disease was the covariate associated with overall survival (p = 0.0150) and disease free survival (p = 0.0052). CONCLUSIONS: In the complete resection of bulky N2 NSCLC in patients with lymph nodes measuring more than 2 cm in short-axis diameter, single-station node involvement suggests a favorable outcome and long-term survival, compared to patients with multi-station involvement. PMID- 21597409 TI - Cerebroprotective effect of piracetam in patients undergoing open heart surgery. AB - OBJECTIVES: Reduction of cognitive function is a possible side effect after the use of cardiopulmonary bypass (CPB) during cardiac surgery. Since it has been proven that piracetam is cerebroprotective in patients undergoing coronary bypass surgery, we investigated the effects of piracetam on the cognitive performance of patients undergoing open heart surgery. METHODS: Patients scheduled for elective open heart surgery were randomized to the piracetam or placebo group in a double blind study. Patients received 12 g of piracetam or placebo at the beginning of the operation. Six neuropsychological subtests from the Syndrom Kurz Test and the Alzheimer's Disease Assessment Scale were performed preoperatively and on day 3, postoperatively. To assess the overall cognitive function and the degree of cognitive decline across all tests after the surgery, we combined the six test scores by principal component analysis. RESULTS: A total of 88 patients with a mean age of 67 years were enrolled into the study. The mean duration of CPB was 110 minutes. Preoperative clinical parameters and overall cognitive functions were not significantly different between the groups. The postoperative combined score of the neuropsychological tests showed deterioration of cognitive function in both groups (piracetam: preoperative 0.19 +/- 0.97 vs. postoperative -0.97 +/- 1.38, p <0.0005 and placebo: preoperative -0.14 +/- 0.98 vs. postoperative -1.35 +/- 1.23, p <0.0005). Patients taking piracetam did not perform better than those taking placebo, and both groups had the same decline of overall cognitive function (p = 0.955). CONCLUSION: Piracetam had no cerebroprotective effect in patients undergoing open heart surgery. Unlike the patients who underwent coronary surgery, piracetam did not reduce the early postoperative decline of neuropsychological abilities in heart valve patients. PMID- 21597410 TI - Surgery offers high cure rates in multidrug-resistant tuberculosis. AB - PURPOSE: Drug resistance has become a major problem in the treatment of tuberculosis, and pulmonary resection in combination with chemotherapy appears to be an effective measure for the treatment. The purpose of this study was to investigate the results of resection for multidrug-resistant pulmonary tuberculosis (MDR-TB). PATIENTS AND METHODS: We retrospectively reviewed case files from January 2003 to December 2006 of 13 patients with MDR-TB underwent pulmonary resection. RESULTS: Of 13 patients, 7 (53.9%) were sputum positive for mycobacterium tuberculosis preoperatively, though after surgery, they were sputum negative. Lobectomy was performed in 8 (61.5%) and pneumonectomy, in 5 (38.5%). In the lobectomy group, 2 patients had an additional superior segmentectomy and 1 had a middle lobectomy for other segmental or lobar lesions. Operative mortality was 7.6% (1/13). There were no late surgical deaths. In the early postoperative period, 3 patients had serious complications (postoperative bleeding, prolonged air leak, expansion deficit, bronchopleural fistula and empyema) that were resolved with surgery (morbidity 23.0%). The 12 patients who survived the operation received appropriate chemotherapy and were followed up for 24-37 months. None of the patients relapsed, and the overall cure rate was 92.3% (12/13). CONCLUSION: Even with high morbidity in the early post-operative period, surgery, in addition to medical therapy, offers higher cure rates than only medical therapy; however, meticulous preoperative evaluation of patients is needed. PMID- 21597411 TI - Cryosurgical left-sided maze procedure in patients with valvular heart disease: medium-term results. AB - PURPOSE: We evaluated medium-term results of the left-sided maze procedure using cryoablation in patients with valvular heart disease. METHODS: We retrospectively evaluated 111 patients with valvular heart disease who underwent the cryosurgical left-sided maze procedure. The mean follow-up period was 36.8 +/- 24.9 months, and the mean duration of atrial fibrillation was 5.6 +/- 6.0 years. The primary surgical procedure was mitral valve replacement in 42 patients, mitral valve plasty in 28, aortic valve replacement in 25, and combined aortic and mitral replacement or plasty in 16. RESULTS: The 7-year actuarial survival rate was 82.9 +/- 11.4% for patients in sinus rhythm and 87.0 +/- 7.0% for patients with atrial fibrillation, showing no difference between the two groups (p = 0.236). At final follow-up, 86 out of 111 patients (77.5%) remained free from atrial fibrillation. Sinus rhythm was maintained in 26 of 42 patients (61.9%) in the mitral valve replacement group, 26 of 28 patients (92.9%) in the mitral valve plasty group, 15 of 17 patients (88.2%) in the aortic valve replacement group, and 18 of 24 patients (75.0%) in the combined aortic and mitral replacement or plasty group. The overall actuarial rate of freedom from atrial fibrillation at 5 years after surgery was 70.4 +/- 6.0%. CONCLUSION: The cryosurgical left-sided maze procedure is a safe, simple, and excellent operation for medically refractory atrial fibrillation. PMID- 21597412 TI - Prosthesis-patient mismatch after mitral valve replacement stratified by referred and measured effective valve area. AB - OBJECTIVE: The aim of this study was to determine the impact of patient prosthesis mismatch (PPM) after mitral valve replacement (MVR) on the late clinical outcome, evaluated from the referred value and measured mitral valve area in the echocardiograph. PATIENTS AND METHOD: The records of 212 patients who underwent MVR between 1995 and 2008 at Funabashi Municipal Medical Center, Japan were studied retrospectively. Exclusions were patients who had a repeat MVR or concomitant aortic valve surgery. Of 212 patients, 163 underwent the Doppler echocardiographic study more than 1 year after surgery. Primary endpoint was late survival, and secondary endpoint was major adverse cardiac event (MACE). The average follow-up period was 53.1 +/- 100.8 months. The effective orifice area index (EOAI) was calculated using the referred effective orifice area (r-EOA) and measured effective orifice area (m-EOA). An EOAI smaller than 1.2 cm2/m2 defined PPM. RESULTS: For r-EOAI, 125 patients (group P) had PPM and 87 patients (group N) did not. Between groups, there was a significant difference in the proportion of males (group P vs. N; 59% vs. 23%; P = 0.0001), postoperative NYHA class (1.02 +/- 6.2 vs. 9.8 +/- 1.6, P = 0.04), late mitral valve area (MVA) (2.50 +/- 0.56 vs. 2.78 +/- 0.60, P = 0.005), and peak transmitral pressure gradient (MPG) 11.9 +/- 6.2 vs 9.8 +/- 1.6, P = 0.04). However, there was no difference in late survival (P = 0.55) or incidence of a major cardiac adverse event (MACE) (P = 0.14). For m-EOAI, 17 patients (group P) had PPM and 146 patients (group N) did not. Between groups, there was a difference in the bioprosthetic valve (group P vs. N; 76% vs. 26%, P = 0.006) and mean MPG (5.2 +/- 2.3 vs. 3.7 +/- 1.8, P = 0.02). However, there was no difference in late survival (P = 0.99) and incidence of MACE (P = 0.86). The r- and m-EOAI were well correlated (correlation coefficient 0.46; 0.33-0.5) CONCLUSIONS: The PPM after MVR was not related to the late survival or the incidence of MACE based on both r- and m-EOAI. The patient group of PPM defined by r-EOAI tended to be male and that defined by m-EOAI tended to be bioprosthetic. PMID- 21597413 TI - Evaluation of a new device for the intraoperative assessment of coronary artery bypasses grafting. AB - PURPOSE: The aim of this study was to evaluate a new flow analyze device that can intraoperatively measure compliance and resistance of coronary artery bypass grafting (CABG) by the parameter identification method. METHODS: Subjects were 95 patients who underwent CABG. Angiography soon after surgery confirmed patency in 90 grafts and graft failure in 5 grafts. Variables of aortic pressure and the graft flow were entered into this new device that includes a mathematical coronary circulation model to extrapolate other information the data; thus, we can estimate intraoperative flow rate, resistance, and compliance. Flow rate, resistance, and compliance were compared between patent and failed graft groups and among three different type grafts. RESULTS: There were no differences in flow rate, resistance, and compliance among the three grafts types. Between the patent and failed graft groups, there were statistically significant differences in flow rate and resistance, and compliance tended to be lower for the failed graft group. CONCLUSIONS: By measuring graft resistance and compliance, this new device is useful for evaluating graft performance during CABG. PMID- 21597414 TI - Intracardiac metastasis of esophageal squamous cell carcinoma -report of a case-. AB - We report a case of a 48-year-old man with a history of violent coughing fits and general fatigue underwent urgent surgery for cardiac tamponade, and who was later diagnosed with metastatic intracardiac squamous cell carcinoma of the esophagus. After admittance to Munakata Suikokai General Hospital, Fukuoka, Japan, echocardiography showed extensive pleural and pericardial effusion and a mass, 4 by 2 cm, with a solid echo pattern in the right ventricular cavity. The working diagnosis was primary malignant cardiac tumor of unknown origin with multiple metastases. To prevent sudden death due to obliteration of the outflow tract of the right ventricle, we performed urgent surgery for cardiac tamponade. Histological examination of the resected tumor revealed squamous cell carcinoma. Fiberoptic esophagoscopy showed hypertrophy of the esophageal wall and a submucosal tumor extending throughout the esophagus. Microscopic examination of the esophagus biopsy specimen showed moderately differentiated squamous cell carcinoma, the histology of which was similar to that of the resected tumor and cytology of pericardial effusion. The patient recovered and was able to return home for a few days; however, he was readmitted, and despite maximal supportive therapy, he died one month after the operation. PMID- 21597415 TI - Malignant melanoma of the lung: report of two cases. AB - Malignant melanoma (MM) is the most fatal cutaneous neoplasm. Primary MM of the lung is quite rare, and late recurrence of MM is also uncommon. We report 2 cases of pulmonary MM, the first involving primary MM of the lung and the second involving late recurrence 8 years after the initial surgery. Bronchoscopic punch biopsy identified MM in both cases. In the first case, work-up of the patient did not reveal any anomalies other than those in the primary site. In the second case, the patient had a history of thumb amputation for MM 8 years ago. For pulmonary MM, extrapulmonary origin of the tumor must be excluded by detailed examination because melanomas involving the lung are almost always metastatic. Whether the diagnosis is primary or metastatic disease, the potential for recurrence should be considered even in patients with a long disease-free survival. PMID- 21597416 TI - Bronchial pleomorphic adenoma coexisting with lung cancer. AB - Pleomorphic adenoma usually occurs in the salivary glands but rarely in the trachea or bronchi. A 71-year-old man had abnormal shadows on a chest X-ray. Chest CT revealed one tumor in the right basal segment of the lung and another, in the left main bronchus. Bronchoscopic biopsy of the right tumor revealed well differentiated squamous cell carcinoma. Right lower lobectomy and lymph node dissection were performed (pT2N0M0, stage IB). At the orifice of the left main bronchus, bronchoscopy identified a polypoid lesion nearly obstructing the airway. The lesion was resected with hot snare ablation. The histological examination revealed a mixture of epithelial and myxoid mesenchymal elements, characterized by ductal structures, squamous metaplasia, and cartilage tissue. The diagnosis was bronchial pleomorphic adenoma coexisting with squamous cell carcinoma of the lung. PMID- 21597417 TI - Adenosquamous carcinoma of the lung in a patient with complete situs inversus. AB - We present a rare case of adenosquamous carcinoma of the lung in a patient with complete situs inversus. The patient was a 76-year-old woman with the chief complaint of hemosputum. Chest X-ray and computed tomography (CT) scans of the thorax showed a mirror image of the organs and vessels and revealed a tumor 3.5 cm in diameter, in the left lower lung field. She was referred and admitted to KKR Hokuriku Hospital, Kanazawa, Japan to undergo surgery. Bronchoscopy showed a mirror image of the usual arrangement of the bronchi, and 5 segmental branches in the left lower bronchi. During surgery, care was exercised when intubation with the Univent bronchial tube for one-lung ventilation. On thoracotomy, the gross appearance of the left lung and the arrangement of the pulmonary vessels and the bronchi corresponded to those normally found on the right side. We were successful in performing a left lower lobectomy. Postoperative diagnosis confirmed an adenosquamous carcinoma with localized pleural dissemination as p t4n1m0, stage IIIa. Preoperative imaging, including CT, bronchoscopy, and angiographic examination of the patient, will be useful for prevention of vascular or bronchial injury during surgery in patients with complete situs inversus undergoing lung resection. Possible vascular or bronchial anomalies should always be taken into consideration while operating on these patients. PMID- 21597418 TI - A complication of thoracic surgery: a late-onset chylomediastinum resulting from a left upper lobectomy and lymph node dissection through a median sternotomy. AB - A 63-year-old male with lung cancer underwent a left upper lobectomy and mediastinal lymph node dissection through a median sternotomy. Postoperatively, he received 4 cycles of adjuvant chemotherapy with cisplatin and gemcitabin. Chest computed-tomography (CT) scan after the adjuvant chemotherapy showed a large cystic mass originating from the tracheal bifurcation. Fiberoptic bronchoscopy (FOB) revealed chylomediastinum during the aspiration biopsy of the mass. The chylous effusion was first removed by aspiration under FOB, though 2 weeks later the patient returned with a fever, and the CT lead us to suspect mediastinitis. After performing primary surgery for the removal of chylomediastinum, there was no recurrence thus we concluded that it was the better method. PMID- 21597419 TI - Advantages of video-assisted thoracoscopic surgery for adult congenital hernia with severe adhesion: report of two cases. AB - Adults who have undergone surgical repair of congenital diaphragmatic hernia have a prolonged illness. They usually have severe adhesions around the intrathoracic hernial sac; therefore, the adhesion itself as well as misidentification of the hernial defect can make surgical repair difficult, even in open surgery. Here, we present the successful video-assisted thoracoscopic surgical repairs of Bochdalek and Morgagni hernias in patients with severe adhesions of the hernial sac (peritoneum) to the parietal pleura lying over the thoracic wall and diaphragm. An 18-year-old woman with a Bochdalek hernia and a 28-year-old woman with a Morgagni hernia underwent thoracoscopic division of severe adhesions, proper minithoracotomy, and precise repairs of diaphragmatic defects. Postoperative courses of both patients were uneventful with no signs of recurrence of the hernia. Thus, we recommend the thoracoscopic approach as the first choice over an open or laparoscopic approach in the management of adult patients with Bochdalek or Morgagni hernias and severe adhesion. PMID- 21597421 TI - Resuspension of the uninfarcted papillary muscle at the time of mitral valve replacement in a patient with post myocardial infarction papillary muscle rupture. AB - A 60-year-old woman was referred to the Department of Cardiovascular Surgery of Social Insurance Chukyo Hospital for the rupture of a postinfarction papillary muscle. The rupture was in the posterior part of the anterolateral papillary muscle, in which more than two-thirds of its posterior leaflet was prolapsed. Mortality from the surgical repair of a papillary muscle rupture is quite high. For this case, we resuspended the uninfarcted papillary muscle heads case to preserve mitral ventricular continuity because the mitral annulus was quite small and more than two-thirds of the posterior leaflet were detached from the papillary muscle. The post-operative course of the patient was uneventful. Resuspension of uninfarcted papillary muscle is a useful technique to repair a rupture in the papillary muscle. PMID- 21597420 TI - Contained rupture of an inflammatory abdominal aortic aneurysm into the iliopsoas muscle: report of a case. AB - A 72-year-old man with a history of old myocardial infarction was admitted to our hospital for surgical treatment of a ruptured abdominal aortic aneurysm. His hemodynamics was stable. He had left lumbar pain on moving his left leg and constipation for ten days without abdominal pain and high fever. Elevation of fat density around the aneurysm and ureter involvement were noted on the computed tomography. These characteristic image findings indicated inflammatory aortic aneurysm. During operation, an infrarenal abdominal aortic aneurysm with an 8 cm maximum diameter was noted. This aneurysm was firm and thick and adhered to some organs due to inflammation. An 5 * 5 cm punched-out defect was found on the lateral wall of the aneurysm. We replaced the ruptured aneurysm with a Dacron graft. Histological examination showed that the aneurysm wall had an infiltrate of inflammatory cells, lymphoid follicles and thickened adventitia. From these findings, the diagnosis was inflammatory aortic aneurysm. PMID- 21597422 TI - Rupture of a pseudo aneurysm of the abdominal aorta in a patient with human immunodeficiency virus infection. AB - Human immunodeficiency virus (HIV) infection has an impact on all systems of the body, including the cardiovascular system. A 54-year-old man presented with abdominal pain. Enhanced computed tomography revealed rupture of a pseudoaneurysm of the abdominal aorta. After surgery, the patient tested positive for HIV. Histological examination of the resected aorta showed leukocytoclastic vasculitis, a characteristic feature of HIV-related vasculitis. PMID- 21597423 TI - Rare bleeding complication of the radial artery conduit after coronary artery bypass grafting with endoscopic harvesting. AB - A 79-year-old man with unstable angina developed localized left atrial tamponade after conventional coronary artery bypass grafting (CABG) with endoscopic radial artery harvesting (ERAH). Hemodynamic instability developed several hours after the systemic heparinization. Transthoracic and later intraoperative transesophageal echocardiography revealed a large, isolated hematoma compressing the left atrium. The radial artery for the circumflex artery bled during an emergent re-sternotomy. Incomplete hemostasis of the radial artery by ERAH was the likely cause of this serious complication. Surgeons, especially those who are new to ERAH, should examine the harvested radial arterial conduit carefully and confirm complete hemostasis before performing the procedure. PMID- 21597424 TI - Bilateral retroperitoneal approach to repairing a ruptured right iliac artery aneurysm in a patient who has undergone transperitoneal abdominal surgery. AB - An 84-year-old woman with a history of surgery for cholangiocarcinoma presented to Akita University Hospital with severe right lower abdominal pain, respiratory distress, and hypotension. Computed tomography scanning revealed a ruptured right common iliac artery aneurysm with a massive right retroperitoneal hematoma and a right internal iliac artery aneurysm. Under the bilateral retroperitoneal approach, we preformed an in-situ repair of an aneurysm rupture from the aorta to the left common and right external iliac arteries using a bifurcated knitted Dacron graft, and then we ligated the right internal iliac artery. The postoperative course of the patient was uneventful. The patient was discharged from hospital 52 days after surgery. In conclusion, a bilateral retroperitoneal approach may be a safe and useful strategy for in-situ repair of a right iliac artery aneurysm rupture in patients with peritoneal adhesions after transperitoneal abdominal surgery. PMID- 21597425 TI - Remission of hepatic hydrothorax after OK-432 pleurodesis. AB - Hepatic hydrothorax in the absence of ascites is a rare complication of liver cirrhosis. A 71-year-old man with liver cirrhosis due to alcohol abuse was referred to our department because of massive pleural effusion on the right side. The properties of pleural effusion and clinical course led to a diagnosis of hepatic hydrothorax. Nonsurgical OK-432 pleurodesis resulted in a marked decrease of pleural effusion. After 2 months of follow-up, effusion was well-controlled. Patients with hepatic hydrothoraces have few options. OK-432 pleurodesis is relatively safe and may provide an effective alternative to peritoneovenous shunt, transjugular intrahepatic portosystemic shunt or surgical pleurodesis. It may also be a bridge toward liver transplantation in patients with few other options. Herein, we report a case of refractory hepatic hydrothorax successfully treated by nonsurgical OK-432 pleurodesis. PMID- 21597426 TI - A case of multiple squamous cell papillomas of the trachea. AB - We report a case of 68-year-old woman suffering from breathlessness on exertion with stridor. A chest computed tomography showed a tumor arising from the posterior wall of the trachea. The diagnosis was squamous cell papilloma of the surgically removed tumor, which had caused the asphyxiation. After removal of the tumor, the patient received radical therapy: semiconductor laser transpiration. Polymerase chain reaction (PCR) detected human papilloma virus (HPV) type 6, thought to be the cause of the respiratory papilloma. PMID- 21597427 TI - Morbidity of teeth in the line of the fracture. AB - AIM: Management of a jaw fracture in which a tooth lies in the fracture line is controversial. In the past, teeth were generally removed because they were thought to be the cause of infections or locus minoris resistentiae. To provide a better indication in the management of teeth in the fracture line and the relate complications we retrospectively reviewed the files particularly in relation to treatment options. METHODS: From 1999 to 2009 a total of 478 patients with jaw fracture were observed at the Maxillofacial Department of the University "Federico II" of Naples. RESULTS: In 63 cases the fracture involved the angle of the mandible and in 48 a tooth lay in the fracture line. Of the 48 teeth in the fracture line, 14 were removed for various causes. Surgical treatment consisted of fracture reduction and fixation by titanium plates and screws. CONCLUSION: We suggest few guiding lines in the management of teeth in fracture lines that need to be extracted only in particular conditions. Finally there are few cases of later dental complications that can affect the teeth in the fracture line after the osseous healing process of the fractures. These cases require a follow-up of three-six months, and the treatment is the same commonly described in Literature for dental trauma. PMID- 21597428 TI - Use of endosseous one-piece yttrium-stabilized zirconia dental implants in premolar region: a two-year clinical preliminary report. AB - AIM: The aim of this work was to clinically and radiographically evaluate survival and success rate of zirconia dental implants positioned in premolar area during a follow-up period of at least 12 months up to 24 months. METHODS: Sixteen patients were treated with 26 zirconia implants. All implants received immediate temporary restorations and 6 months after surgery were definitively restored. Twelve to 14 months after implant insertion, a clinical-radiographical evaluation was performed in order to estimate peri-implant tissues health and peri-implant marginal bone loss. RESULTS: The survival rate was 96.16%. The success rate was 91.6%. CONCLUSION: Because of the limited number of implants, conclusions may not be considered significant even if results are encouraging. Further scientific information regarding clinical use of zirconia dental implants are needed, as well as prospective long-term clinical studies in order to understand if zirconia implants may represent a valid alternative to titanium implants. PMID- 21597429 TI - Diseases of the maxillary sinus: an overview for the dentists. AB - Because of the intimate relationship between the upper dentition and the maxillary sinus, it is no surprise that inflammatory, cystic and neoplastic odontogenic diseases may extend into the maxillary sinus and, occasionally, into the nasal cavity. On the other hand, diseases of the maxillary sinus may extend into the oral cavity or may cause symptoms that mimic those of diseases of odontogenic origin. An overview is presented of the various odontogenic and nonodontogenic diseases that may involve the maxillary sinus. PMID- 21597430 TI - Implant overdentures: recommendations and analysis of the clinical benefits. AB - Due to the progress made in implantology, in recent years the interest in prosthetic rehabilitation in edentulous mouths using overdentures has increased considerably. Indications to the treatment of implant supported overdenture could be classified in three groups: the first group consists of younger members of the elderly population who have an edentulous upper jaw rehabilitated with a conventional complete denture but experience discomfort with it and therefore desire a stable prosthesis and greater comfort in the mouth; the second group, for which the use of implant overdentures is recommended, consists of older patients who require greater stability from a complete mandibular denture; the third group consists of compromised patients and those with acquired or congenital maxillofacial conditions. Moreover, advantages of overdentures supported by implants are analyzed; in fact, they allow a lower bone reabsorption, a better retention and stability of the prosthesis than the traditional complete denture, an increased masticatory effectiveness, a reduction of pain during mastication tanks to the higher stability, a better sensory perception, a considerable patient satisfaction, and the option of making an immediate prosthetic rehabilitation with implants through immediate load. PMID- 21597431 TI - Treatment of severe facial asymmetry secondary to osteochondroma of the mandibular condyle: case report. AB - Osteochondroma (OC) is the most common benign tumor of long bones. However it is rarely found in the facial skeleton, being the coronoid process and mandibular condyle the most affected sites in this region. It basically consists in bone growth covered by cartilage. The etiology is still controversial: neoplastic, developmental, reparative and traumatic origins have been discussed in literature. The treatments of these lesions include total condylectomy or local resection of the lesion. This paper aims to report a case of a patient with history of trauma and possible fracture of the mandibular condyle in childhood, which in youth developed dentofacial deformity with severe facial asymmetry. The treatment consisted of resection of lesion both with maxillary and mandibular osteotomies associated with graft from the iliac crest bone. Actually, the patient is with a favorable aesthetic, without functional deficit and absence of lesion's recurrence. PMID- 21597432 TI - Evidence (and research) are the only possible basis of medicine. PMID- 21597433 TI - Chronic coccydynia in adolescents. A series of 53 patients. AB - BACKGROUND: Little is known about coccydynia in adolescents. AIM: The aim of this study was to explore causes, clinical and imaging features and response to treatment of chronic coccydynia in adolescents. DESIGN: This was a cohort study. SETTING: The study included patients followed up at a specialized consultation in a university hospital. METHODS: A series of 53 adolescent patients with chronic coccydynia were followed for 1-4 years. Investigations included dynamic X-ray films, with a magnetic resonance imaging scan of the coccyx in 26/53. Treatment was by coccygeal steroid injection or non-steroidal anti-inflammatory drugs (NSAIDs). Amitriptyline or coccygectomy were used as second-line treatment. Outcomes were assessed at a consultation two months after the treatment, then between one to four years later, by telephone interview, questionnaires and by a visual analogue scale (VAS). Fifty-one adult patients with coccydynia formed the control group. RESULTS: In 20 cases (37.7%) the coccydynia was subsequent to trauma. Obesity was not a risk factor. Abnormal mobility was rarer and spicules more frequent compared to adult patients (P<0.001); 11/27 MRI scans showed a hypersignal within the disc or adjacent bone and 6/27 a hypersignal surrounding the tip of the coccyx (bursitis). Initial treatment was a coccygeal steroid injection for 41 patients and NSAIDs for 12. Ten were given amitriptyline and 3 a coccygectomy. At final assessment, there was no pain or almost no pain in 32/53 (60.4%), moderate pain and functional impairment in 12/53 (22.6%) and severe pain and functional impairment in 9/53 (17%). CONCLUSION: Coccydynia in adolescents differs from coccydynia in adults. A MRI scan is helpful and should be obligatory for diagnosis. Prognosis is relatively good. CLINICAL REHABILITATION IMPACT: Our results should help clinicians manage this rare and debilitating condition. PMID- 21597434 TI - Rehabilitation after hip fracture in older people. PMID- 21597435 TI - Factors affecting functional prognosis of patients with hip fracture. AB - Having a hip fracture is considered one of the most fatal fractures for elderly people, resulting in impaired function, and increased morbidity and mortality. This challenges clinicians in identifying patients at risk of worse outcome, in order to optimise and intensify treatment in these patients. A variety of factors such as age, prefracture function and health status, fracture type, pain, anaemia, muscle strength, and the early mobility level have been shown to influence patient outcome. Thus, the outcome of patients with hip fracture is considered multi-factorial, and can therefore not be related to just one or two single factors. The current article reviews important factors affecting the functional prognosis, and clinicians are encouraged to include all factors potentially influencing the outcome of patients with hip fracture in their individualised treatment and rehabilitation plan. Especially, older age and having a low prefracture functional level are considered strong factors. PMID- 21597436 TI - Comprehensive care. AB - Comprehensive care (CC) represents the basic approach of orthogeriatric comanaged care with the overall objectives of improving results regarding physical and psychological functions and reducing hospitalization, long-term care placement and mortality. It is a two-stage process that includes the Comprehensive Geriatric Assessment (CGA) and the development and implementation of an interdisciplinary treatment plan based on priority interventions and unmet needs. In older hip fracture patients CC has to face crucial issues such as treatment choice and surgical options, clinical stabilization of patients before surgery and the prevention and treatment of complication in the postoperative phase. The main aim are to avoid inappropriate surgical delays and reduce the overall number of days of immobility endorsing an early ambulation with full weight bearing as tolerated. Multiprofessional CC must also ensure uninterrupted care for transition between the different care levels that patients need after fracture before returning home. Therefore another important issue is a structured discharge plan tailored to the individual patient identifying subjects that could benefit from a skilled or more intensive rehabilitation, identifying patients and family that will probably need a higher level of care even after rehabilitation, determining timing of discharge, defining the continuing care that needs to be provided and finally ensuring the patient has access to available services and resources. However, the implementation of a comprehensive and multidisciplinary co-care model in an orthopedic unit is a difficult task because it is necessary a great effort to change cultural attitudes related to traditional model of care. PMID- 21597437 TI - EJPRM systematic continuous update on Cochrane reviews in rehabilitation: news from February 2011 to April 2011. AB - AIM: Since 2007 we focused our attention as EJPRM to the best available clinical evidence as offered by the Cochrane Collaboration. Due to the absence of a specific Rehabilitation Group.only a Field exists), reviews of PRM interest are in different groups and not easy to find. Consequently, the EJPRM offer the service of listing and presenting all these reviews systematically. The aim of the present paper is to systematically review all the new rehabilitation papers published from February 2011 up to April 2011 from the Cochrane Library in order to provide to physicians involved in the field a summary of the best evidence nowadays available. METHODS: The authors systematically searched all the new papers of rehabilitative interest in the 2nd of February 2011 to the 22nd of April 2011 in the Cochrane Library. The retrieved papers have been then divided in subgroups on the base of the topic and the Cochrane Groups. RESULTS: The number of included papers was 5, 3 new reviews and 2 updates reviews. Three reviews deals with neurological rehabilitation, 2 with musculoskeletal disorders and one with orthoses. CONCLUSION: The Cochrane Collaboration and his product, the Cochrane Library, are really relevant instruments to improve EBM in medical practice and thus also in the Rehabilitation Field. The present paper can help Rehabilitation Specialists to easily retrieve the conclusions of the most relevant and updated reviews in order to change their clinical practice in a more rapid and effective way. PMID- 21597442 TI - The association of lactate and vasopressor need for mortality prediction in survivors of cardiac arrest. AB - BACKGROUND: Currently there are few tools available for clinicians to predict outcomes in cardiac arrest survivors. Our objective was to determine if the combination of simple clinical parameters (initial blood lactate and vasopressor use) can predict outcome in post-cardiac arrest patients. METHODS: The design was a retrospective medical record review. The study was carried on in two urban, tertiary-care, university teaching hospitals. As for patients, inclusion criteria were: 1) age >=18 years; 2) non-traumatic out-of-hospital cardiac arrest with return of spontaneous circulation; 3) lactic acid measured within one hour of return of circulation. No interventions was performed. RESULTS: Patients were divided into groups based on two variables: 1) vasopressor status (receipt of vasopressors vs. no vasopressors); and 2) initial blood lactate (categories defined as lactate <5 mmol/L, lactate 5 to 10 mmol/L, lactate >=10 mmol/L); 128 out-of-hospital cardiac arrest patients met study inclusion criteria. Overall mortality was 71% (95%CI 63-79%). Patients who received vasopressors had significantly higher mortality rates compared to patients who did not receive vasopressors (80% vs. 52%; P=0.002). A stepwise increase in mortality is associated with increasing lactate levels (39% lactate <5 mmol/L, 67% lactate 5 mmol/L to10 mmol/L, and 92% lactate >=10 mmol/L; P<0.001). The AUC for our model was 0.82. CONCLUSION: The combination of two clinical parameters, vasopressor need and lactic acid levels, is an accurate severity of illness classification system and can predict mortality in patients following out-of-hospital cardiac arrest. Prospective validation of these variables in post-cardiac arrest is needed. PMID- 21597441 TI - Prospective multicenter study on epidemiology of acute kidney injury in the ICU: a critical care nephrology Italian collaborative effort (NEFROINT). AB - Acute kidney injury (AKI) is an independent risk factor for mortality in critically ill patients whose epidemiology has been made unclear in the past by the use of different definitions across various studies. The RIFLE consensus definition has provided a unifying definition for AKI leading to large retrospective studies in different countries. The present study is a prospective observational multicenter study designed to prospectively evaluate all incident admissions in 10 Intensive Care Units (ICUs) in Italy and the relevant epidemiology of AKI. A simple user-friendly web-based data collection tool was created with the scope to serve for this study and to facilitate future multicenter collaborative efforts. We enrolled 601 consecutive patients into the study; 25 patients with End-Stage Renal Disease were excluded leaving 576 patients for analysis. The median age was 66 (IQR 53-76) years, 59.4% were male, while median SAPS II and APACHE II scores were 43 (IQR 35-54) and 18 (IQR 13-24), respectively. The most common diagnostic categories for ICU admission were: respiratory (27.4%), followed by neurologic (17%), trauma (14.4%), and cardiovascular (12.1%). Crude ICU and hospital mortality were 21.7% and median ICU length of stay was 5 days (IQR 3, 14). Of 576 patients, 246 patients (42.7%) had AKI within 24 hours of ICU admission while 133 developed new AKI later during their ICU stay. RIFLE-initial class was Risk in 205 patients (54.1%), Injury in 99 (26.1%) and Failure in 75 (19.8%). Progression of AKI to a worse RIFLE class was seen in 114 patients (30.8% of AKI patients). AKI patients were older, with higher frequency of common risk factors. 116 AKI patients (30.6%) fulfilled criteria for sepsis during their ICU stay, compared to 33 (16.7%) of non-AKI patients (P<0.001). 48 patients (8.3%) were treated with renal replacement therapy (RRT) in the ICU. Patients were started on RRT a median of 2 (IQR 0-6) days after ICU admission. Among AKI patients, they were started on RRT a median of 1 (IQR 0-4) days after fulfilling criteria for AKI. Median duration of RRT was 5 (IQR 2-10) day. AKI patients had a higher crude ICU mortality (28.8% vs. non AKI 8.1%, P<0.001) and longer ICU length of stay (median 7 days vs. 3 days [non AKI], P<0.001). Crude ICU mortality and ICU length of stay increased with greater severity of AKI. Two hundred twenty five patients (59.4% of AKI patients) had complete recovery of renal function, with a SCr at time of ICU discharge which was <=120% of baseline; an additional 51 AKI patients (13.5%) had partial renal recovery, while 103 (27.2%) had not recovered renal function at the time of death or ICU discharge. Septic patients had more severe AKI, and were more likely to receive RRT with less frequency of renal function recovery. Patients with sepsis had higher ICU mortality and longer ICU stay. The study confirms previous analyses describing RIFLE as an optimal classification system to stage AKI severity. AKI is indeed a deadly complication for ICU patients where the level of severity correlated with mortality and length of stay. The tool developed for data collection resulted user friendly and easy to implement. Some of its features including a RIFLE class alert system, may help the treating physician to collect systematically AKI data in the ICU and possibly may guide specific decision on the institution of renal replacement therapy. PMID- 21597443 TI - Pharmacokinetics of free ertapenem in critically ill septic patients: intermittent versus continuous infusion. AB - BACKGROUND: The aim of this paper was to compare the pharmacokinetic and pharmacodynamic (PK/PD) parameters of continuous (CI) and intermittent infusion (ITI) of ertapenem into critically ill patients with severe abdominal infections. METHODS: Twenty septic patients hospitalized in a university hospital intensive care unit were enrolled in the study. Half of the patients received ertapenem as an ITI 1 g bolus once daily, and the other half of the patients received the same dose via CI over 24 h following a 1-g loading dose. Blood was drawn 1, 12 and 24 h after terminating ITI or on days 2, 3 and 5 after starting CI for each patient. After centrifugation, the drawn blood was frozen at -80 degrees C until being examined by high-performance liquid-chromatography analysis. RESULTS: Median serum-free ertapenem concentrations were as follows: fCmax = 98.9 mg/L and fCmin = 2.5 mg/L for ITI, and fCss=15.9 mg/L for CI. The ITI and CI median total clearance and volumes of distribution were 2.2 L/h vs. 2.5 L/h and 15.4 L vs. 21.0 L, respectively. The ertapenem MIC ranges were as follows: Escherichia coli (0.006 to 0.5 mg/L), Enterobacter cloacae (0.023 to 0.5 mg/L), Klebsiella oxytoca (0.023 to 0.5 mg/L), Staphylococcus aureus (0.38 to 3 mg/L), Streptococcus viridians (0.38 to 3 mg/L) and Enterococcus faecalis (0.38 to 3 mg/L). ITI and CI provided steady-state serum-free ertapenem concentrations constantly above the MIC for all bacteria. CONCLUSION: Ertapenem exhibited satisfactory PK/PD parameters and achieved serum-free concentrations 100% of the time, above even the high MIC of extracellular pathogens normally encountered during severe abdominal infections. CI administration resulted in equally effective PK/PD parameters as ITI in normal weight, good renal-function patients. PMID- 21597444 TI - Incidence of postoperative urinary retention (POUR) after joint arthroplasty and management using ultrasound-guided bladder catheterization. AB - BACKGROUND: Postoperative urinary retention (POUR) following lower limb arthroplasty is a common complication. The aim of this observational study was to establish the incidence of POUR and assess the usefulness of an ultrasonographic nurse-driven protocol, thereby avoiding elective bladder catheterization. METHODS: Two-hundred and eighty six consecutive patients undergoing elective hip and knee arthroplasty were retrospectively studied. None of the patients received elective bladder catheterization. Data on risk factors for POUR, urinary tract infections, length of hospital stay and analgesia were collected. Student's t, Wilcoxon rank-sum, ANOVA and Kruskall-Wallis tests were performed for comparison among two or more groups. Categorical variables were studied using Pearson's chi2 test. Results were considered significant when the P value <0.05. RESULTS: Of the 286 patients studied, 49 (17%) required indwelling catheter for 24-48 h. Patients who had POUR had more risk factors (P<0.05) and had longer hospital stays (P<0.05). When comparing analgesia, continuous peripheral nerve block (CPNB) had the least impact on POUR (15.8%), while epidural analgesia had the greatest impact (48.1%). CONCLUSION: Bladder scanners timely detect POUR following lower joint arthroplasty, making elective bladder catheterization unnecessary. PMID- 21597448 TI - West Nile Virus encephalitis in intensive care: a small mosquito, a tremendous danger. AB - The authors describe two of three cases of West Nile virus (WNV) meningoencephalitis admitted to ICU in Ferrara (south of Po River) underlying the main common features. They focus on the difficulties in diagnosis, with key points including seasonality (late summer in Italy), unspecific flu-like symptoms at the beginning, as hyperpyrexia, myalgia and asthenia, followed by neurological impairment, and use of steroids in the patient clinical history. Special attention is deserved to the poor outcome at both short and long term. PMID- 21597452 TI - Estimated burden of acute otitis externa--United States, 2003-2007. AB - Acute otitis externa (AOE) (swimmer's ear) is inflammation of the external auditory canal most often caused by bacterial infection. AOE is characterized by pain, tenderness, redness, and swelling of the external ear canal, and occasionally, purulent exudate. AOE is associated with water exposure (e.g., recreational water activities, bathing, and excessive sweating) and warm, humid environments. Because the overall burden and epidemiology of AOE in the United States have not been well described, data from national ambulatory-care and emergency department (ED) databases were analyzed to characterize the incidence, demographics, and seasonality of AOE and associated health-care costs. The analysis showed that in 2007, an estimated 2.4 million U.S. health-care visits (8.1 visits per 1,000 population) resulted in a diagnosis of AOE. Estimated annual rates of ambulatory-care visits for AOE during 2003-2007 were highest among children aged 5-9 years (18.6) and 10-14 years (15.8); however, 53% of visits occurred among adults aged >=20 years (5.3). Incidence peaked during summer months, and the regional rate was highest in the South (9.1). Direct health-care costs for nonhospitalized AOE visits total as much as $0.5 billion annually, and ambulatory-care clinicians spend nearly 600,000 hours annually treating AOE. Suggested AOE prevention measures include reducing exposure of the ears to water (e.g., using ear plugs or swim caps and using alcohol-based ear drying solutions) (3-5). To reduce the national incidence of AOE, additional preventive measures should be investigated, and effective prevention messages should be developed and disseminated. PMID- 21597453 TI - Reasons for not seeking eye care among adults aged >=40 years with moderate-to severe visual impairment--21 States, 2006-2009. AB - In 2000, an estimated 3.4 million U.S. residents aged >=40 years were blind or visually impaired. Vision problems place a substantial burden on individuals, caregivers, health-care payers, and the U.S. economy, with the total cost estimated at $51.4 billion annually. Although regular comprehensive eye examinations are essential for timely treatment of eye disease to maintain vision health, a previous study has shown that substantial percentages of persons do not seek eye care, despite having visual impairment. To ascertain why adults aged >=40 years with moderate-to-severe visual impairment did not seek eye care in the preceding year, CDC analyzed data for 21 states from 2006-2009 Behavioral Risk Factor Surveillance System (BRFSS) surveys. This report summarizes the results of that analysis, which found that eye-care cost or lack of insurance (39.8%) and perception of no need (34.6%) were the most common reasons given for not seeking eye care. Among those aged 40-64 years, cost or lack of health insurance was the most common reason (42.8%); among those aged >=65 years, the most common reason was no need (43.8%). Identifying the reasons for unmet eye-care needs might enable development of targeted interventions to improve vision health among those with moderate-to-severe visual impairment. PMID- 21597454 TI - Arthritis as a potential barrier to physical activity among adults with obesity- United States, 2007 and 2009. AB - Adults with obesity are less likely than adults without obesity to follow physical activity recommendations, despite the known benefits of physical activity for weight loss and weight maintenance). Arthritis is a common comorbidity of adults with obesity, and arthritis-related joint pain and functional limitation might contribute substantially to low rates of physical activity among adults with obesity. CDC analyzed combined 2007 and 2009 Behavioral Risk Factor Surveillance System (BRFSS) data for adults aged >= 18 years to estimate overall and state-specific prevalence of 1) self-reported doctor-diagnosed arthritis among adults with self-reported obesity, and 2) prevalence of self-reported physical inactivity among adults with obesity by arthritis status. This report describes the results of that analysis, which indicted that, overall, arthritis affected 35.6% of adults with obesity. After adjusting for age, sex, race/ethnicity, and education level, adults with obesity and arthritis were 44% more likely to be physically inactive compared with persons with obesity but without arthritis. Among states, the median prevalence of arthritis among adults with obesity was 35.6%. In every state/area except Guam, the prevalence of physical inactivity among adults with obesity was at least 5 percentage points higher (range: 5.4--15.9 percentage points) among persons with arthritis than those without arthritis. Arthritis might be a special barrier to increasing physical activity among many adults with obesity. Safe and effective self-management education and physical activity programs for adults with arthritis exist to address this barrier, are offered in many communities, and can help adults with obesity and arthritis become more physically active. PMID- 21597455 TI - Ten great public health achievements--United States, 2001-2010. AB - During the 20th century, life expectancy at birth among U.S. residents increased by 62%, from 47.3 years in 1900 to 76.8 in 2000, and unprecedented improvements in population health status were observed at every stage of life. In 1999, MMWR published a series of reports highlighting 10 public health achievements that contributed to those improvements. This report assesses advances in public health during the first 10 years of the 21st century. Public health scientists at CDC were asked to nominate noteworthy public health achievements that occurred in the United States during 2001-2010. From those nominations, 10 achievements, not ranked in any order, have been summarized in this report. PMID- 21597456 TI - Emergency department visits after use of a drug sold as "bath salts"--Michigan, November 13, 2010-March 31, 2011. AB - On February 1, 2011, in response to multiple news reports, the Michigan Department of Community Health (MDCH) contacted the Children's Hospital of Michigan Poison Control Center (PCC) regarding any reports of illness in the state caused by the use of recreational designer drugs sold as "bath salts." Unlike traditional cosmetic bath salts, which are packaged and sold for adding to bath water for soaking and cleaning, the drugs sold as "bath salts" have no legitimate use for bathing and are intended for substance abuse. These products can contain stimulant compounds such as 3,4-methylenedioxypyrovalerone (MDPV) or 4-methylmethcathinone (mephedrone). The PCC told MDCH that, earlier in the day, the PCC had learned that numerous persons had visited the local emergency department (ED) in Marquette County with cardiovascular and neurologic signs of acute intoxication. This report summarizes the subsequent investigation, which identified 35 persons who had ingested, inhaled, or injected "bath salts" and visited a Michigan ED during November 13, 2010-March 31, 2011. Among the 35 patients, the most common signs and symptoms of toxicity were agitation (23 patients [66%]), tachycardia (22 [63%]), and delusions/hallucinations (14 [40%]). Seventeen patients were hospitalized, and one was dead upon arrival at the ED. The coordinated efforts of public health agencies, health-care providers, poison control centers, and law enforcement agencies enabled rapid identification of this emerging health problem. Mitigation of the problem required the execution of an emergency public health order to remove the toxic "bath salts" from the marketplace. Lessons from the Michigan experience could have relevance to other areas of the United States experiencing similar problems. PMID- 21597457 TI - Notes from the field: update on human Salmonella Typhimurium infections associated with aquatic frogs--United States, 2009-2011. AB - CDC is collaborating with state and local public health departments in an ongoing investigation of human Salmonella Typhimurium infections associated with African dwarf frogs (ADFs). ADFs are aquatic frogs of the genus Hymenochirus commonly kept in home aquariums as pets. From April 1, 2009 to May 10, 2011, a total of 224 human infections with a unique strain of S. Typhimurium were reported from 42 states. The isolates are indistinguishable by pulsed-field gel electrophoresis and multiple-locus variable-number tandem repeat analysis. This outbreak likely includes considerably more than the 224 laboratory-confirmed cases reported to CDC; only an estimated 3% of Salmonella infections are laboratory confirmed and reported to surveillance systems. Surveillance for additional cases continues through PulseNet, the national molecular subtyping network for foodborne disease surveillance. PMID- 21597458 TI - Surveillance of health status in minority communities - Racial and Ethnic Approaches to Community Health Across the U.S. (REACH U.S.) Risk Factor Survey, United States, 2009. AB - PROBLEM: Substantial racial/ethnic health disparities exist in the United States. Although the populations of racial and ethnic minorities are growing at a rapid pace, large-scale community-based surveys and surveillance systems designed to monitor the health status of minority populations are limited. CDC conducts the Racial and Ethnic Approaches to Community Health across the U.S. (REACH U.S.) Risk Factor Survey annually in minority communities. The survey focuses on black, Hispanic, Asian (including Native Hawaiian and Other Pacific Islander), and American Indian (AI) populations. REPORTING PERIOD COVERED: 2009. DESCRIPTION OF SYSTEM: An address-based sampling design was used in the survey in 28 communities located in 17 states (Arizona, California, Georgia, Hawaii, Illinois, Massachusetts, Michigan, New Mexico, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Virginia, West Virginia, and Washington). Self reported data were collected through telephone, questionnaire mailing, and in person interviews from an average of 900 residents aged >= 18 years in each community. Data from the community were compared with data derived from the Behavioral Risk Factor Surveillance System (BRFSS) for the metropolitan and micropolitan statistical area (MMSA), county, or state in which the community was located and also compared with national estimates. RESULTS: Reported education level and household income were markedly lower in black, Hispanic, and AI communities than that among the general population living in the comparison MMSA, county, or state. More residents in these minority populations did not have health-care coverage and did not see a doctor because of the cost. Substantial variations were identified in self-perceived health status and prevalence of selected chronic conditions among minority populations and among communities within the same racial/ethnic population. In 2009, the median percentage of men who reported fair or poor health was 15.8% (range: 8.3%-29.3%) among A/PI communities and 26.3% (range: 22.3%-30.8%) among AI communities. The median percentage of women who reported fair or poor health was 20.1% (range: 13.3% 37.2%) among A/PI communities, whereas it was 31.3% (range: 19.4%-44.2%) among Hispanic communities. AI and black communities had a high prevalence of self reported hypertension, cardiovascular disease, and diabetes. For most communities, prevalence was much higher than that in the corresponding MMSA, county, or state in which the community was located. The median percentages of persons who knew the signs and symptoms of a heart attack and stroke were consistently lower in all four minority communities than the national median. Variations were identified among racial/ethnic populations in the use of preventive services. Hispanics had the lowest percentages of persons who had their cholesterol checked, of those with high blood pressure who were taking antihypertensive medication, and of those with diabetes who had a glycosylated hemoglobin (HbA1C) test in the past year. AIs had the lowest mammography screening rate within 2 years among women aged >=40 years (median: 72.7%; range: 69.4%-76.2%). A/PIs had the lowest Pap smear screening rate within 3 years (median: 74.4%; range: 60.3%-80.8%). The median influenza vaccination rates in adults aged >=65 years were much lower among black (57.3%) and Hispanic communities (63.3%) than the national median (70.1%) among the 50 states and DC. Pneumococcal vaccination rates also were lower in black (60.5%), Hispanic (58.5%), and A/PI (59.7%) communities than the national median (68.5%). INTERPRETATIONS: Data from the REACH U.S. Risk Factor Survey demonstrate that residents in most of the minority communities continue to have lower socioeconomic status, greater barriers to health-care access, and greater risks for and burden of disease compared with the general populations living in the same MMSA, county, or state. Substantial variations in prevalence of risk factors, chronic conditions, and use of preventive services among different minority populations and different communities within the same racial/ethnic population provide opportunities for public health intervention. These variations also indicate that different priorities are needed to eliminate health disparities for different communities. PUBLIC HEALTH ACTION: These community level survey data are being used by CDC and community coalitions to implement, monitor, and evaluate intervention programs in each community. Continuous surveillance of health status in minority communities is necessary so that community-specific, culturally sensitive strategies that include system, environmental, and individual-level changes can be tailored to these communities. PMID- 21597459 TI - E3 ubiquitin ligase Hades negatively regulates the exonuclear function of p53. AB - Following DNA damage, p53 translocates to the cytoplasm and mitochondria, where it triggers transcription-independent apoptosis by binding to Bcl-2 family proteins. However, little is known about how this exonuclear function of p53 is regulated. Here, we identify and characterize a p53-interacting protein called Hades, an E3 ligase that interacts with p53 in the mitochondria. Hades reduces p53 stability via a mechanism that requires its RING-finger domain with ubiquitin ligase activity. Hades polyubiquitinates p53 in vitro independent of Mdm2 and targets a critical lysine residue in p53 (lysine 24) distinct from those targeted by Mdm2. Hades inhibits a p53-dependent mitochondrial cell death pathway by inhibiting p53 and Bcl-2 interactions. These findings show that Hades-mediated p53 ubiquitination is a novel mechanism for negatively regulating the exonuclear function of p53. PMID- 21597460 TI - Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3'-deoxyadenosine. AB - The unfolded protein response (UPR) is involved in a diverse range of pathologies triggered by endoplasmic reticulum (ER) stress. Endeavor to seek selective regulators of the UPR is a promising challenge towards therapeutic intervention in ER stress-related disorders. In the present report, we describe aberrant, differential and bidirectional regulation of the UPR by 3'-deoxyadenosine (cordycepin) towards cell survival. 3'-Deoxyadenosine blocked ER stress-induced apoptosis via inhibiting the IRE1-JNK pro-apoptotic pathway. 3'-Deoxyadenosine also inhibited apoptosis through reinforcement of the pro-survival eIF2alpha signaling without affecting PERK activity. It was associated with depression of GADD34 that dephosphorylates eIF2alpha, and dephosphorylation of eIF2alpha by salubrinal mimicked the anti-apoptotic effect of 3'-deoxyadenosine. Unexpectedly, although 3'-deoxyadenosine caused activation of eIF2alpha, it inhibited downstream pro-apoptotic events including induction of ATF4 and expression of CHOP. Cooperation of adenosine transporter and A3 adenosine receptor, but not A1/A2 receptors, mediated the pluripotent effects of 3'-deoxyadenosine. In mice, ER stress caused activation of JNK, expression of CHOP and induction of apoptosis in renal tubules. The apoptosis was significantly attenuated by administration with 3'-deoxyadenosine, and it was correlated with blunted induction of JNK and CHOP in the kidney. These results disclosed atypical pro-survival regulation of the UPR by 3'-deoxyadenosine, which may be advantageous for the treatment of intractable, ER stress-related disorders. PMID- 21597461 TI - Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases. AB - The pathological processes of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases engender synaptic and neuronal cell damage. While mild oxidative and nitrosative (nitric oxide (NO)-related) stress mediates normal neuronal signaling, excessive accumulation of these free radicals is linked to neuronal cell injury or death. In neurons, N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation and subsequent Ca(2+) influx can induce the generation of NO via neuronal NO synthase. Emerging evidence has demonstrated that S nitrosylation, representing covalent reaction of an NO group with a critical protein thiol, mediates the vast majority of NO signaling. Analogous to phosphorylation and other posttranslational modifications, S-nitrosylation can regulate the biological activity of many proteins. Here, we discuss recent studies that implicate neuropathogenic roles of S-nitrosylation in protein misfolding, mitochondrial dysfunction, synaptic injury, and eventual neuronal loss. Among a growing number of S-nitrosylated proteins that contribute to disease pathogenesis, in this review we focus on S-nitrosylated protein-disulfide isomerase (forming SNO-PDI) and dynamin-related protein 1 (forming SNO-Drp1). Furthermore, we describe drugs, such as memantine and newer derivatives of this compound that can prevent both hyperactivation of extrasynaptic NMDARs as well as downstream pathways that lead to nitrosative stress, synaptic damage, and neuronal loss. PMID- 21597462 TI - Metacaspases. AB - Metacaspases are cysteine-dependent proteases found in protozoa, fungi and plants and are distantly related to metazoan caspases. Although metacaspases share structural properties with those of caspases, they lack Asp specificity and cleave their targets after Arg or Lys residues. Studies performed over the past 10 years have demonstrated that metacaspases are multifunctional proteases essential for normal physiology of non-metazoan organisms. This article provides a comprehensive overview of the metacaspase function and molecular regulation during programmed cell death, stress and cell proliferation, as well as an analysis of the first metacaspase-mediated proteolytic pathway. To prevent further misapplication of caspase-specific molecular probes for measuring and inhibiting metacaspase activity, we provide a list of probes suitable for metacaspases. PMID- 21597463 TI - Bax inhibitor-1: a highly conserved endoplasmic reticulum-resident cell death suppressor. AB - In spite of fundamental differences between plant and animal cells, it is remarkable that some cell death regulators that were identified to control cell death in metazoans can also function in plants. The fact that most of these proteins do not have structural homologs in plant genomes suggests that they may be targeting a highly conserved 'core' mechanism with conserved functions that is present in all eukaryotes. The ubiquitous Bax inhibitor-1 (BI-1) is a common cell death suppressor in eukaryotes that has provided a potential portal to this cell death core. In this review, we will update the current status of our understanding on the function and activities of this intriguing protein. Genetic, molecular and biochemical studies have so far suggested a consistent view that BI 1 is an endoplasmic reticulum (ER)-resident transmembrane protein that can interact with multiple partners to alter intracellular Ca(2+) flux control and lipid dynamics. Functionally, the level of BI-1 protein has been hypothesized to have the role of a rheostat to regulate the threshold of ER-stress inducible cell death. Further, delineation of the cell death suppression mechanism by BI-1 should shed light on an ancient cell death core-control pathway in eukaryotes, as well as novel ways to improve stress tolerance. PMID- 21597465 TI - Recommendations to meet statistical challenges arising from endpoints beyond overall survival in clinical trials on chronic myeloid leukemia. AB - The aim of this work was to provide guidelines for appropriate statistical analyses regarding most common endpoints in clinical trials on chronic myeloid leukemia: hematologic, cytogenetic and molecular results, failure-free and event free survival, and progression-free and overall survival. The reasons for the specified recommendations are explained and important issues are outlined by comprehensive examples. Particular attention is paid to the warning of the application of suboptimal methods that may lead to seriously biased results and conclusions. In the presence of a competing risk like death, Kaplan-Meier analysis should not be applied for time-to-remission endpoints. The appropriate method to estimate the probabilities of a time-to-remission endpoint is the calculation of its cumulative incidence function. However, the exact date of remission is hardly known. Detection of remission depends strongly on evaluation frequencies. Complex composite endpoints comprising many events with considerably heterogeneous severity imply difficulties with interpretation. Time-to-remission and complex composite endpoints are not recommended for primary judgment on efficacy. It is rather advisable to investigate remission status at a fixed time point as a primary endpoint, followed by progression-free and overall survival. For patients with the intended remission success at the time point of interest, relapse-free survival provides an additional primary outcome. PMID- 21597464 TI - Caspase-3 deficiency reveals a physiologic role for Smac/DIABLO in regulating programmed cell death. AB - Inhibitor of apoptosis protein (IAP)-binding proteins such as Grim, Reaper and HID have been shown to exert a critical role in regulating caspase activity in species such as D. Melanogaster. However, a comparable role for the mammalian homologue of second mitochondrial-derived activator of caspase/direct IAP-binding protein with low pI (Smac/DIABLO) has yet to be clearly established in vivo. Despite tremendous interest in recent years in the use of so-called Smac mimetics to enhance chemotherapeutic potency, our understanding of the true physiologic nature of Smac/DIABLO in regulating programmed cell death (PCD) remains elusive. In order to critically evaluate the role of Smac/DIABLO in regulating mammalian PCD, deficiency of caspase-3 was used as a sensitizing mutation in order to reduce aggregate levels of executioner caspase activity. We observe that combinatorial deletion of Diablo and Casp3, but neither alone, results in perinatal lethality in mice. Consistent with this, examination of both intrinsic and extrinsic forms of PCD in lines of murine embryonic fibroblasts demonstrate that loss of Smac/DIABLO alters both caspase-dependent and caspase-independent intrinsic PCD. Comparative small interfering RNA inhibition studies of X-linked inhibitor of apoptosis, cellular inhibitor of apoptosis (cIAP)-1, cIAP-2, caspase 6 and -7 in both wild-type and Casp3/Diablo DKO mouse embryonic fibroblast lineages, supports a model in which Smac/DIABLO acts to enhance the early phase executioner caspase activity through the modulation of inhibitory interactions between specific IAP family members and executioner caspases-3 and -7. PMID- 21597466 TI - Antagonistic regulation of EMT by TIF1gamma and Smad4 in mammary epithelial cells. AB - TGF-beta is a potent inducer of epithelial-to-mesenchymal transition (EMT), a process involved in tumour invasion. TIF1gamma participates in TGF-beta signalling. To understand the role of TIF1gamma in TGF-beta signalling and its requirement for EMT, we analysed the TGF-beta1 response of human mammary epithelial cell lines. A strong EMT increase was observed in TIF1gamma-silenced cells after TGF-beta1 treatment, whereas Smad4 inactivation completely blocked this process. Accordingly, the functions of several TIF1gamma target genes can be linked to EMT, as shown by microarray analysis. As a negative regulator of Smad4, TIF1gamma could be crucial for the regulation of TGF-beta signalling. Furthermore, TIF1gamma binds to and represses the plasminogen activator inhibitor 1 promoter, demonstrating a direct role of TIF1gamma in TGF-beta-dependent gene expression. This study shows the molecular relationship between TIF1gamma and Smad4 in TGF-beta signalling and EMT. PMID- 21597468 TI - Transformation of eEF1Bdelta into heat-shock response transcription factor by alternative splicing. AB - Protein translation factors have crucial roles in a variety of stress responses. Here, we show that eukaryotic elongation factor 1Bdelta (eEF1Bdelta) changes its structure and function from a translation factor into a heat-shock response transcription factor by alternative splicing. The long isoform of eEF1Bdelta (eEF1BdeltaL) is localized in the nucleus and induces heat-shock element (HSE) containing genes in cooperation with heat-shock transcription factor 1 (HSF1). Moreover, the amino-terminal domain of eEF1BdeltaL binds to NF-E2-related factor 2 (Nrf2) and induces stress response haem oxygenase 1 (HO1). Specific inhibition of eEF1BdeltaL with small-interfering RNA completely inhibits Nrf2-dependent HO1 induction. In addition, eEF1BdeltaL directly binds to HSE oligo DNA in vitro and associates with the HSE consensus in the HO1 promoter region in vivo. Thus, the transcriptional role of eEF1BdeltaL could provide new insights into the molecular mechanism of stress responses. PMID- 21597470 TI - Autoimmune disease: Blocking the drivers. PMID- 21597469 TI - UV irradiation resistance-associated gene suppresses apoptosis by interfering with BAX activation. AB - Ultraviolet irradiation resistance-associated gene (UVRAG) is a well-known regulator of autophagy by promoting autophagosome formation and maturation. However, little is known about the non-autophagic functions of UVRAG. Here, we present evidence that UVRAG functions as an unusual BCL2-associated X protein (Bax) suppressor to regulate apoptosis. Chemotherapy and radiation induces UVRAG expression and subsequently upregulates autophagy and apoptosis in tumour cells. Depletion of UVRAG expression by RNA interference renders tumour cells more sensitive to chemotherapy- and radiation-induced apoptosis in vitro and in vivo. Moreover, UVRAG interacts with Bax, which inhibits apoptotic stimuli-induced mitochondrial translocation of Bax, reduction of mitochondrial membrane potential, cytochrome c release and activation of caspase-9 and -3. Our findings show that UVRAG has an essential role in the intrinsic mitochondrial pathway of apoptosis by regulating the localization of Bax. This pathway represents a target for clinical intervention against tumours. PMID- 21597471 TI - An NIH National Center for Advancing Translational Sciences: is a focus on drug discovery the best option? PMID- 21597472 TI - Fibrocytes: emerging effector cells in chronic inflammation. AB - Fibrocytes are mesenchymal cells that arise from monocyte precursors. They are present in injured organs and have both the inflammatory features of macrophages and the tissue remodelling properties of fibroblasts. Chronic inflammatory stimuli mediate the differentiation, trafficking and accumulation of these cells in fibrosing conditions associated with autoimmunity, cardiovascular disease and asthma. This Opinion article discusses the immunological mediators controlling fibrocyte differentiation and recruitment, describes the association of fibrocytes with chronic inflammatory diseases and compares the potential roles of fibrocytes in these disorders with those of macrophages and fibroblasts. It is hoped that this information prompts new opportunities for the study of these unique cells. PMID- 21597474 TI - Cytokines: GM-CSF in focus. PMID- 21597473 TI - Mitochondria in innate immune responses. AB - The innate immune system has a key role in the mammalian immune response. Recent research has demonstrated that mitochondria participate in a broad range of innate immune pathways, functioning as signalling platforms and contributing to effector responses. In addition to regulating antiviral signalling, mounting evidence suggests that mitochondria facilitate antibacterial immunity by generating reactive oxygen species and contribute to innate immune activation following cellular damage and stress. Therefore, in addition to their well appreciated roles in cellular metabolism and programmed cell death, mitochondria appear to function as centrally positioned hubs in the innate immune system. Here, we review the emerging knowledge about the roles of mitochondria in innate immunity. PMID- 21597475 TI - Signalling: PI3Kbeta - linking signals for neutrophil activation. PMID- 21597476 TI - T cells: T cell fate in the (im)balance. PMID- 21597479 TI - Neurotransmitter receptors: Negotiating the cytoskeletal tracks in neurons. PMID- 21597477 TI - The insider's guide to leukocyte integrin signalling and function. AB - The activation of leukocyte integrins through diverse receptors results in transformation of the integrin from a bent, resting form to an extended conformation, which has at least two states of ligand-binding activity. This highly regulated activation process is essential for T cell migration and the formation of an immunological synapse. The signalling events that drive integrin activation are complex. Some key players have been well-characterized, but other aspects of the signalling mechanisms involved are still unclear. This Review focuses on the integrin lymphocyte function-associated antigen 1 (LFA1; also known as alphaLbeta2 integrin), which is expressed by T cells, and explores how disparate signalling pathways synergize to regulate LFA1 activity. PMID- 21597480 TI - Molecular neuroscience: Synaptotagmin 10-mediated release. PMID- 21597482 TI - Association between intraocular pressure and adherence: is there one? PMID- 21597485 TI - One-year outcome after intravitreal ranibizumab for large, serous pigment epithelial detachment secondary to age-related macular degeneration. AB - AIM: To report the effects of intravitreal ranibizumab therapy for large, serous pigment epithelial detachment (PED), secondary to age-related macular degeneration, and occupying more than 50% of the total lesion area. MATERIALS AND METHODS: In a retrospective case series, visual acuity, ocular coherence tomography (OCT), and safety data were collected for 19 eyes of 19 patients, with serous PED and evidence of disease progression. Intravitreal ranibizumab of 0.5 mg was given with a loading phase of three consecutive monthly injections, followed by monthly review with further treatment, as indicated according to visual acuity and OCT findings. The change in visual acuity and maximum PED height from baseline to month 12 was determined. RESULTS: Moderate visual loss was avoided in 18/19 eyes (95%) at the 12-month examination. In all, 12 eyes (63%) had an increase in ETDRS letter score from baseline, and five eyes (26%) had a gain of 15 or more letters. Although there was a trend for the PED height to reduce with treatment, in none of the cases was the PED seen to resolve completely. There was no difference in functional or anatomical outcome between the avascular and vascularised serous PED. A single eye developed a retinal pigment epithelium rip, complicated by extensive sub-retinal haemorrhage, during the study period. CONCLUSIONS: Visual acuity outcomes of intravitreal ranibizumab for large serous PED are comparable to those seen in multicentre, phase 3 trials of other lesion types, and were obtained without the need for either monthly, fixed treatment, or for continued treatment until the PED resolves. PMID- 21597488 TI - Channeling the power of scorpion venom. PMID- 21597483 TI - Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration. AB - PURPOSE: There is evidence for complement dysfunction in age-related macular degeneration (AMD). Complement activation leads to formation of the membrane attack complex (MAC), known to assemble on retinal pigment epithelial (RPE) cells. Therefore, the effect of sub-lytic MAC on RPE cells was examined with regard to pro-inflammatory or pro-angiogenic mediators relevant in AMD. METHODS: For sub-lytic MAC induction, RPE cells were incubated with an antiserum to complement regulatory protein CD59, followed by normal human serum (NHS) to induce 5% cell death, measured by a viability assay. MAC formation was evaluated by immunofluorescence and FACS analysis. Interleukin (IL)-6, -8, monocytic chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) were quantified by enzyme-linked immunosorbent assay (ELISA). Intracellular MCP-1 was analysed by immunofluorescence, vitronectin by western blotting, and gelatinolytic matrix metalloproteinases (MMPs) by zymography. RESULTS: Incubation of RPE cells with the CD59 antiserum followed by 5% NHS induced sub-lytic amounts of MAC, verified by FACS and immunofluorescence. This treatment stimulated the cells to release IL-6, -8, MCP-1, and VEGF. MCP-1 staining, production of vitronectin, and gelatinolytic MMPs were also elevated in response to sub-lytic MAC. CONCLUSIONS: MAC assembly on RPE cells increases the IL-6, -8, and MCP-1 production. Therefore, sub-lytic MAC might have a significant role in generating a pro-inflammatory microenvironment, contributing to the development of AMD. Enhanced vitronectin might be a protective mechanism against MAC deposition. In addition, the increased expression of gelatinolytic MMPs and pro-angiogenic VEGF may be associated with neovascular processes and late AMD. PMID- 21597486 TI - Appearance concerns in ophthalmic patients. AB - AIMS: This study aimed to determine the psychosocial and appearance-related concerns of a sample of ophthalmic patients by measuring a range of psychological, social, and demographic factors. METHODS: Standardized psychological measures including anxiety, depression, appearance-related distress, self-discrepancy, appearance salience and valence were administered to 98 participants attending ophthalmic outpatient clinics in either London, Bristol, Sheffield or Bradford. Differences between groups were explored using t tests and ANOVA, relationships between all variables were investigated using Pearson's correlation coefficient. RESULTS: Although mean scores for psychological adjustment were within the normal range, some participants were experiencing considerable levels of generalized anxiety. Being older, male, and married or living with a partner was related to significantly better adjustment. Better adjustment was also related to a less visible area of concern, greater disguisability of the affected area, a more positive evaluation of their own appearance, less engagement in comparing themselves with others, greater feelings of being accepted by others, appearance being less important to their self concept, and a smaller discrepancy between the persons ideal and actual appearance. CONCLUSIONS: A majority of ophthalmic patients adjust positively to the demands placed on them. By identifying the variables that are associated with successful adaptation, the specific psychological interventions and appropriate systems of support can be put in place to help those who are adversely affected. PMID- 21597489 TI - Unraveling sleep. PMID- 21597490 TI - Clearer view of 'acute' glaucoma. PMID- 21597491 TI - Monkeys can recall. PMID- 21597494 TI - Restraint and distress in wild mice. PMID- 21597495 TI - Restraint and distress in wild mice: perhaps a pilot study. PMID- 21597496 TI - Restraint and distress in wild mice: further modifications recommended. PMID- 21597497 TI - Restraint and distress in wild mice: sampling method counts, too. PMID- 21597498 TI - Weight loss, weakness and lymphadenopathy in two vervet monkeys (Chlorocebus spp.). PMID- 21597500 TI - Preventative dental care for dogs in research facilities. AB - For dogs in research facilities, every effort is made to meet the challenge of providing for their exercise needs and environmental enrichment. Another important factor in maintaining their health may be overlooked, however. It is rare that routine dental care and evaluation is provided or that any effort is made to maintain good oral health. PMID- 21597501 TI - Writing clear animal activity proposals. AB - Although IACUC-related topics are frequently discussed in the literature, there is little published information about how to write animal activity proposals. In this article, the author discusses key considerations in the writing and review of animal activity proposals. The author then describes a framework for developing and writing clear animal activity proposals that highlight animal welfare concerns. Though these recommendations are aimed at individuals writing and reviewing research proposals, the framework can be modified for other types of animal activity proposals. PMID- 21597502 TI - A truly global career. AB - An interview with Kathryn Bayne, MS, PhD, DVM, DACLAM, CAAB, Global Director, Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International, Frederick, MD. PMID- 21597504 TI - Healthcare... it's out there! AB - Ensuring that all Australians have access to high quality healthcare has been a longstanding passion for me. Indeed, it is a driving concern for the majority of general practitioners I know. Taking maternity leave from my clinical work has given me the mental space to wonder if my clinical practice adequately reflects these beliefs. When we're all swamped helping 'our' patients (the ones that turn up at least sometimes) it's hard to fathom making policy or practice changes to try to attract in those 'others'; the people that choose not to be patients; the ones that can't, won't or simply don't access general practice. PMID- 21597505 TI - Rural health education. AB - Thirty-five health sciences students and four mentors, including myself, were participating in a 'Country Week' rural health experience in the catchment area of the Murchison River in the midwest of Western Australia. The Murchison, once a gold mining centre, now has a population of about 2500, many of whom live on sheep and cattle stations. PMID- 21597503 TI - Identification of microRNA-target interaction in APRIL-knockdown colorectal cancer cells. AB - MicroRNAs (miRNAs) regulate mammalian gene expression by targeting mRNAs and have key roles in several cellular processes, including differentiation, development, apoptosis and cancer pathomechanisms. Our previous studies have confirmed that a proliferation-inducing ligand (APRIL) gene is overexpressed in colorectal cancer (CRC) tumors and SW480 cells. To study the potential mechanisms of APRIL gene in the occurrence and development of the CRC, herein, we investigated whether APRIL knockdown had the inhibitory effect on the growth of SW480 cells and had the simultaneous expression changes of miRNAs and mRNAs by microarrays. Our results suggest that siRNA-APRIL can effectively inhibit the growth of SW480 cells in vitro and in vivo and several miRNAs via specific pathways might be involved in regulating the phenotype of loss-of-function in APRIL-knockdown SW480 cells. Thus, our study highlights the possible mechanisms of miRNA-target regulating the function of APRIL gene in CRC cells, moreover, siRNA-APRIL holds great promise as a novel gene therapy approach for APRIL- positive CRC treatment. PMID- 21597506 TI - Contraception. AB - From April 2006 to March 2010 in BEACH (Bettering the Evaluation and Care of Health), for females aged 14-17 years, contraception was managed at a rate of 8.8 per 100 encounters, second only to acute upper respiratory infections (10.1 per 100 encounters) as the most common problem managed for this age group. PMID- 21597507 TI - Is this normal? Assessing mental health in young people. AB - BACKGROUND: Mental ill-health is a key health issue facing young Australians today. While the physical health of young people has improved in recent decades, their mental health appears to have worsened. Mental health and substance use disorders now account for over 50% of the burden of disease in the 15-25 years age group, and 75% of mental health disorders that will affect people across the lifespan will have emerged for the first time by the age of 25 years. OBJECTIVE: This article provides the general practitioner with key factors in assessing the young person with a mental illness: when to worry and what the early stages of mental illness look like; and provides guidance and tips for effective treatment. DISCUSSION: Mental ill-health in young people is all too often accepted as a 'normal' feature of adolescence. However, the short and long term consequences of mental illness include impaired social functioning, poor educational achievement, substance abuse, self harm, suicide and violence. Distinguishing between what represents transitory and normative changes in behaviour and disturbances that may represent the early signs of the onset of a potentially serious mental illness is difficult, particularly in young people, where emotional disturbance and distress is such a common experience. The primary goal of initial assessment is not to make a definitive diagnosis but rather to assess risk and the need for clinical care. The GP has an important role to play in longitudinal assessment and ongoing review, and facilitating access to treatment and mobilising support networks. PMID- 21597508 TI - Bullying - effects, prevalence and strategies for detection. AB - BACKGROUND: The mental, physical, social and academic consequences of bullying have an enormous impact on human and social capital. OBJECTIVE: This article describes the effects and prevalence of bullying on young people and presents strategies for its detection. Strategies for the facilitation of a multidisciplinary approach to bullying in adolescents are also presented. DISCUSSION: Given the existing high rate of bullying, assessment should be incorporated into a standard psychosocial screening routine in the general practitioner's clinic. Effective management is a multidisciplinary effort, involving parents, teachers and school officials, the GP, and mental health professionals. Given the variable effectiveness of schools in tackling bullying, GPs play an important role in identifying at risk patients, screening for psychiatric comorbidities, counselling families about the problem, and advocating for bullying prevention in their communities. PMID- 21597509 TI - Combining energy drinks and alcohol - a recipe for trouble? AB - BACKGROUND: Combining energy drinks (such as 'Red Bull((r))') with alcohol is becoming increasingly popular, particularly among young people. However, as yet, limited research has been conducted examining the harms associated with this form of drinking. OBJECTIVE: To review current evidence associated with combining energy drinks with alcohol and provide recommendations for addressing this issue within primary care. DISCUSSION: Combining alcohol with energy drinks can mask the signs of alcohol intoxication, resulting in greater levels of alcohol intake, dehydration, more severe and prolonged hangovers, and alcohol poisoning. It may also increase engagement in risky behaviours (such as drink driving) as well as alcohol related violence. General practitioners should be aware of the harms associated with this pattern of drinking, and provide screening and relevant harm reduction advice. PMID- 21597510 TI - Eating disorders - early identification in general practice. AB - BACKGROUND: Eating disorders are complex illnesses that impact on both the physical and socio-emotional health of young people, and contribute to significant morbidity. Dieting behaviours and body image concerns are common in adolescence and it can be challenging to identify those at the extreme end of this spectrum who are at risk of an eating disorder. OBJECTIVE: This article presents a brief overview of eating disorders, with a focus on early identification in general practice. An approach to diagnosis is outlined together with an update on evidence based treatments. DISCUSSION: General practitioners are uniquely placed to recognise early onset eating disorders, offer intervention and help coordinate and monitor treatment. Early detection and management may contribute to better outcomes. PMID- 21597511 TI - Liver function tests. AB - This article forms part of our 'Tests and results' series for 2011 which aims to provide information about common tests that general practitioners order regularly. It considers areas such as indications, what to tell the patient, what the test can and cannot tell you, and interpretation of results. Liver function tests (LFTs) are a panel of blood markers (Table 1) used to assess and monitor several diseases. However, they are not all true tests of liver function and abnormalities may not reflect liver disease. PMID- 21597512 TI - Diagnosing colorectal polyps and masses - the use of CT colonography. AB - BACKGROUND: Colorectal cancer is common, over 13,000 cases were diagnosed in Australia in 2005. The pathogenesis of colorectal cancer has been well investigated and usually occurs in a predictable sequence progressing from dysplasia, to carcinoma in situ before becoming an invasive malignancy. The symptoms and signs of colorectal polyps and masses are often nonspecific, however, given that polyps are easily cured with polypectomy, it is vital to have an accurate and acceptable diagnostic test. Traditional tests include conventional (optical) colonoscopy and double contrast barium enema. Computed tomographic (CT) colonography is a newer, minimally invasive method for examining the colon for colorectal polyps. OBJECTIVE: To inform general practitioners about CT colonography, its evidence, indications, controversies and extracolonic ancillary findings. DISCUSSION: The evidence supporting CT colonography is discussed along with how it is performed, as well as a discussion of the factors unique to it, such as extracolonic findings and polyp management. PMID- 21597513 TI - Smelly foot rash. AB - A previously healthy Caucasian girl, 6 years of age, presented with pruritic rash on both heels of 6 months duration. The lesions appeared as multiple depressions 1-2 mm in diameter that progressively increased in size. There was no history of trauma or insect bite. She reported local pain when walking, worse with moisture and wearing sneakers. On examination, multiple small craterlike depressions were present, some coalescing into a larger lesion on both heels (Figure 1). There was an unpleasant 'cheesy' odour and a moist appearance. Wood lamp examination and potassium hydroxide testing for fungal hyphae were negative. PMID- 21597514 TI - An odd looking lesion. AB - Mark, 54 years of age, has a nontender lump on his praecordium that has been present 'for a long time'. He vaguely recalls a smaller lump at the same site years ago, which he squeezed, with subsequent resolution. Mark denies any bleeding, however, he has noticed occasional yellowish-brown stains on his shirt. PMID- 21597515 TI - Recurrent haemoptysis. AB - A man, 56 years of age, presents to his general practitioner after coughing up half a cupful of fresh, bright red blood every day for 1 week. He has no other medical complaints. He reports previous pulmonary tuberculosis 12 years ago treated with 6 months of standard therapy. Routine follow up was discontinued after 5 years after no evidence of reactivation. He is a nonsmoker, does office clerical duties and is not known to have diabetes or hypertension. PMID- 21597516 TI - Blood pressure devices - research supports their use in general practice. AB - Should you be using that new blood pressure device on your desk - or is it still in its box? Feedback from focus group sessions suggested that general practitioners were suspicious of the oscillometric blood pressure devices distributed by the High Blood Pressure Research Council of Australia (HBPRCA) as they give 'high' and 'unstable' readings. PMID- 21597517 TI - Anterior shoulder dislocation - seated versus traditional reduction technique. AB - BACKGROUND: Anterior dislocation of the shoulder joint is a common presentation to hospital emergency departments (EDs). AIM: To compare the requirement for sedation and length of ED stay utilising the author's seated shoulder reduction technique (SRT) with traditional shoulder reduction (TSR) techniques in the ED. METHOD: A retrospective chart review of patients presenting to the ED between January 2005 and December 2007 was conducted. The review assessed technique, mean length of stay, sedation requirements and incidence of complications in patients who were treated with either the author's SRT or with TSR. RESULTS: A total of 486 patient charts were reviewed and 404 met inclusion criteria. Patients were categorised into the SRT group: 66 (16.3%) and TSR group: 338 (83.7%). Mean age of the groups was 30 years (SRT) vs. 29 years (TSR), with 80% being male. Mean length of stay in the SRT group was 1.5 hours (95% CI: 1.1-1.9) vs. TSR 2.9 hours (95% CI: 2.3-2.9; p<0.001). Sedation was not required in patients in the SRT group, but was required for all patients in the TSR group. No complications were reported in either group. CONCLUSION: In this study group, the author's technique was successful in reducing anterior shoulder dislocation, without the need for sedation, and reduced length of ED stay when compared to TSR techniques. PMID- 21597518 TI - PORRIGE - a cohort study of general practice registrars. AB - BACKGROUND: Current general practitioner shortages need to be addressed, especially in areas of need. This study was designed to investigate which registrar characteristics were associated with retention in the field of general practice (and in the region of training). METHOD: The authors performed a retrospective cohort study of people who entered general practice training in Tasmania from 1995-2005, and included a crosssectional survey conducted between November 2008 and April 2009 that assessed the association between baseline characteristics and current field of practice and practice location. RESULTS: Fifty-four percent of the cohort was working in general practice in Tasmania at the time of the survey. General practice registrars were more likely to be a GP working in Tasmania if they were nonmedically partnered (OR 14.42, p=0.001). They were also more likely to be living in Tasmania if they were older (OR 1.47, p=0.029) or nonmedically partnered (OR 23.4, p=0.014). DISCUSSION: Regional training providers may best be able to serve their training region by addressing the specific needs of the general practice registrar family unit. PMID- 21597519 TI - Disease awareness advertising - women's intentions following exposure. AB - BACKGROUND: In Australia, where direct to consumer advertising of prescription medicines is prohibited, pharmaceutical companies can sponsor disease awareness advertising targeting consumers. This study examined the impact of disease awareness advertising exposure on older women's reported behavioural intentions. METHOD: Women were approached in a shopping centre and randomly assigned mock advertisements for two health conditions. Disease information and sponsors were manipulated. RESULTS: Two hundred and forty-one women responded to 466 advertisements. Almost half reported an intention to ask their doctor for a prescription or referral as a result of seeing the advertisement, but more reported they would talk to their doctor and ask about treatments and tests. Participants were more likely to report an intention to ask for prescriptions if they perceived the health condition to be severe and themselves susceptible or if they had viewed advertisements containing limited information on the disease. DISCUSSION: Disease awareness advertising may stimulate demand for prescription medicine products. This has serious implications for general practitioners and regulators. PMID- 21597520 TI - Recurrent vulvovaginal candidiasis - current management. AB - BACKGROUND: Management of recurrent vulvovaginal candidiasis can be problematic, and current guidelines are limited by scant evidence. METHOD: The authors found no research on how clinicians manage this condition and whether existing guidelines were followed. To ascertain how recurrent vulvovaginal candidiasis is managed in current clinical practice, a survey was conducted of delegates at a seminar for health professionals with a special interest in vulval conditions. RESULTS: Of the 160 delegates 66 completed the survey, providing a response rate of 41%. The authors found little adherence to current guidelines - only 50% reported using the recommended suppression and maintenance therapy, and only 57% reported using confirmatory diagnostic testing. DISCUSSION: The wide variation in health professionals' management of recurrent vulvovaginal candidiasis reflects the difficulty in treating and managing this condition. The results suggest that clinicians are 'tailoring' treatment to their patients due to a lack of good evidence of effective treatments to guide them. PMID- 21597521 TI - Improving health outcomes in young people - a holistic, team based approach. AB - BACKGROUND: Young people aged 12-25 years are poorly serviced by current models of healthcare; they are under represented in Medicare data and are poor seekers of healthcare. However, the majority of mental health problems commence during this age span, significant sexual health issues arise, and there is poor compliance with treatment for chronic disease. OBJECTIVE: This article describes a holistic, multisector primary healthcare delivery model which may provide a way forward to improve both access and outcomes for young people. DISCUSSION: The 'headspace Gold Coast' model incorporates the relationship the young person has with both the organisation and the individuals within it; a focus on social and vocational rehabilitation; and a team based approach. The model provided at headspace serves an unmet need for young people in urban settings. However, more and ongoing support is crucial, including options for integration into existing primary care. PMID- 21597522 TI - Consent to medical treatment: the mature minor. AB - Can children and young people consent to their own medical treatment? Consent issues involving children and young people are complex. This article examines the legal obligations of general practitioners when obtaining consent to medical treatment from patients who are less than 18 years of age. PMID- 21597523 TI - Department of Veterans' Affairs forms - a guide for GPs. AB - The Department of Veterans' Affairs delivers government programs for eligible veterans and their dependants. General practitioners may be required to fill in forms for clients at two points in the process: to determine initial eligibility for compensation benefits and to request services from providers. This article describes the range of documents used to determine initial eligibility for compensation benefits, healthcare services potentially covered and how to access these services. PMID- 21597524 TI - A division's worth of data. AB - Throughout the international community there is an increasing focus on the benefits of collecting, pooling and analysing patient data. General practice provides a great opportunity to create a comprehensive database of the Australian population as 90% of Australians visit their general practitioner each year and general practices are increasingly computerised. This article discusses the facilitatory role divisions of general practice can play in harnessing quality data from general practice and the benefits that may follow. It describes experience from 3 years of data pooling by the Melbourne East General Practice Network in Victoria and makes recommendations for other organisations interested in data collection. PMID- 21597525 TI - Intellectual disability. AB - From April 2000 to March 2010 in BEACH (Bettering the Evaluation and Care of Health), intellectual disability was managed at a rate of 5 per 10,000 encounters, suggesting it was managed by general practitioners about 49,000 times per year nationally. PMID- 21597526 TI - Sex and intellectual disability--dealing with sexual health issues. AB - BACKGROUND: Sexual health is a vital but often neglected aspect of healthcare for people with intellectual disability. It may initially be difficult for the general practitioner to raise sexuality issues with patients with intellectual disability, but there is potential for simple interventions that offer great benefit. OBJECTIVE: This article describes ways in which the GP may be able to assist people with an intellectual disability with their sexual health needs. DISCUSSION: It is important to engage the person with intellectual disability directly, preferably alone. A person with intellectual disability is likely to have the same range of sexual and relationship needs as other adults. However, there may be multiple barriers to forming healthy, equal sexual relationships. Sexual abuse is widespread. Reporting abuse may be difficult for a person with limited verbal skills, and prevention and support services are limited. The GP is well placed to offer sexual health services such as information, contraception and cervical and sexually transmissible infection screening, and to discourage inappropriate treatments such as sterilisation for social rather than medical reasons, and androgen suppression. PMID- 21597527 TI - Cerebral palsy in childhood. AB - BACKGROUND: Cerebral palsy is the most common cause of physical disability in childhood. While some children have only a motor disorder, others have a range of problems and associated health issues. OBJECTIVE: This article describes the known causes of cerebral palsy, the classification of motor disorders and associated disabilities, health maintenance, and the consequences of the motor disorder. The importance of multidisciplinary assessment and treatment in enabling children to achieve their optimal potential and independence is highlighted. DISCUSSION: General practitioners play an important role in the management of children with cerebral palsy. Disability is a life-long problem which impacts on the child, their parents and their siblings. After transition to adult services, the GP may be the only health professional that has known the young person over an extended period, providing important continuity of care. PMID- 21597528 TI - Behavioural concerns--assessment and management of people with intellectual disability. AB - BACKGROUND: General practitioners often care for people with an intellectual disability, and challenging behaviours are a common presentation, whether the patient lives with their family or in a group home. OBJECTIVE: This article aims to give practical advice on the assessment and treatment of behavioural issues in patients with intellectual disabilities. DISCUSSION: General practitioners can make a significant contribution to improving the quality of life of intellectually disabled persons. Collecting a careful description of the behaviour, assessing for physical causes and considering specific psychiatric diagnoses will help the GP target appropriate intervention. Psychological support under the Better Outcomes in Mental Health Care program can assist in developing behavioural strategies. The role of medication is also discussed. PMID- 21597529 TI - Australians with Down syndrome--health matters. AB - BACKGROUND: The health and life expectancy of Australians with Down syndrome has improved dramatically over recent decades, resulting in more people living into adulthood and accessing community and hospital based health and social services. OBJECTIVE: This article presents information and resources helpful to general practitioners providing healthcare to patients who have Down syndrome. Healthcare issues through the lifespan are explored, the importance of proactive management is emphasised and strategies are outlined. DISCUSSION: Australians with Down syndrome are an interesting and rewarding group of people with whom to work. They present us with particular challenges in the way we provide healthcare and, in doing so, offer us an opportunity to improve the way we work with other patients who have cognitive and communication difficulties; chronic, complex health and social needs; family or paid carers involved in health management and those who require health advocacy as a part of healthcare provision. PMID- 21597530 TI - People with disabilities--a rewarding challenge in general practice. AB - Welcome to an issue of Australian Family Physician that is particularly close to my heart. My son has an intellectual disability, and I understand firsthand the importance and challenges of maintaining optimal health in this group of patients. PMID- 21597531 TI - Bladder cancer--current management. AB - BACKGROUND: Over 2000 cases of bladder cancer were diagnosed in Australia in 2005. Bladder cancer is a relatively common disease with high morbidity if left untreated. Bladder cancer is categorised as either 'nonmuscle invasive bladder cancer' or 'muscle invasive bladder cancer'. Treatment varies significantly for each type. OBJECTIVE: This article provides an update on the presentation of bladder cancer, its risk factors, investigations and treatment, and discusses the role of chemotherapy as a neoadjuvant and adjuvant treatment. DISCUSSION: Bladder cancer most commonly presents with microscopic or macroscopic haematuria. Evaluation is required of all patients with macroscopic haematuria, patients with persistent microscopic haematuria, and at risk patients with a single episode of microscopic haematuria. Evaluation consists of imaging, urine cytology and cystoscopy. Nonmuscle invasive bladder cancer patients can undergo tumour resection with adjuvant intravesical treatments, while muscle invasive bladder cancer patients are optimally treated with cystectomy and urinary diversion. PMID- 21597532 TI - Spirometry. AB - Spirometry measures the flow and volume of air entering and leaving the lungs. It is used to assess ventilatory function and differentiates between normality and diseases causing obstructive and possibly restrictive defects. PMID- 21597533 TI - Patient information--spirometry. PMID- 21597534 TI - S-plasty--clinical applications for skin surgery. AB - Elliptical excision is a simple, cosmetically satisfying and popular technique for surgically removing skin lesions. However, in certain situations, elliptical excision can produce resulting permanent skin deformity that is cosmetically unsightly. This article provides a series of cases that demonstrate clinical applications using S-plasty to produce a more cosmetically satisfying outcome. PMID- 21597535 TI - Women with intellectual disabilities--a study of sexuality, sexual abuse and protection skills. AB - BACKGROUND: Sexual abuse and abusive relationships are known to be especially common in people with intellectual disability. This study explored how women with intellectual disability understand sex, relationships and sexual abuse, the effects of sexual abuse on their lives, and how successfully they protect themselves from abuse. METHODS: Semistructured narrative interviews with nine women with mild intellectual disability in Queensland, Australia. Interviews were audio recorded, transcribed, coded and analysed qualitatively. RESULTS: Major themes that emerged were: sexual knowledge and sources of knowledge; negotiating sexual relationships; declining unwanted sexual contact; self protection strategies; sexual abuse experiences; and sequelae of sexual abuse. DISCUSSION: Most participants reported unwanted or abusive sexual experiences. They described sequelae such as difficulties with sex and relationships, and anxiety and depression. They described themselves as having inadequate self protection skills and difficulty reporting abuse and obtaining appropriate support. Their understanding of sex was limited and they lacked the literacy and other skills to seek information independently. It is important for general practitioners to be aware of the possibility of sexual abuse against women with intellectual disability, and to offer appropriate interventions. PMID- 21597536 TI - Diabetic retinopathy--screening and management by Australian GPs. AB - AIM: To describe current diabetic retinopathy (DR) screening and management practices among Australian general practitioners. METHODS: A self administered questionnaire on DR management was mailed to 2000 rural and urban GPs across Australia in 2007-2008. RESULTS: Only 29% of the GP respondents had read the National Health and Research Council guidelines at least once and 41% had a 'moderate' to 'strong' desire to screen for DR. A majority of GPs (74%) reported not routinely examining their diabetic patients for DR. Lack of confidence in detecting DR changes (86.4%) and time constraints (73.4%) were the two major barriers to GPs performing dilated fundoscopy on diabetic patients. DISCUSSION: Given that access to optometry is not evenly distributed across the country, and that ophthalmology is underresourced, GPs are the healthcare providers most able to manage and screen for DR in the community. PMID- 21597537 TI - Opioid substitution therapy--a study of GP participation in prescribing. AB - BACKGROUND: Opioid substitution therapy (OST) is the most commonly provided treatment for heroin dependence in Australia and has been shown to be effective. Access to OST outside of specialised public clinics and prisons relies on the participation of general practitioners. In Australia there is a shortage of GPs available to prescribe OST, which results in an unmet need for OST services. Studies have reported barriers to GP involvement in drug and alcohol work and there is little research looking at the perceptions and experiences of GPs involved in prescribing OST. METHODS: Semistructured qualitative interviews were conducted with eight experienced prescribers of OST in general practice settings in South Australia. RESULTS: All participants described similar positive and negative aspects associated with prescribing OST. Some participants commenced prescribing in such a manner as to limit the scope of their involvement. Ceasing OST prescribing was not necessarily linked to negative experiences. Exprescribers indicated that they were unlikely to recommence prescribing. DISCUSSION: This study has limited generalisability due to the small sample size but it does highlight some insights that can be gained from talking to experienced OST prescribers. PMID- 21597538 TI - Legal medicine--how to prepare a report. AB - Legal medicine often requires the provision of a report by the general practitioner. This may be either as the treating doctor or as the expert witness providing peer evaluation of a colleague, or to assess professional standards and/or delivery of health services. This article reviews the process and obligations attached to the provision of such a report. PMID- 21597539 TI - Capacity to consent to treatment. AB - A competent adult patient has an ethical and legal right to give, or withhold, consent to an examination, investigation or treatment. Depending on the nature and complexity of an intervention, a patient with an intellectual disability may be capable of consenting to their own medical treatment. In circumstances in which an adult patient does not have the capacity to consent, there is specific guardianship legislation enacted in each state and territory which provides for valid consent by a substitute decision maker. PMID- 21597540 TI - Opportunity cost. AB - Opportunity cost and trade-off - similar concepts with slightly different meanings and definitions in different fields - are concepts that we were all probably first exposed to as a toddler. For most women however, opportunity cost and trade-off is a part of their daily lives as they try to balance their needs, including their health needs, with the demands of their families, careers and never-ending 'to do' lists. PMID- 21597541 TI - Menopause 2000-2010. AB - We used 10 years of data from BEACH (Bettering the Evaluation and Care of Health) to examine changes in rates of menopause management and prescribing of hormone therapy (HT). PMID- 21597542 TI - Menopausal transition -- assessment in general practice. AB - BACKGROUND: The presentation of a woman in midlife can be an opportunity for both the woman and her doctor to consider a wide range of issues that may be impacting on quality of life or that present a risk to her future health. OBJECTIVE: This article considers the assessment of a woman in the menopausal transition. DISCUSSION: The aim of assessment is to manage acute menopausal symptoms (eg. hot flushes); the complications of menopause (eg. osteoporosis); to avoid risk factors for complications (eg. fracture, thromboembolism); and to ensure a preventive healthcare plan is in place. PMID- 21597543 TI - Sex and perimenopause. AB - BACKGROUND: Sexual difficulties are common across the female lifespan, increasing at midlife. Although changing hormone levels at menopause may contribute to the development of female sexual dysfunction, other factors, including relationship issues; psychological wellbeing; physical wellbeing; and medication use, such as antidepressants, need to be taken into consideration. The most common sexual difficulties reported by women across the perimenopause include dyspareunia, diminished desire, arousal capacity and difficulty in achieving orgasm. OBJECTIVE: This article summarises female sexual dysfunction in the perimenopausal woman, and discusses advice the general practitioner can offer women and possible treatment options. DISCUSSION: Many women experience loss of libido, reduced desire, difficulty in achieving orgasm and dyspareunia during their late reproductive and perimenopausal years. It is important that a woman is assessed in the context of her personal circumstances, partnership status, sexual experiences and cultural expectations. Management options range from informative discussions through to counselling and therapeutic intervention. PMID- 21597544 TI - Hormone therapy -- where are we now? AB - BACKGROUND: Menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity. The characteristic symptoms of a fall in oestrogen are vasomotor and urogenital atrophy symptoms; with symptoms reported by up to 85% of women over a mean duration of 5.2 years. Long term consequences of menopause include osteoporosis and cardiovascular disease. Menopause management is highly controversial and can be confusing for both clinicians and their women patients. OBJECTIVE: To explore menopausal management options including comprehensive evaluation; lifestyle modification for symptom relief and risk prevention; hormone therapy or nonhormonal alternatives for symptom relief; prevention and treatment of long term risks; and education and psychological support and therapy. DISCUSSION: Use of hormone therapy involves consideration of the woman's risk-benefit profile. We attempt to clarify this complex topic and focus on the impact of hormone therapy in women aged 50-59 years, including the benefits of relief of hot flushes and urogenital atrophy symptoms and the prevention of fractures and diabetes; and the risks, including venothrombotic episodes, stroke, cholecystitis and breast cancer (with combined oestrogen and progestogen only). Nonhormonal options are also explored. PMID- 21597545 TI - What works? Evidence for lifestyle and nonprescription therapies in menopause. AB - BACKGROUND: Effective prescription medications are available to treat menopausal symptoms. However, due to adverse effects and risks associated with use, many women are seeking complementary and alternative options to treat their symptoms. Nonpharmacological options for the management of menopausal symptoms are widely available and frequently used. OBJECTIVE: This article outlines the use of, and evidence for, nonprescription therapies and complementary therapies for menopausal symptom management. DISCUSSION: There are a large number of studies on complementary and alternative therapies for the management of menopausal symptoms. Lifestyle changes are beneficial and studies on relaxation training are revealing encouraging results. Studies of the benefits of yoga have mixed results. Current evidence from systematic reviews does not support the use of over-the-counter complementary therapies or acupuncture. A large placebo effect exists for the management of hot flushes, therefore further research against active controls is required. Management options should be collaboratively explored. PMID- 21597546 TI - Audiology. AB - An audiogram is a hearing test conducted under ideal listening conditions in a soundproof booth. The test includes different pitches and intensities and the results are conveyed in graphical form. If there is hearing loss an audiogram helps distinguish conductive loss (outer/middle ear) from sensorineural loss (cochlea/cochlear nerve). PMID- 21597547 TI - Just a sore throat? AB - A man, 43 years of age, presents to his general practitioner with a 6 day history of sore throat. There are no other symptoms of an upper respiratory tract infection. In passing, the patient mentions that 6 days ago he experienced an episode of exertional chest pain. On further questioning it is found the chest pain was central with no radiation, it lasted 30 minutes, resolved spontaneously and was associated with nausea. He did not seek medical assessment at the time and has no cardiac history. He takes no regular medication and has no allergies. He is an exsmoker with a 15 pack-year history (he quit 7 years ago) but has no other known cardiac risk factors. He does not drink alcohol or take illicit drugs. On examination, he appears well built with a body mass index of 27. He is not in distress apart from a moderate sore throat. He is afebrile. His heart rate is 66 bpm, regular and his blood pressure is 122/80 mmHg. His tonsils and uvula are neither inflamed nor swollen. He has no cervical lymphadenopathy. His lungs are clear on auscultation and his heart sounds are dual with no murmur. His electrocardiogram is shown in Figure 1. PMID- 21597548 TI - Acute unilateral facial nerve palsy. AB - Mrs PS, 78 years of age, presented with acute left-sided otalgia, ear swelling and subsequent unilateral facial paralysis (Figure 1). She denied any otorrhoea or hearing loss. Past medical history relevant to the presenting complaint included: * Bell palsy diagnosed 20 years ago with no residual effect * biopsy confirmed benign parotid lump (diagnosed 3 years previously). Histopathology revealed a pleomorphic adenoma. Mrs PS declined surgical intervention at the time * chicken pox as a child * normal fasting blood glucose 1 month previously and no known immune compromise. Examination revealed yellow crusts and small vesicles on the external acoustic meatus (Figure 2). A 10 mm well defined firm and nontender nodule was palpable at the ramus of the mandible. PMID- 21597549 TI - Cough from megaoesophagus. AB - Mrs FW, 83 years of age, presented to the emergency department with repeated episodes of attacks of vomiting over several months, coughing, weight loss and worsening shortness of breath. On examination she was not distressed, but mildly dehydrated. Chest examination revealed decreased air entry in both sides of the chest. Heart sounds were muffled. Other examination was within normal limits. PMID- 21597550 TI - Polymyalgia rheumatica -- diagnosis and management. AB - BACKGROUND: Polymyalgia rheumatica (PMR) is a common inflammatory rheumatic disease and an indication for long term treatment with oral steroids. Its incidence rises progressively beyond the age of 50 years. For the most part, PMR is managed in primary care. OBJECTIVE: This article highlights the main points in the British Society for Rheumatology and the British Health Professionals in Rheumatology guidelines that may be useful to general practitioners in the primary care setting. DISCUSSION: Different levels of awareness of the condition between practitioners, and a lack of uniform diagnostic criteria may impede correct diagnosis and management of PMR. Updated international guidelines produced by the British Society for Rheumatology and the British Health Professionals in Rheumatology can aid diagnosis and direct treatment and disease monitoring. PMID- 21597551 TI - Cardiovascular absolute risk assessment -- a research journey in general practice. AB - General practitioners are asked to implement new tools or approaches often without attention being paid to whether these are acceptable, feasible and effective in the primary care context. Cardiovascular absolute risk (CVAR) assessment is recommended in clinical practice guidelines and assessment tools have been disseminated. It combines multiple risk factors to estimate the probability that an individual will develop cardiovascular disease (CVD) in a given period of time. Australian guidelines state that 'it is reasonable to expect that a CVD prevention strategy based on estimated absolute risk will be more effective and enable more efficient use of resources, than the traditional clinical management approach based on identifying and correcting individual risk factors through the application of several separate guidelines'. PMID- 21597552 TI - Follow up after breast cancer -- views of Australian women. AB - BACKGROUND: Survivorship care after breast cancer treatment is increasingly complex as it aims to manage the long term effects of cancer and its treatment, including psychosocial needs. While survivorship care is traditionally delivered by surgeons and specialist oncologists in Australia, general practitioners are ideally placed to manage these issues. METHODS: This study explored the attitudes of 20 breast cancer survivors to GP involvement in follow up care through semi structured telephone interviews, which were analysed using qualitative methods. RESULTS: Women were reluctant to change from specialist based care but identified many potential benefits of GP involvement in long term cancer care. They expressed an interest in shared care programs between specialists and GPs. Some participants thought that additional training may be required if GPs were to deliver this care. CONCLUSION: This study shows cautious interest from breast cancer survivors for increasing GP involvement in follow up care. These views should be considered as alternative models of care are developed. PMID- 21597553 TI - Long term persistence with statin therapy -- experience in Australia 2006-2010. AB - BACKGROUND: Long term persistence on statin drugs has been shown to be unsatisfactory, however, there is little recent Australian data. This study examines current persistence Australia-wide in patients who have been newly prescribed a statin drug. METHOD: We conducted a longitudinal assessment of Pharmaceutical Benefit Scheme claim records dating from April 2005 to March 2010. Main outcome measures were the proportion of patients who were not filling a first repeat prescription at 1 month, and median persistence time during follow up. RESULTS: For 77,867 patients initiated to statin, 86% of prescriptions came from general practitioners. Forty-three percent of patients discontinued statin within 6 months, 23% failed to collect their first repeat at 1 month, and median persistence time was only 11 months. In those aged 65--74 years, median persistence time was 19 months but only 3--6 months for those less than 55 years. DISCUSSION: Unsatisfactory long term persistence on statin therapy has changed little over the past 10 years. There may be an opportunity for early intervention within 3--4 weeks of initiation to improve persistence, as valuable resources are being wasted and an opportunity for disease prevention missed. PMID- 21597554 TI - Antibiotics for URTI and UTI -- prescribing in Malaysian primary care settings. AB - BACKGROUND: Overprescription of antibiotics is a continuing problem in primary care. This study aims to assess the antibiotic prescribing rates and antibiotic choices for upper respiratory tract infections (URTI) and urinary tract infections (UTI) in Malaysian primary care. METHOD: Antibiotic prescribing data for URTI and UTI was extracted from a morbidity survey of randomly selected primary care clinics in Malaysia. RESULTS: Analysis was performed of 1,163 URTI and 105 UTI encounters. Antibiotic prescribing rates for URTI and UTI were 33.8% and 57.1% respectively. Antibiotic prescribing rates were higher in private clinics compared to public clinics for URTI, but not for UTI. In URTI encounters, the majority of antibiotics prescribed were penicillins and macrolides, but penicillin V was notably underused. In UTI encounters, the antibiotics prescribed were predominantly penicillins or cotrimoxazole. DISCUSSION: Greater effort is needed to bring about evidence based antibiotic prescribing in Malaysian primary care, especially for URTIs in private clinics. PMID- 21597556 TI - Depression in general practice -- consultation duration and problem solving therapy. AB - BACKGROUND: General practitioners have expressed concern that consultations offering psychological therapy approaches will take up too much time. However, problem solving therapy (PST) for depression may be able to be used within the time constraints of general practice. This study investigates whether GPs' concerns that PST would result in unacceptably long consultations are justified. METHOD: general practitioners were observed providing PST in simulated consultations before and after PST training - PST skill and duration of consultations were measured. RESULTS: Twenty-four GPs participated. Problem solving therapy skill increased markedly, but mean consultation duration changed minimally: 17.3 minutes and 17.9 minutes. DISCUSSION: This research suggests that GPs can provide an evidence supported psychological treatment for depression within the time constraints of routine practice. The structured nature of PST may allow GPs to provide additional mental healthcare for depression, without significantly increasing consultation duration. It suggests GPs' concerns about the time PST may take up in practice may be unjustified and that further research into the use of PST in routine general practice should be undertaken. PMID- 21597555 TI - Indigenous community care -- documented depression in patients with diabetes. AB - AIM: This article reports on documented levels of depression among people with diabetes attending indigenous primary care centres. METHOD: Between 2005 and 2009, clinical audits of diabetes care were conducted in 62 indigenous community health centres from four Australian states and territories. RESULTS: The overall prevalence of documented depression among people with diabetes was 8.8%. Fourteen (23%) of the 62 health centres had no record of either diagnosed depression or prescription of selective serotonin reuptake inhibitors among people with diabetes. For the remaining 48 centres, 3.3-36.7% of people with diabetes had documented depression. DISCUSSION: The results of this study are inconsistent with the evidence showing high prevalence of mental distress among indigenous people. A more thorough investigation into the capacity, methods and barriers involved in diagnosing and managing depression in indigenous primary care is needed. PMID- 21597557 TI - Centrelink forms -- a guide for GPs. AB - Centrelink is a Commonwealth Government agency that delivers payments and services to the Australian community. This article highlights the range of forms general practitioners are commonly asked to complete for Centrelink clients and provides tips on accurate completion of these forms. This article is based on information outlined in the Centrelink factsheet 'Helpful information for medical practitioners: Centrelink medical report - Disability Support Pension' and on the Centrelink and Department of Families, Housing, Community Services and Indigenous Affairs website. The information contained within this article has been checked for accuracy by Centrelink. PMID- 21597558 TI - Mifepristone in South Australia -- the first 1343 tablets. AB - BACKGROUND: Mifepristone has recently become available in Australia but its use is restricted. OBJECTIVE: To describe the use of mifepristone in South Australia in the period 2009-2010 and to explore options that may become available to general practitioners. DISCUSSION: Mifepristone has been added to regimens for early and second trimester abortions - both medical and surgical abortions. It has been most commonly used in early medical abortions. In this audit the complication rates of early medical abortion with mifepristone compared favourably to early surgical abortion. There are implications in service delivery of early medical abortion compared to early surgical abortion. PMID- 21597559 TI - Cardiac stress tests - which one should I choose? AB - Chest pain is a common cause of presentation to the Acute Medical Unit and the use of cardiac stress imaging in these patients is becoming more widespread. This article aims to provide Acute Physicians with a basic understanding of the different modalities and how to select a particular test for a given patient. PMID- 21597560 TI - Critical care outreach: a review of current practice and evidence. AB - Critical Care Outreach teams have been developed in most acute hospitals within the UK. This article aims to summarise the evidence behind the development of this service and some of the outcomes which have been demonstrated to-date. PMID- 21597561 TI - Tension pneumocephalus with cerebrospinal fluid rhinorrhoea in a post craniotomy patient. AB - Tension pneumocephalus is an uncommon but important complication of neurosurgery, often requiring urgent surgical intervention. It should be considered in any patient presenting with neurological symptoms after recent craniotomy, particularly if they also have clinical features consistent with cerebrospinal fluid (CSF) leak. We describe a patient who presented four weeks post-craniotomy with fluctuating neurological signs and CSF rhinorrhoea, who made a full recovery following repair of a frontal sinus defect and dural tear. PMID- 21597562 TI - Septic pulmonary embolism in an intravenous drug user. AB - A recent case of septic pulmonary embolism in an intravenous drug user, complicated by issues of recurrent self discharge and delays in diagnosis yields opportunity to increase awareness of this uncommon yet life-threatening disorder. The literature is reviewed and includes suggested aids to raise clinical suspicion and improve subsequent management. PMID- 21597563 TI - Melanomatous Leptomeningeal Carcinomatosis masquerading as Guillain-Barre Syndrome. AB - A 49 year old man presented with rapid onset paraparesis, evidence of lower motor neurone features and sensory impairment following a respiratory tract infection. Initially he was treated with intravenous immunoglobulins for suspected Guillain Barre syndrome (GBS). Subsequent cerebrospinal fluid (CSF) analysis identified unexpectedly high protein levels (attributable to Froin's syndrome1) and magnetic resonance imaging (MRI) was highly suggestive of leptomeningeal carcinomatosis and cerebral metastases secondary to disseminated malignant melanoma. The disease progressed with rapid deterioration despite high dose corticosteroids and the patient died 12 days after admission. This case brings several key points to the attention of the acute physician, in particular the need to give serious consideration to the differential diagnosis of cancer in a patient presenting with lower limb weakness. PMID- 21597564 TI - Lead Poisoning presenting as acute severe myalgia: Why was the diagnosis delayed and what lessons can we learn as acute physicians? AB - Patients presenting to the "front door" with acute neuromuscular symptoms are challenging. Toxins need consideration as possible causative agents if there is the possibility of relevant exposure. This requires a thorough history1 and an awareness of local ethnic, social and industrial cultures within the practice locality. We describe a case of lead poisoning in a 35 year old man who presented with severe, progressive, myalgia. We consider that basic errors in clinical processing delayed a potentially difficult and serious diagnosis and these are discussed. The importance of maintaining a thorough initial clerking process within the Acute Medical Unit is highlighted. This should include a comprehensive occupational history. Acute physicians should familiarize themselves with local industry and the toxic syndromes they can produce. PMID- 21597565 TI - Not just a rash! AB - Henoch-Schonlein Purpura (HSP) is the most common systemic vasculitis in childhood and can present in adults. It is a self-limiting disease characterised by a tetrad of manifestations including the mandated typical cutaneous hallmark. We present a classic case of HSP complicated by gastrointestinal haemorrhage associated with hidradenitis suppurativa. PMID- 21597566 TI - Emphysematous Pyelonephritis in a non-diabetic post-operative Transsexual patient. AB - We describe the rare condition of emphysematous pyelonephritis (EPN) in a non diabetic patient who had previously undergone gender reassignment surgery. The report discusses the acute management and treatment and then provides background to the aetiology and historical aspects of the condition. PMID- 21597567 TI - Picture quiz: 'the upper hand'. AB - A 76 year-old right-handed man presented acutely with a sudden onset of weakness affecting his right hand only. This happened while working in the garden. On detailed history taking, he denied any previous symptoms, trauma or prodromal illnesses. He denied any other neurological symptoms. PMID- 21597568 TI - Minimising delays in commencing therapeutic hypothermia after out-of-hospital cardiac arrest: the importance of a multi-disciplinary team approach. AB - Therapeutic hypothermia (TH) is now a well established therapy in resuscitation guidelines. We retrospectively analysed our first 18 months' data for all patients who underwent TH for out-of-hospital cardiac arrest (OHCA), measuring delays incurred during each patient episode, safety, and ICU outcomes. Sixteen patients received TH for OHCA. A mean delay of 248mins occurred following hospital admission to commencing therapy. Seven patients survived to hospital discharge with a 6 month Glasgow Outcome Score of 4-5 in 100%. A questionnaire evaluating 30 first responders' familiarity and knowledge of TH demonstrated poor awareness and knowledge, with most viewing it with low priority. TH is a safe and easy to achieve therapy, however in practice there are significant delays in commencing treatment. PMID- 21597569 TI - Patients' perception of physical aspects of an Emergency Assessment Unit: a questionnaire study. AB - OBJECTIVE: To explore patient's perceptions regarding the physical environment of an Emergency Assessment Unit (EAU). DESIGN/SETTING: Questionnaire study at the time of discharge from the EAU of a UK District General Hospital Participants: All patients who were admitted through the EAU for three consecutive days. RESULTS: Availability of modern facilities, close proximity to home and cleanliness were considered important parameters by <75% of patients. More than half of the patients considered presence of quiet space, good ward aesthetics and hospital food, provision of telephone and television facility, good ward security and ample hospital parking to be important aspects of an EAU. CONCLUSIONS: Patient views should form a key part of design when considering the physical environment of an EAU. PMID- 21597571 TI - Selected abstracts from the 3rd international meeting of the society for acute medicine. AB - Over 100 posters were presented at the 3rd International meeting of the Society for Acute Medicine, held on 1st-2nd October at the National Exhibition Centre in Birmingham. The following are abstracts from the posters which were awarded 'best poster' prizes by the judging panel, in the categories for Case Reports, Service Organisation and Delivery and Audit/Research. PMID- 21597570 TI - Picture quiz: answer. AB - While peripheral lesions account for a significant proportion of cases presenting with isolated motor hand weakness (Box 1), this case illustrates the importance of recognizing infarction of the hand knob area as a cause for such a presentation. An accurate history is essential, along with a detailed systemic and neurological examination performed, particularly looking for other neurological findings that may hint towards a peripheral cause or involvement of more areas cortically. The presence of weakness of all muscle groups is unusual in peripheral nerve lesions and led in this case to the initial investigation with cerebral MRI, which provided the diagnosis. PMID- 21597572 TI - Aortic dissection: a review of the diagnosis and initial management. AB - Aortic dissection is a medical emergency which carries a high mortality, particularly if undiagnosed and untreated. The diagnosis may be overlooked because the 'classical' history, examination and imaging signs are present in only a minority of cases. After reflecting on the underlying pathophysiology, this review examines aspects of the history and examination which should alert Acute Physicians to a possible diagnosis of aortic dissection. The relative benefits of different imaging techniques are summarised, along with the prognosis and treatment for different types of aortic dissection. Finally a case of aortic dissection which went undiagnosed for a month is presented to illustrate some of the key teaching points raised in this article. PMID- 21597573 TI - Hypernatraemia in adults: a clinical review. AB - Dysnatraemic disorders are becoming more common with increased use of biochemical tests in routine practice. Although hyponatraemia is generally much commoner than hypernatraemia, the latter is found in a variety of clinical situations. This review article aims to explain the approach to assessment and strategies for management of hypernatraemia, complications of its treatment and the steps that can be taken for prevention of recurrence. PMID- 21597574 TI - A review of the clinical and legal issues surrounding refusal of treatment following overdose. AB - This article reviews the clinical and legal issues involved in dealing with patients who refuse medical treatment following an overdose. We first describe a real case that has been made anonymous, before discussing a general approach to management. We then review the relevant legislation, including the Mental Capacity Act (2005), the Mental Health Act (1983) and legal issues surrounding the treatment of young people. We discuss how this legislation may be applied in practice and then conclude with the outcome of the case, sources of further information and some key learning points. PMID- 21597575 TI - Angioedema caused by bupropion treatment. AB - Reports of urticaria and rash with bupropion are common, with an estimated incidence of 1-4%. Serious adverse reactions, including seizures and angioedema occur less commonly, but may be dose related. Rarely patients present with fever, arthralgia and myalgia resembling a serumsickness reaction. A case of a 30 year old man presenting with a rash, angioedema, and arthralgia 19 days after commencing bupropion treatment to aid smoking cessation is described. Treatment with antihistamines and steroids, resulted in improvement within 3 hours, and complete resolution after 3 days. Management also included identifying and discontinuing the causative agent. Recent concerns over neuropsychiatric side effects of bupropion are highlighted. The literature is reviewed and recommendations for safer prescribing discussed. PMID- 21597576 TI - A successful case of repeat thrombolysis in acute prosthetic valve thrombosis. AB - Acute heart failure is an important presentation in the Acute Medical Unit. We describe a case of successful repeat thrombolysis in an elderly woman presenting as an emergency with severe pulmonary oedema, due to acute prosthetic mitral valve thrombosis. The diagnostic imaging and therapeutic modalities available are also described.This case highlights the need for acute physicians to consider prosthetic valve thrombosis in the differential for patients with metallic heart valves who present with acute heart failure or cardiogenic shock. PMID- 21597577 TI - Spontaneous spinal extradural haematoma presenting with chest pain: a case report and literature review. PMID- 21597578 TI - Scombrotoxin poisoning: an important differential diagnosis for anaphylaxis. AB - We report a case of scombrotoxin poisoning, an acute illness that develops within minutes to hours of eating poorly processed oily fish, such as tuna or mackerel. It presents with symptoms that can mimic an anaphylactic reaction. It is presumed to arise due to ingestion of histamine that is formed by contaminating bacteria that have flourished during periods of suboptimal refrigeration, following capture. Knowledge of this underdiagnosed malady as a potential differential diagnosis for patients presenting with symptoms suggestive of histamine release is important. It is a notifiable condition. The alternative diagnosis of anaphylaxis may have significant lifestyle implications for the patient. This article reports on one such presentation and the way that the diagnosis was explored. PMID- 21597579 TI - Buttock cellulitis as a presentation of psoas abscess: a clinical reminder. AB - Cellulitis is a common condition that is frequently managed by the general physicians on an acute medical take. This case report describes buttock cellulitis as a presentation of an iliopsoas abscess and illustrates the importance of considering a deep abscess when there are atypical features, when the cellulitis is in an unusual location or when the patient fails to improve with standard anti-microbial therapy. PMID- 21597580 TI - Acute sarcoidosis: 3 cases in an acute medical clinic. AB - Sarcoidosis is a cryptogenic multisystem granulomatous disorder. We present three patients who presented acutely with erythema nodosum in our Medical Assessment Unit (MAU) or attended our clinic, subsequently diagnosed with acute sarcoidosis. In doing so, we aim to demonstrate that this presentation can easily be seen on the acute medical take, focussing on the management of acute sarcoidosis in association with erythema nodosum. Although patients will often not display florid systemic upset on presentation, we recommend follow-up after initial presentation, to ensure good resolution of symptoms. PMID- 21597581 TI - Training requirements for point of care ultrasound in acute medicine. AB - The aim of the study was to explore the ultrasound training requirements in acute medicine by comparing the ultrasound skill of an acute medicine trainee (AMT) with that of the radiology department following short ultrasound training. RESULTS: 43 participants (34 males and 9 females).The mean age was 58 (range 20 93 years). Liver: AMT reported 15/17 as normal (Specificity 88%) and diagnosed ascites in 100% (NPV 93%). Gallbladder: There was 100% sensitivity and NPV for excluding gallstone. CBD: Sensitivity and specificity of 83 and 95% for dilated CBD (NPV 95%). Kidneys: AMT identified 100% of normal kidneys. Spleen: Splenomegaly diagnosed with 95% specifity and NPV. CONCLUSION: The AMT achieved a high level of accuracy in diagnosing and excluding gallstone, dilated CBD, ascites and splenomegaly. CBD = Common Bile Duct, NPV=Negative Predictive Value. PMID- 21597582 TI - A profile of nurses working in acute medicine units: what is the future? AB - A survey of registered nurses working in two acute medicine acute medicine units (AMUs) was conducted between May & September 2009 to enable a focussed understanding of nursing recruitment and retention, to guide nurse managers for future workforce planning. The NHS collects national information regarding recruitment, retention and leavers, but this is sporadic and hampered by a lack of feedback to clinical areas. In this study, fifty completed questionnaires were collated, totalling a response rate of 57.5%. The results demonstrate that while recruitment is currently buoyant, nurses with significant experience are becoming dissatisfied through lack of opportunity to advance. It concludes that further national research is required to inform a strategy fit for the future development of nursing in acute medicine. PMID- 21597584 TI - The NICE Guideline on chest pain of recent onset: what does it mean for the acute physician? PMID- 21597583 TI - Picture quiz: all in the head? Behcet disease. PMID- 21597587 TI - Management of acute ischaemic stroke in the acute medical unit. AB - Ischaemic stroke is a major cause of death and disability which costs the NHS L2.8 billion/year. Acute stroke care is developing rapidly in line with an increasing evidence base. Intravenous thrombolysis is now recommended by NICE. For this guidance to be effectively implemented stroke must be viewed as a medical emergency by both the public and professionals. Emergency medical services must work in partnership with stroke services to establish systems and protocols which offer high quality acute stroke care. This provides challenges, both in systems design and delivery of clinical care. PMID- 21597588 TI - Takayasu's Arteritis: an important cause of stroke in younger patients. AB - Stroke in young patients is important and early diagnosis of Takayasu's Arteritis as the cause will assist in acute management. A retrospective notes review of six patients presenting with acute neurological symptoms secondary to TA was performed. Three male and three female patients (mean age of 32.2 years) were identified. Neurological presentations included four ischaemic strokes, one TIA, and one syncopal episode. Pulse loss, bruit, or a difference in brachial blood pressures was evident in five patients at presentation. 4 patients had a previous history of TIA, 3 had prior ischaemic limb symptoms and 1 had prodromal symptoms. A history of limb ischaemia, prodromal symptoms, absent pulses and asymmetric blood pressure should alert the clinician to possible TA. PMID- 21597589 TI - A simple educational programme substantially reduces unnecessary use of coagulation screening testing in an acute medical department. AB - A review suggested that coagulation screening tests (CST) were frequently performed unnecessarily in our Acute Medical Department. We reviewed the records of all patients for whom CST was ordered in one week (n141) before designing and delivering an e-mail, poster and presentation based educational programme to clinicians. We repeated the review of records three weeks after this programme (n79). The proportion of patients in whom CST was ordered was significantly lower (22% versus 32%, p0.0014) and proportion of CSTs sent with a valid indication was significantly higher (87% versus 49%, p 0.0001) in the second review period. This study demonstrates that a simple educational programme substantially reduces unnecessary use of CST in an acute medical department with significant potential efficiency savings. PMID- 21597590 TI - General medical follow-up clinics - does the traditional model need to be updated for new traditional model need to be updated for new acute physicians? AB - The follow up arrangements were reviewed for 212 patients discharged from our Medical Admissions Unit (MAU) prior to the appointment of an acute medical consultant. 19 patients (9%) were referred to speciality clinics, with only 1 patient being followed-up in a 'general' medical clinic; the patient's GP was requested to follow up the majority of the outstanding results. Based on these results there appears little need or acute medical consultants to undertake 'traditional' outpatient follow-up clinics. Acute medical clinics may have other roles in enabling admission avoidance and reducing length of hospital stay. PMID- 21597591 TI - Following National Guidelines in Acute Care can improve emergency access and patient flow. AB - This paper describes how a Foundation Trust was able to meet emergency access targets. The Acute Medical Unit (AMU) was expanded from 29 to 81 beds and patients with expected length of stay (LOS( of less than 5 days were managed by the acute medical team only. Acute physicians provided twice-daily ward rounds on the expanded facility, including weekends, supported by specialist teams, allied healthcare professionals and investigation facilities. Within three weeks, the admission process had improved dramatically. Average LOS had decreased by 1.3 days and bed-occupancy was reduced from 98% to 91%. Having failed to achieve the 98% target for 4 consecutive months prior to these changes, the target was subsequently attained consistently. Re-admission rates, percentage mortality rate and numbers of complaints were unaffected. PMID- 21597592 TI - Epinephrine induced leucocytosis in a non-infective exacerbation of asthma. AB - In life-threatening cases of Acute Asthma the administration of epinephrine may be given as part of the initial management by paramedics. Concurrent infection is a frequent precipitant of an asthma exacerbation and consequently a leucocytosis is often found in such a situation. This case illustrates that marked leucocytosis can occur without an underlying infective process following epinphrine use. PMID- 21597593 TI - Pneumo-peritoneum following PEG insertion: a clinical dilemma. AB - We present the case of a 48 year old male with multiple sclerosis who later became unwell with fever and vague abdominal pain 2 days after inserting a percutanous endoscopic gastrostomy (PEG) tube. His chest x-ray showed gas under the diaphragm. As a result of this, a laparotomy was performed which found no evidence of intra-abdominal sepsis. We discuss the importance of recognising 'benign' pneumoperitoneum following PEG insertion. Further imaging, such as abdominal CT scan is desirable prior to consideration of laparotomy when diagnostic uncertainty exists. PMID- 21597594 TI - DRESS Syndrome caused by allopurinol. AB - DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome is a potentially fatal and probably underrecognized complication of allopurinol. We present the case of a 33 year old male with this condition who required intensive care support and subsequently improved following corticosteroid therapy. We review the literature considering optimal strategies for treatment and prevention of this condition. We believe that acute physicians clinicians should have greater awareness of this complication of allopurinol therapy. PMID- 21597595 TI - Headache and high ESR: A cautionary tale. AB - A 69-year-old woman with new persistent right temporal headache and high ESR was diagnosed with temporal arteritis in primary care. She was started on steroids, but developed a right 6th nerve palsy with continuing headache and raised inflammatory markers. Investigation revealed a sphenoid sinus abscess with intracranial extension and extensive cerebral venous sinus thrombosis. The abscess was drained endoscopically and she was treated with antibiotics and anticoagulation. Over the course of two months she made a complete recovery. PMID- 21597596 TI - Cardiac arrest following paracetamol overdose complicated by hypokalaemia. AB - We present a case of paracetamol overdose in a 34-year-old female with a history of depression and alcoholism. Following treatment with N-acetylcysteine (Parvolex(r)) our patient developed ventricular tachycardia resulting in cardiac arrest from which she was successfully resuscitated. Subsequent ECG demonstrated prolongation of the QTc interval and repeat blood tests revealed a significant fall in serum potassium from 4.2mmol/l on admission to 2.2mmol/l. The possible mechanisms contributing to the development of hypokalaemia after overdose with paracetamol are discussed. The existing literature relating to paracetamol induced hypokalaemia is briefly reviewed. PMID- 21597597 TI - Picture quiz: a bad case of the flu. AB - A 51-year-old man who was normally fit and well, presented with a one-week history of fever, cough, shortness of breath, myalgia and diarrhoea. On examination he was febrile at 37.8 degrees C, acutely short of breath with oxygen saturations of 75% on 15L of oxygen via a non re-breath mask and a respiratory rate of 25. PMID- 21597598 TI - Aortic dissection. AB - Dear Editor, We read with interest the article "Aortic dissection: a review of the diagnosis and initial management" by Thompson-Moore and Papouchado1; the authors do not mention pleural effusion as a presenting x-ray feature of this condition. A case in our unit highlights the importance of considering aortic dissection for patients with unexplained haemothorax. PMID- 21597599 TI - The changing face of chest pain. AB - I read with interest the article " The NICE Guideline on chest pain of recent onset: What does it mean for the Acute Physician?".1 I struggle to recall a day's take occurring without at least one or two patients presenting to the Acute Medical Unit (AMU) with chest pain, awaiting Troponin results. To admit the majority of these patients for prolonged observation, and ECG monitoring may waste resources, but needs to be weighed up against the risk of missing the one 'troponin negative' acute coronary syndrome with an atypical history. PMID- 21597600 TI - Picture quiz: a bad case of the flu (answers). AB - Our case highlights an uncommon complication of nasogastric tube insertion. Enteral feeding plays an essential role in recovery from critical illness. Benefits include increasing blood flow... PMID- 21597601 TI - Acute medicine journal survey. AB - A short survey was circulated by email to members of the Society for Acute Medicine receiving the Acute Medicine journal in January 2010. Responses to the questions relating to journal content and layout are summarised in the figures below (Figures 1-5). There were 75 responses in total, representing just over 10% of those surveyed. PMID- 21597603 TI - Selected abstracts from the 4th international meeting of the society of acute medicine. AB - Delegates at the 4th International conference of the Society for Acute Medicine in October were treated to some un-seasonal sunshine, as well as a programme of exceptional quality. More than 200 abstracts were submitted for consideration of inclusion; 6 were selected for oral presentation and 130 posters were displayed. The oral presentation abstracts and those from the 3 prize-winning posters are included here. PMID- 21597602 TI - The 4 hour emergency access target - a patient journey. AB - During the late nineties it was not uncommon for patients to wait over 12 hours for admission to hospital and there were isolated reports of patients waiting between 24 and 48 hours on trolleys in accident and emergency and sometimes in corridors. My interest in this problem and the long delays experienced by patients in Emergency Departments in the UK developed during early work with the Modernisation Agency. PMID- 21597604 TI - Towards cleaner combustion engines through groundbreaking detailed chemical kinetic models. AB - In the context of limiting the environmental impact of transportation, this critical review discusses new directions which are being followed in the development of more predictive and more accurate detailed chemical kinetic models for the combustion of fuels. In the first part, the performance of current models, especially in terms of the prediction of pollutant formation, is evaluated. In the next parts, recent methods and ways to improve these models are described. An emphasis is given on the development of detailed models based on elementary reactions, on the production of the related thermochemical and kinetic parameters, and on the experimental techniques available to produce the data necessary to evaluate model predictions under well defined conditions (212 references). PMID- 21597605 TI - The role of the environment in electronic energy transfer: a molecular modeling perspective. AB - The key role of the environment in electronic energy transfer has been underscored in recent experimental and theoretical studies. In this perspective, we provide an overview of novel quantum-mechanical methodologies aimed at describing environment effects in energy transfers. The techniques described include continuum dielectric and atomistic descriptions of the surroundings. We discuss the advantages and limitations of each technique, as well as the main insights that have emerged from their application to solvated dyads and photosynthetic pigment-protein complexes. We finally highlight the aspects that still need to be solved in order to provide a full theoretical route to the study of energy transfer phenomena in complex environments. PMID- 21597606 TI - Structures and IR/UV spectra of neutral and ionic phenol-Ar(n) cluster isomers (n <= 4): competition between hydrogen bonding and stacking. AB - The structures, binding energies, and vibrational and electronic spectra of various isomers of neutral and ionic phenol-Ar(n) clusters with n <= 4, PhOH((+)) Ar(n), are characterized by quantum chemical calculations. The properties in the neutral and ionic ground electronic states (S(0), D(0)) are determined at the M06 2X/aug-cc-pVTZ level, whereas the S(1) excited state of the neutral species is investigated at the CC2/aug-cc-pVDZ level. The Ar complexation shifts calculated for the S(1) origin and the adiabatic ionisation potential, DeltaS(1) and DeltaIP, sensitively depend on the Ar positions and thus the sequence of filling the first Ar solvation shell. The calculated shifts confirm empirical additivity rules for DeltaS(1) established recently from experimental spectra and enable thus a firm assignment of various S(1) origins to their respective isomers. A similar additivity model is newly developed for DeltaIP using the M06-2X data. The isomer assignment is further confirmed by Franck-Condon simulations of the intermolecular vibrational structure of the S(1) <- S(0) transitions. In neutral PhOH-Ar(n), dispersion dominates the attraction and pi-bonding is more stable than H-bonding. The solvation sequence of the most stable isomers is derived as (10), (11), (30), and (31) for n <= 4, where (km) denotes isomers with k and m Ar ligands binding above and below the aromatic plane, respectively. The pi interaction is somewhat stronger in the S(1) state due to enhanced dispersion forces. Similarly, the H-bond strength increases in S(1) due to the enhanced acidity of the OH proton. In the PhOH(+)-Ar(n) cations, H-bonds are significantly stronger than pi-bonds due to additional induction forces. Consequently, one favourable solvation sequence is derived as (H00), (H10), (H20), and (H30) for n <= 4, where (Hkm) denotes isomers with one H-bound ligand and k and m pi-bonded Ar ligands above and below the aromatic plane, respectively. Another low-energy solvation motif for n = 2 is denoted (11)(H) and involves nonlinear bifurcated H bonding to both equivalent Ar atoms in a C(2v) structure in which the OH group points toward the midpoint of an Ar(2) dimer in a T-shaped fashion. This dimer core can also be further solvated by pi-bonded ligands leading to the solvation sequence (H00), (11)(H), (21)(H), and (22) for n <= 4. The implications of the ionisation-induced pi -> H switch in the preferred interaction motif on the isomerisation and fragmentation processes of PhOH((+))-Ar(n) are discussed in the light of the new structural and energetic cluster parameters. PMID- 21597607 TI - Role of spacer lengths of gemini surfactants in the synthesis of silver nanorods in micellar media. AB - In this work, we have prepared Ag-nanorods using biscationic gemini surfactant micelles as the media by a seed-mediated wet synthesis method. Towards this end, we first synthesized Ag-nanoseeds of diameter ~7 nm stabilized by trisodium citrate (as the capping agent). Then these Ag-nanoseeds were used to synthesize Ag-nanorods of different aspect ratios. With decreasing Ag-nanoseed concentration, the aspect ratios of the Ag-nanorods stabilized by these gemini surfactants increased gradually. Various Ag-nanoseeds and Ag-nanospecies were characterized using UV-Vis spectroscopy (to know the surface plasmon bands), transmission electron microscopy (to find out their particle sizes and distribution), energy-dispersive X-ray spectroscopy and X-ray diffraction. When we used micelles derived from gemini surfactants of shorter spacer -(CH(2))(n)- (n = 2 or 4) to stabilize the Ag-nanorods, the lambda(max) of the longitudinal band shifted more towards the blue region compared to that of the gemini surfactant micelles with a longer spacer -(CH(2))(n)- (n = 5, 12) at a given amount of the Ag-nanoseed solution. So, the growth of Ag-nanorods in the gemini micellar solutions depends on the spacer-chain length of gemini surfactants employed. PMID- 21597608 TI - Strong photoluminescence enhancement of silicon quantum dots by their near resonant coupling with multi-polar plasmonic hot spots. AB - Localization of quantum dots (QDs) in the vicinity of metal nanoparticles (NPs) is known as one of the most efficient ways to increase their photoluminescence (PL). Despite the important recent advances achieved in II-VI QDs, only a seven fold plasmon-induced PL enhancement is reported for Si QDs. In our paper we show that the plasmon-induced strong local PL enhancement of Si QDs in an SiN matrix can reach a 60-fold gain level. This important result was achieved on original tunable "nano-Ag/SiN(X)" plasmonic structures. In particular, we show that (i) localization of Si QDs in hot spot regions created by several randomly arranged Ag NPs and (ii) careful tuning of the multi-polar plasmon bands of Ag NPs to match resonant absorption and emission wavelengths of Si QDs, lead to the important enhancement of their PL intensity. PMID- 21597609 TI - Infrared study of the influence of reducible iron(III) metal sites on the adsorption of CO, CO2, propane, propene and propyne in the mesoporous metal organic framework MIL-100. AB - The present study illustrates the importance of the oxidation state of iron within the mesoporous iron trimesate [{Fe(3)O(H(2)O)(2)F(0.81)(OH)(0.19)}{C(6)H(3)(CO(2))(3)}(2)] denoted MIL-100(Fe) (MIL= Material from Institut Lavoisier) during adsorption of molecules that can interact with the accessible metal sites through pi-back donation. Adsorption of CO has been first followed by FTIR spectroscopy to quantify the Lewis acid sites in the dehydrated Fe(III) sample, outgassed at 150 degrees C, and on the partially reduced Fe(II/III), outgassed at 250 degrees C. The exposure of MIL 100(Fe) to CO(2), propane, propene and propyne has then been studied by FTIR spectroscopy and microcalorimetry. It appears that pi-back donating molecules are strongly adsorbed on reduced iron(II) sites despite the weaker Lewis acidity of cus Fe(2+) sites compared to that of Fe(3+) ones, as shown by pyridine adsorption. PMID- 21597610 TI - Carbene-based ruthenium photosensitizers. AB - A new series of N-heterocyclic carbene (NHC)-pyridine ruthenium complexes incorporating a carbene unit as an ancillary ligand were designed and successfully synthesized by using simple synthetic methods. The photophysical, electrochemical and photovoltaic properties of these NHC-pyridine based ruthenium complexes were investigated. These complexes showed photoelectric conversion efficiencies in the range of 6.43 ~ 7.24% under the illumination of AM 1.5 (100 mW cm(-2)). Interestingly, the modifications on the ancillary ligand of these sensitizers by removal of an alkoxyl group and replacement of the octyl chain with a 3,5-difluorobenzyl group showed a 13% increase in the conversion efficiency for the CifPR dye. These results demonstrated that structural modifications on the NHC-pyridine ancillary ligand of ruthenium complexes results in dye-sensitized solar cells exhibiting a comparable cell performance to that obtained using the standard N719 dye. PMID- 21597611 TI - Reconstitution of bacterial photosynthetic unit in a lipid bilayer studied by single-molecule spectroscopy at 5 K. AB - As a model of photosynthetic unit (PSU), self-assembled aggregates of pigment protein complexes from photosynthetic bacteria were prepared in a lipid bilayer by reconstitution of the light-harvesting 2 (LH2) complex and light-harvesting 1 reaction center (LH1-RC) complex through detergent removal of their micelles in the presence of lipids. By performing polarization-controlled fluorescence and fluorescence-excitation spectroscopy on single aggregates at a temperature of 5 K, the composition of individual aggregates was determined and excitation energy transfer (EET) between constituent complexes was observed. LH2 and LH1-RC from a bacterium, Rhodobacter (Rb.) sphaeroides, were found to form a trimeric aggregate in which EET takes place from one LH2 to two LH1-RCs. In contrast, a heterodimer of LH2 and LH1-RC in which EET works was found to assemble from a combination of complexes of different bacterial species, that is, LH2 from Rb. sphaeroides and LH1-RC from Rhodopseudomonas (Rps.) palustris. PMID- 21597612 TI - Water induced electrical hysteresis in germanium nanowires: a theoretical study. AB - We apply DFT calculations to evaluate the electronic properties of germanium nanowires (GeNWs) upon adsorption of water molecules and reveal the possible causes of the experimentally observed electrical hysteresis in GeNWs based electronic devices. We show that the absorption of water molecules on the GeNW surface would lead to the formation of hydroxyl passivated GeNWs (OH-GeNWs). The first step of the formation mechanism is physisorption of water molecules toward a Ge atom then followed by dissociation of water molecules to form OH-GeNWs, consistent with experimental observation of reversible and irreversible electrical hystereses. More importantly, we also predict that the effective masses of OH-GeNWs depend strongly on their growth orientation and depend nonlinearly on the OH coverage percentage. We propose that the electrical hysteresis phenomenon observed in experiment can be attributed to the formation of OH-GeNWs with different OH coverage percentages, along with different alignments of the OH groups on the GeNW surface, and also the presence of surface trap state defects, during the different stages of I-V measurement. PMID- 21597613 TI - Inelastic X-ray scattering and vibrational effects at the K-edges of gaseous N2, N2O, and CO2. AB - We report non-resonant inelastic X-ray scattering experiments of several gaseous samples in the inner-shell excitation energy range. The experimental near-edge spectra from all the K-edges of N(2), N(2)O, and CO(2) including the momentum transfer dependence are presented. The results are analyzed using density functional theory calculations that accurately reproduce the experimental spectral features. We observe vibrational effects in the measured spectrum and in the calculations the atomic motion is modeled using the Franck-Condon approximation and the linear coupling model. Our findings show that vibrational effects cannot be neglected in the analysis of high resolution inelastic X-ray scattering spectroscopy. The results also support the validity of the transition potential approximation for calculating core excited state potential energy surfaces. PMID- 21597614 TI - A combined quantum mechanical and molecular mechanical method using modified generalized hybrid orbitals: implementation for electronic excited states. AB - The generalized hybrid orbital (GHO) method is implemented at the second-order approximate coupled cluster singles and doubles (CC2) level for quantum mechanical (QM)/molecular mechanical (MM) electronic excited state calculations. The linear response function of CC2 in the GHO scheme is derived and implemented. The new implementation is applied to the first singlet excited states of three aromatic amino acids, phenylalanine, tyrosine, and tryptophan, and also bacteriorhodopsin for assessment. The results obtained for aromatic amino acids agreed well with the full QM CC2 calculations, while the calculated excitation energies of bacteriorhodopsin and its chromophore, all-trans retinal, reproduced the environmental shift of the experimental data. For the bacteriorhodopsin case, the environmental shift of GHO also showed good agreements with the experimental data. The contribution of the quantum effect of certain moieties in the excited states is elucidated by changing the partitioning of QM and MM regions. PMID- 21597616 TI - Unsymmetrical (R)PNP(R') pincer ligands and their group 10 complexes. AB - Two new unsymmetrical (R)PNP(R')-type pincer ligands based on a bis(tolyl)amine framework have been synthesized and characterized by a variety of techniques, including X-ray crystallography. These ligands have been coordinated to Ni, Pd, and Pt precursors to provide a number of well-characterized group 10 halides. Conversion of these metal halides to metal hydrides was accomplished using borohydride reagents, or by direct interaction of the ligand with the zerovalent metal precursor. The insertion of oxygen into these hydrides in an attempt to prepare metal hydroperoxides has been examined; however, we were unable to obtain stable and isolable hydroperoxide species. PMID- 21597615 TI - Distribution of BODIPY-labelled phosphatidylethanolamines in lipid bilayers exhibiting different curvatures. AB - In this paper we have investigated the behaviour of newly synthesised mono palmitoyl- and dipalmitoyl-phosphatidylethanolamine probes (abbreviated as mPE and dPE, respectively) labelled in the polar headgroup region by either the FL BODIPY or the 564/570-BODIPY fluorophore and solubilised in lipid systems that exhibit different curvatures. Because of the bulky BODIPY-groups, the monoacyl form derivatives have a conic-like shape, whereas that for the diacyl derivatives is rather cylindrical. A careful analysis of time-resolved resonance energy transfer experiments by means of analytical models as well as Monte Carlo simulations shows that the mPE derivatives have a comparable affinity to highly curved bilayer regions (torroidal pores formed by magainin-2 in lipid bilayers, or the rims of discoid bicelles) and to planar bilayer regions (i.e. the flat region of lipid bilayers and bicelles). Furthermore, the monoacyl-probes are as compared to the diacyl-probes effectively closer to each other in a lipid bilayer, while none of these probes seems to be randomly distributed. Self aggregation is most efficiently induced by the larger aromatic 564/570-BODIPY chromophore, but it is suppressed when using the diacyl instead of the monoacyl form, and/or by attaching BODIPY-groups to the acyl-chain. PMID- 21597617 TI - Equilibrium studies of the reactions of palladium(II) bis(imidazolin-2-imine) complexes with biologically relevant nucleophiles. The crystal structures of [(TLtBu)PdCl]ClO4 and [(BLiPr)PdCl2]. AB - The kinetics and the mechanism of the substitution reactions of the complex [(TL(tBu))PdCl](+), where TL(tBu) is 2,6-bis[(1,3-di-tert-butylimidazolin-2 imino)methyl]pyridine, with nucleophiles (guanosine-5'-monophosphate (5'-GMP), l Methionine (l-Met) and l-Histidine (l-His)) were studied using variable temperature stopped-flow techniques in aqueous 0.1 M NaClO(4) with 10 mM NaCl at 298 K. The order of reactivity is: l-Met > 5'-GMP > l-His. The formation equilibria of [(BL(iPr))Pd(H(2)O)(2)](2+), where BL(iPr) is 1,2 bis(1,3diisopropyl-4,5-dimethylimidazolin-2-imino)ethane, and [(TL(tBu))Pd(H(2)O)](2+) with some biologically relevant ligands (l-Met, 5'-GMP and l-His) were also studied. The stoichiometry and stability constants of the newly formed complexes are reported, and the concentration distribution of the various complex species has been evaluated as a function of pH. Comparing the values of logbeta(1,1,0) for 5'-GMP, l-His and l-Met complexes, the most stable complex is with 5'-GMP followed by l-His and l-Met for both complexes, [(BL(iPr))Pd(H(2)O)(2)](2+) and [(TL(tBu))Pd(H(2)O)](2+). The crystal structures of [(TL(tBu))PdCl]ClO(4) and [(BL(iPr))PdCl(2)] were determined by X-ray diffraction. The coordination geometries around the palladium atoms are distorted square-planar, with the Pd-N1 distance to the central nitrogen atom of the TL(tBu) ligand, 1.944(2) A, being shorter than those to the other two nitrogen atoms of TL(tBu), viz. 2.034(3) and 2.038(2) A. The BL(iPr) complex displays similar Pd-N distances of 2.031(2) and 2.047(2) A. PMID- 21597618 TI - Orientation of GST-tagged lectins via in situ surface modification to create an expanded lectin microarray for glycomic analysis. AB - Herein we describe the orientation of GST-tagged lectins on NHS-activated slides via a one-step deposition of the protein and a glutathione (GSH) scaffold. This technology overcomes the need for a premade GSH-surface to orient GST-tagged proteins, enabling us to rapidly expand the analytical capacity of lectin microarrays through addition of oriented lectins, while maintaining lectin diversity. PMID- 21597619 TI - Collagen stimulation of platelets induces a rapid spatial response of cAMP and cGMP signaling scaffolds. AB - Intracellular communication is tightly regulated in both space and time. Spatiotemporal control is important to achieve a high level of specificity in both dimensions. For instance, cAMP-dependent kinase (PKA) attains spatial resolution by interacting with distinct members of the family of A-kinase anchoring proteins (AKAPs) that position PKA at specific loci within the cell. To control the cAMP induced signal in time, distinct signal terminators such as phosphodiesterases and phosphatases are often co-localized at the AKAP scaffold. In platelets, high levels of cAMP/cGMP maintain the resting state to allow free circulation. Exposure to collagen, for instance when the vessel is damaged, triggers platelet activation through initiation of the GPVI (glycoprotein VI)/FcRgamma-chain forming the onset of a plethora of signaling pathways. Consequently overall intra-platelet cAMP and cGMP levels drop, however detail on how PKA, but also cGMP-dependent protein kinase (PKG) respond in relation to their localized signaling scaffolds is currently missing. To investigate this, we employed a quantitative chemical proteomics approach in activated human platelets enabling the specific enrichment of cAMP/cGMP signaling nodes. Our data reveal that within a few minutes several specific PKA and PKG signaling nodes respond significantly to the activating signal, whereas others do not, suggesting a rapid adaption of specific localized cAMP and cGMP pools to the stimulus. Using protein phosphorylation data gathered we touch upon the potential cross-talk between protein phosphorylation and signaling scaffold function as a general theme in platelet spatiotemporal control. PMID- 21597620 TI - Oxidation of 4-substituted TEMPO derivatives reveals modifications at the 1- and 4-positions. AB - Potenital pathways for the deactivation of hindered amine light stabilisers (HALS) have been investigated by observing reactions of model compounds--based on 4-substituted derivatives of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO)--with hydroxyl radicals. In these reactions, dilute aqueous suspensions of photocatalytic nanoparticulate titanium dioxide were irradiated with UV light in the presence of water-soluble TEMPO derivatives. Electron spin resonance (ESR) and electrospray ionisation mass-spectrometry (ESI-MS) data were acquired to provide complementary structural elucidation of the odd- and even-electron products of these reactions and both techniques show evidence for the formation of 4-oxo-TEMPO (TEMPONE). TEMPONE formation from the 4-substituted TEMPO compounds is proposed to be initiated by hydrogen abstraction at the 4-position by hydroxyl radical. High-level ab initio calculations reveal a thermodynamic preference for abstraction of this hydrogen but computed activation barriers indicate that, although viable, it is less favoured than hydrogen abstraction from elsewhere on the TEMPO scaffold. If a radical is formed at the 4-position however, calculations elucidate two reaction pathways leading to TEMPONE following combination with either a second hydroxyl radical or dioxygen. An alternate mechanism for conversion of TEMPOL to TEMPONE via an alkoxyl radical intermediate is also considered and found to be competitive with the other pathways. ESI-MS analysis also shows an increased abundance of analogous 4 substituted piperidines during the course of irradiation, suggesting competitive modification at the 1-position to produce a secondary amine. This modification is confirmed by characteristic fragmentation patterns of the ionised piperidines obtained by tandem mass spectrometry. The conclusions describe how reaction at the 4-position could be responsible for the gradual depletion of HALS in pigmented surface coatings and secondly, that modification at nitrogen to form the corresponding secondary amine species may play a greater role in the stabilisation mechanisms of HALS than previously considered. PMID- 21597621 TI - Synthesis of pyrrole and indole quinoxalinone and oxazinone derivatives by intramolecular copper-catalyzed reactions. AB - Intramolecular N-arylation of pyrrole and indole carboxamides and carboxylates linked with a pendant haloarene by Cu-catalyzed reactions to synthesize pyrrole and indole quinoxalinone and oxazinone derivatives is reported. The ring closure reactions were carried out by conventional heating and MW irradiation. The use of conventional heating affords moderate to good yields of the quinoxalinone and oxazinone derivatives (34-72%), while by using MW heating the best results are obtained (41-99%). PMID- 21597622 TI - The clerodane ring system: investigating the viability of a direct Diels-Alder approach. AB - A direct synthetic approach to the spiro-gamma-lactone clerodane ring system has been investigated. This work builds on that of Jung and highlights the inherent difficulties associated with the otherwise obvious Diels-Alder approach. PMID- 21597623 TI - Polyelectrolyte adsorption onto oppositely charged interfaces: unified approach for plane, cylinder, and sphere. AB - A universal description is presented for weak adsorption of flexible polyelectrolyte chains onto oppositely charged planar and curved surfaces. It is based on the WKB (Wentzel-Kramers-Brillouin) quantum mechanical method for the Green function equation in the ground state dominance limit. The approach provides a unified picture for the scaling behavior of the critical characteristics of polyelectrolyte adsorption and the thickness of the adsorbed polymer layer formed adjacent to the interface. We find, particularly at low-salt conditions, that curved convex surfaces necessitate much larger surface charge densities to trigger polyelectrolyte adsorption, as compared to a planar interface in the same solution. In addition, we demonstrate that the different surface geometries yield very distinct scaling laws for the critical surface charge density required to initiate chain adsorption. Namely, in the low-salt limit, the surface charge density scales cubical with the inverse Debye screening length for a plane, quadratic for an adsorbing cylinder, and linear for a sphere. As the radius of surface curvature grows, the parameter of critical chain adsorption onto a rod and a sphere turns asymptotically into that of a planar interface. The transition occurs when the radius of surface curvature becomes comparable to the Debye screening length. The general scaling trends derived appear to be consistent with the complex-formation experiments of polyelectrolyte chains with oppositely charged spherical and cylindrical micelles. Finally, the WKB results are compared with the existing theories of polyelectrolyte adsorption and future perspectives are outlined. PMID- 21597624 TI - On the weak O-H...halogen hydrogen bond: a rotational study of CH3CHClF...H2O. AB - We measured the molecular beam Fourier transform microwave spectra of six isotopologues of the 1 : 1 adduct of CH(3)CHClF with water. Water prefers to form an O-H...F rather than an O-H...Cl hydrogen bond. This is just the contrary of what was observed in the chlorofluoromethane-water adduct, where an O-H...Cl link was formed (W. Caminati, S. Melandri, A. Maris and P. Ottaviani, Angew. Chem., Int. Ed., 2006, 45, 2438). The water molecule is linked with an O-H...F bridge to the fluorine atom, with r(F...H(w)) = 2.14 A, and with two C-H...O contacts to the alkyl hydrogens with r(C(1)-H(1)...O(w)) = 2.75 A and r(C(2)-H(2)...O(w)) = 2.84 A, respectively. Besides the rotational constants, the quadrupole coupling constants of the chlorine atom have been determined. In addition, information on the internal dynamics has been obtained. PMID- 21597625 TI - Studies on transannulation reactions across a nine-membered ring: the synthesis of natural product-like structures. AB - A series of diverse natural product-like structures have been synthesised by the use of a number of novel transannulation reactions across a cyclononene ring. Transannular cyclisations through oxygen functionality have generated a number of bicyclo[5.3.1]systems containing bridged cyclic ethers and bicyclo[5.2.2]lactones, as well as a tetrahydrofuran-containing bridged analogue of hexacyclinic acid. An unprecedented Bronsted acid mediated transannular cyclisation between proximal carbons generated bicyclo[4.3.0]nonanes which form the core of the pinguisane and austrodorane families of sesquiterpenoids. In all cases the key factor that determined the mode of reactivity was the conformation of the nine-membered ring and the distance between the reacting centres. PMID- 21597626 TI - Observation of a double C-H...pi interaction in the CH2ClF...HCCH weakly bound complex. AB - The structure of the CH(2)ClF...HCCH dimer has been determined using both chirped pulse and resonant cavity Fourier-transform microwave spectroscopy. The complex has C(s) symmetry and contains both a double C-H...pi interaction, in which one pi-bond acts as acceptor to two hydrogen atoms from the CH(2)ClF donor, and a weak C-H...Cl interaction, with acetylene as the donor. Analysis of the rotational spectra of four isotopologues (CH(2)(35)ClF...H(12)C(12)CH, CH(2)(37)ClF...H(12)C(12)CH, CH(2)(35)ClF...H(13)C(13)CH, and CH(2)(37)ClF H(13)C(13)CH) has led to a structure with C-H...pi distances of 3.236(6) A and a C-H...Cl distance of 3.207(22) A, in good agreement with ab initio calculations at the MP2/6-311++G(2d,2p) level. Both weak contacts are longer than those observed in similar complexes containing a single C-H...pi interaction that lies in the C(s) plane; however, this appears to be the first double C-H...pi contact to be studied by microwave spectroscopy, so there is little data for direct comparison. The rotational and chlorine nuclear quadrupole coupling constants for the most abundant isotopologue are: A = 5262.899(14) MHz, B = 1546.8074(10) MHz, C = 1205.4349(7) MHz, chi(aa) = 28.497(5) MHz, chi(bb) = -65.618(13) MHz, and chi(cc) = 37.121(8) MHz. PMID- 21597627 TI - The synthetic and biological studies of discorhabdins and related compounds. AB - Various analogues of the marine alkaloids, discorhabdins, have been synthesized. The strategy contains spirocyclization with phenyliodine(III) bis(trifluoroacetate) (PIFA), oxidative fragmentation of the beta-amino alcohols with the hypervalent iodine reagent C(6)F(5)I(OCOCF(3))(2), the detosylation and dehydrogenation reaction of the pyrroloiminoquinone unit in the presence of a catalytic amount of NaN(3) and the bridged ether synthesis with HBr-AcOH as the key reactions. All the synthesized compounds were evaluated by in vitro MTT assay for cytotoxic activity against the human colon cancer cell line HCT-116. Furthermore, the discorhabdin A oxa analogues were also evaluated against four kinds of tumor model cells, a human colon cancer cell line (WiDr), a human prostate cancer cell line (DU-145) and murine leukemia cell lines (P388 and L1210). For the identification of the target, discorhabdin A and the discorhabdin A oxa analogue were evaluated by an HCC panel assay. In the test, discorhabdins could have a novel mode of action with the tumor cells. PMID- 21597628 TI - Reduction of hydrazines to amines with aqueous solution of titanium(III) trichloride. AB - N-N bond cleavage in hydrazines is widely used in the preparation of amines and thus occupies a significant place in organic synthesis. In this paper, we report a new method for the reductive cleavage of N-N bonds in hydrazines by commercially available and cheap aqueous titanium(III) trichloride. The reaction proceeds smoothly under a broad pH range from acidic to neutral and basic conditions to afford amines in good yields. This method is compatible with substrates containing functionalities such as C-C double bonds, benzyl-nitrogen bonds, benzyloxy and acyl groups. PMID- 21597629 TI - A reverse transcription-free real-time PCR assay for rapid miRNAs quantification based on effects of base stacking. AB - A rapid and reverse transcription-free real-time PCR microRNA assay was developed based on effects of base stacking. This microRNA assay has been shown to be highly specific to homogenous miRNAs, and the procedure can be completed within 30 min starting from total RNA. PMID- 21597630 TI - Size-modulated catalytic activity of enzyme-nanoparticle conjugates: a combined kinetic and theoretical study. AB - A series of experiments were performed to systematically analyze the effect of nanoparticle (NP) size on the catalytic behavior of enzyme-NP conjugates, and a shielding model based on diffusion-collision theory was developed to explain the correlation between the size effects and the kinetic responses. PMID- 21597631 TI - Shape-dependent electrocatalytic activity of monodispersed gold nanocrystals toward glucose oxidation. AB - We systematically explore the shape-dependent catalytic activities of Au nanocrystals toward glucose oxidation in alkaline electrolytes, which is strongly dependent on the shape of the Au nanocrystals. The {100}-bounded cubic Au nanocrystals are significantly more active than the {110}-bounded rhombic dodecahedral and {111}-bounded octahedral Au nanocrystals. PMID- 21597632 TI - On the intrinsic optical absorptions by tetrathiafulvalene radical cations and isomers. AB - Gas-phase action spectroscopy shows unambiguously that the low-energy absorptions by tetramethylthiotetrathiafulvalene and tetrathianaphthalene cations in solution phase are due to monomers and not pi-dimers. PMID- 21597633 TI - Three-state molecular shuttles operated using acid/base stimuli with distinct outputs. AB - This paper describes the acid/base-mediated three-state translational isomerization of two [2]rotaxanes, each containing N-alkylaniline and N,N dialkylamine centers as binding sites for threaded dibenzo[24]crown-8 units. Under neutral conditions, the dialkylamine unit predominantly recognized the crown ether component through cooperative binding of a proton; when both amino units were protonated under acidic conditions, both translational isomers were generated; the addition of a strong base caused aniline-crown ether interactions to dominate. The three states of the [2]rotaxane featuring the 3,5 diphenylaniline terminus in its dumbbell-shaped component were accompanied by distinct absorptive outputs that were detectable using UV spectroscopy. PMID- 21597634 TI - Distinct magnetic dynamic behavior for two polymorphs of the same Dy(III) complex. AB - Two polymorphs of the same Dy(III) complex show distinct slow magnetic relaxation behaviors due to the different local environments of Dy(III) in the crystal. This work represents the first example where the magnetic dynamic property of neutral rare earth complexes could be tuned by growing polymorphic crystals without changing the ligand. PMID- 21597635 TI - Hierarchical N-doped TiO2 hollow microspheres consisting of nanothorns with exposed anatase {101} facets. AB - A green solvothermal synthesis approach employing water as a hollowing controller and diethylenetriamine as both crystal growth stabilizer and N dopant source to the preparation of hierarchical N-doped TiO(2) hollow microspheres comprised of nanothorns with exposed anatase {101} facets is established. The superstructured TiO(2) shows excellent photocatalytic activities in degrading dyes under visible light irradiation. PMID- 21597636 TI - Electrocatalytic properties of Au@Pt nanoparticles: effects of Pt shell packing density and Au core size. AB - A detailed study of electrocatalytic properties of Au@Pt nanoparticles (NPs) as functions of Pt shell packing density and Au core size in terms of CO/methanol oxidation and oxygen reduction reactions is reported here. While most samples studied showed inferior catalytic activities to those of the commercial Pt black that fall reasonably well in a d-band-center up-shift (i.e., stronger surface bonding) regime, the steepest activity recovery trend as manifested by the smallest Au-core samples suggests a plausible transition to a d-band-center down shift (i.e., weaker surface bonding) regime as the Au core becomes smaller. PMID- 21597637 TI - Oxygen-isotope labeled titania: Ti(18)O2. AB - (18)O-isotope labelled titania (anatase, rutile) was synthesized. The products were characterized by Raman spectra together with their quantum chemical modelling. The interaction with carbon dioxide was investigated using high resolution FTIR spectroscopy, and the oxygen isotope exchange at the Ti(18)O(2)/C(16)O(2) interface was elucidated. PMID- 21597638 TI - Transition states for cysteine redox processes modeled by DFT and solvent assisted proton exchange. AB - Oxidation and disulfide coupling of cysteine, processes central to oxidative stress and biochemical signaling, are modeled using DFT and solvent-assisted proton exchange, a method of microsolvation. Calculated barriers are consistent with experimental kinetics and observed product ratios and suggest a dependence on the polarity of the surrounding medium. PMID- 21597639 TI - Addition of halide to pi-bond directly from aqueous NaX solution: a general strategy for installation of two different functional groups. AB - Activation of pi-bond with organic Lewis acid and cationic surfactant mediated direct transfer of halides to alkyne and alkene are demonstrated to afford alpha,alpha-dihaloketones and other valuable synthons with outstanding selectivities. PMID- 21597640 TI - High activity acetylene polymerisation with a bis(imino)pyridine iron(II) catalyst. AB - A catalyst system composed of a 2,6-bis(arylimino)pyridineiron(II) dichloride complex and methylaluminoxane is found to be extremely active for acetylene polymerisation. The formation of poly(acetylene) gels and surface films occurs at very low catalyst concentrations, around three orders of magnitude lower than traditional catalyst systems. PMID- 21597641 TI - Organophosphorus acid anhydrolase bio-template for the synthesis of CdS quantum dots. AB - A direct conjugation of organophosphorus acid anhydrolase (OPAA) with CdS quantum dots was prepared via arrested precipitation within the enzyme matrix. The bio conjugate was found not only to retain enzyme conformational structure but also to retain enzyme activity and be effective at detecting diisopropyl fluorophosphate (DFP) at the micro molar level. PMID- 21597642 TI - Mixed (phthalocyaninato)(porphyrinato) heterometal complexes with sandwich quadruple-decker molecular structure. AB - Two novel mixed (phthalocyaninato)(porphyrinato) rare-earth and cadmium heterometal complexes have been fabricated in one-pot reaction and their sandwich quadruple-decker nature is unambiguously revealed by X-ray single crystal analysis. PMID- 21597643 TI - High hole mobility of 1,2-bis[4'-(diphenylamino)biphenyl-4-yl]-1,2-diphenylethene in field effect transistor. AB - Triphenylamine-functionalized tetraphenylethene shows aggregation-induced emission feature with unity solid-state fluorescence efficiency. Its amorphous film can function in a p-type FET device with field effect mobility up to 2.6 * 10(-3) cm(2)/Vs. PMID- 21597644 TI - Influence of a collapsed coastal landfill on metal levels in sediments and biota- a portent for the future? AB - In May 2008 a coastal landslide deposited landfill debris onto the shore near Lyme Regis, UK. Six months later, intertidal sediments and biota from the area were sampled to determine whether the landslip had affected distribution and bioavailability of metals in the area and if there were any biological effects. Highest sediment concentrations for the majority of metals occurred near the landslip zone and in several cases exceeded Threshold Effects or Probable Effects Levels (As, Cu, Hg, Ni, Pb, Zn). The 1 M HCl-extractable fraction of Cd, Pb and Zn in sediments also increased near the landslip. Metal bioaccumulation by intertidal biota showed variability between different species and metals, but there were several instances of increased accumulation near the landslip through increased availability from seawater, sediment and dietary sources. In most cases, metal concentrations in molluscs exceeded Oslo and Paris Commission (OSPAR) background concentrations (BCs) together with background assessment concentrations (BACs) at some sites. Kidney tissues in winkles (Littorina littorea) were measured for evidence of oxidative stress using the Total Oxyradical Scavenging Capacity (TOSC) assay. Responses to peroxynitrite, peroxyl and hydroxyl radicals suggested raised levels of TOSC in animals from the sites close to or east of the landfill waste. There have been very few studies of direct impact of landfills on the marine environment and this study could serve as a practical model for similar events driven by sea level rise. PMID- 21597645 TI - Medial radio-carpal arthrodesis in three cats with a 2.0 mm locking maxillofacial plate system. AB - The medical records of three cats that were presented with severe carpal injury requiring radiocarpal arthrodesis were reviewed. Medial plating using the Compact 2.0 LOCKTM system was performed in all three cases. Although screw positioning may be difficult because of the large distance between the holes of the plate and the relatively large size of screws, plate loosening or metacarpal fractures did not occur. Long-term clinical and radiographic follow-up (6 months to 4.5 years) revealed excellent outcome in two cats. In the third cat, the radiocarpal joint did not undergo complete fusion. At four and a half years following surgery, recurrence of forelimb lameness was associated with breakage of the plate. PMID- 21597646 TI - Mechanical evaluation of a tapered thread-run-out half-pin designed for external skeletal fixation in small animals. AB - An in vitro mechanical study was performed to compare the stiffness, maximum load, and cyclic load-to-failure of a new external fixation half-pin design utilizing a tapered thread-run-out (TRO) feature with currently available positive profile thread (PP) half-pins. Five different sizes of each of the two pin types were evaluated. Under static loading, TRO pins were significantly stiffer and had a higher maximum load compared to the similar sized PP pins (p <0.0001 for all comparisons). In cyclic fatigue testing, TRO pins lasted 2.3- to 4.9-fold more cycles than PP pins of similar size (p <0.0001 for all comparisons). The increased pin stiffness and improved cyclic lifespan provided by TRO pins may be especially valuable in the stabilization of biologically and mechanically challenging fracture cases where healing is prolonged. PMID- 21597647 TI - The use of cyclosporine-A in dogs with chronic osteoarthritis: a pilot study. AB - OBJECTIVE: To evaluate the efficacy of cyclosporine-A in dogs with radiographic and physical evidence of chronic stifle osteoarthritis. MATERIALS AND METHODS: Ten hound-type dogs with osteoarthritis induced by surgical transection of a cranial cruciate ligament followed by immediate stabilization of the stifle four years prior to study start were randomized to two groups. Cyclosporine-A was administered orally once daily at 5 mg/kg to one group for one month while the other group served as control. After a two week wash-out period during which the animals were not treated, and the degree of lameness was allowed to return to baseline, the treatments were switched so that the second group received treatment with cyclosporine-A and the first group served as control. Ground reaction forces were measured using a force platform in all animals at day zero and then every two weeks until the end of the study. RESULTS: Cyclosporine-A did not alter the degree of lameness based on assessment of ground reaction forces. CONCLUSIONS: At a dose of 5 mg/kg/day for 28 days, cyclosporine-A was not effective in decreasing lameness of dogs with chronic osteoarthritis induced by surgical transection of the cranial cruciate ligament. PMID- 21597648 TI - Treatment of a nonunion, secondary to gunshot fracture, of the distal radius with circular external fixation and rhBMP-2 in a cat. AB - OBJECTIVE: To report the successful use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in the treatment of an antebrachial non-union, secondary to gunshot fracture, stabilized with circular external fixation in a cat. PROCEDURE: Following a diagnosis of a highly comminuted gunshot fracture of the distal right radius and ulna, the fracture was stabilized with a circular external fixation. A two-ring frame was placed in closed fashion. RESULTS: The skin wound healed uneventfully by second intention in 21 days. Twenty-eight weeks after external fixation, bone healing was absent. 0.8mL of 0.2mg/mL of rhBMP-2 in two collagen sponges was placed in the bone defect. Eight weeks after rhBMP-2 implantation, an early bone healing response was noted on radiographic evaluation. Sixteen weeks after rhBMP-2 implantation, fracture union was achieved. DISCUSSION: To the authors' knowledge, 160 MUg is the lowest reported dose of rhBMP-2 that leads to bony union in a cat. However as an individual case study, this report can not be used as evidence that rhBMP-2 at this lower dose is appropriate for use in all cats. Further studies are needed to establish the minimum efficient dose of rhBMP 2 in cats. PMID- 21597649 TI - Risk of canine cranial cruciate ligament rupture is not associated with the major histocompatibility complex. AB - OBJECTIVES: To investigate the association of the major histocompatability (MHC) class II allele haplotype frequencies with the diagnosis of cranial cruciate ligament (CCL) rupture in two breeds of dog. METHODS: DNA samples from populations of Labrador Retrievers and Golden Retrievers with CCL rupture and general populations of the same breeds were characterised for three DLA class II loci (DRB1*, DQA1* and DQB1*) alleles using sequence-based typing or reference strand-mediated conformation analysis. RESULTS: Although distinct differences in haplotype types, frequencies and homozygozity were observed between the two breeds, no disease specific association could be identified for the development of the CCL rupture within either population. CLINICAL SIGNIFICANCE: The risk for developing CCL rupture was not associated with DLA haplotype group(s) in Labrador Retrievers or Golden Retrievers, thus the hypothesis that there is an autoimmune basis to CCL rupture was not supported. PMID- 21597650 TI - Admission hyperglycemia is a reliable outcome predictor in children with severe traumatic brain injury. AB - OBJECTIVE: To identify the relationship between admission hyperglycemia and outcome in children with severe brain injury at hospital discharge and 6 months later. METHOD: A retrospective analysis of blood glucose levels was conducted in 61 children with severe brain injury admitted to the Pediatric Intensive Care Unit between November 1, 2005 and October 30, 2009. Hyperglycemia was considered for a cut off value of > 150 mg/dL, based on literature. Outcome was measured with the Glasgow Outcome Scale at hospital discharge and 6 months after discharge. Death was also analyzed as an outcome measure. RESULTS: Mean admission blood glucose of the patients was 251 mg/dL (68-791). Hyperglycemia was noted on admission in 51 (83.6%) patients. A moderately significant positive correlation was found between admission blood glucose and severity of head trauma according to Abbreviated Injury Score (r = 0.46). Mean admission glucose level of non survivors was significantly higher (207 mg/dL vs. 455 mg/dL, p < 0.001). Mean blood glucose level of the patients in bad outcome group was found significantly higher compared to that of the patients in good outcome group at hospital discharge and 6 months after discharge (185 mg/dL vs. 262 mg/dL, p < 0.15 and 184 mg/dL vs. 346 mg/dL, p < 0.04, respectively). CONCLUSIONS: Hyperglycemia could be considered as a marker of brain injury and, when present upon admission, could reflect extensive brain damage, frequently associated with mortality and bad outcome. Further studies are needed to investigate the effect of strict glycemic control on mortality and outcomes. PMID- 21597651 TI - [Aneurysmal subarachnoid hemorrhage: group of study of cerebrovascular pathology of the Spanish society of neurosurgery management guideline]. AB - An actualized revision of the most important aspects of aneurismal subarachnoid hemorrhage is presented from the guidelines previously published by the group of study of cerebrovascular pathology of the Spanish Society of Neurosurgery. The proposed recommendations should be considered as a general guide for the management of this pathological condition. However, they can be modified, even in a significant manner according to the circumstances relating each clinical case and the variations in the therapeutic and diagnostic procedures available in the center attending each patient. PMID- 21597652 TI - [Symptomatic vasospasm. Clinical manifestations]. AB - INTRODUCTION: Symptomatic vasospasm in the setting of a subarachnoid hemorrhage is a complication of difficult diagnosis in some clinical situations. Objectives. Describe the clinical characteristics of cerebral vasospasm demonstrated by neurovascular studies in patients with ruptured saccular aneurysm. PATIENTS AND METHODS: 19 consecutive patients with symptomatic vasospasm, evaluated with TCD and any variant of neurovascular study with contrast injection. All these cases were in degrees between 1 and 3 of the World Federation of Neurological Surgeons Scale. RESULTS: The cognitive and behavioral manifestations were the most frequent (53%), followed by neurological focal deficits (26%). Clinical vasospasm occurred most frequently between day 9 and 10. Vasospasm is predominant in the arteries of the anterior circulation. The high mortality (42%) and the antecedent of arterial hypertension characterized the group with symptomatic vasospasm. There was no statistical relationship between the result of the scale of Fisher and the symptomatic vasospasm. All the TCD parameters had statistical significance. CONCLUSIONS: The clinical manifestations more frequently associated with symptomatic vasospasm were cognitive and behavioral. This group of patients is characterized by a high mortality. The TCD is a test of great value to predict cerebral ischemia due to vasospasm. PMID- 21597653 TI - [Intraoperative identification of the supplementary motor area in neurooncological surgery]. AB - OBJECTIVES: The main objective of the present work was to identify, by means of intraoperative electrical stimulation, the supplementary motor area (SMA) region which is implicated in complex motor function. The functional prognostic relevance of the surgical preservation of this area was also analyzed. METHOD: Fifteen patients with tumors infiltrating the premotor cortex were selected. All patients were operated under awake conditions. Primary motor cortex was identified with intraoperative electrical stimulation (IES). To identify the SMA, patients were asked to do a finger opposition motor task with their hand contralateral to the lesion, that was blocked by electrically stimulating the premotor cerebral cortex. RESULTS: SMA was identified in all patients with IES. Complete surgical resection was achieved in 13 patients (86.6%) and subtotal in 2 patients (13.3%). SMA function was preserved in 14 patients (93.3%). In only one patient the SMA was partially resected because of tumor infiltration (6.6%). In the immediate postoperative period, 8 patients (53.3%) did not show changes in comparison to their preoperative clinical status, and 2 patients improved. At 6 months follow up, 5 patients (33.3%) were asymptomatic and 10 patients showed permanent deficits. In this last group, five patients (33.3%) showed mild deficits that did not interfere with a normal life. In the other 5 patients (33.3%), permanent deficits interfered with daily life activities: two patients presented severe hemiparesis 3/5 (same similar to their preoperative status with no improvement), one patient had motor aphasia, and two other patients (13.3%) showed permanent left SMA syndrome. In two patients with severe postoperative hemiparesis, tumor infiltration of primary motor cortex and piramidal pathway was observed; severe preoperative motor deficit (KPS <70) was associated with poor functional outcome. CONCLUSIONS: Intraoperative electrical cortical stimulation is useful to identify the SMA. Once identified, SMA preservation decreases the risk of postoperative symptoms and permanent SMA syndrome. When SMA is infiltrated by the tumor, radical resection may cause permanent neurological deficits, specially in the dominant hemisphere. Severe preoperative motor deficit was associated with poor outcome. PMID- 21597654 TI - [Olfactory groove meningiomas. Radical microsurgical treatment through the bifrontal approach]. AB - OBJECTIVES: To describe the microsurgical technique for the radical removal of olfactory groove meningiomas through the bifrontal approach. To review the diagnostic elements to be taken into account in the selection of the surgical approach to these tumours. MATERIALS AND METHODS: A microsurgical series of 35 olfactory groove meningiomas operated on through a bifrontal craniotomy is reviewed. RESULTS: The mean tumoral volume was 85cc (4.4cm diameter). A relevant peritumoral brain edema was found in 65.7% of cases, hyperostosis in the implantation base in 80% and paranasal sinus invasion in 28.6%. A Sipmson grade 1 resection was achieved in every case. A patient died due to a postoperative pneumonia. Postoperative hospitalization time was between 3 and 20 days and at discharge all patients had a Glasgow Outcome Scale grade 4-5. The mean follow-up was 55.2 months. Two patients had postoperative transient rhinolicuorrhea and an additional patient developed hydrocephalus. An asymptomatic recurrence have been identified in a patient four years after surgery. CONCLUSIONS: In our experience the bifrontal approach allowed the radical removal of huge olfactory groove meningiomas. The microdissection of the anterior cerebral artery A2 segments is possible thanks to the arachnoidal plane between vessels and tumor. Tumoral blood flow is secured by the early approaching of the base of the tumor and preoperative embolization is not necessary. Bifrontal approach allows an aggressive treatment of the hyperostosis, bone infiltration and paranasal sinus invasion. Anterior fossa reconstruction is done using a vascularized periosteal flap. PMID- 21597655 TI - [Posterior C1-C2 arthrodesis. Experience in transarticular and interarticular fixation in 36 patients]. AB - OBJECTIVE: The stabilization of C1-C2 segment has evolved with the appearance of several techniques from sublaminar, transarticular or interarticular fixation and over recent years with the introduction of neuronavegation systems. The aim of the study was to review patients treated in our center with transarticular and interarticualr fixation and compare the results obtained with both techniques. METHODS: Thirty six patients with C1-C2 instability that required a surgical fixation between 1995-2008 were retrostpectively analized. The causes of instability were principaly traumatic (18 cases) or degeneritive (16) and two cases of neoplasic lesions. In the first period (1995-2001) 20 patients were treated with transarticular fixation (Magerl's technique), and later (2002-2008) with interarticular fixation (Goel-Harms technique) in another 16 patients. Data was obtainned regarding complications, radiological evolution and clinical results (EVA pain score) and functionals (PROLO score) at 3, 6, 12 and >12 months post-op, as well as post-op cervical mobility and signs of bone fusion. A good result was considered if clinical improvement exi ted with decrease in EVA pain score > 5 points and funcional if a PROLO score > 4, regular if EVA decreased but <5 and PROLO <3 , and bad if there was no clinical or functional improvement. The results were statistically compared between both techniques. RESULTS: Of the 20 patients treated with transarticular fixation, good results were obtained in 17 cases (85%) , regular in 2 (10%), and bad in 1 (5%). Complications included 1 case of vertebral artery lesion and 3 screw misplacements, one case in contact with vertebral artery. Regarding those treated with interarticualr fixation, in 14 (89%), good results were obtained, regular in 2 (12.5%) with 1 case of screw misplacement and another of postsurgical infection. No statistical significant differences were recorded between both techniques, although in those treated with interarticular fixation there was a higher rate of bone fusion and no cases of vertebral arterial lesions were recorded. CONCLUSIONS: Transarticular and interarticular C1- C2 fixation is safe and provides a high rate of good results with few complications. The introduction of neuronavigation systems can increase the efficacy and safety of these techniques. PMID- 21597656 TI - [Adult spontaneous cerebrospinal fluid otorrhea. Report of two cases and review of the literature]. AB - INTRODUCTION: Spontaneous cerebrospinal fluid otorrhea is a relatively rare entity and can be easily missed in adults. Every adult older than 50 years with a negative history of otologic disease who has recurrent serous otitis media should be evaluated for this pathology. Meningitis is the most serious complication, so there is no doubt that the condition needs immediate attention and correction. OBJECTIVE: We present two patients who were diagnosed with spontaneous CSF otorrhea and make a review of what is reported about this topic. CONCLUSION: Surgical repair is mandatory to seal these nontraumatic CSF leaks. There are two main surgical approaches, the middle fossa craniotomy and the transmastoid approach. A multilayered closure technique in which autologous and artificial materials are combined is considered to result in the highest rate of success. PMID- 21597657 TI - Normal ventricular-CSF may comfound the diagnosis of tuberculous meningitis hydrocephalus. AB - BACKGROUND: The standard procedure for the diagnosis of central nervous system (CNS) infections consists of cerebrospinal fluid (CSF) sampling, which is usually accomplished by a lumbar puncture. However, in some patients presenting with acute hydrocephalus submitted to immediate CSF drainage, the fluid is customarily obtained from the placed draining system. In addition, the CSF obtained from the ventricular and lumbar spaces in some cases may show unusual differences, both in physiological and pathological conditions. ILLUSTRATIVE CASES: We report two children who presented with confounding results in the initial studies of their ventricular and lumbar CSF who were subsequently diagnosed with tuberculous meningitis, causing delay in diagnosis and treatment. AIM. By reporting these cases, we wanted to alert the treating physician about the possibility of this discrepancy to avoid the delayed diagnosis and management of the affected patients. DISCUSSION: We comment on the possible pathophysiological mechanisms that may result in this dissociation in ventricular and lumbar CSF composition. CONCLUSIONS; Normal results in CSF studies, especially those of the ventricular fluid, do not always rule out the presence of tuberculous meningitis. We suggest obtaining a CSF sample from the lumbar subarachnoid space in doubtful, or suspicious, cases of CNS infection even in the presence of a normal ventricular CSF. PMID- 21597658 TI - [Ureteral injury after posterior lumbar surgery. Case report]. AB - INTRODUCTION: The percentage of complications in posterior lumbar spine surgery varies from 1,9 to 10,8%. Injury to retroperitoneal structures is a severe but unfrequent complication. Ureter injury is an extremely rare complication with only 24 documented cases up to date. CASE REPORT: 43 year old woman. A deep bleeding was observed while performing a L4-L5 microdiscectomy. It was controlled with firm pressure and hemostatic agents. 36 hours later the patient developed a distended and painful abdomen associated with anemia and an increase in white blood cell count. Abdominal CT and retrograde pyelography confirmed the diagnosis of ureter injury. An emergency laparotomy was perfomed and a total section of the left ureter was treated with a end to end anastomosis. DISCUSSION: Ureter injury in posterior lumbar spine surgery can happen due to its close anatomical relationship with the vertebral body and disc. L4-L5 is the level most often affected. Due to the fact the ureter is surrounded by retroperitoneal fat, injury is less likely to happen and thus the low number of documented cases. Although the initial symptomatology may be inespecific, an early diagnosis is essential in order to avoid further complications such as a sepsis or a kidney loss. There are several treatment options although the most often used is the end to end anastomosis specially if there is a complete ureter injury. PMID- 21597659 TI - Earlier detection of COPD. PMID- 21597660 TI - Interpreting the diagnostic accuracy of tools for early detection of COPD. PMID- 21597661 TI - Bronchiectasis: why the diagnosis shouldn't be missed in primary care. PMID- 21597662 TI - Action needed on asthma plans. PMID- 21597663 TI - Adherence to asthma medication: a question of ability? PMID- 21597664 TI - Translating guidelines into community practice: signs and symptoms are not enough. PMID- 21597665 TI - Bronchopulmonary dysplasia: the challenges for primary care. PMID- 21597666 TI - A combination of the IPAG questionnaire and PiKo-6(r) flow meter is a valuable screening tool for COPD in the primary care setting. AB - AIMS: To investigate the validity of the International Primary Care Airways Guidelines (IPAG) questionnaire and PiKo-6(r) (Ferraris Respiratory Europe Ltd.) flow meter as screening tools for diagnosing chronic obstructive pulmonary disease (COPD) in the primary care setting. METHODS: The first 50 patients in 25 general practice offices completed the IPAG questionnaire and underwent spirometry with the handheld PiKo-6(r) flow meter. The results were compared with official spirometry parameters after bronchodilation. All participants had no previous medical diagnosis of respiratory diseases. RESULTS: Data from 1,078 out of 1,250 subjects (462 males, mean age 65.3 +/- 11.4 years) were analysed. The percentage of smokers was 48.4% (38 +/- 29 pack-years). COPD was diagnosed in 111 (10.3%) patients. In the subgroup of smokers the sensitivity and specificity for COPD diagnosis were 91% and 49%, respectively, for the IPAG questionnaire; 80% and 95% respectively for the PiKo-6(r) spirometer; and 72% and 97% for their combination. The negative predictive value of the questionnaire was 97%, whereas the positive predictive value of the questionnaire/ PiKo-6(r) combination was 82%. Using a cut-off score of 19 points for the IPAG questionnaire, we calculated the best combination of sensitivity (75%) and specificity (72%). CONCLUSIONS: The IPAG questionnaire and the hand-held PiKo-6(r) spirometer can be used in combination to increase the possibility of an early and accurate diagnosis of COPD in the primary care setting. PMID- 21597667 TI - Simplified COPD screening: validation of the PiKo-6(r) in primary care. AB - AIMS: To determine the accuracy of the forced expiratory volume ratio at one and six seconds (FEV1/FEV6) using a hand-held, expiratory flow meter (PiKo-6(r), nSpire Health, Inc.) to screen for chronic obstructive pulmonary disease (COPD) in primary care settings. METHODS: Current and former smokers (>= 50 years old) with no previous respiratory diagnosis (case finding [CF] = 204 subjects) or with an asthma diagnosis (differential diagnosis [DD] = 93 subjects) were evaluated using validated questionnaires, pre-bronchodilator (BD) FEV1/FEV6 and post-BD FEV1/forced vital capacity (FVC) spirometry. RESULTS: The PiKo-6(r) FEV1/FEV6 showed good sensitivity and specificity (areas under the Receiver Operating Characteristic curves [95% confidence intervals]: CF = 0.85 [0.79, 0.90]; DD = 0.88 [0.80, 0.96]) and exceeded the accuracy of the questionnaires. An FEV1/FEV6 cutoff < 0.75 provided optimal sensitivity (CF = 81%; DD = 86%) and specificity (CF = 71%; DD = 67%) for COPD screening. CONCLUSIONS: The PiKo-6(r) allows simple and reliable screening for COPD which could optimise early referral for spirometry and early, targeted interventions for COPD. PMID- 21597668 TI - Oral mucous membrane pemphigoid: complete response to topical tacrolimus. PMID- 21597669 TI - A case of phacomatosis pigmentokeratotica in Japanese monozygotic twins. PMID- 21597670 TI - Recurrent subacute cutaneous lupus erythematosus following exposure to different drugs. PMID- 21597671 TI - Pseudoleucoderma after injections of afamelanotide in a patient with atopic dermatitis. PMID- 21597672 TI - High prevalence of mental disorders and emotional distress in patients with chronic spontaneous urticaria. AB - Quality of life, which is impaired in patients with chronic spontaneous urticaria (CSU), is influenced by comorbid mental disorders. The aim of this study was to assess the prevalence and spectrum of mental disorders and to determine levels of emotional distress in patients with CSU. One hundred patients with CSU were investigated for mental disorders (by specialized diagnostic interviews and psychometric instruments), levels of emotional distress (by the Global Severity Index of the Symptom Check List; SCL-90R GSI) and underlying causes of their urticaria (by dermatological assessment). Forty-eight percent of patients with CSU were diagnosed with one or more psychosomatic disorders; most common were anxiety disorders (especially phobias), followed by depressive and somatoform disorders. The use of psychometric instruments confirmed these findings. Levels of emotional distress were significantly higher and more commonly increased in patients with CSU with mental disorders. In conclusion, patients with CSU frequently experience anxiety, depression, and somatoform disorders, and these disorders are linked to increased emotional distress. These findings call for screening of patients with CSU for mental disorders in routine clinical practice as well as for controlled clinical trials. PMID- 21597673 TI - Anti-inflammatory effects of topical formulations containing sea silt and sea salt on human skin in vivo during cutaneous microdialysis. PMID- 21597674 TI - Fluorescence diagnostics of basal cell carcinomas comparing methyl aminolaevulinate and aminolaevulinic acid and correlation with visual clinical tumour size. AB - Fluorescence diagnostics based on aminolaevulinic acid (ALA) fluorescence has been suggested as an in vivo pre-surgical tool for tumour demarcation. We performed fluorescence diagnostics of 35 basal cell carcinomas (BCCs) undergoing photodynamic therapy (PDT) using methyl-aminolaevulinate (MAL). In addition, a semi-automated thresholding algorithm was implemented to detect the potential tumour region. The mean tumour fluorescence contrast was found to be 1.65 +/- 0.06 during the first MAL-PDT session, and increased to 1.84 +/- 0.07 at the second treatment (p < 0.01). This could imply that disruption of the skin barrier and inflammatory responses after the first session of PDT led to higher accumulation of proto-porphyrin IX during the second session of PDT. The tumour areas detected based on fluorescence in small BCCs (< 1 cm(2)) were in general (n = 18/23) larger than the visual clinical tumour size. In addition, the fluorescence contrast using MAL (1.65 +/- 0.06) was found to be significantly higher (p<10(-4)) than the contrast (data from previous study) after application of ALA (1.20 +/- 0.06). Thus, MAL generally provides higher tumour contrast than ALA in BCCs, and should be preferred for use in fluorescence diagnostics. Correlation between fluorescence, lack of treatment response and/or pain was not observed. PMID- 21597675 TI - Clinical analysis of skin lesions in 796 Chinese HIV- positive patients. AB - Skin lesions are often associated with human immunodeficiency virus (HIV) infection, reflecting the immunocompromised status of the individual. We investigated the relationship between skin lesions and immune function in a retrospective study of 796 Chinese HIV patients with and without highly active antiretroviral therapy (HAART). Of the 651 patients who had not received HAART, we found that 531 (81.6%) had apparent skin lesions. The incidence of infectious skin diseases (fungi, viruses, bacteria, spirochetes and parasites) and non infectious skin diseases (excluding skin cancer) was 68.8% and 34.9%, respectively. Mean CD4(+) T-cell counts and CD4(+)/CD8(+) ratios were lower in patients with skin lesions than in patients without lesions (178 +/- 96/ul vs. 306 +/- 189/ul (p < 0.05) and 0.22 vs. 0.34 (p < 0.01), respectively). Candidiasis (25.8%), eczema (19.2%), nodular prurigo (13.8%), dermatophyte infections (10.6%) and herpes zoster (9.4%) were most common in Chinese patients with HIV. Among the 145 patients who had started HAART, there was a significantly lower prevalence of skin diseases (29.0%), although drug eruptions (12.4%) were more commonly observed. These findings indicate that HAART often reduces the incidence of infectious and non-infectious skin lesions in patients with HIV, but can itself be the cause of drug eruptions. PMID- 21597676 TI - Palmoplantar hyperkeratoses and hypopigmentation. Cole disease. PMID- 21597677 TI - Generalized fixed drug eruption caused by pazufloxacin. PMID- 21597678 TI - Insulin resistance is increased in patients with vitiligo. AB - The aim of this study was to evaluate the relationship between vitiligo and insulin resistance (IR). A total of 96 subjects were included in the study; 57 patients with vitiligo and 39 subjects in an age and a body mass index-matched control group. In fasting blood samples, insulin, C-peptide, glucose, total cholesterol, triglyceride, low-density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C) were measured. IR was calculated with the homeostasis model assessment-IR (HOMA-IR) method. Comparison of the vitiligo and the control groups revealed that patients with vitiligo had higher IR (2.3 vs. 2.0, p < 0.01), higher insulin and C-peptide levels (p < 0.001, p < 0.001, respectively), higher LDL/HDL ratio and lower HDL-C levels (p < 0.01, p < 0.0001, respectively). Systolic blood pressures of patients with vitiligo were also higher compared with control subjects (p < 0.01). Further experimental and clinical studies are needed to elucidate the molecular mechanisms underlying this association. PMID- 21597679 TI - Negative regulation of fibronectin gene-transcription by ej-ha-ras and C-sis oncogenes in BALB/c 3t3 cells. AB - Down-regulation of fibronectin gene expression at cell surfaces by various oncogenes is an important phenotypic change of many transformed cells. Mechanisms effecting this loss of cell surface fibronectin remain poorly understood. An isogenic mouse fibroblast system, Balb/c 3T3, was used to investigate the effect of oncogene transformation on fibronectin gene transcription. Fibronectin mRNA levels were shown to decrease by >80% when 3T3 cells became stably transformed by EJ-Ha-ras or c-sis oncogenes. The mouse fibronectin gene promoter was subsequently cloned from a mouse genomic library and inserted into reporter gene constructs. Transient transfection assays with the 1.2 kb fibronectin promoter demonstrated that its activity was also decreased in the two transformed cell lines to a similar extent as fibronectin mRNA levels. Co-transfections into 3T3 cells with both the promoter construct and either Ha-ras or c-sis expression constructs provided further support for negative regulation of fibronectin gene transcription by oncogene expression. Potential mechanisms for such transcriptional regulation are proposed based on deletion analysis of the fibronectin promoter. These data suggest that down-regulation of fibronectin gene transcription can contribute directly to the loss of cell surface fibronectin in transformed murine fibroblasts. PMID- 21597680 TI - New cancer strategy - apoptosis based therapy by growth-factors (review). AB - Both epidermal growth factor (EGF) and transforming growth factor type-beta1 (TGF beta1) have positive and negative growth effects on cell growth. In this review, signal transduction of EGF and TGF-beta1 from their receptor to cell cycle or apoptosis is reviewed and discussed. New evidence that high concentration of EGF induces apoptosis in breast and esophageal cancer in vivo is reported. p53 and RB gene is emphasized as a key gene in induction of cell cycle progression and apoptosis. This review indicates that apoptosis based therapy by EGF and TGF beta1 is a useful cancer strategy. PMID- 21597681 TI - Novel germ-cell tumor-cell line established from a testicular feminization syndrome. AB - We analyzed a novel cell line established from a testicular feminization syndrome. The original tumor was an endodermal sinus tumor with seminoma. The doubling time, the saturation density and the mitotic index were 36.1 hours, 3.65x10(4) cells/cm2 and 4.3%, respectively. The mode number of chromosomes was 102. Results of the MTT assay showed that the cell line had an IC50/PPC of less than 0.1 for methotrexate and actinomycin D. The effects of methotrexate were schedule dependent; the effects of actinomycin D were both schedule and dose dependent. PMID- 21597682 TI - Chemosensitivity of gastric-cancer using adhesive tumor-cell culture system. AB - A total of 91 specimens of surgically resected tumors from 80 patients with gastric cancer were assayed for chemosensitivity using an adhesive tumor cell culture system (Life Trac ATCCS assay). Seventy-eight specimens of 91 had sufficient number of cells to grow in culture and 64 (82%) were evaluable excluding 8 low growth and 6 fungus contaminations. Cells (3x10(3)/ml/well) were cultured for 14 days and exposed to drugs on days 3-8. The growing cells were confirmed as cancer cells by immunohistochemical staining using monoclonal antibody to cytokeratin, epithelial membrane antigen and vimentin. IC90 value against (ADM, CDDP, CPM, 5-FU, MMC, MTX, VP-16, CBDCA and MMC+5-FU+MTX) was determined and population distribution of IC90 for each drug was obtained to serve as basic data for judging sensitivity. The 10th percentile of IC90 (mug/ml) was 0.01, 0.43, 1.23, 0.23, 0.01, 0.005, 0.14, 1.56 and 0.009+0.05+0.003 and median of IC90 was 0.02, 0.99, 2.31, 0.30, 0.06, 0.01, 0.39, 3.19 and 0.02+0.10+0.005, respectively. Population distribution of IC90 against each drug showed a specific pattern. Profiles of IC90 against various anticancer drugs differed in individual patients. Chemosensitivity of lymph node metatases seemed to be more resistant than that of their primary tumors. The ATTCS test was found to be useful as a sensitivity test for anti-cancer agents because of its reliability and excellent quantification. PMID- 21597683 TI - Hydroxyapatite beads containing Doxorubicin hydrochloride (dox) and buthionine sulfoximine (bso) - a new anticancer drug design for local treatment with multiple-drugs. AB - Doxorubicin hydrochloride (DOX) and buthionine sulfoximine (BSO) were adsorbed on to a drug-carrier, hydroxyapatite (HAP), to form a DOX and BSO-HAP complex. The time-course of the release of these drugs from the complex into phosphate buffered saline (PBS) was measured photometrically at 37-degrees-C in vitro. After 3 h of incubation, almost all the BSO in the DOX and BSO-HAP complex was released into the PBS, whereas 48.7% of the DOX was released during this period. DOX was released continuously over 10 h of incubation, the rate of release being 7.3%h of the total amount released. Both DOX and BSO were eluted from the DOX and BSO-HAP complex over the first 3 h of incubation. From the 4 h of incubation, only DOX was released, indicating a slow-release property of the complex. The DOX and BSO-HAP complex developed in this study may in future have an in vivo application. It is possible that intracellular glutathione could be depleted first by the rapidly released BSO and that DNA strand breaks could then be intensified by the slowly released DOX. Therefore, this complex has potential as a new drug delivery system (DDS) in cancer chemotherapy. PMID- 21597684 TI - Streptozotocin-induced diabetes accelerates mammary tumorigenesis in shn and sln mice. AB - Virgin female SHN and SLN mice, a high and a low spontaneous mammary tumor strains, respectively, were given a single intravenous injection of streptozotocin (2 mg/10 g body weight), resulting in a significant rise of blood glucose levels and of mammary tumor incidence. The growth rate of mammary tumors was also accelerated by streptozotocin-induced diabetes in SHN mice, but not in SLN mice. The incidence and progression of uterine adenomyosis and adenocarcinoma were not affected by diabetes in SHN and SLN mice. These findings indicate that spontaneous mammary tumorigenesis in SHN and SLN mice is accelerated by streptozotocin-induced diabetes. PMID- 21597685 TI - Resistance proteins in human kidney, breast, ovarian and lung-carcinoma - a comparative-analysis. AB - The expression of P-glycoprotein (P-170), glutathione S-transferase-pi (GST-pi), dihydrofolate reductase (DHFR) and thymidylate synthase (TS) was analyzed immunohistochemically in human tumors of different origin. The resistance proteins were expressed at varying degree: all kidney carcinomas (n=25), 40 of 56 non-small cell lung carcinomas (NSCLC) (71%), 8 of 15 ovarian carcinomas (53%), 5 of 11 breast carcinomas (46%) and 3 of 14 small cell lung carcinomas (SCLC) (21%) expressed more than one resistance protein. A comparison of the immunohistochemical data with the clinical response rates as reported in literature, demonstrates an evident correlation between the number of resistance proteins and the clinical outcome. PMID- 21597686 TI - Effects of melatonin administration on cytokine production in patients with advanced solid tumors. AB - There is growing evidence that the pineal gland has antineoplastic properties, which include the action of melatonin (MLT) on the immune system through the release of cytokines by activated T-cells and monocytes. Despite these intriguing preliminary findings, only few studies have been undertaken to date on MLT's action in cancer patients. The present study was carried out on 23 patients (15 males and 8 females, range 48-71 years), with advanced solid tumors, who received MLT (10 mg/day orally for a month) after conventional therapy. Blood was assayed for tumor necrosis factor alpha (TNF-alpha), Interleukin-2 (IL-2) and human interferon gamma (IFN-gamma). Blood samples were taken immediately before the start of MLT administration and 30 days after therapy. Plasma was collected in EDTA tubes on ice, centrifuged immediately at 4-degrees-C and stored frozen at 80-degrees-C until assayed. Cytokines were quantified by immunoradiometric assays. Circulating levels of TNF-alpha, IL-2 and IFN-gamma increased by 28%, 51% and 41% respectively after MLT administration. These increments were statistically significant (paired Student's t-test, p<0.01). These findings are consistent with the hypothesis that MLT modulates immune functions in cancer patients by activating the cytokine system. PMID- 21597687 TI - Clinical-evaluation of serum basic fetoprotein as a marker in urogenital malignant-tumors. AB - Serum basic fetoprotein (BFP) and other markers were assessed for use in urogenital malignant tumors. Useful in gastric, hepatic, pancreatic and mammary carcinomas, BFP is not very organ specific. Studies of its marker efficiency in urogenital tumors seem fitting. 190 untreated urogenital cancer patients were studied. Serum BFP was examined by EIA using a MoAb and compared with seven non specific other cancer markers. Serum BFP efficiency in renal cell carcinoma was higher than TPA and lower than IAP and did not correlate with either; in seminoma it was lower than AFP and similar to beta-hCG; in prostatic carcinoma it was lower than PSA and higher than PAP and showed a comparatively stronger correlation with PSA. In three cancers it increased with tumor stage. Indispensable in diagnosing testicular tumors, some marker are, unlike BFP in our study, not effective in assessing and monitoring seminoma and are less efficient in the diagnosis of early prostatic carcinoma. A combination assay involving BFP and these antigens would be useful. PMID- 21597688 TI - The relationship between the expression of proliferating cell nuclear antigen and clinicopathological variables of gastric-cancer. AB - A monoclonal antibody against proliferating cell nuclear antigen (PCNA), PC10, was applied to 96 gastrectomy specimens obtained from patients with gastric cancer. Resected tissue was routinely processed and stained immunohistochemically with PC10. One thousand tumor cells were counted and the ratio of the number of stained cells to total tumor cells was calculated as the PCNA index, which ranged from 13.8% to 88.8% with a mean of 61.4%. Although the PCNA index did not correlate with pathological variables including histological type, lymph node metastasis, growth pattern and venous invasion, it was significantly lower in mucosal carcinomas compared with submucosal and advanced carcinomas. PMID- 21597689 TI - Sensitive colorimetric cytotoxicity measurement using alarmar blue. AB - Cytotoxicity testing of anticancer drugs requires techniques which are sensitive, reproductible and applicable to large scale testing using automated instruments. End point staining of cells or viability stains are reliable but they are often not sensitive enough or not suitable for automation. We have already described a fluorometric cytotoxicity assay using a non fluorescent substrate, Alarmar Blue, which upon reduction in living cells, yields a fluorescent product. This assay is sensitive and highly reproductible but it is limited since automated fluorescent plate readers are not found frequently in laboratories. The conditions are now described for using Alamar Blue as a substrate in a colorimetric cytotoxicity assay. This new economical assay could be used with advantage for large scale screening of cytotoxic agents in microtitration plates. PMID- 21597690 TI - Clinical and endocrine effects of megestrol-acetate in women with pretreated advanced breast-cancer. AB - Megestrol acetate (MA) is one of the most widely used progestins in the palliation of advanced breast cancer, but its optimal dose level has yet to be defined. Forty-six women with progressive advanced disease were given MA according to a monthly loading-dose-schedule (320 mg/day orally) followed by standard-dose maintenance (160 mg/day). Most of the patients had been heavily pretreated with endocrine and/or chemotherapy; all the cases were evaluable. The response rate was 20% (95% CI: 9-31%), with 9 subjects achieving PR. The median time to response was 3 months (range 2-11), the median response duration being 3 months (range 3+-12+). After a median follow-up period of 8 months (range 7-16), only 3 of the patients achieving PR are still on treatment. No increased toxicity or potentially detrimental endocrine effects were observed and all of the patients showed good compliance to treatment. Although the loading-dose schedule used in the present series proved to be feasible, it does not appear to provide any clinical advantage over standard-dose MA treatment. PMID- 21597691 TI - Lack of diagnostic-value of DNA content and p53 immunostaining in normal, hyperplastic and neoplastic parathyroid tissue. AB - The aim of this project was to study the diagnostic value of DNA content and p53 protein expression in normal, hyperplastic and neoplastic parathyroid lesions. Tissue samples of 74 parathyroid glands from 34 patients with primary hyperparathyroidism were studied by DNA flow cytometry and p53 immunostaining. In 9 of 23 patients (39%) with parathyroid adenoma, a nondiploid cell population was present. Some normal looking glands removed from the same patients also had a nondiploid DNA index. Multiglandular hyperplasia was found in 11 patients, and in 5 of these (45%) the histograms showed nondiploid cells. The proliferative activity was generally low and S-phase fraction did not differ in glands with hyperplasia or adenoma, when compared with normal looking glands. One single case of hyperplasia showed a weak p53 positivity in scattered nuclei, probably representing wild type p53 protein. Thus, our present results suggest that DNA content and p53 protein staining are of no value in the routine work up of parathyroid glands removed from patients with primary hyperparathyroidism. PMID- 21597692 TI - 5-Fluorouracil combined with the pure L-stereoisomer of leukovorin calcium to treat advanced colon-cancer patients - a phase-ii study. AB - A theoretical superiority of 5-fluorouracil (FUra) activity when combined with l leucovorin (LV) might be postulated on the basis of a possible interference of the inactive d-stereoisomer of LV with the active l-form. We treated 47 patients by means of FUra (370 mg/m2/day) and l-LV (100 mg/m2/day), for 5 consecutive days, every 4 weeks. An objective response was observed in 12 patients (25.5%, 95% confidence interval: 12.5-38.5%), with 2 complete responses. As regards toxicity, 53.1% of the patients experienced mucositis, 51% diarrhea, 31.9% nausea and vomiting, 12.7% leukocytopenia, 8.5% cutaneous toxicity, 4.25% neurotoxicity, conjunctivitis and phlebitis. This regimen appears to be substantially superimposible to the classic FUra/d,l-LV combination. Therefore, the use of l LV, in those countries where this compound is commercially available, should not be discouraged. PMID- 21597693 TI - Selected prooxidative - antioxidative parameters in blood of adult vegetarians. AB - Selected prooxidative - antioxidative parameters (conjugated dienes of fatty acids CD, vitamin C, vitamin E, catalase activity CAT, glutathione peroxidase GSH Px activity) were investigated in blood of 81 vegetarians aged 20-40 years. The average period of consuming vegetarian food was 3.5 years. The results were compared to corresponding values of non-vegetarians of the same age and from the same geographical region (Bratislava). The levels of conjugated dienes of fatty acids were significantly lower in vegetarians. Significantly higher values of molar ratio vitamin E/cholesterol, vitamin E/triacylglycerols and vitamin E/polyunsaturated fatty acids found in vegetarians imply a higher protective effect against lipid peroxidation - antioxidative status in vegetarians is indicated also by significantly higher levels of vitamin C in plasma, significantly increased catalase activity and insignificantly increased activity of glutathione peroxidase in erythrocytes. PMID- 21597694 TI - Cell-type-specific regulation of p53 expression in nonsmall cell lung-carcinoma cells. AB - The expression of an exogenous wild-type p53 protein in different non-small cell lung carcinoma (NSCLC) cell types, harboring endogenous wild-type or mutant p53 or lacking p53 altogether, was investigated to determine whether the status of endogenous p53 protein determined the level of expression of exogenous wild-type p53 protein. NSCLC cells were transfected with wild-type p53 by adenovirus mediated transfer. When the cells began to express exogenous wild-type p53 protein, the highest levels were observed in p53-null H358 and H1299 cells, whereas the lowest levels, below those of the endogenous wild-type protein, were observed in both H460a and H226b cells. In both H322j and H596b cells, which expressed high levels of endogenous mutant p53, the levels of expression of exogenous wild-type p53 were higher than those in cell lines expressing low levels of endogenous wild-type protein. Northern analyses showed that the differences in the expression of exogenous wild-type p53 protein among the various NSCLC cell lines could not be explained completely by differences in the expression of exogenous p53 mRNA. The results indicated that the level of expression of exogenous wild-type p53 protein in NSCLC cells was determined by the status of endogenous p53. Cell lines that lacked p53 exhibited an intracellular environment more conducive toward overexpression of the protein, in part as a result of differences in the expression of factors that control expression of p53 at the post-transcriptional level. PMID- 21597695 TI - Allelic loss at markers of chromosomal band 7q31 is not a frequent event in human breast-cancer. AB - Loss of heterozygosity (LOH) at loci from the long arm of chromosome 7 was shown to occur in breast carcinomas. However, the frequency with which this alteration is observed varies from 0 to 40%. We report LOH at three microsatellite markers located at 7q3 in 16 of 66 (24%) breast tumor samples. PMID- 21597696 TI - Cytotoxic effect of herbal medicine sho-saiko-to on human lung-cancer cell-lines in-vitro. AB - The cytotoxic effect of a herbal medicine Shosaiko-to (TJ-9) was examined by the MTT assay on 7 human lung cancer cell lines (4 non-small cell carcinomas, 3 small cell carcinomas) and on 5 hepatocellular carcinoma cell lines. TJ-9 showed a dose dependent cytotoxicity in all cell lines except one (SBC-5). Of the seven herbs in TJ-9, Scutellaria root showed the strongest cytotoxicity followed by the Glycyrrhiza root. Among baicalin, baicalein and wogonin from the Scutellaria root, cytotoxicity was observed only with baicalin. The SBC-5 cell line which was resistant to TJ-9 showed a lesser sensitivity to both Scutellaria root and baicalin. TJ-9 showed almost equal cytotoxicity in cisplatin (CDDP)-sensitive PC 10 and CDDP-resistant SBC-4 cell lines, and in H69 and H69/CDDP cell lines. TJ-9, Scutellaria root and baicalin were all less cytotoxic for human lymphocytes and bone marrow cells than for a lung cancer cell line of SBC-4. These results suggest that TJ-9 and its components may be useful anticancer agents for the treatment of lung cancer. PMID- 21597697 TI - Antagonism of 2 virus-infections in the development of cervical-cancer - (review hypothesis). AB - The recent detection of DNA of the human adeno-associated viruses in the majority of biopsies of the cervix uteri suggests an interaction of these tumor suppressive parvoviruses with human papillomaviruses which are causally linked to the development of cervical cancer. Based on available virological and pathological data, a hypothesis is presented on a probably antagonistic action of the two viruses in cells of the cervical epithelium. The presence of viruses with oncosuppressive properties in the tissue which is the main target of transformation by papillomaviruses should stimulate investigations on interactions of these two viruses to improve prevention and therapy of genital cancer. PMID- 21597698 TI - Proliferating cell nuclear antigen (pcna) and C-erbb-2 oncoprotein in breast carcinoma with correlations to histopathological parameters and prognosis. AB - Overexpression of PCNA (more than 25% positive tumour cells) and positivity of c erbB-2 oncoprotein were immunohistochemically demonstrated in 490 formalin-fixed and paraffin-embedded breast carcinomas. Overexpression of PCNA and c-erbB-2 correlated with large tumour size, presence of lymph node metastases, high histological grade (poor differentiation), and absence of steriod hormone receptors features indicating an aggressive phenotype. In univariate analysis overexpression of PCNA correlated with poor overall survival (p<0.05), whereas c erbB-2 was of no prognostic significance. In multivariate analysis both PCNA and c-erbB-2 failed to be of independent prognostic significance. In order to identify women with different prognosis an index termed immunoscore, based upon the results of the immunoreactivity of both PCNA and c-erbB-2 was constructed. The immunoscore was correlated with tumour size, lymph node status, histological grade, and steroid hormone receptor status. In univariate analysis of survival data the immunoscore was a prognostic parameter of poor overall survival. In multivariate analysis the classical histopathological parameters such as tumour size, histological grade and progesterone receptor status turned out to be of independent prognostic significance. The immunoscore was associated with poor prognosis but did not reach independent statistical significance (p=0.08). Further studies including a larger number of patients must be carried out in order to determine the prognostic significance of the immunoscore in multivariate analysis. PMID- 21597699 TI - A novel methotrexate-albumin (mtx-rsa)-conjugate causes significant growth delay of o-342 ovarian-carcinoma in-vivo. AB - The increased uptake of native serum albumin in tumors is well described. In previous approaches to use this distribution pattern for tumor therapy, albumin molecules were loaded with maximum quantities of antineoplastic drugs. To preserve the properties of native albumin and to avoid enhanced phagocytotic clearance, we used methotrexate (MTX)-albumin-conjugates with a molar loading ratio of 1:1. In this study we evaluated the effects of single injections of MTX rat-serum albumin (MTX-RSA) containing 50, 20 and 10 mug MTX on 40 BDIX rats bearing O-342 ovarian carcinoma. Tumor volume post treatment and area-under-the curve of tumor volumes over treatment were compared with an untreated group using the Mann-Whitney U-test. MTX-RSA treatment caused dose dependent effects and in the 50 mug MTX-dosage significant (P 0.01) growth delay. Additional distribution studies with indirectly radio-iodinated MTX-RSA confirmed the prominent tumor uptake of this compound. We conclude that MTX-albumin-conjugates created with optimized labeling techniques and loading ratios cause significant effects even with very low MTX-doses. Thus these compounds may contribute to enhance the efficacy of MTX-treatment. PMID- 21597700 TI - Expression of e-cadherin, alpha-catenins and Beta-catenins in human gastric carcinomas - correlation with histology and tumor progression. AB - The expression of cell-cell adhesion molecule, E-cadherin and its associated proteins, alpha- and beta-catenins in human gastric carcinomas was examined by Western blotting. All the seven gastric carcinoma cell lines expressed E-cadherin except KATOIII, which was derived from pleural effusion of a scirrhous type stomach cancer or Borrmann's type-4 carcinoma. The expression of alpha-catenin was not detected in HSC43 derived from scirrhous carcinoma, while HSC39 expressed abnormal beta-catenin caused by genetic alteration. In gastric carcinoma cases, the levels of E-cadherin and alpha-catenin were significantly lower in poorly differentiated adenocarcinomas and scirrhous carcinomas when compared to other types of gastric carcinomas. Deeply invasive carcinomas expressed E-cadherin and alpha-catenin at lower levels. However, the expression level of alpha-catenin was not necessarily consistent with that of E-cadherin. One of 10 gastric carcinomas examined showed complete deletion of alpha-catenin gene in Southern blotting. beta-catenin was expressed at lower level in poorly differentiated adenocarcinomas than in well-differentiated adenocarcinomas. These findings suggest that reduction in the expression of E-cadherin and its associated molecules, catenins, is involved in the development and infiltrative growth of scirrhous type gastric carcinomas. PMID- 21597701 TI - Cyfra 21-1 - a new tumor-marker for lung-cancer. AB - Among 20 known cytokeratins, cytokeratin fragment 19 is a 40 kD acidic molecule whose distibution is restricted to simple or pseudo-stratified epitelia, such as the epithelial layer of the bronchial tree. An immunoradiometric assay, CYFRA 21 1, was used to detect a fragment of cytokeratin 19 in the serum of 90 subjects and compared with serum levels of CEA, NSE and TPA. Sixty-seven consecutive patients with lung cancer and 23 healthy subjects were tested. Cut-off values for tumor markers were considered as the 95% of specificity versus controls. There were 32 adenocarcinomas, 29 squamous carcinomas and 6 other tumors. Increased serum levels of CYFRA 21-1 were found in lung cancer patients compared to controls [1.6 (0.2-3.2) versus 0.5 (0.2-1.8): p<0.001]. In our study TPA was more sensitive than CYFRA 21-1: 49% versus 40%; when we combined both markers the sensitivity increased to 63%. Significant difference in values were found before and after surgery in serum levels of 34 operated patients: p<0.01. We found higher levels of soluble cytokeratin 19 in lung cancer patients and in the adenocarcinoma subgroup. This study does not support the exclusive use of soluble cytokeratin 19 as a specific marker of lung cancer and not only in squamous carcinoma subgroup. This suggested that diagnostic and prognostic sensitivity increase when CYFRA 21-1 and TPA or other markers are combined. PMID- 21597702 TI - Inhibitory effect of transient administration of flutamide (sch-13521, 4'-nitro 3'-trifluoromethylisobutyranilide) on diethyl-nitrosamine (den) induced liver tumors in male b6c3f1 mice. AB - In order to understand the role of androgen in DEN induced liver tumorigenesis in mice, we studied the influence of anti-androgenic compound, flutamide (SCH 13521, 4'-Nitro-3'-trifluoromethylisobutyranilide) on liver tumors, in B6C3F1 male mice. At 6 weeks of age mice were treated with DEN, (0.2 muM/g body weight). Transient administration of flutamide (0.5 mg/g food) in diet to male mice for (i) three weeks immediately after diethylnitrosamine (DEN) treatment, for (ii) three weeks starting at the age of 25 weeks and (iii) starting at 25 weeks of age until end of experiment inhibited liver tumors incidence to 63%, 50% and 53%, respectively, compared to that of DEN alone, 81.3% (significantly different). However, continuous administration of this drug throughout the experimental period (58 weeks) produced 96.9% liver tumor incidence. The time-dependent sacrifice of DEN alone treated mice at 25, 30, 38, 44 and 58 weeks of age produced liver tumor incidence of 0, 12.5, 31.5, 43.8 and 81.3%, respectively (r = 0.99). Mean tumor number and size were also correlatively increased with the prolongation of latency and highest value was noted at 58 weeks of age. Implantation of testosterone pellet after castration significantly increased cytosolic androgen receptor levels but decreased in mice treated with flutamide. Three weeks administration of flutamide to male B6C3F1 mice enhanced nuclear BrdU incorporated cells in the liver. Our results suggested that flutamide reduces cytosolic androgen receptor levels and increases DNA synthesis. These factors may in part be responsible for the liver tumor inhibitory effect of flutamide in male mice. PMID- 21597703 TI - Inhibition of the proliferation of androgen-dependent sc-3 cells by methylcobalamin. AB - Methylcobalamin decreased the proliferation of androgen-dependent SC-3 cells, derived from androgen-dependent mouse mammary tumor SC115, in a dose dependent manner at high concentrations without remarkable change of the cell viability. The androgen-induced growth factor activity in the conditioned medium of SC-3 cells cultured in the presence of androgen was shown to be decreased by the addition of methylcobalamin. In SC-3 cells incubated with [methyl-H 3]methylcobalamin, [H-3]methyl moiety was incorporated into the DNA fraction. These results indicate an antiproliferative effect of methylcobalamin on SC-3 cells at high concentrations and suggest a possibility that methylcobalamin can act as a donor of methyl moiety into DNA. PMID- 21597704 TI - Inflammatory effects of the tumor promoter croton-oil in BALB/c mice skin. AB - A single dose of 0.25% croton oil induced an edema when applied to the ears of BALB/c mice. The maximal edematous response resulted from a single application of 4% croton oil. At any dose level, edema maximized 6-7 h after croton oil application, waning thereafter to the control level by 30 h. When topically applied on the shaved back skin, a single dose of 0.25% croton oil induced an inflammatory effect characterized by epidermal hyperplasia and infiltration of polymorphonuclear leucocytes (PMNs) in the dermis. Higher doses of croton oil caused more remarkable inflammatory response. The histological changes which were slightly detected in the skin 4 h after application of croton oil, reached a maximal level by 20-27 h, but substantially subsided by 72 h. Results proved that the tumor-promoter croton oil induces an inflammation in mice skin in a dose- and time-dependent process. PMID- 21597705 TI - The clinical relevance of lymphatic and blood-vessel invasion in breast-cancer patients. AB - We reviewed 795 patients treated between 1978 and 1988 at the Department of Radiation Oncology of the University of Wuerzburg to study the influence of lymphatic vessel (LVI), blood vessel (BVI) invasion within the primary tumor on distant recurrence and survival following mastectomy or conservative treatment. Among them there were 140 patients with LVI and 18 patients with BVI. In the LVI positive group 75% of patients had axillary lymph nodes involved. In the BVI positive group 94% were nodal positive. The mean number of involved axillary nodes was higher in the group with LVI (4.6) as well as in the group with BVI (9.6) in comparison to the groups with absence of LVI (1.2) or BVI (1.7). LVI and BVI have a distinct impact on survival (P<0.001, P<0.01 respectively) and metastatic-free interval (P<0.001, P<0.01 respectively). The 2- and 5-year survival rates were 78% and 42% for the LVI group compared to 89% and 71% respectively for the LVI negative group. The corresponding 2- and 4.5-year survival rates for the BVI positive group were 68% and 40% compared to 87% and 70% respectively for the BVI negative group. The 5-year metastatic-free rate was 50% in the LVI group compared to 68% in the group without LVI. In the BVI group 53% were free of distant disease at 5 years compared to 66% in the group without BVI. This study suggests that from the biological point of view, LVI and BVI is a sign of agressive disease with poor prognosis. Patients with intra- or peritumoral LVI or BVI represent high risk groups for distant recurrence. PMID- 21597706 TI - The clinical relevance of p53 oncoprotein determination in cancer-diagnosis and prognosis. AB - The role of p53 overexpression in tumorous tissues and in blood of cancerous patients is reviewed. It has been shown that neither immunohistochemical nor immunochemical methods can be presently regarded as being highly significant in diagnosis or prognosis of cancer. The data of the literature and our preliminary studies showed that overexpression of p53 not only has a role in oncogenesis but can also be regarded as a protein which accumulates in cells under stress conditions. The overexpression of p53 protein can be found not only in cancerous patients but also in patients with non-cancerous diseases. Further investigations should be undertaken to better understand the diagnostic and prognostic role of p53 in clinical practice. PMID- 21597707 TI - Prevention of liver-tumor colonization by combined immunomodulation and liver lectin blocking. AB - The protective effect of combined treatment (immunomodulation with Propionibacterium avidum KP-40; liver lectin blocking by D-galactose administration) on the liver colonization of RAW 117-H10 lymphosarcoma was investigated in BALB/c-mice. Both, immunomodulation with P. avidum KP-40 as well as liver lectin blocking by D-galactose treatment significantly decreased the number of liver tumor colonies in this experimental model. However, the combination of P. avidum KP-40 and D-galactose obviously proved to be superior to each monotherapy since the liver colonization by RAW 117-H 10 lymphosarcoma could be completely inhibited. PMID- 21597708 TI - Recovery of the hepatic carcinogen-metabolizing capacity in schistosome-infected mice after treatment with the antischistosomal praziquantel. AB - The influence of Schistosoma mansoni infection on the capacity of the carcinogen metabolizing enzymes was investigated prior to and after treatment of the infected male mice with praziquantel, an anti-schistosomal agent. The drug was administered in a daily dose of 60 mg/kg body weight for three days before decapitation at various infection intervals. After 20 and 30 days post-infection the hepatic content of cytochrome P-450 and cytochrome b-5 and the activity of aryl hydrocarbon hydroxylase were markedly increased. However, the constitutive levels of the above mentioned enzymes were significantly decreased at 45, 60 and 75 days post-infection. Treatment of the infected mice with praziquantel for three days, however, recovered the changes in these activities at each individual time point. Praziquantel showed no effect on either of the studied enzymes when administered alone except for that of NADPH-cytochrome C reductase activity which exhibited significant increase. The activity of NADPH-cytochrome C reductase gave inconsistent results after treatment of the infected animals with praziquantel. It is concluded that praziquantel can be considered as a safe and useful drug for the chemotherapy of schistosomiasis and it possessed a recovery for the activities of the drug-metabolizing enzyme. PMID- 21597709 TI - Antitumor-activity and toxicity of continuous-infusion versus bolus administration of bleomycin in 2 heterotransplanted human testicular cancer cell lines. AB - The continuous infusion of the glycopeptide antibiotic cytotoxic agent bleomycin in comparison to bolus application has been postulated to be associated with increased antitumour activity and decreased toxicity, particularly pulmonary fibrosis. In the treatment of patients with testicular cancer, bleomycin is an essential agent and is currently used in continuous infusion and bolus application schedules in cisplatin-based combination therapy regimens. The current study addresses the antitumour activity and general toxicity of bleomycin given as continuous intraperitoneal infusion versus bolus application in human testicular cancer cell lines heterotransplanted into nude mice. Maximally tolerated doses for each administration route, defined as being the LD20 were applied (8.7 or 17.5 mg/kg days 1-7 continuous intraperitoneal infusion via osmotic mini pump or 40 mg/kg intraperitoneal bolus application on days 1, 5, 9). Bleomycin demonstrated antitumour efficacy at all concentrations used in comparison to untreated controls. There was no significant difference in antitumour activity between continuous or bolus application of bleomycin when the same cumulative doses were compared. Neither was there any difference with respect to bleomycin toxicity with 11 +/- 4 or 12 +/- 5% losses of body weight for continuous infusion regimens compared to 13 +/- 3% for bolus application. In a small subgroup of mice histological examination of the lungs demonstrated no signs of pulmonary fibrosis. In summary, using an established testicular cancer xenograft model in nude mice bolus application of bleomycin was as active as continuous infusion of this drug with no apparent difference in overall toxicity. Current standard treatment regimens using bolus application of bleomycin should not be altered without necessary reasons. Bleomycin pulmonary toxicity needs to be studied in clinical trials taking into account possible drug interactions in combination chemotherapy regimens and additional risk factors for pulmonary toxicity. PMID- 21597710 TI - Pathological-changes of the blood-cells in griseofulvin treated toads. AB - Griseofulvin is a valuable oral antifungal drug, used extensively in the treatment of superficial fungal infections of man and animals. Electron microscopical studies of peripheral blood of toads force-fed with griseofulvin revealed pronounced alterations of the blood cells more or less similar to the criteria of monocytic leukaemia and were all comparable to those observed after the administration of the carcinogenic chemical 7,12 dimethylbenz(a)anthracene. PMID- 21597711 TI - A model of transcription replication enhancers. AB - A model is pesented arguing that all transcription enhancers function also as replication enhancers; replication enhancers are thus defined as DNA elements that interact with the core origin to enhance manyfold replication efficiency. This interaction is via proteins bound to the enhancer region with proteins bound to the core ORI and loopig out of DNA. Core ORI by itself functions as a transcriptional enhancer for the gene(s) in the same chromatin loop. One core ORI may require more than one transcription enhancer for its activation. Replication specificity is conferred by a class of replication initiator proteins, comprising cruciform-binding proteins, that need to interact with transcription factors at the core ORI for origin firing; transcription specificity is provided by the interaction of the transcription/replication enhancer with the immediate 5' flanking promoter region. Core ORIs in this model possess a great number of transcription factor binding sites in addition to the initiator protein sites; both initiator proteins and transcription factors cooperate in origin firing. The developmental programs leading to inactivation of specific genes during cell type formation are proposed to be tightly linked with programs leading to the inactivation of ORIs; thus active ORIs are also active enhancers whereas inactive ORIs are linked with transcriptionally-inactive genes and are identical to enhancers inactivated during development or differentiation. Tumor cells are expected to be able to assemble a larger number of active enhancers because of activation of early embryo- or fetal stage-specific transcription factors; this would result in the activation of early developmental stage-specific ORIs. PMID- 21597712 TI - Hepatitis-B x-antigen in the pathogenesis of hepatocellular-carcinoma (review). AB - Chronic infection with hepatitis B virus (HBV) is associated with a high incidence of liver diseases, including hepatocellular carcinoma (HCC). The persistent expression of hepatitis B x antigen (HBxAg) is important to transformation, although the mechanism(s) involved remain to be firmly established. This review presents the functions of HBxAg which may be important to the pathogenesis of HCC. PMID- 21597713 TI - Oncoprotein fos activation in epithelial-cells induces an epitheliomesenchymal conversion and changes the receptor encoded by the fgfr-2 messenger-RNA from k sam to bek. AB - Activation of c-Fos, by using an inducible c-Fos estrogen receptor fusion protein, triggers the epitheliofibroblastoid cell conversion of mouse mammary epithelial cells. We show that this change in phenotype is accompanied by a definitive switch of the fibroblast growth factor receptor 2 from K-SAM to BEK. This splicing switch occurs a few hours after estrogen stimulation. Our data suggest that Fos proteins could be important in modulating the FGFR-2 splicing choice. Moreover, these observations reinforce previous evidence that the BEK/K SAM choice is strictly tissue-specific: the K-SAM exon is expressed exclusively in epithelial cells, the BEK exon in cells of the fibroblastic type. PMID- 21597714 TI - Expression of an alternatively spliced ercc1 messenger-RNA species, is related to reduced DNA-repair efficiency in human T-lymphocytes. AB - We have previously shown that in non-drug-selected human T lymphocytes, DNA repair is the primary determinant of cellular resistance to cisplatin (1). In this system, we have assessed mRNA levels of expression of the nucleotide excision repair (NER) genes ERCC1 and XPA, as well as the alternatively spliced species of ERCC1 which lacks exon VIII. The focus of these studies, was to try to identify the possible relative roles of normal XPA, full-length ERCC1, and alternatively spliced ERCC1, in a system where DNA repair is a clear determinant of cisplatin resistance. ERCC1 expression was directly related to cisplatin-DNA adduct repair capability, as well as directly related to cisplatin resistance, suggesting a primary role for ERCC1 in effecting DNA repair. XPA expression was approximately equivalent in each cell line, regardless of the level of DNA repair activity, suggesting a helper role for the product of this gene. The mRNA levels of the alternatively spliced species of ERCC1 were strongly inversely related to DNA repair activity, suggesting a possible inhibitory influence on the DNA repair process. This interpretation is consistent with alternative splicing of several known oncogenes, where the alternatively spliced species has an inhibitory effect on the full-length gene product. The NER pathway appears to be vitally important in effecting cisplatin resistance in non-drug-selected T lymphocytes. Further, it appears that NER may have at least one inhibitory regulatory component. PMID- 21597715 TI - Elevations of serum C-reactive protein occur independently of circulating interleukin-6 concentrations in patients with lung-cancer. AB - It has been suggested that a proportion of patients with cancer have an ongoing acute phase response indicated by a raised C-reactive protein (CRP). To examine whether an acute phase protein response is associated with circulating interleukin-6 (IL-6) concentrations in patients with lung cancer, we measured serum levels of CRP and interleukin (IL)-6 in 176 patients with lung cancer and 48 patients with other pulmonary diseases (28 diffuse pulmonary infiltrates, 15 benign lung tumors, and 5 bronchial asthmas). Serum CRP was detectable (greater than-or-equal-to 2.5 mg/liter) in 57.4% of patients with lung cancer, 78.6% of patients with diffuse pulmonary infiltrates, 46.7% of patients with benign lung tumors, and 40.0% of patients with bronchial asthma. Serum IL-6 was detectable in all patients by a highly sensitive enzyme-immunoassay, the concentration ranging from 0.126 to 35.115 pg/ml. Although there was no significant difference in serum IL-6 levels among the histologic types of lung cancer, the IL-6 concentration was significantly higher in patients with advanced cancers than in those with early ones. Correlation analyses showed that there was no significant relationship between the CRP and IL-6 concentrations in the 176 patients with lung cancer (r=0.212, P=0.1243), while a highly significant correlation between both levels was observed in the 28 patients with diffuse pulmonary infiltrates (r=0.783, P=0.0005). These results indicate that the serum IL-6 level in patients with lung cancer is closely associated with the disease stage, but that a raised CRP concentration occurs independently of circulating IL-6 concentrations in patients with lung cancer. PMID- 21597716 TI - Establishment of human bladder-cancer cell-line (hamt-1) and long-term subculture in nude-mice. AB - Human bladder cancer cell line (HAMT-1) was established from a transitional cell carcinoma of the bladder (T4N3M0, grade 3) of a 61-year-old male by using a serum free medium. HAMT-1 cells in serum-free medium were non-adhesive to the flask wall or to other cells. The cells grew in attached form by the addition of fetal calf serum. Heterotransplantation of HAMT-1 cells into nude mice and the long term subculture were successful. Tumor bearing nude mice showed an elevated serum tissue polypeptide antigen as in the patient. PMID- 21597717 TI - Early g1 induction of p21/waf1/cip1 in synchronized osteosarcoma cells is independent of p53. AB - Enzymatic activities of cyclin-dependent protein kinases (cdks) are tightly regulated at the level of subunit composition, involving both positive (cyclins) and negative (p21Wafl/Cipl); p16Ink4; p27Kipl) effectors. In the present study, we examined the expression of p21/WAF1/CIP1 in highly synchronized human MG-63 osteosarcoma cells in which the sequential induction of specific cyclins was characterized previously (1). Two distinct peaks of p21/WAF1/CIP1 expression were detected by Northern analysis of serum-stimulated cells: one peak was detectable by 1 hour, reached a maximum at approximately 3 hours, and diminished markedly by 4-6 hours; and a second peak was observed during S phase. The early G1 induction of the 21 kDa gene product was further demonstrated by Western blotting. Both Northern analysis and Western blotting for the p53 tumor suppressor confirmed previous reports that its expression is not detectable in MG-63 cells at any time. The transient induction of p21/WAF1/CIP1 in early G1 was correlated with a transient decrease in p9Ckshs1-agarose precipitable histone H1 kinase activity, as determined by in vitro kinase assays. In contrast, the myelin basic protein kinase activity of anti-Cdk4 immune complexes was not attenuated to a significant extent. Taken together, these studies identify a novel biochemical pathway of p21/WAF1/CIP1 induction operating in p53-deficient osteosarcoma cells; a pathway whose independence from p53 may conceivably be exploited to therapeutic advantage in the treatment of proliferative disorders. PMID- 21597718 TI - Immunohistochemical detection of p53 protein and proliferating cell nuclear antigen (pcna) in salivary-gland tumors. AB - The expression of p53 protein and PCNA was immunohistochemically examined in 161 cases of salivary gland tumors. The p53 protein was positive in 23.8% (24/101) of malignant salivary gland tumors, while only one case of 60 pleomorphic adenomas was positive. p53 protein was frequently detectable in salivary duct carcinoma (60%), basal cell adenocarcinoma (66.7%), acinic cell carcinoma (53.3%) and undifferentiated carcinoma (50%), but was rarely seen in adenoid cystic carcinoma (17.2%) and mucoepidermoid carcinoma (0%). p53 protein was more frequently detectable in PCNA positive cases than in negative cases (p=0.0074). PMID- 21597719 TI - Breast-tumor xenograft targeting and therapy studies using radiolabeled chimeric anti-cea monoclonal-antibody t84.66. AB - Carcinoembryonic antigen (CEA) is expressed in approximately 60% of breast carcinomas. T84.66 is a well characterized anti-CEA murine monoclonal antibody (MAb) that does not cross-react with other CEA-related proteins. It has been humanized and used extensively after radiolabeling in clinical/experimental protocols for localization/therapy of colorectal cancer. MCF-7 human breast cancer cell line expresses CEA and is tumorigenic in athymic mice. In order to determine if anti-CEA MAb could specifically target breast cancer CEA, biodistribution, radiolocalization and therapy studies were performed in the animal model. Five tumor-bearing animals per time point were injected with 15 muCi of In-111-cT84.66. Mice were imaged and sacrificed at 24, 48, 72 and 144 h and biodistribution studies performed. For therapy studies, 19 tumor-bearing mice were injected either with 120 muCi of 90Y-cT84.66 or PBS. The tumors were measured tri-weekly and weighed at autopsy 21 days post therapy. Activity accumulation steadily increased in the tumors reaching 21% of the injected dose per gram of tumor (ID/g) at 144 h. At that time, the %ID/g in the tumor was 3 times higher than that in blood and the liver and 8 times higher than in other major organs. On day 10 post-therapy, 16 of the 19 control mice had tumor volumes between 1 and 3 cm3, while none of the treated tumors ever reached 1 cm3 in size. At autopsy, a 12-fold tumor weight difference (p=0.0001) was observed between control and treated mice (2.4g vs. 0.2g average weight, respectively). In summary, breast cancer CEA was specifically targeted with T84.66 allowing good tumor localization as well as significant tumor growth inhibition. Given the significant expression of CEA in breast cancer, this tumor should be included into the CEA-expressing malignancies for targeting with anti-CEA MAbs. PMID- 21597720 TI - Malignant schwannoma of the inferior dental nerve. AB - Malignant schwannomas of the oral cavity and especially inferior dental nerve tumours, are rare malignancies. Mostly arising de novo as solitary tumours, some cases have occurred in Von Recklinghausen neurofibromatosis (25% of cases) or, as in the present report, at the time of a relapse by transformation of a benign schwannoma. Long survival is only observed in selected early diagnosed patients additionally treated by extended surgery. Support of magnetic resonance imaging and immunohistological techniques in diagnosis are stressed. Advances in reconstructive surgical devices after debulking surgery have contributed to enhance the performance of more curative procedures (hemimandibulectomy, intra oral resections) and to improve the functional and esthetic results in these bad prognosis nerve tumours of the oral cavity. PMID- 21597721 TI - Immunohistochemical studies of basement-membrane in colorectal-cancer and primary cultured-cells. AB - The basement membrane (BM), a structure of crucial importance in the invasion and metastasis of cancers, was studied immunohistochemically using colorectal cancer tissues. In addition, BM-like structures formed in the primary culture of cancer cells were compared to the BM of primary cancers. BM was stained with antibodies specific for laminin, type IV collagen, fibronectin, and heparan sulfate proteoglycan. In the normal colon these compounds were detected in the glandular BM, vascular BM and perinervium by immunostaining. Components of the BM were not stained in some cancer tissues, and BM staining essentially disappeared in the invasive front of cancer in several cases. Of whole cancer tissues, 10 of 23 cases (43.5%) were BM positive and the remaining 13 cases (56.5%) were negative. A three dimensional primary culture of colorectal cancer cells was performed in collagen gel. The cancer cells obtained from primary cancers which had densely stained for BM formed a BM-like structure in primary culture, but those from negatively stained cancer tissues showed no BM-like structures. The BM-like structure in the primary culture was shown to have the same components as the true BM by immunohistochemistry, and this membranous structure was shown to have originated in the cancer cells. In the primary culture without any BM-like structures, granules containing BM components were observed around tumor cell clusters. The primary culture of tumor cells in collagen gel is closely related to the original tumor tissues and therefore may provide a good model system for the investigation of BM in cancer. PMID- 21597722 TI - Hla-dr expression in tumor-tissue and cell-lines of renal-cell carcinoma. AB - The expression of MHC class II antigens in renal cell carcinoma may be important for the response to interleukin-2 based immunotherapy. Therefore, we determined the HLA-DR expression in 50 primary tumors, in 45 specimens of non-transformed renal tissue of tumor bearing kidneys and in two newly established cell lines (DNT-11 and DNT-63) derived from metastases by indirect immunofluorescence. The systematic examination of the adjacent normal kidney for the expression of HLA-DR revealed that 33 (73%) specimens were positive, 12 (27%) intermediate, however no negative results were obtained. Of 50 tumor specimens 24 (48%) were regarded as positive and 26 (52%) as negative. There was no correlation between HLA-DR expression and tumor stage or grading, respectively. Both cell lines were HLA-DR negative over a time period of 4 years. PMID- 21597723 TI - Microcystic adnexal carcinoma (sclerosing sweat-duct carcinoma) of the head and neck. AB - We report 7 cases of microcystic adnexal carcinoma (MAC) that involved the face (n=6) and neck. The neck case occurred in a 10-year-old boy. MAC are tumors that typically extend far beyond their assessed clinical margins. This report emphasizes the need for early microscopically controlled excision of lesions because of the unreliability of clinical assessment and frequent perineural and bone extension. Treatment results of 35 cases treated by Mohs surgery are tabulated. PMID- 21597724 TI - Effect of biochanin-a or testosterone on liver-tumors induced by a combined treatment of den and fission neutron in bcf1 mice. AB - To determine the biological effect of biochanin A, miso or NaCl and sexual influence of testosterone on liver tumor induction, male and female BCF1 mice were i.p. injected once with DEN at a dose of 5 mug/g body weight at 15 days of age. In order to shorten the latency of liver tumor occurrence, the whole body of mice were exposed to 2 Gy of Cf-252 fission neutrons at four weeks of age. Three days later, female mice were surgically ovariectomized and given the various doses of testosterone melted into a cholesterol pellet. Male mice were fed on 10 ppm, 20 ppm biochanin A, 10% miso or 2% NaCl supplemented diet for 8 weeks (from 21 to 28 weeks of age) and 4 weeks (from 32 to 36 weeks of age). All mice were sacrificed at 40 weeks of age. Multiplicity of liver tumors was expressed in four different size ranges by <2, 3-5, 6-10 and >10 mm2. Incidence of liver tumors in all experimental groups except in group 1 at 20 weeks were observed at 100%. Average tumor size and multiplicity were smaller at 20 weeks compared to those of 40-week groups. Male groups fed 20 ppm biochanin A and 2% NaCl had an increase in body weight with significant difference from control by p<0.01. Liver weights were more-or-less the same in all groups except an increase was seen in the group of 20 ppm biochanin A (p<0.01). In female groups, both 0.2 mg and 1 mg of testosterone administration resulted in an increase of tumor multiplicities and a decrease of liver weight compared to that of control group with significant differences. In both male and female groups, majority of liver tumor sizes were in the range of 3-5 mm2. Tumor multiplicities and size in less than 2 mm2 in biochanin A groups, 10% miso and 2% NaCl decreased significantly from control group. These findings suggest that 15-20 weeks is the time in which 1-2 mm2 size of liver tumors start to appear. Among others, biochanin A is a component of miso. The potent anti-tumorigenic effect of dietary miso for mouse liver tumorigenesis may be strenghtened by a combination of factors such as the presence of Biochanin A, protease inhibitors and various fermented enzymes. PMID- 21597725 TI - Association between gene alteration and drug-sensitivity in human lung-carcinoma cell-lines. AB - The association between gene alterations (K-ras, p53, N-myc) and drug resistance (CDDP, CBDCA, MMC, Epi-ADM) was examined in 29 human lung carcinoma cell lines using the in vitro MTT assay. There was no significant difference in the IC50 values of four drugs between K-ras or p53 gene alteration-positive and -negative groups. However, two cell lines with N-myc amplification showed a higher resistance than those without N-myc amplification to all four drugs. This preliminary study suggests that K-ras or p53 gene alteration is probably not related to drug resistance, but N-myc might be. PMID- 21597726 TI - Distribution of epidermal growth-factor receptors in normal and neoplastic mammary tissues. AB - Epidermal growth factor (EGF) is considered to be mitogenic for proliferation of mammary glands in animals. The action of EGF is mediated by specific EGF receptors (EFG-R). In the present study, we investigated distribution of EGF receptors during various physiological stages of mammary glands, N-methyl-N nitrosourea (MNU)-induced mammary tumors in rats and human breast cancer samples. EGF receptor concentrations were determined by Scatchard analyses in the membrane fraction of the tissues. Results showed increased EGF receptor levels in the structurally differentiated mammary tissues from pregnant rats; whereas lower concentrations were observed in the functionally differentiated glands from lactating rats. EGF receptors were absent in the majority of the tumors induced by MNU. The loss of EGF receptor was not observed during the first 20 days post carcinogen treatment, but appeared to be correlated with the onset of the tumor. Consistent with the literature, the majority of the steroid receptor positive human breast cancer samples were EGF receptor negative, whereas steroid receptor negative samples contained EGF receptors. These results suggest that the loss of EGF receptors in ovarian hormone dependent mammary tumors does not occur gradually during carcinogenesis but appears to be a characteristic of hormone dependent mammary tumor cells. PMID- 21597727 TI - Effect of interferons on hormone-receptor levels of endometrial cancer-cells. AB - Endometrial cancer is a hormone sensitive tumor. Hormone receptor positive tumors respond better to progestins than hormone receptor negative tumors. Interferon has been shown to increase the hormone receptor level of melanocytes, breast and endometrial cancer. We have previously shown that interferons enhance the progesterone receptor level of AE-7 endometrial cancer cell line, which has a considerably high baseline level of progesterone receptors (201+/-19.7 fmole/mg of proteins). In this study the effect of interferons of two other endometrial cancer cell lines (HEC-1A and HEC-1B), with a low baseline level of estrogen and progesterone receptor levels (25+/-7-32+/-8 fmole/mg of proteins), was studied. Interferons have shown to possess similar cytostatic activity in the endometrial cancer cells studied, regardless of their hormone receptor status. However, hormone receptor levels in cells with low baseline hormone receptor levels were not significantly affected by the four interferons studied. PMID- 21597728 TI - Feasibility and reliability of flow-cytometry (fcm) DNA analysis of fresh and fixed urine samples. AB - The qualitative results of FCM DNA analysis on fresh and fixed urine specimens (28 and 97, respectively) from 68 normal subjects and 10 patients with a past history of bladder cancer were compared. FCM DNA evaluability was not significantly different in fresh and fixed samples (63% vs 73%, respectively) whereas mean CV was significantly higher (7.3% vs 5.7%, respectively; p=0.04). A double FCM analysis on fresh and fixed urine was also performed in 16 cases. In this subgroup, the percentage of evaluable histograms from fixed urine specimens was slightly higher than that from fresh specimens. Aneuploid cases were found only in the fixed urine samples but the CVs from fresh and fixed cell suspensions did not differ. The absence of inflammatory cells with cytological analysis of the same samples was associated with low percentages of FCM evaluability and higher CVs. The use of fixed samples improves the quality of FCM DNA analysis permitting its use for screening programs. PMID- 21597729 TI - The in-vitro response of 4 antisteroid receptor agents on the hormone-responsive prostate-cancer cell-line lncap. AB - Previous reports indicate that flutamide withdrawal is associated with PSA declines and tumor shrinkage in selected patients with 'hormone-refractory' prostate cancer. Though the mechanisms underlying this effect are not clear, investigators have hypothesized that these effects are mediated by mutant androgen receptors recognizing hydroxy-flutamide as an androgenic agonist. Such receptors have been well described in the human prostate cancer cell line LNCaP. Despite the finding that the androgen receptor of LNCaP aberrantly recognizes a variety of steroids, including estrogen and progesterone, as androgenic agonists, there are no studies which examine the effect of estrogen antagonists and progesterone antagonist on baseline and androgen-stimulated LNCaP growth. In this report, LNCaP cells were cultured in phenol red-free media using charcoal stripped sera. As previously reported, flutamide enhanced LNCaP growth and bicalutamide inhibited androgen-stimulated LNCaP proliferation. Neither tamoxifen nor RU486 influenced LNCaP growth (either in the presence or absence of exogenous androgens). From these data we conclude that antagonists of estrogen and progesterone action have no anti-proliferative effect on LNCaP cells and that the mutant androgen receptor expressed in these cells is quite restrictive in the recognition of compounds with antagonistic activity. The clinical implications of these findings are discussed. PMID- 21597730 TI - Cisplatin plus vp16 as salvage treatment for advanced breast-carcinoma resistant or recurrent after 1st line chemotherapy for metastatic disease. AB - Forty patients with chemotherapy refractory metastatic breast carcinoma were enrolled in a phase II study of cisplatin 80 mg/m2 on day 1 plus VP16 100 mg/m2 on days 1-3 every 28 days. The overall response rate was 32% (95% CL 17-47%), with 2 patients (5%) showing a CR with a mean duration of 11.3 months, and 11 patients (27%) a PR with a mean duration of 7.8+ months. Seven patients (17%) had stable disease, and 20 patients (50%) progressed despite chemotherapy. One complete response and 4 partial responses were obtained in patients previously untreated with antracyclines. The overall survival was 10.2+ months. The mean survival of responding patients (CR+PR) was 15.5+ months, while that of non responders (NC+PD) was 8.6+ months. A total of 188 cycles were administered (4.7 cycles/patient) and the most frequent toxicities were gastrointestinal and hematological side-effects. The most severe toxicities were intense vomiting and anemia. Grade 3 vomiting was seen in 11 patients (27%), and grade 1-2 anemia in 30% of cases. Severe grade 3 leukopenia was seen in only 12% of cases. Mild renal toxicity was recorded only in 2 cases, while alopecia was observed in almost all patients. In conclusion, although CDDP plus VP16 regimen, may be safely given on an outpatient basis, its routine use as salvage treatment for chemotherapy refractory metastatic breast carcinoma is not recommended. This regimen may, however, be employed as second line chemotherapy in selected cases. PMID- 21597731 TI - Differential-effects of fibroblast coculture on mcf-7 and mda-231 breast carcinoma cell invasion through matrigel. AB - The stimulative effect of conditioned media collected from fibroblasts or breast epithelial cells on breast carcinoma cell invasion through Matrigel was studied. Fibroblast conditioned medium was more efficient than media collected from breast epithelial cells in stimulating chemoinvasion of highly invasive MDA-MB-231 and MDA-MB-436 cells. In contrast, fibroblast conditioned medium was found to be less effective than breast epithelial cell conditioned medium in stimulating invasion of weakly metastatic MCF-7 cells. These data suggest that fibroblasts preferentially enhance the invasive capacity of highly malignant breast carcinoma cells. PMID- 21597732 TI - Fotemustine in patients with relapsing malignant gliomas - a phase-ii trial. AB - Eleven patients with relapsing malignant glioma were treated with fotemustine chemotherapy, a new nitrosourea derivative. One partial response of 13 months duration occurred, resulting in a marked improvement of the quality of life of the patient. Seven patients had stable disease for a median duration of 5 months. Median survival from inclusion in the study was 6 months. Toxicity was mainly hematologic and manageable. We confirm that fotemustine has some activity in patients with relapsing malignant glioma. PMID- 21597733 TI - Relationship between mdr-1 messenger-RNA expression and anticancer drug sensitivity in human hepatocellular-carcinoma cell-lines. AB - We examined the relationship between chemosensitivity and the expression of mdr-1 and P-gp in ten human HCC cell lines. Expression of P-gp was detected immunohistochemically and the expression of mdr-1 mRNA by the reverse transcriptase polymerase chain reaction (RT-PCR). Chemosensitivity was determined by the MTT assay. P-gp was positive in nine of the ten lines. mdr-1 mRNA expression was found in five. All cells lines positive for mdr-1 mRNA expression expressed P-gp. We could not demonstrate a correlation between mdr-1 or P-gp expression and drug resistance. We conclude that drug-resistance in HCC cells depends not only on mdr-1 but also on other factor(s). PMID- 21597734 TI - Pathogenesis of AIDS-related kaposis-sarcoma - (review). AB - Kaposi's sarcoma (KS) was described as a clinical marker in some of the first identified cases of acquired immunodeficiency syndrome (AIDS) in the USA, and remains the most common tumor associated with human immunodeficiency virus (HIV) infection. The KS lesion contains several cell types, including spindle and endothelial, which express surface markers consistent with vascular, lymphatic or smooth muscle lineages. The growth characteristics of KS in vivo and in vitro are influenced by an array of cytokines, growth factors, and viral gene products, especially in an underlying immunosuppression, suggesting that it is more a reactive tumor than a typical malignancy. Epidemiological analysis strongly suggests that AIDS-associated KS is caused by a sexually-transmitted agent in concert with HIV. The epidemiology and pathogenesis of KS is reviewed, focusing on the two major explanations of KS etiology: alterations in growth factor circuits and infection with non-HIV viruses. PMID- 21597735 TI - Case of leiomyomatosis peritonealis disseminata treated with a gn-rh analog. AB - We report a rare case of leiomyomatosis peritonealis disseminata (LPD) which we attempted to treat by administering the Gn-RH superagonist, buserelin. A 48-year old woman presented with a 6-month history of hypermenorrhea. Hysterectomy revealed a benign leiomyoma. Light and electron microscopic studies revealed that the tumors were composed of well- or poorly-differentiated smooth muscle cells. Their clinical appearance together with the mitotic figures found in tumor sections suggested an uncertain malignant potential. In the immunohistochemical study of intermediate filaments, antidesmin and anti-actin antibody reacted with tumor cells. Tumor re-growth in the pelvic cavity led to a second operation. The administration of the Gn-RH analogue, 900 mu g daily for two months, decreased the tumor size. The average final volume was 68.7% of the original. However, the tumors recurred during the next four weeks. The combined administration of the Gn RH analogue and etoposide (25 mg x 2/day) did not prevent recurrence after a third operation. The serum level of immune-suppressive acid protein (IAP) was useful in monitoring the clinical course of this patient, finally diagnosed as having LPD. PMID- 21597736 TI - Proliferating cell nuclear antigen in adenoid cystic carcinomas of the head and neck. AB - This retrospective study was performed on formalin fixed, paraffin-embedded specimens from 50 patients with adenoid cystic carcinomas to investigate if proliferating cell nuclear antigen (PCNA) correlated with DNA ploidy and S-phase value. Moreover, we have analysed whether PCNA could be used in the prediction of treatment failures, i.e. inability to eradicate the disease or recurrences. The PCNA expression showed values ranging from 0-78%. The mean PCNA value for DNA aneuploid and DNA diploid tumours were 9.5% and 4.8% respectively. No correlation was found between PCNA expression and S-phase value. Nor did we find any relation between the PCNA expression and treatment failure. Our results indicate that PCNA expression of archival material from adenoid cystic carcinomas is not a reliable prognostic factor. PMID- 21597737 TI - Induction of resistance-proteins and oncoproteins in murine and human tumor-cell lines after irradiation. AB - The aim of this investigation was to analyze whether or not ionizing radiation can induce the expression of resistance- and oncoproteins in murine sarcoma 180 cells and several human carcinoma cell lines. For assessment of the proteins the streptavidin-biotin peroxidase-complex method was performed using specific antibodies. Expression of glutathione S-transferase-pi and thymidylate-synthase was increased after a single dose of irradiation which was accompanied by a lower sensitivity against cisplatin and 5-fluorouracil. No differences in protein expression could be detected for P-glycoprotein 170 and topoisomerase II. Differences in the expression of the oncoproteins c-Fos and c-ErbB1 were also found after irradiation. In contrast, a decreased expression of topoisomerase II was found after fractionated irradiation. This was confirmed by mRNA analysis. PMID- 21597738 TI - DNA-flow cytometry (ploidy and s-phase fraction) as prognostic factor in a retrospective series of 515 primary breast-cancer. AB - Paraffin-embedded tissues are used in retrospective studies to evaluate the prognostic significance of DNA-flow cytometry (DNA-FCM) in human breast cancer. Although paraffin-embedded samples yield information on disease-free survival (DFS) and overall survival (GAS) of homogeneously selected patients, the resulting DNA-histograms have a lower resolution of aneuploid subpopulations and higher debris levels than those of fresh tumor samples. The aim of this study was to evaluate, retrospectively, the prognostic value of ploidy and the S-phase fraction (SPF) using 515 samples of paraffin-embedded consecutive primary breast cancer tissue (median follow-up: 75.4 months). Ploidy was detectable in 89% cases (34% diploid and 66% aneuploid) and SPF in 77%. The optimal cut-off for SPF was 6%. High SPF values were significantly correlated with shorter DFS (p=0.028) and OAS (p=0.018); aneuploidy was significantly correlated only with a shorter OAS (p=0.0058). Using the Cox proportional hazards regression model to evaluate the independence of DNA-FCM derived parameters, only high SPF was able to predict both a shorter DFS (p=0.02) and OAS (p=0.002). Furthermore, high SPF values were found correlated to aneuploidy (p<0.00001), tumor necrosis (p<0.015) and high histopathological grade (p<0.03). The data reported confirm that SPF is a valuable single independent prognostic factor in human breast, cancer and strongly support the use of archival tumor specimens to study the prognostic role of DNA-FCM in human cancer. PMID- 21597739 TI - Relationship between icam-1 serum levels and thymostimulin therapy in patients with liver-cirrhosis associated with hepatocellular-carcinoma. AB - Intercellular adhesion molecule-1 (ICAM-1), is a cell surface molecule involved in many immunological processes. Recently, ICAM-1 has also been detected as a soluble form in sera of patients affected by different pathologies and often associated with severity of the disease. However, all these studies were carried out in patients before drug treatment. Since in vitro experiments and recent evidence in humans has indicated the possibility that some cytokines may be responsible of ICAM-1 release, we have considered the possibility of quantitating ICAM-1 in sera of patients undergoing therapy with drugs influencing cytokine regulation. Thymostimulin, which seems to belong to this category, has been used in a pilot study by some of us in the treatment of patients with liver cirrhosis associated with hepatocellular carcinoma. By using an enzymatic sandwich assay, we found significantly high circulating ICAM-1 mean values in patients affected by liver cirrhosis alone or associated with hepatocellular carcinoma or non Hodgkin lymphoma compared to control subjects (p<0.001), Moreover, in patients with hepatocellular carcinoma or liver cirrhosis who were treated with thymostimulin, serial detection of c-ICAM-1 was carried out and patients responsive to the drug showed significantly increased values of c-ICAM-1 (p=0.006), Our study suggests that an evaluation of c-ICAM-1 levels needs to be considered in the context of the therapeutic approach, with particular attention to those drugs which may affect the regulation of the cytokine pathway. PMID- 21597740 TI - Altered messenger-RNA expression of glutathione-dependent enzymes after single and repeated exposure to ethanol. AB - 1The effect of ethanol (0.2-2.5%) on glutathione S-transferase-pi and glutathione peroxidase mRNA expression was studied in NIH 3T3 mouse fibroblasts after single and fractionated exposure to ethanol. After single exposure to 1.5% ethanol an elevation of about 1.6 fold of glutathione S-transferase-pi mRNA level was found, while a reduction of about two fold of glutathione peroxidase mRNA expression in treated cells was measured compared to control cells. Similar effects were found in cells after fractionated ethanol administration. Therefore, repeated exposure to ethanol (1.5%, 2.5%) showed no stronger alterations in the mRNA expression of both glutathione dependent enzymes. PMID- 21597741 TI - Effect of aspirin on the induction of apoptosis in colorectal adenocarcinoma cell lines. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit experimental carcinogenesis and their use in humans has been related epidemiologically to a reduced risk of colorectal polyps and cancer, although the mechanism involved is not known. We found that aspirin triggered the death of SW948 human colorectal adenocarcinoma cells through activation of an apoptotic pathway. Exposure of SW480 and SW948 cells to 25 mu M aspirin for 5 h resulted in the detatchment of cells from the monolayer culture at 48 h. SW948 cells with continuous exposure to 25 mu M aspirin exhibited various morphological and biochemical characteristics of apoptosis, including compact patches of condensed nuclear chromatin, and DNA fragmentation. These in vitro data suggest that apoptosis may play a role in the antitumor effect of aspirin and other NSAIDs and that the induction of apoptosis may provide an attractive therapeutic target in colorectal carcinogenesis. PMID- 21597742 TI - Mitoxantrone, Etoposide and bleomycin (meb) chemotherapy in non-hodgkins-lymphoma patients non-elegible for standard cyclophosphamide, Doxorubicin, vincristine and prednisone (chop) combination. AB - The antitumor activity and toxicity profile of a new therapeutic combination was investigated for patients with non-Hodgkin's lymphoma (NHL). The regimen consisted of mitoxantrone (10 mg/m(2)/day by intravenous (i.v.) bolus injection on day 1), etoposide (100 mg by 24 hours continuous i.v. infusion on days 1, 2, 3) and bleomycin (4 mg by i.v. bolus injection on day 1 followed by 24 hours continuous i.v. infusion at 4 mg/m2/day dose on days 1, 2, 3) (MEB). MEB chemotherapy was administered to 22 patients affected by intermediate/high grade or clinically symptomatic low grade NHL who were considered non-elegible for standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. Major responses were achieved in 11/22 (50%) patients with 5 (23%) complete responses. Grade 3-4 neutropenia occurred in 59% of patients. The results of this study demonstrate that MEB chemotherapy possesses good antitumor activity and a manageable toxicity in a prognostically unfavourable subset of lymphoma patients. PMID- 21597743 TI - Strain differences in mouse skin tumorigenesis by the promotion of 12-o tetradecanoylphorbol-13-acetate or benzoyl peroxide. AB - Strain difference of mouse skin tumorigenesis was studied with 12-O tetradecanoylphorbol-13-acetate (TPA) and benzoyl peroxide (BzP) both in 8-week old hypocatalasemic C3H mice (C-s(b)) and in normal C3H/HeNCrj mice (C3H). Two weeks after initiation by 4 mu mole MNNG, both strains of female mice were promoted by 10 nmole TPA or 10 mg, 20 mg BzP twice weekly for 30 and 52 weeks. The incidence of skin tumors in C-b(s) was significantly increased as compared to that in C3H mice promoted by TPA for 30 weeks but after 52 weeks of TPA promotion there was no difference between the 2 strains. By the promotion with 10 mg or 20 mg BzP, the incidence of skin tumor in C3H was 5% at both levels after 30 weeks of promotion and 19% and 38%, respectively, after 52 weeks of promotion. No skin tumors appeared in C-b(s) mice with BzP treatment after 30 weeks of promotion. After 52 weeks of promotion by 10 mg BzP, skin tumors were induced in only 15% of C-b(s) mice. The results show that genetic factors, especially radical scavenging enzymes, controlled susceptibility to skin tumorigenesis by promotion with either TPA or BzP. PMID- 21597744 TI - Weekly 24-hour infusion with high-dose 5-Fluorouracil and 6s-leucovorin as a 2nd line therapy in advanced colorectal-cancer resistant to a 5-fluorouracil/6s leucovorin bolus combination. AB - Recently, experimental data suggested the possibility that resistance to 5FU may be overcome by administering the drug in a different schedule. To test this hypothesis we treated seventeen patients, who failed to respond to a common 5FU/leucovorin bolus regimen, with an intravenous infusion of 6S-leucovorin, at a dose of 250 mg/m(2), concurrently with 5FU at 2,600 mg/m(2) over a 24-hour period. Treatment was repeated every week. No patient achieved an objective response. Six patients showed stable disease and 11 progressed on therapy. The treatment with 5FU infusion, at least in this schedule, is not effective in patients with 5FU bolus resistant colon cancer. PMID- 21597745 TI - Epidermal growth-factor receptors and erbb2 protein expression in esophageal cancer and normal mucosa. AB - The epidermal growth factor receptor (EGFr) and the erbB2 protein (p185) concentrations were assessed in 31 esophageal cancer specimens and in the corresponding normal mucosa, in order to investigate the possible links with the main clinical and pathological parameters. Detectable and high affinity EGFr was found in 27/31 cancer and in 18/31 normal tissue samples. EGFr concentrations were not significantly different between cancer and normal tissue, although a trend toward higher levels in cancer was found. No relationships were found with histologic type, tumor bulk, lymph node status, pathologic stage, ploidy and type of surgical resection. A significant negative correlation between EGFr levels and overall survival was found. Detectable levels of p185 were found in all the tissues examined, but the expression was higher in adenocarcinoma than in squamous cell carcinoma samples. The EGFr role in malignant transformation still has to be established, but the determination could be of clinical use. As for p185, its role in the onset of esophageal cancer could be confined to the subgroup of the adenocarcinomas. PMID- 21597746 TI - Modulation of the response of a rodent fibrosarcoma to photodynamic therapy by hyperbaric-oxygen treatment. AB - The ability of hyperbaric oxygen (HBO) treatment to modulate the response of a rodent fibrosarcoma to interstitial photodynamic therapy (PDT) using 630 nm light and intravenous polyhaematoporphyrin (PHP) was examined. Application of HBO for 30 min immediately prior to PDT resulted in a light dose-dependent increase in tumour growth retardation, maximum effect (+227%) being observed with 100J light, and no enhancement being seen at or above 400J. Application of HBO during or immediately after PDT had no effect on response. Reducing the interval between giving PHP and administering light from the usual 48 h to just 1 h increased the efficacy of PDT even in the absence of HBO pre-treatment. Under these circumstances, application of HBO did not realise any further increase in tumour response at any light dose. Our findings suggest that manipulation of tumour oxygenation may be able to improve the outcome of PDT under some circumstances, but that careful consideration of other treatment variables, such as light dose and drug-to-light interval, may provide similar, more easily achievable, improvements in efficacy. PMID- 21597747 TI - Palliative radiotherapy for brain metastases. AB - Several studies have confirmed that results of different hypofractionated radiotherapy schedules for palliative purpose are similar to those of conventional higher doses. From 1992 to 1993, 56 consecutive patients with brain metastases were irradiated at our Institution. Three different schedules were used ranging between 18 and 40 Gy. Overall survival, clinical and radiological responses were evaluated with regard to schedules and prognostic characteristics of patient population. There were no significant differences between the treatments, even though patients with shorter estimated life expectancy were more likely to be irradiated with more hypofractionated radiotherapy. Short, cost effective treatments appear to be the best therapeutic option both for institution and patients in most palliative cases. PMID- 21597748 TI - Theoretical basis of paraneoplastic autoimmune disorders - (review). AB - The close correlation found between malignancies and autoimmune disorders suggests that a common pathogenetic mechanism plays a role in both disorders. Recent results obtained by analysis of V-H and V-L genes of autoreactive immunocytes reveal their oligo-clonality. They are essentially autoreactive with developmental antigens since these clones are prepared to recognize normal antigens without somatic mutations. Under the concept that immunity recognize developmental antigens as well as foreign antigens, it is conceivable that auto reactivity is induced by an autonomy of immunocytes, when antigenic duality between self and non-self is an essential feature of immunity. In this process, autoimmunity due to malignancy is non-teleologic, since autoimmunity programmed a priori within immunocytes is expressed in an autonomic manner caused by cellular selfishness. On the other hand, paraneoplastic autoimmunity with non-immunocyte tumors suggests a mechanism differing from autonomic expansion of immunocytes. In order to explain this phenomenon, there are two possibilities: the first is that tumor cells secrete immune molecules including immunoglobulins and the second is that so-called antigen drive is related with curious MHC expression of tumor cells, with or without molecular mimicry due to somatic mutations. Both mechanisms are essentially non-teleological. PMID- 21597749 TI - Morphologic changes of Doxorubicin-sensitive and resistant lovo cells treated in vitro by calcium channels blockers. AB - A morphological analysis by scanning electron microscopy (SEM) of the effect of two Ca++ channel blockers (verapamil and dilazep) on LoVo S (doxorubicin sensitive) and LoVo R (doxorubicin resistant) plated together with 3T3 in order to cause an experimental ground of metastasis was performed. Ca++ channel blockers have been previously tested alone and combined with doxorubicin. The increasing effect on the sensitivity of inherently antiblastic drug resistance and their possible role as antimetastatic agent according to the experiments of Tsuruo et al (Cancer Chemother Pharmacol 14: 30-33, 1985) is reported. PMID- 21597750 TI - The expression of mmp-7 messenger-RNA in primary and metastatic human colorectal adenocarcinoma. AB - MMP-7 mRNA expression was examined by RT-PCR and Southern blot hybridisation following cDNA synthesis of extracted tissue RNA in a total of 33 colorectal cancer patients. Expression was studied in tumour tissues and compared to adjacent non-neoplastic tissues. MMP-7 mRNA was detected in all tumour samples, with no qualitative difference between primary and metastatic tumours and there was no relation to Dukes' clinical stage. Adjacent nonneoplastic colon and rectum (65%) and liver (100%) also expressed MMP-7, although the signal intensity was weaker. In contrast, only 31% of adjacent non-neoplastic lymph nodes expressed MMP-7. The results suggest that MMP-7 is probably expressed early in the neoplastic transformation in patients with colorectal adenocarcinoma. PMID- 21597751 TI - Activating mutations of ras family genes in prostatic-cancer. AB - ras family genes (H-, K- and N-ras) encode for a 21 kD membrane protein which possesses GTPase activity and participates in a signal transduction pathway. Activating mutations of the ras family genes occur at codons 12, 13 and 61 and have been detected in a variety of human tumours, including colonic, bladder and pancreatic cancers. Prostatic cancer is among the most common malignancies throughout the world and a major cause of death from cancer in males. Data reported on the implication of the ras family genes in the development of the disease are conflicting. The aim of this study was to determine the incidence of mutations at codon 12 of H-ras, codon 12 of K-ras and codon 61 of N-ras proto oncogenes, in a Greek population with prostatic cancer. Our analysis revealed that 4 out of 20 (20%) samples harboured a K-ras codon 12 point mutation, 1 out of 20 (5%) specimens contained mutations at codon 12 of the H-ras and 1 out of 20 (5%) at codon 61 of the N-ras, indicating a role for the ras genes in the development of the disease. PMID- 21597752 TI - Is nasopharyngeal carcinoma more common in hakkas than in fukienese - a comparison within the taiwanese population. AB - This study is to ascertain whether Hakkas have a higher incidence of nasopharyngeal carcinoma (NPC) than Fukienese as being proposed. A total of 949 NPC patients during 1990-1993 were serially recruited. Their ethnicity and residential area since childhood were compared to the census data in 1956. The 95% confidence interval of odds ratios for Hakkas to Fukienese in various counties were found to overlap within a range from 0.85 to 1.15 without showing statistically significant difference from unity. This result indicates that there is no extra ethnic risk between the two groups in Taiwan. PMID- 21597753 TI - Bilateral renal-cell carcinoma of the native kidneys after renal-transplantation. AB - We report the case of a 45-year-old man who received a cadaveric renal transplant and subsequently developed a bilateral neoplasm of the native kidneys. Two tumors per each kidney were detected and in the left kidney they were cytologically different, one granular and one clear cell type. Bilateral nephrectomy with radical lymphadenectomy was performed, immunosuppression was withdrawn and medrossiprogesterone was administered. A control CT scan 3 months after surgery demonstrated no evidence of neoplastic recurrence, while ultrasonography detected a liver metastasis. The patient subsequently developed a para-neoplastic syndrome and died 7 months after surgery. We believe that all long-term immunosuppressed transplant patients need close observation. Regular imaging of the native kidneys, by ultrasound or CT, should be carried out yearly. Prophylactic bilateral nephrectomy is not desirable because of the loss of the important mechanism of pressure control. mediated by the renine-angiotensin system. PMID- 21597754 TI - Cultured chinese-hamster ovary cells lack a transferable x-radiation resistance factor. AB - We determined if we could transfer X-radiation resistance from CHO AA8 cells to their radiosensitive, mutant V3 cells by several methods. These methods include co-incubating the two cell lines for three days before irradiation, adding heavily-irradiated AA8 to V3 cells following irradiation of the latter and then co-incubating these cells for at least eight days during the colony-forming assay and lastly, adding conditioned medium from unirradiated, subconfluent AA8 cells to V3 cultures and incubating for two days before irradiation. None of these procedures enhanced the clonogenic survival of the V3 cells to a single dose of 4 Gy X-radiation. Adding heavily-irradiated V3, instead of AA8, cells did not increase the clonogenic survival of the 4 Gy-irradiated V3 cells either, indicating that there was no autocrine mode of action. Moreover, adding conditioned medium from a related CHO cell line, K1, to its own radiosensitive, mutant 5-11 and incubating for two days before irradiation did not enhance clonogenic survival of the latter to a single dose of 3 Gy X-radiation. We therefore conclude that it is unlikely that CHO cells have the X-radiation resistance factor that has been reported in some mouse melanoma cell lines by other investigators. PMID- 21597755 TI - Cardiotoxicity of high-dose-rate epirubicin evaluated by angiocardioscintigraphy. AB - Cardiotoxicity of high dose rate epirubicin (140-160 mg/m(2) as a bolus every 21 days up to a cumulative dose of 1280 mg/m(2)) was evaluated by angiocardioscintigraphy in 121 patients with advanced neoplastic disease and no preexisting cardiac risk factors. LVEF was measured in each patient before chemotherapy and during the treatment at different epirubicin cumulative dosages. The cases were subdivided into 3 groups: Group A=121 basal studies; Group B=93 studies performed under 800 mg/m(2); Group C=44 studies performed over 800 mg/m(2). A statistically significant decrease of LVEF was observed only at cumulative doses over 800 mg/m(2) (mean LVEF: 53% +/- 11% in Group C vs 64% +/- 7% in Group A). In no case was chemotherapy stopped prematurely and no case of heart failure was observed. A decrease of LVEF 10 units was recorded in 15 patients and 12 of them had been treated with over 800 mg/m(2). No clinical signs of severe cardiac failure were observed in these patients during a follow-up of 5 17 months. In conclusion, epirubicin treatment at high dose rate up to a cumulative dose of 1000 mg/m(2) does not increase the risk of clinically relevant cardiomyopathy and an LVEF decrease of 10 units should not in itself lead to chemotherapy termination in responsive patients. PMID- 21597756 TI - Is hairy-cell leukemia more common among farmers - a pilot-study. AB - Hairy cell leukaemia (HCL) is a rare non-Hodgkin lymphoma of unknown aetiology most frequently diagnosed in males. In earlier epidemiological studies of HCL, exposures to benzene and chemicals appear to be risk factors. Since 1984, 48 patients (36 men and 12 women) with HCL has been treated in Uppsala. Information on occupation was collected from the medical records. 29 percent (13 men and one woman) worked in farming. One additional man worked in gardening. Of the men, 39 percent had this kind of work giving an OR of 7.5 (CI. 4.2-13.2) compared with the general Swedish population in 1970. A larger case control study is now being conducted. PMID- 21597757 TI - Posttranscriptional regulation of epidermal growth-factor receptor expression by retinoic Acid in a human lung epithelial-cell line. AB - Retinoic acid transiently induced expression of high levels of epidermal growth factor receptor (EGFR) in the human non-small cell lung carcinoma cell line H460a. Scatchard analysis revealed a 40-fold increase in the expression of EGFR on the cell surface of H460a cells within 48 h of treatment with 5 mu M concentrations of retinoic acid. RNase protection and nuclear run-off assays established that increases in EGFR expression in retinoic acid-treated cells were not the result of increased promoter activity of EGFR gene, but were more likely the result of a posttranscriptional mechanism. Immune complex kinase assays demonstrated that the EGFR induced by retinoic acid was functionally active. We conclude that retinoic acid exerts its control over expression of the EGFR in H460a cells through a posttranscriptional mechanism. Moreover, elevated EGFR might play a role in the increased tumorigenic potential exhibited by retinoic acid-treated H460a cells. PMID- 21597758 TI - Selective cytotoxic effect of tamoxifen on epithelial and fibroblastic cells transformed by different oncogenes. AB - To study the correlation between oncogenes and the cytotoxic effect of tamoxifen in estrogen negative (ER) cells, we transformed mouse keratinocyte and fibroblastic cell lines with several oncogenes and studied cell viability, thymidine incorporation and PKC levels. We show that v-myc and v-H-ras oncogenes increase sensitivity in both cell types and that Neu and mutant p53 also increase sensitivity to tamoxifen, more significantly in the epithelial cells. Conversely, transformation with adenovirus E1a oncogene induces resistance to tamoxifen in both cell types. These results indicate that tamoxifen may be effective in different kinds of malignant cells depending on the oncogenic alterations present in the cells. PMID- 21597759 TI - Apoptosis as an indicator for steroid sensitivity of lymphocytes in B-chronic lymphocytic-leukemia. AB - Apoptosis, programmed cell death, occurs in a variety of cellular systems and in response to many different stimuli. One group of apoptosis inducers are glucocorticosteroids which are also found in the battery of cytotoxic drugs used to treat CLL. In the present study we have examined the potency of the glucocorticosteroid-dexamethasone to induce apoptosis in lymphocytes of patients with B-CLL. Lymphocytes of 15 nontreated patients and 5 controls were isolated and incubated for 24 h in the presence or absence of dexamethasone (2 mu M) Following incubation the cells were harvested and their DNA extracted. The extracted DNA samples were analysed for internucleosomal DNA cleavage by UV illumination after electrophoresis on agarose slab gel containing ethidium bromide. Five patients showed neither spontaneous nor dexamethasone induced apoptosis. Whereas, 10 patients, showed a dexamethasone-non-dependent spontaneous apoptosis which appeared 24 h after the start of incubation. The cells of these patients were the only ones to respond to dexamethasone showing an enhanced apoptosis effect. This study shows that apoptosis monitoring in CLL may provide important information regarding susceptibility of the cells to steroid induced apoptosis. PMID- 21597760 TI - Tnf-alpha induces gm-csf secretion in leukemic-cell lines u-937 and kg-1a. AB - GM-CSF is constitutively secreted by myeloblasts of some patients with AML. Recently it has been shown that IL-1 and TNF-alpha can induce GM-CSF production in fresh leukemic cells of patients who do not release GM-CSF spontaneously. To further characterize this phenomenon we investigated GM-CSF induction by TNF alpha in two leukemic cell lines, U 937 and KG-1a. KG-1a constitutively expresses GM-CSF mRNA as demonstrated by Northern blots and PCR analysis. Unstimulated U 937 cells contained no detectable GM-CSF transcripts. After incubation with TNF alpha, GM-CSF specific m-RNA was found in U 937 cells. Only slight increases of GM-CSF transcripts were noted in KG-1a cells after TNF-alpha treatment. In unstimulated cultures, GMCSF concentrations were below 1 pg/ml. After 3 days of culture detectable levels of GM-CSF were found after stimulation with 1 ng/ml TNF alpha and reached a mean of 11.9 pg/ml for U 937 and 59.3 pg/ml for KG-1a after incubation in 50 ng/ml TNF-alpha. Therefore mechanisms of GM-CSF expression are regulated differently in each of these cell lines. PMID- 21597761 TI - The influence of the thymic preparation thymex-L on deficient antitumor-activity of monocytes from melanoma patients in-vitro. AB - Recently we demonstrated that, in vitro, prothymosin alpha 1 (ProT alpha), a polypeptide from calf thymus, was able to enhance the deranged tumoristatic activity of peripheral blood monocytes from melanoma patients. Now we report, that the thymic preparation Thymex-L significantly enhanced the level of depressed monocyte activity from 19% to 26%, whereas in normal donor groups no significant change of basal activity (35%) was seen. Although the improvement of median levels of killer cell activity was found to be independent from the disease stage, the Thymex-L effect was only statistically significant in stage I and melanoma patients after chemotherapy. In contrast to ProT alpha, Thymex-L did not further enhance monocyte-mediated cytotoxicity when it was applied in combination with rIFN-gamma. However, after stimulation with rIFN-gamma, the median level of TNF-alpha secretion by melanoma monocytes significantly increased (about 2-fold) when preincubated with Thymex-L. These results indicate that depressed monocyte functions in selected melanoma patients may be partially improved by Thymex-L. PMID- 21597762 TI - Preoperative superselective intraarterial chemotherapy in the combined treatment of gastric-carcinoma. AB - 146 patients were included in this prospective, randomized study: 50 patients were treated with surgery alone (S), 49 patients received pre-operative intravenous (systemic) chemotherapy (IVCH) and 47 patients received pre-operative superselective intra-arterial chemotherapy (IACH). Left gastric and right gastroepiploic arteries were catheterized for IACH. After IACH a measurable tumor response was registered in 87.1% of the patients; in 61.6% no residual tumor was found in the resected stomach. IVCH produced no survival benefit compared to surgery alone. IACH plus S improved 3-year survival relative to surgery alone (89.3+/-2.1% vs 35.5+/-4.9%; p<0.01). Projected 5-year survival in the IACH+S group is 78.1% vs. 30.1% with surgery alone (p<0.01). IACH provided substantial survival benefit when used as a component of combined modality gastric cancer treatment. PMID- 21597763 TI - Direct correlation between IL-2-R gene-transcription and natural cell-mediated cytotoxicity in patients with gastric-carcinoma. AB - The relationship between IL-2-R gene transcription and natural cell mediated cytotoxicity (NKCMC) in the peripheral blood lymphocytes of 15 patients with gastric carcinoma and 6 normal healthy controls were studied. NKCMC and ADCC assessed against radiolabelled K-562 and sensitized chicken RBC as respective target cells in Cr-51 release assay revealed significant reduction in patients as compared to controls. The impairment in the natural cytotoxicity was associated with decreased IL-2-R gene expression at the mRNA level in these patients. Expression of both IL-2 R alpha transcripts (3.5 and 1.5 Kb) were either not detectable or only weakly detectable on T lymphocytes from patients even after mitogenic stimulation. In contrast, a significant rise in the expression of both IL-2 R alpha transcripts was observed on T cells from normal controls followed by mitogenic challenge. We interpret our findings to reflect the direct correlation between NKCMC and IL-2-R gene transcription in gastric carcinoma patients. PMID- 21597764 TI - Regulation of her2/neu gene-expression (review). AB - Transcriptional regulation of the HER2/neu protooncogene (also known as c-erbB2) has been the topic of many recent reports. The importance of these studies lies in the fact that HER2/neu overexpression occurs in about 30% of breast and ovarian cancers and to varying degrees in other cancers, including gastric, colorectal, lung, salivary, ovarian, bladder, pancreas, endometrial, cervical, oral, and prostate cancers. Furthermore, increased levels of the gene product play an important role during the neoplastic process of certain tumors. This review summarizes the recent work studying the regulation of HER2/neu expression in cells that overexpress the gene and reviews the current knowledge on general regulation of the HER2/neu promoter. PMID- 21597765 TI - Combination chemotherapy with methotrexate and 5-Fluorouracil and surgery for advanced gastric-cancer with liver and lymph-node metastases - a case-report. AB - We report on a case of advanced gastric cancer with multiple liver metastasis and lymph node metastases in a 65-year-old Japanese man. He was treated with sequential intravenous administration of moderate-dose methotrexate 1 (MTX) and 5 fluorouracil (5-FU) preoperatively. After eleven cycles of the combination chemotherapy, the findings of liver and lymph node metastases diminished dramatically and the tumor could be resected for a potential cure, using a total gastrectomy and combined hepatectomy. The resected specimen revealed a slightly elevated lesion and a somewhat shallow ulceration due to chemotherapy. Histologically, there was an infiltration of poorly differentiated adenocarcinomas with medullary structure in the muscularis mucosae with fibrous change. The liver was metastasized, but there was no evidence-of lymph node metastasis. We believe that combination chemotherapy of MTX and 5-FU can be effective against gastric cancer. PMID- 21597766 TI - Antitumor effects of Doxorubicin hydrochloride (dox) and buthionine sulfoximine (bso)-hydroxyapatite (hap) complex on transplanted tumors in-vivo. AB - We prepared hydroxyapatite (HAP) beads containing doxorubicin hydrochloride (DOX) and buthionine sulfoximine (BSO), as a DOX and BSO-HAP complex. When the complex was implanted into mice bearing sarcoma 180 tumor, the antitumor effect of the complex was intensified 1.5-fold, as assessed using tumor volume, on day 27 as compared with that of a complex of DOX-HAP only. Therefore, we concluded that the antitumor effect of the DOX and BSO-HAP complex was increased through depletion of the intracellular radical scavenger glutathione (GSH) by released BSO and subsequently free radicals produced by released DOX. PMID- 21597767 TI - A phase-ii trial of 5-Fluorouracil, folinic Acid, vinorelbine in pretreated patients with metastic colorectal-cancer. AB - 43 patients with metastatic colorectal Cancer pretreated with 5-fluorouracil based chemotherapy received vinorelbine plus 5-fluorouracil plus folinic acid with the aim of evaluating vinorelbine activity in advanced colorectal cancer and its potential synergism with commonly used drugs. 9 partial responses were observed, for an;overall objective response rate of 20.9%. 20 additional patients had stable disease (46.5%). Median duration of response was 7 months. Median survival from the start of treatment was 6 months. The main toxic effect was myelosuppression. We conclude that our regimen is active enough to warrant further evaluation in advanced colorectal cancer. PMID- 21597768 TI - In-vitro cytotoxicity in ovarian-cancer of low-dose continuous exposure to microtubule inhibitors (Paclitaxel taxotere) combined with Cisplatin. AB - We present our data on the cytotoxicity of microtubule inhibitors (paclitaxel and taxotere) and their mode of action against cisplatin-sensitive or -resistant ovarian cancer cell lines in vitro. To try to establish an optimal administration schedule in clinical use, the cytotoxicity of microtubule inhibitors alone and in sequential combination with cisplatin was investigated. With microtubules alone, a marked dose- and schedule-dependent growth inhibition was demonstrated in lower concentrations and only schedule-dependency in higher concentrations. The cytotoxicity of taxotere was approximately 0.8- to 132-fold that of paclitaxel. No cross resistance to cisplatin was observed. In the relation between assay AUC (area under the concentration curve) and growth inhibition, increasing AUC by dose escalation seemed not to be advantageous. In a combination with cisplatin, the treatment of microtubules over 48 h followed by cisplatin administration demonstrated the most effective cytotoxicity in cisplatin-resistant cell line. PMID- 21597769 TI - Expression of urokinase-type plasminogen-activator in various human thyroid tissues. AB - High levels of urokinase-type plasminogen activator (u-PA) have been detected in malignant tissues of various organs and these are thought to be related to the local invasion and distant metastasis of carcinomas. In the present study, the expression of u-PA was immunohistochemically investigated in various thyroid tissues by using formaline-fixed, paraffin-embedded tissue sections. Normal thyroid expressed hardly any u-PA. In some hyperplasias, weak u-PA immunoreactivity was observed in small follicles and in clusters of follicular cells in the process of regenerating hyperplastic follicles. However very intense u-PA staining was observed in all cases of chronic thyroiditis in the small follicules surrounded by numerous lymphocytes. This indicates that u-PA must be strongly implicated in this disease together with various cytokines. As much as 90% of the carcinomas in our study expressed u-PA in the cytoplasm of carcinoma cells and the expression in carcinomas was much more extensive than that in benign adenomas. Although this carcinoma is known to have a generally good prognosis, our findings suggest that u-PA reflects malignancy in tumoral growth of the thyroid and modulates this growth from its early stage. PMID- 21597770 TI - Deletion of tp53 exon-1 in human epithelial ovarian-cancer. AB - In ovarian cancer, allelic loss within 17p 13.1-13.3, which contains the tumor suppressor TP53, occurs with a frequency of 66%, and mutations within conserved TP53 exons are reported in approximately 50% of cases. We examined DNA from 26 Stage III/IV ovarian carcinomas and 7 non-malignant ovaries by Southern blot hybridization and PCR for gene rearrangement or deletion within the,TP53 locus. Deletion specifically involving loss of the transcription-regulatory exon 1/intron 1 region on at least one allele was detected in 24/26 (92%) cases, and 0/7 noncancerous ovaries. Immunocytochemical analysis confirmed absence of expression of mutant p53 protein in those tumors where loss of the exon 1 region involved both alleles. PMID- 21597771 TI - A comparison of positron emission tomography (pet) utilizing C-11 methionine and computerized-tomography in the diagnosis of renal-cell adenocarcinoma. AB - Positron emission tomography (PET) is a radionuclide method that quantifies physiological and metabolic parameters in vivo. PET with L-methyl-C-11-methionine as a tracer was performed in 13 patients with advanced renal cell carcinoma and twenty-two lesions were evaluated. Two of 13 patients still had their primary renal tumours. The PET images of all the patients showed a good correlation with the computerized tomography (CT) images, and detected not only the primary tumour but also metastases. PET utilizing 11-methionine was efficient in visualizing metastatic lesions in the thorax. The conclusion of this pilot study is that the PET technique with C-11-methionine as a tracer can be used in the diagnosis of advanced renal cell adenocarcinoma to visualize and characterize the primary renal tumour and its metastases in vivo. PMID- 21597772 TI - Positron emission tomography utilizing C-11 5-hydroxytryptophan, plasma biochemistry and neuroendocrine immunohistochemistry of metastatic renal-cell carcinoma. AB - The aim of this study was to characterise metastatic renal cell carcinoma in 18 patients with positron emission tomography (PET) utilising C-11-5 hydroxytryptophan, plasma biochemistry and neuroendocrine immunochemistry. Of these 18 patients, ten underwent the PET investigations. The standardised uptake values (SUVs) in hepatic deposits were higher than those in pulmonary lesions, with mean values of 3.15 and 2.35, respectively. The immunohistochemical study included staining of 10/18 surgical tumour specimens with antibodies reactive with chromogranin (Cg), neurone-specific enolase (NSE), and synaptophysin (Sy). In 17/18 patients, plasma measurements of the neuroendocrine peptides, CgA, CgB, pancreastatin, and serotonin, were performed. The results obtained in this study show that PET with C-11-5-hydroxytryptophan, a precursor in serotonin synthesis in neuroendocrine cells, can be utilised to visualise primary renal cell cancer and its secondaries in vivo. The results obtained also suggest that neuroendocrine differentiation may occur in human RCC. PMID- 21597773 TI - Expression of ras p21 and myc p64 oncoproteins in imprint smears of lung-cancer. AB - The expression of ras p21 and myc p64 was examined in imprint smears of 52 patients with lung cancer and 44 patients with benign disorders, by immunochemistry. Imprint smears were-taken from fresh bronchial biopsies during diagnostic bronchoscopy. Both ras and mye oncoproteins were found to give negative reaction in all benign examined cases; Of the 52 malignant bronchial tissue imprint smears, 28 (54%) and 30 (58%) were positively stained with ms p21 and mye p64 antibodies respectively. Positive staining of ras p21 was demonstrated in 54.5% of squamous cell carcinoma, in 80% of adenocarcinoma and in 0% of small cell carcinoma imprint smears. Positive staining of myc p64 was demonstrated in 45.4% of squamous cell carcinoma, in 50% of adeno-carcinoma and in 100% of small cell carcinoma. The results of this study indicate that both ras and myc oncoproteins detected in bronchial biopsies, may play a crucial role in lung cancer. PMID- 21597774 TI - Vascular complications in patients receiving chemotherapy - what role do 3rd generation antiemetics play. AB - Vascular diseases in oncology are often attributed to several factors (hospitalisation, paraneoplastic syndrome, probable damaging effect on epithelium by chemotherapeutic agents) however they are reasonably infrequent events. From 7/10/1993 to 21/3/1994 we observed 8 cases of vascular diseases (venous and arterial) of varying intensity in patients receiving anticancer chemotherapy in association with third generation antiemetics. On the basis of similar experiences reported in the literature of patients undergoing chemotherapy and serotonin-antagonist antiemetics, we performed a detailed analysis of these 8 cases. Few-cases of vascular diseases have been observed in phase II and III studies inpatients treated with ondansetron but the physiopathological mechanism is still not well understood. Of our 8 patients, 5 were female and 3 male, with ages ranging from 36 to 73 years. All cases had different types of solid tumors and had been treated with different chemotherapeutic schemes (two containing cisplatin). All the patients had received varying doses (from 16 to 96 mg for 5 days) of ondansetron. Vascular complications occurred 1 to 3 weeks after treatment and 3 cases are still receiving therapy. It can be noted that two patients who had previously been treated with ondansetron did not develop vascular problems. This drug has been in use in our department since May 1991, but problems of a vascular nature only arose in October 1993. At present a final conclusion cannot be reached as to the link between ondansetron and vascular complications. PMID- 21597775 TI - Metastases observed autopsy in 70 women with ovarian-cancer - relationship to treatment. AB - We conducted a 20-year retrospective survey of 6.457 autopsied cases to select those women who died of primary ovarian carcinoma. Our objective was to determine the incidence and the sites of the metastases in those treated with or without combination chemotherapy based on cis-diamine dichloride platinum (CDDP). In the 70 cases so identified, epithelial ovarian tumors were the most common, found in 52 of the 70 cases. There were 14 cases of germ cell tumors and 2 cases each of sarcoma and stromal cell tumors. Metastases involved the peritoneum in the majority of cases (87%). The liver was the next most frequently affected (73%), followed by the spleen (47%) and the lung (44%). Of the 70 cases, 33 (47%) had received CDDP, while a regimen of 5-fluorouracil, doxorubicin, mitomycin C and toyomycin (FAMT) was administered to 11 cases (15.7%) and radiotherapy to 10 cases (14.3%). Patients who received a CDDP regimen survived longer (23.4 months) than those treated with FAMT (19.2 months) or with other regimens (13.6 months). The most common cause of death was carcinomatosis (48/70 cases). The high incidence of pulmonary, hepatic and splenic metastases in women with primary ovarian cancer indicates the need to direct anticancer treatment toward those sites to thus improve survival. PMID- 21597776 TI - Preoperative detection of C-erbb-2 gene amplification as a predictor of local recurrence after conservative treatment for breast-carcinoma. AB - The presence of comedo carcinoma in the intraductal component is an important pathologic feature for predicting local recurrence after breast conserving treatment. Furthermore, the c-erbB-2 gene is frequently overexpressed in comedo carcinoma and it correlates well with gene amplification. This study revealed that 77.0% of the c-erbB-2 amplification positive tumors had intraductal lesions of the comedo type; while only 6.7% of the amplification negative tumors had comedo carcinoma (X(2)=106.6, p<0.0001). Accordingly, when c-erbB-2 amplification is detected in the invasive tumor, intraductal lesions which may co-exist in the tumor are likely to be comedo carcinoma. To predict the presence of comedo type intraductal carcinoma, c-erbB-2 gene amplification was analysed by means of polymerase chain reaction (PCR) from small samples of fine-needle aspiration biopsies. Breast tumors from ten patients were analysed and one had a 3.4-fold amplification of c-erbB-2 gene. The pathological appearance of this case was pure ductal carcinoma in situ with comedo carcinoma. The preoperative detection of c erbB-2 gene amplification by PCR will be a useful means of selecting patients at high risk for local recurrence after breast conserving treatment. PMID- 21597777 TI - Tissue polypeptide antigen-specific (tps) and carcinoembryonic antigen (cea) levels in cancerous and precancerous lesions in human colon. AB - Serum levels of tissue polypeptide antigen specific (TPS), a cytokeratin 18 marker, were determined and compared with serum levels of carcinoembryonic antigen (CEA) in 45 patients with colon adenocarcinoma and in 34 patients with benign diseases (adenomatous polyps and ulcerative colitis) at the time of diagnosis. In colon carcinoma patients 58% had an elevated TPS level (cut-off 100 U/l) and 53% had an elevated CEA level (cut-off 3.0 ng/ml). The sensitivity of the cytokeratin marker TPS was related to the stage of the disease. Significant correlation was observed between TPS and Dukes stages in colon cancer patients and the highest TPS values were achieved in Dukes stage D. The combined use of the two markers increased the sensitivity to 82% compared with the use of only one. Simultaneous raise of both serum markers TPS and CEA was observed in 36% of cases. In the majority of the patients with adenomatous polyps and ulcerative colitis the serum TPS and CEA levels were below the upper reference limit. However the initial high levels in some patients could be considered as a prognostic indicator for identifying a group of patients with increased risk of cancer development. No significant correlation was observed between serum TPS and CEA concentrations in individual patients with benign diseases. PMID- 21597778 TI - Preliminary-study of the effect of selected chinese natural drugs on human ovarian-cancer cells. AB - This study investigated the in vitro anti-cancer effects of four Chinese natural drugs on the human ovarian cancer cell lines A2780 (cisplatin-sensitive) and A2780/CP70 (cisplatin-resistant). Cells were treated with series of concentrations of drug preparations for 24 h. Vincristine prepared by the same pharmaceutical firm in China; was used as an internal control. As assessed by colony formation assays, harringtonine induced similar growth inhibiting effects in A2780 and A2780/CP70 cell lines with a 50% inhibitory dose (IC50) of 0.195 mu g/ml in both. Rabdosia rubescens Hara demonstrated a cytotoxic effect on cisplatin-sensitive A2780 cells with an IC50 of 0.58 mg/ml; but there was no effect on A2780/CP70 cells. The data suggest direct anti-proliferative activity for at least two Chinese natural medicines used in the clinical treatment of cancer in China. Further investigation of Chinese natural medicines may be valuable in the identification of new and effective anti-cancer drugs with minimal side effects. PMID- 21597779 TI - Advanced breast-cancer - a randomized study of different doses of epirubicin associated with fixed doses of cyclophosphamide and 5-Fluorouracil. AB - A moderate increase in the dose of anthracycline could be feasible and of clinical benefit in advanced breast cancer. Between April 1991 and April 1994, 69 consecutive patients with recurrent or metastatic breast cancer were randomly treated with two regimens, including different dosages of epirubicin (75 versus 100 mg/m(2)) associated with the same dosage (600 mg/m(2)) of cyclophosphamide and 5-fluoruracil (75-FEC vs 100-FEC). Patients were planned to receive 6 courses at 21 day-intervals. Thirty-six patients received the 75-FEC regimen and 33 received the 100-FEC regimen. The two groups were comparable for age, menopausal status, disease-free interval, previous therapy, performance status and sites of disease: Over the whole study, the 100-FEC regimen has allowed a 18% actual increase in the epirubicin dosage over the 75-FEC regimen. Overall response rate was 56% for the 100-FEC and 51% for the 75-FEC, with the 100-FEC inducing some more complete responses than the 75-FEC (38% vs 23%). Survival (but not time to progression) tended to be longer with the 100- than with the 75-FEC (median: 20 vs 13 mos, p<0.09). Nonhematologic side effects Were similar. Hematologic toxicity was slightly higher with 100- than with 75-FEC, with granulocyte colony stimulating factors used to recycle in the scheduled time in the 15 and 4% of courses, respectively. PMID- 21597780 TI - Effects of tnp-470 (agm-1470) on tumor-growth, angiogenesis and serum copper levels in liver-cancer bearing rats. AB - Administration of TNP-470 (AGM-1470), a newly developed angiogenesis inhibitor, elevated serum copper concentrations (SCu) in a dose-dependent manner in normal rats as well as tumor-bearing rats. After discontinuation of TNP-470, SCu returned to the normal range in normal rats. In tumor-bearing rats, however, SCu decreased and then became elevated in relation to the tumor growth and capillary density in this hepatic tumor. The mechanisms leading to serum copper elevation may reflect a specific pharmacologic action of TNP-470, though it may also be related to tumor growth and reactivation of tumor angiogenesis after cessation of TNP-470. PMID- 21597781 TI - Epidemiologic-study of nonsteroidal antiinflammatory drugs and breast-cancer. AB - The association of nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer risk was examined in a case-control study of 303 breast cancer patients and 906 population control subjects. Breast cancer cases reported a significantly lower frequency of regular NSAID use than controls (19.1% versus 26.8%, p<0.01) and the resulting odds ratio adjusted for other risk factors was significantly less than 1 (OR=0.65, 95% CI=0.5-0.9, p<0.01). Regular intake of NSAIDs (greater than or equal to 3 times per week for greater than or equal to 6 months) was associated with a 36% reduction in the risk of breast cancer (OR=0.64, 95% CI=0.4 0.9, p<0.01). Greater use (greater than or equal to 7 times per week for greater than or equal to 5 years) resulted in a 40% risk reduction (OR=0.60, 95% CI=0.4 0.9, p<0.05). The observed effects of non-prescription and prescription NSAIDs were similar, although sample sizes were small for individual compounds. These results suggest that NSAIDs may have chemopreventive potential against the development of breast cancer. PMID- 21597782 TI - Streamline phenomena in liver metastasis of gastrointestinal tumors - a clinical study based upon 172 patients. AB - Location and number of liver metastasis of gastrointestinal tumors were detected preoperatively and intraoperatively. The distribution of the liver segment(s) occupied by metastatic tumors varied significantly (p<0.05). Significantly more frequent distributions were demonstrated in the lateral segment with gastric cancer (p<0.05), in the posterior segment with left colic cancer (p<0.001), in the medial segment with rectal cancer (p<0.01), in the anterior segment with bile duct cancer (p<0.05) and the whole of the liver with pancreatic cancer (p<0.05). Significantly less frequent distribution was demonstrated in the posterior segment with gastric cancer (p<0.01). When the liver was divided into the right and the left halves, the distribution of each half of the liver occupied by metastatic tumors varied significantly (p<0.05). Liver metastases of whole colic cancer were significantly more frequent in the right half of the liver (p<0.05). The results suggest that the tumor distribution in liver metastases of gastrointestinal tumors differ depending upon the primary tumors, basically in accordance with the 'streamline' phenomena. PMID- 21597783 TI - Preoperative neuroimmunotherapy with subcutaneons low-dose interleukin-2 and melatonin in patients with gastrointestinal tumors - its efficacy in preventing surgery-induced lymphocytopenia. AB - Our previous studies have shown that a preoperative injection of high dose IL-2 is able to abrogate surgery-induced immunosuppression in colorectal cancer patients. Moreover, our previous clinical investigations have indicated the possibility of amplifying IL-2 activity by a concomitant administration of the pineal immunomodulating hormone melatonin (MLT). On this basis, a biological study was performed to investigate the immune effects of a preoperative biotherapy consisting of low-dose IL-2 plus MLT in patients with gastrointestinal tumors. The study included 20 consecutive patients with gastrointestinal tract tumors, who underwent radical or palliative surgery. Patients were randomized to receive no preoperative treatment or a presurgical neuroimmunotherapeutic regimen consisting of low dose of IL-2 and MLT. IL-2 was injected subcutaneously at 3 million IU twice/day for 5 days in combination with MLT at 40 mg/day in the evening. Patients underwent surgery within 36 h from the last IL-2 injection. The mean number of lymphocytes, T lymphocytes and NK cells significantly decreased during the postoperative period in control patients, whereas it increased in patients pre-treated by immunotherapy. CD25-positive mean cell number increased in both groups of patients; however, postoperative mean number of CD25 expressing cells was significantly higher in patients pretreated with IL-2 and MLT than in controls. No immunotherapy-related toxicity occurred. This preliminary study would suggest that a neuroimmunotherapeutic regimen with low-dose IL-2 and MLT given preoperatively is a well tolerated therapy, which is able to prevent surgery-induced lymphocytopenia in cancer patients. This perioperative manipulation of host anticancer defenses could have a prognostic role in the clinical course of the neoplastic disease. PMID- 21597784 TI - Hormonal-therapy in patients with stage-iv breast-cancer at diagnosis. AB - The incidence of stage IV breast cancer at diagnosis is low, representing about 8% of all new cases. We report on the results obtained with a new aromatase inhibitor, formestane (500 mg i.m. fortnightly), given as a first treatment to fifteen postmenopausal patients with metastatic breast cancer. The overall response rate was 40%, with one complete remission in a patient with soft tissue and bone lesions and five partial remissions. The drug was well. tolerated and no significant systemic or local side effects were observed. We conclude that first treatment of stage IV breast cancer appears to be feasible with a hormonal drug such as formestane. PMID- 21597785 TI - Phase-ii trial of oral doxifluridine plus oral levo-leucovorin in unresectable hepatocellular-carcinoma. AB - Systemic chemotherapy with currently available agents in unresectable HCC has a minimal impact on disease progression and a predictable response rate of <20%. Doxifluridine (5 deoxy-5-fluorouridine, dFUR) is a new fluropyrimidine derivative that demonstrated higher antitumoral activity than other fluoropyrimidines in murine tumors and optimal gastrointestinal absorption when administered orally. Therefore, we evaluated the activity and feasibility of a combination of dFUR and l-leucovorin in unresectable HCC by the following schedule: l-leucovorin 25 mg orally followed 2 hours later by dFUR 1,200 mg/m(2), day 1 through 5, cycles being repeated every 10 days. Thirtyseven patients with unresectable HCC entered the study and are evaluable for response and toxicity. Three partial responses have been observed, to a global response rate of 8% (95% confidence interval 2 22%). After a median observation time of 12 months, the median survival was 7 months, with a median time to progression of 4 months; Main toxicity was diarrhea; severe in 30% of the patients. One patient died as a result of uncontrollable diarrhea. In view of the limited activity observed, further trials with this schedule are not warranted. PMID- 21597786 TI - Glutathione sulfhydryl transferase-pi expression in testicular germ-cell tumors - an immunohistochemical study of 30 cases. AB - Glutathione sulfhydryl transferase (GST) is believed to play a major role in the detoxification of chemotherapeutic agents and therefore is thought to be important in chemoresistance. Thirty primary testicular germ cell tumors were stained immunohistochemically for GST pi using a rabbit polyclonal antibody and formalin-fixed paraffin-embedded tissue. There were 12 pure seminomas and 18 mixed germ cell tumors (GCTs). Immunostaining of each element present was graded as negative (-), weakly positive (+), or strongly positive (++). The results were as follows: seminoma (8/17 +, 9/17 ++); embryonal carcinoma (1/13 -, 7/13 +, 5/13 ++); mature teratoma (9/9 ++); immature teratoma (7/7 +); endodermal sinus tumor (7/8 +, 1/8 ++); and choriocarcinoma (1/1 -). These results show that variability exists in the expression of GST pi between different tumor types and between different examples of the same tumor type. Strongest expression was seen in seminomas and mature teratomas while other germ cell elements tended to show weaker staining. The staining patterns showed no apparent correlation with stage or response to therapy. PMID- 21597787 TI - Late relapse of testicular cancer presenting as differentiated teratoma - report of a case and discussion of the clinical implications. AB - This report describes the unusual case of a patient with late relapse of testicular cancer, histologically defined as differentiated teratoma occurring 76 months after primary therapy for metastatic non-seminomatous germ cell cancer. During initial treatment the patient received 4 cycles of cisplatin-based chemotherapy followed by secondary resection of residual retroperitoneal and pulmonary metastases which had histologically revealed necrotic tissue. The patient had been without evidence of disease during the follow-up until May 1994 when a cystic mass was noted in the left fossa obturatoria. There was no concomitant elevation of serum tumour markers, while alpha-fetoprotein (AFP) could be detected in fluid gained by fine-needle aspiration from inside the cystic structure. Histological resection showed a differentiated teratoma. Late relapses defined as tumour recurrences later than 24 months after primary chemotherapy for metastatic testicular cancer are rather rare and affect only 2 5% of patients. However, the prognosis of patients with late relapse is poor with only 20-30% of patients achieving a second remission after chemotherapy +/- surgery. Patients presenting with only differentiated teratoma at late relapse and in whom the tumour can be completely surgically resected have the best prognosis among the subgroup of patients with late relapses with a long-term survival in approximately 50% of patients. The incidence and clinical implications of late relapses after chemotherapy for testicular cancer are discussed in the current report. PMID- 21597788 TI - Serum levels of scc, cea, ca-125 and tpa in the management of cervical-carcinoma. AB - Serum levels of squamous cell carcinoma antigen (SCC), carcinoembryonic antigen (CEA), CA 125 and tissue polypeptide antigen (TPA) were serially determined in 116 patients with cervical carcinoma. Serum levels of SCC or TPA levels were elevated in the 12 patients with residual tumour after primary therapy. In patients who were clinically in complete remission, SCC and TPA levels were elevated in 7/69 and 5/70 patients, respectively. Three of the 7 with positive SCC and 4 of the 5 patients with positive TPA levels had a recurrence during follow-up. Elevated levels of SCC or CA 125 or TPA preceded the clinical detection of recurrence in 13 of 18 patients (median time was 7 months for SCC and 6 months for CA 125 and TPA). PMID- 21597789 TI - Gonadotropin-releasing-hormone (gn-rh) receptor in the reproductive-tract tumor - physiological-role and signal-transduction pathway. AB - Gonadotropin-releasing hormoen (Gn-RH) analogs have been used in the therapy of the endocrine-dependent cancers including the repductive tract-originated tumors. Gn-RH receptor and its transmembrane signaling pathways have been demonstrated in a high proportion of these tumors. The demonstration of existence of receptors for a hormone can better predict hormonal dependency, and might be a first step towards an effective hormonal treatment. These findings suggest the merit of further therapeutic investigations of Gn-RH analogs alone or in combination with traditional therapies in the management of Gn-RH receptor-positive tumors. PMID- 21597790 TI - Survival after pelvic lymphadenectomy and radical cystectomy in patients with lymph-node metastatic transitional-cell carcinoma of the bladder. AB - The objective of this study was to determine the clinical outcome of patients with invasive transitional cell carcinoma of the bladder and pelvic lymph node metastases treated by radical cystectomy and bilateral pelvic lymphadenectomy in a single institution. From January 1980 to December 1993, 116 patients with transitional cell carcinoma of the bladder underwent bilateral pelvic lymphadenectomy and radical cystectomy at the Montreal General Hospital. Of these patients, 25 (21.6%) were found to have nodal metastases and form the basis of this retrospective analysis. Extent of nodal disease was as follows: 7 (28%) with N1, 17 (68%) with N2, and 1 (4%) patient with N3 disease. Of the 25 patients, 9 (36%) were alive with no evidence of disease and 1 (4%) died at 42 months from cardiovascular disease without clinical evidence of cancer recurrence. The median follow-up interval for these 10 patients was 26.5 months (mean, 31.4 months; range, 7-104 months). Fourteen (56%) patients died of recurrent bladder cancer and one patient was alive with systemic disease at 14 months. The median survival was estimated at 27 months, with 73% alive at 1 year, 51% alive at 2 years, and 33% alive at 3 years. Our data suggests that long-term survival free of disease can be achieved by radical surgery in some patients with node-positive bladder cancer. PMID- 21597791 TI - Prognosis and lung-cancer - the contribution of plasma-proteins. AB - In this prospective study we aimed at assessing the potential prognostic significance of the serum protein content. We studied 388 consecutive patients, newly diagnosed for lung cancer during the last 6 years, by measuring the serum concentration of immunoglobulins (IgG, IgA, IgM), transferrin (T), haptoglobin (HP), alpha-1-acid glycoprotein (AGP), alpha-1-antitrypsin (AT) and alpha-2 macroglobulin (MG). In all patients, the values of other 9 clinical variables (age, sex, weight loss, ECOG performance status, stage- of disease, TNM factors and histology) were also available. Univariate analysis showed that patients with transferrin above 218 mg/dl had a median survival of 9 months, as compared to the 7 months for the remaining subjects (p<0.01). Patients with AT above 281 mg/dl had a significantly shorter survival than patients with low AT (11 months vs 6 months, p<0.01). High AP and AGP were also significantly associated with a poor prognosis (p<0.01 and 0.05 respectively). A multivariate analysis of survival (the Cox's proportional hazards regression analysis), selected, in decreasing order of significance, the following variables: (i) stage of disease; (ii) ECOG performance status; (iii) sex; (iv) alpha-1-acid glycoprotein; (v) weight loss; (vi) histology. We conclude that serum proteins (particularly AGP, T and AT) do have some prognostic significance in lung cancer. PMID- 21597793 TI - 1-o-octadecyl-2-o-methyl-glycerophosphoscholine inhibits the adhesion of ras transformed fibroblasts to human endothelial-cells. AB - The adhesion of tumor cells to the endothelium is a key step in haematogenic metastasis. Because alkyllysophospholipids decrease tumor metastasis, we investigated the effect of 1-O-octadecyl-2-O-methyl-glycerophosphocholine (ET18 OCH3) on the adhesion of two highly metastatic ras-transformed 10T1/2 cell lines, CIRAS-2 and CIRAS-3, to confluent endothelial cells. The order of adhesion to the endothelial cells was CIRAS-2 > 10T1/2 > CIRAS-3. RGD peptides were unable to inhibit the binding of the cells suggesting that adhesion was not mediated by fibronectin or vitronectin. Treatment of the cell lines with 20 mu M ET18-OCH3 for 24 h decreased the adhesion of CIRAS-2, CIRAS-3 and 10T1/2 to the endothelial cells by 50, 43 and 36% respectively. Thus interference in the adhesion of tumor cells to the endothelium could contribute to decreased metastasis. PMID- 21597792 TI - The serum level of manganese superoxide-dismutase in patients with ovarian epithelial malignancy. AB - The serum level of a scavenging enzyme, manganese superoxide dismutase (MnSOD) was examined in 95 patients with ovarian epithelial malignancy. The MnSOD values were variable according to the differences of surgical stage, histologic type and histological grade. Factors affecting the MnSOD level were statistically analyzed. The stage and histologic type were less effective than the histological grade in determining the serum MnSOD value. The level increased significantly in accordance with the elevation of grade. Although the mechanism remains unclear, the MnSOD determination may be useful in predicting the histological grade of ovarian carcinoma. PMID- 21597794 TI - Oncogene-associated transformation of rodent fibroblasts is accompanied by large morphologic and metabolic alterations. AB - Cellular growth, proliferative activity, cell volume and metabolism of four differently transformed cell lines were investigated. Studies were carried out with spontaneously immortalized and poorly tumorigenic Rat1 cells, c-mycl transfected and non-tumorigenic M1 fibroblasts, as well as their T24Ha-ras-(co) transfected counterparts Rat1-T1 and MR1. Ras-transfection of both Rat1 and M1 cells, which is associated with aggressive tumor growth in vivo, caused significant morphological alterations, namely a 30-50% decrease in cell volume. A negative linear correlation between cell number and cell volume at confluence was observed. Furthermore, the expected stimulation of cellular growth rate after T24Ha-rastransfection was documented. Growth inhibition in Rat1 and M1 cultures was reflected by a dramatic decrease in the [H-3]thymidine labeling index (TLI) to below 3% while entering the stationary growth phase. In contrast, Rat1-T1 and MR1 cells had a TLI of greater than or equal to 18% even at confluence. Glucose uptake and lactate production were not different on a per cell basis: between parental cell line and the T24Ha-ras-transfected transformants. However, when these parameters were normalized for differences in cell volume, ras-transfection resulted in increased glucose consumption and lactate release. The behavior of cellular and cell volume-related oxygen uptake throughout the growth period examined was remarkably different between the parental lines and the ras transformed descendants. Oxygen consumption rates (QO(2)) of Rat1-T1 and MR1 cells were significantly less than those of Rat1 and M1 fibroblasts and showed different changes as a function of time in monolayer culture. Whereas the cellular QO(2) of the highly tumorigenic cell clones either decreased or leveled off throughout the entire period of plateau phase, a decline in cellular oxygen uptake was observed in the partly transformed cells until days 4-5 only. The decline was then followed by an increase with values almost returning to those recorded during the early exponential phase. The data presented demonstrate for the first time an impact of well-defined oncogenic alterations on the metabolic characteristics of cells which is a further step in the understanding of the pathophysiology of ras-associated tumor cells. PMID- 21597795 TI - Therapeutic activity of 9-chloro-2-methylellipticinium acetate in an orthotopic model of human brain cancer. AB - A series of ellipticinium derivatives with selective cytotoxicity towards brain tumor cell lines has been identified through in vitro screening against disease oriented panels of human tumor cell lines. Unfortunately 9-methoxy-2 methylellipticinium, the lead compound of this series, has shown only very limited evidence for in vivo activity when examined in a variety of human tumor xenograft models. This lack of activity has been postulated to be due to metabolism. To address this issue, a derivative was synthesized which was blocked at the theoretically vulnerable 9-position and yet could be shown to retain brain tumor selectivity in vitro. In vivo xenograft testing was performed to assess the therapeutic potential of this second generation compound. To maintain continuity with the in vitro screening data, in vivo experimental therapeutic models were devised employing one of the in vitro sensitive cell lines, the U-251 glioblastoma. Cells were cultivated in vitro and injected into female athymic nude mice for therapeutic studies. The 9-chloro-derivative of the lead compound produced growth delay of subcutaneously implanted tumor cells when. administered by seven-day continuous infusion. Based on this evidence for activity in a systemic chemotherapy mode, further studies were conducted using an orthotopic brain cancer model. In three separate experiments, intracranial implantation of 1x10(7) tumor cells resulted in 100% mortality of control mice with median survival ranging from 15-18.5 days. In all experiments, mice treated by subcutaneous infusion with 9-chloro-2-methylellipticinium acetate showed increases in survival. Statistically significant effects and individual long-term survivors were observed in two experiments; These results provide support for the further preclinical development of 9-chloro-2-methylellipticinium acetate as a candidate for clinical trials against human brain cancer. PMID- 21597796 TI - Clinical-study of multiple-myeloma in the elderly. AB - From January 1989 until December 1992, 120 elderly patients over 65 years old with multiple myeloma (MM) were enrolled with the Elderly Hematology Study Group (EHSG) with 14 institutions participating. Several courses of chemotherapy were conducted in 103 of the 120 patients, 33 patients with alpha-interferon (IFN) and 70 patients without IFN. The response rate (CR+PR) was 24.0% of all 120 cases, 24.2% of the group treated with IFN and 25.7% of those treated without IFN. Similarly, the efficacy rate (CR+PR+MR) of these groups were 78.8%, 81.8% and 78.8%, respectively. The 50% survival time was 31 months in the 120 cases as a whole, 44 months in the group treated with IFN and 38 months in the group treated without IFN. No significant difference was observed either in response rate (p=0.243) or survival time (p=0.262) in the groups treated with or without IFN. PMID- 21597797 TI - Regulation by calcium-ion of choriocarcinoma aromatase-activity. AB - Intratumoral estrogen could function as an autocrine or paracrine growth factor. We investigated the regulation of estrogen synthetase (aromatase) activity by Ca2+ in choriocarcinoma JAr cell line. Aromatase enzymatic activity was measured in whole intact cells and microsome fractions by quantitating (H2O)-H-3 released from [1-H-3]-androstenedione and [H-3]estrone converted from [1,2,6,7-H 3]androstenedione. Exposure of JAr cells to calcium ionophore A23187 brought about dose-dependent decreases in the cellular aromatization rate by up to 75%; a half-maximal inhibition occurred at 1 nM. In membrane fractions, free Ca-2+ inhibited aromatase activity in a noncompetitive manner. Maximal effect (approximately 50%-inhibition) occurred at 1 mM Ca2+ and a half-maximal inhibition occurred at 10 mu M. These results on both intact cells and membrane fractions suggest that the increase in intracellular calcium concentration modulates the estrogen production by JAr cells. Physiological factors that might have been considered as likely candidates to raise. intracellular Ca2+ level may be applicable to control of choriocarcinoma proliferation. PMID- 21597798 TI - Isolation of p53 protein from the serum of colon-cancer and noncancer patients. AB - A new method for the isolation of p53 protein from the sera of cancer and non cancer patients has been developed. The method is based on the utilization of a new modification of a support for affinity chromatography in the form of gel fiberglass (GFG) (R. Zusman, patent applications, Israel, 1992; USA 1993). The sera were percolated through GFG columns with entrapped rabbit IgG generated against the colon cancer antigens. Tumor-associated antigens were eluted from sera of cancer patients in large amounts, up to 2.4 mg/ml serum/column. Concentrations of these antigens in different sera and their affinity to anti tumoral antibodies were detected by ELISA. Western immunoblotting with commercial monoclonal antibodies and SDS-PAGE identified the isolated antigens as the p53 protein. This protein has been isolated in the highest concentration yet reported from the serum of cancer patients, up to 1 mg/ml. The same protein has been found in the serum of healthy people and non-cancer patients but in significantly lower concentrations. Isolation of p53 protein from sera of noncancer patients confirms the opinion of some investigators that this protein should be considered not only as an oncogene but also as a protein correlated with different changes in the cell cycle. PMID- 21597799 TI - Recurrent sclerosing Basal-cell carcinomas requiring ablative cranio facial surgery - a 3-case report. AB - The authors report on 3 cases of facial recurrent sclerosing basal cell carcinomas requiring large ablative cranio facial surgery and reconstruction involving regional or even free flaps. Special emphasis is made on the aggressive behavior of this specific histological form and on the necessity of an early diagnosis, a radical initial treatment and a close life time follow-up. Surgery with careful histological control of the margins is the treatment of choice whereas radiotherapy is an alternative for small lesions or nonsurgical patients. This early and aggressive therapeutic management is essential in order to avoid recurrences often requiring disfiguring surgery. PMID- 21597800 TI - Inhibition of mammary-gland tumorigenesis in the rat by caraway seeds and dried leaves of watercress. AB - The effect of consumption of caraway seeds and dried leaves of watercress on 7,12 dimethylbenz(alpha)anthracene (DMBA)-induced mammary gland tumorigenesis in female Sprague-Dawley rats was determined. At 6 weeks of age, animals were fed a basal (control) diet and experimental diets containing caraway or watercress (20%). Animals were maintained on their diets till termination of the experiment (25 weeks after DMBA). At 8 weeks of age, all rats were given DMBA 10 mg, one dose, p.o. in oily formulation). Neither caraway nor watercress affected the body weight or the rate of growth of animals. By week 25 after DMBA, 77% of the control rats developed mammary tumors, with a mean of 2.27 tumors per rat. Caraway decreased significantly (P<0.05) the percentage of rats with tumors (42.8% protection) and the mean number of tumors per rat (50.6% protection) and increased significantly (P<0.05) the mean latency period of tumor appearance. Watercress, though decreased the percentage of rats with tumors (28.5% protection) and the mean number of tumors per rat (31.7% protection), this decrease was significant (P < 0.05) during some week intervals only. The increase in the mean latency period of tumor appearance by watercress was not significant. The results of this study suggest that caraway and watercress possess chemopreventive effects against DMBA-induced mammary gland tumorigenesis in rats. PMID- 21597801 TI - Cross-resistance to antineoplastic agents in a human small-cell lung-cancer subline resistant to okadaic Acid. AB - We report on a human small cell lung cancer subline (H69/OA100) resistant to okadaic acid, an inhibitor of protein phosphatases. H69/OA100 showed cross resistance to cis-diamminedichloroplatinum(II) (CDDP), adriamycin, and vinca alkaloids. Intracellular retention of adriamycin and CDDP in H69/OA100 was the same as those in H69. H69/OA100 was not shown to express MDR-1 by the reverse transcription polymerase chain reaction method. Expression level of mRNA of multidrug resistance-associated protein (MRP) in H69/OA100 was the same as that in H69. These data suggest that the mechanism of drug resistance in H69/OA100 might be due to a new mechanism of non-P-glycoprotein mediated multidrug resistance. PMID- 21597802 TI - The estimation of proliferative activity by pcna and AgNORs in leukoplakia and squamous-cell carcinoma of the oral cavity. AB - The proliferating activity of leukoplakia and squamous cell carcinoma (SCC) was estimated using proliferating cell nuclear antigen (PCNA) immunostaining and silver-binding argyrophilic nucleolar organizer region (AgNOR) staining. Twenty eight leukoplakias and 15 SCCs of the oral cavity were used in this study. The mean+/-S.D. of PCNA LI and AgNOR counts were 7.7+/-6.0% and 2.43+/-0.68/nucleus in leukoplakias, and 22.3+/-11.6% and 4.77+/-1.49/nucleus in SCCs. Both of PCNA LI and AgNOR counts were significantly higher in SCCs than in leukoplakias. There was a significant linear correlation between PCNA LI and AgNOR counts (p=0.0022) in leukoplakias, but not in SCCs. In the series of leukoplakias, PCNA LI apparently increased in leukoplakias with dysplasia and malignant transformed cases. Our data suggest that PCNA LI and AgNOR counts are useful markers of proliferating activity, and PCNA LI might be a prognostic factor of leukoplakias. PMID- 21597803 TI - Mao-a enzyme binding in bladder-cancer characterized with [C-11] harmine in frozen-section autoradiography. AB - Operative specimens from 7 patients with urinary bladder cancer and with only inflammatory tissue in the operative sample from one patient, were used for frozen section autoradiography using [C-11]harmine to characterize the expression of the enzyme monoamine oxidase A (MAO-A). Tissue sections (25 mu m thick) were incubated with [C-11]harmine at concentrations of 2 and 10 nM for 45 minutes, washed and exposed on a phosphor imaging plate system. Rat brain sections were included in each experiment and used as a standard to which the binding in the tumor sections were related. Non-specific binding was estimated by incubation in the presence of 1 mu M harmine. Displacement experiments were performed with both harmine and clorgyline. Good visualization was obtained in all tumor and rat brain samples, although several tumor samples included areas with variable binding. Quantitatively, the binding in the tumor samples was on the average 1.4 times that of rat brain (range 0.4-3.3); One section with only inflammatory cells had a ratio of 0.08, and in one specimen from a patient given preoperative chemotherapy, the ratio was -0.1. Binding inhibition experiments demonstrated an IC50 of approximately 5 nM for harmine and approximately 10 nM for clorgyline. These results indicate that specimens from urinary bladder cancer have a high expression of the enzyme MAO-A. With the availability of [C-11]harmine and positron emission tomography (PET) it is reasonable to believe that in vivo characterization of MAO-A in bladder cancer is feasible and could be used for diagnostic purposes or for treatment monitoring. The physiological significance of the high expression of MAO-A in bladder cancer remains to be elucidated. PMID- 21597804 TI - Pathological and enzymatic features of 1,2-dimethylhydrazine induced colorectal carcinomas in rats. AB - Well- and moderately well-differentiated colorectal adenocarcinomas accounted for 86% of all tumors induced by 1,2-dimethylhydrazine in rats, and were distributed throughout the colorectal tract. Poorly differentiated carcinomas, 14% of all tumors, were markedly restricted to the proximal half of colon, i.e., 94% of the poorly differentiated type was found in the proximal colon and caecum. Thymidylate synthetase and thymidine kinase, key enzymes in the de novo and salvage pathways, respectively, for pyrimidine nucleotide synthesis were found to be reduced and elevated, respectively, with increasing cellular differentiation. These results suggest that biochemical differences in colorectal tumors may be associated with differences in tumor frequency, distribution, and histological type. PMID- 21597805 TI - Neoadjuvant chemotherapy in locally advanced gastric-cancer - preliminary-results of a phase-ii trial with a modified famtx combination. AB - Twenty-two patients with locally advanced inoperable gastric cancer received neoadjuvant chemotherapy with a modified 5-fluorouracil, doxorubicin, methotrexate (FAMTX) regimen. The patients who achieved at least a stable disease were considered eligible for surgery with curative intent, which was performed in 19 cases. 16 patients (all responsive to neoadjuvant chemotherapy) were rendered disease-free by the combined approach. No treatment-related deaths occurred; grade III leukopenia was observed in only 3 cases. The preliminary results of this study indicate the feasibility of our treatment approach; randomized trials are awaited to properly evaluate the role of neoadjuvant chemotherapy in locally advanced gastric cancer. PMID- 21597806 TI - Long-term follow-up results of patients with stage ic-iv ovarian-cancer treated with Cisplatin, epirubicin and Ifosfamide chemotherapy. AB - Sixty-three patients with stage Ic-IV ovarian cancer received cisplatin, epirubicin and ifosfamide chemotherapy following a staging surgery between 1985 and 1992. The optimal surgery (without macroscopic residual was completed in 44 patients including 12 stage III cases. A 5-year survival of 97.5% was obtained for the optimal cases; whereas that for suboptimal cases was only 24.0%. From the results, the regimen proved to be a promising adjuvant therapy for ovarian cancer after optimal surgery; moreover a need for a drastic amelioration of strategy is emphasized in the treatment of advanced ovarian cancer with extensive metastases. PMID- 21597807 TI - 5-fu dose-dependency in mtx/s-fu sequential therapy assessed by in-vitro assay using gastric-cancer cell-lines. AB - The sequential administration of methotrexate (MTX) and 5-fluorouracil (5-FU) (MTX/5-FU therapy) on gastric cancers has shown higher response rates than standard chemotherapy. The response rate of these cancers, however, still showed from 18 to 48%. The purpose of this study was to determine the appropriate interval time and doses of MTX/5-FU therapy using a panel of 4 cell lines originated from the poorly-differentiated gastric cancers. The 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used as the chemosensitivity test. The sequential administration of MTX and 5-FU inhibited the growth of 2 cell lines more than 5-FU alone. In one cell line (GCIY), it inhibited the growth 6 times, and the longest interval time (6 h) was the most effective. In the other cell line (KATOIII), it inhibited growth 3 times, and the shortest interval time (O h) was the most effective. The growth inhibition in these cases did not depend on the dose of MTX (0.01 mu g/ml to 100 mu g/ml), but on the dose of 5-FU. In conclusion, 2 out of 4 cell lines showed a synergic effect between MTX and 5-FU. While the appropriate interval time between the two drugs varied between two cell lines, 5-FU dose was more critical than that of MTX. If 5-FU dose were to be increased in future trials with MTX, its efficacy might be higher. This model should also be good to screen other anti cancer drugs combined with MTX/5-FU therapy. PMID- 21597808 TI - P53 gene alterations in differentiated thyroid cancers. AB - Analysis of 22 human thyroid cancers including papillary, follicular and medullary subtypes (PTC, FTC, MTC) by PCR-SSCP, and immunohistochemistry detected 4 deletions and 3 mutations. Deletions involved exons 1, 2-3 and 5-6 in 3 PTCs, mutations exons 2-3 in 2 MTCs and exons 8-9 in PTC4. p53 alterations occurred in 2/5 recurrent tumors and 2/3 tumors developing to cell lines. Immuno histochemistry detected p53 mutations in differentiated areas of papillary thyroid cancers as frequent events occurring at stage T1 to T4 in contrast to prior findings by other authors which restrict p53 alterations to undifferentiated stages. PMID- 21597809 TI - Adipose-tissue concentrations of dioxins and dibenzofurans in potentially exposed patients with malignant-lymphoma or sarcoma. AB - Epidemiological studies have suggested an association between exposure to phenoxyacetic acids, chlorophenols or their contaminating dioxins (PCDDs) and dibenzofurans (PCDFs) and soft-tissue sarcoma and malignant lymphoma. In this study adipose tissue concentrations of PCDDs and PCDFs were measured in nine patients with sarcoma or malignant lymphoma who had been exposed to phenoxyacetic acids or chlorophenols, or who had other potential exposure to dioxins and dibenzofurans. For comparison concentrations of PCDDs and PCDFs in a group of twelve healthy persons without any known exposure to the above chemicals and living in the same geographical area are presented. Even if no consistent pattern of PCDDs and PCDFs concentrations in the patients was demonstrated, the finding of increased concentrations in all three cases with non-Hodgkin's lymphoma is of special interest. The exposure profiles in relation to measured concentrations of PCDDs and PCDFs are discussed for all patients. PMID- 21597810 TI - No occurrence of DNA-polymerase Beta-gene mutation in human lung-carcinoma cell lines with k-ras as, p53, or rb gene alterations. AB - In order to investigate the relationship between a potential defect in the DNA repair system and human lung carcinogenesis, we examined the entire coding region of the human DNA polymerase beta gene using the reverse transcription-polymerase chain reaction (RT-PCR)/single-strand conformation polymorphism (SSCP) method in 31 human lung carcinoma cell lines (18 non-small cell lung carcinoma (NSCLC) cell lines and 13 small cell lung carcinoma (SCLC) cell lines, 4 cell lines with K-ras point mutation, 9 with p53 point mutation, 3 with retinoblastoma susceptibility (Rb) gene alteration). Mutation of the polymerase beta gene was undetectable in all of them. These results suggest that mutations of the DNA polymerae beta gene is extremely rare if it occurs at all in human lung cancer, and may have no relation with K-ras, p53, or Rb gene alterations. PMID- 21597811 TI - Soluble C-erbb-2 (p185) in breast-cancer patients in relation to prognosis. AB - Serum levels of P185-HER-2 were measured in 137 breast cancer patients and in 40 controls. The patients were divided into 4 groups: group A - 40 newly diagnosed patients; group B - 57 patients on long-term follow-up without active disease; group C - 26 patients with metastatic disease and group D - 5 patients with locally advanced inoperable tumors. The median level in controls was 4.8 U/l. The median P185 serum levels in groups C and D were significantly higher compared to groups A and B. In group C 60% and in group D 100% of patients had baseline elevated levels of serum P185 (>5 U/l) compared to 28% in groups A and B. Of the 14 patients in group A with elevated baseline levels of serum P185, 6 (43%) developed metastasis during the 24-month follow-up period. On serial measurements during follow-up in 23 patients of group A, 3 relapsed and the P185 level increased. In group C, serial measurements in patients with elevated baseline levels of P185 correlated with clinical response to therapy. These data suggest that serum levels of P185 are elevated in patients with metastatic disease. High initial P185 serum levels in new patients may have prognostic significance. Serial measurements of P185 in asymptomatic patients may help in monitoring disease state. In metastatic patients, serial P185 determination may be of benefit in assessing response to therapy. PMID- 21597812 TI - A role of glutathione in resistance mechanisms to cis diamminedichloroplatinum(ii) in human ovarian-cancer cell-lines in-vitro. AB - The effects of D,L-buthionine-S, R-sulphoximine (BSO) on the cellular glutathione (GSH) levels and cis-diamminedichloroplatinum (II) (CDDP) sensitivity of human ovarian cancer cell lines (HRA, KK and MH) with different sensitivity to CDDP were examined. HRA cells were derived from ascites of a patient with serous cystadenocarcinoma of the ovary who responded well to CDDP-based combination chemotherapy. KK and MH cells were also established from ascites of a patient with clear cell carcinoma of the ovary and with serous cystadenocarcinoma of the ovary, respectively who did not respond to CDDP-based combination chemotherapy. The KK and MH cell lines showed 2.93- and 7.80-fold higher resistance to CDDP in vitro than HRA cells, respectively and had also cross-resistance to its analogues. Although GSH levels in the CDDP sensitive HRA cells were 33.4 nmol/10(7) cells, the CDDP resistant KK and MH cells showed 5.61-and 10.48-fold higher GSH levels, respectively. The higher the GSH levels the more rapid depletion of the cellular GSH by BSO occurred. Cystine, a component of GSH, resulted in an increase of the cellular GSH in these cell lines. When the cellular GSH levels were changed by BSO or cystine, changes of the IC50 to CDDP and its analogues of the CDDP resistant KK and MH cells correlated with those of the cellular GSH levels while the IC50 values of the CDDP sensitive HRA cells remained unchanged. In addition, when these resistant cell lines (but not HRA cells) were incubated with CDDP, the cellular GSH levels markedly increased. From these results, we conclude that GSH may have a role in the mechanisms of intrinsic resistance to CDDP and its analogues of the KK and MH cell lines. PMID- 21597813 TI - Detection of activating mutations in the ras family genes in cytological specimens from lung-tumors. AB - Mutations in the ras family genes (K-ras mainly) represent a common event in lung tumorigenesis which is frequently associated with poor clinical outcome. In order to investigate whether K-ras mutations are detectable in cytological material obtained from patients with lung cancer, 37 cytological specimens (16 fine needle aspiration and 21 bronchoscopy) were assessed for codon 12 point mutations in the H-, K- and N-ras genes by combined polymerase chain reaction-restriction fragment length polymorphism. K-ras codon 12 point mutations were found in 8 out of 37 (22%) specimens while no mutations were found in the H-ras and N-ras genes. Mutations were found in 27% (3 out of 11) of adenocarcinomas while in squamous cell carcinomas the incidence of mutations was 18% (3 out of 17). In addition, a K-ras codon 12 point mutation was found in one (12%) among 8 small cell carcinomas and in the only Hodgkin's lymphoma with metastasis in the lung. Our results are in agreement with previous results that recognise high incidence of K ras activation in lung carcinomas, and indicate that detection of mutant ras alleles is possible in cytological material. PMID- 21597814 TI - Radiofrequency capacitive hyperthermia combined with irradiation or chemotherapy for patients with invasive bladder-cancer. AB - The immediate therapeutic clinical efficacy and long-term outcome of hyperthermia in combination with irradiation or chemotherapeutic agent was evaluated in 46 patients with invasive bladder cancer. Radiohyperthermia was performed in 19 cases and chemohyperthermia in 27 cases. Complete response (CR) was obtained in 5 and partial response (PR) in 15 of the 46 cases. Five-year survival rates by the Kaplan-Meier method were 43.8% in the CR/PR group and 18.3% in the no change (NC)/progressive disease (PD) group, showing no difference of survival rate between the CR/PR group and the NC/PD group. The overall median survival period for the CR/PR group without metastasis was 61.6 months compared to 32.3 months for the NC/PD group without metastasis (P<0.05). PMID- 21597815 TI - The conditioning effect of rk-28 in a combined treatment with irradiation against v-79 cells. AB - The conditioning effect of RK-28, one of the nitroimidazole nucleoside analogues, in a combined treatment with irradiation against aerobic V-79 cells in an exponentially-growing phase was investigated. The growth rate of the V-79 cells in 5% DMEM was not different from that in the medium containing 0.2 mM RK-28. The growth of V-79 cells treated with 6 Gy-irradiation in the medium containing 0.2 mM RK-28 showed a statistically more significant inhibition than that with a single modality treatment of irradiation. The number (3.3x10(3) cells/dish at 24 h after irradiation) of cells incubated for 24 straight hours in the medium containing RK-28 was significantly lower than that (9.5x10(3) cells/dish at 24 h after irradiation) of the cells which were placed into a fresh medium immediately after irradiation. Moreover, the number of the cells, in which the medium was changed to a conditioned medium containing 0.2 mM RK-28 immediately after irradiation with the same dose of RK-28, was 2.1x10(3) cells/dish at 24 h after irradiation, and thereafter did not increase. These results indicated that RK-28 induced growth inhibition factors from exponentially-growing V-79 cells in an aerobic state, due to the combined treatment with irradiation. PMID- 21597816 TI - Breast-cancer associated brachial plexopathy - still a diagnostic and treatment challenge. AB - Brachial plexopathy (BP) in breast cancer patients is a rare event, attributed mainly to radiation damage or tumor infiltration of the plexus. Differentiation between these etiologies is a diagnostic challenge. We have studied retrospectively eight female patients with breast cancer who developed a clinical syndrome of brachial plexopathy following the treatment of the primary disease, out of more than 900 during the last 10 years. None of the available ancillary tests such as plain films, CT or MRI studies, EMG or tumor markers, provided reliable data regarding the cause of the plexopathy. Biopsy, on the other hand, was not always feasible. In our series, all the patients who developed BP did not have any blood-borne metastases before developing the syndrome. In 3 of the patients BP was the first sign of recurrence. In the other 5, only local or locoregional relapse preceded. In 7 of the 8 patients the left side was affected. Treatment should be tailored in each case according to course of the disease. The optimal treatment has not yet been defined. PMID- 21597817 TI - Antiproliferative effects of garlic constituents in cultured human breast-cancer cells. AB - The medicinal uses of garlic (Allium sativum) and its constituents have been known for centuries, though its mode of action is still undetermined. Several epidemiological and laboratory studies indicate a potential anti-carcinogenic effect of garlic and some of its constituents. In this study we investigated the effect of aged garlic extract (AGE) and two of its components, S-allylcysteine (SAC), and S-allyl-mercaptocysteine (SAMC) on human breast cancer cells, MCF-7 and MCF-7(ras). Transfection of v-H-ras in MCF-7 cells gives rise to a highly aggressive subset of cells that is estrogen independent and has a five fold greater colony forming efficiency in soft agar than the parent cell line. The modulatory effect of AGE, SAC and SAMC on growth and glutathione cycle was examined in the two cell lines. We noted an anti-proliferative response to SAC and SAMC on both anchorage dependent and independent conditions and an alteration in glutathione level without significant concurrent changes in the glutathione metabolizing enzymes. PMID- 21597818 TI - Combination effect of an angiogenesis inhibitor agm-1470 with 5'-deoxy-5 fluorouridine, and with hormonal drugs in dmba-induced rat mammary-tumors. AB - AGM-1470, a potent angiogenesis inhibitor, is known to suppress the growth of solid tumors in vivo. In this study, we investigated the combination effect of AGM-1470 with 5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5-FU by pyrimidine nucleoside phosphorylase, with tamoxifen (TAM), and with medroxyprogesterone acetate (MPA) in dimethylebenz(a)-anthracene (DMBA) induced rat mammary tumors. Since 5'-DFUR and MPA are noted to have antiangiogenic activity, this combination study might imply not only the addition to chemotherapeutic or hormonal drugs for the angiogenesis inhibitor but also the combination of two angiogenesis inhibitors. The combination of AGM-1470 (20 mg/kg) with 5'-DFUR (200 mg/kg) and with TAM (0.8 mg/kg) markedly suppressed the tumor growth. There was a significant difference in the suppression of tumor growth between the combination group and either drug alone group (p<0.01). No statistical combination effect between AGM-1470 and MPA was found, however MPA markedly reversed the body weight loss induced by AGM-1470. This result will be informative for clinical studies on the combination effect of AGM-1470. PMID- 21597819 TI - A novel re-regulator of cancer growth - a commentary. AB - Tumor cells should not necessarily be viewed as 'alien invaders' that must be killed in order to cure the host harboring them. Rather, the successful re regulation of their growth, even without total tumor eradication, could provide much greater overall benefit to the host. Therefore, the criteria for a meaningful evaluation of clinical benefit of cancer treatment must be re assessed, and the length of survival and its quality should be considered the two most important parameters. Tumor cells differ from the normal 'self' counterparts only in certain respects, often very narrowly, and primarily with regard to the de-regulation of cell growth and proliferation. The potentially reversible overall malignant phenotype is manifested by the growth largely independent of external factors, increased invasiveness, loss of contact inhibition, and development of the metastatic capabilities. This phenotype evolves in time and represents an inherently heterogeneous process. ONCONASE(R), a novel RNase from the eggs of the leopard bb frog (Rana pipiens) has demonstrated, both pre clinically in vitro and in vivo as well as in clinical trials, a broad spectrum of anti-cancer activity. The favorable safety profile (e.g., lack of myelosuppression), broad spectrum of anti-cancer activity, synergistic interactions with multiple drugs, and the ability to induce apoptosis and to overcome multiple drug resistance, make ONCONASE(R) especially attractive as a re regulator of the cancerous growth. PMID- 21597820 TI - Feasibility and tolerance of Cisplatin and Fluorouracil infusion in elderly patients with squamous-cell carcinoma. AB - Many head and neck and esophageal cancers are diagnosed in patients over 65 years old, but limited data are available on the tolerance of elderly patients to chemotherapy protocols designed for adults. We therefore retrospectively evaluated tolerance of cisplatin (100 mg/m(2) day 1) plus fluorouracil (1,000 mg/m(2)/day as a 120 h infusion) in a group of patients over 65 years of age with squamous cell carcinoma (n=20, group A) and compared it with a second group of younger patients (n=20, group B). Baseline patient characteristics were well balanced between the 2 groups. The median age was 69 years (range, 66-76) in group A and 47 years (range, 19-61) in group B. A total of 54 cycles (range, 1-6) and 65 cycles (range, 1-7) were delivered respectively in group A and B. Dose reductions were required in 9% (group A) and in 10% (group B) of the cycles. No toxic death was recorded in either group. No statistical difference in hematological toxicity was observed between the 2 groups of patients. Although the incidence of grade 1-2 renal toxicity was higher in elderly patients (5 vs 1), the difference was not significant (p=0.09). A similar incidence of mucositis (25%), nausea/vomiting (40%) and diarrhea (5%) was observed for each group. In conclusion, selected elderly patients with good performance status and adequate organ function can be safely treated with CDDP and FU without significantly increased toxicity. PMID- 21597821 TI - Instability at microsatellite sequences in spontaneously aborted human embryos provides evidence for a novel mechanism for recurrent miscarriages. AB - Several factors have been proposed to confer a risk for abortion of the embryo. However, the aetiology of spontaneous abortions remains unclear. In the present study we investigated if an increased mutational rate occurs in the embryonic tissue and whether this phenomenon is associated with recurrent miscarriage. The mutational rate was assessed in 30 spontaneously aborted embryos using a bank of 8 highly polymorphic microsatellite markers, each one located on a different chromosome. The microsatellite sequences of DNA extracted from distal sites of each embryo were amplified by the polymerase chain reaction and the electrophoretic patterns were compared. Shifts in the mobility of the microsatellites indicating instability were scored for 12 among 30 (40%) specimens, thus suggesting that microsatellite instability (MI) is a relatively common feature of spontaneously aborted embryonic tissues. Association was found between instability and the absence of normal childbirth: 11 among 18 cases without a normal childbirth exhibited evidence of MI while only one among 12 cases with normal childbirth was positive for MI. Our results suggest that instability at microsatellite sequences which indicate decreased fidelity in DNA replication and repair are associated with the recurrent abortion of the embryo, particularly in cases without a normal childbirth. PMID- 21597822 TI - Human prostatic-carcinoma cells modulate lymphocyte-proliferation by an immunosuppressive activity. AB - We have identified an immunosuppressive activity from the conditioned medium of an androgen-independent human prostatic carcinoma cell line, JCA-1. This activity is constitutively produced by JCA-1 cells and is capable of suppressing normal human peripheral blood lymphocyte proliferation irreversibly in a dose-dependent manner. Immunosuppressive activity was semi-purified by a combination of ion exchange chromatography and gel filtration with an apparent molecular weight of 40-55 kDa. The immunosuppressive activity was not cytolytic to lymphocytes and was sensitive to 56 degrees C, reducing agent as well as to protease digestion. Cell cycle analysis revealed that the suppressive activity did not induce apoptosis, but it prevented some G(1) lymphocytes from entering into the S phase of the cell cycle. PMID- 21597823 TI - Inadequacy of combined 5-Fluorouracil, very-high-dose leucovorin, mitomycin-C and Cisplatin as 2nd-line therapy for advanced colon-cancer. AB - Fourteen patients with metastatic colon cancer which had progressed under fluoro folates chemotherapy were treated with MM-C (10 mg/m(2) on day 1), 5-FU (370 mg/m(2) for 5 consecutive days), l-LV (500 mg/m(2) for 5 consecutive days) and CDDP (70 mg/m(2) on day 4), every 29th day till further disease progression. Neither CR nor PR were observed; 3 patients only had stable disease, while the extant 11 patients progressed. Resulting toxicity was severe. Since no antitumor effects were evidenced in the first 14 patients, the study was discontinued according to commonly accepted criteria. PMID- 21597824 TI - Increased expression and phosphorylation of sh-ptp2 (syp) in human gastric carcinomas. AB - The expression of SH-PTP2 (SYP), a novel protein tyrosine phosphatase with src homology 2, was examined in human gastric carcinoma cell lines and gastric carcinoma tissues as well as corresponding non-neoplastic mucosas by Northern and Western blotting. The expression of SH-PTP2 mRNA was detected in all 8 gastric carcinoma cell lines at various levels. Most of the cell lines expressed SH-PTP2 protein of 70 kd which corresponds to tyrosine-phosphorylated form, whereas only one cell line expressed unphosphorylated form of SH-PTP2; Fourteen (66.6%) of 21 gastric carcinomas expressed SH-PTP2 mRNA at higher level than non-neoplastic mucosas. Furthermore, most of the gastric carcinomas displayed higher levels of tyrosine-phosphorylated form of SH-PTP2, while non-neoplastic mucosas tended to express unphosphorylated SH-PTP2 protein. These results suggest that the increased expression and tyrosine-phosphorylation of SH-PTP2 may participate in stomach carcinogenesis. PMID- 21597825 TI - Sublocalization of smallest common regions of deletion on chromosome 17q12-q23 in sporadic primary breast-tumors. AB - Frequent loss of heterozygosity (LOH) on the long arm of chromosome 17 has been described in breast tumor DNAs by a number of groups, and recent fine genetic mapping and cloning of an inherited breast-ovarian cancer susceptibility locus (BRCA1) to a small region of 17q12-q21 has focused interest on this area. The absence of sporadic mutations in the BRCA1 gene in breast tumors studied so far suggests that there may be other tumor suppressor genes in the region involved in sporadic breast cancer. We studied 28 sporadic breast cancers with 14 highly polymorphic markers on chromosome 17 (2 on 17p and 12 on 17q). Most of the 17q markers are located within the 17q12-q23 region. We confirmed that 50% of tumors have deletions of at least one locus on chromosome arm 17q, and that half the deleted cases probably correspond to monosomies 17 or 17q. The other half correspond to a partial deletion on 17q and were used to identify 2 smallest common deleted regions (SCDR1 and SCDR2) on 17q12-q23. SCDR1 comprised the THRA1 gene, but not the 2 flanking loci tested (D17S250 and D17S800); while SCDR2 was defined by loci GIP and GH. BRCA1 was deleted in half the cases but it is outside the SCDR1. Moreover, breast tumors in young women frequently showed chromosome 17 alterations. PMID- 21597826 TI - P-glycoprotein expression in chronic lymphocytic-leukemia - association with chemotherapy. AB - P-glycoprotein (PgP), a transmembrane protein, has been associated with multiple drug resistance. We examined 42 patients with chronic lymphocytic leukemia immunohistochemically using the monoclonal antibody JSB-1 to determine the prevalence of PgP expression and its relationship with chemotherapy exposure. Of the 42 patients, 31 (74%) had detectable PgP. No relationship was found between PgP expression, patient age, duration of disease or stage. Moderate and strong intensity staining was found in 22% of untreated patients versus 56% patients treated with chemotherapy (p<0.05). Temporal fluctuations in P-glycoprotein staining intensity was seen in 6 of 7 cases which paralleled the initiation or withdrawal of the therapy. PMID- 21597827 TI - Cisplatin-induced alterations of serotonin metabolism in patients with or without emesis following chemotherapy. AB - Serotonin (5-HT)(3) receptor antagonists are very effective in the control of cisplatin induced emesis. Nevertheless, a significant proportion of patients still experience emesis despite the use of these antiemetics. The aim of this study was to evaluate if cisplatin treated patients who vomit differ from patients who are completely protected from emesis with respect to measurable alterations of serotonin metabolism. We measured the urinary excretion of 5 hydroxyindole-acetic-acid (5-HIAA), the main metabolite of serotonin, in 24 patients with 42 courses of cisplatin containing chemotherapies. Patterns of 5 HIAA excretion were compared between patients with emesis and patients who are completely protected from vomiting. Three groups of patients without chemotherapy served as control. The first group did not receive any medication. The second and third group were given a single dose of ondansetron or metoclopramide. The median 5-HIAA/creatinine ratios in the control group ranged from 3.8 to 6.9 with a median of 6.2 (mu g 5-HIAA/mg creatinine). Neither ondansetron nor metoclopramide given without chemotherapy induced significant changes in 5-HIAA excretion patterns. 23 courses (55%) were associated with acute cisplatin-induced emesis. The median interval from the start of the cisplatin infusion to the peak 5-HIAA excretion was shorter in patients with acute emesis, but the cumulative amount of urinary 5-HIAA did not differ between patients with or without emesis. Patients who are efficiently protected from vomiting as well as patients who experience emesis show a comparable increase in urinary 5-HIAA following cisplatin therapy. The present study failed to show elevated 5-HIAA excretion levels occurring later than 24 hours following cisplatin administration. Nevertheless, patients experienced cisplatin-induced delayed emesis. Further studies are warranted to identify the pathomechanisms responsible for delayed emesis as well as that proportion of acute emesis which is refractory to 5-HT3 antagonism. PMID- 21597828 TI - A non-hodgkin-lymphoma of the breast, occurring 20 years after the treatment of a hodgkins-disease. AB - We report on a woman in whom the fortuitous diagnosis of a non-Hodgkin lymphoma of the breast was made. She had been treated 20 years earlier elsewhere for Hodgkin's disease stage III. The remarkable association of an extranodal lymphoma with a previously treated Hodgkin's disease is discussed. PMID- 21597829 TI - Alteration of the C-met oncogene locus in human head and neck-carcinoma. AB - The c-met proto-oncogene encodes the receptor for the hepatocyte growth factor/scatter factor (HGF/SF) which induces eel proliferation and motility. We have analysed the genetic alteration involving the c-met locus on chromosome 7q31 using the pMet H polymorphic probe, in tumor and normal DNA from 87 patients with head and neck squamous cell carcinomas (HNSCC). We report the observation of loss of heterozygosity (LOH) at this locus in 23% of informative cases, contrasting with the previously reported 40% LOH detected in breast cancer. Further, gain of genetic material was also observed in 13% of the HNSCCs. The alterations of c-met gene were not significantly associated with standard pronostic features including tumor size and lymph node status. Involvement of the c-met locus in allelic imbalance, either loss or gain of genetic material, is relatively consistent with complex karyotype patterns detected in head and neck squamous cell carcinomas through previous cytogenetic studies. PMID- 21597830 TI - Protective effects of human interleukin-1 on hematopoietic progenitor cells from L-phenylalanine mustard. AB - The effects of interleukin-1 (IL-1) on protecting both human and murine bone marrow cells were studied using in vitro clonogenic assays, long-term bone marrow cultures and in vivo mouse studies. Incubation with 100 ng/ml human recombinant IL-1 beta for 20 hours prior to a one hour exposure to L-phenylalanine mustard (L PAM) provided significant protection of bone marrow colony forming cells when compared to bone marrow cells not exposed to IL-1. Complete inhibition of colony formation was observed above 40 mu M L-PAM in the absence of IL-1 preincubation; whereas, colonies were still detectable in cultures which were initiated with IL 1-treated bone marrow cells. Similar results demonstrating greater protection with IL-1 incubation from L-PAM were seen when murine bone marrow cells were assayed for long-term culture-initiating cells. Furthermore, IL-1 protects long term repopulating hematopoietic stem cells from L-PAM when studied using an in vivo irradiated mouse assay. In contrast, incubation with IL-1 does not protect colony formation by K562, KG-1 or HL-60 leukemic cell lines implying that protection by IL-1 may be selective. Finally, the protection observed by IL-1 preincubation could be abrogated by incubation with 50 mu M L-buthionine sulfoximine (BSO). This result indicates that IL-1 may increase the amount of glutathione in hematopoietic cells and be responsible for the observed protection from L-PAM. PMID- 21597831 TI - Growth-control of human ovarian-carcinoma cells by insulin-like growth-factors. AB - The role of the insulin-like growth factors (IGFs) in 3 cultured human ovarian cancer cell lines (PEO1, PEO4, PEO14) was investigated. All three cell lines express mRNA for IGF-I and the PEO14 cell line expresses mRNA for IGF-II. Protein expression of IGF-II was demonstrated in the PEO14 and PEO4 cell lines. All 3 cell lines expressed mRNA for the IGF type I, IGF type II and insulin receptors; the presence of type I IGF receptors was confirmed by immuno-cytochemistry. IGF-I and insulin markedly stimulated the proliferation of PEO1 and PEO4 but not PEO14 cells while all 3 lines were insensitive to the addition of exogenous IGF-II. PMID- 21597832 TI - The use of artificial-intelligence neural networks in the evaluation of treatment plans for external-beam radiotherapy. AB - The purpose of our study was to evaluate whether a neural network is capable of evaluating different treatment plans for external radiotherapy produced by a 3D treatment planning system and presented as dose-volume histograms (DVHs). Three radiotherapists evaluated 27 treatment plans for the external radiotherapy of prostatic adenocarcinoma. DVHs for the dose delivered to the rectum and the bladder were presented. A commercially available neural network with 5x10 input nodes and two output nodes was modified to categorize the plans according to the score of the radiotherapists. The DVHs of the treatment plans were used as the inputs and accepted or not accepted were presented as the outputs. A comparison was made with different models for assessing complication probabilities. The neural network was able to accept or not accept the treatment plans according to the scoring made by the radiotherapists. If the radiotherapists disagreed, the network also expressed the span of opinions. Neural networks can be adapted to evaluate 3D dose-planning treatment plans presented as DVHs. It should be noted that the relation between the amount of data and the size of the neural network in this study was not optimal. PMID- 21597833 TI - A randomized study of tamoxifen alone versus tamoxifen plus melatonin in estrogen receptor-negative heavily pretreated metastatic breast-cancer patients. AB - Recent experiments suggest the possibility of modulating the efficacy of cancer endocrine therapy by the pineal hormone melatonin (MLT). In particular, it has been demonstrated that MLT may stimulate estrogen receptor (ER) expression and enhance tamoxifen (TMX) effects other than the antiestrogenic action. Therefore, MLT could amplify the efficacy of TMX also in patients with negative ER. On this basis, a randomized study was performed with TMX versus TMX plus MLT in ER negative metastatic breast cancer patients, who were unable to tolerate further chemotherapy, because of age, low performance status and/or heavy chemotherapeutic pretreatment. The study included 40 ER-negative post-menopausal, metastatic breast cancer patients, who were randomized to receive TMX alone (20 mg/day orally) or TMX plus MLT (20 mg/day orally in the evening). No complete response was seen. Partial response rate was significantly higher in patients treated with TMX and MLT than in those, who received TMX alone (7/19 vs 2/21, p<0.05). Moreover, the percent of survival at 1 year was significantly higher in patients treated with TMX plus MLT than in those treated with TMX alone (12/19 vs 5/21, p<0.01). No MLT-related toxicity was observed; on the contrary, most patients receiving MLT experienced a relief of anxiety and of depression. This preliminary study suggests that the association of the pineal hormone MLT may make TMX effective also in ER-negative metastatic breast cancer patients. PMID- 21597834 TI - Can the loss of negative regulation theory be compatible with the development of hematological malignancies - (review). AB - The hematological malignancies evolution exhibits significant differences with the solid tissue tumor development, especially in the initiation step. The loss of negative regulation theory of carcinogenesis was unambiguously demonstrated in the field of colorectal neoplasia, but up to date, several lines of inquiry failed to imply the dysregulation of suppressor genes as an etiologic event in the pathogenesis of leukemias and lymphomas. Considering the peculiarities of self-renewing hemopoietic cells, we propose in this communication a reconciliation of the loss of negative regulation theory with the blood malignancies development. PMID- 21597835 TI - The effect of hyperthermia and verapamil on primary and metastatic colon adenocarcinoma cell-lines - inhibition of proliferation, cell-cycle distribution and onset of apoptosis. AB - Administration of the combination of hyperthermia and verapamil significantly decreased proliferation of HT-29 and SW-620 cells while hyperthermia or verapamil alone did not cause such growth inhibition. DNA histograms showed no significant changes in the cell cycle distribution of either cell line after hyperthermia treatment. After the administration of verapamil, a significant increase in both cell lines of the G(2)-M fraction was seen at 6, 20, and 30 hours in comparison to control with a concomitant decrease in G(1) phase population. The combination of hyperthermia and verapamil resulted in an accumulation of cells in G(2)-M phase with subsequent release from the arrest and appearence the cells showing fragmentation of chromatin into nucleosomal oligomers, the hallmark of programmed cell death (apoptosis). PMID- 21597836 TI - Silver nucleolar organizer region assessment in tumor-cells from breast-cancer patients treated by extremely-low-frequency magnetic-field. AB - This study assessed the value of silver staining of nucleolar organizer regions (AgNORs) in tumor cells as a potential technique for the estimation of the action of ELF magnetic field on breast cancer. The light and electron microscopy was used for analysis of tissue specimens from 4 breast cancer patients after ELF magnetotherapy and 18 untreated persons with malignant and benign breast lesions. All patients had surgical removal of neoplasms. The mean number of AgNORs and the distribution of cells according to the AgNOR number in tissue samples from patients after successful ELF magnetotherapy were closer to those of persons with benign tumors, as compared to malignant ones. The effect of ELF magnetic field at the electron microscopic level is discussed. PMID- 21597837 TI - Mitogen-induced lymphoproliferative response and phagocytic-activity of monocytes in renal-cell carcinoma patients treated by interferon a alone or in combination with vinblastine. AB - The functions of T cells and monocytes were studied in relation to the clinical stage and clinical course of renal cell carcinoma (RCC) patients, treated by interferon alpha (LFN-alpha). Lymphoproliferative response (LPR) to phytohemagglutinin and phagocytic activity of peripheral blood monocytes were estimated before, immediately after, and six months after completion of therapy with IFN-alpha alone (applied in stage II RCC) or in combination with vinblastine (in stages III and IV). The number of total T cells and their mitogen-induced proliferative response were diminished in all patient groups before therapy, the decrease of LPR being more pronounced in advanced (III and IV) stages of the disease. The pretreatment number of monocytes and their phagocytic activity were increased in RCC patients regardless of clinical stage. The initial level of the lymphocyte and monocyte functions did not correlate with the clinical course of the disease. The pretreatment levels of LPR and phagocytic activity were not changed immediately after IFN treatment, irrespective of the clinical response to therapy. Similar results were obtained six months after therapy; the only exception was the increased LPR in stage III patients, which was unrelated to clinical response to the therapy, since it was seen in patients with progression of the disease. These findings suggest that the pretreatment level of LPR and monocyte phagocytic activity in RCC patients in different clinical stages of RCC were not predictive of the clinical response to IFN therapy. IFN-alpha, as used in this study, had no major influence on LPR and phagocytic activity of monocytes irrespective of the clinical stage or clinical course of the disease. PMID- 21597838 TI - Immunocytochemical analysis of oncoproteins and growth-factors in human-malignant mesothelioma. AB - To understand the mechanism of carcinogenesis of human malignant mesothelioma, the role of oncogenes and growth factors, which are involved in the development of the tumor should be clarified. In this study we investigated immunocytochemical expression of oncoproteins including p53, PAN-RAS, c-myc, c jun, c-erb-B2 and WT-1, as well as growth factor receptors such as PDGF-beta and EGF in original tumor cells obtained from 10 cases of human malignant mesothelioma, since these markers have been suggested immunocytochemically or molecular biologically to be involved in the carcinogenesis of the tumor. We found a high incidence of immunocytochemical expression for c-myc, WT-1, p53 and PDGF-beta receptor in the cells suggesting strongly that these markers are playing certain roles in the development of human malignant mesothelioma. To elucidate this hypothesis, however, molecular analysis of the gene-abnormality in these markers is essential as the next step. PMID- 21597839 TI - Regulation of cll by interleukin-10 - role of antisense IL-10. AB - The role of IL-10 on the in vitro growth of B cells from patients with B-chronic lymphocytic leukemia (CLL) was investigated. Previous work on a murine model of CLL demonstrated that the malignant B-l cells produce significantly higher levels of IL-10 mRNA than normal B-1 or B cells and antisense oligodeoxynucleotides specific for IL-10 mRNA inhibited their growth. In the present study, peripheral blood cells from CLL patients were found to be varied in the amount of IL-10 mRNA present. Several CLL samples underwent apoptosis in response to culturing in the presence of antisense IL-10. There was a correlation between the levels of IL-IO mRNA and the sensitivity to growth inhibition by antisense IL-10. This may indicate that, antisense IL-10 inhibits cell growth in a sub-population of CLL in which IL-10 is an autocrine cytokine. PMID- 21597840 TI - Immunostaining of ductal breast carcinomas with the monoclonal-antibody-h. AB - Twenty cases of infiltrating ductal breast carcinomas were stained with the mouse monoclonal antibody H, an IgM, in order to estimate the distribution of the epitope (a carbohydrate moiety) recognized by this antibody in the malignant cells. The results showed that in all cases examined, the epitope was present in the cytoplasm of the neoplastic cells arranged mainly in a diffuse pattern. To identify the polypeptides that carry this epitope, we used extracts from the MCF 7 human breast carcinoma eel line in immunoblotting experiments. In addition to cytokeratin 8 this epitope was also found on five polypeptides originating from Triton X-100-soluble (M(r)x10(-3) of 232, 67, and 37) and from the Triton X-100 insoluble (M(r)x10(-3) of 51, and 50) fractions, respectively. The contribution, if any, of these polypeptides to the staining patterns is not known. These data reveal the existence of a common epitope between cytokeratin 8 and other cellular polypeptides. They also serve as a note of caution in the interpretation of immunohistochemical staining when anti-cytokeratin antibodies are used. PMID- 21597841 TI - Integrin b4 expression in peripheral-nerve tumors. AB - The alpha 6 beta 4 integrin complex is expressed in epithelial, endothelial and nerve cells. We analyzed the immunohistochemical expression of the beta 4 subunit in normal peripheral nerves, in neurofibromas associated with type 1 neurofibromatosis and in sporadic neurofibrosarcomas. In normal peripheral nerves (4 samples), the beta 4 integrin was diffusely expressed at the level of the perinevrium and at the interface between axons and Schwann cells. In neurofibromas (6 cases), beta 4 was undetectable or markedly decreased relative to normal peripheral nerves. Neurofibrosarcomas (3 cases) were immunohistochemically negative for beta 4 expression. These observations suggest that a down-regulation of the alpha 6 beta 4 integrin is associated with the neoplastic progression of peripheral nerve tumors. PMID- 21597842 TI - Neural networks in chemotherapy-induced delayed nausea - a pilot-study using positron emission tomography. AB - Acute but not delayed nausea is well controlled by serotonergic receptor antagonists implicating different mediation of delayed as compared to acute nausea and vomiting. We report on differences in central neural activity using positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF) in two chemotherapy treated cancer patients during delayed severe and mild nausea. Subtractive image methodology where rCBF during moderate nausea was subtracted from rCBF during mild nausea revealed increased neural activity in the anterior hypothalamus, the vermis, the anterior cingulate gyrus and the thalamus as well as decreased activity in the pens and the substantia nigra. These results may reveal central nervous system substrates underlying delayed nausea and vomiting and are consistent with an interpretation in terms of activation both of serotonergic and noradrenergic but not dopaminergic transmitter systems. It is concluded that noradrenergic mediation of delayed nausea is not an unlikely possibility. PMID- 21597843 TI - Expression of gamma-glutamyl transpeptidase during pouch carcinogenesis is not oncofetal. AB - gamma-glutamyl transpeptidase (GGT) is not histochemically detectable in normal adult hamster pouch epithelium but markedly increased during pouch carcinogenesis. The possibility that the increase in GGT activity during pouch carcinogenesis reflects dedifferentiation of cells remains to be answered. The distribution of GGT in fetal and neonatal hamster tissues is unknown. The objective of this study was to determine GGT activity histochemically during hamster pouch development and during development of hamster oral and peri-oral structures, and several extra-oral tissues and organs. High GGT activity was seen mainly in epithelial cells exhibiting marked secretory or absorptive functions. Occasionally, GGT activity was also seen in mesenchymal cells. No GGT activity was noted at any stage of pouch development. The results suggest that the expression of GGT during pouch carcinogenesis represents an acquired phenotype instead of re-expression of a phenotype that is present during normal embryonic development. The results also support the hypothesis that GGT plays an important role in transportation. PMID- 21597844 TI - Enhancement of benzo(a)pyrene metabolism mediated by retinol acetate in cultured human bronchial epithelial-cells. AB - As suggested by animal studies and human epidemiological data, retinoids possess significant cancer chemopreventive activity. Although the majority of studies in this area have focused on the ability of retinoids to prevent the promotion or progression of carcinogenesis, a significant amount of data suggest retinoids can alter initiation events. In the current report, we have evaluated the potential of retinol acetate to modulate benzo(a)pyrene metabolism in low-passage human bronchial epithelial cells in monolayer cultures, Of 16 different cell cultures, benzo(a)pyrene metabolism was increased in 14, decreased in one, and unchanged in one, when retinol acetate was added to the media, In a preliminary study with one of the cell cultures in which retinol acetate significantly enhanced benzo(a)pyrene metabolism, binding of carcinogen metabolites to;DNA was unaffected, Since retinoids are known cancer chemopreventive agents and carcinogen binding to DNA is the key event in the initiation of carcinogenesis, these results suggest that retinoids may decrease carcinogenic risk by increasing the detoxification of procarcinogens such as benzo(a)pyrene ina manner that does not yield a concomitant increase in damage to critical cellular targets such as DNA. PMID- 21597845 TI - Primary lymphoma of the liver - a case-report and a review of the literature. AB - A case of primary lymphoma of the liver in a 72-year-old man is reported. The patient showed a three to four month history of abdominal ache, low grade fever, and weight loss. The presence of a large mass occupying the V and VT hepatic segments was demonstrated; no other organs were involved and no evidence of lymphoadenopathy was found. Laboratory tests showed a remarkable increase in ESR, LDH and alkaline phosphatase while CEA and alpha-1 fetoprotein were within the normal values. Two ultrasound-guided needle biopsies on the hepatic lesion did not produce any significant tissue for diagnosis. Therefore the V and VI hepatic segments were excised; a hard, greyish mass with the largest diameter of 6.5 cm, was found at laparatomy. Histology of the surgical specimen showed the presence of a malignant non-Hodgking's B-cell lymphoma, centroblastic-centrocytic, diffuse type (working formulation: G) of intermediate grade of malignancy. Staging was completed with lymphography, and bone marrow biopsy; both proved normal. After the operation adjuvant chemotherapy was commenced (COP for six cycles). Follow-up has so far shown no signs of recurrence after 24 months. In conclusion, the diagnosis of primary lymphoma of the liver is very difficult and is often reached only after histologic evaluation of the surgical specimen. Moreover, this disease has a much more favourable prognosis than the hepatocellular carcinoma and other primary or secondary liver cancers; therefore accurate investigations are important to reach the correct diagnosis. PMID- 21597846 TI - Mutagen sensitivity and cancer susceptibility in patients with multiple primary cancers. AB - Thirty-two patients with multiple cancers were evaluated for in vitro sensitivity to mutagens and were compared with normal controls, Mutagen sensitivity was evaluated by exposing lymphocytes to mitomycin-C in vitro and estimating the mitomycin-induced chromosomal gaps and breaks (G/B) and sister chromatid exchanges (SCE) per cell. The results show significant differences between control and patient groups when spontaneous and induced G/B and SCE were evaluated. In addition, establishing the limit of normality for G/B and SCE, among the control group, the examined patients show largely positive levels in respect to both of the parameters used. In this study we discuss the usefulness of mutagen sensitivity as an indirect measure of DNA repair and genetic susceptibility to multiple primary cancers. PMID- 21597847 TI - Adriamycin and Cisplatin induce apoptosis in 2 lines of human gastric-cancer cells (mkn-28 and hsc-39). AB - Many anticancer agents induce an active process that leads to cell death, known as, apoptosis, in sensitive tumor cells. The fragmentation of DNA, an indicator of apoptosis, was analyzed in two different lines of human gastric cancer cells (HSC-39 and MKN-28) that had been exposed to adriamycin and cisplatin. The fragmentation of DNA was detected in HSC-39 cells (signet ring cell gastric carcinoma) after a 1-h incubation with 0.18 mu M and after a 6-h incubation with 0.09 mu M adriamycin, as well as after a 1-h incubation with 1.67 mu M cisplatin. However, in MKN-28 cells (moderately differentiated gastric adenocarcinoma), the fragmentation of DNA was not detected after a 6-h incubation with 0.18 mu M adriamycin or a 6-h incubation with 3.33 mu M cisplatin. The results suggest that signet ring cell gastric carcinoma is more sensitive to adriamycin and to cisplatin than moderately differentiated gastric adenocarcinoma. PMID- 21597848 TI - Oral escalating dose of cyclosporine-a combined with 4-epidoxorubicin in advanced colorectal-cancer - a phase-I study. AB - Multidrug resistance, a major factor in the resistance to drugs, can be reversed by cyclosporin A. It is generally given by intravenous route. The aim of the present study was to assess the possibility of achieving useful plasma levels, giving cyclosporin A orally in advanced colorectal cancer patients treated with 4 epidoxorubicin. Cyclosporin A was given orally twice a day, for four days. The starting study dose was 5 mg/kg. Dose in cohorts of 3 patients was escalated to 10, 15, 20, 30, 40 mg/kg if the previous dose was not able to determine the target blood level (2,000 ng/ml). Cyclosporin A blood levels were analyzed by a specific fluorescence polarization immunoassay method (TDx; Abbot Laboratoires, North Chigaco, IL). 4-epidoxorubicin was given at a fixed dose of 75 mg/m(2), every 3 weeks. None of the dose levels of cyclosporin A given orally produced the target blood level. Only two patients, receiving cyclosporin at a dose of 30 mg/kg, and two after a CsA dose of 40 mg/kg, presented blood levels higher than 1,000 ng/ml, but however, lower than 1,500 ng/ml. In conclusion, the oral route of administration of cyclosporin does not seem recommendable in order to reverse multidrug resistance because it is not able to produce sufficient plasma levels. PMID- 21597849 TI - Analysis of mechanisms of Cisplatin resistance in 3 pairs of human tumor-cell lines expressing normal and resistant responses to Cisplatin. AB - Three pairs of human tumour cell Lines each having a cisplatin sensitive parental cell line (normal) and a cisplatin resistant derivative were tested for their cisplatin responses and expression for three reputed mechanisms of resistance. In each case, the derivative cell lines showed resistance to cisplatin when treated either in exponential or plateau growth phase. For both the resistant and the normal cell line there was greater resistance to cisplatin treatment when cells were treated in exponential growth phase. Mechanisms of resistance were expressed in all three resistant variants. The cervical carcinoma resistant variant expressed higher GSH levels and lower cisplatin uptake levels but not elevated polymerase levels. The other two variant cell lines for the glioma and the lung cancer expressed all three of the mechanisms (increased GSH, decreased cisplatin uptake and increased polymerases) associated with resistance. There was no correlation to the level of resistance expressed and the number of mechanisms expressed but the change in response of the parental line to becoming a resistant variant may be related to the basal level of expression of some of the factors that are associated with resistance. PMID- 21597850 TI - Cytotoxic impacts on the tumorigenesis and transplantability of ovarian teratoma in lt/sv mouse. AB - The incidence and transplantability of ovarian teratoma in LT/Sv mice were examined following cisplatin treatment at the age of 16 days, and compared to those in the control group. Cisplatin had not affected the emergence of egg cleavage, which simultaneously appeared in the mouse ovaries in both groups. Although 7 teratomas, occasionally transplantable, developed in the control mice aged over 30 days, only 2 tumors occurred in cisplatin-treated mice at the age of 120 days and they were not transplantable. The results suggest that cisplatin might influence the tumorigenic process after egg cleavage, or transplantability of teratoma. PMID- 21597851 TI - Stereologic estimation of nuclear volume in glottic squamous-cell carcinoma. AB - By means of a newly developed stereologic model, the point sample intercept technique, we estimated the mean nuclear volume (nuclear (V) over bar v) in 106 T1-4 glottic carcinomas. The original formalin fixed, routinely processed H&E stained diagnostic sections were used. The overall average nuclear (V) over bar v was 782 mu m(3). Neither T- nor N-stage revealed significant differences in nuclear (V) over bar v. Patients dying from glottic carcinoma had a higher nuclear (V) over bar v compared to survivors/patients dying from intercurrent diseases, 917 and 713 mu m(3) respectively (p=0.0042). The distribution of nuclear (V) over bar v suggested that a cut-off level of 900 mu m(3) would give a better separation between clinically favourable and poor prognostic cases (p=0.0004). Both T- and N-stage were highly significant in relation to survival by univariate analysis. Multivariate analysis retained only N-stage (p=0.0001) and nuclear (V) over bar v (p=0.0022). Our results suggest that nuclear (V) over bar v is a strong independent prognostic marker in glottic carcinomas. PMID- 21597852 TI - Phosphotyrosine phosphatase-activity in membranes from endometrial carcinoma. AB - The phosphotyrosine phosphatase (PTPase) decreases the level of phosphotyrosine of intracellular protein substrates, thereby reversing the action of tyrosine phosphorylation to promote cell growth and differentiation. We determined the activities of PTPases in normal and cancerous tissues of the endometrium. The PTPase activity was determined with the synthetic substrate p-nitrophenyl in a spectrophotometric assay. Over 90% of the activity was particulate and the values in proliferative- and secretory-phase endometria and endometrial carcinomas fell within a similar range. This work demonstrates the existence of PTPase activity, counterbalancing the growth-promoting effects of tyrosine kinases, in endometrial carcinoma. PMID- 21597853 TI - Vascular endothelial growth-factor production is stimulated in response to growth factors in human glioma-cells. AB - Neovascularization is essential for tumour growth and is mediated by physiological substances produced by tumours. Vascular endothelial growth factor (VEGF) is one such potent angiogenic factor. Human gliomas, the most important class of intrinsic brain tumours, express VEGF both in vivo and in vitro. Factors involved in the control of VEGF production by glioma cells are not well known. In this study, we investigated the role of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and platelet derived growth factors (PDGF) on VEGF production by four different glioma cell lines in vitro. With the exception of PDGF A/A and B/B in one cell line, all growth factors differentially stimulated VEGF production in all cell lines investigated. These data suggest that VEGF production in human glioma may be regulated by other growth factors which are also known to be expressed in such tumours. PMID- 21597854 TI - Efficacy and tolerability of cancer neuroimmunotherapy with subcutaneous low-dose interleukin-2 and the pineal hormone melatonin - a progress report of 200 patients with advanced solid neoplasms. AB - The recent advances in psychoneuroimmunology have demonstrated the existence of a psychoneuroendocrine control of the antitumor immunity. Our previous preliminary studies indicated the possibility of amplifying the biological and therapeutic efficacy of IL-2 cancer immunotherapy by immunomodulating neurohormones, mainly the pineal indole melatonin (MLT), in most advanced solid tumors, including those which generally do not respond to IL-2 alone. This study reports on the results obtained by low-dose IL-2 plus MLT in 200 patients with advanced solid neoplasms, for whom no other effective standard therapy was available. Non-small cell lung cancer, pancreatic adenocarcinoma, hepatocarcinoma, colon cancer and gastric cancer were the neoplasms most frequently detected in our patients. In addition, all patients had a life expectancy less than 6 months. IL-2 was given subcutaneously at 3 million IU/day for 6 days/week for 4 weeks; MLT was given orally at 40 mg/day. In non-progressing patients, a second cycle was given after a 21-day rest period; then, patients underwent a maintenance period consisting of one week of therapy every month until progression. A complete response (CR) was achieved in 4 patients (hepatocarcinoma 2; pancreas 1; gastric cancer 1), a partial reasponse (PR) was achieved in 36 patients (lung 12; liver 6; stomach 4; pancreas 3; colon 3; breast 2; miscellaneous 6). Tumor response rate (CR+PR) was 40/200 (20%) patients. Longer than one year survival was achieved in 79 (39%) patients. Toxicity was mild in all patients, and therapy was administered as a home therapy. The present study confirms in a great number of patients the possibility to induce objective tumor regressions in most advanced solid tumor histotypes by low-dose IL-2 plus MLT. Thus, immunotherapy with IL-2 and MLT may be considered as a new well tolerated and effective therapy of almost all advanced solid tumors, including those which do not respond to IL-2 alone or to chemotherapy. PMID- 21597855 TI - Prospective multicenter study on the clinical utility of ca-72.4 in postmenopausal patients with pelvic mass. AB - The study objective was to evaluate the sensitivity and specificity as well as the positive predictive value and negative predictive value of CA 72.4 and CA 125 determination, separately and in combination, for diagnosing ovarian tumors in post-menopausal women with pelvic mass. The 299 patients recruited in this study underwent gynecological examination, plasma determination of CA 72.4 and CA 125, and laparotomy with histological definition of pelvic mass. CA 72.4 assay values were under 3.9 U/ml in 194 cases (70.8%); values ranged from 3.9 to 4.5 U/ml in 7 cases (2.5%) and were greater than 4.5 U/ml in 73 cases (26.6%). CA 72.4 assay was positive (>4.5 U/ml) in 56 cases (57.1%) of malignant ovarian pathology, in 4 cases (25%) of malignant extra-ovarian pathology as well as in 9 cases (7.1%) of benign ovarian pathology and in 4 cases (11.8%) of benign extra-ovarian pathology. With a cut-off at 3.9 U/ml, CA 72.4 showed a specificity of 91.3% and a sensitivity of 62.2%, whereas with a cut-off at 4.5 U/ml specificity was 92.9% and sensitivity 57.1%. Results of CA 125 assay for diagnosing a pelvic neoplasia (ovarian or extra-ovarian), showed a specificity of 85.3% and sensitivity of 68.8%. The agreement of the two markers (CA 125 and CA 72.4) as negative or positive shows a specificity of 77% and a sensitivity of 84.7% for ovarian cancer and a specificity of 73.5% and sensitivity of 75% for the diagnosis of pelvic neoplasias. PMID- 21597856 TI - The use of peripheral-blood hematopoietic progenitors mobilized with standard dose chemotherapy plus granulocyte-colony-stimulating factor to support multicyclic dose-intensive chemotherapy for advanced breast-cancer. AB - This study was aimed at determining: (a) the degree of mobilization of peripheral blood hematopoietic progenitors (PBSC) induced by a single course of standard dose chemotherapy (CT) followed by G-CSF and the feasibility and safety of the administration of multiple courses of intensified CT with repeated PBSC reinfusions; (b) the relationship between the number of mononuclear cells (MC) in S-phase of the cell cycle (as evaluated by DNA flow cytometry, FCM), the CRT-GM and the CD34(+) cells in the leukapheresis product. Six patients with metastatic breast cancer received a course of standard FEC (5-FU 600 mg/m(2), epirubicin 75 mg/m(2), cyclophosphamide, CTX, 600 mg/m(2), day 1) followed by G-CSF (5 mu g/kg twice a day, from day 3 until leukapheresis), which served as both initial treatment for their disease as well as the PBSC mobilization technique. Collected PBSC were fractionated and reinfused, without G-CSF, following each of further 5 subsequent intensified FEC (HD-FEC: 5-FU 750 mg/m(2), epirubicin 100 mg/m(2), CTX 1,000 mg/m(2)) courses planned at 21-day intervals. The individual hematopoietic reconstitution curves showed superimposable profiles for all patients, and the leukaphereses were performed between days 7 and 10 after the first CT course. A median of 18.8x10(9) (10.4-35.6) MC, 9.3 (2.6-23.3) CD34(+) cells x 10(6)/kg body weight and 9.8 (1.6-27.3) CFU-GM x 10(4)/kg body weight were collected from each patient (with 1 or 2 phereses). All patients received the planned 5 courses of HD FEC followed by PBSC reinfusion, without experiencing haematological cumulative toxicity >WHO grade 3 for WBC and >grade 2 for PLT. No >grade 3 non-hematological toxicity was recorded. There were no treatment-related delays in CT administration so that the delivered average relative dose-intensity (ARDI) was 1.65. A good correlation was seen between the percentage of MC in S-phase and the number of CFU-GM (R(2)=0.566, p<0.0065) or the number of CD34(+) cells (R(2)=0.625, p<0.0031) in the leukapheresis product. A single course of standard FEC+G-CSF is effective in mobilizing sufficient amounts of PBSC to support 5 additional courses of HD-FEC, which could represent an alternative to single, myelo-suppressive CT programs. DNA analysis by FCM should be further investigated as a rapid method for PBSC quantification, since proliferating MC and CFU-GM were closely related. PMID- 21597857 TI - Inhibition of experimental metastasis of human adenocarcinoma by cilostazol, a platelet phosphodiesterase inhibitor. AB - Cilostazol, an inhibitor of platelet phosphodiesterase, was used to inhibit the platelet aggregating potential and metastasis of human adenocarcinoma cell lines. In vitro platelet aggregation potential of HAL8 and HAL33 cell lines was inhibited by cilostazol in a concentration dependent manner. Fatal acute thromboembolism of nude mice induced injection of HAL8 and HAL33 cell was completely inhibited by cilostazol/10 mg/kg p.o. Retention of injected (125)IdUrd labeled cells in the lungs was also inhibited by cilostazol pretreatment. Cilostazol given 2 h before cell injection inhibited by 87 and 100% respectively, experimental lung metastasis of HAL8 and HAL33. Cilostazol given 72 h after cell injection had no effect on HAL8 and HAL33 metastasis. These results show that platelet aggregation of HAL8 and HAL33 cells play an important role in metastatic systems and that cilostazol inhibits human cancer metastasis. PMID- 21597858 TI - Hpv detection in stained cytological cervical specimens and correlation with cytology and histology. AB - It has been suggested that detection of high risk human papillomavirus (HPV) in low grade cervical intraepithelial neoplasia contributes to transition to high grade lesions and cancer. Currently, the PAP smear is the primary screening tool to identify women with cervical disease, specifically cervical intraepithelial neoplasia (GIN). In the present study we examined the utility of HPV detection and typing by PCR, in women with cytological and/or histological evidence of low grade squamous lesion (LGSL), using stained PAP cervical smears. HPV infection was confirmed in 21 out of the 31 (68%) specimens examined. PMID- 21597859 TI - Idarubicin in the intravesical treatment of superficial transitional-cell carcinoma of the bladder (ta-t1) - a phase I-ii study. AB - Local recurrences of superficial transitional cell carcinoma of the bladder (TCCB) can be significantly reduced by intravesical treatment following transurethral resection (TUR) but they are not fully abolished. There is a need to gain experience with new agents. Anthracyclines, such as doxorubicin and epirubicin, have been clearly demonstrated to be active against superficial TCCB by intravesical route. Idarubicin is an anthracycline, much more lipophilic than doxorubicin, inhibiting tumour cell growth at lower concentrations. The aim of this study was to evaluate the tolerability and the ablative efficacy on a marker lesion of weekly intravesical instillations of idarubicin given at different doses and concentrations. Seventeen patients, affected by superficial TCCB, Ta-T1 G1-G2, after TUR of all tumours except one, that was used as a 'marker lesion', were treated intravesically with idarubicin weekly for two months. The drug, in the first 4 patients, was administered at the dose of 15 mg diluted in 30 mi of normal saline solution and maintained in the bladder for one hour. Because of severe chemical cystitis, the dose was reduced to 10 mg in 40 mi in the following 13 patients. The study was closed because of the severe local toxicity. In eight (47%) patients the treatment was interrupted for local toxicity between the first and sixth week and in 5 more patients pharmacological therapy was required because of severe chemical cystitis. No systemic toxicity was evident. Three patients achieved a complete response. Our experience shows that idarubicin is not indicated in the intravesical therapy of superficial TCCB because of severe chemical cystitis limiting the administration of doses able to explicate a relevant antitumoral action. PMID- 21597860 TI - Human papillomavirus type-16 DNA integration in nuclear matrix and chromosome scaffold associated DNA in a cervical-carcinoma cell-line. AB - MARs (matrix attachment region) and SARs (scaffold attachment region) are fragments of DNA that associated with nuclear matrix and chromosome scaffold even after extensive removal of most of the nuclear proteins and chromatin. The present study showed the association of human papillomavirus type 16 DNA with these fragments by polymerase chain reaction in a cervical carcinoma cell line, CC3/CUHK3. This finding proposed an alternative evidence for the elevated transcription rate of the viral genome in transformed cells as nuclear matrix has been proposed to be sites of DNA replication and transcription. PMID- 21597861 TI - Myocardial-infarction after adjuvant chemotherapy for resected stage-ii nonseminomatous testicular cancer. AB - Although acute toxicity of cisplatin-based chemotherapy of germ cell tumors is considerable, major vascular complications have been reported infrequently. This report describes the case of a 36-year-old man developing myocardial infarction after the first cycle of adjuvant cisplatin-based chemotherapy for resected stage II testicular cancer. A close temporal association between the administration of chemotherapy and the vascular event suggests a cause and effect relationship. A drug-induced endothelial cell damage may be an important pathogenetic factor. Although reports on vascular accidents following treatment of testicular cancer raise concern with regard to the safety of chemotherapy, at present the very low incidence of such complications should not enter into therapeutic decisions. PMID- 21597863 TI - Expression of messenger-RNA cd44 splice variants in primary colon-cancer and liver metastases. AB - CD44 splice variants have been implicated in metastasis. We studied CD44 variants in 39 patients with colonic neoplasia and 8 without malignant disease using RT PCR. CD44 splice variants were detected in most liver metastases and primary tumours and expression was unrelated to lymph node involvement. Non-neoplastic tissue was negative for variant expression. The finding that virtually all primary colorectal tumours expressed the variants studied, suggests that this early expression of polymorphism is not sufficient to confer metastasis in colorectal cancer. PMID- 21597862 TI - Prostate-specific antigen changes before and after administration of an angiogenesis inhibitor (tnp-470). AB - A 61-year-old man with progressive prostate cancer after initial hormonal therapy was treated with TNP-470, an experimental agent with potent antiangiogenesis properties. During the period of TNP-470 treatment, the concentration of serum prostate-specific antigen (PSA) rapidly increased from 28.4 to 89.9 ng/ml. After termination of TNP-470 therapy, the concentration of PSA decreased from 89.9 to 10.3 ng/ml. This pattern of PSA change was previously unanticipated and may eventually provide additional insight into the pharmacological actions of TNP 470. PMID- 21597864 TI - Characterization of the protein protecting RNA from Acid precipitation and its evaluation as tumor-marker in gastrointestinal and gynecological cancer. AB - In a previous study, we observed increased protective activity against acid precipitation of poly (U) in the serum of tumor bearing mice and hepatoma patients. In the present study we purified and partially characterized the protein responsible for this phenomenon and measured the activity in the serum of patients with various cancers. Evidence is presented that this protein forms a complex with serum ribonucleases which results in the inactivation of enzymes and protection of RNA from acid precipitation. The serum protective activity against acid precipitation of poly (U) was measured in 37 patients with gastrointestinal cancer and 79 with gynecological cancer, along with 15 male subjects with nonmalignant diseases of the gastrointestinal system, 15 with uterine leiomyoma, 19 healthy men and 30 healthy women from the hospital personnel. The mean values found in patients with various tumors were about three times higher than those found in healthy individuals, while no significant overlapping of values was observed between cancer patients and controls. On the other hand, the activity was not increased in patients with nonmalignant diseases of gastrointestinal system and uterus. PMID- 21597865 TI - Genotypic and phenotypic alterations of p53 in head and neck squamous-cell carcinoma. AB - p53 is the most frequently altered suppressor gene in human cancers. The genotypic and corresponding phenotypic abnormalities of this gene in head and neck squamous cell carcinoma (HNSCC) remain undefined. We analyzed the loss of heterozygosity (LOH) by restriction fragment length polymorphism (RFLP) at three polymorphic loci in the p53 gene and performed immunohistochemistry (MC) for its protein on paraffin-embedded tumor tissue from 20 previously sequenced tumor specimens. LOH was noted at one or more of the three polymorphic sites within the p53 gene in 12 (67%) of the 18 informative samples. Concordance between LOH and mutations was observed in 14 (78%) cases. Twelve (60%) tumors with point mutations were immunohistochemically reactive to p53 antibody and two (10%) lacked both genetic and immunohistochemical alterations. In six tumors (30%) contradictory results between immunohistochemistry and molecular analysis were observed. Our data indicate that: (i) simultaneous deletion and mutation of both p53 alleles was observed in the majority of head and neck squamous carcinomas and implicate this gene in the oncogenesis of these neoplasms, (ii) p53 immunohistochemical analysis may not fully account for the different molecular alterations of this gene, and (iii) no correlation between p53 abnormalities and clinicopathologic or DNA content characteristics of HNSCC was found. PMID- 21597867 TI - Cell-kinetics and the in-vivo vs in-vitro response of human tumors to chemotherapy drugs - a commentary. AB - The response of tumors to chemotherapy is complex. Of the many factors that affect the in vivo response to drugs, cell proliferation kinetics and intrinsic chemosensitivity play important roles. The response of primary tumor cells to drugs in vitro is likewise complex. Data from this laboratory shows that quiescent reproductive cells from fresh tumors are recruited into the cell cycle within the first four days of culture. As quiescent cells are inherently chemoresistant, their recruitment into the cell cycle during incubation artifactually increases drug sensitivity and complicates the interpretation of sensitivity or resistance. It is suggested that the limited positive predictive accuracy and the poor impact on survival of chemosensitivity assays may be improved by considering cell proliferation kinetics in the interpretation of in vitro chemosensitivity measurements. PMID- 21597866 TI - Cisplatin, 5-Fluorouracil, and leucovorin in the therapy of adenocarcinomas of the pancreas. AB - Pancreatic cancer is resistant to most chemotherapeutic regimens. Based upon evidence of synergy between 5-fluorouracil (5-FU) and cisplatin (CDDP), and of enhanced 5-FU activity in the presence of leucovorin in other neoplasms, a phase II study of CDDP, 5-FU, and leucovorin was conducted to determine the efficacy of this regimen in patients with unresectable adenocarcinomas of the pancreas. Nineteen patients were enrolled, and all were evaluable for toxicity and response. One complete and two partial responses were observed (15.8%). Adverse effects were reversible and tolerable. This regimen has limited activity against pancreatic cancer, and cannot be recommended as standard therapy in this disease. PMID- 21597868 TI - A pilot-study of Paclitaxel in previously treated patients with metastatic unknown primary carcinomas. AB - We enrolled 12 patients in a pilot phase II study to evaluate the efficacy and toxicity of paclitaxel as a single agent in the salvage treatment of patients with metastatic unknown primary carcinoma (UPC). Patients were given 175 mg/m(2) of paclitaxel as a three-hour infusion. One patient was enrolled into the study with a diagnosis of poorly differentiated carcinoma but was found after another biopsy to have a soft tissue sarcoma and was therefore not included in this study. All patients had progressive disease after receiving at least one prior chemotherapy regimen containing cisplatin. Two patients had also received radiation therapy. Seven patients had adenocarcinomas, two patients had poorly differentiated adenocarcinomas and two had poorly differentiated carcinomas (PDC). Four patients experienced grade IV granulocytopenia and two patients experienced grade II nausea and vomiting. No responses were observed, and the study was terminated without enrolling more patients. At the dose level used in this study, paclitaxel was inactive in the treatment of patients with UPC whose cancer was resistant to cisplatin. PMID- 21597869 TI - Acute hypertensive crisis following octreotide administration in a patient with malignant pheochromocytoma. AB - A patient with a known history of resected pheochromocytoma was evaluated for recurrent paroxysmal hypertension. The recurrent tumor was localized by magnetic resonance imaging and by somatostatin receptor scintigraphy. Since this scintigraphy demonstrated the presence of somatostatin receptors, empiric treatment with the somatostatin analogue octreotide was initiated in an attempt to stabilize catecholamine secretion prior to attempted surgical resection. The patient experienced a paradoxical reaction manifested by an acute hypertensive crisis which was rapidly responsive to intravenous nicardipine. Stimulation of such a hypertensive crisis by octreotide has not previously been reported. The etiology of this reaction is unclear. We conclude that octreotide and other somatostatin analogues should be administered with extreme caution to patients with known or suspected pheochromocytomas. PMID- 21597870 TI - A phase-I study of cpt-11, weekly bolus 5-fu and leucovorin in patients with metastatic cancer. AB - CPT-11 is a topoisomerase I inhibitor with activity against colorectal cancer. This study was designed to explore the potential for combining CPT-11 with fluorouracil and leucovorin. 5-FU (500 mg/m(2)) and leucovorin (500 mg/m(2)) were administered for 4 consecutive weeks and CPT-11 was given on weeks 1 and 4 of each 6 week cycle. The starting dose of CPT-11 was 25 mg/m(2) and the dosage was escalated by increments of 25 mg/m(2) in cohorts of 3 patients. Nine patients were treated on study. Grade 4 diarrhea was the dose limiting toxicity at 50 mg/m(2). Alternative strategies to combine CPT-11 with 5-FU and leucovorin are being explored. PMID- 21597871 TI - Diagnostic usefulness of 5 tumor-markers in patients with primary lung-cancer. AB - Thymidine kinase (TK), carbohydrate antigen 19-9 (CA 19-9), carbohydrate antigen 125 (CA 125), squamous cell carcinoma antigen (SCC) and tissue polypeptide antigen (TPA), were evaluated in 104 untreated patients with primary lung cancer acid 55 patients with benign lung disease. The mean concentrations of TPA and CA 125 were significantly higher in lung cancer patients than in benign controls (p<0.001). The concentrations of all the tumor markers were well correlated with the stage of lung cancer. In respect to sensitivity, specificity and accuracy, TPA was superior to the other tumor markers tested (70.2%, 88.8% and 75.8% respectively). When TPA was combined with the other markers, sensitivity increased from 70.2% to 98%, but as the number of combined markers became larger, specificity decreased (from 88.8% to 40%). Nevertheless, the combination of TPA and CA 19-9 showed significantly higher sensitivity in patients with resectable non small eel lung cancer (NSCLC) and limited small cell lung cancer (SCLC) than TPA alone (87% vs 49% and 88.8% vs 44.4% respectively) without significant differences in specificity. The relative possibility of lung cancer was 15% when one tumor marker was positive. This possibility increased to 82%-100% when more than three markers were positive. PMID- 21597872 TI - Biochemical modulation of tumor-growth, metastasis and host metabolism. AB - Exogenous nutrients, hormones and metabolites can significantly alter tumor growth, metastasis, and host nutritional status. Arginine, serine and methionine are critical amino acids required for protein, DNA and RNA synthesis and, thus, for cellular proliferation. To determine the effect of these specific amino acids on host metabolism, primary tumor growth and metastasis, 48 Lewis rats bearing the mammary adenocarcinoma MAC-33 were randomized to receive similar diets with 3% supplements of serine, arginine, methionine or glycine (control). After 25 days on each diet, animals were sacrificed to determine primary tumor biochemical composition and growth kinetics, number of lung metastases and carcass weight. A significant reduction in lung metastases occurred with serine and methionine supplementation (p<0.01) with no significant change in primary tumor size. However, increased mortality (p<0.001) and low carcass weight (p<0.05) were found in the methionine group indicating significant host toxicity. Serine-supplemented animals had a mortality rate and carcass weight comparable to the control group. Arginine supplementation had no effect on primary tumor growth, metastasis or carcass weight; however, increased mortality was observed in this group compared to controls. These results suggest that serine supplementation selectively supports host growth and inhibits metastasis in tumor-bearing animals. This study demonstrates the potential to differentially effect host and tumor growth with exogenous amino acid supplements. PMID- 21597873 TI - Expression of vascular endothelial growth-factor in the cyst fluid of human cerebral gliomas. AB - Vascular endothelial growth factor (VEGF) or vascular permeability factor (VPF) has been shown to play a key role in angiogenesis in several solid tumours including human brain neoplasms. Its expression has also been found to be correlated to malignancy in the major class of these tumours, gliomas. Moreover, it has been suggested that cyst fluids (CFs) associated with human gliomas may contain a permeability factor responsible for the formation of brain edema and disruption of the blood-brain barrier generally observed in these tumours. We demonstrate that VEGF is present in low and high grade gliomas of seven patients. We also show that VEGF concentration increases with increasing malignancy of the tumours. Although further cases should be investigated, these results suggest that the amount of CF-VEGF may be of value in the diagnosis of human gliomas. PMID- 21597874 TI - Thyroid-nodules in the elderly - clinical management and incidence of malignancy as determined by fine-needle aspiration biopsy. AB - The demographics and clinical management of nodular thyroid disease in the elderly has rarely been documented using fine needle aspiration biopsy (FNAB). We retrospectively reviewed 100 thyroid FNABs from 88 elderly patients. All cases had surgical and/or clinical follow-up. The cases were classified as: 12 insufficient, 69 benign, 15 suspicious and 4 malignant. There were no false positives and one false negative diagnosis. Overall, 14 patients (16%) had malignant nodules, including 3 papillary carcinomas and 3 lymphomas. We conclude that because of its high diagnostic accuracy, FNAB is useful in the management of elderly patients with thyroid nodules. PMID- 21597875 TI - Growth-inhibition of human-melanoma cells by vitamin-d analogs. AB - The antiproliferative activity of 1,25(OH)(2)-vitamin D-3, and four vitamin D analogs was assessed in RPMI-7951, a human melanoma cell line which expresses the vitamin D receptor. Proliferation assays consisted of a [H-3]-thymidine incorporation assay, and a 6-day growth study. The affinity of vitamin D analogs for vitamin D receptor relative to 125(OH)(2)-vitamin D-3 was determined with a hydroxyapatite-based competitive binding assay. For the proliferation assays, cells were treated with 10(-8) M 1,25(OH)(2)-vitamin D-3, 1,25(OH)(2)-16-ene-23 yne-vitamin D-3 (Ro 23-7553), 1,25(OH)(2)-16-ene-23-yne-26,27-hexafluoro-vitamin D-3 (Ro 24-5531), 1,25(OH),-16,23Z-diene-26,27-hexafluoro-vitamin D-3 (Ro 25 5317), and 1 alpha-fluoro-25(OH)- 16-ene-23-yne-hexafluoro-vitamin D-3 (Ro 24 5583). 1,25(OH)(2)-vitamin D-3 and the four analogs all significantly inhibited melanoma cell growth (P<0.05). Competitive binding of the vitamin D analogs to vitamin D receptor ranged from 51% to 72% that of 1,25(OH)(2)-vitamin D-3, suggesting a receptor-mediated response. These results demonstrate that analogs of 1,25(OH)(2)-vitamin D-3 are potent antiproliferative agents in human melanoma cells in vitro. PMID- 21597876 TI - The clinical relevance of metastatic pattern in breast-cancer - the heterogeneity of metastatic disease. AB - Patients with metastatic breast cancer are considered as a homogeneous group because of the relative rarity of data relating to specific organ metastases. In this study, the clinical course of metastatic breast cancer was documented for 278 female patients registered from 1978 through 1988 at the Clinic for Radiotherapy of the University of Wurzburg. We analysed these 278 patients with metastatic disease to work out the clinical significance of specific organ metastases (SOM). A comparison of the six most frequent specific organ metastatases (SOM), i.e., bone, lung, CNS, liver, lymph node and skin metastases, is presented. Our findings indicate, that the group of patients with metastatic disease is heterogenous relating to age at time of metastatic disease, to metastatic-free intervall and to the influence of specific organ metastases on survival. The heterogeneity in the group of patients with distant metastatic disease has to be taken in consideration, when the results of chemotherapy are reported. PMID- 21597877 TI - The state of immortalized, transforming and suppressor genes in rat-cells, transfected by polyomavirus large-T and hpv18 e6+e7 genes. AB - Several novel cell clones (A1-A6) derived from the rat embryo fibroblasts immortalized by the polyoma virus T-antigen (LT) gene and transformed by HPV18 E6 and E7 genes were explored. Using E6 or E7 peptide antisera we detected E6 and E7 proteins with approximate molecular masses of 16 kDa and 20 kDa, respectively. Monoclonal antibody to p53 PAb421 but not PAb240 precipitated different but appreciable amounts of p53 protein in all cell clones, indicating that wild-type p53 is expressed in these cells. So expression of HPV18 E6 protein in cells does not always lead to a complete reduction in p53 levels. The quantity of p53 protein in cell clones did not correlate with the level of polyoma virus large T antigen expression. Variations in levels of p53 protein in clones did not influence on such cell biological properties as anchorage-independence and tumorigenicity for nude mice which were similar in all cell clones. PMID- 21597878 TI - P53 mutations may be related to tumor invasiveness of human hepatocellular carcinoma in china. AB - A combined polymerase chain reaction (PCR) with the enzyme HaeIII restriction analysis and DNA sequencing have been employed to study the mutations at codon 249 of p53 gene in two human hepatocellular carcinoma (HCC) cell lines and 28 surgical specimens of HCC. 14 of the 28 HCC samples (50%) had p53 point mutations at codon 249. All of point mutations at codon 249 in 10 cases sequenced are AGG to AGT transversion. p53 gene mutated more frequently in invasive HCCs than that in non-invasive HCCs. This suggested that the codon 249 was a mutational hotspot of p53 gene in human HCCs in China, and p53 mutations may be related to tumor invasiveness of human HCC. PMID- 21597879 TI - Microvessel quantification as a measure of angiogenic activity in benign breast tissue lesions - a marker for precancerous disease. AB - Neovascularization is a key step in the transformation of normal breast tissue into a cancerous phenotype. We investigated the angiogenic activity of 58 cases of histologically confirmed benign breast lesions quantitating angiogenic activity by factor VIII highlighting of endothelial cells. The mean microvessel count (MVC) for all patients was 51 per 0.19 mm(2) in the area of highest angiogenic activity at x400 magnification (range 21-113 per mm(2)). MVC in benign tissues were similar to those found previously in cancer tissues. These data suggest that the 'angiogenic switch' occurs early in breast transformation and that a role may exist for the use of MVC in the identification of persons at heightened risk for subsequent development of breast cancer. PMID- 21597880 TI - Training of attention functions in children with attention deficit hyperactivity disorder. AB - Pharmacological treatment of children with ADHD has been shown to be successful; however, medication may not normalize attention functions. The present study was based on a neuropsychological model of attention and assessed the effect of an attention training program on attentional functioning of children with ADHD. Thirty-two children with ADHD and 16 healthy children participated in the study. Children with ADHD were randomly assigned to one of the two conditions, i.e., an attention training program which trained aspects of vigilance, selective attention and divided attention, or a visual perception training which trained perceptual skills, such as perception of figure and ground, form constancy and position in space. The training programs were applied in individual sessions, twice a week, for a period of four consecutive weeks. Healthy children did not receive any training. Alertness, vigilance, selective attention, divided attention, and flexibility were examined prior to and following the interventions. Children with ADHD were assessed and trained while on ADHD medications. Data analysis revealed that the attention training used in the present study led to significant improvements of various aspects of attention, including vigilance, divided attention, and flexibility, while the visual perception training had no specific effects. The findings indicate that attention training programs have the potential to facilitate attentional functioning in children with ADHD treated with ADHD drugs. PMID- 21597881 TI - The evolution of respiratory chain complex I from a smaller last common ancestor consisting of 11 protein subunits. AB - The NADH:quinone oxidoreductase (complex I) has evolved from a combination of smaller functional building blocks. Chloroplasts and cyanobacteria contain a complex I-like enzyme having only 11 subunits. This enzyme lacks the N-module which harbors the NADH binding site and the flavin and iron-sulfur cluster prosthetic groups. A complex I-homologous enzyme found in some archaea contains an F(420) dehydrogenase subunit denoted as FpoF rather than the N-module. In the present study, all currently available whole genome sequences were used to survey the occurrence of the different types of complex I in the different kingdoms of life. Notably, the 11-subunit version of complex I was found to be widely distributed, both in the archaeal and in the eubacterial kingdoms, whereas the 14 subunit classical complex I was found only in certain eubacterial phyla. The FpoF containing complex I was present in Euryarchaeota but not in Crenarchaeota, which contained the 11-subunit complex I. The 11-subunit enzymes showed a primary sequence variability as great or greater than the full-size 14-subunit complex I, but differed distinctly from the membrane-bound hydrogenases. We conclude that this type of compact 11-subunit complex I is ancestral to all present-day complex I enzymes. No designated partner protein, acting as an electron delivery device, could be found for the compact version of complex I. We propose that the primordial complex I, and many of the present-day 11-subunit versions of it, operate without a designated partner protein but are capable of interaction with several different electron donor or acceptor proteins. PMID- 21597882 TI - Functional lumen imaging probe to assess geometric changes in the esophagogastric junction following endolumenal fundoplication. AB - BACKGROUND: The functional lumen imaging probe (FLIP) uses impedance planimetry to measure the geometry of a distensible organ. The purpose of this study was to evaluate FLIP as a method to determine structural changes at the gastroesophageal junction (GEJ) following transoral incisionless fundoplication (TIF) and compare these findings with the accepted methods of esophageal testing. METHODS: Two different approaches (TIF1.0 and 2.0) using the EsophyXTM device were performed in six and five animals, respectively. Three dogs underwent a sham procedure. FLIP measurements were performed pre- and post-procedure and at 2-week follow-up. Upper endoscopy, manometry, and 48-h pH testing were also performed at each time point. FLIP was performed in ten patients before and 3 months after TIF. RESULTS: Following TIF procedures, there was a significant decrease in cross-sectional area (CSA) of GEJ compared to baseline; however, the CSA of both groups returned to baseline at 2-week follow-up. The FLIP results were supported with pH testing and correlated highly with both measures of GEJ structural integrity (LES and cardia circumference). Following TIF in humans, there was a decrease in GEJ distensibility compared to baseline that persisted to the 3-month evaluation. CONCLUSION: FLIP is able to measure and display changes in tissue distensibility at the GEJ, and results correlate with established methods of testing. FLIP may represent a single testing modality by which to diagnose GERD and evaluate the outcome after antireflux surgery. PMID- 21597883 TI - Open versus minimally invasive esophagectomy: what is the best approach? Minimally invasive esophagectomy. AB - INTRODUCTION: Esophageal cancer is a complex disease that is typically discovered at a late stage and is associated with a poor overall survival rate. DISCUSSION: Regardless of surgical approach, esophagectomy carries a significant morbidity and mortality. The surgeon should choose the surgical approach based on her comfort level, training and experience. Further investigation is required to evaluate the translatability of minimally invasive esophagectomy on a large scale. PMID- 21597884 TI - Effects of erythropoietin on frataxin levels and mitochondrial function in Friedreich ataxia--a dose-response trial. AB - Friedreich ataxia (FRDA) is an autosomal recessive inherited neurodegenerative disorder leading to reduced expression of the mitochondrial protein frataxin. Previous studies showed frataxin upregulation in FRDA following treatment with recombinant human erythropoietin (rhuEPO). Dose-response interactions between frataxin and rhuEPO have not been studied until to date. We administered escalating rhuEPO single doses (5,000, 10,000 and 30,000 IU) in monthly intervals to five adult FRDA patients. Measurements of frataxin, serum erythropoietin levels, iron metabolism and mitochondrial function were carried out. Clinical outcome was assessed using the "Scale for the assessment and rating of ataxia". We found maximal erythropoietin serum concentrations 24 h after rhuEPO application which is comparable to healthy subjects. Frataxin levels increased significantly over 3 months, while ataxia rating did not reveal clinical improvement. All FRDA patients had considerable ferritin decrease. NADH/NAD ratio, an indicator of mitochondrial function, increased following rhuEPO treatment. In addition to frataxin upregulation in response to continuous low dose rhuEPO application shown in previous studies, our results indicate for a long-lasting frataxin increase after single high-dose rhuEPO administration. To detect frataxin-derived neuroprotective effects resulting in clinically relevant improvement, well-designed studies with extended time frame are required. PMID- 21597885 TI - Thickening of peripapillar retinal fibers for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay. AB - Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is characterized by the presence of myelinated retinal fibers. This typical feature is very helpful for the diagnosis but is not always observed in patients outside Quebec. Apart from phenotype variations, misinterpretation of the funduscopy may explain discrepancies and misdiagnosis. We analyze the modification of retinal fibers layer using the funduscopy and the optical coherence tomography (OCT) in two French patients having spinocerebellar ataxia associated with a spastic paraparesia with genetically confirmed ARSACS. In both patients the funduscopy showed a swollen and striated aspect of peripapillar fibers along the retinal vessels and in the intermaculopapillar region. The OCT displayed an important thickening of the optical fibers layer mainly in upper and lower temporal area without attenuation of deep layers, as well as a filling in of the foveolar depression with thickening of the ganglion cell layer normally absent from the foveola. The aspect of funduscopy and OCT in our patients does not correspond to the classical description of myelin fibers encountered in 0.3% to 1% of the population. Thus, ARSACS might be underdiagnosed because of an erroneous interpretation of funduscopy. When considering the diagnosis of ARSACS, the neurologist should ask the ophthalmologist to search for thickening of peripapillar retinal fibers by both funduscopy and OCT rather than myelinated retinal fibers. This ophthalmological consideration has avoided misdiagnosis and led to the description of new mutations in our cases. PMID- 21597886 TI - Liver packing during elective surgery: an option that can be considered. AB - BACKGROUND: Packing is a life-saving procedure in patients undergoing emergency surgery for blunt hepatic trauma, especially when massive blood transfusions, acidosis, or hypothermia have resulted in coagulation disorders. The purpose of this study was to apply this concept to the setting of elective liver surgery. METHODS: Elective packing was performed in 7 patients who had sustained prolonged bleeding mainly related to partial outflow obstruction during the course of liver resection (n = 3) or transplantation (n = 4). At the time of packing, conventional methods of hemostasis had failed and surgery had lasted for 490 (range, 380-695) minutes, blood loss was 5,700 (range, 2,100-13,700) ml, and all patients had coagulation disorders (prothrombin time PT <30%, platelets <45 g/l), hypothermia (body temperature 35.4 degrees C), acidosis (median blood pH 7.24; serum lactate 6.5 mmol/l) and required catecholamine support. RESULTS: Unpacking was performed after a median of 37 (range, 26-60) hours. At that time, all patients were normothermic, with platelet counts >45 g/l, PT >30%, and restored acid-base balance. Active bleeding had stopped, and secondary fascia closure was feasible. With a minimum follow-up of 6 months, all patients are alive without sequel. CONCLUSIONS: Packing is a safe and efficient means to control venous bleeding when conventional methods of hemostasis have failed, knowing that commonly the reason for failure of conventional method of hemostasis is partial outflow obstruction. PMID- 21597887 TI - Outcome of radical resection and postoperative radiotherapy for thyroid carcinoma showing thymus-like differentiation. AB - BACKGROUND: Carcinoma showing thymus-like differentiation (CASTLE) is a rare disease that is difficult to diagnose. The aim of this study was to assess the effects of combined-modality treatment in CASTLE patients. METHODS: We retrospectively studied patients identified between January 1, 2000 and December 31, 2009 as having CASTLE and who subsequently underwent surgery and radiotherapy or chemotherapy. Preoperative laboratory findings, ultrasonographic (US) and computed tomographic (CT) features, and fine-needle aspiration biopsy (FNAB) specimens were evaluated. RESULTS: Seven patients with CASTLE were identified (four men, three women). The median age at initial diagnosis was 48 years (range 25-56 years). The five newly diagnosed patients were treated with curative surgery and postoperative radiotherapy, whereas two patients with recurrent disease were treated with salvage surgery plus radiotherapy or chemotherapy. All patients were disease-free at a median follow-up period of 34 months (range 12-61 months). The pattern of immunohistochemical staining was similar to that of thymic carcinoma. Specimens from all seven patients stained positively for CD5, CD117, and cytokeratin but were uniformly negative for thyroglobulin, thyroid transcription factor 1 (TTF-1), and calcitonin. CONCLUSIONS: Patients with CASTLE have excellent outcomes after curative resection and postoperative radiotherapy compared with patients with anaplastic thyroid carcinoma. Even patients with local recurrent disease benefited from salvage surgery with subsequent operation and/or radiotherapy. CD5 immunohistochemical staining on FNAB samples may help identify the possible entities that are part of the differential diagnosis. PMID- 21597888 TI - Venous thromboembolism after surgery for benign prostatic hyperplasia. AB - A systematic review has been performed on venous thromboembolism after surgery for benign prostatic hyperplasia. The risk of deep vein thrombosis is two to four times higher after open surgery than after transurethral resection. The risk after the newer transurethral methods (laser, radiofrequency, heat) is not known. Specific studies on thromboprophylaxis are few and have limited numbers of patients. Nonetheless, thromboprophylaxis (heparin) reduces the frequency of postoperative deep vein thrombosis after open surgery. Studies on patients undergoing transurethral resection are lacking. Antifibrinolytic treatment to diminish bleeding does not seem to increase the risk of thrombosis. PMID- 21597889 TI - Late recurrence of hepatocellular carcinoma after liver transplantation. AB - BACKGROUND: Long-term survival of patients with hepatocellular carcinoma (HCC) after liver transplantation is affected mainly by recurrence of HCC. There is the opinion that the chance of recurrence after 2 years post-transplantation is remote, and therefore lifelong surveillance is not justified because of limited resources. The aims of the present study were to determine the rate of late HCC recurrence (>= 2 years after transplantation) and to compare the long-term patient survival outcomes between cases of early recurrence (<2 years after transplantation) and late recurrence. PATIENTS: A total of 139 adult HCC patients having liver transplantation during the period from July 1994 to December 2007 were included in the analysis. The median follow-up period was 55 months. Thirty two patients received deceased-donor grafts and 107 received living-donor grafts. RESULTS: Hepatocellular carcinoma recurrence occurred in 24 (17.3%) patients, among them 22 (86%) had living-donor grafts and 7 (5%) developed late recurrence. Patients in the early recurrence group and patients in the late recurrence group had comparable demographics and disease pathology. The former group, when compared with the latter, had significantly worse overall survival at 3 years (13.3 versus 100%) and 5 years (6.67 versus 71.4%) (log-rank test; p < 0.001). CONCLUSIONS: Both early recurrence and late recurrence of HCC after liver transplantation were not uncommon, mostly detected at a subclinical stage. Regular and long-term surveillance with imaging and blood tests is essential for early detection. PMID- 21597890 TI - Development and validation of a surgical workload measure: the surgery task load index (SURG-TLX). AB - BACKGROUND: The purpose of the present study was to develop and validate a multidimensional, surgery-specific workload measure (the SURG-TLX), and to determine its utility in providing diagnostic information about the impact of various sources of stress on the perceived demands of trained surgical operators. As a wide range of stressors have been identified for surgeons in the operating room, the current approach of considering stress as a unidimensional construct may not only limit the degree to which underlying mechanisms may be understood but also the degree to which training interventions may be successfully matched to particular sources of stress. METHODS: The dimensions of the SURG-TLX were based on two current multidimensional workload measures and developed via focus group discussion. The six dimensions were defined as mental demands, physical demands, temporal demands, task complexity, situational stress, and distractions. Thirty novices were trained on the Fundamentals of Laparoscopic Surgery (FLS) peg transfer task and then completed the task under various conditions designed to manipulate the degree and source of stress experienced: task novelty, physical fatigue, time pressure, evaluation apprehension, multitasking, and distraction. RESULTS: The results were supportive of the discriminant sensitivity of the SURG TLX to different sources of stress. The sub-factors loaded on the relevant stressors as hypothesized, although the evaluation pressure manipulation was not strong enough to cause a significant rise in situational stress. CONCLUSIONS: The present study provides support for the validity of the SURG-TLX instrument and also highlights the importance of considering how different stressors may load surgeons. Implications for categorizing the difficulty of certain procedures, the implementation of new technology in the operating room (man-machine interface issues), and the targeting of stress training strategies to the sources of demand are discussed. Modifications to the scale to enhance clinical utility are also suggested. PMID- 21597892 TI - Immunological diseases of the pancreatico-hepatobiliary system: update on etiopathogenesis and cross-sectional imaging findings. AB - Immunological diseases of the hepatobiliary system and the pancreas include a broad spectrum of disorders that manifest characteristic histopathology/serology and variable clinical features and imaging findings. Recent studies have thrown fresh light on the complex role of genetics and autoimmunity in the pathogenesis and natural history of these diverse disorders that include autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, IgG4-related cholangitis, overlap/outlier syndromes, and autoimmune pancreatitis. PMID- 21597893 TI - Detection, classification, and characterization of focal liver lesions: Value of diffusion-weighted MR imaging, gadoxetic acid-enhanced MR imaging and the combination of both methods. AB - AIM: To evaluate diffusion-weighted MR imaging (DWI), gadoxetic acid-enhanced MR imaging and the combination of both methods in the detection, classification, and characterization of focal liver lesions (FLL). METHODS: A total of 119 FLL (28 HCCs, 39 metastases, 15 FNHs, 11 adenomas, 13 hemangiomas, 13 cysts) were retrospectively analyzed in 36 patients. In those patients MR imaging of the liver comprising respiratory-triggered DWI (b values of 50, 300, and 600 s/mm(2)) and gadoxetic acid-enhanced MR imaging including image acquisition in the hepatocyte-selective phase (20 min post injection) had been performed. Three image sets were assigned and compared: DWI only (set A), gadoxetic acid-enhanced MR imaging only (set B), and both modalities in combination (set C). Two readers independently interpreted the images in random order. For each reader and image set, the area under the receiver operating characteristic curve (Az) and sensitivity in the detection of FLL was determined as well as the accuracy in the classification and characterization of FLL. RESULTS: There was no significant difference between the three image sets in the detection of FLL with regards to Az. However, when only lesions with a diameter of 10 mm or less were analyzed, the Az values of set C were significantly higher than those of sets A and B for both readers. For classifying and characterizing FLL both set B and C were significantly superior to set A. CONCLUSION: Adding DWI to gadoxetic acid enhanced MR imaging significantly increases the accuracy in the detection of small FLL. PMID- 21597896 TI - Is duloxetine more effective than amitriptyline for painful diabetic neuropathy? PMID- 21597895 TI - Coarse-grained event tree analysis for quantifying Hodgkin-Huxley neuronal network dynamics. AB - We present an event tree analysis of studying the dynamics of the Hodgkin-Huxley (HH) neuronal networks. Our study relies on a coarse-grained projection to event trees and to the event chains that comprise these trees by using a statistical collection of spatial-temporal sequences of relevant physiological observables (such as sequences of spiking multiple neurons). This projection can retain information about network dynamics that covers multiple features, swiftly and robustly. We demonstrate that for even small differences in inputs, some dynamical regimes of HH networks contain sufficiently higher order statistics as reflected in event chains within the event tree analysis. Therefore, this analysis is effective in discriminating small differences in inputs. Moreover, we use event trees to analyze the results computed from an efficient library-based numerical method proposed in our previous work, where a pre-computed high resolution data library of typical neuronal trajectories during the interval of an action potential (spike) allows us to avoid resolving the spikes in detail. In this way, we can evolve the HH networks using time steps one order of magnitude larger than the typical time steps used for resolving the trajectories without the library, while achieving comparable statistical accuracy in terms of average firing rate and power spectra of voltage traces. Our numerical simulation results show that the library method is efficient in the sense that the results generated by using this numerical method with much larger time steps contain sufficiently high order statistical structure of firing events that are similar to the ones obtained using a regular HH solver. We use our event tree analysis to demonstrate these statistical similarities. PMID- 21597898 TI - Comments on Shuzhen Li et al. "Systematic review of patellar resurfacing in total knee arthroplasty". PMID- 21597894 TI - Risk factors for gallbladder cancer and cholangiocarcinoma: similarities, differences and updates. AB - INTRODUCTION: Far-ranging variation in the incidence of gallbladder cancer (GBC) and cholangiocarcinoma (CCA) in different geographic regions on the globe may reflect the risk factor distribution for these tumors METHODS: The authors give a comprehensive review on the known risk factors for GBC and CCA, and analyze both similarities and differences between the risk factors for the two main types of biliary cancer DISCUSSION AND CONCLUSION: Leading risk factors for GBC include gallstones, female gender, and advancing age. Primary sclerosing cholangitis, nitrosamine exposure, choledochal cysts, Clonorchis sinensis and Opisthorchis viverrini represent important risk factors for CCA, although a specific risk factor cannot be identified for many patients. While both cancers affect mostly individuals in their sixth decade or older, CCA has a male predominance and GBC- a predilection for females. Although the current level of understanding of the molecular pathogenesis of GBC and CCA at the interface with specific risk factors is significantly lower than for other gastrointestinal malignancies, it continues to evolve and may soon open new avenues for the therapy of biliary cancers. PMID- 21597899 TI - Electron microscopic study of the effects of antimicrobial agents on the cellular architecture of Leptospira. AB - Morphological changes of Leptospira induced by ampicillin, streptomycin, or ciprofloxacin were studied by transmission electron microscopy after staining with uranyl acetate. Irregularities in coiling, loss of hooks, spherical swellings, membrane vesicle formation, disruption of outer membrane, exposure and detachment of flagella, penetration of dye, and lysis of cells were observed. These changes appeared in a time-dependent manner and appeared to be associated with the sites of action of antimicrobial agents. This is the first report delineating the action of aminoglycoside and new quinolone on the morphology of Leptospira cells. PMID- 21597900 TI - A retrospective study of health care-associated pneumonia patients at Aichi Medical University hospital. AB - Health care-associated pneumonia (HCAP) was defined in the American Thoracic Society/Infectious Disease Society of America guidelines on hospital-acquired pneumonia in 2005. However, little is known about the occurrence of HCAP in Japan. A retrospective review of background characteristics, pathological conditions, causative organisms, initial treatments, and risk factors for HCAP was conducted to determine the relationship of HCAP to community-acquired pneumonia and hospital-acquired pneumonia. Thirty-five patients who were admitted to our hospital for pneumonia acquired outside our hospital were included and were stratified by disease severity according to the Japanese Respiratory Society risk stratification guidelines (A-DROP [age, dehydration, respiratory failure, orientation disturbance, and shock blood pressure] criteria). All patients had an underlying disease. A total of 70 microbial strains (25 gram-positive, 37 gram negative, 6 anaerobic, and 2 causative of atypical pneumonia) were isolated from sputum cultures, showing high isolation frequencies of Pseudomonas aeruginosa and Staphylococcus aureus and extremely low isolation frequencies of Streptococcus pneumoniae and Haemophilus influenzae. "History of hospitalization within 90 days before the onset of pneumonia" was the most common risk factor, and most of the patients had two or three risk factors. Initially, monotherapy [mainly tazobactam/piperacillin (TAZ/PIPC), sulbactam/ampicillin (SBT/ABPC), ceftriaxone (CTRX), cefepime (CPFM), carbapenems, or fluoroquinolones] or combination therapy (beta-lactam and fluoroquinolone) were administered and gave clinical effects in 63% (22/35) of cases. Bacteriological effects were seen in most strains (57%; 40/70). Since the causative organisms of HCAP were closely related to those of hospital-acquired pneumonia and not to community-acquired pneumonia, we believe that aggressive chemotherapy using broad-spectrum antimicrobials is needed in the initial treatment. PMID- 21597901 TI - Sensitivity and specificity of NT-proBNP to detect heart failure at post mortem examination. AB - NT-proBNP, a marker of cardiac failure, has been shown to be stable in post mortem samples. The aim of this study was to assess the accuracy of NT-proBNP to detect heart failure in the forensic setting. One hundred sixty-eight consecutive autopsies were included in the study. NT-proBNP blood concentrations were measured using a chemiluminescent immunoassay kit. Cardiac failure was assessed by three independent forensic experts using macro- and microscopic findings complemented by information about the circumstances of body discovery and the known medical story. Area under the receiving operator curve was of 65.4% (CI 95%, from 57.1 to 73.7). Using a standard cut-off value of >220 pg/mL for NT proBNP blood concentration, heart failure was detected with a sensitivity of 50.7% and a specificity of 72.6%. NT-proBNP vitreous humor values were well correlated to the ones measured in blood (r (2) = 0.658). Our results showed that NT-proBNP can corroborate the pathological findings in cases of natural death related to heart failure, thus, keeping its diagnostic properties passing from the ante mortem to the post mortem setting. Therefore, biologically inactive polypeptides like NT-proBNP seem to be stable enough to be used in forensic medicine as markers of cardiac failure, taking into account the sensitivity and specificity of the test. PMID- 21597902 TI - The patient with asthma in the emergency department. AB - Asthma is a highly prevalent disease that presents commonly to the emergency department (ED) in acute exacerbation. Recent asthma treatment guidelines have added content dedicated to the management of acute exacerbations. Effective management of an exacerbation requires rapid assessment of severity through physical examination, measurement of peak expiratory flow rate, and response to initial treatment. Most therapies are directed at alleviating bronchospasm and decreasing airway inflammation. While inhaled short-acting beta-agonists, systemic corticosteroids, and supplemental oxygen are the initial and often only therapies required for patients with mild moderate exacerbations, high-dose beta agonists and inhaled anti-cholinergics should also be given to patients with severe exacerbations. Adjunctive therapy with intravenous magnesium and Heliox driven nebulization of bronchodilators should be considered for patients presenting with severe and very severe exacerbations. Early recognition and appropriate management of respiratory failure are required to mitigate the risk of complications including death. Disposition should be determined based on serial assessments of the response to therapy over the first 4 h in the ED. Patients stable for discharge should receive medications, asthma education including a written asthma action plan, and should have follow-up scheduled for them by ED staff. Rapid implementation of evidence-based, multi-disciplinary care is required to ensure the best possible outcomes for this potentially treatable disease. PMID- 21597904 TI - The photo-instrument as a health care intervention. AB - The aim of this study is to describe how hermeneutic photography and one application of hermeneutic photography in particular, namely the photo instrument, can be used as a health care intervention that fosters meaning (re )construction of mental illness experiences. Studies into the ways how patients construct meaning in illness narratives indicate that aesthetic expressions of experiences may play an important role in meaning making and sharing. The study is part of a larger research project devoted to understanding the photostories that result from groups of psychiatric patients using the photo-instrument. Within a focused ethnography approach we employed a qualitative design of a single case study. Text analysis of photostories was combined with observational data. Data were analyzed using hermeneutic theory. Participant observations were used for triangulation and complementarity. The interaction and collaboration between health care professionals and patients in the context of a photo group emerged as core concept that underlies the photo-instrument. The interaction triggered a reframing of meaning in the patient's illness narrative that offered new perspectives on positive identity growth. The role of visualizing meaning in images was found to lend a dynamic power to the process and triggered a dialectic between real life circumstances and imagination played out in the context of situated action. The findings suggest that a positive reframing of meaning in illness narratives is facilitated by the photo-instrument. PMID- 21597905 TI - Malignant pigmented clear cell epithelioid cell tumor (PEComa) in an adolescent boy with widespread metastases: a rare entity in this age group. AB - Malignant pigmented clear cell epithelioid cell tumor of the kidney is a rare variant of perivascular epithelioid cells tumors (PEComa) or epithelioid angiomyolipoma (AML). PEComa is characteristically composed purely of epitheloid cells. The fat cells and the blood vessels that are typical of classic AML are absent. Most epithelioid AML cases are benign; however, malignant epithelioid AML of the kidney has been occasionally reported in adults in association with tuberous sclerosis. We report the radiological-pathological features of a malignant pigmented clear cell epithelioid renal tumor in a 15-year-old boy presenting with extensive metastases but without clinical evidence of tuberous sclerosis. PMID- 21597906 TI - Brain magnetic resonance findings in symptomatic congenital cytomegalovirus infection. AB - BACKGROUND: Congenital cytomegalovirus (CMV) infection can lead to severe neurological sequelae, but a defined brain magnetic resonance (MR) pattern and MR predictors of clinical outcome are still lacking. MATERIALS AND METHODS: Clinical and MR findings of 14 children with symptomatic congenital CMV infection were retrospectively reviewed. RESULTS: Microcephaly, cerebral palsy and epilepsy were found in eight, six and seven patients, respectively (all concomitant in 6); 12 children developed sensory-neural hearing loss (SNHL). At first MRI (mean age 21 months, range 5-54 months), white matter (WM) involvement was not assessable in two children due to incomplete myelination. WM abnormalities were common (11/12 patients); deep WM was predominantly involved in 5/11; the largest WM lesion was in the parietal lobe in 6/11. Anterior temporal lobe abnormalities were found in 13/14. Six children underwent MRI examination after 2 years of life; in this subgroup, WM abnormalities were extensive and confluent (4/6), bilateral and multifocal (1/6) or absent (1/6). Four children showed a progression of myelination. Ventriculomegaly (9/14), migration disorders (6/14 polymicrogyria and 1/14 pachygyria-lissencephaly) and hippocampal dysplasia (6/14) correlated with severe neurological sequelae (p < 0.05, Fisher exact test), while the presence of WM abnormalities (11/12), periventricular cysts (6/14) and cerebellar hypoplasia (4/14) did not predict the outcome. CONCLUSIONS: The spectrum of brain MR abnormalities in symptomatic congenital CMV infection is extremely wide. WM involvement is variable, difficult to evaluate at a very young age and unrelated to clinical outcome, while cortical malformations, ventriculomegaly and hippocampal dysplasia seem to be strong predictors of poor outcome except for SNHL. PMID- 21597903 TI - Cutting edge issues in rheumatic fever. AB - Although the incidence of acute rheumatic fever and rheumatic heart disease has decreased significantly in regions of the world where antibiotics are easily accessible, there remains a high incidence in developing nations as well as in certain regions where there is a high incidence of genetic susceptibility. These diseases are a function of poverty, low socioeconomic status, and barriers to healthcare access, and it is in the developing world that a comprehensive prevention program is most critically needed. Development of group A streptococcal vaccines has been under investigation since the 1960s and 50 years later, we still have no vaccine. Factors that contribute to this lack of success include a potential risk for developing vaccine-induced rheumatic heart disease, as well as difficulties in covering the many serological subtypes of M protein, a virulence factor found on the surface of the bacterium. Yet, development of a successful vaccine program for prevention of group A streptococcal infection still offers the best chance for eradication of rheumatic fever in the twenty first century. Other useful approaches include continuation of primary and secondary prevention with antibiotics and implementation of health care policies that provide patients with easy access to antibiotics. Improved living conditions and better hygiene are also critical to the prevention of the spread of group A streptococcus, especially in impoverished regions of the world. The purpose of this article is to discuss current and recent developments in the diagnosis, pathogenesis, and management of rheumatic fever and rheumatic heart disease. PMID- 21597907 TI - Double effect, all over again: the case of Sister Margaret McBride. AB - As media reports have made widely known, in November 2009, the ethics committee of St. Joseph's Hospital in Phoenix, Arizona, permitted the abortion of an eleven week-old fetus in order to save the life of its mother. This woman was suffering from acute pulmonary hypertension, which her doctors judged would prove fatal for both her and her previable child. The ethics committee believed abortion to be permitted in this case under the so-called principle of double effect, but Thomas J. Olmsted, the bishop of Phoenix, disagreed with the committee and pronounced its chair, Sister Margaret McBride, excommunicated latae sententiae, "by the very commission of the act." In this article, I take the much discussed Phoenix case as an occasion to subject the principle of double effect to another round of philosophical scrutiny. In particular, I examine the third condition of the principle in its textbook formulation, namely, that the evil effect in question may not be the means to the good effect. My argument, in brief, is that the textbook formulation of the principle does not withstand philosophical scrutiny. Nevertheless, in the end, I do not claim that we should then "do away" with the principle altogether. Instead, we do well to understand it within the context of casuistry, the tradition of moral reasoning from which it issued. PMID- 21597908 TI - Sex differences in chondrocyte maturation in the mandibular condyle from a decreased occlusal loading model. AB - Temporomandibular joint disorders (TMDs) predominantly afflict women of childbearing age. Defects in mechanical loading-induced temporomandibular joint (TMJ) remodeling are believed to be a major etiological factor in the development of TMD. The goal of this study was to determine if there are sex differences in CD-1 and C57BL/6 mice exposed to a decreased occlusal loading TMJ remodeling model. Male and female CD-1 and C57BL/6 mice, 21 days old, were each divided into two groups. They were fed either a normal pellet diet (normal loading) or a soft diet and had their incisors trimmed out of occlusion (decreased occlusal loading) for 4 weeks. The mandibular condylar cartilage was evaluated by histology, and the subchondral bone was evaluated by micro-CT analysis. Gene expression from both was evaluated by real-time PCR analysis. In both strains and sexes of mice, decreased occlusal loading caused similar effects in the subchondral bone, decreases in bone volume and total volume compared with their normal loading controls. However, in both strains, decreased occlusal loading caused a significant decrease in the expression of collagen type II (Col2) and Sox9 only in female mice, but not in male mice, compared with their normal loading controls. Decreased occlusal loading causes decreased bone volume in both sexes and a decrease in early chondrocyte maturation exclusively in female mice. PMID- 21597909 TI - Measuring differences in compositional properties of bone tissue by confocal Raman spectroscopy. AB - The full range of fracture risk determinants arise from each hierarchical level comprising the organization of bone. Raman spectroscopy is one tool capable of characterizing the collagen and mineral phases at a near submicron-length scale, but the ability of Raman spectra to distinguish compositional differences of bone is not well defined. Therefore, we analyzed multiple Raman peak intensities and peak ratios to characterize their ability to distinguish between the typically less mineralized osteonal tissue and the more mineralized interstitial tissue in intracortical human bone. To further assess origins of variance, we collected Raman spectra from embedded specimens and for two orientations of cut. Per specimen, Raman peak intensities or ratios were averaged among multiple sites within five osteons and five neighboring interstitial tissue. The peak ratios of nu(1) phosphate (PO(4)) to proline or amide III detected the highest increases of 15.4 or 12.5%, respectively, in composition from osteonal to interstitial tissue. The coefficient of variance was less than 5% for each as opposed to a value of ~8% for the traditional nu(1)PO(4)/amide I, a peak ratio that varied the most between transverse and longitudinal cuts for each tissue type. Although embedding affected Raman peaks, it did not obscure differences in most peak ratios related to mineralization between the two tissue types. In studies with limited sample size but sufficient number of Raman spectra per specimen for spatial averaging, nu(1)PO(4)/amide III or nu(1)PO(4)/proline is the Raman property that is most likely to detect a compositional difference between experimental groups. PMID- 21597911 TI - Perfusion method for bone marrow cell collection in poor mobilizer lymphoma patient. AB - We previously described a unique procedure for the collection of bone marrow cells (BMCs) using a perfusion method (PM). In cynomolgus monkeys, this method resulted in lower contamination with T cells (<10%). Here, we performed PM on a poor mobilizer lymphoma patient. We confirmed the safety of the intra-bone marrow injection of saline to collect the BMCs. The collected BMCs showed minimal contamination with T cells (<15%) and red blood cells (RBCs) (<4%) from the peripheral blood. It took a total of only 30 min to collect the BMCs. Moreover, transfusion of RBCs was unnecessary. There were no relevant post-operative side effects except for self-limiting pain at the sites of collection, and the patient was able to walk around the hospital after the operation. PMID- 21597910 TI - Frequency and clinical correlates of radiographic patterns of bronchopulmonary dysplasia in very low birth weight infants by term age. AB - Our aim was to study the frequency and clinical correlates of two radiographic patterns of bronchopulmonary dysplasia (BPD), the cystic BPD (cBPD) and the leaky lung syndrome (LLS). Radiographic findings of BPD from sixth day of life until term in a cohort of 82 very low birth weight (VLBW) infants were evaluated and scored independently by a neonatologist and a paediatric radiologist. Data on prenatal factors and events during the first hospitalisation were collected prospectively. Forty-four (53.7%) infants showed radiographic evidence of BPD, 19 (23.2%) cBPD and 25 (30.5%) LLS. In multivariate analysis, the best predictors for radiographic BPD were oxygen dependency at 28 days (odds ratio (OR) 10.2 [95% confidence interval (CI) 2.49-41.4]), more than 2 days on ventilator (OR 10.4 [95% CI 1.8-61.5]) and volume expanders in the first 2 h (OR 7.36 [95% CI 1.32 41.2]). During the first week of life, infants with radiographic BPD received less energy per kilogram (p < 0.001) and more daily fluids per kilogram of body weight (p = 0.013). Sixty-two percent of the infants with radiographic BPD were not oxygen dependent at 36 weeks postmenstrual age (PMA). Seventeen (89.5%) of the 19 infants who needed oxygen supplementation at 36 weeks PMA also had abnormal chest X-rays. CONCLUSIONS: Radiographic BPD findings appeared to be common in VLBW infants. In addition to the well-known respiratory risk factors (oxygen and ventilator therapy), poor nutrition and excessive fluid administration in early life seem to be significantly associated with radiological findings of lung injury in these patients. PMID- 21597912 TI - A large population genetic study of 15 autosomal short tandem repeat loci for establishment of Korean DNA profile database. AB - Genotyping of highly polymorphic short tandem repeat (STR) markers is widely used for the genetic identification of individuals in forensic DNA analyses and in paternity disputes. The National DNA Profile Databank recently established by the DNA Identification Act in Korea contains the computerized STR DNA profiles of individuals convicted of crimes. For the establishment of a large autosomal STR loci population database, 1805 samples were obtained at random from Korean individuals and 15 autosomal STR markers were analyzed using the AmpFlSTR Identifiler PCR Amplification kit. For the 15 autosomal STR markers, no deviations from the Hardy-Weinberg equilibrium were observed. The most informative locus in our data set was the D2S1338 with a discrimination power of 0.9699. The combined matching probability was 1.521 * 10(-17). This large STR profile dataset including atypical alleles will be important for the establishment of the Korean DNA database and for forensic applications. PMID- 21597913 TI - Crustacean neuroendocrine systems and their signaling agents. AB - Decapod crustaceans have long served as important models for the study of neuroendocrine signaling. For example, the process of neurosecretion was first formally demonstrated by using a member of this order. In this review, the major decapod neuroendocrine organs are described, as are their phylogenetic conservation and neurochemistry. In addition, recent advances in crustacean neurohormone discovery and tissue mapping are discussed, as are several recent advances in our understanding of hormonal control in this group of animals. PMID- 21597914 TI - Catecholamine biosynthesis and secretion: physiological and pharmacological effects of secretin. AB - Pituitary adenylyl cyclase activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) augment the biosynthesis of tyrosine hydroxylase (TH). We tested whether secretin belonging to the glucagon/PACAP/VIP superfamily would increase transcription of the tyrosine hydroxylase (Th) gene and modulate catecholamine secretion. Secretin activated transcription of the endogenous Th gene and its transfected promoter (EC(50) ~4.6 nM) in pheochromocytoma (PC12) cells. This was abolished by pre-treatment with a secretin receptor (SCTR) antagonist and by inhibition of protein kinase A (PKA), mitogen-activated protein kinase, or CREB (cAMP response element-binding protein). In agreement, secretin increased PKA activity and induced phosphorylation of CREB and binding to Th CRE, suggesting secretin signaling to transcription via a PKA-CREB pathway. Secretin stimulated catecholamine secretion (EC(50) ~3.5 MUM) from PC12 cells, but this was inhibited by pre-treatment with VIP-preferring receptor (VPAC1)/PACAP preferring receptor (PAC1) antagonists. Secretin-evoked secretion occurred without extracellular Ca(2+) and was abolished by intracellular Ca(2+) chelation. Secretin augmented phospholipase C (PLC) activity and increased inositol-1,4,5 triphosphate (IP(3)) levels in PC12 cells; PLC-beta inhibition blocked secretin induced catecholamine secretion, indicating the participation of intracellular Ca(2+) from a phospholipase pathway in secretion. Like PACAP, secretin evoked long-lasting catecholamine secretion, even after only a transient exposure. Thus, transcription is triggered by nanomolar concentrations of the peptide through SCTR, with signaling along the cAMP-PKA and extracellular-signal-regulated kinase 1/2 pathways and through CREB. By contrast, secretion is triggered only by micromolar concentrations of peptide through PAC1/VPAC receptors and by utilizing a PLC/intracellular Ca(2+) pathway. PMID- 21597916 TI - Current perception of nutrition education in U.S. medical schools. AB - Historically, physicians have perceived the quality of nutrition training during medical school as inadequate. A literature review suggests that this perception has not significantly changed since the 1950s. Many schools have worked to create clinical nutrition curricula for use during medical school. Interestingly, data suggest that medical students' perception of the importance of clinical nutrition can decrease during medical school. Recent data support the importance of targeted nutritional therapy to reduce morbidity and mortality, yet the number of physicians interested in nutrition appears to be declining, and fewer hours of nutrition training are occurring in medical school. One possible solution to improve both training and awareness of the problem is to implement a certification program for both students and preceptors modeled after the Cardiac Life Support training offered by the American Heart Association. PMID- 21597915 TI - Hydrolyzed eggshell membrane immobilized on phosphorylcholine polymer supplies extracellular matrix environment for human dermal fibroblasts. AB - We have found that a water-soluble alkaline-digested form of eggshell membrane (ASESM) can provide an extracellular matrix (ECM) environment for human dermal fibroblast cells (HDF) in vitro. Avian eggshell membrane (ESM) has a fibrous meshwork structure and has long been utilized as a Chinese medicine for recovery from burn injuries and wounds in Asian countries. Therefore, ESM is expected to provide an excellent natural material for biomedical use. However, such applications have been hampered by the insolubility of ESM proteins. We have used a recently developed artificial cell membrane biointerface, 2 methacryloyloxyethyl phosphorylcholine polymer (PMBN) to immobilize ASESM proteins. The surface shows a fibrous structure under the atomic force microscope, and adhesion of HDF to ASESM is ASESM-dose-dependent. Quantitative mRNA analysis has revealed that the expression of type III collagen, matrix metalloproteinase-2, and decorin mRNAs is more than two-fold higher when HDF come into contact with a lower dose ASESM proteins immobilized on PMBN surface. A particle-exclusion assay with fixed erythrocytes has visualized secreted water binding molecules around the cells. Thus, HDF seems to possess an ECM environment on the newly designed PMBN-ASESM surface, and future applications of the ASESM PMBN system for biomedical use should be of great interest. PMID- 21597918 TI - Associations between polymorphisms of tumor necrosis factor-alpha gene and breast cancer risk. PMID- 21597917 TI - Mothers' pre-pregnancy BMI and weight gain during pregnancy and risk of breast cancer in daughters. AB - Previous studies have established that higher birthweight is associated with increased risk of breast cancer. However, the mechanisms underlying this association remain unclear. We explored whether maternal pregnancy weight gain and pre-pregnancy body mass index (BMI), which influence birthweight, are associated with risk of breast cancer in offspring. The Nurses' Mothers case control study of breast cancer was nested in the Nurses' Health Study I and II cohorts. Mothers of 814 nurses with and 1,809 nurses without breast cancer completed questionnaires with information on pre-pregnancy height and weight, pregnancy weight gain, and other aspects of their pregnancies with the nurse daughters. We calculated odds ratios for breast cancer using conditional logistic regression. Mean pregnancy weight gain was 23 lb, and average pre-pregnancy BMI was 21 kg/m2. Mothers' weight gain during pregnancy was not associated with the daughters' risk of breast cancer. Compared to women whose mothers gained 20-29 lb, women whose mothers gained less than 10 lb had a relative risk of 0.92 (95% confidence interval [CI]: 0.62-1.36), adjusting for the age of the nurses. Women whose mothers gained 40 or more pounds had a relative risk of 0.82 (95% CI: 0.55 1.23). Mothers' pre-pregnancy BMI was not associated with the daughters' risk of breast cancer. Women whose mothers had a pre-pregnancy BMI of 30 or more had a relative risk of 0.77 (95% CI: 0.34-1.74) compared to those with BMI less than 20. Additional adjustment for prenatal factors or for nurses' characteristics later in life had no effect on the results. The association between birthweight and breast cancer risk is likely due to factors independent of mothers' weight gain during pregnancy or pre-pregnancy BMI. Because BMIs and pregnancy weight gains were lower in this population than today, we cannot rule out associations for very high pre-pregnancy BMIs or pregnancy weight gains. PMID- 21597919 TI - RAD51C germline mutations in Chinese women with familial breast cancer. PMID- 21597920 TI - Regarding the article "The p160 ER co-regulators predict outcome in ER negative breast cancer" by Spears, Oesterreich, Migliaccio et al. published in Breast Cancer Res Treat, March 2011. PMID- 21597921 TI - Biologic markers determine both the risk and the timing of recurrence in breast cancer. AB - Breast cancer has a long natural history. Established and emerging biologic markers address overall risk but not necessarily timing of recurrence. 346 adjuvant naive breast cancer cases from Guy's Hospital with 23 years minimum follow-up and archival blocks were recut and reassessed for hormone-receptors (HR), HER2-receptor and grade. Disease-specific survival (DSS) was analyzed by recursive partitioning. To validate insights from this analysis, gene-signatures (proliferative and HR-negative) were evaluated for their ability to predict early versus late metastatic risk in 683 node-negative, adjuvant naive breast cancers annotated with expression microarray data. Risk partitioning showed that adjuvant naive node-negative outcome risk was primarily partitioned by tumor receptor status and grade but not tumor size. HR-positive and HER2-negative (HRpos) risk was partitioned by tumor grade; low grade cases have very low early risk but a 20% fall-off in DSS 10 or more years after diagnosis. Higher grade HRpos cases have risk over >20 years. Triple-negative (Tneg) and HER2-positive (HER2pos) cases DSS events occurred primarily within the first 5 years. Among node-positive cases, only low grade conferred late risk, suggesting that proliferative gene signatures that identify proliferation would be important for predicting early but not late recurrence. Using pooled data from four publicly available data sets for node-negative tumors annotated with gene expression and outcome data, we evaluated four prognostic gene signatures: two proliferation-based and two immune function-based. Tumor proliferative capacity predicted early but not late metastatic risk for HRpos cases. The immune function or HRneg specific signatures predicted only early metastatic risk in Tneg and HER2pos cases. Breast cancer prognostic signatures need to inform both risk and timing of metastatic events and may best be applied within subsets. Current signatures predict for outcome risk within 5 years of diagnosis. Predictors of late risk for HR positive disease are needed. PMID- 21597922 TI - Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane treated human breast epithelial cells reveals common expression profiles. AB - Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a potent inhibitor of experimental mammary carcinogenesis and may be an effective, safe chemopreventive agent for use in humans. SFN acts in part on the Keap1/Nrf2 pathway to regulate a battery of cytoprotective genes. In this study, transcriptomic and proteomic changes in the estrogen receptor negative, non tumorigenic human breast epithelial MCF10A cell line were analyzed following SFN treatment or KEAP1 knockdown with siRNA using microarray and stable isotopic labeling with amino acids in culture (SILAC), respectively. Changes in selected transcripts and proteins were confirmed by PCR and Western blot in MCF10A and MCF12A cells. There was strong correlation between the transcriptomic and proteomic responses in both the SFN treatment (R = 0.679, P < 0.05) and KEAP1 knockdown (R = 0.853, P < 0.05) experiments. Common pathways for SFN treatment and KEAP1 knockdown were xenobiotic metabolism and antioxidants, glutathione metabolism, carbohydrate metabolism, and NADH/NADPH regeneration. Moreover, these pathways were most prominent in both the transcriptomic and the proteomic analyses. The aldo-keto reductase family members, AKR1B10, AKR1C1, AKR1C2 and AKR1C3, as well as NQO1 and ALDH3A1, were highly upregulated at both the transcriptomic and the proteomic levels. Collectively, these studies served to identify potential biomarkers that can be used in clinical trials to investigate the initial pharmacodynamic action of SFN in the breast. PMID- 21597923 TI - Type III Klippel-Feil syndrome: case report and review of associated craniofacial anomalies. AB - Klippel-Feil syndrome (KFS) is a complex syndrome of osseous and visceral anomalies that include the classical clinical triad of short neck, limitation of head and neck movements and low posterior hairline. It may also be associated with anomalies of the genitourinary, musculoskeletal, neurologic and cardiac systems. We report a case of type III KFS with associated rib anomalies such as cervical rib, fusion and bifid ribs, scoliosis and fused crossed renal ectopia. The aim of this paper was to summarize all craniofacial anomalies that occur in association with KFS, so that clinicians would be aware of them during diagnosis and treatment planning. PMID- 21597926 TI - A computational model of perception and action for cognitive robotics. AB - Robots are increasingly expected to perform tasks in complex environments. To this end, engineers provide them with processing architectures that are based on models of human information processing. In contrast to traditional models, where information processing is typically set up in stages (i.e., from perception to cognition to action), it is increasingly acknowledged by psychologists and robot engineers that perception and action are parts of an interactive and integrated process. In this paper, we present HiTEC, a novel computational (cognitive) model that allows for direct interaction between perception and action as well as for cognitive control, demonstrated by task-related attentional influences. Simulation results show that key behavioral studies can be readily replicated. Three processing aspects of HiTEC are stressed for their importance for cognitive robotics: (1) ideomotor learning of action control, (2) the influence of task context and attention on perception, action planning, and learning, and (3) the interaction between perception and action planning. Implications for the design of cognitive robotics are discussed. PMID- 21597927 TI - Vertigo is associated with advanced degenerative changes in patients with cervical spondylosis. AB - Since vascular risk factors that predispose to vertebrobasilar ischemia are common findings in elderly, cervical spondylosis-which is also common in such age group-as a cause of vertigo is sometimes considered as a myth. The purpose of this study is to investigate the effect of cervical spondylosis on blood flow velocity of VAs during cervical rotation and to identify the possible association of vertigo with the decreased blood flow velocity through VAs during head rotation in these patients. The incidence of cervical spondylosis was estimated in patients with and without vertigo. Patients with vertigo proved to have spondylosis are further compared with patients having spondylosis but not complaining of vertigo and patients who neither have spondylosis nor complain of vertigo who served as controls. Plain cervical radiography was used to evaluate cervical degenerative changes using cervical degenerative index. Color duplex sonography was used to measure vertebral artery blood flow with the cervical spine in the neutral position then with 60 degrees rotation and 30 degrees extension to measure the opposite vertebral artery. A significantly higher prevalence of cervical spondylosis was found among patients complaining of vertigo than those in non-vertigo group (71.4% vs. 32.9%, respectively). Furthermore, among patients with cervical spondylosis, patients having vertigo showed significantly more evident degenerative changes (P = 0.003). Despite Doppler ultrasound examination with head in neutral position was similar in all groups; cervical spondylosis patients with vertigo had statistically significant lower blood flow parameters with contralateral head rotation in the left and right vertebral arteries than cervical spondylosis patients without vertigo and controls. The decreased vertebral artery blood flow that occurs with cervical rotation can be observed in patients with cervical spondylosis. In patients with high-grade cervical spondylosis with more extensive osteophyte formation, the decreased blood flow becomes prominent and symptomatic presenting as vertigo. PMID- 21597928 TI - The subclinic autonomic dysfunction in patients with Behcet disease: an electrophysiological study. AB - Studies that have evaluated autonomic nervous system (ANS) function in Behcet disease (BD) are rare and have indicated conflicting results with different degrees of involvement. The aim of this study was to investigate ANS function by using electrophysiological tests in patients with BD and to determine the relationship between the disease activity parameters and the indicators of autonomic activity. We included 70 BD patients and 50 healthy controls. Demographic characteristics including age, sex, and disease duration were recorded. A detailed neurological examination was performed, and clinical autonomic symptoms were recorded. The Behcet Disease Current Activity Form (BDCAF) was used to determine the disease activity. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were determined for laboratory activity. The electrophysiological assessments of ANS function were performed by sympathetic skin response (SSR) and R-R interval variation (RRIV) tests. The mean values of sympathetic (SSR latency and amplitude) and parasympathetic (RRIV at rest [R%] and deep breathing [D%], D% - R%, and D%/R%) parameters were compared, and any correlations between ANS parameters and clinical disease characteristics were determined. Seventy BD patients (23 males, 47 females) with a mean age of 41.2 +/- 10.01 years and 50 control subjects (18 males, 32 females) with a mean age of 39.5 +/- 8.94 years were included in the study. All the subjects were totally symptom free with respect to ANS involvement, and the subjects in both groups had normal neurological examination findings. The demographic characteristics were similar between the groups. The mean latency of SSR was increased (1.4 +/- 0.4 vs 0.7 +/- 0.8), and R% (0.3 +/- 0.3 vs 0.5 +/- 0.4) and D% (0.3 +/- 0.3 vs 0.6 +/- 0.5) values were decreased in BD patients compared to control subjects. No correlation was found between BDCAF scores and ANS variables. However, there was a significant correlation between SSR latency and ESR and CRP values (p < 0.01, r = -0.25, r = -0.31, respectively) in the patient group, indicating a more sympathetic dysautonomia in patients with active laboratory parameters. In conclusion, our study indicates a subclinical sympathetic and parasympathetic autonomic dysfunction in patients with BD, which may be related with disease activity. As the early recognition of abnormalities in ANS may be very important in order to prevent excessive morbidity, simple electrophysiological methods are suggested to identify Behcet patients at high risk for symptomatic dysautonomia. PMID- 21597929 TI - It is all me: the effect of viewpoint on visual-vestibular recalibration. AB - Participants performed a visual-vestibular motor recalibration task in virtual reality. The task consisted of keeping the extended arm and hand stable in space during a whole-body rotation induced by a robotic wheelchair. Performance was first quantified in a pre-test in which no visual feedback was available during the rotation. During the subsequent adaptation phase, optical flow resulting from body rotation was provided. This visual feedback was manipulated to create the illusion of a smaller rotational movement than actually occurred, hereby altering the visual-vestibular mapping. The effects of the adaptation phase on hand stabilization performance were measured during a post-test that was identical to the pre-test. Three different groups of subjects were exposed to different perspectives on the visual scene, i.e., first-person, top view, or mirror view. Sensorimotor adaptation occurred for all three viewpoint conditions, performance in the post-test session showing a marked under-compensation relative to the pre test performance. In other words, all viewpoints gave rise to a remapping between vestibular input and the motor output required to stabilize the arm. Furthermore, the first-person and mirror view adaptation induced a significant decrease in variability of the stabilization performance. Such variability reduction was not observed for the top view adaptation. These results suggest that even if all three viewpoints can evoke substantial adaptation aftereffects, the more naturalistic first-person view and the richer mirror view should be preferred when reducing motor variability constitutes an important issue. PMID- 21597930 TI - "Graspability" of objects affects gaze patterns during perception and action tasks. AB - When grasping an object, our gaze marks key positions to which the fingertips are directed. In contrast, eye fixations during perceptual tasks are typically concentrated on an object's centre of mass (COM). However, previous studies have typically required subjects to either grasp the object at predetermined sites or just look at computer-generated shapes "as a whole". In the current study, we investigated gaze fixations during a reaching and grasping task to symmetrical objects and compared these fixations with those made during a perceptual size estimation task using real (Experiment 1) and computer-generated objects (Experiment 2). Our results demonstrated similar gaze patterns in both perception and action to real objects. Participants first fixated a location towards the top edge of the object, consistent with index finger location during grasping, followed by a subsequent fixation towards the object's COM. In contrast, during the perceptual task to computer-generated objects, an opposite pattern in fixation locations was observed, where first fixations were closer to the COM, followed by a subsequent fixation towards the top edge. Even though differential fixation patterns were observed between studies, the area in which these fixations occurred, between the centre of the object and top edge, was the same in all tasks. These results demonstrate for the first time consistencies in fixation locations across both perception and action tasks, particularly when the same type of information (e.g. object size) is important for the completion of both tasks, with fixation locations increasing relative to the object's COM with increases in block height. PMID- 21597932 TI - Present status of autoimmune hepatitis in Japan: a nationwide survey. AB - BACKGROUND: A nationwide survey of autoimmune hepatitis (AIH) was conducted in Japan, and the clinical features of patients with AIH were analyzed. METHODS: A total of 1,056 patients were enrolled through questionnaires sent to 153 hospitals and clinics with hepatology specialists. RESULTS: The clinical features of Japanese AIH were as follows: (1) most patients were middle-aged women, with ages peaking in the 60s; (2) serum immunoglobulin G (IgG) levels were high, but more than 30% of the patients had serum IgG levels less than 2,000 mg/dl; the cutoff level of IgG to distinguish between patients with AIH and those with chronic hepatitis resulting from hepatitis virus was approximately 2,000 mg/dl; (3) autoantibodies, particularly the antinuclear antibody, were frequently present; (4) most patients showed histological features of chronic hepatitis or liver cirrhosis, but 10.9% of the patients showed histological features of acute hepatitis; (5) approximately 75% of the patients were treated with corticosteroids and showed a favorable response to treatment, whereas ursodeoxycholic acid was administered to 60% of the patients. CONCLUSIONS: The clinical features of patients with AIH in Japan were clarified. The mean age at diagnosis was higher than that in previous studies. In addition, the number of patients with AIH having the histological features of acute hepatitis increased. Diagnosis of AIH does not preclude the presence of acute hepatitis and/or serum IgG levels less than 2,000 mg/dl. PMID- 21597931 TI - Current management of symptomatic intracranial stenosis. AB - Intracranial arterial stenosis (IAS) is the cause of about 10% of all ischemic strokes in the United States, but may account for about 40% of strokes in some populations. After a stroke or transient ischemic attack due to IAS, patients face a 12% annual risk of recurrent stroke on medical therapy, with most strokes occurring in the first year. Warfarin is no better than aspirin in preventing recurrent strokes but poses a higher risk of serious bleeding and death. Groups with the highest risk of recurrent stroke are those with high-grade (>= 70%) stenosis, those with recent symptom onset, those with symptoms precipitated by hemodynamic maneuvers, and women. Endovascular treatment of IAS is a rapidly evolving therapeutic option. Antiplatelet agents are currently recommended as the primary treatment for symptomatic IAS, with endovascular therapy reserved for appropriate high-risk cases refractory to medical therapy. PMID- 21597933 TI - Feasibility study of corticosteroid treatment for esophageal ulcer after EMR in a canine model. AB - BACKGROUND: Intralesional or systemic steroid administration is a promising strategy for the prevention of esophageal stricture after endoscopic therapy. The aim of this study was to evaluate the influence of steroid therapy on the process of healing of defects in the esophageal mucosa after endoscopic mucosal resection (EMR). METHODS: Nine beagle dogs were divided into three equal groups: group A, intralesional injection (n = 3), group B, peroral administration (n = 3), and group C, untreated control (n = 3). In group A, triamcinolone acetonide 1 ml (10 mg) was injected directly into the exposed submucosal layer immediately after EMR, and again on postoperative day (POD) 7. In group B, dogs were administered prednisolone 0.5 mg/kg/day orally for 14 days after EMR. In group C, 1 ml normal saline was injected by the same method as that used for group A. On POD 28, histological examination was performed to evaluate epithelialization, inflammation, angiogenesis, and atrophy of the muscularis propria. RESULTS: In groups A, B, and C, the mean ulcer area was 50.1, 22.7, and 7.4 mm(2), respectively. The difference between groups A and C was significant (p < 0.01). Inflammatory cells were significantly more evident in the lesions of group A than in those of group C (p < 0.05). In all groups, atrophy of the muscularis propria was evident. However, transmural destruction and fibrosis were observed only in group A. CONCLUSION: It was speculated that the esophageal ulcer causes the fibrosis of the submucosa and atrophy of the muscularis propria during process of healing. Intralesional steroid injection deepened the esophageal ulcers and delayed epithelialization, whereas systemic administration did not clearly improve the lesion healing process. PMID- 21597934 TI - Serum glutamine synthetase has no value as a diagnostic biomarker for Alzheimer's disease. AB - In order to test whether serum glutamine synthetase (GS) is of potential diagnostic value for Alzheimer's disease (AD), we set up a study to compare serum GS concentrations between AD patients and control subjects. The study population (n = 165) consisted of AD patients (n = 94) and age-matched (n = 41) and age unmatched (n = 30) control subjects. Serum GS analysis was performed by means of ELISA. No significant differences in serum GS levels were found between the AD group and age-matched controls. Age correlated positively with serum GS concentrations in AD patients and control subjects. This study suggests that serum GS levels have no diagnostic value for AD. PMID- 21597935 TI - Synergistic effects of sodium butyrate, a histone deacetylase inhibitor, on increase of neurogenesis induced by pyridoxine and increase of neural proliferation in the mouse dentate gyrus. AB - We previously observed that pyridoxine (vitamin B(6)) significantly increased cell proliferation and neuroblast differentiation without any neuronal damage in the hippocampus. In this study, we investigated the effects of sodium butyrate, a histone deacetylase (HDAC) inhibitor which serves as an epigenetic regulator of gene expression, on pyridoxine-induced neural proliferation and neurogenesis induced by the increase of neural proliferation in the mouse dentate gyrus. Sodium butyrate (300 mg/kg, subcutaneously), pyridoxine (350 mg/kg, intraperitoneally), or combination with sodium butyrate were administered to 8 week-old mice twice a day and once a day, respectively, for 14 days. The administration of sodium butyrate significantly increased acetyl-histone H3 levels in the dentate gyrus. Sodium butyrate alone did not show the significant increase of cell proliferation in the dentate gyrus. But, pyridoxine alone significantly increased cell proliferation. Sodium butyrate in combination with pyridoxine robustly enhanced cell proliferation and neurogenesis induced by the increase of neural proliferation in the dentate gyrus, showing that sodium butyrate treatment distinctively enhanced development of neuroblast dendrites. These results indicate that an inhibition of HDAC synergistically promotes neurogenesis induced by a pyridoxine and increase of neural proliferation. PMID- 21597936 TI - Climate change and future temperature-related mortality in 15 Canadian cities. AB - The environmental changes caused by climate change represent a significant challenge to human societies. One part of this challenge will be greater heat related mortality. Populations in the northern hemisphere will experience temperature increases exceeding the global average, but whether this will increase or decrease total temperature-related mortality burdens is debated. Here, we use distributed lag modeling to characterize temperature-mortality relationships in 15 Canadian cities. Further, we examine historical trends in temperature variation across Canada. We then develop city-specific general linear models to estimate change in high- and low-temperature-related mortality using dynamically downscaled climate projections for four future periods centred on 2040, 2060 and 2080. We find that the minimum mortality temperature is frequently located at approximately the 75th percentile of the city's temperature distribution, and that Canadians currently experience greater and longer lasting risk from cold-related than heat-related mortality. Additionally, we find no evidence that temperature variation is increasing in Canada. However, the projected increased temperatures are sufficient to change the relative levels of heat- and cold-related mortality in some cities. While most temperature-related mortality will continue to be cold-related, our models predict that higher temperatures will increase the burden of annual temperature-related mortality in Hamilton, London, Montreal and Regina, but result in slight to moderate decreases in the burden of mortality in the other 11 cities investigated. PMID- 21597937 TI - Early nutritional support in non-metastatic stage IV oral cavity cancer patients undergoing adjuvant concurrent chemoradiotherapy: analysis of treatment tolerance and outcome in an area endemic for betel quid chewing. AB - PURPOSE: Non-metastatic stage IV oral cavity cancer patients undergoing concurrent chemoradiotherapy (CCRT) are at risk of malnutrition because of postoperative eating problems and CCRT-related complications. A high percentage of betel quid use, which is associated with metabolic disorders, is found in oral cavity cancer patients in Taiwan. The aim of this study is to evaluate the effect of an early and intensive nutritional support program, comprising individualized counseling, nasogastric tube feeding, and mandatory hospitalization, throughout the CCRT period for such cases in an area where betel quid use is prevalent. METHODS: We retrospectively analyzed 35 patients with nutritional support (NI) and 23 patients with no specifically designed nutrition program (NC). RESULTS: The NI group had better maintenance of body weight (p < 0.001) and higher serum albumin levels (p < 0.002) than the NC group. There was no difference in the total dose of radiation completed in the two groups; in contrast, the percentage of NI group patients who had radiation therapy (RT) breaks was lower and who completed planned chemotherapy was higher than in the NC group. Furthermore, more NC group patients suffered from sepsis during the treatment period, and fewer were alive 2 years after treatment. CONCLUSIONS: An early and intensive nutrition support may be beneficial to minimizing body weight loss, offering better treatment tolerance and probable survival benefits for patients with non metastatic stage IV oral cavity cancers undergoing CCRT in endemic betel quid chewing areas. PMID- 21597938 TI - Prospective evaluation of HSV, Candida spp., and oral bacteria on the severity of oral mucositis in pediatric acute lymphoblastic leukemia. AB - BACKGROUND: Oral mucositis is a common collateral effect among the secondary complications resulting from chemotherapy. The objective of this study was to prospectively evaluate the association of HSV-1, Candida spp., and oral bacteria on the severity of oral mucositis in pediatric acute lymphoblastic leukemia (ALL). PROCEDURE: Seventy-one prospective patients were included. Analyses of oral microbiota were conducted on days 14 (D14) and 56 (D56) of the Brazilian GBTLI-99 treatment protocol. Herpes simplex virus (HSV) identification was performed by PCR followed by DNA sequencing analysis. Bacteria and fungi identification was obtained by standard microbiological culture tests. RESULTS: HSV-1 was found in 10.37% of individual patient samples. One sample was positive for HSV-4. On D14, we found an association between the severity of mucositis and the presence of HSV (p = 0.0347) and Candida spp. (p = 0.0078). At D56, we found an association between the severity of mucositis and the presence of HSV on D14 (p < 0.0001) and HSV presence (p = 0.0317). CONCLUSION: The presence of HSV, mainly HSV-1, and Candida spp. was associated with mucositis severity in pediatric ALL. No association could be found between bacterial CFU and severity of mucositis. PMID- 21597939 TI - Are different groups of cancer patients offered rehabilitation to the same extent? A report from the population-based study "The Cancer Patient's World". AB - PURPOSE: The number of cancer survivors is growing and cancer is now viewed as a chronic disease. This has highlighted the importance of providing adequate rehabilitation to prevent physical, psychological, and social sequelae of cancer. However, it is unclear whether those in need of rehabilitation are offered this. METHODS: Using patient-observer agreement and cognitive interviews, we validated a seven-item questionnaire designed to assess cancer patients' perception of the sufficiency of the offered rehabilitation. A cross-sectional study among 2,202 Danish cancer patients affiliated with hospitals was carried out. RESULTS: The questionnaire was well understood, indicating good validity. In the cross sectional study, 1,490 patients (68%) participated. Up to 39% of cancer patients did not receive the physical rehabilitation they felt they needed. About half of those who had felt a need to talk to a psychologist were offered this. Insufficiency of other rehabilitation offers was reported by 10-24%. Age most consistently predicted insufficient rehabilitation; higher age predicted insufficient information about support from other sources (than hospital staff) and younger age predicted lack of help to manage symptoms, return to everyday life, and deal with financial and especially work-related consequences. We found no consistent signs of traditional social inequality in the perception of rehabilitation, but we observed some signs of social inequality for unemployed or divorced/separated patients. CONCLUSIONS: Age predicted sufficiency of the rehabilitation in two directions, possibly reflecting different needs in younger and older patients. When tailoring rehabilitation programs, it should be ensured that the different needs are met. PMID- 21597940 TI - Community structure and function of planktonic Crenarchaeota: changes with depth in the South China Sea. AB - Marine Crenarchaeota represent a widespread and abundant microbial group in marine ecosystems. Here, we investigated the abundance, diversity, and distribution of planktonic Crenarchaeota in the epi-, meso-, and bathypelagic zones at three stations in the South China Sea (SCS) by analysis of crenarchaeal 16S rRNA gene, ammonia monooxygenase gene amoA involved in ammonia oxidation, and biotin carboxylase gene accA putatively involved in archaeal CO(2) fixation. Quantitative PCR analyses indicated that crenarchaeal amoA and accA gene abundances varied similarly with archaeal and crenarchaeal 16S rRNA gene abundances at all stations, except that crenarchaeal accA genes were almost absent in the epipelagic zone. Ratios of the crenarchaeal amoA gene to 16S rRNA gene abundances decreased ~2.6 times from the epi- to bathypelagic zones, whereas the ratios of crenarchaeal accA gene to marine group I crenarchaeal 16S rRNA gene or to crenarchaeal amoA gene abundances increased with depth, suggesting that the metabolism of Crenarchaeota may change from the epi- to meso- or bathypelagic zones. Denaturing gradient gel electrophoresis profiling of the 16S rRNA genes revealed depth partitioning in archaeal community structures. Clone libraries of crenarchaeal amoA and accA genes showed two clusters: the "shallow" cluster was exclusively derived from epipelagic water and the "deep" cluster was from meso- and/or bathypelagic waters, suggesting that niche partitioning may take place between the shallow and deep marine Crenarchaeota. Overall, our results show strong depth partitioning of crenarchaeal populations in the SCS and suggest a shift in their community structure and ecological function with increasing depth. PMID- 21597942 TI - Corrugator supercilii transection for headache emanating from the frontal region: a clinical evaluation of ten patients. AB - Chronic daily headache (CDH) located in the frontal region is a common problem. We have previously described the positive results that were achieved with botulinum toxin (BTX) injections in the musculus corrugator supercilii (MCS) for this disorder. Nowadays, we offer transection of this muscle to patients following a minimum of two BTX injections, provided these injections result in a significant reduction of pain. This procedure is based on the assumption that the pathophysiological mechanism in some of these patients suffering from CDH is a neural entrapment of the supratrochlear nerve in the corrugator muscle. To assess the effect of transection, we have evaluated all the consecutive patients (n = 10) so far. Treatment was successful in nine of these patients. Prior to the treatment, the mean pain score in the 9 successfully treated patients was 8.1 (range 6-9), after transection this had been reduced to 0.8 (range 0-3). All of these successfully treated patients ceased their daily use of pain relief medication for their frontally localised headaches. Moreover, they stated that they would definitely undergo surgery, if they were to find themselves in the same situation again. Therefore, we conclude that transection of the MCS is an efficient and successful procedure for a carefully selected group of patients suffering from CDH in the frontal region. Most of all we intend to popularise this pathophysiological concept based on the distinct possibility that some headaches might be due to neural entrapment. PMID- 21597943 TI - Gender and binegativity: men's and women's attitudes toward male and female bisexuals. AB - This study assessed the influence of gender on attitudes about bisexuals. A total of 164 heterosexual female and 89 heterosexual male undergraduates completed the Biphobia Scale (Mulick & Wright, 2002), rewritten to refer to bisexual men and bisexual women and thus re-named the Gender-Specific Binegativity Scale. A mixed design ANOVA revealed an interaction between rater's sex and target's sex: women equally accepted bisexual men and bisexual women, but men were less accepting of bisexual men than bisexual women. A mediation analysis indicated the relationship between rater's sex and greater acceptance of bisexual women was partially explained by eroticization of female same-sex sexuality. Finally, participants also responded to two open-ended items, which provided additional information about the content of binegativity: participants described male bisexuals negatively, as gender-nonconforming, and labeled them "really gay," whereas participants described female bisexuals positively, as sexy, and labeled them "really heterosexual." These findings suggest multiple underlying beliefs about bisexuals that contribute to binegativity, particularly against bisexual men. Results also confirm the importance of considering gender (of both the target and the rater) when assessing sexual prejudice. PMID- 21597944 TI - Breeding state and season affect interspecific interaction types: indirect resource competition and direct interference. AB - Indirect resource competition and interference are widely occurring mechanisms of interspecific interactions. We have studied the seasonal expression of these two interaction types within a two-species, boreal small mammal system. Seasons differ by resource availability, individual breeding state and intraspecific social system. Live-trapping methods were used to monitor space use and reproduction in 14 experimental populations of bank voles Myodes glareolus in large outdoor enclosures with and without a dominant competitor, the field vole Microtus agrestis. We further compared vole behaviour using staged dyadic encounters in neutral arenas in both seasons. Survival of the non-breeding overwintering bank voles was not affected by competition. In the spring, the numbers of male bank voles, but not of females, were reduced significantly in the competition populations. Bank vole home ranges expanded with vole density in the presence of competitors, indicating food limitation. A comparison of behaviour between seasons based on an analysis of similarity revealed an avoidance of costly aggression against opponents, independent of species. Interactions were more aggressive during the summer than during the winter, and heterospecific encounters were more aggressive than conspecific encounters. Based on these results, we suggest that interaction types and their respective mechanisms are not either-or categories and may change over the seasons. During the winter, energy constraints and thermoregulatory needs decrease direct aggression, but food constraints increase indirect resource competition. Direct interference appears in the summer, probably triggered by each individual's reproductive and hormonal state and the defence of offspring against conspecific and heterospecific intruders. Both interaction forms overlap in the spring, possibly contributing to spring declines in the numbers of subordinate species. PMID- 21597941 TI - Deep brain stimulation for movement disorders. Considerations on 276 consecutive patients. AB - The links between Stn DBS and advanced Parkinson disease, and between GPi DBS and dystonia are nearly universally accepted by the neurologists and neurosurgeons. Nevertheless, in some conditions, targets such as the ventral thalamus and the Zona Incerta may be considered to optimize the results and avoid the side effects. Positive and negative aspects of current DBS treatments justify the research of new targets, new stimulation programs and new hardware. Since 1993, at the Istituto Nazionale Neurologico "Carlo Besta" in Milan, 580 deep brain electrodes were implanted in 332 patients. 276 patients were affected by movement disorders. The DBS targets included Stn, GPi, Voa, Vop, Vim, CM-pf, cZi, IC. The long-term follow-up is reported and related to the chosen target. DBS gave a new therapeutic option to patients affected by severe movement disorders, and in some cases resolved life-threatening pathological conditions that would otherwise result in the death of the patient, such as in status dystonicus, and post-stroke hemiballismus. Nevertheless, the potential occurrence of severe complications still limit a wider use of DBS. At today, the use of DBS in severe movement disorders is strongly positive even if further investigations and studies are needed to unveil potential new applications, and to refine the selection criteria for the actual indications and targets. The experience of different targets may be useful to guide and tailor the target choice to the individual clinical condition. PMID- 21597945 TI - Association between acute lymphoblastic leukemia (ALL) and der(8;9)(q10;q10): a novel case of double der(8;9) in Ph+ adult B cell ALL. PMID- 21597946 TI - Pigment dispersion secondary to anterior chamber angle recession. PMID- 21597947 TI - Effect of menthol on ocular drug delivery. AB - BACKGROUND: To assess how safe and effective it is to use menthol as a permeability enhancer in ophthalmic drug delivery systems. METHODS: In this study, the effect of menthol on permeability of dexamethasone disodium phosphate in the cornea and sclera was investigated in vitro. Application of topical drops and subconjunctival injection of dexamethasone disodium phosphate with or without 0.1% menthol was administered to rabbit eyes, and the drug concentration was detected in aqueous humor, cornea, vitreous, and retinochoroidal tissues. The safety of menthol was assessed on the basis of corneal hydration level, Draize test, electroretinography (ERG), and histological examination. RESULTS: 0.05% and 0.1% menthol significantly enhanced the penetration of dexamethasone in the cornea, but did not change the dexamethasone penetration in sclera in vitro. When topical drops of dexamethasone containing 0.1% menthol were administered, a significantly increased concentration of dexamethasone in the cornea and aqueous humor tissues was reported, but dexamethasone concentrations remained unaffected in the retina-choroid tissues. On the other hand, increased drug concentration in aqueous humor, cornea, vitreous and retinochoroidal tissues was achieved through subconjunctival injection. No signs of irritation were observed when menthol was administered at concentrations ranging from 0.025%-0.1%; moreover, no substantial toxic reactions were observed in corneal hydration level, electrophysiological, or histological examinations after the addition of 0.1% menthol. CONCLUSIONS: Menthol may improve the ocular penetration of a drug in a transcorneal and transscleral drug delivery system without causing toxic reactions. PMID- 21597949 TI - Treatment of bisphosphonate-induced osteonecrosis of the jaws with Nd:YAG laser biostimulation. PMID- 21597948 TI - The effects of low-level laser irradiation on differentiation and proliferation of human bone marrow mesenchymal stem cells into neurons and osteoblasts--an in vitro study. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) are promising for use in regenerative medicine. Several studies have shown that low-level laser irradiation (LLLI) could affect the differentiation and proliferation of MSCs. The aim of this study was to examine the influence of LLLI at different energy densities on BMSCs differentiation into neuron and osteoblast. Human BMSCs were cultured and induced to differentiate to either neuron or osteoblast in the absence or presence of LLLI. Gallium aluminum arsenide (GaAlAs) laser irradiation (810 nm) was applied at days 1, 3, and 5 of differentiation process at energy densities of 3 or 6 J/cm(2) for BMSCs being induced to neurons, and 2 or 4 J/cm(2) for BMSCs being induced to osteoblasts. BMSCs proliferation was evaluated by MTT assay on the seventh day of differentiation. BMSCs differentiation to neurons was assessed by immunocytochemical analysis of neuron-specific enolase on the seventh day of differentiation. BMSCs differentiation to osteoblast was tested on the second, fifth, seventh, and tenth day of differentiation via analysis of alkaline phosphatase (ALP) activity. LLLI promoted BMSCs proliferation significantly at all energy densities except for 6 J/cm(2) in comparison to control groups on the seventh day of differentiation. LLLI at energy densities of 3 and 6 J/cm(2) dramatically facilitated the differentiation of BMSCs into neurons (p < 0.001). Also, ALP activity was significantly enhanced in irradiated BMSCs differentiated to osteoblast on the second, fifth, seventh, and tenth day of differentiation (p < 0.001 except for the second day). Using LLLI at 810 nm wavelength enhances BMSCs differentiation into neuron and osteoblast in the range of 2-6 J/cm(2), and at the same time increases BMSCs proliferation (except for 6 J/cm(2)). The effect of LLLI on differentiation and proliferation of BMSCs is dose-dependent. Considering these findings, LLLI could improve current in vitro methods of differentiating BMSCs prior to transplantation. PMID- 21597950 TI - Leuconostoc bacteremia in a patient with amyloidosis secondary to rheumatoid arthritis and tuberculosis arthritis. AB - Leuconostoc infections are rare and usually occur in immunocompromised patients. This report describes a case of Leuconostoc lactis bacteremia in a patient with coexisting rheumatoid arthritis and tuberculosis arthritis. A disrupted gastrointestinal barrier due to gastrointestinal amyloidosis in long-standing rheumatoid arthritis and tuberculosis arthritis could be a risk factor for Leuconostoc bacteremia. Despite aggressive antibiotic treatment, the patient progressed to septic shock and multi-organ failure. The fatal course might have been caused by rapid progression of gastrointestinal pathology, which could be a risk factor for Leuconostoc bacteremia. PMID- 21597951 TI - Guidance on using tocilizumab for juvenile idiopathic arthritis. AB - Medical care for rheumatic disease in children has been supported by advances in rheumatology. In the past few years and based on knowledge about cytokines, particularly marked advances have been made in treatments using biological products. The fact that patients showed a marked response to treatment with biological products also provided uniform direction to treatment choice, which had previously been chaotic. On the other hand, biological products inhibit the action of physiologically essential substances, such as inflammatory cytokines or their receptors. This led to concerns about the risk of fatal or life-threatening adverse reactions, and rheumatologists are now required to take a disciplined approach to the use of these products. Thus, we sincerely hope that this guidance on using tocilizumab for juvenile idiopathic arthritis serves as a desk reference for pediatric rheumatologists and other healthcare professionals treating children with rheumatic diseases by biological drugs. PMID- 21597952 TI - Investigation of a dual fetal infection model with bovine viral diarrhoea viruses (BVDV)-1 and BVDV-2. AB - Two studies were performed in pregnant heifers to determine whether inoculation with two bovine viral diarrhoea viruses (BVDV), one BVDV-1 and one BVDV-2, inoculated separately into either nostril, results in fetal infection with both viruses. Dual transplacental infection of the fetus with BVDV-1 and BVDV-2 was observed in one case, but not consistently. PMID- 21597954 TI - Continuum limits of pattern formation in hexagonal-cell monolayers. AB - Intercellular signalling is key in determining cell fate. In closely packed tissues such as epithelia, juxtacrine signalling is thought to be a mechanism for the generation of fine-grained spatial patterns in cell differentiation commonly observed in early development. Theoretical studies of such signalling processes have shown that negative feedback between receptor activation and ligand production is a robust mechanism for fine-grained pattern generation and that cell shape is an important factor in the resulting pattern type. It has previously been assumed that such patterns can be analysed only with discrete models since significant variation occurs over a lengthscale concomitant with an individual cell; however, considering a generic juxtacrine signalling model in square cells, in O'Dea and King (Math Biosci 231(2):172-185 2011), a systematic method for the derivation of a continuum model capturing such phenomena due to variations in a model parameter associated with signalling feedback strength was presented. Here, we extend this work to derive continuum models of the more complex fine-grained patterning in hexagonal cells, constructing individual models for the generation of patterns from the homogeneous state and for the transition between patterning modes. In addition, by considering patterning behaviour under the influence of simultaneous variation of feedback parameters, we construct a more general continuum representation, capturing the emergence of the patterning bifurcation structure. Comparison with the steady-state and dynamic behaviour of the underlying discrete system is made; in particular, we consider pattern-generating travelling waves and the competition between various stable patterning modes, through which we highlight an important deficiency in the ability of continuum representations to accommodate certain dynamics associated with discrete systems. PMID- 21597953 TI - Uniformity of rotavirus strain nomenclature proposed by the Rotavirus Classification Working Group (RCWG). AB - In April 2008, a nucleotide-sequence-based, complete genome classification system was developed for group A rotaviruses (RVs). This system assigns a specific genotype to each of the 11 genome segments of a particular RV strain according to established nucleotide percent cutoff values. Using this approach, the genome of individual RV strains are given the complete descriptor of Gx-P[x]-Ix-Rx-Cx-Mx-Ax Nx-Tx-Ex-Hx. The Rotavirus Classification Working Group (RCWG) was formed by scientists in the field to maintain, evaluate and develop the RV genotype classification system, in particular to aid in the designation of new genotypes. Since its conception, the group has ratified 51 new genotypes: as of April 2011, new genotypes for VP7 (G20-G27), VP4 (P[28]-P[35]), VP6 (I12-I16), VP1 (R5-R9), VP2 (C6-C9), VP3 (M7-M8), NSP1 (A15-A16), NSP2 (N6-N9), NSP3 (T8-T12), NSP4 (E12 E14) and NSP5/6 (H7-H11) have been defined for RV strains recovered from humans, cows, pigs, horses, mice, South American camelids (guanaco), chickens, turkeys, pheasants, bats and a sugar glider. With increasing numbers of complete RV genome sequences becoming available, a standardized RV strain nomenclature system is needed, and the RCWG proposes that individual RV strains are named as follows: RV group/species of origin/country of identification/common name/year of identification/G- and P-type. In collaboration with the National Center for Biotechnology Information (NCBI), the RCWG is also working on developing a RV specific resource for the deposition of nucleotide sequences. This resource will provide useful information regarding RV strains, including, but not limited to, the individual gene genotypes and epidemiological and clinical information. Together, the proposed nomenclature system and the NCBI RV resource will offer highly useful tools for investigators to search for, retrieve, and analyze the ever-growing volume of RV genomic data. PMID- 21597957 TI - Dr. Hiroaki Takekura. A tribute to a life of science. PMID- 21597956 TI - A systematic review of quality of life in adults with muscle disease. AB - We reviewed the literature on how muscle disease affects quality of life compared to healthy controls, and the factors that influence the effects of muscle disease on quality of life. We also wanted to know whether quality of life differed between muscle diseases. We searched online databases and identified 26 relevant studies. The quality of each study was assessed, results sections analysed and a database of factors associated with quality of life developed. We graded the level of evidence supporting the association between each factor and quality of life as inconclusive, moderate or high. Compared to controls, muscle disease compromised quality of life in all areas of functioning. There was little evidence to suggest that quality of life differed significantly between muscle diseases. There was a high level of evidence suggesting that disease severity, pain, fatigue, and mood significantly affect quality of life. There was a moderate level of evidence suggesting that illness perceptions, coping strategies, age and gender affect quality of life. Several factors had an inconsistent level of evidence. PMID- 21597958 TI - Generation of a monoclonal antibody reactive to prefusion myocytes. AB - We established a novel monoclonal antibody, Yaksa that is specific to a subpopulation of myogenic cells. The Yaksa antigen is not expressed on the surface of growing myoblasts but only on a subpopulation of myogenin-positive myocytes. When Yaksa antigen-positive mononucleated cells were freshly prepared from a murine myogenic cell by a cell sorter, they fused with each other and formed multinucleated myotubes shortly after replating while Yaksa antigen negative cells scarcely generated myotubes. These results suggest that Yaksa could segregate fusion-competent, mononucleated cells from fusion-incompetent cells during muscle differentiation. The Yaksa antigen was also expressed in developing muscle and regenerating muscle in vivo and it was localized at sites of cell-cell contact between mono-nucleated muscle cells and between mono nucleated muscle cells and myotubes. Thus, Yaksa that marks prefusion myocytes before myotube formation can be a useful tool to elucidate the cellular and molecular mechanisms of myogenic cell fusion. PMID- 21597959 TI - Sarcocystis sp. from the herring gull (Larus argentatus) identity to Sarcocystis wobeseri based on cyst morphology and DNA results. AB - Having studied 11 herring gulls (Larus argentatus) Sarcocystis cysts were found in neck and leg muscles of 4 birds. One type of sarcocysts (cyst type I) that have a thin (~1.0 MUm), smooth, or slightly wavy cyst wall without clearly visible protrusions and small (6.0-8.0 MUm) lancet- or banana-shaped cystozoites was identified by the light microscopy. Sarcocysts extracted from one herring gull were used for electron microscopy and DNA analysis. Ultrastructurally, Sarcocystis sp. from the herring gull had the same tissue cyst wall type-1 as S. calchasi, S. columbae, and S. wobeseri parasitizing in birds. According to first internal transcribed spacer (ITS-1) region, 18S rRNA and 28S rRNA gene sequences, Sarcocystis sp. from the herring gull belongs to S. wobeseri. Nevertheless, without evidences of cross-transmission experiment sarcocysts extracted from herring gull at present time are named as S. wobeseri-like. PMID- 21597960 TI - Left ventricular assist device support with a centrifugal pump for 2 months in a 5-kg child. AB - The mid-term and long-term results of left ventricular assist device (LVAD) implantation for small children are still unsatisfactory. There have been few reports of LVAD implantation for more than a month in children weighing under 5 kg. We report the case of a 4-month-old female infant who survived for 2 months after being diagnosed with dilated cardiomyopathy (DCM) with extracorporeal centrifugal pump support. In recent years, although pumps designed for small children have been introduced and are used as a bridge to transplantation or recovery, mid-term or long-term mechanical support for small children with heart failure is still difficult. We managed to successfully provide support for a low body-weight child with a centrifugal pump over a mid-term period. We achieved acceptable control of thrombosis, but eventually the infant died of sepsis. Autopsy revealed no prominent thrombosis in the perfusion cannula, drainage cannula, the pump, or the left ventricle. This is the first case report of LVAD support with the centrifugal pump, ROTAFLOW((r)) (Maquet, Rastatt, Germany), for 2 months in a child weighing under 5 kg. Our method may potentially save severe heart failure children who need mid-term LVAD support. PMID- 21597961 TI - Expression of a wheat MYB gene in transgenic tobacco enhances resistance to Ralstonia solanacearum, and to drought and salt stresses. AB - MYB transcription factors play diverse roles in plant growth, developmental processes and stress responses. A full-length cDNA sequence of a MYB gene, namely TaPIMP1, was isolated from wheat (Triticum aestivum L.). The TaPIMP1 transcript level was significantly up-regulated by inoculation with a fungal pathogen Bipolaris sorokiniana and by drought treatment. TaPIMP1 encodes the MYB protein TaPIMP1 consisting of 323 amino acids. TaPIMP1 contains two MYB DNA binding domains (R2, R3), two putative nuclear localization sites and two putative transcription activation domains. TaPIMP1 is a new member of the R2R3-MYB transcription factor subfamily. Transient expression in onion epidermal cells of GFP fused with TaPIMP1 proved that subcellular localization of TaPIMP1 occurred in the nucleus. The TaPIMP1 gene was transferred into tobacco (Nicotiana tabacum L.) cultivar W38 by Agrobacterium-mediated transformation. After screening through PCR and RT-PCR analyses, transgenic tobacco lines expressing TaPIMP1 were identified and evaluated for pathogen resistance, and drought and salt tolerance. Compared to untransformed tobacco host plants, TaPIMP1 expressing plants displayed significantly enhanced resistance to Ralstonia solanacearum and exhibited improved tolerances to drought and salt stresses. In these transgenic lines, the activities of phenylalanine ammonia-lyase (PAL) and superoxide dismutase (SOD) were significantly increased relative to wild-type tobacco plants. The results suggested that the wheat R2R3-MYB transcription factor plays an important role in modulating responses to biotic and abiotic stresses. PMID- 21597962 TI - Computational characterization of the molecular structure and properties of Dye 7 for organic photovoltaics. AB - Organic dyes have great potential for its use in solar cells. In this recent work, the molecular structure and properties of Dye 7 were obtained using density functional theory (DFT) and different levels of calculation. Upon comparing the molecular structure and the ultraviolet visible spectrum with experimental data reported in the literature, it was found that the M05-2X/6-31G(d) level of calculation gave the best approximation. Once the appropriate methodology had been obtained, the molecule was characterized by obtaining the infrared spectrum, dipole moment, total energy, isotropic polarizability, molecular orbital energies, free energy of solvation in different solvents, and the chemical reactivity sites using the condensed Fukui functions. PMID- 21597963 TI - Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivation. AB - X-chromosome inactivation (XCI) results in the differential marking of the active and inactive X with epigenetic modifications including DNA methylation. Consistent with the previous studies showing that CpG island-containing promoters of genes subject to XCI are approximately 50% methylated in females and unmethylated in males while genes which escape XCI are unmethylated in both sexes; our chromosome-wide (Methylated DNA ImmunoPrecipitation) and promoter targeted methylation analyses (Illumina Infinium HumanMethylation27 array) showed the largest methylation difference (D = 0.12, p < 2.2 E-16) between male and female blood at X-linked CpG islands promoters. We used the methylation differences between males and females to predict XCI statuses in blood and found that 81% had the same XCI status as previously determined using expression data. Most genes (83%) showed the same XCI status across tissues (blood, fetal: muscle, kidney and nerual); however, the methylation of a subset of genes predicted different XCI statuses in different tissues. Using previously published expression data the effect of transcription on gene-body methylation was investigated and while X-linked introns of highly expressed genes were more methylated than the introns of lowly expressed genes, exonic methylation did not differ based on expression level. We conclude that the XCI status predicted using methylation of X-linked promoters with CpG islands was usually the same as determined by expression analysis and that 12% of X-linked genes examined show tissue-specific XCI whereby a gene has a different XCI status in at least one of the four tissues examined. PMID- 21597965 TI - Short-term effects of unilateral lesion of the primary motor cortex (M1) on ipsilesional hand dexterity in adult macaque monkeys. AB - Although the arrangement of the corticospinal projection in primates is consistent with a more prominent role of the ipsilateral motor cortex on proximal muscles, rather than on distal muscles involved in manual dexterity, the role played by the primary motor cortex on the control of manual dexterity for the ipsilateral hand remains a matter a debate, either in the normal function or after a lesion. We, therefore, tested the impact of permanent unilateral motor cortex lesion on the manual dexterity of the ipsilateral hand in 11 macaque monkeys, within a time window of 60 days post-lesion. For comparison, unilateral reversible pharmacological inactivation of the motor cortex was produced in an additional monkey. Manual dexterity was assessed quantitatively based on three motor parameters derived from two reach and grasp manual tasks. In contrast to the expected dramatic, complete deficit of manual dexterity of the contralesional hand that persists for several weeks, the impact on the manual dexterity of the ipsilesional hand was generally moderate (but statistically significant) and, when present, lasted less than 20 days. Out of the 11 monkeys, only 3 showed a deficit of the ipsilesional hand for 2 of the 3 motor parameters, and 4 animals had a deficit for only one motor parameter. Four monkeys did not show any deficit. The reversible inactivation experiment yielded results consistent with the permanent lesion data. In conclusion, the primary motor cortex exerts a modest role on ipsilateral manual dexterity, most likely in the form of indirect hand postural control. PMID- 21597966 TI - Infusion-based manganese-enhanced MRI: a new imaging technique to visualize the mouse brain. AB - Manganese-enhanced magnetic resonance imaging is a technique that employs the divalent ion of the paramagnetic metal manganese (Mn(2+)) as an effective contrast agent to visualize, in vivo, the mammalian brain. As total achievable contrast is directly proportional to the net amount of Mn(2+) accumulated in the brain, there is a great interest in optimizing administration protocols to increase the effective delivery of Mn(2+) to the brain while avoiding the toxic effects of Mn(2+) overexposure. In this study, we investigated outcomes following continuous slow systemic infusion of manganese chloride (MnCl(2)) into the mouse via mini-osmotic pump administration. The effects of increasing fractionated rates of Mn(2+) infusion on signal enhancement in regions of the brain were analyzed in a three-treatment study. We acquired whole-brain 3-D T1-weighted images and performed region of interest quantitative analysis to compare mean normalized signal in Mn(2+) treatments spanning 3, 7, or 14 days of infusion (rates of 1, 0.5, and 0.25 MUL/h, respectively). Evidence of Mn(2+) transport at the conclusion of each infusion treatment was observed throughout the brains of normally behaving mice. Regions of particular Mn(2+) accumulation include the olfactory bulbs, cortex, infralimbic cortex, habenula, thalamus, hippocampal formation, amygdala, hypothalamus, inferior colliculus, and cerebellum. Signals measured at the completion of each infusion treatment indicate comparable means for all examined fractionated rates of Mn(2+) infusion. In this current study, we achieved a significantly higher dose of Mn(2+) (180 mg/kg) than that employed in previous studies without any observable toxic effects on animal physiology or behavior. PMID- 21597967 TI - Neurodegeneration in the somatosensory cortex after experimental diffuse brain injury. AB - Disruption and consequent reorganization of central nervous system circuits following traumatic brain injury may manifest as functional deficits and behavioral morbidities. We previously reported axotomy and neuronal atrophy in the ventral basal (VB) complex of the thalamus, without gross degeneration after experimental diffuse brain injury in adult rats. Pathology in VB coincided with the development of late-onset aberrant behavioral responses to whisker stimulation, which lead to the current hypothesis that neurodegeneration after experimental diffuse brain injury includes the primary somatosensory barrel cortex (S1BF), which receives projection of VB neurons and mediates whisker somatosensation. Over 28 days after midline fluid percussion brain injury, argyrophilic reaction product within superficial layers and layer IV barrels at 1 day progresses into the cortex to subcortical white matter by 7 days, and selective inter-barrel septa and subcortical white matter labeling at 28 days. Cellular consequences were determined by stereological estimates of neuronal nuclear volumes and number. In all cortical layers, neuronal nuclear volumes significantly atrophied by 42-49% at 7 days compared to sham, which marginally attenuated by 28 days. Concomitantly, the number of healthy neurons was reduced by 34-45% at 7 days compared to sham, returning to control levels by 28 days. Progressive neurodegeneration, including argyrophilic reaction product and neuronal nuclear atrophy, indicates injury-induced damage and reorganization of the reciprocal thalamocortical projections that mediate whisker somatosensation. The rodent whisker barrel circuit may serve as a discrete model to evaluate the causes and consequences of circuit reorganization after diffuse brain injury. PMID- 21597964 TI - Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers. AB - Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews. PMID- 21597968 TI - Hippocampal pyramidal cells: the reemergence of cortical lamination. AB - The increasing resolution of tract-tracing studies has led to the definition of segments along the transverse axis of the hippocampal pyramidal cell layer, which may represent functionally defined elements. This review will summarize evidence for a morphological and functional differentiation of pyramidal cells along the radial (deep to superficial) axis of the cell layer. In many species, deep and superficial sublayers can be identified histologically throughout large parts of the septotemporal extent of the hippocampus. Neurons in these sublayers are generated during different periods of development. During development, deep and superficial cells express genes (Sox5, SatB2) that also specify the phenotypes of superficial and deep cells in the neocortex. Deep and superficial cells differ neurochemically (e.g. calbindin and zinc) and in their adult gene expression patterns. These markers also distinguish sublayers in the septal hippocampus, where they are not readily apparent histologically in rat or mouse. Deep and superficial pyramidal cells differ in septal, striatal, and neocortical efferent connections. Distributions of deep and superficial pyramidal cell dendrites and studies in reeler or sparsely GFP-expressing mice indicate that this also applies to afferent pathways. Histological, neurochemical, and connective differences between deep and superficial neurons may correlate with (patho-) physiological phenomena specific to pyramidal cells at different radial locations. We feel that an appreciation of radial subdivisions in the pyramidal cell layer reminiscent of lamination in other cortical areas may be critical in the interpretation of studies of hippocampal anatomy and function. PMID- 21597969 TI - The PDGF family in renal fibrosis. AB - The platelet-derived growth factor (PDGF) family plays an important role in embryonic development, malignancy, wound healing, atherosclerosis, and fibrosis in multiple organs. It belongs to the best-characterized growth factor systems in normal and diseased kidneys, and there is accumulating evidence that members of the PDGF family are key players in the development of renal fibrosis independent of the underlying kidney disease. All components of the PDGF system, consisting of four isoforms (PDGF-A, -B, -C, -D) and two receptor chains (PDGFR-alpha and beta), are constitutively or inducibly expressed in most renal cells. They regulate multiple pathophysiologic events, ranging from cell proliferation and migration, extracellular matrix accumulation and production of pro- and anti inflammatory mediators, to tissue permeability and hemodynamics. This review focuses on advances in defining the roles of different PDGF isoforms in the development of glomerulosclerosis and tubulointerstitial fibrosis. The recent identification of endogenous PDGF inhibitors offers additional novel therapeutic strategies. PMID- 21597970 TI - Sotos syndrome, infantile hypercalcemia, and nephrocalcinosis: a contiguous gene syndrome. AB - Sotos syndrome is characterized by overgrowth, a typical facial appearance, and learning difficulties. It is caused by heterozygous mutations, including deletions, of NSD1 located at chromosome 5q35. Here we report two unrelated cases of Sotos syndrome associated with nephrocalcinosis. One patient also had idiopathic infantile hypercalcemia. Genetic investigations revealed heterozygous deletions at 5q35 in both patients, encompassing NSD1 and SLC34A1 (NaPi2a). Mutations in SLC34A1 have previously been associated with hypercalciuria/nephrolithiasis. Our cases suggest a contiguous gene deletion syndrome including NSD1 and SLC34A1 and provide a potential genetic basis for idiopathic infantile hypercalcemia. PMID- 21597971 TI - Hepatoblastoma and prune belly syndrome: a potential association. AB - Prune belly syndrome (PBS) is a congenital anomaly characterized by the clinical triad of lax abdominal musculature, bilateral cryptorchidism, and abnormalities of the kidney and urinary tract. Previous reports of malignancy in patients with PBS have been limited to germ cell tumors. Hepatoblastoma (HBL) is the most common hepatic malignancy of childhood, affecting approximately 100 children each year in the USA. We describe a set of 4 pediatric patients with PBS and HBL. All individuals were born after 2002. These subjects lacked genetic, natal, or environmental factors known to confer risk of HBL. The occurrence of PBS and HBL in these patients constitutes a novel potential association. PMID- 21597972 TI - Relevance of a "Dear Doctor letter" to alert healthcare providers to new recommendations for vitamin D administration. AB - PURPOSE: After reports of malaise in infants immediately after the oral administration of two brands of vitamin D solutions, a "Dear Doctor letter" (DDL) containing recommendations for the administration of vitamin D was sent to all French paediatricians and pharmacies and a large number of French general practitioners (GPs) with a predominantly paediatric practice. The DDL and a press release were published on the French Medicines Agency website and distributed via a mailing list. The objective of this study was to assess the effectiveness of such a DDL and to collect the opinions of healthcare professionals on the best way to provide them with information. METHODS: A questionnaire was sent to a national random sample of 145 paediatricians, 680 GPs and 230 pharmacists. RESULTS: Only 49% of responding paediatricians, 48% of GPs and 67% of pharmacists were aware of the warning. Among the participating healthcare professionals aware of the warning and who prescribed/dispensed these vitamins, 50% of paediatricians and 68% of GPs stated that they had changed their prescribing behaviour, and 68% of pharmacists stated that they had modified their advice when dispensing. According to the responding healthcare professionals, postal letters remained the best way to issue safety warnings. Some of the respondents suggested that the DDL be more distinctive in terms of being a DDL and that the information be more widely disseminated to other stakeholders involved in the healthcare system. CONCLUSIONS: This survey of a national random sample of healthcare professionals revealed that many of the respondents paid little attention to the DDL and were therefore unlikely to change their practices. A potential supplementary method for disseminating recommendations for medicine administration could be to apply stickers on medicine boxes, as this approach has the additional advantage of directly informing the concerned population, i.e. the parents. PMID- 21597973 TI - Pituicytoma: overview of treatment strategies and outcome. AB - The pituicytoma is an extremely rare and little-studied primary tumour of the adult neurohypophysis. With total resection, the pituicytoma appears to have a good prognosis. However, its highly vascular nature makes total resection difficult and local recurrence after subtotal resection is not uncommon. To date, only 40 cases of pituicytoma have been reported in literature. In addition to our own case of a suprasellar pituicytoma, we are reviewing and discussing these with particular attention paid on the surgical management and outcome of this rare neoplasm. PMID- 21597974 TI - Dopamine 2 receptor expression in various pathological types of clinically non functioning pituitary adenomas. AB - Clinically non-functioning pituitary adenomas account for about one-third of pituitary tumors. The majority of them are pathologically classified as gonadotropinomas or null-cell adenomas without hormonal expression. The rest represent silent corticotroph adenomas and plurihormonal tumors. Conservative therapy with dopamine agonists is effective in some cases only depending on the expression of dopamine 2 receptors (D2R). The aim of this study was to quantitatively estimate D2R expression in clinically non-functioning pituitary adenomas and correlate the results with adenoma type according to pathological classification. Out of the 87 adenomas investigated, 63 expressed gonadotropins, 7 were silent corticotroph adenomas, 7 were plurihormonal tumors, and only 6 did not express any pituitary hormone on immunohistochemical investigation. With the use of the reverse transcriptase PCR technique, D2R mRNA was expressed in all adenomas with very heterogeneous quantity. The expression was very low in corticotroph adenomas (relative median quantity after normalization to housekeeping gene 0.01) and lower in plurihormonal tumors (median 0.4) than in gonadotroph (median 1.3) and null-cell adenomas (median 1.9). The difference between corticotroph adenomas and plurihormonal tumors in comparison with other pathological types was statistically significant. The expression of D2R did not depend on the presence or absence of gonadotropins. We conclude that D2R expression is very low in corticotroph adenomas and significantly lower in plurihormonal tumors. The positivity of gonadotropins does not predict the D2R quantity. PMID- 21597975 TI - Clinical, quality of life, and economic value of acromegaly disease control. AB - Although acromegaly is a rare disease, the clinical, economic and health-related quality of life (HRQoL) burden is considerable due to the broad spectrum of comorbidities as well as the need for lifelong management. We performed a comprehensive literature review of the past 12 years (1998-2010) to determine the benefit of disease control (defined as a growth hormone [GH] concentration <2.5 MUg/l and insulin-like growth factor [IGF]-1 normal for age) on clinical, HRQoL, and economic outcomes. Increased GH and IGF-1 levels and low frequency of somatostatin analogue use directly predicted increased mortality risk. Clinical outcome measures that may improve with disease control include joint articular cartilage thickness, vertebral fractures, left ventricular function, exercise capacity and endurance, lipid profile, and obstructive apnea events. Some evidence suggests an association between controlled disease and improved HRQoL. Total direct treatment costs were higher for patients with uncontrolled compared to controlled disease. Costs incurred for management of comorbidities, and indirect cost could further add to treatment costs. Optimizing disease control in patients with acromegaly appears to improve outcomes. Future studies need to evaluate clinical outcomes, as well as HRQoL and comprehensive economic outcomes achieved with controlled disease. PMID- 21597976 TI - Comparison of a high-density genetic linkage map to genome features in the model grass Brachypodium distachyon. AB - The small annual grass Brachypodium distachyon (Brachypodium) is rapidly emerging as a powerful model system to study questions unique to the grasses. Many Brachypodium resources have been developed including a whole genome sequence, highly efficient transformation and a large germplasm collection. We developed a genetic linkage map of Brachypodium using single nucleotide polymorphism (SNP) markers and an F(2) mapping population of 476 individuals. SNPs were identified by targeted resequencing of single copy genomic sequences. Using the Illumina GoldenGate Genotyping platform we placed 558 markers into five linkage groups corresponding to the five chromosomes of Brachypodium. The unusually long total genetic map length, 1,598 centiMorgans (cM), indicates that the Brachypodium mapping population has a high recombination rate. By comparing the genetic map to genome features we found that the recombination rate was positively correlated with gene density and negatively correlated with repetitive regions and sites of ancestral chromosome fusions that retained centromeric repeat sequences. A comparison of adjacent genome regions with high versus low recombination rates revealed a positive correlation between interspecific synteny and recombination rate. PMID- 21597977 TI - Infliximab-induced autoimmune hepatitis with successful switch to adalimumab in a patient with Crohn's disease: the index case. PMID- 21597978 TI - Characteristics of small bowel tumors detected by double balloon endoscopy. AB - BACKGROUND: A few reports suggest that the emergence of double balloon endoscopy (DBE) has likely changed the clinical picture of small bowel tumors (SBTs). AIM: To further clarify the characteristics of SBTs detected by DBE. METHODS: A retrospective chart review was conducted in 227 patients who had undergone DBE. RESULTS: The SBT group contained more symptomatic patients than the non-SBT group (90% vs. 49%, P<0.0005) with a significantly higher rate of gastrointestinal symptoms at presentation (72% vs. 33%, P<0.005). Twenty patients (8.8%) were eventually diagnosed with SBT, and their indications for DBE were obscure gastrointestinal bleeding (n=5), abdominal pain (n=5), abdominal fullness (n=5), vomiting (n=2), and diarrhea (n=1). Tumors were located in the jejunum in 14 patients (70%) and in the ileum in 6 (30%). A final histological diagnosis was assigned to all 20 patients: primary adenocarcinoma (n=8, 40%), malignant lymphoma (n=5, 25%), metastatic cancer (n=4, 20%), gastrointestinal stromal tumor (n=1, 5%), carcinoid tumor (n=1, 5%) and inflammatory fibroid polyp (n=1, 5%). Stenosis or ulceration were the most frequently observed endoscopic findings (n=13, 65%). All primary adenocarcinomas and three of four (75%) metastatic cancers showed stenosis or ulceration. Three of five (60%) malignant lymphomas showed multiple lymphomatous polyps. All patients but one underwent surgical resection or chemotherapy or both. CONCLUSION: DBE is a safe and useful procedure that enables a precise diagnosis of SBTs. PMID- 21597979 TI - Evaluation of DNA fragments covering the entire genome of a monopartite begomovirus for induction of viral resistance in transgenic plants via gene silencing. AB - Tomato-infecting begomoviruses, a member of whitefly-transmitted geminivirus, cause the most devastating virus disease complex of cultivated tomato crops in the tropical and subtropical regions. Numerous strategies have been used to engineer crops for their resistance to geminiviruses. However, nearly all have concentrated on engineering the replication-associated gene (Rep), but not on a comprehensive evaluation of the entire virus genome. In this study, Tomato leaf curl Taiwan virus (ToLCTWV), a predominant tomato-infecting begomovirus in Taiwan, was subjected to the investigation of the viral gene fragments conferring resistance to geminiviruses in transgenic plants. Ten transgenic constructs covering the entire ToLCTWV genome were fused to a silencer DNA, the middle half of N gene of Tomato spot wilt virus (TSWV), to induce gene silencing and these constructs were transformed into Nicotiana benthamiana plants. Two constructs derived from IRC1 (intergenic region flanked with 5' end Rep) and C2 (partial C2 ORF) were able to render resistance to ToLCTWV in transgenic N. benthamiana plants. Transgenic plants transformed with two other constructs, C2C3 (overlapping region of C2 and C3 ORFs) and Rep2 (3' end of the C1 ORF), significantly delayed the symptom development. Detection of siRNA confirmed that the mechanism of resistance was via gene silencing. This study demonstrated for the first time the screening of the entire genome of a monopartite begomovirus to discover viral DNA fragments that might be suitable for conferring virus resistance, and which could be potential candidates for developing transgenic plants with durable and broad-spectrum resistance to a DNA virus via a gene silencing approach. PMID- 21597980 TI - A randomized controlled trial of mindfulness-based stress reduction to manage affective symptoms and improve quality of life in gay men living with HIV. AB - To determine whether MBSR groups would help gay men living with HIV improve psychosocial functioning and increase mindfulness compared to treatment-as-usual (TAU). METHODS: 117 participants were randomized 2:1 to MBSR or TAU. No new psychosocial or psychopharmacological interventions were initiated within 2 months of baseline. Standardized questionnaires were administered pre-, postintervention and at 6 months. An intent-to-treat analysis found significant benefits of MBSR: at post-intervention and 6 months follow up, MBSR participants had significantly lower avoidance in IES and higher positive affect compared to controls. MBSR participants developed more mindfulness as measured by the Toronto Mindfulness Scale (TMS) including both TMS subscales, curiosity and decentering, at 8-week and 6 months. For the sample as a whole, increase in mindfulness was significantly correlated with reduction in avoidance, higher positive affect and improvement in depression at 6 months. MBSR has specific and clinically meaningful effects in this population. PMID- 21597982 TI - Defining a moment in history: parent communication with adolescents about September 11, 2001. AB - Parents play an important role in helping their children process and interpret significant sociohistorical events. However, little is known about how parents frame these experiences or the specific social, cultural, and civic messages they may communicate about the event. In this study, we examined self-reported communication of parents from six communities in the United States with their adolescents about the September 11, 2001 terrorist attacks. Parents' (N = 972) open-ended responses about September 11th were analyzed to assess whether communication with their adolescents occurred and for thematic content. Results revealed marked variability in parents' communication and suggest that many parents used September 11th as an opportunity to impart sociocultural, emotional, and civic messages. Identifying the diversity in parents' responses aligns with the tenets of Terror Management Theory and provides insights into the roles of parents in translating pivotal historical moments. Collectively, these findings yield important implications for civic socialization. PMID- 21597981 TI - Suppression of anger and subsequent pain intensity and behavior among chronic low back pain patients: the role of symptom-specific physiological reactivity. AB - Suppression of anger may be linked to heightened pain report and pain behavior during a subsequent painful event among chronic low back patients, but it is not clear whether these effects are partly accounted for by increased physiological reactivity during suppression. Chronic low back pain patients (N = 58) were assigned to Suppression or No Suppression conditions for a "cooperative" computer maze task during which a confederate harassed them. During baseline and maze task, patients' lower paraspinal and trapezius muscle tension, blood pressure and heart rate were recorded. After the maze task, patients underwent a structured pain behavior task (behaviors were videotaped and coded). Results showed that: (a) Suppression condition patients revealed greater lower paraspinal muscle tension and systolic blood pressure (SBP) increases during maze task than No Suppression patients (previously published results showed that Suppression condition patients exhibited more pain behaviors than No Suppression patients); (b) residualized lower paraspinal and SBP change scores were related significantly to pain behaviors; (c) both lower paraspinal and SBP reactivity significantly mediated the relationship between Condition and frequency of pain behaviors. Results suggest that suppression-induced lower paraspinal muscle tension and SBP increases may link the actual suppression of anger during provocation to signs of clinically relevant pain among chronic low back pain patients. PMID- 21597983 TI - Metastatic pulmonary adenocarcinoma deposit arising within a cutaneous basal cell carcinoma: a case report. AB - Skin metastases are rare complications of internal malignancies, and most commonly arise from primary lung carcinoma (Brownstein and Helwig in Arch Dermatol 105:82-68, 1972). Metastatic cutaneous lesions have not previously been documented to arise within other skin tumours. We report our experience of a solitary pulmonary adenocarcinoma metastasis that arose within a pre-existing basal cell carcinoma in a patient with undiagnosed lung cancer. Immunohistochemistry was invaluable in confirming both the metastatic nature of the secondary skin lesion and its site of origin. PMID- 21597984 TI - Partitioning characteristics of perfluorooctane sulfonate between water and foods. AB - As a persistent, bioaccumulative, and toxic organic pollutant, perfluorooctane sulfonate (PFOS) has been found ubiquitously in the environment, including in tap water. For the first time, we studied PFOS sorption from water to foods (nine commonly consumed vegetables, three meats, and cereals) at two temperatures to estimate the daily intake of PFOS attributable to cooking and food preparation. The values of the food water-distribution coefficient (KF/W, l/kg) of PFOS ranged from 7 to 19 l/kg for most vegetables and from 19 to 38 l/kg for meats. Celery exhibited the highest affinity toward PFOS (KF/W=39.8+/-3.4 l/kg), whereas onions showed the lowest affinity toward PFOS (KF/W=1.1+/-0.4 l/kg). Adding table salt (sodium chloride) greatly increased PFOS sorption in most foods, except for celery and meats. The results indicate that human exposure to PFOS could result from the sorption of PFOS from water to food during food preparation, especially when using table salt. The average daily intake of PFOS through this route was estimated. Furthermore, raw and unprocessed foods (vegetables, meats, and cereals) bought from farmers' markets and grocery stores were basically free of PFOS and other long-chain perfluoroalkyl acids. PMID- 21597985 TI - Medication use during pregnancy in Omani women. AB - OBJECTIVE: The aim of this study was to evaluate medication use pattern in a university tertiary hospital in the Sultanate of Oman. SETTING: The study was conducted at the Sultan Qaboos University Hospital (SQUH) and the SQUH Family and Community Medicine clinic (FAMCO), Muscat, Sultanate of Oman during 7th to 25th June 2008. METHOD: The medication use pattern was evaluated in women attending FAMCO and the standard antenatal clinics at the hospital. Women were interviewed in different gestational ages using a structured questionnaire. The Electronic Patient Record (EPR) was reviewed to acquire additional information on medication use. Medications were classified according to the US FDA risk classification. MAIN OUTCOME MEASURE: Medication used including prescribed medications, OTC medications, or herbal treatment during the current pregnancy and 3 months prior to conception. RESULTS: The study included a total of 139 pregnant mothers with an overall mean age of 28 +/- 5 years ranging from 19 to 45 years. There was a slight overall reduction in the medication use including prescribed medications. However, there was a significant increase in utilization of vitamins and supplements (84-95% vs. 12% in the 3-months prior, P < 0.001) as well as herbal preparations (16-19% vs. 7% in the 3-months prior, P = 0.011) throughout pregnancy (P < 0.010). The use of category A medications increased in all trimester (43-52% vs. 13% in the 3 months prior, P < 0.010) while a reduction in the use of category C (for first and third trimester, P < 0.050) and D medications was seen. A reduction in the use of teratogenic drugs in all trimesters (P < 0.010) was also observed. CONCLUSION: The prescribing of vitamins and minerals was optimal. However, the common use of herbal supplements observed warrants special attention due to their unknown risks. The conclusions should be interpreted in light of the study's limitations. PMID- 21597986 TI - Influence of coronary artery disease prevalence on predictive values of coronary CT angiography: a meta-regression analysis. AB - OBJECTIVE: To evaluate the impact of coronary artery disease (CAD) prevalence on the predictive values of coronary CT angiography. METHODS: We performed a meta regression based on a generalised linear mixed model using the binomial distribution and a logit link to analyse the influence of the prevalence of CAD in published studies on the per-patient negative and positive predictive values of CT in comparison to conventional coronary angiography as the reference standard. A prevalence range in which the negative predictive value was higher than 90%, while at the same time the positive predictive value was higher than 70% was considered appropriate. RESULTS: The summary negative and positive predictive values of coronary CT angiography were 93.7% (95% confidence interval [CI] 92.8-94.5%) and 87.5% (95% CI, 86.5-88.5%), respectively. With 95% confidence, negative and positive predictive values higher than 90% and 70% were available with CT for a CAD prevalence of 18-63%. CT systems with >16 detector rows met these requirements for the positive (P < 0.01) and negative (P < 0.05) predictive values in a significantly broader range than systems with <=16 detector rows. CONCLUSION: It is reasonable to perform coronary CT angiography as a rule-out test in patients with a low-to-intermediate likelihood of disease. PMID- 21597987 TI - Over-expression of the beta-carboxysomal CcmM protein in Synechococcus PCC7942 reveals a tight co-regulation of carboxysomal carbonic anhydrase (CcaA) and M58 content. AB - Carboxysomes, containing the cell's complement of RuBisCO surrounded by a specialized protein shell, are a central component of the cyanobacterial CO(2) concentrating mechanism. The ratio of two forms of the beta-carboxysomal protein CcmM (M58 and M35) may affect the carboxysomal carbonic anhydrase (CcaA) content. We have over-expressed both M35 and M58 in the beta-cyanobacterium Synechococcus PCC7942. Over-expression of M58 resulted in a marked increase in the amount of this protein in carboxysomes at the expense of M35, with a concomitant increase in the observed CcaA content of carboxysomes. Conversely, M35 over-expression diminished M58 content of carboxysomes and led to a decrease in CcaA content. Carboxysomes of air-grown wild-type cells contained slightly elevated CcaA and M58 content and slightly lower M35 content compared to their 2% CO(2)-grown counterparts. Over a range of CcmM expression levels, there was a strong correlation between M58 and CcaA content, indicating a constant carboxysomal M58:CcaA stoichiometry. These results also confirm a role for M58 in the recruitment of CcaA into the carboxysome and suggest a tight regulation of M35 and M58 translation is required to produce carboxysomes with an appropriate CA content. Analysis of carboxysomal protein ratios, resulting from the afore mentioned over-expression studies, revealed that beta-carboxysomal protein stoichiometries are relatively flexible. Determination of absolute protein quantities supports the hypothesis that M35 is distributed throughout the beta carboxysome. A modified beta-carboxysome packing model is presented. PMID- 21597988 TI - Bovine IFNGR2, IL12RB1, IL12RB2, and IL23R polymorphisms and MAP infection status. AB - Mycobacterium avium ssp. paratuberculosis (MAP) infection causes a chronic granulomatous inflammatory condition of the bovine gut that is characterized by diarrhea, progressive weight loss, and emaciation, and ultimately leads to loss in productivity and profitability of dairy operations. The host cytokine machinery is known to play an important role in protecting against MAP infection. Therefore, the goal of the present study was to assess whether polymorphisms in candidate genes encoding important cytokines and cytokine receptors are associated with MAP infection status of dairy cattle. MAP infection status was evaluated based on serum and milk enzyme-linked immunosorbent assays (ELISAs) for MAP-specific antibodies. Twenty previously reported polymorphisms in genes encoding bovine interferon gamma (IFNG), IFNGR1, IFNGR2, IL22, IL22RA1, IL12RB1, IL12RB2, and IL23R were genotyped in a resource population of 446 dairy Holsteins with known MAP infection status, and logistic regression was used to assess the statistical association with a binomial MAP infection status phenotype. Four SNPs in IFNGR2, IL12RB1, IL12RB2, and IL23R were found to be associated with the MAP infection status of the resource population. These results underscore the importance of cytokines and their receptors in conferring protection against MAP infection and warrant further functional characterization of these associations. PMID- 21597989 TI - Contingent negative variation as a dopaminergic biomarker: evidence from dose related effects of methylphenidate. AB - RATIONALE: The basal ganglia play an important role in motor control, which is dependent on dopaminergic input. Preparation of a motor response has been associated with dopamine release in the basal ganglia, and response readiness may therefore serve as a pharmacodynamic marker of dopamine activity. METHODS: We measured response readiness using the amplitude of the contingent negative variation (CNV), a slow negative shift in the electroencephalogram. The CNV is evoked in a paradigm in which a warning stimulus (S1) signals the occurrence of the imperative stimulus (S2) 4 s later, to which the participant has to respond. CNV was assessed in healthy volunteers after administration of placebo or 10, 20 or 40 mg of methylphenidate, a catecholamine re-uptake blocker which primarily enhances the synaptic concentration of dopamine and to a lesser extent also noradrenaline. In addition, participants filled out two visual analogue scales measuring subjective ratings of mood and alertness: Profile of Mood States and Bond and Lader. RESULTS: Methylphenidate dose dependently increased CNV amplitude and decreased reaction times. Furthermore, participants reported improved mood, feeling more alert, vigorous and content and less angry and tired after methylphenidate. CONCLUSIONS: These results indicate that dopamine availability increases response readiness as measured by the CNV paradigm. The CNV appears to be a good candidate biomarker for assessing changes in dopaminergic function by treatments that either directly or indirectly target the dopaminergic system. PMID- 21597990 TI - Systematic review of the relationship between the 3-hydroxycotinine/cotinine ratio and cigarette dependence. AB - RATIONALE: Individual differences in the rate of nicotine metabolism (RNM) could be related to dependence and success in stopping smoking. A range of studies have examined RNM measured by the ratio of trans-3'-hydroxycotinine and cotinine in body fluids (the ratio). A systematic review of this literature is needed to draw conclusions and identify gaps in evidence. OBJECTIVE: The aim of this study is to review evidence on the association of the ratio to cigarette dependence and its role in individual tailoring of smoking cessation pharmacotherapy. RESULTS: We reviewed 27 studies of the ratio related to its reliability, validity, and relationship to dependence. The ratio is a reasonably accurate proxy for RNM. There is little evidence that the ratio is related to questionnaire measures of dependence, though the existing data are limited and the ratio has been linked to smoking at night and to some aspects of smoking topography. The ratio is also only weakly associated with cigarette consumption. Its relationship to the severity of withdrawal symptoms seems also weak at best, but limited data exist. One study suggests the ratio predicts outcome of unaided quitting. Importantly, the ratio seems to predict responses both to NRT and bupropion, and thus could guide pharmacotherapy. CONCLUSIONS: The evidence that the ratio is related to smoking behaviours and to cigarette dependence is limited, but the ratio seems to influence treatment response to two stop smoking medications. Further studies of the relationship between the ratio and cigarette dependence and trials of ratio guided pharmacotherapy are needed. PMID- 21597991 TI - Effects of acute ethanol on corticotropin-releasing hormone and beta-endorphin systems at the level of the rat central amygdala. AB - RATIONALE: The endogenous opioid and corticotropin-releasing hormone (CRH) systems, present in the central amygdala (CeA), are implicated in alcohol consumption. OBJECTIVES: The purpose of this study is to investigate the hypothesis that, in CeA, alcohol stimulates CRH release, which then stimulates beta-endorphin release. MATERIALS AND METHODS: Rats were unilaterally implanted with a guide cannula to aim microdialysis probes in CeA. Experiment 1: rats received an intraperitoneal (IP) injection of various ethanol doses (0.0, 2.0, 2.4, or 2.8 g ethanol/kg body weight) and microdialysates were sampled at 30-min intervals to determine the effects over time of acute alcohol on the extracellular CRH concentrations in CeA. Experiment 2: phosphate-buffered saline, CRH, or CRH receptor (CRHR) antagonists (antalarmin or anti-sauvagine-30) was microinjected into CeA followed by a saline or 2.8 g/kg ethanol IP injection to determine the effects of CRHR activation or blockade in CeA on the basal and alcohol-stimulated release of beta-endorphin. CRH and beta-endorphin dialysate contents were determined using specific radioimmunoassays. RESULTS: Acute alcohol induced a delayed increase in the extracellular CRH levels in CeA. Behavioural data showed no difference in locomotion between alcohol- and saline-treated rats. However, a transient increase in grooming was observed which did not correspond with alcohol-induced changes in CRH. Local CRH microinjections increased the extracellular beta-endorphin concentrations in CeA. CRHR1 and CRHR2 blockade with microinjections of antalarmin and anti-sauvagine-30, respectively, attenuated the alcohol-induced increase of extracellular beta-endorphin in CeA. CONCLUSIONS: Acute alcohol exerts indirect actions on CRH release and induced interactions of the CRH and beta-endorphin systems in CeA. PMID- 21597992 TI - Docking glycosaminoglycans to proteins: analysis of solvent inclusion. AB - Glycosaminoglycans (GAGs) are anionic polysaccharides, which participate in key processes in the extracellular matrix by interactions with protein targets. Due to their charged nature, accurate consideration of electrostatic and water mediated interactions is indispensable for understanding GAGs binding properties. However, solvent is often overlooked in molecular recognition studies. Here we analyze the abundance of solvent in GAG-protein interfaces and investigate the challenges of adding explicit solvent in GAG-protein docking experiments. We observe PDB GAG-protein interfaces being significantly more hydrated than protein protein interfaces. Furthermore, by applying molecular dynamics approaches we estimate that about half of GAG-protein interactions are water-mediated. With a dataset of eleven GAG-protein complexes we analyze how solvent inclusion affects Autodock 3, eHiTs, MOE and FlexX docking. We develop an approach to de novo place explicit solvent into the binding site prior to docking, which uses the GRID program to predict positions of waters and to locate possible areas of solvent displacement upon ligand binding. To investigate how solvent placement affects docking performance, we compare these results with those obtained by taking into account information about the solvent position in the crystal structure. In general, we observe that inclusion of solvent improves the results obtained with these methods. Our data show that Autodock 3 performs best, though it experiences difficulties to quantitatively reproduce experimental data on specificity of heparin/heparan sulfate disaccharides binding to IL-8. Our work highlights the current challenges of introducing solvent in protein-GAGs recognition studies, which is crucial for exploiting the full potential of these molecules for rational engineering. PMID- 21597993 TI - The correlation between exaggerated fluid in lumbar facet joints and degenerative spondylolisthesis: prospective study of 52 patients. AB - BACKGROUND: Magnetic resonance imaging (MRI) is often used to evaluate low back pain; however, MRI in the supine position does not always reveal degenerative spondylolisthesis. The existence of a linear correlation between increased fluid in the facet joints seen on the supine axial T2 MRI of the lumbosacral spine and lumbar instability seen on standing lateral flexion-extension lumbosacral radiographs has recently been reported. The objective of this prospective study was to determine the incidence of increased fluid in the lumbar facet joints seen on the supine axial T2 MRI, and to evaluate the correlation of this finding with radiographic evidence of lumbar instability. MATERIALS AND METHODS: We prospectively analyzed weight-bearing flexion-extension lumbosacral radiographs and lumbosacral MRI in the supine position for 52 patients (mean age 64.7 years) seen at our institution for low back pain and/or radiculopathy. The statistical analysis was performed with Fisher's exact test. A difference was considered statistically significant if P < 0.05. RESULTS: In all but 5 of the 52 patients, degenerative disc disease and facet joint disease were observed on the supine MRI of the lumbosacral spine. Fifteen patients had exaggerated fluid in the lumbar facets on the axial T2 MRI (28.8%). Radiographic signs of degenerative lumbar spondylolisthesis were observed in 12 patients (23.1%), and the degenerative spondylolisthesis was not evident on the supine sagittal MRI in 10 of these 12 patients (83.3%). Among these 12 patients, the axial T2 MRI showed exaggerated fluid in the facet joints at the corresponding level in 8 patients (66%). Increased fluid in the lumbar facet joints was present on the supine axial T2 MRI in 7 patients (13.4%), even though there were no radiographic signs of corresponding lumbar instability. CONCLUSION: We observed a statistical correlation between increased fluid in the lumbar facet joints on the supine axial T2 MRI and degenerative spondylolisthesis seen on standing lateral flexion extension lumbosacral radiographs. PMID- 21597994 TI - Spontaneous bilateral distal ulna fracture: an unusual complication in a rheumatoid patient. AB - Bilateral ulna stress fractures are extremely rare. Patients with rheumatoid arthritis have osteopenic bone secondary to a variety of causes. We report a case of bilateral stress fractures of the ulna in an elderly patient with rheumatoid arthritis, and literature on this condition is reviewed. Prompt recognition and activity modification are essential to treat this rare injury. Recovery can take up to 12 weeks. PMID- 21597995 TI - PCDH10 is a candidate tumour suppressor gene in medulloblastoma. AB - PURPOSE: The aim of this study was to investigate the genetic and epigenetic mechanisms contributing to PCDH10 down-regulation in medulloblastoma. We examined the role of PCDH10 as a mediator of medulloblastoma cell proliferation, cell cycle progression, and cell migration. METHODS: We identified a focal homozygous deletion of PCDH10 in medulloblastoma by surveying a cohort of 212 tumours by Affymetrix SNP array analysis. PCDH10 expression was assessed by quantitative reverse transcriptase PCR in a series of 26 tumours. The promoter methylation status of PCDH10 was determined using methylation specific PCR and Sequenom MassCLEAVE analysis. Functional studies examining the role of PCDH10 in medulloblastoma development were performed by re-expression of PCDH10 in the DAOY medulloblastoma cell line, and then, cell proliferation, cell cycle distribution, and cell migration assays were performed. RESULTS: We report a very focal homozygous deletion on chromosome 4q28.3 harbouring the PCDH10 gene. We demonstrate that PCDH10 transcription is down-regulated in 19/26 (73%) of medulloblastomas suggesting that other mechanisms also could be involved in gene repression. We found that DNA hypermethylation contributed to the deregulation of PCDH10 in 11/44 (25%) of medulloblastoma cell lines and primary tumours. Using a stable cell line (DAOY) re-expressing PCDH10, we observed that cell migration was impaired upon restoration of PCDH10 expression. CONCLUSIONS: Our findings suggest that genetic and epigenetic deregulation of PCDH10 occurs in a significant portion of medulloblastoma patients. Failure to express PCDH10 may result in loss of inhibition of cell migration, thereby contributing to medulloblastoma progression. PMID- 21597996 TI - Early symptomatic and late seizures in Kosovar children with bacterial meningitis. AB - INTRODUCTION: Despite the dramatic decrease of mortality rate among children with bacterial meningitis in recent decades, some patients are left with neurologic sequelae. The purpose of this study was to analyze the occurrence of seizures as predictors for meningitis-related deaths or neurological sequelae including late seizures. METHODS: This study uses a retrospective chart review of 277 children (aged 0-16 years, median 2 years, 162 boys) treated for bacterial meningitis in University Clinical Centre in Prishtina (Kosovo). RESULTS: Of the 277 children treated for bacterial meningitis, 60 children (22%) manifested seizures prior to admission, 57 children (21%) had seizures after admission, and late seizures were diagnosed in 24 children (9%). The risk for adverse outcome was significantly higher in patients who had seizures prior to admission (52/60) and in patients who manifested seizures later than 24 h (41/41; RR 8.17 and 6.78 respectively, p < 0.0001). All children who manifested late seizures were diagnosed with meningitis-related acute neurologic complications: subdural effusion (18), hydrocephalus (6), intracranial bleeding (1), and subdural empyema (2). Of the 60 children who presented seizures prior to admission, only 11 manifested late seizures. CONCLUSIONS: Seizures prior to admission were predictors of high risk of adverse outcome in bacterial meningitis in children. The risk of secondary epilepsy (9%) occurred only in children with evident structural neurologic complications during the acute phase of bacterial meningitis. PMID- 21597997 TI - Immunohistochemical analysis of the relationship between islet cell proliferation and the production of the enteroviral capsid protein, VP1, in the islets of patients with recent-onset type 1 diabetes. AB - AIMS/HYPOTHESIS: The enteroviral capsid protein, VP1, was recently shown to be present in some beta cells in more than 60% of patients with recent-onset type 1 diabetes but in very few age-matched controls. The rate of proliferation of islet cells was also markedly increased in the type 1 diabetic patients. As it has been suggested that enteroviruses replicate most efficiently in proliferating cells, we have investigated whether VP1 is preferentially present in proliferating beta cells in type 1 diabetes. METHODS: Combined immunoperoxidase and immunofluorescence staining was used to record the presence of enteroviral VP1, insulin and Ki67 in the islets of recent-onset type 1 diabetic patients. RESULTS: From a total of 1,175 islets, 359 (30.5%) contained insulin. VP1-producing endocrine cells were found in 72 islets (6.1% of total), all of which retained insulin. Ki67(+) endocrine cells were present in 52 (4.4%) islets, with 44 (84.6%) of these being insulin-positive. Overall, 28 of 1,175 (2.4%) islets contained both Ki67(+) cells and VP1(+) cells. Dual positivity of these markers accounted for 38.9% of the total VP1(+) islets and 53.8% of the total Ki67(+) islets. No individual islet cells were dual-positive for Ki67 and VP1. CONCLUSIONS/INTERPRETATION: Ki67(+) cells were frequently observed in islets that also contained VP1(+) cells, suggesting that the factors facilitating viral replication may also drive islet cell proliferation. However, in an individual cell, VP1 production does not require concurrent beta cell proliferation. PMID- 21597998 TI - The influence of sex and puberty on the progression of diabetic nephropathy and retinopathy. PMID- 21597999 TI - Effectiveness of medical equipment donations to improve health systems: how much medical equipment is broken in the developing world? AB - It is often said that most of the medical equipment in the developing world is broken with estimates ranging up to 96% out of service. But there is little documented evidence to support these statements. We wanted to quantify the amount of medical equipment that was out of service in resource poor health settings and identify possible causes. Inventory reports were analyzed from 1986 to 2010, from hospitals in sixteen countries across four continents. The UN Human Development Index was used to determine which countries should be considered developing nations. Non-medical hospital equipment was excluded. This study examined 112,040 pieces of equipment. An average of 38.3% (42,925, range across countries: 0.83 47%) in developing countries was out of service. The three main causes were lack of training, health technology management, and infrastructure. We hope that the findings will help biomedical engineers with their efforts toward effective designs for the developing world and NGO's with efforts to design effective healthcare interventions. PMID- 21598000 TI - Prediction of persistence of combined evidence-based cardiovascular medications in patients with acute coronary syndrome after hospital discharge using neural networks. AB - In the PREVENIR-5 study, artificial neural networks (NN) were applied to a large sample of patients with recent first acute coronary syndrome (ACS) to identify determinants of persistence of evidence-based cardiovascular medications (EBCM: antithrombotic + beta-blocker + statin + angiotensin converting enzyme inhibitor ACEI and/or angiotensin-II receptor blocker-ARB). From October 2006 to April 2007, 1,811 general practitioners recruited 4,850 patients with a mean time of ACS occurrence of 24 months. Patient profile for EBCM persistence was determined using automatic rule generation from NN. The prediction accuracy of NN was compared with that of logistic regression (LR) using Area Under Receiver Operating Characteristics-AUROC. At hospital discharge, EBCM was prescribed to 2,132 patients (44%). EBCM persistence rate, 24 months after ACS, was 86.7%. EBCM persistence profile combined overweight, hypercholesterolemia, no coronary artery bypass grafting and low educational level (Positive Predictive Value = 0.958). AUROC curves showed better predictive accuracy for NN compared to LR models. PMID- 21598001 TI - Mitochondria-localized NAD biosynthesis by nicotinamide mononucleotide adenylyltransferase in Jerusalem artichoke (Helianthus tuberosus L.) heterotrophic tissues. AB - Current studies in plants suggest that the content of the coenzyme NAD is variable and potentially important in determining cell fate. In cases that implicate NAD consumption, re-synthesis must occur to maintain dinucleotide pools. Despite information on the pathways involved in NAD synthesis in plants, the existence of a mitochondrial nicotinamide mononucleotide adenylyltransferase (NMNAT) activity which catalyses NAD synthesis from nicotinamide mononucleotide (NMN) and ATP has not been reported. To verify the latter assumed pathway, experiments with purified and bioenergetically active mitochondria prepared from tubers of Jerusalem artichoke (Helianthus tuberosus L.) were performed. To determine whether NAD biosynthesis might occur, NMN was added to Jerusalem artichoke mitochondria (JAM) and NAD biosynthesis was tested by means of HPLC and spectroscopically. Our results indicate that JAM contain a specific NMNAT inhibited by Na-pyrophosphate, AMP and ADP-ribose. The dependence of NAD synthesis rate on NMN concentration shows saturation kinetics with K (m) and V (max) values of 82 +/- 1.05 MUM and 4.20 +/- 0.20 nmol min(-1) mg(-1) protein, respectively. The enzyme's pH and temperature dependence were also investigated. Fractionation studies revealed that mitochondrial NMNAT activity was present in the soluble matrix fraction. The NAD pool needed constant replenishment that might be modulated by environmental inputs. Thus, the mitochondrion in heterotrophic plant tissues ensures NAD biosynthesis by NMNAT activity and helps to orchestrate NAD metabolic network in implementing the survival strategy of cells. PMID- 21598002 TI - Malignant fibrous histiocytoma is a rare Lynch syndrome-associated tumor in two German families. AB - Lynch syndrome is characterized by germline mutations of the DNA mismatch repair genes MLH1 and MSH2. The tumor spectrum includes early onset colorectal, urogenital and other cancers. Soft tissue sarcomas have been anecdotally reported in patients with Lynch syndrome, but coincidental manifestation could not be excluded. In this report, we screened a cohort of Lynch syndrome families for tumors outside the established tumor spectrum. We identified two patients with Lynch syndrome and a malignant fibrous histiocytoma (MFH). In both families a causative MSH2 germline mutation (MSH2 c.2038C >= T or MSH2 c.942 +/- 3A >= T) could be detected. Archival tumor material from both resected MFH was analyzed for microsatellite instability expression of MLH1 and MSH2. A mutator phenotype was detected in both MFH with loss of MSH2 protein expression. Subsequently, the causative MSH2 germline mutation was confirmed in both patients. Of note, both tumors were diagnosed at a local advanced stage but could be curatively resected 21 and 11 year ago, respectively. Both patients are alive without local or distant recurrence. In conclusion, our data further support that patients with Lynch syndrome are at increased risk for rare tumors such as MFH. However, the prognosis compared to sporadic MFH seems to be favorable. PMID- 21598003 TI - A novel pathogenic germline mutation in the adenomatous polyposis coli gene in a Tunisian family with FAP. AB - Familial adenomatous polyposis (FAP) is an autosomal dominant disorder which typically presents with colorectal cancer in early adult life, secondary to extensive adenomatous polyps of the colon. In addition to the colonic manifestations, the syndrome presents several extracolonic features including, congenital hypertrophy of the retinal pigment, osteomata and desmoid tumors. In this study, we aimed to investigate the clinical and genetic features in a Tunisian family with FAP. Sequence of the APC gene (Adenomatous Polyposis Coli) revealed a novel mutation (c.2016-2017 del TA) in exon 15, present in all affected individuals in an heterozygous state. The frameshift mutation generates a premature stop codon at amino acid 677 of the APC protein (p. H672Qfs X5). The unaffected family members did not harbor this mutation, however, a first degree relative of the patient aged of 32-year-old was phenotypically normal but carries the c.2016-2017 del TA mutation. This discrepancy can be explained by the effect of modifier gene which can affect the expressivity of the disease. PMID- 21598004 TI - Dendritic cell and macrophage infiltration in microsatellite-unstable and microsatellite-stable colorectal cancer. AB - High level microsatellite instability (MSI-H) is a hallmark of Lynch syndrome associated colorectal cancer (CRC). MSI-H CRC express immunogenic tumour antigens as a consequence of DNA mismatch repair deficiency-induced frameshift mutations. Consequently, frameshift antigen-specific immune responses are commonly observed in patients with Lynch syndrome-associated MSI-H CRC. Dendritic cells (DC) and macrophages play a crucial role in the induction and modulation of immune responses. We here analysed DC and macrophage infiltration in MSI-H and microsatellite-stable CRC. Sixty-nine CRC (MSI-H, n = 33; microsatellite-stable, n = 36) were examined for the density of tumour-infiltrating DC, Foxp3-positive regulatory T cells, and CD163-positive macrophages. In MSI-H lesions, S100 positive and CD163-positive cell counts were significantly higher compared to microsatellite-stable lesions (S100: epithelium P = 0.018, stroma P = 0.042; CD163: epithelium P < 0.001, stroma P = 0.046). Additionally, numbers of CD208 positive mature DC were significantly elevated in the epithelial compartment of MSI-H CRC (P = 0.027). High numbers of tumour-infiltrating Foxp3-positive T cells were detected in tumours showing a low proportion of CD208-positive, mature DC among the total number of S100-positive cells. Our study demonstrates that infiltration with DC, mature DC, and macrophages is elevated in MSI-H compared to microsatellite-stable CRC. The positive correlation of Foxp3-positive Treg cell density with a low proportion of mature DC suggests that impaired DC maturation may contribute to local immune evasion in CRC. Our results demonstrate that DC and macrophages in the tumour environment likely play an important role in the induction of antigen-specific immune responses in Lynch syndrome. Moreover, impaired DC maturation might contribute to local immune evasion in CRC. PMID- 21598005 TI - Phylogenetic analysis of Puumala virus subtype Bavaria, characterization and diagnostic use of its recombinant nucleocapsid protein. AB - Puumala virus (PUUV) is the predominant hantavirus species in Germany causing large numbers of mild to moderate cases of haemorrhagic fever with renal syndrome (HFRS). During an outbreak in South-East Germany in 2004 a novel PUUV subtype designated Bavaria was identified as the causative agent of HFRS in humans [1]. Here we present a molecular characterization of this PUUV strain by investigating novel partial and almost entire nucleocapsid (N) protein-encoding small (S-) segment sequences and partial medium (M-) segment sequences from bank voles (Myodes glareolus) trapped in Lower Bavaria during 2004 and 2005. Phylogenetic analyses confirmed their classification as subtype Bavaria, which is further subdivided into four geographical clusters. The entire N protein, harbouring an amino-terminal hexahistidine tag, of the Bavarian strain was produced in yeast Saccharomyces cerevisiae and showed a slightly different reactivity with N specific monoclonal antibodies, compared to the yeast-expressed N protein of the PUUV strain Vranica/Hallnas. Endpoint titration of human sera from different parts of Germany and from Finland revealed only very slight differences in the diagnostic value of the different recombinant proteins. Based on the novel N antigen indirect and monoclonal antibody capture IgG-ELISAs were established. By using serum panels from Germany and Finland their validation demonstrated a high sensitivity and specificity. In summary, our investigations demonstrated the Bavarian PUUV strain to be genetically divergent from other PUUV strains and the potential of its N protein for diagnostic applications. PMID- 21598006 TI - FTO mRNA expression in extremely obese and type 2 diabetic human omental and subcutaneous adipose tissues. AB - BACKGROUND: Fat mass and obesity-associated protein (FTO) gene expression is known to correlate with obesity. Our aim was to investigate the FTO gene expression in paired omental and subcutaneous human adipose tissues from morbid and obese patients. To understand the role of CD68-positive macrophages in adipose tissues, the correlation with adiposity parameters such as adipocyte diameter and adipocyte radius was also measured. Drug and adiposity correlations were also analyzed. METHODS: Paired omental and subcutaneous adipose tissue were excised during elective surgery from morbidly obese (n = 9) and obese (n = 5) patients. FTO expressions were determined by quantitative PCR. Tissue sections were analyzed for their CD68 protein expressions by immunuhistochemistry. RESULTS: Omental and subcutaneous adipose tissue FTO gene expression levels were not found to differ significantly among morbidly obese and obese study groups. Serum aspartate aminotransferase e and alanine transaminase levels were found to be in negative correlation with subcutaneous fat tissue FTO expression rate. Antidiabetic drug use was found to be in correlation with adiposity. Both subcutaneous and omental fat cell diameters were found to have correlation with antidiabetic drug use. Omental fat cell diameter was found to enlarge together with omental CD68 protein expression. Subcutaneous macrophage number decreased while omental fat cell radius increased. Omental macrophage number was found in correlation with subcutaneous macrophage number. CONCLUSIONS: Antidiabetic therapy was found to increase adiposity in omental and subcutaneous fat. Further research is needed with larger samples to explore the exact role of FTO in obesity. PMID- 21598007 TI - Clinical predictors of different grades of nonalcoholic fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the comorbidities related to obesity. Liver biopsy has been used as the "gold standard" for the diagnosis, grading, and prognosis of obese patients. The objective of the present study was to evaluate clinical predictors of more advanced stages of NAFLD. METHODS: In this retrospective study we assessed several physical and laboratorial factors, including some cytokines, in morbidly obese patients submitted to Roux-en-Y gastric bypass that could be related to the diagnosis and staging of NAFLD. Fragments of the livers were obtained from wedge biopsies during operation. RESULTS: The medical records of 259 patients were studied. The patients were divided into four groups: normal hepatic biopsy, steatosis, mild nonalcoholic steatohepatitis (NASH), and moderate and severe NASH. There were no differences in cytokine levels among groups. The triglyceride levels were the only variable that could stratify the grades of NAFLD and also differentiate from normal livers in the female patients. Also in this group, the aminotransferases and GGT levels and fasting glucose were predictors of the more advanced stages of NASH, while BMI and weight were predictors of the more advanced stages of NASH in male patients. CONCLUSIONS: There are no available markers in clinical practice to detect the initial stages of NAFLD. It is very important to perform a liver biopsy in all patients submitted to bariatric surgery and in obese patients with no indication to be operated in the presence of elevated blood levels of aminotransferases, GGT, and fasting glucose. PMID- 21598008 TI - Oral administration of coenzyme Q10 reduces MPTP-induced loss of dopaminergic nerve terminals in the striatum in mice. AB - The neuroprotective effect of coenzyme Q(10) (CoQ(10)) has been reported in 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. In this study, we investigated whether oral administration of CoQ(10) could protect the striatal dopaminergic (DAergic) nerve terminals against MPTP-induced toxicity in C57BL/6N mice using immunoisolation technique for DAergic synaptosomes. CoQ(10) significantly attenuated decrease in dopamine transporter as well as in synaptophysin and actin protein levels in DAergic synaptosomes from MPTP-treated mice. The effect of CoQ(10) was also observed in crude synaptosomes fraction, but not in homogenate. Our results indicate that the nerve terminals are a site for the action of CoQ(10) against the MPTP-induced DAergic neurodegeneration. PMID- 21598009 TI - What are the factors of residual pain after uncomplicated TKA? AB - PURPOSE: Residual pain during activities of daily living and/or at rest is a major cause of a patient's dissatisfaction after total knee arthroplasty (TKA). The management of a painful TKA, which has no obvious clinical or radiological explanation, requires further investigation with more sensitive imaging modalities (CT scan and bone scan) and hematological tests. It is often challenging for the physician to determine what level of pain warrants these more complex and expensive medical examinations. A precise knowledge of the natural history of postoperative pain following TKA is therefore of fundamental importance. METHODS: We reviewed the literature and highlighted the studies that investigated the evolution of pain after uncomplicated TKAs and the impact of demographic and psychosocial variables on a postoperative painful TKA. RESULTS: Factors that are associated with a more painful knee include female sex, a younger age at the time of surgery, and a higher than normal depressive or anxiety state. In particular, the Pain Catastrophizing Scale (PCS), a scale that quantifies a patient's negative or exaggerated orientation to pain, appears to significantly influence a patient's outcome after TKA. CONCLUSION: The identification of these high-risk patients is critical so that a surgeon can provide detailed preoperative education in order to give these patients a realistic expectation of their possible satisfaction following TKA. PMID- 21598010 TI - Total knee arthroplasty--what do we know and what don't. PMID- 21598011 TI - Occurrence of Vibrio parahaemolyticus and Vibrio alginolyticus in the German Bight over a seasonal cycle. AB - Bacteria of the genus Vibrio are an important component of marine ecosystems worldwide. The genus harbors several human pathogens, for instance the species Vibrio parahaemolyticus, a main cause for foodborne gastroenteritis in Asia and the USA. Pathogenic V. parahaemolyticus strains emerged also in Europe, but little is known about the abundance, pathogenicity and ecology of V. parahaemolyticus especially in Northern European waters. This study focuses on V. parahaemolyticus and its close relative Vibrio alginolyticus in the North Sea (Helgoland Roads, Germany). Free-living, plankton-attached and shellfish associated Vibrio spp. were quantified between May 2008 and January 2010. CFUs up to 4.3 * 10(3) N l(-1) and MPNs up to 240 N g(-1) were determined. Phylogenetic classification based on rpoB gene sequencing revealed V. alginolyticus as the dominant Vibrio species at Helgoland Roads, followed by V. parahaemolyticus. We investigated the intraspecific diversity of V. parahaemolyticus and V. alginolyticus using ERIC-PCR. The fingerprinting disclosed three distinct groups at Helgoland Roads, representing V. parahaemolyticus, V. alginolyticus and one group in between. The species V. parahaemolyticus occurred mainly in summer months. None of the strains carried the virulence-associated genes tdh or trh. We further analyzed the influence of nutrients, secchi depth, temperature, salinity, chlorophyll a and phytoplankton on the abundance of Vibrio spp. and the population structure of V. parahaemolyticus. Spearman Rank analysis revealed that particularly temperature correlated significantly with Vibrio spp. numbers. Based on multivariate statistical analyses we report that the V. parahaemolyticus population was structured by a complex combination of environmental parameters. To further investigate these influences is the key to understanding the dynamics of Vibrio spp. in temperate European waters, where this microbial group and especially the pathogenic species, are likely to gain in importance. PMID- 21598014 TI - Antifeedant and termiticidal activities of 6-alkoxycoumarins and related analogs against Coptotermes formosanus Shiraki. AB - We synthesized 23 6-alkoxycoumarin derivatives, 20 of which are novel compounds. The structures of all compounds were confirmed by NMR, MS, and elemental analysis, and their antifeedant and termiticidal activities against Coptotermes formosanus Shiraki were examined. In a no-choice test, 6-(2-pentynyloxy)coumarin (2v), 6-(2-butynyloxy)coumarin (2u), 6-(2-octynyloxy)coumarin (2w), and 6 methoxycoumarin (2a), demonstrated high termiticidal activity at a concentration of 10 MUmol. At a concentration of 5 MUmol, 6-(2-butynyloxy)coumarin (2u) produced the highest mortality among the compounds tested. On the other hand, all of the 6-alkoxycoumarins showed antifeedant activity at both concentrations, except 6-octadecyloxycoumarin (2j) that was inactive at 5 MUmol. Among the 23 compounds and the control, 6-ethoxycoumarin (2b), 6-isopropoxycoumarin (2d), and 6-isobutoxycoumarin (2f) exhibited the highest antifeedant activity with no mass loss (0.00%) at a concentration of 10 MUmol. Our findings indicate that the presence of alkenyloxy and alkynyloxy groups was important for the termiticidal activity, while the incorporation of alkoxy groups with longer alkyl chains tended to reduce both the termiticidal and antifeedant activities. Furthermore, short chain alkoxy and arylalkoxy-substituted analogs showed good antifeedant activity, but methoxy groups on the benzene ring had a negative effect. PMID- 21598013 TI - Thymic involution and corticosterone level in Sandhoff disease model mice: new aspects the pathogenesis of GM2 gangliosidosis. AB - Sandhoff disease (SD) is a lysosomal disease caused by a mutation of the HEXB gene associated with excessive accumulation of GM2 ganglioside (GM2) in lysosomes and neurological manifestations. Production of autoantibodies against the accumulated gangliosides has been reported to be involved in the progressive pathogenesis of GM2 gangliosidosis, although the underlying mechanism has not been fully elucidated. The thymus is the key organ in the acquired immune system including the development of autoantibodies. We showed here that thymic involution and an increase in cell death in the organ occur in SD model mice at a late stage of the pathogenesis. Dramatic increases in the populations of Annexin V(+) cells and terminal deoxynucletidyl transferase dUTP nick end labeling (TUNEL) (+) cells were observed throughout the thymuses of 15-week old SD mice. Enhanced caspase-3/7 activation, but not that of caspase-1/4, -6 ,-8, or -9, was also demonstrated. Furthermore, the serum level of corticosterone, a potent inducer of apoptosis of thymocytes, was elevated during the same period of apoptosis. Our studies suggested that an increase in endocrine corticosterone may be one of the causes that accelerate the apoptosis of thymocytes leading to thymic involution in GM2 gangliosidosis, and thus can be used as a disease marker for evaluation of the thymic condition and disease progression. PMID- 21598012 TI - Genetic testing in the European Union: does economic evaluation matter? AB - OBJECTIVE: We review the published economic evaluation studies applied to genetic technologies in the EU to know the main diseases addressed by these studies, the ways the studies were conducted and to assess the efficiency of these new technologies. The final aim of this review was to understand the possibilities of the economic evaluations performed up to date as a tool to contribute to decision making in this area. METHODS: We have reviewed a set of articles found in several databases until March 2010. Literature searches were made in the following databases: PubMed; Euronheed; Centre for Reviews and Dissemination of the University of York-Health Technology Assessment, Database of Abstracts of Reviews of Effects, NHS Economic Evaluation Database; and Scopus. The algorithm was "(screening or diagnosis) and genetic and (cost or economic) and (country EU27)". We included studies if they met the following criteria: (1) a genetic technology was analysed; (2) human DNA must be tested for; (3) the analysis was a real economic evaluation or a cost study, and (4) the articles had to be related to any EU Member State. RESULTS: We initially found 3,559 papers on genetic testing but only 92 articles of economic analysis referred to a wide range of genetic diseases matched the inclusion criteria. The most studied diseases were as follows: cystic fibrosis (12), breast and ovarian cancer (8), hereditary hemochromatosis (6), Down's syndrome (7), colorectal cancer (5), familial hypercholesterolaemia (5), prostate cancer (4), and thrombophilia (4). Genetic tests were mostly used for screening purposes, and cost-effectiveness analysis is the most common type of economic study. The analysed gene technologies are deemed to be efficient for some specific population groups and screening algorithms according to the values of their cost-effectiveness ratios that were below the commonly accepted threshold of 30,000?. CONCLUSIONS: Economic evaluation of genetic technologies matters but the number of published studies is still rather low as to be widely used for most of the decisions in different jurisdictions across the EU. Further, the decision bodies across EU27 are fragmented and the responsibilities are located at different levels of the decision process for what it is difficult to find out whether a given decision on genetic tests was somehow supported by the economic evaluation results. PMID- 21598015 TI - [Travel medicine]. PMID- 21598016 TI - [Vaccination prior to travelling for patients with rheumatic diseases]. AB - Rheumatologists increasingly face patient questions about the need, the safety and the effectiveness of travel-related vaccinations. Currently, there are no guidelines on travel vaccinations for patients with inflammatory rheumatic diseases. The use of live attenuated vaccines remains contraindicated in patients receiving relevant immunosuppressive therapy despite some encouraging results from initial pilot studies. However, many inactivated travel vaccines can safely be used for patients with rheumatic diseases. Furthermore, rheumatologists should be vigilant in identifying and closing gaps in the routine vaccinations for patients. PMID- 21598017 TI - Idiopathic deep venous thrombosis and arterial endothelial dysfunction in the elderly. AB - Arterial and venous thrombosis have always been regarded as different pathologies and epidemiological studies have examined the association between venous thrombosis and indicators of atherosclerosis and/or arterial thromboembolic events. We measured the flow-mediated dilation (FMD), a well-known marker of arterial endothelial dysfunction, in young-middle-aged and old-aged patients with and without unprovoked deep venous thrombosis (DVT). The aim of this study was to investigate whether DVT was a significant predictor for impaired FMD, considering all the patients and young-middle-aged (age < 65 years) and old-aged (age >= 65 years) patients separately. FMD was measured in the brachial artery on a population of 120 subjects with the same atherosclerosis risk factors, 68 male and 52 female, 70 young-middle-aged subjects (mean age +/- SD 49.5 +/- 10.5 years) and 50 old-aged subjects (76.2 +/- 7.7 years). Patients with DVT showed a significant decrease of FMD compared to patients without DVT (6.8 +/- 5.5% vs. 10.9 +/- 3.5%, p < 0.001). Moreover, old-aged patients showed a significant decrease of FMD compared to the young-middle-aged subjects (7.4 +/- 4.1% vs. 9.8 +/- 5.3%, p = 0.005). In the whole study population, DVT was strongly associated with FMD (risk factors adjusted beta = -4.14, p < 0.001). A significant interaction between age and the presence of DVT on predicting FMD was found (p = 0.003) suggesting a differential behavior of DVT as predictor of FMD. In young middle-aged group, multivariate model confirmed that DVT was the most significant predictor of continuous FMD (beta = -6.06, p < 0.001). On the contrary, DVT was no more a predictor of FMD in the old age group (beta = -0.73, p = 0.556). Furthermore, old-aged patients without DVT showed a statistically significant decrease of FMD compared to the young-middle-aged subjects without DVT (8.2 +/- 2.1% vs. 12.6 +/- 2.7%, p<0.001) and old-aged patients with DVT showed a not statistically significant decrease of the FMD compared to the young-middle-aged patients with DVT (6.7 +/- 5.3% vs. 6.8 +/- 5.7%, p = 0.932). In conclusion, young-middle-aged patients with spontaneous DVT show an impaired FMD, whereas this impairment in old-aged subjects is evident independently from the presence or absence of DVT. Aging per se may be associated with physiologic abnormalities in the systemic arteries and with endothelial dysfunction. PMID- 21598019 TI - The functional RNA domain 5BSL3.2 within the NS5B coding sequence influences hepatitis C virus IRES-mediated translation. AB - Hepatitis C virus (HCV) translation is mediated by an internal ribosome entry site (IRES) located at the 5' end of the genomic RNA. The 3' untranslatable region (3'UTR) stimulates translation by the recruitment of protein factors that simultaneously bind to the 5' end of the viral genome. This leads to the formation of a macromolecular complex with a closed loop conformation, similar to that described for the cap-translated mRNAs. We previously demonstrated the existence of a long-range RNA-RNA interaction involving subdomain IIId of the IRES region and the stem-loop 5BSL3.2 of the CRE element at the 3' end of the viral genome. The present study provides evidence that the enhancement of HCV IRES-dependent translation mediated by the 3'UTR is negatively controlled by the CRE region in the human hepatoma cell lines Huh-7 and Hep-G2 in a time-dependent manner. Domain 5BSL3.2 is the major partner in this process. Mutations in this motif lead to an increase in IRES activity by up to eightfold. These data support the existence of a functional high order structure in the HCV genome that involves two evolutionarily conserved RNA elements, domain IIId in the IRES and stem-loop 5BSL3.2 in the CRE region. This interaction could have a role in the circularisation of the viral genome. PMID- 21598020 TI - Alpha T-catenin (CTNNA3): a gene in the hand is worth two in the nest. AB - Alpha-T-Catenin (CTNNA3) is a key protein of the adherens junctional complex in epithelial cells playing a crucial role in cellular adherence. What makes this gene particularly interesting is that it is located within a common fragile site, is epigenetically regulated, is transcribed through multiple promoters, and generates a variety of alternate transcripts. Finally, CTNNA3 has a nested gene (LRTMM3) embedded within its genomic context transcribed in the opposite direction. Apart from the complexity of its regulation, alterations in both CTNNA3 and LRTMM3 are implicated in human disease. PMID- 21598021 TI - "Add-on" domains of Drosophila beta1,4-N-acetylgalactosaminyltransferase B in the stem region and its pilot protein. AB - The glycolipid specific Drosophila melanogaster beta1,4-N acetylgalactosaminyltransferase B (beta4GalNAcTB) depends on a zinc finger DHHC protein family member named GalNAcTB pilot (GABPI) for activity and translocation to the Golgi. The six-membrane spanning protein actually lacks the cysteine in the cytoplasmic DHHC motif, displaying DHHS instead. Here we show that the whole conserved region around the DHHS sequence, which is essential for palmitoylation in DHHC proteins, is not required for GABPI to interact with beta4GalNAcTB. In contrast, the two luminal loops between transmembrane domain 3-4 and 5-6 contain conserved amino acids, which are crucial for activity. Besides the dependence on GABPI, beta4GalNAcTB requires its exceptional short stem region for activity. A few hydrophobic amino acids positioned close to the transmembrane domain are essential for the interaction with GABPI. Along with its catalytic domain, beta4GalNAcTB, thus, requires an area in its own stem region and two small luminal loops of GABPI as "add-on" domains. Moreover, some inactive GABPI mutants could be rescued by fusion with beta4GalNAcTB, indicating their importance in direct GABPI-beta4GalNAcTB interaction. PMID- 21598022 TI - Beyond natural antimicrobial peptides: multimeric peptides and other peptidomimetic approaches. AB - Naturally occurring antimicrobial peptides (AMPs) present several drawbacks that strongly limit their development into therapeutically valuable antibiotics. These include susceptibility to protease degradation and high costs of manufacture. To overcome these problems, researchers have tried to develop mimics or peptidomimetics endowed with better properties, while retaining the basic features of membrane-active natural AMPs such as cationic charge and amphipathic design. Protein epitope mimetics, multimeric (dendrimeric) peptides, oligoacyllysines, ceragenins, synthetic lipidated peptides, peptoids and other foldamers are some of the routes explored so far. The synthetic approach has led to compounds that have already entered clinical evaluation for the treatment of specific conditions, such as Staphylococcus (MRSA) infections. Should these trials be successful, an important proof-of-concept would be established, showing that synthetic oligomers rather than naturally occurring molecules could bring peptide-based antibiotics to clinical practice and the drug market for local and systemic treatment of medical conditions associated with multi-drug resistant pathogens. PMID- 21598023 TI - Exercise among breast and prostate cancer survivors--what are their barriers? AB - INTRODUCTION: Despite proven benefits of regular physical activity, estimates indicate that few cancer survivors meet physical activity guidelines. The purpose of this paper is to identify and compare exercise barriers among cancer survivors, both cross-sectionally and longitudinally as they undergo home-based behavioral interventions. METHODS: Data on a sample of 452 breast and prostate cancer survivors who completed the FRESH START trial were analyzed collectively, as well as separately by cancer type. RESULTS: More total barriers (3.5 vs. 2.4; p < 0.01) were reported among breast cancer survivors compared with prostate cancer survivors. Commonly reported baseline exercise barriers among both groups were "too busy" (breast, 52% and prostate, 45%) and "no willpower" (breast, 51% and prostate, 44%). At baseline, breast cancer survivors who reported "no willpower" also reported 18.7 fewer minutes of physical activity compared with those not reporting this barrier (p < 0.01). Among prostate cancer survivors, this difference was 39.5 min (p < 0.01). Change in barriers was not associated with change in minutes of physical activity from baseline to post-intervention in either cancer survivor group. CONCLUSIONS: This is the largest study evaluating barriers and physical activity over time among cancer survivors. There are similarities and differences that both need to be taken into consideration when promoting physical activity among subgroups of survivors. IMPLICATIONS FOR CANCER SURVIVORS: Knowledge concerning barriers associated with reported physical activity may be helpful in designing optimally targeted physical activity interventions among breast and prostate cancer survivors. PMID- 21598024 TI - Comparative analysis of the behavioral and biomolecular parameters of four mouse strains. AB - The use of mice as experimental models in pharmacological and biochemical research began over 100 years ago, during which time different mice strains with specific features were developed. Numerous studies demonstrate that the pharmacological efficacy of various compounds significantly varies among different animal strains, a factor which must be considered when analyzing experimental data. The Sabra strain, developed more than 35 years ago, is widely used for research in Israel but has an unclear origin and is not characterized as well as other strains. Comparative analyses of the molecular characteristics of Sabra and other strains should help to understand their characteristics and to enhance the validity of their experimental use. Thus, four mouse strains-outbred ICR and Sabra as well as inbred C57Bl/6J and Balb/c were compared. Animals' weight, blood corticosterone and hippocampal BDNF mRNA levels were measured, and animals' behavior was compared using the EPM, open field, FST, and hot plate tests. We found that although Sabra mice are bigger and heavier than other tested lines, this is not reflected in behavior or in biomolecular features, wherein Sabra mice lay within the diapason of other tested animals. Thus, behavioral tests of anxiety-like behavior and locomotor activity revealed that Sabra mice scored close to the mean of all tested lines. Analysis of blood corticosterone levels did not show significant differences among tested strains. We also found a correlation between general and locomotor activity of the tested strains and their hippocampal BDNF mRNA expression. In summary, we may conclude that Sabra mice have traits similar to the better known lines, and therefore they are good subjects for neuroscience research. PMID- 21598025 TI - Persistence and effect of processing on reduction of chlorpyriphos residues in okra fruits. AB - Residue levels of chlorpyriphos were determined in unprocessed and processed okra fruits to evaluate the effect of different processes (washing and washing followed by boiling/cooking) on reduction of residues of this pesticide in okra. The study was carried out on okra crop (Variety, Varsha Uphar) in research farm of Chaudhary Charan Singh, Haryana Agricultural University, Hisar with application of chlorpyriphos (Radar 20 EC) at 200 g a.i./ha and 400g a.i./ha (Single Dose, T(1)) and 400 g a.i./ha (Double Dose, T(2)). Samples of okra fruits were collected on 0, 1, 3, 5, 7, 10, 15 days and at harvest after treatment. Residues were estimated by GC-ECD system and reached BDL of 0.010 mg kg(-1) on 7th and 15th day in case of single and double dose, respectively. The residues dissipated with half-life period of 3.15 days at lower dose and 3.46 days at higher dose following biphasic first order kinetics. Processing was found very effective in reducing the levels of chlorpyriphos residues in okra fruits. Maximum reduction (64-77%) was observed by washing + boiling followed by washing (13-35%). PMID- 21598026 TI - Development of dispersive liquid-liquid microextraction based on solidification of floating organic drop for the determination of trace nickel. AB - A liquid-phase microextraction technique was developed using dispersive liquid liquid microextraction based on solidification of floating organic drop combined with flame atomic absorption spectrometry, for the extraction and determination of trace amounts of nickel in water samples. Microextraction efficiency factors, such as the type and volume of extraction and dispersive solvents, pH, extraction time, the chelating agent amount, and ionic strength, were investigated and optimized. Under optimum conditions, the calibration graph was linear in the range of 4.23-250 MUg L(-1) with a detection limit of 1.27 MUg L(-1). The relative standard deviation for ten replicate measurements of 10 and 100 MUg L( 1) of nickel were 3.21% and 2.55%, respectively. The proposed method was assessed through the analysis of certified reference water or recovery experiments. PMID- 21598027 TI - A case report of Gorham-Stout syndrome remission. PMID- 21598028 TI - Dorsoepitrochlearis muscle: an unknown cause of shoulder motion limitation and axilla deformity. PMID- 21598029 TI - Infarct tissue characteristics of patients with versus without early revascularization for acute myocardial infarction: a contrast-enhancement cardiovascular magnetic resonance imaging study. AB - Histopathological studies have suggested that early revascularization for acute myocardial infarction (MI) limits the size, transmural extent, and homogeneity of myocardial necrosis. However, the long-term effect of early revascularization on infarct tissue characteristics is largely unknown. Cardiovascular magnetic resonance (CMR) imaging with contrast enhancement (CE) allows non-invasive examination of infarct tissue characteristics and left ventricular (LV) dimensions and function in one examination. A total of 69 patients, referred for cardiac evaluation for various clinical reasons, were examined with CE-CMR >1 month (median 6, range 1-213) post-acute MI. We compared patients with (n = 33) versus without (n = 36) successful early revascularization for acute MI. Cine-CMR measurements included the LV end-diastolic and end-systolic volumes (ESV), LV ejection fraction (LVEF, %), and wall motion score index (WMSI). CE images were analyzed for core, peri, and total infarct size (%), and for the number of transmural segments. In our population, patients with successful early revascularization had better LVEFs (46 +/- 16 vs. 34 +/- 14%; P < 0.01), superior WMSIs (0.53, range 0.00-2.29 vs. 1.42, range 0.00-2.59; P < 0.01), and smaller ESVs (121 +/- 70 vs. 166 +/- 82; P = 0.02). However, there was no difference in core (9 +/- 6 vs. 11 +/- 6%), peri (9 +/- 4 vs. 10 +/- 4%), and total infarct size (18 +/- 9 vs. 21 +/- 9%; P > 0.05 for all comparisons); only transmural extent (P = 0.07) and infarct age (P = 0.06) tended to be larger in patients without early revascularization. CMR wall motion abnormalities are significantly better after revascularization; these differences are particularly marked later after infarction. The difference in scar size is more subtle and does not reach significance in this study. PMID- 21598030 TI - In vitro activity of dietary flavonol congeners against human cancer cell lines. AB - BACKGROUND: Flavonoids have physiological activity and a variety of pharmacological properties, including anticancer activity in vitro, but structure anticancer activity relationships are unclear. AIM: The objectives of this work were to investigate the activity of dietary flavonol congeners against cell lines derived from human solid tumours and to examine whether the in vitro activity was associated with specific structural feature(s) of the molecules. METHODS: Antiproliferative activity of the flavonol congeners was investigated against eight different human cancer cell lines representing different types of human solid tumour, using the sulforhodamine B (SRB) assay in accordance with the instructions published by the NCI. Cell cycle perturbations caused by the congeners were monitored by flow-cytometric analysis of DNA stained with propidium iodide. RESULTS: Most of the flavonols examined had weak antiproliferative and cytotoxic activity. Of all the flavonol congeners tested peracetylated tiliroside found to be the most powerful, with significant antiproliferative and cytotoxic activity. Most flavonols induced similar cell cycle perturbations, whereas induction of apoptosis was significant only for cells treated with peracetylated tiliroside. CONCLUSIONS: These findings indicated that the -OH groups of aromatic ring B were not linked to the cytotoxic and antiproliferative activity of the tested flavonols whereas peracetylation of the glycosides resulted in moderate improvement. In contrast, acetylation of tiliroside esterified with coumaric acid at position 5 of the sugar moiety greatly improved the activity of this congener. Overall, the results of this study suggest a critical role of sugar moiety substituents in the anticancer activity of the flavonols. PMID- 21598031 TI - Depression and neurocognitive performance in Portuguese patients infected with HIV. AB - This study focused on neurocognitive disorders associated with HIV infection, characterizes the most affected neuropsychological domains and their potential as factors related with depression. 130 HIV-positive individuals with CD4 >200 cells/mm(3), undetectable viral load, treated with HAART and with all kinds of risk behaviors were included. A structured interview composed by seven sections was used and relevant clinical and laboratory data was assessed. For the neuropsychological and depression assessment the HIV Neurobehavioral Research Center (HNRC) Battery and Hamilton Rating Scale for Depression (HAM-D) were chosen. Univariate nonparametric statistics and multivariate regression model were performed. Among 34% of depressed subjects, 20.7% had attempted suicide, 45.4% were under psychiatric medication and only 19% had no diagnostic criteria for HIV Associated Neurocognitive Disorders (HAND). The effect of depression on cognitive function revealed a significant deterioration in five of the eight measures. In the multivariate analysis, five variables significantly determined depression: sex, social class, antidepressant medication, history of suicide attempt and Dexterity and motor speed (neuropsychological test battery). Despite good patient adherence to treatment (HAART and antidepressive) and good immune status, the prevalence of HAND and depression are high and suggest a significant relation between severity of depression and cognitive functioning. PMID- 21598032 TI - Disproportionate impact of combination antiretroviral therapy on AIDS incidence in Australia: results from a modified back-projection model. AB - The objective of the current study is to describe the impact of Combination antiretroviral therapy (cART) on trends in AIDS incidence over time for selected population groups in Australia, specifically, men who have sex with men (MSM) and injecting drug users (IDUs). A modified back-projection modeling technique was used to predict the number of AIDS diagnoses without cART based on Australia's HIV/AIDS surveillance system database. Modelled estimates indicate that since 1996, the effective cART has reduced overall AIDS cases by ~70 and ~10% among MSM and IDUs respectively. The predicted reduction in AIDS cases among IDUs aged less than 40 years was 36% while there was no reduction predicted for those aged 40 years or older. The impact of cART on AIDS diagnoses has been modest among IDUs. Late presentation, poor access to health services and barriers to uptake of cART may account for the divergence between these population groups. PMID- 21598033 TI - Partner violence and HIV risk among female sex workers in China. AB - Global literature suggests that partner violence contributes to HIV-related vulnerability and risk among women. Female sex workers (FSWs) play a significant role in China's skyrocketing increase of heterosexual transmission of HIV. The aim of this article is to examine the association between partner violence and HIV risk among FSWs in China. This study, based on a cross-sectional survey of 1,022 FSWs recruited from communities in China, attempted to address the relationship between partner violence and HIV risk among this vulnerable population. About 58% of the FSWs had experienced violence from their stable partners (including 55.5% reporting emotional violence, 20.1% physical violence, and 16.2% sexual violence) and 45% from their clients (including 39.7% reporting emotional violence, 17.1% physical violence, and 16.8% sexual violence). Partner violence perpetuated by either stable partners or clients was strongly associated with most of the HIV risk measures we assessed. This study confirmed the association of partner violence and HIV risk among FSWs. We call for culturally appropriate interventions for both partner violence and HIV risk reduction among FSWs in China. PMID- 21598034 TI - Are peer interventions for HIV efficacious? A systematic review. AB - Behavioral interventions to prevent HIV or assist HIV-positive persons often incorporate peers, yet empirical support for their efficacy is only recently accumulating. We describe the results of a review of the global literature, identifying 117 studies evaluating the efficacy of peer-based interventions in the area of HIV/AIDS. About half were conducted in the developing world and half in Western nations. Across a range of populations and intervention modalities, the majority of studies provided some support for peer interventions according to outcome indicators in the domains of sexual risk behavior, attitudes and cognitions, HIV knowledge, and substance use. However, outcomes assessed using biomarkers and other non-self-report variables were less likely to indicate intervention efficacy. Overall, findings suggest that we can have some confidence in peer interventions, yet more data are needed demonstrating an effect in the most rigorous study designs and with outcomes that are not potentially affected by respondent bias. PMID- 21598035 TI - Geographic profiling to assess the risk of rare plant poaching in natural areas. AB - We demonstrate the use of an expert-assisted spatial model to examine geographic factors influencing the poaching risk of a rare plant (American ginseng, Panax quinquefolius L.) in Shenandoah National Park, Virginia, USA. Following principles of the analytic hierarchy process (AHP), we identified a hierarchy of 11 geographic factors deemed important to poaching risk and requested law enforcement personnel of the National Park Service to rank those factors in a series of pair-wise comparisons. We used those comparisons to determine statistical weightings of each factor and combined them into a spatial model predicting poaching risk. We tested the model using 69 locations of previous poaching incidents recorded by law enforcement personnel. These locations occurred more frequently in areas predicted by the model to have a higher risk of poaching than random locations. The results of our study can be used to evaluate resource protection strategies and to target law enforcement activities. PMID- 21598037 TI - Inhibition of morphine-induced cAMP overshoot: a cell-based assay model in a high throughput format. AB - Opiates are not only potent analgesics but also drugs of abuse mainly because they produce euphoria. Chronic use of opiates results in the development of tolerance and dependence. Dr Marshall Nirenberg's group at the National Institutes of Health (NIH) was the first to use a cellular model system of Neuroblastoma * Glioma hybrid cells (NG108-15) to study morphine addiction. They showed that opiates affect adenylyl cyclase (AC) by two opposing mechanisms mediated by the opiate receptor. Although the cellular mechanisms that cause addiction are not yet completely understood, the most observed correlative biochemical adaptation is the upregulation of AC. This model also provides the opportunity to look for compounds which could dissociate the acute effect of opiates from the delayed response, upregulation of AC, and thus lead to the discovery of non-addictive drugs. To identify small molecule compounds that can inhibit morphine-induced cAMP overshoot, we have validated and optimized a cell based assay in a high throughput format that measures cellular cAMP production after morphine withdrawal. The assay performed well in the 1536-well plate format. The LOPAC library of 1,280 compounds was screened in this assay on a quantitative high-throughput screening (qHTS) platform. A group of compounds that can inhibit morphine-induced cAMP overshoot were identified. The most potent compounds are eight naloxone-related compounds, including levallorphan tartrate, naloxonazine dihydrochloride, naloxone hydrochloride, naltrexone hydrochloride, and naltriben methanesulfonate. The qHTS approach we used in this study will be useful in identifying novel inhibitors of morphine induced addiction from a larger scale screening. PMID- 21598036 TI - p65/RelA-Ser529 NF-kappaB subunit phosphorylation induces autophagic astroglial death (Clasmatodendrosis) following status epilepticus. AB - Clasmatodendrosis is an irreversible astroglial degenerative change, which includes extensive swelling and vacuolization of cell bodies and disintegrated and beaded processes. This study was designed to elucidate whether clasmatodendrosis may be one of the autophagy-related degeneration of astrocytes. In this study, clasmatodendritic astrocytes were observed only in the stratum radiatum in the CA1 region. Vacuoles in clasmatodendritic astrocytes showed LAMP 1 immunoreactivity. In addition, both LC3-II and Beclin-1 expression were detected in most of clasmatodendritic astrocytes as well as a few non-vacuolized astrocytes. Clasmatodendritic astrocytes also showed p65/RelA-Ser529 phosphorylation in the nuclei. The neutralization of TNF-alpha by sTNFp55R infusion reduced clasmatodendritic astrocytes with nuclear p65/RelA-Ser529 phosphorylation. Therefore, these findings suggest that clasmatodendrosis may be autophagic astroglial death in response to epileptic seizures through TNF-alpha mediated p65/RelA-Ser529 phosphorylation. PMID- 21598038 TI - Laser surface modification of titanium substrate for pulsed laser deposition of highly adherent hydroxyapatite. AB - Biomedical implant devices made out of titanium and its alloys are benefited by a modified surface or a bioactive coating to enhance bone bonding ability and to function effectively in vivo for the intended period of time. In this respect hydroxyapatite coating developed through pulsed laser deposition is a promising approach. Since the success of the bioactive ceramic coated implant depends mainly on the substrate-coating strength; an attempt has been made to produce micro patterned surface structure on titanium substrate for adherent hydroxyapatite coating. A pulsed Nd-YAG laser beam (355 nm) with 10 Hz repetition rate was used for surface treatment of titanium as well as hydroxyapatite deposition. The unfocussed laser beam was used to modify the substrate surface with 500-18,000 laser pulses while keeping the polished substrate in water. Hydroxyapatite deposition was done in a vacuum deposition chamber at 400 degrees C with the focused laser beam under 1 * 10-3 mbar oxygen pressure. Deposits were analyzed to understand the physico-chemical, morphological and mechanical characteristics. The obtained substrate and coating surface morphology indicates that laser treatment method can provide controlled micro-topography. Scratch test analysis and microindentation hardness values of coating on laser treated substrate indicate higher mechanical adhesion with respect to coatings on untreated substrates. PMID- 21598039 TI - Shogaols at proapoptotic concentrations induce G(2)/M arrest and aberrant mitotic cell death associated with tubulin aggregation. AB - Shogaols have been previously reported to induce cancer cell death via multiple mechanisms, among which one analog 6-shogaol has been reported to cause microtubule damage through specific reaction with sulfhydryl groups in tubulin. In this study, a series of shogaols with different side chain lengths (4-, 6-, 8- and 10-shogaol) was synthesized and evaluated for antiproliferative activity in HCT 116 colon carcinoma and SH-SY5Y neuroblastoma cells. 4- and 6-shogaol were identified as lead compounds possessing the strongest antiproliferative activity. In the soft agar assay, the lead shogaols displayed dose-dependent inhibition on cancer cell colony formation under anchorage-independent conditions. Using HCT 116 as the selected cancer cell line, the molecular events linking shogaols induced G(2)/M cell cycle arrest to apoptosis characterized by caspase 3 and PARP cleavage were investigated. At sublethal concentrations, the halt at G(2)/M phase was alleviated along time and cells survived. Conversely, proapoptotic concentrations of 4- and 6-shogaol induced irreversible G(2)/M arrest that was at least in part associated with down-regulation of cell cycle checkpoint proteins cdk1, cyclin B and cdc25C, as well as spindle assembly checkpoint proteins mad2, cdc20 and survivin. A dose- and time-dependent accumulation of insoluble tubulin in the insoluble fractions of cell lysates provided evidence that G(2) checkpoint failure led to disruption of microtubule turnover. In summary, our results conclude that shogaols cause apoptosis by inducing aberrant mitosis at least through the attenuation of cell cycle and spindle assembly checkpoint proteins. PMID- 21598040 TI - Wide, short bore magnetic resonance at 1.5 t: reducing the failure rate in claustrophobic patients. AB - PURPOSE: Claustrophobic reactions in patients undergoing magnetic resonance imaging (MRI) have a significant impact on the workflow, patient acceptance and ultimately the costs involved in obtaining a diagnostic scan. The purpose of this study was to determine if the use of a wide, short bore MRI scanner could reduce the need for general anesthesia assistance in these cases. METHODS: Between September 2006 and March 2008, all patients for whom MRI examinations of the head and/or spine were canceled or prematurely terminated due to claustrophobia on a standard 60 cm bore, 1.5 T scanner were scheduled to be re-scanned on a 70 cm wide bore, 1.25 m long 1.5 T scanner. This re-scanning attempt was made 2 or more days prior to a scheduled anesthesia-assisted MRI appointment. If the patient successfully completed the wide bore MRI examination then the anesthesia-assisted MRI appointment was canceled. RESULTS: A total of 56 patients were included in this study. The examinations included individual body regions as well as combination examinations (head and cervical spine, entire spine etc.). A total of 72 body regions were examined in 56 patients. Of these regions, 65 (90%) were completed successfully, 50 patients (89%) successfully completed a diagnostic examination on the 70 cm scanner and 6 patients (11%), all of whom were scheduled for examinations which included the head, were unable to complete the examination on the wide bore scanner. CONCLUSIONS: A 1.5 T wide short bore scanner increases the examination success rate in patients with claustrophobia and substantially reduces the need for anesthesia-assisted MRI examinations even when claustrophobia is severe. PMID- 21598041 TI - Early severe hypoalbuminemia is an independent risk factor for intestinal failure in gastroschisis. AB - OBJECTIVE: This study attempted to evaluate the association of early hypoalbuminemia with the risk of intestinal failure in gastroschisis patients. PATIENTS AND METHODS: Neonates with gastroschisis treated at a tertiary children's hospital over a 10-year period were initially categorized into groups based on the lowest serum albumin measurement during the first 7 days of life. Based on preliminary analysis, patients with serum albumin <1.5 g/dL were considered to have early severe hypoalbuminemia. Intestinal failure was defined as inability of the patient to wean from parenteral nutrition (PN) during the initial hospital admission, thus requiring home PN. Logistic regression modeling was performed to adjust for sex, gestational age, birth weight, and concomitant intestinal complications. RESULTS: One hundred and thirty-five gastroschisis patients were included, of whom 21% had early severe hypoalbuminemia. Patients with early severe hypoalbuminemia had a significantly higher risk of intestinal failure compared to those with higher albumin levels (26 vs. 8%, p = 0.015). On multivariable logistic regression modeling, early severe hypoalbuminemia was strongly associated with intestinal failure (OR 6.4, 95% CI 1.8-23.3, p = 0.005). CONCLUSIONS: Early severe hypoalbuminemia appears to be an independent risk factor for long-term intestinal compromise rather than merely an indicator of overall illness. Further interventional studies are needed to determine whether clinical protocols utilizing judicious fluid administration, exogenous albumin, and early enteral feeding can improve clinical outcomes in gastroschisis. PMID- 21598042 TI - Hypoxia-related protein expression and its clinicopathologic implication in carcinoma of unknown primary. AB - Carcinoma of unknown primary (CUP) is a heterogeneous entity with different clinical and histological features. The aim of this study was to investigate the clinicopathological features and expression of proteins associated with carcinogenesis and tumor environment in different histological subtypes of CUP. Sixty-nine cases of CUP were subjected to immunohistochemistry for EGFR, phospho EGFR, HER-2, phospho-HER-2, p53, ERCC1, RRM1, REDD1, HIF1alpha, COX-2, GLUT-1, 14 3-3sigma, Phospho-mTOR, Phospho-S6, AMPKalpha1, Phospho-Akt, PDGF-beta receptor, and caveolin-1, and fluorescence in situ hybridization for HER-2 gene amplification. Fourteen (20.3%) cases were poorly differentiated carcinoma, 24 (34.8%) were adenocarcinoma (AD), 17 (24.6%) were squamous cell carcinoma (SC), and 14 (20.3%) were undifferentiated carcinoma (UD). AD were mostly carcinomatosis type, while SC and UD were mostly nodal type (p < 0.001). SC showed more frequent EGFR overexpression (p < 0.001) and Glut-1 (p = 0.001). AD (p = 0.001) and carcinomatosis (p < 0.001) types showed shorter overall survival. SCs expressing Glut-1, HIF1alpha, and COX2 showed a poor prognosis (p = 0.048, 0.029, and 0.042, respectively). CUP shows various clinicopathological features according to the histological subtypes. SC is mainly associated with nodal metastasis in the head and neck, and frequent EGFR overexpression and Glut-1 expression. Glut-1, HIF1alpha, and COX2 expression in SC is associated with a poor prognosis. PMID- 21598043 TI - The effect of methylated oligonucleotide targeting Ki-67 gene in human 786-0 renal carcinoma cells. AB - To investigate the effect of methylated oligonucleotide (MON) targeting Ki-67 promoter on the expression of Ki-67 gene and the proliferation and apoptosis of the human 786-0 renal carcinoma cells, human 786-0 cells were transfected with MON. The activity of Ki-67 promoter was detected by dual-luciferase reporter assay system. Among the five methylated oligonucleotides (MON(1)-MON(5)), MON(4) is the best excellent one in the inhibition of the Ki-67 promoter activity. The activity of Ki-67 promoter is decreased to 77.88% in 40-nM group, 50.07% in 80-nM group, 35.63% in 120-nM group, 26.09% in 160-nM group, and 16.98% in 200-nM group compared with 0-nM group. The activity of Ki-67 promoter in MON group is decreased to 61.96% at 8 h, 48.93% at 12 h, 15.97% at 24 h, 26.00% at 36 h, 35.01% at 48 h, 46.08% at 72 h, and 66.12% at 96 h compared with pGLBK235 group. These results show that the effect of MON is time- and dose-dependent. The activity of Ki-67 in MON group is decreased to 16.73% compared with pGLBK235 group, while the control groups have no significant difference. The expression of Ki-67 gene in 786-0 cells was detected by RT-PCR and immunohistochemistry, respectively. The expression of Ki-67 mRNA is decreased to 61.04% and that of Ki 67 protein is decreased to 32.07% in MON group compared with the blank group. The proliferation of 786-0 cells was determined by WST-8. The cell proliferation in MON group is decreased to 61.02% at 24 h, 73.78% at 48 h, 79.72% at 72 h, and 91.53% at 96 h compared with the blank group. The cell apoptosis was measured by annexin V and propidium iodide. The number of apoptosis cells in MON group is 2.42 times of that in the blank group at earlier period and 2.57 times at mid anaphase. We detected the effect of MON on the expression of bax and p53 by Western blot. Compared with the blank group, the expression of bax protein in MON group is increased by 66.12%, while the expression of p53 is decreased to 67.31%. Our study demonstrates that the methylated oligonucleotide targeting Ki-67 promoter has a remarkable effect on the inhibition of Ki-67 expression and the proliferation of the human 786-0 renal carcinoma cells and can induce apoptosis of the 786-0 cells. PMID- 21598044 TI - Non-ideal mixing and fluid-fluid immiscibility in phosphatidic acid phosphatidylethanolamine mixed bilayers. AB - Differential scanning calorimetry (DSC) was used to study the miscibility of phosphatidic acids (PAs) with phosphatidylethanolamines (PEs) as a function of chain length (n = 14, 16) and degree of ionization of PAs at pH 4, pH 7, and pH 12. Phase diagrams were constructed using temperature data for onset and end of the phase transition obtained from the direct simulation of the heat-capacity curves. The phase diagrams were analyzed by simulations of the coexistence curves utilizing a four-parameter regular solution model. For PA-PE mixtures, the non ideality parameters are a function of composition indicating non-symmetric non ideal mixing behavior. At pH 7, where the PA component is negatively charged, the systems DMPA:DMPE and DPPA:DPPE have positive non-ideality parameters rho (1) in both phases, indicating a preferred aggregation of like molecules. In contrast, DMPA:DPPE and DPPA:DMPE mixtures had negative rho (1) values. Measurements at pH 4 showed that mixed pair formation is favored when PA is protonated. At pH 12 where PA is doubly charged, highly positive rho (l1) parameters are obtained for the liquid-crystalline phase except for the system DPPA:DPPE (rho (1) < 0). This indicates clustering of like molecules and possibly domain formation in the liquid-crystalline phase. DPPA:DMPE at pH 12 even shows a miscibility gap in the liquid-crystalline phase. Obviously, despite the presence of doubly charged PA a fluid-fluid immiscibility is induced. PMID- 21598045 TI - Impact of pretherapeutic routine clinical staging for the individualization of treatment in gastric cancer patients. AB - PURPOSE: The usefulness and prognostic impact of a pretherapeutic clinical staging is still a matter of discussion. However, a pretherapeutic estimation of the prognosis would be essential to adjust the patient's therapy. Our aim was to compare clinical and histopathological staging and to analyze the predictive value of routine clinical staging and its significance for the individualization of treatment. PATIENTS AND METHODS: We analyzed the data of 368 patients treated with gastric cancer in the University of Heidelberg, Department of Surgery, from January 2001 to June 2009. Pretherapeutic parameters including sex, age, cTNM, grading, Lauren classification, tumor localization, as well as posttherapeutic parameters were analyzed, and their impact for survival was evaluated. Follow-up data was obtained for all patients (2.17% lost to follow-up). RESULTS: The overall accuracy was 64.1% for pT category, 54.5% for pN category, and 80.3% for M category for the primary resected patients. For the patients treated neoadjuvantly, the overall accuracy was 21.8% for the pT category, 58.0% for the pN category, and 80.0% for the M category. The prognosis was associated to the age (p = 0.017), tumor localization (p < 0.001), grading (p = 0.041), cT category (p < 0.001), cN category (p < 0.001), and cM category (p = 0.001). The multivariate analysis, including pre- and postoperative factors, revealed tumor localization (p = 0.002), cN category (p = 0.019), and metastatic lymph node rate (p < 0.001) as independent prognostic factors. CONCLUSION: The accordance between clinical and histopathological staging is limited, but nevertheless pretherapeutic parameters have a high prognostic impact and could be used for individualized therapy planning. The relevant pretherapeutic prognostic factors can all be determined by routine clinical staging including CT and endoscopy. Consequently pretherapeutic prognostic evaluation and therapy planning seem to be feasible with routine staging methods. PMID- 21598046 TI - Predictors and course of daily living skills development in toddlers with autism spectrum disorders. AB - Self-sufficiency is central to child and family well-being. This report focuses on predictors of adaptive daily living skills (DLS) development in young children with ASD and whether DLS gains predict decreases in parenting stress. Participants were 162 toddlers with ASD and their parents, assessed at 3 annual timepoints. Hierarchical Linear Models showed that age, DQ, and autism symptom severity uniquely predicted initial DLS and DLS growth. Child problem behaviors predicted initial DLS only. DLS was associated with change in parenting stress above and beyond DQ, autism symptom severity, and problem behaviors. Children with lower IQ and more severe symptoms showed slower DLS gains. Given its relation to parenting stress, DLS are an important intervention target in young children with ASD. PMID- 21598047 TI - Characterization of Neurospora crassa alpha-actinin. AB - alpha-Actinin, an actin-binding protein of the spectrin superfamily, is present in most eukaryotes except plants. It is composed of three domains: N-terminal CH domains, C-terminal calcium-binding domain (with EF-hand motifs), and a central rod domain. We have cloned and expressed Neurospora crassa alpha-actinin as GST and GFP fusion proteins for biochemical characterization and in vivo localization, respectively. The intracellular localization pattern of alpha actinin suggests that this protein is intimately associated with actin filaments and plays an important role in the processes of germination, hyphal elongation, septum formation, and conidiation. These functions were confirmed by the experiments on the effect of alpha-actinin gene deletion in N. crassa. PMID- 21598048 TI - [Spastic equinus foot]. AB - Pes equinus is the most common deformity in cerebral palsy. A primarily dynamic pes equinus without shortening of the calf muscle in many cases turns into a structural pes equinus. This is due to insufficient linear growth of the calf muscle compared to bone growth. Structural pes equinus has to be distinguished from marked, compensatory and forefoot pes equinus. Conservative as well as operative treatment options are often applied in combination or sequentially. In dynamic pes equinus botulinum toxin A is the therapy of choice. Only slight structural pes equinus may improve under botulinum toxin A injection with and without additional casting. Usually, structural pes equinus requires operative treatment or lengthening of the gastrocnemius and/or soleus muscle (operation according to Baumann). Because of its side effect of inducing loss of power of the calf muscle, lengthening of the Achilles tendon should only be performed with caution. Especially in bilateral spastic cerebral palsy, the increased risk of causing talipes calcaneovalgus and crouch gait has to be considered. PMID- 21598049 TI - Ethical issues of medical missions: the clinicians' view. AB - Surgery is an important part of health care worldwide. Without access to surgical treatments, morbidity and mortality increase. Access to surgical treatment is a significant problem in global public health because surgical services are not equally distributed in the world. There is a disproportionate scarcity of surgical access in low-income countries. There are many charitable organizations around the world that sponsor surgical missions to under served nations. One such organization is Operation Smile International, a group with which both authors have volunteered. This paper will describe the purpose and processes involved in Operation Smile and identify some of the key ethical issues that arise in short term medical volunteer work highlighting the importance of sustainability. PMID- 21598050 TI - Ethical concerns regarding operations by volunteer surgeons on vulnerable patient groups: the case of women with obstetric fistulas. AB - By their very nature, overseas medical missions (and even domestic medical charities such as "free clinics") are designed to serve "vulnerable populations." If these groups were capable of protecting their own interests, they would not need the help of medical volunteers: their medical needs would be met through existing government health programs or by utilizing their own resources. Medical volunteerism thus seems like an unfettered good: a charitable activity provided by well-meaning doctors and nurses who want to give of their time, skills, and resources to help those who would not otherwise be able to take care of their medical needs. In this article, I argue that if medical volunteerism is to be "good," however, it must always meet certain basic ethical requirements. These requirements may be (and perhaps often are) overlooked in the rush to organize and carry out short-term medical missions. I illustrate my point with special reference to short-term medical missions designed to provide surgical repair of obstetric vesico-vaginal fistula, a condition in which the tissues that normally separate the bladder from the vagina are destroyed by obstetric trauma, leading to continuous and unremitting incontinence in the affected woman. PMID- 21598051 TI - Medical students in developing countries. PMID- 21598052 TI - Purple urine bag syndrome. PMID- 21598054 TI - [Therapy of tumors of the anterior orbit]. AB - Tumors of the orbit are diagnosed on clinical and neuroradiological criteria. A biopsy may histologically confirm uncertain mass lesions. The patients' age and medical history predispose for certain tumor entities among the rather heterogenous spectrum of possible diagnoses. The therapy depends on the degree of malignancy and its location within the orbit. Among the different options, surgical excision is the most common followed by radiation therapy either in combination with surgery or alone. Chemotherapy plays a subsidiary role in certain lymphomas or metastases. This review covers the surgical techniques and treatment principles for tumors of the anterior orbit, explains radiotherapy techniques and briefly covers chemotherapy. Pediatric tumors of the orbit are covered separately. PMID- 21598053 TI - Prevalence of practice system tools for improving depression care among primary care clinics: the DIAMOND initiative. AB - BACKGROUND: Practice system tools improve chronic disease care, but are generally lacking for the care of depression in most primary care settings. OBJECTIVE: To describe the frequency of various depression-related practice system tools among Minnesota primary care clinics interested in improving depression care. DESIGN: Cross-sectional survey. PARTICIPANTS: Physician leaders of 82 clinics in Minnesota. MAIN MEASURES: A survey including practice systems recommended for care of depression and chronic conditions, each scored on a 100-point scale, and the clinic's priority for improving depression care on a 10-point scale. KEY RESULTS: Fewer practice systems tools were present and functioning well for depression care (score = 24.4 [SD 1.6]) than for the care of chronic conditions in general (score = 43.9 [SD 1.6]), p < 0.001. The average priority for improving depression care was 5.8 (SD 2.3). There was not a significant correlation between the presence of practice systems for depression or chronic disease care and the priority for depression care except for a modest correlation with the depression Decision Support subscale (r = 0.29, p = 0.008). Certain staffing patterns, a metropolitan-area clinic location, and the presence of a fully functional electronic medical record were associated with the presence of more practice system tools. CONCLUSIONS: Few practice system tools are in place for improving depression care in Minnesota primary care clinics, and these are less well developed than general chronic disease practice systems. Future research should focus on demonstrating whether implementing these tools for depression care results in much-needed improvements in care for patients with depression. PMID- 21598055 TI - Scene context influences without scene gist: eye movements guided by spatial associations in visual search. AB - Although the use of semantic information about the world seems ubiquitous in every task we perform, it is not clear whether we rely on a scene's semantic information to guide attention when searching for something in a specific scene context (e.g., keys in one's living room). To address this question, we compared contribution of a scene's semantic information (i.e., scene gist) versus learned spatial associations between objects and context. Using the flash-preview-moving window paradigm Castelhano and Henderson (Journal of Experimental Psychology: Human Perception and Performance 33:753-763, 2007), participants searched for target objects that were placed in either consistent or inconsistent locations and were semantically consistent or inconsistent with the scene gist. The results showed that learned spatial associations were used to guide search even in inconsistent contexts, providing evidence that scene context can affect search performance without consistent scene gist information. We discuss the results in terms of hierarchical organization of top-down influences of scene context. PMID- 21598056 TI - Correlation of circulating angiogenic factors with circulating tumor cells and disease recurrence in patients undergoing curative resection for colorectal liver metastases. AB - BACKGROUND: Circulating angiogenic factors (CAF) have been shown as therapeutic targets and prognostic biomarkers in metastatic colorectal cancer. However, their correlation with circulating tumor cells (CTC) is unknown, as is their role as prognostic biomarkers in patients amenable for curative resection. METHODS: Preoperative blood samples were collected in patients undergoing potentially curative resection of colorectal liver metastases. Serum levels of eight CAF and CTC were analyzed by using ELISA and CK20 RT-PCR, respectively. Prognostic factors were identified by a Cox proportional hazards model. RESULTS: A total of 107 patients were eligible for final analyses. Circulating levels of PlGF, EGF, and bFGF were increased, whereas PDGF-A and Ang-1 levels were decreased in patients compared with healthy control subjects. CTC were detected in 36 of 63 patients (57%) and were associated with significantly lower levels of EGF and bFGF. On univariate analyses, multiple metastases (p = 0.04), a MSKCC risk score >2 (p = 0.004), and detection of CTC (p = 0.05) were associated with disease recurrence. Multivariate analysis, including the panel of eight CAF, revealed a MSKCC score >2 [hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.11-3.82; p = 0.02] and low levels of circulating PlGF (HR, 0.26; 95% CI, 0.08-0.81; p = 0.02) as independent predictors of poor recurrence-free survival. CONCLUSIONS: CAF may indicate patients who are at high risk for disease recurrence. The notion that CAF may identify patients who benefit from adjuvant therapy or antiangiogenic agents warrants further investigation. PMID- 21598057 TI - Validation of the DeLiT Trial intravenous insulin infusion algorithm for intraoperative glucose control in noncardiac surgery: a randomized controlled trial. AB - PURPOSE: A safe and effective insulin infusion algorithm that achieves rigorous intraoperative glycemic control in noncardiac surgery has yet to be formally characterized and evaluated. We therefore report the validation of the DeLit Trial insulin infusion algorithm. METHODS: Patients scheduled for major noncardiac surgery were randomized to a target intraoperative blood glucose concentration of 4.4-6.1 mmoL.L(-1) (80-110 mg.dL(-1)) intensive group or 10-11.1 mmoL.L(-1) (180-200 mg.dL(-1)) conventional group. Glucose was managed with a dynamic intravenous insulin infusion algorithm. We compared the randomized groups on glucose time-weighted average (TWA), proportion of time spent within target, number of severe (< 2.2 mmoL.L(-1) or < 40 mg.dL(-1)) or moderate (< 2.8 mmoL.L( 1) or < 50 mg.dL(-1)) hypoglycemic episodes, and within-patient variability in glucose concentrations expressed as standard deviation from the patient mean. RESULTS: One hundred eighty-seven patients were assigned to intensive glucose control, and 177 patients were assigned to conventional glucose control. Median (lower quartile value [Q1], upper quartile value [Q3]) of intraoperative TWA for the intensive vs conventional groups was 6 [5.6, 6.7] mmoL.L(-1) vs 7.7 [6.9, 9.2] mmoL.L(-1), respectively; P < 0.001. The intensive group spent 49% (29, 71) of the time within target, substantially more time than the conventional group spent either within the intensive target or within its own target (both P < 0.001). The intensive group had slightly lower within-patient glucose variability than the conventional group (0.9 [0.7, 1.3] mmoL.L(-1) vs 1.3 [0.8, 1.8] mmoL.L( 1), respectively; P < 0.001). Three patients had moderate hypoglycemia (intensive group), but none experienced severe episodes. CONCLUSION: Tight intraoperative glucose control in noncardiac surgery can be maintained successfully without serious hypoglycemic episodes. (ClinicalTrials.gov number, NCT00433251). PMID- 21598058 TI - Making contact: rooting out the potential for exposure of commercial production swine facilities to feral swine in North Carolina. AB - Despite North Carolina's long history with feral swine, populations were low or absent in eastern counties until the 1990s. Feral swine populations have since grown in these counties which also contain a high density of commercial production swine (CPS) facilities. Sixteen of the highest swine producing U.S. counties also populated with feral swine are in North Carolina. Disconcertingly, since 2009, positive tests for exposure to swine brucellosis or pseudorabies virus have been found for feral swine. We surveyed 120 CSP facilities across four eastern counties to document the level and perception of feral swine activity around CSP facilities and to identify disease transmission potential to commercial stock. Nearly all facility operators (97%) recognized feral swine were in their counties. Far fewer said they had feral swine activity nearby (18%). Our inspections found higher presence than perceived with feral swine sign at 19% of facilities where operators said they had never observed feral swine or their sign. Nearly 90% expressed concern about feral to domestic disease transmission, yet only two facilities had grain bins or feeders fenced against wildlife access. Due to increasing feral swine populations, recent evidence of disease in feral populations, the importance of swine production to North Carolina's economy and the national pork industry, and potential for feral-domestic contact, we believe feral swine pose an increasing disease transmission threat warranting a stringent look at biosecurity and feral swine management at North Carolina CPS facilities. PMID- 21598059 TI - Schistosomiasis in Lake Malawi villages. AB - Historically, open shorelines of Lake Malawi were free from schistosome, Schistosoma haematobium, transmission, but this changed in the mid-1980s, possibly as a result of over-fishing reducing density of molluscivore fishes. Very little information is available on schistosome infections among people in lake-shore communities and therefore we decided to summarise data collected from 1998 to 2007. Detailed knowledge of the transmission patterns is essential to design a holistic approach to schistosomiasis control involving the public health, fisheries and tourism sectors. On Nankumba Peninsula, in the southern part of the lake, inhabitants of villages located along the shores of Lake Malawi have higher prevalence of S. haematobium infection than those living in inland villages. Overall prevalence (all age classes combined) of urinary schistosomiasis in 1998/1999 ranged from 10.2% to 26.4% in inland villages and from 21.0% to 72.7% in lakeshore villages; for school children prevalence of infection ranged from 15.3% to 57.1% in inland schools and from 56.2% to 94.0% in lakeshore schools. Inhabitants on the islands, Chizumulu and Likoma, also have lower prevalence of infection than those living in lakeshore villages on Nankumba Peninsula. This increased prevalence in lakeshore villages is not necessarily linked to transmission taking place in the lake itself, but could also be due to the presence of more numerous typical inland transmission sites (e.g., streams, ponds) being close to the lake. Temporal data witness of intense transmission in some lakeshore villages with 30-40% of children cleared from infection becoming reinfected 12 months later (also lakeshore village). The level of S. mansoni infection is low in the lakeshore communities. Findings are discussed in relation to fishing in the lake. PMID- 21598061 TI - [Early esophageal cancer: pro surgical resection]. AB - Endoscopic methods are increasingly propagated as oncologically adequate and less invasive treatment modalities for early esophageal cancer compared to surgery. The superiority or equality of endoscopic treatment has, however, so far not been proven by controlled trials. Current guidelines and an analysis of recently published data support surgical resection and lymphadenectomy as the standard of care for early esophageal cancer. This is based on the following arguments: 1) a reliable complete tumor resection with clear margins in all directions (R0 resection) including removal of all precancerous and precursor lesions can currently only be achieved by surgical resection, 2) none of the currently available staging tools allows definitive exclusion of lymphatic spread. A potentially curative surgical lymphadenectomy should thus only be omitted in well defined subgroups. 3) In experienced hands surgical resection and lymphadenectomy can be performed with low mortality and morbidity, 4) reproducible and reliable data on long-term recurrence-free survival and quality of life are currently only available for surgical series. Thus, endoscopic therapy for early esophageal cancer is an alternative to surgical resection with lymphadenectomy only in patients unfit for surgery and in strictly defined low-risk situations. PMID- 21598060 TI - The hidden health burden of environmental degradation: disease comorbidities and dryland salinity. AB - Previous studies have linked poor mental human health with environmental degradation, but none have assessed additional diseases that may co-exist with these mental disorders. In previous work, depression was found to be associated with a major form of environmental degradation; dryland salinity. However, little is known about diseases co-morbid with depression in this environmental setting. In rural Australia, dryland salinity is a major form of environmental degradation contributing widely to deterioration and non-viability of farmland. Using georeferenced health record data, Bayesian spatial methods were used to determine the relationship between dryland salinity and a range of human health outcomes. Initial modelling found an increased relative risk for asthma, suicide and ischaemic heart disease in relation to dryland salinity (adjusted for Indigenous and socio-economic status). However, in this follow-up study, a further evaluation of the role of co-morbidities in this population revealed that: (i) the presence of depression was consistently linked to residence in areas with high salinity and (ii) the association of asthma, suicide and heart disease with salinity was most likely attributable to the co-morbidity of the conditions with depression. Given the predicted increase in dryland salinity and the elevated relative risk of depression in impacted areas, the relative risk of the co-morbid conditions can be expected to increase in rural areas in the future, further adding to the burden of disease associated with environmental degradation. PMID- 21598062 TI - Circulating levels of a biomarker of collagen metabolism are associated with health-related quality of life in patients with chronic heart failure. AB - PURPOSE: Assessment of circulating levels of collagen-derived peptides has been proposed as a useful tool to monitor indirectly myocardial collagen metabolism in chronic heart failure (CHF) patients. The potential link between circulating concentrations of collagen metabolism biomarkers and health-related quality of life (HRQOL) has not been adequately evaluated. With the present study, we investigated the association between serum levels of collagen-derived peptides and HRQOL. METHODS: We studied 280 consecutive outpatients (of mean age 67 +/- 10 years, 180 men) with CHF. Serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP)-a marker of collagen type I degradation-were measured in all patients both at baseline and during a period of 6 months follow-up. HRQOL was assessed by Minnesota living with heart failure questionnaire (MLHFQ). RESULTS: CITP levels were significantly associated with MLHFQ scores both at baseline (r = 0.231, P < 0.001) and at 6 months follow-up (r = 0.145, P = 0.044). CITP levels remained significantly associated with MLHFQ score in multivariable linear regression analysis. Higher CITP levels were observed with higher MLHFQ scores (poor HRQOL) both at baseline (P = 0.001) and at 6 months (P = 0.041). Unadjusted analysis demonstrated a significant relationship between increasing CITP levels during 6 months follow-up and worsening HRQOL (r = 0.204, P = 0.001). The aforementioned correlation remained significant in multivariable linear regression analysis. CONCLUSION: Our findings show that increased CITP levels are associated with poorer HRQOL in patients with CHF. These findings are consistent with a link between a pathophysiologic mechanism, i.e., collagen metabolism and patient self-assessed health status in CHF. PMID- 21598063 TI - Evaluation of the quality of life of children with celiac disease and their parents: a case-control study. AB - PURPOSE: The purpose of the present study was to evaluate the quality of life (QoL) of children with CD and of their parents and to compare it with that of children without CD and of their parents. METHODS: A case-control study was conducted to evaluate the quality of life of children (5-12 years) with CD and one of their parents, compared to the QoL of children without CD (and their parents as their caregivers ). The QoL was assessed by applying the following questionnaires: AUQUEI (children) and WHOQOL-BREF (parents). RESULTS: QoL was evaluated in 33 children with CD, 63 children without CD, and of their respective parents as their parent caregivers (96 adults). QoL total scores were similar between the groups of children with and without CD. However, in the Leisure dimension, the scores of children with CD were significantly lower than those of the controls (P = 0.029). Similarly, when assessing the QoL of the parents, we found scores significantly lower in the social dimension (P = 0.0196) for parents of children with CD compared to parents of children without CD. Family income presented an impact on the QoL in adults, but did not affect children. In CD group, children of mothers who had lower educational levels presented better scores in the function dimension, regarding self-care and autonomy. CONCLUSIONS: There is an impairment of the QoL of children with CD and of their parents, with regard to social life, particularly in the leisure (children) and social (adults) dimensions. PMID- 21598064 TI - Development of a self-report measure of capability wellbeing for adults: the ICECAP-A. AB - PURPOSE: The benefits of health and social care are not confined to patient health alone and therefore broader measures of wellbeing may be useful for economic evaluation. This paper reports the development of a simple measure of capability wellbeing for adults (ICECAP-A). METHODS: In-depth, informant-led, interviews to identify the attributes of capability wellbeing were conducted with 36 adults in the UK. Eighteen semi-structured, repeat interviews were carried out to develop a capability-based descriptive system for the measure. Informants were purposively selected to ensure variation in socio-economic status, age, sex, ethnicity and health. Data analysis was carried out inductively and iteratively alongside interviews, and findings were used to shape the questions in later interviews. RESULTS: Five over-arching attributes of capability wellbeing were identified for the measure: "stability", "attachment", "achievement", "autonomy" and "enjoyment". One item, with four response categories, was developed for each attribute for the ICECAP-A descriptive system. CONCLUSIONS: The ICECAP-A capability measure represents a departure from traditional health economics outcome measures, by treating health status as an influence over broader attributes of capability wellbeing. Further work is required to value and validate the attributes and test the sensitivity of the ICECAP-A to healthcare interventions. PMID- 21598065 TI - Rasch analysis of the Patient and Observer Scar Assessment Scale (POSAS) in burn scars. AB - PURPOSE: The Patient and Observer Scar Assessment Scale (POSAS) is a questionnaire that was developed to assess scar quality. It consists of two separate six-item scales (Observer Scale and Patient Scale), both of which are scored on a 10-point rating scale. After many years of experience with this scale in burn scar assessment, it is appropriate to examine its psychometric properties using Rasch analysis. METHODS: Cross-sectional data collection from seven clinical trials resulted in a data set of 1,629 observer scores and 1,427 patient scores of burn scars. We examined the person-item map, item fit statistics, reliability, response category ordering, and dimensionality of the POSAS. RESULTS: The POSAS showed an adequate fit to the Rasch model, except for the item surface area. Person reliability of the Observer Scale and Patient Scale was 0.82 and 0.77, respectively. Dimensionality analysis revealed that the unexplained variance by the first contrast of both scales was 1.7 units. Spearman correlation between the Observer Scale Rasch measure and the overall opinion of the clinician was 0.75. CONCLUSION: The Rasch model demonstrated that the POSAS is a reliable and valid scale that measures the single-construct scar quality. PMID- 21598066 TI - Transfer of calibration between hand and foot: functional equivalence and fractal fluctuations. AB - Transfer of competency in a perceptual task often depends on shared information between anatomically different perceptual subsystems. The problem of studying transfer involves isolating conditions of similarity and then trying to account for any resulting differences in transfer. To respect this twofold aspect, this article takes a two-pronged approach to transfer in dynamic touch. The present research first tests the hypothesis that functional equivalence supports the transfer of dynamic touch. Participants were trained to wield unseen objects with the hand or foot and were then tested on anatomically disparate limbs (i.e., the foot or hand, respectively). Next, we examined motion capture of these wielding behaviors for predictors of any asymmetry in transfer. Temporally fractal fluctuations of exploratory behavior can modulate information detection, and we tested whether the fractality of wielding might predict asymmetries in transfer across disparate limbs. Results suggest that transfer of training to anatomically disparate limbs respects functional conditions of similarity and also that the degree of temporally fractal fluctuations predicted limb differences in transfer. PMID- 21598067 TI - Adaptation to biological motion leads to a motion and a form aftereffect. AB - Recent models have proposed a two-stage process of biological motion recognition. First, template or snapshot neurons estimate the body form. Then, motion is estimated from body form change. This predicts separate aftereffects for body form and body motion. We tested this prediction. Observers viewing leftward- or rightward-facing point-light walkers that walked forward or backward subsequently experienced oppositely directed aftereffects in stimuli ambiguous in the facing or the walking direction. These aftereffects did not originate from adaptation to the motion of the individual light points, because they occurred for limited lifetime stimuli that restrict local motion. They also occurred when the adaptor displayed a random sequence of body postures that did not induce the walking motion percept. We thus conclude that biological motion gives rise to separate form and motion aftereffects and that body form representations are involved in biological motion perception. PMID- 21598068 TI - A rare case of resistance to thyroid hormone coexisting with Graves' disease. PMID- 21598069 TI - Aberrant cortisol responses to physiological stimuli in patients presenting with bilateral adrenal incidentalomas. AB - Aberrant receptors have been implicated in the pathogenesis of several types of adrenal tumours. So far the presence of aberrant receptors has been investigated in patients with massively enlarged adrenals due to ACTH-independent macronodular adrenal hyperplasia (AIMAH) and unilateral adrenal adenomas associated with overt or subclinical Cushing's syndrome. The likelihood of aberrant responses in patients presenting with bilateral adrenal incidentalomas (BI) presenting as discrete solitary bilateral adenomas has not been thoroughly addressed. This is an observational cross-sectional prospective study conducted in a secondary/tertiary care centre. We studied 33 patients; 28 with incidentally discovered bilateral discrete adrenal adenomas and five with massive bilateral adrenal macronodular hyperplasia. We probed responses to physiological stimuli, namely upright posture and meal; in a subgroup of menopausal women the presence of aberrant gonadotropin receptors was assessed by the LHRH test. Abnormal responses obtained in tests performed with no dexamethasone suppression were always repeated and confirmed under dexamethasone suppression. Aberrant cortisol responses were confirmed in 10 patients; 9 to posture, 1 to meal (along with a positive response to posture) and 1 to LHRH tests. Patients who responded to any test compared to those who tested negative had larger adenomas, higher post-LDDST and midnight cortisol and a trend for lower ACTH levels. Patients without subclinical hypercortisolism (SH) did not respond to any test while 50% of patients with SH had an aberrant response (P = 0.002). A greater prevalence of aberrant responses was noted in patients with bilateral macronodular hyperplasia compared to those with solitary bilateral adenomas (80 vs. 21.4%, P = 0.02). Aberrant cortisol responses, primarily to posture testing, are present in a substantial proportion of patients with bilateral adrenal incidentalomas. Such cortisol responses are observed only in patients with subclinical hypercortisolism and especially in those patients with larger adrenal lesions. PMID- 21598070 TI - Vorinostat modulates cell cycle regulatory proteins in glioma cells and human glioma slice cultures. AB - Chromatin modification through histone deacetylase inhibition has shown evidence of activity against malignancies. The mechanism of action of such agents are pleiotropic and potentially tumor specific. In this study, we studied the mechanisms of vorinostat-induced cellular effects in gliomas. The effects of vorinostat on proliferation, induction of apoptosis and cell cycle effects were studied in vitro (D54, U87 and U373 glioma cell lines). To gain additional insights into its effects on human gliomas, vorinostat-induced changes were examined ex vivo using a novel organotypic human glioma slice model. Vorinostat treatment resulted in increased p21 levels in all glioma cells tested in a p53 independent manner. In addition, cyclin B1 levels were transcriptionally downregulated and resulted in reduced kinase activity of the cyclin B1/cdk1 complex causing a G2 arrest. These effects were associated with a dose- and time dependent inhibition of cellular proliferation and anchorage-independent growth in association with hyperacetylation of core histones and induction of apoptosis. Of particular significance, we demonstrate histone hyperacetylation and increased p21 levels in freshly resected human glioma specimens maintained as organotypic slice cultures and exposed to vorinostat similar to cell lines suggesting that human glioma can be targeted by this agent. Our data suggest that the effects of vorinostat are associated with modulation of cell cycle related proteins and activation of a G2 checkpoint along with induction of apoptosis. These effects are mediated by both transcriptional and post-translational mechanisms which provide potential options that can be exploited to develop new therapeutic approaches against gliomas. PMID- 21598071 TI - Effects of renal function on the pharmacokinetics and pharmacodynamics of prophylactic cefazolin in cardiothoracic surgery. AB - The purpose of this investigation was to study the effects of renal function on the pharmacokinetics and pharmacodynamics (PK-PD) of free cefazolin administered prophylactically in cardiothoracic surgery. Patients received an initial 2-g dose of cefazolin, followed by 1-g doses 6, 12, 18 and 24 h after the first dose. In patients who underwent cardiopulmonary bypass, 1 g was added to the priming solution. In 35 patients with a normal estimated creatinine clearance (CLcr) >=50 ml/min, a free cefazolin concentration <4 MUg/ml was observed in 11.4, 5.7 and 54.3% of patients before the second dose, at the end and 24 h after operation, respectively. In contrast, only 7.4% of 27 patients with CLcr <49 ml/min had a free cefazolin concentration <4 MUg/ml 24 h after the operation. There was a high negative correlation between CLcr and time above the target minimal inhibitory concentration (MIC) when the CLcr was <50 ml/min (r(2) = 0.807), and no correlation when the CLcr was >=50 ml/min. Renal function has a significant impact on the PK-PD of prophylactic cefazolin in cardiothoracic surgery. The postoperative drug dosing intervals should be <6 h in order to achieve a 100% time above the MIC in patients with CLcr >= 50 ml/min. PMID- 21598072 TI - Peripheral T regulatory cells and cytokines in hepatitis E infection. AB - This study addresses the involvement of regulatory T cells in hepatitis E (HE) infection. The study population comprised 77 acute viral HE patients, 52 recovered individuals (overall, 129 individuals with HE) and 53 healthy controls. Peripheral CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3(+) frequencies by flow cytometry and HE-specific cytokines/chemokines quantitation were carried out. The median percentage of CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3(+) T cells in acute patients were significantly higher compared to controls and recovered individuals. Both of the T regulatory (Treg) subset populations in overall HE were significantly elevated compared to controls. Comparisons of cytokines/chemokines revealed that the levels of IL-10 were elevated in: (a) acute viral hepatitis E (AVH-E) versus recovered individuals and controls, and (b) HE versus controls. Overall, the elevation of CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3(+) frequencies and the rise in IL-10 suggest that Treg cells might be playing a pivotal role in hepatitis E virus (HEV) infection. PMID- 21598073 TI - Candida glabrata strain relatedness by new microsatellite markers. AB - We investigated six microsatellite markers to type 85 unrelated and 118 related isolates of Candida glabrata from 36 patients. Three new markers were selected from the complete sequence of CBS138 and three previously described markers, RPM2, MTI and ERG3 were used. We found a genetic diversity of 0.949 by combining four of them. By applying the new microsatellite markers GLM4, GLM5 and GLM6 we were able to discriminate 29 isolates, originally identified by the more established markers, RPM2, MTI and ERG3. When epidemiologically closely related isolates from 36 patients were typed, 25 patients (72%) exhibited identical or highly related multilocus genotypes. We noted a microvariation in 4 of the patients. This minor change of one locus could be explained by a single step mutation. Since one of these patients had not received antifungal treatment; thus, the relationship between genome variation and antifungal therapy remains controversial. We can conclude from our analysis of these new microsatellite markers that they are highly selective and therefore should be considered as a useful typing system for differentiating related and unrelated isolates of C. glabrata, as well as being able to detect microvariation. PMID- 21598074 TI - c-Myc influences olaquindox-induced apoptosis in human hepatoma G2 cells. AB - Olaquindox, a synthetic antimicrobial compound, was banned as feed additives in the U.S. and the EU. In China, the use of olaquindox is banned in poultry and aquaculture feed, restricted in livestock feed for growth promotion. Olaquindox's safety is the object of increasing attention. The present study was undertaken to investigate whether and how olaquindox elevates expression of c-Myc, which influences olaquindox-induced apoptosis in HepG2 cells. For a better understanding of c-Myc's role in susceptibility of human hepatoma G2 cells to olaquindox-induced apoptosis, two vectors (the pSilencer-cmyc(Si-cmyc) and the control vector) were transfected to HepG2 cells. The cells were pretreated with Si-cmyc, which expressed only 35-65% c-Myc protein levels compared to those of the parental cells and the control cells. We examined effects of olaquindox on reactive oxygen species (ROS) production in these c-Myc low-expressing cells, and on apoptosis. Our data revealed that ROS production induced by olaquindox treatment was partially blocked by Si-cmyc transfection and partly inhibited olaquindox-induced apoptosis through decreased ROS generation. Further data showed that olaquindox induced decreased ROS by Si-cmyc transfection through decreased cytochrome c release to cytosol, which inhibited apoptosis of the cells. These results suggest that c-Myc might be important during olaquindox induced apoptosis in human hepatoma G2 cells. PMID- 21598075 TI - Persistent dyspnea following thyroid hematoma after neck blunt trauma. AB - Thyroid hemorrhage as a result of blunt trauma is a very rare condition. The choice between surgery/conservative management might be tailored over patient's health conditions. This report describes a case of neck blunt trauma causing acute thyroid hemorrhage treated first conservatively and further surgically due to a persistent dyspnea for tracheal compression. PMID- 21598076 TI - MRI-based volumetric assessment of joint effusion in knee osteoarthritis using proton density-weighted fat-suppressed and T1-weighted contrast-enhanced fat suppressed sequences. PMID- 21598077 TI - The role of ultrasound and magnetic resonance imaging in the evaluation of the forearm interosseous membrane. A review. AB - The interosseous membrane of the forearm is an important structure to consider in cases of elbow and forearm trauma; it can be injured after elbow or forearm fractures, leading to longitudinal forearm instability. Diagnosis of interosseous membrane injuries is challenging, and failure in diagnosis may result in poor clinical outcomes and complications. Magnetic resonance imaging and ultrasound have shown to be valuable methods for the evaluation of this important structure. Both techniques have advantages and limitations, and its use should be adapted to each specific clinical scenario. This article presents an up-to-date literature review regarding the use of ultrasound and magnetic resonance imaging in the forearm interosseous membrane evaluation. PMID- 21598078 TI - Perturbation of rat heart plasma membrane fluidity due to metabolites of permethrin insecticide. AB - Due to increased global use, acute and chronic exposures to pyrethroid insecticides in humans are of clinical concern. Pyrethroids have a primary mode of action that involves interference with the sodium and calcium channels in excitable cells, which may include cardiac myocytes. Here, we investigated the possible cardiac toxicity of permethrin metabolites (METP), 3-phenoxy-benzyl alcohol (3PBA), 3-phenoxy-benzaldehyde (3PBALD), and 3-phenoxybenzoic acid (3PBACID). Plasma membrane fluidity, polarity, lipid, and protein oxidation were studied in isolated rat heart cells. Laurdan was chosen as probe to detect the lateral mobility and polarity of its environment and thus water penetration into the hydrophobic part of the bilayer, while 1,6-diphenyl-1,3,5-hexatriene permits to measure changes in fluidity in the inner part of the bilayer. Results show that METP can change membrane fluidity at different depths of the bilayer according to their partition coefficient. Consequently, 3PBA, at all concentration used, decreases membrane fluidity and polarity in the hydrophilic hydrophobic region of the bilayer, and similar effect was observed with 20 MUM 3PBALD or 10 or 20 MUM 3 PBACID. Membrane dynamics in the hydrophobic core resulted decreased by 3PBALD, while it was increased by 20 MUM 3PBACID. All METP increase protein and lipid oxidation, and the peroxidative lipid damage decreases with the type of METP produced during the transformation pathway from parent compound to 3PBACID. Consequently, 3PBA induced the highest lipid peroxidation, while 3PBACID was the stronger inducer of protein damage. PMID- 21598079 TI - Assessment of P-glycoprotein activity in the Blood-Brain Barrier (BBB) using Near Infrared Fluorescence (NIRF) imaging techniques. AB - PURPOSE: To examine functional activity of P-glycoprotein (P-gp) in the blood brain barrier (BBB) using near infrared fluorescence (NIRF) imaging techniques. METHODS: Cellular accumulation and bi-directional permeability of the NIRF probe, rhodamine 800 (R800) was determined in MDCKMDR1 and MDCKwt monolayers under normal conditions and following P-gp inhibition with GF120918. Functional P-gp activity was also assessed in mice following administration of R800 alone and with GF230918. Quantitative analysis of R800 fluorescence in brain tissue and blood was measured ex-vivo using Odyssey Near Infrared imaging. RESULTS: R800 accumulation was reduced in MDCKMDR1 compared to MDCKwt monolayers. Addition of GF120918, resulted in increased R800 accumulation in MDCKMDR1 monolayers. Permeability of R800 in MDCKMDR1 monolayers was significantly enhanced (4-fold) in the basolateral to apical direction under control conditions and was abolished following treatment with GF120918. With the exception of the choriod plexus, there was very little penetration of R800 into the brain under control conditions. Treatment of mice with GF120918 resulted in a nearly 4-fold increase in R800 fluorescence in the brain. In contrast, GF120918 had no effect on brain penetration of a vascular permeability marker. CONCLUSIONS: In vitro studies demonstrate the P-gp transporter properties of the NIRF probe R800. Preliminary in vivo studies confirm the P-gp transporter liabilities of R800 and suggest this probe may be useful as a molecular imaging agent for examining P-gp activity in the BBB. PMID- 21598080 TI - Optimisation of stir bar sorptive extraction and in-tube derivatisation-thermal desorption-gas chromatography-mass spectrometry for the determination of several endocrine disruptor compounds in environmental water samples. AB - The analysis of organic pollutants in environmental water samples requires a pre concentration step. Pre-concentration techniques such as stir bar sorptive extraction (SBSE) have gained popularity since they minimise the use of toxic organic solvents and can be considered as green analytical techniques. Similar to other pre-concentration techniques, one of the problems when SBSE is used is the matrix effect, which often occurs during the analysis of environmental water samples such as estuarine or wastewater samples. The present work studied the matrix effect during SBSE coupled to in-tube derivatisation-thermal desorption (TD)-gas chromatography-mass spectrometry for the determination of several endocrine disruptor compounds, such as alkylphenols, bisphenol A, estrogens and sterols, in environmental water samples, after optimisation of the major variables affecting the determination. Variables such as the addition of methanol or an inert salt to the donor phase, the extraction temperature, the volume of the donor phase, the stirring rate and the extraction time were studied during the SBSE optimisation. In the case of the in-tube derivatisation and TD step, the volume of the derivatisation reagent (N,O-bis(trimethylsilyl)triufloroacetamide with 1% of trimethylchlorosilane (BSTFA + 1% TMCS)) and the cryo-focusing temperature were fixed (2 MUL and -50 degrees C, respectively) according to a consensus between maximum signal and optimal operation conditions. Good apparent recovery values (78-124%) were obtained for most of the analytes in Milli-Q water, except for 4-tert-octylphenol (4-tOP), which showed apparent recovery values exceeding 100%. Precision (n = 4) was in the 2-27%, and method detection limits were in the low nanogrammes per litre level for most of the analytes studied. The matrix effect was studied using two different approaches. On the one hand, Milli-Q water samples were spiked with humic acids, and apparent recovery values were studied with and without correction with the corresponding deuterated analogue. On the other hand, estuarine water and wastewater samples were spiked with known concentrations of target analytes, and apparent recoveries were studied as explained above. In general, the matrix effect could be corrected with the use of deuterated analogues, except for 4-tOP and nonylphenols for which [(2)H(4)]-n-nonylphenol did not provide good corrections. PMID- 21598081 TI - Development of headspace SPME method for analysis of volatile organic compounds present in human biological specimens. AB - In recent years, interest has increased regarding the identification of volatile organic compounds (VOCs) for metabolic profiling, human scent identification of the living and deceased, and diagnostic potentials for certain diseases that are known for its association with distinct odor. In this study, a method has been developed that is capable of sampling, identifying, and differentiating the VOCs present in various biological specimens of forensic importance (blood, breath, buccal cells, and urine) taken from the same individuals. The developed method requires a pretreatment step to remove targeted VOCs from the sampling apparatus prior to sampling of the individual specimens. The VOCs collected from the biological specimens were characterized by solid-phase microextraction and gas chromatography/mass spectrometry with ratios of the most abundant and frequent VOCs compared using qualitative and semiquantitative methods. Blood, breath, and buccal cells required extraction procedures ranging from 18 to 21 h in order to optimize the limit of detection, which averaged 5-15 ng across these specimens. The optimal method for measuring urine VOCs was complete in less than an hour; however, the limit of detection was higher with a range of 10-40 ng quantifiable. The demonstrated sensitivity and reproducibility of the methods developed allow for population studies of human scent VOCs from various biological specimen collection kits used in the forensic and clinical fields. PMID- 21598082 TI - Physico-mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide. AB - The focus of this investigation was to prepare the cocrystal of carbamazepine (CBZ) using nicotinamide as a coformer and to compare its preformulation properties and stability profile with CBZ. The cocrystal was prepared by solution cooling crystallization, solvent evaporation, and melting and cryomilling methods. They were characterized for solubility, intrinsic dissolution rate, chemical identification by Fourier transform infrared spectroscopy, crystallinity by differential scanning calorimetry, powder X-ray diffraction, and morphology by scanning electron microscopy. Additionally, mechanical properties were evaluated by tensile strength and Heckel analysis of compacts. The cocrystal and CBZ were stored at 40 degrees C/94% RH, 40 degrees C/75% RH, 25 degrees C/60% RH, and 60 degrees C to determine their stability behavior. The cocrystals were fluffy, with a needle-shaped crystal, and were less dense than CBZ. The solubility profiles of the cocrystals were similar to CBZ, but its intrinsic dissolution rate was lower due to the high tensile strength of its compacts. Unlike CBZ, the cocrystals were resistant to hydrate transformation, as revealed by the stability studies. Plastic deformation started at a higher compression pressure in the cocrystals than CBZ, as indicated by the high yield pressure. In conclusion, the preformulation profile of the cocrystals was similar to CBZ, except that it had an advantageous resistance to hydrate transformation. PMID- 21598083 TI - Analysis of trehalose-6-phosphate synthase (TPS) gene family suggests the formation of TPS complexes in rice. AB - Trehalose-6-phosphate (T6P), an intermediate in the trehalose biosynthesis pathway, is emerging as an important regulator of plant metabolism and development. T6P levels are potentially modulated by a group of trehalose-6 phosphate synthase (TPS) and trehalose-6-phosphate phosphatase (TPP) homologues. In this study, we have isolated 11 TPS genes encoding proteins with both TPS and TPP domains, from rice. Functional complement assays performed in yeast tps1 and tps2 mutants, revealed that only OsTPS1 encodes an active TPS enzyme and no OsTPS protein possesses TPP activity. By using a yeast two-hybrid analysis, a complicated interaction network occurred among OsTPS proteins, and the TPS domain might be essential for this interaction to occur. The interaction between OsTPS1 and OsTPS8 in vivo was confirmed by bimolecular fluorescence complementation and coimmunoprecipitation assays. Furthermore, our gel filtration assay showed that there may exist two forms of OsTPS1 (OsTPS1a and OsTPS1b) with different elution profiles in rice. OsTPS1b was particularly cofractionated with OsTPS5 and OsTPS8 in the 360 kDa complex, while OsTPS1a was predominantly incorporated into the complexes larger than 360 kDa. Collectively, these results suggest that OsTPS family members may form trehalose-6-phosphate synthase complexes and therefore potentially modify T6P levels to regulate plant development. PMID- 21598084 TI - Acculturation and perceived mental health need among older Asian immigrants. AB - The demographic landscape of the United States is changing as the general population ages and the size of racial/ethnic minority groups grows. Most prior studies on mental health service use among Asians in America have overlooked older adults. A deeper understanding of the way acculturation factors impact help seeking behaviors among older Asian Americans will inform behavioral health practice and program planners as they address the disparities affecting a diverse racial group. The California Health Interview Survey was used to examine the correlates of perceived mental health need among 980 older Asian immigrants. The study found that English proficiency and other covariates affected how Asian Americans perceived mental health need. Implications for understanding the help seeking behaviors of older Asian immigrants are discussed. PMID- 21598085 TI - Perioperative temporary occlusion of the internal iliac arteries as prophylaxis in cesarean section at risk of hemorrhage in placenta accreta. AB - PURPOSE: The purpose of this study was to describe the preliminary results of prophylactic temporary balloon occlusion of the internal iliac arteries for bleeding control in patients with placenta accreta during cesarean hysterectomy. METHODS: From May 2006 to March 2010, 21 patients diagnosed with placenta accreta using ultrasound and/or magnetic resonance imaging were submitted to prophylactic balloon occlusion before hysterectomy. Fluoroscopy, balloon occlusion time, surgical duration, intraoperative blood loss, transfusion volume, and procedure complications were analyzed. RESULTS: The mean age was 30.5 years with a mean of 3.6 previous gestations. Imaging studies revealed that all patients had placenta accreta and all were submitted to cesarean hysterectomy. One hysterectomy was due to previous diagnosis of fetal death and another due to cesarean with uterine curettage. Mean fluoroscopy time was 7.5 min, balloon occlusion time was 164 min, and surgery duration was 260 min. Estimated blood loss was 1,671.5 ml with mean reposition fluids of 3,538 ml of crystalloids, 309.5 ml of colloids, and 1.24 ml of packed red blood cells. Two patients were submitted to thromboembolectomy due to prolonged surgical time. There was no maternal or fetal mortality related to the procedure. CONCLUSIONS: The results demonstrated that prophylactic balloon occlusion of internal iliac artery is a safe method and appears to reduce blood loss and transfusion requirements in patients diagnosed with placenta accreta who undergo cesarean hysterectomy. Antenatal imaging diagnosis of placenta accreta enables preoperative planning. PMID- 21598087 TI - Relation priming in established compounds: facilitation? AB - Gagne and Spalding (Brain and Language, 90, 478-486, 2004, Journal of Memory and Language, 60, 20-35, 2009) have shown that the difficulty of interpreting an established compound (e.g., snowball) can be influenced by recent exposure to a compound with the same modifier and that this influence depends on the relation linking the constituents of the compound. For example, snowball (a ball made of snow) was processed more quickly following snowfort (a fort made of snow; same relation) than following snowshovel (a shovel for snow; different relation). In three experiments, we investigated the basis of this relation-priming effect. The results indicated that the relation-priming effect in established compounds is due to slower processing in the different-relation condition rather than to faster processing in the same-relation condition. These results pose a challenge for most models of compound-word processing. PMID- 21598088 TI - Role of heme oxygenase-1 in inflammatory response induced by mechanical stretch in synovial cells. AB - OBJECTIVE: The purpose of this study was to investigate the mechanism by which heme oxygenase-1 (HO-1) regulates inflammatory responses induced by mechanical stretch in human fibroblast-like synoviocyte (HFLS) cells. MATERIALS AND METHODS: HFLS cells were cultured in the presence of hemin and seeded into fibronectin coated silicon chambers. The chambers were attached to a stretching apparatus which applied a uniaxial sinusoidal stretching force. The genetic expressions of cyclooxygenase-2 (COX-2), interleukin-1beta (IL-1beta) and HO-1 were analyzed using real-time RT-PCR. The expression and localization of HO-1 protein were detected by immunofluorescence staining. The amounts of prostaglandin E(2) (PGE(2)) released into the culture medium were determined using ELISA. RESULTS: Mechanical stretch enhanced the expressions of COX-2 and IL-1beta, and the amount of PGE(2) synthesis in HFLS cells, whereas that of HO-1 was slightly increased. In contrast, treatment with hemin enhanced HO-1 gene expression and mechanical stretch enhanced this expression in hemin-pretreated cells. In addition, hemin pretreatment suppressed PGE(2) synthesis induced by mechanical stretch. CONCLUSION: We found that constitutive HO-1 expression in hemin-pretreated HFLS cells suppressed mechanical stretch-induced inflammatory responses, suggesting that HO-1 may play a role as a regulation factor in synovial tissue inflammation. PMID- 21598086 TI - NADPH oxidases in cardiovascular disease: insights from in vivo models and clinical studies. AB - NADPH oxidase family enzymes (or NOXs) are the major sources of reactive oxygen species (ROS) that are implicated in the pathophysiology of many cardiovascular diseases. These enzymes appear to be especially important in the modulation of redox-sensitive signalling pathways that underlie key cellular functions such as growth, differentiation, migration and proliferation. Seven distinct members of the family have been identified of which four (namely NOX1, 2, 4 and 5) may have cardiovascular functions. In this article, we review our current understanding of the roles of NOX enzymes in several common cardiovascular disease states, with a focus on data from genetic studies and clinical data where available. PMID- 21598089 TI - Generalist-feeding subterranean mites as potential biological control agents of immature corn rootworms. AB - Predatory mites are important components of subterranean food webs and may help regulate densities of agricultural pests, including western corn rootworms (Chrysomelidae: Diabrotica virgifera virgifera). Implementing conservation and/or classical biocontrol tactics could enhance densities of specialist or generalist predatory mites and lead to pest suppression, but first relevant mite species must be identified and their predatory capabilities evaluated. We conducted lab assays to quantify consumption of immature rootworms and oviposition rates of various mite species. Our study indicates that rootworms are a sub-optimal food source for the mite taxa tested. However, all mite species fed upon rootworms to some degree, although consumption by nematophagous Eviphis ostrinus was extremely low. Predators consumed more rootworm larvae than eggs, and mite size was correlated with prey consumption, with larger predators eating more prey. Four mite taxa (Gaeolaelaps sp., S. miles, Gl. americana, and G. aculeifer) had detrimental effects on survival of rootworm larvae, and the latter two species also had negative impacts on densities of pest eggs. Although it is unlikely that any of these mite species by itself has a major impact on rootworm control, the community of generalist soil-dwelling mites may play an important role in regulating immature rootworm populations in the field. PMID- 21598091 TI - Nonparametric estimation of the conditional mean residual life function with censored data. AB - The conditional mean residual life (MRL) function is the expected remaining lifetime of a system given survival past a particular time point and the values of a set of predictor variables. This function is a valuable tool in reliability and actuarial studies when the right tail of the distribution is of interest, and can be more informative than the survivor function. In this paper, we identify theoretical limitations of some semi-parametric conditional MRL models, and propose two nonparametric methods of estimating the conditional MRL function. Asymptotic properties such as consistency and normality of our proposed estimators are established. We investigate via simulation study the empirical properties of the proposed estimators, including bootstrap pointwise confidence intervals. Using Monte Carlo simulations we compare the proposed nonparametric estimators to two popular semi-parametric methods of analysis, for varying types of data. The proposed estimators are demonstrated on the Veteran's Administration lung cancer trial. PMID- 21598092 TI - Plasma adipocytokine and ghrelin levels in relation to bone mineral density in prepubertal rhythmic gymnasts. AB - The aim of the present study was to investigate possible differences in plasma adipocytokine and ghrelin levels and body composition parameters in prepubertal rhythmic gymnasts (RG) and untrained controls (UC), and to examine the relationships of bone mineral density (BMD) with hormonal status in prepubertal children with different physical activity patterns. Eighty-nine 7- to 9-year-old girls participated in the study (RG, n = 46; UC, n = 43). Body composition and BMD were measured by dual-energy X-ray absorptiometry. Bone maturity was estimated by using a radiograph of the nondominant hand. The measured whole-body, lumbar spine (LS), and femoral neck (FN) BMD values were significantly higher (P < 0.05) in gymnasts than in controls. In addition, RG presented significantly lower and higher values (P < 0.05) for leptin and ghrelin concentrations, respectively, in comparison with UC. No differences were observed for adiponectin levels between the studied groups. No relationships between measured BMD values with leptin and ghrelin were observed even after adjustment for age and fat mass (FM) in RG. Whole-body and LS BMD values were significantly correlated with leptin after controlling for age and FM (r = 0.32, P < 0.05) in UC. Femoral neck BMD remained significantly correlated with ghrelin after adjusting for age and FM (r = -0.4, P < 0.05) in UC. No relationships were found between measured BMD values and adiponectin even after controlling for age and FM values in both groups. In conclusion, although all measured BMD values were significantly higher in RG, plasma adipocytokine and ghrelin concentrations were not directly related to bone mineralization in prepubertal RG in contrast to UC. PMID- 21598094 TI - Stem cell sources for regenerative medicine: the immunological point of view. AB - Stem cell transplantation consists in the introduction of stem cells or derived products in a diseased organism. Because of the differentiation properties of stem cells, the goal is to replace damaged cells or tissues. Numbers of stem cell were identified and isolated from embryos, fetuses, or adult organs, harboring different properties, and thus providing multiple strategies of regenerative medicine for different diseases. More recently, the artificial induction of stemness properties in adult somatic cells has proposed a new way to generate stem cells. One important concern of stem cell therapy is the possible risk that transplanted stem cells could be rejected by the recipient's immune system. Depending on their source, stem cell transplantation is associated with diverse immunological situations. If some sources allow autologous transplantation, others cannot bypass an allogeneic context between the donor and the recipient. This review summarizes all of the stem cell sources for regenerative medicine and the immunological questions associated to their use. Regarding the emerging strategies compatible with autologous transplantation, this article points notably the complexity of the choice between the immunological safety and the specific advantages of allogeneic stem cells. PMID- 21598095 TI - Abstracts of the 36th Annual IUGA (International Urogynecological Association) Meeting. Lisbon, Portugal. June 28-July 2, 2011. PMID- 21598096 TI - Solid-state (19)F-NMR of peptides in native membranes. AB - To understand how membrane-active peptides (MAPs) function in vivo, it is essential to obtain structural information about them in their membrane-bound state. Most biophysical approaches rely on the use of bilayers prepared from synthetic phospholipids, i.e. artificial model membranes. A particularly successful structural method is solid-state NMR, which makes use of macroscopically oriented lipid bilayers to study selectively isotope-labelled peptides. Native biomembranes, however, have a far more complex lipid composition and a significant non-lipidic content (protein and carbohydrate). Model membranes, therefore, are not really adequate to address questions concerning for example the selectivity of these membranolytic peptides against prokaryotic vs eukaryotic cells, their varying activities against different bacterial strains, or other related biological issues.Here, we discuss a solid-state (19)F-NMR approach that has been developed for structural studies of MAPs in lipid bilayers, and how this can be translated to measurements in native biomembranes. We review the essentials of the methodology and discuss key objectives in the practice of (19)F-labelling of peptides. Furthermore, the preparation of macroscopically oriented biomembranes on solid supports is discussed in the context of other membrane models. Two native biomembrane systems are presented as examples: human erythrocyte ghosts as representatives of eukaryotic cell membranes, and protoplasts from Micrococcus luteus as membranes from Gram positive bacteria. Based on our latest experimental experience with the antimicrobial peptide gramicidin S, the benefits and some implicit drawbacks of using such supported native membranes in solid-state (19)F-NMR analysis are discussed. PMID- 21598093 TI - In vivo imaging of lymph node migration of MNP- and (111)In-labeled dendritic cells in a transgenic mouse model of breast cancer (MMTV-Ras). AB - PURPOSE: The authors present a protocol for the in vivo evaluation, using different imaging techniques, of lymph node (LN) homing of tumor-specific dendritic cells (DCs) in a murine breast cancer model. PROCEDURES: Bone marrow DCs were labeled with paramagnetic nanoparticles (MNPs) or (111)In-oxine. Antigen loading was performed using tumor lysate. Mature DCs were injected into the footpads of transgenic tumor-bearing mice (MMTV-Ras) and DC migration was tracked by magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT). Ex vivo analyses were performed to validate the imaging data. RESULTS: DC labeling, both with MNPs and with (111)In-oxine, did not affect DC phenotype or functionality. MRI and SPECT allowed the detection of iron and (111)In in both axillary and popliteal LNs. Immunohistochemistry and gamma counting revealed the presence of DCs in LNs. CONCLUSIONS: MRI and SPECT imaging, by allowing in vivo dynamic monitoring of DC migration, could further the development and optimization of efficient anti-cancer vaccines. PMID- 21598097 TI - Atypical prion diseases in humans and animals. AB - Although prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep, have long been recognized, our understanding of their epidemiology and pathogenesis is still in its early stages. Progress is hampered by the lengthy incubation periods and the lack of effective ways of monitoring and characterizing these agents. Protease-resistant conformers of the prion protein (PrP), known as the "scrapie form" (PrP(Sc)), are used as disease markers, and for taxonomic purposes, in correlation with clinical, pathological, and genetic data. In humans, prion diseases can arise sporadically (sCJD) or genetically (gCJD and others), caused by mutations in the PrP-gene (PRNP), or as a foodborne infection, with the agent of bovine spongiform encephalopathy (BSE) causing variant CJD (vCJD). Person-to-person spread of human prion disease has only been known to occur following cannibalism (kuru disease in Papua New Guinea) or through medical or surgical treatment (iatrogenic CJD, iCJD). In contrast, scrapie in small ruminants and chronic wasting disease (CWD) in cervids behave as infectious diseases within these species. Recently, however, so-called atypical forms of prion diseases have been discovered in sheep (atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble sporadic or genetic human prion diseases and might be their animal equivalents. This hypothesis also raises the significant public health question of possible epidemiological links between these diseases and their counterparts in humans. PMID- 21598098 TI - Neuroprotective and neurotoxic signaling by the prion protein. AB - Prion diseases in humans and animals are characterized by progressive neurodegeneration and the formation of infectious particles called prions. Both features are intimately linked to a conformational transition of the cellular prion protein (PrP(C)) into aberrantly folded conformers with neurotoxic and self replicating activities. Interestingly, there is increasing evidence that the infectious and neurotoxic properties of PrP conformers are not necessarily coupled. Transgenic mouse models revealed that some PrP mutants interfere with neuronal function in the absence of infectious prions. Vice versa, propagation of prions can occur without causing neurotoxicity. Consequently, it appears plausible that two partially independent pathways exist, one pathway leading to the propagation of infectious prions and another one that mediates neurotoxic signaling. In this review we will summarize current knowledge of neurotoxic PrP conformers and discuss the role of PrP(C) as a mediator of both stress-protective and neurotoxic signaling cascades. PMID- 21598099 TI - Chronic wasting disease. AB - Chronic wasting disease (CWD) is a prion disease of free-ranging and farmed ungulates (deer, elk, and moose) in North America and South Korea. First described by the late E.S. Williams and colleagues in northern Colorado and southern Wyoming in the 1970s, CWD has increased tremendously both in numerical and geographical distribution, reaching prevalence rates as high as 50% in free ranging and >90% in captive deer herds in certain areas of USA and Canada. CWD is certainly the most contagious prion infection, with significant horizontal transmission of infectious prions by, e.g., urine, feces, and saliva. Dissemination and persistence of infectivity in the environment combined with the appearance in wild-living and migrating animals make CWD presently uncontrollable, and pose extreme challenges to wild-life disease management. Whereas CWD is extremely transmissible among cervids, its trans-species transmission seems to be restricted, although the possible involvement of rodent and carnivore species in environmental transmission has not been fully evaluated. Whether or not CWD has zoonotic potential as had Bovine spongiform encephalopathy (BSE) has yet to be answered. Of note, variant Creutzfeldt-Jakob disease (vCJD) was only detected because clinical presentation and age of patients were significantly different from classical CJD. Along with further understanding of the molecular biology and pathology of CWD, its transmissibility and species restrictions and development of methods for preclinical diagnosis and intervention will be crucial for effective containment of this highly contagious prion disease. PMID- 21598100 TI - Chemical x-ray photodiffraction: principles, examples, and perspectives. AB - X-ray photodiffraction (in the chemical literature also referred to as photocrystallography), which is based on the combination of X-ray diffraction methods with samples excited by UV or visible light to solve fundamental photochemical or photophysical issues, has developed in the last couple of decades into a very promising technique for direct observation of photoinduced chemical species in the solid state. The capability of providing direct information on very small perturbations in atomic positions and thus on the minute changes in molecular geometry during (or as a consequence of) photoexcitation appears to be the most important asset of this emerging analytical technique. When combined with other physicochemical methods, X-ray photodiffraction can be a powerful tool for analysis of steady-state photoinduced structures as well as slow or very fast time-dependent phenomena. Despite being a very useful approach, however, due to a number of practical requirements that it places with regard to the system to be studied, at the present stage of developments the technique is not widely and indiscriminately applicable to any photoinduced process. In some particular chemical systems the inherent pitfalls could be practically overcome by practical or theoretical means. In this short chapter, the basic principles of X-ray photodiffraction are briefly summarized, and the prospects of its application to "physical" and "chemical" problems is illustrated with selected examples from recent literature. Some possible future developments and alternative approaches with this and related methods are also presented. PMID- 21598101 TI - Peptide bond cis/trans isomerases: a biocatalysis perspective of conformational dynamics in proteins. AB - Peptide bond cis/trans isomerases (PCTIases) catalyze an intrinsically slow rotational motion taking part in the conformational dynamics of a protein backbone in all of its folding states. In this way, PCTIases assist other proteins to shape their functionally active structure. They have been associated with viral, bacterial, and parasitic infection, signal transduction, cell differentiation, altered metabolic activity, apoptosis, and many other physiological and pathophysiological processes. The need to understand, characterize, and control biochemical steps which contribute to the folding of proteins is a problem being addressed in many laboratories today. This review discusses the biochemical basis that the peptidyl prolyl cis/trans isomerase (PPIase) family of PCTIases uses for the control of bioactivity. Special emphasis is given to recent developments in the field of biocatalytic features of PPIases, the mechanism of catalysis, and enzyme inhibition. PMID- 21598102 TI - Basic technologies for droplet microfluidics. AB - In recent years droplet microfluidics has become a quickly evolving research field. The availability of a wide range of technologies for droplet generation and manipulation has enabled the applications of droplet microfluidics in a wide variety of fields, from single cell analysis to material synthesis. In this review we summarize the main technologies for droplet microfluidics and discuss the recent advances in technologies that enable droplets as microreactors with complete functions. Applications of microdroplets in chemical reactions, particle synthesis, and single cell analysis are also briefly reviewed. PMID- 21598103 TI - Cells in microfluidics. AB - Microfluidic devices offer a realistic environment for cell cultures as it is related to scales found in biological systems. The aim is to create more in vivo like systems, in comparison to 2D plate cultures. Creating 3D cell culture constructs increase the cell's functionality. By controlling the microenvironment (e.g., cell matrix, flow rate, temperature) cell functionality can be increased even more. As microfluidic devices allow for precise control of the microenvironment, they are a paramount tool to study stem cells and their differentiation caused by external factors. We will give an overview of the use of microfluidic devices for some biological problems, and especially as a cell culture platforms. We focus on 3D cell cultures and stem cells and their microenvironment. PMID- 21598104 TI - Immunological approaches for tolerance induction in allergy. AB - Allergy is the consequence of an inappropriate inflammatory immune response generated against harmless environmental antigens. In allergic disorders such as asthma and rhinitis, the Th2 mediated phenotype is a result of loss of peripheral tolerance mechanisms. In cases such as these, approaches such as immunotherapy attempt to treat the underlying cause of allergic disease by restoring tolerance. Immunotherapy initiates many complex mechanisms within the immune system that result in initiation of innate immunity, activation of both cellular and humoral B cell immunity, as well as triggering T regulatory subsets which are major players in the establishment of peripheral tolerance. Though studies clearly demonstrate immunotherapy to be efficacious, research to improve this treatment is ongoing. Investigation of allergenicity versus immunogenicity, native versus modified allergens, and the use of adjuvant and modality of dosing are all current strategies for immunotherapy advancement that will be reviewed in this article. PMID- 21598105 TI - Cell-based therapy in allergy. AB - IgE-mediated allergy is an immunological disorder occurring in response to otherwise harmless environmental antigens (i.e., allergens). Development of effective therapeutic or preventive approaches inducing robust tolerance toward allergens remains an unmet goal. Several experimental tolerance approaches have been described. The therapeutic use of regulatory T cells (Tregs) and the establishment of molecular chimerism are two cell-based strategies that are of particular interest. Treg therapy is close to clinical application, but its efficacy remains to be fully defined. Recent proof-of-concept studies demonstrated that transplantation of syngeneic hematopoietic stem cells modified in vitro to express a major allergen leads to molecular chimerism and robust allergen-specific tolerance. Here we review cell-based tolerance strategies in allergy, discussing their potentials and limitations. PMID- 21598106 TI - Prevalence of the NKG2D Thr72Ala polymorphism in patients with systemic lupus erythematosus. AB - Multiple studies have indicated that SLE incidence exhibits a strong genetic background. We studied the frequency of the natural killer group 2, member D (NKG2D) receptor Thr72Ala (rs2255336) polymorphism in patients with SLE (n = 243) and controls (n = 502) in a sample of the Polish population. The p value for SLE patients with the Thr/Thr genotype was 0.0455 and Odds Ratio (OR) = 0.3846 (95% CI = 0.1458-1.014). For the Thr/Thr and Ala/Thr genotypes we found p = 0.0135 and OR = 0.6556 (95% CI = 0.4684-0.9177). The frequency of the NKG2D 72Thr allele in patients and controls was respectively, 15 and 21%, P = 0.0046, OR = 0.6547 (95% CI = 0.4877-0.8789). Our studies may confirm that the NKG2D 72Thr gene variant may protect against the incidence of SLE. PMID- 21598107 TI - Genetic diversity of the sulfotransferase-like gene and one nonsynonymous SNP associated with growth traits of clam, Meretrix meretrix. AB - The sulfotransferase (SULT) is an important factor in phase II metabolism. Three single nucleotide polymorphisms (SNPs; MmeSUl-696, MmeSUl-714 and MmeSUl-806) were discovered in a SULT-like gene of Meretrix meretrix. A modified allele specific PCR detection assay was developed to perform polymorphism analysis of the three SNPs in two families and two populations of M. meretrix. Results showed that the genotype of the three SNPs is accordance to the expected Mendelian segregation ratios and conforms to Hardy-Weinberg Equilibrium (HWE) in families and populations, respectively. Moreover, sampled clams (n = 151) from the two populations were tested for the associations between SNPs and growth traits. The single SNP association analysis indicated MmeSUl-806 significantly (P < 0.05) correlated with growth traits of M. meretrix. A further haplotype-trait association analysis confirmed that the three SNPs were in linkage disequilibrium and showed that the haplotype TTG and TCG associated with low growth in the two populations, respectively, which supported that MmeSUl-806 was a growth related marker. This study suggested SULT gene might be a candidate gene related to growth in bivalves and MmeSUl-806 could be a gene marker in linkage map construction and breeding programs of M. meretrix. PMID- 21598108 TI - The complete mitochondrial genome of the grand jackknife clam, Solen grandis (Bivalvia: Solenidae): a novel gene order and unusual non-coding region. AB - Molluscs in general, and bivalves in particular, exhibit an extraordinary degree of mitochondrial gene order variation when compared with other metazoans. The complete mitochondrial genome of Solen grandis (Bivalvia: Solenidae) was determined using long-PCR and genome walking techniques. The entire mitochondrial genome sequence of S. grandis is 16,784 bp in length, and contains 36 genes including 12 protein-coding genes (atp8 is absent), 2 ribosomal RNAs, and 22 tRNAs. All genes are encoded on the same strand. Compared with other species, it bears a novel gene order. Besides these, we find a peculiar non-coding region of 435 bp with a microsatellite-like (TA)(12) element, poly-structures and many hairpin structures. In contrast to the available heterodont mitochondrial genomes from GenBank, the complete mtDNA of S. grandis has the shortest cox3 gene, and the longest atp6, nad4, nad5 genes. PMID- 21598109 TI - Role of microRNA let-7 and effect to HMGA2 in esophageal squamous cell carcinoma. AB - To investigated the role of microRNA (miRNA) let-7 and its regulation on high mobility group A2 (HMGA2) protein expression in esophageal squamous cell carcinoma (ESCC). Let-7 expressions were detected in esophageal cancer cell line Eca109, and 45 paired of fresh ESCC and normal adjacent tissues (NAT) by real time quantitative PCR (qRT-PCR). To evaluate the role of let-7 and HMGA2, cell proliferations were analyzed with synthetic let-7 mimics- or its inhibitor transfected cells. Moreover, expressions of HMGA2 were performed by western blotting and further confirmed by 150 paired of formalin-fixed, paraffin-embeded (FFPE) ESCC and NAT by immunohistochemistry (IHC). In Eca109, when transfected with let-7 mimics, accumulation of let-7 was obviously suppressed cell proliferation with approximately 14%. Conversely, when Eca109 transfected with let-7 inhibitor, expression of let-7 was declined, which promoted cell proliferation with approximately 16%. Both of them had no effect on the level of HMGA2 mRNA. The transcription of let-7 inversely correlated with HMGA2 protein. Compared with the NAT, expression of let-7 was significantly lower in ESCC tissues (P < 0.05), and there was a significant correlation between low expression of let-7 and lymph node metastasis in ESCC (P < 0.05). Moreover, the protein expression of HMGA2 was significantly higher in ESCC compared with NAT (P < 0.05). However, mRNA expression of HMGA2 had no obvious significance between them. The present results demonstrated that let-7 and HMGA2 involved in ESCC carcinogenesis. Let-7 could inhibit cell proliferation and lower expressed in ESCC, and there was a correlation between let-7 lower expression and lymph node metastasis in ESCC patients. As well as, HMGA2 protein expression was significantly higher in ESCC than that in NAT, and HMGA2 may negatively regulated by let-7 at the post- transcriptional level in ESCC. PMID- 21598110 TI - The prevalence of molecular and immunologic infective markers of hepatitis viruses in patients with hematological malignancies. AB - Acute and chronic viral hepatitis infections are corresponding to increase the risk of different types of hematological malignancies especially with leukemia. In this study the serological and molecular markers of hepatitis viruses were evaluated in patients with different types of leukemia in comparing with control group. In this cross sectional study, 100 EDTA-treated blood samples were collected from leukemia patients and also from healthy control group, respectively. Serological and molecular markers of HBV, HCV and HDV viruses were analyzed for determination of the role of these hepatitis viruses in clinical outcomes of leukemia disorders. Increasing risk factors of leukemia were evaluated statistically in two studied groups by SPSS software. One of molecular and immunological markers of HBV, HDV and HCV was found in 24 of 100 (24%), 22 of 100 (22%), and 1 of 100 (1%) patients with leukemia and in 12 of 100 (12%), 6 of 100 (6%), and 2 of 100 (2%) control patients. Significant differences were detected in detection of HBsAg (P = 0.02), HBeAb (P = 0.009), and HCV-RNA (P = 0.05) between leukemia patients and control group, respectively. The high prevalence of HBV and HCV infective markers were detected in ALL and AML patients. Identification of high prevalence of HBV and HCV infective markers in leukemia patients proposed strong association between hepatitis viral infections and leukemia. Therefore, evaluation of the prevalence of viral hepatitis infections in larger groups of patients with long lasting follow up is suggesting. PMID- 21598111 TI - Molecular diversity of bacteria in Yunnan yellow cattle (Bos taurs) from Nujiang region, China. AB - The rumen content of four Yunnan Yellow Cattle (Bos taurs) were collected to determine the bacteria diversity by using 16S rRNA gene sequence analysis. A total of 129 sequences were examined and the sequences were referred as 107 OTU (Operational Taxonomy Unit) according to the similarity level of 97% in gene sequence. Similarity analysis revealed that Yunnan Yellow Cattle had 12 sequences (10 OTU) shared 97% or greater similarity with cultured rumen bacteria Butyrivibrio fibrisolvens, Succiniclasticum ruminis, Ruminococcus bromii, Clostridium proteoclasticum, Ruminococcus flavefaciens, Pseudobutyrivibrio ruminis, Jeotgalicoccus psychrophilus, and Prevotella ruminicola, which accounting for 9.3% of the total clones (9.2% of the total OTU). The further 12 sequences (9 OTU) shared 90-97% similarity with cultured bacteria Clostridium aminobutyricum, butyrate-producing bacterium, Schwartzia succinivorans, Prevotella ruminicola, Eubacterium ruminantium, Ruminococcus albus, and Clostridium termitidis, also accounting for 9.3% of the total sequences (8.3% of the total OTU). The remaining 105 sequences (90 OTU) shared less than 90% similarity with cultured bacteria, accounting for 81.4% of the total sequences (82.5% of the total OTU). According to the phylogenetic analysis, all sequences were phylogenetically placed within phyla of low G+C subdivision (accounting for 72.1 and 72.5% of the total clones and OTU, respectively) and CFB subdivision (Cytophaga-Flexibacter-Bacteroides; accounting for 27.9 and 27.5% of the total clones and OTU, respectively). Among the examined clones, rare bacteria Jeotgalicoccus psychrophilus was detected in the rumen of cattle. PMID- 21598113 TI - DNA typing of Pakistani cattle breeds Tharparkar and Red Sindhi by microsatellite markers. AB - Microsatellite markers are used for any individual identity and breed characterization in animals that is an efficient and successful way of investigation. They are used for multiple purposes as genetic detectors including, rapid mutation rate, high level of polymorphism, and range of variety of microsatellite markers available. A panel of 19 microsatellite markers was developed for breed characterization in Tharparkar and Red Sindhi breeds of cattle in Pakistan. Forty four blood samples of cattle (each breed) were collected from Department of Livestock Management, Sindh Agriculture University, Tandojam, Tando Qaiser, Tharparkar Cattle Farm Nabi sar Road, Umer Kot, Sindh, and Govt. Red Sindhi Cattle Breeding Farm, Tando Muhammad Khan Pakistan. Breed characterization was 100% successful. Average PIC, He and Power of Exclusion values were found to be 0.91, 0.62 and 13.28, respectively. Pattern of allelic frequencies of most of the microsatellite markers were clearly distinct between two breeds. As a result of present study a reliable, efficient and very informative panel of microsatellite markers was successfully developed which was capable to interpret individual identity, forensic cases and breed characterization in cattle. This facility is ready to be provided to local cattle breeder at commercial level for DNA testing of cattle. This study will also be highly helpful for breed conservation of cattle. In addition this study can also become a basis to open up new disciplines of animal forensics in Pakistan. PMID- 21598112 TI - Methylated promoters of genes encoding protocadherins as a new cancer biomarker family. AB - Protocadherins are a major subfamily of the cadherin superfamily. Their functions and intracellular signal transduction are poorly understood, although some have been explored in nervous system development. However, recent researches have shown that protocadherins frequently act as tumor suppressor genes (TSGs) and inactivation of these genes through promoter methylation is closely correlated with tumor development. Furthermore, these methylated protocadherins may serve as tumor biomarkers in various body fluids, stool and scrapings not only for early cancer diagnosis, but also for assessing prognosis and monitoring response to therapy. Thus, methylated promoters of genes encoding protocadherins show promise as a new cancer biomarker family. PMID- 21598114 TI - Characteristics and evolution of the PUF gene family in Bombyx mori and 27 other species. AB - The Pumilio protein is the founding member of the PUF family of RNA-binding proteins, which contains 8 repeat Puf domains and plays important roles during embryogenesis and post-embryogenesis by binding the Nanos response element (NRE) of specific target genes in eukaryotes. In addition, many other proteins containing the Puf domain were identified but with different functions from the Pumilio protein in various species. Taking advantage of the newly assembled genome sequences, in this study we performed a genome-wide analysis of PUF genes in silkworm and other 27 species. In the silkworm, three PUF genes were identified, named Bmpumilio, Bmpenguin and Bmnop by homology analysis. In fungi and animals, four evolutionarily conservational PUF gene families were identified, Group-A, -B, -C and -D. While Group-A, -C, and -D are present in all fungi and animals, Group-B was only identified in fungi. Interestingly, the number and features of the Puf domains are distinct in each group, suggesting different roles for these proteins in every group. The EST and microarray data showed that the mRNA of the three PUF genes can be widely detected in all tissues of the silkworm. Our results provide some new insights into the functions and evolutionary characteristics of PUF proteins. PMID- 21598115 TI - Specific conformational epitope features of pathogenesis-related proteins mediating cross-reactivity between pollen and food allergens. AB - Selected members of plant pathogenesis-related and seed storage proteins represent specific groups of proteins with potential characteristics of allergens. Efforts to understand the mechanism by which pathogenesis-related proteins mediate a broad cross-reactivity in pollen-plant food allergens are still limited. In this study, computational biology approach was used to reveal specific structural implications and conservation of different epitopes from members of Bet v 1 and nsLTP protein families mediating cross-reactivity between pollen and food (fruits, vegetables, legumes, and nut/seeds) allergens. A commonly shared epitope conservation was found among all pollen and food Bet v 1 and nsLTP protein families, respectively. However, other allergenic epitopes were also specifically detected in each family. The implication of these conserved epitopes in a broad cross-reactivity for allergy clinical trials is here discussed. PMID- 21598116 TI - Association between polymorphisms in cathepsin and cystatin genes with meat production and carcass traits in Italian Duroc pigs: confirmation of the effects of a cathepsin L (CTSL) gene marker. AB - We genotyped single nucleotide polymorphisms (SNPs) in 5 cathepsin or cystatin genes (cathepsin F, CTSF; cathepsin L, CTSL; cathepsin S, CTSS; cathepsin Z, CTSZ; cystatin B, CSTB) in two groups of Italian Duroc pigs: the first group (n. 100) was chosen using a selective genotyping approach with extreme estimated breeding value (EBV) for visible intermuscular fat (VIF); the second group (n. 218) was made of performance-tested Duroc pigs not selected by any criteria. CTSL marker showed a tendency towards association (P<0.10) with VIF (first group) and back fat thickness (BFT) and average daily gain (ADG; second group). In the second group, the CTSL polymorphism was associated with weight of lean cuts (LC; P<0.05). Additive effects for all mentioned traits in the second group was significant (P<0.05). The results we obtained in the Italian Duroc pigs confirmed the results and the direction of the effects already reported for the Italian Large White breed. PMID- 21598117 TI - Isolated intramedullary neurosarcoidosis of the thoracic spine: case report and review of the literature. AB - Sarcoidosis can involve the central nervous system in approximately 5-15% of cases. Any part of the nervous system can be involved, so presentation can be quite varied. Isolated disease of the spinal cord is even less common and reports are limited to single cases and small series. Although in the setting of systemic disease the diagnosis can be made with skin or lymph node biopsy, isolated disease of the spinal cord presents a diagnostic challenge. We present a case of isolated intramedullary neurosarcoidosis of the distal thoracic spinal cord presenting with posterior column dysfunction. Imaging demonstrated T2 changes in the patient's lower thoracic cord adjacent to disc herniation. Over time, however, his symptoms progressed despite decompression, and the abnormal region began to exhibit focal contrast enhancement. The persistence of symptoms as well as the new enhancement led us to perform a spinal cord biopsy, which demonstrated histopathological findings consistent with sarcoidosis. Further workup failed to reveal any evidence of systemic disease. Intramedullary sarcoidosis without systemic sarcoidosis is extremely rare. With its variable imaging appearance and inconsistent clinical manifestations, it can be difficult to diagnose. It should be considered in the differential diagnosis of a mass-like intramedullary lesion with progressive symptoms. Biopsy with histopathological correlation may be the only definite management option. PMID- 21598119 TI - Clinically relevant strategies for treating cartilage and meniscal pathology: editorial comment. PMID- 21598118 TI - Parameters that effect spine biomechanics following cervical disc replacement. AB - Total disc replacement (TDR) is expected to provide a more physiologic alternative to fusion. However, long-term clinical data proving the efficacy of the implants is lacking. Limited clinical data suggest somewhat of a disagreement between the in vitro biomechanical studies and in vivo assessments. This conceptual paper presents the potential biomechanical challenges affecting the TDR that should be addressed with a hope to improve the clinical outcomes and our understanding of the devices. Appropriate literature and our own research findings comparing the biomechanics of different disc designs are presented to highlight the need for additional investigations. The biomechanical effects of various surgical procedures are analyzed, reiterating the importance of parameters like preserving uncinate processes, disc placement and its orientation within the cervical spine. Moreover, the need for a 360 degrees dynamic system for disc recipients who may experience whiplash injuries is explored. Probabilistic studies as performed already in the lumbar spine may explore high risk combinations of different parameters and explain the differences between "standard" biomechanical investigations and clinical studies. Development of a patient specific optimized finite element model that takes muscle forces into consideration may help resolve the discrepancies between biomechanics of TDR and the clinical studies. Factors affecting long-term performance such as bone remodeling, subsidence, and wear are elaborated. In vivo assessment of segmental spine motion has been, and continues to be, a challenge. In general, clinical studies while reporting the data have placed lesser emphasis on kinematics following intervertebral disc replacements. Evaluation of in vivo kinematics following TDR to analyze the quality and quantity of motion using stereoradiogrammetric technique may be needed. PMID- 21598120 TI - Shoulder arthroplasty for fracture: does a fracture-specific stem make a difference? AB - BACKGROUND: Arthroplasty for shoulder fractures is a technically challenging and unpredictable procedure and its use is controversial. QUESTIONS/PURPOSES: We therefore asked (1) to what degree function would be restored, (2) whether tuberosity healing would reliably occur, and (3) whether stem design would influence function in patients treated with hemiarthroplasty for proximal humerus fracture. PATIENTS AND METHODS: We retrospectively reviewed all patients treated with a hemiarthroplasty for proximal humeral fracture between September 2001 and May 2006. The first 58 patients (September 2001 to March 2004) were treated with a conventional humeral prosthesis. The next 112 patients (April 2004 to May 2006) were treated with a fracture-specific humeral prosthesis. Clinical measures (American Shoulder and Elbow Surgeons scores, visual analog pain scores, and goniometric measurements of glenohumeral motion) and radiographic evaluation of tuberosity healing were performed at minimum 24-month followup (mean, 32 months; range, 24-96 months). RESULTS: Mean active anterior elevation was 118 degrees , mean active external rotation 37.6 degrees , and mean American Shoulder and Elbow Surgeons score 66. Overall, 127 of 170 (75%) greater tuberosities healed. With respect to stem design, active anterior elevation, active external rotation, and American Shoulder and Elbow Surgeons score were better with fracture-specific stems (129.8 degrees , 39 degrees , and 72, respectively) than with conventional stems (95.4 degrees , 33.0 degrees , and 55, respectively). Fewer tuberosities healed with conventional stems (38 of 58, 66%) than with fracture-specific stems (89 of 112, 79%). CONCLUSIONS: The use of fracture-specific stems during proximal humeral hemiarthroplasty for fracture appears to improve functional use of the injured shoulder and tuberosity healing compared to conventional stems. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21598121 TI - The 2011 ABJS Nicolas Andry Award: 'Lab'-in-a-knee: in vivo knee forces, kinematics, and contact analysis. AB - BACKGROUND: Tibiofemoral forces are important in the design and clinical outcomes of TKA. We developed a tibial tray with force transducers and a telemetry system to directly measure tibiofemoral compressive forces in vivo. Knee forces and kinematics traditionally have been measured under laboratory conditions. Although this approach is useful for quantitative measurements and experimental studies, the extrapolation of results to clinical conditions may not always be valid. QUESTIONS/PURPOSES: We therefore developed wearable monitoring equipment and computer algorithms for classifying and identifying unsupervised activities outside the laboratory. METHODS: Tibial forces were measured for activities of daily living, athletic and recreational activities, and with orthotics and braces, during 4 years postoperatively. Additional measurements included video motion analysis, EMG, fluoroscopic kinematic analysis, and ground reaction force measurement. In vivo measurements were used to evaluate computer models of the knee. Finite element models were used for contact analysis and for computing knee kinematics from measured knee forces. A third-generation system was developed for continuous monitoring of knee forces and kinematics outside the laboratory using a wearable data acquisition hardware. RESULTS: By using measured knee forces and knee flexion angle, we were able to compute femorotibial AP translation (-12 to +4 mm), mediolateral translation (-1 to 1.5 mm), axial rotation (-3 degrees to 12 degrees ), and adduction-abduction (-1 degrees to +1 degrees ). The neural network-based classification system was able to identify walking, stair-climbing, sit-to-stand, and stand-to-sit activities with 100% accuracy. CONCLUSIONS: Our data may be used to improve existing in vitro models and wear simulators, and enhance prosthetic designs and biomaterials. PMID- 21598123 TI - Development of silver-containing austenite antibacterial stainless steels for biomedical applications part I: microstructure characteristics, mechanical properties and antibacterial mechanisms. AB - The as-quenched (AQ) microstructure of the Ag-containing alloys was found to be essentially a mixture of austenite (gamma) and Ag phases. The Ag phase precipitates had a face-centered-cubic structure and lattice parameter a = 4.09 A. When the alloy contained Ag >=0.2 wt%, the mechanical properties were slightly enhanced because of the precipitate strengthening by the Ag phase precipitates. Moreover, the Ag-containing alloys exhibited ductile fracture after tensile testing. The results of an antibacterial test revealed that the Ag phase precipitates play a key role in the antibacterial mechanism of Ag-containing alloys: Ag(+) ions released from the Ag phase precipitates can kill bacteria. It is suggested that as AISI 316L alloy has an Ag content >=0.2 wt%, it will have excellent antibacterial properties against both Staphylococcus aureus and Escherichia coli, with an antibacterial rate of nearly 100%. PMID- 21598124 TI - The physico-chemical characterization of casein-modified surfaces and their influence on the adhesion of spores from a Geobacillus species. AB - To gain a better understanding of the factors influencing spore adhesion in dairy manufacturing plants, casein-modified glass surfaces were prepared and characterized and their effect on the adhesion kinetics of spores from a Geobacillus sp., isolated from a dairy manufacturing plant (DMP) was assessed using a flow chamber. Surfaces were produced by initially silanizing glass using (3-glycidyloxypropyl) trimethoxysilane (GPS) or (3-aminopropyl) triethoxysilane to form epoxy-functionalized (G-GPS) or amino-functionalized glass (G-NH(2)) substrata. Casein was grafted to the G-GPS directly by its primary amino groups (G-GPS-casein) or to G-NH(2) by employing glutaraldehyde as a linking agent (G NH(2)-glutar-casein). The surfaces were characterised using streaming potential measurements, contact angle goniometry, infrared spectroscopy and scanning electron microscopy. The attachment rate of spores suspended in 0.1 M KCl at pH 6.8, was highest on the positively charged (+14 mV) G-NH(2) surface (333 spores cm(-2) s(-1)) compared to the negatively charged glass (-22 mV), G-GPS (-20 mV) or G-GPS-casein (-21 mV) surfaces (162, 17 or 6 spores cm(-2) s(-1) respectively). Whilst there was a clear decrease in attachment rate to negatively charged casein-modified surfaces compared to the positively charged amine surface, there was no clear relationship between surface hydrophobicity and spore attachment rate. PMID- 21598122 TI - Assessment of oxidative status in chronic pancreatitis and its relation with zinc status. AB - BACKGROUND: Oxidative stress-induced free radicals have been implicated in the pathology of chronic pancreatitis (CP). AIM: We aimed to estimate oxidative stress and antioxidant status in tropical chronic pancreatitis (TCP) and alcoholic chronic pancreatitis (ACP) and correlate with zinc status. METHODS: One hundred and seventy-five CP patients (91 TCP, 84 ACP) and 113 healthy subjects were prospectively studied. Disease characteristics and imaging features were recorded. Erythrocyte reduced glutathione, glutathione peroxidase (GPx), superoxide dismutase (SOD), plasma vitamin C, and erythrocyte thiobarbituric acid reactive substance (TBARS) were estimated by spectrophotometry. Erythrocyte zinc was estimated by flame atomic absorption spectrophotometry. RESULTS: Enhanced lipid peroxidation with concomitant decrease in antioxidant status was observed in both TCP and ACP patients (p < 0.05). The findings were comparable in both diabetic and non-diabetic CP patients. Significantly, lower plasma vitamin C and elevated levels of erythrocyte TBARS was noted in TCP as compared to ACP patients. The erythrocyte zinc significantly correlated with SOD activity (r = 0.450, p < 0.001). CONCLUSIONS: Our study corroborates the role of oxidative stress in CP and suggests some differences in oxidative status in TCP and ACP patients. Zinc deficiency appears to affect oxidative status in CP patients. PMID- 21598125 TI - Direct and indirect measures of spider fear predict unique variance in children's fear-related behaviour. AB - This study investigated whether direct and indirect measures predict unique variance components of fearful behaviour in children. One hundred eighty-nine children aged between 9 and 12 performed a pictorial version of the emotional Stroop task (EST), filled out the Spider Anxiety and Disgust Screening for Children (SADS-C), the Spider Phobia Questionnaire for Children (SPQ-C), and took part in a Behavioural Assessment Test (BAT). The EST did not correlate with self reports. Correlations of the self-reports and the BAT remained significant after partialling out EST performance. Likewise, the EST and the BAT still correlated significantly with each other when controlling for the self-reports. This indicates that both direct and indirect measures are useful for predicting unique variance components of fearful behaviour in children. Moreover, it may explain why some previous studies have not found a relationship between self-reported fear and EST performance. PMID- 21598126 TI - Task relevance modulates processing of distracting emotional stimuli. AB - Numerous studies have claimed that emotional stimuli are able to capture attention automatically when presented outside the main focus of attention. In the current study this claim was tested by using task-relevant and task irrelevant emotional stimuli. Specifically, in two experiments the effect of emotional stimuli presented in the periphery of attention was tested by using a flanker task. Results showed that emotional stimuli did not capture attention in an unconditional manner. Emotional distracting stimuli created interference only when they were relevant to the task. The findings suggest that "task relevance" is determined by (a) task requirements, and/or (b) target characteristics. The current results have implications for the concept of cognitive load and automaticity of processing emotional stimuli. PMID- 21598127 TI - Prediction of quantitative intrathoracic fluid volume to diagnose pulmonary oedema using LabVIEW. AB - Pulmonary oedema is a life-threatening disease that requires special attention in the area of research and clinical diagnosis. Computer-based techniques are rarely used to quantify the intrathoracic fluid volume (IFV) for diagnostic purposes. This paper discusses a software program developed to detect and diagnose pulmonary oedema using LabVIEW. The software runs on anthropometric dimensions and physiological parameters, mainly transthoracic electrical impedance (TEI). This technique is accurate and faster than existing manual techniques. The LabVIEW software was used to compute the parameters required to quantify IFV. An equation relating per cent control and IFV was obtained. The results of predicted TEI and measured TEI were compared with previously reported data to validate the developed program. It was found that the predicted values of TEI obtained from the computer-based technique were much closer to the measured values of TEI. Six new subjects were enrolled to measure and predict transthoracic impedance and hence to quantify IFV. A similar difference was also observed in the measured and predicted values of TEI for the new subjects. PMID- 21598128 TI - Geometrical optimisation of a biochip microchannel fluidic separator. AB - This article reports on the geometric optimisation of a T-shaped biochip microchannel fluidic separator aiming to maximise the separation efficiency of plasma from blood through the improvement of the unbalanced separation performance among different channel bifurcations. For this purpose, an algebraic analysis is firstly implemented to identify the key parameters affecting fluid separation. A numerical optimisation is then carried out to search the key parameters for improved separation performance of the biochip. Three parameters, the interval length between bifurcations, the main channel length from the outlet to the bifurcation region and the side channel geometry, are identified as the key characteristic sizes and defined as optimisation variables. A balanced flow rate ratio between the main and side channels, which is an indication of separation effectiveness, is defined as the objective. It is found that the degradation of the separation performance is caused by the unbalanced channel resistance ratio between the main and side channel routes from bifurcations to outlets. The effects of the three key parameters can be summarised as follows: (a) shortening the interval length between bifurcations moderately reduces the differences in the flow rate ratios; (b) extending the length of the main channel from the main outlet is effective for achieving a uniformity of flow rate ratio but ineffective in changing the velocity difference of the side channels and (c) decreasing the lengths of side channels from upstream to downstream is effective for both obtaining a uniform flow rate ratio and reducing the differences in the flow velocities between the side branch channels. An optimisation process combining the three parameters is suggested as this integration approach leads to fast convergent process and also offers flexible design options for satisfying different requirements. PMID- 21598129 TI - The development, calibration and validation of a numerical total knee replacement kinematics simulator considering laxity and unconstrained flexion motions. AB - Kinematics testing is essential during the development of total knee replacement (TKR) designs. Although computational analysis cannot replace physical testing, it offers repeatability and consistency at a much lower cost and shorter time, making it an excellent complement to experiments. Previous numerical models have been limited by several factors: the validity of the models is usually only considered for a single TKR design, friction models are typically overly simplified and the determination of simulation parameters is often inadequate, or tedious and expensive. The objective of this study is to develop, calibrate and validate a TKR kinematics simulation considering multiple TKR geometries, an accurate friction model and simulation parameters determined using a systematic optimisation method. The calibrated model was able to predict TKR kinematics for different TKR geometries, and is ideal for screening new implant designs, reducing the number of experiments required at the design stage. PMID- 21598130 TI - Feature selection based on a fuzzy complementary criterion: application to gait recognition using ground reaction forces. AB - An efficient wavelet-based feature selection (FS) method is proposed in this paper for subject recognition using ground reaction force measurements. Our approach relies on a local fuzzy evaluation measure with respect to patterns that reveal the adequacy of data coverage for each feature. Furthermore, FS is driven by a fuzzy complementary criterion (FuzCoC) which assures that those features are iteratively introduced, providing the maximum additional contribution with regard to the information content given by the previously selected features. On the basis of the principles of FuzCoC, we develop two novel techniques. At Stage 1, wavelet packet (WP) decomposition of gaits is accomplished to obtain a set of discriminating frequency sub-bands. A computationally simple FS method is then applied at Stage 2, providing a compact set of powerful and complementary features, from WP coefficients. The quality of our approach is validated via comparative analysis against existing methods on gait recognition. PMID- 21598131 TI - Modelling 3D control of upright stance using an optimal control strategy. AB - A 3D balance control model of quiet upright stance is presented, based on an optimal control strategy, and evaluated in terms of its ability to simulate postural sway in both the anterior-posterior and medial-lateral directions. The human body was represented as a two-segment inverted pendulum. Several assumptions were made to linearise body dynamics, for example, that there was no transverse rotation during upright stance. The neural controller was presumed to be an optimal controller that generates ankle control torque and hip control torque according to certain performance criteria. An optimisation procedure was used to determine the values of unspecified model parameters including random disturbance gains and sensory delay times. This model was used to simulate postural sway behaviours characterised by centre-of-pressure (COP)-based measures. Confidence intervals for all normalised COP-based measures contained unity, indicating no significant differences between any of the simulated COP based measures and corresponding experimental references. In addition, mean normalised errors for the traditional measures were < 8%, and those for most statistical mechanics measures were ~3-66%. On the basis these results, the proposed 3D balance control model appears to have the ability to accurately simulate 3D postural sway behaviours. PMID- 21598132 TI - Probabilistic acute dietary exposure assessment of the Chinese population to cypermethrin residues. AB - A probabilistic estimation of dietary exposure to cypermethrin residues for the Chinese population was performed. Cypermethrin residue data were obtained from the national food contamination monitoring program for 2001-2006, encompassing 14,096 samples from 36 commodities with a detection rate of 10.4%. Food consumption data were gathered from the national nutrition and health survey conducted in 2002, comprising 65,915 consumers aged 2-100 years and 3701 children of 2-6 years old. The whole country was roughly divided into six regions and the ranges of the median and of P99.9 exposure estimated for these regions were 0.018 0.026 and 3.131-7.095 ug kg(-1 )bw day(-1), respectively. Pak-choi and Chinese cabbage contributed 33.9 and 13.2%, respectively, to the cypermethrin intake for the general population, while pak-choi and citrus covered 30.7 and 22.5% of the total intake for children, respectively. The exposure of the rural population was higher than urban populations. Rural areas mainly located in the plains of central China had among the highest exposure of the six regions, accounting for 17.7% of the ARfD at P99.9, while the 99.99th percentile of exposure for children, especially rural children, far exceeded the ARfD, which is a cause for concern. PMID- 21598134 TI - Simultaneous analysis of four sulfonamides in chicken muscle tissue by HPLC. AB - The aim of this study was to develop a simple high-performance liquid chromatography (HPLC) with UV detection method for the determination of four sulfonamides in chicken muscle tissue. The sulfonamides were extracted with acetonitrile, acetone and dichloromethane. Separation was carried out on a C18 column using as the mobile phase a mixture of 60/00 disodium hydrogen phosphate and methanol. The analytes were detected by UV in one run. Calibration curves were linear with very good correlation coefficients for concentration ranging from 30 to 150 ug kg(-1). The limits of detection (LOD) for sulfonamides ranged from 6.5 to 0.14 ug kg(-1). The recovery for spiked chicken muscle with 50-150 ug kg(-1) was more than 70%. The relative standard deviations (RSDs) of the sulfonamides for six measurements at 50, 100 and 150 ug kg(-1) were less than 15%. These parameters met the European Union criteria for method validation. The results were confirmed by LC-MS/MS using multiple reaction monitoring as the operating mode. Confirmation required the retention times of the analytes to be within +/-2.5% of the retention times of the standards, the presence of the parent ion and two characteristic fragment ions (product ions) per analyte, as well as the relative ion abundance ratios of the fragment ions corresponding to ratios obtained for the standards, within permitted limits. The transition of two common product ions at m/z 155.7 and 107.5 were monitored for all sulfonamides. Each of the analytes, in all tested samples, met the confirmation criteria. Thus, the applicability of the HPLC-UV method for routine analysis of chicken muscle tissue was demonstrated. PMID- 21598133 TI - Natural deoxynivalenol occurrence and genotype and chemotype determination of a field population of the Fusarium graminearum complex associated with soybean in Argentina. AB - Soybean (Glycine max L.), the main source of protein throughout the world, is used both as a food and a feedstuff. Currently, limited information about the occurrence of Fusarium species and mycotoxins in soybean grain and by-products is available. The aims of the present study were: (1) to identify toxigenic Fusarium species associated with soybean during crop reproductive stages; (2) to determine the occurrence of deoxynivalenol (DON) and nivalenol (NIV) in soybean seeds; (3) to determine the genotype and chemotype of selected Fg complex strains using molecular and chemical analysis, respectively; and (4) to characterize the strains using AFLP(s) markers. One soybean field located at Cordoba Province, Argentina, was monitored and samples of soybean tissue were harvested at three reproductive stages: flowering (R2), full seed (R6) and full maturity (R8). A total of 389 Fusarium strains F. equiseti (40%) was the most frequently species recovered followed by F. semitectum (27%) and F. graminearum (Fg) (11%). From the 40 soybean samples analysed, only two presented detectable DON levels. Based on DON occurrence on soybean seeds at ripening stages, the toxigenic ability of Fg complex strains isolated from soybean seeds, pods and flowers were analysed. The trichothecene genotype was determined by a multiplex PCR using primers based on Tri3, Tri5 and Tri7 toxin genes and then the chemotype was verified by chemical analysis. Most Fg complex strains showed 15-ADON genotype and five strains presented a DON/NIV; these also produced both toxins under in vitro culture. Neither the NIV nor the 3-ADON genotypes were detected among the members of the population evaluated. All the 15-ADON genotype strains were characterized as F. graminearum sensu stricto (lineage 7), while the strains presented a DON/NIV genotype were characterized as F. meridionale (lineage 2). The present study contributes new information on the occurrence of Fusarium species and trichothecenes toxins on soybean at the pre-harvest stages. Also, this is the first report on the chemotype, genotype and lineages among Fg complex isolated from soybean. PMID- 21598135 TI - Distribution of aflatoxins in shelling and milling fractions of naturally contaminated rice. AB - The objective of this study was to determine the distribution of an economically important class of mycotoxins, the aflatoxins, in rice milling fractions. Rice plants grown under field production conditions are frequently infected with types of pathogenic fungi that produce toxic metabolites (mycotoxins). Paddy (seeds) rice from healthy plants in the field was collected and stored on a farm under humid, poorly ventilated conditions. Samples were milled into four fractions (hulls, brown rice, bran and white rice) and analysed for aflatoxins (B(1), B(2), G(1) and G(2)) using a validated method. Rice fractions from healthy plants, which contained low levels of aflatoxins (less than 1 ug kg(-1)), were used to determine the efficiency of the extraction method. Seeds stored under poor conditions were found to be contaminated with aflatoxins B(1) and B(2) as were the fractions. The sums of AFB(1) and AFB(2) in stored paddy rice, hulls, brown rice, bran and white rice were 141, 39, 158, 367 and 56 ug kg(-1), respectively. The ratio of aflatoxin B(1) and B(2) was about 10 : 1. AFG(1) and AFG(2) were less than 1 ug kg(-1). Thus, brown rice contained 92.9% of the aflatoxins in paddy rice, whereas white rice contained only 27.9%. PMID- 21598136 TI - Quantitative dietary exposure assessment of the Catalonian population (Spain) to the mycotoxin deoxynivalenol. AB - The mycotoxin deoxynivalenol (DON) is one of the most common contaminants of cereals worldwide, and its occurrence has been widely reported in raw foods and foodstuffs, around the European region, including Catalonia. In the present work, a stochastic methodology has been applied to accurately assess the exposure of the Catalonian population (Spain) to DON through food consumption. Raw contamination data was provided by a large survey conducted in this region, in addition to the raw consumption data from a nutritional study specifically designed to assess the dietary intake of the main foodstuffs related to DON contamination for all population age groups. Contamination and consumption data were combined by simulation using an essentially parametric (P-P) method. The P-P method draws sampling values from distribution functions fitted to consumption and contamination data sets. Moreover, to quantify the accuracy and reliability of the statistics estimates, we built the related confidence intervals using a pseudo-parametric bootstrap method. Considering the results drawn from the P-P simulation method, the Catalonian population should be expected to be exposed at moderated levels of deoxynivalenol, the infants and individuals with ethnic dietary patterns being the most exposed population groups. PMID- 21598137 TI - Immunoassay based on monoclonal antibodies versus LC-MS: deoxynivalenol in wheat and flour in Southern Brazil. AB - An indirect competitive enzyme-linked immunosorbent assay (ELISA) method using a monoclonal antibody for deoxynivalenol (DON) detection in wheat and flour was standardised and validated (detection limit = 177.1 ug kg(-1)) and its performance was compared with LC-MS, quantification limit =140 ug kg(-1)). DON recovery ranged from 88.7% to 122.6% for wheat grain and from 70.6% to 139.3% for flour. Among the 38 wheat samples evaluated, DON was detected in 29 samples (76.3%) by ic-ELISA (281.6-12 291.4 ug kg(-1)) and in 22 samples (57.9%) by LC-MS (155.3-9906.9 ug kg(-1)). The 0.93 correlation coefficient between ic-ELISA and LC-MS data in 19 positive DON wheat samples demonstrated the reliability and efficiency of ic-ELISA. Results indicated that standardised ic-ELISA was suitable for DON screening in wheat samples and the need for continuous monitoring of mycotoxin levels in foodstuffs. PMID- 21598138 TI - Optimization and validation of a HPLC method for simultaneous determination of aflatoxin B1, B2, G1, G2, ochratoxin A and zearalenone using an experimental design. AB - A reversed-phase HPLC optimization strategy is presented for investigating the separation and retention behavior of aflatoxin B1, B2, G1, G2, ochratoxin A and zearalenone, simultaneously. A fractional factorial design (FFD) was used to screen the significance effect of seven independent variables on chromatographic responses. The independent variables used were: (X1) column oven temperature (20 40 degrees C), (X2) flow rate (0.8-1.2 ml/min), (X3) acid concentration in aqueous phase (0-2%), (X4) organic solvent percentage at the beginning (40-50%), and (X5) at the end (50-60%) of the gradient mobile phase, as well as (X6) ratio of methanol/acetonitrile at the beginning (1-4) and (X7) at the end (0-1) of gradient mobile phase. Responses of chromatographic analysis were resolution of mycotoxin peaks and HPLC run time. A central composite design (CCD) using response surface methodology (RSM) was then carried out for optimization of the most significant factors by multiple regression models for response variables. The proposed optimal method using 40 degrees C oven temperature, 1 ml/min flow rate, 0.1% acetic acid concentration in aqueous phase, 41% organic phase (beginning), 60% organic phase (end), 1.92 ratio of methanol to acetonitrile (beginning) and 0.2 ratio (end) for X1-X7, respectively, showed good prediction ability between the experimental data and predictive values throughout the studied parameter space. Finally, the optimized method was validated by measuring the linearity, sensitivity, accuracy and precision parameters, and has been applied successfully to the analysis of spiked cereal samples. PMID- 21598139 TI - Analysis of molluscicide metaldehyde in vegetables by dispersive solid-phase extraction and liquid chromatography-tandem mass spectrometry. AB - This paper describes the development and validation of a new reverse-phase liquid chromatography-electrospray ionisation tandem mass spectrometric method (RP-HPLC ESI-MS/MS) for the determination of metaldehyde in different kinds of vegetables. Metaldehyde was extracted with 20 ml acetonitrile from 10 g vegetable and followed by dispersive solid-phase extraction (Bondesil-primary secondary amine, PSA). The identification of metaldehyde was established by chromatographic retention times, analyte-specific fragmentation patterns and relative peak area ratios of two precursor/product ion pairs. The limit of detection of this method was 0.01 mg kg(-1) using an injection volume of 5 ul. The repeatability of this method is excellent and the relative standard deviation (RSD) is less than 4%. PMID- 21598140 TI - Comparison of manual and automatic sampling for monitoring ochratoxin A in barley grain. AB - Automatic and manual sampling for ochratoxin A (OTA) in barley grain was compared under industrial conditions considering sampling uncertainty as well as practical and technical aspects. Ten tonnes of barley inoculated with Penicillium verrucosum were incubated until the OTA concentration reached approximately 15 ug kg(-1) and sampled with manual and automatic sampling. A nested experimental design and ANOVA was used to estimate variance components from sampling, sample reduction, sample preparation and analysis. Manual sampling resulted in a high sampling uncertainty and OTA concentrations in aggregate samples ranged from 2 to 80 ug kg(-1). When aggregate samples were formed by automatic sampling the uncertainty arising from nugget effects and spatial distribution was practically eliminated. Results from this study show that an automatic sampler mounted after a mixer or conveyer can provide representative samples of OTA from a moving stream of barley. Automatic sampling might present a practical and economical alternative to manual sampling for feed mill operators when monitoring low levels of mycotoxins in grain or other commodities. Despite careful precautions, sample preparation and analysis resulted in a relative uncertainty of +/-40% (p = 0.95), which was attributed to the sub-sampling following the two grinding steps. Size fractionation of the coarsely ground barley showed that 40% of the total amount of OTA was present in a small fraction of fine particles with a strong tendency to aggregate or stick to equipment and containers. Thus, in order to take advantage of the automatic sampling, it is crucial to apply an appropriate sub sampling to prevent segregation of particles which may affect the OTA measurements. PMID- 21598141 TI - Surveillance study of a number of synthetic and natural growth promoters in bovine muscle samples using liquid chromatography-tandem mass spectrometry. AB - A simple, new method permitting the simultaneous determination and confirmation of trace residues of 24 different growth promoters and metabolites using liquid chromatography-mass spectrometry was developed and validated. The compounds were extracted from bovine tissue using acetonitrile; sodium sulphate was also added at this stage to aid with purification. The resulting mixture was then evaporated to approximately 1 ml and subsequently centrifuged at high speed and an aliquot injected onto the LC-MS/MS system. The calculated CCalpha values ranged between 0.11 and 0.46 ug kg(-1); calculated CCbeta were in the range 0.19-0.79 ug kg(-1). Accuracy, measurement of uncertainty, repeatability and linearity were also determined for each analyte. The analytical method was applied to a number of bovine tissue samples imported into Ireland from third countries. Levels of progesterone were found in a number of samples at concentrations ranging between 0.28 and 30.30 ug kg(-1). Levels of alpha- and beta-testosterone were also found in a number of samples at concentrations ranging between 0.22 and 8.63 ug kg(-1) and between 0.16 and 2.08 ug kg(-1) respectively. PMID- 21598142 TI - Indirect competitive enzyme-linked immuno-sorbent assay (ELISA) for nitroimidazoles in food products. AB - Ronidazole was used as the starting material to prepare an immunogen and coating antigen. An anti-nitroimidazole monoclonal antibody was produced and an indirect competitive ELISA was established to detect nitroimidazole compounds in food products. The IC(50) values were determined to be 0.20 ng/ml for metronidazole, 4.0 ng/ml for tinidazole, 0.17 ng/ml for dimetridazole and 0.24 ng/ml for ornidazole. Considering that nitroimidazoles were commonly used as veterinary drugs, nitroimidazole residues in food products of animal origin were detected by the method. The coefficient of variation for nitroimidazoles determination in contaminated chicken, chicken liver and shrimp were all <14% and the recovery rate was in the range 74.0-90.6%. The results proved that the developed method was successful in detecting nitroimidazoles in food products. PMID- 21598143 TI - Multi-residue method for the confirmation of four avermectin residues in food products of animal origin by ultra-performance liquid chromatography-tandem mass spectrometry. AB - A confirmatory method was developed for the rapid determination of abamectin, ivermectin, doramectin and eprinomectin residues in various food products of animal origin, such as pork muscle, pork liver, fish and milk. Samples were homogenized, extracted and de-proteinized by acetonitrile, cleaned via two-step cleaning procedure using Bond Elut C(18) SPE columns and then alumina-N cartridges. All the four avermectin residues in different animal-food products were simultaneously separated and determined by ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) within 3.5 min. Data acquisition under positive ESI-MS/MS was performed by applying multiple reaction monitoring (MRM) for both identification and quantification, and mass spectrometric conditions were optimized to increase selectivity and sensitivity. The matrix-matched calibration curves for different matrices, such as pork muscle, pork liver, fish and milk, were constructed and the interference effect of different sample matrices on the ionization was effectively eliminated. The UPLC-MS/MS method was validated with satisfactory linearity, recovery, precision and stability. Matrix-matched calibration curves of abamectin, ivermectin, doramectin and eprinomectin in four different matrices were linear (r(2)( )>= 0.990, goodness-of-fit coefficients <=12.8%) in the range 2.5-200 ug kg(-1). The limits of detection and quantification for the four avermectins were in the range 0.05-0.68 and 0.17-2.27 ug kg(-1), respectively. Recoveries were 62.4-104.5% with good intra- and inter-day precision. The method was rapid, sensitive and reliable, and can be applied to the quantitative analysis of avermectin residues in different animal-food products. PMID- 21598144 TI - Calculation of the dietary exposure of Chinese consumers to acephate residues using deterministic and probabilistic approaches. AB - This paper compares the exposure for the Chinese populations and sub-groups to acephate, a widely applied organophosphorus pesticide, using deterministic and probabilistic approaches. Acephate residue data were obtained from the national food contamination monitoring program 2001-2006, collected by multi-stage stratified sampling and with a detection rate of 3.3%. Food consumption data were gathered from the national diet and nutrition survey conducted in 2002 over three consecutive days by the 24-h recall method, and included 22,563 families or 65,886 consumers aged 2-100 years. For point estimate, it was evident that exposures were higher than the acute reference dose (ARfD) in many cases. For the probabilistic approach, the P99.9 exposures for the general population and children accounted for 11.88 and 24.15% of the ARfD, respectively, in acute intake calculations and 52.86 and 68.75%, respectively, of the acceptable daily intake (ADI) in chronic intake calculations. The exposure level of rural people was higher than urban dwellers, and vegetables contributed most to acephate intake. PMID- 21598145 TI - The level of willingness to evacuate among older adults. AB - The issues of rising numbers of disasters, overwhelming increases in number of older adults, and historically flawed evacuations present real challenges. During the next two decades, the number of American baby boomers, who turn 65, will increase by 40%. As evidenced by recent disasters, the imperfections and vulnerabilities of flawed evacuations for older adults are still present. This study examined the level of willingness to evacuate among older adults in the event of a disaster. Despite the extensive literature on disasters and evacuation, a significant question regarding evacuation and older adults has not been addressed. The study addressed the following concern: What is the level of willingness among older adults to evacuate when asked to do so by emergency management officials? The sample population consisted of 765 voluntary participants aged 60 years and older from 30 senior/community centers within seven counties within a midwestern state. A group administered survey (The Disaster Evacuation Survey) included a total of 15 questions. The findings revealed that older adults are more likely to comply with a mandatory evacuation order. Important practical implications for emergency officials responding to vulnerable older adults in disaster situations are also provided. PMID- 21598146 TI - Tuning them in versus turning them on: how do we interest students in working with older adults? AB - As a nation, we face a shortage of individuals to serve our aging population. Therefore, the recruitment of undergraduate students into gerontology programs is an important, although challenging task. The purpose of this study was to determine if students who do not choose to major in gerontology do so because they simply are unaware of the opportunities or because they are uninterested. College students who were not gerontology majors (N = 226) were surveyed to determine whether they were aware of a gerontology major at their university, whether they could define gerontology, and their reasons for not pursuing gerontology. Results suggest that a lack of awareness, rather than a lack of interest, may be responsible for the challenges of recruiting college students into the field of gerontology. This implies that the most efficient path to bolstering our gerontology workforce may be to make students aware of the diverse and rewarding career opportunities in the field of aging. PMID- 21598147 TI - Improving the long-term care referral process: insights from patients and caregivers. AB - Large increases in the need for long-term care (LTC) services are expected as baby boomers age. Little has been published about patient and caregiver preferences for information about LTC. However, our qualitative research findings suggest that potential consumers may find it difficult to obtain accurate and timely information about LTC programs and services. In-person, semistructured interviews were conducted with 47 subjects, including patients (n = 25) within 90 days of their referral to a LTC placement (including NH, assisted living, home care, and community) and their caregivers (n = 22). Interview questions addressed the events that seemed to trigger their need for a LTC referral, the resources they used to become more informed about LTC options and the issues they confronted with the LTC referral process. Qualitative analyses identified a number of patient and informal caregiver-reported barriers to making decisions about LTC services, including insufficient information about LTC programs and community resources, unclear funding requirements and inadequate funding, and difficulty knowing how to plan for LTC or make LTC decisions. A potential solution may be an online LTC Guide designed to provide accurate information about the range of LTC services, with an emphasis on home and community-based services. This Guide was developed to address the gap in comprehensive LTC information identified in the findings of this study. PMID- 21598148 TI - The impact of an end-of-life communication skills intervention on physicians-in training. AB - The palliative medicine literature consistently documents that physicians are poorly prepared to help patients experience a "good death" and are often unaware of their ill patients' preferences for end-of-life care. The present study, enrolling 150 physicians, sought to improve their communication skills for end-of life care. We found significant attitudinal changes and a greater degree of self rated competence in delivering end-of-life care for those in the intervention group. This study used a novel approach to train physicians to be better equipped to conduct difficult goals of care conversations with patients and their families at end-of-life. PMID- 21598149 TI - The ELDER Project: educational model and three-year outcomes of a community-based geriatric education initiative. AB - The purpose of the ELDER (Expanded Learning and Dedication to Elders in the Region) Project was to address the needs of underserved older adults by providing worksite education to individuals who provide nursing care to older adults in community health centers, home health agencies, and long-term care facilities. Four agencies located in a Health Professional Shortage and Medically Underserved Area participated. Project staff conducted separate focus groups with administrators and staff at each agency to determine educational needs and preferences. Curricula from the Hartford Institute, End-of-Life Nursing Education Consortium, and Geriatric Education Centers were adapted to design unique curricula for each agency and level of personnel (licensed nurse or unlicensed caregiver). Activities included focus group meetings to tailor content to the needs of each agency, on-site educational sessions, and identification of an agency champion to sustain the program after the funding ended. A case-based simulation-learning approach was used in the final year to validate application of knowledge and to facilitate teamwork and interprofessional communication. Over 100 nurses and nursing assistants and eight administrators and allied health professionals participated over the three-year period of the project. Retention over this period, independent evaluations, and simulations demonstrated participants' ability to integrate best practices into typical clinical scenarios and revealed improved communication among care providers. Tailored on-site education incorporating simulation was an effective model for translating gerontological knowledge into practice and improving the care of older adults in these multiple settings. PMID- 21598150 TI - Engaging community-based organizations in fall prevention education. AB - Falls are a major public health problem for older adults, and community-based organizations play a key role in educating seniors about falls prevention (FP). We conducted a qualitative process evaluation at six sites to report community based centers' perspectives on adoption, adaptation, and sustainability of an evidence-based multifactorial FP model. Wide dissemination of new health-oriented programs requires marketing to center directors, who must consider sustainability options. The diversity and independence of community-based organizations, together with current staffing and funding limitations, suggest that fidelity to multifactorial evidence-based interventions will be difficult to achieve. PMID- 21598151 TI - Breaking bad news: the patient's viewpoint. AB - The objective of this study was to ascertain how patients judge the acceptability of physicians' communication of bad news. Two hundred forty-five adults, who had in the past received bad medical news, indicated the acceptability of physicians' conduct in 48 vignettes of giving bad news to patients. Vignettes were all combinations of five factors: level of bad news (infection with hepatitis C, cirrhosis of the liver, or liver cancer); request or not to the patient to come with spouse or partner; attempt or not by the physician to find out the patient's expectations about the test results; presence or absence of emotional supportiveness; and provision or not of complete and understandable information. In addition, nine physicians rated the same vignettes. Quality of information and emotional supportiveness explained more than 95% of the variance in patients' acceptability judgments, while the degree of badness of the news had no impact. In addition, for patients, low emotional supportiveness could not be fully compensated by high quality of information, nor the inverse. Physicians, in contrast, responded as if such compensations were possible. Physicians must appreciate that patients expect high levels of both empathy and information quality, no matter how bad the news. PMID- 21598152 TI - A formative evaluation of shared family mealtime for parents of toddlers and young children. AB - Shared family mealtime offers numerous health benefits for young children. Unfortunately, only a few studies examine the benefits and barriers to eating together as a family. The present study seeks to fill this gap in the literature by applying the health belief model to understand parents' perceptions about the challenges of preparing and executing family mealtime for toddlers and young children. Six focus groups were conducted with parents of toddlers and/or young children (n = 24). Results revealed that parents identified several benefits to shared family mealtime, including good teaching moments for their children, enhanced family connectedness, and encouraging nutritious meals. Parents also identified barriers to eating together as a family, including child behavioral issues, scheduling difficulties, and ill-prepared husbands. The risks associated with not eating together as a family were seldom mentioned; however, parents highlighted several issues related to self-efficacy, such as difficulty in selecting meals and challenges with cooking. Potential cues to action include print materials encouraging parents by emphasizing the benefits of eating together as a family. Results are discussed with an emphasis on message design strategies for health practitioners interested in advocating this important yet under-studied phenomenon. PMID- 21598153 TI - Prenatal exposure to cigarette smoke and childhood externalizing behavioral problems: a propensity score matching approach. AB - We examined the possibility that the association between maternal smoking during pregnancy and childhood behavioral problems is the result of confounding. Data from the first three waves of the Fragile Families and Child Wellbeing Study were analyzed. We estimated the association between maternal smoking during pregnancy and externalizing problems in three-year olds using a propensity score matching approach. After successfully matching children based on their mother's propensities to smoke during pregnancy, the results indicate that maternal cigarette smoking is related to childhood externalizing behavioral problems, but only among mothers who smoked more than a pack per day while pregnant. At lower levels of exposure, the association between exposure to cigarette smoke in utero and externalizing behavioral problems in childhood can be explained by confounding. The results of this study support prevention efforts intended to reduce prenatal exposure to cigarette smoke, especially by mothers who smoke heavily. PMID- 21598154 TI - The influence of emotional target cues on prospective memory performance in depression. AB - This study investigated the impact of emotional valence on event-based prospective memory performance in depression. Thirty individuals with depression and 29 healthy adults performed a prospective memory task in which the emotional valence of the prospective targets was manipulated (positive, neutral, negative). Collapsed across all valence conditions, healthy adults outperformed individuals with depression in the prospective memory task. This effect was qualified by planned contrasts indicating that the two groups only differed when responding to positively valenced cues, reflecting a positivity effect in healthy adults. These data are in line with previous research, which shows that healthy participants better remember positively valenced cues, but are the first to show an absence of this effect in those with depression. PMID- 21598156 TI - The death of handwriting: secondary effects of frequent computer use on basic motor skills. AB - The benefits of modern technologies such as personal computers, in-vehicle navigation systems, and electronic organizers are evident in everyday life. However, only recently has it been proposed that the increasing use of personal computers in producing written texts may significantly contribute to the loss of handwriting skills. Such a fundamental change of human habits is likely to have generalized consequences for other basic fine motor skills as well. In this article, the authors provide evidence that the skill to produce precisely controlled arm-hand movements is related to the usage of computer keyboards in producing written text in everyday life. This result supports the notion that specific cultural skills such as handwriting and typing shape more general perceptual and motor skills. More generally, changing technologies are associated with generalized changes of the profile of basic human skills. PMID- 21598155 TI - Traumatic brain injury and secondary attention-deficit/hyperactivity disorder in children and adolescents: the effect of reward on inhibitory control. AB - Poor inhibitory control and abnormalities in responding to rewards are characteristic of the developmental or primary form of attention deficit/hyperactivity disorder (P-ADHD). A secondary form of ADHD (S-ADHD) may occur as a consequence of childhood traumatic brain injury (TBI), but the similarities and differences between these two forms of ADHD have not been well characterized. To address these issues, we studied two inhibitory control tasks under different reward conditions in four groups of children and adolescents: TBI who did not exhibit S-ADHD, TBI who did exhibit S-ADHD, P-ADHD, and healthy controls. Participants with TBI exhibited poor cancellation inhibition relative to controls. Although reward facilitated both cancellation and restraint inhibition similarly across groups, poor performance persisted in the P-ADHD group, and participants with S-ADHD exhibited a selective deficit in cancellation inhibition. PMID- 21598157 TI - Kinematic markers of distance-specific control in linear hand movements. AB - In this article, the authors analyze kinematic characteristics of reaching movements to memorized visual target locations. An increase in target distance was associated with a decrease in correlation between peak acceleration and movement distance and with a simultaneous increase in correlation between peak acceleration and movement time. According to the previous work on motor control in isometric force responses and in reaching movements these results seem to indicate a continuous transition from a rather preplanned to a more corrective mode of movement control, which may be associated with an adaptive mechanism serving to counteract an increase in signal-dependent noise of the motor system. PMID- 21598158 TI - Specific sequence effects in the serial reaction time task. AB - The Serial Reaction Time (SRT) task was used in 2 experiments to determine if the specific sequence used by the task influences implicit learning. In Experiment 1, participants performed the SRT task with the locations of the stimuli determined by a commonly used fixed sequence (taken from P. J. Reber & L. R. Squire, 1998), by a fixed sequence that was uniquely generated for each participant, or at random. Experiment 2 used the same basic design, but the random condition was changed so that each possible transition between responses was seen the same number of times, making it more comparable to the fixed-sequence conditions. Results from both experiments indicate that the specific sequence used in the SRT task influences the strength of implicit learning effects. Follow-up analyses show that the strength of implicit learning can be linked to the presence of particular types of triads within the sequence. The authors suggest that future researchers should not use on a single fixed sequence across all participants when using the SRT task but should instead generate different fixed sequences for each participant to enhance the generalizability of their results. PMID- 21598159 TI - Impulse-variability theory: implications for ballistic, multijoint motor skill performance. AB - Impulse-variability theory (R. A. Schmidt, H. N. Zelaznik, B. Hawkins, J. S. Frank, & J. T. Quinn, 1979) accounts for the curvilinear relationship between the magnitude and resulting variability of the muscular forces that influence the success of goal-directed limb movements. The historical roots of impulse variability theory are reviewed in the 1st part of this article, including the relationship between movement speed and spatial error. The authors then address the relevance of impulse-variability theory for the control of ballistic, multijoint skills, such as throwing, striking, and kicking. These types of skills provide a stark contrast to the relatively simple, minimal degrees of freedom movements that characterized early research. However, the inherent demand for ballistic force generation is a strong parallel between these simple laboratory tasks and multijoint motor skills. Therefore, the authors conclude by recommending experimental procedures for evaluating the adequacy of impulse variability as a theoretical model within the context of ballistic, multijoint motor skill performance. PMID- 21598160 TI - Food security in older adults. PMID- 21598161 TI - Home food environment of older adults transitioning from hospital to home. AB - Only anecdotal information is known about foods available in the home of hospital discharged older adults. This study describes the home food environment of this population and examines associations between health/nutrition risk factors and ability to shop and prepare meals. Data were collected from 512 hospital discharged older adults residing in 6 U.S. states; food available within the home was assessed. Most households had a variety of food present; however, 20% of households lacked fresh fruit, 15% lacked fresh vegetables, and 35% had no fresh meat. About 35% of participants reported an inability to both prepare meals and shop for food. Among those unable to do both activities, the prevalence of depressive symptoms, food-related anxiety, and poor self-rated health was significantly (p < 0.01) higher than those able to do both activities. Homebound older adults may face additional challenges to recuperation from illness based on inability to prepare meals, regardless of availability of food following hospital discharge. PMID- 21598162 TI - Older Americans Act Nutrition Program improves participants' food security in Georgia. AB - It is critical to use convincing research methodology to demonstrate the benefits of nutrition assistance programs targeted to vulnerable older adults. We examined the impact of Older Americans Act Nutrition Program (OAANP) participation on food security in participants and waitlisted people in Georgia using two waves of self administered mail surveys conducted 4 months apart (n = 717, mean age 74.6 +/- 9.5, 70.9% female, 33.2% black). At baseline, 54% of the sample was food insecure. Waitlisted people reported higher levels of persistent food insecurity (45.9%) or becoming food insecure (10.0%) than participants (29.3% and 7.1%, respectively) over 4 months. While considering potential confounders, the estimated odds of achieving food security were 1.65 times (95% CI: 1.10-2.48) higher in participants than in waitlisted people over 4 months. Our data suggest the feasibility of using food insecurity measures to detect the benefits of OAANP participation as well as the need to increase the capacity of OAANP. PMID- 21598163 TI - Smoking modifies the association between food insecurity and physical performance. AB - Few studies have examined the association between food insecurity and physical performance among older adults. To our knowledge, the effect modification of smoking status has never been examined in previous studies of food insecurity and physical performance. Using data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES), we examined if the association between food insecurity and physical performance including gait speed and knee extensor power varied by smoking status among a nationally representative sample of men and women (>=50 y). Responses to the U.S. Household Food Security Survey Module (HFSSM) were used to assign participants to study categories. Multiple linear regression models controlling for age, gender, race/ethnicity, education, and income were used. The association between food insecurity and gait speed varied by smoking status (p = 0.005). For nonsmokers, those who were marginally food secure (0.91 m/s, p = 0.016) and food insecure (0.94 m/s, p = 0.004) had significantly slower gait speeds than food secure participants (1.04 m/s). Similar findings were found for knee extensor power. An association between food insecurity and either physical performance measures was not detected among smokers. Given the magnitude of the effects of smoking on physical performance, smoking appears to obscure the relationship between food insecurity and physical performance. PMID- 21598164 TI - Indicators of material hardship and depressive symptoms among homebound older adults living in North Carolina. AB - This study used the concept of material hardship to understand how unmet needs related to food, housing, and health influence depressive symptoms among homebound older adults (N = 345) in North Carolina. Using data from the Nutrition and Function Study, 37% reported high levels of depressive symptoms and 17.4% indicated not receiving needed health care. Approximately 10% of respondents were food insecure; 30.7% were at risk for food insecurity; and 39.7% reported having to choose between either food and medication or food and paying bills. Adjusted logistic regression model revealed that food insecurity status (OR = 4.9) and age 60-74 y (OR = 2.4) were significantly associated with a greater number of depressive symptoms. Other indicators of material hardship, such as having a major financial difficulty, unmet health need, and inadequate housing, were not significant. By far, food insecurity was the most salient influence on depressive symptoms. These findings have important implications for service providers, researchers, and policymakers. PMID- 21598165 TI - Food insecurity is associated with social capital, perceived personal disparity, and partnership status among older and senior adults in a largely rural area of central Texas. AB - This study examined the association of compositional measures of collective social functioning, composed of community and familial social capital and perceived personal disparity, with food security among older (aged 50-59 y) and senior (aged >= 60 y) adult residents of the largely rural Brazos Valley in Central Texas using data from the 2006 Brazos Valley Community Health Assessment (analytic N = 1059, 74% response rate). Among older adults and seniors, 18.6% reported food insecurity (5.5% often and 13.1% sometimes), defined as running out of food and not having money to buy more. Low community social capital was reported by 22.4% of participants, and 30.8% indicated they were single, widowed, or divorced, an indicator of limited familial social capital. A robust multinomial regression model found the odds of reporting greater food insecurity increased for individuals who were women, African American, residents of a household with a low or poverty-level income, individuals who perceived themselves to be worse off than others within their community, and those who had low social capital. The odds of being food insecure decreased for older respondents, partnered respondents and persons with more education (pseudo r(2) = 0.27, p < 0.0000). Compositional level measures of collective social functioning are important associates of food insecurity among older adults and seniors, regardless of severity. PMID- 21598166 TI - Country of birth is associated with very low food security among Mexican American older adults living in colonias along the south Texas border with Mexico. AB - The availability of an adequate household food supply is critical for the older population. There is little work that has examined food security and the influence of nativity on food security among older Mexican Americans living along the Texas-Mexico border. Using data from 140 older women (age >= 50 y) who participated in the 2009 Colonia Household and Community Food Resource Assessment (C-HCFRA), we examined demographic characteristics, health characteristics, food access and mobility, federal and community food and nutrition assistance programs, quality of food environment, food security, eating behaviors, and alternative food sources. 77% of participants experienced food insecurity, with 68% experiencing very low food security. Very low food security was associated with being born in Mexico, adjusting for household income and food assistance program participation. This article provides compelling evidence for enhanced research efforts that will better understand coping strategies and the use of food and nutrition assistance programs for reducing hardship associated with very low food security among older U.S.- and Mexico-born Mexican American women. PMID- 21598167 TI - Impact of a medical waste incinerator on mercury levels in lagoon fish from a small tropical island in the Western Pacific. AB - In 2004-2005, several species of marine fish were collected for mercury (Hg) analysis from Saipan Lagoon, Saipan, Commonwealth of the Northern Mariana Islands. Relatively high concentrations were found in representatives from the Hafa Adai Beach area located some distance from known sources of Hg contamination. A follow-up investigation aimed at identifying additional land based sources of Hg in the area was launched in early 2007. The study identified a medical waste incinerator as the primary source of Hg enrichment. The incinerator was operational for about 20 years before it was closed down by the U.S. Environmental Protection Agency (EPA) in January 2006, for multiple violations of the Clean Air Act. Stormwater runoff from this facility entered a drainage network that discharged into the ocean at the southern end of Hafa Adai Beach, about 1 km away. At the time of this investigation storm drain sediments at the coast were only marginally enriched with mercury although values some 50x above background were detected in drainage deposits a few meters down-gradient of the incinerator site. Mercury concentrations in fish from the Hafa Adai Beach area were also significantly lower than those determined in similar species 3 yr earlier. The implications of the data are briefly discussed. PMID- 21598168 TI - Formation of vascular S-nitrosothiols and plasma nitrates/nitrites following inhalation of diesel emissions. AB - Epidemiological studies have associated traffic-related airborne pollution with adverse cardiovascular outcomes. Nitric oxide (NO) is a common component of fresh diesel and gasoline engine emissions that rapidly transforms both in the atmosphere and once inhaled. Because of this rapid transformation, limited information is available in terms of potential human exposures and adverse health effects. Young rats were exposed to whole diesel emissions (DE) adjusted to 300 MUg/m(3) of particulate matter (containing 3.5 ppm NO) or 0, 3, or 10 ppm NO as a positive control. Animals were also pre-injected (ip) with either saline or N acetylcysteine (NAC), a precursor of glutathione. Predictably, pure NO exposures led to a concentration-dependent increase in plasma nitrates compared to controls, which lasted for roughly 4 h postexposure. Whole DE exposure for 1 h also led to a doubling of plasma NOx. NAC injection increased the levels of plasma nitrates and nitrites (NOx) in the DE exposure group. Inhibition of nitric oxide symthase (NOS) by N(G)-nitro-L-arginine (L-NNA) did not block the rise in plasma NOx, demonstrating that the increase was entirely due to exogenous sources. Both DE and pure NO exposures paradoxically led to elevated eNOS expression in aortic tissue. Furthermore, coronary arterioles from NO-exposed animals exhibited greater constriction to endothelin-1 compared to controls, consistent with a derangement of the NOS system. Thus, NO may be an important contributor to traffic-related cardiovascular morbidity, although further research is necessary for proper hazard identification. PMID- 21598169 TI - Skin exposure to chronic but not acute UV radiation affects peripheral T-cell function. AB - Ultraviolet (UV) radiation (UVR) produces deleterious effects that may finally lead to carcinogenesis. These adverse effects include tissue inflammation, free radical formation with consequent oxidation of proteins and lipids, DNA damage, and immune function suppression. The aim of this study was to evaluate the effects of UVR at the local and systemic levels following acute (4 consecutive days with 0.5 minimal erythema dose [MED]) or chronic (20 consecutive days with 0.25 MED) exposure. Locally, histological alterations and epidermal T-cell populations were studied. Systemically, inguinal lymph-node and spleen T cells were analyzed with respect to proliferative response and cytokine production against a nonspecific mitogen. Lymph-node T-cell populations were also characterized. Our results indicated that while both acute and chronic UVR produced epidermal hyperplasia and a decrease in epidermal T-cell density, acute UVR increased T-cell proliferative response, while chronic UVR produced the opposite effect, shifting the cytokine production toward a Th2/Treg profile. Therefore, even though acute irradiation produced a direct effect on skin, it did not correlate with a marked modification of overall T-cell response, which is in contrast to marked effects in chronically irradiated animals. These findings may contribute to understanding the clinical relevance of occupational UVR exposure, typically related to outdoor activities, which is associated with nonmelanoma skin carcinogenesis. PMID- 21598170 TI - Effects of whole cigarette smoke on human gingival fibroblast adhesion, growth, and migration. AB - The aim of this study was to investigate the effects of a single exposure to whole cigarette smoke on human gingival fibroblast behavior. Normal oral mucosa fibroblasts were exposed once to whole cigarette smoke for 5, 15, or 30 min, and then were used to analyze cell adhesion, beta1-integrin expression, cell growth and viability, cell capacity to contract collagen gel, and cell migration following wound infliction. Our findings showed that when gingival fibroblasts were exposed once to whole cigarette smoke, this resulted in a significant inhibition of cell adhesion, a decrease in the number of beta1-integrin-positive cells, increased LDH activity in the target cells, and reduced growth. The smoke exposed fibroblasts were also not able to contract collagen gel matrix and migrate following insult. Overall results demonstrate that a single exposure to whole cigarette smoke produced significant morphological and functional deregulation in gingival fibroblasts. This may explain the higher predisposition of tobacco users to oral infections and diseases such as cancer. PMID- 21598171 TI - Locational differences in mercury and selenium levels in 19 species of saltwater fish from New Jersey. AB - Individuals who fish, and their families that ingest self-caught fish, make decisions about where to fish, what type of fish to eat, and the quantity of fish to eat. While federal and state agencies often issue consumption advisories for some fish with high mercury (Hg) concentrations, advisories seldom provide the actual metal levels to the general public. There are few data for most saltwater fish, and even less information on variations in Hg levels in fish within a state or geographical region. The objective of this study was to provide Hg concentrations from 19 species of fish caught in different locations in New Jersey to (1) test the hypothesis that mean metal levels vary geographically, (2) provide this information to individuals who fish these coastal waters, and (3) provide a range of values for risk assessors who deal with saltwater fish exposure in the Northeastern United States. Selenium (Se) was also examined because of its purported moderating effect on the toxicity of Hg. Hg levels showed significant geographical variation for 10 of 14 species that were caught in more than one region of New Jersey, but there were significant locational differences for Se in only 5 of the fish. Mercury levels were significantly lower in fish collected from northern New Jersey (except for ling, Molva molva), compared to other regions. As might be expected, locational differences in Hg levels were greatest for fish species with the highest Hg concentrations (shark, Isurus oxyrinchus; tuna, Thunnus thynnus and T. albacares; striped bass, Morone saxatilis; bluefish, Pomatomus saltatrix). Fishers and their families might reduce their risk from Hg exposure not only by selecting fish generally lower in Hg, but by fishing predominantly in some regions over others, further lowering the potential risk. Health professionals might use these data to advise patients on which fish are safest to consume (in terms of Hg exposure) from particular geographical regions. PMID- 21598172 TI - Uptake, tissue distribution, and excretion of 14C-sulfur mustard vapor following inhalation in F344 rats and cutaneous exposure in hairless guinea pigs. AB - Sulfur mustard (SM), a vessicating agent, has been used in chemical warfare since 1918. The purpose of this study was to quantitate SM vapor deposition, tissue distribution, and excretion following intratracheal inhalation in rats and cutaneous exposure in guinea pigs. 14C-SM vapors for inhalation studies were generated by metering liquid 14C-SM into a heated J tube. Vapors were transported via carrier air supplemented with oxygen and isoflurane to an exposure plenum. Anesthetized rats with transorally placed tracheal catheters were connected to the plenum port via the catheter hub for exposure (approximately 250 mg 14C-SM vapor/m(3); 10 min). For dermal exposure, 3 Teflon cups (6.6 cm(2) exposure area per cup) were applied to the backs of each animal and vapors (525 mg 14C-SM/m(3); 12 min) were generated by applying 6 MUl 14C-SM to filter paper within each cup. Animals were euthanized at selected times up to 7 d postexposure. SM equivalents deposited in rats and guinea pigs were 18.1 +/- 3 MUg and 29.8 +/- 5.31 MUg, respectively. Inhaled SM equivalents rapidly distributed throughout the body within 2 h postexposure, with the majority (>70%) of material at that time located in carcass and pelt. In guinea pigs, >90% of deposited SM equivalents remained in skin, with minor distribution to blood and kidneys. Urine was the primary route of excretion for both species. Results indicate inhaled SM is rapidly absorbed from the lung and distributed throughout the body while there is limited systemic distribution following cutaneous exposure. PMID- 21598173 TI - Semantic organisation and handedness: mixed-handedness is associated with more diffuse activation of ambiguous word associates. AB - Research indicates that there are individual differences in the flexibility and ease with which one retrieves and uses concepts stored in memory. Based on prior research suggesting that mixed-handedness is associated with greater cognitive flexibility, it was hypothesised that mixed-handers have access to a relatively diffuse associative network, where link strengths for closely related and distantly related concepts are not as disparate as in the case of strong-handers. This idea was explored using ambiguous words for stimuli, as ambiguous words are known to have both strong (concepts related via dominant meaning) and weak associates (concepts related via subordinate meaning). Consistent with the prediction, mixed-handers showed equal ease in accessing both strongly and weakly related concepts. In Experiment 1 mixed-handers exhibited equivalent priming for dominant and subordinate associates, while strong-handers exhibited priming for dominant associates only. In Experiment 2 ratings of strength of association for dominant versus subordinate associates were examined. Mixed-handedness was associated with lesser disparity of dominant and subordinate association ratings. PMID- 21598174 TI - Physico-chemical comparison of betulinic acid, betulin and birch bark extract and in vitro investigation of their cytotoxic effects towards skin epidermoid carcinoma (A431), breast carcinoma (MCF7) and cervix adenocarcinoma (HeLa) cell lines. AB - Betulin and betulinic acid are pentacyclic triterpenes present in the bark of the birch tree and other vegetal sources. Quantitatively, in birch bark betulin is more significant than betulinic acid; therefore, birch can be a large and feasible source of raw material for betulin extraction. Betulin can be used as extracted or, after chemical modification, as a starting compound for its acid, betulinic acid, with both substances possessing various interesting pharmacological properties. The purpose of this study is to analyse the betulin and betulinic acid content of a birch tree bark extract, as well as its cytotoxic activity. The extraction was done using a Soxhlet extractor and chloroform/dichlormethane/methanol (1 : 1 : 1) as solvent. The betulin and betulinic acid content of the extract was estimated using standards of pure betulin and betulinic acid, by thermal analysis as opposed to pure substance (thermogravimetric and differential thermal analysis). The extract and the main compounds were also analysed by NMR. The results indicated a high amount of betulin in the final extract (up to 50%), and an important quantity of betulinic acid: over 3%. The cytotoxic activity indicated a high proliferation inhibition for the birch tree extract but was still comparable with betulinic acid and betulin. PMID- 21598175 TI - The appearance of new phantom fingers post-amputation in a phocomelus. AB - We report the unusual case of a woman with right upper limb phocomelia who, post amputation of her right hand following trauma, sprouted a phantom hand that contained five digits, including a phantom thumb and index finger that had been absent since her birth. These two phantom digits were initially half normal size, however, more than three decades later, with mirror visual feedback treatment, she was able to elongate them to normal length. This suggests that a hardwired representation of a complete hand had always been present in her brain, but inhibited by the presence of afferents from the phocomelic hand. Amputation of the phocomelic hand then led to disinhibition of this dormant representation, and the emergence of a phantom hand with five fingers, which was then further enhanced by false visual feedback from a mirror. The case powerfully demonstrates the interaction of nature and nurture in creating and sustaining body image. PMID- 21598176 TI - Nonverbal and verbal learning: a comparative study of children and adolescents with 22q11 deletion syndrome, non-syndromal Nonverbal Learning Disorder and memory disorder. AB - The 22q11 deletion syndrome (DS) is a common genetic disorder, and a Nonverbal Learning Disorder (NLD) is considered as a predominant part of the phenotype. The focus of our study was to investigate the role of learning in this NLD characteristic. We compared results of children and adolescents with 22q11 DS; with non-syndromal NLD and with memory disorders on multi-trial verbal and nonverbal learning tests. Better verbal and worse nonverbal IQs were significantly discrepant for the 22q11 DS sample and for the NLD sample; the memory sample had a FS-IQ in the normal range with lower verbal IQ. General IQ was lowest for the 22q11 DS group. Similar differences in normal verbal and worse nonverbal learning resulted for the 22q11 sample and NLD-sample, while memory sample showed low performances on both tasks. Error analysis in the visual learning task indicated that lacking integration of visual-spatial information affected impaired visual memory performances in 22q11 DS and NLD. Our results reflected a common neurological basis with visual-spatial and visual memory deficits in NLD and in the 22q11 DS sample. To further investigate the issue of cross modal novelty learning deficits we recommend the use of abstract verbal learning material. PMID- 21598177 TI - Specialty supplements and prostate cancer risk in the VITamins and Lifestyle (VITAL) cohort. AB - Although there is evidence from studies of prostate cancer cell lines and rodent models that several supplements may have antiinflammatory, antioxidant, or other anticancer properties, few epidemiologic studies have examined the association between nonvitamin, nonmineral, "specialty" supplement use and prostate cancer risk. Participants, 50-76 yr, were 35,239 male members of the VITamins and Lifestyle (VITAL) cohort who were residents of western Washington state, and who completed an extensive baseline questionnaire in 2000-2002. Participants responded about their frequency (days/wk) and duration (yr) of specialty supplement uses. 1,602 incident invasive prostate cancers were obtained from the Surveillance, Epidemiology, and End Results registry. Multivariate-adjusted hazards ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazards models. Any use of grapeseed supplements was associated with a 41% (HR 0.59, 95% CI: 0.40-0.86) reduced risk of total prostate cancer. There were no associations for use of chondroitin, coenzyme Q10, fish oil, garlic, ginkgo biloba, ginseng, glucosamine, or saw palmetto. Grapeseed may be a potential chemopreventive agent; however, as current evidence is limited, it should not yet be promoted for prevention of prostate cancer. PMID- 21598178 TI - Colorectal polyp type and the association with charred meat consumption, smoking, and microsomal epoxide hydrolase polymorphisms. AB - We determined the association between charred meat consumption, cigarette smoking, microsomal epoxide hydrolase (mEH) polymorphisms (rs1051740 and rs2234922), and colorectal adenomas and hyperplastic polyps (HPs) and explored gene-environment interactions. Men and women with colorectal adenomas (n = 519), HPs (n = 691), or concurrently with both types of polyps (n = 227) and polyp-free controls (n = 772) receiving a colonoscopy from December 2004 to September 2007 were recruited. Participants completed telephone interviews and provided buccal cell samples; genotyping of mEH was completed using Taqman assays. We conducted polytomous regression and calculated odd ratios (OR) and 95% confidence intervals. Interactions were evaluated using Wald chi-square tests. Consumption of >3 servings of charred meat per week was associated with distal HPs (OR = 2.0, 1.2-3.4) but not adenomas nor either type of proximal polyp. Heavy cigarette smoking (>= 22 pack-years) was associated with an increased risk for colorectal adenomas (OR = 1.7, 95% CI: 1.2-2.4), HPs (OR = 2.4, 95% CI: 1.7-3.3), and both types (OR = 2.8, 95% CI: 1.8-4.3) with the strongest association for distal polyps. There was no association between mEH genotype and colorectal polyps, nor were any statistically significant gene-environment interactions identified. Future investigation of BaP exposure and colorectal neoplasia should analyze whether associations are dependent upon anatomic location. PMID- 21598179 TI - Impact of polyphenol metabolites produced by colonic microbiota on expression of COX-2 and GSTT2 in human colon cells (LT97). AB - Polyphenols may play an important role in colon cancer prevention. After entering the colon, they are subjected to metabolism by the human gut microbiota. The objective of the present study was to analyze the impact of selected intestinal metabolites on modulation of enzymes involved in detoxification and inflammation in human adenoma cells LT97. LT97 cells were incubated with 3,4 dihydroxyphenylacetic acid (ES) and 3-(3,4-dihydroxyphenyl)-propionic acid (PS), metabolites of quercetin and chlorogenic acid/caffeic acid, respectively. The effect on cell number was analyzed using 4'- 6-diamino-2-phenylindole dihydrochloride (DAPI)-staining. Modulation of glutathione S-transferase T2 (GSTT2) and cyclooxygenase-2 (COX-2) was measured by real-time PCR and Western blot. Comet assay was performed to assess the impact on DNA damage caused by the GSTT2 substrate cumene hydroperoxide (CumOOH). Polyphenol metabolites did not affect cell number but significantly upregulated GSTT2 expression and decreased COX-2. The latter was confirmed via Western blot. CumOOH-induced DNA damage was significantly reduced compared to the control. An upregulation of GSTT2 and downregulation of COX-2 could possibly contribute to the chemopreventive potential of polyphenols after degradation in the gut. Working with polyphenol metabolites is an important prerequisite to better understand the in vivo effects of pure polyphenols. PMID- 21598180 TI - The relationship between self-control and health: The mediating effect of avoidant coping. AB - Trait self-control is related to a number of positive outcomes, including mental health, interpersonal success, academic success and health-related behaviours. This study sought to explore the relationships between self-control, reports of mental and physical health symptoms and coping styles. The results revealed that higher self-control was related to fewer mental and physical health symptoms and less avoidance coping. There was not a significant relationship between self control and problem-focused or emotion-focused coping styles. Further, the relationships between self-control and mental and physical health outcomes were partially mediated by avoidance coping style. Specifically, the data suggest lower self-control is associated with unhealthy coping strategies (avoidance coping), which in turn are associated with worse mental health outcomes and greater reports of physical health symptoms. Thus lower trait self-control can serve as an indicator, suggesting circumstances in which individuals' tendencies to engage in unhealthy coping strategies are increased. These findings add to a growing body of literature underscoring the importance of trait self-control. PMID- 21598181 TI - Support during birth interacts with prior trauma and birth intervention to predict postnatal post-traumatic stress symptoms. AB - BACKGROUND: Many women experience childbirth as traumatic and 2% develop post traumatic stress disorder. This study examined the role of health practitioner support and personal control during birth as predictors of post-traumatic stress (PTS) symptoms, adjusting for vulnerability factors of prior trauma, depression, control beliefs and birth intervention. It also investigated interactions between support, prior trauma and birth intervention and their association with PTS symptoms. METHODS: A prospective longitudinal survey of 138 women recruited from UK NHS maternity clinics. Measures were taken in pregnancy, 3 weeks and 3 months after the birth. RESULTS: Support and control during birth were not predictive of postnatal PTS symptoms. However, support was predictive of PTS symptoms in a subset of women with prior trauma (beta = -0.41, R(2) = 16%) at both 3-weeks and 3-months postpartum. The interaction of birth intervention and support was associated with PTS symptoms 3 months after birth, the relationship between support and PTS symptoms was stronger in women experiencing more intervention. CONCLUSIONS: Low support from health practitioners is predictive of postnatal PTS symptoms in women who have a history of trauma. Longer term effects of low support on postnatal PTS symptoms are also found in women who had more intervention during birth. PMID- 21598182 TI - How social context moderates the self-evaluative emotions experienced due to health risk behaviour. AB - When people are confronted with the potential negative physical outcomes of their own health risk behaviour, they experience a self-threat. This threat is felt as negative self-evaluative emotions. We hypothesise that the threat will lead to more private self-evaluative emotions (e.g. regret) in a private social context, whereas more public self-evaluative emotions (e.g. embarrassment) will be felt in a public social context with negative norms. Consistent with our hypotheses, we show that participants anticipate feeling more private self-evaluative emotions when confronted with the negative consequences of their unhealthy behaviour when alone, and more public self-evaluative emotions when in a group (Study 1). They further anticipate more public self-evaluative emotions in response to a health self-threat when the group norm is negative, and more private self-evaluative emotions when the group norm is lenient (Study 2). Finally, in a cross-sectional study amongst smokers, we show that private but not public negative self evaluative emotions concerning their own smoking habits are positively correlated with the intent to quit smoking (Study 3). These studies show that a distinction needs to be made between public and private self-evaluative emotions, in terms of their antecedents and effects. Theoretical implications and further lines of research are discussed. PMID- 21598183 TI - Water clubs in residential care: is it the water or the club that enhances health and well-being? AB - Recent research suggests that establishing water clubs in care homes can counteract the dangers of dehydration and enhance residents' health and well being. This study provided an experimental test of this idea, and also explored the possibility that it is the social interaction that clubs provide which delivers health-related benefits. Consistent with this hypothesis, the study found no evidence that, on its own, increased focus on water consumption enhanced residents' health or well-being. However, residents who took part in water clubs showed improved levels of perceived social support, and those who participated in water and control clubs showed beneficial outcomes in terms of the number of General Practitioner calls they required. Consistent with a social identity approach to health and well-being, a mediation analysis also indicated that clubs achieve these positive outcomes by providing social support that helps to build a shared sense of social identity among residents. PMID- 21598184 TI - Perceived partner support and psychosexual adjustment to breast cancer. AB - Support from a partner can play a key role in a woman's emotional adjustment to breast cancer. However, little is known about the influence of partner behaviours on a woman's sexual adjustment. This study examined the prospective relationship between baseline levels of several types of perceived partner support (instrumental, informational, emotional and negative) and psychosexual adjustment (sexual functioning and relationship satisfaction) over the course of 12 months post-surgery in a sample of 130 women with breast cancer. Results indicated that perceptions of greater emotional and informational support from the partner at baseline were associated with less sexual difficulties among breast cancer patients concurrently and 6 months post-surgery. Baseline perceptions of greater emotional and instrumental support from a partner were associated with greater relationship satisfaction at all time points. Perceptions of informational support at baseline were related to greater concurrent relationship satisfaction. Baseline perceptions of negative partner support were related to less relationship satisfaction, but only concurrently. These findings suggest that the perception of a partner's provision of emotional, instrumental and informational support may each play a role in facilitating sexual adjustment and relationship satisfaction. PMID- 21598185 TI - Emotion recognition and emotional theory of mind in chronic fatigue syndrome. AB - BACKGROUND: Difficulties with social function have been reported in chronic fatigue syndrome (CFS), but underpinning factors are unknown. Emotion recognition, theory of mind (inference of another's mental state) and 'emotional' theory of mind (eToM) (inference of another's emotional state) are important social abilities, facilitating understanding of others. This study examined emotion recognition and eToM in CFS patients and their relationship to self reported social function. METHODS: CFS patients (n = 45) and healthy controls (HCs; n = 50) completed tasks assessing emotion recognition, basic or advanced eToM (for self and other) and a self-report measure of social function. RESULTS: CFS participants were poorer than HCs at recognising emotion states in the faces of others and at inferring their own emotions. Lower scores on these tasks were associated with poorer self-reported daily and social function. CFS patients demonstrated good eToM and performance on these tasks did not relate to the level of social function. CONCLUSIONS: CFS patients do not have poor eToM, nor does eToM appear to be associated with social functioning in CFS. However, this group of patients experience difficulties in emotion recognition and inferring emotions in themselves and this may impact upon social function. PMID- 21598186 TI - Embodied cognition and skilled health behaviour. AB - The present research examines health persuasion from an embodied cognition perspective by proposing that engaging the motor system during presentation of a health message will lead individuals to become more skilled at performing the prescribed behaviour. Participants watched a video on the importance of flossing while either imaging themselves flossing or imaging themselves flossing while minimally engaging the motor system (i.e. touching a piece of floss). Females (but not males) who touched an individual floss while watching the video demonstrated better flossing skills 1 week later. Over time, participants (both males and females) who engaged the motor system also developed more accessible attitudes and had a stronger relationship between their perceived flossing efficacy and actual flossing skill. Implications for the theories of embodied cognition and health interventions are discussed. PMID- 21598187 TI - Exploring attentional disruption in fibromyalgia using the attentional blink. AB - Disrupted attentional function in individuals with fibromyalgia syndrome (FMS) has been noted in a number of previous studies. The cognitive mechanisms related to this disruption are not well-understood. This study sought to identify whether differences exist in early attentional processing and attentional capacity in individuals with FMS measuring the attentional blink (AB). Early attentional function was assessed in 16 females with FMS and compared with 16 healthy age matched females without FMS. Simple early visual stimulus target detection accuracy was not significantly different between groups. However, as target detection difficulty increased, individuals in the FMS group showed significantly poorer performance compared to healthy participants. Our findings suggest that attentional disruption in individuals with FMS is associated with deficits in the early allocation of attentional resources during the completion of tasks with higher attentional demand. PMID- 21598188 TI - The persuasive effects of framing messages on fruit and vegetable consumption according to regulatory focus theory. AB - According to Regulatory Focus theory (RFT), outcomes in persuasive messages can be framed in four different ways, as gains, non-gains, losses or non-losses. In study 1, the persuasiveness of all four frames was compared and the presence/absence effect that was expected on the basis of the feature-positive effect was verified: Statements about present outcomes (gain, loss) were more persuasive than those about absent outcomes (non-gain, non-loss). However, this study failed to support the prediction that a gain-framed message would be more persuasive than a loss-framed message when promoting a prevention behaviour. Study 2 was designed to examine the latter finding. It was hypothesised that the threat posed by the loss-framed message in study 1 was too low to elicit a defensive reaction. Therefore, in study 2, the personal relevance of the gain and the loss framed message was manipulated. Consistent with predictions, the gain framed message was more persuasive than the loss-framed message, but only when the message was personalised to increase self-relevance. Moreover, the effect was due to a significant drop in persuasion in the loss condition, probably caused by a defensive reaction. These data shed a new light on the findings of past framing studies. PMID- 21598189 TI - Developing ways to encourage early detection and presentation of oral cancer: what do high-risk individuals think? AB - The aim of this pilot research was to improve understanding of individuals at risk of oral cancer, to determine their attitudes towards and responses to early detection interventions. In-depth interviews with the target group (n = 25) were used to determine their views, attitudes and requirements for an intervention to encourage early detection of oral cancer. This data was used in combination with theory-based constructs to develop written material that aimed to increase awareness of oral cancer, encourage mouth self-examination (MSE) and early presentation. A second pilot study used a think-aloud protocol to assess the target groups' (n = 14) reactions to the written information. In both studies the tape-recorded responses were analysed using framework analysis. The target group had limited knowledge about oral cancer, particularly the signs and symptoms. Participants saw benefits in performing MSE but noted the main barriers were not knowing what signs to look for or where to look. The written information was generally well-received but required some modifications. In particular, the target group required further persuasion that their lifestyle contributed to an increased risk of oral cancer. The results of these pilot studies have informed the development of a theory-based intervention for the early detection of oral cancer. PMID- 21598190 TI - The relative role of nicotine dependence and smoking-related cognitions in adolescents' process of smoking cessation. AB - The present study evaluates the role of distinct components of nicotine dependence (craving, withdrawal, behavioural dependence) in comparison to smoking related cognitions (attitudes, perceived social approval, self-efficacy) in adolescent smoking cessation. In the process towards smoking cessation, we distinguish between distinct behavioural transitions, respectively, short-term abstinence, reduction in smoking behaviour and prolonged cessation, to evaluate differences in cessation-related antecedents as a function of varying behavioural outcomes. A total of 850 adolescent smokers (age 14-16) participated in the present study. Smoking behaviour was assessed 1 year after baseline. Results showed that all dependence components had a distinct role in the prediction of behavioural change towards cessation. Furthermore, each behavioural transition was predicted by a distinct set of variables, indicating that contributions of cessation-related factors vary across the course towards cessation. Overall, our findings suggest that smoking-related cognitions are particularly relevant in the initiation of behavioural change, such as short-term abstinence, whereas nicotine dependence, craving in particular, becomes increasingly important in the prediction of maintained behavioural change, such as prolonged cessation. Implications encompass enhanced attention to the multidimensional nature of nicotine dependence and the value of comparing different behavioural outcomes in a comprehensive understanding of cessation-related factors. PMID- 21598191 TI - Attachment relationships and physical activity motivation of college students. AB - This study was designed to assess the link of attachment relationships with physical activity motivation. Potential mediators of this link were examined in a cross-sectional study targeting college student physical activity motivation and behaviour. Participants completed self-reports of attachment relationships (with mother, father and best friend), self-determined motivation for physical activity, physical activity behaviour and the hypothesised mediator variables of perceived competence, autonomy and relatedness. The results provide support for the mediating role of these variables in the association of father attachment with self-determined motivation. Meaningful variance in self-determined motivation for physical activity and physical activity behaviour was explained. Overall, attachment relationships appear to be relevant, albeit modestly, to physical activity motivation of college students. The findings support continued efforts to integrate attachment and motivational perspectives in the study of college student health behaviour. PMID- 21598192 TI - On some novel extended topochemical atom (ETA) parameters for effective encoding of chemical information and modelling of fundamental physicochemical properties. AB - Extended topochemical atom (ETA) indices developed by our group have been extensively applied in our previous reports for toxicity and ecotoxicity modelling in the field of quantitative structure-activity relationships (QSARs). In the present study these indices have been further explored by defining additional novel parameters to model n-octanol-water partition coefficient (two data sets; n = 168 and 139), water solubility (n = 193), molar refractivity (n = 166), and aromatic substituent constants pi, MR, sigma (m), and sigma (p) (n = 99). All the models developed in the present study have undergone rigorous internal and external validation tests and the models have high statistical significance and prediction potential. In terms of Q2 and r2 values the models developed for the datasets of whole molecules are better than those previously reported, with topochemically arrived unique (TAU) indices on the same datasets of chemicals. An attempt has also been made to develop models using non-ETA topological and information indices. Interestingly, ETA and non-ETA models have been found to have similar predictive capacity. PMID- 21598193 TI - CoMFA and CoMSIA analysis of tetrahydroquinolines as potential antimalarial agents. AB - Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used on a dataset of compounds, some of them having been reported to inhibit Plasmodium falciparum protein, farnesyltransferase. The co-crystal structure of the lead molecule, BMS-214662 bound to Rat-PFT was used as a template. CoMFA yielded a good model, with r2(ncv) = 0.909, r2(cv) = 0.617 and was validated using an external set r2(pred) = 0.748). It compared favourably with CoMSIA. In the CoMFA model the steric and electrostatic fields exerted an almost equal influence on activity. The contour maps indicated the necessity for sterically large electropositive groups with electronegative tail to be present in these molecules for activity, and sterically large electronegative moieties on the sulfonamide linker. By incorporating these features some new compounds have been identified for further investigation. PMID- 21598194 TI - Androgen receptor binding affinity: a QSAR evaluation. AB - The multiparameter formulation of the COmmon REactivity PAttern (COREPA) approach has been used to describe the structural requirements for eliciting rat androgen receptor (AR) binding affinity, accounting for molecular flexibility. Chemical affinity for AR binding was related to the distances between nucleophilic sites and structural features describing electronic and hydrophobic interactions between the receptor and ligands. Categorical models were derived for each binding affinity range in terms of specific distances, local (maximal donor delocalizability associated with the oxygen atom of the A ring), global nucleophilicity (partial positive surface areas and energy of the highest occupied molecular orbital) and hydrophobicity (log Kow) of the molecules. An integral screening tool for predicting binding affinity to AR was constructed as a battery of models, each associated with different activity bins. The quality of the screening battery of models was assessed using a high value (0.9) of the Pearson contingency coefficient. The predictability of the model was assessed by testing the model performance on external validation sets. A recently developed technique for selection of potential androgenically active chemicals was used to test the performance of the model in its applicability domain. Some of the selected chemicals were tested for AR transcriptional activation. The experimental results confirmed the theoretical predictions. PMID- 21598195 TI - QSAR modelling of integrin antagonists using enhanced Bayesian regularised genetic neural networks. AB - Bayesian regularised genetic neural network (BRGNN) has been used for modelling the inhibition activity of 141 biphenylalanine derivatives as integrin antagonists. Three local pattern search (PS) methods, simulated annealing and threshold acceptance were combined with BRGNN in the form of a hybrid genetic algorithm (HGA). The results obtained revealed that PS is a suitable method for improving the ability of BRGNN to break out from the local minima. The proposed HGA technique is able to retrieve important variables from complex systems and nonlinear search spaces for optimisation. Two models with 8-3-1 artificial neural network (ANN) architectures were developed for describing alpha4beta7 and alpha4beta1 modulatory activities of integrin antagonists. Monte Carlo cross validation was performed to validate the models and Q2 values of 0.75 and 0.74 were obtained for alpha4beta7 and alpha4beta1 inhibitory activities, respectively. The scrambling technique was used for sensitivity analysis of descriptors appearing in ANN models. Frequencies of repetition and sensitivity analysis of molecular descriptors revealed that 3D-Morse descriptors are influential factors for describing alpha4beta7 inhibitory activity, while in the case of alpha4beta1 inhibitory activity, the Randic shape index, the lowest eigenvalue of the Burden matrix and the number of rotatable bonds are important parameters. PMID- 21598196 TI - Using molecular docking to investigate the anti-breast cancer activity of low molecular weight compounds present on wild mushrooms. AB - Mushrooms represent an unlimited source of compounds with anti-tumour and immunostimulating properties, and their intake has been shown to reduce the risk of breast cancer. A large number of low molecular weight (LMW) compounds present in mushrooms have been identified, including phenolic acids, flavonoids, tocopherols, carotenoids, sugars and fatty acids. In order to evaluate which wild mushroom LMW compounds may be involved in anti-breast cancer activity we selected a representative dataset of 43 LMW compounds and performed molecular docking against three known protein targets involved in breast cancer (aromatase, estrone sulfatase and 17beta-HSD-1) using AutoDock4 as docking software. The estimated inhibition constants for all LMW compounds were determined, and the potential structure-activity relationships for the compounds with the best estimated inhibition constants are discussed for each compound family. 4-O-caffeoylquinic, naringin and lycopene stand out as the top-ranked potential inhibitors for aromatase, estrone sulfatase and 17beta-HSD1, respectively, and the 3-D docked conformations for these compounds are discussed in detail. This information provides several interesting starting points for further development of aromatase, estrone sulfatase and 17beta-HSD1 inhibitors. PMID- 21598197 TI - Does the oestrogen receptor encourage oestrogenicity in environmental pollutants? The case of 4-nonylphenol. AB - A computer-aided docking study was conducted to explore in detail the binding interactions between the structurally unlikely environmental oestrogen 4 nonylphenol (4NP) and three of its metabolites with the human oestrogen receptor alpha (hERalpha). Docking was done within the Schrodinger Suite 2008 using both a conventional rigid receptor with flexible ligand and the induced-fit docking protocol. Induced-fit docking allows side-chain and backbone movement in the receptor to accommodate the ligand. This study has revealed unconventional interactions between the ligands and the hERalpha binding pocket that could explain the observed oestrogen-like behaviour of 4NP and suggests some of the metabolites of 4NP may also be oestrogenic. PMID- 21598198 TI - Screening for low aquatic bioaccumulation (2): physico-chemical constraints. AB - Physico-chemical properties related to the bioavailability of xenobiotics in aquatic environments have been tested for their ability to identify chemicals with low bioconcentration potential. Cut-offs in lipophilicity (log K(OW) < 3 or > 10), solubility and volatility (log Henry constant <-11 [atm (mol L(-1))(-1)]), degradability (ready biodegradability, hydrolysis) and ionisation (>5% ionisation at pH 7) have been adopted and combined into a decision tree based on 382 industrial chemicals. The five-parameter classification scheme was externally validated with 49 pesticides and successfully confirmed with 83 bioaccumulative compounds. The applicability domain of the model has been described in terms of chemical classes (excluding polybrominated compounds (>4 Br), organometallics, compounds with perfluorinated fragments, substances with an acyclic alkyl moiety (chain length > C7) and thiols) and ranges of physico-chemical properties. The present tool allows to securely de-prioritize more than 50% chemicals of low concern with regard to the B criterion (BCF < 2000). Bioassays with compounds with these physico-chemical constraints may be waived because testing may be technically not possible and does not appear scientifically necessary in persistent, bioaccumulative, toxic (PBT) substances and risk assessments. PMID- 21598199 TI - Modelling of serotonin reuptake inhibitory and histamine H3antagonistic activity of piperazine and diazepane amides: QSAR rationales for co-optimization of the activity profiles. AB - Selective human serotonin reuptake transporter (hSERT) inhibition is the first line of treatment to deal with the depression. In clinical practice for managing depression, the stimulants are co-prescribed to overcome cognitive impairment and fatigue. Recently, histamine H(3) antagonists with serotonin reuptake inhibition activity have been proposed as alternative approach for the treatment of depression. In this context, a QSAR study of hSERT inhibitory and H(3) antagonistic activity of piperazine and diazepane amide derivatives has been carried out using the combinatorial protocol in multiple linear regression (CP MLR) with 0D- to 2D-Dragon descriptors. The derived QSAR models have provided a rational approach for the development of new piperazine and diazepane amide derivatives as hSERT inhibitors and H(3) antagonists. In a concomitant partial least-squares (PLS) analysis of the hSERT and histamine H(3) activities, the fraction contributions of identified descriptors revealed their importance in modulating these activities. The PLS analysis of other biological endpoints, namely hNET, hDAT, and histamine H(3) activity in functional assay (H(3)pA(2)) of these analogues with the identified descriptors has further highlighted their scope in modulating these activities. PMID- 21598200 TI - Fragment-similarity-based QSAR (FS-QSAR) algorithm for ligand biological activity predictions. AB - Quantitative structure-activity relationship (QSAR) studies are useful computational tools often used in drug discovery research and in many scientific disciplines. In this study, a robust fragment-similarity-based QSAR (FS-QSAR) algorithm was developed to correlate structures with biological activities by integrating fragment-based drug design concept and a multiple linear regression method. Similarity between any pair of training and testing fragments was determined by calculating the difference of lowest or highest eigenvalues of the chemistry space BCUT matrices of corresponding fragments. In addition to the BCUT similarity function, molecular fingerprint Tanimoto coefficient (Tc) similarity function was also used as an alternative for comparison. For validation studies, the FS-QSAR algorithm was applied to several case studies, including a dataset of COX2 inhibitors and a dataset of cannabinoid CB2 triaryl bis-sulfone antagonist analogues, to build predictive models achieving average coefficient of determination (r(2)) of 0.62 and 0.68, respectively. The developed FS-QSAR method is proved to give more accurate predictions than the traditional and one-nearest neighbour QSAR methods and can be a useful tool in the fragment-based drug discovery for ligand activity prediction. PMID- 21598201 TI - The integration of stimulus dimensions in the perception of music. AB - A central aim of cognitive psychology is to explain how we integrate stimulus dimensions into a unified percept, but how the dimensions of pitch and time combine in the perception of music remains a largely unresolved issue. The goal of this study was to test the effect of varying the degree of conformity to dimensional structure in pitch and time (specifically, tonality and metre) on goodness ratings and classifications of melodies. The pitches and durations of melodies were either presented in their original order, as a reordered sequence, or replaced with random elements. Musically trained and untrained participants (24 each) rated melodic goodness, attending selectively to the dimensions of pitch, time, or both. Also, 24 trained participants classified whether or not the melodies were tonal, metric, or both. Pitch and temporal manipulations always influenced responses, but participants successfully emphasized either dimension in accordance with instructions. Effects of pitch and time were mostly independent for selective attention conditions, but more interactive when evaluating both dimensions. When interactions occurred, the effect of either dimension increased as the other dimension conformed more to its original structure. Relative main effect sizes (| pitch eta(2) - time eta(2) |) predicted the strength of pitch-time interactions (pitch * time eta(2)); interactions were stronger when main effect sizes were more evenly matched. These results have implications for dimensional integration in several domains. Relative main effect size could serve as an indicator of dimensional salience, such that interactions are more likely when dimensions are equally salient. PMID- 21598202 TI - Interference and the representation of order within associations. AB - In the presence of interference, recall of pairs can critically depend on the diagnostic power of memory of the order of items within the pair. Models of pair memory make different assumptions about whether and how such order information is stored, from convolution-based models, which assume no explicit storage of order, to matrix models and several models that assume a pair is learned by concatenating the representations of the constituent items, which lead to perfect within-pair order memory (given retrieval of the pair). Here we investigate memory for associations and within-pair order by examining the relationship between forward and backward probes of pairs subject to order-dependent associative interference in a double-function list paradigm. Associative interference disrupted the high correlation between forward and backward recall accuracy that is typically observed in standard paired-associate learning, challenging matrix and concatenation-based models. However, participants could overcome some interference due to within-pair order ambiguity, challenging directionally ambiguous convolution-based models. Unexpectedly, the test-retest correlation was reduced for pairs under the influence of interference compared to control pairs. This finding is incompatible with all existing implementations of the model classes we consider. Any model must include an assumption that order encoding (but not retrieval) is unreliable, and the form of this additional mechanism may depend intimately on how a given model is designed. In sum, our findings suggest that within-pair order memory is neither poor nor perfect, pointing to a fallible mechanism for within-pair order learning in verbal association-memory tasks. PMID- 21598203 TI - [Clinical manifestation of extravasation caused by infusion and its therapeutic management]. AB - INTRODUCTION: Extravasal application of chemo-therapeutic agents may cause necrosis of surrounding tissue. Often tendons, nerves and muscles are destroyed. In some cases a surgical excision with an additional coverage is indicated. PATIENTS AND METHODS: In the last ten years we have treated 44 patients with necrosis after extravasation. The defects were mostly localised at the hand or distal forearm, but the cubital fossa and the thorax were affected, too. Excision of the infiltrated tissue was performed and the defect covered with local or free flaps, split skin graft or primary closure. RESULTS: In nearly all cases a stable coverage was achieved. An amputation of the hand was never necessary. Patients with immunosuppression or comorbidity sometimes had wound-healing difficulties that in some cases necessitated further operations. Serious complications were in one case a flap necrosis and another patient died 2 days after the operation because of his nephrotic syndrome. CONCLUSION: Chemotherapy extravasation is an important oncological complication that may cause permanent functional disability of the anatomic region. A variety of free and local flaps with tolerable donor site morbidity can be used for -coverage. We prefer a two-step procedure with radical resection of the area and conditioning of the wound with vacuum therapy or temporary wound coverage and in the next step the definitive wound closure. Conservative treatment is -often followed by a high rate of complications. Early radical debridement and coverage with an adequate flap offers a cure with good functional results. PMID- 21598204 TI - [Volvulus of the small intestine - diagnostic and therapeutic management of a rare surgical finding in adults demonstrated with an entity-specific modern imaging using impressive CT scan-based video sequence]. PMID- 21598205 TI - [Whiplash and Werther effect: the potential of google insights for search for medical research and public health]. AB - Illness behaviour involves cultural, situational and personal predispositions. World Wide Web search statistics provided by internet applications like Google Insights for Search have the potential to facilitate our research on the distribution of mental disorders, our understanding of both sociocultural imprintings and trends in psychophenomenology and could make a remarkable contribution to medical research and public health. PMID- 21598206 TI - [Neuropsychopharmaca influence the intracellular pH value of central neurons]. AB - The intracellular pH (pHi) of neurons is tightly regulated, mainly by membrane bound transporters acting as acid extruders or acid loaders. Regulation of pHi helps to control neuronal excitability, as increased bioelectric activity moderately lowers pHi and, in the sense of a negative feedback loop, intracellular acidosis mostly reduces neuronal excitability. Moreover, a change of pHi widely influences complex cellular functions. With respect to neuropsychopharmaca, little is known about whether or not they may affect neuronal H ( + )-homeostasis. To this aim, we tested several antipsychotics, antidepressants, anticonvulsants, and lithium for effects on neuronal pHi, using guinea pig hippocampal slice preparations in which CA 3 pyramidal neurons were loaded with the pHi-sensitive dye BCECF-AM. All antipsychotics, most antidepressants and about half of the anticonvulsants tested so far elicited reversible changes of neuronal pHi when applied at therapeutic and supratherapeutic concentrations. Although these results await confirmatory in vivo experiments, we believe that the pHi activity of neuropsychopharmaca needs further attention, especially when therapeutic mechanisms or even harmful side effects are discussed. PMID- 21598207 TI - [Efficacy of an occupational group therapy in degenerative dementias: a controlled study in the nursing home setting]. AB - OBJECTIVE: We investigated the effectiveness of an occupational group therapy, tailored to dementia patients, performed regularly 6 days a week, on everyday practical capabilities and dementia-related behavior. METHODS: Fifty-six dementia patients in one nursing home in Northern Bavaria (Germany) were observed for 6 months: 28 patients in a therapy group and 28 patients in a matched controlled group. Performance tests, ADAS-kog and E-ADL-Test, were carried out blinded. Data were analyzed using adjusted mean differences for baseline and 6-months follow-up data and multiple regression analysis. RESULTS: The therapy leads to stabilization of everyday-practical capabilities (adjusted mean difference 4.0; 95 % CI 1.6-6.3; p = 0.002) and of dementia-related behavior (adjusted mean difference -6.8; 95 % CI -11.8--1.8; p = 0.009) compared to deterioration in the control group who received treatment as usual. The effect power (Cohen d) on everyday-practical capabilities is |0.83|. The therapy had no significant effect on cognitive capacity. CONCLUSIONS: An occupational therapy program directed particularly to everyday-practical activities cannot slow the progression of all dementia-related symptoms, but has a main target effect on everyday-practical capabilities. PMID- 21598208 TI - [Psychiatric basic documentation in practice: how reliable is the data?]. AB - OBJECTIVES: To assess the quality of data recorded using a modified version of the German Psychiatric Basic Documentation (BADO) and to use this assessment as the basis for the development of a short version of the BADO. METHODS: BADO codings of a random sample of 200 admitted cases in 2007 were compared to information retrieved from computer-based records for the same patients. RESULTS: In general, the quality of data recorded using the BADO was good, particularly in terms of the accuracy and the completeness of the data. However, a comparative analysis of the data suggests that ambiguities in the coding of particular BADO items might reduce their sensitivity and precision. CONCLUSIONS: Data recorded using the BADO is fit for the purposes of quality management and, with some limitations, for research applications. The short version of the BADO developed using the results of the evaluation, significantly enhances its user-friendliness and increases the reliability of the coded data. PMID- 21598209 TI - ["In psychiatry, nothing more degrading can happen to you"]. AB - OBJECTIVE The subjective view of psychiatric patients on mechanical restraint is to be examined and the necessity of dealing with this issue consciously is to be pointed out. METHODS 14 patients, who experienced mechanical restraint during a stay in a psychiatric hospital, were questioned in a problem-centered, semi structured interview. Data analysis was based on inductive category formation, using Mayring's qualitative content analysis. RESULTS Mechanical restraint is primarily experienced as stressful or traumatizing. Patients complain about a lack of information, support and response when referring to mechanical restraint. CONCLUSION Reports of patients who have experienced coercive measures should be increasingly integrated into clinical practice. PMID- 21598210 TI - [Validity of the geriatric depression scale in nursing home residents: comparison of GDS-15, GDS-8, and GDS-4]. AB - OBJECTIVE: To assess and compare the validity of the German 15-item version and shortened versions of the Geriatric Depression Scale (GDS) for early detection of depression in nursing home residents with mild to moderate cognitive impairment (MMSE >= 15). METHODS: Data from 92 patients were analysed. The Structural Clinical Interview for DSM-IV (SCID) was used as the gold standard. The diagnoses covered in this assessment were current major depression (MD) and minor depression (MinD). The performance of the GDS scales was evaluated using receiver operating characteristics (ROC). Main outcome measures were AUC (area under curve) values, as well as sensitivity and specificity. RESULTS: Overall diagnostic validity of the GDS-15 was better for MD than for MinD (AUC: 89.7 % and 73.4 %, respectively). In assessing MD, AUC values as well as sensitivity and specificity were comparable for the GDS-15 and the GDS-8. A cut-off point >= 5 on the GDS-8 gave optimum performance (sensitivity: 76.9 %, specificity: 88.6 %). For the best cut-off point >= 2, the corresponding values of the GDS-4 were 53.8 % and 92.4 %. CONCLUSIONS: The GDS-8 appears to be a less time-consuming alternative for the nursing home setting. However, the GDS-4 is not suitable for this population. PMID- 21598212 TI - TP53 codon 72 polymorphism and P53 protein expression in colorectal cancer specimens in Isfahan. AB - The TP53 tumor suppressor gene plays important roles in genomic stability. A common polymorphism at codon 72 of TP53 gene has been associated with increased risk for many human cancers. The p53 protein is expressed in colorectal cancer, but the reported prevalence of its expression varies widely. In the present study, the p53 protein expression in different genotypes of its codon 72 , was investigated. We undertook a case-control study on 250 controls and 250 paraffin block specimens of sporadic colorectal adenocarcinomas from the city of Isfahan. PCR amplification of TP53 codon 72 polymorphism: TP53 codon 72 genotypes were detected by PCR using specific primer pairs for amplifying the proline or the arginine Alleles. The PCR reaction was done separately for each of the two polymorphic variants. The amplified products were subjected to electrophoresis on 1% agarose gel in 1* TBE buffer and visualized on a transilluminator using ethidium bromide. Immunohistochemical Staining: We evaluated the expression patterns of p53 protein, as potential prognostic marker in colorectal cancer specimens by immunohistochemical staining. STATISTICAL ANALYSES: The chi2-test was used to assess the significance of any difference in the prevalence of TP53 codon 72 polymorphism between colorectal cancer patients and controls. The odds ratio and 95% CI (confidence intervals) was used as a measure of the strength of the association. Statistical significance level was set to P<=0.05. In control samples, the genotype distribution for TP53 polymorphism showed 30.4%, 45.2% and 24.4% for the arginine/arginine, arginine/proline and proline/proline genotypes, respectively. Allelic frequencies corresponded to 0.663 for the arginine allele and 0.338 for the proline allele. In the cancer group 38.8% of the cases were arginine/arginine, 40.4% were arginine/proline and 20.8% were proline/proline. The corresponding frequencies were 0.590 for the arginine allele and 0.410 for the proline allele. A significant difference between cases and controls was found for the arginine/arginine genotype compared with (grouped) arginine/proline and proline/proline genotypes (Odds Ratio = 1.451 (1.002-2.103), P=0.048). Overexpression of p53 was observed in 50.8 percent of cancer specimens which most of them were arginine/arginine genotype (P<0.001). TP53 polymorphism and arginine/arginine genotype may be correlated with overexpression of p53 and increased risk for colorectal cancer in city of Isfahan. PMID- 21598213 TI - An evidence against the effect of chronic cytomegalovirus infection in unstable angina pectoris. AB - Recent reports have suggested that cytomegalovirus (CMV) infection may contribute to risk of cardiovascular disease. However, relationship between CMV infection and unstable angina (UA) is controversial and studies about this subject in Iran and even region are lacking. The aim of this study was to determine whether unstable angina is related to seropositivity to chronic cytomegalovirus infection. We measured serum CMV IgG levels in a case control study participants in CCU in Razi Hospital, Ahvaz, Iran, from 2004 to 2005. Blood samples were drawn during study period from 96 patients (mean age 56 years) with UA according to American Heart Association Criteria and from 96 participants free of cardiovascular disease (mean age 58 years) and stored at -20 degrees C. Blood samples of patients were undertaken for investigating the specific anti CMV-IgG by ELISA method. Data were analyzed in SPSS 11.5 by using chi square test, odds ratios (OR) with 95% confidence intervals (CI). Ninety three percent of patients with unstable angina and 96.7% in the control group presented a positive anti CMV IgG. Odds ratio was 0.52 with 95% CI: 0.10 to 2.42. There was no significant correlation between CMV-IgG positivity and unstable angina (P>0.05). There was also no differences in CMV-IgG positivity in clinical groups of UA (P>0.05). The relationship between seropositivity of CMV-IgG and unstable angina has been restituted by the results of this study. However, further population based cohort studies for relationship between CMV infection and coronary artery disease must be conducted. PMID- 21598214 TI - Random urine protein creatinine ratio as a preadmission test in hypertensive pregnancies with urinary protein creatinine ratio. AB - To evaluate the value of random urinary protein creatinine ratio in prediction of 24h proteinuria in hypertensive pregnancies. METHOD: Random urine samples and routine 24h urine collections were collected from hypertensive pregnant women (n=100). Reliability of random urinary protein-creatinine ratio was assessed by receiver operator characteristic (ROC) curve to detect significant proteinuria (>=300mg/day) using 24h. Urine protein as a gold standard. Forty six patients (46%) had significant proteinuria. The random protein creatinine ratio was correlated to 24h urine protein excretion (r(2)=0.777, P<0.001) Area under ROC curve to predict proteinuria was 0.926 (95% CI: 0.854-0.995, P<0.001). A cut off value of 0.22mg/mg for protein creatinine ratio best predicted significant proteinuria with sensitivity, specificity, positive and negative predictive values of 87%, 92.6%, 90.6% and 89.3% respectively. Random urinary protein creatinine ratio is a simple inexpensive and excellent alternative to 24h urine collection. It's helpful in diagnosis of preeclampsia and can be used as a pre admission test in PIH cases. PMID- 21598215 TI - FNA diagnostic value in patients with neck masses in two teaching hospitals in Iran. AB - The FNA (fine needle aspiration) procedure is simple, inexpensive, available and a safe method for the diagnosis of a neck mass. FNA has numerous advantages over open surgical biopsies as an initial diagnostic tool; therefore we decided to compare the accuracy of this method with open biopsy. This retrospective as well as descriptive study comparing preoperative FNA results with existing data in the Pathology Department in Bu-Ali and Amir Alam Hospitals. Our study included 100 patients with neck masses of which 22 were thyroid masses, 31 were salivary gland masses, and 47 were other masses. Age ranged from 3 years to 80 years with the mean age of 42.6 years. There were 59 men and 41 women. The Sensitivity was 72%, Specificity 87%, PPV 85%, NPV 75% and diagnostic Accuracy 79%. In this study we had also 26% false negative and 15% false positive. FNA is a valuable diagnostic tool in the management of neck masses; also it has been used for staging and planning of treatment for the wide and metastatic malignancy. This technique reduces the need for more invasive and costly procedures. According to the high sensitivity and high accuracy in this study, FNA can be used as the first step of diagnoses test in neck masses. PMID- 21598216 TI - Relation between preoperative mild increased in serum creatinine level and early outcomes after coronary artery bypass grafting. AB - This study evaluates the effect of preoperative increased level of serum creatinine (Cr) on early outcomes after coronary artery bypass graft surgery (CABG). 1140 patients who underwent CABG in our center were studied. Patients with Cr >2.25 mg/dl or preoperative dialysis and who had off-pump operations were excluded. Group 1 consisted of 892 patients with normal Cr (0.5-1.2 mg/dl) and group 2 consisted of 248 (21.8%) patients with mild increased level of serum Cr (1.3-2.2 mg/dl). Patients in group 1 were younger than group 2. There were more patients with hypertension in group 2, but there were not statistically significant difference between two groups in terms of the frequency of diabetes, smoking, cerebrovascular disease and New York Heart Association (NYHA) class. Left ventricular ejection fraction (LVEF) was lower in group 2. Cardiopulmonary bypass time (CPB) was longer in group 2. Early mortality was 3.2% in group 1 and 8.4% in group 2 (P<0.001). Prolonged ICU stay, low cardiac output, prolonged mechanical ventilation, postoperative atrial fibrillation, postoperative re exploration and sepsis were more frequent in group 2. Mild increase in serum Cr level preoperatively is a marker of increased early mortality and outcome after CABG. PMID- 21598217 TI - The relationship between thyroxine level and short term clinical outcome among sick newborn infants. AB - Premature and critically sick infants frequently experience several interventions, including blood transfusions, parentral nutrition, and prescriptions during hospitalization that could affect the result of thyroid function test. This study aims to investigate the correlation between thyroxine level and clinical short term outcome among the newborn infants in the neonatal intensive care unit (NICU). We assessed serum levels of thyroxine and thyroid stimulating hormone of 99 neonates who were admitted in the NICU from September 1(st) 2004 to March 30(th) 2005. Number of patients with low thyroxin level (less than 6.5 ug/dl) was determined and the relation between serum total thyroxine level and birth weight, gestational age, duration of hospitalization, clinical diagnosis, and final outcome was investigated. Short term outcome was considered as duration of hospitalization and discharge alive from hospital. Prevalence of hypothyroxinemia was 26 percent. Later assessment of thyroxine level within 3 weeks revealed normal level of this parameter (8.12 ug/dl +/-1.36). Patients with lower gestational age and lower birth weight had lower thyroxine level (7.15 ug/dl +/-2.56, and P=0.03, 6.72 ug/dl +/-3.03, and P=0.08). Low thyroxine level was not associated with adverse short-term clinical outcome (mortality rates; 3(11%) and 9(12%), and duration of hospitalization among 17.7+/-9.8 vs 16.7+/- 13.0 in patients with hypothyroxinemia and low thyroxine level respectively). Hypothyroxinemia has considerable prevalence in neonatal intensive care setting and is related with lower birth weight and gestational age. Whether thyroxin levels are a marker or mediator of short term clinical outcome remains to be determined by further studies. PMID- 21598218 TI - Pulmonary adverse effects of welding fume in automobile assembly welders. AB - Welding is one of the key components of numerous manufacturing industries, which has potential physical and chemical health hazards. Many components of welding fumes can potentially affect the lung function. This study investigates the effects of welding fumes on lung function and respiratory symptoms among welders of an automobile manufacturing plant in Iran. This historical cohort study assesses 43 male welders and 129 office workers by a questionnaire to record demographic data, smoking habits, work history and respiratory symptoms as well as lung function status by spirometry. The average pulmonary function values of welders were lower relative to controls with dose-effect relationship between work duration and pulmonary function impairment. The prevalence of chronic bronchitis was higher in welders than controls. Our findings suggest that welders are at risk for pulmonary disease. PMID- 21598219 TI - Growth status of Iranian children with hemodynamically important congenital heart disease. AB - The relationship between congenital heart disease (CHD) and growth retardation is well documented. We investigated the growth condition of Iranian children with several types of congenital heart disease (CHD) and compared it with worldwide researches. Growth condition was investigated in 469 patients with important CHD aged from 1 month to 18 years. The patients were divided into two groups; infants (aged 12 months or less), and children (1-18 yrs of age). Children with hemodynamically unimportant small VSDs or small ASDs were not studied. Other exclusion criteria were prematurity, known genetic disorders and neurologic disease affecting growth. All patients' cardiac diagnoses were made on the basis of clinical and laboratory examinations; including electrocardiography, echocardiography, cardiac catheterization, and angiography. Body weight and height of all patients were measured using conventional methods and compared with standard growth charts. In all patients body weights and heights were significantly lower than normal population. This difference was greater in the weight of female children. Other risk factors for growth failure were large left to-right intracardiac shunts, pulmonary hypertension and cyanosis. Iranian children with CHD have growth failure somewhat different from other countries. Lower body weights of cyanotic patients and female children indicated that these patients need more nutritional and psychosocial attention. PMID- 21598220 TI - Hearing status in neonatal hyperbilirubinemia by auditory brain stem evoked response and transient evoked otoacoustic emission. AB - Hyperbilirubinemia at neonatal period is one of the major deteriorating factors of the auditory system. If left untreated, it may cause certain cerebral damage. This study aims to evaluate the impact of hyperbilirubinemia on the hearing of neonate. This study was conducted on 35 newborn babies with jaundice (bilirubin more than 20 mg/dL). Auditory brainstem response (ABR) and transient evoked otoacoustic emission (TEOAE) tests were performed, after treatment and one year after. ABR test results indicated that 26 children (74.3%) had normal hearing but 9 (25.7%) suffered from an impairment. As for TEOAE test, 30 children (85.7%) passed whereas the remaining (14.3%) seemed to be failures. The comparative results of the two tests pointed to autonomic neuropathy /autonomic dysreflexia symptoms in 5 babies. Due to the high incidence of autonomic neuropathy/autonomic dysreflexia among hyperbilirubinemic babies, screening in this regard seems reasonable. Our result emphasizes the necessity of more experiments on the afflicted areas. PMID- 21598221 TI - Diabetic ketoacidosis and its complications among children. AB - In order to recognize of DKA and its complications among children with DM type I, we conducted a descriptive study and all of the children with the final diagnosis of DKA. Data regarding their demographics, disease characteristics, treatment features and outcome derived from patients' medical files and registered in a data sheet. Data were analyzed using SPSS 11.0 and exhibited in the form of frequency tables and charts. There were 33 females and 30 males (53.1% and 46.9%, respectively). They were involved with ketoacidosis most commonly in summer (42.2%). Autumn, winter and spring seasons were in the next turns (29.7%, 15.6%, and 12.5%, respectively). Data analysis showed a clear improvement in the time taken to correct the acidosis with respect to the date of admission (more than 40 hours in the initial year to less than 28 hours at the final year). It seems that the management of diabetic ketoacidosis has improved during recent years. We concluded to consider ketoacidosis even in the first admission of a diabetic child. PMID- 21598222 TI - Metastatic brain tumors: a retrospective review in East Azarbyjan (Tabriz). AB - A set of one hundred and twenty nine patients with known primary malignancy and suspected brain metastasis was reviewed in present study. The patients were selected among patients presented to the MRI section of Imam Khomeini Hospital or a private MRI center in Tabriz (Iran). Primary tumor site, clinical manifestations, number and site of lesions were identified in this patient population. The primary tumor site was breast in 55 patients (42.6%), followed by lung (40.3%), kidney (7.7%), colorectal (4.6%), lymphoma (3.1%) and melanoma (1.5%). Most patients were presented with features of increased intracranial pressure (headaches and vomiting), seizures and focal neurologic signs. Single brain metastasis occurred in 16.3% of patients, while multiple lesions accounted for 83.7% of patients. Ninety seven patients had supratentorial metastases (75.2%). Twenty cases (15.5%) had metastases in both compartments. Infratentorial lesions were observed only in twelve patients (9.3%). PMID- 21598223 TI - Huge myxoid liposarcoma of the esophagus: a case report. AB - Although esophageal liposarcoma is an extremely rare tumor, liposarcoma is the most common soft tissue sarcoma in adults. Liposarcoma is currently classified into the types of well-differentiated, myxoid, round cell, pleomorphic and dedifferentiated liposarcoma. Up to now only a few cases of esophagus liposarcoma have been described in the world literature. We describe a myxoid type liposarcoma of the esophagus in a 68 year old man presented with hoarseness and intermittent dysphagea to solid food. He had a huge mass in his mouth which was mobile with gag reflex. A barium swallow, esophageal manometery and CT scan of the esophagus have not clearly revealed the mass. After endoscopic surgical resection of the tumor the histological examination revealed a myxoid liposarcoma. Both the presenting signs and symptoms and the histology type are rare for such tumor. This case demonstrate a rare differential diagnosis of intermittent dysphagia as early diagnosis is so important in those tumors and should kept in mind them, although they are quite rare. PMID- 21598224 TI - Stopping insulin and achieving a good metabolic control in a heavy drinker five months after stopping alcohol. AB - In this case study, we describe a 25 year-old male who showed the symptoms of diabetes after a period of heavy drinking. (HbA1c=13%). Treatment was started with 120 units of insulin. After stopping alcohol consumption and taking an appropriate diet, insulin was tapered down. Five months after the start of treatment, insulin was stopped (HbA1c=5%). The results showed that he was in a good metabolic control after 18 months (HbA1c=5.9%). PMID- 21598225 TI - Tuberculosis of the breast: a case report. AB - Primary tuberculosis of the breast is a rare disease. It usually occurs in female of reproductive age. Any form of tuberculosis mastitis may present with feature of malignancy. Diagnosis is mainly based on identification of tubercle bacilli. We report a 42-year-old woman with primary tuberculosis abscess of the breast, who underwent surgical resection. Fine needle biopsy failed to achieve specific diagnosis before surgical operation. She responded to anti-TB therapy postoperatively. In endemic area, tuberculosis should be considered in the differential diagnosis of breast tumors. PMID- 21598226 TI - Preparation and quality control of 177Lu-[tris(1,10-phenanthroline) lutetium(III)] complex for therapy. AB - The 177Lu-[tris(1,10-phenanthroline)lutetium(III)] complex (177Lu-PQ3) was prepared successfully with high radiochemical purity (> 99%). Lu-177 chloride was obtained by thermal neutron flux (4 * 1013 n.cm-2.s-1) of natural Lu2(NO3)3 sample, dissolved in acidic media. The radiochemical yield was checked by measuring the radiochemical purity of the (177)Lu-PQ complex by ITLC (10 mM DTPA, pH = 5, as mobile phase). The final complex solution was injected intravenously into wild-type male rats and bio-distribution of the complex was checked for up to 48 hours. The dose limiting organs were shown to be the reticulu-endothelial system. The bio-distribution of the labelled compounds in tumour-bearing animals is under investigation. PMID- 21598227 TI - Biokinetics of 131I after endogenous and exogenous stimulation of TSH in patients with DTC. AB - BACKGROUND: The effective radioiodine treatment of patients with DTC is possible only after raising the TSH value over 30 MUUI/ml. This effect might be obtained by either endogenous or exogenous stimulation. The aim of this study was to evaluate differences in (131)I biokinetics of selected regions of interest (ROIs) in cases of endogenous and exogenous stimulation. MATERIAL AND METHODS: Two groups of 50 patients were enrolled in the study. All patients were treated with 3.7 GBq of 131I; the first group after thyroid hormone withdrawal (THW), the second group after rhTSH administration (rhTSH). On the basis of post-treatment images, the uptake ratios over selected ROIs (thyroid remnants, mediastinum, liver, stomach, abdomen, and whole-body) were compared between groups. RESULTS: In the case of uptake over the whole-body and the liver, statistically significant higher values were received for the THW group. For the remaining regions, the differences between groups were statistically insignificant, but uptake ratios in the rhTSH group were generally numerically lower compared to the THW group. CONCLUSIONS: The revealed difference in radioiodine biokinetics after thyroid hormone withdrawal or administration of recombinant human TSH may influence many important aspects of patients with DTC treatment, such as the choice of proper therapeutic scheme, the cost of therapy, and the dose assessment. PMID- 21598228 TI - The value of the Duke Activity Status Index (DASI) in predicting ischaemia in myocardial perfusion scintigraphy - a prospective study. AB - BACKGROUND: Functional capacity assessment may be a useful tool to stratify patients according to risk of coronary artery disease (CAD). The Duke Activity Status Index (DASI) is a functional assessment based on activities of daily living and cardiovascular fitness, assessed using a self-administered questionnaire. MATERIAL AND METHODS: We assessed the relationship between established clinical risk factors for CAD and the DASI with results of myocardial perfusion scintigraphy (MPS). The MPS results used in the analysis were the presence of reversible ischaemia and the resting left ventricular ejection fraction (LVEF). A DASI self-administered questionnaire was completed by 117 consecutive participants, and a patient history was taken to ascertain established risk factors. All participants underwent a stress test, and myocardial perfusion scintigraphy was performed. Statistical analysis consisted of logistic and linear regression using a statistical software package. RESULTS: The DASI was the only factor that correlated significantly with reversible ischaemia on MPS. None of the previously established risk factors had a significant association with reversible ischaemia within the model. Our study found a potential relationship between the DASI score and the left ventricular ejection fraction (LVEF) although this was not statistically significant. CONCLUSIONS: Our study findings suggest that the DASI may represent a powerful tool for risk stratification prior to investigation of CAD. A further study with a larger sample size will be required to investigate the predictive value of the DASI and the association with LVEF. PMID- 21598229 TI - The effect of image translation table on diagnostic efficacy of myocardial perfusion SPECT studies. AB - BACKGROUND: The aim of this study was to determine which of the most popular colour scales used in the Xeleris processing system (GE) should preferably be used during a clinical interpretation of myocardial perfusion images, and to find out whether a colour scale saturation level affects the diagnostic efficacy of the study. MATERIAL AND METHODS: From among 100 patients in whom a myocardial perfusion scintigraphy had been performed, a subgroup of people referred for coronary angiography, with neither prior history nor ECG signs of a myocardial infarction has been selected retrospectively. This group consisted of 41 patients (14 females) in the age group 46 to 76 years. All patients underwent two-day myocardial perfusion SPECT imaging using 99mTc-MIBI as a radiopharmaceutical. Reconstructed slices were interpreted in 3 colour scales: white-red-yellow-green blue-black with computer-assigned thresholds (French 100%), the same French scale but without a white colour (image maximum set manually to a border value between red and white - French w.w.), and a white-yellow-violet- pink-blue-black scale (GEcolor), by consensus of two experienced nuclear medicine specialists. A semiquantitative method for evaluation of perfusion images was applied, based on myocardium segmentation. Perfusion in each segment was scored using a five-point system. Study interpretation (normal/ abnormal perfusion) was based on summed stress scores (SSS), being equal/above or below a given threshold value. The choice of optimal SSS threshold value was based on sensitivity and specificity of the study in detection of perfusion defects resulting from critical stenoses of main coronary arteries RESULTS: SSS values differed among colour scales (p < 0.00001). The lowest values were obtained for a French 100% scale (mean value = 5.0, SD = 8.0), the highest for French w.w. (mean values = 8.1, SD = 8.7), and for GE colour scale - mean value - 5.6, SD - 7.9. A French 100% scale gave high sensitivity (88%), as well as specificity (83%), but only when a low SSS threshold value of 2, hardly acceptable for study interpreters, was used. When higher threshold values were applied, they compromised the sensitivity of the study. A French w.w. scale with SSS threshold values lower than 3 provided a slightly higher sensitivity (94%), but with a significant reduction in specificity (to values below 50%). Only a threshold value of 4 provided acceptable, but still low specificity (63%) with preserved high sensitivity (88%). At the same time, the scale GE colour provided indices of diagnostic efficacy with the SSS threshold value of 3 as high as a scale French 100% with threshold value of 2. CONCLUSIONS: A French scale (Xeleris, GE) is not the scale of choice for the interpretation of myocardial perfusion SPECT images. It seems that a GE colour scale is better suited for this purpose. SSS threshold values accepted as diagnostic criteria for the detection of myocardial perfusion abnormalities should be suited separately for every translation table. The choice of optimal value should be verified by results of coronary angiography. PMID- 21598230 TI - Detection of melanoma lesions using 131I-IMBA obtained by electrophilic substitution of 131I for metal organic substituent - a preliminary communication. AB - BACKGROUND: Compounds of N-alkylated benzamide derivatives have been the subject of investigations in the last few decades from the standpoint of their possible application for scintigraphic detection of melanoma. Positive results have been observed in studies on biodistribution when using animal models and the compound IMBA (N-(2-diethylaminoethyl)-3-iodo-4-metoxybenzamide). The present study presents preliminary results of scintigraphic studies in patients with documented melanoma metastases, who were administered 131I-IMBA synthesized by modified labelling procedure (electrophilic substitution of radioactive 131I to metal organic substituent). MATERIAL AND METHODS: The study was made in three patients with diagnosed melanoma metastases to tissues and organs. To each patient 111 MBq of 131I-IMBA was intravenously administered and whole body scintigraphy was performed 4 and 24 hours post injection of the radiopharmaceutical. Additionally, after 24 hours, SPECT/CT of selected regions of the body was performed. RESULTS: In 3 patients a total of 20 lesions of increased activity were found (15 were detected previously by other methods, 5 in the head, 4 in thorax, 2 in liver and spleen, 3 in abdomen and 6 in extremities). In the scintigrams performed 4 hours after 131I-IMBA administration, there were found 12 lesions of enhanced accumulation of the radiopharmaceutical. After 24 hours, due to reduction of background activity, there were 8 additional hot lesions detected. The mean activity tumour/background ratio for 20 lesions 4 hours post injection amounted to 1.51 +/- 0.64, and the ratio increased to 2.94 +/- 2.32 24 hours after administration of a radiopharmaceutical. CONCLUSIONS: 131I-IMBA preparation, obtained by a modified labelling procedure, enabled detection of metastatic lesions in the patients. This may indicate that there is a possibility of using radioiodinated IMBA (with 123I or 131I) for diagnosis of melanoma in humans. From our results it follows that scintigraphy should be performed 24 hours post injection. Further studies on diagnostic efficacy (sensitivity and specificity) of the method are necessary. PMID- 21598231 TI - Role of F-18-FDG-PET/CT in restaging of patients affected by gastrointestinal stromal tumours (GIST). AB - BACKGROUND: Gastrointestinal stromal tumours (GISTs) are a subset of mesenchymal tumours that represent the most common mesenchymal neoplasms of the gastrointestinal (GI) tract and account for less than 1% of all gastrointestinal tumours. MATERIAL AND METHODS: We retrospectively evaluated 19 patients (6 females and 13 males; median age: 61 years +/- 15 standard deviation) affected by GIST histologically documented after surgical intervention or biopsy. RESULTS: F18-FDG-PET/CT had identified pathologic uptakes and was considered positive for neoplastic tissue in 10 patients (53%) and negative in 9 (47%), in concordance with radiological findings. CONCLUSIONS: F18-FDG-PET/CT is a feasible, reliable, and accurate method to restage patients affected by previously histologically confirmed GIST, also in the absence of a staging study. PMID- 21598232 TI - The usefulness of sentinel lymph node detection in vulvar cancer - a short communication. AB - BACKGROUND: The sentinel lymph node (SLN) biopsy is a solution for decreasing the extent of surgery with a significant reduction of the incidence of complications without influencing treatment results. MATERIAL AND METHODS: We performed the sentinel lymph node procedure in 24 women with vulvar cancer. In 14 cases, only the blue dye technique was applied, and in 10 cases (99m)Tc-labelled nanocolloid with blue dye was administered simultaneously. The extent of the surgery included radical vulvectomy in 23 patients and a wide local excision in 1 patient. In 15 patients unilateral inguinofemoral lymphadenectomy was performed and in 9 cases bilateral lymphadenectomy. The total number of operated groins was 39. RESULTS: SLNs were detected in 34/39 of operated groins (87.2%). In 4 cases (16.6%) tumour metastases to the lymph nodes were found. In total, 10 metastatic lymph nodes were detected in 9 sentinel-nodes and in 1 non-sentinel node. In three patients the nodal metastases were found only in the sentinel nodes. In one patient the metastases were found in the contralateral groin in two SLNs. There were no false negative sentinel lymph nodes. With the sole use of blue dye, SLNs were found in 79.5% of groins. The additional administration of the radiocolloid improved SLN detection to 88.9% of groins. CONCLUSIONS: The parallel use of the (99m)Tc labelled radiocolloid and blue dye enables high sentinel node detection rates by adequately trained surgeons. PMID- 21598233 TI - Abnormal Tc99m sulesomab in Klippel-Trenaunay syndrome. AB - Tc-99m sulesomab is indicated in bone and joint infection, but reading of scans can be affected by pre-existing conditions. This case report describes a case of Klippel-Trenaunay syndrome (KTS) which results in vascular malformations of one or more limbs. Tc-99m sulesomab imaging demonstrated persistent blood pool activity up to 20 hours post injection. However, despite this, septic arthritis could be identified with confidence in the same limb. PMID- 21598234 TI - F18-FDG-PET/CT in a patient affected by Lynch syndrome. AB - Lynch syndrome (LS) is the most common hereditary syndrome that predisposes patients to colorectal cancer, and it accounts for 2-5% of the total burden of colorectal cancer. We report a case of a 61-year-old female affected by Lynch syndrome who underwent multiple adenocarcinoma resections, studied by F18-FDG PET/CT for 5 years. This case report suggests a potential role of F18-FDG-PET/CT in the evaluation of patients affected by Lynch syndrome. PMID- 21598235 TI - Influenza vaccination responses in human systemic lupus erythematosus: impact of clinical and demographic features. AB - OBJECTIVE: Vaccination against common pathogens, such as influenza, is recommended for patients with systemic lupus erythematosus (SLE) to decrease infections and improve health. However, most reports describing the vaccination response are limited to evaluations of SLE patients with quiescent disease. This study focuses on understanding the clinical, serologic, therapeutic, and demographic factors that influence the response to influenza vaccination in SLE patients with a broad range of disease activity. METHODS: Blood specimens and information on disease activity were collected from 72 patients with SLE, at baseline and at 2, 6, and 12 weeks after influenza vaccination. Influenza specific antibody responses were assessed by determining the total serum antibody concentration (B(max)), relative affinity (K(a)), and level of hemagglutination inhibition in the plasma. Using a cumulative score, the patients were evenly divided into groups of high or low vaccine responders. Autoantibody levels were evaluated at each time point using immunofluorescence tests and standard enzyme linked immunosorbent assays. RESULTS: Compared to high responders, low responders to the vaccine were more likely to have hematologic criteria (P = 0.009), to have more American College of Rheumatology classification criteria for SLE (P = 0.05), and to be receiving concurrent prednisone treatment (P = 0.04). Interestingly, European American patients were more likely to be low responders than were African American patients (P = 0.03). Following vaccination, low responders were more likely to experience disease flares (P = 0.01) and to have increased titers of antinuclear antibodies (P = 0.04). Serum interferon-alpha activity at baseline was significantly higher in patients in whom a flare occurred after vaccination compared to a matched group of patients who did not experience a disease flare (P = 0.04). CONCLUSION: Ancestral background, prednisone treatment, hematologic criteria, and evidence of increased likelihood of disease flares were associated with low antibody responses to influenza vaccination in SLE patients. PMID- 21598236 TI - Long-term survival following delayed presentation and resection of colorectal liver metastases. AB - BACKGROUND: Long-term survival from metastatic colorectal cancer is partly dependent on favourable tumour biology. Large case series have shown improved survival following hepatectomy for colorectal liver metastases (CRLM) in patients diagnosed with metastases more than 12 months after index colorectal surgery (metachronous), compared with those with synchronous metastases. This study investigated whether delayed hepatic resection for CRLM affects long-term survival. METHODS: Consecutive patients undergoing hepatic resection for CRLM in a single centre (1987-2007) were grouped according to the timing of hepatectomy relative to index bowel surgery: less than 12 months (synchronous; group 1), 12 36 months (group 2) and more than 36 months (group 3). Cancer-specific survival was calculated using Kaplan-Meier analysis. RESULTS: There were 577 patients (48.0 per cent) in group 1, 467 (38.9 per cent) in group 2 and 158 (13.1 per cent) in group 3. The overall 5-year cancer-specific survival rate after liver surgery was 42.3 per cent, with no difference between groups. However, when measured from the time of primary colorectal surgery, group 3 showed a survival advantage at both 5 and 10 years (94.1 and 47.6 per cent respectively) compared with groups 1 (46.3 and 24.9 per cent) and 2 (57.1 and 35.0 per cent) (P = 0.003). Survival graphs showed a steeper negative gradient from 5 to 10 years for group 3 compared with groups 1 and 2 (-0.80 versus - 0.34 and - 0.37), indicating an accelerated mortality rate. CONCLUSION: Patients undergoing delayed liver resection for CRLM have a survival advantage that is lost during long-term follow up. PMID- 21598237 TI - Omitting elective nodal irradiation and irradiating postinduction versus preinduction chemotherapy tumor extent for limited-stage small cell lung cancer: interim analysis of a prospective randomized noninferiority trial. AB - BACKGROUND: Controversies exist with regard to thoracic radiotherapy volumes for limited-stage small cell lung cancer (SCLC). This study compared locoregional progression and overall survival between limited-stage SCLC patients who received thoracic radiotherapy to different target volumes after induction chemotherapy. METHODS: Chemotherapy consisted of 6 cycles of etoposide and cisplatin. After 2 cycles of etoposide and cisplatin, patients were randomly assigned to receive thoracic radiotherapy to either the postchemotherapy or prechemotherapy tumor extent as study arm or control. Elective nodal irradiation was omitted for both arms. Forty-five Gy/30Fx/19 days thoracic radiotherapy was administered concurrently with cycle 3 chemotherapy. Prophylactic cranial irradiation was administered to patients who achieved complete remission. An interim analysis was planned when the first 80 patients had been followed for at least 6 months, for consideration of potential inferiority in the study arm. RESULTS: Forty-two and 43 patients were randomly assigned to a study arm and a control, respectively. The local recurrence rates were 31.6% (12 of 38) and 28.6% (12 of 42), respectively (P = .81). The isolated nodal failure rates were 2.6% (1 of 38) and 2.4% (1 of 42), respectively (P = 1.00). All isolated nodal failure sites were in the ipsilateral supraclavicular fossa. Mediastinal N3 was the only factor to predict isolated nodal failure (P = .004; odds ratio [OR], 29.33; 95% CI, 2.94 292.38). One-year and 3-year overall survival rates were 80.6%, 36.2%, and 78.9%, 36.4%, respectively (P = .54). CONCLUSIONS: Preliminary results indicated that irradiated postchemotherapy tumor extent and omitted elective nodal irradiation did not decrease locoregional control in the study arm, and the overall survival difference was not statistically significant between the 2 arms. Further investigation is warranted. PMID- 21598238 TI - Hormone-receptor expression and activity of trastuzumab with chemotherapy in HER2 positive advanced breast cancer patients. AB - BACKGROUND: The relationship between quantitative immunohistochemical hormone receptor expression and response to the combination of trastuzumab with chemotherapy in HER2-positive advanced breast cancer is currently unknown. METHODS: Estrogen receptor (ER) and progesterone receptor expression was studied both as a dichotomous variable (positivity set at >= 1% of positive cells) and as a continuous variable. The effect of hormone receptor expression on overall response rate and progression-free survival in patients receiving trastuzumab based treatment was studied by univariate and multivariate analysis. RESULTS: One hundred eleven of 227 consecutive advanced breast cancer patients treated at 2 Institutions had hormone receptor-positive tumors (49%). High expression of ER (>= 30% of tumor cells) predicted reduced probability of tumor response to trastuzumab plus chemotherapy (multivariate odds ratio, 0.422; 95% confidence interval [CI], 0.222-0.803; P = .009). In patients with hormone receptor-positive tumors (>= 1% of tumor cells), maintenance endocrine therapy added to trastuzumab upon the completion of chemotherapy was associated with a significant progression free survival benefit (hazard ratio, 0.521; 95% CI, 0.3325-0.836; P = .007). CONCLUSIONS: Our results suggest a predictive role of hormone receptor expression in HER2-positive tumors. Further investigation in this patient subset is warranted to optimize the use of HER2-targeting agents, chemotherapy, and endocrine therapy. PMID- 21598239 TI - Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer. AB - BACKGROUND: Germline mutations in the BRCA2 cancer susceptibility gene are associated with an increased risk of pancreatic cancer (PC). Breast-pancreas cancer families with BRCA1 mutations have also been observed. The influence of a family history (FH) of PC on BRCA mutation prevalence in patients with breast cancer (BC) is unknown. METHODS: A clinical database review (2000-2009) identified 211 Ashkenazi Jewish (AJ) BC probands who 1) underwent BRCA1/2 mutation analysis by full gene sequencing or directed testing for Ashkenazi founder mutations (BRCA1: 185delAG and 5382insC; BRCA2: 6174delT) and 2) had a FH of PC in a first-, second-, or third-degree relative. For each proband, the pretest probability of identifying a BRCA1/2 mutation was estimated using the Myriad II model. The observed-to-expected (O:E) mutation prevalence was calculated for the entire group. RESULTS: Of the 211 AJ BC probands with a FH of PC, 30 (14.2%) harbored a BRCA mutation. Fourteen (47%) of the mutations were in BRCA1 and 16 (53%) were in BRCA2. Patients diagnosed with BC at age <= 50 years were found to have a higher BRCA1/2 mutation prevalence than probands with BC who were diagnosed at age > 50 years (21.1% vs 6.9%; P = .003). In patients with a first-, second-, or third-degree relative with PC, mutation prevalences were 15.4%, 15.3%, and 8.6%, respectively (P = .58). In the overall group, the observed BRCA1/2 mutation prevalence was 14.2% versus an expected prevalence of 11.8% (O:E ratio, 1.21; P = .15). CONCLUSIONS: BRCA1 and BRCA2 mutations are observed with nearly equal distribution in AJ breast-pancreas cancer families, suggesting that both genes are associated with PC risk. In this population, a FH of PC was found to have a limited effect on mutation prevalence. PMID- 21598240 TI - Pleomorphic liposarcoma: clinical observations and molecular variables. AB - BACKGROUND: Pleomorphic liposarcoma (PLS) is a rare high-grade sarcoma that has lipoblastic differentiation. In this study, the authors evaluated PLS natural history, patient outcomes, and commonly deregulated protein biomarkers. METHODS: Medical records from patients (n = 155) who had PLS from 1993 to 2010 were reviewed. Univariate and multivariate analyses were conducted to identify independent prognosticators. A PLS tissue microarray (TMA) (n = 56 patient specimens) was constructed for immunohistochemical analysis of molecular markers, and p53 gene sequencing (exons 5-9) was conducted. RESULTS: The average patient age was 57 years, and the patients presented with primary disease (n = 102), recurrent disease (n = 16), and metastatic disease (n = 37). Lower extremity was the most common disease site (40%), and the average tumor size was 11 cm. Complete follow-up data were available for 83 patients, and their median follow up was 22.6 months. The 5-year disease-specific survival rate was 53%; and recurrent disease, unresectability, and microscopic positive margins were identified as predictors of a poor prognosis. Systemic relapse (the strongest poor prognostic determinant) developed in 35% of patients with localized PLS. Immunohistochemical analysis revealed increased expression of peroxisome proliferator-activated receptor gamma (an adipogenic marker), B-cell leukemia 2 and survivin (survival factors), vascular endothelial growth factor (an angiogenic factor), matrix metalloproteinase 2, and other biomarkers. Frequent loss of retinoblastoma protein expression and high p53 mutation rates (approximately 60%) were observed. CONCLUSIONS: PLS is an aggressive, metastasizing sarcoma. Identifying ubiquitous molecular events underlying PLS progression is crucial for progress in patient management and outcomes. PMID- 21598242 TI - Cost-effectiveness of combination versus sequential docetaxel and carboplatin for the treatment of platinum-sensitive, recurrent ovarian cancer. AB - BACKGROUND: In a randomized controlled trial (RCT) of patients with recurrent, platinum-sensitive ovarian cancer, the combination weekly docetaxel and carboplatin was associated a with progression-free survival (PFS) of 13.7 months compared with 8.4 months for sequential, single-agent docetaxel followed by carboplatin. The objective of the current study was to construct a cost-utility model to compare these 2 regimens with the incorporation of prospectively collected quality-of-life (QoL) data. METHODS: An RCT of concurrent docetaxel and carboplatin (cDC) versus docetaxel followed by carboplatin (sequential docetaxel and carboplatin [sDC]) was the basis for a Markov decision model, and the primary effectiveness outcome was PFS. Costs were estimated using US dollars based on Medicare reimbursements for chemotherapy regimens, bone marrow support, and management of adverse events. QoL data obtained using the Functional Assessment of Cancer Therapy-General questionnaire were converted to utilities. Costs and incremental cost-effectiveness ratios (ICERs) were reported in US dollars per quality-adjusted life year (QALY). Extensive 1-way sensitivity analyses and a Monte Carlo probabilistic sensitivity analysis were performed. RESULTS: The least expensive strategy was sDC, which cost an average of $20,381, compared with cDC, which cost an average of $25,122. cDC had an ICER of $25,239 per QALY compared with sDC. cDC remained cost-effective, with an ICER <$50,000 per QALY, over a range of costs and estimates. In Monte Carlo sensitivity analysis using a $50,000 per QALY willingness-to-pay threshold, cDC was either dominant or cost-effective with an ICER <$50,000 per QALY in 83% of simulations. CONCLUSIONS: Combined weekly cDC appeared to be cost-effective compared with sDC as treatment strategy for patients with platinum-sensitive ovarian cancer, even when accounting for slightly lower QoL during treatment. PMID- 21598241 TI - Early cytogenetic and molecular response during first-line treatment of chronic myeloid leukemia in chronic phase: long-term implications. AB - Chronic myeloid leukemia (CML) depends on the kinase activity of the BCR-ABL1 fusion protein. This dependency has led to the development of BCR-ABL1 inhibitors, such as imatinib, dasatinib, and nilotinib, which have proved to be highly efficacious treatments for CML. The European LeukemiaNet guidelines have established the importance of achieving a certain depth of response at different time points during imatinib therapy for patients with newly diagnosed CML in chronic phase. Patients who achieve a complete cytogenetic response by 12 months or a major molecular response by 18 months are classified as optimal responders and deemed to have excellent long-term outcomes. Conversely, failing to achieve such milestones is associated with an increased risk of worse long-term outcomes, such as loss of response, disease progression, or death. With ongoing treatment, patients not in complete cytogenetic response face a decreasing probability of ever achieving a complete cytogenetic response or major molecular response and increasing risk of disease progression. Available data therefore support treatment recommendations based on achieving defined levels of response within a specified duration of treatment. Recent data have shown that dasatinib and nilotinib used as frontline CML therapy result in higher response rates that are achieved at earlier time points compared with standard-dose imatinib therapy. Future analyses will need to determine whether these higher rates of deep and fast responses translate into improved long-term survival. PMID- 21598243 TI - Q-TWiST analysis of ixabepilone in combination with capecitabine on quality of life in patients with metastatic breast cancer. AB - BACKGROUND: Combination therapy with ixabepilone and capecitabine (cape) is approved for use in patients with locally advanced/metastatic breast cancer that is resistant to treatment with anthracyclines or taxanes. The current study evaluated the trade-off between quality and quantity of life using quality adjusted time without symptoms or toxicity (Q-TWiST) outcomes. METHODS: Within the trial, 752 women were randomly assigned to receive either the combination of ixabepilone and cape (once every 21 days) or cape alone (on days 1-14). The area under the survival curve was partitioned into 3 health states: toxicity (TOX), time without symptoms of disease progression or toxicity, and recurrence (relapse [REL]). The mean time in each health state was weighted by a range of utilities and summed to estimate quality-adjusted survival (QAS). Patient-reported outcomes were also evaluated using the Functional Assessment of Cancer Therapy (FACT) Breast Symptom Index (FBSI). RESULTS: A statistically significant difference between groups with regard to change from baseline FBSI scores favoring the cape group was observed (P = .0002), but no differences were observed after adjusting for deaths in the analysis. All combinations of utilities for REL and TOX resulted in an observed difference in QAS favoring combination therapy. Differences were found to be statistically significant for comparisons, with higher tolerance for TOX. QAS was found to be greater for the combination therapy group (42.2 weeks vs 38.4 weeks), assuming the base case scenario of utility equal to 0.5 for both TOX and REL (P = .0227). CONCLUSIONS: The Q-TWiST analysis supports a positive benefit-risk ratio for the combination of ixabepilone plus cape in patients with advanced/metastatic breast cancer that is refractory to anthracyclines and taxanes versus cape alone, despite the potential for added toxicities with combination therapy. PMID- 21598244 TI - A review of body size and breast cancer risk in Hispanic and African American women. AB - Obesity is an epidemic in the United States, especially among Hispanics and African Americans. Studies of obesity and breast cancer risk have been conducted primarily in non-Hispanic whites. There have been few studies of the association between body mass index (BMI) or weight gain and the risk of breast cancer in minorities, and the results have been inconsistent. Because most studies are conducted primarily in non-Hispanic whites, the etiology of breast cancer in minorities is not well understood. The authors of the current report reviewed the literature on the association between obesity, weight, and weight gain and breast cancer in minorities using a combination of the Medical Subject Heading (MeSH) terms "obesity," "body mass index," "weight," "weight gain," "Hispanic," and "African American." Only publications in English and with both risk estimates and 95% confidence intervals were considered. Forty-five studies of body size and breast cancer risk in non-Hispanic whites were identified. After an exhaustive search of the literature, only 3 studies of body size and breast cancer were conducted in Hispanic women were identified, and only 8 such studies in African American women were identified. The results were inconsistent in both race/ethnicity groups, with studies reporting positive, inverse, and null results. Thus, as obesity rates among Hispanics and African Americans continue to rise, there is an urgent need to identify the roles that both obesity and adult weight gain play in the development of breast cancer in these minorities. Additional studies are needed to provide more understanding of the etiology of this disease and to explain some of the disparities in incidence and mortality. PMID- 21598245 TI - Efficient delivery of radical cystectomy after neoadjuvant chemotherapy for muscle-invasive bladder cancer: a multidisciplinary approach. AB - BACKGROUND: Cystectomy delay >90 days after a diagnosis of muscle-invasive bladder cancer (MIBC) adversely affects pathologic stage and survival outcomes in patients who undergo primary surgery. After neoadjuvant chemotherapy (NAC), the impact of the timing of cystectomy delivery on these outcomes is uncertain. Poor communication between urologic and medical oncologists can result in cystectomy delay after systemic treatment. The authors of this report hypothesized that a delay in cystectomy delivery after NAC is associated with adverse survival outcomes. METHODS: An eligible cohort of 153 patients with MIBC received NAC and underwent radical cystectomy between 1990 and 2007. At the authors' institution, the genitourinary team strives to schedule patients for surgery at the time of initial evaluation or after their first chemotherapy cycle. Clinicopathologic characteristics, including timing of cystectomy, chemotherapy delivery, vital status, and reasons for excessive surgical delay, were analyzed retrospectively using an institutional database. A Cox proportional regression model was used to test the association between the timing of cystectomy delivery and survival. RESULTS: The median follow-up for all patients was 3.6 years. The median time to cystectomy was 16.6 weeks and 6.9 weeks from the first and last day of NAC, respectively. In multivariate analyses, the timing of cystectomy delivery from the termination of NAC did not significantly alter the risk of survival. The most common reason for cystectomy delivery beyond 10 weeks (28 patients; 18%) was procedural scheduling. CONCLUSIONS: Cystectomy delivery within 10 weeks after NAC did not compromise patient survival and, thus, provided a reasonable window for patient recovery and surgical intervention. PMID- 21598246 TI - Ongoing Dll4-Notch signaling is required for T-cell homeostasis in the adult thymus. AB - The essential role of the Delta-like ligand 4 (Dll4)-Notch signaling pathway in T lymphocyte development is well established. It has been shown that specific inactivation of Dll4 on thymic stromal cells during early post-natal development leads to a deregulation in T-cell differentiation. However, whether ongoing Dll4 Notch signaling is required for T-cell development in the adult thymus is unknown. The use of anti-Dll4 Abs allowed us to confirm and expand previous studies by examining the kinetics and the reversibility of Dll4-Notch signaling blockade in T-cell development in adult mice. We found that anti-Dll4 treatment reduced thymic cellularity after 7 days, as a consequence of a developmental delay in T-cell maturation at the pro-T-cell double negative 1 (CD4(-) CD8(-) c kit(+) CD44(+) CD25(-) ) stage, leading to decreased numbers of immature double positive (CD4(+) CD8(+) ) T cells without affecting the frequency of mature single positive CD4(+) and CD8(+) thymocytes, while promoting alternative thymic B-cell expansion. This cellular phenotype was similarly observed in both young adult and aged mice (>1.5 years), extending our understanding of the ongoing role for Dll4-Notch signaling during T-cell development in the adult thymus. Finally, after cessation of Dll4 Ab treatment, thymic cellularity and thymocyte subset ratios returned to normal levels, indicating reversibility of this phenotype in both adult and aged mice, which has important implications for potential clinical use of Dll4-Notch inhibitors. PMID- 21598247 TI - Notch3 signalling promotes tumour growth in colorectal cancer. AB - Increased Notch1 activity has been observed in intestinal tumours, partially accomplished by beta-catenin-mediated up-regulation of the Notch ligand Jagged-1. Whether further mechanisms of Notch activation exist and other Notch receptors might be involved is unclear. Microarray data indicated that Notch3 transcript levels are significantly up-regulated in primary and metastatic CRC samples compared to normal mucosa. Moreover, Notch3 protein was expressed at strong/moderate levels by 19.7% of 158 CRC samples analysed, and at weak levels by 51.2% of the samples. Intrigued by these findings, we sought to investigate whether Notch3 modulates oncogenic features of CRC cells. By exploiting xenografts of CRC cells with different tumourigenic properties in mice, we found that the aggressive phenotype was associated with altered expression of components of the Notch pathway, including Notch3, Delta-like 4 (DLL4), and Jagged-1 ligands. Stimulation with immobilized recombinant DLL4 or transduction with DLL4-expressing vectors dramatically increased Notch3 expression in CRC cells, associated with accelerated tumour growth. Forced expression of an active form of Notch3 mirrored the effects of DLL4 stimulation and increased tumour formation. Conversely, attenuation of Notch3 levels by shRNA resulted in perturbation of the cell cycle followed by reduction in cell proliferation, clonogenic capacity, and inhibition of tumour growth. Altogether, these findings indicate that Notch3 can modulate the tumourigenic properties of CRC cells and contributes to sustained Notch activity in DLL4-expressing tumours. PMID- 21598248 TI - Transition from cylindroma to spiradenoma in CYLD-defective tumours is associated with reduced DKK2 expression. AB - Patients carrying heterozygous germline truncating mutations in the CYLD gene develop multiple primary hair follicle-related tumours. A highly patterned tumour, termed cylindroma, and a highly disorganized tumour, termed spiradenoma, may both develop in the same patient. Furthermore, histological features of both tumour types have been described within the same tumour specimen. We used three dimensional computer-aided reconstruction of these tumours to demonstrate contiguous growth of cylindromas into spiradenomas, thus suggesting a transition between the two tumour types. To explore factors that may influence cutaneous tumour patterning, genome-wide transcriptomic analysis of 32 CYLD-defective tumours was performed. Overexpression of the Wnt/beta-catenin signalling pathway was observed relative to normal perilesional tissue. Morphometric analysis was used to investigate the relationship between Wnt pathway-related gene expression and tumour organization. This revealed an association between reduced Dickkopf 2 (DKK2-a negative regulator of the Wnt/beta-catenin signalling pathway) expression and loss of tumour patterning. Reduced DKK2 expression was associated with methylation of the DKK2 gene promoter in the majority of tumour samples assayed. RNA interference-mediated silencing of DKK2 expression in cylindroma primary cell cultures caused an increase in colony formation, cell viability, and anchorage independent growth. Using these data, we propose a model where epigenetic programming may influence tumour patterning in patients with CYLD mutations. PMID- 21598249 TI - Insulin-like growth factor-1 receptor inhibition overcomes gefitinib resistance in mucinous lung adenocarcinoma. AB - The appropriate selection of patients is a major challenge in the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Prospective trials in adenocarcinoma demonstrated that the mucinous subtype presents a poorer outcome under EGFR-TKI treatment than the non-mucinous subtype. Our aim was to determine the molecular characteristics associated with resistance to EGFR-TKIs in mucinous and non-mucinous adenocarcinoma. Eighty adenocarcinoma samples, including 34 tumours from patients treated with gefitinib in a phase II clinical trial (IFCT0401), were classified as mucinous (n = 32) or non-mucinous (n = 48) adenocarcinoma. We demonstrated that four biological markers were differentially expressed between the two subtypes: mucinous tumours that overexpressed IGF1R (p < 0.0001) and amphiregulin (p = 0.004) with a tendency for more frequent KRAS mutations, in contrast to non mucinous tumours that overexpressed EGFR (p < 0.0001) and TTF-1 (p < 0.0001) with more frequent EGFR mutations (p = 0.037). Higher IGF1R (p = 0.02) and lower TTF-1 (p = 0.02) expression was associated with disease progression under gefitinib treatment. We observed in vitro cross-talk between EGFR and IGF1R signalling pathways in gefitinib-resistant H358 mucinous cells. Anti-amphiregulin siRNAs and anti-IGF1R treatments sensitized the H358 cells to gefitinib-induced apoptosis with additive effects, suggesting that these treatments could overcome the resistance of mucinous tumours to EGFR-TKIs, including those with KRAS mutation. Our results highlighted that mucinous and non-mucinous adenocarcinoma subtypes are different entities with different therapeutic responses to EGFR-TKIs. These data will foster the development of therapeutic strategies for treating adenocarcinoma with mucinous component. PMID- 21598250 TI - IL-32 up-regulation is associated with inflammatory cytokine production in allergic rhinitis. AB - IL-32 is a described pro-inflammatory cytokine produced by T lymphocytes, natural killer cells, monocytes, and epithelial cells. However, the specific mechanism of IL-32 on allergic rhinitis (AR) has not been elucidated. Here, we report a significant increase of IL-32 protein and mRNA in the nasal mucosa of AR patients. In addition, in nasal mucosa tissue from AR patients, the level of IL 32 production correlated with inflammation, IL-1beta, IL-18, and granulocyte macrophage colony-stimulating factor (GM-CSF). In an AR animal model, IL-32 significantly increased IgE and inflammatory cytokine levels. IL-32 expression was induced by recombinant human GM-CSF via activation of caspase-1 in eosinophils. In addition, depletion of IL-32 prevents the production of inflammatory cytokines in eosinophils. In conclusion, IL-32 is an important cytokine involved in the inflammation of AR. The regulation of IL-32 expression may form the basis of a new strategy for the treatment of AR. PMID- 21598251 TI - Genetic polymorphisms in AURKA and BRCA1 are associated with breast cancer susceptibility in a Chinese Han population. AB - Centrosome defects can result in aneuploidy and genomic instability, and have important implications for breast cancer development. The Aurora-A and BRCA1 proteins interact and both are strongly involved in centrosome regulation. Genetic variants in these two genes may have an effect on breast cancer development. Here, we report a comprehensive single nucleotide polymorphism (SNP) and haplotype-tagging association study on these two genes in 1334 breast cancer cases and 1568 unaffected controls among the Chinese Han population. Apart from a missense SNP, rs2273535 (Phe31Ile), and a probable risk SNP, rs2064863, six htSNPs were analysed in three high-LD blocks of AURKA spanning from 10 kb upstream to 2 kb downstream of AURKA. For BRCA1, six htSNPs were analysed in a large high-LD region covering 98 kb (10 kb was extended to each end of BRCA1). The results showed that four SNPs in AURKA (data in recessive model, rs2273535: OR = 2.19, 95% CI = 1.03-4.66, p = 0.0422; rs2298016: OR = 0.38, 95% CI = 0.18 0.82, p = 0.0141; rs6024836: OR = 1.54, 95% CI = 1.18-2.00, p = 0.0014; rs10485805: OR = 0.68, 95% CI = 0.47-0.98, p = 0.0380) and one SNP in BRCA1 (rs3737559, dominant model OR = 1.35, 95% CI = 1.11-1.64, p = 0.0030) were associated with breast cancer susceptibility. After correction for multiple comparisons (FDR = 0.05), only rs6024836 and rs3737559 remained significant. Two haplotypes (CC of block 2, OR = 20.74, 95% CI = 4.35-98.88, p = 0.0001; GG of block 3, OR = 1.32, 95% CI = 1.12-1.56, p = 0.0010) and one diplotype (AG-GG of block 3, OR = 1.63, 95% CI = 1.18-2.26, p = 0.0031) within AURKA showed strong associations with breast cancer risk. One haplotype of BRCA1 (CTGTTG, OR = 1.30, 95% CI = 1.06-1.59, p = 0.0118) was also associated with breast cancer risk. However, women harbouring both at-risk genotypes of Aurora-A and BRCA1 were at a slightly increased risk compared with those harbouring either at-risk variant alone. Common genetic variants in the AURKA and BRCA1 genes may contribute to breast cancer development. PMID- 21598252 TI - Down-regulation of spinophilin in lung tumours contributes to tumourigenesis. AB - The scaffold protein spinophilin (Spn, PPP1R9B) is one of the regulatory subunits of phosphatase-1a (PP1), targeting it to distinct subcellular locations and to its target. Loss of Spn reduces PPP1CA levels, thereby maintaining higher levels of phosphorylated pRb. This effect contributes to an increase in p53 activity. However, in the absence of p53, reduced levels of Spn increase the tumourigenic properties of cells. In addition, Spn knockout mice have a reduced lifespan, an increased number of tumours and increased cellular proliferation in some tissues, such as the mammary ducts. In addition, the combined loss of Spn and p53 activity leads to an increase in mammary carcinomas, confirming the functional relationship between p53 and Spn. In this paper, we report that Spn is absent in 20% and reduced in another 37% of human lung tumours. Spn reduction correlates with malignant grade. Furthermore, the loss of Spn also correlates with p53 mutations. Analysis of miRNAs in a series of lung tumours showed that miRNA106a* targeting Spn is over-expressed in some patients, correlating with decreased Spn levels. Proof-of-concept experiments over-expressing miRNA106a* or Spn shRNA in lung tumour cells showed increased tumourigenicity. In conclusion, our data showed that miRNA106a* over-expression found in lung tumours might contribute to tumourigenesis through Spn down-regulation in the absence of p53. PMID- 21598253 TI - Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is highly expressed in liposarcoma and promotes migration and proliferation. AB - Aberrations of specialized metabolic pathways might be implicated in the development of neoplasias. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with important functions in metabolism. PPARbeta/delta and PPARgamma act in the proliferation and differentiation of adipose tissue progenitor cells. Thus, a potential use of PPARgamma agonists for the treatment of liposarcoma had been suggested, but clinical trials failed to detect beneficial effects. We show here that PPARdelta is highly expressed in liposarcoma compared to lipoma and correlates with proliferation. Stimulation of liposarcoma cell lines with a specific PPARdelta agonist increases proliferation, which is abolished by a PPARdelta-siRNA or a specific PPARdelta antagonist. Expression of the adipose tissue secretory factor leptin is lower in liposarcoma compared to lipoma and leptin reduces proliferation of liposarcoma cell lines. PPARdelta activation stimulates cell migration whereas leptin diminishes it. We demonstrate that PPARdelta directly represses leptin as: (a) leptin becomes down-regulated upon PPARdelta activation; (b) PPARdelta represses leptin promoter activity in different sarcoma cell lines; (c) deletion of a PPAR/RxR binding element in the leptin promoter abolishes repression by PPARdelta; and (d) in chromatin immunoprecipitation we confirm in vivo binding of PPARdelta to the leptin promoter. Our data suggest inhibition of PPARdelta as a potential novel strategy to reduce liposarcoma cell proliferation. PMID- 21598255 TI - IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. AB - Somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in gliomas and acute myeloid leukaemia (AML). Since patients with multiple enchondromas have occasionally been reported to have these conditions, we hypothesized that the same mutations would occur in cartilaginous neoplasms. Approximately 1200 mesenchymal tumours, including 220 cartilaginous tumours, 222 osteosarcomas and another ~750 bone and soft tissue tumours, were screened for IDH1 R132 mutations, using Sequenom((r)) mass spectrometry. Cartilaginous tumours and chondroblastic osteosarcomas, wild-type for IDH1 R132, were analysed for IDH2 (R172, R140) mutations. Validation was performed by capillary sequencing and restriction enzyme digestion. Heterozygous somatic IDH1/IDH2 mutations, which result in the production of a potential oncometabolite, 2-hydroxyglutarate, were only detected in central and periosteal cartilaginous tumours, and were found in at least 56% of these, ~40% of which were represented by R132C. IDH1 R132H mutations were confirmed by immunoreactivity for this mutant allele. The ratio of IDH1:IDH2 mutation was 10.6 : 1. No IDH2 R140 mutations were detected. Mutations were detected in enchondromas through to conventional central and dedifferentiated chondrosarcomas, in patients with both solitary and multiple neoplasms. No germline mutations were detected. No mutations were detected in peripheral chondrosarcomas and osteochondromas. In conclusion, IDH1 and IDH2 mutations represent the first common genetic abnormalities to be identified in conventional central and periosteal cartilaginous tumours. As in gliomas and AML, the mutations appear to occur early in tumourigenesis. We speculate that a mosaic pattern of IDH-mutation-bearing cells explains the reports of diverse tumours (gliomas, AML, multiple cartilaginous neoplasms, haemangiomas) occurring in the same patient. PMID- 21598254 TI - Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. AB - Brain glucose metabolism is impaired in Alzheimer's disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin-PI3K-AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM-AD and seven control cases. We found decreases in the levels and activities of several components of the insulin-PI3K-AKT signalling pathway in AD and T2DM cases. The deficiency of insulin-PI3K-AKT signalling was more severe in individuals with both T2DM and AD (T2DM-AD). This decrease in insulin-PI3K-AKT signalling could lead to activation of glycogen synthase kinase-3beta, the major tau kinase. The levels and the activation of the insulin-PI3K-AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O GlcNAcylation, suggesting that impaired insulin-PI3K-AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin-PI3K-AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer's disease. PMID- 21598256 TI - In vitro and in vivo characteristics of celecoxib in situ formed suspensions for intra-articular administration. AB - The objective of the present study was to explore the potential of using an in situ suspension forming drug delivery system of celecoxib to provide sustained drug exposure in the joint cavity following intra-articular administration. In vitro, precipitates were formed upon addition of a 400 mg/mL solution of celecoxib in polyethylene glycol 400 (PEG 400) to phosphate buffer, pH 7.4, or synovial fluid. The in vitro release profiles of the in situ formed suspensions were characterized by an initial fast release followed by a slower constant flux. In buffer solutions, these fluxes were comparable to those determined for a preformed suspension containing celecoxib in its most stable crystal form despite the in situ formed precipitates contained a mixture of two crystal forms of celecoxib as determined by X-ray powder diffraction. In situ suspension formation in synovial fluid was subject to considerable variation. A relatively high dose of celecoxib, corresponding to 1.25 mg/kg, in the form of PEG 400 solution (400 mg/mL) was injected into the radiocarpal joint in four horses. Celecoxib was present in serum samples taken over 10 days and in the joint tissue (post mortem), strongly indicating that joint sustained celecoxib exposure can be achieved using in situ suspension formation. PMID- 21598257 TI - Global health delivery and implementation research: a new frontier for global health. PMID- 21598258 TI - Principles and practice of disaster relief: lessons from Haiti. AB - Disaster relief is an interdisciplinary field dealing with the organizational processes that help prepare for and carry out all emergency functions necessary to prevent, prepare for, respond to, and recover from emergencies and disasters caused by all hazards, whether natural, technological, or human-made. Although it is an important function of local and national governing in the developed countries, it is often wanting in resource-poor, developing countries where, increasingly, catastrophic disasters tend to occur and have the greatest adverse consequences. The devastating January 12, 2010, Haiti earthquake is a case study of the impact of an extreme cataclysm in one of the poorest and most unprepared settings imaginable. As such, it offers useful lessons that are applicable elsewhere in the developing world. Emergency preparedness includes 4 phases: mitigation or prevention, preparedness, response, and recovery. Periods of normalcy are the best times to develop disaster preparedness plans. In resource poor countries, where dealing with the expenses of daily living is already a burden, such planning is often neglected; and, when disasters strike, it is often with great delay that the assistance from international community can be deployed. In this increasingly interconnected world, the Haiti earthquake and the important international response to it make a strong case for a more proactive intervention of the international community in all phases of emergency management in developing countries, including in mitigation and preparedness, and not just in response and recovery. Predisaster planning can maximize the results of the international assistance and decrease the human and material tolls of inevitable disasters. There should be a minimum standard of preparedness that every country has to maintain and the international assistance to achieve that. International academic medical centers interested in global health could strengthen their programs by prospectively including in them contingency planning for international relief operations. Healthcare professionals of these institutions who travel to disaster zones should rigorously prepare themselves and make provisions for collecting and reporting data, which will enrich the knowledge of this growing activity. PMID- 21598259 TI - Cervical cancer screening in low- and middle-income countries. AB - Cervical cancer is a leading cause of death among women in the developing world. Conventional cytology-based cervical cancer screening programs have been largely ineffectual at reducing the cervical cancer burden in low-resource settings. In response, alternative strategies have been tested, such as visual inspection with acetic acid (VIA) screening and human papillomavirus (HPV) DNA-based testing. This manuscript reviews literature addressing the programmatic approaches to implementing cervical cancer screening programs in low-resource settings, highlighting the challenges, barriers, and successes related to the use of cytology, VIA, and HPV-DNA based screening programs. PMID- 21598260 TI - Surgery in global health delivery. AB - Surgical conditions account for a significant portion of the global burden of disease and have a substantial impact on public health in low- and middle-income countries. This article reviews the significance of surgical conditions within the context of public health in these settings, and describes selected approaches to global surgery delivery in specific contexts. The discussion includes programs in global trauma care, surgical care in conflict and disaster, and anesthesia and perioperative care. Programs to develop surgical training in Botswana and pediatric surgery through international partnership are also described, with a final review of broader approaches to training for global surgical delivery. In each instance, innovative solutions, as well as lessons learned and reasons for program failure, are highlighted. PMID- 21598262 TI - Obstetric fistula in low and middle income countries. AB - Vesicovaginal fistula secondary to obstructed labor continues to be an all-too common occurrence in underdeveloped nations throughout Africa and Asia. Vesicovaginal fistula remains largely an overlooked problem in developing nations as it affects the most marginalized members of society: young, poor, illiterate women who live in remote areas. The formation of obstetric fistula is a result of complex interactions of social, biologic, and economic influences. The key underlying causes of fistula are the combination of a lack of functional emergency obstetric care, poverty, illiteracy, and low status of women. In order to prevent fistula, some strategies include creation of governmental policy aimed toward reducing maternal mortality/morbidity and increasing availability of skilled obstetric care, as well as attempts to increase awareness about its prevention and treatment among policymakers, service providers, and communities. Whereas prevention will require the widespread development of infrastructure within these developing countries, treatment of fistula is an act which can be done "in the now." Treatment and subsequent reintegration of fistula patients requires a team of specialists including surgeons, nurses, midwives, and social workers, which is largely unavailable in developing countries. However, there is increasing support for training of fistula surgeons through standardized programs as well as establishment of rehabilitation centers in many nations. The eradication of fistula is dependent upon building programs that target both prevention and treatment. PMID- 21598261 TI - HIV care for geographically mobile populations. AB - The interaction between geographic mobility and risk for human immunodeficiency virus infection is well recognized, but what happens to those same individuals, once infected, as they transition to living with the infection? Does mobility affect their transition into medical care? If so, do mobile and nonmobile populations achieve similar success with antiretroviral treatment? The definition of mobility has changed over the centuries to encompass a complex phenotype including permanent migration, frequent travel, circular migration, and travel to and from treatment centers. The heterogeneity of these definitions leads to discordant findings. Investigations show that mobility has an impact on infection risk, but fewer data exist on the impact of geographic mobility on medical care and treatment outcomes. This review will examine existing data regarding the impact of geographic mobility on access to and maintenance in medical care and on adherence to antiretroviral therapy for those living with human immunodeficiency virus infection. It will also expand the concept of mobility to include data on the impact of the distance from residence to clinic on medical care and treatment adherence. Our conclusions are that the existing literature is limited by varying definitions of mobility and the inherent oversimplification necessary to apply a "mobility measure" in a statistical analysis. The impact of mobility on antiretroviral treatment outcomes deserves further exploration to both define the phenomenon and target interventions to these at-risk populations. PMID- 21598263 TI - American Indian youth substance abuse: community-driven interventions. AB - Substance abuse among American Indians has a long history that dates back to the colonial era. American Indian youth today continue to have one of the highest substance abuse rates when compared with other groups. Researchers have implemented American Indian youth substance abuse interventions that previously have worked in the general population, but studies have found that they are generally unprepared and poorly designed for American Indian populations. The lack of inclusion of American Indian populations in the interventional studies, poor understanding of American Indian diversity and cultures, and lack of consideration for the unique historical and sociopolitical context of each tribe were cited as reasons the interventions failed. It has been suggested that historical trauma plays a considerable role in American Indian youth substance abuse; however, much of this theoretical framework has yet to be rigorously tested. Contemporary trauma appears to contribute significantly more to American Indian youth substance abuse. The data on American Indian substance abuse are limited, but what is currently available appears to show a vast heterogeneity in the level of substance abuse among American Indian youth that varies across different American Indian tribes and geographical distribution. In summary, this article seeks to describe the special relationship American Indian tribes have with the federal government, review historical and contemporary trauma, review American Indian youth substance abuse and interventions today, and finally describe a unique intervention strategy that tribes in the Pacific Northwest are implementing in order to combat American Indian youth substance abuse. PMID- 21598264 TI - Role of students in global health delivery. AB - What role do students have in global health activities? On one hand, students have much to offer, including innovative ideas, fresh knowledge and perspective, and inspiring energy. At the same time, students lack technical credentials and may drain resources from host communities. Here, we examine the dynamic, contemporary roles of students in global health activities, including health delivery. We focus on 3 themes that guide engagement: (1) fostering an enabling policy environment (eg, toward greater health equity); (2) understanding and working within the local context and governments' needs; and (3) leading bidirectional partnerships. We next study the implications of short-term exposure and long-term engagement programs. We conclude with 4 recommendations on how to better equip students to engage in the next frontier of global health education and future action. PMID- 21598265 TI - Improving the delivery of global tobacco control. AB - Tobacco control must remain a critical global health priority given the growing burden of tobacco-induced disease in the developing world. Insights from the emerging field of global health delivery suggest that tobacco control could be improved through a systematic, granular analysis of the processes through which it is promoted, implemented, and combated. Using this framework, a critical bottleneck to the delivery of proven health promotion emerges in the role that the tobacco industry plays in promoting tobacco use and blocking effective tobacco-control policies. This "corporate bottleneck" can also be understood as a root cause of massive disease and suffering upon vulnerable populations worldwide, for the goal of maximizing corporate profit. Naming, understanding, and responding to this corporate bottleneck is crucial to the success of tobacco control policies. Three case studies of tobacco-control policy--South Africa, the Framework Convention on Tobacco Control, and Uruguay--are presented to explore and understand the implications of this analysis. PMID- 21598266 TI - Linking population, health, and the environment: an overview of integrated programs and a case study in Nepal. AB - Population, health, and environment programs are cross-sectoral development initiatives that link conservation, health, and family planning interventions. These programs are generally located in biodiversity hotspots, where population pressure is among the factors contributing to environmental degradation. This review describes the general structure of population, health, and environment programs and provides selected examples to highlight various aspects of this approach. We focus in depth on a case study from the Integrating Population and Health into Forestry Management Agendas program in Nepal that simultaneously addressed deforestation from fuel-wood harvesting, indoor air pollution from wood fires, acute respiratory infections related to smoke inhalation, as well as family planning in communities in Nepal's densely populated forest corridors. Keys to the success of the Nepal project included empowerment of community forest user groups with population, health, and environment program know-how and appropriate technology. Lessons learned in Nepal point to the critical role that nongovernmental organizations can play as catalysts of cross-sectoral responses to complex development issues such as this one. The population, health, and environment approach can be an effective method for achieving sustainable development and meeting both conservation and health objectives. PMID- 21598267 TI - Mobile phone tools for field-based health care workers in low-income countries. AB - In low-income regions, mobile phone-based tools can improve the scope and efficiency of field health workers. They can also address challenges in monitoring and supervising a large number of geographically distributed health workers. Several tools have been built and deployed in the field, but little comparison has been done to help understand their effectiveness. This is largely because no framework exists in which to analyze the different ways in which the tools help strengthen existing health systems. In this article we highlight 6 key functions that health systems currently perform where mobile tools can provide the most benefit. Using these 6 health system functions, we compare existing applications for community health workers, an important class of field health workers who use these technologies, and discuss common challenges and lessons learned about deploying mobile tools. PMID- 21598268 TI - Community health workers in global health: scale and scalability. AB - Community health worker programs have emerged as one of the most effective strategies to address human resources for health shortages while improving access to and quality of primary healthcare. Many developing countries have succeeded in deploying community health worker programs in recognition of the potential of community health workers to identify, refer, and in many cases treat illnesses at the household level. However, challenges in program design and sustainability are expanded when such programs are expanded at scale, particularly with regard to systems management and integration with primary health facilities. Several nongovernmental organizations provide cases of innovation on management of community health worker programs that could support a sustainable system that is capable of being expanded without being stressed in its functionality nor effectiveness--therefore, providing for stronger scalability. This paper explores community health worker programs that have been deployed at national scale, as well as scalable innovations found in successful nongovernmental organization-run community health worker programs. In exploration of strategies to ensure sustainable community health worker programs at scale, we reconcile scaling constraints and scalable innovations by mapping strengths of nongovernmental organizations' community health worker programs to the challenges faced by programs currently deployed at national scale. PMID- 21598269 TI - Post-Soviet transition: improving health services delivery and management. AB - During the post-Soviet transition of the last 2 decades, ex-Communist countries of the Eastern Bloc, including eastern and central Europe, the Soviet Union, and its satellite and aligned states, have undergone major health system reforms. Many health systems of those countries--previously adopting a Soviet-type Semashko model--are currently called "in transition," as reform agendas, such as shifting to a Bismarck, Beveridge, or mixed financing scheme or adopting new health delivery management policies, are still in development. In this article, we first review common characteristics of Semashko health systems (the predominant health system of Communist countries during the Soviet era) and then discuss the "new public management" principles that ex-Communist countries have recently started to adopt with various degrees of success. We then illustrate experiences with these principles using 2 case studies, from Russia and Albania, and propose health policy options for both cases. Based on a review of the literature and on the our work experience in Russia and Albania, we found that the 2 ex-Semashko systems have not fully capitalized on expected positive outcomes of new public management principles due to low local healthcare financing levels, depreciated healthcare infrastructure and operational capacities, overlapping and contradicting ideology and policies of the former and newer health systems, and finally, lack of leadership that has successful experience with these principles. In the case of pharmaceutical pricing, reimbursement, and access in Russia, we show how a well-intentioned but suboptimally designed and managed pharmaceutical coverage scheme has suffered moral hazard and adverse selection and has adversely impacted the new public management promise of efficient medicine coverage. In the case of Albania, the delayed investment in human resource reform within a depreciated and underfinanced delivery system has adversely affected the implementation of new public management principles. PMID- 21598270 TI - Confronting intimate partner violence: a global health priority. AB - Intimate partner violence--physical, psychological, or sexual abuse of women perpetrated by intimate partners--is one of the most common forms of violence against women, and is associated with adverse women's reproductive and maternal health outcomes. We review the opportunities for addressing intimate partner violence by the health system, examine promising approaches, and outline future challenges for developing effective health-systems responses to violence. Evidence shows that women seldom approach support services in response to violence, but do seek health care at some point in their lives. In fact, women's utilization of reproductive-health services in particular has been increasing globally. These services have a broad reach and represent an important opportunity to engage in violence prevention. Although health systems-based responses to intimate partner violence have emerged, rigorous evaluations to guide program planning and policy efforts to reduce violence are limited. Programs in the United States have expanded from improving individual provider prevention practices to instituting system-wide changes to ensure sustainability of these practices. Developing-country program responses, though limited, have been system-wide and multisectoral right from the start. Our review highlights 3 challenges for developing and expanding health-systems responses to violence. First, interventions should focus on creating a supportive environment within the health system and strengthening linkages across health care and allied sectors. Second, rigorous evaluations of health sector-based interventions are needed for a sound evidence base to guide programmatic and policy decisions. Finally, research is needed to identify the entry points for engaging men on violence prevention, and to examine the feasibility and effectiveness of such interventions. PMID- 21598271 TI - Strategic, value-based delivery in global health care: innovations at Harvard University and Brigham and Women's Hospital. AB - Investments in global health have more than doubled over the past decade, generating a cadre of new institutions. To date, most of the funded research in global health has focused on discovery, and, more recently, on the development of new tools, which has tightened the implementation bottleneck. This article introduces the concept of global health delivery and the need to catalog and analyze current implementation efforts to bridge gaps in delivery. Global health delivery is complex and context-dependent and requires an interdisciplinary effort, including the application of strategic principles. Furthermore, delivery is necessary to ensure that the investments in research, discovery, and development generate value for patients and populations. This article discusses the application of value-based delivery to global health. It provides some examples of approaches to aggregating implicit knowledge to inform practice. With global health delivery, the aim is to transform global health scale-up from a series of well-intentioned but often disconnected efforts to a value-based movement based upon 21st-century technology, standards, and efficiency. PMID- 21598273 TI - Harmonic vibrational frequencies: scale factors for pure, hybrid, hybrid meta, and double-hybrid functionals in conjunction with correlation consistent basis sets. AB - Scale factors for (a) low (<1000 cm(-1)) and high harmonic vibrational frequencies, (b) thermal contributions to enthalpy and entropy, and (c) zero point vibrational energies have been determined for five hybrid functionals (B3P86, B3PW91, PBE1PBE, BH&HLYP, MPW1K), five pure functionals (BLYP, BPW91, PBEPBE, HCTH93, and BP86), four hybrid meta functionals (M05, M05-2X, M06, and M06-2X) and one double-hybrid functional (B2GP-PLYP) in combination with the correlation consistent basis sets [cc-pVnZ and aug-cc-pVnZ, n = D(2),T(3),Q(4)]. Calculations for vibrational frequencies were carried out on 41 organic molecules and an additional set of 22 small molecules was used for the zero-point vibrational energy scale factors. Before scaling, approximately 25% of the calculated frequencies were within 3% of experimental frequencies. Upon application of the derived scale factors, nearly 90% of the calculated frequencies deviated less than 3% from the experimental frequencies for all of the functionals when the augmented correlation consistent basis sets were used. PMID- 21598272 TI - New academic partnerships in global health: innovations at Mount Sinai School of Medicine. AB - Global health has become an increasingly important focus of education, research, and clinical service in North American universities and academic health centers. Today there are at least 49 academically based global health programs in the United States and Canada, as compared with only one in 1999. A new academic society, the Consortium of Universities for Global Health, was established in 2008 and has grown significantly. This sharp expansion reflects convergence of 3 factors: (1) rapidly growing student and faculty interest in global health; (2) growing realization-powerfully catalyzed by the acquired immune deficiency syndrome epidemic, the emergence of other new infections, climate change, and globalization-that health problems are interconnected, cross national borders, and are global in nature; and (3) rapid expansion in resources for global health. This article examines the evolution of the concept of global health and describes the driving forces that have accelerated interest in the field. It traces the development of global health programs in academic health centers in the United States. It presents a blueprint for a new school-wide global health program at Mount Sinai School of Medicine. The mission of that program, Mount Sinai Global Health, is to enhance global health as an academic field of study within the Mount Sinai community and to improve the health of people around the world. Mount Sinai Global Health is uniting and building synergies among strong, existing global health programs within Mount Sinai; it is training the next generation of physicians and health scientists to be leaders in global health; it is making novel discoveries that translate into blueprints for improving health worldwide; and it builds on Mount Sinai's long and proud tradition of providing medical and surgical care in places where need is great and resources few. PMID- 21598274 TI - On the applicability of cluster models to study the chemical reactivity of carbon nanotubes. AB - We have performed a comparative study on the reactivity of metallic and semiconducting nanotubes using infinite and finite models. Infinite models were created using periodic boundary conditions while finite ones were constructed by means of hydrogen terminated nanotubes sections. Cluster models systematically underestimate the reactivity of metallic single wall carbon nanotube (SWCNT)s. We have confirmed that metallic nanotubes are more reactive than semiconducting species, in disagreement with previous works. The differences can be attributed to the presence of an instability in the singlet ground state of the wavefunction corresponding to semiconducting nanotubes clusters. When lower electronic states of the pristine cluster are considered, semiconducting nanotubes become less reactive as compared with metallic SWCNTs. Particularly, if an antiferromagnetic solution is considered for the semiconducting (10,0) SWCNT cluster, it becomes less reactive than the (5,5) SWCNT, as observed for infinite models. Because semiconducting nanotubes are less reactive than metallic counterparts, their reaction energies converge faster to the values observed for graphene. For a 1.6 nm diameter semiconducting nanotube, the addition energy is comparable with graphene. Thus, semiconducting nanotubes with diameters larger than 1.6 nm are going to be as reactive as graphene and the effects of curvature will be unimportant. PMID- 21598275 TI - He 2++ molecular ion in a strong time-dependent magnetic field: a current-density functional study. AB - The He 2++ molecular ion exposed to a strong ultrashort time-dependent (TD) magnetic field of the order of 10(9) G is investigated through a quantum fluid dynamics (QFD) and current-density functional theory (CDFT) based approach using vector exchange-correlation (XC) potential and energy density functional that depend not only on the electronic charge-density but also on the current density. The TD-QFD-CDFT computations are performed in a parallel internuclear-axis and magnetic field-axis configuration at the field-free equilibrium internuclear separation R = 1.3 au with the field-strength varying between 0 and 10(11) G. The TD behavior of the exchange- and correlation energy of the He 2++ is analyzed and compared with that obtained using a [B-TD-QFD-density functional theory (DFT)] approach based on the conventional TD-DFT under similar computational constraints but using only scalar XC potential and energy density functional dependent on the electronic charge-density alone. The CDFT based approach yields TD exchange- and correlation energy and TD electronic charge-density significantly different from that obtained using the conventional TD-DFT based approach, particularly, at typical magnetic field strengths and during a typical time period of the TD field. This peculiar behavior of the CDFT-based approach is traced to the TD current-density dependent vector XC potential, which can induce nonadiabatic effects causing retardation of the oscillating electronic charge density. Such dissipative electron dynamics of the He 2++ molecular ion is elucidated by treating electronic charge density as an electron-"fluid" in the terminology of QFD. PMID- 21598276 TI - Computer simulation of trifluoromethane properties with ab initio force field. AB - Intermolecular interaction potentials of the trifluoromethane dimer in 15 orientations have been calculated using the Hartree-Fock (HF) self-consistent theory and the second-order Moller-Plesset (MP2) perturbation theory. Single point energies at important geometries were also calibrated by the coupled cluster with single and double and perturbative triple excitation [CCSD(T)] calculations. We have employed Pople's medium size basis sets [up to 6 311++G(3df,3pd)] and Dunning's correlation consistent basis sets (up to aug-cc pVQZ). Basis set limit potential values were obtained through well-studied extrapolation methods. The calculated MP2 potential data were employed to parameterize a 5-site force field for molecular simulations. We performed molecular dynamics simulations using the constructed ab initio force field and compared the simulation results with experiments. Quantitative agreements for the atom-wise radial distribution functions and the self-diffusion coefficients over a wide range of experimental conditions can be obtained, thus validating the ab initio force field without using experimental data a priori. PMID- 21598277 TI - A dissected ring current model for assessing magnetic aromaticity: a general approach for both organic and inorganic rings. AB - A model based on classical electrodynamics is used to measure the strength of ring currents of different molecular orbitals, i.e., sigma- and pi-orbitals, and characteristics of ring current loops, i.e., ring current radii and height of current loops above/below the ring planes, among a number of organic as well as inorganic molecules. For the pi-current, the present model represents an improvement of previous approaches to determine ring current intensity. It is proven that the present model is more precise than previous models as they could not explain presence of the minimum in the plot of NICS(pizz) versus distance close to the ring plane. Variations in the charge of molecules and the types of constituent atoms of each species affect the ring current radii of both sigma- and pi-current loops as well as the height of pi-current loops above/below the ring plane. It is suggested that variation in the distribution of the one electron density in different systems is the main source of differences of the ring current characteristics. PMID- 21598278 TI - The structure, properties, and nature of HArF-HOX (X = F, Cl, Br) complex: an ab initio study and an unusual short hydrogen bond. AB - The structure and properties (geometric, energetic, electronic, spectroscopic, and thermodynamic properties) of HArF-HOX (X = F, Cl, Br) complex have been investigated at the MP2/aug-cc-pVTZ level. Three types of complexes are formed through a hydrogen bond or a halogen bond. The HArF-HOX complex is the most stable, followed by the FArH-OHX complex, and the HArF-XOH complex is the most unstable. The binding distance in FArH-OHX complex is very short (1.1-1.7 A) and is smaller than that in HArF-HOX complex. However, the interaction strength in the former is weaker than that in the latter. Thus, an unusual short hydrogen bond is present in FArH-OHX complex. The associated H-Ar bond exhibits a red shift, whereas the distant one gives a blue shift. A similar result is also found for the O-H and O-X bonds. The isotropic chemical shift is negative for the associated hydrogen atom but is positive for the associated halogen atom. However, a reverse result is found for the anisotropic chemical shift. The analyses of natural bond orbital and atoms in molecules have been performed for these complexes to understand the nature and properties of hydrogen and halogen bonds. PMID- 21598280 TI - Point atomic multipole moments for simulation of electrostatic potential and field in all-siliceous zeolites. AB - Calibration method of atomic multipole moments (AMMs) is presented with respect to geometries of all-siliceous zeolite models obtained with X-ray diffraction (XRD) methods. Mulliken atomic charges and AMMs are calculated for all-siliceous types possessing small size elementary unit cells at the hybrid density functional theory (DFT) (B3LYP) and general gradient approximation (GGA) Perdew Burke-Ernzerhof (PBE) levels and then used to fit the dependences versus geometry variables for the Mulliken charges and versus special coordinate for the AMMs. Fitted and exact charges and AMMs are used to compute electrostatic potential (EP) and electric field (EF) for all-siliceous zeolites with CRYSTAL. A possibility of application of the point AMMs to quantum mechanical/molecular mechanics computations or classic simulation of physical adsorption is evaluated. The considered models expand over wide range of structural parameters and could be applied even to amorphous all-siliceous systems. PMID- 21598279 TI - Application of a ligand-based theoretical approach to derive conversion paths and ligand conformations in CYP11B2-mediated aldosterone formation. AB - The biosynthesis of the mineralocorticoid hormone aldosterone involves a multistep hydroxylation of 11-deoxycorticosterone at the 11- and 18-positions, resulting in the formation of corticosterone and 18-hydroxycorticosterone, the final precursor of aldosterone. Two members of the cytochrome P450 11B family, CYP11B1 and CYP11B2, are known to catalyze these 11- and 18-hydroxylations, however, only CYP11B2 can oxidize 18-hydroxycorticosterone to aldosterone. It is unknown what sequence of hydroxylations leads to the formation of 18 hydroxycorticosterone. In this study we have investigated which of the possible conversion paths towards formation of 18-hydroxycorticosterone and aldosterone are most likely from the ligand perspective. Therefore, we combined quantum mechanical investigations on the steroid conformations of 11-deoxycorticosterone and its ensuing reaction intermediates with Fukui indices calculations to predict the reactivity of their carbon atoms for an attack by the iron-oxygen species. Both F(-) and F(0) were calculated to account for different mechanisms of substrate conversion. We show which particular initial conformations of 11 deoxycorticosterone and which conversion paths are likely to result in the successful synthesis of aldosterone, and thereby may be representative for the mechanism of aldosterone biosynthesis by CYP11B2. Moreover, we found that the most likely path for aldosterone synthesis coincides with the substrate conformation proposed in an earlier publication. To summarize, we show that on a theoretical and strictly ligand-directed basis only a limited number of reaction paths in the conversion of 11-deoxycorticosterone to aldosterone is possible. Despite its theoretical nature, this knowledge may help to understand the catalytic function of CYP11B1 and CYP11B2. PMID- 21598281 TI - Theoretical study of valance photoelectron spectra of hypoxanthine, xanthine, and caffeine using direct symmetry-adapted cluster/configuration interaction methodology. AB - UV photoelectron spectra of hypoxanthine, xanthine, and caffeine, up to 20 eV, were calculated and compared with the experimental spectra reported in literature. The calculations were performed using a novel version of the quantum mechanical symmetry-adapted cluster/configuration interaction (SAC-CI) method termed, direct SAC-CI. The Duning/Huzinaga valance double-zeta D95+(d,p) Gaussian basis set was also employed with this method. The ionization energies and intensities were calculated, and the corresponding spectral bands were assigned. Natural bonding orbital (NBO) calculations were employed for better spectral band assignment. The calculated ionization energies and intensities reasonably produced the experimental photoelectron spectra. PMID- 21598282 TI - Alkaline hydrolysis of ethylene phosphate: an ab initio study by supermolecule model and polarizable continuum approach. AB - The alkaline hydrolysis reaction of ethylene phosphate (EP) has been investigated using a supermolecule model, in which several explicit water molecules are included. The structures and single-point energies for all of the stationary points are calculated in the gas phase and in solution at the B3LYP/6-31++G(df,p) and MP2/6-311++G(df,2p) levels. The effect of water bulk solvent is introduced by the polarizable continuum model (PCM). Water attack and hydroxide attack pathways are taken into account for the alkaline hydrolysis of EP. An associative mechanism is observed for both of the two pathways with a kinetically insignificant intermediate. The water attack pathway involves a water molecule attacking and a proton transfer from the attacking water to the hydroxide in the first step, followed by an endocyclic bond cleavage to the leaving group. While in the first step of the hydroxide attack pathway the nucleophile is the hydroxide anion. The calculated barriers in aqueous solution for the water attack and hydroxide attack pathways are all about 22 kcal/mol. The excellent agreement between the calculated and observed values demonstrates that both of the two pathways are possible for the alkaline hydrolysis of EP. PMID- 21598283 TI - Theoretical study on the ring-opening isomerization reaction mechanism of the ring isomers of N8H8. AB - Ring-opening isomerization from ring-shaped isomers to chain-shaped isomers of N(8)H(8) has been studied by a density function B3LYP method at 6-311+ +G** level. 20 ring-shaped isomers have been found to be able to transform into chain shaped isomers, with 20 possible transition states got by ring-opening structure optimization. Furthermore, the ring-openings have been found in the longer N-N single bond by analyzing the length change of N-N bond of ring-shaped isomers in ring-opening processes. In addition, with the activation energies in ring-opening processes, the differences of the activation energies in isomerization between the isomers have been found according to the classification of rings. The activation energies in ring-opening isomerization of six-membered ring-shaped isomers are higher than that of the four-membered ring-shaped isomers. It indicates that six-membered ring-shaped isomers difficult in ring-opening in the isomerization are the steadiest ring-shaped isomers of N(8)H(8) while four membered ring-shaped isomers easy in ring-opening are the most unstable. PMID- 21598284 TI - Molecular mechanical study of halogen bonding in drug discovery. AB - A halogen bond is a noncovalent bond between a halogen atom (X) and a Lewis base (Y). This type of bond is attributed to the anisotropic distribution of the charge density on the halogen atom, resulting in the formation of a positive cap (called the sigma-hole) centered on the A-X axis. The current research is the first reported molecular mechanical study of halogen bonding, the positive region centered on the halogen atom was represented by an extra-point (EP) of charge. The correlation between the X-EP distance and the X...Y bond length was explored to determine the optimal position of the EP. A test set of 27 halogen-containing molecules complexed to various Lewis bases was studied using molecular mechanical potentials. The molecular mechanical minimized halogen bond lengths and binding energies were in good agreement with the corresponding quantum mechanical values. The EP inclusion on the halogen atom resulted in an improvement in the accuracy of the electrostatic-potential derived charges. The solvation free energies of halobenzene molecules relative to benzene were calculated with and without EP inclusion to assess the accuracy of the developed approach. Molecular mechanical study of halo derivatives of benzotriazole complexed to cyclin-dependent protein kinase 2 (CDK2) was performed, and MM-PB(GB)SA binding energies were calculated as a case study in finding potent halogenated inhibitors that can serve as antitumor drugs. PMID- 21598285 TI - Accurate assessment of the strain energy in a protein-bound drug using QM/MM X ray refinement and converged quantum chemistry. AB - An ongoing question regarding the energetics of protein-ligand binding has been; what is the strain energy that a ligand pays (if any) when binding to its protein target? The traditional method to estimate strain energy uses force fields to calculate the energy difference between the ligand bound conformation and its nearest local minimum/global minimum on the gas-phase or aqueous phase potential energy surface. This makes the implicit assumption that the underlying force field as well as the reference crystal structure is accurate. Herein, we use ibuprofen as a test case and compare MMFF and ab initio QM methods to identify the local and global minimum conformations. Nine low energy conformations were identified with HF/6-31G* geometry optimization in vacuo. We also obtained highly accurate relative energies for ibuprofen's conformational energy surface based on M06/aug-cc-pVXZ (X = D and T), MP2/aug-cc-pVXZ (X = D and T) and the MP2/CBS method (with and without solvent corrections). Moreover, we curate and re-refine the ibuprofen-protein complex (PDB 2BXG) using QM/MM X-ray refinement approaches (HF/6-31G* was the QM method and the MM model was the AMBER force field ff99sb), which were compared with the low energy conformers to calculate the strain energy. The result indicates that there was an 88% reduction in ibuprofen conformation strain using the QM/MM refined structure versus the original PDB ibuprofen conformations. Furthermore, our results indicate that, due to its inherent limitations in estimating electrostatic interactions, force fields are not suitable to gauge strain energy for charged drug molecules like ibuprofen. The present work offers a carefully validated conformational potential energy surface for a drug molecule as well as a reliable QM/MM re-refined X-ray structure that can be used to test current structure-based drug design approaches. PMID- 21598286 TI - A large-scale study on subjective perception of discomfort during 7 and 1.5 T MRI examinations. AB - A study on subjective perception has been carried out in order to gain further insight into subjective discomfort and sensations experienced during 7 T magnetic resonance imaging (MRI). This study provides information about subjective acceptance, which is essential if 7 T MRI is to become a clinical diagnostic tool. Of 573 subjects who underwent 7 T MRI, 166 were also examined at 1.5 T, providing a means of discriminating field-dependent discomfort. All subjects judged sources of discomfort and physiological sensations on an 11-point scale (0 = no side effects, 10 = intolerable side effects) and scores were analyzed separately for exam phases, with and without table movement at each field strength. Results revealed that 7 T MRI was, in general, judged more uncomfortable than 1.5 T; however, most subjects rated the effects as being non critical (mean scores between 0.5 and 3.5). Significant differences were detected regarding vertigo and sweating between subjects positioned "head-first" and "feet first" at 7 T (worse in "head-first") and between 7 and 1.5 T (worse at 7 T), with the effects being more pronounced in the moving compared to the stationary table position. The most unpleasant factor at 7 T was the extensive examination duration, while potentially field-dependent sensations were rated less bothersome. In summary, our study indicates that although certain sensations increase at 7 T compared to 1.5 T, they are unlikely to hinder the use of 7 T MRI as a clinical diagnostic tool. PMID- 21598287 TI - Atractyloside induces low contractile reaction of arteriolar smooth muscle through mitochondrial damage. AB - Atractyloside is the principal naturally occurring active ingredient in ethnomedicines and animal grazing forage. Evidence that atractyloside can induce opening of the mitochondrial permeability transition pore (mPTP) indicates that mitochondrial mechanisms may play an important role in pathophysiological lesions of the heart, liver and kidney after atractyloside poisoning. Therefore, in this study we investigated the association of atractyloside-induced mitochondrial damage in arteriolar smooth muscle cells (ASMCs) with contractile reaction. Atractyloside led to depolarized and swollen or damaged ASMC mitochondria, which might be related to the concentration-dependent induction of mPTP opening. Relative ATP content in ASMCs was significantly reduced by 48%, 63% and 66% of control when cells were treated with 7.5, 10, and 15 um atractyloside for 10 min, respectively, and ASMCs were hyperpolarized. In addition, the contractile responsiveness of ASMCs was eventually weakened. These results suggest that atractyloside has a toxic effect on vasoreactivity, which is possibly related to mitochondrial damage. PMID- 21598288 TI - A statistical model for under- or overdispersed clustered and longitudinal count data. AB - We propose a likelihood-based model for correlated count data that display under- or overdispersion within units (e.g. subjects). The model is capable of handling correlation due to clustering and/or serial correlation, in the presence of unbalanced, missing or unequally spaced data. A family of distributions based on birth-event processes is used to model within-subject underdispersion. A computational approach is given to overcome a parameterization difficulty with this family, and this allows use of common Markov Chain Monte Carlo software (e.g. WinBUGS) for estimation. Application of the model to daily counts of asthma inhaler use by children shows substantial within-subject underdispersion, between subject heterogeneity and correlation due to both clustering of measurements within subjects and serial correlation of longitudinal measurements. The model provides a major improvement over Poisson longitudinal models, and diagnostics show that the model fits well. PMID- 21598289 TI - Sex- and brain region-specific role of cytochrome c oxidase in 1-methyl-4 phenylpyridinium-mediated astrocyte vulnerability. AB - Parkinson's disease is a neurodegenerative disorder characterized by a sex and brain region specificity, showing a higher incidence in men than in women, which is caused by cell death of mainly dopaminergic neurons in the mesencephalon. Mitochondrial toxins are often used to trigger and mimic neurodegenerative processes. Thus, systemic application of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induces Parkinsonian symptoms, indicating a causative or consequent involvement of mitochondria. Therefore, mitochondria of neural cells may demonstrate a sex and brain region specificity with respect to structural and functional characteristics of these organelles during toxic and degenerative processes. The application of MPTP in vivo and its toxic derivative 1-methyl-4-phenylpyridinium (MPP(+) ) in vitro represent a well-accepted experimental model of Parkinson's disease. Aside from the known effects of MPP(+) on mitochondria and neural cell survivability and with respect to the supportive role of astrocytes for neuronal function, we aimed to demonstrate the involvement of cytochrome c oxidase subunit IV isoform expression in energy and reactive oxygen species production taking part in an impairment of astrocyte survival. MPP(+) caused a specific increase of COX IV-2 transcript and protein levels in male mesencephalic astrocytes, accompanied by decreased ATP and increased reactive oxygen species levels and elevated apoptotic cell death, which were more pronounced in mesencephalic than in cortical astrocytes from male than from female mice. Our data suggest that MPP(+) acts on astrocytes in a sex- and brain region-specific manner involving cytochrome c oxidase isoform expression in an impairment of energy production and elevated oxidative stress levels, which represent hallmarks of neurodegenerative diseases. PMID- 21598290 TI - Development of the excretory system in the polyplacophoran mollusc, Lepidochitona corrugata: the protonephridium. AB - A single pair of protonephridia is the typical larval excretory organ of molluscs. Their presence in postlarval developmental stages was discovered only recently. We found that the protonephridia of the polyplacophoran mollusc, Lepidochitona corrugata, achieve their most elaborate differentiation and become largest during the postlarval period. This study describes the protonephridia of L. corrugata using light and electron microscopy and interactive three dimensional visualization. We focus on the postlarval developmental period, in which the protonephridia consist of three parts: the terminal part with the ultrafiltration sites at the distal end, the voluminous protonephridial kidney, and the efferent nephroduct leading to the nephropore. The ultrafiltration sites show filtration slits between regularly arranged thin pedicles. The ciliary flame originates from both the terminal cell and the duct cells of the terminal portion. The efferent duct also shows ciliation. The most conspicuous structures, the protonephridial kidneys, are voluminous swellings composed of reabsorptive cells ("nephrocytes"). These cells exhibit strong vacuolization and an infolding system increasing the basal surface. The protonephridial kidneys, previously not reported at such a level of organization in molluscs, strikingly resemble (metanephridial) kidneys of adult molluscan excretory systems. PMID- 21598291 TI - Morphological variation of the palatal organ and chewing pad of catostomidae (teleostei: cypriniformes). AB - We studied the morphology and shape variation of the palatal organ and chewing pad of sucker fishes, family Catostomidae. The palatal organ is a muscularized structure that forms a large mass on the roof of the posterior part of the buccopharyngeal cavity in cypriniform fishes. It functions in coordination with the branchial arches to separate food items from inorganic debris during feeding. The palatal organ exhibits considerable variability in morphology among catostomids. It is shorter, narrower, and thinner in species of the subfamily Cycleptinae (e.g., Cycleptus elongatus) than in other catostomid subfamilies. The thickest and widest palatal organ is seen in species of the subfamily Ictiobinae (e.g., Ictiobus cyprinellus). The shape and size of the palatal organ generally varies between these extremes in species of subfamily Catostominae (e.g., Catostomus and Moxostoma species). Principal components analysis and analysis of variance has differentiated means of various palatal organ measurements for each monophyletic subfamily and tribe of Catostomidae with statistical significance. These results corroborate previously established typological classification of catostomids based on pharyngeal tooth count, pharyngeal tooth morphology, and diet. A keratinized chewing pad forms on the posterior surface of the palatal organ in catostomids or on a skeletal process in cyprinids and serves as an occlusion surface for pharyngeal teeth. The chewing pad is lunate in catostomids and generally ovoid in cyprinids. It is absent from the species of loaches (e.g., botiids, cobitids, and nemacheilids) and gyrinocheilids examined. A synonymy of terms used in the past to describe the palatal organ and chewing pad of Cypriniformes is provided. PMID- 21598292 TI - Immunohistological classification of ionocytes in the external gills of larval Japanese black salamander, Hynobius nigrescens Stejneger. AB - In this cytological and immunohistological study, we clarified the localization of the membrane transporters Na(+) , K(+) -ATPase (NKA), vacuolar-type H(+) ATPase (VHA), and epithelial sodium channel (ENaC) and distinguished ionocyte subtypes in the gill of the Japanese salamander (Hynobius nigrescens). In larvae (IY stages 43-65), NKA immunoreactivity was observed on the basolateral plasma membrane in more than 60% cells and less than 20% cells in the primary filaments and secondary lamellae of the external gills, respectively. VHA immunoreactivity was observed on the apical membrane of some epithelial cells in the secondary lamellae of the external gills. High ENaCalpha immunoreactivity was widely observed on the apical cell membrane of a population of squamous cells, presumably pavement cells (PVCs), and mitochondria-rich cells (MRCs), in the primary filaments and secondary lamellae of the external gills. Using double immunofluorescence microscopy, epithelial cell types involved in ionic regulation were characterized and divided into three ionocyte types: NKA-, NKA- and ENaC-, and VHA-positive cells. VHA-immunoreactive cells as well as NKA-positive cells were observed during IY stages 43-65 of the salamander larvae. During late stages of metamorphosis, NKA, VHA, and ENaCalpha immunoreactivities in the external gills decreased and finally disappeared during the completion of metamorphosis (IY stage 68). PVCs and MRCs in the external gills are probably involved in acid base balance regulation and osmoregulation in urodele amphibian larvae. The results are discussed in relation to the ionocytes previously reported in fish gills and the frog skin epithelium. PMID- 21598293 TI - Evaluating neurophylogenetic patterns in the larval nervous systems of brachiopods and their evolutionary significance to other bilaterian phyla. AB - Recent structural analyses of invertebrate nervous systems have supported hypotheses stating that specific developmental and cytological aspects of larval and adult brains are conserved among bilaterian animals. Opposing views argue that structural similarities in larval nervous systems may be the result of convergent evolution and that the developmental diversity of adult brains is more indicative of several independent origins. Here, I use various cytological probes, confocal microscopy, and reconstruction techniques to investigate the cellular diversity within the larval nervous systems of Glottidia pyramidata and Terebratalia transversa (Brachiopoda). Neuronal cell types are compared among the rhynchonelliform, linguliform, and craniiform brachiopods as well as the phoronids. Although the respective larval types of the previously mentioned systematic groups clearly diverge in the neuroarchitecture of their larval apical organs (and nervous systems in general), a ground plan is proposed based on shared, centrally-located, peptidergic neuronal cell types that can be compared with similar cell types in other lophotrochozoan phyla (bryozoans and spiralians). Assessing hierarchal levels of homology within and among the nervous systems of morphologically disparate phyla is challenging in that many phyla share early developmental signals that induce the specification of the neural ectoderm, clouding our ability to discern divergent larval and juvenile brain structure. Solving these problems will require a combined effort involving both traditional and more recent cytological techniques with a diversity of molecular probes that will better map the neuronal complexity of diverse invertebrate nervous systems. PMID- 21598294 TI - Oropharyngeal morphology in the basal tortoise Manouria emys emys with comments on form and function of the testudinid tongue. AB - In tetrapods, the ability to ingest food on land is based on certain morphological features of the oropharynx in general and the feeding apparatus in particular. Recent paleoecological studies imply that terrestrial feeding has evolved secondarily in turtles, so they had to meet the morphological oropharyngeal requirements independently to other amniotes. This study is designed to improve our limited knowledge about the oropharyngeal morphology of tortoises by analyzing in detail the oropharynx in Manouria emys emys. Special emphasis is placed on the form and function of the tongue. Even if Manouria is considered a basal member of the only terrestrial turtle clade and was hypothesized to have retained some features reflecting an aquatic ancestry, Manouria shows oropharyngeal characteristics found in more derived testudinids. Accordingly, the oropharyngeal cavity in Manouria is richly structured and the glands are large and complexly organized. The tongue is large and fleshy and bears numerous slender papillae lacking lingual muscles. The hyolingual skeleton is mainly cartilaginous, and the enlarged anterior elements support the tongue and provide insertion sides for the well-developed lingual muscles, which show striking differences to other reptiles. We conclude that the oropharyngeal design in Manouria differs clearly from semiaquatic and aquatic turtles, as well as from other reptilian sauropsids. PMID- 21598295 TI - Cytotoxic property of surfactant-cobalt(III) complexes on a human breast cancer cell line. AB - The cancer chemotherapeutic potential of surfactant-cobalt(III) complexes, cis [Co(bpy)(2)(C(14)H(29)NH(2))Cl](ClO(4))(2).3 H(2)O (1) and cis [Co(phen)(2)(C(14)H(29)NH(2))Cl](ClO(4))(2).3 H(2)O (2) (bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline) on MCF-7 breast cancer cell was determined adopting MTT assay and specific staining techniques. The complexes affected the viability of the cells significantly and the cells succumbed to apoptosis as seen in the changes in the nuclear morphology and cytoplasmic features. Since the complex 2 appeared to be more potent, further assays were carried out on the complex 2. Single-cell electrophoresis indicated DNA damage. The translocation of phosphatidyl serine and loss of mitochondrial potential was revealed by annexin V Cy3 staining and JC-1 staining respectively. Western blot analysis revealed up regulation of pro-apoptotic p53 and down-regulation of anti-apoptotic Bcl-2 protein. Taken together, the surfactant-cobalt(III) complex 2 would be a potential candidate for further investigation for application as a chemotherapeutic for cancers in general and estrogen receptor-positive breast cancer in particular. PMID- 21598296 TI - Synthesis and pharmacological evaluation of a potent and selective sigma1 receptor antagonist with high antiallodynic activity. AB - Based on the pharmacophore model of Glennon the conformationally restricted sigma(1) receptor ligand 2 with a 1,3-dioxane moiety has been designed and synthesized. The three step synthesis (transacetalization with pentane-1,3,5 triol, tosylation, and nucleophilic substitution with benzylamine) provided diastereoselectively the cis-configured 1,3-dioxane 2 in good yields. The 1,3 dioxane 2 represents a potent sigma(1) receptor ligand (K(i) = 19 nM) with moderate selectivity over the sigma(2) subtype (K(i) = 92 nM) and excellent selectivity against more than 60 other targets. Additionally the hERG K(+) channel is not affected by 2. In the capsaicin assay 2 showed extraordinarily high analgesic activity with more than 70% analgesia at the very low dose of 0.25 mg/kg body weight, which indicates sigma(1) antagonistic activity. Since 2 does only interact with sigma(1) receptors, the in-vivo antiallodynic activity of 2 must be attributed to the sigma(1) antagonistic activity. PMID- 21598297 TI - Synthesis and biological activities of 2-amino-thiazole-5-carboxylic acid phenylamide derivatives. AB - In an attempt to develop potent and selective anti-tumor drugs, a series of novel 2-amino-thiazole-5-carboxylic acid phenylamide derivatives were designed based on the structure of dasatinib. All compounds were synthesized by a systematic combinatorial chemical approach. Biological evaluation revealed that N-(2-chloro 6-methylphenyl)-2-(2-(4-methylpiperazin-1-yl)acetamido)thiazole-5-carboxamide (6d) exhibited high antiproliferative potency on human K563 leukemia cells comparable to dasatinib. Against mammary and colon carcinoma cells 6d was either inactive (MDA-MB 231) or distinctly less active (MCF-7 and HT-29: IC(50) = 20.2 and 21.6 uM, respectively). Dasatinib showed at each cell line IC(50) < 1 uM. The results of this structure activity relationship study clearly documented that the pyrimidin-4-ylamino core of dasatinib is responsible for the anti-tumor activity against non-leukemia cell lines. PMID- 21598298 TI - Thienopyrimidines as novel inhibitors of Mycobacterium tuberculosis: synthesis and in-vitro studies. AB - A series of novel 5,6-unsubstituted thieno-[2,3-d]-pyrimidines has been synthesized and tested for growth inhibition of Mycobacterium tuberculosis H37Rv. Of twelve compounds synthesized eleven have shown antimycobacterial activity that differs in potency. Compounds 7b, 7c, 7d, 7e, 7f, and 7g exhibited good antimycobacterial activity. MIC values of the compounds tested were comparable with pyrazinamide. Six compounds which have shown good antimycobacterial activity were also subjected for cytotoxicity studies and were found to possess poor cytotoxicity. The study indicates the definite need for focusing attention on thienopyrimidines for further lead optimization. PMID- 21598299 TI - EBP50 is involved in the regulation of vascular smooth muscle cell migration and cytokinesis. AB - Ezrin, Radixin, Moesin binding phosphoprotein 50 (EBP50) is a scaffold protein that possesses two PDZ interacting domains. We have shown that, in isolated artery stimulated with noradrenaline, EBP50 interacts with several elements of the cytoskeleton. However, the contribution of EBP50 to the organization of the cytoskeleton is unknown. We have used primary cultured vascular smooth muscle cells to investigate the involvement of EBP50 in the regulation of cell architecture, motility and cell cycle, and to identify its target proteins and subsequent action mechanism. The results showed that depletion of EBP50 by siRNA transfection induced changes in cell architecture and increased cell migration. The same phenotype was induced by inhibition of myosin IIa and this effect was not additive in cells depleted for EBP50. Moreover, a larger proportion of binucleated cells was observed after EBP50 depletion, indicating a defect in cytokinesis. The identification, after co-immunoprecipitation, of a direct interaction of EBP50 with both tubulin and myosin IIa suggested that EBP50 could regulate cell migration and cytokinesis by linking myosin IIa fibers and microtubule network. Indeed, depletion of EBP50 also dismantled myosin IIa fibers and induced the formation of stable microtubules in lamellae expansions and Rac1 activation. This signaling cascade leads to the formation of lamellipodia, trailing tails and decrease of focal adhesion formation, triggering cell migration. PMID- 21598300 TI - Inhibition of cell growth and induction of apoptosis in non-small cell lung cancer cells by delta-tocotrienol is associated with notch-1 down-regulation. AB - Lung cancer is the leading cause of death among all cancers. Non-small cell lung cancer accounts for 80% of lung cancer with a 5-year survival rate of 16%. Notch pathway, especially Notch-1 is up-regulated in a subgroup of non-small cell lung cancer patients. Since Notch-1 signaling plays an important role in cell proliferation, differentiation, and apoptosis, down-regulation of Notch-1 may exert anti-tumor effects. The objective of this study was to investigate whether delta-tocotrienol, a naturally occurring isoform of Vitamin E, inhibits non-small cell lung cancer cell growth via Notch signaling. Treatment with delta tocotrienol resulted in a dose and time dependent inhibition of cell growth, cell migration, tumor cell invasiveness, and induction of apoptosis. Real-time RT-PCR and western blot analysis showed that antitumor activity by delta-tocotrienol was associated with a decrease in Notch-1, Hes-1, Survivin, MMP-9, VEGF, and Bcl-XL expression. In addition, there was a decrease in NF-kappaB-DNA binding activity. These results suggest that down-regulation of Notch-1, via inhibition of NF kappaB signaling pathways by delta-tocotrienol, could provide a potential novel approach for prevention of tumor progression in non-small cell lung cancer. PMID- 21598302 TI - Complement C3a and C5a modulate osteoclast formation and inflammatory response of osteoblasts in synergism with IL-1beta. AB - There is a tight interaction of the bone and the immune system. However, little is known about the relevance of the complement system, an important part of innate immunity and a crucial trigger for inflammation. The aim of this study was, therefore, to investigate the presence and function of complement in bone cells including osteoblasts, mesenchymal stem cells (MSC), and osteoclasts. qRT PCR and immunostaining revealed that the central complement receptors C3aR and C5aR, complement C3 and C5, and membrane-bound regulatory proteins CD46, CD55, and CD59 were expressed in human MSC, osteoblasts, and osteoclasts. Furthermore, osteoblasts and particularly osteoclasts were able to activate complement by cleaving C5 to its active form C5a as measured by ELISA. Both C3a and C5a alone were unable to trigger the release of inflammatory cytokines interleukin (IL)-6 and IL-8 from osteoblasts. However, co-stimulation with the pro-inflammatory cytokine IL-1beta significantly induced IL-6 and IL-8 expression as well as the expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) indicating that complement may modulate the inflammatory response of osteoblastic cells in a pro-inflammatory environment as well as osteoblast-osteoclast interaction. While C3a and C5a did not affect osteogenic differentiation, osteoclastogenesis was significantly induced even in the absence of RANKL and macrophage-colony stimulating factor (M-CSF) suggesting that complement could directly regulate osteoclast formation. It can therefore be proposed that complement may enhance the inflammatory response of osteoblasts and increase osteoclast formation, particularly in a pro-inflammatory environment, for example, during bone healing or in inflammatory bone disorders. PMID- 21598301 TI - Cooperative DNA and histone binding by Uhrf2 links the two major repressive epigenetic pathways. AB - Gene expression is regulated by DNA as well as histone modifications but the crosstalk and mechanistic link between these epigenetic signals are still poorly understood. Here we investigate the multi-domain protein Uhrf2 that is similar to Uhrf1, an essential cofactor of maintenance DNA methylation. Binding assays demonstrate a cooperative interplay of Uhrf2 domains that induces preference for hemimethylated DNA, the substrate of maintenance methylation, and enhances binding to H3K9me3 heterochromatin marks. FRAP analyses revealed that localization and binding dynamics of Uhrf2 in vivo require an intact tandem Tudor domain and depend on H3K9 trimethylation but not on DNA methylation. Besides the cooperative DNA and histone binding that is characteristic for Uhrf2, we also found an opposite expression pattern of uhrf1 and uhrf2 during differentiation. While uhrf1 is mainly expressed in pluripotent stem cells, uhrf2 is upregulated during differentiation and highly expressed in differentiated mouse tissues. Ectopic expression of Uhrf2 in uhrf1(-/-) embryonic stem cells did not restore DNA methylation at major satellites indicating functional differences. We propose that the cooperative interplay of Uhrf2 domains may contribute to a tighter epigenetic control of gene expression in differentiated cells. PMID- 21598303 TI - Tumor necrosis factor-alpha treatment of HepG2 cells mobilizes a cytoplasmic pool of ERp57/1,25D3-MARRS to the nucleus. AB - ERp57/PDIA3/1,25-MARRS has diverse functions and multiple cellular locations in various cell types. While classically described as an endoplasmic reticulum (ER) resident protein, ERp57 has a nuclear location sequence (NLS) and can enter the nucleus from the cytosol to alter transcription of target genes. Dysregulation and variable expression of ERp57 is associated with a variety of cancers including hepatocellular carcinoma (HCC). We investigated the dynamic mobility of ERp57 in an HCC cell line, HepG2, to better understand the movement and function of the non-ER resident pool of ERp57. Subcellular fractionation indicated ERp57 is highly expressed in the ER with a smaller cytoplasmic pool in HepG2 cells. Utilizing an ERp57 green fluorescent protein fusion construct created with and without a secretory signal sequence, we found that cytoplasmic ERp57 translocated to the nucleus within 15 min after tumor necrosis factor-alpha (TNF-alpha) treatment. Protein kinase C activators including 1,25-dihydroxyvitamin D(3) and phorbol myristate acetate did not trigger nuclear translocation of ERp57, indicating translocation is PKC independent. To determine if an interaction between the rel homology binding domain in ERp57 and the nuclear factor-kappaB subunit, p65, occurred after TNF-alpha treatment and could account for nuclear movement, co-immunoprecipitation was performed under control and conditions that stabilized labile disulfide bonds. No support for a functional interaction between p65 and ERp57 after TNF-alpha treatment was found in either case. Immunostaining for both ERp57-GFP and p65 after TNF-alpha treatment indicated that nuclear translocation of these two proteins occurs independently in HepG2 cells. PMID- 21598304 TI - Apolipoprotein A-I mimetic peptide L-4F prevents myocardial and coronary dysfunction in diabetic mice. AB - Diabetes is a major health problem associated with adverse cardiovascular outcomes. The apolipoprotein A-I mimetic peptide L-4F is a putative anti-diabetic drug, has antioxidant and anti-inflammatory proprieties and improves endothelial function. In obese mice L-4F increases adiponectin levels, improving insulin sensitivity, and reducing visceral adiposity. We hypothesized that the pleiotropic actions of L-4F can prevent heart and coronary dysfunction in a mouse model of genetically induced Type II diabetes. We treated db/db mice with either L-4F or vehicle for 8 weeks. Trans-thoracic echocardiography was performed; thereafter, isolated hearts were subjected to ischemia/reperfusion (IR). Glucose, insulin, adiponectin, and pro-inflammatory cytokines (IL-1beta, TNF-alpha, MCP-1) were measured in plasma and HO-1, pAMPK, peNOS, iNOS, adiponectin, and superoxide in cardiac tissue. In db/db mice L-4F decreased accumulation of subcutaneous and total fat, and increased insulin sensitivity and adiponectin levels while lowering inflammatory cytokines (P < 0.05). L-4F normalized in vivo left ventricular (LV) function of db/db mice, increasing (P < 0.05) fractional shortening and decreasing (P < 0.05) LV dimensions. In I/R experiments, L-4F prevented coronary microvascular resistance from increasing and LV function from deteriorating in the db/db mice. These changes were associated with increased cardiac expression of HO-1, pAMPK, peNOS, and adiponectin and decreased levels of superoxide and iNOS (P < 0.01). In the present study we showed that L-4F prevented myocardial and coronary functional abnormalities in db/db mice. These effects were associated with stimulation of HO-1 resulting in increased levels of anti-inflammatory, anti-oxidative, and vasodilatatory action through a mechanism involving increased levels of adiponectin, pAMPK, and peNOS. PMID- 21598305 TI - Effects of nonylphenol on the production of progesterone on the rats granulosa cells. AB - We investigated the effects of nonylphenol (NP) on release of progesterone (PG) by granulosa cells (GCs) of rats in vitro and in vivo. First, GCs were treated with different doses of NP for 2-24 h alone or with human chorionic gonadotropin (hCG). Maximal PG secretion at 8 h noted, GCs were treated for 2 h with hCG, 8 bromo-adenosine 3':5'-cyclic monophosphate (8-Br-cAMP), forskolin, A23187, nifedipine, and pregnelonone to evaluate the NP effects on PG steroidogenesis. Results indicated that all of chemicals except nifedipine stimulated the PG release compared to vehicle, but the stimulatory effects could not be enhanced by different doses of NP. Second, GCs were isolated to react with hCG, 8-Br-cAMP and PD98059 after the immature female rats gavaged with different doses of NP (ONP) for 7 days. PG released significantly when rats treated with oral NP 100 compared to 0 ug/kg/day. Third, GCs collected from the female offspring of mother rats which gavaged with NP 100 ug/kg/day for 21 days during pregnancy (MONP) reacted with different doses of chemicals. The results showed that PG release in the presence of chemicals was significantly higher in ONP and MONP groups; however, this stimulation was not noted by dose-dependent. The plasma concentration of PG was higher in ONP (100 ug/kg/day) and the offspring of MONP groups. The steroidogenic acute regulatory (StAR) protein expressed higher in all three groups by Western blotting. This study results indicated that low dose of NP stimulated PG release in rat GCs by activation of StAR protein. PMID- 21598306 TI - C-kit mutations and PKC crosstalks: PKC translocates to nucleous only in cells HMC560,816. AB - The human mast cell lines HMC-1(560) and HMC-1(560,816) were used to study histamine release, Ca(2+) signaling and protein kinase C (PKC) localization and expression, with phorbol 12-myristate 13-acetate (PMA). Both sublines carry activating mutations in the proto-oncogene of c-kit that cause autophosphorylation and permanent c-kit tyrosine kinase activation. Both have the Gly-560 -> Val mutation but only the second carries the Asp-816 -> Val mutation. In this study, it was observed that the stimulation of PKC has different effects in HMC-1(560) and HMC-1(560,816) and this would be related to the difference in activating mutations in both mast cell lines. PKC activation increases ionomycin induced histamine release in HMC-1(560) . This article demonstrates an opposite histamine response in HMC-1(560,816) cells, even though classical PKCs are the family of isozymes responsible for this effect in both cellular lines. Furthermore, it can be observed that upon cell stimulation with PMA, primarily cytosolic PKC translocates to the nucleous in HMC-1(560,816) cells, but not in HMC-1(560) cell line. PMID- 21598307 TI - Retraction: Genistein protects genioglossus myocyte against hypoxia-induced injury through PI3K-Akt and ERK MAPK pathways. AB - RETRACTION: The following article from Journal of Cellular Biochemistry, Genistein protects genioglossus myocyte against hypoxia-induced injury through PI3K-Akt and ERK MAPK pathways by Wanghui Ding and Yuehua Liu, posted online on May 19, 2011 in Wiley Online Library (onlinelibrary.wiley.com), has been retracted by agreement between the authors, the journal Editor in Chief, Dr. Gary S. Stein and Wiley-Liss, Inc. The retraction has been made as authorization to publish was not granted by one of the funding bodies. PMID- 21598308 TI - Bisphosphonate treatment delays stress fracture remodeling in the rat ulna. AB - Because bisphosphonates (BPs) are potent inhibitors of bone resorption, we hypothesized that they would retard direct remodeling of stress fractures. The aim of this study was to determine the effect of risedronate on direct remodeling and woven bone callus formation following stress fracture formation in the rat ulna. In 135 adult female Wistar rats, cyclic loading of the ulna created stress fractures. Rats were treated daily with oral saline, or risedronate at 0.1 or 1.0 mg/kg. From each bone, histomorphometry was performed on sections stained with toluidine blue at a standard level along the fracture. The high dose of risedronate caused a significant decrease in the percentage of repaired stress fracture and bone resorption along the stress fracture line at 6 and 10 weeks after loading (p < 0.05). At this dose, intracortical resorption was significantly reduced at 10 weeks after loading and intracortical new bone area was significantly reduced at 6 and 10 weeks. Woven bone formation and consolidation phases of stress fracture repair were not affected by low or high doses of risedronate. In conclusion, high dose bisphosphonate treatment impaired healing of a large stress fracture line by reducing the volume of bone resorbed and replaced during remodeling. We also confirmed that periosteal callus formation was not adversely affected by risedronate treatment. PMID- 21598309 TI - Differential gene expression and immunolocalization of insulin-like growth factors and insulin-like growth factor binding proteins between experimental nonunions and standard healing fractures. AB - Insulin-like growth factors (IGF-I/II) are important growth factors in bone, and their actions are regulated by six IGF binding proteins (IGFBPs). However, little is known about their exact functions in fracture healing. The aim of this study was to compare the gene expression and immunolocalization of IGFs and IGFBPs between standard healing fractures and nonunions using rat experimental models. Standard healing fractures and nonunions produced by periosteal cauterization at the fracture site were created in rat femurs. At postfracture days 3, 7, 10, 14, 21, and 28, total RNA was extracted from the callus of the healing fractures and the fibrous tissue of the nonunions, and gene expression were analyzed by real time PCR. Additionally, immunolocalization of these proteins was studied by immunohistochemistry at postfracture days 7, 14, and 21. In nonunions, the gene expression of IGF-I/II and IGFBP-6 was significantly higher, and that of IGFBP-5 was significantly lower at several time points. The immunolocalization of IGF I/II and IGFBP-5 was widely distributed in both models. In contrast, that of IGFBP-6 was barely detected in the fracture callus. In conclusion, our results suggest that IGFs/IGFBPs may have important roles not only in fracture healing but also in nonunion formation. PMID- 21598310 TI - Mechanisms of proton spin dephasing in a system of magnetic particles. AB - For protons diffusing among a system of magnetic particles, the process by which initial phase coherence is lost depends substantially on particle size. In this article, evidence for three dephasing mechanisms is presented: an incremental process at small particle sizes (motional averaging regime), a discrete process at intermediate particle sizes (visit limited regime), and a continuous process at large particle sizes (static dephasing regime). While motional averaging regime and static dephasing regime are well known, the distinct dynamics in visit limited regime are often overlooked. Revisiting earlier analytic treatments for the dynamics in this regime, Monte Carlo simulations are performed to extract the details of dephasing and to test the concept of an inner zone of rapid dephasing herein named the full dephasing zone. It is shown that the emergence of a full dephasing zone marks the transition from motional averaging regime to visit limited regime since protons can be fully dephased in a single encounter. Moving from the visit limited regime to the static dephasing regime, a crossover between a purely discrete process and a purely continuous process occurs. Developing a simple model of the dephasing process, the average dephasing time is demonstrated to be relatively constant thus giving insight into the long lasting plateau in the relaxation rate. PMID- 21598311 TI - Extensive aspartoacylase expression in the rat central nervous system. AB - Aspartoacylase (ASPA) catalyzes deacetylation of N-acetylaspartate (NAA) to generate acetate and aspartate. Mutations in the gene for ASPA lead to reduced acetate availability in the CNS during development resulting in the fatal leukodystrophy Canavan disease. Highly specific polyclonal antibodies to ASPA were used to examine CNS expression in adult rats. In white matter, ASPA expression was associated with oligodendrocyte cell bodies, nuclei, and some processes, but showed a dissimilar distribution pattern to myelin basic protein and oligodendrocyte specific protein. Microglia expressed ASPA in all CNS regions examined, as did epiplexus cells of the choroid plexus. Pial and ependymal cells and some endothelial cells were ASPA positive, as were unidentified cellular nuclei throughout the CNS. Astrocytes did not express ASPA in their cytoplasm. In some fiber pathways and nerves, particularly in the brainstem and spinal cord, the axoplasm of many neuronal fibers expressed ASPA, as did some neurons. Acetyl coenzyme A synthase immunoreactivity was also observed in the axoplasm of many of the same fiber pathways and nerves. All ASPA-immunoreactive elements were unstained in brain sections from tremor rats, an ASPA-null mutant. The strong expression of ASPA in oligodendrocyte cell bodies is consistent with a lipogenic role in myelination. Strong ASPA expression in cell nuclei is consistent with a role for NAA-derived acetate in nuclear acetylation reactions, including histone acetylation. Expression of ASPA in microglia may indicate a role in lipid synthesis in these cells, whereas expression in axons suggests that some neurons can both synthesize and catabolize NAA. PMID- 21598314 TI - Nanoporous gyroid nickel from block copolymer templates via electroless plating. PMID- 21598313 TI - White electroluminescence from star-like single polymer systems: 2,1,3 benzothiadiazole derivatives dopant as orange cores and polyfluorene host as six blue arms. PMID- 21598312 TI - Transcription factor p53 influences microglial activation phenotype. AB - Several neurodegenerative diseases are influenced by the innate immune response in the central nervous system (CNS). Microglia have proinflammatory and subsequently neurotoxic actions as well as anti-inflammatory functions that promote recovery and repair. Very little is known about the transcriptional control of these specific microglial behaviors. We have previously shown that in HIV-associated neurocognitive disorders (HAND), the transcription factor p53 accumulates in microglia and that microglial p53 expression is required for the in vitro neurotoxicity of the HIV coat glycoprotein gp120. These findings suggested a novel function for p53 in regulating microglial activation. Here, we report that in the absence of p53, microglia demonstrate a blunted response to interferon-gamma, failing to increase expression of genes associated with classical macrophage activation or secrete proinflammatory cytokines. Microarray analysis of global gene expression profiles revealed increased expression of genes associated with anti-inflammatory functions, phagocytosis, and tissue repair in p53 knockout (p53(-/-)) microglia compared with those cultured from strain matched p53 expressing (p53(+/+)) mice. We further observed that p53(-/-) microglia demonstrate increased phagocytic activity in vitro and expression of markers for alternative macrophage activation both in vitro and in vivo. In HAND brain tissue, the alternative activation marker CD163 was expressed in a separate subset of microglia than those demonstrating p53 accumulation. These data suggest that p53 influences microglial behavior, supporting the adoption of a proinflammatory phenotype, while p53 deficiency promotes phagocytosis and gene expression associated with alternative activation and anti-inflammatory functions. PMID- 21598315 TI - Stretchable conductors with ultrahigh tensile strain and stable metallic conductance enabled by prestrained polyelectrolyte nanoplatforms. PMID- 21598316 TI - High-speed flexible organic field-effect transistors with a 3D structure. PMID- 21598317 TI - A facile approach to superhydrophilic-superhydrophobic patterns in porous polymer films. PMID- 21598320 TI - Azobenzene-based colorimetric chemosensors for rapid naked-eye detection of mercury(II). AB - Two new highly selective colorimetric chemosensors for Hg(2+), based on azobenzene and highly selective Hg(2+)-promoted deprotection of a dithioacetal have been designed and synthesized. In the presence of as little as 20 MUM Hg(2+), the sensors change their color from light yellow to deep red, which can easily be observed by the naked eye. The underlying signaling mechanism is intramolecular charge transfer (ICT). The sensors have good selectivity for Hg(2+) with respect to several common alkali, alkaline earth, and transition metal ions. Furthermore, they can be used for in-the-field measurements by virtue of a dipstick approach without any additional equipment. PMID- 21598321 TI - Unique self-anhydride formation in the degradation of cytidine-5' monophosphosialic acid (CMP-Neu5Ac) and cytidine-5'-diphosphosialic acid (CDP Neu5Ac) and its application in CMP-sialic acid analogue synthesis. AB - Sialyloligosaccharides are synthesised by various glycosyltransferases and sugar nucleotides. All of these nucleotides are diphosphate compounds except for cytidine-5'-monophosphosialic acid (CMP-Neu5Ac). To obtain an insight into why cytidine-5'-diphosphosialic acid (CDP-Neu5Ac) has not been used for the sialyltransferase reaction and why it is not found in biological organisms, the compound was synthesised. This synthesis provided the interesting finding that the carboxylic acid moiety of the sialic acid attacks the attached phosphate group. This interaction yields an activated anhydride between carboxylic acid and the phosphate group and leads to hydrolysis of the pyrophosphate linkage. The mechanism was demonstrated by stable isotope-labelling experiments. This finding suggested that CMP-Neu5Ac might also form the corresponding anhydride structure between carboxylic acid and phosphate, and this seems to be the reason why CMP Neu5Ac is acid labile in relation to other sugar nucleotides. To confirm the role of the carboxylic acid, CMP-Neu5Ac derivatives in which the carboxylic acid moiety in the sialic acid was substituted with amide or ester groups were synthesised. These analogues clearly exhibited resistance to acid hydrolysis. This result indicated that the carboxylic acid of Neu5Ac is associated with its stability in solution. This finding also enabled the development of a novel chemical synthetic method for CMP-Neu5Ac and CMP-sialic acid derivatives. PMID- 21598322 TI - Nanosized vanadium, tungsten and molybdenum oxide clusters grown in porous chitosan microspheres as promising hybrid materials for selective alcohol oxidation. AB - The ability of chitosan biopolymer to coordinate vanadium, tungsten and molybdenum metallic species and to control their mineralisation growth provides a new family of surface-reactive organic-inorganic hybrid microspheres. Drying the resulting materials under supercritical conditions allowed the gel network dispersion to be retained, thereby leading to a macroporous catalyst with surface areas ranging from 253 to 278 m(2) g(-1). On account of the open framework structure of these microspheres, the redox species entangled within the fibrillar network of the polysaccharide aerogels were found to be active, selective and reusable catalysts for cinamylalcohol oxidations. PMID- 21598323 TI - Chiral donor photoinduced-electron-transfer (d-PET) boronic acid chemosensors for the selective recognition of tartaric acids, disaccharides, and ginsenosides. AB - A modular approach was proposed for the preparation of chiral fluorescent molecular sensors, in which the fluorophore, scaffold, and chirogenic center can be connected by ethynyl groups, and these modules can easily be changed to other structures to optimize the molecular sensing performance of the sensors. This modular strategy to assembly chiral sensors alleviated the previous restrictions of chiral boronic acid sensors, for which the chirogenic center, fluorophore, and scaffold were integrated, thus it was difficult to optimize the molecular structures by chemical modifications. We demonstrated the potential of our new strategy by the preparation of a sensor with a larger scaffold. The photoinduced electron-transfer (PET) effect is efficient even with a large distance between the N atom and the fluorophore core. Furthermore, the rarely reported donor-PET (d-PET) effect, which was previously limited to carbazole, was extended to phenothiazine fluorophore. The contrast ratio, that is, PET efficiency of the new d-PET sensor, is increased to 8.0, compared to 2.0 with the previous carbazole d PET sensors. Furthermore, the ethynylated phenothiazine shows longer excitation wavelength (centered at 380 nm) and emission wavelength (492 nm), a large Stokes shift (142 nm), and high fluorescence quantum yield in aqueous solution (Phi=0.48 in MeOH/water, 3:1 v/v). Enantioselective recognition of tartaric acid was achieved with the new d-PET boronic acid sensors. The enantioselectivity is up to 10 (ratio of the binding constants toward D- and L-tartaric acid, k(D)/k(L)). A consecutive fluorescence enhancement/decrease was observed, thus we propose a transition of the binding stoichiometry from 1:1 to 1:2 as the analyte concentration increases, which is supported by mass spectra analysis. The boronic acid sensors were used for selective and sensitive recognition of disaccharides and glycosylated steroids (ginsenosides). PMID- 21598324 TI - Furan-oxidation-triggered inducible DNA cross-linking: acyclic versus cyclic furan-containing building blocks--on the benefit of restoring the cyclic sugar backbone. AB - Oligodeoxynucleotides incorporating a reactive functionality can cause irreversible cross-linking to the target sequence and have been widely studied for their potential in inhibition of gene expression or development of diagnostic probes for gene analysis. Reactive oligonucleotides further show potential in a supramolecular context for the construction of nanometer-sized DNA-based objects. Inspired by the cytochrome P450 catalyzed transformation of furan into a reactive enal species, we recently introduced a furan-oxidation-based methodology for cross-linking of nucleic acids. Previous experiments using a simple acyclic building block equipped with a furan moiety for incorporation into oligodeoxynucleotides have shown that cross-linking occurs in a very fast and efficient way and that substantial amounts of stable, site-selectively cross linked species can be isolated. Given the destabilization of duplexes observed upon introduction of the initially designed furan-modified building block into DNA duplexes, we explore here the potential benefits of two new building blocks featuring an extended aromatic system and a restored cyclic backbone. Thorough experimental analysis of cross-linking reactions in a series of contexts, combined with theoretical calculations, permit structural characterization of the formed species and allow assessment of the origin of the enhanced cross-link selectivity. Our experiments clearly show that the modular nature of the furan modified building blocks used in the current cross-linking strategy allow for fine tuning of both yield and selectivity of the interstrand cross-linking reaction. PMID- 21598325 TI - The truth about false unicorn (Chamaelirium luteum): total synthesis of 23R,24S chiograsterol B defines the structure and stereochemistry of the major saponins from this medicinal herb. AB - Chamaelirium luteum is used in traditional medicine systems and commercial botanical dietary supplements for the treatment of female reproductive health problems. Despite the wide use of this herb, only very limited phytochemical characterisation is available. Our investigation of C. luteum roots led to the isolation of two new steroidal saponins 1 and 2 that contain an unusual aglycone 3. The absolute configurations of these molecules were unable to be determined spectroscopically and thus the total synthesis of 3 was undertaken and achieved in 16 steps and 1.6 % overall yield from pregnenolone. The key step in the synthesis was the stereoselective installation of the side chain at C-17 and C 20, which employed anion-accelerated oxy-Cope methodology. The relative configuration of aglycone 3 was determined by X-ray crystallography of an advanced synthetic intermediate. The absolute configuration was based upon that of the pregnenolone-derived steroidal skeleton and determined to be 23R,24S. PMID- 21598326 TI - Preparation and photodynamic activities of silicon(IV) phthalocyanines substituted with permethylated beta-cyclodextrins. AB - A series of silicon(IV) phthalocyanines linked to two permethylated beta cyclodextrin moieties through different spacers at the axial positions have been synthesized and characterized. The effects of these spacers on the photophysical properties and in vitro photodynamic activities have also been examined. Having two bulky hydrophilic substituents, all of these compounds are soluble and essentially nonaggregated in DMF and even in aqueous media. The fluorescence and singlet oxygen quantum yields in DMF are lower for the analogue with the shortest separation between the amino group in the spacer and the phthalocyanine ring. The fluorescence quantum yield of this compound increases in water probably due to protonation of the amino group, which inhibits the reductive quenching process. This series of compounds also exhibit photocytotoxicity toward HT29 human colon adenocarcinoma and HepG2 human hepatocarcinoma cells with IC(50) values in the range of 0.04-1.32 MUM. The analogue with an alpha,omega-aminohydroxypentyl linker shows the highest potency, which can be ascribed to its high cellular uptake and high efficiency in generating intracellular reactive oxygen species. This compound also shows preferential localization in the lysosome, induces cell death mainly through apoptosis, and inhibits the growth of tumor in vivo. The results suggest that it is a promising photosensitizer for photodynamic therapy. PMID- 21598327 TI - Syntheses of spirocyclic oxindole-butenolides by using three-component cycloadditions of isocyanides, allenoates, and isatins. PMID- 21598328 TI - Formation of aluminium, aluminium nitride and nitrogen clusters via laser ablation of nano aluminium nitride. Laser Desorption Ionisation and Matrix Assisted Laser Desorption Ionisation Time-of-Flight Mass Spectrometry. AB - Laser Desorption Ionisation (LDI) and Matrix-Assisted Laser Desorption Ionisation (MALDI) Time-of-Flight Mass Spectrometry (TOFMS) were used to study the pulsed laser ablation of aluminium nitride (AlN) nano powder. The formation of Al(m)(+) (m=1-3), N(n)(+) (n=4, 5), AlN(n)(+) (n=1-5, 19, 21), Al(m)N(+) (m=2-3), Al(3)N(2)(+), Al(9)N(n)(+) (n=5, 7, 9, 11 and 15), Al(11)N(n)(+) (n=4, 6, 10, 12, 19, 21, 23, and 25), and Al(13)N(n)(+) (n=25, 31, 32, 33, 34, 35, and 36) clusters was detected in positive ion mode. Similarly, Al(m)(-) (m=1-3), AlN(n)( ) (n=1-3, 5), Al(m)N(-) (n=2, 3), Al(2)N(n)(-) (n=2-4, 28, 30), N(n)(-) (n=2, 3), Al(4)N(7)(-) Al(8)N(n)(-) (n=1-6), and Al(13)N(n)(-) (n=9, 18, 20, 22, 24, 26, 28, 33, 35, 37, 39, 41 and 43) clusters were observed in negative ion mode. The formation of the stoichiometric Al(10) N(10) cluster was shown to be of low abundance. On the contrary, the laser ablation of nano-AlN led mainly to the formation of nitrogen-rich Al(m)N(n) clusters in both negative and positive ion mode. The stoichiometry of the Al(m)N(n) clusters was determined via isotopic envelope analysis and computer modelling. PMID- 21598329 TI - Correlations of carbon isotope discrimination with element and ash contents in two Sabina evergreen trees in northwest China: patterns and implications. AB - Foliar carbon isotope discrimination (Delta) is widely used as an integrator of physiological plant responses to environmental change. However, the relationship between foliar Delta and mineral nutrient accumulation is still not well-known. The foliar Delta, K, Ca, Mg, Si and ash contents of S. przewalskii Kom. (SP) and S. chinensis (Lin.) Ant. (SC), two over-winter trees distributed on high altitude plateaux and lower altitude plains, respectively, were measured at monthly intervals over two years under the same growing conditions to examine the genetic and seasonal variation in foliar nutrient concentrations in relation to foliar Delta. The foliar Delta, Mg, K and ash contents were markedly lower in SP than in SC, and the foliar Si content was significantly higher in SP than SC, while the differences in Ca contents between the two Sabina trees were not significant. There was higher foliar Delta in winter than in summer for both Sabina trees. Close negative correlations of foliar Delta with K and Mg content, and significant positive correlations between foliar Delta and Si contents, were observed in SP but not in SC. Thus, higher water-use efficiency of SP than of SC is related to higher Si and lower Mg and K contents that have positive effects on the reduction of transpiration rates or stomatal conductances. The results obtained by the present study will advance the understanding of the adaptive strategies of mineral nutrition and water use in harsh environments. PMID- 21598330 TI - Seasonal variations in metabolite profiling of the fruits of Ligustrum lucidum Ait. AB - The metabolite profiling of fruits of the herb Ligustrum lucidum Ait collected during different months has been performed using ultra-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC/QTOFMS) and multivariate statistical analysis techniques. The markers such as oleuropein acid, neonuezhenide, specnuezhenide, oleuropein and ligustrosidic acid accountable for such variations were identified through the loadings plot of principal component analysis (PCA), and the tentative identification of the markers is completed by comparing the mass spectra and retention times with those of reference compounds and/or tentatively assigned by matching empirical molecular formulae and MS/MS data with those of the known compounds published. Furthermore, one of the chemical markers, such as specnuezhenide, which is water soluble, biologically active and also the predominant compound in this crude drug, was quantified by ultra-performance liquid chromatography coupled with a tunable UV detector (UPLC-TUV). The developed UPLC method provides good linearity (r(2)=0.9991), repeatability (RSD=2.96%), intra- and inter-day precisions (RSD=0.21%, 0.96%), with accuracies of 99.18-100.26% and a recovery of specnuezhenide of 97.57%. The fruits of L. lucidum Ait collected from August to December were tested. The results clearly show that the fruits of L. lucidum Ait harvested in October have the highest yields of specnuezhenide. It is also noted that the variations of content of specnuezhenide obtained by both methods have a strong correlation. This suggests that the newly proposed strategy is a reliable and simple method for the rapid discrimination of subtle variations, within the same plant species or strains, due to different seasonal collection times. PMID- 21598331 TI - Liquid chromatography/tandem mass spectrometry based targeted proteomics quantification of P-glycoprotein in various biological samples. AB - P-Glycoprotein (P-gp/ABCB1) is expressed in membrane barriers to exclude pharmacological substrates from cells, and therefore influences the ADME/Tox properties and efficacy of therapeutics. In the present study, a liquid chromatography/tandem mass spectrometry (LC/MS/MS)-mediated targeted proteomics was developed to quantitate P-gp protein. With the aid of in silico predictive tools, a unique 9-mer tryptic peptide of P-gp protein was synthesized (with the stable isotope labeled (SIL) peptide as internal standard) and applied for quantitative LC/MS/MS method development. For LC/MS/MS quantification, the N glycosylation of the peptide, polymorphism and transmembrane region was intended to be excluded during the peptide selection. The lower limit of quantification was established to be 0.025 nM with the linearity of the standard curve ranging to 20 nM of P-gp signature peptides in the matrix digested surrogate bovine serum albumin. The digestion efficiency, both the accuracy (relative error) and the precision (coefficient of variation) of the method, was verified by using the synthetic quantification peptide and the synthetic surrogate substrate peptide that mimics the sequence of tryptic peptide and associated flanking tryptic cleavage sites at the N- and C-terminals. By applying the method developed, the absolute amounts of human, dog and mouse P-gp (Mdr1a) were quantified in various biological samples. LC/MS/MS-mediated P-gp quantification was achieved as a highly sensitive, selective and reproducible assay and could be directly applicable to many current research needs related to P-gp. PMID- 21598332 TI - Possible conformational change within the desolvated and cationized sBBI/trypsin non-covalent complex during the collision-induced dissociation process. AB - Electrospray ionization mass spectrometry (ESI-MS) has become an analytical technique widely used for the investigation of non-covalent protein-protein and protein-ligand complexes due to the soft desolvation conditions that preserve the stoichiometry of the interacting partners. Dissociation studies of solvated or desolvated complexes (in the source and in the collision cell, respectively) allow access to information on protein conformation and localization of the metal ions involved in protein structure stabilization and biological activity. The complex of bovine trypsin and small soybean Bowman-Birk inhibitor (sBBI) was studied by ESI-MS to determine changes occurring within the complex during its transfer from droplets to the gas phase independently of the ion polarity. Under collision-induced dissociation (CID) conditions, unexpected binding of the Ca(2+) ion (cofactor of native trypsin) to the inhibitor molecule was observed within the desolvated sBBI/trypsin/Ca(2+) complex (with a 1:1:1 stoichiometry). This formal gas-phase migration of the calcium ion from trypsin to the inhibitor may be related to conformational rearrangements in the solvent-free and likely collapsed complex. However, under conditions leading to the increase in complex charge state, the appearance of the cationized trypsin molecule was detected during complex dissociation, thus reflecting different pathways of the evolution of complex conformation. PMID- 21598333 TI - An unusual kynurenine-containing opioid tetrapeptide from the skin gland secretion of the Australian red tree frog Litoria rubella. Sequence determination by electrospray mass spectrometry. AB - The Kyn-containing peptide FP-Kyn-L(NH(2)) is an unusual minor component of the skin peptide profile of the Australian red tree frog Litoria rubella collected from an area within a 20 kilometre radius of Alice Springs in central Australia. The structure was determined by electrospray mass spectrometry and synthesis. The major component of the skin secretion is the analogous tryptophyllin peptide FPWL(NH(2)). Both peptides show opioid activity at 10(-7) M, and are likely to act via the MU opioid receptor. PMID- 21598334 TI - Identification of individual acids in a commercial sample of naphthenic acids from petroleum by two-dimensional comprehensive gas chromatography/mass spectrometry. AB - The identification of most individual members of the complex mixtures of carboxylic acids found in petroleum ('naphthenic acids') has eluded chemists for over a century; they remain unresolved by conventional gas chromatographic methods. Recently, however, we successfully used two-dimensional comprehensive gas chromatography/mass spectrometry to identify numerous individual diamondoid acids in the naphthenic acids of oil sands process water (OSPW). We have now applied the same methods to a study of a mixture of commercially available naphthenic acids originally refined from petroleum. The results confirm that OSPW and refined petroleum contain very different distributions of acids, as noted previously, although some of the diamondoid acids recently identified in OSPW were detectable in both. Rather, two-dimensional comprehensive gas chromatography/time-of-flight mass spectrometry (GCxGC/ToF-MS) of the methyl esters of the petroleum acids and of numerous acids synthesised for comparison showed that the former comprised mainly C(8-18) straight-chain, methyl-branched, acyclic isoprenoid, cyclohexyl and isomeric octahydropentalene, perhydroindane and perhydronaphthalene (decalin) acids. Some of the latter bicyclic acids occurred as both the non-alkyl-substituted isomers and the bicyclic ethanoic and propanoic acids. Also present in minor quantities was a range of phenyl carboxylic and substituted phenyl alkanoic acids, and traces of non-acids, including trimethylnaphthalenes, again identified by comparison with the synthesised compounds. These results represent some of the first identifications of multiple individual naphthenic acids in commercial mixtures originating from petroleum and provide a basis for future studies of the petroleum geochemistry, toxicities and environmental impacts of the acids. Furthermore, characterisation of the acids will be important for improving the understanding of the role of naphthenic acids in petroleum engineering, particularly for oil pipeline deposition problems. PMID- 21598335 TI - Determining the relationship between tree-stem respiration and CO2 efflux by deltaO2/Ar measurements. AB - Respiration in forest tree stems is an important component of the global carbon cycle. This respiration is traditionally estimated by measurements of the CO(2) efflux from the stem. However, recent studies have suggested that movement of CO(2) in the transpiration stream causes large errors in the respiration estimated by the CO(2) efflux. Here we demonstrate a new approach for determining the ratio of respiration to CO(2) efflux, which is based on specially designed chambers, and combined CO(2) and O(2) measurements. The high accuracy O(2) measurement is performed by mass spectrometric measurement of the O(2)/Ar ratio. Testing the method gave repeatable results which point that in some conditions up to 40% of the respired CO(2) can be carried away from the site of respiration. PMID- 21598336 TI - Lipid fingerprinting of gram-positive lactobacilli by intact--matrix-assisted laser desorption/ionization mass spectrometry using a proton sponge based matrix. AB - A method of direct lipid analysis by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) in intact membranes, without prior extraction/separation steps, is described. Here, we demonstrate the efficacy of a strong base, 1,8-bis(dimethylamino)naphthalene (DMAN; proton sponge), as a novel matrix for MALDI-time-of-flight (TOF) MS analysis of whole cell bacteria. Initially, individual acidic low-molecular-weight analytes such as standard free fatty acids and phospholipids were analyzed using DMAN as matrix. Clear negative mode MALDI-TOF MS spectra of all analytes show only deprotonated analyte signals at a low picomole limit of detection with the complete absence of matrix-related signals. These results indicate that DMAN represents a suitable matrix for MALDI TOF MS analysis of mixtures of complex lipids as the intact membranes of microorganisms. DMAN was successfully applied to the analysis of Lactobacillus sanfranciscensis and L. plantarum microorganisms. Different components were sensitively detected in a single spot, including 16:0, 18:2, 18:3, and 21:0 free acids, glycolipids, phosphatidylglycerols (PGs) and cardiolipins. This method might be of general application, offering the advantage of quickly gaining information about lipid components of other gram-positive bacterial membranes. PMID- 21598337 TI - Analysis of different synthetic homopolymers by the use of a new calculation software for tandem mass spectra. AB - The manual interpretation of tandem mass spectra of synthetic polymers is very time-consuming. Therefore, a new software tool was developed to accelerate the interpretation of spectra obtained without requiring any further knowledge about the polymer class or the fragmentation behavior under high-energy collision induced dissociation (CID) conditions. The software only requires an alphabetical list of elements and a peak list of the measured substance as an xml file for the evaluation of the chosen mass spectrum. Tandem mass spectra of different homopolymers, like poly(2-oxazoline)s, poly(ethylene glycol) and poly(styrene), were interpreted by the new software tool. This contribution describes a fast and automated software tool for the rapid analysis of homopolymers. PMID- 21598338 TI - 3-Mercaptopropionic acid modified ZnSe quantum dots as the matrix for direct surface-assisted laser desorption/ionization mass spectrometric analysis of peptides/proteins from sodium salt solution. AB - This study describes a strategy of using zinc selenium quantum dots (ZnSe QDs) modified with 3-mercaptopropionic acid (3-MPA) as the matrix for direct analysis of peptides and proteins from sodium salt solution in surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS). The enhancement of detection sensitivity for these biomolecules was due to the adsorption of positively charged peptides or proteins onto the surfaces of negatively charged ZnSe-3MPA QDs via electrostatic interactions resulting in an increase in ionization efficiency for sodium adduct ions ([M+Na](+)). The applicability of the current approach was demonstrated for a variety of peptides, including leucine enkephalin, methione-enkephalin, HW6, substance P and angiotensin II, and proteins (cytochrome c, myoglobin and lysozyme). Signal intensities of these peptides or proteins can be enhanced by 25-95 times compared with those obtained by LDI-MS in the absence of ZnSe-3MPA QDs. Applying ZnSe-3MPA QDs to serve as the matrix in SALDI-MS is a simple and effective approach for direct analysis of peptide and protein molecules from sodium salt solution without any pretreatment as the peptides and proteins can be successfully detected as sodium adduct ions ([M+Na](+)). PMID- 21598339 TI - A nanocage for nanomedicine: polyhedral oligomeric silsesquioxane (POSS). AB - Ground-breaking advances in nanomedicine (defined as the application of nanotechnology in medicine) have proposed novel therapeutics and diagnostics, which can potentially revolutionize current medical practice. Polyhedral oligomeric silsesquioxane (POSS) with a distinctive nanocage structure consisting of an inner inorganic framework of silicon and oxygen atoms, and an outer shell of organic functional groups is one of the most promising nanomaterials for medical applications. Enhanced biocompatibility and physicochemical (material bulk and surface) properties have resulted in the development of a wide range of nanocomposite POSS copolymers for biomedical applications, such as the development of biomedical devices, tissue engineering scaffolds, drug delivery systems, dental applications, and biological sensors. The application of POSS nanocomposites in combination with other nanostructures has also been investigated including silver nanoparticles and quantum dot nanocrystals. Chemical functionalization confers antimicrobial efficacy to POSS, and the use of polymer nanocomposites provides a biocompatible surface coating for quantum dot nanocrystals to enhance the efficacy of the materials for different biomedical and biotechnological applications. Interestingly, a family of POSS-containing nanocomposite materials can be engineered either as completely non-biodegradable materials or as biodegradable materials with tuneable degradation rates required for tissue engineering applications. These highly versatile POSS derivatives have created new horizons for the field of biomaterials research and beyond. Currently, the application of POSS-containing polymers in various fields of nanomedicine is under intensive investigation with expectedly encouraging outcomes. PMID- 21598340 TI - Crystalline complex of syndiotactic polystyrene with poly(ethylene glycol) dimethyl ethers. AB - It has been clarified that syndiotactic polystyrene (sPS) forms co-crystalline structures with polyethylene glycol dimethyl ethers (PEGDMEs) with molecular weights ranging from 178 to 1,000 g.mol(-1) through a guest exchange procedure assisted by a plasticizing agent. The PEGDME molecules are incorporated into the spaces between sPS polymer sheets consisting of (T(2)G(2))(2) helices. The results of X-ray diffraction and gravimetric measurements suggest that one or less molecules are included per unit cell for PEGDME with average molecular weight of 1,000 g.mol(-1), which indicates the possibility that longer polymeric molecules can be introduced into sPS lattices with multiple site occupation. PMID- 21598341 TI - The beta phase formation limit in two poly(9,9-di-n-octylfluorene) based copolymers. AB - Random copolymers of poly(9,9-di-n-octylfluorene) (PF8) incorporating 0, 8, 12, 15, and 20% dibenzothiophene (DBT), and copolymers with 2, 5, 8, 12, and 15% dibenzothiophene-S,S-dioxide (S-unit) were synthesised. Absorption and emission spectra of thin films indicate that the DBT system shows a linear decrease of toluene vapour induced beta phase with increasing DBT content to a 20% cutoff, whilst in the S-unit copolymers the beta phase is present up to 12% co-monomer content, and at 15% the characteristic absorption peak is absent or masked. These results demonstrate the limits, in thin films, at which the beta phase can be formed in widely used PF8 copolymer systems for device applications and clearly show that it is practical to use copolymers having electron or hole transport units in the polyfluorene backbone and still be able to form efficient beta phase emission sites. PMID- 21598342 TI - Quantitative assessment of cardiac output and left ventricular function by noninvasive phase-contrast and cine MRI: validation study with invasive pressure volume loop analysis in a swine model. AB - PURPOSE: To validate noninvasive cardiac output measurements of phase-contrast magnetic resonance imaging (PC-MRI) and cine MRI using an invasive pressure volume (PV) loop technique on a swine model. MATERIALS AND METHODS: We compared three methods for evaluating cardiac function at rest and under pharmaceutical low-dose inotropic infusion conditions: 1) phase-contrast MRI, 2) cine MRI, and 3) PV loop relationship. These measurements were made in 14 domestic pigs under rest conditions. Identical MRI acquisitions and PV loop analysis were performed on six pigs from the same group that received an infusion of dobutamine 2.5 MUg/kg/min. Cardiac outputs from all measurements were analyzed and compared using linear regression and Bland-Altman analysis. RESULTS: Noninvasive PC-MRI and cine MRI did not show any significant differences compared to an invasive PV loop technique for measurement of cardiac output under both rest (PC-MRI, cine MRI, and PV loop, 3.17 +/- 0.45, 3.18 +/- 0.61, 3.45 +/- 0.41 L/min, respectively) and pharmaceutical low-dose inotropic infusion conditions (PC-MRI, cine MRI, and PV loop, 4.78 +/- 0.53, 4.7 +/- 0.6, 4.96 +/- 0.48 L/min, respectively). Statistical analysis showed good agreement of cardiac output measurements at rest (R(2) = 0.83) and under low-dose inotropic infusion conditions (R(2) = 0.74) using PC-MRI and PV loop techniques. Cardiac output measurement using cine MRI and PV loop techniques also showed good agreement at rest (R(2) = 0.85) and under low-dose inotropic infusion conditions (R(2) = 0.76). Furthermore, cardiac outputs determined with the three modalities showed good agreement over a wide range of heart rates (90-180 bpm). CONCLUSION: MRI can provide a reliable, noninvasive measurement of cardiac output that can be carried out without the complications that are inherent with current invasive procedures. PMID- 21598343 TI - Additional value of gadoxetic acid-DTPA-enhanced hepatobiliary phase MR imaging in the diagnosis of early-stage hepatocellular carcinoma: comparison with dynamic triple-phase multidetector CT imaging. AB - PURPOSE: To assess the value of hepatobiliary phase gadoxetic acid (EOB)-enhanced magnetic resonance imaging (MRI) for the diagnosis of early stage hepatocellular carcinoma (HCC) (<3 cm) compared to triple-phase dynamic multidetector computed tomography (MDCT). MATERIALS AND METHODS: In all, 52 patients with 60 pathologically proven HCCs underwent both EOB-enhanced MRI and triple-phase dynamic MDCT. Two radiologists independently and blindly reviewed three image sets: 1) MDCT, 2) dynamic MRI (unenhanced and EOB-enhanced dynamic MR images), and 3) combined MRI (dynamic MRI + hepatobiliary phase images) using a five-point rating scale on a lesion-by-lesion basis. Receiver operating characteristics (ROC) analysis was performed, and sensitivity and specificity were calculated. RESULTS: The area under the ROC curve (Az) of dynamic MRI was equivalent to that of MDCT for both readers. For both readers, Az and sensitivity of combined MRI for smaller lesions (<1.5 cm) were significantly higher than that of dynamic MRI and MDCT (P < 0.0166). The majority of false-negative nodules on dynamic MRI or MDCT (75% and 62%, respectively) were due to a lack of identified washout findings. CONCLUSION: Hepatobiliary phase images can increase the value of EOB enhanced MRI in the diagnosis of early stage HCC. The sensitivity and accuracy were significantly superior to MDCT for the diagnosis of lesions less than 1.5 cm. PMID- 21598344 TI - Simultaneous bilateral magnetic resonance imaging of the femoral arteries in peripheral arterial disease patients. AB - PURPOSE: To image the femoral arteries in peripheral arterial disease (PAD) patients using a bilateral receive coil. MATERIALS AND METHODS: An eight-channel surface coil array for bilateral MRI of the femoral arteries at 3T was constructed and evaluated. RESULTS: The bilateral array enabled imaging of a 25 cm segment of the superficial femoral arteries (SFA) from the profunda to the popliteal. The array provided improved the signal-to-noise ratio (SNR) at the periphery and similar SNR in the middle of a phantom compared to three other commercially available coils (4-channel torso, quadrature head, whole body). Multicontrast bilateral images of the in vivo SFA with 1 mm in-plane resolution made it possible to directly compare lesions in the index SFA to the corresponding anatomical site in the contralateral vessel without repositioning the patient or coil. A set of bilateral time-of-flight, T1-weighted, T2-weighted, and proton density-weighted images was acquired in a clinically acceptable exam time of ~45 minutes. CONCLUSION: The developed bilateral coil is well suited for monitoring dimensional changes in atherosclerotic lesions of the SFA. PMID- 21598345 TI - Distinguishing hemangiomas from malignant solid hepatic lesions: a comparison of heavily T2-weighted images obtained before and after administration of gadoxetic acid. AB - PURPOSE: To compare the use of heavily T2-weighted images obtained before and after administration of gadoxetic acid in differentiating hemangiomas from malignant solid hepatic lesions. MATERIALS AND METHODS: Heavily T2-weighted images (TE=150 msec) were obtained for 70 patients (42 men and 28 women) with 74 focal hepatic lesions (25 hepatocellular carcinomas [HCC], 22 metastases, and 27 hemangiomas) <=3 cm in diameter before and after gadoxetic acid-enhanced dynamic magnetic resonance imaging (MRI). Quantitative analysis was performed using receiver operating characteristic (ROC) curves with lesion-to-liver signal intensity difference-to-noise ratio (SDNR) on precontrast and postcontrast images. Qualitative analysis was also performed by two blinded reviewers. RESULTS: The SDNR of the solid lesions was significantly higher on the postcontrast (1.66 +/- 1.18) than on the precontrast (1.38 +/- 1.07) images (P=0.0012), while the SDNR of hemangiomas was comparable for pre- and postcontrast images (P=0.8164). The best SDNR cutoff values for distinguishing solid lesions from hemangiomas were <=1.85 (Az=0.948) for precontrast and <=2.58 (Az=0.901) for postcontrast images (P=0.057). Reader performances for distinguishing hemangiomas from solid lesions were comparable between the precontrast (Az=0.975 and 0.970 for readers 1 and 2) and postcontrast (Az=0.977 and 0.972) images (P=0.899 and 0.946). CONCLUSION: Heavily T2-weighted images obtained after administration of gadoxetic acid have a diagnostic capability comparable to precontrast images for differentiating between small hemangiomas and malignant solid lesions of the liver. PMID- 21598346 TI - To excel or to confirm? That is the question. PMID- 21598347 TI - Left main and high-risk PCI: what, exactly, is it high risk for? PMID- 21598348 TI - Effect of PCI on quality of life: "good always triumphs". PMID- 21598349 TI - Drug-eluting stent implantation for the treatment of cardiac transplant vasculopathy: the jury is still out. PMID- 21598350 TI - The impact of noncardiac surgery on selection of a revascularization strategy. PMID- 21598352 TI - Competing pharmacological strategies during PCI-analysis of a prematurely terminated trial. PMID- 21598353 TI - Each generation improves on the last (in cardiology): Bayesian thinking, the randomized clinical trial, and directed evolution. PMID- 21598354 TI - Should serum troponin after PCI be used to predict long-term outcomes?.......Not quite yet! PMID- 21598355 TI - Advances in the treatment of coronary artery aneurysms. PMID- 21598356 TI - High-risk percutaneous coronary intervention: how far will 6-Fr take you? PMID- 21598357 TI - Radial access site inflammatory reaction to a recently available hydrophilic coated sheath. AB - A sterile inflammatory reaction at the radial access site has been described in the literature as an adverse local reaction to Cook hydrophilic coated sheaths during transradial catheterization. To date, this reaction has not been observed with non-Cook hydrophilic sheaths. Here, we describe two cases of such a reaction with GlidesheathsTM at our institution. PMID- 21598358 TI - Never say never. PMID- 21598359 TI - What is lining your full metal jacket? PMID- 21598360 TI - A pharmacogenetic approach to identify mutant forms of alpha-galactosidase A that respond to a pharmacological chaperone for Fabry disease. AB - Fabry disease is caused by mutations in the gene (GLA) that encodes alpha galactosidase A (alpha-Gal A). The iminosugar AT1001 (GR181413A, migalastat hydrochloride, 1-deoxygalactonojirimycin) is a pharmacological chaperone that selectively binds and stabilizes alpha-Gal A, increasing total cellular levels and activity for some mutant forms (defined as "responsive"). In this study, we developed a cell-based assay in cultured HEK-293 cells to identify mutant forms of alpha-Gal A that are responsive to AT1001. Concentration-dependent increases in alpha-Gal A activity in response to AT1001 were shown for 49 (60%) of 81 mutant forms. The responses of alpha-Gal A mutant forms were generally consistent with the responses observed in male Fabry patient-derived lymphoblasts. Importantly, the HEK-293 cell responses of 19 alpha-Gal A mutant forms to a clinically achievable concentration of AT1001 (10 uM) were generally consistent with observed increases in alpha-Gal A activity in peripheral blood mononuclear cells from male Fabry patients orally administered AT1001 during Phase 2 clinical studies. This indicates that the cell-based responses can identify mutant forms of alpha-Gal A that are likely to respond to AT1001 in vivo. Thus, the HEK-293 cell-based assay may be a useful aid in the identification of Fabry patients with AT1001-responsive mutant forms. PMID- 21598362 TI - Nanocelluloses: a new family of nature-based materials. AB - Cellulose fibrils with widths in the nanometer range are nature-based materials with unique and potentially useful features. Most importantly, these novel nanocelluloses open up the strongly expanding fields of sustainable materials and nanocomposites, as well as medical and life-science devices, to the natural polymer cellulose. The nanodimensions of the structural elements result in a high surface area and hence the powerful interaction of these celluloses with surrounding species, such as water, organic and polymeric compounds, nanoparticles, and living cells. This Review assembles the current knowledge on the isolation of microfibrillated cellulose from wood and its application in nanocomposites; the preparation of nanocrystalline cellulose and its use as a reinforcing agent; and the biofabrication of bacterial nanocellulose, as well as its evaluation as a biomaterial for medical implants. PMID- 21598361 TI - LPAR1 and ITGA4 regulate peripheral blood monocyte counts. AB - We recently mapped a quantitative trait locus for monocyte counts to chromosome 9q31 (rs7023923). Here we extend this work by showing with two independent approaches that rs7023923 regulates the expression levels of the nearby LPAR1 gene (P<0.0001), specifically implicating this gene in monocyte development. Furthermore, we tested 10 additional loci identified in the original analysis for replication in 1,122 individuals and confirm that rs6740847 near the alpha-4 integrin gene (ITGA4) associates with variation in monocyte counts (combined P=2.7*10(-10)). This variant is in complete linkage disequilibrium (r(2) =1) with a previously reported eQTL for ITGA4 (rs2124440), indicating that this is the likely causal gene in the region. Our results indicate that rs7023923 and rs6740847 respectively upregulate LPAR1 and downregulate ITGA4 expression and this increases the number of monocytes circulating in the peripheral blood. Further studies that investigate the downstream mechanism involved and the impact on immune function are warranted. PMID- 21598363 TI - Photoelectric protein nanofibrils of alpha-synuclein with embedded iron and phthalocyanine tetrasulfonate. PMID- 21598364 TI - Solid-state NMR spectroscopic analysis of the Ca2+-dependent mannose binding of pradimicin A. PMID- 21598351 TI - A randomized two-by-two comparison of high-dose bolus tirofiban versus abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary revascularization and stent placement: the tirofiban evaluation of novel dosing versus abciximab with clopidogrel and inhibition of thrombin (TENACITY) study trial. AB - BACKGROUND: In the absence of high-dose thienopyridines, placebo-controlled trials have demonstrated a reduction in ischemic events with intravenous glycoprotein IIb/IIIa antagonists during percutaneous coronary intervention (PCI). One head-to-head trial comparing abciximab and tirofiban among PCI patients found tirofiban to be inferior, and laboratory evidence confirmed that the bolus dose of tirofiban tested in that trial to be less effective than abciximab. Whether a higher bolus dose of tirofiban would be as efficacious as abciximab during PCI is uncertain. METHODS AND RESULTS: Patients undergoing PCI were randomized equally to abciximab or to tirofiban, given as high-dose bolus (25 MUg/kg) plus 12-hr infusion (0.15 MUg/kg/min). All patients received aspirin and clopidogrel and were additionally randomized to unfractionated heparin or bivalirudin. Approximately 8,000 patients were to be studied, but after 383 were enrolled, the study sponsor discontinued the trial for financial reasons. The primary endpoint of 30-day death, myocardial infarction, or urgent target vessel revascularization occurred in 8.8% of patients randomized to abciximab and 6.9% of those randomized to tirofiban. The respective rates of major bleeding were 1.5 and 1.6%. Additionally, the primary endpoint occurred in 8.1% of patients randomized to unfractionated heparin and 7.6% of those randomized to bivalirudin. The respective rates of major bleeding were 2.5% and 0.5%. CONCLUSION: With limited assessment, this direct comparison of high-dose bolus tirofiban versus abciximab produced encouraging results and suggests that further study of this tirofiban dose regimen is warranted. The limited assessments comparing heparin and bivalirudin are consistent with prior observations. PMID- 21598365 TI - Ab initio powder diffraction structure analysis of a host-guest network: short contacts between tetrathiafulvalene molecules in a pore. PMID- 21598366 TI - Activation energies for diffusion of defects in silicon: the role of the exchange correlation functional. PMID- 21598368 TI - Polyelectrolyte multilayer films for building energetic walking devices. PMID- 21598367 TI - Thermosensitive molecular assemblies from poly(amidoamine) dendron-based lipids. PMID- 21598370 TI - Autotransporters with GDSL passenger domains: molecular physiology and biotechnological applications. AB - Autotransporters are large proteins produced and secreted by Gram-negative bacteria. They consist of an N-terminal passenger domain, which typically harbours enzymatic activity and exerts a virulence function, and a C-terminal membrane anchor domain. Somehow, the membrane domain facilitates the transport of the passenger domain into the extracellular space. Several autotransporters possess hydrolase passenger domains that belong to the GDSL family of lipolytic enzymes. GDSL autotransporters represent a functionally distinct family and are characterized by several features of their passenger domains; these include 1) the absence of a conserved right-handed parallel beta-helix, 2) lipolytic activity, and thus the capability to hydrolyse membranes, and 3) covalent attachment to the respective C-terminal beta-domain, with the hydrolase domain exposed to the exterior. The esterase EstA of Pseudomonas aeruginosa is a typical enzyme of this type. Its physiological role was studied, its potential biotechnological application has been demonstrated, and its crystal structure was solved recently. Furthermore, it is capable of displaying different classes of enzymes in a range of Gram-negative bacteria including Escherichia coli, and FACS based high-throughput screening for enantioselective esterases could be achieved using EstA. PMID- 21598371 TI - Site-selective traceless Staudinger ligation for glycoprotein synthesis reveals scope and limitations. PMID- 21598372 TI - Role of disulfide bridges in archaeal family-B DNA polymerases. AB - The family-B DNA polymerases obtained from the order Thermococcales, for example, Pyrococcus furiosus (Pfu-Pol) are commonly used in the polymerase chain reaction (PCR) because of their high thermostability and low error rates. Most of these polymerases contain four cysteines, arranged as two disulfide bridges. With Pfu Pol C429-C443 forms one of the disulfides (DB1) and C507-C510 (DB2) the other. Although the disulfides are well conserved in the enzymes from the hyperthermophilic Thermococcales, they are less prevalent in euryarchaeal polymerases from other orders, and tend to be only found in other hyperthermophiles. Here, we report on the effects of deleting the disulfide bridges by mutating the relevant cysteines to serines. A variety of techniques, including differential scanning calorimetry and differential scanning fluorimetry, have shown that both disulfides make a contribution to thermostability, with DB1 being more important than DB2. However, even when both disulfides are removed, sufficient thermostability remains for normal (identical to the wild type) performance in PCR and quantitative (real-time) PCR. Therefore, polymerases totally lacking cysteine are fully compatible with most PCR-based applications. This observation opens the way to further engineering of polymerases by introduction of a single cysteine followed by appropriate chemical modification. PMID- 21598373 TI - Kinetic magnetic-field effect involving the small biologically relevant inorganic radicals NO and O2(.-). AB - Oxidation of dihydrorhodamine 123 (DHR) to rhodamine 123 (RH) by oxoperoxonitrite (ONOO(-)), formed through recombination of NO and O(2)(.-) radicals resulting from thermal decomposition of 3-morpholinosydnonimine (SIN-1) in buffered aerated aqueous solution at pH 7.6, represents a kinetic model system of the reactivity of NO and O(2)(.-) in biochemical systems. A magnetic-field effect (MFE) on the yield of RH detected in this system is explored in the full range of fields between 0 and 18 T. It is found to increase in a nearly linear fashion up to a value of 5.5+/-1.6 % at 18 T and 23 degrees C (3.1+/-0.7 % at 40 degrees C). A theoretical framework to analyze the MFE in terms of the magnetic-field-enhanced recombination rate constant k(rec) of NO and O(2)(.-) due to magnetic mixing of T(0) and S spin states of the radical pair by the Deltag mechanism is developed, including estimation of magnetic properties (g tensor and spin relaxation times) of NO and O(2)(.-) in aqueous solution, and calculation of the MFE on k(rec) using the theoretical formalism of Gorelik at al. The factor with which the MFE on k(rec) is translated to the MFE on the yield of ONOO(-) and RH is derived for various kinetic scenarios representing possible sink channels for NO and O(2)(. ). With reasonable assumptions for the values of some unknown kinetic parameters, the theoretical predictions account well for the observed MFE. PMID- 21598374 TI - Dip-coating-induced fiber growth of a soluble heterotriangulene. PMID- 21598375 TI - Effects of a self-assembled molecular capsule on the ultrafast photodynamics of a photochromic salicylideneaniline guest. PMID- 21598376 TI - Hypomethylation of the serotonin receptor type-2A Gene (HTR2A) at T102C polymorphic site in DNA derived from the saliva of patients with schizophrenia and bipolar disorder. AB - Several lines of evidence indicate that dysfunction of serotonin signaling and HTR2A receptor are involved in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BD). DNA methylation of HTR2A at T102C polymorphic site influences HTR2A expression and aberrant DNA methylation of HTR2A promoter was reported in postmortem brain of patients with SCZ and BD. Hypothesizing that the brain's epigenetic alteration of HTR2A may also exist in peripheral tissues that can be used as a diagnostic/therapeutic biomarker, we analyzed HTR2A promoter DNA methylation in DNA extracted from the saliva of patients with SCZ and BD, and their first degree relatives versus normal controls. Bisulfite sequencing was used to screen DNA methylation status of the HTR2A promoter CpGs and qMSP was used to quantify the degree of cytosine methylation at differentially methylated sites. Most of the cytosines of the HTR2A promoter were unmethylated. However, CpGs of the -1438A/G polymorphism site, -1420 and -1223 were >95% methylated. The CpG at T102C polymorphic site and neighboring CpGs were ~70% methylated both in the patients and controls. qMSP analysis revealed that the cytosine of the T102C polymorphic site was significantly hypo-methylated in SCZ, BD, and their first degree relatives compared to the controls. Cytosine methylation of HTR2A at T102C polymorphic site in DNA derived from the saliva can potentially be used as a diagnostic, prognostic, and/or therapeutic biomarker in SCZ and BD. However, these preliminary observations need to be replicated in other populations with a larger sample size to be considered for clinical applications. PMID- 21598377 TI - Replacement of homologous mouse DNA sequence with pathogenic 6-base human CREB1 promoter sequence creates murine model of major depressive disorder. AB - Major depressive disorder (MDD) is a leading cause of disability worldwide. Families with recurrent, early-onset MDD (RE-MDD), a severe, familial form of MDD, have provided an important resource for identifying and characterizing genetic variants that confer susceptibility to MDD and related disorders. Previous studies identified a rare, highly penetrant A(-115)G transition within the human CREB1 promoter that reduced promoter activity in vitro and was associated with depressive disorders in RE-MDD families. The development of an etiology-based recombinant animal model for MDD would facilitate the advancement of our limited understanding of the pathophysiology of MDD, as well as the development of improved treatments. Here we report the construction and initial characterization of a congenic mutant C57BL/6NTac mouse model that carries the human pathogenic sequence at the homologous position of the mouse Creb1 promoter. The recombinant strain exhibited decreases in reproductive capacity and pup survival that may be related to increased infant mortality observed in RE-MDD families; enlargement of the cerebral ventricles; reduced levels of CREB protein in the mouse cerebral cortex, as predicted from transfection experiments employing the pathogenic human CREB1 promoter; and alterations in two standardized behavioral tests, the forced swim and marble burying tests. These initial findings support the pathogenicity of the human A(-115)G promoter variant, and invite further characterization of this etiology-based recombinant animal model for MDD. Human promoter variants that have highly penetrant effects on disease expression provide an attractive opportunity for creating etiology based mouse models of human diseases, with minimal disruption of the mouse genome. PMID- 21598378 TI - Novel pathogenic mutations and copy number variations in the VPS13A gene in patients with chorea-acanthocytosis. AB - Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc. PMID- 21598379 TI - Evaluation of alginate dialdehyde cross-linked gelatin hydrogel as a biodegradable sealant for polyester vascular graft. AB - Vascular grafts are devices intended to replace compromised arteries in the body and grafts made of polyethylene terephthalate (PET) fabric have been used mainly for synthetic grafting procedures involving medium to large diameter vascular grafts. Though porosity of the graft permits tissue in-growth, it would lead to bleeding through the graft walls immediately after implantation. So it is essential to seal the pores either by preclotting with patient's own blood or by other sealing materials prior to implantation in order to prevent blood leakage through the graft wall. Biodegradable hydrogel materials are ideal candidates for this purpose. Apart from sealing the pores, they offer biocompatible and low thrombogenic surfaces when coated on vascular graft. In the present study, a biodegradable hydrogel, derived from oxidized alginate and gelatin, has been deposited on PET grafts by dip coating and were characterized for its efficacy on sealing the pores of the graft. Water permeability in the static and pulsatile conditions, burst strength, in vitro cell culture cytotoxicity, hemocompatibility, and endothelial cell adhesion and proliferation of the coated grafts were investigated. Results showed that the alginate dialdehyde cross linked gelatin hydrogel was nontoxic, hemocompatible, and was efficient in sealing the pores of the graft. Blood perfusion study showed that when hydrogel coated grafts were exposed to blood for 30 min, they showed little affinity toward platelets or leukocytes. Hemolytic potential of PET was significantly reduced when it was coated with hydrogel. Improved adhesion and proliferation of endothelial cells were observed when PET grafts were coated with hydrogel. Results also showed that coating with hydrogel did not affect the burst strength of the PET graft. PMID- 21598380 TI - Friction, wear, and tensile properties of vacuum hot pressing crosslinked UHMWPE/nano-HAP composites. AB - Ultra high molecular weight polyethylene (UHMWPE) is a thermoplastic engineering plastic with excellent mechanical properties. In this study, nonirradiated and irradiated UHMWPE/nano-hydroxyapatite (nano-HAP) composites were prepared by vacuum hot-pressing method, and then friction, wear, and tensile properties were investigated. To explore mechanisms of these properties, differential scanning calorimetry, infrared spectrum, and scanning electron microscopy with energy dispersive spectrometry analysis were carried out on the samples. The results in this study indicated that reduced friction coefficients and wear rate could be obtained when nonirradiated and irradiated UHMWPE were filled with 7% nano-HAP. The irradiated UHMWPE/7% nano-HAP also had a synergistic function of wear reduction as compared with irradiated UHMWPE and nonirradiated UHMWPE/7% nano HAP. Samples filled with 7% nano-HAP showed a brittle fracture behavior, and a linear relationship between modulus and crystallinity for a nonirradiated and irradiated sample was found in this study. PMID- 21598381 TI - Dynamic microcontact printing for patterning polymer-brush microstructures. PMID- 21598382 TI - Hydrophilic interaction chromatography separation mechanisms of tetracyclines on amino-bonded silica column. AB - Effects of mobile-phase variations on the chromatographic separation on amino bonded silica column in hydrophilic interaction chromatography (HILIC) were investigated for four zwitterionic tetracyclines (TCs): oxytetracycline, doxycycline, chlortetracycline, and tetracycline. A mixed-mode retention mechanism composed of partitioning, adsorption, and ion exchange interactions was proposed for the amino HILIC retention process. Buffer type and pH significantly influenced the retention of TCs, but showed similar separation selectivity for the tested analytes. Experiments varying buffer salt concentration and pH demonstrated the presence of ion exchange interactions in TCs retention. The type and concentration of organic modifier also affected the retention and selectivity of the analytes, providing direct evidence supporting the Alpert retention model for HILIC. The retention time of the analytes increased in the following order of organic modifiers: tetrahydrofuran < methanol < isopropanol < acetonitrile. The linear relationships of logk' versus %water (v/v) curve and logk' versus logarithm of %water (v/v) in the mobile phase indicated that TCs separation on the amino phase was controlled by partitioning and adsorption. The developed method was successfully utilized in the detection of TCs in both river water and wastewater samples using solid-phase extraction (SPE) for sample cleanup. PMID- 21598383 TI - Facile preparation of monolithic immobilized metal affinity chromatography capillary columns for selective enrichment of phosphopeptides. AB - The selective enrichment of phosphopeptides with good reproducibility is vital for the in-depth study of the phosphoproteome. Herein, we presented a novel method to prepare monolithic Ti(4+) or Zr(4+) immobilized metal affinity chromatography (IMAC) columns. Since succinimide was of high reaction activity with nitrilotriacetic acid (NTA) than traditional epoxy group, through the reaction of succinimide group on the monolithic matrix with nitrilotriacetic acid, the preparation of monolithic IMAC columns became facile. By the developed new method, not only the time required for Ti(4+) or Zr(4+) immobilization could be shortened from 10 to 1 h, but also the RSD of obtained phosphopeptide peak area was below 13%, even with IMAC columns prepared in different batches (n=3). With such monolithic Ti(4+)- and Zr(4+)-IMAC columns, ten and seven phosphopeptides were effectively identified from the digests of a mixture of beta casein and BSA, even with the molar ratio as low as 1:100, respectively. The phosphopeptide recovery was over 73%, and the loading capacity was over 0.8 MUmol/mL. Compared with commercial IMAC beads, the monolithic IMAC columns provide outstanding reproducibility, good selectivity, large loading capacity, and high recovery, which demonstrates that such monolithic IMAC columns might facilitate the in-depth analysis of phosphoproteomes. PMID- 21598384 TI - Fluorescence derivatization of single-walled carbon nanotubes for analysis by means of conventional CE-LIF. AB - Single-walled carbon nanotubes (SWNTs) are now widely used in many fields, and while many analytical methods for SWNTs have been reported, there are few practical analytical methods that combine the necessary levels of selectivity and sensitivity. We have developed a highly sensitive separation method for fluorescence-derivatized SWNTs by means of conventional CE with laser-induced fluorescence. First, SWNTs were dispersed using a triphenylene derivative into the water, and the excess dispersant was removed by nitric acid treatment. The dispersed SWNTs were then derivatized with a fluorescence reagent, 4 aminofluorescein. Finally, the derivatized SWNTs were analyzed using a conventional apparatus CE-LIF detection. The SWNTs migrated within 20 min. The detection sensitivity of SWNTs was improved by about 170 times with LIF detection as compared with UV detection. We anticipate that the derivatized SWNTs can also be detected with high sensitivity using LC. PMID- 21598385 TI - Membrane proteomic signatures of karyotypically normal and abnormal human embryonic stem cell lines and derivatives. AB - Cultured human embryonic stem cells (hESCs) and derived derivatives contain heterogeneous cell populations with varying degrees of differentiation and karyotypic stability. The inability to isolate homogenous population presents a challenge toward cell-based applications and therapies. A proteomics approach was utilized to discover novel membrane proteins able to distinguish between the hESC lines BG01, WA09, and abBG02 (trisomy 12, 14, 17 and an extra copy of the X chromosome), along with WA09-derived human neural progenitor (hNP) cells. Membrane protein signatures were developed using sucrose-gradient isolation, 1-D gel electrophoresis followed by in-gel digestion and analysis by reverse phase chromatography coupled to ion trap-FT-ICR. At a <=1.0% false discovery rate, 1918 proteins were identified; 775 were annotated as membrane proteins and 720 predicted to contain transmembrane spanning regions. Flow cytometry was used to validate cell surface expression of selected proteins. Junctional adhesion molecule 1 expression was shared by BG01, BG02 and abBG02 hESC lines. Dysferlin expression was specific to the WA09 hESC line and not the derived neural or mesenchymal progenitors. Ciliary neurotrophic factor receptor distinguished WA09 derived human neural progenitor cells from the parent hESC population, and WA09 derived mesenchymal progenitor cells. This study expands the current membrane protein data set for hESCs. PMID- 21598386 TI - Identification of proteins secreted by head and neck cancer cell lines using LC MS/MS: Strategy for discovery of candidate serological biomarkers. AB - In search of blood-based biomarkers that would enhance the ability to diagnose head and neck/oral squamous cell carcinoma (HNOSCC) in early stages or predict its prognosis, we analyzed the HNOSCC secretome (ensemble of proteins secreted and/or shed from the tumor cells) for potential biomarkers using proteomic technologies. LC-MS/MS was used to identify proteins in the conditioned media of four HNOSCC cell lines (SCC4, HSC2, SCC38, and AMOSIII); 140 unique proteins were identified on the basis of 5% global false discovery rate, 122 of which were secretory proteins, with 29 being previously reported to be overexpressed in HNOSCC in comparison to normal head and neck tissues. Of these, five proteins including alpha-enolase, peptidyl prolyl isomerase A/cyclophilin A, 14-3-3 zeta, heterogeneous ribonucleoprotein K, and 14-3-3 sigma were detected in the sera of HNOSCC patients by Western blot analysis. Our study provides the evidence that analysis of head and neck cancer cells' secretome is a viable strategy for identifying candidate serological biomarkers for HNOSCC. In future, these biomarkers may be useful in predicting the likelihood of transformation of oral pre-malignant lesions, prognosis of HNOSCC patients and evaluate response to therapy using minimally invasive tests. PMID- 21598387 TI - Identification of 14-3-3beta in human gastric cancer cells and its potency as a diagnostic and prognostic biomarker. AB - Gastric cancer is the second most common cause of cancer deaths worldwide and due to its poor prognosis, it is important that specific biomarkers are identified to enable its early detection. Through 2-D gel electrophoresis and MALDI-TOF-TOF based proteomics approaches, we found that 14-3-3beta, which was one of the proteins that were differentially expressed by 5-fluorouracil-treated gastric cancer SC-M1 cells, was upregulated in gastric cancer cells. 14-3-3beta levels in tissues and serum were further validated in gastric cancer patients and controls. The results showed that 14-3-3beta levels were elevated in tumor tissues (n=40) in comparison to normal tissues (n=40; p<0.01), and serum 14-3-3beta levels in cancer patients (n=145) were also significantly higher than those in controls (n=63; p<0.0001). Elevated serum 14-3-3beta levels highly correlated with the number of lymph node metastases, tumor size and a reduced survival rate. Moreover, overexpression of 14-3-3beta enhanced the growth, invasiveness and migratory activities of tumor cells. Twenty-eight proteins involved in anti apoptosis and tumor progression were also found to be differentially expressed in 14-3-3beta-overexpressing gastric cancer cells. Overall, these results highlight the significance of 14-3-3beta in gastric cancer cell progression and suggest that it has the potential to be used as a diagnostic and prognostic biomarker in gastric cancer. PMID- 21598388 TI - A comparative MudPIT analysis identifies different expression profiles in heart compartments. AB - Cardiomyopathies indistinctly affect atrial and ventricular cardiac compartments with alterations of their mechanical and/or electrical activity. To understand the main mechanisms involved in these pathological alterations, a detailed knowledge of the physiology of the healthy heart is critical. In the present work, we utilize multidimensional protein identification technology to characterize the murine left ventricle (LV), right ventricle (RV), and atria (A) proteomes, identifying thousands of distinct proteins. Moreover, using multidimensional algorithm protein map tool, relative abundances of proteins among the heart chambers were investigated. In sum, we found 16 and 55 proteins were more abundant in LV compared to RV and A, respectively; 47 and 60 proteins were more abundant in RV than LV and A, respectively; and, 81 and 74 proteins were more abundant in A than LV and RV, respectively. This detailed characterization of myocardial compartment proteome represents an important advancement in the knowledge of heart physiology, and may contribute to the identification of key features underlying the onset of cardiomyopathy. PMID- 21598389 TI - Direct quantitation of MHC-bound peptide epitopes by selected reaction monitoring. AB - We describe a cell-free approach that employs selected reaction monitoring (SRM) in tandem mass spectrometry to identify and quantitate T-cell epitopes. This approach utilises multiple epitope-specific SRM transitions to identify known T cell epitopes and an absolute quantitation (AQUA) peptide strategy to afford AQUA. The advantage of a mass spectrometry-based approach over more traditional cell-based assays resides in the robustness and transferability of an SRM approach between laboratories and the ability of this strategy to detect multiple peptides simultaneously without the requirement of epitope-specific reagents such as T-cell lines. Thus, the SRM strategy for epitope quantitation will find application in studies of antigen density, the link between epitope abundance and immunogenicity, the dynamic range of epitope presentation and the abundance of T cell epitopes in disease. PMID- 21598390 TI - Systematic evaluation of alternating CID and ETD fragmentation for phosphorylated peptides. AB - CID has become a routine method for fragmentation of peptides in shotgun proteomics, whereas electron transfer dissociation (ETD) has been described as a preferred method for peptides carrying labile PTMs. Though both of these fragmentation techniques have their obvious advantages, they also have their own drawbacks. By combining data from CID and ETD fragmentation, some of these disadvantages can potentially be overcome because of the complementarity of fragment ions produced. To evaluate alternating CID and ETD fragmentation, we analyzed a complex mixture of phosphopeptides on an LTQ-Orbitrap mass spectrometer. When the CID and ETD-derived spectra were searched separately, we observed 2504, 491, 2584, and 3249 phosphopeptide-spectrum matches from CID alone, ETD alone, decision tree-based CID/ETD, and alternating CID and ETD, respectively. Combining CID and ETD spectra prior to database searching should, intuitively, be superior to either method alone. However, when spectra from the alternating CID and ETD method were merged prior to database searching, we observed a reduction in the number of phosphopeptide-spectrum matches. The poorer identification rates observed after merging CID and ETD spectra are a reflection of a lack of optimized search algorithms for carrying out such searches and perhaps inherent weaknesses of this approach. Thus, although alternating CID and ETD experiments for phosphopeptide identification are desirable for increasing the confidence of identifications, merging spectra prior to database search has to be carefully evaluated further in the context of the various algorithms before adopting it as a routine strategy. PMID- 21598391 TI - Benefits of heat treatment to the protease packed neutrophil for proteome analysis: halting protein degradation. AB - Neutrophils, cells of the innate immune system, contain an array of proteases and reactive oxygen species-generating enzymes that assist in controlling the invasion of bacteria and pathogens. The high content of intracellular proteolytic enzymes makes them difficult cells to work with as they can degrade proteins of potential interest. Here, we describe the benefits of heat treatment of neutrophils in reducing protein degradation for subsequent proteome analysis. Neutrophils isolated from four healthy volunteers were each divided into three aliquots and subjected to different preparation methods for 2-DE: (i) Heat treatment, (ii) resuspension in NP40 lysis buffer and (iii) resuspension in standard 2-DE lysis buffer. Representative spots found to be statistically significant between groups (p<0.01) were excised and identified by LC-MS/MS, three of which were validated by immunoblotting. Heat-treated samples contained proteins in the high-molecular-weight range that were absent from NP40-treated samples. Moreover, NP40-treated samples showed an increase in spot number and volume at lower molecular weights suggestive of protein degradation. Incorporating heat treatment into sample preparation resulted in the identification of proteins that may not have previously been detected due to sample degradation, thus leading to a more comprehensive 2-DE map of the human neutrophil proteome. PMID- 21598392 TI - Proteomic analysis of Escherichia coli associated with urinary tract infections. AB - Escherichia coli is a major cause of urinary tract infections (UTIs) where the initial infection arises from bacteria originating in the bowel. However, significant differences are observed between the genomes of intestinal and urinary E. coli strains with the latter possessing many adaptations that promote growth in the urinary tract. To define further the adaptation of urinary E. coli isolates, the cellular proteomes of 41 E. coli strains, collected from cases of UTIs or random faecal samples, were compared by 2-D gel electrophoresis and principal component analysis. The data indicated that individual patients carried relatively homogenous E. coli populations, as defined by their cellular proteomes, but the populations were distinct between patients. For one patient, E. coli, isolated during two recurrent infections 3 months apart, were indistinguishable, indicating that for this patient the infections were possibly caused by the same bacterial population. To understand the basis of the discrimination of the bacteria, selected protein spots were identified by peptide fragment fingerprinting. The identified proteins were involved in a variety of metabolic and structural roles. The data obtained for these E. coli strains provide a basis from which to target key bacterial proteins for further investigation into E. coli pathogenesis. PMID- 21598393 TI - The extracellular proteome of Bifidobacterium animalis subsp. lactis BB-12 reveals proteins with putative roles in probiotic effects. AB - Probiotics are live microorganisms that exert health-promoting effects on the human host, as demonstrated for numerous strains of the genus Bifidobacterium. To unravel the proteins involved in the interactions between the host and the extensively used and well-studied probiotic strain Bifidobacterium animalis subsp. lactis BB-12, proteins secreted by the bacterium, i.e. belonging to the extracellular proteome present in the culture medium, were identified by 2-DE coupled with MALDI-TOF MS. Among the 74 distinct proteins identified, 31 are predicted to carry out their physiological role either outside the cell or on its surface. These proteins include solute-binding proteins for oligosaccharides, amino acids and manganese, cell wall-metabolizing proteins, and 18 proteins that have been described to interact with human host epithelial cells or extracellular matrix proteins. The potential functions include binding of plasminogen, formation of fimbriae, adhesion to collagen, attachment to mucin and intestinal cells as well as induction of immunomodulative response. These findings suggest a role of the proteins in colonization of the gastrointestinal tract, adhesion to host tissues, or immunomodulation of the host immune system. The identification of proteins predicted to be involved in such interactions can pave the way towards well targeted studies of the protein-mediated contacts between bacteria and the host, with the goal to enhance the understanding of the mode of action of probiotic bacteria. PMID- 21598394 TI - Two novel ficolin-like proteins act as pattern recognition receptors for invading pathogens in the freshwater crayfish Pacifastacus leniusculus. AB - To isolate pathogen-associated molecular patterns (PAMPs)-binding molecules, the bacterium, Staphylococcus aureus was used as an affinity matrix to find bacteria binding proteins in the plasma of the freshwater crayfish, Pacifastacus leniusculus. Two new bacteria-binding ficolin-like proteins (FLPs) were identified by 2-DE and MS analysis. The FLPs have a fibrinogen-related domain (FReD) in their C-terminal and a repeat region in their N-terminal regions with putative structural similarities to the collagen-like domain of vertebrate ficolins and mannose binding lectins (MBLs). Phylogenetic analysis shows that the newly isolated crayfish FLP1 and FLP2 cluster separately from other FReD containing proteins. A tissue distribution study showed that the mRNA expression of FLP occurred mainly in the hematopoietic tissue (Hpt) and in the hepatopancreas. Recombinant FLPs exhibited agglutination activity of Gram negative bacteria Escherichia coli and Aeromonas hydrophila in the presence of Ca(2+) . The FLPs could bind to A. hydrophila, E. coli as well as S. aureus as judged by bacteria adsorption. Moreover, the FLPs may help crayfish to clear Gram negative bacteria, but not Gram-positive bacteria which had been injected into the hemolymph. When Gram-negative bacteria coated with FLPs were incubated with Hpt cells, a lower death rate of the cells was found compared with control treatment. Our results suggest that FLPs function as pattern recognition receptors in the immune response of crayfish. PMID- 21598395 TI - Time resolved protein-based stable isotope probing (Protein-SIP) analysis allows quantification of induced proteins in substrate shift experiments. AB - The detection of induced proteins after introduction of specific substrates in culture is of high interest for a comparative description of organisms growing under different conditions. In this study, protein-based stable isotope probing (Protein-SIP) is used for a fast and reliable detection of newly synthesized proteins in a substrate shift experiment. Therefore, Pseudomonas putida ML2 cells precultured on (12)C-acetate and (12)C-benzene, respectively, were incubated with (13)C-benzene as a stable-isotope-labeled substrate. Protein samples from early to stationary growth phase were separated by one-dimensional gel electrophoresis (1-DE), subsequently tryptically digested, and analyzed by UPLC Orbitrap MS/MS measurements. Identified peptides from proteins involved in aerobic benzene degradation as well as from housekeeping proteins were chosen to calculate the labeling ratio (proportion of labeled protein to total protein) at different time points. A comparison of parameters from a nonlinear regression analysis of the calculated data enabled a clear differentiation between induced and constitutively expressed proteins. Thus, Protein-SIP has proven to be a valuable tool for quantitative analysis of induced proteins in substrate shift experiments. PMID- 21598396 TI - Lobe-specific proteome changes in the dorsal-lateral and ventral prostate of TRAMP mice versus wild-type mice. AB - The transgenic adenocarcinoma of mouse prostate (TRAMP) is the most widely used transgenic model for prostate cancer chemoprevention studies. Although two lobe specific lineages of carcinogenesis have been described, the molecular mechanisms are still poorly defined. Here, we concurrently profiled the proteome of dorsal lateral (DLP) and ventral (VP) prostate lobes of both TRAMP and littermate WT C57BL/6 mice of 18 wk by 2-D LC-MALDI-TOF/TOF with iTRAQ labeling. A total of 483 and 748 proteins were identified at critical false discovery rates of 1 and 5%. In WT mice, 84 proteins were found to have different expression levels between DLP and VP. In TRAMP mice, 118 proteins significantly changed in DLP and/or VP during TRAMP carcinogenesis. Among them, 55 and 36 proteins were uniquely changed in DLP or VP lobe, respectively, and 27 proteins in both DLP and LP lobe. Ingenuity Pathway Analysis was able to segregate proteins changed in two lobes into different pathway networks. In addition to serving as reference for prostate proteomic profiles, our data suggest that different sets of proteins are involved in the carcinogenesis in DLP versus VP in the TRAMP model. PMID- 21598397 TI - Novel mechanism of cathepsin B inhibition by antibiotic nitroxoline and related compounds. PMID- 21598399 TI - A succinct synthesis of the vaulted biaryl ligand vanol via a dienone-phenol rearrangement. AB - Vanol is a member of the vaulted biaryl family of ligands and it has been proven to be very effective in a number of asymmetric catalytic reactions. The previous synthesis of vanol, while effective, is limited by the cost of reagents involved. The present work evaluates three different approaches to the synthesis of 3 phenyl-1-naphthol, a key intermediate in the synthesis of vanol. The first approach has its key step as the Michael addition of a benzyl Grignard to methyl cinnamate. In the second approach the key step is the first step, a Reformatsky reaction of ethyl bromoacetate and deoxybenzoin. The final and most-efficient approach involves a dienone-phenol rearrangement of a 4-aryl-1-tetralenone generated in-situ from the reaction of 4-chloro-1-naphthol with AlCl(3) and benzene, and preliminary results are reported on the extension of this method to substituted vanol derivatives. PMID- 21598400 TI - Highly selective iron-catalyzed synthesis of alkenes by the reduction of alkynes. AB - Herein, the iron-catalyzed reduction of a variety of alkynes with silanes as a reductant has been examined. With a straightforward catalyst system composed of diiron nonacarbonyl and tributyl phosphane, excellent yields and chemoselectivities (>99%) were obtained for the formation of the corresponding alkenes. After studying the reaction conditions, and the scope and limitations of the reaction, several attempts were undertaken to shed light on the reaction mechanism. PMID- 21598398 TI - Delineation of the molecular mechanisms of nucleoside recognition by cytidine deaminase through virtual screening. AB - Cytidine deaminase (EC 3.5.4.5, CDA), an enzyme of the pyrimidine salvage pathways, is responsible for the degradation and inactivation of several cytidine based antitumor drugs such as cytarabine, gemcitabine, decitabine, and azacytidine. Thus, CDA inhibitors are highly sought after as compounds to be co administered with said drugs to improve their effectiveness. Alternatively, the design of antitumor drugs not susceptible to the action of CDA is also regarded as an attractive solution. Herein we describe a virtual screen for CDA ligands based on chemical similarity and molecular docking. The campaign led to the identification of three novel inhibitors and one novel substrate, with a 19 % hit rate, and allowed a significant extension of the structure-activity relationships, also in light of the compounds that resulted inactive. The most active compound identified through the screen is the inhibitor pseudoisocytidine, which has the potential to serve as a lead for highly stable compounds. The study also delineated the detrimental effect of 5-aza and 6-aza substitutions, the incompatibility of the presence of an amino group at the 3'-position, as well as the presence of very strict steric requirements around the 2'-arabino position and, even more, the N4-position. Importantly, these features can be exploited for the design of novel anti-neoplastic agents resistant to the action of CDA. PMID- 21598401 TI - Imidazole as a donor/acceptor unit in charge-transfer chromophores with extended pi-linkers. AB - Eleven new, stable, push-pull systems that feature 4,5-bis[4-(N,N dimethylamino)phenyl]imidazole and 4,5-dicyanoimidazole as the donor and acceptor moieties and the systematically extended and varied pi-linker were prepared and investigated. Evaluation of the measured UV/Vis spectra, electrochemical data (cyclic voltammetry (CV), rotating-disc voltammetry (RDV), and polarography) and calculated beta and gamma polarizabilities showed efficient charge transfer (CT) in biimidazole-type chromophores. Push-pull system 27, which features a planar thiophene-derived pi-linker, was revealed to be the most efficient chromophore within the studied series. This chromophore possessed the most bathochromically shifted CT band, the lowest electrochemical gap, and highest beta and gamma polarizabilities. The CT transition was most significantly affected by structural features such as pi-linker length, planarity, conjugating arrangement, and the presence of olefinic/acetylenic or 1,4-phenylene/thiophene subunits in the pi linker. PMID- 21598402 TI - Solid-phase parallel synthesis of a tetrahydroindazolone library containing three unique core skeletons. AB - We have developed a practical strategy for the regioselective synthesis of a 1 (hetero)aryl-3-substituted tetrahydroindazolone library. The condensation of in situ generated arylhydrazine on solid supports with 2-acylcyclohexane-1,3-diones ensured the efficiency of solid-phase parallel synthesis. In addition, we introduced three unique core skeletons containing nitrophenyl, anilyl, and pyridyl groups to maximize the molecular diversity through a diverse display of polar surface area in 3D chemical space. A 162-membered drug-like tetrahydroindazolone library was constructed in an average purity of 92% without further purification. PMID- 21598403 TI - Nanoparticle-based indicator-displacement assay for pyrophosphate. AB - Silica nanoparticles functionalized with a Zn(II) -dipicolylamine derivative are used as the receptor component of a sensing ensemble for an indicator displacement assay. The nano-ensemble system, constructed with pyrocatechol violet as an indicator, selectively senses pyrophosphate over other anions including hydrogen phosphate, thus showing a visible blue-to-yellow color change and the corresponding absorption spectral changes in a buffer solution of pH 7. A distinct recognition behavior--the nano-ensemble does not sense hydrogen phosphate that was sensed by the traditional ensemble with the same molecular receptor--is explained by an incomplete-displacement model in the case of the integrated receptor system. The present work demonstrates that the nanoparticle based competition assay is as effective as the traditional approach with molecular receptors. Furthermore, such an integrated receptor system can provide distinct recognition behavior from its molecular receptor. PMID- 21598404 TI - Crystal-to-crystal transformation from a chain compound to a layered coordination polymer. PMID- 21598405 TI - Recent advances in vegetable oil-based polyurethanes. AB - Polyurethanes are among the most versatile polymers because of the wide range of monomers, particularly diols or polyols, that can be utilized in their synthesis. This Review focuses on the most recent advances made in the production of polyurethane materials from vegetable oils. Over the past several years, increasing attention has been given to the use of vegetable oils as feedstocks for polymeric materials, because they tend to be very inexpensive and available in large quantities. Using various procedures, a very broad range of polyols or diols and in some cases, poly- or diisocyanates, can be obtained from vegetable oils. The wide range of vegetable oil-based monomers leads to a wide variety of polyurethane materials, from flexible foams to ductile and rigid plastics. The thermal and mechanical properties of these vegetable oil-based polyurethanes are often comparable to or even better than those prepared from petroleum and are suitable for applications in various industries. PMID- 21598406 TI - Catalytic conversion of dihydroxyacetone to lactic acid using metal salts in water. AB - We herein present a study on the application of homogeneous catalysts in the form of metal salts on the conversion of trioses, such as dihydroxyacetone (DHA), and glyceraldehyde (GLY) to lactic acid (LA) in water. A wide range of metal salts (26 in total) were examined. Al(III) salts were identified as the most promising and essentially quantitative LA yields (>90 mol%) were obtained at 140 degrees C and a reaction time of 90 min. A reaction pathway is proposed and a kinetic model using the power law approach was developed for the conversion of DHA to LA with pyruvaldehyde (PRV) as the intermediate. Good agreement between experimental data and the model was obtained. Model predictions, supported by experiments, indicate that a high yield of LA is favoured in dilute solutions of DHA (0.1 M) at elevated temperatures (180 degrees C) and reaction times less than 10 min. PMID- 21598407 TI - Metal phosphonate hybrid mesostructures: environmentally friendly multifunctional materials for clean energy and other applications. AB - The synthesis of porous hybrid materials has been extended to mesoporous non silica-based organic-inorganic hybrid materials, in which mesoporous metal phosphonates represent an important family. By using organically bridged polyphosphonic acids as coupling molecules, the homogeneous incorporation of a considerable number of organic functional groups into the metal phosphonate hybrid framework has been realized. Small amounts of organic additives and the pH value of the reaction solution have a large impact on the morphology and textural properties of the resultant hybrid mesoporous metal phosphonate solids. Cationic and nonionic surfactants can be used as templates for the synthesis of ordered mesoporous metal phosphonates. The materials are used as efficient adsorbents for heavy metal ions, CO2, and aldehydes, as well as in the separation of polycyclic aromatic hydrocarbons. They are also useful photocatalysts under UV and simulated solar light irradiation for organic dye degradation. Further functionalization of the synthesized mesoporous hybrids makes them oxidation and acid catalysts, both with impressive performances in the fields of sustainable energy and environment. PMID- 21598408 TI - A non-aqueous synthesis of TiO2/SiO2 composites in supercritical CO2 for the photodegradation of pollutants. AB - Titania/silica composites with different Ti/Si ratios are synthesized via a nonconventional synthesis route. The synthesis involves non-aqueous reaction of metal alkoxides and formic acid at 75 degrees C in supercritical carbon dioxide. The as-prepared composite materials contain nanometer-sized anatase crystallites and amorphous silica. Large specific surface areas are obtained. The composites are evaluated in the photocatalytic degradation of phenol in aqueous medium, and in the elimination of acetaldehyde from air. The highest photocatalytic activity in both processes is achieved with a composite containing 40 wt % TiO2. PMID- 21598409 TI - A full-spectrum visible-light-responsive organophotocatalyst film for removal of trimethylamine. PMID- 21598410 TI - A new technique for spectrophotometric determination of pseudoephedrine and guaifenesin in syrup and synthetic mixture. AB - The accuracy in predicting different chemometric methods was compared when applied on ordinary UV spectra and first order derivative spectra. Principal component regression (PCR) and partial least squares with one dependent variable (PLS1) and two dependent variables (PLS2) were applied on spectral data of pharmaceutical formula containing pseudoephedrine (PDP) and guaifenesin (GFN). The ability to derivative in resolved overlapping spectra chloropheniramine maleate was evaluated when multivariate methods are adopted for analysis of two component mixtures without using any chemical pretreatment. The chemometrics models were tested on an external validation dataset and finally applied to the analysis of pharmaceuticals. Significant advantages were found in analysis of the real samples when the calibration models from derivative spectra were used. It should also be mentioned that the proposed method is a simple and rapid way requiring no preliminary separation steps and can be used easily for the analysis of these compounds, especially in quality control laboratories. PMID- 21598411 TI - Acupuncture in obstetrics and gynecology: an overview of systematic reviews. AB - Acupuncture is often recommended for obstetrical and gynecological conditions but the evidence is confusing. We aim to summarize all recent systematic reviews in this area. Western and Asian electronic databases were searched for systematic reviews of any type of acupuncture for any type of gynecological conditions. Our own files were hand-searched. Systematic reviews of any type of acupuncture for any type of gynecological conditions were included. Non-systematic reviews and systematic reviews published before 2004 were excluded. No language restrictions were applied. Data were extracted according to predefined criteria and analysed narratively. Twenty-four systematic reviews were included. They relate to a wide range of gynecological conditions: hot flashes, conception, dysmenorrhea, premenstrual syndrome, nausea/vomiting, breech presentation, back pain during pregnancy, and procedural pain. Nine systematic reviews arrived with clearly positive conclusions; however, there were many contradictions and caveats. The evidence for acupuncture as a treatment of obstetrical and gynecological conditions remains limited. PMID- 21598412 TI - Effects of auricular acupressure on weight reduction and abdominal obesity in Asian young adults: a randomized controlled trial. AB - The current study was designed to test the efficacy of auricular acupressure on weight reduction and changes of waist circumference and waist-to-hip ratio. This study used a randomized design with one control group and one experimental group consisting of Asian young adults with a waist circumference >=80 cm in the females and >=90cm in the males. At completion of eight weeks of auricular therapy, the total sample size was 55 young adults who ranged in age from 18 to 20 years old. Each participant was treated weekly for ear acupressure in ten minute sessions. Sessions continued for eight weeks wherein the control group received acupressure only while the experimental group received acupressure with the Japanese Magnetic Pearl on the ear acupoints. While both the control and treatment groups showed significant reduction (p <= 0.05) to body weight and waist circumference after eight weeks of treatment, only the group treated with Japanese Magnetic Pearls showed decreased waist to hip ratio. Thus, auricular acupressure may be a beneficial addition to weight loss programs for young adults. Auricular acupressure is thus a reasonable option in the treatment of overweight and obesity in young adults. PMID- 21598413 TI - Effects of Panax ginseng supplementation on muscle damage and inflammation after uphill treadmill running in humans. AB - The purpose of this investigation was to determine whether Panax ginseng extract intake would influence exercise-induced muscle damage and inflammation responses. Eighteen male college students were randomly assigned to either an RG intake group (RG, n = 9) or a placebo group (P, n = 9). All subjects performed a high intensity uphill treadmill running task (two rounds of 45 min at 10 km/h speed with a 15 degree uphill slope separated by 5 min of rest). The RG group ingested 20 g/day of Korean red ginseng extract (mixed with 200 ml of water) three times/day for seven days prior to performing the uphill treadmill exercise test and for four days after the treadmill test, while the P group ingested 200 ml of water containing Agastachis Herba on the same schedule. Plasma creatine kinase activity (CK) and interlukin-6 (IL-6) levels were measured at pre-exercise and 24, 48, 72, and 96 h post-exercise; the IL-6 level was also measured at 1 and 2 h post-exercise. To evaluate insulin sensitivity, the oral glucose tolerance test (OGTT) was performed 24 h post-exercise. Plasma CK level in RG was significantly lower than that in P 72 h post-exercise (p < 0.05), and IL-6 level was significantly decreased in RG during the 2 h and 3 h recovery period compared to that of P (p < 0.05). Plasma glucose and insulin responses in RG were significantly reduced compared to those of P (p < 0.05). The results of this study suggest that RG supplementation could reduce exercise-induced muscle damage and inflammatory responses, resulting in improvements in insulin sensitivity. PMID- 21598414 TI - Efficacy and safety of orally administered Lentinula edodes mycelia extract for patients undergoing cancer chemotherapy: a pilot study. AB - Lentinula edodes mycelia extract (L.E.M.) is extensively utilized as an herbal medicine. However, its safety and effectiveness have not yet been scientifically verified. In this study, we investigated its safety and its influence on quality of life (QOL) and the immune response in patients undergoing cancer chemotherapy. Seven patients were studied in total. The patients were undergoing postoperative adjuvant chemotherapy for breast cancer (n = 3) or gastrointestinal cancer (n = 2), or were receiving chemotherapy to prevent recurrence of gastrointestinal cancer (n = 2). The first course of treatment was chemotherapy alone and the second was chemotherapy plus concomitant administration of L.E.M. Adverse events and changes in the QOL score, lymphocyte subpopulations, lymphocyte activity and serum immune indices were evaluated during the study period. No adverse events attributable to L.E.M. were observed. Compared to the pre-chemotherapy state, no changes in QOL or immune parameters were noted after the first chemotherapy course. In contrast, following the second course of combined therapy, improvements were noted in QOL (p < 0.05), NK cell activity (p < 0.05) and immunosuppressive acidic protein (IAP) (p < 0.01) levels. Although a future large scale investigation is necessary to confirm these results, these data suggest that the concomitant of L.E.M. with chemotherapy is safe and improves the QOL and immune function of patients undergoing chemotherapy. PMID- 21598415 TI - A pilot study of qigong practice and upper respiratory illness in elite swimmers. AB - Upper respiratory tract infections (URIs) are a common complaint in competitive swimmers and can adversely affect performance. No intervention has yet been shown to reduce URI incidence in intensively trained athletes. The University of Virginia varsity swim team received three weeks of training in qigong for the purpose of reducing stress and improving health. Our primary objective was to assess the relationship between qigong practice and symptoms of URI during a time when swimmers would be at high URI risk. Secondary objectives were to assess degree of compliance with a qigong practice regimen, to evaluate differences between qigong practitioners and non-practitioners, and to determine the response rate and reliability of a newly developed internet-based, self-report survey. The design was observational, cross-sectional, and prospective. Weekly data on cold and flu symptoms, concurrent health problems and medication use, and qigong practice were gathered for seven weeks. Retrospective information on health and qigong training response was also collected. Participants were 27 of the 55 members of the University of Virginia Swim Team in the Virginia Athletic Department. Main outcomes were measures of aggregated cold/flu symptoms and Qigong practice. Survey completion was 100%, with no missing data, and reliability of the instrument was acceptable. Cold and flu symptoms showed a significant non-linear association with frequency of qigong practice (R(2) = 0.33, p < 0.01), with a strong, inverse relationship between practice frequency and symptom scores in swimmers who practised qigong at least once per week (R(2) = 0.70, p < 0.01). Qigong practitioners did not differ from non-practitioners in demographic or lifestyle characteristics, medical history, supplement or medication use, or belief in qigong. These preliminary findings suggest that qigong practice may be protective against URIs among elite swimmers who practice at least once per week. PMID- 21598416 TI - Proteomic analysis of effects on natural herb additive containing immunoglobulin Yolksac (IgY) in pigs. AB - Thirty male pigs were infected orally with E. coli and Salmonella typhimurium, and divided into a control group and two additive groups to determine the effect of an additive mixture on the changes in protein expression. The pigs were given a food supplemented with a natural herbal additive containing immunoglobulin yolksac (IgY) at concentrations of 0.5% or 1%. On the 1st day and after eight weeks of feeding, the body weight gain, food intake and serum GOT/GPT levels were examined. The GOT/GPT levels on the 1st day were similar in the three groups. However, after eight weeks of feeding, the GOT level was significantly lower in the additive treatment groups (0.5% and 1.0%). In addition, the changes in the spleen proteome as a response to the herbal additive were examined using two dimensional polyacrylamide gel electrophoresis. A total of 31 differentially expressed protein spots were identified by comparing the protein profiles of the control and additive treated porcine spleens. Finally, 19 proteins were detected by MALDI-TOF/MS. Overall, the proteins detected are involved in a range of biological process, such as metabolic processes, biological processes, transport, carbohydrate metabolic processes, generation of precursors and energy. In conclusion, these results support of the hypothesis that a natural herbal additive containing IgY can affect the immune regulation system and reduce the stress of microbial infections. PMID- 21598417 TI - Protective effects of Atractylodes macrocephala polysaccharide on liver ischemia reperfusion injury and its possible mechanism in rats. AB - Atractylodes macrocephala polysaccharide (AMP), a traditional Chinese medicine, is thought to have protective effects against liver injury. Therefore, this study was designed to explore the effects of AMP on hepatic ischemia-reperfusion injury (IRI) and elucidate the possible mechanisms. Ninety-six Sprague-Dawley rats were randomly divided into four groups with 24 rats per group: a normal control group, an IRI group, an AMP-treated group (0.4 g/kg/d) and a bifendate-treated group (100 mg/kg). Rats were treated with AMP or bifendate once daily for seven days by gastric gavage. The normal control group and the IRI model group received an equivalent volume of physiological saline. At 1, 6 and 24 h after surgery, the rats were killed and liver tissue samples were obtained to determine interleukin 1 (IL-1) expression by Western blotting and nuclear factor-kappaB (NF-kappaB) expression by immunohistochemistry. Liver morphology was assessed by microscopy and transmission electron microscopy. Blood samples were obtained to measure liver function (alanine aminotransferase, aspartate aminotransferase, total bilirubin and direct bilirubin). AMP significantly reduced the elevated expression of markers of liver dysfunction and the hepatic morphologic changes induced by hepatic IRI in rats. AMP also markedly inhibited IRI-induced lipid peroxidation and altered the activities of the antioxidant enzyme superoxide dismutase and malondialdehyde levels. Moreover, pretreatment with AMP suppressed the expression of interleukin-1beta and NF-kB in IRI-treated rats. These results suggest that AMP exerts protective and therapeutic effects against hepatic IRI in rats, which might be associated with its antioxidant properties and inhibition of NF-kappaB activation. More studies are needed to better understand the mechanisms underlying the protective effects of AMP on hepatic IRI. PMID- 21598418 TI - Hepatoprotective effect of Crossostephium chinensis (L.) Makino in rats. AB - The hepatoprotective potential of Crossostephium chinensis (L.) Makino water extract (CCW) on carbon tetrachloride (CCl(4)) induced liver damage was evaluated in preventive and curative rat models. Not only were indicators of hepatic damage including GPT, GOT, lipid peroxides and TBARS were examined, the activities of antioxidant enzymes (SOD, CAT, GPx) and GSH were examined as well. The results showed that CCW (0.1, 0.5 and 1.0 g/kg) significantly reduced the elevated levels of GPT and GOT by CCl(4) administration (p < 0.05). TBARS level was dramatically reduced, and SOD, CAT, GPx and GSH activities were significantly increased. In addition, CCW decreased NO production and TNF-alpha activation in CCl(4)-treated rats. Therefore, we speculate that CCW protects against acute liver damage through its radical scavenging ability. CCW inhibited the expression of MMP-9 protein, indicating that MMP-9 played an important role in the development of CCl(4)-induced chronic liver damage in rats. In LC-MS-MS analysis, the chromatograms of CCW with good hepatoprotective activities were established. Scopoletin may be an important bioactive compound in CCW. PMID- 21598419 TI - Cordyceps sobolifera extract ameliorates lipopolysaccharide-induced renal dysfunction in the rat. AB - Cordyceps Sobolifera (CS), an economic traditional Chinese herb, may ameliorate nephrotoxicity-induced renal dysfunction in the rat via antioxidant, anti apoptosis, and anti-autophagy mechanisms. We investigated the water extract of fermented whole broth of CS on lipopolysaccharide (LPS)-induced renal cell injury in vitro and in vivo. CS effect on LPS-induced epithelial Lilly pork kidney (PK1) and Madin-Darby canine kidney epithelial (MDCK) cell death was detected with MTT assay. Two-month treatment of CS effects on renal blood flow (RBF), glomerular filtration rate (GFR), plasma blood urea nitrogen, creatinine level and leukocytes (WBC) count were determined in the LPS-treated rats. We further examined the effects of CS supplement on renal tubular oxidative stress, endoplasmic reticulum stress, apoptosis and autophagy by Western blot analysis. LPS dose-dependently induced PK1 and MDCK cell death, which can be ameliorated by CS treatment. LPS significantly decreased RBF and GFR and increased blood leukocyte counts, plasma blood urea nitrogen and creatinine level in the rat after 24 hours of injury. LPS enhanced renal tubular ER stress, autophagy and apoptosis via by increase protein expressions of GRP78, caspase 12, Beclin-1 and Bax/Bcl-2 ratio. These findings are associated with the significant staining in renal proximal and distal tubular ED-1, GRP78, Beclin-1 autophagy, and TUNEL apoptosis in the LPS-treated kidneys. Two months of CS supplement significantly improved RBF, GFR and WBC values and reduced ED-1, GRP78, Beclin-1 autophagy and TUNEL apoptosis in the LPS-treated kidneys. Long-term CS treatment reduced LPS induced stress responses and tissue damage possibly via blocking LPS-triggered signaling pathways. PMID- 21598421 TI - Diosgenin ameliorates cognition deficit and attenuates oxidative damage in senescent mice induced by D-galactose. AB - This study attempted to access the neuroprotective effect of diosgenin on the senescent mice induced by d-galactose (D-gal). The mice in the experiments were orally administered with diosgenin (1, 5, 25 and 125 mg/kg), for four weeks from the sixth week. The learning and memory abilities of the mice in Morris water maze test and the mechanism involved in the neuroprotective effect of diosgenin on the mice brain tissue were investigated. Diosgenin (5, 25 and 125 mg/kg, p.o.) showed significantly improved learning and memory abilities in Morris water maze test compared to D-gal treated mice (200 mg/kg, ten weeks). Diosgenin also increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and decreased the malondialdehyde (MDA) level in the brain of D-gal treated mice. These results indicated that diosgenin has the potential to be a useful treatment for cognitive impairment. In addition, the memory enhancing effect of diosgenin may be partly mediated via enhancing endogenous antioxidant enzymatic activities. PMID- 21598420 TI - Effects and mechanisms of Acremoniumterricola milleretal mycelium on liver fibrosis induced by carbon tetrachloride in rats. AB - Acremoniumterricola milleretal mycelium (AMM) is one of the most precious traditional Chinese medicines. It has numerous protective effects on organs, and has been used in Chinese herb prescription to treat refractory diseases. Our preliminary studies demonstrated that AMM had hepatoprotective activity in acute liver injury. We further investigated the effects of AMM on liver fibrosis in rats induced by carbon tetrachloride (CCl(4)) and explore its possible mechanisms. The animal model was established by injection with 50% CCl(4) subcutaneously in male Sprague-Dawley rats twice a week for eight weeks. Meanwhile, AMM (175, 350 and 700 mg/kg) was administered intragastrically per day until sacrifice. We found that treatment with AMM (175, 350 and 700 mg/kg) decreased CCl(4)-induced elevation of serum transaminase activities, hyaluronic acid, laminin and procollagen type III levels, and contents of hydroxyproline in liver tissues. It also restored the decreased SOD and GSH-Px activities and inhibited the formation of lipid peroxidative products during CCl(4) treatment. Moreover, AMM (350 and 700 mg/kg) decreased the elevation of TGF-beta1 by 19.6% and 34.3%, respectively. In the pathological study, liver injury and the formation of liver fibrosis in rates treated by AMM were improved significantly. Immunoblot analysis showed that AMM (175, 350 and 700 mg/kg) inhibited Smad 2/3 phosphorylation, and elevated inhibitor Smad 7 expression. These results suggested that AMM could protect liver damage and inhibit the progression of hepatic fibrosis induced by CCl(4), and its mechanisms might be associated with its ability to scavenge free radicals, decrease the level of TGF-beta1 and block TGF-beta/Smad signaling pathway. PMID- 21598422 TI - The protective effect of Cassia obtusifolia on DSS-induced colitis. AB - Cassia obtusifolia (CO) has been traditionally used in Korea to treat eye inflammation, photophobia, and lacrimation. However, the regulatory effect and molecular mechanism of CO in intestinal inflammation has not been understood. In this study, we investigate the protective effect of CO in dextran sulfate sodium (DSS)-induced colitis. CO reduced clinical signs of DSS-induced colitis, including body weight loss, shortened colon length, and increased disease activity index. The results show that CO significantly suppressed the levels of interleukin (IL)-6 and expression of cyclooxygenase-2 in DSS-treated colon tissues. Additionally, we observed that CO reduced the activation of transcription nuclear factor-kappaB p65 in DSS-treated colon tissues. Taken together, these findings suggest that CO has improving effects on DSS-induced ulcerative colitis, which may explain its beneficial effect in the regulation of chronic intestinal inflammation. PMID- 21598423 TI - Corydalis yanhusuo W.T. Wang extract inhibits MCF-7 cell proliferation by inducing cell cycle G2/M arrest. AB - Corydalis yanhusuo W.T. Wang (YHS) is a traditional Chinese herb widely prescribed for promoting blood circulation, reinforcing vital energy and alleviating pain. Our previous studies showed that an ethanol extract of YHS inhibits metastasis of breast cancer cells in vitro. In the present study, the anti-proliferative effect of the extract was determined by MTT assay and the LDH release was measured with a commercial kit. Intracellular reactive oxygen species (ROS) production and mitochondrial membrane potential (DeltaPsim) were monitored by CM- H(2)DCF-DA and JC-1 staining, respectively. Cell cycle was analyzed with propidium iodide (PI) staining by flow cytometry and protein expressions were measured by Western blotting. The YHS extract significantly inhibited MCF-7 cell proliferation in a dose-dependent manner. Significant increase of ROS formation and decrease of DeltaPsim were observed. Furthermore, it induced MCF-7 cell cycle arrest at the G2/M phases. In addition, the p-cdc-2/cdc-2 protein expression ratio was increased while Rb and p21 protein expressions were decreased. The YHS extract inhibited MCF-7 proliferation by inducing G2/M cell cycle arrest, which might be mediated by inducing ROS formation, decreasing DeltaPsim and regulating cell cycle related protein expressions. PMID- 21598424 TI - Protective effect of a Chrysanthemum indicum containing formulation in cadmium induced ototoxicity. AB - Chungshinchongyitang (CSCYT) is an herbal drug formula containing Chrysanthemum indicum and 13 other herbs used for treating auditory diseases. Irreversible hearing loss is a characteristic effect of a number of heavy metals. Cadmium (Cd(2+)) is an environmental contaminant that causes a variety of adverse effects. In the present study, we investigate the protective effects of CSCYT against Cd(2+) induced ototoxicity in vitro and ex vivo. The findings of this study show that CSCYT prevents the destruction of hair cell arrays induced by Cd(2+) in the rat organ of Corti primary explants. CSCYT inhibited cell death, release of cytochrome c and generation of reactive oxygen species induced by Cd(2+) in HEI-OC1 auditory cell line. In addition, we also demonstrated that CSCYT exerted its effect by modulating of apoptosis via the caspase-3 activation and extracellular signal-regulated kinase activation. These results are expected to improve the understanding of the pharmacological mechanism of CSCYT and aid in the development of potential therapeutic strategies against ototoxicity. PMID- 21598425 TI - Effect of Orostachys japonicus on cell growth and apoptosis in human hepatic stellate cell line LX2. AB - Orostachys japonicus (O. japonicus), used to treat diseases such as various cancers, gastric ulcers, fever, hepatitis, arthritis, eczema, for hemostasis, and intoxication in folk medicine, has been an important constituent in many herbal formulae. We demonstrated that the water extract of O. japonicus led to growth inhibition of LX2 cells by inducing apoptosis through the caspase activation, related to the MAPK pathway. O. japonicus inhibited proliferation of LX2 cells in a dose- and time-dependent manner, increased the apoptosis fraction at cell cycle progression with an accompanying DNA fragmentation, and resulted in a significant decrease in Bcl-2 and an increase in Bax mRNA levels. Exposure of LX2 cells to O. japonicus induced caspase-3 activation, however when the LX2 cells were also treated with the pan-caspase inhibitor Z-VAD-FMK and the caspase-3 inhibitor Z DEVE-FMK, apoptosis was blocked. O. japonicus inhibited anti-apoptotic Mcl-1 protein and MEK/ERK phosphorylation in LX2 cells. The results indicate that O. japonicus inhibits the cell growth of LX2 cells by inducing apoptosis through caspase activity. O. japonicus down-regulated Mcl-1 protein levels and inhibited the phosphorylation of MEK/ERK, suggesting that it mediates cell death in LX2 cells through the down-regulation of Mcl-1 protein via a MEK/ERK-independent pathway. PMID- 21598426 TI - Chemical composition analysis, antioxidant, antiglycating activities and neuroprotective effects of S. choloroleuca, S. mirzayanii and S. santolinifolia from Iran. AB - This study was designed to examine antioxidant activities, antiglycating abilities and neuroprotective effects of methanolic extracts of Salvia choloroleuca, Salvia santolinifolia and Salvia mirzayanii from Iran. The extracts were screened for their possible antioxidant activities by several biochemical assays such as DPPH, FRAP, beta-carotene bleaching and TEAC assays. HPLC analysis of these extracts led to the separation of a number of components such as catechine and rosmarinic acid. Based on our results, all these plants had antioxidant and antiglycating activities, among them S. choloroleuca seems to be the most effective one. Furthermore, these species not only showed no cytotoxic effects in neuron-like PC12 cells, but also protected them against oxidative stress-induced cell death, exerted by H(2)O(2). We further showed that these plants increase superoxide dismutase and catalase levels, reduce lipid peroxidation and up regulate hemeoxygenase-1 and glutamylcysteine synthetase proteins. This study raised the possibility of developing these plants as potential neuroprotective agents. PMID- 21598427 TI - Influence of graft-host interface on the quality of vision after deep anterior lamellar keratoplasty in patients with keratoconus. AB - PURPOSE: To investigate the influence of graft-host interface on the quality of vision after deep anterior lamellar keratoplasty (DALK). METHODS: Retrospective, nonrandomized, comparative case series. Sixty patients (60 eyes) with advanced keratoconus underwent DALK using the big-bubble technique. Twenty-eight patients had complete stromal excision with Descemet membrane (DM) exposure[DALK with DM baring (DM-DALK)], whereas in 32 cases, a layer of stroma was left adherent to the recipient DM [DALK without DM baring (pre-DM-DALK)]. Twenty-two patients with keratoconus (22 eyes) who underwent penetrating keratoplasty (PK) were chosen for comparison. Main outcome measures were uncorrected visual acuity, best spectacle corrected visual acuity, low-contrast visual acuity(LCVA), and Pelli-Robson contrast sensitivity. RESULTS: Uncorrected visual acuity was equal in the 3 groups. Median best spectacle-corrected visual acuity was 0.1 logarithm of the minimum angle of resolution (logMAR) in the PK group, compared with 0.06 logMAR in the DM-DALK group (P = 0.66) and 0.12 logMAR in the pre-DM-DALK group (P = 0.016). Pre-DM-DALK patients exhibited worse LCVA than PK (P = 0.029) and DM-DALK patients (P = 0.022), whereas PK and DM-DALK patients showed comparable LCVA (P = 0.974). Pelli-Robson contrast sensitivity was equivalent in PK and DM-DALK groups (P = 0.408) and greater in DM-DALK group than in pre-DM-DALK group (P = 0.038). CONCLUSIONS: In selected patients, quality of vision after DALK was comparable to that after PK when stromal excision was extended to the DM and inferior to vision after PK when layers of stroma were left adherent to the DM. Advances in DALK technique are required to allow easier and repeatable baring of the DM. PMID- 21598428 TI - Post-laser assisted in situ keratomileusis epithelial ingrowth and its relation to pretreatment refractive error. AB - PURPOSE: To assess the incidence of epithelial ingrowth after laser in situ keratomileusis and its correlation with myopic or hyperopic treatment. METHODS: This retrospective study analyzed 1000 consecutive LASIK procedures performed by 3 surgeons using identical surgical technique with a Hansatome microkeratome. Eyes that developed epithelial ingrowth were evaluated using the Machat grading system. Patients were subdivided into 2 groups (myopic or hyperopic) based on the preoperative refractive error. RESULTS: The total incidence of epithelial ingrowth was 4.7%. The incidence after primary treatment was 3.9%. The incidence after enhancement was 12.8%. The total incidence of epithelial ingrowth was 3% in the myopic group compared with 23% in the hyperopic group. After primary myopic treatment, there was a 3% incidence of epithelial ingrowth compared with 17% after primary hyperopic treatment. The incidence after enhancement was 7% in the myopic group and 43% in the hyperopic group. CONCLUSIONS: Patients undergoing hyperopic laser in situ keratomileusis have a greater incidence of epithelial ingrowth than those undergoing myopic treatment. In addition, enhancement procedures have a higher incidence than primary procedures. PMID- 21598429 TI - Topical anesthetic abuse keratopathy: a commonly overlooked health care problem. AB - PURPOSE: To evaluate the clinical course, treatment modality, factors affecting the epithelization period, and visual outcome in patients with topical anesthetic abuse keratopathy. METHODS: The medical records of 19 patients with a confirmed diagnosis of topical anesthetic abuse keratopathy were retrospectively examined; occupation, initiating event, biomicroscopic findings, treatment modality, epithelization period, and best-corrected visual acuity (BCVA) were noted. The Wilcoxon signed rank test was used to compare BCVA before and after treatment; P values <0.05 were considered statistically significant. RESULTS: In all, 26 eyes in 19 men aged 21-44 (mean age: 31 +/- 6) years were included. Initiating events included exposure to arc welding flash (8 patients), metallic foreign body injury (8 patients), and chemical injury (3 patients). On admission to hospital, 10 patients (52.6%) reported that they were using topical anesthetics. Upon admission to the hospital, 10 patients (52.6%) self reported that they were using topical anesthetics. The remaining 9 subjects were discovered to be using topical anaesthetic drops during hospitalization. Twelve patients (63.2%) were found to continue using these agents during their hospitalization. Oval corneal epithelial defect, stromal infiltrate, ring-shaped keratitis, and hypopyon were noted in 100%, 46.2%, 57.7%, and 42.3% of the eyes, respectively. Topical antibiotics (fluoroquinolones or combined fortified cephalosporins and aminoglycosides), preservative-free lubricants/autologous serum, and bandage contact lens/eye patches were used for treatment. Mean epithelization period was 19.96 +/- 11.16 days (range: 6-50 days). Mean pretreatment and posttreatment BCVA was 0.12 +/- 0.16 (range: 0.001-0.7) and 0.66 +/- 0.30 (range: 0.0-1.0), respectively (P < 0.001). CONCLUSIONS: Ophthalmologists should be suspicious of topical anesthetic abuse keratopathy in young male manual laborers specialized in welding business and foundry work presenting with persistent epithelial defects, ring-shaped keratitis, and accompanying severe ocular pain. PMID- 21598430 TI - A stepwise approach to donor preparation and insertion increases safety and outcome of Descemet membrane endothelial keratoplasty. AB - PURPOSE: Lamellar techniques for selective replacement of diseased corneal structures have recently been improved. Descemet membrane endothelial keratoplasty (DMEK) allows the sole replacement of the endothelium--Descemet membrane layer (EDM). However, wide-spread use of DMEK is currently limited because of problems with donor preparation namely the tearing of the Descemet membrane and the difficulty to unfold the EDM graft in the anterior chamber (AC). METHODS: A standardized DMEK procedure that allows safe preparation of EDM, atraumatic introduction of EDM into the AC, reliable orientation of EDM during surgery, and stepwise unfolding within the AC is described in 80 patients. Visual acuity and corneal endothelial cell density were assessed. RESULTS: A stepwise approach using a novel bimanual underwater technique to harvest EDM from donor corneal buttons allows reproducible generation of grafts without tearing the Descemet membrane. Injection of the EDM roll into the AC is achieved by use of a standard injector cartridge, whereas the depth of AC is maintained by an irrigation handpiece. Marks at the margin of EDM allow orientation. Finally, unfolding EDM in the AC is achieved by sequential use of water jets and air bubbles. In the early phase of the learning curve, 4 patients were regrafted because of graft failure. Endothelial cell density decreased from 2600 6 252 to 1526 6 341 cells per square millimeter 1 month after DMEK. CONCLUSIONS: A novel technique for graft preparation and EDM injection results in improved safety with a high rate of successful DMEKs. PMID- 21598431 TI - Fibrin glue aided sutureless sclerokeratoplasty with maintenance of chamber angle. AB - We describe a technique of lamellar penetrating sclerokeratoplasty to treat a patient with total corneal ulcer with scleral extension along with impending perforation. The partial-thickness scleral and full-thickness corneal bed was prepared. A donor lenticule with partial-thickness sclera and full-thickness cornea was fixed on the prepared recipient bed with the help of fibrin glue. This technique is less painful, less time consuming, induces less postoperative inflammation, and seems safe and effective in managing such cases. PMID- 21598432 TI - Vernal keratoconjunctivitis with limbal stem cell deficiency. AB - PURPOSE: To describe the clinical features of patients affected with vernal keratoconjunctivitis (VKC) with associated limbal stem cell deficiency (LSCD). METHODS: In a retrospective observational case series, data relating to 49 eyes of 27 patients with VKC and features of LSCD seen from January 2000 to August 2005 at the Cornea Service of LV Prasad Eye Institute were reviewed. Detailed history, visual acuity at presentation,clinical findings, disease activity, duration of complaints, and extent of LSCD and management were noted. The presence of concurrent keratoconus and other ocular or systemic disorders if any were recorded. RESULTS: During this period, 2225 patients with VKC were seen at our institute. Of the 49 eyes, (1.2%) showed features of LSCD. The mean age was 21.37 6 10.14 years. The male to female ratio was 4 to 1. Twenty-two cases had bilateral disease, and 5 had unilateral affection. The visual acuity at presentation ranged from hand motions to 20/20. The duration of disease ranged from 1 to 25 years, with a mean of 10 6 6.66 years. Total LSCD was seen in 33 eyes (67.3%), and partial LSCD was seen in 16 (33%). Disease at the time of presentation was active in 15 cases (55.5%) and was quiescent in 12 cases (44.5%). Pannus resection with amniotic membrane graft was done in 5 eyes. Live related allolimbal transplantation was done in 6 eyes of 3 patients. VKC patients with or without associated LSCD had similar characteristics, but the age of presentation was lower inpatients without LSCD (P = 0.0005, unpaired Student t test), and the duration of disease was shorter (P , 0.0001, unpaired Student t test). CONCLUSIONS: LSCD seems to be one of the complications of long-standing VKC, contributing to severe visual impairment in young individuals. The chronic nature and prolonged duration of the disease may be responsible for this secondary ocular surface affection, leading to the clinical manifestation of LSCD. PMID- 21598434 TI - Evaluation of the corneal endothelium using noncontact and contact specular microscopy. AB - PURPOSE: To determine the difference between the endothelial cell density (ECD) and the morphologic measurements assessed with a recently developed noncontact specular microscope compared with a contact endothelial microscope. The agreement between the 2 independent operators was also investigated. METHODS: The central corneal endothelium was examined in the right eyes of 41 healthy individuals using automated image analysis programs without correction for a noncontact specular microscope and a contact specular microscope (EM-3000, EM-1000; Tomey, Tennenlohe, Germany). The evaluated parameters such as ECD,average cell area (AVG), and coefficient of variation of the cell area were determined by 2 operators. Conversion factors were also considered to adjust the ECD values. RESULTS: ECD measurements obtained with the noncontact instrument (2734 +/- 287 cells per square millimeter, first operator; 2726 +/- 282 cells per square millimeter, second operator) were significantly higher (P < 0.0001) in comparison with the contact microscope (2283 +/- 206 cells per square millimeter, first operator; 2274 +/- 242 cells per square millimeter, second operator) by both investigators. The contact specular microscope significantly overestimated (P < 0.0001) AVG and coefficient of variation of the cell area values. Statistically significant correlation (P < 0.0001) was detected in ECD (r = 0.77, first operator) and AVG measurements (r = 0.72, first operator) between the 2 endothelial microscopes. Higher degree of agreement between operators was given when using the noncontact specular microscope compared with the contact instrument. CONCLUSIONS: The significant differences and the poor agreement between the automated software options disclosed that the 2 instruments cannot be used interchangeably. PMID- 21598436 TI - Trauma associated coagulation disorders: acidosis, hypothermia and coagulopathy. PMID- 21598437 TI - Anaemia and massive bleeding apart from the aspect of oxygenation. PMID- 21598438 TI - Standard coagulation tests versus viscoelastic POC monitoring. PMID- 21598439 TI - Detection and impact of hyperfibrinolysis in trauma. PMID- 21598440 TI - Do we really need FFP in Austria? PMID- 21598441 TI - Fibrinogen and prothrombin complex concentrate for the management of massive bleeding. PMID- 21598442 TI - Hemostyptic wound bandages: are there any differences? PMID- 21598443 TI - Point of care diagnostic: thromboelastometry (ROTEM(r)). PMID- 21598444 TI - Acquired fibrinogen deficiency caused by artificial colloid plasma expanders. PMID- 21598445 TI - Prothrombin complex concentrate (PCC) for the treatment of coagulopathy associated with massive bleeding. PMID- 21598446 TI - NICE guidance on azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia, and acute myeloid leukaemia. PMID- 21598447 TI - Carcinogenicity of chemicals in industrial and consumer products, food contaminants and flavourings, and water chlorination byproducts. PMID- 21598448 TI - 2011 ASCO Genitourinary Cancers Symposium. PMID- 21598449 TI - Alex's Lemonade. PMID- 21598450 TI - Abstracts of the 2011 In Vitro Biology Meeting. June 4-8, 2011. Raleigh, North Carolina, USA. PMID- 21598451 TI - Abstracts of EUROHAND 2011, Combined XVIth FESSH (Federation of the European Societies for Surgery of the Hand) Congress and Xth EFSHT (European Federation of Societies for Hand Therapy) Congress. Oslo, Norway. May 26-28, 2011. PMID- 21598452 TI - Abstracts of the 34th Annual Scientific Meeting of the Research Society on Alcoholism. June 25-29, 2011. Atlanta, Georgia, USA. PMID- 21598453 TI - [A rare case of a gunshot wound in the ethmoid bone with the right-hand frontobasal skull fracture]. PMID- 21598454 TI - [Somatosensorial disorders. Alterations in the quality of life in patients presenting with peripheral vestibular dysfunction]. AB - The authors undertook the assessment of the available methods for the analysis of the sensations of patients suffering pathology of the vestibular analyzer. The fact that such conditions as dizziness and disequilibrium have great influence on the social status of a patient and his (her) position in society accounts for the use of functional stabilometry in the clinical practice along with the evaluation of quality of life. It is emphasized that the timely diagnosis of these disorders and elucidation of their primary causes are as important for the successful treatment of this pathology as the choice of an adequate course of medicamental and rehabilitative therapy. PMID- 21598455 TI - Abstracts of the SAEM (Society for Academic Emergency Medicine) Annual Meeting. June 1-5, 2011. Boston, Massachusetts, USA. PMID- 21598456 TI - Abstracts of the 52nd Congress of the German Society for Pneumology and Ventilatory Support . April 7-10, 2011. Dresden, Germany. PMID- 21598457 TI - The cost of sustaining playground related extremity fractures in Singapore. AB - PURPOSE: To study the cost of sustaining a fracture of the extremity caused by playground equipment. These costs include financial, psychological, clinical and others like loss of school days. METHOD: This is a prospective study of 226 children seen at the Paediatric Orthopaedic Department for a1-year period starting June 2005. Once confirmed to have a playground related fracture by the Orthopaedic specialist, three sets of data are collected. First is the clinical data. Second is the playground related data. This is done on site independently by another investigator. Third is the radiological data,which is assessed independently by an Orthopaedic surgeon to ensure consistency. RESULTS: Out of the 226 children seen, two-thirds were boys. The average age was 7.5 years. 35.8% were forearm fractures and 28.8% were supracondylar fractures with the rest being mostly fractures in the upper limb. 64.2% were treated with immobilisation only whilst 24.2% required closed manipulation and reduction. 1.2% required admission for treatment of their fractures. The average period of cast immobilisation was 34 days. The average number of consults, including that at the emergency department, was 4 with an average length of follow up of 67.2 days. Based on the above, in our institution, the average cost for outpatient treatment would be about S$680.00 (US$485.71) (US$1.00 = S$1.40; 1/1/2010) per injury. The inpatient cost for non-surgical treatment cost would be S$1000.00 and for surgical stabilisation the average cost would be S$3300.00 (US$2357.14). CONCLUSION: Playgrounds are meant for children to play safely. Yet, there appears to be a significant number of injuries sustained. Whilst these fractures are relatively minor, requiring outpatient treatment,there are costs. Besides the financial costs, there are hidden psychological costs of loss of school days and inability to participate in sports. Finally, as with any injury, there can be long-term complications which present further clinical costs. SIGNIFICANCE: Most studies on playground injuries tend to concentrate on the equipment and very superficially cover the clinical aspects, less so the costs. This paper looks at the clinical aspects in greater depth and emphasises that there are significant costs, beyond financial, when a child sustains a playground injury. The next thing to do is to examine what playgrounds factors significantly contribute to these injuries and remedy them when planning the construction of playgrounds. PMID- 21598458 TI - Forensics: The call of the crime lab. PMID- 21598459 TI - Who pays for obesity? AB - Adult obesity is a growing problem. From 1962 to 2006, obesity prevalence nearly tripled to 35.1 percent of adults. The rising prevalence of obesity is not limited to a particular socioeconomic group and is not unique to the United States. Should this widespread obesity epidemic be a cause for alarm? From a personal health perspective, the answer is an emphatic "yes." But when it comes to justifications of public policy for reducing obesity, the analysis becomes more complex. A common starting point is the assertion that those who are obese impose higher health costs on the rest of the population-a statement which is then taken to justify public policy interventions. But the question of who pays for obesity is an empirical one, and it involves analysis of how obese people fare in labor markets and health insurance markets. We will argue that the existing literature on these topics suggests that obese people on average do bear the costs and benefits of their eating and exercise habits. We begin by estimating the lifetime costs of obesity. We then discuss the extent to which private health insurance pools together obese and thin, whether health insurance causes obesity, and whether being fat might actually cause positive externalities for those who are not obese. If public policy to reduce obesity is not justified on the grounds of external costs imposed on others, then the remaining potential justification would need to be on the basis of helping people to address problems of ignorance or self-control that lead to obesity. In the conclusion, we offer a few thoughts about some complexities of such a justification. PMID- 21598460 TI - [Ear wax removal in general practice. Medical care of a "trivial" complaint]. PMID- 21598461 TI - [Novel adjuvants in vaccine development]. PMID- 21598462 TI - [Treatment with solifenacin reduces urinary urgency and improves quality of life. Results of the non-interventional CAP-study]. PMID- 21598463 TI - [Application of a seven-day buprenorphine transdermal patch in multimorbid patients on long-term ibuprofen or diclofenac]. AB - The objective of this study was to evaluate the benefit of a seven-day buprenorphine transdermal patch for patients with chronic musculoskeletal pain previously receiving long-term treatment with ibuprofen or diclofenac alone. Data of a subgroup of 703 patients were analysed which were part of a multicenter observational study with 3,295 patients. These patients had previously received ibuprofen or diclofenac and were characterized by older age,the presence of gastrointestinal, cardiovascular, and renal risk factors and the existence of chronic musculoskeletal pain. The switch to the seven-day buprenorphine patch resulted in a clinically significant decrease of the mean pain intensity at rest during the day from 5.3 to 2.9, on physical effort during the day from 7.1 to 3.3, and at night from 4.9 to 1.9 at the end of the study (11-point NRS scale, p group II > group III. The operator factors in root canal therapy difficulty group I and group II were not significantly different P > 0.05). But in root canal therapy difficulty group III, the endodontic specialist group have highest success rate in root canal preparation. CONCLUSION: The cases of root canal treatment should be treated by endodontist of corresponding level according to the difficulty. In difficult cases, endodontic specialist can provide better root canal preparation result. PMID- 21598485 TI - [Incidence of oral hairy leukoplakia in human immunodeficiency virus-seropositive adult patients in Yunnan, China]. AB - OBJECTIVE: To study the incidence rates, clinical characteristics of oral hairy leukoplakia (OHL) and its relation to the immune status in a sample of human immunodeficiency virus (HIV)-infected adults in Yunan, China. METHODS: 1 060 adult patients with HIV from January 2008 to June 2010 were evaluated. The age, gender, education grade, diagnosis time of HIV-infected, route of transmission, xerostomia, oral candidiasis, high active antiretroviral therapy and CD4 lymphocytes counts. The occurrence of OHL was recorded by oral examination. The relationship of CD4 lymphocytes counts and the incidence of OHL were analyzed by statistical methods. RESULTS: There were 94 OHL patients in 1 060 HIV patients (8.9%). The average age of the OHL patients was (39.33 +/- 10.45) years old. 90% OHL was found on the two lateral aspect of the tongue. The CD4 lymphocytes of 70.2% OHL patients were less than 200 mm-3. CONCLUSION: OHL is a frequent finding in patients with indicates severe immunosuppression and associated with the reduction of CD4 lymphocytes. PMID- 21598486 TI - [A survey of perception differences of malocclusion between 16 to 22-year-old young adults and orthodontists]. AB - OBJECTIVE: To investigate 16 to 22-year-old young adults' perception of malocclusion, dental health and aesthetic firstly. To investigate the perception differences between young adults and orthodontists, and factors on perception difference. METHODS: A sample of 16 to 22-year-old young adults was selected randomly in Department of Stomatology, Hospital of Nanjing Army Command College. A questionnaire, which consisted of socioeconomic status, index of orthodontic treatment need and dental health component (DHC) questionnaire, was proposed to them. Index of orthodontic treatment need comprised aesthetic component (AC) and DHC. An orthodontist measured orthodontic dental models of participants. Participants chose AC degree and DHC degree by their subjective perception. An orthodontist chose AC degree and DHC degree by their objective measurement. RESULTS: 71.08% and 70.59% of 204 participants respectively chose 'no need treatment' of AC degree and DHC degree by their subjective perception. 19.12% and 9.80% of participants were respectively chosen 'no need treatment' of AC degree and DHC degree by orthodontist's objective measurement. Objective measurement degree of orthodontist was higher than subjective perception degree of participants. Subjective perception of participants was little related to objective measurement of orthodontists. AC degree of male participants' subjective perception was lower than the female. DHC degree of urban participants' subjective perception was higher than the rural. DHC and AC degree of only child participants' subjective perception was higher than non-only child. CONCLUSION: Perception about malocclusion, dental health and aesthetic had significant difference between 16 to 22-year-old young adults and orthodontists. Young adults tended to think that their teeth were more beautiful and healthy. The female young adults than the male tended to think that their teeth were not enough beautiful. Urban young adults were more unsatisfactory about their dental health than the rural. Only child young adults were more unsatisfactory about their dental aesthetic and health than the non-only child. PMID- 21598487 TI - [Epidemiological survey of dentine hypersensitivity of 630 adults in rural of Sichuan province]. AB - OBJECTIVE: To investigate the prevalence and potential risk factors of dentine hypersensitivity of adults in rural of Sichuan province. METHODS: All representative samples, including 630 adults living in rural of Sichuan Province, were selected by multi-stage, stratified and random sampling. The dentine hypersensitivity of all 630 cases was surveyed with questionnaire and oral clinical examination. SPSS 18.0 software was used for statistical analysis. RESULTS: 27.9% of all subjects were suffered from dentine hypersensitivity, sour was the most common stimulus of dentine hypersensitivity. The first premolar was the most common tooth with dentine hypersensitive, which occupied 27.4% of the total affected teeth. Female, acid regurgitation symptom, low frequency of toothbrush replacement (over 3 months), high tooth-brushing force and frequency of fresh fruits consumption (over 2 times per week) probably were high risk factors of dentine hypersensitivity. CONCLUSION: The prevalence of dentine hypersensitivity occurs in rural of Sichuan province is high, thus for future the publicity and education on dentine hypersensitivity preventive should be strengthened. PMID- 21598488 TI - [Measurement of tooth length of upper canines in complete unilateral cleft lip and palate patients with cone-beam computed tomography]. AB - OBJECTIVE: The objective of this study is to investigate with cone-beam computed tomography (CBCT) the tooth length of permanent upper canines near the cleft area in patients with complete unilateral cleft lip palate (UCLP) and to compare the findings with its contralateral tooth, including full length, crown length, root length and top root ratio. Meanwhile, the teeth near the cleft area having anomalies are also recorded. METHODS: A sample of 20 patients with complete UCLP who accepted the CBCT scan were selected. The raw data were constructed along the longitudinal axis of the upper canines, and the full lengths, crown lengths, root lengths of upper canines of all patients were measured using 3 -D measurement software associated to CBCT. The fall lengths, crown lengths, root lengths and top root ratios of the upper canines accepted paired-t test. The anterior teeth near the cleft area having anomalies and positions of the clefts were also recorded. RESULTS: The fall lengths, root lengths and top root ratios of the upper canines had statistical difference between the cleft side and non-cleft side (P < 0.01), except the crown lengths (P > 0.05). 20 lateral incisors near the cleft area had anomalies (100%). CONCLUSION: The lengths of upper canines on the cleft side are shorter than those of the non-cleft side, and the root lengths are affected more. The teeth near the cleft side prove to be abnormal, especially the lateral incisors. PMID- 21598489 TI - [Clinicopathologic study on reactive hyperplasia of lymph nodes in maxillofacial regions]. AB - OBJECTIVE: To investigate the clinicopathologic features of reactive hyperplasia of lymph nodes in maxillofacial regions. METHODS: Thirty-two patients with lymph node reactive hyperplasia (LRH) were analyzed clinicopathologically including pathomorphologic manifestation and immunohistochemical expression. RESULTS: Histopathology of 32 patients showed significant hyperplasia in folliculus lymphaticus, marginal zone lymph, paracortical area lymph, and seldom mixed hyperplasia. Immunohistochemical study showed that the hyperplastic lymphocytes were mainly composed of CD20 positive B cells positive in 23 cases(72%), CD3 positive T cell in 7 cases (22%), CD20 positive T cell and CD3 positive B cell partially as well as histiocytes in 2 cases (6%). Atypical hyperplasia was found in 10 cases. CONCLUSION: Hyperplastic lymphocytes in LRH of maxillofacial regions are mainly composed of B cells. Malignant transformation may occur in these patients with atypical hyperplasia. Regularity follow up is necessary for these patients. PMID- 21598490 TI - [A comparative study of marginal microleakage using different cements in porcelain-fused-to-metal crown]. AB - OBJECTIVE: To evaluate the marginal microleakage of porcelain-fused-to-metal crown using four different cements. METHODS: Sixteen porcelain-fused-to-metal crowns were built and randomly divided into 4 group, luted onto standard prepared human forward molars using four different cements (glass ionomer cement, resin modified glass ionomer cement, PanaviaF, Super-Bond C&B adhesive luting system). After temperature cycling test, all the crowns were then submerged in 2% fuchsin for 24 h. The marginal microleakage at tooth cement interfaces was observed using light stereomicroscopy and evaluated in classification index. The marginal microleakage grade of 4 groups were analyzed by SPSS 13.0. RESULTS: The PanaviaF demonstrated the least marginal microleakage, Super-Bond C&B adhesive luting system, resin-modified glass ionomer cement showed an intermediate level of marginal microleakage, glass ionomer cement was associated with severe marginal microleakage (total, Chi2 = 157.60, P < 0.01; among the different groups, P<0.05). CONCLUSION: Adhesive resin luting system which is the first selection in clinical is better than glass ionomer cement and is good at porcelain-fused-to metal crown. PMID- 21598491 TI - [Clinical effect of reattachment of permanent anterior teeth with crown fracture]. AB - OBJECTIVE: To compare the clinical effect between reattachment of permanent anterior teeth with crown fracture using dual-cured resin combined with dentin pin and conventional method. METHODS: 49 permanent anterior teeth of 38 patients which had intact incisal edge segments were divided into two groups. In experimental group reattachment was conducted by dual-cured resin combined with dentin pin, while in control group only dual-cured resin was adopted. Cases were assessed clinically by one year's followed up. RESULTS: The success rate was 95% in experimental group and 64% in control group after one-year's follow-up (P < 0.05). CONCLUSION: The clinical effect of reattachment with dual-cured resin combined dentin pin to treat anterior crown fracture is superior to conventional method. PMID- 21598492 TI - [Orthodontic retention and adjustment of the occlusion after orthognathic surgery]. AB - OBJECTIVE: To investigate the orthodontic retention and adjustment of the occlusion after orthognathic surgery. METHODS: 18 patients were divided into three groups. Group I: Cases with skeletal Class I bimaxillary protrusion treated by subapical osteotomy; Group II: Cases with skeletal Class II mandibular retrusion treated by sagittal split mandibular advancement surgery; Group III: Cases with skeletal Class III treated by Le Fort I osteotomy on maxilla and sagittal split osteotomy on mandible. There were 6 patients in each group. Three kinds of orthodontic elastic tractions were used based on different categories of malocclusion and different types of operation. RESULTS: 18 patients attained functional occlusion after the orthodontic occlusion adjustment. There was no relapse and malocclusion by surgery. CONCLUSION: Intermaxillary elastics based on different categories of occlusion and different kinds of surgery can improve the occlusion after orthognathic surgery and attatin the functional occlusion. PMID- 21598493 TI - [Application of quantum dots fluorescent probes in tissue of human tongue squamous cell carcinoma]. AB - OBJECTIVE: To study if quantum dots fluorescent probes can be applied to detect P53 protein and Bcl-2 protein in tissue of human tongue squamous cell carcinoma. METHODS: By indirect immunofluorescence assay the same particle size quantum dots fluorescent probes were applied to detect P53 protein and Bcl-2 protein respectively. Different particle size quantum dots fluorescent probes were applied to detect P53 protein and Bcl-2 protein simultaneously in paraffin embedded tissue section of human tongue squamous cell carcinoma under fluorescent microscope. RESULTS: P53 protein and Bcl-2 protein can be combined with quantum dots fluorescent probes and specific fluorescene can be observed with ultraviolet light excited. P53 protein was mainly distributed in the nucleus, and Bcl-2 protein major in the cytoplasm. P53 protein and Bcl-2 protein can be combined with different particle size quantum dots fluorescent probes respectively in the same paraffin-embedded tissue section of human tongue squamous cell carcinoma and two kinds of fluorescene can be observed. CONCLUSION: Quantum dots fluorescent probes can be applied to detect two kinds of specific protein in paraffin embedded tissue section of human tongue squamous cell carcinoma. PMID- 21598494 TI - [Expression of interleukin-12p40 and interferon-gamma in local lesions of human oral lichen planus]. AB - OBJECTIVE: To investigate the significance of cytokine interleukin-12p40 (IL 12p40) and interferon-gamma (IFN-gamma) in tissues formation and development of human oral lichen planus (OLP). METHODS: The tissues of 11 cases of normal oral epithelium and 43 cases of OLP were investigated for the expression of IL-12p40 and IFN-gamma proteins by using Envision two-step immunohistochemistry. The correlations between the expressions of these two cytokines, and their clinical and pathological significance in OLP were analyzed. RESULTS: 1) IL-12p40 and IFN gamma proteins were up-regulated in OLP comparing with that in normal oral mucosa and there was statistical significance between their difference (P < 0.05). 2) The percentage of positive IL-12p40 staining in OLP of IFN-gamma positive group was higher than IFN-gamma negative group and there was statistical significance between their difference (Chi2 = 5.828, P = 0.016). A positive correlation was found between IL-12p40 and IFN-gamma proteins in OLP (Spearman r = 0.357, P = 0.019). 3) The percentage of positive IL-12p40 staining in OLP with short course (< 6 months) was higher than that in OLP with long course (> 6 months; Chi2 = 7.935, P = 0.005), and a significant association was found between IFN-gamma over expression and the degeneration of base cells in OLP lesions (Chi2 = 9.070, P = 0.011). CONCLUSION: These results indicate that at the primary phase of OLP, IL 12 may drive the pathological destruction in OLP lesions by elevating IFN-gamma protein locally. IFN-gamma may play an important role for the pathological destruction in OLP lesions. PMID- 21598495 TI - [Expression of ligand-gated cation channels P2X3 receptor in rat pulp during experimental tooth movement]. AB - OBJECTIVE: To investigate ligand-gated cation channels P2X3 receptors changes in rat pulp during experimental tooth movement (ETM), and preliminarily find their possible effect during ETM. METHODS: 54 male SD rats (200-250 g) were selected and randomly divided into blank group (5 rats), control group (14 rats) and experimental group (35 rats). The left maxillary first molar was selected as observation object, the pulp tissue biopsies was taken at different time points to carry out immunohistochemical study. RESULTS: Predominant up regulation of P2X3 receptors immunoactivity was found in pulp from 1/6 d to 7 d after experimental tooth movement. It started to significantly increase at 1/6 d, peaked at 3 d, and then decreased continuously until 7 d as compared with the beginning. CONCLUSION: P2X3 receptors have a rhythm change in rat pulp as a result of ETM, speculated that P2X3 receptors is closely related to the tooth movement injury, but the mechanism of action need further researches. PMID- 21598496 TI - [Study on total glucosides of peony preventing non-obese diabetic mice from sialoadenitis]. AB - OBJECTIVE: To investigate the immunosuppressive effect of total glucosides of peony (TGP) on sialoadenitis in non-obese diabetic mice (NOD mice) and explore its possible mechanism. METHODS: 27 female five-week-old NOD mice were randomly divided into three groups: TGP, hydroxychloroquine (HCQ) and normal saline (NS) group. One week later, they were administered intragastrically in TGP, HCQ and NS respectively. Three mice from each group were sacrificed at the age of 10, 15 and 20 weeks. The saliva flow, serum and submandibular glands were collected at these time points. Histological changes of submandibular glands were examined by HE staining. The expression of autoantibodies (SSA, SSB and anti-alpha-fodrin) and associated cytokines in serum were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the NS group, salivary flow was significantly increased, the extent of the histological changes were ameliorated, the autoantibodies in serum were significantly decreased and the imbalance of Th1/Th2 cytokines was remedied in the mice treated with TGP and HCQ. There were no significant differences between the two groups treated with TGP and HCQ (P > 0.05). CONCLUSION: TGP can effectively ameliorate sialoadenitis on NOD mice. The mechanism was thought to be associated with the protection of submandibular gland from intense inflammation and the correction of Th1/Th2 cytokines imbalance. PMID- 21598497 TI - [Influence of zirconia content on translucency of zirconia-toughened alumina glass-infiltrated ceramic]. AB - OBJECTIVE: The objective of this study is to investigate the influence of zirconia content which is 0-30.0% weight percentage of matrix on translucency of zirconia-toughened alumina glass-infiltrated ceramics. METHODS: Seven groups were divided according to different weight percentage of zirconia (0, 2.5%, 5.0%, 7.5%, 10.0%, 20.0% and 30.0%). After sintering, infiltrating and polishing, spectral transmittance was determined with spectrophotometer under D65 standard source. Contrast ratio was also tested by whiteness colorimeter. RESULTS: With mass fraction of zirconia increasing from 0 to 30.0%, spectral transmittance reduced from 0.406% to 0.058%, while contrast ratio value increased from 0.849 +/ 0.005 to 1.015 +/- 0.006. When zirconia content was 10.0%, contrast ratio was 0.990 +/- 0.008. When it was more than 10.0%, transmission rate of the downward trend and contrast ratio of the rising trend became flat. CONCLUSION: Zirconia content has a direct impact on translucency of zirconia-toughened alumina glass infiltrated ceramic, which is essentially opaque when zirconia content is 10.0%. When mass fraction of zirconia is more than 10.0%, the influence of zirconia content is reduced. PMID- 21598498 TI - [Influence of nano-silica content on flexural properties of the aluminum borate whisker and silica filler composite resins]. AB - OBJECTIVE: To discuss the influence of nano-silica content which was hydrolyzed by tetraethyl orthosioate (TEOS) on the aluminum borate whisker (AlBw) and silica filler composite resins on flexural properties. METHODS: The nanometer-size silicon dioxide (SiO2) particles were prepared by sol-gel method based on tetraethyl orthosioate. Different proportion of AlBw and SiO2 were fused and attached onto the surface of AlBw through high temperature, then polymerized with resin matrix after surface siliconization and their flexural strength and flexural modulus were determined. The effects of heat treatment to the surface morphology of AlBw and the shapes of the mixture at various proportions were characterized by TEM. RESULTS: The flexural properties of dental composite resins with AlBw-SiO2 compound as inorganic fillers were significantly improved. The flexural property of a new type of dental composite resins was(130.29 +/- 8.38) MPa, when the mass ratio of AlBw and nano-SiO2 particle was 3:1. CONCLUSION: Nano silica content which was hydrolyzed by tetraethyl orthosioate improved flexural properties of the aluminum borate whisker and silica filler composite resins. PMID- 21598499 TI - [Cloning of the glyceraldehydes 3-phosphate dehydrogenase gene of porphyromonas gingivalis and its expression in E. coli]. AB - OBJECTIVE: To clone the glyceraldehydes 3-phosphate dehydrogenase (GAPDH) gene of Porphyromonas gingivalis (P. gingivalis) and to induce its fusion expression in E. coli. METHODS: GAPDH was obtained by PCR and was inserted into cloning vector pMD-18-T to construct clone recon. Double enzymes digest the recon pMD18-T-GAPDH and the prokaryotic expression vector pET-32a and then connect to get the expressing recon pET-32a-GAPDH. The recombinant expression plasmid which had been confirmed by enzymes digestion was transformed to E. coli competent cells BL21 and induced the expression of GAPDH with isopropyl beta-D-1-thiogalactopyranoside (IPTG) of different density. RESULTS: DNA sequencing showed that the fragment was 99.802% the same to the sequence published in NCBI. Under the best density, IPTG could be highly expressed. CONCLUSION: The GAPDH had been successfully cloned and expressed in E. coli which gets ready for the following experiment to study the immunity of GAPDH and the homologues antibody preparation. PMID- 21598500 TI - [Study of corrosion behavior of titanium with anodized oxidation film]. AB - OBJECTIVE: To investigate the variation of the corrosion resistance of anodized oxidation film on titanium by electrochemical methods. METHODS: TiO2 nanotube layer was formed on Ti surface by anodization. The morphology was observed with scanning electron microscope (SEM) and the crystal phase was analyzed using X-ray diffraction(XRD) before and after annealing. Polarization curves were examined by electrochemical methods. RESULTS: Titanium oxide nanotubes with 80 nm diameter and 400 nm length was seen on Ti after anodization. The annealing nanotubes was anatase crystalline phase by X-ray diffraction analysis. The self-corrosion potential and break-down potential of smooth Ti were significantly lower than TiO2 nanotubes by anodization (P < 0.05). The self-corrosion current and passived current were significantly higher than TiO2 nanotubes by anodization (P < 0.05). Annealing improved the corrosion resistance of anodized oxidation film on titanium. CONCLUSION: The results of electrochemical examinations indicate that the TiO2 nanotubes by anodization increases the corrosion resistance of titanium. PMID- 21598501 TI - [Study on the in vitro effects of dexamethasone at different concentrations on the growth of murine embryonic palatal mesenchymal cell]. AB - OBJECTIVE: To observe the effect of dexamethasone on the proliferation and apoptosis of embryonic palatal mesenchymal (EPM) cells, and chose a proper concentration of dexamethasone which can effect the ordinary growth of embryonic palatal mesenchymal cells. METHODS: The primary EPM cells were isolated and cultured in vitro, then we did biological assay. EPM cells were treated with different concentration dexamethasone (1 x 10(-9), 1 x 10(-8), 1 x 10(-7) and 1 x 10(-6) mol x L(-1)) respectively. The proliferation of EPM cells was evaluated using MTT method. Apoptosis was examined quantitatively with fluorescein stain. RESULTS: In the condition of blood serum's concentration at 10%, optical density step down following the raise of dexamethasone's concentration. The effect of dexamethasone got to a summit at 3 days. Inhibition rate of dexamethasone at 1 x 10(-6) mol x L(-1) was the highest. CONCLUSION: Dexamethasone at 1 x 10(-6) mol x L(-1) can not only inhibit the growth of the EPM cells, but also will not lead to a large number of cells death. Therefore, this concentration can be used as a reference standard in future research. The most significant drug action time of dexamethason appears at the third day after administration, then the effect became weaken following the drug metabolism. PMID- 21598502 TI - [Effect of different irrigating solutions on bonding strength of fiber post to root canal]. AB - OBJECTIVE: The purpose of this study is to find some appropriate treatments on the dentin of root canal wall to obtain better bonding strength of fiber posts. METHODS: 36 new extracted non-caries single root canal anterior teeth were collected and post spaces were prepared. The teeth were divided into six groups randomly and processed by different post-space treatments: Sodium chloride irrigation (group I , control group); irrigation with 2% chlorhexidine solution followed by 17% EDTA solution (group II ); irrigation with 3% hydrogen peroxide followed by 17% EDTA solution (group II); irrigation with 5.25% sodium hypochlorite (NaClO) followed by 17% EDTA solution (group IV); etching with 35% phosphoric acid-gel for 30 s (group V); 17% EDTA-gel for 1 min (group VI). After each post-space treatment, sodium chloride irrigation was applied in II-VI group. Fiber posts were then luted in the treated roots using 3M ESPE RelyX Unicem and the thin-slice push-out test was performed. The dentin surfaces and bonding interface were examined under scanning electron microscope. Fracture mode of fiber posts were observed by stereo microscope. RESULTS: Group II-VI were effective in getting rid of smear layer. Resin rags of dentin bonding interface were observed in group II and group V. The majority fracture mode of specimens in each group were mixed mode which contained dentin destruction. Compared with control group, the bonding strength of group II, V increased obviously (P < 0.05). CONCLUSION: Irrigation with 2% chlorhexidine solution followed by 17% EDTA solution and 35% phosphoric acid-gel etching improved the bonding strength of fiber posts. The depth of post space has no influence of bond strength. PMID- 21598503 TI - [Transient expression of exogenous human platelet-derived growth factor-B in gingival fibroblasts of dog]. AB - OBJECTIVE: To explore transient expression of the eukaryotic expression plasmid carrying human platelet-derived growth factor-B (hPDGF-B) in gingival fibroblasts of Beagle dog. METHODS: Plasmid carrying hPDGF-B (EX-A0380-M03) was amplified and identified, and then transfected into gingival fibroblasts of Beagle dog. Reverse transcription polymerase chain reaction (RT-PCR), immunocytochemistry, enzyme linked immunosorbent assay (ELISA) and Western bolt were choose to detect the expression of hPDGF-B. RESULTS: Target gene carried by EX-A0380-M03 was hPDGF-B. Green fluorescence protein (GFP) expressed by transfected gingival fibroblasts was observed under inverted phase contrast fluorescence microscope (IPCFM) (after 24 hours) and the transfection efficiency was 18%-38% (after 48 hours). Serials other methods (RT-PCR, immunocytochemistry, and ELISA) mentioned above also convinced that cells expressed hPDGF-B, and the protein that was a kind of fusion protein composed of PDGF-BB and GFP was identified by Western blot. CONCLUSION: Eukaryotic expression plasmid carrying hPDGF-B was transfected into gingival fibroblasts successfully, and a kind of fusion protein was expressed. PMID- 21598504 TI - [Discussing displacemental trend on nontractional side of canine mandible with finite element method when distraction osteogenesis with unilateral incomplete osteotomy]. AB - OBJECTIVE: To discuss the trend of displacement on the side of nondistraction when distraction osteogenesis with unilateral incomplete osteotomy of canine mandible. METHODS: The method of finite element analysis was used to simulate distraction osteogenesis with unilateral incomplete osteotomy and the displacement of six marked point such as the temporomandibular joint and the angle of mandible and coracoid process and teeth were observed on nondistractional side when the transport disc was distracted with a distance and without a distance. RESULTS: When the transport disc was distracted without a distance, the Von Mises stress was 0 in the six marked point of nondisractional side and their displacement in 3 dimensions (X, Y, Z axis) was 0. When the transport disc was distracted with 1 mm width, all marked point had some displacement. CONCLUSION: When distracted and observed from the side of distraction, the mandible at the side of nondistraction has the trend of contrarotation round the center of the transverse ridge mid-point of condyle process on the plane of sagittal, whereas it has the trend of parallel movement approximately in the direction of opposite side on the plane of coronary. PMID- 21598505 TI - [Alcohol withdrawal syndrome associated with oral cancer operation: a case report]. AB - Alcohol withdrawal syndrome (AWS) is a rare complication associated with oral cancer operation. This article reported a case of AWS after resection of squamous cell cancer of the right floor of mouth combined with radical neck dissection and trapezius myocutaneous flap reconstruction. The discussion included diagnosis, treatment and prevention of AWS. PMID- 21598506 TI - [Developments and applications of microfluidic chip-based chromatographic technique]. AB - Microfluidic chip-based chromatographic technique has undergone rapid progress in recent years. The progress in the fabrication of chromatographic columns, the design of valves and pumps, the integration of these components into a single chip and the applications of the chip-based chromatographic systems, are reviewed, and 66 references are cited. PMID- 21598507 TI - [Progress in the analysis of brassinosteroids]. AB - Brassinosteroids have been considered as a class of plant hormones with high activity. However, the complex matrix of the plant samples and the ultra-trace level of naturally occurring brassinosteroids make their separation and determination very difficult. This review summarizes the progress in the development of sample pretreatment and determination of brassinosteroids. PMID- 21598508 TI - [Speciation analysis of arsenic in seaweeds by capillary electrophoresis inductively coupled plasma mass spectrometry]. AB - A method for the detection of trace As (III), As (V), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), arsenocholine (AsC) and arsenobetaine (AsB) in seaweeds by capillary electrophoresis-inductively coupled plasma mass spectrometry (CE-ICP-MS) was developed. The optimized conditions of CE including chemical component, pH and concentration of the buffer, separation voltage and injection time were studied in detail. The results showed that the above six species of arsenic were baseline separated within 25 min under the optimized conditions. The relative standard deviations (n = 6) of the peak areas were smaller than 5%, and the detection limits (calculated as As) (S/N = 3) were 0.08 0.12 microg/L for all the above six species of arsenic. The method has been successfully applied to the determination of the species of arsenic in kelp samples. The recoveries were 90% - 103%. The method has good reproducibility, high sensitivity, short analytical time and strong resistance to complex matrix, and can be used for the speciation analysis of arsenic in real seafood samples. PMID- 21598509 TI - [Simultaneous determination of 2,4-dinitrotoluene and tris (2-chloroethyl) ester in environmental waters by dispersive liquid-liquid microextraction combined with gas chromatography-mass spectrometry]. AB - A method based on dispersive liquid-liquid microextraction-gas chromatography mass spectrometry (DLLME-GC-MS) was developed for the simultaneous determination of trace 2,4-dinitrotoluene (2,4-DNT) and tris(2-chloroethyl) ester (TCEP) in environmental water samples. The types of extraction solvent, dispersive solvent, extraction time and ionic strength were investigated and optimized to obtain the best extraction efficiency for the target analytes. The analysis performance evaluation and the real sample analysis were performed as follows: 0.8 mL of ethanol as dispersive solvent and 60 microL of chloroform as extraction solvent were rapidly added into 5.0 mL of the aqueous solution, and the solution was vibrated about 120 s and centrifuged. Then the sediment phase to be analyzed was directly injected into a GC-MS. Under the optimized conditions,, the limits of detection (LODs, S/N = 3) for the target analytes were 0.01 microg/L and 0.04 microg/L with the enrichment factors (EFs) of 96.6 and 127.5. The real environmental water samples were analyzed and the recoveries of 102.1% - 110.9% were obtained. The method is simple, fast, efficient and inexpensive. PMID- 21598510 TI - [Determination of sulfonamides, quinolones, benzimidazoles and the metabolites of benzimidazoles in chicken livers by dispersive solid-phase extraction and ultra performance liquid chromatography-tandem mass spectrometry]. AB - A method for the determination of 12 sulfonamides, 19 quinolones and 8 benzimidazoles and the metabolites of benzimidazoles in chicken livers by quick, easy, cheap, effective, rugged and safe (QuEChERS) extraction and ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed. The samples were extracted with 1% acetic acid-acetonitrile solution, cleaned up with amine (NH2) sorbent and defatted with n-hexane. The identification and quantification were achieved by using electrospray ionization in positive ion mode (ESI+) with multiple reaction monitoring (MRM). The matrix matched internal standard calibration curves were used for quantitative determination. The linear range was from 5 to 100 microg/kg. The average recoveries and relative standard deviations were 72% - 121% and 1.5% -23.4% respectively in the spiked range of 10 -50 microg/kg. The limits of detection were 5 microg/kg and the limits of quantification were 10 microg/kg for the 39 drugs. The method is simple, rapid, sensitive and accurate. It is suitable for the quantitative determination and confirmation of 12 sulfonamides, 19 quinolones, 8 benzimidazoles and the metabolites of benzimidazoles. PMID- 21598511 TI - [Determination of perfluorinated compounds in human urine by ultra high performance liquid chromatography-tandem mass spectrometry]. AB - A method for the analysis of 12 perfluorinated compounds (PFCs) in human urine by ultra high performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) was developed and validated. One mL 2% formic acid in methanol was added into the urine. After ultrasonication and centrifugation, the samples were purified by a solid phase extraction column and examined by UPLC-MS/MS. The target compounds were quantified by stable isotope dilution technique. The linear range was 0.05 -50 microg/L for the 12 PFCs and the correlation coefficient > or = 0.992. The limits of detection of 12 PFCs were in the range of 0.44 - 3.47 ng/L. The matrix recoveries of the method for the 12 PFCs in three spiked levels (20, 100, 500 ng/L) ranged from 80.3% to 116.2%. The relative standard deviations (RSDs, n = 5) were between 5.5% and 13.8%. The sensitive and accurate method was successfully applied to the analysis of PFCs in human urine. PMID- 21598512 TI - [Effects of ionic liquids on micellar microstructures and separation performance in micellar electrokinetic chromatography]. AB - The effects of ionic liquids on micellar microstructures and separation performance in micellar electrokinetic chromatography (MEKC) were investigated. The experimental results showed that the addition of ionic liquids into micellar system would result in a decreased micellar surface charge density, an enlarged size of micelle and a slight enhancement of the polarity in the inner core of micelle. Prednisone, hydrocortisone and prednisolone were analyzed with MEKC to evaluate the separation performance. Hydrocortisone and prednisolone could not be separated in sodium lauryl sulfate (SDS) micellar system. However, the three analytes could be baseline separated in the mixed system of ionic liquids and SDS (20 mmol/L SDS-10 mmol/L 1-butyl-3-methyl imidazolium tetrafluoroborate-50 mmol/L borax, pH 8.4) within 17 min. Notably, the linearities of the three analytes ranged from 2 to 100 mg/L and the detection limits based on the ratio of signal to noise of 3 were 1.0, 1.1 and 1.0 mg/L for prednisone, hydrocortisone and prednisolone, respectively. The method has been used in the analysis of corticosteroids in cosmetic samples. The recoveries for the three analytes were between 95. 1% and 117%. This method has the advantages of simple pretreatment, high accuracy, good reproducibility, and can be applied to the quality control of cosmetics. PMID- 21598513 TI - [Determination of salbutamol sulfate in medicaments by capillary electrophoresis with contactless conductivity detection]. AB - A method for the determination of salbutamol sulfate in medicaments by capillary electrophoresis with contactless conductivity detection has been developed. The effects of several important factors, such as nonaqueous and aqueous solvents, background electrolyte and its concentration as well as the pH, separation voltage, sample injection time, excitation voltage and excitation frequency, were investigated. The optimized separation conditions were as follows: the running buffer was an aqueous solution (pH 2.7) containing 15 mmol/L lactic acid, the separation voltage was 10 kV, the electrokinetic injection time was 3 s at 10 kV, the excitation voltage was 60 V, and the excitation frequency was 120 kHz. The results have shown that there was a linear relationship (r = 0.995) between the response of the peak area and the mass concentration of salbutamol sulfate in the range from 9.60 to 48.0 mg/L, and the limits of detection (S/N = 3) was 1.92 mg/L. The relative standard deviation for the migration time of salbutamol sulfate was 2.7%. The method has been successfully applied in the determination of the contents in the tablet and aerosol of salbutamol sulfate, separately. The results were in accordance with the values marked by the pharmaceutical industry. Moreover, the recoveries were 90% - 113%. This simple and quick analytical method can be used for determining salbutamol sulfate. PMID- 21598514 TI - [Determination of nitrogen compounds in gasoline by gas chromatography-surface ionization detector]. AB - Nitrogen compounds in gasoline were extracted by liquid-liquid extraction and analyzed by gas chromatography-surface ionization detector (GC-SID). Compared with the chromatograms obtained from GC-flame ionization detector (FID), GC thermal ionization detector (NPD) and GC-mass spectrometry (MS), the peaks in the chromatogram obtained by GC-SID were assigned to the nitrogen compounds in gasoline. Most of these nitrogen compounds could not be detected by FID or NPD, which demonstrated the high selectivity and sensitivity of the SID. The types of nitrogen compounds in three gasoline samples (90#, 93#, 97#) were similar, but their contents varied with different gasoline brands. The extracted nitrogen compounds were mainly anilines, the amounts of which in the three gasoline samples were different. Trace amounts of several high boiling point nitrogen compounds were successfully detected because of the high sensitivity of SID. The SID is superior to the commercial NPD in detecting the nitrogen compounds in gasoline samples. In view of its high sensitivity and selectivity, the SID is a promising GC detector. PMID- 21598515 TI - [Simultaneous detection of 8 monoamine neurotransmitters in the different sections of rat brains by high performance liquid chromatography with fluorescence detection]. AB - A method for the simultaneous detection of L-dihydroxyphenylalanine, norepinephrine, epinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, serotonin hydrochloride, 5-hydroxyindole-3-acetic acid and homovanillic acid in the different sections of mouse brains was established by using high performance liquid chromatography (HPLC) with fluorescence detection and isocratic elution. Before analysis, the sample was deproteinized by 0.60 mol/L perchloric acid, followed by adjusting pH value of the sample with 1.20 mol/L K2HPO4, addition of 0.1 g/L L-cysteine as antioxidant and 0.50 mmol/L Na2EDTA as complexing agent. The separation column was a Shim-pack C18 column (250 mm x 4.6 mm, 5 microm) and the mobile phase (pH 3.8) was 13% methanol containing 50 mmol/L citric acid, 50 mmol/L sodium acetate, 0.5 mmol/L 1-heptanesulfonic acid sodium salt, 5 mmol/L triethylamine and 0.5 mmol/L Na2EDTA. The flow rate was 1.0 mL/min. The injection volume was 10 microL. The emission and excitation wavelengths were 330 nm and 280 nm, respectively. Under the optimized separation conditions, the calibration curves showed good linearity within the concentrations of 1.25 - 5000 microg/L (r > 0.9999). The limits of detection were between 0.20 - 5.00 microg/L, the average recoveries were between 94.83% and 99.19%, and the relative standard deviations (RSDs) were between 0.08% and 2.51%. The advantages of the method include easy and prompt operation, high recovery, low detection limit, good separation effect, high accuracy and precision. The method has practical value for detecting 8 monoamine neurotransmitters in biological samples. PMID- 21598516 TI - [Retention behavior of statins in microemulsion liquid chromatography]. AB - The effects of the concentration of surfactant, co-surfactant and lipophilic organic solvent and the pH value of mobile phase on the retention behavior of statins in microemulsion liquid chromatography have been investigated using pravastatin sodium, atorvastatin calcium, lovastatin and simvastatin as model compounds. The experimental results showed that the effects of the concentration of surfactant, co-surfactant and lipophilic organic solvent on the retention behavior of statins in microemulsion liquid chromatography were fully consistent with the theoretical modeling. The effect of the pH value of the mobile phase on the retention behavior of acid statins was fully consistent with the theoretical modeling. The relationship between the retention factor of neutral statins and the concentration of hydrogen ion was an implicit function. The retention modeling can reflect the effect of composition of microemulsion solution on the retention behavior of statins drugs. PMID- 21598517 TI - [Determination of netilmicin in rat serum using high performance liquid chromatography and resonance Rayleigh scattering]. AB - A method was developed for the direct determination of netilmicin in rat serum using high performance liquid chromatography and resonance Rayleigh scattering (RRS). The separation was carried out on a C18 column with the isocratic elution of the mixture of 20 mmol/L sodium acetate aqueous solution and methanol containing 0.22% trifluoroacetic acid (92:8, v/v). With the molecular recognition probe of pontamine sky blue, netilmicin formed an ion-association complex and enhanced the intensity of RRS. The RRS signal was detected by a commercial fluorescence detector at 365 nm of both excitation wavelength (lambda ex) and emission wavelength (lambda em). Under the optimized conditions, the limit of detection (LOD, S/N = 3) for the netilmicin was 0.7 mg/L. With the internal standard (IS) of tobramycin, a linear calibration curve ranged from 1.2 mg/L to 30 mg/L was obtained. The presented method can be used for the pharmacokinetics study of netilmicin in rat serum, and can be a new choice for the determination of aminoglycoside antibiotics in biological samples. PMID- 21598518 TI - [Simultaneous determination of 15 industrial synthetic dyes in condiment by solid phase extraction-high performance liquid chromatography]. AB - A new method was established for the determination of 15 industrial synthetic dyes in condiment by solid phase extraction-high performance liquid chromatography (SPE-HPLC). The samples were extracted by methanol-water (1:1, v/v) and purified by a solid phase extraction column. Then, the chromatographic separation was achieved on a Luna C18 column by linear gradient elution. The mobile phase was 10 mmol/L ammonium acetate-acetonitrile (containing 1% acetic acid). The results showed that the 15 industrial synthetic dyes can be separated efficiently. The recoveries of the 15 industrial synthetic dyes spiked in condiment were between 84.6% and 114.2% with the relative standard deviations of 0.9% - 10.3%. The limits of detection of this method was 0.05 - 0.18 mg/kg for the 15 industrial synthetic dyes. The method is simple, sensitive, accurate, repeatable and can be used for simultaneous determination of the 15 illegally added industrial synthetic dyes. PMID- 21598519 TI - [Determination of tetrabromobisphenol-A in electronic products by gas chromatography-mass spectrometry]. AB - A method for the determination of tetrabromobisphenol-A (TBBP-A) in electronic products was developed by gas chromatography-mass spectrometry (GC-MS). The TBBP A was extracted from electronic products by automatic digestion oven with acetone and concentrated by the evaporation of solvent. It was redissolved in methylene chloride, back-extracted by potassium carbonate solution and reacted with acetic anhydride. The derivative was extracted by hexane and determined by GC-MS. The linear calibration curve was obtained in the range of 0.25 - 5.0 mg/L with a correlation coefficient of 0.996. The detection limit of the method was 0.05 mg/kg. The recoveries were 87.3% - 104.1% and the relative standard deviations were 5.6% - 8.5%. The method is accurate and sensitive, and it is suitable for the analysis of tetrabromobisphenol-A in electronic products. PMID- 21598520 TI - [Determination of ethyl glucuronide in human urine by solid phase extraction-gas chromatography-mass spectrometry]. AB - A solid phase extraction (SPE) and gas chromatography (GC) with mass spectrometry (MS) method for determination of ethyl glucuronide (EtG) in human urine was established. One mL urine sample was deproteinated by 100 microL 3 mol/L hydrochloric acid and cleaned up through a solid phase extraction column. The target analytes were eluted from an NH2-column with 4% ammonia solution and then treated with bis (trimethylsilyl) trifluoroacetamide (BSTFA) + trimethylchlorosilane (TMCS) (99:1) for derivatization. The derivatized samples were analyzed by GC-MS. Data were acquired in the selected ion monitoring (SIM) mode and the quantitation of EtG was done through internal standard method. Good linearity was obtained at the mass concentration range of 0.1 - 3.2 mg/L with a correlation coefficient (r) of 0.9921. The limit of detection (LOD) was 28.4 microg/L. The range of recoveries was 92.5% - 108.7%, and the relative standard deviations (RSDs) of intra-day and inter-day were all less than 5%. This method is sensitive, specific, accurate and can be applied to the determination of EtG for medicolegal identification and clinical laboratory. PMID- 21598521 TI - [Simultaneous determination of four alkaloids in Corydalis decumbens (Thunb.) Pers. by high performance liquid chromatography-tandem mass spectrometry]. AB - A method for the analysis of 4 alkaloids in Corydalis decumbens (Thunb.) Pers. was developed by high performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-MS/MS). The sample was extracted in methanol by ultrasonic, filtered and diluted with methanol for further analysis. The analysis was performed on a C18 column (150 mm x 2.1 mm, 3.5 microm) using a gradient elution program with the mobile phase of 0.2% acetic acid solution and acetonitrile. The analyte was determined by an electrospray ionization tandem mass spectrometry in multiple reactions monitoring (MRM) mode. The qualitative and quantitative analyses were based on the retention times and characteristic ion pairs consisting of one parent ion and two fragment ions of the analyte. The limits of detection (LODs) for 4 alkaloids were in the range of 0.02 - 0.2 microg/L, and the limits of quantification (LOQs) were in the range of 0.07 - 0.66 microg/L. The average recoveries were in the range of 93.6% - 103.5% for 4 alkaloids with the relative standard deviations below 3.8%. This method is reliable, sensitive and reproducible, and it can be used for the quality control of Corydalis decumbens (Thunb.) Pers. sample. PMID- 21598522 TI - [Determination of paraquat residue in plant-derived foodstuffs by high performance liquid chromatography-tandem mass spectrometry]. AB - A sensitive and selective method is presented for the determination of paraquat residue in fruits, vegetables, beans and grain by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Paraquat in samples was extracted with water and cleaned-up with a weak cation exchange (WCX) column to obtain an extract suitable for analysis using HPLC-MS/MS. The paraquat was separated by a CAPCELL PAK ST column (150 mm x 2.0 mm) and with acetonitrile-10 mmol/L ammonium acetate solution (adjusted to pH 4.0 by formic acid) as the mobile phase, and multiple reaction monitoring (MRM) was used with electrospray ionization in the positive ion mode. The calibration curve was linear between the peak area and the mass concentration of paraquat from 0.01 to 0.1 mg/L with the correlation coefficient of 0.993. Recoveries of paraquat spiked in samples at three levels ranged from 84.0% to 106.0% with the relative standard deviations of 7.8% - 18.8%. The limits of detection (LODs) of paraquat were 0.01 mg/kg in fruits and vegetables and 0.05 mg/kg in beans and grain. The LODs can meet the requirements of international maximum residue limit. PMID- 21598523 TI - [Determination of residual N,N-dimethylformamide in fluorescent brightening agent CBS by reversed-phase high performance liquid chromatography]. AB - A method for the determination of N,N-dimethylformamide (DMF) residue in fluorescent brightening agent CBS by reversed-phase high performance liquid chromatography (RP-HPLC) was established. An Ameritech Accurasil C18 column (150 mm x 4.6 mm, 5 microm) was used with methanol-water as the mobile phase with gradient elution. The flow rate of the mobile phase was 1.0 mL/min and the detection wavelength was 205 nm. The column temperature was 30 degrees C and the injection volume was 5 microL. There was a good linear relationship between the peak area and the concentration of DMF in the range of 0.19 - 141 mg/L. The recoveries of DMF were 98.4% - 107.3% at the spiked levels of 0.2344% and 0.4678%. The limit of detection was 0.019%. The relative standard deviation was 1.73%. This method can be used for the determination of DMF in fluorescent brightening agent CBS quickly and accurately. PMID- 21598524 TI - [Determination of tetrodotoxin in fermentation broth of distiller's yeast by ion chromatography]. AB - A method was developed for the quantitative analysis of tetrodotoxin (TTX) in fermentation broth of distiller's yeast by ion chromatography. After extraction with acetonitrile solution (containing 0.1% phosphoric acid) and purification with an ion-exchange column, the tetrodotoxin was separated by ion chromatography and detected by a ultraviolet-visible (UV-VIS) absorbance detector. The experimental results showed that the tetrodotoxin had a good linearity (r2 = 0.997) in the range of 10 - 100 mg/L and the detection limit (3 of signal-to noise ratio) was 1.0 mg/L. The average recoveries were between 90% - 103% with a relative standard deviation lower than 4.9%. The analysis of real samples verified the reliability of this method and demonstrated that the ion chromatography can be used for the quantification detection of the tetrodotoxin. The degradation experiment results suggested that distiller's yeast had a remarkable effect on the tetrodotoxin degradation. PMID- 21598525 TI - [Review: autotoxicity in medicinal plants and means to overcome]. AB - The review deals with the phenomenon of autotoxicity in medical plants. The autotoxic potential could be attributed to direct inhibition of plant growth and some diseases could be promoted by autotoxin. Factors affecting autotoxicity include species and cultivars, soil microbes, plant's nutrient situation and soil type etc. Autotoxicity could be overcome or alleviated by plant residues removal, adding beneficial microbes, using organic fertilizer, proper rotation, and grading management to different plant' autotoxic force. PMID- 21598526 TI - [Establishment and research progress of food pharmacy]. AB - OBJECTIVE: To introduce the establishment of food pharmacy research progress. METHOD: To overview research situations of food pharmacy development according to edible product. RESULT: Food pharmacy development in China has been set up preliminarily, and needs to be developed further. CONCLUSION: The trend of the functional food will be safe, effective and its quality will be control. PMID- 21598527 TI - [Advances in determination of multi-residue pesticides in traditional Chinese medicine by GC-MS]. AB - The current methods of preparation of pesticide residue analysis in traditional Chinese medicine were summarized in this paper. And the new preparation techniques used in recent years were reviewed, which included solid-phase micro extraction (SPME), QuECHERS, matrix solid-phase dispersion (MSPD). In addition, the determination method of the pesticide residue methods in the traditional Chinese medicine were also included in the paper, and analysed the problem in the determination based on the characteristics of TCMs. PMID- 21598528 TI - [Review on experiment of traditional Chinese medicine treating to osteoporosis]. AB - Searched the articles between 2000 and 2010, found out and summarized the articles with the topic on the experiment and new techniques of traditional Chinese medicine treating to osteoporosis. The preventive and therapeutic effect to osteoporosis by traditional Chinese medicine had been developed in the past 10 years. The study on standardization of experimental drugs, and the mechanism study with modern cell culture techniques should be enhanced. PMID- 21598529 TI - [Research on abatement measures of allelopathic autotoxicity of Rehmannia glutinosa]. AB - OBJECTIVE: To explore effects on allelopathic autotoxicity of Rehmannia glutinosa of different abatement measures. METHOD: The experiments for abating allelopathic effects of R. glutinosa were designed with the reducing rate as a indication, three measures of the treating soil with lime nitrogen, and water washing were employed, R. glutinosa- Achyranthes bidentata rotation system and using Achyranthes bidentata as green manure, and seedling transplant were also studied for the abatement effect. RESULT: Effect of seedling transplant was the best, reducing rate of transplant and bare root transplant on the 20th day after emergence was 76.80%, 71.70%, respectively. The reducing rate of the treating soil with microorganism reached 54.25%. The effects of water washing and R. glutinosa-A. bidentata rotation system and using A. bidentata as green manure were not satisfied. Especially only using A. bidentata as green manure without rotation system worsened the allelopathic effects of R. glutinosa. CONCLUSION: All measures can abate allelopathic effects of R. glutinosa to some extent except only using A. bidentata as green manure. PMID- 21598530 TI - [Preliminary study of reproductive allocation in Cistanche deserticola]. AB - OBJECTIVE: Discuss the trade-off between vegetative growth and reproductive growth. METHOD: Vegetative modules and reproductive modules by large sampling were separated and quantitative charecters of organs and pattern of reproductive allocation were analysed of reproductive allocation were analysed. RESULT: The phenotype plasticity of quantitative charecters were significant. Reproductive biomass was increasing at different stages. The mass of reproductive investment increased significantly with increasing individual size, the opposite of reproductive allocation. There were all significant positive correlations between the seeds weight and height, total biomass, vegetative biomass, reproductive biomass, fruit numbers, fruit weight. CONCLUSION: The significance of phenotype plasticity is the cause of multiple elements. In the process of transferring from vegetative growth to reproductive growth, there was a trade-off between organs. Under individual growth and reproductive strategy, the variation of biomass was allocated coordinately. PMID- 21598531 TI - [Analysis of genetic differentiation and phylogenetic relationship between Whitmania pigra and Hirudo nipponia based on ITS sequence]. AB - OBJECTIVE: To evaluate the genetic differentiation and phylogenetic relationship between Whitmania pigra Whitman and Hirudo nipponia Whitman. METHOD: By the sequences of the rDNA internal transcribed spacer (ITS) the molecular phylogenetic tree was constructed by MP method using software MEGA 4.0. RESULT: The average length of ITS was 857.2-861.2 bp. The A, T, G and C contents in this fragment were 25.12%, 28.28%, 17.34%, 29.29%, respectively. The GC content was higher than the AT content. Little sequence variation was observed in ITS gene fragments with in species, and transition in only 45 loci was revealed in 14 populations. 14 W. pigra and H. nipponia populations were clustered into 2 groups by MP phylogenetic tree. CONCLUSION: The results also showed that the intraspecific variation was dominated in variation types of W. pigra and H. nipponia. The classification result of W. pigra and H. nipponia and its adulterants based on DNA sequences are not totally consistent with those based on classification. It showed that a little of mutation of base in ITS sequences had occurred in the process of evolution, such as transition cites, transvertion cites among base or base gap. PMID- 21598532 TI - [Study on modules biomass structure of Epimedium acuminatum in different habitats]. AB - OBJECTIVE: To study the biomass structure of Epimedium acuminatum Franch in the different ecological environments for the development and protection. METHOD: Through the scientific investigation in four typical habitats, the sampling spots were set up, the functional modules' biomass structure and relationship of E. acuminatum were researched. RESULT: The average of rhizome, as the largest biomass, and the average total biomass had the same pattern: the open areas of forest edge > shrub lumber > shrub-weed > stream drains. The ratio of the functional modules' biomass had different rates under different habitat conditions. By analyzing and combining investigation, the aerial part of E. acuminatum in the shrub-weed were comparative advantage, and the roots of nutrient accumulation of E. acuminatum in the open areas of forest edge were the highest efficient. Under different ecological condition, the distribution of water metabolism was different strategies. CONCLUSION: In the open areas of forest edge, E. acuminatum growing well, followed by shrub-weed. These two habitats are the ideal ecological environments while the rhizome or the whole plant used as medicine, but also the protection of E. acuminatum. PMID- 21598533 TI - [Impact on membrane separation process of volatile oil-bearing water body of notopterygii rhizoma et radix by inorganic salting pretreatment]. AB - OBJECTIVE: To explore the best pretreatment condition of inorganic salting on volatile oil-bearing water body of Notopterygii Rhizoma et Radix before membrane separation. METHOD: The simulative system of volatile oil-bearing water body of Notopterygii Rhizoma et Radix was pre-treated before membrane separation by salting. The best conditions of salting were determined by selecting types and amounts of inorganic salt as investigate factors and comparing membrane flux and oil retention rate. RESULT: The best pretreatment condition of inorganic salting on volatile oil-bearing water body of Notopterygii Rhizoma et Radix before membrane separation was to add 2% sodium chloride (NaCl) according to the amount of oil-bearing water body. Gas chromatographic fingerprint showed that inorganic salting did not affect the active ingredient of volatile oil. CONCLUSION: Adding NaCl to volatile oil-bearing water body of Notopterygii Rhizoma et Radix before membrane separation can optimize membrane processes by improving membrane flux. PMID- 21598534 TI - [Study on new extraction technology and protective effect of hugan buzure granule on liver injury in mice]. AB - OBJECTIVE: To study on the new preparation technology of Hugan Buzure granule and to compare protective effect on liver injury in rats by different extraction processes. METHOD: Volatile oil extraction technology, inclusion condition and ethanol extraction condition were selected by orthogonal experiments. The experiment models of liver injury were induced by carbon tetrachloride, bacillus calmette-guerin (BCG) and plus lipolysaccharides (LPS) in rats, respectively. ALT, AST in serum, and MDA, SOD in liver were measured and the rats were killed to calculate the liver coefficient to evaluate the protective effect of Hugan Buzure granule on experimental injury in rats. RESULT: The optimum conditions of volatile oil extraction were 1:12 of solid-liquid ratio, 2 h of soaking time, and 8 h of extracting time. The optimal beta-cyclodextrin inclusion complex condition was as follows: the volatile oils formed complex with the beta-CD in a ratio of 1: 6 and stirring for 1 h at 40 degrees C. The optimum ethanol extraction was as follows: refluxing and extracting 3 times with 10-fold 50% ethanol, 2 h for each time. Compared with the model group, the new technology extraction of Hugan Buzure granule could obviously inhibite the elevation of serum ALT (P < 0.01), AST (P < 0.05) of liver injury induced by BCG + LPS, and elevate the contents of SOD, and obviously inhibite the elevation of serum AST (P < 0.01) of liver injury induced by carbon tetrachloride. CONCLUSION: The new preparation technology was feasible. The new extraction could protect the liver injury in rats, which was better than extraction of current preparation technology. PMID- 21598535 TI - [Study on chemical changes of salvianolic acid B and lithospermic acid aqueous under conditions of high temperature and high pressure]. AB - OBJECTIVE: To study the chemical changes of salvianolic acid B and lithospermic acid of Salvia miltiorrhiza under the conditions of high temperature and high pressure and explore the reaction mechanism. METHOD: S. miltiorrhiza extracts, salvianolic acid B and lithospermic acid were put in the reactor under the conditions of high temperature and high pressure (120 degrees C, 0.2 MPa), and the chemical changes and stability was studied. RESULT: Salvianolic acid A was the primary product in salvianolic acid B and lithospermic acid's conversion process, and lithospermic acid was an intermediate in the conversion process of salvianolic acid B. Compared with salvianolic acid B, lithospermic acid could convert into more salvianolic acid A and fewer other products in the same conditions. Salvianolic acid A was not stable under the conditions of high temperature and high pressure, and could sequentially convert into other small molecules. CONCLUSION: Referring to the chemical conversion of salvianolic acid B and lithospermic acid, a method of large-scale preparation of salvianolic acid A can be developed. PMID- 21598536 TI - [Preparation and properties of sustained-release pellets of active components from Ligusticun chuanxiong]. AB - OBJECTIVE: To prepare sustained-release pellets of active components from Ligusticun chuanxiong by coating in the fluid-bed. METHOD: The fast-release pellets were prepared by the extrusion-spheronization process. The coating formulation was optimized with the release of ferulic acid as criteria. The micromeritic properties and drug dissolution behaviors of the prepared pellets were evaluated. RESULT: The pellets presented perfect sphericity. The obviously sustained-release effects were shown in 12 h. The coating weight gain was the major factor impacting drug release. CONCLUSION: The coating pellets show the obviously sustained-release effects. PMID- 21598537 TI - [Metabolism of mangiferin by human intestinal bacteria in vitro]. AB - OBJECTIVE: To study the metabolism of mangiferin by human intestinal bacteria in vitro. METHOD: Human intestinal bacteria and mangiferin were incubated under anaerobic conditions in vitro. The metabolite was separated and purified by D101 macroporous resin column and preparation high performance liquid chromatography, and its structure was identified by MS and NMR. RESULT: After 12 h incubation with human intestinal bacteria, the content of mangiferin metabolite reached the maximum, and it was determined as 1, 3, 6, 7-tetrahydroxyxanthen by MS and NMR. CONCLUSION: Mangiferin can be metabolized in vitro by human intestinal bacteria into its aglycone (1, 3, 6, 7-tetrahydroxyxanthen). PMID- 21598538 TI - [Hydrolysis technology optimization of phorbol esters by orthogonal experiment]. AB - OBJECTIVE: To establish the best hydrolytic conditions from phorbol esters. METHOD: The orthogonal experiment was used to optimize 4 factors, which were reaction time, ratio of solid-to-liquid, hydrolytic times, and temperature. Diamonsil C18 column (4. 6 mm x 250 mm, 5 microm) was used and the mobile phase was consisted of acetonitrile and water for HPLC detection. The detection wavelength was set at 234 nm, the flow rate was 1 mL x min(-1), and the column temperature was 25 degrees C. RESULT: The optimum conditions were 10 h of reaction time, 1:6 of solid-to-liquid (BaOH/MeOH) ratio, 25 degrees C of temperature, and one time of hydrolysis. There was a good linear relationship of phorbol in the range of 4.28-107 mg x L(-1) (r = 0.999 9), and the average recovery was 97.89%, with RSD 0.78%. CONCLUSION: The method is steady, reliable and reproducible, and it provides a mean for future study. PMID- 21598539 TI - [Study on preparation and tissue distribution of hydroxycamptothecin liposomes]. AB - OBJECTIVE: To develop HCPT liposome with small diameter and to study the tissue distribution of the HCPT liposome in rats. METHOD: Modified solvent-injection method was used to prepare HCPT liposome. The entrapment efficiency, morphology, size and zeta potential were also investigated. The transformation temperature and the ratio of cholesterol to phospholipids were determined by fluorescence spectrophotometry. HCPT liposome and HCPT injection (5 mg x kg(-1)) were injected by tail vein in mice, respectively. The tissue concentrations of HCPT were determined by LC-MS/MS. RESULT: Under selected process conditions, the HCPT liposomes were spherical and integrated with the mean entrapment efficiency of (96.83 +/- 2.32)%, the size of (180.5 +/- 4.5) nm and the zeta potential of- (32.1 +/- 1.3) mV. It showed that the optimum proportion of cholesterol to phospholipids was 1.5: 10, the optimum transformation temperature was 32.5 degrees C; HCPT liposome at a dose of 5 mg x kg(-1) led to higher concentration and longer duration of action compared with HCPT injection on market. CONCLUSION: HCPT liposome prepared by solvent-injection method was characteristic of small mean diameter, high encapsulation efficiency and long circulation in vivo. PMID- 21598540 TI - [Separation and determination of hesperidin in huoxiangzhengqi water by hollow fiber ultrafiltration-high performance liquid chromatography]. AB - A simple hollow fiber based centrifuge ultrafiltration pretreatment procedure has been developed for the analysis of active components with high polarity in Chinese traditional and herbal drugs which usually contain macromolecule impurities. The procedure combined with HPLC was applied to the determination of hesperidin in Huoxiangzhengqi water. Sample solutions were purified by our patent hollow fiber centrifuge ultrafiltration device. Under the effect of the centrifgual force, micromolecules were removed from solution samples, thus it increased the service life of the column. The accuracy and repeatability of this method have also been improved. The separation was carried out on a Promosil C18 column (4.6 mm x 150 mm, 5 microm) with methanol -0.5% acetic acid solution (35:65) as mobile phase at a flow rate of 1.0 mL x min(-1). The detector wavelength was 283 nm and the column temperature was 30 degrees C. A good linear relation was obtained in the range of 4.69 - 150 mg x L(-1) (r = 0.999 7) and the average recovery was 103.0% with RSD of 1.9%. This method is simple, rapid and accurate, and it provides a simple and cheap ultrafiltration means for the analysis of the polar components in Chinese traditional and herbal drugs. PMID- 21598541 TI - [Chemical constituents in herb of Polygonum orientale II]. AB - OBJECTIVE: To study the chemical constituents of the essential substance from the Polygonum oriental. METHOD: Chromatographic techniques were employed for isolation and purification of the constituents and their structures were determined by spectral analysis and chemical evidence. RESULT: Seven compounds were obtained and identified as ombuine-3-O-beta-D-galactopyranoside (1), ombuine 3-O-rutinoside (2), tryptophan (3), quercetin-3-O-methyl ether (4), kaempferol-3 O-(2"-O-alpha-L-rhamnopyranosyl) -beta-D-glucuronopyranoside (5), quercetin-3-O (2"-O-alpha-L-rhamnopyranosyl)-beta-D-glucuronopyranoside (6), quercetin-3-O-beta D-glucuronide (7). CONCLUSION: Compounds 4-7 were isolated from P. oriental for the first time and compounds 1-3 were firstly obtained from the genus Polygonum. The total 1H and 13C-NMR date of compound 1 were assigned for first time. PMID- 21598542 TI - [Chemical constituents of Chinese red ginseng]. AB - The chemical constituents of Chinese red ginseng (Panax ginseng) were investigated. The chemical constituents were isolated and purified by silca gel, ODS, and Sephedex LH-20, column chromatography, and preparative HPLC. Their chemical structures were elucidated on the basis of physicochemical properties and spectra data. Fourteen compounds were isolated and identified as: notoginsenoside R2 (1), 20(S) -ginsenoside Rg3 (2), 20(R) -ginsenoside Rg3 (3), 20 (S)-ginsenoside Rg2 (4), 20(R) -ginsenosideRg2 (5), 20 (S)-ginsenoside Rh1 (6), 20(R) -ginsenoside Rh1 (7), ginsenoside Rh4 (8), -Ro (9), -Rb1 (10), -Rg1 (11), Re-(12), Rf (13), maltol (14). Compounds 1, 4, 6, were obtained from red ginseng for the first time. Compounds 2 and 3, 4 and 5-7 were enantiomers respectively, enantiomers 6 and 7 were isolated as monomer for the first time. PMID- 21598543 TI - [Constituents and bioactivities of Lamiophlomis rotata]. AB - OBJECTIVE: To investigate the chemical constituents from Lamiophlomis rotata and the bioactivities of 8-epideoxyloganic acid. METHOD: The constituents were isolated by using a combination of various chromatographic techniques including column chromatography over ployamide, silica gel and Sephadex LH-20. Structures of the isolates were identified by spectroscopic data analysis. Bioactivities were screened by using models in vivo. RESULT: Five constituents were isolated. 8 epideoxyloganic acid was isolated for the first time in L. rotata and also in lamioplomis genus. 8-epideoxyloganic acid could significantly inhibit aectic acid induced twisting times and slower the time of homeostatsis, also inhibit xylene induced ear edema in mice. CONCLUSION: 8-epideoxyloganic acid possesses bioactivities of analgesia, homeostasis and anti-inflammatory. PMID- 21598544 TI - [Analysis of non-alkaloids from radix sophorae tonkinensis by GC-MS]. AB - OBJECTIVE: To analyze the chemical compositions and their contents in non alkaloids fraction from Radix Sophorae Tonkinensis. METHOD: The non-alkaloids from Radix Sophorae Tonkinensis were analyzed by gas chromatography/mass spectrometry after trimethylsilyl derivatization. The chemical compositions were identified by comparison of the authentic sample and NIST database; the contents of 19 identified components were determined by linear regression equation. RESULT: 19 compounds constituting 34.72% of the non-alkaloids were identified. The major components were saccharides (5 compounds constituting 22.62%), organic acid (9 compounds constituting 11.81%), and others (5 compounds constituting 0.29%). CONCLUSION: The GC-MS is a simple, rapid and sensitive method to investigate the complex primary metabolites in plants. PMID- 21598545 TI - [Simultaneous determination of two saponnins in anemarrhenae rhizoma by HPLC ELSD]. AB - OBJECTIVE: To establish an HPLC-ELSD method for determination of Anemarsaponin C and Anemarsaponin A III in Anemarrhenae Rhizoma. METHOD: Kromasil C18 column(4.6 mm x 250 mm, 5 microm) was used as stationary phase. Mobile phase was methanol water gradient with the flow rate of 1 mL x min(-1); the temperature of the drift tube and evaporation was 50 degrees C and 70 degrees C respectively. The gas pressure was 1.03 x 10(5) Pa. RESULT: There are good linearity in the range 0.310 3.10 microg of anemarsaponin C (lgA = 1.254 2lgM + 5.734 7, r = 0.999 5) and in the range 0.323-3.23 microg (lgA = 1.328 41gM + 5. 937, r = 0.999 6) of anemarsaponin A III. The average recovery of anemarsaponin C and anemarsaponin A III was 98.1% with RSD 2.1% and 97.3% with RSD 1.5% (n = 6) respectively. CONCLUSION: The method is rapid and accurate. It is suitable for quality control of Anemarrhenae Rhizoma. The result of determination reveals that the quality of Anemarrhenae Rhizoma from different places of north China are of notable difference. PMID- 21598546 TI - [Optimization of a HPLC determination method for Evodia rutaecarpa]. AB - A HPLC method for determination of limonin, evodiamine and rutaecarpine in Evodia rutaecarpa was optimized. The mobile phase was [acetonitrile-tetrahydrofuran (25: 15)] -0.02% H3 PO4 (35:65). The detection wavelength was 220 nm and the flow rate was 1.0 mL x min(-1). Limonin, evodiamine and rutaecarpine were all well separated from other substances and their UV spectrums were essentially the same to the standards . The liner ranges of limonin, evodiamine and rutaecarpine were 0.196 8-3.936, 0.153 6-3.072, 0.097 4-1.948 microg. The average recoveries were 97.8%, 100.7% and 98.4%. RSD were 1.7%, 1.3% and 1.1% (n = 6). The method of this article is accurate, reproducible and can be used to enhance the quality control of E. rutaecarpa. PMID- 21598547 TI - [HPLC determination of the contents chlorogenic acid and hydrochlorothiazide in zhenjujiangyapian]. AB - OBJECTIVE: To establish an HPLC method for determination of chlorogenic acid and hydrochlorothiazide in Zhenjujiangyapian. METHOD: The HPLC method was carried on C18 column using methanol-0.1% phosphoric acid(20: 80) as mobile phase, and the detection wavelength was 327 nm, the flow rate was 1.0 mL x min(-1) and the temperature of column was 40 degrees C. RESULT: In the HPLC method, the calibration curve for chlorogenic acid, hydrochlorothiazide were linear in the range of 0.049 6-0.496 (r = 0.999 5) and 1.002-10.02 microg (r = 0.999 8). The average recovery for chlorogenic acid, hydrochlorothiazide were 101.0% and 100. 1%. RSD were 2.0% and 1.4% (n = 9), respectively. CONCLUSION: The method is convenient, precise and reliable for determining the content of chlorogenic acid and hydrochlorothiazide in Zhenjujiangyapian. PMID- 21598548 TI - [Toxicity of monocrotaline on in vitro cultured mouse embryos]. AB - OBJECTIVE: To investigate the fetotoxicity of monocrotaline. METHOD: Mouse whole embryo culture (WEC) was applied. Post-implantation (8.5 d) mouse embryos were isolated from their mothers and put into the medium of immediately centrifuged serum (ICS) prepared from rats. Different concentrations of monocrotaline (100, 50, 25, 12.5 mg x L(-1)) were added into the WEC. Development (yolk sac diameter, crown-rump length, head length, somite number) and organic morphodifferentiation (yolk sac circulation, allantois, embryonic flexion, heart, brain, optic-otic olfactory organ, branchial arch, maxillary, mandible, bud) of embryos were observed at 48 h after treatment. RESULT: Obvious fetotoxicity could be observed in various monocrotaline treatment groups in a dose-dependent manner. Development of embryos was delayed significantly at dose 12.5-100 mg x L(-1). Malformations were shown in all organic morphodifferentiation indice, especially in opti-otic organ, mandible and bud. CONCLUSION: Monocrotaline had obvious fetotoxicity in vitro WEC, indicating that exposure of pregnant mice to monocrotaline may have potential risk on fetus. PMID- 21598549 TI - [Development of animal model for anaphylactoid test of rodent]. AB - OBJECTIVE: To establish a simple and feasible method of anaphylactoid test on awaked small animals for screening and assessing anaphylactoid reaction of traditional Chinese medicine (TCM) injection with different concentration of tween 80. METHOD: Test substances containing 0.4% Evans blue were intravenously injected into mice at volume of 20 mL x kg(-1) or guinea pigs at a volume of 30 mL x kg(-1). The behaviors were observed and the vascular permeability of ears evaluated by the extent of ear blue staining and absorbance of Evans blue extraction of ears were tested at 30 min after injection. RESULT: Tween 80 solution, Yuxingcao injection with tween 80, and Shuanghuanglian powder injection obviously increased vascular permeability of ears characterized as ear blue staining and increased absorbance of the Evans blue extract from ears extracted by acetone saline both in mice and in guinea pigs in a concentration-dependent (in the case of tween 80) or a dose-dependent (Shuanghuanglian) manner. CONCLUSION: Ear vascular permeability test in mice and guinea pigs can be used as animal models to screen and test anaphylactoid reaction induced by injections. PMID- 21598550 TI - [In vitro inhibition of five traditional Chinese medicine injections on rat liver microsomal CYP3A]. AB - OBJECTIVE: Qingkailing injection (QKLI), Jinnaduo injection (JNDI), Shuxuetong injection (SXTI), Shenmai injection (SMI) and Kangai injection (KAI) are widely used in China. To predict the herb-drug interactions in clinical application, they were evaluated for their in vitro inhibition effect on CYP3A in rat liver microsomes. METHOD: The rat liver microsomes were incubated with different doses of 5 kinds of traditional Chinese medicine injections (TCMIs) in the present of testosterone, a specific substrate of CYP3A. 6beta-hydroxytestosterone, the metabolite of testosterone, was monitored by HPLC to compare the inhibition effect of 5 TCMIs on CYP3A in rat liver microsomes. Ketoconazole was used as a positive control. RESULT: 10% QKLI reduced the formation of 6beta hydroxytestosterone by approximately 93.0%, which is more significant than other four TCMIs. The half maximal inhibitory concentration (IC50) and the enzyme inhibitor constant K(i) were 1.0% and 0.7% respectively. CONCLUSION: QKLI showed much stronger inhibition activity against CYP3A, comparing to other 4 TCMIs. The results revealed that QKLI may be involved in herb-drug interactions by inhibition of CYP3A. PMID- 21598551 TI - [Inhibition of three pentacyclic triterpenoids on calcium-induced liver mitochondrial permeability transition in mice]. AB - OBJECTIVE: To study effects of three pentacyclic triterpenoids, oleanolic acid (OA), ursolic acid (UA) and asiatic acid (AA) on Ca(2+)-induced liver mitochondrial permeability transition (MPT). METHOD: Effects of three compounds on liver MPT induced by Ca2+ were assessed by measuring the change in mitochondrial swelling, mitochondrial membrane potential and release of matrix Ca2+ in vitro. RESULT: Obvious mitochondrial swelling, loss of mitochondrial membrane potential and release of matrix Ca2+ occurred after the addition of 50 micromol x L(-1) Ca2+. However, preincubation with 50 mg x L(-1) OA, UA or AA significantly blocked the above changes. In addition, it was also found that there are differences in the inhibitions of three compounds on liver MPT induced by Ca2+. CONCLUSION: Three pentacyclic triterpenoids, OA, UA and AA, have significant mitochondrial protection through blocking on liver MPT and the inhibition on liver MPT of AA is stronger than that of UA and OA. PMID- 21598552 TI - [Effect of serum containing tengcha total flavonoid and dihydromyricetin on proliferation and apoptosis of HepG2 cells]. AB - OBJECTIVE: To observe the effect of serum containing Tengcha total flavonoid and dihydromyricetin on proliferation and apoptosis of HepG2 cells. METHOD: Serum containing respectively Tengcha total flavonid, dihydromyricetins and CTX and control serum were prepared by serological pharmacology method. MTT assay was used to observe the proliferation inhibition rate of HepG2 cells after incubated with different kinds of serum. Inverted microscope was utilized to observe the morphological changes after HepG2 cells were treated with different serum. AnnexinV/7AAD double label method was used to detect earlier period apoptosis cells. RESULT: Both serum containing 20% Tengcha total flavonid and serum containing 20% dihydromyricetin could restrain the HepG2 cells proliferation at different levels and the morpholological changes of apoptosis were observed. AnnexinV/7AAD double label method showed that the earlier period apoptosis cells rates were increased by serum containing 20% Tengcha total flavonoid, but serum containing 20% dihydromyricetin did not show influence on the earlier period apoptosis cells. CONCLUSION: Tengcha total flavonoid can restrain the HepG2 cells proliferation and induce earlier period apoptosis cells. PMID- 21598553 TI - [Studies on antitumor activities of triterpene glycoside colochiroside A from sea cucumber Colochirus anceps]. AB - OBJECTIVE: To study the antitumor activities of the triterpene glycoside colochiroside A (CA) from the sea cucumber Colochirus anceps. METHOD: The tests of antitumor activities in vitro and in vivo were applied to demonstrate the effect of CA. RESULT: The preliminary cytotoxic assay of CA exhibited significant cytotoxic activity against 6 types cultured tumor cell lines of p388, HL60, A 549, SpC-A4, MKN-28, and SGC-7901, the mean of IC50 were (3.61 +/- 0.55) mg x L( 1). The preliminary antitumor assay of CA indicated that this saponin exhibited high inhibiting activity against the H22 live cancer and the S180 sarcoma cells in mouse. The inhibition ratio to H22 liver cancer were 34.8%, 43.9% and 52.2%, while the ratio to S180 sarcoma were 36.4%, 70.0%, the immunoregulatory founction study indicated CA has not significant effect on the developments of thymus and spleen. CONCLUSION: The saponin CA exhibited remarkable antineoplastic activities in vitro and in vivo, and could not reduce the immunoregulatory founction of mice. PMID- 21598554 TI - [Effects of buzhong yiqi decoction on adriamycin induced heart failure in rats]. AB - OBJECTIVE: To study the effects and mechanism of Buzhong Yiqi decoction on adriamycin-induced acute myocardial injury in rats. METHOD: 50 rats were randomly divided to five groups: control group, heart failure group, low dose Buzhong Yiqi decoction, high dose Buzhong Yiqi decoction and captopril group. Adriamycin was injected into the latter four groups to built a model of heart failure. Then, the effects of different doses of Buzhong Yiqi decoction on hemodynamics, cardiac tissue histological changes, antioxidant capacity and apoptosis of the damaged hearts were studied. RESULT: Adriamycin led to myocardial fiber swelling and fracture, Buzhong Yiqi decoction could reduce myocardial lesions. Buzhong Yiqi decoction could also improve heart antioxidant capacity and inhibit adriamycin induced cardiomyocyte apoptosis. CONCLUSION: Buzhong Yiqi decoction could significantly ease adriamycin induced heart failure in rats, and the mechanism is related to anti-oxidation and inhibiting apoptosis. PMID- 21598555 TI - [Immunologic functions of total flavone of Epimedium of two species in Guizhou]. AB - OBJECTIVE: Comparative study on the immunologic functions of total flavones of Epimedium (TFE) in two species in Guizhou on CTX mice. METHOD: To set up a hypoimmunity mouse model by CTX and give TFE in 10 days, the enhancement of immunologic functions of TFE of two species were observed with the indice of the weight of body and spleen, the spleen-index, the serum level of hemolysin, TNF alpha and IL-2. RESULT: The spleen-index, the level of hemolysin, TNF-alpha and IL-2 of the mice decreased apparently (P < 0.01) by single ip in CTX 80 mg x kg( 1). The weight of body and spleen, the spleen-index of the mice increased, the decreased serum level of hemolysin TNF-alpha and IL-2 increased significantly (P < 0.01), by TFE of two species of 1.3, 0.65 g x kg(-1) from the mice ig. CONCLUSION: The TFE of two species of Epimedium in Guizhou have an obvious immune enhancement effect on the non-specific immunity and specific immunity of CTX model mice. But the immune enhancement effects of the TFE from the stem and leaves of two species of Epimedium contrast insignificantly. This indicates that in addition to ICA, there must be other bioactive components that can enhance immunity. PMID- 21598556 TI - [Effects of shenghua decoction on hemorheology, thrombosis and microcirculation]. AB - OBJECTIVE: To investigate the effects of Shenghua decoction on hemorheology, thrombosis and microcirculation, and explore its approach and mechanism. METHOD: The main hemorheological indexes and endothelial function were detected in acute stress blood stasis rats. The thrombus wet weight and thrombus dry weight were measured in the rat model of venous thrombosis, and the inhibitory rates in the formation of venous thrombosis were calculated. The number of paralysis or dead after 1-15 min was calculated in mice, induced by tail intravenous injection of a mixture of collagen and Epinephrine. Blood flow and the across netting were also determined on capillary vessel of uterus microcirculation. RESULT: Shenghua decoction reduce blood viscidity of the rats, reduce the thrombosis of the murine, and promote the microcirculation of the uterus in rats. CONCLUSION: Shenghua decoction has the ability of blood-activating and stasis-eliminating. It also has an anti-thrombotic effect and can promote microcirculation. PMID- 21598557 TI - [Thinking and practice of animal ethology in study of cold and hot nature of traditional Chinese medicine]. AB - From the view of macroscopic animal ethology combined with computer and modem image processing technique, by monitoring the temperature tropism of animal affected by traditional Chinese medicine (TCM) with different Cold and Hot natures and obtaining many behavior parameters which were difficult to assess in direct observation, the differences between the Cold and Hot nature of TCM were evaluated and presented. This method could real-time, intuitively and objectively, qualitatively and quantitatively monitor the temperature tropism of experimental animals with no disturbance. Further, the Cold and Hot nature of TCM can be expressed from the whole animal level. This method met to the application peculiarity of TCM and suited for the TCM theoretical system. It is a attempt for the study of drug nature of TCM. It also contributed to elucidate the objective authenticity and scientific connotation of Cold and Hot nature of TCM, and express the inherent connection of this nature and the temperature tropism of animal. In this review, a new point and technology platform was provided for establishing an objective method for evaluating the Cold and Hot nature of TCM, which are corresponding with the feature of the application of TCM. PMID- 21598558 TI - [Child psychoanalysis and child psychiatry in Russia, from Lenin to the present day]. AB - Russian child psychiatry and psychoanalysis painfully recover after being brought under the subjection of "paedology", a synthetic so-called science, and enslaved to the utopian Soviet expectation of building a "new man" in 1920-1930. Later on, in 1940-1980, under the precarious shelter of Soviet social work, they could indulge in the psychodynamic viewpoint. Liberated in 1985-1991, Russian child psychiatry and psychoanalysis take up again with Western science to answer the urgent demand for care for the psychic sufferings of young Russians. PMID- 21598559 TI - [Military physicians disseminating the vaccine from the beginning of the occupation of Algeria]. AB - Smallpox was an endemic illness in Algeria when Chevreau started the first jennerian inoculation in 1831. Immediately after the conquest of Algeria the army medical doctors organized the inoculation of cowpox among the European poor as well as among his native people during the period of 1831-1847. The vaccination against smallpox increased with the arrival of numerous medical doctors after 1847. PMID- 21598560 TI - [Management of patients at the Saint-Jean de Jerusalem hospital in the 12th Century]. AB - The Order of the Hospital Saint John of Jerusalem founded in the Holy Land on the 15th February 1113 was devoted to give the pilgrims board and lodging. Since 1125 the Hospitaliers took in sick and ensured supplies and cares for them as they recruited physicians and surgeons. A hierarchical organization lasted during the 13th century until the fall of Acre and the loss of the Holy Land. The author describes the day of a patient in this lazaret during the years of 1177 to 1187. PMID- 21598561 TI - ["Recherche de la vraye anathomie des dents, nature et propriete d'icelles", the first French dentistry book by the surgeon from Rouergue, Urbain Hemard (Benoist Rigaud, Lyon, 1582]. AB - Recherche sur la vraye anathomie des dents, nature & propriete d'icelles (1582) is the last dental book of the 16th century and the first in France. The part borrowed from Libellus de dentibus by Bartolommeo Eustachio is not the most interesting part of the book; the better part is when Hemard tells personal experiences with his picturesque words, showing violent situations of care at this epoch. PMID- 21598562 TI - [Jean Chieze (1898-1975), medical engraver and illustrator]. AB - As an imaginative and sensitive woodcutter Jean Chieze illustrated more than 130 books and realised many draws, paintings and lithographs and about 2000 engravings. He took part in some editions about Rabelais, Hippocrates, Galen and Ambroise Pare. PMID- 21598563 TI - [Saint Anthony's Fire or gangrenous ergotism and its medieval iconography]. AB - The frequent epidemics of ergotism were called Holy Fire or st-Antony's Fire in the Middle Ages, because of the burning sensations resulting in gangrene of limbs. It was caused by eating rye bread contaminated with the fungus Claviceps purpurea. The hospitable Order of st-Antony was founded near Vienne in France with 300 establishements in Europe until 1777. In coptic and byzantine art st Antony is the father of the monks, whereas in Occident he is the the master of fire, thaumaturgic, resulting a very important iconography in statuary and painworks in all regions, especially in Lorraine, the catholic and tridentin Lotharingia and in Corsica thanks to the franciscan pastoral. Woodcuts show not only the temptations of st-Antony, with strange and diabolic scenes, patients with gangrenous limbs. Germanic woodcuts of the 15th century show patients with different stages of ergotism and hands and feet like ex-voto. Triptycs of H. Bosch and M. Gunewald are witnesses of the frequency and seriousness of this disease still at the beginning of the 16th century. PMID- 21598564 TI - [Issenheim's altarpiece: does the disease depicted on the altarpiece correspond to ergotism?]. AB - The Issenheim altar by Mathias Grunenwald (Unterlinden museum in Colmar) shows various scenes from the life of St Antony, abbot. The Tentation panel has been considered as an illustration of the sacer ignis, or St Antony's disease (ergotism). In fact, it may more likely indicate an early representation of Syphilis, or the French disease, as discussed here. PMID- 21598565 TI - [The plants in the Issenheim's altarpiece]. AB - On the decorated panels an altar, the so-called "retable d'Issenheim", in Colmar, several painted plants can be easily identified. PMID- 21598566 TI - [The 14 plants in Issenheim's altarpiece. An updated pharmaco-chemical approach]. AB - Fourteen vegetal species were identified by Kuhn in 1948 among which scrophualaria, veronica, lamium and vincetoxicum. These exhibit antigangrenous, antiinflammatory and antimicrobial activities due to iridoid components, mainly aucubin, catalpol and harpagosid. PMID- 21598567 TI - [Ergotism in Limoges province around the year 1000]. AB - Saint-Martial, a former bishop in Limoges, is supposed to protect from ergotism. His relies are still publicly shown every 7 year. PMID- 21598568 TI - [Petit-Saint-Antoine, Parisian hospice for the treatment of ergotism from the 11th to the 16th Century]. AB - Petit-Saint-Antoine was for six centuries a Parisian hospital specialized in the treatment of the so-called "mal des ardents", or ergotism. PMID- 21598569 TI - [General Counsel for Administration of Public Hospitals in Paris: creation of a public health institution]. AB - In 1801, Napoleon Bonaparte established the Conseil General des Hospices de Paris, as the first centralized authority to manage all Parisian civilian hospitals. Through an examination of the debates and statements surrounding its creation, and its founding rules and regulations, its purpose will be shown to be twofold: to enforce the values of proper administration and morality, and to support certain medical advancements. The Conseil heralded the birth of a public health institution which would become, some 50 years later, the Assistance Publique. PMID- 21598570 TI - [The "Marseillaise", lives and deaths of physicians and pharmacists of the first promotion of the "Pharo"]. AB - Pharo military school for tropical medicine in Marseilles was opened in 1907. Documents in the Service historique de la defense in Vincennes have been scrutinized in order to know about the life and career of the 43 students first chosen (39 doctors, 4 pharmacists). A great page in the history of French military medicine. PMID- 21598571 TI - [The management in Marseille of facial injuries during the First World War]. AB - World War I is still present for its millions of dead and wounded soldiers. New types of wounds came unexpected, and the military services were necessarily unprepared. Wounds in the face were so frequent and awful that new wards had to be organized and new methods to be invented. Among great persalities in the field are to be listed Morestin, Dufourmentel, Ginestet, Gillies, Joseph, and Kazandjian. PMID- 21598572 TI - [Anatomo-clinical collections carried out in Marseille during the 1914-1918 war and kept at the museum of the health services of the army in Paris]. AB - The creation in full war, in Val-de-Grace in Paris, of the center "Archives and documents of war" by Justin Godart brought together nearly 100,000 archivistic files, 10,000 objects or anatomopatholocal pieces among which 1500 wax casts or plaster casts and their technical and photographic documents. The reports and the objects realized in Marseilles in the XVth military region, show certainly the progress of that surgery during the 1st world War but also provide a better understanding of the functioning of the major specialized services created in this city for the nerves surgery, orthopedic or the maxillofacial surgery. PMID- 21598573 TI - [Plague in Marseille: comparison with other plague epidemics in Western Europe]. AB - Plague in Marseilles in 1720 is compared with other epidemics in other European cities. PMID- 21598574 TI - [Painters as history witnesses (plague in Marseille in 1720)]. AB - Plague in Marseilles in 1720: what about its painted representation? PMID- 21598575 TI - [Antoine Deidier, his experimental approach to the contagious nature of plague in Marseille in 1720]. AB - Born in 1670 Deidier became a medical doctor at the age of 21. The son-in-law, of Vieussens, he took care of the inhabitants of Marseilles during the plague of 1720. A contagionist and an experimenter, he was considered as a strange scientist by his colleagues. It is time now to rehabilitate his memory. PMID- 21598576 TI - [The Caroline hospital on the Ratonneau island]. AB - Yellow fever killed 20000 in Barcelona in 1821. In Marseilles, the mayor and other authorities are afraid and decide to build a new hospital in Ratonneau island. It will first be named after Princess Carolina, for dynastic reasons, then after Pr Proust. It will always be underused, and will close in the end in 1941 after an epidemic of typhus. PMID- 21598577 TI - [Marseille and Jacques Daviel]. AB - Jacques Daviel, soon an orphan, was educated by his uncle, Dr Sallou. When plague burst in Southern France, he decided to help there, and realised it was good to use "vinaigre des quatre voleurs" to chase fleas. He was taken as a chirurg at the hotel-Dieu in Marseilles and there developed a new technique to remove cataract. PMID- 21598579 TI - [Antoine Barthelemy Clot-Bey, a physician from Marseille founder of Western medicine in Egypt]. AB - Born in Grenoble in 1793 Clot was first a doctor in Marseilles with great success and honour. But for unclear reasons he had to resign, and then decided to be recruited in Egypt, where he was soon called "Clot-Bey" (Bey = officer)": he contributed greatly to modernizing Egyptian medical system: he founded the School of medicine, that of pharmacy, and that of obstetrics, and promoted hygiens and variolisation. After Mehmet Ali abdicated he lost most of his influence, and left Egypt for ever in 1858. PMID- 21598578 TI - [The hygienist Adrien Proust, his universe, plague and his ideas on international health policy]. AB - Adrien Proust, Marcel's father, was a remarkable specialist of hygiens. He felt very responsible for the fight against epidemics, and his part was decisive at the Venice conference in 1896. In Marseilles and nearby islands quarantines were sill useful afterwards, especially in 1901. PMID- 21598580 TI - [Arthur Fallot (1850-1911) and blue disease]. AB - Arthur Fallot (1850-1911) described for the first time the so-called "maladie bleue", or "blue disease". His discovery was published in Marseille Medical, and therefore remained little known. Present cardiologists know what they owe him and therefore call "tetralogy of Fallot" this congenital heart condition. PMID- 21598581 TI - [From anencephaly to the myth of headless men]. AB - Among ancient fanciful creatures, men without a head have often been represented since the end of the Middle-ages, especially during the Renaissance and until the 18th century. They are probably inspired from new-born anencephalic infants. PMID- 21598582 TI - [The health philosophy of the Seventh Day Adventists exemplified by their health system]. PMID- 21598583 TI - [The history of the hospital system in Viersen]. PMID- 21598584 TI - [The constitution and attribution of government research agencies. A matter of need for science-generated policy knowledge?]. AB - Government research agencies are a form of extra-university research institutions. In contrast to other extra-university research facilities they are subordinate to and financed by respective German governmental departments. As their mission they provide science-generated information, services, and monitoring to support the governmental departments. In science studies researchers proclaim a rigid association between the installation, attribution, and development of government research agencies and the increasing need for science-generated policy knowledge. The article examines this assumed association based on the personal, institutional, financial, and mission specific development of government research agencies between the years 1965 and 2005. According to the results the expansion of government research agencies stagnates--like science in general. PMID- 21598585 TI - [Biophysical double-lives, 1939-1946. Or: spaces of boredom. On 'information discourse' and (dis)continuities in the life sciences]. AB - Arguably, few things have shaped the historiography of the mid-twentieth century psy-sciences (and indeed, of the life sciences and science/technology/intellectual life quite generally) more profoundly than the story of cybernetics. This essay aims to undermine this technofuturistic picture of epistemological upheavals, of cyborg regimes of knowing, and of the incipient post-human, by reinserting back into the story the rather dull and unspectacular lives (and occupations) of the great majority of British, 'diverted' biologists during World War II. Instead of Ratio Clubbers or Macy-Conference frequenters, this essay is concerned with a much larger population of would-be biologists and their most pedestrian appropriations of, and exposures to, electronics. What I argue is that the prevalence and systematicity of such exposures in the course of the personnel-hungry radio-war points to a very different--low-key--picture of the war/technology-induced deflections of biological science at mid-century. As an example of how deeply at odds narrations of cybernetic's ascent tend to sit with developments on ground level, special attention will be devoted to the physiologists-turned-radar-scientists Alan Hodgkin and Andrew Huxley, and their war-time, or more properly, spare-time investigations into the biophysics of nerve. The latter--technical, difficult, and utterly unphilosophical--while absent from the cyber-theme-focused historiography, provided the basis for the tremendous impact Hodkgin and Huxley would in fact have on the mainstream, disciplinarily conservative physiological sciences; the larger aim however is to weave these far from peculiar biographical trajectories into a somewhat bigger picture of the intersections between radar electronics and biological science: a picture which does not centre on sensational discourses but on mundane electronic practices; and thus, on the generational experience of those who were known at the time as "ex radar folk with biological leanings". PMID- 21598586 TI - [The 'Kruppelfursorge' during the Weimar Republic. Oscillating between an own position and the adoption of eugenic arguments]. AB - This article examines the discourse about physical disability led by the German 'Kruppelfursorge'. It deals with the exhibition GeSoLei (Gesundheitspflege, soziale Fursorge and Leibesubungen), which took place in Dusseldorf in 1926. The GeSoLei was one of the most popular platforms of the healthy and aesthetic body in the 1920s. It stood in the context of the German 'national recovery' after World War I and collected all types of medical, social and athletic professionals to expose their work to a broader audience. Also representatives of the so called 'Kruppelfursorge' presented themselves and at the same time their perspective on people with physical disabilities on this exhibition. The article points out the ambivalent character of their perspective and shows the mixture of including and excluding people with physical disabilities, which was typical for the view of the 'Kruppelfursorge'. It demonstrates that the 'Kruppelfursorger' on the one hand were quite progressive towards people with disabilities, but on the other hand showed a striking openness towards eugenic values. PMID- 21598587 TI - [Observations on the origins of the core thesis in Freud's "comparative study" of organic and hysterical paralyses (1893)]. AB - Proceeding from two discrepant published transcriptions of a letter of Charcot to Freud, the author discusses the historical and theoretical background of Freud's paper. She emphasizes the influence of Charcot on Freud's early theory formation, as opposed to that of Janet. PMID- 21598588 TI - ["... my friend Leopold was percussing her through her bodice...". Leopold von Auenbrugger in Sigmund Freud's dream of Irma's injection]. AB - This paper provides a psychoanalytic interpretation of an element in the Irma dream that Freud had ignored in his own interpretation. The allusion to Leopold von Auenbrugger, the originator of percussion as a method of clinical investigation, which appears in the manifest dream reflects Freud's hopes and fears about how his Interpretation of Dreams and the new human science established there would be received by his medical colleagues. PMID- 21598589 TI - [Doctor and poet as rivals. Sigmund Freud, Alfred von Berger and the narrative of female homosexuality]. AB - Starting from a passage in the Dora case history where Freud suggests some differences between a literary and a clinical narrative of female homosexuality, this paper presents examples which he might have had in mind. Besides Balzac's "La fille aux yeux d'or" (1834/35) it is in particular Alfred v. Berger's novella "Die Italienerin [The Italian woman]" (1904) which may have served as a model and counterpoint to the literary strategies used in Freud's case history. Freud had a relationship of long standing with Berger. This newly discovered source may provide a clue for the date at which Freud finalized the Dora manscript which he had held back for years. PMID- 21598590 TI - [Solving a riddle--on the tracks of a love-story]. AB - This article outlines the development of a research project initiated by the discovery of new material: a set of letters, written by Mathilde, Freud's eldest daughter, to Eugen Pachmayr, a doctor's son from Munich. On the face of it, these letters do not actually answer the question whether the two young people were in love. But the answer could be found elsewhere. PMID- 21598591 TI - [Freud's abstract of "A contribution to the option of neurosis" (1913). Publication and commentary]. AB - The text, which is published here for the first time, summarizes the paper Freud presented to the IPA congress in Munich. A short commentary highlights the circumstances under which the paper was written and the reasons why the abstract remained unpublished. It also sketches the historical significance of the paper in terms of the problem of the option of neurosis, in particular obsessional neurosis, of the development of Freud's sexual theory and of the relation of his views to those of Ernest Jones. PMID- 21598592 TI - ["A magical atmosphere was our vision when we founded the institution". The sanatorium "Schloss Tegel" in statu nascendi (1904-1907)]. AB - This contribution addresses the early years of the sanatorium, founded by the medical doctor and later psychoanalyst Johann Jaroslaw Marcinowski. His approach to therapy, his ideas about interior design as well as landscape gardening were of significant influence on the sanatorium in which Ernst Simmel opened his psychoanalytical clinic in 1927. PMID- 21598593 TI - ["Snooping" analysts and the project of a rivalling journal. Two little known aspects of the Rank crisis (1924)]. AB - This paper details 1) the attempts of Berlin analysts to ferret out information about Rank's technique by interviewing one of his analysands, and 2) Berlin plans to found a new journal called Psychoanalytische Klinik. PMID- 21598594 TI - [A letter from the outpost of the psychoanalytic movement: Georg Wanke to Max Eitingon, 2 April 1926]. AB - The authors publish and contextualize a letter from a pioneer of the reception of Freudian thought in Germany, psychiatrist Georg Wanke (1866-1928) who owned a psychoanalytic sanatorium in Friedrichroda (Thuringia). In response to a fund raising request for Freud's 70th birthday, he told Eitingon about his financial hardships. Although a member of the Berlin Society, Wanke remained on the margins of the Freudian school. Nevertheless he was committed, both before and after World War I, to publicly promoting the new method. PMID- 21598595 TI - ["Ladies and gentlemen, the zeitgeist is among us". Wednesday, 6th of May, Hotel Esplanade in Berlin]. AB - In this paper, the celebration of Freud's 70th birthday in Berlin is used as "time slot" to demonstrate the interconnectedness of psychoanalysis in the public sphere and its journalistic reflection. When central figures of public life had to emigrate and in some cases were even killed, this connection between institutionalised psychoanalysis and the political and cultural space was permanently destroyed. PMID- 21598596 TI - [Denaturalized psychoanalysts]. AB - This paper presents hitherto unknown material from the German Foreign Office referring to the denaturalization of Therese Benedek, Bruno Bettelheim, Adolf Storfer and Wilhelm Reich by Nazi Germany. It corroborates the finding that nobody was persecuted by the Nazis solely on the basis of psychoanalytic activities or membership in a psychoanalytic organization. PMID- 21598597 TI - [Winnicott's arabesques. The wit of a psychotherapeutic technique]. AB - This article analyzes Winnicott's technique of the so-called "squiggle game". Its basic principle can be traced back to early attempts in psychiatry at using patients' drawings and paintings as diagnostic tools around 1900. Winnicott's technique, however, by being rooted in his theory of "transition phemomena", is conducive to a new relationship between patient and therapist. PMID- 21598598 TI - [The border zone between psychosomatic medicine, neurology and neuropsychology. About the book by Siri Hustvedt: "A shaking woman"]. PMID- 21598599 TI - [Notes on psychoanalysis and historiography]. AB - This essay presents some ideas about the potential use of psychoanalysis for historical studies, based on the work of Michel de Certeau who highlighted the fictional structure and the problematisation of time as two aspects which Freud introduced into historiography. PMID- 21598600 TI - [Johann Jaroslaw Marcinowski (1868-1935) and his sanatorium "Haus Sielbeck" at lake Uklei. Psychoanalysis in an in-patient setting]. AB - Marcinowski came from an aristocratic family. He first joined the army as a lieutenant and later worked as a medical doctor. From 1908 to 1920, Marcinowski was a follower of Freud, additionally influenced by Oskar Vogt. This article describes his restless life in Breslau, Berlin, Sielbeck, Bad Heilbrunn, and Tubingen, with a special focus on his psychoanalytic activities. Freud had high expectations of Marcinowski. In his sanatorium "Haus Sielbeck", Marcinowski treated patients psychoanalytically and published the results in medical journals. This application of psychoanalysis in a sanatorium was virtually unique at that time. Even though Marcinowski could not fulfill Freud's expectations in the long term, he is still one of the pioneers who described phenomena of transference in inpatient settings.--The article is complemented by Freud's letters to Marcinowski, edited by G. Fichtner and M. Schroter. These are mainly concerned with the conflict between Freud and Wilhelm Stekel who was and remained a good friend of Marcinowski. PMID- 21598602 TI - [What we can know using optical coherence tomography]. PMID- 21598601 TI - [From passionate sucking to oral-aggressive destruction wishes: really a revolution? A rejoinder to Ulrike May]. AB - The author discusses May's paper on the history and relevance of oral sadism, published in the last issue of LUZIFER-AMOR. He doubts that the oral-sadistic organisation was an exclusive feature of Abraham's theory and that for Freud sadism never predated the anal stage. He misses a distinction between internal and external objects and criticizes that May did not really consider other readings of the texts she explored. By characterizing Abraham's ideas as a "revolution" the author feels that May has disputed their being rooted in Freud's thought, thereby divesting Abraham and his followers of the connection to Freud which is essential for every psychoanalyst. PMID- 21598603 TI - [Effects of carteolol hydrochloride on experimental choroidal neovascularization]. AB - PURPOSE: To investigate the effects of carteolol hydrochloride on choroidal neovascularization (CNV). METHODS: Laser photocoagulation was performed to induce CNV in C 57 BL/6 mice. The response of CNV was assessed by fluorescein isothiocyanate-isolectin B 4 staining. The expression of intercellular adhesion molecule (ICAM)-1 and monocyte chemotactic protein (MCP)-1 in the retinal pigment epithelium (RPE)-choroid complex and tumor necrosis factor (TNF)-alpha in the RAW 264.7 macrophage culture was evaluated by enzyme-linked immunosorbent assay. RESULTS: Carteolol hydrochloride application led to significant suppression of the generation of CNV, the production of ICAM-1 and MCP-1 in the RPE-choroid, and macrophage expression of TNF-alpha. CONCLUSION: Carteolol hydrochloride prevented CNV development through its anti-inflammatory action. PMID- 21598604 TI - [Investigation of the correlation between the right-left differences of visual field defects and the right-left differences of ocular anatomical factors in patients with normal-tension glaucoma]. AB - PURPOSE: To investigate the effects of optic disc area to visual field (VF) defects of normal-tension glaucoma (NTG), the correlation between the right-left differences of VF defects and those of diurnal variations of intraocular pressure and the ocular anatomical factors were evaluated in patients with NTG. METHODS: One hundred eighteen eyes of 59 NTG patients with the right-left difference value of mean deviation (MD) of between 2 dB and 12 dB obtained with Humphrey field analyzer program 30-2 were enrolled in the study. The correlation between the right-left differences of MD values and those of refraction, axial length, central cornea thickness, diurnal variation of intraocular pressure, and disc area measured with Heidelberg Retina Tomograph were evaluated by multiple regression analysis. RESULTS: The multiple correlation coefficient was 0.520, and the coefficient of determination was 0.271. The right-left differences of axial length (p = 0.041) and disc area(p = 0.002) were judged to be the statistically significant factors correlated with those of VF defects. CONCLUSIONS: These results suggest that the right-left differences of axial length and disc area are associated with the right-left differences of VF defects in patients with NTG. PMID- 21598605 TI - [Comparing anterior segment shape of keratoconic eyes and normal eyes by anterior segment optical coherence tomography]. AB - PURPOSE: To compare the shape of the anterior segment of eyes with keratoconus and normal controls using anterior segment optical coherence tomography (AS-OCT). SUBJECTS AND METHODS: Included in the study were eyes with keratoconus (60 eyes of 40 patients), eyes with suspected keratoconus (10 eyes of 10 patients), and normal controls (21 eyes of 13 persons). Anterior segment imaging was performed in these eyes with AS-OCT, and the distance for angle to angle, anterior chamber depth and distribution of corneal thickness including the increasing ratio from center to periphery were compared. RESULTS: There was no significant difference in the distance of angle to angle among the three groups. The ratio of eyes with anterior chamber depth of more than 3.6 mm in the eyes with keratoconus was significantly higher than in the normal group. Although the corneal thickness from the center to the 3 mm periphery in the keratoconus group and in the keratoconus suspect group was significantly thinner than those in the normal group, there were no significant differences in the corneal thickness at the 4 mm superior or temporal areas among the three groups. Increasing ratio of the corneal thickness from the center to the periphery showed the higher value in the keratoconus group than in the others. CONCLUSION: AS-OCT enabled us to understand the configuration of the anterior segment of the eye and the distribution of the corneal thickness quantitatively even for the advanced keratoconus cases with corneal scar. AS-OCT may be useful as an aid to contact lens prescription and surgical planning. PMID- 21598606 TI - [Evaluation of recovery process of photoreceptor outer segment after retinal detachment repair]. AB - PURPOSE: To evaluate the relations in the recovery process between the photoreceptor outer segment and visual acuity of repaired macula-off rhegmatogenous retinal detachment (RRD), using spectral-domain optical coherence tomography (SD-OCT). SUBJECTS AND METHODS: Twenty-three eyes with repaired macula off RRD were examined to assess the photoreceptor inner and outer segment junctions (IS/OS), the external limiting membranes (ELM) and the thickness of the outer nuclear layer (ONL). The correlation between this recovery process and log MAR visual acuity was assessed at three months and six months after surgery. RESULTS: The mean logMAR visual acuity of the group with IS/OS disruptions at three months and without IS/OS disruptions at six months was 0.34 +/-0.09 (mean +/- SE, n=7) at three months and significantly improved to 0.06 +/- 0.08 at six months. In the group with IS/OS disruptions and without ELM disruptions at three months, the mean logMAR visual acuity was 0.36 +/- 0.27 (n=6) at three months and improved significantly to 0.07 +/- 0.24 at six months. CONCLUSIONS: There was a correlation between the reduction of visual acuity with repaired macula-off RRD and the disruption of IS/OS, and a correlation was also found between the improvement in visual acuity after repaired macula-off rhegmatogenous retinal detachment and reduction of IS/OS disruptions. The results suggest that absence of ELM disruptions is a requirement for improvement of IS/ OS disruptions. PMID- 21598608 TI - [Outcome of conjunctival autograft with amniotic membrane transplantation for recurrent pterygium]. AB - PURPOSE: To investigate the outcome of conjunctival autograft with amniotic membrane transplantation without the use of mitomycin C for cases of recurrent pterygium. CASES AND METHODS: Thirty-nine eyes of 35 patients (aged 27 to 76 years) who underwent the surgical procedure for recurrent pterygium at Yamaguchi University Hospital from November 1998 to July 2007 were evaluated retrospectively from their medical records. Patients who did not undergo postoperative follow-up examination for at least 6 months were excluded. The mean number of prior surgeries was 2.9 (range, 2 to 10), and the mean +/- SD follow-up time was 42.0 +/- 29.6 months. RESULTS: Twenty seven of 29 eyes (93.1%) with recurrent grade 3 pterygium showed a reduction in the size of the new growth after surgery. The symblepharon improved postoperatively in 5 of 15 eyes (33.3%) and restriction of ocular movement improved in 11 of 24 eyes (45.8%). Most recurrences occurred within 6 months after surgery, although one case did not show a recurrence until 2 years postsurgery. CONCLUSION: Conjunctival autograft with amniotic membrane transplantation without the use of mitomycin C reduced the size of the recurrent pterygium. However, 6 of the 16 eyes (37.5%) required subsequent surgery, suggesting that the procedure has limitations. Mitomycin C should therefore possibly be considered for cases with severe symblepharon or restriction of ocular movement. In choosing the surgical procedure for recurrent pterygium, diplopia can be an important indicator of the severity of a symblepharon or restriction of ocular movement. PMID- 21598607 TI - [Medium-term effects of intravitreal bevacizumab for macular edema associated with central retinal vein occlusion]. AB - PURPOSE: To report the medium term effects of intravitreal injection of bevacizumab for central retinal vein occlusion (CRVO) with macular edema. PATIENTS AND METHODS: Twenty-two eyes of 22 patients receiving intravitreal injections of 1.25 mg/0.05 ml of bevacizumab (IVB) were included. All patients were followed up for 6 months or longer after the final IVB. The visual acuity and central retinal thickness (CRT) were measured at baseline, one week and every three months after the first IVB. RESULTS: The mean follow-up after the final IVB was 12.5 months (6-30 months). The mean visual acuity (baseline : 0.63 +/- 0.39) temporarily improved at one week (0.38 +/- 0.33 : p=0.0002), but there was no significant visual improvement at the final visit (0.73 +/- 0.67 : p=1.0). The mean CRT significantly decreased at one week, three months and six months after IVB and at the last visit. There were no differences in either visual or anatomical outcomes between the ischemic type and non-ischemic type. CONCLUSION: Intravitreal injections of bevacizumab should be initially considered as a possible treatment in eyes with macular edema associated with central retinal vein occlusion. PMID- 21598609 TI - [A case of non-atherothrombotic cerebroretinal small vessel disease]. AB - BACKGROUND: There is an increasing interest in the relation between retinal artery abnormalities and cerebral small-vessel diseases (SVD), because retinal vessels share common properties with cerebral small vessels. We report a case of juvenile cerebrovascular disease presenting retinal vessel abnormalities, which clinically resembled cerebral autosomal dominant arteriopathy with stroke and ischemic leukoencephalopathy (CADASIL) but in which Notch3 gene mutations were not detected. CASE: A 42-year old woman was hospitalized at the department of Neurology in our hospital, complaining of headache and dysarthria. MRI showed bilateral spotted white matter lesions in the paraventricular area and the temporal lobe, and an ovoid lesion in the right corona radiata. Despite steroid pulse therapy, she developed right incomplete hemiparesis and new lesions were detected in the anterior temporal pole and external capsule. Her genetic analysis showed no mutations in the Notch 3 gene. Ophthalmological examination revealed arterial sheathing in the peripapillary region. Fluorescein angiography showed narrowing of the retinal arterioles and distinguished a peripheral vascular network. CONCLUSION: In this case, ophthalmological examination revealed retinal vessel abnormalities in a relatively young woman with no risk factors such as hypertention or artheriosclerosis, presenting recurrent subcortical strokes. This actual case indicates the association between retinal vessel abnormalities and cerebral SVDs. PMID- 21598610 TI - [Poliomyelitis in Tajikistan. Protection of Russia from emergence and spread of wild poliomyelitis virus]. AB - Problem of emergence and spread of poliomyelitis in Russian Federation and neighboring states is examined. Measures taken in Russian Federation to prevent emergence of poliomyelitis cases caused by wild type virus are discussed, as well as treaties and agreements between Russia, Commonwealth of Independent States, Shanghai Cooperation Organization states regarding epidemiological control of poliomyelitis and acute flaccid paralysis. Measure planned by Federal Service for Surveillance for Protection of Consumers Rights and Human Welfare to prevent emergence of poliomyelitis and acute flaccid paralysis cases in Russian Federation and neighboring countries are presented. PMID- 21598611 TI - [Genetic characteristics of Neisseria meningitidis strains obtained from healthy carriers during meningococcal infection outbreaks]. AB - AIM: Genetic and antigenic characterization of Neisseria meningitidis strains isolated during meningococcal infection outbreaks from individuals in contact with patients with generalized form of meningococcal infection. MATERIALS AND METHODS: Strains obtained in 2007 - 2009 in Moscow during examination of individuals that were in contact with patients during meningococcal infection outbreaks were analyzed. Multilocus sequence typing, genetic subtyping and typing of VR fragment (FetA) techniques were used. RESULTS: Data regarding investigated strains were submitted to the database at http://pubmlst.org/neisseria/. Previously undescribed sequence types were found in 12 strains, sequence-type could not be determined in 2 strains, 2 strains lacked VR fragment (FetA). Serogroup A meningococci had "P1.5-2,10: F3-5" antigenic profile and belonged to ST-75 and ST-3349 sequence-type, these data does not support the emergence of epidemically significant strains in the territory under surveillance. All typed serogroup C strains and 1 serogroup B strain are of "ST-41/44 complex/Lineage 3" clonal complex. Subtypes of serogroup C meningococci strains match subtypes of strains that cause generalized forms of infection, while serogroup B strains isolated from the carriers and strains isolated from the patients had different antigenic profiles. Ungrouppable strains had notably higher level of genetic and antigenic diversity: only 6 of 16 strains (37.5%) could be sequence-typed using earlier data, all these strains are of clonal complex "ST-53 complex" that consists mostly of strains isolated from the carriers. CONCLUSION. Ratio of meningococci population circulating in Moscow and subpopulation capable of causing generalized form of meningococcal infection (GFMI) is different for meningococci of various serogroups. Ungrouppable strains isolated from the carriers are highly different from strains causing GFMI. PMID- 21598612 TI - [Genotyping of West Nile fever virus strains circulating in southern Russia as an epidemiological investigation method: principles and results]. AB - AIM: Characteristic of West Nile fever (WNF) virus strains circulating in southern Russia. MATERIALS AND METHODS: WNF RNA was amplified directly from clinical samples, mosquitoes and bird tissues by PCR, nucleotides were sequenced directly and analyzed comparatively. RESULTS: Related but different genovariants of WNF lineage 1a--"Volgograd" and "Astrakhan"--circulated during WNF outbreaks of 1999 and 2000-2003 in Volgograd and Astrakhan regions. In 2005 "Volgograd" WNF variant emerged in Astrakhan region and along with "Astrakhan" variant caused a new morbidity increase. In 2004 in sera of 2 WNF patients from Rostov region WNF lineage 2 RNA was detected, this was the first WNF clinical case caused by WNF lineage 2 outside of Africa. WNF outbreak in Volgograd region in 2007 was caused by this unique WNF lineage that may preliminary be called Russian. Finally, during a major WNF outbreak in 2010 in Volgograd and Rostov regions in clinical samples only russian genovariant WNF lineage 2 RNA was detected again. CONCLUSION: After emergence of a certain WNF genovariant the virus is capable of persisting in natural foci in southern Russia. A near disappearance of one of the WNF clones by substitution or displacement with another maybe possible. Determination of genetic characteristics of WNF strains circulating in Russia is an important element of WNF epidemiological surveillance and control of this disease. PMID- 21598613 TI - [Immunobiological properties of recombinant atoxic forms of the Pseudomonas aeruginosa exotoxin A]. AB - AIM: Evaluation of immunobiological properties of recombinant atoxic forms of the Pseudomonas aeruginosa exotoxin. MATERIALS AND METHODS. 3 recombinant atoxic forms of the P. aeruginosa exotoxin A were produced and studied: aTox1, consisting only of exotoxin A domain 1; aTox1,2, consisting of domain 1 and 2; and aTox1,2,delta3, consisting of both domain 1 and 2, and part of domain 3. RESULTS: aToxl,2 and aTox1,2,delta3 had distinctive antigenic properties. Formulations based on these recombinant proteins were immunogenic and protected animals from exotoxin A in experimental conditions. CONCLUSION: These results maybe used to construct direct-action immunobiological formulations. PMID- 21598614 TI - [Immunogenic and protective properties of nanosized constructs based on tubular immunostimulating complexes and pore forming protein of Yersinia pseudotuberculosis]. AB - AIM: Evaluation of immunogenic and protective properties of constructs based on subunit porin antigen from Yersinia pseudotuberculosis, immunostimulating complexes (ISCOM) and tubular immunostimulating (TI) complexes. MATERIALS AND METHODS: Porin antibodies and blood serum cytokines were determined by using EIA. Porin-specific cell immunity was evaluated by DTH reaction inflammation index. Protective activity of porin formulations was determined by measuring specific gravity of animals surviving Yersinia pseudotuberculosis lethal challenge. RESULTS: Porin in TI complexes develops higher immunogenicity when compared with individual protein or protein with complete Freunds adjuvant. Porin in TI complexes develops higher protective activity, inhibits interferon synthesis in mice. Incorporation of porin into TI complexes results in neutralization of porin suppressive activity against DTH mechanisms and interferon system. CONCLUSION: TI complexes may be used as perspective carriers for bacterial antigens. TI complexes have adjuvant properties and can provide protective properties to porin vaccine constructs. PMID- 21598616 TI - [Influence of microbial-epithelial interactions on biological characteristics of vaginal microflora]. AB - AIM: Evaluation of influence of microbial epithelial interactions on growth properties and antagonistic activity of dominant and associated vaginal microflora. MATERIALS AND METHODS: Growth characteristics and antagonistic activity changes were studied in associated (Staphylococcus aureus, Escherichia coli, Corynebacterium spp.) and dominant (Lactobacilus spp.) microflora during contact with vaginal epitheliocytes and influence of vaginal epitheliocyte secretory products by using the developed technique. RESULTS: Secretory products of vaginal epitheliocytes and vaginal epitheliocytes differentially influence growth factors of vaginal microbiocenosis. Suppression of S. aureus and E. coli biomass growth based predominately on extracellular secretory products of epitheliocytes was observed. Stimulation of growth properties was prevalent for lactobacilli and corynebacteria and was observed in contact interaction as well as during effect of epitheliocyte extracellular secretory products. CONCLUSION: The resulting bacterial-epithelial interaction is a differentiating feature between autochthonous and allochthonous microflora due to the creation of selective advantages for dominant microsymbionts by growth properties and antagonistic activity stimulation, and biomass growth suppression of associated symbionts. PMID- 21598615 TI - [Serum alpha-fetoprotein levels in pregnant women with indeterminate result of anti hepatitis C virus antibodies analysis]. AB - AIM: Comparison of alpha-fetoprotein (AFP) levels in blood sera samples of women in the early stages of pregnancy with positive or indeterminate results of anti HCV. MATERIALS AND METHODS: Blood sera samples of women in the first trimester of pregnancy were analyzed by using microplate test systems for enzyme immunoassay (EIA) with complex and separate detection of antibodies against hepatitis C virus (HCV) antigens. RESULTS: AFP levels were higher in women in the first trimester of pregnancy with anti-HCV than in women without anti-HCV. AFP levels in blood sera samples of pregnant women with indeterminate results of anti-HCV analysis were higher than in blood sera samples of pregnant women without anti-HCV. No differences in serum AFP levels were observed between anti-HCV positive samples and samples with indeterminate results of analysis. CONCLUSION: Increased AFP level in the first trimester of pregnancy was observed not only in women with HCV infection, but also in women with indeterminate results of anti-HCV analysis. The data suggest that these groups may have epidemiological similarity. PMID- 21598617 TI - [Adhesive properties of microorganisms colonizing rheumatoid arthritis and systemic lupus erythematosus patients]. AB - AIM: Evaluation of adhesive properties of microorganisms colonizing rheumatoid arthritis and systemic lupus erythematosus patients. MATERIALS AND METHODS: Nose mucosa and urinal microflora from 62 rheumatoid patients (32--rheumatoid arthritis and 30--systemic lupus erythematosus patients) was studied. 57 opportunistic microorganisms were isolated: including representatives of Staphylococcus, Escherichia, Klebsiella, Morganella, Enterobactergenera. Adhesive properties on erythrocyte model of microorganisms isolated in patients with rheumatoid disease, museum cultures and clinical strains were analyzed by using standard technique. RESULTS: Bacteria isolated in rheumatoid disease patients were characterized by pronounced adhesive potential. Bacteria of Enterobacteriaceae family have shown significantly higher adhesive properties. Heterogeneity of adhesive properties levels, and genera and species adhesive potential of bacteria was determined. CONCLUSION: Microorganisms colonizing rheumatoid disease patients have a high adhesive potential that can increase the risk of patient infections. PMID- 21598618 TI - [Micro technologies in express diagnostics of toxigenic Corynebacterium diphtheriae strains]. AB - AIM: Development of micro technologies based approach for express diagnostics of toxigenic C. diphtheriae strains. MATERIALS AND METHODS: Corynebacterium diphtheriae 10648 (tox+) and C. diphtheriae NCTC 10356 (tox-) from Central Health Laboratory (London) reference strains were used as positive and negative controls respectively. Diagnostic kit was created by using fractions of antibodies with high avidity that were obtained by consecutive fractioning of positive antitoxic blood sera and then loaded onto polyacrylamide latex particles with the diameter of 0.81 microm. 20 Elek test positive C. diphtheriae strains and 20 tox gene PCR negative C. diphtheriae strains (i.e. non toxigenic) (Pasteur Research Institute of Epidemiology and Microbiology) were used as control. Indirect hemagglutination with anti-diphtheria antibody diagnostic kit was used as a quantitative control. PCR, Elek test and ICS test were used as quality control. RESULTS: The diagnostic kit obtained had specificity of 97%, sensitivity of 98%. Specimen preparation time is 15 - 20 minutes, reaction time - 2 - 3 minutes, and up to 93 specimens can be analyzed on a single microchip. CONCLUSION: The developed approach has high sensitivity and specificity, is easy to use, and fast in regard to preparation and reaction time. Portability of the apparatus allows the use of reagents in micro volumes. PMID- 21598619 TI - [Character of lipopolysaccharide-binding protein level changes in different pathological conditions and dysbiosis]. AB - AIM: To evaluate diagnostic value of lipopolysaccharide-binding protein (LBP) level in different infectious processes and dysbiosis. MATERIALS AND METHODS: Serum samples of patients with salmonellosis, urogenital chlamydiosis, community acquired pneumonia, polypous rhinosinusitis, and bacterial vaginosis were studied. RESULTS: LBP level were lower in patients with salmonellosis compared to healthy persons and decreased with increasing severity of the disease. Higher levels of LBP were detected in patients with chlamydiosis. Direct correlation between LBP level and etiology and severity of community-acquired pneumonia was demonstrated. In patients with polypous sinusitis, LBP level correlated directly with duration of disease, and inversely--with duration of remission. Twofold increase of mean LBP blood concentration and its correlation with duration of dysbiosis in patients with bacterial vaginosis were revealed. CONCLUSION: Multidirectional modulation of antiendotoxin defense was observed in different pathological conditions. PMID- 21598620 TI - [Influence of cultivation temperature and Yersinia pestis fra-operon carriage on morphological features of Yersinia pseudotuberculosis]. AB - AIM: Studies of influence of Yersinia pestis fra-operon carriage on morphological properties of Y. pseudotuberculosis recipient strain cells and colonies at different temperature and cultivation time. MATERIALS AND METHODS: Cultures of Y. pseudotuberculosis isogenic variants were grown on solid nutrient medium at 4 - 6, 9 - 11, 26 - 28 and 36 - 38 degrees C. Indirect hemagglutination was used to determine F1 antigen production. Cytorefractometry was used to determine live cell percentage in colonies. Size and dividing cells percentage was evaluated by using phase-contrast microscope "Lyumam-I2". RESULTS: Time period between appearance of micro-colonies and achievement of maximum colony size increased with cultivation temperature decrease. Size of fra+ and fra- variant colony was not significantly different for every temperature regiment used and was significantly lower at the temperature of 36 - 38 degrees C. CONCLUSION: Temperature has a significant influence on population growth, colony size and form. PMID- 21598621 TI - [Contamination of health care institutions environmental objects by Legionella pneumophila]. AB - AIM. The extent of environmental objects contamination by Legionella pneumophila in Nizhny Novgorod and Nizhny Novgorod region hospitals evaluation, and detection of potentially hazardous objects. MATERIALS AND METHODS: 433 swabs of environmental objects, and 43 hot water supply and pool water samples from various departments of 4 multi-disciplinary hospitals were studies. DNA from environmental samples was detected by using real time PCR. RESULTS: L. pneumophila DNA was detected in 41 (9,47%) samples from environmental objects and in 2 (4,65%) samples from hot water supply. These bacteria were more frequently detected in environmental samples from physiotherapy departments. Repeated detection of legionellae from the same objects was registered. CONCLUSION: Circulation of legionellae in multidisciplinary hospitals was determined. Circulation high risk departments and risk objects--reservoirs of L. pneumophila in health care institutions were determined. PMID- 21598622 TI - [Serological activity of vaccine and circulating Bordetella pertussis strains]. AB - AIM: To study activity of vaccine and circulating strains of Bordetella pertussis in serological reactions with serum samples from healthy vaccinated children and children with pertussis infection. MATERIALS AND METHODS: One hundred forty-six serum samples from children with pertussis infection as well as 158 samples from healthy vaccinated children aged 3 - 5 years old were studied. Serologic activity of 3 vaccine strains and 7 strains of B. pertussis isolated from patients with pertussis in 2001 - 2005 against sera of children with pertussis infection or vaccinated children was assessed with hemagglutination assay (HA), radial gel immunodiffusion (RGI), and immunoelectrophoresis (IEP). RESULTS: In HA both serum samples of infected and vaccinated children were equally active in agglutination of microbial preparations prepared from vaccine or recently isolated strains of B. pertussis. RGI assay showed that 81 - 84% of serum samples from infected children and 17 -19% of samples from healthy vaccinated children reacted with vaccine strains, and 81 - 85% of samples from infected children and 16 - 20% of samples from healthy vaccinated children reacted with circulating strains: Sera from patients with pertussis formed identical lines of precipitation with vaccine and circulating strains in RGI assay and three types of precipitation arches profile in IEP. Sera from healthy vaccinated children formed identical precipitation arches with vaccine and circulating strains in RGI assay and one type of precipitation arches profile in IEP. CONCLUSION: Antibodies of patients with pertussis were equally active against vaccine and circulating strains of B. pertussis. Antibodies of vaccinated children were also equally active against vaccine and circulating strains although revealed more narrow spectrum of antigens compared to children with pertussis infection. PMID- 21598623 TI - [Prognostic value of lipopolysaccharide and lipopolysaccharide-binding protein serum levels in cancer patients with sepsis]. AB - AIM: Analysis of LPS and LPS-binding protein (LBP) serum levels and prognostic value evaluation in cancer patients with sepsis. MATERIALS AND METHODS: Blood samples of 17 healthy donors and 46 cancer patients with sepsis were analyzed by using "Hycult biotechnology" kits (The Netherlands). RESULTS: Serum LPS level in cancer patients with sepsis was increased significantly. A substantial decrease of LBP level was detected in blood samples of deceased patients. CONCLUSION: Dynamic increase of LPS serum level and decrease of LPS-binding protein serum level in cancer patients should be considered as an unfavorable factor for sepsis. PMID- 21598624 TI - [Use of plant-origin components in roller cultivation of vaccine reassortant influenza virus strain H5N2]. AB - AIM: To study the optimal conditions for roller cultivation of cold-adapted reassortant vaccine strain of influenza virus A/17/Duck/ Potsdam/86/92 (H5N2) in MDCK and Vero cell cultures grown on nutrient medium based on soy and rice flour hydrolysates obtained using trypsin and bromeline. MATERIALS AND METHODS: Vaccine strain was cultivated on MDCK and Vero cells in rollers in the presence of plant proteases. Obtained culture samples of vaccine strains were lyophilized and their infectivity was assessed. RESULTS: Cultivation of vaccine strain on MDCK and Vero cells grown in experimental media containing reduced quantity (2 and 3% respectively) of fetal calf serum ("Gibco", USA) resulted in high titers of the virus in the presence of plant proteases (4 mcg/ml of papain and 20 mcg/ml bromeline). CONCLUSION: Use of plant enzymes and nutrient media based on enzymic plant hydrolysates, including those obtained with bromeline, for cultivation of vaccine strain on MDCK and Vero cell cultures in rollers could make the manufacturing process of live influenza vaccines safer and more cost effective. PMID- 21598626 TI - [Current state of problem of improving tools for plague vaccine prophylaxis]. AB - Literature data on main immunobiological characteristics of 1st generation plague vaccines as well as ways of development of new tools for specific prophylaxis of plague: recombinant live, chemical, antiidiotypic, and DNA vaccines are presented in the review. Their expected advantages and disadvantages, perspectives of development and practical use in system of antiepidemic measures are assessed. PMID- 21598625 TI - [In vitro and in vivo efficacy of Ingavirin against strains of pandemic influenza virus A(H1N1/09)v]. AB - AIM: To study efficacy of Ingavirin in vitro and in vivo against strains of pandemic influenza virus A(H1N1/09)v and influenza virus A(H5N1) and A(H3N2). MATERIALS AND METHODS: Changes in hemagglutinating and cytopathic activity of influenza virus strains A(H1N1/09)v, A(H5N1) and A(H3N2) during their incubation in the presence of Ingavirin or Remantadin on MDCK cell culture were studied. In mice infected by influenza strains A(H1N1/09)v and A(H3N2) and orally treated with Ingavirin, Tamiflu or Remantadin virus titers in lungs were measured. RESULTS: There was decrease in hemagglutinating and cytopathic activity of influenza virus strains after incubation with Ingavirin in vitro. Ingavirin effectively inhibited reproduction of influenza virus strains A(H1N1/09)v and A(H3N2) in lungs of infected mice. Titers of these strains in lung homogenates decreased when Ingavirin was orally administered to infected mice. CONCLUSION: Strains of influenza virus A(H1N1/09)v were susceptible to Ingavirin and Tamiflu but resistant to Remantadin. Reference strains of A(H5N1) and A(H3N2) were susceptible to Ingavirin, Tamiflu and Remantadin. PMID- 21598627 TI - [MHC-multimers and their application in studies of antiviral immune response]. AB - Application of main histocompatibility complex tetrames (MHC-tetramers) for antigen specific T-cells detection and analysis coupled with flow cytometry opened new opportunities for T-cell response analysis. MHC-multimers allow the detection of T-cells against viral, cancer and vaccine antigens with exceptional sensitivity and specificity. This approach has become the "gold standard" for quantative analysis of T-cell immune response. Certain aspects of analysis using MHC-tetramer are examined, and importance of this approach in T-cell response efficacy evaluation in anti-HIV vaccine trials as well as in HIV positive patients are discussed. PMID- 21598628 TI - [Effect of new adenine derivative on emotional status of rats under conditions of "voluntary alcoholization" model]. AB - In continuation of the study of pharmacological properties of the new drug VMA-99 82 (9-[2-(4-isopropylphenoxy)ethyl]adenine), the influence of this drug on the psycho-emotional status of rats was evaluated using a voluntary alcoholization model. It is established that VMA-99-82 administered at doses of 10 and 50 mg/kg produces a positive effect on impaired cognitive functions in alcoholized rats and eliminated the depression caused by the consumption of excess ethanol. PMID- 21598630 TI - [Studying hemostimulating activity of new compound BIV-30 under conditions of cyclophosphan-induced myelosupression]. AB - The effects of the new chemical substance BIV-30 on bone marrow hemopoiesis has been studied in laboratory mices on the background of myelosupression induced by a single intraperitoneal injection of cyclophosphan in a dose 160 mg/kg. The injection of BIV-30 significantly accelerated lymphocyte, monocyte, granulocyte regeneration branches of bone-marrow hemopoiesis. These results showed evidence of the hemostimulating activity of BIV-30 on the model of bone-marrow hemopoiesis deficiency. PMID- 21598629 TI - [Effects of 5-HT1 and 5-HT2 serotonin receptors on anxiety- and depression-like behavior in female rats]. AB - The influence of the chronic (14-day) administration of 5-HT1A receptor agonist 8 OH-DPAT (0.05 mg/kg, s.c.) and 5-HT2B/2C receptor agonist m-CPP (0.5 mg/kg, i.p.) on the anxiety- and depression-like behavior has been studied in adult female rats during key phases of the ovarian cycle. The chronic administration of m-CPP at the estrous phase produced an anxiolytic effect, while at the proestrous phase, the same drug produced an anxiogenic effect. At the same time, both 8-OH DPAT and m-CPP exhibited pronounced antidepressant effect irrespective of the ovarian cycle phase. PMID- 21598631 TI - [Dimephosphone shows anti-inflammatory and anti-oxidative activity on chronic autoimmune inflammation model]. AB - The anti-inflammatory activity of dimephosphone, xydiphone (ethidronate), and ionol (dibunol) and their effects on lipid peroxidation (LPO) indices and the activity of antioxidant enzymes in blood were studied on the model of Freund adjuvant induced arthritis in white laboratory rats. The Freund adjuvant induced chronic arthritis and increased the concentrations of PLO products and nitrite ions in the blood plasma. Only dimephosphone showed an anti-inflammatory action. Dimephosphone and ionol inhibited the LPO, whereas xydiphone did not influence the LPO indices in the blood. PMID- 21598632 TI - [Effect of antiviral drugs with various mechanisms of action on morphogenesis of infection caused by extremely pathogenic influenza virus strains in animals]. AB - The effect of meglumine salt of acridonoacetic acid (cycloferon) on the in vivo morphogenesis of influenza infection caused by viruses of different origin (avian, swine and human) and variable susceptibility to antivirals (rimantadine and oseltamivir) has been studied. The administration of cycloferon results in stimulation of the immune response, restriction of the foci of post-influenza pneumonia, and normalization of the structure of respiratory zones independently of the susceptibility or resistance of infectious virus to the drugs. Among virions formed in the lungs of cycloferon-treated mice, prevalence of irregular shaped virions with defects of surface glycoproteins was observed. The data obtained suggest that cycloferon is a drug with the complex mechanism of activity. PMID- 21598633 TI - [Intracellular accumulation and antitumor activity of various nanosomal formulations of paclitaxel]. AB - Paclitaxel-loaded poly(lactic-glycolic) copolymer nanoparticles have been prepared using a precipitation technique. The cytotoxic activity of nanosomal paclitaxel was studied on the model of highly resistant cell line Jurkat WT (human T-cell leukemia) using various biochemical assays. It is found that the inhibitory concentration (IC50) for the experimental formulation of paclitaxel falls within 10(-4)-10(-6) M. Accumulation of nanoparticles in the highly resistant Jurkat/WT cells was revealed by fluorescence microscopy. PMID- 21598634 TI - [Study of detoxifying efficacy of remaxol in experimental model of cisplatin induced toxicosis]. AB - The detoxifying efficacy of remaxol in the experimental model of cisplatin induced toxicosis has been studied and the possibility of using this drug in cancer patients therapy is evaluated. Remaxol exhibited pronounced dose-dependent detoxifying effect in the model of toxicosis induced by cisplatin in a toxic dose (LD50). It reduced the death rate in test animals about three times when used at a 130 ml/kg dose, and prevented lethal outcome at a 500 ml/kg dose. Remaxol also normalized biochemical blood indices that characterized liver and kidney functions in survived animals. Remaxol did not stimulate growth of experimental carcinoma, sarcoma, melanoma, and lympholeukosis. The drug did not interfere with the anti-tumor efficacy of cisplatin in the schemes with combined treatment of animals bearing tumors of various histogenesis. Remaxol can be recommended for clinical study as a detoxifying preparation for cancer patients with various malignancies. PMID- 21598635 TI - [Geroprotective properties of dimebon: morphological characterization of organs and tissues in mice after long-term treatment]. AB - It has been experimentally established that dimebon reliably increased the average and maximum life span and significantly improved the general state of C57BL/6 female mice. Compared to the control group, the animals of the test group were more active, had better hair (greater number of hair follicles per unit area of histological section of skin), and lower age-related reduction of the body weight. PMID- 21598636 TI - [Method for determining cumulation factor in toxicological studies]. AB - A new method for determining the cumulation factor is proposed, which quantitatively describes the cumulative effect and allows the dosage regimes for repeated drug administration to be planned. PMID- 21598637 TI - [Influence of suprachiasmatic nuclei of hypothalamus and clock genes on chronotropic activity of psychotropic drugs]. AB - Review summarizes recent data on morphofunctional features of circadian cycle mediator - suprachiasmatic nuclei of hypothalamus--including their molecular organization with participation of clock genes. The role of these mechanisms in the action of neuropsychotropic drugs is discussed. PMID- 21598638 TI - [Role of the priority national health project in implementing HIV epidemic control strategy in the Russian Federation]. AB - According to the data of the UN AIDS control program, the estimated number of persons living with HIV infection worldwide is close to 36 million. There is only one way to reduce HIV infection treatment and care costs; this is to develop large-scale HIV prevention programs. The geography of the HIV infection epidemic is inhomogeneous; about 70% of the absolute number of all notified HIV cases are concentrated in 15 subjects of Russia; bulk of them are industrially developed high-income areas. The laboratory base of AIDS prevention and control centers has been drastically renewed; about 400 units of up-to-date laboratory equipment have been purchased. The problem of preventing the prevalence of HIV infection is being primarily solved within the framework of the priority national project. The programs to prevent HIV infection among particularly vulnerable population groups have been elaborated with regard to the realities and specific features of development of the epidemic of HIV infection. PMID- 21598639 TI - [Human health risk from the chemical composition of drinking water]. AB - The maintenance and development of the centralized household underground water supply system in the closed administrative-territorial entity Seversk, Tomsk Region, when the aquifers are inadequately protected and there is a hydrological association of individual aquifers with polluted surface waters require a hygienic estimation based on the use of a risk methodology, including that considering the regional feature of sanitary situation establishment. No risk realization has been ascertained for damage to critical organs and systems in pediatric and adult populations under the population influence of the chemical substances available in drinking water. PMID- 21598640 TI - [Evaluation of the efficiency of Angara River water protection measures against pollution by petroleum products]. AB - The process installations and storage reservoirs of a petroleum refinery have leaks of petroleum products (PP) that pollute soil, underground waters, and eventually nearest water objects, by worsening their hygienic state. Environmental and economic assessments of the Angara River water protection system that is in operation at the petroleum refinery OAO "Angara Petroleum Company", which comprises well clusters, a gravel-filled trench, and a drainage system, have shown the high values of preventable relative natural and economic damages and other economic indicators. At the same time, comparison of the amount of PPs accumulated at the industrial site with their annual withdrawal has demonstrated a need for further development of a river protection system. Therefore the environmental protection system efficacy evaluated by the quality of goal attainment and by means of a matrix of algorithmized statements was 60% or 5 of 20 scores, which shows the necessity of special measures to protect Angara River waters. The elaboration and implementation of these measures associated with considerable expenditures make it possible not only to increase the environmental efficiency of water protection of the Angara River, but also to do the hygienic quality of water use in its related localities. PMID- 21598641 TI - [Enteric microbiocenosis in the population of an industrial city]. AB - According to the state of atmosphere, Irkutsk has been among 45 cities and towns of Russia with high levels of air pollution for tens of years. The body's normal microflora is directly related to environmental factors. The degree of a risk for dysbiotic disorders in intestinal microbiocenosis was estimated in the persons living in the industrial city's areas with different levels of ambient air pollution. A total of 400 apparently healthy individuals aged 1-14 and 15 years or older who lived in different areas of the city. Within one industrial city, the persons living in the "dirtiest" areas showed negative trends associated with bifidobacterium and lactobacillus deficiency and the widespread of Staphylococcus aureus and Candida albicans. PMID- 21598642 TI - [Spread of carcinogenic and mutagenic effects in the population of Gornaia Shoria]. AB - Mutagenic and carcinogenic effects were studied in the population of Gornaya Shoria, Kemerovo Region. The carcinogenic effects were evaluated on the basis of the data given by the Kemerovo regional cancer registry over 1990-2008. The standardized cancer morbidity index in Gornaya Shoria (342 per 100,000 population) exceeded the average index in the Kemerovo Region (286 per 100,000) in the same period. The mutagenic effects were estimated on the basis of the monitoring data on the frequency and spectrum of chromosomal aberrations in the peripheral blood lymphocytes of the dwellers of Gornaya Shoria for the 1992-2009 period. The mean level of chromosomal aberrations (5.31%) in the residents of Gornaya Shoria was found to be greater than the regional background mutation rate (2.86%) (p < 0.001). The values of individual aberration types (chromatid and chromosomal breaks, as well as chromosome-type exchange aberrations) were significantly higher in the dwellers of Gornaya Shoria than those in the basic control group. The revealed high mutagenic load in the inhabitants of Tashtagol District, Kemerovo Region, allows this area to be assigned to high genetic risk ones. PMID- 21598643 TI - [Impact of ambient air pollution on the prevalence of main symptoms of asthma in children]. AB - The impact of ambient air pollution on the prevalence of main symptoms of asthma was analyzed in children. A total of 3,506 children were interviewed using the ISAAC questionnaire. The prevalence of the abnormality was studied via continuous questioning in children aged 7-8 and 13-14 years, who lived in areas with varying aerogenic loads. The higher rates of main asthma-like symptoms and clinically diagnosed asthma were ascertained in the children living in higher ambient air pollution areas. PMID- 21598644 TI - [Hygienic aspects of the use of light-emitting diode sources in the communal artificial lighting systems]. AB - To estimate the possibilities of using light-emitting diode energy-saving lighting in the residential and public houses, industrial buildings and structures is one of society's most important tasks. The concept of these researches was to study comparative psychophysiological and functional changes in the volunteers working under general lighting generated by light-emitting diodes and luminescent lamps. The results of the study permit one to recommend the use of light-emitting diodes in general lighting systems in the rooms wherein visual and mental load work is done, i.e. in the industrial, office, and public buildings intended for adult users for different purposes, as well as in rail transport objects. PMID- 21598645 TI - [Bronchopulmonary diseases in workers engaged in carbonyl production of nickel in the Kola Arctic]. AB - The paper gives data on the prevalence and pattern of chronic bronchopulmonary diseases (CBPD) in 188 workers engaged in carbonyl production of nickel versus 162 auxiliary process workers. Chronic bronchitis was the most common disease in both groups (11.2 and 5.6%, respectively). 9.6% of the carbonyl production workers were found to have toxic pneumofibrosis developing mainly in those having a service length of more than 20 years. As compared with auxiliary process workers, the nickel production process workers had a higher risk of CBPD (odds ratio 1.80; 95% confidence interval 1.00-3.22; p = 0.04496) who also came to the front in the pattern of occupational diseases (73.2% of all cases). PMID- 21598646 TI - [Effect of harmful chemical air impurities on some parameters of the oral cavity]. AB - The paper describes guidelines for studying the role of harmful chemical air impurities at work in the development of diseases of the teeth and periodontium, by applying the nonparametric methods that can substantiate conclusions on the nature and mechanism of a cause-and-effect relation when the number of observations is limited. PMID- 21598647 TI - [The microflora associated with anatomical embalming as a harmful factor of a working process]. AB - The paper describes the first attempt to isolate and identify the microbiocenosis associated with the objects of a morphological laboratory that uses formalin. The study identified the following microorganisms: the bacteria Bacillus sp., Providencia alcalifaciens, and Staphylococcus aureus, the micromycetes Scopulariopsis brevicaulis, Aspergillus sp., Hormodendron sp., and the mites Dermatophagoides pterronissimus. There is experimental evidence that these organisms are resistant to formalin. The representatives of this cenosis can negatively affect the health of the workers, which requires the development of the optimal technologies of biomaterial fixation. PMID- 21598648 TI - [Assessment of risk for occupationally induced diseases in purification plant workers at a petroleum refinery]. AB - The risk for occupationally induced diseases was assessed in purification plant workers at a petroleum refinery. The auxiliary process (purification and prepurification plants, biochemical purification) of the refinery OAO "Naftan" was the study object. Epidemiological, sanitary-and-hygienic studies were conducted to examine the negative influence of dangerous and harmful production factors on the workers' health status. The harmful and dangerous production factors recorded at this enterprise have been found to have a negative influence on the workers' health workers, which leads to the development of occupationally induced diseases in them. PMID- 21598649 TI - [Working adaptation in brain workers: sociohygienic aspects]. AB - The parameters of subjective well-being in teachers and their significance in a possible reduction in work capacity and precocious retirement were studied. The teachers with low need satisfaction levels were found to have increased subjective stress or fatigability on doing their work and decreased rest recovery of work capacity. Lower need satisfaction levels with negative reasons for refusal to continue work activities appear to be one of the factors of professional aging and its related reduction in their active work period. PMID- 21598651 TI - [The manifestations of toxicity of nanoparticles (a review)]. AB - The analysis of the data available in the literature has shown that nanoparticles (NP) have a high toxicity than usual microparticles, can penetrate unchanged across the cell barriers, the blood-brain barrier into the central nervous system, circulate and accumulate in the organs and tissues, by inducing more significant pathomorphological lesions in the visceral organs, and have a long elimination half-life. The toxicity of HPs is determined by their shape and sizes; moreover, minute fusiform particles cause more destructive effects than similar spherical particles; upon exposure, there is a clear dose-effect relationship. According to exposure to NPs, the classical target organs for the latter are the lung, liver, kidney, brain, gastrointestinal tract. PMID- 21598650 TI - [Microbiological rationale for using whey on salting salmon caviar]. AB - The paper provides a rationale for the use of whey to salt salmon fishes instead of traditional preservatives, including those exported from low industrial potential countries, which do not undergo comprehensive sanitary and hygienic tests. On the basis of the performed studies, the authors recommend to use whey to salt salmon caviar, which ensures the ecological purity of the product containing the minimum amount of preservatives and other substances that fail to affect its organoleptic properties. PMID- 21598652 TI - [Development of sanitary microbiology researches at the A. N. Marzeyev Institute for Hygiene and Medical Ecology, Academy of Medical Sciences of Ukraine (Kiev)]. AB - The paper describes the main stages of development of sanitary bacteriological studies at the leading hygiene research institute of Ukraine--the A. N Marzeyev Institute for Hygiene and Medical Ecology. These researches have made a substantial contribution to the formation and development of hygiene science in the former Soviet Union. The current and promising areas in sanitary microbiology in Ukraine are considered. PMID- 21598653 TI - [Analysis of phylogenetic criteria for estimation of the rank of taxa in methane oxidizing bacteria]. AB - To determine a possibility of application of phylogenetic criteria for estimating the taxa rank, the intra- and interspecies, as well as intergeneric relatedness of methanotrophs on the basis of 16S rRNA gene sequences was estimated. We used sequences of 16S rRNA genes of the studied isolates of obligate methanotrophs which have been deposited in UCM (Ukrainian Collection of Microorganisms), and of type strains of other obligate methanotrophs species (from GenBank database). It is shown, that the levels of interspecies and intergeneric relatedness in different families of methanotrophs are not identical, and therefore they can be used for differentiation of taxa only within one family. The carried out analysis has shown, that it is necessary to reconsider taxonomic position: (1) of two phenotypically similar species of Methylomonas (M. aurantiaca and M. fodinarum), similarity of 16S rRNA genes which is 99.4%, similarity of their total DNA--up to 80% that rather testifies to strain differences, than to species differences; (2) of species Methylomicrobium agile and M album which are phylogenetically more related to genus Methylobacter (97% of affinity), than Methylomicrobium (94% of affinity); (3) of genera of the family Beijerinckiaceae (Methylocella and Methylocapsa), and also genera of the family Methylocystaceae (Methylosinus and Methylocystis), whereas high level of relatedness (97% and more) of these bacteria with other methanotrophic genera (within one family) practically corresponds to a range of relatedness of species (within some genera) in the family Methylococcaceae. When determining phylogenetic criteria which can characterize the ranks of taxa, it was revealed, that the levels of interspecies relatedness of methanotrophic genera of the families Methylocystaceae and Beijerinckiaceae (97.8-99.1% and 97.8%, accordingly) considerably exceed the level of genera formation in the family Methylococcaceae (94.0-98.2%) and, moreover, approach the value of intraspecies relatedness of the family Methylococcaceae (97.5-99.3%). Coefficients of intraspecies relatedness of methanotrophs of the families Methylocystaceae and Beijerinckiaceae are sometimes equal to interspecies relatedness. Hence, taxa of various rank can have the identical level of genes divergence. Thus, methanotrophic taxons of the families Methylocystaceae and Beijerinckiaceae have not demonstrated precise phylogenetic criteria which could correspond both to the species rank, or the genus rank. At the same time, the criteria, being adequate to the rank of certain taxa, are revealed in methanotrophs of the family Methylococcaceae. The level of genotypic relatedness of strains of the same species is in the range of 97.5-99.3%, species of the same genus--94-98%, the highest levels of relatedness between genera of this family are 90-96%. PMID- 21598654 TI - [Optimization of nutrient medium for cultivation of Bacillus subtilis IMV V 7023]. AB - Nutrient medium for cultivation of Bacillus subtilis IMV V-7023 was optimized by the method of the orthogonal Latin rectangles. Optimum concentrations were investigated in the medium of carbon source (15.0 g/l of molasses), nitrogen (2.0 g/l of corn extract) and content of phosphorus-containing inorganic salts (0.4 g/l). When growing this strain in periodic conditions at 28 degrees C, the value of oxygen mass transport in the liquid (0.4-0.6 g O2/l per 1 h) and the initial number of cells of each bacterial species was 1 x 10(6) cells/ml. The numbers of bacteria reached the maximum after 24 hours of cultivation and corresponded to 1.3 x 10(10) cells/ml. Nutrient medium that was optimized can be recommended for cultivation of B.subtilis IMV V-7023 in production conditions. The paper is presented in Russian. PMID- 21598655 TI - [Beta-lactamases of clinical isolates of Enterobacteriaceae family]. AB - Among 62 clinical strains of enterobacteria, isolated from intestinal tract, representatives of genus Escherichia made--67.4%, Klebsiella--4.84%, Citrobacter- 4.84%, Enterobacter--8.06%, Proteus--6.45%, Morganella of 8.06%. Preparations of fluorquinolone group--gatifloxacin and moxifloxacin, the number of steady strains being from 0.0% to 33.3%, were the most effective in respect of enterobacteria The investigated strains of enterobacteria showed considerable resistance to beta lactam antibiotics. The highest sensitivity has been noted to cefotaxim: Escherichia spp.--7.1%, Citrobacter spp.-0.0%, Klebsiella spp.--33.3%, Enterobacter spp.--20.0%, Proteus spp.--25.0%, Morganella spp.--20.0% of steady strains. Among 62 isolated strains of enterobacteria 48 produced beta-lactamases. Production of extended-spectrum beta-lactamases (ESBL) has been found out in 100% of strains of Klebsiella spp., 81.8% of Escherichia spp., 66.7% of Enterobacter spp., 33.3% of Citrobacter spp. and Proteus spp.--from total amount of strains producing beta-lactamases. PMID- 21598656 TI - [Influence of different types of ionizing radiation on fatty acid profiles of cell lipids in microscopic fungi with radioadaptive properties]. AB - The fatty acid profiles of strains of dark-pigmented (melanin-containing) species Cladosporium cladosporioides and Hormoconis resinae, and light-pigmented Aspergillus versicolor and Paecilomyces lilacinus, showing radioadaptive properties in comparison with control strains of the same species, which did not have such properties and the influence on them of two (121Sn; 137Cs) types of ionizing radiation have been studied. It was established that the most important fatty acids were hexadecanoic acid (C16:0), octadecanoic acid (C18:0), octadecenoic acid (C18:1) and octadecadienoic acid (C18:2). The strains, showing radioadaptive properties in comparison with control differed in the relative concentrations of saturated and unsaturated fatty acids and some minor components. The two types of radiation had different influence on the fatty acid profiles of the investigated strains. At dark-pigmented species C. cladosportoides, H. resinae the fatty acid unsaturation rate was higher, at strains showing radioadaptive properties (0.98) as against control ones (0.73; 0.9), and at light-pigmented species A. versicolor and P lilacinus--it was lower at strains with radioadaptive properties (1.00; 0.83) as against control ones (1.08; 0.92). The paper is presented in Ukrainian. PMID- 21598657 TI - [Regulation of sulfates, hydrogen sulfide and heavy metals in technogenic reservoirs by sulfate-reducing bacteria]. AB - Sulfate-reducing bacteria Desulfovibrio desulfuricans Ya-11 in the presence of sulfates and organic compounds in the medium reduce sulfates to hydrogen sulfide (dissimilatory sulfate reduction). Heavy metals in concentration over 2 mM inhibit this process. Pb2+, Zn2+, Ni2+, Co2+, Fe2+ and Cd2+ ions in concentration 1-1.5 mM display insignificant inhibiting effect on sulfate reduction process, and metals precipitate in the form of sulfides. At concentrations of heavy metals 2-3 mM one can observe a decrease of sulfates reduction intensity, and a percent of metals binding does not exceed 72%. Obtained results give reason to confirm, that sulfate-reducing bacteria play an important role in regulation of the level of sulfates, hydrogen sulfide and heavy metals in reservoirs and they may be used for purification of water environment from these compounds. PMID- 21598659 TI - [Symbiotic bacteria, which modify reproduction processes of Drosophila melanogaster]. AB - Cytoplasmic bacteria-symbionts are actively investigated all over the world for the last ten years. The scale of their spreading in natural and laboratory populations of invertebrates, especially arthropods, is impressing scientists' imagination. Ways of their intraspecific and interspecific transmission are various. The nature and mechanisms of their interaction both between themselves and with their hosts are extremely diverse. Cytoplasmic incompatibility, parthenogenesis, male-killing, feminization, tissue degeneration and others are those phenotypic effects, which intracellular bacteria can cause in their hosts. Moreover, the same bacterium can have diverse influences on different hosts. So it is possible to talk about many-sidedness of endosymbiont interaction with a host, which is determined both by bacterium and host biology. However, majority of phenotypic effects is directed to the successful colonization of hosts' populations by increasing the number of infected females. Alas, the mechanisms of interaction are still not enough investigated. Besides, intracellular bacteria symbionts can be one of the factors of the so-called "infectious species formation". In any investigation, model organisms, Drosophila melanogaster belonging to them, take a special place. Among drosophila's endosymbionts, only bacteria from genera Wolbachia, Spiroplasma and Cardinium were broadly investigated: their spreading in Drosophila melanogaster populations all over the world, the infecting level and those phenotypic effects, which they can cause. So this review is dedicated to analysis of these studies. PMID- 21598658 TI - [Activity of oxidative enzymes in plant cells under conditions of experimental mycoplasmosis]. AB - Changes in activity of oxidative enzymes was shown when infecting the callus culture of sugar beet cells by phytopathogenic mollicute Acholeplasma laidlawii var granulum 118. Maximum indices of the enzyme activity were fixed 3 hours after infecting with regard to control: it was 49% for peroxidase, 38% for catalase and 45% for polyfenoloxidase. The decrease of enzymatic activity to 22%, 12% and 19%, respectively, was registered 5 hours after infecting, and after that all these indices became stabilized. Changes in the activity of components of antioxidative protection were probably connected with induction of plants' protective mechanisms in response to penetration of pathogenic mollicutes. PMID- 21598660 TI - [Structural stability of DNA of the transposon derivatives of pCA25 plasmid]. AB - Mutants of Erwinia carotovora subsp. carotovra 48A carrying plasmid pCA25 and its transposon variant and resistant to mitomycin C, nalidixic acid and streptomycin were used in the research. It has been shown that the presence of transposon in plasmid pCA25 (strain 48A-7/4b[pCA25::Tn9]) does not practically affect the frequency of appearance of the stable bacterial mutants under the effect of all three antibiotics. Several variants, the plasmid profile of which differs from the initial one were found only in the case of this strain clones resistant to mitomycin C. Electrophoretic mobility of the plasmid DNA of the mutant clones 31 and 32 decreased and approached mobility of the initial plasmid pCA25, the mutant plasmid 13 had high electrophoretic mobility compared to pCA25::Tn9. Some plasmids are the deletion variants of pCA25::Tn9, one of two IS1-elements of the transposon Tn9 being absent in them. The obtained results indicate that the studied plasmid pCA25 is stable, is not eliminated from the cells under different treatments and confirm once more the hypothesis of the prophage origin of the plasmid. The paper is presented in Russian. PMID- 21598661 TI - [Peculiarities of morphogenetical development of erwiniophage ZF40 virulent mutants ]. AB - The distortion of morphopoiesis or tail attachment to the capsid is a characteristic feature of morphogenetical development not only of a reproductive infection but also of the lysogenic induction of the defective bacteriophage Erwinia carotovora subsp. carotovora (Ecc). A model system for studying morphogenetical development and assembling of the virion was created on the basis of the phage ZF40 and its two virulent mutants ZF40-421 and ZF40(5/5), as well as the indicator culture Ecc M2-4/50 R1 being nontraditional host for these phages. It has helped to establish that the diameter of the phage capsid is not a conservative value. The presence of capsids of two types with the average diameters 60.3 and 65.0 nm is characteristic of the virmutant ZF40c(5/5)/50RI, while in the course of morphogenesis the phage ZF40-421/50RI forms only one type of heads of 65 nm in size. These heads are probably not firmly connected to the tails since the degree of the secondary destruction of the virions of the phage Zf40-421/50RI is considerably higher, than that of the virions of the phage ZF40c(5/5)/50RI. The number of capsids being 60.3 nm in diameter prevails considerably in the latter. The both virulent mutants as a whole are essentially more stable than their isogenic partners obtained on Ecc RC5297 which helps to make a conclusion about considerable influence of specific bacterial proteins of the host-cell on morphogenesis and morphopoiesis. PMID- 21598662 TI - [Effect of isonicotinic acid derivates on reproduction of Epstein-Barr virus]. AB - Current approaches to the treatment of herpes infection, particularly Epstein Barr virus (EBV), include the use of etiotropic medicines, as well as sensitizing therapy. This virus plays an important role in the etiology of nasopharyngeal carcinoma, adenocarcinoma of the parotid glands, gastric carcinoma, Burkitt's lymphoma and lymphoproliferative syndromes [1, 2, 3]. The spectrum of drugs active against EBV remains very limited, and gancyclovir and acyclovir are used in medical practice, so the search of new compounds active against EBV remains urgent. The purpose of this work was to study antiEBV activity of isonicotinic acid derivatives in the cultures of lymphoblastoid Raji cells, B95-8, Namalwa. The indices of cytotoxicity (CC50) which amounted to 840, 1250 and 3000 microg/ml and the concentration of drugs, which inhibit the virus (IC50) reproduction is 0.1, 2.5 and 50 microg/ml, respectively, in cell cultures were identified. It was detected, the drug 4-(n-benzyl)aminocarbonyl-1-methylpyridinium iodide (PV-1) had an ability to inhibit reproduction of the Epstein-Barr virus in all studied cells cultures. The compounds PV-2 and PV-10 were less toxic in respect of the initial preparation PV-1, but their antiviral activity was manifested at 25 and 500 times higher concentrations. It, respectively, influenced the decrease of their selectivity index, which was 8400 for PV-1, 400 and 440--for PV-2 and PV-10. These studies suggest possible ways of further modification of the PV-1 molecule to create highly specific inhibitors of Epstein-Barr virus. The paper is presented in Ukrainian. PMID- 21598663 TI - [The infection of ixodid ticks collected from humans with the tick-borne encephalitis virus in Tomsk city and its suburbs]. AB - The ticks Ixodes persulcatus and I. pavlovskyi collected from people visited gardens and suburban forests have been examined by the IFA methods on the presence of tick-borne encephalitis virus (TEV). It was established, that the most part of ticks collected from humans belongs to I. persulcatus, despite the fact that I. pavlovskyi dominates on the territory of the city and its suburbs. TEV infection was registered more often in fed ticks, in comparison with those without signs of preceding feeding. Infected specimens constituted 9.4% of 53 I. persulcatus individuals examined. In I. pavlovskyi 3.7% of 27 examined specimens were infected. In fed ticks (41 specimens of I. persulcatus and 20 I. pavlovskvi) the rates of infected specimens were higher and constituted 48.8 and 35%, respectively. In suburban forests, as well as in the city, I. persulcatus was found to attack humans more often than I. pavlovskyi. TEV infection was recorded in 12.7% of 220 unfed I. persulcatus specimens examined and in 41.6% of 142 fed individuals. In I. pavlovskyi, 6.6% of unfed and 25% of fed specimens was infected (33 unfed and 24 fed specimens were examined). Thus, in all territories examined, percent of infected specimens was significantly lower in I. pavlovskyi, and in fed ticks of both species, TEV was recorded more often. PMID- 21598664 TI - [First description of the Prosimulium candicans Rubzov, 1956 males (Diptera: Simuliidae)]. AB - First description of the previously unknown Prosimulium candicans males is given. Belonging of this species to the genus Prosimulium Roubaud, 1906 rather than to the genus Taeniopterna Enderlein, 1925 is confirmed. PMID- 21598665 TI - [Fecundity of Thominx neopulchra (Nematoda:Capillariidae) from bats of the genus Myotis (Chiroptera:Vespertilionidae)]. AB - Variability of absolute fecundity of nematode Thominx neopulchra from three species of genus Myotis was studies on the territory Zhiguli State Reserve in 2007, 2008. Significant differences in the fecundity of the nematode females depending on host species and sex, size of the parasite, number of the helminthes in a given host, and season of year were revealed. PMID- 21598666 TI - [Peculiarities of the parasitofauna of Atlantic salmon parr (Salmo salar L.), brown trout (Salmo truttae L.), and char (Salvelinus alpinus L.) in the Utsjoki River system (Northern Finland)]. AB - Data on the parasite diversity in Salmonidae fish parr from different parts of the Utsjoki River obtained during 1993-1995 and 2006-2007 are presented. Three fish species, Salmo salar L., S. truttae L., and Salvelinus alpinus L., were examined on the presence of helminthes. Twenty species of salmon parasites were found, the majority of which are the parasites with complicated life cycles. Infusorians C apriniana piscium, myxosporidia Chloromyxum januaricus and Myxobolus neurobius, metacercaria of the genera Diplostomum and Apatemon, and the nematode Raphidascaris acus larvae were the most numerous in salmon parasite fauna. Brown trout had the most number of specific parasite species, whereas char was infested by protozoan parasites only. PMID- 21598667 TI - [Some results of the trematode fauna investigation in the freshwater mollusk Melanopsis praemorsa (L.) from water bodies of Azerbaijan. 2. New species of virgulate cercaria]. AB - Two closely related forms of virgulate cercaria, Cercaria agstaphensis 9 and C. agstaphensis 10 of the superfamily Lecithodendroidea from water bodies of Azerbaijan are described. Morphological data, including chaetotaxic traits, fugures, and differential diagnoses are provided. Descriptions of armature, glandular apparatus, excretory and digestive systems, inclusions of parenchyma, and other structures of the cercaria, characteristic for the superfamily, are presented. PMID- 21598668 TI - [Dependence of the infestation intensity of zope Abramis ballerus with Dactylogyrus chranilowi Bychowsky, 1931 on the level of antimicrobial effect of the host's blood serum]. AB - Infestation of zope Abramis ballerus with Dactylogyrus chranilowi Bychowsky, 1931 depending on the bactericidal activity of the host's blood serum was investigated. Connection of the infestation intensity with the level of antimicrobial effect of the host's blood serum is demonstrated. PMID- 21598669 TI - [Artyfechinostomum sufratyfex Lane, 1915 (Trematoda:Echinostomatidae), a parasite of mammals in Southern Vietnam]. AB - Trematoda Artyfechinostomumn sufratyfex Lane, 1915 was found in different mammal species of Southern Vietnam. Original measurements of this species from domestic pig, black rat, and Asian palm civet are given. PMID- 21598670 TI - [On the methods of investigation of the actinosporean developmental phase of myxosporidians]. AB - The paper describes the techniques of the actinospores investigation under field and laboratory conditions. The methylene blue solution for staining of actinospore processes and estimating of daughter cells of sporoplasm is proposed. PMID- 21598672 TI - [Retinotopic organization of the lateral suprasylvian sulcus' posterior-medial area as revealed by analysis of the pattern of cortico-cortical connection with the cat 17th area]. AB - Using cortico-cortical connection analysis technique, the cat visual area PMLS (the area located on posterior medial wall of the lateral suprasylvian sulcus) retinotopic organization was investigated. A retrograde axonal tracer: horseradish peroxidase (HRP), was injected in the PMLS, and initial neurons were investigated in area 17. It was shown that after HRP injection in PMLS locus, where a central vision field is located, a labelled cell pattern in area 17 corresponded to the L. Palmer et al., 1978, retinotopic map. On the contrary, after HRP injection in PMLS locus, where an upper vision field must be located, as L. Palmer et al., 1978 predicted, initial neurons are visualized in area 17 loci where low visual periphery is displayed: -10 degrees to -60 degrees in vertical meridian and 40 degrees to 80 degrees in horizontal meridian. Such discrepancy in upper and lower visual field representation was also obtained in electrophysiological and topographic investigations by Grant, Shipp, 1991. The data suggest necessity of S. Grant and S. Shipp's retinotopic map use in the cat area PMLS morphofunctional investigation. PMID- 21598671 TI - [Formalin fixation in the method of the Ixodes persulcatus (ixodidae) age estimation by the state of fat reserves]. AB - Formalin fixation is proved to be the useful tool in the method of age estimation for the taiga ticks collected in field. Formalin does not deform fixed material and does not dissolve fat; hence, it is the best fixing fluid when tick age is estimated by the state of fat reserves in its organism. The ticks preserved in 9% formalin were shown to be suitable for age estimation 1.5-2 months after fixation. PMID- 21598673 TI - [Ensemble activity of visual and frontal cortex in the conditions of choice of different value food reinforcement in cats]. AB - The method of "low choice" of food value reinforcement depending on delayed response to its reception demonstrated various strategy of behaviour, showing short or delayed responses of pressing pedal for reception of low or high value of food reinforcement. In trained cats, multiunit activity was recorded in investigated brain areas and functional interneuron interactions were subsequently analysed. Significant prevalence of interneuron interactions was revealed in "impulsive" animals in both cortical zones as well as intergroup differences during the pre-signal and signal periods in visual and frontal cortex. PMID- 21598674 TI - [The dynamics of activation processes in persons with different ability to recognize speech emotional expressions]. AB - The frequency-amplitude characteristics of the brain electrical activity were studied in two groups of subjects: (1) with high and (2) with low indexes of "emotional ear" (the ability to successfully recognize emotions in speech). Comparison of EEG power characteristics between the two groups of subjects permitted the authors to make a conclusion that the persons with lower indexes of "emotional ear" had a much higher EEG activation level as compared to the persons with higher "emotional ear" indexes. A different dynamics of the cortical activation was also observed in the process of recognition of emotions by alpha rhythm amplitude. It was shown that the persons with higher indexes of recognition had higher alpha-rhythm amplitude, whereas the persons who were less successful in recognition of speech emotions had a contrary tendency: the amplitude on the alpha band decreased in the process of the experiment. PMID- 21598675 TI - [Effects of the neurogenesis stimulator Ro 25-6981 upon formation of spatial skill in adult rats depend on the term of its administration and the animals' ability to learn]. AB - Effect of administration of selective N-methyl-D-aspartate (NMDA) receptor antagonist Ro 25-6981 on learning and memory in a dose which is known to stimulate neoneurogenesis was assessed in adult rats with different abilities to formation of spatial skills in different time periods after the antagonist injection. Wistar male rats were trained to find hidden platform in the Morris water maze for 5 consecutive days. Rats' learning ability for spatial skill formation was evaluated depending on platform speed achievements. In re-training sessions (cues and platform location changed), it was found that all rats received Ro 25-6981 13 days before the re-training demonstrated impaired spatial memory. At the same time the inhibitor injected 29 days before re-training selectively facilitated the formation of spatial skill in animals with initially low learning abilities. PMID- 21598676 TI - [Effects of human cultural neuronal and mesenchymal stem cells on the rat learning and brain state after acute hypoxia]. AB - The aim of the study was to compare the effects of neurotransplantation of cultural neural stem cells (NSC) and mesenchymal stem cells (MSC) on the rat behaviour and brain state after acute hypoxia. It was shown that development of two-way avoidance defensive conditioning in a shuttle box improved in rats recipients with NSC, but not MSC as compared to control. Both the transplants of NSC and transplants of MSC exert neuroprotective influence on the rat brain. NSC both in vitro (before transplantation) and in vivo (on day 27 after transplantation) gave rise to all neural cell types: stem/progenitor cells, precursors of neurons and glia, neurons and glial cells. MSC population in vitro and in vivo (on day 10 after transplantation) consisted of fibroblast-like cells which were eliminated by day 20 after transplantation and were surrounded by reactive glia. We suggest that effects of NSC may be connected with their good survival and potential to differentiate into neurons and with trophic influence on the brain of recipient, whereas MSC only have possible positive trophic effect at early stages after transplantation. PMID- 21598677 TI - [Regulatory influence of hippocampus CA1 and CA3 areas on bulbar respiratory neurons under hypoxia]. AB - We studied the influence of stimulation of the CA1 and CA3 areas of the hippocampus on the impulse activity of respiratory neurons (RN) of the medulla oblongata under normal and oxygen deficiency conditions. Under conditions of normal atmospheric pressure, the electrical stimulation of the CA1 and CA3 areas of the hippocampus had mainly an inhibiting influence. In the initial phase, at a 4-5-thousand meter altitude, activation of frequent discharge of neurons occurred. In this situation, stimulation of the CA1 and CA3 areas was more accentuated than under conditions of normoxia. In the second phase (an altitude of 7.5-8 thousand meters), on the reduction of the impulse activity of neurons, stimulation of the CA1 and CA3 areas of the hippocampus induced untypical responses of these neurons. PMID- 21598678 TI - [The extended amygdala system and self-stimulation of the lateral hypothalamus in rats: modulation with opiates and opioids]. AB - Wistar male rats were implanted with bipolar electrodes in the lateral hypothalamus to study self-stimulation reaction in the Skinner box. Simultaneously, the microcanules were implanted into the central nucleus of the amygdala to inject the drugs studied (1 microl in volume for each injection). The blockade of CRF receptors (astressin 1 microg) or sodium influx ionic currents (xycaine, or lidocain 1 microg) by means of intrastructural administration of drugs into the amygdala descreased self-stimulation reaction of the lateral hypothalamus in rats by 29-55%. The inhibition of D2 and D2 dopamine receptors in the amygdala with SCH23390 (1 microg) or sulpiride (1 microg), respectively. reduced self-stimulation too, but in less degree. On the background of blockade of CRF (astressin) and dopamine (sulpiride) receptors, as well as sodium influx ionic currents (lidocain) in the amygdala neurons, psychomotor stimulant amphetamine (1 mg/kg) and barbiturate sodium ethaminal (5 mg/kg) supported their psychoactivating effect on self-stimulation (+30-37%), but fentanyl (0.1 mg/kg) had got no effect. Fentanyl activated self-stimulation moderately only after blockade D1 dopamine receptors with SCH23390. After blockade of CRF receptors, leu-enkephaline strengthened its depressant effect on self-stimulation reaction ( 89%). Therefore, if the modulating influence of the amygdala on the hypothalamus is diminished, the reinforcing effects of opiated (fentanyl) and opioids (leuencephaline) will block, but there will be no effect for psychomotor stimulant amphetamine and barbiturate sodium ethaminal. PMID- 21598679 TI - [Effects of chronic buspirone treatment on female mice exposed to the long lasting psychoemotional influence]. AB - The effects of chronic treatment (30 days) with the 5-HT1A receptor partial agonist buspirone (0.05, 1 and 10 mg/kg i.p.) on the behaviour of C57BL/6J female mice exposed to long-lasting psychoemotional influence were studied. The influence involved forced living of each female with an aggressive male separated with a perforated transparent partition in the same cage and daily female's presence during 10-min intermale confrontations behind a partition caused by introducing of another male to the aggressive male. Chronic buspirone injection (in all used doses) did not affect the behaviour of females estimated in the "partitions" and "open field" tests at the end of the drug treatment. The anxiolytic effect of buspirone only at the dose of 1 mg/kg on the female's plus maze behaviour was revealed. In the Porsolt, test buspirone in the dose of 1 mg/kg caused a slight increase in the duration of immobility indicating a slight pro-depressive effect. Thus, chronic buspirone treatment of females exposed to the long-lasting psychoemotional impact has a different effect on their behaviour depending on the dose and test conditions. PMID- 21598680 TI - [Early ischemic preconditioning against focal transient and permanent brain ischemia in rats: role of collateral circulation]. AB - We hypothesize that early ischemic preconditioning (IPC) can afford protection against focal brief and prolonged cerebral ischemia with subsequent reperfusion as well as permanent brain ischemia in rats by amelioration of regional cerebral blood flow. Adult male Wistar rats (n=97) were subjected to transient (30 and 60 minutes) and permanent middle cerebral artery (MCA) occlusion. IPC protocol consisted of two episodes of 5-min common carotid artery occlusion + 5-min reperfusion prior to test ischemia either followed by 48 hours of reperfusion or not. Triphenyltetrazolium chloride and Evans blue were used for delineation of infarct size and anatomical area at risk (comprises ischemic penumbra and ischemic core), respectively. Blood flow in the MCA vascular bed was measured with use of Doppler ultrasound. The IPC resulted in significant infarct size limitation in both transient and permanent MCA occlusion. Importantly, IPC caused significant reduction of area at risk after 30 min of focal ischemia as compared to controls [med(min-max) 11.4% (3.59-2 0.35%) vs. 2.47% (0.8-9.31%), p = 0.018] but it failed to influence area at risk after 5 min of ischemia [med(min-max) 7.61% (6.32-10.87%) vs. 8.2% (4.87-9.65%), p > 0.05]. No differences in blood flow were found between IPC and control groups using Doppler ultrasound. This is suggestive of the fact that IPC does not really influence blood flow in the large cerebral arteries such as MCA but it might have some effect on smaller arteries. It seems that, along with well established cytoprotective effects of IPC, IPC mediated reduction of area at risk by means of improvement in local cerebral blood flow may contribute to infarct size limitation after focal transient and permanent brain ischemia in rats. PMID- 21598681 TI - [Dehydroepiandrosterone sulfate effect at aldosterone level under cold exposure]. AB - It had been shown that the blockade with dehydroepiandrosterone sulfate (DHEAS) affects enhanced aldosterone level in doses 1, 5 and 30 mg/kg without the dose dependence under multi-repeated cold exposure. These DHEAS effects are realized through micro-opioid receptors. The DHEAS (30 mg/kg) blocking effect was manifested too, but not through micro-opioid receptors under acute cold exposure. PMID- 21598682 TI - [Effect of TRPM8 ion channel activation on thermoregulatory response to cooling]. AB - In rats, the effect of activation of the cold- and menthol-sensitive TRPM8 ion channel on different thermoregulatory parameters: total oxygen consumption, carbon dioxide release, respiration coefficient, constriction response of skin blood vessels, muscle activity, was studied. Activation of TRPM8 with menthol even in thermoneutral conditions produces an increase in oxygen consumption and a decrease in respiratory coefficient, which may suggest enhanced non-shivering thermogenesis and lipolysis. Rapid cooling against the background of TRPM8 activation is characterized by a decrease in the temperature thresholds of all thermoregulatory responses without associated changes in sequences of their initiation as well as in enhancement of metabolic component of emergency thermogenesis which leads to improved maintenance of core temperature in conditions when external cold acts on the organism. The obtained data on the effect of TRPM8 activation on metabolic parameters in thermoneutral conditions and under cooling suggest acontinuous involvement of this receptor in regulation of total metabolism and, possibly, in determination of the type of organism's metabolism as well as in determination of organism's response to external cooling. PMID- 21598683 TI - [The mammalian and the human primary germ cells. Differentiation, identification, migration]. AB - Last years' many new facts on gene expression at the different stages of PGC development were obtained. The process of germline segregation in different species realizes in different manner--as preformation or epigenesis. In the review the mechanisms of the mammalian and the human initial germ cell lineage specification are dicussed. Analysis of data on the identification of PGC from the moment of initial detection in epiblast up to completion of migration to gonadal anlages was performed. Information on the PGC markers of the different stages of development, the mechanisms of PGC migration towards genital ridges and the chemokines that direct migration is discussed. PMID- 21598684 TI - [Stability of bone marrow stromal cells to low temperatures during differentiation]. AB - On the bases of earlier conducted research about the stability of heterogeneous population of keratinocytes to low temperatures according to their stages of differentiation this experiment' studies in vitro the stability to low temperatures of rat bone marrow stromal cells before and after their adipocyte and osteocyte differentiation. Results show that bone marrow stromal cells after their differentiation into either adipocytes or octeocytes became least stable to low temperatures. Findings may serve as foundation for further studies that may explain the changes of processes and mechanisms that play a major role in BMSC stability to low temperatures according to their stage of differentiation. PMID- 21598685 TI - [Change in localization of cellular vesicular apparatus during differentiation of myoblasts into myotubules in cell culture]. AB - The study of changes in the intracellular processes during differentiation of myoblasts into myotubules is of great importance for understanding several fundamental problems of cell biology. At first, this concerns the spatial organization of vacuolar apparatus that reflects the alterations in the properties of cell membranes, cytoskeleton elements and dynamics of vesicular transport in the course of differentiation. The distribution of acidic membrane organelles (lysosomes, late endosomes, Golgi cisternae) during the myotubule formation was revealed. It was shown that perinuclear localization of acidic organelles in myoblasts was replaced by diffuse distribution of these structures in the whole volume of myotubules. Using lipophilic fluorescent dyes, RH 414 and di-8-ANEPPS, the process of formation and dynamics of endocytic vesicles in myoblasts and myotubules was investigated. In the present work, semiconductive nanocrystals, quantum dots (QDs), conjugated with TAT-peptide, which belongs to cell-penetrating peptides, were used to characterize nonspecific endocytosis. It was shown that QDs--TAT complexes penetrate myoblasts but do not penetrate myotubules even after 24 h incubation, which might be connected with plasma membrane changes during the process of skeletal muscle differentiation. PMID- 21598686 TI - [DNA repeated sequences may be involved in the synaptonemal complexes formation]. AB - Synatonemal complexes (SCs) are the intranuclear structures which facilitate reversible lateral synapsis of the homologous chromosomes in the course of meiosis. It is still unclear which DNA nucleotide sequences are responsible for the chromatin attachment to the SC lateral elements. Considering the features of the dispersed repeated sequences (RS) it is worth to assume their participation in the structure functional organization of the meiotic chromosome. Using numerical analysis we have investigated the relationship between RS and the distribution of events of the meiotic recombination in mouse chromosome 1. Using in situ hybridization on spread mouse spermatocytes, we have demonstrated the arrangement of different types of RS relative to SCs. Hybridization signals of B1(Alu), B2, and minisatellite probes were localizating predominantly in the SCs regions. Our results allow us to suggest the model of the meiotic chromosome organization with the RS as the sequences, participating in the attachment of chromatin loops and SCs. PMID- 21598687 TI - [Distribution and ultrastructure of the tyrosine hydroxylase-positive neurons of the central nervous system of bivalve mollusc Megangulus venulosus under the influence of increased temperature and hypoxia]. AB - Using immunocytochemistry combined with light and electron microscopy, the distribution and ultrastructure of tyrosine hydroxylase (TH)-immunoreactive neurons in the CNS of bivalve mollusc, Megangulus venulosus, have been studied under the influence of increased temperature and hypoxia. It has been established, that the stress causes changes in the amount of TH and in the structure of TH-immunopositive neurons in all ganglia. The most essential changes in CNS of M. venulosus were revealed after 60 min exposure to increased temperature and hypoxia; degenerative changes in large neurons, reduction of the synapses and reduction of TH-immunoreactivity in neurons and neuropil. PMID- 21598688 TI - [Regulation of proliferation and viability of tumor cells in vitro by alloferon-1 and allostatin-1]. AB - Alloferon-1 (AF) and allostatin-1 (AS) cytotoxic and growth modulating activities have been compared. AF is cationic oligopeptide isolated from the hemolymph of experimentally infected blow fly Calliphora vicina. AS is AF synthetic analog that differs from the parent molecule in two amino acids substituted. It has been shown that both AF and AS have no direct cytotoxic activity in concentrations ranging from 1 x 10(-1) to 10 microg/ml, however, the peptides demonstrated significant effect on tumor cells proliferation in vitro. Both peptides displayed growth modulating activity in mass cell cultures and boosted growth inhibiting activity of doxorubicin in the course of P388D1 cells cloning, although AS potentated doxorubicin cytostatic activity to a greater extent. Similarly, AS boosted anti-clonogenic activity of cyclophosphamide applied in a subthreshold concentration. Experiments with peptide-fluorescein complex have demonstrated that AF and AS belong to the group of cell-penetrating peptides. Moreover, the experiments displayed AF ability to bind with chromosomes. PMID- 21598689 TI - [Cyclic structural changes in endoplasmic reticulum and Golgi apparatus in the hippocampal neurons of ground squirrels during hibernation]. AB - Repetitive remodeling and renewal of the cytoplasmic structures realizing synthesis of proteins accompanies the cycling of ground squirrels between torpor and arousal states during hibernation season. Earlier we have shown partial loss of ribosomes and nucleolus inactivation in CA3 hippocampal pyramidal neurons in each bout of torpor with rapid and full recovery after warming up. Here we describe reversible structural changes in endoplasmic reticulum (ER) and Golgi complex (G) in these neurons. Transformation of ER from mainly cysternal to tubular form and from mainly granular to smooth type occurs at every entrance in torpor, while the opposite change occurs at arousal. Torpor state is also associated with G fragmentation and loss of its flattened cisternae. Appearance in torpor of the autophagosomal vacuoles containing fragments of membrane structures and ribosomes is a sign of their partial destruction. Granular ER restoration, perhaps through assembly from the multilamellar membrane structures, whorls or bags, begins as early as in the middle of the torpor bout, while G flattened cisternae reappear only at warming. ER and G completely restore their structure 2-3 hours after the provoked arousal. Thus, hibernation represents and example of nerve cell structural adaptation to alterations in functional and metabolic activity through both active destruction and renewal of ribosomes, ER, and G. Perhaps, it is the incomplete ER autophagosomal degradation at torpor provides its rapid renewal at arousal by reassembly from the preserved fragments. PMID- 21598690 TI - [Non-histone skeleton of mitotic chromosome in situ]. AB - Studying giant nuclei of Chironomus plumosus in situ (Makarov, Chentsov, 2010), we concluded that polythene chromosome structure appears after 2 M NaCl and DNase treatment in presence of 2 mM CuCl2. Cu2+ -ions may stabilize bonds between specific non-histone components, arranged into non-histone matrix of polythene chromosome. Here, we investigated the non-histone matrix of pig embryo mitotic chromosomes in situ, using 2 mM CuCl2-stabilization method. In 2 mM CuCl2 stabilized cells the residual chromosome body (non-histone matrix) could be visualized in every stage of mitosis. Mitotic chromosome non-histone matrix had the same reaction on preliminary hypotonic treatment as normal chromosome: different decondensation of non-histone material was observed. Topoisomerase IIalpha and SMC 1 had uniform localization inside chromosomal body and did not form any axial structures. PMID- 21598691 TI - [Cell senescence induced by histone deacetylase inhibitor sodium butyrate in rodent transformed cells resistant to apoptosis]. AB - The capacity of HDAC inhibitor sodium butyrate to induce senescence in cells derived from rat embryonic fibroblasts transformed by E1A+E1B19 kDa oncogenes has been studied. These transformants are resistant to apoptosis in response to gamma irradiation and growth factor deprivation. The process of cell senescence was investigated by the analysis of cell growth curves, G1/S and G2/M cell cycle arrest, and senescent associated beta-galactosidase expression. The irreversibility of sodium butyrate antiproliferative activity was analyzed by clonogenic assay. We show that sodium butyrate suppresses proliferation and induces senescence in the E1A+E1B19 kDa transformed cells. Interestingly, NaB induces growth arrest due to accumulation of cells in G2/M phase, these cells are not tetraploid but mainly binuclear. Thus, in case of NaB induced senescence in E1A+E1B19 kDa transformed fibroblasts, the observed suppression of cell proliferation may be the result of cytokinesis failure leading to formation of binuclear and multinuclear cells incapable to proliferate. PMID- 21598692 TI - [DNA contents in nuclei of Cyclops kolensis and C. insignis (Crustacea, Copepoda)]. AB - Chromatin diminution (CD) in two Cyclopoida species, Cyclops kolensis and C. insignis, was studied by static digital Feulgen cytophotometry. DNA content (pg/cell) was evaluated by standard curves builded up using blood cells of five organisms with known DNA content, which ranged from 1.25 to 14.70 pg. According to data obtained, diploid genome of C. kolensis has about 40 pg DNA before CD and 1.8-2.0 pg DNA after CD. These values are similar for both Moscow and Baikal populations of C. kolensis and 6-10 times exceed estimates made earlier (Grishanin, 2008), Our data confirm that CD in C. kolensis is 94-96% of DNA. In mitotic dividing cells of C. insignis, DNA content was about 7.5 pg both in early and late embryos, and CD was not revealed for this species. The data obtained show that, among Cyclopoida studied, the genome of C. kolensis before CD has a maximum content of DNA. PMID- 21598693 TI - [Does a lateral gradient of membrane potential on the plasma membrane of growing pollen tube of germinating pollen grain exist?]. AB - The data presented in the article by Breigina et al. (2009) "Changes in the membrane potential during pollen grain germination and pollen tube growth" (Tsitologiya. 51 (10): 815-823) and concerning the measurement of electric membrane potential (Delta Psi) on the plasma membrane of growing pollen tube of germinating pollen grain with the use of fluorescent potential-sensitive dye, di 4-ANEPPS, were critically analyzed in order to clarify whether a lateral gradient of Delta Psi on this membrane indeed exists. This analysis showed that the main conclusion of the authors of the above article on the existence of polar distribution of Delta Psi along the pollen tube plasma membrane is not in accordance with a number of known peculiarities of di-4-ANEPPS behavior in biological membranes and requires a significant revision. The findings in question reported by the authors, in my opinion, might be interpreted as evidence for the presence on the plasma membrane of growing pollen tube not only the membrane potential Delta Psi but also lateral gradient of so called intra membrane dipole potential. Based on the comments made, another interpretation of the experimental results described by Breigina et al. has been offered. In addition, some drawbacks in the methodology used by the authors for measurement of Delta Psi with other fluorescent potential-sensitive dye, DiBAC3(3), are also shortly considered. PMID- 21598695 TI - [Siliconorganic reversible inhibitors of cholinesterases of various animals]. AB - The review present data on cholinesterase effects of 28 specially synthesized siliconorganic compounds (monoonium, clementorganic, and bisonium derivatives) studied as reversible inhibitors of acetylcholinesterase (acetyl-ChE) of human erythrocytes, butyryl-ChE of horse blood serum, ChE of brain of common frog Rana temporaria, ChE of the optical ganglia tissue of Pacific squid Todarodes pacificus and of individuals of Commandor squid Berryteuthis magister from various habitats in the Northwestern aquatoria of the Pacific ocean. Among the tested compounds, there are revealed highly specific inhibitors of mammalian ChE as well as of ChE of the B. magister individuals from various habitats. PMID- 21598694 TI - [Neuropeptide Y and autonomic nervous system]. AB - Neuropeptide Y (NPY) containing 36 amino acid residues belongs to peptides widely spread in the central and peripheral nervous system. NPY and its receptors play an extremely diverse role in the nervous system, including regulation of satiety, of emotional state, of vascular tone, and of gastrointestinal secretion. In mammals, NPY has been revealed in the majority of sympathetic ganglion neurons, in a high number of neurons of parasympathetic cranial ganglia as well as of intramural ganglia of the metasympathetic nervous system. At present, six types of receptors to NPY (Y1-Y6) have been identified. All receptors to NPY belong to the family of G-bound proteins. Action of NPY on peripheral organs-targets is predominantly realized through postsynaptic receptors Y1, Y3-Y5, and presynaptic receptors of the Y2 type. NPY is present in large electron-dense vesicles and is released at high-frequency stimulation. NPY affects not only vascular tone, frequency and strength of heart contractions, motorics and secretion of the gastrointestinal tract, but also has trophic effect and produces proliferation of cells of organs-targets, specifically of vessels, myocardium, and adipose tissue. In early postnatal ontogenesis the percent of the NPY-containing neurons in ganglia of the autonomic nervous system increases. In adult organisms, this parameter decreases. This seems to be connected with the trophic NPY effect on cells-targets as well as with regulation of their functional state. PMID- 21598696 TI - [Role of creatine kinase and its substrates in the central nervous system in norm and in various pathologies]. AB - There is presented review of recent publications providing current understanding of role of the creatine kinase-creatine phosphate system and creatine, substrate of creatine kinase, in metabolism of cell and specifically of cells of the central nervous system. Particularly noted are the protector role of creatine at mitochondrial and bioenergetic cell dysfunction and potential significance of creatine supplements at treatment of neurodegenerative and other diseases. PMID- 21598697 TI - [Effect of natural amino acids and sugars on cyclase activities in infusoria Tetrahymena pyriformis and Dileptus anser]. AB - Natural amino acids and sugars in intracellular eukaryotes are known to regulate adenylyl cyclase (AC) and guanylyl cyclase (GC) systems that control the most important cell processes. The goal of the present work consisted in study of effects of natural amino acids and sugars and some of their derivatives on AC and GC activities of infusoria Tetrahymena pyriformis and Dileptus anser. Methionine, arginine, lysine, and tryptamine stimulated basic AC activity of T. pyriformis, whereas alanine, thyrosine, and cysteine decreased it. Methionine, glycine, alanine, thyrosine, arginine, and to the lesser degree tryptamine and histidine stimulated AC of D. anser. The GC activity of T. pyriformis are increased in the presence of tryptamine, tryptophane, histidine, arginine, and lysine, whereas glycine and aspartic acid, on the contrary, decreased it. Tryptamine, tryptophan, leucine, glutamic acid, serine, histidine, and alanine stimulated the GC activity of D. anser. Glucose, fructose, and sucrose stimulated the basal AC activity of both infusorians and GC of T. pyriformis, with glucose and sucrose increasing AC of T. pyriformis twice, while that of D. anser 4.5 times. Lactose stimulated AC and GC of T. pyriformis and was inefficient with respect to the D. anser cyclases, whereas mannose and galactose did not affect the enzyme activities in both infusorians. The study of the chemotactic response of infusorians to amino acids and sugars indicates that involved in realization of this response can be signaling pathways both dependent on and independent of cyclic nucleotides. Thus, it has been established for the first time that several amino acids and sugars affect functional activity of enzymes with cyclase activity of the infusorians T. pyriformis and D. anser. This confirms the hypothesis that at early stages of evolution the large spectrum of comparatively simple natural molecules has a hormone-like action. PMID- 21598698 TI - [Total protein in crawfish hemolymph as a parameter of functional state of animals and biomarker of quality of habitat]. AB - Analysis of total protein in hemolymph was performed by Lowry method on sexually mature crawfish Pontastacus leptodactylus. The total protein content in the crawfish hemolymph was studied for one year. The protein concentration varied widely, amounted to from 12 to 95 mg/ml, and depended on season and the moulting cycle phase. There are presented histograms for distribution of animals for the protein level for different seasons and their character is analyzed. In summer the amount of protein is maximal prior to moult and decreases by 40 % at once after it. There is studied the diapason of total protein concentrations in hemolymph, in which survival of crawfish at unfavorable changes in habitat is maximal. The adaptive possibilities of crawfish with the low protein content are reduced. The crawfish with the protein concentration in hemolymph lower than the "critical" one were submitted for different time by action of hydroquinone (1 g/l) used as a model toxicant. A brief action did not affect the protein content in hemolymph. At a long toxic action the protein level in hemolymph fell, on average, by 40%, which preceded the death of the animals. Possible mechanisms of positive correlation of the protein concentration in the crawfish hemolymph and of their survival at deterioration of quality of the water medium are discussed. PMID- 21598699 TI - [Proteinases of hydrobionts--potential objects of fish feeding]. AB - The review analyzes data on activities and characteristics of proteinases of digestive system and of cathepsins of various tissues in potential preys of fish differing by the character of feeding. There are presented data on multiple forms and molecular mass of proteinases, species-related differences, dependence of proteinase activities on the life cycle stages, type of nutrition, and biochemical food composition as well as on temperature and pH optima. Role of cathepsin in evolution of enzymatic systems providing degradation of food protein components in fish is discussed. PMID- 21598700 TI - [Comparative analysis of phospholipid composition in erythrocytes of mouse-like rodents of different species]. AB - Comparative analysis of phospholipid quantitative composition of blood erythrocytes has been performed in white (laboratory mice and rats) and wild (tundra voles) mouse-like rodents. A non-characteristic of mammals low relative content of sphingomyelin is revealed in erythrocyte phospholipids in tundra voles. A hypothesis is put forward that the unique composition of erythrocyte lipids is a peculiar evolutionary developed strategy of adaptation aimed at survival under condition of constant circulation of agents of leptospirosis in populations of this species. PMID- 21598701 TI - [Dynamics of lipid peroxidation of membranes in cells and mitochondrial fraction of neocortex in non- and preconditioned rats after severe hypobaric hypoxia]. AB - There was studied effect of severe hypobaric hypoxia and subsequent reoxygenation on level and dynamics of lipid peroxidation in membranes of neocortex cells and in mitochondria-enriched neocortex fraction of non-preconditioned rats and of rats preconditioned thrice with a moderate hypobaric hypoxia. The threefold hypoxic preconditioning increasing brain resistance has been shown to significantly prevent disturbance of lipid peroxidation processes in neocortex- one of the most hypoxia-sensitive brain structures--and to modify development of these processes in mitochondria. PMID- 21598702 TI - [Stem cells--targets for antitumor therapy]. PMID- 21598703 TI - [Breast cancer therapy with combination of endocrine and target drugs]. PMID- 21598704 TI - [Computer-assisted diagnosis of nodular lesions in the lung]. PMID- 21598705 TI - [Application of automated quantitative cytometry in diagnosis of lung cancer]. AB - The paper deals with evaluation of the literature data and our experience with automated quantitative cytometric examination of sputum for diagnosis of lung cancer and, in particular, early one. This novel procedure uses measurement of quantitative indices which characterise tumors-induced alterations. The LungSign computerized system was employed to scan cellular nuclei. The results were evaluated by linear discriminative analysis with the aid of ROC-curves and underlying areas. The procedures were run in 248 cases and its sensitivity was significantly higher that of a standard cytological one (36.6% and 13.3%, respectively; p = 0.033), albeit a slight decrease in specificity (93.7% and 100%, respectively; p = 0.003). Automated quantitative cytometric indices varied significantly in cohorts of patients with confirmed (-0.275871) and false ( 1.24990) diagnosis of lung cancer (p = 0.0001). PMID- 21598706 TI - [Investigation of the association of mammographic breast tissue density with glucose effects and circulating stem cells]. AB - Our study involving healthy postmenopausal females established that mammographic breast tissue density was lower in cases of more intensive stimulation by glucose of reactive insulinemia and glucose-induced glyoxalase I activity in bood mononuclears as well as in women with higher concentrations of circulating CD90+stem cells. Conversely, the density tended to increase in those with higher ratio of glucose-induced generation of reactive oxygen species in mononuclears. Our data point to possible mechanisms of increased density as a breast cancer factor when concomitant with relative predominance of progenotoxic effect of glucose and lower CD90+stem cells levels which are believed by some authors to be capable of suppressing the growth of certain tumors. PMID- 21598707 TI - [Locus HS.633957 expression in human gastrointestinal tract and tumors]. AB - Human locus HS.633957 corresponds to its namesake cluster in the UniGene database http:/www.ncbi.nlm.nih.gov/unigene. It is located on chromosome 7 and is 3.7 tpn in size. It does not seem to encode proteins nor has its function been identified. According to bioinformation evidence, its expression is tumor specific. PCR assay on kDNA samples from different intact human tissues detected its slight expression in liver, heart, embryonal brain and kidney as well as in a wide spectrum of tumors. This work features locus Hs.633957 expression in different parts of human gastrointestinal tract and tumors. PMID- 21598708 TI - [Use of sunitinib in metastatic renal cell carcinoma patients with poor prognosis]. AB - We evaluated overall and relapse-free survival in patients with metastatic renal cell carcinoma (MRCC) with poor prognosis. The study involved 92 patients (median age 54.1 years, male 63%, female 29%), retrospectively; 48.9% had poor prognosis. They received oral sunitinib 59 mg/day in 6 cycles (4 weeks on, 2 weeks off). Median overall survival was 17.6 months, relapse-free--10.8 months. Risk of progression in the poor and good prognosis groups was identical (HR=09). Overall response was 29% in poor prognosis and 40%--in good one (p = 0.07). Drug tolerability was acceptable in both groups. Sunitinib was effective in both groups of MRCC patients. PMID- 21598709 TI - [Quality of life, social and psychological rehabilitation of surgical patients with vulvar cancer]. AB - A questionnaire was used to evaluate quality of life of surgical patients with vulvar cancer (stages Ia-Iva). Overall and 5-year survival after combined and surgical treatment (combination of epidermato-fascial plasty unrestricted by closure of wound defects with adjacent tissues) was 86.05 +/- 3.2%, relapse-free- 97.3% and 45.08 +/- 3.5% 57.1 +/- 4.1%, respectively, (p < or = 0.05) in group 1. Screening showed that surgical patients need more as far as quality of life and social rehabilitation are concerned. PMID- 21598710 TI - [A simplified model of growth of solid tumors]. AB - In contrast with a previous work, we suggest that non-proliferating cells remainants in tumor are not depleted throughout its growth. Hence, two scenarios- exponential and logarithmic--are possible. They are essentially in good agreement with experimental data. PMID- 21598711 TI - [Role of tumor-associated macrophages in the regulation of protein biosynthesis in Ehrlich carcinoma cells]. AB - The paper discusses the role of peritoneal macrophages in uptake and metabolic degradation of high-density proteins of lipoproteins in mice with Ehrlich ascites carcinoma. These processes were found to be influenced by cortisol. Distinctions in spectra of endocellular proteins in tumor-associated macrophages and peritoneal ones in intact mice were identified and, in particular, relative to apolipoprotein E level. Our study demonstrated participation of macrophages in tumor cell-mediated regulation of protein biosynthesis rate under the influence of high-density lipoproteins and cortisol. Apolipoprotein E may play a role of mediator of negative feedback in the mechanism of accelerating protein biosynthesis in tumor cells. PMID- 21598712 TI - [Preclinical evaluation of the effect of Metrop GP on acute toxicity and hepatotoxicity of chemotherapy]. AB - Our paper presents the results of preclinical evaluation of the mitigating effect of Metrop GP on the acute toxicity and hepatotoxicity induced by paclitaxel and doxorubicin treatment using functional samples and biochemical and morphological techniques. PMID- 21598713 TI - [Study of photodynamic treatment for P-388 lympho-leukemia in mice]. AB - Data are presented on the results of photodynamic treatment (PDT) of mice DBA2 with transplantable lympho-leukemia P-388. Different regimens of photosensitizer Dimegin and emission were used. Both intravenous PDT and in combination with local PDT should be recommended. PMID- 21598714 TI - [Potential of prevention of metastasizing with the aid of tumor-specific transfer factor]. AB - The report discusses our experimental data in support of biotherapy which uses chemotherapy and antitumor immune treatment with in vivo xenogenic transfer factor polypeptides (TFP) isolated from lymphocytes sensitized to antigens of given tumor. After excision of primary tumor--lung carcinoma of Lewis--mice C57BL/6 were injected intraperitoneally with xenogenic TFP (200 pg/body, twice) and a cytostaic dose of cyclophosphamide. Such adjuvant chemotherapy was found to prevent metastases from spreading to the lung in 100%. The marked anti-metastatic effect of the treatment correlated with recovery of splenic cell mass and its cellular structure, higher levels of large granular lymphocytes in peripheral blood and enhanced functional activity of cytotoxic cells in vitro. Our results point to a possibility of raising efficacy of treating solid malignancies with adjuvant chemotherapy in combination with adoptive immune therapy. PMID- 21598715 TI - [Psychooncology in the making and perspectives]. PMID- 21598716 TI - [MRI features of space-occupying lesions in the breast]. AB - Our study evaluates the correlation between benign and malignant breast masses contrast enhancement, on the one hand, and the type of the vascular net and histological prognosis, on the other. We reviewed the preoperative images of 298 breast masses (benign--95 (32%), malignant--203 (68%)) after dynamic contrast enhancement as well as on the basis of pathomorphological data. Due to use of high-concentration paramagnetic contrast agents in ultra-fast sequences, benign and malignant tumors could be differentiated. The quantitative data on both intensive contrast and ring-shaped enhancement corresponded to the low capillary density in the center of carcinoma which correlated with poor prognosis. PMID- 21598717 TI - [Long-term results of surgery and preoperative hypoxyradiotherapy for colorectal cancer]. AB - Combined treatment for colorectal cancer involving preoperative hypooxyradiotherapy was used to boost targeted irradiation of tumor cells. End results were significantly improved due to the decrease in the number of distant metastases even in cases of poor prognosis because of lymph node involvement. PMID- 21598718 TI - [Postoperative ventral hernia in cancer patients]. AB - Surgical patients with cancer of the stomach, colon and genitals (316) were followed up. Frequencies of postoperative ventral hernia and certain factors of their development were evaluated. It was found that surgical complication occurred in 29.4%, aged 4-192 months. Hernia was mostly registered in gynecological and colorectal cancer patients who had had laparotomy and radiotherapy in their case history. Considering its frequency, postoperative ventral hernia is a serious health problem. PMID- 21598719 TI - [The 85-th anniversary of establishing the first Russian experimental oncology laboratory]. PMID- 21598720 TI - [Cardiac pathology in patients after therapy for Hodgkin's lymphoma]. PMID- 21598721 TI - [Intra-arterial therapy of breast cancer]. PMID- 21598722 TI - [Beyond borders]. PMID- 21598723 TI - [Antiseptic anaphylaxis]. AB - Antiseptics are widely used in medical practice. Their cutaneous secondary effects such as allergic contact dermatitis are well known. However, anaphylactic reactions are less. The scope of this article is to describe antiseptics currently used which cause immediate hypersensitivity reactions. Finally, the diagnostic tools and therapeutic approach will be discussed. PMID- 21598724 TI - [Hymenoptera venom allergy: new diagnostic tools and management]. AB - Anaphylactic reactions to hymenoptera venoms are common and, in our latitudes, mainly concern wasps and bees. Recently, molecular biology techniques have contributed to identifying and to sequencing the major allergens of insect venoms and led to the production of recombinant allergens. Assays for specific IgE directed against these recombinant allergens have recently been made available in clinical practice. They provide considerable assistance in identifying the insect responsible for an anaphylactic reaction, in particular when standard tests are positive for both wasp and bee. This article focuses on these new laboratory tests and also reviews the management of patients experiencing an anaphylactic reaction after hymenoptera sting. PMID- 21598725 TI - [Allergen specific immunotherapy: review of new perspectives]. AB - Allergic diseases constitute a health problem worldwide. More than just a treatment option, the classical desensitization (SIT--Specific immunotherapy) by subcutaneous injection has profiled over time as a unique approach, able to attenuate the immune response to allergic stimuli proved. For a long time conservative, desensitization has now progressed in the knowledge of allergens, in the understanding of the mechanisms involved in immune response and in production techniques. From recombinants to alternative routes of allergen delivery, this article gives an overview of new perspectives and assesses SIT in order to provide guidance to the general physician before choosing to initiate such treatment or not in patients with respiratory allergy. PMID- 21598726 TI - [What to expect from allergy tests?]. AB - Diagnosis in allergology is facing novel challenges because of the availability not only of purified or recombinant allergens, but also of multitests such as allergen micro-arrays. These new diagnostic opportunities contribute to a better understanding of crossreactivities between respiratory and food allergens. In comparison to current diagnosis based on whole allergen extracts, this novel generation of specific IgE tests is expected to provide better information on the risk of reaction to allergens as well as on its severity. However these new technologies are expensive, and will have to be carefully analyzed in terms of medical usefulness and public health costs. PMID- 21598727 TI - [Biomarkers in neuroimmunology]. AB - Biomarkers of clinical relevance are very important in the workup of patients presenting with neurological autoimmune diseases. Nervous biopsy remains often the "gold standard procedure" but is limited in practice due to the risk of complication and insufficient yield. These biomarkers, most often auto antibodies, can be the direct cause of the neurological syndrome or be detected as an epiphenomenon of the pathogenic process. The detection of these biomarkers, when performed in well defined clinical conditions, may help the clinician to establish a definite diagnosis which may in turn facilitate the therapeutic decision. The purpose of this article is to review the biomarkers that are available in daily practice to investigate immune-mediated neurological conditions. PMID- 21598728 TI - [Cardiovascular risk in autoimmune and inflammatory disorders]. AB - Atherosclerosis (ATS) is characterized by an inflammatory process initiated by oxidized LDL in the vessel wall, where activation of cells of the innate and adaptive immune system takes place. ATS is accelerated with an increased risk of cardiovascular (CV) events in systemic autoimmune disorders (AID) such as systemic lupus erythematosus or rheumatoid arthritis (RA). In addition to the traditional CV risk factors, which are over-represented in AID, the underlying chronic inflammation and dysregulation of the immune system play an amplifying role in ATS. Although certain drugs used in AID can increase the CV risk, the control of the disease as permitted by TNF-blocking agents in RA, reduces this risk. The strategies specific to AID to reduce the CV risk remain to be better defined. PMID- 21598729 TI - [The problem of blood pressure targets]. PMID- 21598730 TI - [How are you with patient privacy?]. PMID- 21598731 TI - [Under French law, the mother is the one who gives birth]. PMID- 21598732 TI - [Rene FrydmanL "sorcerer's apprentice" and moralist ]. PMID- 21598733 TI - [Resisting antibiotic resistance]. PMID- 21598734 TI - [Where do we come from?]. PMID- 21598735 TI - [The impact of the cognitive impairment]. AB - Cognitive impairment has a significant medical, social and economic impact. In the aging population there is an increase in the incidence of age-related, chronic, not transmissible pathologies. Among them, an outstanding place is occupied by entities that affect the brain and cause cognitive and behavioral disorders. Neurodegeneration, the main cause of these disorders, is an intrinsic neuronal process ensued from different interacting mechanisms that alter cellular structure and function. As a result, the physiopathologic process of cognitive impairment is partially known, with the consequent lack of antipathogenic medication. Late consultation and diagnosis are consequences of both cultural factors and low medical awareness. The high direct and indirect costs generated by the dementia, maximum expression of the cognitive impairment, strike hardly on patients, family and health systems. Medical and sociosanitary education, prevention by means of the modification of risk factors and the suitable use of symptomatic therapeutic resources are today's available weapons to face the problem. PMID- 21598736 TI - [Diagnosis of Alzheimer's disease for general practitioners: screening instruments and early symptoms]. AB - Despite the increasing prevalence and the potential benefits of early identification, dementias continue to be under-diagnosed. By some estimates, fewer than half of all dementia patients have been diagnosed. AD is particularly under-diagnosed in primary care settings perhaps because patients with early AD may appear entirely appropriate in the context of a brief office visit. This, coupled with increasingly abbreviated office visits and the lack of routine use of mental status exams, make identification of cognitive deficit challenging in the primary care setting. Detection of these patients must be made by the general practitioners, who must know the possibilities to detect and guide the study of them. Patients' screening must include discrimination of forgetfulness and use of mini mental examination. Once the cognitive impairment is suspected we need to continue with neuropsychological assessment for cognitive profile, ancillary studies and CT scan to exclude structural diseases. The appropriate knowledge and training of general practitioners will allow the early diagnosis of these patients and the beginning of preventive actions and adequate symptomatic treatment. PMID- 21598737 TI - [Basis of treatment of dementia. Pros and cons of early versus delayed treatment. Rationale]. AB - The objective of this analysis was to review the clinical benefits of early treatment of Alzheimer's disease focusing on data on the use of inhibitors of acetylcholinesterase. A number of well-done clinical trials show that therapy is effective in dropping the progressive deterioration of cognition and behavior. They also reveal significant benefits to start treatment early. These benefits include behavioral stabilization preserving the independence, in addition to delay cognitive impairment. There is evidence that favors initiating treatment early in the course of dementia and reinforces the need to estimate the behavior and activities to precisely evaluate treatment response. PMID- 21598739 TI - [The dementia patient caregiver]. AB - Dementia results in an important economic, social and personal burden. To care for a patient with dementia can be a trascendent learning experience. At the same time, the caregiver's role can become strenuous physical and mental work. This article reviews the importance of assessing the caregiver from the moment of diagnostic work up, the stages the caregiver goes through in the disease evolution, and the "Caregiver syndrome" where the caregiver can become the "second victim" of dementia. PMID- 21598738 TI - [Cholinesterase inhibitors for treating dementia. Review]. AB - Alzheimer's disease is the most common form of dementia seen in the clinical practice. The principal risk factor is aging. There is not currently any available curative medication. However, there a family of drugs call the cholinesterase inhibitors (donepezile, galantamine and rivastigmine) the enhances cholinergic activity in the CNS. Also, memantine is available is a NMDA receptor modulator. A new transdermal way of administration is available now for rivastigmine. The rivastigmines patches are now a rational alternative focusing in getting more tolerance, better blood levels of the drug and compliance to treatment in Alzheimer's disease patients. PMID- 21598740 TI - Contribution of thebesian veins to the physiologic shunt in anesthetized man. AB - The purpose of the present study is to quantitate the contribution of the thebesian veins to the total physiologic shunt in anesthetized man. The subjects were adults, free of septal defects, who were undergoing a variety of open-heart procedures for the correction of diseased valves. The studies were completed following thoracotomy but prior to the placement of catheters. Subjects were anesthetized, intubated, and ventilated with a constant-volume respirator. Prior to blood sampling 100% oxygen was administered for at least 3 min. Samples were simultaneously drawn from the left atrium and the aorta and analyzed for Po2 with a microelectrode which had been calibrated with tonometered blood. Only studies in which aortic Po2 exceeded 150 mm Hg were accepted. Pco2 and pH were also measured. From the difference in Po2 between left atrium and aorta the contribution of left ventricular thebesian veins to the physiologic shunt was calculated using a modification of the shunt equation. Values found ranged from 0.12 to 0.43% of the aortic flow. Mixed thebesian oxygen content was assumed to be 6 vol % in this calculation, but the value chosen can be shown not to be critical. PMID- 21598741 TI - It's about time. PMID- 21598742 TI - Industry. PMID- 21598743 TI - Environmental tobacco smoke (ETS). PMID- 21598744 TI - Air. PMID- 21598746 TI - Understanding aging and disability perspectives on home care: uncovering facts and values in public-policy narratives and discourse. AB - Every public-policy problem can be defined in terms of its empirical ("facts") and normative ("values") dimensions and the interrelationship between them. An understanding of the connection between facts and values at the foundation of the home care policy debate in the Canadian health-care system is developed through the application of an analytical framework based on the concept of "narrative frame" analysis. The literature on home care policy reports and recommendations is examined within this conceptual structure - including especially publications and reports from the federal government, national organizations, and the aging and disability communities. Finally, observations and conclusions about the significance of home care policy discourse, and of the differences between the aging and disability constituencies in this debate, are offered as a guide for deconstructing the public-policy process. PMID- 21598747 TI - Out of place: mediating health and social care in Ontario's long-term care sector. AB - The paper discusses two reforms in Ontario's long-term care. The first is the commercialization of home care as a result of the implementation of a "managed competition" delivery model. The second is the Ministry of Health and Long-Term Care's privileging of "health care" over "social care" through changes to which types of home care and home support services receive public funding. It addresses the effects of these reforms on the state-non-profit relationship, and the shifting balance between public funding of health and social care. At a program level, and with few exceptions, homemaking services have been cut from home care, and home support services are more medicalized. With these changes, growing numbers of people no longer eligible to receive publicly funded home care services look for other alternatives: they draw available resources from home support, they draw on family and friend networks, they hire privately and pay out of pocket, they leave home and enter an institution, or they do without. PMID- 21598748 TI - To pay or not to pay: examining underlying principles in the debate on financial support for family caregivers. AB - In many countries one approach to supporting family-and-friend caregivers is direct financial or monetary support. Debates about the benefits and consequences of such policies pervade the literature. Building on the premise that values underlie public policy, the paper examines four policy paradoxes in the literature and uses selected examples from an international policy analysis to illustrate the underlying objectives and values upon which many of the policies were developed. These include the responsibility to care, economic or social objectives, gender equity, and the autonomy of care receivers. The authors conclude that policy makers need to be cautious about the unintended effects of financial support policy and develop a menu of policies and services to support caregivers. Future policy development in Canada must enable legitimate choice across the life course and ensure that neither the caregiver nor the care receiver will experience short- or long-term financial consequences of his or her choice. PMID- 21598749 TI - Clinical roundtable monograph. Integrating recent data in managing adverse events in the treatment of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a major cause of cancer-related morbidity and mortality worldwide. In the United States, HCC is the main cause of death in patients with cirrhosis, and the incidence of this malignancy is on the rise. Because HCC is associated with a particularly poor prognosis, emphasis is placed on surveillance of high-risk patients. Early detection allows a greater chance of diagnosing HCC before it has spread, thus increasing the chances that the patient can be potentially cured with surgical techniques such as resection and transplantation. However, most cases of HCC are not diagnosed until at least some of the cancer has spread or multiple nodules exist. For these patients, treatment options include percutaneous and transarterial ablation, as well as systemic chemotherapy. Systemic therapy is now considered the standard of care for patients with advanced tumors. Traditional treatment was based on cytotoxic chemotherapeutic agents, such as doxorubicin. This approach was associated with minimal benefit and a high rate of toxicity. Recently, targeted agents have proven more effective and safer in this setting. The oral multikinase inhibitor sorafenib is now approved for the treatment of unresectable HCC and is currently the only approved agent for advanced HCC. In order to maximize the benefit of sorafenib and other investigational agents for patients with advanced disease, effective interventions have been designed to mitigate their associated adverse events, such as hand-foot skin reactions and hypertension. PMID- 21598750 TI - [Designing of the management of head and neck cancer in Japan--a viewpoint of local medical universities]. PMID- 21598751 TI - [Designing of the management of head and neck cancers--based on the coordinated cancer care system adopted in Osaka District]. PMID- 21598752 TI - [Current status of super-selective arterial infusion therapy]. PMID- 21598753 TI - ["Omics" study of diseases]. PMID- 21598754 TI - [Expectations on otorhinolaryngology by other medical specialties--expectations by clinical researchers of internal medicine]. PMID- 21598755 TI - [Conservative treatment of deglutition disorders--toward the practice of deglutition rehabilitation based on scientific findings]. PMID- 21598756 TI - [Day surgery to correct chronic nasal obstruction--with a special reference to cautery of the mucosa of the inferior nasal turbinate]. PMID- 21598757 TI - [Diagnostic sequence for olfactory disorders]. PMID- 21598759 TI - [Health service research (6). Evaluation of regional care activities]. PMID- 21598758 TI - [Social determining factors in health (9). Falls and fractures of the aged]. PMID- 21598760 TI - [Public health with scientific examination of the society and health (2). Socio epidemiology--its methodological characteristics and examples of their application]. PMID- 21598761 TI - Pseudoangiomatous stromal hyperplasia with giant cells in the female breast. No association with neurofibromatosis? AB - A simultaneous finding of pseudoangiomatous stromal hyperplasia (PASH) and stromal multinucleated giant cells (MGC) in mammary tissue was previously observed in patients with type-1 neurofibromatosis, indicating that it can represent a morphologic marker for this syndrome. Here, we present PASH with MGC occurring in the left breast of a 39-years-old woman who does not have neurofibromatosis. This case, along with two additional ones reported previously, indicates that PASH with MGC in the female breast may not be associated with neurofibromatosis. PMID- 21598762 TI - Immunolocalization of protein-bound 3-nitrotyrosine in inflammatory myopathies. AB - 3-nitrotyrosine (3NT) is regarded as a "footprint" of nitric oxide generation. The study aimed at documenting the presence and distribution of 3-nitrotyrosine (3NT) in muscle tissue samples from patients with idiopathic inflammatory myopathies (IIM) as well as from those with non-inflammatory myopathies to consider whether polymyositis (PM) and dermatomyositis (DM) could be distinguished based on 3NT immunohistochemistry in muscle biopsy. Cryosections prepared from muscle biopsies of 54 patients with either IIM, i.e., PM and DM, or various non-inflammatory myopathies were immunostained using monoclonal antibody against 3NT. The 3NT immunostaining was localized to endothelial cells and their close surroundings in muscle biopsies of DM and PM patients but only in those areas of tissue sections where inflammatory cell infiltrates were present. No 3NT positivity was found in tissue sections of IIM patients without inflammatory infiltrates in the studied sample as well as in muscle tissue sections of patients with non-inflammatory myopathies. However, the endothelial cells were also positive in cases of confirmed non-inflammatory myopathies with secondary lymphocytic infiltration (myodystrophies, myasthenia gravis). Despite the pathogenetic significance, the 3NT immunohistochemistry is of low diagnostic value for the differential diagnosis of IIM in muscle biopsy. PMID- 21598763 TI - Study of morphological changes in the skin of the neck in suicidal cases by hanging. AB - PURPOSE: the morphologic changes in specimens from people who have committed suicide by hanging have mainly centered on macroscopic findings. Pour purpose is to inestigate the microscopis changes in the ligature marks. METHODS: we report the histopathologic features of the ligature mark on the neck of three people who committed suicide by hanging themselves. RESULTS: the main Finding was coagulative necrosis of all cutaneous layers and the subjacent striated muscle. In the areas close to the ligature, blood vessels appeared congestive with a mild inflammatory perivasculary infiltrate. In some other areas, we found preserved sebaceous and eccrine glands, underneath the epidermis with marked necrotic changes. CONCLUSIONS: These findings suggest that neither pressure nor hypoxia is enough to induce necrosis in cutaneous adnexa. PMID- 21598764 TI - Influence of the application renewal of glutamate and tartrate on Cd, Cu, Pb and Zn distribution between contaminated soil and Paulownia tomentosa in a pilot scale assisted phytoremediation study. AB - The influence of repeated applications of tartrate (TAR) and glutamate (GLU) at 50-mmol kg(-1) of soil on Cd, Cu, Pb, and Zn distribution between a contaminated soil and Paulownia tomentosa was investigated. TAR and GLU were applied by a single or a double dosage, the latter carried out with an interval between the two applications of thirty days. The comparison of the differences in mean amounts of metals accumulated in the whole plant at the end of single and double TAR and GLU application experiments indicated the positive effect of repeated GLU applications on the accumulation of Cu, Pb, and Zn by Paulownia tomentosa as compared to untreated controls. A similar effect was not observed for the TAR treatments. When soil treated with either TAR or GLU was compared with untreated controls, no significant effect on heavy-metal concentrations in the soil solution was observed 30 days after treatment, suggesting the absence of an increase of the long-term leaching risk of heavy metals in aquifers and surface waters due to the ligand application. A cost analysis of the treatment is also reported. PMID- 21598765 TI - Revegetation of a uranium mine dump by using fertilizer treated sessile oaks. AB - The rehabilitation of contaminated sites and the establishment of suitable trees for revegetation purposes is often problematic due to the mostly suboptimal nutrient supply and the poor humus reservoir. For these reasons hydrogels (Stockosorb) and novel humus substitutes (NOVIHUM), serving as long lasting fertilizer (LLF), were recently tested successfully. At the beginning of this multiyear study, those LLFs were administered to the root zone of young sessile oaks (Quercus petraea (Mattuschka) Liebl.), growing in test trials on a uranium mine dump in Schlema (Germany). To quantify the effect of LLFs on plant vitality, chlorophyll a fluorescence measurements and JIP test analyses were used. The results revealed up to 49% higher average photosynthetic vitality (PI(ABS)) of the LLF treated plants compared to controls. Particularly in the first test year, the efficiency of photosynthetic electron transport was strongly increased. This stimulation of photosynthetic activity was supported by direct measurements showing up to 129% increased diameter growth of the treated plants after a four year experimental period. Furthermore an increase of the maximum water holding capacity of the dump soil was attained by using LLFs. Overall, the findings reported here represent a feasible, ecologically justifiable reforestation method with a low environmental hazard potential. PMID- 21598766 TI - Phytoremediation of arsenic in submerged soil by wetland plants. AB - Wetland aquatic plants including Canna glauca L., Colocasia esculenta L. Schott, Cyperus papyrus L. and Typha angustifolia L. were used in the phytoremediation of submerged soil polluted by arsenic (As). Cyperus papyrus L. was noticed as the largest biomass producer which has arsenic accumulation capacity of 130-172 mg As/kg plant. In terms of arsenic removal rate, however, Colocasia esculenta L. was recognized as the largest and fastest arsenic remover in this study. Its arsenic removal rate was 68 mg As/m2/day while those rates of Canna glauca L., Cyperus papyrus L. and Typha angustifolia L. were 61 mg As/m2/day, 56 mg As/m2/day, and 56 mg As/m2/day, respectively. Although the 4 aquatic plants were inferior in arsenic accumulation, their high arsenic removal rates were observed. Phytostabilization should be probable for the application of these plants. PMID- 21598767 TI - Economic incentive for applying vetiver grass to remediate lead, copper and zinc contaminated soils. AB - The application of vetiver grass (Chrysopogon zizaniodes) for phytoremediation of heavy metal contaminated soils can be promoted by economic return through essential oil production. Four levels of lead (0, 500, 2000, and 8000 mg kg(-1) dry soil), copper (0, 100, 400, and 1600 mg kg(-1) dry soil) and zinc (0, 400, 1600, and 6400 mg kg(-1) dry soil) were used to study their effects on vetiver growth, essential oil composition and yield. This study also investigated the effect of nitrogen concentrations on vetiver oil yield. Vetiver accumulated high concentrations of Pb, Cu and Zn in roots (3246, 754 and 2666 mg kg(-1), respectively) and small amounts of contaminants in shoots (327, 55, and 642 mg kg(-1), respectively). Oil content and yield were not affected at low and moderate concentrations of Cu and Zn. Only the application of Pb had a significant detrimental effect on oil composition. Extraction of vetiver essential oils by hydrodistillation produced heavy metal free products. High level of nitrogen reduced oil yields. Results show that phytoremediation of Cu and Zn contaminated soils by vetiver can generate revenue from the commercialization of oil extracts. PMID- 21598768 TI - Mycorrhizo-remediation of lead/zinc mine tailings using vetiver: a field study. AB - A field study of Pb/Zn mine tailings was conducted to assess the influence of AM fungi and refuse compost on phytoremediation using vetiver grass slips. Our investigation revealed that vetiver could thrive on Pb/Zn mine tailings. The addition of refuse compost resulted in biomass that was more than 3-times higher when compared with the control, and were mainly attributed to an improvement of soil properties, as well as better nutrient supply than untreated control. AMF inoculation also significantly increased the dry matter of vetiver by a rate of 8.1-13.8%. It was observed that concentrations of N and P in the shoots were significantly higher in mycorrhizal treatments than those without AMF inoculation. However, AMF inoculation significantly decreased the metal concentrations in root, but not in shoot. Based on the results, it seems clear that AMF can play an essential role in the phytostabilization of metal contaminated soils. PMID- 21598769 TI - Hydroponic screening of willows (Salix L.) for lead tolerance and accumulation. AB - Lead tolerance and accumulation in five willow clones were investigated using a nutrient film technique. Plants were exposed to 0, 48, 121, 169, or 241 microM Pb for 14 days. Tolerance indices (TI) and critical toxicity thresholds (EC50) were determined for five willow clones. SX61 had the highest TI values (92%) in the 48 and 121 microM Pb treatments, as well as the highest EC50 threshold values (70.5 microM for roots, 155.9 microM for aboveground tissue), indications of a high degree of tolerance to Pb. This clone also developed the highest biomass of all the clones tested. We found significant variation in willows' lead accumulation. The highest Pb content in roots (24 mg plant(-1)) and aboveground tissue (7.6 mg plant(-1)) was recorded in the 48 microM Pb treatment in SX61. Based on high biomass, TI, ECso, and Pb content in plant tissues, SX61 holds promise for phytoextraction of lead. PMID- 21598770 TI - Cadmium triggers Elodea canadensis to change the surrounding water pH and thereby Cd uptake. AB - This study was aimed to investigate the influence of Elodea canadensis shoots on surrounding water pH in the presence of cadmium and the effect of plant-induced pH on cadmium uptake. The pH change in the surrounding nutrient solution and Cd uptake by Elodea shoots were investigated after cultivation of various plant densities (1, 3, 6 plants per 500 ml) in hydroponics at a starting pH of 4.0 and in the presence of different concentrations of cadmium (0, 0.1, 0.5 microM). Cadmium uptake was also investigated at different constant pH (4.0, 4.5, 5.5 and 6.5). To investigate if the pH change arose from photosynthetic activities, plants were grown under light, darkness or in the presence of a photosynthetic inhibitor, 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), and 0.5 microM cadmium in the solution. Elodea had an ability to increase the surrounding water pH, when the initial pH was low, which resulted in increased accumulation of Cd. The higher the plant density, the more pronounced was the pH change. The pH increase was not due to the photosynthetic activity since the pH rise was more pronounced under darkness and in the presence of DCMU. The pH increase by Elodea was triggered by cadmium. PMID- 21598771 TI - Chromium bioaccumulation in rice grown in contaminated soil and irrigated mine wastewater--a case study at South Kaliapani chromite mine area, Orissa, India. AB - The level of chromium (Cr) contamination in soils and irrigated mine wastewater at South Kaliapani chromite mine region of Orissa, (India) were investigated. Chromium bioaccumulation in rice plants (Oryza sativa L. cv. Khandagiri) irrigated with Cr+6 contaminated mine wastewater was analyzed along with its attenuation from mine wastewater. The levels of Cr+6 in irrigated mine wastewaters in successive rice grown plots were analyzed on 75 days and 100 days after transplantation of seedlings. Total chromium content in different parts of rice plants and soil samples from different plots was analyzed during harvesting stage (125 days after transplantation). Cr accumulation was significantly high in surface soils (0-20 cm) with a mean value of 11,170 mg kg(-1), but it decreased significantly after the crop harvest. About 70% to 90% reduction of Cr+6 levels was observed in irrigated mine wastewater when passed through successive rice plots. High bio-concentration of Cr in leaves with values ranging from 125-498 mg kg(-1) as compared to stem (25-400 mg kg(-1)) and grain (5-23 mg kg(-1)) was noticed. The reduction of Cr+6 levels is related to plant age, high biomass and area of water passage and was attributed to rhizofiltration technique. PMID- 21598772 TI - Removal of chromium on Polyalthia longifolia leaves biomass. AB - Adsorption is an environmental friendly process for removal and/or recovery of heavy metals from wastewater. In recent years, it has been substantiated as a popular technique to treat industrial waste effluents, with significant advantages. In this work, batchwise removal of chromium (III) ions from water by Polyalthia longifolia leaves was studied as a function of adsorbent dose, pH, contact time, and agitation speed. Surface characteristics of the leaves were evaluated by recording IR spectra. The Langmuir, Freundlich, and Temkin adsorption isotherms were employed to explain the sorption process. It was found that one gram of leaves can remove 1.87 mg of trivalent chromium when working at pH 3.0. It has been concluded that Polyalthia longifolia leaves can be used as cost-effective and benign adsorbents for removal of Cr(III) ions from wastewater. PMID- 21598773 TI - Exploration of the ability of Coleus blumei to accumulate aluminum. AB - In this study, the capacity of an ornamental species (Coleus blumei) to extract and accumulate aluminum was evaluated. The analyzed parameters were amount of soluble aluminum, radical growth, tolerance rate, bioaccumulation factor, and tissues aluminum concentration. The main limiting factor for aluminum accumulation is the availability of the metal. However, Coleus blumei can grow and accumulate up to 1445.7 mg kg(-1) of aluminum dry base. This plant can play an important role in the treatment of polluted water with metals, since it can grow in conditions with a pH of around 4.8. The aluminum tolerance rate showed for this plant ranged between 18.8% and 25%. Therefore, this species behaves as a non-accumulator, even though the bioaccumulation factor was 3098.5 L kg(-1). PMID- 21598774 TI - Chelator-buffered nutrient solution is ineffective in extracting Ni from seeds of Alyssum. AB - Hyperaccumulator species of the genera Alyssum can accumulate 100 times more Ni than normal crops and are therefore used for phytomining and phytoextraction of nickel contaminated soils. Basic studies on the physiology and metal uptake mechanisms of these plants are needed to increase efficiency and uptake capacity of Nickel (Ni) by hyperaccumulators. Recent attempts to disclose if those hyperaccumulator species require higher Ni level than normal plants failed because of the high Ni content in the seeds (7000-9000 microg g(-1)). In this study, we attempted to use chelator buffered nutrient solution to deplete Ni from the seed/seed coat and to obtain low Ni seedlings of Alyssum cultivars to be used in physiology studies. HEDTA-buffered nutrient solution did not deplete Ni from the seeds, perhaps because Ni was mainly localized within the seedling embryonic tissues with greatest Ni enrichment in the cotyledons and hypocotyls. We could not observe any positive correlation between seed fitness and germination capacity with seed Ni content. Investigation of nickel localization in Alyssum seeds using synchrotron X-ray microfluorescence (micro-SXRF) showed that nickel is localized in the embryonic tissues with greatest Ni enrichment observed in the cotyledons and hypocotyl. PMID- 21598775 TI - Responses of bioaugmented ryegrass to PAH soil contamination. AB - The physiological and biochemical responses of ryegrass (Lolium multiflorum) to PAH induced stress in soils contaminated with phenanthrene and pyene were investigated, in the presence of PAH-degrading bacteria (Acinetobacteria junii) or arbuscular mycorrhizal fungi (AM fungi, Glomus mossae). The parameters monitored included chlorophyll content, chlorophyll a/b ratio, soluble carbohydrate content, soluble-protein, malondialdehyde and electrolyte leakage, and superoxide dismutase (SOD) and peroxidase (POD) activities. Ryegrass showed good resistance and acclimation to PAH stress in soil, however, PAH contamination resulted in adverse effects such as damage of photosynthetic function and acceleration of shoot senescence. At PAH level of 100 mg kg(-1), chlorophyll contents were 14% lower than control (no PAH). Activities of SOD and POD were more sensitive indicators of PAH stress as compared to other parameters. However, all parameters showed trends based on either the bioaugmentation of the plants or PAH treatment level. It was concluded that the inoculation of AMF and PAH degrading bacteria, especially the former, have a positive effect on alleviation of PAH toxicity to ryegrass plants. Furthermore, the inoculation of AMF increased the shoot and biomass of ryegrass by 11-19% and 18-78%, respectively. Bioaugmented ryegrass plants show promise as a host plants in the phytoremediation of PAH contaminated soils. PMID- 21598776 TI - Physiological responses of mangrove Sonneratia apetala Buch-Ham plant to wastewater nutrients and heavy metals. AB - Mangroves play an important role for removing nutrients, heavy metals, and other pollutants in wetland ecosystems. This study investigated the physiological responses of a mangrove plant (i.e., Sonneratia apetala Buch-Ham) to different wastewater pollution levels. Four different treatments, namely three concentration levels (i.e., normal, five-time-greater than normal, and ten-time greater than normal) of wastewaters and one control (i.e., salted water), were used to grow the mangrove plants. Results showed that the height and biomass of the plant increased with wastewater pollution levels. No significant differences in root and catalase activities were observed among different treatments, whereas the increases in peroxidase and superoxide dismutase activities were attributed to the need for detoxification. In general, leaf chlorophyll content increased with wastewater pollution levels due to the increase in nutrient contents. PMID- 21598777 TI - Phytoremediation of Cr(VI) by Spirodela polyrrhiza (L.) Schleiden employing reducing and chelating agents. AB - Phytoremediation of Cr(VI) by Spirodela polyrrhiza in binary combinations with low molecular weight organic compounds (LMWOCs) with a reducing or chelating potential, viz., ascorbic acid, citric acid, tartaric acid, oxalic acid, lactic acid, and glycerol was studied in Cr(VI) containing hydroponic media. Significant increase in the relative dry weight of plants with respect to Cr(VI) treated controls was observed with ascorbic acid and glycerol. The uptake of chromium by S. polyrrhiza followed Michaelis-Menten kinetics of active ion uptake. Interaction between Cr and ascorbic acid, oxalic acid, and lactic acid decreased Cr uptake, whereas citric acid, glycerol, and tartaric acid increased it. Supplementation of LMWOCs to Cr(VI) containing media decreased the MDA content of the plants. Multiple regression models revealed that LMWOCs decrease lipid peroxidation independently, as well as that induced by Cr(VI). It was found that superoxide dismutase (SOD), guaiacol peroxidase (GPX), and catalase (CAT) activities were increased significantly in plants growing in media containing Cr(VI). The study established that lactic acid, citric acid, ascorbic acid, and glycerol were most effective in increasing the Cr(VI) phytoremediating potential of S. polyrrhiza and LMWOCs with reducing or chelating properties decrease Cr(VI) stress in S. polyrrhiza. PMID- 21598778 TI - Effects of exogenous glycinebetaine and trehalose on lead accumulation in an aquatic plant (Lemna gibba L.). AB - This study was aimed at investigating and comparing the effects of exogenous glycinebetaine (GB) and trehalose (TR) on lead (Pb) accumulation in Lemna gibba. Two-way ANOVA showed that both GB and TR had significant effects on Pb accumulation. However, TR seemed to be more effective than GB. It was determined that 5 mM GB application decreased Pb accumulation whereas 0.5 mM TR increased and 2 and 5 mM decreased Pb accumulation. The results obtained from this study will be useful for examining the phytoremediation of polluted water using aquatic plants. PMID- 21598779 TI - Inorganic materials as ameliorants for soil remediation of metal toxicity to wild mustard (Sinapis arvensis L.). AB - The ameliorating effects of different inorganic materials were investigated on a soil originating from a zinc smelter dumping site contaminated by toxic metals. Wild mustard (Sinapis arvensis L.) was used as a test plant. The soil was amended with different doses of mining sludge, Perferric Red Latosol (LVj), steel shots, cyclonic ash, silifertil, and superphosphate. The most effective amendments improved plant growth with 45% and reduced metal uptake by over 70% in comparison to untreated soil. Reductions in availability as estimated by BaCl2-extractable metals reached up to 90% for Zn and 65% for Cd as compared to unamended soil. These reductions were associated with lower shoot and root metal contents. Shoot Zn content was reduced from 1,369 microg g(-1) in plants grown on untreated soil to 377 microg g(-1) when grown on cyclonic ash amended soil while Cd decreased from 267 to 44 microg g(-1) in steel shots amended soil. Superphosphate addition had no ameliorating effect. On the contrary, it increased BaCl2-extractable amounts of Zn. Considering all parameters we determined, steel shots, cyclonic ash and silifertil are the most promising for remediating metal contaminated soil in the tropics. Further studies evaluating impacts, cost-effectiveness and durability of effects will be conducted. PMID- 21598780 TI - Efficacy of lime, biosolids, and mycorrhiza for the phytostabilization of sulfidic copper tailings in Chile: a greenhouse experiment. AB - Inadequate abandonment of copper mine tailings under semiarid Mediterranean climate type conditions has posed important environmental risks in Chile due to wind and rain erosion. There are cost-effective technologies for tailings stabilization such as phytostabilization. However, this technology has not been used in Chile yet. This study evaluated in a greenhouse assay the efficacy of biosolids, lime, and a commercial mycorrhiza to improve adverse conditions of oxidized Cu mine tailings for adequate establishment and grow of Lolium perenne L. var nui. Chemical characterization of experimental substrates and pore water samples were performed; plant density, biomass production, chlorophyll content, and metal content in shoots was evaluated in rye grass plants after an eight-week growth period. Results showed that neutralization of tailings and superficial application of biosolids increased both aerial biomass production and chlorophyll content of rye grass. Increased Cu solubilization and translocation to shoots occurred after biosolids application (mixed), particularly on unlimed tailings, due to formation of soluble organometallic complexes with dissolved organic carbon (DOC) which can be readily absorbed by plant roots. Positive effects of mycorrhizal inoculation on rye grass growth were restricted to treatments with superficial application of biosolids, probably due to Cu toxicity effects on commercial mycorrhiza used (Glomulus intraradices). PMID- 21598781 TI - Inoculation of Ni-resistant plant growth promoting bacterium Psychrobacter sp. strain SRS8 for the improvement of nickel phytoextraction by energy crops. AB - This study was conducted to elucidate effects of inoculating plant growth promoting bacterium Psychrobacter sp. SRS8 on the growth and phytoextraction potential of energy crops Ricinus communis and Helianthus annuus in artificially Ni contaminated soils. The toxicity symptom in plants under Ni stress expressed as chlorophyll, protein content, growth inhibition, and Fe, P concentrations were studied, and the possible relationship among them were also discussed. The PGPB SRS8 was found capable of stimulating plant growth and Ni accumulation in both plant species. Further, the stimulation effect on plant biomass, chlorophyll, and protein content was concomitant with increased Fe and P assimilation from soil to plants. Further, the induction of catalase and peroxidase activities was also involved in the ability of SRS8 to increase the tolerance in both plant species under Ni stress. The findings suggest that strain SRS8 play an important role in promoting the growth and phytoextraction efficiency of R. communis and H. annuus, which may be used for remediation of metal contaminated sites. PMID- 21598782 TI - Accumulation and soil-to-plant transfer of radionuclides in the Nile Delta coastal black sand habitats. AB - The radionuclide content was estimated in the soil of three black sand habitats in the Mediterranean coast of Egypt, namely, sand mounds and coastal sand planes and dunes. In addition, a total of 14 heavy minerals found in the soils were characterized. The soil to plant transfer of uranium and thorium was tested on three black sand species, namely, Cakile maritima Scop., Senecio glaucus L. and Rumex Pictus Forssk. The transfer of thorium and uranium radionuclides from the soil to plant is complex process that is subjected to many variables; among which are the organic matter and clay content of the soil, the type of radionuclides and plant species. The study revealed a strong negative relationship between uranium and thorium uptake by S. glaucus and R. pictus and the clay and organic matter content of soil. Concentration of thorium in the soil has a negative correlation with soil-to-plant transfer factor. The study results suggest the possibility of using black sand species for phytoremediation of soils contaminated with radioactive elements. The potentiality of S. glaucus as phytoremediator of radionuclides polluted soils is greater than R. pictus which in turn outweigh C. maritima. PMID- 21598783 TI - The potential of established turf cover for cleaning oily desert soil using rhizosphere technology. AB - The rhizosphere of two turf cover sorts; Bermuda grass and American grass contained high numbers, 8.1 to 16.8 x 10(6) g(-1) of cultivable oil-utilizing and diazotrophic bacteria belonging predominantly to the genera Agrobacterium, Arthrobacter, Pseudomonas, Gordonia, and Rhodococcus. Those bacteria also grew on a nitrogen-free medium and demonstrated the ability to reduce acetylene to ethylene. These isolates grew on a wide range of n-alkanes (C9 to C40) and aromatic hydrocarbons, as sole sources of carbon. Quantitative determinations revealed that predominant bacteria consumed crude oil and representative aliphatic (n-octadecane) and aromatic (phenanthrene) hydrocarbons efficiently. The fact that those organisms had the combined activities of hydrocarbon utilization and nitrogen-fixation makes them suitable tools for bioremediating oily desert areas that are normally poor in nitrogenous compounds. Phytoremediation experiments showed that spreading turf cover on oily desert soil inhibited oil volatilization and enhanced oil loss in soil by about 15%. Oil loss was also enhanced in turf free soil samples fertilized with NH4NO3. In conclusion, covering this oil-polluted soil with turf cover minimized atmospheric pollution, increased the numbers of the oil-utilizing/nitrogen-fixing bacteria by about 20 to 46% thus, encouraging oil attenuation. PMID- 21598784 TI - Mercury uptake and translocation in Impatiens walleriana plants grown in the contaminated soil from Oak Ridge. AB - Mercury (Hg) contaminated soils from Oak Ridge, Tennessee were investigated for phytoavailability of mercury as measured by degree of Hg translocation in aboveground biomass of Impatiens walleriana plants grown in the soils. After 90 days of incubation, results revealed a higher concentration of total Hg in the leaves than in the flowers or the stems. Plants that were grown in the soils with higher Hg concentrations showed significantly higher Hg uptake and translocation in the aboveground plant-biomass, and the correlation with the initial soil-Hg was significant for the leaves and the stems in the plants that were tested. On an average, only 4.06 microg of Hg could be found in the above ground plant biomass of all the plants, compared to an average 3673.50 microg of initial total Hg concentrations in these soils. Statistical analysis revealed a greater affinity of Hg for the soil carbon, which supported the finding of this study on low soil Hg bioavailability. PMID- 21598785 TI - The potential of Thelypteris palustris and Asparagus sprengeri in phytoremediation of arsenic contamination. AB - The potential of two plants, Thelypteris palustris (marsh fern) and Asparagus sprengeri (asparagus fern), for phytoremediation of arsenic contamination was evaluated. The plants were chosen for this study because of the discovery of the arsenic hyperaccumulating fern, Pteris vittata (Ma et al., 2001) and previous research indicating asparagus fern's ability to tolerate > 1200 ppm soil arsenic. Objectives were (1) to assess if selected plants are arsenic hyperaccumulators; and (2) to assess changes in the species of arsenic upon accumulation in selected plants. Greenhouse hydroponic experiments arsenic treatment levels were established by adding potassium arsenate to solution. All plants were placed into the hydroponic experiments while still potted in their growth media. Marsh fern and Asparagus fern can both accumulate arsenic. Marsh fern bioaccumulation factors (> 10) are in the range of known hyperaccumulator, Pteris vittata Therefore, Thelypteris palustris is may be a good candidate for remediation of arsenic soil contamination levels of < or = 500 microg/L arsenic. Total oxidation of As (III) to As (V) does not occur in asparagus fern. The asparagus fern is arsenic tolerant (bioaccumulation factors < 10), but is not considered a good potential phytoremediation candidate. PMID- 21598786 TI - Role of mycorrhizal colonization in plant establishment on an alkaline gold mine tailing. AB - The potential role of arbuscular mycorrhizal fungi (AMF) in the revegetation of an alkaline gold mine tailing was studied in Barberton, South Africa. The tailing, characterized by a slow spontaneous plant succession, is colonized by the shrub Dodonaea viscosa and the grasses, Andropogon eucomus and Imperata cylindrica, all colonized by AMF. The effectiveness of mycorrhizal colonization in grasses was tested under laboratory conditions using fungal isolates of various origins. Both grasses were highly mycorrhiza dependent, and the presence of mycorrhizal colonization significantly increased their biomass and survival rates. The fungi originating from the gold tailing were better adapted to the special conditions of the tailing than the control isolate. Although the total colonization rate found for native fungi was lower than for fungi from non polluted sites, they were more vital and more effective in promoting plant growth. The results obtained might serve as a practical approach to the phytostabilization of alkaline gold tailings. PMID- 21598787 TI - Technical note: Vetiver can grow on coal fly ash without DNA damage. AB - Fly ash is a by-product of coal-fired electricity generation plants. The prevalent practice of disposal is as slurry of ash and water to open lands or ash ponds located near power plants and this has lain to waste thousands of hectares all over the world. Wind and leaching are often the causes of off-site contamination from fly ash dumpsites. Vetiver (Vetiveria zizanioides) grown on fly ash for three months showed massive, mesh-like growth of roots which could have a phytostabilizing effect. The plant achieved this without any damage to its nuclear DNA as shown by comet assay done on the root nuclei, which implies the long-term survival of the plant on the remediation site. Also, when Vetiver is used for phytoremediation of coal fly ash, its shoots can be safely grazed by animals as very little of heavy metals in fly ash were found to be translocated to the shoots. These features make planting of Vetiver a practical and environmentally compatible method for restoration of fly ash dumpsites. Lack of DNA damage in Vetiver has been compared to that in a sensitive plant i.e. Allium cepa. Our results suggested that apart from traditional end-points viz. growth parameters like root length, shoot length and dry weight, comet assay could also be included in a battery of tests for initial, rapid and effective selection of plants for restoration and phytoremediation of polluted sites. PMID- 21598788 TI - Effects of amendments on copper, cadmium, and lead phytoextraction by Lolium perenne from multiple-metal contaminated solution. AB - Chemical amendments can increase metal uptake by plant roots and translocation to shoots, however their effectiveness can be influenced by the presence of other amendments and metal ions in a multiple-metal environment. A range of amendments and combinations were tested to explore their effect on phytoextraction of Cu, Cd, and Pb by perennial ryegrass (Lolium perenne) from solutions containing one or more of these metals. The amendments studied included EDDS (an aminopolycarboxylic acid), histidine (an amino acid), citric acid (an organic acid), rhamnolipid (a biosurfactant) and sulfate (an inorganic ligand). For all amendment treatments, the presence of multiple metals in solution reduced shoot concentrations of Cd and Cu, while Pb levels in shoots were generally enhanced by the presence of Cu. Although slightly toxic to the plants, EDDS (1 mM) was the most effective individual amendment for enhancing shoot metal uptake and translocation from solution without significantly reducing biomass yield. The combination Rhm+Cit+EDDS resulted in the highest shoot metal concentrations of all the treatments but also caused severe phytotoxicity. Amendment combinations Rhm+His and Sulf+Cit were less toxic for plant growth while moderately enhancing metal mass accumulation in shoots and thus could be considered as alternative treatments for enhanced phytoextraction. PMID- 21598789 TI - Endophytic fungus improves growth and metal uptake of Lolium arundinaceum Darbyshire ex. Schreb. AB - The effect of endophyte infection on plant growth, cadmium (Cd) uptake, and Cd translocation was investigated using tall fescue (Lolium arundinaceum) grown in greenhouses in contaminated solution. Endophyte infection significantly increased tiller number and biomass of the host grass under both control and Cd-stress conditions. Endophyte infection not only enhanced Cd accumulation in tall fescue, but also improved Cd transport from the root to the shoot. Under 20 mg L(-1) Cd stress, the phytoextraction efficiency of endophyte-infected (EI) tall fescue was 2.41-fold higher than endophyte-free plants. Although the total Cd accumulation in EI tall fescue was insufficient for practical phytoextraction applications, the observed high biomass production and tolerance of stress from abiotic factors including heavy metals, gives endophyte/plant associations the potential to be a model for endophyte-assisted phytoremediation of metal-polluted soils. PMID- 21598790 TI - Endophytes and their potential to deal with co-contamination of organic contaminants (toluene) and toxic metals (nickel) during phytoremediation. AB - The aim was to investigate if engineered endophytes that are capable of degrading organic contaminants, and deal with or ideally improve uptake and translocation of toxic metals, can improve phytoremediation of mixed organic-metal pollution. As a model system, yellow lupine was inoculated with the endophyte Burkholderia cepacia VM1468 possessing (a) the pTOM-Bu61 plasmid, coding for constitutive toluene/TCE degradation, and (b) the chromosomally inserted ncc-nre Ni resistance/sequestration system. As controls, plants were inoculated with B. vietnamiensis BU61 (pTOM-Bu61) and B. cepacia BU72 (containing the ncc-nre Ni resistance/sequestration system). Plants were exposed to mixes of toluene and Ni. Only inoculation with B. cepacia VM1468 resulted in decreased Ni and toluene phytotoxicity, as measured by a protective effect on plant growth and decreased activities of enzymes involved in antioxidative defence (catalase, guaiacol peroxidase, superoxide dismutase) in the roots. Besides, plants inoculated with B. cepacia VM1468 and B. vietnamiensis BU61 released less toluene through the leaves than non-inoculated plants and those inoculated with B. cepacia BU72. Ni uptake in roots was slightly increased for B. cepacia BU72 inoculated plants. These results indicate that engineered endophytes have the potential to assist their host plant to deal with co-contamination of toxic metals and organic contaminants during phytoremediation. PMID- 21598791 TI - Native plant communities in an abandoned Pb-Zn mining area of northern Spain: implications for phytoremediation and germplasm preservation. AB - Plants growing on metalliferous soils from abandoned mines are unique because of their ability to cope with high metal levels in soil. In this study, we characterized plants and soils from an abandoned Pb-Zn mine in the Basque Country (northern Spain). Soil in this area proved to be deficient in major macronutrients and to contain toxic levels of Cd, Pb, and Zn. Spontaneously growing native plants (belonging to 31 species, 28 genera, and 15 families) were botanically identified. Plant shoots and rhizosphere soil were sampled at several sites in the mine, and analyzed for Pb, Zn and Cd concentration. Zinc showed the highest concentrations in shoots, followed by Pb and Cd. Highest Zn concentrations in shoots were found in the Zn-Cd hyperaccumulator Thlaspi caerulescens (mean = 18,254 mg Zn kg(-1) DW). Different metal tolerance and accumulation patterns were observed among the studied plant species, thus offering a wide germplasm assortment for the suitable selection of phytoremediation technologies. This study highlights the importance of preserving metalliferous environments as they shelter a unique and highly valuable metallicolous biodiversity. PMID- 21598792 TI - Prospective application of Leucaena leucocephala for phytoextraction of Cd and Zn and nitrogen fixation in metal polluted soils. AB - The study deals with phytoextraction of Zn and Cd by Leucaena leucocephala grown on effluent fed and low nitrogen soils collected from S1, S2, and S3 sites, representing decreasing metal content with increasing distance from the effluent drain. Plant nitrogen fixation potential and soil micro-biochemical attributes against metal stress were also assessed. Increasing soil metal content and plant growth enhanced metal accumulation. Relatively greater amount of Zn than Cd was accumulated by L. leucocephala, which exceeded in roots with that of other parts. Remediation factor for Cd was maximum (3.6%) in S2 grown plant. Nodule numbers, their biomass, nitrogenase activity, and leghaemoglobin content were maximum in plants grown in S3 and minimum in S1 soil having maximum metals. Maximum soil organic C, total N, C(mic), and N(mic), respiration rate, ATP content, and enzymatic activities in response to phytoremediation was recorded in S3 followed by S2 and S1. Phytoremediation for a year enhanced extractable Zn and Cd by 36% and 45%, and their total removal by 20% and 30%, respectively from S2, which suggests the possible application of L. leucocephala for the remediation of metal contaminated sites and their fertility restoration by improving microbial functionalities and N-pool. PMID- 21598793 TI - Accumulation of Cu, Zn, Pb, and Cd in edible parts of four commonly grown crops in two contaminated soils. AB - Soil heavy metal pollution resulting from human activities is causing major concern due to its potential risk. In this study, four crop species with different cultivars were planted in 2 levels (heavily and slightly) of heavy metal contaminated soils, and the accumulation of Cu, Zn, Pb, and Cd in the edible parts of the crops were investigated. Metal concentrations in sesame seeds grown in both soils exceeded both the Chinese Food Hygiene Standard (CFHS) and Codex Alimentarius Commission Standard (CACS), while the metal concentrations in all pepper cultivars in the slightly contaminated soil were below the CFHS and CACS. Other crops were generally in between in both soils. Among the tested crops, the order of soil-plant transfer factor (TF) was: sesame > green soybean > cowpea > pepper. Additionally, old fruit of cowpea contained larger amounts of metals than young fruit. It suggests that sesame should not be planted in the metal contaminated area, while pepper cultivar "Chaobianjiao No.1" may be an alternative to be grown in the slightly contaminated soil. There were differences in individual human susceptibilities to metals. Therefore, a comprehensive risk assessment should consider the frequency, amount and species consumed by human besides metal concentrations in crops. PMID- 21598794 TI - Chelator-enhanced lead accumulation in Agropyron elongatum cv Szarvasi-1 in hydroponic culture. AB - Hydroponic culture was applied to compare the efficiency of K2EDTA and citrate in mobilizing Pb for accumulation in Agropyron elongatum cv. Szarvasi-1 and their effects on some physiological characteristics of the plants. The plants were grown in nutrient solutions containing 0, 10, and 100 microM Pb(NO3)2 combined with chelating agents added to the nutrient solutions after 21 days of growth, in 3 concentrations (0, 100, and 500 microM). The effects were measured after eight days. The energy grass proved to be greatly resistant to the treatments, as was reflected in the slight inhibition of growth, the resistance of the photosynthetic electron transport chain and the chlorophyll composition and the lack of change in the malone-dialdehyde content. Fundamental differences can be identified between the effects of EDTA and citrate. Citrate had only a little effect on the physiological parameters, which may be due to the strongly increasing lead accumulation with increasing concentration of Pb in the nutrient solution. Additionally, citrate ensured a higher biomass yield with higher shoot Pb accumulation compared to EDTA in almost all treatments. Concerning biomass reduction, 10 microM Pb applied together with K2EDTA has the most deleterious effects on energy grass. The effects correlated with the concentration of EDTA. PMID- 21598795 TI - Hydrocarbon phytoremediation in the family Fabaceae--a review. AB - Currently, studies often focus on the use of Poaceae species (grasses) for phytoremediation of hydrocarbon-contaminated soils. Research into the use of Fabaceae species (legumes) to remediate hydrocarbons in soils has been conducted, but these plants are commonly overlooked due to slower recorded rates of degradation compared with many grass species. Evidence in the literature suggests that in some cases Fabaceae species may increase total degradation of hydrocarbons and stimulate degradative capacity of the soil microbial community, particularly for contaminants which are normally more recalcitrant to degradation. As many recalcitrant hydrocarbons have negative impacts on human and ecosystem health, development of remediation options is crucial. Reconsideration of Fabaceae species for removal of such contaminants may lead to environmentally and economically sustainable technologies for remediation of contaminated sites. PMID- 21598796 TI - Competitive uptake and phytomonitoring of chlorinated contaminant mixtures by Redosier dogwood (Cornus sericea). AB - Plant uptake is an important process in phytoremediation. The robust uptake of volatile organic compounds (VOCs) by plants offers opportunities to establish quantitative relationships between VOCs in plant tissues and in groundwater for the purpose of phytoscreening or phytomonitoring. Most previous research pertaining to phytoremediation neglected the competitive effects of co contaminants on the uptake of VOCs by plants, yet recent studies appeared to indicate high competitive effects of co-contamination. This study investigated the competitive uptake of three chlorinated compounds in the presence and absence of other co-contaminants by Redosier dogwood in a greenhouse and examined the implications of this competitive phenomenon for phytomonitoring of contaminant mixtures in groundwater. Concentrations of VOCs in stems decreased along the height in both single and bi-solute systems, in agreement with previous observations in the literature. Examination of the VOCs in single and bi-solute systems showed that concentrations of individual compounds are comparable in single and bi-solute systems, yet the ratios of contaminants along the height in bi-solute systems revealed interesting trends. TCE/PCE ratio increased along height while TCE/1,1,2-TCA ratio was roughly constant. The result indicated that sampling point as well as the physicochemical properties of co-contaminants is highly important in phytomonitoring of contaminant mixtures. PMID- 21598797 TI - Nickel accumulation in rape shoots (Brassica napus L.) increased by putrescine. AB - Application of exogenous putrescine (Put) increases nickel accumulation in rape shoots (Brassica napus), improving potential for phytoremediation of contaminated soils. Plants were grown within a growth chamber in water culture for five weeks, then 250-500 microM NiCl2 was added to rooting media. Within 5 days of treatment, damaging effects of nickel manifested as a reduction of root system size and a decrease of Cu and especially Fe content in young leaves. Spraying leaves of adult plants with Put markedly reduced toxic effects of Ni on root growth, enhanced leaf supply with Fe, and increased Ni content in young leaves by 2.5 times. Plant growth in medium with elevated levels of Ni stimulated accumulation of endogenous spermidine (Spd), spermine (Spm), and especially Put (by 4 times as compared with the control). Results suggest that Ni-induced accumulation of endogenous polyamines in rape leaves is caused by activation of long-distance metal transport within the plant and reduction of its toxicity due to Put chelating action. PMID- 21598798 TI - Decolorization of the textile dyes using purified banana pulp polyphenol oxidase. AB - Polyphenol oxidase (PPO) purified using DEAE-cellulose and Biogel P-100 column chromatography from banana pulp showed 12.72-fold activity and 2.49% yield. The optimum temperature and pH were found to be 30 degrees C and 7.0, respectively for its activity. Catechol was found to be a suitable substrate for banana pulp PPO that showed V(max), 0.041 mM min(-1) and K(m), 1.6 mM. The enzyme activity was inhibited by sodium metabisulfite, citric acid, cysteine, and beta mercaptoethanol at 10 mM concentration. The purified enzyme could decolorize (90%) Direct Red 5B (160 microg mL(-1)) dye within 48 h and Direct Blue GLL (400 microg mL(-1)) dye up to 85% within 90 h. The GC-MS analysis indicated the presence of 4-hydroxy-benzenesulfonic acid and Naphthalene-1,2,3,6-tetraol in the degradation products of Direct Red 5B, and 5-(4-Diazenyl-naphthalene-1-ylazo)-8 hydroxy-naphthalene-2-sulfonic acid and 2-(4-Diazenyl-naphthalene-1-ylazo) benzenesulfonic acid in the degradation products of Direct Blue GLL. PMID- 21598799 TI - Evaluation and decontamination of crude oil-polluted soils using Centrosema pubescen Benth and amendment-support options. AB - Growth performance and phytoremediation of soil of the Niger Delta Region of Nigeria artificially-contaminated with crude oil (up to 100 mL/2 kg soil) using centrosema pubescen Benth was investigated for 12 weeks. The soil samples in which the plants were established were either un-amended, or amended with NPK, or UREA or chicken manure. The extents of removal of PAHs and BTEX were measured as well as the rates of growth of the plants. Gas Chromatographic analysis confirmed the degradation of carcinogenic hydrocarbons like BTEXs and PAHs with this technique. At the highest dose of crude, the contaminant concentrations were 43 mg/kg PAHs, 10 mg/kg BTEX, and 5,613 mg/kg O&G. The greatest percent removal of BTEX was observed at the highest contaminant dose, and with the manure amendment. Similar trends were observed with PAHs and although they were less marked, the trends with PAHs may have been more highly statistically significant. There was no measurable plant uptake of contaminants. Inhibition of plant growth (measured as leaf area, shoot length and production of dry weight) was proportional to the dose of crude oil, but the manure amendment was very effective at reducing the growth inhibition. Interestingly, manure amendment reduced the phytotoxicity significantly in this study. PMID- 21598800 TI - Removal of chlorpyrifos by water lettuce (Pistia stratiotes L.) and duckweed (Lemna minor L.). AB - The potential of water lettuce (Pistia stratiotes L.) and duckweed (Lemna minor L.) to remove chlorpyrifos in water was investigated under laboratory greenhouse conditions. At initial chlorpyrifos concentrations of 0.0, 0.1 and 0.5 mg/L, the relative growth rates (RGR) of L. minor and P. stratiotes were not significantly different. In contrast, in the presence of 1 mg/L chlorpyrifos the RGR was significantly inhibited, giving an observed fresh weight based RGR(FW) for P. stratiotes and L. minor from day 0 to 7 of -0.036 and -0.023 mg/g/day, respectively. The maximum removal of chlorpyrifos by P. stratiotes and L. minor, when chlorpyrifos was at an initial culture concentration of 0.5 mg/L, was 82% and 87%, respectively, with disappearance rate constants under these conditions of 2.94, 10.21 and 12.14 microg h(-1) for the control (no plants), and with P. stratiotes and L. minor, respectively, giving actual corrected plant removal rate constants of 7.27 and 9.20 microg h(-1) for P. stratiotes and L. minor, respectively. The bioconcentration factor (BCF) of L. minor was significantly greater than that for P. stratiotes and therefore, at least under these greenhouse-based conditions, L. minor was more efficient than P. stratiotes for the accelerated removal of chlorpyrifos from water. PMID- 21598801 TI - Amortality. Why acting your age is a thing of the past. PMID- 21598802 TI - Evil lurking at your corner store. PMID- 21598803 TI - Familial mediterranean fever: a continuously challenging disease. PMID- 21598804 TI - The structural effect of the E148Q MEFV mutation on the pyrin protein: a study using a quantum chemistry model. AB - BACKGROUND: Familial Mediterranean fever (FMF) is a recessively inherited disease with a variety of clinical presentations. The disease is associated with mutations in the FMF gene (MEFV), which encodes for the pyrin protein. The role of the E148Q pyrin mutation in the FMF phenotype remains inconclusive, and some authors even view it as a disease-insignificant polymorphism. The calculated change imposed by this mutation on pyrin structure may help to understand the role of this mutation. OBJECTIVES: To calculate the relative electrochemical effect of the E148Q mutation on the structure of pyrin protein. METHODS: The electronic properties of the wild-type pyrin molecule and its common mutated forms were computed for the full-length molecule and its segments, encoded by exons 2 and 10, using the HyperChem 7.5 program with one of the molecular mechanical methods (MM+). The change in the structure of the molecule, expressed as a change in energy gain, conferred by the mutations was determined. RESULTS: The E148Q mutation caused deviation from the wildtype pyrin segment encoded by exon 2 by 1.15% and from the whole pyrin molecule by 0.75%, which was comparable to the R202Q mutation and less than the M694V mutation which caused a deviation from the wild-type structure of the whole pyrin molecule by 1.5%. CONCLUSIONS: A quantum chemistry-based model suggests that the structural effect of the E148Q mutation is indeed low but not zero. PMID- 21598805 TI - Serum amyloid A levels in kidney-transplanted patients with familial Mediterranean fever-amyloidosis. AB - BACKGROUND: Amyloidosis of familial Mediterranean fever (FMF) may lead to end stage renal failure, culminating in kidney transplantation. Since amyloidosis is prompted by high serum amyloid A (SAA) levels, increased SAA is expected to persist after transplantation. However, no data are available to confirm such an assumption. OBJECTIVES: To determine SAA levels in kidney-transplanted FMF amyloidosis patients and evaluate risk factors for the expected high SAA levels in this patient group. METHODS: SAA, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values were obtained from 16 kidney-transplanted FMF amyloidosis patients, 18 FMF patients without amyloidosis and 20 kidney transplanted patients with non-inflammatory underlying disease. Demographic, clinical and genetic risk factors evaluation was based on data extracted from files, interviews and examination of the patients. RESULTS: SAA level in FMF patients who underwent kidney transplantation due to amyloidosis was elevated with a mean of 21.1 +/- 11.8 mg/L (normal < or = 10 mg/L). It was comparable to that of transplanted patients with non-inflammatory disorders, but tended to be higher than in FMF patients without amyloidosis (7.38 +/- 6.36, P = 0.08). Possible risk factors for the elevated SAA levels in kidney transplant patients that were excluded were ethnic origin, MEFV mutations, gender, age and disease duration. CONCLUSIONS: Kidney-transplanted patients with FMF-amyloidosis and with other non-FMF causes displayed mildly elevated SAA levels, possibly resulting from exposure to foreign tissue rather than from various FMF-related factors. PMID- 21598806 TI - Expanding the panel of MEFV mutations for routine testing of patients with a clinical diagnosis of familial Mediterranean fever. AB - BACKGROUND: Since the identification of the MEFV gene 198 mutations have been identified, not all of which are pathologic. The screening methods used in Israel to test patients suspected of having FMF include a kit that tests for the five main mutations (M694V, V726A, M680Ic/g, M694I, E148Q), and the sequencing of MEFV exon 10 in combination with restriction analysis for detecting additional mutations OBJECTIVES: To determine the contribution of testing Ifor five additional mutations - A744S, K695R, M680Ic/t, R761H and P369S - to the molecular diagnosis of patients clinically suspected of having FMF. METHODS: A total of 1637 patients were tested for FMF mutations by sequencing exon 10 and performing restriction analysis for mutations E148Q and P369S. RESULTS: Nearly half the patients (812, 49.6%) did not have any detectable mutations, 581 (35.5%) had one mutation, 241 (14.7%) had two mutations, of whom 122 were homozygous and 119 compound heterozygous, and 3 had three mutations. Testing for the additional five mutations enabled us to identify 46 patients who would have been missedby the molecular diagnosis kit and 22 patients in whom only one mutation would have been found. Altogether, 4.3%of the patients would not have been diagnosed correctly had only the kit that tests for the five main mutations been used. CONCLUSIONS: This study suggests that testing for the additional five mutations as well as the five main mutations in patients with a clinical presentation of FMF adds significantly to the molecular diagnosis of FMF in the Israeli population. PMID- 21598807 TI - Atypical Henoch-Schonlein purpura: a forerunner of familial Mediterranean fever. AB - Insuception is the most common cause of intestinal obstruction in early childhood. The cause of most intussusceptions is unknown but it can complicate the course of Henoch-Schonlein purpura (HSP) as a result of the vasculitic process. Familial Mediterranean fever (FMF), a common disease in Israel, is also associated with HSP. In a few patients, particularly in children, HSP has been reported to precede the diagnosis of FMF. We describe two patients with an unusual clinical course of severe abdominal pain as a result of intusucception. The correlation between intusucception, HSP and FMF are discussed. PMID- 21598808 TI - Increased vitamin D serum levels correlate with clinical improvement of rheumatic diseases after Dead Sea climatotherapy. AB - BACKGROUND: Ultraviolet B (UVB) rays are required by the skin for the production of vitamin D. The intensity of UVB at the Dead Sea area is the lowest in the world. Low vitamin D levels are often associated with musculoskeletal symptoms. OBJECTIVES: To assess the effectiveness of climatotherapy at the Dead Sea on the production of vitamin D in Norwegian patients suffering from various rheumatic diseases and to investigate possible associations between increased vitamin D serum levels, musculoskeletal symptoms and disease severity. METHODS: Sixty Norwegian patients who came to the Dead Sea area for 21 days of medical rehabilitation were divided into three groups according to their diagnosis: chronic pain syndromes, i.e., low back pain or fibromyalgia (Group 1, n=33); rheumatoid arthritis (Group 2, n=16); and osteoarthritis (Group 3, n=11). Serum 25-hydroxyvitamin D (25-OH-D) levels were determined at arrival and prior to departure. The treatment protocol included daily sun exposure (climatotherapy), bathing in the Dead Sea and mineral spring water (balneotherapy), mud applications and fitness classes. RESULTS: 25-OH-D serum levels increased significantly from 71.3 +/- 26.6 nM at arrival to 89.3 +/- 23.2 nM prior to departure (P < 0.001). Adjusted for the initial levels of pain (assessed by a visual analog scale) and disease severity, a direct correlation was observed between increased 25-OH-D serum levels and pain reduction (P = 0.012) and reduction of disease severity (P = 0.02). CONCLUSIONS: Climatotherapy at the Dead Sea induces significant changes in vitamin D. Increased 25-OH-D serum levels are associated with reduced musculoskeletal pain and disease severity. PMID- 21598809 TI - Bypassing the emergency room to reduce door-to-balloon time and improve outcomes of patients with ST elevation myocardial infarction: the Acute Coronary Syndrome Israeli Survey experience. AB - BACKGROUND: Rapid reperfusion of an infarct-related artery is crucial for the successful treatment of ST elevation myocardial infarction. Every effort should be made to shorten door-to-balloon time. OBJECTIVES: To investigate whether bypassing the emergency room (ER) has a positive influence on door-to-balloon time in patients presenting with ST elevation myocardial infarction (STEMI) and whether the reduction in door-to-balloon time improves patients' clinical outcome. METHODS: We analyzed data of 776 patients with STEMI from the 2004 and the 2006 Acute Coronary Syndrome Israeli Survey (ACSIS) registry. The ACSIS is a biennial survey on acute myocardial infarction performed in all 25 intensive cardiac care units in Israel during a 2-month period. Twenty-five percent of patients (193 of 776) arrived directly to the intensive cardiac care unit (ICCU) and 75% (583 of 776) were assessed first in the ER. We compared door-to-balloon time, ejection fraction, 30 days MACE (major adverse cardiac and cerebrovascular events) and 30 days mortality in the two study groups. RESULTS: There was significantly shorter door-to-balloon time in the direct ICCU group as compared with the ER group (45 vs. 79 minutes, P< 0.002). Patients in the direct ICCU group were more likely to have door-to-balloon time of less than 90 minutes in accordance with ACC/AHA guidelines (88.7% vs. 59.2%, P < 0.0001). Moreover, patients in the direct ICCU group were less likely to have left ventricular ejection fraction < 30% (5.4% vs. 12.2%, P= 0.045) and less likely to have symptoms of overt congestive heart failure. Lastly, 30 days MACE was significantly lower in the direct ICCU group (22 vs. 30%, P< 0.004). CONCLUSIONS: There is significant reduction of the door-to-balloon time in the direct ICCU admission strategy. This reduction translates into improvement in clinical outcome of patients. It is reasonable to apply the direct ICCU strategy to patients with STEMI. PMID- 21598810 TI - The effect of the Internet on the patient-doctor relationship from the patient's perspective: a survey from primary care. AB - BACKGROUND: Internet use by patients as a source of information on health and disease is expanding rapidly with obvious effects on the doctor-patient relationship. Many of these effects remain undocumented or are poorly understood. OBJECTIVES: To assess the use of the internet for health information by patients in primary care in Israel and their perception of the effects of internet use on their relationship with their doctor. METHODS: A cross-sectional survey was conducted among a convenience sample of patients visiting 10 primary care clinics in central Israel using a questionnaire developed for this survey. The survey examined attitudes to using the internet for health-related information and attitudes to sharing this information with doctors. Associations between demographic variables, internet use and patient satisfaction with the doctor's response were tested using the chi-square statistic and t-tests. RESULTS: Completed questionnaires were received from 138 patients; the response rate was 69%. Patients in the study sample had a high rate of internet access (87%), with many using the internet as a source of health information (41%) although most patients using the internet never share this information with their doctor (81%). Among those who share information with the doctor, most felt that this has a positive effect on the relationship (870/%). Few patients reported being referred to websites by the doctor (28%). CONCLUSIONS: Internet use is prevalent in this population, though physicians may be unaware of this. Future study could examine the effects of doctors who ask patients actively about their internet use and inform them of relevant health information sources online. PMID- 21598811 TI - Usefulness of various inflammatory markers to differentiate pulmonary edema from pneumonia. AB - BACKGROUND: Community-acquired pneumonia requiring hospitalization is a severe illness with high mortality, especially if the appropriate treatment is delayed. Sometimes diagnosis is difficult due to an equivocal clinical picture or chest film, or to accompanying diseases that mask or simulate pneumonia. OBJECTIVES: To assess the usefulness of certain inflammatory markers in differentiating pulmonary edema from pneumonia throughout the hospital stay in patients admitted for pneumonia or pulmonary edema of non-infectious origin and to monitor the response to treatment. METHODS: The study group comprised 50 patients admitted for pneumonia, 50 admitted for pulmonary edema and 30 healthy individuals. Blood samples for determination of leukocyte count, erythrocyte sedimentation rate (ESR), fibrinogen, C-reactive protein (CRP), albumin, sCD14 and oxidized fibrinogen were drawn upon admission, at 48 and 72 hours after admission, and at discharge from the intensive care unit. RESULTS: The levels of sCD14 were similar in both patient groups but higher than control levels during the first 48 hours (P< 0.03). They decreased gradually with hospital stay. The concentration of oxidized fibrinogen was similar in both patient groups and significantly lower than that of the healthy control group throughout the hospitalization period. CONCLUSIONS: Oxidized fibrinogen and sCD14 are not reliable markers for the diagnosis of pneumonia, for its differential diagnosis from pulmonary edema, and for patient follow-up throughout hospitalization. The finding of elevated levels of oxidized fibrinogen in the group of healthy controls warrants further study to identify the factors responsible for altering fibrinogen oxidation. The other markers are more indicative. PMID- 21598812 TI - Insertion of removable self-expanding metal stents as a treatment for postoperative leaks and perforations of the esophagus and stomach. AB - BACKGROUND: Esophageal perforations and postoperative esophageal leaks are associated with substantial morbidity and mortality and pose a difficult therapeutic challenge. OBJECTIVES: Toevaluate the outcome ofremovableself expanding metallic stents (SEMS) as a treatment for postoperative leaks and perforations of the esophagus and stomach. METHODS: We conducted a retrospective study of all patients in one medical center who underwent temporary insertion of a covered plastic stent for postoperative leaks and perforations of the esophagus and stomach from June 2009 to February 2010. Data were retrieved from hospital and outpatient clinical data charts. Data included indication for insertion, post insertion outcome including stent complications, and follow-up after stent removal. RESULTS: The indications for stent insertion were postoperative leak in four patients and postoperative esophagopleural fistula in one patient. Three of the patients had a leak at the gastroesophageal junction following laparoscopic sleeve gastrectomy. In all cases the stent insertion was completed successfully. In three patients the stent migrated distally. In two of these three it was repositioned or replaced endoscopically, and in the third it was excreted in the feces. Stents were removed electively after 6 to 7 weeks. All patients recovered fully and were discharged from the hospital. CONCLUSIONS: SEMS insertion may have an important role in the management of postoperative leaks and perforations of the esophagus and stomach and should be considered in such cases. PMID- 21598813 TI - Is vitamin D a new therapeutic agent in autoinflammatory and pain syndromes? PMID- 21598814 TI - Possibilities for improved early breast cancer detection by Pade-optimized magnetic resonance spectroscopy. AB - There are major dilemmas regarding the optimal modalities for breast cancer screening. This is of particular relevance to Israel because of its high-risk population. It was suggested that an avenue for further research would be to incorporate advances in signal processing through the fast Pade transform (FPT) to magnetic resonance spectroscopy (MRS). We have now applied the FPT to time signals that were generated according to in vitro MRS data as encoded from extracted breast specimens from normal, non-infiltrated breast tissue, fibroadenoma and cancerous breast tissue. The FPT is shown to resolve and precisely quantify the physical resonances as encountered in normal versus benign versus malignant breast. The FPT unambiguously delineated and quantified diagnostically important metabolites such as lactate, as well as phosphocholine, which very closely overlaps with glycerophosphocholine and phosphoethanolamine, and may represent a magnetic resonance-visible molecular marker of breast cancer. These advantages of the FPT could clearly be of benefit for breast cancer diagnostics via MRS. This line of investigation should continue with encoded data from benign and malignant breast tissue, in vitro and in vivo. We anticipate that Pade-optimized MRS will reduce the false positive rates of MR-based modalities and further improve their sensitivity. Once this is achieved, and given that MR entails no exposure to ionizing radiation, new possibilities for screening and early detection emerge, especially for risk groups. For example, Pade-optimized MRS together with MR imaging could be used with greater surveillance frequency among younger women with high risk of breast cancer. PMID- 21598815 TI - Gender medicine in gastroenterology. AB - The cause for gender differences in the epidemiology, natural history and response to therapy in many diseases is unknown and has seldom been investigated in depth. Sex hormones are blamed for many of these changes, mostly without any scientific evidence. In this review I will describe some of the evidence for gender differences in gastrointestinal diseases. Gender medicine and its application for gastroenterology is a new field and one warranting research. PMID- 21598816 TI - Metastatic malignant struma ovarii. PMID- 21598817 TI - H1N1 vaccine-related acute transverse myelitis. PMID- 21598819 TI - Occupational contact dermatitis in a nurse due to thimerosal. PMID- 21598818 TI - Anterior ischemic optic neuropathy in a patient with hepatitis C treated with interferon-alpha and ribavirin. PMID- 21598820 TI - Uremic pericarditis. PMID- 21598822 TI - 'Not going to be a problem'. Most healthcare programs safe from shutdown. PMID- 21598821 TI - Acrodermatitis enteropathica in a 9 month old infant. PMID- 21598823 TI - Branching out. Providers create consortium to exchange data. PMID- 21598824 TI - Is it 2012 already? Starting gun has sounded on presidential politics, next round of budget battles. PMID- 21598825 TI - One size fits some. Children, Medicaid would benefit from models of care based on needs. PMID- 21598826 TI - New tools in germ warfare. Hospitals turn to IT to help curb overuse of antibiotics, fight drug resistance. PMID- 21598827 TI - High rates of macrolide resistance among clinical isolates of Streptococcus agalactiae in Tunisia. AB - One hundred sixty non duplicate erythromycin resistant Streptococcus agalactiae isolates were collected in Tunisia from January 2005 to December 2007 They were investigated to determine their resistance level to different macrolides and the mechanisms involved. Most erythromycin resistant S. agalactiae isolates were isolated from urinary specimens (38.75%, 62/160). The constitutive MLSB phenotype (cMLS) showed in 84.3% (135/160) with high MICs of macrolides and lincosamides (MIC90>256 microg/mL) and 8.2% (13/160) inducible MLSB phenotype (iMLS) with high MICs of macrolides (MIC90>256 microg/mL) and moderately increased MICs of lincosamides (MIC90=8 microg/mL). The M phenotype showed in 7.5% (12/160) with moderately increased MICs of macrolides (MIC90=32 microg/mL) and low MICs of lincosamides (MIC90=0.75 microg/mL). All strains were susceptible to quinupristun dalfopristin association and linezolid (MIC90: 05 and 0.38 microg/mL respectively). Strains with MLSB phenotype harboured erm(B) gene with 825% (n=132), erm(TR) gene with 8.12% (n=13) and erm(B) plus mef (A) with 1.88% (n=3). All strains categorized as M phenotype carried the mef(A) gene (75%, n=12). cMLSB phenotype conferring cross resistance to macrolides, lincosamides and streptogramins B with high level of resistance was the most prevalent. PMID- 21598828 TI - Association of specific amino acid sequence (QRRAA) of HLA-DRB1*0405 with rheumatoid arthritis in a Tunisian population. AB - This study aimed to investigate HLA-DRB1 alleles in rheumatoid arthritis (RA) patients from Tunisia and to examine the effect of these alleles on disease severity. HLA-DRBI alleles and sub-typing of DRBI*04 and *01 were determined in 90 patients and 100 healthy controls, by PCR-SSP. HLA-DRB1*04 was significantly higher in patients (51.1%) than in controls (27%) [OR=2.83, p=0.00066]. DRBJ*0405 was found to be the unique DR4 allele associated with RA (28.88% vs 6%) [OR=6.36, p=0.000059]. A significant decrease in the frequency of HLA-DRB1*0701 was observed in RA patients (16.66%) compared to controls (36%) [p=0.0026]. However, the frequency of patients carrying the shared epitope (SE) QRRAA, was slightly increased compared with controls (37.8% vs 23%) [OR=2.03, p=0.039]. We found that the presence of rheumatoid factor, HLA-DR4 and HLA-DRBI*0405 were not significantly associated with bone erosions or the presence of extra-joint involvement. In our population, the SE (QRRAA) expressed in DRBI*04 alleles is related to the susceptibility to RA but it is not involved in RA severity in Tunisia, while DRBI*0701 might protect against this disease. PMID- 21598829 TI - Presence of STRA-STRB linked streptomycin-resistance genes in clinical isolate of Escherichia coil 2418. AB - The streptomycin resistance of Escherichia coli 2418 strain has been shown to be associated with a 1.2-kb DNA fragment found in the naturally occurring plasmid R2418S. Here, nucleotide sequence analysis of the 1.2-kb DNA fragment revealed the presence of the strB gene which is located immediately downstream of the strA gene. Both sequences are identical to those of strA and strB genes in plasmid RSF1010. Thus, the observed resistance in the clinical isolate is due to the presence of strA-strB genes encoding streptomycin-modifying enzymes. The sequence downstream of strB gene showed a perfect homology with that of RSF1010. In addition, it contained the right inverted repeat of the transposon Tn5393 that has been suggested to be a relic of this transposon found in DNA plasmids isolated from human- and animal-associated bacteria. PMID- 21598830 TI - Readmission relationship. But costs put damper on raising RN staffing levels. PMID- 21598831 TI - Going after fraud. Tactics hold corporations, individuals accountable. An interview by Joe Carlson. PMID- 21598832 TI - Setting higher standards. Nursing home quality measures offer guide. PMID- 21598833 TI - What's the rush? Court's move could mean reform ruling will land in the heat of 2012 elections. PMID- 21598834 TI - Timeless truths. NCHL to promote leadership development that works whatever future holds. PMID- 21598835 TI - Bumpy road ahead. Rural hospitals confront the challenges of establishing ACOs and medical homes with limited resources and thinner margins. PMID- 21598836 TI - Building equity. Private investors continue to see strong value in many healthcare sectors. PMID- 21598837 TI - Isolation and identification of a novel Candida sp. H2 producing D-arabitol and optimization of D-arabitol production. AB - OBJECTIVE: To isolate a new osmophilic yeast for producing D-arabitol and research its optimal fermentation conditions for highest yield of D-arabitol from glucose. METHODS: The isolated strain was characterized by electron microscopy, Biolog (GN) test, G + C content measurement and 26S rDNA D1/D2 domain sequences analysis. The purified fermentation product was identified by IR, 1H-NMR, 13C NMR, MS and optical rotation analysis. Then the fermentation conditions for D arabitol production were optimized. RESULTS: A new osmophilic yeast was isolated and identified as Candida sp. H2. Through the single factor experiment,the optimum conditions of 250 g/L glucose,10 g/L yeast extract, initial pH 6.0, 35 degrees C of culture temperature, 200 r/min of agitation, 200 mL medium in a 1000 mL flask of broth content, 1% (v/v) of inoculum size, 96 h of fermentation time were achieved. Based on the conditions above,weight yield of 35% (86.55 g D arabitol from 250 g glucose) was obtained and 10% higher than the conditions not optimized. CONCLUSIONS: Candida sp. H2 was a novel strain for producing D arabitol and valuable for further study. PMID- 21598838 TI - Rational design of alpha-helical antimicrobial peptide with Val and Arg residues. AB - OBJECTIVE: The amphipathic alpha-helical peptide is an important class of antimicrobial peptides. In this study, a 16-residue-long peptide (VGR16) composed of 8 Val residues in the nonpolar face and 5 Arg residues in the polar face was designed based on the helical wheel projection to produce antimicrobial peptide with improved antibacterial activity accompanied by decreased toxicity. METHODS: Antimicrobial activity and toxicity against red blood cells and mammalian cells were investigated to evaluate the biological function of the peptide. In addition, bactericidal kinetics was tested. RESULTS: Antimicrobial assays revealed that the peptide VGR16 showed antimicrobial activity and their MICs against gram-negative and gram-positive bacteria ranged from 16 microg/ml to 64 microg/ml. VGR16 also exhibited rapid bactericidal action. It was surprisingly found that the peptide displayed no hemolytic activity even at a concentration of 256 microg/ml. Cell culture assays indicated that the peptide VGR16 had low cytotoxicity against mammalian cells. CONCLUSION: The results showed that the peptide could be a likely candidate for future antimicrobial applications. PMID- 21598839 TI - The effects of encoding in hypnosis and post-hypnotic suggestion on academic performance. AB - This study examined the relationship between proactive learning in hypnosis, post hypnotic suggestion, and academic performance. Participants (N = 56) were randomly assigned to a control group or a treatment group. The treatment group was hypnotized and read a passage while in hypnosis. Concurrently, they were given a post-hypnotic suggestion, which attempted to aid recognition and performance on a test immediately following the hypnosis session. Both groups completed a multiple-choice test based on the aforementioned passage. An analysis of covariance discerned the effect of proactive learning and post-hypnotic suggestion on test performance, while controlling for the variance introduced by scholastic aptitude as measured by the ACT. Results indicated that the hypnosis sessions predicted significantly impaired test performance. PMID- 21598840 TI - Solving crimes with hypnosis. AB - Following a brief review of the literature on hypnosis and memory, this paper overviews the procedures that are used in conducting forensic hypnosis interviews. Ten forensic hypnosis cases are then described. These real world cases are in stark contrast to research done in an artificial laboratory setting where the information to be recalled lacks personal relevance and was not associated with emotionally arousing situations. These cases illustrate how forensic hypnosis can result in obtaining important additional investigative leads which lead to the solving of crimes. PMID- 21598841 TI - Tandem hypnosis with identical bulimic twins: case report. AB - Hypnosis has been used in the treatment of bulimia nervosa from the early 1980s. Dissociation theory identified a certain subgroup of eating disordered patients with dissociative signs and symptoms. These patients react well to hypnotherapy. Simultaneous hypnosis ("tandem hypnosis") in the treatment of two female 19-year old monozygotic twins led to a very successful outcome after 6 sessions. During the therapy, attempts were made to work through the physical abuse the subjects suffered from their father. Hypnobehavioural methods were used and treatment was combined with five individual sessions. In the cases presented here, the subjects' traumatic history, their high hypnotic susceptibility, and the effectiveness of hypnotherapy seem to support the dissociative mechanism of symptom development. A systemic approach involving the integration of family therapeutical and hypnotherapeutical interventions proved to be useful. The role of these types of hypnotherapy interventions is still undervalued. PMID- 21598842 TI - Hypnosis and acupuncture (hypnopuncture) for prurigo nodularis: a case report. AB - Prurigo Nodularis (PN) is a chronic pruritic skin condition for which current conventional therapies are of limited benefit and with potentially toxic effects. Acupuncture--the insertion of thin needles at specific points on the skin--has been shown to alleviate itching through a number of itch-associated mediator effects. Hypnosis has been shown to modify and reduce the intensity of itching as well. A 44 year-old woman presented with a 30-year history of a diffuse itchy rash diagnosed as PN. She had tried various antihistamine and corticosteroid medications, to no avail. A treatment regimen using hypnosis and acupuncture (hypnopuncture) was initiated, with significant reduction in the itching, size and number of skin lesions. Hypnopuncture may offer a synergistic and augmented response to treatment, though further research is needed to understand the true benefits of this combined regimen. PMID- 21598843 TI - How will Obama handle Ryancare? PMID- 21598844 TI - Impartiality and disability discrimination. AB - Cost-effectiveness analysis is the standard analytical tool for evaluating the aggregate health benefits of treatments and health programs. According to a common objection, however, its use may lead to unfair discrimination against people with disabilities. Since the disability discrimination objection is seldom articulated in a precise way, I first provide a formulation that avoids some implausible implications. Then I turn to the standard defense of cost effectiveness analysis and argue that it does not succeed. But this does not settle the question of whether the use of cost-effectiveness analysis leads to unfair discrimination. Rather, it shows that the controversy should be approached in a different way. Thus, I conclude by outlining an alternative strategy for answering the question. PMID- 21598845 TI - Board oversight of community benefit: an ethical imperative. AB - Board oversight of community benefit responsibility in tax-exempt organizations in the nonprofit health care sector is attracting considerable attention. Scrutiny by the IRS and other official bodies has led to stricter measures of compliance with the community benefit standard. But stricter compliance does not sufficiently engage the underlying ethical imperative for boards to provide effective oversight--an imperative that recent research suggests has not been sufficiently honored. This analysis considers why there is a distinctively ethical imperative for board oversight, the organizational nature of the imperative involved, and practical ways to fulfill its obligations. We adopt an organizational ethics paradigm to illuminate the constituent components of the ethical imperative and to clarify emerging benchmarks as flexible guidelines. As these emerging benchmarks enhance board oversight of community benefit they also can shed light on what it means to be a virtuous organization. PMID- 21598846 TI - Early stopping of clinical trials: charting the ethical terrain. AB - The decision to terminate a clinical trial earlier than planned is often described as ethically problematic, but it is rarely systematically analyzed as an ethical issue in its own right. This paper provides an overview of the main ethical considerations at stake in such decisions and of the main tensions between these considerations. Arguments about informed consent and the impact of early stopping on research and society are explored. We devote particular attention to a familiar conflict that arises with special urgency when early data suggest that the experimental treatment is superior. Should the trial be stopped so that participants in the control group will not be allocated a seemingly inferior treatment, or should it continue in pursuit of evidence conclusive enough to improve the care of future patients? We scrutinize three ways to address this problem. Rather than dissolving the tension, they represent different trade-offs between the respective welfare interests of subjects and future patients. PMID- 21598847 TI - The cultural moral right to a basic minimum of accessible health care. AB - (1) The conception of a cultural moral right is useful in capturing the social moral realities that underlie debate about universal health care. In asserting such rights, individuals make claims above and beyond their legal rights, but those claims are based on the society's existing commitments and moral culture. In the United States such a right to accessible basic health care is generated by various empirical social facts, primarily the conjunction of the legal requirement of access to emergency care with widely held principles about unfair free riding and just sharing of costs between well and ill. The right can get expressed in social policy through either single-payer or mandated insurance. (2) The same elements that generate this right provide modest assistance in determining its content, the structure and scope of a basic minimum of care. They justify limits on patient cost sharing, require comparative effectiveness, and make cost considerations relevant. They shed light on the status of expensive, marginally life extending, last-chance therapies, as well as life support for PVS patients. They are of less assistance in settling contentious debates about screening for breast and prostate cancer and treatments for infertility and erectile dysfunction, but even there they establish a useful framework for discussion. Scarcity of resources need not be a leading conceptual consideration in discerning a basic minimum. More important are the societal elements that generate the cultural moral right to a basic minimum. PMID- 21598848 TI - Keeping their attention: innovative strategies for nursing education. AB - Providing nursing education in clinical and other educational settings presents several challenges. Changes in learners, vast amounts of material to be taught, and decreasing educational resources require increased effectiveness of nurse educators and each educational experience. Current teaching strategies may be enhanced to meet learners' expectations and address the reduced attention spans characteristic of today's learners. This article provides 20 strategies and additional helpful hints to increase learner engagement, improve retention of material, and make nursing education more enjoyable for instructors and learners. PMID- 21598849 TI - Nurses' perception of evidence-based practice at the National University Hospital of Singapore. AB - BACKGROUND: A study was conducted at Singapore's National University Hospital to elicit registered nurses' attitudes, knowledge, barriers, facilitating factors, education, and training regarding evidence-based practice. METHODS: A 13-question survey that was administered to all registered nurses yielded 1,114 (75.4%) usable returns for analysis. RESULTS: Findings showed that Singapore nurses had a positive and supportive attitude toward evidence-based practice but lacked the competence and knowledge to conduct it. Time constraints were identified as the main barrier to implementing evidence-based practice. There is a need for proper training, mentoring by senior nurses, and adequate time for evidence-based practice. Nurses with a higher level of nursing education who indicated the greatest perceived barriers tended to have less difficulty applying evidence based practice but identified a need for more training in information skills. CONCLUSION: Evidence-based practice is still in its infancy in Singapore compared with hospitals in other developed countries. PMID- 21598850 TI - Perceptions of professional practice and work environment of new graduates in a nurse residency program. AB - New nurses continue to face challenging work environments and high expectations for professional competence as they enter practice. Nurse residency programs are gaining prominence as a mechanism to ease new graduates' transition to practice. This study examined new graduates' perceptions of their professional practice competence and work environment throughout a yearlong nurse residency program. Employing a repeated measures design, data were collected at baseline, at 6 months, and at 12 months. Results showed that job satisfaction was significantly lowest at 6 months and highest at 12 months. Job stress was found to be lowest at 12 months and organizational commitment was highest at baseline. Of the variables related to professional practice, clinical decision-making was highest at 12 months and quality of nursing performance significantly increased at each measurement point. These data add to the growing evidence supporting the efficacy of nurse residency programs. PMID- 21598851 TI - The Faculty Learning About Geriatrics (FLAG) program: bringing together experts in geriatric nursing education. AB - Strengthening geriatric content in schools of nursing is a key initiative for the Minnesota Hartford Center of Geriatric Nursing Excellence. The first Faculty Learning About Geriatrics (FLAG) program was implemented in the summer of 2008. Selected nursing faculty from across the Upper Midwest and tribal colleges have successfully completed the FLAG program in the last 2 years. Participants completed a 5-day summer institute at the University of Minnesota and a 1-year mentorship program. The FLAG program is designed to broaden expertise in geriatric nursing through building teaching and academic leadership skills and to increase content knowledge through collaboration with academic and geriatric leaders. This article provides an overview of the educational experience of FLAG participants who have earned the title of FLAG program fellow. The perspectives of the FLAG mentors and fellows are highlighted. PMID- 21598852 TI - Perceived value of national certification for pediatric nurses. AB - PURPOSE: This study evaluated whether pediatric nurses who were certified valued national certifications to a greater degree than those who were not certified. METHODS: The Gaberson, Schroeter, Killen, and Valentine (2003) Perceived Value of Certification Tool (PVCT) was used to measure nurses' perceptions of certification. The PVCT includes 18 certification-related value statements, using a five-point Likert scale response ranging from strongly agree to strongly disagree. A principal factor analysis was performed to identify clusters of related variables. RESULTS: Certified pediatric nurses valued national certifications to a greater degree than those who were not certified. More favorable views of certification were moderately associated with favorable views of the effects of certification on salary. The PVCT was found to have one factor, not two, as previously reported in the literature. Lower perceived relationships were reported between certification and salary, clinical competence, and consumer confidence compared with feelings of professionalism and personal satisfaction. CONCLUSION: Efforts to improve the relationship between certification and its perceived value at one institution were addressed. More attention may be needed to strengthen relationships, perceived or otherwise, between certification and competency skills, public awareness, and compensation of nurses for holding national certification. PMID- 21598853 TI - Stretching to prevent musculoskeletal injuries. An approach to workplace wellness. AB - A pre-shift stretching protocol to reduce employee injuries was initiated at a beverage company and a tin mill in the northeastern United States. The primary goal of this study was to determine the effects of a pre-shift stretching program on work-related musculoskeletal injuries. A secondary goal was to evaluate daily participation compliance during the 90-day program. Data on employee injuries during the stretching program were collected and compared to injury events during the same time period 1 year earlier. Comparison to injury events of the total eligible population during the study time frame was also included. Results of this pilot program in terms of injury rate reduction and participant compliance are promising. Study results may be useful for employers considering implementing similar programs and also suggest the need for further study in this area. PMID- 21598854 TI - Implementation of occupational health service improvements through application of total quality management processes. AB - The occupational health services department for a manufacturing division of a high-technology firm was redesigned from an outsourced model, in which most services were provided by an outside clinic vendor, to an in-house service model, in which services were provided by an on-site nurse practitioner. The redesign and implementation, accomplished by a cross-functional team using Total Quality Management processes, resulted in a comprehensive occupational health services department that realized significant cost reduction, increased compliance with regulatory and company requirements, and improved employee satisfaction. Implications of this project for occupational health nurses are discussed. PMID- 21598855 TI - Vision-related quality of life assessment using the NEI-VFQ-25 in adolescents and young adults with a history of congenital cataract. AB - PURPOSE: To assess vision-specific health-related quality of life in adolescents and young adults with a history of congenital cataract using the National Eye Institute 25-item Visual Function Questionnaire (NEI-VFQ-25). METHODS: A retrospective chart review was performed for patients who underwent surgery aged younger than 24 months. Those 13 years or older at follow-up were selected for inclusion. Educational attainment was determined. A control group of healthy individuals of similar age with no visual complaints also completed the questionnaire. RESULTS: Sixteen patients with a history of unilateral cataract (mean age: 17.8 +/- 2.8 years), 22 with bilateral cataract (19.5 +/- 4.6 years), and 15 controls (17.9 +/- 2.5 years) were included in the study. The bilateral cataract group had greater difficulty with near and distance activities compared with the unilateral group, and had significantly lower vision-specific social functioning, role difficulties, mental health, and composite scores. Comparing the unilateral cataract and control groups, there was no significant difference in ocular pain, vision-specific social functioning, role difficulties, and dependency scores between both groups. CONCLUSION: Patients with unilateral cataract had fewer difficulties performing near and distance activities and certain vision-specific tasks than the bilateral group, but both groups were comparable in terms of general vision scores. The control group had better scores than the unilateral group in some, but not all, categories and better than the bilateral group in most. Educational achievements were high in both cataract groups. All attended main stream school and many attended university. PMID- 21598856 TI - Changes in the interpupillary distance following general anesthesia in children with intermittent exotropia: a predictor of surgical outcomes. AB - PURPOSE: To determine whether changes in ocular alignment following general anesthesia, as measured by interpupillary distance, can be used as a predictor for surgical outcomes in children with intermittent exotropia. METHODS: The authors obtained digital photographs of 40 children with exotropia and 20 children with epiblepharon (control group) before and immediately after induction of general anesthesia in the primary supine position. Differences in the anatomic interpupillary distance (aIPD) for each patient were measured and compared with the preoperative angles of deviation. They were also correlated with surgical outcomes on the first day and 1 year after surgery. RESULTS: All 60 patients demonstrated an increase in aIPD following general anesthesia. The mean change in aIPD in patients with exotropia was similar to that in patients with epiblepharon (3.78% +/- 2.53% and 3.15% +/- 1.05%, respectively). In patients with exotropia, there was a significant positive linear correlation between the preoperative distance deviation (P) and the change in eye position (A): A = 0.362 P - 4.488, r(2) = 0.476 (P < .001). Five (71%) of seven patients whose changes were outside the 80% confidence interval for expected values had poor surgical outcomes on the first postoperative day and four had unsatisfactory results 1 year after surgery. CONCLUSIONS: Changes in aIPD following general anesthesia were strongly correlated with preoperative angle of deviation. Therefore, they may be a useful predictor of surgical outcomes in children with exotropia. PMID- 21598857 TI - Multiple attempts on a nursing admissions examination: effects on the total score. AB - Colleges and universities throughout the United States use a wide variety of admissions criteria, including admissions examinations, when deciding who to admit into their program. This research used a nationally administered nursing school entrance examination, the TEAS((r)), to investigate the effects of multiple attempts, test version, and the number of days between repeated attempts on an examinee's total score. Overall, the results indicated that scores earned on repeated attempts at the TEAS were significantly greater than those on the previous attempts regardless of whether the same or parallel version of the examination was completed. In addition, the study found that the number of days between attempts did not greatly influence the score earned on the repeated attempt. PMID- 21598858 TI - The role of analogy-guided learning experiences in enhancing students' clinical decision-making skills. AB - The purpose of this study was to address the need for effective educational interventions to promote students' clinical decision making (CDM) within clinical practice environments. Researchers used a quasi-experimental, non-equivalent groups, posttest-only design to assess differences in CDM ability between intervention group students who participated in analogy-guided learning activities and control group students who participated in traditional activities. For the intervention, analogy-guided learning activities were incorporated into weekly group discussions, reflective journal writing, and questioning with clinical faculty. The researcher-designed Assessment of Clinical Decision Making Rubric was used to assess indicators of CDM ability in all students' reflective journal entries. Results indicated that the intervention group demonstrated significantly higher levels of CDM ability in their journals compared with the control group (ES(sm) = 0.52). Recommendations provide nurse educators with strategies to maximize students' development of CDM ability, better preparing students for the demands they face when they enter the profession. PMID- 21598859 TI - Characteristics of unsafe undergraduate nursing students in clinical practice: an integrative literature review. AB - Providing quality clinical experiences for nursing students is vital to the development of safe and competent professional nurses. However, clinical educators often have difficulty identifying and coping with students whose performance is unsatisfactory. The purposes of this integrative review were to examine the extent and quality of the literature focusing on unsafe nursing students in clinical settings and to describe the characteristics of nursing students considered unsafe in clinical settings. A structured literature search yielded 11 relevant articles: five theoretical articles and six research studies. Analysis of findings revealed three themes: ineffective interpersonal interactions, knowledge and skill incompetence, and unprofessional image. The themes reflected the attitudes, actions, and behaviors that influenced students' ability to develop a safe milieu for client care. The findings provide clarity for early identification of students in need of increased support and facilitate clinical educators in meeting students' learning needs to ensure patient safety. PMID- 21598860 TI - Exploration of nursing doctoral admissions and performance outcomes. AB - This research aims to identify current admission criteria and academic performance outcomes in nursing PhD programs. A descriptive exploratory design was used to survey all American Association of Colleges of Nursing PhD programs (N = 110) via a Web-mediated standardized survey; the response rate was 51% (n = 56). Conclusions indicate six diverse yet complementary admission criteria: graduate grade point average (GPA), Graduate Record Examinations (r) scores, writing samples, letters of recommendation, interviews, and research match with faculty. Findings also indicated that admission criteria largely lack predictive validity testing in regard to academic performance outcomes and are deficient in internal reliability. Academic performance outcomes included comprehensive examination, ongoing minimum graduate GPA of 3.0, formal dissertation, time to degree attainment, degree attainment, time to candidacy, type of employment after graduation, and publications and grants as a student and at 5 years postgraduation. PMID- 21598861 TI - Using unfolding case studies in a subject-centered classroom. AB - The recently published report of the Carnegie Foundation's National Study of Nursing Education points out significant problems with classroom teaching in schools of nursing. This article suggests Palmer's idea of the subject-centered classroom as a way to transform nursing school classrooms into collaborative learning communities. For Palmer, the subject is the big idea of nursing practice the nurse-patient/client/family/community relationship-that should take the lead in stimulating inquiry and discussion. The article goes on to describe how teachers can develop and use unfolding case studies to bring the subject to the center of the classroom. By doing so, the classroom becomes a place where students learn a sense of salience, develop their clinical imagination, and begin their formation as professional nurses. PMID- 21598862 TI - Teaching theoretical thinking for a sense of salience. AB - Using a thought-provoking photograph, blank paper, and a series of questions, graduate students were asked to engage in an interactive classroom exercise that helps them understand the process and usefulness of theoretical thinking. This one-time exercise helps students envision ways they will be able to use theoretical thinking when they enter their advanced practice roles. The exercise is followed by a short, debriefing lecture on the four levels of theory as originally described by Dickoff, James, and Weidenbach. Students engage in a four stage, systematic process of theoretical thinking that can be used as a model for clinical reasoning and problem solving, especially for ambiguous situations. PMID- 21598863 TI - Caring for our own: the role of institutionalized support structures in Native American nursing student success. AB - In this project, the authors asked 19 Native American baccalaureate nursing students to discuss their experiences with a formal institutionalized student support program called "Caring for Our Own: A Reservation/University Partnership Program." The authors investigated the importance of different types of support structures within this program, as viewed by Native American nursing students. They distinguished between four institutionalized support structures: tangible, informational, emotional, and belonging. The authors found that students consider tangible support (such as stipends) to be comparatively less important than other types of support, particularly emotional and belonging support. Responses also revealed the importance of a fifth type of institutionalized support motivational. The authors further discuss how these institutionalized support structures might lead to successful outcomes for Native American nursing students. PMID- 21598864 TI - Methodological issues in fall prevention research involving older adults in long term care facilities. AB - The purpose of this study was to conduct a systematic review of the current fall prevention literature, examining methodological issues resulting from variations in fall definitions, methods of data collection, and standards for reporting fall rates in studies involving older adults in long-term care settings. This systematic review used the five stages of Whittemore and Knafl's review methodology to extract data from the databases, summarize, and synthesize the findings of the 10 studies included. The Critical Appraisal Skill Program checklist for randomized controlled trials criteria was used to appraise the methodological quality of the studies. Inconsistencies in fall definitions, methods of data collection, and standards for reporting fall rates were apparent across the studies reviewed. Standardized approaches to defining falls, collecting data, and reporting fall rates are necessary to interpret, make comparisons among, and disseminate the findings of studies. PMID- 21598865 TI - Failure to identify behavioral symptoms of people with dementia and the need for follow-up physical assessment. AB - This descriptively designed study examined the sensitivity and specificity of staff nurses' identification of behavior change in nursing home residents with dementia. Behavior changes and whether further physical assessment was indicated were described and compared with judgments made by one expert advanced practice nurse. The convenience sample included 155 residents and 38 staff nurses from 11 nursing homes. Verbal symptoms and body part cues were the most prevalent behaviors, regardless of the assessor. Sensitivity, or probability of identifying a real behavior change, was generally low for the staff nurses, ranging from 35% to 65% for the different types of behaviors, while specificity was high at more than 95%. Additional assessment was believed to be needed for 51% of residents by the staff nurse and for 73% of residents by the expert. This study found that staff nurses are under-identifying behavior changes and the need for additional physical assessment. PMID- 21598866 TI - Drug therapies for tardive dyskinesia: Part 1. AB - Blocking dopamine (DA) receptors in the basal ganglia can cause parkinsonian symptoms, acute dystonia, akathisia, tardive dyskinesia (TD), and neuroleptic malignant syndrome. TD is characterized by abnormal, involuntary, irregular motor movements involving muscles of the head, limbs, or trunk. Many drug therapies have been tried for TD, but none are approved by the U.S. Food and Drug Administration. The second-generation antipsychotic drugs should be considered as a treatment of first choice for clinically significant TD, because they will also be potentially effective as a primary treatment for the underlying disorder. Dopamine-depleting drugs are effective for TD, but their practical use is severely limited because of tolerability and safety concerns. Various DA modulating drugs have been tried; clinical evidence of efficacy suggests that amantadine (Symmetrel(r)) and naloxone (Narcan(r)) are worthwhile to try. Although efficacy evidence for buspirone (Buspar(r)) in TD is limited, this drug is safe and well tolerated and would be reasonable to try. Bromocriptine (Parlodel(r)), selegiline (Deprenyl(r)), and cholinergic-modulating drugs are not considered effective for TD. PMID- 21598867 TI - Does your older adult client have a gambling problem? AB - Pathological gambling is becoming an increasing problem in today's culture, particularly because opportunities and inducements to gamble abound. This article describes symptoms, consequences, and comorbidities experienced by pathological gamblers. Gambling pathology is often invisible because pathological gamblers seldom disclose gambling problems to their primary care provider. Thus, nurses will benefit from knowledge of the physical and emotional signs of the disorder. A two-question assessment tool, the Lie/Bet Questionnaire, is useful in helping nurses identify pathological gamblers. Interventions and treatment options, including group therapy and environmental modification, are also discussed. As always, education concerning problems and consequences of pathological gambling is a first step. Because research has indicated that visits to casinos by older adults have doubled since 1975, the authors use an example of an older adult to clarify the issues. Although the article's content is applicable to clients across the life span, it has particular significance for older adults. PMID- 21598868 TI - Using art to empower clients during a facility move. AB - Eastern State Hospital, a state psychiatric facility in Williamsburg, Virginia, moved from its old campus into a single new building in 2010. Adult clients were given the opportunity to decorate a portion of the new facility with ceramic tiles they designed using permanent markers. The purpose of this project was to empower the clients so they felt involved in the transition. This article describes the project from inception to fruition and is accented with images and descriptions of some of the tiles. PMID- 21598869 TI - Update on international adoption: focus on Russia. AB - American families will continue to adopt children from foreign countries; the desire to have a child transcends national boundaries. Sadly, not all adoptions have happy outcomes. A recent and well-reported incident involved an American mother, who, exasperated with her adopted son's severe behavioral problems, returned him to Russia, alone, on an aircraft. Other tragic reports involve internationally adopted children who have died at the hands of their American parents. This article provides an overview of the consequences of institutionalization as a risk factor for behavioral health of children; implications for nursing care of adoptive families follow. PMID- 21598870 TI - Alcohol-related content in undergraduate nursing curricula in the northeastern United States. AB - Societal alcohol abuse and misuse is disproportionate to the number of related didactic and clinical hours reported by traditional baccalaureate nursing programs in the United States. Because no recent research re-examines the findings from earlier studies, a survey was developed and then electronically distributed to all nursing department deans or program chairs of traditional baccalaureate nursing programs in the Northeast (N=117). Twenty-seven (23%) schools responded. Results showed limited didactic and clinical offerings. Most schools cover content related to definition, psychological and medical complications, and treatment and rehabilitation. Clinical applications were limited as was content addressing public dimensions of alcohol misuse. The current findings showed little change from those of studies conducted more than 20 years ago. Based on the current findings, further survey development is encouraged with the intent of continuing exploration of curricular offerings related to alcohol misuse. PMID- 21598871 TI - Performance of the Sulcoflex piggyback intraocular lens in pseudophakic patients. AB - PURPOSE: To present our experience with a pseudophakic piggyback intraocular lens (IOL) (Sulcoflex; Rayner Intraocular Lenses Ltd) in five eyes of four patients. One patient desired increased spectacle independence after bilateral LASIK and refractive lens exchange with an accommodating IOL. The remaining three patients with residual refractive error desired increased spectacle independence following cataract surgery with a monofocal IOL. METHODS: Four eyes received a multifocal Sulcoflex IOL and one eye received a toric Sulcoflex IOL. RESULTS: All patients achieved uncorrected distance visual acuity (UDVA) of 0.1 logMAR (Snellen 20/25) or better and those who received the multifocal Sulcoflex achieved uncorrected near visual acuity (UNVA) of N6 (Jaeger 4) or better. CONCLUSIONS: The Sulcoflex IOL may be a safe and effective method for enhancing the refractive outcome in pseudophakic eyes, providing good UDVA and UNVA when using the multifocal platform. PMID- 21598872 TI - Comparative analysis of clinical outcomes obtained with a new diffractive multifocal toric intraocular lens implanted through two types of corneal incision. AB - PURPOSE: To analyze and compare the clinical outcomes obtained after cataract surgery with the implantation of a new multifocal toric intraocular lens (IOL) using two different types of corneal incision. METHODS: Retrospective study including 64 eyes of 35 patients who underwent surgery with implantation of the AT LISA 909M multifocal toric IOL (Carl Zeiss Meditec) in 2 different ophthalmologic centers using different criteria for corneal incision size: sub 1.8 mm (micro-incision surgery [MICS] group) and 2.2 mm (mini-incision group). Visual, refractive, and corneal topographic outcomes were evaluated during 6 month follow-up. Additionally, refractive astigmatic changes were analyzed using the Alpins vectorial method. RESULTS: Significant reductions of refractive sphere and cylinder were observed postoperatively (P<.03), with associated visual improvements for near and distance (P<.01) in both groups. Mean postoperative magnitudes of difference vector, torque, and magnitude of error in the overall sample were 0.52+/-0.36 diopters (D), 0.36 +/- 0.36 D, and 0.08 +/- 0.38 D, respectively. A mean overcorrection of 4% in refractive astigmatism was found. Mean angle of error was 0.37+/- 5.50 degrees and -4.51+/-13.16 degrees for the MICS and mini-incision groups, respectively (P=.09). Significant positive correlations were found between the magnitudes of torque and difference vector (r=0.78, P<.01) as well as between the magnitude of torque and absolute angle of error (r=0.76, P<.01). CONCLUSIONS: Implantation of the AT LISA toric IOL using corneal incisions <2.2 mm provides excellent predictability for astigmatic correction. PMID- 21598873 TI - Contamination of contact lens storage cases of asymptomatic refractive surgery candidates. AB - PURPOSE: To examine the rates of contamination of contact lens storage cases of refractive surgery candidates and compare the growth yields of the traditional method of culturing and a broth-based method. METHODS: Thirty contact lens storage cases of 16 asymptomatic refractive surgery candidates were studied. Samples from the lens storage case fluid were inoculated into Bactec Peds Plus F broth (Becton Dickinson) and also directly onto blood agar, chocolate agar, and Sabouraud dextrose agar ("traditional method"). Another sample was processed for amoebal contamination. The rate of contamination of cases and the types of pathogens were evaluated for the broth-based and traditional culturing methods. Correlation between right and left storage cases of the same patient was defined as contamination of the two compartments with the same pathogen or pathogens. To avoid statistical bias, only one compartment was included in the study for these patients. RESULTS: Four storage cases were omitted due to growth correlation between right and left storage cases. Of the remaining 26 storage cases, 16 (61.5%) were found to be contaminated using the broth-based method and 10 (38.5%) using the traditional method (P=.011). High contamination rates were observed regardless of the type of disinfecting solution or type of contact lens used. CONCLUSIONS: The broth-based method had significantly greater culture yield than the traditional method. The high rates of contamination of contact lens storage cases of refractive surgery patients may put this cohort at greater risk than non contact lens wearing candidates for developing postoperative infections. PMID- 21598874 TI - A 7-year-old child seeking treatment for progressive myopia. PMID- 21598875 TI - What's your diagnosis? Spontaneous resolution of infantile primary congenital glaucoma. PMID- 21598876 TI - Glaucoma following infantile cataract surgery. AB - PURPOSE: To examine incidence, risk factors, and outcomes of glaucoma following infantile cataract extraction. METHODS: A retrospective chart review of all patients who underwent cataract extraction between January 1, 1993, and December 31, 2006, at the Children's Medical Center in Dallas. RESULTS: Sixty-four eyes met inclusion criteria, of which 11 eyes (17.2%) developed glaucoma during a mean follow-up of 65.1 +/- 4.3 months. Age younger than 3 months at cataract diagnosis (odds ratio 4.89, P = .05) or cataract extraction (odds ratio 4.4, P = .047) and the presence of anterior chamber anomalies (odds ratio 8.0, P = .01) were the only risk factors found to have statistical significance for the development of glaucoma. Eight of 11 eyes with glaucoma (72.2%) required at least one surgical intervention. Three of 10 eyes (30%) had a final best-corrected visual acuity below 20/400 and another 4 eyes (40%) demonstrated some degree of amblyopia. CONCLUSION: Despite modern microsurgical techniques, infantile cataract surgery continues to pose a risk of secondary glaucoma. This was particularly true when cataract was diagnosed and/or extracted in patients younger than 3 months of age. Most eyes that developed glaucoma required surgical management and visual outcomes continue to be poor in this group. PMID- 21598877 TI - Glaucoma and reoperations following infantile cataract surgery. PMID- 21598879 TI - Anterior pyramidal congenital cataract. PMID- 21598880 TI - Surgical treatment and prognosis of acetabular fractures associated with ipsilateral femoral neck fractures. AB - Combined ipsilateral acetabular and femoral neck fractures are the result of high energy trauma. Satisfactory treatment for this injury pattern remains a challenge, since traditional open reduction and internal fixation (ORIF) is always accompanied by a high prevalence of posttraumatic arthritis and avascular necrosis of the femoral head. Eight of 502 acetabular fractures from 1990 to 2008 were diagnosed with combined ipsilateral femoral neck fracture, in which 5 patients' fractures were associated with hip dislocation. These patients were injured from falls, traffic accidents, or crushing accidents. Radiographs and computed tomography scans were taken to check acetabular and femoral neck fractures. All of the patients underwent surgery using appropriate approaches and techniques. Postoperative radiographs demonstrated anatomic or satisfactory reduction for acetabular fractures as well as excellent or good reduction for femoral neck fractures in all of the patients. Follow-up radiographs showed femoral head necrosis in the 5 patients with femoral head dislocations, but not in the other 3 patients. We have seen few patients with this injury pattern, which makes us unable to detect significant differences between the patients associated with femoral head dislocation and those without femoral head dislocation. But by considering the results of our study and those reported in the literature, we believe that for patients with ipsilateral acetabular and femoral neck fractures without hip dislocation, satisfactory results could be expected after ORIF. But for those cases associated with hip dislocation, alternative methods such as acute THR as primary treatment are worthy of consideration. PMID- 21598881 TI - Iliopsoas cyst causing persistent pain after total hip arthroplasty. AB - Persistent pain after total hip arthroplasty (THA) has many potential causes. The most common are aseptic loosening, infection, and heterotopic ossification. Irritation of the iliopsoas tendon due to the acetabular component is an underestimated cause of persistent groin pain and functional disability after THA with rare incidence. Pain specific to iliopsoas tendonitis includes activities such as hyperextension of the hip, forced flexion, and activities of daily living (eg, ascending stairs). This article presents a case of a 50-year old man with clinical and radiological signs of osteoarthritis of the right hip joint. A THA was performed. After a symptom-free interval of several weeks postoperatively, the patient reported pain projecting from the right groin and radiating ventromedially along the leg. Magnetic resonance imaging of the hip showed a fluid-filled cyst in anatomical proximity to the femoral nerve causing an iliopsoas tendonitis. The patient underwent surgical resection of the cyst was performed by an anterior approach; a conjunction to the hip joint was not present. The implanted components of the prosthesis showed good osseointegration with no signs of loosening. The cyst was removed and the iliopsoas tendon was released. A few weeks after the operation, the patient was pain free. At 17-month follow-up, no problems were reported. In cases such as this, finding the correct diagnosis may be difficult and misleading. Conservative and operative therapeutic options are discussed and compared with divergent findings in the literature. PMID- 21598882 TI - Transphyseal anterior cruciate ligament reconstruction in a skeletally immature knee using anterior tibialis allograft. AB - Anterior cruciate ligament (ACL) injury in the skeletally immature individual is being recognized with increasing frequency. Nonoperative treatment of ACL injuries in skeletally immature patients have not been favorable. Surgical treatment options for complete ACL tears include primary ligament repair, extraarticular tenodesis, transphyseal reconstruction, partial transphyseal reconstruction, and physeal-sparing reconstruction. The advantage of transphyseal reconstruction is placement of the graft tissue in an isometric position, which provides better results, according to the literature. The potential disadvantage is angular or limb-length discrepancy caused by physeal violation. Controversy exists in allograft selection about whether bone or soft tissue passes into physes. The use of standard tunnels provides reliable results, but carries the risk of iatrogenic growth disturbance from physeal injury.This article presents 4 cases of transphyseal ACL reconstruction using anterior tibialis allograft in skeletally immature patients that had satisfactory functional outcomes with no growth disturbances. This is the first report of transphyseal ACL reconstruction using anterior tibialis allograft in skeletally immature patients in the English speaking literature. All patients underwent transphyseal ACL reconstruction using anterior tibialis tendon allograft. None of the patients had angular deformities. No early physeal arrest was measured between the preoperative and postoperative radiographs. At last follow-up, the results of the Lachman test were normal for 3 patients and nearly normal for 1 patient. All patients demonstrated full range of knee motion (comparing the reconstructed knee to the contralateral knee). The results of the pivot-shift test were normal for 3 patients and nearly normal for 1 patient. No patients reported giving way. PMID- 21598883 TI - Recession wedge osteotomy of the greater tuberosity for proximal humeral varus. AB - Proximal humeral varus has multiple etiologies and may lead to impingement and reduced shoulder range of motion, particularly abduction and forward elevation. Valgus osteotomies have been described at the level of the surgical neck yielding acceptable results. This article describes a case of a male electrician who was treated for symptoms associated with proximal humeral varus of the right shoulder. He underwent an osteotomy of the greater tuberosity designed to reduce impingement and improve range of motion. The patient had previously undergone two separate surgical procedures for a simple bone cyst, but continued to have reduced shoulder function secondary to a prominent greater tuberosity. Preoperative and follow-up radiographs, physical examinations, and shoulder function were retrospectively reviewed for 32 months. Following treatment, active forward elevation improved from 130 degrees preoperatively to 170 degrees , abduction from 90 degrees to 170 degrees , external rotation from 45 degrees to 70 degrees , and internal rotation from T10 to T7. The patient reported relief of pain, impingement-free range of motion, and full symmetric function equal to that of his contralateral shoulder. Radiographs demonstrated osteotomy union, improved greater tuberosity/acromial clearance, and no impingement with abduction. Postoperative stiffness was the only complication noted for which a shoulder manipulation was performed under anesthesia. Thus, recession wedge osteotomy of the prominent greater tuberosity may serve as a viable surgical approach to reducing impingement and improving clinical function in proximal humeral varus. PMID- 21598884 TI - Fracture dislocation of carpometacarpal joints: a missed injury. AB - Fracture dislocation of the carpometacarpal joints on the ulnar side of the hand is an uncommon injury. These are high-energy injuries seen in motorcyclists and boxers. The mechanism of injury involves violent, forceful dorsiflexion of the wrist combined with longitudinal impact on the closed hand. This article reports a case of fracture of the base of the middle finger with dislocation of the ring and little finger carpometacarpal joints. On first examination, a diagnosis of isolated, minimally-displaced, middle-metacarpal base fracture was made and deemed suitable for nonoperative management. The hand was splinted in a plaster of-Paris slab. Later, a true lateral radiograph showed the exact nature of the injury. The fracture was successfully treated with closed reduction under general anesthesia and transfixation using Kirschner wires. Functional results were excellent with return to work at 10 weeks and excellent grip strength at 14 weeks. This injury may be missed in an acute setting in a busy accident and emergency unit. Swelling around the wrist with shortening of the knuckle should alert the clinician towards the possibility of such an injury. On routine anteroposterior view, overlap of joint surfaces, loss of parallelism, and asymmetry at the carpometacarpal joints should raise suspicion of the possibility of a subtle carpometacarpal injury. This article highlights the importance of a high index of suspicion, a true lateral radiograph, and careful evaluation of radiographs in diagnosing these injuries. Intensive postoperative physiotherapy is vital to achieving a satisfactory outcome. PMID- 21598885 TI - Recurrent fluctuant mass of the wrist and forearm associated with chronic tenosynovitis by Mycobacterium kansasii. AB - This article presents a case of a painless fluctuant mass on the volar aspect of the wrist and forearm of an immunocompetent 45-year-old man with no history of significant underlying disease. This mass proved to be a chronic tenosynovitis associated with Mycobacterium kansasii infection. The patient, who had a history of multiple minor cuts and abrasions plus exposure to an aquatic environment, had a wide resection of the lesion and elective tenosynovectomy. Operative findings revealed a marked tenosynovitis of flexor tendons. Several rice bodies lesions were also observed along the course of the involved flexor tendons.Biopsy showed a granulomatous inflammatory reaction. Specimens of affected tissue were sent to a laboratory for solid (at 30 degrees C and at 37 degrees C) and liquid (at 37 degrees C) mycobacterial culture. The initial Ziehl-Neelsen stain for acid-fast bacilli was positive. After 8 days of incubation, acid-fast bacilli were recovered. In accordance with the diagnosis of M kansasii tenosynovitis and the results of antibiotic susceptibility testing, triple therapy with rifampicin, isoniazid and clarithromycin was initiated. After 3 months of therapy, the patient experienced improvement in the swelling and is due to receive 12 months of antibiotic therapy. Despite awareness of atypical mycobacterial infections, diagnosis is frequently delayed, leading to increased morbidity. Patients with exposure to these atypical pathogens require a broadened differential to include appropriate testing and culture of specimens to obtain an accurate diagnosis. PMID- 21598886 TI - Operative versus nonoperative management of Pipkin type-II fractures associated with posterior hip dislocation. AB - Little has been written on randomized, controlled studies of operative versus nonoperative management of Pipkin type-II fractures associated with posterior dislocation of the hip. It is difficult to validate the optimal management of these fractures. The goals of this study were to (1) evaluate the results of conservative and surgical treatment for Pipkin type-II fractures associated with posterior dislocation of the hip and supply the optimal management for these fractures and (2) identify whether the Smith-Petersen approach is a safe and reliable surgical approach for Pipkin type-II fractures.Twenty-four patients were randomly divided into 2 groups: the conservative group (n=12) was treated by closed reduction, and the surgical group (n=12) was treated by primary open reduction internal fixation (ORIF) by bioabsorbable screws via a Smith-Petersen approach. Minimum follow-up was 24 months. Functional outcome was measured using the Thompson and Epstein score and the d'Aubigne-Postel score. Heterotopic ossification was classified based on the Brooker classification. The outcome of the conservative group was worse than that of the surgical group (P=.037). Two patients in the conservative group needed joint replacement for avascular necrosis of the femoral head. Heterotopic ossification was found in 6 patients (1 patient in the conservative group and 5 in the surgical group).Primary ORIF by bioabsorbable screws via a Smith-Petersen approach is an effective treatment for Pipkin type-II fractures associated with posterior dislocation. PMID- 21598887 TI - The new proximal femoral nail antirotation-Asia: early results. AB - The proximal femoral nail antirotation system was introduced by the Arbeitsgemeinschaft fur Osteosynthesfragen/Association for the Study of Internal Fixation (AO/ASIF) in 2003 and is suitable for treating unstable trochanteric fractures. However, proximal femoral nail antirotation was designed according to the geometric proportions of the White population, and it is known that important differences exist between Asians and Americans with regard to femoral geometry. Reports of serious postoperative complications also exist when used for the elderly Asian population. Therefore, geometrical mismatch between proximal femoral nail antirotation and the femora of Asians has led the AO/ASIF to design a new proximal femoral nail antirotation for Asia with adapted sizes and geometry. This article reports early clinical results of using proximal femoral nail antirotation for Asians in 84 consecutive patients to stabilize unstable trochanteric fractures (AO classification, 31.A2 and A3). Patients were followed up for an average 8 months (range, 4-11 months). Intraoperative and postoperative complications, surgical details, and outcome measurements were evaluated. Fractures were treated by closed reduction and intramedullary fixation. The proximal femoral nail antirotation Asia position was ideal in 80 cases (95%). No patients showed complication related to the mismatch between the nail and femora. The mean time to bone healing was 14 weeks. Functionally, 90% of the patients regained pretrauma mobility. According to the Harris hip scoring system, 63 patients (78%) had an excellent or good outcome. The new proximal femoral nail antirotation Asia yields better results in the treatment of unstable trochanteric fractures in elderly patients by closely matching Asian femoral anatomy and thereby reducing complications related to the implants. PMID- 21598888 TI - Clinical features and treatment of the hip in multiple epiphyseal dysplasia in childhood. AB - Multiple epiphyseal dysplasia is a rare congenital osteochondrodysplasia disorder characterized by a delay in the appearance of the epiphyses; irregular, symmetric epiphyseal formation; mild short stature; and early-onset osteoarthritis. Peripheral weight-bearing and nonweight-bearing joints can be affected. Treatment of the hip deformity in multiple epiphyseal dysplasia is a challenge for orthopedic surgeons.We reviewed the clinical features and treatment options of hip joints affected by multiple epiphyseal dysplasia in 6 young patients (4 boys and 2 girls). Average patient age was 8.8 years (range, 5-14 years). The spectrum of hip joint deformity ranged from mild to severe. Surgical procedures included intertrochanteric extension osteotomy of the femur in 2 patients (4 hips), Staheli acetabular augmentation in 1 patient (2 hips), and trochanter arthroplasty associated with Dega osteotomy in 2 patients (4 hips). One patient did not undergo surgical treatment. All patients were followed up for an average 7.2 years. Joint function improved in the patients treated surgically. The coxa vara deformity was corrected satisfactorily, and the femoral head was covered completely by the acetabulum.Good mid-term outcomes were obtained for the treatment of severe hip deformity by using intertrochanteric extension osteotomy and trochanter arthroplasty. However, because of the inherent nature of this disorder, long-term follow-up of the patients is required. PMID- 21598889 TI - Trends in femoroacetabular impingement research over 11 years. AB - Femoroacetabular impingement is the abutment between the proximal femur and the rim of the acetabulum. It is a common cause of labral injury that has been identified as an early cause of hip osteoarthritis. The diagnosis of femoroacetabular impingement of the hip is currently well defined in orthopedic surgery but should attract the attention of physicians in other disciplines. Conversely, much less is known about the etiology and natural history of femoroacetabular impingement.The goal of this study was to assess the number of articles published on femoroacetabular impingement over 11 years in orthopedic vs nonorthopedic medical journals, and to evaluate the quality of available evidence. PubMed and OvidSP databases were searched for articles on femoroacetabular impingement published from 1999 to 2009. Articles were characterized by publication type and journal type per year. Regression analysis was used to determine the effect of publication year on number of publications of each type. The search yielded 206 publications on femoroacetabular impingement during the evaluation period. Seventy-two percent were published in orthopedic journals. Overall, the number of publications increased exponentially with time. There was an increase in clinical trials over the course of the study period. However, studies with high-quality evidence were scarce. The increase in data from orthopedic and nonorthopedic disciplines is welcome. Nevertheless, high quality evidence on femoroacetabular impingement is lacking. We believe the current trend toward evidence-based orthopedic surgery will impact future research on this relatively new disorder. PMID- 21598890 TI - Effect of a perioperative intra-articular injection on pain control and early range of motion following bilateral TKA. AB - Pain control after total knee arthroplasty (TKA) is integral in the immediate postoperative period for early rehabilitation. Numerous different methods of postoperative analgesia are available, but each has its own risk of adverse side effects. This study was performed to prospectively evaluate the benefits of an intra-articular analgesic injection in patients undergoing bilateral TKA.Thirty consecutive patients undergoing bilateral TKA were enrolled in this prospective, randomized, controlled study. Each patient was randomized to receive (1) a perioperative intra-articular mixture of morphine, bupivacaine with epinephrine, and ketorolac in 1 knee, and (2) injectable sterile saline in the contralateral knee. Each patient acted as his or her own internal control. The pharmacologically injected knee had statistically significantly less pain immediately postoperatively when compared to the control knee and displayed significantly increased range of motion within the first week of rehabilitation.The use of an intraoperative intra-articular injection with the above drug combination significantly reduces patient pain and increases postoperative mobility with no apparent risks following bilateral TKA. PMID- 21598891 TI - Analysis of medial flexion gap after medial release for varus deformity by navigation-guided TKA. AB - The goal of this study was to analyze medial flexion gaps after medial release for varus deformity by navigation-guided total knee arthroplasty (TKA). In each patient, a preoperative standing anteroposterior (AP) radiograph of the lower extremity and an AP valgus stress radiograph of the knee were used to measure preoperative mechanical axis angle and valgus stress angle, respectively. The correlation between preoperative varus deformities and medial flexion gap increases as measured by navigation was examined. Patients were assigned to 2 groups: group A (25 knees), in which the difference between the lateral flexion gap (LFG) and the medial flexion gap (MFG) (LFG-MFG) was <= 1 mm; and group B (73 knees), with an LFG-MFG of >1 mm.Mean preoperative mechanical axis angles in groups A and B were 13.21 degrees +/- 5.01 degrees varus (range, 3.7 degrees 23.6 degrees ) and 10.05 degrees +/- 3.70 degrees varus (range, 1.9 degrees - 23.7 degrees ), respectively. Mean preoperative valgus stress angles in groups A and B were 1.72 degrees +/- 0.89 degrees valgus (range, 0.1 degrees - 4.0 degrees ) and 4.84 degrees +/- 2.61 degrees valgus (range, 0.1 degrees - 11.7 degrees ), respectively. A significant difference was observed between the groups in terms of mechanical axis angle (P = .002) and valgus stress angle (P<.001). Furthermore, valgus stress angle was found to be more strongly correlated with medial flexion gap increase than mechanical axis angle. The cutoff values of mechanical axis angle and valgus stress angle in group A were 13.4 degrees and 2.45 degrees , respectively.This study shows that preoperative valgus stress angle measurements can be used to predict the extent of medial release for varus deformity. PMID- 21598892 TI - Variations in the quality of care delivered to patients undergoing total knee replacement at 3 affiliated hospitals. AB - While excellent clinical results have been seen with total knee replacement (TKR), extensive documentation exists in variations in outcomes due to factors such as hospital and surgeon volume. The hypothesis of this study was that statistically significant variation exists in the processes of care delivered to patients undergoing TKR at 3 affiliated hospitals.Retrospective chart review was used to compare the quality of care delivered to a sample of patients from an academic medical center, public county hospital, and private community hospital. Two hundred twenty-four patients undergoing primary TKR were included. Quality of care was measured by determining adherence to a set of 31 evidence-based quality indicators created using the RAND/UCLA modified Delphi expert panel methodology. The overall rate of adherence to the quality indicators was 53% (95% confidence interval [CI], 52%-55%) for the 224 patients. There was a statistically significant difference between sites, with patients treated at the high-volume academic center demonstrating a 58% rate of adherence (95% CI, 56%-61%) compared with 50% (95% CI, 48-51%; P =.008) at the lower-volume public hospital and 52% (95% CI, 51%-54%; P =.03) at the lower-volume private hospital.Further study is warranted to determine the extent of variation in the delivery of care and its relationship to variation in outcomes of care for patients undergoing TKR. PMID- 21598893 TI - The connection between strong social support and joint replacement outcomes. AB - A myriad of emotional, informational, and tangible needs can easily overwhelm patients as they seek to navigate a complicated surgical procedure. This article demonstrates that a dedicated family member or friend supporting their loved one before, during, and after joint replacement surgery measurably impacts quality and outcomes. The multidisciplinary, multihospital study team developed the following Opportunity Statement: "To define, measure, and implement a progressive family/friend support system across the continuum of care promoting optimal patient recovery after total joint arthroplasty." The team used the modified Groningen Orthopedic Social Support Scale to measure levels of social support and associated these levels with other patient outcomes.Analysis of 1722 observations across 4 hospitals found that patients with strong social support have shorter hospital stays, are more likely to be discharged home, to meet ambulation and transfer-out-of-bed targets, and to score hospital quality of care higher, and are more confident and ready to go home on discharge. Three presence intervals were also found to be significant predictors of key outcome measures: family/friend presence during the preoperative classes, in the preoperative holding area, and during the last physical therapy session. These intervals may serve as reasonable social support proxies for organizations desiring to measure social support to ultimately affect quality and outcomes. PMID- 21598894 TI - Application of locking plate in long-bone atrophic nonunion following external fixation. AB - The treatment of atrophic fracture nonunion continues to represent a therapeutic challenge. Large segmental osteopenia is often seen in patients who received uniplanar or hybrid external fixators as the definitive method of fixation for high-energy fractures, and this adds more difficulties to the treatment of fracture nonunion. This retrospective study was designed to assess the outcome of locking compression plating with autologous bone grafting in patients with long bone atrophic nonunion following external fixation.From January 2004 to December 2009, a series of consecutive patients with atrophic nonunion of the long bone following external fixation were treated with this method in our institution. The clinical outcomes and complications of these patients were retrospectively analyzed. Twenty-seven patients with 28 fracture nonunions were involved in this study. Mean follow-up was 14.2+/-3.4 months. Bony union was achieved in all 27 patients within a mean 18.6+/-4.8 weeks after revision surgery. Two patients developed superficial wound infections. No deep infections were found, and no implant failure was seen. Three patients reported minor pain in the donor site of the bone graft, and no other donor site complications were found.Revision osteosynthesis of long-bone atrophic nonunion following external fixation by locking compression plating with autologous iliac crest bone grafting represents a safe and efficacious modality for the treatment of these challenging conditions. PMID- 21598895 TI - Avascular necrosis of the femoral head after osteosynthesis of femoral neck fracture. AB - The reported incidence of avascular necrosis after femoral neck fracture fixation varies widely, and there is no consensus regarding its risk factors. We evaluated the incidence of avascular necrosis of the femoral head with the use of contemporary techniques for femoral neck fracture fixation. We then sought to determine what potential risk factors influenced the development of avascular necrosis.Between 1990 and 2005, one hundred sixty-three intracapsular femoral neck fractures in 163 patients were treated with internal fixation at our level-I trauma center. All patients were monitored until conversion to total hip arthroplasty or for a minimum of 2 years postoperatively. Ten patients (10 hips) died and 7 patients (7 hips) were lost to follow-up. The remaining 146 patients (146 hips) had a mean 5.2 years of follow-up (range, 3 months to 17 years). The incidence of avascular necrosis was 25.3% (37 hips). The average time to diagnosis of avascular necrosis was 18.8 months (range, 3-47 months). Patient sex, age, interval from injury to surgery, and mechanism of injury were statistically not associated with the development of avascular necrosis. The quality of fracture reduction, adequacy of fixation, degree of displacement, and comminution of the posterior cortex were significantly associated. After we controlled for patient and radiographic characteristics, multivariate analyses indicated that the important predictors for avascular necrosis are poor reduction (odds ratio=13.889) and initial displacement of the fracture (odds ratio=4.693). PMID- 21598896 TI - Evaluation of the calori et Al nonunion scoring system in a retrospective case series. AB - Nonunion is one of the most challenging orthopedic complications. Although current definitions are accepted, they fail to provide a satisfactory definition of nonunion. Different classifications for nonunion have been described, but these systems did not take all required factors and requirements of nonunion treatment into account for fracture healing. Calori et al recently developed a new comprehensive nonunion scoring system, which takes into account the whole fracture personality that influences non-union. The aim of this study is to evaluate the validity of the Calori et al system in the treatment of nonunions. We retrospectively reviewed our database for lower extremity nonunion from 2002 to 2009. The demographic and clinical data, laboratory, and radiological investigations were collected from medical records and phone interviews. Forty cases were identified: 32 men and 8 women. Mean patient age was 39.75 years (range, 6-102 years). Seventeen were femoral and 23 were tibial. Our patients were divided into 3 groups according to the database treatment: group 1 standard treatment (3 patients), group 2 specialized care and treatment (33 patients), group 3 amputations (4 patients). If we apply the recommended management by Calori et al to our patients, they will be divided into groups similar to the database treatments. Statistical analysis showed significant correlation between our actual treatment and those recommended by the Calori system where the P value was <.01. We concluded that the Calori et al scoring system could be valid as a guideline for lower extremity nonunion treatment. PMID- 21598897 TI - Suspected nonaccidental trauma and femoral shaft fractures in children. AB - The question of suspected nonaccidental trauma as a possible cause of injury for femoral shaft fractures in children is a troubling but common issue facing orthopedic surgeons. The purpose of this study is to analyze femoral shaft fractures at a major pediatric level I trauma center in a large metropolitan area over a 5-year period to determine the incidence of suspected nonaccidental trauma and the risk factors associated with that diagnosis. This study is a retrospective review of all children younger than 5 years at a large trauma center in a southwestern metropolitan area who presented with a femoral shaft fracture. Patient charts were reviewed to determine demographics, mechanism of injury, and fracture type. Referrals to social work and Child Protective Services were also reviewed to determine an overall incidence of suspected nonaccidental trauma.Over the 5-year study period, 137 patients presented to our institution with a femoral shaft fracture. Mean patient age at the time of injury was 2.2 years (range, 1 month to 4 years). Overall, 43 patients with a mean age of 1.8 years were determined to have injuries suspicious of nonaccidental trauma and were referred to Child Protective Services, giving an overall incidence of 31%. Age younger than 1 year was a highly significant risk factor for suspected nonaccidental trauma. Of the 20 children younger than 1 year, 18 (90%) were referred to Child Protective Services, comprising 42% of those children suspicious of nonaccidental trauma. The presence of either Medicaid or no insurance was a highly statistically significant risk factor for suspected nonaccidental trauma. PMID- 21598898 TI - Review of the current literature as a preparatory tool for the trauma content of the Orthopaedic in-Training Examination. AB - Currently, the only standardized evaluation of trauma knowledge throughout orthopedic training is found in the Orthopaedic In-Training Examination, which is administered annually to all residents by the American Academy of Orthopaedic Surgeons. Our goals were to assess the Orthopaedic In-Training Examination to (1) determine the content of the trauma questions, (2) identify the content of the 3 most frequently referenced journals on the answer keys, and (3) evaluate the correlation between those contents.We reviewed the trauma-related Orthopaedic In Training Examination questions and answer keys for 2002 through 2007. Content for test questions and cited literature was assessed with the same criteria: (1) category type, (2) anatomic location, (3) orthopedic focus, and (4) treatment type. For each of the 3 most frequently referenced journals, we weighted content by dividing the number of times it was referenced by the number of its trauma related articles. We then compared the journal data individually and collectively to the data from the Orthopaedic In-Training Examination trauma questions. A chi square analysis with Yates correction was used to determine differences. Questions and literature were similar in the most frequently addressed items in each of the 4 areas: category type (taxonomy 3, treatment), 52.4% and 60.7%, respectively; anatomic location (femur), 23.3% and 27.7%, respectively; orthopedic focus (fracture), 51.0% and 56.5%, respectively; and treatment type (multiple/nonspecific), 39.0% and 35.4%, respectively.The content correlation found between the questions and literature supports the idea that reviewing current literature may help prepare for the trauma content on the Orthopaedic In Training Examination. PMID- 21598899 TI - Incidence of False Positive Rotator Cuff Pathology in MRIs of Patients with Adhesive Capsulitis. AB - The purpose of this study was to compare the incidence of presumed rotator cuff pathology based on radiologist and surgeon interpretation of preoperative magnetic resonance images (MRIs) with actual rotator cuff pathology found intraoperatively in patients undergoing arthroscopic capsular release for adhesive capsulitis.The medical records of 38 consecutive patients who underwent arthroscopic glenohumeral capsular release for adhesive capsulitis between September 2001 and May 2007 were retrospectively reviewed. Radiologist and surgeon predicted status of the rotator cuff by prospective MRI interpretation was compared to the actual status of the rotator cuff intraoperatively. Radiologists' preoperative MRI interpretations predicted a 57.9% incidence of rotator cuff pathology, while operative findings revealed a true incidence of only 13.2% (P<.0001). Radiologists accurately predicted the absence or presence of a rotator cuff tear in 19 of 38 cases (50%), compared to the surgeon, who correctly interpreted 29 of 38 MRIs (76.3%).Interpretations of shoulder MRIs in patients with adhesive capsulitis may provide misleading information regarding rotator cuff pathology. The actual findings of shoulder MRI scans may lead to the appearance of false rotator cuff pathology in this population, and a high percentage of false positive MRI reports of rotator cuff tears was observed in these patients. If MRI is chosen as a diagnostic adjunct in this patient population, careful consideration should be given to its interpretation to avoid unnecessary or possibly aggravating surgical intervention. PMID- 21598900 TI - Micro-CT Density Analysis of the Medial Wall of the Human Medial Cuneiform. AB - The human medial cuneiform is incompletely characterized with regard to anatomical morphology, including mineral density and bone quality. Clinically, we have observed failures of fixation by pull-through of devices through relatively soft medial bone. Defining patterns of relative density may provide valuable information regarding implant placement as higher cortical density bone may offer better resistance to such failures. We sought to identify an area of greatest density along the medial wall of the medial cuneiform.Ten fresh-frozen human cadaveric medial cuneiforms underwent micro-computed tomography imaging. Images were analyzed to obtain densities in 4 quadrants along the medial wall of the medial cuneiform. Seven of 10 specimens revealed a maximum density in the plantar distal quadrant of the medial wall of the medial cuneiform. Chi-square goodness of-fit testing indicated that the density of this quadrant was significantly different from 3 other quadrants (P<.009). Using the Principle of Standard Residuals, the density of the plantar distal quadrant was significantly different than the other 3.We conclude that the plantar distal quadrant of the medial cuneiform contains bone of maximal density when compared to 3 other quadrants. Surgeons who place implants in this region should be aware that this area might offer better resistance to fixation failure. PMID- 21598901 TI - Short-term outcome of bilateral decompression via a unilateral paramedian approach for transforaminal lumbar interbody fusion with unilateral pedicle screw fixation. AB - The purpose of this study was to evaluate the clinical and radiologic outcomes of bilateral decompression via a unilateral paramedian approach for transforaminal lumbar interbody fusion. Forty consecutive patients satisfying the inclusion criteria were divided randomly into groups 1 and 2. Patients were treated with unilateral (group 1) or bilateral (group 2) pedicle screw fixation and bilateral decompression via 1-sided (group 1) or bilateral (group 2) paramedian approach. Perioperative parameters (operation time, blood loss, hospital stay, complications, and implant cost), clinical outcome parameters (Japanese Orthopedic Association [JOA] scores, visual analog scale [VAS] scores, and Oswestry Disability Index [ODI] preoperatively and at 1 week and 3 months postoperatively), and radiologic parameters (radiograph and computed tomography [CT] scan preoperatively and at 1 week postoperatively) were compared.No differences were seen between groups 1 and 2 with respect to operation time, blood loss, or hospital stay. No complications were observed in either group. The ODI, JOA, and VAS values of both groups showed significant differences between the preoperative and 1-week or 3-month postoperative values. No significant differences were seen in the improvements of the ODI, JOA, and VAPS values between groups 1 and 2 at any postoperative time point. Postoperative CT indicated that the contralateral decompression was sufficient in both groups.The short-term results indicate that bilateral decompression via a unilateral paramedian approach for transforaminal lumbar interbody fusion with unilateral pedicle screw fixation is safe, feasible, and effective over the short-term and is more cost-efficient than a bilateral paramedian approach. PMID- 21598902 TI - Lower extremity bypass graft occlusion after intramedullary fixation of intertrochanteric hip fracture on a fracture table. AB - This article presents a case of a 90-year-old woman who previously underwent a common femoral to anterior tibial artery bypass grafting with a Gore-Tex graft (Gore Medical, Flagstaff, Arizona). She subsequently sustained an ipsilateral intertrochanteric hip fracture after a mechanical fall and underwent internal fixation with an intramedullary nail using a fracture table. In the immediate postoperative period, she developed limb-threatening ischemia in her leg due to graft thrombosis. The patient underwent a successful thrombectomy and embolectomy. However, she subsequently developed nonhealing ulcers to this extremity over the course of weeks, requiring surgical debridement. Gangrene ensued and she underwent a below-the-knee amputation.Complications from the use of fracture tables have been described for perineal soft tissue injury, leg malrotation or malalignment, neurologic injury, and iatrogenic compartment syndrome of the healthy leg. Arterial complications after intramedullary fixation of femur fractures are rare and may be caused by direct arterial trauma during placement of the locking screws through the intramedullary nail. This article is the first, to our knowledge, to describe an occlusion of a lower extremity bypass graft after intramedullary fixation on a fracture table. Surgeons should be aware of potential limb threatening ischemia in patients with peripheral vascular disease, especially in those with prior lower extremity bypass grafts. Proper preoperative counseling should be given to these patients when using fracture tables during hip fracture surgery. PMID- 21598903 TI - Crystal structure of Agaricus bisporus mushroom tyrosinase: identity of the tetramer subunits and interaction with tropolone. AB - Tyrosinase catalyzes the conversion of phenolic compounds into their quinone derivatives, which are precursors for the formation of melanin, a ubiquitous pigment in living organisms. Because of its importance for browning reactions in the food industry, the tyrosinase from the mushroom Agaricus bisporus has been investigated in depth. In previous studies the tyrosinase enzyme complex was shown to be a H(2)L(2) tetramer, but no clues were obtained of the identities of the subunits, their mode of association, and the 3D structure of the complex. Here we unravel this tetramer at the molecular level. Its 2.3 A resolution crystal structure is the first structure of the full fungal tyrosinase complex. The complex comprises two H subunits of ~392 residues and two L subunits of ~150 residues. The H subunit originates from the ppo3 gene and has a fold similar to other tyrosinases, but it is ~100 residues larger. The L subunit appeared to be the product of orf239342 and has a lectin-like fold. The H subunit contains a binuclear copper-binding site in the deoxy-state, in which three histidine residues coordinate each copper ion. The side chains of these histidines have their orientation fixed by hydrogen bonds or, in the case of His85, by a thioether bridge with the side chain of Cys83. The specific tyrosinase inhibitor tropolone forms a pre-Michaelis complex with the enzyme. It binds near the binuclear copper site without directly coordinating the copper ions. The function of the ORF239342 subunits is not known. Carbohydrate binding sites identified in other lectins are not conserved in ORF239342, and the subunits are over 25 A away from the active site, making a role in activity unlikely. The structures explain how calcium ions stabilize the tetrameric state of the enzyme. PMID- 21598904 TI - Chemical, thermal, and electric field induced unfolding of single protein molecules studied using nanopores. AB - Single-molecule experimental techniques have recently shown to be of significant interest for use in numerous applications in both the research laboratory and industrial settings. Although many single-molecule techniques exist, the nanopore platform is perhaps one of the more popular techniques due to its ability to act as a molecular sensor of biological macromolecules. For example, nanopores offer a unique, new method for probing various properties of proteins and can contribute to elucidating key biophysical information in conjunction with existing techniques. In the present study, various forms of bovine serum albumin (BSA) are detected including thermally refolded BSA, urea-denatured BSA, and multiple forms of BSA detected at elevated electric field strengths (with and without urea). We also provide excluded volume measurements for each of these states that normally are difficult to obtain due to unknown and unstable protein conformations. PMID- 21598905 TI - Synthesis of dendritic polyglycerol anions and their efficiency toward L-selectin inhibition. AB - A versatile route for the synthesis of highly functionalized, polyanionic macromolecules based on dendritic polyglycerol was applied by means of the Huisgen-Sharpless-Meldal 1,3-dipolar cycloaddition ("click-reaction") of polyglycerolazide precursors and alkyne-functionalized anions such as sulfonates, carboxylates, phosphonates, and bisphosphonates. In addition, the corresponding polyglycerol phosphate has been synthesized via direct hydroxyl interconversion of polyglycerol to the corresponding phosphate with a degree of functionalization >80% by analogy to the synthesis of previously reported polyglycerol sulfates (dPGS). On the basis of the finding that dPGS exhibits high affinity for L- and P selectin, the potential of these novel polyanionic, multivalent macromolecules of varying anionic nature as L-selectin inhibitors has been evaluated in vitro by means of a competitive concentration dependent binding assay. Affinity of all polyanions toward L-selectin was demonstrated with distinct IC(50) values ranging from the low nanomolar to the high micromolar range. The efficiency of L-selectin inhibition increases in the order carboxylate < phosphate < phosphonate ~ sulfonate < bisphosphonate < sulfate. Additional DLS and zeta-potential measurements of these polyanions were performed to correlate their binding affinity toward L-selectin with their anionic nature. However, a direct correlation of effective charge and particle size with the determined IC(50) values turned out to require further in-depth studies on the microstructure of the polyanions but clearly indicate an exceptional position of dPGS among the studied dendritic polyelectrolytes. PMID- 21598906 TI - A comparison of different QSAR approaches to modeling CYP450 1A2 inhibition. AB - Prediction of CYP450 inhibition activity of small molecules poses an important task due to high risk of drug-drug interactions. CYP1A2 is an important member of CYP450 superfamily and accounts for 15% of total CYP450 presence in human liver. This article compares 80 in-silico QSAR models that were created by following the same procedure with different combinations of descriptors and machine learning methods. The training and test sets consist of 3745 and 3741 inhibitors and noninhibitors from PubChem BioAssay database. A heterogeneous external test set of 160 inhibitors was collected from literature. The studied descriptor sets involve E-state, Dragon and ISIDA SMF descriptors. Machine learning methods involve Associative Neural Networks (ASNN), K Nearest Neighbors (kNN), Random Tree (RT), C4.5 Tree (J48), and Support Vector Machines (SVM). The influence of descriptor selection on model accuracy was studied. The benefits of "bagging" modeling approach were shown. Applicability domain approach was successfully applied in this study and ways of increasing model accuracy through use of applicability domain measures were demonstrated as well as fragment-based model interpretation was performed. The most accurate models in this study achieved values of 83% and 68% correctly classified instances on the internal and external test sets, respectively. The applicability domain approach allowed increasing the prediction accuracy to 90% for 78% of the internal and 17% of the external test sets, respectively. The most accurate models are available online at http://ochem.eu/models/Q5747 . PMID- 21598908 TI - Open-framework copper adeninate compounds with three-dimensional microchannels tailored by aliphatic monocarboxylic acids. AB - A series of isostructural copper(II) coordination polymers containing the nucleobase adenine and different monocarboxylic acids as bridging ligands, [Cu(2)(MU(3)-ade)(2)(MU(2)-OOC(CH(2))(n)CH(3))(2)].xH(2)O (n from 0 to 5), have been prepared. Single-crystal X-ray analysis of acetate (n = 0) and butanoate (n = 2) compounds shows a covalent three-dimensional network in which the copper(II) centers are bridged by MU-N3,N7,N9-adeninato and MU-O,O'-carboxylato ligands, with crystallization water molecules trapped in the pores, which are decorated by the Watson-Crick faces of the adenine. The tunable permanent porosity of guest free compounds was confirmed by gas adsorption measurements. PMID- 21598909 TI - EPR, 1H and 2H NMR, and reactivity studies of the iron-oxygen intermediates in bioinspired catalyst systems. AB - Complexes [(BPMEN)Fe(II)(CH(3)CN)(2)](ClO(4))(2) (1, BPMEN = N,N'-dimethyl-N,N' bis(2-pyridylmethyl)-1,2-diaminoethane) and [(TPA)Fe(II)(CH(3)CN)(2)](ClO(4))(2) (2, TPA = tris(2-pyridylmethyl)amine) are among the best nonheme iron-based catalysts for bioinspired oxidation of hydrocarbons. Using EPR and (1)H and (2)H NMR spectroscopy, the iron-oxygen intermediates formed in the catalyst systems 1,2/H(2)O(2); 1,2/H(2)O(2)/CH(3)COOH; 1,2/CH(3)CO(3)H; 1,2/m-CPBA; 1,2/PhIO; 1,2/(t)BuOOH; and 1,2/(t)BuOOH/CH(3)COOH have been studied (m-CPBA is m chloroperbenzoic acid). The following intermediates have been observed: [(L)Fe(III)(OOR)(S)](2+), [(L)Fe(IV)?O(S)](2+) (L = BPMEN or TPA, R = H or (t)Bu, S = CH(3)CN or H(2)O), and the iron-oxygen species 1c (L = BPMEN) and 2c (L = TPA). It has been shown that 1c and 2c directly react with cyclohexene to yield cyclohexene oxide, whereas [(L)Fe(IV)?O(S)](2+) react with cyclohexene to yield mainly products of allylic oxidation. [(L)Fe(III)(OOR)(S)](2+) are inert in this reaction. The analysis of EPR and reactivity data shows that only those catalyst systems which display EPR spectra of 1c and 2c are able to selectively epoxidize cyclohexene, thus bearing strong evidence in favor of the key role of 1c and 2c in selective epoxidation. 1c and 2c were tentatively assigned to the oxoiron(V) intermediates. PMID- 21598910 TI - Structural, electronic, and magnetic properties of quasi-1D quantum magnets [Ni(HF2)(pyz)2]X (pyz = pyrazine; X = PF6(-), SbF6(-)) exhibiting Ni-FHF-Ni and Ni-pyz-Ni spin interactions. AB - [Ni(HF(2))(pyz)(2)]X {pyz = pyrazine; X = PF(6)(-) (1), SbF(6)(-) (2)} were structurally characterized by synchrotron X-ray powder diffraction and found to possess axially compressed NiN(4)F(2) octahedra. At 298 K, 1 is monoclinic (C2/c) with unit cell parameters, a = 9.9481(3), b = 9.9421(3), c = 12.5953(4) A, and beta = 81.610(3) degrees while 2 is tetragonal (P4/nmm) with a = b = 9.9359(3) and c = 6.4471(2) A and is isomorphic with the Cu-analogue. Infinite one dimensional (1D) Ni-FHF-Ni chains propagate along the c-axis which are linked via MU-pyz bridges in the ab-plane to afford three-dimensional polymeric frameworks with PF(6)(-) and SbF(6)(-) counterions occupying the interior sites. A major difference between 1 and 2 is that the Ni-F-H bonds are bent (~157 degrees ) in 1 but are linear in 2. Ligand field calculations (LFT) based on an angular overlap model (AOM), with comparison to the electronic absorption spectra, indicate greater pi-donation of the HF(2)(-) ligand in 1 owing to the bent Ni-F-H bonds. Magnetic susceptibility data for 1 and 2 exhibit broad maxima at 7.4 and 15 K, respectively, and lambda-like peaks in dchiT/dT at 6.2 and 12.2 K that are ascribed to transitions to long-range antiferromagnetic order (T(N)). Muon-spin relaxation and specific heat studies confirm these T(N)'s. A comparative analysis of chi vs T to various 1D Heisenberg/Ising models suggests moderate antiferromagnetic interactions, with the primary interaction strength determined to be 3.05/3.42 K (1) and 5.65/6.37 K (2). However, high critical fields of 19 and 37.4 T obtained from low temperature pulsed-field magnetization data indicate that a single exchange constant (J(1D)) alone is insufficient to explain the data and that residual terms in the spin Hamiltonian, which could include interchain magnetic couplings (J(?)), as mediated by Ni-pyz-Ni, and single-ion anisotropy (D), must be considered. While it is difficult to draw absolute conclusions regarding the magnitude (and sign) of J(?) and D based solely on powder data, further support offered by related Ni(II)-pyz compounds and our LFT and density functional theory (DFT) results lead us to a consistent quasi-1D magnetic description for 1 and 2. PMID- 21598911 TI - Theoretical studies on reactions of the stabilized H2COO with HO2 and the HO2...H2O complex. AB - The reactions of H(2)COO with HO(2) and the HO(2)...H(2)O complex are studied by employing the high-level quantum chemical calculations with B3LYP and CCSD(T) theoretical methods, the conventional transition-state theory (CTST), and the Rice-Ramsperger-Kassel-Marcus (RRKM) with Eckart tunneling correction. The calculated results show that the proton transfer plus the addition reaction channel (TS1A) is preferable for the reaction of H(2)COO with HO(2) because the barriers are -10.8 and 1.6 kcal/mol relative to the free reactants and the prereactive complex, respectively, at the CCSD(T)/6-311++G(3df,2p)//B3LYP/6 311++G(d,p) level of theory. Furthermore, the rate constant via TS1A (2.23 * 10( 10) cm(3) molecule(-1) s(-1)) combined with the concentrations of the species in the atmosphere demonstrates that the HO(2) radical would be the dominant sink of H(2)COO in some areas, where the concentration of water is less than 10(17) molecules cm(-3). In addition, although the single water molecule would lower the activated barrier of TS1A from 1.0 to 0.1 kcal/mol with respect to the respective complexes, the rate constant is lower than that of the reaction of HO(2) with H(2)COO. PMID- 21598912 TI - Theoretical unimolecular kinetics for CH4 + M ? CH3 + H + M in eight baths, M = He, Ne, Ar, Kr, H2, N2, CO, and CH4. AB - Ensembles of classical trajectories are used to study collisional energy transfer in highly vibrationally excited CH(4) for eight bath gases. Several simplifying assumptions for the CH(4) + M interaction potential energy surface are tested against full dimensional direct dynamics trajectory calculations for M = He, Ne, and H(2). The calculated energy transfer averages are confirmed to be sensitive to the shape of the repulsive wall of the intermolecular potential, with an exponential repulsive wall required for quantitative predictions. For the diatomic baths, the usual "separable pairwise" approximation for the interaction potential is unable to describe the orientation dependence of the interaction potential accurately, and the ambiguity in the resulting parametrizations contributes an additional uncertainty to the predicted energy transfer averages of 20-40%. On the other hand, the energy transfer averages are shown to be insensitive to the level of theory used to describe the intramolecular CH(4) potential, with a computationally efficient semiempirical tight binding potential for hydrocarbons performing equally well as an MP2 potential. The relative collisional energy transfer efficiencies of the eight bath gases are discussed and shown to be a function of temperature. The ensemble-averaged energy transferred in deactivating collisions for each bath is used to parametrize a single-exponential-down model for collisional energy transfer in master equation calculations. The predicted decomposition rate coefficients for CH(4) agree well with available experimental rate coefficients for M = He, Ar, Kr, and CH(4). The effect of vibrational anharmonicity on the predicted rate coefficients is considered briefly. PMID- 21598913 TI - Electrolyte-induced inversion layer Schottky junction solar cells. AB - A new type of crystalline silicon solar cell is described. Superficially similar to a photoelectrochemical cell a liquid electrolyte creates a depletion (inversion) layer in an n-type silicon wafer, however no regenerative redox couple is present to ferry charge between the silicon and a counter electrode. Instead holes trapped in the electrolyte-induced inversion layer diffuse along the layer until they come to widely spaced grid lines, where they are extracted. The grid lines consist of a single-walled carbon nanotube film etched to cover only a fraction of the n-Si surface. Modeling and simulation shows the inversion layer to be a natural consequence of the device electrostatics. With electronic gating, recently demonstrated to boost the efficiency in related devices, the cell achieves a power conversion efficiency of 12%, exceeding the efficiency of dye sensitized solar cells. PMID- 21598914 TI - Multifunctional, polymorphic, ionic fullerene supramolecular materials: self assembly and thermotropic properties. AB - An N-methylfulleropyrrolidine (2) bearing three eicosyloxy chains on the laterally substituted phenyl group can be further functionalized to give the ionic fullerene derivative, i.e., N,N-dimethylfulleropyrrolidinium iodide (1). The spectroscopic, electrochemical, self-assembly, and liquid crystalline properties of 1 have been investigated and compared to its neutral precursor 2. Changes in electronic structure upon ionization are observed in the UV spectra. Additionally, a positive potential shift of electrochemical reductions for 1 compared to those of 2 is noted in both homogeneous solution and film state. Driven by the pi-pi, van der Waals, and electrostatic interactions, the ionic compound 1 is able to form a variety of functional and polymorphic self-assembled structures both from solution and on substrates, including hierarchically organized flakelike microparticles with high water repellency, doughnut-shaped objects with rough surfaces, and long one-dimensional C(60) nanowires (>1 MUm). The thermotropic behavior of 1 has also been investigated, and a smectic liquid crystalline phase was observed at elevated temperatures. Further investigations of the thermotropic behavior of 1 revealed that a deionization back-reaction from 1 to the neutral precursor 2 gradually occurred. The mechanism of this deionization reaction is presented and discussed. These investigations provide insight into the effects of added ionicity to alkylated fullerene derivatives, in particular on their self-assembly features and functionality. PMID- 21598915 TI - Geometrically designing the kinematic behavior of catalytic nanomotors. AB - Catalytic nanomotors with silica microbead heads and TiO(2) arms are systematically designed by dynamic shadowing growth. The swimming trajectories are fine tuned by altering the arm length and orientation exploiting geometry dependent hydrodynamic interactions at low Reynolds number. The curvature, angular frequency, and radius of curvature of the trajectories change as a function of arm length. Simulations based on the method of regularized Stokeslets are also described and correctly capture the trends observed in the experiments. PMID- 21598916 TI - Electroaddressing agarose using Fmoc-phenylalanine as a temporary scaffold. AB - Electroaddressing, the use of imposed electrical stimuli to guide assembly, is attractive because electrical stimuli can be conveniently applied with high spatial and temporal resolution. Several electroaddressing mechanisms have been reported in which electrode-induced pH gradients trigger stimuli-responsive materials to undergo localized sol-gel transitions to form hydrogel matrices. A common feature of existing hydrogel electrodeposition mechanisms is that the deposited matrix retains residual charged, acidic, or basic (macro)molecules. Here, we report that pH-responsive fluorenyl-9-methoxycarbonyl-phenylalanine (Fmoc-Phe) can be used to codeposit the neutral and thermally responsive polysaccharide agarose. Upon cooling, an agarose network is generated and Fmoc Phe can be removed. The Fmoc-Phe-mediated codeposition of agarose is simple, rapid, spatially selective, and allows for the electroaddressing of a bioactive matrix. PMID- 21598917 TI - Using the 19F NMR chemical shift anisotropy tensor to differentiate between the zigzag and chiral forms of fluorinated single-walled carbon nanotubes. AB - The structural characterization of different kinds of zigzag and chiral single walled carbon nanotubes (SWNTs) has been investigated theoretically using (19)F NMR spectroscopy. The chemical shift anisotropy (CSA) tensor is computed at different levels of theory for the (19)F nuclei in different forms of functionalized fluorinated carbon nanotubes (CNT). A set of fluorine CSA parameters comprising the span, skew, and isotropic chemical shift is computed for each form of the fluoronanotubes and multidimensional CSA parameter correlation maps are constructed. We show that these correlations are able to clearly distinguish between the chiral and zigzag forms of fluorinated carbon nanotubes (F-SWNTs). Implications for solid-state and liquid-state NMR experiments are discussed. PMID- 21598918 TI - Organocatalytic asymmetric synthesis of sulfoxides from sulfenic acid anions mediated by a Cinchona-derived phase-transfer reagent. AB - Preliminary results concerning a conceptually novel route to chiral sulfoxides based on the asymmetric alkylation of sulfenate salts with alkyl halides mediated by a chiral phase-transfer catalyst are described. As a representative example, o anisyl methyl sulfoxide was produced in 96% yield and with an enantiomeric excess of 58% using commercial cinchonidinium derivative 2a. PMID- 21598919 TI - Designing novel materials through functionalization of carbon nanotubes for application in nuclear waste management: speciation of uranyl. AB - Understanding the behavior of radioactive nuclide elements in different environmental conditions is an active area of research. In this work, we have investigated the possible interaction mechanism between carbon nanotubes and uranyl using density functional theory. It is shown that functionalized carbon nanotubes can be used to bind uranyl ions much more efficiently as compared to their unfunctionalized counterpart. The uranyl binding energies are sensitive to the nature of the functional groups rather than the carbon nanotube itself. The binding takes place preferably at the functionalized sites, although pH could determine the strength of uranyl binding. Our predicted results correlate well with the recent experimental uranyl sorption studies on carbon nanotubes. These finding are new and can open up a new era for actinide speciation and separation chemistry using carbon nanotubes. PMID- 21598920 TI - Single particle nonlinear optical imaging of trace crystallinity in an organic powder. AB - Microscopic characterization of crystallinity in powders can reveal information lost in ensemble-averaged measurements. Nonlinear optical imaging based on second harmonic generation (SHG) provides rapid and highly selective detection of individual chiral microcrystals, enabling insights into the fundamental mechanism of action for the observed crystallinity loss of an organic powder induced by mechanical grinding. Using griseofulvin as the model compound, the results from second order nonlinear optical imaging of chiral crystals (SONICC) compared favorably with those of powder X-ray diffraction (PXRD) over the linear dynamic range of the PXRD measurements. However, the SHG measurements demonstrated three decade improvements in linear dynamic range. The detection limit of SHG was estimated to be 4 ppm crystallinity in the powder. The rate of crystallinity loss induced by milling followed a first order process with a half-life of 15 +/- 1 min. Recrystallization of cryomilled powder is ~40 times faster than that prepared by melt-quenched powder, suggesting that the disordered state obtained by exhaustive cryomilling appears to contain ordered domains that are larger than the critical nucleation size, but below the detection limit of SONICC. The presence of such domains provides a barrier-less nucleation source resulting in rapid crystallization, the kinetics of which depends only on crystal growth. PMID- 21598921 TI - Metabolic capabilities and systems fluctuations in Haloarcula marismortui revealed by integrative genomics and proteomics analyses. AB - The 1310 Haloarcula marismortui proteins identified from mid-log and late-log phase soluble and membrane proteomes were analyzed in metabolic and cellular process networks to predict the available systems and systems fluctuations upon environmental stresses. When the connected metabolic reactions with identified proteins were examined, the availability of a number of metabolic pathways and a highly connected amino acid metabolic network were revealed. Quantitative spectral count analyses suggested 300 or more proteins might have expression changes in late-log phase. Among these, integrative network analyses indicated approximately 106 were metabolic proteins that might have growth-phase dependent changes. Interestingly, a large proportion of proteins in affected biomodules had the same trend of changes in spectral counts. Disregard the magnitude of changes, we had successfully predicted and validated the expression changes of nine genes including the rimK, gltCP, rrnAC0132, and argC in lysine biosynthesis pathway which were downregulated in late-log phase. This study had not only revealed the expressed proteins but also the availability of biological systems in two growth phases, systems level changes in response to the stresses in late-log phase, cellular locations of identified proteins, and the likely regulated genes to facilitate further analyses in the postgenomic era. PMID- 21598922 TI - Quantitative analysis of cytokine-induced hepatocyte nuclear factor-4alpha phosphorylation by mass spectrometry. AB - Hepatocyte nuclear factor-4alpha (HNF-4alpha), a liver-enriched transcription factor, is essential for liver development and function. HNF-4alpha regulates a large number of liver-specific genes, many of which are modulated by injury. While HNF-4alpha function is regulated by phosphorylation, only a limited number of phosphorylation sites in HNF-4alpha have been identified, and the roles of HNF 4alpha phosphorylation after injury are unexplored. To address these issues, we have carried out an extensive quantitative mass spectrometry (MS)-based analysis of HNF-4alpha serine and threonine phosphorylation in response to cytokine stimulation. Studies were performed in HNF-4alpha-enriched HepG2 cells treated with cytokines for 3 h or left untreated, followed by chemical derivatization of the phosphoserine and phosphothreonine residues using stable isotopic variants of dithiothreitol (DTT) and MS analysis. This has allowed the identification and relative quantification of 12 serine/threonine phosphorylation sites in HNF 4alpha. Eight of these phosphorylation sites and their sensitivity to cytokine stimulation have not been previously reported. We found that cytokine treatment leads to an increase of HNF-4alpha phosphorylation in several phosphopeptides. The phosphorylation of HNF-4alpha mediated by protein kinase A (PKA) significantly reduces HNF-4alpha binding activity, which mimics the repressive effect of cytokines on HNF-4alpha binding, and the inhibition of PKA activity by PKA inhibitor can partially recover the reduced HNF-4alpha binding activity induced by cytokines. These results suggest that the mechanism that alters HNF 4alpha binding after cytokine stimulation involves modulation of specific HNF 4alpha phosphorylation dependent, in part, on a PKA signaling pathway. PMID- 21598923 TI - Quantum chemical analysis of the unfolding of a penta-alanyl 3(10)-helix initiated by HO(*), HO2(*) and O2(-*). AB - In order to elucidate the mechanisms of radical-initiated unfolding of a helix, the thermodynamic functions of hydrogen abstraction from the C(alpha), C(beta), and amide nitrogen of Ala(3) in a homopeptapeptide (N-Ac-AAAAA-NH(2); A5) by HO(*), HO(2)(*), and O(2)(-*) were computed using the B3LYP density functional. The thermodynamic functions, standard enthalpy (DeltaH(o)), Gibbs free energy (DeltaG(o)), and entropy (DeltaS(o)), of the reactants and products of these reactions were computed with A5 in the 3(10)-helical (A5(Hel)) and fully extended (A5(Ext)) conformations at the B3LYP/6-31G(d) and B3LYP/6-311+G(d,p) levels of theory, both in the gas phase and using the C-PCM implicit water model. With quantum chemical calculations, we have shown that H abstraction is the most favorable at the C(alpha), followed by the C(beta), then amide N in a model helix. The secondary structure has a strong influence on the bond dissociation energy of the H-C(alpha), but a negligible effect on the dissociation energy of the H-CH(2) and H-N bonds. The HO(*) radical is the strongest hydrogen abstractor, followed by HO(2)(*) and finally O(2)(-*). More importantly, secondary structure elements, such as H-bonds in the 3(10)-helix, protect the peptide from radical attack by hindering the potential electron delocalization at the C(alpha) when the peptide is in the extended conformation. We also show that he unfolding of the A5 peptide radicals have a significantly higher propensity to unfold than the closed shell A5 peptide and confirm that only the HO(*) can initiate the unfolding of A5(Hel) and the formation of A5(Ext)(*). By comparing the structures, energies, and thermodynamic functions of A5 and its radical derivatives, we have shown how free radicals can initiate the unfolding of helical structures to beta-sheets in the cellular condition known as oxidative stress. PMID- 21598924 TI - First-principles studies on the efficient photoluminescent iridium(III) complexes with C^N?N ligands. AB - The electronic structures and photophysical properties of several homoleptic iridium complexes IrL(3) with C^N?N ligands, including 1 (L = 3,6 diphenylpyridazine), 2 (L = 1,4-diphenylphthalazine), 3 (L = 3-phenyl-5H indeno[1,2-c]pyridazine), and 4 (L = 3-phenylbenzo[h]cinnoline), are investigated using the density functional method. The comparison between the calculated results of the four complexes shows that the assumed complex 4 may possess higher photoluminescent quantum efficiency than complexes 1-3 and is the potential candidate to be an efficient green-emitting material. The photophysical properties of the assumed complex 3 can be comparable to that of experimentally found complex 1. For 1 and 3, the emission energies are nearly the same, consistent with their similar HOMO-LUMO energy gaps. Their emission characters are also similar and mainly dominated by one ligand. For 4 and the experimentally found complex 2, although they have similar HOMO-LUMO energy gaps, and their luminescent nature is nearly the same and dominated by the three ligands, the emission spectrum of 4 is blue-shifted as compared to that of 2. PMID- 21598925 TI - Kinetics of the reversible reaction of CO2(aq) with ammonia in aqueous solution. AB - The kinetics of the interactions of aqueous ammonia with aqueous carbon dioxide/carbonate species has been investigated using stopped-flow techniques by monitoring the pH changes via indicators. The reactions include the reversible formation of ammonium carbamate/carbamic acid. A complete reaction mechanism has been established, and the temperature dependence of all rate and equilibrium constants including the protonation constant of the amine between 15 and 45 degrees C are reported and analyzed in terms of Arrhenius, Eyring, and van't Hoff relationships. PMID- 21598927 TI - Vibrational spectra and structure of cyclopentane and its isotopomers. AB - The infrared and Raman spectra of vapor, liquid, and solid state cyclopentane and its d(1), 1,1-d(2), 1,1,2,2,3,3-d(6), and d(10) isotopomers have been recorded and analyzed. The experimental work was complemented by ab initio and density functional theory (DFT) calculations. The computations confirm that the two conformational forms of cyclopentane are the twist (C(2)) and bent (C(s)) structures and that they differ very little in energy, less than about 10 cm(-1) (0.1 kJ/mol). The bending angle for the C(s) form is 41.5 degrees and the dihedral angle of twisting is 43.2 degrees for the C(2) form. A reliable and complete vibrational assignment for each of the isotopomers has been achieved for the first time, and these agree very well with the DFT (B3LYP/cc-pVTZ) computations. The ab initio CCSD/cc-pVTZ calculations predict a barrier to planarity of 1887 cm(-1), which is in excellent agreement with the experimental value of 1808 cm(-1). PMID- 21598926 TI - B-DNA to zip-DNA: simulating a DNA transition to a novel structure with enhanced charge-transport characteristics. AB - The forced extension of a DNA segment is studied in a series of steered molecular dynamics simulations, employing a broad range of pulling forces. Throughout the entire force range, the formation of a zipper-like (zip-) DNA structure is observed. In that structure, first predicted by Lohikoski et al., the bases of the DNA strands interdigitate with each other and form a single-base aromatic stack. Similar motifs, albeit only a few base pairs in extent, have been observed in experimental crystal structures. Analysis of the dynamics of structural changes in pulled DNA shows that S-form DNA, thought to be adopted by DNA under applied force, serves as an intermediate between B-DNA and zip-DNA. Therefore, the phase transition plateau observed in force-extension curves of DNA is suggested to reflect the B-DNA to zip-DNA structural transition. Electronic structure analysis of purine bases in zip-DNA indicates a several-fold to order of magnitude increase in the pi-pi electronic coupling among nearest-neighbor nucleobases, compared to B-DNA. We further observe that zip-DNA does not require base pair complementarity between DNA strands, and we predict that the increased electronic coupling in zip-DNA will result in a much higher rate of charge transfer through an all-purine zip-DNA compared to B-DNA of equal length. PMID- 21598929 TI - Synthesis of magnetic noble metal (nano)particles. AB - Noble metal particles can be made strongly ferromagnetic or diamagnetic provided that they are synthesized in a sufficiently strong magnetic field. Here we outline two synthesis methods that are fast, reproducible, and allow broad control over particle sizes ranging from nanometers to millimeters. From magnetometry and light spectroscopy, it appears that the cause of this anomalous magnetism is the surface anisotropy in the noble metal particles induced by the applied magnetic field. This work offers an elegant alternative to composite materials of noble metals and magnetic impurities. PMID- 21598930 TI - Stabilization of noncondensed (As(III)S3)(3-) anions by coordinating to [Mn(II)(phen)](2+) complex cations: a mixed-valent thioarsenate (III, V) {[Mn(phen)]3(As(V)S4)(As(III)S3)}(n).nH2O showing the coexistence of antiferromagnetic order, photoluminescence, and nonlinear optical properties. AB - A novel one-dimensional (1-D) mixed-valent thioarsenate (III, V), {[Mn(phen)](3)(As(V)S(4))(As(III)S(3))}(n).nH(2)O (1), with a noncentrosymmetric (NCS) polar packing arrangement has been obtained under solvothermal conditions. The noncondensed (As(III)S(3))(3-) anion in 1 is stabilized by coordinating to [Mn(II)(phen)](2+) complex cations and exhibits an unprecedented MU(3) 1,2kappaS:2,3kappaS':3kappaS'' linkage mode. Compound 1 represents the first example of the stabilization of noncondensed (MQ(3))(3-) (M = As, Sb; Q = S, Se) species only in the coordination of TM(II) complex cations (TM = transition metal) and the first observation of the coexistence of the (As(V)S(4))(3-) tetrahedron and the noncondensed (As(III)S(3))(3-) pyramid in a single compound. Of particular interest, compound 1 is also an antiferromagnet with T(N) = 31 K, and exhibits photoluminescence (PL) with a maximum emission at about 438 nm and a second harmonic generation (SHG) response. PMID- 21598928 TI - Transformation of isosteviol lactam by fungi and the suppressive effects of its transformed products on LPS-induced iNOS expression in macrophages. AB - From the screening of 21 microbial strains, Absidia pseudocylindrospora ATCC 24169 and Aspergillus niger BCRC 32720 were found to reproducibly transform isosteviol lactam (4alpha-carboxy-13alpha-amino-13,16-seco-ent-19-norbeyeran-16 oic acid 13,16-lactam) (3) into various compounds. Preparative-scale transformation of 3 with Abs. pseudocylindrospora yielded two new hydroxylated compounds (4 and 5), with conservation of the lactam ring. Preparative-scale transformation of 3 with Asp. niger afforded seven new compounds, 6 and 9-14, together with the known compounds 7 and 8. A single-crystal X-ray diffraction experiment confirmed the structure of 14. The suppressive effects of compounds 1 14 on the lipopolysaccharide-induced expression of the inducible nitric oxide synthase gene in RAW 264.7 macrophages were examined by a reverse-transcription real-time PCR analysis. With the exception of 7, all other compounds significantly reduced levels of iNOS mRNA relative to control cells, which were induced by LPS alone. Compounds 2, 3, and 5 were similar in activity to dexamethasone, while 9 was more potent. PMID- 21598931 TI - Critical role of water and the structure of inverse micelles in the Brust Schiffrin synthesis of metal nanoparticles. AB - Although Brust-Schiffrin two-phase synthesis is a popular method for synthesizing ligand-protected metal nanoparticles with an average size of less than 5 nm, the details on how the reactions can be controlled from a mechanistic point of view are still unclear, therefore hindering efforts to synthesize monodisperse metal nanoparticles. It was recently discovered that this method is basically an inverse-micelle-based synthesis (Li, Y.; Zaluzhna, O.; Xu, B.; Gao, Y.; Modest, J. M.; Tong, Y. Y. J. J. Am. Chem. Soc.2011, 133, 2092). In this letter, the critical role of water and the structure of inverse micelles in typical synthesis of gold nanoparticles were further investigated. We found that (1) water encapsulated in the inverse micelles of [TOA](+) that also hosted metal ions formed a hydrophilic microenvironment that acted as a reaction-enabling proton accepting medium for the thiol protons (RS-H) and (2) not only the presence but also the amount of water in the reaction medium has a profound effect on the Au(I) precursor species (a pure [TOA][AuX(2)] complex or a mixture of a [TOA][AuX(2)] complex and polymeric [Au(I)SR](n) species), the reduction of Au(III) by thiols, and the formation of uniform small metal nanoparticles. A quantitative analysis of the (1)H NMR of the encapsulated water enabled an estimation of the size and composition of the involved inverse micelles. PMID- 21598932 TI - Interactions between planar grafted neurofilament side-arms. AB - The side-arms of neurofilaments (NFs) have been proposed to be highly disordered, leading to an entropically and electrostatically based repulsion that modulates interfilament spacing. To characterize the behavior of two interacting polymer brushes in a system of this type, we performed molecular dynamics simulations of neurofilament brushes using a four bead reduced amino acid set coarse-grained model. In these simulations, we examined components of the neurofilament brush, NF-L, NF-M, and phosphorylated NF-H (NF-HP), individually. Each protein type was grafted to planar surfaces and simulations were performed for a range of separations of two apposed grafted surfaces. The calculated force-separation curves show the force increases as the reciprocal separation as predicted for polyelectrolyte brushes at high salt. All three systems can be overlapped on a single force-separation curve, which is not expected given the variation in amino acid sequence and charges on the polymers. Examination of structural properties shows scaling behavior in the average brush height, end-to-end distance, and the density interpenetration. Some of this scaling can be understood in terms of treating the NF proteins as effective polyelectrolytes, but some cannot suggesting a distinct polyampholyte behavior. Correlations are found between oppositely charged residues in opposite brushes. However, these correlations are weak in comparison to the strong correlations within each brush. In comparison with recent experimental data that observes condensed and expanded gel states, our results suggest that the condensed state structure involves significant interdigitation of the side-arms. PMID- 21598933 TI - Self-alignment of dye molecules in micelles and lamellae for three-dimensional imaging of lyotropic liquid crystals. AB - We report alignment of anisotropic amphiphilic dye molecules within oblate and prolate anisotropic micelles and lamellae, the basic building blocks of surfactant-based lyotropic liquid crystals. Absorption and fluorescence transition dipole moments of these dye molecules orient either parallel or orthogonal to the liquid crystal director. This alignment enables three dimensional visualization of director structures and defects in different lyotropic mesophases by means of fluorescence confocal polarizing microscopy and two-photon excitation fluorescence polarizing microscopy. The studied structures include nematic tactoids, Schlieren texture with disclinations in the calamitic nematic phase, oily streaks in the lamellar phase, developable domains in the columnar hexagonal phase, and various types of line defects in the discotic cholesteric phase. Orientational three-dimensional imaging of structures in the lyotropic cholesterics reveals large Burgers vector dislocations in cholesteric layering with singular disclinations in the dislocation cores that are not common for their thermotropic counterparts. PMID- 21598934 TI - Analysis of kinetic isotope effects in enzymatic carbon-hydrogen cleavage reactions. AB - The instanton approach, as previously applied to proton tunneling in molecular systems, is adapted to carbon-hydrogen bond cleavage catalyzed by enzymes. To compensate for the complexity of enzymatic reactions, simplifications are introduced based on the observation in numerous X-ray measurements that enzymes tend to form compact structures, which is assumed to have led toward optimization of specific parameters that govern the tunneling rate in the instanton formalism. On this basis, semiempirical equations are derived that link observed kinetic data directly to these parameters. These equations provide an analytical relation between the kinetic isotope effect and its temperature dependence for each hydrogen isotope, from which mechanistic and structural information can be extracted, including the nature of the hydrogen acceptor, the magnitude of the hydrogen transfer distance, the presence of endothermicity, and the contribution and frequency of skeletal vibrations that assist the tunneling. The method is used to analyze kinetic data reported for eight enzymatic CH-cleavage reactions; the enzymes or models thereof studied include methylmalonyl-coenzyme A mutase (coenzyme B(12)), galactose oxidase, lipoxygenase-1 with six mutants, methylamine dehydrogenase, an oxoiron(IV)porphyrin radical cation, phenylalanine hydroxylase, a bis(MU-oxo)dicopper complex, and rice alpha-oxygenase. PMID- 21598935 TI - Algorithms for sampling a quantum microcanonical ensemble of harmonic oscillators at potential minima and conical intersections. AB - Algorithms are presented for sampling quantum microcanonical ensembles for a potential energy minimum and for the conical intersection at the minimum energy crossing point of two coupled electronic states. These ensembles may be used to initialize trajectories for chemical dynamics simulations. The unimolecular dynamics of a microcanonical ensemble about a potential energy minimum may be compared with the dynamics predicted by quantum Rice-Ramsperger-Kassel-Marcus (RRKM) theory. If the dynamics is non-RRKM, it will be of particular interest to determine which states have particularly long lifetimes. Initializing a microcanonical ensemble for the electronically excited state at a conical intersection is a model for electronic nonadiabatic dynamics. The trajectory surface-hopping approach may be used to study the ensuing chemical dynamics. A strength of the model is that zero-point energy conditions are included for the initial nonadiabatic dynamics at the conical intersection. PMID- 21598936 TI - Catalytic asymmetric synthesis of trisubstituted aziridines. AB - A method is described which provides for the direct asymmetric catalytic synthesis of trisubstituted aziridines from imines and diazo compounds. While unactivated imines were not reactive to alpha-diazo carbonyl compounds in which the diazo carbon was disubstituted, N-Boc imines react with both alpha-diazo esters and alpha-diazo-N-acyloxazolidinones to give trisubstituted aziridines with excellent diastereo- and enantioselectivities. PMID- 21598938 TI - DFT studies on a high energy density cage compound 4-trinitroethyl-2,6,8,10,12 pentanitrohezaazaisowurtzitane. AB - Polynitro cage compound 4-trinitroethyl-2,6,8,10,12 pentanitrohexaazaisowurtzitane has the same framework with but higher stability than CL-20 and is a potential new high energy density compound (HEDC). In this paper, the B3LYP/6-31G(d,p) method of density functional theory (DFT) has been used to study its heat of formation, IR spectrum, and thermodynamic properties. The stability of the compound was evaluated by the bond dissociation energies. The calculated results show that the first step of pyrolysis is the rupture of the N-NO(2) bond in the side chain and verify the experimental observation that the title compound has better stability than CL-20. The crystal structure obtained by molecular mechanics belongs to the P2(1)2(1)2(1) space group, with lattice parameters a = 12.59 A, b = 10.52 A, c = 12.89 A, Z = 4, and rho = 2.165 g.cm(-3). Both the detonation velocity of 9.767 km.s(-1) and the detonation pressure of 45.191 GPa estimated using the Kamlet-Jacobs equation are better than those of CL-20. Considering that this cage compound has a better detonation performance and stability than CL-20, it may be a superior HEDC. PMID- 21598939 TI - Microfabricated electrochemical detector for high-performance liquid chromatography. AB - A microfabricated electrochemical cell has been developed as a disposable detector for flow injection analysis (FIA) and high-performance liquid chromatography (HPLC). The simplicity of the fabrication process allows this detector to be used as a low-cost, disposable device that can be replaced easily if its performance degrades rather than disassembling the detector and polishing the electrode surface, which is the usual procedure. The detector consists of thin film-metal electrodes-platinum working electrode, platinum auxiliary electrode, and silver/silver chloride coated on Pt reference electrode-deposited on a polyimide substrate with a locking layer of chromium in between. A microfluidic cover made of polyimide directs the solution flow across the electrodes. The detector was evaluated with FIA of ferrocyanide and HPLC of ascorbic acid and acetaminophen and a mixture of two pharmaceutical compounds dextrorphan and levallorphan-with acetaminophen internal standard. The HPLC calibration curves showed good linearity (R(2) > 0.99). Limits of detection were 1 nM for acetaminophen, 1 nM for ascorbic acid, 50 nM for dextrorphan, and 80 nM for levallorphan. When detected with a commercial detector dextrorphan and levallorphan had lower limits of detection, 3 and 5 nM, respectively. Chromatograms of the mixture were comparable to those obtained with a commercial detector. The detector could be used continuously for about 48 h with FIA and about 10-20 h with HPLC after which performance gradually degraded as the AgCl on the reference electrode dissolved causing loss of potential control. PMID- 21598941 TI - Dynamic solubility limits in nanosized olivine LiFePO4. AB - Because of its stability, nanosized olivine LiFePO(4) opens the door toward high power Li-ion battery technology for large-scale applications as required for plug in hybrid vehicles. Here, we reveal that the thermodynamics of first-order phase transitions in nanoinsertion materials is distinctly different from bulk materials as demonstrated by the decreasing miscibility gap that appears to be strongly dependent on the overall composition in LiFePO(4). In contrast to our common thermodynamic knowledge, that dictates solubility limits to be independent of the overall composition, combined neutron and X-ray diffraction reveals strongly varying solubility limits below particle sizes of 35 nm. A rationale is found based on modeling of the diffuse interface. Size confinement of the lithium concentration gradient, which exists at the phase boundary, competes with the in bulk energetically favorable compositions. Consequently, temperature and size diagrams of nanomaterials require complete reconsideration, being strongly dependent on the overall composition. This is vital knowledge for the future nanoarchitecturing of superior energy storage devices as the performance will heavily depend on the disclosed nanoionic properties. PMID- 21598940 TI - Enzymatic properties and regulation of the native isozymes of retinal membrane guanylyl cyclase (RetGC) from mouse photoreceptors. AB - Mouse photoreceptor function and survival critically depend on Ca(2+)-regulated retinal membrane guanylyl cyclase (RetGC), comprised of two isozymes, RetGC1 and RetGC2. We characterized the content, catalytic constants, and regulation of native RetGC1 and RetGC2 isozymes using mice lacking guanylyl cyclase activating proteins GCAP1 and GCAP2 and deficient for either GUCY2F or GUCY2E genes, respectively. We found that the characteristics of both native RetGC isozymes were considerably different from other reported estimates made for mammalian RetGCs: the content of RetGC1 per mouse rod outer segments (ROS) was at least 3 fold lower, the molar ratio (RetGC2:RetGC1) 6-fold higher, and the catalytic constants of both GCAP-activated isozymes between 12- and 19-fold higher than previously measured in bovine ROS. The native RetGC isozymes had different basal activity and were accelerated 5-28-fold at physiological concentrations of GCAPs. RetGC2 alone was capable of contributing as much as 135-165 MUM cGMP s(-1) or almost 23-28% to the maximal cGMP synthesis rate in mouse ROS. At the maximal level of activation by GCAP, this isozyme alone could provide a significantly high rate of cGMP synthesis compared to what is expected for normal recovery of a mouse rod, and this can help explain some of the unresolved paradoxes of rod physiology. GCAP-activated native RetGC1 and RetGC2 were less sensitive to inhibition by Ca(2+) in the presence of GCAP1 (EC(50Ca) ~132-139 nM) than GCAP2 (EC(50Ca) ~50-59 nM), thus arguing that Ca(2+) sensor properties of GCAP in a functional RetGC/GCAP complex are defined not by a particular target isozyme but the intrinsic properties of GCAPs themselves. PMID- 21598942 TI - Adsorption of arabinoxylan on cellulosic surfaces: influence of degree of substitution and substitution pattern on adsorption characteristics. AB - This study presents results that show that the fine structure of arabinoxylan affects its interaction with cellulosic surfaces, an important understanding when designing and evaluating properties of xylan-cellulose-based materials. Arabinoxylan samples, with well-defined structures, were prepared from a wheat flour arabinoxylan with targeted enzymatic hydrolysis. Turbidity measurements and analyses using NMR diffusometry showed that the solubility and the hydrodynamic properties of arabinoxylan are determined not only by the degree of substitution but also by the substitution pattern. On the basis of results obtained from adsorption experiments on microcrystalline cellulose particles and on cellulosic model surfaces investigated with quartz crystal microbalance with dissipation monitoring, it was also found that arabinoxylan adsorbs irreversibly on cellulosic surfaces and that the adsorption characteristics, as well as the properties of the adsorbed layer, are controlled by the fine structure of the xylan molecule. PMID- 21598943 TI - Combined structural and functional investigation of a C-3''-ketoreductase involved in the biosynthesis of dTDP-L-digitoxose. AB - l-Digitoxose is an unusual dideoxysugar found attached to various pharmacologically active natural products, including the antitumor antibiotic tetrocarcin A and the antibiotics kijanimicin and jadomycin B. Six enzymes are required for its production starting from glucose 1-phosphate. Here we describe a combined structural and functional investigation of KijD10, an NADPH-dependent C 3''-ketoreductase that catalyzes the third step of l-digitoxose biosynthesis in the African soil-dwelling bacterium Actinomadura kijaniata. KijD10 belongs to the glucose-fructose oxidoreductase superfamily. For this investigation, both binary and ternary complexes of KijD10 were crystallized, and their structures were determined to 2.0 A resolution or better. On the basis of these high-resolution structures, two potential active site acids were identified, Lys 102 and Tyr 186. These residues were individually mutated and the resultant proteins investigated both kinetically and structurally. The Y186F mutant protein demonstrated significant catalytic activity, and its structure was virtually identical to that of the wild-type enzyme except for the positioning of the nicotinamide ring. All lysine mutations, on the other hand, resulted in proteins with either abolished or drastically reduced catalytic activities. Structures for the K102A and K102E mutant proteins were determined and showed that the abrogation of catalytic activity was not a result of large conformational changes. Taken together, these data suggest that Lys 102 donates a proton to the C-3'' keto group during the reaction and that Tyr 186 serves only an auxiliary role. This is in contrast to that proposed for glucose-fructose oxidoreductase and other family members in which the tyrosines, or in some cases similarly positioned histidines, are thought to play major catalytic roles. PMID- 21598944 TI - MOF-5: enthalpy of formation and energy landscape of porous materials. AB - The first experimental thermodynamic analysis of a metal-organic framework (MOF) has been performed. Measurement of the enthalpy of formation of MOF-5 from the dense components zinc oxide (ZnO), 1,4-benzenedicarboxylic acid (H(2)BDC), and occluded N,N-diethylformamide (DEF) (if any) gave values of 78.64 +/- 2.95 and 99.47 +/- 3.62 kJ.[mol of Zn(4)O(BDC)(3).xDEF](-1) for the as-made form and the desolvated structure, respectively. These as-made and desolvated enthalpies correspond to the values 19.66 +/- 0.74 and 24.87 +/- 0.94 kJ.(mol of Zn)(-1), respectively. The energetics of desolvated MOF-5 per mole of Zn falls in line with trends relating the enthalpy of inorganic porous materials (zeolites, zeotypes, and mesoporous materials) to molar volume. MOF-5 extends a plateauing trend first suggested by thermodynamic studies of mesoporous materials. This leveling off of the destabilization energetics as the void space swells suggests that additional void volume beyond a certain point may begin to act as a parameter "external" to the structure and not destabilize it further. This could help explain the rich landscape of large-volume MOFs and their ease of desolvation. PMID- 21598945 TI - An aza cyclopropylcarbinyl-homoallyl radical rearrangement-radical cyclization cascade. Synthesis of dibenzoimidazoazepine and oxazepine derivatives. AB - The cycloaddition of the dibenzoxazepinium W-ylides, generated by heating of trans-1-aryl-7,11b-dihydro-1H-azirino[1,2-a]dibenzo[c,f]azepines, to the C?N double bond of 3-aryl-2H-azirines proceeds endo-stereoselectively giving regioisomeric cycloadducts in ca. 1:1 ratio, in good overall yields. In contrast to the dibenzoxazepinium ylides, the cycloaddition of the dibenzazepinium W-ylide proceeds regioselectively but without exo-endo-stereoselectivity. The reasons for this selectivity of the cycloaddition theoretically were studied at the DFT B3LYP/6-31G(d) level. Heating adducts, (2aRS,13SR,13aRS)-13,13a-diaryl-13,13a dihydro-1H,2aH-azireno[1',2':3,4]imidazo[1,2-d]dibenzo[b,f][1,4]oxazepines and (2aRS,13SR,13aRS)-13,13a- diphenyl-2a,7,13,13a-tetrahydro-1H azireno[1',2':3,4]imidazo[1,2-a]dibenzo[c,f]azepine, with an excess of AIBN in toluene gave new polyheterocyclic systems via a novel aza cyclopropylcarbinyl homoallyl radical rearrangement-radical cyclization cascade. The energy profile of the cascade was studied at the DFT UB3LYP/6-31G(d) level. The transient imidazolinylmethyl radical was trapped by the use of other radical initiators as the corresponding peroxide or alcohol. PMID- 21598946 TI - Copper-mediated synthesis of substituted 2-aryl-N-benzylbenzimidazoles and 2 arylbenzoxazoles via C-H functionalization/C-N/C-O bond formation. AB - An efficient method for the transformation of N-benzyl bisarylhydrazones and bisaryloxime ethers to functionalized 2-aryl-N-benzylbenzimidazoles and 2 arylbenzoxazoles is described. The protocol involves a copper(II)-mediated cascade C-H functionalization/C-N/C-O bond formation under neutral conditions. Substrates having either electron-donating or -withdrawing substituents undergo the cyclization to afford the target heterocycles at moderate temperature. PMID- 21598947 TI - Control of the mutual arrangement of cyclometalated ligands in cationic iridium(III) complexes. Synthesis, spectroscopy, and electroluminescence of the different isomers. AB - Synthetic control of the mutual arrangement of the cyclometalated ligands (C^N) in Ir(III) dimers, [Ir(C^N)(2)Cl](2), and cationic bis-cyclometalated Ir(III) complexes, [Ir(C^N)(2)(L^L)](+) (L^L = neutral ligand), is described for the first time. Using 1-benzyl-4-(2,4-difluorophenyl)-1H-1,2,3-triazole (HdfptrBz) as a cyclometalating ligand, two different Ir(III) dimers, [Ir(dfptrBz)(2)Cl](2), are synthesized depending on the reaction conditions. At 80 degrees C, the dimer with an unusual mutual cis-C,C and cis-N,N configuration of the C^N ligands is isolated. In contrast, at higher temperature (140 degrees C), the geometrical isomer with the common cis-C,C and trans-N,N arrangement of the C^N ligand is obtained. In both cases, an asymmetric bridge, formed by a chloro ligand and two adjacent nitrogens of the triazole ring of one of the cyclometalated ligands, is observed. The dimers are cleaved in coordinating solvents to give the solvento complexes [Ir(dfptrBz)(2)Cl(S)] (S = DMSO or acetonitrile), which maintain the C^N arrangement of the parent dimers. Controlling the C^N ligand arrangement in the dimers allows for the preparation of the first example of geometrical isomers of a cationic bis-cyclometalated Ir(III) complex. Thus, N,N-trans [Ir(dfptrBz)(2)(dmbpy)](+) (dmbpy = 4,4'-dimethyl-2,2'-bipyridine), with cis-C,C and trans-N,N arrangement of the C^N ligands, as well as N,N-cis [Ir(dfptrBz)(2)(dmbpy)](+), with cis-C,C and cis-N,N C^N ligand orientation, are synthesized and characterized. Interestingly, both isomers show significantly different photophysical and electroluminescent properties, depending on the mutual arrangement of the C^N ligands. Furthermore, quantum chemical calculations give insight into the observed photophysical experimental data. PMID- 21598948 TI - Comparative analyses of total phenols, antioxidant activity, and flavonol glycoside profile of cladode flours from different varieties of Opuntia spp. AB - The phenolic, flavonoid, and antioxidant contents of methanol extracts of nine samples of Mexican cactus ( Opuntia spp.) cladodes processed into flours were studied. Opuntia undulata contained the highest amount of phenols [905.08 +/- 64.51 MUg of gallic acid equivalents (GAE)/g]. The oxygen radical absorbance capacity (ORAC) of the cladode flour extracts indicated that Opuntia robusta var. Gavia [738.8 +/- 89.9 MUmol of Trolox equivalents (TE)/g] contained the highest antioxidant capacity. ORAC values significantly correlated to total phenols but not to flavonoid contents and were comparable to cranberries and blackberries. Glycosidic forms of isorhamnetin and kaempferol were identified via high performance liquid chromatography-photodiode array (HPLC-PDA) and HPLC-mass spectrometry (MS), with isorhamnetin being the most abundant flavonol in all samples, except for Opuntia lindheimeri . The effectiveness of acid hydrolysis varied among species because of the different flavonol profiles. For some varieties, the triglycosidic forms were partially acid-hydrolyzed, giving an increase in the content of diglycosides. Optimization of hydrolysis for each species is required to estimate the total amount of each flavonol. PMID- 21598949 TI - Cuban and Brazilian red propolis: botanical origin and comparative analysis by high-performance liquid chromatography-photodiode array detection/electrospray ionization tandem mass spectrometry. AB - Chemical composition of propolis depends on the specificity of the local flora at the site of collection and thus on the geographic and climatic characteristics of this place. This paper describes a comparative analysis of Cuban red propolis (CRP), Brazilian red propolis (BRP), and Dalbergia ecastophyllum exudates (DEE) by high-performance liquid chromatography with diode-array detection and tandem mass spectrometry. The aim of this study was to investigate the overall chemical profile and the botanical origin of red propolis and to suggest similarities and differences between samples collected in different tropical regions. Isoliquiritigenin (1), liquiritigenin and naringenin (2 and 17), isoflavones (3-4 and 16), isoflavans (5-7 and 18), and pterocarpans (8-13) were detected in CRP, BRP, and DEE, whereas polyisoprenylated benzophenones (PPBs) guttiferone E/xanthochymol (14a,b) and oblongifolin A (15) were detected only in BRP. Pigments responsible for the red color of DEE and red propolis were also identified as two C30 isoflavans, the new retusapurpurin B (19) and retusapurpurin A (20). PPBs and pigments were isolated and unambiguously characterized by 1D and 2D NMR analysis. These results show that red propolis samples from different tropical zones have a similar chemical composition. DEE is the main red propolis source, but the presence of PPBs in BRP suggests the contribution of different botanical sources for Brazilian samples. This chemical information is important for quality control of red propolis and its commercial products and for biological study. PMID- 21598950 TI - Effect of chemical systemic acquired resistance elicitors on avenanthramide biosynthesis in oat (Avena sativa). AB - Oats produce a group of phenolic antioxidants termed avenanthramides. These metabolites are, among food crops, unique to oats and have shown, in experimental systems, certain desirable nutritional characteristics such as inhibiting atherosclerotic plaque formation and reducing inflammation. Avenanthramides occur in both the leaves and grain of oat. In the leaves they are expressed as phytoalexins in response to crown rust (Puccina coronata) infection. The experiments reported here demonstrate that avenanthramide levels in vegetative tissue can be enhanced by treatment with benzothiadiazole (BTH), an agrochemical formulated to elicit systemic acquired resistance (SAR). The response to BTH was dramatically stronger than those produced with salicylic acid treatment. The roots of BTH treated plants also showed a smaller but distinct increase in avenanthramides. The dynamics of the root avenanthramide increase was substantially slower than that observed in the leaves, suggesting that avenanthramides might be transported from the leaves. PMID- 21598951 TI - Photoinduced singlet charge transfer in a ruthenium(II) perylene-3,4:9,10 bis(dicarboximide) complex. AB - Elucidation of photoinduced charge transfer behavior in organic dye/metal hybrids is important for developing photocatalytic systems for solar energy conversion. We report the synthesis and photophysical characterization of a perylene-3,4:9,10 bis(dicarboximide) (PDI)-ruthenium(II) complex, bis-PDI-2,2' bipyridineRu(II)Cl(2)(CN(t)butyl)(2), which has favorable energetics, DeltaG(CS) ~ -1.0 eV, for singlet electron transfer from the Ru complex to PDI. Time resolved optical spectroscopy reveals that upon selective photoexcitation of PDI, ultrafast charge transfer (<150 fs) from the Ru complex to (1*)PDI generates the Ru(III)-PDI(-*) ion pair. The resulting vibrationally hot Ru(III)-PDI(-*) ion pair exhibits fast relaxation (tau = 3.9 ps) and charge recombination (tau(CR) = 63 ps). Our experimental and computational (DFT and TDDFT) studies show that energy-preserving photodriven singlet electron transfer can dominate in properly designed organic dye/metal complexes, making them of particular interest for use in artificial photosynthetic systems for solar fuels formation. PMID- 21598952 TI - Kinetics study of crystallization with the disorder-bcc-fcc phase transition of charged colloidal dispersions. AB - Structure transformation (disorder-bcc-fcc) in charged colloidal dispersions, as a manifestation of the Ostwald's step rule, was confirmed by means of reflection spectrum (RS) measurements in our previous study. By taking advantage of a reflection spectrum containing plenty of information about the crystallization behaviors, time-dependent changes of parameters associated with the crystal structure and composition during the disorder-bcc-fcc transition are reported by treating the data from RS in this article. In addition, Avrami's model is adopted to analyze the transition process and investigate the transition rate. On the basis of the above investigations, associated kinetic features of crystallization with the disorder-bcc-fcc transition are described. PMID- 21598954 TI - Adsorption and conformation behavior of biotinylated fibronectin on streptavidin modified TiO(X) surfaces studied by SPR and AFM. AB - It is well-known that protein-modified implant surfaces such as TiO(2) show a higher bioconductivity. Fibronectin is a glycoprotein from the extracellular matrix (ECM) with a major role in cell adhesion. It can be applied on titanium oxide surfaces to accelerate implant integration. Not only the surface concentration but also the presentation of the protein plays an important role for the cellular response. We were able to show that TiO(X) surfaces modified with biotinylated fibronectin adsorbed on a streptavidin-silane self-assembly multilayer system are more effective regarding osteoblast adhesion than surfaces modified with nonspecifically bound fibronectin. The adsorption and conformation behavior of biotinylated and nonbiotinylated (native) fibronectin was studied by surface plasmon resonance (SPR) spectroscopy and atomic force microscopy (AFM). Imaging of the protein modification revealed that fibronectin adopts different conformations on nonmodified compared to streptavidin-modified TiO(X) surfaces. This conformational change of biotinylated fibronectin on the streptavidin monolayer delivers a fibronectin structure similar to the conformation inside the ECM and therefore explains the higher cell affinity for these surfaces. PMID- 21598956 TI - Large surface dipole moments in ZnO nanorods. AB - A self-consistent linear scaling three-dimensional fragment (LS3DF) method is used to study the dipole moments and internal electric fields of large ZnO nanorods. Our ab initio calculations reveal that the ZnO nanorod with unpassivated (1010) side surface has a side surface contribution per Zn-O dimer 10 times larger than the bulk contribution per Zn-O bond. Detailed analysis is used to decompose the total dipole moment into different contributions. It is found that the total dipole moment of a nanorod can be calculated from the different parts with their dielectric screening described by a continuous model. We also show the effect of the dipole moment on the interior electronic structure of the nanorod. PMID- 21598955 TI - Focal complex maturation and bridging on 200 nm vitronectin but not fibronectin patches reveal different mechanisms of focal adhesion formation. AB - The effects of protein type and pattern size on cell adhesion, spreading, and focal adhesion development are studied. Fibronectin and vitronectin patterns from 0.1 to 3 MUm produced by colloidal lithography reveal important differences in how cells adhere to and bridge focal adhesions across protein nanopatterns versus micropatterns. Vinculin and zyxin in focal adhesions but not integrins are seen to bridge ligand gaps. Differences in protein mechanical properties are implicated as important factors in focal adhesion development. PMID- 21598957 TI - Electron-phonon coupling in CdSe nanocrystals from an atomistic phonon model. AB - Phonon frequencies and eigenvectors, electron-phonon couplings, and the associated resonance Raman spectra have been calculated for approximately spherical, wurtzite form CdSe nanocrystals having radii of 1.4 to 2.3 nm and containing 318 to 1498 atoms. Calculations of the equilibrium geometries and phonon modes are carried out using an empirical force field, and the electron and hole wave functions are calculated as particle-in-a-sphere envelope functions multiplying the Bloch functions, with valence-band mixing included for the hole functions. The coupling of each phonon mode to the 1S(e)-1S(3/2) and 1S(e) 2S(3/2) excitations is evaluated directly from the change in Coulombic energy along the phonon coordinate. Ten to 50 different modes in each crystal have significant Huang-Rhys factors, clustered around two frequency regions: acoustic phonons at 20-40 cm(-1) depending on crystal size, and optical phonons at 185-200 cm(-1). The Huang-Rhys factors are larger for the acoustic modes than for the optical modes and decrease with increasing crystal size, and the Huang-Rhys factors for each group of modes are smaller for the 1S(e)-2S(3/2) than for the 1S(e)-1S(3/2) excitation. These results are compared with measurements of electron-phonon coupling in CdSe nanocrystals using different experimental techniques. PMID- 21598958 TI - Fine tuning micellar core-forming block of poly(ethylene glycol)-block poly(epsilon-caprolactone) amphiphilic copolymers based on chemical modification for the solubilization and delivery of doxorubicin. AB - This study aimed to optimize poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG-b-PCL)-based amphiphilic block copolymers for achieving a better micellar drug delivery system (DDS) with improved solubilization and delivery of doxorubicin (DOX). First, the Flory-Huggins interaction parameters between DOX and the core-forming segments [i.e., poly(epsilon-caprolactone) (PCL) and poly[(epsilon-caprolactone-co-gamma-(carbamic acid benzyl ester)-epsilon caprolactone] (P(CL-co-CABCL))] was calculated to assess the drug-polymer compatibility. The results indicated a better compatibility between DOX and P(CL co-CABCL) than that between DOX and PCL, motivating the synthesis of monomethoxy poly(ethylene glycol)-b-poly[(epsilon-caprolactone-co-gamma-(carbamic acid benzyl ester)-epsilon-caprolactone] (mPEG-b-P(CL-co-CABCL)) block copolymer. Second, two novel block copolymers of mPEG-b-P(CL-co-CABCL) with different compositions were prepared via ring-opening polymerization of CL and CABCL using mPEG as a macroinitiator and characterized by (1)H NMR, FT-IR, GPC, WAXD, and DSC techniques. It was found that the introduction of CABCL decreased the crystallinity of mPEG-b-PCL copolymer. Micellar formation of the copolymers in aqueous solution was investigated with fluorescence spectroscopy, DLS and TEM. mPEG-b-P(CL-co-CABCL) copolymers had a lower critical micelle concentration (CMC) than mPEG-b-PCL and subsequently led to an improved stability of prepared micelles. Furthermore, both higher loading capacity and slower in vitro release of DOX were observed for micelles of copolymers with increased content of CABCL, attributed to both improved drug-core compatibility and favorable amorphous core structure. Meanwhile, DOX-loaded micelles facilitated better uptake of DOX by HepG2 cells and were mainly retained in the cytosol, whereas free DOX accumulated more in the nuclei. However, possibly because of the slower intracellular release of DOX, DOX-loaded micelles were less potent in inhibiting cell proliferation than free DOX in vitro. Taken together, the introduction of CABCL in the core forming block of mPEG-b-PCL resulted in micelles with superior properties, which hold great promise for drug delivery applications. PMID- 21598959 TI - Palladium-catalyzed oxidative C-H bond coupling of steered acetanilides and aldehydes: a facile access to ortho-acylacetanilides. AB - A palladium-catalyzed oxidative C-H bond functionalization/ortho-acylation of acetanilides using easily accessible aldehyde as the acyl source is described. In the presence of a Pd(TFA)(2) catalyst and tert-butylhydroperoxide at 90 degrees C in general, an array of ortho-acylacetanilides can be afforded in good yields. PMID- 21598960 TI - Long-range effects of a peripheral mutation on the enzymatic activity of cytochrome P450 1A2. AB - The human cytochrome P450 1A2 is an important drug metabolizing and procarcinogen activating enzyme. An experimental study found that a peripheral mutation, F186L, at ~26 A away from the enzyme's active site, caused a significant reduction in the enzymatic activity of 1A2 deethylation reactions. In this paper, we explored the effects of this mutation by carrying out molecular dynamics simulations and structural analyses. We found that the long-range effects of the F186L mutation were through a change in protein flexibility and a collective protein motion that caused the main substrate access channel to be mostly closed in the mutant. Our work is the first that combined both access channel analysis and protein motion analysis to elucidate mechanisms of mutation-induced allostery in a CYP protein. Such structural modeling and analysis approaches may be applied to other CYP proteins and other enzymes with buried active sites and may help guide protein engineering and drug design. PMID- 21598962 TI - Thermal conduction in aligned carbon nanotube-polymer nanocomposites with high packing density. AB - Nanostructured composites containing aligned carbon nanotubes (CNTs) are very promising as interface materials for electronic systems and thermoelectric power generators. We report the first data for the thermal conductivity of densified, aligned multiwall CNT nanocomposite films for a range of CNT volume fractions. A 1 vol % CNT composite more than doubles the thermal conductivity of the base polymer. Denser arrays (17 vol % CNTs) enhance the thermal conductivity by as much as a factor of 18 and there is a nonlinear trend with CNT volume fraction. This article discusses the impact of CNT density on thermal conduction considering boundary resistances, increased defect concentrations, and the possibility of suppressed phonon modes in the CNTs. PMID- 21598961 TI - Control of on-off or off-on fluorescent and optical [Cu2+] and [Hg2+] responses via formal Me/H substitution in fully characterized thienyl "scorpionate"-like BODIPY systems. AB - One 8-phenyl and two 8-mesityl-substituted "scorpionate"-like BODIPY-type species of the formula [3,4,4-tris(5-R-(2-thienyl))-8-(2,4,6-R'-phenyl)-4-bora-3a,4a diaza-s-indacene (R = H, R' = H, 3a; R, = H, R' = Me, 2a; R, = Me, R' = Me, 2b)] have been synthesized and fully characterized. Importantly, differences in their solution (MeCN) optical Cu(2+) and Hg(2+) probing capacity via SSS-chelation were investigated. Compounds 2a-3a were prepared from the requisite 8-substituted BODIPY complexes. They were characterized first by complete (1)H, (11)B and (13)C NMR spectroscopic assignments (CD(3)Cl or CD(3)C(O)CD(3)); the molecular structures of 2a and 3a were determined by X-ray crystallography. Compounds 2a-3a were studied by UV-vis and fluorescence spectroscopy [Phi(F) = 0.27 +/- 0.013 (2a); 0.024 +/- 0.0016 (2b); 0.0034 +/- 0.00047 (3a)]. Importantly, low [Cu(2+)] with 3a (<3.0 * 10(-5) M) gave rise to an increase of fluorescence intensity (off on; 6.3-fold), whereas with 2a it decreased (on-off). When [Hg(2+)] (<3.0 * 10( 5) M) was added to 2b, the lambda(em,max) value increased (off-on; 3.2-fold), and for 2a, it decreased (on-off). The association constant (K(a)) for Hg(2+).2a was determined to be 3120 +/- 307 M(-1). An approximate stoichiometric 1:1 binding determined by Job plot analysis is in line with successful DFT modeling of SSS Cu(2+) binding for this system type. (1)H NMR spectroscopy also revealed tentative sets of product complex peaks. These simple differences caused by formal ligand Me-group incorporation are the first for any related fluorophores, to the best of our knowledge. PMID- 21598963 TI - Concentration of bisphenol A in highly consumed canned foods on the U.S. market. AB - Metal food and drink cans are commonly coated with epoxy films made from phenolic polymers produced from bisphenol A (BPA). It is well established that residual BPA monomer migrates into can contents during processing and storage. While a number of studies have reported BPA concentrations in foods from foreign markets and specialty foods on the U.S. market, very few peer-reviewed data for the BPA concentrations in canned food from the U.S. market were available. This study quantified BPA concentrations in 78 canned and two frozen food products from the U.S. market using an adaptation of a previously reported liquid chromatography tandem mass spectrometry method. The tested products represented 16 different food types that are from the can food classifications that constitute approximately 65% of U.S. canned food sales and canned food consumption. BPA was detected in 71 of the 78 canned food samples but was not detected in either of the two frozen food samples. Detectable BPA concentrations across all foods ranged from 2.6 to 730 ng/g. Large variations in BPA concentrations were found between different products of the same food type and between different lots of the same product. Given the large concentration ranges, the only distinguishable trend was that fruits and tuna showed the lowest BPA concentrations. Experiments with fortified frozen vegetables and brine solutions, as well as higher BPA concentrations in canned food solids over liquid portions, clearly indicated that BPA partitions into the solid portion of foods. PMID- 21598964 TI - Functional properties of bioplastics made from wheat gliadins modified with cinnamaldehyde. AB - Cinnamaldehyde is a naturally occurring alpha,beta-unsaturated aldehyde. Its potential as a natural cross-linker to improve the physical performance of cast wheat gliadin films was evaluated. The cross-linking reaction was found to be dependent on the pH of the reaction medium, with pH 2 as the optimum. The water resistance (weight loss after immersion), mechanical properties (Young's modulus, tensile strength and elongation at break), thermal properties (T(g) and decomposition behavior), optical properties and morphology of films were evaluated. Cross-linked films showed high transparency, maintained their integrity after immersion, and displayed significant improvements in tensile strength and Young's modulus without impairment of their elongation properties. These effects, which were proportional to the amount of cinnamaldehyde added, highlight the possible formation of intermolecular covalent bonds between "monomeric" gliadins, leading to a polymerized network. Thus, this treatment could provide a new alternative to the toxic cross-linkers commonly employed and so extend the use of gliadin films. PMID- 21598966 TI - A codoping route to realize low resistive and stable p-type conduction in (Li, Ni):ZnO thin films grown by pulsed laser deposition. AB - We report on the growth of Li-Ni codoped p-type ZnO thin films using pulsed laser deposition. Two mole percent Li monodoped ZnO film shows highly insulating behavior. However, a spectacular decrease in electrical resistivity, from 3.6 * 10(3) to 0.15 Omega cm, is observed by incorporating 2 mol % of Ni in the Li doped ZnO film. Moreover, the activation energy drops to 6 meV from 78 meV with Ni incorporation in Li:ZnO lattice. The codoped [ZnO:(Li, Ni)] thin film shows p type conduction with room temperature hole concentration of 3.2 * 10(17) cm(-3). Photo-Hall measurements show that the Li-Ni codoped p-ZnO film is highly stable even with UV illumination. XPS measurements reveal that most favorable chemical state of Ni is Ni(3+) in (Li, Ni): ZnO. We argue that these Ni(3+) ions act as reactive donors and increase the Li solubility limit. Codoping of Li, with other transitional metal ions (Mn, Co, etc.) in place of Ni could be the key to realize hole-dominated conductivity in ZnO to envisage ZnO-based homoepitaxial devices. PMID- 21598965 TI - The structure of ions and zwitterionic lipids regulates the charge of dipolar membranes. AB - In pure water, zwitterionic lipids form lamellar phases with an equilibrium water gap on the order of 2 to 3 nm as a result of the dominating van der Waals attraction between dipolar bilayers. Monovalent ions can swell those neutral lamellae by a small amount. Divalent ions can adsorb onto dipolar membranes and charge them. Using solution X-ray scattering, we studied how the structure of ions and zwitterionic lipids regulates the charge of dipolar membranes. We found that unlike monovalent ions that weakly interact with all of the examined dipolar membranes, divalent and trivalent ions adsorb onto membranes containing lipids with saturated tails, with an association constant on the order of ~10 M(-1). One double bond in the lipid tail is sufficient to prevent divalent ion adsorption. We suggest that this behavior is due to the relatively loose packing of lipids with unsaturated tails that increases the area per lipid headgroup, enabling their free rotation. Divalent ion adsorption links two lipids and limits their free rotation. The ion-dipole interaction gained by the adsorption of the ions onto unsaturated membranes is insufficient to compensate for the loss of headgroup free-rotational entropy. The ion-dipole interaction is stronger for cations with a higher valence. Nevertheless, polyamines behave as monovalent ions near dipolar interfaces in the sense that they interact weakly with the membrane surface, whereas in the bulk their behavior is similar to that of multivalent cations. Advanced data analysis and comparison with theory provide insight into the structure and interactions between ion-induced regulated charged interfaces. This study models biologically relevant interactions between cell membranes and various ions and the manner in which the lipid structure governs those interactions. The ability to monitor these interactions creates a tool for probing systems that are more complex and forms the basis for controlling the interactions between dipolar membranes and charged proteins or biopolymers for encapsulation and delivery applications. PMID- 21598967 TI - Formal total synthesis of (+)-lysergic acid via zinc(II)-mediated regioselective ring-opening reduction of 2-alkynyl-3-indolyloxirane. AB - Asymmetric formal synthesis of (+)-lysergic acid was achieved with a reductive ring-opening reaction of chiral 2-alkynyl-3-indolyloxirane with NaBH(3)CN as the key step. With Zn(OTf)(2) as an additive, the ring-opening reaction proceeded regioselectively at the 3-position to give the corresponding propargyl alcohol, which was a precursor of the allenic amide for palladium-catalyzed domino cyclization to construct the ergot alkaloid core structure. PMID- 21598968 TI - Kinetics and mechanisms of the allyl + allyl and allyl + propargyl recombination reactions. AB - The kinetics and mechanisms of the self-reaction of allyl radicals and the cross reaction between allyl and propargyl radicals were studied both experimentally and theoretically. The experiments were carried out over the temperature range 295-800 K and the pressure range 20-200 Torr (maintained by He or N(2)). The allyl and propargyl radicals were generated by the pulsed laser photolysis of respective precursors, 1,5-hexadiene and propargyl chloride, and were probed by using a cavity ring-down spectroscopy technique. The temperature-dependent absorption cross sections of the radicals were measured relative to that of the HCO radical. The rate constants have been determined to be k(C(3)H(5) + C(3)H(5)) = 1.40 * 10(-8)T(-0.933) exp(-225/T) cm(3) molecule(-1) s(-1) (Delta log(10)k = +/- 0.088) and k(C(3)H(5) + C(3)H(3)) = 1.71 * 10(-7)T(-1.182) exp(-255/T) cm(3) molecule(-1) s(-1) (Delta log(10)k = +/- 0.069) with 2sigma uncertainty limits. The potential energy surfaces for both reactions were calculated with the CBS-QB3 and CASPT2 quantum chemical methods, and the product channels have been investigated by the steady-state master equation analyses based on the Rice Ramsperger-Kassel-Marcus theory. The results indicated that the reaction between allyl and propargyl radicals produces five-membered ring compounds in combustion conditions, while the formations of the cyclic species are unlikely in the self reaction of allyl radicals. The temperature- and pressure-dependent rate constant expressions for the important reaction pathways are presented for kinetic modeling. PMID- 21598969 TI - Sulfidation processes of PVP-coated silver nanoparticles in aqueous solution: impact on dissolution rate. AB - Despite the increasing use of silver nanoparticles (Ag-NPs) in nanotechnology and their toxicity to invertebrates, the transformations and fate of Ag-NPs in the environment are poorly understood. This work focuses on the sulfidation processes of PVP-coated Ag-NPs, one of the most likely corrosion phenomena that may happen in the environment. The sulfur to Ag-NPs ratio was varied in order to control the extent of Ag-NPs transformation to silver sulfide (Ag2S). A combination of synchrotron-based X-ray Diffraction (XRD) and Extended X-ray Absorption Fine Structure spectroscopy shows the increasing formation of Ag2S with an increasing sulfur to Ag-NPs ratio. TEM observations show that Ag2S forms nanobridges between the Ag-NPs leading to chain-like structures. In addition, sulfidation strongly affects surface properties of the Ag-NPs in terms of surface charge and dissolution rate. Both may affect the reactivity, transport, and toxicity of Ag NPs in soils. In particular, the decrease of dissolution rate as a function of sulfide exposure may strongly limit Ag-NPs toxicity since released Ag+ ions are known to be a major factor in the toxicity of Ag-NPs. PMID- 21598970 TI - Fluorescent "barcode" multiblock co-micelles via the living self-assembly of di- and triblock copolymers with a crystalline core-forming metalloblock. AB - We describe the self-assembly in 2-propanol (2-PrOH) of the triblock copolymer, poly(ferrocenyldimethylsilane-b-2-vinylpyridine-b-2,5-di(2'-ethylhexyloxy)-1,4 phenylvinylene) (PFS(30)-b-P2VP(300)-b-PDEHPV(13), the subscripts refer to the degree of polymerization). The intense fluorescence of the PDEHPV moieties rendered the resulting cylindrical micelles and their aggregates visible in solution by laser confocal fluorescence microscopy (LCFM). Sonication yielded micelle fragments that could be grown into elongated fiber-like micelles 10 nm in width and nearly monodisperse in length by adding additional block polymer as a solution in tetrahydrofuran. The presence of the conjugated block in the corona promoted slow aggregation of the micelles into hierarchical flower-like structures, but this secondary assembly could be reversed by warming the solution to 50 degrees C for 30 min. When a solution of 500 nm long micelles of PFS(30)-b P2VP(300)-b-PDEHPV(13) in 2-PrOH was treated sequentially with controlled amounts of the diblock copolymer PFS(30)-b-P2VP(300), and in intervals of 24 h, with additional aliquots of PFS(30)-b-P2VP(300)-b-PDEHPV(13), PFS(30)-b-P2VP(30), and PFS(30)-b-P2VP(300)-b- PDEHPV(13), uniform rod-like multiblock co-micelles were obtained with remarkable optical properties: a banded light-emitting "barcode" structure with fluorescent segments of the triblock copolymer separated by nonemissive segments made up of the diblock copolymer. PMID- 21598971 TI - Total synthesis and bioactivity of 18(R)-hydroxyeicosapentaenoic acid. AB - Resolvins are family of lipid mediators derived from omega-3 polyunsaturated fatty acids, which are generated during the resolution phase of acute inflammation. Resolvin E1 is biosynthesized from eicosapentaenoic acid via 18(R) hydroxyeicosapentaenoic acid (18R-HEPE) in the Cox-2 and lipoxygenase mediated pathway and has proven to exhibit potent anti-inflammatory activity. We report herein the first total chemical synthesis of 18R-HEPE and demonstrate that this compound displays in vivo bioactivity by blocking neutrophil infiltration in a murine model of zymosan-induced peritonitis. PMID- 21598972 TI - Iron-catalyzed intermolecular [2pi+2pi] cycloaddition. AB - The bis(imino)pyridine iron dinitrogen compounds, ((iPr)PDI)Fe(N(2))(2) and [((Me)PDI)Fe(N(2))](2)(MU(2)-N(2)) ((R)PDI = 2,6-(2,6-R(2) C(6)H(3)N?CMe)(2)C(5)H(3)N; R = (i)Pr, Me), promote the catalytic intermolecular [2pi + 2pi] cycloaddition of ethylene and butadiene to form vinylcyclobutane. Stoichiometric experiments resulted in isolation of a catalytically competent iron metallocycle intermediate, which was shown to undergo diene-induced C-C reductive elimination. Deuterium labeling experiments establish competitive cyclometalation of the bis(imino)pyridine aryl substituents during catalytic turnover. PMID- 21598973 TI - Toward complementary ionic circuits: the npn ion bipolar junction transistor. AB - Many biomolecules are charged and may therefore be transported with ionic currents. As a step toward addressable ionic delivery circuits, we report on the development of a npn ion bipolar junction transistor (npn-IBJT) as an active control element of anionic currents in general, and specifically, demonstrate actively modulated delivery of the neurotransmitter glutamic acid. The functional materials of this transistor are ion exchange layers and conjugated polymers. The npn-IBJT shows stable transistor characteristics over extensive time of operation and ion current switch times below 10 s. Our results promise complementary chemical circuits similar to the electronic equivalence, which has proven invaluable in conventional electronic applications. PMID- 21598974 TI - Oxidation of zinc-thiolate complexes of biological interest by hydrogen peroxide: a theoretical study. AB - Zinc-thiolate complexes play a major structural and functional role in the living cell. Their stability is directly related to the thiolate reactivity toward reactive oxygen species naturally present in the cell. Oxidation of some zinc thiolate complexes has a functional role, as is the case of zinc finger redox switches. Herein, we report a theoretical investigation on the oxidation of thiolate by hydrogen peroxide in zinc finger cores of CCCC, CCHC, and CCHH kinds containing either cysteine or histidine residues. In the case of the CCCC core, the calculated energy barrier for the oxidation to sulfenate of the complexed thiolate was found to be 16.0 kcal mol(-1), which is 2 kcal mol(-1) higher than that for the free thiolate. The energy barrier increases to 19.3 and 22.2 kcal mol(-1) for the monoprotonated and diprotonated CCCC cores, respectively. Substitution of cysteine by histidine also induces an increase in the magnitude of the reaction energy barrier: It becomes 20.0 and 20.9 kcal mol(-1) for the CCCH and CCHH cores, respectively. It is concluded that the energy barrier for the oxidation of zinc fingers is strictly dependent on the type of ligands coordinated to zinc and on the protonation state of the complex. These changes in the thiolate reactivity can be explained by the lowering of the nucleophilicity of complexed sulfur and by the internal reorganization of the complex (changes in the metal-ligand distances) upon oxidation. The next reaction steps subsequent to sulfenate formation are also considered. The oxidized thiolate (sulfenate) is predicted to dissociate very fast: For all complexes, the calculated dissociation energy barrier is lower than 3 kcal mol(-1). It is also shown that the dissociated sulfenic acid can interact with a free thiolate to form a sulfur sulfur (SS) bridge in a reaction that is predicted to be quasi-diffusion limited. The interesting biological consequences of the modulation of thiolate reactivity by the chemical composition of the zinc finger cores are discussed. PMID- 21598975 TI - Mechanical unfolding of the beet western yellow virus -1 frameshift signal. AB - Using mechanical unfolding by optical tweezers (OT) and steered molecular dynamics (SMD) simulations, we have demonstrated the critical role of Mg(2+) ions for the resistance of the Beet Western Yellow Virus (BWYV) pseudoknot (PK) to unfolding. The two techniques were found to be complementary, providing information at different levels of molecular scale. Findings from the OT experiments indicated a critical role of stem 1 for unfolding of the PK, which was confirmed in the SMD simulations. The unfolding pathways of wild type and mutant appeared to depend upon pH and nucleotide sequence. SMD simulations support the notion that the stability of stem 1 is critical for -1 frameshifting. The all-atom scale nature of the SMD enabled clarification of the precise role of two Mg(2+) ions, Mg45 and Mg52, as identified in the BWYV X-ray crystallography structure, in -1 frameshifting. On the basis of simulations with "partially" and "fully" hydrated Mg(2+) ions, two possible mechanisms of stabilizing stem 1 are proposed. In both these cases Mg(2+) ions play a critical role in stabilizing stem 1, either by directly forming a salt bridge between the strands of stem 1 or by stabilizing parallel orientation of the strands in stem 1, respectively. These findings explain the unexpected drop in frameshifting efficiency to null levels of the C8U mutant in a manner consistent with experimental observations. PMID- 21598976 TI - Increase in cone biomass and terpenophenolics in hops ( Humulus lupulus L.) by treatment with prohexadione-calcium. AB - Humulus lupulus L. (hop), a specialty crop bred for flavor characteristics of the inflorescence, is an essential ingredient in beer. Hop inflorescences, commonly known as hop cones, contain terpenophenolic compounds, which are important for beer flavoring and of interest in biomedical research. Hop breeders focus their efforts on increasing cone biomass and terpenophenolic content. As an alternative to traditional breeding, hops were treated with prohexadione-calcium (Pro-Ca), a growth inhibitor previously shown to have positive agronomic effects in several crops. Application of Pro-Ca to hop plants during cone maturation induced increases in cone biomass production by 1.5-19.6% and increased terpenophenolic content by 9.1-87.3%; however, some treatments also induced significant decreases in terpenophenolic content. Induced changes in cone biomass production and terpenophenolic accumulation were most dependent on cultivar and the developmental stage at which plants were treated. PMID- 21598977 TI - Vibrational mode analysis of isotope-labeled electronically excited riboflavin. AB - Isotope-labeled riboflavin in DMSO was employed in conjunction with femtosecond time-resolved infrared vibrational spectroscopy and quantum chemical calculations to analyze and assign the electronically excited state vibrational modes of the isoalloxazine unit as a prototype for the cofactors in flavin binding blue-light receptors. Using the riboflavin (13)C-analogues RF-2-(13)C and RF-4,10a-(13)C, the carbonyl vibrations, in particular, were studied. Various quantum chemical models were applied that take into account a polarizable environment or the impact of hydrogen bonds. The CIS quantum-chemistry method was successfully applied to describe the lowest singlet excited electronic state in riboflavin. The experimentally observed frequencies and isotope-shifts as well as their variability in the diverse model calculations are discussed. On these grounds, a consistent assignment of the electronic ground and excited state vibrations is presented. PMID- 21598978 TI - Noncovalent ligand-to-ligand interactions alter sense of optical chirality in luminescent tris(beta-diketonate) lanthanide(III) complexes containing a chiral bis(oxazolinyl) pyridine ligand. AB - Highly luminescent tris[beta-diketonate (HFA, 1,1,1,5,5,5-hexafluoropentane-2,4 dione)] europium(III) complexes containing a chiral bis(oxazolinyl) pyridine (pybox) ligand--[(Eu(III)(R)-Ph-pybox)(HFA)(3)], [(Eu(III)(R)-i-Pr pybox)(HFA)(3)], and [(Eu(III)(R)-Me-Ph-pybox)(HFA)(3)])--exhibit strong circularly polarized luminescence (CPL) at the magnetic-dipole ((5)D(0) -> (7)F(1)) transition, where the [(Eu(III)(R)-Ph-pybox)(HFA)(3)] complexes show virtually opposite CPL spectra as compared to those with the same chirality of [(Eu(III)(R)-i-Pr-pybox)(HFA)(3)] and [(Eu(III)(R)-Me-Ph-pybox)(HFA)(3)]. Similarly, the [(Tb(III)(R)-Ph-pybox)(HFA)(3)] complexes were found to exhibit CPL signals almost opposite to those of [(Tb(III)(R)-i-Pr-pybox)(HFA)(3)] and [(Tb(III)(R)-Me-Ph-pybox)(HFA)(3)] complexes with the same pybox chirality. Single-crystal X-ray structural analysis revealed ligand-ligand interactions between the pybox ligand and the HFA ligand in each lanthanide(III) complex: pi pi stacking interactions in the Eu(III) and Tb(III) complexes with the Ph-pybox ligand, CH/F interactions in those with the i-Pr-pybox ligand, and CH/pi interactions in those with the Me-Ph-pybox ligand. The ligand-ligand interactions between the achiral HFA ligands and the chiral pybox results in an asymmetric arrangement of three HFA ligands around the metal center. The metal center geometry varies depending on the types of ligand-ligand interaction. PMID- 21598979 TI - Reagents for stereoselective preparation of N-carbamyl beta-D-glucuronides. AB - Carbamyl glucuronidation is an increasingly well-recognized route of metabolism for secondary amine drugs. Proper characterization of these metabolites requires the synthesis of authentic standards. O-protected glucuronyl p-nitrophenyl carbonates can be prepared with high selectivity for the beta-configuration at the anomeric center and efficiently transfer the beta-glucuronylcarbonyl group to secondary amines, constituting an effective and versatile method for preparation of these metabolites. PMID- 21598980 TI - Dramatic reduction of surface recombination by in situ surface passivation of silicon nanowires. AB - Nanowires have unique optical properties and are considered as important building blocks for energy harvesting applications such as solar cells. However, due to their large surface-to-volume ratios, the recombination of charge carriers through surface states reduces the carrier diffusion lengths in nanowires a few orders of magnitude, often resulting in the low efficiency (a few percent or less) of nanowire-based solar cells. Reducing the recombination by surface passivation is crucial for the realization of high-performance nanosized optoelectronic devices but remains largely unexplored. Here we show that a thin layer of amorphous silicon (a-Si) coated on a single-crystalline silicon nanowire, forming a core-shell structure in situ in the vapor-liquid-solid process, reduces the surface recombination nearly 2 orders of magnitude. Under illumination of modulated light, we measure a greater than 90-fold improvement in the photosensitivity of individual core-shell nanowires, compared to regular nanowires without shell. Simulations of the optical absorption of the nanowires indicate that the strong absorption of the a-Si shell contributes to this effect, but we conclude that the effect is mainly due to the enhanced carrier lifetime by surface passivation. PMID- 21598981 TI - Strain patterning and direct measurement of Poisson's ratio in nanoparticle monolayer sheets. AB - Close-packed monolayers self-assembled from ligated nanoparticles can form 10 nm thin sheets that stretch over micrometer-wide holes. Employing electron and focused ion beams, we show that one can locally tailor the strain in such sheets while they remain clamped around their perimeter, making it possible to imprint strain fields by design. Furthermore, using the nanoparticles themselves to track imposed strain gradients allows for the first direct measurement of Poisson's ratio in these two-dimensional materials. PMID- 21598982 TI - Hierarchical construction of self-standing anodized titania nanotube arrays and nanoparticles for efficient and cost-effective front-illuminated dye-sensitized solar cells. AB - We report on the influence of hierarchical structures, constructed via layer-by layer assembly of self-standing titania nanotube arrays and nanoparticles, upon charge recombination and photoelectric performance of front-illuminated dye sensitized solar cells. Both nanotubes and nanoparticles were produced by anodization rather than additionally employing other methods, providing low cost and great simplicity. Electrochemical impedance spectroscopy under AM 1.5 illumination indicates the construction of hybrid morphology has superior recombination characteristics and a longer electron lifetime than nanoparticulate systems. This enhancement with the incorporation of anodized titania nanoparticles with 1D architectures is unprecedented for solar cells. Owing to the better light harvesting efficiency, extended electron lifetime and desirable electron extraction, the short-circuit photocurrent density of solar cell is 18.89 mA cm(-2) with an overall power conversion efficiency of 8.80% and an incident photon-to-current conversion efficiency of 84.6% providing a very promising candidate for sustainable energy production with a high performance/cost ratio. PMID- 21598983 TI - Protective role of 14-deoxy-11,12-didehydroandrographolide, a noncytotoxic analogue of andrographolide, in allergic airway inflammation. AB - Our group recently reported novel anti-inflammatory effects of andrographolide (2), a bioactive molecule isolated from Andrographis paniculata, in a mouse asthma model. However, 2 has been shown to possess cytotoxic activity. 14-Deoxy 11,12-didehydroandrographolide (1) is an analogue of 2 that can be isolated from A. paniculata. We hypothesized that 1 retains the anti-inflammatory effects for asthma but is devoid of cytotoxicity. In contrast to 2, 1 did not elicit any cytotoxic activity in A549 and BEAS-2B human lung epithelial cells and rat basophilic leukemia (RBL)-2H3 cells using a MTS assay. Compound 1 dose dependently inhibited ovalbumin (OVA)-induced increases in total and eosinophil counts, IL-4, IL-5, and IL-13 levels in lavage fluid, and serum OVA-specific IgE level in a mouse asthma model. Compound 1 attenuated OVA-induced airway eosinophilia, mucus production, mast cell degranulation, pro-inflammatory biomarker expression in lung tissues, and airway hyper-responsiveness. This substance also blocked p65 nuclear translocation and DNA-binding activity in the OVA-challenged lung and in TNF-alpha-stimulated human lung epithelial cells. The present findings reveal for the first time that 1 retains the anti-inflammatory activities of 2 for asthma probably through the inhibition of NF-kappaB. 14-Deoxy 11,12-didehydroandrographolide (1) may be considered as a safer analogue of 2 for the potential treatment of asthma. PMID- 21598985 TI - Water-soluble phosphonate-substituted BODIPY derivatives with tunable emission channels. AB - Water-soluble BODIPY dyes have been readily obtained by introduction of phosphonate fragments either on the boron for the green and yellow emitting dyes or on the side chain for the red emitting dyes. Hydrolysis of the phosphonate is realized at the end of the reaction sequence and allows isolation of the targets by precipitation. All these novel dyes are soluble and fluorescent in water with quantum yields in the 23-59% range and emission wavelength spanning from 667 to 509 nm. PMID- 21598984 TI - Multicomponent assembly and diversification of novel heterocyclic scaffolds derived from 2-arylpiperidines. AB - A collection of structurally diverse, polyheterocyclic scaffolds comprising a 2 arylpiperidine subunit were synthesized using a Mannich-type multicomponent assembly process, followed by appropriately sequenced ring-forming reactions. An improved procedure for removal of N-4-pentenoyl groups was developed; one-pot sequences for tandem urea/thiourea formation and cyclization and tandem enolate arylation/alkylation were discovered. A novel entry to bridged tetrahydroquinoline scaffolds exploiting A(1,3) strain was also invented. Derivatization of several scaffolds was achieved by cross-coupling and N functionalization. PMID- 21598986 TI - Biocatalytic methods for the synthesis of enantioenriched odor active compounds. PMID- 21598987 TI - Chiral optical films based on achiral chromophore guests. AB - Films constituted by an achiral host polymer and an achiral guest chromophore, which exhibit intense chiral optical responses for both host and guest peaks in the infrared as well as in the UV-visible regions, have been obtained. Such films can have any thickness from the nanoscale up to the macroscopic scale. This unexpected chiral optical behavior is easily achieved by crystallization of a robust commercial stereoregular host polymer (syndiotactic polystyrene, s-PS) from the amorphous phase as induced by a nonracemic guest, followed by exchange of the nonracemic guest with the achiral guest, leading to the formation of polymer-host/chromophore-guest cocrystalline phases. This finding opens the possibility to achieve s-PS-based films with chiral optical response at selected wavelengths. It has been also found that the chiral optical cocrystalline phase of s-PS with azulene exhibits a monoclinic delta-clathrate form with equal proportions of left- and right-handed helices. This confirms that the observed chiral optical behavior arises by the nonracemic native morphology of the crystalline regions, which has been induced by the temporary nonracemic guest. PMID- 21598988 TI - Synthesis of indenoporphyrins, highly modified porphyrins with reduced diatropic characteristics. AB - Indene-fused porphyrins have been synthesized starting from 2-indanone. Knorr type reaction of oximes derived from benzyl or tert-butyl acetoacetate with 2 indanone and zinc dust in propionic acid gave good yields of indenopyrroles. Treatment with N-chlorosuccinimide then gave 8-chloro derivatives, and these reacted with 5-unsubstituted pyrroles to give dipyrroles incorporating the fused indene unit. Hydrogenolysis of the benzyl ester protective groups afforded the related dicarboxylic acids, but condensation with a dipyrrylmethane dialdehyde under MacDonald "2 + 2" reaction conditions gave poor yields of the targeted indenoporphyrins. However, when an indene-fused dipyrrole was converted into the corresponding dialdehyde with TFA-trimethyl orthoformate and then reacted with a dipyrrylmethane dicarboxylic acid, an indenoporphyrin was isolated in 26% yield. The porphyrin gave a highly modified UV-vis absorption spectrum with three strong bands showing up in the Soret region and a series of Q bands that extended beyond 700 nm. The proton NMR spectrum also showed a significantly reduced diamagnetic ring current where the meso-protons gave resonances near 9.3 ppm instead of typical porphyrin values of 10 ppm. Nickel(II), copper(II), and zinc complexes were also prepared, and these exhibited unusual UV-vis absorption spectra with bathochromically shifted Soret and Q absorptions. The diamagnetic nickel(II) and zinc complexes also showed reduced diatropic character compared to typical nickel(II) and zinc porphyrins. PMID- 21598989 TI - 1,2,3,4,6-penta-O-galloyl-beta-D-glucose, quercetin, curcumin and lycopene induce cell-cycle arrest in MDA-MB-231 and BT474 cells through downregulation of Skp2 protein. AB - The F-box protein S-phase kinase-associated protein 2 (Skp2), which acts as an oncogene through targeting p27 for degradation, is overexpressed in many different human cancers. Skp2 can play an important role in breast cancer progression and may also be a novel molecular target for the treatment of breast cancer, especially estrogen receptor (ER)/human epidermal growth factor 2 (HER2) negative breast cancers. Unfortunately, specific drugs that target Skp2 are unavailable at present. Therefore, it is important to explore whether commonly used chemopreventive agents may downregulate Skp2 expression. In this study, we examined the effects of 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (pentagalloylglucose, 5gg), quercetin, curcumin and lycopene on the expression of Skp2 in MDA-MB-231 (ER/HER2-negative) and BT474 (ER-negative/HER2-positive) cells. We found that all four phytochemicals studied induced cell growth inhibition in MDA-MB-231 cells. The mechanism of the initial growth inhibitory events involves blocking the cell cycle progression. Further, we found that quercetin and curcumin induced growth arrest by inhibition of Skp2, and induced p27 expression in MDA-MB-231 cells. However, the decrease in Skp2 levels in cells treated with 5gg or lycopene did not translate to p27 upregulation. Consequently, the downregulation of Skp2 did not always correlate with the upregulation of p27, suggesting that phytochemical-dependent downregulation of Skp2 can influence cell growth in several ways. Several studies have demonstrated that Skp2 directs the ubiquitylation and subsequent degradation of forkhead box protein O1 (FoxO1). Furthermore, our results reveal that FoxO1 protein was increased after 5gg, quercetin, curcumin and lycopene treatment. The therapeutic strategies designed to reduce Skp2 may therefore play an important clinical role in treatment of breast cancer cells, especially ER/HER2-negative breast cancers. PMID- 21598990 TI - Asymmetric total synthesis of (+)-luciduline: toward a general approach to related Lycopodium alkaloids. AB - As part of a research program directed toward the synthesis of Lycopodium alkaloids, a multigram scale asymmetric synthesis of intermediate 11 was achieved in 11 steps from pyridine (17). In addition to our alkene metathesis strategy, a key feature of this synthetic approach consists of a Fukuyama's Diels-Alder cycloaddition between 1,2-dihydropyridine and acrolein using MacMillan's catalyst (18) on a 50 g scale. This led to a 12-step catalytic asymmetric synthesis of (+) luciduline (1). A broader subset of Lycopodium alkaloids could also be obtained, as demonstrated by the derivatization of 11 into advanced intermediates for the synthesis of some of these natural products. PMID- 21598991 TI - Bichromophoric rhodamine-iridium(III) sensory system: modulation of the energy transfer process through a selective sensing behavior. AB - A newly designed bichromophoric rhodamine-iridium(III) system was found to show color/electronic absorption spectral changes and modulation of the energy transfer process from rhodamine 6G to the iridium(III) luminophore upon selective Hg(II) ion binding. PMID- 21598992 TI - Raman spectroscopic signatures of noncovalent interactions between trimethylamine N-oxide (TMAO) and water. AB - The effects of hydration on vibrational normal modes of trimethylamine N-oxide (TMAO) are investigated by Raman spectroscopy and electronic structure computations. Microsolvated networks of water are observed to induce either red or blue shifts in the normal modes of TMAO with increasing water concentration and to also exhibit distinct spectral signatures. By taking advantage of the selective and gradual nature of the water-induced shifts and using comparisons to theoretical predictions, the assignments of TMAO's normal modes are re-examined and the structure of the hydrogen-bonded network in the vicinity of TMAO is elucidated. Agreement between experiment and theory suggests that the oxygen atom in TMAO accepts on average at least three hydrogen bonds from neighboring water molecules and that water molecules are likely not directly interacting with TMAO's methyl groups. PMID- 21598993 TI - A novel water-soluble heptaplatin analogue with improved antitumor activity and reduced toxicity. AB - A novel water-soluble heptaplatin analogue, cis-[(4R,5R)-4,5-bis-(aminomethyl)-2 isopropyl-1,3-dioxolane](3-hydroxy-1,1-cyclobutanedicarboxylato)platinum(II), has been synthesized and biologically evaluated. The complex shows more activity and less toxicity than its parent drug heptaplatin, exhibiting the great potential for further development. PMID- 21598994 TI - Ruthenium-catalyzed conversion of sp3 C-O bonds in ethers to C-C bonds using triarylboroxines. AB - Catalytic conversion of unreactive sp(3) C-O bonds in alkyl ethers to C-C bonds is described. Alkyl ethers bearing 2- or 4-pyridyl groups were coupled with triarylboroxines in the presence of a ruthenium catalyst. Triarylboroxines bearing a variety of functional groups including electron-withdrawing and donating groups can be used for the reaction. No additional base was required for the coupling with the organoboron reagents, and base-sensitive groups can be tolerated. The reaction is considered to proceed via dehydroalkoxylation followed by addition of triarylboroxines to form C-C bonds. PMID- 21598995 TI - Synchrotron SAXS and WAXS study of the interactions of NSAIDs with lipid membranes. AB - Cell membranes often constitute the first biological structure encountered by drugs, and binding or interactions of drugs with lipid components of the membrane may explain part of their mechanism of activity or their side effects. The present study provides evidence of alterations in the structural properties of phospholipid bilayers at acidic conditions that can be correlated with the mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) and with their local action effect on the gastrointestinal tract lipids, aiming a molecular biophysical approach to the interaction of these drugs with lipid membranes. In this context, the structural modifications of the 1,2-dipalmitoyl sn-glycero-3-phosphocholine bilayers at pH 5.0, induced by increasing concentrations of five NSAIDs (piroxicam, meloxicam, tolmetin, indomethacin, and nimesulide), were studied by small-angle and wide-angle X-ray scattering. Results obtained highlight the effect of each NSAID in modulating the membrane structure properties. All the NSAIDs promoted distinct biophysical effects by perturbing the membrane arrangement to different degrees that are intimately related to their different physicochemical properties as well as with the initial organization of the lipids, depending if they are in the gel (L(beta')) or in the liquid-crystalline phase (L(alpha)). PMID- 21598996 TI - Biomimetic solid lipid nanoparticles for oral bioavailability enhancement of low molecular weight heparin and its lipid conjugates: in vitro and in vivo evaluation. AB - Low molecular weight heparin (LMWH) is an anionic oligosaccharide macromolecule, which is commonly administered via parenteral routes for the treatment of vascular disorders like deep vein thrombosis (DVT) and pulmonary embolism (PE). Oral heparin delivery can tremendously improve the treatment of such disorders but is restricted due to its large size and anionic character. The present investigation describes synthesis of LMWH-lipid conjugates and their encapsulation in phosphatidylcholine stabilized biomimetic solid lipid nanoparticles (SLNs) for LMWH's oral bioavailability enhancement. Briefly, LMWH was conjugated with different saturated lipids of varying chain length (stearic acid, palmitic acid and myristic acid) using carbodiimide chemistry. The conjugation was confirmed with IR and (1)H NMR spectroscopy. The LMWH-lipid conjugate loaded SLNs were characterized for various parameters like shape, size, zeta potential, entrapment efficiency and in vitro release behavior in different simulated GIT pH mediums. The GIT toxicity of LMWH-lipid conjugate loaded SLNs to different tissues of intestinal epithelium was observed using H&E staining followed by microscopic observation at cellular level. The LMWH-lipid conjugate loaded SLNs were found to be safe for oral administration. The plasma concentration of LMWH was estimated using anti-FXa chromogenic assay. A significantly higher bioavailability (p < 0.05) of LMWH was observed using LMWH lipid conjugates loaded SLNs in comparison to LMWH loaded SLNs and free LMWH. The order of different conjugates in bioavailability enhancement was LMWH-stearic acid > LMWH-palmitic acid > LMWH-myristic acid. This strategy holds promise for future applications of oral delivery of LMWH conjugates in the form of SLNs particularly for the treatment of cardiovascular disease like DVT and PE. PMID- 21598997 TI - Enantioselective synthesis of diverse sulfinamides and sulfinylferrocenes from phenylglycine-derived chiral sulfinyl transfer agent. AB - A new chiral sulfinyl transfer auxiliary derived from readily available phenylglycine was developed. This auxiliary is utilized to synthesize a diverse array of alkyl- and arylsulfinamides and sulfinylferrocenes in high yields and excellent ee's. The desired products are produced in a one-pot sequence from the oxathiazolidine 2-oxide by two sequential nucleophilic additions that proceed in a stereospecific manner. PMID- 21598998 TI - Catalytic asymmetric Friedel-Crafts/protonation of nitroalkenes and N heteroaromatics. AB - The catalytic asymmetric Friedel-Crafts/protonation of indoles and pyrroles with alpha-substituted nitroalkenes to give the corresponding adducts in a highly anti selective manner was achieved by an imidazoline-aminophenol (L2)-Cu complex. The anti-adducts could be successfully transformed to biochemically important alpha substituted beta-heteroarylalkylamines. PMID- 21598999 TI - Improving in vivo hepatic transfection activity by controlling intracellular trafficking: the function of GALA and maltotriose. AB - The successful control of intracellular trafficking (i.e., endosomal escape and nuclear delivery) is prerequisite for the development of a gene delivery system. In the present study, we developed an in vivo hepatic gene delivery system using a plasmid DNA (pDNA)-encapsulating lipid envelope-type nanoparticle, to which we refer as a multifunctional envelope-type nanodevice (MEND). The critical structural elements of the MEND are a DNA/protamine condensed core coated with lipid bilayers including serum-resistant cationic lipids. Intravenous administration of bare MEND represents minimal transfection activity. For the surface modification of functional devices, hydrophobic moieties were chemically attached, which are shed in the spontaneous orientation outward from the MEND surface by anchoring to the lipid bilayers. Modification of the pH-dependent fusogenic peptide GALA as an endosome escape induced transfection activity by 1 and 2 orders of magnitude. In an attempt to induce the nuclear delivery of pDNA, maltotriose, a recently characterized nuclear localization signal, was additionally modified. As a result, transfection activity further enhanced by 1 order of magnitude, and it reached to the higher level obtained for a conventional lipoplex and an in vivo jetPEI-Gal, with less hepatic toxicity. The data show that the combination of GALA and maltotriose results in a highly potent functional device that shows an enhanced endosomal escape and nuclear delivery in vivo. PMID- 21599000 TI - Discovery of 4-anilinofuro[2,3-b]quinoline derivatives as selective and orally active compounds against non-small-cell lung cancers. AB - We have reported the preparation and anticancer evaluation of certain 4 anilinofuro[2,3-b]quinolines. However, drawbacks such as lack of selective cytotoxicity, poor oral bioavailability, and poor water solubility exhibited by these compounds prompted us to search for newer derivatives. Among them, (E)-1-(4 (furo[2,3-b]quinolin-4-ylamino)phenyl)ethanone O-2-aminoethyloxime (13a) is selectively active against the growth of NCI-H460 and is highly water-soluble (63 MUg/mL). Its hydrochloride salt, 13a.HCl exhibited not only excellent water solubility (1049 MUg/mL) but also a high oral bioavailability (57.1%). Compound 13a may cause cancer cell apoptosis through inducing mitotic arrest and mitotic catastrophe mechanism. Xenographic studies indicated the tumor size with 13a.HCl treated nude mice was significantly lower than control. Further evaluation in an orthotopic lung cancer model indicated that 13a.HCl can be absorbed readily through oral administration, distributed to lung tissue, and exhibited significant efficacy in inhibiting the growth of lung cancers. PMID- 21599001 TI - Novel flavonoids with antiproliferative activities against breast cancer cells. AB - A series of flavone analogues were synthesized and evaluated for their antiproliferation activity against breast cancer cells. The IC(50) of compound 10 and 24 were determined to be at 5 MUM. These compounds were used as baits to screen breast cancer cDNA expression phage display proteome library. DNA sequencing of the binding phages suggests that eEF1A1 is a target protein for 10 and 24. Further optimization of these compounds led to the discovery of 39 with higher cytotoxic potency (IC(50) = 1 MUM) and binding to eEF1A2. Biological and biochemical data suggest that eEF1A2 might be a therapeutic target and that 39 is an excellent lead compound for further development. PMID- 21599002 TI - Structure-activity relationships of carboline and carbazole derivatives as a novel class of ATP-competitive kinesin spindle protein inhibitors. AB - The kinesin spindle protein (KSP) is a mitotic kinesin involved in the establishment of a functional bipolar mitotic spindle during cell division. It is considered to be an attractive target for cancer chemotherapy with reduced side effects. Based on natural product scaffold-derived fused indole-based inhibitors and known biphenyl-type KSP inhibitors, various carboline and carbazole derivatives were synthesized and biologically evaluated. beta-Carboline and lactam-fused carbazole derivatives exhibited remarkably potent KSP inhibitory activity and mitotic arrest in prometaphase with formation of an irregular monopolar spindle. The planar tri- and tetracyclic analogs inhibited KSP ATPase in an ATP-competitive manner just like biphenyl-type inhibitors. PMID- 21599003 TI - Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. AB - Drug-drug interactions (DDIs) are major causes of serious adverse drug reactions. Most DDIs have a pharmacokinetic basis in which one drug reduces the elimination of a second drug, leading to potentially toxic drug levels. As a major organ of drug elimination, the kidney represents an important site for DDIs. Here, we screened a prescription drug library against the renal organic cation transporter OCT2/SLC22A2, which mediates the first step in the renal secretion of many cationic drugs. Of the 910 compounds screened, 244 inhibited OCT2. Computational analyses revealed key properties of inhibitors versus noninhibitors, which included overall molecular charge. Four of six potential clinical inhibitors were transporter-selective in follow-up screens against additional transporters: OCT1/SLC22A1, MATE1/SLC47A1, and MATE2-K/SLC47A2. Two compounds showed different kinetics of interaction with the common polymorphism OCT2-A270S, suggesting a role of genetics in modulating renal DDIs. PMID- 21599004 TI - Transition-state analysis of Trypanosoma cruzi uridine phosphorylase-catalyzed arsenolysis of uridine. AB - Uridine phosphorylase catalyzes the reversible phosphorolysis of uridine and 2' deoxyuridine to generate uracil and (2-deoxy)ribose 1-phosphate, an important step in the pyrimidine salvage pathway. The coding sequence annotated as a putative nucleoside phosphorylase in the Trypanosoma cruzi genome was overexpressed in Escherichia coli , purified to homogeneity, and shown to be a homodimeric uridine phosphorylase, with similar specificity for uridine and 2' deoxyuridine and undetectable activity toward thymidine and purine nucleosides. Competitive kinetic isotope effects (KIEs) were measured and corrected for a forward commitment factor using arsenate as the nucleophile. The intrinsic KIEs are: 1'-(14)C = 1.103, 1,3-(15)N(2) = 1.034, 3-(15)N = 1.004, 1-(15)N = 1.030, 1' (3)H = 1.132, 2'-(2)H = 1.086, and 5'-(3)H(2) = 1.041 for this reaction. Density functional theory was employed to quantitatively interpret the KIEs in terms of transition-state structure and geometry. Matching of experimental KIEs to proposed transition-state structures suggests an almost synchronous, S(N)2-like transition-state model, in which the ribosyl moiety possesses significant bond order to both nucleophile and leaving groups. Natural bond orbital analysis allowed a comparison of the charge distribution pattern between the ground-state and the transition-state models. PMID- 21599005 TI - Design and synthesis of highly reactive dienophiles for the tetrazine-trans cyclooctene ligation. AB - Computation was used to design a trans-cyclooctene derivative that displays enhanced reactivity in the tetrazine-trans-cycloctene ligation. The optimized derivative is an (E)-bicyclo[6.1.0]non-4-ene with a cis-ring fusion, in which the eight-membered ring is forced to adopt a highly strained 'half-chair' conformation. Toward 3,6-dipyridyl-s-tetrazine in MeOH at 25 degrees C, the strained derivative is 19 and 27 times more reactive than the parent trans cyclooctene and 4E-cyclooct-4-enol, respectively. Toward 3,6-diphenyl-s-tetrazine in MeOH at 25 degrees C, the strained derivative is 160 times more reactive than the parent trans-cyclooctene. PMID- 21599006 TI - Pressure-induced cooperative spin transition in ironII 2D coordination polymers: room-temperature visible spectroscopic study. AB - For the 2D coordination polymers [Fe(3-Fpy)(2)M(II)(CN)(4)] (M(II) = Ni, Pd, Pt), the pressure-induced spin crossover behavior has been investigated at 298 K by monitoring the distinct optical properties associated with each spin state. Cooperative first-order spin transition characterized by a piezohysteresis loop ca. 0.1 GPa wide was observed for the three derivatives. Application of the mean field regular solution theory has enabled estimation of the cooperative parameter, Gamma(p), and the enthalpy, DeltaH(HL)(p), associated with the spin transition for each derivative. These values, found in the intervals 6.8-7.9 and 18.6-20.8 kJ mol(-1), respectively, are consistent with those previously reported for thermally induced spin transition at constant pressure for the title compounds (Chem.-Eur. J.2009, 15, 10960). Relevance of the elastic energy, Delta(elast), as a corrective parameter accounting for the pressure dependence of the critical temperature of thermally induced spin transitions (Clausius Clapeiron equation) is also demonstrated and discussed. PMID- 21599007 TI - A short desymmetrization protocol for the coordination environment in bis-salphen scaffolds. AB - A remarkable short preparation of desymmetrized bis-salphen scaffolds is presented. The protocol consists of an hydroxide-mediated hydrolysis of Lewis acidic bis-Zn(salphen) complexes yielding C(s)-symmetric diimine/amine salts that can be selectively transformed into bis-salphens with dissymmetric substitution patterns within each salphen unit under mild conditions. These isolated nonsymmetrical bis-salphen derivatives do not show signs of imine scrambling or decomposition due to a metal template effect. A possible rationale is provided for the formation and isolation of one of the intermediate bis-phenolate salts, and the hypothesis involves H-bond directed hydrolysis of the nearest located imine bond across the bis-salphen scaffold. PMID- 21599009 TI - Local nature of substituent effects in stacking interactions. AB - Popular explanations of substituent effects in pi-stacking interactions hinge upon substituent-induced changes in the aryl pi-system. This entrenched view has been used to explain substituent effects in countless stacking interactions over the past 2 decades. However, for a broad range of stacked dimers, it is shown that substituent effects are better described as arising from local, direct interactions of the substituent with the proximal vertex of the other ring. Consequently, substituent effects in stacking interactions are additive, regardless of whether the substituents are on the same or opposite rings. Substituent effects are also insensitive to the introduction of heteroatoms on distant parts of either stacked ring. This local, direct interaction viewpoint provides clear, unambiguous explanations of substituent effects for myriad stacking interactions that are in accord with robust computational data, including DFT-D and new benchmark CCSD(T) results. Many of these computational results cannot be readily explained using traditional pi-polarization-based models. Analyses of stacking interactions based solely on the sign of the electrostatic potential above the face of an aromatic ring or the molecular quadrupole moment face a similar fate. The local, direct interaction model provides a simple means of analyzing substituent effects in complex aromatic systems and also offers simple explanations of the crystal packing of fluorinated benzenes and the recently published dependence of the stability of protein-RNA complexes on the regiochemistry of fluorinated base analogues [J. Am. Chem. Soc.2011, 133, 3687-3689]. PMID- 21599008 TI - Comparison of active and passive targeting of docetaxel for prostate cancer therapy by HPMA copolymer-RGDfK conjugates. AB - N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-docetaxel-RGDfK conjugate was synthesized, characterized, and evaluated in vitro and in vivo in comparison with untargeted low and high molecular weight HPMA copolymer-docetaxel conjugates. The targeted conjugate was designed to have a hydrodynamic diameter below renal threshold to allow elimination post treatment. All conjugates demonstrated the ability to inhibit the growth of DU145 and PC3 human prostate cancer cells and the HUVEC at low nanomolar concentrations. The targeted conjugate showed active binding to alpha(v)beta(3) integrins in both HUVEC and DU145 cells, whereas the untargeted conjugate demonstrated no evidence of specific binding. Efficacy at two concentrations (20 mg/kg and 40 mg/kg) was evaluated in nu/nu mice bearing DU145 tumor xenografts treated with a single dose of conjugates and compared with controls. RGDfK targeted and high molecular weight nontargeted conjugates exhibited the highest antitumor efficacy as evaluated by tumor regression. These results demonstrate that alpha(v)beta(3) integrin targeted polymeric conjugates with improved water solubility, reduced toxicity and ease of elimination post treatment in vivo are promising candidates for prostate cancer therapy. PMID- 21599010 TI - IsoformResolver: A peptide-centric algorithm for protein inference. AB - When analyzing proteins in complex samples using tandem mass spectrometry of peptides generated by proteolysis, the inference of proteins can be ambiguous, even with well-validated peptides. Unresolved questions include whether to show all possible proteins vs a minimal list, what to do when proteins are inferred ambiguously, and how to quantify peptides that bridge multiple proteins, each with distinguishing evidence. Here we describe IsoformResolver, a peptide-centric protein inference algorithm that clusters proteins in two ways, one based on peptides experimentally identified from MS/MS spectra, and the other based on peptides derived from an in silico digest of the protein database. MS/MS-derived protein groups report minimal list proteins in the context of all possible proteins, without redundantly listing peptides. In silico-derived protein groups pull together functionally related proteins, providing stable identifiers. The peptide-centric grouping strategy used by IsoformResolver allows proteins to be displayed together when they share peptides in common, providing a comprehensive yet concise way to organize protein profiles. It also summarizes information on spectral counts and is especially useful for comparing results from multiple LC MS/MS experiments. Finally, we examine the relatedness of proteins within IsoformResolver groups and compare its performance to other protein inference software. PMID- 21599011 TI - Viral quantitative capillary electrophoresis for counting intact viruses. AB - The quantification of a virus plays an important role in vaccine development, clinical diagnostics, and environmental contamination assays. In all these cases, it is essential to calculate the concentration or number of intact virus particles (ivp) and estimate the degree of degradation and contamination of virus samples. In this work, we propose a cost-efficient, robust method for the quantification and characterization of intact viruses based on capillary zone electrophoresis. This separation method is demonstrated on vaccinia virus (VV) with oncolytic properties. After virus sample preparation, the solution contains intact VV as well as broken viruses and residual DNA from the host cell used for preparation. Regulatory requirements limit the amount of the host cell DNA that can be present in vaccines or human therapeutics. We apply capillary electrophoresis to separate intact virus particles and the residual DNA and to measure the level of virus contamination with DNA impurities. Intercalating YOYO 1 dye is used to detect the encapsulated and free DNA by laser-induced fluorescence. After soft lysis of VV with proteinase K, all encapsulated DNA is dissolved to the free DNA. The change in peak areas and a DNA calibration curve help determine the initial concentration of intact viruses. This viral quantitative capillary electrophoresis (Viral qCE) is able to quantify the oncolytic vaccinia virus in the range of 10(6) to 10(12) ivp/mL. PMID- 21599012 TI - Catechol-functionalized chitosan/pluronic hydrogels for tissue adhesives and hemostatic materials. AB - Bioinspired from adhesion behaviors of mussels, injectable and thermosensitive chitosan/Pluronic composite hydrogels were synthesized for tissue adhesives and hemostatic materials. Chitosan conjugated with multiple catechol groups in the backbone was cross-linked with terminally thiolated Pluronic F-127 triblock copolymer to produce temperature-sensitive and adhesive sol-gel transition hydrogels. A blend mixture of the catechol-conjugated chitosan and the thiolated Pluronic F-127 was a viscous solution state at room temperature but became a cross-linked gel state with instantaneous solidification at the body temperature and physiological pH. The adhesive chitosan/Pluronic injectable hydrogels with remnant catechol groups showed strong adhesiveness to soft tissues and mucous layers and also demonstrated superior hemostatic properties. These chitosan/Pluronic hydrogels are expected to be usefully exploited for injectable drug delivery depots, tissue engineering hydrogels, tissue adhesives, and antibleeding materials. PMID- 21599013 TI - Carbon electrode fabrication from pyrolyzed parylene C. AB - Carbon electrodes coupled with electrochemical detection have been used extensively for the investigation of biogenic amines. Herein we report the fabrication and characterization of carbonaceous electrodes prepared from pyrolyzed parylene C (PPC) films. High-aspect ratio carbonaceous microelectrodes have been prepared by masking PPC coated pipets with an insulating parylene C film. PPC thin film electrodes were characterized electrochemically, spectroscopically, and with electron microscopy. The procedures described here offer a route to fabrication of thin film carbon electrodes that can be patterned and produced in parallel. These electrodes are similar to carbon electrodes derived from pyrolyzed photoresist films but do not require spin-coating or lithography and can readily coat three-dimensional surfaces. PMID- 21599014 TI - Chemical-stimuli-controllable circularly polarized luminescence from anion responsive pi-conjugated molecules. AB - Introduction of a BINOL-boron moiety to dipyrrolyldiketones as precursors of anion-responsive pi-conjugated molecules results in the formation of a chiral environment in the form of anion-free receptors and anion-binding complexes. Conformation changes by inversion (flipping) of two pyrrole rings as a result of anion binding can control the chiroptical properties of the anion receptors. In particular, appropriate pyrrole beta-substituents induce distorted receptor pi planes and, as a result, give larger circularly polarized luminescence (CPL), which can be tuned by chemical stimuli (anions). This is the first example of chemical-stimuli-responsive CPL properties. PMID- 21599015 TI - Highly selective ligand binding by Methylophilus methylotrophus cytochrome c''. AB - Cytochrome c'' (cyt c'') from Methylophilus methylotrophus is unusual insofar as the heme has two axial histidine ligands in the oxidized form but one is detached when the protein is reduced. Despite cyt c'' having an axial site available for binding small ligands, we show here that only NO binds readily to the ferrous cyt c''. Binding of CO, as well as CN(-), on the other hand requires considerable structural reorganization, or reduction of the disulfide bridge close to the heme. Standard free energies for the binding of NO and CO reveal high selectivity of the ferrous cyt c'' for NO, indicating its putative physiological role. In this work, we characterize in detail the kinetics of NO binding and the structural features of the Fe(2+)-NO adduct by stopped-flow and resonance Raman spectroscopy, respectively. PMID- 21599016 TI - Asymptotic exchange energy of heteronuclear dimers. AB - A simple expression for the asymptotic exchange energy of heteronuclear dimers is derived from the surface integral method. A five-dimensional hypersurface, consisting of all spherical surfaces centered at the nucleus of the atom with higher ionization energy, more appropriate for the case where the two atoms have different ionization energies, is used in the surface integral. All integrals are carried out analytically. Compared with the exchange energy of Smirnov and Chibisov, which is also obtained from the surface integral method with a hypersurface consisting of all infinite planes perpendicular to the internuclear axis, the present result is much simpler. The exchange energies of alkali hydrides are computed as an illustration. It is shown that the present method and the method of Smirnov and Chibisov are complementary to each other. PMID- 21599017 TI - Effect of jasmonates on ethylene biosynthesis and aroma volatile emission in Japanese apricot infected by a pathogen (Colletotrichum gloeosporioides). AB - The effects of the application of the jasmonic acid derivative n-propyl dihydrojasmonate (PDJ) on ethylene biosynthesis, volatile compounds, and endogenous jasmonic acid (JA) and methyl jasmonate (MeJA) were examined in Japanese apricot (Prunus mume Sieb.) infected by a pathogen (Colletotrichum gloeosporioides). The fruit were dipped into 0.4 mM PDJ solution before inoculation with the pathogen and stored at 25 degrees C for 6 days. The inoculation induced an increase in 1-aminocyclopropane-1-carboxylic acid (ACC), ethylene, JA, and MeJA. In contrast, PDJ application reduced the endogenous JA, MeJA, and ethylene production and expression of the ACC oxidase gene (PmACO1) caused by the pathogen infection. The lesion diameter with C. gloeosporioides decreased upon PDJ application. The alcohol, ester, ketone, and lactone concentrations and alcohol acyltransferase (AAT) activity increased in the pathogen-infected fruit, but were decreased by PDJ application. These results suggest that PDJ application might influence ethylene production through PmACO1 and that aroma volatile emissions affected by pathogen infection can be correlated with the ethylene production, which is mediated by the levels of jasmonates. PMID- 21599018 TI - Discovery of new lactones in sweet cream butter oil. AB - Sweet cream butter oil was analyzed to identify new volatile compounds that may contribute to its flavor, with an emphasis on lactones. The volatile part of butter oil was obtained by using short-path distillation. As some previously unknown lactones were detected in this first extract, it was fractionated further. The fatty acids were removed, and the extract was fractionated by flash chromatography. Three lactonic fractions possessing a creamy, buttery, and fatty character were investigated in depth by gas chromatography (GC) and mass spectrometry (MS) (EI and CI) and high-resolution GC-time-of-flight MS. Many lactones were identified by their mass fragmentation and by comparison with reference materials synthesized during this work. Six gamma-lactones, five delta lactones, and one epsilon-lactone were identified for the first time in butter oil, seven of them for the first time in a natural product. The possible contribution of these new lactones to the aroma of butter oil is briefly discussed. PMID- 21599019 TI - Anthocyanin-rich blackberry extract suppresses the DNA-damaging properties of topoisomerase I and II poisons in colon carcinoma cells. AB - In the present study, we addressed the question whether cyanidin-3-glucoside (C3G) or complex C3G-rich blackberry extracts affect human topoisomerases with special emphasis on the contribution of the potential degradation products phloroglucinol aldehyde (PGA) and protocatechuic acid (PCA). In HT29 colon carcinoma cells a C3G-rich blackberry extract suppressed camptothecin- (CPT-) or doxorubicin- (DOX-) induced stabilization of the covalent DNA-topoisomerase intermediate, thus antagonizing the effects of these classical topoisomerase poisons on DNA integrity. As a single compound, C3G (100 MUM) decreased the DNA damaging effects of CPT as well, but did not significantly affect those induced by DOX. At the highest applied concentration (100 MUM), cyanidin protected DNA from CPT- and DOX-induced damage. Earlier reports on DNA-damaging properties of cyanidin were found to result most likely from the formation of hydrogen peroxide as an artifact in the cell culture medium when the incubation was performed in the absence of catalase. The suppression of hydrogen peroxide accumulation, achieved by the addition of catalase, demonstrated that cyanidin does not exhibit DNA-damaging properties in HT29 cells (up to 100 MUM). The observed effects on topoisomerase interference and DNA protection against CPT or DOX were clearly limited to the parent compound and were not observed for the potential cyanidin degradation products PGA and PCA. PMID- 21599021 TI - Ferromagnetic spin coupling between endohedral metallofullerene La@C82 and a cyclodimeric copper porphyrin upon inclusion. AB - The cyclic host cyclo-[P(Cu)](2) carrying two covalently connected Cu(II) porphyrin units can accommodate La@C(82), a paramagnetic endohedral metallofullerene, in its cavity to form the inclusion complex cyclo [P(Cu)](2)?La@C(82), which can be transformed into the caged complex cage [P(Cu)](2)?La@C(82) by ring-closing olefin metathesis of its side-chain olefinic termini. On the basis of electron spin resonance (ESR) and electron spin transient nutation (ESTN) studies, cyclo-[P(Cu)](2)?La@C(82) is the first ferromagnetically coupled inclusion complex featuring La@C(82), whereas cage [P(Cu)](2)?La@C(82) is ferrimagnetic. PMID- 21599020 TI - Total synthesis and pharmacological characterization of solomonsterol A, a potent marine pregnane-X-receptor agonist endowed with anti-inflammatory activity. AB - Recently, we reported the identification of a novel class of pregnane-X-receptor (PXR) agonists, solomonsterols A and B, isolated from the marine sponge Theonella swinhoei. Preliminary pharmacological studies demonstrated that these natural compounds are potential leads for the treatment of human disorders characterized by dysregulation of innate immunity. In this article, we describe the first total synthesis of solomonsterol A and its in vivo characterization in animal models of colitis. Using transgenic mice expressing the human PXR, we found that administration of synthetic solomonsterol A effectively protects against development of clinical signs and symptoms of colitis and reduced the generation of TNFalpha, a signature cytokine for this disorder. In addition, we have provided the first evidence that solomonsterol A might act by triggering the expression of TGFbeta and IL-10, potent counter-regulatory cytokines in inflammatory bowel diseases (IBD). Finally, we have shown that solomonsterol A inhibits NF-kappaB activation by a PXR dependent mechanism. In summary, solomonsterol A is a marine PXR agonist that holds promise in the treatment of inflammation-driven immune dysfunction in clinical settings. PMID- 21599022 TI - Bivalent dopamine D2 receptor ligands: synthesis and binding properties. AB - Dopamine D(2) receptor homodimers might be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising target proteins for the discovery of atypical antipsychotics. A highly attractive approach to investigate and control GPCR dimerization may be provided by the exploration and characterization of bivalent ligands, which can act as molecular probes simultaneously binding two adjacent binding sites of a dimer. The synthesis of bivalent dopamine D(2) receptor ligands of type 1 is presented, incorporating the privileged structure of 1,4-disubstituted aromatic piperidines/piperazines (1,4 DAPs) and triazolyl-linked spacer elements. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for bivalent ligands with particular spacer lengths and a comparative analysis with respective monovalent control ligands and unsymmetrically substituted analogues indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites. PMID- 21599023 TI - Ultrasensitive immunoassay of protein biomarker based on electrochemiluminescent quenching of quantum dots by hemin bio-bar-coded nanoparticle tags. AB - A hemin bio-bar-coded nanoparticle probe labeled antibody was designed by the assembly of antibody and alkylthiol-capped bar-code G-quadruplex DNA on gold nanoparticles and the interaction of hemin with the DNA to form a G quadruplex/hemin bio-bar-code. An ultrasensitive immunoassay method was developed by combining the labeled antibody with an electrochemiluminescent (ECL) immunosensor for protein. The ECL immunosensor was constructed by a layer-by layer modification of carbon nanotubes, CdS quantum dots (QDs), and capture antibody on a glassy carbon electrode. In air-saturated pH 8.0 PBS the immunosensor showed a carbon-nanotube-enhanced cathodic ECL emission of QDs. Upon the formation of immunocomplex, the ECL intensity decreased owing to the consumption of ECL coreactant in bio-bar-code electrocatalyzed reduction of dissolved oxygen. Using alpha-fetoprotein as model analyte, the quenched ECL could be used for immunoassay with a linear range of 0.01 pg mL(-1) to 1 ng mL( 1) and a detection limit of 1.0 fg mL(-1). The wide detection range and high sensitivity resulted from the enhanced ECL emission and highly efficient catalysis of the bio-bar-code. The immunosensor exhibited good stability and acceptable fabrication reproducibility and accuracy, showing great promise for clinical application. PMID- 21599024 TI - Thiol-quinone adduct formation in myofibrillar proteins detected by LC-MS. AB - Protein oxidation in meat is considered to decrease meat tenderness due to protein disulfide cross-link formation of thiol-containing amino acid residues. An LC-MS method for detection of thiol-quinone adducts (RS-QH(2)) in myofibrillar proteins was developed to investigate the interaction between phenols, as protective antioxidants, and proteins from meat under oxidative conditions using aqueous solutions of (i) cysteine (Cys), (ii) glutathione (GSH), (iii) bovine serum albumin (BSA), or (iv) a myofibrillar protein isolate (MPI). The aqueous solutions were incubated at room temperature (30 min) with 4-methyl-1,2 benzoquinone (4MBQ) prepared from oxidation of 4-methylcatechol (4MC) by periodate resin or incubated at room temperature (5 h) with 4MC and Fe(II)/H(2)O(2). GSH, BSA, and MPI were hydrolyzed (6 N HCl, 110 degrees C, 22 h) after incubation, and the cysteine-quinone adduct, Cys-QH(2) (m/z 244.2) was identified according to UV and mass spectra after separation on an RP-C18 column. The thiol-quinone adduct was present in all thiol systems after incubation with 4MBQ or 4MC oxidized by Fe(II)/H(2)O(2). Direct reaction with 4MBQ resulted in each case in increased Cys-QH(2) formation compared to simultaneous oxidation of thiol source and 4MC with Fe(II)/H(2)O(2). The covalent bonds between quinones and thiol groups may act as a potential antioxidant by inhibiting disulfide protein cross-link formation. PMID- 21599025 TI - Fabrication of isoreticular metal-organic framework coated capillary columns for high-resolution gas chromatographic separation of persistent organic pollutants. AB - The unusual properties of metal-organic frameworks (MOFs), such as permanent nanoscale porosity, high surface area, uniformly structured cavities, and the availability of in-pore functionality and outer-surface modification, are advantageous for diverse applications. However, most existing methods for the synthesis of nanosized MOFs require an activation procedure or auxiliary stabilizing agents. Here we report a 1-min, room-temperature approach for the synthesis of nanosized isoreticular MOFs (IRMOFs) to fabricate IRMOF coated capillary columns for the high-resolution gas chromatographic separation of persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), polyaromatic hydrocarbons (PAHs), polybrominated diphenylethers (PBDEs), and hexachlorocyclohexanes (HCHs). The developed method allows the synthesis of well shaped nanosized IRMOFs within 1 min at room temperature without the need for any activation procedure or auxiliary stabilizing agents. The IRMOF coated capillary columns offer good separation efficiency that is generally comparable to that of a commercial HP-5MS column for POPs. The IRMOF-1 and IRMOF-3 coated capillary columns gave the theoretical plate values of 2293 and 2063 plates m(-1) for naphthalene, respectively, which are slightly smaller than those with a HP-5MS column (2845 plates m(-1)). The IRMOF-1 coated capillary column offered good resolution for the separation of several intractable PAH isomer pairs, such as anthracene/phenanthrene, benzo[a]anthracene/chrysene, and benzo[b]fluoranthene/benzo[k]fluoranthene, with resolutions of 3.0, 1.1, and 4.1, respectively, which were difficult to be baseline separated on a HP-5MS column with a resolution of 1.0. In addition, the IRMOF-1 and IRMOF-3 coated capillary columns offered a clear group separation of the PCB isomers and a linear range covering three orders of magnitude. The relative standard deviations for the five replicate separations of PAHs were 0.23-0.26% and 2.1-4.5% for retention time and peak area, respectively. The fabricated IRMOF coated capillary columns have been shown to be very promising for the separation of POPs with good reproducibility, high resolution, great selectivity, and a wide linear range. PMID- 21599027 TI - Dissociation of vibrational state-selected O2(+) Ions in the B(2)Sigma(g)- state using threshold photoelectron-photoion coincidence velocity imaging. AB - Using the recently developed threshold photoelectron-photoion coincidence (TPEPICO) velocity imaging mass spectrometer (Tang et al. Rev. Sci. Instrum.2009, 80, 113101), dissociation of vibrational state-selected O(2)(+)(B(2)Sigma(g)(-), v(+) = 0-6) ions was investigated. Both the speed and angular distributions of the O(+) fragments dissociated from individually vibronic levels of the B(2)Sigma(g)(-) state were obtained directly from the three-dimensional time sliced TPEPICO velocity images. Two dissociation channels, O(+)((4)S) + O((3)P) and O(+)((4)S) + O((1)D), were respectively observed, and their branching ratios were found to be heavily dependent on the vibrational states. A new intersection mechanism was suggested for the predissociation of O(2)(+)(B(2)Sigma(g)(-)) ions, especially for dissociation at the energy of the v(+) = 4 level. In addition, the anisotropic parameters for O(+) fragments from different dissociative pathways were determined to be close to zero, indicating that the v(+) = 0-6 levels of B(2)Sigma(g)(-) predissociate on a time scale that is much slower than that of molecular rotation. PMID- 21599028 TI - Identification of N-glycans displaying mannose-6-phosphate and their site of attachment on therapeutic enzymes for lysosomal storage disorder treatment. AB - Characterization of mono- and bis-mannose-6-phosphate (M6P) bearing oligosaccharides present on acid hydrolase enzymes poses a considerable analytical challenge. In the current paper, we investigated the use of UPLC profiling on a 1.7 MUm HILIC phase and capillary electrophoresis with laser induced fluorescence detection (CE-LIF) combined with exoglycosidase digestion and weak anion exchange fractionation for the characterization of M6P bearing glycans on recombinant beta-glucuronidase expressed in Chinese Hamster Ovary (CHO) cells. Using this multidimensional approach a number of peaks were observed to resist digestion, suggesting the presence and blocking activity of the M6P tag. To investigate further, mixed oxide affinity purification on a combined TiO(2)/ZrO(2) resin facilitated the selective enrichment of oligosaccharides bearing mono- or diphospho-esters that corresponded to those peaks previously identified to resist exoglycosidase digestion. Alkaline phosphatase digestion identified Man(6)GlcNAc(2) and Man(7)GlcNAc(2) glycans as the primary carriers of the M6P tag. Site-specific glycoproteomic analysis revealed that Man(7)GlcNAc(2) M6P oligosaccharides were present at asparagine 272 and 420, while asparagine 631 displayed Man(6)GlcNAc(2)-M6P. The analytical strategy applied herein represents a novel yet simple approach for the qualitative and semiquantitative structural characterization of M6P containing oligosaccharides on therapeutic enzymes. PMID- 21599029 TI - Dielectric barrier discharge molecular emission spectrometer as multichannel GC detector for halohydrocarbons. AB - A novel microplasma molecular emission spectrometer based on an atmospheric pressure dielectric barrier discharge (DBD) is described and further used as a promising multichannel GC detector for halohydrocarbons. The plasma is generated in a DBD device consisting of an outer electrode (1.2 mm in diameter) and an inner electrode (1.7 mm in diameter) within a small quartz tube (3.0 mm i.d. * 5.0 mm o.d. * 50 mm), wherein analyte molecules are excited by the microplasma to generate molecular emission. Therefore, the analytes are selectively and simultaneously detected with a portable charge-coupled device (CCD) via multichannel detection of their specific emission lines. The performance of this method was evaluated by separation and detection of a model mixture of chlorinated hydrocarbons (CHCl(3) and CCl(4)), brominated hydrocarbons (CH(2)Br(2) and CH(2)BrCH(2)Br), and iodinated hydrocarbons (CH(3)I and (CH(3))(2)CHI) undergoing GC with the new detector. The completely resolved identification of the tested compounds was achieved by taking advantages of both chromatographic and spectral resolution. Under the optimized conditions with the CCD spectrometer set at 258, 292, and 342 nm channels for determination of chlorinated hydrocarbons, brominated hydrocarbons, and iodinated hydrocarbons, respectively, this detector with direct injection provided detection limits of 0.07, 0.06, 0.3, 0.04, 0.05, and 0.02 MUg mL(-1) for CCl(4), CHCl(3), CH(2)Cl(2), CH(3)I, CH(3)CH(2)I, and (CH(3))(2)CHI, respectively. PMID- 21599031 TI - Contribution of disulfide S2(2-) anions to the crystal and electronic structures in ternary sulfides, Ba12In4S19, Ba4M2S8 (M=Ga, In). AB - Three semiconducting ternary sulfides have been synthesized from the mixture of elements with about 20% excess of sulfur (to establish oxidant rich conditions) by solid-state reactions at high temperature. Ba(12)In(4)S(19) = (Ba(2+))(12)(In(3+))(4)(S(2-))(17)(S(2))(2-), 1, crystallizes in the trigonal space group R 3 with a = 9.6182(5) A, b = 9.6182(5) A, c = 75.393(7) A, and Z = 6, with a unique long period-stacking structure of a combination of monometallic InS(4) tetrahedra, linear dimeric In(2)S(7) tetrahedra, disulfide S(2)(2-) anions, and isolated sulfide S(2-) anions that is further enveloped by Ba(2+) cations. Ba(4)In(2)S(8) = (Ba(2+))(4)(In(3+))(2)(S(2-))(6)(S(2))(2-), 2, crystallizes in the triclinic space group P 1 with a = 6.236(2) A, b = 10.014(4) A, c = 13.033(5) A, alpha = 104.236(6) degrees , beta = 90.412(4) degrees , gamma = 91.052(6) degrees , and Z = 2. Ba(4)Ga(2)S(8) = (Ba(2+))(4)(Ga(3+))(2)(S(2 ))(6)(S(2))(2-), 3, crystallizes in the monoclinic P2(1)/c with a = 12.739(5) A, b = 6.201(2) A, c = 19.830(8) A, beta = 104.254(6) degrees and Z = 4. Compounds 2 and 3 represent the first one-dimensional (1D) chain structure in ternary Ba/M/S (M = In, Ga) systems. The optical band gaps of 1 and 3 are measured to be around 2.55 eV, which agrees with their yellow color and the calculation results. The CASTEP calculations also reveal that the disulfide S(2)(2-) anions in 1-3 contribute mainly to the bottom of the conduction bands and the top of valence bands, and thus determine the band gaps. PMID- 21599030 TI - Synthesis of NanoQ, a copper-based contrast agent for high-resolution magnetic resonance imaging characterization of human thrombus. AB - A new site-targeted molecular imaging contrast agent based on a nanocolloidal suspension of lipid-encapsulated, organically soluble divalent copper has been developed. Concentrating a high payload of divalent copper ions per nanoparticle, this agent provides a high per-particle r1 relaxivity, allowing sensitive detection in T1-weighted magnetic resonance imaging when targeted to fibrin clots in vitro. The particle also exhibits a defined clearance and safety profile in vivo. PMID- 21599032 TI - C-H bond arylations and benzylations on oxazol(in)es with a palladium catalyst of a secondary phosphine oxide. AB - An air-stable, well-defined palladium complex derived from secondary phosphine oxide (SPO) (1-Ad)(2)P(O)H enabled efficient C-H bond functionalizations with ample scope, which set the stage for direct arylations and benzylations of (benz)oxazoles, as well as unprecedented palladium-catalyzed C-H bond arylations on nonaromatic oxazolines. PMID- 21599033 TI - Gold-catalyzed approach to multisubstituted fulvenes via cycloisomerization of furan/ynes. AB - A new approach to functionalized fulvenes with an enone or enal moiety has been developed through gold-catalyzed intramolecular cycloisomerization of furan/ynes with a two-carbon tether in between the furan and the triple bond. The reaction proceeds with complete regioselectivity via a 6-endo-cyclization and high stereoselectivity. Moreover, the E- or Z-stereochemistry of the double bond in fulvene products can be easily controlled by performing the reaction in different solvents. PMID- 21599034 TI - Spray-dried zein capsules with coencapsulated nisin and thymol as antimicrobial delivery system for enhanced antilisterial properties. AB - Food grade antimicrobial delivery systems were studied in this work to enhance the effectiveness of antimicrobials inhibiting the growth of Listeria monocytogenes during storage. Corn zein was used as a carrier biopolymer and nisin and thymol as antimicrobials. Capsules produced by spray drying demonstrated different microstructures and release characteristics of nisin at different usage levels of thymol. Better release profiles were achieved when glycerol was additionally used to prepare capsules. Capsules showing sustained release of significant amounts of both antimicrobials effectively inhibited the growth of L. monocytogenes at pH 6.0 and 30 degrees C in the growth medium. Capsules were also more effective than free antimicrobials in inhibiting the growth of L. monocytogenes in 2% reduced fat milk at 25 degrees C. Our work showed that engineered delivery systems have promise to fulfill the antimicrobial effectiveness during shelf life storage of foods to ensure microbiological safety. PMID- 21599035 TI - Using QALYs in cancer: a review of the methodological limitations. AB - The objective of this paper is to examine how well the QALY captures the health gains generated by cancer treatments, with particular focus on the methods for constructing QALYs preferred by the UK National Institute for Health and Clinical Excellence (NICE). Data were obtained using a keyword search of the MEDLINE database and a hand search of articles written by leading researchers in the subject area (with follow up of the references in these articles). Key arguments were discussed and developed at an oncology workshop in September 2009 at the Office of Health Economics. Three key issues emerged. First, the EQ-5D, NICE's preferred measure of health-related quality of life (QOL) in adults, has been found to be relatively insensitive to changes in health status of cancer patients. Second, the time trade-off, NICE's preferred technique for estimating the values of health states, involves making assumptions that are likely to be violated in end-of-life scenarios. Third, the practice of using valuations of members of the general population, as recommended by NICE, is problematic because such individuals typically display a misunderstanding of what it is really like for patients to live with cancer. Because of the way in which it is constructed, the QALY shows important limitations in terms of its ability to accurately capture the value of the health gains deemed important by cancer patients. A research agenda for addressing these limitations is proposed. PMID- 21599036 TI - Communication: exploring the reorientation of benzene in an ionic liquid via molecular dynamics: effect of temperature and solvent effective charge on the slow dynamics. AB - The rotational time correlation function (RTCF) of solute benzene molecules in the ionic liquid (1-butyl-3-methylimidazolium chloride) has been studied using classical molecular dynamics simulation. The effect of solvent charge on the functional form of RTCF was investigated by comparing four force fields for the solvent where the total charge on the anion and the cation was set to +/-1e, +/ 0.7e, +/-0.5e, and 0, respectively. For all three charged solvent models, the RTCF exhibits a long-time tail where the relaxation rate exhibits a significant slowdown. This feature is strengthened by higher solvent charges as well as lower temperatures, indicating the influence of the strong Coulombic fields arising from the solvent charges. The long-time tail is caused by the extraordinarily slow solvent structural relaxation of ionic liquids compared to the time scale of their local vibrational and librational dynamics. PMID- 21599037 TI - Communication: probing the entrance channels of the X+CH4->HX+CH3 (X = F, Cl, Br, I) reactions via photodetachment of X(-)-CH4. AB - The entrance channel potentials of the prototypical polyatomic reaction family X + CH(4) -> HX + CH(3) (X = F, Cl, Br, I) are investigated using anion photoelectron spectroscopy and high-level ab initio electronic structure computations. The pre-reactive van der Waals (vdW) wells of these reactions are probed for X = Cl, Br, I by photodetachment spectra of the corresponding X(-) CH(4) anion complex. For F-CH(4), a spin-orbit splitting (~1310 cm(-1)) much larger than that of the F atom (404 cm(-1)) was observed, in good agreement with theory. This showed that in the case of the F-CH(4) system the vertical transition from the anion ground state to the neutral potentials accesses a region between the vdW valley and transition state of the early-barrier F + CH(4) reaction. The doublet splittings observed in the other halogen complexes are close to the isolated atomic spin-orbit splittings, also in agreement with theory. PMID- 21599038 TI - Poisson-Boltzmann-Nernst-Planck model. AB - The Poisson-Nernst-Planck (PNP) model is based on a mean-field approximation of ion interactions and continuum descriptions of concentration and electrostatic potential. It provides qualitative explanation and increasingly quantitative predictions of experimental measurements for the ion transport problems in many areas such as semiconductor devices, nanofluidic systems, and biological systems, despite many limitations. While the PNP model gives a good prediction of the ion transport phenomenon for chemical, physical, and biological systems, the number of equations to be solved and the number of diffusion coefficient profiles to be determined for the calculation directly depend on the number of ion species in the system, since each ion species corresponds to one Nernst-Planck equation and one position-dependent diffusion coefficient profile. In a complex system with multiple ion species, the PNP can be computationally expensive and parameter demanding, as experimental measurements of diffusion coefficient profiles are generally quite limited for most confined regions such as ion channels, nanostructures and nanopores. We propose an alternative model to reduce number of Nernst-Planck equations to be solved in complex chemical and biological systems with multiple ion species by substituting Nernst-Planck equations with Boltzmann distributions of ion concentrations. As such, we solve the coupled Poisson Boltzmann and Nernst-Planck (PBNP) equations, instead of the PNP equations. The proposed PBNP equations are derived from a total energy functional by using the variational principle. We design a number of computational techniques, including the Dirichlet to Neumann mapping, the matched interface and boundary, and relaxation based iterative procedure, to ensure efficient solution of the proposed PBNP equations. Two protein molecules, cytochrome c551 and Gramicidin A, are employed to validate the proposed model under a wide range of bulk ion concentrations and external voltages. Extensive numerical experiments show that there is an excellent consistency between the results predicted from the present PBNP model and those obtained from the PNP model in terms of the electrostatic potentials, ion concentration profiles, and current-voltage (I-V) curves. The present PBNP model is further validated by a comparison with experimental measurements of I-V curves under various ion bulk concentrations. Numerical experiments indicate that the proposed PBNP model is more efficient than the original PNP model in terms of simulation time. PMID- 21599039 TI - Molecular density functional theory of solvation: from polar solvents to water. AB - A classical density functional theory approach to solvation in molecular solvent is presented. The solvation properties of an arbitrary solute in a given solvent, both described by a molecular force field, can be obtained by minimization of a position and orientation-dependent free-energy density functional. In the homogeneous reference fluid approximation, limited to two-body correlations, the unknown excess term of the functional approximated by the angular-dependent direct correlation function of the pure solvent. We show that this function can be extracted from a preliminary MD simulation of the pure solvent by computing the angular-dependent pair distribution function and solving subsequently the molecular Ornstein-Zernike equation using a discrete angular representation. The corresponding functional can then be minimized in the presence of an arbitrary solute on a three-dimensional cubic grid for positions and Gauss-Legendre angular grid for orientations to provide the solvation structure and free-energy. This two-step procedure is proved to be much more efficient than direct molecular dynamics simulations combined to thermodynamic integration schemes. The approach is shown to be relevant and accurate for prototype polar solvents such as the Stockmayer solvent or acetonitrile. For water, although correct for neutral or moderately charged solute, it tends to underestimate the tetrahedral solvation structure around H-bonded solutes, such as spherical ions. This can be corrected by introducing suitable three-body correlation terms that restore both an accurate hydration structure and a satisfactory energetics. PMID- 21599040 TI - Density-functional expansion methods: generalization of the auxiliary basis. AB - The formulation of density-functional expansion methods is extended to treat the second and higher-order terms involving the response density and spin densities with an arbitrary single-center auxiliary basis. The two-center atomic orbital products are represented by the auxiliary functions centered about those two atoms, and the mapping coefficients are determined from a local constrained variational procedure. This two-center variational procedure allows the mapping coefficients to be pretabulated and splined as a function of internuclear separation for efficient look up. The splines of mapping coefficients have a range no longer than that of the overlap integrals, and the auxiliary density appears as a single point-multipole expansion to all nonoverlapping atoms, thus allowing for the trivial implementation of a linear-scaling algorithm. The method is tested using Gaussian multipole expansions, and the effect of angular and radial completeness is explored. Several auxiliary basis sets are parametrized and compared to an auxiliary basis analogous to that used in the self-consistent charge density-functional tight-binding model, and the method is demonstrated to greatly improve the representation of the density response with respect to a reference expansion model that does not use an auxiliary basis. PMID- 21599041 TI - Local orbitals by minimizing powers of the orbital variance. AB - It is demonstrated that a set of local orthonormal Hartree-Fock (HF) molecular orbitals can be obtained for both the occupied and virtual orbital spaces by minimizing powers of the orbital variance using the trust-region algorithm. For a power exponent equal to one, the Boys localization function is obtained. For increasing power exponents, the penalty for delocalized orbitals is increased and smaller maximum orbital spreads are encountered. Calculations on superbenzene, C(60), and a fragment of the titin protein show that for a power exponent equal to one, delocalized outlier orbitals may be encountered. These disappear when the exponent is larger than one. For a small penalty, the occupied orbitals are more local than the virtual ones. When the penalty is increased, the locality of the occupied and virtual orbitals becomes similar. In fact, when increasing the cardinal number for Dunning's correlation consistent basis sets, it is seen that for larger penalties, the virtual orbitals become more local than the occupied ones. We also show that the local virtual HF orbitals are significantly more local than the redundant projected atomic orbitals, which often have been used to span the virtual orbital space in local correlated wave function calculations. Our local molecular orbitals thus appear to be a good candidate for local correlation methods. PMID- 21599042 TI - Analog of Rabi oscillations in resonant electron-ion systems. AB - Quantum coherence between electron and ion dynamics, observed in organic semiconductors by means of ultrafast spectroscopy, is the object of recent theoretical and computational studies. To simulate this kind of quantum coherent dynamics, we have introduced in a previous article [L. Stella, M. Meister, A. J. Fisher, and A. P. Horsfield, J. Chem. Phys. 127, 214104 (2007)] an improved computational scheme based on Correlated Electron-Ion Dynamics (CEID). In this article, we provide a generalization of that scheme to model several ionic degrees of freedom and many-body electronic states. To illustrate the capability of this extended CEID, we study a model system which displays the electron-ion analog of the Rabi oscillations. Finally, we discuss convergence and scaling properties of the extended CEID along with its applicability to more realistic problems. PMID- 21599043 TI - Exploring the top and bottom of the quantum control landscape. AB - A controlled quantum system possesses a search landscape defined by the target physical objective as a function of the controls. This paper focuses on the landscape for the transition probability P(i -> f) between the states of a finite level quantum system. Traditionally, the controls are applied fields; here, we extend the notion of control to also include the Hamiltonian structure, in the form of time independent matrix elements. Level sets of controls that produce the same transition probability value are shown to exist at the bottom P(i -> f)=0.0 and top P(i -> f)=1.0 of the landscape with the field and/or Hamiltonian structure as controls. We present an algorithm to continuously explore these level sets starting from an initial point residing at either extreme value of P(i -> f). The technique can also identify control solutions that exhibit the desirable properties of (a) robustness at the top and (b) the ability to rapidly rise towards an optimal control from the bottom. Numerical simulations are presented to illustrate the varied control behavior at the top and bottom of the landscape for several simple model systems. PMID- 21599044 TI - A universal state-selective approach to multireference coupled-cluster non iterative corrections. AB - A new form of the asymmetric energy functional for multireference coupled cluster (MRCC) theories is discussed from the point of view of an energy expansion in a quasidegenerate situation. The resulting expansion for the exact electronic energy can be used to define the non-iterative corrections to approximate MRCC approaches. In particular, we show that in the proposed framework the essential part of dynamic correlation can be encapsulated in the so-called correlation Hamiltonian, which in analogy to the effective Hamiltonian, is defined in the model space (M(0)). The proper parametrization of the exact/trial wavefunctions leads to the cancellation of the overlap-type numerators and to a connected form of the correlation Hamiltonian and size-extensive energies. Within this parametrization, when the trial wavefunctions are determined without invoking a specific form of the MRCC sufficiency conditions, the ensuing correction can be universally applied to any type of the approximate MRCC method. The analogies with other MRCC triples corrections to MRCC theories with singles and doubles (MRCCSD) are outlined. In particular, we discuss the approach, which in analogy to the Lambda-Mk-MRCCSD(T) method [F. A. Evangelista, E. Prochnow, J. Gauss, H. F. Schaefer III, J. Chem. Phys. 132, 074107 (2010)], introduces an approximate form of the triply-excited clusters into the effective and correlation Hamiltonians. Since the discussed corrections can be calculated as a sum of independent reference-related contributions, possible parallel algorithms are also outlined. PMID- 21599045 TI - Global minimum structures and structural phase diagrams of modified Morse clusters: 11 <= N <= 30. AB - The energetically favored structures of clusters are determined by the interactions among particles. Using the modified Morse pair potential, which has two parameters that can freely control the interactions at the minimum, short range, and long range, we systematically investigated how the interactions determines the global minimum structures of clusters and gave the structural phase diagram at 0 K for each cluster size at the range 11 <= N <= 30. Compared to the Morse potential, a number of new structures are found, and some of them are unexpected. The global minimum structures of modified Morse clusters can act as structural bank, which will be helpful in the optimization of certain real clusters. PMID- 21599046 TI - Using force-matching to reveal essential differences between density functionals in ab initio molecular dynamics simulations. AB - The exchange-correlation (XC) functional and value of the electronic fictitious mass MU can be two major sources of systematic errors in ab initio Car-Parrinello Molecular Dynamics (CPMD) simulations, and have a significant impact on the structural and dynamic properties of condensed-phase systems. In this work, an attempt is made to identify the origin of differences in liquid water properties generated from CPMD simulations run with the BLYP and HCTH/120 XC functionals and two different values of MU (representative of "small" and "large" limits) by analyzing the effective pairwise atom-atom interactions. The force-matching (FM) algorithm is used to map CPMD interactions into non-polarizable, empirical potentials defined by bonded interactions, pairwise short-ranged interactions in numerical form, and Coulombic interactions via atomic partial charges. The effective interaction models are derived for the BLYP XC functional with MU=340 a.u. and MU=1100 a.u. (BLYP-340 and BLYP-1100 simulations) and the HCTH/120 XC functional with MU=340 a.u. (HCTH-340 simulation). The BLYP-340 simulation results in overstructured water with slow dynamics. In contrast, the BLYP-1100 and HCTH-340 simulations both produce radial distribution functions (indicative of structure) that are in reasonably good agreement with experiment. It is shown that the main difference between the BLYP-340 and HCTH-340 effective potentials arises in the short-ranged nonbonded interactions (in hydrogen bonding regions), while the difference between the BLYP-340 and BLYP-1100 interactions is mainly in the long-ranged electrostatic components. Collectively, these results demonstrate how the FM method can be used to further characterize various simulation ensembles (e.g., density-functional theory via CPMD). An analytical representation of each effective interaction water model, which is easy to implement, is presented. PMID- 21599047 TI - Two more approaches for generating trajectory-based dynamics which conserves the canonical distribution in the phase space formulation of quantum mechanics. AB - We show two more approaches for generating trajectory-based dynamics in the phase space formulation of quantum mechanics: "equilibrium continuity dynamics" (ECD) in the spirit of the phase space continuity equation in classical mechanics, and "equilibrium Hamiltonian dynamics" (EHD) in the spirit of the Hamilton equations of motion in classical mechanics. Both ECD and EHD can recover exact thermal correlation functions (of even nonlinear operators, i.e., nonlinear functions of position or momentum operators) in the classical, high temperature, and harmonic limits. Both ECD and EHD conserve the quasi-probability within the infinitesimal volume dx(t)dp(t) around the phase point (x(t), p(t)) along the trajectory. Numerical tests of both approaches in the Wigner phase space have been made for two strongly anharmonic model problems and a double well system, for each potential auto-correlation functions of both linear and nonlinear operators have been calculated. The results suggest EHD and ECD are two additional potential useful approaches for describing quantum effects for complex systems in condense phase. PMID- 21599048 TI - Development of a general time-dependent absorbing potential for the constrained adiabatic trajectory method. AB - The constrained adiabatic trajectory method (CATM) allows us to compute solutions of the time-dependent Schrodinger equation using the Floquet formalism and Fourier decomposition, using matrix manipulation within a non-orthogonal basis set, provided that suitable constraints can be applied to the initial conditions for the Floquet eigenstate. A general form is derived for the inherent absorbing potential, which can reproduce any dispersed boundary conditions. This new artificial potential acting over an additional time interval transforms any wavefunction into a desired state, with an error involving exponentially decreasing factors. Thus, a CATM propagation can be separated into several steps to limit the size of the required Fourier basis. This approach is illustrated by some calculations for the H(2)(+) molecular ion illuminated by a laser pulse. PMID- 21599049 TI - Exchange-correlation generalized gradient approximation for gold nanostructures. AB - We compare the performance of different exchange-correlation functionals, based on the Perdew-Burke-Ernzerhof (PBE) generalized gradient approximation, for the structural and electronic properties of gold nanostructures. In particular we consider PBEsol (constructed to correctly describe solid-state systems) and PBEint [Phys. Rev. B 82, 113104 (2010)] which was recently introduced for hybrid interfaces and preserves the correct second-order gradient expansion of exchange energy (as in PBEsol) providing as well a significant nonlocality for higher density variation (as in PBE). We find that the PBEint functional gives a well balanced description of atomization energies, structural properties, energy differences between isomers, and bulk properties. Results indicate that PBEint is expected to be the most accurate functional for medium and large size gold clusters of different shapes. PMID- 21599050 TI - Zero-field splittings from density functional calculations: analysis and improvement of known methods. AB - Several different approaches have been proposed to calculate the zero-field splitting tensor with density functional methods. In this work, our own derivation is presented in some detail, to allow a theoretical analysis and a comparison with other methods [M. R. Pederson and S. N. Khanna, Phys. Rev. B 60, 9566 (1999); F. Neese, J. Am. Chem. Soc. 128, 10213 (2006); J. Chem. Phys. 127, 164112 (2007)]. Pederson's method can be improved by properly taking into account the quantum nature of spin when extracting the zero field splitting tensor from the magnetic anisotropy. A closed-shell molecule at large distance from an open shell complex will have a spurious contribution to the zero-field splitting tensor calculated with Neese's methods. We thus have analyzed his approach in some detail and found that it can be corrected if one properly transforms the equations used in wave function based theory to a sum-over-states type expression before one interprets it as an energy derivative. If improved along these lines, Neese's and Pederson's methods become identical down to the working equations. The theoretical analysis is illustrated by sample calculations on the well studied Mn(III)-tris-acetylacetonato complex Mn(acac)(3), both as an isolated molecule and with a Pd(II) dichloro diammine complex at large distance as an innocent spectator. PMID- 21599051 TI - Refinement of the experimental energy levels of higher 2D Rydberg states of the lithium atom with very accurate quantum mechanical calculations. AB - Very accurate variational non-relativistic calculations are performed for four higher Rydberg (2)D states (1s(2)nd(1), n = 8,..., 11) of the lithium atom ((7)Li). The wave functions of the states are expanded in terms of all-electron explicitly correlated Gaussian functions and finite nuclear mass is used. The exponential parameters of the Gaussians are optimized using the variational method with the aid of the analytical energy gradient determined with respect to those parameters. The results of the calculations allow for refining the experimental energy levels determined with respect to the (2)S 1s(2)2s(1) ground state. PMID- 21599053 TI - Transport and dynamic properties of O2+(X2Pig) in Kr under the action of an electrostatic field: single or multiple potential energy surface treatment. AB - Ion transport and dynamic properties are calculated through molecular dynamics simulation of the motion of O(2)(+) in Kr under the action of an electrostatic field. The two lower potential energy surfaces X(2)A(") and A(2)A(') are considered for the interaction of the Pi ground state of the ion with a closed shell noble gas. First, we study the reproduction of experimental mobility data through the use of single and multiple potential energy surfaces and establish the contribution of both lower energy states to the interactions. Further, we obtain mean energies and components of the diffusion coefficient parallel and perpendicular to the field, the latter through calculation of the velocity correlation functions. We also calculate components of the angular momentum which provide a measure of the collisional rotational alignment of the ions at high field strength. PMID- 21599052 TI - Calculating solvation energies by means of a fluctuating charge model combined with continuum solvent model. AB - Continuum solvent models have shown to be very efficient for calculating solvation energy of biomolecules in solution. However, in order to produce accurate results, besides atomic radii or volumes, an appropriate set of partial charges of the molecule is needed. Here, a set of partial charges produced by a fluctuating charge model-the atom-bond electronegativity equalization method model (ABEEMsigmapi) fused into molecular mechanics is used to fit for the analytical continuum electrostatics model of generalized-Born calculations. Because the partial atomic charges provided by the ABEEMsigmapi model can well reflect the polarization effect of the solute induced by the continuum solvent in solution, accurate and rapid calculations of the solvation energies have been performed for series of compounds involving 105 small neutral molecules, twenty kinds of dipeptides and several protein fragments. The solvation energies of small neutral molecules computed with the combination of the GB model with the fluctuating charge protocol (ABEEMsigmapi/GB) show remarkable agreement with the experimental results, with a correlation coefficient of 0.97, a slope of 0.95, and a bias of 0.34 kcal/mol. Furthermore, for twenty kinds of dipeptides and several protein fragments, the results obtained from the analytical ABEEMsigmapi/GB model calculations correlate well with those from ab initio and Poisson-Boltzmann calculations. The remarkable agreement between the solvation energies computed with the ABEEMsigmapi/GB model and PB model provides strong motivation for the use of ABEEMsigmapi/GB solvent model in the simulation of biochemical systems. PMID- 21599054 TI - Rovibrational eigenenergy structure of the [H,C,N] molecular system. AB - The vibrational-rotational eigenenergy structure of the [H,N,C] molecular system is one of the key features needed for a quantum mechanical understanding of the HCN?HNC model reaction. The rotationless vibrational structure corresponding to the multidimensional double well potential energy surface is well established. The rotational structure of the bending vibrational states up to the isomerisation barrier is still unknown. In this work the structure of the rotational states for low and high vibrational angular momentum is described from the ground state up to the isomerisation barrier using hot gas molecular high resolution spectroscopy and rotationally assigned ab initio rovibronic states. For low vibrational angular momentum the rotational structure of the bending excitations splits in three regions. For J < 40 the structure corresponds to that of a typical linear molecule, for 40 < J < 60 has an approximate double degenerate structure and for J > 60 the splitting of the e and f components begins to decrease and the rotational constant increases. For states with high angular momentum, the rotational structure evolves into a limiting structure for v(2) > 7--the molecule is locked to the molecular axis. For states with v(2) > 11 the rotational structure already begins to accommodate to the lower rotational constants of the isomerisation states. The vibrational energy begins to accommodate to the levels above the barrier only at high vibrational excitations of v(2) > 22 just above the barrier whereas this work shows that the rotational structure is much more sensitive to the double well structure of the potential energy surface. The rotational structure already experiences the influence of the barrier at much lower energies than the vibrational one. PMID- 21599055 TI - Tunnelling under a conical intersection: application to the product vibrational state distributions in the UV photodissociation of phenols. AB - When phenol is photoexcited to its S(1) (1(1)pipi*) state at wavelengths in the range 257.403 <= lambda(phot) <= 275.133 nm the O-H bond dissociates to yield an H atom and a phenoxyl co-product, with the available energy shared between translation and well characterised product vibration. It is accepted that dissociation is enabled by transfer to an S(2) (1(1)pisigma*) state, for which the potential energy surface (PES) is repulsive in the O-H stretch coordinate, R(O-H). This S(2) PES is cut by the S(1) PES near R(O-H) = 1.2 A and by the S(0) ground state PES near R(O-H) = 2.1 A, to give two conical intersections (CIs). These have each been invoked-both in theoretical studies and in the interpretation of experimental vibrational activity-but with considerable controversy. This paper revisits the dynamic mechanisms that underlie the photodissociation of phenol and substituted phenols in the light of symmetry restrictions arising from torsional tunnelling degeneracy, which has been neglected hitherto. This places tighter symmetry constraints on the dynamics around the two CIs. The non-rigid molecular symmetry group G(4) necessitates vibronic interactions by a(2) modes to enable coupling at the inner, higher energy (S(1)/S(2)) CI, or by b(1) modes at the outer, lower energy (S(2)/S(0)) CI. The experimental data following excitation through many vibronic levels of the S(1) state of phenol and substituted phenols demonstrate the effective role of the nu(16a) (a(2)) ring torsional mode in enabling O-H bond fission. This requires tunnelling under the S(1)/S(2) CI, with a hindering barrier of ~5000 cm( 1) and with the associated geometric phase effect. Quantum dynamic calculations using new ab initio PESs provide quantitative justification for this conclusion. The fates of other excited S(1) modes are also rationalised, revealing both spectator modes and intramolecular vibrational redistribution between modes. A common feature in many cases is the observation of an extended, odd-number only, progression in product mode nu(16a) (i.e., the parent mode which enables S(1)/S(2) tunnelling), which we explain as a Franck-Condon consequence of a major change in the active vibration frequency. These comprehensive results serve to confirm the hypothesis that O-H fission following excitation to the S(1) state involves tunnelling under the S(1)/S(2) CI-in accord with conclusions reached from a recent correlation of the excited state lifetimes of phenol (and many substituted phenols) with the corresponding vertical energy gaps between their S(1) and S(2) PESs. PMID- 21599056 TI - The dissociation of vibrationally excited CH3OSO radicals and their photolytic precursor, methoxysulfinyl chloride. AB - The dissociation dynamics of methoxysulfinyl radicals generated from the photodissociation of CH(3)OS(O)Cl at 248 nm is investigated using both a crossed laser-molecular beam scattering apparatus and a velocity map imaging apparatus. There is evidence of only a single photodissociation channel of the precursor: S Cl fission to produce Cl atoms and CH(3)OSO radicals. Some of the vibrationally excited CH(3)OSO radicals undergo subsequent dissociation to CH(3) + SO(2). The velocities of the detected CH(3) and SO(2) products show that the dissociation occurs via a transition state having a substantial barrier beyond the endoergicity; appropriately, the distribution of velocities imparted to these momentum-matched products is fit by a broad recoil kinetic energy distribution extending out to 24 kcal/mol in translational energy. Using 200 eV electron bombardment detection, we also detect the CH(3)OSO radicals that have too little internal energy to dissociate. These radicals are observed both at the parent CH(3)OSO(+) ion as well as at the CH(3)(+) and SO(2)(+) daughter ions; they are distinguished by virtue of the velocity imparted in the original photolytic step. The detected velocities of the stable radicals are roughly consistent with the calculated barriers (both at the CCSD(T) and G3B3 levels of theory) for the dissociation of CH(3)OSO to CH(3) + SO(2) when we account for the partitioning of internal energy between rotation and vibration as the CH(3)OSOCl precursor dissociates. PMID- 21599057 TI - The depolarized Raman 2nu3 overtone of CO2: a line-mixing shape analysis. AB - In a recent article we showed that the 2nu(3) transition of CO(2) gives rise to a Raman spectrum that is almost entirely depolarized [M. Chrysos, I. A. Verzhbitskiy, F. Rachet, and A. P. Kouzov, J. Chem. Phys. 134, 044318 (2011)]. In the present article, we go further forward in the study of this overtone by reporting a first-principles shape analysis of its depolarized spectrum at room temperature. As a first step in our analysis, a model assuming isolated Lorentzian line shapes was applied, which at low gas densities turns out to be sufficient for qualitative conclusions. As the next step, a sophisticated approach was developed on the basis of the extended strong-collision model in order to properly account for the heavy line mixing between rotational lines. Whereas a marked deviation between model and measured spectra was observed upon application of the simpler model, striking agreement even at the highest CO(2) density was found on applying the sophisticated one. Accurate calculated data were used for the rotational line broadening coefficients without resort to arbitrary parameters. Values for the vibrational shift scaling linearly with the density of the gas are given. PMID- 21599058 TI - The infrared spectra of BF3+ and BF2OH+ trapped in solid neon. AB - Observations on a Ne:BF(3) = 400:1 mixture into which a trace of normal or isotopically enriched water had been introduced, codeposited at 4.3 K with a beam of neon atoms that had been excited in a microwave discharge, demonstrate that a pair of absorptions at 1662 cm(-1) and 1722 cm(-1) that were previously assigned to the two boron-isotopic species of BF(3)(+) should be reassigned to a BF(2) stretching fundamental of BF(2)OH(+). The OH stretching fundamental of that product was identified for the first time at 3240 cm(-1). The degenerate BF(3) stretching fundamental of (11)BF(3)(+) appears at an unusually high frequency, 1790 cm(-1), consistent with strong pseudo-Jahn-Teller interaction of that ground state fundamental with the B(2)E(') electronic state, as predicted by theory. The recent availability of detailed ab initio and density functional calculations of the vibrational fundamentals of BF(2)(-) and BF(3)(-) facilitates assignment of the infrared absorptions of those two products. PMID- 21599059 TI - The weakly bound states and resonances of the BeHe2 triatomic system. AB - In the present study, we carry out a full search of the bound states and resonances of the He(2)Be triatomic system, with its isotopic variants (3)He(2)(9)Be, (3)He(4)He(9)Be, and (4)He(2)(9)Be using the hyperspherical method. Three-body long-range effects are also included in the computation by adding to the additive potential the Axilrod-Teller triple-dipole term. In addition, the possibility of the occurrence of Efimov-type states in these systems is discussed. We have found a bound state for each of the (3)He(2)(9)Be and (3)He(4)He(9)Be trimers, while one weakly bound excited state is also found to exist for the (4)He(2)(9)Be system. PMID- 21599060 TI - Calculation of inelastic helium atom scattering from H2/NaCl(001). AB - The one-phonon inelastic low energy helium atom scattering theory is adapted to cases where the target monolayer is a p(1 * 1) commensurate square lattice. Experimental data for para-H(2)/NaCl(001) are re-analyzed and the relative intensities of energy loss peaks in the range 6 to 9 meV are determined. The case of the H(2)/NaCl(001) monolayer for 26 meV scattering energy is computationally challenging and difficult because it has a much more corrugated surface than those in the previous applications for triangular lattices. This requires a large number of coupled channels for convergence in the wave-packet-scattering calculation and a long series of Fourier amplitudes to represent the helium target potential energy surface. A modified series is constructed in which a truncated Fourier expansion of the potential is constrained to give the exact value of the potential at some key points and which mimics the potential with fewer Fourier amplitudes. The shear horizontal phonon mode is again accessed by the helium scattering for small misalignment of the scattering plane relative to symmetry axes of the monolayer. For 1 degrees misalignment, the calculated intensity of the longitudinal acoustic phonon mode frequently is higher than that of the shear horizontal phonon mode in contrast to what was found at scattering energies near 10 meV for triangular lattices of Ar, Kr, and Xe on Pt(111). PMID- 21599061 TI - A global ab initio potential energy surface for HNO (a3A") and quantum mechanical studies of vibrational states and reaction dynamics. AB - A new global potential energy surface for the lowest triplet electronic state (a(3)A") of HNO has been developed by a three-dimensional cubic spline interpolation of more than 13,000 ab initio points, which were calculated at the multireference configuration interaction level with Davidson correction using the augmented correlation-consistent polarized valence quintuple zeta basis set. Two minima and five saddle points were found on the potential energy surface. Low lying vibrational states were obtained in this new potential using the Lanczos method and assigned. In addition, thermal rate constants for the N + OH -> H + NO reactions were obtained using an exact wave packet method. Reasonably good agreement with experimental data was obtained. PMID- 21599062 TI - Nuclear spin dependence of the reaction of H(3)+ with H2. I. Kinetics and modeling. AB - The chemical reaction H(3)(+) + H(2) -> H(2) + H(3)(+) is the simplest bimolecular reaction involving a polyatomic, yet is complex enough that exact quantum mechanical calculations to adequately model its dynamics are still unfeasible. In particular, the branching fractions for the "identity," "proton hop," and "hydrogen exchange" reaction pathways are unknown, and to date, experimental measurements of this process have been limited. In this work, the nuclear-spin-dependent steady-state kinetics of the H(3)(+) + H(2) reaction is examined in detail, and employed to generate models of the ortho:para ratio of H(3)(+) formed in plasmas of varying ortho:para H(2) ratios. One model is based entirely on nuclear spin statistics, and is appropriate for temperatures high enough to populate a large number of H(3)(+) rotational states. Efforts are made to include the influence of three-body collisions in this model by deriving nuclear spin product branching fractions for the H(5)(+) + H(2) reaction. Another model, based on rate coefficients calculated using a microcanonical statistical approach, is appropriate for lower-temperature plasmas in which energetic considerations begin to compete with the nuclear spin branching fractions. These models serve as a theoretical framework for interpreting the results of laboratory studies on the reaction of H(3)(+) with H(2). PMID- 21599063 TI - Nuclear spin dependence of the reaction of H(3)+ with H2. II. Experimental measurements. AB - The nuclear spin dependence of the chemical reaction H(3)(+)+ H(2) -> H(2) + H(3)(+) has been studied in a hollow cathode plasma cell. Multipass infrared direct absorption spectroscopy has been employed to monitor the populations of several low-energy rotational levels of ortho- and para-H(3)(+) (o-H(3)(+) and p H(3)(+)) in hydrogenic plasmas of varying para-H(2) (p-H(2)) enrichment. The ratio of the rates of the proton hop (k(H)) and hydrogen exchange (k(E)) reactions alpha = k(H)/k(E) is inferred from the observed p-H(3)(+) fraction as a function of p-H(2) fraction using steady-state chemical models. Measurements have been performed both in uncooled (T(kin) ~ 350 K) and in liquid-nitrogen-cooled (T(kin) ~ 135 K) plasmas, marking the first time this reaction has been studied at low temperature. The value of alpha has been found to decrease from 1.6 +/- 0.1 at 350 K to 0.5 +/- 0.1 at 135 K. PMID- 21599064 TI - Elimination mechanisms of Br(2)+ and Br+ in photodissociation of 1,1- and 1,2 dibromoethylenes using velocity imaging technique. AB - Elimination pathways of the Br(2)(+) and Br(+) ionic fragments in photodissociation of 1,2- and 1,1-dibromoethylenes (C(2)H(2)Br(2)) at 233 nm are investigated using time-of-flight mass spectrometer equipped with velocity ion imaging. The Br(2)(+) fragments are verified not to stem from ionization of neutral Br(2), that is a dissociation channel of dibromoethylenes reported previously. Instead, they are produced from dissociative ionization of dibromoethylene isomers. That is, C(2)H(2)Br(2) is first ionized by absorbing two photons, followed by the dissociation scheme, C(2)H(2)Br(2)(+) + hv->Br(2)(+) + C(2)H(2). 1,2-C(2)H(2)Br(2) gives rise to a bright Br(2)(+) image with anisotropy parameter of -0.5 +/- 0.1; the fragment may recoil at an angle of ~66 degrees with respect to the C=C bond axis. However, this channel is relatively slow in 1,1-C(2)H(2)Br(2) such that a weak Br(2)(+) image is acquired with anisotropy parameter equal to zero, indicative of an isotropic recoil fragment distribution. It is more complicated to understand the formation mechanisms of Br(+). Three routes are proposed for dissociation of 1,2-C(2)H(2)Br(2), including (a) ionization of Br that is eliminated from C(2)H(2)Br(2) by absorbing one photon, (b) dissociation from C(2)H(2)Br(2)(+) by absorbing two more photons, and (c) dissociation of Br(2)(+). Each pathway requires four photons to release one Br(+), in contrast to the Br(2)(+) formation that involves a three-photon process. As for 1,1-C(2)H(2)Br(2), the first two pathways are the same, but the third one is too weak to be detected. PMID- 21599065 TI - Photodissociation dynamics of 3-bromo-1,1,1-trifluoro-2-propanol and 2 (bromomethyl) hexafluoro-2-propanol at 234 nm: resonance-enhanced multiphoton ionization detection of Br (2P(j)). AB - The photodissociation dynamics of 3-bromo-1,1,1-trifluoro-2-propanol (BTFP) and 2 (bromomethyl) hexafluoro-2-propanol (BMHFP) have been studied at 234 nm, and the C-Br bond dissociation investigated using resonance-enhanced multiphoton ionization coupled with time-of-flight mass spectrometer (REMPI-TOFMS). Br formation is a primary process and occurs on a repulsive surface involving the C Br bond of BTFP and BMHFP. Polarization dependent time-of-flight profiles were measured, and the translational energy distributions and recoil anisotropy parameters extracted using forward convolution fits. A strong polarization dependence of time-of-flight profiles suggest anisotropic distributions of the Br((2)P(3/2)) and Br((2)P(1/2)) fragments with anisotropy parameter, beta, of respectively 0.5 +/- 0.2 and 1.2 +/- 0.2 for BTFP, and 0.4 +/- 0.1 and 1.0 +/- 0.3 for BMHFP. The measured velocity distributions consist of a single velocity component. The average translational energies for the Br((2)P(3/2)) and Br((2)P(1/2)) channels are 9.2 +/- 1.0 and 7.4 +/- 0.9 kcal/mol for BTFP, and 15.4 +/- 1.8 and 15.1 +/- 2.0 kcal/mol for BMHFP. The relative quantum yields of Br((2)P(3/2)) and Br((2)P(1/2)), which are 0.70 +/- 0.14 and 0.30 +/- 0.06 in BTFP and 0.81 +/- 0.16 and 0.19 +/- 0.04 in BMHFP, indicate that the yield of the former is predominant. The measured anisotropy parameters for the Br((2)P(3/2)) and Br((2)P(1/2)) channels suggest that the former channel has almost equal contributions from both the parallel and the perpendicular transitions, whereas the latter channel has a significant contribution from a parallel transition. Non adiabatic curve crossing plays an important role in the C-Br bond dissociation of both BTFP and BMHFP. The estimated curve crossing probabilities suggest a greater value in BTFP, which explains a greater observed value of the relative quantum yield of Br((2)P(1/2)) in this case. PMID- 21599066 TI - Ultraviolet photodissociation of iodine monochloride (ICl) at 235, 250, and 265 nm. AB - ICl photolysis in the ultraviolet region of the spectrum (235-265 nm) is studied using the Slice Imaging technique. The Cl*((2)P(1/2))/Cl((2)P(3/2)) and the I*((2)P(1/2))/I((2)P(3/2)) branching ratio between the I((2)P(3/2)) + Cl((2)P(3/2))/Cl*((2)P(1/2)) and I*((2)P(1/2)) + Cl((2)P(3//2))/Cl*((2)P(1/2)) channels is extracted from the respective iodine and chlorine photofragment images. We find that ground state chlorine atoms (Cl((2)P(3/2))) are formed nearly exclusively with excited state iodine atoms (I*((2)P(1/2))), while excited spin-orbit chlorine atoms (Cl*((2)P(1/2))) are concurrently produced only with ground state iodine atoms (I((2)P(3/2))). We conclude that photolysis of ICl in this UV region is a relatively "clean" source of spin-orbit excited chlorine atoms that can be used in crossed molecular beam experiments. PMID- 21599067 TI - Photolysis of pure solid O3 and O2 films at 193 nm. AB - We studied quantitatively the photochemistry of solid O(3) and O(2) films at 193 nm and 22 K with infrared spectroscopy and microgravimetry. Photolysis of pure ozone destroyed O(3), but a small amount of ozone remained in the film at high fluence. Photolysis of pure O(2) produced O(3) in an amount that increased with photon fluence to a stationary level. For both O(2) and O(3) films, the O(3):O(2) ratio at large fluences is ~0.07, about two orders of magnitude larger than those obtained in gas phase photolysis. This enhancement is attributed to the increased photodissociation of O(2) due to photoabsorption by O(2) dimers, a process significant at solid-state densities. We obtain initial quantum yield for ozone synthesis from solid oxygen, Phi(O(3)) = 0.24 +/- 0.06, and quantum yields for destruction of O(3) and O(2) in their parent solids, Phi(-O(3)) = 1.0 +/- 0.2 and Phi(-O(2)) = 0.36 +/- 0.1. Combined with known photoabsorption cross sections, we estimate probabilities for geminate recombination of 0.5 +/- 0.1 for O(3) fragments and 0.88 +/- 0.03 for oxygen atoms from O(2) dissociation. Using a single parameter kinetic model, we deduce the ratio of reaction cross sections for an O atom with O(2) vs. O(3) to be 0.1-0.2. The general good agreement of the model with the data suggests the validity of the central assumption of efficient energy and spin relaxation of photofragments in the solid prior to their reactions with other species. PMID- 21599068 TI - Simulation and theory of a model for tetrahedral colloidal particles. AB - We study the thermodynamic and structural properties of a five-site tetrahedral molecular model by means of different Monte Carlo simulation techniques, and the reference interaction site model (RISM) theory of molecular fluids. Simulations and theory signal the onset, at sufficiently low temperatures, of two different tetrahedral molecular arrangements, with a more open topology progressively giving place to a fully bonded one, as the temperature decreases. The RISM theory reproduces the splitting of the static structure factor at low temperatures, a feature intimately related to the onset of the tetrahedral ordering. Less accurate predictions are obtained for the liquid-vapor coexistence and the short range correlations. PMID- 21599069 TI - The potential energy landscape contribution to the dynamic heat capacity. AB - The dynamic heat capacity of a simple polymeric, model glassformer was computed using molecular dynamics simulations by sinusoidally driving the temperature and recording the resultant energy. The underlying potential energy landscape of the system was probed by taking a time series of particle positions and quenching them. The resulting dynamic heat capacity demonstrates that the long time relaxation is the direct result of dynamics resulting from the potential energy landscape. Moreover, the equilibrium (low frequency) portion of the potential energy landscape contribution to the heat capacity is found to increase rapidly at low temperatures and at high packing fractions. This increase in the heat capacity is explained by a statistical mechanical model based on the distribution of minima in the potential energy landscape. PMID- 21599070 TI - Electronic excitations of potassium intercalated manganese phthalocyanine investigated by electron energy-loss spectroscopy. AB - The electronic excitations of manganese phthalocyanine (MnPc) films were studied as a function of potassium doping using electron energy-loss spectroscopy in transmission. Our data reveal doping induced changes in the excitation spectrum, and they provide evidence for the existence of three doped phases: K(1)MnPc, K(2)MnPc, and K(4)MnPc. Furthermore, the addition of electrons first leads to a filling of orbitals with strong Mn 3d character, a situation which also affects the magnetic moment of the molecule. PMID- 21599071 TI - Proton conduction in hydrous glasses of the join CaAl2Si2O8-CaMgSi2O6: an impedance and infrared spectroscopic study. AB - Hydrous silicate glasses with compositions along the join diopside-anorthite (An, CaAl(2)Si(2)O(8))-(Di, CaMgSi(2)O(6)) containing up to 3 wt. % H(2)O were synthesized at temperatures 1523-1723 K and pressures of 200 MPa in an internally heated gas pressure vessel. The water content of the glasses was analyzed by Karl Fischer titration. Infrared microspectroscopy was used to test the homogeneity of the water distribution and to measure the concentrations of OH groups and H(2)O molecules before and after conductivity measurements. The electrical conductivity was measured by impedance spectroscopy at temperature up to 685 K. A positive correlation between water content and conductivity was observed for An(100) from 0 to 1.8 wt.% H(2)O, for An(50)Di(50) (in mol.%) from 1.5 to 2.8 wt.% H(2)O, and for Di(100) from 0 to 1.2 wt.% H(2)O. At same water content of ~1.2 wt.%, the conductivity was three orders of magnitude higher in Di(100) than in the other two glasses, emphasizing the importance of non-bridging oxygens on the transport of hydrous charge carriers. Consistent with findings in literature, we conclude that protons are the predominant mobile charge carriers in alkali-free hydrous silicate glasses. Conductivity data were evaluated in terms of proton diffusivity by the Nernst-Einstein equation. The obtained diffusion coefficients range from 10(-17) m(2)/s for An(50)Di(50) with 1.50 wt.% of H(2)O at 596 K to 10(-12) m(2)/s for An(50)Di(50) with 2.77 wt.% of H(2)O at 685 K. PMID- 21599072 TI - The calculation of vapor-liquid coexistence curve of Morse fluid: application to iron. AB - The vapor-liquid coexistence curve of Morse fluid was calculated within the integral equations approach. The critical point coordinates were estimated. The parameters of Morse potential, fitted for elastic constants in solid phase, were used here to apply the results of present calculations to the determination of iron binodal. The properties of copper and sodium were considered in an analogous way. The calculations of pair correlation functions and isobars at liquid phase have shown that only for sodium these potential parameters allow one to obtain agreement with the measurements data. For iron another parameters are necessary to get this agreement in liquid phase. However, they give rise to very low critical temperature and pressure with respect to the estimates of other authors. Consequently, one can suppose that Morse potential is possibly inapplicable to the calculation of high temperature properties of non-alkali metals in disordered phases. PMID- 21599073 TI - Third harmonics nonlinear susceptibility in supercooled liquids: a comparison to the box model. AB - The box model, originally introduced to account for the nonresonant hole burning (NHB) dielectric experiments in supercooled liquids, is compared to the measurements of the third harmonics P(3) of the polarisation, reported recently in glycerol, close to the glass transition temperature T(g) [C. Crauste Thibierge, C. Brun, F. Ladieu, D. L'Hote, G. Biroli, and J.-P. Bouchaud, Phys. Rev. Lett. 104, 165703 (2010)]. In this model, each box is a distinct dynamical relaxing entity (hereafter called dynamical heterogeneity (DH)) which follows a Debye dynamics with its own relaxation time tau(dh). When it is submitted to a strong electric field, the model posits that a temperature increase deltaT(dh), depending on tau(dh), arises due to the dissipation of the electrical power. Each DH has thus its own temperature increase, on top of the temperature increase of the phonon bath deltaT(ph). Contrary to the "fast" hole burning experiments where deltaT(ph) is usually neglected, the P(3) measurements are, from a thermal point of view, fully in a stationary regime, which means that deltaT(ph) can no longer be neglected a priori. This is why the version of the box model that we study here takes deltaT(ph) into account, which implies that the deltaT(dh) of the DHs are all coupled together. The value of P(3), including both the "intrinsic" contribution of each DH as well as the "spurious" one coming from deltaT(ph), is computed within this box model and compared to the P(3) measurements for glycerol, in the same range of frequencies and temperatures T. Qualitatively, we find that this version of the box model shares with experiments some nontrivial features, e.g., the existence of a peak at finite frequency in the modulus of P(3) as well as its order of magnitude. Quantitatively, however, some experimental features are not accounted for by this model. We show that these differences between the model and the experiments do not come from deltaT(ph) but from the "intrinsic" contribution of the DHs. Finally, we show that the interferences between the 3omega response of the various DHs are the most important issue leading to the discrepancies between the box model prediction and the experiments. We argue that this could explain why the box model is quite successful to account for some kinds of nonlinear experiments (such as NHB) performed close to T(g), even if it does not completely account for all of them (such as the P(3) measurements). This conclusion is supported by an analytical argument which helps understanding how a "space-free" model as the box model is able to account for some of the experimental nonlinear features. PMID- 21599074 TI - Simulation of the two-dimensional electronic spectra of the Fenna-Matthews-Olson complex using the hierarchical equations of motion method. AB - We apply the Liouville space hierarchical equations of motion method to calculate the linear and two-dimensional (2D) electronic spectra of the Fenna-Matthews Olson (FMO) protein complex from Chlorobium tepidum, using a widely used model Hamiltonian. The absorption and linear dichroism spectra of the FMO complex, as well as the main features of the 2D spectra are well reproduced. However, comparison with the recent experimental 2D spectra reveals several limitations of the current model: (1) The homogeneous and inhomogeneous broadening seems to be overestimated for the first exciton peak, but may be underestimated for several other exciton peaks. (2) The calculated oscillations of the diagonal and off diagonal peaks in the 2D spectra are much weaker than the experimental observations, which indicates that an improved model is needed for the excitonic dynamics of the FMO complex. PMID- 21599075 TI - The role of activation energy and reduced viscosity on the enhancement of water flow through carbon nanotubes. AB - Molecular dynamics simulations are carried out to study the pressure driven fluid flow of water through single walled carbon nanotubes. A method for the calculation of viscosity of the confined fluid based on the Eyring theory of reaction rates is proposed. The method involves the calculation of the activation energy directly from the molecular dynamics trajectory information. Computations are performed using this method to study the effect of surface curvature on the confined fluid viscosity. The results indicate that the viscosity varies nonlinearly with the carbon nanotube diameter. It is concluded that the reason behind the observed enhancement in the rate of fluid flow through carbon nanotubes could be the nonlinear variation of viscosity. PMID- 21599076 TI - Thermal decomposition mechanisms of methylamine, ethylamine, and 1-propylamine on Si(100)-2 * 1 surface. AB - The thermal decomposition reactions of methylamine, ethylamine, and 1-propylamine absorbed on Si(100)-2 * 1 surface were theoretically investigated. Eight decomposition channels were found leading to desorption products of imine, H(2), alkyl cyanide, ammonia, aziridine, alkene, azetidine, and cyclopropane, which supports the experimental assignments. Our mechanistic studies strongly suggest that the alkyl cyanide (hydrogen cyanide in the case of methylamine) channel is coupled with the hydrogen desorption step. The beta-hydrogen of ethylamine and 1 propylamine was found to undergo additional decomposition reactions producing aziridine and alkene, which were classified as gamma- and beta-eliminations, respectively. It was also found that the gamma-hydrogen of 1-propylamine undergoes azetidine and cyclopropane producing decompositions, which were classified as delta- and gamma-eliminations. In general, gamma- and delta hydrogen involved decomposition reactions are kinetically less favorable than beta-hydrogen involved ones. Consequently, it is expected that the thermal decompositions of the primary alkyl amines with longer alkyl chains would not add additional favorable decomposition channels. Except alkyl cyanide and ammonia desorption channels, the decompositions occur in a concerted fashion. PMID- 21599077 TI - The initial growth behavior of perylene on Cu(100). AB - Using scanning tunneling microscopy (STM) together with density functional theory (DFT) the growth behavior of perylene on the Cu(100) substrate has been investigated. As revealed by STM images, perylene molecules prefer to adopt lying configuration with their molecular plane parallel to the substrate, and two symmetrically equivalent ordered domains were observed. DFT calculations show that perylene molecule prefers to adsorb on the top site of substrate Cu atoms with its long molecular axis aligning along the [011] or [01-1] azimuth of the substrate which is the most stable adsorption geometry according to its highest binding energy. Consequently, two adsorption structures of c(8*4) and c(8*6), each containing two perylene molecules per unit cell, are proposed based on our STM images. The growth mechanism for ordered perylene domains on Cu(100) can be attributed to the balance between weak adsorbate-adsorbate interaction and comparable adsorbate-substrate interaction. PMID- 21599078 TI - Adsorption properties versus oxidation states of rutile TiO2(110). AB - Using density functional theory we have studied the adsorption properties of different atoms and molecules deposited on a stoichiometric, reduced, and oxidized rutile TiO(2)(110) surface. Depending on the oxidation state of the surface, electrons can flow from or to the substrate and, therefore, negatively or positively charged species are expected. In particular, we have found that a charge transfer process from or to the surface always occurs for highly electronegative or highly electropositive species, respectively. For atoms or molecules with intermediate electron affinity, the direction of the charge flow depends on the oxidation state of the rutile surface and on the adsorption site. Generally, the charging effect leads to more stable complexes. However, the increase in the binding energy of the adsorbates is highly dependent on the electronic states of the surface prior to the adsorption event. In this work we have analyzed in details these mechanisms and we have also established a direct correlation between the enhanced binding energy of the adsorbates and the induced gap states. PMID- 21599079 TI - Evolution of glassy gratings with variable aspect ratios under surface diffusion. AB - The structural evolution of surface gratings on a glassy material is investigated by means of molecular simulations. The gratings provide a means to probe surface diffusion in the vicinity of the glass transition temperature. A theory by Mullins [J. Appl. Phys. 30, 77 (1959)] is used to extract qu-antitative measures of surface diffusivity that rely on calculation of grating amplitude as a function of time. The simulations are implemented in the context of a model binary glass mixture [S. S. Ashwin and S. Sastry, J. Phys.: Condens. Matter 15, S1253 (2003)]. We find that surface diffusion is faster than bulk diffusion by several orders of magnitude, consistent with recent experimental data for an organic glass former. The diffusivities extracted by the grating-decay approach are consistent with those estimated on the basis of mean-squared particle displacements. The grating-decay approach, however, is more efficient than traditional techniques based on Einstein's diffusion equation. Grating decay is also more versatile and is shown to be applicable in a variety of sample geometries. PMID- 21599080 TI - Dynamic information for cardiotoxin protein desorption from a methyl-terminated self-assembled monolayer using steered molecular dynamics simulation. AB - Dynamic information, such as force, structural change, interaction energy, and potential of mean force (PMF), about the desorption of a single cardiotoxin (CTX) protein from a methyl-terminated self-assembled monolayer (SAM) surface was investigated by means of steered molecular dynamics (SMD) simulations. The simulation results indicated that Loop I is the first loop to depart from the SAM surface, which is in good agreement with the results of the nuclear magnetic resonance spectroscopy experiment. The free energy landscape and the thermodynamic force of the CTX desorption process was represented by the PMF and by the derivative of PMF with respect to distance, respectively. By applying Jarzynski's equality, the PMF can be reconstructed from the SMD simulation. The PMFs, calculated by different estimators based upon Jarzynski's equality, were compared with the conventional umbrella sampling method. The best estimation was obtained by using the fluctuation-dissipation estimator with a pulling velocity of v = 0.25 nm/ns for the present study. PMID- 21599081 TI - Properties of copper (fluoro-)phthalocyanine layers deposited on epitaxial graphene. AB - We investigate the atomic structure and electronic properties of monolayers of copper phthalocyanines (CuPc) deposited on epitaxial graphene substrate. We focus in particular on hexadecafluorophthalocyanine (F(16)CuPc), using both theoretical and experimental (scanning tunneling microscopy - STM) studies. For the individual CuPc and F(16)CuPc molecules, we calculated the electronic and optical properties using density functional theory (DFT) and time-dependent DFT and found a red-shift in the absorption peaks of F(16)CuPc relative to those of CuPc. In F(16)CuPc, the electronic wavefunctions are more polarized toward the electronegative fluorine atoms and away from the Cu atom at the center of the molecule. When adsorbed on graphene, the molecules lie flat and form closely packed patterns: F(16)CuPc forms a hexagonal pattern with two well-ordered alternating alpha and beta stripes while CuPc arranges into a square lattice. The competition between molecule-substrate and intermolecular van der Waals interactions plays a crucial role in establishing the molecular patterns leading to tunable electron transfer from graphene to the molecules. This transfer is controlled by the layer thickness of, or the applied voltage on, epitaxial graphene resulting in selective F(16)CuPc adsorption, as observed in STM experiments. In addition, phthalocyanine adsorption modifies the electronic structure of the underlying graphene substrate introducing intensity smoothing in the range of 2-3 eV below the Dirac point (E(D)) and a small peak in the density of states at ~0.4 eV above E(D). PMID- 21599082 TI - Sterically stabilized lock and key colloids: a self-consistent field theory study. AB - A self-consistent field theory study of lock and key type interactions between sterically stabilized colloids in polymer solution is performed. Both the key particle and the lock cavity are assumed to have cylindrical shape and their surfaces are uniformly grafted with polymer chains. The lock-key potential of mean force is computed for various model parameters, such as length of free and grafted chains, lock and key size matching, free chain volume fraction, grafting density, and various enthalpic interactions present in the system. The lock-key interaction is found to be highly tunable, which is important in the rapidly developing field of particle self-assembly. PMID- 21599083 TI - Complete solution of the problem of one-dimensional non-covalent non-cooperative self-assembly in two-component systems. AB - Equations for the mass conservation law and the molecular parameters observed in spectroscopic experiments have been derived for non-covalent, non-cooperative, one-dimensional self-assembly in systems containing two types of interacting molecules (hetero-association), taking into account "reflected" complexes and "edge effects." PMID- 21599084 TI - A molecular view of vapor deposited glasses. AB - Recently, novel organic glassy materials that exhibit remarkable stability have been prepared by vapor deposition. The thermophysical properties of these new "stable" glasses are equivalent to those that common glasses would exhibit after aging over periods lasting thousands of years. The origin of such enhanced stability has been elusive; in the absence of detailed models, past studies have discussed the formation of new polyamorphs or that of nanocrystals to explain the observed behavior. In this work, an atomistic molecular model of trehalose, a disaccharide of glucose, is used to examine the properties of vapor-deposited stable glasses. Consistent with experiment, the model predicts the formation of stable glasses having a higher density, a lower enthalpy, and higher onset temperatures than those of the corresponding "ordinary" glass formed by quenching the bulk liquid. Simulations reveal that newly formed layers of the growing vapor deposited film exhibit greater mobility than the remainder of the material, thereby enabling a reorganization of the film as it is grown. They also reveal that "stable" glasses exhibit a distinct layered structure in the direction normal to the substrate that is responsible for their unusual properties. PMID- 21599085 TI - Landau theory description of observed isotropic to anisotropic phase transition in mixed clay gels. AB - A characteristic new cooperative dehydration transition, in 1:1 Laponite-MMT cogel, was observed at T(c) ~ 60 degrees C, a temperature at which the storage modulus (G(')) and depolarization ratio (D(p)) showed sharp increase, and the isotropic cogel turned into an anisotropic one. The dehydration dynamics could be described through power-law relations: G(') ~ (T(c)-T)(-gamma) and D(p) ~ (T(c) T)(-beta) with gamma ~ beta = 0.40 +/- 0.05. The x-ray diffraction data revealed that the crystallite size decreased from 17 nm (at 20 degrees C) to 10 nm (at 80 degrees C) implying loss of free and inter-planar water. When this cogel was spontaneously cooled below T(c), it exhibited much larger storage modulii values which implied the existence of several metastable states in this system. This phase transition could be modeled through Landau theory, where the depolarization ratio was used as experimental order parameter (psi). This parameter was found to scale with temperature, as psi ~ (T(c)-T)(-alpha), with power-law exponent alpha = 0.40 +/- 0.05; interestingly, we found alpha ~ beta ~ gamma. PMID- 21599086 TI - Primitive chain network simulations for asymmetric star polymers. AB - For branched polymers, the curvilinear motion of the branch point along the backbone is a significant relaxation source but details of this motion have not been well understood. This study conducts multi-chain sliplink simulations to examine effects of the spatial fluctuation and curvilinear hopping of the branch point on the viscoelastic relaxation. The simulation is based on the primitive chain network model that allows the spatial fluctuations of sliplink and branch point and the chain sliding along the backbone according to the subchain tension, chemical potential gradients, drag force against medium, and random force. The sliplinks are created and/or disrupted through the motion of chain ends. The curvilinear hopping of the branch point along the backbone is allowed to occur when all sliplinks on a branched arm are lost. The simulations considering the fluctuation and the hopping of the branch point described well the viscoelastic data for symmetric and asymmetric star polymers with a parameter set common to the linear polymer. On the other hand, the simulations without the branch point motion predicted unreasonably slow relaxation for asymmetric star polymers. For asymmetric star polymers, further tests with and without the branch point hopping revealed that the hopping is much less important compared to the branch point fluctuation when the lengths of the short and long backbone arms are not very different and the waiting time for the branch point hopping (time for removal of all sliplinks on the short arm) is larger than the backbone relaxation time. Although this waiting time changes with the hopping condition, the above results suggest a significance of the branch point fluctuation in the actual relaxation of branch polymers. PMID- 21599087 TI - Effect of bidispersity in grafted chain length on grafted chain conformations and potential of mean force between polymer grafted nanoparticles in a homopolymer matrix. AB - In efforts to produce polymeric materials with tailored physical properties, significant interest has grown around the ability to control the spatial organization of nanoparticles in polymer nanocomposites. One way to achieve controlled particle arrangement is by grafting the nanoparticle surface with polymers that are compatible with the matrix, thus manipulating the interfacial interactions between the nanoparticles and the polymer matrix. Previous work has shown that the molecular weight of the grafted polymer, both at high grafting density and low grafting density, plays a key role in dictating the effective inter-particle interactions in a polymer matrix. At high grafting density nanoparticles disperse (aggregate) if the graft molecular weight is higher (lower) than the matrix molecular weight. At low grafting density the longer grafts can better shield the nanoparticle surface from direct particle-particle contacts than the shorter grafts and lead to the dispersion of the grafted particles in the matrix. Despite the importance of graft molecular weight, and evidence of non-trivial effects of polydispersity of chains grafted on flat surfaces, most theoretical work on polymer grafted nanoparticles has only focused on monodisperse grafted chains. In this paper, we focus on how bidispersity in grafted chain lengths affects the grafted chain conformations and inter-particle interactions in an implicit solvent and in a dense homopolymer polymer matrix. We first present the effects of bidispersity on grafted chain conformations in a single polymer grafted particle using purely Monte Carlo (MC) simulations. This is followed by calculations of the potential of mean force (PMF) between two grafted particles in a polymer matrix using a self-consistent Polymer Reference Interaction Site Model theory-Monte Carlo simulation approach. Monte Carlo simulations of a single polymer grafted particle in an implicit solvent show that in the bidisperse polymer grafted particles with an equal number of short and long grafts at low to medium grafting density, the short grafts are in a more coiled up conformation (lower radius of gyration) than their monodisperse counterparts to provide a larger free volume to the longer grafts so they can gain conformational entropy. The longer grafts do not show much difference in conformation from their monodisperse counterparts at low grafting density, but at medium grafting density the longer grafts exhibit less stretched conformations (lower radius of gyration) as compared to their monodisperse counterparts. In the presence of an explicit homopolymer matrix, the longer grafts are more compressed by the matrix homopolymer chains than the short grafts. We observe that the potential of mean force between bidisperse grafted particles has features of the PMF of monodisperse grafted particles with short grafts and monodisperse grafted particles with long grafts. The value of the PMF at contact is governed by the short grafts and values at large inter-particle distances are governed by the longer grafts. Further comparison of the PMF for bidisperse and monodisperse polymer grafted particles in a homopolymer matrix at varying parameters shows that the effects of matrix chain length, matrix packing fraction, grafting density, and particle curvature on the PMF between bidisperse polymer grafted particles are similar to those seen between monodisperse polymer grafted particles. PMID- 21599088 TI - Stochastic dynamics of complexation reaction in the limit of small numbers. AB - We study stochastic dynamics of the non-linear bimolecular reaction A + B<->AB. These reactions are common in several bio-molecular systems such as binding, complexation, protein multimerization to name a few. We use master equation to compute the full distribution of several stochastic equilibrium properties such as number of complexes formed (N(c)), equilibrium constant (K). We provide exact analytical and simpler approximate expression for equilibrium fluctuation quantities to quickly estimate the amount of noise as a function of reactant molecules and rates. We construct the phase diagram for a fluctuational quantity f, defined as the ratio of standard deviation to average (f=?(DeltaN(c))(2)/N(c)), as a function of different number of reactant molecules and reaction rates. One of the striking result is, it is possible to have f as high as 45% or higher in significant regions of the phase diagram even when number of reactants involved are around 20 40, typical in biology. Our finding indicates studying averages alone using mass action law needs careful scrutiny. We also outline possible application of our findings in gene expression. Furthermore, we compute average and fluctuation properties of time dependent quantities and derive equations of motion for different moments such as N(c)(t) and N(c)(t)(2). While mean-field mass action law fails to reproduce the exact time dependence, approximate solutions of coupled equations of motions for different moments, capturing fluctuation, is in good agreement with exact results. This may be a way to compute time development of averages and fluctuations in such non-linear systems where mass action law breaks down. Moreover, for this reaction, we outline connection to variational principle of maximum caliber and other more traditional approaches such as chemical Langevin equation. We derive noise statistics for the equivalent Langevin equation and show possible departure from Gaussian white noise. We believe quantitative estimates of phase diagrams for noise, time dependent quantities, and simple analytical expression for equilibrium quantities will be particularly useful to guide experiments involving such non-linear reactions with small numbers of reactants that are often encountered in biology. PMID- 21599089 TI - Note: the role of Peierls-like distortions in the modification of electronic bandgaps of graphene nanoribbons under uniaxial strain. PMID- 21599090 TI - Note: on the critical supersaturation for nucleation. PMID- 21599092 TI - Comparison of LES of steady transitional flow in an idealized stenosed axisymmetric artery model with a RANS transitional model. AB - In this study, two different turbulence methodologies are investigated to predict transitional flow in a 75% stenosed axisymmetric experimental arterial model and in a slightly modified version of the model with an eccentric stenosis. Large eddy simulation (LES) and Reynolds-averaged Navier-Stokes (RANS) methods were applied; in the LES simulations eddy viscosity subgrid-scale models were employed (basic and dynamic Smagorinsky) while the RANS method involved the correlation based transitional version of the hybrid k-epsilon/k-omega flow model. The RANS simulations used 410,000 and 820,000 element meshes for the axisymmetric and eccentric stenoses, respectively, with y(+) less than 2 viscous wall units for the boundary elements, while the LES used 1,200,000 elements with y(+) less than 1. Implicit filtering was used for LES, giving an overlap between the resolved and modeled eddies, ensuring accurate treatment of near wall turbulence structures. Flow analysis was carried out in terms of vorticity and eddy viscosity magnitudes, velocity, and turbulence intensity profiles and the results were compared both with established experimental data and with available direct numerical simulations (DNSs) from the literature. The simulation results demonstrated that the dynamic Smagorinsky LES and RANS transitional model predicted fairly comparable velocity and turbulence intensity profiles with the experimental data, although the dynamic Smagorinsky model gave the best overall agreement. The present study demonstrated the power of LES methods, although they were computationally more costly, and added further evidence of the promise of the RANS transition model used here, previously tested in pulsatile flow on a similar model. Both dynamic Smagorinsky LES and the RANS model captured the complex transition phenomena under physiological Reynolds numbers in steady flow, including separation and reattachment. In this respect, LES with dynamic Smagorinsky appeared more successful than DNS in replicating the axisymmetric experimental results, although inflow conditions, which are subject to caveats, may have differed. For the eccentric stenosis, LES with Smagorinsky coefficient of 0.13 gave the closest agreement with DNS despite the known shortcomings of fixed coefficients. The relaminarization as the flow escaped the influence of the stenosis was amply demonstrated in the simulations, graphically so in the case of LES. PMID- 21599093 TI - A microstructurally driven model for pulmonary artery tissue. AB - A new constitutive model for elastic, proximal pulmonary artery tissue is presented here, called the total crimped fiber model. This model is based on the material and microstructural properties of the two main, passive, load-bearing components of the artery wall, elastin, and collagen. Elastin matrix proteins are modeled with an orthotropic neo-Hookean material. High stretch behavior is governed by an orthotropic crimped fiber material modeled as a planar sinusoidal linear elastic beam, which represents collagen fiber deformations. Collagen dependent artery orthotropy is defined by a structure tensor representing the effective orientation distribution of collagen fiber bundles. Therefore, every parameter of the total crimped fiber model is correlated with either a physiologic structure or geometry or is a mechanically measured material property of the composite tissue. Further, by incorporating elastin orthotropy, this model better represents the mechanics of arterial tissue deformation. These advancements result in a microstructural total crimped fiber model of pulmonary artery tissue mechanics, which demonstrates good quality of fit and flexibility for modeling varied mechanical behaviors encountered in disease states. PMID- 21599094 TI - Validation of a new method for finding the rotational axes of the knee using both marker-based roentgen stereophotogrammetric analysis and 3D video-based motion analysis for kinematic measurements. AB - In a previous paper, we reported the virtual axis finder, which is a new method for finding the rotational axes of the knee. The virtual axis finder was validated through simulations that were subject to limitations. Hence, the objective of the present study was to perform a mechanical validation with two measurement modalities: 3D video-based motion analysis and marker-based roentgen stereophotogrammetric analysis (RSA). A two rotational axis mechanism was developed, which simulated internal-external (or longitudinal) and flexion extension (FE) rotations. The actual axes of rotation were known with respect to motion analysis and RSA markers within +/- 0.0006 deg and +/- 0.036 mm and +/- 0.0001 deg and +/- 0.016 mm, respectively. The orientation and position root mean squared errors for identifying the longitudinal rotation (LR) and FE axes with video-based motion analysis (0.26 deg, 0.28 m, 0.36 deg, and 0.25 mm, respectively) were smaller than with RSA (1.04 deg, 0.84 mm, 0.82 deg, and 0.32 mm, respectively). The random error or precision in the orientation and position was significantly better (p=0.01 and p=0.02, respectively) in identifying the LR axis with video-based motion analysis (0.23 deg and 0.24 mm) than with RSA (0.95 deg and 0.76 mm). There was no significant difference in the bias errors between measurement modalities. In comparing the mechanical validations to virtual validations, the virtual validations produced comparable errors to those of the mechanical validation. The only significant difference between the errors of the mechanical and virtual validations was the precision in the position of the LR axis while simulating video-based motion analysis (0.24 mm and 0.78 mm, p=0.019). These results indicate that video-based motion analysis with the equipment used in this study is the superior measurement modality for use with the virtual axis finder but both measurement modalities produce satisfactory results. The lack of significant differences between validation techniques suggests that the virtual sensitivity analysis previously performed was appropriately modeled. Thus, the virtual axis finder can be applied with a thorough understanding of its errors in a variety of test conditions. PMID- 21599095 TI - Estimation of in vivo ACL force changes in response to increased weightbearing. AB - Accurate knowledge of in vivo anterior cruciate ligament (ACL) forces is instrumental for understanding normal ACL function and improving surgical ACL reconstruction techniques. The objective of this study was to estimate the change in ACL forces under in vivo loading conditions using a noninvasive technique. A combination of magnetic resonance and dual fluoroscopic imaging system was used to determine ACL in vivo elongation during controlled weightbearing at discrete flexion angles, and a robotic testing system was utilized to determine the ACL force-elongation data in vitro. The in vivo ACL elongation data were mapped to the in vitro ACL force-elongation curve to estimate the change in in vivo ACL forces in response to full body weightbearing using a weighted mean statistical method. The data demonstrated that by assuming that there was no tension in the ACL under zero weightbearing, the changes in in vivo ACL force caused by full body weightbearing were 131.4 +/- 16.8 N at 15 deg, 106.7 +/- 11.2 N at 30 deg, and 34.6 +/- 4.5 N at 45 deg of flexion. However, when the assumed tension in the ACL under zero weightbearing was over 20 N, the change in the estimated ACL force in response to the full body weightbearing approached an asymptotic value. With an assumed ACL tension of 40 N under zero weightbearing, the full body weight caused an ACL force increase in 202.7 +/- 27.6 N at 15 deg, 184.9 +/- 22.5 N at 30 deg, and 98.6 +/- 11.7 N at 45 deg of flexion. The in vivo ACL forces were dependent on the flexion angle with higher force changes at low flexion angles. Under full body weightbearing, the ACL may experience less than 250 N. These data may provide a valuable insight into the biomechanical behavior of the ACL under in vivo loading conditions. PMID- 21599096 TI - A robotic cadaveric flatfoot analysis of stance phase. AB - The symptomatic flatfoot deformity (pes planus with peri-talar subluxation) can be a debilitating condition. Cadaveric flatfoot models have been employed to study the etiology of the deformity, as well as invasive and noninvasive surgical treatment strategies, by evaluating bone positions. Prior cadaveric flatfoot simulators, however, have not leveraged industrial robotic technologies, which provide several advantages as compared with the previously developed custom fabricated devices. Utilizing a robotic device allows the researcher to experimentally evaluate the flatfoot model at many static instants in the gait cycle, compared with most studies, which model only one to a maximum of three instances. Furthermore, the cadaveric tibia can be statically positioned with more degrees of freedom and with a greater accuracy, and then a custom device typically allows. We created a six degree of freedom robotic cadaveric simulator and used it with a flatfoot model to quantify static bone positions at ten discrete instants over the stance phase of gait. In vivo tibial gait kinematics and ground reaction forces were averaged from ten flatfoot subjects. A fresh frozen cadaveric lower limb was dissected and mounted in the robotic gait simulator (RGS). Biomechanically realistic extrinsic tendon forces, tibial kinematics, and vertical ground reaction forces were applied to the limb. In vitro bone angular position of the tibia, calcaneus, talus, navicular, medial cuneiform, and first metatarsal were recorded between 0% and 90% of stance phase at discrete 10% increments using a retroreflective six-camera motion analysis system. The foot was conditioned flat through ligament attenuation and axial cyclic loading. Post-flat testing was repeated to study the pes planus deformity. Comparison was then made between the pre-flat and post-flat conditions. The RGS was able to recreate ten gait positions of the in vivo pes planus subjects in static increments. The in vitro vertical ground reaction force was within +/- 1 standard deviation (SD) of the in vivo data. The in vitro sagittal, coronal, and transverse plane tibial kinematics were almost entirely within +/- 1 SD of the in vivo data. The model showed changes consistent with the flexible flatfoot pathology including the collapse of the medial arch and abduction of the forefoot, despite unexpected hindfoot inversion. Unlike previous static flatfoot models that use simplified tibial degrees of freedom to characterize only the midpoint of the stance phase or at most three gait positions, our simulator represented the stance phase of gait with ten discrete positions and with six tibial degrees of freedom. This system has the potential to replicate foot function to permit both noninvasive and surgical treatment evaluations throughout the stance phase of gait, perhaps eliciting unknown advantages or disadvantages of these treatments at other points in the gait cycle. PMID- 21599097 TI - Evaluating the bending response of two osseointegrated transfemoral implant systems using 3D digital image correlation. AB - Osseointegrated transfemoral implants have been introduced as a prosthetic solution for above knee amputees. They have shown great promise, providing an alternative for individuals who could not be accommodated by conventional, socket based prostheses; however, the occurrence of device failures is of concern. In an effort to improve the strength and longevity of the device, a new design has been proposed. This study investigates the mechanical behavior of the new taper-based assembly in comparison to the current hex-based connection for osseointegrated transfemoral implant systems. This was done to better understand the behavior of components under loading, in order to optimize the assembly specifications and improve the useful life of the system. Digital image correlation was used to measure surface strains on two assemblies during static loading in bending. This provided a means to measure deformation over the entire sample and identify critical locations as the assembly was subjected to a series of loading conditions. It provided a means to determine the effects of tightening specifications and connection geometry on the material response and mechanical behavior of the assemblies. Both osseoinegrated assemblies exhibited improved strength and mechanical performance when tightened to a level beyond the current specified tightening torque of 12 N m. This was shown by decreased strain concentration values and improved distribution of tensile strain. Increased tightening torque provides an improved connection between components regardless of design, leading to increased torque retention, decreased peak tensile strain values, and a more gradual, primarily compressive distribution of strains throughout the assembly. PMID- 21599098 TI - A mixed boundary representation to simulate the displacement of a biofluid by a biomaterial in porous media. AB - Characterization of the biomaterial flow through porous bone is crucial for the success of the bone augmentation process in vertebroplasty. The biofluid, biomaterial, and local morphological bone characteristics determine the final shape of the filling, which is important both for the post-treatment mechanical loading and the risk of intraoperative extraosseous leakage. We have developed a computational model that describes the flow of biomaterials in porous bone structures by considering the material porosity, the region-dependent intrinsic permeability of the porous structure, the rheological properties of the biomaterial, and the boundary conditions of the filling process. To simulate the process of the substitution of a biofluid (bone marrow) by a biomaterial (bone cement), we developed a hybrid formulation to describe the evolution of the fluid boundary and properties and coupled it to a modified version of Darcy's law. The apparent rheological properties are derived from a fluid-fluid interface tracking algorithm and a mixed boundary representation. The region- specific intrinsic permeability of the bone is governed by an empirical relationship resulting from a fitting process of experimental data. In a first step, we verified the model by studying the displacement process in spherical domains, where the spreading pattern is known in advance. The mixed boundary model demonstrated, as expected, that the determinants of the spreading pattern are the local intrinsic permeability of the porous matrix and the ratio of the viscosity of the fluids that are contributing to the displacement process. The simulations also illustrate the sensitivity of the mixed boundary representation to anisotropic permeability, which is related to the directional dependent microstructural properties of the porous medium. Furthermore, we compared the nonlinear finite element model to different published experimental studies and found a moderate to good agreement (R(2)=0.9895 for a one-dimensional bone core infiltration test and a 10.94-16.92% relative error for a three-dimensional spreading pattern study, respectively) between computational and experimental results. PMID- 21599099 TI - Characterizing heterogeneous properties of cerebral aneurysms with unknown stress free geometry: a precursor to in vivo identification. AB - Knowledge of elastic properties of cerebral aneurysms is crucial for understanding the biomechanical behavior of the lesion. However, characterizing tissue properties using in vivo motion data presents a tremendous challenge. Aside from the limitation of data accuracy, a pressing issue is that the in vivo motion does not expose the stress-free geometry. This is compounded by the nonlinearity, anisotropy, and heterogeneity of the tissue behavior. This article introduces a method for identifying the heterogeneous properties of aneurysm wall tissue under unknown stress-free configuration. In the proposed approach, an accessible configuration is taken as the reference; the unknown stress-free configuration is represented locally by a metric tensor describing the prestrain from the stress-free configuration to the reference configuration. Material parameters are identified together with the metric tensor pointwisely. The paradigm is tested numerically using a forward-inverse analysis loop. An image derived sac is considered. The aneurysm tissue is modeled as an eightply laminate whose constitutive behavior is described by an anisotropic hyperelastic strain energy function containing four material parameters. The parameters are assumed to vary continuously in two assigned patterns to represent two types of material heterogeneity. Nine configurations between the diastolic and systolic pressures are generated by forward quasi-static finite element analyses. These configurations are fed to the inverse analysis to delineate the material parameters and the metric tensor. The recovered and the assigned distributions are in good agreement. A forward verification is conducted by comparing the displacement solutions obtained from the recovered and the assigned material parameters at a different pressure. The nodal displacements are found in excellent agreement. PMID- 21599100 TI - Differential passive and active biaxial mechanical behaviors of muscular and elastic arteries: basilar versus common carotid. AB - Cerebrovascular disease continues to be responsible for significant morbidity and mortality. There is, therefore, a pressing need to understand better the biomechanics of both intracranial arteries and the extracranial arteries that feed these vessels. We used a validated four-fiber family constitutive relation to model passive biaxial stress-stretch behaviors of basilar and common carotid arteries and we developed a new relation to model their active biaxial responses. These data and constitutive relations allow the first full comparison of circumferential and axial biomechanical behaviors between a muscular (basilar) and an elastic (carotid) artery from the same species. Our active model describes the responses by both types of vessels to four doses of the vasoconstrictor endothelin-1 (10(-10)M, 10(-9)M, 10(-8)M, and 10(-7)M) and predicts levels of smooth muscle cell activation associated with basal tone under specific in vitro testing conditions. These results advance our understanding of the biomechanics of intracranial and extracranial arteries, which is needed to understand better their differential responses to similar perturbations in hemodynamic loading. PMID- 21599101 TI - Technical issues in using robots to reproduce joint specific gait. AB - Reproduction of the in vivo motions of joints has become possible with improvements in robot technology and in vivo measuring techniques. A motion analysis system has been used to measure the motions of the tibia and femur of the ovine stifle joint during normal gait. These in vivo motions are then reproduced with a parallel robot. To ensure that the motion of the joint is accurately reproduced and that the resulting data are reliable, the testing frame, the data acquisition system, and the effects of limitations of the testing platform need to be considered. Of the latter, the stiffness of the robot and the ability of the control system to process sequential points on the path of motion in a timely fashion for repeatable path accuracy are of particular importance. Use of the system developed will lead to a better understanding of the mechanical environment of joints and ligaments in vivo. PMID- 21599102 TI - Noise-induced dynamical phase transitions in long-range systems. AB - In the thermodynamic limit, the time evolution of isolated long-range interacting systems is properly described by the Vlasov equation. This equation admits nonequilibrium dynamically stable stationary solutions characterized by a zero order parameter. We show that the presence of external noise sources, such as a heat bath, can reduce their lifetime and induce at a specific time a dynamical phase transition marked by a nonzero order parameter. This transition may be used as a distinctive experimental signature of the temporary existence of nonequilibrium Vlasov-stable states. In particular, we present evidence of a regime characterized by an order parameter pulse. Our analytical results are corroborated by numerical simulations of a paradigmatic long-range model. PMID- 21599103 TI - Dynamics of a thin liquid film with surface rigidity and spontaneous curvature. AB - The effect of rigid surfaces on the dynamics of thin liquid films that are amenable to the lubrication approximation is considered. It is shown that the Helfrich energy of the layer gives rise to additional terms in the time-evolution equations of the liquid film. The dynamics is found to depend on the absolute value of the spontaneous curvature, irrespective of its sign. Due to the additional terms, the effective surface-tension can be negative and an instability at intermediate wavelengths is observed. Furthermore, the dependence of the shape of a droplet on the bending rigidity as well as on the spontaneous curvature is discussed. PMID- 21599104 TI - Helicopter rotation and smectic-isotropic coexistence of strongly attractive rods. AB - Hydrodynamic simulations of strongly attractive rodlike colloids are performed with and without shear flow. In the absence of flow, the isotropic-nematic coexistence becomes isotropic-smectic A, and the interfacial properties clearly vary with increasing attraction strength. In the presence of shear flow, a new collective rotation appears in which the director rotates in the vorticity-flow plane in a similar fashion to the movement of the rotor of a helicopter. PMID- 21599105 TI - Probing structural and dynamical transitions in polymer globules by force. AB - The dynamics of proteins and biopolymers play a crucial role in their function. By using Brownian dynamics we show that polymer globules, which serve as a model system for proteins, undergo a size-dependent dynamical transition from a liquid like state at high T to a frozen state at low T with a relaxation time that diverges at the transition point. Furthermore, a stretch-induced melting transition is shown to be readily controlled by external forces that exploit the polymer connectivity to modify the size of the globule. This pathway could be a general route to enhance the rate of conformational changes in naturally occurring biopolymers. PMID- 21599106 TI - Modeling DNA response to terahertz radiation. AB - Collective response of DNA to terahertz electric fields is studied in a simple pair bond model. We confirm, with some caveats, a previous observation of destabilizing DNA breather modes and explore the parameter dependence of these modes. It is shown that breather modes are eliminated under reasonable physical conditions and that thermal effects are significant. PMID- 21599107 TI - Supernormal conduction in cardiac tissue promotes concordant alternans and action potential bunching. AB - Supernormal conduction (SNC) in excitable cardiac tissue refers to an increase of pulse (or action potential) velocity with decreasing distance to the preceding pulse. Here we employ a simple ionic model to study the effect of SNC on the propagation of action potentials (APs) and the phenomenology of alternans in excitable cardiac tissue. We use bifurcation analysis and simulations to study attraction between propagating APs caused by SNC that leads to AP pairs and bunching. It is shown that SNC stabilizes concordant alternans in arbitrarily long paced one-dimensional cables. As a consequence, spiral waves in two dimensional tissue simulations exhibit straight nodal lines for SNC in contrast to spiraling ones in the case of normal conduction. PMID- 21599108 TI - Imaging three-dimensional rotational diffusion of plasmon resonant gold nanorods using polarization-sensitive optical coherence tomography. AB - We demonstrate depth-resolved viscosity measurements within a single object using polarized optical scattering from ensembles of freely tumbling plasmon resonant gold nanorods (GNRs) monitored with polarization-sensitive optical coherence tomography. The rotational diffusion coefficient of the GNRs is shown to correlate with viscosity in molecular fluids according to the Stokes-Einstein relation. The plasmon resonant and highly anisotropic properties of GNRs are favorable for microrheological studies of nanoscale properties. PMID- 21599109 TI - Dynamics of the Blume-Capel model with quenched diluted single-ion anisotropy in the neighborhood of equilibrium states. AB - The relaxation dynamics of a Blume-Capel model with a quenched diluted crystal field is formulated by a method combining the statistical equilibrium theory and the thermodynamics of linear irreversible processes. Using a mean-field approximation for the magnetic Gibbs free-energy production, a generalized force and a current are defined within the irreversible thermodynamics. Next the kinetic equation for the magnetization is obtained within linear response theory. Finally, the temperature dependence of the relaxation time in the neighborhood of the phase-transition points is obtained by solving the kinetic equation of the magnetization. We find that the relaxation time of the order parameter diverges near the critical and multicritical points, which corresponds to the familiar critical slowing down. On the other hand, it displays different behavior at the first-order phase transitions. It has a jump discontinuity at the first-order phase-transition temperatures. Moreover, the z dynamic critical exponent is calculated and compared with the z values obtained for a diverse class of systems, and good agreement is found with our results. PMID- 21599110 TI - Distribution of first-return times in correlated stationary signals. AB - We present an analytical expression for the first return time (FRT) probability density function of a stationary correlated signal. Precisely, we start by considering a stationary discrete-time Ornstein-Uhlenbeck (OU) process with exponential decaying correlation function. The first return time distribution for this process is derived by adopting a well-known formalism typically used in the study of the FRT statistics for nonstationary diffusive processes. Then, by a subordination approach, we treat the case of a stationary process with power-law tail correlation function and diverging correlation time. We numerically test our findings, obtaining in both cases a good agreement with the analytical results. We notice that neither in the standard OU nor in the subordinated case a simple form of waiting time statistics, like stretched-exponential or similar, can be obtained while it is apparent that long time transient may shadow the final asymptotic behavior. PMID- 21599111 TI - Harmonic oscillator in heat bath: exact simulation of time-lapse-recorded data and exact analytical benchmark statistics. AB - The stochastic dynamics of the damped harmonic oscillator in a heat bath is simulated with an algorithm that is exact for time steps of arbitrary size. Exact analytical results are given for correlation functions and power spectra in the form they acquire when computed from experimental time-lapse recordings. Three applications are discussed: (i) The effects of finite sampling rate and time, described exactly here, are similar for other stochastic dynamical systems--e.g., motile microorganisms and their time-lapse-recorded trajectories. (ii) The same statistics is satisfied by any experimental system to the extent that it is interpreted as a damped harmonic oscillator at finite temperature-such as an AFM cantilever. (iii) Three other models of fundamental interest are limiting cases of the damped harmonic oscillator at finite temperature; it consequently bridges their differences and describes the effects of finite sampling rate and sampling time for these models as well. PMID- 21599112 TI - Non-Markovian dynamics of an open quantum system with nonstationary coupling. AB - The spectral, dissipative, and statistical properties of the damped quantum oscillator are studied in the case of non-Markovian and nonstationary system-heat bath coupling. The dissipation of collective energy is shown to be slowed down, and the decoherence rate and entropy grow with modulation frequency. PMID- 21599113 TI - How many eigenvalues of a Gaussian random matrix are positive? AB - We study the probability distribution of the index N(+), i.e., the number of positive eigenvalues of an N*N Gaussian random matrix. We show analytically that, for large N and large N(+) with the fraction 0<=c=N(+)/N<=1 of positive eigenvalues fixed, the index distribution P(N(+)=cN,N)~exp[-betaN(2)Phi(c)] where beta is the Dyson index characterizing the Gaussian ensemble. The associated large deviation rate function Phi(c) is computed explicitly for all 0<=c<=1. It is independent of beta and displays a quadratic form modulated by a logarithmic singularity around c=1/2. As a consequence, the distribution of the index has a Gaussian form near the peak, but with a variance Delta(N) of index fluctuations growing as Delta(N)~lnN/betapi(2) for large N. For beta=2, this result is independently confirmed against an exact finite-N formula, yielding Delta(N)=lnN/2pi(2)+C+O(N(-1)) for large N, where the constant C for even N has the nontrivial value C=(gamma+1+3ln2)/2pi(2)?0.185 248... and gamma=0.5772... is the Euler constant. We also determine for large N the probability that the interval [zeta(1),zeta(2)] is free of eigenvalues. Some of these results have been announced in a recent letter [Phys. Rev. Lett. 103, 220603 (2009)]. PMID- 21599114 TI - Quantum transport through hierarchical structures. AB - The transport of quantum electrons through hierarchical lattices is of interest because such lattices have some properties of both regular lattices and random systems. We calculate the electron transmission as a function of energy in the tight-binding approximation for two related Hanoi networks. HN3 is a Hanoi network with every site having three bonds. HN5 has additional bonds added to HN3 to make the average number of bonds per site equal to five. We present a renormalization group approach to solve the matrix equation involved in this quantum transport calculation. We observe band gaps in HN3, while no such band gaps are observed in linear networks or in HN5. We provide a detailed scaling analysis near the edges of these band gaps. PMID- 21599115 TI - Statistics of reciprocal distances for random walks of three particles in one dimension. AB - We investigate the collective properties of three particles performing both independent and interacting random walks on an infinite line by studying the problem on the corresponding distance graph. In the large times limit, we obtain the asymptotically exact behavior of several probability functions regarding maximum and minimum mutual distances among particles. Finally, we suggest possible applications of our results. PMID- 21599116 TI - Diffusion over a fluctuating barrier in underdamped dynamics. AB - We apply a Langevin model by imposing additive and multiplicative noises to study thermally activated diffusion over a fluctuating barrier in underdamped dynamics. The barrier fluctuation is characterized by Gaussian colored noise with exponential correlation. We present the exact solutions for the first and second moments. Furthermore, we use direct simulations to calculate the asymptotic probability for a Brownian particle passing over the fluctuating barrier. The results indicate that the correlation of the fluctuating barrier is crucial for barrier crossing dynamics. PMID- 21599117 TI - Ground state entropy of the Potts antiferromagnet on homeomorphic expansions of kagome lattice strips. AB - We present exact calculations of the chromatic polynomial and resultant ground state entropy of the q-state Potts antiferromagnet on lattice strips that are homeomorphic expansions of a strip of the kagome lattice. The dependence of the ground state entropy on the form of homeomorphic expansion is elucidated. PMID- 21599118 TI - Nonequilibrium phase transition in a driven Potts model with friction. AB - We consider magnetic friction between two systems of q-state Potts spins which are moving along their boundaries with a relative constant velocity nu. Due to the interaction between the surface spins there is a permanent energy flow and the system is in a steady state, which is far from equilibrium. The problem is treated analytically in the limit nu=infinity (in one dimension, as well as in two dimensions for large-q values) and for v and q finite by Monte Carlo simulations in two dimensions. Exotic nonequilibrium phase transitions take place, the properties of which depend on the type of phase transition in equilibrium. When this latter transition is of first order, a sequence of second- and first-order nonequilibrium transitions can be observed when the interaction is varied. PMID- 21599119 TI - Minimal model of financial stylized facts. AB - In this work we propose a statistical characterization of a linear stochastic volatility model featuring inverse-gamma stationary distribution for the instantaneous volatility. We detail the derivation of the moments of the return distribution, revealing the role of the inverse-gamma law in the emergence of fat tails and of the relevant correlation functions. We also propose a systematic methodology for estimating the parameters and we describe the empirical analysis of the Standard & Poor's 500 index daily returns, confirming the ability of the model to capture many of the established stylized facts as well as the scaling properties of empirical distributions over different time horizons. PMID- 21599120 TI - Bose-Einstein condensation and a two-dimensional walk model. AB - We introduce a two-dimensional walk model in which a random walker can only move on the first quarter of a two-dimensional plane. We calculate the partition function of this walk model using a transfer matrix method and show that the model undergoes a phase transition. Surprisingly the partition function of this two-dimensional walk model is exactly equal to that of a driven-diffusive system defined on a discrete lattice with periodic boundary conditions in which a phase transition occurs from a high-density to a low-density phase. The driven diffusive system can be mapped to a zero-range process where the particles can accumulate in a single lattice site in the low-density phase. This is very reminiscent of real-space Bose-Einstein condensation. PMID- 21599121 TI - Force measurement in the presence of Brownian noise: equilibrium-distribution method versus drift method. AB - The study of microsystems and the development of nanotechnologies require alternative techniques to measure piconewton and femtonewton forces at microscopic and nanoscopic scales. Among the challenges is the need to deal with the ineluctable thermal noise, which, in the typical experimental situation of a spatial diffusion gradient, causes a spurious drift. This leads to a correction term when forces are estimated from drift measurements [G. Volpe, L. Helden, T. Brettschneider, J. Wehr, and C. Bechinger, Phys. Rev. Lett. 104, 170602 (2010)]. Here we provide a systematic study of such an effect by comparing the forces acting on various Brownian particles derived from equilibrium-distribution and drift measurements. We discuss the physical origin of the correction term, its dependence on wall distance and particle radius, and its relation to the convention used to solve the respective stochastic integrals. Such a correction term becomes more significant for smaller particles and is predicted to be on the order of several piconewtons for particles the size of a biomolecule. PMID- 21599122 TI - Influence of measurements on the statistics of work performed on a quantum system. AB - The recently demonstrated robustness of fluctuation theorems against measurements [M. Campisi, P. Talkner, and P. Hanggi, Phys. Rev. Lett. 105, 140601 (2010).] does not imply that the probability distributions of nonequilibrium quantities, such as heat and work, remain unaffected. We determine the impact of measurements that are performed during a running force protocol on the characteristic function of work. The results are illustrated by means of the Landau-Zener(-Stuckelberg Majorana) model. In the limit of continuous measurements the quantum Zeno effect suppresses any unitary dynamics. It is demonstrated that the characteristic function of work is the same as for an adiabatic protocol when the continuously measured quantity coincides with the Hamiltonian governing the unitary dynamics of the system in the absence of measurements. PMID- 21599123 TI - Anomalies and absence of local equilibrium, and universality, in one-dimensional particles systems. AB - One-dimensional systems are under intense investigation, both from theoretical and experimental points of view, since they have rather peculiar characteristics which are of both conceptual and technological interest. We analyze the dependence of the behavior of one-dimensional, time-reversal invariant, nonequilibrium systems on the parameters defining their microscopic dynamics. In particular, we consider chains of identical oscillators interacting via hard-core elastic collisions and harmonic potentials, driven by boundary Nose-Hoover thermostats. Their behavior mirrors qualitatively that of stochastically driven systems, showing that anomalous properties are typical of physics in one dimension. Chaos, by itself, does not lead to standard behavior, since it does not guarantee local thermodynamic equilibrium. A linear relation is found between density fluctuations and temperature profiles. This link and the temporal asymmetry of fluctuations of the main observables are robust against modifications of thermostat parameters and against perturbations of the dynamics. PMID- 21599124 TI - Prediction of the collapse point of overloaded materials by monitoring energy emissions. AB - A bundle of many fibers with stochastically distributed breaking thresholds is considered as a model of composite materials. The fibers are assumed to share the load equally and to obey Hookean elasticity up to the breaking point. The bundle is slightly overloaded which leads to complete failure. We study the properties of emission bursts in which an amount of energy E is released. The analysis shows that the size of the energy bursts has a minimum when the system is halfway from the collapse point. PMID- 21599125 TI - Maximum-power quantum-mechanical Carnot engine. AB - In their work [J. Phys. A 33, 4427 (2000)], Bender, Brody, and Meister have shown by employing a two-state model of a particle confined in the one-dimensional infinite potential well that it is possible to construct a quantum-mechanical analog of the Carnot engine through changes of both the width of the well and the quantum state in a specific manner. Here, a discussion is developed about realizing the maximum power of such an engine, where the width of the well moves at low but finite speed. The efficiency of the engine at the maximum power output is found to be universal independently of any of the parameters contained in the model. PMID- 21599126 TI - Harmonic oscillator under Levy noise: unexpected properties in the phase space. AB - A harmonic oscillator under the influence of noise is a basic model of various physical phenomena. Under Gaussian white noise the position and velocity of the oscillator are independent random variables which are distributed according to the bivariate Gaussian distribution with elliptic level lines. The distribution of phase is homogeneous. None of these properties hold in the general Levy case. Thus, the level lines of the joint probability density are not elliptic. The coordinate and the velocity of the oscillator are strongly dependent, and this dependence is quantified by introducing the corresponding parameter ("width deficit"). The distribution of the phase is inhomogeneous and highly nontrivial. PMID- 21599127 TI - Work statistics of charged noninteracting fermions in slowly changing magnetic fields. AB - We consider N fermionic particles in a harmonic trap initially prepared in a thermal equilibrium state at temperature beta^{-1} and examine the probability density function (pdf) of the work done by a magnetic field slowly varying in time. The behavior of the pdf crucially depends on the number of particles N but also on the temperature. At high temperatures (beta?1) the pdf is given by an asymmetric Laplace distribution for a single particle, and for many particles it approaches a Gaussian distribution with variance proportional to N/beta(2). At low temperatures the pdf becomes strongly peaked at the center with a variance that still linearly increases with N but exponentially decreases with the temperature. We point out the consequences of these findings for the experimental confirmation of the Jarzynski equality such as the low probability issue at high temperatures and its solution at low temperatures, together with a discussion of the crossover behavior between the two temperature regimes. PMID- 21599128 TI - Numerical study of the phase transitions in the two-dimensional Z(5) vector model. AB - We investigate the critical properties of the two-dimensional Z(5) vector model. For this purpose, we propose a cluster algorithm, valid for Z(N) models with odd values of N. The two-dimensional Z(5) vector model is conjectured to exhibit two phase transitions with a massless intermediate phase. We locate the position of the critical points and study the critical behavior across both phase transitions in details. In particular, we determine various critical indices and compare the results with analytical predictions. PMID- 21599129 TI - Generating function formula of heat transfer in harmonic networks. AB - We consider heat transfer across an arbitrary classical harmonic network connected to two heat baths at different temperatures. The network has N positional degrees of freedom, of which N(L) are connected to a bath at temperature T(L) and N(R) are connected to a bath at temperature T(R). We derive an exact formula for the cumulant generating function for heat transfer between the two baths. The formula is valid even for N(L)?N(R) and satisfies the Gallavotti-Cohen fluctuation symmetry. Since harmonic crystals in three dimensions are known to exhibit different regimes of transport such as ballistic, anomalous, and diffusive, our result implies validity of the fluctuation theorem in all regimes. Our exact formula provides a powerful tool to study other properties of nonequilibrium current fluctuations. PMID- 21599130 TI - Resonant activation in piecewise linear asymmetric potentials. AB - This work analyzes numerically the role played by the asymmetry of a piecewise linear potential, in the presence of both a Gaussian white noise and a dichotomous noise, on the resonant activation phenomenon. The features of the asymmetry of the potential barrier arise by investigating the stochastic transitions far behind the potential maximum, from the initial well to the bottom of the adjacent potential well. Because of the asymmetry of the potential profile together with the random external force uniform in space, we find, for the different asymmetries: (1) an inversion of the curves of the mean first passage time in the resonant region of the correlation time tau of the dichotomous noise, for low thermal noise intensities; (2) a maximum of the mean velocity of the Brownian particle as a function of tau; and (3) an inversion of the curves of the mean velocity and a very weak current reversal in the miniratchet system obtained with the asymmetrical potential profiles investigated. An inversion of the mean first passage time curves is also observed by varying the amplitude of the dichotomous noise, behavior confirmed by recent experiments. PMID- 21599131 TI - Cyclotron-Bloch dynamics of a quantum particle in a two-dimensional lattice. AB - This paper studies the quantum dynamics of a charged particle in a two dimensional square lattice, under the influence of electric and magnetic fields, the former being aligned with one of the lattice axes and the latter perpendicular to the lattice plane. While in free space these dynamics consist of uniform motions in the direction orthogonal to the electric field vector, we find that, in a lattice, this directed drift takes place only for specific initial conditions and for electric field magnitudes smaller than a critical value. Otherwise, the quantum wave packet spreads ballistically in both directions orthogonal to the electric field. We quantify this ballistic spreading and identify the subspace of initial conditions ensuring directed transport with the drift velocity. We also describe the effect of disorder in the system. PMID- 21599132 TI - Reaction-rate theory with account of the crystal anharmonicity. AB - Reaction rate theory in solids is modified taking into account intrinsic localized modes or discrete breathers (DBs) that can appear in crystals with sufficient anharmonicity, resulting in violation of Arrhenius' law. Large amplitude oscillations of atoms about their equilibrium positions in the lattice cause local potentials of alternating sign, which are described in terms of time periodic modulations of the potential barriers for chemical reactions taking place in the vicinity of DBs. The reaction rate averaged over large macroscopic volumes and times including many DBs is increased by a factor that depends on the DB statistics. The breather statistics in thermal equilibrium and in thermal spikes in solids under irradiation with swift particles is considered, and the corresponding reaction rate amplification factors are derived. PMID- 21599133 TI - Smoluchowski dynamics and the ergodic-nonergodic transition. AB - We use the recently introduced theory for the kinetics of systems of classical particles to investigate systems driven by Smoluchowski dynamics. We investigate the existence of ergodic-nonergodic (ENE) transitions near the liquid-glass transition. We develop a self-consistent perturbation theory in terms of an effective two-body potential and work to second order in this potential. At second order, we have an explicit relationship between the static structure factor and the effective potential and choose the static structure factor in the case of hard spheres to be given by the solution of the Percus-Yevick approximation for hard spheres. Then, using the analytically determined ENE equation for the ergodicity function, we find an ENE transition for packing fraction eta greater than a critical value eta(*)=0.76, which is physically unaccessible. The existence of a linear fluctuation-dissipation theorem in the problem is shown and used to great advantage. PMID- 21599134 TI - Fluctuation-dissipation relation for nonlinear Langevin equations. AB - It is shown that the fluctuation-dissipation theorem is satisfied by the solutions of a general set of nonlinear Langevin equations with a quadratic free energy functional (constant susceptibility) and field-dependent kinetic coefficients, provided the kinetic coefficients satisfy the Onsager reciprocal relations for the irreversible terms and the antisymmetry relations for the reversible terms. The analysis employs a perturbation expansion of the nonlinear terms, and a functional integral calculation of the correlation and response functions, and it is shown that the fluctuation-dissipation relation is satisfied at each order in the expansion. PMID- 21599135 TI - Determinantal correlations of Brownian paths in the plane with nonintersection condition on their loop-erased parts. AB - As an image of the many-to-one map of loop-erasing operation L of random walks, a self-avoiding walk (SAW) is obtained. The loop-erased random walk (LERW) model is the statistical ensemble of SAWs such that the weight of each SAW zeta is given by the total weight of all random walks pi that are inverse images of zeta, {pi:L(pi)=zeta}. We regard the Brownian paths as the continuum limits of random walks and consider the statistical ensemble of loop-erased Brownian paths (LEBPs) as the continuum limits of the LERW model. Following the theory of Fomin on nonintersecting LERWs, we introduce a nonintersecting system of N-tuples of LEBPs in a domain D in the complex plane, where the total weight of nonintersecting LEBPs is given by Fomin's determinant of an N*N matrix whose entries are boundary Poisson kernels in D. We set a sequence of chambers in a planar domain and observe the first passage points at which N Brownian paths (gamma_{1},...,gamma_{N}) first enter each chamber, under the condition that the loop-erased parts [L(gamma(1)),...,L(gamma(N))] make a system of nonintersecting LEBPs in the domain in the sense of Fomin. We prove that the correlation functions of first passage points of the Brownian paths of the present system are generally given by determinants specified by a continuous function called the correlation kernel. The correlation kernel is of Eynard-Mehta type, which has appeared in two-matrix models and time-dependent matrix models studied in random matrix theory. Conformal covariance of correlation functions is demonstrated. PMID- 21599136 TI - Density of states and quantum phase transition in the thermodynamic limit of the Mermin central-spin model. AB - We apply a spin-coherent states formalism to study the simplest version of a central-spin model, the so-called Mermin model, in which a given (central) spin 1/2 interacts symmetrically with a "bath" composed of N spins 1/2, characterized by a common frequency. The symmetric interaction allows one to restrict the problem to the fully symmetric sector of the Hilbert space associated with these N spins and therefore to treat these as one large N/2 spin. In particular, we derive analytic expressions for the integrated density of states in the thermodynamic limit when the number of bath spins is taken to infinity. From the thermodynamic limit spectrum we show the phase diagram for the system can be divided into four regions, partitioned, on the one hand, into a symmetric (nondegenerate) phase or a broken symmetry (degenerate) phase, and, on the other hand, by the case of overlapping or nonoverlapping energy surfaces. The nature and position of singularities appearing in the energy surfaces change as one moves from region to region. Our spin-coherent states formalism naturally leads us to the Majorana representation, which is useful to transform the Schrodinger equation into a Ricatti-like form that can be solved in the thermodynamic limit to obtain closed-form expressions for the integrated density of states. The energy surface singularities correspond with critical points in the density of states. We then use our results to compute expectation values for the system that help to characterize the nature of the quantum phase transition between the symmetric and broken phases. PMID- 21599137 TI - Realm of validity of the Crooks relation. AB - We consider the distribution P(Phi) of the Hatano-Sasa entropy, Phi, in reversible and irreversible processes, finding that the Crooks relation for the ratio of the probability density functions of the forward and backward processes, P(F)(Phi)/P(R)(-Phi)=e(Phi), is satisfied not only for reversible, but also for irreversible processes, in general, in the adiabatic limit of "slow processes." Focusing on systems with a finite set of discrete states (and no absorbing states), we observe that two-state systems always fulfill detailed balance, and obey the Crooks relation. We also identify a wide class of systems, with more than two states, that can be "coarse grained" into two-state systems and obey the Crooks relation despite their irreversibility and violation of detailed balance. We verify these results in selected cases numerically. PMID- 21599138 TI - Irreversible thermodynamics in multiscale stochastic dynamical systems. AB - This work extends the results of a recently developed theory of a rather complete thermodynamic formalism for discrete-state, continuous-time Markov processes with and without detailed balance. We investigate whether and in what way the thermodynamic structure is invariant in a multiscale stochastic system, that is, whether the relations between thermodynamic functions of state and process variables remain unchanged when the system is viewed at different time scales and resolutions. Our results show that the dynamics on a fast time scale contribute an entropic term to the internal energy function u(S)(x) for the slow dynamics. Based on the conditional free energy u(S)(x), we can then treat the slow dynamics as if the fast dynamics is nonexistent. Furthermore, we show that the free energy, which characterizes the spontaneous organization in a system without detailed balance, is invariant with or without the fast dynamics: The fast dynamics is assumed to reach stationarity instantaneously on the slow time scale; it has no effect on the system's free energy. The same cannot be said for the entropy and the internal energy, both of which contain the same contribution from the fast dynamics. We also investigate the consequences of time-scale separation in connection to the concepts of quasi-stationarity and steady adiabaticity introduced in the phenomenological steady-state thermodynamics. PMID- 21599139 TI - Autonomous modular quantum systems: contextual Jarzynski relations. AB - For autonomous quantum systems with modular structure we demonstrate that the Jarzynski relation can be reinterpreted to apply even locally: For this purpose certain contexts have to be introduced by selecting the system of interest versus its environment. The respective energy exchange is then divided into heat and work based on a generalized definition of these notions. In this way we are able to identify functional parts of the environment as either heat or work sources, respectively. We investigate different combinations of these functional parts with respect to contextual Jarzynski relations. Our analytical results are confirmed by numerical investigations on small multipartite systems. PMID- 21599140 TI - Continuous-time random walk with a superheavy-tailed distribution of waiting times. AB - We study the long-time behavior of the probability density associated with the decoupled continuous-time random walk which is characterized by a superheavy tailed distribution of waiting times. It is shown that, if the random walk is unbiased (biased) and the jump distribution has a finite second moment, then the properly scaled probability density converges in the long-time limit to a symmetric two-sided (an asymmetric one-sided) exponential density. The convergence occurs in such a way that all the moments of the probability density grow slower than any power of time. As a consequence, the reference random walk can be viewed as a generic model of superslow diffusion. A few examples of superheavy-tailed distributions of waiting times that give rise to qualitatively different laws of superslow diffusion are considered. PMID- 21599141 TI - Ideal quantum gas in an expanding cavity: nature of nonadiabatic force. AB - We consider a quantum gas of noninteracting particles confined in the expanding cavity and investigate the nature of the nonadiabatic force which is generated from the gas and acts on the cavity wall. First, with use of the time-dependent canonical transformation, which transforms the expanding cavity to the nonexpanding one, we can define the force operator. Second, applying the perturbative theory, which works when the cavity wall begins to move at time origin, we find that the nonadiabatic force is quadratic in the wall velocity and thereby does not break the time-reversal symmetry, in contrast with general belief. Finally, using an assembly of the transitionless quantum states, we obtain the nonadiabatic force exactly. The exact result justifies the validity of both the definition of the force operator and the issue of the perturbative theory. The mysterious mechanism of nonadiabatic transition with the use of transitionless quantum states is also explained. The study is done for both cases of the hard- and soft-wall confinement with the time-dependent confining length. PMID- 21599142 TI - Renormalization-group computation of the critical exponents of hierarchical spin glasses: large-scale behavior and divergence of the correlation length. AB - In a recent work [M. Castellana and G. Parisi, Phys. Rev. E 82, 040105(R) (2010)], the large-scale behavior of the simplest non-mean-field spin-glass system has been analyzed, and the critical exponent related to the divergence of the correlation length has been computed at two loops within the epsilon expansion technique by two independent methods. By performing the explicit calculation of the critical exponents at two loops, one obtains that the two methods yield the same result. This shows that the underlying renormalization group ideas apply consistently in this disordered model, in such a way that an epsilon-expansion can be set up. The question of the extension to high orders of this epsilon-expansion is particularly interesting from the physical point of view. Indeed, once high orders of the series in epsilon for the critical exponents are known, one could check the convergence properties of the series, and find out if the ordinary series resummation techniques, yielding very accurate predictions for the Ising model, work also for this model. If this is the case, a consistent and predictive non-mean-field theory for such a disordered system could be established. In that regard, in this work we expose the underlying techniques of such a two-loop computation. We show with an explicit example that such a computation could be quite easily automatized, i.e., performed by a computer program, in order to compute high orders of the epsilon expansion, and so eventually make this theory physically predictive. Moreover, all the underlying renormalization group ideas implemented in such a computation are widely discussed and exposed. PMID- 21599143 TI - Network inference using asynchronously updated kinetic Ising model. AB - Network structures are reconstructed from dynamical data by respectively naive mean field (nMF) and Thouless-Anderson-Palmer (TAP) approximations. TAP approximation adds simple corrections to the nMF approximation, taking into account the effect of the focused spin on itself via its influence on other neighboring spins. For TAP approximation, we use two methods to reconstruct the network: (a) iterative method; (b) casting the inference formula to a set of cubic equations and solving it directly. We investigate inference of the asymmetric Sherrington-Kirkpatrick (aS-K) model using asynchronous update. The solutions of the set of cubic equations depend on temperature T in the aS-K model, and a critical temperature T(c)~2.1 is found. The two methods for TAP approximation produce the same results when the iterative method is convergent. Compared to nMF, TAP is somewhat better at low temperatures, but approaches the same performance as temperature increases. Both nMF and TAP approximation reconstruct better for longer data length L, but for the degree of improvement, TAP performs better than nMF. PMID- 21599144 TI - Binary dusty plasma Coulomb balls. AB - We investigated the mixing and segregation of a system consisting of two different species of particles, having different charges, interacting through a pure Coulomb potential, and confined in a three-dimensional parabolic trap. The structure of the cluster and its normal mode spectrum are analyzed as a function of the relative charge and the relative number of different types of particles. We found that (a) the system can be in a mixed or segregated state depending on the relative charge ratio parameter and (b) the segregation process is mediated by a first or second order structural phase transition which strongly influences the magic cluster properties of the system. PMID- 21599145 TI - Collision densities and mean residence times for d-dimensional exponential flights. AB - In this paper we analyze some aspects of exponential flights, a stochastic process that governs the evolution of many random transport phenomena, such as neutron propagation, chemical or biological species migration, and electron motion. We introduce a general framework for d-dimensional setups and emphasize that exponential flights represent a deceivingly simple system, where in most cases closed-form formulas can hardly be obtained. We derive a number of exact (where possible) or asymptotic results, among which are the stationary probability density for two-dimensional systems, a long-standing issue in physics, and the mean residence time in a given volume. Bounded or unbounded domains as well as scattering or absorbing domains are examined, and Monte Carlo simulations are performed so as to support our findings. PMID- 21599146 TI - Zwanzig-Mori equation for the time-dependent pair distribution function. AB - We develop a microscopic theoretical framework for the time-dependent pair distribution function starting from the Liouville equation. An exact Zwanzig-Mori equation of motion for the time-dependent pair distribution function is derived based on the projection-operator formalism. It is demonstrated that, under the Markovian approximation, our equation reduces to the so-called telegraph equation that includes the potential of mean force acting between the pair particles. With the additional approximation neglecting the inertia term, our equation takes the form of Smoluchowski's equation, which has been previously introduced with intuitive arguments and shown to satisfactorily reproduce the simulation results of the particle-pair dynamics. PMID- 21599147 TI - Local origins of volume fraction fluctuations in dense granular materials. AB - Fluctuations of the local volume fraction within granular materials have previously been observed to decrease as the system approaches jamming. We experimentally examine the role of boundary conditions and interparticle friction MU on this relationship for a dense granular material of bidisperse particles driven under either constant volume or constant pressure. Using a radical Voronoi tessellation, we find the variance of the local volume fraction Phi monotonically decreases as the system becomes more dense, independent of boundary condition and MU. We examine the universality and origins of this trend using experiments and the recent granocentric model [M. Clusel, E. I. Corwin, A. O. N. Siemens, and J. Brujic, Nature (London) 460, 611 (2009); E. I. Corwin, M. Clusel, A. O. N. Siemens, and J. Brujic, Soft Matter 6, 2949 (2010)], modified to draw particle locations from an arbitrary distribution P(s) of neighbor distances s. The mean and variance of the observed P(s) are described by a single length scale controlled by Phi. Through the granocentric model, we observe that diverse functional forms of P(s) all produce the trend of decreasing fluctuations, but only the experimentally observed P(s) provides quantitative agreement with the measured Phi fluctuations. Thus, we find that both P(s) and P(Phi) encode similar information about the ensemble of observed packings and are connected to each other by the local granocentric model. PMID- 21599148 TI - Viscoelastic behaviors in polymeric nanodroplet collisions. AB - Viscoelastic behaviors in the head-on collisions of polymeric nanodroplets are reported. We propose a new model for normal forces between two colliding droplets. By decomposing the force into an elastic component and a dissipative component and carefully analyzing the equation of motion, we obtain some conditions on the model parameters imposed by the thermodynamic arguments. By employing molecular dynamics simulations, we can explicitly determine the corresponding model parameters by fitting. We compare the model predictions with the simulation results. PMID- 21599149 TI - Fluctuating Navier-Stokes equations for inelastic hard spheres or disks. AB - Starting from the fluctuating Boltzmann equation for smooth inelastic hard spheres or disks, closed equations for the fluctuating hydrodynamic fields to Navier-Stokes order are derived. This requires deriving constitutive relations for both the fluctuating fluxes and the correlations of the random forces. The former are identified as having the same form as the macroscopic average fluxes and involving the same transport coefficients. On the other hand, the random force terms exhibit two peculiarities as compared with their elastic limit for molecular systems. First, they are not white but have some finite relaxation time. Second, their amplitude is not determined by the macroscopic transport coefficients but involves new coefficients. PMID- 21599150 TI - Two-ball problem revisited: limitations of event-driven modeling. AB - The main precondition of simulating systems of hard particles by means of event driven modeling is the assumption of instantaneous collisions. The aim of this paper is to quantify the deviation of event-driven modeling from the solution of Newton's equation of motion using a paradigmatic example: If a tennis ball is held above a basketball with their centers vertically aligned, and the balls are released to collide with the floor, the tennis ball may rebound at a surprisingly high speed. We show in this article that the simple textbook explanation of this effect is an oversimplification, even for the limit of perfectly elastic particles. Instead, there may occur a rather complex scenario including multiple collisions which may lead to a very different final velocity as compared with the velocity resulting from the oversimplified model. PMID- 21599151 TI - Rheology of evolving bidisperse granular media. AB - We investigate the mixing of bidisperse distributions of spherical particles for slowly rotating vanes by pouring smaller beads, diameter d(1), onto a monodisperse bed composed of larger beads, diameter d(0), and monitoring the torque and lift forces. If the mixing beads are too small, d(1)/d(0)<0.05, the drag and lift are unaltered. Otherwise smaller beads displace larger beads from the shearing region, and if present in sufficient quantity both the drag and lift diminish to values of a monodisperse bed composed entirely of the smaller beads. We observe reductions in the torque up to 70%. The rate at which smaller beads leave the shearing region decreases as their size relative to the larger beads increases, and for d(1)/d(0)>0.155 the smaller beads remain inside the shearing region. PMID- 21599152 TI - Renormalized jellium mean-field approximation for binary mixtures of charged colloids. AB - In this work the renormalized jellium model of colloidal suspensions, originally proposed by Trizac and Levin [Phys. Rev. E 69, 031403 (2004)], is extended to study mechanisms of charge renormalization in binary mixtures of charged colloids. We here apply our recent reformulation that introduces the requirement of self-consistency directly into the Poisson-Boltzmann equation, i.e., the background charge is explicitly replaced by the effective one, thus facilitating the whole charge renormalization scheme. We briefly discuss the reformulated model for monodisperse charged suspensions composed of either spheres or rods. In particular, we put emphasis on the effects of the surface charge variation, mixture composition, and particle size on the charge regulation of charge stabilized colloidal suspensions. PMID- 21599153 TI - Strain-accelerated dynamics of soft colloidal glasses. AB - We have investigated strain-accelerated dynamics of soft glasses theoretically and experimentally. Mechanical rheology measurements performed on a variety of systems reveal evidence for the speeding-up of relaxation at modest shear strains in both step and oscillatory shear flows. Using the soft glassy rheology (SGR) model framework, we show that the observed behavior is a fundamental, but heretofore unexplored attribute of soft glasses. PMID- 21599154 TI - Colloidal ionic complexes on periodic substrates: ground-state configurations and pattern switching. AB - We theoretically and numerically studied ordering of "colloidal ionic clusters" on periodic substrate potentials such as those generated by optical trapping. Each cluster consists of three charged spherical colloids: two negatively and one positively charged. The substrate is a square or rectangular array of traps, each confining one such cluster. By varying the lattice constant from large to small, the observed clusters are first rodlike and form ferro- and antiferrolike phases, then they bend into a bananalike shape, and finally they condense into a percolated structure. Remarkably, in a broad parameter range between single cluster and percolated structures, we have found stable supercomplexes composed of six colloids forming grapelike or rocketlike structures. We investigated the possibility of macroscopic pattern switching by applying external electrical fields. PMID- 21599155 TI - Elastoplastic flow of a foam around an obstacle. AB - We simulate quasistatic flows of an ideal two-dimensional monodisperse foam around different obstacles, both symmetric and asymmetric, in a channel. We record both pressure and network contributions to the drag and lift forces and study them as a function of obstacle geometry. We show that the drag force increases linearly with the cross section of an obstacles. The lift on an asymmetric aerofoil-like shape is negative and increases with its arc length, mainly due to the pressure contribution. PMID- 21599156 TI - Percolation-induced conductor-insulator transition in a system of metal spheres in a dielectric fluid. AB - We develop a model to investigate the insulator-conductor transition observed in a system of spherical metal particles suspended in a quasi-two-dimensional viscous liquid between planar electrodes when the voltage of the electrodes is increased. Our model captures the main ingredients of the process in experimental system, and reveals the insulator-conductor transition at a well-defined critical voltage. Based on the simulation data we demonstrate that characteristic quantities of the system show power-law scaling in the vicinity of the critical point. These scaling analysis show clearly that the transition between the insulating and conducting phases is analogous to second-order phase transitions. PMID- 21599157 TI - Activated dynamics in dense fluids of attractive nonspherical particles. I. Kinetic crossover, dynamic free energies, and the physical nature of glasses and gels. AB - We apply the center-of-mass versions of naive mode coupling theory and nonlinear Langevin equation theory to study how short-range attractive interactions modify the onset of localization, activated single-particle dynamics, and the physical nature of the transiently arrested state of a variety of dense nonspherical particle fluids (and the spherical analog) as a function of volume fraction and attraction strength. The form of the dynamic crossover boundary depends on particle shape, but the reentrant glass-fluid-gel phenomenon and the repulsive glass-to-attractive glass crossover always occur. Diverse functional forms of the dynamic free energy are found for all shapes including glasslike, gel-like, a glass-gel form defined by the coexistence of two localization minima and two activation barriers, and a "mixed" attractive glass characterized by a single, very short localization length but an activation barrier located at a large displacement as in repulsive-force caged glasses. For the latter state, particle trajectories are expected to be of a two-step activated form and can be accessed at high attraction strength by increasing volume fraction, or by increasing attraction strength at fixed high enough volume fraction. A new classification scheme for slow dynamics of fluids of dense attractive particles is proposed based on specification of both the nature of the localized state and the particle displacements required to restore ergodicity via activated barrier hopping. The proposed physical picture appears to be in qualitative agreement with recent computer simulations and colloid experiments. PMID- 21599158 TI - Activated dynamics in dense fluids of attractive nonspherical particles. II. Elasticity, barriers, relaxation, fragility, and self-diffusion. AB - In paper II of this series we apply the center-of-mass version of Nonlinear Langevin Equation theory to study how short-range attractive interactions influence the elastic shear modulus, transient localization length, activated dynamics, and kinetic arrest of a variety of nonspherical particle dense fluids (and the spherical analog) as a function of volume fraction and attraction strength. The activation barrier (roughly the natural logarithm of the dimensionless relaxation time) is predicted to be a rich function of particle shape, volume fraction, and attraction strength, and the dynamic fragility varies significantly with particle shape. At fixed volume fraction, the barrier grows in a parabolic manner with inverse temperature nondimensionalized by an onset value, analogous to what has been established for thermal glass-forming liquids. Kinetic arrest boundaries lie at significantly higher volume fractions and attraction strengths relative to their dynamic crossover analogs, but their particle shape dependence remains the same. A limited universality of barrier heights is found based on the concept of an effective mean-square confining force. The mean hopping time and self-diffusion constant in the attractive glass region of the nonequilibrium phase diagram is predicted to vary nonmonotonically with attraction strength or inverse temperature, qualitatively consistent with recent computer simulations and colloid experiments. PMID- 21599159 TI - Tunable Brownian vortex at the interface. AB - A general kind of Brownian vortices is demonstrated by applying an external nonconservative force field to a colloidal particle bound by a conservative optical trapping force at a liquid-air interface. As the liquid medium is translated at a constant velocity with the bead trapped at the interface, the drag force near the surface provides enough rotational component to bias the particle's thermal fluctuations in a circulatory motion. The interplay between the thermal fluctuations and the advection of the bead in constituting the vortex motions is studied, and we infer that the angular velocity of the circulatory motion offers a comparative measure of the interface fluctuations. PMID- 21599160 TI - Electric-field-induced ordering and pattern formation in colloidal suspensions. AB - The long-time dynamics and pattern formation in semidilute suspensions of colloidal spheres in a viscous electrolyte under a uniform electric field are investigated using numerical simulations. The rapid chain formation that occurs in the field direction as a result of dipolar interactions is found to be followed by a slow coarsening process by which chains coalesce into hexagonal sheets and eventually rearrange to form mesoscale cellular structures, in qualitative agreement with recent experiments. The morphology and characteristic wavelength of the patterns that emerge at steady state are shown to depend on the suspension's volume fraction, electrode spacing, and field strength, suggesting additional ways of controlling effective suspension properties in practical applications. PMID- 21599161 TI - Poisson-Boltzmann theory for two parallel uniformly charged plates. AB - We solve the nonlinear Poisson-Boltzmann equation for two parallel and like charged plates both inside a symmetric electrolyte, and inside a 2:1 asymmetric electrolyte, in terms of Weierstrass elliptic functions. From these solutions we derive the functional relation between the surface charge density, the plate separation, and the pressure between plates. For the one plate problem, we obtain exact expressions for the electrostatic potential and for the renormalized surface charge density, both in symmetric and in asymmetric electrolytes. For the two plate problems, we obtain new exact asymptotic results in various regimes. PMID- 21599162 TI - Computer simulations of colloidal transport on a patterned magnetic substrate. AB - We study the transport of paramagnetic colloidal particles on a patterned magnetic substrate with kinetic Monte Carlo and Brownian dynamics computer simulations. The planar substrate is decorated with point dipoles in either parallel or zigzag stripe arrangements and exposed to an additional external magnetic field that oscillates in time. For the case of parallel stripes we find that the magnitude and direction of the particle current is controlled by the tilt angle of the external magnetic field. The effect is reliably obtained in a wide range of ratios between temperature and magnetic permeability. Particle transport is achieved only when the period of oscillation of the external field is greater than a critical value. For the case of zigzag stripes a current is obtained using an oscillating external field normal to the substrate. In this case, transport is possible only in the vertex of the zigzag, giving rise to a narrow stream of particles. The magnitude and direction of the particle current are found to be controlled by a combination of the zigzag angle and the distance of the colloids from the substrate. Metropolis Monte Carlo and Brownian dynamics simulations predict results that are in good agreement with each other. Using kinetic Monte Carlo we find that at high density the particle transport is hindered by jamming. PMID- 21599163 TI - Anisotropic sliding dynamics, peak effect, and metastability in stripe systems. AB - A variety of soft and hard condensed matter systems are known to form stripe patterns. Here we use numerical simulations to analyze how such stripe states depin and slide when interacting with a random substrate and with driving in different directions with respect to the orientation of the stripes. Depending on the strength and density of the substrate disorder, we find that there can be pronounced anisotropy in the transport produced by different dynamical flow phases. We also find a disorder-induced "peak effect" similar to that observed for superconducting vortex systems, which is marked by a transition from elastic depinning to a state where the stripe structure fragments or partially disorders at depinning. Under the sudden application of a driving force, we observe pronounced metastability effects similar to those found near the order-disorder transition associated with the peak effect regime for three-dimensional superconducting vortices. The characteristic transient time required for the system to reach a steady state diverges in the region where the flow changes from elastic to disordered. We also find that anisotropy of the flow persists in the presence of thermal disorder when thermally induced particle hopping along the stripes dominates. The thermal effects can wash out the effects of the quenched disorder, leading to a thermally induced stripe state. We map out the dynamical phase diagram for this system, and discuss how our results could be explored in electron liquid crystal systems, type-1.5 superconductors, and pattern-forming colloidal assemblies. PMID- 21599164 TI - Predicting microstructures in polymer blends under two-step quench in two dimensional space. AB - The formation of nanostructures during two-step quench in binary polymer systems having various types of liquid miscibility gaps are investigated systematically via computer simulations using the phase field method. Coupled liquid spinodal decomposition and fluid flow processes are considered by solving simultaneously the Cahn-Hilliard and Navier-Stokes equations. Various interesting phenomena and morphological patterns are predicted. It is found that the primary microstructures developed at the first quench and isothermal holding temperature greatly affect the secondary microstructures developed during the second quench and isothermal holding. Depending on the morphology and scale of the primary microstructure, either multicore and multishell or unicore and unishell structures are predicted. The breakup of annuluses in a core-shell structure in two dimensions is analyzed. The effects of viscosity on the formation of core shell structure and on the growth and coarsening behaviors of bimodal droplets produced by the two-step quench in systems are also investigated. PMID- 21599165 TI - Tests of mode-coupling theory in two dimensions. AB - We analyze the glassy dynamics of binary mixtures of hard disks in two dimensions. Predictions of the mode-coupling theory (MCT) are tested with extensive Brownian dynamics simulations. Measuring the collective particle density correlation functions in the vicinity of the glass transition, we verify four predicted mixing effects. For instance, for large size disparities, adding a small amount of small particles at a fixed packing fraction leads to a speedup in the long-time dynamics, while for small size disparities it leads to a slowing down. Qualitative features of the nonergodicity parameters and the beta relaxation, which both depend in a nontrivial way on the mixing ratio, are found in the simulated correlators. Studying one system in detail, we are able to determine its ideal MCT glass transition point as phi(c)=0.7948 and test MCT predictions quantitatively. PMID- 21599166 TI - Phase-field model of solid-liquid phase transition with density difference and latent heat in velocity and elastic fields. AB - We present a phase-field model of solid-liquid transitions with inhomogeneous temperature in one-component systems, including hydrodynamics and elasticity. Our model can describe plastic deformations at large elastic strains. We use it to investigate the melting of a solid domain, accounting for the latent heat effect, where there appears a velocity field in liquid and an elastic field in solid. We present simulation results in two dimensions for three cases of melting. First, a solid domain is placed on a heated wall, which melts mostly near the solid-liquid wall contact region. Second, a solid domain is suspended in a warmer liquid under shear flow, which rotates as a whole because of elasticity and melts gradually. Cooling of the surrounding liquid is accelerated by convection. Third, a solid rod is under high compression in liquid, where slips appear from the solid-liquid interface, leading to a plastic deformation. Subsequently, melting starts in the plastically deformed areas, eventually resulting in the fracture of the rod into pieces. In these phase-transition processes, the interface temperature is kept nearly equal to the coexisting temperature T(cs)(p) away from the heated wall, but this local equilibrium is not attained near the the contact region. We also examine a first-order liquid-liquid phase transition under heating from a boundary in one-component liquids. PMID- 21599167 TI - Density scaling in viscous systems near the glass transition. AB - In this paper, a general equation of state (EOS) valid for fluids in the vicinity of the glass transition is derived on the basis of its isothermal precursor. This EOS is able to predict the density scaling of both isobaric and isothermal PVT data and it explicitly involves the scaling exponent gamma(EOS), which is most likely straightforwardly related to the exponent of the inverse power law of some effective potential valid for viscous systems. This EOS and the density scaling are very successfully tested for representatives of several material classes (van der Waals liquids, polymer melts, ionic liquids, and even strongly hydrogen bonded systems). Additionally, if the thermodynamic scaling of primary relaxation times can be achieved with the scaling exponent gamma for a given material, then the value gamma(EOS) found from fitting its PVT data to the EOS enables us to evaluate the value gamma, which is always considerably smaller than gamma(EOS). PMID- 21599168 TI - Time-dependent correlations in a supercooled liquid from nonlinear fluctuating hydrodynamics. AB - We solve numerically the equations of nonlinear fluctuating hydrodynamics (NFH). A coarse graining of the density field is applied at each time step to avoid instabilities which otherwise plague the algorithm at long times. The equilibrium correlation of the density fluctuations at different times obtained directly from the solutions of the NFH equations are shown here to be in quantitative agreement with corresponding molecular dynamics simulation data. Low-order perturbative treatment of the these NFH equations obtains the mode coupling model. The latter has been widely studied for understanding the slow dynamics characteristic of the supercooled state. A crucial aspect of this theory is a rounded version of a possible ergodic-nonergodic transition in the supercooled liquid at a temperature T(c) between melting point T(m) and the glass transition temperature T(g). In the present work we demonstrate numerically the role of strongly coupled density fluctuations in giving rise to slow dynamics and how the 1/rho nonlinearity in the NFH equations of motion is essential in restoring the ergodic behavior in the liquid. The relaxation data indicate that at moderate supercooling near T(c), the time temperature superposition holds. The relaxation gets increasingly stretched with increased supercooling. The relaxation time tau shows an initial power-law divergence approaching a transition temperature T(c) generally identified as the mode coupling temperature. From the direct solutions we obtain a value for T(c) much lower than that typically estimated from solution of low-order integral equations of mode coupling theory. This is in agreement with the trend seen in computer simulations. PMID- 21599169 TI - Global theory of steady deep-cellular growth in directional solidification. AB - The present paper is concerned with the global asymptotic theory of steady deep cellular growth in directional solidification of binary mixtures. We consider the two-dimensional model with nonzero isotropic surface tension and obtain the global uniformly valid asymptotic solutions for the steady state of the system in the limit of the Peclet number epsilon->0; epsilon is defined as the ratio of the radius of the cell's tip and mass diffussion length. The whole physical space is divided into the outer region and root region; the solutions in each subregion are solved, respectively, and matched with each other in the intermediate region. The results show that given growth conditions and material properties, the global solutions for steady state of the system contain two free parameters: the Peclet number and asymptotic width parameter lambda(0), which are related to the geometry of cellular structure: the cell tip radius and primary spacing. One of the most important conclusions drawn from this analysis is that the steady-state solutions of cellular growth have a complicated structure with three internal layers in the root region; for given (epsilon,lambda(0)), there exists a discrete set of the global steady-state solutions subject to the quantization condition that are profoundly affected by the surface tension. Each eigenvalue calculated from this quantization condition determines the total length of the finger described by the corresponding global steady-state solution. PMID- 21599170 TI - Thermal conductivity of interfacial layers in nanofluids. AB - Thermal conductivity of interfacial layers is an essential parameter for determining how the ordered liquid layering around the particle-liquid interface contributes to the unusual high thermal conductivity of nanofluids. However, so far there is no experimental data regarding this parameter. Using nonequilibrium molecular dynamics simulations of an inhomogeneous Au-Ar system in which the solid-liquid interactions are assumed to be much stronger than the liquid-liquid interactions, we show explicitly that the thermal conductivity of a 1-nm-thick interfacial layer is 1.6 ~ 2.5 times higher than that of the base fluid. The simulation results are incorporated into a three-level clustering model to calculate the effective thermal conductivity of nanofluids. The results show that the contribution of the interfacial layer to thermal conductivity enhancements should be considered if there are particle clusters in nanofluids. PMID- 21599171 TI - Molecular dynamics study of the dewetting of copper on graphite and graphene: implications for nanoscale self-assembly. AB - Thin-film dewetting can be exploited to self-assemble and organize nanoparticles. Crucial to this effort is the understanding of the nanoscale liquid phase dynamics, and molecular dynamics simulations (MD) provide a powerful tool in this respect. In this paper we demonstrate that MD simulations utilizing a Lennard Jones (LJ) interface potential can be effectively used to study various wetting regimes of nanoscale Cu disks on graphite. It was found that both the dewetting velocity and the equilibrium contact angle increase with a decrease in the Cu-C potential, and that the retraction velocities obtained are characteristic of dewetting phenomena governed by inertial and capillary forces. This phenomena leads to a change in morphology, from disks to nanodroplets, which, in turn, when using the most accurate LJ potential, jump off the graphitic substrate with a velocity on the order of 140 m/s. This ejection velocity is consistent with the previous experimental observation that nanoscale Au triangles deposited on graphite or glass jump when exposed to a pulsed laser above the melting threshold. Interestingly, the Cu ejection velocity decreases when the liquid Cu disks are deposited on a suspended graphene membrane. Finally, a Rayleigh-Plateau like instability, which leads to the breakup of a pseudo-one-dimensional liquid Cu nanowire in nanodroplets, is revealed when the MD simulations are performed using different LJ interface potentials. PMID- 21599172 TI - Crossover from layering to island formation in Langmuir-Blodgett growth: role of long-range intermolecular forces. AB - Combined studies by atomic force microscopy, x-ray reflectivity, and Fourier transform infrared spectroscopy on transition-metal stearate (M-St, M = Mn, Co, Zn, and Cd) Langmuir-Blodgett films clearly indicate association of bidentate coordination of the metal-carboxylate head group to layer-by-layer growth as observed in MnSt and CoSt and partially in ZnSt. Crossover to islandlike growth, as observed in CdSt and ZnSt, is associated with the presence of unidentate coordination in the head group. Morphological evolutions as obtained from one, three, and nine monolayers (MLs) of M-St films are consistent with Frank van der Merwe, Stranski-Krastanov, and Volmer Weber growth modes for M=Mn/Co, Zn, and Cd, respectively, as previously assigned, and are found to vary with number (n) of metal atoms per head group, viz. n=1 (Mn/Co), n=0.75 (Zn), and n=0.5 (Cd). The parameter n is found to decide head-group coordination such that n=1.0 corresponds to bidentate and n=0.5 corresponds to unidentate coordination; the intermediate value in Zn corresponds to a mixture of both. The dependence of the growth mode on head-group structure is explained by the fact that in bidentate head groups, with the in-plane dipole moment being zero, intermolecular forces between adjacent molecules are absent and hence growth proceeds via layering. On the other hand, in unidentate head groups, the existence of a nonzero in-plane dipole moment results in the development of weak in-plane intermolecular forces between adjacent molecules causing in-plane clustering leading to islandlike growth. PMID- 21599173 TI - Scaling in film growth by pulsed laser deposition and modulated beam deposition. AB - The scalings in film growth by pulsed laser deposition (PLD) and modulated beam deposition (MBD) were investigated by Monte Carlo simulations. In PLD, an atomic pulse beam with a period t(0) were deposited instantaneously on a substrate, whereas in MBD, adatoms were deposited during a short time interval t(1) (0<=t(1)<=t(0)) within each period. If t(1)=0, MBD will be identical to PLD and, if t(1)=t(0), MBD will become usual molecular beam epitaxy (MBE). Specifically, logarithmic scaling was investigated for the nucleation density reported for PLD, and the scaling of island density was studied regarding the growth for 0=1 neither the generalized scaling form nor the standard scaling form N(s)(theta)=theta/S(2)f(s/S) lead to scaling of the entire ISD for finite values of the ratio R of the monomer diffusion rate to deposition flux. Instead, the scaled ISD becomes more sharply peaked with increasing R and coverage. This is in contrast to models of epitaxial growth with limited cluster mobility for which good scaling occurs over a wide range of coverages. PMID- 21599180 TI - Theory and simulation of the confined Lebwohl-Lasher model. AB - We discuss the Lebwohl-Lasher model of nematic liquid crystals in a confined geometry, using Monte Carlo simulation and mean-field theory. A film of material is sandwiched between two planar, parallel plates that couple to the adjacent spins via a surface strength epsilon(s). We consider the cases where the favored alignments at the two walls are the same (symmetric cell) or different (asymmetric cell). In the latter case, we demonstrate the existence of a single phase transition in the slab for all values of the cell thickness. This transition has been observed before in the regime of narrow cells, where the two structures involved correspond to different arrangements of the nematic director. By studying wider cells, we show that the transition is in fact the usual isotropic-to-nematic (capillary) transition under confinement in the case of antagonistic surface forces. We show results for a wide range of values of film thickness and discuss the phenomenology using a mean-field model. PMID- 21599181 TI - Maier-Saupe theory in four dimensions. AB - Maier-Saupe theory is the canonical mean field description of thermotropic nematic liquid crystals. In this paper, we examine the predictions of the theory in four spatial dimensions. Representations of the order parameter tensor and the existence of new phases are discussed. The phase diagram, based on numerical solution of the self-consistent equations and Landau theory, is presented. Orientational order decreases as the number of spatial dimensions is increased. PMID- 21599182 TI - Random disorder and the smectic-nematic transition in liquid-crystalline elastomers. AB - We report effects of disorder due to random cross-linking on the nematic to smectic-A phase transition in smectic elastomers. Thermoelastic data, stress strain relations and high-resolution x-ray scattering profiles have been analyzed for two related compounds with a small and a larger nematic range, respectively, each for 5% as well as 10% cross-links. At 5% cross-link density the algebraic decay of the positional correlations of the smectic layers survives in finite size domains, providing a sharp smectic-nematic transition. At an increased cross link concentration of 10% the smectic order disappears and gives way to extended short-range layer correlations. In this situation neither a smectic-nematic nor a nematic-isotropic transition is observed anymore. The occurrence of disorder at a relatively large cross-link concentration only, indicates that smectic elastomers are rather resistant to a random field. The temperature dependence of the correlation lengths and thermoelastic behavior suggest a shift to a "parasmectic" regime of a first-order smectic-isotropic transition. PMID- 21599184 TI - Frederiks transition in ferroelectric liquid-crystal nanosuspensions. AB - We construct a theoretical model of the dielectric properties of a ferroelectric LC nanosuspension (FLCNS), using a generalized Maxwell-Garnett picture. The theory supposes that an FLCNS may as a first approximation be considered as a complex homogeneous dielectric ceramic, thus neglecting positional correlations of the colloidal particles. The FLCNS then consists of an anisotropic matrix with a very low concentration (<1% by volume) of impurity particles. The impurity particles possess both shape and dielectric anisotropy, as well as a permanent electric polarization and strong liquid-crystal director anchoring on the particle surface. We show that the effective dielectric properties for capacitance properties and for effective liquid-crystal free energies do not coincide. We calculate the effect of doping a liquid crystal with ferroelectric impurities on the Frederiks transition. The theory takes account of inclusion shape, dielectric susceptibility, and local field effects. We neglect the possibility of dielectric particle chaining, which appears experimentally not to occur in general. Our calculations suggest, in qualitative agreement with experiment, that doping a nematic liquid crystal with ferroelectric particles, even at very low particle concentration, can in some cases significantly decrease the electric Frederiks threshold field. PMID- 21599183 TI - Nonstandard electroconvection in a bent-core oxadiazole material. AB - Electroconvection (EC) phenomena have been investigated in the nematic phase of a bent-core oxadiazole material with negative dielectric anisotropy and a frequency dependent conductivity anisotropy. The formation of longitudinal roll (LR) patterns is one of the predominant features observed in the complete frequency and voltage range studied. At voltages much above the LR threshold, various complex patterns such as the "crisscrossed" pattern, bimodal varicose, and turbulence are observed. Unusually, the nonstandard EC (ns-EC) instability in this material, is observed in a regime in which we measure the dielectric and conductivity anisotropies to be negative and positive respectively. A further significant observation is that the EC displays distinct features in the high and low temperature regimes of the nematic phase, supporting an earlier report that EC patterns could distinguish between regions that have been reported as uniaxial and biaxial nematic phases. PMID- 21599185 TI - Dispersion relation on the Kerr constant of a polymer-stabilized optically isotropic liquid crystal. AB - The dispersion relation on the Kerr constant (K) of a polymer-stabilized isotropic phase (PSIP) liquid-crystal (LC) composite is investigated. Our experimental results show that K decreases as the wavelength (lambda) increases. The single-band birefringence dispersion model is used to fit the lambdaK values of the PSIP LC composite. Very good agreement between the experiment and physical model is obtained. PMID- 21599186 TI - Nematic electroclinic effect in a carbon-nanotube-doped achiral liquid crystal. AB - A small quantity of carbon nanotubes (CNTs) dispersed in an achiral liquid crystal (LC) matrix transmits chirality a short distance into the LC, and the LC+CNT mixture is found to exhibit a bulklike electroclinic effect in the nematic phase. The magnitude of the effect increases rapidly on cooling, showing significant pretransitional behavior on approaching the nematic-smectic-A transition temperature (T(NA)) from above. The variation of the electroclinic coefficient is negligible over the frequency range 100 Hz to 100 kHz in the in the nematic phase well above T(NA) and in the smectic-A phase, whereas the electroclinic coefficient falls off significantly with increasing frequency just above T(NA). PMID- 21599187 TI - Effect of cadmium telluride quantum dots on the dielectric and electro-optical properties of ferroelectric liquid crystals. AB - We present here the dielectric and electro-optical studies of cadmium telluride quantum dots (CdTe QDs) doped ferroelectric liquid crystals (FLCs). It has been observed that the doping of CdTe QDs not only induced a pronounced memory effect but also affected the physical parameters of FLC material (LAHS19). The modifications in the physical parameters and memory effect of LAHS19 are found to depend on the concentration ratio of CdTe QDs. The lower concentration of CdTe QDs (1-3 wt%) enhanced the values of spontaneous polarization and rotational viscosity of LAHS19 material but did not favor the memory effect, whereas a higher concentration of CdTe QDs (>5 wt%) degraded the alignment of LAHS19 material. The doping of ~5 wt% of CdTe QDs is found to be the most suitable for achieving good memory effect without significantly affecting the material parameters. PMID- 21599188 TI - Square colloidal lattices and pair interaction in a binary system of quadrupolar nematic colloids. AB - Spherical colloidal particles with normal and tangential surface director alignment in a nematic liquid crystal induce elastic quadrupoles of opposite signs that attract one another along and perpendicular to the director. We utilize this unique angular profile of the mixed quadrupolar interaction to build 2D crystals with square lattices by laser tweezers. PMID- 21599189 TI - Surface structure of ultrathin smectic films on silicon substrates: pores and islands. AB - We present an atomic force microscopy (AFM) and ellipsometry study of ultrathin smectic films on silicon substrates. By controlling the amount of the liquid crystal material that is spin coated on the substrate, we are able to prepare films consisting of a defined small number (ranging from 1 to 4) of smectic layers. AFM measurements show that the films possess a specific surface structure with a lateral feature size of a few microns and steplike height variations of 3.3 nm. The height of the steps corresponds to the smectic layer spacing of the material used, indicating that the surface structure is the result of a partial formation of the topmost smectic layer of these films. The pattern of the surface structure either corresponds to isolated islands (regions in which the film thickness is enhanced by one smectic layer) or consists of pores (film thickness decreased by one layer). A smooth surface is only obtained if the amount of the liquid-crystal material is precisely tuned to certain values, indicating the formation of a complete smectic top layer. A well-defined relation exists between the liquid crystal concentration in the spin-coating solution and the obtained structure, enabling the controlled generation of island structures, pore structures, or smooth surfaces. The two-dimensional island or pore structure is stable on the time scale of a few days. Preliminary results concerning the thermal stability are reported. Our study highlights the usefulness of AFM measurements for the study of smectic liquid-crystal surfaces. PMID- 21599190 TI - Blue-shifted random-laser-mode selection in gain-assisted anisotropic complex fluids. AB - Random laser action in organic materials is of great topical interest that is fueled by the rapid development of active compounds and new dye molecules. We propose a pure-diffusive model to describe the strong connection established between a dye-host interaction and the scattering when considering an anisotropic complex fluid. The model considers multiple scattering induced by dielectric tensor fluctuations and a suitable quantistic description for light amplification in order to explain the generation of the narrow-band blue-shifted lasing mode experimentally observed in such systems. We also find that the introduction of a strong intermolecular force field provides the condition to enhance diffusive processes. The agreement between experimental observations and simulations advances the understanding of the physical mechanism behind mode selection in these systems. PMID- 21599191 TI - Density-functional-theory investigation of conformations, 13C shielding, and magnetic field interactions in a V-shaped phenylene bis carboxylate homologous series. AB - Density functional theory (DFT) has been employed in a conformational study of a bent-core PBBC homologous series. IR spectra, GIAO-DFT chemical shielding tensors (CSTs), and molecular susceptibility tensors (MSTs) are theoretically calculated for various optimized conformations established by searching the potential energy surface of each PBBC V-shaped molecule. The IR results could aid the understanding of vibration normal modes, while the MST results can illuminate the alignment properties of the V-shaped molecules in an external magnetic field. CSTs of the aromatic carbons, and those previously measured by the 2D-NMR SUPER technique (with some (13)C NMR peaks reassigned for correctness based on new DFT calculations), were found to be in good agreement. These verified experimental CSTs are then used to revisit the (13)C NMR data to yield structural and local orientational order parameters for two members of the PBBC series. The PBBC series studied using the combined DFT-(13)C NMR approach strongly supports the notion that lesser populated conformational states found by DFT could be reached in the studied mesogens 10DClPBBC and 11ClPBBC upon decreasing temperature, as revealed by the change in the bend angle determined by NMR and identified with those of the DFT molecular structures optimized for various conformers. PMID- 21599192 TI - Phase diagram of the Pluronic L64-H2O micellar system from mechanical spectroscopy. AB - The linear viscoelastic properties of aqueous Pluronic L64 solutions have been investigated at high copolymer concentrations (25-62 wt%) using our modified low frequency mechanical spectroscopy. The concentration-temperature phase diagram of the L64/H(2)O system was constructed by studying the evolution of the loss modulus and loss tangent as temperature is increased at a fixed frequency. A particular attention was focused on the dynamics approaching the beginning and ending points (39% and 60%) of the fusiform gel region in the phase diagram. The dynamics is found to have a similar viscoelastic behavior at the low and high concentrations, where a frequency scaling expected for a static percolated network is exhibited. Moreover, with increasing temperature, the system above the critical gel concentration undergoes a transition from a viscoelastic liquid to a solid gel through a percolated particle network. Therefore, our results suggest that the formation of the gel is dominated by the percolation of the particle clusters. PMID- 21599194 TI - Manning free counterion fraction for a rodlike polyion: aqueous solutions of short DNA fragments in presence of very low added salt. AB - We quantified the Manning free (uncondensed) counterions fraction theta for dilute aqueous solutions of rodlike polyions: 150 bp DNA fragments, in the presence of a very low concentration of monovalent salt c(salt)<0.05 mM. Conductivity measurements of these solutions for DNA base pair concentration range 0.015<=c<=8 mM were complemented by fluorescence correlation spectroscopy (FCS) measurements of the DNA polyion diffusion coefficient D(p)(c). We observed a crossover in the normalized conductivity sigma(c)/c that nearly halved across the c=0.05-1 mM range, while D(p)(c) remained rather constant, as we established by FCS. Analyzing these data we extracted theta(c)=0.30-0.45, and taking the Manning asymmetry field effect on polyelectrolyte conductivity into account we got theta(c)=0.40-0.60. We relate the theta(c) variation to gradual DNA denaturation occurring, in the very low salt environment, with the decrease in DNA concentration itself. The extremes of the experimental theta(c) range occur toward the highest, above 1 mM, and the lowest, below 0.05 mM, DNA concentrations and correspond to the theoretical theta values for dsDNA and ssDNA, respectively. Therefore, we confirmed Manning condensation and conductivity models to be valuable in description of dilute solutions of rodlike polyions. PMID- 21599193 TI - Influence of the standard free energy on swelling kinetics of gels. AB - Classical theories of gel swelling employ the mixing free energy, thereby ignoring any effects of the free energy of the pure phases,i.e., the polymer standard free energy. In this paper we present a model for the swelling kinetics of gels that incorporates the free energy, including the polymer standard free energy. We provide a complete analysis of how the swelling kinetics and stable states and sizes of the swelled gel depends on the free energy parameters and show that theories that use only the mixing free energy cannot correctly describe equilibrium states or the swelling kinetics. PMID- 21599195 TI - Random-walk-based stochastic modeling of three-dimensional fiber systems. AB - For the simulation of fiber systems, there exist several stochastic models: systems of straight nonoverlapping fibers, systems of overlapping bending fibers, or fiber systems created by sedimentation. However, there is a lack of models providing dense, nonoverlapping fiber systems with a given random orientation distribution and a controllable level of bending. We introduce a new stochastic model in this paper that generalizes the force-biased packing approach to fibers represented as chains of balls. The starting configuration is modeled using random walks, where two parameters in the multivariate von Mises-Fisher orientation distribution control the bending. The points of the random walk are associated with a radius and the current orientation. The resulting chains of balls are interpreted as fibers. The final fiber configuration is obtained as an equilibrium between repulsion forces avoiding crossing fibers and recover forces ensuring the fiber structure. This approach provides high volume fractions up to 72.0075%. PMID- 21599196 TI - Work fluctuations in an elastic dumbbell model of polymers in planar elongational flow. AB - We use a path-integral approach to calculate the distribution P(w,t) of the fluctuations in the work w at time t of a polymer molecule (modeled as an elastic dumbbell in a viscous solvent) that is acted on by an elongational flow field having a flow rate gamma. We find that P(w,t) is non-Gaussian and that, at long times, the ratio P(w,t)/P(-w,t) is equal to exp[w/(k(B)T)], independent of gamma. On the basis of this finding, we suggest that polymers in elongational flows satisfy a fluctuation theorem. PMID- 21599197 TI - Unifying model for two-state and downhill protein folding. AB - A protein-folding model is proposed at the amino acid level, in which the folding process is divided into two successive stages: the rate-determining step, dominated by the "stochastic interactions"of solvent molecules, and the rapid phase, dominated by the "order interactions"among atoms in polypeptide. The master equation approach is used to investigate the folding kinetics, and an analytical treatment of the master equation yields a simple three-parameter expression for folding time. It is found that both two-state and downhill protein folding kinetics can be described by a unifying model. PMID- 21599198 TI - Surface adsorption and hopping cause probe-size-dependent microrheology of actin networks. AB - A network of filaments formed primarily by the abundant cytoskeletal protein actin gives animal cells their shape and elasticity. The rheological properties of reconstituted actin networks have been studied by tracking micron-sized probe beads embedded within the networks. We investigate how microrheology depends on surface properties of probe particles by varying the stickiness of their surface. For this purpose, we chose carboxylate polystyrene (PS) beads, silica beads, bovine serum albumin (BSA) -coated PS beads, and polyethylene glycol (PEG) grafted PS beads, which show descending stickiness to actin filaments, characterized by confocal imaging and microrheology. Probe size dependence of microrheology is observed for all four types of beads. For the slippery PEG beads, particle-tracking microrheology detects weaker networks using smaller beads, which tend to diffuse through the network by hopping from one confinement "cage" to another. This trend is reversed for the other three types of beads, for which microrheology measures stiffer networks for smaller beads due to physisorption of nearby filaments to the bead surface. We explain the probe size dependence with two simple models. We also evaluate depletion effect near nonadsorption bead surface using quantitative image analysis and discuss the possible impact of depletion on microrheology. Analysis of these effects is necessary in order to accurately define the actin network rheology both in vitro and in vivo. PMID- 21599199 TI - Mean-field study of the role of lateral cracks in microtubule dynamics. AB - A link between dimer-scale processes and microtubule (MT) dynamics at macroscale is studied by comparing simulations obtained using computational dimer-scale model with its mean-field approximation. The novelty of the mean-field model (MFM) is in its explicit representation of inter-protofilament cracks, as well as in the direct incorporation of the dimer-level kinetics. Due to inclusion of both longitudinal and lateral dimer interactions, the MFM is two dimensional, in contrast to previous theoretical models of MTs. It is the first analytical model that predicts and quantifies crucial features of MT dynamics such as (i) existence of a minimal soluble tubulin concentration needed for the polymerization (with concentration represented as a function of model parameters), (ii) existence of steady-state growth and shortening phases (given with their respective velocities), and (iii) existence of an unstable pause state near zero velocity. In addition, the size of the GTP cap of a growing MT is estimated. Theoretical predictions are shown to be in good agreement with the numerical simulations. PMID- 21599200 TI - Neural complexity: a graph theoretic interpretation. AB - One of the central challenges facing modern neuroscience is to explain the ability of the nervous system to coherently integrate information across distinct functional modules in the absence of a central executive. To this end, Tononi et al. [Proc. Natl. Acad. Sci. USA. 91, 5033 (1994)] proposed a measure of neural complexity that purports to capture this property based on mutual information between complementary subsets of a system. Neural complexity, so defined, is one of a family of information theoretic metrics developed to measure the balance between the segregation and integration of a system's dynamics. One key question arising for such measures involves understanding how they are influenced by network topology. Sporns et al. [Cereb. Cortex 10, 127 (2000)] employed numerical models in order to determine the dependence of neural complexity on the topological features of a network. However, a complete picture has yet to be established. While De Lucia et al. [Phys. Rev. E 71, 016114 (2005)] made the first attempts at an analytical account of this relationship, their work utilized a formulation of neural complexity that, we argue, did not reflect the intuitions of the original work. In this paper we start by describing weighted connection matrices formed by applying a random continuous weight distribution to binary adjacency matrices. This allows us to derive an approximation for neural complexity in terms of the moments of the weight distribution and elementary graph motifs. In particular, we explicitly establish a dependency of neural complexity on cyclic graph motifs. PMID- 21599201 TI - Towards quantitative classification of folded proteins in terms of elementary functions. AB - A comparative classification scheme provides a good basis for several approaches to understand proteins, including prediction of relations between their structure and biological function. But it remains a challenge to combine a classification scheme that describes a protein starting from its well-organized secondary structures and often involves direct human involvement, with an atomary-level physics-based approach where a protein is fundamentally nothing more than an ensemble of mutually interacting carbon, hydrogen, oxygen, and nitrogen atoms. In order to bridge these two complementary approaches to proteins, conceptually novel tools need to be introduced. Here we explain how an approach toward geometric characterization of entire folded proteins can be based on a single explicit elementary function that is familiar from nonlinear physical systems where it is known as the kink soliton. Our approach enables the conversion of hierarchical structural information into a quantitative form that allows for a folded protein to be characterized in terms of a small number of global parameters that are in principle computable from atomary-level considerations. As an example we describe in detail how the native fold of the myoglobin 1M6C emerges from a combination of kink solitons with a very high atomary-level accuracy. We also verify that our approach describes longer loops and loops connecting alpha helices with beta strands, with the same overall accuracy. PMID- 21599202 TI - Stochastic differential equation models for ion channel noise in Hodgkin-Huxley neurons. AB - The random transitions of ion channels between conducting and nonconducting states generate a source of internal fluctuations in a neuron, known as channel noise. The standard method for modeling the states of ion channels nonlinearly couples continuous-time Markov chains to a differential equation for voltage. Beginning with the work of R. F. Fox and Y.-N. Lu [Phys. Rev. E 49, 3421 (1994)], there have been attempts to generate simpler models that use stochastic differential equation (SDEs) to approximate the stochastic spiking activity produced by Markov chain models. Recent numerical investigations, however, have raised doubts that SDE models can capture the stochastic dynamics of Markov chain models.We analyze three SDE models that have been proposed as approximations to the Markov chain model: one that describes the states of the ion channels and two that describe the states of the ion channel subunits. We show that the former channel-based approach can capture the distribution of channel noise and its effects on spiking in a Hodgkin-Huxley neuron model to a degree not previously demonstrated, but the latter two subunit-based approaches cannot. Our analysis provides intuitive and mathematical explanations for why this is the case. The temporal correlation in the channel noise is determined by the combinatorics of bundling subunits into channels, but the subunit-based approaches do not correctly account for this structure. Our study confirms and elucidates the findings of previous numerical investigations of subunit-based SDE models. Moreover, it presents evidence that Markov chain models of the nonlinear, stochastic dynamics of neural membranes can be accurately approximated by SDEs. This finding opens a door to future modeling work using SDE techniques to further illuminate the effects of ion channel fluctuations on electrically active cells. PMID- 21599203 TI - Noise-aided computation within a synthetic gene network through morphable and robust logic gates. AB - An important goal for synthetic biology is to build robust and tunable genetic regulatory networks that are capable of performing assigned operations, usually in the presence of noise. In this work, a synthetic gene network derived from the bacteriophage lambda underpins a reconfigurable logic gate wherein we exploit noise and nonlinearity through the application of the logical stochastic resonance paradigm. This biological logic gate can emulate or "morph" the AND and OR operations through varying internal system parameters in a noisy background. Such genetic circuits can afford intriguing possibilities in the realization of engineered genetic networks in which the actual function of the gate can be changed after the network has been built, via an external control parameter. In this article, the full system characterization is reported, with the logic gate performance studied in the presence of external and internal noise. The robustness of the gate, to noise, is studied and illustrated through numerical simulations. PMID- 21599204 TI - Nonlinear dynamics and rheology of active fluids: simulations in two dimensions. AB - We report simulations of a continuum model for (apolar, flow aligning) active fluids in two dimensions. Both free and anchored boundary conditions are considered, at parallel confining walls that are either static or moving at fixed relative velocity. We focus on extensile materials and find that steady shear bands, previously shown to arise ubiquitously in one dimension for the active nematic phase at small (or indeed zero) shear rate, are generally replaced in two dimensions by more complex flow patterns that can be stationary, oscillatory, or apparently chaotic. The consequences of these flow patterns for time-averaged steady-state rheology are examined. PMID- 21599205 TI - Postfragmentation density function for bacterial aggregates in laminar flow. AB - The postfragmentation probability density of daughter flocs is one of the least well-understood aspects of modeling flocculation. We use three-dimensional positional data of Klebsiella pneumoniae bacterial flocs in suspension and the knowledge of hydrodynamic properties of a laminar flow field to construct a probability density function of floc volumes after a fragmentation event. We provide computational results which predict that the primary fragmentation mechanism for large flocs is erosion. The postfragmentation probability density function has a strong dependence on the size of the original floc and indicates that most fragmentation events result in clumps of one to three bacteria eroding from the original floc. We also provide numerical evidence that exhaustive fragmentation yields a limiting density inconsistent with the log-normal density predicted in the literature, most likely due to the heterogeneous nature of K. pneumoniae flocs. To support our conclusions, artificial flocs were generated and display similar postfragmentation density and exhaustive fragmentation. PMID- 21599206 TI - Discrete persistent-chain model for protein binding on DNA. AB - We describe and solve a discrete persistent-chain model of protein binding on DNA, involving an extra sigma(i) at a site i of the DNA. This variable takes the value 1 or 0, depending on whether or not the site is occupied by a protein. In addition, if the site is occupied by a protein, there is an extra energy cost E. For a small force, we obtain analytic expressions for the force-extension curve and the fraction of bound protein on the DNA. For higher forces, the model can be solved numerically to obtain force-extension curves and the average fraction of bound proteins as a function of applied force. Our model can be used to analyze experimental force-extension curves of protein binding on DNA, and hence deduce the number of bound proteins in the case of nonspecific binding. PMID- 21599207 TI - Quantifying evenly distributed states in exclusion and nonexclusion processes. AB - Spatial-point data sets, generated from a wide range of physical systems and mathematical models, can be analyzed by counting the number of objects in equally sized bins. We find that the bin counts are related to the Polya distribution. New measures are developed which indicate whether or not a spatial data set, generated from an exclusion process, is at its most evenly distributed state, the complete spatial randomness (CSR) state. To this end, we define an index in terms of the variance between the bin counts. Limiting values of the index are determined when objects have access to the entire domain and when there are subregions of the domain that are inaccessible to objects. Using three case studies (Lagrangian fluid particles in chaotic laminar flows, cellular automata agents in discrete models, and biological cells within colonies), we calculate the indexes and verify that our theoretical CSR limit accurately predicts the state of the system. These measures should prove useful in many biological applications. PMID- 21599208 TI - Approximation scheme based on effective interactions for stochastic gene regulation. AB - Since gene regulatory systems sometimes contain only a small number of molecules, these systems are not described well by macroscopic rate equations; a master equation approach is needed for such cases. We develop an approximation scheme for dealing with the stochasticity of the gene regulatory systems. Using an effective interaction concept, original master equations can be reduced to simpler master equations, which can be solved analytically. We apply the approximation scheme to self-regulating systems with monomer or dimer interactions, and a two-gene system with an exclusive switch. The approximation scheme can recover the bistability of the exclusive switch adequately. PMID- 21599209 TI - Electrostatic self-energy of a partially formed spherical shell in salt solution: application to stability of tethered and fluid shells as models for viruses and vesicles. AB - We investigate the electrostatics of a partially formed, charged spherical shell in a salt solution. We solve the problem numerically at the Poisson-Boltzmann level and analytically in the Debye-Huckel regime. From the results on energetics of partially formed shells we examine the stability of tethered (crystalline) and fluid shells toward rupture. We delineate different regimes of stability, where, for fluid shells, we also include the effects of bending elasticity of the shells. Our analysis shows how charging of the shell induces its instability toward rupture but also provides insight regarding growth of charged shells. PMID- 21599210 TI - Periodic three-dimensional assemblies of polyhedral lipid vesicles. AB - We theoretically study the structure of periodic bulk assemblies of identical lipid vesicles. In our model, each vesicle is represented as a convex polyhedron with flat faces, rounded edges, and rounded vertices. Each vesicle carries an elastic and an adhesion energy and in the limit of strong adhesion, the minimal energy shape of cells minimizes the weighted total edge length. We calculate exactly the shape of the rounded edge and show that it can be well described by a cylindrical surface. By comparing several candidate space-filling polyhedra, we find that the oblate shapes are preferred over prolate shapes for all volume-to surface ratios. We also study periodic assemblies of vesicles whose adhesion strength on lateral faces is different from that on basal or apical faces. The anisotropy needed to stabilize prolate shapes is determined and it is shown that, at any volume-to-surface ratio, the transition between oblate and prolate shapes is very sharp. The geometry of the model vesicle assemblies reproduces the shapes of cells in certain simple animal tissues. PMID- 21599211 TI - Comparison between spring network models and continuum constitutive laws: application to the large deformation of a capsule in shear flow. AB - A capsule is a liquid drop enclosed by a solid, deformable membrane. To analyze the deformation of a capsule accurately, both the fluid mechanics of the internal and external fluids and the solid mechanics of the membrane must be solved precisely. Recently, many researchers have used discrete spring network models to express the membrane mechanics of capsules and biological cells. However, it is unclear whether such modeling is sufficiently accurate to solve for capsule deformation. This study examines the correlations between the mechanical properties of the discrete spring network model and continuum constitutive laws. We first compare uniaxial and isotropic deformations of a two-dimensional (2D) sheet, both analytically and numerically. The 2D sheet is discretized with four kinds of mesh to analyze the effect of the spring network configuration. We derive the relationships between the spring constant and continuum properties, such as the Young modulus, Poisson ratio, area dilation modulus, and shear modulus. It is found that the mechanical properties of spring networks are strongly dependent on the mesh configuration. We then calculate the deformation of a capsule under inflation and in a simple shear flow in the Stokes flow regime, using various membrane models. To achieve high accuracy in the flow calculation, a boundary-element method is used. Comparing the results between the different membrane models, we find that it is hard to express the area incompressibility observed in biological membranes using a simple spring network model. PMID- 21599212 TI - Ergodicity convergence test suggests telomere motion obeys fractional dynamics. AB - Anomalous diffusion, observed in many biological processes, is a generalized description of a wide variety of processes, all obeying the same law of mean square displacement. Identifying the basic mechanisms of these observations is important for deducing the nature of the biophysical systems measured. We implement a previously suggested method for distinguishing between fractional Langevin dynamics, fractional Brownian motion, and continuous time random walk based on the ergodic nature of the data. We apply the method together with the recently suggested P-variation test and the displacement correlation to the lately measured dynamics of telomeres in the nucleus of mammalian cells and find strong evidence that the telomeres motion obeys fractional dynamics. The ergodic dynamics are observed experimentally to fit fractional Brownian or Langevin dynamics. PMID- 21599213 TI - Acoustic signatures of sound source-tract coupling. AB - Birdsong is a complex behavior, which results from the interaction between a nervous system and a biomechanical peripheral device. While much has been learned about how complex sounds are generated in the vocal organ, little has been learned about the signature on the vocalizations of the nonlinear effects introduced by the acoustic interactions between a sound source and the vocal tract. The variety of morphologies among bird species makes birdsong a most suitable model to study phenomena associated to the production of complex vocalizations. Inspired by the sound production mechanisms of songbirds, in this work we study a mathematical model of a vocal organ, in which a simple sound source interacts with a tract, leading to a delay differential equation. We explore the system numerically, and by taking it to the weakly nonlinear limit, we are able to examine its periodic solutions analytically. By these means we are able to explore the dynamics of oscillatory solutions of a sound source-tract coupled system, which are qualitatively different from those of a sound source filter model of a vocal organ. Nonlinear features of the solutions are proposed as the underlying mechanisms of observed phenomena in birdsong, such as unilaterally produced "frequency jumps," enhancement of resonances, and the shift of the fundamental frequency observed in heliox experiments. PMID- 21599214 TI - Kernel canonical-correlation Granger causality for multiple time series. AB - Canonical-correlation analysis as a multivariate statistical technique has been applied to multivariate Granger causality analysis to infer information flow in complex systems. It shows unique appeal and great superiority over the traditional vector autoregressive method, due to the simplified procedure that detects causal interaction between multiple time series, and the avoidance of potential model estimation problems. However, it is limited to the linear case. Here, we extend the framework of canonical correlation to include the estimation of multivariate nonlinear Granger causality for drawing inference about directed interaction. Its feasibility and effectiveness are verified on simulated data. PMID- 21599216 TI - Cooperative protein transport in cellular organelles. AB - Compartmentalization into biochemically distinct organelles constantly exchanging material is one of the hallmarks of eukaryotic cells. In the most naive picture of interorganelle transport driven by concentration gradients, concentration differences between organelles should relax. We determine the conditions under which cooperative transport, i.e., based on molecular recognition, allows for the existence and maintenance of distinct organelle identities. Cooperative transport is also shown to control the flux of material transiting through a compartmentalized system, dramatically increasing the transit time under high incoming flux. By including chemical processing of the transported species, we show that this property provides a strong functional advantage to a system responsible for protein maturation and sorting. PMID- 21599215 TI - Mechanics of membrane bulging during cell-wall disruption in gram-negative bacteria. AB - The bacterial cell wall is a network of sugar strands crosslinked by peptides that serve as the primary structure for bearing osmotic stress. Despite its importance in cellular survival, the robustness of the cell wall to network defects has been relatively unexplored. Treatment of the gram-negative bacterium Escherichia coli with the antibiotic vancomycin, which disrupts the crosslinking of new material during growth, leads to the development of pronounced bulges and eventually of cell lysis. Here, we model the mechanics of the bulging of the cytoplasmic membrane through pores in the cell wall. We find that the membrane undergoes a transition between a nearly flat state and a spherical bulge at a critical pore radius of ~20 nm. This critical pore size is large compared to the typical distance between neighboring peptides and glycan strands, and hence pore size acts as a constraint on network integrity. We also discuss the general implications of our model to membrane deformations in eukaryotic blebbing and vesiculation in red blood cells. PMID- 21599217 TI - Nucleation at the DNA supercoiling transition. AB - Twisting DNA under a constant applied force reveals a thermally activated transition into a state with a supercoiled structure known as a plectoneme. Using transition-state theory, we predict the rate of this plectoneme nucleation to be of order 10(4) Hz. We reconcile this with experiments that have measured hopping rates of order 10 Hz by noting that the viscous drag on the bead used to manipulate the DNA limits the measured rate. We find that the intrinsic bending caused by disorder in the base-pair sequence is important for understanding the free-energy barrier that governs the transition. Both analytic and numerical methods are used in the calculations. We provide extensive details on the numerical methods for simulating the elastic rod model with and without disorder. PMID- 21599218 TI - Theory on the dynamic memory in the transcription-factor-mediated transcription activation. AB - We develop a theory to explain the origin of the static and dynamical memory effects in transcription-factor-mediated transcription activation. Our results suggest that the following inequality conditions should be satisfied to observe such memory effects: (a) tau(L)?max(tau(R),tau(E)), (b) tau(LT)?tau(T), and (c) tau(I)>=(tau(EL)+tau(TR)) where tau(L) is the average time required for the looping-mediated spatial interactions of enhancer-transcription-factor complex with the corresponding promoter--RNA-polymerase or eukaryotic RNA polymerase type II (PolII in eukaryotes) complex that is located L base pairs away from the cis acting element, (tau(R),tau(E)) are respectively the search times required for the site-specific binding of the RNA polymerase and the transcription factor with the respective promoter and the cis-regulatory module, tau(LT) is the time associated with the relaxation of the looped-out segment of DNA that connects the cis-acting site and promoter, tau(T) is the time required to generate a complete transcript, tau(I) is the transcription initiation time, tau(EL) is the elongation time, and tau(TR) is the termination time. We have theoretically derived the expressions for the various searching, looping, and loop-relaxation time components. Using the experimentally determined values of various time components we further show that the dynamical memory effects cannot be experimentally observed whenever the segment of DNA that connects the cis regulatory element with the promoter is not loaded with bulky histone bodies. Our analysis suggests that the presence of histone-mediated compaction of the connecting segment of DNA can result in higher values of looping and loop relaxation times, which is the origin of the static memory in the transcription activation that is mediated by the memory gene loops in eukaryotes. PMID- 21599219 TI - Complex conjugate eigenvalues in the spectrum of an operator for resonant activation. AB - We consider the exit problem for an overdamped Brownian particle in a potential undergoing dichotomic fluctuations. The system exhibits resonant activation. We compute the corresponding exit times distribution and show that the resonance is associated with the presence of a finite number of complex conjugate eigenvalue pairs in the spectrum of the evolution equation. The properties of these eigenvalues and their influence on the exit times distribution and on the possible dynamics of the system are discussed in detail. PMID- 21599220 TI - Evidence for a bicritical point in the XXZ Heisenberg antiferromagnet on a simple cubic lattice. AB - The classical Heisenberg antiferromagnet with uniaxial exchange anisotropy (XXZ model) in a field on a simple cubic lattice is studied with the help of extensive Monte Carlo simulations. We analyze, in particular, various staggered susceptibilities and Binder cumulants and present clear evidence for the triple point of the antiferromagnetic, spin-flop, and paramagnetic phases being a bicritical point with Heisenberg symmetry. Results are compared to previous predictions applying various theoretical approaches. PMID- 21599221 TI - Non-Gaussianity as a data analysis artifact. AB - Non-Gaussian effects are important features in many fields of physics, and the search for non-Gaussianity motivates several new experiments. Here I show that an insidious form of non-Gaussianity can easily arise as a finite-size effect in a data analysis tool that is guaranteed to be asymptotically Gaussian. This means that experimental searches for non-Gaussianity should also include an extremely careful scrutiny of the statistical tools used to analyze data. PMID- 21599222 TI - Directed motion of C60 on a graphene sheet subjected to a temperature gradient. AB - Nonequilibrium molecular dynamics simulations are used to study the motion of a C(60) molecule on a graphene sheet subjected to a temperature gradient. The C(60) molecule is actuated and moves along the system while it just randomly dances along the perpendicular direction. Increasing the temperature gradient increases the directed velocity of C(60). It is found that the free energy decreases as the C(60) molecule moves toward the cold end. The driving mechanism based on the temperature gradient suggests the construction of nanoscale graphene-based motors. PMID- 21599223 TI - Solitons induced by alternating electric fields in surface-stabilized ferroelectric liquid crystals. AB - Propagation of solitary waves activated in thin ferroelectric liquid crystal cells under external, sinusoidally alternating electric fields is investigated using the electro-optic technique. It is shown that solitons give contributions only to the loss component of the response spectrum, within rather narrow ranges of frequencies and in sufficiently strong fields. The limit frequency, at which the amplitude of the velocity of the solitary waves is greatest, is found to be related to material constants of liquid crystals. Measuring this threshold frequency provides the capability to determine the elastic constant of surface stabilized liquid crystalline materials in the bookshelf or chevron layer geometries. PMID- 21599224 TI - Neural dynamics in parkinsonian brain: the boundary between synchronized and nonsynchronized dynamics. AB - Synchronous oscillatory dynamics is frequently observed in the human brain. We analyze the fine temporal structure of phase-locking in a realistic network model and match it with the experimental data from Parkinsonian patients. We show that the experimentally observed intermittent synchrony can be generated just by moderately increased coupling strength in the basal ganglia circuits due to the lack of dopamine. Comparison of the experimental and modeling data suggest that brain activity in Parkinson's disease resides in the large boundary region between synchronized and nonsynchronized dynamics. Being on the edge of synchrony may allow for easy formation of transient neuronal assemblies. PMID- 21599225 TI - Charge transport in purple membrane monolayers: a sequential tunneling approach. AB - Current-voltage (I-V) characteristics in proteins are sensitive to conformational changes induced by an external stimulus (photons, chemical, etc.). This sensitivity can be used in medical and industrial applications as well as shedding new light on the microscopic structure of biological materials. Here, we show that a sequential tunneling model of carrier transfer between neighboring amino acids in a single protein is the basic mechanism responsible for the electrical properties measured over a wide range of applied potentials. We also show that such a strict correlation between the protein structure and the electrical response can lead to a new generation of nanobiosensors that mimic the sensorial activity of living species. To demonstrate the potential usefulness of protein electrical properties, we provide a microscopic interpretation of recent I-V experiments carried out in bacteriorhodopsin at a nanoscale length. PMID- 21599226 TI - Length-dependent translation of messenger RNA by ribosomes. AB - A simple measure for the efficiency of protein synthesis by ribosomes is provided by the steady state amount of protein per messenger RNA (mRNA), the so-called translational ratio, which is proportional to the translation rate. Taking the degradation of mRNA into account, we show theoretically that both the translation rate and the translational ratio decrease with increasing mRNA length, in agreement with available experimental data for the prokaryote Escherichia coli. We also show that, compared to prokaryotes, mRNA degradation in eukaryotes leads to a less rapid decrease of the translational ratio. This finding is consistent with the fact that, compared to prokaryotes, eukaryotes tend to have longer proteins. PMID- 21599227 TI - Enhancing synchronization by directionality in complex networks. AB - We propose a method called the residual edge-betweenness gradient (REBG) to enhance the synchronizability of networks by assigning the link direction while keeping the topology and link weights unchanged. Direction assignment has been shown to improve the synchronizability of undirected networks in general, but we find that in some cases incommunicable components emerge and networks fail to synchronize. We show that the REBG method improves the residual degree gradient (RDG) method by effectively avoiding the synchronization failure. Further experiments show that the REBG method enhances the synchronizability in networks with a community structure compared with the RDG method. PMID- 21599228 TI - Dynamical strength of social ties in information spreading. AB - We investigate the temporal patterns of human communication and its influence on the spreading of information in social networks. The analysis of mobile phone calls of 20 million people in one country shows that human communication is bursty and happens in group conversations. These features have the opposite effects on the reach of the information: while bursts hinder propagation at large scales, conversations favor local rapid cascades. To explain these phenomena we define the dynamical strength of social ties, a quantity that encompasses both the topological and the temporal patterns of human communication. PMID- 21599229 TI - Vorticity statistics in the direct cascade of two-dimensional turbulence. AB - For the direct cascade of steady two-dimensional (2D) Navier-Stokes turbulence, we derive analytically the probability of strong vorticity fluctuations. When pi is the vorticity coarse-grained over a scale R, the probability density function (PDF), P(pi), has a universal asymptotic behavior lnP~-pi/pi(rms) at pi?pi(rms)=[Hln(L/R)](1/3), where H is the enstrophy flux and L is the pumping length. Therefore, the PDF has exponential tails and is self-similar, that is, it can be presented as a function of a single argument, pi/pi(rms), in distinction from other known direct cascades. PMID- 21599230 TI - Passive scalar structures in supersonic turbulence. AB - We conduct a systematic numerical study of passive scalar structures in supersonic turbulent flows. We find that the degree of intermittency in the scalar structures increases only slightly as the flow changes from transonic to highly supersonic, while the velocity structures become significantly more intermittent. This difference is due to the absence of shocklike discontinuities in the scalar field. The structure functions of the scalar field are well described by the intermittency model of She and Leveque [Phys. Rev. Lett 72, 336 (1994)], and the most intense scalar structures are found to be sheetlike at all Mach numbers. PMID- 21599231 TI - Optimal kinematics and morphologies for spermatozoa. AB - We investigate the role of hydrodynamics in the evolution of the morphology and the selection of kinematics in simple uniflagellated microorganisms. We find that the most efficient swimming strategies are characterized by symmetrical, nonsinusoidal bending waves propagating from the base of the head to the tip of the tail. In addition, we show that the ideal tail-to-head length ratio for such a swimmer is ~12 and that this predicted ratio is consistent with data collected from over 400 species of mammalian sperm. PMID- 21599232 TI - Transverse plasma-wave localization in multiple dimensions. AB - Plasma-wave behavior in multiple dimensions is studied using two- and three dimensional particle-in-cell simulations. We find that large-amplitude waves with klambda(D)?0.2, where k is the wave number of the wave and lambda(D) is the Debye length, localize in the transverse direction around their axis due to nonlinear, local damping caused by transiting particles. The center of the wave behaves like a plane wave in which trapped particles maintain a quasisteady state at approximately constant amplitude, while the transverse edges damp away. PMID- 21599233 TI - Accuracy of the lattice Boltzmann method for low-speed noncontinuum flows. AB - Simulation of noncontinuum gas flows presents tremendous challenges, especially for nanoscale devices that usually exhibit low speeds and isothermal conditions. Such simulations are often achieved through use of the Boltzmann Bhatnagar-Gross Krook equation, which forms the foundation for the lattice Boltzmann (LB) method. Accuracy of the LB method in noncontinuum flows is widely assumed to depend on the order of quadrature used. Here, we study noncontinuum Couette flow and discover that interaction of the lattice with the solid boundaries is the dominant mechanism controlling accuracy--quadrature order plays a comparatively minor role. This suggests the applicability of low-order quadrature in LB simulation of wall bounded isothermal noncontinuum flows, and leads to a framework and rationale for accurate implementation of LB models in noncontinuum flows. PMID- 21599234 TI - Information filtering in complex weighted networks. AB - Many systems in nature, society, and technology can be described as networks, where the vertices are the system's elements, and edges between vertices indicate the interactions between the corresponding elements. Edges may be weighted if the interaction strength is measurable. However, the full network information is often redundant because tools and techniques from network analysis do not work or become very inefficient if the network is too dense, and some weights may just reflect measurement errors and need to be be discarded. Moreover, since weight distributions in many complex weighted networks are broad, most of the weight is concentrated among a small fraction of all edges. It is then crucial to properly detect relevant edges. Simple thresholding would leave only the largest weights, disrupting the multiscale structure of the system, which is at the basis of the structure of complex networks and ought to be kept. In this paper we propose a weight-filtering technique based on a global null model [Global Statistical Significance (GloSS) filter], keeping both the weight distribution and the full topological structure of the network. The method correctly quantifies the statistical significance of weights assigned independently to the edges from a given distribution. Applications to real networks reveal that the GloSS filter is indeed able to identify relevant connections between vertices. PMID- 21599235 TI - Numerical study of a three-state host-parasite system on the square lattice. AB - We numerically study the phase diagram of a three-state host-parasite model on the square lattice motivated by population biology. The model is an extension of the contact process, and the three states correspond to an empty site, a host, and a parasite. We determine the phase diagram of the model by scaling analysis. In agreement with previous results, three phases are identified: the phase in which both hosts and parasites are extinct (S(0)), the phase in which hosts survive but parasites are extinct (S(01)), and the phase in which both hosts and parasites survive (S(012)). We argue that both the S(0)-S(01) and S(01)-S(012) boundaries belong to the directed percolation class. In this model, it has been suggested that an excessively large reproduction rate of parasites paradoxically extinguishes hosts and parasites and results in S(0). We show that this paradoxical extinction is a finite size effect; the corresponding parameter region is likely to disappear in the limit of infinite system size. PMID- 21599236 TI - Role of feedback and broadcasting in the naming game. AB - The naming game (NG) describes the agreement dynamics of a population of agents that interact locally in a pairwise fashion, and in recent years statistical physics tools and techniques have greatly contributed to shed light on its rich phenomenology. Here we investigate in details the role played by the way in which the two agents update their states after an interaction. We show that slightly modifying the NG rules in terms of which agent performs the update in given circumstances (i.e., after a success) can either alter dramatically the overall dynamics or leave it qualitatively unchanged. We understand analytically the first case by casting the model in the broader framework of a generalized NG. As for the second case, on the other hand, we note that the modified rule reproducing the main features of the usual NG corresponds in fact to a simplification of it consisting in the elimination of feedback between the agents. This allows us to introduce and study a very natural broadcasting scheme on networks that can be potentially relevant for different applications, such as the design and implementation of autonomous sensor networks, as pointed out in the recent literature. PMID- 21599237 TI - Network community-detection enhancement by proper weighting. AB - In this paper, we show how proper assignment of weights to the edges of a complex network can enhance the detection of communities and how it can circumvent the resolution limit and the extreme degeneracy problems associated with modularity. Our general weighting scheme takes advantage of graph theoretic measures and it introduces two heuristics for tuning its parameters. We use this weighting as a preprocessing step for the greedy modularity optimization algorithm of Newman to improve its performance. The result of the experiments of our approach on computer-generated and real-world data networks confirm that the proposed approach not only mitigates the problems of modularity but also improves the modularity optimization. PMID- 21599238 TI - Car-following model with relative-velocity effect and its experimental verification. AB - In driving a vehicle, drivers respond to the changes of both the headway and the relative velocity to the vehicle in front. In this paper a new car-following model including these maneuvers is proposed. The acceleration of the model becomes infinite (has a singularity) when the distance between two vehicles is zero, and the asymmetry between the acceleration and the deceleration is incorporated in a nonlinear way. The model is simple but contains enough features of driving for reproducing real vehicle traffic. From the linear stability analysis, we confirm that the model shows the metastable homogeneous flow around the critical density, beyond which a traffic jam emerges. Moreover, we perform experiments to verify this model. From the data it is shown that the acceleration of a vehicle has a positive correlation with the relative velocity. PMID- 21599239 TI - Effect of the interparticle potential on the yield stress of amorphous solids. AB - A crucially important material parameter for all amorphous solids is the yield stress, which is the value of the stress for which the material yields to plastic flow when it is strained quasistatically at zero temperature. It is difficult in laboratory experiments to determine what parameters of the interparticle potential affect the value of the yield stress. Here we use the versatility of numerical simulations to study the dependence of the yield stress on the parameters of the interparticle potential. We find a very simple dependence on the fundamental scales that characterize the repulsive and attractive parts of the potential, respectively, and offer a scaling theory that collapses the data for widely different potentials and in different space dimensions. PMID- 21599240 TI - Amplification of signal response at an arbitrary node of a complex network. AB - Signal detection is generally related to network structure in both biological and engineering systems, and enormous effort has been putting into understanding the mechanism of amplification of weak signals in the aspects of self-tuning and scale-free topology. Here, we show that a third way of signal amplification exists, which does not require the scale-free topology as a necessary condition. This approach can effectively amplify the signal at an arbitrary node in a complex network by adaptively adjusting the coupling weights between the signal node and its neighbors, and thus can be used in both the local and global areas of a complex network. A theory is provided to explain its mechanism. PMID- 21599241 TI - Local dynamics of a randomly pinned crack front during creep and forced propagation: an experimental study. AB - We have studied the propagation of a crack front along the heterogeneous weak plane of a transparent poly(methyl methacrylate) (PMMA) block using two different loading conditions: imposed constant velocity and creep relaxation. We have focused on the intermittent local dynamics of the fracture front for a wide range of average crack front propagation velocities spanning over four decades. We computed the local velocity fluctuations along the fracture front. Two regimes are emphasized: a depinning regime of high velocity clusters defined as avalanches and a pinning regime of very low-velocity creeping lines. The scaling properties of the avalanches and pinning lines (size and spatial extent) are found to be independent of the loading conditions and of the average crack front velocity. The distribution of local fluctuations of the crack front velocity are related to the observed avalanche size distribution. Space-time correlations of the local velocities show a simple diffusion growth behavior. PMID- 21599242 TI - Earthquake correlations and networks: a comparative study. AB - We quantify the correlation between earthquakes and use the same to extract causally connected earthquake pairs. Our correlation metric is a variation on the one introduced by Baiesi and Paczuski [M. Baiesi and M. Paczuski, Phys. Rev. E 69, 066106 (2004)]. A network of earthquakes is then constructed from the time ordered catalog and with links between the more correlated ones. A list of recurrences to each of the earthquakes is identified employing correlation thresholds to demarcate the most meaningful ones in each cluster. Data pertaining to three different seismic regions (viz., California, Japan, and the Himalayas) are comparatively analyzed using such a network model. The distribution of recurrence lengths and recurrence times are two of the key features analyzed to draw conclusions about the universal aspects of such a network model. We find that the unimodal feature of recurrence length distribution, which helps to associate typical rupture lengths with different magnitude earthquakes, is robust across the different seismic regions. The out-degree of the networks shows a hub structure rooted on the large magnitude earthquakes. In-degree distribution is seen to be dependent on the density of events in the neighborhood. Power laws, with two regimes having different exponents, are obtained with recurrence time distribution. The first regime confirms the Omori law for aftershocks while the second regime, with a faster falloff for the larger recurrence times, establishes that pure spatial recurrences also follow a power-law distribution. The crossover to the second power-law regime can be taken to be signaling the end of the aftershock regime in an objective fashion. PMID- 21599243 TI - Effect of state-dependent delay on a weakly damped nonlinear oscillator. AB - We consider a weakly damped nonlinear oscillator with state-dependent delay, which has applications in models for lasers, epidemics, and microparasites. More generally, the delay-differential equations considered are a predator-prey system where the delayed term is linear and represents the proliferation of the predator. We determine the critical value of the delay that causes the steady state to become unstable to periodic oscillations via a Hopf bifurcation. Using asymptotic averaging, we determine how the system's behavior is influenced by the functional form of the state-dependent delay. Specifically, we determine whether the branch of periodic solutions will be either sub- or supercritical as well as an accurate estimation of the amplitude. Finally, we choose a few examples of state-dependent delay to test our analytical results by comparing them to numerical continuation. PMID- 21599244 TI - Study and characterization of interfaces in a two-dimensional generalized voter model. AB - We propose and study, by means of numerical simulations, the time evolution of interfaces in a generalized voter model in d=2 dimensions. In this model, a randomly selected voter can change his or her opinion (state) with a certain probability that is an algebraic function of the average opinion of his or her nearest neighbors. By starting with well-defined (sharp) interfaces between two different states of opinion, we measure the time dependence of the interface width (w), which behaves as a power law, i.e., w alpha t(delta). In this way we characterized three different types of interfaces: (i) between an ordered phase (consensus) and a disordered one (delta=1/2); (ii) between ordered phases having different states of opinion (delta=1/2), which corresponds to interface coarsening without surface tension; and (iii) as in (ii) but considering surface tension. Here, we observe a finite-size induced crossover with exponents delta=1/4 and delta=1/2 for early and longer times, respectively. So, our study allows for the characterization of interfaces of quite different nature in a unified fashion, providing insight into the understanding of interface coarsening with and without surface tension. PMID- 21599245 TI - Using explosive percolation in analysis of real-world networks. AB - We apply a variant of the explosive percolation procedure to large real-world networks and show with finite-size scaling that the university class, ordinary or explosive, of the resulting percolation transition depends on the structural properties of the network, as well as the number of unoccupied links considered for comparison in our procedure. We observe that in our social networks, the percolation clusters close to the critical point are related to the community structure. This relationship is further highlighted by applying the procedure to model networks with predefined communities. PMID- 21599246 TI - Optimal-path cracks in correlated and uncorrelated lattices. AB - The optimal path crack model on uncorrelated surfaces, recently introduced by Andrade et al. [Phys. Rev. Lett. 103, 225503 (2009).], is studied in detail and its main percolation exponents computed. In addition to beta/nu=0.46+/-0.03, we report gamma/nu=1.3+/-0.2 and tau=2.3+/-0.2. The analysis is extended to surfaces with spatial long-range power-law correlations, where nonuniversal fractal dimensions are obtained when the degree of correlation is varied. The model is also considered on a three-dimensional lattice, where the main crack is found to be a surface with a fractal dimension of 2.46+/-0.05. PMID- 21599247 TI - Community detection in graphs using singular value decomposition. AB - A spectral algorithm for community detection is presented. The algorithm consists of three stages: (1) matrix factorization of two matrix forms, square signless Laplacian for unipartite graphs and rectangular adjacency matrix for bipartite graphs, using singular value decompostion (SVD); (2) dimensionality reduction using an optimal linear approximation; and (3) clustering vertices using dot products in reduced dimensional space. The algorithm reveals communities in graphs without placing any restriction on the input network type or the output community type. It is applicable on unipartite or bipartite unweighted or weighted networks. It places no requirement on strict community membership and automatically reveals the number of clusters, their respective sizes and overlaps, and hierarchical modular organization. By representing vertices as vectors in real space, expressed as linear combinations of the orthogonal bases described by SVD, orthogonality becomes the metric for classifying vertices into communities. Results on several test and real world networks are presented, including cases where a mix of disjointed, overlapping, or hierarchical communities are known to exist in the network. PMID- 21599248 TI - Crackling noise in three-point bending of heterogeneous materials. AB - We study the crackling noise emerging during single crack propagation in a specimen under three-point bending conditions. Computer simulations are carried out in the framework of a discrete element model where the specimen is discretized in terms of convex polygons and cohesive elements are represented by beams. Computer simulations revealed that fracture proceeds in bursts whose size and waiting-time distributions have a power-law functional form with an exponential cutoff. Controlling the degree of brittleness of the sample by the amount of disorder, we obtain a scaling form for the characteristic quantities of crackling noise of quasibrittle materials. Analyzing the spatial structure of damage we show that ahead of the crack tip a process zone is formed as a random sequence of broken and intact mesoscopic elements. We characterize the statistics of the shrinking and expanding steps of the process zone and determine the damage profile in the vicinity of the crack tip. PMID- 21599249 TI - Rescaling citations of publications in physics. AB - We analyze the citation distributions of all papers published in Physical Review journals between 1985 and 2009. The average number of citations received by papers published in a given year and in a given field is computed. Large variations are found, showing that it is not fair to compare citation numbers across fields and years. However, when a rescaling procedure by the average is used, it is possible to compare impartially articles across years and fields. We make the rescaling factors available for use by the readers. We also show that rescaling citation numbers by the number of publication authors has strong effects and should therefore be taken into account when assessing the bibliometric performance of researchers. PMID- 21599250 TI - Centrality measures and thermodynamic formalism for complex networks. AB - In the study of small and large networks it is customary to perform a simple random walk where the random walker jumps from one node to one of its neighbors with uniform probability. The properties of this random walk are intimately related to the combinatorial properties of the network. In this paper we propose to use the Ruelle-Bowens random walk instead, whose probability transitions are chosen in order to maximize the entropy rate of the walk on an unweighted graph. If the graph is weighted, then a free energy is optimized instead of the entropy rate. Specifically, we introduce a centrality measure for large networks, which is the stationary distribution attained by the Ruelle-Bowens random walk; we name it entropy rank. We introduce a more general version, which is able to deal with disconnected networks, under the name of free-energy rank. We compare the properties of those centrality measures with the classic PageRank and hyperlink induced topic search (HITS) on both toy and real-life examples, in particular their robustness to small modifications of the network. We show that our centrality measures are more discriminating than PageRank, since they are able to distinguish clearly pages that PageRank regards as almost equally interesting, and are more sensitive to the medium-scale details of the graph. PMID- 21599251 TI - Forest-fire model with natural fire resistance. AB - Observations suggest that contemporary wildfire suppression practices in the United States have contributed to conditions that facilitate large, destructive fires. We introduce a forest-fire model with natural fire resistance that supports this theory. Fire resistance is defined with respect to the size and shape of clusters; the model yields power-law frequency-size distributions of model fires that are consistent with field observations in the United States, Canada, and Australia. PMID- 21599252 TI - Creep rupture of materials: insights from a fiber bundle model with relaxation. AB - I adapted a model recently introduced in the context of seismic phenomena to study creep rupture of materials. It consists of linear elastic fibers that interact in an equal load sharing scheme, complemented with a local viscoelastic relaxation mechanism. The model correctly describes the three stages of the creep process; namely, an initial Andrade regime of creep relaxation, an intermediate regime of rather constant creep rate, and a tertiary regime of accelerated creep toward final failure of the sample. In the tertiary regime, creep rate follows the experimentally observed creep rate over time-to-failure dependence. The time of minimum strain rate is systematically observed to be about 60%-65 % of the time to failure, in accordance with experimental observations. In addition, burst size statistics of breaking events display a -3/2 power law for events close to the time of failure and a steeper decay for the all-time distribution. Statistics of interevent times shows a tendency of the events to cluster temporarily. This behavior should be observable in acoustic emission experiments. PMID- 21599253 TI - Communicability across evolving networks. AB - Many natural and technological applications generate time-ordered sequences of networks, defined over a fixed set of nodes; for example, time-stamped information about "who phoned who" or "who came into contact with who" arise naturally in studies of communication and the spread of disease. Concepts and algorithms for static networks do not immediately carry through to this dynamic setting. For example, suppose A and B interact in the morning, and then B and C interact in the afternoon. Information, or disease, may then pass from A to C, but not vice versa. This subtlety is lost if we simply summarize using the daily aggregate network given by the chain A-B-C. However, using a natural definition of a walk on an evolving network, we show that classic centrality measures from the static setting can be extended in a computationally convenient manner. In particular, communicability indices can be computed to summarize the ability of each node to broadcast and receive information. The computations involve basic operations in linear algebra, and the asymmetry caused by time's arrow is captured naturally through the noncommutativity of matrix-matrix multiplication. Illustrative examples are given for both synthetic and real-world communication data sets. We also discuss the use of the new centrality measures for real-time monitoring and prediction. PMID- 21599254 TI - Quantifying and modeling long-range cross correlations in multiple time series with applications to world stock indices. AB - We propose a modified time lag random matrix theory in order to study time-lag cross correlations in multiple time series. We apply the method to 48 world indices, one for each of 48 different countries. We find long-range power-law cross correlations in the absolute values of returns that quantify risk, and find that they decay much more slowly than cross correlations between the returns. The magnitude of the cross correlations constitutes "bad news" for international investment managers who may believe that risk is reduced by diversifying across countries. We find that when a market shock is transmitted around the world, the risk decays very slowly. We explain these time-lag cross correlations by introducing a global factor model (GFM) in which all index returns fluctuate in response to a single global factor. For each pair of individual time series of returns, the cross correlations between returns (or magnitudes) can be modeled with the autocorrelations of the global factor returns (or magnitudes). We estimate the global factor using principal component analysis, which minimizes the variance of the residuals after removing the global trend. Using random matrix theory, a significant fraction of the world index cross correlations can be explained by the global factor, which supports the utility of the GFM. We demonstrate applications of the GFM in forecasting risks at the world level, and in finding uncorrelated individual indices. We find ten indices that are practically uncorrelated with the global factor and with the remainder of the world indices, which is relevant information for world managers in reducing their portfolio risk. Finally, we argue that this general method can be applied to a wide range of phenomena in which time series are measured, ranging from seismology and physiology to atmospheric geophysics. PMID- 21599255 TI - Income dynamics with a stationary double Pareto distribution. AB - Once controlled for the trend, the distribution of personal income appears to be double Pareto, a distribution that obeys the power law exactly in both the upper and the lower tails. I propose a model of income dynamics with a stationary distribution that is consistent with this fact. Using US male wage data for 1970 1993, I estimate the power law exponent in two ways--(i) from each cross section, assuming that the distribution has converged to the stationary distribution, and (ii) from a panel directly estimating the parameters of the income dynamics model -and obtain the same value of 8.4. PMID- 21599256 TI - Deterministic ripple-spreading model for complex networks. AB - This paper proposes a deterministic complex network model, which is inspired by the natural ripple-spreading phenomenon. The motivations and main advantages of the model are the following: (i) The establishment of many real-world networks is a dynamic process, where it is often observed that the influence of a few local events spreads out through nodes, and then largely determines the final network topology. Obviously, this dynamic process involves many spatial and temporal factors. By simulating the natural ripple-spreading process, this paper reports a very natural way to set up a spatial and temporal model for such complex networks. (ii) Existing relevant network models are all stochastic models, i.e., with a given input, they cannot output a unique topology. Differently, the proposed ripple-spreading model can uniquely determine the final network topology, and at the same time, the stochastic feature of complex networks is captured by randomly initializing ripple-spreading related parameters. (iii) The proposed model can use an easily manageable number of ripple-spreading related parameters to precisely describe a network topology, which is more memory efficient when compared with traditional adjacency matrix or similar memory expensive data structures. (iv) The ripple-spreading model has a very good potential for both extensions and applications. PMID- 21599257 TI - Optimal modularity for nucleation in a network-organized Ising model. AB - We study the nucleation dynamics of the Ising model in a topology that consists of two coupled random networks, thereby mimicking the modular structure observed in real-world networks. By introducing a variant of a recently developed forward flux sampling method, we efficiently calculate the rate and elucidate the pathway for the nucleation process. It is found that as the network modularity worsens the nucleation undergoes a transition from a two-step to one-step process. Interestingly, the nucleation rate shows a nonmonotonic dependence on the modularity, in which a maximal nucleation rate occurs at a moderate level of modularity. A simple mean-field analysis is proposed to qualitatively illustrate the simulation results. PMID- 21599258 TI - Judging model reduction of complex systems. AB - Model reduction is a common goal in the study of complex systems, consisting of many components with a complex interaction structure. The quality of such reduction, however, may not be reflected correctly in the stepwise prediction error in the model since it ignores the global geometry of the dynamics. Here we introduce a general two-step framework, consisting of dimensionality reduction of the time series followed by modeling of the resulting time series, and propose the use of the shadowing distance to measure the quality of the second step. Using coupled oscillator networks as a prototypical example, we demonstrate that our approach can outperform those based on stepwise error and suggest that it sheds light on the problem of identifying and modeling low-dimensional dynamics in large-scale complex systems. PMID- 21599259 TI - Statistical model with two order parameters for ductile and soft fiber bundles in nanoscience and biomaterials. AB - Traditional fiber bundles models (FBMs) have been an effective tool to understand brittle heterogeneous systems. However, fiber bundles in modern nano- and bioapplications demand a new generation of FBM capturing more complex deformation processes in addition to damage. In the context of loose bundle systems and with reference to time-independent plasticity and soft biomaterials, we formulate a generalized statistical model for ductile fracture and nonlinear elastic problems capable of handling more simultaneous deformation mechanisms by means of two order parameters (as opposed to one). As the first rational FBM for coupled damage problems, it may be the cornerstone for advanced statistical models of heterogeneous systems in nanoscience and materials design, especially to explore hierarchical and bio-inspired concepts in the arena of nanobiotechnology. Applicative examples are provided for illustrative purposes at last, discussing issues in inverse analysis (i.e., nonlinear elastic polymer fiber and ductile Cu submicron bars arrays) and direct design (i.e., strength prediction). PMID- 21599260 TI - Vertex centralities in input-output networks reveal the structure of modern economies. AB - Input-output tables describe the flows of goods and services between the sectors of an economy. These tables can be interpreted as weighted directed networks. At the usual level of aggregation, they contain nodes with strong self-loops and are almost completely connected. We derive two measures of node centrality that are well suited for such networks. Both are based on random walks and have interpretations as the propagation of supply shocks through the economy. Random walk centrality reveals the vertices most immediately affected by a shock. Counting betweenness identifies the nodes where a shock lingers longest. The two measures differ in how they treat self-loops. We apply both to data from a wide set of countries and uncover salient characteristics of the structures of these national economies. We further validate our indices by clustering according to sectors' centralities. This analysis reveals geographical proximity and similar developmental status. PMID- 21599261 TI - Spread of information and infection on finite random networks. AB - The modeling of epidemic-like processes on random networks has received considerable attention in recent years. While these processes are inherently stochastic, most previous work has been focused on deterministic models that ignore important fluctuations that may persist even in the infinite network size limit. In a previous paper, for a class of epidemic and rumor processes, we derived approximate models for the full probability distribution of the final size of the epidemic, as opposed to only mean values. In this paper we examine via direct simulations the adequacy of the approximate model to describe stochastic epidemics and rumors on several random network topologies: homogeneous networks, Erdos-Renyi (ER) random graphs, Barabasi-Albert scale-free networks, and random geometric graphs. We find that the approximate model is reasonably accurate in predicting the probability of spread. However, the position of the threshold and the conditional mean of the final size for processes near the threshold are not well described by the approximate model even in the case of homogeneous networks. We attribute this failure to the presence of other structural properties beyond degree-degree correlations, and in particular clustering, which are present in any finite network but are not incorporated in the approximate model. In order to test this "hypothesis" we perform additional simulations on a set of ER random graphs where degree-degree correlations and clustering are separately and independently introduced using recently proposed algorithms from the literature. Our results show that even strong degree-degree correlations have only weak effects on the position of the threshold and the conditional mean of the final size. On the other hand, the introduction of clustering greatly affects both the position of the threshold and the conditional mean. Similar analysis for the Barabasi-Albert scale-free network confirms the significance of clustering on the dynamics of rumor spread. For this network, though, with its highly skewed degree distribution, the addition of positive correlation had a much stronger effect on the final size distribution than was found for the simple random graph. PMID- 21599262 TI - Dependence of kinetic friction on velocity: master equation approach. AB - We investigate the velocity dependence of kinetic friction with a model that makes minimal assumptions on the actual mechanism of friction so that it can be applied at many scales, provided the system involves multicontact friction. Using a recently developed master equation approach, we investigate the influence of two concurrent processes. First, at a nonzero temperature, thermal fluctuations allow an activated breaking of contacts that are still below the threshold. As a result, the friction force monotonically increases with velocity. Second, the aging of contacts leads to a decrease of the friction force with velocity. Aging effects include two aspects: the delay in contact formation and aging of a contact itself, i.e., the change of its characteristics with the duration of stationary contact. All these processes are considered simultaneously with the master equation approach, giving a complete dependence of the kinetic friction force on the driving velocity and system temperature, provided the interface parameters are known. PMID- 21599263 TI - Bounds and self-consistent estimates for elastic constants of polycrystals composed of orthorhombics or crystals with higher symmetries. AB - Methods for computing Hashin-Shtrikman bounds and related self-consistent estimates of elastic constants for polycrystals composed of crystals having orthorhombic symmetry have been known for about three decades. However, these methods are underutilized, perhaps because of some perceived difficulties with implementing the necessary computational procedures. Several simplifications of these techniques are introduced, thereby reducing the overall computational burden, as well as the complications inherent in mapping out the Hashin-Shtrikman bounding curves. The self-consistent estimates of the effective elastic constants are very robust, involving a quickly converging iteration procedure. Once these self-consistent values are known, they may then be used to speed up the computations of the Hashin-Shtrikman bounds themselves. It is shown furthermore that the resulting orthorhombic polycrystal code can be used as well to compute both bounds and self-consistent estimates for polycrystals of higher-symmetry tetragonal, hexagonal, and cubic (but not trigonal) materials. The self consistent results found this way are shown to be the same as those obtained using the earlier methods, specifically those methods designed specially for each individual symmetry type. But the Hashin-Shtrikman bounds found using the orthorhombic code are either the same or (more typically) tighter than those found previously for these special cases (i.e., tetragonal, hexagonal, and cubic). The improvement in the Hashin-Shtrikman bounds is presumably due to the additional degrees of freedom introduced into the available search space. PMID- 21599264 TI - Fractal snapshot components in chaos induced by strong noise. AB - In systems exhibiting transient chaos in coexistence with periodic attractors, the inclusion of weak noise might give rise to noise-induced chaotic attractors. When the noise amplitude exceeds a critical value, an extended attractor appears along the fractal unstable manifold of the underlying nonattracting chaotic set. A further increase of noise leads to a fuzzy nonfractal pattern. By means of the concept of snapshot attractors and random maps, we point out that the fuzzy pattern can be decomposed into well-defined fractal components, the snapshot attractors belonging to a given realization of the noise and generated by following an ensemble of noisy trajectories. The pattern of the snapshot attractor and its characteristic numbers, such as the finite time Lyapunov exponents and numerically evaluated fractal dimensions, change continuously in time. We find that this temporal fluctuation is a robust property of the system which hardly changes with increasing ensemble size. The validity of the Kaplan Yorke formula is also investigated. A superposition of about 100 snapshot attractors provides a good approximant to the fuzzy noise-induced attractor at the same noise strength. PMID- 21599265 TI - Characterizing the phase synchronization transition of chaotic oscillators. AB - The chaotic phase synchronization transition is studied in connection with the zero Lyapunov exponent. We propose a hypothesis that it is associated with a switching of the maximal finite-time zero Lyapunov exponent, which is introduced in the framework of a large deviation analysis. A noisy sine circle map is investigated to introduce this hypothesis and it is tested in an unidirectionally coupled Rossler system by using the covariant Lyapunov vector associated with the zero Lyapunov exponent. PMID- 21599266 TI - Using bivariate signal analysis to characterize the epileptic focus: the benefit of surrogates. AB - The disease epilepsy is related to hypersynchronous activity of networks of neurons. While acute epileptic seizures are the most extreme manifestation of this hypersynchronous activity, an elevated level of interdependence of neuronal dynamics is thought to persist also during the seizure-free interval. In multichannel recordings from brain areas involved in the epileptic process, this interdependence can be reflected in an increased linear cross correlation but also in signal properties of higher order. Bivariate time series analysis comprises a variety of approaches, each with different degrees of sensitivity and specificity for interdependencies reflected in lower- or higher-order properties of pairs of simultaneously recorded signals. Here we investigate which approach is best suited to detect putatively elevated interdependence levels in signals recorded from brain areas involved in the epileptic process. For this purpose, we use the linear cross correlation that is sensitive to lower-order signatures of interdependence, a nonlinear interdependence measure that integrates both lower- and higher-order properties, and a surrogate-corrected nonlinear interdependence measure that aims to specifically characterize higher-order properties. We analyze intracranial electroencephalographic recordings of the seizure-free interval from 29 patients with an epileptic focus located in the medial temporal lobe. Our results show that all three approaches detect higher levels of interdependence for signals recorded from the brain hemisphere containing the epileptic focus as compared to signals recorded from the opposite hemisphere. For the linear cross correlation, however, these differences are not significant. For the nonlinear interdependence measure, results are significant but only of moderate accuracy with regard to the discriminative power for the focal and nonfocal hemispheres. The highest significance and accuracy is obtained for the surrogate-corrected nonlinear interdependence measure. PMID- 21599267 TI - Length scale of interaction in spatiotemporal chaos. AB - Extensive systems have no long scale correlations and behave as a sum of their parts. Various techniques are introduced to determine a characteristic length scale of interaction beyond which spatiotemporal chaos is extensive in reaction diffusion networks. Information about network size, boundary condition, or abnormalities in network topology gets scrambled in spatiotemporal chaos, and the attenuation of information provides such characteristic length scales. Space-time information flow associated with the recovery of spatiotemporal chaos from finite perturbations, a concept somewhat opposite to the paradigm of Lyapunov exponents, defines another characteristic length scale. High-precision computational studies of asymptotic spatiotemporal chaos in the complex Ginzburg-Landau system and transient spatiotemporal chaos in the Gray-Scott network show that these different length scales are comparable and thus suitable to define a length scale of interaction. Preliminary studies demonstrate the relevance of these length scales for stable chaos. PMID- 21599268 TI - Paucity of attractors in nonlinear systems driven with complex signals. AB - We study the probability of multistability in a quadratic map driven repeatedly by a random signal of length N, where N is taken as a measure of the signal complexity. We first establish analytically that the number of coexisting attractors is bounded above by N. We then numerically estimate the probability p of a randomly chosen signal resulting in a multistable response as a function of N. Interestingly, with increasing drive signal complexity the system exhibits a paucity of attractors. That is, almost any drive signal beyond a certain complexity level will result in a single attractor response (p=0). This mechanism may play a role in allowing sensitive multistable systems to respond consistently to external influences. PMID- 21599269 TI - Phase and frequency entrainment in locally coupled phase oscillators with repulsive interactions. AB - Recent experiments in one- and two-dimensional microfluidic arrays of droplets containing Belousov-Zhabotinsky reactants show a rich variety of spatial patterns [M. Toiya et al., J. Phys. Chem. Lett. 1, 1241 (2010)]. The dominant coupling between these droplets is inhibitory. Motivated by this experimental system, we study repulsively coupled Kuramoto oscillators with nearest-neighbor interactions, on a linear chain as well as a ring in one dimension, and on a triangular lattice in two dimensions. In one dimension, we show using linear stability analysis as well as numerical study that the stable phase patterns depend on the geometry of the lattice. We show that a transition to the ordered state does not exist in the thermodynamic limit. In two dimensions, we show that the geometry of the lattice constrains the phase difference between two neighboring oscillators to 2pi/3. We report the existence of domains with either clockwise or anticlockwise helicity, leading to defects in the lattice. We study the time dependence of these domains and show that at large coupling strengths the domains freeze due to frequency synchronization. Signatures of the above phenomena can be seen in the spatial correlation functions. PMID- 21599271 TI - Excited-state phase transition and onset of chaos in quantum optical models. AB - We study the critical behavior of excited states and its relation to order and chaos in the Jaynes-Cummings and Dicke models of quantum optics. We show that both models exhibit a chain of excited-state quantum phase transitions demarcating the upper edge of the superradiant phase. For the Dicke model, the signatures of criticality in excited states are blurred by the onset of quantum chaos. We show that the emergence of quantum chaos is caused by the precursors of the excited-state quantum phase transition. PMID- 21599270 TI - Delay and diversity-induced synchronization transitions in a small-world neuronal network. AB - The synchronized behaviors of a noisy small-world neuronal network with delay and diversity is numerically studied by calculating a synchronization measure and plotting firing pattern. We show that delay in the information transmission can induce fruitful synchronization transitions, including transition from phase locking to antiphase synchronization, and transition from antiphase synchronization to complete synchronization. Furthermore, the delay-induced complete synchronization can be changed by diversity, which causes the oscillatory-like transition between antiphase synchronization and complete synchronization. PMID- 21599272 TI - Using dynamical barriers to control the transmission of light through slowly varying photonic crystals. AB - We use semiclassical Hamiltonian optics to investigate the propagation of light rays through two-dimensional photonic crystals when slow spatial modulation of the lattice parameters induces mixed stable-chaotic ray dynamics. This modulation changes both the shape and frequency range of the allowed frequency bands, thereby bending the resulting semiclassical ray trajectories and confining them within particular regions of the crystal. The curved boundaries of these regions, combined with the bending of the orbits themselves, creates a hierarchy of stable and unstable chaotic trajectories in phase space. For certain lattice parameters and electromagnetic wave frequencies, islands of stable orbits act as a dynamical barrier, which separates the chaotic trajectories into two distinct regions of the crystal, thereby preventing the rays propagating through the structure. We show that changing the frequency of the electromagnetic wave strongly affects the distribution of stable and unstable orbits in both real and phase space. This switches the dynamical barriers on and off and thus modulates the transmission of rays through the crystal. We propose microwave analogs of the photonic crystals as a route to the experimental study of the transport effects that we predict. PMID- 21599273 TI - Detecting chaos in heavy-noise environments. AB - Detecting chaos and estimating the limit of prediction time in heavy-noise environments is an important and challenging task in many areas of science and engineering. An important first step toward this goal is to reduce noise in the signals. Two major types of methods for reducing noise in chaotic signals are chaos-based approaches and wavelet shrinkage. When noise is strong, chaos-based approaches are not very effective, due to failure to accurately approximate the local chaotic dynamics. Here, we propose a nonlinear adaptive algorithm to recover continuous-time chaotic signals in heavy-noise environments. We show that it is more effective than both chaos-based approaches and wavelet shrinkage. Furthermore, we apply our algorithm to study two important issues in geophysics. One is whether chaos exists in river flow dynamics. The other is the limit of prediction time for the Madden-Julian oscillation (MJO), which is one of the most dominant modes of low-frequency variability in the tropical troposphere and affects a wide range of weather and climate systems. Using the adaptive filter, we show that river flow dynamics can indeed be chaotic. We also show that the MJO is weakly chaotic with the prediction time around 50 days, which is considerably longer than the prediction times determined by other approaches. PMID- 21599274 TI - Nonstationary regimes in a Duffing oscillator subject to biharmonic forcing near a primary resonance. AB - An analytical investigation of nonstationary processes in a Duffing oscillator subject to biharmonic forcing, under conditions of primary resonance, is carried out. The earlier developed methodology of limiting phase trajectories (LPTs) for studying highly nonstationary regimes, characterized by intense energy exchanges between the different degrees of freedom, is successfully applied to the system under investigation. Two distinct types of LPT trajectories are described in the first part of the study. Conditions for the recurrent transitions in time from one type of LPT to another were derived in the first part of the analysis corresponding to the undamped case. An approximation of the LPT related to the higher amplitude of oscillations was derived using nonsmooth transformations. An analysis carried out in the study has revealed the necessary and sufficient conditions for excitation of relaxation oscillations exhibited by a lightly damped system. It was also demonstrated that the mechanism of relaxations may be approximated and explained by the methodology of LPTs, characterized by strong energy exchanges between the coupled oscillators or, alternatively, a single oscillator and an external source of energy. The results of analytical approximations and numerical simulations are observed to be in quite satisfactory agreement. PMID- 21599275 TI - Route to hyperchaos in a system of coupled oscillators with multistability. AB - This work presents the results of a detailed experimental study into the transition between synchronized, low-dimensional, and unsynchronized, high dimensional dynamics using a system of coupled electronic chaotic oscillators. Novel data analysis techniques have been employed to reveal that a hyperchaotic attractor can arise from the amalgamation of two nonattracting sets. These originate from initially multistable low-dimensional attractors which experience a smooth transition from low- to high-dimensional chaotic behavior, losing stability through a bubbling bifurcation. Numerical techniques were also employed to verify and expand on the experimental results, giving evidence on the locally unstable invariant sets contained within the globally stable hyperchaotic attractor. This particular route to hyperchaos also results in the possibility of phenomena (such as unstable dimension variability) that can be a major obstruction to shadowing and predictability in chaotic systems. PMID- 21599276 TI - Brittle fracture in viscoelastic materials as a pattern-formation process. AB - A continuum model of crack propagation in brittle viscoelastic materials is presented and discussed. Thereby, the phenomenon of fracture is understood as an elastically induced nonequilibrium interfacial pattern formation process. In this spirit, a full description of a propagating crack provides the determination of the entire time dependent shape of the crack surface, which is assumed to be extended over a finite and self-consistently selected length scale. The mechanism of crack propagation, that is, the motion of the crack surface, is then determined through linear nonequilibrium transport equations. Here we consider two different mechanisms, a first-order phase transformation and surface diffusion. We give scaling arguments showing that steady-state solutions with a self-consistently selected propagation velocity and crack shape can exist provided that elastodynamic or viscoelastic effects are taken into account, whereas static elasticity alone is not sufficient. In this respect, inertial effects as well as viscous damping are identified to be sufficient crack tip selection mechanisms. Exploring the arising description of brittle fracture numerically, we study steady-state crack propagation in the viscoelastic and inertia limit as well as in an intermediate regime, where both effects are important. The arising free boundary problems are solved by phase field methods and a sharp interface approach using a multipole expansion technique. Different types of loading, mode I, mode III fracture, as well as mixtures of them, are discussed. PMID- 21599277 TI - Lyapunov decoherence rate in classically chaotic systems. AB - We provide a path integral treatment of the decoherence process induced by a heat bath on a single particle whose dynamics is classically chaotic and show that the decoherence rate is given by the Lyapunov exponent. The loss of coherence is charaterized by the purity, which is calculated semiclassically within diagonal approximation, when the particle initial state is a single Gaussian wave packet. The calculation is performed for weak dissipation and in the high-temperature limit. This situation allows us to simplify the heat bath description to a single random potential. Although the dissipative term is neglected in such approach, the fluctuating one can be treated phenomenologically to fit with the above regime. Our results are therefore valid for times shorter than the inverse of the dissipation rate. PMID- 21599278 TI - Energy growth rate in smoothly oscillating billiards. AB - Particle motion in a smoothly oscillating nonintegrable billiard is known to result in unbounded energy growth. The asymptotic energy growth rate of an ensemble of particles in a smoothly oscillating chaotic billiard is known to be quadratic in time. In this paper, it is shown that although this holds for the case of small oscillations, large oscillations in chaotic billiards can lead to faster than quadratic-in-time energy growth. It is also shown that the energy growth rate in oscillating pseudo-integrable billiards could be exponential in time. This is important for applications since slower than exponential-in-time energy growth can be annihilated by dissipation. PMID- 21599279 TI - Lyapunov modes as fields. AB - The numerically observed approximate functional forms for the transverse and longitudinal-momentum proportional (LP) Gram-Schmidt Lyapunov modes have been studied for some time. We construct a field theory for a system where the number of particles is large enough so the Lyapunov mode contributions from each particle can be considered to change continuously with particle position, whose solution gives the observed functional forms for all modes. The wave equations obtained as solutions of the field theory are derived either phenomenologically or from the exact dynamics of two-dimensional hard particles. The wave speed of the LP modes is predicted to reasonable accuracy for a range of densities and system sizes. PMID- 21599280 TI - Renormalized waves and thermalization of the Klein-Gordon equation. AB - We study the thermalization of the classical Klein-Gordon equation under a u(4) interaction. We numerically show that even in the presence of strong nonlinearities, the local thermodynamic equilibrium state exhibits a weakly nonlinear behavior in a renormalized wave basis. The renormalized basis is defined locally in time by a linear transformation and the requirement of vanishing wave-wave correlations. We show that the renormalized waves oscillate around one frequency, and that the frequency dispersion relation undergoes a nonlinear shift proportional to the mean square field. In addition, the renormalized waves exhibit a Planck-like spectrum. Namely, there is equipartition of energy in the low-frequency modes described by a Boltzmann distribution, followed by a linear exponential decay in the high-frequency modes. PMID- 21599281 TI - Experimental observation of Loschmidt time reversal of a quantum chaotic system. AB - We have performed an experiment to demonstrate the approximate time reversal of a "chaotic" time evolution of atomic de Broglie waves. We use ultracold atoms from a Bose-Einstein condensate in a quantum delta-kicked rotor experiment, and show that an initial state can be approximately re-created even after a period of "chaotic" evolution (a number of kicks). As this mechanism only works for a very narrow range of momenta, the net effect is a narrowing of the momentum distribution after the kick sequence. PMID- 21599282 TI - Enhancement of "logical" responses by noise in a bistable optical system. AB - We verify numerically the phenomenon of logical stochastic resonance in a polarization bistable laser. Namely, we show that when one presents two weak binary inputs to the laser system, the response mirrors a logical OR(NOR) output. The reliability of the logic operation is dependent on the noise intensity. As one increases the noise, the probability of the output reflecting the desired OR(NOR) operation increases to nearly unity and then decreases. We also demonstrate that changing the bias morphs the output into another logic operation, AND(NAND), whose probability displays analogous behavior. Furthermore, we highlight the possibility of processing two logic gates in parallel in our laser system by exploiting two coupled orthogonal polarizations that can be detected simultaneously. This suggests that the computational power of the optical system may be enhanced by this additional potential for parallel processing. PMID- 21599283 TI - Turing instability in oscillator chains with nonlocal coupling. AB - We investigate analytically and numerically the conditions for the Turing instability to occur in a one-dimensional chain of nonlinear oscillators coupled nonlocally, in such a way that the coupling strength decreases with the spatial distance as a power law. A range parameter makes it possible to cover the two limiting cases of local (nearest-neighbor) and global (all-to-all) couplings. We consider an example from a nonlinear autocatalytic reaction-diffusion model. PMID- 21599284 TI - Synchronization and stimulated emission in an array of mechanical phase oscillators on a resonant support. AB - Inspired by recent laboratory observations, we propose a mechanical model for eccentrically weighted motors coupled through a vibrating plate. The equations are found to generalize those of Kuramoto to frequency- and position-dependent coupling. The behavior of the model, as determined analytically for no disorder and numerically for systems with and without quenched disorder, shows the key features observed in the laboratory, including hysteresis, bistability, and a spectral gap. The model exhibits stimulated emission and discontinuous lasinglike transitions. PMID- 21599285 TI - Synchronization of chaotic networks with time-delayed couplings: an analytic study. AB - Networks of nonlinear units with time-delayed couplings can synchronize to a common chaotic trajectory. Although the delay time may be very large, the units can synchronize completely without time shift. For networks of coupled Bernoulli maps, analytic results are derived for the stability of the chaotic synchronization manifold. For a single delay time, chaos synchronization is related to the spectral gap of the coupling matrix. For networks with multiple delay times, analytic results are obtained from the theory of polynomials. Finally, the analytic results are compared with networks of iterated tent maps and Lang-Kobayashi equations, which imitate the behavior of networks of semiconductor lasers. PMID- 21599286 TI - Role of delay for the symmetry in the dynamics of networks. AB - The symmetry in a network of oscillators determines the spatiotemporal patterns of activity that can emerge. We study how a delay in the coupling affects symmetry-breaking and -restoring bifurcations. We are able to draw general conclusions in the limit of long delays. For one class of networks we derive a criterion that predicts that delays have a symmetrizing effect. Moreover, we demonstrate that for any network admitting a steady-state solution, a long delay can solely advance the first bifurcation point as compared to the instantaneous coupling regime. PMID- 21599287 TI - Mechanism of phase splitting in two coupled groups of suprachiasmatic-nucleus neurons. AB - The phase-splitting behavior of coupled suprachiasmatic-nucleus neurons has been observed in many mammals, and its mechanism is still not completely understood. Based on our previous work [C. Gu, J. Wang, and Z. Liu, Phys. Rev. E 80, 030904(R) (2009)] on the free-running periods of neurons in the suprachiasmatic nucleus, we present here a modified Goodwin oscillator model to explain the mechanism of phase splitting. In contrast to the previous phase model, the modified Goodwin oscillator model contains the information on both the phase and amplitude and, thus, can show more features than the purely phase model, including all three behaviors of synchronization, phase splitting, and amplitude death and the distributed periodicity in the regions of synchronization and phase splitting, etc. An analytic phase model is extracted from the modified Goodwin oscillator model to explain the dependence of periodicity on the parameters. Moreover, both the modified Goodwin oscillator model and the analytic phase model show that the ensemble frequency can be enhanced or reduced by the time delay. PMID- 21599288 TI - Working conditions for safe detection of nonlinearity and noise titration. AB - Even if noise titration cannot be satisfactorily used to prove the presence of chaos, it can still be used to detect nonlinear component in dynamics. Nevertheless, since the technique have the use of nonlinear models for one-step ahead predictions, it requires an acute choice of modeling parameters, i.e., the number of terms and the nonlinearity degree of the models. Based on illustrative examples, we propose conditions under which the method of noise titration can be reliably applied to characterize nonlinearity in the time series. It is thus possible to compare different time series and state which one is governed by the strongest nonlinearity. For instance, it is shown that, when there is a single nonlinear term in the equations describing the system, the variable on which it acts can be identified among the others. PMID- 21599289 TI - Methodology for artificial microswimming using magnetic actuation. AB - We propose a methodology for swimming at low-Reynolds-number flows based on ciliary motion of a microswimmer using magnetic actuation of artificial cilia. By solving the coupled magnetic-elastic-hydrodynamic problem, we demonstrate nonreciprocal effective and recovery strokes for cilia that nicely mimic natural cilia beating. Cilia drag forces, microswimmer net displacement, velocity, and efficiency are calculated, and we show the model can swim using a prespecified magnetic actuation. The proposed methodology can be used for devising biomedical microdevices that swim in viscous flows inside the human body. PMID- 21599290 TI - Evolution of droplets of perfectly wetting liquid under the influence of thermocapillary forces. AB - We consider the evolution of sessile droplets of a nonvolatile perfectly wetting liquid on differentially radially heated solid substrates. The heating induces thermocapillary Marangoni forces that affect the contact line dynamics. Our experiments involving a particular heating pattern reveal that the Marangoni effect suppresses the spreading of a drop, typical for perfectly wetting liquids. The result is a rather slow receding motion and a distinctive thinning of the liquid layer in the region close to the contact line. Our theoretical model, based on the lubrication approximation and incorporating the Marangoni effect, recovers the main features observed in the experiments, and in addition predicts novel features that are still to be observed. PMID- 21599291 TI - Wave turbulence on the surface of a ferrofluid in a horizontal magnetic field. AB - We report observations of wave turbulence on the surface of a ferrofluid submitted to a magnetic field parallel to the fluid surface. The magnetic wave turbulence shows several differences compared to the normal field case reported recently. The inertial zone of the magnetic wave turbulence regime is notably found to be strongly increased with respect to the normal field case and to be well described by our theoretical predictions. The dispersion relation of linear waves is also measured and differs from the normal field case due to the absence of the Rosensweig instability. PMID- 21599292 TI - Convection patterns in a spherical fluid shell. AB - Symmetry-breaking bifurcations have been studied for convection in a nonrotating spherical shell whose outer radius is twice the inner radius, under the influence of an externally applied central force field with a radial dependence proportional to 1/r(5). This work is motivated by the GeoFlow experiment, which is performed under microgravity condition at the International Space Station where this particular central force can be generated. In order to predict the observable patterns, simulations together with path-following techniques and stability computations have been applied. Branches of axisymmetric, octahedral, and seven-cell solutions have been traced. The bifurcations producing them have been identified and their stability ranges determined. At higher Rayleigh numbers, time-periodic states with a complex spatiotemporal symmetry are found, which we call breathing patterns. PMID- 21599293 TI - Tank-treading and tumbling frequencies of capsules and red blood cells. AB - This study is motivated in part by the discrepancy that exists in the literature with regard to the dependence of the tank-treading frequency of red blood cells on the shear rate and suspending medium viscosity. Here we consider three dimensional numerical simulations of deformable capsules of initially spherical and oblate spheroidal shapes and biconcave discoid representing the red blood cell resting shape. By considering a much broader range of the viscosity ratio (ratio of capsule or cell interior to suspending fluid viscosity), shear rate, and aspect ratio (ratio of minor to major axes) than that considered in the previous experiments, we find several new characteristics of the tank-treading and tumbling frequencies that have not been reported earlier. These new characteristics are the result of the large shape deformation and the coupling between shape and angular oscillations of the capsules or cells. For the spherical and oblate spheroidal capsules, the tank-treading frequency shows a nonmonotonic trend that is characterized by an initial decrease leading to a minimum followed by an increase with increasing viscosity ratio. For red blood cells, we find two regimes of the viscosity dependence of the tank-treading frequency: an exponential regime in which the tank-treading frequency decreases at a slower rate with increasing viscosity ratio, and a logarithmic range in which it decreases at a much faster rate. While this trend agrees well with different theoretical models of shape-preserving capsules, it was not evident in previous experimental results. When the shear rate dependence is considered, the tank-treading frequency of red blood cells and capsules of highly elongated initial shapes exhibits a nonmonotonic trend that is characterized by an initial increase leading to a maximum followed by a sharp decrease with decreasing shear rate. This anomalous behavior of the tank-treading frequency is shown to be due to a breathing-like dynamics of the capsule or cell that is characterized by a repeated emergence and absence of deep, crater-like dimples, and a large swinging motion. We further observe that the tumbling frequency exhibits a decreasing trend with increasing viscosity ratio that is in contrast to the theoretical result for the shape-preserving capsules and is due to the periodic deformation and preferential alignment of the capsules in the extensional quadrant of the flow. PMID- 21599294 TI - Luminescence from laser-induced bubbles in water-glycerol mixtures: effect of viscosity. AB - The luminescence pulses emitted from collapsing laser-induced bubbles in water glycerol mixtures are studied as a function of the mixture concentration and applied hydrostatic pressure. The primary effect of increasing the glycerol concentration is to increase the viscosity of the fluid. The pulse duration of the luminescence is found to increase by more than a factor of two as the concentration increases up to 33% glycerol by volume, where the viscosity is nearly four times that of pure water. At higher glycerol concentrations the pulse duration remains nearly unchanged, until no luminescence can be observed at concentrations above 60%, corresponding to a viscosity greater than 15 times that of water. The pulse duration further increases with applied pressures up to 8 bar, similar to that observed earlier in pure water. PMID- 21599295 TI - Self-destabilizing mechanism of a laminar inviscid liquid jet issuing from a circular nozzle. AB - A laminar inviscid liquid (typically water) jet issuing from a circular nozzle into otherwise quiescent air disintegrates into droplets periodically at a distance from the nozzle. The Plateau-Rayleigh instability theory and others cannot determine this breakup length because they do not have any logic that determines the initial amplitude of the unstable wave responsible for the breakup. In this paper, a closed spatial evolution solution is derived for a uniformly issued liquid jet by applying a theory that identifies the origin of the unstable wave. This solution describes the self-destabilizing mechanism of the liquid jet in the steady breakup state, showing that the initial amplitude of the unstable wave is determined by the capillary wave with upstream propagating speed that is created by the tip contraction at every breakup. Finally, the developed theory is extended to allow for the self-destabilizing mechanism of a liquid jet issuing from a long nozzle, which initially has a parabolic velocity profile and results in a long breakup length. PMID- 21599296 TI - Alignment statistics of active and passive scalar gradients in turbulent stratified flames. AB - The scalar gradient alignment statistics for active and passive scalar gradients (e.g., fuel mass fraction gradient and mixture fraction gradient) are presented here for turbulent stratified flames. It has been shown that, under some conditions, the active scalar gradient may align with the most extensive principal strain rate in contrast to the passive scalar gradient that remains aligned with the most compressive principal strain rate even when the active scalar gradient aligns preferentially with the most extensive principal strain rate. Physical explanations are provided for the observed behaviors. PMID- 21599297 TI - Vesicle electrohydrodynamics. AB - A small amplitude perturbation analysis is developed to describe the effect of a uniform electric field on the dynamics of a lipid bilayer vesicle in a simple shear flow. All media are treated as leaky dielectrics and fluid motion is described by the Stokes equations. The instantaneous vesicle shape is obtained by balancing electric, hydrodynamic, bending, and tension stresses exerted on the membrane. We find that in the absence of ambient shear flow, it is possible that an applied stepwise uniform dc electric field could cause the vesicle shape to evolve from oblate to prolate over time if the encapsulated fluid is less conducting than the suspending fluid. For a vesicle in ambient shear flow, the electric field damps the tumbling motion, leading to a stable tank-treading state. PMID- 21599298 TI - Dissipation in peristaltic pumping of a compressible viscous fluid through a planar duct or a circular tube. AB - When a compressible viscous fluid is pumped through a linear channel by means of a running surface wave on the wall, energy is dissipated in the fluid. The rate of dissipation can be evaluated effectively from the work performed on the fluid by the wavy wall. Explicit expressions are derived for the rate of dissipation for a planar duct and a circular tube, valid to second order in the amplitude of the surface wave. In both cases the rate of dissipation shows a resonance as a function of frequency when the phase velocity of the surface wave equals the sound velocity of the fluid. PMID- 21599299 TI - Inertial effects on rotating Hele-Shaw flows. AB - We examine the finite surface tension radial viscous fingering problem in a rotating Hele-Shaw cell, and focus on the action of inertial effects on the stability and morphology of the emerging patterns. To study such a flow we use an alternative version of the usual Darcy's law derived by gap-averaging the Navier Stokes equation, but retaining its inertial terms. The importance of inertial forces is pertinently characterized by a rotational Reynolds number. Linear and weakly nonlinear stages of the dynamics are described analytically through a mode coupling approach. The linear stability results indicate that inertia has a stabilizing role. However, the characteristic number of fingers and the width of the band of linearly unstable modes are not altered by inertia. In the early nonlinear regime we find that inertia acts to favor the development of fingers with narrower tips than those obtained in its absence. We have also verified that finger competition events are affected by inertial effects which tend to restrain finger length variability among inward-moving fingers. PMID- 21599300 TI - Onset of convection in a porous medium in the presence of chemical reaction. AB - Using scaling, we show that the stability of a buoyant boundary layer in a porous medium in the presence of a first-order chemical reaction is fully determined by the nondimensional number Da/Ra(2)=k(r)aDphiMU(2)/(kDeltarho(0)g)(2), where Da=k(r)aL(Z)(2)/k(r)aL(Z)(2)(Dphi) is the Damkohler number and Ra=kDeltarho(0)gL(Z)/kDeltarho(0)gL(Z)(MUDphi) is the solutal Rayleigh number. The time for onset of convection is shown to increase with rising Da/Ra(2). Above a critical Da/DaRa(2)~2*10(-3) Ra(2)~2*10(-3), no convection occurs as reaction stabilizes the diffusive layer at a finite thickness. This thickness decreases with increasing Da/Ra(2), becoming zero at Da/Ra(2)~O(1). As applied to CO(2) geostorage, our results suggest distinct regimes for CO(2) transport in saline aquifers. PMID- 21599301 TI - Asymmetry and bifurcations in three-dimensional sudden-contraction channel flows. AB - This study reports the presence of two different stable modes of bifurcation in the near field of a three-dimensional sudden contraction. To be precise, flow downstream of a symmetric sudden contraction undergoes a transition from a symmetric state to an asymmetric state through a symmetry-breaking pitchfork bifurcation following an increase in the channel aspect ratio or the Reynolds number. In addition, the oncoming (upstream) symmetry-plane flow exhibits spanwise bifurcations along the topological core lines of each of the salient roof and floor eddies. Small aspect-ratio (contraction) channels are noted to facilitate interesting splitting of the salient roof and floor eddies into multicore forms with accompanying spanwise flow bifurcations along the respective vortical core lines. Herein extensive three-dimensional simulations performed with various aspect and contraction ratios and Reynolds numbers clearly suggest that flow transition in the sudden-contraction channels should indeed occur primarily through these two generically distinct modes of bifurcation. PMID- 21599302 TI - Transverse permeability of fibrous porous media. AB - In this study, the transverse permeability of fibrous porous media is studied both experimentally and theoretically. A scale analysis technique is employed for determining the transverse permeability of various fibrous matrices including square, staggered, and hexagonal arrangements of unidirectionally aligned fibers, as well as simple two-directional mats and simple cubic structures. In the present approach, the permeability is related to the porosity, fiber diameter, and tortuosity of the medium. In addition, the pressure drop in several samples of tube banks of different arrangements and metal foams are measured in the creeping flow regime. The pressure-drop results are then used to calculate the permeability of the samples. The developed compact relationships are successfully verified through comparison with these experimental results and the data reported by others. Our results suggest that fiber orientation has an important effect on the permeability; however, these effects are more pronounced in low porosities, i.e., E<0.7. PMID- 21599303 TI - Convection in nanofluids with a particle-concentration-dependent thermal conductivity. AB - Thermal convection in nanofluids is investigated by means of a continuum model for binary-fluid mixtures, with a thermal conductivity depending on the local concentration of colloidal particles. The applied temperature difference between the upper and the lower boundary leads via the Soret effect to a variation of the colloid concentration and, therefore, to a spatially varying heat conductivity. An increasing difference between the heat conductivity of the mixture near the colder and the warmer boundary results in a shift of the onset of convection to higher values of the Rayleigh number for positive values of the separation ratio psi>0 and to smaller values in the range psi<0. Beyond some critical difference of the thermal conductivity between the two boundaries, we find an oscillatory onset of convection not only for psi<0, but also within a finite range of psi>0. This range can be extended by increasing the difference in the thermal conductivity, and it is bounded by two codimension-2 bifurcations. PMID- 21599304 TI - Gas-driven displacement of a liquid in a partially filled radial Hele-Shaw cell. AB - The displacement of liquids from confined geometries by using a gas phase is a problem that is relevant to many technologies. Efficient removal of the liquid phase is achieved when an extremely thin residual fluid film is produced as it is displaced. Here the dynamics of air, at constant pressure, displacing a glycerol water drop in a radial Hele-Shaw cell is studied in this context at low Reynolds numbers. Empirically derived expressions relating the input parameters (fluid viscosity, pressure, and drop volume) to characteristic gas flow and liquid displacement rates, and the steady-state film thickness, are proposed and compared with experiments. The experiments consist of measuring cross-sectional areas of the penetrating gas (air) and displaced liquid using glycerol-water mixtures with viscosities ranging from 4 to 280 cSt and with inlet pressures ranging from 3.5 to 10.5 kPa at gap spacings of 50-100 MUm. We estimate that the system produces residual film thicknesses in the range of 5-95 MUm. PMID- 21599305 TI - Mathematical model of Rayleigh-Taylor and Richtmyer-Meshkov instabilities for viscoelastic fluids. AB - We extended the Goncharov model [V. N. Goncharov, Phys. Rev. Lett. 88, 134502 (2002)] for nonlinear Rayleigh-Taylor instability of perfect fluids to the case of Rivlin-Ericksen viscoelastic fluids [R. S. Rivlin and J. L. Ericksen, Rat. Mech. Anal. 4, 323 (1955)], with surface tension. For Rayleigh-Taylor instability, viscosity, surface tension, and viscoelasticity decrease the exponential growth rate predicted by linear stability analysis. In particular, we find that viscosity and surface tension decrease the terminal bubble velocity, whereas viscoelasticity is found to have no effect. All three properties increase the saturation height of the bubble. In Richmyer-Meshkov instability, the decay of the asymptotic velocity depends on the balance between viscosity and surface tension, and viscoelasticity tends to slow the asymptotic velocity decay. PMID- 21599306 TI - Simulation of the droplet-to-bubble transition in a two-fluid system. AB - Recent experiments by Burton and Taborek have demonstrated a droplet-to-bubble transition in the pinchoff behavior of one inviscid fluid inside another. With D the relative densities rho(E)/rho(I), they find transition from (D=0) droplet-to bubble behavior at D~4. Numerical simulations of this two-fluid system, up to and beyond the initial breakup of the inner fluid, have been carried out utilizing level set and boundary integral methods. A droplet-to-bubble transition is predicted: For D sufficiently large, the volume of the satellite droplet shrinks to zero and there is no overturning of the fluid at separation. The calculated self-similar scaling exponents and the pinchoff region shapes match the known behavior at the droplet and bubble extremes (D=0, D=100). For intermediate D values, the simulations presented here indicate that the transition range between droplet and bubble behavior depends upon initial drop geometry. When the neck separates two nonequal inner fluid masses the transition is mild and occurs in the range 4=100 GeV) gamma-ray signal from self annihilating particle dark matter (DM) is performed towards a region of projected distance r~45-150 pc from the Galactic center. The background-subtracted gamma ray spectrum measured with the High Energy Stereoscopic System (H.E.S.S.) gamma ray instrument in the energy range between 300 GeV and 30 TeV shows no hint of a residual gamma-ray flux. Assuming conventional Navarro-Frenk-White and Einasto density profiles, limits are derived on the velocity-weighted annihilation cross section (sigmav) as a function of the DM particle mass. These are among the best reported so far for this energy range and in particular differ only little between the chosen density profile parametrizations. In particular, for the DM particle mass of ~1 TeV, values for (sigmav) above 3*10(-25) cm(3) s(-1) are excluded for the Einasto density profile. PMID- 21599356 TI - Evidence for a bound H dibaryon from lattice QCD. AB - We present evidence for the existence of a bound H dibaryon, an I=0, J=0, s=-2 state with valence quark structure uuddss, at a pion mass of m(pi)~389 MeV. Using the results of lattice QCD calculations performed on four ensembles of anisotropic clover gauge-field configurations, with spatial extents of L~2.0, 2.5, 3.0, and 3.9 fm at a spatial lattice spacing of b(s)~0.123 fm, we find an H dibaryon bound by B(infinity)(H)=16.6+/-2.1+/-4.6 MeV at a pion mass of m(pi)~389 MeV. PMID- 21599357 TI - Bound H dibaryon in flavor SU(3) limit of lattice QCD. AB - The flavor-singlet H dibaryon, which has strangeness -2 and baryon number 2, is studied by the approach recently developed for the baryon-baryon interactions in lattice QCD. The flavor-singlet central potential is derived from the spatial and imaginary-time dependence of the Nambu-Bethe-Salpeter wave function measured in N(f)=3 full QCD simulations with the lattice size of L?2,3,4 fm. The potential is found to be insensitive to the volume, and it leads to a bound H dibaryon with the binding energy of 30-40 MeV for the pseudoscalar meson mass of 673-1015 MeV. PMID- 21599358 TI - Jets, Mach cones, hot spots, ridges, harmonic flow, dihadron, and gamma-hadron correlations in high-energy heavy-ion collisions. AB - Within the AMPT Monte Carlo model, fluctuations in the initial transverse parton density are shown to lead to harmonic flows. The net back-to-back dihadron azimuthal correlation after subtraction of contributions from harmonic flows still has a double peak that is independent of the initial geometric triangularity and unique to the jet-induced Mach cone and expanding hot spots distorted by radial flow. The longitudinal structure of hot spots also leads to a nearside ridge in dihadron correlation with a large rapidity gap. By successively randomizing the azimuthal angle of the transverse momenta and positions of initial partons, one can isolate the effects of jet-induced medium excitation and expanding hot spots on the dihadron azimuthal correlation. The double peaks in the net dihadron and gamma-hadron correlation are quantitatively different since the later is caused only by jet-induced Mach cone. PMID- 21599359 TI - Explanation of dijet asymmetry in Pb-Pb collisions at the Large Hadron Collider. AB - We investigate the medium modification of a partonic jet shower traversing in a hot quark-gluon plasma. We derive and solve a differential equation that governs the evolution of the radiated gluon distribution as the jet propagates through the medium. Energy contained inside the jet cone is lost by dissipation through elastic collisions with the medium and by scattering of shower partons to larger angles. We find that the jet energy loss at early times is dominated by medium effects on the vacuum radiation, and by medium-induced radiation effects at late times. We compare our numerical results for the nuclear modification of the dijet asymmetry with that recently reported by the ATLAS Collaboration. PMID- 21599361 TI - Proposal for a nuclear gamma-ray laser of optical range. AB - A possibility of the amplification of the 7.6 eV gamma radiation by the stimulated gamma emission of the ensemble of the (229m)Th isomeric nuclei in a host dielectric crystal is proved theoretically. This amplification is a result of (1) the excitation of a large number of (229m)Th isomers by laser radiation, (2) the creation of the inverse population of nuclear levels in a cooled sample owing to the interaction of thorium nuclei with the crystal electric field or with an external magnetic field, (3) the emission or absorption of the optical photons by thorium nuclei in the crystal without recoil, and (4) the nuclear spin relaxation through the conduction electrons of the metallic covering. PMID- 21599360 TI - New Measurement of the pi0 radiative decay width. AB - High precision measurements of the differential cross sections for pi0 photoproduction at forward angles for two nuclei, 12C and 208Pb, have been performed for incident photon energies of 4.9-5.5 GeV to extract the pi0 >gammagamma decay width. The experiment was done at Jefferson Lab using the Hall B photon tagger and a high-resolution multichannel calorimeter. The pi0 >gammagamma decay width was extracted by fitting the measured cross sections using recently updated theoretical models for the process. The resulting value for the decay width is Gamma(pi0->gammagamma)=7.82+/-0.14(stat)+/-0.17(syst) eV. With the 2.8% total uncertainty, this result is a factor of 2.5 more precise than the current Particle Data Group average of this fundamental quantity, and it is consistent with current theoretical predictions. PMID- 21599362 TI - Knockout reactions from p-shell nuclei: tests of ab initio structure models. AB - Absolute cross sections have been determined following single neutron knockout reactions from 10Be and 10C at intermediate energy. Nucleon density distributions and bound-state wave function overlaps obtained from both variational Monte Carlo (VMC) and no core shell model (NCSM) ab initio calculations have been incorporated into the theoretical description of knockout reactions. Comparison to experimental cross sections demonstrates that the VMC approach, with the inclusion of 3-body forces, provides the best overall agreement while the NCSM and conventional shell-model calculations both overpredict the cross sections by 20% to 30% for 10Be and by 40% to 50% for 10C, respectively. This study gains new insight into the importance of 3-body forces and continuum effects in light nuclei and provides a sensitive technique to assess the accuracy of ab initio calculations for describing these effects. PMID- 21599363 TI - High energy proton ejection from hydrocarbon molecules driven by highly efficient field ionization. AB - We investigated the ejection of energetic protons from a series of polyatomic hydrocarbon molecules exposed to 790 nm 27 fs laser pulses. Using multiparticle coincidence imaging we were able to decompose the observed proton energy spectra into the contributions of individual fragmentation channels. It is shown that the molecules can completely fragment already at relatively low peak intensities of a few 10(14) W/cm(2), and that the protons are ejected in a concerted Coulomb explosion from unexpectedly high charge states. The observations are in agreement with enhanced ionization taking place at many C-H bonds in parallel. PMID- 21599364 TI - Continuous loading of a conservative potential trap from an atomic beam. AB - We demonstrate the fast accumulation of 52Cr atoms in a conservative potential from a guided atomic beam. Without laser cooling on a cycling transition, a dissipative step involving optical pumping allows us to load atoms at a rate of 2*10(7) s(-1) in the trap. Within less than 100 ms we reach the collisionally dense regime, from which we produce a Bose-Einstein condensate with subsequent evaporative cooling. This constitutes a new approach to degeneracy where Bose Einstein condensation can be reached without a closed cycling transition, provided that a slow beam of particles can be produced. PMID- 21599365 TI - Bound states and scattering resonances induced by spatially modulated interactions. AB - We study the two-body problem with a spatially modulated interaction potential using a two-channel model, in which the interchannel coupling is provided by an optical standing wave and its strength modulates periodically in space. As the modulation amplitudes increase, there will appear a sequence of bound states. Part of them will cause a divergence of the effective scattering length, defined through the phase shift in the asymptotic behavior of scattering states. We also discuss how the local scattering length, defined through short-range behavior of scattering states, modulates spatially in different regimes. These results provide a theoretical guideline for a new control technique in the cold atom toolbox, in particular, for alkaline-earth(-like) atoms where the inelastic loss is small. PMID- 21599366 TI - Controlling light by light with an optical event horizon. AB - A novel concept for an all-optical transistor is proposed and verified numerically. This concept relies on cross-phase modulation between a signal and a control pulse. Other than previous approaches, the interaction length is extended by temporally locking control and the signal pulse in an optical event horizon, enabling continuous modification of the central wavelength, energy, and duration of a signal pulse by an up to sevenfold weaker control pulse. Moreover, if the signal pulse is a soliton it may maintain its solitonic properties during the switching process. The proposed all-optical switching concept fulfills all criteria for a useful optical transistor in [Nat. Photon. 4, 3 (2010)], in particular, fan-out and cascadability, which have previously proven as the most difficult to meet. PMID- 21599367 TI - Long-tail statistics of the Purcell factor in disordered media driven by near field interactions. AB - In this Letter, we study the Purcell effect in a 3D disordered dielectric medium through fluorescence decay rates of nanosized light sources. We report distributions of Purcell factor with non-Gaussian long-tailed statistics and an enhancement of up to 8 times the average value. We attribute this large enhancement to strong fluctuations of the local density of states induced by near field scattering sustained by more than one particle. Our findings go beyond standard diagrammatic and single-scattering models and can be explained only by taking into account the full near-field interaction. PMID- 21599368 TI - Asymmetric wave propagation in nonlinear systems. AB - A mechanism for asymmetric (nonreciprocal) wave transmission is presented. As a reference system, we consider a layered nonlinear, nonmirror-symmetric model described by the one-dimensional discrete nonlinear Schrodinger equation with spatially varying coefficients embedded in an otherwise linear lattice. We construct a class of exact extended solutions such that waves with the same frequency and incident amplitude impinging from left and right directions have very different transmission coefficients. This effect arises already for the simplest case of two nonlinear layers and is associated with the shift of nonlinear resonances. Increasing the number of layers considerably increases the complexity of the family of solutions. Finally, numerical simulations of asymmetric wave packet transmission are presented which beautifully display the rectifying effect. PMID- 21599369 TI - Phase-field model of long-time glasslike relaxation in binary fluid mixtures. AB - We present a new phase-field model for binary fluids, exhibiting typical signatures of soft-glassy behavior, such as long-time relaxation, aging, and long term dynamical arrest. The present model allows the cost of building an interface to vanish locally within the interface, while preserving positivity of the overall surface tension. A crucial consequence of this property, which we prove analytically, is the emergence of free-energy minimizing density configurations, hereafter named "compactons," to denote their property of being localized to a finite-size region of space and strictly zero elsewhere (no tails). Thanks to compactness, any arbitrary superposition of compactons still is a free-energy minimizer, which provides a direct link between the complexity of the free-energy landscape and the morphological complexity of configurational space. PMID- 21599355 TI - Measurement of the forward-backward asymmetry in the B->K*MU(+)MU(-) decay and first observation of the B(s)0->phiMU(+)MU(-) decay. AB - We reconstruct the rare decays B(+)->K(+)MU(+0MU(-0, B90)->K*(892)(0)MU(+)MU(-), and B(s)(0)->phi(1020)MU(+)MU(-) in a data sample corresponding to 4.4 fb(-1) collected in pp collisions at ?[s]=1.96 TeV by the CDF II detector at the Tevatron Collider. Using 121+/-16 B(+)->K(+)MU(+)MU(-) and 101+/-12 B(0) >K(*0)MU(+)MU(-) decays we report the branching ratios. In addition, we report the differential branching ratio and the muon forward-backward asymmetry in the B(+) and B(0) decay modes, and the K(*0) longitudinal polarization fraction in the B(0) decay mode with respect to the squared dimuon mass. These are consistent with the predictions, and most recent determinations from other experiments and of comparable accuracy. We also report the first observation of the B(s)(0) >phiMU(+)MU(-) decay and measure its branching ratio BR(B(s)(0)->phiMU(+)MU( ))=[1.44+/-0.33+/-0.46]*10(-6) using 27+/-6 signal events. This is currently the most rare B(s)(0) decay observed. PMID- 21599370 TI - Decay of cystalline order and equilibration during the solid-to-plasma transition induced by 20-fs microfocused 92-eV free-electron-laser pulses. AB - We have studied a solid-to-plasma transition by irradiating Al foils with the FLASH free electron laser at intensities up to 10(16) W/cm(2). Intense XUV self emission shows spectral features that are consistent with emission from regions of high density, which go beyond single inner-shell photoionization of solids. Characteristic features of intrashell transitions allowed us to identify Auger heating of the electrons in the conduction band occurring immediately after the absorption of the XUV laser energy as the dominant mechanism. A simple model of a multicharge state inverse Auger effect is proposed to explain the target emission when the conduction band at solid density becomes more atomiclike as energy is transferred from the electrons to the ions. This allows one to determine, independent of plasma simulations, the electron temperature and density just after the decay of crystalline order and to characterize the early time evolution. PMID- 21599371 TI - Experimental demonstration of wakefield acceleration in a tunable dielectric loaded accelerating structure. AB - We report on a collinear wakefield experiment using the first tunable dielectric loaded accelerating structure. By introducing an extra layer of nonlinear ferroelectric, which has a dielectric constant sensitive to temperature and dc bias, the frequency of a dielectric loaded accelerating structure can be tuned. During the experiment, the energy of a witness bunch at a fixed delay with respect to the drive beam was measured while the temperature of the structure was scanned over a 50 degrees C range. The energy change corresponded to a change of more than half of the nominal structure wavelength. PMID- 21599372 TI - Generating optical orbital angular momentum in a high-gain free-electron laser at the first harmonic. AB - A scheme to generate intense coherent light that carries orbital angular momentum (OAM) at the fundamental wavelength of an x-ray free-electron laser (FEL) is described. The OAM light is emitted as the dominant mode of the system until saturation provided that the helical microbunching imposed on the electron beam is larger than the shot-noise bunching that leads to self-amplified emission. Operating at the fundamental, this scheme is more efficient than alternate schemes that rely on harmonic emission, and can be applied to x-ray FELs without using external optical mode conversion elements. PMID- 21599373 TI - Plasma jet braking: energy dissipation and nonadiabatic electrons. AB - We report in situ observations by the Cluster spacecraft of wave-particle interactions in a magnetic flux pileup region created by a magnetic reconnection outflow jet in Earth's magnetotail. Two distinct regions of wave activity are identified: lower-hybrid drift waves at the front edge and whistler-mode waves inside the pileup region. The whistler-mode waves are locally generated by the electron temperature anisotropy, and provide evidence for ongoing betatron energization caused by magnetic flux pileup. The whistler-mode waves cause fast pitch-angle scattering of electrons and isotropization of the electron distribution, thus making the flow braking process nonadiabatic. The waves strongly affect the electron dynamics and thus play an important role in the energy conversion chain during plasma jet braking. PMID- 21599374 TI - New ion-wave path in the energy cascade. AB - We present the results of kinetic numerical simulations that demonstrate the existence of a novel branch of electrostatic nonlinear waves driven by particle trapping processes. These waves have an acoustic-type dispersion with phase speed comparable to the ion thermal speed and would thus be heavily Landau damped in the linear regime. At variance with the ion-acoustic waves, this novel electrostatic branch can exist at a small but finite amplitude even for low values of the electron to ion temperature ratio. Our results provide a new interpretation of observations in space plasmas, where a significant level of electrostatic activity is observed in the high frequency region of the solar-wind turbulent spectra. PMID- 21599375 TI - Energy transfer and dual cascade in kinetic magnetized plasma turbulence. AB - The question of how nonlinear interactions redistribute the energy of fluctuations across available degrees of freedom is of fundamental importance in the study of turbulence and transport in magnetized weakly collisional plasmas, ranging from space settings to fusion devices. In this Letter, we present a theory for the dual cascade found in such plasmas, which predicts a range of new behavior that distinguishes this cascade from that of neutral fluid turbulence. These phenomena are explained in terms of the constrained nature of spectral transfer in nonlinear gyrokinetics. Accompanying this theory are the first observations of these phenomena, obtained via direct numerical simulations using the gyrokinetic code AstroGK. The basic mechanisms that are found provide a framework for understanding the turbulent energy transfer that couples scales both locally and nonlocally. PMID- 21599376 TI - Measurements of intrinsic ion Bernstein waves in a tokamak by collective Thomson scattering. AB - In this Letter we report measurements of collective Thomson scattering (CTS) spectra with clear signatures of ion Bernstein waves and ion cyclotron motion in tokamak plasmas. The measured spectra are in accordance with theoretical predictions and show clear sensitivity to variation in the density ratio of the main ion species in the plasma. Measurements with this novel diagnostic demonstrate that CTS can be used as a fuel ion ratio diagnostic in burning fusion plasma devices. PMID- 21599377 TI - Density gradient stabilization of electron temperature gradient driven turbulence in a spherical tokamak. AB - In this Letter we report the first clear experimental observation of density gradient stabilization of electron temperature gradient driven turbulence in a fusion plasma. It is observed that longer wavelength modes, k(?)rho(s) ? 10, are most stabilized by density gradient, and the stabilization is accompanied by about a factor of 2 decrease in the plasma effective thermal diffusivity. PMID- 21599378 TI - Dissipative dynamics of a harmonically confined Bose-Einstein condensate. AB - We study the dissipation of the center of mass oscillation of a harmonically confined condensate in the presence of a disorder potential. An extension of the harmonic potential theorem allows one to formulate the dynamics from the point of view of an oscillating disorder potential. This formulation leads to a rigorous result for the damping rate in the limit of weak disorder. PMID- 21599379 TI - Ground-state structures of atomic metallic hydrogen. AB - Ab initio random structure searching using density functional theory is used to determine the ground-state structures of atomic metallic hydrogen from 500 GPa to 5 TPa. Including proton zero-point motion within the harmonic approximation, we estimate that molecular hydrogen dissociates into a monatomic body-centered tetragonal structure near 500 GPa (r(s)=1.23) that remains stable to 1 TPa (r(s)=1.11). At higher pressures, hydrogen stabilizes in an ...ABCABC... planar structure that is similar to the ground state of lithium, but with a different stacking sequence. With increasing pressure, this structure compresses to the face-centered cubic lattice near 3.5 TPa (r(s)=0.92). PMID- 21599380 TI - Anharmonic stabilization of the high-pressure simple cubic phase of calcium. AB - The phonon spectrum of the high-pressure simple cubic phase of calcium, in the harmonic approximation, shows imaginary branches that make it mechanically unstable. In this Letter, the phonon spectrum is recalculated by using density functional theory ab initio methods fully including anharmonic effects up to fourth order at 50 GPa. Considering that the perturbation theory cannot be employed with imaginary harmonic frequencies, a variational procedure based on the Gibbs-Bogoliubov inequality is used to estimate the renormalized phonon frequencies. The results show that strong quantum anharmonic effects make the imaginary phonons become positive even at zero temperature so that the simple cubic phase becomes mechanically stable, as experiments suggest. Moreover, our calculations find a superconducting T(c) in agreement with experiments and predict an anomalous behavior of the specific heat. PMID- 21599381 TI - Size effects and stochastic behavior of nanoindentation pop in. AB - A statistical model for pop in initiated at preexisting dislocations during nanoindentation is developed to explain size-dependent pop-in stresses. To verify theoretical predictions of this model, experiments were performed on single crystal Mo, utilizing indenter radii that vary by over 3 orders of magnitude. The stress where plastic deformation begins ranges from the theoretical strength in small volumes, to 1 order of magnitude lower in larger volumes. An intermediate regime shows wide variability in the stress to initiate plastic deformation. Our theory accurately reproduces the experimental cumulative probability distributions, and predicts a scaling behavior that matches experimental behavior. PMID- 21599382 TI - Universal evolution of perfect lenses. AB - This Letter is a theoretical attempt to answer two questions. First how long does it takes for perfect lensing to be observed, and second how does loss diminish the performance of a general perfect lens. The method described in this Letter is universal, in the sense that it can be applied to perfect lenses of any arbitrary geometry. We shall show that the dynamics of perfect lensing is equivalent to the dynamics of 2 coupled simple harmonic oscillators. Moreover we shall derive quantitatively, the effects of losses on a compact perfect lens. PMID- 21599383 TI - Evidence of deep water penetration in silica during stress corrosion fracture. AB - We measure the thickness of the heavy water layer trapped under the stress corrosion fracture surface of silica using neutron reflectivity experiments. We show that the penetration depth is 65-85 A, suggesting the presence of a damaged zone of ~100 A extending ahead of the crack tip during its propagation. This estimate of the size of the damaged zone is compatible with other recent results. PMID- 21599384 TI - Undulating slip in Laves phase and implications for deformation in brittle materials. AB - By combining density-functional theory calculations and aberration-corrected transmission electron microscopy, dislocations in Laves phase (a typical complex intermetallic compound) are shown to slip in an undulating path. During the slip, the dislocation cores jump up and down between a weakly bound plane and an adjacent strongly bound plane for gliding and atomic shuffling, respectively. This is different from the conventional slip process in simple metals, which is continuous within a single plane, as described in the paradigm of the generalized stacking fault energy. PMID- 21599385 TI - Nonequilibrium evolution thermodynamics of vacancies. AB - An alternative approach, nonequilibrium evolution thermodynamics, is compared with the classical Landau approach. A statistical justification of the approach is done with the help of a probability distribution function on an example of a solid with vacancies. Two kinds of kinetic equations are derived in terms of the internal energy and the modified free energy. PMID- 21599386 TI - Dynamic stimulation of quantum coherence in systems of lattice bosons. AB - Thermal fluctuations tend to destroy long-range phase correlations. Consequently, bosons in a lattice will undergo a transition from a phase-coherent superfluid as the temperature rises. Contrary to common intuition, however, we show that nonequilibrium driving can be used to reverse this thermal decoherence. This is possible because the energy distribution at equilibrium is rarely optimal for the manifestation of a given quantum property. We demonstrate this in the Bose Hubbard model by calculating the nonequilibrium spatial correlation function with periodic driving. We show that the nonequilibrium phase boundary between coherent and incoherent states at finite bath temperatures can be made qualitatively identical to the familiar zero-temperature phase diagram, and we discuss the experimental manifestation of this phenomenon in cold atoms. PMID- 21599387 TI - Noise-induced dynamical transition in systems with symmetric absorbing states. AB - We investigate the effect of noise strength on the macroscopic ordering dynamics of systems with symmetric absorbing states. Using an explicit stochastic microscopic model, we present evidence for a phase transition in the coarsening dynamics, from an Ising-like to a voter-like behavior, as the noise strength is increased past a nontrivial critical value. By mapping to a thermal diffusion process, we argue that the transition arises due to locally-absorbing states being entered more readily in the high-noise regime, which in turn prevents surface tension from driving the ordering process. PMID- 21599388 TI - Broken even-odd symmetry in self-selection of distances between nanoclusters due to the presence or absence of topological solitons. AB - Depositing particles randomly on a 1D lattice is expected to result in an equal number of particle pairs separated by even or odd lattice units. Unexpectedly, the even-odd symmetry is broken in the self-selection of distances between indium magic-number clusters on a Si(100)-2*1 reconstructed surface. Cluster pairs separated by even units are less abundant because they are linked by silicon atomic chains carrying topological solitons, which induce local strain and create localized electronic states with higher energy. Our findings reveal a unique particle-particle interaction mediated by the presence or absence of topological solitons on alternate lattices. PMID- 21599389 TI - Structure of the rutile TiO2(011) surface in an aqueous environment. AB - First principles simulations are carried out to investigate the structure and stability of the rutile TiO2(011) surface in contact with liquid water. Whereas this surface exhibits a (2*1) reconstruction in vacuo, our results show that the interaction with water leads to an inversion of the stabilities of the reconstructed and unreconstructed surfaces. This indicates that surface structures determined in vacuo or at low water coverages are not generally representative of those occurring in the aqueous environments typical of most photocatalytic applications of TiO2. PMID- 21599390 TI - Giant out-of-plane spin component and the asymmetry of spin polarization in surface Rashba states of bismuth thin film. AB - We have performed high-resolution spin- and angle-resolved photoemission spectroscopy of bismuth thin film on Si(111) to investigate the spin structure of surface states. Unlike the conventional Rashba splitting, the magnitude of the in plane spin polarization is asymmetric between the two elongated surface hole pockets across the zone center. Moreover, we uncovered a giant out-of-plane spin polarization as large as the in-plane counterpart which switches the sign across the Gamma-M line. We discuss the present finding in terms of the symmetry breaking and the many-body effects. PMID- 21599391 TI - Intrinsic impurity-band Stoner ferromagnetism in C60Hn. AB - We identify Stoner ferromagnetism in fcc C60H(n) (n=odd) by using a local density approximation in the framework of the density functional theory. Hydrogen chemisorption on fullerenes creates quasilocalized pi electrons on the fullerene surface, overlapping of their wave functions giving rise to a narrow half filled impurity band in the fcc C60H(n). The Stoner-type ferromagnetic exchange between the itinerant electrons leads to spin-split impurity bands. The magnetic moment per C60H(n) molecule is 1 MU(B) (for n=odd) or 0 (for n=even, including zero), only one of the hydrogens contributing to the spin-split states. Direct overlapping of the quasilocalized pi-electron orbitals is essential for the ferromagnetism. PMID- 21599392 TI - Band dispersion and electronic lifetimes in crystalline organic semiconductors. AB - The consequences of several microscopic interactions on the photoemission spectra of crystalline organic semiconductors are studied theoretically. It is argued that their relative roles can be disentangled by analyzing both their temperature and their momentum-energy dependence. Our analysis shows that the polaronic thermal band narrowing, which is the foundation of most theories of electrical transport in organic semiconductors, is inconsistent in the range of microscopic parameters appropriate for these materials. An alternative scenario is proposed to explain the experimental trends. PMID- 21599393 TI - Trimers, molecules, and polarons in mass-imbalanced atomic Fermi gases. AB - We consider the ground state of a single "spin-down" impurity atom interacting attractively with a "spin-up" atomic Fermi gas. By constructing variational wave functions for polarons, molecules, and trimers, we perform a detailed study of the transitions between these dressed bound states as a function of mass ratio r=m?/m? and interaction strength. Crucially, we find that the presence of a Fermi sea enhances the stability of the p-wave trimer, which can be viewed as a Fulde Ferrell-Larkin-Ovchinnikov molecule that has bound an additional majority atom. For sufficiently large r, we find that the transitions lie outside the region of phase separation of the imbalanced Fermi gas and should thus be observable in experiment, unlike the well-studied equal-mass case. PMID- 21599394 TI - Robust quantum dot exciton generation via adiabatic passage with frequency-swept optical pulses. AB - The energy states in semiconductor quantum dots are discrete as in atoms, and quantum states can be coherently controlled with resonant laser pulses. Long coherence times allow the observation of Rabi flopping of a single dipole transition in a solid state device, for which occupancy of the upper state depends sensitively on the dipole moment and the excitation laser power. We report on the robust population inversion in a single quantum dot using an optical technique that exploits rapid adiabatic passage from the ground to an excited state through excitation with laser pulses whose frequency is swept through the resonance. This observation in photoluminescence experiments is made possible by introducing a novel optical detection scheme for the resonant electron hole pair (exciton) generation. PMID- 21599395 TI - Surface-quantized anomalous Hall current and the magnetoelectric effect in magnetically disordered topological insulators. AB - We study theoretically the role of quenched magnetic disorder at the surface of topological insulators by numerical simulation and scaling analysis based on the massive Dirac fermion model. This addresses the problem of Anderson localization on chiral anomaly. It is found that all the surface states are localized, while the transverse conductivity is quantized to be +/-e2/2h as long as the Fermi energy is within the bulk gap. This greatly facilitates the realization of the topological magnetoelectric effect proposed by Qi et al. [Phys. Rev. B 78, 195424 (2008)] with the surface magnetization direction being controlled by the simultaneous application of magnetic and electric fields. PMID- 21599396 TI - Rings and boxes in dissipative environments. AB - We study a particle on a ring in presence of a dissipative Caldeira-Leggett environment and derive its response to a dc field. We find, through a 2-loop renormalization group analysis, that a large dissipation parameter eta flows to a fixed point eta(R)=eta(c)=h/2pi. We also reexamine the mapping of this problem to that of the Coulomb box and show that the relaxation resistance, of recent interest, is quantized for large eta. For finite eta>eta(c) we find that a certain average of the relaxation resistance is quantized. We propose a box experiment to measure a quantized noise. PMID- 21599397 TI - Gradient catastrophe and Fermi-edge resonances in Fermi gas. AB - Any smooth spatial disturbance of a degenerate Fermi gas inevitably becomes sharp. This phenomenon, called the gradient catastrophe, causes the breakdown of a Fermi sea to multiconnected components characterized by multiple Fermi points. We argue that the gradient catastrophe can be probed through a Fermi-edge singularity measurement. In the regime of the gradient catastrophe the Fermi-edge singularity problem becomes a nonequilibrium and nonstationary phenomenon. We show that the gradient catastrophe transforms the single-peaked Fermi-edge singularity of the tunneling (or absorption) spectrum to a sequence of multiple asymmetric singular resonances. An extension of the bosonic representation of the electronic operator to nonequilibrium states captures the singular behavior of the resonances. PMID- 21599398 TI - Impurity effect on weak antilocalization in the topological insulator Bi2Te3. AB - We study the weak antilocalization (WAL) effect in topological insulator Bi(2)Te(3) thin films at low temperatures. The two-dimensional WAL effect associated with surface carriers is revealed in the tilted magnetic field dependence of magnetoconductance. Our data demonstrate that the observed WAL is robust against deposition of nonmagnetic Au impurities on the surface of the thin films, but it is quenched by the deposition of magnetic Fe impurities which destroy the pi Berry phase of the topological surface states. The magnetoconductance data of a 5 nm Bi(2)Te(3) film suggests that a crossover from symplectic to unitary classes is observed with the deposition of Fe impurities. PMID- 21599399 TI - Color-dependent conductance of graphene with adatoms. AB - We study ballistic transport properties of graphene with a low concentration of vacancies or adatoms. The conductance of graphene doped to the Dirac point is found to depend on the relative distribution of impurities among different sites of the honeycomb lattice labeled in general by six colors. The conductivity is shown to be sensitive to the crystal orientation if adatom sites have a preferred color. Our theory is confirmed by numerical simulations using recursive Green's functions with no adjustable parameters. PMID- 21599400 TI - Spontaneous 2-dimensional carrier confinement at the n-type SrTiO3/LaAlO3 interface. AB - We describe the intrinsic mechanism of 2-dimensional electron confinement at the n-type SrTiO3/LaAlO3 interface as a function of the sheet carrier density n(s) via advanced first-principles calculations. Electrons localize spontaneously in Ti 3d(xy) levels within a thin (?2 nm) interface-adjacent SrTiO3 region for n(s) lower than a threshold value n(c)~10(14) cm(-2). For n(s)>n(c) a portion of charge flows into Ti 3d(xz)-d(yz) levels extending farther from the interface. This intrinsic confinement can be attributed to the interface-induced symmetry breaking and localized nature of Ti 3d t(2g) states. The sheet carrier density directly controls the binding energy and the spatial extension of the conductive region. A direct, quantitative relation of these quantities with n(s) is provided. PMID- 21599401 TI - Theoretical investigation of the four-layered self-doped high-Tc superconductors: evidence of the pair tunneling effect. AB - Based on a four-layered self-doped t-J type model and the slave-boson mean-field approach, we study theoretically the superconductivity in the electron-doped and hole-doped layers. The neighbor layers are coupled through both the single electron interlayer hopping and pair tunneling effect. The superconducting gap magnitude for the electron-doped band is nearly twice that of the hole-doped one, which contrasts with our previous understanding of the electron-hole asymmetry in high-T(c) superconductors but is consistent with recent angle-resolved photoemission spectroscopy experiments in four-layered materials Ba2Ca3Cu4O8F2. Our results propose that the pair tunneling effect is important to examine the multilayered superconducting materials. PMID- 21599402 TI - Circuit QED with a nonlinear resonator: ac-Stark shift and dephasing. AB - We have performed spectroscopic measurements of a superconducting qubit dispersively coupled to a nonlinear resonator driven by a pump microwave field. Measurements of the qubit frequency shift provide a sensitive probe of the intracavity field, yielding a precise characterization of the resonator nonlinearity. The qubit linewidth has a complex dependence on the pump frequency and amplitude, which is correlated with the gain of the nonlinear resonator operated as a small-signal amplifier. The corresponding dephasing rate is found to be close to the quantum limit in the low-gain limit of the amplifier. PMID- 21599403 TI - Reaffirming the d(x2-y2) superconducting gap using the autocorrelation angle resolved photoemission spectroscopy of Bi1.5Pb0.55Sr1.6La0.4CuO(6+delta). AB - Knowledge of the gap function is important to understand the pairing mechanism for high-temperature (T(c)) superconductivity. However, Fourier transform scanning tunneling spectroscopy (FT STS) and angle-resolved photoemission spectroscopy (ARPES) in the cuprates have reported contradictory gap functions, with FT-STS results deviating strongly from a canonical d(x2-y2) form. By applying an "octet model" analysis to autocorrelation ARPES, we reveal that a contradiction occurs because the octet model does not consider the effects of matrix elements and the pseudogap. This reaffirms the canonical d(x2-y2) superconducting gap around the node, which can be directly determined from ARPES. Further, our study suggests that the FT-STS reported fluctuating superconductivity around the node at far above T(c) is not necessary to explain the existence of the quasiparticle interference at low energy. PMID- 21599404 TI - Number fluctuations of sparse quasiparticles in a superconductor. AB - We have directly measured quasiparticle number fluctuations in a thin film superconducting Al resonator in thermal equilibrium. The spectrum of these fluctuations provides a measure of both the density and the lifetime of the quasiparticles. We observe that the quasiparticle density decreases exponentially with decreasing temperature, as theoretically predicted, but saturates below 160 mK to 25-55/MUm(3). We show that this saturation is consistent with the measured saturation in the quasiparticle lifetime, which also explains similar observations in qubit decoherence times. PMID- 21599405 TI - Eliashberg analysis of tunneling experiments: support for the pairing glue hypothesis in cuprate superconductors. AB - Evidence for the validity of the pairing glue interpretation of high temperature superconductivity is presented using a modified Eliashberg analysis of experimental superconductor-insulator-superconductor (SIS) tunneling data in B2Sr2CaCu2O8 (Bi2212) over a wide range of doping. This is accomplished by extracting detailed information on the diagonal and anomalous contributions to the quasiparticle self-energy. In particular, a comparison of the imaginary part of the anomalous self-energy ImPhi(omega) and the pairing glue spectral function alpha2F(omega) used in the model is consistent with Hubbard model simulations in the literature. In addition, the real part of the diagonal self-energy for optimal doped Bi2212 bears a strong resemblance to that obtained from photoemission experiments. PMID- 21599406 TI - Negative tunneling magnetoresistance by canted magnetization in MgO/NiO tunnel barriers. AB - The influence of the insertion of an ultrathin NiO layer between the MgO barrier and the ferromagnetic electrodes in magnetic tunnel junctions has been investigated from measurements of the tunneling magnetoresistance and via x-ray magnetic circular dichroism (XMCD). The magnetoresistance shows a high asymmetry with respect to bias voltage, giving rise to a negative value of up to -16% at 2.8 K. We attribute this effect to the formation of noncollinear spin structures at the interface of the NiO layer as inferred from XMCD measurements. The magnetic moments of the interface Ni atoms tilt from their easy axis due to exchange coupling with the neighboring ferromagnetic electrode, and the tilting angle decreases with increasing NiO thickness. The experimental observations are further supported by noncollinear spin density functional calculations. PMID- 21599407 TI - Images of a spin-torque-driven magnetic nano-oscillator. AB - We present the first space- and time-resolved images of the spin-torque-induced steady-state oscillation of a magnetic vortex in a spin-valve nanostructure. We find that the vortex structure in a nanopillar is considerably more complicated than the 2D idealized structure often-assumed, which has important implications for the driving efficiency. The sense of the vortex gyration is uniquely determined by the vortex core polarity, confirming that the spin-torque acts as a source of negative damping even in such a strongly nonuniform magnetic system. The orbit radius is ~10 nm, in agreement with micromagnetic simulations. PMID- 21599408 TI - Ground state of the quasi-1D compound BaVS3 resolved by resonant magnetic x-ray scattering. AB - Resonant magnetic x-ray scattering near the vanadium L2,3-absorption edges has been used to investigate the low temperature magnetic structure of high quality BaVS3 single crystals. Below T(N)=31 K, the strong resonance revealed a triple incommensurate magnetic ordering at the wave vector (0.226 0.226 xi) in hexagonal notation, with xi=0.033. The azimuthal-angle dependence of the scattering signal and time-dependent density functional theory simulations indicate an antiferromagnetic order within the ab plane with the spins polarized along a in the monoclinic structure. PMID- 21599409 TI - Rapid and robust spin state amplification. AB - Electron and nuclear spins have been employed in many of the early demonstrations of quantum technology. However, applications in real world quantum technology are limited by the difficulty of measuring single spins. Here we show that it is possible to rapidly and robustly amplify a spin state using a lattice of ancillary spins. The model we employ corresponds to an extremely simple experimental system: a homogenous Ising-coupled spin lattice in one, two, or three dimensions, driven by a continuous microwave field. We establish that the process can operate at finite temperature (imperfect initial polarization) and under the effects of various forms of decoherence. PMID- 21599410 TI - Ground-state cooling of a suspended nanowire through inelastic macroscopic quantum tunneling in a current-biased Josephson junction. AB - We demonstrate that a suspended nanowire forming a weak link between two superconductors can be cooled to its motional ground state by a supercurrent flow. The predicted cooling mechanism has its origins in magnetic field induced inelastic tunneling of the macroscopic superconducting phase associated with the junction. Furthermore, we show that the voltage drop over the junction is proportional to the average population of the vibrational modes in the stationary regime, a phenomenon which can be used to probe the level of cooling. PMID- 21599411 TI - Magnetic-field induced competition of two multiferroic orders in a triangular lattice helimagnet MnI2. AB - Magnetic and dielectric properties with varying magnitude and direction of magnetic-field H have been investigated for a triangular-lattice helimagnet MnI_{2}. The in-plane electric polarization P emerges in the proper screw magnetic ground state below 3.5 K, showing the rearrangement of six possible multiferroic domains as controlled by the in-plane H. With every 60 degrees rotation of H around the [001] axis, discontinuous 120 degrees flop of the P vector is observed as a result of the flop of magnetic modulation vector q. With increasing the in-plane H above 3 T, however, the stable q direction changes from q||(110[ -over 0]) to q||(110), leading to a change of P-flop patterns under rotating H. At the critical field region (~3 T), due to the phase competition and resultant enhanced q flexibility, the P vector smoothly rotates clockwise twice while the H vector rotates counterclockwise once. PMID- 21599412 TI - Electronic structure of warm dense copper studied by ultrafast x-ray absorption spectroscopy. AB - We use time-resolved x-ray absorption spectroscopy to investigate the unoccupied electronic density of states of warm dense copper that is produced isochorically through the absorption of an ultrafast optical pulse. The temperature of the superheated electron-hole plasma, which ranges from 4000 to 10 000 K, was determined by comparing the measured x-ray absorption spectrum with a simulation. The electronic structure of warm dense copper is adequately described with the high temperature electronic density of state calculated by the density functional theory. The dynamics of the electron temperature is consistent with a two temperature model, while a temperature-dependent electron-phonon coupling parameter is necessary. PMID- 21599413 TI - Ion specificity and the theory of stability of colloidal suspensions. AB - A theory is presented which allows us to accurately calculate the critical coagulation concentration of hydrophobic colloidal suspensions. For positively charged particles, the critical coagulation concentrations follow the Hofmeister (lyotropic) series. For negatively charged particles, the series is reversed. We find that strongly polarizable chaotropic anions are driven towards the colloidal surface by electrostatic and hydrophobic forces. Within approximately one ionic radius from the surface, the chaotropic anions lose part of their hydration sheath and become strongly adsorbed. The kosmotropic anions, on the other hand, are repelled from the hydrophobic surface. The theory is quantitatively accurate without any adjustable parameters. We speculate that the same mechanism is responsible for the Hofmeister series that governs stability of protein solutions. PMID- 21599414 TI - Ring polymers in melts and solutions: scaling and crossover. AB - We propose a simple mean-field theory for the structure of ring polymer melts. By combining the notion of topological volume fraction and a classical van der Waals theory of fluids, we take into account many-body effects of topological origin in dense systems. We predict that although the compact statistics with the Flory exponent nu=1/3 is realized for very long chains, most practical cases fall into the crossover regime with the apparent exponent nu?2/5 during which the system evolves toward a topological dense-packed limit. PMID- 21599415 TI - Minimum energy path to membrane pore formation and rupture. AB - We combine dynamic self-consistent field theory with the string method to calculate the minimum energy path to membrane pore formation and rupture. In the regime where nucleation can occur on experimentally relevant time scales, the structure of the critical nucleus is between a solvophilic stalk and a locally thinned membrane. Classical nucleation theory fails to capture these molecular details and significantly overestimates the free energy barrier. Our results suggest that thermally nucleated rupture may be an important factor for the low rupture strains observed in lipid membranes. PMID- 21599416 TI - Crowding-induced structural alterations of random-loop chromosome model. AB - We investigate structural alterations of random-loop polymers due to changes in the crowding condition, as a model to study environmental effects on the structure of chromosome subcompartments. The polymer structure is changed in a nonmonotonic fashion with an increasing density of crowders: condensed at small volume fractions; decondensed at high crowding volume fractions. The nonmonotonic behavior is a manifestation of the nontrivial distance dependence of the depletion interactions. We also show that crowding-induced structural alterations affect the access of binding proteins to the surface of polymer segments and are distinguished from structural changes due to the increased number of specific polymer loops. PMID- 21599417 TI - Role of fluctuations in ligand binding cooperativity of membrane receptors. AB - Signal transduction upon binding of a ligand to a membrane protein can occur not only via allosteric conformational changes but also through fluctuations. We report a numerical study on the influence of conformational fluctuations on the cooperativity of a binding reaction in a simple model of an integral membrane receptor consisting of transmembrane helices. We find that small fluctuations lateral as well as perpendicular to the membrane can increase the cooperativity, with the former more dominant. Moreover, too much fluctuation induces negative cooperativity. Proteins with fewer than four helices do not show positive cooperativity under any circumstances. This behavior is rather robust, and independent of the receptor topology or ligand size. Fluctuations measured in all atom molecular dynamics simulations of a G-protein coupled receptor fall within the predicted region of maximum cooperativity. PMID- 21599418 TI - Experimental control of transport and current reversals in a deterministic optical rocking ratchet. AB - We present an experimental demonstration of a deterministic optical rocking ratchet. A periodic and asymmetric light pattern is created to interact with dielectric microparticles in water, giving rise to a ratchet potential. The sample is moved with respect to the pattern with an unbiased time-periodic rocking function, which tilts the potential in alternating opposite directions. We obtain a current of particles whose direction can be controlled in real time and show that particles of different sizes may experience opposite currents. Moreover, we observed current reversals as a function of the magnitude and period of the rocking force. PMID- 21599419 TI - Polymer-brush lubricated surfaces with colloidal inclusions under shear inversion. AB - We characterize the response of compressed, sheared polymer-brush bilayers with colloidal inclusions to highly nonstationary inversion processes by means of molecular dynamics simulations and scaling theory. Bilayers with a simple (dimeric) solvent reveal an overshoot for the shear stress, while simulations of dry brushes without explicit solvent molecules fail to display this effect. We demonstrate that mechanical instabilities can be controlled by the inclusion of macromolecular structures, such as colloids of varying softness. Based on a recently developed theory, we suggest a scaling approach to determine a characteristic time for conformational and collective responses. PMID- 21599420 TI - New first and second generation inhibitors of human immunodeficiency virus-1 integrase. AB - INTRODUCTION: The use of inhibitors of HIV-1 integrase for treating HIV-1 infection has proven to be very beneficial. Raltegravir, a strand transfer inhibitor, has been approved for use both as a first-line therapy and in treatment-experienced patients. A second compound in this class, elvitegravir, is in Phase III clinical trials and is being developed as part of a once daily fixed dose combination pill. With widespread use of raltegravir, viral resistance has emerged with surprising facility. Attempts to use raltegravir on a once daily dosing regimen have been unsuccessful whilst elvitegravir cannot be delivered daily without the aid of a pharmacokinetic (PK)-enhancing agent. Thus, there is a need for second generation compounds to address these issues. AREAS COVERED: Patent applications claiming compounds useful as inhibitors of HIV-1 integrase are reviewed in this paper, along with compounds related to the strand transfer inhibitors. EXPERT OPINION: The field appears to be more focused on developing compounds which address the issues identified for the first generation compounds, raltegravir and elvitegravir. Patent activity around new strand transfer inhibitors claims compounds active against first generation resistant mutations and having PK profiles suitable for daily dosing. Advancements in this area have been rapid and several compounds described in these patent applications are currently in clinical trials. Bolstered by recent mechanistic discoveries, compounds inhibiting processes other than strand transfer have begun to emerge. It is foreseeable that a second generation integrase inhibitor could be approved for treatment in the coming years. PMID- 21599421 TI - Checkpoint kinase inhibitors: a patent review (2009 - 2010). AB - INTRODUCTION: Cells that suffer DNA damage activate the checkpoint kinases CHK1 and CHK2, which signal to initiate repair processes, limit cell-cycle progression and prevent cell replication, until the damaged DNA is repaired. Due to their potential application as novel anticancer therapies, inhibitors of CHK1 and CHK2 have become the focus of numerous drug discovery projects. AREAS COVERED: This patent review examines the chemical structures and biological activities of recently reported CHK1 and CHK2 inhibitors. The chemical abstract and patent databases SciFinder and esp@cenet were used to locate patent applications that were published between September 2008 and December 2010, claiming chemical structures for use as CHK1 or CHK2 inhibitors. EXPERT OPINION: This is an exciting time for checkpoint kinase inhibitors, with several currently in Phase I or II clinical trials. Many of the CHK1 inhibitors contained within this patent review have shown preclinical efficacy in combination with DNA-damaging chemotherapies. CHK1 inhibitors have recently been demonstrated to be efficacious as single agents in preclinical models of tumors with constitutive activation of CHK1 or high intrinsic DNA damage due to replication stress. The level of newly published patent applications covering CHK1 and CHK2 inhibitors remains high and a diverse range of scaffolds has been claimed. PMID- 21599422 TI - MPO-ANCA-positive anti-glomerular basement membrane antibody disease successfully treated by plasma exchange and immunosuppressive therapy. AB - Anti-glomerular basement membrane (GBM) antibody disease is clinically manifested as rapidly progressive glomerulonephritis (RPGN) with crescentic changes. The renal prognosis is poor. We report here the case of a 61-year-old woman with myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive anti-GBM antibody disease. This patient was referred to our hospital because of RPGN. Anti GBM antibody was positive with a titer of 38 EU. The MPO-ANCA titer was 65 EU. Chest imaging examination revealed pulmonary multiple nodules. ANCA-associated vasculitis was suspected. Renal pathology revealed cellular crescents in 13 out of 17 glomeruli. Immunofluorescence with anti-IgG antibody, anti-C3 antibody, and anti-fibrin antibody showed linear staining along the glomerular capillary walls. Based on these findings, the patient was diagnosed with anti-GBM antibody disease. Hemodialysis was started because of uremic syndrome with elevated serum creatinine (6.84 mg/dL). In addition, treatment with plasma exchange using 3.6 L (90 mL/kg) of fresh frozen plasma combined with an oral dose of 40 mg of prednisolone was initiated. Within 3 weeks, both types of autoantibodies became undetectable. Subsequently, this patient achieved dialysis independence and remission of glomerulonephritis. No adverse effects were observed. In patients with MPO-ANCA-positive anti-GBM antibody disease, intensive therapy predominantly with plasma exchange might be operative, even though renal function is less likely to recover. PMID- 21599423 TI - The significance of interleukin 12 and interferon-gamma in thrombotic thrombocytopenic purpura/hemolytic uremic syndrome and Crohn's disease. PMID- 21599424 TI - Effects of chronic renal failure on gastrointestinal motility: a study on the changes of gastric emptying, small intestinal transit, interdigestive myoelectric complex, and fecal water content. AB - BACKGROUND: Gastrointestinal (GI) dysfunction may lead to malnutrition in patients with chronic renal failure (CRF). This study investigated the effects of CRF on GI motility. METHODS: Forty-eight Sprague Dawley rats (180 +/- 20 g) were randomly classified into CRF group and sham-operated (Sham) group, and each group was further assigned for gastric emptying (GE), small intestinal transit (SIT), interdigestive myoelectric complex (IMC), and fecal water content (FWC) experiments (6 CRF and 6 Sham rats per experiment). The CRF model was established by 5/6 nephrectomy. The body weight (BT), GE, SIT, IMC, and FWC of the rats were observed. ANOVA and Student-Newman-Keuls q-test were utilized to do statistical analysis. RESULTS: The BT of the rats in the two groups had no statistical difference before surgery. But in the ninth week after surgery, the CRF rats (230 +/- 20 g) weighed less than the Sham rats (260 +/- 15 g) (p < 0.05). The GE rate and SIT rate in CRF rats were significantly lower than that of Sham rats (GE 33.08 +/- 7.50 vs. 53.37 +/- 9.78%; SIT 42.92 +/- 8.96 vs. 58.67 +/- 9.12%) (p < 0.05). Compared with the IMC of the Sham rats, the CRF rats showed obvious alterations in (a) IMC cycle; (b) phase II and phase III duration; and (c) phase III cycling frequency, amplitude, and percentage (p < 0.05). FWC of the CRF rats increased significantly (p < 0.05). CONCLUSION: The GI motility of the CRF rats is obviously impaired. This finding may indicate that the effects of CRF on GI motility might be relatively prevalent. PMID- 21599425 TI - The United States-Mexico border: an area in need of cancer screening interventions. PMID- 21599426 TI - Pregnancy complications and prevention of cardiovascular disease in women: stay tuned. PMID- 21599427 TI - Transition to overweight or obesity among women of reproductive age. AB - BACKGROUND: Nearly two thirds of reproductive-aged women in the United States are currently overweight or obese, placing them at elevated risk for adverse health outcomes. This study identifies factors associated with transition in body mass index (BMI) category to overweight or obesity status over a 2-year period among women of reproductive age. METHODS: Data were collected in the Central Pennsylvania Women's Health Study (CePAWHS), a longitudinal cohort study of reproductive-aged women. Participants were 689 women with normal or overweight BMI at baseline who were not pregnant at either baseline or 2-year follow-up. Separate multiple logistic regression analyses were estimated to model adverse change in weight category for women who were normal weight at baseline and to model transition to obesity among women who were overweight at baseline. RESULTS: Among women of normal weight at baseline, 18% became overweight or obese by follow-up; 25% of women overweight at baseline became obese. In multiple regression analyses, low physical activity at baseline was significantly associated with a 2-fold elevation in the odds of transitioning from normal BMI to overweight/obesity (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.06 4.20), as was having an interim live birth (OR 2.75, 95%CI 1.27-5.95). In contrast, demographics (lower education, younger age) were the only significant predictors of transition from overweight to obesity. CONCLUSIONS: Meeting physical activity guidelines should be encouraged among normal weight women of reproductive age as well as those who are overweight or obese, as low physical activity is a risk for transitioning from normal to overweight status. Younger overweight women are particularly at risk for transition to obesity. PMID- 21599430 TI - The proceedings of the 19Th international conference on chelation held in London, United Kingdom: major changes in iron chelation therapy in the last 25 years using deferiprone (L1) has resulted in the complete treatment of iron overload. AB - Major advances were presented at the 19th International Conference on Chelation (ICOC) in London, UK including changes in iron chelation therapy that led to the complete treatment of transfusional iron overload. The first oral iron chelation results in animals using deferiprone (L1) were published in 1985, and effective iron removal in thalassemia and myelodysplasia patients were reported 2 years later. The results of multicenter clinical trials of L1 were presented at the 1st ICOC in London, UK in 1989. Long-term use of L1 resulted in the reduction of the mortality rate in thalassemia patients due to the effective removal of all excess iron from the heart. In 2008, specific combinations of L1 and deferoxamine (DFO) were reported to cause the complete removal of excess iron load and the achievement of normal range body iron store levels (NRBISL) in thalassemia patients. Patients with NRBISL were identified to require lower doses of L1 for the maintenance of negative iron balance. The introduction of deferasirox (DFRA) may benefit patients not tolerating L1, DFO or their combination. A simple, inexpensive synthesis of L1 has encouraged its manufacture in developing countries for the benefit of patients who could not afford the expensive imported chelating drugs or formulations. PMID- 21599428 TI - Group A streptococcal peritonitis and ruptured tubo-ovarian abscess three years after Essure(r) insertion: a case report. AB - We describe a complicated ruptured Streptococcus pyogenes tubo-ovarian abscess (TOA) and peritonitis in a 24-year-old woman, necessitating eventual hysterectomy and a prolonged intensive care unit (ICU) admission 3 years after successful tubal occlusion with Essure(r) (Conceptus, Inc., Mountain View, CA) microinsert devices. The patient is a 24-year-old gravida 3, para 2, aborta 1 (G3P2Ab1) who had a 1-day history of worsening right lower quadrant pain without associated fever or cervical motion tenderness. Patient's medical history was complicated by mitochondrial neurogastrointestinal encephalopathy (MNGIE). Upon her admission to the hospital, an exploratory laparoscopy was performed. Intraoperative findings revealed a ruptured right-sided TOA. S. pyogenes was isolated from the peritoneal fluid and cervicovaginal cultures. After the laparoscopy, the patient experienced initial improvement but abruptly worsened and on postoperative day 7 was returned to the operating room for a planned repeat exploration and total abdominal hysterectomy. Gross pathological examination of the uterus showed appropriate Essure insert placement. Based on this case, tubal occlusion by induced fibrosis may not be a sufficient obstacle in preventing ascending pelvic infections. PMID- 21599431 TI - Efficacy, compliance and toxicity factors are affecting the rate of normalization of body iron stores in thalassemia patients using the deferiprone and deferoxamine combination therapy. AB - The international committee on chelation (ICOC) of deferiprone (L1) and deferoxamine (DFO) combination therapy was the first protocol reported to have achieved normal range body iron store levels (NRBISL) in beta-thalassemia major (beta-TM) patients. A follow-up study in eight beta-TM patients has been designed to investigate the factors affecting the rate of iron removal leading to NRBISL. The patients had variable serum ferritin [mean +/- SE (standard error) =1692 +/- 366, range 539-3845 MUg/L)] and magnetic resonance imaging (MRI) T2* relaxation times cardiac (mean +/- SE =11.1 +/- 2.5, range 4.5-24.2 ms) and liver (mean +/- SE = 4.3 +/- 1.8, range 1.4-14 ms). Organ function, blood and other biochemical parameters were regularly monitored for toxicity. The ICOC L1 (80-100 mg/kg/day) and DFO (40-60 mg/kg, at least 3 days per week) combination therapy caused an increase in cardiac (mean +/- SE =30.2 +/- 2.3, range 22-41 ms) and liver (mean +/- SE =27.6 +/- 2.8, range 9.1-35 ms) T2* and reduction in serum ferritin (mean +/- SE = 158 +/- 49, range 40-421 MUg/L) to within the NRBISL. The rate of normalization was variable and in one case was achieved within 9 months, whereas the longest was about 3 years. The initial iron load, the rate of transfusions, the combination dose protocol and the level of compliance were the major factors affecting the rate of normalization of the iron stores. No serious toxicity was observed during the study period, which lasted a total of 24.7 patient years. PMID- 21599432 TI - Intermediate-term evaluation of a pratical chelation protocol based on stratification of thalassemic patients by serum ferritin and magnetic resonance imaging cardiac t2*. AB - A standardized chelation protocol was applied by stratifying transfusion dependent thalassemic patients into three groups, namely well chelated group (A), inadequately chelated group without (B) or with (C) risk of cardiac complications based on serum ferritin (SF) levels and magnetic resonance imaging (MRI) cardiac T2* measurements. Group A patients were advised to continue with deferoxamine (DFO) (Regimen Ic). Group B patients were given options of either intensification of DFO alone (Regimen Ii), deferiprone (L1) alone (Regimen II) or combined therapy with L1 and DFO (Regimen III). Group C patients were advised to take either Regimen Ii or Regimen III. The 1-year result showed that the combined therapy (Regimen III) significantly reduced SF level, cardiac and liver iron in the groups of inadequately chelated patients. The same set of outcome parameters was repeated at 2.5 years of treatment so as to evaluate the intermediate-term effects of this risk stratified chelation protocol. The number of patients with cardiac T2* <20 ms decreased from 34 (60%) at baseline to 17 (30%) of the whole cohort of 57 patients at the end of the study. There were further improvements in SF, cardiac and liver T2* in Group C patients. Significant improvement in left ventricular ejection fraction (LVEF) was demonstrated after 2.5 years of the combined therapy group in which the change was not initially apparent after the first year of assessment. PMID- 21599433 TI - Sequential alternating deferiprone and deferoxamine treatment compared to deferiprone monotherapy: main findings and clinical follow-up of a large multicenter randomized clinical trial in -thalassemia major patients. AB - In beta-thalassemia major (beta-TM) patients, iron chelation therapy is mandatory to reduce iron overload secondary to transfusions. Recommended first line treatment is deferoxamine (DFO) from the age of 2 and second line treatment after the age of 6 is deferiprone (L1). A multicenter randomized open-label trial was designed to assess the effectiveness of long-term alternating sequential L1-DFO vs. L1 alone iron chelation therapy in beta-TM patients. Deferiprone 75 mg/kg 4 days/week and DFO 50 mg/kg/day for 3 days/week was compared with L1 alone 75 mg/kg 7 days/week during a 5-year follow-up. A total of 213 thalassemia patients were randomized and underwent intention-to-treat analysis. Statistically, a decrease of serum ferritin level was significantly higher in alternating sequential L1-DFO patients compared with L1 alone patients (p = 0.005). Kaplan Meier survival analysis for the two chelation treatments did not show statistically significant differences (log-rank test, p = 0.3145). Adverse events and costs were comparable between the groups. Alternating sequential L1-DFO treatment decreased serum ferritin concentration during a 5-year treatment by comparison to L1 alone, without significant differences of survival, adverse events or costs. These findings were confirmed in a further 21-month follow-up. These data suggest that alternating sequential L1-DFO treatment may be useful for some beta-TM patients who may not be able to receive other forms of chelation treatment. PMID- 21599434 TI - Efficacy and safety of administration of oral iron chelator deferiprone in patients with early myelodysplastic syndrome. AB - Forty-eight patients with early myelodysplastic syndrome (MDS) without excess of blasts, with average initial serum ferritin levels of 2739.5 MUg/L (range 825 11287 MUg/L), were treated with deferiprone (L1) in a daily dose of 40-90 mg/kg. Median duration of chelation treatment was 10.9 months (range 4-24 months). Chelation was effective (maintained or decreased iron stores) in 16 out of 22 patients (73%) with serum ferritin levels <2000 MUg/L in contrast to only 12 out of 26 patients with serum ferritin levels >2000 MUg/L. Combination of L1 with recombinant human erythropoietin (rHuEPO) (30-40 kU/week) resulted in effective chelation in five additional patients with serum ferritin levels >3000 MUg/L. Incidence of adverse effects was comparable to that in thalassemic patients. Gastrointestinal symptoms represented the most frequent adverse effect of L1 therapy (37.5% of patients) that limited an effective escalation of the daily dose of the drug and led to discontinuation of the treatment for six patients. A decreased number of granulocytes was observed in five (13%) patients and agranulocytosis occurred in two patients (4%). Granulocyte counts were restored after cessation of L1 treatment and administration of granulocyte colony stimulating factor (G-CSF) in all but one patient. Administration of L1 in a daily dose of at least 75 mg/kg may represent an alternative approach in treatment of mild and moderate iron overload in MDS patients who cannot be treated with deferasirox (DFRA) or deferoxamine (DFO). PMID- 21599435 TI - Molecular lesion frequency of hemoglobin gene disorders in Taiwan. AB - Hemoglobin (Hb) gene disorders are common inherited diseases in Taiwan. The alpha and beta-thalassemias are among the well-known Hb diseases in this area. We reviewed abnormal hematological data in 3578 cases, identified between 1998 and 2009, as being at-risk for alpha-thalassemia (alpha-thal) (n = 1909; 53.3%), beta thal (n = 743; 20.8%), non-alpha, beta-thal (n = 872; 24.4%), and alpha-thal combined with beta-thal (n = 54; 1.5%), and collected fetal blood samples for prenatal testing. The most common types of alpha(0)- and alpha(+)-thal were the SEA (Southeast Asian) deletion and the -alpha(3.7) rightward deletion, with frequencies of 87.79 and 4.85%, respectively. The frequency of the IVS-II-654 (C>T) mutation, the most common beta-thal mutation in this region, was 38.6%. Hb E [beta26(B8)Glu->Lys, GAG>AAG] was found to be the most common Hb variant, and it was concluded that Hb Tak [beta147 (+AC)], Hb G -Taichung (also known as Hb Q Thailand) [alpha74(EF3)Asp->His, GAC>CAC (alpha1)], Hb Owari [alpha121(H4)Val >Met (GTG>ATG)], and Hb Phnom Penh [alpha117(GH5)Phe-Ile-alpha118(H1)Thr (alpha1)] were very rare. The results of this study provide a primary reference for designing a locally relevant antenatal diagnostic test for controlling the spread of thalassemia. PMID- 21599436 TI - Interactions of hydroxycarbamide (hydroxyurea) with iron and copper: implications on toxicity and therapeutic strategies. AB - Presented at the 19th International Conference on Chelation, London, UK, 13-16 November 2009 Preliminary spectrophotometric and potentiometric studies have shown that hydroxycarbamide or hydroxyurea (HU) can interact with copper(II) [Cu(II)], iron(II) [Fe(II)] and Fe(III) ions and form complexes, for example, a ratio of 1 HU:1 metal at pH 5. The affinity for Cu (log beta1 = 3.1) and Fe (log beta1 = 5) by HU is much lower than that of the Fe and Cu chelating drug deferiprone (L1), which is used for the treatment of iron overload. It is anticipated that under certain conditions of high concentrations of these metal ions such as in transfusional iron overload, the therapeutic, pharmacological and toxicological properties of HU could be affected. It is also suggested that excess chelatable and labile forms of Fe or Cu ions, such as non transferrin bound iron (NTBI) or intracellular low molecular weight labile iron, are among the main factors that may cause variations in the therapeutic response to HU in cancer, sickle cell anemia, thalassemia intermedia and other groups of patients. Further studies are needed to clarify the interaction mechanisms of HU with metal ions in vitro, in vivo and in clinical conditions. PMID- 21599437 TI - A quantitative evaluation of redox-active compounds in human blood lipids. AB - Endogenous low molecular weight redox active compounds (RACs) comprise antioxidants, pro-oxidants, transition metal cations and metal chelators. Traditional electrochemical methods of measuring RACs are limited to aqueous solutions, thus providing information of only hydrophilic RAC pools. In a large number of diseases associated with oxidative stress and/or with metal toxicity, redox states of hydrophilic as well as hydrophobic compartments are modified, and therefore development of methods for their detection is both necessary and important. The pools of lipid soluble RACs in reduced and oxidized forms in n hexane extracts obtained from blood plasma, erythrocytes and whole blood of healthy donors were determined by spectrophotometric detection of the 1,1 diphenyl-2-picrylhydrazyl (DPPH) free radicals, which stoichiometrically interacts with hydrogen donors in non polar solutions. Measurements of RACs in extracts before and after treatment with NaBH(4) provided information about the levels of both reduced and oxidized RACs. Vitamin E was also determined using a fluorescence method. The results have shown that vitamin E is the major RAC in blood plasma lipids but not in blood cell lipids, where other phenols and quinones appear to predominate. PMID- 21599438 TI - The effect of the oral iron chelator deferiprone on the liver damage induced by tamoxifen in female rats. AB - Tamoxifen (TAM) is a non-steroidal antiestrogen used in the treatment and prevention of hormone-dependent breast cancer. Tamoxifen therapy may be accompanied with hepatic injury and iron accumulation in this organ. The present study investigates the influence of the effective oral iron chelator, deferiprone (L1), in TAM-induced acute liver injury. Four groups of female Wistar rats were used: I, control; II, TAM; III, TAM+L1; IV, L1. Tamoxifen (75 mg/kg) was administered orally on the first and second day; L1 (50 mg/kg) was administered orally on the first, second and third day of the experiment. On the fourth day, parameters of oxidative state: lipid peroxidation (LP), glutathione (GSH) and catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities were estimated in liver homogenates. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH) levels and iron hepatic content were also evaluated. The TAM-induced oxidative damage was demonstrated by increased LP (52% above controls) and decreased GPx activity (to 92% of controls). The protective effect of L1 was manifested by attenuation of LP (p <0.05) and preserving of GPx activity. The TAM-induced increase of serum ALT and AST activity remained unchanged by L1 treatment. Significant increase of hepatic iron (Fe) level (41% above controls) was found in TAM-treated rats. Hepatic Fe accumulation was completely prevented by L1 treatment. PMID- 21599439 TI - Stability and reactivity of free radicals: a physicochemical perspective with biological implications. AB - Several factors control the reactivity of radicals and can provide the strategies to convert highly reactive species into more persistent species that are easier to detect in an experiment. A reaction can only proceed if sufficient mobility and thermodynamic driving force are provided and the reaction is allowed by steric considerations and by electronic states of the reagents and products. A violation of at least one of these conditions can make the radical relatively stable. In certain cases, these factors occur naturally, in other situations, they can be purposefully manipulated to reduce the reactivity of highly reactive radicals, prolonging their lifetime and increasing their concentration. The discussed examples cover a vast range of lifetimes, from 10(-9) seconds to 10(9) years, at concentration levels down to 10(3) radicals per sample (10(-18) M), and stress that stability and reactivity are not independent notions and are the two sides of the same coin. PMID- 21599440 TI - Multidentate terephthalamidate and hydroxypyridonate ligands: towards new orally active chelators. AB - The limitations of current therapies for the treatment of iron overload or radioisotope contamination have stimulated efforts to develop new orally bioavailable iron and actinide chelators. Siderophore-inspired tetradentate, hexadentate and octadentate terephthalamidate and hydroxypyridonate ligands were evaluated in vivo as selective and efficacious iron or actinide chelating agents, with several metal loading and ligand assessment procedures, using (59)Fe, (238)Pu, and (241)Am as radioactive tracers. The compounds presented in this study were compared to commercially available therapeutic sequestering agents [deferoxamine (DFO) for iron and diethylenetriaminepentaacetic acid (DPTA) for actinides] and are unrivaled in terms of affinity, selectivity and decorporation efficacy, which attests to the fact that high metal affinity may overcome the low bioavailability properties commonly associated to multidenticity. PMID- 21599441 TI - 1-(2-Hydroxyethoxy) methyl-2-methyl-3-hydroxyl-4-pyridinone: a targeted, bifunctional chelating agent for potential uranic detoxification in the kidney. AB - The only proposed treatment for uranium (U) internal decontamination is chelation therapy, and so far, there is no effective chelating drug available for this purpose. A modified iron chelator of deferiprone (L1) has been investigated for its chemical and pharmacological properties as a new U chelating agent. The results have demonstrated that the chelator, 1-(2-hydroxyethoxy)methyl-2-methyl-3 hydroxyl-4-pyridinone (HEML1), has the ability to chelate uranyl ion, forming a stable complex with 2:1 (chelator/U) stoichiometry. The chelator, HEML1, does not pose any adverse effects on cultured human kidney cells, and shows the capability of protecting the cells against U-associated cytotoxicity and hydrogen peroxide induced free radical damage. Moreover, because of the hydrophilic property of both HEML1 and its U-complex, the chelator has the potential to target the kidneys where the U prefer to deposit, and to leave the organ after complexing U. These results suggest that HEML1 may be able to serve as a bifunctional therapeutic for internal radionuclide decontamination. PMID- 21599442 TI - A record of 1320 suspect, deferasirox-related, patient deaths reported in 2009: insufficient toxicity testing, low efficacy and lack of transparency may endanger the lives of iron loaded patients. PMID- 21599443 TI - Spinal cord compression secondary to a thoracic vertebral osteochondroma. AB - The authors describe a case of spinal cord compression due to an osteochondroma arising from the T-6 vertebral body in a patient with hereditary multiple exostoses. This 16-year-old boy presented with spastic paraparesis. Surgical decompression was followed by resolution of the neurological impairments. Osteochondroma is the most common bone tumor. The distribution of osteochondromas greatly favors the extremities and these lesions rarely arise in the vertebral column. Osteochondromas occur in 2 distinct clinical settings--as solitary or multiple tumors, the latter being often associated with hereditary multiple exostoses. Osteochondromas are more commonly found in the posterior elements of the vertebrae. Intraspinal presentation of these tumors is usually limited to the cervical regions, with few tumors reported in the thoracic vertebrae. Based on the presented case and literature review, the authors conclude that osteochondromas of the thoracic spine that cause myelopathy usually arise from the vertebral body and pedicle. Prompt and systematic radiological investigations are important in planning surgical management. Surgical excision usually yields good results. PMID- 21599444 TI - Comparison of instrumented posterolateral fusion versus percutaneous pedicle screw fixation combined with anterior lumbar interbody fusion in elderly patients with L5-S1 isthmic spondylolisthesis and foraminal stenosis. AB - OBJECT: The purpose of this study was to compare the clinical and radiological outcomes of treating L5-S1 isthmic spondylolisthesis and foraminal stenosis in elderly patients with instrumented posterolateral fusion (PLF) versus percutaneous pedicle screw fixation (PSF) combined with anterior lumbar interbody fusion (ALIF). METHODS: Forty-nine patients older than 65 years of age with L5-S1 isthmic spondylolisthesis and symptomatic foraminal stenosis who underwent ALIF were retrospectively analyzed. An ALIF with instrumented PLF (Group A) was performed in 23 patients, and ALIF with percutaneous PSF (Group B) was performed in 26 patients. Data were collected preoperatively and at 3 months, 6 months, 1 year, and every subsequent year. A comparative analysis was made between the 2 groups using clinical (visual analog pain scale [VAS] and modified MacNab criteria) and radiological (dynamic plain radiographs and CT scans) measures. RESULTS: The mean follow-up duration was 30.3 months (range 24-47 months). The mean preoperative scores on the VAS for low-back pain in Groups A and B were 5.9 and 5.7, respectively, decreasing to 1.4 and 3.6, respectively, at 6 months after surgery (p = 0.001), whereas VAS scores for low-back pain in Groups A and B at 2 years postoperatively were 1.3 and 2.3, respectively (p = 0.005). The mean preoperative scores on the VAS for leg pain in Groups A and B were 7.5 and 7.8, respectively, decreasing at 6 months after surgery to 1.2 and 1.6, respectively (p = 0.201), whereas VAS scores for leg pain in Groups A and B at 2 years postoperatively were 1.3 and 1.4, respectively (p = 0.803). The rates of patients with excellent or good outcomes in terms of the modified MacNab criteria in Groups A and B were 91.3% and 69.2%, respectively, at 6 months after surgery (p = 0.010). Those rates in Groups A and B at 2 years after the operation were 91.3% and 84.6%, respectively (p = 0.203). The fusion rates in Groups A and B were 91.3% and 57.7%, respectively, at 6 months after surgery (p = 0.008), whereas the fusion rates in Groups A and B were 91.3% and 76.9%, respectively, at 2 years after surgery (p = 0.103). There was no significant difference in terms of the complication rate between Group A (4.3%) and B (3.8%) (p = 0.691). CONCLUSIONS: A relatively longer time until, and lower rate for, fusion in the patients treated with ALIF and percutaneous PSF were noted, which may be correlated with a relatively lower rate of patients with excellent or good outcomes. These results seem to favor ALIF with instrumented PLF rather than ALIF with percutaneous PSF in the treatment of elderly patients with L5-S1 isthmic spondylolisthesis and foraminal stenosis. However, additional long-term follow-up, a larger number of patients, and well-designed studies are necessary for a more rigorous evaluation of the outcome of patients treated using these surgical techniques. PMID- 21599445 TI - Neuroprotective effects of gabapentin on spinal cord ischemia-reperfusion injury in rabbits. AB - OBJECT: Extensive research has been focused on neuroprotection after spinal cord trauma to alleviate the effects of secondary injury. This study aims to investigate the neuroprotective effects of gabapentin in an experimental spinal cord ischemia reperfusion injury. METHODS: Thirty-two adult male New Zealand white rabbits received spinal cord ischemic injury using the aortic occlusion model. Animals were divided into 4 groups (sham, control, low-dose, and high-dose treatment groups; 8 rabbits in each group). High (200 mg/kg) and low (30 mg/kg) doses of gabapentin were administered to the animals in the treatment groups after spinal cord ischemic injury. Neurological status of the animals, ultrastructural findings in injured tissue samples, and levels of tissue injury markers in these 2 groups were compared with findings in the animals that did not receive the ischemic procedure (sham-operated group) and those that received normal saline after administration of ischemia. RESULTS: Regarding levels of tissue injury marker levels after ischemic injury, animals in the gabapentin treated groups demonstrated better results than animals in the other groups. The ultrastructural findings and caspase-3 activity were similar. The treatment groups demonstrated better results than the other groups. CONCLUSIONS: Gabapentin demonstrated significant neuroprotection after early phases of ischemic injury. Further studies with different experimental settings including neurological outcome are required to achieve conclusive results. PMID- 21599446 TI - Tethered cord syndrome in adults. AB - OBJECT: The treatment of tethered cord syndromes in adults is discussed regarding the natural history and surgical indications. The author analyzes data obtained in patients who were diagnosed with a tethered cord in adulthood and either underwent surgical or conservative therapy between 1991 and 2009. METHODS: Since 1991, data obtained in 2515 patients with spinal cord pathologies were entered into the spinal cord database, and prospective follow-up was performed through outpatient visits and questionnaires. Of the 2515 patients, 85 adults with a tethered cord syndrome formed the basis of this study. The tethering effect was caused either by a split cord malformation, a thick filum terminale, a conus medullaris lipoma with extradural extension, or various combinations of these mechanisms. The mean age of the patients was 46 +/- 13 years (range 23-74 years) and the mean follow-up duration was 61 +/- 62 months. Two groups were distinguished based on the absence (Group A, 43 patients) or presence (Group B, 42 patients) of an associated lipoma or dysraphic cyst (that is, dermoid, epidermoid, or neurenteric cyst). Surgery was recommended for patients with symptoms only. Short-term results were determined within 3 months of surgery, whereas long-term outcomes (clinical recurrences) were evaluated using Kaplan Meier statistics. RESULTS: For all patients, pain was the most common major complaint. Severe neurological deficits were rare. In Group A, 20 of 43 patients underwent surgery, whereas in Group B 23 of 42 patients underwent surgery. Among individuals who did not undergo surgery, 17 patients refused surgery and 25 patients underwent recommended conservative treatment. Short-term postoperative results indicated a significant improvement of pain and a stabilization of neurological symptoms. Long-term results showed a good prognosis in patients in whom first-time (that is, nonrevision) surgery achieved successful untethering, with a 10-year rate of neurological stabilization in 89% of Group A and a 10-year rate of neurological stabilization in 81% of Group B patients. The benefit of secondary operations in Group B was limited, with eventual clinical deterioration occurring in all patients within 10 years. For patients treated conservatively, follow-up information could be obtained in 33 of 42 patients. Twenty-eight patients remained in stable clinical condition. Only 5 of the conservatively treated patients experienced clinical deterioration over time; in 4 of these individuals with deterioration, surgery had been recommended but was refused by the patient. The clinical recurrence rate in all conservatively treated patients was 21% after 10 years. With a recommendation for surgery this figure rose to 47% within 5 years. CONCLUSIONS: Surgery in adult patients with a tethered cord syndrome should be reserved for those with symptoms. In surgically treated patients, pain relief can often be achieved, and long-term neurological stabilization tends to persist more often than it does in conservatively treated patients. A conservative approach is warranted, however, in adult patients without neurological deficits. Revision surgery in patients with complex dysraphic lesions should be performed in exceptional cases only. PMID- 21599447 TI - Axial interbody fusion. PMID- 21599448 TI - Complications of axial lumbar interbody fusion. AB - OBJECT: Axial lumbar interbody fusion (AxiaLIF) is a novel minimally invasive approach for fusion of L4-5 and L5-S1. This technique uses the presacral space for percutaneous access to the anterior sacrum. The AxiaLIF procedure has the potential to decrease patient recovery time, length of hospital stay, and overall occurrence of surgical complications. It can be used alone or in combination with minimally invasive or traditional open fusion procedures. The purpose of this study was to evaluate complications of the AxiaLIF procedure at the authors' institutions. METHODS: Patients who underwent AxiaLIF surgery between October 2005 and June 2009 at the authors' institutions were identified. The authors retrospectively reviewed these patients' charts, including operative reports and postoperative medical records, to determine what complications were encountered. RESULTS: A total of 68 patients underwent AxiaLIF surgery, with an average follow up time of 34 months. Sixteen patients (23.5%) experienced a total of 18 complications (26.5%); this group included 8 men and 8 women (mean age 52.1 years). These complications included pseudarthrosis (8.8%), superficial infection (5.9%), sacral fracture (2.9%), pelvic hematoma (2.9%), failure of wound closure (1.5%), transient nerve root irritation (1.5%), and rectal perforation (2.9%). CONCLUSIONS: The complication rate associated with AxiaLIF in the present study was relatively low (26.5%). The most common complications were superficial infection and pseudarthrosis. There were 2 cases of rectal perforation associated with AxiaLIF; one case was found intraoperatively and the other presented 4 days postoperatively. Both patients underwent emergency repair by a general surgeon and had no long-term sequelae as a result of the rectal injuries. It is important for surgeons to be aware of the potential for these complications. Many of these complications can probably be avoided with proper patient selection and operative planning. Preoperative MR imaging, a detailed patient physical examination and history, full bowel preparation, and the use of live fluoroscopy can all help to prevent complications with AxiaLIF surgery. PMID- 21599449 TI - Rupture of anterior communicating artery aneurysms during computed tomography angiography: description of the pathway for intraseptal and intraventricular hemorrhage. AB - Intraventricular hemorrhage is common after the rupture of anterior communicating artery (ACoA) aneurysms, although the anatomical pathway has not been described. Knowledge of the mechanism of hemorrhage may enhance understanding of its prognosis. Using CT angiography, the authors analyzed this pathway in 2 cases of ACoA aneurysm rupture associated with intraventricular hemorrhage. The initial hemorrhages created a hyperdense ventriculographic image on which the subsequent contrast medium ejection could be followed. The contrast medium entered the subarachnoid space of the anterior interhemispheric fissure and broke through the lamina rostralis into the septum pellucidum and into the frontal horns of the lateral ventricles. Thus, the authors provide an explanation for bleeding from ACoA aneurysms into the ventricular system in the presence of an intact lamina terminalis. The septum pellucidum may act as a buffer before extension of the bleeding into the ventricular system. PMID- 21599450 TI - Ventricular catheter exchange using a peel-away outer catheter. AB - Ventricular catheter replacement can be challenging, especially in patients with small ventricles. Shunt malfunction due to ventricular catheter obstruction can occur without ventricular enlargement, such as in the setting of slit-ventricle syndrome or benign intracranial hypertension. The authors describe a simple technique for ventricular catheter exchange using a peel-away catheter. In the limited initial experience of the senior author (G.S.C.), this technique appears to be safe and effective. To the authors' knowledge, this method has not been described in the neurosurgical literature before. PMID- 21599451 TI - Antihypertensive therapy and cancer risks? PMID- 21599452 TI - Atrioventricular conduction in the hypertensive patient: influence of aging, pulse pressure, and arterial stiffness. AB - Atrioventricular (AV) conduction time (PR interval) lengthens with age. Hypertension is often presented as an accelerated aging of the heart and arteries. The principal marker of arterial aging is an increase in arterial stiffness and pulse pressure. We were interested to find out whether parameters of blood pressure and arterial stiffness were related to the PR interval and whether they influenced its long-term progression. We examined factors linked to the PR interval at baseline in a cohort of untreated hypertensive patients including office and 24-hr blood pressure and arterial stiffness (QKD(100-60)). Long-term evolution of the PR interval and related factors were obtained during follow-up of this population. Baseline data were obtained in 1,034 untreated hypertensive patients. At baseline, four variables emerged as significantly and independently correlated with PR interval: Gender, age, weight, and heart rate. During follow-up (137 +/- 78 months), 328 of these patients were re-examined. In this group, PR increased from 159 +/- 20 to 167 +/- 25 msec (p<0.001), a mean alteration of 8 +/- 19 msec. This change was correlated with the baseline 24 hr PP (r=0.17, p=0.004) and with the duration of follow-up (r=0.13, p=0.02). In the group with baseline evaluation of arterial stiffness (n=141), QKD(100-60) was correlated with the change in PR interval (r= -0.33, p<0.0001) along with the duration of follow-up (r=0.22, p=0.005). This study shows a link between baseline increased pulse pressure or arterial stiffness with the prolongation of the PR interval with aging. Because this link was observed during follow-up, it is possible that increased arterial stiffness favors the increase in the PR interval with age. PMID- 21599453 TI - Blood pressure and heart rate variability complexity analysis in pregnant women with hypertension. AB - BACKGROUND: In this work, we perform a comparative analysis of blood pressure and heart rate variability complexity during pregnancy between normal, hypertensive, and preeclamptic women. METHODS AND RESULTS: A total of 563 short electrocardiographic (10 min) records were obtained from 217 pregnant women (135 normal, 55 hypertensive, and 27 preeclamptic) during several gestational ages in sitting position. We used a mixed unbalanced model for the longitudinal statistical analysis and besides the conventional spectral analysis, we applied Lempel-Ziv complexity, sample entropy, approximated entropy, and detrended fluctuation analysis in the complexity measurement. CONCLUSIONS: The obtained results revealed significant differences between pathological and normal states with important considerations related to pregnancy adaptability and evolution as well as the relationship of complexity and blood pressure with factors such as maternal age, familial history of diabetes or hypertension, and parity. PMID- 21599454 TI - Relationship between heart rate variability indexes and common biochemical markers in normal and hypertensive third trimester pregnancy. AB - BACKGROUND: In this study, we explored the correlations between heart rate variability indexes and some biochemical markers during the third trimester of normal, hypertensive, and preeclamptic pregnancies. METHODS AND RESULTS: The obtained indexes are associated with complexity and spectral variables calculated from short electrocardiographic records. CONCLUSIONS: Including all the subjects in the analysis, we found that complexity indexes are positively related with hemoglobin concentration in the pathologic group and uric acid blood levels whereas low frequency (LF) was negatively correlated with uric acid and creatinine concentration as well as positively correlated with platelet levels. The LF was the only spectral region with significant correlation. Through an independent analysis of groups, only significant correlations were found in normal and preeclamptic groups between LF and uric acid concentration and in normal and hypertensive groups for LF and creatinine blood levels. PMID- 21599455 TI - Objective assessment of contact lens wear-associated conjunctival squamous metaplasia by linear measures of cell size, shape and nucleus-to-cytoplasm ratios. AB - PURPOSE: To objectively assess the cell and nucleus dimensions of human bulbar conjunctival cells in female soft contact lens wearers to illustrate a method for assessment of the nucleus-to-cytoplasm ratio based on simple linear measures. METHODS: Impression cytology samples were taken from the nasal side exposed bulbar conjunctiva surface from 12 young adult, white European females with a history of successful daily soft contact lens wear. A Millcell((r))-CM filter was used after topical anesthesia, which was stained with Giemsa. Color images of portions of the cells, in a monolayer at 200* magnification by light microscopy, were graded by the Nelson scale and then a projection overlay method was used to outline the cell and nucleus borders. The cell longest dimension (LONG), shorter dimension (SHORT), and the longest dimension of the nucleus (NUCLONG) were measured. A nucleus-to-cytoplasm N:C ratio was calculated from (LONG NUCLONG)/NUCLONG. RESULTS: Cells had appearances consistent with a grade 2 or 3 squamous metaplasia and were moderately enlarged (mean LONG +/- SD of 46.0 +/- 3.8 microm), only slightly elongated (mean LONG:SHORT ratio of 1.397 +/- 0.101) and the nucleus size was consistently greater than normal (man 12.8 +/- 1.3 microm). A calculation of N:C showed a relatively wide range of values with average values from 1:2.143 to 1:3.317 (for an overall mean of 2.675 +/- 0.371). CONCLUSIONS: These studies further indicate that grade 2 to 3 squamous metaplasia of the exposed bulbar conjunctival cells is an expected consequence of soft contact lens wear. The cell enlargement is not associated with a significant change in cell shape (i.e., the LONG:SHORT ratio is little different from grade 0 cells) but is associated in a slight increase in nucleus size. The calculated N:C ratio based on linear measures is no higher than 1:5 and more likely closer to 1:2.5. PMID- 21599456 TI - Human T lymphoblast cell line expresses FP receptor. AB - PURPOSE: To identify the presence of prostanoid FP receptor in human T lymphoblast (MOLT-3) cell line, which was known not to express FP receptor. METHODS: Western blot analysis and mass spectrometry were performed on the cell lysates. RESULTS: The expression of FP receptor was detected by western blot analysis and mass spectrometry. CONCLUSIONS: MOLT-3 cell does express prostanoid FP receptor. PMID- 21599457 TI - Polymorphisms of the DNA repair genes XPD and XRCC1 and the risk of age-related cataract development in Han Chinese. AB - PURPOSE: Epidemiological evidence suggests that ultraviolet (UV) irradiation and oxidative stress play an important role in age-related cataract pathogenesis. UV irradiation and oxidative stress can produce a wide range of DNA damage. Polymorphisms of DNA repair enzymes may affect repair efficiency and the role of DNA repair mechanisms has received attention recently in age-related cataract pathogenesis. In this case-control study, The aim was to determine the frequency of polymorphisms in two DNA repair enzyme genes, xeroderma pigmentosum complementation group D (XPD) codon 751 and x-ray cross-complementing group 1 (XRCC1) codon 399, in patients with age-related cataract and in healthy controls. METHODS: Polymerase chain reaction and restriction fragment length polymorphisms were used to analyze XPD T751G and XRCC1 G399A in 180 patients with age-related cataract and 174 healthy individuals as controls. RESULTS: There was a significant difference between the case and control groups in the XRCC1399 genotype. The odds ratio of the XRCC1 G/A polymorphism compared with the G/G wild type genotype was 1.92 (95% CI = 1.17-3.15, p = 0.01). Moreover, individuals who carried at least one A-allele (G/A or A/A) had a 1.68-fold increased risk of developing age-related cataract compared with those who carried the G/G wild type genotype (OR = 1.68; 95% CI: 1.05-2.68, p = 0.030). No statistically significant difference was found in the genotypic and allelic distributions of the polymorphisms in the XPD gene between the groups. CONCLUSIONS: These results suggest that polymorphisms in XRCC1 codon 399 may be associated with the development of age-related cataract in Han Chinese. PMID- 21599458 TI - Protective effects of rosiglitazone on retinal neuronal damage in diabetic rats. AB - PURPOSE: To investigate whether rosiglitazone has a protective effect on retinal neural cells in diabetic rats, and to determine a possible anti-apoptotic mechanism. METHODS: Streptozotocin-induced diabetic rats and control animals were randomized evenly to receive rosiglitazone or not, effects were examined after 24 weeks. Retinal histology was examined and quantified using light microscopy; Apoptosis of retinal neural cells was determined by terminal dUTP nick-end labeling assay; Retinal ultrastructure was examined by transmission electron microscopy; Proteins levels of cleaved caspase-3, signal transduction and activators of transcription-3 (STAT3), phospho-STAT3 (p-STAT3), and suppressors of cytokine signaling 3 (SOCS3) in the retinal tissues were also determined by western blotting. RESULTS: Compared with the control group, the thickness of the overall retina, inner plexiform layer, inner nuclear layer reduced by 13.8%, 27.4% and 4.2%, respectively (p < 0.05) in the diabetic group after 24 weeks; The number of cells in the ganglion cell layer was also decreased by 18.6% (p < 0.05). There was apoptosis of retinal neurons in the diabetic rats. Diabetes also induced mitochondrial metamorphosis in ganglion cells and evident pyknosis in the outer nuclear layer. These effects were associated with increased levels of cleaved caspase-3, p-STAT3, and decreased levels of SOCS3. After treatment of rosiglitazone, the thickness of the retina and the number of cells in the ganglion cell layer were significantly greater than those in the diabetic group (p < 0.05). Rosiglitazone also attenuated the diabetic-induced apoptosis of retinal neurons and mitochondrial metamorphosis in ganglion cells. Consistent with these effects, rosiglitazone treatment also decreased cleaved caspase-3 and p-STAT3 expression and, at the same time, increased SOCS3 expression. CONCLUSIONS: Rosiglitazone attenuated diabetes-induced apoptosis in retinal neurons through activities that may involve inhibition of p-STAT3 by induction of SOCS3, which suggested that rosiglitazone might be used to prevent retinal neuronal damage in diabetes mellitus. PMID- 21599459 TI - Effects of quantum dots on different renal proximal tubule cell models and on gel free renal tubules generated in vitro. AB - We investigated the interactions of different types of human and porcine renal proximal tubule-derived cells with core-shell CdSe@ZnS quantum dots (QDs) coated with polymerized histidine-formaldehyde (pHF). The results revealed that porcine and human proximal tubule cells showed a markedly different uptake behavior. This applied to flat epithelial monolayers, as well as to proximal tubules formed on two-dimensional (2D) surfaces in vitro. Primary human cells were most sensitive to the cytotoxic effects of QDs, but displayed inter-donor variability, which appeared to depend on the state of differentiation. The results suggested that human proximal tubule-derived cells were more appropriate than porcine cells for in vitro nanotoxicology. Primary human cells might be suitable when their state of differentiation and inter-donor variability were well-controlled. Furthermore, the results suggested that gel-free proximal tubules formed in vitro could be used as test system to address uptake and transport of nanometer-sized particles in human renal structures. PMID- 21599460 TI - Cross-linking of dimeric CitS and GltS transport proteins. AB - CitS of Klebsiella pneumoniae and GltS of Escherichia coli are Na+-dependent secondary transporters from different families that are believed to share the same fold and quaternary structure. A 10 kDa protein tag (Biotin Acceptor Domain [BAD]) was fused to the N-terminus of both proteins (CitS-BAD1 and GltS-BAD1, respectively) and inserted in the central cytoplasmic loop that connects the two halves of the proteins (CitS-BAD260 and GltS-BAD206). Both CitS constructs and GltS-BAD206 were produced and shown to be active transporters, but GltS-BAD1 could not be detected in the membrane. Distance relationships in the complexes were studied by cross-linking studies. Both CitS constructs were shown to be in the dimeric state after purification in detergent by cross-linking with glutaraldehyde. The concentration of glutaraldehyde resulting in 50% cross linking was significantly higher for CitS-BAD1 than for CitS and CitS-BAD260. Remarkably, GltS and GltS-BAD260 were not cross-linked by glutaraldehyde because of the lack of productive reactive sites. Cross-linking of GltS was observed when the N-terminal 46 residues of CitS with or without BAD at the N-terminus were added to the N-terminus of GltS. The stretch of 46 residues contains the first transmembrane segment of CitS that is missing in the GltS structure. The data support an orientation of the monomers in the dimer with the N-termini close to the dimer interface and the central cytoplasmic loops far away at the ends of the long axis of the dimer structure in a view perpendicular to the membrane. PMID- 21599462 TI - Chemical composition, dietary fibre, tannins and minerals of grain amaranth genotypes. AB - The objective of this study was to determine the chemical composition of 28 white and coloured grain amaranth (Amaranthus spp.) genotypes. Neutral detergent fibre (NDF) concentration was greater while strach concentration was lower for coloured seeds genotypes than white seeds genotypes. Total dietary fibre followed a similar trend to that observed for NDF. Total tannin concentrations ranged between 20.7 and 0 g/kg with total and hydrolysed tannin concentrations being higher for white than for coloured seeds genotypes. Coloured seeds genotypes contained higher Mg and Ca concentrations than white seeds genotypes. However, seed colour had no influence on K, Na and P concentrations. Copper and Fe were the most variable micro-minerals in the evaluated genotypes with no significant effect of seed colour on the concentration of either mineral. PMID- 21599461 TI - Hydrogen peroxide modulates immunoglobulin expression by targeting the 3'Igh regulatory region through an NFkappaB-dependent mechanism. AB - Reactive oxygen species such as hydrogen peroxide (H(2)O(2)) appear to play a role in signal transduction in immune cells and have been shown to be synthesized upon antigen-mediated activation and to facilitate cellular activation in B- and T-cells. However, an effect of H(2)O(2) on B-cell function (i.e. immunoglobulin (Ig) expression) has been less well-characterized. The effects of H(2)O(2) exposure on lymphocytes may be partly mediated by oxidative modulation of the NFkappaB signal transduction pathway, which also plays a role in Ig heavy chain (Igh) gene expression. Igh transcription in B lymphocytes is an essential step in antibody production and is governed through a complex interaction of several regulatory elements, including the 3'Igh regulatory region (3'IghRR). Utilizing an in vitro mouse B-cell line model, this study demonstrates that exposure to low MUM concentrations of H(2)O(2) can enhance 3'IghRR-regulated transcriptional activity and Igh gene expression, while either higher concentrations of H(2)O(2) or the expression of a degradation resistant inhibitory kappaB (IkappaBalpha super-repressor) can abrogate this effect. Furthermore, suppressive H(2)O(2) concentrations increased protein levels of the p50 NFkappaB sub-unit, IkappaBalpha, and an IkappaBalpha immunoreactive band which was previously characterized as an IkappaBalpha cleavage product exhibiting stronger inhibitory function than native IkappaBalpha. Taken together, these observations suggest that exposure of B lymphocytes to H(2)O(2) can alter Igh transcriptional activity and Ig expression in a complex biphasic manner which appears to be mediated by NFkappaB and altered 3'IghRR activity. These results may have significant implications to disease states previously associated with the 3'IghRR. PMID- 21599463 TI - Evaluation of polyphenol contents in differently processed apricots using accelerated solvent extraction followed by high-performance liquid chromatography diode array detector. AB - Concentrations of 17 polyphenols in ripe-fresh, sun-dried and sulfited-dried apricots either harvested from organic or pesticide-treated trees before harvest were determined using reverse-phase high-performance liquid chromatography with UV-Vis diode array detector, and the change of polyphenol profile with origin of the apricot product was established. Extraction of polyphenols was achieved using the accelerated solvent extraction technique (ASE). A mixture of methanol, water (70:30 v/v) including 0.1 g of tert-butylhydroquinone as solvent, 60 min extraction time, 60 degrees C temperature and 1,500 psi pressure were found the most productive operating conditions for ASE. Concentrations of polyphenols in organic apricots were higher than pesticide-treated samples, and roughly the same in ripe-fresh and sun-dried apricots. Polyphenol concentrations of either organic or pesticide-treated sulfited-dried apricots were lower than the ripe-fresh apricots. Considering the organic ripe-fresh apricots, there was a decrease in some polyphenol concentration in the sulfited-dried apricots compared with the ripe-fresh apricot, and the range of decrease is between 1.4 and 53%. PMID- 21599465 TI - Customized aspheric IOL design by raytracing through the eye containing quadric surfaces. AB - PURPOSE: The purpose of the present study was to demonstrate a method of how to calculate intraocular lenses with a customized asphericity and how to apply this strategy to clinical examples in cases where biometric data of the cornea (front and back surface topography) as well as distances in the eye are known. METHODS: (1) we demonstrated an algebraic method for tracing a bundle of rays through a schematic eye containing surfaces which can be represented by 2nd order surfaces (quadric surfaces), and (2) we introduced a strategy for customization of the lens' back surface for compensating the optical path length differences of the rays from object to image in terms of a wave front correction while predefining the lens front surface. RESULTS: The presented method was applied to three working examples: example 1 referred to a centered optical system with a spherical cornea (front and back surfaces) and a predefined spherical lens front surface, example 2 referred to a centered optical system with aspherical surfaces for the corneal front and back surfaces and a predefined spherical lens front surface, and example 3 referrred to a non-centered system with a decentered aspherical cornea (front and back surface), and a predefined spherical lens front surface. The parameterized ray intersection points with the lens back surface were optimized in terms of equalizing the ray path lengths and a quadric surface was fitted to these ray intersection points to characterize the customized lens. The fitting error, ray spot diagram, and the optical path length of the rays are provided. CONCLUSION: This simple calculation strategy may be the first step in developing individual aspherical lenses, which have the potential to fully compensate spherical aberrations based on individual measures of the eye. PMID- 21599464 TI - In vitro antioxidant and hypoglycemic activities of Ethiopian spice blend Berbere. AB - The metal chelating activity, antioxidant properties, and the effect on carbohydrate-hydrolyzing enzymes of Ethiopian spice blend Berbere have been investigated. Berbere contains a total amount of phenols corresponding to 71.3 mg chlorogenic acid equivalent per gram of extract and a total flavonoid content of 32.5 mg quercetin equivalent per gram of extract. An increase of the resistance towards forced oxidation was obtained when Berbere was added to sunflower oil. In order to evaluate the bioactivity of the non-polar constituents, an n-hexane extract was obtained from Berbere. The gas chromatography-mass spectrometry analysis revealed the presence of 19 fatty acids constituents (98.1% of the total oil content). Among them, linoleic acid was the major component (72.0% of the total lipids). The ethanolic extract had the highest ferric-reducing ability power (35.4 MUM Fe(II)/g) and DPPH scavenging activity with a concentration giving 50% inhibition (IC(50)) value of 34.8 MUg/ml. Moreover, this extract exhibited good hypoglycemic activity against alpha-amylase (IC(50) = 78.3 MUg/ml). In conclusion, Ethiopian spice blend Berbere showed promising antioxidant and hypoglycemic activity via the inhibition of carbohydrate digestive enzymes. These activities may be of interest from functional point of view and for the revalorization of the spice blend in gastronomy also outside the African country. PMID- 21599466 TI - Effect of pulp preconditioning on acidification, proteolysis, sugars and free fatty acids concentration during fermentation of cocoa (Theobroma cacao) beans. AB - Changes in acidification, proteolysis, sugars and free fatty acids (FFAs) concentrations of Ghanaian cocoa beans as affected by pulp preconditioning (pod storage or PS) and fermentation were investigated. Non-volatile acidity, pH, proteolysis, sugars (total, reducing and non-reducing) and FFAs concentrations were analysed using standard methods. Increasing PS consistently decreased the non-volatile acidity with concomitant increase in pH during fermentation of the beans. Fermentation decreased the pH of the unstored beans from 6.7 to 4.9 within the first 4 days and then increased slightly again to 5.3 by the sixth day. Protein, total sugars and non-reducing sugars decreased significantly (p < 0.05) during fermentation, whereas reducing sugars and FFA increased. PS increased the FFA levels, reduced the protein content but did not have any effect on the sugars. The rate of total and non-reducing sugars degeneration with concomitant generation of reducing sugars in the cocoa beans was largely affected by fermentation than by PS. PMID- 21599467 TI - An evolutionary perspective on the trans-generational basis of obesity. AB - Until recently, obesity was considered the product of interactions between genotype and lifestyle. However, recent work suggests that the genetic heritability of adiposity has been over-estimated, whilst epidemiological studies show that although many genes are associated with nutritional status, the effect of each is very small. A polygenic basis of obesity risk may arise through bet hedging of numerous traits to accommodate diverse unpredictable environments, rather than through systematic local adaptation. Such 'fragmentation' of the genetic component of metabolism across multiple alleles may be a necessary pre requisite for complementary enhancement of phenotypic plasticity. The inter generational component of obesity refers to phenotypic effects transmitted across generations, arising from exposure to maternal, familial and environmental niches during development. Inter-generational transfers of somatic capital (height, lean mass) may respond to ecological conditions through a slow-response damping system, through the influence of maternal phenotype on offspring growth and body composition. The primary traits subject to inter-generational effects may be physique and life history strategy, with adiposity both aiding and responding as a flexible risk management strategy. The biological processes that underpin the offspring's developmental plasticity appear sensitive to the obesogenic niche. Through this sensitivity, diverse environmental factors can induce excess weight gain from childhood onwards. PMID- 21599468 TI - Comparison of growth between native and immigrant infants between 0-3 years from the Dutch ABCD cohort. AB - BACKGROUND: In the Netherlands separate reference charts have been developed for native and immigrant groups to deal with differences in growth patterns in later childhood. The use of these charts, however, is complicated by methodological issues; they do not represent all large Dutch immigrant groups in separate charts despite the differences that have been suggested and the evidence of ethnic disparities in growth dates back to 1997. AIM: Anthropometric measurements from a contemporary multi-ethnic cohort study were created to quantify differences in childhood growth by creating growth charts, separately for boys and girls between the ages of 0-3 years. SUBJECTS AND METHODS: The infants modelled in the charts had a mother born in the Netherlands (n = 3107), Suriname (n = 225), Turkey (n = 203) and Morocco (n = 336). Charts with and without correction for country of origin of the mother were created by using the LMST method. RESULTS: All models including the covariate country of origin of the mother fitted the data better (p < 0.0005), but the observed differences were small. CONCLUSION: Most remarkable differences were found in the BMI and weight measurements for age charts. Especially girls from mothers born in Turkey and Morocco had an increasingly heavier weight for their age than girls from mothers born in the Netherlands. PMID- 21599469 TI - Rabbit rubeosis iridis induced by intravitreal latex-derived angiogenic fraction. AB - PURPOSE: To describe the presence of iris neovascularization in a rabbit-model of retinal neovascularization induced by the intravitreal injection of latex-derived angiogenic fraction microspheres (LAF). MATERIALS AND METHODS: Eight New Zealand rabbits received one intravitreal injection of PLGA (L-lactide-co-glycolide) microspheres with 50 ug of LAF in the right eye (Group A). Microspheres without the LAF (0.1 ml) were injected in controls (Group B; n = 8). Follow-up with clinical evaluation and iris fluorescein angiography was performed after 4 weeks when eyes were processed for light microscopy. RESULTS: All eyes from Group A showed significant vascular dilation, conjunctival hyperemia and neovascularization on the iris surface, after LAF injection. No vascular changes were observed in Group B. CONCLUSIONS: The intravitreal injection of microspheres containing the LAF can induce rubeosis iridis in rabbits and could be used as a simple experimental model for iris neovascularization. PMID- 21599470 TI - PKCgamma, role in lens differentiation and gap junction coupling. AB - PURPOSE: To determine the role of PKCgamma in the regulation of gap junction coupling in the normal lens, we have compared the properties of coupling in lenses from wild type (WT) and PKC-gamma knockout (KO) mice. METHODS: Western blotting, confocal immunofluorescence microscopy, immunoprecipitation, RT-PCR and quantitative real time PCR were used to study gap junction protein and message expression; gap junction coupling conductance and pH gating were measured in intact lenses using impedance studies. RESULTS: There were no gross differences in size, clarity, or expression of full-length Cx46 or Cx50 in lenses from WT and PKCgamma KO mice. However, total Cx43 protein expression was ~150% higher in the KO lenses. In WT lenses, Cx43 was found only in epithelial cells whereas in KO lenses, its expression continued into the fiber cells. Gap junction coupling conductance in the differentiating fibers (DF) of PKCgamma KO lenses was 34% larger than that of WT. In the mature fiber (MF), the effect was much larger with the KO lenses having an 82% increase in coupling over WT. pH gating of the DF fibers was not altered by the absence of PKCgamma. CONCLUSION: PKCgamma has a major role in the regulation of gap junction expression and coupling in the normal lens. PMID- 21599472 TI - Alarms pose challenges to healthcare facilities. PMID- 21599471 TI - Signal to noise. PMID- 21599473 TI - Improving clinical alarms: fall summit aims to develop action plan. PMID- 21599474 TI - A roundtable discussion alarm safety: a collaborative effort. PMID- 21599475 TI - Spotlight on medical alarms in home healthcare. PMID- 21599476 TI - An FDA response on alarm systems issues. PMID- 21599477 TI - Why clinical alarms are a 'top ten' hazard: how you can help reduce the risk. PMID- 21599478 TI - Taking alarm standardization to the floors with a telemetry training system. PMID- 21599479 TI - Physiologic monitoring alarm load on medical/surgical floors of a community hospital. AB - It has been known to the public that high frequency of false and/or unnecessary alarms from patient monitoring devices causes "alarm fatigue" in critical care. But little is known about the impact to care on the less acute patients located outside the critical care areas, such as the traditional medical/surgical (med/surg) floor. METHODS: As part of a larger population management study, we initiated continuous physiological monitoring to 79 beds of floor patients in a community hospital. In order to qualify the patient monitoring alarm load for subacute medical and surgical floor patients, we assessed alarm data from April 2009 to January 2010. A standard critical care monitoring system (Philips IntelliVue MP-5 and Telemetry) was installed and set to the default alarm limits. All waveform data available for the patient (typically ECG, RESP, PPG at 125hz 8 bit), all alarm conditions declared by the monitoring system, and 1 minute parameter trend data were saved to disk every 8 hours for all patients. A monitoring care protocol was created to determine whether the patient was monitored via the hardwired bedside or wirelessly via telemetry. Alarms were not announced on the care unit but instead notifications were the responsibility of remote telehealth center personnel. We retrospectively evaluated the frequency of alarms over specific physiologic thresholds (n= 4104 patients) and conducted adjudication of all alarms based on a smaller sampling (n=30 patients). RESULTS: For all patients, the average hours of monitoring per patient were 16.5 hours with a standard deviation (s) of 8.3 hours and a median of 22 hours. The average number of alarms (all severities) per patient was 69.7 (s =90.3, median =28) alarms. When this is adjusted to the duration of monitoring, the average per patient, per day rate was 95.6 (s =124.2, median =34.2) alarms. The adjudicated sample (n=30 patients) resulted in 34% of critical alarms (lethal arrhythmias, extreme high or low heart rate [HR], extreme desaturation, apnea) being true and 63% of the high priority alarms (high or low HR, high or low RR, Low SpO(2), pause, Missed Beat, Pair PVCs, Pacer Not Pace, Non Sustain VT, Irregular HR, Multiform) being true. Analysis of alarm history resulted in the ability to reduce the HR alarm load by more than 50% with a simple limit adjustment of high HR from 120 to 130 bpm and a 36% or 65% reduction in SpO(2) alarm load by reducing the SpO(2) limit from 90% to 85% or 80% respectively. CONCLUSION: 1) Standard critical care alarm limits appear be too sensitive for subacute care areas of the hospital. 2) For most patients these alarm limits do not create a significant alarm load; however, for a small number of patients they cause a significant alarm load. 3) Alarm loads can be controlled with alarm limit settings appropriate to the population. 4) Current technology for HR and SpO(2) appear suitable for continuous monitoring of this population. PMID- 21599480 TI - Cardiopulmonary monitors and clinically significant events in critically ill children. AB - Cardiopulmonary monitors (CPMs) generate false alarm rates ranging from 85%-99% with few of these alarms actually representing serious clinical events. The overabundance of clinically insignificant alarms in hospitals desensitizes the clinician to true-positive alarms and poses significant safety issues. In this IRB-approved externally funded study, we sought to assess the clinical conditions associated with true and false-positive CPM alarms and attempted to define optimal alarm parameters that would reduce false-positive alarm rates (as they relate to clinically significant events) and thus improve overall CPM performance in critically ill children. Prior to the study, clinically significant events (CSEs) were defined and validated. Over a seven-month period in 2009, critically ill children underwent evaluation of CSEs while connected to a CPM. Comparative CPM and CSE data were analyzed with an aim to estimate sensitivity, specificity, and positive and negative predictive values for CSEs. CPM and CSE data were evaluated in 98 critically ill children. Overall, 2,245 high priority alarms were recorded with 68 CSEs noted in 45 observational days. During the course of the study, the team developed a firm understanding of CPM functionality, including the pitfalls associated with aggregation and analysis of CPM alarm data. The inability to capture all levels of CPM alarms represented a significant study challenge. Selective CPM data can be easily queried with standard reporting, however the default settings with this reporting exclude critical information necessary in compiling a coherent study denominator database. Although the association between CPM alarms and CSEs could not be comprehensively evaluated, preliminary analysis reflected poor CPM alarm specificity. This study provided the necessary considerations for the proper design of a future study that improves the positive predictive value of CPM alarms. In addition, this investigation has resulted in improved awareness of CPM alarm parameter settings and associated false-positive alarms. This information has been incorporated into nursing educational programs. PMID- 21599481 TI - An evidence-based approach to reduce nuisance alarms and alarm fatigue. PMID- 21599482 TI - Highlights of the new international standard: alarm systems and ventilators in critical care. PMID- 21599483 TI - Point-counterpoint: IEC 62D medical monitor standards will make alarms worse. PMID- 21599484 TI - Experts debate international alarm standards: changes to the alarm standard are crucial to ensure patient safety. PMID- 21599485 TI - Complementing medical device alarms with animated guidance. PMID- 21599486 TI - Beyond sound: using systems integration to advance alarm functionality. PMID- 21599487 TI - Functional basics of third-party alarm notification systems. PMID- 21599488 TI - Toward better medical alarm systems. PMID- 21599489 TI - Hydration and transparency of the rabbit cornea irradiated with UVB-doses of 0.25 J/cm(2) and 0.5 J/cm(2) compared with equivalent UVB radiation exposure reaching the human cornea from sunlight. AB - PURPOSE: Exposure of the cornea to UV radiation from sunlight evokes intraocular inflammation, photokeratitis. Photokeratitis is caused by UVB radiation. It is accompanied by changes of corneal hydration and light absorption. The aim of this study was to examine the effect of two UVB doses on corneal optics in rabbits and to compare these UVB doses with the equivalent exposure of UVB radiation reaching the human cornea from sunlight. MATERIALS AND METHODS: Rabbit corneas were irradiated with a daily UVB dose of 0.25 J/cm(2) or 0.5 J/cm(2) for 4 days. One day after finishing the irradiations the rabbits were sacrificed and corneal light absorption measured using our spectrophotometrical method. Corneal hydration was examined using an ultrasonic Pachymeter every experimental day before the irradiation procedure and the last day before sacrificing the animals. RESULTS: Changes in corneal optics appeared after the repeated exposure of the cornea to a UVB dose of 0.25 J/ cm(2) and massively increased after the repeated exposure of the cornea to a UVB dose of 0.5 J/cm(2). The first significant changes in corneal hydration appeared after a single exposure of the cornea to a UVB dose of 0.25 J/cm(2). CONCLUSIONS: Changes in corneal hydration appeared after the exposure of the rabbit cornea to a single UVB dose equivalent to 2.6 hours of solar UVB radiation reaching the human cornea, as measured by UVB sensors embedded in the eyes of mannequin heads facing the sun on a beach at noon in July. Repeated exposure of the rabbit cornea to the same UVB dose evoked profound changes in corneal optics. Although comparison of experimental and outdoor conditions are only approximate, the results in rabbits point to the danger for the human eye from UVB radiation when short stays in sunlight are repeated for several consecutive days without UV protection. PMID- 21599490 TI - The solution, solid state stability and kinetic investigation in degradation studies of lercanidipine: study of excipients compatibility of lercanidipine. AB - The objectives of this research were to evaluate the stability of lercanidipine in solution state and solid state and explore the compatibility of drug with oils, surfactants and cosurfactants as excipients. The effect of pH on the degradation in solution state was studied through pH-rate profile of lercanidipine in constant ionic strength buffer solutions in pH range 1-8 which gives the pH of maximum stability. Powdered lercanidipine was stored under 40 degrees C/0%~75% relative humidities (RH) or 0% RH/5~50 degrees C to study the influence of RH and temperature on the stability of lercanidipine in solid state. Binary mixtures of lercanidipine and different excipients were stored at 40 degrees C/75% RH, 40 degrees C and at room temperature for excipient compatibility evaluation. The degradation of lercanidipine at different pH appears to fit a typical first-order reaction, but in solid state, it does not fit any obvious reaction model. Moisture content and temperature both play important roles affecting the degradation rate. Lercanidipine exhibits good compatibility with surfactants, cosurfactants and oils as excipients under stressed conditions of different storage temperature in a 3-week screening study. Moreover, the proposed high-performance liquid chromatography method was utilized to investigate the kinetics of the acidic and alkaline degradation processes of lercanidipine at different temperatures. PMID- 21599491 TI - How do control-based approaches enter into biology? AB - Control is intrinsic to biological organisms, whose cells are in a constant state of sensing and response to numerous external and self-generated stimuli. Diverse means are used to study the complexity through control-based approaches in these cellular systems, including through chemical and genetic manipulations, input output methodologies, feedback approaches, and feed-forward approaches. We first discuss what happens in control-based approaches when we are not actively examining or manipulating cells. We then present potential methods to determine what the cell is doing during these times and to reverse-engineer the cellular system. Finally, we discuss how we can control the cell's extracellular and intracellular environments, both to probe the response of the cells using defined experimental engineering-based technologies and to anticipate what might be achieved by applying control-based approaches to affect cellular processes. Much work remains to apply simplified control models and develop new technologies to aid researchers in studying and utilizing cellular and molecular processes. PMID- 21599492 TI - Microglial contribution to secondary injury evaluated in a large animal model of human spinal cord trauma. AB - Spinal cord injury (SCI) in dogs is a well recognized animal model to study pathogenesis and treatment modalities of the debilitating human disease. To define the contributing role of microglial cell activation to the secondary wave following SCI, microglia from 15 dogs with SCI confirmed by imaging, gross, and histopathological examination were isolated and characterized in terms of morphology, immunophenotype, and function ex vivo by flow cytometry, allowing single cell analysis. The results were compared to region-specific findings obtained from healthy control dogs. Light microscopy revealed a significant enhancement of myelinophagia within the traumatized spinal cord of dogs who had had SCI for >=5 days. Immunophenotypical characterization revealed increased expression of B7-1, B7-2, MHC II, CD1c, ICAM 1, CD14, CD44, and CD45 emphasizing the enhanced function of microglia as co-stimulators of T cells, in leukocyte adhesion and aggregation, and for lipid or glycolipid presentation. In addition, phagocytosis and reactive oxygen species (ROS) generation were significantly increased in dogs with spinal cord trauma. Regional differences within the spinal cord were observed by demonstrating disparities in microglial immunophenotypes in the traumatized cervical compared to the thoracolumbar spinal cord. In contrast to histopathology, microglia activation analyzed on a single cell basis did not depend upon the time span following SCI. PMID- 21599493 TI - Dynamin: functional design of a membrane fission catalyst. AB - Dynamin, best studied for its role in clathrin-mediated endocytosis, is the prototypical member of a family of multidomain GTPases involved in fission and remodeling of multiple organelles. Recent studies have shown that dynamin alone can catalyze fission of membrane tubules and vesicle formation from planar lipid templates. Thus, dynamin appears to be a self-sufficient fission machine. Here we review the biochemical activities and structural features of dynamin required for fission activity. As all changes in membrane topology require energetically unfavorable rearrangements of the lipid bilayer, we discuss the interplay between dynamin and its lipid substrates that are critical to defining a nonleaky pathway to membrane fission. We propose a two-stage model for dynamin-catalyzed fission. In stage one, dynamin's mechanochemical activities induce localized curvature stress and position its lipid-interacting pleckstrin homology domains to create a catalytic center that, in stage two, guides lipid remodeling through hemifission intermediates to drive membrane fission. PMID- 21599494 TI - Diversity of Puccinia striiformis on cereals and grasses. AB - Yellow (stripe) rust is a common fungal disease on cereals and grasses. It is caused by Puccinia striiformis sensu lato, which is biotrophic and heteroecious. The pathogen is specialized on the primary host at both species and cultivar levels, whereas several Berberis spp. may serve as alternate hosts. One lineage infects mainly cereals and at least two lineages are restricted to grasses. P. striiformis on cereals has a typical clonal population structure in many areas, resulting from asexual reproduction, but high diversity, suggesting frequent recombination, has been observed in certain areas in Asia. Yellow rust is spreading by airborne spores potentially across long distances, which may contribute to sudden disease epidemics in new areas. This has been the case since 2000, where large-scale epidemics in warmer wheat-growing areas have been ascribed to the emergence of two closely related yellow rust strains with increased aggressiveness and tolerance to warm temperatures. PMID- 21599495 TI - Revision of the nomenclature of the differential host-pathogen interactions of Venturia inaequalis and Malus. AB - The apple scab (Venturia inaequalis-Malus) pathosystem was one of the first systems for which Flor's concept of gene-for-gene (GfG) relationships between the host plant and the pathogen was demonstrated. There is a rich resource of host resistance genes present in Malus germplasm that could potentially be marshalled to confer durable resistance against this most important apple disease. A comprehensive understanding of the host-pathogen interactions occurring in this pathosystem is a prerequisite for effectively manipulating these host resistance factors. An accurate means of identification of specific resistance and consistent use of gene nomenclature is critical for this process. A set of universally available, differentially resistant hosts is described, which will be followed by a set of defined pathogen races at a later stage. We review pertinent aspects of the history of apple scab research, describe the current status and future directions of this research, and resolve some outstanding issues. PMID- 21599496 TI - Neuroprotective activity of Matricaria recutita against fluoride-induced stress in rats. AB - CONTEXT: Oxidative stress plays a key role in pathophysiology of many neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and so on. Although Matricaria recutita L. (Asteraceae), German chamomile, is traditionally used for central nervous system (CNS)-related diseases, its antistress properties have received little attention. OBJECTIVE: The present study evaluated the neuroprotective effect of German chamomile against aluminium fluoride (AlF4-)-induced oxidative stress in rats. MATERIALS AND METHODS: The Sprague-Dawley rats of either sex (200-250 g) were selected and grouped as: group I received normal saline; group II received AlF4- (negative control); groups III, IV, and V received 100, 200, and 300 mg/kg, orally, German chamomile methanol extract (GCME) along with AlF4-; and group VI received quercetin (25 mg/kg, i.p.) + AlF4-, respectively. After 10 days treatment with GCME, oxidative stress was induced by administering AlF4- through drinking water for 7 days. Then, the protective antioxidant enzyme levels were measured and the histopathological studies were carried out. RESULTS: The GCME showed dose dependent neuroprotective activity by significant decrease in lipid peroxidation (LPO) and increase in the superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and total thiol levels in extract-treated animals as compared with negative control group (P < 0.001). The histopathological studies also revealed the potent neuroprotective action of German chamomile against oxidative brain damage. CONCLUSION: The present study for the first time shows potent neuroprotective activity of the methanol extract of German chamomile against AlF4 -induced oxidative stress in rats. PMID- 21599497 TI - Novel drugs from marine microorganisms. AB - Marine microorganisms have expected mounting consideration on the basis of bioactive metabolites and propose an exclusive prospect to both enhance the amount of aquatic natural foodstuffs in clinical trials as well as speed up their progress. This review focuses particularly on those molecules, originated from marine microorganisms, presently in the medical pipeline that have been recognized or highly expected to be identified based on growing incidental evidence. Particularly karlotoxin class compounds, isolated from dinoflagellate Karlodinium veneficum, offer chances to create new molecules for control of cancer and high serum cholesterol levels. PMID- 21599498 TI - The epidemiology, pathogenesis, and diagnosis of vulvovaginal candidosis: a mycological perspective. AB - Vulvovaginal candidosis (VVC) is the second most common cause of vaginitis after bacterial vaginosis, and it is diagnosed in up to 40% of women with vaginal complaints in the primary care setting. Reliable diagnosis of VVC requires a correlation of clinical features with mycological evidence. The mycological methods used for diagnosis include microscopic examination, fungal culture, and antigen tests. Fungal culture can reveal the species of organism(s) responsible for the infection and provide epidemiological data. This report reviews current knowledge about the available diagnostic methods and tests that accurately diagnose VVC, and highlights the importance of fungal culture. PMID- 21599499 TI - Drugs and the media: an introduction. AB - Mass media accounts of drugs and drug use are a daily occurrence and the focus of much inquiry and debate. In this special issue, nine articles consider the role and impact of a specific type of mass medium in the depiction of drugs, drug use, and drug users. Media include television programs, newspapers, films, public service advertising and product-specific marketing campaigns, and the world of the Internet, including YouTube and message boards. Media accounts of alcohol, tobacco, marijuana, and prescription drugs such as antidepressants, and more broadly, drug abuse and addictions are examined through a variety of methods from the humanities and social sciences. PMID- 21599500 TI - Everybody hurts: addiction, drama, and the family in the reality television show Intervention. AB - This article employs the literature on reality television as well as empirical studies on addiction to analyze Intervention's narrative. We look at the narrative structure of the Intervention's first six seasons (2005-2009), its repeated emphases on the causes of addiction, and the show's purported success rate. Highlighting disturbing discrepancies between the show's representations and assertions versus empirical research, Intervention's notions of what constitutes effective remedies are those treatments generally available only to the financially affluent, and the program's depictions of addiction and intervention practices reinforce a popular culture, rather than a science-based understanding, of the family and of addiction itself. PMID- 21599501 TI - Addiction to melodrama. AB - Addiction films have been shaped by the internal demands of a commercial medium. Specifically, melodrama, as a genre, has defined the limits of the visual representation of addiction. Similarly, the process of intermedialization has tended to induce a metamorphosis that shapes disparate narratives with diverse goals into a generic filmic form and substantially alters the meanings of the texts. Ultimately, visual representations shape public perceptions of addiction in meaningful ways, privileging a moralistic understanding of drug addiction that makes a complex issue visually uncomplicated by reinforcing "common sense" ideas of moral failure and redemption. PMID- 21599502 TI - Public enemy number one: the US Advertising Council's first drug abuse prevention campaign. AB - This article explores the Advertising Council's first national drug abuse prevention campaign in the 1970s. Scholarship thus far has demonstrated the ways in which the issue of drug abuse represented a chief political strategy for President Nixon. Evidence from major trade press publications, congressional hearings, and an array of archival sources suggest that this campaign was also part of a public relations crusade on behalf of the advertising industry in response to public criticism of its role in abetting a culture of drug dependence. These institutional and political pressures helped shape drug abuse prevention in the 1970 s and for the decades that followed. PMID- 21599503 TI - Banning smoking in New Jersey casinos--a content analysis of the debate in print media. AB - New Jersey's (NJ's) 2006 statewide smoking ban controversially exempted Atlantic City casinos. This study presents a content analysis of 210 NJ newspaper articles printed between November 2005 and February 2007, and describes the different frames and supporting information used to argue for or against exempting casinos from the smoking ban. Those in favor of exempting casinos framed the issue in terms of economics and compromise, while those opposing it framed the issue in terms of equity and health. Implications for policy initiatives and media advocacy are discussed. This work was supported in part by funding from the NJ Department of Health & Senior Services. PMID- 21599504 TI - Alcohol marketing in the 21st century: new methods, old problems. AB - Marketing and advertising for alcoholic beverages is abundant throughout the United States and the rest of the world. Despite the fact that alcohol advertising is related to earlier initiation of drinking, higher rates of consumption, and positive expectancies among youth populations, alcohol companies continue to design new products and related campaigns with youth-friendly attributes. Alcopops and caffeinated alcoholic beverages are two particularly dangerous types of products, and new social networking technologies make direct promotion easy and voluminous. In order to stop the harm from these alcohol products and promotion, advocacy from the research community is imperative. PMID- 21599505 TI - An investigation of smoking cessation video content on YouTube. AB - This study examines smoking cessation content posted on youtube.com. The search terms "quit smoking" and "stop smoking" yielded 2,250 videos in October 2007. We examined the top 100 as well as 20 randomly selected videos. Of these, 82 were directly relevant to smoking cessation. Fifty-one were commercial productions that included antismoking messages and advertisements for hypnosis and NicoBloc fluid. Thirty-one were personally produced videos that described personal experiences with quitting, negative health effects, and advice on how to quit. Although smoking cessation content is being shared on YouTube, very little is based on strategies that have been shown to be effective. PMID- 21599506 TI - "Most of the time you already know": pharmaceutical information assembly by young adults on the internet. AB - This study examined the utilization of the Internet by young adults as a source of information for the misuse of prescription drugs. Collected during 2008-2009, the data presented here comes from semistructured interviews (N=62) conducted in a northwestern city of the United States through support from the National Institute on Drug Abuse. Previous studies characterize young adults as particularly vulnerable to online prescription drug information that analysts portray as having a significant, invariably detrimental, impact on youth drug use behaviors. The results presented here suggest that young adults are more skeptical and information savvy than many substance abuse analysts acknowledge. In addition, knowledge and experiences generated from legitimate medical uses of pharmaceuticals influence individuals' information assessment and evaluation practices employed in the nonmedical misuse of prescription drugs. PMID- 21599507 TI - Smoking the Other: marijuana and counterhegemony in Weeds. AB - Subverting suburban modernity, the SHOWTIME television series Weeds invites its audiences to situate their opinions about marijuana amid spheres of bourgeois soccer-moms, class politics, turf wars, raw economics, violent milieux, and multiculti heterogeneity. I argue that Weeds encourages us to "smoke the Other"; that is, to hesitantly accept difference, in line with many drug circles' etiquette. The phrase "smoking the Other" is a critical alteration of bell hooks' (1992, Black looks: Race and representation. Boston: South End Press) conception of whites' ethnic "devouring" as "eating the Other," a rather rigid schematic itself problematized by Weeds' transgressive self-conscious playfulness with stereotyped ethnicities, loopy plotlines, and counterhegemonic dialogue. Cultural/political implications follow. PMID- 21599508 TI - Miracle drug, poison, or placebo: patients' experiences with antidepressant medications as described in postings on an online message board. AB - Messages posted on the MSN Health message board in response to a news story reporting that antidepressant medications are placebos were examined. Over 37 days, 1,624 messages were posted by 1,238 unique authors. The sampling unit consisted of 960 authors who were users. Users' messages were gathered in real time and content analyzed. Few users explicitly responded to the question posed in the article: 2.5% of the users stated their antidepressant was a miracle drug, 2.0% stated it was a poison, and only 0.2% stated it was a placebo. Users reported positive experiences with antidepressants more than twice as often as they reported negative experiences. PMID- 21599510 TI - Interferon-alpha induces G1 cell-cycle arrest in renal cell carcinoma cells via activation of Jak-Stat signaling. AB - The purpose of this study was to clarify the mechanism of IFN-alpha resistance in RCC. The effects of IFN-alpha on induction of apoptosis and cell-cycle arrest were analyzed by flow cytometric analysis. Jak-Stat pathway components induced by IFN-alpha was evaluated using Western blotting. The results suggested that IFN alpha caused growth inhibition of RCC cell lines via arrest in the G1 phase without inducing apoptosis. The resistance of RCC to IFN-alpha was associated with the low expression of Stat1. This study indicated that the Jak-Stat pathway should be considered a primary target for improving the response of RCC to IFN alpha treatment. PMID- 21599511 TI - Direct comparison of four adeno-associated virus serotypes in mediating the production of antiangiogenic proteins in mouse muscle. AB - To determine the adeno-associated virus (AAV) serotype that most efficiently mediates muscle expression of antiangiogenic proteins, we injected four different serotype (1, 2, 7, and 8) AAV vectors encoding mouse endostatin (mEnd) or human soluble FLK-1 (hsFLK-1) into a quadriceps muscle of C57BL/6 mice. The highest plasma levels of therapeutic protein were observed in AAV8-injected mice (8 > 7 > 1 > 2). Sustained expression of mEnd was detected for 6 months, whereas concentrations of hsFLK-1 declined to the background level within 2 weeks caused by neutralizing anti-hsFLK-1 antibody. These data demonstrate that AAV8 (mEnd) serotype is the most efficient mediator for protein expression. PMID- 21599512 TI - Analysis of somatic hypermutations of immunoglobulin gene rearrangements in childhood acute lymphoblastic leukemia. AB - The current study investigated the presence, frequency, and status of somatic hypermutations as well as their role in children with B lineage ALL. The obtained sequences were analyzed using IMGT/V-QUEST. Totally, 150 IGH sequences were evaluated; 139 from the 111 patients at the time of diagnosis and 11 from 8/111 patients at the time of relapse. The findings of the current report revealed the presence of somatically mutated V genes in childhood B lineage ALL. A higher frequency of somatic hypermutations was noted in unproductive rearrangements and was generally attributed to nucleotide mutation type, region, and IGHV gene subgroup biases. PMID- 21599513 TI - HER-2 positive and p53 negative breast cancers are associated with poor prognosis. AB - p53 and HER-2 coexpression in breast cancer has been controversial. These markers were tested using immunohistochemistry and HercepTest. HER-2 expression is related to reduced breast cancer survival (p = .02) . p53 expression relates to HER-2 expression (p = .029). Coexpression between p53 and HER-2 has no relation to prognosis. On univariate and multivariate analysis, combination of HER-2 positive and p53 negative expression was associated with a poor prognosis (p = .018 and p = .027, respectively), while the combination of HER-2 negative and p53 positive expression was associated with a favorable prognosis (p = .022 and p = .010, respectively). Therefore the expression of these markers should be considered collectively. PMID- 21599514 TI - Characterizing and predicting pathologic spine fractures in myeloma patients with FDG PET/CT and MR imaging. AB - OBJECTIVES: To determine if FDG PET/CT scans can be used to discriminate between old and new pathologic spine fractures in myeloma patients and also to determine if there is any combination of PET/CT and MR imaging findings that may indicate an impending spine fracture. MATERIALS AND METHODS: Retrospective review, after IRB approval, by two musculoskeletal radiologists and one nuclear medicine physician was done. PET/CT database was searched to identify studies performed in myeloma patients, using the search terms myeloma, plasmacytoma, or plasma cell. Records, for this group of 176 patients, were searched for concurrent spine MR imaging and report of fracture. The SUV(max) was recorded for each vertebral level from C2 through L5. All other imaging studies carried out in each patient (spine radiographs, spine CTs, and spine MRIs) and clinical records also were reviewed. Spine fractures were identified using the Genant system. MR imaging findings noted included signal intensity, pattern of involvement, as well as the size and location, within the vertebral body, of individual focal lesions. RESULTS: 31 of the 176 patients had concurrent spine MR imaging and report of fracture. Five of these 31 patients were excluded because they had no documentation of the age of fracture prior to PET/CT imaging. The 26 remaining patients (598 vertebral levels) included 17 men and 9 women. There were a total of 59 PET/CTs, 104 spine X-ray studies, 25 spine CT exams, and 71 spine MRI exams. There were a total of 134 vertebral body fractures: 27 were determined to be acute/subacute and pathologic due to active myeloma, 1 was determined to be new but owing to simple osteoporosis, and 106 were determined to be old. The mean SUV(max) in the acute/subacute pathologic fractures was 2.9 with a range from 1.1 to 4.3 (standard deviation 0.98). The old fractures had a mean SUV(max) of 1.6 with a range from 0.6 to 3.1 (standard deviation 0.55). This was a statistically significant difference with p value <.0001. The 464 vertebral bodies without fracture had a mean SUV(max) of 1.8. SUV(max) >=2.5 was seen at 49 vertebral levels, including 27 with a fracture and 22 without a fracture. SUV(max) >=3.5 was found at 9 vertebral levels, including 6 with a fracture and 3 without a fracture. The combination of diffuse or multifocal MR patterns and SUV > 3.5 was seen at 7 levels, all but one with new pathologic fractures. CONCLUSION: PET/CT SUV > 3.2 alone can be used in myeloma patients to discriminate between old and new pathologic fractures, just as it has been reported in other types of cancer patients. The combination of PET/CT SUV > 3.5 and MR findings of diffuse or multifocal vertebral body involvement seems to indicate an impending fracture. PMID- 21599515 TI - Preventing exercise-induced hypoglycemia in type 1 diabetes using real-time continuous glucose monitoring and a new carbohydrate intake algorithm: an observational field study. AB - BACKGROUND: Real-time (RT) continuous glucose monitoring (CGM) offers the possibility to better manage glucose levels during exercise in active individuals with type 1 diabetes mellitus (T1DM). However, studies have yet to determine the appropriate actions to take when glucose levels are trending toward hypoglycemia. The purpose of this observational field study was to test the effectiveness of RT GCM and a new carbohydrate intake algorithm designed for maintaining euglycemia during sports. METHODS: During a 2-week sports camp, 25 adolescents (8-17 years old) with T1DM were fitted with a RT-CGM device and instructed to ingest fast acting carbohydrates (8-20 g, depending on the concentration of glucose at the time of RT-CGM alert and rates of change in glycemia) when glucose levels were trending toward hypoglycemia. Rates of change in glucose were measured before and after algorithm use, and the incidence of hypoglycemia was documented. RESULTS: With RT-CGM and algorithm use, euglycemia was largely maintained with modest amounts of carbohydrate intake, even when glucose levels were initially dropping at an elevated rate (>0.55 mmol/L per 5 min). Mild biochemical hypoglycemia (3.0 3.9 mmol/L) occurred just twice out of 22 uses of the algorithm (9%) when trend arrows alerted the subjects that glucose levels were dropping. When glucose levels were already below target (<5.0 mmol/L), mild hypoglycemia occurred five times out of 13 events (38%), despite 16 g of carbohydrate being ingested. Average glucose levels during sports in the 60 min following algorithm use were 5.8 +/- 1.2 mmol/L, 5.3 +/- 1.0 mmol/L, and 6.2 +/- 0.8 mmol/L in the 20-, 16-, and 8-g carbohydrate intake protocols when glucose levels were initially on target but dropping toward hypoglycemia. CONCLUSION: When coupled with RT-CGM, a new carbohydrate intake algorithm prevents hypoglycemia and maintains euglycemia during exercise, particularly if patients ingest carbohydrate when trend arrows alert them of a drop in glycemia. PMID- 21599516 TI - Painless skin electroporation as a novel way for insulin delivery. AB - BACKGROUND: Rigorous research efforts have been undertaken worldwide to develop a needle-free insulin delivery for many decades with limited success. This translational study aims to deliver insulin through skin with painless electroporation. METHODS: A recently designed microelectrode array was used to deliver insulin in mice with diabetes under electroporation conditions that are painless and harmless on human skin. RESULTS: Under such condition, a therapeutic amount of insulin was delivered successfully through mouse skin. Electroporation alone increased insulin transport around 100-fold compared with passive diffusion. Increased skin temperature to 40 degrees C for 20 min augmented insulin transport to 237-fold more than the control value. Repeated electroporation showed no harm on human skin. CONCLUSION: The results indicate the potential of painless delivery of insulin through human skin in future clinical practice. PMID- 21599517 TI - DNA methylation in peripheral blood cells of pigs cloned by somatic cell nuclear transfer. AB - To date, the genome-wide DNA methylation status of cloned pigs has not been investigated. Due to the relatively low success rate of pig cloning by somatic cell nuclear transfer, a better understanding of the epigenetic reprogramming and the global methylation patterns associated with development in cloned pigs is required. In this study we applied methylation-specific digital karyotyping tag sequencing by Solexa technology and investigated the genome-wide DNA methylation profiles of peripheral blood cells in cloned pigs with normal phenotypes in comparison with their naturally bred controls. In the result, we found that globally there was no significant difference of DNA methylation patterns between the two groups. Locus-specifically, some genes involved in embryonic development presented a generally increased level of methylation. Our findings suggest that in cloned pigs with normal phenotypes, the DNA methylation pattern is quite normal, and that DNA methylation changes in some genomic regions are compatible with normal development. PMID- 21599518 TI - Toward transgene-free induced pluripotent stem cells: lessons from transdifferentiation studies. AB - Abstract Regenerative medicine has received much attention over the years due to its clinical and commercial potential. The excitement around regenerative medicine waxes and wanes as new discoveries add to its foundation but are not immediately clinically applicable. The recent discovery of induced pluripotent stem cells has lead to a sustained effort from many research groups to develop clinically relevant regenerative medicine therapies. A major focus of cellular reprogramming is to generate safe cellular products through the use of proteins or small molecules instead of transgenes. The successful reprogramming of somatic nuclei to generate pluripotential cells capable of embryo development was pioneered over 50 years ago by Briggs and King and followed by Gurdon in the early 1960s. The success of these studies, the cloning of Dolly, and more current studies involving adult stem cells and transdifferentiation provide us with a large repository of potential candidate molecules and experimental systems that will assist in the generation of safe, transgene-free pluripotential cells. PMID- 21599519 TI - Computational analysis of simulated SNP interactions between 26 growth factor related genes in a breast cancer association study. AB - Many association studies analyze the genotype frequencies of case and control data to predict susceptibility to diseases and cancers. Without providing the raw data for genotypes, many association studies cannot be interpreted fully. Often, the interactions of the single nucleotide polymorphisms (SNPs) are not addressed and this limits the potential of such studies. To solve these problems, we propose a novel computational method with source codes to generate a stimulated genotype dataset based on published SNP genotype frequencies. In this study we evaluate the combined effect of 26 SNP combinations related to eight published growth factor-related genes involved in carcinogenesis pathways of breast cancer. The genetic algorithm (GA) was chosen to provide simultaneous analysis of multiple independent SNPs. The GA can perform feature selection from different SNP combinations via their corresponding genotype (called the SNP barcode), and the approach is able to provide a specific SNP barcode with an optimized fitness value effectively. The best SNP barcode with the maximal occurrence difference between groups for the control and breast cancer, together with an odds ratio analysis, is used to evaluate breast cancer susceptibility. When they are compared to their corresponding non-SNP barcodes, the estimated odds ratios for breast cancer are less than 1 (about 0.85 and 0.87; confidence interval: 0.7473~0.9585, p < 0.01) for specific SNP barcodes with two to five SNPs. Therefore, we were able to identify potential combined growth factor-related genes together with their SNP barcodes that were protective against breast cancer by in silico analysis. PMID- 21599520 TI - Diagnostic ability of obesity measures to identify metabolic risk factors in South African women. AB - BACKGROUND: Currently, guidelines for obesity thresholds relating to metabolic risk in South African women have not been established. Therefore, the aim of the study was to investigate the level and diagnostic ability of obesity measures [waist circumference (WC), waist-to-height ratio (WHtR), and visceral adipose tissue (VAT) area] to identify black and white South African women with elevated blood pressure, dyslipidemia, and insulin resistance. METHODS: Blood pressure, fasting insulin, glucose, and lipids were measured in 241 black and 188 white South African women. Receiver operator characteristic (ROC) curve analyses were performed to determine the diagnostic ability of WC, WHtR, and computer tomography (CT)-derived VAT to identify subjects above metabolic risk thresholds. The Youden index was used to calculate obesity thresholds for metabolic risk variables. RESULTS: WC, WHtR, and VAT were significant determinants of all metabolic risk variables (P<0.05), and differences in the ROC area under the curve (AUC) between obesity measures were small (~0.08) for all metabolic risk variables, in both ethnic groups. However, the ROC AUC vales for all obesity measures were greater in white compared to black women (P<0.01). WC and VAT thresholds were lower in black women compared to white women, whereas WHtR thresholds varied less between ethnicities. CONCLUSIONS: Due to the cost, access, and radiation exposure, CT-derived VAT is not recommended above the use of simple anthropometric measures (WC and WHtR) for the determination of metabolic risk. Furthermore, thresholds of WHtR, due to low variability between ethnicities, may be more useful than WC for ethnic comparisons of risk. PMID- 21599527 TI - Comparison of supracostal versus infracostal percutaneous nephrolithotomy using the novel prone-flexed patient position. AB - BACKGROUND AND PURPOSE: Percutaneous nephrolithotomy (PCNL) is considered standard therapy for large and complex renal calculi. The optimal patient position and puncture site for collecting system access remains controversial. This purpose of this retrospective review is to analyze our PCNL series with respect to puncture tracts, success, and complications using our novel prone flexed position. PATIENTS AND METHODS: Perioperative data were collected on consecutive PCNL cases for renal calculi performed in the prone-flexed position from 2004 to 2009. Patient demographic, stone, operative, postoperative, and follow-up data were collected. Successful treatment was defined as stone free or sandlike (<=1 mm) particles visible on CT scan at 3 months. RESULTS: A total of 318 patients, with a mean age of 52.9 years and body mass index of 27.8 kg/m(2), underwent PCNL in the prone-flexed position (57.9% male). Sixteen tracts were above the 11th rib, 138 were above the 12th rib, and 164 were infracostal. Multiple tracts were used in 16 patients. There were no significant differences between patients undergoing supracostal vs infracostal puncture with respect to side, stone area, number of tracts, number of stones, or the presence of staghorn or struvite calculi. Success in the supracostal group (89.8%) was not statistically different from the infracostal group (94.1%), P>0.05. Overall complication rates across groups was low (11.6%), with a significant difference in complications between the supracostal and infracostal puncture groups across Clavien grades, P<0.01. No patients needed blood transfusions or angioembolization. CONCLUSION: Regardless of supracostal or infracostal renal access, our novel prone-flexed position assists with percutaneous renal access and ease of nephrolithotomy, while maintaining excellent success rates and minimizing procedural morbidity. PMID- 21599528 TI - Clinically insignificant residual fragments after percutaneous nephrolithotomy: medium-term follow-up. AB - BACKGROUND AND PURPOSE: Clinically insignificant residual fragments (CIRFs), defined as asymptomatic, noninfectious, <=4 mm fragments, are sometimes observed after percutaneous nephrolithotomy (PCNL). Because the natural history of these fragments is unclear, we investigated the medium-term outcome of these fragments. PATIENTS AND METHODS: During a 3-year period, 430 patients underwent PCNL. Overall stone-free rate was 74.5%, and CIRFs were encountered in 22% of cases 3 months after surgery. A total of 38 patients who had CIRFs immediately after PCNL with at least 24 months of follow-up were included in the study. All patients were subjected to periodic follow-up with detailed history, clinical examination, and radiographic follow-up. Serum biochemistry together with urine metabolic evaluation was also performed. RESULTS: The median follow-up was 28.4+/-5.3 months (range 24-38 mos). Ten (26.3%) patients had a symptomatic episode that necessitated medical therapy during follow-up while others remained asymptomatic. Radiologic assessment showed an increase in the size of the fragments in 8 (21.1%) patients, while the size of the fragments was stable or decreased in 27 (71.1%) cases. Three (7.9%) patients had spontaneous stone passage. Metabolic evaluation revealed abnormalities in 10 (26.3%) patients. Stone analysis revealed magnesium ammonium phosphate in three of eight patients who had an increase in residual fragment size. Also, only two of these eight patients had a metabolic abnormality (one hypocitraturia and one hypercalciuria). CONCLUSION: Medium-term follow-up of CIRFs after PCNL revealed that progression within 2 years is relatively common. Increase in fragment size is common in patients with struvite stones, and presence of risk factors on 24-hour urine metabolic analysis does not seem to predict growth of observed fragments. PMID- 21599529 TI - Dermatological diagnostic acumen improves with use of a simple telemedicine system for underserved areas of South Africa. AB - OBJECTIVE: Telemedicine holds promise as a tool for improving the delivery of specialty care, especially in underserved regions, including those in South Africa. However, data that demonstrate the extent of its sustainable benefits to referring providers are currently insufficient. This study investigates whether utilization of a teledermatology network enhances the diagnostic acumen of primary care providers (PCPs) in underserved areas of South Africa. MATERIALS AND METHODS: A longitudinal descriptive pilot study was conducted after establishing a telemedicine network linking University of Cape Town dermatology consultants to six providers from five underserved primary care sites using store-and-forward technology between October 2004 and January 2007. Of 120 total referrals, trend analysis was performed using 72 sets of patient histories, digital images, and corresponding consultant responses to evaluate the diagnostic concordance between six PCPs and teleconsultants over 12 consecutive referrals. RESULTS: Strong positive Spearman rank-order correlations were observed between the number of referrals sent per PCP and proportion of primary diagnostic agreement with teledermatologists, rs=0.86 (p <0.001). The mean primary diagnostic concordance trend that started at 13% for the first four referrals increased nearly fourfold after referring as few as nine patients to the network. CONCLUSIONS: If a simple and inexpensive teledermatology solution is carefully implemented in a resource limited setting, an improvement of PCP diagnostic acumen can be achieved with a relatively small number of referrals. This educational benefit to referring PCPs could be sustainable and would ultimately enhance the quality of dermatological care in these underserved regions. PMID- 21599530 TI - Humidified high-flow nasal oxygen utilization in patients with cancer at Memorial Sloan-Kettering Cancer Center. AB - BACKGROUND: Respiratory signs and symptoms are commonly encountered by physicians who care for cancer patients. Supplemental oxygen (SOx) has long been used for treatment of hypoxic respiratory insufficiency, but data reveal mixed efficacy results. The use and outcome patterns of technologically advanced oxygen delivery devices, such as humidified high-flow nasal oxygen (HHFNOx), are incompletely understood. METHODS: Institutional database search of the number of patient cases in which the current HHFNOx device was used, and abstraction of 183 patient medical records for usage characteristics. RESULTS: Patients have been treated with HHFNOx at Memorial Sloan Kettering Cancer Center (MSKCC) since 2008. Of the 183 patients randomly selected for our study, 72% received HHFNOx in the intensive care unit (ICU) because of hypoxia. Patients usually improved (41%) or remained stable (44%) while on the device, whereas 15% declined. At study completion, 45% of patients were living, and 55% had died. The median time on HHFNOx was 3 days (range: 1-27). A do not resuscitate (DNR) order was present in 101 (55%) patients, either before (12%) or after (43%) device utilization. The majority (78%) of these 101 patients died at MSKCC. CONCLUSION: Dyspnea is a common and important symptom in cancer patients for which SOx traditionally has had no clear basis except in select cases of hypoxia and patient preference. Our institutional experience with HHFNOx contributes to the understanding of the applications and challenges surrounding the use of new medical devices in the cancer population. Physiologic and quality-of-life benefits of HHFNOx compared with traditional oxygen delivery methods should be studied prospectively. PMID- 21599531 TI - Palliative care online: a pilot study on a pancreatic cancer website. AB - CONTEXT: Patients with pancreatic cancer and their families are candidates for palliative care given the physical, emotional, and existential aspects of this serious illness. However, they may not have access to it while pursuing aggressive treatment, or due to physical location or lack of awareness of these services. The Internet may offer a way to overcome these barriers as it is quickly becoming an important health resource and link between patients, families, and health care providers. OBJECTIVES: To determine 1) the number and geographic location of those visiting an interactive webpage where patients and families could access a palliative care nurse practitioner (PCNP); 2) the number and type of questions posted to the PCNP and whether those posting were patients or family members/other; and 3) to evaluate their experience with the PCNP webpage. DESIGN: Descriptive study. RESULTS: The PCNP webpage was added to the Johns Hopkins Pancreatic Cancer Center's website and was visited 707 times by 395 unique computer addresses/visitors over the eight-week study period. Forty-eight participants posted 55 questions or sent individual emails to the PCNP. Most questions (85%) had to do with physical issues related to pancreatic cancer and its treatment. Twenty participants completed an online survey. Most survey respondents found the PCNP website helpful, and easy to use, and recommended that the PCNP page be an on-going resource. CONCLUSION: This experience provides preliminary evidence that the Internet can be used to offer palliative care specific information and support to patients and families dealing with pancreatic cancer. PMID- 21599532 TI - Family caregivers and palliative care: current status and agenda for the future. AB - The quality of life of the person confronting the end stages of their life may be severely compromised without the support of family caregivers. Indeed, most people requiring palliative care would not be able to fulfill their preferences, such as care at home, without significant family caregiver input. As a consequence, health services are mandated to support the family alongside the person diagnosed with a life-threatening illness. In short, palliative care is supposed to be family centred. However, the quality and type of support made available to family caregivers has been questioned. The purpose of this review is to outline a succinct and empirically informed account of family caregiving within the context of palliative care and to propose an agenda for the future. The appraisal is underpinned by several systematic reviews, and other seminal publications from the last decade. PMID- 21599533 TI - Pharmacokinetics and tolerability of BAY41-6551 in subjects with chronic kidney disease. AB - Abstract Background: BAY41-6551, a drug-device combination in development for adjunctive treatment of Gram-negative pneumonia in mechanically ventilated patients, consists of amikacin formulated for inhalation coupled with the Pulmonary Drug Delivery System (PDDS) Clinical aerosol delivery platform. This study evaluated safety, tolerability, and pharmacokinetics (PK) of BAY41-6551 in subjects with chronic kidney disease (CKD). METHODS: Single doses of BAY41-6551 (400 mg amikacin) were administered using the PDDS Clinical handheld device to six subjects with mild-to-moderate (Group 1) and six subjects with severe renal impairment (Group 2). Seven subjects with end-stage renal disease (ESRD; Group 3) received single doses of BAY41-6551 on days 1 and 9, with hemodialysis (HD) scheduled 24 h postdose on day 1 and 3 h postdose on day 9. PK analysis was performed on serum, urine, and dialysate samples (Group 3). RESULTS: Individual serum amikacin concentrations in Groups 1 and 2 were below 6 mg/L at all times [mean maximum serum drug concentration (C(max)) 0.94 mg/L and 2.46 mg/L, respectively). In Group 3, serum amikacin concentrations decreased after each HD session, and amikacin area under the serum concentration-time curve from zero to 72 h (AUC(72)) and C(max) values were lower on day 9 than on day 1 (mean AUC(72) 71.5 mg . h/L vs. 151.5 mg . h/L; mean C(max) 2.09 mg/L vs. 6.16 mg/L). The amounts of amikacin removed by HD and the dialysate clearance rates were similar on days 1 and 9. No serious adverse events were reported. CONCLUSIONS: Single doses of BAY41-6551 were well tolerated in subjects with CKD. HD effectively removed amikacin from serum in subjects with ESRD, and the timing relative to BAY41-6551 administration was an important determinant of systemic amikacin exposure. Nevertheless, standard precautionary measures for intravenous amikacin should apply for patients receiving BAY41-6551, and dose adjustments and/or dialysis should be considered for subjects with severe renal impairment. PMID- 21599535 TI - Insulin signaling to hepatic lipid metabolism in health and disease. AB - The increasing prevalence of overnutrition and reduced activity has led to a worldwide epidemic of obesity. In many cases, this is associated with insulin resistance, an inability of the hormone to direct its physiological actions appropriately. A number of disease states accompany insulin resistance such as type 2 diabetes mellitus, the metabolic syndrome, and non-alcoholic fatty liver disease. Though the pathways by which insulin controls hepatic glucose output have been of intense study in recent years, considerably less attention has been devoted to how lipid metabolism is regulated. Thus, both the proximal signaling pathways as well as the more distal targets of insulin remain uncertain. In this review, we consider the signaling pathways by which insulin controls the synthesis and accumulation of lipids in the mammalian liver and, in particular, how this might lead to abnormal triglyceride deposition in liver during insulin resistant states. PMID- 21599537 TI - Hemoglobin conjugates with antioxidant enzymes (hemoglobin-superoxide dismutase catalase) via poly(ethylene glycol) crosslinker for protection of pancreatic beta RINm5F cells in hypoxia. AB - A low p50 hemoglobin (Hb) (p50 indicates O(2) tension at which Hb is half saturated)-based oxygen carrier conjugated to antioxidant enzymes via dicarboxymethylated poly(ethylene glycol) (PEG) linker may have the beneficial effect in protecting pancreatic beta cells from severe hypoxia at transplantation sites. In this study, the oxygen dissociation curves, Hill plots, Bohr Effect, and oxygen content of Hb conjugates were measured. The protective effect due to incubation of Hb-conjugates (Hb/PEG molar ratio 1:10) with pancreatic beta cells (RINm5F) against hypoxia (6%, 3%, and 1% oxygen) was evaluated by an MTT assay and confocal microscopy. Quantitatively, Hb conjugates with antioxidant enzymes offered statistically significant protection (p<0.01, increased viability ~80%) from hypoxia compared to control cells in 1% oxygen environment. Confocal images also showed that the low p50 Hb conjugates with antioxidants protected RINm5F cells from hypoxia. PMID- 21599538 TI - Effect of nucleus pulposus cells having different phenotypes on chondrogenic differentiation of adipose-derived stromal cells in a coculture system using porous membranes. AB - In this study, adipose-derived stem cells (ASCs) were cocultured with nucleus pulposus (NP) cells using a porous membrane to investigate the effect of NP cell phenotype on ASC chondrogenic differentiation. Human NP cells were collected from 14 patients and classified into two groups (normal vs. degenerative) depending on the level of type II collagen, aggrecan (AGG), type I collagen, and bax gene expression. Human ASCs were then cocultured with each group of NP cells on porous membranes in the absence of chondrogenic supplements. After 2 weeks, real-time polymerase chain reaction results showed that ASCs cocultured with normal NP cells had much higher type II collagen and AGG gene expression than ASCs cocultured with degenerative NP cells. The production of AGG was also observed only in the group cocultured with normal NP cells. Additionally, coculture of ASC pellets with normal NP cells promoted the production of AGG as compared to coculture of ASC monolayer with normal NP cells. These data demonstrate that a coculture system using porous membranes can induce ASC differentiation into NP cells without chondrogenic supplements. Further, the phenotype of cocultured NP cells significantly influences the extent of ASC differentiation. PMID- 21599539 TI - Stem cells, nitrogen-rich plasma-polymerized culture surfaces, and type X collagen suppression. AB - Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into chondrocytes, osteoblasts, myocytes, adipocytes, and a variety of other cell types. Several studies have been directed toward using MSCs from patients with osteoarthritis (OA) for cartilage repair, not only because these are the ones that will require a source of autologous stem cells if biological repair of cartilage lesions is to be a therapeutic option, but also to further an understanding of stem cell differentiation. Previous studies have shown that a major drawback of current cartilage and intervertebral disc tissue repair is that human MSCs from OA patients express type X collagen (COL X). COL X, a marker of late-stage chondrocyte hypertrophy, is implicated in endochondral ossification. However, those studies also revealed that a novel plasma-polymerized thin film material, named nitrogen-rich plasma-polymerized ethylene (PPE:N), was able to inhibit COL X expression in committed MSCs. The specific aim of this present study was to determine if the suppression of COL X by PPE:N is maintained when MSCs are transferred to pellet cultures in serum-free media. Our results confirmed the potential of two different types of PPE:N surfaces (low-pressure PPE:N [L-PPE:N] and high-pressure-PPE:N [H-PPE:N]) in suppressing COL X expression, more so on the latter. Interestingly, when MSCs were transferred to pellet cultures, the expression level of COL X was further decreased by preincubation on H-PPE:N, suggesting that these kinds of coatings show promise for tissue engineering of cartilage and disc tissues. Further studies are needed to assess the relative importance of surface-chemistry versus surface-morphology in the mechanism of COL X suppression. PMID- 21599534 TI - Metabolism as a key to histone deacetylase inhibition. AB - There is growing interest in the epigenetic mechanisms that are dysregulated in cancer and other human pathologies. Under this broad umbrella, modulators of histone deacetylase (HDAC) activity have gained interest as both cancer chemopreventive and therapeutic agents. Of the first generation, FDA-approved HDAC inhibitors to have progressed to clinical trials, vorinostat represents a "direct acting" compound with structural features suitable for docking into the HDAC pocket, whereas romidepsin can be considered a prodrug that undergoes reductive metabolism to generate the active intermediate (a zinc-binding thiol). It is now evident that other agents, including those in the human diet, can be converted by metabolism to intermediates that affect HDAC activity. Examples are cited of short-chain fatty acids, seleno-alpha-keto acids, small molecule thiols, mercapturic acid metabolites, indoles, and polyphenols. The findings are discussed in the context of putative endogenous HDAC inhibitors generated by intermediary metabolism (e.g. pyruvate), the yin-yang of HDAC inhibition versus HDAC activation, and the screening assays that might be most appropriate for discovery of novel HDAC inhibitors in the future. PMID- 21599540 TI - Scaffold porosity and oxygenation of printed hydrogel constructs affect functionality of embedded osteogenic progenitors. AB - Insufficient supply of oxygen and nutrients throughout the graft is considered one of the principal limitations in development of large, tissue-engineered bone grafts. Organ or tissue printing by means of three-dimensional (3D) fiber deposition is a novel modality in regenerative medicine that combines pore formation and defined cell placement, and is used here for development of cell laden hydrogel structures with reproducible internal architecture to sustain oxygen supply and to support adequate tissue development. In this study we tested the effect of porosity on multipotent stromal cells (MSCs) embedded in hydrogel constructs printed with a 3D fiber deposition (3DF) machine. For this, porous and solid alginate hydrogel scaffolds, with MSCs homogeneously dispersed throughout the construct, were printed and analyzed in vitro for the presence of hypoxia markers, metabolism, survival, and osteogenic differentiation. We demonstrated that porosity promotes oxygenation of MSCs in printed hydrogel scaffolds and supported the viability and osteogenic differentiation of embedded cells. Porous and solid printed constructs were subsequently implanted subcutaneously in immunodeficient mice to analyze tissue formation in relation to hypoxia responses of embedded cells. Implantation of printed grafts resulted in ingrowth of vascularized tissue and significantly enhanced oxygenation of embedded MSCs. In conclusion, the introduction of pores significantly enhances the conductive properties of printed hydrogel constructs and contributes to the functionality of embedded osteogenic progenitors. PMID- 21599541 TI - Matrix metalloproteinase-9 is a diagnostic marker of heterotopic ossification in a murine model. AB - Heterotopic ossification (HO) is a serious disorder that occurs when there is aberrant bone morphogenic protein (BMP) signaling in soft tissues. Currently, there are no methods to detect HO before mineralization occurs. Yet once mineralization occurs, there are no effective treatments, short of surgery, to reverse HO. Herein, we used in vivo molecular imaging and confirmatory ex vivo tissue analyses of an established murine animal model of BMP-induced HO to show that matrix metalloproteinase-9 (MMP-9) can be detected as an early-stage biomarker before mineralization. Ex vivo analyses show that active MMP-9 protein is significantly elevated within tissues undergoing HO as early as 48 h after BMP induction, with its expression co-localizing to nerves and vessels. In vivo molecular imaging with a dual-labeled near-infrared fluorescence and micro positron emission tomography (MUPET) agent specific to MMP-2/-9 expression paralleled the ex vivo observations and reflected the site of HO formation as detected from microcomputed tomography 7 days later. The results suggest that the MMP-9 is a biomarker of the early extracellular matrix (ECM) re-organization and could be used as an in vivo diagnostic with confirmatory ex vivo tissue analysis for detecting HO or conversely for monitoring the success of tissue-engineered bone implants that employ ECM biology for engraftment. PMID- 21599542 TI - Microbial proteases: detection, production, and genetic improvement. AB - Microbial proteases are one of the important groups of industrially and commercially produced enzymes contributing approximately 2/3 of all enzyme sales. Though proteases are produced by many microorganisms, emphasis is on the microorganisms producing proteases with desired characters. As demand for novel proteases is increasing day by day the initial screening methods and assays for protease detection are of utmost importance. This review focuses attention on present status of knowledge on the various methods and protocols available for protease screening, detection, and quantification starting from plate assays to spectrophotometric, fluorometric, and nanoparticles based assays. The review will help in making strategies for exploitation of protease resources and improvement of enzymes to obtain more robust proteases. PMID- 21599536 TI - Presynaptic filament dynamics in homologous recombination and DNA repair. AB - Homologous recombination (HR) is an essential genome stability mechanism used for high-fidelity repair of DNA double-strand breaks and for the recovery of stalled or collapsed DNA replication forks. The crucial homology search and DNA strand exchange steps of HR are catalyzed by presynaptic filaments-helical filaments of a recombinase enzyme bound to single-stranded DNA (ssDNA). Presynaptic filaments are fundamentally dynamic structures, the assembly, catalytic turnover, and disassembly of which must be closely coordinated with other elements of the DNA recombination, repair, and replication machinery in order for genome maintenance functions to be effective. Here, we reviewed the major dynamic elements controlling the assembly, activity, and disassembly of presynaptic filaments; some intrinsic such as recombinase ATP-binding and hydrolytic activities, others extrinsic such as ssDNA-binding proteins, mediator proteins, and DNA motor proteins. We examined dynamic behavior on multiple levels, including atomic- and filament-level structural changes associated with ATP binding and hydrolysis as evidenced in crystal structures, as well as subunit binding and dissociation events driven by intrinsic and extrinsic factors. We examined the biochemical properties of recombination proteins from four model systems (T4 phage, Escherichia coli, Saccharomyces cerevisiae, and Homo sapiens), demonstrating how their properties are tailored for the context-specific requirements in these diverse species. We proposed that the presynaptic filament has evolved to rely on multiple external factors for increased multilevel regulation of HR processes in genomes with greater structural and sequence complexity. PMID- 21599543 TI - Shear stress responses of adult blood outgrowth endothelial cells seeded on bioartificial tissue. AB - Human blood outgrowth endothelial cells (HBOECs) are expanded from circulating endothelial progenitor cells in peripheral blood and thus could provide a source of autologous endothelial cells for tissue-engineered vascular grafts. To examine the suitability of adult HBOECs for use in vascular tissue engineering, the shear stress responsiveness of these cells was examined on bioartificial tissue formed from dermal fibroblasts entrapped in tubular fibrin gels. HBOECs adhered to this surface, deposited collagen IV and laminin, and remained adherent when exposed to 15 dyn/cm(2) shear stress for 24 h. The shear stress responses of HBOECs were compared to human umbilical vein endothelial cells (HUVECs). As with HUVECs, HBOECs upregulated vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 when exposed to tumor necrosis factor (TNF)-alpha and shear stress decreased the expression of these adhesion molecules on TNF-alpha-activated monolayers. Nitric oxide production was elevated by shear stress, but did not vary between cell types. Both cell types decreased platelet adhesion to the bioartificial tissue, whereas pre-exposing the cells to flow decreased platelet adhesion further. These results illustrate the potential utility for HBOECs in vascular tissue engineering, as not only do the cells adhere to bioartificial tissue and remain adherent under physiological shear stress, they are also responsive to shear stress signaling. PMID- 21599544 TI - Amphiphilic polyanhydride films promote neural stem cell adhesion and differentiation. AB - Several challenges currently exist for rational design of functional tissue engineering constructs within the host, which include appropriate cellular integration, avoidance of bacterial infections, and low inflammatory stimulation. This work describes a novel class of biodegradable, amphiphilic polyanhydrides with many desirable protein-material and cell-material attributes capable of confronting these challenges. The biocompatible amphiphilic polymer films were shown to release laminin in a stable and controlled manner, promote neural cell adhesion and differentiation, and evade inflammatory responses of the immune system. Using high-throughput approaches, it was shown that polymer chemistry plays an integral role in controlling cell-film interactions, which suggests that these polyanhydrides can be tailored to achieve the desired cell adhesion and differentiation while minimizing immune recognition. These findings have important implications for development of engineered constructs to regulate differentiation and target the growth of transplanted cells in stem cell-based therapies to treat nervous system disorders. PMID- 21599545 TI - Measures of individual recovery. PMID- 21599546 TI - The relationship among proton pump inhibitors, bone disease and fracture. AB - INTRODUCTION: There is growing concern about a possible association between the use of proton pump inhibitors (PPIs) and the development of fragility fractures, most notably hip and vertebral fractures. As PPIs are widely used in clinical practice, this association is of paramount clinical importance. AREAS COVERED: The authors review the published papers analyzing the relationship between PPI use and the occurrence of fragility fractures. The authors also explore the data supporting possible mechanisms through which PPIs may increase the risk of fracture, including the effects of PPIs on calcium homeostasis, bone mineral density and direct effects of PPIs on bone metabolism. EXPERT OPINION: Overall, though multiple observational studies have demonstrated an association between PPIs and fragility fractures, the lack of a proven mechanism through which PPIs increase the risk of fracture suggests that this association may not be causal. At this time, the authors do not recommend discontinuing PPIs in patients with a history of fracture or those at increased risk of fracture. However, clinicians should still endeavor to avoid using PPIs in situations where benefits are minimal or clinical indications are lacking. PMID- 21599547 TI - Intracranial haemorrhage associated with cerebral infections: a review. AB - We present a review of the different viral, bacterial, parasitic and fungal infections that are associated with intracranial haemorrhages. We summarize the clinical presentation of the infection and its cerebral complication. We elucidate the pathology and pathophysiology of the haemorrhage as being spontaneous or secondary to vasculitis, thrombosis, embolization or aneurysmal formation. PMID- 21599549 TI - Development of a mandarin monosyllable test material with homogenous items (II): lists equivalence evaluation. AB - CONCLUSIONS: A set of Chinese Mandarin monosyllable test lists with good reliability and sensitivity was established. OBJECTIVES: The primary purpose of this study was to evaluate the equivalence of a group of monosyllable lists. METHODS: A genetic algorithm was adopted to reorganize the material based on the Phoneme Allocation Table; 10 lists with 25 monosyllabic test items in each were generated. A two-factor design was used for the equivalence evaluation test. A total of 80 normal-hearing and native Mandarin-speaking university students (40 males and 40 females) participated in the trial. Every subject was tested with all 10 lists in sequence at 5 presentation levels (-5, 0, 5, 10, and 15 dB HL). Performance-intensity (P-I) function of each list was fit before P-I curve slope and recognition threshold were calculated. RESULTS: Equivalence evaluation results indicated good psychophysical equivalence between the 10 lists except for list 2. List 9 has a reused item. After the elimination of lists 2 and 9, multivariate ANOVA revealed a good equivalence between the remaining eight lists (p = 0.136). The mean threshold of eight equivalent lists was 10.32 +/- 0.38 dB HL, while the mean slope was 5.00 +/- 0.29%/dB. PMID- 21599548 TI - CD4(+) CD28(+) lymphocytes on day 5 after high-dose melphalan for multiple myeloma predict a low risk of infections during severe neutropenia and are associated with the number of reinfused T lymphocytes of the autologous stem cell graft. AB - BACKGROUND AIMS: Neutropenia following high-dose chemotherapy is associated with a substantial risk of infectious complications. The aim of this study was to identify variables in residual leukocyte subsets during neutropenia that are predictive for neutropenic fever. METHODS: Residual leukocytes in the peripheral blood on day 5 after autologous blood stem cell transplantation were analyzed by three-color flow cytometry in 55 consecutive patients with multiple myeloma. Furthermore, the number of T cells transfused with the autografts was determined. RESULTS: Neutrophil counts at day 5 and neutrophil engraftment were similar in patients with and without neutropenic fever. Low absolute lymphocyte, CD4(+) CD28(+) and CD45RO(+) CD28(+) counts at day 5 were associated with neutropenic fever. T-cell counts at day 5 correlated with the CD3(+) cell number in the graft. CONCLUSIONS: Our data show that the absolute lymphocyte, CD4(+) CD28(+) and CD45RO(+) CD28(+) counts play a role in host defense during severe neutropenia. The T-cell number in the graft may help to identify patients at high risk of neutropenic infections. PMID- 21599550 TI - Antifungal susceptibility of ocular fungal pathogens recovered from around the world against itraconazole, voriconazole, amphotericin B, and caspofungin. AB - Although fungal infections of the eye are rare, they create an intractable clinical problem in ophthalmology because of the limited number of intravitreal and systemic therapeutic options. In this investigation, the in vitro efficacies of itraconazole (ITR), voriconazole (VOR), amphotericin B (AMB), and caspofungin (CAS) against 29 globally-collected ocular fungal isolates were assessed, following the standards that are outlined in the Clinical and Laboratory Standards Institute (CLSI) M38-A2 document. AMB [Geometric Mean (GM) MIC (Minimum Inhibitory Concentration): 0.49 MUg/ml] was the most active drug, followed by VOR, CAS, and ITR (GM MICs: 0.52, 1.07, and 2.86 MUg/ml, respectively). For the Exophiala strains (n = 8), VOR was the most active drug, followed by AMB, ITR, and CAS (GM MICS: 0.21, 0.27, and 1.09 MUg/ml, respectively). ITR had no activity against Fusarium spp. (n = 9; GM MIC: 32 MUg/ml), but AMB was found to be the most effective antifungal against the tested members of this genus, followed by CAS and VOR (GM MICs: 0.86, 1.59, and 2.72 MUg/ml, respectively). These data should be used to design future targeted clinical efficacy trials. We also report on several fungal species that are rarely encountered in the clinical laboratory, for which little information about drug sensitivities was previously available. PMID- 21599551 TI - An adjusted indirect comparison of everolimus and sorafenib therapy in sunitinib refractory metastatic renal cell carcinoma patients using repeated matched samples. AB - OBJECTIVE: To date, no trial data exist comparing treatment outcomes for everolimus versus sorafenib. The current analysis indirectly compares the overall survival (OS) benefit of everolimus and sorafenib as second-line treatment options. RESEARCH DESIGN AND METHODS: A single-arm sorafenib study is selected as a basis to match an everolimus sunitinib-refractory subpopulation of the RECORD-1 trial. Only patients with clear cell histology are included. An adjusted matching approach is taken where 1000 repeated random samples matched to the sorafenib population on risk score distribution are produced, and a 95% CI around the mean of all sampled median OS is generated. MAIN OUTCOME MEASURES: The main outcome measures include adjusted median OS and progression-free survival. RESULTS: In all, 45 clear cell histology sorafenib patients and 1000 samples of N=41 sunitinib-refractory everolimus patients are considered for analysis. After adjusted matching, the estimated median OS benefit is 32.0 [corrected] weeks (95% CI: 22, 64) and 81.5 weeks (95% CI:78, 86) for sorafenib and everolimus patients, respectively. CONCLUSION: Results suggest that sunitinib-refractory metastatic renal cell carcinoma patients treated with everolimus may experience significantly improved OS outcomes compared to those treated with sorafenib. However, because this is not a randomized controlled trial, the results should be interpreted as those from an observational study. PMID- 21599552 TI - Pharmacokinetic evaluation of pemetrexed. AB - INTRODUCTION: Pemetrexed is a multi-targeted antifolate cytotoxic agent that has demonstrated activity in a number of very common cancer types including NSCLC in both first- and second-line settings and in the treatment of malignant mesothelioma. AREAS COVERED: This article focuses on all of the currently published pharmacokinetic data of pemetrexed reviewing a number of different scenarios and patient populations. All the articles reviewed in this manuscript are from peer-reviewed English-spoken literature without any limitations to the time of publication. EXPERT OPINION: Pemetrexed's clearance correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance >= 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic or targeted agents. It is the author's opinion that pemetrexed is already a valuable cytotoxic agent which has proved useful in several malignancies. However, future trials might expand on the combined use of pemetrexed with other targeted agents that could be beneficial to other selected patients harboring relevant mutations or other biological features. PMID- 21599553 TI - Impact of weight gain on outcomes in type 2 diabetes. AB - BACKGROUND: The majority of patients with type 2 diabetes mellitus (T2DM) are overweight or obese. Obesity is a significant risk factor for increased morbidity and mortality in people with T2DM, and increased weight has been shown to worsen glycemic control and increase the risk of diabetes progression. METHODS: A search was conducted of the National Library of Medicine (PubMed) for articles published from 1990 to 2009 about the treatments of T2DM, relationship between T2DM and weight gain, obesity-related comorbidities of T2DM, and T2DM therapies associated with increased weight. Reference lists of retrieved articles were reviewed for additional publications. FINDINGS: Results from large, prospective clinical trials have shown that weight reduction significantly improves glycemic control and blood pressure in T2DM patients and lowers the risk of progression of T2DM as well as CV disease and cancer. Treatment-related weight gain is a side effect of many oral antidiabetes agents and insulin. The thiazolidinediones (TZD), sulfonylureas, and glinides are associated with weight gain. Despite the weight gain, TZDs also redistribute fat from the central to peripheral compartments, which may lead to a beneficial effect on insulin resistance. Among insulin products, the basal insulin analog detemir is typically associated with a smaller weight increase than human insulin and insulin analog preparations, including glargine, biphasic, and prandial insulin regimens. Alpha-glucosidase inhibitors and dipeptidyl peptidase-4 inhibitors are weight neutral, whereas glucagon-like peptide1-R agonists and metformin are associated with weight loss. DISCUSSION: An effective approach to management of the obese patient with diabetes is to communicate the significant benefits of a 1 kg reduction in body weight or prevention of weight gain on glycemic control and reduced morbidity and mortality. LIMITATION: This article is based on an extensive literature review rather than the prospective studies needed to define further the effect of weight gain on the management of T2DM. CONCLUSION: Weight management should be an integral part of a T2DM treatment strategy that includes selecting oral antidiabetes medications and insulin products that are weight beneficial. PMID- 21599554 TI - Variation in adherence with Global Initiative for Chronic Obstructive Lung Disease (GOLD) drug therapy guidelines: a retrospective actuarial claims data analysis. AB - OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is an irreversible and often progressive disease that requires lifelong adherence to complicated drug therapy regimens. The well established Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend specific drug therapy protocols, yet patient adherence to drug therapy and physician adherence to prescribing guidelines is reported to be suboptimal. In this claims based analysis of COPD patients, drug therapy treatment patterns including inhaled corticosteroids and long acting bronchodilator use were evaluated by COPD severity level. METHODS: A cohort of patients with COPD (without co-existing asthma) was identified in Thomas Reuters MarketScan Commercial Database 2007 (diagnosis codes 491.xx, 492.xx, 496.xx). Using one year (2007) of claims data, a COPD severity risk score was calculated for each patient using established claim logic. Severity levels of mild, moderate, severe, and very severe were established to mimic the GOLD severity levels. Each patient's claim experience was examined for inhaled corticosteroid and long acting bronchodilator use for compliance with GOLD guidelines. RESULTS: Prevalence of COPD (without co-existing asthma) was 0.7% (44,366 cases). The distribution of COPD subjects into claim based severity levels was 30% mild, 53% moderate, 14% severe and 3% very severe. Claims for inhaled corticosteroid therapy were identified for 8% of mild and 19% of moderate COPD patients; claims for short acting bronchodilator therapy without concomitant use of long acting bronchodilators were identified for 20% of moderate, 14% of severe and 8% of very severe COPD patients; and claims for single long acting bronchodilator therapy in combination with inhaled corticosteroid therapy were identified for 12% of moderate, 19% of severe and 2% of very severe COPD patients. CONCLUSIONS: This analysis suggests less than optimal compliance with recommended drug therapy treatment for COPD patients based on GOLD guidelines. This study further suggests the utility of claims data analyses for providing reasonable aggregate distributions of COPD severity which allows for health plans and disease management programs to stratify COPD patients by severity level and examine opportunities for improved drug therapy management. Study findings should be considered in the context of the study limitations. PMID- 21599555 TI - Reasons for encounters, investigations, referrals, diagnoses and treatments in general practice in Sweden--a multicentre pilot study using electronic patient records. AB - OBJECTIVE: To investigate reasons for encounters, investigations, referrals, diagnoses and treatments in everyday general practice, using electronic patient records (EPR), and possible related differences concerning gender, socio-economic status (SES) and practice location. METHOD: Four Swedish primary care centres using EPR participated. Distributions of symptoms, investigations, diagnoses and prescribed drugs were registered. RESULTS: In 1055 encounters, the mean patient age was 53; 59% were women. The most common reasons for the encounter were musculoskeletal (21.5%) and respiratory (15.2%) symptoms. A total of 1534 diagnoses were coded, on average 1.5 per encounter. The predominant diagnostic groups, i.e. ICD-10 chapters, were musculoskeletal (17.2%) and respiratory (12.4%). The most common specific diagnoses were essential hypertension (8.1%) and acute upper respiratory infections (3.7%). A total of 1687 prescriptions were issued, on average 1.6 per encounter. The most frequent pharmaceutical groups were nervous (17.7%), respiratory system (16.2%), and cardiovascular (15.7%). The most frequent drugs were phenoxymethyl penicillin (3.7%), diclofenac (2.9%) and acetylsalicylic acid (2.5%). An average of 1.3 laboratory tests was performed per encounter. In 7.5% of encounters, radiology referrals were made; in 12.3% referrals were made to other specialists/therapists, while sick-list certificates were written in 11.7%. There were significant differences concerning symptoms, diagnoses and investigations between female and male patients, urban and rural practices and SES. CONCLUSION: The musculoskeletal, respiratory and circulatory systems predominated, both as reasons for the encounter and in the diagnoses, but with significant differences concerning gender, SES and practice location. PMID- 21599556 TI - EQUIP: recent quality-related developments in the Turkish health sector. PMID- 21599557 TI - EGPRN: European General Practice Research Network. PMID- 21599558 TI - IPCRG: International Primary Care Respiratory Group. PMID- 21599560 TI - Changes in total IgE plasma concentration measured at the third month during anti IgE treatment predict future exacerbation rates in difficult-to-treat atopic asthma: a pilot study. AB - In severe, difficult-to-treat atopic asthma with sensitization to perennial allergens, monoclonal antibodies directed against immunoglobulin E (IgE) are recognized to be clinically effective. Omalizumab, a recombinant monoclonal antibody, selectively binds to the high-affinity C-epsilon 3 site of human IgE and inhibits the inflammatory cascade in response to antigenic stimuli. Currently, no indicator is available for predicting patients' responsiveness to long-term omalizumab treatment. This study aims to assess the relationship between early changes in plasma IgE concentration and major outcome variables over a 12-month course of omalizumab. METHODS: Twenty-three nonsmoking, severe asthmatics (14 females; mean age 47.3 years +/- 12.0 SD; mean BMI 25.8 kg/m(2) +/ 9.6 SD) sensitized to perennial allergens and unresponsive to high doses of common therapies were evaluated during a 12-month period of omalizumab treatment. Variables included total IgE plasma concentrations, Forced Expiratory Volume 1 second (FEV(1)) symptom complaints (Asthma Control Test (ACT) score), number of emergency visits, hospitalizations, and exacerbations. The Wilcoxon signed-rank test was used to compare changes observed after the 1-year omalizumab treatment versus baseline. Statistical modelization was used to determine possible relationships between changes in outcomes after 12 months and early changes in plasma IgE (after 3 months of treatment). RESULTS: The number of emergency visits, hospitalizations, and exacerbations decreased (p < .004, p < .001, and p < .001, respectively) over the 12-months. In contrast, FEV(1) and ACT score substantially increased (both p < .001); the ACT score reaching maximum after only 3 months. The S model showed the best fit and proved the strict relationship between the increase in IgE after 3 months and the exacerbation rate over the 1 year survey (threshold value of >=250 IU/ml, p < .001). The improvement in FEV(1) was independent of the increase in IgE. CONCLUSIONS: When confirmed on a larger population, early changes in IgE may be used as a predictor of future responders to omalizumab in terms of exacerbation rate, thus minimizing the economic burden of anti-IgE therapy. PMID- 21599561 TI - Associations of age, gender, and BMI with prevalence of allergic diseases in children: PATCH study. AB - BACKGROUND: Little is known about the prevalence of allergic diseases in children of different ages. This study aimed to investigate the prevalence of allergic diseases and allergic sensitization in children over a wide age range, with emphasis on the influence of age, gender, and body mass index (BMI). METHODS: In a cross-sectional study, we assessed 5351 Taiwanese children aged 4-18 years using an International Study of Asthma and Allergies in Childhood questionnaire, BMI, and total and specific serum immunoglobulin E. RESULTS: Forty-eight percent were currently symptomatic for at least one of three allergic diseases. Prevalence of wheeze ever, current wheeze, and diagnosed asthma were 17.0%, 7.5%, and 9.8%, respectively; analogous features for rhinitis were 47.8%, 44.2%, and 39.8%. Allergic sensitization was very common (57.3%). Half of the children (50.6%) with current wheeze had not been diagnosed with asthma by physicians, whereas undiagnosed rates were 32.3% for rhinitis and 25.3% for eczema. The male to-female prevalence ratios of current wheeze increased with age from <1 at 4-5 years, peaked at 10-11 years (2.24), then reversed to 0.57 at 16-18 years. Childhood wheezing tended to remit with age, but rhinitis and eczema were more persistent. Total immunoglobulin E levels increased with age until 14-15 years, and declined thereafter. Elevated BMI was associated with greater prevalence of wheezing and eczema, with no evidence of significant effect modification by either gender or age. Multivariate analyses revealed that younger age, boys, and obesity were significantly and independently associated with current wheezing in children (all p < .01). CONCLUSIONS: The burden and co-morbidity of childhood allergies are substantial. There are striking age-dependent gender differences in asthma prevalence, exhibiting an inverted U-shaped curve for male-to-female prevalence ratios by age. Obesity is associated with a greater prevalence of asthma in children with no evidence of a significant modulation by either gender or age. PMID- 21599563 TI - Latent toxoplasmosis reduces gray matter density in schizophrenia but not in controls: voxel-based-morphometry (VBM) study. AB - OBJECTIVES: To address the role of latent T. gondii infection in schizophrenia we studied the influence of latent toxoplasmosis on brain morphology. METHODS: An optimized voxel-based morphometry of magnetic resonance imaging was analyzed by analysis of variance with diagnosis and seropositivity as factors in 44 schizophrenic patients (12 T. gondii positive) and 56 controls (13 T. gondii positive). RESULTS: Grey matter (GM) volume was reduced in schizophrenia patients compared with controls in the cortical regions, hippocampus and in the caudate. In the schizophrenia sample we found a significant reduction of GM volume in T. gondii positive comparing with T. gondii-negative patients bilaterally in the caudate, median cingulate, thalamus and occipital cortex and in the left cerebellar hemispheres. T. gondii-positive and -negative controls did not differ in any cluster. Among participants seropositive to T. gondii the reduction of GM in the schizophrenia subjects was located in the same regions when comparing the entire sample (11,660 over-threshold voxels (P <= 0.05, FWR corrected). The differences between T. gondii-negative patients and controls consisted only of 289 voxels in temporal regions. CONCLUSIONS: Our study is the first to document that latent toxoplasmosis reduces GM in schizophrenia but not in controls. PMID- 21599562 TI - A pilot study to enhance preventive asthma care among urban adolescents with asthma. AB - BACKGROUND: Low-income, minority teens have disproportionately high rates of asthma morbidity and are at high risk for nonadherence to preventive medications. OBJECTIVE: To assess the feasibility and preliminary effectiveness of an innovative school-based asthma program to enhance the delivery of preventive care for 12-15 year olds with persistent asthma. We hypothesized that this intervention would (1) be feasible and acceptable among this population and (2) yield reduced asthma morbidity. DESIGN/METHODS: SUBJECTS/SETTING: Teens with persistent asthma and a current preventive medication prescription in Rochester, NY. DESIGN: Single group pre-post pilot study during the 2009-2010 school year. INTERVENTION: Teens visited the school nurse daily for 6-8 weeks at the start of the school year to receive directly observed therapy (DOT) of preventive asthma medications; 2-4 weeks following DOT initiation, they received three counseling sessions (one in-home and two via telephone) using motivational interviewing (MI) to explore attitudes about asthma management, build motivation for medication adherence, and support transition to independent preventive medication use. PRIMARY OUTCOME: Number of symptom-free days (SFDs)/2 weeks; outcome data were collected 2 months after baseline and at the end of school year. RESULTS: We enrolled 30 teens; 28 participated in the intervention. All teens initiated a trial of school-based DOT. All in-home MI visits were completed successfully, and 89% completed both follow-up sessions. Teens experienced an overall reduction of symptoms with more SFDs/2 weeks from baseline to 2-month and final (end of school year) assessments (8.71 vs. 10.79 vs. 12.89, respectively, p = .046 and p = .004). Teens also reported fewer days with symptoms, less activity limitation, and less rescue medication use (all p < .05). Exhaled nitric oxide levels decreased (p = .012), suggesting less airway inflammation. At the final assessment, teens reported significantly higher motivation to take their preventive medication every day (p = .043). At the end of the study, 79% of teens stated that they were better at managing asthma on their own, and 93% said they would participate in a similar program again. CONCLUSIONS: This pilot study provides preliminary evidence of the feasibility and effectiveness of a novel school-based intervention to promote independence in asthma management and improve asthma outcomes in urban teens. PMID- 21599564 TI - Mucoadhesive nanomedicines: characterization and modulation of mucoadhesion at the nanoscale. AB - INTRODUCTION: The benefits of mucoadhesive systems are related to the increased in situ residence and intimate contact of the delivery vehicle with the mucosa. The recent emergence of nanomedicine and the properties of nanoparticulate systems have created new challenges in understanding the nature and mechanisms of nanoscale mucoadhesion and in the development of methodologies for measuring its mucoadhesive potential. Even when usually regarded as an advantageous property, mucoadhesion can be an inconvenience for nanosystems, and strategies have been developed for minimizing interactions with the mucosal tissues/fluids. AREAS COVERED: This article summarizes the basic concepts of mucoadhesion at the nanoscale, different techniques used for measuring the mucoadhesive potential of nanosystems and strategies for increasing/decreasing mucoadhesive interactions. EXPERT OPINION: The mucoadhesion behavior of materials in bulk and at the nanoscale can significantly differ. Advances in the methodology used for studying the mucoadhesion phenomenon have contributed to its better understanding and, more importantly, the development of strategies to increase/decrease mucoadhesion. However, development of new methodologies for studying mucoadhesion at the nanoscale and the refinement of existing methodologies are still required. Also, a substantial amount of information is still lacking, particularly related to formulation issues, on how to translate lessons learnt at the bench top to the bed side. PMID- 21599565 TI - Main approaches for delivering antioxidant vitamins through the skin to prevent skin ageing. AB - INTRODUCTION: One of the major contributions to skin photoageing and diseases is oxidative stress, caused by UV radiation inducing reactive oxygen and nitrogen species. Successful prophylaxis and therapy would necessitate control of the oxidant/antioxidant balance at the affected site, which can be achieved through the external supply of endogenous antioxidants. AREAS COVERED: This review discusses possible strategies for dermal delivery of the antioxidant vitamins E and C, as oral supplementation has proved insufficient. These antioxidants have low skin bioavailability, owing to their poor solubility, inefficient skin permeability, or instability during storage. These drawbacks can be overcome by various approaches, such as chemical modification of the vitamins and the use of new colloidal drug delivery systems. New knowledge is included about the importance of: enhancing the endogenous skin antioxidant defense through external supply; the balance between various skin antioxidants; factors that can improve the skin bioavailability of antioxidants; and new delivery systems, such as microemulsions, used to deliver vitamins C and E into the skin simultaneously. EXPERT OPINION: A promising strategy for enhancing skin protection from oxidative stress is to support the endogenous antioxidant system, with antioxidants containing products that are normally present in the skin. PMID- 21599566 TI - Metabolic and toxicological considerations for diuretic therapy in patients with acute heart failure. AB - INTRODUCTION: Diuretics are widely recommended in patients with acute heart failure (AHF). However, loop diuretics predispose patients to electrolyte imbalance and hypovolemia, which in turn leads to neurohormonal activation and worsening renal function (WRF). Unfortunately, despite their widespread use, limited data from randomized clinical trials are available to guide clinicians with the appropriate management of this diuretic therapy. AREAS COVERED: This review focuses on the current management of diuretic therapy and discusses data supporting the efficacy and safety of loop diuretics in patients with AHF. The authors consider the challenges in performing clinical trials of diuretics in AHF, and describe ongoing clinical trials designed to rigorously evaluate optimal diuretic use in this syndrome. The authors review the current evidence for diuretics and suggest hypothetical bases for their efficacy relying on the complex relationship among diuretics, neurohormonal activation, renal function, fluid and sodium management, and heart failure syndrome. EXPERT OPINION: Data from several large registries that evaluated diuretic therapy in hospitalized patients with AHF suggest that its efficacy is far from being universal. Further studies are warranted to determine whether high-dose diuretics are responsible for WRF and a higher rate of coexisting renal disease are instead markers of more severe heart failure. The authors believe that monitoring congestion during diuretic therapy in AHF would refine the current approach to AHF treatment. This would allow clinicians to identify high-risk patients and possibly reduce the incidence of complications secondary to fluid management strategies. PMID- 21599567 TI - Perindopril for the treatment of hypertension. AB - INTRODUCTION: Treatment of hypertension is fundamental for the prevention of cardiovascular events and mortality. This review focuses on the specific benefits of the ACE inhibitor perindopril. AREAS COVERED: A systematic literature search is undertaken for supporting the pharmacological proprieties and clinical efficacy of perindopril in the treatment of hypertension. Good tissue penetration, strong affinity for ACE and a long duration of action support the dose-dependent blood pressure lowering efficacy. Perindopril in combination with amlodipine significantly reduced total and cardiovascular mortality as compared to atenolol/diuretic in large-scale clinical trials of hypertensive patients. A greater reduction in blood pressure variability, central blood pressure and specific vascular protective proprieties of perindopril (improvement in arterial stiffness and endothelial function) might explain these results. Cardiovascular prevention with perindopril, in combination with indapamide, has been also shown in the elderly and patients with diabetes, cardio- and cerebrovascular diseases. EXPERT OPINION: Perindopril is effective and safe for blood pressure control with a dose-dependent effect. Combination therapy with indapamide or amlodipine reduces cardiovascular events and mortality in hypertensive patients. Pharmacological proprieties and results of clinical trials support the choice of perindopril as an appropriate treatment for hypertensive patients. PMID- 21599568 TI - Brief assessment of motor function: content validity and reliability of the upper extremity gross motor scale. AB - Content validity and reliability of the Brief Assessment of Motor Function (BAMF) Upper Extremity Gross Motor Scale (UEGMS) were evaluated in this prospective, descriptive study. The UEGMS is one of five BAMF ordinal scales designed for quick documentation of gross, fine, and oral motor skill levels. Designed to be independent of age and diagnosis, it is intended for use for infants through young adults. An expert panel of 17 physical therapists and 13 occupational therapists refined the content by responding to a standard questionnaire comprised of questions, which asked whether each item should be included, is clearly worded, should be reordered higher or lower, is functionally relevant, and is easily discriminated. Ratings of content validity exceeded the criterion except for two items, which may represent different perspectives of physical and occupational therapists. The UEGMS was modified using the quantitative and qualitative feedback from the questionnaires. For reliability, five raters scored videotaped motor performances of 10 children. Coefficients for inter-rater (0.94) and intra-rater (0.95) reliability were high. The results provide evidence of content validity and reliability of the UEGMS for the assessment of UEGM skill. PMID- 21599569 TI - Tactile assessment in children with cerebral palsy: a clinimetric review. AB - This review evaluates the clinimetric properties of tactile assessments for children with cerebral palsy. Assessment of registration was reported using Semmes Weinstein Monofilaments (SWMs) or exteroception. Assessment of two-point discrimination was reported using the Disk-Criminator(r) or paperclip methods; Single point localization and double simultaneous were reported from the Neurosensory Motor Developmental Assessment (NSMDA); graphaesthesia was reported from the Sensory Integration and Praxis Test (SIPT); and stereognosis was assessed using Manual Form Perception from the SIPT and the Klingels method (Klingels, K. et al. (2010). Upper limb motor and sensory impairments in children with hemiplegic cerebral palsy. Can they be measured reliably? Disability and Rehabilitation, 32(5), 409-416) and the Cooper method (Cooper, J., Majnemer, A., Rosenblatt, B., & Birnbaum, R. (1995). The determination of sensory deficits in children with hemiplegic cerebral palsy. Journal of Child Neurology, 10, 300 309). The SIPT and NSMDA demonstrated stronger content validity. Inter-rater reliability was excellent for SIPT (ICC = 0.99) and exteroception (k = 0.88). Test-retest reliability was excellent for exteroception (k = 0.89) and stereognosis (ICC = 0.86; 100%), moderate for SIPT (r = 0.69-0.74) and poor for SWM (k = 0.22). Together these assessments measure tactile registration and spatial perception. Temporal and textural tests are to be developed for comprehensive tactile examination. PMID- 21599570 TI - Carvedilol pharmacokinetics and pharmacodynamics in relation to CYP2D6 and ADRB pharmacogenetics. AB - AIMS: Carvedilol is an effective treatment in hypertension and chronic heart failure. The medical impact of polymorphisms in CYP2D6 and in the beta-adrenergic receptors ADRB1 and ADRB2 on the pharmacokinetics and pharmacodynamics of carvedilol is controversial. METHODS: After carvedilol 25 mg was administered to 110 volunteers, concentrations were enantioselectively quantified and effects on resting and exercise-induced heart rate and blood pressure were analyzed using population pharmacokinetic, pharmacodynamic and pharmacogenetic modeling. RESULTS: There were significant CYP2D6 allele-specific differences in carvedilol pharmacokinetics, but the CYP2D6 genotype had no effect on heart rate, blood pressure or adverse effects. ADRB1 Gly49 was associated with higher baseline heart rates and with greater carvedilol effects on exercise heart rates. Carriers of ADRB2 Gln27 had greater reduction in resting blood pressure by carvedilol compared with Glu27. CONCLUSION: Carvedilol is a drug where CYP2D6-related pharmacokinetic variation is apparently not carried forward into pharmacodynamic variation. Although current knowledge does not allow utilizing ADRB1 and ADRB2 genotypes for clinical treatment decisions, our data should stimulate further research on the impact of these genotypes in health and disease. PMID- 21599571 TI - Quality of life of adolescents and young adults born at high risk. AB - Research on quality of life (QoL) of adolescents and young adults born preterm and those with congenital heart disease (CHD) was systematically reviewed, and factors associated with QoL were identified. Forty-five studies met the inclusion criteria for review. Although the majority of studies found that self-reported QoL of adolescents and young adults born preterm did not differ from term controls, several studies reported lower QoL among individuals born preterm, especially those who had additional impairments. Most studies on adolescents and young adults with CHD reported lower QoL compared with healthy peers, which may be in part due to real or perceived physical activity limitations of individuals with CHD. Overall, parents reported that their adolescents born at high risk had a less favorable QoL compared with those who served as controls. Encouraging age appropriate, safe, and enjoyable physical activity and avoiding unnecessary restrictions and overprotection are considerations for optimizing QoL. PMID- 21599572 TI - Analysis of the sensory profile in children with Smith-Magenis syndrome. AB - This study systematically assessed sensory processing in 34 children, aged 3-14 years, with Smith-Magenis syndrome (SMS) using the Sensory Profile Caregiver Questionnaire. Scores for the SMS cohort were significantly different from scores of the national sample of children with and without disabilities in all Sensory Profile categories and quadrants (p < .001). No main effects of age or gender were found, but an interaction effect of age by gender was found in Modulation of Sensory Input Affecting Emotional Responses, in which older females presented with the lowest scores. A significant decline over time was found in the Seeking pattern, reflecting increased vulnerability (p < .05). Nonsignificant trends suggest more vulnerabilities for older versus younger children, especially older females. The neurobehavioral phenotype in children with SMS is expanded by this description of sensory processing. How children with SMS experience and respond to everyday sensations informs multidisciplinary team decisions. PMID- 21599573 TI - Effects of moderate red wine consumption on liver fat and blood lipids: a prospective randomized study. AB - BACKGROUND: There have been no human prospective randomized studies of the amount of alcohol that can induce hepatic steatosis. METHODS: Thirty-two healthy women and twelve healthy men (34 +/- 9 years of age) were randomized to consume 150 ml of red wine/day for women (16 g ethanol/day) or double that amount for men (33 g ethanol/day), or to alcohol abstention for 90 days. Participants underwent proton nuclear magnetic-resonance spectroscopy for measurement of hepatic triglyceride content (HTGC). Blood samples for assessment of cardiovascular risk were drawn before and after the intervention. RESULTS: After exclusion of three subjects with steatosis at baseline a trend towards increased HTGC was apparent for red wine (before median: 1.1%, range 0.2-3.9%, after median: 1.1%, range 0.5-5.2 %, P = 0.059) a difference that was statistically significant compared with abstainers (p = 0.02). However, no subject developed hepatic steatosis. Low-density lipoprotein (LDL)-cholesterol was lowered by red wine (-0.3 mmol/l, SE -0.1, 95% CI -0.6 to -0.04). CONCLUSIONS: Moderate consumption of red wine during three months increased HTGC in subjects without steatosis at baseline. However, since not a single participant developed steatosis we suggest that the threshold of alcohol consumption to define nonalcoholic fatty liver disease should not be lower than the amount in our study. PMID- 21599574 TI - Myeloproliferative neoplasms 5 years after discovery of JAK2V617F: what is the impact of JAK2 inhibitor therapy? AB - The watershed discovery of the JAK2V617F mutation in 2005, and the high prevalence of this mutation in the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), has led to a renaissance in the science and therapy of these disorders. Inhibitors of JAK2 entered clinical trials in 2007 and ushered in an unprecedented era of trials with agents specifically designed for MPNs. Currently 10 different JAK2 inhibitors have been tested in myelofibrosis (MF) with varying degrees of specificity for the JAK2 kinase. In MF these agents have shown near universal ability to decrease pathologic splenomegaly and improve disease-associated symptoms. However, the ability of these agents to significantly impact disease-associated cytopenias, JAK2 allele burden, or bone marrow histologic features remains unclear. JAK2 inhibition in polycythemia vera (PV) and essential thrombocythemia (ET) for this class of agents appears promising to reduce myeloproliferations, symptoms, and perhaps prevent thrombohemorrhagic events. Alternative agents (with alternative targets), used either alone or in combination, might perhaps further augment the spectrum of efficacy and therapeutic options for MPNs. PMID- 21599575 TI - Enhanced invasiveness in multidrug resistant leukemic cells is associated with overexpression of P-glycoprotein and cellular inhibitor of apoptosis protein. AB - Multidrug resistance (MDR) and multi-organ infiltration are the major obstacles to the successful treatment of leukemia. It is known that the drug efflux protein, P-glycoprotein (P-gp), and inhibitors of apoptosis proteins (IAPs) are involved in the MDR of leukemic cells, but their roles in leukemia infiltration have not been clearly elucidated. In this study, leukemic cell lines K562 and HL60 and their MDR variants K562R and HL60R have been used to analyze their infiltrative ability. MDR variants display enhanced invasion compared with parental cells. Results from xenografts in SCID (severe combined immunodeficiancy) mice are consistent with these in vitro observations. Furthermore, P-gp and cIAP are overexpressed and co-localize with protein kinase C-epsilon (PKC-epsilon) in MDR variants. Our study shows that overexpression of P gp and cIAP may enhance the infiltration of leukemic cells. PMID- 21599576 TI - Treatment recommendations for radioimmunotherapy in follicular lymphoma: a consensus conference report. AB - Radioimmunotherapy (RIT) with (90)Y-ibritumomab tiuxetan or (131)I-tositumomab combines a radiation-emitting radionuclide with an antibody targeting CD20 to treat B-cell non-Hodgkin lymphoma. Multiple studies demonstrate favorable RIT efficacy and safety profiles in follicular lymphoma (FL). The primary toxicity is reversible myelosuppression. Various FL treatment options include single-agent immunotherapy, radiation, chemoimmunotherapy, and RIT. Examining RIT clinical effects and position within treatment algorithms is important to optimal patient benefit. Clinical studies support using single-agent RIT in relapsed/refractory FL, in selected patients with new, untreated FL, and as consolidation after induction chemotherapy or chemoimmunotherapy. RIT as consolidation enhances response rates (with conversion of partial to complete responses following induction therapy) and prolongs disease control versus observation. The overall response rate is 60-80% in the relapsed setting. Time to progression is longer with low-bulk disease, fewer prior therapies, and retained rituximab sensitivity. RIT apparently does not preclude subsequent therapies or increase risk of secondary malignancies compared with chemotherapy's known risk. This article summarizes consensus recommendations for RIT and presents RIT treatment algorithms developed by hematologists/oncologists who regularly treat patients with FL. Maximizing RIT benefit requires healthcare providers to utilize algorithms assisting with treatment decisions. PMID- 21599577 TI - Multicenter study of comparative outcomes of hematopoietic stem cell transplant for peripheral T cell lymphoma and natural killer/T-cell lymphoma. PMID- 21599578 TI - Prognostic value of bone marrow microvessel density and angiogenic cytokines in patients with multiple myeloma undergoing autologous stem cell transplant. AB - Angiogenesis is important for the proliferation and metastasis of most malignant neoplasms including multiple myeloma (MM). The aim of this study was to evaluate the role of bone marrow angiogenesis and angiogenic cytokines in patients with MM prior to and after autologous stem cell transplant (ASCT). Twenty-nine patients with MM who underwent ASCT had serial samples of serum and bone marrow biopsies at diagnosis, prior to ASCT, and at the 3rd and 6th months post-transplant. Besides bone marrow microvessel density (MVD), serum angiogenic cytokines including vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) and markers of disease activity such as interleukin-6 (IL-6), IL-1beta, C reactive protein (CRP), beta(2)-microglobulin, and bone marrow plasma cells (BMPCs) were also determined. Bone marrow MVD, serum levels of IL-6, CRP, and beta(2)-microglobulin, and BMPCs decreased significantly from diagnosis to the 6th month post-transplant (p < 0.05). Serum FGF and IL-1beta levels decreased significantly until 3 months post-transplant, however lost this significance at the 6th month. Serum VEGF levels did not vary significantly during follow-up. MVD, serum angiogenic cytokine levels, and parameters reflecting disease activity were similar in responders and non-responders to induction chemotherapy. Cytokines and MVD both at diagnosis and prior to transplant did not show any correlation with overall survival (OS) and progression-free survival (PFS) after a median follow-up of 55 months after transplant (p > 0.05). Our findings suggest that bone marrow MVD decreases significantly with ASCT in MM, however without an impact on OS and PFS. PMID- 21599579 TI - Description of a novel Janus kinase 3 P132A mutation in acute megakaryoblastic leukemia and demonstration of previously reported Janus kinase 3 mutations in normal subjects. AB - Gain-of-function (GOF) mutations of Janus kinase 2 (JAK2) are frequently seen in myeloproliferative disorders (MPDs). Meanwhile, JAK3 activating substitutions have been found in a few megakaryocytic cell lines and in primary myeloid leukemia (AMKL). Here, we sought to discover novel leukemogenetic mutations in de novo acute myeloid leukemia of non-Down syndrome (N-DS) by DNA sequencing. A total of 191 normal Caucasian individuals were studied to define single nucleotide polymorphisms (SNPs) within the JH2 and JH6 domains. Although known activating substitutions were observed in rare cases of acute myeloid leukemia (AML) (V722I [2/134] or P132T [1/119]), all samples were wild-type (WT) for the oncogenic A572V (119/119). Interestingly, a novel homozygous mutation (P132A) was discovered in a patient with acute megakaryoblastic leukemia and in vivo studies demonstrated that its ectopic expression was oncogenic in a mouse xenotransplant model. This study defines a novel JAK3 mutation among patients with N-DS AML and demonstrates that normal individuals can also display germline JAK3 substitutions, previously proven to have oncogenic properties, in vitro and in vivo. The discovery of these substitutions in normal donors encourages future studies to define new risk factors among patients with MPDs. PMID- 21599580 TI - Intratumoral plasmacytoid dendritic cells associate with increased survival in patients with follicular lymphoma. AB - Gene array studies on follicular lymphoma (FL) have associated non-malignant tumor-infiltrating immune cells with patient survival. We examined the role of such cells detectable by immunohistochemistry in a tissue microarray, focusing on plasmacytoid dendritic cells (pDCs). These cells physiologically produce interferon-alpha, which has been used in the therapy of FL. High numbers of pDCs are associated with increased survival, and so are high numbers of CD3+ T cells. The regular distribution of pDCs within T cell areas is reflected by a weak but significant correlation between pDCs and T cells. However, in multivariate Cox models, CD123 proved to be an independent prognostic factor. These findings support the hypothesis of an association of pDCs with better prognosis by producing interferon. Furthermore, due to a linear relationship between pDCs and survival shown by means of Kaplan-Meier plots, immunohistochemical staining of CD123 could serve as a prognostic tool for patients with FL. PMID- 21599581 TI - The mammalian target of rapamycin pathway as a therapeutic target in multiple myeloma. AB - The mammalian target of rapamycin (mTOR) is centrally located, linking proximal oncogenic cascades to critical downstream pathways that drive tumor growth. mTOR regulates such diverse functions as protein translation, proliferation, viability, autophagy, metabolism homeostasis, monitoring of energy reserves, and induction of angiogenesis. Given its fundamental role in tumorigenesis, it is not surprising that a huge effort is being made to develop mTOR inhibitors. The existence of feedback pathways that become activated subsequent to mTOR inhibition has complicated these efforts. However, the fact that mTOR exists in two separate complexes, TORC1 and TORC2, and rapalogs primarily inhibit only TORC1 and TORC2 is actually a key activator of AKT, has injected new energy into the quest to find inhibitors that can inhibit both complexes. In myeloma models, preclinical studies confirm the activity of rapalogs as well as newer TORC1/TORC2 inhibitors, and early phase clinical trials have begun. In addition, the recent finding of up-regulated myeloma cell expression of DEPTOR, an mTOR binding protein that restricts mTOR activity, suggests an additional future therapeutic target specific to the myeloma tumor model. PMID- 21599582 TI - Alemtuzumab (Campath-1H) for chronic lymphocytic leukemia: a drug in search of its optimal schedule. PMID- 21599583 TI - 1q triplication as sole cytogenetic abnormality in myelodysplastic syndrome. PMID- 21599584 TI - Allogeneic hematopoietic stem cell transplantation for advanced extranodal natural killer/T-cell lymphoma, nasal type. AB - The prognosis for patients with advanced or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL) is extremely poor. Thus, allogeneic stem cell transplantation (allo-HSCT) should be considered for this disease. However, reports of allo-HSCT for ENKL are limited because of the rarity of the disease. Here, we describe the clinical course of 12 cases of advanced and refractory ENKL treated with allo-HSCT, including five cases with cord blood transplant. With a median follow-up of 13 months (range, 1-168 months), seven patients are alive in remission, five have died, and one treatment-related death occurred. All patients with disease progression at transplant died of disease progression, whereas seven of eight patients with a complete or partial response are long-term survivors. Allo-HSCT is a feasible and promising consolidation therapy for advanced and relapsed ENKL. The disease status before allo-HSCT is well associated with general outcome, and thus induction treatment is very important for this disease. PMID- 21599585 TI - Strategies to optimize collection of hematopoietic stem cells in patients with mantle cell lymphoma receiving hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone combined with cytarabine and methotrexate (Hyper CVAD) chemotherapy. PMID- 21599586 TI - Allogeneic transplant for peripheral T-cell lymphoma: a sparkle of hope and many questions. PMID- 21599587 TI - Old versus frail: why it matters in lymphoma. PMID- 21599588 TI - Genotyping chronic lymphocytic leukemia in China: East meets West. PMID- 21599589 TI - The significance of quantifiable residual normal karyotype hematopoietic cells for toxicity and outcome. PMID- 21599590 TI - Long-term outcomes of patients with newly diagnosed extranodal natural killer/T cell lymphoma treated by etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin regimen: a single-institution experience. AB - One possible reason for the relapse and refractoriness of extranodal natural killer/T-cell (NK/T) lymphoma (ENKL) is resistance to a CHOP-like regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). To evaluate the outcome of first-line EPOCH chemotherapy (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) for ENKL, 34 patients, including 30 with nasal ENKL (88.2%) and four with extranasal ENKL (11.8%), were studied. Involved-field radiation therapy (IFRT) was administered to patients with localized nasal focus after chemotherapy. Thirty-three cases were eligible for response evaluation. The response rate (RR) was 60.6% (20/33) with a complete remission (CR) rate of 45.5% (15/33). For patients with localized nasal ENKL, the CR rate was 57.7% (15/26). The 3-year progression-free survival and overall survival rates were 53.6% and 69.0%, respectively. After initial EPOCH chemotherapy followed by IFRT, the CR rate was 75.0% and the 3-year overall survival rate was 75.0%. However, patients with disseminated and extranasal disease responded poorly. These results indicate that EPOCH followed by IFRT yields promising outcomes for patients with localized nasal ENKL. PMID- 21599591 TI - Dose-dense high-dose methylprednisolone and rituximab in the treatment of relapsed or refractory high-risk chronic lymphocytic leukemia. AB - This study evaluated the efficacy and safety of dose-dense high-dose methylprednisolone (HDMP) plus rituximab (Rtx) in patients with high-risk CLL. Twenty-nine patients with relapsed or progressive CLL with adverse cytogenetics (17p deletion, TP53 mutation, 11q deletion, and/or trisomy 12) and/or progression within 12 months of fludarabine treatment were included. HDMP (1 g/m(2)) was administered daily for 5 days of each treatment course. Rtx was administered on days 1 (375 mg/m(2)) and 5 (500 mg/m(2)) of the first treatment course, on days 1 (500 mg/m(2)) and 5 (500 mg/m(2)) of the second course, and on day 1 (500 mg/m(2)) of courses 3-6. The cycles were repeated every 21 days. The overall response rate (ORR) was 62%, and 28% of patients had stable disease. In 13 patients with 17p deletion/TP53 mutation, ORR was 69%. After 22 months, the median progression-free and overall survivals were 12 and 31 months, respectively. The most frequent toxicity was hyperglycemia, and three deaths occurred in the study. Dose-dense treatment with HDMP and Rtx is an effective therapy with a favorable safety profile in patients with high-risk CLL, including those with 17p deletion/TP53 mutation. PMID- 21599592 TI - Stem-like tumor cells confer drug resistant properties to mantle cell lymphoma. AB - We recently identified clonogenic malignant stem cell populations in human mantle cell lymphoma (MCL), a particularly deadly subtype of non-Hodgkin lymphoma (NHL). We discovered that CD45+CD19- MCL cells, which we termed MCL-initiating cells (MCL-ICs), are highly tumorigenic and display self-renewal capacity in vivo; in contrast, CD45+CD19+ MCL cells, which constitute the vast majority of cells within the tumors, show no self-renewal capacity and greatly reduced tumorigenicity. Given the newly appreciated role of cancer-initiating cells in the drug resistance of cancers, it is critical to investigate whether CD45+CD19- MCL-ICs play a role in the drug resistance of human MCL. We discovered that MCL ICs were more resistant to clinically relevant chemotherapeutic agents, in combination or in a single regimen, compared to CD45+CD19+ cells, and that this drug resistance was largely due to quiescent properties with enriched ABC transporters. In conclusion, designing novel therapies to kill CD45+CD19- MCL-ICs may prevent relapse and increase patient survival. PMID- 21599593 TI - Aberrant overexpression of membrane-associated mucin contributes to tumor progression in adult T-cell leukemia/lymphoma cells. AB - Aberrant overexpression of membrane-associated mucin (MUC1) is implicated in the pathogenesis of cancer, particularly of adenocarcinomas. Adult T-cell leukemia/lymphoma (ATL), an aggressive neoplasm etiologically associated with human T-lymphotropic virus type-1 (HTLV-1), exhibits invasive tropism into various organs, resulting in disease progression and resistance to treatment. In the present study, we showed that MUC1 is overexpressed exclusively in cells of ATL among hematological malignancies. Furthermore, increased expression of MUC1 correlated with a poor prognosis, suggesting MUC1 to be a prognostic marker in ATL. Various functional analyses with knockdown experiments using a specific siRNA for MUC1 revealed that MUC1 is involved in cell growth, cell aggregation, and resistance to apoptosis. Although it has been shown that the anti-adhesive properties of MUC1 facilitate migration and metastasis of tumor cells, our findings indicated that MUC1 contributes to cell-cell adhesion. Mucins thus seem to play a role in the pathogenesis and/or progression of ATL. PMID- 21599594 TI - Clostridium subterminale sepsis in adult acute lymphoblastic leukemia. PMID- 21599595 TI - Familial occurrence of myelodysplastic syndrome with del(5q). PMID- 21599597 TI - Virological response and resistance profiles after 18 to 30 months of first- or second-/third-line antiretroviral treatment: a cross-sectional evaluation in HIV type 1-infected children living in the Central African Republic. AB - A total of 242 HIV-1-infected children were followed up at the Complexe Pediatrique of Bangui, Central African Republic, including 165 receiving antiretroviral treatment in first- (n=150) or second-/third-line (n=15) regimens. They were prospectively included in a study, in 2009, to assess their virological status and prevalence of antiretroviral drug-resistance mutations in cases of virological failure, according to revised 2010 WHO criteria (e.g., HIV-1 RNA >3.7 log(10) copies/ml). Detectable plasma HIV-1 RNA was observed in 53% of children under first-line treatment, and virological failure was diagnosed in 40%, which was associated in 85% of cases with viruses harboring at least one drug resistance mutation to nucleoside reverse transcriptase inhibitors (NRTI) or nonnucleoside reverse transcriptase inhibitors (NNRTI), and in 36% of cases with at least one major drug-resistance mutation to NRTI or NNRTI when excluding the M184V mutation. Overall, the proportion of children receiving a first-line regimen for a median of 18 months with virological failure associated with drug resistance mutations, and thus eligible for a second-line treatment, was estimated at 34% of the whole cohort. In children under second-/third-line therapy, virological failure occurred in 47%, plus at least one major drug resistance mutation to NRTI or NNRTI, though less commonly to protease inhibitors. Taken together, these findings argue in favor of the urgent need to improve distribution of pediatric antiretroviral drugs in the Central African Republic, to increase adherence by treated children, and to offer adequate HIV biological monitoring. PMID- 21599600 TI - Fifty years of hairy cell leukemia treatments. AB - Treatment of hairy cell leukemia (HCL), a disease first described in 1958, has evolved from splenectomy, which resulted in a normalization of blood counts in about 41% of patients and an improvement in the remaining 59% of patients but with a time to failure of only approximately 19 months, through treatment in the early 1980s with interferon, which resulted in the same high overall response rate but with a time to failure of approximately 31 months. Subsequently, therapy with either pentostatin or cladribine showed an increase in the complete remission (CR) rate to approximately 80-90%, with only a small percentage of patients relapsing at approximately 30 months. More recently, patients who have failed either or both of these drugs have been shown to respond to rituximab or the experimental drug, BL22 (HA22). With these documented successes, the outlook for patients diagnosed with HCL, 50 years after the disease was first described, is so positive that patients with HCL have survival curves similar to those for the appropriate age-related cohorts. PMID- 21599601 TI - Surface topography of hairy cell leukemia cells compared to other leukemias as seen by scanning electron microscopy. AB - This short review deals with the ultrastructural surface architecture of hairy cell leukemia (HCL) compared to other leukemic cells, as seen by scanning electron microscopy (SEM). The development of improved techniques for preparing blood cells for SEM in the 1970s readily enabled these features to be visualized more accurately. This review returns us to the earlier history of SEM, when the surface topography of normal and neoplastic cells was visualized and reported for the first time, in an era before the emergence and use of monoclonal antibodies and flow cytometry, now used routinely to define cells by their immunophenotype. Surface microvilli are characteristic for normal and leukemic lymphoid cells, myelo-monocytic cells lack microvilli and show surface ruffles, while leukemic plasma and myeloma cells and megakaryocytes display large surface blebs. HCL cell surfaces are complex and typically 'hybrid' in nature, displaying both lymphoid and monocytic features with florid ruffles of varying sizes interspersed with clumps of short microvilli cytoplasm. The surface features of other leukemic cells and photomicrographs of immuno-SEM labeling of cells employing antibodies and colloidal gold, reported more than 20 years ago, are shown. PMID- 21599602 TI - Historical treatments of in hairy cell leukemia, splenectomy and interferon: past and current uses. AB - The management of hairy cell leukemia has undergone historic unprecedented changes since three decades ago. This review summarizes treatment approaches utilized before the adenosine deaminase inhibitors. These historic approaches may still be utilized in patients with relapsed or refractory disease. PMID- 21599603 TI - Long-term results for pentostatin and cladribine treatment of hairy cell leukemia. AB - Over the past 25 years we have collected data at our institution from 242 patients with hairy cell leukemia (HCL), treated with pentostatin (n = 188) or cladribine (n = 54), with a median follow-up of 16 years. From this we have been able to conclude that there is no significant difference in outcome between the two agents either at first or subsequent lines of therapy. Overall, the complete response (CR) rate is 81% and the median disease-free survival (DFS) is 16 years. After relapse or non-response patients can be successfully retreated with pentostatin or cladribine achieving a lower rate of CRs with each line of therapy, although these remain equally durable. Complete response and pretreatment counts of hemoglobin >10 g/dL together with platelets >100 * 10(9)/L are associated with the longest DFS. Importantly, for patients achieving a CR the DFS is five times as long as for those achieving a partial response (PR). Patients still in CR at 5 years have only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease have improved with the addition of rituximab to either purine analog. Overall, only eight patients have died of HCL related causes. Patients with HCL who achieve a CR can expect a normal lifespan. PMID- 21599604 TI - Hairy cell leukemia: a successful model for experimental therapeutics- pentostatin and new ideas. AB - Hairy cell leukemia (HCL) was once considered an untreatable form of chronic lymphoid malignancy. Based upon the recognition of the importance of adenosine deaminase to the normal B cell survival and proliferation, a hypothesis was developed that temporary inhibition of this enzyme might be therapeutically successful in treating chronic B cell leukemias. Pentostatin was initially explored in patients with refractory chronic lymphocytic leukemia (CLL). Both pentostatin and cladribine, purine nucleoside analogs, have been utilized to successfully treat HCL. The high degree of complete and durable remission observed with either agent resulted in many believing that the treatment of this rare disease had been fully optimized. However, a considerable number of patients will relapse. While tremendous progress has been made in initial management, the issues related to optimal therapy, timing of initiation of treatment, and discovery of novel agents that may be effective in those who have relapsed are important. Investigational agents currently being explored in chronic lymphocytic leukemia may also have benefit for those patients who have relapsed or are resistant to therapy of hairy cell leukemia. Many important questions remain (e.g. importance of minimal residual disease) and will require international collaboration to fully address these unanswered questions. The Hairy Cell Leukemia Consortium was established to address these unanswered questions. PMID- 21599605 TI - Hairy cell leukemia: epidemiology, pharmacokinetics of cladribine, and long-term follow-up of subcutaneous therapy. AB - Hairy cell leukemia is often reported as a disease of young males. The male predominance is strong, 4:1, but the median age in the Swedish national compulsory cancer registry is similar to that of follicular lymphoma, i.e. 62 years. The overall 6-year survival in the Swedish registry of patients diagnosed since 2000 is 80%, 93% of patients <60 years, and 68% of those >60 years. The yearly risk of secondary cancers is 1.75%. Cladribine is a prodrug which is selectively activated intracellularly. The intracellular initial half-life is 13 h and the terminal half-life is 30 h. Subcutaneous injection once daily is simple and effective due to 100% bioavailability and no local side effects from injection, and self-administration is easy. Long-term follow-up of Scandinavian patients treated with cladribine (mostly as subcutaneous injections) in the early 1990s shows a >80% 15-year survival from cladribine treatment in <60 years of age, but <50% in older patients. Survival from diagnosis of these patients was similar for those previously treated and untreated. PMID- 21599606 TI - Management of hairy cell leukemia variant. AB - Hairy cell leukemia variant (HCL-V) is now included in the World Health Organization (WHO) classification as a provisional entity and is no longer considered to be biologically related to classic HCL (HCL-C). The clinical course of HCL-V is variable but usually more aggressive, and the median survival of patients with HCL-V is significantly shorter than that of HCL-C. The therapeutic approach to HCL-V is still debated. Various treatment approaches active in HCL-C achieve partial response (PR) or no response in HCL-V, and remission is usually shorter than in HCL-C. In addition, HCL-V seems to be resistant to therapeutic modalities usually highly effective in the treatment of HCL-C. Cladribine (2-CdA) is significantly less active in HCL-V than in HCL-C. In addition, the majority of patients with HCL-V require more than one cycle of 2-CdA to maintain PR. Patients with HCL-V treated with pentostatin also have a poorer clinical outcome and a lower response rate than those of patients with HCL-C. Recently, some reports indicate that monoclonal antibodies, rituximab and alemtuzumab, are active in HCL V. Promising results have also been obtained with anti-CD22 immunotoxin, BL22. A new generation of CD22-specific immunotoxins, moxetumomab pasudotox (CAT-8015, HA22), highly active in refractory/relapsed HCL-C, also need clinical investigation in HCL-V. Currently, immunochemotherapy with rituximab and purine nucleoside analogs (PNAs) should be considered as the treatment of choice in previously untreated patients. PMID- 21599607 TI - Unusual clinical manifestations, rare sites of involvement, and the association of other disorders with hairy cell leukemia. AB - Unusual clinical manifestations, rare sites of involvement, and associations with other disorders and malignancies occurring in patients with hairy cell leukemia (HCL) are uncommon events encountered in a relatively rare disease. The exact prevalence of these associations is difficult to determine accurately in HCL as they are often anecdotal case reports and not always detailed in all larger series of patients. This short review deals with the unusual clinical manifestations and rare sites of involvement of the disease and lists some of the disorders associated with HCL, based on what has been reported in the literature as well as from personal experience. No attempts are made here to establish the true prevalence of these phenomena and only selected references are included. Some details of the coexistence of HCL with other neoplasias, hematological disorders, and 'paraneoplastic' autoimmune disorders are provided, while opportunistic infections in HCL, particularly atypical mycobacterial disease, are briefly discussed. For the sake of brevity many of the details are provided in tabular form. PMID- 21599608 TI - Enhancing immunotoxin cell-killing activity via combination therapy with ABT-737. AB - Immunotoxins are antibody-toxin fusion proteins directed to kill cancer cells displaying specific target antigens on their surface. Remarkably, immunotoxins directed to CD22 on hairy cell leukemia have produced complete remissions in approximately 60% of patients enrolled in phase I/II trials. For reasons that are not yet clear, 40% of patients responded less well. In addition, patients with other CD22-positive malignancies have not yet achieved complete remissions. In trying to understand 'resistance' to immunotoxin therapy, a number of challenging issues have been raised. These include insufficient dosing, the production of neutralizing anti-immunotoxin antibodies, poor access to malignant cells, and resistance to toxin killing. In designing immunotoxins, we employ truncated Pseudomonas exotoxin, which enzymatically inactivates protein synthesis and produces cell death in sensitive cells. To begin to address toxin resistance we have explored combination therapy with the BH3-only mimetic, ABT-737. Our results indicate that immunotoxin-ABT combinations often exhibit greater killing activity than either compound alone and in some instances overcome resistance. Expression of high levels of prosurvival Bcl-2 proteins may contribute to toxin resistance. PMID- 21599610 TI - Molecular variant of hairy cell leukemia with poor prognosis. AB - Hairy cell leukemia variant (HCLv), described 30 years ago, was reported to present with high disease burden and less often leukopenia, and later was reported to be resistant to purine analogs. Patients with HCLv were overrepresented among patients with HCL seeking relapsed/refractory trials. To compare clinical and molecular features of classic HCL (HCLc) and HCLv, 85 rearrangements expressing immunoglobulin variable heavy chain were sequenced, taken from 20 patients with HCLv and 62 with HCLc. The gene VH4-34, commonly used in autoimmune disorders, was found in eight patients (40%) with HCLv versus six (10%) with HCLc (p = 0.004). Ninety-three percent of the VH4-34 rearrangements were unmutated, defined as >98% homologous to the germline sequence. Clinical features of VH4-34+ patients that were similar to those with HCLv included higher white blood cell counts at diagnosis (p = 0.002) and lower response (p = 0.00001) and progression-free survival (p = 0.007) after first-line cladribine, and shorter overall survival from diagnosis (p < 0.0001). It was found that VH4-34 was independent from HCLv and a stronger predictor than HCLv in associating with poor prognosis. We conclude that VH4-34+ hairy cell leukemia, which only partly overlaps with HCLv, is associated with poor prognosis after single-agent cladribine. However, cases are observed which respond well to antibody therapy either alone or in combination with purine analog. PMID- 21599609 TI - Recombinant immunotoxins and other therapies for relapsed/refractory hairy cell leukemia. AB - Standard treatment for hairy cell leukemia (HCL) is markedly effective, but the constant decrease in disease-free survival, together with the presence of minimal residual disease (MRD), suggests that few if any are cured. HCL cells in MRD are always strongly CD20 + and CD22 + , and also CD25 + unless the patient has the poor-prognosis variant HCLv. To target relapsed/refractory HCL, immunotherapy has been developed using anti-CD25 and anti-CD22 recombinant immunotoxins, or the anti-CD20 monoclonal antibody (mAb) rituximab alone or combined with purine analogs. The recombinant immunotoxins contain an Fv fragment of a mAb fused to a truncated form of Pseudomonas exotoxin called PE38. BL22 targeting CD22, in phase I and II testing of relapsed/refractory HCL, achieved 47-61% complete remissions (CRs), several of them ongoing after 9-10 years. A completely reversible form of hemolytic uremic syndrome (HUS) was observed in 12% of patients, several of whom could later achieve a partial remission (PR) or CR with LMB-2 targeting CD25. A higher-affinity version of BL22, termed HA22, CAT-8015, or moxetumomab pasudotox, developed to more effectively treat other hematologic malignancies, also achieves CRs in HCL, and with only non-dose-limiting HUS. In separate randomized trials, rituximab is undergoing phase II testing with cladribine for early HCL and with bendamustine or pentostatin for multiply relapsed HCL. PMID- 21599611 TI - Stroke prediction using mean platelet volume in patients with atrial fibrillation. AB - Platelet size, measured as mean platelet volume (MPV), is associated with platelet reactivity. MPV has been identified as an independent risk factor for future stroke and myocardial infarction. The aim of this study was to determine the association of MPV with the development of stoke in patients with atrial fibrillation (AF). MPV, N-terminal pro B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) were analysed in 200 patients with AF (mean age 69 years; 56% male). The primary endpoint was ischaemic stroke event. The mean MPV was 8.5 +/- 1.0 fL and the median NT-proBNP was 1916.5 (IQR 810-4427) pg/mL. The median hsCRP was 0.47 (IQR 0.32-2.46) mg/dL. There were 14 stroke events during a mean of 15.1 months of follow up. Kaplan-Meier analysis revealed that the higher tertile MPV group (>=8.9 fL) had a significantly higher stroke rate compared to the lower tertile MPV group (<8.0 fL) (14.7% vs. 3.1%, log-rank: P = 0.01). A higher MPV was an independent predictor of stroke risk after adjusting for age, gender, and other CHADS(2) (congestive heart failure, hypertension, diabetes, and previous stroke or transient ischemic attack (TIA) history) score components (hazard ratio: 5.03, 95% CI 1.05-24.05, P = 0.043) in Cox proportional hazard analysis. When the MPV cut-off level was set to 8.85 fL using the receiver operating characteristic curve, the sensitivity was 71% and the specificity was 69% for differentiating between the group with stroke and the group without stroke. This value was more useful in patients with a low to intermediate traditional thromboembolic risk (CHADS(2) score <2). Furthermore, AF patients with an MPV over 8.85 fL had high stroke risk without anticoagulation, especially in the low thromboembolic risk group (Log-Rank <0.0001). The results of this study show that MPV was a predictive marker for stroke; its predictive power for stroke was independent of age, gender, and other CHADS(2) score components in patients with AF. These findings suggest that anticoagulation may be needed in patients with a high MPV, even if they have low to intermediate traditional thromboembolic risk (CHADS(2) score <2). PMID- 21599612 TI - Bleomycin, neocarzinostatin and ionising radiation-induced bystander effects in normal diploid human lung fibroblasts, bone marrow mesenchymal stem cells, lung adenocarcinoma cells and peripheral blood lymphocytes. AB - PURPOSE: To determine whether the bystander effects induced by chemotherapeutic agents are similar to those induced by ionising radiation and to analyse the cell dependency, if any, in different human cell types such as normal lung fibroblasts (WI-38), human bone marrow mesenchymal stem cells (hBMSC), lung adenocarcinoma (A 549, NCI-H23) and peripheral blood lymphocytes (PBL). MATERIALS AND METHODS: The cells mentioned above were exposed to two different concentrations of bleomycin (BLM) and neocarzinostatin (NCS) and to X-irradiation. Co-culture methodology was adopted to study the in vitro bystander effects. DNA damage was measured using a micronucleus (MN) assay as an endpoint to study the bystander response. High performance liquid chromatography (HPLC) was performed to rule out any residual activity of BLM and NCS. To further investigate if this bystander response is mediated through reactive oxygen species (ROS), the bystander cells were pretreated with dimethyl sulphoxide (DMSO), an ROS scavenger, and co-cultured with cells exposed to BLM. RESULTS: Bystander response was observed in all five types of human cells (WI-38, hBMSC, NCI-H23, A-549 and PBL) co-cultured with exposed cells. While all cell types showed a bystander response, undifferentiated hBMSC and PBL showed a higher magnitude of bystander response. A reduction in the MN frequency was observed in co-cultured hBMSC and PBL pretreated with DMSO. CONCLUSION: These results suggest that the chemotherapeutic agents, BLM and NCS, induce bystander response which is similar to that induced by radiation. Furthermore, it is observed that the bystander effect is independent of the cell type studied. Our results further support the involvement of ROS in mediating the bystander response induced by BLM. PMID- 21599613 TI - Development and evaluation of the Mandarin speech signal content on the acceptable noise level test in listeners with normal hearing in mainland China. AB - OBJECTIVE: To develop and evaluate the Mandarin speech signal content on the acceptable noise level (ANL) test in listeners with normal hearing in mainland China. DESIGN: The Mandarin ANL tests were conducted using three different sets of Mandarin running speech materials which were chosen from textbooks for primary school, secondary school, and high school, respectively. For each discourse, two ANL measurements were obtained and averaged for each experimental condition using ANL test procedures. STUDY SAMPLE: Thirty-one normal-hearing listeners participated in this study. RESULTS: There were significant differences for ANLs among the normal-hearing listeners, but no differences were found for MCLs and ANLs for the three sets of test materials. The Pearson correlations suggested significant correlations between MCL and ANL among the three test materials; also the results showed that the correlation coefficient between MCL-ANL of the primary material was much better than other two materials. CONCLUSIONS: (1) The contents of different Mandarin running speeches may not affect the acceptable noise level in Mandarin normal-hearing listeners; (2) The running speech selected from the primary school ought to be used as the Mandarin acceptable noise level test material to evaluate the outcomes of hearing aid fitting. PMID- 21599614 TI - Speech perception in noise: exploring the effect of linguistic context in children with and without auditory processing disorder. AB - OBJECTIVE: The objective of this study was to investigate whether the speech perception problems in noise of children with auditory processing disorder (APD) stem from an auditory or a higher order dysfunction. DESIGN: A repeated measures design comparing the sentence key word recognition scores of children with APD and a control group was used. Four sentence lists from the Test de phrases dans le bruit (TPB) were presented with a babble masker at four different signal-to noise ratios. The TPB is a Canadian French adaptation of the speech perception in noise test. STUDY SAMPLE: Ten participants between 9-12 years with APD participated in this study, as well as ten age- and gender-matched children with no sign of APD. RESULTS: Group analyses revealed that children with APD had poorer overall sentence key word recognition scores than the control group. Analysis of the difference scores between the high and low predictability sentences indicated that the benefit derived from linguistic context is similar between the groups. However, individual patterns of results revealed different profiles within the APD group. CONCLUSION: Further study using a larger sample is warranted to deepen our understanding of the nature of APD and identify characteristic profiles to enable better tailoring of therapeutic programs. PMID- 21599615 TI - Long-term effects of non-linear frequency compression for children with moderate hearing loss. AB - OBJECTIVE: To evaluate non-linear frequency compression (NLFC) as a means to improve speech recognition for children with moderate to moderately-severe hearing loss following a six-month acclimatization period. DESIGN: Within subject design with repeated measures across test conditions. STUDY SAMPLE: Fifteen children, ages 5 to 13 years, with moderate to moderately-severe high-frequency sensorineural hearing loss were fitted with Phonak Nios, micro-sized, BTE hearing aids and evaluated after two six-week intervals with and without NLFC and again after a six-month period of consecutive NLFC use. RESULTS: Using repeated measures analyses, the six-month results were compared to data that was collected following six-week trials with and without NLFC hearing aids (Wolfe et al, in press). Improvements seen with NLFC in the initial study (Wolfe et al, in press) were maintained or significantly increased in the present study. When compared to the six-week data, aided non-sense syllable speech recognition thresholds in quiet and speech recognition in noise were significantly better at the six-month interval. CONCLUSIONS: These results suggest that NLFC improves audibility for and recognition of high-frequency speech sounds for children with moderate to moderately-severe hearing loss. In many cases, improvements found with NLFC increased with a longer period of acclimatization to the technology. PMID- 21599616 TI - Toll-like receptors, inflammation, metabolism and obesity. AB - Obesity is a highly prevalent health problem in Western countries that leads to many important diseases such as type 2 diabetes and metabolic syndrome being now considered an inflammatory chronic disease. Adipocytes are no longer considered passive cells storing fat since they are major producers of inflammatory cytokines during obesity. Adipocytes and macrophages share many biological properties including the synthesis of similar molecules regulating inflammation. Fatty acid levels are elevated in obesity and induce inflammatory pathways by yet a mostly unknown mechanism, leading to the development of insulin and leptin resistance. Recent studies suggest that these effects could be mediated through the activation of toll-like receptors (TLR). TLR signalling pathways might contribute to the development of obesity-associated insulin resistance, thus representing a connection between innate immunity and metabolism. Here, we summarize the recent evidence for the important role that TLRs play in adipose tissue, obesity and insulin resistance. PMID- 21599617 TI - Investigational antibody drug conjugates for solid tumors. AB - INTRODUCTION: Despite the progress made in the past 20 years in understanding the molecular events leading to the formation of cancer, the success of targeted antitumor agents in solid tumors has lagged behind the scientific discoveries. The most difficult to treat patient segments are those with refractory solid tumors, resistant to standard chemotherapy, and novel therapeutic compounds with improved therapeutic indexes are needed. Antibody drug conjugates (ADCs) are poised to become an important class of cancer therapeutics, as evidenced by the promising objective response rates when administered as single agents to chemorefractory cancer patients. AREAS COVERED: The basic concept for ADCs is to combine the strengths of the two most successful classes of therapeutic compounds developed in oncology, the high selectivity of antibodies with the unrivaled potency of small molecules, with the goal to improve the therapeutic index. Currently, approximately 60 ADCs are being developed in oncology. Among them, about 20 are undergoing clinical testing, the majority of which are tubulin inhibitor-based immunoconjugates. Herein, we review ADCs targeting solid tumors, with the focus on 11 programs currently undergoing clinical development. EXPERT OPINION: Key challenges the ADC field is facing, including potency and safety, can be addressed effectively by introducing novel research concepts with transformational potential for ADC development. PMID- 21599618 TI - Oxidative stress in the vascular wall: a useful physiological process or a therapeutic target in vascular disease? PMID- 21599619 TI - The role of minocycline in ischemia-reperfusion injury: a comprehensive review of an old drug with new implications. AB - Minocycline is a semi-synthetic tetracycline that inhibits bacterial protein synthesis and hence is used for the treatment of many infectious diseases. Over the years, many other interesting properties of minocycline have been identified and been used to make patents which include anti-inflammatory, anti-apoptotic, matrix metalloproteinase inhibitor and free oxygen radical scavenger activity. Ischemia-reperfusion injury is a concern for almost every clinical specialty and minocycline seems to be an attractive cytoprotective agent that can ameliorate the damage due to these properties. Ischemia-reperfusion injury is a complex process and involves various pathways that lead to cell death. This review focuses on the body of evidence describing various proposed mechanisms of action of minocycline and its current experimental use in various animal models of ischemia-reperfusion injury. PMID- 21599620 TI - Why so few drug targets: a mathematical explanation? AB - The apparently paradoxical lack of correlation between the huge increase in the discovery of new potential drug targets made possible by the post-genomic sciences and new drugs development has stimulated many different interpretations. Here we illustrate the general principle of redundancy of biological pathways on hand of simplified mathematical approaches applied to different models of biological regulation. The simulation was based on the analysis of the 'degree of autonomy' of network architectures in which the possibility for an external stimulus (e.g. a drug) impinging into a specific node to be sensed by the entire network, and eventually amplified up to a macroscopic consequence, was demonstrated to be limited to strictly linear pathways. The implications of such a result for poly-pharmacology and computational approaches to drug development are described as well. PMID- 21599621 TI - Brave new world? Arrestin pathway bias in drug design. PMID- 21599622 TI - Lectin Microarray: A Powerful Tool for Glycan Related Biomarker Discovery. AB - Glycosylation is one of the most important posttranslational modification processes, which is regulated by a large number of enzymes. Cell surface, especially mammalian cell surface is heavily coated with glycans. Cell surface glycans are highly related to cell-cell communication, host-pathogen interaction, cell matrix interaction and etc. The aberrations of glycosylation, either intercellular or intracellular, usually indicate the onset of certain diseases, such as cancer and cancer metastasis, thus could be used as biomarkers. Lectin microarray, by far, is the most powerful technologies for high-throughput glycan profiling and comparison. It is highly suitable for both live cell and cell lysate analysis and has the potential for high-throughput, low-cost and fast discovery of glycan related biomarkers. In this review, we will focus on the basic concept and the latest advances of lectin microarray technology. We will emphasize the application of lectin microarrays for biomarker discovery. We will also discuss the challenges that lectin microarrays are facing and the possible future directions. We strongly believe that lectin microarrays will soon become an indispensible and invaluable tool for glycosylation related biomarker discovery. PMID- 21599623 TI - NMR experiments for the analysis of mixtures: beyond 1D 1H spectra. AB - State-of-the-art technologies and methodologies in NMR spectroscopy make it possible to obtain very informative and high-quality spectra in much less experimental time than classical methods by making better choices of NMR pulse sequences and acquisition parameters. This review presents some recent NMR methods allowing rapid identification, assignment and structural characterization of the components in mixtures. The relative merits of the different NMR pulse sequences are briefly discussed and recommendations are made for the preferred choice of sequences to obtain rapidly artifact-free data. This review covers diffusion experiments (DOSY), HSQC and HMBC experiments, ultra-resolved 2D spectra exploiting the property of aliasing and NOESY/ROESY experiments. It will be in particular shown that selective 1D NOESY/ROESY sequences can be more informative and reach higher resolution in less experimental time than the corresponding 2D sequences. PMID- 21599624 TI - Beyond Ugi and Passerini reactions: multicomponent approaches based on isocyanides and alkynes as an efficient tool for diversity oriented synthesis. AB - The reaction of isocyanides with electron deficient alkynes has been first reported in 1969, about ten years after the first reports on the famous Ugi four component reaction. However it took about thirty years to realise that the zwitterionic intermediate originating from interaction of the two species could be trapped by a third component, thus giving the start to a novel class of isocyanide-based multicomponent reactions. From that first report dated 1996 there has been an ongrowing interest that has produced, so far, about 150 distinct scientific papers. This review is aimed at rationalising and cathegorising these reports and at offering an overview of all the possible applications of this novel methodology. PMID- 21599625 TI - Quantitative structure-wavelength relationship modeling of porphin: derivative photosensitizers. AB - A linear quantitative structure-visible light absorption wavelength (lambda) relationship model for one hundred and forty-two photosensitizers was proposed using heuristic method and multiple linear regression analysis. The statistical parameters of the model were R2 = 0.916; F = 372.16; and RMSE = 5.0873. A fivefold cross-validation algorithm was applied, and the results indicated that the model has a satisfactory statistical stability and validity. The proposed model was evaluated for predictive ability with an external validation set, and the statistical parameters obtained were and R2EXT = 0.908; Q2EXT = 0.897; F = 118.14; and RMSEEXT = 5.6338 for the external test set. The results obtained demonstrated that the simple linear quantitative structure-wavelength relationship model was robust and satisfactory. It could be a feasible and effective tool for predicting lambda of photosensitizers, which is an important parameter for their effect on photodynamic therapy for cancer, and could be a potential way for instructing synthesis of this kind of new photosensitizers. PMID- 21599626 TI - Screening beta-fructofuranosidases mutant libraries to enhance the transglycosylation rates of beta-(2->6) fructooligosaccharides. AB - beta-Fructofuranosidases can divert their hydrolytic activity towards transglycosylation for the synthesis of high value-added products, including prebiotic fructooligosaccharides (FOS). A directed evolution strategy has been employed to enhance the transferase rate of the beta-fructofuranosidase (SoINV) from the Schwanniomyces occidentalis yeast for the production of beta-(2->6) linked FOS. To screen for transferase activity of the SoINV functionally expressed in Saccharomyces cerevisiae, a high-throughput screening protocol based on two colorimetric assays was validated (with coefficient of variance below 11%). Mutagenic libraries were constructed by error-prone PCR and clones showing higher glucose:fructose ratio with respect to the parental type were identified. Further analysis by anion-exchange chromatography coupled with pulsed amperometric detection helped to identify mutants with improved yields for the synthesis of beta-(2->6) fructooligosaccharides. Selected mutants displayed transferase initial rates enhanced ~2-fold over parent type, reaching production levels up to 47 g/L after 48 h of reaction for the formation of 6-kestose. PMID- 21599627 TI - Alternative medicine safety: Agaricus blazei and propolis. AB - All medicines pose a potential health risk, be they Eastern or Western medicines. Newly developed Western drugs must undergo rigorous testing to ensure their efficacy and safety, while with Eastern drugs, safety has generally been established because of their long histories of safe usage as traditional medicines. The regulation of Western medicines is much stronger than that of Eastern medicines, partly as pure chemicals are used and their effects and side effects are more likely to be acute. Eastern medicines consist of multiple components, generally extracted from a single or several plants or other natural sources, and their effects are not so acute, with delayed onset of side effects. However, the chronic usage of many Eastern medicines may result in the gradual accumulation of toxic compounds in the body. For example, Agaricus blazei extracts have been used as alternative medicines for cancer, but contain the known carcinogen agaritine (this carcinogen is also present in Agaricus bisporus). To ensure the safety of this alternative medicine, agaritine should be removed or its content reduced if the extract is to be taken chronically. Clearly, the safety of not only pure medicines, but also alternative medicines and daily foods, should be carefully controlled. PMID- 21599628 TI - Promising medications for cocaine dependence treatment. AB - Cocaine dependence is characterized by compulsive drug seeking and high vulnerability to relapse. Overall, cocaine remains one of the most used illicit drugs in the world. Given the difficulty of achieving sustained recovery, pharmacotherapy of cocaine addiction remains one of the most important clinical challenges. Recent advances in neurobiology, brain imaging and clinical trials suggest that certain medications show promise in the treatment of cocaine addiction. The pharmacotherapeutic approaches for cocaine dependence include medications able to target specific subtypes of dopamine receptors, affect different neurotransmitter systems (i.e. noradrenergic, serotonergic, cholinergic, glutamatergic, GABAergic and opioidergic pathways), and modulate neurological processes. The systematic reviews concerning the pharmacological treatment of cocaine dependence appear to indicate controversial findings and inconclusive results. The aim of future studies should be to identify the effective medications matching the specific needs of patients with specific characteristics, abandoning the strategies extended to the entire population of cocaine dependent patients. In the present review we summarize the current pharmacotherapeutic approaches to the treatment of cocaine dependence with a focus on the new patents. PMID- 21599629 TI - Molecular targeted therapy of hepatocellular carcinoma - results of the first clinical studies. AB - Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis and worldwide rising incidence during the last years. Although orthotopic liver transplatation, surgical resection and local destruction (alcohol or acetic acid and thermal ablation) are the only curative approaches, this can be accomplished in a minority of patients, since most of them present with advanced disease. In addition, those patients who have undergone curative treatment experience a high tumor recurrence rate. Non-resectable HCC is associated with a poor prognosis due to wide resistance to chemotherapeutic agents. It is therefore essential to search for new therapeutical approaches. After several years of preclinical research, the first clinical study data on molecular targeting therapy are now available for this tumor entity. Inhibitors of the epidermal growth factor receptor (EGFR) family, such as erlotinib and lapatinib were recently investigated. Furthermore, bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), sunitinib, a multiple kinase inhibitor that blocks several receptor tyrosine kinases, and sorafenib (BAY 43-9006), a multiple kinase inhibitor that blocks not only receptor tyrosine kinases but also serine/threonine kinases along the RAS/RAF/MEK/ERK pathway, were studied, as well. Until now, the only agent that has to be proven to be effective in terms of survival outcome in two phase III placebo-controlled studies is sorafenib, which became the current standard for palliative treatment. PMID- 21599630 TI - Novel approaches to target pancreatic cancer. AB - Despite remarkable progress that has been made in the recent years in the treatment of gastrointestinal tumors, in particular colorectal cancer, the prognosis of pancreatic cancer remains dismal. Five years after diagnosis almost all patients have died. At early stages of the disease surgery is the only modality to achieve long term survival. In the palliative setting gemcitabine confers some benefit to patients with advanced pancreatic cancer. A large number of chemotherapy combinations has been tested in patients with advanced pancreatic cancer. Only one combination showed significant improvement of survival, however also increased toxicity. The introduction of targeted therapies raised hopes for a better treatment of pancreatic cancer. However, most of the compounds tested so far failed to improve the survival of patients with pancreatic cancer. This review summarizes molecular targets examined so far in pancreatic cancer including matrix metalloproteinase inhibitors, farnesyltransferase inhibitors, vascular endothelial growth factor and epidermal growth factor receptor inhibitors and points out novel promising strategies for this difficult-to-treat tumor. PMID- 21599631 TI - Molecular targeted therapy of gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors (GIST) are mesenchymal tumors that occur predominantly in the stomach and the small bowel. Their pathogenesis is generally based on primary activating mutations in the KIT or PDGFRalpha genes that result in constitutive activation of receptor tyrosine kinase activity. Imatinib, first designed to competitively inhibit the ATP-binding pocket of the BCR-ABL tyrosin kinase exhibits inhibition also in the KIT and PDGFRalpha tyrosine kinases, which revolutionized the therapy of gastrointestinal stromal tumors, a disease without any systemic treatment options prior to imatinib. Clinical benefit is achieved in approximately 85% of patients with unresectable or metastatic disease with a median progression-free survival of 19 to 26 months and an overall survival approaching 5 years. Disease progression results from different mechanisms of resistance most frequently involving the emergence of secondary mutations in KIT exons 13, 14, or 17. Several newer drugs have been studied in patients failing or being intolerant to imatinib, including the multitargeted agent sunitinib as well as other KIT targeting tyrosine kinase inhibitors like nilotinib or agents targeting alternative pathways like anti-angiogenic agents, mTOR-, RAF kinase- and chaperone inhibitors. PMID- 21599632 TI - alpha(2)-Adrenoceptors enhance cell proliferation and mammary tumor growth acting through both the stroma and the tumor cells. AB - We have previously described enhanced human breast cancer cell proliferation and mouse mammary tumor growth induced by alpha(2)-adrenoceptor (alpha(2)-AR) expression in epithelial cells. The aim of the present work was to assess if stromal fibroblasts can contribute to this effect. alpha(2)-AR expression was assessed by immunocytochemistry and immunohistochemistry, cell proliferation by [(3)H]-Thymidine incorporation and tumor growth by measuring with caliper. All tested mouse and human fibroblasts expressed at least two alpha(2)-AR subtypes and alpha(2)-adrenergic agonists enhanced fibroblast proliferation. In vivo, the alpha(2)-adrenergic agonist clonidine significantly enhanced tumor growth. The alpha(2)-adrenergic antagonist rauwolscine reversed this effect, but when administered alone, significantly inhibited tumor growth. Clonidine significantly stimulated cell proliferation in the epithelial-enriched fraction, the cancer associated fibroblast-enriched fraction and the co-culture of both fractions in primary cultures from both tumors (IBH-4 and IBH-6). Rauwolscine reversed clonidine stimulation in every fraction. However, when incubated alone, the inhibitory effect was observed in fractions from IBH-4 tumors but not from IBH-6 tumors. These experiments show that fibroblasts from tumor stroma are also influenced by alpha(2)-adrenergic compounds through the alpha(2)-ARs expressed in these cells. Moreover, the alpha(2)-adrenergic antagonist rauwolscine could eventually block in both epithelial and stromal cells, the mitogenic effect of catecholamines released during stress, providing a potential additional treatment for breast cancer patients. Chemists synthesizing adrenergic compounds should consider their action in breast cancer patients. PMID- 21599633 TI - Polyisoprenylation potentiates the inhibition of polyisoprenylated methylated protein methyl esterase and the cell degenerative effects of sulfonyl fluorides. AB - The polyisoprenylation pathway incorporates a reversible step that metabolizes polyisoprenylated methylated proteins from the ester to the carboxylate form. Polyisoprenylated protein methyl transferase (PPMTase) catalyses the esterification whereas polyisoprenylated methylated protein methyl esterase (PMPMEase) hydrolyzes them. Significant changes in the balance between the two enzymes may alter polyisoprenylated protein function possibly resulting in disease. Previous studies show that PMPMEase is the serine hydrolase, Sus scrofa carboxylesterase. Its susceptibility to the nonspecific serine hydrolase inhibitor, phenylmethylsulfonyl fluoride (PMSF) paved the way for its use as a prototypical compound to design and synthesize a series of putative high affinity specific inhibitors of PMPMEase. Pseudo first-order kinetics revealed an over 680 fold increase in k(obs)/[I] values from PMSF (6 M(-1)-1s(-1)), S-phenyl (L-50, 180 M(-1)s(-1)), S-benzyl (L-51, 350 M(-1)s(-1)), S-trans, trans-farnesyl (L-28, 2000 M(-1)s(-1)), to S-trans-geranylated (L-23, 4100 M(-1)s(-1)) 2 thioethanesulfonyl fluorides. C10 S-alkyl substitution revealed a k(obs)/[I] value (1800 M(-1)s(-1)) that was 298 times greater than that for PMSF. The compounds induced the degeneration of human neuroblastoma SH-SY5Y cells with EC(50) values of 49, 130 and >1000 uM for L-28, L-23 and PMSF, respectively. The increased affinity with the polyisoprenyl derivatization is consistent with the observed substrate specificity and the reported hydrophobic nature of the active site. These results suggest that (1) PMPMEase is a key enzyme for polyisoprenylated protein metabolism, (2) regulation of its activity is essential for maintaining normal cell viability, (3) abnormal activities may be involved in degenerative diseases and cancers and (4) its specific inhibitors may be useful in combating cancers. PMID- 21599635 TI - Cellular and molecular effects of sirtuins in health and disease. AB - Sirtuins are NAD+-dependent protein deacetylases that are broadly conserved from bacteria to humans. Because sirtuins extend the lifespan of yeast, worms and flies, much attention has been paid to their mammalian homologues. Recent studies have revealed diverse physiological functions of sirtuins that are essentially similar to those of their yeast homologue, Sir2 (silent information regulator 2). Sirtuins are implicated in the pathology of many diseases, for which sirtuin activators such as resveratrol have great promise as potential treatments. In the present review, we describe the functions of sirtuins in cell survival, inflammation, energy metabolism, cancer and differentiation, and their impact on diseases. We also discuss the organ-specific functions of sirtuins, focusing on the brain and blood vessels. PMID- 21599636 TI - Hypobaric hypoxia preconditioning attenuates acute lung injury during high altitude exposure in rats via up-regulating heat-shock protein 70. AB - HHP (hypobaric hypoxia preconditioning) induces the overexpression of HSP70 (heat shock protein 70), as well as tolerance to cerebral ischaemia. In the present study, we hypothesized that HHP would protect against HAE (high-altitude exposure)-induced acute lung injury and oedema via promoting the expression of HSP70 in lungs prior to the onset of HAE. At 2 weeks after the start of HHP, animals were exposed to a simulated HAE of 6000 m in a hypobaric chamber for 24 h. Immediately after being returned to ambient pressure, the non-HHP animals had higher scores of alveolar oedema, neutrophil infiltration and haemorrhage, acute pleurisy (e.g. increased exudate volume, increased numbers of polymorphonuclear cells and increased lung myeloperoxidase activity), increased pro-inflammatory cytokines [e.g. TNF-alpha (tumour necrosis factor-alpha), IL (interleukin)-1beta and IL-6], and increased cellular ischaemia (i.e. glutamate and lactate/pyruvate ratio) and oxidative damage [glycerol, NOx (combined nitrate+nitrite) and 2,3 dihydroxybenzoic acid] markers in the BALF (bronchoalveolar fluid). HHP, in addition to inducing overexpression of HSP70 in the lungs, significantly attenuated HAE-induced pulmonary oedema, inflammation, and ischaemic and oxidative damage in the lungs. The beneficial effects of HHP in preventing the occurrence of HAE-induced pulmonary oedema, inflammation, and ischaemic and oxidative damage was reduced significantly by pretreatment with a neutralizing anti-HSP70 antibody. In conclusion, HHP may attenuate the occurrence of pulmonary oedema, inflammation, and ischaemic and oxidative damage caused by HAE in part via up-regulating HSP70 in the lungs. PMID- 21599634 TI - Myeloid-derived suppressor cells: general characteristics and relevance to clinical management of pancreatic cancer. AB - Recent studies describe a heterogeneous population of cells of the myeloid lineage, termed myeloid derived suppressor cells (MDSC), which are observed with increased prevalence in the peripheral blood and tumor microenvironment of cancer patients, including pancreatic cancer. Accumulation of MDSC in the peripheral circulation has been related to extent of disease, and correlates with stage. MDSC have primarily been implicated in promoting tumor growth by suppressing antitumor immunity. There is also compelling evidence MDSC are also involved in angiogenesis and metastatic spread. Two main subsets of MDSC have been identified in cancer patients: a monocytic subset, characterized by expression of CD14, and a granulocytic subset characterized by expression of CD15. Both subsets of MDSC actively suppress host immunity through a variety of mechanisms including production of reactive oxygen species and arginase. Just as in humans, accumulation of monocytic and granulocytic MDSC has been noted in the bone marrow, spleen, peripheral circulation, and tumors of tumor bearing mice. Successful targeting of MDSC in mice is associated with improved immune responses, delayed tumor growth, improved survival, and increased efficacy of vaccine therapy. By further elucidating mechanisms of MDSC recruitment and maintenance in the tumor environment, strategies could be developed to reverse immune tolerance to tumor. We discuss here what is currently known about MDSC as well as some potential strategies targeting MDSC in the context of our work on pancreatic cancer and recent literature. Due to the number of new reports on MDSC, the most pertinent ones have been selected. PMID- 21599638 TI - Recent advances in Membrane Biochemistry. AB - This Biochemical Society Annual Symposium on Recent Advances in Membrane Biochemistry was organized to bring together experts from across the spectrum of biomembrane disciplines from the biological to the biophysical/structural, with the intention of promoting interactions and collaborations across the field. We were keen that the potential for improving human health that stems from a deeper understanding of membrane structure/function should be acknowledged, especially in the light of the increasing numbers of membrane protein structures that continue to be made available to the biomembrane community. This foreword provides an idea of what was communicated in the various sessions and, we hope, gives an impression of the excitement generated by the speakers and delegates at this over-subscribed Symposium. PMID- 21599637 TI - Canonical Wnt signalling requires the BMP pathway to inhibit oligodendrocyte maturation. AB - OLs (oligodendrocytes) are the myelinating cells of the CNS (central nervous system), wrapping axons in conductive sheathes to ensure effective transmission of neural signals. The regulation of OL development, from precursor to mature myelinating cell, is controlled by a variety of inhibitory and inductive signalling factors. The dorsal spinal cord contains signals that inhibit OL development, possibly to prevent premature and ectopic precursor differentiation. The Wnt and BMP (bone morphogenic protein) signalling pathways have been identified as dorsal spinal cord signals with overlapping temporal activity, and both have similar inhibitory effects on OL differentiation. Both these pathways feature prominently in many developmental processes and demyelinating events after injury, and they are known to interact in complex inductive, inhibitive and synergistic manners in many developing systems. The interaction between BMP and Wnt signalling in OL development, however, has not been extensively explored. In the present study, we examine the relationship between the canonical Wnt and BMP pathways. We use pharmacological and genetic paradigms to show that both Wnt3a and BMP4 will inhibit OL differentiation in vitro. We also show that when the canonical BMP signalling pathway is blocked, neither Wnt3a nor BMP4 have inhibitory effects on OL differentiation. In contrast, abrogating the Wnt signalling pathway does not alter the actions of BMP4 treatment. Our results indicate that the BMP signalling pathway is necessary for the canonical Wnt signalling pathway to exert its effects on OL development, but not vice versa, suggesting that Wnt signals upstream of BMP. PMID- 21599639 TI - Endogenous ion channel complexes: the NMDA receptor. AB - Ionotropic receptors, including the NMDAR (N-methyl-D-aspartate receptor) mediate fast neurotransmission, neurodevelopment, neuronal excitability and learning. In the present article, the structure and function of the NMDAR is reviewed with the aim to condense our current understanding and highlight frontiers where important questions regarding the biology of this receptor remain unanswered. In the second part of the present review, new biochemical and genetic approaches for the investigation of ion channel receptor complexes will be discussed. PMID- 21599640 TI - Understanding the yeast host cell response to recombinant membrane protein production. AB - Membrane proteins are drug targets for a wide range of diseases. Having access to appropriate samples for further research underpins the pharmaceutical industry's strategy for developing new drugs. This is typically achieved by synthesizing a protein of interest in host cells that can be cultured on a large scale, allowing the isolation of the pure protein in quantities much higher than those found in the protein's native source. Yeast is a popular host as it is a eukaryote with similar synthetic machinery to that of the native human source cells of many proteins of interest, while also being quick, easy and cheap to grow and process. Even in these cells, the production of human membrane proteins can be plagued by low functional yields; we wish to understand why. We have identified molecular mechanisms and culture parameters underpinning high yields and have consolidated our findings to engineer improved yeast host strains. By relieving the bottlenecks to recombinant membrane protein production in yeast, we aim to contribute to the drug discovery pipeline, while providing insight into translational processes. PMID- 21599641 TI - Crystallizing membrane proteins for structure-function studies using lipidic mesophases. AB - The lipidic cubic phase method for crystallizing membrane proteins has posted some high-profile successes recently. This is especially true in the area of G protein-coupled receptors, with six new crystallographic structures emerging in the last 31/2 years. Slowly, it is becoming an accepted method with a proven record and convincing generality. However, it is not a method that is used in every membrane structural biology laboratory and that is unfortunate. The reluctance in adopting it is attributable, in part, to the anticipated difficulties associated with handling the sticky viscous cubic mesophase in which crystals grow. Harvesting and collecting diffraction data with the mesophase grown crystals is also viewed with some trepidation. It is acknowledged that there are challenges associated with the method. However, over the years, we have worked to make the method user-friendly. To this end, tools for handling the mesophase in the pico- to nano-litre volume range have been developed for efficient crystallization screening in manual and robotic modes. Glass crystallization plates have been built that provide unparalleled optical quality and sensitivity to nascent crystals. Lipid and precipitant screens have been implemented for a more rational approach to crystallogenesis, such that the method can now be applied to a wide variety of membrane protein types and sizes. In the present article, these assorted advances are outlined, along with a summary of the membrane proteins that have yielded to the method. The challenges that must be overcome to develop the method further are described. PMID- 21599642 TI - Sensing bilayer tension: bacterial mechanosensitive channels and their gating mechanisms. AB - Mechanosensitive channels sense and respond to changes in bilayer tension. In many respects, this is a unique property: the changes in membrane tension gate the channel, leading to the transient formation of open non-selective pores. Pore diameter is also high for the bacterial channels studied, MscS and MscL. Consequently, in cells, gating has severe consequences for energetics and homoeostasis, since membrane depolarization and modification of cytoplasmic ionic composition is an immediate consequence. Protection against disruption of cellular integrity, which is the function of the major channels, provides a strong evolutionary rationale for possession of such disruptive channels. The elegant crystal structures for these channels has opened the way to detailed investigations that combine molecular genetics with electrophysiology and studies of cellular behaviour. In the present article, the focus is primarily on the structure of MscS, the small mechanosensitive channel. The description of the structure is accompanied by discussion of the major sites of channel-lipid interaction and reasoned, but limited, speculation on the potential mechanisms of tension sensing leading to gating. PMID- 21599643 TI - The pumps that fuel a sperm's journey. AB - The sole purpose of a sperm cell is to carry genetic information from a male to a female egg. In order to accomplish this quest, the sperm cell must travel a long distance through a constantly changing environment. The success of this journey depends on membrane proteins that are uniquely expressed in sperm cells. One of these proteins is the alpha4 isoform of the sodium pump. This pump is optimized to cope with the ionic environment characteristic of the female reproductive tract, and its activity may be tightly coupled with secondary transporters that maintain cytoplasmic pH. Pharmacological inhibition of alpha4 is sufficient to inhibit sperm motility, and significant differences around the inhibitor-binding site compared with the ubiquitous alpha1 isoform, make alpha4 a feasible target in rational drug development. PMID- 21599644 TI - Membrane proteins: from bench to bits. AB - Membrane proteins currently receive a lot of attention, in large part thanks to a steady stream of high-resolution X-ray structures. Although the first few structures showed proteins composed of tightly packed bundles of very hydrophobic more or less straight transmembrane alpha-helices, we now know that helix-bundle membrane proteins can be both highly flexible and contain transmembrane segments that are neither very hydrophobic nor necessarily helical throughout their lengths. This raises questions regarding how membrane proteins are inserted into the membrane and fold in vivo, and also complicates life for bioinformaticians trying to predict membrane protein topology and structure. PMID- 21599645 TI - Unravelling the folding and stability of an ABC (ATP-binding cassette) transporter. AB - Prokaryotic importers from the large family of ABC (ATP-binding cassette) transporters comprise four separate subunits: two membrane-embedded and two cytoplasmic ATP-binding subunits. This modular construction makes them ideal candidates for studies of the intersubunit interactions of membrane protein complexes that contain both hydrophobic and hydrophilic subunits. In the present paper, we focus on the vitamin B12 importer of Escherichia coli, BtuCD, that contains two transmembrane BtuC subunits and two ATP-binding BtuD subunits. We have studied the factors that induce subunit dissociation and unfolding in vitro. The BtuCD complex remains intact in alcohol and mild detergents, but urea or SDS separate the BtuC and BtuD subunits, with 6 M urea causing 80% of BtuD to be removed from BtuCD. ATP is found to stabilize the complex as a result of its binding to the BtuD subunits. In the absence of ATP, low concentrations of urea (0.5-3 M) also induce some unfolding, with approximately 14% reduction in helicity in 3 M urea, whereas, in the presence of ATP, no changes are observed. Disassembly at the BtuD-BtuD dimeric interface in BtuCD can be achieved with smaller concentrations of urea (0.5-3 M) than that required to cause disassembly at the BtuC-BtuD transmission interface (3-8 M), suggesting a stronger interaction of the latter. The results also suggest that unfolding and disassociation of subunits appear to be coupled processes. Our work provides insights into the subunit interactions of an ABC transporter and lays the foundation for studies of the reassembly of BtuCD. PMID- 21599646 TI - Lipid-protein interactions. AB - Intrinsic membrane proteins are solvated by a shell of lipid molecules interacting with the membrane-penetrating surface of the protein; these lipid molecules are referred to as annular lipids. Lipid molecules are also found bound between transmembrane alpha-helices; these are referred to as non-annular lipids. Annular lipid binding constants depend on fatty acyl chain length, but the dependence is less than expected from models based on distortion of the lipid bilayer alone. This suggests that hydrophobic matching between a membrane protein and the surrounding lipid bilayer involves some distortion of the transmembrane alpha-helical bundle found in most membrane proteins, explaining the importance of bilayer thickness for membrane protein function. Annular lipid binding constants also depend on the structure of the polar headgroup region of the lipid, and hotspots for binding anionic lipids have been detected on some membrane proteins; binding of anionic lipid molecules to these hotspots can be functionally important. Binding of anionic lipids to non-annular sites on membrane proteins such as the potassium channel KcsA can also be important for function. It is argued that the packing preferences of the membrane-spanning alpha-helices in a membrane protein result in a structure that matches nicely with that of the surrounding lipid bilayer, so that lipid and protein can meet without either having to change very much. PMID- 21599647 TI - Lipid-protein interactions as determinants of membrane protein structure and function. AB - To determine how the lipid environment affects membrane protein structure and function, strains of Escherichia coli were developed in which normal phospholipid composition can be altered or foreign lipids can be introduced. The properties of LacY (lactose permease) were investigated as a function of lipid environment. Assembly of LacY in membranes lacking PE (phosphatidylethanolamine) results in misorientation of the N-terminal six-TM (transmembrane domain) helical bundle with loss of energy-dependent uphill transport and retention of energy independent downhill transport. Post-assembly introduction of PE results in nearly native orientation of TMs and restoration of uphill transport. Foreign lipids with no net charge can substitute for PE in supporting native LacY topology, but restoration of uphill transport is dependent on native topology and the proper folding of a solvent-exposed domain. Increasing the positive charge density of the cytoplasmically exposed surface of LacY counters TM misorientation in the absence of neutral lipids, demonstrating that charge interactions between these domains and the surface of the membrane bilayer are determinants of TM orientation. Therefore membrane protein organization or reorganization is determined either during initial assembly or post-insertionally through direct interactions between the protein and the lipid environment, which affects the topogenic potency of opposing charged residues as topological signals independent of the translocon. PMID- 21599648 TI - Mapping lipid and detergent molecules at the surface of membrane proteins. AB - Electron-density maps for the crystal structures of membrane proteins often show features suggesting binding of lipids and/or detergent molecules on the hydrophobic surface, but usually it is difficult to identify the bound molecules. In our studies, heavy-atom-labelled phospholipids and detergents have been used to unequivocally identify these binding sites at the surfaces of test membrane proteins, the reaction centres from Rhodobacter sphaeroides and Blastochloris viridis. The generality of this method is discussed in the present article. PMID- 21599649 TI - Improving cardiac Ca+2 transport into the sarcoplasmic reticulum in heart failure: lessons from the ubiquitous SERCA2b Ca+2 pump. AB - As a major Ca2+ pump in the sarcoplasmic reticulum of the cardiomyocyte, SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a) controls the relaxation and contraction of the cardiomyocyte. It is meticulously regulated by adapting its expression levels and affinity for Ca2+ ions to the physiological demand of the heart. Dysregulation of the SERCA2a activity entails poor cardiomyocyte contractility, resulting in heart failure. Conversely, improving cardiac SERCA2a activity, e.g. by boosting its expression level or by increasing its affinity for Ca2+, is a promising strategy to rescue contractile dysfunction of the failing heart. The structures of the related SERCA1a Ca2+ pump and the Na+/K+-ATPase of the plasma membrane exposed the pumping mechanism and conserved domain architecture of these ion pumps. However, how the Ca2+ affinity of SERCA2a is regulated at the molecular level remained unclear. A structural and functional analysis of the closely related SERCA2b Ca2+ pump, i.e. the housekeeping Ca2+ pump found in the endoplasmic reticulum and the only SERCA isoform characterized by a high Ca2+ affinity, aimed to fill this gap. We demonstrated the existence of a novel and highly conserved site on the SERCA2 pump mediating Ca2+ affinity regulation by the unique C-terminus of SERCA2b (2b-tail). It differs from the earlier-described target site of the affinity regulator phospholamban. Targeting this novel site may provide a new approach to improve SERCA2a function in the failing heart. Strikingly, the intramembrane interaction site of the 2b-tail in SERCA2b shares sequence and structural homology with the binding site of the beta subunit on the alpha Na+/K+-ATPase. Thus P-type ATPases seem to have developed related mechanisms of regulation, and it is a future challenge for us to discover these general principles of P-type regulation. PMID- 21599650 TI - A diversity of SERCA Ca2+ pump inhibitors. AB - The SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) is probably the most extensively studied membrane protein transporter. There is a vast array of diverse inhibitors for the Ca2+ pump, and many have proved significant in helping to elucidate both the mechanism of transport and gaining conformational structures. Some SERCA inhibitors such as thapsigargin have been used extensively as pharmacological tools to probe the roles of Ca2+ stores in Ca2+ signalling processes. Furthermore, some inhibitors have been implicated in the cause of diseases associated with endocrine disruption by environmental pollutants, whereas others are being developed as potential anticancer agents. The present review therefore aims to highlight some of the wide range of chemically diverse inhibitors that are known, their mechanisms of action and their binding location on the Ca2+ ATPase. Additionally, some ideas for the future development of more useful isoform-specific inhibitors and anticancer drugs are presented. PMID- 21599651 TI - The mitochondrial-encoded subunits of respiratory complex I (NADH:ubiquinone oxidoreductase): identifying residues important in mechanism and disease. AB - Complex I (NADH:ubiquinone oxidoreductase) is crucial to respiration in many aerobic organisms. The hydrophilic domain of complex I, containing nine or more redox cofactors, and comprising seven conserved core subunits, protrudes into the mitochondrial matrix or bacterial cytoplasm. The alpha-helical membrane-bound hydrophobic domain contains a further seven core subunits that are mitochondrial encoded in eukaryotes and named the ND subunits (ND1-ND6 and ND4L). Complex I couples the oxidation of NADH in the hydrophilic domain to ubiquinone reduction and proton translocation in the hydrophobic domain. Although the mechanisms of NADH oxidation and intramolecular electron transfer are increasingly well understood, the mechanisms of ubiquinone reduction and proton translocation remain only poorly defined. Recently, an alpha-helical model of the hydrophobic domain of bacterial complex I [Efremov, Baradaran and Sazanov (2010) Nature 465, 441-447] revealed how the 63 transmembrane helices of the seven core subunits are arranged, and thus laid a foundation for the interpretation of functional data and the formulation of mechanistic proposals. In the present paper, we aim to correlate information from sequence analyses, site-directed mutagenesis studies and mutations that have been linked to human diseases, with information from the recent structural model. Thus we aim to identify and discuss residues in the ND subunits of mammalian complex I which are important in catalysis and for maintaining the enzyme's structural and functional integrity. PMID- 21599652 TI - The choreography of multidrug export. AB - Multidrug transporters have a crucial role in causing the drug resistance that can arise in infectious micro-organisms and tumours. These integral membrane proteins mediate the export of a broad range of unrelated compounds from cells, including antibiotics and anticancer agents, thus reducing the concentration of these compounds to subtoxic levels in target cells. In spite of intensive research, it is not clear exactly how multidrug transporters work. The present review focuses on recent advancements in the biochemistry and structural biology of bacterial and human multidrug ABC (ATP-binding cassette) transporters. These advancements point to a common mechanism in which polyspecific drug-binding surfaces in the membrane domains are alternately exposed to the inside and outside surface of the membrane in response to the ATP-driven dimerization of nucleotide-binding domains and their dissociation following ATP hydrolysis. PMID- 21599653 TI - Surfactant-free purification of membrane proteins with intact native membrane environment. AB - In order to study the structure and function of a protein, it is generally required that the protein in question is purified away from all others. For soluble proteins, this process is greatly aided by the lack of any restriction on the free and independent diffusion of individual protein particles in three dimensions. This is not the case for membrane proteins, as the membrane itself forms a continuum that joins the proteins within the membrane with one another. It is therefore essential that the membrane is disrupted in order to allow separation and hence purification of membrane proteins. In the present review, we examine recent advances in the methods employed to separate membrane proteins before purification. These approaches move away from solubilization methods based on the use of small surfactants, which have been shown to suffer from significant practical problems. Instead, the present review focuses on methods that stem from the field of nanotechnology and use a range of reagents that fragment the membrane into nanometre-scale particles containing the protein complete with the local membrane environment. In particular, we examine a method employing the amphipathic polymer poly(styrene-co-maleic acid), which is able to reversibly encapsulate the membrane protein in a 10 nm disc-like structure ideally suited to purification and further biochemical study. PMID- 21599654 TI - Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease. AB - AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic Abeta (amyloid beta-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between Abeta neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of Abeta. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of Abeta, which is consistent with the lack of any Abeta effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the Abeta-mediated inhibition on PMCA. PMID- 21599655 TI - The Plasmodium falciparum Ca(2+)-ATPase PfATP6: insensitive to artemisinin, but a potential drug target. AB - The disease malaria, caused by the parasite Plasmodium falciparum, remains one of the most important causes of morbidity and mortality in sub-Saharan Africa. In the absence of an efficient vaccine, the medical treatment of malaria is dependent on the use of drugs. Since artemisinin is a powerful anti-malarial drug which has been proposed to target a particular Ca2+-ATPase (PfATP6) in the parasite, it has been important to characterize the molecular properties of this enzyme. PfATP6 is a 139 kDa protein composed of 1228 amino acids with a 39% overall identity with rabbit SERCA1a (sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 1a). PfATP6 conserves all sequences and motifs that are important for the function and/or structure of a SERCA, such as two high-affinity Ca2+-binding sites, a nucleotide-binding site and a phosphorylation site. We have been successful in isolating PfATP6 after heterologous expression in yeast and affinity chromatography in a pure, active and stable detergent-solubilized form. With this preparation, we have characterized and compared with the eukaryotic SERCA1a isoform the substrate (Ca2+ and ATP) -dependency for PfATP6 activity as well as the specific inhibition/interaction of the protein with drugs. Our data fully confirm that PfATP6 is a SERCA, but with a distinct pharmacological profile: compared with SERCA1a, it has a lower affinity for thapsigargin and much higher affinity for cyclopiazonic acid. On the other hand, we were not able to demonstrate any inhibition by artemisinin and were also not able to monitor any binding of the drug to the isolated enzyme. Thus it is unlikely that PfATP6 plays an important role as a target for artemisinin in the parasite P. falciparum. PMID- 21599656 TI - Membrane microenvironment regulation of carnitine palmitoyltranferases I and II. AB - CPT (carnitine palmitoyltransferase) 1 and CPT2 regulate fatty acid oxidation. Recombinant rat CPT2 was isolated from the soluble fractions of bacterial extracts and expressed in Escherichia coli. The acyl-CoA chain-length-specificity of the recombinant CPT2 was identical with that of the purified enzyme from rat liver mitochondrial inner membranes. The Km for carnitine for both the mitochondrial preparation and the recombinant enzyme was identical. In isolated mitochondrial outer membranes, cardiolipin (diphosphatidylglycerol) increased CPT1 activity 4-fold and the Km for carnitine 6-fold. It decreased the Ki for malonyl-CoA inhibition 60-fold, but had no effect on the apparent Km for myristoyl-CoA. Cardiolipin also activated recombinant CPT2 almost 4-fold, whereas phosphatidylglycerol, phosphatidylserine and phosphatidylcholine activated the enzyme 3-, 2- and 2-fold respectively. Most of the recombinant CPT2 was found to have substantial interaction with cardiolipin. A model is proposed whereby cardiolipin may hold the fatty-acid-oxidizing enzymes in the active functional conformation between the mitochondrial inner and outer membranes in conjunction with the translocase and the acyl-CoA synthetase, thus combining all four enzymes into a functional unit. PMID- 21599657 TI - ZNF580, a novel C2H2 zinc-finger transcription factor, interacts with the TGF beta signal molecule Smad2. AB - ZNF580 (gene ID 51157), a novel gene encoding a C2H2 (Cys2-His2) zinc-finger transcription factor, may be involved in the maintenance of vascular endothelium homoeostasis. To investigate the physiological role of the transcription factor ZNF580, we screened human foetal brain cDNA library with a yeast two-hybrid system and identified 14 proteins that interact with ZNF580. The interaction between ZNF580 and Smad2 was confirmed by co-immunoprecipitation. Co-localization between endogenous ZNF580 and Smad2 was mainly found in the nuclei of EA.hy926 endothelial cells with immunofluorescence and confocal microscopy. Our results suggest that ZNF580 is a binding partner of Smad2 and is involved in the signal transduction of the TGF-beta (transforming growth factor-beta) signalling pathway, which provides a basis for additional research to investigate the role of ZNF580 in the maintenance of vascular endothelium homoeostasis and the onset of atherosclerotic diseases. PMID- 21599658 TI - Towards sustainable groundwater use: setting long-term goals, backcasting, and managing adaptively. AB - The sustainability of crucial earth resources, such as groundwater, is a critical issue. We consider groundwater sustainability a value-driven process of intra- and intergenerational equity that balances the environment, society, and economy. Synthesizing hydrogeological science and current sustainability concepts, we emphasize three sustainability approaches: setting multigenerational sustainability goals, backcasting, and managing adaptively. As most aquifer problems are long-term problems, we propose that multigenerational goals (50 to 100 years) for water quantity and quality that acknowledge the connections between groundwater, surface water, and ecosystems be set for many aquifers. The goals should be set by a watershed- or aquifer-based community in an inclusive and participatory manner. Policies for shorter time horizons should be developed by backcasting, and measures implemented through adaptive management to achieve the long-term goals. Two case histories illustrate the importance and complexity of a multigenerational perspective and adaptive management. These approaches could transform aquifer depletion and contamination to more sustainable groundwater use, providing groundwater for current and future generations while protecting ecological integrity and resilience. PMID- 21599659 TI - Human fetal hyoid body origin revisited. AB - The hyoid body is traditionally believed to have a dual origin from second and third arch mesenchyme, but this theory remains controversial. We examined paraffin-embedded sections from the hyoid region of 12 embryos and fetuses at 5-7 weeks of gestation (11-22 mm cranio-rump length). We found that the second (Reichert's cartilage) and third arch mesenchymal condensations did not reach the median area at the base of the tongue. Rather, a midline mesenchymal condensation was seen, and it separated from these arches at an early stage. This condensation was triangular and plate-like, and the cranial part was narrow between the bilateral Reichert's cartilages, while the caudal part was wide along the mediolateral axis between the bilateral primitive greater horns. We considered the midline mesenchymal condensation as the hyoid body anlage. At 7 weeks, a cartilaginous mass appeared in the midline condensation. The hypoglossal nerve changed its direction at the superolateral ends of the midline condensation. We propose that: (i) the hyoid body originates from the hypobranchial eminence via the midline condensation; (ii) the lesser horn originates from the caudal end of Reichert's cartilage; and (iii) the greater horn of the hyoid and the superior cornu of the thyroid cartilage originate from the third arch cartilage. The second and third arches may not regulate early hyoid body morphology. PMID- 21599660 TI - Ontogeny of the cranial skeleton in a Darwin's finch (Geospiza fortis). AB - Darwin's finches are a model system in ecological and evolutionary research, but surprisingly little is known about their skull morphology and development. Indeed, only the early beak development and external variation in adult beak shape has been studied. Understanding the development of the skull from embryo up to the adult is important to gain insights into how selection acts upon, and drives, variation in beak shape. Here, we provide a detailed description of the skeletal development of the skull in the medium ground finch (Geospiza fortis). Although the ossification sequence of the cranial elements is broadly similar to that observed for other birds, some differences can be observed. Unexpectedly, our data show that large changes in skull shape take place between the nestling and the juvenile phases. The reorientation of the beak, the orbit and the formation of well-developed processes and cristae suggest that these changes are likely related to the use of the beak after leaving the nest. This suggests that the active use of the jaw muscles during seed cracking plays an important role in shaping the adult skull morphology and may be driving some of the intra-specific variation observed in species such as G. fortis. Investigating the development of the jaw muscles and their interaction with the observed ossification and formation of the skull and lower jaw would allow further insights into the ecology and evolution of beak morphology in Darwin's finches. PMID- 21599661 TI - Development of the early axon scaffold in the rostral brain of the chick embryo. AB - The arrangement of the early nerve connections in the embryonic vertebrate brain follows a well-conserved pattern, forming the early axon scaffold. The early axon tracts have been described in a number of anamniote species and in mouse, but a detailed analysis in chick is lacking. We have used immunostaining, axon tracing and in situ hybridisation to analyse the development of the early axon scaffold in the embryonic chick brain in relation to the neuromeric organisation of the brain. The first tract to be formed is the medial longitudinal fascicle (MLF), shortly followed by the tract of the postoptic commissure to pioneer the ventral longitudinal tract system. The MLF was found to originate from three different populations of neurones located in the diencephalon. Neurones close to the dorsal midline of the mesencephalon establish the descending tract of the mesencephalic nucleus of the trigeminus. Their axons pioneer the lateral longitudinal tract. At later stages, the tract of the posterior commissure emerges in the caudal pretectum as the first transversal tract. It is formed by dorsally projecting axons from neurones located in the ventral pretectum, and by ventrally projecting axons from neurones located in the dorsal pretectum. The organisation of neurones and axons in the chick brain is similar to that described in the mouse, though tracts form in a different order and appear more clearly distinguished than in the mammalian model. PMID- 21599662 TI - The central projections of the laryngeal nerves in the rat. AB - The larynx serves respiratory, protective, and phonatory functions. The motor and sensory innervation to the larynx controlling these functions is provided by the superior laryngeal nerve (SLN) and the recurrent laryngeal nerve (RLN). Classical studies state that the SLN innervates the cricothyroid muscle and provides sensory innervation to the supraglottic cavity, whereas the RLN supplies motor innervation to the remaining intrinsic laryngeal muscles and sensory innervation to the infraglottic cavity, but recent data suggest a more complex anatomical and functional organisation. The current neuroanatomical tracing study was undertaken to provide a comprehensive description of the central brainstem connections of the axons within the SLN and the RLN, including those neurons that innervate the larynx. The study has been carried out in 41 adult male Sprague-Dawley rats. The central projections of the laryngeal nerves were labelled following application of biotinylated dextran amines onto the SLN, the RLN or both. The most remarkable result of the study is that in the rat the RLN does not contain any afferent axons from the larynx, in contrast to the pattern observed in many other species including man. The RLN supplied only special visceromotor innervation to the intrinsic muscles of the larynx from motoneurons in the nucleus ambiguus (Amb). All the afferent axons innervating the larynx are contained within the SLN, and reach the nucleus of the solitary tract. The SLN also contained secretomotor efferents originating from motoneurons in the dorsal motor nucleus of the vagus, and special visceral efferent fibres from the Amb. In conclusion, the present study shows that in the rat the innervation of the larynx differs in significant ways from that described in other species. PMID- 21599663 TI - Testing effects of consumer richness, evenness and body size on ecosystem functioning. AB - 1. Numerous studies have revealed (usually positive) relationships between biodiversity and ecosystem functioning (B-EF), but the underpinning drivers are rarely addressed explicitly, hindering the development of a more predictive understanding. 2. We developed a suite of statistical models (where we combined existing models with novel ones) to test for richness and evenness effects on detrital processing in freshwater microcosms. Instead of using consumer species as biodiversity units, we used two size classes within three species (six types). This allowed us to test for diversity effects and also to focus on the role of body size and biomass. 3. Our statistical models tested for (i) whether performance in polyculture was more than the sum of its parts (non-additive effects), (ii) the effects of specific type combinations (assemblage identity effects) and (iii) whether types behaved differently when their absolute or relative abundances were altered (e.g. because type abundance in polyculture was lower compared with monoculture). The latter point meant we did not need additional density treatments. 4. Process rates were independent of richness and evenness and all types performed in an additive fashion. The performance of a type was mainly driven by the consumers' metabolic requirements (connected to body size). On an assemblage level, biomass explained a large proportion of detrital processing rates. 5. We conclude that B-EF studies would benefit from widening their statistical approaches. Further, they need to consider biomass of species assemblages and whether biomass is comprised of small or large individuals, because even if all species are present in the same biomass, small species (or individuals) will perform better. PMID- 21599664 TI - The relationship between juvenile psychopathic traits, delinquency and (violent) recidivism: a meta-analysis. AB - A meta-analysis of k = 53 studies containing 60 non-overlapping samples and 10,073 participants was conducted to investigate whether psychopathy was associated with delinquency and (violent) recidivism in juveniles. The results showed that psychopathy was moderately associated with delinquency, general recidivism, and violent recidivism. Moderator effects revealed that various study and participant characteristics influenced the strength of the association between psychopathy, delinquency, and (violent) recidivism. It was concluded that screening for the (early) detection of psychopathy is important, as delinquent behavior and recidivism can be predicted from psychopathy as early as the transition from middle childhood to adolescence. PMID- 21599665 TI - Increasing axial resolution of 3D data sets using deconvolution algorithms. AB - Deconvolution algorithms are tools for the restoration of data degraded by blur and noise. An incorporation of regularization functions into the iterative form of reconstruction algorithms can improve the restoration performance and characteristics (e.g. noise and artefact handling). In this study, algorithms based on Richardson-Lucy deconvolution algorithm are tested. The ability of these algorithms to improve axial resolution of three-dimensional data sets is evaluated on model synthetic data. Finally, unregularized Richardson-Lucy algorithm is selected for the evaluation and reconstruction of three-dimensional chromosomal data sets of Drosophila melanogaster. Problems concerning the reconstruction process are discussed and further improvements are proposed. PMID- 21599666 TI - Autophagy deregulation in neurodegenerative diseases - recent advances and future perspectives. AB - Autophagy is an evolutionarily conserved homeostatic process for the turnover of cellular contents, organelles and misfolded proteins through the lysosomal machinery. Recently, the involvement of autophagy in the pathophysiology of neurodegenerative diseases has attracted considerable interest because autophagy deregulation has been linked to some of these neurodegenerative disorders. This interest is further heightened by the demonstration that various autophagic pathways, including macroautophagy and chaperone-mediated autophagy, are implicated in the turnover of proteins that are prone to aggregation in cellular or animal disease models. These observations have stimulated new awareness in the pivotal role of the autophagic pathways in neurodegenerative disease pathophysiology, and have sparked extensive research aimed at deciphering the mechanisms by which autophagy is altered in these disorders. Here, we summarize the latest advances in our understanding of the role of autophagy deregulation in Parkinson's, Alzheimer's and Huntington's disease. PMID- 21599667 TI - Protective effect of the octadecaneuropeptide on hydrogen peroxide-induced oxidative stress and cell death in cultured rat astrocytes. AB - Oxidative stress, resulting from accumulation of reactive oxygen species (ROS), plays a critical role on astrocyte death associated with neurodegenerative diseases. Astroglial cells produce endozepines, a family of biologically active peptides that have been implicated in cell protection. Thus, the purpose of the present study was to investigate the potential protective effect of one of the endozepines, the octadecaneuropeptide ODN, on hydrogen peroxide (H(2) O(2) ) induced oxidative stress and cell death in rat astrocytes. Incubation of cultured astrocytes with graded concentrations of H(2) O(2) for 1 h provoked a dose dependent reduction of the number of living cells as evaluated by lactate dehydrogenase assay. The cytotoxic effect of H(2) O(2) was associated with morphological modifications that were characteristic of apoptotic cell death. H(2) O(2) -treated cells exhibited high level of ROS associated with a reduction of both superoxide dismutases (SOD) and catalase activities. Pre-treatment of astrocytes with low concentrations of ODN dose-dependently prevented cell death induced by H(2) O(2) . This effect was accompanied by a marked attenuation of ROS accumulation, reduction of mitochondrial membrane potential and activation of caspase 3 activity. ODN stimulated SOD and catalase activities in a concentration dependent manner, and blocked H(2) O(2) -evoked inhibition of SOD and catalase activities. Blockers of SOD and catalase suppressed the effect of ODN on cell survival. Taken together, these data demonstrate for the first time that ODN is a potent protective agent that prevents oxidative stress-induced apoptotic cell death. PMID- 21599668 TI - Arabidopsis thaliana nucleosidase mutants provide new insights into nucleoside degradation. AB - A central step in nucleoside and nucleobase salvage pathways is the hydrolysis of nucleosides to their respective nucleobases. In plants this is solely accomplished by nucleosidases (EC 3.2.2.x). To elucidate the importance of nucleosidases for nucleoside degradation, general metabolism, and plant growth, thorough phenotypic and biochemical analyses were performed using Arabidopsis thaliana T-DNA insertion mutants lacking expression of the previously identified genes annotated as uridine ribohydrolases (URH1 and URH2). Comprehensive functional analyses of single and double mutants demonstrated that both isoforms are unimportant for seedling establishment and plant growth, while one participates in uridine degradation. Rather unexpectedly, nucleoside and nucleotide profiling and nucleosidase activity screening of soluble crude extracts revealed a deficiency of xanthosine and inosine hydrolysis in the single mutants, with substantial accumulation of xanthosine in one of them. Mixing of the two mutant extracts, and by in vitro activity reconstitution using a mixture of recombinant URH1 and URH2 proteins, both restored activity, thus providing biochemical evidence that at least these two isoforms are needed for inosine and xanthosine hydrolysis. This mutant study demonstrates the utility of in vivo systems for the examination of metabolic activities, with the discovery of the new substrate xanthosine and elucidation of a mechanism for expanding the nucleosidase substrate spectrum. PMID- 21599669 TI - Genetic and physiological analysis of the relationship between partial resistance to clubroot and tolerance to trehalose in Arabidopsis thaliana. AB - In Arabidopsis thaliana the induction of plant trehalase during clubroot disease was proposed to act as a defense mechanism in the susceptible accession Col-0, which could thereby cope with the accumulation of pathogen-synthesized trehalose. In the present study, we assessed trehalose activity and tolerance to trehalose in the clubroot partially resistant accession Bur-0. We compared both accessions for several trehalose-related physiological traits during clubroot infection. A quantitative trait loci (QTLs) analysis of tolerance to exogenous trehalose was also conducted on a Bur-0xCol-0 RIL progeny. Trehalase activity was not induced by clubroot in Bur-0 and the inhibition of trehalase by validamycin treatments resulted in the enhancement of clubroot symptoms only in Col-0. In pathogen-free cultures, Bur-0 showed less trehalose-induced toxicity symptoms than Col-0. A QTL analysis identified one locus involved in tolerance to trehalose overlapping the confidence interval of a QTL for resistance to Plasmodiophora brassicae. This colocalization was confirmed using heterogeneous inbred family (HIF) lines. Although not based on trehalose catabolism capacity, partial resistance to clubroot is to some extent related to the tolerance to trehalose accumulation in Bur-0. These findings support an original model where contrasting primary metabolism-related regulations could contribute to the partial resistance to a plant pathogen. PMID- 21599670 TI - Allopolyploid origins of the Galeopsis tetraploids--revisiting Muntzing's classical textbook example using molecular tools. AB - Whole-genome duplication coupled with hybridization is of prime importance in plant evolution. Here we reinvestigate Muntzing's classical example of allopolyploid speciation; the first report of experimental synthesis of a naturally occurring allopolyploid species, Galeopsis tetrahit. Various molecular markers (cpDNA, NRPA2, amplified fragment length polymorphisms (AFLPs)) and flow cytometry were surveyed in population samples of subgenus Galeopsis, including two allopolyploid species and their potential diploid parents. The presence of two divergent copies of single-copy NRPA2 confirms the allopolyploid origins of G. tetrahit and Galeopsis bifida. However, the two allopolyploids do not share the same maternal genome, as originally suggested by Muntzing. The results support independent origins, but not recurrent formation, of the two allotetraploids. Data further indicate frequent gene flow and introgression within ploidy levels, but less so between ploidy levels. Our results confirm and elaborate on Muntzing's classical conclusion about allopolyploid origins of G. tetrahit and G. bifida. We address questions of general interest within polyploidy research, such as recurrent formation, gene flow and introgression within and between ploidy levels. PMID- 21599671 TI - Processing of hematopoietic stem cells from peripheral blood before cryopreservation: use of a closed automated system. AB - BACKGROUND: Hematopoietic stem cell transplantation is commonly used to treat several oncohematologic diseases. The autologous hematopoietic progenitor cells collected through apheresis (HPC-A) must be cryopreserved and stored before use in vivo. Cell processing that precedes cryopreservation of HPC-A includes volume reduction aimed at reducing the amount of dimethyl sulfoxide used, as well as storage space. STUDY DESIGN AND METHODS: The aim of our study was to assess the effectiveness of volume reduction performed with an automated closed system, namely, the Sepax S100 cell separation device (Biosafe SA). A total of 165 procedures were carried out on concentrates collected from 104 adult and pediatric patients. As a control group, 30 HPC-A units processed according to the standard method (i.e., centrifugation at a speed of 850 * g for 10 minutes, followed by manual plasma reduction) were evaluated. RESULTS: The volume reduction obtained was 59% (range, 20.54%-84.21%; standard deviation [SD], +/- 12.19%), going from 236 mL (range, 100-443 mL; SD, +/- 80.41 mL) to 97 mL (range, 33.00-263.00 mL; SD, +/- 47.41 mL); recovery of nucleated cells was 90% (range, 64.84%-105.93%; SD, +/- 8.76%), while that of CD34+ cells was 91% (range, 59.30% 119.37%; SD, +/- 13.30%). These values did not differ from those obtained using the standard method. Automated processing required 20 minutes versus 40 minutes of manual processing. DISCUSSION: Our data demonstrate that volume reduction carried out with the Sepax S100 automated system was particularly effective; cell recovery was excellent and the time spent was short. Moreover, the closed system allows cell processing to be carried out in a contamination-controlled environment, in accordance with good manufacturing practice guidelines. PMID- 21599672 TI - Adjudicating bleeding events in a platelet dose study: impact on outcome results and challenges. AB - BACKGROUND: In the SToP platelet dose study, the World Health Organization (WHO) bleeding grade was assigned using adjudication. This study describes the challenges associated with adjudicating bleeding events and compares the adjudicated and bedside results for bleeding grade. STUDY DESIGN AND METHODS: To categorize bleeding, the following information was provided to adjudicators: daily bleeding assessments, interventions to stop or control bleeding, daily blood counts, and transfused blood components. Each daily assessment was sent to two adjudicators who independently assigned a grade and anatomic site of bleeding. Discordant cases where disagreement occurred were sent to a third adjudicator and subsequently to a fourth or fifth adjudicator in an attempt to reach agreement. Disagreement after five adjudicators was resolved by consensus. The final adjudicated grade was compared with the grade of bleeding assigned at the bedside by study personnel. RESULTS: A total of 1150 case report forms were adjudicated. Disagreement on grade of bleeding was common: 31.2% after the first two adjudicators, 4.0% after the third adjudicator, 0.7% after four, and 0.05% after five. Disagreement on anatomic site was less but still occurred in 17% of cases after two adjudicators. The frequency of bleeding (>= Grade 2) based on adjudication was higher than bedside grading (standard-dose arm, 47.5% vs. 34.4%; low-dose arm, 50.0% vs. 43.1%). CONCLUSION: The frequency of WHO bleeding varies depending on the method used to assign grade. Adjudication to assign bleeding grade resulted in significant disagreement when two adjudicators were used. PMID- 21599673 TI - Platelet refractoriness in acquired hemophagocytic syndrome. AB - BACKGROUND: Acquired hemophagocytic syndrome (AHPS) is a severe inflammatory disorder often caused by Epstein-Barr virus (EBV). Proliferation of activated macrophages produces uncontrolled cytokine production. Thrombocytopenia is common in AHPS, previously attributed to inadequate or ineffective marrow platelet (PLT) production. PLT transfusion response is not well reported. Two patients with fatal AHPS developed unexplained PLT transfusion refractoriness before definitive diagnosis. CASE REPORTS: PLT refractoriness was noted during the care of two patients. The refractoriness was determined to be nonimmune and both demonstrated various clinical signs and laboratory findings consistent with AHPS. The first patient's AHPS was attributable to EBV infection. In the other patient, no underlying cause could be found. Both patients had an aggressive clinical course and succumbed to this relatively rare syndrome. The PLT refractoriness was evident before the AHPS diagnosis was made. DISCUSSION: AHPS is not generally a consideration in the evaluation of nonimmune PLT refractoriness. However, these illustrative cases make an argument for its consideration in the differential diagnosis of PLT refractoriness in severely ill patients. Once present, it is unclear if the refractoriness can be reversed by AHPS-targeted therapy. PMID- 21599674 TI - Reliability of capillary hemoglobin screening under routine conditions. AB - BACKGROUND: Capillary hemoglobin (Hb) measurement before admission for whole blood donation is performed in many blood donation services, in spite of several studies reporting many donors with low Hb values being missed by capillary Hb screening. STUDY DESIGN AND METHODS: Predonation capillary and venous Hb levels of 9209 first-time donors presenting for whole blood donation were compared. Hb testing was conducted by photometric determination of finger-stick samples with a photometric method (Donor Checker, HemoCue) and using a hematology analyzer for venous samples. RESULTS: Both capillary and venous Hb measurements were available for 8910 donors (96.8%). The arithmetic mean deviation of the capillary Hb from the venous sample was +1.5 +/- 6.8 g/L, and the mean deviation was 5.4 +/- 4.5 g/L. In 7865 donors (88%), capillary and venous Hb values differed less than 10 g/L from each other, but in 86 donors (1.0%) the difference was at least 20 g/L, and in 10 donors (0.1%), even 30 g/L or more. In 93.3% of females and 98.7% of males, the categorization as having sufficient or too low Hb for blood donation was concordant between capillary and venous measurements. A total of 34.4% of donors with too low results of capillary Hb screening had sufficient venous Hb levels. Only one donor (0.01%) passed the capillary Hb screening despite venous Hb values below 110 g/L. CONCLUSION: The currently available methods for capillary Hb screening allow reliable determination of predonation Hb values under routine conditions. Additional venous Hb measurements in donors with too low capillary Hb values might reduce the rate of deferred donors by approximately one-third. PMID- 21599675 TI - In vivo neutralization of anti-A and successful transfusion of A antigen incompatible red blood cells in an animal model. AB - BACKGROUND: Our aim was to determine if the historical principle of Lewis glycolipid neutralization of antibody and subsequent Lewis-incompatible transfusion could be extended and applied to the ABO blood group system using synthetic glycolipid-like constructs. STUDY DESIGN AND METHODS: In vitro experiments with human blood and blood group A function-spacer-lipid constructs (FSL-A) were used to determine rates and concentrations that caused antigen transformation and anti-A neutralization. FSL-A constructs were intravenously infused into naive and anti-A-immunized mice to determine in vivo antigen transformation, anti-A inhibition, and tolerance to A antigen-incompatible transfusions (A+biotin kodecytes). RESULTS: FSL-A was able to cause in vivo transformation of circulating mouse cells into A antigen-positive cells (in vivo A kodecytes) without consequence in animals either with or without circulating anti-A. FSL-A was able to neutralize circulating anti-A and allow for successful transfusion of incompatible A kodecytes. In the absence of FSL-A neutralization incompatible cells were rapidly destroyed. CONCLUSIONS: FSL constructs have the potential to neutralize circulating antibodies and allow for, or mitigate, the consequences of ABO-incompatible red blood cell transfusion. PMID- 21599677 TI - Change... and a holiday? The 24th National Conference and Exhibition. PMID- 21599676 TI - Blood product positive patient identification: comparative simulation-based usability test of two commercial products. AB - BACKGROUND: The blood product administration process has been subject to various quality improvement initiatives aimed at reducing errors, including blood product labels that are missing, inaccessible, unreadable, or mismatched to orders and/or patients. This article reports the results of a formal simulation-based usability test of two comparable technologies designed to reduce blood product administration errors. STUDY DESIGN AND METHODS: Nineteen nurses and three anesthesia providers evaluated one of the two products during simulated use in realistic scenarios during 90-minute test sessions. Both products required additional learning despite 15 minutes of dedicated vendor-provided pretest training. RESULTS: There were significant effectiveness differences between the two products, but use of both devices was less efficient than manual checking. Usability issues included poor access to subtasks, lack of process feedback, inadequate error messaging, and confusing device interactions. CONCLUSION: While clinicians' subjective ratings of both devices were similarly high, both products had significant usability issues likely to lead to clinician frustration and workarounds during actual use. This study suggests that usability testing is a valuable and more effective method than preference surveys of determining the ability of blood administration products to meet clinicians' needs in the complex world of patient care. PMID- 21599678 TI - The Model of Children's Active Travel (M-CAT): a conceptual framework for examining factors influencing children's active travel. AB - BACKGROUND: The current decline in children's participation in physical activity has attracted the attention of those concerned with children's health and wellbeing. A sustainable approach to ensuring children engage in adequate amounts of physical activity is to support their involvement in incidental activity such as active travel (AT), which includes walking or riding a bicycle to or from local destinations, such as school or a park. Understanding how we can embed physical activity into children's everyday occupational roles is a way in which occupational therapists can contribute to this important health promotion agenda. AIMS: To present a simple, coherent and comprehensive framework as a means of examining factors influencing children's AT. METHODS: Based on current literature, this conceptual framework incorporates the observable environment, parents' perceptions and decisions regarding their children's AT, as well as children's own perceptions and decisions regarding AT within their family contexts across time. CONCLUSION: The Model of Children's Active Travel (M-CAT) highlights the complex and dynamic nature of factors impacting the decision making process of parents and children in relation to children's AT. The M-CAT offers a way forward for researchers to examine variables influencing active travel in a systematic manner. Future testing of the M-CAT will consolidate understanding of the factors underlying the decision-making process which occurs within families in the context of their communities. PMID- 21599679 TI - Dinnertime and bedtime routines and rituals in families with a young child with an autism spectrum disorder. AB - BACKGROUND/AIM: Routines are thought to be critical in laying the foundation for ritual development, and in turn rituals are considered important for forming a strong and healthy family unit. This article provides a description of the experiences of dinnertime and bedtime routines and rituals in Australian families with a young child with an Autism Spectrum Disorder (ASD), as well as common challenges experienced. METHODS: Fourteen Australian mothers with a young child with an ASD between the ages of two and five years were interviewed about their performance of dinnertime and bedtime routines and rituals and their perceptions of both occupations. Descriptive qualitative interviews were audio taped and transcribed. Transcripts were analysed using thematic content analysis. RESULTS: Two overarching themes emerged, including 'centred on ASD' and 'ASD alters meaning'. Mothers' descriptions revealed that families with a young child with an ASD experienced unstructured and chaotic routines at dinnertime. In contrast, bedtime involved the performance of more structured, and at times, non-functional routines. Moreover, dinnertime was bereft of meaningful interactions and rituals, whereas bedtime contained some positive meaningful interactions and rituals. CONCLUSIONS: Occupational therapists need to consider supporting mothers and the child with an ASD in enhancing their participation within all aspects of family life, by encouraging them to develop structured and more predictable dinnertime and bedtime routines inclusive of all family members. In doing so, this action will support mothers to develop a strong and cohesive family unit. PMID- 21599680 TI - Occupational therapy practice in Australia with people with dementia: a profile in need of change. AB - BACKGROUND/AIM: Dementia significantly impacts on the individual's and caregiver's quality of life. The aim of this study was to describe Australian occupational therapy practice with people with dementia. METHODS: A questionnaire was piloted and sent to occupational therapists in Australia working with people with dementia. Participants were recruited in one of three ways: (i) identified by OT AUSTRALIA as working in aged care; (ii) through dementia-specific facilities in Australia; or (iii) through occupational therapy aged care list serves. The questionnaire asked occupational therapists about referrals received, assessments and interventions used, perceived barriers to the delivery of interventions and perceived educational needs. Data were analysed descriptively and presented as frequencies and percentages. RESULTS: One hundred and thirty four occupational therapists responded to this survey. Referrals were predominantly for environmental modification, home assessment or falls prevention and for assessment of activities of daily living. Therapists spent most of their time on assessment, with brief cognitive and functional assessments used most frequently. The most common interventions were environmental modification advice and prescription of assistive equipment. Lack of time was the most commonly reported barrier to the delivery of interventions with therapists also identifying concerns about staffing and role restrictions imposed by organisations. Therapists also identified that further training in this area would be useful. CONCLUSIONS: Therapists working in dementia care indicated that they are constrained in terms of time, staffing and organisational restrictions. Recommendations include enhanced training, further research into the most viable occupational therapy interventions, and advocating for improved funding, staffing and resources. PMID- 21599681 TI - Meeting the needs of elderly with bathing disability. AB - BACKGROUND/AIMS: Difficulties with bathing are frequent among older people and are associated with an increasing need for societal support. As loss of independence has a negative impact on health and wellbeing, it is important to study interventions that can provide the required support for people to be able to remain independent. Occupational therapy interventions can improve clients' abilities enabling them to bathe themselves, thus reducing the need for other, more long-term societal support from, e.g. a home help. In this study, two groups of elderly people with difficulties in bathing were compared; the clients in the intervention group were engaged in occupational therapy. METHODS: A quasi experimental non-equivalent control group design was used, in which participants with reported difficulties in bathing were recruited consecutively from two municipalities. The clients in the intervention group routinely received occupational therapy, whereas clients in the control group received assistance from a home help for bathing. Activities of daily living, quality of life and home-help allocation were assessed at the baseline and after 15 weeks. RESULTS: Clients in the intervention group received less than three home visits on average, with majority of interventions consisting of graded activity and the use of an encouraging approach. Seventy per cent of the interventions were adaptive. Activities of daily living and quality of life of both groups improved, but the differences of being allocated a home help were significant. CONCLUSION: Occupational therapy interventions seem beneficial in terms of supporting older people in becoming independent of home help in bathing but the results must be interpreted with caution as there were differences at baseline between the groups. PMID- 21599682 TI - Survey of current pre-discharge home visiting practices of occupational therapists. AB - BACKGROUND/AIM: Discharge planning frequently involves occupational therapy pre discharge home visiting as one component of intervention. Pre-discharge home visits aim to maximise a person's functional performance within the context of their home and community environment, bridging the transition between hospital and home. The aim of this study was to describe the pre-discharge home visiting practices of occupational therapy departments. METHODS: This descriptive study used a postal survey which was sent to occupational therapists in 215 public and privately funded hospitals in New South Wales, Australia. The survey enquired about the number of pre-discharge home visits completed per month, who went on visits and time spent on visits. Descriptive statistics were used in analyses. RESULTS: Surveys were returned by occupational therapists from 53 departments, representing a response rate of 25%. Respondents estimated that they conducted approximately 13 pre-discharge home visits per month (range: 1-60). Visits were estimated to take an average of 1 hour and 20 minutes (excluding travel time). Approximately one-quarter of respondents felt that there was pressure to reduce the number of pre-discharge home visits conducted. Using their local hospital records, nine hospital departments estimated that the number of home visits completed per month had reduced by 50% compared with the number of home visits five years previously. DISCUSSION: Findings suggest a wide variation in current pre-discharge home visiting practice. There is a need for well-designed clinical trials that investigate the effectiveness of these costly and time-consuming visits on functional performance. PMID- 21599684 TI - Clinical utility of the four-quadrant model of facilitated learning: perspectives of experienced occupational therapists. AB - BACKGROUND/AIMS: This study explored perspectives of experienced occupational therapists regarding teaching-learning approaches used during intervention. The aim was to ascertain the clinical utility of the Four-Quadrant Model of Facilitated Learning (4QM) (Greber, Ziviani, & Rodger, 2007a) by understanding how it might enhance clinical competency when applying teaching-learning modalities. METHODS: Mixed methods were used to ascertain the perspectives of two groups of therapists with seven or more years experience in either adult (n=8) or paediatric (n=7) practice. A pre-discussion questionnaire was used to prime participants for an initial focus group centred on understanding how participants used teaching-learning within occupational therapy intervention. Following a brief description of the 4QM, a further session explored the perspectives of participants regarding the 4QM as a means of conceptualising and planning teaching-learning interventions. RESULTS: Irrespective of practice area, therapists considered teaching-learning approaches core to their practice, without necessarily identifying a clear process to guide their implementation. Proficiency in teaching-learning was generally seen to be gained through trial and error. Participants identified potential clinical applications for the 4QM as a useful structure to support the application of teaching-learning interventions, speculating that it would be particularly useful for novice clinicians. CONCLUSIONS: Participants endorsed the 4QM as a useful integrating framework to support the development of professional competencies related to planning interventions that use a teaching-learning approach. PMID- 21599683 TI - Evidence-based practice and research utilisation: perceived research knowledge, attitudes, practices and barriers among Australian paediatric occupational therapists. AB - BACKGROUND/AIM: Evidence-based practice (EBP) and research utilisation (RU) are promoted as ways for clients to receive the best level of care. However, limited research has evaluated the use of these approaches by occupational therapists. This study investigated the knowledge, attitudes, practices of and barriers to EBP and RU of a group of paediatric occupational therapists from Australia. METHODS: Questionnaires were received from 138 participants (response rate 46%) who completed the Research Knowledge, Attitudes and Practices of Research Survey, the Edmonton Research Orientation Survey and the Barriers to Research Utilisation Scale. RESULTS: The participants held positive attitudes towards research, and were willing to access new information to guide practice approaches. However, participants were less confident in their research knowledge and practices and implemented research findings into clinical practice. Multiple barriers to RU were perceived, particularly associated with the presentation and accessibility of research. Participants reported limited engagement in conducting research studies, although the majority of the participants reported implementing the findings of research into their clinical practice to some extent. CONCLUSION: Additional research education and support within organisations would be beneficial to ensure that children and families are receiving occupational therapy services that are based on sound, high-quality research evidence. The findings of this study provide insight into the perceived research knowledge, attitudes, practices of and barriers to Australian paediatric occupational therapists, enabling specific strategies to be implemented to increase the use of EBP and RU within the profession. PMID- 21599685 TI - What makes a quality occupational therapy practice placement? Students' and practice educators' perspectives. AB - BACKGROUND/AIM: Practice placement experiences are crucial to enable students to integrate theory with practice, demonstrate professional and interpersonal skills and build confidence in their practice skills. This study addressed practice educators' and students' perspectives regarding quality practice placement experiences. METHOD: In total 29 students, 41 practice educators and eight practice education staff members across three Queensland universities participated in focus groups or individual interviews (N=78) focusing on their views about quality learning experiences on placements. RESULTS: Key themes described university preparation and processes, a welcoming learning environment, detailed orientation and clear expectations, graded program of learning experiences, quality modelling and practice, consistent approach and expectations, quality feedback, open and honest relationships and supervisor experience and skills. These findings were consistent with research previously undertaken in Australia and Canada that had investigated either student or practice educator perspectives. CONCLUSIONS: This article synthesises the perspectives of these stakeholder groups and has led to the development of quality indicators across the phases of placement establishment, preparation, maintenance and review. Although having sufficient placements can be challenging for university programmes, ensuring that the experiences provided are of high quality is also important and requires significant attention by university academics and practice education staff, practice educators, managers and practice organisations alike. PMID- 21599686 TI - Reliability and validity of a measure of role functioning among people with psychiatric disabilities. AB - AIM: The aim was to investigate the reliability and validity of the Socially Valued Role Classification Scale (SRCS), a domain-specific measure of role functioning designed for use with community residents with psychiatric disabilities. Test-retest reliability, concurrent validity, face validity, consumer and clinician acceptability and utility were examined. METHODS: Sixty community residents with schizophrenia or schizoaffective disorder participated in this study where the SRCS was administered by telephone. RESULTS: Test-retest reliability showed good or very good agreement for subscale scores (intraclass correlations (ICCs): 0.78-0.89) and for items capturing amount of participation in domain-specific activities (ICC: 0.67-1.00). Greater variation was observed for items capturing assistance required with activities (kappa: 0.40-0.75), and standard of activities performed (kappa: 0.43-1.00). Concurrent validity was supported by moderate to very good associations in the directions expected. Face validity, user acceptability and utility in telephone interviews were adequate. CONCLUSIONS: These findings add to previous psychometric evidence and support the continued development of the SRCS for use in community mental health settings. The SRCS has promising utility for occupational therapists involved in psychiatric rehabilitation outcome measurement. PMID- 21599688 TI - Virtual reality stroke rehabilitation--hype or hope? PMID- 21599687 TI - Collaboration between occupational therapists and teachers: definitions, implementation and efficacy. AB - AIM: The aim of this article is to present a critical review of available health and education literature to ascertain how collaboration is defined, what the barriers to collaboration are, how effective collaboration between occupational therapists and teachers is, and to determine implications for research and future practice in Australia. METHODS: A comprehensive electronic search process was undertaken, identifying studies from health and education databases. Manual searching of reference lists was then conducted for retrieved articles. Studies were reviewed to determine quality and relevance to the review question. RESULTS: Nine research articles were reviewed, which included six qualitative and three quantitative articles. An additional seven discussion papers and three literature reviews were also included. It is apparent that the available literature is predominantly written about USA and UK contexts, and empirical evidence is limited. Definitions of collaboration differ, and although professionals agree that it is important to collaborate, the evidence of effectiveness is scant. CONCLUSIONS: Although there is much anecdotal desire for collaboration, empirical evidence is limited, but positive. Professionals express desire for collaboration, but the implementation appears inconsistent, and poorly researched. The literature outlines factors, which support collaboration in practice including interactional, organisational and systemic factors. Using this model, strategies for successful collaboration can be formulated. Results indicate a need for research into appropriate models of practice for an Australian context, and particularly for states, where the health and education systems are not well integrated. PMID- 21599689 TI - Stimulating the need for healthy critique in occupational therapy. PMID- 21599690 TI - The importance of scientific collecting and natural history museums for comparative neuroanatomy. AB - The comparative study of vertebrate brains is inherently dependent upon access to a sufficient number of species and specimens to perform meaningful comparisons. Although many studies rely on compiling published information, continued specimen collection, in addition to more extensive use of existing brain collections and natural history museums, are crucial for detailed neuroanatomical comparisons across species. This review highlights the importance of collecting species through a variety of means, details a marsupial brain collection, and stresses the potential of natural history museums as a resource for comparative neuroanatomy. By taking advantage of as many of these resources as possible, researchers can rapidly increase species coverage and generate a better understanding of how the brain evolves. PMID- 21599691 TI - The Zagreb Collection of human brains: a unique, versatile, but underexploited resource for the neuroscience community. AB - The Zagreb Collection of developing and adult human brains was founded in 1974 by Ivica Kostovic and consists of 1,278 developing and adult human brains, including 610 fetal, 317 children, and 359 adult brains. It is one of the largest collections of developing human brains. The collection serves as a key resource for many focused research projects and has led to several seminal contributions on mammalian cortical development, such as the discovery of the transient fetal subplate zone and of early bilaminar synaptogenesis in the embryonic and fetal human cerebral cortex, and the first description of growing afferent pathways in the human fetal telencephalon. The Zagreb Collection also serves as a core resource for ever-growing networks of international collaboration and represents the starting point for many young investigators who now pursue independent research careers at leading international institutions. The Zagreb Collection, however, remains underexploited owing to a lack of adequate funding in Croatia. Funding could establish an online catalog of the collection and modern virtual microscopy scanning methods to make the collection internationally more accessible. PMID- 21599693 TI - High-resolution digital brain atlases: a Hubble telescope for the brain. AB - We describe implementation of a method for digitizing at microscopic resolution brain tissue sections containing normal and experimental data and for making the content readily accessible online. Web-accessible brain atlases and virtual microscopes for online examination can be developed using existing computer and internet technologies. Resulting databases, made up of hierarchically organized, multiresolution images, enable rapid, seamless navigation through the vast image datasets generated by high-resolution scanning. Tools for visualization and annotation of virtual microscope slides enable remote and universal data sharing. Interactive visualization of a complete series of brain sections digitized at subneuronal levels of resolution offers fine grain and large-scale localization and quantification of many aspects of neural organization and structure. The method is straightforward and replicable; it can increase accessibility and facilitate sharing of neuroanatomical data. It provides an opportunity for capturing and preserving irreplaceable, archival neurohistological collections and making them available to all scientists in perpetuity, if resources could be obtained from hitherto uninterested agencies of scientific support. PMID- 21599692 TI - The Geneva brain collection. AB - The University of Geneva brain collection was founded at the beginning of the 20th century. Today, it consists of 10,154 formaldehyde- or buffered formaldehyde fixed brains obtained from the autopsies of the Department of Psychiatry and, since 1971, from the Department of Geriatrics. More than 100,000 paraffin embedded blocks and 200,000 histological slides have also been collected since 1901. From the time of its creation, this collection has served as an important resource for pathological studies and clinicopathological correlations, primarily in the field of dementing illnesses and brain aging research. These materials have permitted a number of original neuropathological observations, such as the classification of Pick's disease by Constantinidis, or the description of dyshoric angiopathy and laminar sclerosis by Morel. The large number of cases, including some very rare conditions, provides a unique resource and an opportunity for worldwide collaborations. PMID- 21599694 TI - Virtual endocasts: an application of computed tomography in the study of brain variation among hyenas. AB - Reliable brain volume measurements are crucial in identifying factors that influence the course of brain evolution. Here, we demonstrate the potential for using virtual endocasts (VEs) to examine inter- and intraspecific variation in brain volume in members of the family Hyaenidae. Total endocranial volume (adjusted for body size) and anterior cerebrum volume (adjusted for endocranial volume) were greater in the spotted hyena, the most gregarious of the species, than in the other hyaenids, all of which are less gregarious. An intraspecific analysis of spotted hyenas revealed that anterior cerebrum volume is significantly larger in males than females, although total endocranial volume does not differ between the sexes. Greater total endocranial and anterior cerebrum volume of spotted hyenas, relative to those of other hyena species, may be related to increased neural processing mediating cognitive demands associated with a complex social life. These data demonstrate that computed tomographic (CT) technology can be used to create VEs in species for which actual brains are rare or unavailable, and suggest that this approach can be applied systematically to explore intra- and interspecies brain variations in studies of brain evolution. PMID- 21599695 TI - Visualizing myeloarchitecture with magnetic resonance imaging in primates. AB - The pattern of myelination over the cerebral cortex, termed myeloarchitecture, is an established and often-used feature to visualize cortical organization with histology in a variety of primate species. In this paper, we use in vivo magnetic resonance imaging (MRI) and advanced image processing using surface rendering to visualize and characterize myeloarchitecture in a small nonhuman primate, the common marmoset (Callithrix jacchus). Through images made in four female adult marmosets, we produce a representative 3D map of marmoset myeloarchitecture and flatten and annotate this map to show the location and extent of a variety of major areas of the cortex, including the primary visual, auditory, and somatosensory areas. By treating our MRI data as a surface, we can measure the surface area of cortical areas, and we present these measurements here to summarize cortical organization in the marmoset. PMID- 21599697 TI - Brain collections at the National Museum of Health and Medicine. AB - Owing in large part to the foresight and efforts of Wally Welker, the National Museum of Health and Medicine has become a major repository for collections of brain specimens vital to the study of neurobehavioral evolution. From its origins in the Armed Forces Institute of Pathology, with the collection of largely pathological specimens assembled by Paul Yakovlev, the museum has added to its resources four additional extensive collections, largely consisting of specimens acquired specifically for comparative and evolutionary studies: Welker's collection from the University of Wisconsin-Madison, John I. Johnson's collection from Michigan State University, the Adolf Meyer Collection from the Johns Hopkins University, and the Elizabeth Crosby collections from the University of Michigan. We describe here the history and contents of each of these five collections, to inform the scientific field of the extent and details of these remarkable resources. PMID- 21599696 TI - The human brain: rewired and running hot. AB - The past two decades have witnessed tremendous advances in noninvasive and postmortem neuroscientific techniques, advances that have made it possible, for the first time, to compare in detail the organization of the human brain to that of other primates. Studies comparing humans to chimpanzees and other great apes reveal that human brain evolution was not merely a matter of enlargement, but involved changes at all levels of organization that have been examined. These include the cellular and laminar organization of cortical areas; the higher order organization of the cortex, as reflected in the expansion of association cortex (in absolute terms, as well as relative to primary areas); the distribution of long-distance cortical connections; and hemispheric asymmetry. Additionally, genetic differences between humans and other primates have proven to be more extensive than previously thought, raising the possibility that human brain evolution involved significant modifications of neurophysiology and cerebral energy metabolism. PMID- 21599698 TI - Diversity of spatial relationships of the claustrum and insula in branches of the mammalian radiation. AB - Using digital images of stained sections, we conducted a comparative survey of the visible gross morphology of the insular cortex and the claustrum in 26 mammalian species, representing most of the major mammalian radiations. We observed several features that are conserved in the mammals that we examined, including the absence of expansion of the insular cortex into out-branching lobes, the adherence of the claustrum to the fundus of the rhinal sulcus and to endopiriform cellular regions, and several features that varied, including the colocation of the insular and claustrocortex, the cortical origin of the operculations that cover the insula, the locations of large accumulations of claustral cells, and the presence of thin extensions of groups of claustral cells. We suggest that the final shape of the claustrum is highly influenced by the expansion of two medially adjacent subcortical structures, the striatum and amygdala. We further suggest that the neighboring locations of the claustrum and insula may be due to a dependence of each of these structures upon proximity to olfactory cortex, rather than to any connectional relationships between them. PMID- 21599699 TI - The C. U. Ariens Kappers brain collection. AB - The C. U. Ariens Kappers brain collection, at the Netherlands Institute for Neuroscience in Amsterdam, is one of the largest and oldest of the world's catalogued repositories of specimens that reveal the course of brain evolution and the resulting panoply of neural biodiversity. Established a century ago, it has served since then as the basis of the encyclopedic texts authored by its founder, as well as research publications into the current time. It consists of 726 specimens: these include 309 mammals, 134 birds, 81 reptiles, 21 amphibians, and 179 "pisces"--a grouping of bony fish, sharks, and cyclostomes. We present here accounts of the history and contents of this treasure trove of research materials. PMID- 21599700 TI - Collectibles and collections for comparative and evolutionary neurobiological research in Africa. AB - The scientific investigation of brains of different vertebrates, both extant and extinct, is of interest for several reasons: for translating medical research on rodent models into practice, for understanding the animals investigated in order to improve conservation and management strategies, and for understanding the evolution of the human brain. The African continent has vast resources that are incredibly valuable to this endeavor, including an enormous variety of extant species, as well as a rich fossil record covering human evolution and many aspects of vertebrate evolution. This paper briefly outlines the current situation in terms of collections in Africa, most of which are found in South Africa. It is hoped that these brief descriptions will increase international scientific interest in the available collections. PMID- 21599701 TI - Three brain collections for comparative neuroanatomy and neuroimaging. AB - In the context of increasing extinction rates and the potential loss of essential evolutionary biological and anthropological information, it is an important task to support efforts to prepare, preserve, and curate collections of histological brain sections; to disseminate information on such collections in the neuroscience community; and to make the collections publicly available. This review emphasizes the importance of complete, serially sectioned human brains of different ontogenetic stages as well as those of adult and old human individuals for neurobiological and medical research. Such histological sections enable microstructural analyses and anatomical evaluations of functional and structural neuroimaging data, for example, based on magnetic resonance imaging. Here, this review provides the first detailed and updated account of the content of the Stephan, Zilles, and Zilles-Amunts collections, which consist of serially sectioned and cell body- and myelin-stained histological preparations. Finally, this review will give an overview of past and recent research using these collections to increase our understanding of the detailed patterns of divergent brain evolution in primates as well as of the structural organization of the human brain. PMID- 21599703 TI - Time trends of contact allergy to a modified European baseline series in Beijing between 2001 and 2006. AB - BACKGROUND: Monitoring trends of sensitivity rates in a population is useful for epidemiological surveillance. The time trends for sensitivity rates of allergens have not previously been reported in China. OBJECTIVES: The aim of the present study was to determine the prevalence and trends of contact allergy in patients with suspected allergic contact dermatitis in Beijing, China. PATIENTS/METHODS: A retrospective analysis of all patch test data from our database was performed. A total of 1354 patients with suspected allergic contact dermatitis between 2001 and 2006 were studied. Patch tests with 20 allergens or mixtures of allergens were performed and analysed. RESULTS: Sensitivity to potassium dichromate (50.1%) was most frequent, and sensitivity to imidazolidinyl urea (3.0%) was least frequent. Increasing trends in sensitivity rates for 10 allergens with significant linear regression were observed (p < 0.05), including mercapto mix, black rubber mix, potassium dichromate, formaldehyde, epoxy resin, benzocaine, ethylenediamine dihydrochloride, paraben mix, tixocortol-21-pivalate, and sesquiterpene lactone mix. Sensitivity rates for the other 10 allergens remained stable or showed only a trend (fragrance mix) towards an increase (p(trend) > 0.05). CONCLUSIONS: High sensitivity rates were observed in the study. Significant increasing trends in sensitivity rates for 10 allergens, probably reflecting increasing changes in exposure, were found. PMID- 21599704 TI - Association between childhood asthma and ADHD symptoms in adolescence--a prospective population-based twin study. AB - BACKGROUND: Cross-sectional studies report a relationship between childhood asthma and attention-deficit hyperactivity disorder (ADHD) symptoms, but the mechanisms are yet unclear. Our objective was to investigate the longitudinal link between childhood asthma and the two dimensions of ADHD (hyperactivity impulsivity, HI, and inattention, IN) in adolescence. We also aimed to explore the genetic and environmental contributions and the impact of asthma medication. METHODS: Data on asthma, HI and IN, birth weight, socioeconomic status, zygosity, and medication were collected from the Swedish Medical Birth Register and through parental questionnaires at ages 8-9 and 13-14 years on 1480 Swedish twin pairs born 1985-1986. The association between asthma at age 8-9 and ADHD symptoms at age 13-14 was assessed with generalized estimating equations, and twin analyses to assess the genetic or environmental determinants were performed. RESULTS: Children with asthma at age 8-9 had an almost twofold increased risk of having one or more symptom of HI (OR 1.88, 95% CI 1.18-3.00) and a more than twofold increased risk to have three symptoms or more of HI (OR 2.73, 95% CI 1.49-5.00) at age 13-14, independent of asthma medication. For IN, no significant relationship was seen. Results from twin modeling indicate that 68% of the phenotypic correlation between asthma and HI (r=0.23, 0.04-0.37) was because of genetic influences. CONCLUSIONS: Our findings suggest that childhood asthma is associated with subsequent development of HI in early adolescence, which could be partly explained by genetic influences. Early strategies to identify children at risk may reduce burden of the disease in adolescence. PMID- 21599705 TI - Protein tyrosine phosphatase-22 (PTPN-22) polymorphism in the pathogenesis of chronic urticaria. PMID- 21599706 TI - Mechanisms of chemical-induced innate immunity in allergic contact dermatitis. AB - Allergic contact dermatitis (ACD) is one of the most prevalent occupational skin diseases and causes severe and long-lasting health problems in the case of chronification. It is initiated by an innate inflammatory immune response to skin contact with low molecular weight chemicals that results in the priming of chemical-specific, skin-homing CD8(+) Tc1/Tc17 and CD4(+) Th1/Th17 cells. Following this sensitization step, T lymphocytes infiltrate the inflamed skin upon challenge with the same chemical. The T cells then exert cytotoxic function and secrete inflammatory mediators to produce an eczematous skin reaction. The recent characterization of the mechanisms underlying the innate inflammatory response has revealed that contact allergens activate innate effector mechanisms and signalling pathways that are also involved in anti-infectious immunity. This emerging analogy implies infection as a potential trigger or amplifier of the sensitization to contact allergens. Moreover, new mechanistic insights into the induction of ACD identify potential targets for preventive and therapeutic intervention. We summarize here the latest findings in this area of research. PMID- 21599707 TI - C-shaped root canal system in mandibular second molars in a Chinese population evaluated by cone-beam computed tomography. AB - AIM: To evaluate the anatomical features of C-shaped canal systems in Chinese mandibular second molars by cone-beam computed tomography (CBCT). METHODOLOGY: A total of 608 patients of Chinese descent with healthy, well-developed mandibular second molars were enrolled. These patients were referred to the West China Hospital of Stomatology and required radiographic examination by CBCT as part of their routine dental treatment. Of the 608 examined CBCT images, 528 showed unilateral intact molars and 80 showed bilateral intact molars. Bilateral molar data were only used to analyse the distribution of unilateral and bilateral occurrences of C-shaped canals. The following in vivo CBCT observations were made: (i) frequency and type of root; (ii) frequency of C-shaped canals by gender, age and tooth position (left versus right); (iii) the classification of cross-sectional canal images of C-shaped canals; and (iv) unilateral and bilateral occurrences of C-shaped canals. RESULTS: Fused roots were present in 39% of molars. A C-shaped canal system was present in 39% of the teeth. This prevalence did not differ with gender, age and tooth position. Most (81%) of the C-shaped canals in individuals with bilateral molars were symmetrical. Most of the canals with uninterrupted 'C'-shapes appeared to divide into two or more canals towards the canal terminus. CONCLUSION: There was high prevalence of C shaped canals in the mandibular second molars of Chinese population. The canal systems varied considerably in their anatomical configuration. PMID- 21599708 TI - Clinical reproducibility of three electronic apex locators. AB - AIM: To compare the reproducibility of three electronic apex locators (EALs), Dentaport ZX, RomiApex A-15 and Raypex 5, under clinical conditions. METHODOLOGY: Forty-eight root canals of incisors, canines and premolars with or without radiographically confirmed periapical lesions required root canal treatment in 42 patients. In each root canal, all three EALs were used to determine the working length (WL) that was defined as the zero reading and indicated by 'Apex', '0.0' or 'red square' markings on the EAL display. A new K-file of the same size was used for each measurement. The file length was fixed with a rubber stop and measured to an accuracy of 0.01 mm. Measurements were undertaken by two calibrated operators. Differences in zero readings between the three EALs in the same root canal were statistically analysed using paired t-tests with the Bonferroni correction, Bland-Altman plot and Linn's concordance correlation coefficients at alpha = 0.05. RESULTS: Mean and standard deviation values measured by the three EALs showed no statistically significant differences. Identical readings by all three EALs were found in 10.4% of root canals. Forty three per cent of readings differed by less than +/- 0.5 mm and 31.3% exceeded a difference of +/- 1 mm. CONCLUSIONS: The clinical reproducibility of Dentaport ZX, RomiApex A-15 and Raypex 5 was confirmed with the majority of readings within the +/- 1.0 mm range. However, the small number of identical zero readings suggests that EALs are not reliable as the sole means of WL determination under clinical conditions. PMID- 21599710 TI - Does group identification facilitate or prevent collective guilt about past misdeeds? Resolving the paradox. AB - The influence of group identification on collective guilt and attitudes towards reparation was examined in the context of the Belgian colonization of Congo. People should experience collective emotions to the extent that being a member of the relevant group is part of their self-concept. Yet, the acknowledgement of ingroup responsibility for past misdeeds is particularly threatening for high identifiers and may lead to defensive reactions aimed at avoiding guilt. We therefore predicted, and found, a curvilinear effect of identification on collective guilt. Attitudes towards reparation of past wrongdoings were also assessed and yielded a linear trend: identification predicted less favourable attitudes towards reparation but this effect was marginally stronger as identification increased. PMID- 21599709 TI - New knowledge for old credences: asymmetric information search about in-group and out-group members. AB - Three experiments examined how people gather information on in-group and out group members. Previous studies have revealed that category-based expectancies bias the hypothesis-testing process towards confirmation through the use of asymmetric-confirming questions (which are queries where the replies supporting the prior expectancies are more informative than those falsifying them). However, to date there is no empirical investigation of the use of such a question-asking strategy in an intergroup context. In the present studies, participants were asked to produce (Study 1) or to choose (Studies 2 and 3) questions in order to investigate the presence of various traits in an in-group or an out-group member. Traits were manipulated by valence and typicality. The results revealed that category-based expectancies do not always lead to asymmetric-confirming testing: whereas participants tended to ask questions that confirmed positive in-group and negative out-group stereotypical attributes, they used a more symmetric strategy when testing for the presence of negative in-group or positive out-group traits. Moreover, Study 3 also revealed a moderation effect of in-group identification. The findings point to the role played by motivational factors associated with preserving a positive social identity. Possible consequences of these hypothesis testing processes in preserving a positive social identity for intergroup relations are discussed. PMID- 21599711 TI - Preventing disparities in alcohol screening and brief intervention: the need to move beyond primary care. AB - The alcohol treatment field has focused on promoting screening and brief intervention (SBI) in medically based settings, particularly primary care. In this Commentary, we consider the potential unintended consequences for disparities in access to care for alcohol problems. National data show significant racial/ethnic and socioeconomic differences in the rates at which at risk drinkers and persons with alcohol use disorders come into contact with primary care providers. This suggests that implementing SBI in mostly primary care settings could inadvertently widen the gap in alcohol-related health disparities. To ensure that all populations in need benefit from this evidence based treatment, SBI should be considered and adapted for a wider range of service venues, including Federally Qualified Health Centers and venues frequented by racial/ethnic minorities and the uninsured. PMID- 21599713 TI - Ethanol impairs differentiation of human adipocyte stromal cells in culture. AB - BACKGROUND: Bioinformatic resources suggest that adipose tissue expresses mRNAs for alcohol dehydrogenases (ADHs) and ALDH2, and epidemiological studies indicate that heavy alcohol use reduces adipose tissue mass. We therefore characterized the expression of alcohol metabolizing enzymes in human, rat and mouse adipose tissue, preadipocytes, and adipocytes, the ability of adipocytes to metabolize ethanol, and the effects of ethanol on differentiation of human adipose stromal cells (hASCs). METHODS: Adipose tissue, preadipocytes, and adipocytes were collected from rodents or from humans undergoing bariatric surgery. hASCs were differentiated in vitro using standard methods. Gene expression and cellular differentiation were analyzed by Western blotting, RT-PCR, and microscopy. RESULTS: Class I ADH was expressed in human > mouse > rat adipose tissue, whereas ALDH2 was high in all samples. ADH, catalase, and ALDH2 were induced during differentiation of hASCs. The presence of 50 mM ethanol markedly reduced the differentiation of hASCs; this effect was associated with inhibition of expression of transcription factors required for differentiation, but did not depend on the ability of the cells to metabolize ethanol. CONCLUSIONS: Human adipose tissue expresses alcohol oxidizing enzymes. The presence of ethanol at physiologically relevant concentrations inhibits differentiation of hASCs. Ethanol could alter adipose tissue biology, inducing a form of acquired lipodystrophy, which is consistent with epidemiological studies. PMID- 21599712 TI - Ethanol induces endoplasmic reticulum stress in the developing brain. AB - BACKGROUND: Ethanol exposure during brain development causes profound damages to the central nervous system (CNS). The underlying cellular/molecular mechanisms remain unclear. The endoplasmic reticulum (ER) is involved in posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress, which is characterized by translational attenuation, synthesis of ER chaperone proteins, and activation of transcription factors. Sustained ER stress ultimately leads to cell death. ER stress is implicated in various neurodegenerative processes. METHODS: Using a third trimester equivalent mouse model of ethanol exposure, we tested the hypothesis that ethanol induces ER stress in the developing brain. Seven-day-old C57BL/6 mice were acutely exposed to ethanol by subcutaneous injection and the expression of ER stress-inducible proteins (ERSIPs) and signaling pathways associated with ER stress were examined. RESULTS: Ethanol exposure significantly increased the expression of ERSIPs and activated signaling pathways associated with ER stress; these include ATF6, CHOP/GADD153, GRP78, and mesencephalic astrocyte-derived neurotrophic factor as well as the phosphorylation of IRE1alpha, eIF2alpha, PERK, and PKR. The ethanol-induced increase in ERSIPs occurred within 4 hours of ethanol injection, and levels of some ERSIPs remained elevated after 24 hours of ethanol exposure. Ethanol-induced increase in phosphorylated eIF2alpha, caspase-12, and CHOP was distributed in neurons of specific areas of the cerebral cortex, hippocampus, and thalamus. CONCLUSIONS: Our finding indicates that ethanol induces ER stress in immature neurons, providing novel insight into ethanol's detrimental effect on the developing CNS. PMID- 21599714 TI - Lmo genes regulate behavioral responses to ethanol in Drosophila melanogaster and the mouse. AB - BACKGROUND: Previous work from our laboratory demonstrated a role for the Drosophila Lim-only (dLmo) gene in regulating behavioral responses to cocaine. Herein, we examined whether dLmo influences the flies' sensitivity to ethanol's sedating effects. We also investigated whether 1 of the mammalian homologs of dLmo, Lmo3, is involved in behavioral responses to ethanol in mice. METHODS: To examine dLmo function in ethanol-induced sedation, mutant flies with reduced or increased dLmo expression were tested using the loss of righting (LOR) assay. To determine whether mouse Lmo3 regulates behavioral responses to ethanol, we generated transgenic mice expressing a short-hairpin RNA targeting Lmo3 for RNA interference-mediated knockdown by lentiviral infection of single cell embryos. Adult founder mice, expressing varying amounts of Lmo3 in the brain, were tested using ethanol loss-of-righting-reflex (LORR) and 2-bottle choice ethanol consumption assays. RESULTS: We found that in flies, reduced dLmo activity increased sensitivity to ethanol-induced sedation, whereas increased expression of dLmo led to increased resistance to ethanol-induced sedation. In mice, reduced levels of Lmo3 were correlated with increased sedation time in the LORR test and decreased ethanol consumption in the 2-bottle choice protocol. CONCLUSIONS: These data describe a novel and conserved role for Lmo genes in flies and mice in behavioral responses to ethanol. These studies also demonstrate the feasibility of rapidly translating findings from invertebrate systems to mammalian models of alcohol abuse by combining RNA interference in transgenic mice and behavioral testing. PMID- 21599715 TI - Greater discounting of delayed rewards in young adults with family histories of alcohol and drug use disorders: studies from the Oklahoma family health patterns project. AB - BACKGROUND: Increased discounting of delayed rewards may be a premorbid characteristic and possible risk factor for alcohol and other drug use disorders; however, previous studies have found no or minimal differences in delay discounting in individuals at risk for substance use disorders based on family history. It is possible that increased delay discounting may be more closely associated with antisocial traits, evident in a subset of individuals with positive family histories of alcohol and drug use disorders, and that previous studies were underpowered for detecting subtle to modest overall group differences. METHODS: In this study, we compared 143 young adults with family histories of alcohol and other drug use disorders (FH+) and 155 young adults with no such histories (FH-) on delay discounting and subsequently examined how delay discounting was related to antisocial traits and other selected psychological and demographic variables. RESULTS: The FH+ group discounted delayed rewards more than the FH- group. Subsequent analyses revealed that increased delay discounting was correlated with having more parents and grandparents with alcohol and drug use disorders, more antisocial traits, more depressive tendencies and lower IQs, and lower income. After controlling for all these relationships, more antisocial traits and lower IQ still predicted greater delay discounting, and subsequent analysis revealed that the greater delay discounting in the FH+ group was mediated by this group's greater number of individuals with antisocial traits. CONCLUSION: FH+ individuals who discount delayed rewards more may be at increased risk for developing alcohol and other drug use disorders; however, additional descriptive studies and longitudinal studies are needed. PMID- 21599717 TI - Dissociation between affective and cognitive empathy in alcoholism: a specific deficit for the emotional dimension. AB - BACKGROUND: Emotional impairments constitute a crucial and widely described dimension of alcoholism, but several affective abilities are still to be thoroughly explored among alcohol-dependent patients. This is particularly true for empathy, which constitutes an essential emotional competence for interpersonal relations and has been shown to be highly impaired in various psychiatric states. The present study aimed at exploring empathic abilities in alcoholism, and notably the hypothesis of a differential deficit between emotional and cognitive empathy. METHODS: Empathy abilities were evaluated among 30 recently detoxified inpatients diagnosed with alcohol dependence and 30 paired healthy controls, using highly validated questionnaires (Interpersonal Reactivity Index [J Pers Soc Psychol44:113] and Empathy Quotient [J Autism Dev Disord34:163]). Correlational analyses were performed to evaluate the links between empathy scores and psychopathological measures (i.e., depression, anxiety, interpersonal problems, and alexithymia). RESULTS: When psychiatric comorbities are controlled for, alcoholism is not associated with a general empathy deficit, but rather with a dissociated pattern combining impaired emotional empathy and preserved cognitive one. Moreover, this emotional empathy deficit is not associated with depression or anxiety scores, but is negatively correlated with alexithymia and the severity of interpersonal problems. CONCLUSIONS: At the theoretical level, this first observation of a specific deficit for emotional empathy in alcoholism, combined with the exact inverse pattern observed in other psychiatric populations, leads to a double dissociation, which supports the notion that emotional and cognitive empathy are 2 distinct abilities. At the clinical level, this deficit calls for considering emotional empathy rehabilitation as a crucial concern in psychotherapy. PMID- 21599716 TI - Age differences in the expression of acute and chronic tolerance to ethanol in male and female rats. AB - BACKGROUND: Ontogenetic differences in response to ethanol (EtOH) challenge have been observed under a variety of circumstances, including varying reports of developmental differences in the expression of tolerance to EtOH. The purpose of the present experiment was to further explore potential differences in acute (AT) and chronic (CT) tolerance expression between adolescent and adult, male and female Sprague-Dawley rats, using the social interaction test. METHODS: AT and CT to the social suppressing effects of a moderate dose of EtOH was assessed in adolescent and adult rats following intraperitoneal injections of 2.0 g/kg EtOH or saline daily for 10 days. At test, adults and adolescents were challenged with 1.0 or 1.25 g/kg EtOH, respectively, with AT and CT assessed at 5 and 25 minutes postinjection using ratios of impairment to brain ethanol concentrations (BrECs) at each time period (CT) and within-session declines in impairment relative to BrECs (AT). RESULTS: In adolescents, 10 days of EtOH pre-exposure resulted in evidence of CT at 25 minutes postinjection, perhaps associated with an enhanced expression of AT. Among adults, signs of CT were seen at 5 minutes postinjection in adults, and may reflect neuroadaptations unassociated with AT, as with evidence of tolerance emerging only in adult control animals repeatedly exposed to saline injection prior to EtOH challenge on test day. Sex differences in tolerance expression were not observed at either age. CONCLUSIONS: Our results show ontogenetic differences between adolescents and adults in the short- and long-term neuroadaptations that they express in response to repeated perturbations with EtOH. Together these findings add age of exposure and time of testing within the intoxication period as critical variables to be considered when exploring the complex relationship between AT and CT. PMID- 21599718 TI - Effects of alcoholism and continued abstinence on brain volumes in both genders. AB - BACKGROUND: Alcohol abuse has detrimental effects on cerebral function, metabolism, and volume. Some of these effects were found to be at least partially reversible with continued abstinence. Furthermore, it has been reported that there are different effects of alcohol on brain volumes for women compared with men, but the results concerning the interaction between alcohol dependence and gender are inconsistent. With this study, we aimed to further investigate this question by examining the global gray matter (GM) and white matter (WM) changes as well as regional and local GM changes detected by voxel-based morphometry (VBM) in male and female alcoholic patients a few weeks after detoxification and the corresponding changes in a subgroup of these patients 3 months later. METHODS: A total of 50 patients, consecutively admitted for alcohol withdrawal treatment, participated in this study and were followed up for at least 3 months into abstinence. High-resolution structural images were processed with SPM8 using an optimized VBM protocol. RESULTS: Global cerebrospinal fluid (CSF) volume was increased and WM and GM volume decreased equally in male and female patients. A gender by diagnosis interaction was found neither for global nor for regional volumes or VBM data. VBM whole brain analysis yielded a significant GM volume loss in the patient group in the cingulate gyrus and the insula in both hemispheres. Region of interest analysis for the initial and 3 months follow-up scans yielded significant gains in regional volumes, particularly the cingulate gyrus and the insula in the group of abstinent patients, whereas no volume change at all is found in the patients who had relapsed. CONCLUSIONS: Our study confirms widespread cerebral volume loss in recently detoxified alcoholics. The effects of alcohol dependence seem to have equally adverse effects on brain morphometry in males and females. PMID- 21599720 TI - Potential mechanisms for muscle-powered cardiac support. AB - Biomechanical actuation of an implanted ventricular assist device (VAD) is an attractive means of providing long-term circulatory support. Studies show that energy from electrically stimulated skeletal muscle can, in principle, be used to provide tether-free cardiac assistance without the need for percutaneous drivelines or bulky energy transmission hardware. A mechanical prosthesis designed to harness the contractile power of in situ skeletal muscle has been developed in this laboratory that collects energy from the latissimus dorsi muscle and transmits it in the form of hydraulic power. In order to use this technique to pump blood however, a practical means to deliver this energy to the bloodstream must be devised. Presented here are six prospective mechanisms designed to accomplish this task, five of which also eliminate blood contacting surfaces that often lead to thromboembolic complications in chronic VAD patients. PMID- 21599719 TI - Alcohol and maternal uterine vascular adaptations during pregnancy-part I: effects of chronic in vitro binge-like alcohol on uterine endothelial nitric oxide system and function. AB - BACKGROUND: Pregnancy-induced utero-placental growth, angiogenic remodeling, and enhanced vasodilation are all partly regulated by estradiol-17beta-mediated activation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production. However, very little is known about the effects of alcohol on these maternal utero-placental vascular adaptations during pregnancy and its potential role in the pathogenesis of fetal alcohol spectrum disorders (FASDs). In this study, we hypothesized that in vitro chronic binge-like alcohol will decrease uterine arterial endothelial eNOS expression and alter its multisite phosphorylation activity state via disruption of AKT signaling. To study the direct effects of alcohol on uterine vascular adaptations, we further investigated the effects of alcohol on estradiol-17beta-induced uterine angiogenesis in vitro. METHODS: Uterine artery endothelial cells were isolated from pregnant ewes (gestational day 120 to 130; term = 147), fluorescence activated cell sorted, validated, and maintained in culture to passage 4. To mimic maternal binge drinking patterns, cells were cultured in the absence or presence of a lower (LD) or higher dose (HD) of alcohol in a compensating sealed humidified chamber system equilibrated with aqueous alcohol for 3 hours on 3 consecutive days. Immunoblotting was performed to assess expression of NO system associated proteins and eNOS multi-site phosphorylation. Following this treatment paradigm, control and binge alcohol-treated cells were passaged, grown for 2 days, and then treated with increasing concentrations of estradiol-17beta (0.1, 1, 10, 100 nM) in the absence or presence of LD or HD alcohol to evaluate estradiol-17beta-induced angiogenesis index using BrdU proliferation assay. RESULTS: LD and HD binge-like alcohol decreased uterine arterial eNOS expression (p = 0.009). eNOS multisite phosphorylation activation state was altered: P(635) eNOS was decreased (p = 0.017), P(1177) eNOS was not altered, and P(495) eNOS exhibited an inverse U-shaped dose-dependent relationship with alcohol. LD and HD alcohol decreased the major eNOS-associated protein cav-1 (p < 0.001). However, the commonly implicated AKT pathway did not correlate with eNOS posttranslational modifications. Assessment of uterine vascular adaptation via angiogenesis demonstrated that alcohol abrogated the dose-dependent proliferative effects of estradiol-17beta and thus blunted angiogenesis. CONCLUSIONS: Thus, the maternal uterine vasculature during pregnancy may be vulnerable to chronic binge-like alcohol. Altered eNOS multisite phosphorylation also suggests that alcohol produces specific effects at the level of posttranslational modifications critical for pregnancy-induced uterine vascular adaptations. Finally, the alcohol and estradiol-17beta data suggest a negative impact of alcohol on estrogen actions on the uterine vasculature. PMID- 21599721 TI - A colorimetric assay of 1-aminocyclopropane-1-carboxylate (ACC) based on ninhydrin reaction for rapid screening of bacteria containing ACC deaminase. AB - AIMS: 1-Aminocyclopropane-1-carboxylate (ACC) deaminase activity is an efficient marker for bacteria to promote plant growth by lowering ethylene levels in plants. We aim to develop a method for rapidly screening bacteria containing ACC deaminase, based on a colorimetric ninhydrin assay of ACC. METHODS AND RESULTS: A reliable colorimetric ninhydrin assay was developed to quantify ACC using heat resistant polypropylene chimney-top 96-well PCR plates, having the wells evenly heated in boiling water, preventing accidental contamination from boiling water and limiting evaporation. With this method to measure bacterial consumption of ACC, 44 ACC-utilizing bacterial isolates were rapidly screened out from 311 bacterial isolates that were able to grow on minimal media containing ACC as the sole nitrogen source. The 44 ACC-utilizing bacterial isolates showed ACC deaminase activities and belonged to the genus Burkholderia, Pseudomonas or Herbaspirillum. CONCLUSIONS: Determination of bacterial ACC consumption by the PCR-plate ninhydrin-ACC assay is a rapid and efficient method for screening bacteria containing ACC deaminase from a large number of bacterial isolates. SIGNIFICANCE AND IMPACT OF THE STUDY: The PCR-plate ninhydrin-ACC assay extends the utility of the ninhydrin reaction and enables a rapid screening of bacteria containing ACC deaminase from large numbers of bacterial isolates. PMID- 21599722 TI - Genotype of the LMNA 1908C>T variant is associated with generalized obesity in Asian Indians in North India. AB - OBJECTIVE: To determine the frequency distribution of LMNA 1908C>T SNP and its association with generalized obesity, abdominal obesity and coexistent metabolic disorders in nondiabetic Asian Indians living in a metropolitan city of north India. DESIGN: A cross-sectional population-based study of LMNA 1908C>T polymorphism with obesity and insulin resistance as outcome. PATIENTS: Five hundred and fifty-one Asian Indians, with 240 obese and 289 nonobese subjects. MEASUREMENTS: Allelic and genotypic frequency of LMNA 1908C>T were determined by PCR-RFLP. Association of LMNA alleles and genotypes was analysed with various measures of obesity [BMI >= 25 kg/m(2) , percentage body fat (by DEXA); subcutaneous and intra-abdominal fat at L2-3 level by single slice MRI in a subsample and surrogate marker of insulin resistance (fasting serum insulin levels >10 MUU/ml in men and >11 MUU/ml in women). RESULTS: Forty-six per cent of the subjects had generalized obesity while 54% had abdominal obesity. Frequency of C and T alleles was 0.71 and 0.29, respectively. Higher frequency of variant allele (T) was observed in obese than nonobese individuals (P = 0.001). On multivariate analysis adjusting for age, gender and serum insulin levels, subjects with LMNA1908T/T genotype were at 5.6 times higher risk [OR (95% CI): 5.6 (2.5-12.2), P = 0.001], while individuals with genotypes with at least one T allele, i.e. 1908C/T and T/T genotypes, were at 2.7 times higher odds to develop generalized obesity [OR (95% CI): 2.7 (1.8-4.1), P = 0.001]. CONCLUSION: LMNA 1908T/T and C/T genotypes emerged as independent genetic risk factors for generalized obesity in Asian north Indians. PMID- 21599723 TI - Hair follicles contribute significantly to penetration through human skin only at times soon after application as a solvent deposited solid in man. AB - AIMS: The aim of this study was to define the underlying relative penetration of caffeine through hair follicles and through intact stratum corneum with time in vivo through pharmacokinetic modelling. METHODS: Caffeine plasma concentration time profiles after topical application into skin with or without hair follicle blocking were modelled using the Wagner-Nelson method or a compartmental model with first order absorption and elimination. Pharmacokinetic parameters describing absorption rate and extent of absorption through hair follicles or the stratum corneum were determined separately and compared with each other. RESULTS: The obtained pharmacokinetic parameters from the two methods were similar. The absorption rate constant of caffeine for hair follicles was nearly 10 times higher than that for the stratum corneum and the percentage of absorption from hair follicles was more than half of that of the stratum corneum. In addition, the absorption from the stratum corneum showed an approximately 10 min delay while there was no delay for absorption from hair follicles. All caffeine absorbed by hair follicles occurs within 30 min of application and accounts for 10.5 to 33.8% of the total amount absorbed across the skin for all subjects, whereas absorption of caffeine through the stratum corneum can occur over several hours. CONCLUSION: Hair follicles contribute significantly to percutaneous absorption of caffeine after topical application in man in vivo only at times soon after application. PMID- 21599724 TI - Effect of nicotine on cytochrome P450 1A2 activity. PMID- 21599725 TI - Suicidal or self-harming ideation in military personnel transitioning to civilian life. AB - Suicides have markedly increased among military personnel in recent years. We used path analysis to examine factors associated with suicidal/self-harming ideation among male Navy and Marine Corps personnel transitioning to civilian life. Roughly 7% of men (Sailors = 5.3%, Marines = 9.0%) reported ideation during the previous 30 days. Results suggest that combat exposure, substance abuse, and resilience are associated with suicidal ideation/self-harming thoughts through the mediation of posttraumatic stress disorder symptoms and/or depression symptoms. Substance abuse plays a moderating role. Resilience had a direct effect only among the Marines. Implications for improving the transition to civilian life are discussed. PMID- 21599727 TI - Posttraumatic stress disorder, traumatic brain injury, and suicide attempt history among veterans receiving mental health services. AB - History of posttraumatic stress disorder (PTSD) or traumatic brain injury (TBI) has been found to increase risk of suicidal behavior. The association between suicide attempt history among veterans with PTSD and/or TBI was explored. Cases (N = 81) and 2:1 matched controls (N = 160) were randomly selected from a Veterans Affairs Medical Center clinical database. PTSD history was associated with an increased risk for a suicide attempt (OR = 2.8; 95% CI: 1.5, 5.1). This increased risk was present for those with and without a history of TBI. Results support incorporating PTSD history when assessing suicide risk among veterans with and without TBI. PMID- 21599726 TI - Risk for suicidal thoughts and behavior after childhood sexual abuse in women and men. AB - Earlier studies have found an elevated risk for psychopathology and suicidal behavior associated with childhood sexual abuse (CSA); however, the degree to which risk is mediated by depression and posttraumatic stress disorder (PTSD) in women and men remains unclear. We examined these issues in data from a family study of childhood maltreatment (N = 2,559). We found significant CSA-associated risk for depression, PTSD, and suicidal behavior for women and men. In survival analyses controlling for these disorders, we observed persistent but somewhat reduced CSA-associated risk for suicidal ideation and suicide attempt. Our findings suggest that these disorders partially mediate CSA-associated risk. PMID- 21599728 TI - Facultative methanotrophy: false leads, true results, and suggestions for future research. AB - Methanotrophs are a group of phylogenetically diverse microorganisms characterized by their ability to utilize methane as their sole source of carbon and energy. Early studies suggested that growth on methane could be stimulated with the addition of some small organic acids, but initial efforts to find facultative methanotrophs, i.e., methanotrophs able to utilize compounds with carbon-carbon bonds as sole growth substrates were inconclusive. Recently, however, facultative methanotrophs in the genera Methylocella, Methylocapsa, and Methylocystis have been reported that can grow on acetate, as well as on larger organic acids or ethanol for some species. All identified facultative methanotrophs group within the Alphaproteobacteria and utilize the serine cycle for carbon assimilation from formaldehyde. It is possible that facultative methanotrophs are able to convert acetate into intermediates of the serine cycle (e.g. malate and glyoxylate), because a variety of acetate assimilation pathways convert acetate into these compounds (e.g. the glyoxylate shunt of the tricarboxylic acid cycle, the ethylmalonyl-CoA pathway, the citramalate cycle, and the methylaspartate cycle). In this review, we summarize the history of facultative methanotrophy, describe scenarios for the basis of facultative methanotrophy, and pose several topics for future research in this area. PMID- 21599729 TI - In silico comparative study of the genomic islands of Vibrio cholerae MJ1236 with those of Classical and El Tor N16961 strains of Vibrio cholerae. AB - The evolution of microbial genomes is greatly influenced by horizontal gene transfer (HGT), where large blocks of horizontally acquired foreign sequences, often encoding virulence determinants, occur in chromosomes of pathogenic bacteria. A program design-island developed in our laboratory was used on three completely sequenced Vibrio cholerae genomes, V. cholerae Classical O395, El Tor N16961 and MJ1236, in order to identify the putative horizontally acquired regions. The putative genomic islands (GIs) were graphically represented and analyzed. The study identified distinct regions in the GIs of V. cholerae MJ1236 which were shared either with the Classical or the El Tor strain of V. cholerae. A cluster comprising of 38 ORFs was common to V. cholerae strains of MJ1236 and Classical O395 but absent in El Tor N16961. About 5% of the predicted GIs of V. cholerae MJ1236 were unique to itself. Among these unique ORFs, a region of mostly hypothetical genes was identified, where the ORFs were present in a large cluster. The results show that the HGT had played a significant role in the evolution and the differentiation of V. cholerae MJ1236. PMID- 21599730 TI - Guideline-centered care: a two-edged sword. PMID- 21599731 TI - Is a rising cesarean delivery rate inevitable? Trends in industrialized countries, 1987 to 2007. AB - BACKGROUND: Cesarean delivery rates have been rising rapidly in many countries in the last decade. The objective of this research is to examine cesarean rates in industrialized countries and assess patterns in the trends toward increasing rates. METHODS: We examined cesarean delivery rates per 1,000 live births from 1987 to 2007 in 22 industrialized countries. To enhance comparability, the inclusion criteria were at least 50,000 births annually and a per capita gross domestic product of at least U.S.$10,000 in 2007. Poisson regression was selected to model the cesarean delivery rates of countries across time. RESULTS: We examined overall cesarean delivery rates, absolute changes in these rates, and changes in trend lines for cesarean rates for the period from 1987 to 2007. In 2007, 11 of the 21 countries reported overall cesarean rates of more than 25 percent, led by Italy (39%), Portugal (35%), the United States (32%), and Switzerland (32%). Five countries, the Slovak Republic, Czech Republic, Ireland, Austria, and Hungary more than doubled their cesarean delivery rate between 1992 and 2007. Comparing changes in rates across time periods, 14 countries experienced a greater increase in rates in the period between 1998 and 2002 compared with the period between 1993 and 1997. Comparing trends from 2003-2007 to 1998-2002, eighteen countries experienced a slowing down of rate increases across these two periods. CONCLUSION: Although cesarean delivery rates continue to rise, the rate of increase appears to be slowing down in most industrialized countries. PMID- 21599732 TI - Long-term effects of epidural analgesia in labor: a randomized controlled trial comparing high dose with two mobile techniques. AB - BACKGROUND: Epidural analgesia provides the most effective pain relief in labor, but it is not known if it causes adverse long-term effects. The objective of this study was to assess the long-term effects of two mobile epidural techniques relative to high-dose epidural analgesia in a randomized controlled trial. METHODS: A total of 1,054 nulliparous women were randomized to traditional high dose epidural, combined spinal epidural, or low-dose infusion. Women in all groups were followed-up at 12 months postpartum by postal questionnaire to assess long-term symptoms. The primary long-term outcome was backache occurring within 3 months of the birth persisting for longer than 6 weeks. Secondary outcomes were frequent headaches and fecal and urinary stress incontinence. RESULTS: No significant differences were found in long-term backache after combined spinal epidural or low-dose infusion relative to high-dose epidural. Significantly less headache occurred in combined spinal epidural analgesia than high-dose epidural (OR: 0.57, 95% CI: 0.36-0.92), but no difference was found for low-dose infusion. Significantly less fecal incontinence (OR: 0.51, 95% CI: 0.30-0.87) and stress incontinence (OR: 0.65, 95% CI: 0.42-1.00) occurred with low-dose infusion. CONCLUSION: Trial evidence showed no long-term disadvantages and possible benefits of low-dose mobile relative to high-dose epidural analgesia. PMID- 21599733 TI - Planned place of birth in New Zealand: does it affect mode of birth and intervention rates among low-risk women? AB - BACKGROUND: Midwives providing care as lead maternity caregivers in New Zealand provide continuity of care to women who may give birth in a variety of settings, including home, primary units, and secondary and tertiary level hospitals. The purpose of this study was to compare mode of birth and intrapartum intervention rates for low-risk women planning to give birth in these settings under the care of midwives. METHODS: Data for a cohort of low-risk women giving birth in 2006 and 2007 were extracted from the Midwifery Maternity Provider Organisation database. Mode of birth, intrapartum interventions, and neonatal outcomes were compared with results adjusted for age, parity, ethnicity, and smoking. RESULTS: Women planning to give birth in secondary and tertiary hospitals had a higher risk of cesarean section, assisted modes of birth, and intrapartum interventions than similar women planning to give birth at home and in primary units. The risk of emergency cesarean section for women planning to give birth in a tertiary unit was 4.62 (95% CI: 3.66-5.84) times that of a woman planning to give birth in a primary unit. Newborns of women planning to give birth in secondary and tertiary hospitals also had a higher risk of admission to a neonatal intensive care unit (RR: 1.40, 95% CI: 1.05-1.87; RR: 1.78, 95% CI: 1.31-2.42) than women planning to give birth in a primary unit. CONCLUSIONS: Planned place of birth has a significant influence on mode of birth and rates of intrapartum intervention in childbirth. PMID- 21599734 TI - In-hospital birth center with the same medical guidelines as standard care: a comparative study of obstetric interventions and outcomes. AB - BACKGROUND: A challenge of obstetric care is to optimize maternal and infant health outcomes and the mother's experience of childbirth with the least possible intervention in the normal process. The aim of this study was to investigate the effects of modified birth center care on obstetric procedures during delivery and on maternal and neonatal outcomes. METHODS: In a cohort study 2,555 women who signed in for birth center care during pregnancy were compared with all 9,382 low risk women who gave birth in the standard delivery ward in the same hospital from March 2004 to July 2008. Odds ratios (OR) were calculated with 95% confidence interval (CI) and adjusted for maternal background characteristics, elective cesarean section, and gestational age. RESULTS: The modified birth center group included fewer emergency cesarean sections (primiparas: OR: 0.69, 95% CI: 0.58 0.83; multiparas: OR: 0.34, 95% CI: 0.23-0.51), and in multiparas the vacuum extraction rate was reduced (OR: 0.42, 95% CI: 0.26-0.67). In addition, epidural analgesia was used less frequently (primiparas: OR: 0.47, 95% CI: 0.41-0.53; multiparas: OR: 0.25, 95% CI: 0.20-0.32). Fetal distress was less frequently diagnosed in the modified birth center group (primiparas: OR: 0.72, 95% CI: 0.59 0.87; multiparas: OR: 0.45, 95% CI: 0.29-0.69), but no statistically significant differences were found in neonatal hypoxia, low Apgar score less than 7 at 5 minutes, or proportion of perinatal deaths (OR: 0.40, 95% CI: 0.14-1.13). Anal sphincter tears were reduced (primiparas: OR: 0.73, 95% CI: 0.55-0.98; multiparas: OR: 0.41, 95% CI: 0.20-0.83). CONCLUSION: Midwife-led comprehensive care with the same medical guidelines as in standard care reduced medical interventions without jeopardizing maternal and infant health. PMID- 21599735 TI - Attitudes of the new generation of Canadian obstetricians: how do they differ from their predecessors? AB - BACKGROUND: Attitudes drive practice, perhaps more than evidence. The objective of this study was to determine if the new generation of Canadian obstetricians has attitudes differing from those of their predecessors. METHODS: Employing a cross-sectional, Internet, and paper-based survey, we conducted an in-depth study of obstetricians responding to the Canadian National Maternity Care Attitudes Survey. RESULTS: Of the 800 Canadian obstetricians providing intrapartum care, 549 (68.6%) responded. Participants were stratified by age less than or equal to 40 years compared with those over 40 years; 81 percent of those 40 years or younger were women versus 40 percent over 40 years of age. Younger obstetricians were significantly more likely to favor use of routine epidural analgesia and believed that it did not interfere with labor or lead to instrumentation; were more concerned and feared the perineal and pelvic floor consequences of vaginal birth compared with cesarean section; and were significantly less supportive of vaginal birth after prior cesarean section, home birth, birth plans, routine episiotomy, and routine electronic fetal monitoring as providing maternal or fetal benefits. They were less positive than the older generation about a range of approaches to reducing the cesarean section rate, the importance of maternal choice and role in their own birth, and peer review, and they were more likely to believe that women having a cesarean section were not missing an important experience. No significant generational differences were found for ambivalent attitudes to vaginal breech birth. CONCLUSIONS: Younger obstetricians were more evidence-based for some issues and less for others. In general younger obstetricians were more supportive of the role of birth technology in normal birth, including routine epidural analgesia, and they were less appreciative of the role of women in their own birth. They saw cesarean section as a solution to many perceived labor and birth problems. Results suggest a need to examine how obstetricians acquire their favorable attitudes to birth technology in normal birth. PMID- 21599736 TI - "The times, they are a-changin'"*. PMID- 21599737 TI - Barriers to managing diabetes during pregnancy: the perceptions of health care practitioners. AB - BACKGROUND: Uncontrolled pregestational diabetes in pregnancy is associated with an increased risk for a major birth defect and additional adverse pregnancy outcomes. The study objective was to investigate the concerns of health care practitioners who care for women with a history of diabetes during pregnancy and their perceptions of attitudes and barriers to achieving good glycemic control. METHODS: Focus groups were conducted with physicians, midlevel practitioners, and certified diabetes educators in Atlanta, Georgia. Practitioners were eligible if they actively practiced, primarily in outpatient facilities in Atlanta, and were neither students nor interns. Six focus groups, two of each practitioner type, were conducted. RESULTS: Practitioners stated that few of their patients planned their pregnancies. Practitioners perceived that pregnant women were concerned primarily about their babies and might not be aware of complications with their personal health. Their perceptions of the greatest barriers to glycemic control for women involved lack of knowledge, lack of access, and attitude. CONCLUSIONS: Educating women with diabetes about the importance of using effective birth control until they have achieved good glycemic control can help reduce the risk for adverse pregnancy outcomes. Motivators and barriers for a woman with diabetes to achieve glycemic control before, during, and after pregnancy should be considered when developing approaches to improve outcomes. Helping practitioners know what and how to address the needs of childbearing women with or at risk for diabetes can be beneficial. Additional efforts to increase women's knowledge about diabetes and pregnancy and to develop effective strategies to encourage women's achievement and maintenance of glycemic control before, during, and after pregnancy are needed. PMID- 21599738 TI - Swedish parents' experiences of parenthood and the need for support to siblings when a baby is stillborn. AB - BACKGROUND: It has been argued that having a stillborn baby in the family affects older siblings more than parents realize. The aim of this study was to describe parenthood and the needs of siblings after stillbirth from the parents' perspective. METHODS: Six focus groups were held with 27 parents who had experienced a stillbirth and who had had children before the loss. The discussion concerned parents' support to the siblings, and the sibling's meeting, farewell, and memories of their little sister or brother. Data were analyzed using qualitative content analysis. RESULTS: The overall theme of the findings was parenthood in a balance between grief and everyday life. In the analysis, three categories emerged that described the construction of the theme: support in an acute situation, sharing the experiences within the family, and adjusting to the situation. CONCLUSIONS: The siblings' situation is characterized by having a parent who tries to maintain a balance between grief and everyday life. Parents are present and engaged in joint activities around the stillbirth together with the siblings of the stillborn baby. Although parents are aware of the sibling's situation, they feel that they are left somewhat alone in their parenthood after stillbirth and therefore need support and guidance from others. PMID- 21599739 TI - Report of a breech cesarean section maternal death. AB - In Australia in 2007, a woman with two previous normal vaginal deliveries underwent an emergency cesarean section at full dilatation of the cervix with a breech presentation. The woman died after a severe hemorrhage. The official Coroner's Report attributed the cause of death to postpartum hemorrhage, whereas the breech presentation was barely mentioned, suggesting that complications with breech cesarean deliveries are under-appreciated and under-reported. PMID- 21599740 TI - Commentary: routine cesarean section for breech: the unmeasured cost. PMID- 21599741 TI - Commentary: the freezing aftermath of a hot randomized controlled trial. PMID- 21599742 TI - Women's use of nonprescribed methods to induce labor: a brief report. AB - BACKGROUND: Sometimes pregnant women take it on themselves to hasten labor to alleviate the discomforts of pregnancy. This study sought to identify how frequently women attempt to induce labor through nonprescribed methods, and what factors are associated with the use of such methods. METHODS: Surveys were distributed to postpartum women who had delivered at a Midwestern academic hospital. Women were asked what methods they had used to induce labor on their own, where they heard about these methods, and whether they had discussed it with their physician. Information about demographics and mode and timing of delivery was also collected. RESULTS: Of the 201 women who responded, 99 (49.3%) did not try to induce labor themselves, whereas 102 (50.7%) used some type of nonprescribed method to induce labor. The most common method was walking (43.3%), followed by intercourse (22.9%), ingesting of spicy food (10.9%), and nipple stimulation (7.5%). Very few respondents used laxatives, heavy exercise, masturbation, acupuncture, or herbal preparations to induce labor. Women who used any nonprescribed method to induce labor were younger, had a lower parity, greater gestational age, and were more likely to have had a vaginal birth. CONCLUSIONS: A substantial portion of women used nonprescribed methods to induce labor, often without discussing them with a physician. Maternity caregivers may want to inquire about such issues, especially where interventions may do more harm than good. PMID- 21599743 TI - One baby, four parents: assisted reproduction for two couples in New Zealand. AB - PREFACE: Egg donation by another woman in New Zealand and elsewhere has become a successful solution for childless couples who want to have a baby. In vitro fertilization (IVF) was first undertaken in New Zealand in 1983 (1). Approximately 5 in 100 couples have IVF in New Zealand, and 450 IVF babies are born each year (2). In this article, two women and two men who underwent this assisted reproductive process describe, in question-and-answer format, their experiences from their initial meeting and proposal, evaluation, egg retrieval and implantation, and pregnancy, to the birth of a healthy infant. Petra is the egg donor and genetic mother and Adam is her husband, Donna is the recipient and biological mother, and Erich is her husband and the genetic/biological father. Lorelai, the baby, was born on 27 November 2009 in Auckland, New Zealand. PMID- 21599744 TI - Birthing a mother: the surrogate body and the pregnant self. PMID- 21599746 TI - Corneal decompensation due to spontaneously dislocated crystalline lens: initial management can be conservative. PMID- 21599747 TI - Central corneal iron line arising from hyperopic orthokeratology. PMID- 21599748 TI - Presumed sterile corneal ulcer following autologous limbal stem cell and amniotic membrane transplantation: report of an unusual complication. PMID- 21599749 TI - Pupillary block glaucoma secondary to vitreous prolapse after Nd:YAG capsulotomy. PMID- 21599750 TI - Detection of Chlamydia trachomatis in the subretinal fluid of a patient with rhegmatogenous retinal detachment. PMID- 21599751 TI - Treatment of a giant coronary artery aneurysm: intravascular ultrasound and optical coherence tomography findings. AB - A giant coronary aneurysm (GCA) partially thrombosed was demonstrated in a 77 year-old patient evaluated for an inferior myocardial infarction. Primary angioplasty (balloon only) with suboptimal result was initially obtained. After triple antiplatelet and anticoagulation therapy (4 days), a new angiography was performed and a fusiform GCA was clearly delineated. A second percutaneous intervention was performed using a "scaffolding technique" with conventional stent and subsequent implantation of 2 polytetrafluoroethylene-covered stents to successfully exclude the aneurysm. This case demonstrates a novel technique to treat long GCA. PMID- 21599752 TI - A case of a bloated face: SVC syndrome relieved by an endovascular approach. AB - Superior vena cava (SVC) syndrome, or obstruction of blood returning from the head and upper extremities, is a syndrome that is rapidly increasing in the cardiovascular patient population due to the increasing use of transvenous devices such as permanent pacemakers, implantable cardioverter defibrillators (ICDs), and indwelling venous access devices for hemodialysis. This syndrome in the past has been seen predominately in the cancer population with malignancy being the most common reason for SVC syndrome. The management of this syndrome has largely been with a medical/supportive care approach or with surgical bypass. Given the advancement in the field of endovascular interventions and the increasing expertise in performing these procedures, an endovascular approach to relieving the SVC obstruction is rapidly becoming the treatment of choice for these patients. We describe a case of a patient who had a chronic indwelling port a-cath who developed SVC syndrome, which was treated with an endovascular approach with stenting of the SVC/brachiocephalic vein junction. PMID- 21599753 TI - Pre-engraftment graft-versus-host disease after allogeneic hematopoietic cell transplantation for acute leukemia. AB - OBJECTIVES: Acute graft-versus-host disease (GVHD) usually occurs with neutrophil engraftment following allogeneic hematopoietic cell transplantation (HCT), but it can also occur before engraftment. We intended to analyze the effects of timing of acute GVHD on leukemia relapse and mortality. METHODS: The outcomes of pre- and postengraftment GVHD were investigated in 384 patients who underwent allogeneic HCT for acute leukemia. RESULTS: Acute GVHD occurred in 100 patients, pre-engraftment in 22 and postengraftment in 78. Compared with postengraftment GVHD, pre-engraftment GVHD was more severe, as assessed by overall grade, with more frequent and more severe skin involvement and higher incidences of non infectious fever, diarrhea, hepatic dysfunction, renal insufficiency, and weight gain. Compared with patients without acute GVHD, those with postengraftment GVHD had lower cumulative incidence of relapse [CIR; hazard ratio (HR), 0.470; P=0.006] and higher cumulative incidence of non-relapse mortality (CINRM; HR, 2.568; P<0.001), while those with pre-engraftment GVHD had similar CIR (HR, 0.815; P=0.059) and higher CINRM (HR, 2.872; P=0.036). Overall survival of patients with pre-engraftment GVHD was lower than that of those without acute GVHD (HR, 1.976; P=0.017), which was similar to that of those with postengraftment GVHD (HR, 0.969; P=0.878). Separate analyses of the effects of timing of acute GVHD on post-transplant outcomes in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) showed similar trends. CONCLUSION: Pre-engraftment GVHD might be a 'cytokine storm' type syndrome rather than 'real' GVHD, indicating the need for separate analyses of pre- and postengraftment GVHD in future trials. PMID- 21599754 TI - Exercise and relaxation intervention for patients with advanced lung cancer: a qualitative feasibility study. AB - Lung cancer patients experience loss of physical capacity, dyspnea, pain, reduced energy and psychological distress. The aim of this study was to explore feasibility, health benefits and barriers of exercise in former sedentary patients with advanced stage lung cancer, non-small cell lung cancer (NSCLC) (III IV) and small cell lung cancer (SCLC) (ED), undergoing chemotherapy. The intervention consisted of a hospital-based, supervised, group exercise and relaxation program comprising resistance-, cardiovascular- and relaxation training 4 h weekly, 6 weeks, and a concurrent unsupervised home-based exercise program. An explorative study using individual semi-structured interviews (n=15) and one focus group interview (n=8) was conducted among the participants. Throughout the intervention the patients experienced increased muscle strength, improvement in wellbeing, breathlessness and energy. The group exercise and relaxation intervention showed an adherence rate of 76%, whereas the patients failed to comply with the home-based exercise. The hospital-based intervention initiated at time of diagnosis encouraged former sedentary lung cancer patients to participation and was undertaken safely by cancer patients with advanced stages of disease, during treatment. The patients experienced physical, functional and emotional benefits. This study confirmed that supervised training in peer-groups was beneficial, even in a cancer population with full-blown symptom burden and poor prognosis. PMID- 21599755 TI - Submaximal exercise responses in tetraplegic, paraplegic and non spinal cord injured elite wheelchair athletes. AB - It remains unclear whether similar exercise prescription, based on physiological markers, can be applied to subgroups of wheelchair athletes with different disabilities. Therefore, 25 wheelchair athletes, divided into three subgroups [eight tetraplegic (TETRA), nine paraplegic (PARA) and eight non spinal cord injured (NON-SCI)], performed an exercise test consisting of incremental submaximal stages, covering a range from 40% to 80% peak oxygen uptake (%VO(2peak) ). Oxygen uptake (VO(2)), heart rate (HR), blood lactate concentration (BLa) and rating of perceived exertion (RPE) were obtained for each stage. Expressed as a function of BLa, no differences were found between subgroups with respect to %VO(2peak) (group mean +/- SD: 1.0 mmol/L: 53.9 +/- 9.9%; 2.0 mmol/L: 70.7 +/- 7.5%; 3.0 mmol/L: 78.5 +/- 7.7%) and RPE [group mean (lower and upper quartile): 1.0 mmol/L: 10.8 (9.9, 12.2); 2.0 mmol/L: 13.6 (12.7, 14.3); 3.0 mmol/L: 14.9 (13.7, 16.5)]. Furthermore, no differences were found in the coefficient of determination (R(2) ) of the HR-VO(2) relationship in any of the subgroups (TETRA: 0.90 +/- 0.12; PARA: 0.97 +/- 0.02; NON-SCI: 0.96 +/- 0.04). These results suggest that exercise prescription using measurements of VO(2), BLa or RPE can be based on the same recommendations in all the subgroups studied. This finding has added value for TETRA athletes, as it offers alternatives to HR monitoring. PMID- 21599758 TI - Urology in Asia - Singapore. PMID- 21599756 TI - Relationship between quadriceps femoris muscle volume and muscle torque at least 18 months after anterior cruciate ligament reconstruction. AB - The purpose of this study was to evaluate motor unit recruitment in the quadriceps femoris (QF) after anterior cruciate ligament (ACL) rupture and repair. Subjects included 24 patients at >= 18 months after ACL reconstruction and 22 control subjects with no history of knee injury. A series of cross sectional magnetic resonance images were obtained to compare the QF of patients' injured side with that of their uninjured sides and that of uninjured control subjects. Muscle torque per muscle volume was calculated as isokinetic peak torque divided by QF muscle volume (cm(3)). The mean muscle torque per unit volume of the injured side of patients was not significantly different from that of the uninjured side or control subjects (one-way ANOVA) Results of the present study were contrary to the results of a previous study that evaluated patients at <= 12 months after ACL reconstruction. The present study found that high threshold motor unit recruitment was restored at >= 18 months after ACL reconstruction. Thus, clinicians must develop techniques that increase the recruitment of high-threshold motor units in the QF from the period immediately after the injury until approximately 18 months after ACL reconstruction. PMID- 21599759 TI - Exploring immune therapy for renal cancer. PMID- 21599760 TI - Editorial comment to erythrocyte sedimentation rate kinetics as a marker of treatment response and predictor of prognosis in Chinese metastatic renal cell carcinoma patients treated with sorafenib. PMID- 21599761 TI - Editorial comment to postoperative renal function after partial nephrectomy for renal cell carcinoma in patients with pre-existing chronic kidney disease: a comparison with radical nephrectomy. PMID- 21599762 TI - Nutritionally induced relationships between insulin levels during the weaning-to ovulation interval and reproductive characteristics in multiparous sows: I. Luteinizing hormone, follicle development, oestrus and ovulation. AB - To get more insight in how insulin secretion patterns and corresponding insulin like growth factor-1 (IGF-1) levels are related to luteinizing hormone (LH) secretion, follicle development and ovulation, 32 multiparous sows were fed either a dextrose plus lactose-containing diet at 4 h intervals (DL; each 150 g/day) or an isocaloric control diet at 12 h intervals (CTRL; containing soybean oil) during the weaning-to-ovulation interval (WOI). Insulin parameters (basal, peak levels and mean insulin) and IGF-1 levels during the WOI were similar for both treatments, but the insulin secretion pattern differed (related with feeding frequency and meal sizes). Oestrus and ovulation characteristics were not influenced by treatment. The LH surge was higher in CTRL compared with DL sows (3.73 vs 3.00 ng/ml; p = 0.03). Average diameter (6.5 vs 6.1 mm; p = 0.08) and uniformity (CV: 11 vs 15%, p = 0.02) of follicles >=3 mm at day 4 after weaning was higher in CTRL compared with DL sows. Basal insulin levels were positively related with follicle diameter at ovulation (beta = 0.05 mm/(MUU/ml); p = 0.04) and negatively related with LH surge level (beta = -0.07 (ng/ml)/(MUU/ml); p = 0.01). Insulin area under the curve (AUC) (beta = 0.037 (ng/ml)/1000 MUU; p = 0.02) and IGF-1 levels (beta = 0.002 (ng/ml)/(ng/ml); p < 0.01) were positively related to basal LH level around the LH surge. From these data, we conclude that insulin and IGF-1 levels during the WOI are related to LH secretion and follicle development. Not only the absolute level of insulin seems important, but also the pattern within a day in which insulin is secreted seems to affect LH secretion and development of pre-ovulatory follicles. PMID- 21599763 TI - Nutritionally induced relationships between insulin levels during the weaning-to ovulation interval and reproductive characteristics in multiparous sows: II. Luteal development, progesterone and conceptus development and uniformity. AB - Insulin-stimulating sow diets before mating improve piglet uniformity. We studied effects of nutritionally induced differences in insulin levels during the weaning to-ovulation interval (WOI) on luteal development, progesterone secretion and pre implantation conceptus development and uniformity (d10). To create insulin contrasts, 32 multiparous sows were fed either a dextrose plus lactose containing diet (each 150 g/day) at 4 h intervals (DL treatment) or an isocalorically control diet (containing soybean oil) at 12 h intervals (CTRL treatment) during the WOI. After ovulation, all sows received a standard gestation diet at 12 h intervals. Ovulation rate, plasma progesterone levels, pregnancy rate and embryo survival did not differ between treatments. CTRL sows had a higher total luteal weight (11.2 vs 9.7 g; p = 0.03) than DL sows. Conceptus diameter at d10 of pregnancy tended to be larger in CTRL sows (diameter: 7.1 vs 6.4 mm; p = 0.07). Conceptus uniformity was not influenced by treatment. Insulin area under the curve (AUC) and mean insulin during the WOI were positively related with mean progesterone (beta values were 0.78 (ng/ml)/1000 MUU and 0.14 (ng/ml)/(MUU/ml) for AUC and mean, respectively; p < 0.05) and maximal progesterone (beta values were 1.46 (ng/ml)/1000 MUU and 0.27 (ng/ml)/(MUU/ml) for AUC and mean, respectively; p < 0.05) levels during the first 10 days of pregnancy, but not with conceptus development and uniformity. In conclusion, high insulin levels during the WOI seem to be beneficial for progesterone secretion in sows, probably mediated through beneficial effects of insulin on follicle development. PMID- 21599764 TI - Differential gene expression between the porcine morula and blastocyst. AB - The survival and development of pre-implantation embryos are determinant factors affecting the outcome of animal reproduction. It is essential to transfer the expression of the genetic material from maternal sources, that is the ovum to the zygote before implantation to ensure successful development. Differentiation and transformation of blastomeres initiated during the morula and blastocyst stages is an important step of the embryonic development prior to implantation. We collected morula and early blastocyst samples from pure-bred Landrace pigs in vivo to study the differential gene expression patterns at these two stages. Total RNA was extracted from individual embryos and two rounds of amplification were employed. Two micrograms of antisense RNA, targets, were prepared and hybridized with each of four custom made oligo microarrays representing 24,000 porcine genes. The analyses of replicate hybridizations showed that among the 24,000 genes, 162 genes were expressed fivefold or greater in the morula compared to early blastocysts and 2126 genes were expressed fivefold or greater in early blastocysts compared to the morula. Of these differentially expressed genes, 1429 genes were functionally annotated with related human Gene Ontology terms. In addition to basic metabolic processes, genes related to signal transduction, transportation and cell differentiation were found in both stages and were up regulated as embryo development proceeded. Real time polymerase chain reaction was utilized to quantify 12 genes differentially expressed in the 2 embryonic stages and validated the reliability of major evidences shown in microarrays. In conclusion, we have obtained a preliminary landscape of genes differentially expressed during the transition from morula to early blastocysts in pigs and showed a generally increased transcriptional activity, perhaps in preparation for implantation. Our results provide an opportunity to study the functions of these genes in relation to the development and survival of pre-implantation porcine embryos. PMID- 21599765 TI - Comparative study on 15-ketodihydro-PGF(2alpha) plasma concentrations in newborn horses, donkeys and calves. AB - The aim of this study was to compare the plasma profiles of 15-ketodihydro PGF(2alpha) (PGM) in healthy neonates of three different species from birth until the third week of life. Twenty-four horse foals, 12 donkey foals, and 9 calves were studied. Blood samples were collected at 10, 20 and 30 min after birth, at 3, 24 and 72 h after birth, and at 7, 10, 17 and 21 days of life. All mothers experienced normal gestation lengths and normal, spontaneous deliveries. All newborns were judged mature and viable. Hormone concentrations were higher (p < 0.05) in horse foals 20 and 30 min after birth compared to later samples, and at 10 min in donkey foals compared to later samples (p < 0.05). In calves, higher (p < 0.05) concentrations of PGM were observed 10, 20, 30 min and 3 hours from parturition compared to later samples. These findings may be related to increased fetal placental unit production during parturition, while the relatively high PGF(2alpha) levels in the days after parturition may be connected with their role in completing organ maturation. Despite the existing differences between these species, the statistical analysis did not discover significant differences in PGM profiles during the first 3 weeks of life in donkey, horse and cattle newborns. The low levels observed 10 days after birth are possibly due to a fast completion of maturational development in these species. PMID- 21599766 TI - Long-term central infusion of adiponectin improves energy and glucose homeostasis by decreasing fat storage and suppressing hepatic gluconeogenesis without changing food intake. AB - Adiponectin is known to be an anti-diabetic adipocytokine. However, the action mechanism by which it produces this effect remains controversial. In the present study, we investigated the long-term central effect of adiponectin on energy homeostasis, peripheral insulin resistance, beta-cell function and mass in rats and aimed to determine the mechanism by which its effect was achieved. Intracerebroventricular infusion of adiponectin (50 ng/h) and artificial cerebrospinal fluid (CSF) was conducted by means of an osmotic pump for 4 weeks on nondiabetic rats and 90% pancreatectomised diabetic rats that were both fed 45% energy fat diets. After 4-weeks of treatment, i.c.v. adiponectin improved hypothalamic insulin/leptin signalling in nondiabetic and diabetic rats compared to i.c.v. CSF but it did not change the phosphorylation of AMP kinase (AMPK) in the hypothalamus. Adiponectin infusion decreased epididymal fats, representing visceral fat, by increasing energy expenditure and fat oxidation. During the euglycaemic hyperinsulinaemic clamp, i.c.v. adiponectin improved whole body insulin sensitivity and decreased hepatic glucose output in the hyperinsulinaemic state by attenuating hepatic insulin resistance. Central infusion of adiponectin did not modulate glucose-stimulated insulin secretion during the hyperglycaemic clamp compared to i.c.v. CSF infusion but it enhanced insulin sensitivity at a hyperglycaemic state. Although there were no changes in insulin secretion capacity, central adiponectin increased pancreatic beta-cell mass in nondiabetic and diabetic rats as a result of decreasing beta-cell death. In conclusion, long term central infusion of adiponectin enhanced energy homeostasis by increasing energy expenditure via activating hypothalamic leptin and insulin signalling pathways but without potentiating AMPK signalling; it also improved glucose homeostasis by attenuating insulin resistance. PMID- 21599768 TI - Terbinafine pharmacokinetics after single dose oral administration in the dog. AB - Terbinafine is an allylamine antifungal prescribed for the treatment of mycoses in humans. It is increasingly being used in veterinary patients. The purpose of this study was to evaluate the pharmacokinetic properties of terbinafine in dogs after a single oral dose. Ten healthy adult dogs were included in the study. A single dose of terbinafine (30-35 mg/kg) was administered orally, and blood samples were periodically collected over a 24 h period during which dogs were monitored for adverse effects. Two of 10 dogs developed transient ocular changes. A high-performance liquid chromatography assay was developed and used to determine plasma terbinafine concentrations. Pharmacokinetic analysis was performed using PK Solutions((r)) computer software. Area under the curve (AUC) from time 0 to 24 h was 15.4 MUg.h/mL (range 5-27), maximal plasma concentration (C(max) ) was 3.5 MUg/mL (range 3-4.9 MUg/mL) and time to C(max) (T(max) ) was 3.6 h (range 2-6 h). The time above minimal inhibitory concentration (T > MIC) as well as AUC/MIC was calculated for important invasive fungal pathogens and dermatophytes. The T > MIC was 17-18 h for Blastomyces dermatitidis, Histoplasma capsulatum and dermatophytes (Microsporum spp. and Trichophyton mentagrophytes), while the MIC for Sporothrix schenckii and Coccidioides immitis was exceeded for 9.5-11 h. The AUC/MIC values ranged from 9 to 13 MUg h/mL for these fungi. Our results provide evidence supporting the use of terbinafine as an oral therapeutic agent for treating systemic and subcutaneous mycoses in dogs. PMID- 21599767 TI - Oral vitamin A as an adjunct treatment for canine sebaceous adenitis. AB - Medical records of dogs with sebaceous adenitis diagnosed by histopathology over an 18-year period were reviewed. From a total of 40 cases, 24 were treated with oral vitamin A. Dogs ranged from 9 months to 12 years of age at the time of disease onset. Purebred as well as mixed-breed dogs were affected. Akitas represented approximately one-third of the affected population. No sex predilections were observed. Vitamin A was administered for a minimum of 1 month. Doses varied from 380 to 2667 IU/kg/day, with a mean of 1037 IU/kg/day. Two dogs received oral vitamin A exclusively. Concurrent treatments included systemic antibiotics, systemic antifungal medications, fatty acid supplementation and various topical treatments. Of 24 dogs treated with vitamin A, three were lost to follow-up. Twelve owners were satisfied with the overall appearance of their dogs, reporting >=25% improvement in clinical signs, including level of pruritus, amount of scale, alopecia and overall coat quality, compared with pretreatment appearance. Three owners observed adequate initial improvement, with regression to pretreatment state within 6 months of starting treatment. Two owners reported 25-50% improvement in clinical signs while on oral vitamin A supplementation; however, changes were attributed to concurrent topical treatment. Six owners reported no improvement and discontinued oral administration of vitamin A within 7 months. No correlations could be made between vitamin A dosage and response to treatment; prognoses could not be made based on clinical and histopathological findings. PMID- 21599769 TI - Changes in facial morphology after adenotonsillectomy in mouth-breathing children. AB - BACKGROUND: Morphological and dentofacial alterations have been attributed to impaired respiratory function. OBJECTIVE: To examine the influence of mouth breathing (MB) on children facial morphology before and after adenoidectomy or adenotonsillectomy. METHODS: Thirty-three MB children who restored nasal breathing (NB) after surgery and 22 NB children were evaluated. Both groups were submitted to lateral cephalometry, at time 1 (T1) before and at time 2 (T2) 28 months on average postoperatively. RESULTS: Comparison between the MB and NB groups at T1 showed that mouth breathers had higher inclination of the mandibular plane; more obtuse gonial angle; dolichofacial morphology; and a decrease in the total and inferior posterior facial heights. Twenty-eight months after the MB surgical intervention, they still presented a dolichofacial morphologic pattern. During this period, MB altered the face growth direction and decreased their mandible plane inclination, with reduction in the SN.GoGn, PP.MP, SNGn, and ArGo.GoMe parameters as well as an increase in BaN.PtGn. CONCLUSION: After the MB rehabilitation, children between 3 and 6 years old presented significant normalization in the mandibular growth direction, a decrease in the mandible inclination, and an increase in the posterior facial height. Instead, they still persisted with a dolichofacial pattern when compared with nasal breathers. PMID- 21599770 TI - Rapid parallel evolution of aberrant traits in the diversification of the Gulf of Guinea white-eyes (Aves, Zosteropidae). AB - Archipelago-endemic bird radiations are familiar to evolutionary biologists as key illustrations of evolutionary patterns. However, such radiations are in fact rare events. White-eyes (Zosteropidae) are birds with an exceptionally high colonization and speciation potential; they have colonized more islands globally than any other passerine group and include the most species-rich bird genus. The multiplication of white-eye island endemics has been consistently attributed to independent colonizations from the mainland; the white-eyes of the Gulf of Guinea archipelago had been seen as a classic case, spanning as great a breadth of phenotypic diversity as the family worldwide. Contrary to this hypothesis, our molecular phylogenetic analysis places the Gulf of Guinea white-eyes in just two radiations, one grouping all five oceanic island taxa and the other grouping continental island and land-bridge taxa. Numerous 'aberrant' phenotypes (traditionally grouped in the genus Speirops) have evolved independently over a short space of time from nonaberrant (Zosterops) phenotypes; the most phenotypically divergent species have separated as recently as 0.22 Ma. These radiations rival those of Darwin's finches and the Hawaiian honeycreepers in terms of the extent of adaptive radiation per unit time, both in terms of species numbers and in terms of phenotypic diversity. Tempo and patterns of morphological divergence are strongly supportive of an adaptive radiation in the oceanic islands driven by ecological interactions between sympatric white-eyes. Here, very rapid phenotypic evolution mainly affected taxa derived from the youngest wave of colonization, in accordance with the model of asymmetric divergence owing to resource competition in sympatry. PMID- 21599772 TI - Frequency and inheritance of non-male producing clones in Daphnia magna: evolution towards sex specialization in a cyclical parthenogen? AB - In Daphnia (Cladocera, Crustacea), parthenogenetic reproduction alternates with sexual reproduction. Individuals of both sexes that belong to the same parthenogenetic line are genetically identical, and their sex is determined by the environment. Previously, non-male producing (NMP) genotypes have been described in species of the Daphnia pulex group. Such genotypes can only persist through phases of sexual reproduction if they co-occur with normal (MP) genotypes that produce both males and females, and thus the breeding system polymorphism is similar to gynodioecy (coexistence of females with hermaphrodites), which is well known in plants. Here we show that the same breeding system polymorphism also occurs in Daphnia magna, a species that has diverged from D. pulex more than 100 MY ago. Depending on the population, between 0% and 40% of D. magna females do not produce males when experimentally exposed to a concentration of the putative sex hormone methyl farnesoate that normally leads to male-only clutches. Natural broods of these NMP females never contained males, contrasting with high proportions of male offspring in MP females from the same populations. The results from a series of crossing experiments suggest that NMP is determined by a dominant allele at a single nuclear locus (or a several closely linked loci): NMP * MP crosses always yielded 50% NMP and 50% MP offspring, whereas MP * MP crosses always yielded 100% MP offspring. Based on cytochrome c oxidase subunit I sequences, we found that NMP genotypes from different populations belong to three highly divergent mitochondrial lineages, potentially representing three independent evolutionary origins of NMP in D. magna. Thus, the evolution of NMP genotypes in cyclical parthenogens may be more common than previously thought. Moreover, MP genotypes that coexist with NMP genotypes may have responded to the presence of the latter by partially specializing on male production. Hence, these populations of D. magna may be a model for an evolutionary transition from a purely environmental to a partially genetic sex determination system. PMID- 21599773 TI - Phenotypic plasticity, heterochrony and ontogenetic repatterning during juvenile development of divergent Arctic charr (Salvelinus alpinus). AB - Phenotypic plasticity is a developmental process that plays a role as a source of variation for evolution. Models of adaptive divergence make the prediction that increasing ecological specialization should be associated with lower levels of plasticity. We tested for differences in the magnitude, rate and trajectory of morphological plasticity in two lake populations of Arctic charr (Salvelinus alpinus) that exhibited variation in the degree of resource polymorphism. We reared offspring on diet treatments that mimicked benthic and pelagic prey. Offspring from the more divergent population had lower levels of morphological plasticity. Allometry influenced the rate of shape change over ontogeny, with differences in rate among ecomorphs being minimal when allometric variation was removed. However, plasticity in the spatial trajectory of development was extensive across ecomorphs, both with and without the inclusion of allometric variation, suggesting that different aspects of shape development can evolve independently. PMID- 21599771 TI - Inter-island divergence within Drosophila mauritiana, a species of the D. simulans complex: Past history and/or speciation in progress? AB - Speciation with gene flow may be more common than generally thought, which makes detailed understanding of the extent and pattern of genetic divergence between geographically isolated populations useful. Species of the Drosophila simulans complex provide a good model for speciation and evolutionary studies, and hence understanding their population genetic structure will increase our understanding of the context in which speciation has occurred. Here, we describe genetic diversity and genetic differentiation of two distant populations of D. mauritiana (Mauritius and Rodrigues Islands) at mitochondrial and nuclear loci. We surveyed the two populations for their mitochondrial haplotypes, eight nuclear genes and 18 microsatellite loci. A new mitochondrial type is fixed in the Rodrigues population of D. mauritiana. The two populations are highly differentiated, their divergence appears relatively ancient (100,000 years) compared to the origin of the species, around 0.25MYA, and they exhibit very limited gene flow. However, they have similar levels of divergence from their sibling, D. simulans. Both nuclear genes and microsatellites revealed contrasting demographic histories between the two populations, expansion for the Mauritius population and stable population size for the Rodrigues Island population. The discovery of pronounced geographic structure within D. mauritiana combined to genetic structuring and low gene flow between the two island populations illuminates the evolutionary history of the species and clearly merits further attention in the broad context of speciation. PMID- 21599775 TI - Competition, breeding success and ageing rates in female meerkats. AB - Competition between females is particularly intense in cooperatively breeding mammals, where one female monopolises reproduction in each group. Chronic competition often affects stress and may therefore have long-term consequences for fitness, but no studies have yet investigated whether intrasexual competition has effects of this kind and, in particular, whether it affects rates of reproductive senescence. Here, we use long-term data from a wild population of meerkats to test whether reproductive success and senescence in dominant females are affected by the degree of intrasexual competition experienced prior to dominance acquisition. Females that experienced greater competition had lower breeding success and higher rates of reproductive senescence. Furthermore, females that were evicted from the group more frequently as subordinates had lower breeding success when dominant. We conclude that the intense intrasexual competition between females in cooperatively breeding groups may carry fitness costs over a longer period than is usually recognised. PMID- 21599776 TI - Experimental coevolution leads to a decrease in parasite-induced host mortality. AB - Host-parasite coevolution can lead to a variety of outcomes, but whereas experimental studies on clonal populations have taken prominence over the last years, experimental studies on obligately out-crossing organisms are virtually absent so far. Therefore, we set up a coevolution experiment using four genetically distinct lines of Tribolium castaneum and its natural obligately killing microsporidian parasite, Nosema whitei. After 13 generations of experimental coevolution, we employed a time-shift experiment infecting hosts from the current generation with parasites from nine different time points in coevolutionary history. Although initially parasite-induced mortality showed synchronized fluctuations across lines, a general decrease over time was observed, potentially reflecting evolution towards optimal levels of virulence or a failure to adapt to coevolving sexual hosts. PMID- 21599774 TI - Migratory divides and their consequences for dispersal, population size and parasite-host interactions. AB - Populations of migratory birds differ in their direction of migration with neighbouring populations often migrating in divergent directions separated by migratory divides. A total of 26% of 103 passerine bird species in Europe had migratory divides that were located disproportionately often along a longitudinal gradient in Central Europe, consistent with the assumption of a Quaternary glacial origin of such divides in the Iberian and Balkan peninsulas followed by recolonization. Given that studies have shown significant genetic differentiation and reduced gene flow across migratory divides, we hypothesized that an absence of migratory divides would result in elevated rates of gene flow and hence a reduced level of local adaptation. In a comparative study, species with migratory divides had larger population sizes and population densities and longer dispersal distances than species without migratory divides. Species with migratory divides tended to be habitat generalists. Bird species with migratory divides had higher richness of blood parasites and higher growth rates of Staphylococcus on their eggs during the incubation period. There was weaker cell-mediated immunity in adults and stronger cell lysis in species with migratory divides. These findings may suggest that migratory divides constitute barriers to dispersal with consequences for ecology and evolution of distributions, population sizes, habitats and parasite-host interactions. They also suggest that migratory divides may play a role in local adaptation in host-parasite interactions. PMID- 21599777 TI - Resolving the iterated prisoner's dilemma: theory and reality. AB - Pairs of unrelated individuals face a prisoner's dilemma if cooperation is the best mutual outcome, but each player does best to defect regardless of his partner's behaviour. Although mutual defection is the only evolutionarily stable strategy in one-shot games, cooperative solutions based on reciprocity can emerge in iterated games. Among the most prominent theoretical solutions are the so called bookkeeping strategies, such as tit-for-tat, where individuals copy their partner's behaviour in the previous round. However, the lack of empirical data conforming to predicted strategies has prompted the suggestion that the iterated prisoner's dilemma (IPD) is neither a useful nor realistic basis for investigating cooperation. Here, we discuss several recent studies where authors have used the IPD framework to interpret their data. We evaluate the validity of their approach and highlight the diversity of proposed solutions. Strategies based on precise accounting are relatively uncommon, perhaps because the full set of assumptions of the IPD model are rarely satisfied. Instead, animals use a diverse array of strategies that apparently promote cooperation, despite the temptation to cheat. These include both positive and negative reciprocity, as well as long-term mutual investments based on 'friendships'. Although there are various gaps in these studies that remain to be filled, we argue that in most cases, individuals could theoretically benefit from cheating and that cooperation cannot therefore be explained with the concept of positive pseudo-reciprocity. We suggest that by incorporating empirical data into the theoretical framework, we may gain fundamental new insights into the evolution of mutual reciprocal investment in nature. PMID- 21599779 TI - Refugees and good Samaritans. PMID- 21599778 TI - Blood parasites mediate morph-specific maintenance costs in a colour polymorphic wild bird. AB - Parasites can mediate profound negative effects on host fitness. Colour polymorphism has been suggested to covary genetically with intrinsic physiological properties. Tawny owl colour polymorphism is highly heritable with two main morphs, grey and brown. We show that experimental medication acts to reduce blood parasites and that medicated grey females maintain body mass during breeding, whereas medicated brown females decline in body mass similar to control females of both morphs. We find no effect of medication on general immunoglobulin levels, antigen-specific humoral response or H/L ratio. In the descriptive data, both morphs have similar blood parasite infection rates, but blood parasite infection is associated with decreased body mass in brown but not in grey females. We conclude that blood parasite infection primarily has somatic costs, which differ between the two highly heritable tawny owl colour morphs with more pronounced costs in the grey (little pigmented) morph than in the brown (heavily pigmented) morph. Because our descriptive results imply the opposite pattern, our findings highlight the need of experimental manipulation when studying heritable variation in hosts' response to parasitism. PMID- 21599780 TI - The raisin why. PMID- 21599781 TI - Sacrococcygeal teratoma: the 13-year experience of a tertiary paediatric centre. AB - AIM: To describe the management, morbidity and mortality of infants admitted to a tertiary paediatric hospital in New South Wales, Australia with a diagnosis of sacrococcygeal teratoma (SCT). METHODS: All neonates admitted to the neonatal intensive care unit with a SCT between January 1996 and December 2008 were included in this retrospective review. Data collected included maternal and neonatal demographics, time of diagnosis, tumour characteristics, surgical treatment, operative complications and outcomes. RESULTS: Seventeen infants with a diagnosis of SCT were included in the study. Of these infants, the majority (70%) were born at term, and eight had a prenatal diagnosis made during the second trimester. Associated anomalies were detected in seven infants (41.8%), with renal anomalies being the most common. Tumour histology included mature (50%, n= 8), yolk sac tumour (18.75%, n= 3), immature (6.25%, n= 1) and mature with mixed elements (25%, n= 4). Recurrent disease occurred in two infants within 4-18 months of the primary resection, with one infant suffering a second recurrence. Only one child died prior to surgery, giving a survival rate of 94%, and mean age at follow-up was 32 months. Long-term sequelae found in four babies included revision of scar, vesicoureteric reflux, post-surgical neurogenic bladder and osteotomy for hip dysplasia. CONCLUSIONS: The overall survival of neonatal SCT is high. While this is a small series, our results are consistent with the literature. Important components of management include timely diagnosis, multidisciplinary planning, long-term follow-up and intervention for functional sequelae. PMID- 21599783 TI - Bluish discoloration of hemiscrotum. PMID- 21599784 TI - Does pre-preparing endotracheal tubes increase the risk of contamination with potentially pathogenic bacteria? PMID- 21599785 TI - Vitamin K deficiency because of ceftriaxone usage and prolonged diarrhoea. PMID- 21599786 TI - Renal vein thrombosis with pulmonary embolism: first manifestation of lupus nephritis. PMID- 21599787 TI - Aortic coarctation and twin pregnancy. PMID- 21599788 TI - Hypernatraemia in a newborn because of salting of the skin. PMID- 21599789 TI - Famous first words. PMID- 21599791 TI - Positive contrast magnetic resonance bursography for assessment of the navicular bursa and surrounding soft tissues. AB - Magnetic resonance (MR) imaging is often performed to determine the cause of palmar heel pain. We evaluated how distension of the navicular bursa affected the MR appearance of the navicular bursa and associated structures. An MR evaluation was performed on normal cadaver limbs and cadaver limbs from horses with lameness localized to the foot. The normal navicular bursae were injected with 2, 4, or 6 ml of solution. The bursae of the feet from lame horses were injected with 4 or 6 ml, and the MR study was repeated. All bursae were examined grossly to verify the presence or absence of adhesions. Clinical patients that had initial MRI abnormalities suggesting adhesions were also evaluated. Distension of the proximal recess of the normal navicular bursa, proximal to the collateral sesamoidean ligament was achieved with 2 ml. Separation of the collateral sesamoidian ligament from the deep digital flexor tendon (DDFT) was achieved with 4 ml. The separation of the navicular bone from the DDFT and distal sesamoidian impar ligament required 6 ml. Adhesions were more clearly defined in the bursa of the two pathologic cadaver limbs following distension. MR bursography used on clinical patients allowed the determination of the presence or absence of adhesions. In these horses, this determination could not have been definitively made without this technique. MR bursography is useful in horses where the presence of adhesions cannot be clearly defined by MRI. PMID- 21599792 TI - Fractures of the distal phalanx and associated soft tissue and osseous abnormalities in 22 horses with ossified sclerotic ungual cartilages diagnosed with magnetic resonance imaging. AB - Ungual cartilage ossification in the forelimb is a common finding in horses. Subtle abnormalities associated with the ungual cartilages can be difficult to identify on radiographs. Magnetic resonance (MR) imaging findings of 22 horses (23 forelimbs) with a fracture of the distal phalanx and ossified ungual cartilage were characterized and graded. All horses had a forelimb fracture. Eleven involved a left forelimb (seven medial; four lateral), and 12 involved a right forelimb (five medial; seven lateral). All fractures were nonarticular, simple in configuration, and nondisplaced. The fractures were oriented in an axial proximal to abaxial distal and palmar to dorsal direction, and extended from the base of the ossified ungual cartilage into the distal phalanx. The fracture involved the fossa of the collateral ligament on the distal phalanx in 17 of 23 limbs. The palmar process and ossified ungual cartilage was abnormally mineralized in all horses. Ligaments and soft tissues adjacent to the ossified ungual cartilages were affected in all horses. The routine site of fracture in this study at the base of the ossified ungual cartilage extending into the distal phalanx suggests a biomechanical cause or focal stress point from cycling. The ligamentous structures associated with the ungual cartilages were often affected, showed altered signal intensity as well as enlargement and were thought to be contributing to the lameness. In conclusion, ossified ungual cartilages may lead to fracture of the palmar process of the distal phalanx and injury of the ungual cartilage ligaments. PMID- 21599793 TI - Anatomy of extrahepatic portosystemic shunts in dogs as determined by computed tomography angiography. AB - Congenital extrahepatic portosystemic shunts are anomalous vessels joining portal and systemic venous circulation. These shunts are often diagnosed sonographically, but computed tomography (CT) angiography produces high resolution images that give a more comprehensive overview of the abnormal portal anatomy. CT angiography was performed on 25 dogs subsequently proven to have an extrahepatic portosystemic shunt. The anatomy of each shunt and portal tributary vessels was assessed. Three-dimensional images of each shunt type were created to aid understanding of shunt morphology. Maximal diameter of the extrahepatic portosystemic shunt and portal vein cranial and caudal to shunt origin was measured. Six general shunt types were identified: splenocaval, splenoazygos, splenophrenic, right gastric-caval, right gastric-caval with a caudal shunt loop, and right gastric-azygos with a caudal shunt loop. Slight variations of tributary vessels were seen within some shunt classes, but were likely clinically insignificant. Two shunt types had large anastomosing loops whose identification would be important if surgical correction were attempted. A portal vein could not be identified cranial to the shunt origin in two dogs. In conclusion, CT angiography provides an excellent overview of extrahepatic portosystemic shunt anatomy, including small tributary vessels and loops. With minor variations, most canine extrahepatic portosystemic shunts will likely be one of six general morphologies. PMID- 21599794 TI - Radiographic diameter of the colon in normal and constipated cats and in cats with megacolon. AB - Radiographs of 50 cats with no history of gastrointestinal disease were evaluated to establish a normal reference range for radiographic diameter of the feline colon. Thirteen cats with constipation and 26 with megacolon were also evaluated and compared with the normal cats to characterize the accuracy of the reference range and to identify a cutoff to distinguish constipation from megacolon. A ratio of maximal diameter of the colon to L5 length was the most repeatable and accurate measurement. A ratio <1.28 is a strong indicator of a normal colon (sensitivity 96%, specificity 87%). A value >1.48 is a good indicator of megacolon (sensitivity 77%, specificity 85%). PMID- 21599795 TI - Imaging diagnosis-heterobilharzia americana infection in a dog. AB - An approximately three-year-old mixed breed female dog was evaluated for peritoneal effusion, anorexia, intermittent vomiting, and diarrhea. Radiographically, there was mineralization of the wall of small intestinal segments. Sonographic findings were consistent with multisystemic mineralization of liver, small intestinal wall, and pancreas. Multifocal granulomas containing schistosome eggs (Heterobilharzia americana) were identified histologically. The mineralization pattern described herein is an uncommon presentation of severe diffuse heterobilharziasis in a dog. PMID- 21599796 TI - Molecular and immunohistochemical detection of rotavirus in urinary sediment cells of children with rotavirus gastroenteritis. AB - This is the first report showing that rotavirus infects the urinary sediment cells in immunocompetent children with rotavirus gastroenteritis. We found that inclusion-bearing cells were frequently detected in the urine samples of patients with rotavirus gastroenteritis. These cells were positive for cytokeratin, which was sometimes coexpressed with rotavirus antigen, in our immunohistochemical analysis. Moreover, in nested RT-PCR experiments, we detected rotavirus double stranded RNA in some urine samples of patients with rotavirus gastroenteritis. We concluded that rotavirus could lead to infection of the urinary sediment cells concomitantly with rotavirus gastroenteritis. PMID- 21599797 TI - Mechanisms of resistance in clinical isolates of Pseudomonas aeruginosa less susceptible to cefepime than to ceftazidime. AB - The MIC of cefepime determined with the MicroScan WalkAway system was >=2 times higher than that of ceftazidime for 105 clinical isolates of Pseudomonas aeruginosa. This phenotype was confirmed by reference microdilution in 68 (64.8%) isolates, corresponding to 48 different rep-PCR patterns. The PSE-1 blactamase was identified in only 13.2% isolates, while oxacillinases were not identified in any of the 68 isolates. The level of expression of mexB, mexD and mexY was determined by real-time RT-PCR in eight clinical isolates representative of the different clones and patterns of susceptibility to cefepime and ceftazidime and in strain PAO1. All clinical strains overexpressed the mexY gene (18.3- to 152.7 fold in comparison with PAO1), although there was not a linear relationship between MIC of cefepime and level of mexY expression. Five of these strains contained mutations in the regulatory gene mexZ. mexD and mexB were also overexpressed in three and two isolates, respectively. Different mutations were observed in the regulatory genes nalD, mexR, nfxB and nalC. In conclusion, we have documented in our institution a polyclonal spread of P. aeruginosa with higher MICs of cefepime than of ceftazidime, related to overexpression of MexXY OprM, coincident in some isolates with the production of PSE-1, MexCD-OprJ or MexAB-OprM. PMID- 21599798 TI - Gestational choriocarcinoma of Fallopian tube diagnosed with a combination of p57KIP2 immunostaining and short tandem repeat analysis: case report. AB - Tubal choriocarcinoma is an extremely rare condition and can be of gestational or non-gestational origin. The appropriate management of choriocarcinoma begins with the categorization of the tumor. However, it is difficult to discriminate the two types by routine histological examination. We report the first case of gestational choriocarcinoma of the Fallopian tube to be confirmed by a combination of p57(KIP2) immunostaining and DNA polymorphism analysis at 15 short tandem repeat loci, along with X and Y chromosome markers. The patient had no detectable metastasis or evidence of recurrence 15 months after treatment, which involved surgery without adjuvant chemotherapy. This case demonstrates the usefulness of a combination of p57(KIP2) immunostaining and DNA polymorphism analysis in determining the origin of extrauterine choriocarcinoma (i.e. gestational or non-gestational), which helps to determine the strategy for treatment of the disease. PMID- 21599799 TI - Effects of intermittent high glucose on BeWo choriocarcinoma cells in culture. AB - AIM: The aim of this study was to investigate the cellular effects of intermittent high glucose on the human BeWo placental choriocarcinoma cell line, used as a model of the effects of glucose fluctuation in diabetic pregnancies. MATERIALS AND METHODS: BeWo cells were subjected to three different glucose conditions for 48 h: 7 mmol/L (control), 42 mmol/L (high glucose), or 7 and 42 mmol/L glucose (intermittent, alternated every 6 h). Cell viability was assessed using cell counts, a cell proliferation assay, and a cell viability assay. Apoptosis was also studied using a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay and by immunocytochemistry of fractin, the N terminal fragment of actin, which can distinguish apoptotic from necrotic cells. Furthermore, the expression of the well-known survival factors of trophoblast cells, heparin-binding epidermal growth factor-like growth factor and leptin, was evaluated by real-time polymerase chain reaction and Western blot analyses. RESULTS: Intermittent high-glucose conditions significantly decreased cell viability and enhanced apoptosis compared with control or continuous high-glucose conditions. Furthermore, the expression of heparin-binding epidermal growth factor-like growth factor, but not that of leptin, was significantly increased under intermittent high-glucose conditions compared to its expression under either control or continuous high-glucose conditions. CONCLUSIONS: These data indicate that intermittent high glucose is more deleterious to BeWo cells than continuous high-glucose conditions. Although further in vitro and in vivo study is necessary, excess fluctuation of glucose levels in the placental circulation might be involved in the impairment of placental development leading to the placental dysfunction. PMID- 21599800 TI - Gravid hysterectomy following history of recurrent ruptured uterus: case report. AB - The risk of uterine rupture and its associated morbidities increases as the incidence of cesarean deliveries increases. There is little evidence guiding the management of pregnancy termination in patients with a history of uterine rupture. A 21-year-old woman with a history of a classical cesarean delivery and four subsequent uterine ruptures presented for termination of pregnancy at 17 weeks and 2 days. Ultrasound study noted anterior wall implantation of the placenta covering the classical cesarean scar as well as the subsequent cesarean section scars. A scheduled gravid hysterectomy was performed to complete the pregnancy termination and avoid recurrent uterine rupture. Pathological examination revealed marked attenuation and fibrosis of the anterior uterine wall with diffuse placenta accreta and focal placenta percreta justifying the decision for hysterectomy in this young patient. We therefore suggest that gravid hysterectomy rather than dilatation and evacuation should be considered for pregnancy termination in patients with history of recurrent uterine rupture and suspicion for abnormal placentation. PMID- 21599801 TI - Comparing the effects of intrauterine progestin system and oral progestin on health-related quality of life and Kupperman index in hormone replacement therapy. AB - AIM: The aim of this study was to compare the effects of intrauterine-system releasing 20 ug daily of levonorgestrel (LNG IUS) plus 1 mg 17 beta-estradiol daily, orally with combined oral pill containing 1 mg 17 beta-estradiol/2 mg drospirenone daily as hormone replacement therapy, on health-related quality of life (HRQoL) and climacteric symptoms in postmenopausal women. MATERIALS AND METHODS: A 6-month prospective clinical trial was conducted at the Department of Obstetrics and Gynecology, Dr Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey. Ninety postmenopausal women were accepted to be part of the study. The Euro Quality of Life-5 Dimensions (EQ-5D) and Euro Quality of Life Visual Analogue Scale (EQ VAS) indexes for HRQoL and Kupperman indexes were compared between two groups of patients. RESULTS: Kupperman indexes of both treatment groups decreased gradually over 6 months, but indexes decreased significantly more in the group with intrauterine-system-releasing 20 ug daily of levonorgestrel. Elevations were observed in EQ-5D indexes and VAS values of both groups. EQ VAS values significantly increased in the group on intrauterine progestogen system. Similar changes were observed in the EQ-5D indexes of both groups. CONCLUSION: A hormone replacement therapy regimen that includes an intrauterine progestin system decreased climacteric symptoms and increased HRQoL in postmenopausal women during a follow-up period of 6 months. The extent of the relief of symptoms was greater in this group than in women receiving oral combined hormone replacement therapy. It seems therefore that the intrauterine progestin system could represent a method of choice for endometrial suppression in women using estrogen replacement therapy with distinct advantages over systemically administered progestogens, which have been the subject of considerable debate as reported in the recent literature. PMID- 21599802 TI - Case of asymptomatic portal vein thrombosis after cesarean delivery. AB - We report a case of acute portal vein thrombosis (PVT) after a cesarean delivery. The patient was admitted for treatment of severe pre-eclampsia. On the second day after cesarean delivery, the elevations of aspartic aminotransferase and alanine aminotransferase were observed. Thereafter, acute PVT was diagnosed with ultrasonography. Although early anticoagulant therapy seems to be effective in the treatment of acute PVT, close observation must be made due to the risk of bleeding. PMID- 21599803 TI - Intra-abdominal adhesion formation: does surgical approach matter? Questionnaire survey of South Asian surgeons and literature review. AB - AIM: The impact of postsurgical intra-abdominal adhesions, which represent a considerable burden for patients and health services, is often underestimated. Various factors influence adhesion formation, including the surgical approach. This study aimed to further understand the condition by investigating surgeons' perceptions of adhesion formation, particularly differences after laparoscopic and open surgery, and by performing a selective literature review. MATERIALS AND METHODS: South Asian surgeons attending endoscopy symposia in India and in Germany completed Likert-scale-based questionnaires on awareness of adhesion formation and associated consequences in gynecology. MEDLINE and PubMed were searched for articles published in 2000-2010 comparing laparoscopy and laparotomy in relation to adhesion formation. The results of the questionnaire study were then considered in view of findings from this review. RESULTS: In total, 43.1% (97/225) of questionnaires were completed. Respondents considered that laparoscopy caused fewer adhesions than laparotomy for all gynecological procedures. Although they believed their knowledge of adhesion formation was satisfactory, they widely underestimated the risk, giving estimated rates of 12.5% after laparoscopy and 36.3% after laparotomy. Twenty-eight studies were identified in the review. Most concluded that laparoscopy was less likely to cause adhesions than laparotomy but further statistical analysis was precluded because so many different definitions and classifications of adhesions had been used. CONCLUSIONS: The risk of adhesion formation was widely underestimated in the study group. Both the questionnaire study and the review concluded that laparoscopy results in less adhesion than laparotomy but further statistical comparison necessitates the development of standard definitions and classifications of adhesions. PMID- 21599804 TI - Prenatal diagnosis and management of vasa previa: a 6-year review. AB - AIM: To evaluate the methods of screening and prenatal diagnosis of vasa previa. MATERIAL AND METHODS: We reviewed cases of vasa previa in our hospital between January 2002 and December 2007. During this period, we visualized the site of cord insertion using transabdominal ultrasonography and observed the internal os using gray-scale transvaginal ultrasonography. A diagnosis of vasa previa was confirmed by transvaginal color Doppler imaging. RESULTS: We encountered 10 cases of vasa previa among 5131 deliveries. All cases had one or more known risk factors. In all of the four cases that underwent screening in the second trimester (i.e. between 20 and 25 weeks of gestation), the diagnosis was correct. Routine ultrasonography detected in only three of the other six cases of vasa previa that were referred to our hospital after 26 weeks of gestation. Of the other three cases referred after 26 weeks of gestation, in two cases vasa previa was detected by detailed examination using color Doppler transvaginal ultrasonography after fetal heart rate monitoring detected the presence of non reassuring fetal status; in the remaining case, we were unable to make an antenatal diagnosis. Non-reassuring fetal status was seen on fetal heart rate monitoring in four of the five detected cases complicated by preterm labor. CONCLUSION: We consider that the best timing of antenatal screening for vasa previa is the second trimester. Non-reassuring fetal heart rate pattern without other possible causes warrants detailed examination of vasa previa. PMID- 21599805 TI - Bilateral serous retinal detachment as a complication of acquired peripartum thrombotic thrombocytopenic purpura bout. AB - We report a case of a 26-year-old primigravid woman, believed to have HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet count) syndrome, which turned out to be a thrombotic thrombocytopenic purpura (TTP) bout. At the 40th gestational week, based on the clinical picture of HELLP syndrome, a cesarean section was performed and a dysmature male newborn was delivered. Afterwards, clinical symptoms and laboratory abnormalities persisted. Severe ADAMTS13 deficiency with the presence of inhibitory anti-ADAMTS13 antibodies revealed acquired thrombotic thrombocytopenic purpura bout, which was complicated with bilateral vision decrease due to bilateral retinal detachment. At the first ophthalmological examination, ultrasonography and binocular indirect ophthalmoscopy confirmed the diagnosis of the serous retinal detachment. After the diagnosis of acquired TTP bout, the patient was treated with multiple plasmapheresis and intravenous immunoglobulin with rapid improvement of the clinical and laboratory parameters. The ophthalmologic complications disappeared later without sequelae. At the 18-month examination, substantial visual acuity improvement without serous retinal detachment and full best corrected visual acuity were observed. PMID- 21599806 TI - Isolated broad ligament leiomyomatosis. AB - Leiomyomas of an extrauterine nature are rare and often present a more challenging diagnosis process for the clinician. Our patient presented with lower abdominal pain associated with menorrhagia over a period of 6 months. Laparoscopic surgery revealed a right-sided broad ligament myoma consisting of multiple soft and diffused fibroids, of more than 400 in total. The myomas were enucleated and completely removed by laparoscopic surgery with minimal blood loss. Histopathological examination and analysis revealed the multiple nodules to be benign leiomyomatosis. The finding of isolated broad ligament leiomyomatosis rates this case as a unique kind of leiomyoma. PMID- 21599807 TI - Cardiovascular risk factors in healthy women with previous small for gestational age infants. AB - AIM: To investigate whether healthy women with a previous pregnancy complicated by a small for gestational age (SGA) infant have normal endothelial function, carbohydrate and lipid metabolism, and normal inflammation parameters. MATERIAL AND METHODS: Brachial artery flow-mediated dilatation (FMD, endothelium dependent) was measured in 16 subjects with previous SGA, and in 15 controls (CTR) with previous normal pregnancies. Lipid panel, glucose, insulin, tumor necrosis factor alpha (TNF-alpha), soluble intercellular adhesion molecule-1 (s ICAM), soluble vascular (s-VCAM-1) adhesion molecule-1 (s-VCAM-1), and androgens were also measured. RESULTS: FMD was reduced in women with previous SGA compared to controls (P < 0.0001). SGA women showed increased insulin resistance (P < 0.0001), s-ICAM-1 (P = 0.008), TNF-alpha (P = 0.02), testosterone (P = 0.03), and diastolic blood pressure (P = 0.01) than CTR. CONCLUSION: Endothelial dysfunction, reduced insulin sensitivity and subclinical inflammation are present in otherwise healthy women with previous SGA. These abnormalities show that the presence of a SGA infant in the obstetric history should be considered as a risk factor for cardiovascular disease later in life. PMID- 21599808 TI - Cervical varix complicating marginal placenta previa: a unique coexistence. AB - Uterine cervical varix (CV) is a very rare condition during pregnancy and may cause moderate to severe hemorrhage. We present the third reported case of huge CV coexisting with placenta previa in the English literature. A 40-year-old chronic hypertensive patient with marginal placenta previa also had cervical varix causing hemorrhage. At the 38th gestational week emergent cesarean section was performed because of placental abruption. Placenta previa is a risk factor for CV and patients with placenta previa who have moderate bleeding should be examined for this coexistence. The choice of management is close follow-up and cesarean section close to term. PMID- 21599809 TI - Stercoral perforation of the colon during pregnancy. AB - A 39-year-old Japanese woman was referred to our hospital for severe abdominal pain at 22 weeks and 2 days of gestation. Abdominal computed tomography (CT) suggested perforation of the gastrointestinal tract and emergency surgery was conducted. There was a fibrous adhesion between an enlarged uterus and the sigmoid colon. There was a 5.0-cm perforation near the adhesion in the posterior wall of the sigmoid colon. We performed a partial resection of the sigmoid colon and Hartmann's procedure with copious intraperitoneal lavage. Five hours following the laparotomy, uterine contractions could not be controlled and the patient delivered vaginally. The neonate died almost immediately after delivery. We conclude that although stercoral bowel perforation is rare, poor prognosis after perforation emphasizes the need to carry out a CT scan for patients who present with undiagnosed severe abdominal pain and compatible medical history, even if the patient is pregnant. PMID- 21599810 TI - T-cell receptor beta polymorphism is not associated with endometriosis. AB - AIM: We carried out an association study between T-cell receptor beta polymorphism (TCRB) and endometriosis to investigate the difference in allelic frequency. Polymorphisms in T-cell receptor genes can provide important information for the study of the immune response and autoimmune diseases; indeed, rs1800907, a very common single nucleotide polymorphism (SNP) of the TCRB, has been extensively studied in autoimmune diseases in the 1990s using Southern blot analysis and more recently polymerase chain reaction (PCR) and sequencing. An autoimmune etiology for endometriosis has been strongly suggested for the presence of antibodies against endometrium, high rates of autoimmune disorders and associated atopic diseases. MATERIAL AND METHODS: We investigated 70 patients with endometriosis and 120 controls. DNA of patients and controls was studied by PCR followed by restriction digestion and sequencing to determine genotype and presence of linkage disequilibrium (LD). Statistical analysis was carried out using STATA Routine GENHW (StataCorp, College Station, TX, USA) for estimation of Hardy-Weinberg equilibrium and test power calculation. The difference of allele distribution between patients and controls was calculated according to Pearson's and Fisher's tests. Test power for the estimation of linkage disequilibrium is low (0.16). RESULTS: We performed an association study of the SNP rs1800907 of TCRB between 70 patients with endometriosis and 120 controls, and did not find any significant difference (chi(2) = 0.27 and P = 0.87). Fisher's test confirmed a P-value of 0.872. CONCLUSION: Our study does not suggest an evidential and major involvement of TCRB in the pathogenesis of endometriosis in an Italian population in a small case control study. PMID- 21599811 TI - Prognostic role of CD10+ myeloid cells in association with tumor budding at the invasion front of colorectal cancer. AB - The expression of CD10 in tumor cells has been reported to correlate with liver metastasis in colorectal cancer (CRC). However, fibroblasts and immune cells positive for CD10 at the tumor invasion front have not been comprehensively studied. We classified CD10 expression patterns into three types of cells, tumor cells (tCD10), stromal myofibroblasts (sCD10), and immune cells (iCD10), and investigated their correlation with the expression of transforming growth factor beta (TGF-beta1) protein and tumor budding grade. Several cell surface markers were stained to detect the phenotype of iCD10(+) cells, including CD3, CD20, CD11b, CD14, CD15, and CD163. Specimens and follow-up data of 206 CRC patients were examined. In multivariate analysis, iCD10 could be an independent prognostic factor for both recurrence-free survival and overall survival in stage I-III CRC (hazard ratio, 2.522 [1.299-4.896], P = 0.006; 2.890 [1.357-6.157], P = 0.006, respectively). The expression of sCD10 and iCD10 was strongly correlated with TGF beta1 expression in tumor cells and tumor budding grade. The phenotype of iCD10(+) cells was CD11b(+) and CD15(+) granulocytes. The infiltration of sCD10(+) fibroblasts and iCD10(+) granulocytes at the tumor invasion front might interact with TGF-beta1 protein expression and enhance tumor budding grade. The expression level of iCD10 at the tumor invasion front represented an independent prognostic biomarker in stage I-III CRC and could be integrated into a new staging system. PMID- 21599812 TI - NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy. AB - BACKGROUND AND PURPOSE: Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterized in the 'pure' phenotype by progressive spasticity and weakness of the lower limbs. In the 'complex' phenotype, additional neurologic symptoms or signs are found. Mutations in the NIPA1 gene have been reported to cause spastic paraplegia type 6 (SPG6) in 10 families. SPG6 is a rare form of autosomal dominantly inherited HSP associated with a pure phenotype; however, in one complex SPG6 family, idiopathic generalized epilepsy (IGE) has been described and in addition, recurrent microdeletions at 15q11.2 including NIPA1 have been identified in patients with IGE. The purpose was to identify NIPA1 mutations in patients with pure and complex HSP. METHODS: Fifty-two patients with HSP were screened for mutations in NIPA1. RESULTS: One previously reported missense mutation c.316G>A, p.Gly106Arg, was identified in a complex HSP patient with spastic dysarthria, facial dystonia, atrophy of the small hand muscles, upper limb spasticity, and presumably IGE. The epilepsy co-segregated with HSP in the family. CONCLUSION: NIPA1 mutations were rare in our population of patients with HSP, but can be found in patients with complex HSP. Epilepsy might be more common in SPG6 than in other forms of HSP because of a genetic risk factor closely linked to NIPA1. PMID- 21599813 TI - Diverse bacterial groups are associated with corrosive lesions at a Granite Mountain Record Vault (GMRV). AB - AIMS: This study applied culture-dependent and molecular approaches to examine the bacterial communities at corrosion sites at Granite Mountain Record Vault (GMRV) in Utah, USA, with the goal of understanding the role of microbes in these unexpected corrosion events. METHODS AND RESULTS: Samples from corroded steel chunks, rock particles and waters around the corrosion pits were collected for bacterial isolation and molecular analyses. Bacteria cultivated from these sites were identified as members of Alphaproteobacteria, Gammaproteobacteria, Firmicutes and Actinobacteria. In addition, molecular genetic characterization of the communities via nested-polymerase chain reaction-denaturing gradient gel electrophoresis (DGGE) indicated the presence of a broad spectrum of bacterial groups, including Alphaproteobacteria, Betaproteobacteria, Deltaproteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. However, neither cultivation nor molecular approaches identified sulfate-reducing bacteria (SRB), the bacteria commonly implicated as causative organisms were found associated with corrosive lesions in a process referred to as microbially influenced corrosion (MIC). The high diversity of bacterial groups at the corrosion sites in comparison with that seen in the source waters suggested to us a role for the microbes in corrosion, perhaps being an expression of a redox-active group of microbes transferring electrons, harvesting energy and producing biomass. CONCLUSIONS: The corrosion sites contained highly diverse microbial communities, consistent with the involvement of microbial activities along the redox gradient at corrosion interface. We hypothesize an electron transport model for MIC, involving diverse bacterial groups such as acid-producing bacteria (APB), SRB, sulfur-oxidizing bacteria (SOB), metal-reducing bacteria (MRB) and metal-oxidizing bacteria (MOB). SIGNIFICANCE AND IMPACT OF THE STUDY: The characterization of micro-organisms that influence metal-concrete corrosion at GMRV has significant implications for corrosion control in high-altitude freshwater environments. MIC provides a potential opportunity to further our understandings of extracellular electron transfer and interspecies communications. PMID- 21599814 TI - Isolation and phenotypic characterization of Lactobacillus casei and Lactobacillus paracasei bacteriophage-resistant mutants. AB - AIMS: To isolate and characterize bacterial strains derived from Lactobacillus casei and Lactobacillus paracasei strains and resistant to phage MLC-A. METHODS AND RESULTS: Two of nine assayed strains rendered resistant mutants with recovery efficiencies of 83% (Lact. paracasei ATCC 27092) and 100% (Lact. casei ATCC 27139). DNA similarity coefficients (RAPD-PCR) confirmed that no significant genetic changes occurred while obtaining resistant mutants. Neither parent nor mutant strains spontaneously released phages. Phage-resistant mutants were tested against phages PL-1, J-1, A2 and MLC-A8. Lactobacillus casei ATCC 27092 mutants showed, overall, lower phage resistance than Lact. paracasei ATCC 27092 ones, but still higher than that of the parent strain. Lactobacillus paracasei ATCC 27092 mutants moderately adsorbed phage MLC-A only in calcium presence, although their parent strain successfully did it with or without calcium. Adsorption rates for Lact. casei ATCC 27139 and its mutants were highly influenced by calcium. Again, phage adsorption was higher on the original strain. CONCLUSIONS: Several isolates derived from two Lact. casei and Lact. paracasei strains showed resistance to phage MLC-A but also to other Lact. casei and Lact. paracasei phages. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights isolation of spontaneous bacteriophage-resistant mutants from Lact. casei and Lact. paracasei as a good choice for use in industrial rotation schemes. PMID- 21599815 TI - Incidence and survival of non-O157 verocytotoxigenic Escherichia coli in soil. AB - AIMS: This study estimated the incidence of non-O157 verocytotoxigenic Escherichia coli (VTEC) in farm pasture soils and investigated the survival of non-O157 VTEC in clay and sandy loam soils. METHODS AND RESULTS: Twenty farms were tested over a 12-month period by sample enrichment in tryptone soya broth plus vancomycin, followed by PCR screening for the presence of vt1 and vt2 genes. Of the 600 soil samples, 162 (27%), across all farms, were found to contain vt1 and/or vt2 genes. The enrichment cultures from the 162 PCR-positive samples were plated onto Chromocult tryptone bile X-glucuronide agar (TBX), presumptive VTEC colonies recovered, confirmed as VTEC by PCR and serotyped. Samples of the two predominant soil types in Ireland (clay and sandy) were homogenized, characterized in terms of pH, boron, cobalt, copper, potassium, magnesium, manganese, phosphorus, zinc and organic matter content, inoculated with washed suspensions of eight non-O157:H7 soil isolates and six bovine faecal isolates and stored at 10 degrees C for up to 201 days. Inoculum survival rates were determined at regular intervals by recovering and plating soil samples on TBX. All inoculated non-O157 serotypes had highest D-values in the sandy loam soil with D-values ranging from 50.26 to 75.60 days. The corresponding range in clay loam soils was 31.60-48.25 days. CONCLUSIONS: This study shows that non-O157 VTEC occur widely and frequently in pasture soils and can persist in such environments for several months, with considerable opportunity for recycling through farm environments, and cattle, with clear potential for subsequent transmission into the human food chain. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first such study of non-O157 VTEC in farm soils and found that these VTEC are frequent and persistent contaminants in farm soils. In light of recent epidemiological data, non-O157 VTEC should be seen as an emerging risk to be controlled within the food chain. PMID- 21599816 TI - Impact of posterior urethral valves on pediatric renal transplantation: a single center comparative study of 297 cases. AB - OBJECTIVE: This is a retrospective long-term evaluation of the renal allografts and bladder functions in pediatric recipients who had posterior urethral valves (PUV). PATIENTS AND METHODS: Between March 1976 and February 2009, 2033 live donor renal transplantations were carried out in our center. Of these, 297 (14.2%) were in the pediatric age (<=18 yr). The pediatric recipients included 20 (6.7%) boys who developed end-stage renal disease as a late complication of PUV and recognized as group I while the remaining 277 pediatric recipients were defined as group II. Demographic characteristics, post-transplant complications and graft function were compared among both groups. Patient and graft survivals of both groups were also estimated. Moreover, the bladder function of the study group was evaluated by urodynamic studies. RESULTS: Patients with PUV (group I) were significantly younger than group II. Although the overall rate of urological complications in both groups was essentially similar, the incidence of urinary fistulae and urinary tract infection were higher in group I. The mean (SD) follow up periods for group I and II were 4.7 (4.1) and 6.4 (4.8) yr, respectively. At last follow up the serum creatinine values were similar among patients of both groups. Moreover, there were no differences in graft or patient survival at five and 10 yr. Detrusor over-activity could be elicited in only one of group I patients. Schafer nomogram showed non-obstructed pattern in all cases. CONCLUSION: Good functional outcome could be achieved for patients with PUV if renal transplantation is necessary. Pre-transplant surgical procedures may be required such as nephroureterectomy, cytoplasty or injection of refluxing ureters. A robust anti-refluxing uretero-vesical anastomosis is important, and can be achieved by a Lich-Gregoir procedure. PMID- 21599818 TI - Preemptive versus prophylactic protocol to prevent cytomegalovirus infection after renal transplantation: a meta-analysis and systematic review of randomized controlled trials. AB - OBJECTIVE: This review was conducted to assess the efficacy of preemptive versus prophylactic protocols for the prevention and treatment of cytomegalovirus (CMV) infection and disease after renal transplantation. METHODS: PubMed, EMBASE, the Cochrane Library, SCI, the China Journal Full-text Database, the Chinese Biomedical Database, the Chinese Scientific Journals Full-text Database, and the CMA Digital Periodicals were searched to collect randomized controlled trials (RCTs) of preemptive versus prophylactic protocols for the prevention and treatment of CMV infections after renal transplantation (up to April 2010). Two reviewers independently extracted data using a designed extraction form. The quality of the included trials was evaluated according to the Cochrane Handbook. RevMan 5.0 software was used for data analysis. RESULTS: Seven RCTs, involving 560 patients, were included. The results of the meta-analysis were as follows: the prophylactic protocol was significantly more effective than the preemptive protocol in reducing CMV infections and the recurrence rates of CMV infection; both the preemptive protocol and the prophylactic protocol reduced the risk of CMV disease, with no significant differences; no significant differences were observed in the risks of mortality, acute rejection, graft loss, other infections, or neutropenia between preemptive therapy and prophylaxis. CONCLUSION: Preemptive protocols are as effective as prophylaxis in reducing the risk of CMV disease in renal transplant recipients, whereas the prophylactic protocols could more effectively reduce the CMV recurrence rates. However, the trial data were very sparse, so further observations of the long-term effects of the protocols are needed. PMID- 21599817 TI - Blood stream infections after allogeneic stem cell transplantation: a single center experience with the use of levofloxacin prophylaxis. AB - Blood stream infections (BSIs) remain one of the major causes of morbidity and mortality for patients receiving an allogeneic hematopoietic stem cell transplantation (HSCT). In the present study, we evaluated the incidence and characteristics of BSI within 1 year after allogeneic HSCT in 269 consecutive adult patients who received antibacterial prophylaxis with levofloxacin. Cumulative incidence of BSI was 12% (95% confidence interval, 8-16%). Bacteria were responsible for 30 out of the 32 BSI, while fungi were responsible for 2 episodes of BSI. The median onset of BSI was day 8 (range 1-328 days) post transplant, and 66% of BSI occurred before neutrophil recovery. Gram-positive organisms accounted for 60% (n=18) of bacteremia, and gram-negative isolates for 40% (n=12) of the cases. Coagulase-negative staphylococci were the most commonly isolated gram-positive pathogens (53% of the cases), while Escherichia coli was the most commonly isolated gram-negative bacteria (58% of the cases). Candida albicans and Candida guillermondii were isolated from patients with candidemia. Resistance to fluoroquinolones (FQ) was common with 13% of gram-positive isolates being susceptible to FQ, while 50% of the gram-negative rods were susceptible to FQ. Crude mortality and mortality attributable to BSI were both 3% (1 of 32). In conclusion, our data suggest that despite the emergence of antibiotic resistance, FQ prophylaxis may be considered an appealing approach in allogeneic HSCT recipients and is also worth evaluating in randomized studies. PMID- 21599819 TI - Safety and efficacy of raltegravir in patients with HIV-1 and hepatitis B and/or C virus coinfection. AB - OBJECTIVE: The aim was to examine the long-term safety and efficacy of raltegravir in patients with HIV-1 and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) coinfection in three double-blind, randomized, controlled Phase III studies. METHODS: In STARTMRK, treatment-naive patients received raltegravir 400 mg twice a day (bid) or efavirenz 600 mg at bedtime, both with tenofovir/emtricitabine. In BENCHMRK-1 and -2, highly treatment-experienced patients with multi-drug resistant virus and prior treatment failure received raltegravir 400 mg bid or placebo, both with optimized background therapy. Patients with chronic HBV and/or HCV coinfection were enrolled if baseline liver function tests were <=5 times the upper limit of normal. HBV infection was defined as HBV surface antigen positivity for all studies; HCV infection was defined as HCV RNA positivity for STARTMRK and HCV antibody positivity for BENCHMRK. RESULTS: Hepatitis coinfection was present in 6% (34 of 563) of treatment-naive patients (4% HBV only, 2% HCV only and 0.2% HBV+HCV) and 16% (114 of 699) of treatment-experienced patients (6% HBV only, 9% HCV only and 1% HBV+HCV). The incidence of drug-related adverse events was similar in raltegravir recipients with and without hepatitis coinfection in both STARTMRK (50 vs. 47%) and BENCHMRK (34 vs. 38.5%). Grade 2-4 liver enzyme elevations were more frequent in coinfected vs. monoinfected patients, but were not different between the raltegravir and control groups. At week 96, the proportion of raltegravir recipients with HIV RNA <50 HIV-1 RNA copies/mL was similar between coinfected and monoinfected patients (93 vs. 90% in STARTMRK; 63 vs. 61% in BENCHMRK). CONCLUSION: Raltegravir was generally well tolerated and efficacious up to 96 weeks in HIV-infected patients with HBV/HCV coinfection. PMID- 21599820 TI - Hyperlactataemia in HIV-infected subjects initiating antiretroviral therapy in a large randomized study (a substudy of the INITIO trial). AB - OBJECTIVE: The aim of the study was to evaluate the predictive value of clinical and molecular risk factors, including peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), for the development of lactic acidosis (LA) and symptomatic hyperlactataemia (SHL). METHODS: In a substudy of a large multicentre, randomized trial of three antiretroviral regimens, all containing didanosine (ddI) and stavudine (d4T), in antiretroviralnaive, HIV-1-infected patients, patients with LA/SHL ('cases') were compared with those without LA/SHL in a univariate analysis, with significant parameters analysed in a multivariate model. In a molecular substudy, PBMC mtDNA and mtRNA from cases and matched controls at baseline and time of event were examined. RESULTS: In 911 subjects followed for a median of 192 weeks, 24 cases were identified (14 SHL and 10 LA). In univariate analysis, cases were more likely to be female (P=0.05) and to have a high body mass index (BMI) (P=0.02). In multivariate analyses, only BMI remained an independent predictor of the development of LA/SHL (P=0.03). Between cases and controls there was no significant difference in mtDNA copy number at baseline (389 vs. 411 copies/cell, respectively; P=0.60) or at time of event (329 vs. 474 copies/cell, respectively; P=0.21), in the change in mtDNA copy number from baseline to event (-65 vs. +113 copies/cell, respectively; P=0.12), in mtRNA expression at baseline or time of event, or in the change in mtRNA expression from baseline to event. CONCLUSION: The development of LA/SHL was associated with increased BMI, but PBMC mtDNA and mtRNA did not predict LA/SHL. This demonstrates the ineffectiveness of routine measurement of PBMC mtDNA in patients on ddI and d4T as a means of predicting development of LA/SHL. PMID- 21599821 TI - Sequential use of sorafenib and sunitinib in advanced renal-cell carcinoma (RCC): an Italian multicentre retrospective analysis of 189 patient cases. AB - OBJECTIVE: *To conduct a retrospective, multicentre, cohort analysis to assess the sequential use of the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib. PATIENTS AND METHODS: *Records of 189 patients with renal-cell carcinoma (RCC) who were treated with sorafenib and sunitinib sequentially between March 2004 and April 2009 at 12 Italian study centres were analysed. *Patients were treated under European Expanded Access Programmes or, following market approval, in general clinical practice. *Interventions were sorafenib (800 mg/day) and sunitinib (50 mg every day; 4 weeks on and 2 weeks off). *Progression free survival (PFS) during treatment with the first and second TKI was evaluated. RESULTS: *In all, 99 patients were treated with sunitinib followed by sorafenib (SuSo) and 90 were treated with sorafenib followed by sunitinib (SoSu); 104 (55%) patients had received prior systemic therapy, mostly with cytokines. *The median (range) PFS on the first TKI was similar between treatment groups [sorafenib 8.4 (1.1-28.9) months; sunitinib 7.8 (0.5-30.4) months; hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.78-1.40, P=0.758]. Multivariate analysis showed that good Memorial Sloan-Kettering Cancer Center status was associated with increased PFS. *After the second TKI, patients in the SoSu group had a longer median PFS than those in the SuSo group (7.9 months vs 4.2 months, respectively; HR 0.54, 95% CI 0.39-0.74, P<0.001). *Multivariate analysis showed only treatment and Eastern Cooperative Oncology Group performance status (and not age, gender, study centre or previous treatment) were significantly associated with duration of PFS. CONCLUSION: *Our findings suggest a limited cross-resistance between sorafenib and sunitinib and that the sequence SoSu may result in a longer combined PFS than SuSo. This is the largest retrospective study to date, though its findings are limited in part by the retrospective nature. PMID- 21599822 TI - Increases in bone turnover marker levels at an early phase after starting zoledronic acid predicts skeletal-related events in patients with prostate cancer with bone metastasis. AB - OBJECTIVE: To examine whether bone turnover markers could be predictive markers of the probability of newly arising skeletal-related events (SRE) after the start of zoledronic acid treatment in patients with prostate cancer with bone metastasis. PATIENTS AND METHODS: In all, 30 patients with prostate cancer with bone metastasis were treated with zoledronic acid infusion every 4 weeks. Serum C terminal crosslinking telopeptide of type 1 collagen (1CTP), bone alkaline phosphatase (BAP), and prostate-specific antigen (PSA) levels were measured at the start of zoledronic acid treatment to establish baseline values, and every 4 weeks thereafter. To judge in the early phase whether zoledronic acid is effective in these patients, we retrospectively compared 1CTP, BAP, and PSA levels at 1, 3, and 6 months after starting zoledronic acid treatment with those at baseline. RESULTS: SRE-free survival of patients with increases of 1CTP levels at 1 and 3 months and BAP levels at 3 months were significantly poorer than those of patients with decreases in 1CTP or BAP levels (P = 0.001, P = 0.042, and P = 0.004, respectively). Overall survival of patients with increases of 1CTP levels at 1 and 3 months and of BAP levels at 6 months were significantly poorer than those of patients with decreases of 1CTP or BAP levels (P = 0.013, P = 0.027, and P = 0.035, respectively). CONCLUSION: The measurement of 1CTP and BAP levels at an early phase after starting zoledronic acid treatment may be useful for physicians to inform patients of their prognosis and to determine the subsequent treatment plan. PMID- 21599823 TI - How often are patients with diabetes or hypertension being treated with partial nephrectomy for renal cell carcinoma? A population-based analysis. AB - What's known on the subject? and What does the study add? We know that a major benefit of partial nephrectomy (PN) over radical nephrectomy (RN) is greater preservation of kidney function. Emerging evidence also suggests that chronic kidney disease (CKD) correlates with survival, likely as a result of increased cardiovascular morbidity. We also know that Diabetes Mellitus (DM) followed by Hypertension (HTN) are the two most frequent causes of end-stage renal disease (ESRD). Given the strong association between renal functional decline and the surgical treatment of small renal masses, one would expect utilization of PN in patients with HTN or DM to be high, however minimal data exist on PN use in these populations. We are thus unable to determine whether these patients are being managed optimally. Our large study demonstrates that PN is being underutilized in patients at risk for CKD, particularly patients with Diabetes Mellitus and Hypertension. Unlike previously published reports, our population-level study provides a description of the landscape of care for patients with renal masses in general practice, and does not simply reflect treatment patterns at tertiary referral centers. The finding of low PN use in patients at risk for CKD deserves further study. Future studies should focus on determining the specific factors contributing to PN underutilization in these susceptible patients, as well as developing clinical tools to reliably identify those patients in whom the benefits of PN outweigh the risks. OBJECTIVE: * To determine partial nephrectomy (PN) use in patients at risk of chronic kidney disease (CKD), such as those with diabetes mellitus (DM) and hypertension (HTN). PATIENTS AND METHODS: * We conducted a national, population-based, retrospective, observational study using the Canadian Institute for Health Information Discharge Abstract Database. * We included all patients treated surgically for renal cell carcinoma from 1 April 1998 to 31 March 2008. * Patients with DM and HTN were identified using specific diagnosis codes. * The proportions of patients treated with PN were compared in patients with and without DM and HTN using multivariable logistic regression adjusting for covariates. RESULTS: * A total of 24,579 patients were treated for a renal mass; of these, 4292 (17.5%) underwent PN. * In our sample, 5613 (22.8%) patients were identified as having HTN, and 2738 (11.1%) were identified as having DM. * PN was used in 17.3% of patients with HTN compared to 17.5% of those without HTN, whereas, in patients with DM, PN was used in 18.6% compared to 17.3% of patients without DM. * After adjusting for covariates, neither HTN, nor DM were found to be independently associated with increased PN use (odds ratio, 1.07; 95% CI, 0.98-1.16 and odds ratio, 1.08; 95% CI, 0.96-1.20, respectively). CONCLUSIONS: * In this contemporary national analysis, PN appears to be underutilized in DM and HTN, despite their known relationship with chronic renal failure. * Further studies are needed to elucidate the specific factors contributing to PN underutilization in these susceptible patients. PMID- 21599826 TI - Hernan Cortes (1485-1547). PMID- 21599824 TI - Intratesticular pressure after testicular torsion as a predictor of subsequent spermatogenesis: a rat model. AB - OBJECTIVE: To assess the correlation between intratesticular pressure (ITP) after testicular torsion and subsequent testicular function using a rat model and to show that ITP at surgery is a useful predictor of future spermatogenesis. MATERIALS AND METHODS: Fourteen rats were divided into a torsion group (n= 7) and a control group with sham operation (n= 7). Torsion was created by 720 degrees rotation of the left testis in a counter-clockwise direction. Using a handheld compartment monitor, the ITP of the torsed testes was measured three times: before torsion (pre-torsion), just before torsion repair (pre-detorsion) and 5 min after torsion repair (post-detorsion). We evaluated the correlation between ITP and testicular weight, epididymal sperm count or pathological findings, such as the seminiferous tubule diameter (STD) and the modified Johnsen's score, 4 weeks after surgery. RESULTS: Mean (se) pre-torsion, pre-detorsion and post detorsion ITP values in the torsion group were 5.9 (2.5), 19.7 (10.7) and 8.2 (4.8) cm H(2) O, respectively. The ITP in torsed testes significantly increased after torsion (P < 0.01) and decreased after detorsion (P < 0.01). Strong correlations were observed between the reduction of ITP after detorsion and testicular weight (r= 0.87, P < 0.05), epididymal sperm count (r= 0.94, P < 0.05), STD (r= 0.87, P < 0.05) or the Johnsen's score (r= 0.99, P < 0.001). CONCLUSION: A smaller reduction in ITP after detorsion can be a risk factor for subsequent disturbance of spermatogenesis, suggesting that ITP can be an index for determining whether the affected testis should be removed after testicular torsion. PMID- 21599827 TI - Four-millimeter implants supporting fixed partial dental prostheses in the severely resorbed posterior mandible: two-year results. AB - BACKGROUND: Reduced alveolar bone volume complicates implant dentistry. PURPOSE: In this prospective multicenter study, a new, 4-mm long Straumann SLActive implant (O 4.1 mm) supporting a fixed dental prosthesis (FDP) in the severely resorbed posterior mandible was evaluated for two years. MATERIAL AND METHODS: Thirty-two patients (11 men, 21 women; mean age 64.1 years) participated. Ten to 12 weeks after single-stage surgery, a screw-retained FDP was attached to three or four 4-mm implants. RESULTS AND DISCUSSION: One hundred implants were inserted. Three failed at surgery and four were lost before loading. Twenty-eight patients received FDPs (93 implants). Two patients were discontinued because of secondary exclusion criteria; therefore, 26 patients were followed up from baseline (BL). After 1 year, one patient insisted on removal of all implants and one patient died because of nonstudy-related complications. Twenty-four patients (87 implants) were eligible for examination 2 years post-loading. All implants were found to be stable [survival rate 95.7% (confidence interval, CI 88.8-98.3) after 1 year and 92.3% (CI 84.5-96.2) after 2 years]. The mean change from BL to 12 months was - 0.43 mm (CI 0.31-0.59; p < .001) and from 12 to 24 months - 0.11 mm (CI -0.01-0.23; p = .056). The survival rate is only slightly lower than in similar studies on 6 to 8.5 mm implants. This may be related to high initial stability and effective use of the residual bone volume with high primary bone-to implant contact in dense bone structures. The surgical handling of the tested implant was found to be similar to that of implants of common length. However, the preparation procedure must be done with great care to avoid overdrilling. Careful planning and design of the prosthetic construction is mandatory to prevent unfavorable occlusion and avoid harmful shear forces. CONCLUSION: This study showed that 4 mm implants can support an FDP in severely resorbed posterior mandibles for at least 2 years and with healthy peri-implant conditions. PMID- 21599828 TI - Oral lichen planus and dental implants--a retrospective study. AB - OBJECTIVES: To examine whether oral lichen planus (OLP) affects the success rate of dental implants and if the manifestations of OLP are altered by implant-borne prostheses. MATERIALS AND METHODS: OLP patients, treated in the oral medicine department, with (the study group) and without (control group) dental implants were included. Pocket depth, mobility, bleeding on probing, erythema, pain and radiolucency around the implants, as well as clinical findings and OLP symptoms were recorded. Follow-up ranged from 12-24 months. Ordinal variables and visual analog scale score were compared using the Mann-Whitney test. The significance of the trend within each of the groups was assed using the Friedman test. Categorical variables were compared using Pearson chi-squared test and Fisher's exact test. RESULTS: Fourteen patients in the study group with 1-15 implants per patient and 15 in the control group were included. No implant failures were recorded. Comparison between the clinical manifestations of OLP in both groups did not reveal any significant differences. CONCLUSIONS: Success of implant rehabilitation among treated OLP patients does not seem to be different from the success rate in the general population. Nor does implant placement influence the disease manifestations. PMID- 21599829 TI - Localized management of sinus floor technique for implant placement in fresh molar sockets. AB - BACKGROUND: The use of osteotome for vertical bone augmentation and localized sinus elevation with minimal surgical trauma represents a suitable procedure to increase the vertical dimension of available bone for implant placement. PURPOSE: The aim of this study was to report clinical and radiographic results of localized management of sinus floor (LMSF) in fresh molar sockets at 13-year follow-up. MATERIALS AND METHODS: Fifty-three patients, needing one or two maxillary molar extraction, were enrolled in this study. LMFS procedure was performed and 68 implants were positioned. A presurgical distance from the alveolar crest to the floor of the maxillary sinus and the amount of new radiopacity between the sinus floor and alveolar crest were measured from the mesial and distal surfaces of each dental implant surface. RESULTS: After a mean follow-up period of 9.76 +/- 5.27 years (ranged from 4 to 17 years) a survival rate of 100% was reported. Mean bone height at temporary prosthesis placement was 7.99 +/- 1.16 mm. They were stable over time, reporting a mean value of 8.01 +/- 1.46 mm at 13-year follow-up. CONCLUSIONS: The results of this study demonstrated that LMSF procedure in fresh molar sockets allowed to expand the dimensions of resorbed posterior maxillary alveolar bone both vertically and horizontally with a success rate of 100% of implant osseointegration over time. PMID- 21599830 TI - The effects of cortical bone thickness and trabecular bone strength on noninvasive measures of the implant primary stability using synthetic bone models. AB - PURPOSE: This study investigated how the primary stability of a dental implant as measured by the insertion torque value (ITV), Periotest value (PTV), and implant stability quotient (ISQ) is affected by varying thicknesses of cortical bone and strengths of trabecular bone using synthetic bone models. MATERIALS AND METHODS: Four synthetic cortical shells (with thicknesses of 0, 1, 2, and 3 mm) were attached to four cellular rigid polyurethane foams (with elastic moduli of 137, 47.5, 23, and 12.4 MPa) and one open-cell rigid polyurethane foam which mimic the osteoporotic bone (with an elastic modulus 6.5 MPa), to represent the jawbones with various cortical bone thicknesses and strengths of trabecular bone. A total of 60 bone specimens accompanied with implants was examined by a torque meter, Osstell resonance frequency analyzer, and Periotest electronic device. All data were statistically analyzed by two-way analysis of variance. In addition, second order nonlinear regression was utilized to assess the correlations of the primary implant stability with the four cortex thicknesses and five strengths of trabecular bone. RESULTS: ITV, ISQ, and PTV differed significantly (p < .05) and were strongly correlated with the thickness of cortical bone (R(2) > 0.9) and the elastic modulus of trabecular bone (R(2) = 0.74-0.99). CONCLUSIONS: The initial stability at the time of implant placement is influenced by both the cortical bone thickness and the strength of trabecular bone; however, these factors are mostly nonlinearly correlated with ITV, PTV, and ISQ. Using ITV and PTV seems more suitable for identifying the primary implant stability in osteoporotic bone with a thin cortex. PMID- 21599831 TI - Peri-implant bone density in senile osteoporosis-changes from implant placement to osseointegration. AB - PURPOSE: The aim of this study was to examine healing over time after implant body placement in a senile osteoporosis model and a control group. MATERIALS AND METHODS: In this study, 16-week-old male mice were used. The senile osteoporosis model consisted of senescence-accelerated prone 6 mice and the control group consisted of senescence-accelerated resistant 1 mice. Titanium-coated plastic implants were used as experimental implants whose dimensions were 3.0 mm in length, 1.1 mm in apical diameter, and 1.2 mm in coronal diameter. Bone samples were collected at 5, 7, 14, 21, and 28 days after implant placement. A micro quantitative computed tomography (QCT) system was used to scan these samples and a phantom in order to quantitate bone mineral measurements. Bone mineral density (BMD) of each sample was measured. Each sample was also examined by light microscopy after QCT imaging. At 14 and 28 days after implant placement, the bone implant contact (BIC) ratios were calculated from light microscopy images and were divided into cortical bone and bone marrow regions. RESULTS: When BMD was compared between the osteoporosis and control groups using micro-QCT, the osteoporosis group had a significantly lower BMD in the region 0-20 um from the implant surface in the bone marrow region at 14 days onward after implant placement. Compared with the control group, the osteoporosis model also had significantly lower BMD in all regions 0-100 um from the implant surface in the bone marrow region at 14 days after placement. However, in the cortical bone region, no statistically significant difference was observed in the regions at the bone-implant interface. Light microscopy revealed osseointegration for all implants 28 days after implant placement. The osteoporosis model tended to have lower BICs compared with that of the control group, although this did not reach statistical significance. DISCUSSION: Our results showed that osseointegration was achieved in the osteoporosis model. However, the BMD was 30-40% lower than that of the control group in the region closest to the implant surface in bone marrow region. Peri-implant BMD was lower in a relatively large area in the osteoporosis model during an important time for osseointegration. Therefore, this result suggests that osteoporosis might be considered as a risk factor in implant therapy. CONCLUSION: The osteoporosis model had a lower BMD than the control group in the region closest to the implant during an important time for osseointegration. This result suggests that senile osteoporosis might be a risk factor in implant therapy. However, the osteoporosis model and the control group had no difference in peri-implant BMD in the cortical bone region. This suggests that risk might be avoided by implant placement that effectively uses the cortical bone. PMID- 21599832 TI - Clinical outcome of dental implants placed with high insertion torques (up to 176 Ncm). AB - BACKGROUND: Primary stability can be improved by using a tapered implant in a slightly underprepared implant site. This may lead to high compression forces and elevated insertion torques. It has been postulated that disturbance of the local microcirculation may occur, leading to necrosis of the osteocytes and bone resorption. PURPOSE: Report on the clinical outcome of 42 implants placed with an insertion torque equal or greater than 70 Ncm and evaluate bone levels around these implants. MATERIALS AND METHODS: This prospective study included 48 patients treated with 66 4.5 mm diameter Tapered Screw-Vent implants (Zimmer Dental(r), Carlsbad, CA, USA). Maximum insertion torque (MIT) was recorded with an electronic torque measuring device (Tohnichi(r) STC200CN, Hitachi, Tokyo, Japan). Nine implants (control group) presented MIT between 30 and 50 Ncm (mean = 37.1 Ncm) and 42 implants (experimental group) MIT greater than 70 Ncm (mean = 110.6 Ncm, range: 70.8-176 Ncm). Marginal bone levels were recorded at the time of loading and 1 year later for the two groups. RESULTS: After 2-3 months of non sumerged healing, all implants were clinically stable. Mean marginal bone resorption was 1.03 mm (SD = 0.44) for the control group (low torque) and 0.72 mm (SD = 0.56) for the experimental group (high torque) at time of loading, and 1.09 (SD = 0.62) and 1.24 mm (SD = 0.75), respectively, after 1 year. There were no significant differences between the two groups for bone stability and implant success rate. CONCLUSIONS: The use of high insertion torques (up to 176 Ncm) did not prevent osseointegration. Marginal bone levels in the control and experimental groups were similar both at the time of loading and 1 year later. PMID- 21599833 TI - Effect of smoking habits on accuracy of implant placement using mucosally supported stereolithographic surgical guides. AB - BACKGROUND: Smoking is considered as a factor for implant survival and peri implant bone loss of dental implants. Several studies revealed the negative effect of smoking on osseointegration and its dose-related effect. PURPOSE: To evaluate the effect of smoking habits on accuracy of implant placement using mucosally supported stereolithographic surgical guides. MATERIAL AND METHODS: Six OsseoSpeedTM implants (Astra Tech AB, Molndal, Sweden) were inserted into the maxilla in 13 patients. Patients were excluded if they suffered from any systemic disease or if they were actually taking any kind of medication. Software (Mimics(r) 9.0) was used to fuse images of the virtually planned and actually placed implants, and locations and axes were compared between the nonsmoking and smoking subgroups. As the mucosal biotype could probably influence accuracy data, 12 reference points were defined within each patient to define a mean mucosal thickness value. RESULTS: In the smoking subgroup, 36 implants were placed compared with 42 in the nonsmoking subgroup. Mean coronal deviation was 1.04mm (range: 0.29-2.45mm) among the smokers compared with 0.80mm among the nonsmokers (range: 0.29-1.67mm). At apical point, mean deviation was 1.26mm (range: 0.39 3.01mm) among the smokers compared with 1.02mm among the nonsmokers (range: 0.32 2.59mm). Mean angular deviation was 2.64 degrees (range: 0.41-6.81 degrees ) among the smokers compared with 2.57 degrees among the nonsmokers (range: 0.16 degrees -8.86 degrees ). Significant differences were found when comparing global coronal and apical deviation between the smokers and the nonsmokers (p<.05). Evaluating mucosal thickness, mean value was 3.19mm (range: 2.39-4.01mm) among the smokers compared with 2.43mm among the nonsmokers (range: 1.44-3.03mm). CONCLUSIONS: Statistically significant differences were found when comparing the accuracy of dental implant placement of the smokers with the nonsmokers. Smokers have significant thicker supporting mucosal tissues compared with nonsmokers, which may explain inaccuracy due to less stability of the surgical guide or the scanning prosthesis. PMID- 21599834 TI - Discriminating between the activities of human cathepsin G and chymase using fluorogenic substrates. AB - Cathepsin G (CG) (EC 3.4.21.20) and chymase (EC 3.4.21.39) are two closely related chymotrypsin-like proteases that are released from cytoplasmic granules of activated mast cells and/or neutrophils. We investigated the potential for their substrate-binding subsites to discriminate between their substrate specificities, aiming to better understand their respective role during the progression of inflammatory diseases. In addition to their preference for large aromatic residues at P1, both preferentially accommodate small hydrophilic residues at the S1' subsite. Despite significant structural differences in the S2' subsite, both prefer an acidic residue at that position. The Ala226/Glu substitution at the bottom of the CG S1 pocket, which allows CG but not chymase to accommodate a Lys residue at P1, is the main structural difference, allowing discrimination between the activities of these two proteases. However, a Lys at P1 is accommodated much less efficiently than a Phe, and the corresponding substrate is cleaved by beta2-tryptase (EC 3.4.21.59). We optimized a P1 Lys containing substrate to enhance sensitivity towards CG and prevent cleavage by chymase and beta2-tryptase. The resulting substrate (ABZ-GIEPKSDPMPEQ-EDDnp) [where ABZ is O-aminobenzoic acid and EDDnp is N-(2,4-dinitrophenyl) ethylenediamine] was cleaved by CG but not by chymase and tryptase, with a specificity constant of 190 mM(-1).s(-1). This allows the quantification of active CG in cells or tissue extracts where it may be present together with chymase and tryptase, as we have shown using a HMC-1 cell homogenate and a sputum sample from a patient with severe asthma. PMID- 21599835 TI - Experimental gentamicin nephrotoxicity and agents that modify it: a mini-review of recent research. AB - The aminoglycoside antibiotic gentamicin (GM) is still widely used against infections by Gram-positive and Gram-negative aerobic bacteria. Its therapeutic efficacy, however, is limited by renal impairment that occurs in up to 30% of treated patients. The drug may accumulate in epithelial tubular cells causing a range of effects starting with loss of the brush border in epithelial cells and ending in overt tubular necrosis, activation of apoptosis and massive proteolysis. GM also causes cell death by generation of free radicals, phospholipidosis, extracellular calcium-sensing receptor stimulation and energetic catastrophe, reduced renal blood flow and inflammation. Many drugs have been shown to either ameliorate or potentiate GM nephrotoxicity. This article aims at updating the literature that has been published in the past decade on the effects of agents that either ameliorate or augment the nephrotoxicity of this aminoglycoside. Notable among the new ameliorating procedures are gene therapy, such as intravenous cell therapy with serum amyloid A protein-programmed cells, and the use of some novel antioxidant agents and oils of natural origin. These include, for example, green tea, garlic saffron, grape seed extracts as well as sesame and oleanolic oils. Agents that may augment GM nephrotoxicity include indomethacin, cyclosporin, uric acid and the Ca(++) -channel blocker verapamil. Most of the nephroprotective agents mentioned here have not been tested in large controlled clinical trials. Because of their relative safety and effectiveness, antioxidant agents seem to be good candidates for testing in humans. PMID- 21599836 TI - Local ocular renin-angiotensin system - a target for glaucoma therapy? AB - An active local intraocular renin-angiotensin system (RAS) has recently been shown to exist in the human eye, and evidence is now accumulating that antihypertensive drugs acting on RAS can also lower intraocular pressure. They seem also to work as neuroprotective agents against retinal ganglion cell loss in vivo; though no compounds are in ophthalmological use at present. Classically, the highly vasoconstrictive angiotensin II (Ang II) is the key peptide in the circulatory RAS. However, the final effect of RAS activation at tissue level is more complex, being based not only on the biological activity of Ang II but also on the activities of other products of angiotensinogen metabolism, often exerting opposite effects to Ang II action. PMID- 21599837 TI - The pharmacological effect of positive KCNQ (Kv7) modulators on dopamine release from striatal slices. AB - Retigabine is an anti-epileptic drug that inhibits neuronal firing by stabilizing the membrane potential through positive modulation of voltage-dependent KCNQ potassium channels in cortical neurons and in mesencephalic dopamine (DA) neurons. The purpose of this study was to compare the effect of retigabine with other positive KCNQ modulators on the KCl-induced release of DA in rat striatal slices. Retigabine was found to inhibit KCl-dependent release of DA, and the IC(50) was estimated to be 0.7 MUM. The KCNQ channel blocker XE-991 enhanced striatal DA release and completely abolished the effect of retigabine. Other compounds of the same class but with some preferences for different KCNQ subtypes such as ICA-27243, BMS-204352 and S-(1) were also tested. All three compounds produced a significant effect albeit weaker than retigabine. The potency of ICA 27243 was in the range of retigabine, and with a lower potency of BMS-204352 and S-(1). This study demonstrates that KCNQ channel openers inhibit KCl-induced DA release at relevant concentrations. The equal potency of ICA-27243 and retigabine suggests that the KCNQ2/3 isoform is likely the dominant subtype mediating this effect. PMID- 21599838 TI - A quantitative meta-analysis on cue-induced male sexual arousal. AB - INTRODUCTION: Visually induced sexual arousal is a common occurrence in human behavior. The cerebral underpinnings of this response have been explored in recent neuroimaging studies. AIM: We set out to test the strength of evidence for the presence of a core network of brain regions involved in male sexual arousal elicited by erotic stimuli. METHODS: Eleven functional magnetic resonance imaging studies that presented erotic visual stimuli and compared the associated brain activity with the brain activity elicited by neutral visual stimuli were identified. MAIN OUTCOMES MEASURES: Activation likelihood estimation was employed to perform quantitative meta-analyses on coordinates of brain activation in order to assess significant concordance across studies. RESULTS: The meta-analysis included studies on heterosexual males and revealed consistent activation in the hypothalamus, thalamus, amygdala, anterior cingulate gyrus (ACC), insula, fusiform gyrus, precentral gyrus, parietal cortex, and occipital cortex across studies. Moreover, we explored brain responses associated with a physiological marker of sexual arousal (penile tumescence) and found concurrence in hypothalamus, thalamus, bilateral insula, ACC, postcentral gyrus, and occipital gyrus. CONCLUSIONS: This is the first quantitative meta-analysis on sexual cue reactivity and identifies a neural network consisting of cognitive (parietal cortex, ACC, thalamus, insula), emotional (amygdala, insula), motivational (precentral gyrus, parietal cortex), and physiological (hypothalamus/thalamus, insula) components constituting a core circuit of male sexual arousal in humans. PMID- 21599839 TI - Mechanics of knowledge translation. PMID- 21599840 TI - Effectiveness of educational interventions to raise men's awareness of bladder and bowel health. AB - BACKGROUND: Urinary incontinence is a common health problem with significant medical, psychological and economic burdens. Health education is capable of improving perceptions about and attitudes towards incontinence in turn encouraging them to seek help. AIM: The aim of the present study was to determine the effectiveness of educational interventions at raising men's awareness of bladder and bowel health. INCLUSION CRITERIA: Types of participants. Adult and adolescent men (age 12 years and over) and it was anticipated that some interventions/promotions may be directed at family members or carers of, and health professionals caring for, adult men and therefore these would also be considered for inclusion. Types of intervention. Any intervention, program or action that provided information, or attempted to raise awareness of men's bladder and bowel health. Type of outcome. Any measure defined by included studies such as: bladder and bowel management and treatment, increased knowledge of bladder and bowel health and number of attendees at promotion. Type of studies. Concurrent controls, such as: systematic reviews of concurrently controlled trials, meta-analysis, randomised controlled trials, controlled clinical trials, interrupted time series and controlled before after designs and observational design (cohort, case-control). Search strategy. A search for published and unpublished studies in the English language was undertaken restricted by a publication date of 10 years prior, with the exception of a review of seminal papers before this time. METHODOLOGICAL QUALITY: Each study was appraised independently by two reviewers using the standard Joanna Briggs Institute instruments. DATA COLLECTION AND ANALYSIS: Information was extracted from studies meeting quality criteria using the standard Joanna Briggs Institute tools. For two studies with similar population types, interventions and outcomes quantitative results were combined into a meta-analysis using Revman 5.0 software. However, the majority of studies were heterogenous and results are presented in a narrative form. RESULTS: With the exception of instruction for pelvic floor muscle exercises for men after prostatectomy, little quantitative research has been performed that establishes the effectiveness of interventions on men's awareness of bladder and bowel health. While numerous interventions have been trialled on mixed gender populations, and these trials suggest that the interventions would be effective, their effectiveness on the male component cannot be definitively established. CONCLUSION: There is little quantitative evidence for the effectiveness of interventions to improve men's awareness of bladder and bowel health therefore few recommendations can be made. Well-designed controlled trials using male sample populations only are needed. PMID- 21599841 TI - The effect of nurse staffing on clinical outcomes of children in hospital: a systematic review. AB - AIM: The aim of the present study was to identify any association between nurse staffing and clinical outcomes in hospitalised children. INCLUSION CRITERIA: Quantitative studies that evaluated the effect of nurse staffing on clinical outcomes of hospitalised children aged from 0-18 years. Measures of nurse staffing included nursing hours per patient day, nurse-to-patient ratio, skill mix and nurse characteristics such as level of education and years of experience. The clinical outcomes were those believed to be potentially sensitive to nursing care. Specifically, where the provision, or lack, of competent nursing care have made a difference to the outcome for the child (a nursing-sensitive outcome). Examples included mortality, healthcare-associated infections, failure to rescue, medication administration errors, postoperative complications and pressure ulcers. SEARCH STRATEGY: The search strategy aimed to find published and unpublished studies written in English between 1993 and 2010. Following an initial search of the Cochrane and Joanna Briggs Institute Libraries of Systematic Reviews, a three-step search strategy was utilised. First, a limited search of MEDLINE and CINAHL using keywords was undertaken and the words contained in the titles, abstracts and the index terms used to describe each article were analysed. A second search using all identified keywords and index terms was done. Third, the reference lists of all identified reports and articles were searched for additional relevant studies. METHODOLOGICAL QUALITY: Using the critical appraisal instrument from the Joanna Briggs Institute, each article was assessed by two independent reviewers for methodological quality before inclusion. RESULTS: Eight studies were included of which six were cohort, one case-control and one cross-sectional. Comparison across studies was limited as few clinical outcomes were the same; similarly there was a lack of consistency in the measures of nurse staffing. Fourteen different healthcare-associated infections and ten further clinical outcomes, of which eight were adverse events, were reported. Predictor variables were 10 different definitions of nurse staffing. Measures of Registered Nurse staffing were used most frequently. Increased Registered Nurse nursing hours per patient day was associated with decreases in eight adverse events. Similarly, higher Registered Nurse skill mix contributed positively to three clinical outcomes in children. However, there appears to be a level where increasing Registered Nurse hours no longer has a significant effect on decreasing adverse events. Results reporting association between children's outcomes and casual/agency nurses are equivocal. CONCLUSIONS: There is evidence that levels of nurse staffing are associated with clinical outcomes of children. Standardisation of nurse-sensitive indicators and measures of nurse staffing will enable empirical research. Further research to find the levels of Registered Nurse hours per patient day and proportion of Registered Nurse in the skill mix that maximises children's clinical outcomes is still required. PMID- 21599842 TI - Periodontal treatment during pregnancy and birth outcomes: a meta-analysis of randomised trials. AB - OBJECTIVE: The objective of this review was to conduct a meta-analysis of all up to-date randomised control trials to determine whether periodontal treatment during pregnancy has the potential of reducing preterm birth and low birth weight incidence. METHODS: Bibliographic databases MEDLINE (1966-present), EMBASE (1980 present), CINAHL (1982-present) and the Cochrane library up to and including 2010 Issue 10 were searched. The reference list of included studies and reviews were also searched for additional literature. Eligible studies were, published and ongoing randomised control trials that compared pregnancy outcomes for pregnant women who received periodontal treatment during the prenatal period. Two of the investigators independently assessed the studies and then extracted and summarised data from eligible trials. Extracted data were entered into Review Manager software and analysed. RESULTS: A total of 5645 pregnant women participated in the 10 eligible trials. Meta-analysis found that periodontal treatment significantly lowered preterm birth (odd ratio 0.65; 95% confidence interval, 0.45-0.93; P = 0.02) and low birth weight (odd ratio 0.53; 95% confidence interval, 0.31-0.92; P = 0.02) rates while no significant difference was found for spontaneous abortion/stillbirth (odd ratio 0.71; 95% confidence interval, 0.43-1.16; P = 0.17). Moderate heterogeneity was observed among the studies for preterm birth and low birth weight. Subgroup analysis showed significant effect of periodontal treatment in pregnant women with low rate of previous preterm birth/low birth weight (odd ratio 0.35; 95% confidence interval, 017-0.70; P = 0.003) and less severe periodontal disease (odd ratio 0.49; confidence interval, 028-0.87; P = 0.01) as defined by probing depth. CONCLUSION: The cumulative evidence suggests that periodontal treatment during pregnancy may reduce preterm birth and low birth weight incidence. However, these findings need to be further validated through larger more targeted randomised control trials. PMID- 21599843 TI - Identification and nursing management of dysphagia in individuals with acute neurological impairment (update). AB - AIM: Dysphagia, or difficulty in swallowing, is a serious and life-threatening medical condition that affects a significant number of individuals with neurological impairment. We conducted an update of a previous systematic review to examine the evidence regarding the nursing role in the recognition and management of dysphagia in adults with neurological impairment and the effectiveness of nursing interventions in the recognition and management of dysphagia. METHODS: We conducted extensive database and internet searches and retrieved original quantitative research studies published between January 1998 and January 2008. Quantitative papers selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the review. Any disagreements that arose between the reviewers were resolved through discussion, or with a third reviewer. The data extracted included specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Due to significant variability in study methodology, populations and interventions, no statistical meta-analysis was possible. RESULTS: Forty-two quantitative studies were retrieved and, of these, 17 met the inclusion and quality criteria, representing a wide range of quantitative research methodologies. The evidence from this updated review indicates that nurses are well placed to conduct dysphagia screening and that there are several tools available that may be suitable for them to use. It is important that formal dysphagia screening protocols are in place and that nurses are trained to use them. If nurses screen patients with an acute neurological impairment within 24 h of admission, it may reduce the time that patients spend without appropriate methods of nutrition and hydration and improve clinical outcomes. Dysphagia screening by nurses does not replace assessment by other health professionals; instead it enhances the provision of care to patients at risk by allowing for early recognition and intervention to occur. Dysphagia screening by nurses is an important initial step in the care of patients with acute neurological impairment, but in order to achieve the best outcomes, it needs to be followed up with careful, consistent management of food and fluid intake. PMID- 21599844 TI - Factors affecting effective communication between registered nurses and adult cancer patients in an inpatient setting: a systematic review. AB - AIM: To establish the best available evidence regarding the factors affecting effective communication between registered nurses and inpatient cancer adults. METHOD: Electronic databases (CINAHL, Ovid, PubMed, ScienceDirect, Scopus and Wiley InterScience) were searched using a three-step search strategy to identify the relevant quantitative and qualitative studies published in English. The grey literature was not included in the review. The identified studies were evaluated using the guidelines from the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information. A total of three studies were included in the quantitative component of the review, and the data were presented in a narrative summary. Five studies were included in the qualitative component of the review, and the findings were categorised in a meta-synthesis which generated four synthesised findings. RESULTS: The factors that were found to influence effective communication were identified in the characteristics of nurses, patients and the environment. The promoting factors in nurses included genuineness, competency and effective communication skills. The role of post basic training in improving nurse-patient communication remained inconclusive. Conversely, nurses who were task-orientated, who feared death and who had low self-awareness of their own verbal behaviours inhibited communication. Nurses were also observed to communicate less effectively when delivering psychosocial aspects of care and in emotionally charged situations. On the other hand, patients who participated actively in their own care and exhibited information seeking behaviour promoted communication with the nurses. However, patients' unwillingness to discuss their disease/feelings, their preference to seek emotional support from their family/friends and their use of implicit cues were some of the factors that were found to inhibit communication. A supportive ward environment increased facilitative behaviour in nurses, whereas conflict among the staff led to increased use of blocking behaviours. Cultural norms within the Chinese society were also found to inhibit nurse-patient communication. CONCLUSION: Within the constraints of the study and the few quality papers available, it appeared that personal characteristics of patients and nurses are the key factors that influence effective nurse-patient communication within the oncology setting. Very little evidence exists to explain the role of environment in effective nurse-patient communication, particularly within an Asian setting. IMPLICATIONS FOR PRACTICE: Training can be implemented to inform nurses about the communication challenges, to equip them with effective communication skills and improve their receptivity to patient cues. Information-sharing can be used as a non-threatening approach to initiate rapport-building and open communication. Nurses should consider patients' psychological readiness to communicate and respect their preference as to whom they wish to share their thoughts/emotions with. Hospitals/institutions also need to ensure a supportive ward culture and appropriate workload that will enable nurses to provide holistic care to patients. IMPLICATIONS FOR RESEARCH: Further research on the effect of the Asian culture on effective communication within the oncology setting is required to expand the knowledge in this area. Studies to ascertain the effect of the patient's age and place within the oncology treatment cycle are also warranted. The lack of evidence on the effectiveness of post-basic communication education also requires further investigation. PMID- 21599845 TI - Implementation of a protocol for the prevention and management of extravasation injuries in the neonatal intensive care patient. AB - AIM: This project sought to determine nurses' understanding and management of infants with intravenous (IV) therapy. There were three specific aims: * To improve identification and management of extravasation injuries in neonates * To ensure management of extravasation injuries in neonates is classified according to IV extravasation staging guidelines * To develop a protocol that outlined actions required to manage extravasation injuries. METHODS: This project utilised a pre- and post-implementation audit strategy using the Joanna Briggs Institute (JBI) Getting Research into Practice (GRIP) program. This method has been used to improve clinical practice by utilising an audit, feedback and re-audit sequence. The project was implemented in four stages over a 7-month period from 21 October 2009 to 30 May 2010. RESULTS: Initially, there was poor compliance with all four criteria, ranging from zero to 63%. The GRIP phase of the project identified five barriers which were addressed throughout this project. These related to education of staff and the development of a protocol for the prevention and management of extravasation injuries in the neonatal population. Following implementation of best practice, the second audit showed a marked improvement in all four criteria, ranging from 70 to 100% compliance. CONCLUSIONS: Overall, this project has led to improvements in clinical practice in line with current evidence. This has resulted in enhanced awareness of the risks associated with IV therapy and of measures to prevent an injury occurring within this clinical setting. PMID- 21599846 TI - Translating evidence into nursing practice: oral hygiene for care dependent adults. AB - BACKGROUND: Oral hygiene is necessary to maintain the health and well-being of hospitalised patients. However, studies indicated that nurses lacked the evidence based knowledge to deliver proper care. A prior survey conducted on nurses working in the intensive care and high dependency units in our institution revealed that oral care practices varied and highlighted the need for an oral care protocol. These triggered us to embark on an evidence-based project on oral care to improve patients' oral health during their hospitalisation. AIM: We aimed to translate the best available evidence to improve our oral care practices. METHODS: We followed the Iowa Model of Evidence-based Practice. Having identified a problem, we formed a team. We searched for best available evidence on oral care management and appraised them using the Scottish Intercollegiate Guidelines Network checklists. We developed an evidence-based oral care protocol and outlined key changes necessary to improve patients' oral care during hospitalisation. We chose the medical intensive care unit and a neurology ward to pilot the changes. The changes included introducing an oral assessment guide to assess patients' oral condition and intervening appropriately according to their risk levels, recommending 0.2% chlorhexidine solution as the main oral cleaning solution, and standardising oral care documentation. We compared the pre- and post-audits to assess improvement in the nurses' knowledge and compliance to the protocol. Auditors also physically inspected the oral health of functionally dependent patients under the charge of the audited nurses. RESULTS: The team involved 25 patients and 25 nurses in each pre- and post-audits. The median pre- and post-scores were 60% and 100%, respectively. The results revealed that the project led to improvements in nurses' oral care knowledge and practices, especially in nurses taking appropriate interventions as recommended, and in correctly using oral care products to clean patients' mouths. Auditors reported improvement in patients' oral care during their physical assessments of patients' oral cavities. This finding was supported by feedback from other healthcare providers. CONCLUSIONS: This evidence-based project heightened nurses' awareness and knowledge on oral care, and led to nurses providing practices based on best available evidence. These have translated to improvements in patients' oral health. PMID- 21599847 TI - Knowledge translation in the discourse of professional practice. AB - Clients and practitioners desire up-to-date, safe and effective healthcare. Knowledge translation, a term used to describe the interchange of knowledge between its producers and users, aims to support this desire. Knowledge, and by extension knowledge translation, is subject to varying perspectives ranging from the objective truth-tested knowledge of empiricism, associated by some with academia, to knowledge in the practitioner realm. This latter knowledge is often based on multiple users' experiences and contexts, thus constructed to meet their needs. The goal of this paper is to compare and contrast knowledge and knowledge translation from empirical and constructivist perspectives. It then relates knowledge translation to professional practice discourse and concludes with thoughts on constructivist knowledge translation strategies, including practitioner-driven strategies derived from practice. For example, knowledge translation can be woven into processes to train/integrate new graduates into the healthcare system, it can be captured in practitioner-driven provision of continuing education, and/or it can be facilitated through practitioner collaboration in research via action research approaches. Regardless of the perspective taken, delivery of up-to-date, safe and effective care requires useful, relevant knowledge available when necessary and applicable to real-life issues as perceived, critically, by the knowledge end-user. PMID- 21599852 TI - Distribution of the HLA class II frequency alleles in patients with leprosy from the mid-west of Brazil. AB - In an attempt to clarify the issue of genetic predisposition to leprosy, we examined the distribution of class II human leucocyte antigen variants (DR and DQ) in 70 patients from around the city of Goiania, Brazil. Only two of the patients presented the tuberculoid form of the disease, whereas 17 fell into the lepromatous category; 51 were intermediate. The allele frequencies found were compared with those in a group of 77 healthy controls. We found an increased frequency of the HLA-DRB1*11 allele in patients with lepromatous leprosy compared with healthy controls (P=0.0132; RR=4.130, 95% Cl: 1.338 to 12.747). These results suggest that the DRB1*11 allele could be related with susceptibility to lepromatous leprosy in Brazil. PMID- 21599853 TI - Analysis of CTLA4 gene variant in infertile Brazilian women with and without endometriosis. AB - An autoimmune aetiology has been suggested for endometriosis mostly on the basis of an increased prevalence of autoimmune diseases in affected women. Cytotoxic T lymphocyte antigen (CTLA) 4 gene is recognized as a primary determinant for autoimmunity, since specific polymorphisms have been associated with predisposition to most autoimmune disorders. Thus, the objective of the study was to evaluate CTLA4 polymorphism (+49A/G) in a group of infertile women with and without endometriosis and controls. Case-control study comprising 244 infertile women (177 with endometriosis and 67 without endometriosis) and 172 fertile women as controls. CTLA4 polymorphism was identified by qPCR. The results were analysed statistically and a P-value <0.05 was considered significant. We found relatively similar CTLA4 polymorphisms genotype frequencies in women with and without endometriosis and controls (P=0.158 and P=0.262, respectively). When the patients with minimal/mild endometriosis and moderate/severe endometriosis were studied separately, no difference was also found related to controls (P=0.560 and P=0.11, respectively). The data suggest that the CTLA4 polymorphism is not associated with endometriosis and/or infertility in Brazilian women. PMID- 21599854 TI - Interaction between the antibiotic tetracycline and the elongation factor 1alpha from the archaeon sulfolobus solfataricus. AB - The interaction between tetracycline and the archaeal elongation factor 1alpha from Sulfolobus solfataricus was investigated. The effects produced by this eubacterial antibiotic indicated that this interaction involved the G-domain of the elongation factor 1alpha from S. solfataricus, although also the M-domain was required. In fact, in the presence of the antibiotic, an increase in the fluorescence quantum yield of the aromatic region was observed for elongation factor 1alpha from S. solfataricus and its truncated form lacking the C-terminal domain, but not for that lacking also the M-domain. The increase in quantum yield was restored when the G-domain of elongation factor 1alpha from S. solfataricus was fused to the M and the C-domains of the eubacterial analogue elongation factor Tu. Tetracycline inhibits protein synthesis catalysed by elongation factor 1alpha from S. solfataricus; this is accompanied by an increase in the GDP/GTP exchange rate and a slight inhibition of the intrinsic GTPase, suggesting that a main effect of the antibiotic was exerted on the GTP-bound form of the enzyme. Furthermore, the mixed inhibition observed for GTPase confirmed that the interaction, besides the G-domain, involved also other region(s) of elongation factor 1alpha from S. solfataricus. These results can be useful for studying potential side effects arising from the interaction between tetracycline and eukaryotic elongation factors. PMID- 21599855 TI - Diagnostic value of anti-GBV-C antibodies in HIV-infected patients. AB - The beneficial effect of co-infection by GB virus C (GBV-C) in the course of the disease in human immunodeficiency virus (HIV)-infected patients has been described, although its mechanism of action is yet to be determined. The role of anti-GBV-C antibodies in HIV-infected patients also remains unknown. At present, there are no commercial systems to detect specific markers of GBV-C infection. The research presented follows our previous work from which we obtained chimeric molecules formed by two domains of different GBV-C proteins with good sensitivity/specificity balances in the detection of anti-GBV-C antibodies in hemodialyzed and chronic hepatitis patient samples. It has been investigated the ability of the synthetic peptides to recognize specific anti-GBV-C antibodies in HIV and HCV/HIV co-infected patients by a peptide-based ELISA immunoassay. The results showed that human immunodeficiency virus-infected patients have a significantly higher frequency of anti-GBV-C antibodies than healthy controls. A comparison between HCV(+) /HIV(+) and HCV(-) /HIV(+) was analyzed. Although a higher percentage of HCV/HIV-positive sera were positive for antibodies against GBV-C peptides, the difference was not significant. The presence of anti-GBV-C antibodies could represent a good marker of exposure to GBV-C in HIV-infected patients to facilitate a further analysis of the effect of this exposure in the progression of illness caused by HIV infection. PMID- 21599856 TI - Role of interactions and volume variation in discriminating active and inactive forms of cyclin-dependent kinase-2 inhibitor complexes. AB - Molecular recognition process occurs through various non-bonded interactions in protein-ligand complexes. Analysis and visualization of interactions in a set of protein-ligand complexes provide insight for structure-based drug design. In the present study, we have made a comprehensive analysis on similarities and differences observed in hydrophobic interactions and hydrogen bond interactions of 170 X-ray crystal structures of active and inactive cyclin-dependent kinase-2 (CDK-2) ligand complexes obtained from the Protein Data Bank. We have also systematically analyzed variation of protein binding cavity volume (PCV) and ligand volume (LV) in CDK-2 ligand complexes. Hierarchical clustering of interaction patterns of CDK-2 ligands have been carried out in active and inactive forms. In PCV and LV analysis, PCV variation was observed to be high for inactive conformation and less for active conformation; the latter was found to bind ligands with higher volume. Further, correlation of interactions, PCV, and LV with the binding affinity was analyzed in active and inactive forms. Analysis of interactions and volume changes revealed the marked difference in CDK-2 active and inactive conformations. In conclusion, this study highlights the importance of considering inactive conformation in the docking and scoring methods to attain selectivity and potency. PMID- 21599857 TI - Exploring QSARs for 5-lipoxygenase (5-LO) inhibitory activity of 2-substituted 5 hydroxyindole-3-carboxylates by CoMFA and CoMSIA. AB - A series of indole and related benzo[g]indole compounds displaying potent activities against 5-lipoxygenase were selected to establish three-dimensional quantitative structure-activity relationships using comparative molecular field analysis and comparative molecular similarity indices analysis methods. A training set of 37 active compounds was used to develop the models, which were then valuated by a series of internal and external cross-validation techniques. A test set of seven compounds was used for the external validation. Models with greater than 70% predictive ability, as determined by external validation, and high internal validity (cross-validated q(2)>0.5) have been developed. The satisfactory comparative molecular field analysis model predicted a q(2) value of 0.779 and an r(2) value of 0.957 and revealed that electrostatic and steric properties play a significant role in potency. The best comparative molecular similarity indices analysis model, based on a combination of steric, hydrophobic, and H-bond donor effects, predicted a q(2) value of 0.816 and an r(2) value of 0.953. The models were graphically interpreted using comparative molecular field analysis and comparative molecular similarity indices analysis contour plots that provided insight into the structural requirements for increasing the activity of a compound. The results obtained from this study provide a solid basis for future rational design of more active 5-lipoxygenase inhibitors. PMID- 21599858 TI - Transformations of 3-hydroxy steroids with lewis and anhydrous protic acids: the case of pregn-4-en-3beta,17alpha,20beta-triol. AB - The acid-catalyzed dehydration is one of the most important processes, which transforms 3-hydroxy steroids into their corresponding unsaturated derivatives. This reaction is of great importance because it can produce molecules that play a key role in the understanding of the natural metabolism of steroids. Sterol dehydration is generally performed with aqueous acidic systems, and the treatment often affords low yields of the desired compounds and/or complex mixtures of by products. In this paper, we report the results obtained from the study of the structural and stereochemical effects of the acid-induced reaction of pregn-4-en 3beta,17alpha,20beta-triol in anhydrous systems. In particular, the treatment of this trihydroxy steroid model with Lewis acids leads to the corresponding Delta(3,5) -steradiene as the only product and in very high yields. With Lewis acids, no modifications of the 1,2-diol function on the D-ring are observed, even when the reactions are performed at high temperatures. Protic acid catalysis in non-aqueous organic solvents causes the formation of an epimeric mixture of the corresponding Delta(3,5) -steradiene derivatives by a partial stereochemical inversion of the asymmetric C-17. The reactivity of the 17alpha,20beta-diolic residue is also evaluated by exposing pregn-4-en-3beta,17alpha,20beta-triol and the corresponding Delta(3,5) -steradiene to the prolonged action of anhydrous protic acid systems under thermal conditions. PMID- 21599859 TI - Oral presentations--the heart of the matter. PMID- 21599860 TI - Marketing code of ethics for pediatric cardiology programs. PMID- 21599861 TI - Diabetes in youth: a dilemma of pathogenesis. PMID- 21599862 TI - Self-monitoring of blood glucose: role in type 2 diabetes. PMID- 21599863 TI - 4th International Conference on Advanced Technologies and Treatments for Diabetes. PMID- 21599864 TI - Education and management of diabetes at The University of Tokyo Hospital. AB - Along with reduced physical activity, increased fat intake, and intensified psychological stresses associated with work and social life, the number of diabetic patients and diabetes-related complications has increased significantly in Japan. Our aim at The University of Tokyo Hospital is to provide comprehensive diabetes treatment, including the use a diabetes handbook with guidelines for the diagnosis and treatment of diabetes consistent with evidence-based medicine. Diabetes specialists and certified diabetes educators work together to provide the best possible treatment. In addition, we have established a diabetic foot care service for outpatients, with the objective of preventing diabetes-related foot disease. The inpatients wards offer the most ideal diabetes treatments, including diet therapy, exercise therapy, guided self-monitoring of blood glucose, daily body weight measurement, and diabetes seminars. All these services provide guidelines that encourage patient self-management even after discharge from hospital. Management dietitians use food samples and a Food Exchange Table to brief patients about nutrition guidelines. Exercise therapy programs are developed according to the specific needs of each individual patient. We have also established a diabetes seminar series for the patients, to which physicians, nurses, dietitians, pharmacists, clinical laboratory technicians, and other professionals are invited to give talks on their respective areas of expertise. The aim of our ongoing efforts to implement diet and exercise therapies and improve the living habits of the patients is to achieve an ideal standard for diabetes education and management. PMID- 21599866 TI - Cardiovascular risk in diabetic end-stage renal disease patients. AB - Diabetes mellitus is the leading cause of end-stage renal disease (ESRD), accounting for 54% of all incident cases according to the US Renal Data System. These patients suffer an extremely high mortality rate due to the very high incidence of cardiovascular disease. A significant proportion of these patients already has established cardiovascular disease at the time of initiation of dialysis treatment. More importantly, as these patients develop progressive kidney dysfunction, they are not only subjected to traditional Framingham risk factors, but, more importantly, to a whole host of "kidney disease-related risk factors" that further accelerate the progression of cardiovascular disease and thus contribute to adverse cardiovascular outcomes. The present article provides an updated view on the multitude of traditional Framingham risk factors and kidney disease-related risk factors that diabetic ESRD patients are subjected to. A better understanding of the different cardiovascular risk factors will be fundamental to institute early detection programs, as well as to provide aggressive cardiovascular management of these patients. PMID- 21599865 TI - Comprehensive risk assessments of diabetic patients from seven Asian countries: The Joint Asia Diabetes Evaluation (JADE) program. AB - BACKGROUND: The aim of the web-based Joint Asia Diabetes Evaluation (JADE) program is to establish a registry for quality assurance, monitoring, and evaluation. METHODS: The JADE electronic portal provides templates for data collection, supplemented by risk stratification, care protocols, and decision support. Herein, data from 3687 patients with Type 2 diabetes, enrolled over 15 months in 2007-2009 from seven Asian countries, are reported. RESULTS: Of the patients, 46.1% were men, the median (range) age was 58 (15-93 years), and median disease duration was 6.5 (0-71) years; 16.2% had at least one cardiovascular renal complication (10.0% coronary heart disease, 3.3% stroke, 3.1% peripheral vascular disease, 0.4% end-stage renal disease), 20.4% had diabetic retinopathy, 15.0% had sensory neuropathy, 7.5% had chronic kidney disease, and 20.7% of men had erectile dysfunction. Hypertension, dyslipidemia, and central obesity affected 84.6%, 76.8%, and 53.5% of patients, respectively. Treatment targets were HbA1c <7% in 35.3%, blood pressure <130/80 mmHg in 32.3%, and low-density lipoprotein-cholesterol <2.6 mmol/L in 34.0%. The rate of attaining one, two, and three targets was 38.7%, 23.4%, and 5.4%, respectively. Using the JADE Risk Engine, 60% of patients with clinical complications and 20% of those with multiple risk parameters were predicted to have a major event within 5 years. Older age, short disease duration, adherence to diet, control of other risk factors, and not smoking were independently associated with HbA1c <7% (all P < 0.05). CONCLUSIONS: It is possible to use a web-based protocol to establish a registry for risk stratification and facilitate early intervention. PMID- 21599867 TI - Is diabetes-specific health literacy associated with diabetes-related outcomes in older adults? AB - BACKGROUND: The present study examined the association between a measure of diabetes-specific health literacy and three different Type 2 diabetes outcome indicators in a national sample of older adults. METHODS: Data were taken from the Health and Retirement Study (HRS) 2003 Diabetes module and the HRS 2002 core wave. Analysis was performed on data from 1318 respondents aged 42-96 years [mean (+/-SD) 67.96 +/- 8.65 years] who submitted responses on all relevant independent variable measures along with an HbA1c test kit. The index of diabetes-specific health literacy was constructed from responses to 10 diabetes self-care regimen items (alpha = 0.927). RESULTS: Using a multivariate regression strategy to analyze weighted data, the diabetes-specific health literacy index was significantly and positively associated with self-graded assessment of diabetes self-care (R2 = 0.231). However, diabetes-specific health literacy was not independently associated with the HbA1c level or the average number of days five recommended self-management behaviors were practiced each week. CONCLUSIONS: No previous single study has focused on the relationship between diabetes-specific health literacy and multiple diabetes-related outcomes. The direct association of diabetes-specific health literacy with patients' assessment of their self-care practice acumen is useful information for the design of effective patient intervention and/or communication strategies. Health literacy is a broad, multidimensional construct that bridges basic literacy skills and various health and illness contexts. Because it is so important to adults engaged in the self management of chronic illness, indicators of disease-specific knowledge and/or understanding should be included in efforts to measure health literacy. PMID- 21599868 TI - Association between self-monitoring of blood glucose and diet among minority patients with diabetes. AB - BACKGROUND: Self-monitoring of blood glucose (SMBG) is used to regulate glucose control. It is unknown whether SMBG can motivate adherence to dietary recommendations. We predicted that participants who used more SMBG would also report lower fat and greater fruit and vegetable consumption. METHODS: The present study was a cross-sectional study of 401 primarily minority individuals living with diabetes in East Harlem, New York. Fat intake and fruit and vegetable consumption were measured with the Block Fruit/Vegetable/Fiber and Fat Screeners. RESULTS: Greater frequency of SMBG was associated with lower fat intake (r(s) = 0.15; P < 0.01), but not fruit and vegetable consumption. The effects of SMBG were not moderated by insulin use; thus, the relationship was significant for those individuals both on and not on insulin. A significant interaction was found between frequency of SMBG and changing one's diet in response to SMBG on total fat intake. The data suggest that participants who use SMBG to guide their diet do not have to monitor multiple times a day to benefit. CONCLUSION: The present study found that the frequency of SMBG was associated with lower fat intake. Patients are often taught to use SMBG to guide their self-management. This is one of the first studies to examine whether SMBG is associated with better dietary intake. PMID- 21599869 TI - Does poor early metabolic control predict subsequent poor control in young children with type 1 diabetes: an exploratory study. AB - BACKGROUND: We sought to determine whether poor metabolic control during the early stages of type 1 diabetes mellitus predicts control during subsequent years. We hypothesized that poor control in the first year after diagnosis would predict poor control in the following year, and that poor control in the second year after diagnosis would predict poor metabolic control in subsequent years. METHODS: We conducted a retrospective review of a cohort of urban children treated for diabetes at our institution who were diagnosed between 1992 and 2005. We calculated odds ratios to determine whether control in year 1 or in year 2 predicted control in Years 3-6. Cox regression analyses were used to determine whether poor early control predicted progression to subsequent poor control. RESULTS: Metabolic control in the first year after diagnosis was not a good predictor of future control. However, poor metabolic control in the second year after diagnosis was highly predictive of poor control in subsequent years and predicted faster progression to poor control. CONCLUSION: The findings suggest that poor metabolic control in year 2 may be a predictor of subsequent poor metabolic control. Targeting prevention interventions to reduce non-adherence and to enhance metabolic control to families that show poor metabolic control in Year 2 may prove to be an optimum investment in terms of improved medical outcomes and enhanced quality of life. PMID- 21599870 TI - Effect of hydroxypropyl methylcellulose on obesity and glucose metabolism in a diet-induced obesity mouse model. AB - BACKGROUND: To investigate the effect of hydroxypropyl methylcellulose (HPMC) on weight loss and metabolic disorders associated with obesity using a high-fat diet induced obese mouse model under a high-fat diet regimen. METHODS: Obese male C57BL/6J (B6) mice were fed either a high-fat (60% kcal), low-fat (10% kcal), or high-fat diet plus HPMC (4% and 8%) for 5 weeks. Body, mesenteric adipose, and liver weights were determined at the end of the study. In addition, plasma cholesterol, insulin, glucose, adiponectin, and leptin were analyzed to determine the effects of HPMC. Hepatic and fecal lipids were measured to determine the effect of HPMC on lipid absorption and metabolism. RESULTS: Supplementation of the high-fat diet with 4% and 8% HPMC resulted in significant weight loss in obese B6 mice. Furthermore, significant decreases were seen in adipose (30%-40%), liver weights (15%-26%), and concentrations of plasma cholesterol (13%-20%) and hepatic lipids (13%-36%). Supplementation with 8% HPMC led to significant improvements in glucose homeostasis and leptin concentrations. Reductions in plasma cholesterol, glucose, and insulin levels were strongly correlated with reduced leptin concentrations. Moreover, increases in fecal secretion of total bile acids, sterols, and fats indicated altered fat absorption when HPMC was incorporated in the diet. CONCLUSION: The data indicate that HPMC not only reduces body weight, but also normalizes the metabolic abnormalities associated with obesity and suggest that the effects of HPMC on glucose and lipid homeostasis in B6 mice are mediated by improvements in leptin sensitivity resulting from reduced fat absorption. PMID- 21599872 TI - Correlation of optic disc morphology and ocular perfusion parameters in patients with primary open angle glaucoma. AB - PURPOSE: Little information is available about the relationship between glaucomatous visual field defects, morphological changes of the optic disc and ocular blood flow. In this study, ocular blood flow parameters were correlated with parameters of optic nerve head (ONH) morphology and visual field performance in a cross-sectional study. METHODS: A total of 103 patients with primary open angle glaucoma were included. Choroidal and ONH blood flow was assessed using laser Doppler flowmetry. Retinal blood velocities and retinal vessel diameters were measured with laser Doppler velocimetry and a Retinal Vessel Analyzer, respectively. To evaluate the ONH morphology, fundus photographs were taken and confocal laser scanning tomography was performed. RESULTS: Among all measured ocular hemodynamic parameters, the ONH blood flow was most strongly correlated to structural parameters of ONH damage and visual field loss. Reduced retinal vessel diameters were only slightly correlated with the degree of glaucomatous damage. CONCLUSION: Reduced blood flow in the ONH was associated with increasing amount of visual field defect and morphological changes of the ONH. Retinal vessel diameters were only marginally associated with glaucomatous optic nerve damage. Based on retinal vessel diameter determination alone, it is not possible to assess whether reduced retinal blood flow is causative or secondary in glaucoma. PMID- 21599871 TI - Differential LEF1 and TCF4 expression is involved in melanoma cell phenotype switching. AB - Recent observations suggest that melanoma cells drive disease progression by switching back and forth between phenotypic states of proliferation and invasion. Phenotype switching has been linked to changes in Wnt signalling, and we therefore looked for cell phenotype-specific differences in the levels and activity of beta-catenin and its LEF/TCF co-factors. We found that while cytosolic beta-catenin distribution is phenotype-specific (membrane-associated in proliferative cells and cytosolic in invasive cells), its nuclear distribution and activity is not. Instead, the expression patterns of two beta-catenin co factors, LEF1 and TCF4, are both phenotype-specific and inversely correlated. LEF1 is preferentially expressed by differentiated/proliferative phenotype cells and TCF4 by dedifferentiated/invasive phenotype cells. Knock-down experiments confirmed that these co-factors are important for the phenotype-specific expression of M-MITF, WNT5A and other genes and that LEF1 suppresses TCF4 expression independently of beta-catenin. Our data show that melanoma cell phenotype switching behaviour is regulated by differential LEF1/TCF4 activity. PMID- 21599873 TI - Effects of acutely lowering intraocular pressure on the results of multifocal visual evoked potential testing. AB - PURPOSE: There have been many reports in the literature on the apparent reversal of optic nerve cupping in patients with glaucoma after lowering intraocular pressure (IOP) on clinical examination, as well as improvement in visual field testing, and increased nerve fibre layer thickness on optical coherence tomography. No studies to date have looked at improvement of multifocal visually evoked potentials (mfVEP) after lowering IOP. METHODS: This was a prospective study of twenty consecutive patients with elevated IOP seen in the glaucoma department of Wills Eye Institute. Patients who met the inclusion criteria for this study had a complete eye examination including IOP measurement and underwent testing with mfVEP, Heidelberg Retinal Tomograph (HRT) and static achromatic automated perimetry with SITA-Standard 24-2 program Humphrey visual field (HVF) studies at baseline and 2 h post-IOP reduction. A minimum of 30% IOP reduction was required. IOP changes were then compared with various parameters of mfVEP, HRT and HVF using Spearman rank correlation coefficients. RESULTS: The Spearman rank correlation values between change in IOP versus various parameters were calculated: Accumap severity index (ASI), 0.37 (p = 0.14); Accumap superior hemifield, 0.049 (p = 0.85); Accumap inferior hemifield, 0.030 (p = 0.91); HVF mean deviation, 0.081 (p = 0.76); HRT rim area, 0.17 (p = 0.51); HRT cup area, 0.006 (p = 0.98). Weak positive but insignificant correlations were seen for all parameters except cup area. CONCLUSIONS: This pilot study failed to confirm statistically significant correlations between IOP reduction and changes in Accumap, HVF and HRT measures, although positive correlations were seen for most measures. PMID- 21599874 TI - Influence of sex on treatment and outcome in chronic heart failure. AB - The population is aging, the prevalence of heart failure increases with age, and on average women live longer than men. There is evidence for sex-specific effects of individual, guideline-recommended drugs used for treatment of chronic heart failure. Women are underrepresented in most clinical trials and only a minority of drug applications to regulatory authorities have included sex analyses. The present review focuses on the potential female survival benefit in heart failure, the influence of sex on medical treatment in a broader sense, and the potential benefit to be derived from guideline recommended treatment and common adjunctive heart failure medication. PMID- 21599875 TI - Evaluation of sexual communication message strategies. AB - Parent-child communication about sex is an important proximal reproductive health outcome. But while campaigns to promote it such as the Parents Speak Up National Campaign (PSUNC) have been effective, little is known about how messages influence parental cognitions and behavior. This study examines which message features explain responses to sexual communication messages. We content analyzed 4 PSUNC ads to identify specific, measurable message and advertising execution features. We then develop quantitative measures of those features, including message strategies, marketing strategies, and voice and other stylistic features, and merged the resulting data into a dataset drawn from a national media tracking survey of the campaign. Finally, we conducted multivariable logistic regression models to identify relationships between message content and ad reactions/receptivity, and between ad reactions/receptivity and parents' cognitions related to sexual communication included in the campaign's conceptual model. We found that overall parents were highly receptive to the PSUNC ads. We did not find significant associations between message content and ad reactions/receptivity. However, we found that reactions/receptivity to specific PSUNC ads were associated with increased norms, self-efficacy, short- and long term expectations about parent-child sexual communication, as theorized in the conceptual model. This study extends previous research and methods to analyze message content and reactions/receptivity. The results confirm and extend previous PSUNC campaign evaluation and provide further evidence for the conceptual model. Future research should examine additional message content features and the effects of reactions/receptivity. PMID- 21599876 TI - Family eczema-history in 2-year-olds with eczema; a prospective, population-based study. The PACT-study, Norway. AB - BACKGROUND: A maternal line of inheritance regarding eczema has been described in several studies, whereas others find associations to both a maternal as well as a paternal line of inheritance. When studying family history of eczema symptoms, cohort studies including siblings are rare. Time point for assessing family eczema-history could be of importance when studying the associations between family eczema-history and children with eczema, as parents with unaffected children may not recall mild symptoms in other siblings or their own disease history. We therefore aimed to study the associations between reported eczema in mother, father and siblings and reported eczema in index child where information on family history was collected at two different ages of index child. METHODS: Parents/children participating in The Prevention of Allergy among Children in Trondheim (PACT) study were given questionnaires on reported eczema symptoms in mother, father and siblings at 6 weeks and 1 year. When index child was 2 years of age, a detailed questionnaire on different health issues with emphasize on different allergy related disorders were filled in. RESULTS: Both maternal and paternal reports on eczema were significantly associated with eczema in index child. Reporting family eczema-history at 1 year (N = 3087), "eczema sibling only" [adjusted odds ratio (aOR) = 3.13 (2.27-4.33)] as well as all other family groups containing siblings with eczema were strongly associated with eczema 2 years. When family eczema-history was reported at 6 weeks (N = 2657), reporting of "eczema sibling only" was not associated to reported eczema at 2 years in index child [aOR = 1.31 (0.77-2.23)]. CONCLUSIONS: Having sibling(s) with eczema strengthened the associations between maternal and paternal reports on eczema with eczema in index child only when exposure was reported at 1 year. These findings indicate that results from questionnaires-based studies of family eczema history depend on whether or not index child has yet developed eczema. PMID- 21599877 TI - Concomitant pulmonary tuberculosis and tuberculous appendicitis in a recipient of a renal transplant: a case report. AB - INTRODUCTION: Tuberculosis is still a serious infection among recipients of renal transplants. Although the ileocecal region is the most affected part in intestinal tuberculosis, acute tuberculous appendicitis is quite a rare entity. We report a case of concomitant pulmonary tuberculosis and tuberculous appendicitis in a recipient of a renal transplant. CASE PRESENTATION: A 27-year old Iranian woman, who had been the recipient of a renal transplant five years earlier, presented with a two-week history of coughing, fever and weight loss. The cause of her end-stage renal disease was chronic pyelonephritis. There were fine crackles noted during a chest examination, and a plain chest radiography showed fine miliary nodules throughout her entire lung fields. Sputum and bronchial aspirate examination was positive for acid-fast bacilli, suggestive of Mycobacterium tuberculosis infection. A chest computed tomography scan revealed widespread miliary nodules, compatible with miliary tuberculosis. She developed severe abdominal pain and abdominal surgery disclosed a perforated appendicitis. Histopathological examination of the resected appendix revealed widespread caseating epithelioid granulomas, suggestive of tuberculosis. CONCLUSION: Our case report highlights a rare presentation of tuberculosis in a patient who has undergone renal transplant. Such unusual presentation of tuberculosis, particularly among patients receiving potent immunosuppressive protocols, should be considered by clinicians. PMID- 21599878 TI - Impact of accessory gene regulator (agr) dysfunction on vancomycin pharmacodynamics among Canadian community and health-care associated methicillin resistant Staphylococcus aureus. AB - BACKGROUND: The accessory gene regulator (agr) is a quorum sensing cluster of genes which control colonization and virulence in Staphylococcus aureus. We evaluated agr function in community- (CA) and healthcare-associated (HA) MRSA, to compare the pharmacodynamics and bactericidal activity of vancomycin against agr functional and dysfunctional HA-MRSA and CA-MRSA. METHODS: 40 clinical isolates of MRSA from the Canadian Nosocomial Infection Surveillance Program were evaluated for delta-haemolysin production, as a surrogate marker of agr function. Time kill experiments were performed for vancomycin at 0 to 64 times the MIC against an initial inoculum of 10(6) and 10(8) cfu/ml of agr functional and dysfunctional CA-MRSA and HA-MRSA and these data were fit to a hill-type pharmacodynamic model. RESULTS: 15% isolates were agr dysfunctional, which was higher among HA-MRSA (26.3%) versus CA-MRSA (4.76%). Against a low initial inoculum of 10(6) cfu/ml of CA-MRSA, vancomycin pharmacodynamics were similar among agr functional and dysfunctional strains. However, against a high initial inoculum of 10(8) cfu/ml, killing activity was notably attenuated against agr dysfunctional CA-MRSA (USA400) and HA-MRSA (USA100). CA-MRSA displayed a 20.0 fold decrease in the maximal reduction in bacterial counts (Emax) which was 3.71 log(10) CFU/ml for agr functional vs. 2.41 log(10) CFU/ml for agr dysfunctional MRSA (p = 0.0007). CONCLUSIONS: Dysfunction in agr was less common among CA-MRSA vs. HA-MRSA. agr dysfunction demonstrated an impact on vancomycin bactericidal activity and pharmacodynamics against a high initial inoculum of CA-MRSA and HA MRSA, which may have implications for optimal antimicrobial therapy against persistent, difficult to treat MRSA infections. PMID- 21599879 TI - A simple Bayesian estimate of direct RNAi gene regulation events from differential gene expression profiles. AB - BACKGROUND: Microarrays are commonly used to investigate both the therapeutic potential and functional effects of RNA interfering (RNAi) oligonucleotides such as microRNA (miRNA) and small interfering RNA (siRNA). However, the resulting datasets are often challenging to interpret as they include extensive information relating to both indirect transcription effects and off-target interference events. METHOD: In an attempt to refine the utility of microarray expression data when evaluating the direct transcriptional affects of an RNAi agent we have developed SBSE (Simple Bayesian Seed Estimate). The key assumption implemented in SBSE is that both direct regulation of transcription by miRNA, and siRNA off target interference, can be estimated using the differential distribution of an RNAi sequence (seed) motif in a ranked 3' untranslated region (3' UTR) sequence repository. SBSE uses common microarray summary statistics (i.e. fold change) and a simple Bayesian analysis to estimate how the RNAi agent dictated the observed differential expression profile. On completion a trace of the estimate and the location of the optimal partitioning of the dataset are plotted within a simple graphical representation of the 3'UTR landscape. The combined estimates define the differential distribution of the query motif within the dataset and by inference are used to quantify the magnitude of the direct RNAi transcription effect. RESULTS: SBSE has been evaluated using five diverse human RNAi microarray focused investigations. In each instance SBSE unambiguously identified the most likely location of the direct RNAi effects for each of the differential gene expression profiles. CONCLUSION: These analyses indicate that miRNA with conserved seed regions may share minimal biological activity and that SBSE can be used to differentiate siRNAs of similar efficacy but with different off-target signalling potential. PMID- 21599881 TI - TreeRipper web application: towards a fully automated optical tree recognition software. AB - BACKGROUND: Relationships between species, genes and genomes have been printed as trees for over a century. Whilst this may have been the best format for exchanging and sharing phylogenetic hypotheses during the 20th century, the worldwide web now provides faster and automated ways of transferring and sharing phylogenetic knowledge. However, novel software is needed to defrost these published phylogenies for the 21st century. RESULTS: TreeRipper is a simple website for the fully-automated recognition of multifurcating phylogenetic trees (http://linnaeus.zoology.gla.ac.uk/~jhughes/treeripper/). The program accepts a range of input image formats (PNG, JPG/JPEG or GIF). The underlying command line c++ program follows a number of cleaning steps to detect lines, remove node labels, patch-up broken lines and corners and detect line edges. The edge contour is then determined to detect the branch length, tip label positions and the topology of the tree. Optical Character Recognition (OCR) is used to convert the tip labels into text with the freely available tesseract-ocr software. 32% of images meeting the prerequisites for TreeRipper were successfully recognised, the largest tree had 115 leaves. CONCLUSIONS: Despite the diversity of ways phylogenies have been illustrated making the design of a fully automated tree recognition software difficult, TreeRipper is a step towards automating the digitization of past phylogenies. We also provide a dataset of 100 tree images and associated tree files for training and/or benchmarking future software. TreeRipper is an open source project licensed under the GNU General Public Licence v3. PMID- 21599880 TI - "Test and treat" or presumptive treatment for malaria in high transmission situations? A reflection on the latest WHO guidelines. AB - Recent WHO guidelines recommend a universal "test and treat" strategy for malaria, mainly by use of rapid diagnostic test (RDT) in all areas. The evidence for this approach is questioned here as there is a risk of over-reliance on parasitological diagnosis in high transmission situations, which still exist. In such areas, when a patient has fever or other malaria symptoms, the presence of Plasmodium spp neither reliably confirms malaria as the cause of the fever, nor excludes the possibility of other diseases. This is because the patient may be an asymptomatic carrier of malaria parasites and suffer from another disease. To allow clinicians to perform their work adequately, local epidemiologic data are necessary. One size does not fit all. If parasite prevalence in the population is low, a diagnostic test is relevant; if the prevalence is high, the test does not provide information of any clinical usefulness, as happens with any test in medicine when the prevalence of the tested characteristic is high in the healthy population. It should also be remembered that, if in some cases anti-malarials are prescribed to parasite-negative patients, this will not increase selection pressure for drug resistance, because the parasite is not there. In high transmission situations at least, other diagnoses should be sought in all patients, irrespective of the presence of malaria parasites. For this, clinical skills (but not necessarily physicians) are irreplaceable, in order to differentiate malaria from other causes of acute fever, such as benign viral infection or potentially dangerous conditions, which can all be present with the parasite co-existing only as a "commensal" or silent undesirable guest. PMID- 21599882 TI - Psychosocial stress at work and perceived quality of care among clinicians in surgery. AB - BACKGROUND: Little is known about the association between job stress and job performance among surgeons, although physicians' well-being could be regarded as an important quality indicator. This paper examines associations between psychosocial job stress and perceived health care quality among German clinicians in surgery. METHODS: Survey data of 1,311 surgeons from 489 hospitals were analysed. Psychosocial stress at work was measured by the effort-reward imbalance model (ERI) and the demand-control model (job strain). The quality of health care was evaluated by physicians' self-assessed performance, service quality and error frequency. Data were collected in a nationwide standardised mail survey. 53% of the contacted hospitals sent back the questionnaire; the response rate of the clinicians in the participating hospitals was about 65%. To estimate the association between job stress and quality of care multiple logistic regression analyses were conducted. RESULTS: Clinicians exposed to job stress have an increased risk of reporting suboptimal quality of care. Magnitude of the association varies depending on the respective job stress model and the indicator of health care quality used. Odds ratios, adjusted for gender, occupational position and job experience vary between 1.04 (CI 0.70-1.57) and 3.21 (CI 2.23 4.61). CONCLUSION: Findings indicate that theoretical models of psychosocial stress at work can enrich the analysis of effects of working conditions on health care quality. Moreover, results suggest interventions for job related health promotion measures to improve the clinicians' working conditions, their quality of care and their patients' health. PMID- 21599883 TI - Tuberculosis patients' reasons for, and suggestions to address non-uptake of HIV testing: a cross-sectional study in the Free State Province, South Africa. AB - BACKGROUND: South Africa endorses the global policy shift from primarily client initiated voluntary counselling and testing (VCT) to routine/provider-initiated testing and counselling (PITC). The reason for this policy shift has been to facilitate uptake of HIV testing amongst at-risk populations in high-prevalence settings. Despite ostensible implementation of routine/PITC, uptake amongst tuberculosis (TB) patients in this country remains a challenge. This study presents the reasons that non-tested TB patients offered for their refusal of HIV testing and reflects on all TB patients' suggestions as to how this situation may be alleviated. METHODS: In February-March 2008, a cross-sectional survey was conducted amongst 600 TB patients across 61 primary health care facilities in four sub-districts in the Free State. Patient selection was done proportionally to the numbers registered at each facility in 2007. Data were subjected to bivariate tests and content analysis of open-ended questions. RESULTS: Almost one third (32.5%) of the respondents reported that they had not undertaken HIV testing, with the most often offered explanation being that they were 'undecided' (37.0%). Other self-reported reasons for non-uptake included: fear (e.g. of testing HIV-positive, 19.0%); perception of being at low risk of HIV infection (13.4%); desire first to deal with TB 'on its own' (12.5%); and because HIV testing had not been offered to them (12.0%). Many patients expressed the need for support and motivation not only from health care workers (33.3%), but also from their significant others (56.6%). Patients further expressed a need for (increased) dissemination of TB-HIV information by health care workers (46.1%). CONCLUSIONS: Patients did not undergo HIV testing for various patient-/individual related reasons. Non-uptake of HIV testing was also due to health system limitations such as the non-offer of HIV testing. Other measures may be necessary to supplement routine/provider-initiation of HIV testing. From the TB patient's perspective, there is a need for (improved) dissemination of information on the TB-HIV link. Patients also require (repeated) motivation and support to undergo HIV testing, the onus for which rests not only on the public health authority and health care workers, but also on other people in the patients' social support networks. PMID- 21599884 TI - Factors promoting health-related quality of life in people with rheumatic diseases: a 12 month longitudinal study. AB - BACKGROUND: Rheumatic diseases have a significant adverse impact on the individual from physical, mental and social aspects, resulting in a low health related quality of life (HRQL). There is a lack of longitudinal studies on HRQL in people with rheumatic diseases that focus on factors promoting HRQL instead of risk factors. The aim of this study was to investigate the associations between suggested health promoting factors at baseline and outcome in HRQL at a 12 month follow-up in people with rheumatic diseases. METHODS: A longitudinal cohort study was conducted in 185 individuals with rheumatic diseases with questionnaires one week and 12 months after rehabilitation in a Swedish rheumatology clinic. HRQL was assessed by SF-36 together with suggested health factors. The associations between SF-36 subscales and the health factors were analysed by multivariable logistic regressions. RESULTS: Factors predicting better outcome in HRQL in one or several SF-36 subscales were being younger or middle-aged, feeling painless, having good sleep structure, feeling rested after sleep, performing low effort of exercise more than twice per week, having strong sense of coherence (SOC), emotional support and practical assistance, higher educational level and work capacity. The most important factors were having strong SOC, feeling rested after sleep, having work capacity, being younger or middle-aged, and having good sleep structure. CONCLUSIONS: This study identified several factors that promoted a good outcome in HRQL to people with rheumatic diseases. These health factors could be important to address in clinical work with rheumatic diseases in order to optimise treatment strategies. PMID- 21599885 TI - No evidence for association between SLC11A1 and visceral leishmaniasis in India. AB - BACKGROUND: SLC11A1 has pleiotropic effects on macrophage function and remains a strong candidate for infectious disease susceptibility. 5' and/or 3' polymorphisms have been associated with tuberculosis, leprosy, and visceral leishmaniasis (VL). Most studies undertaken to date were under-powered, and none has been replicated within a population. Association with tuberculosis has replicated variably across populations. Here we investigate SLC11A1 and VL in India. METHODS: Nine polymorphisms (rs34448891, rs7573065, rs2276631, rs3731865, rs17221959, rs2279015, rs17235409, rs17235416, rs17229009) that tag linkage disequilibrium blocks across SLC11A1 were genotyped in primary family-based (313 cases; 176 families) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association between SLC11A1 variants and VL. Quantitative RT/PCR was used to compare SLC11A1 expression in mRNA from paired splenic aspirates taken before and after treatment from 24 VL patients carrying different genotypes at the functional promoter GTn polymorphism (rs34448891). RESULTS: No associations were observed between VL and polymorphisms at SLC11A1 that were either robust to correction for multiple testing or replicated across primary and replication samples. No differences in expression of SLC11A1 were observed when comparing pre- and post-treatment samples, or between individuals carrying different genotypes at the GTn repeat. CONCLUSIONS: This is the first well-powered study of SLC11A1 as a candidate for VL, which we conclude does not have a major role in regulating VL susceptibility in India. PMID- 21599886 TI - Factors influencing the approaches to studying of preclinical and clinical students and postgraduate trainees. AB - BACKGROUND: Students can be classified into three categories depending on their approaches to studying; namely, deep approach (DA), strategic approach (SA) and surface apathetic or superficial approach (SAA). The aim of this study was to identify factors affecting the approaches to studying among Sri Lankan medical undergraduates and post graduate trainees and to analyze the change in the pattern of study skills with time and experience. METHOD: Pre-clinical and clinical students of the Faculty of Medicine, University of Colombo and postgraduate trainees in Surgery at the National Hospital of Sri Lanka were invited to complete the Approaches and Study Skills Inventory for Students (ASSIST) questionnaire. RESULTS: A total of 187 pre clinical (M: F = 96:91), 124 clinical (M: F = 61:63) and 53 post graduate trainees (M: F = 50:3) participated in the study. Approaches of male and female students were similar. SA was significantly affected by age among the preclinical students (p = 0.01), but not in other groups. Among pre-clinical students, males preferred a teacher who supported understanding (p = 0.04) but females preferred a passive transmission of information (p < 0.001). This, too, was not visible among other groups. A linear regression performed on group (batch), gender, island rank at GCE Advance Level (AL) examination, self appraisal score and the preference scores of type of teacher only managed to explain 35% or less of variance observed for each approach in individual groups. CONCLUSION: Different factors affect the approach to studying in different groups but these explain only a small fraction of the variance observed. PMID- 21599887 TI - Hypercapnic cerebral edema presenting in a woman with asthma: a case report. AB - INTRODUCTION: Common causes of non-traumatic acute cerebral edema include malignant hypertension, hyponatremia, anoxia, and cerebral vascular accident. The computed tomographic images and data obtained during care of the patient described in this case report provide evidence that hypercarbia can cause increased intracranial pressure and coma without permanent brain injury. Partial pressure of carbon dioxide evaluation for coma is essential to provide faster diagnosis and therapeutic correction in certain common critical disease states. We present the case of a patient in a coma associated with cerebral edema during a typical asthma exacerbation with hypercapnic respiratory failure. CASE PRESENTATION: An obese 63-year-old African American woman with asthma presented to our hospital with facial swelling and shortness of breath. Immediately following intubation for hypercapnic respiratory failure, she was noted to have a dilated, unresponsive right pupil. An emergent computed tomographic head scan revealed that she had increased intracranial pressure. A neurosurgeon agreed with the computed tomography interpretation and recommended no surgical intervention. The patient's respiratory acidosis was corrected with ventilatory management over several hours in the intensive care unit. Nine and one-half hours later a follow up head computed tomographic scan was read as normal without cerebral edema. At 12 hours, the patient's right pupil was 5 mm in diameter and reactive. By 24 hours, her pupils were symmetrically equal and reactive. Her symptoms had improved, and she was extubated. A brain magnetic resonance imaging scan revealed no abnormalities. CONCLUSION: Alteration of consciousness related to hypercapnia during respiratory failure is not generally thought to be related to cerebral edema. Respiratory acidosis resulting from hypercarbia is known to produce carbon dioxide narcosis and coma, but no current treatment algorithm suggests that rapid hypercapnia correction can be critical to neurologic outcome. To the best of our knowledge, our case is a unique example of the physiological changes that may occur in relation to arterial carbon dioxide concentration in the normal brain in the setting of typical hypercapnic respiratory failure. Correction of respiratory acidosis reversed the neurologic symptoms and physiology causing cerebral edema and coma in our patient. Rare similar cases have been sporadically reported in the medical literature, typically in children. Our case is also unusual in that rapid deterioration and clinical status were directly observed on simultaneous computed tomographic scans. Had this patient been found unresponsive, or had she had brief respiratory or cardiac arrest, the scan could have been interpreted as global anoxic injury leading to a different therapeutic course. PMID- 21599888 TI - Early infant HIV-1 diagnosis programs in resource-limited settings: opportunities for improved outcomes and more cost-effective interventions. AB - Early infant diagnosis (EID) of HIV-1 infection confers substantial benefits to HIV-infected and HIV-uninfected infants, to their families, and to programs providing prevention of mother-to-child transmission (PMTCT) services, but has been challenging to implement in resource-limited settings. In order to correctly inform parents/caregivers of infant infection status and link HIV-infected infants to care and treatment, a 'cascade' of events must successfully occur. A frequently cited barrier to expansion of EID programs is the cost of the required laboratory assays. However, substantial implementation barriers, as well as personnel and infrastructure requirements, exist at each step in the cascade. In this update, we review challenges to uptake at each step in the EID cascade, highlighting that even with the highest reported levels of uptake, nearly half of HIV-infected infants may not complete the cascade successfully. We next synthesize the available literature about the costs and cost effectiveness of EID programs; identify areas for future research; and place these findings within the context of the benefits and challenges to EID implementation in resource-limited settings. PMID- 21599889 TI - In vitro antimicrobial activity of ten medicinal plants against clinical isolates of oral cancer cases. AB - BACKGROUND: Suppression of immune system in treated cancer patients may lead to secondary infections that obviate the need of antibiotics. In the present study, an attempt was made to understand the occurrence of secondary infections in immuno-suppressed patients along with herbal control of these infections with the following objectives to: (a) isolate the microbial species from the treated oral cancer patients along with the estimation of absolute neutrophile counts of patients (b) assess the in vitro antimicrobial activity medicinal plants against the above clinical isolates. METHODS: Blood and oral swab cultures were taken from 40 oral cancer patients undergoing treatment in the radiotherapy unit of Regional Cancer Institute, Pt. B.D.S. Health University,Rohtak, Haryana. Clinical isolates were identified by following general microbiological, staining and biochemical methods. The absolute neutrophile counts were done by following the standard methods. The medicinal plants selected for antimicrobial activity analysis were Asphodelus tenuifolius Cav., Asparagus racemosus Willd., Balanites aegyptiaca L., Cestrum diurnum L., Cordia dichotoma G. Forst, Eclipta alba L., Murraya koenigii (L.) Spreng. , Pedalium murex L., Ricinus communis L. and Trigonella foenum graecum L. The antimicrobial efficacy of medicinal plants was evaluated by modified Kirby-Bauer disc diffusion method. MIC and MFC were investigated by serial two fold microbroth dilution method. RESULTS: Prevalent bacterial pathogens isolated were Staphylococcus aureus (23.2%), Escherichia coli (15.62%), Staphylococcus epidermidis (12.5%), Pseudomonas aeruginosa (9.37%), Klebsiella pneumonia (7.81%), Proteus mirabilis (3.6%), Proteus vulgaris (4.2%) and the fungal pathogens were Candida albicans (14.6%), Aspergillus fumigatus (9.37%). Out of 40 cases, 35 (87.5%) were observed as neutropenic. Eight medicinal plants (A. tenuifolius, A. racemosus, B. aegyptiaca, E. alba, M. koenigii, P. murex R. communis and T. foenum graecum) showed significant antimicrobial activity (P < .05) against most of the isolates. The MIC and MFC values were ranged from 31 to 500 MUg/ml. P. aeruginosa was observed highest susceptible bacteria (46.6%) on the basis of susceptible index. CONCLUSION: It can be concluded that treated oral cancer patients were neutropenic and prone to secondary infection of microbes. The medicinal plant can prove as effective antimicrobial agent to check the secondary infections in treated cancer patients. PMID- 21599890 TI - Antioxidant potential of bitter cumin (Centratherum anthelminticum (L.) Kuntze) seeds in in vitro models. AB - BACKGROUND: Bitter cumin (Centratherum anthelminticum (L.) Kuntze), is a medicinally important plant. Earlier, we have reported phenolic compounds, antioxidant, and anti-hyperglycemic, antimicrobial activity of bitter cumin. In this study we have further characterized the antioxidative activity of bitter cumin extracts in various in vitro models. METHODS: Bitter cumin seeds were extracted with a combination of acetone, methanol and water. The antioxidant activity of bitter cumin extracts were characterized in various in vitro model systems such as DPPH radical, ABTS radical scavenging, reducing power, oxidation of liposomes and oxidative damage to DNA. RESULTS: The phenolic extracts of bitter cumin at microgram concentration showed significant scavenging of DPPH and ABTS radicals, reduced phosphomolybdenum (Mo(VI) to Mo(V)), ferricyanide Fe(III) to Fe(II), inhibited liposomes oxidation and hydroxyl radical induced damage to prokaryotic genomic DNA. The results showed a direct correlation between phenolic acid content and antioxidant activity. CONCLUSION: Bitter cumin is a good source of natural antioxidants. PMID- 21599891 TI - A review of metallothionein isoforms and their role in pathophysiology. AB - The Metallothionein (MT) is a protein which has several interesting biological effects and has been demonstrated increase focus on the role of MT in various biological systems in the past three decades. The studies on the role of MT were limited with few areas like apoptosis and antioxidants in selected organs even fifty years after its discovery. Now acknowledge the exploration of various isoforms of MT such as MT-I, MT-II, MT-III and MT-IV and other isoforms in various biological systems.Strong evidence exists that MT modulates complex diseases and the immune system in the body but the primary function of MT still remains unknown. This review's main objective is to explore the capability to specifically manipulate MT levels in cells and in animals to provide answers regarding how MT could impact those complex disease scenarios.The experimental result mentioned in this review related among MT, zinc, cadmium, diabetic, heart disease, bone retardation, neuro toxicity, kidney dysfunction, cancer, and brain suggest novel method for exploration and contribute significantly to the growing scientist to research further in this field. PMID- 21599893 TI - Teratoma of the mediastinum: a case report. AB - INTRODUCTION: This case report illustrates a rare case of teratoma of the mediastinum which was continuous to the pericardium and caused extrinsic compression to the right atrium. CASE PRESENTATION: A 22-year-old Caucasian man with no complaints or comorbid conditions presented to our hospital with obliteration of the right cardiophrenic sinus by a mass. A non-invasive investigation demonstrated a tumoral mass which was continuous to the pericardium and caused extrinsic compression to the right atrium. The clinical suspicion was a pericardial or bronchogenic cyst. Surgical and anatomopathologic findings led to the diagnosis of a mature cystic teratoma with atrophic thymic tissue at the external teratoma surface. CONCLUSION: We present an original report of a mature teratoma causing obliteration of the right cardiophrenic sinus with extrinsic heart compression. The diagnosis of this tumor is very difficult through non invasive investigation. PMID- 21599892 TI - The enigmatic mitochondrial genome of Rhabdopleura compacta (Pterobranchia) reveals insights into selection of an efficient tRNA system and supports monophyly of Ambulacraria. AB - BACKGROUND: The Hemichordata comprises solitary-living Enteropneusta and colonial living Pterobranchia, sharing morphological features with both Chordata and Echinodermata. Despite their key role for understanding deuterostome evolution, hemichordate phylogeny is controversial and only few molecular data are available for phylogenetic analysis. Furthermore, mitochondrial sequences are completely lacking for pterobranchs. Therefore, we determined and analyzed the complete mitochondrial genome of the pterobranch Rhabdopleura compacta to elucidate deuterostome evolution. Thereby, we also gained important insights in mitochondrial tRNA evolution. RESULTS: The mitochondrial DNA of Rhabdopleura compacta corresponds in size and gene content to typical mitochondrial genomes of metazoans, but shows the strongest known strand-specific mutational bias in the nucleotide composition among deuterostomes with a very GT-rich main-coding strand. The order of the protein-coding genes in R. compacta is similar to that of the deuterostome ground pattern. However, the protein-coding genes have been highly affected by a strand-specific mutational pressure showing unusual codon frequency and amino acid composition. This composition caused extremely long branches in phylogenetic analyses. The unusual codon frequency points to a selection pressure on the tRNA translation system to codon-anticodon sequences of highest versatility instead of showing adaptations in anticodon sequences to the most frequent codons. Furthermore, an assignment of the codon AGG to Lysine has been detected in the mitochondrial genome of R. compacta, which is otherwise observed only in the mitogenomes of some arthropods. The genomes of these arthropods do not have such a strong strand-specific bias as found in R. compacta but possess an identical mutation in the anticodon sequence of the tRNALys. CONCLUSION: A strong reversed asymmetrical mutational constraint in the mitochondrial genome of Rhabdopleura compacta may have arisen by an inversion of the replication direction and adaptation to this bias in the protein sequences leading to an enigmatic mitochondrial genome. Although, phylogenetic analyses of protein coding sequences are hampered, features of the tRNA system of R. compacta support the monophyly of Ambulacraria. The identical reassignment of AGG to Lysine in two distinct groups may have occurred by convergent evolution in the anticodon sequence of the tRNALys. PMID- 21599894 TI - Act In case of Depression: the evaluation of a care program to improve the detection and treatment of depression in nursing homes. Study Protocol. AB - BACKGROUND: The aim of this study is evaluating the (cost-) effectiveness of a multidisciplinary, evidence based care program to improve the management of depression in nursing home residents of somatic and dementia special care units. The care program is an evidence based standardization of the management of depression, including standardized use of measurement instruments and diagnostical methods, and protocolized psychosocial, psychological and pharmacological treatment. METHODS/DESIGN: In a 19-month longitudinal controlled study using a stepped wedge design, 14 somatic and 14 dementia special care units will implement the care program. All residents who give informed consent on the participating units will be included. Primary outcomes are the frequency of depression on the units and quality of life of residents on the units. The effect of the care program will be estimated using multilevel regression analysis. Secondary outcomes include accuracy of depression-detection in usual care, prevalence of depression-diagnosis in the intervention group, and response to treatment of depressed residents. An economic evaluation from a health care perspective will also be carried out. DISCUSSION: The care program is expected to be effective in reducing the frequency of depression and in increasing the quality of life of residents. The study will further provide insight in the cost effectiveness of the care program. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1477. PMID- 21599896 TI - Study protocol: Phase III single-blinded fast-track pragmatic randomised controlled trial of a complex intervention for breathlessness in advanced disease. AB - BACKGROUND: Breathlessness in advanced disease causes significant distress to patients and carers and presents management challenges to health care professionals. The Breathlessness Intervention Service (BIS) seeks to improve the care of breathless patients with advanced disease (regardless of cause) through the use of evidence-based practice and working with other healthcare providers. BIS delivers a complex intervention (of non-pharmacological and pharmacological treatments) via a multi-professional team. BIS is being continuously developed and its impact evaluated using the MRC's framework for complex interventions (PreClinical, Phase I and Phase II completed). This paper presents the protocol for Phase III. METHODS/DESIGN: Phase III comprises a pragmatic, fast-track, single-blind randomised controlled trial of BIS versus standard care. Due to differing disease trajectories, the service uses two broad service models: one for patients with malignant disease (intervention delivered over two weeks) and one for patients with non-malignant disease (intervention delivered over four weeks). The Phase III trial therefore consists of two sub-protocols: one for patients with malignant conditions (four week protocol) and one for patients with non-malignant conditions (eight week protocol). Mixed method interviews are conducted with patients and their lay carers at three to five measurement points depending on randomisation and sub-protocol. Qualitative interviews are conducted with referring and non-referring health care professionals (malignant disease protocol only). The primary outcome measure is 'patient distress due to breathlessness' measured on a numerical rating scale (0-10). The trial includes economic evaluation. Analysis will be on an intention to treat basis. DISCUSSION: This is the first evaluation of a breathlessness intervention for advanced disease to have followed the MRC framework and one of the first palliative care trials to use fast track methodology and single-blinding. The results will provide evidence of the clinical and cost-effectiveness of the service, informing its longer term development and implementation of the model in other centres nationally and internationally. It adds to methodological developments in palliative care research where complex interventions are common but evidence sparse. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00678405ISRCTN: ISRCTN04119516. PMID- 21599897 TI - Psychological treatment of depressive symptoms in Chinese elderly inpatients with significant medical comorbidity: a meta-analysis. AB - BACKGROUND: As it is uncertain whether psychological treatments for depressive symptoms are effective in elderly inpatients with significant medical comorbidity, we aimed to assess the treatment effectiveness not only on depressive symptoms but also on somatic symptoms in these inpatients. METHODS: We performed a meta-analysis of randomized controlled studies assessing the effects of psychological treatments in Chinese older inpatients with significant medical comorbidity based upon extensive searches of the most comprehensive computerized Chinese academic database. RESULTS: The overall effect size for depressive symptoms of twelve studies which compared psychological treatments with a care-as usual control group was d = 0.80 (95% Confidence Intervals (CI) = 0.60-0.99; p < 0.001). The relative risk of psychological intervention of being effective or not, compared to control condition, was 1.52 (95% CI = 1.25-1.85; p < 0.001). CONCLUSIONS: We conclude that psychological treatments of depressive symptoms are effective for Chinese elderly inpatients with significant medical comorbidity which should receive more attention in medical settings. PMID- 21599895 TI - An untargeted multi-technique metabolomics approach to studying intracellular metabolites of HepG2 cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. AB - BACKGROUND: In vitro cell systems together with omics methods represent promising alternatives to conventional animal models for toxicity testing. Transcriptomic and proteomic approaches have been widely applied in vitro but relatively few studies have used metabolomics. Therefore, the goal of the present study was to develop an untargeted methodology for performing reproducible metabolomics on in vitro systems. The human liver cell line HepG2, and the well-known hepatotoxic and non-genotoxic carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), were used as the in vitro model system and model toxicant, respectively. RESULTS: The study focused on the analysis of intracellular metabolites using NMR, LC-MS and GC-MS, with emphasis on the reproducibility and repeatability of the data. State of the art pre-processing and alignment tools and multivariate statistics were used to detect significantly altered levels of metabolites after exposing HepG2 cells to TCDD. Several metabolites identified using databases, literature and LC nanomate-Orbitrap analysis were affected by the treatment. The observed changes in metabolite levels are discussed in relation to the reported effects of TCDD. CONCLUSIONS: Untargeted profiling of the polar and apolar metabolites of in vitro cultured HepG2 cells is a valid approach to studying the effects of TCDD on the cell metabolome. The approach described in this research demonstrates that highly reproducible experiments and correct normalization of the datasets are essential for obtaining reliable results. The effects of TCDD on HepG2 cells reported herein are in agreement with previous studies and serve to validate the procedures used in the present work. PMID- 21599898 TI - Brunn: an open source laboratory information system for microplates with a graphical plate layout design process. AB - BACKGROUND: Compound profiling and drug screening generates large amounts of data and is generally based on microplate assays. Current information systems used for handling this are mainly commercial, closed source, expensive, and heavyweight and there is a need for a flexible lightweight open system for handling plate design, and validation and preparation of data. RESULTS: A Bioclipse plugin consisting of a client part and a relational database was constructed. A multiple step plate layout point-and-click interface was implemented inside Bioclipse. The system contains a data validation step, where outliers can be removed, and finally a plate report with all relevant calculated data, including dose-response curves. CONCLUSIONS: Brunn is capable of handling the data from microplate assays. It can create dose-response curves and calculate IC50 values. Using a system of this sort facilitates work in the laboratory. Being able to reuse already constructed plates and plate layouts by starting out from an earlier step in the plate layout design process saves time and cuts down on error sources. PMID- 21599899 TI - The interleukin-6 and noradrenaline mediated inflammation-stress feedback mechanism is dysregulated in metabolic syndrome: effect of exercise. AB - BACKGROUND: Metabolic syndrome (MS) is a metabolic disorder associated with obesity, type-II diabetes, and "low grade inflammation", with the concomitant increased risk of cardiovascular events. Removal of the inflammatory mediator signals is a promising strategy to protect against insulin resistance, obesity, and other problems associated with MS such as cardiovascular disease. The aim of the present investigation was to determine the "inflammatory and stress status" in an experimental model of MS, and to evaluate the effect of a program of habitual exercise and the resulting training-induced adaptation to the effects of a single bout of acute exercise. METHODS: Obese Zucker rats (fa/fa) were used as the experimental model of MS, and lean Zucker rats (Fa/fa) were used for reference values. The habitual exercise (performed by the obese rats) consisted of treadmill running: 5 days/week for 14 weeks, at 35 cm/s for 35 min in the last month. The acute exercise consisted of a single session of 25-35 min at 35 cm/s. Circulating concentrations of IL-6 (a cytokine that regulates the inflammatory and metabolic responses), CRP (a systemic inflammatory marker), and corticosterone (CTC) (the main glucocorticoid in rats) were determined by ELISA, and that of noradrenaline (NA) was determined by HPLC. Glucose was determined by standard methods. RESULTS: The genetically obese animals showed higher circulating levels of glucose, IL-6, PCR, and NA compared with the control lean animals. The habitual exercise program increased the concentration of IL-6, CRP, NA, and glucose, but decreased that of CTC. Acute exercise increased IL-6, CRP, and NA in the sedentary obese animals, but not in the trained obese animals. CTC was increased after the acute exercise in the trained animals only. CONCLUSION: Animals with MS present a dysregulation in the feedback mechanism between IL-6 and NA which can contribute to the systemic low-grade inflammation and/or hyperglycaemia of MS. An inappropriate exercise intensity can worsen this dysregulation, contributing to the metabolic, inflammatory, and stress disorders associated with MS. Habitual exercise (i.e., training) induces a positive adaptation in the response to acute exercise. PMID- 21599900 TI - Antenatal care in practice: an exploratory study in antenatal care clinics in the Kilombero Valley, south-eastern Tanzania. AB - BACKGROUND: The potential of antenatal care for reducing maternal morbidity and improving newborn survival and health is widely acknowledged. Yet there are worrying gaps in knowledge of the quality of antenatal care provided in Tanzania. In particular, determinants of health workers' performance have not yet been fully understood. This paper uses ethnographic methods to document health workers' antenatal care practices with reference to the national Focused Antenatal Care guidelines and identifies factors influencing health workers' performance. Potential implications for improving antenatal care provision in Tanzania are discussed. METHODS: Combining different qualitative techniques, we studied health workers' antenatal care practices in four public antenatal care clinics in the Kilombero Valley, south-eastern Tanzania. A total of 36 antenatal care consultations were observed and compared with the Focused Antenatal Care guidelines. Participant observation, informal discussions and in-depth interviews with the staff helped to identify and explain health workers' practices and contextual factors influencing antenatal care provision. RESULTS: The delivery of antenatal care services to pregnant women at the selected antenatal care clinics varied widely. Some services that are recommended by the Focused Antenatal Care guidelines were given to all women while other services were not delivered at all. Factors influencing health workers' practices were poor implementation of the Focused Antenatal Care guidelines, lack of trained staff and absenteeism, supply shortages and use of working tools that are not consistent with the Focused Antenatal Care guidelines. Health workers react to difficult working conditions by developing informal practices as coping strategies or "street-level bureaucracy". CONCLUSIONS: Efforts to improve antenatal care should address shortages of trained staff through expanding training opportunities, including health worker cadres with little pre-service training. Attention should be paid to the identification of informal practices resulting from individual coping strategies and "street-level bureaucracy" in order to tackle problems before they become part of the organizational culture. PMID- 21599901 TI - Study protocol: the DESPATCH study: delivering stroke prevention for patients with atrial fibrillation - a cluster randomised controlled trial in primary healthcare. AB - BACKGROUND: Compelling evidence shows that appropriate use of anticoagulation in patients with nonvalvular atrial fibrillation reduces the risk of ischaemic stroke by 67% and all-cause mortality by 26%. Despite this evidence, anticoagulation is substantially underused, resulting in avoidable fatal and disabling strokes. METHODS: DESPATCH is a cluster randomised controlled trial with concealed allocation and blinded outcome assessment designed to evaluate a multifaceted and tailored implementation strategy for improving the uptake of anticoagulation in primary care. We have recruited general practices in South Western Sydney, Australia, and randomly allocated practices to receive the DESPATCH intervention or evidence-based guidelines (control). The intervention comprises specialist decisional support via written feedback about patient specific cases, three academic detailing sessions (delivered via telephone), practice resources, and evidence-based information. Data for outcome assessment will be obtained from a blinded, independent medical record audit. Our primary endpoint is the proportion of nonvalvular atrial fibrillation patients, over 65 years of age, receiving oral anticoagulation at any time during the 12-month posttest period. DISCUSSION: Successful translation of evidence into clinical practice can reduce avoidable stroke, death, and disability due to nonvalvular atrial fibrillation. If successful, DESPATCH will inform public policy, providing quality evidence for an effective implementation strategy to improve management of nonvalvular atrial fibrillation, to close an important evidence-practice gap. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12608000074392. PMID- 21599902 TI - A simple approach to ranking differentially expressed gene expression time courses through Gaussian process regression. AB - BACKGROUND: The analysis of gene expression from time series underpins many biological studies. Two basic forms of analysis recur for data of this type: removing inactive (quiet) genes from the study and determining which genes are differentially expressed. Often these analysis stages are applied disregarding the fact that the data is drawn from a time series. In this paper we propose a simple model for accounting for the underlying temporal nature of the data based on a Gaussian process. RESULTS: We review Gaussian process (GP) regression for estimating the continuous trajectories underlying in gene expression time-series. We present a simple approach which can be used to filter quiet genes, or for the case of time series in the form of expression ratios, quantify differential expression. We assess via ROC curves the rankings produced by our regression framework and compare them to a recently proposed hierarchical Bayesian model for the analysis of gene expression time-series (BATS). We compare on both simulated and experimental data showing that the proposed approach considerably outperforms the current state of the art. CONCLUSIONS: Gaussian processes offer an attractive trade-off between efficiency and usability for the analysis of microarray time series. The Gaussian process framework offers a natural way of handling biological replicates and missing values and provides confidence intervals along the estimated curves of gene expression. Therefore, we believe Gaussian processes should be a standard tool in the analysis of gene expression time series. PMID- 21599903 TI - Developmental regulation of the neuroinflammatory responses to LPS and/or hypoxia ischemia between preterm and term neonates: An experimental study. AB - BACKGROUND: Preterm and term newborns are at high risk of brain damage as well as subsequent cerebral palsy and learning disabilities. Indeed, hypoxia-ischemia (HI), pathogen exposures, and associated intracerebral increase of pro inflammatory cytokines have all been linked to perinatal brain damage. However, the developmental effects of potential variations of pro- and anti-inflammatory cytokine ratios remain unknown. METHODS: Using rat models of perinatal brain damage induced by exposures to lipopolysaccharide (LPS) and/or HI at distinct levels of maturity, we compared cytokine expression at stages of cerebral development equivalent to either preterm (postnatal day 1, P1) or term (P12) newborns. RESULTS: At P1, expression of anti-inflammatory cytokine within the brain was either not modulated (IL-6, IL-10) or down-regulated (IL-1ra, TGF beta1) by HI, LPS or LPS+HI. In contrast, there was at P12 an up-regulation of all anti-inflammatory cytokines studied in HI or LPS+HI condition, but not after LPS exposure. Interestingly, IL-1beta was the main pro-inflammatory cytokine up regulated moderately at P1, and strongly at P12, with a weak co-expression of TNF alpha observed mainly at P12. These age-dependant inflammatory reactions were also accompanied, under HI and LPS+HI conditions, at P12 only, by combined: (i) expression of chemokines CINC-1 and MCP-1, (ii) blood-brain barrier (BBB) leakage, and (iii) intracerebral recruitment of systemic immune cells such as neutrophils. In contrast, sole LPS induced IL-1beta responses mainly within white matter at P1 and mainly within gray matter at P12, that were only associated with early MCP-1 (but no CINC-1) induction at both ages, without any recruitment of neutrophils and CD68+ cells. CONCLUSION: HI and LPS+HI induce pro-inflammatory oriented immune responses in both preterm and term like brains, with a maximal inflammatory response triggered by the combination of LPS+HI. The profile of these neuroinflammatory responses presented striking variations according to age: no or down-regulated anti-inflammatory responses associated with mainly IL-1beta release in preterm-like brains (P1), in sharp contrast to term-like brains (P12) presenting stronger anti-and pro-inflammatory responses, including both IL-1beta and TNF-alpha releases, and BBB leakage. These developmental-dependant variations of neuroinflammatory response could contribute to the differential pattern of brain lesions observed across gestational ages in humans. This also highlights the necessity to take into consideration the maturation stage, of both brain and immune systems, in order to develop new anti-inflammatory neuroprotective strategies. PMID- 21599904 TI - Factors associated with teenage marital pregnancy among Bangladeshi women. AB - BACKGROUND: Teenage pregnancy is a public health concern both in developed and developing world. In Bangladesh, most of the first pregnancies occur immediately after marriage, especially among teenagers. Although women aged 15-29 years are the most fertility contributing women in Bangladesh, studies are not yet conducted on teenage pregnancy within this group of women. In the current study, an attempt had been made to identify the factors affecting teenage marital pregnancy in women aged 15-29 years. METHODS: A cross sectional survey was carried out in 389 women, selected with a convenience sampling technique. Participants were selected on the basis of two criteria, such as married women and age within 15-29 years. We excluded women aged more than 29 years as we attempted to conduct study within high fertility contributing women and with the assumption that they may provide data subjected to relatively high level of recall bias as marital pregnancy may be a longer past event to them. In the analysis, we applied bi-variate and multi-variate logistic regression technique to find out odds ratio of teenage marital pregnancy. RESULTS: Result revealed that 72.5% of the participants experienced first marital pregnancy during their teenage, with a mean age of 17.88 years (SD = 2.813). Multivariate logistic regression analysis revealed that participants aged 20-24 years had higher likelihood (OR 1.971, 95% CI 1.132 to 3.434), whereas participants aged 25-29 years had lower likelihood (OR 0.054, 95% CI 0.016 to 0.190) of experiencing teenage marital pregnancy compared to participants aged 15-19 years. In addition, participants desired for >2 children had significant higher odds (OR 3.573, 95% CI 1.910 to 6.684) and participants born in urban area had significant lower odds (OR 0.458, 95% CI 0.228 to 0.919) for teenage marital pregnancy. CONCLUSIONS: Based on the findings, we conclude that in order to reduce teenage marital pregnancy, consideration should be given on women's desired number of children and birth place so that women's desired number of children is limited to within two children, and that rural women get increased working and other related opportunities that may contribute in delaying teenage pregnancy. PMID- 21599906 TI - Metagenome of the gut of a malnourished child. AB - BACKGROUND: Malnutrition, a major health problem, affects a significant proportion of preschool children in developing countries. The devastating consequences of malnutrition include diarrhoea, malabsorption, increased intestinal permeability, suboptimal immune response, etc. Nutritional interventions and dietary solutions have not been effective for treatment of malnutrition till date. Metagenomic procedures allow one to access the complex cross-talk between the gut and its microbial flora and understand how a different community composition affects various states of human health. In this study, a metagenomic approach was employed for analysing the differences between gut microbial communities obtained from a malnourished and an apparently healthy child. RESULTS: Our results indicate that the malnourished child gut has an abundance of enteric pathogens which are known to cause intestinal inflammation resulting in malabsorption of nutrients. We also identified a few functional sub systems from these pathogens, which probably impact the overall metabolic capabilities of the malnourished child gut. CONCLUSION: The present study comprehensively characterizes the microbial community resident in the gut of a malnourished child. This study has attempted to extend the understanding of the basis of malnutrition beyond nutrition deprivation. PMID- 21599905 TI - Metabolic regulation of Escherichia coli and its phoB and phoR genes knockout mutants under phosphate and nitrogen limitations as well as at acidic condition. AB - BACKGROUND: The phosphorus compounds serve as major building blocks of many biomolecules, and have important roles in signal transduction. The phosphate is involved in many biochemical reactions by the transfer of phosphoryl groups. All living cells sophisticatedly regulate the phosphate uptake, and survive even under phosphate-limiting condition, and thus phosphate metabolism is closely related to the diverse metabolism including energy and central carbon metabolism. In particular, phosphorylation may play important roles in the metabolic regulation at acidic condition and nitrogen limiting condition, which typically appears at the late growth phase in the batch culture. Moreover, phosphate starvation is a relatively inexpensive means of gene induction in practice, and the phoA promoter has been used for overexpression of heterologous genes. A better understanding of phosphate regulation would allow for optimization of such processes. RESULTS: The effect of phosphate (P) concentration on the metabolism in Escherichia coli was investigated in terms of fermentation characteristics and gene transcript levels for the aerobic continuous culture at the dilution rate of 0.2 h-1. The result indicates that the specific glucose consumption rate and the specific acetate production rate significantly increased, while the cell concentration decreased at low P concentration (10% of the M9 medium). The increase in the specific glucose uptake rate may be due to ATP demand caused by limited ATP production under P-limitation. The lower cell concentration was also caused by less ATP production. The less ATP production by H+-ATPase may have caused less cytochrome reaction affecting in quinone pool, and caused up regulation of ArcA/B, which repressed TCA cycle genes and caused more acetate production. In the case of phoB mutant (and also phoR mutant), the fermentation characteristics were less affected by P-limitation as compared to the wild type where the PhoB regulated genes were down-regulated, while phoR and phoU changed little. The phoR gene knockout caused phoB gene to be down-regulated as well as PhoB regulated genes, while phoU and phoM changed little. The effect of pH together with lower P concentration on the metabolic regulation was also investigated. In accordance with up-regulation of arcA gene expression, the expressions of the TCA cycle genes such as sdhC and mdh were down-regulated at acidic condition. The gene expression of rpoS was up-regulated, and the expression of gadA was up-regulated at pH 6.0. In accordance with this, PhoB regulated genes were up-regulated in the wild type under P-rich and P-limited conditions at pH 6.0 as compared to those at pH 7.0. Moreover, the effect of nitrogen limitation on the metabolic regulation was investigated, where the result indicates that phoB gene was up-regulated, and PhoB regulated genes were also up-regulated under N-limitation, as well as nitrogen-regulated genes. CONCLUSION: The present result shows the complicated nature of the metabolic regulation for the fermentation characteristics upon phosphate limitation, acidic condition, and nitrogen limitation based on the transcript levels of selected genes. The result implies that the regulations under phosphate limitation, acidic condition, and nitrogen limitation, which occur typically at the late growth phase of the batch culture, are interconnected through RpoS and RpoD together with Pho genes. PMID- 21599907 TI - The usefulness of case reports in managing emerging infectious disease. AB - Emerging infectious diseases are an important problem in medicine. Case reports usually document episodes in the early emerging phase or in a small outbreak. Although the case report is considered weak evidence in medical literature, it is usually the first report when there is a new emerging infectious disease. There is no doubt that case reports can provide useful information for further case series, reviews and studies. This editorial focuses on the usefulness of the case report on emerging infectious disease to the medical society. Publication in this area is highly welcomed by the journal and can serve as a future point of reference. PMID- 21599908 TI - MRSA prevalence in European healthcare settings: a review. AB - BACKGROUND: During the past two decades, methicillin-resistant Staphylococcus aureus (MRSA) has become increasingly common as a source of nosocomial infections. Most studies of MRSA surveillance were performed during outbreaks, so that results are not applicable to settings in which MRSA is endemic. This paper gives an overview of MRSA prevalence in hospitals and other healthcare institutions in non-outbreak situations in Western Europe. METHODS: A keyword search was conducted in the Medline database (2000 through June 2010). Titles and abstracts were screened to identify studies on MRSA prevalence in patients in non outbreak situations in European healthcare facilities. Each study was assessed using seven quality criteria (outcome definition, time unit, target population, participants, observer bias, screening procedure, swabbing sites) and categorized as 'good', 'fair', or 'poor'. RESULTS: 31 observational studies were included in the review. Four of the studies were of good quality. Surveillance screening of MRSA was performed in long-term care (11 studies) and acute care (20 studies). Prevalence rates varied over a wide range, from less than 1% to greater than 20%. Prevalence in the acute care and long-term care settings was comparable. The prevalence of MRSA was expressed in various ways - the percentage of MRSA among patients (range between 1% and 24%), the percentage of MRSA among S. aureus isolates (range between 5% and 54%), and as the prevalence density (range between 0.4 and 4 MRSA cases per 1,000 patient days). The screening policy differed with respect to time points (on admission or during hospital stay), selection criteria (all admissions or patients at high risk for MRSA) and anatomical sampling sites. CONCLUSIONS: This review underlines the methodological differences between studies of MRSA surveillance. For comparisons between different healthcare settings, surveillance methods and outcome calculations should be standardized. PMID- 21599909 TI - Malaria chemoprophylaxis recommendations for immigrants to Europe, visiting relatives and friends--a Delphi method study. AB - BACKGROUND: Numbers of travellers visiting friends and relatives (VFRs) from Europe to malaria endemic countries are increasing and include long-term and second generation immigrants, who represent the major burden of malaria cases imported back into Europe. Most recommendations for malaria chemoprophylaxis lack a solid evidence base, and often fail to address the cultural, social and economic needs of VFRs. METHODS: European travel medicine experts, who are members of TropNetEurop, completed a sequential series of questionnaires according to the Delphi method. This technique aims at evaluating and developing a consensus through repeated iterations of questionnaires. The questionnaires in this study included questions about professional experience with VFRs, controversial issues in malaria prophylaxis, and 16 scenarios exploring indications for prescribing and choice of chemoprophylaxis. RESULTS: The experience of participants was rather diverse as was their selection of chemoprophylaxis regimen. A significant consensus was observed in only seven of 16 scenarios. The analysis revealed a wide variation in prescribing choices with preferences grouped by region of practice and increased prescribing seen in Northern Europe compared to Central Europe. CONCLUSIONS: Improving the evidence base on efficacy, adherence to chemoprophylaxis and risk of malaria and encouraging discussion among experts, using techniques such as the Delphi method, may reduce the variability in prescription in European travel clinics. PMID- 21599910 TI - Establishment and interspecific associations in two species of Ichthyocotylurus (Trematoda) parasites in perch (Perca fluviatilis). AB - BACKGROUND: Co-infections of multiple parasite species in hosts may lead to interspecific associations and subsequently shape the structure of a parasite community. However, few studies have focused on these associations in highly abundant parasite species or, in particular, investigated how the associations develop with time in hosts exposed to co-infecting parasite species for the first time. We investigated metacercarial establishment and interspecific associations in the trematodes Ichthyocotylurus variegatus and I. pileatus co-infecting three age cohorts of young perch (Perca fluviatilis). RESULTS: We found that the timing of transmission of the two Ichthyocotylurus species was very similar, but they showed differences in metacercarial development essentially so that the metacercariae of I. pileatus became encapsulated faster. Correlations between the abundances of the species were significantly positive after the first summer of host life and also within the main site of infection, the swim bladder. High or low abundances of both parasite species were also more frequent in the same host individuals than expected by chance, independently of host age or size. However, the highest abundances of the species were nevertheless observed in different host individuals and this pattern was consistent in all age cohorts. CONCLUSIONS: The results suggest similar temporal patterns of transmission, non-random establishment, and facilitative rather than competitive associations between the parasite species independently of the age of the infracommunities. However, we suggest that spatial differences in exposure are most likely responsible for the segregation of the parasite species observed in the few most heavily infected hosts. Regardless of the underlying mechanism, the result suggests that between species associations should be interpreted with caution along with detailed examination of the parasite distribution among host individuals. PMID- 21599911 TI - Reconstruction of the esophagojejunostomy by double stapling method using EEATM OrVilTM in laparoscopic total gastrectomy and proximal gastrectomy. AB - Here we report the method of anastomosis based on double stapling technique (hereinafter, DST) using a trans-oral anvil delivery system (EEATM OrVilTM) for reconstructing the esophagus and lifted jejunum following laparoscopic total gastrectomy or proximal gastric resection. As a basic technique, laparoscopic total gastrectomy employed Roux-en-Y reconstruction, laparoscopic proximal gastrectomy employed double tract reconstruction, and end-to-side anastomosis was used for the cut-off stump of the esophagus and lifted jejunum. We used EEATM OrVilTM as a device that permitted mechanical purse-string suture similarly to conventional EEA, and endo-Surgitie. After the gastric lymph node dissection, the esophagus was cut off using an automated stapler. EEATM OrVilTM was orally and slowly inserted from the valve tip, and a small hole was created at the tip of the obliquely cut-off stump with scissors to let the valve tip pass through. Yarn was cut to disconnect the anvil from a tube and the anvil head was retained in the esophagus. The end-Surgitie was inserted at the right subcostal margin, and after the looped-shaped thread was wrapped around the esophageal stump opening, assisting Maryland forceps inserted at the left subcostal and left abdomen were used to grasp the left and right esophageal stump. The surgeon inserted anvil grasping forceps into the right abdomen, and after grasping the esophagus with the forceps, tightened the end Surgitie, thereby completing the purse-string suture on the esophageal stump. The main unit of the automated stapler was inserted from the cut-off stump of the lifted jejunum, and a trocar was made to pass through. To prevent dropout of the small intestines from the automated stapler, the automated stapler and the lifted jejunum were fastened with silk thread, the abdomen was again inflated, and the lifted jejunum was led into the abdominal cavity. When it was confirmed that the automated stapler and center rod were made completely linear, the anvil and the main unit were connected with each other and firing was carried out. Then, DST-based anastomosis was completed with no dog-ear. The method may facilitate safe laparoscopic anastomosis between the esophagus and reconstructed intestine. This is also considered to serve as a useful anastomosis technique for upper levels of the esophagus in laparotomy. PMID- 21599912 TI - Protein alignment algorithms with an efficient backtracking routine on multiple GPUs. AB - BACKGROUND: Pairwise sequence alignment methods are widely used in biological research. The increasing number of sequences is perceived as one of the upcoming challenges for sequence alignment methods in the nearest future. To overcome this challenge several GPU (Graphics Processing Unit) computing approaches have been proposed lately. These solutions show a great potential of a GPU platform but in most cases address the problem of sequence database scanning and computing only the alignment score whereas the alignment itself is omitted. Thus, the need arose to implement the global and semiglobal Needleman-Wunsch, and Smith-Waterman algorithms with a backtracking procedure which is needed to construct the alignment. RESULTS: In this paper we present the solution that performs the alignment of every given sequence pair, which is a required step for progressive multiple sequence alignment methods, as well as for DNA recognition at the DNA assembly stage. Performed tests show that the implementation, with performance up to 6.3 GCUPS on a single GPU for affine gap penalties, is very efficient in comparison to other CPU and GPU-based solutions. Moreover, multiple GPUs support with load balancing makes the application very scalable. CONCLUSIONS: The article shows that the backtracking procedure of the sequence alignment algorithms may be designed to fit in with the GPU architecture. Therefore, our algorithm, apart from scores, is able to compute pairwise alignments. This opens a wide range of new possibilities, allowing other methods from the area of molecular biology to take advantage of the new computational architecture. Performed tests show that the efficiency of the implementation is excellent. Moreover, the speed of our GPU based algorithms can be almost linearly increased when using more than one graphics card. PMID- 21599914 TI - Isolation and analysis of high quality nuclear DNA with reduced organellar DNA for plant genome sequencing and resequencing. AB - BACKGROUND: High throughput sequencing (HTS) technologies have revolutionized the field of genomics by drastically reducing the cost of sequencing, making it feasible for individual labs to sequence or resequence plant genomes. Obtaining high quality, high molecular weight DNA from plants poses significant challenges due to the high copy number of chloroplast and mitochondrial DNA, as well as high levels of phenolic compounds and polysaccharides. Multiple methods have been used to isolate DNA from plants; the CTAB method is commonly used to isolate total cellular DNA from plants that contain nuclear DNA, as well as chloroplast and mitochondrial DNA. Alternatively, DNA can be isolated from nuclei to minimize chloroplast and mitochondrial DNA contamination. RESULTS: We describe optimized protocols for isolation of nuclear DNA from eight different plant species encompassing both monocot and eudicot species. These protocols use nuclei isolation to minimize chloroplast and mitochondrial DNA contamination. We also developed a protocol to determine the number of chloroplast and mitochondrial DNA copies relative to the nuclear DNA using quantitative real time PCR (qPCR). We compared DNA isolated from nuclei to total cellular DNA isolated with the CTAB method. As expected, DNA isolated from nuclei consistently yielded nuclear DNA with fewer chloroplast and mitochondrial DNA copies, as compared to the total cellular DNA prepared with the CTAB method. This protocol will allow for analysis of the quality and quantity of nuclear DNA before starting a plant whole genome sequencing or resequencing experiment. CONCLUSIONS: Extracting high quality, high molecular weight nuclear DNA in plants has the potential to be a bottleneck in the era of whole genome sequencing and resequencing. The methods that are described here provide a framework for researchers to extract and quantify nuclear DNA in multiple types of plants. PMID- 21599913 TI - Exhaled nitric oxide and clinical phenotypes of childhood asthma. AB - Whether exhaled NO helps to identify a specific phenotype of asthmatic patients remains debated. Our aims were to evaluate whether exhaled NO (FENO(0.05)) is independently associated (1) with underlying pathophysiological characteristics of asthma such as airway tone (bronchodilator response) and airway inflammation (inhaled corticosteroid [ICS]-dependant inflammation), and (2) with clinical phenotypes of asthma.We performed multivariate (exhaled NO as dependent variable) and k-means cluster analyses in a population of 169 asthmatic children (age +/- SD: 10.5 +/- 2.6 years) recruited in a monocenter cohort that was characterized in a cross-sectional design using 28 parameters describing potentially different asthma domains: atopy, environment (tobacco), control, exacerbations, treatment (inhaled corticosteroid and long-acting bronchodilator agonist), and lung function (airway architecture and tone). Two subject-related characteristics (height and atopy) and two disease-related characteristics (bronchodilator response and ICS dose > 200 MUg/d) explained 36% of exhaled NO variance. Nine domains were isolated using principal component analysis. Four clusters were further identified: cluster 1 (47%): boys, unexposed to tobacco, with well controlled asthma; cluster 2 (26%): girls, unexposed to tobacco, with well controlled asthma; cluster 3 (6%): girls or boys, unexposed to tobacco, with uncontrolled asthma associated with increased airway tone, and cluster 4 (21%): girls or boys, exposed to parental smoking, with small airway to lung size ratio and uncontrolled asthma. FENO(0.05) was not different in these four clusters.In conclusion, FENO(0.05) is independently linked to two pathophysiological characteristics of asthma (ICS-dependant inflammation and bronchomotor tone) but does not help to identify a clinically relevant phenotype of asthmatic children. PMID- 21599915 TI - The incidence, root-causes, and outcomes of adverse events in surgical units: implication for potential prevention strategies. AB - BACKGROUND: We need to know the scale and underlying causes of surgical adverse events (AEs) in order to improve the safety of care in surgical units. However, there is little recent data. Previous record review studies that reported on surgical AEs in detail are now more than ten years old. Since then surgical technology and quality assurance have changed rapidly. The objective of this study was to provide more recent data on the incidence, consequences, preventability, causes and potential strategies to prevent AEs among hospitalized patients in surgical units. METHODS: A structured record review study of 7,926 patient records was carried out by trained nurses and medical specialist reviewers in 21 Dutch hospitals. The aim was to determine the presence of AEs during hospitalizations in 2004 and to consider how far they could be prevented. Of all AEs, the consequences, responsible medical specialty, causes and potential prevention strategies were identified. Surgical AEs were defined as AEs attributable to surgical treatment and care processes and were selected for analysis in detail. RESULTS: Surgical AEs occurred in 3.6% of hospital admissions and represented 65% of all AEs. Forty-one percent of the surgical AEs was considered to be preventable. The consequences of surgical AEs were more severe than for other types of AEs, resulting in more permanent disability, extra treatment, prolonged hospital stay, unplanned readmissions and extra outpatient visits. Almost 40% of the surgical AEs were infections, 23% bleeding, and 22% injury by mechanical, physical or chemical cause. Human factors were involved in the causation of 65% of surgical AEs and were considered to be preventable through quality assurance and training. CONCLUSIONS: Surgical AEs occur more often than other types of AEs, are more often preventable and their consequences are more severe. Therefore, surgical AEs have a major impact on the burden of AEs during hospitalizations. These findings concur with the results from previous studies. However, evidence-based solutions to reduce surgical AEs are increasingly available. Interventions directed at human causes are recommended to improve the safety of surgical care. Examples are team training and the surgical safety checklist. In addition, specific strategies are needed to improve appropriate use of antibiotic prophylaxis and sustainable implementation of hygiene guidelines to reduce infections. PMID- 21599916 TI - Effect of priming injections of luteinizing hormone-releasing hormone on spermiation and ovulation in Gupsilonnther's toadlet, Pseudophryne guentheri. AB - BACKGROUND: In the majority of vertebrates, gametogenesis and gamete-release depend on the pulsatile secretion of luteinizing hormone-releasing hormone (LHRH) from the hypothalamus. Studies attempting to artificially stimulate ovulation and spermiation may benefit from mimicking the naturally episodic secretion of LHRH by administering priming injections of a synthetic analogue (LHRHa). This study investigated the impact of low-dose priming injections of LHRHa on gamete-release in the Australian toadlet Pseudophryne guentheri. METHODS: Toadlets were administered a single dose of two micrograms per. gram LHRHa without a priming injection (no priming), or preceded by one (one priming) or two (two priming) injections of 0.4 micrograms per. gram LHRHa. Spermiation responses were evaluated at 3, 7 and 12 hrs post hormone administration (PA), and sperm number and viability were quantified using fluorescent microscopy. Oocyte yields were evaluated by stripping females at 10-11 hrs PA. A sub-sample of twenty eggs per female was then fertilised (with sperm obtained from testis macerates) and fertilisation success determined. RESULTS: No priming induced the release of the highest number of spermatozoa, with a step-wise decrease in the number of spermatozoa released in the one and two priming treatments respectively. Peak sperm-release occurred at 12 hrs PA for all priming treatments and there was no significant difference in sperm viability. Females in the control treatment failed to release oocytes, while those administered an ovulatory dose without priming exhibited a poor ovulatory response. The remaining two priming treatments (one and two priming) successfully induced 100% of females to expel an entire clutch. Oocytes obtained from the no, or two priming treatments all failed to fertilise, however oocytes obtained from the one priming treatment displayed an average fertilisation success of 97%. CONCLUSION: Spermiation was most effectively induced in male P. guentheri by administering a single injection of LHRHa without priming. In contrast, female P. guentheri failed to ovulate without priming. A single priming injection induced the release of oocytes of high viability compared to oocytes obtained from females in the two priming treatment which underwent a process of over-ripening. PMID- 21599917 TI - Gout treatment and comorbidities: a retrospective cohort study in a large US managed care population. AB - BACKGROUND: Gout prevalence increased in recent years to become one of the most common causes of inflammatory arthritis in most industrialised countries. Comorbidities may affect the disease severity and treatment patterns. We describe the main characteristics of gout patients, gout-related treatment patterns and prevalent comorbidities in a managed care population. METHODS: From the large US PharMetrics Patient-Centric Database, patients aged 20-89 with at least 2 claims for a diagnosis of gout (ICD9 274.xx) and related prescriptions between January 1, 1996 and December 31, 2008 were included. Gout flares were ascertained during follow-up. Sex-specific multivariable Poisson regression models were used to assess factors associated with number of flares. RESULTS: 177,637 gout patients were included (mean age 55.2 years; men 75.6%). Overall, more than half (58.1%) had any of the considered comorbidities; hypertension (36.1%), dyslipidemia (27.0%) and diabetes (15.1%) being the most common. Nonselective NSAIDs were the most commonly dispensed (in 38.7% of patients). Notably, 39% of patients did not receive any prescription medication for gout. Patients with comorbidities were significantly more likely to receive anti-gout prescriptions. During an acute episode the prescription of NSAIDs and colchicine increased; and 29.9% of patients received allopurinol. The risk of flares was associated with cardiometabolic comorbidities and older age in women (highest at age 60-69), while in men it decreased by age. Women with these conditions were 60% more likely to have flares (incidence rate ratio, IRR 1.60;1.48-1.74), while men were 10% (IRR 1.10; 1.06-1.13) more likely. CONCLUSIONS: Comorbidities affected gout treatment patterns and the occurrence and frequency of acute attacks. Cardiometabolic comorbidities, common in this patients' population, were associated with an increased risk of flares. PMID- 21599918 TI - Factors and processes shaping the population structure and distribution of genetic variation across the species range of the freshwater snail radix balthica (Pulmonata, Basommatophora). AB - BACKGROUND: Factors and processes shaping the population structure and spatial distribution of genetic diversity across a species' distribution range are important in determining the range limits. We comprehensively analysed the influence of recurrent and historic factors and processes on the population genetic structure, mating system and the distribution of genetic variability of the pulmonate freshwater snail Radix balthica. This analysis was based on microsatellite variation and mitochondrial haplotypes using Generalised Linear Statistical Modelling in a Model Selection framework. RESULTS: Populations of R. balthica were found throughout North-Western Europe with range margins marked either by dispersal barriers or the presence of other Radix taxa. Overall, the population structure was characterised by distance independent passive dispersal mainly along a Southwest-Northeast axis, the absence of isolation-by-distance together with rather isolated and genetically depauperated populations compared to the variation present in the entire species due to strong local drift. A recent, climate driven range expansion explained most of the variance in genetic variation, reducing at least temporarily the genetic variability in this area. Other factors such as geographic marginality and dispersal barriers play only a minor role. CONCLUSIONS: To our knowledge, such a population structure has rarely been reported before. It might nevertheless be typical for passively dispersed, patchily distributed taxa (e.g. freshwater invertebrates). The strong local drift implied in such a structure is expected to erode genetic variation at both neutral and coding loci and thus probably diminish evolutionary potential. This study shows that the analysis of multiple factors is crucial for the inference of the processes shaping the distribution of genetic variation throughout species ranges. PMID- 21599919 TI - MACI - a new era? AB - Full thickness articular cartilage defects have limited regenerative potential and are a significant source of pain and loss of knee function. Numerous treatment options exist, each with their own advantages and drawbacks. The goal of this review is to provide an overview of the problem of cartilage injury, a brief description of current treatment options and outcomes, and a discussion of the current principles and technique of Matrix-induced Autologous Chondrocyte Implantation (MACI). While early results of MACI have been promising, there is currently insufficient comparative and long-term outcome data to demonstrate superiority of this technique over other methods for cartilage repair. PMID- 21599920 TI - Would school closure for the 2009 H1N1 influenza epidemic have been worth the cost?: a computational simulation of Pennsylvania. AB - BACKGROUND: During the 2009 H1N1 influenza epidemic, policy makers debated over whether, when, and how long to close schools. While closing schools could have reduced influenza transmission thereby preventing cases, deaths, and health care costs, it may also have incurred substantial costs from increased childcare needs and lost productivity by teachers and other school employees. METHODS: A combination of agent-based and Monte Carlo economic simulation modeling was used to determine the cost-benefit of closing schools (vs. not closing schools) for different durations (range: 1 to 8 weeks) and symptomatic case incidence triggers (range: 1 to 30) for the state of Pennsylvania during the 2009 H1N1 epidemic. Different scenarios varied the basic reproductive rate (R(0)) from 1.2, 1.6, to 2.0 and used case-hospitalization and case-fatality rates from the 2009 epidemic. Additional analyses determined the cost per influenza case averted of implementing school closure. RESULTS: For all scenarios explored, closing schools resulted in substantially higher net costs than not closing schools. For R(0) = 1.2, 1.6, and 2.0 epidemics, closing schools for 8 weeks would have resulted in median net costs of $21.0 billion (95% Range: $8.0 - $45.3 billion). The median cost per influenza case averted would have been $14,185 ($5,423 - $30,565) for R(0) = 1.2, $25,253 ($9,501 - $53,461) for R(0) = 1.6, and $23,483 ($8,870 - $50,926) for R(0) = 2.0. CONCLUSIONS: Our study suggests that closing schools during the 2009 H1N1 epidemic could have resulted in substantial costs to society as the potential costs of lost productivity and childcare could have far outweighed the cost savings in preventing influenza cases. PMID- 21599921 TI - 2-Hydroxylated sphingomyelin profiles in cells from patients with mutated fatty acid 2-hydroxylase. AB - Fatty acid 2-hydroxylase (FA2H) is the enzyme responsible for the hydroxylation of free fatty acids prior to their incorporation into 2-hydroxylated sphingolipids, which are the major constituents of the myelin leaflet. Mutated FA2H has been associated with neurodegenerative diseases. Decreased FA2H activity was demonstrated only in vitro, but not in patient tissues. In this study we characterized the 2-hydroxylated sphingomyelin (SM) profiles in blood and fibroblasts from patients harboring a deleterious FA2H mutatation, and found that hydroxylated fatty acid sphingomyelin is present in normal amounts in patient lymphocytes, but decreased to a different extent in fibroblasts and erythrocytes. PMID- 21599923 TI - Down-regulation of NKD1 increases the invasive potential of non-small-cell lung cancer and correlates with a poor prognosis. AB - BACKGROUND: As a negative modulator of the canonical Wnt signaling pathway, Naked1 (NKD1) is widely expressed in many normal tissues. However, the expression pattern and clinicopathological significance of NKD1 in patients with non-small cell lung cancer (NSCLC) is still unclear. METHODS: Immunohistochemical studies were performed on 35 cases of normal lung tissues and 100 cases of NSCLC, including 66 cases with complete follow-up records. The NKD1 protein and mRNA expressions were detected by western blot and Real-time PCR, respectively. To examine the effect of NKD1 on the invasiveness of lung cancer cells, NKD1 was down-regulated by siRNA in lung cancer cell lines and the invasive ability was then evaluated by the Matrigel invasion assay. In addition, the expressions of Dishevelled-1 and beta-catenin proteins, as well as MMP mRNA were also examined in NKD1 knockdown cells. RESULTS: In 35 fresh lung cancer tissues examined, 27(79%) of them exhibited lower levels of NKD1 protein in comparison with their corresponding normal tissue (P = 0.009). However, the NKD1 mRNA level was significantly higher in cancerous lung tissues, compared with the adjacent normal tissues. In 100 NSCLC tissues, NKD1 was significantly lower in 78 cases (78%) than in the normal specimens, determined by immunohistochemical staining. The reduced NKD1 expression was correlated with histological type (P = 0.003), poor differentiation (P = 0.004), lymph node metastasis (P = 0.013), TNM stage (P = 0.002) and poor survival (62.88 +/- 3.23 versus 23.61 +/- 2.18 months, P = 0.03). In addition, NKD1 knockdown could up-regulate Dishevelled-1 and beta-catenin protein levels, as well as increased MMP-7 transcription and the invasive ability of lung cancer cells. Furthermore, when the NKD1-knockdown cells were treated with Dishevelled-1 antibody, their invasive potential was significantly reduced. CONCLUSION: NKD1 protein is reduced but NKD1 mRNA is elevated in NSCLC. Reduced NKD1 protein expression correlates with a poor prognosis in NSCLC. NKD1 might inhibit the activity of the canonical Wnt pathway through Dishevelled-1. PMID- 21599922 TI - Histone deacetylase activity is necessary for left-right patterning during vertebrate development. AB - BACKGROUND: Consistent asymmetry of the left-right (LR) axis is a crucial aspect of vertebrate embryogenesis. Asymmetric gene expression of the TGFbeta superfamily member Nodal related 1 (Nr1) in the left lateral mesoderm plate is a highly conserved step regulating the situs of the heart and viscera. In Xenopus, movement of maternal serotonin (5HT) through gap-junctional paths at cleavage stages dictates asymmetry upstream of Nr1. However, the mechanisms linking earlier biophysical asymmetries with this transcriptional control point are not known. RESULTS: To understand how an early physiological gradient is transduced into a late, stable pattern of Nr1 expression we investigated epigenetic regulation during LR patterning. Embryos injected with mRNA encoding a dominant negative of Histone Deacetylase (HDAC) lacked Nr1 expression and exhibited randomized sidedness of the heart and viscera (heterotaxia) at stage 45. Timing analysis using pharmacological blockade of HDACs implicated cleavage stages as the active period. Inhibition during these early stages was correlated with an absence of Nr1 expression at stage 21, high levels of heterotaxia at stage 45, and the deposition of the epigenetic marker H3K4me2 on the Nr1 gene. To link the epigenetic machinery to the 5HT signaling pathway, we performed a high-throughput proteomic screen for novel cytoplasmic 5HT partners associated with the epigenetic machinery. The data identified the known HDAC partner protein Mad3 as a 5HT-binding regulator. While Mad3 overexpression led to an absence of Nr1 transcription and randomized the LR axis, a mutant form of Mad3 lacking 5HT binding sites was not able to induce heterotaxia, showing that Mad3's biological activity is dependent on 5HT binding. CONCLUSION: HDAC activity is a new LR determinant controlling the epigenetic state of Nr1 from early developmental stages. The HDAC binding partner Mad3 may be a new serotonin-dependent regulator of asymmetry linking early physiological asymmetries to stable changes in gene expression during organogenesis. PMID- 21599924 TI - Infection control in delivery care units, Gujarat state, India: a needs assessment. AB - BACKGROUND: Increasingly, women in India attend health facilities for childbirth, partly due to incentives paid under government programs. Increased use of health facilities can alleviate the risks of infections contracted in unhygienic home deliveries, but poor infection control practices in labour and delivery units also cause puerperal sepsis and other infections of childbirth. A needs assessment was conducted to provide information on procedures and practices related to infection control in labour and delivery units in Gujarat state, India. METHODS: Twenty health care facilities, including private and public primary health centres and referral hospitals, were sampled from two districts in Gujarat state, India. Three pre-tested tools for interviewing and for observation were used. Data collection was based on existing infection control guidelines for clean practices, clean equipment, clean environment and availability of diagnostics and treatment. The study was carried out from April to May 2009. RESULTS: Seventy percent of respondents said that standard infection control procedures were followed, but a written procedure was only available in 5% of facilities. Alcohol rubs were not used for hand cleaning and surgical gloves were reused in over 70% of facilities, especially for vaginal examinations in the labour room. Most types of equipment and supplies were available but a third of facilities did not have wash basins with "hands-free" taps. Only 15% of facilities reported that wiping of surfaces was done immediately after each delivery in labour rooms. Blood culture services were available in 25% of facilities and antibiotics are widely given to women after normal delivery. A few facilities had data on infections and reported rates of 3% to 5%. CONCLUSIONS: This study of current infection control procedures and practices during labour and delivery in health facilities in Gujarat revealed a need for improved information systems, protocols and procedures, and for training and research. Simply incentivizing the behaviour of women to use health facilities for childbirth via government schemes may not guarantee safe delivery. PMID- 21599926 TI - What causes treatment failure - the patient, primary care, secondary care or inadequate interaction in the health services? AB - BACKGROUND: Optimal treatment gives complete relief of symptoms of many disorders. But even if such treatment is available, some patients have persisting complaints. One disorder, from which the patients should achieve complete relief of symptoms with medical or surgical treatment, is gastroesophageal reflux disease (GERD). Despite the fact that such treatment is cheap, safe and easily available; some patients have persistent complaints after contact with the health services. This study evaluates the causes of treatment failure. METHODS: Twelve patients with GERD and persistent complaints had a semi-structured interview which focused on the patients' evaluation of treatment failure. The interviews were taped, transcribed and evaluated by 18 physicians, (six general practitioners, six gastroenterologists and six gastrointestinal surgeons) who completed a questionnaire for each patient. The questionnaires were scored, and the relative responsibility for the failure was attributed to the patient, primary care, secondary care and interaction in the health services. RESULTS: Failing interaction in the health services was the most important cause of treatment failure, followed by failure in primary care, secondary care and the patient himself; the relative responsibilities were 35%, 28%, 27% and 10% respectively. There was satisfactory agreement about the causes between doctors with different specialities, but significant inter-individual differences between the doctors. The causes of the failures differed between the patients. CONCLUSIONS: Treatment failure is a complex problem. Inadequate interaction in the health services seems to be important. Improved communication between parts of the health services and with the patients are areas of improvement. PMID- 21599925 TI - The role of nitric-oxide-synthase-derived nitric oxide in multicellular traits of Bacillus subtilis 3610: biofilm formation, swarming, and dispersal. AB - BACKGROUND: Bacillus subtilis 3610 displays multicellular traits as it forms structurally complex biofilms and swarms on solid surfaces. In addition, B. subtilis encodes and expresses nitric oxide synthase (NOS), an enzyme that is known to enable NO-mediated intercellular signalling in multicellular eukaryotes. In this study, we tested the hypothesis that NOS-derived NO is involved in the coordination of multicellularity in B. subtilis 3610. RESULTS: We show that B. subtilis 3610 produces intracellular NO via NOS activity by combining Confocal Laser Scanning Microscopy with the NO sensitive dye copper fluorescein (CuFL). We further investigated the influence of NOS-derived NO and exogenously supplied NO on the formation of biofilms, swarming motility and biofilm dispersal. These experiments showed that neither the suppression of NO formation with specific NOS inhibitors, NO scavengers or deletion of the nos gene, nor the exogenous addition of NO with NO donors affected (i) biofilm development, (ii) mature biofilm structure, and (iii) swarming motility in a qualitative and quantitative manner. In contrast, the nos knock-out and wild-type cells with inhibited NOS displayed strongly enhanced biofilm dispersal. CONCLUSION: The results suggest that biofilm formation and swarming motility in B. subtilis represent complex multicellular processes that do not employ NO signalling and are remarkably robust against interference of NO. Rather, the function of NOS-derived NO in B. subtilis might be specific for cytoprotection against oxidative stress as has been proposed earlier. The influence of NOS-derived NO on dispersal of B. subtilis from biofilms might be associated to its well-known function in coordinating the transition from oxic to anoxic conditions. Here, NOS-derived NO might be involved in fine-tuning the cellular decision-making between adaptation of the metabolism to (anoxic) conditions in the biofilm or dispersal from the biofilm. PMID- 21599927 TI - Duration and determinants of birth interval among women of child bearing age in Southern Ethiopia. AB - BACKGROUND: Longer intervals between consecutive births decrease the number of children a woman can have. This results in beneficial effects on population size and on the health status of mothers and children. Therefore, understanding the practice of birth interval and its determinants is helpful to design evidence based strategies for interventions. The objective of this study was to determine duration and determinants of birth interval among women of child bearing age in Lemo district, southern Ethiopia in March 2010. METHODS: A community based cross sectional study design with stratified multistage sampling technique was employed. A sample of 844 women of child bearing age were selected by using simple random sampling technique after complete census was conducted in selected kebeles prior to data collection. Structured interviewer administered questionnaire was used for data collection. Actual birth interval was measured with the respondents' memory since majority of the women or their children in the area had no birth certificate. RESULTS: Majority (57%) of women were practicing short birth interval length with the median birth interval length of 33 months. Actual birth interval length is significantly shorter than preferred birth interval length. Birth interval showed significant variation by contraceptive use, residence, wealth index, breast feeding and occupation of husbands. CONCLUSION: low proportion of optimal birth spacing practices with short actual birth interval length and longer preferred birth interval lengths were evident among the study subjects. Hence interventions to enhance contraceptive utilization behaviors among women in Lemo district would be helpful to narrow the gap between optimal and actual birth spacing. PMID- 21599928 TI - Cost-effectiveness analysis of antimuscarinics in the treatment of patients with overactive bladder in Spain: a decision-tree model. AB - BACKGROUND: Fesoterodine, a new once daily antimuscarinic, has proven to be an effective, safe, and well-tolerated treatment in patients with overactive bladder (OAB). To date, no analysis has evaluated the economic costs and benefits associated with fesoterodine, compared to antimuscarinics in Spain. The purpose of this analysis was to assess the economic value of OAB treatment with fesoterodine relative to extended release tolterodine and solifenacin, from the societal perspective. METHODS: The economic model was based on data from two 12 week, randomized, double-blind, and multicenter trials comparing fesoterodine and tolterodine extended released (ER). Treatment response rates for solifenacin were extracted from the published literature. Discontinuation and efficacy were based on the results of a 12-week multinational randomized clinical trial extrapolated to 52 weeks. Changes in health related quality of life were assessed with the King's Health Questionnaire, which was transformed into preference-based utility values. Medical costs included (expressed in ? 2010) were antimuscarinics, physician visits, laboratory tests, incontinence pads and the costs of OAB related comorbidities, fractures, skin infections, urinary tract infections, depression, and nursing home admissions associated with incontinence. Time lost from work was also considered. Univariate sensitivity analyses were also performed. RESULTS: At week 12, continents accounted for 50.6%, 40.6% and 47.2% of patients in the fesoterodine, tolterodine, and solifenacin groups, respectively. By week 52, the projected proportions of patients remaining on therapy were 33.1%, 26.5% and 30.8%, respectively. The projected quality- adjusted life years (QALY) gain (compared to baseline) over the 52-week simulation period were 0.01014, 0.00846 and 0.00957, respectively. The overall treatment cost was estimated at ?1,937, ?2,089 and ?1,960 for fesoterodine, tolterodine and solifenacin, respectively. Therefore, treatment with fesoterodine resulted in similar overall costs and greater QALY gain than treatment with either tolterodine or solifenacin. Sensitivity analysis showed that these results were robust to all changes performed. CONCLUSIONS: The results of this economic analysis suggest that fesoterodine is a cost-effective alternative to tolterodine and solifenacin for the treatment of patients with OAB in Spain. Fesoterodine provides additional health benefits while maintain a similar level of costs being a cost-effective treatment strategy from a societal perspective. PMID- 21599930 TI - The influence of behavioural and health problems on alcohol and drug use in late adolescence - a follow up study of 2 399 young Norwegians. AB - BACKGROUND: Both early alcohol debut, behavioural and health problems are reported to enhance adolescence substance use. This prospective study investigate the influence of behavioural and health problems on adolescents' alcohol and drug use. METHOD: Prospective population based cohort study of 2 399 adolescents attending the Young-HUNT study, aged 13-15 at baseline in 1995/97, and 17-19 at follow-up 4 years later. Exposure variables were self reported conduct problems, attention problems, anxiety and depressive symptoms, and muscular pain and tension. Outcome variables at follow-up were frequent alcohol use and initiation of drug use. Associations were estimated by logistic regression models, influence of gender and drinking status at baseline were controlled for by stratification. RESULTS: At follow-up 19% of the students drank alcohol once a week or more frequently. Baseline conduct problems (OR 2.2, CI 1.7-3.0) and attention problems (OR 1.5, CI 1.2-2.0) increased the risk for frequent alcohol use at follow-up in the total population. Girls who had experienced alcohol-intoxications at baseline showed strong association between baseline problems and frequent alcohol use at follow-up. Conduct problems (OR 2.5, CI 1.3-4.8), attention problems (OR 2.1, CI 1.2-3.4), anxiety/depressive symptoms (OR 1.9, CI 1.1-3.1) and muscular pain and tension (OR 1.7, CI 1.0-2.9) all were associated with frequent alcohol use among early intoxicated girls.14% of the students had tried cannabis or other drugs at follow-up. Conduct problems at baseline increased the odds for drug use (OR 2.6, CI 1.9-3.6). Any alcohol intoxications at baseline, predicted both frequent alcohol use (boys OR 3.6, CI 2.4-5.2; girls OR 2.8, CI 1.9-4.1), and illegal drug use (boys OR 4.7; CI 3.2-7.0, girls OR 7.7, CI 5.2-11.5) within follow-up. CONCLUSIONS: Conduct problems in high-school more than doubles the risk for both frequent alcohol use and initiation of drug use later in adolescence. The combination of health problems and alcohol intoxication in early adolescence was closely associated with more frequent drinking later in adolescence among girls.Overall, early alcohol intoxication was closely associated with both frequent alcohol use and drug use at follow up in both genders. PMID- 21599929 TI - CLOTU: an online pipeline for processing and clustering of 454 amplicon reads into OTUs followed by taxonomic annotation. AB - BACKGROUND: The implementation of high throughput sequencing for exploring biodiversity poses high demands on bioinformatics applications for automated data processing. Here we introduce CLOTU, an online and open access pipeline for processing 454 amplicon reads. CLOTU has been constructed to be highly user friendly and flexible, since different types of analyses are needed for different datasets. RESULTS: In CLOTU, the user can filter out low quality sequences, trim tags, primers, adaptors, perform clustering of sequence reads, and run BLAST against NCBInr or a customized database in a high performance computing environment. The resulting data may be browsed in a user-friendly manner and easily forwarded to downstream analyses. Although CLOTU is specifically designed for analyzing 454 amplicon reads, other types of DNA sequence data can also be processed. A fungal ITS sequence dataset generated by 454 sequencing of environmental samples is used to demonstrate the utility of CLOTU. CONCLUSIONS: CLOTU is a flexible and easy to use bioinformatics pipeline that includes different options for filtering, trimming, clustering and taxonomic annotation of high throughput sequence reads. Some of these options are not included in comparable pipelines. CLOTU is implemented in a Linux computer cluster and is freely accessible to academic users through the Bioportal web-based bioinformatics service (http://www.bioportal.uio.no). PMID- 21599931 TI - The clinical burden of malaria in Nairobi: a historical review and contemporary audit. AB - BACKGROUND: Widespread urbanization over the next 20 years has the potential to drastically change the risk of malaria within Africa. The burden of the disease, its management, risk factors and appropriateness of targeted intervention across varied urban environments in Africa remain largely undefined. This paper presents a combined historical and contemporary review of the clinical burden of malaria within one of Africa's largest urban settlements, Nairobi, Kenya. METHODS: A review of historical reported malaria case burdens since 1911 within Nairobi was undertaken using archived government and city council reports. Contemporary information on out-patient case burdens due to malaria were assembled from the National Health Management and Information System (HMIS). Finally, an audit of 22 randomly selected health facilities within Nairobi was undertaken covering 12 months 2009-2010. The audit included interviews with health workers, and a checklist of commodities and guidelines necessary to diagnose, treat and record malaria. RESULTS: From the 1930's through to the mid-1960's malaria incidence declined coincidental with rapid population growth. During this period malaria notification and prevention were a priority for the city council. From 2001-2008 reporting systems for malaria were inadequate to define the extent or distribution of malaria risk within Nairobi. A more detailed facility review suggests, however that malaria remains a common diagnosis (11% of all paediatric diagnoses made) and where laboratories (n = 15) exist slide positivity rates are on average 15%. Information on the quality of diagnosis, slide reading and whether those reported as positive were imported infections was not established. The facilities and health workers included in this study were not universally prepared to treat malaria according to national guidelines or identify foci of risks due to shortages of national first-line drugs, inadequate record keeping and a view among some health workers (17%) that slide negative patients could still have malaria. CONCLUSION: Combined with historical evidence there is a strong suggestion that very low risks of locally acquired malaria exist today within Nairobi's city limits and this requires further investigation. To be prepared for effective prevention and case-management of malaria among a diverse, mobile population in Nairobi requires a major paradigm shift and investment in improved quality of malaria diagnosis and case management, health system strengthening and case reporting. PMID- 21599932 TI - A spatial epidemiological analysis of self-rated mental health in the slums of Dhaka. AB - BACKGROUND: The deprived physical environments present in slums are well-known to have adverse health effects on their residents. However, little is known about the health effects of the social environments in slums. Moreover, neighbourhood quantitative spatial analyses of the mental health status of slum residents are still rare. The aim of this paper is to study self-rated mental health data in several slums of Dhaka, Bangladesh, by accounting for neighbourhood social and physical associations using spatial statistics. We hypothesised that mental health would show a significant spatial pattern in different population groups, and that the spatial patterns would relate to spatially-correlated health determining factors (HDF). METHODS: We applied a spatial epidemiological approach, including non-spatial ANOVA/ANCOVA, as well as global and local univariate and bivariate Moran's I statistics. The WHO-5 Well-being Index was used as a measure of self-rated mental health. RESULTS: We found that poor mental health (WHO-5 scores < 13) among the adult population (age >=15) was prevalent in all slum settlements. We detected spatially autocorrelated WHO-5 scores (i.e., spatial clusters of poor and good mental health among different population groups). Further, we detected spatial associations between mental health and housing quality, sanitation, income generation, environmental health knowledge, education, age, gender, flood non-affectedness, and selected properties of the natural environment. CONCLUSIONS: Spatial patterns of mental health were detected and could be partly explained by spatially correlated HDF. We thereby showed that the socio-physical neighbourhood was significantly associated with health status, i.e., mental health at one location was spatially dependent on the mental health and HDF prevalent at neighbouring locations. Furthermore, the spatial patterns point to severe health disparities both within and between the slums. In addition to examining health outcomes, the methodology used here is also applicable to residuals of regression models, such as helping to avoid violating the assumption of data independence that underlies many statistical approaches. We assume that similar spatial structures can be found in other studies focussing on neighbourhood effects on health, and therefore argue for a more widespread incorporation of spatial statistics in epidemiological studies. PMID- 21599933 TI - A potential role for the clathrin adaptor GGA in Drosophila spermatogenesis. AB - BACKGROUND: GGAs (Golgi-localised, gamma-ear containing, ADP ribosylation factor binding) are a family of clathrin adaptors that sort a number of biologically important transmembrane proteins into clathrin-coated vesicles. Knockout and knockdown studies to determine GGA function are confounded by the fact that there are 3 GGA genes in mammalian cells. Thus Drosophila melanogaster is a useful model system to study tissue expression profiles and knockdown phenotypes as there is a single GGA ortholog. RESULTS: Here we have quantified protein expression in Drosophila and show that there is >3-fold higher expression of GGA in male flies relative to female flies. In female flies the majority of GGA expression is in the head. In male flies GGA is not only expressed at high levels in the head but there is a gender specific increased expression which is due to the abundant expression of GGA in the testes. Using a highly specific antibody we have localised endogenous GGA protein in testes squashes, and visualised it in somatic and germ line cells. We show that GGA is expressed during multiple stages of sperm development, and co-stains with a marker of the trans-Golgi Network. This is most striking at the acroblast of early spermatids. In spite of the high expression of GGA in testes, knocking down its expression by >95% using transgenic RNAi fly lines did not affect male fertility. Therefore spermatogenesis in the male flies appears to progress normally with <5% GGA, most likely because alternative adaptors may be able to substitute partially or completely for the function of GGA. We also identify 'cueball' as a novel cargo for GGA, and mutants of cueball have been shown to have a male sterility phenotype. CONCLUSION: In Drosophila we have uncovered a potential role for GGA in the testes of male flies. The gender specific higher expression of GGA, its specific enrichment in testes and its localisation to developing spermatocytes and at the acroblast of spermatids supports a role for GGA function in Drosophila spermatogenesis, even though spermatogenesis still occurs when GGA expression is depleted to <5% of control. PMID- 21599934 TI - Analysis of expressed sequence tags generated from full-length enriched cDNA libraries of melon. AB - BACKGROUND: Melon (Cucumis melo), an economically important vegetable crop, belongs to the Cucurbitaceae family which includes several other important crops such as watermelon, cucumber, and pumpkin. It has served as a model system for sex determination and vascular biology studies. However, genomic resources currently available for melon are limited. RESULT: We constructed eleven full length enriched and four standard cDNA libraries from fruits, flowers, leaves, roots, cotyledons, and calluses of four different melon genotypes, and generated 71,577 and 22,179 ESTs from full-length enriched and standard cDNA libraries, respectively. These ESTs, together with ~35,000 ESTs available in public domains, were assembled into 24,444 unigenes, which were extensively annotated by comparing their sequences to different protein and functional domain databases, assigning them Gene Ontology (GO) terms, and mapping them onto metabolic pathways. Comparative analysis of melon unigenes and other plant genomes revealed that 75% to 85% of melon unigenes had homologs in other dicot plants, while approximately 70% had homologs in monocot plants. The analysis also identified 6,972 gene families that were conserved across dicot and monocot plants, and 181, 1,192, and 220 gene families specific to fleshy fruit-bearing plants, the Cucurbitaceae family, and melon, respectively. Digital expression analysis identified a total of 175 tissue-specific genes, which provides a valuable gene sequence resource for future genomics and functional studies. Furthermore, we identified 4,068 simple sequence repeats (SSRs) and 3,073 single nucleotide polymorphisms (SNPs) in the melon EST collection. Finally, we obtained a total of 1,382 melon full-length transcripts through the analysis of full-length enriched cDNA clones that were sequenced from both ends. Analysis of these full-length transcripts indicated that sizes of melon 5' and 3' UTRs were similar to those of tomato, but longer than many other dicot plants. Codon usages of melon full length transcripts were largely similar to those of Arabidopsis coding sequences. CONCLUSION: The collection of melon ESTs generated from full-length enriched and standard cDNA libraries is expected to play significant roles in annotating the melon genome. The ESTs and associated analysis results will be useful resources for gene discovery, functional analysis, marker-assisted breeding of melon and closely related species, comparative genomic studies and for gaining insights into gene expression patterns. PMID- 21599935 TI - Can we use digital life-log images to investigate active and sedentary travel behaviour? Results from a pilot study. AB - BACKGROUND: Active travel such as walking and cycling has potential to increase physical activity levels in sedentary individuals. Motorised car travel is a sedentary behaviour that contributes to carbon emissions. There have been recent calls for technology that will improve our ability to measure these travel behaviours, and in particular evaluate modes and volumes of active versus sedentary travel. The purpose of this pilot study is to investigate the potential efficacy of a new electronic measurement device, a wearable digital camera called SenseCam, in travel research. METHODS: Participants (n = 20) were required to wear the SenseCam device for one full day of travel. The device automatically records approximately 3,600 time-stamped, first-person point-of-view images per day, without any action required by the wearer. Participants also completed a self-report travel diary over the same period for comparison, and were interviewed afterwards to assess user burden and experience. RESULTS: There were a total of 105 confirmed journeys in this pilot. The new SenseCam device recorded more journeys than the travel diary (99 vs. 94). Although the two measures demonstrated an acceptable correlation for journey duration (r = 0.92, p < 0.001) self-reported journey duration was over-reported (mean difference 154 s per journey; 95% CI = 89 to 218 s; 95% limits of agreement = 154 +/- 598 s (-444 to 752 s)). The device also provided visual data that was used for directed interviews about sources of error. CONCLUSIONS: Direct observation of travel behaviour from time-stamped images shows considerable potential in the field of travel research. Journey duration derived from direct observation of travel behaviour from time-stamped images appears to suggest over-reporting of self reported journey duration. PMID- 21599936 TI - LeishVet guidelines for the practical management of canine leishmaniosis. AB - The LeishVet group has formed recommendations designed primarily to help the veterinary clinician in the management of canine leishmaniosis. The complexity of this zoonotic infection and the wide range of its clinical manifestations, from inapparent infection to severe disease, make the management of canine leishmaniosis challenging. The recommendations were constructed by combining a comprehensive review of evidence-based studies, extensive clinical experience and critical consensus opinion discussions. The guidelines presented here in a short version with graphical topic displays suggest standardized and rational approaches to the diagnosis, treatment, follow-up, control and prevention of canine leishmaniosis. A staging system that divides the disease into four stages is aimed at assisting the clinician in determining the appropriate therapy, forecasting prognosis, and implementing follow-up steps required for the management of the leishmaniosis patient. PMID- 21599938 TI - Timing the tides: genetic control of diurnal and lunar emergence times is correlated in the marine midge Clunio marinus. AB - BACKGROUND: The intertidal zone of seacoasts, being affected by the superimposed tidal, diurnal and lunar cycles, is temporally the most complex environment on earth. Many marine organisms exhibit lunar rhythms in reproductive behaviour and some show experimental evidence of endogenous control by a circalunar clock, the molecular and genetic basis of which is unexplored. We examined the genetic control of lunar and diurnal rhythmicity in the marine midge Clunio marinus (Chironomidae, Diptera), a species for which the correct timing of adult emergence is critical in natural populations. RESULTS: We crossed two strains of Clunio marinus that differ in the timing of the diurnal and lunar rhythms of emergence. The phenotype distribution of the segregating backcross progeny indicates polygenic control of the lunar emergence rhythm. Diurnal timing of emergence is also under genetic control, and is influenced by two unlinked genes with major effects. Furthermore, the lunar and diurnal timing of emergence is correlated in the backcross generation. We show that both the lunar emergence time and its correlation to the diurnal emergence time are adaptive for the species in its natural environment. CONCLUSIONS: The correlation implies that the unlinked genes affecting lunar timing and the two unlinked genes affecting diurnal timing could be the same, providing an unexpectedly close interaction of the two clocks. Alternatively, the genes could be genetically linked in a two-by two fashion, suggesting that evolution has shaped the genetic architecture to stabilize adaptive combinations of lunar and diurnal emergence times by tightening linkage. Our results, the first on genetic control of lunar rhythms, offer a new perspective to explore their molecular clockwork. PMID- 21599937 TI - Childhood lead exposure in France: benefit estimation and partial cost-benefit analysis of lead hazard control. AB - BACKGROUND: Lead exposure remains a public health concern due to its serious adverse effects, such as cognitive and behavioral impairment: children younger than six years of age being the most vulnerable population. In Europe, the lead related economic impacts have not been examined in detail. We estimate the annual costs in France due to childhood exposure and, through a cost benefit analysis (CBA), aim to assess the expected social and economic benefits of exposure abatement. METHODS: Monetary benefits were assessed in terms of avoided national costs. We used results from a 2008 survey on blood-lead (B-Pb) concentrations in French children aged one to six years old. Given the absence of a threshold concentration being established, we performed a sensitivity analysis assuming different hypothetical threshold values for toxicity above 15 MUg/L, 24 MUg/L and 100 MUg/L. Adverse health outcomes of lead exposure were translated into social burden and economic costs based on literature data from literature. Direct health benefits, social benefits and intangible avoided costs were included. Costs of pollutant exposure control were partially estimated in regard to homes lead-based paint decontamination, investments aiming at reducing industrial lead emissions and removal of all lead drinking water pipes. RESULTS: The following overall annual benefits for the three hypothetical thresholds values in 2008 are: ?22.72 billion, ?10.72 billion and ?0.44 billion, respectively. Costs from abatement ranged from ?0.9 billion to 2.95 billion/year. Finally, from a partial CBA of lead control in soils and dust the estimates of total net benefits were ? 3.78 billion, ? 1.88 billion and ?0.25 billion respectively for the three hypothesized B-Pb effect values. CONCLUSIONS: Prevention of childhood lead exposure has a high social benefit, due to reduction of B-Pb concentrations to levels below 15 MUg/L or 24 MUg/L, respectively. Reducing only exposures above 100 MUg/L B-Pb has little economic impact due to the small number of children who now exhibit such high exposure levels. Prudent public policies would help avoiding future medical interventions, limit the need for special education and increase future productivity, and hence lifetime income for children exposed to lead. PMID- 21599939 TI - Validation of a multifactorial risk factor model used for predicting future caries risk with Nevada adolescents. AB - BACKGROUND: The objective of this study was to measure the validity and reliability of a multifactorial Risk Factor Model developed for use in predicting future caries risk in Nevada adolescents in a public health setting. METHODS: This study examined retrospective data from an oral health surveillance initiative that screened over 51,000 students 13-18 years of age, attending public/private schools in Nevada across six academic years (2002/2003-2007/2008). The Risk Factor Model included ten demographic variables: exposure to fluoridation in the municipal water supply, environmental smoke exposure, race, age, locale (metropolitan vs. rural), tobacco use, Body Mass Index, insurance status, sex, and sealant application. Multiple regression was used in a previous study to establish which significantly contributed to caries risk. Follow-up logistic regression ascertained the weight of contribution and odds ratios of the ten variables. Researchers in this study computed sensitivity, specificity, positive predictive value (PVP), negative predictive value (PVN), and prevalence across all six years of screening to assess the validity of the Risk Factor Model. RESULTS: Subjects' overall mean caries prevalence across all six years was 66%. Average sensitivity across all six years was 79%; average specificity was 81%; average PVP was 89% and average PVN was 67%. CONCLUSIONS: Overall, the Risk Factor Model provided a relatively constant, valid measure of caries that could be used in conjunction with a comprehensive risk assessment in population-based screenings by school nurses/nurse practitioners, health educators, and physicians to guide them in assessing potential future caries risk for use in prevention and referral practices. PMID- 21599940 TI - Slug down-regulation by RNA interference inhibits invasion growth in human esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive carcinomas of the gastrointestinal tract. We assessed the relevance of Slug in measuring the invasive potential of ESCC cells in vitro and in vivo in immunodeficient mice. METHODS: We utilized RNA interference to knockdown Slug gene expression, and effects on survival and invasive carcinoma were evaluated using a Boyden chamber transwell assay in vitro. We evaluated the effect of Slug siRNA-transfection and Slug cDNA-transfection on E-cadherin and Bcl-2 expression in ESCC cells. A pseudometastatic model of ESCC in immunodeficient mice was used to assess the effects of Slug siRNA transfection on tumor metastasis development. RESULTS: The EC109 cell line was transfected with Slug-siRNA to knockdown Slug expression. The TE13 cell line was transfected with Slug-cDNA to increase Slug expression. EC109 and TE13 cell lines were tested for the expression of apoptosis related genes bcl-2 and metastasis-related gene E-cadherin identified previously as Slug targets. Bcl-2 expression was increased and E-cadherin was decreased in Slug siRNA-transfected EC109 cells. Bcl-2 expression was increased and E-cadherin was decreased in Slug cDNA-transfected TE13 cells. Invasion of Slug siRNA transfected EC109 cells was reduced and apoptosis was increased whereas invasion was greater in Slug cDNA-transfected cells. Animals injected with Slug siRNA transfected EC109 cells exhibited fewer seeded nodes and demonstrated more apoptosis. CONCLUSIONS: Slug down-regulation promotes cell apoptosis and decreases invasion capability in vitro and in vivo. Slug inhibition may represent a novel strategy for treatment of metastatic ESCC. PMID- 21599943 TI - Understanding, comprehensibility and acceptance of an evidence-based consumer information brochure on fall prevention in old age: a focus group study. AB - BACKGROUND: Evidence-based patient and consumer information (EBPI) is an indispensable component of the patients' decision making process in health care. Prevention of accidental falls in the elderly has gained a lot of public interest during preceding years. Several consumer information brochures on fall prevention have been published; however, none fulfilled the criteria of an EBPI. Little is known about the reception of EBPI by seniors. Therefore we aimed to evaluate a recently developed EBPI brochure on fall prevention with regard to seniors' acceptance and comprehensibility in focus groups and to explore whether the participants' judgements differed depending on the educational background of the study participants. METHODS: Seven focus groups were conducted with 40 seniors, aged 60 years or older living independently in a community. Participants were recruited by two gatekeepers. A discussion guide was used and seniors were asked to judge the EBPI brochure on fall prevention using a Likert scale 1-6. The focus group discussions were tape recorded, transcribed verbatim, and analysed using content analysis. RESULTS: The participants generally accepted the EBPI brochure on fall prevention. Several participants expressed a need for more practical advice. The comprehensibility of the brochure was influenced positively by brief chapter summaries. Participants dismissed the statistical illustrations such as confidence intervals or a Fagan nomogram and only half of them agreed with the meta-information presented in the first chapter. The detailed information about fall prevalence was criticised by some seniors. The use of a case story was well tolerated by the majority of participants. CONCLUSION: Our findings indicate that the recently developed EBPI brochure on fall prevention in old age was generally well accepted by seniors, but some statistical descriptions were difficult for them to understand. The brochure has to be updated. However, not all issues raised by the participants will be taken into account since some of them are contrary to the principles of EBPI. PMID- 21599942 TI - Glucose-6-phosphatase deficiency. AB - Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed by G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis, and the indications of liver biopsy to measure G6P activity are getting rarer and rarer. Differential diagnoses include the other GSDs, in particular type III (see this term). However, in GSDIII, glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I). Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but are easily ruled out through clinical and ultrasound data. Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may also be discussed. Genetic counseling should be offered to patients and their families. The dietary treatment aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch) and acidosis (restricted fructose and galactose intake). Liver transplantation, performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib. Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. Prognosis is usually good: late hepatic and renal complications may occur, however, with adapted management, patients have almost normal life span. DISEASE NAME AND SYNONYMS: Glucose-6-phosphatase deficiency or G6P deficiency or glycogen storage disease type I or GSDI or type I glycogenosis or Von Gierke disease or Hepatorenal glycogenosis. PMID- 21599941 TI - Specific treatment of problems of the spine (STOPS): design of a randomised controlled trial comparing specific physiotherapy versus advice for people with subacute low back disorders. AB - BACKGROUND: Low back disorders are a common and costly cause of pain and activity limitation in adults. Few treatment options have demonstrated clinically meaningful benefits apart from advice which is recommended in all international guidelines. Clinical heterogeneity of participants in clinical trials is hypothesised as reducing the likelihood of demonstrating treatment effects, and sampling of more homogenous subgroups is recommended. We propose five subgroups that allow the delivery of specific physiotherapy treatment targeting the pathoanatomical, neurophysiological and psychosocial components of low back disorders. The aim of this article is to describe the methodology of a randomised controlled trial comparing specific physiotherapy treatment to advice for people classified into five subacute low back disorder subgroups. METHODS/DESIGN: A multi-centre parallel group randomised controlled trial is proposed. A minimum of 250 participants with subacute (6 weeks to 6 months) low back pain and/or referred leg pain will be classified into one of five subgroups and then randomly allocated to receive either physiotherapy advice (2 sessions over 10 weeks) or specific physiotherapy treatment (10 sessions over 10 weeks) tailored according to the subgroup of the participant. Outcomes will be assessed at 5 weeks, 10 weeks, 6 months and 12 months following randomisation. Primary outcomes will be activity limitation measured with a modified Oswestry Disability Index as well as leg and back pain intensity measured on separate 0-10 Numerical Rating Scales. Secondary outcomes will include a 7-point global rating of change scale, satisfaction with physiotherapy treatment, satisfaction with treatment results, the Sciatica Frequency and Bothersomeness Scale, quality of life (EuroQol-5D), interference with work, and psychosocial risk factors (Orebro Musculoskeletal Pain Questionnaire). Adverse events and co-interventions will also be measured. Data will be analysed according to intention to treat principles, using linear mixed models for continuous outcomes, Mann Whitney U tests for ordinal outcomes, and Chi-square, risk ratios and risk differences for dichotomous outcomes. DISCUSSION: This trial will determine the difference in outcomes between specific physiotherapy treatment tailored to each of the five subgroups versus advice which is recommended in guidelines as a suitable treatment for most people with a low back disorder. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12609000834257. PMID- 21599944 TI - Performance of a dipstick dye immunoassay for rapid screening of Schistosoma japonicum infection in areas of low endemicity. AB - BACKGROUND: The dipstick dye immunoassay (DDIA), recently commercially available in the People's Republic of China (P.R. China), is a rapid and simple test to detect human antibodies against Schistosoma Japonicum. Its performance and utility for screening schistosome infection in low endemic areas is little known. We therefore carried out a cross-sectional survey in seven villages with low endemicity of schistosomiasis in P.R. China and assessed the performance and utility of DDIA for diagnosis of schistosomiasis. Stool samples were collected and examined by the Kato-Katz method and the miracidium hatching technique. Serum samples, separated from whole blood of participants, were tested by DDIA. RESULTS: 6285 individuals aged 6-65 years old participated in this study, with a prevalence of schistosomiasis of 4.20%. Using stool examination as a gold reference standard, DDIA performed with a high overall sensitivity of 91.29% (95% CI: 87.89-94.69%) and also a high negative predictive value, with a mean value of 99.29% (95% CI: 98.99-99.58%). The specificity of DDIA was only moderate (53.08%, 95% CI: 51.82-54.34%). Multivariate analysis indicated that age, occupation and history of schistosome infection were significantly associated with the false positive results of DDIA. CONCLUSIONS: DDIA is a sensitive, rapid, simple and portable diagnostic assay and can be used as a primary approach for screening schistosome infection in areas of low endemicity. However, more sensitive and specific confirmatory assays need to be developed and combined with DDIA for targeting chemotherapy accurately. PMID- 21599945 TI - Study protocol: ICONS: identifying continence options after stroke: a randomised trial. AB - BACKGROUND: Urinary incontinence following acute stroke is common, affecting between 40%-60% of people in hospital after a stroke. Despite the availability of clinical guidelines for urinary incontinence and urinary incontinence after stroke, national audit data suggest incontinence is often poorly managed. Conservative interventions (e.g. bladder training, pelvic floor muscle training and prompted voiding) have been shown to have some effect with participants in Cochrane systematic reviews, but have not had their effectiveness demonstrated with stroke patients. METHODS/DESIGN: A cluster randomised controlled pilot trial designed to assess the feasibility of a full-scale cluster randomised trial and to provide preliminary evidence of the effectiveness and cost-effectiveness of a systematic voiding programme for the management of continence after stroke. Stroke services will be randomised to receive the systematic voiding programme, the systematic voiding programme plus supported implementation, or usual care. The trial aims to recruit at least 780 participants in 12 stroke services (4 per arm). The primary outcome is presence/absence of incontinence at six weeks post stroke. Secondary outcomes include frequency and severity of incontinence, quality of life and cost-utility. Outcomes will be measured at six weeks, three months and (for participants recruited in the first three months) twelve months after stroke. Process data will include rates of recruitment and retention and fidelity of intervention delivery. An integrated qualitative evaluation will be conducted in order to describe implementation and assist in explaining the potential mediators and modifiers of the process. TRIAL REGISTRATION: ISRCTN: ISRCTN08609907 PMID- 21599946 TI - The impact of FADS genetic variants on omega6 polyunsaturated fatty acid metabolism in African Americans. AB - BACKGROUND: Arachidonic acid (AA) is a long-chain omega-6 polyunsaturated fatty acid (PUFA) synthesized from the precursor dihomo-gamma-linolenic acid (DGLA) that plays a vital role in immunity and inflammation. Variants in the Fatty Acid Desaturase (FADS) family of genes on chromosome 11q have been shown to play a role in PUFA metabolism in populations of European and Asian ancestry; no work has been done in populations of African ancestry to date. RESULTS: In this study, we report that African Americans have significantly higher circulating levels of plasma AA (p = 1.35 * 10(-48)) and lower DGLA levels (p = 9.80 * 10(-11)) than European Americans. Tests for association in N = 329 individuals across 80 nucleotide polymorphisms (SNPs) in the Fatty Acid Desaturase (FADS) locus revealed significant association with AA, DGLA and the AA/DGLA ratio, a measure of enzymatic efficiency, in both racial groups (peak signal p = 2.85 * 10(-16) in African Americans, 2.68 * 10(-23) in European Americans). Ancestry-related differences were observed at an upstream marker previously associated with AA levels (rs174537), wherein, 79-82% of African Americans carry two copies of the G allele compared to only 42-45% of European Americans. Importantly, the allelic effect of the G allele, which is associated with enhanced conversion of DGLA to AA, on enzymatic efficiency was similar in both groups. CONCLUSIONS: We conclude that the impact of FADS genetic variants on PUFA metabolism, specifically AA levels, is likely more pronounced in African Americans due to the larger proportion of individuals carrying the genotype associated with increased FADS1 enzymatic conversion of DGLA to AA. PMID- 21599947 TI - A cross-sectional study of different patterns of oral contraceptive use among premenopausal women and circulating IGF-1: implications for disease risk. AB - BACKGROUND: Insulin-like growth factor-1 (IGF-1) is important in normal growth, development, and homeostasis. Current use of oral contraceptives (OC) decreases IGF-1 concentrations; however, the effect of past use, age/timing of use, and type of OC used on IGF-1 levels is unknown. OC are the most commonly used form of birth control worldwide. Both IGF-1 and OC use have been linked to premenopausal breast and colorectal cancers, osteoporosis and cardiovascular disease (CVD). Understanding the effects of different patterns of OC use on IGF-1 levels may offer insight into its influence on disease risk in young women. METHODS: In a cross-sectional study of 328 premenopausal women ages 18 to 21 and 31 to 40 we examined the relationship between different patterns of OC use and circulating IGF-1 using adjusted linear regression analysis. Information on OC use was obtained through an interviewer administered questionnaire. Plasma IGF-1 was assessed with enzyme linked immunosorbent assay (ELISA). RESULTS: Among women aged 18 to 21, ever OC use was significantly associated with decreased IGF-1 levels compared to never use (beta = -57.2 ng/ml, 95% confidence interval (CI): 88.7, -25.8). Among women aged 31 to 40, past users who first used OC at 25 years of age or older (beta = 43.8 ng/ml, 95% CI: 8.8, 78.8), in the last 15 years (beta = 35.1 ng/ml, 95% CI: 9.3, 61.0) or after 1995 (beta = 46.6 ng/ml, 95% CI: 13.4, 79.8) had significantly higher IGF-1 levels compared to never users. CONCLUSION: This is the first study to highlight the long term effects of OC use after cessation on IGF-1 levels among premenopausal women, which previously were thought to be transitory. Future studies of past use and IGF-1 levels are required and must consider age/timing of use and type/generation of OC used. Additional studies are needed to confirm the potential mediation of IGF-1 levels in the links between OC use and health outcomes. PMID- 21599948 TI - Understanding Streptococcus suis serotype 2 infection in pigs through a transcriptional approach. AB - BACKGROUND: Streptococcus suis serotype 2 (S. suis 2) is an important pathogen of pigs. S suis 2 infections have high mortality rates and are characterized by meningitis, septicemia and pneumonia. S. suis 2 is also an emerging zoonotic agent and can infect humans that are exposed to pigs or their by-products. To increase our knowledge of the pathogenesis of meningitis, septicemia and pneumonia in pigs caused by S. suis 2, we profiled the response of peripheral blood mononuclear cells (PBMC), brain and lung tissues to infection with S. suis 2 strain SC19 using the Affymetrix Porcine Genome Array. RESULTS: A total of 3,002 differentially expressed transcripts were identified in the three tissues, including 417 unique genes in brain, 210 in lung and 213 in PBMC. These genes showed differential expression (DE) patterns on analysis by visualization and integrated discovery (DAVID). The DE genes involved in the immune response included genes related to the inflammatory response (CD163), the innate immune response (TLR2, TLR4, MYD88, TIRAP), cell adhesion (CD34, SELE, SELL, SELP, ICAM 1, ICAM-2, VCAM-1), antigen processing and presentation (MHC protein complex) and angiogenesis (VEGF), together with genes encoding cytokines (interleukins). Five selected genes were validated by qRT-PCR analysis. CONCLUSIONS: We studied the response to infection with S. suis 2 strain SC19 by microarray analysis. Our findings confirmed some genes identified in previous studies and discovered numerous additional genes that potentially function in S. suis 2 infections in vivo. This new information will form the foundation of future investigations into the pathogenesis of S. suis. PMID- 21599949 TI - Literature survey on epidemiology and pathology of gangliocytic paraganglioma. AB - BACKGROUND: Although gangliocytic paraganglioma (GP) has generally been regarded as a neuroendocrine tumor, its origin remains unclear. We therefore aimed to investigate the details of this disease by carefully analyzing and extracting common features of the disease as presented in selected publications. METHODS: We searched for English and Japanese cases of GP using the PubMed and IgakuChuoZasshi databases on August 2010. We then extracted and sampled raw data from the selected publications and performed appropriate statistical analyses. Additionally, we evaluated the expression of hormone receptors based on our previously reported case. RESULTS: 192 patients with GP were retrieved from the databases. Patient ages ranged from 15 y to 84 y (mean: 52.3 y). The gender ratio was 114:76 (male to female, 2 not reported). Maximum diameter of the tumors ranged from 5.5 mm to 100 mm (mean: 25.0 mm). The duodenum (90.1%, 173/192) was found to be the most common site of the disease. In 173 patients with duodenal GP, gastrointestinal bleeding (45.1%, 78/173) was found to be the most common symptom of the disease, followed by abdominal pain (42.8%, 74/173), and anemia (14.5%, 25/173). Rate of lymph node metastasis was 6.9% (12/173). Our statistical analysis indicated that significant differences were found for gender between GP within the submucosal layer and exceeding the submucosal layer. Furthermore, our immunohistochemical evaluation showed that both epithelioid and pancreatic islet cells showed positive reactivity for progesterone receptors. CONCLUSIONS: Our literature survey revealed that there were many more cases of GP exceeding the submucosal layer than were expected. Meanwhile, our statistical analyses and immunohistochemical evaluation supported the following two hypotheses. First, vertical growth of GP might be affected by progesterone exposure. Second, the origin of GP might be pancreatic islet cells. However, it is strongly suspected that our data have been affected by publication bias and to confirm these hypotheses, further investigation is required. PMID- 21599950 TI - The aspartic proteinase family of three Phytophthora species. AB - BACKGROUND: Phytophthora species are oomycete plant pathogens with such major social and economic impact that genome sequences have been determined for Phytophthora infestans, P. sojae and P. ramorum. Pepsin-like aspartic proteinases (APs) are produced in a wide variety of species (from bacteria to humans) and contain conserved motifs and landmark residues. APs fulfil critical roles in infectious organisms and their host cells. Annotation of Phytophthora APs would provide invaluable information for studies into their roles in the physiology of Phytophthora species and interactions with their hosts. RESULTS: Genomes of Phytophthora infestans, P. sojae and P. ramorum contain 11-12 genes encoding APs. Nine of the original gene models in the P. infestans database and several in P. sojae and P. ramorum (three and four, respectively) were erroneous. Gene models were corrected on the basis of EST data, consistent positioning of introns between orthologues and conservation of hallmark motifs. Phylogenetic analysis resolved the Phytophthora APs into 5 clades. Of the 12 sub-families, several contained an unconventional architecture, as they either lacked a signal peptide or a propart region. Remarkably, almost all APs are predicted to be membrane bound. CONCLUSIONS: One of the twelve Phytophthora APs is an unprecedented fusion protein with a putative G-protein coupled receptor as the C-terminal partner. The others appear to be related to well-documented enzymes from other species, including a vacuolar enzyme that is encoded in every fungal genome sequenced to date. Unexpectedly, however, the oomycetes were found to have both active and probably-inactive forms of an AP similar to vertebrate BACE, the enzyme responsible for initiating the processing cascade that generates the Abeta peptide central to Alzheimer's Disease. The oomycetes also encode enzymes similar to plasmepsin V, a membrane-bound AP that cleaves effector proteins of the malaria parasite Plasmodium falciparum during their translocation into the host red blood cell. Since the translocation of Phytophthora effector proteins is currently a topic of intense research activity, the identification in Phytophthora of potential functional homologues of plasmepsin V would appear worthy of investigation. Indeed, elucidation of the physiological roles of the APs identified here offers areas for future study. The significant revision of gene models and detailed annotation presented here should significantly facilitate experimental design. PMID- 21599951 TI - Response: Infant EEG activity as a biomarker for autism: a promising approach or a false promise? PMID- 21599952 TI - Infant EEG activity as a biomarker for autism: a promising approach or a false promise? AB - The ability to determine an infant's likelihood of developing autism via a relatively simple neurological measure would constitute an important scientific breakthrough. In their recent publication in this journal, Bosl and colleagues claim that a measure of EEG complexity can be used to detect, with very high accuracy, infants at high risk for autism (HRA). On the surface, this appears to be that very scientific breakthrough and as such the paper has received widespread media attention. But a close look at how these high accuracy rates were derived tells a very different story. This stems from a conflation between "high risk" as a population-level property and "high risk" as a property of an individual. We describe the approach of Bosl et al. and examine their results with respect to baseline prevalence rates, the inclusion of which is necessary to distinguish infants with a biological risk of autism from typically developing infants with a sibling with autism. This is an important distinction that should not be overlooked. Please see research article: http://www.biomedcentral.com/1741 7015/9/18 and correspondence article: http://www.biomedcentral.com/1741 7015/9/60. PMID- 21599953 TI - An evolutionary conserved region (ECR) in the human dopamine receptor D4 gene supports reporter gene expression in primary cultures derived from the rat cortex. AB - BACKGROUND: Detecting functional variants contributing to diversity of behaviour is crucial for dissecting genetics of complex behaviours. At a molecular level, characterisation of variation in exons has been studied as they are easily identified in the current genome annotation although the functional consequences are less well understood; however, it has been difficult to prioritise regions of non-coding DNA in which genetic variation could also have significant functional consequences. Comparison of multiple vertebrate genomes has allowed the identification of non-coding evolutionary conserved regions (ECRs), in which the degree of conservation can be comparable with exonic regions suggesting functional significance. RESULTS: We identified ECRs at the dopamine receptor D4 gene locus, an important gene for human behaviours. The most conserved non-coding ECR (D4ECR1) supported high reporter gene expression in primary cultures derived from neonate rat frontal cortex. Computer aided analysis of the sequence of the D4ECR1 indicated the potential transcription factors that could modulate its function. D4ECR1 contained multiple consensus sequences for binding the transcription factor Sp1, a factor previously implicated in DRD4 expression. Co transfection experiments demonstrated that overexpression of Sp1 significantly decreased the activity of the D4ECR1 in vitro. CONCLUSION: Bioinformatic analysis complemented by functional analysis of the DRD4 gene locus has identified a) a strong enhancer that functions in neurons and b) a transcription factor that may modulate the function of that enhancer. PMID- 21599954 TI - Bilateral dilation of the urinary tract due to iliopsoas pyomyositis: a case report. AB - INTRODUCTION: Pyomyositis is an acute bacterial infection of the skeletal muscles that arises from hematogenous spread and is caused predominantly by Gram-positive cocci. CASE PRESENTATION: We report a case of iliopsoas pyomyositis in a 25-year old Greek Caucasian woman with a history of intravenous drug use. Her condition was complicated by bilateral dilation of the ureters and renal calyces as a result of mechanical pressure from inflammation and edema of the involved muscle. The patient did not present aggravation of renal function and was treated successfully solely with intravenous antibiotics, without surgical intervention. This is the first case report describing iliopsoas pyomyositis with reversible bilateral dilation of the urinary tract that was treated successfully with intravenous antibiotics, without surgical intervention. CONCLUSION: We present the first described case of iliopsoas pyomyositis with reversible bilateral hydroureteronephrosis that was treated successfully with intravenous antibiotics, without the necessity of surgical intervention. To our knowledge, this is the first report of its kind in the literature regarding an unexpected event in the course of treating a patient with iliopsoas pyomyositis, and it should be of particular interest to different clinical medical specialties such as internal medicine, infectious disease and urology. PMID- 21599955 TI - Association between proximity to and coverage of traditional fast-food restaurants and non-traditional fast-food outlets and fast-food consumption among rural adults. AB - OBJECTIVE: The objective of this study is to examine the relationship between residential exposure to fast-food entrees, using two measures of potential spatial access: proximity (distance to the nearest location) and coverage (number of different locations), and weekly consumption of fast-food meals. METHODS: Traditional fast-food restaurants and non-traditional fast-food outlets, such as convenience stores, supermarkets, and grocery stores, from the 2006 Brazos Valley Food Environment Project were linked with individual participants (n = 1409) who completed the nutrition module in the 2006 Brazos Valley Community Health Assessment. RESULTS: Increased age, poverty, increased distance to the nearest fast food, and increased number of different traditional fast-food restaurants, non-traditional fast-food outlets, or fast-food opportunities were associated with less frequent weekly consumption of fast-food meals. The interaction of gender and proximity (distance) or coverage (number) indicated that the association of proximity to or coverage of fast-food locations on fast-food consumption was greater among women and opposite of independent effects. CONCLUSIONS: Results provide impetus for identifying and understanding the complex relationship between access to all fast-food opportunities, rather than to traditional fast-food restaurants alone, and fast-food consumption. The results indicate the importance of further examining the complex interaction of gender and distance in rural areas and particularly in fast-food consumption. Furthermore, this study emphasizes the need for health promotion and policy efforts to consider all sources of fast-food as part of promoting healthful food choices. PMID- 21599956 TI - Coexistence of pulmonary sclerosing hemangioma and primary adenocarcinoma in the same nodule of lung. AB - Pulmonary sclerosing hemangiomas (PSH) of the lung are uncommon tumors and may present cytological atypia with unusual manifestations. The development of PSH combined with other different tumors in lung is extremely rare. We report a case of coexistence of PSH and primary adenocarcinoma in a young female occurring in the same pulmonary nodular mass of right lower lobe. The solitary mass of lung was well-circumscribed on chest computed tomography (CT) and gross examination. Histologically, the mass contained two separated portions and displayed typically histological features of PSH and acinar adenocarcinoma, respectively. In PSH portion, the tumor was composed of sheets of round cells with scattered surface cuboidal cells forming small tubules. Both round and surface cells were diffusely positive for epithelial membrane antigen (EMA) and thyroid transcription factor-1 (TTF-1), but lack immunoreactivity for pancytokeratin in round cells. In adenocarcinoma portion, the tumor cells formed irregular-shaped glands with cytologically malignant cells infiltrating in fibroblastic stroma, and no TTF-1 positive round cells could be observed in this portion. Under the microscopy, there was no gradual transition of these two portions observed in mass. A diagnosis of PSH combined with primary adenocarcinoma of lung was made. There was no evidence of tumor recurrence during the period of postoperative 6-month follow up. To our knowledge, this is the first case of coexistence of PSH and adenocarcinoma in the same nodule of lung. In addition, the biological behavior and histological differential diagnosis of this tumor were also discussed. PMID- 21599957 TI - Association of the rs3743205 variant of DYX1C1 with dyslexia in Chinese children. AB - BACKGROUND: Dyslexia is a learning disability that is characterized by difficulties in the acquisition of reading and spelling skills independent of intelligence, motivation or schooling. Studies of western populations have suggested that DYX1C1 is a candidate gene for dyslexia. In view of the different languages used in Caucasian and Chinese populations, it is therefore worthwhile to investigate whether there is an association of DYX1C1 in Chinese children with dyslexia. METHOD AND RESULTS: Eight single nucleotide polymorphisms (SNPs) were genotyped from three hundred and ninety three individuals from 131 Chinese families with two which have been reported in the literature and six tag SNPs at DYX1C1. Analysis for allelic and haplotypic associations was performed with the UNPHASED program and multiple testing was corrected using false discovery rates. We replicated the previously reported association of rs3743205 in Chinese children with dyslexia (p(corrected) = 0.0072). This SNP was also associated with rapid naming, phonological memory and orthographic skills in quantitative trait analysis. CONCLUSION: Our findings suggest that DYX1C1 is associated with dyslexia in people of Chinese ethnicity in Hong Kong. PMID- 21599959 TI - Protein profiling reveals inter-individual protein homogeneity of arachnoid cyst fluid and high qualitative similarity to cerebrospinal fluid. AB - BACKGROUND: The mechanisms behind formation and filling of intracranial arachnoid cysts (AC) are poorly understood. The aim of this study was to evaluate AC fluid by proteomics to gain further knowledge about ACs. Two goals were set: 1) Comparison of AC fluid from individual patients to determine whether or not temporal AC is a homogenous condition; and 2) Evaluate the protein content of a pool of AC fluid from several patients and qualitatively compare this with published protein lists of cerebrospinal fluid (CSF) and plasma. METHODS: AC fluid from 15 patients with temporal AC was included in this study. In the AC protein comparison experiment, AC fluid from 14 patients was digested, analyzed by LC-MS/MS using a semi-quantitative label-free approach and the data were compared by principal component analysis (PCA) to gain knowledge of protein homogeneity of AC. In the AC proteome evaluation experiment, AC fluid from 11 patients was pooled, digested, and fractionated by SCX chromatography prior to analysis by LC-MS/MS. Proteins identified were compared to published databases of proteins identified from CSF and plasma. AC fluid proteins not found in these two databases were experimentally searched for in lumbar CSF taken from neurologically-normal patients, by a targeted protein identification approach called MIDAS (Multiple Reaction Monitoring (MRM) initiated detection and sequence analysis). RESULTS: We did not identify systematic trends or grouping of data in the AC protein comparison experiment, implying low variability between individual proteomic profiles of AC.In the AC proteome evaluation experiment, we identified 199 proteins. When compared to previously published lists of proteins identified from CSF and plasma, 15 of the AC proteins had not been reported in either of these datasets. By a targeted protein identification approach, we identified 11 of these 15 proteins in pooled CSF from neurologically-normal patients, demonstrating that the majority of abundant proteins in AC fluid also can be found in CSF. Compared to plasma, as many as 104 proteins in AC were not found in the list of 3017 plasma proteins. CONCLUSIONS: Based on the protein content of AC fluid, our data indicate that temporal AC is a homogenous condition, pointing towards a similar AC filling mechanism for the 14 patients examined. Most of the proteins identified in AC fluid have been identified in CSF, indicating high similarity in the qualitative protein content of AC to CSF, whereas this was not the case between AC and plasma. This indicates that AC is filled with a liquid similar to CSF. As far as we know, this is the first proteomics study that explores the AC fluid proteome. PMID- 21599958 TI - Anti-malarial effect of gum arabic. AB - BACKGROUND: Gum Arabic (GA), a nonabsorbable nutrient from the exudate of Acacia senegal, exerts a powerful immunomodulatory effect on dendritic cells, antigen presenting cells involved in the initiation of both innate and adaptive immunity. On the other hand GA degradation delivers short chain fatty acids, which in turn have been shown to foster the expression of foetal haemoglobin in erythrocytes. Increased levels of erythrocyte foetal haemoglobin are known to impede the intraerythrocytic growth of Plasmodium and thus confer some protection against malaria. The present study tested whether gum arabic may influence the clinical course of malaria. METHODS: Human erythrocytes were in vitro infected with Plasmodium falciparum in the absence and presence of butyrate and mice were in vivo infected with Plasmodium berghei ANKA by injecting parasitized murine erythrocytes (1 * 106) intraperitoneally. Half of the mice received gum arabic (10% in drinking water starting 10 days before the day of infection). RESULTS: According to the in vitro experiments butyrate significantly blunted parasitaemia only at concentrations much higher (3 mM) than those encountered in vivo following GA ingestion (<1 MUM). According to the in vivo experiments the administration of gum arabic slightly but significantly decreased the parasitaemia and significantly extended the life span of infected mice. DISCUSSION: GA moderately influences the parasitaemia and survival of Plasmodium infected mice. The underlying mechanism remained, however, elusive. CONCLUSIONS: Gum arabic favourably influences the course of murine malaria. PMID- 21599960 TI - Monosodium iodoacetate-induced joint pain is associated with increased phosphorylation of mitogen activated protein kinases in the rat spinal cord. AB - BACKGROUND: Intra-articular injection of monosodium iodoacetate (MIA) in the knee joint of rats disrupts chondrocyte metabolism resulting in cartilage degeneration and subsequent nociceptive behavior that has been described as a model of osteoarthritis (OA) pain. Central sensitization through activation of mitogen activated protein kinases (MAPKs) is recognized as a pathogenic mechanism in chronic pain. In the present studies, induction of central sensitization as indicated by spinal dorsal horn MAPK activation, specifically ERK and p38 phosphorylation, was assessed in the MIA-OA model. RESULTS: Behaviorally, MIA injected rats displayed reduced hind limb grip force 1, 2, and 3 weeks post-MIA treatment. In the same animals, activation of phospho ERK1/2 was gradually increased, reaching a significant level at post injection week 3. Conversely, phosphorylation of p38 MAPK was enhanced maximally at post injection week 1 and decreased, but remained elevated, thereafter. Double labeling from 3-wk MIA rats demonstrated spinal pERK1/2 expression in neurons, but not glia. In contrast, p p38 was expressed by microglia and a subpopulation of neurons, but not astrocytes. Additionally, there was increased ipsilateral expression of microglia, but not astrocytes, in 3-wk MIA-OA rats. Consistent with increased MAPK immunoreactivity in the contralateral dorsal horn, mechanical allodynia to the contralateral hind-limb was observed 3-wk following MIA. Finally, intrathecal injection of the MEK1 inhibitor PD98059 blocked both reduced hind-limb grip force and pERK1/2 induction in MIA-OA rats. CONCLUSION: Results of these studies support the role of MAPK activation in the progression and maintenance of central sensitization in the MIA-OA experimental pain model. PMID- 21599961 TI - Use, tolerability and compliance of spironolactone in the treatment of heart failure. AB - BACKGROUND: Risk of morbidity and mortality in patients with severe heart failure (HF) is reduced by blockade of aldosterone receptors with spironolactone. However, benefits of spironolactone are potentially limited by treatment compliance and adverse events profile. The aim of this study was to estimate use of spironolactone by patients with HF, incidence of key adverse events, and patient compliance. METHODS: This study was performed using data from the Quebec provincial medical and drug plans (Regie de l'Assurance Maladie du Quebec, RAMQ) for patients who had a diagnosis of HF. Relative incidence of gynecomastia and hyperkalemia was estimated for users and non-users of spironolactone. Treatment adherence was estimated for users of spironolactone and compared to adherence with angiotensin converting enzyme (ACE) inhibitors, beta-blockers (beta blockers), and angiotensin receptor blockers (ARBs). RESULTS: RAMQ data were obtained for a total of 82,018 patients with a diagnosis of HF. Of these patients, 59.9% used an ACE inhibitor, 59.5% used a beta-blocker, 28.4% used an ARB, and 15.1% (n = 12,344) used spironolactone. Despite underestimation due to limitation of the database, the documented incidence of hyperkalemia (3.3% versus 1.4%) and gynecomastia (1.8% versus 0.7%) was significantly higher in spironolactone users than non-users (p < 0.001). Treatment compliance was significantly lower with spironolactone compared to ACE inhibitors, beta blockers, and ARBs (45.6% versus 56.1%, 59.7%, and 57.0%, respectively; p < 0.001). Persistence to treatment over a one-year period was also lower with spironolactone compared to ACE inhibitors, beta-blockers, and ARBs (50.7% versus 64.5%, 70.4%, and 66.3%, respectively; p < 0.001). CONCLUSION: Use of spironolactone is associated with an incidence of adverse events, which may have an impact on treatment compliance. PMID- 21599962 TI - How is Telemedicine perceived? A qualitative study of perspectives from the UK and India. AB - BACKGROUND: Improvements in communication and information technologies have allowed for the globalisation of health services, especially the provision of health services from other countries, such as the use of telemedicine. This has led countries to evaluate their position on whether and to what extent they should open their health systems to trade. This often takes place from the context of multi-lateral trade agreements (under the auspices of the World Trade Organisation), which is misplaced as a significant amount of trade takes place regionally or bi-laterally. We report here the results of a qualitative study assessing stakeholders' views on the potential for a bi-lateral trade relationship between India and the UK, where India acts as an exporter and the UK as an importer of telemedicine services. METHODS: 19 semi-structured interviews were carried out with stakeholders from India and the UK. The themes discussed include prospects on the viability of a bi-lateral relationship between the UK and India on telemedicine, current activities and operations, barriers, benefits and risks. RESULTS: The participants in general believed there were good prospects for telemedicine trade, and that this could bring benefits to "importing" countries in terms of cost-savings and faster delivery of care and to "exporting" countries in the form of foreign exchange and quality improvement. However, there were some concerns regarding quality of care, regulation, accreditation and data security. CONCLUSIONS: There is potential for trade in this type of health services to succeed and bring about important benefits to the countries involved. However, issues around data security and accreditation need to be taken into consideration. Countries may wish to consider entering bi lateral agreements, as they provide more potential to address the concerns and capitalise on the benefits. Finally, this paper concludes that more data should be collected, both on the volume of telemedicine trade and on the impact it is having on health systems, as currently there is very limited data on this. PMID- 21599963 TI - Design of a factorial experiment with randomization restrictions to assess medical device performance on vascular tissue. AB - BACKGROUND: Energy-based surgical scalpels are designed to efficiently transect and seal blood vessels using thermal energy to promote protein denaturation and coagulation. Assessment and design improvement of ultrasonic scalpel performance relies on both in vivo and ex vivo testing. The objective of this work was to design and implement a robust, experimental test matrix with randomization restrictions and predictive statistical power, which allowed for identification of those experimental variables that may affect the quality of the seal obtained ex vivo. METHODS: The design of the experiment included three factors: temperature (two levels); the type of solution used to perfuse the artery during transection (three types); and artery type (two types) resulting in a total of twelve possible treatment combinations. Burst pressures of porcine carotid and renal arteries sealed ex vivo were assigned as the response variable. RESULTS: The experimental test matrix was designed and carried out as a split-plot experiment in order to assess the contributions of several variables and their interactions while accounting for randomization restrictions present in the experimental setup. The statistical software package SAS was utilized and PROC MIXED was used to account for the randomization restrictions in the split-plot design. The combination of temperature, solution, and vessel type had a statistically significant impact on seal quality. CONCLUSIONS: The design and implementation of a split-plot experimental test-matrix provided a mechanism for addressing the existing technical randomization restrictions of ex vivo ultrasonic scalpel performance testing, while preserving the ability to examine the potential effects of independent factors or variables. This method for generating the experimental design and the statistical analyses of the resulting data are adaptable to a wide variety of experimental problems involving large scale tissue-based studies of medical or experimental device efficacy and performance. PMID- 21599964 TI - Hong Kong Chinese school children with elevated urine melamine levels: a prospective follow up study. AB - BACKGROUND: In 2008, the outbreak of kidney stones in children fed by melamine tainted milk products in Mainland China has caused major public concern of food safety. We identified Hong Kong school children with elevated urine melamine level from a community-based school survey in 2007-08 and reviewed their clinical status in 2009. METHODS: In 2007-08, 2119 school children participated in a primary and secondary school survey in Hong Kong using a cluster sampling method. Urine aliquots from 502 subjects were assayed for melamine level. High urine melamine level was defined as urine melamine/creatinine ratio >7.1 MUg/mmol. Subjects with high urine melamine level were invited for clinical evaluation in 2009 including urinalysis and ultrasound imaging of the urinary system. RESULTS: The age range of this subcohort was 6 - 20 years with 67% girls (335 female and 167 male subjects). The spot urine melamine/creatinine ratio of the 502 urine aliquots ranged from undetectable to 1467 MUg/mmol (median 0.8 MUg/mmol). Of these, 213 subjects had undetectable level (42%). We invited 47 (9%) subjects with high urine melamine level for re-evaluation and one subject declined. The median duration of follow-up was 23.5 months (interquartile range: 19.8 - 30.6 months). None of the 46 subjects (28% boys, mean age 13.9 +/- 2.9 years) had any abnormality detected on ultrasound study of the urinary system. All subjects had stable renal function with a median urine albumin-creatinine ratio of 0.70 mg/mmol (interquartile range: 0.00 - 2.55 mg/mmol). CONCLUSIONS: Hong Kong Chinese school children with high urine melamine levels appeared to have benign clinical course in the short term although a long term follow-up study is advisable in those with persistently high urine melamine level. PMID- 21599965 TI - Genotype-specific responses in Atlantic salmon (Salmo salar) subject to dietary fish oil replacement by vegetable oil: a liver transcriptomic analysis. AB - BACKGROUND: Expansion of aquaculture is seriously limited by reductions in fish oil (FO) supply for aquafeeds. Terrestrial alternatives such as vegetable oils (VO) have been investigated and recently a strategy combining genetic selection with changes in diet formulations has been proposed to meet growing demands for aquaculture products. This study investigates the influence of genotype on transcriptomic responses to sustainable feeds in Atlantic salmon. RESULTS: A microarray analysis was performed to investigate the liver transcriptome of two family groups selected according to their estimated breeding values (EBVs) for flesh lipid content, 'Lean' or 'Fat', fed diets containing either FO or a VO blend. Diet principally affected metabolism genes, mainly of lipid and carbohydrate, followed by immune response genes. Genotype had a much lower impact on metabolism-related genes and affected mostly signalling pathways. Replacement of dietary FO by VO caused an up-regulation of long-chain polyunsaturated fatty acid biosynthesis, but there was a clear genotype effect as fatty acyl elongase (elovl2) was only up-regulated and desaturases (Delta5 fad and Delta6 fad) showed a higher magnitude of response in Lean fish, which was reflected in liver fatty acid composition. Fatty acid synthase (FAS) was also up-regulated by VO and the effect was independent of genotype. Genetic background of the fish clearly affected regulation of lipid metabolism, as PPARalpha and PPARbeta were down regulated by the VO diet only in Lean fish, while in Fat salmon SREBP-1 expression was up-regulated by VO. In addition, all three genes had a lower expression in the Lean family group than in the Fat, when fed VO. Differences in muscle adiposity between family groups may have been caused by higher levels of hepatic fatty acid and glycerophospholipid synthesis in the Fat fish, as indicated by the expression of FAS, 1-acyl-sn-glycerol-3-phosphate acyltransferase and lipid phosphate phosphohydrolase 2. CONCLUSIONS: This study has identified metabolic pathways and key regulators that may respond differently to alternative plant-based feeds depending on genotype. Further studies are required but data suggest that it will be possible to identify families better adapted to alternative diet formulations that might be appropriate for future genetic selection programmes. PMID- 21599966 TI - Highly efficient concentration of lenti- and retroviral vector preparations by membrane adsorbers and ultrafiltration. AB - BACKGROUND: Lentiviral vectors (LVs) can efficiently transduce a broad spectrum of cells and tissues, including dividing and non-dividing cells. So far the most widely used method for concentration of lentiviral particles is ultracentrifugation (UC).An important feature of vectors derived from lentiviruses and prototypic gamma-retroviruses is that the host range can be altered by pseudotypisation. The most commonly used envelope protein for pseudotyping is the glycoprotein of the Vesicular Stomatitis Virus (VSV.G), which is also essential for successful concentration using UC. RESULTS: Here, we describe a purification method that is based on membrane adsorbers (MAs). Viral particles are efficiently retained by the anionic exchange MAs and can be eluted with a high-salt buffer. Buffer exchange and concentration is then performed by utilizing ultrafiltration (UF) units of distinct molecular weight cut off (MWCO). With this combined approach similar biological titers as UC can be achieved (2 to 5*109 infectious particles (IP)/ml). Lentiviral particles from small starting volumes (e.g. 40 ml) as well as large volumes (up to 1,000 ml) cell culture supernatant (SN) can be purified. Apart from LVs, vectors derived from oncoretroviruses can be efficiently concentrated as well. Importantly, the use of the system is not confined to VSV.G pseudotyped lenti- and retroviral particles and other pseudotypes can also be purified. CONCLUSIONS: Taken together the method presented here offers an efficient alternative for the concentration of lenti- as well as retroviral vectors with different pseudotypes that needs no expensive equipment, is easy to handle and can be used to purify large quantities of viral vectors within a short time. PMID- 21599967 TI - Mortality and cause of death in hip fracture patients aged 65 or older: a population-based study. AB - BACKGROUND: The high mortality of hip fracture patients is well documented, but sex- and cause-specific mortality after hip fracture has not been extensively studied. The purpose of the present study was to evaluate mortality and cause of death in patients after hip fracture surgery and to compare their mortality and cause of death to those in the general population. METHODS: Records of 428 consecutive hip fracture patients were collected on a population-basis and data on the general population comprising all Finns 65 years of age or older were collected on a cohort-basis. Cause of death was classified as follows: malignant neoplasms, dementia, circulatory disease, respiratory disease, digestive system disease, and other. RESULTS: Mean follow-up was 3.7 years (range 0-9 years). Overall 1-year postoperative mortality was 27.3% and mortality after hip fracture at the end of the follow-up was 79.0%. During the follow-up, age-adjusted mortality after hip fracture surgery was higher in men than in women with hazard ratio (HR) 1.55 and 95% confidence interval (95% CI) 1.21-2.00. Among hip surgery patients, the most common causes of death were circulatory diseases, followed by dementia and Alzheimer's disease. After hip fracture, men were more likely than women to die from respiratory disease, malignant neoplasm, and circulatory disease. During the follow-up, all-cause age- and sex-standardized mortality after hip fracture was 3-fold higher than that of the general population and included every cause-of-death category. CONCLUSION: During the study period, the risk of mortality in hip fracture patients was 3-fold higher than that in the general population and included every major cause of death. PMID- 21599968 TI - HPV16 E2 could act as down-regulator in cellular genes implicated in apoptosis, proliferation and cell differentiation. AB - BACKGROUND: Human Papillomavirus (HPV) E2 plays several important roles in the viral cycle, including the transcriptional regulation of the oncogenes E6 and E7, the regulation of the viral genome replication by its association with E1 helicase and participates in the viral genome segregation during mitosis by its association with the cellular protein Brd4. It has been shown that E2 protein can regulate negative or positively the activity of several cellular promoters, although the precise mechanism of this regulation is uncertain. In this work we constructed a recombinant adenoviral vector to overexpress HPV16 E2 and evaluated the global pattern of biological processes regulated by E2 using microarrays expression analysis. RESULTS: The gene expression profile was strongly modified in cells expressing HPV16 E2, finding 1048 down-regulated genes, and 581 up regulated. The main cellular pathway modified was WNT since we found 28 genes down-regulated and 15 up-regulated. Interestingly, this pathway is a convergence point for regulating the expression of genes involved in several cellular processes, including apoptosis, proliferation and cell differentiation; MYCN, JAG1 and MAPK13 genes were selected to validate by RT-qPCR the microarray data as these genes in an altered level of expression, modify very important cellular processes. Additionally, we found that a large number of genes from pathways such as PDGF, angiogenesis and cytokines and chemokines mediated inflammation, were also modified in their expression. CONCLUSIONS: Our results demonstrate that HPV16 E2 has regulatory effects on cellular gene expression in HPV negative cells, independent of the other HPV proteins, and the gene profile observed indicates that these effects could be mediated by interactions with cellular proteins. The cellular processes affected suggest that E2 expression leads to the cells in to a convenient environment for a replicative cycle of the virus. PMID- 21599969 TI - Distinct DNA methylation epigenotypes in bladder cancer from different Chinese sub-populations and its implication in cancer detection using voided urine. AB - BACKGROUND: Bladder cancer is the sixth most common cancer in the world and the incidence is particularly high in southwestern Taiwan. Previous studies have identified several tumor-related genes that are hypermethylated in bladder cancer; however the DNA methylation profile of bladder cancer in Taiwan is not fully understood. METHODS: In this study, we compared the DNA methylation profile of multiple tumor suppressor genes (APC, DAPK, E-cadherin, hMLH1, IRF8, p14, p15, RASSF1A, SFRP1 and SOCS-1) in bladder cancer patients from different Chinese sub populations including Taiwan (104 cases), Hong Kong (82 cases) and China (24 cases) by MSP. Two normal human urothelium were also included as control. To investigate the diagnostic potential of using DNA methylation in non-invasive detection of bladder cancer, degree of methylation of DAPK, IRF8, p14, RASSF1A and SFRP1 was also accessed by quantitative MSP in urine samples from thirty bladder cancer patients and nineteen non-cancer controls. RESULTS: There were distinct DNA methylation epigenotypes among the different sub-populations. Further, samples from Taiwan and China demonstrated a bimodal distribution suggesting that CpG island methylator phentotype (CIMP) is presented in bladder cancer. Moreover, the number of methylated genes in samples from Taiwan and Hong Kong were significantly correlated with histological grade (P < 0.01) and pathological stage (P < 0.01). Regarding the samples from Taiwan, methylation of SFRP1, IRF8, APC and RASSF1A were significantly associated with increased tumor grade, stage. Methylation of RASSF1A was associated with tumor recurrence. Patients with methylation of APC or RASSF1A were also significantly associated with shorter recurrence-free survival. For methylation detection in voided urine samples of cancer patients, the sensitivity and specificity of using any of the methylated genes (IRF8, p14 or sFRP1) by qMSP was 86.7% and 94.7%. CONCLUSIONS: Our results indicate that there are distinct methylation epigenotypes among different Chinese sub-populations. These profiles demonstrate gradual increases with cancer progression. Finally, detection of gene methylation in voided urine with these distinct DNA methylation markers is more sensitive than urine cytology. PMID- 21599970 TI - Comparisons of resistance of CF and non-CF pathogens to hydrogen peroxide and hypochlorous acid oxidants in vitro. AB - BACKGROUND: Cystic fibrosis (CF) lung disease has a unique profile of pathogens predominated by Pseudomonas aeruginosa (PsA) and Staphylococcus aureus (SA). These microorganisms must overcome host immune defense to colonize the CF lungs. Polymorphonuclear neutrophils are a major component of the host defense against bacterial infection. A crucial microbicidal mechanism is the production of oxidants including hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) by neutrophils to achieve efficient bacterial killing. To determine to what degrees various CF pathogens resist the oxidants relative to non-CF pathogens, we compared the susceptibility of PsA, SA, Burkholderia cepacia (BC), Klebsiella pneumoniae (KP), and Escherichia coli (EC) to various concentrations of H2O2 or HOCl, in vitro. The comparative oxidant-resistant profiles were established. Oxidant-induced damage to ATP production and cell membrane integrity of the microbes were quantitatively assessed. Correlation of membrane permeability and ATP levels with bacterial viability was statistically evaluated. RESULTS: PsA was relatively resistant to both H2O2 (LD50 = 1.5 mM) and HOCl (LD50 = 0.035 mM). SA was susceptible to H2O2 (LD50 = 0.1 mM) but resistant to HOCl (LD50 = 0.035 mM). Interestingly, KP was extremely resistant to high doses of H2O2 (LD50 = 2.5-5.0 mM) but was very sensitive to low doses of HOCl (LD50 = 0.015 mM). BC was intermediate to resist both oxidants: H2O2 (LD50 = 0.3-0.4 mM) and HOCl (LD50 = 0.025 mM). EC displayed the least resistance to H2O2 (LD50 = 0.2-0.3 mM) and HOCl (LD50 = 0.015 mM). The identified profile of H2O2-resistance was KP > PsA > BC > EC > SA and the profile of HOCl-resistance PsA > SA > BC > EC > KP. Moreover, both oxidants affected ATP production and membrane integrity of the cells. However, the effects varied among the tested organisms and, the oxidant-mediated damage correlated differentially with the bacterial viability. CONCLUSIONS: The order of HOCl-resistance identified herein best fits the clinical profile of CF infections. Even though oxidants are able to disrupt ATP production and cell membrane integrity, the degrees of damage vary among the organisms and correlate differentially with their viability. PMID- 21599971 TI - Blood culture status and mortality among patients with suspected community acquired bacteremia: a population-based cohort study. AB - BACKGROUND: Comparison of mortality among patients with positive and negative blood cultures may indicate the contribution of bacteremia to mortality. This study (1) compared mortality among patients with community-acquired bacteremia with mortality among patients with negative blood cultures and (2) determined the effects of bacteremia type and comorbidity level on mortality among patients with positive blood cultures. METHODS: This cohort study included 29,273 adults with blood cultures performed within the first 2 days following hospital admission to an internal medical ward in northern Denmark during 1995-2006. We computed product limit estimates and used Cox regression to compute adjusted mortality rate ratios (MRRs) within 0-2, 3-7, 8-30, and 31-180 days following admission for bacteremia patients compared to culture-negative patients. RESULTS: Mortality in 2,648 bacteremic patients and 26,625 culture-negative patients was 4.8% vs. 2.0% 0-2 days after admission, 3.7% vs. 2.7% 3-7 days after admission, 5.6% vs. 5.1% 8 30 days after admission, and 9.7% vs. 8.7% 31-180 days after admission, corresponding to adjusted MRRs of 1.9 (95% confidence interval (CI): 1.6-2.2), 1.1 (95% CI: 0.9-1.5), 0.9 (95% CI: 0.8-1.1), and 1.0 (95% CI: 0.8-1.1), respectively. Mortality was higher among patients with Gram-positive (adjusted 0 2-day MRR 1.9, 95% CI: 1.6-2.2) and polymicrobial bacteremia (adjusted 0-2-day MRR 3.5, 95% CI: 2.2-5.5) than among patients with Gram-negative bacteremia (adjusted 0-2-day MRR 1.5, 95% CI 1.2-2.0). After the first 2 days, patients with Gram-negative bacteremia had the same risk of dying as culture-negative patients (adjusted MRR 0.8, 95% CI: 0.5-1.1). Only patients with polymicrobial bacteremia had increased mortality within 31-180 days following admission (adjusted MRR 1.3, 95% CI: 0.8-2.1) compared to culture-negative patients. The association between blood culture status and mortality did not differ substantially by level of comorbidity. CONCLUSIONS: Community-acquired bacteremia was associated with an increased risk of mortality in the first week of medical ward admission. Higher mortality among patients with Gram-positive and polymicrobial bacteremia compared with patients with Gram-negative bacteremia and negative cultures emphasizes the prognostic importance of these infections. PMID- 21599972 TI - The role of historical and contemporary processes on phylogeographic structure and genetic diversity in the Northern Cardinal, Cardinalis cardinalis. AB - BACKGROUND: Earth history events such as climate change are believed to have played a major role in shaping patterns of genetic structure and diversity in species. However, there is a lag between the time of historical events and the collection of present-day samples that are used to infer contemporary population structure. During this lag phase contemporary processes such as dispersal or non random mating can erase or reinforce population differences generated by historical events. In this study we evaluate the role of both historical and contemporary processes on the phylogeography of a widespread North American songbird, the Northern Cardinal, Cardinalis cardinalis. RESULTS: Phylogenetic analysis revealed deep mtDNA structure with six lineages across the species' range. Ecological niche models supported the same geographic breaks revealed by the mtDNA. A paleoecological niche model for the Last Glacial Maximum indicated that cardinals underwent a dramatic range reduction in eastern North America, whereas their ranges were more stable in Mexico. In eastern North America cardinals expanded out of glacial refugia, but we found no signature of decreased genetic diversity in areas colonized after the Last Glacial Maximum. Present-day demographic data suggested that population growth across the expansion cline is positively correlated with latitude. We propose that there was no loss of genetic diversity in areas colonized after the Last Glacial Maximum because recent high levels of gene flow across the region have homogenized genetic diversity in eastern North America. CONCLUSION: We show that both deep historical events as well as demographic processes that occurred following these events are critical in shaping genetic pattern and diversity in C. cardinalis. The general implication of our results is that patterns of genetic diversity are best understood when information on species history, ecology, and demography are considered simultaneously. PMID- 21599973 TI - Apple skin patterning is associated with differential expression of MYB10. AB - BACKGROUND: Some apple (Malus * domestica Borkh.) varieties have attractive striping patterns, a quality attribute that is important for determining apple fruit market acceptance. Most apple cultivars (e.g. 'Royal Gala') produce fruit with a defined fruit pigment pattern, but in the case of 'Honeycrisp' apple, trees can produce fruits of two different kinds: striped and blushed. The causes of this phenomenon are unknown. RESULTS: Here we show that striped areas of 'Honeycrisp' and 'Royal Gala' are due to sectorial increases in anthocyanin concentration. Transcript levels of the major biosynthetic genes and MYB10, a transcription factor that upregulates apple anthocyanin production, correlated with increased anthocyanin concentration in stripes. However, nucleotide changes in the promoter and coding sequence of MYB10 do not correlate with skin pattern in 'Honeycrisp' and other cultivars differing in peel pigmentation patterns. A survey of methylation levels throughout the coding region of MYB10 and a 2.5 Kb region 5' of the ATG translation start site indicated that an area 900 bp long, starting 1400 bp upstream of the translation start site, is highly methylated. Cytosine methylation was present in all three contexts, with higher methylation levels observed for CHH and CHG (where H is A, C or T) than for CG. Comparisons of methylation levels of the MYB10 promoter in 'Honeycrisp' red and green stripes indicated that they correlate with peel phenotypes, with an enrichment of methylation observed in green stripes. CONCLUSIONS: Differences in anthocyanin levels between red and green stripes can be explained by differential transcript accumulation of MYB10. Different levels of MYB10 transcript in red versus green stripes are inversely associated with methylation levels in the promoter region. Although observed methylation differences are modest, trends are consistent across years and differences are statistically significant. Methylation may be associated with the presence of a TRIM retrotransposon within the promoter region, but the presence of the TRIM element alone cannot explain the phenotypic variability observed in 'Honeycrisp'. We suggest that methylation in the MYB10 promoter is more variable in 'Honeycrisp' than in 'Royal Gala', leading to more variable color patterns in the peel of this cultivar. PMID- 21599975 TI - Quantitative metric profiles capture three-dimensional temporospatial architecture to discriminate cellular functional states. AB - BACKGROUND: Computational analysis of tissue structure reveals sub-visual differences in tissue functional states by extracting quantitative signature features that establish a diagnostic profile. Incomplete and/or inaccurate profiles contribute to misdiagnosis. METHODS: In order to create more complete tissue structure profiles, we adapted our cell-graph method for extracting quantitative features from histopathology images to now capture temporospatial traits of three-dimensional collagen hydrogel cell cultures. Cell-graphs were proposed to characterize the spatial organization between the cells in tissues by exploiting graph theory wherein the nuclei of the cells constitute the nodes and the approximate adjacency of cells are represented with edges. We chose 11 different cell types representing non-tumorigenic, pre-cancerous, and malignant states from multiple tissue origins. RESULTS: We built cell-graphs from the cellular hydrogel images and computed a large set of features describing the structural characteristics captured by the graphs over time. Using three-mode tensor analysis, we identified the five most significant features (metrics) that capture the compactness, clustering, and spatial uniformity of the 3D architectural changes for each cell type throughout the time course. Importantly, four of these metrics are also the discriminative features for our histopathology data from our previous studies. CONCLUSIONS: Together, these descriptive metrics provide rigorous quantitative representations of image information that other image analysis methods do not. Examining the changes in these five metrics allowed us to easily discriminate between all 11 cell types, whereas differences from visual examination of the images are not as apparent. These results demonstrate that application of the cell-graph technique to 3D image data yields discriminative metrics that have the potential to improve the accuracy of image based tissue profiles, and thus improve the detection and diagnosis of disease. PMID- 21599974 TI - Glial TNFalpha in the spinal cord regulates neuropathic pain induced by HIV gp120 application in rats. AB - BACKGROUND: HIV-associated sensory neuropathy (HIV-SN) is one of the most common forms of peripheral neuropathy, affecting about 30% of people with acquired immune deficiency syndrome (AIDS). The symptoms of HIV-SN are dominated by neuropathic pain. Glia activation in the spinal cord has become an attractive target for attenuating chronic pain. This study will investigate the role of spinal TNFalpha released from glia in HIV-related neuropathic pain. RESULTS: Peripheral gp120 application into the rat sciatic nerve induced mechanical allodynia for more than 7 weeks, and upregulated the expression of spinal TNFalpha in the mRNA and the protein levels at 2 weeks after gp120 application. Spinal TNFalpha was colocalized with GFAP (a marker of astrocytes) and Iba1 (a marker of microglia) in immunostaining, suggesting that glia produce TNFalpha in the spinal cord in this model. Peripheral gp120 application also increased TNFalpha in the L4/5 DRG. Furthermore, intrathecal administration of TNFalpha siRNA or soluble TNF receptor reduced gp120 application-induced mechanical allodynia. CONCLUSIONS: Our results indicate that TNFalpha in the spinal cord and the DRG are involved in neuropathic pain, following the peripheral HIV gp120 application, and that blockade of the glial product TNFalpha reverses neuropathic pain induced by HIV gp120 application. PMID- 21599976 TI - Atypical epigenetic mark in an atypical location: cytosine methylation at asymmetric (CNN) sites within the body of a non-repetitive tomato gene. AB - BACKGROUND: Eukaryotic DNA methylation is one of the most studied epigenetic processes, as it results in a direct and heritable covalent modification triggered by external stimuli. In contrast to mammals, plant DNA methylation, which is stimulated by external cues exemplified by various abiotic types of stress, is often found not only at CG sites but also at CNG (N denoting A, C or T) and CNN (asymmetric) sites. A genome-wide analysis of DNA methylation in Arabidopsis has shown that CNN methylation is preferentially concentrated in transposon genes and non-coding repetitive elements. We are particularly interested in investigating the epigenetics of plant species with larger and more complex genomes than Arabidopsis, particularly with regards to the associated alterations elicited by abiotic stress. RESULTS: We describe the existence of CNN methylated epialleles that span Asr1, a non-transposon, protein-coding gene from tomato plants that lacks an orthologous counterpart in Arabidopsis. In addition, to test the hypothesis of a link between epigenetics modifications and the adaptation of crop plants to abiotic stress, we exhaustively explored the cytosine methylation status in leaf Asr1 DNA, a model gene in our system, resulting from water-deficit stress conditions imposed on tomato plants. We found that drought conditions brought about removal of methyl marks at approximately 75 of the 110 asymmetric (CNN) sites analysed, concomitantly with a decrease of the repressive H3K27me3 epigenetic mark and a large induction of expression at the RNA level. When pinpointing those sites, we observed that demethylation occurred mostly in the intronic region. CONCLUSIONS: These results demonstrate a novel genomic distribution of CNN methylation, namely in the transcribed region of a protein-coding, non-repetitive gene, and the changes in those epigenetic marks that are caused by water stress. These findings may represent a general mechanism for the acquisition of new epialleles in somatic cells, which are pivotal for regulating gene expression in plants. PMID- 21599977 TI - Identification of factors required for meristem function in Arabidopsis using a novel next generation sequencing fast forward genetics approach. AB - BACKGROUND: Phenotype-driven forward genetic experiments are powerful approaches for linking phenotypes to genomic elements but they still involve a laborious positional cloning process. Although sequencing of complete genomes now becomes available, discriminating causal mutations from the enormous amounts of background variation remains a major challenge. METHOD: To improve this, we developed a universal two-step approach, named 'fast forward genetics', which combines traditional bulk segregant techniques with targeted genomic enrichment and next-generation sequencing technology RESULTS: As a proof of principle we successfully applied this approach to two Arabidopsis mutants and identified a novel factor required for stem cell activity. CONCLUSION: We demonstrated that the 'fast forward genetics' procedure efficiently identifies a small number of testable candidate mutations. As the approach is independent of genome size, it can be applied to any model system of interest. Furthermore, we show that experiments can be multiplexed and easily scaled for the identification of multiple individual mutants in a single sequencing run. PMID- 21599979 TI - Inhibition of hepatitis C virus 3a genotype entry through Glanthus Nivalis Agglutinin. AB - BACKGROUND: Hepatitis C Virus (HCV) has two envelop proteins E1 and E2 which is highly glycosylated and play an important role in cell entry. Inhibition of virus at entry step is an important target to find antiviral drugs against HCV. Glanthus Nivalis Agglutinin (GNA) is a mannose binding lectin which has tendency for specific recognition and reversible binding to the sugar moieties of a wide variety of glycoproteins of enveloped viruses. RESULTS: In the present study, HCV pseudoparticles (HCVpp) for genotype 3a were produced to investigate the ability of GNA to block the HCV entry. The results demonstrated that GNA inhibit the infectivity of HCVpp and HCV infected serum in a dose-dependent manner and resulted in 50% reduction of virus at 1 +/- 2 MUg concentration. Molecular docking of GNA and HCV glycoproteins (E1 and E2) showed that GNA inhibit HCV entry by binding N-linked glycans. CONCLUSION: These results demonstrated that targeting the HCV glycans is a new approach to develop antiviral drugs against HCV. PMID- 21599978 TI - Elucidating the domain architecture and functions of non-core RAG1: the capacity of a non-core zinc-binding domain to function in nuclear import and nucleic acid binding. AB - BACKGROUND: The repertoire of the antigen-binding receptors originates from the rearrangement of immunoglobulin and T-cell receptor genetic loci in a process known as V(D)J recombination. The initial site-specific DNA cleavage steps of this process are catalyzed by the lymphoid specific proteins RAG1 and RAG2. The majority of studies on RAG1 and RAG2 have focused on the minimal, core regions required for catalytic activity. Though not absolutely required, non-core regions of RAG1 and RAG2 have been shown to influence the efficiency and fidelity of the recombination reaction. RESULTS: Using a partial proteolysis approach in combination with bioinformatics analyses, we identified the domain boundaries of a structural domain that is present in the 380-residue N-terminal non-core region of RAG1. We term this domain the Central Non-core Domain (CND; residues 87-217). CONCLUSIONS: We show how the CND alone, and in combination with other regions of non-core RAG1, functions in nuclear localization, zinc coordination, and interactions with nucleic acid. Together, these results demonstrate the multiple roles that the non-core region can play in the function of the full length protein. PMID- 21599980 TI - Spatial distribution of the risk of dengue fever in southeast Brazil, 2006-2007. AB - BACKGROUND: Many factors have been associated with circulation of the dengue fever virus and vector, although the dynamics of transmission are not yet fully understood. The aim of this work is to estimate the spatial distribution of the risk of dengue fever in an area of continuous dengue occurrence. METHODS: This is a spatial population-based case-control study that analyzed 538 cases and 727 controls in one district of the municipality of Campinas, Sao Paulo, Brazil, from 2006-2007, considering socio-demographic, ecological, case severity, and household infestation variables. Information was collected by in-home interviews and inspection of living conditions in and around the homes studied. Cases were classified as mild or severe according to clinical data, and they were compared with controls through a multinomial logistic model. A generalized additive model was used in order to include space in a non-parametric fashion with cubic smoothing splines. RESULTS: Variables associated with increased incidence of all dengue cases in the multiple binomial regression model were: higher larval density (odds ratio (OR) = 2.3 (95%CI: 2.0-2.7)), reports of mosquito bites during the day (OR = 1.8 (95%CI: 1.4-2.4)), the practice of water storage at home (OR = 2.5 (95%CI: 1.4, 4.3)), low frequency of garbage collection (OR = 2.6 (95%CI: 1.6-4.5)) and lack of basic sanitation (OR = 2.9 (95%CI: 1.8-4.9)). Staying at home during the day was protective against the disease (OR = 0.5 (95%CI: 0.3-0.6)). When cases were analyzed by categories (mild and severe) in the multinomial model, age and number of breeding sites more than 10 were significant only for the occurrence of severe cases (OR = 0.97, (95%CI: 0.96 0.99) and OR = 2.1 (95%CI: 1.2-3.5), respectively. Spatial distribution of risks of mild and severe dengue fever differed from each other in the 2006/2007 epidemic, in the study area. CONCLUSIONS: Age and presence of more than 10 breeding sites were significant only for severe cases. Other predictors of mild and severe cases were similar in the multiple models. The analyses of multinomial models and spatial distribution maps of dengue fever probabilities suggest an area-specific epidemic with varying clinical and demographic characteristics. PMID- 21599981 TI - Inside athletes' minds: preliminary results from a pilot study on mental representation of doping and potential implications for anti-doping. AB - BACKGROUND: Despite the growing body of literature and putative links between the use of ergogenic nutritional supplements, doping and illicit drugs, it remains unclear whether, in athletes' minds, doping aligns with illicit behaviour or with functional use of chemical or natural preparations. To date, no attempt has been made to quantitatively explore athletes' mental representation of doping in relation to illegality and functionality. METHODS: A convenience sample of student athletes from a large South-Eastern Australian university responded to an on-line survey. Competitive athletes (n = 46) were grouped based on self-reported use as follows: i) none used (30%), ii) supplement only (22%), iii) illicit only (26%) and iv) both supplements and illicit drug use (22%). Whereas no athlete reported doping, data provided on projected supplement-, doping- and drug use by the four user groups allowed evaluation of doping-related cognition in the context of self-reported supplement- and illicit drug taking behaviour; and comparison between these substances. RESULTS: A significantly higher prevalence estimation was found for illicit drug use and a trend towards a biased social projection emerged for supplement use. Doping estimates by user groups showed mixed results, suggesting that doping had more in common with the ergogenic nutritional supplement domain than the illicit drug domain. CONCLUSIONS: Assessing the behavioural domain to which doping belongs to in athletes' mind would greatly advance doping behaviour research toward prevention and intervention. Further investigation refining the peculiarity of the mental representation of doping with a larger study sample, controlling for knowledge of doping and other factors, is warranted. PMID- 21599982 TI - Src mediates cytokine-stimulated gene expression in airway myocytes through ERK MAPK. AB - The p38 and extracellular signal-regulated kinases (ERK) mitogen-activated protein kinases (MAPK) participate in cytokine-stimulated inflammatory gene expression in airway smooth muscle cells. The following study was undertaken to determine whether Src tyrosine kinases are signaling intermediaries upstream of cytokine-stimulated MAPK activation and gene expression. Treating human airway myocytes with interleukin (IL)-1beta, tumor necrosis factor (TNF) alpha and interferon (IFN) gamma caused a rapid 1.8-fold increase in Src family tyrosine kinase activity within 1 minute that remained 2.3 to 2.7 fold above basal conditions for 15 minutes. This activity was blocked by addition of 30 MUM PP1, a pyrimidine inhibitor specific for Src family tyrosine kinases, in immune-complex assays to confirm that this stimulus activates Src tyrosine kinase. Addition of PP1 also blocked cytokine-stimulated expression of IL-1beta, IL-6 and IL-8, while decreasing phosphorylation of ERK, but not p38 MAPK. Since this inflammatory stimulus may activate additional inflammatory signaling pathways downstream of Src, we tested the effects of PP1 on phosphorylation of signal transducers and activators of transcription (STAT). PP1 had no effect on cytokine-stimulated STAT 1 or STAT 3 phosphorylation. These results demonstrate that Src tyrosine kinases participate in the regulation of IL-1beta, IL-6 and IL-8 expression and that these effects of Src are mediated through activation of ERK MAPK and not p38 MAPK or STAT1/STAT3 phosphorylation. PMID- 21599983 TI - Feasibility and safety of setting up a donor breastmilk bank in a neonatal prem unit in a resource limited setting: An observational, longitudinal cohort study. AB - BACKGROUND: The beneficial effects of human milk on decreasing rates of paediatric infections such as necrotizing enterocolitis (NEC) and sepsis have been clearly demonstrated. Donor breastmilk has been encouraged as the milk of choice when a mother's own breastmilk is not available. The objectives of this study were to assess feasibility of providing donor breastmilk to infants in a resource limited Neonatal Prem Unit (NPU). In addition we sought to determine whether donor breastmilk could be safely pasteurized and administered to infants without any adverse events. METHODS: Low birth weight infants < 1800 g and under 32 weeks gestational age were followed up in the NPU over a 3 week period; feeding data and morbidity data was collected in order to determine if there were any adverse events associated with donor breastmilk. Samples of pasteurized breastmilk were cultured to check for any bacterial contamination. RESULTS: 191 infants met the inclusion criteria of whom 96 received their mother's own breastmilk. Of the 95 infants who were potentially eligible to receive donor milk, only 40 did in fact receive donor milk. There was no evidence of bacterial contamination in the samples analyzed, and no evidence of adverse events from feeding with donor breastmilk. CONCLUSION: It is feasible to supply donor breastmilk to infants in an NPU in a resource limited setting, however staff needs to be sensitized to the importance of donor breastmilk to improve uptake rates. Secondly we showed that it is possible to supply donor breastmilk according to established guidelines with no adverse events therefore making it possible to prevent NEC and other side effects often associated with formula feeding of premature infants. PMID- 21599984 TI - Experience of violence and adverse reproductive health outcomes, HIV risks among mobile female sex workers in India. AB - BACKGROUND: Female sex workers (FSWs) are a population sub-group most affected by the HIV epidemic in India and elsewhere. Despite research and programmatic attention to FSWs, little is known regarding sex workers' reproductive health and HIV risk in relation to their experiences of violence. This paper therefore aims to understand the linkages between violence and the reproductive health and HIV risks among a group of mobile FSWs in India. METHODS: Data are drawn from a cross sectional behavioural survey conducted in 22 districts from four high HIV prevalence states (Andhra Pradesh, Karnataka, Maharashtra, Tamil Nadu) in India between September 2007 and July 2008. The survey sample included 5,498 FSWs who had moved to at least two different places for sex work in the past two years, and are classified as mobile FSWs in the current study. Analyses calculated the prevalence of past year experiences of violence; and adjusted logistic regression models examined the association between violence and reproductive health and HIV risks after controlling for background characteristics and program exposure. RESULTS: Approximately one-third of the total mobile FSWs (30.5%, n = 1,676) reported experiencing violence at least once in the past year; 11% reported experiencing physical violence, and 19.5% reported experiencing sexual violence. Results indicate that FSWs who had experienced any violence (physical or sexual) were significantly more likely to be vulnerable to both reproductive health and HIV risks. For example, FSWs who experienced violence were more likely than those who did not experience violence to have experienced a higher number of pregnancies (adjusted odds ratio [OR] = 1.2, 95% confidence interval [CI] = 1.0 1.6), ever experienced pregnancy loss (adjusted OR = 1.4, 95% CI = 1.2-1.6), ever experienced forced termination of pregnancy (adjusted OR = 2.4, 95% CI = 2.0 2.7), experienced multiple forced termination of pregnancies (adjusted OR = 2.2, 95% CI = 1.7-2.8), and practice inconsistent condom use currently (adjusted OR = 1.97, 95% CI: 1.4-2.0). Among FSWs who experienced violence, those who experienced sexual violence were more likely than those who had experienced physical violence to report inconsistent condom use (adjusted OR = 1.8, 95% CI: 1.4-2.3), and experience STI symptoms (adjusted OR = 1.3, 95% CI: 1.1-1.7). CONCLUSION: The pervasiveness of violence and its association with reproductive health and HIV risk highlights that the abuse in general is an important determinant for reproductive health risks; and sexual violence is significantly associated with HIV risks among those who experienced violence. Existing community mobilization programs that have primarily focused on empowering FSWs should broaden their efforts to promote reproductive health in addition to the prevention of HIV among all FSWs, with particular emphasis on FSWs who experienced violence. PMID- 21599985 TI - Modularity-based credible prediction of disease genes and detection of disease subtypes on the phenotype-gene heterogeneous network. AB - BACKGROUND: Protein-protein interaction networks and phenotype similarity information have been synthesized together to discover novel disease-causing genes. Genetic or phenotypic similarities are manifested as certain modularity properties in a phenotype-gene heterogeneous network consisting of the phenotype phenotype similarity network, protein-protein interaction network and gene disease association network. However, the quantitative analysis of modularity in the heterogeneous network and its influence on disease-gene discovery are still unaddressed. Furthermore, the genetic correspondence of the disease subtypes can be identified by marking the genes and phenotypes in the phenotype-gene network. We present a novel network inference method to measure the network modularity, and in particular to suggest the subtypes of diseases based on the heterogeneous network. RESULTS: Based on a measure which is introduced to evaluate the closeness between two nodes in the phenotype-gene heterogeneous network, we developed a Hitting-Time-based method, CIPHER-HIT, for assessing the modularity of disease gene predictions and credibly prioritizing disease-causing genes, and then identifying the genetic modules corresponding to potential subtypes of the queried phenotype. The CIPHER-HIT is free to rely on any preset parameters. We found that when taking into account the modularity levels, the CIPHER-HIT method can significantly improve the performance of disease gene predictions, which demonstrates modularity is one of the key features for credible inference of disease genes on the phenotype-gene heterogeneous network. By applying the CIPHER HIT to the subtype analysis of Breast cancer, we found that the prioritized genes can be divided into two sub-modules, one contains the members of the Fanconi anemia gene family, and the other contains a reported protein complex MRE11/RAD50/NBN. CONCLUSIONS: The phenotype-gene heterogeneous network contains abundant information for not only disease genes discovery but also disease subtypes detection. The CIPHER-HIT method presented here is effective for network inference, particularly on credible prediction of disease genes and the subtype analysis of diseases, for example Breast cancer. This method provides a promising way to analyze heterogeneous biological networks, both globally and locally. PMID- 21599986 TI - A novel COMP mutation in a pseudoachondroplasia family of Chinese origin. AB - BACKGROUND: Pseudoachondroplasia (PSACH) is caused exclusively by mutations in the gene for cartilage oligomeric matrix protein (COMP). Only a small number of studies have documented the clinical phenotype and genetic basis in Chinese PSACH patients. CASE PRESENTATION: We investigated a four-generation PSACH pedigree of Chinese Han origin. Two patients and two unaffected individuals were recruited for clinical evaluation and molecular genetic analysis. The genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction (PCR) was adopted to amplify the 8-19 exons of COMP gene. Then the products were sequenced bi-directionally for screening mutation. Clinical evaluation revealed that PSACH patients in this pedigree had a severe disproportionate short stature (-10SD). A heterozygous TGTCCCTGG insertion in exon 13, between nucleotide 1352T and 1353G, were identified in the patients except the unaffected individuals, which resulted in a three-amino-acid insertion (451V_452P ins VPG) in the sixth calmodulin-like repeat of the COMP protein. CONCLUSION: This c. 1352_1353ins TGTCCCTGG is a novel mutation responsible for severe familial PSACH. PMID- 21599987 TI - Polyunsaturated fatty acid intake and prevalence of eczema and rhinoconjunctivitis in Japanese children: the Ryukyus Child Health Study. AB - BACKGROUND: The recent increase in the prevalence of allergic disorders might be a consequence of increased intake of n-6 polyunsaturated fatty acids (PUFAs) and reduced intake of n-3 PUFAs. The current cross-sectional study examined the association between intake levels and the prevalence of eczema and rhinoconjunctivitis in Japanese children. METHODS: Subjects were 23,388 schoolchildren aged 6-15 years residing in Okinawa. The presence of eczema and/or rhinoconjunctivitis was determined according to the criteria of the International Study of Asthma and Allergies in Childhood. A brief diet history questionnaire for children and adolescents was administered to acquire information on dietary factors. Adjustment was made for age, sex, residential municipality, number of siblings, smoking in the household, body mass index, paternal and maternal history of allergic diseases, and paternal and maternal educational level. RESULTS: The prevalences of eczema and rhinoconjunctivitis in the previous 12 months were 7.0% and 8.0%, respectively. Consumption of PUFAs, n-3 PUFAs, alpha linolenic acid, n-6 PUFAs, and linoleic acid was positively associated with the prevalence of eczema: the adjusted odds ratios (ORs) between extreme quintiles (95% confidence intervals [CIs], P for trend) were 1.26 (1.07-1.48, 0.04), 1.31 (1.11-1.54, 0.009), 1.31 (1.12-1.55, 0.003), 1.26 (1.07-1.48, 0.01), and 1.27 (1.08-1.49, 0.01), respectively. Arachidonic acid intake was independently inversely related to eczema: the adjusted OR between extreme quintiles was 0.81 (0.69-0.95, 0.0008). Eczema was not associated with eicosapentaenoic or docosahexaenoic acid intake, or with the ratio of n-3 to n-6 PUFA intake. Only arachidonic acid intake was statistically significantly related to the prevalence of rhinoconjunctivitis, showing a clear inverse linear trend: the adjusted OR between extreme quintiles was 0.86 (0.74-0.997, 0.03). CONCLUSIONS: Consumption of n-3 and n-6 PUFAs, especially alpha-linolenic acid and linoleic acid, may be positively associated with eczema. Arachidonic acid intake may be inversely related to eczema and rhinoconjunctivitis. PMID- 21599989 TI - Prostate cancer metastases to the rectum: a case report. AB - Prostate cancer rarely metastasis to the rectum. Findings in the patient reported here emphasize the importance of the relationship between urinary and gastrointestinal symptoms in detecting prostatic neoplasms in older male patients. PMID- 21599988 TI - Deficiency of maize starch-branching enzyme I results in altered starch fine structure, decreased digestibility and reduced coleoptile growth during germination. AB - BACKGROUND: Two distinct starch branching enzyme (SBE) isoforms predate the divergence of monocots and dicots and have been conserved in plants since then. This strongly suggests that both SBEI and SBEII provide unique selective advantages to plants. However, no phenotype for the SBEI mutation, sbe1a, had been previously observed. To explore this incongruity the objective of the present work was to characterize functional and molecular phenotypes of both sbe1a and wild-type (Wt) in the W64A maize inbred line. RESULTS: Endosperm starch granules from the sbe1a mutant were more resistant to digestion by pancreatic alpha-amylase, and the sbe1a mutant starch had an altered branching pattern for amylopectin and amylose. When kernels were germinated, the sbe1a mutant was associated with shorter coleoptile length and higher residual starch content, suggesting that less efficient starch utilization may have impaired growth during germination. CONCLUSIONS: The present report documents for the first time a molecular phenotype due to the absence of SBEI, and suggests strongly that it is associated with altered physiological function of the starch in vivo. We believe that these results provide a plausible rationale for the conservation of SBEI in plants in both monocots and dicots, as greater seedling vigor would provide an important survival advantage when resources are limited. PMID- 21599990 TI - Randomised-controlled trial of a web-based dietary intervention for patients with type 2 diabetes mellitus: study protocol of myDIDeA. AB - BACKGROUND: The potential of web-based interventions in dietary behaviour modification of the diabetics has not been fully explored. We describe the protocol of a 12-month match-design randomised controlled trial of a web-based dietary intervention for type 2 diabetic patients with primary aim to evaluate the effect of the intervention on their dietary knowledge, attitude and behaviour (KAB). The secondary objective of this study is to improve the participants' dietary practices, physical measurements and biomarkers. METHODS/DESIGN: A minimum total sample of 82 Type 2 diabetics will be randomised, either to the control group, who will receive the standard diabetes care or the e-intervention group, who will participate in a 6-month web-based dietary intervention in addition to the standard care. The dietary recommendations are based on existing guidelines, but personalised according to the patients' Stages of Change (SOC). The participants will be followed up for 6 months post-intervention with data collection scheduled at baseline, 6-month and 12-month. DISCUSSION: We are aiming for a net improvement in the KAB score in participants of the e-intervention group, besides investigating the impact of the e-intervention on the dietary practices, physical measurements and blood biomarkers of those patients. The successful outcome of this study can be a precursor for policy makers to initiate more rigorous promotion of such web-based programmes in the country. TRIAL REGISTRATION: Clinicaltrials.gov NCT01246687. PMID- 21599991 TI - Chiropractic at the crossroads or are we just going around in circles? AB - BACKGROUND: Chiropractic in Australia has seen many changes over the past 30 years. Some of these changes have advanced the professional status of chiropractic, improved undergraduate training and paved the way for a research culture. Unfortunately, other changes or lack of changes, have hindered the growth, public utilisation and professional standing of chiropractic in Australia. This article explores what influences have impacted on the credibility, advancement and public utilisation of chiropractic in Australia. DISCUSSION: The 1970's and 1980's saw a dramatic change within the chiropractic profession in Australia. With the advent of government regulation, came government funded teaching institutions, quality research and increased public acceptance and utilisation of chiropractic services. However, since that time the profession appears to have taken a backward step, which in the author's opinion, is directly linked to a shift by sections of the profession to the fundamentalist approach to chiropractic and the vertebral subluxation complex. The abandonment, by some groups, of a scientific and evidenced based approach to practice for one founded on ideological dogma is beginning to take its toll. SUMMARY: The future of chiropractic in Australia is at a crossroads. For the profession to move forward it must base its future on science and not ideological dogma. The push by some for it to become a unique and all encompassing alternative system of healthcare is both misguided and irrational. PMID- 21599992 TI - Autologous chondrocyte implantation (ACI) for the treatment of large and complex cartilage lesions of the knee. AB - BACKGROUND: Complex cartilage lesions of the knee including large cartilage defects, kissing lesions, and osteoarthritis (OA) represent a common problem in orthopaedic surgery and a challenging task for the orthopaedic surgeon. As there is only limited data, we performed a prospective clinical study to investigate the benefit of autologous chondrocyte implantation (ACI) for this demanding patient population. METHODS: Fifty-one patients displaying at least one of the criteria were included in the present retrospective study: (1.) defect size larger than 10 cm2; (2.) multiple lesions; (3.) kissing lesions, cartilage lesions Outerbridge grade III-IV, and/or (4.) mild/moderate osteoarthritis (OA). For outcome measurements, the International Cartilage Society's International Knee Documentation Committee's (IKDC) questionnaire, as well as the Cincinnati, Tegner, Lysholm and Noyes scores were used. Radiographic evaluation for OA was done using the Kellgren score. RESULTS AND DISCUSSION: Patient's age was 36 years (13-61), defects size 7.25 (3-17.5) cm2, previous surgical procedures 1.94 (0-8), and follow-up 30 (12-63) months. Instruments for outcome measurement indicated significant improvement in activity, working ability, and sports. Mean ICRS grade improved from 3.8 preoperatively to grade 3 postoperatively, Tegner grade 1.4 enhanced to grade 3.39. The Cincinnati score enhanced from 25.65 to 66.33, the Lysholm score from 33.26 to 64.68, the Larson score from 43.59 to 79.31, and Noyes score from 12.5 to 46.67, representing an improvement from Cincinnati grade 3.65 to grade 2.1. Lysholm grade 4 improved to grade 3.33, and Larson grade 3.96 to 2.78 (Table 1), (p < 0.001). Patients with kissing cartilage lesions had similar results as patients with single cartilage lesions. CONCLUSION: Our results suggest that ACI provides mid-term results in patients with complex cartilage lesions of the knee. If long term results will confirm our findings, ACI may be a considered as a valuable tool for the treatment of complex cartilage lesions of the knee. PMID- 21599993 TI - Withdrawal of life-support in paediatric intensive care--a study of time intervals between discussion, decision and death. AB - BACKGROUND: Scant information exists about the time-course of events during withdrawal of life-sustaining treatment. We investigated the time required for end-of-life decisions, subsequent withdrawal of life-sustaining treatment and the time to death. METHODS: Prospective, observational study in the ICU of a tertiary paediatric hospital. RESULTS: Data on 38 cases of withdrawal of life-sustaining treatment were recorded over a 12-month period (75% of PICU deaths). The time from the first discussion between medical staff and parents of the subject of withdrawal of life-sustaining treatment to parents and medical staff making the decision varied widely from immediate to 457 hours (19 days) with a median time of 67.8 hours (2.8 days). Large variations were subsequently also observed from the time of decision to actual commencement of the process ranging from 30 minutes to 47.3 hrs (2 days) with a median requirement of 4.7 hours. Death was apparent to staff at a median time of 10 minutes following withdrawal of life support varying from immediate to a maximum of 6.4 hours. Twenty-one per cent of children died more than 1 hour after withdrawal of treatment. Medical confirmation of death occurred at 0 to 35 minutes thereafter with the physician having left the bedside during withdrawal in 18 cases (48%) to attend other patients or to allow privacy for the family. CONCLUSIONS: Wide case-by-case variation in timeframes occurs at every step of the process of withdrawal of life sustaining treatment until death. This knowledge may facilitate medical management, clinical leadership, guidance of parents and inform organ procurement after cardiac death. PMID- 21599994 TI - Delivery practices and associated factors among mothers seeking child welfare services in selected health facilities in Nyandarua South District, Kenya. AB - BACKGROUND: A measure of the proportion of deliveries assisted by skilled attendants is one of the indicators of progress towards achieving Millennium Development Goal (MDG) 5, which aims at improving maternal health. This study aimed at establishing delivery practices and associated factors among mothers seeking child welfare services at selected health facilities in Nyandarua South district, Kenya to determine whether mothers were receiving appropriate delivery care. METHODS: A hospital-based cross-sectional survey among women who had recently delivered while in the study area was carried out between August and October 2009. Binary Logistic regression was used to identify factors that predicted mothers' delivery practice. RESULTS: Among the 409 mothers who participated in the study, 1170 deliveries were reported. Of all the deliveries reported, 51.8% were attended by unskilled birth attendants. Among the deliveries attended by unskilled birth attendants, 38.6% (452/1170) were by neighbors and/or relatives. Traditional Birth Attendants attended 1.5% (17/1170) of the deliveries while in 11.7% (137/1170) of the deliveries were self administered. Mothers who had unskilled birth attendance were more likely to have <3 years of education (Adjusted Odds ratio [AOR] 19.2, 95% confidence interval [CI] 1.7 - 212.8) and with more than three deliveries in a life time (AOR 3.8, 95% CI 2.3 - 6.4). Mothers with perceived similarity in delivery attendance among skilled and unskilled delivery attendants were associated with unsafe delivery practice (AOR 1.9, 95% CI 1.1 - 3.4). Mother's with lower knowledge score on safe delivery (%) were more likely to have unskilled delivery attendance (AOR 36.5, 95% CI 4.3 - 309.3). CONCLUSION: Among the mothers interviewed, utilization of skilled delivery attendance services was still low with a high number of deliveries being attended by unqualified lay persons. There is need to implement cost effective and sustainable measures to improve the quality of maternal health services with an aim of promoting safe delivery and hence reducing maternal mortality. PMID- 21599995 TI - Diagnostic performance of contrast enhanced CT and 18F-FDG PET/CT in suspicious recurrence of biliary tract cancer after curative resection. AB - BACKGROUND: Because of the late clinical presentation of biliary tract cancer (BTC), only 10% of patients are eligible for curative surgery. Even among those patients who have undergone curative surgery, most patients develop recurrent cancer. This study is to determine the clinical role of 18F-FDG PET/CT during post-operative surveillance of suspected recurrent BTC based on symptoms, laboratory findings and contrast-enhanced CT (ceCT) findings. METHODS: We consecutively enrolled 50 patients with BTC who underwent curative surgery. An 18F-FDG PET/CT was obtained for assessment of recurrence based on clinical suspicion during post-operative surveillance. The final confirmation of recurrence was determined pathologically or clinically. When a pathologic confirmation was impossible or inconclusive, a clinical confirmation was used by radiologic correlation with subsequent follow-up ceCT at a minimum of 3-month intervals. Diagnostic efficacy was evaluated by comparing the results of ceCT and 18F-FDG PET/CT with the final diagnosis. RESULTS: Among the 50 patients, 34(68%) were confirmed to have a recurrence. PET/CT showed higher sensitivity (88% vs. 76%, p=0.16) and accuracy (82% vs. 66%, p=0.11) for recurrence compared to ceCT, even though the difference was not significant. The positive (86% vs. 74%, p=0.72) and negative predictive values for recurrence (73% vs. 47%, p=0.55) were not significantly different between PET/CT and ceCT. However, an additional PET/CT on ceCT significantly improved the sensitivity than did a ceCT alone (94% [32/34] for PET/CT on ceCT vs. 76% [26/34] for ceCT alone, p=0.03) without increasing the specificity, positive predictive value, and negative predictive value. CONCLUSIONS: 18F-FDG PET/CT alone is not more sensitive or specific than ceCT in the detection of recurrent BTC after curative surgery. These results do not reach statistical significance, probably due to the low number of patients. However, an additional 18F-FDG PET/CT on ceCT significantly improves the sensitivity of detecting recurrences. PMID- 21599996 TI - Storage and use of residual newborn screening dot blood samples in Italy. PMID- 21599997 TI - SULFs in human neoplasia: implication as progression and prognosis factors. AB - BACKGROUND: The sulfation pattern of heparan sulfate chains influences signaling events mediated by heparan sulfate proteoglycans located on cell surface. SULF1 and SULF2 are two endosulfatases able to cleave specific 6-O sulfate groups within the heparan chains. Their action can modulate signaling processes, many of which with key relevance for cancer development and expansion. SULF1 has been associated with tumor suppressor effects in various models of cancer, whereas SULF2 dysregulation was in relation with protumorigenic actions. However, other observations argue for contradictory effects of these sulfatases in cancer, suggesting the complexity of their action in the tumor microenvironment. METHODS: We compared the expression of the genes encoding SULF1, SULF2 and heparan sulfate proteoglycans in a large panel of cancer samples to their normal tissue counterparts using publicly available gene expression data, including the data obtained from two cohorts of newly-diagnosed multiple myeloma patients, the Oncomine Cancer Microarray database, the Amazonia data base and the ITTACA database. We also analysed prognosis data in relation with these databases. RESULTS: We demonstrated that SULF2 expression in primary multiple myeloma cells was associated with a poor prognosis in two independent large cohorts of patients. It remained an independent predictor when considered together with conventional multiple myeloma prognosis factors. Besides, we observed an over representation of SULF2 gene expression in skin cancer, colorectal carcinoma, testicular teratoma and liver cancer compared to their normal tissue counterpart. We found that SULF2 was significantly over-expressed in high grade uveal melanoma compared to low grade and in patients presenting colorectal carcinoma compared to benign colon adenoma.We observed that, in addition to previous observations, SULF1 gene expression was increased in T prolymphocytic leukemia, acute myeloid leukemia and in renal carcinoma compared to corresponding normal tissues. Furthermore, we found that high SULF1 expression was associated with a poor prognosis in lung adenocarcinoma.Finally, SULF1 and SULF2 were simultaneously overexpressed in 6 cancer types: brain, breast, head and neck, renal, skin and testicular cancers. CONCLUSIONS: SULF1 and SULF2 are overexpressed in various human cancer types and can be associated to progression and prognosis. Targeting SULF1 and/or SULF2 could be interesting strategies to develop novel cancer therapies. PMID- 21599998 TI - Diagnosis of spontaneous bacterial peritonitis in infants and children with chronic liver disease: A cohort study. AB - BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a serious complication in infants and children with chronic liver disease (CLD); however its diagnosis might be difficult. We aimed to study the feasibility of diagnosing SBP by routine ascitic fluid tapping in infants and children with CLD. METHODS: We enrolled thirty infants and children with biopsy-proven CLD and ascites. Ascitic fluid was examined for biochemical indices, cytology and cell count. Aerobic and anaerobic bacteriological cultures of ascitic fluid were preformed. Direct smears were prepared from ascitic fluid deposit for Gram and Zheil-Nelson staining. RESULTS: Patients were divided into three groups: Group I included five patients with SBP in which the cell count was >= 250/mm3 and culture was positive (16.7%), Group II, eight patients with culture negative neutrocytic ascites (CNNA) with cells >= 250/mm3 and negative culture (26.7%) and Group III, seventeen negative patients (56.6%) in which cells were <250/mm3 and culture was negative. None of our patients had bacteriascites (i.e. culture positive with cells <250/mm3). Presence of fever was significantly higher in SBP and CNNA. The mean lactate dehydrogenase (LDH) level was significantly higher in ascitic fluid in the infected versus sterile cases (p < 0.002). A ratio of ascitic/serum LDH >= 0.5 gave a sensitivity of 80%, specificity of 88%, positive predictive value (PPV) of 66.7%, negative predictive value (NPV) of 93.7% and accuracy of 63.3%. The mean pH gradient (arterial - ascitic) was significantly higher in SBP and CNNA cases when compared to the negative cases (p < 0.001). Ascitic fluid protein level of <= 1 gm/dl was found in 13/30 (43.3%) of studied cases with a sensitivity of 100%, specificity of 64.7%, PPV of 45.5%, NPV of 100% and diagnostic accuracy of 53.3% (p = 0.0001). CONCLUSIONS: SBP is a rather common complication in children with CLD. Culture of the ascitic fluid is not always diagnostic of infection. Biochemical parameters of the ascitic fluid definitely add to the diagnostic accuracy. LDH ascitic/serum ratio >= 0.5, an arterial-ascitic pH gradient >= 0.1 and total ascitic fluid protein <= 1 gm/dl are the most significant parameters suggesting infection. PMID- 21599999 TI - The combined effect of determinants on coverage of intermittent preventive treatment of malaria during pregnancy in the Kilombero Valley, Tanzania. AB - BACKGROUND: Intermittent preventive treatment during pregnancy (IPTp) at routine antenatal care (ANC) clinics is an important and efficacious intervention to reduce adverse health outcomes of malaria infections during pregnancy. However, coverage for the recommended two IPTp doses is still far below the 80% target in Tanzania. This paper investigates the combined impact of pregnant women's timing of ANC attendance, health workers' IPTp delivery and different delivery schedules of national IPTp guidelines on IPTp coverage. METHODS: Data on pregnant women's ANC attendance and health workers' IPTp delivery were collected from ANC card records during structured exit interviews with ANC attendees and through semi structured interviews with health workers in south-eastern Tanzania. Women's timing of ANC visits and health worker's timing of IPTp delivery were analyzed in relation to the different national IPTp schedules and the outcome on IPTp coverage was modelled. RESULTS: Among all women eligible for IPTp, 79% received a first dose of IPTp and 27% were given a second dose. Although pregnant women initiated ANC attendance late, their timing was in line with the national guidelines recommending IPTp delivery between 20-24 weeks and 28-32 weeks of gestation. Only 15% of the women delayed to the extent of being too late to be eligible for a first dose of IPTp. Less than 1% of women started ANC attendance after 32 weeks of gestation. During the second IPTp delivery period health workers delivered IPTp to significantly less women than during the first one (55% vs. 73%) contributing to low second dose coverage. Simplified IPTp guidelines for front-line health workers as recommended by WHO could lead to a 20 percentage point increase in IPTp coverage. CONCLUSIONS: This study suggests that facility and policy factors are greater barriers to IPTp coverage than women's timing of ANC attendance. To maximize the benefit of the IPTp intervention, revision of existing guidelines is needed. Training on simplified IPTp messages should be consolidated as part of the extended antenatal care training to change health workers' delivery practices and increase IPTp coverage. Pregnant women's knowledge about IPTp and the risks of malaria during pregnancy should be enhanced as well as their ability and power to demand IPTp and other ANC services. PMID- 21600000 TI - The Hannover experience: surgical treatment of tongue cancer--a clinical retrospective evaluation over a 30 years period. AB - OBJECTIVES: In this retrospective study, we present a clinical review of our experience with tongue cancer in order to obtain valid criteria for therapeutic decision-making. MATERIALS AND METHODS: Between 1980 and 2009, a total of 341 patients with squamous cell carcinoma of the tongue were treated at our Department. The average follow-up was 5.2 years. 309 patients received surgical treatment, which was combined in nearly 10% with neoadjuvant and in nearly 20% with postoperative radio(chemo)therapy. 32 patients were excluded from surgery and received primary radiation. RESULTS: Local and regional failure occurred in 23.9% and 20.4%, leading to a total failure rate of 37.2% after an average duration of 1,6 years. N-Status, extracapsular spread and clear margins were identified as the dominant factors for survival, which was calculated with 54.5% after 5 years. CONCLUSIONS: We recommend categorical bilateral neck dissection in order to reliably remove occult lymph node metastases. Adjuvant treatment modalities should be applied more frequently in controlled clinical trials and should generally be implemented in cases with unclear margins and lymphatic spread. CLINICAL RELEVANCE: This study provides new treatment strategies for primary tumour disease and for tumour recurrence. PMID- 21600001 TI - Inflammatory pseudotumor of the liver: a case report and review of the literature. AB - INTRODUCTION: Inflammatory pseudotumor of the liver represents a fairly uncommon pathology. Although it is a benign tumor, the correct diagnosis can be missed. CASE PRESENTATION: We report the case of a 55-year-old Caucasian man, who presented with a one-month history of abdominal pain and weight loss. He was diagnosed with a primary liver tumor by computed tomography and magnetic resonance imaging. Alpha-fetoprotein levels ranged within normal limits. A right posterior sectorectomy was performed. Histopathology revealed an inflammatory pseudotumor of the liver. Our patient remains in good condition one year later. CONCLUSION: Although inflammatory pseudotumor of the liver is usually a benign process, controversy regarding its management still exists. With this case report we review the existing literature and consider hepatectomy as a safe treatment approach. PMID- 21600002 TI - Key factors leading to reduced recruitment and retention of health professionals in remote areas of Ghana: a qualitative study and proposed policy solutions. AB - BACKGROUND: The ability of many countries to achieve national health goals such as the Millennium Development Goals remains hindered by inadequate and poorly distributed health personnel, including doctors. The distribution of doctors in Ghana is highly skewed, with a majority serving in two major metropolitan areas (Accra and Kumasi), and inadequate numbers in remote and rural districts. Recent policies increasing health worker salaries have reduced migration of doctors out of Ghana, but made little difference to distribution within the country. This qualitative study was undertaken to understand how practicing doctors and medical leaders in Ghana describe the key factors reducing recruitment and retention of health professionals into remote areas, and to document their proposed policy solutions. METHODS: In-depth interviews were carried out with 84 doctors and medical leaders, including 17 regional medical directors and deputy directors from across Ghana, and 67 doctors currently practicing in 3 regions (Greater Accra, Brong Ahafo, and Upper West); these 3 regions were chosen to represent progressively more remote distances from the capital of Accra. RESULTS AND DISCUSSION: All participants felt that rural postings must have special career or monetary incentives given the loss of locum (i.e. moonlighting income), the higher workload, and professional isolation of remote assignments. Career 'death' and prolonged rural appointments were a common fear, and proposed policy solutions focused considerably on career incentives, such as guaranteed promotion or a study opportunity after some fixed term of service in a remote or hardship area. There was considerable stress placed on the need for rural doctors to have periodic contact with mentors through rural rotation of specialists, or remote learning centers, and reliable terms of appointment with fixed end-points. Also raised, but given less emphasis, were concerns about the adequacy of clinical equipment in remote facilities, and remote accommodations. CONCLUSIONS: In-depth discussions with doctors suggest that while salary is important, it is career development priorities that are keeping doctors in urban centers. Short-term service in rural areas would be more appealing if it were linked to special mentoring and/or training, and led to career advancement. PMID- 21600004 TI - Climate change and climate variability: personal motivation for adaptation and mitigation. AB - BACKGROUND: Global climate change impacts on human and natural systems are predicted to be severe, far reaching, and to affect the most physically and economically vulnerable disproportionately. Society can respond to these threats through two strategies: mitigation and adaptation. Industry, commerce, and government play indispensable roles in these actions but so do individuals, if they are receptive to behavior change. We explored whether the health frame can be used as a context to motivate behavioral reductions of greenhouse gas emissions and adaptation measures. METHODS: In 2008, we conducted a cross sectional survey in the United States using random digit dialing. Personal relevance of climate change from health threats was explored with the Health Belief Model (HBM) as a conceptual frame and analyzed through logistic regressions and path analysis. RESULTS: Of 771 individuals surveyed, 81% (n = 622) acknowledged that climate change was occurring, and were aware of the associated ecologic and human health risks. Respondents reported reduced energy consumption if they believed climate change could affect their way of life (perceived susceptibility), Odds Ratio (OR) = 2.4 (95% Confidence Interval (CI): 1.4-4.0), endanger their life (perceived severity), OR = 1.9 (95% CI: 1.1-3.1), or saw serious barriers to protecting themselves from climate change, OR = 2.1 (95% CI: 1.2-3.5). Perceived susceptibility had the strongest effect on reduced energy consumption, either directly or indirectly via perceived severity. Those that reported having the necessary information to prepare for climate change impacts were more likely to have an emergency kit OR = 2.1 (95% CI: 1.4-3.1) or plan, OR = 2.2 (95% CI: 1.5-3.2) for their household, but also saw serious barriers to protecting themselves from climate change or climate variability, either by having an emergency kit OR = 1.6 (95% CI: 1.1-2.4) or an emergency plan OR = 1.5 (95%CI: 1.0-2.2). CONCLUSIONS: Motivation for voluntary mitigation is mostly dependent on perceived susceptibility to threats and severity of climate change or climate variability impacts, whereas adaptation is largely dependent on the availability of information relevant to climate change. Thus, the climate change discourse could be framed from a health perspective to motivate behaviour change. PMID- 21600003 TI - Ambient pollutants, polymorphisms associated with microRNA processing and adhesion molecules: the Normative Aging Study. AB - BACKGROUND: Particulate air pollution has been associated with cardiovascular morbidity and mortality, but it remains unclear which time windows and pollutant sources are most critical. MicroRNA (miRNA) is thought to be involved in cardiovascular regulation. However, little is known about whether polymorphisms in genes that process microRNAs influence response to pollutant exposure. We hypothesized that averaging times longer than routinely measured one or two day moving averages are associated with higher soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) levels, and that stationary and mobile sources contribute differently to these effects. We also investigated whether single nucleotide polymorphisms (SNPs) in miRNA processing genes modify these associations. METHODS: sICAM-1 and sVCAM-1 were measured from 1999-2008 and matched to air pollution monitoring for fine particulate matter (PM2.5) black carbon, and sulfates (SO42-). We selected 17 SNPs in five miRNA-processing genes. Mixed-effects models were used to assess effects of pollutants, SNPs, and interactions under recessive inheritance models using repeated measures. RESULTS: 723 participants with 1652 observations and 1-5 visits were included in our analyses for black carbon and PM2.5. Sulfate data was available for 672 participants with 1390 observations. An interquartile range change in seven day moving average of PM2.5 (4.27 MUg/m3) was associated with 3.1% (95%CI: 1.6, 4.6) and 2.5% (95%CI: 0.6, 4.5) higher sICAM-1 and sVCAM-1. Interquartile range changes in sulfates (1.39 MUg/m3) were associated with 1.4% higher (95%CI: 0.04, 2.7) and 1.6% (95%CI: -0.4, 3.7) higher sICAM-1 and sVCAM-1 respectively. No significant associations were observed for black carbon. In interaction models with PM2.5, both sICAM-1 and sVCAM-1 levels were lower in rs1062923 homozygous carriers. These interactions remained significant after multiple comparisons adjustment. CONCLUSIONS: PM2.5 seven day moving averages are associated with higher sICAM-1 and sVCAM-1 levels. SO4-2 seven day moving averages are associated with higher sICAM-1 and a suggestive association was observed with sVCAM-1 in aging men. SNPs in miRNA-processing genes may modify associations between ambient pollution and sICAM-1 and sVCAM-1, which are correlates of atherosclerosis and cardiovascular disease. PMID- 21600005 TI - Multiple micronutrient supplementation improves vitamin B12 and folate concentrations of HIV infected children in Uganda: a randomized controlled trial. AB - BACKGROUND: The effect of multiple micronutrient supplementation on vitamin B12 and folate has hither to not been reported in African HIV infected children. This paper describes vitamin B12 and folate status of Ugandan HIV infected children aged 1-5 years and reports the effect of multiple micronutrient supplementation on serum vitamin B12 and folate concentrations. METHODS: Of 847 children who participated in a multiple micronutrient supplementation trial, 214 were assessed for vitamin B12 and folate concentrations pre and post supplementation. One hundred and four children were randomised to two times the recommended dietary allowance (RDA) of a 14 multiple micronutrient supplement (MMS) and 114 to a 'standard of care' supplement of 6 multivitamins (MV). Serum vitamin B12 was measured by an electrochemiluminescence immunoassay and folate by a competitive protein-binding assay using Modular E (Roche) automatic analyzer. Vitamin B12 concentrations were considered low if less than 221 picomoles per litre (pmol/L) and folate if < 13.4 nanomoles per litre (nmol/L). The Wilcoxon Signed Ranks test was used to measure the difference between pre and post supplementation concentrations. RESULTS: Vitamin B12 was low in 60/214 (28%) and folate in 62/214 (29.0%) children. In the MMS group, the median concentration (IQR) of vitamin B12 at 6 months was 401.5 (264.3 - 518.8) pmol/L compared to the baseline of 285.5 (216.5 - 371.8) pmol/L, p < 0.001. The median (IQR) folate concentrations increased from 17.3 (13.5-26.6) nmol/L to 27.7 (21.1-33.4) nmol/L, p < 0.001. In the 'standard of care' MV supplemented group, the median concentration (IQR) of vitamin B12 at 6 months was 288.5 (198.8-391.0) pmol/L compared to the baseline of 280.0 (211.5-386.3) pmol/L while the median (IQR) folate concentrations at 6 months were 16.5 (11.7-22.1) nmol/L compared to 15.7 (11.9-22.1) nmol/L at baseline. There was a significant difference in the MMS group in both vitamin B12 and folate concentrations but no difference in the MV group. CONCLUSIONS: Almost a third of the HIV infected Ugandan children aged 1-5 years had low serum concentrations of vitamin B12 and folate. Multiple micronutrient supplementation compared to the 'standard of care' supplement of 6 multivitamins improved the vitamin B12 and folate status of HIV infected children in Uganda. TRIAL REGISTRATION: http://ClinicalTrials.govNCT00122941). PMID- 21600007 TI - Pathological complete response in advanced gastric stromal tumor after imatinib mesylate therapy: a case report. AB - INTRODUCTION: Gastrointestinal stromal tumors are a rare neoplasm exhibiting, in most cases, mutations of c-kit. Imatinib mesylate is the standard treatment for patients who have advanced gastrointestinal stromal tumors. Although the response rate in patients treated with imatinib mesylate in prospective clinical studies is above 50%, a complete response is very rare. We report the case of a patient with a gastric gastrointestinal stromal tumor who had a pathological complete response after neoadjuvant treatment with imatinib mesylate. CASE PRESENTATION: We report the case of a 54-year-old Arab woman with a gastrointestinal stromal tumor who had a pathological complete response after neoadjuvant treatment with imatinib mesylate. CONCLUSION: The pathological examination of our patient documented a complete pathological response after imatinib therapy. Recently, it has been confirmed that the kinase genotype of KIT and platelet-derived growth factor receptor alpha can accurately predict a good response to imatinib mesylate therapy. We propose that this patient had a mutation conferring high sensitivity to imatinib mesylate. PMID- 21600006 TI - Epithelial thymic tumours in paediatric age: a report from the TREP project. AB - BACKGROUND: Thymic epithelial tumours (thymoma and carcinoma) are exceptionally rare in children. We describe a national multicentre series with a view to illustrating their clinical behaviour and the results of treatment. METHODS: From January 2000 all patients under 18 years of age diagnosed with "rare paediatric tumours" were centrally registered by the Italian centres participating in the TREP project (Tumori Rari in Eta Pediatrica [Rare Tumours in Paediatric Age]). The clinical data of children with a thymic epithelial tumour registered as at December 2009 were analyzed for the purposes of the present study. RESULTS: Our series comprised 4 patients with thymoma and 5 with carcinoma (4 males, 5 females; median age 12.4 years). The tumour masses were mainly large, exceeding 5 cm in largest diameter. Based on the Masaoka staging system, 3 patients were stage I, 1 was stage III, 1 was stage IVa and 4 were stage IVb.All 3 patients with stage I thymoma underwent complete tumour resection at diagnosis and were alive 22, 35 and 93 months after surgery. One patient with a thymoma metastasizing to the kidneys died rapidly due to respiratory failure.Thymic carcinomas were much more aggressive, infiltrating nearby organs (in 4 cases) and regional nodes (in 5), and spreading to the bone (in 3) and liver (in 1). All patients received multidrug chemotherapy (platinum derivatives + etoposide or other drugs) with evidence of tumour reduction in 3 cases. Two patients underwent partial tumour resection (after chemo-radiotherapy in one case) and 4 patients were given radiotherapy (45-54 Gy). All patients died of their disease. CONCLUSIONS: Children with thymomas completely resected at diagnosis have an excellent prognosis while thymic carcinomas behave aggressively and carry a poor prognosis despite multimodal treatment. PMID- 21600008 TI - Osteosarcoma in the distal femur two years after an ipsilateral femoral shaft fracture: a case report. AB - INTRODUCTION: The duration of symptoms preceding a definitive diagnosis of osteosarcoma is quite long. Pathological radiological signs are often evident by the time of diagnosis. Although several case reports have been published on osteosarcoma of the femur, to the best of our knowledge this report is the first one with such an unusual clinical course. CASE PRESENTATION: We describe the case of a 58-year-old Caucasian man who presented with a femoral shaft fracture. Two years post-trauma osteosarcoma in the ipsilateral distal femur was diagnosed. Was it coincidence? We think that the history of the trauma is crucial to answering this question. CONCLUSION: This case report underlines the need to keep up awareness of pathological fractures in emergency medicine and trauma surgery. When radiographs do not raise any suspicion but the history of trauma or the physical examination does, we recommend further radiological and/or histological diagnostic examinations. PMID- 21600009 TI - Gangrenous cholecystitis in an asymptomatic patient found during an elective laparoscopic cholecystectomy: a case report. AB - INTRODUCTION: Gangrenous cholecystitis is a severe complication of acute cholecystitis. We present an unusual case of gangrenous cholecystitis which was totally asymptomatic, with normal pre-operative parameters, and was discovered incidentally during a laparoscopic cholecystectomy. We have not found any similar cases in the published literature. CASE PRESENTATION: A 79-year-old British Caucasian man presented initially with acute cholecystitis which responded to conservative management. After six weeks he was asymptomatic and had normal blood parameters. An elective laparoscopic cholecystectomy was performed and our patient was found to have a totally gangrenous gall bladder. CONCLUSION: It is important to keep a high index of suspicion for the diagnosis of gangrenous cholecystitis in order to avoid potentially serious complications. PMID- 21600010 TI - Parent experiences questionnaire for outpatient child and adolescent mental health services (PEQ-CAMHS Outpatients): reliability and validity following a national survey. AB - ABSTACT: BACKGROUND: Development and evaluation of the PEQ-CAMHS Outpatients, a parent completed questionnaire to measure experiences of outpatient child and adolescent mental health services (CAMHS) in Norway. METHODS: Literature review, parent interviews, pre-testing and a national survey of 17,080 parents of children who received care at one of the 86 outpatient CAMHS in Norway in 2006. Telephone interviews were conducted with a random sample of non-respondents. Levels of missing data, factor structure, internal consistency and construct validity were assessed. RESULTS: 7,906 (46.0%) parents or primary caregivers responded to the questionnaire. Low levels of missing data suggest that the PEQ CAMHS is acceptable. The questionnaire includes three scales supported by the results of factor analysis: relationship with health personnel (8 items), information and participation (4 items), and outcome (3 items). Item-total correlations were all above 0.6 and Cronbach's alpha correlations ranged from 0.88-0.94. The results of comparisons of scale scores with several variables relating to global satisfaction, outcome, cooperation, information, involvement and waiting time support the construct validity of the instrument. CONCLUSIONS: The PEQ-CAMHS Outpatients questionnaire includes important aspects of outpatient CAMHS from the perspective of the parent. It has evidence for data quality, internal consistency and validity and is recommended in surveys of parent experiences of these services. Future research should assess test-retest reliability and further tests of construct validity that include clinical data are recommended. PMID- 21600012 TI - Defining socially-based spatial boundaries in the region of Peel, Ontario, Canada. AB - BACKGROUND: The purpose of the project was to delineate a series of contiguous neighbourhood-based "Data Zones" within the Region of Peel (Ontario) for the purpose of health data analysis and dissemination. Zones were to be built on Census Tracts (N = 205) and obey a series of requirements defined by the Region of Peel. This paper explores a method that combines statistical analysis with ground-truthing, consultation, and the use of a decision tree. DATA: Census Tract data for Peel were derived from the 2006 Canadian Census Master file. METHODS: Following correlation analysis to reduce the data set, Principal Component Analysis was applied to the data set to reduce the complexity and derive an index. The Getis-Ord Gi*statistic was then applied to look for statistically significant clusters of like Census Tracts. A detailed decision tree for the amalgamation of remaining zones and ground-truthing with Peel staff verified the resulting zones. RESULTS: A total of 15 Data Zones that are similar with respect to socioeconomic and sociodemographic attributes and that met criteria defined by Peel were derived for the region. CONCLUSION: The approach used in this analysis, which was bolstered by a series of checks and balances throughout the process, gives statistical validity to the defined zones and resulted in a robust series of Data Zones for use by Peel Public Health. We conclude by offering insight into alternative uses of the methodology, and limitations. PMID- 21600013 TI - Risk of breast cancer following exposure to tetrachloroethylene-contaminated drinking water in Cape Cod, Massachusetts: reanalysis of a case-control study using a modified exposure assessment. AB - BACKGROUND: Tetrachloroethylene (PCE) is an important occupational chemical used in metal degreasing and drycleaning and a prevalent drinking water contaminant. Exposure often occurs with other chemicals but it occurred alone in a pattern that reduced the likelihood of confounding in a unique scenario on Cape Cod, Massachusetts. We previously found a small to moderate increased risk of breast cancer among women with the highest exposures using a simple exposure model. We have taken advantage of technical improvements in publically available software to incorporate a more sophisticated determination of water flow and direction to see if previous results were robust to more accurate exposure assessment. METHODS: The current analysis used PCE exposure estimates generated with the addition of water distribution modeling software (EPANET 2.0) to test model assumptions, compare exposure distributions to prior methods, and re-examine the risk of breast cancer. In addition, we applied data smoothing to examine nonlinear relationships between breast cancer and exposure. We also compared a set of measured PCE concentrations in water samples collected in 1980 to modeled estimates. RESULTS: Thirty-nine percent of individuals considered unexposed in prior epidemiological analyses were considered exposed using the current method, but mostly at low exposure levels. As a result, the exposure distribution was shifted downward resulting in a lower value for the 90th percentile, the definition of "high exposure" in prior analyses. The current analyses confirmed a modest increase in the risk of breast cancer for women with high PCE exposure levels defined by either the 90th percentile (adjusted ORs 1.0-1.5 for 0-19 year latency assumptions) or smoothing analysis cut point (adjusted ORs 1.3-2.0 for 0 15 year latency assumptions). Current exposure estimates had a higher correlation with PCE concentrations in water samples (Spearman correlation coefficient = 0.65, p < 0.0001) than estimates generated using the prior method (0.54, p < 0.0001). CONCLUSIONS: The incorporation of sophisticated flow estimates in the exposure assessment method shifted the PCE exposure distribution downward, but did not meaningfully affect the exposure ranking of subjects or the strength of the association with the risk of breast cancer found in earlier analyses. Thus, the current analyses show a slightly elevated breast cancer risk for highly exposed women, with strengthened exposure assessment and minimization of misclassification by using the latest technology. PMID- 21600011 TI - Inhibition of Hazara nairovirus replication by small interfering RNAs and their combination with ribavirin. AB - BACKGROUND: The genus Nairovirus in the family Bunyaviridae contains 34 tick borne viruses classified into seven serogroups. Hazara virus (HAZV) belongs to the Crimean-Congo hemorrhagic fever (CCHF) serogroup that also includes CCHF virus (CCHFV) a major pathogen for humans. HAZV is an interesting model to study CCHFV due to a close serological and phylogenetical relationship and a classification which allows handling in a BSL2 laboratory. Nairoviruses are characterized by a tripartite negative-sense single stranded RNA genome (named L, M and S segments) that encode the RNA polymerase, the Gn-Gc glycoproteins and the nucleoprotein (NP), respectively. Currently, there are neither vaccines nor effective therapies for the treatment of any bunyavirus infection in humans. In this study we report, for the first time, the use of RNA interference (RNAi) as an approach to inhibit nairovirus replication. RESULTS: Chemically synthesized siRNAs were designed to target the mRNA produced by the three genomic segments. We first demonstrated that the siRNAs targeting the NP mRNA displayed a stronger antiviral effect than those complementary to the L and M transcripts in A549 cells. We further characterized the two most efficient siRNAs showing, that the induced inhibition is specific and associated with a decrease in NP synthesis during HAZV infection. Furthermore, both siRNAs depicted an antiviral activity when used before and after HAZV infection. We next showed that HAZV was sensitive to ribavirin which is also known to inhibit CCHFV. Finally, we demonstrated the additive or synergistic antiviral effect of siRNAs used in combination with ribavirin. CONCLUSIONS: Our study highlights the interest of using RNAi (alone or in combination with ribavirin) to treat nairovirus infection. This approach has to be considered for the development of future antiviral compounds targeting CCHFV, the most pathogenic nairovirus. PMID- 21600014 TI - Therapeutic potential of N-acetylcysteine as an antiplatelet agent in patients with type-2 diabetes. AB - BACKGROUND: Platelet hyperaggregability is a pro-thrombotic feature of type-2 diabetes, associated with low levels of the antioxidant glutathione (GSH). Clinical delivery of N-acetylcysteine (NAC), a biosynthetic precursor of GSH, may help redress a GSH shortfall in platelets, thereby reducing thrombotic risk in type-2 diabetes patients. We investigated the effect of NAC in vitro, at concentrations attainable with tolerable oral dosing, on platelet GSH concentrations and aggregation propensity in blood from patients with type-2 diabetes. METHODS: Blood samples (n = 13) were incubated (2 h, 37 degrees C) with NAC (10-100 micromolar) in vitro. Platelet aggregation in response to thrombin and ADP (whole blood aggregometry) was assessed, together with platelet GSH concentration (reduced and oxidized), antioxidant status, reactive oxygen species (ROS) generation, and plasma NOx (a surrogate measure of platelet-derived nitric oxide; NO). RESULTS: At therapeutically relevant concentrations (10-100 micromolar), NAC increased intraplatelet GSH levels, enhanced the antioxidant effects of platelets, and reduced ROS generation in blood from type-2 diabetes patients. Critically, NAC inhibited thrombin- and ADP-induced platelet aggregation in vitro. Plasma NOx was enhanced by 30 micromolar NAC. CONCLUSIONS: Our results suggest that NAC reduces thrombotic propensity in type-2 diabetes patients by increasing platelet antioxidant status as a result of elevated GSH synthesis, thereby lowering platelet-derived ROS. This may increase bioavailability of protective NO in a narrow therapeutic range. Therefore, NAC might represent an alternative or additional therapy to aspirin that could reduce thrombotic risk in type-2 diabetes. PMID- 21600016 TI - Marked increase in etravirine and saquinavir plasma concentrations during atovaquone/proguanil prophylaxis. AB - The case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with a salvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine and saquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasma concentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, but not with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450. PMID- 21600015 TI - The combined transduction of copper, zinc-superoxide dismutase and catalase mediated by cell-penetrating peptide, PEP-1, to protect myocardium from ischemia reperfusion injury. AB - BACKGROUND: Our previous studies indicate that either PEP-1-superoxide dismutase 1 (SOD1) or PEP-1-catalase (CAT) fusion proteins protects myocardium from ischemia-reperfusion-induced injury in rats. The aim of this study is to explore whether combined use of PEP-1-SOD1 and PEP-1-CAT enhances their protective effects. METHODS: SOD1, PEP-1-SOD1, CAT or PEP-1-CAT fusion proteins were prepared and purified by genetic engineering. In vitro and in vivo effects of these proteins on cell apoptosis and the protection of myocardium after ischemia reperfusion injury were measured. Embryo cardiac myocyte H9c2 cells were used for the in vitro studies. In vitro cellular injury was determined by the expression of lactate dehydrogenase (LDH). Cell apoptosis was quantitatively assessed with Annexin V and PI double staining by Flow cytometry. In vivo, rat left anterior descending coronary artery (LAD) was ligated for one hour followed by two hours of reperfusion. Hemodynamics was then measured. Myocardial infarct size was evaluated by TTC staining. Serum levels of myocardial markers, creatine kinase-MB (CK-MB) and cTnT were quantified by ELISA. Bcl-2 and Bax expression in left ventricle myocardium were analyzed by western blot. RESULTS: In vitro, PEP-1-SOD1 or PEP-1-CAT inhibited LDH release and apoptosis rate of H9c2 cells. Combined transduction of PEP-1-SOD1 and PEP-1-CAT, however, further reduced the LDH level and apoptosis rate. In vivo, combined usage of PEP-1-SOD1 and PEP-1-CAT produced a greater effect than individual proteins on the reduction of CK-MB, cTnT, apoptosis rate, lipoxidation end product malondialdehyde, and the infarct size of myocardium. Functionally, the combination of these two proteins further increased left ventricle systolic pressure, but decreased left ventricle end-diastolic pressure. CONCLUSION: This study provided a basis for the treatment or prevention of myocardial ischemia-reperfusion injury with the combined usage of PEP-1-SOD1 and PEP-1-CAT fusion proteins. PMID- 21600017 TI - Inhibition of mitotic kinase Aurora suppresses Akt-1 activation and induces apoptotic cell death in all-trans retinoid acid-resistant acute promyelocytic leukemia cells. AB - BACKGROUND: Aurora kinase ensures accurate chromosome segregation during cell cycle, maintaining genetic integrity in cell division. VX-680, a small-molecule Aurora kinase inhibitor, interferes with mitotic entry and formation of bipolar spindles. Here, we evaluated VX-680 as a potential agent for treatment of all trans retinoid acid (ATRA)-resistant acute promyelocytic leukemia (APL) in vitro. METHODS: CD11b expression was utilized to assess cell differentiation by flow cytometry. Immunofluorescence staining was conducted to analyze formation of cell monopolar spindle. Cell proliferation was evaluated by MTT assay. Sub-G1 population and Annexin V/PI staining were used to measure cell apoptosis. Hoechst 33342 staining was applied for identifying morphological changes in nucleus of apoptotic cell. Aurora-A (Aur-A) activation and the signaling pathways involved in apoptosis were detected by Western blot. JC-1 probe was employed to measure mitochondrial depolarization. RESULTS: VX-680 inhibited Aur-A by reducing autophosphorylation at the activation site, Thr288, accompanied by producing monopolar mitotic spindles in APL cell line NB4-R2 that was resistant to ATRA. In addition, we found that VX-680 inhibited cell proliferation as assessed by MTT assay. Flow cytometry showed that VX-680 led to apoptotic cell death in both dose and time-dependent manners by either Sub-G1 or Annexin V/PI analysis. Hoechst 33342 staining represented typical apoptotic cells with nuclear fragmentation in VX-680 treated cells. Importantly, VX-680 inhibition of Aurora kinase suppressed Akt-1 activation and induced mitochondrial depolarization, which eventually resulted in apoptosis by activation of caspase pathway, as indicated by increasing proteolytic cleavage of procaspase-3 and poly ADP ribose polymerase (PARP) in NB4-R2 cells. CONCLUSIONS: Our study suggested potential clinical use of mitotic Aurora kinase inhibitor in targeting ATRA-resistant leukemic cells. PMID- 21600018 TI - Palliative radiotherapy in patients with a symptomatic pelvic mass of metastatic colorectal cancer. AB - BACKGROUND: To evaluate the palliative role of radiotherapy (RT) and define the effectiveness of chemotherapy combined with palliative RT (CCRT) in patients with a symptomatic pelvic mass of metastatic colorectal cancer. METHODS: From August 1995 to December 2007, 80 patients with a symptomatic pelvic mass of metastatic colorectal cancer were treated with palliative RT at Samsung Medical Center. Initial presenting symptoms were pain (68 cases), bleeding (18 cases), and obstruction (nine cases). The pelvic mass originated from rectal cancer in 58 patients (73%) and from colon cancer in 22 patients (27%). Initially 72 patients (90%) were treated with surgery, including 64 complete local excisions; 77% in colon cancer and 81% in rectal cancer. The total RT dose ranged 8-60 Gy (median: 36 Gy) with 1.8-8 Gy per fraction. When the alpha/beta for the tumor was assumed to be 10 Gy for the biologically equivalent dose (BED), the median RT dose was 46.8 Gy10 (14.4-78). Twenty one patients (26%) were treated with CCRT. Symptom palliation was assessed one month after the completion of RT. RESULTS: Symptom palliation was achieved in 80% of the cases. During the median follow-up period of five months (1-44 months), 45% of the cases experienced reappearance of symptoms; the median symptom control duration was five months. Median survival after RT was six months. On univariate analysis, the only significant prognostic factor for symptom control duration was BED >=40 Gy10 (p < 0.05), and CCRT was a marginally significant factor (p = 0.0644). On multivariate analysis, BED and CCRT were significant prognostic factors for symptom control duration (p < 0.05). CONCLUSIONS: RT was an effective palliation method in patients with a symptomatic pelvic mass of metastatic colorectal cancer. For improvement of symptom control rate and duration, a BED >= 40 Gy10 is recommended when possible. Considering the low morbidity and improved symptom palliation, CCRT might be considered in patients with good performance status. PMID- 21600019 TI - Evolutionary genomics of the pandemic 2009 H1N1 influenza viruses (pH1N 1v). AB - BACKGROUND: A new strain of human H1N1 influenza A viruses was broken out in the April 2009 and caused worldwide pandemic emergency. The present study is trying to estimate a temporal reassortment history of 2009 H1N1 viruses by phylogenetic analysis based on a total 394 sequences of H1N1viruses isolated from swine, human and avian. RESULTS: Phylogenetic trees of eight gene segments showed that viruses sampled from human formed a well-supported clade, whereas swine and avian lineages were intermixed together. A new divergence swine sublineage containing gene segments of 2009 H1N1 viruses was characterized, which were closely related with swine viruses collected from USA and South Korea during 2004 to 2007 in six segments (PB2, PB1, PA, HA, NP and NS), and to swine viruses isolated from Thailand during 2004 to 2005 in NA and M. Substitution rates were varied drastically among eight segments and the average substitution rate was generally higher in 2009 H1N1 than in swine and human viruses (F2,23 = 5.972, P < 0.01). Similarly, higher dN/dS substitution ratios were identified in 2009 H1N1 than in swine and human viruses except M2 gene (F2, 25 = 3.779, P < 0.05). The ages of 2009 H1N1 viruses were estimated around 0.1 to 0.5 year, while their common ancestors with closest related swine viruses existed between 9.3 and 17.37 years ago. CONCLUSION: Our results implied that at least four reassortments or transmissions probably occurred before 2009 H1N1 viruses. Initial reassortment arose in 1976 and avian-like Eurasian swine viruses emerged. The second transmission happened in Asia and North America between 1988 and 1992, and mostly influenced six segments (PB2, PB1, PA, HA, NP and NS). The third reassortment occurred between North American swine and avian viruses during 1998 to 2000, which involved PB2 and PA segments. Recent reassortments occurred among avian-to swine reassortant, Eurasian and classical swine viruses during 2004 to 2005. South Korea, Thailand and USA, were identified as locations where reassortments most likely happened. The co-circulation of multiple swine sublineages and special lifestyle in Asia might have facilitated mixing of diverse influenza viruses, leading to generate a novel virus strain. PMID- 21600020 TI - Intramuscular immunization of mice with live influenza virus is more immunogenic and offers greater protection than immunization with inactivated virus. AB - BACKGROUND: Influenza virus continues to cause significant hospitalization rates in infants and young children. A 2-dose regime of trivalent inactivated vaccine is required to generate protective levels of hemagglutination inhibiting (HAI) antibodies. A vaccine preparation with enhanced immunogenicity is therefore desirable. METHODS: Mice were inoculated intramuscularly (IM) with live and inactivated preparations of A/Wisconsin/67/2005 (H3N2). Serum cytokine levels, hemagglutinin (HA)-specific antibody responses and nucleoprotein (NP)-specific CD8+ T cell responses were compared between vaccinated groups, as well as to responses measured after intranasal infection. The protective efficacy of each vaccine type was compared by measuring virus titers in the lungs and weight loss of mice challenged intranasally with a heterosubtypic virus, A/PR/8/34 (H1N1). RESULTS: Intramuscular administration of live virus resulted in greater amounts of IFN-alpha, IL-12 and IFN-gamma, HA-specific antibodies, and virus-specific CD8+ T cells, than IM immunization with inactivated virus. These increases corresponded with the live virus vaccinated group having significantly less weight loss and less virus in the lungs on day 7 following challenge with a sublethal dose of a heterosubtypic virus. CONCLUSIONS: Inflammatory cytokines, antibody titers to HA and CD8+ T cell responses were greater to live than inactivated virus delivered IM. These increased responses correlated with greater protection against heterosubtypic virus challenge, suggesting that intramuscular immunization with live influenza virus may be a practical means to increase vaccine immunogenicity and to broaden protection in pediatric populations. PMID- 21600021 TI - A bilberry drink with fermented oatmeal decreases postprandial insulin demand in young healthy adults. AB - BACKGROUND: in traditional medicine, blueberries have been used to facilitate blood glucose regulation in type 2 diabetes. Recent studies in diabetic mice have indicated facilitated glycaemic regulation following dietary supplementation with extracts from European blueberries, also called bilberries, (Vaccinium myrtillus). The purpose of the present study was to investigate the impact of fermented oat meal drinks containing bilberries or rosehip (Rosa canina) on glycaemic and insulinaemic responses. METHODS: glycaemic and insulinaemic responses in young healthy adults were measured in two series. In series 1, two drinks based on oat meal (5%), fermented using Lactobacillus plantarum 299v, and added with fruit (10%); bilberries (BFOMD) or rose hip (RFOMD) respectively, were studied. In series 2, BFOMD was repeated, additionally, a drink enriched with bilberries (47%) was tested (BBFOMD). As control a fermented oat meal drink (FOMD) was served. RESULTS: in series 1 the bilberry- and rosehip drinks, gave high glucose responses similar to that after the reference bread. However, the insulin index (II) after the BFOMD was significantly lower (II = 65) (P < 0.05). In series 2 a favourably low insulin demand to BFOMD was confirmed. FOMD gave high glucose response (GI = 95) but, significantly lower insulin response (II = 76). BBFOMD gave remarkably low insulin response II = 49, and tended to lower glycaemia (GI = 79) (P = 0.0684). CONCLUSION: a fermented oat meal drink added with bilberries induced a lower insulin response than expected from the glycaemic response. The mechanism for the lowered acute insulin demand is still unclear, but may be related to some bio-active component present in the bilberries, or to the fermented oat meal base. PMID- 21600022 TI - Validation of the Netherlands physical activity questionnaire in Brazilian children. AB - BACKGROUND: Physical activity instruments can be subjective or objective. There is a need to assess the reliability of these instruments, especially for researches in children. The aim of this study was to determine the validity of the Netherlands Physical Activity Questionnaire (NPAQ). METHODS: Population under study were Brazilian children aged 4 to 11 years old, enrolled in a population based study. Data collection took place in two distinct moments: 1) application of the NPAQ by face-to-face interviews with mothers' children and 2) utilization of accelerometers by children as the reference method. GT1M Actigraph accelerometer was worn for five consecutive days. Validity analyses were performed by sensitivity and specificity and ROC (Receiver Operator Characteristic) curve. RESULTS: Two hundred and thirty nine children participated in both phases of the study. A total of 73.2% children achieved the recommendation of 60 min/day of moderate to vigorous physical activity. The mean and median of the NPAQ score were 25.5 and 26, respectively. The score ranged from 7 to 35 points. The correlation coefficient between the NPAQ and the time spent in moderate to vigorous physical activities was 0.27. Based on the area under the ROC curve, the median value presented the best indicators of sensitivity (59.4%) and specificity (60.9%), and the area under curve was 0.63. The predictive capacity of the NPAQ to identify active children was high regardless the cut-off point chosen. This capacity was even higher if the score was higher than 30. CONCLUSIONS: Based on sensitivity and specificity values, the NPAQ did not show satisfactory validity. The comparison of the reliability of the NPAQ with other instruments is limited, but correlation coefficients found in this study are similar to others. Physical activity level of children estimated from the NPAQ must be interpreted cautiously, and objective measures such as accelerometers should be encouraged. PMID- 21600023 TI - Optimizing cost-efficiency in mean exposure assessment--cost functions reconsidered. AB - BACKGROUND: Reliable exposure data is a vital concern in medical epidemiology and intervention studies. The present study addresses the needs of the medical researcher to spend monetary resources devoted to exposure assessment with an optimal cost-efficiency, i.e. obtain the best possible statistical performance at a specified budget. A few previous studies have suggested mathematical optimization procedures based on very simple cost models; this study extends the methodology to cover even non-linear cost scenarios. METHODS: Statistical performance, i.e. efficiency, was assessed in terms of the precision of an exposure mean value, as determined in a hierarchical, nested measurement model with three stages. Total costs were assessed using a corresponding three-stage cost model, allowing costs at each stage to vary non-linearly with the number of measurements according to a power function. Using these models, procedures for identifying the optimally cost-efficient allocation of measurements under a constrained budget were developed, and applied on 225 scenarios combining different sizes of unit costs, cost function exponents, and exposure variance components. RESULTS: Explicit mathematical rules for identifying optimal allocation could be developed when cost functions were linear, while non-linear cost functions implied that parts of or the entire optimization procedure had to be carried out using numerical methods.For many of the 225 scenarios, the optimal strategy consisted in measuring on only one occasion from each of as many subjects as allowed by the budget. Significant deviations from this principle occurred if costs for recruiting subjects were large compared to costs for setting up measurement occasions, and, at the same time, the between-subjects to within-subject variance ratio was small. In these cases, non-linearities had a profound influence on the optimal allocation and on the eventual size of the exposure data set. CONCLUSIONS: The analysis procedures developed in the present study can be used for informed design of exposure assessment strategies, provided that data are available on exposure variability and the costs of collecting and processing data. The present shortage of empirical evidence on costs and appropriate cost functions however impedes general conclusions on optimal exposure measurement strategies in different epidemiologic scenarios. PMID- 21600024 TI - Rosiglitazone as an option for patients with acromegaly: a case series. AB - INTRODUCTION: In the patient with acromegaly, pituitary surgery is the therapeutic standard. Despite undergoing surgery, a significant number of patients with acromegaly continue to have uncontrolled growth hormone secretion. These patients require other treatments such as external irradiation and/or drug therapy. CASE PRESENTATION: We present the clinical and laboratory responses to six months of treatment with rosiglitazone in four cases. In all four cases, the patients had persistent growth hormone overproduction despite previous surgical treatment and other conventional therapy. Case 1 is a 57-year-old Caucasian woman, case 2 is a 51-year-old Hispanic man, case 3 is a 32-year-old Hispanic woman, and case 4 is a 36-year-old Hispanic man. In three of these patients, basal and nadir growth hormone and insulin-like growth factor 1 levels were significantly decreased (P < 0.05 and P < 0.01, respectively). CONCLUSION: Rosiglitazone could be a treatment option in select patients with acromegaly. PMID- 21600025 TI - Impact and relationship of anterior commissure and time-dose factor on the local control of T1N0 glottic cancer treated by 6 MV photons. AB - BACKGROUND: To evaluate prognostic factors that may influence local control (LC) of T1N0 glottic cancer treated by primary radiotherapy (RT) with 6 MV photons. METHODS: We retrospectively reviewed the medical records of 433 consecutive patients with T1N0 glottic cancer treated between 1983 and 2005 by RT in our institution. All patients were treated with 6 MV photons. One hundred and seventy seven (41%) patients received 52.5 Gy in 23 fractions with 2.5 Gy/fraction, and 256 (59%) patients received 66 Gy in 33 fractions with 2 Gy/fraction. RESULTS: The median follow-up time was 10.5 years. The 10-year LC rates were 91% and 87% for T1a and T1b respectively. Multivariate analysis showed LC rate was adversely affected by poorly differentiated histology (Hazard Ratio [HR]: 7.5, p = 0.035); involvement of anterior commissure (HR: 2.34, p = 0.011); fraction size of 2.0 Gy (HR: 2.17, p = 0.035) and tumor biologically effective dose (BED) < 65 Gy15 (HR: 3.38, p = 0.017). CONCLUSIONS: The negative impact of anterior commissure involvement could be overcome by delivering a higher tumor BED through using fraction size of > 2.0 Gy. We recommend that fraction size > 2.0 Gy should be utilized, for radiation schedules with five daily fractions each week. PMID- 21600026 TI - Using clinical trial data and linked administrative health data to reduce the risk of adverse events associated with the uptake of newly released drugs by older Australians: a model process. AB - BACKGROUND: The study was undertaken to evaluate the contribution of a process which uses clinical trial data plus linked de-identified administrative health data to forecast potential risk of adverse events associated with the use of newly released drugs by older Australian patients. METHODS: The study uses publicly available data from the clinical trials of a newly released drug to ascertain which patient age groups, gender, comorbidities and co-medications were excluded in the trials. It then uses linked de-identified hospital morbidity and medications dispensing data to investigate the comorbidities and co-medications of patients who suffer from the target morbidity of the new drug and who are the likely target population for the drug. The clinical trial information and the linked morbidity and medication data are compared to assess which patient groups could potentially be at risk of an adverse event associated with use of the new drug. RESULTS: Applying the model in a retrospective real-world scenario identified that the majority of the sample group of Australian patients aged 65 years and over with the target morbidity of the newly released COX-2-selective NSAID rofecoxib also suffered from a major morbidity excluded in the trials of that drug, indicating a substantial potential risk of adverse events amongst those patients. This risk was borne out in post-release morbidity and mortality associated with use of that drug. CONCLUSIONS: Clinical trial data and linked administrative health data can together support a prospective assessment of patient groups who could be at risk of an adverse event if they are prescribed a newly released drug in the context of their age, gender, comorbidities and/or co medications. Communication of this independent risk information to prescribers has the potential to reduce adverse events in the period after the release of the new drug, which is when the risk is greatest.Note: The terms 'adverse drug reaction' and 'adverse drug event' have come to be used interchangeably in the current literature. For consistency, the authors have chosen to use the wider term 'adverse drug event' (ADE). PMID- 21600027 TI - A visible, targeted high-efficiency gene delivery and transfection strategy. AB - BACKGROUND: To enhance myocardial angiogenic gene expression, a novel gene delivery strategy was tested. Direct intramyocardial injection of an angiogenic gene with microbubbles and insonation were applied in a dog animal model. Dogs received one of the four different treatments in conjunction with either the enhanced green fluorescence protein (EGFP) gene or the hepatocyte growth factor (HGF) gene: gene with microbubbles (MB) and ultrasound (US); gene with US; gene with MB; or the gene alone. RESULTS: Distribution of MB and the gene in the myocardium was visualized during the experiment. Compared with the EGFP gene group, an average 14.7-fold enhancement in gene expression was achieved in the EGFP+MB/US group (P < 0.01). Compared with the HGF gene group, an average 10.7 fold enhancement in gene expression was achieved in the HGF+MB/US group (P < 0.01). In addition, capillary density increased from 20.8 +/- 3.4/mm2 in the HGF gene group to 146.7 +/- 31.4/mm2 in HGF+MB/US group (P < 0.01). CONCLUSIONS: Thus, direct intramyocardial injection of an angiogenic gene in conjunction with microbubbles plus insonation synergistically enhances angiogenesis. This method offers an observable gene delivery procedure with enhanced expression efficiency of the delivered gene. PMID- 21600028 TI - Use of tranexamic acid is a cost effective method in preventing blood loss during and after total knee replacement. AB - BACKGROUND & PURPOSE: Allogenic blood transfusion in elective orthopaedic surgery is best avoided owing to its associated risks. Total knee replacement often requires blood transfusion, more so when bilateral surgery is performed. Many strategies are currently being employed to reduce the amount of peri-operative allogenic transfusions. Anti-fibrinolytic compounds such as aminocaproic acid and tranexamic acid have been used systemically in perioperative settings with promising results. This study aimed to evaluate the effectiveness of tranexamic acid in reducing allogenic blood transfusion in total knee replacement surgery. METHODOLOGY: This was a retrospective cohort study conducted on patients undergoing total knee replacement during the time period November 2005 to November 2008. Study population was 99 patients, of which 70 underwent unilateral and 29 bilateral knee replacement. Forty-seven patients with 62 (49.5%) knees (group-I) had received tranexamic acid (by surgeon preference) while the remaining fifty-two patients with 66 (51.5%) knees (group-II) had did not received any tranexamic acid either pre- or post-operatively. RESULTS: The mean drop in the post-operative haemoglobin concentration in Group-II for unilateral and bilateral cases was 1.79 gm/dl and 2.21 gm/dl, with a mean post-operative drainage of 1828 ml (unilateral) and 2695 ml (bilateral). In comparison, the mean drop in the post-op haemoglobin in Group-I was 1.49 gm/dl (unilateral) and 1.94 gm/dl (bilateral), with a mean drainage of 826 ml (unilateral) and 1288 ml (bilateral) (p-value < 0.001). INTERPRETATION: Tranexamic acid is effective in reducing post-operative drainage and requirement of blood transfusion after knee replacement. PMID- 21600029 TI - Normalization and centering of array-based heterologous genome hybridization based on divergent control probes. AB - BACKGROUND: Hybridization of heterologous (non-specific) nucleic acids onto arrays designed for model-organisms has been proposed as a viable genomic resource for estimating sequence variation and gene expression in non-model organisms. However, conventional methods of normalization that assume equivalent distributions (such as quantile normalization) are inappropriate when applied to non-specific (heterologous) hybridization. We propose an algorithm for normalizing and centering intensity data from heterologous hybridization that makes no prior assumptions of distribution, reduces the false appearance of homology, and provides a way for researchers to confirm whether heterologous hybridization is suitable. RESULTS: Data are normalized by adjusting for Gibbs free energy binding, and centered by adjusting for the median of a common set of control probes assumed to be equivalently dissimilar for all species. This procedure was compared to existing approaches and found to be as successful as Loess normalization at detecting sequence variations (deletions) and even more successful than quantile normalization at reducing the accumulation of false positive probe matches between two related nematode species, Caenorhabditis elegans and C. briggsae. Despite the improvements, we still found that probe fluorescence intensity was too poorly correlated with sequence similarity to result in reliable detection of matching probe sequence. CONCLUSIONS: Cross species hybridizations can be a way to adapt genome-enabled tools for closely related non-model organisms, but data must be appropriately normalized and centered in a way that accommodates hybridization of nucleic acids with diverged sequence. For short, 25-mer probes, hybridization intensity alone may be insufficiently correlated with sequence similarity to allow reliable inference of homology at the probe level. PMID- 21600030 TI - Loss of correction in unstable comminuted distal radius fractures with external fixation and bone grafting--a long term followup study. AB - Over the years, management of complex distal radius fractures by closed means has often failed leading to late collapse. We have chosen the principle of ligamentotaxis using external fixation and bone grafting in this study to prevent late complications. Eighty one patients with complex distal radius fractures belonging to Type IV A, IV B, IV C of Universal classification were treated with an AO external fixator between 1995 and 2001. Mean age group was 38. 47 years with longest follow up of 7 years. Bone grafting was done primarily in 20 patients and early grafting (within 3 weeks) in 5 patients. Statistically significant differences were observed between the two groups(with or without bone grafting) with respect to postoperative values of (radial length, radial tilt and volar tilt). Results were assessed based on Sarmientos criteria. 56 patients had excellent results, 9 had good results and 16 had poor results. Late collapse with decreased radial length was observed in 18 patients who did not undergo bone grafting. Mean grip strength was 63 percent. Osteoarthritic changes were noted in 20 patients. We conclude that accurate anatomic reduction is necessary for achieving good to excellent functional and cosmetic results. Bone grafting is the mainstay of treatment in comminuted distal radius fractures along with fracture stabilisation. PMID- 21600031 TI - Reduced short term adaptation to robot generated dynamic environment in children affected by Cerebral Palsy. AB - BACKGROUND: It is known that healthy adults can quickly adapt to a novel dynamic environment, generated by a robotic manipulandum as a structured disturbing force field. We suggest that it may be of clinical interest to evaluate to which extent this kind of motor learning capability is impaired in children affected by cerebal palsy. METHODS: We adapted the protocol already used with adults, which employs a velocity dependant viscous field, and compared the performance of a group of subjects affected by Cerebral Palsy (CP group, 7 subjects) with a Control group of unimpaired age-matched children. The protocol included a familiarization phase (FA), during which no force was applied, a force field adaptation phase (CF), and a wash-out phase (WO) in which the field was removed. During the CF phase the field was shut down in a number of randomly selected "catch" trials, which were used in order to evaluate the "learning index" for each single subject and the two groups. Lateral deviation, speed and acceleration peaks and average speed were evaluated for each trajectory; a directional analysis was performed in order to inspect the role of the limb's inertial anisotropy in the different experimental phases. RESULTS: During the FA phase the movements of the CP subjects were more curved, displaying greater and variable directional error; over the course of the CF phase both groups showed a decreasing trend in the lateral error and an after-effect at the beginning of the wash-out, but the CP group had a non significant adaptation rate and a lower learning index, suggesting that CP subjects have reduced ability to learn to compensate external force. Moreover, a directional analysis of trajectories confirms that the control group is able to better predict the force field by tuning the kinematic features of the movements along different directions in order to account for the inertial anisotropy of arm. CONCLUSIONS: Spatial abnormalities in children affected by cerebral palsy may be related not only to disturbance in motor control signals generating weakness and spasticity, but also to an inefficient control strategy which is not based on a robust knowledge of the dynamical features of their upper limb. This lack of information could be related to the congenital nature of the brain damage and may contribute to a better delineation of therapeutic intervention. PMID- 21600032 TI - Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome. AB - The IFAP syndrome is a rare X-linked genetic disorder reported in nearly 40 patients. It is characterized by the triad of Ichthyosis Follicularis, Alopecia, and Photophobia from birth. Other features such as short stature, intellectual disability, and seizures may develop in the first few years of life. Skin histopathology is non-specific and consists of dilated hair follicles with keratin plugs extending above the surface of the skin, decreased or absent sebaceous glands, and decreased desmosomes in number and size. The disorder results from mutations in the MBTPS2 gene that impairs cholesterol homeostasis and the ability to cope with endoplasmic reticulum stress. Follicular hyperkeratosis can be treated using topical keratolytics, emollients and urea preparations. A moderate response to acitretin therapy has been noted in some patients. Intensive lubrication of the ocular surface is essential. Life expectancy in patients with IFAP syndrome can vary from death in the neonatal period to normal surviving. Cardiopulmonary complications remain the major cause of death. PMID- 21600033 TI - SuiteMSA: visual tools for multiple sequence alignment comparison and molecular sequence simulation. AB - BACKGROUND: Multiple sequence alignment (MSA) plays a central role in nearly all bioinformatics and molecular evolutionary applications. MSA reconstruction is thus one of the most heavily scrutinized bioinformatics fields. Evaluating the quality of MSA reconstruction is often hindered by the lack of good reference MSAs. The use of sequence evolution simulation can provide such reference MSAs. Furthermore, none of the MSA viewing/editing programs currently available allows the user to make direct comparisons between two or more MSAs. Considering the importance of MSA quality in a wide range of research, it is desirable if MSA assessment can be performed more easily. RESULTS: We have developed SuiteMSA, a java-based application that provides unique MSA viewers. Users can directly compare multiple MSAs and evaluate where the MSAs agree (are consistent) or disagree (are inconsistent). Several alignment statistics are provided to assist such comparisons. SuiteMSA also includes a graphical phylogeny editor/viewer as well as a graphical user interface for a sequence evolution simulator that can be used to construct reference MSAs. CONCLUSIONS: SuiteMSA provides researchers easy access to a sequence evolution simulator, reference alignments generated by the simulator, and a series of tools to evaluate the performance of the MSA reconstruction programs. It will help us improve the quality of MSAs, often the most important first steps of bioinformatics and other biological research. PMID- 21600034 TI - Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis? AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare lung disease characterised by progressive airflow obstruction. No effective medical treatment is available but therapy with sirolimus has shown some promise. The aim of this observational study was to evaluate sirolimus in progressive LAM. METHODS: Sirolimus (trough level 5 - 10 ng/ml) was administered to ten female patients (42.4 +/- 11.9 years) with documented progression. Serial pulmonary function tests and six-minute-walk distance (6-MWD) assessments were performed. RESULTS: The mean loss of FEV1 was 2.30 +/- 0.52 ml/day before therapy and a significant mean gain of FEV1 of 1.19 +/- 0.26 ml/day was detected during treatment (p = 0.001). Mean FEV1 and FVC at baseline were 1.12 +/- 0.15 l (36.1 +/- 4.5%pred.) and 2.47 +/- 0.25 l (69.2 +/- 6.5%pred.), respectively. At three and six months during follow-up a significant increase of FEV1 and FVC was demonstrated (3 months DeltaFEV1: 220 +/- 82 ml, p = 0.024; 6 months DeltaFEV1: 345 +/- 58 ml, p = 0.001); (3 months DeltaFVC: 360 +/- 141 ml, p = 0.031; 6 months DeltaFVC: 488 +/- 138 ml, p = 0.006). Sirolimus was discontinued in 3 patients because of serious recurrent lower respiratory tract infection or sirolimus-induced pneumonitis. No deaths and no pneumothoraces occurred during therapy. CONCLUSIONS: Our data suggest that sirolimus might be considered as a therapeutic option in rapidly declining LAM patients. However, sirolimus administration may be associated with severe respiratory adverse events requiring treatment cessation in some patients. Moreover, discontinuation of sirolimus is mandatory prior to lung transplantation. PMID- 21600035 TI - Respiratory and mental health effects of wildfires: an ecological study in Galician municipalities (north-west Spain). AB - BACKGROUND: During the summer of 2006, a wave of wildfires struck Galicia (north west Spain), giving rise to a disaster situation in which a great deal of the territory was destroyed. Unlike other occasions, the wildfires in this case also threatened farms, houses and even human lives, with the result that the perception of disaster and helplessness was the most acute experienced in recent years. This study sought to analyse the respiratory and mental health effects of the August-2006 fires, using consumption of anxiolytics-hypnotics and drugs for obstructive airway diseases as indicators. METHODS: We conducted an analytical, ecological geographical- and temporal-cluster study, using municipality-month as the study unit. The independent variable was exposure to wildfires in August 2006, with municipalities thus being classified into the following three categories: no exposure; medium exposure; and high exposure. Dependent variables were: (1) anxiolytics-hypnotics; and (2) drugs for obstructive airway diseases consumption. These variables were calculated for the two 12-month periods before and after August 2006. Additive models for time series were used for statistical analysis purposes. RESULTS: The results revealed a higher consumption of drugs for obstructive airway diseases among pensioners during the months following the wildfires, in municipalities affected versus those unaffected by fire. In terms of consumption of anxiolytics-hypnotics, the results showed a significant increase among men among men overall -pensioners and non-pensioners- in fire affected municipalities. CONCLUSIONS: Our study indicates that wildfires have a significant effect on population health. The coherence of these results suggests that drug utilisation research is a useful tool for studying morbidity associated with environmental incidents. PMID- 21600036 TI - Unleashing their potential: a critical realist scoping review of the influence of dogs on physical activity for dog-owners and non-owners. AB - BACKGROUND: Dog-owners tend to be more physically active than non-owners; however, dogs have also been shown to inhibit physical activity for non-owners, under some circumstances. METHODS: We conducted a scoping review to identify studies pertaining to the influence of dogs on physical activity for both dog owners and non-owners, and adopted a critical realist orientation to draw inferences about the positive and negative impact of dogs via their affect on physical and social environments. RESULTS: We identified 35 studies from disparate literatures for review. These studies confirm that dog and owner behaviors affect shared physical and social environments in ways that may influence physical activity patterns, not only among dog-owners but also among non-owners. The direction of influence appears to be most positive in neighborhoods exhibiting high levels of social cohesion, socioeconomic status, perceived safety, dominant culture, or all of these. In disadvantaged neighborhoods, the health of women as well as older adults may be disproportionately affected by dog and owner behavior. CONCLUSIONS: While dogs have the potential to increase physical activity for both dog-owners and non owners, the presence or absence of dogs will not have a standard effect across the physical and social environments of all neighborhoods. Dogs' contributions to shared environments in ways that support physical activity for all must be leveraged. Thus, specific contextual factors must be considered in relation to dogs when planning neighborhood-level interventions designed to support physical activity. We suggest this population health topic merits further investigation. PMID- 21600037 TI - Rapid identification and quantification of Campylobacter coli and Campylobacter jejuni by real-time PCR in pure cultures and in complex samples. AB - BACKGROUND: Campylobacter spp., especially Campylobacter jejuni (C. jejuni) and Campylobacter coli (C. coli), are recognized as the leading human foodborne pathogens in developed countries. Livestock animals carrying Campylobacter pose an important risk for human contamination. Pigs are known to be frequently colonized with Campylobacter, especially C. coli, and to excrete high numbers of this pathogen in their faeces. Molecular tools, notably real-time PCR, provide an effective, rapid, and sensitive alternative to culture-based methods for the detection of C. coli and C. jejuni in various substrates. In order to serve as a diagnostic tool supporting Campylobacter epidemiology, we developed a quantitative real-time PCR method for species-specific detection and quantification of C. coli and C. jejuni directly in faecal, feed, and environmental samples. RESULTS: With a sensitivity of 10 genome copies and a linear range of seven to eight orders of magnitude, the C. coli and C. jejuni real-time PCR assays allowed a precise quantification of purified DNA from C. coli and C. jejuni. The assays were highly specific and showed a 6-log-linear dynamic range of quantification with a quantitative detection limit of approximately 2.5 * 102 CFU/g of faeces, 1.3 * 102 CFU/g of feed, and 1.0 * 103 CFU/m2 for the environmental samples. Compared to the results obtained by culture, both C. coli and C. jejuni real-time PCR assays exhibited a specificity of 96.2% with a kappa of 0.94 and 0.89 respectively. For faecal samples of experimentally infected pigs, the coefficients of correlation between the C. coli or C. jejuni real-time PCR assay and culture enumeration were R2 = 0.90 and R2 = 0.93 respectively. CONCLUSION: The C. coli and C. jejuni real-time quantitative PCR assays developed in this study provide a method capable of directly detecting and quantifying C. coli and C. jejuni in faeces, feed, and environmental samples. These assays represent a new diagnostic tool for studying the epidemiology of Campylobacter by, for instance, investigating the carriage and excretion of C. coli and C. jejuni by pigs from conventional herds. PMID- 21600038 TI - Effect of haemoglobin concentration on the clinical outcomes in patients with acute myocardial infarction and the factors related to haemoglobin. AB - BACKGROUND: The impact of haemoglobin concentrations on clinical outcomes is still a controversial issue. To determine the association between haemoglobin concentrations on admission and clinical outcomes and the related factors, this study was performed in a Chinese hospital. FINDINGS: We conducted a retrospective study on 1394 Chinese patients with acute myocardial infarction. Patients were categorized according to the haemoglobin concentration on admission, and data were evaluated to determine whether there was an association between the haemoglobin concentrations on admission and 30-day in-hospital MACEs (major cardiovascular events). Patients with hemoglobin values between 141 and 150 g/L were used as the reference, the MACEs increased as hemoglobin concentrations fell below 140 g/L or rose > 150 g/L, with an adjusted OR (odds ratio) of 5.96[95% CI (confidence interval) 2.00 to 17.68, p = 0.0013], 4.39(1.37 to 14.08, p = 0.0128), 3.99(1.46 to 10.92, p = 0.0071), 3.19(1.27 to 8.05, p = 0.0139), 2.37(0.94 to 6.01, p = 0.0687), 2.11(0.66 to 6.74, p = 0.2065), 2.01(0.60 to 6.68, p = 0.2559) in patients with haemoglobin concentrations <100 g/L, 101-110 g/L, 111-120 g/L, 121-130 g/L, 131-140 g/L, 151-160 g/L, and >160 g/L respectively. Partial correlation analysis showed that age, albumin and creatinine were significantly associated with hemoglobin concentration. CONCLUSIONS: Our results demonstrated that haemoglobin concentration affected MACEs in patients with acute myocardial infarction, and that haemoglobin concentration was associated with age, albumin and creatinine. PMID- 21600039 TI - Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells. AB - BACKGROUND: HOX genes encode a family of homeodomain-containing transcription factors involved in the determination of cell fate and identity during embryonic development. They also behave as oncogenes in some malignancies. RESULTS: In this study, we found high expression of the HOXD9 gene transcript in glioma cell lines and human glioma tissues by quantitative real-time PCR. Using immunohistochemistry, we observed HOXD9 protein expression in human brain tumor tissues, including astrocytomas and glioblastomas. To investigate the role of HOXD9 in gliomas, we silenced its expression in the glioma cell line U87 using HOXD9-specific siRNA, and observed decreased cell proliferation, cell cycle arrest, and induction of apoptosis. It was suggested that HOXD9 contributes to both cell proliferation and/or cell survival. The HOXD9 gene was highly expressed in a side population (SP) of SK-MG-1 cells that was previously identified as an enriched-cell fraction of glioma cancer stem-like cells. HOXD9 siRNA treatment of SK-MG-1 SP cells resulted in reduced cell proliferation. Finally, we cultured human glioma cancer stem cells (GCSCs) from patient specimens found with high expression of HOXD9 in GCSCs compared with normal astrocyte cells and neural stem/progenitor cells (NSPCs). CONCLUSIONS: Our results suggest that HOXD9 may be a novel marker of GCSCs and cell proliferation and/or survival factor in gliomas and glioma cancer stem-like cells, and a potential therapeutic target. PMID- 21600040 TI - Screening of soy protein-derived hypotriglyceridemic di-peptides in vitro and in vivo. AB - BACKGROUND: Soy protein and soy peptides have attracted considerable attention because of their potentially beneficial biological properties, including antihypertensive, anticarcinogenic, and hypolipidemic effects. Although soy protein isolate contains several bioactive peptides that have distinct physiological activities in lipid metabolism, it is not clear which peptide sequences are responsible for the triglyceride (TG)-lowering effects. In the present study, we investigated the effects of soy protein-derived peptides on lipid metabolism, especially TG metabolism, in HepG2 cells and obese Otsuka Long Evans Tokushima fatty (OLETF) rats. RESULTS: In the first experiment, we found that soy crude peptide (SCP)-LD3, which was prepared by hydrolyze of soy protein isolate with endo-type protease, showed hypolipidemic effects in HepG2 cells and OLETF rats. In the second experiment, we found that hydrophilic fraction, separated from SCP-LD3 with hydrophobic synthetic absorbent, revealed lipid lowering effects in HepG2 cells and OLETF rats. In the third experiment, we found that Fraction-C (Frc-C) peptides, fractionated from hydrophilic peptides by gel permeation chromatography-high performance liquid chromatography, significantly reduced TG synthesis and apolipoprotein B (apoB) secretion in HepG2 cells. In the fourth experiment, we found that the fraction with 0.1% trifluoroacetic acid, isolated from Frc-C peptides by octadecylsilyl column chromatography, showed hypolipidemic effects in HepG2 cells. In the final experiment, we found that 3 di peptides, Lys-Ala, Val-Lys, and Ser-Tyr, reduced TG synthesis, and Ser-Tyr additionally reduced apoB secretion in HepG2 cells. CONCLUSION: Novel active peptides with TG-lowering effects from soy protein have been isolated. PMID- 21600042 TI - The use of beta-tricalcium phosphate bone graft substitute in dorsally plated, comminuted distal radius fractures. AB - BACKGROUND: Intraarticular distal radius fractures can be treated with many methods. While internal fixation with angle stable implants has become increasingly popular, the use of bone graft substitutes has also been recommended to address comminution zones and thus increase stability. Whether a combination of both methods will improve clinical outcomes was the purpose of the study METHODS: The study was thus conducted as a prospective randomized clinical trial. 39 patients with unilateral, intraarticular fractures of the distal radius were included and randomized to 2 groups, one being treated with internal fixation only, while the second group received an additional bone graft substitute. RESULTS: There was no statistical significance between both groups in functional and radiological results. The occurrence of complications did also not show statistical significance. CONCLUSIONS: No advantage of additional granular bone graft substitutes could be seen in this study. Granular bone graft substitutes do not seem to provide extra stability if dorsal angle stable implants are used. Dorsal plates have considerable complication rates such as extensor tendon ruptures and development of CRPS. PMID- 21600041 TI - Circulating levels of cell adhesion molecule L1 as a prognostic marker in gastrointestinal stromal tumor patients. AB - BACKGROUND: L1 cell adhesion molecule (CD171) is expressed in many malignant tumors and its expression correlates with unfavourable outcome. It thus represents a target for tumor diagnosis and therapy. An earlier study conducted by our group identified L1 expression levels in primary gastrointestinal stromal tumors (GIST) as a prognostic marker. The aim of the current study was to compare L1 serum levels of GIST patients with those of healthy controls and to determine whether levels of soluble L1 in sera could serve as a prognostic marker. METHODS: Using a sensitive enzyme-linked immunosorbent assay (ELISA), soluble L1 was measured in sera of 93 GIST patients und 151 healthy controls. Soluble L1 levels were then correlated with clinicopathological data. RESULTS: Median levels of soluble L1 were significantly higher (p < 0.001; Mann-Whitney U test) in sera of GIST patients compared to healthy individuals. Median soluble L1 levels were particularly elevated in patients with recurrence and relapse (p < 0.05; Mann Whitney U test). CONCLUSION: These results suggest that high soluble L1 levels predict poor prognosis and may thus be a promising tumor marker that can contribute to individualise therapy. PMID- 21600043 TI - A polymorphism in the regulatory region of PRNP is associated with increased risk of sporadic Creutzfeldt-Jakob disease. AB - BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a rare transmissible neurodegenerative disorder. An important determinant for CJD risk and phenotype is the M129V polymorphism of the human prion protein gene (PRNP), but there are also other coding and non-coding polymorphisms inside this gene. METHODS: We tested whether three non-coding polymorphism located inside the PRNP regulatory region (C-101G, G310C and T385C) were associated with risk of CJD and with age at onset in a United Kingdom population-based sample of 131 sporadic CJD (sCJD) patients and 194 controls. RESULTS: We found no disease association for either PRNP C-101G or PRNP T385C. Although the crude analysis did not show a significant association between PRNP G310C and sCJD (OR: 1.5; 95%CI = 0.7 to 2.9), after adjusting by PRNP M129V genotype, it resulted that being a C allele carrier at PRNP G310C was significantly (p = 0.03) associated with a 2.4 fold increased risk of developing sCJD (95%CI = 1.1 to 5.4). Additionally, haplotypes carrying PRNP 310C coupled with PRNP 129M were significantly overrepresented in patients (p = 0.02) compared to controls. Cases of sCJD carrying a PRNP 310C allele presented at a younger age (on average 8.9 years younger than those without this allele), which was of statistical significance (p = 0.05). As expected, methionine and valine homozygosity at PRNP M129V increased significantly the risk of sCJD, alone and adjusted by PRNP G310C (OR MM/MV = 7.3; 95%CI 3.9 to 13.5 and OR VV/MV = 4.0; 95%CI 1.7 to 9.3). CONCLUSIONS: Our findings support the hypothesis that genetic variations in the PRNP promoter may have a role in the pathogenesis of sCJD. PMID- 21600044 TI - Exhaled breath condensate pH as a biomarker of COPD severity in ex-smokers. AB - Endogenous airway acidification, as assessed by exhaled breath condensate (EBC) pH, is present in patients with stable COPD. The aim of this study was to measure EBC pH levels in a large cohort of COPD patients and to evaluate associations with functional parameters according to their smoking status.EBC was collected from 161 patients with stable COPD and 112 controls (current and ex-smokers). EBC pH was measured after Argon deaeration and all subjects underwent pulmonary function testing.EBC pH was lower in COPD patients compared to controls [7.21 (7.02, 7.44) vs. 7.50 (7.40, 7.66); p < 0.001] and ex-smokers with COPD had lower EBC pH compared to current smokers [7.16 (6.89, 7.36) vs 7.24 (7.09, 7.54), p = 0.03]. In ex-smokers with COPD, EBC pH was lower in patients with GOLD stage III and IV compared to patients with stage I disease (p = 0.026 and 0.004 respectively). No differences were observed among current smokers with different disease severity. EBC pH levels in ex-smokers were associated with static hyperinflation (as expressed by IC/TLC ratio), air trapping (as expressed by RV/TLC ratio) and diffusing capacity for carbon monoxide, whereas no associations were observed in current smokers.Endogenous airway acidification is related to disease severity and to parameters expressing hyperinflation and air trapping in ex-smokers with COPD. The possible role of EBC pH in COPD needs to be further evaluated in longitudinal studies. PMID- 21600045 TI - Current use and barriers and facilitators for implementation of standardised measures in physical therapy in the Netherlands. AB - BACKGROUND: In many countries, the need for physical therapists to use standardised measures has been recognised and is recommended in clinical practice guidelines. Research has shown a lack of clinimetric knowledge and clinical application of measurement instruments in daily practice may hamper implementation of these guidelines. OBJECTIVES: The aims of our study were a) to investigate the current use of measurement instruments by Dutch physical therapists; b) to investigate the facilitators and barriers in using measurement instruments. METHODS: To get a complete and valid overview of relevant barriers and facilitators, different methods of data collection were used. We conducted a literature search, semi-structured interviews with 20 physical therapists and an online survey. RESULTS: Facilitators are the fact that most therapists indicated a positive attitude and were convinced of the advantages of the use of measurement instruments. The most important barriers to the use of measurement instruments included physical therapists' competence and problems in changing behaviour, practice organisation (no room; no time) and the unavailability and feasibility of measurement instruments. Furthermore, physical therapists indicated the need to have a core set of measurement instruments with a short user's instruction on application, scoring and interpretation. CONCLUSIONS: The main barriers are on the level of the physical therapist (lack of knowledge; not focusing on the use of outcome measures) and organisation (lack of time; availability; lack of management support).There seems to be a disparity between what physical therapists say and what they do. The majority of participating physical therapists indicated a positive attitude and were convinced of the advantages of the use of measurement instruments. However, the main problem for physical therapists is when to use which instrument for what patient (lack of knowledge). Furthermore, physical therapists indicated a need to compile a core set of measurement instruments with instructions concerning application, scoring and interpretation. Based on the identified factors, a number of strategies will be developed and evaluated in future studies. PMID- 21600046 TI - Elevated soluble cellular adhesion molecules are associated with increased mortality in a prospective cohort of renal transplant recipients. AB - BACKGROUND: Increased plasma levels of cellular adhesion molecules (CAMs) have been shown to be predictors of all cause mortality in individuals with chronic renal failure 12 and patients with end-stage renal disease receiving haemodialysis 3. In renal transplant recipients the predictive value of CAMs has not been well characterised. The aim of this study was to assess the relationship between CAMs and all-cause mortality during prospective follow-up of a renal transplant cohort. METHODS: A total of 378 renal transplant recipients were recruited between June 2000 and December 2002. Soluble vascular CAM-1 (VCAM) and soluble intercellular CAM-1 (ICAM) were measured at baseline and prospective follow-up data was collected at a median of 2441 days after enrolment. RESULTS: In univariate survival analysis the renal transplant recipients with a VCAM or ICAM concentration in the lowest third were significantly more likely to have survived at follow-up (p < 0.001 and p = 0.009 respectively). In multivariate survival analysis VCAM and ICAM remained significant independent predictors of mortality following adjustment for traditional cardiovascular risk factors, hsCRP and estimated GFR (p = 0.030 and p = 0.037 respectively). CONCLUSIONS: The results of this prospective study are the first to show that the CAMs, ICAM and particularly VCAM, are significant independent predictors of mortality in patients with a renal transplant. PMID- 21600047 TI - BUDDY-system: A web site for constructing a dataset of protein pairs between ligand-bound and unbound states. AB - BACKGROUND: Elucidating molecular recognition by proteins, such as in enzyme substrate and receptor-ligand interactions, is a key to understanding biological phenomena. To delineate these protein interactions, it is important to perform structural bioinformatics studies relevant to molecular recognition. Such studies require a dataset of protein structure pairs between ligand-bound and unbound states. In many studies, the same well-designed and high-quality dataset has been used repeatedly, which has spurred the development of subsequent relevant research. Using previously constructed datasets, researchers are able to fairly compare obtained results with those of other studies; in addition, much effort and time is saved. Therefore, it is important to construct a refined dataset that will appeal to many researchers. However, constructing such datasets is not a trivial task. FINDINGS: We have developed the BUDDY-system, a web site designed to support the building of a dataset comprising pairs of protein structures between ligand-bound and unbound states, which are widely used in various areas associated with molecular recognition. In addition to constructing a dataset, the BUDDY-system also allows the user to search for ligand-bound protein structures by its unbound state or by its ligand; and to search for ligands by a particular receptor protein. CONCLUSIONS: The BUDDY-system receives input from the user as a single entry or a dataset consisting of a list of ligand-bound state protein structures, unbound state protein structures, or ligands and returns to the user a list of protein structure pairs between the ligand-bound and the corresponding unbound states. This web site is designed for researchers who are involved not only in structural bioinformatics but also in experimental studies. The BUDDY system is freely available on the web. PMID- 21600048 TI - The SmartHand transradial prosthesis. AB - BACKGROUND: Prosthetic components and control interfaces for upper limb amputees have barely changed in the past 40 years. Many transradial prostheses have been developed in the past, nonetheless most of them would be inappropriate if/when a large bandwidth human-machine interface for control and perception would be available, due to either their limited (or inexistent) sensorization or limited dexterity. SmartHand tackles this issue as is meant to be clinically experimented in amputees employing different neuro-interfaces, in order to investigate their effectiveness. This paper presents the design and on bench evaluation of the SmartHand. METHODS: SmartHand design was bio-inspired in terms of its physical appearance, kinematics, sensorization, and its multilevel control system. Underactuated fingers and differential mechanisms were designed and exploited in order to fit all mechatronic components in the size and weight of a natural human hand. Its sensory system was designed with the aim of delivering significant afferent information to the user through adequate interfaces. RESULTS: SmartHand is a five fingered self-contained robotic hand, with 16 degrees of freedom, actuated by 4 motors. It integrates a bio-inspired sensory system composed of 40 proprioceptive and exteroceptive sensors and a customized embedded controller both employed for implementing automatic grasp control and for potentially delivering sensory feedback to the amputee. It is able to perform everyday grasps, count and independently point the index. The weight (530 g) and speed (closing time: 1.5 seconds) are comparable to actual commercial prostheses. It is able to lift a 10 kg suitcase; slippage tests showed that within particular friction and geometric conditions the hand is able to stably grasp up to 3.6 kg cylindrical objects. CONCLUSIONS: Due to its unique embedded features and human size, the SmartHand holds the promise to be experimentally fitted on transradial amputees and employed as a bi-directional instrument for investigating -during realistic experiments- different interfaces, control and feedback strategies in neuro-engineering studies. PMID- 21600049 TI - Treatment of malignant sinonasal tumours with intensity-modulated radiotherapy (IMRT) and carbon ion boost (C12). AB - BACKGROUND: Most patients with cancers of the nasal cavity or paranasal sinuses are candidates of radiation therapy either due incomplete resection or technical inoperability. Local control in this disease is dose dependent but technically challenging due to close proximity of critical organs and accompanying toxicity. Modern techniques such as IMRT improve toxicity rates while local control remains unchanged. Raster-scanned carbon ion therapy with highly conformal dose distributions may allow higher doses at comparable or reduced side-effects. METHODS/DESIGN: The IMRT-HIT-SNT trial is a prospective, mono-centric, phase II trial evaluating toxicity (primary endpoint: mucositis >= CTCAE degrees III) and efficacy (secondary endpoint: local control, disease-free and overall survival) in the combined treatment with IMRT and carbon ion boost in 30 patients with histologically proven (>=R1-resected or inoperable) adeno-/or squamous cell carcinoma of the nasal cavity or paransal sinuses. Patients receive 24 GyE carbon ions (8 fractions) and IMRT (50 Gy at 2.0 Gy/fraction). DISCUSSION: The primary objective of IMRT-HIT-SNT is to evaluate toxicity and feasibility of the proposed treatment in sinonasal malignancies. TRIAL REGISTRATION: Clinical trial identifier NCT 01220752. PMID- 21600050 TI - Synergy between trastuzumab and pertuzumab for human epidermal growth factor 2 (Her2) from colocalization: an in silico based mechanism. AB - INTRODUCTION: Human epidermal growth factor 2 (Her2), a receptor tyrosine kinase, is overexpressed in breast cancers. It has been successfully targeted by small molecule kinase inhibitors and by antibodies. Recent clinical data show a synergistic response in patients when two antibodies, trastuzumab and pertuzumab, are given in combination. METHODS: This unexpected effect is rationalized through computer models and molecular dynamic simulations by hypothesizing that the two antibodies can co-localize on the same molecule of the Her2 extracellular domain. RESULTS: Simulations suggest that the clinical synergism observed for the two antibodies arises partly from enhanced affinity that originates in cooperative interactions between these two antibodies when they are co-localized on Her2 and "clamp" it; this may inhibit dimerization and possibly higher oligomerizations with neighboring receptors. In the presence of trastuzumab, the receptor becomes highly plastic, especially domains I to III, and this appears to promote increased association with pertuzumab. Further, the presence of pertuzumab evokes novel interactions between the receptor and trastuzumab. Indeed, splicing out of this region in silico results in a big reduction in the interactions of the antibody with the receptor. CONCLUSIONS: If validated, these findings will bring about a new direction in the design of antibodies whereby different epitopes on the same antibody may be targeted to lead to synergistic/cooperative inhibition and contribute to generate more potent therapeutics and to increase clinical efficacy. PMID- 21600051 TI - 25-hydroxyvitamin D concentration is inversely associated with serum MMP-9 in a cross-sectional study of African American ESRD patients. AB - BACKGROUND: Circulating 25-hydroxyvitamin D [25(OH)D] concentration is inversely associated with peripheral arterial disease and hypertension. Vascular remodeling may play a role in this association, however, data relating vitamin D level to specific remodeling biomarkers among ESRD patients is sparse. We tested whether 25(OH)D concentration is associated with markers of vascular remodeling and inflammation in African American ESRD patients. METHODS: We conducted a cross sectional study among ESRD patients receiving maintenance hemodialysis within Emory University-affiliated outpatient hemodialysis units. Demographic, clinical and dialysis treatment data were collected via direct patient interview and review of patients records at the time of enrollment, and each patient gave blood samples. Associations between 25(OH)D and biomarker concentrations were estimated in univariate analyses using Pearson's correlation coefficients and in multivariate analyses using linear regression models. 25(OH) D concentration was entered in multivariate linear regression models as a continuous variable and binary variable (<15 ng/ml and >=15 ng/ml). Adjusted estimate concentrations of biomarkers were compared between 25(OH) D groups using analysis of variance (ANOVA). Finally, results were stratified by vascular access type. RESULTS: Among 91 patients, mean (standard deviation) 25(OH)D concentration was 18.8 (9.6) ng/ml, and was low (<15 ng/ml) in 43% of patients. In univariate analyses, low 25(OH) D was associated with lower serum calcium, higher serum phosphorus, and higher LDL concentrations. 25(OH) D concentration was inversely correlated with MMP-9 concentration (r = -0.29, p = 0.004). In multivariate analyses, MMP-9 concentration remained negatively associated with 25(OH) D concentration (P = 0.03) and anti-inflammatory IL-10 concentration positively correlated with 25(OH) D concentration (P = 0.04). CONCLUSIONS: Plasma MMP-9 and circulating 25(OH) D concentrations are significantly and inversely associated among ESRD patients. This finding may suggest a potential mechanism by which low circulating 25(OH) D functions as a cardiovascular risk factor. PMID- 21600052 TI - Bacteriological and physico-chemical assessment of wastewater in different region of Tunisia: impact on human health. AB - BACKGROUND: In many parts of the world, health problems and diseases have often been caused by discharging untreated or inadequately treated wastewater. In this study, we aimed to control physico-chemical parameters in wastewater samples. Also, microbiological analyses were done to reveal Salmonella strains and each Escherichia coli (E.coli) pathotype. FINDINGS: Sixty wastewater samples were collected from fifteen different regions of Tunisia. All physico-chemical parameters (pH, residual free chlorine, total suspended solids, biological oxygen demand, and chemical oxygen demand) were evaluated.For microbiological analyses, samples were filtered to concentrate bacteria. DNA was extracted by boiling and subjected to polymerase chain reaction (PCR) using different pairs of primers.The mean pH values recorded for the sampling point were above the WHO pH tolerance limit. The total suspended solids (TSS) concentrations varied between 240 mg/L and 733 mg/L in entrance points and between 13 mg/L and 76 mg/L in exit points. In entrance points, the studied wastewater has an average COD concentration that varied between 795 mg/mL to 1420 mg/mL. Whereas, BOD concentration of the wastewater ranged between 270 mg/L to 610 mg/L. In exit points, COD concentration varied between 59 mg/L and 141 mg/L, whereas BOD concentration ranged from 15 mg/L to 87 mg/L.The bacteriological control of wastewaters showed that, in entrance points, Escherichia coli (E.coli) was detected at the rate of 76.6%. Three E.coli pathotypes were found: ETEC (53.3%), EAEC (16.6%) and EIEC (6.6%).Concerning the ETEC isolated strains, 8 of 16 (50%) have only the heat labile toxin gene, 5 of 16 (31.2%) present only the heat-stable toxin gene and 3 of 16 (18.7%) of strains possess both heat-labile toxin gene and heat-stable toxin gene. In exist point, the same pathotypes were found but all detected ETEC strains present only the "est" gene.Concerning Salmonella isolated strains; percentages of 66.6% and 20% were found in entrance and exit points respectively. CONCLUSIONS: Wastewaters contain a large amount of pathogenic bacteria that present a real impact on human health. Assessment wastewater treatment stations have to consider in account enterobacterial pathogens as potential pathogens that should be correctly controlled. PMID- 21600053 TI - Peer mentorship to promote effective pain management in adolescents: study protocol for a randomised controlled trial. AB - BACKGROUND: This protocol is for a study of a new program to improve outcomes in children suffering from chronic pain disorders, such as fibromyalgia, recurrent headache, or recurrent abdominal pain. Although teaching active pain self management skills through cognitive-behavioral therapy (CBT) or a complementary program such as hypnotherapy or yoga has been shown to improve pain and functioning, children with low expectations of skill-building programs may lack motivation to comply with therapists' recommendations. This study will develop and test a new manualized peer-mentorship program which will provide modeling and reinforcement by peers to other adolescents with chronic pain (the mentored participants). The mentorship program will encourage mentored participants to engage in therapies that promote the learning of pain self-management skills and to support the mentored participants' practice of these skills. The study will examine the feasibility of this intervention for both mentors and mentored participants, and will assess the preliminary effectiveness of this program on mentored participants' pain and functional disability. METHODS: This protocol will recruit adolescents ages 12-17 with chronic pain and randomly assign them to either peer mentorship or a treatment-as-usual control group. Mentored participants will be matched with peer mentors of similar age (ages 14-18) who have actively participated in various treatment modalities through the UCLA Pediatric Pain Program and have learned to function successfully with a chronic pain disorder. The mentors will present information to mentored participants in a supervised and monitored telephone interaction for 2 months to encourage participation in skill-building programs. The control group will receive usual care but without the mentorship intervention. Mentored and control subjects' pain and functioning will be assessed at 2 months (end of intervention for mentored participants) and at 4 month follow-up to see if improvements persist. Measures of treatment adherence, pain, disability, and anxiety and depression will be assessed throughout study participation. Qualitative interviews for mentors, mentored participants, and control subjects will also be administered. TRIAL REGISTRATION: ClinicalTrials.gov NCT01118988. PMID- 21600054 TI - Psychometric characteristics of the short form 36 health survey and functional assessment of chronic illness Therapy-Fatigue subscale for patients with ankylosing spondylitis. AB - BACKGROUND: We evaluated the psychometric characteristics of the Short Form 36 (SF-36) Health Survey and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale in patients with ankylosing spondylitis (AS). METHODS: We analyzed clinical and patient-reported outcome (PRO) data collected during 12 week, double-blind, placebo-controlled periods of two randomized controlled trials comparing adalimumab and placebo for the treatment of active AS. The Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, and other clinical measures were collected during the clinical trial. We evaluated internal consistency/reliability, construct validity, and responsiveness to change for the SF-36 and FACIT-Fatigue. RESULTS: The SF-36 (Cronbach alpha, 0.74-0.92) and FACIT-Fatigue (Cronbach alpha, 0.82-0.86) both had good internal consistency/reliability. At baseline, SF-36 and FACIT-Fatigue scores correlated significantly with Ankylosing Spondylitis Quality of Life scores (r = -0.36 to -0.66 and r = -0.70, respectively; all p < 0.0001). SF-36 scores varied by indicators of clinical severity, with greater impairment observed for more severe degrees of clinical activity (all p < 0.0001). FACIT Fatigue scores correlated significantly with SF-36 scores (r = 0.42 to 0.74; all p < 0.0001) and varied by clinical severity (p < 0.05 to p < 0.0001). CONCLUSIONS: The SF-36 is a reliable, valid, and responsive measure of health related quality of life and the FACIT-Fatigue is a brief and psychometrically sound measure of the effects of fatigue on patients with AS. These PROs may be useful in evaluating effectiveness of new treatments for AS. PMID- 21600055 TI - Mutation of the elongin C binding domain of human respiratory syncytial virus non structural protein 1 (NS1) results in degradation of NS1 and attenuation of the virus. AB - BACKGROUND: Human respiratory syncytial virus (RSV) is an important cause of lower respiratory tract disease in the paediatic population, immunocompromised individuals and the elderly worldwide. However, despite global efforts over the past several decades there are no commercially available vaccines. RSV encodes 2 non-structural proteins, NS1 and NS2, that are type I interferon antagonists. RSV restricts type I interferon signaling and the expression of antiviral genes by degrading STAT2. It has been proposed that NS1 binds to elongin C to form a ubiquitin ligase (E3) complex that targets STAT2 for ubiquitination and proteosomal degradation. RESULTS: Here, we have engineered a live recombinant RSV in which the 3 consensus amino acids of the NS1 elongin C binding domain have been replaced with alanine (NS1F-ELCmut). Mutation of this region of NS1 resulted in attenuation of RSV replication in A549 cells to levels similar to that observed when the NS1 gene is completely deleted (DeltaNS1). This mutation also resulted in moderate attenuation in Vero cells. Attenuation was correlated to intracellular degradation of the mutated NS1 protein. Time course analysis showed that mutant NS1 protein accumulated in cytoplasmic bodies that contained the lysosomal marker LAMP1. However lack of cleavage of LC3 suggested that autophagy was not involved. Induction of IFN-beta mRNA expression also was observed in association with the degradation of NS1 protein and attenuation of viral growth. CONCLUSIONS: These results indicate that the elongin C binding region of NS1 is crucial for survival of the protein and that disruption of this region results in the degradation of NS1 and restriction of RSV replication. PMID- 21600056 TI - Methodological problem with comparing increases in different measures of body weight. AB - BACKGROUND: A number of studies have compared proportional increases over time in waist circumference (WC) and body mass index (BMI). However this method is flawed. Here, we explain why comparisons of WC and BMI must take into account the relationship between them. We used data from two cross-sectional US surveys (NHANES 1988-94 and 2005-06), and calculated the percentage change in the average BMI and the average WC between the two surveys, comparing the results with a regression analysis of changes in WC relative to BMI. FINDINGS: The crude percentage change in BMI (5.8%) was marginally greater than for WC (5.1%). But these percentages cannot be directly compared, as the relationship between the measures is described by a regression equation with an intercept term that does not equal zero. The coefficient of time from the regression equation will determine whether or not WC is on average larger for a given BMI at the second compared with the first time point. CONCLUSION: Differences in the percentage change in WC and the percentage change in BMI cannot be usefully directly compared. Comparisons of increases in the two measures must account for the relationship between them as described by the regression equation. PMID- 21600057 TI - A realist evaluation of the role of communities of practice in changing healthcare practice. AB - BACKGROUND: Healthcare organisations seeking to manage knowledge and improve organisational performance are increasingly investing in communities of practice (CoPs). Such investments are being made in the absence of empirical evidence demonstrating the impact of CoPs in improving the delivery of healthcare. A realist evaluation is proposed to address this knowledge gap. Underpinned by the principle that outcomes are determined by the context in which an intervention is implemented, a realist evaluation is well suited to understand the role of CoPs in improving healthcare practice. By applying a realist approach, this study will explore the following questions: What outcomes do CoPs achieve in healthcare? Do these outcomes translate into improved practice in healthcare? What are the contexts and mechanisms by which CoPs improve healthcare? METHODS: The realist evaluation will be conducted by developing, testing, and refining theories on how, why, and when CoPs improve healthcare practice. When collecting data, context will be defined as the setting in which the CoP operates; mechanisms will be the factors and resources that the community offers to influence a change in behaviour or action; and outcomes will be defined as a change in behaviour or work practice that occurs as a result of accessing resources provided by the CoP. DISCUSSION: Realist evaluation is being used increasingly to study social interventions where context plays an important role in determining outcomes. This study further enhances the value of realist evaluations by incorporating a social network analysis component to quantify the structural context associated with CoPs. By identifying key mechanisms and contexts that optimise the effectiveness of CoPs, this study will contribute to creating a framework that will guide future establishment and evaluation of CoPs in healthcare. PMID- 21600058 TI - Reducing psychological distress and obesity in Australian farmers by promoting physical activity. AB - BACKGROUND: Studies have confirmed that the rate of mental illness is no higher in rural Australians than that of urban Australians. However, the rate of poor mental health outcomes, and in particular suicide, is significantly raised in rural populations. This is thought to be due to lack of early diagnosis, health service access, the distance-decay effect, poor physical health determinants and access to firearms. Research conducted by the National Centre for Farmer Health between 2004 and 2009 reveals that there is a correlation between obesity and psychological distress among the farming community where suicide rates are recognised as high. Chronic stress overstimulates the regulation of the hypothalamic-pituitary-adrenal (HPA) axis that is associated with abdominal obesity. Increasing physical activity may block negative thoughts, increase social contact, positively influence brain chemistry and improve both physical and mental health. This paper describes the design of the Farming Fit study that aims to identify the effect of physical activity on psychological distress, obesity and health behaviours such as diet patterns and smoking in farm men and women. METHODS/DESIGN: For this quasi-experimental (convenience sample) control intervention study, overweight (Body Mass Index >=25 kg/m(2)) farm men and women will be recruited from Sustainable Farm FamiliesTM (SFF) programs held across Victoria, Australia. Baseline demographic data, health data, depression anxiety stress scale (DASS) scores, dietary information, physical activity data, anthropometric data, blood pressure and biochemical analysis of plasma and salivary cortisol levels will be collected. The intervention group will receive an exercise program and regular phone coaching in order to increase their physical activity. Analysis will evaluate the impact of the intervention by longitudinal data (baseline and post intervention) comparison of intervention and control groups. DISCUSSION: This study is designed to examine the effect of physical activity on psychological health and other co-morbidities such as obesity, impaired glucose tolerance, hypertension and dyslipidaemia within a high risk cohort. The outcomes of this research will be relevant to further research and service delivery programs, in particular those tailored to rural communities. TRIAL REGISTRATION: ACTRN12610000827033. PMID- 21600059 TI - Academic detailing to increase colorectal cancer screening by primary care practices in Appalachian Pennsylvania. AB - BACKGROUND: In the United States, colorectal cancer (CRC) is the third most frequently diagnosed cancer and second leading cause of cancer death. Screening is a primary method to prevent CRC, yet screening remains low in the U.S. and particularly in Appalachian Pennsylvania, a largely rural area with high rates of poverty, limited health care access, and increased CRC incidence and mortality rates. Receiving a physician recommendation for CRC screening is a primary predictor for patient adherence with screening guidelines. One strategy to disseminate practice-oriented interventions is academic detailing (AD), a method that transfers knowledge or methods to physicians, nurses or office staff through the visit(s) of a trained educator. The objective of this study was to determine acceptability and feasibility of AD among primary care practices in rural Appalachian Pennsylvania to increase CRC screening. METHODS: A multi-site, practice-based, intervention study with pre- and 6-month post-intervention review of randomly selected medical records, pre- and post-intervention surveys, as well as a post-intervention key informant interview was conducted. The primary outcome was the proportion of patients current with CRC screening recommendations and having received a CRC screening within the past year. Four practices received three separate AD visits to review four different learning modules. RESULTS: We reviewed 323 records pre-intervention and 301 post-intervention. The prevalence of being current with screening recommendation was 56% in the pre-intervention, and 60% in the post-intervention (p=0.29), while the prevalence of having been screened in the past year increased from 17% to 35% (p<0.001). Colonoscopies were the most frequently performed screening test. Provider knowledge was improved and AD was reported to be an acceptable intervention for CRC performance improvement by the practices. CONCLUSIONS: AD appears to be acceptable and feasible for primary care providers in rural Appalachia. A ceiling effect for CRC screening may have been a factor in no change in overall screening rates. While the study was not designed to test the efficacy of AD on CRC screening rates, our evidence suggests that AD is acceptable and may be efficacious in increasing recent CRC screening rates in Appalachian practices which could be tested through a randomized controlled study. PMID- 21600060 TI - The prevalence and experience of Australian naturopaths and Western herbalists working within community pharmacies. AB - BACKGROUND: Naturopaths and Western herbal medicine (WHM) practitioners were surveyed to identify their extent, experience and roles within the community pharmacy setting and to explore their attitudes to integration of complementary medicine (CM) practitioners within the pharmacy setting. METHOD: Practising naturopaths and WHM practitioners were invited to participate in an anonymous, self-administered, on-line survey. Participants were recruited using the mailing lists and websites of CM manufacturers and professional associations. RESULTS: 479 practitioners participated. 24% of respondents (n=111) reported they had worked in community pharmacy, three-quarters for less than 5 years. Whilst in this role 74% conducted specialist CMs sales, 62% short customer consultations, 52% long consultations in a private room and 51% staff education. This was generally described as a positive learning experience and many appreciated the opportunity to utilise their specialist knowledge in the service of both customers and pharmacy staff. 14% (n=15) did not enjoy the experience of working in pharmacy at all and suggested pharmacist attitude largely influenced whether the experience was positive or not. Few practitioners were satisfied with the remuneration received. 44% of the total sample provided comment on the issue of integration into pharmacy, with the main concern being the perceived incommensurate paradigms of practice between pharmacy and naturopathy. Of the total sample, 38% reported that they would consider working as a practitioner in retail pharmacy in future. CONCLUSIONS: The level of integration of CM into pharmacy is extending beyond the mere stocking of supplements. Naturopaths and Western Herbalists are becoming utilised in pharmacies. PMID- 21600061 TI - Association of increased plasma adipocyte fatty acid-binding protein with coronary artery disease in non-elderly men. AB - BACKGROUND: Adipocyte fatty acid-binding protein (A-FABP) has been reported to play critical roles in the development of atherosclerosis. We investigated whether an increased in plasma A-FABP level can be independently associated with the presence of coronary artery disease (CAD). METHODS: Two hundred eleven consecutive male patients (mean age: 66 years, range: 33-87 years) were enrolled from inpatients who underwent coronary angiography. Age-matched male subjects (n = 211) having no evidence of CAD served as controls. Plasma A-FABP levels were measured by enzyme-linked immunosorbent assays. RESULTS: Plasma A-FABP levels in CAD patients were significantly higher than in control subjects (median [IQR], 20.6 [15.7-27.8] ng/mL vs. 15.1 [11.7-19.9] ng/mL, p < 0.01). Multivariate logistic regression analysis revealed that an increased plasma A-FABP level was independently associated with the presence of CAD in all subjects (adjusted odds ratio: 1.76, 95% confidence interval: 1.14 to 2.70, p = 0.01). Furthermore, sub analysis based on age showed that this association remained significant in subjects aged < 65 years (adjusted odds ratio: 3.06, 95% confidence interval: 1.34 to 6.98, p < 0.01), but not in subjects aged >=65 years. CONCLUSIONS: Increased plasma A-FABP in non-elderly men had a significant association with the presence of CAD, independent of established CAD risk factors. PMID- 21600063 TI - SNPmplexViewer--toward a cost-effective traceability system. AB - BACKGROUND: Beef traceability has become mandatory in many regions of the world and is typically achieved through the use of unique numerical codes on ear tags and animal passports. DNA-based traceability uses the animal's own DNA code to identify it and the products derived from it. Using SNaPshot, a primer-extension based method, a multiplex of 25 SNPs in a single reaction has been practiced for reducing the expense of genotyping a panel of SNPs useful for identity control. FINDINGS: To further decrease SNaPshot's cost, we introduced the Perl script SNPmplexViewer, which facilitates the analysis of trace files for reactions performed without the use of fluorescent size standards. SNPmplexViewer automatically aligns reference and target trace electropherograms, run with and without fluorescent size standards, respectively. SNPmplexViewer produces a modified target trace file containing a normalised trace in which the reference size standards are embedded. SNPmplexViewer also outputs aligned images of the two electropherograms together with a difference profile. CONCLUSIONS: Modified trace files generated by SNPmplexViewer enable genotyping of SnaPshot reactions performed without fluorescent size standards, using common fragment-sizing software packages. SNPmplexViewer's normalised output may also improve the genotyping software's performance. Thus, SNPmplexViewer is a general free tool enabling the reduction of SNaPshot's cost as well as the fast viewing and comparing of trace electropherograms for fragment analysis. SNPmplexViewer is available at http://cowry.agri.huji.ac.il/cgi-bin/SNPmplexViewer.cgi. PMID- 21600062 TI - Short term effects of exercise training on exercise capacity and quality of life in patients with pulmonary arterial hypertension: protocol for a randomised controlled trial. AB - BACKGROUND: Advances in the understanding and management of pulmonary arterial hypertension have enabled earlier diagnosis and improved prognosis. However, despite best available therapy, symptoms of exertional dyspnoea and fatigue are commonly reported and result in a reduced capacity to perform daily activities and impaired quality of life. Exercise training has demonstrated efficacy in individuals with other respiratory and cardiovascular diseases. Historically, however, exercise training has not been utilised as a form of therapy in pulmonary arterial hypertension due to the perceived risk of sudden cardiac death and the theoretical possibility that exercise would lead to worsening pulmonary vascular haemodynamics and deterioration in right heart function. Now, with the advances in pharmaceutical management, determining the safety and benefits of exercise training in this population has become more relevant. Only three studies of supervised exercise training in pulmonary arterial hypertension have been published. These studies demonstrated improvements in exercise capacity and quality of life, in the absence of adverse events or clinical deterioration. However, these studies have not utilised an outpatient-based, whole body exercise training program, the most common format for exercise programs within Australia. It is uncertain whether this form of training is beneficial and capable of producing sustained benefits in exercise capacity and quality of life in this population. DESIGN/METHODS: This randomised controlled trial will determine whether a 12 week, outpatient-based, supervised, whole body exercise training program, followed by a home-based exercise program, is safe and improves exercise capacity and quality of life in individuals with pulmonary arterial hypertension. This study aims to recruit 34 subjects who will be randomly allocated to the exercise group (supervised exercise training 3 times a week for 12 weeks, followed by 3 sessions per week of home exercise for 12 weeks) or the control group (usual medical care). Subjects will be assessed at baseline, 12 weeks and 24 weeks. DISCUSSION: This study will determine whether outpatient-based, whole body exercise training is beneficial and safe in individuals with pulmonary arterial hypertension. Additionally, this study will contribute to clinical practice guidelines for this patient population. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12609000502235. PMID- 21600064 TI - Structured diabetes care leads to differences in organization of care in general practices: the healthcare professional and patient perspective. AB - BACKGROUND: Care for patients with chronic diseases is challenging and requires multifaceted interventions to appropriately coordinate the entire treatment process. The effect of such interventions on clinical outcomes has been assessed, but evidence of the effect on organization of care is scarce.The aim is to assess the effect of structured diabetes care on organization of care from the perspective of patients and healthcare professionals in routine practice, and to ascertain whether this effect persists METHODS: In a quasi-experimental study the effect of structured care (SC) was compared with care-as-usual (CAU). Questionnaires were sent to healthcare professionals (SC n = 31; CAU n = 11) and to patients (SC n = 301; CAU n = 102). A follow-up questionnaire was sent after formal support of the intervention ended (2007). RESULTS: SC does have an effect on the organization of care. More cooperation between healthcare professionals, less referrals to secondary care and more education were reported in the SC group as compared to the CAU group. These changes were found both at the healthcare professional and at the patient level. Organizational changes remained after formal support for the intervention support had ended. CONCLUSION: According to patients and healthcare professionals, structured care does have a positive effect on the organization of care. The use of these two sources of information is important, not only to assess the value of changes in care for the patient and the healthcare provider but also to ascertain the validity of the results found. PMID- 21600065 TI - Role of redox environment on the oligomerization of higher molecular weight adiponectin. AB - BACKGROUND: Adiponectin is an adipocyte-secreted hormone with insulin-sensitizing and anti-inflammatory actions. The assembly of trimeric, hexameric, and higher molecular weight (HMW) species of adiponectin is a topic of significant interest because physiological actions of adiponectin are oligomer-specific. In addition, adiponectin assembly is an example of oxidative oligomerization of multi-subunit protein complexes in endoplasmic reticulum (ER). RESULTS: We previously reported that trimers assemble into HMW adiponectin via intermediates stabilized by disulfide bonds, and complete oxidation of available cysteines locks adiponectin in hexameric conformation. In this study, we examined the effects of redox environment on the rate of oligomer formation and the distribution of oligomers. Reassembly of adiponectin under oxidizing conditions accelerated disulfide bonding but favored formation of hexamers over the HMW species. Increased ratios of HMW to hexameric adiponectin could be achieved rapidly under oxidizing conditions by promoting disulfide rearrangement. CONCLUSIONS: Based upon these observations, we propose oxidative assembly of multi-subunit adiponectin complexes in a defined and stable redox environment is favored under oxidizing conditions coupled with high rates of disulfide rearrangement. PMID- 21600066 TI - Effectiveness of a Wii balance board-based system (eBaViR) for balance rehabilitation: a pilot randomized clinical trial in patients with acquired brain injury. AB - BACKGROUND: Acquired brain injury (ABI) is the main cause of death and disability among young adults. In most cases, survivors can experience balance instability, resulting in functional impairments that are associated with diminished health related quality of life. Traditional rehabilitation therapy may be tedious. This can reduce motivation and adherence to the treatment and thus provide a limited benefit to patients with balance disorders. We present eBaViR (easy Balance Virtual Rehabilitation), a system based on the Nintendo(r) Wii Balance Board(r) (WBB), which has been designed by clinical therapists to improve standing balance in patients with ABI through motivational and adaptative exercises. We hypothesize that eBaViR, is feasible, safe and potentially effective in enhancing standing balance. METHODS: In this contribution, we present a randomized and controlled single blinded study to assess the influence of a WBB-based virtual rehabilitation system on balance rehabilitation with ABI hemiparetic patients. This study describes the eBaViR system and evaluates its effectiveness considering 20 one-hour-sessions of virtual reality rehabilitation (n = 9) versus standard rehabilitation (n = 8). Effectiveness was evaluated by means of traditional static and dynamic balance scales. RESULTS: The final sample consisted of 11 men and 6 women. Mean +/- SD age was 47.3 +/- 17.8 and mean +/- SD chronicity was 570.9 +/- 313.2 days. Patients using eBaViR had a significant improvement in static balance (p = 0.011 in Berg Balance Scale and p = 0.011 in Anterior Reaches Test) compared to patients who underwent traditional therapy. Regarding dynamic balance, the results showed significant improvement over time in all these measures, but no significant group effect or group-by-time interaction was detected for any of them, which suggests that both groups improved in the same way. There were no serious adverse events during treatment in either group. CONCLUSIONS: The results suggest that eBaViR represents a safe and effective alternative to traditional treatment to improve static balance in the ABI population. These results have encouraged us to reinforce the virtual treatment with new exercises, so an evolution of the system is currently being developed. PMID- 21600067 TI - Collaboration between general practitioners and mental health care professionals: a qualitative study. AB - BACKGROUND: Collaboration between general practice and mental health care has been recognised as necessary to provide good quality healthcare services to people with mental health problems. Several studies indicate that collaboration often is poor, with the result that patient' needs for coordinated services are not sufficiently met, and that resources are inefficiently used. An increasing number of mental health care workers should improve mental health services, but may complicate collaboration and coordination between mental health workers and other professionals in the treatment chain. The aim of this qualitative study is to investigate strengths and weaknesses in today's collaboration, and to suggest improvements in the interaction between General Practitioners (GPs) and specialised mental health service. METHODS: This paper presents a qualitative focus group study with data drawn from six groups and eight group sessions with 28 health professionals (10 GPs, 12 nurses, and 6 physicians doing post-doctoral training in psychiatry), all working in the same region and assumed to make professional contact with each other. RESULTS: GPs and mental health professionals shared each others expressions of strengths, weaknesses and suggestions for improvement in today's collaboration. Strengths in today's collaboration were related to common consultations between GPs and mental health professionals, and when GPs were able to receive advice about diagnostic treatment dilemmas. Weaknesses were related to the GPs' possibility to meet mental health professionals, and lack of mutual knowledge in mental health services. The results describe experiences and importance of interpersonal knowledge, mutual accessibility and familiarity with existing systems and resources. There is an agreement between GPs and mental health professionals that services will improve with shared knowledge about patients through systematic collaborative services, direct cell-phone lines to mental health professionals and allocated times for telephone consultation. CONCLUSIONS: GPs and mental health professionals experience collaboration as important. GPs are the gate keepers to specialised health care, and lack of collaboration seems to create problems for GPs, mental health professionals, and for the patients. Suggestions for improvement included identification of situations that could increase mutual knowledge, and make it easier for GPs to reach the right mental health care professional when needed. PMID- 21600069 TI - Pattern center determination in electron backscatter diffraction microscopy. AB - The pattern center of an electron backscatter diffraction (EBSD) image indicates the relative position of the image with reference to the interaction volume of the sample. As interest grows in high-resolution EBSD techniques, accurate knowledge of this position is essential for precise interpretation of the EBSD features. In a typical EBSD framework, Kikuchi bands are recorded on a phosphor screen. If the flat phosphor were instead shaped as a sphere, with its center at the specimen's electron interaction volume, then the incident backscattered electrons would form Kikuchi bands on that sphere with parallel band edges centered on great circles. In this article, the authors present a method of pattern center (PC) refinement that maps bands from the planar phosphor onto a virtual spherical screen and measures the deviation of bands from a great circle and from possessing parallel edges. Potential sources of noise and error, as well as methods for reducing these, are discussed. Finally, results are presented on the application of the PC algorithm to two types of simulated EBSD patterns and two experimental setups, and the resolution of the method is discussed. PMID- 21600070 TI - Strain-induced selective growth in 1.5% temper-rolled Fe;1%Si. AB - Strain-induced selective growth was investigated in a 1.5% temper-rolled Fe~1%Si alloy using the electron backscatter diffraction (EBSD) technique. The EBSD technique was used to quantify the presence of orientation spreads within grains and to show that this particular case of selective growth can be directly related to differences in stored energy as reflected in the geometrically necessary dislocation content. The differences in stored energy were sufficient to give rise to selective growth as evidenced by bi-modal grain sizes. PMID- 21600071 TI - Bridging the micro-to-macro gap: a new application for micro X-ray fluorescence. AB - X-ray elemental mapping and X-ray spectrum imaging are powerful microanalytical tools. However, their scope is often limited spatially by the raster area of a scanning electron microscope or microprobe. Limited sampling size becomes a significant issue when large area (>10 cm2), heterogeneous materials such as concrete samples or others must be examined. In such specimens, macro-scale structures, inclusions, and concentration gradients are often of interest, yet microbeam methods are insufficient or at least inefficient for analyzing them. Such requirements largely exclude the samples of interest presented in this article from electron probe microanalysis. Micro X-ray fluorescence-X-ray spectrum imaging (MUXRF-XSI) provides a solution to the problem of macro-scale X ray imaging through an X-ray excitation source, which can be used to analyze a variety of large specimens without many of the limitations found in electron excitation sources. Using a mid-sized beam coupled with an X-ray excitation source has a number of advantages, such as the ability to work at atmospheric pressure and lower limits of detection owing to the absence of electron-induced bremsstrahlung. MUXRF-XSI also acts as a complement, where applicable, to electron microbeam X-ray output, highlighting areas of interest for follow-up microanalysis at a finer length scale. PMID- 21600072 TI - Atomic-scale phase composition through multivariate statistical analysis of atom probe tomography data. AB - We demonstrate for the first time that multivariate statistical analysis techniques can be applied to atom probe tomography data to estimate the chemical composition of a sample at the full spatial resolution of the atom probe in three dimensions. Whereas the raw atom probe data provide the specific identity of an atom at a precise location, the multivariate results can be interpreted in terms of the probabilities that an atom representing a particular chemical phase is situated there. When aggregated to the size scale of a single atom (~0.2 nm), atom probe spectral-image datasets are huge and extremely sparse. In fact, the average spectrum will have somewhat less than one total count per spectrum due to imperfect detection efficiency. These conditions, under which the variance in the data is completely dominated by counting noise, test the limits of multivariate analysis, and an extensive discussion of how to extract the chemical information is presented. Efficient numerical approaches to performing principal component analysis (PCA) on these datasets, which may number hundreds of millions of individual spectra, are put forward, and it is shown that PCA can be computed in a few seconds on a typical laptop computer. PMID- 21600073 TI - Ndc80 regulates meiotic spindle organization, chromosome alignment, and cell cycle progression in mouse oocytes. AB - Ndc80 (called Hec1 in human), the core component of the Ndc80 complex, is involved in regulation of both kinetochore-microtubule interactions and the spindle assembly checkpoint in mitosis; however, its role in meiosis remains unclear. Here, we report Ndc80 expression, localization, and possible functions in mouse oocyte meiosis. Ndc80 mRNA levels gradually increased during meiosis. Immunofluorescent staining showed that Ndc80 was restricted to the germinal vesicle and associated with spindle microtubules from the Pro-MI to MII stages. Ndc80 was localized on microtubules and asters in the cytoplasm after taxol treatment, while Ndc80 staining was diffuse after disruption of microtubules by nocodazole treatment, confirming its microtubule localization. Disruption of Ndc80 function by either siRNA injection or antibody injection resulted in severe chromosome misalignment, spindle disruption, and precocious polar body extrusion. Our data show a unique localization pattern of Ndc80 in mouse oocytes and suggest that Ndc80 may be required for chromosome alignment and spindle organization, and may regulate spindle checkpoint activity during mouse oocyte meiosis. PMID- 21600074 TI - Staining of mitochondria with Cy5-labeled oligonucleotides for long-term microscopy studies. AB - Labeling of organelles for microscopy is achieved generally by specific dyes that either accumulate in a cellular compartment such as cyanine dyes in mitochondria or are only fluorescent under specific conditions such as the low pH in the lysosome. Here we demonstrate that Cy5--a fluorescent molecule that does not enter cells by itself--can be loaded into cells by attaching a short oligonucleotide. This very inexpensive labeling procedure can be done in the presence of serum. Therefore, very sensitive cell types should also be amenable to this procedure, and longer observations can be achieved compared to other commercially available dyes as the labeling reagent does not need to be washed out. This also points to the pitfall of using fluorescently labeled oligonucleotides for live cell imaging where the oligonucleotide is supposed to detect a specific target sequence in its subcellular distribution. PMID- 21600076 TI - [The challenge and opportunity of conceptual change of neuromyelitis optica]. PMID- 21600075 TI - [To establish an efficient quality improvement system for stroke]. PMID- 21600077 TI - [The importance of vasculitis factor in the diagnosis of peripheral neuropathy]. PMID- 21600078 TI - [Pay attention to stroke-related pneumonia]. PMID- 21600080 TI - [A case report of neuromyelitis optica with 37 years' interval between optic neuropathy and spinal cord lesion and literature review]. AB - OBJECTIVE: To improve the recolonization of long term interval between optic neuropathy and spinal cord injury of neuromyelitis optica. METHODS: One 51-year old male patient with 37 years' interval between optic neuropathy and spinal cord injury of neuromyelitis optica underwent the examination of plasma and cerebrospinal fluid and head and spinal MRI examinations, who was also followed up. His clinical data were analyzed and related literature was reviewed. RESULTS: The myelin basic protein and IgG index in his cerebrospinal fluid was high, his oligoclonal band of cerebrospinal fluid was positive, and abnormal finding in visual evoked potential. Abnormal intramedullary long T(2) signals was showed in spinal cord MRI at T(1-7) segment. When diagnosed as neuromyelitis optica, the clinical symptom and signs was improved with corticosteroid and gamma globulin therapy. The patient was in stable condition at present. CONCLUSIONS: There could be a long term interval between optic neuritis and myelitis. One should pay attention to clinical features and imaging examination of subclinical lesion in spinal cord and brain and conoid the possibility of developing neuromyelitis optica or multiple sclerosis. PMID- 21600079 TI - [The clinical and magnetic resonance imaging studies of brain damages in neuromyelitis optica]. AB - OBJECTIVE: To investigate the feature brain damage and clinical manifestations in neuromyelitis optica (NMO) patients; To investigate the relationship between serum NMO-IgG antibody and NMO brain damage. METHODS: Clinical data of 37 NMO patients and their head and spinal cord MRI by 1.5T superconducting MR scanner, were analyzed; serum NMO-IgG antibody were measured by immunofluorescence. RESULTS: 17 cases were found to have abnormal signals on MRI, which were mainly in the white matter, pons, medulla, ventricle, aqueduct, and around the corpus callosum; According to pathological changes, brain damage can be divided into scattered irregularity (13 cases), fusion (3 cases), multiple sclerosis-like (1 case), with scattered irregularity more common, 5 cases had clinical manifestations of brain damage: somnolence, vomiting, diplopia, visual rotation, 11 cases patients with brainstem damage show positive serum NMO-IgG antibodies. CONCLUSIONS: Brain damage can be seen in half of NMO patients, they often located in the high expression area of AQP4: brain white matter, periventricular, brainstem and so on. Clinical symptoms has nothing to do with the size of lesions but the location, they often occur when brainstem was involved. Serum NMO-IgG is helpful in differentiating NMO with brain damage and MS. PMID- 21600081 TI - [Neurologic injury after off-pump coronary artery bypass grafting in elder patients with a history of cerebral infarction]. AB - OBJECTIVE: To study neurologic injury after off-pump coronary artery bypass grafting (OPCABG) in elder patients with a history of stroke. METHODS: 108 patients (age >= 60 years) undergoing elective OPCABG with a history of stroke were studied. Each study patient was matched with 1 control patient who had no stroke history and was undergoing elective OPCABG either immediately before or immediately after the study patients by the same surgeon. Preoperative characteristics, ICU stay, hospital stay, hospital mortality, postoperative neurologic injury were compared in the two groups. RESULTS: The incidence of neurologic injury after operation among the study group was higher than those in control group (P < 0.01) (27.8% vs 4.6%). The incidence of delirium and stroke after operation among the study group was higher than those in control group (P < 0.05) (20.4% vs 3.7%, 7.4% vs 0.9%); The study group took longer to stay in ICU and hospital than the control group [(26.5 +/- 16.4) h vs (21.6 +/- 8.8) h, (23.6 +/- 9.2) d vs (19.4 +/- 5.7) d, P < 0.01]. Logistic regression analysis showed that the risk factors of neurologic injury after OPCABG included previous stroke (OR 6.269, 95%CI 2.218 - 17.717), age (OR 1.131, 95%CI 1.032 - 1.239), hypertension (OR 5.072, 95%CI 1.420 - 18.114) and diabetes (OR 2.652, 95%CI 1.123 - 6.260). Stroke after the operations was found in 8 of 108 study patients and included cerebral infarction in 6 and transient ischemic attack in 2. 8 patients had late stroke (> 24 hours). CONCLUSION: The elderly patients with previous stroke undergoing OPCABG are more likely to have neurologic injury after operations, these patients had longer stays in ICU and hospital. PMID- 21600082 TI - [An analysis of disease spectrum of patients admitted to the General Internal Medicine Unit at Peking Union Medical College Hospital from 2004 to 2008, and the value of general internal medicine unit in comprehensive hospitals]. AB - OBJECTIVE: To analyze the disease spectrum of patients admitted to the General Internal Medicine Unit at Peking Union Medical College Hospital, which is the first academic division of general internal medicine in the department of medicine within Chinese medical colleges and universities, and the value of general internal medicine unit in comprehensive hospitals. METHODS: A retrospective data review of patients admitted to the General Internal Medicine Unit from 2004 to 2008 was conducted from hospital information system and partially by chart review manually. Analysis of disease spectrum was performed thereafter. RESULTS: A total of 2593 patients were included in our study. It consisted of 1075 men and 1518 women, with an average age of 45.1 years old. Forty point three percent of these patients were from Beijing, the local city, and the remaining 59.7% were from outside of Beijing. Sixty-four point nine percent (1683/2593) of these patients did not have a clear diagnosis on admission, including 758 fever of unknown origin (FUO) cases and 925 non-FUO cases. The final diagnostic rate of the FUO cases was 89.2% [676/758, with the first three leading causes as diseases of the musculoskeletal system and connective tissue (29.8%), certain infectious and parasitic diseases (26.3%), and neoplasm (14.5%)]. The final diagnostic rate of the 928 non-FUO cases was 86.8% (803/925), with the first three leading causes as musculoskeletal system and connective tissue (24.9%), neoplasm (15.5%), and diseases of blood and blood forming organs (11.4%). Despite most diagnoses fitting into the above categories, the array of diseases was broad with as many as 550 discharge diagnoses from 2004 to 2008. CONCLUSIONS: During 2004 - 2008, there was a high proportion of cases that presented to the General Internal Medicine Unit at Peking Union Medical College Hospital with an unclear diagnosis, and the spectrum of diseases diagnosed was very broad. This kind of patient admitting model might not only benefit patients with no clear admission diagnosis and patients with multidisciplinary medical problems for whom it is usually difficult to be admitted by a specialty unit, but would also benefit medical students and residents by providing a good clinical medicine teaching base. These features show the value of general internal unit in comprehensive hospitals. PMID- 21600083 TI - [A clinical analysis of 61 cases of protein-losing enteropathy]. AB - OBJECTIVE: To increase the understanding in protein-losing enteropathy (PLE). METHODS: Sixty-one PLE patients were enrolled in the study and the clinical characteristics, complicated disease, diagnosis and treatment were analyzed. RESULTS: The age of the patients was 16 - 77 (40 +/- 15) years, and the gender ratio was 35:26 (female:male). The main clinical manifestations were bilateral lower limb edema in 51 cases, ascites in 41 cases, bilateral pleural effusion in 23 cases, pericardial effusion in 13 cases, abdominal pain in 16 cases and diarrhea in 33 cases. The prominent abnormality in laboratory examinations was hypoalbuminemia. The underlying diseases include systemic lupus erythematosus (SLE) in 28 cases, intestinal lymphangiectasia in 12 cases, hepatic cirrhosis in 5 cases, heart diseases in 5 cases, Crohn's disease in 3 cases, membranous nephropathy in 2 cases, Budd-Chiari syndrome in 1 case. Four cases happened after abdominal operation and 1 case after radiation therapy of gastric cardia cancer. Thirty-seven cases were diagnosed by (99)Tc(m)-labelled human serum albumin scintigraphy and 24 cases were diagnosed clinically. Treatment was focused on underlying diseases. The clinical manifestations in 21 cases of SLE improved after SLE was controlled. In 2 cases of intestinal lymphangiectasia and one with Crohn's disease, the clinical manifestations improved after surgery. The other patients had no improvement. CONCLUSIONS: PLE was not uncommon in clinical practice. Its predominant characteristics were severe hypoalbuminemia, edema and dropsy of serous cavity. PLE can complicate other diseases such as SLE, intestinal lymphangiectasia. Treatment should be focused on primary disease. PMID- 21600084 TI - [Combination therapy of azintamid and domperidone in functional dyspepsia: a randomised, double-blind, placebo-controlled trial]. AB - OBJECTIVE: To study the efficacy and safety of combined therapy of compound azintamid and domperidone in functional dyspepsia. METHODS: A randomised, double blind, placebo-controlled trial. Two hundred and eight patients with functional dyspepsia were randomly grouped into group A (experimental group, 102 cases) and group B (control group, 106 cases). The patients in the group A were given 2 tablets of compound azintamid 3 times a day in addition to domperidone 10 mg 3 times per day for four weeks. The patients in the group B were only given domperidone 10 mg 3 times per day for 4 weeks. The therapeutic efficacy was evaluated by modified Severity of Dyspepsia Assessment (mSODA) and Global Patient Assessment (GPA). RESULTS: Subscore in mSODA: the change of bloating/pain intensity score in group A is -12.35 +/- 5.48 while group B is -10.52 +/- 4.65 (P = 0.009), the change of non-bloating/pain symptoms score in group A is -5.75 +/- 3.31 while group B is -4.86 +/- 2.65 (P = 0.033), and the change of satisfaction score in group A is 7.09 +/- 3.78 while group B is 5.62 +/- 3.54 (P = 0.004). The response rate in group A is 89.2% which is significantly higher than 76.4% in group B (P = 0.015). Other symptoms for response assessment included loss of appetite, early satiety, fullness after meal, diarrhea. No severe side-effect was found in both groups. CONCLUSIONS: Combined therapy of compound azintamid and domperidone may lead to bigger improvement in overall efficacy and health related quality of life in patients with functional dyspepsia than use of motility medicine alone. Potential mechanisms that may account for the efficacy of compound azintamide in functional dyspepsia include modulation of visceral sensitivity and/or gastrointestinal motility. PMID- 21600085 TI - [A clinical analysis of 9 cases of pulmonary alveolar proteinosis with secondary infection]. AB - OBJECTIVE: To describe the clinical characteristics of 9 cases of idiopathic pulmonary alveolar proteinosis (iPAP) with secondary infections. METHOD: The clinical and radiological data of 9 patients with iPAP and secondary infections admitted into Peking Union Medical College Hospital from 1st January 1990 to 1st January 2010 were retrospectively analyzed. RESULTS: In that period, there were 97 patients of iPAP were admitted in our hospital. There were 9 patients of iPAP with secondary infections, aged (46.4 +/- 14.6) y. There were 5 males and 4 females. Among them, 6 patients were misdiagnosed as interstitial pneumonia and corticosteroids were given to them. When the infection appeared, corticosteroids were still given to 3 patients, and the other 3 patients had stopped corticosteroids for 3 to 15 and a half months. Five patients had accepted mono lung or whole lung lavage before 1, 2, 9, 14, 24 months. The clinical manifestations were fever (8 cases), cough (9 cases), expectoration (8 cases), hemoptysis (2 cases), chest pain (1 case) and moist rales (1 case). Glass-ground opacities (9 cases) and cavitations (4 case) were the main manifestations of chest radiology. Pleural effusions (1 case) was not common. The locations of infection was limited in chest: 9 cases had pulmonary infection and one case was associated with pleurisy. The infectious pathogens were the acid-fast tubercle bacillus (4 cases), fungus (3 cases, candida albicans, penicillium and aspergillus fumigatus for each one) and nocardia (2 cases, one case was associated with cytomegalovirus infection). FOLLOW-UP: 6 patients were cured, 1 patient was improved and 2 patients were died. CONCLUSIONS: For patients with iPAP, especially when they had been receiving corticosteroids, if they had fever and/or recently exaggerated dyspnea, especially whose chest radiology showed nodules and cavitations, the clinicians should be aware of infections diseases for them. Further specific microbiological studies and sufficient therapy should be obtained as quickly as possible. PMID- 21600086 TI - [The levels of nerve growth factor and IL-4 in induced sputum and characteristics of airway inflammation in cough variant asthma]. AB - OBJECTIVE: To observe sputum cytology counts, the levels of nerve growth factor (NGF) and IL-4 in cough variant asthma (CVA) patients and the change of their levels after using glucocorticoids combined with beta(2)-adrenergic agonists one month, and to investigate CVA's characteristics of airway inflammation. METHODS: Totally 36 patients with untreated CVA were selected, as well as 23 healthy controls. Coughed up sputum cells were obtained and HE strained for differential cell counting in each enrolled patient. In induced sputum's supernatant, the levels of NGF and IL-4 were determined by ELISA. RESULTS: Before treatment, CVA patients had a median eosinophils (EOS) percentage of 8%, which was significantly higher than that after treatment (2%, P < 0.05) and in healthy control group (1%, P < 0.001). The levels of NGF and IL-4 in induced sputum of CVA group were (9.50 +/- 1.69) ng/L and (257.37 +/- 53.57) ng/L. After treatment, they were (8.78 +/- 1.02) ng/L and (228.60 +/- 52.93) ng/L in CVA group, (6.98 +/- 0.69) ng/L and (166.44 +/- 24.75) ng/L in healthy control group. The levels of NGF and IL-4 before and after treatment in the CVA group, as compared with the healthy control group, had statistically significant differences (all P < 0.001). In CVA group before and after treatment, the level of NGF and IL-4 paired difference was significant (P < 0.001). The percentage of induced sputum EOS correlated with sputum supernatant concentrations of NGF and IL-4 (P < 0.01). In induced sputum supernatant, the concentrations of NGF and IL-4 were significant correlated (P < 0.01). CONCLUSIONS: Glucocorticoid joint long-term beta(2) agonist inhaled treatment significantly reduced NGF, IL-4 and EOS levels and reduced eosinophilic inflammation, which are closely related with the nerve-immune mechanism, NGF as well as IL-4 participated the inflammation. Induced sputum examination is non invasive, economical, simple, easily accepted by patients, and repeatable, widely used in clinical. PMID- 21600087 TI - [A multi-center, randomized, controlled, double blind and double dummy clinical trial of antofloxacin hydrochloride tablet versus levofloxacin tablet for the treatment of acute bacterial infections]. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of antofloxacin hydrochloride tablet for the treatment of acute bacterial infections. METHODS: A multi-center randomized control, double blind and double dummy clinical trial was conducted; levofloxacin tablet was closed as controlled drug. The duration of treatment was 7-14 days in both groups. RESULTS: A total of 719 patients were enrolled in the study, in which 359 patients treated with antofloxacin and 360 patients treated with levofloxacin were included. Three hundred and thirty and 337 patients completed the study and met with all the criteria for per-protocol analysis, respectively. By the end of chemotherapy, the cured rates in per protocol set (PPS) population were 79.7% and 77.4%, the effective rates were 95.2% and 96.7%, and the bacterial clearance were 96.7% and 97.5% for the treating and control group, respectively. The clinical and bacterial efficacy of antofloxacin and levofloxacin was comparable by the analysis of infectious sites. Three hundred and fifty-seven and 356 patients in antofloxacin and levofloxacin groups were evaluated the safety. The drug adverse events occurred both in 10.1%, and drug adverse reactions occurred in 7.8% and 7.9% patients in the two groups. The most common drug adverse reactions were mild gastroenteric symptoms. No QTc prolongation was detected in all the patients. One patient in each group had mild blood glucose increase at the end of therapy, but the glucose returned to normal level without any intervention. No statistic significant difference between the two groups in clinical efficacy and safety was detected (P > 0.05). CONCLUSIONS: Antofloxacin hydrochloride tablet was effective and safe for the treatment of acute bacterial infections. PMID- 21600088 TI - [The evaluation of four-year highly active antiretroviral therapy in HIV-1 infected patients]. AB - OBJECTIVE: To observe that antiretroviral efficacy, immune reconstitution of four year highly active antiretroviral therapy (HAART), and evaluate its side effect in Chinese HIV-1-infected patients. METHODS: A total of 258 HIV-1 infected patients, given HAART regimens composed of two nucleoside reverse transcriptase inhibitor (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) for mean 51.5 months, measured HIV RNA viral load (VL) and the counts of CD(4)(+) T cell, CD(8)(+) T cell at the baseline and 6, 12, 24, 36 and 48 months after HAART initiation, respectively, monitoring side effect, blood routine, main biochemical parameters, and other disadvantageous accidents during the 51.5-month treatment. RESULTS: Plasma HIV-1 RNA level was determined by fluorescent quantitative polymerase chain reactions (FQ-PCR) at the baseline and 6, 12, 24, 36 and 48 months after starting HAART, and showed 5.27, 2.97, 2.74, 2.62, 2.67 and 2.75 lg (copies/ml), respectively. The counts of CD(4)(+) T cell from (127 +/ 63) cells/ul at the baseline increased to (190 +/- 115), (248 +/- 93), (269 +/- 127), (296 +/- 156) and (317 +/- 195) cells/ul at 6, 12, 24, 36 and 48 months after starting HAART. A total of 149 treated patients (57.8%)had gastrointestinal side effects, peripheral polyneuropathy, various rashes, central nervous system disorders, fever or baldness. Twenty-two patients changed one of three medicines to another because toxicity. Sixteen changed the regimen to the second line HAART for lactic acidosis or other serious toxicities. CONCLUSIONS: A total of 258 HIV 1 infected Chinese patients treated with two NRTI and one NNRTI as first line HAART regimen during mean 51.5 months, showed a good antiretroviral efficacy and immune reconstitution, but a few side-effects at the parts of patients. It is necessary to treat adverse effect and change HAART regimen for severe toxicity in time. PMID- 21600089 TI - [The effects of soluble epoxide hydrolase inhibitors on cholesterol efflux in adipocytes]. AB - OBJECTIVE: To observe the effects of soluble epoxide hydrolase inhibitors tAUCB on cholesterol efflux in adipocytes. METHODS: 3T3-L1 preadipocytes were induced to differentiation and maturation. Cells were stimulated with 100 ug/L LPS after starved for 24 hours, then tAUCB in various concentrations (1, 10, 50, 100 umol/L)were added for 24 h, or incubated with the peroxisome proliferator activated receptor gamma (PPARgamma) antagonist GW9662 (5 umol/L). 0 umol/L tAUCB treated group was taken as empty control. After then, the mRNA expression of PPARgamma and adenosine triphosphate binding cassette transporter A1(ABCA1) in cells were determined via realtime-PCR, the amounts of protein expression of PPARgamma and ABCA1 in cells were detected by Western blot, the efflux rates of (3)H-cholesterol in cells were detected by means of liquid scintillation counter. RESULTS: tAUCB could dose-dependently increase the apolipoprotein A1 (apoA1) mediated cholesterol efflux in adipocytes. After stimulated by 1, 10, 50, 100 umol/L tAUCB, cholesterol efflux rates were (5.93 +/- 0.66)%, (7.40 +/- 0.43)%, (8.30 +/- 0.34)%, (9.77 +/- 0.42)% respectively, there were significant difference after treated by 10 - 100 umol/L tAUCB compared with control (5.67 +/- 0.17)% (P < 0.05).With the concentration of tAUCB increased, ABCA1, PPARgamma mRNA and protein expression were also dose-dependently up-regulated. GW9662 could significantly inhibit the effects of tAUCB, and then reduce the cholesterol efflux and the expression of PPARgamma and ABCA1 in adipocytes. CONCLUSIONS: tAUCB could up-regulate PPARgamma expression in adipocytes, and promote the cholesterol efflux of adipocytes via apoA1-ABCA1 pathway, which might decrease the cellular cholesterol accumulation in adipocytes. PMID- 21600090 TI - [The efficacy and safety of valproic acid in combination with low dose chemotherapy on intermediate and high-risk myelodysplastic syndrome]. AB - OBJECTIVE: To evaluate the efficacy and adverse effect of valproic acid (VPA) in combination with low dose chemotherapy on intermediate and high-risk myelodysplastic syndrome. METHODS: A total of 41 patients with intermediate (34) and high-risk (7) myelodysplastic syndrome were retrospectively analyzed. Among them, 19 patients received low dose chemotherapy regimen and 22 received low dose chemotherapy plus VPA. Low dose chemotherapy regimen included: homoharringtonine, 1 - 2 mg*m(-2)*d(-1) intravenously, 14 - 28 d; aclarubicin, 5 - 7 mg*m(-2)*d(-1) intravenously, 1 - 8 d, 15 - 23 d; cytarabine 15 mg/m(2) subcutaneously once every 12 h, 14 - 21 d; and subcutaneously use of granulocyte colony-stimulating factor 200 ug.m(-2)*d(-1) when neutrophil deficiency. The outcome and adverse effect were recorded after the treatment. RESULTS: The overall response rate in the low dose chemotherapy regimen group was 47.4% (9/19), 6 patients (31.6%) achieved complete response (CR). The overall response rate in the VPA group was 77.2% (17/22), 9 patients (40.9%) achieved CR. The overall response rate of the low dose chemotherapy in combination with VPA group was significantly higher than that in the low dose chemotherapy group (P < 0.05) while no difference was found in CR rate. The adverse effect of the low dose chemotherapy in combination with VPA regimen was tolerated. CONCLUSION: With acceptable adverse effect, the low dose chemotherapy in combination with VPA regimen is effective for the treatment of intermediate and high-risk myelodysplastic syndrome. Long-term outcome needs further investigation. PMID- 21600091 TI - [Measurement and clinical significance of serum DKK-1 and sRANKL levels in multiple myeloma]. AB - OBJECTIVE: To detect serum concentrations of Dickkopf-1 (DKK-1) and soluble receptor activator of nuclear factor-kappaB ligand (sRANKL) in patients with multiple myeloma (MM) and to investigate its clinical significance. METHODS: Serum DKK-1, sRANKL, osteoprotegerin(OPG) and tartrate-resistant acid phosphatase 5b (TRACP-5b) levels were quantified in 30 newly diagnosed MM patients and 20 healthy control subjects by using sandwich ELISA. RESULTS: The serum DKK-1, sRANKL, OPG and TRACP-5b levels were significantly higher than those in the healthy controls (42.96 ug/L vs 5.33 ug/L, 1.83 pmol/L vs 0.79 pmol/L, 1799.30 pmol/L vs 822.40 pmol/L, 5.81 U/L vs 0.28 U/L, respectively; all P < 0.05). Serum levels of DKK-1 were positively correlated with sRANKL and TRACP-5b, respectively. Serum concentrations of DKK-1 and sRANKL were significantly elevated in stage III vs stages I and II according to International Staging System (ISS) (46.33 ug/L vs 37.91 ug/L, 2.26 pmol/L vs 1.19 pmol/L, respectively, all P < 0.05). Serum concentrations of DKK-1, sRANKL and TRACP-5b were significantly higher in patients with more than 3 lytic bone lesions than those with only 1-3 lytic bone lesions (46.30 ug/L vs 31.98 ug/L, 2.18 pmol/L vs 0.69 pmol/L, 6.02 U/L vs 5.13 U/L, all P < 0.05). CONCLUSIONS: MM patients have increased serum DKK-1, sRANKL, OPG and TRACP-5b levels as compared with the healthy controls. Serum concentrations of DKK-1 and sRANKL have close relationship with MM stage and lytic bone disease. PMID- 21600092 TI - [Targeting to complete remission]. PMID- 21600093 TI - [Tight control of SLE]. PMID- 21600094 TI - [Target therapy of ankylosing spondylitis]. PMID- 21600095 TI - [Target therapy of biological agents]. PMID- 21600096 TI - [Tight control of rheumatoid arthritis]. PMID- 21600097 TI - [Chinese guidelines for diagnosis and management of cognitive impairment and dementia (III): psychometric selection]. PMID- 21600098 TI - [Modulation of RhoA/ROCK pathway on TLR-2 ligand-induced chemokine secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis]. AB - OBJECTIVE: To evaluate the modulation of RhoA/Rho kinase (ROCK) signaling pathway, a small Rho GTPase that is considered as an important modulator in inflammatory responses, on Toll-like receptor-2 mediated chemokine secretion in fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. METHODS: The RhoA activity was measured by a pull-down assay. And the ROCK activity was assessed by Western blot. The secretion of chemokines was measured by ELISA (enzyme-linked immunosorbent assay). MTT test was used to detect the cellular viability. RESULTS: The stimulation of peptidoglycan (PG, 5 mg/L) increased the levels of IL-8 (interleukin-8), RANTES (regulated upon activation normal T cell expressed & secreted) and MCP-2 (monocyte chemotactic protein-2) and boosted the activities of RhoA and ROCK versus the unstimulated RA FLS. And these effects of PG were suppressed by anti-TLR-2 monoclonal antibody. Inhibition of RhoA and ROCK with a specific inhibitor inhibited the secretion of IL-8, RANTES and MCP-2 in PG-induced RA FLS. CONCLUSION: The present study provides novel evidence that the RhoA/ROCK signal pathway modulates the TLR-2-mediated secretion of chemokines in RA FLS. It suggests that the inhibition of RhoA/ROCK may be a new therapeutic approach for RA. PMID- 21600099 TI - [Association study of WNT3A gene polymorphisms with the susceptibility to congenital scoliosis in a Chinese Han population]. AB - OBJECTIVE: To investigate whether the polymorphisms of WNT3A gene are associated with congenital scoliosis (CS) and its various clinical phenotypes in a Chinese Han population. METHODS: A total of 127 CS patients admitted into PUMC were enrolled into this case-control study between October 2005 and September 2007. There were 55 boys and 72 girls with a mean age of 12.90 years old. Another 127 scoliosis-free control subjects at the same hospital during the same study period were frequency-matched with regards to age (+/- 3 years) and gender. Genomic DNA was extracted by QIAamp DNA Blood Mini Kit from peripheral blood leukocytes of each subject who had signed informed consent. Based on the genotypic data from the International HapMap project, the main functional single nucleotide polymorphisms (SNPs) were initially selected. The patients in the case group were classified into different clinical phenotypes according to vertebral defect type, location of deformity, extent of developmental disruption, combined rib malformations and neural canal deformity. The genotying of all selected SNPs was performed by SNPstream technology (Beckman Coulter SNPstream). All data of SNPs with polymorphism were processed by the association analysis based on a single SNP and between phenotypes and SNPs. And the pairwise linkage disequilibrium was calculated in the control population by Haploview 4.1 software. RESULTS: The SNP1 (rs964941) and SNP2 (rs752107) of WNT3A were genotyped. There was no linkage disequilibrium between two SNPs. No association was observed between SNP1 and SNP2 genotypes or allele polymorphisms and risk of CS and various clinical phenotypes (P > 0.05). CONCLUSIONS: The genetic variants of WNT3A gene may not be associated with the susceptibility to CS and various clinical phenotypes of CS in Chinese Han population. PMID- 21600100 TI - [Early clinical outcomes of fixed-bearing versus mobile-bearing total knee arthroplasty]. AB - OBJECTIVE: To compare the early clinical outcomes of primary total knee arthroplasty by a fixed-bearing versus mobile-bearing prosthesis. METHODS: A total of 80 patients with osteoarthritis at our hospital from January 2008 to October 2008 were sequentially and randomly assigned into Group A (fixed-bearing prosthesis) (40 knees) and Group B (mobile-bearing prosthesis) (40 knees). And the data of the range of motion (ROM), Knee Society Score (KSS) and Western Ontario MacMaster (WOMAC) were collected at pre-operation and 6, 12 and 24 months post-operation respectively. RESULTS: The P values were as follows: KSS: 0.754, 0.802, 0.561, 0.764; HSS (Hospital for Special Surgery): 0.737, 0.361, 0.254, 0.330; WOMAC (Western Ontario and McMaster Universities) osteoarthritis index: 0.976, 0.557, 0.946, 0.818; ROM follow-up: 0.519, 0.646, 0.175, 0.276. No significant differences were found in clinical outcomes between two groups. CONCLUSION: The fixed-bearing and mobile-bearing prostheses show no difference in clinical outcomes. PMID- 21600101 TI - [Logistic regression analysis of clinical and ultrasonic features of breast nodules]. AB - OBJECTIVE: To create a breast nodule estimation model based on grayscale and color Doppler ultrasonography using Logistic regression that can screen out the specific features for distinguishing breast malignancy from benignancy. METHODS: From July, 2009 to May, 2010, 217 patients were enrolled in the study in peking university first hospital. Clinical data and ultrasonic features were evaluated in 219 breast nodules of 217 patients confirmed by surgical pathology. Logistic regression model was established to screen out significant ultrasonic indexes for differentiating breast malignancy from benignancy. A receiver operating characteristics curve was made to assess diagnostic value of the Logistic regression model. Correlation was analyzed between the Logistic regression model and surgical pathology. RESULTS: Logistic regression model: Logit(p) = -16.884 + 0.037 * age + 3.228 * longitudinal-transverse axis ratio + 1.412 * border + 2.663 * halo + 1.813 * microcalcium + 1.157 * resistance index + 2.204 * enlarged axillary lymph node (chi(2) = 167.107, P = 000). The areas of ROC curve for probability and identification of breast malignant and benign nodule were 0.948 and 0.882 respectively. Diagnostic sensitivity, specificity and accuracy were 91.6%, 84.9% and 88.9%. Logistic regression model positively correlated with surgical pathology (r = 0.768, P = 0.000). CONCLUSION: Our Logistic regression model can effectively differentiate malignant breast nodules from benign and can identify the ultrasonic features associated with breast cancer. PMID- 21600102 TI - [Atherosclerotic stenosis of intracranial and extracranial cerebral arteries in patients with cerebral infarction and the correlative factors]. AB - OBJECTIVE: To investigate the distribution of atherosclerotic stenosis of cerebral arteries in Chinese patients suffered from cerebral infarction, and to determine if there are any factors correlating with intracranial and extracranial atherosclerosis. METHODS: For this study, we enrolled 428 consecutive in-patients with cerebral infarction, All patients were examined with transcranial Doppler ultrasonography (TCD) and carotid duplex ultrasound to detect atherosclerotic lesions in intracranial and extracranial cerebral arteries, some also were examined by magnetic resonance angiography (MRA) and/or digital subtraction angiography (DSA), they were all diagnosed as atherosclerotic cerebral artery stenosis. The patients were divided into three groups according to the different location of lesions, the frequency of risk factors of atherosclerosis and the demographic parameters were compared among these groups. RESULTS: 199 cases (46.5%) had only intracranial artery stenosis, 129 cases (30.1%) had only extracranial artery stenosis, 100 cases (23.4%) had both intracranial and extracranial stenosis (combine group). Compared with the other two groups, the levels of total cholesterol and low density lipoprotein-cholesterol of the intracranial artery group are both significantly higher (TC: P(1) = 0.001, P(2) = 0.000; LDL-C: P(1) = 0.004, P(2) = 0.039), the combine group had a significant higher ratio of male than that of the intracranial artery group(P = 0.003), there were no any other atherosclerosis risk factors had association with the location of cerebral artery stenosis. CONCLUSION: The occurrence of stenosis in intracranial arteries is more frequent than that in extracranial arteries in Chinese patients with cerebral infarction, and the lipid level is higher in the intracranial artery group, most risk factors of atherosclerosis may not be major determinants of location for cerebral atherosclerosis. PMID- 21600103 TI - [Correlation of collateral circulation and prognosis in patients with acute cerebral infarction]. AB - OBJECTIVE: To evaluate the correlation of collateral circulation with prognosis in patients with acute cerebral infarction. METHODS: A total of 260 patients with acute ischemic stroke within 1 week of symptom onset underwent digital subtraction angiogram (DSA). The National Institutes of Health Stroke Scale (NIHSS) scores were obtained at admission. And the Modified Rankin scores (mRS) were assessed at a 3-month follow-up. The follow-up data were acquired through clinic visits or telephone interviews. RESULTS: Among them, 86 were found to have intra- or extra-cranial culprit artery severe stenosis or occlusion. And 36 (75.00%) in 48 patients had collateral arterial circulation while 11 (28.64%) in 38 patients posterior circulation. There were statistical differences in the NIHSS scores at admission and favorite clinical outcome (mRS <= 2) at 3-month follow-up for patients with and without collateral circulation. CONCLUSION: DSA is the golden standard for the assessment of collateral circulation in patients with severe cerebral artery stenosis or occlusion. The prognosis is better in stroke patients with collateral circulation. PMID- 21600104 TI - [Effect of remifentanil or esmolol on stress response during electric shock therapy in psychiatric patients]. AB - OBJECTIVE: To observe the effects of remifentanil or esmolol on the stress responses during electric shock therapy in psychiatric patients. METHODS: Upon the approval of institutional Ethics Committee, Eighty psychiatric patients requiring electric shock therapy were randomly divided into 2 groups:esmolol group (Group E) and remifentanil group (Group R) (n = 40 each). The patients in Groups E and R were injected with esmolol 1 mg/kg or remifentanil 2 ug/kg respectively before induction of anesthesia. Electric shock therapy was performed after a disappearance of fasciculation. MAP (mean arterial pressure) and HR (heart rate) were recorded at the following time points:prior to anesthesia (T0), prior to electric shock therapy (T1) and at 1 min (T2), 3 min (T3) & 5 min (T4) after electric shock therapy. Venous blood samples were collected at (T0) and (T4). The plasma levels of cortisol and norepinephrine were determined by enzyme linked immunosorbent assay. RESULTS: The levels of MAP and HR at T2, T3 were significantly higher than those at T0 in Group E (P < 0.05). And the levels of cortisol and norepinephrine at T4 were significantly higher than those at T0 in 2 groups (P < 0.05). However, their levels were significantly higher in Group E than those in Group R (P > 0.05). CONCLUSION: In modified electric convulsive treatment, remifentanil is superior to esmolol in maintaining the stabilization of cardiovascular system and effectively inhibiting the stress responses. PMID- 21600105 TI - [Preliminary application study of Ligasure in video-assisted thoracic pulmonary surgery]. AB - OBJECTIVE: To investigate the application and techniques of Ligasure in video assisted thoracic pulmonary surgery. METHODS: Use Ligasure to dissect lung parenchyma, small pulmonary vessel and stop bleeding in 15 cases spontaneous pneumothorax and 20 cases peripheral single lung node who undertaken video assisted thoracic surgery during October 2008 to June 2010. RESULT: All the procedures were successful, no severe complications, as active bleeding, continuous air leak occurred. A period of 9.3 months (2 - 18 months) follow-up of all patients shows no delayed bleeding or recurrence pneumothorax. CONCLUSION: Ligasure is safe, easy to use. It can optimize operation and reduce the operation time. PMID- 21600106 TI - [Wedge resection and thermal cautery for malignant pleural effusion caused by lung cancer under vats]. AB - OBJECTIVE: To discuss the treatment effect of wedge resection and thermal cautery of pleura for patients with malignant pleural effusion (MPE) caused by lung cancer under VATS. METHODS: 37 patients with MPE underwent wedge resection and thermal cautery of pleura under VATS, from June 2005 to December 2008. Postoperative tumor markers level was contrasted with the preoperative, and the control rate of pleural effusion and survival rate of the patients were compared with control group, including 25 patients undergoing intrapleural chemotherapeutics in the same period. RESULT: In the group, the control rate of pleural effusion was 100%, but 60% in control group (P = 0.005). The 1-year survival rate of the group and the control group was 78.38% and 60% respectively (P = 0.003). CEA and CA-125 were descended obviously in postoperative day 7 in the group(P = 0.002);in control group, there were no significant change of CEA and CA125 after treatment (P = 0.797). CONCLUSION: Wedge resection and thermal cautery of pleura under VATS can reduce tumor burden of patients with MPE to the maximum, and control MPE effectively and improve the quality of life for lung cancer patients with MPE. PMID- 21600107 TI - [A clinical study on reparation of orbital blowout fracture by bridge hydroxylapatite artificial bone]. AB - OBJECTIVE: To explore a minimally invasive technique with hydroxylapatite artificial bone to repair the orbital blowout fracture. METHODS: Twenty-one cases of orbital blowout fracture from March 2008 to April 2010 were enrolled. And the fractures were repaired with a bridge of hydroxylapatite artificial bone under a nasal endoscope. During a regular 6-month follow-up, anatomic and functional recovery was evaluated. RESULTS: There was neither postoperative visual loss nor infection in all cases. At 3 months post-operation, diplopia vanished completely (n = 17), remained in peripheral vision (n = 2), existed in primary ocular position (n = 2) and the deviation of eyeball (n = 1). At Month 3, diplopia in peripheral vision or in primary position and the deviation of eyeball showed no improvement. Compared with the uninjured side, enophthalmos: <= 2 mm (n = 18), > 2 mm (n = 2) and > 4 mm (n = 1). The passive traction test was positive in one case. On computed tomograph (CT) scanning, there was no bone dislocation or slippage in all cases. CONCLUSION: The surgical efficacy is excellent. The technique of combining the advantages of endoscopic sinus approach and hydroxyapatite artificial bone is worth a wider popularization. PMID- 21600108 TI - [Correlation between the distribution of CD133-positive cells and the proliferation of microvessels in glioblastoma multiforme]. AB - OBJECTIVE: To investigate the expression of CD133 and CD34 in different parts of glioblastoma and its margin and explore the invasive path of glioma stem cells within the tumor and surrounding tissue. METHODS: The surgical specimens were collected from the core of mass, junctional zones between tumor and peritumoral edematous areas and edematous areas in 52 patients with glioblastoma. Immunohistochemical cell staining and Western blot were employed to evaluate the expression of CD133 in different specimens while immunohistochemistry was used to detect the CD34-microvessel postforming. A correlation analysis was performed between them. RESULTS: The expression of CD133 was not detected in the control groups while the scores were 7.3 +/- 1.4, 5.2 +/- 1.1, 2.7 +/- 1.0 in junctional zones, tumor cores and edematous areas with immunohistochemistry and 0.79 +/- 0.03, 0.38 +/- 0.01, 0.20 +/- 0.04 with Western blot respectively. There were significant differences between different groups (P < 0.05). Under light microscope, the CD133-positive cells frequently forming perivascular pseudorosettes were dense in junctional zones and mostly clustered near the microvessels in tumor cores and scattered in edematous areas. At a high magnification (200*), the CD34-MVD (/HP) values were 31.3 +/- 4.0, 21.8 +/- 2.6, 15.3 +/- 2.4, 4.7 +/- 1.5 respectively in junctional zones, tumor cores, edematous areas and control tissues. Significant differences were also found in these groups (P < 0.05). The expression level of CD133-positive cell was positively correlated with the distribution of CD34-microvessels (r = 0.948, P < 0.05). CONCLUSION: Glioma stem cells tend to assemble in the junctional zones where the microvessels are enriched. There is probably an intimate nourishing relationship with the microvessels. The distribution of glioma stem cells may be related with the invasiveness within glioblastoma. PMID- 21600109 TI - [Morphologic and apoptotic changes of cervical posterior longitudinal ligament fibroblasts in response to in vitro mechanical stretch]. AB - OBJECTIVE: To investigate the effect of mechanical stretch force on the morphologic and apoptotic changes of fibroblasts derived from the OPLL (ossification of posterior longitudinal ligaments) patients. METHODS: The third passage cells were collected and subjected to 10% elongations cyclic mechanical stretching for 6 h and 24 h with Flexercell 4000(TM) strain unit. Their morphologic changes were observed and the post-stretching apoptotic rates quantified by flow cytometer. The gene expressions of alkaline phosphatase (ALP), collagen types I (COL I) and osteocalcin (OC) were examined. RESULTS: The treated cells were arranged along the vertical direction of force. Stretch force led to a slight increase of apoptosis rate at 6 h and a significant increase of apoptosis rate at 24 h. No significant difference in cellular senescence was observed between control group and treated group. The mRNA expressions of ALP, COL I and OC were positively up-regulated by cyclic stretch at 24 h. CONCLUSION: Stretching force can affect the cellular morphology, promote the osteogenic differentiation and enhance the cellular apoptosis. PMID- 21600110 TI - [Small world networks of the human brain]. PMID- 21600111 TI - [Chinese guidelines for diagnosis and management of cognitive impairment and dementia (IV): auxiliary examination and selection]. PMID- 21600112 TI - [The comparative study on high field MRI and pathology of Alzheimer's disease transgenic mice]. AB - OBJECTIVE: To observe and investigate the neuroimaging characters in early progression of transgenic Alzheimer's disease (AD) mice model, and make sure the diagnosis value of 7.0 T high field magnetic resonance microimaging (MRMI). METHODS: APP/PS-1 transgenic mice aged 3, 6, 9 months and the same aged wild type mice were each divided into 6 groups (6 mice in every groups) based on age. The mice brains were scaned with 7.0T high magnetic field MR. Then the mice were killed. The Abeta immunohistochemistry examination was analyzed in the mice brains specimens, and pathological changes were in comparison with the T(2) weighted imaging in the mice brains. RESULTS: There were a few Abeta plaques in the brains of 6 months APP/PS-1 transgenic mice, while Abeta plaques were increased both in number and volume in the cerebral cortex and hippocampus of 9 months AD mice. The brains of APP/PS-1 double transgenic mice of 3, 6 months and the control group mice were not showed intensity loss on T(2) weighted MR images, while the signal intensity loss was visualized in the cerebral cortex and hippocampus of 9 months AD mice. CONCLUSION: 7.0T high magnetic field MR could display Abeta plaques in the brains of APP/PS-1 double transgenic mice of 9 months and it is helpful to diagnosis early AD. PMID- 21600113 TI - [The value of MRI and MR DWI in diffuse lesion of the cerebral hemisphere]. AB - OBJECTIVE: To study the MRI and DWI appearance of diffuse lesion in the bilateral cerebral hemisphere. METHODS: 19 patients with diffuse lesion in the cerebral hemisphere were concluded in the study, 9 were male and 10 were female. The age range is from 16 to 70 years old and mean age is 45 years old. All of the patients performed MR scan on Philips 1.5 T MRI system. The parameters of SE-EPI DWI sequence, TR/TE 6225/118.7 ms, ETL 128, FLIP 90 degrees , thickness 5 mm, matrix 128 * 128, b = 1000 mm(2)/s. RESULTS: 3 cases of CJD which showed bilateral diffuse high signal intensity in the cerebral hemisphere on DWI, 4 cases of polyvinyl chloride (PVC) adhesive toxication, 2 cases of viral encephalitis, 3 cases of liver failure-related brain edema, 1 cases of delayed encephalopathy of CO toxication, all of the lesions showed high signal intensity both on DWI and ADC sequences. On the following MRI, most of the high signal recovered and the high signal disappeared. 4 cases of asphyxia with coma, 2 cases of H(2)S toxication, The lesion of them showed high signal intensity on DWI and low signal on ADC. CONCLUSION: DWI can sensitively show the lesion with limited diffusion. The patients with high signal intensity on both DWI and ADC indicating T(2) effect. PMID- 21600114 TI - [Functional connectivity analysis of super acute cerebral ischemia in rats: a resting-state functional MRI empirical study]. AB - OBJECTIVE: To investigate the change of low-frequency blood-oxygenation-level dependent fluctuation (LFBF) after cerebral ischemia by functional connectivity analysis in the resting state. METHODS: Super acute stroke rat-models with middle cerebral artery occlusion (MCAO) were employed in this study. Spontaneous fluctuations were recorded using a series of gradient-recalled echo-planar imaging (EPI) images before creation of the MCAO, and the same scan protocols were duplicated at the time of 60 min, 2 h after creation of the MCAO. FMRI signal time series from the different ROIs of ischemic cortex and normal cortex were preprocessed and low pass filtered. After preprocessing, the serial fMRI data was obtained by fast Fourier transformation to calculate the amplitude of the low-frequency fluctuations. Meanwhile, time course signal changes from a seed voxel of normal cortex were correlated with every voxel in the brain. Statistical analysis was performed across all rats to determine the extent of spatial correlation between regions. RESULTS: The amplitude of LFBF in the ischemic cortex between 0.01 and 0.1 Hz was lightly decreased during the super acute ischemic stroke. Howerever, the amplitude of LFBF in contralateral cortex was increased after 2 hours. Spatial distribution of LFBF, from cross-correlation analysis, indicates that the substantial inter-hemispheric synchrony of ischemic region was decreased and of contralateral cortex was enhanced during the super acute ischemic stroke. CONCLUSION: The contrast behavior of the resting state BOLD signal fluctuations and a intra-hemispheric symmetry in the LFBF with similar phase characteristics in most other regions during super acute ischemic stroke can be implied a new approach to detect the physiological activity functions and the distinct resting neural networks after the acute ischemic stroke takes place. PMID- 21600115 TI - [Effects of ankle-foot orthosis on gait stability and balance control in patients with hemiparetic stroke]. AB - OBJECTIVE: To quantitatively analyze the effects of ankle-foot orthosis (AFO) on gait stability and explore its use for walking capacity, gait stability and balance control in post-stroke patients. METHODS: A total of 25 inpatients with prior chronic hemiparesis from stroke who could walk at least 10 meters without assistance were recruited. The maximal walking speed and gait asymmetry index were examined by a motion analysis system. Functional balance was assessed by the Functional Ambulation Categories, Berg Balance Scale and Five-Times-Sit-to-Stand Test. RESULTS: AFO had positive effects on the hemiplegic gait parameters of improving walking speed, gait stability and functional balance (P < 0.01). Pair wise comparisons suggested that there were significant differences in the maximal walking speed, Functional Ambulation Categories and gait asymmetry index after an immediate use of AFO (P < 0.05). At Week 4, there were significant differences in the parameters of walking speed, gait asymmetry index and functional balance control (P < 0.01). CONCLUSION: The use of AFO may compensate the instability of gait and balance. Functional tests improve significantly with orthosis. PMID- 21600116 TI - [Epidemiological study of hepatolenticular degeneration at Hanshan County, Anhui Province]. AB - OBJECTIVE: To identify the incidence and morbidity rates of hepatolenticular degeneration (HLD) at Hanshan County, Anhui Province. METHODS: According to the principles of age stratification, cluster and random sampling, a total of 112 810 subjects were screened by cornea slit-lamp examination during the period of November 2008 to October 2009. The subjects were from recruited from schools, factories, communities, institutions and villages at Hanshan County. And they belonged to the age group of 7 - 75 years. At the same time, each subject was evaluated by the clinical examination with regards to the presence of such clinical manifestations as brain, liver, kidney, skin and other organ damage. And the examinations of copper biochemistry and abdominal ultrasound were performed for those subjects with K-F rings or their clinical manifestations suspicious of HLD. In order to confirm or exclude HLD, the penicillamine challenge test (PCT) was performed if necessary. RESULTS: Seven HLD patients had a definite diagnosis of HLD. There were classical Wilson type (n = 1), pseudosclerosis type (n = 1), mental disorder type (n = 1), liver type (n = 1) and presymptomatic (n = 3). The incidence rate was 2.66/100 000 and the prevalence rate 6.21/100 000 at Hanshan County, Anhui Province. CONCLUSION: HLD is a common disease. In order to avoid a misdiagnosis and prevent an incorrect treatment, physicians should pay more attention to this curable disease and try their best to achieve early detection, early diagnosis and early treatment. PMID- 21600117 TI - [A prospective randomized trial of comparing the clinical outcome of tension-free vaginal tape and transobturator tape for stress urinary incontinence]. AB - OBJECTIVE: To compare the morbidity and efficacy of tension-free vaginal tape (TVT) and transobturator tape (TVT-O) procedures in the treatment of stress urinary incontinence. METHODS: A total of 315 women were randomly assigned to undergo the procedure of either TVT (n = 160) or TVT-O (n = 155). Some patients underwent vaginal repair, hysterectomy, hysterosalpingo-oophorectomy, posterior intravaginal slingplasty or sacrospinous ligament fixation as concomitant procedures as indicated. RESULTS: Fifteen patients were lost to follow-up. And the median follow-up period was 27 months. The curing rates were 93.5%, 89.6%, 87.2% and 82.9% in the TVT group and 91.1%, 89.8%, 86.2% and 83.3% in the TVT-O group at 6, 12, 24 and 36 months respectively. No significant difference could be found for the curing rates between two groups at the same follow-up time and between 6-36 months follow-up in each group (P > 0.05). The median operative duration of the TVT-O group was significantly shorter than that of the TVT group [(18.7 +/- 4.2) vs (24.3 +/- 4.5) min] (P < 0.01). Compared with the TVT group, the TVT-O group had more patients complaining of groin and thigh pain (P < 0.05). CONCLUSION: Both approaches appear to lower the peri- and post-operative complication rates and have an equal efficacy in the surgical treatment of stress urinary incontinence during a 3-year follow-up. However, TVT-O has a shorter operative duration with a higher rate of groin and thigh pain. PMID- 21600118 TI - [Primary culture and adipogenic process of pre-adipocytes from infrapatellar fat pad of osteoarthritic patients]. AB - OBJECTIVE: To investigate the primary culture and adipogenic process of pre adipocytes from infrapatellar fat pad of osteoarthritic patients. METHODS: The pre-adipocytes were isolated by enzymatic digestion. The morphological changes of cultured cells were observed and the growth curve was drawn by CCK-8 method. During the adipogenic process, the intracytoplasmic lipid of differentiated cells was determined by oil red O staining. And the adiponectin levels in the culture supernatants were measured by ELISA (enzyme-linked immunosorbent assay). RESULTS: The primary cultured fibroblast-like cells were spindle-shaped. In the process of adipogenesis, the intracytoplasmic lipid droplets were observed at Day 3 and over 80% of the cells differentiated into adipocytes at Day 21. With the increasing number of adipocytes, the adiponectin levels in the culture supernatant elevated and peaked at Week 3. The differentiated cells were proven to be adipocytes functioning actively. CONCLUSION: The primary culture and adipogenic process of pre-adipocytes in infrapatellar fat pad of osteoarthritic patients has been successfully established. Thus it may provide an ideal model for the study of endocrine function of infrapatellar fat pad and understanding its role in the pathogenesis of osteoarthritis. PMID- 21600119 TI - [Viral load, genomic integration frequency of human papillomavirus 16 in cervical cancer and precancerous lesions]. AB - OBJECTIVE: To investigate the association between viral load, genomic integration frequency of HPV 16 and cervical carcinogenesis and assess the probability that HPV 16 integration frequency may be utilized as a marker for cervical cancer. METHODS: Forty cases of HPV16 single infection were selected from 337 cervical scrape samples by PCR (polymerase chain reaction) amplification and DNA sequencing. The copy numbers of E2, E6 and beta-actin were quantified to evaluate the viral load and integration status by real-time PCR. RESULTS: (1) The median number of adjusted viral load of normal group, LSIL (low-grade squamous intraepithelial lesion) group, HSIL (high-grade squamous intraepithelial lesion) group and squamous cervical cancer group were 0.11, 18.55, 44.63 and 7.6 copies per cell respectively. The viral load was higher in LSIL-HSIL group than that in normal group while lower in squamous cervical cancer group than that in HSIL group. (2) The median number of E2/E6 was 0.93 in normal group, 0.84 in precancerous group (LSIL-HSIL) and 0.64 in squamous cervical cancer group respectively. It showed a descending trend with the progression of cervical disease. (3) With the disease development, the proportion of episomal form decreased (normal group 4/5, LSIL group 4/6, HSIL group 10/16, cervical squamous cancer group 5/13) whereas that of integrated form (mixed and totally integrated) increased (normal group 1/5, LSIL group 2/6, HSIL group 6/16, cervical squamous cancer group 8/13). Both totally integrated cases were cervical squamous cancer. CONCLUSION: (1) HPV 16 viral load may not be an ideal marker to predict cervical carcinogenesis. (2) Due to a positive correlation between HPV16 genomic integration frequency and cervical neoplastic progression, HPV 16 integration frequency may be a potential marker of early diagnosis for cervical lesion progression. PMID- 21600120 TI - [Significance for the detection of human papillomavirus DNA in cervical atypical glandular cells]. AB - OBJECTIVE: To evaluate the potential link between high-risk human papilloma virus (HPV)DNA testing and histological diagnosis in women referred for atypical glandular cells (AGC) at Pap smear. METHODS: All cervical cytological examinations with the diagnosis of AGC between January 2007 and Dec 2009 were identified by means of a computerized database in 97 patients. The histopathological results of cervix were analyzed by colposcopic biopsy, dilatation and curettage (D&C), cervical loop electrosurgical excision procedure (LEEP) and high-risk human papilloma virus DNA testing. RESULTS: (1) All patient were monitored by colposcopy, histopathology and HPV DNA test. Sixty-four patients had pathologic lesions. (2) In predicting the presence of high-grade of cervical intraepithelial neoplasia, the sensitivity of human papilloma virus was 96%, specificity 92.86%, positive predictive value 96% and negative predictive value 92.86%. (3) 98.9% of the AGC patients received colposcopic, cytological examinations and HPV test at follow-ups: 3 cases of PAP smear and 6 cases of HPV testing were abnormal at the first follow-up, and 100% negative for cytological examination and HPV test at the second follow-up visit. CONCLUSION: HPV DNA test and colposcopic examination are effective in the initial evaluation and subsequent follow-ups of cytological atypical glandular cells. PMID- 21600121 TI - [Effects of fatigue and restraint stress on the expression of carnitine palmitoyltransferase-I and 5-hydroxytryptamine receptors in aorta of rats]. AB - OBJECTIVE: To investigate the effect of fatigue and restraint stress on the expressions of CPT (carnitine palmitoyltransferase)-I, PPAR (peroxisome proliferator-activated receptor) delta, 5-HT (hydroxytryptamine) 1D and 5-HT2A receptors in aorta of rats. METHODS: A total of 45 healthy male Wistar rats were randomly divided into control group, excessive fatigue group and restraint stress group (n = 15 each). The general condition, morphological changes of aortic endothelium cell and the blood levels of ET-1 (endothelin) and NO (nitric oxide) were observed. The real-time reverse transcription PCR (polymerase chain reaction) and Western blot were used to detect the gene and protein expressions of CPT-I, PPAR delta, 5-HT1D and 5-HT2A receptors in aorta. RESULTS: Compared with control group, the structural damages of endothelial cell were induced by excessive fatigue and restraint stress. The plasma levels of ET-1 increased [(124 +/- 18) ng/L vs (161 +/- 18) ng/L, (154 +/- 17) ng/L] (P < 0.01, P < 0.05) while the serum levels of NO decreased [(63 +/- 16) umol/L vs (39 +/- 8) umol/L, (41 +/ 7) umol/L] (P < 0.05); the mRNA expressions of CPT-Iand PPARdelta decreased in excessive fatigue rats, [(1.23 +/- 0.21) vs (0.42 +/- 0.05)], [(1.09 +/- 0.10) vs (0.25 +/- 0.07)] (P < 0.01); the protein expressions of CPT-Iand PPARdelta decreased in excessive fatigue rats, [(1.32 +/- 0.07) vs (0.83 +/- 0.04)], [(1.41 +/- 0.05) vs. (0.75 +/- 0.06)]; the mRNA and protein expressions of 5-HT1D receptor decreased in excessive fatigue rats and restraint stress rats, [(1.10 +/ 0.15) vs (0.46 +/- 0.13), (0.45 +/- 0.02)], [(1.19 +/- 0.05) vs (0.71 +/- 0.06), (0.70 +/- 0.05)] (P < 0.01); the mRNA and protein expressions of 5-HT2A receptor increased in excessive fatigue rats and restraint stress rats, [(0.99 +/- 0.08) vs (6.73 +/- 0.46), (7.01 +/- 1.56)], [(0.64 +/- 0.03) vs (0.79 +/- 0.05), (0.82 +/- 0.03)] (P < 0.01). CONCLUSION: Excessive fatigue and restraint stress can injure the structure and function of endothelial cell. The changes in energy of abnormal carnitine metabolism and 5-HT receptors may play important roles. PMID- 21600122 TI - [Patterns of osteoprotegerin or nuclear factor kappa B ligand gene expression in the treatment of bone defect with bone marrow stem cell transplantation and low frequency vibration]. AB - OBJECTIVE: To explore the effect of low frequency vibration (LFV)on the osteogenic differentiation regulating capability of bone marrow stromal cell (BMSC)and the expressions of OPG (osteoprotegerin) mRNA and RANKL (nuclear factor kappa B ligand) mRNA through living animal experiment. METHODS: Both BMSC transplantation and low-frequency vibration were employed to treat bone defects. The groups were randomized into non-vibration and vibration of different frequencies. The vibration group received vibrating interventions at Day 7 for 5 weeks. After vibrations, the BMSC OPG and RANKL mRNA of different frequency groups were detected. RESULTS: The BMSC OPG and RANKL gene expressions significantly increased (P < 0.05), especially at 25 Hz (P < 0.01). And for the vibration group at 100 Hz, the BMSC OPG and RANKL gene expressions decreased (P < 0.05). CONCLUSION: Low-frequency vibration may promote the osteogenic differentiation capability of BMSC probably through regulating the OPG/RANKL mRNA expression, directly promoting bone formation and inhibiting bone resorption. PMID- 21600123 TI - [Effect of aspirin administration for the treatment of osteoporosis in ovariectomized rat model]. AB - OBJECTIVE: To explore the therapeutic effects of aspirin on postmenopausal osteoporosis and understand its action mechanism. METHODS: Forty three-month-old female SD rats were randomly divided into 5 groups (n = 8 each): sham group, OVX group and aspirin groups (A1, A2 & A3). The OVX and aspirin groups were ovariectomized (OVX). All rats underwent BMD (bone mineral density) scan at the time of OVX and 3 months after OVX. After the animal model of osteoporosis was established, aspirin groups were intragastrically administered at a dose of 8.93 mg*kg(-1)*d(-1) (A1), 26.79 mg*kg(-1)*d(-1) (A2) and 80.36 mg*kg(-1)*d(-1) (A3) daily in OVX rats. Three months later, the BMD and micro-architecture of vertebrae were measured by dual-energy X-ray absorptiometry and microtomography. Alkaline phosphatase and osteocalcin were measured in peripheral blood. The trabecular architecture changes were observed by histomorphology. Axial compression tests were used to evaluate the mechanical properties of vertebral specimens and three-point bending tests used for femur shaft. RESULTS: Three months after ovariectomy, BMD was significantly lower than preoperative. BMD in aspirin treated groups was significantly higher than that in OVX group. Alkaline phosphatase in peripheral blood decreased significantly in aspirin groups than those in OVX, but osteocalcin had no significant difference between aspirin and OVX groups. The microtomography reconstruction analysis also showed that the trabecular thickness, trabecular number and BMD increased significantly in aspirin groups than those in OVX. And there was no significant difference between A3 and sham groups. The results of biomechanical test showed that the maximum compression load of lumbar spine and three-point bending load of femur shaft were significantly higher in aspirin groups than those in OVX group. CONCLUSION: Aspirin can promote trabecular bone remodeling, improve three-dimensional structure of trabecular bone and increase bone density of cancellous in osteoporotic rats by stimulating bone formation. It may become a new drug for the treatment of osteoporosis. PMID- 21600124 TI - [Chinese guidelines for diagnosis and management of cognitive impairment and dementia (I): dementia diagnostic procedures]. PMID- 21600125 TI - [Correlation study on sensory gating P50 and Wisconsin card sorting test in schizophrenics with violent behaviors]. AB - OBJECTIVE: To analyze the variations of sensory gating and executive functions in schizophrenics with violent behaviors, and the relationship between sensory gating and executive functions. METHODS: Thirty-five schizophrenics with violent behaviors (Group V) and 32 healthy control persons (Group C) were recorded by P50 with EGI 256 high density EEG. They were also examined by Wisconsin card sorting test (WCST) and followed up for 3 months. The relationship of sensory gating P50 and WCST was evaluated by Person's analysis. RESULTS: (1) Compared with Group C, Group V showed a higher amplitude of S2-P50 [baseline: (1.8 +/- 1.1) vs (0.9 +/- 0.6) uV; 3-month treatment: (1.9 +/- 1.6) uV]. There was a higher S2/S1 ratio, a lower S1-S2 difference and 100 * (1-S2/S1) at baseline and after 3 months (P < 0.05) [baseline: S2/S1, S1-S2 and 100 * (1-S2/S1) in both groups respectively [(89 +/- 49) vs (42 +/- 25), (0.7 +/- 2.5) vs (1.4 +/- 1.2), (11 +/- 49) vs (58 +/- 25); 3 months treatment: (170 +/- 277, -0.0 +/- 1.8, -70 +/- 277)]; (2) At baseline and after a 3-month treatment, two groups had no difference in learning [baseline (t = -0.585, P = 0.561), 3 months (t = -0.021, P = 0.983)] (P > 0.05) and there were significant differences in other indices (P < 0.05); (3) No relationship was found between S2/S1 ratio, S1-S2 and WCST in two groups at baseline and after a 3-month treatment by Person's analysis. CONCLUSIONS: The schizophrenics with violent behaviors have sensory gating deficits and abnormal executive functions before and after treatment. Sensory gating and executive functions may reflect different brain functions in schizophrenics. PMID- 21600126 TI - [Study of fas-mediated Foxp3+CD4+CD25+ Treg cell apoptosis in patients with systemic lupus erythematosus]. AB - OBJECTIVE: To explore the role of fas apoptosis signal transduction pathway in the abnormal apoptosis of Foxp3+CD4+CD25+ Treg in patients with systemic lupus erythematosus (SLE). METHODS: Twenty-five active SLE patients, 20 remission SLE patients and 25 controls were selected. The level of fas expression on peripheral blood Foxp3+CD4+CD25+ Treg surface was detected in SLE patients. And analyzed the expression rate of Foxp3 on CD4+CD25+ T cells was analyzed to explore the relationship between the expression rate and disease activity. RESULTS: (1) The expression rate of fas on Foxp3+CD4+CD25+ Treg was (23.72 +/- 2.35)%, (14.0 +/- 2.1)% in active and remission SLE groups respectively versus (10.1 +/- 1.2)% in control group. The fas expression rate of active SLE group was significantly higher than those of remission SLE group(P < 0.01)and control group (P < 0.01). And the remission SLE and control groups were not statistically significant (P > 0.05). The expression rate of fas on the Foxp3+CD4+ CD25+ Treg was positively correlated with the SLEDAI (SLE disease activity index) score (r = 0.336, P < 0.05). (2) The expression rate of Foxp3 on CD4+CD25+ T cells was (2.83 +/- 0.30)%, (5.38 +/- 0.63)% in active and remission SLE groups respectively versus (8.12 +/- 0.70)% in control group. The expression rate of Foxp3 was significantly lower in active SLE group than that in remission SLE group (P < 0.01)and control group (P < 0.01). And the Foxp3 expression rate of remission group was also lower than that of control group (P < 0.05). The expression rate of Foxp3 was negatively correlated with the SLEDAI score (r = -0.581, P < 0.01). (3) The expression rate of Foxp3 was negatively correlated with fas (r = -0.349, P < 0.01). CONCLUSION: The abnormal apoptosis of Foxp3+CD4+CD25+ Treg mediated by the fas apoptosis signal transduction pathway may be one of the pathogenic mechanisms of disease activity in SLE patients. PMID- 21600127 TI - [Application value of diffusion-weighted imaging in ischemic-type biliary lesions after liver transplantation]. AB - OBJECTIVE: To discuss the application values of DWI (diffusion-weighted imaging) and ADC (apparent diffusion coefficient) on ischemic-type biliary lesions (ITBL) after orthotopic liver transplantation. METHODS: According to whether there was ITBL after liver transplantation or not, 46 cases of liver transplantation were selected and divided into 2 groups on the basis of PTC (percutaneous transhepatic cholangiography) or ERCP (endoscopic retrograde cholangiopancreatography) examination, pathology or clinical follow-up data: ITBL group (n = 29) and no ITBL group (C group, n = 17). The ADC value was measured for right lobe of graft liver parenchyma (b value = 600 s/mm(2)). And the signal of biliary system of graft on DWI and biliary tract on MRCP were analyzed. RESULTS: (1) The ADC values of liver graft were (1.456 +/- 0.286) * 10(-3) mm(2)/s and (1.716 +/- 0.391) * 10(-3) mm(2)/s in ITBL and C groups respectively. The difference in ADC value was significant between two groups (P = 0.015); (2) the incidence of increased signal of bile duct on DWI was 82.8% (24/29) and 5.9% (1/17) for ITBL and C groups respectively. The lesion was located in porta hepatis and intrahepatic small bile duct was seen in 17 of 24 patients (70.8%) in ITBL group. The difference was significant in signal of bile ducts between ITBL and C groups (P < 0.001). Twenty one cases with sludge on DWI in ITBL group had hyperintensity, isointensity or hypointensity. There was no abnormal signal in the lumen of bile duct in C group. CONCLUSION: The major sign of ITBL is a hyperintensity of porta hepatis and small bile ducts on DWI. And the ADC value of graft liver parenchyma decreases. These reflect the pathological changes to an extent and may be an effective and sensitive monitoring tool of early ITBL. DWI is a novel, non-invasive, simple and practical method in the diagnosis and differential diagnosis of ITBL after liver transplantation. PMID- 21600128 TI - [Effect of pediatric TCI system for propofol plus remifentanil in pediatric short duration surgery with laryngeal mask airway anesthesia]. AB - OBJECTIVE: To study the effect of a pediatric TCI patent system for propofol plus remifentanil in pediatric short-duration surgery with laryngeal mask airway (LMA) anesthesia. METHODS: A total of 120 pediatric patients underwent short-duration elective surgery, aged 3 - 9 years old, weighted 13 - 26 kg, ASAI grade, were randomly divided into 3 groups (n = 40 each). The propofol concentrations of effect compartment were set at 2 ug/ml in Group A, 3 ug/ml in Group B and 4 ug/ml in Group C. The remifentanil initial concentration of plasma compartment was 2 ng/ml and increased stepwise by 0.5 ng/ml until a successful insertion of LMA. The remifentanil concentration was recorded when LMA was successfully inserted and the cases were numerated at the each remifentanil concentration. Heart rate (HR), mean arterial pressure (MAP), BIS (bispectral index) values and postoperative adverse events were also recorded at the time points of pre induction (T0), 2 min post-remifentanil TCI (T1), LMA insertion (T2), skin incision (T3), 5 min post-skin incision (T4), 10 min post-skin incision, (T5) and beginning surgery (T6). RESULTS: The satisfactory ratios of a successful insertion of LMA were highest in remifentanil 3.0 ng/ml (AR subgroup), 2.5 ng/ml (BR subgroup) and 2.0 ng/ml (CR subgroup) respectively. The laryngeal mask satisfactory ratio was high in BR subgroup (P < 0.05). There were significantly differences of T1-T5 values of HR, MAP and BIS in AR and CR subgroups (P < 0.05), but not in BR subgroup. The above-mentioned monitoring indices at T2 in AR subgroup and T3 in CR subgroup were significantly higher than those in BR subgroup. There were more adverse reactions in CR and AR subgroups versus BR subgroup (P < 0.05). CONCLUSION: The patented system for propofol 3 ug/ml effect compartment concentration plus remifentanil 2.5 ng/ml plasma concentration TCI displays stable hemodynamics, less stress, fewer complications and better clinical outcomes in pediatric short-duration surgery with LMA anesthesia. PMID- 21600129 TI - [A comparison of target controlled versus manually controlled infusion of propofol in elderly patients]. AB - OBJECTIVE: To evaluate the impact of anesthesia via target-controlled infusion (TCI) on drug consumption, intraoperative hemodynamic stability and recovery compared with manual-controlled infusion (MCI) in elderly patients. METHODS: Under the approval of the hospital ethics committee, 60 elderly patients undergoing laparoscopic surgery were randomly allocated by random numbers to either the MCI group (n = 30) or the TCI group (n = 30). The patients in MCI group received an infusion of propofol at 200 ml/h while those in TCI group propofol at an initial plasma concentration of 2.0 ug/ml and titrated upwards by 0.5 ug/ml steps until loss of consciousness. Both groups received an infusion of remifentanil. After intubation, the infusion rate or the target concentration of propofol was titrated to maintain BIS (bispectral index) values between 40 and 60. The infusion of remifentanil was adapted to intraoperative hemodynamics. The doses of propofol and remifentanil were recorded, the hemodynamic parameters and the use of vasoactive drugs collected and the recovery times assessed. RESULTS: The time of loss of consciousness and the time to intubation, the doses of propofol and remifentanil during induction and maintenance were not significantly different between two groups. The times of pump adjustment were less in TCI group versus MCI group [(5.8 +/- 2.1) vs (7.8 +/- 3.7) times, P < 0.01]. Blood pressure and heart rates were not statistically different at any time point between two groups. There were no significant differences in BIS or the use of vasoactive drugs between two groups. The recovery times were similar for two groups. CONCLUSION: Although target infusion system is easy to use and requires less time of adjustment, it fails to show added benefit on propofol consumption, hemodynamic stability, anesthesia depth and recovery in elderly patients. PMID- 21600130 TI - [Diagnostic analysis of hospitalized patients with fever of unknown origin at department of infectious diseases]. AB - OBJECTIVE: To explore the etiology, diagnostic methods and procedures for patients with fever of unknown origin (FUO) at department of infectious diseases. METHODS: A total of 368 FUO patients admitted to department of infectious diseases from 2002 to 2009 were retrospectively reviewed. The correlations of etiologies and diagnostic methods with gender, age and progress of fever were analyzed. RESULTS: Among them, 112 (30.4%) cases were recognized in 2 weeks (diagnosis, n = 107; recovery with unknown causes, n = 5). A final diagnosis was established in 241 (94.1%) from the remaining 256 FUO patients (124 males, 132 females). Among them, the causes were infectious diseases (n = 193), rheumatologic/autoimmune diseases (n = 32) and hematological diseases/tumors (n = 16). The etiologies were infectious diseases (n = 95), rheumatologic/autoimmune diseases (n = 10), hematological diseases/tumors (n = 10) and unknown etiology (n = 9) in males respectively; infectious diseases (n = 98), rheumatologic diseases (n = 22), hematological diseases or tumors (n = 6) and unknown etiology (n = 6) in females respectively. Age of patients: < 14 yr (n = 10), 15 - 20 yr (n = 37), 21 - 50 yr (n = 110), 51 - 60 yr (n = 48) and > 61 yr (n = 51). Thermal process was < 4 weeks (n = 83) including 74 infectious diseases cases and > 8 weeks (n = 63), including infectious diseases (n = 21) and rheumatologic disease (n = 20). CONCLUSION: Some FUO outpatients may be promptly confirmed by history taking, physical examination and routine examinations. The major cause is infection. Other causes of FUO are infectious diseases, rheumatological/autoimmune diseases and hematological diseases/tumors. For the diagnosis of FUO patients, gender, age and thermal process should be considered. PMID- 21600131 TI - [Clinical analysis of acute encephalocele during operation in 21 patients with severe craniocerebral injury]. AB - OBJECTIVE: To analyze the clinical features of acute intra-operative encephalocele and the proper prophylactic-therapeutic measures for severe craniocerebral injury. METHODS: The clinical data were collected and analyzed for 21 patients with severe head injuries who suffered acute intra-operative encephalocele from June 2008 to May 2010. There were 12 males and 9 females with an age range of 18 - 69 years old. RESULTS: Among these patients, 6 died with a mortality rate of 28.5%. It was lower than that reported in literatures. One patient died post-operatively of severe brain swelling and intracranial infection secondary to leakage of cerebrospinal fluid. Four patients died of severe craniocerebral injury, brain swelling and brain stem failure. And 1 patient died after his guardian abandoned the treatment. The follow-up period for the remaining 15 surviving patients was 3 - 6 months. According to the Glasgow outcome score (GOS), there were a favorable prognosis (n = 9), moderate disabilities (n = 5) and severe disability (n = 1). CONCLUSION: The probability of acute intra-operative encephalocele may be predicted in advance with a combination of clinical features and computed tomographic scans. The therapeutic success rate of acute encephalocele will be boosted by taking protective and therapeutic measures pre- and intra-operatively. PMID- 21600132 TI - [Expression of orphanin in adenomyosis and its relationship with dysmenorrhea]. AB - OBJECTIVE: To study the expression of nociceptin in adenomyosis tissue and understand its relationship with the severity of dysmenorrhea. METHODS: The myometrial specimens were collected from 55 patients undergoing hysterectomy at our hospital during December 2007 and June 2008. Their mean age was 41 - 52 years old. There were 34 adenomyosis patients in case group and 21 other patients in control group. Immunohistochemical staining was employed to detect nociceptin in eutopic endometrium and ectopic endometrial tissues in case group and normal endometrium and myometrial tissues in control group. RESULTS: The expression of nociceptin was significantly higher in the eutopic endometrial tissue (7.1 +/- 1.7) of case group than those in endometrial (2.7 +/- 2.0) and myometrial tissues of control group (P < 0.05); The expression of nociceptin was higher in the eutopic endometrial tissue (7.4 +/- 1.5) of dysmenorrhea group than that of non dysmenorrhea group (5.0 +/- 1.2) in case group (P < 0.05); The expression of nociceptin in eutopic endometrium and myometrium was the highest in severe dysmenorrhea group (8.4 +/- 1.3). And the non-dysmenorrhea and mild dysmenorrheal groups had no significant differences [(5.0 +/- 1.2) vs (6.8 +/- 1.4)]. And it decreased gradually in moderate dysmenorrhea, mild dysmenorrhea and non dysmenorrhea groups. CONCLUSION: A high expression of nociceptin in adenomyosis may be one of the casual factors of dysmenorrhea. The severity of dysmenorrhea is positively correlated with the expression of nociceptin in eutopic endometrial tissue in case group (r = 0.515, P = 0.034) and ectopic endometrium tissue. And the endometrial expression of nociceptin may be monitored dynamically to track the development of adenomyosis. PMID- 21600133 TI - [Clinical analysis of lymph node metastasis in 695 cases of early invasive cervical carcinoma]. AB - OBJECTIVE: To evaluate the clinical characteristics of pelvic lymph node metastases in patients with early-stage cervical carcinoma. METHODS: The clinical, pathologic and follow-up data of patients with cervical carcinoma treated at our hospital from June 2006 to May 2008 were collected and analyzed retrospectively. The relevant literature was reviewed. RESULTS: The median age at diagnosis was (45.6 +/- 3.8) years old. Among these patients, 587 patients (92.3%) were of squamous cell cervical carcinoma while 49 patients (7.7%) cervical adenocarcinoma.But the differences of pelvic lymph node metastases were not significant(P > 0.05). The overall prevalence of lymph node metastasis was 10.9% (69/636). The rate of pelvic lymph node metastases became significantly high up from the clinical stage I(b1). When the pelvic nodes were positive, the obturator group was involved in 69 cases (69/120). CONCLUSION: There is an increased rate of pelvic lymph node metastasis in the patient groups of clinical stage I(b1)-II. And the obturator group is predominantly involved. Thus a routine pelvic lymphadenectomy is essential. PMID- 21600134 TI - [The diagnostic value of MSCT multi-dimensional reconstructions for congenital vascular ring with tracheal stenosis]. AB - OBJECTIVE: To evaluate the diagnostic value of multi-slice CT (MSCT) reconstructions for congenital vascular rings together with tracheal stenosis. METHODS: 9 cases of children with congenital vascular ring and tracheal stenosis confirmed by surgery were collected in the study, all cases had undergone thin slice CT contrast enhancement, the MSCT data were transmitted to the workstation for multiplanar reconstruction (MPR), volume rendering technique (VRT) and VR transparency reconstruction. With the surgical results as the gold standard, the imaging characteristics of echocardiography (UCG) and MSCT were comparatively analyzed. RESULTS: In 9 cases, there were 4 cases of pulmonary artery sling, 3 cases of right aortic arch combination with left aberrant subclavian artery, 1 case of double aortic arch, 1 case of innominate artery compression syndrome. In this group, 5 cases were accompanied with other cardiac malformations (tetralogy of Fallot in 2 cases, double outlet right ventricle with patent ductus arteriosus and ventricular septal defect in 1 case, ventricular septal defect in 1 case, double superior vena cava in 1 case), 1 case of tetralogy of Fallot demonstrated many tortuous collateral arteries around aorta. All malformations were well displayed by VRT, MPR. VR transparency reconstruction can stereoscopically display trachea and bronchial compression condition, the main trachea was compressed in 6 cases, the main trachea and left main bronchus was compressed in 2 cases, the main trachea and left main bronchus was compressed in 1 cases, UCG detected all intracardiac malformations, 1 case of pulmonary artery sling was misdiagnosed as patent ductus arteriosus, 8 cases of vascular rings, tracheal and bronchial stenosis were missed. CONCLUSION: MSCT reconstruction technology is a noninvasive, rapid diagnostic method, it can clearly show the congenital vascular rings abnormalities and the degree of tracheal stenosis, it has important significance for clinic treatment. PMID- 21600135 TI - [Effect of bronchial intubation for constant-pressure expanding ipsilateral lung on postoperatively intractable atelectasis in hypo-analgesia and muscle relaxation]. AB - OBJECTIVE: To investigate the effect of bronchial intubation for constant pressure expanding ipsilateral lung on postoperative intractable atelectasis. METHODS: For this prospective study, we recruited 18 patients with pulmonary atelectasis who could not been relieved by bronchoscopic suctioning, closed thoracic drainage, backslap, blowing hall and other routine treatments for over a week. After bronchial intubation, ipsilateral lung was expanded with a constant pressure. And the therapeutic effect was evaluated by chest radiographic examination and auscultation at the following day. RESULTS: Collapsed lung tissue were examined in 15 patients (83.3%) after the first treatment and in 2 patients (11.1%) after twice inflation. And another case failed even after three times treatment. During the procedure, the vital signs of all patients were stable and no complication occurred. CONCLUSION: Constant-pressure expanding of ipsilateral lung during bronchial intubation is a safe and effective treatment for postoperative intractable atelectasis. PMID- 21600136 TI - [The application of remifentanil-propofol and remifentanil-midazolam analgesia for choledochofiberscopic dilatation of bile duct]. AB - OBJECTIVE: To evaluate the safety and efficacy of remifentanil-propofol and remifentanil-midazolam analgesia for choledochofiberscopic dilatation of bile duct. METHODS: 95 patients undergoing choledochofiberscopic dilatation of bile duct were reviewed, 43 of which were dealt with remifentanil-propofol (PR) and 52 with remifentanil-midazolam (MR). After medication, changes of HR, MAP, RR and SPO(2) were observed. The effects of sedation and analgesia, the instance of amnesia, and side effects were recorded. RESULTS: HR in group PR and MR were increase at 10 to 20 min and 20 min respectively after medication. MAP in group PR was increased at 20 min, which were decreased in group MR (P < 0.05). Compared with group PR, group MR achieved similar analgesia (P > 0.05), more moderate sedation with modified OAA/S score of 3 - 4 (67% vs 28%, P < 0.01), less memory, less injection pain, and higher satisfaction (P < 0.05). CONCLUSION: Both remifentanil-propofol and remifentanil-midazolam can provide safe and effective sedation and analgesia for choledochofiberscopic dilatation of bile duct. Remifentanil-midazolam provides more stable hemodynamics, more amnesia, moderate sedation duration and less side effects. PMID- 21600137 TI - [Study of injury mechanism for sacral plexus injury resulting from zone-II sacral fractures]. AB - OBJECTIVE: To study the mechanism of sacral plexus injury resulting from zone-II sacral fractures by axial compression. METHODS: Six short-term embalmed pelves were obtained with preserving sacral plexus and resected pubic symphysis. A model of zone-II sacral fractures by axial compression was established. Quantitative analysis for fracture displacement was carried out to observe the characteristics and mechanisms of sacral plexus injury. The experimental data were analyzed by SPSS 10.0 statistic software. RESULTS: In the sacral fracture model of axial compression, the sacral plexus nerves of L5 and S1 were obviously compressed. The sharp border of fracture segment stabbed the nerves as the distal segment of fractures was displaced to superior-anteriorly. When the displacement exceeded 1 cm, the tension injury of sacral plexus nerves became noticeable, especially at L5, S1 and S2. There was no sacral nerve injury when the distal segment of fractures was displaced posteriorly. CONCLUSION: The mechanisms of sacral plexus injury are complicated. And it probably have close correlations with stability, orientation, extent and duration of fracture displacement. PMID- 21600138 TI - [Experimental study of three dimensional navigation assisted spinal surgery by multi-segment registration technology based on structured light scanning]. AB - OBJECTIVE: To study the registration method based on structured light scanning for navigation assisted spinal surgery and assess its accuracy so as to construct a registration system for the navigation assisted spinal surgery using structured light scanning. METHODS: Both the computed tomographic (CT) dataset and the structured light scanning images of thoracic vertebra were obtained. The pre registration and multi-segment iterative closest point (ICP) algorithm were used for the registration of CT images and structured light images. Four segmentations were selected from the surface of thoracic vertebra and placed into different combinations. The accuracy for each combination was studied. Noise and perturbation were exerted to structured light and registration accuracy was studied. And calf vertebra was used for further verification. RESULTS: A combination of pre-registration and multi-segment iterative closest point (ICP) algorithm was competent for the registration of CT scanning data and the structured light scanning data. The registration error was less than 1 mm when two and more segments were selected for registration combination. The registration error was less than 1 mm when noise was exerted. CONCLUSION: With a high accuracy and a perturbation resistance, a combination of pre-registration and multi-segment registration algorithm based on structured light scanning is competent for the registration of CT scanning data and structured light scanning data. PMID- 21600139 TI - [Expression profiles of microRNAs in radioresistant esophageal cell line]. AB - OBJECTIVE: To identify the differential microRNA expression profiles of acquired radioresistant esophageal cell line established by fractionated ionizing radiation (FIR) versus parental cell line. METHODS: MicroRNA microarray was employed for detection. Bioinformatic software tools were used to predict the target genes of identified microRNAs. For an understanding of miRNA functions, the GO analysis of abundantly differentially expressed targets of miRNAs was performed by GeneOntology Browser. RESULTS: Compared with parental cell line, 10 microRNAs (hsa-miR-1539, hsa-miR-1237, hsa-miR-92b, etc.) were up-regulated over 2-fold and 25 microRNAs (hsa-miR-185, hsa-miR-18b, hsa-miR-17, etc.) down regulated in KYSE-150R. Eighteen miRNAs had their target genes, 10 of them had the potential to individually target up to 200 mRNAs. Hsa-let-7a, hsa-miR-185, hsa-miR-141, hsa-miR-92b, hsa-miR-22 and hsa-miR-301a were known as important genes associated with radioresistance. CONCLUSION: These results confirm the involvement of miRNA in radiation resistance. It may potentially help to explain the mechanisms of gene regulation in cellular response to radioresistance. PMID- 21600140 TI - [Attach more importance to recognize hemophagocytic lymphohistiocytosis]. PMID- 21600141 TI - [Strengthening the role of statin therapy in atherosclerosis for the prevention and treatment of cerebrovascular disease]. PMID- 21600142 TI - [Interpretation of CREST trial of endovascular treatment for carotid stenosis]. PMID- 21600143 TI - [The study of gene mutations in unknown refractory viral infection and primary hemophagocytic lymphohistiocytosis]. AB - OBJECTIVE: To study the type and corresponding clinical characteristics of primary hemophagocytic lymphohistiocytosis (HLH) associated immune gene mutations in the refractory virus infection or HLH of unknown causes. METHODS: From December 2009 to July 2010, the patients with refractory virus infection or HLH of unknown causes were screened for the primary HLH associated immune genes mutations by DNA sequence analysis, including PRF1, UNC13D, STX11, STXBP2, SH2D1A and XIAP. The clinical characteristics and outcomes were followed up. RESULTS: Totally 25 patients with refractory virus infection or HLH of unknown causes were investigated for the 6 genes and 13 cases were found carrying gene mutations, composing of 6 of PRF1 mutation, 3 of UNC13D, and each one of STX11, XIAP, SH2D1A and STXBP2, respectively. Among the 13 cases with gene mutations, 5 suffered from Epstein-Barr virus associated HLH (EBV-HLH), 1 human herpes virus 7 associated HLH (HHV7-HLH), 1 HLH without causes, 4 chronic activated EB virus infection (CAEBV) with 1 progressing to Hodgkin's lymphoma carrying abnormal chromosome of t(15;17) (q22;q25) and hyperdiploid, 2 EBV associated lymphoma. Among the other 12 patients without gene mutation, 4 suffered from EBV-HLH with 1 progressing to peripheral T lymphoma, 8 suffered from CAEBV. CONCLUSIONS: Primary HLH associated immune gene mutations are critical causes of refractory virus infection of unknown causes, most patients manifest as HLH, some cases appear in CAEBV and EBV associated lymphoma. DNA sequence analysis is helpful to early diagnosis and correct decision-making for treatment. PMID- 21600144 TI - [Incidence of adult aplastic anemia in Shanghai, China]. AB - OBJECTIVE: To survey the incidence of acquired adult aplastic anemia (AA) in Shanghai, China. Meanwhile, we compared it with the previous data from China in 1986 and other countries in order to explore the trends. METHODS: Newly diagnosed AA patients were registered in 6 districts (Jingan, Xuhui, Huangpu, Changning, Putuo, Yangpu) in Shanghai from 2004 to 2006. Then we calculated the crude and age-adjusted incidence of AA according to the population data from Shanghai Statistic Yearbook. RESULTS: There were 38 adult patients with acquired AA. The average crude incidence of AA was 0.33/100 000 from 2004 to 2006. The incidences per 100 000 persons per year were 0.40, 0.14 and 0.64 in 18 - 34, 35 - 59 and >= 60 years, respectively. The rate of severe AA was 0.17/100 000. CONCLUSION: The incidence of severe AA has no marked change, but the total rate is a little decreased compared with the data from China in 1986. PMID- 21600145 TI - [The efficacy and safety of mismatched hematopoietic stem cell transplantation for treatment of severe aplastic anemia]. AB - OBJECTIVE: To study the efficacy and safety of human leukocyte antigen (HLA) mismatched hematopoietic stem cell transplantation (HSCT) on severe aplastic anemia (SAA). METHODS: From January 2006 to May 2010, 17 patients received mismatched HSCT. HLA antigens were 3-loci-mismatched in 9 patients, 2-loci mismatched in 8. All patients received recombinant human granulocyte colony stimulating factor (rhG-CSF) primed bone marrow cells plus peripheral blood stem cells after modified busulfan/cyclophosphamide + antithymocyte immunoglobulin (BU/CY + ATG) conditioning regimen. RESULTS: All patients achieved full donor type engraftment. Grade III-IV graft versus host disease (GVHD) occurred in 3 patients and extensive chronic GVHD in 1. With a median following-up time of 285 (60 - 1670) d, 11 patients were alive, 9 of them had normal blood counts and the other 2 were blood transfusion independent. Six patients died of transplant related complications. CONCLUSION: Mismatched HSCT is a feasible and safe option for SAA patients without sibling identical donors. PMID- 21600146 TI - [The efficacy and safety of bortezomib plus thalidomide in treatment of newly diagnosed multiple myeloma]. AB - OBJECTIVE: The aim of this phase II study was to determine the efficacy and safety of combined bortezomib and thalidomide (VT) regime as initial treatment for newly diagnosed multiple myeloma (MM) in China. METHODS: Thirty-four patients were enrolled in this study and received VT regime up to 21-day cycles. Bortezomib (1.3 mg/m(2)) was administered intravenously on days 1, 4, 8, and 11, while oral thalidomide (100 mg/day) was given from days 1 to 21. The primary end point was clinical response. The secondary end point was safety. RESULTS: Among the 34 patients, 20 were male, 14 were female, with a median age of 59 years, and 15 in international stage system (ISS) III, 18 in ISS II, 1 in ISS I. Among them, 28 completed 2 cycles' treatment and achieved an overall response rate (ORR) of 92.9%; 26 were able to complete the planned 8 cycles of therapy. After 8 cycles, the ORR was 100% (complete response 30.8%, near-complete response 23.1%, partial response 42.3%, minimal response 3.8%). After followed up with a median time of 12 months, the estimated rate without progress of disease was 62%, and the estimated continuous remission rate of 12 months was 62%. The median survival time was not achieved. The most common adverse events were mild to moderate (grades 1, 2). The main toxicities were hematologic (53.3%), gastrointestinal (40.0%), peripheral neuropathy (38.0%), fatigue (36.6%) and fever (32.0%). CONCLUSIONS: VT regime provides a very high ORR and complete response rate in the treatment of newly diagnosed MM patients. No patients experienced deep venous thrombosis. In conclusion, bortezomib in combination with thalidomide is a very effective regimen for newly diagnosed MM patients and the toxicities are manageable. PMID- 21600147 TI - [The clinical efficacy and safety of intravenous cefmetazole in treatment of 1,522 patients with aspiration pneumonia]. AB - OBJECTIVE: To evaluate the efficacy and safety of intravenous cefmetazole in the treatment of patients with aspiration pneumonia. METHODS: A multicenter, prospective and open-labeled trial was conducted. A total of 1522 patients were enrolled at the beginning, and only 1324 were evaluated at the endpoint. The duration of treatment was 7 - 14 days. During the treatment and follow-up periods, we recorded any unexpected symptoms and abnormal laboratory tests. At last, we evaluated its efficacy and safety. RESULTS: The total effective rate of cefmetazole was 79.8%(1056/1324). The total bacterial eradication rate was 75.0% (342/456). The bacterial eradication rates of Klebsiella pneumonia, Escherichia, Staphylococcus aureus and anaerobic bacteria were 78.2% (97/124), 80.8% (80/99), 89.0% (81/91), 9/11, respectively. CONCLUSIONS: Cefmetazole is effective and safe in the treatment of aspiration pneumonia. PMID- 21600148 TI - [The correlation between hyperinsulinemia and pulse wave velocity]. AB - OBJECTIVE: To study the correlation between hyperinsulinemia (HIns) and arteriosclerosis in one community in Beijing. METHODS: Subjects who received arteriosclerosis screening in physical examination annually were studied. All subjects were received 75g oral glucose tolerance test (OGTT) to evaluate glucose metabolic level, and brachial-ankle pulse wave velocity (baPWV) examination to evaluate arteriosclerosis. The correlation between hyperinsulinemia and pulse wave velocity was analyzed. RESULTS: Among all the 1046 subjects under investigation, baPWV of subjects with HIns was higher than subjects with normoinsulinemic (NIns) in different glucose metabolism status [normal glucose tolerance, (1381.2 +/- 280.8) cm/s vs (1280.3 +/- 218.7) cm/s; imparied glucose regulation, (1557.5 +/- 319.3) cm/s vs (1474.7 +/- 305.1) cm/s; diabetes, (1764.3 +/- 476.6) cm/s vs (1664.2 +/- 374.6) cm/s], especially in subjects with normal glucose tolerance (P < 0.01). The prevalence of cardiovascular risk factors in subjects with HIns was much higher than subjects with NIns (P < 0.01). Multiple logistic regression analysis showed that hyperinsulinemia was the risk factor of arteriosclerosis, and the OR (95%CI) of subjects with HIns was 1.91 (1.169 - 3.105, P < 0.01) as compared to the subjects with NIns. CONCLUSION: The subjects with HIns suffered from much more metabolic risk factors than NIns. Hyperinsulinemia that closely correlated with baPWV was a risk factor of arteriosclerosis. PMID- 21600149 TI - [The effect of admission hyperglycemia on coronary reflow in primary percutaneous coronary intervention]. AB - OBJECTIVE: To assess the association between admission plasma glucose (APG) and no-reflow during primary percutaneous coronary intervention (PCI) in patients with ST-elevation acute myocardial infarction (STEMI). METHODS: A total of 1413 patients with STEMI successfully treated with PCI were divided into no-reflow group and normal reflow group. RESULTS: The no-reflow was found in 297 patients (21.0%) of 1413 patients; their APG level was significantly higher than that of the normal reflow group [(13.80 +/- 7.47) vs (9.67 +/- 5.79) mmol/L, P < 0.0001]. Multivariate logistic regression analysis revealed that current smoking (OR 1.146, 95%CI 1.026 - 1.839, P = 0.031), hyperlipidemia (OR 1.082, 95%CI 1.007 - 1.162, P = 0.032), long reperfusion (> 6 h, OR 1.271, 95%CI 1.158 - 1.403, P = 0.001), admission creatinine clearance (< 90 ml/min, OR 1.046, 95%CI 1.007 - 1.086, P = 0.020), IABP use before PCI (OR 9.346, 95%CI 1.314 - 67.199, P = 0.026), and APG (> 13.0 mmol/L, OR 1.269, 95%CI 1.156 - 1.402, P = 0.027) were the independent no-reflow predictors. The no-reflow incidence was increased as APG increased (14.6% in patients with APG < 7.8 mmol/L and 36.7% in patients with APG > 13.0 mmol/L, P = 0.009). CONCLUSION: APG > 13.0 mmol/L is an independent no reflow predictor in patients with STEMI and PPCI. PMID- 21600150 TI - [The early diagnosis of juvenile germinoma originating from the basal ganglia and thalamus]. AB - OBJECTIVE: To explore the early diagnosis of germinoma originating from the basal ganglia (BG) and thalamus during juveniles. METHODS: Retrospective analysis was done with the clinical cases of germinomas in BG and thalamus from 2000 to 2009. The symptoms, signs, neuroimaging, cerebrospinal fluid (CSF) findings were analyzed and related literature were reviewed. RESULTS: Eight patents were collected. The main symptoms were hemiplegia, associated with aphasia and/or impaired cognition. Brain CT showed high density and calcification. Abnormal T1 and T2 signal were found in brain MRI frequently associated with ipsilateral hemisphere atrophy. MRS showed increased choline and decreased N-acetylaspartate level. Elevated CSF human chorionic gonadotrophin level were found in two of them. CONCLUSIONS: Germinoma in BG and thalamus predominates in a boy. The neuroimaging features are very informative for early diagnosis. PMID- 21600151 TI - [The relationship between major histocompatibility complex class I chain-related antigens A (MICA)-129 gene polymorphism, soluble MICA level and ulcerative colitis]. AB - OBJECTIVE: To investigate the association of the major histocompatibility complex class I chain-related antigens A (MICA)-129 gene polymorphism and soluble MICA (sMICA) levels with ulcerative colitis (UC) in Hubei Han nationality. METHODS: The genetic polymorphism of MICA-129 was examined using a polymerase chain reaction-sequence based test (PCR-SBT) in 256 UC patients and 460 healthy controls. From the above subjects, 80 patients and 90 healthy individuals were randomly selected for determining serum sMICA concentrations by ELISA. RESULTS: The frequencies of variant allele (G) and genotype (GG) in MICA-129 gene were significantly higher in the UC patients than in the controls (76.8% vs 72.2%, P = 0.060; 55.9% vs 46.3%, P = 0.016). Serum sMICA levels were significantly elevated in the patients compared to the controls [(576.47 +/- 279.02) ng/L vs (182.17 +/- 73.11) ng/L, P < 0.001]. In addition, the sMICA levels were higher in the patients carrying MICA-129 GG genotypes than in those carrying (GA + AA) genotypes [(638.87 +/- 347.15) ng/L vs (507.51 +/- 152.87) ng/L, P = 0.035]. CONCLUSIONS: The genetic polymorphism of MICA-129 and sMICA levels are correlated with the UC patients in Hubei Han nationality. Our findings demonstrate that MICA 129 gene may contribute to the pathogenesis of UC. PMID- 21600152 TI - [A meta-analysis of the effects of direct hemoperfusion with polymyxin B immobilized fiber on prognosis in severe sepsis]. AB - OBJECTIVE: To investigate the effects of direct hemoperfusion with polymixin B immobilized fiber (DHP-PMX) in patients with sepsis. METHODS: We searched Pubmed, Embase, Web of Science databases and identified relevant randomized controlled trials (RCT) from January 1995 to May 2010. Meta-analysis of DHP-PMX on mortality and levels of endotoxin in patients with sepsis were conducted using the methods recommended by the Cochrane Collaboration. RESULTS: Eleven RCTs were included. Eight of them included the mortality of patients (sample size: 211 DHP-PMX and 178 conventional medical therapy). In total, the mortalities of patients with sepsis in DHP-PMX group and conventional group were 37.4% (79/211) and 68.5% (122/178) respectively. Compared with the conventional medical therapy, DHP-PMX appeared to significantly reduce mortality (OR = 0.24, 95%CI 0.16 - 0.38, P < 0.000 01). The results were similar when two RCTs enrolling patients with methicillin resistant staphylococcus aureus (MRSA) infections were excluded (OR = 0.27, 95%CI 0.17 - 0.45, P < 0.000 01). When the analysis was limited to the nine studies that reported 28- to 30-day mortality, results were unchanged (OR = 0.29, 95%CI 0.17 - 0.48, P < 0.000 01). Six RCTs had the available data of endotoxin. The level of endotoxin decreased 31 ng/L(95%CI 22.46 - 39.55) after DHP-PMX therapy, and the decreasing was statistically significant (P < 0.000 01), while the level of endotoxin in patients of conventional group did not change (P = 0.94). CONCLUSIONS: This study suggests a favorable effects of DHP-PMX on mortality and endotoxin decreasing in patients with sepsis. However, lack of enough cases and blinding need to be considered. Further investigation with large sample of high quality RCTs is needed. PMID- 21600153 TI - [A study of tracking the superparamagnetic iron oxide and enhanced green fluorescent protein labeled miniature porcine bone marrow stem cells by in vitro MRI]. AB - OBJECTIVES: To track bone marrow stem cells (BMSCs) labeled by enhanced green fluorescent protein (EGFP) and superparamagnetic iron oxide (SPIO)-poly-L-lysine (PLL) compound by MRI in vitro for autotransplantation into pancreas of type 1 diabetes miniature pigs. METHODS: The BMSCs were isolated by density gradient centrifugation and attachment culture from type 1 diabetes minipigs' bone marrow. Expressional intensity of EGFP in BMSCs transfected lentivirus-EGFP with a multiplicity of infection (MOI) of 30:1 reached the highest level after 96 h from transfection, while the positive rate was 43.2%. Different magnetic resonance scanning protocols were carried out on various density BMSCs labeled by different concentration of SPIO in various time-point in vitro. RESULTS: When SPIO concentration was 25 mg/L (count in Fe(3+)), the positive Fe(3+)-labeling rate of BMSCs was 93.1%. Most of SPIO particles in BMSCs' cytoplasm were observed in secondary lysosomes, but they were not detected in important organelle as cell nucleus. Comparing with gelatin the MRI of BMSCs labeled with SPIO in the condition with 1 * 10(4)/ml cells density and 25 mg/L Fe(3+) concentration in vitro, the signal intensity changes (DeltaSI) after BMSCs labeled with SPIO 3 weeks and 6 weeks in TSE T(1)WI, TSE T(2)WI and FLASH T(2) WI sequences were 12%, 41%, 63% and 7%, 28%, 46% respectively (P < 0.01 and P < 0.05, respectively). CONCLUSIONS: The data showed that the porcine BMSCs labeled with SPIO and EGFP could be traced successfully in vitro by MRI in the suitable sequences. PMID- 21600154 TI - [The effect of exogenous glial cell line-derived neurotrophic factor on expression of gastric and colonic Akt, MAPK in slow transit constipation rats]. AB - OBJECTIVE: To study the expression of Akt and MAPK in the stomach and colon of slow transit constipation (STC) in rats, as well as the effect of exogenous glial cell line-derived neurotrophic factor (GDNF) on it. METHODS: Forty-four SD rats were divided into control group and model group randomly. The STC model group was established by gastric irrigation of rhubarb for 3.5 months. The control group was received normal saline. After model building, each group was equally divided into 2 subgroup randomly, administrated with exogenous GDNF and normal saline by vein injection for one week respectively. The expression of Akt and MAPK in stomach and colon was detected by immunohistochemistry. RESULTS: (1) The expression of Akt in the stomach tended to weaker in STC rats comparing with the normal rats (P > 0.05), but it was stronger in STC plus GDNF group than in STC group (P < 0.05). (2) The expression of Akt and MAPK in the colon was weaker in STC group than in the normal group (all P < 0.05), and was stronger in STC plus GDNF group than in STC group (all P < 0.05). (3) The expression of MAPK in the stomach in STC group was weaker than in normal group (P < 0.05), and was stronger in STC plus GDNF group than in STC group (P < 0.01). There was no significant difference among STC plus GDNF group, normal group and GDNF group (P > 0.05). CONCLUSIONS: Long term consumption of rhubarb could induce STC by down-regulating the expression of Akt and MAPK in digestive tract. Exogenous GDNF may have a potential role on the etiology of STC. PMID- 21600155 TI - [It is a decisive move in smoking control to improve the related knowledge, belief, and practice among physicians]. PMID- 21600156 TI - [Hospital size and academic development of major health centers in China]. PMID- 21600157 TI - [Strengthening the construction of smoking cessation clinics in China is imperative]. PMID- 21600158 TI - [Gender difference in association between smoking and metabolic risks among community adults]. AB - OBJECTIVE: Cigarette smoking is a risk factor for the development of insulin resistance. However, whether a smoker has a lesser waist circumference (WC) and whether the potential changes in WC may reduce the benefits of smoking cessation remains in dispute. The aims of this study are to re-examines the relationships between smoking and metabolic risk factors by the data from Beijing adults. METHODS: A total of 3710 men and 6344 women, aged 18 - 92 years old, were sampled from community centers in Beijing for this cross-sectional clinical study between April and August 2007. Their concentrations of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and plasma glucose (PG) were measured. And the anthropometric parameters (WC, body weight and height) and blood pressure (BP) were record according to a standard protocol. Their social, demographic, personal medical history and behavioral characteristics were collected by the well-trained staff. Metabolic syndrome was defined according to the International Diabetes Federation (IDF) criteria. The relationships between smoking and metabolic syndrome were analyzed by chi(2) test and logistic regression. RESULTS: The mean age and glucose concentration were similar in both genders. Males tended to have a higher mean BP (systolic and diastolic), a higher level of TG and a lower HDL C. Among the obesity indices, the mean WC was higher in males than that in females whereas the mean BMI higher in females. The means of BMI and WC were 24.99 kg/m(2) and 89.13 cm for males and 25.49 kg/m(2) and 85.49 cm for females respectively. Smoking was an independent risk factor of metabolic syndrome in male subjects. It was mainly due to a higher prevalence of dyslipidemia, i.e. a higher level of TG and a lower level of HDL-C in smokers. And the trough prevalence of central obesity was higher in former smokers than current smokers. With adjustment for age, alcohol intake, and regular physical activity, the odds ratios [OR (95%CI)] of never smokers, ex-smokers, and current smokers were 1.00, 1.10 (0.92 - 1.47), and 1.36 (1.02 - 1.69) for hypertriglyceridemia (P < 0.05) and 1.00, 1.08 (0.79 - 1.32), and 1.59 (1.13 - 1.89) for low HDL-C respectively (P < 0.05). The odds ratios of the MS were 1.00 (referent), 1.10 (0.76 - 1.43), and 1.49 (1.06 - 1.89) for never smokers, ex-smokers, and current smokers respectively (P < 0.05). Cessation of smoking had a general trend of lowering the risk of metabolic syndrome in a year-dependent manner in males. In females, the prevalence of metabolic syndrome and obesity was similar between smokers and nonsmokers. Among the features of metabolic syndrome, only a low HDL-C was associated with chronic smoking in females. CONCLUSION: Although smokers tend to have a lower waist circumference than nonsmokers, the males have higher risk factors for metabolic disorders. There is no significant relationship between smoking and metabolic syndrome in female subjects. PMID- 21600159 TI - [Relationship between the prevalence study of smoking and metabolic syndrome among the males of Uygur and Kazakh in Xinjiang]. AB - OBJECTIVE: To investigate the prevalence and risk factors of smoking and metabolic syndrome (MS) among male Uygur and Kazakh adults residing in Xinjiang. METHODS: Four-stage selected random sampling was used to analyze the prevalence and the relationship between the risk factors of smoking and metabolic syndrome. The sampled adult populations over 35 years old were collected 6 localities (Urumqi, Kelamayi, Fukang, Turfan Basin locality, Hetian locality & Yili Kazakh Autonomous Prefecture) in Xinjiang, China. The subjects were 4019 males of Uygur and Kazakh. Each individual answered a questionnaire, received physical examinations and a biochemical indicator survey. The smoking patients were divided into two groups: one complicated with metabolic syndrome and the other not. A logistic regression analysis was also made to identify the possible risk factors and their powers on the prevalence of metabolic syndrome with smoking. RESULTS: With regards to the habit of smoking, the smokers of Uygur and Kazakh were 869 and 1114 respectively. The prevalence of MS was 24.74% and 29.62% for Uygur and Kazakh smokers respectively. And 16.75% and 24.72% for Uygur and Kazakh non-smokers respectively. The comparison of baseline information showed that, in Uygur males, the mean values of diastolic blood pressure, waist circumference and triglyceride were higher in smoker group than those in non-smoker group (P < 0.05); in Kazakh males, the mean values of systolic blood pressure, diastolic blood pressure and waist circumference were higher than nonsmoker group (P < 0.05). Logistic regression analysis showed that the OR value of smoking was 1.698 (95%CI 1.129 - 2.553) in Uygur and 1.845 (95%CI 1.544 - 2.206) in Kazakh of MS patients. CONCLUSION: The prevalence of MS is higher in male smokers than that in non-smokers in Uygur and Kazakh. Perhaps smoking is one of the risk factors for MS. PMID- 21600160 TI - [Smoking cessation rate in cardiovascular patients after percutaneous coronary intervention]. AB - OBJECTIVE: To investigate the smoking cessation rate and its related factors in cardiovascular patients after percutaneous coronary intervention. METHODS: A cross-sectional survey of 1241 outpatients or inpatients fulfilling the inclusion criteria was conducted at 14 hospitals across China. RESULTS: The survey population mainly consisted of middle-aged male patients with an average age of (59.9 +/- 10.7) years old. Their median time after surgery was 1.5 years. Among them, 77.4% tried to quit smoking while 55.4% succeed. The elder men were more likely to try to quit smoking and succeed eventually (OR values: 1.02 vs 1.03). The higher number of cigarettes smoked daily, the greater possibility of trying to quit smoking (OR = 1.03), but less likely to quit smoking eventually (OR = 0.97). Furthermore the years of smoking and cessation motivation had impacts on the cessation behaviors as well. CONCLUSION: Smoking cessation was achieved in more than half of the patients at one year after PCI. Age, years of smoking, daily number of cigarettes, concurrent diseases and physician recommendations are the influencing factors of smoking cessation. PMID- 21600162 TI - [Causes of chronic obstructive pulmonary disease-related death and influencing factors of survival time]. AB - OBJECTIVE: To study the causes of chronic obstructive pulmonary disease (COPD) related death and influencing factors of survival time from first hospitalization due to acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: All patients with a primary or secondary diagnosis of COPD (International Classification of Diseases (ICD)-10 Codes J40-J47) were continuously enrolled at our hospital from January 2006 to December 2008. A retrospective review was performed on the medical records of COPD patients who died during hospitalization. The causes of death were coded and analyzed according to the International Classification of Diseases (ICD)-10. The underlying causes of death were identified and ranked in order of prevalence. The medical records of first hospitalization due to AECOPD were reviewed. Retrospective analysis was performed for the clinical data. And Cox regression analysis was used to select the independent risk factors of influencing the survival time. RESULTS: Sixty-seven patients died during hospitalization. The median FEV(1) (forced expiratory volume in 1 second percentage) was 34%. The causes of death in the COPD inpatients were as follows: respiratory diseases (n = 39), cardio-cerebrovascular diseases (n = 16), malignant tumors (n = 10), diabetes mellitus (n = 1) and suicide (n = 1). Among them, 54 patients had a history of hospitalization due to AECOPD. Thirteen deceased patients were never hospitalized because of AECOPD. The mean interval between the first admission with AECOPD as the primary diagnosis and death was 38 months (range: 1 - 159). The independent risk factors of influencing the survival time were as follows: complications with coronary artery disease & severe pulmonary hypertension, age, body mass index (BMI) and serum level of C-reactive protein (CRP) (all P < 0.05). CONCLUSION: The major cause of death in moderate-severe COPD patients is respiratory disease. complicated with coronary artery disease & severe pulmonary hypertension, age, BMI and serum level of CRP are the independent risk factors of affecting the survival time from first hospitalization due to AECOPD. PMID- 21600161 TI - [Temporal changes and interaction of serum cytokines in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention]. AB - OBJECTIVE: To investigate the temporal changes of serum cytokines IL-6, IL-8, MCP 1 and IL-10 immediately before and after primary PCI (percutaneous coronary intervention) in patients with ST-segment elevation myocardial infarction (STEMI) and explore the interaction of these cytokines. METHODS: A total of 59 STEMI patients were recruited. And their serum concentrations of IL-6, IL-8, MCP-1 and IL-10 were measured by ELISA before primary PCI and 4-6 hours, 12 hours, 24 hours and 7 days post-intervention. For each cytokine, the level at each time-point post-PCI was compared to that at pre-PCI. Correlation coefficient test was used to analyze the interactions of these four cytokines. RESULTS: At 12 hours post PCI, the median serum levels of IL-6 and IL-8 were higher than those before PCI (IL-6: 8.51 ng/L vs 6.76 ng/L, IL-8: 4.67 ng/L vs 2.95 ng/L, both P < 0.05). At 4 6 hours and 12 hours post-PCI, the median values of MCP-1 were increasing significantly compared to those at pre-PCI (35.04 ng/L, 34.24 ng/L vs 30.45 ng/L, both P < 0.05) while those of IL-10 decreased (18.15 ng/L, 18.82 ng/L vs 20.95 ng/L, both P < 0.05). The levels of IL-6 and IL-10 at pre-PCI were associated with the Killip classification on admission (IL-6: r = 0.293, P < 0.05; IL-10: r = -0.287, both P < 0.05). Except for IL-8, other cytokines had no significant relation with the time length from onset to admission (P > 0.05). Additionally, these four cytokines were not found to be related with the location and extension of myocardial infarction, ejection fraction and NT-proBNP. At each time-point, there were a positive relationship among the natural logarithms of the concentrations of IL-6, IL-8 and MCP-1 (P < 0.01), all of which were inverse to the natural logarithm of the concentration of IL-10 (P < 0.01). CONCLUSIONS: The pro-inflammatory cytokines increase while the anti-inflammatory cytokines decrease after myocardial ischemia/reperfusion. An imbalance of inflammatory cytokines may be present. PMID- 21600163 TI - [A comparison of remifentanil versus sufentanil with target-controlled infusion in combined inhalation anesthesia for surgical patients: effects on hemodynamics and postoperative recovery]. AB - OBJECTIVE: To compare the effect of remifentanil versus sufentanil with target controlled infusion in combination with inhalation anesthesia for surgical patients on the parameters of hemodynamics and postoperative recovery. METHODS: Forty ASA I-II patients aged 18 - 65 years old with BMI (body mass index) < 30, undergoing colectomy or pedical screw interfix were enrolled. Upon the approval of institutional Ethics Committee, they were randomized to receive remifentanil or sufentanil at a target plasma concentration of 3 ng/ml and 0.3 ng/ml respectively in combination of inhalated anesthesia at 0.9 MAC (minimal alveolar concentration). The infusion of remifentanil was discontinued at the end of surgery while the infusion of sufentanil at 40 - 60 minutes before the end of surgery. The arterial blood pressure (ABP), heart rate (HR), electrocardiogram (ECG) and pulse blood oxygen saturation during anesthesia were monitored. The time between the termination of anesthetic use and recovery of spontaneous breathing and extubation were observed. And the incidence of postoperative pain and respiratory depression were recorded. RESULTS: As compared with the baseline values, BP and HR decreased significantly in both groups. BP was similar in both groups whereas HR was lower in Group R than that in Group S at post-induction, post-intubation, incision, the end of surgery and extubation (P < 0.05). The time from termination of anesthesia to recovery of spontaneous breathing was 1.8 +/- 1.4 min in Group R. And it was significantly shorter than that in Group S (2.9 +/ 1.5 min) (P < 0.05). The time from termination of anesthetic use to extubation was 6.8 +/- 3.9 min in Group R. And it was also significantly shorter than that in Group S (9.1 +/- 2.8 min) (P < 0.05). Seven patients experienced postoperative pain with visual analogue scale (VAS) > 4. And morphine was used for rescue analgesia in recovery room. CONCLUSION: When combined with inhalation anesthesia, the effects on hemodynamics are similar between the patients receiving the target controlled infusions of remifentanil and sufentanil. Remifentanil offers a shorter time to recovery of spontaneous breathing and tracheal extubation. PMID- 21600164 TI - [Effects of heart rate variability and smoothness index on the reversal of hypertensive left ventricular hypertrophy]. AB - OBJECTIVE: To investigate the relationship of reversal of hypertensive left ventricular hypertrophy (LVH) with heart rate variability (HRV) and smoothness index (SI). METHODS: A total of 127 patients with untreated essential hypertension associated with LVH were enrolled to receive a 20-week treatment. The drugs included losartan potassium & hydrochlorothiazide (1 tablet/day) and metoprolol (12.5 mg - 50 mg twice daily). The sitting systolic and diastolic blood pressures (SBP & DBP), M-mode and pulsed Doppler echocardiography, 24-hour ambulatory blood pressure monitoring (ABPM) and 24-hour ambulatory ECG (Holter) were performed at pre- and post-treatment. The changes in various parameters such as echocardiography left ventricular end-systolic dimension (LVDs), left ventricular end-diastolic dimension (LVDd) and the thickness of interventricular septum (IVST) and posterior wall (PWT) were measured. And left ventricular mass index (LVMI) and smoothness index (SI) were also examined. The evaluated parameters of ABPM were average 24-hour, daytime and nighttime SBP & DBP. As to 24-hour ambulatory ECG (Holter), the parameters were standard deviation of normal to normal intervals (SDNN), rate mean square of the differences of successive RR intervals (RMSSD), percentage of RR intervals differing > 50 ms (PNN50), high frequency (HF) and low frequency (LF). RESULTS: After a 20-week treatment, the levels of sitting blood pressure (SBP 158.72 +/- 12.11 mm Hg vs 132.21 +/- 14.03 mm Hg; DBP 97.20 +/- 7.71 vs 86.36 +/- 6.48 mm Hg, P < 0.001), parameters of 24 hour ABPM (24-hour mean SBP 146.20 +/- 10.11 mm Hg vs 129.68 +/- 6.12 mm Hg, P < 0.001; 24-hour mean DBP 93.45 +/- 5.46 mm Hg vs 81.77 +/- 6.71 mm Hg, P < 0.01; daytime mean SBP 149.53 +/- 8.67 mm Hg vs 133.60 +/- 6.27 mm Hg, P < 0.001; daytime mean DBP 94.68 +/- 4.96 mm Hg vs 83.55 +/- 7.03 mm Hg, P < 0.001; nighttime mean SBP 137.21 +/- 8.73 mm Hg vs 122.74 +/- 7.58 mm Hg, P < 0.001; nighttime mean DBP 86.75 +/- 6.22 mm Hg vs 72.81 +/- 5.47 mm Hg, P < 0.001) and LVMI significantly decreased (128.90 +/- 32.35 g/m(2) vs 118.39 +/- 31.10 g/m(2), P < 0.01) while the indicators of HRV changes such as SDNN, RMSSD, PNN50 and HF significantly increased (SDNN 97.28 +/- 16.67 ms vs 152.27 +/- 34.23 ms, P < 0.01; RMSSD 21.32 +/- 8.70 ms vs 41.91 +/- 10.38 ms, P < 0.001; PNN50 3.17 +/- 1.23 vs 5.89 +/- 2.18, P < 0.01; HF 239.82 +/- 98.26 ms(2)/Hz vs 367.32 +/- 188.37 ms(2)/Hz, P < 0.01)accompanied by the decreases in LF and LF/HF (LF 485.22 +/- 217.34 ms(2)/Hz vs 287.94 +/- 128.61 ms(2)/Hz, P < 0.01; LF/HF 2.03 +/- 0.56 vs 0.79 +/- 0.38, P < 0.001). The post-treatment SIs of SBP and DBP were 1.35 and 1.2 respectively. CONCLUSION: The combination treatment of angiotensin II receptor blocker (ARB), diuretics and beta1-receptor blockers can lower the blood pressures stably, improve heart rate variability and lead to a reversal of hypertensive LVH. PMID- 21600165 TI - [Effect of furazolidone quadruple regimen plus dental plaque removal procedures as rescue treatment of refractory Helicobacter pylori infection]. AB - OBJECTIVE: To observe the effect of furazolidone quadruple regimen plus dental plaque removal procedures as rescue treatment of refractory H. pylori infection. METHODS: A total of 104 patients with H. pylori positive [(13)C-urea breath test (UBT) or rapid urease test positive] failing in previous treatment two or more were enrolled and divided into 2 groups. One group (n = 64) were given quadruple regimen [proton pump inhibitor (PPI) + bismuth + amoxicillin + furazolidone, 10 days] treatment and dental plaque removal treatment. And the others (n = 40) received only quadruple regimen treatment. The status of H. pylori was detected by (13)C-UBT at 4 weeks post-therapy and the eradication rates of two groups were compared. RESULTS: The eradication rate of quadruple regimen + dental treatment group was 85.9% (55/64) while that of the other group 72.5% (29/40) (P = 0.091). CONCLUSION: The PPI + bismuth quadruple regimen plus dental plaque removal procedures as rescue treatment may boost the eradication rate of refractory H. pylori infection patients. And the furazolidone quadruple therapy can be chosen for the treatment of refractory H. pylori infection. Oral H. pylori infection may play a role in the failure of H. pylori infection treatment. PMID- 21600166 TI - [Effects of cholecystokinin octapeptide on the contractile activity of guinea-pig colonic smooth muscles, L-type calcium currents and membrane potentials of myocytes]. AB - OBJECTIVE: To investigate the effects and mechanism of cholecystokinin octapeptide (CCK-8S) on the contractile activity of smooth muscles, L-type calcium current and membrane potentials of proximal colon myocytes in guinea pig. METHODS: (1) Strips of proximal colon were obtained from adult guinea pigs. The contraction of these stripes was measured by a RM6240 multi-channel physiological signal system. (2) Suspension of single smooth muscle cells (SMCs) were obtained from proximal colon and isolated by enzymatic digestion. The effect of CCK-8S on intracellular calcium concentration ([Ca(2+)]i) of SMCs was examined by fura-2 loaded microfluorimetric measurement. (3) Resting potential (RP), action potential (AP) and L-type calcium current (I(Ca-L)) were recorded by patch-clamp technique. RESULTS: (1) The contractile amplitude and frequency of muscle stripes enhanced by CCK-8S (10(-7) mol/L) were (149 +/- 12)% and (132 +/- 13)% respectively of those of control group (all P < 0.05). They were significantly attenuated by pretreating strips with CCK1 receptor antagonist devazepide (10(-7) mol/L), L-type calcium channel blocker nifedipine (10(-5) mol/L), Ca(2+)-ATPase inhibitor TG (thapsigargin) (10(-5) mol/L) and BA (boric acid) (10(-5) mol/L) respectively. (2) [Ca(2+)]i of SMCs intensified by CCK-8S was (738 +/- 24)% of that of control group. And it was inhibited by pretreating SMCs with devazepide (all P < 0.05). (3) After the superfusion of CCK-8S, RP depolarized to (52 +/- 9)%, the exogenously stimulated peak values of AP rose to (140 +/- 4)% and fast repolarization time of AP decreased to (61 +/- 13)% (all P < 0.05). They were significantly inhibited when these cells were pretreated with devazepide and/or nifedipine (n = 8, P < 0.05 for each group) whereas CI 988 had little effect. (4) The CCK-8S-evoked I(Ca-L) of SMCs at the voltage of + 10 mV was boosted to (138 +/- 7)%. Such an effect was suppressed by a pretreatment with nifedipine, devazepide, TG and BA respectively. In the presence of an inhibitor of inositol 1,4,5-trisphosphate (IP3) receptors, heparin (10(-6) mol/L) and an protein kinase C (PKC) inhibitor, saurosporine (10(-6) mol/L), CCK-8S did not significantly intensify I(Ca-L) (all P > 0.05). CONCLUSION: CCK-8S promotes proximal colon contraction by CCK1 receptors through the activation of IP3-mediated PKC pathway. PMID- 21600167 TI - [Cathepsin B promoted the apoptosis of vascular smooth muscle cells as induced by tumor necrosis factor-alpha]. AB - OBJECTIVE: To establish the cathepsin B over-expression group and cathepsin B gene-silencing group so as to investigate whether cathepsin B was capable of promoting the apoptosis of VSMC (vascular smooth muscle cell) induced by TNF alpha/act D. METHODS: Human aortic smooth muscle cell (HA-VSMC) was transfected with pcDNA3.1-cathepsin B and pSilencer2.1-cathepsin B plasmids by lipofection to establish the over-expression and gene-silencing groups. Through TNF-alpha induced apoptosis, the cell viability was observed by MTT assay, morphological observation and assays of apoptotic proteins as indicators of apoptosis. RESULTS: The cathepsin B over-expression and gene-silencing group were successfully established. MTT assay showed no significant difference between the transfected cell and blank control. After the intervention of TNF-alpha, the HA-VSMC viability decreased significantly. As compared with control group, the over expression group significantly decreased (9.98% +/- 1.04% vs 14.60% +/- 1.34%). As compared with the over-expression group, the E64d and CA-074ME groups (18.23% +/- 1.05%, 17.40% +/- 1.03%) increased significantly while the silent group (21.30% +/- 2.37%) significantly increased. The analysis of acridine orange/ethidium bromide staining showed similar results. Western blot showed the Bcl-2 protein were significantly higher in the silent group than that in the control group. And the over-expression group was significantly lower than the control group. The E64d and CA-074ME groups were significantly higher than that in the over-expression group. But the Bax protein level had no significant difference among all groups. CONCLUSION: The over-expression of cathepsin B promotes TNF-alpha-induced VSMC apoptosis while Cathepsin B gene silencing and the addition of cathepsin inhibitor in over-expression group inhibit the TNF alpha induced VSMC apoptosis. PMID- 21600168 TI - [Individual evaluation of biological aging and its relationship with advance prevention and treatment of cardiovascular disease]. PMID- 21600169 TI - [Chinese guidelines for diagnosis and management of cognitive impairment and dementia (II): dementia subtypes and their criteria]. PMID- 21600170 TI - [Clinical application guide of blood glucose monitoring in China (Edition 2011)]. PMID- 21600171 TI - [Experts consensus on diagnosis and treatment of Gaucher disease in China]. PMID- 21600172 TI - [Estimation of individual biological aging and individualized evaluation of biomarkers of aging in healthy people]. AB - OBJECTIVE: To estimate the degree of biological aging for healthy people by the biological age score equation and observe the differences of various aging biomarkers so as to provide targets for clinical anti-aging intervention. METHODS: A total of 2876 subjects aged 30 - 98 years old were recruited from 3 Chinese cities in 2003. After screening, 852 healthy subjects were finally selected and assigned into 4 groups according to ages: young group (< 45 yr), middle-aged group (45 - 59 yr), young-elder group (60 - 74 yr) and elder group (>= 75 yr). They received a total of 108 physical, morphological, physiologic and biochemical examinations. The biological age score equation was employed to compute the individual biological age scores for all subjects. Then the biological age score was taken as a dependent variable and the chronological age as an independent variable for linear regression. Based on the confidence interval with +/- 1 standard deviation of regression line, they were divided into 3 groups (delayed aging, normal aging and early aging). According to the chronological ages and degrees of aging, two-way analysis of variance was conducted for the following 7 biomarkers: end diastolic velocity (EDV), intima media thickness (IMT), ratio of peak velocity of early filling to atrial filling (E/A), mitral valve annulus lateral wall of peak velocity of early filling (MVEL), arterial pulse pressure (PP), fibrinogen (FIB) and cystatin C (CYSC). At the same time, the differences of 7 biomarkers were observed in different aging groups in 4 age groups. RESULTS: (1) A comparison of biological age score: there were no significant differences in chronological age among 3 biological aging groups in same chronological age groups. However, there were some significant differences in biological age score (young group: F = 91.8, P < 0.01; middle-aged group: F = 134.5, P < 0.01; young-elder group: F = 199.5, P < 0.01; elder group: F = 82.1, P < 0.01). (2) Two-way analysis of variance (aging groups and chronological age groups for biomarkers): there were significant differences of 7 biomarkers in different chronological age groups and different aging groups. (3) A comparison of biomarkers among aging groups: there were significant differences in PP among 3 aging groups in 4 age groups. PP increased significantly in early aging group to normal aging group and delayed aging group (young group: 49.0 +/- 6.9, 37.6 +/- 6.4, 30.8 +/- 7.6 mm Hg, F = 93.2, P < 0.01; middle-aged group: 52.9 +/- 7.3, 44.3 +/- 5.9, 32.7 +/- 8.4 mm Hg, F = 125.7, P < 0.01; young-elder group: 61.9 +/- 7.6, 51.6 +/- 6.6, 37.1 +/- 8.7 mm Hg, F = 196.5, P < 0.01; elder group: 72.2 +/- 13.7, 61.1 +/- 6.8, 43.8 +/- 10.8 mm Hg, F = 60.2, P < 0.01). There were significant differences in EDV among 3 aging groups in 4 age groups. EDV increased significantly in early aging group to normal aging group and delayed aging group. There were significant changes in IMT, MVEL, E/A, CYSC and FIB among aging groups in different age groups. CONCLUSION: (1) Biological age score plays an essential role in the evaluation of aging. Based on individual evaluation of biological age score, the degrees of aging can be categorized by grouping so that a clinician may provide clinical anti-aging interventions within the target groups. (2) The above 7 biomarkers are competent for the evaluation of aging. They can not only be used to construct biological age score equation, but also provide clinical targeted interventions for aging. PMID- 21600173 TI - [High-resolution melting analysis for the detection of EGFR mutations in circulating DNA of lung cancer patients]. AB - OBJECTIVE: To discuss the practicability of detecting epidermal growth factor receptor (EGFR) mutations in plasma circulating DNA of lung cancer patients by high-resolution melting (HRM). METHODS: The sensitivity of HRM was analyzed by the detection of samples containing different proportions of EGFR-mutated plasmids. The mutations in exons 19 and 21 of EGFR were detected by HRM in 96 lung cancer patients from September 2009 to May 2010. And the results of HRM were compared with those of sequencing. RESULTS: The HRM detection could identify the EGFR mutations in a proportion of 5% of mutated plasmid DNA. And the EGFR mutations were detected in 17 (17.7%, 17/96) cases. Among which, the number of exons 19 and 21 mutations was 15 (88.2%, 15/17) and 2 (11.8%, 2/17) respectively. The results of sequencing were consistent. CONCLUSION: The HRM analysis may be an optimal method for clinical screening of EGFR mutation due to its simplicity and promptness with a high sensitivity. PMID- 21600174 TI - [Clinical values of triptorelin stimulating test in assessing hypothalamus pituitary-gonad axis function in male patients with hypothalamus-pituitary-gonad axis disorders]. AB - OBJECTIVE: To investigate the clinical values of luteinizing hormone-releasing hormone (LHRH) alpha (triptorelin) stimulating test in the differential diagnoses of hypothalamus-pituitary-gonad axis (HPGA) disorders. METHODS: A total of 229 male patients with various HPGA disorders were recruited for triptorelin stimulating test. And all patients were followed up for 12 - 48 months until a definite diagnosis was made. The values of triptorelin stimulating test in the differential diagnoses of HPGA disorders were assessed by examining the close relationship between LHmax and the final clinical diagnosis. RESULTS: (1) LH levels rose steady after an intramuscular injection of triptorelin 100 ug and the time of LHmax appeared at 45 - 60 min. (2) LHmax < 4 U/L indicated the function of HPGA was not activated. LHmax in the range of 4 - 12 U/L indicated the patients might have constitutional delayed puberty development. LHmax > 12 U/L indicated the fulfilled puberty development. CONCLUSION: Triptorelin stimulating test can precisely evaluate the functions of HPGA in various HPGA disorders and provide valuable information for the differential diagnoses in constitutional delayed puberty development, hypogonadotropic hypogonadism, central and peripheral precocious puberty disorders. PMID- 21600175 TI - [Viviperception on renal vessel variation by retroperitoneal laparoscopy a report of 525 cases]. AB - OBJECTIVE: To study the variation of renal vessels with retroperitoneal laparoscopy so as to increase the safety of retroperitoneal laparoscopic surgeries. METHODS: A total of 525 patients underwent retroperitoneal laparoscopic nephrectomy or partial nephrectomy at our hospital between January 2004 and June 2008. There were 316 males and 209 females with a mean age of (58 +/- 13) years old. The procedures were as follows: (1) patients lay on one side with their waist up and the retroperitoneal cavity was established with our institutional method; (2) gerota's fascia was separated widely along the ventral surface of major psoas muscle; (3) the tissues around renal arteries and veins were isolated by ultrasonic scalpel. Careful observation was performed to explore if there were duplicated or accessory renal vessels; (4) renal vessels were cut by Endo-GIA/Hem-o-lok or blocked by bulldog clamps; (5) whole or partial kidney was finally resected (remaining procedures omitted). RESULTS: Among all patients, 58 patients (11.0%, 58/525) had a variation of renal vessels. There were double renal arteries on one side (n = 18), double renal veins (n = 10), 3 renal veins (n = 1) and double arteries and veins on one side (n = 3). Twenty-five patients (4.8%, 25/525) had one accessory renal artery on one side while 19 (76.0%, 19/25) accessory renal arteries went toward the upper kidney pole. The diameter of one patient's left spermatic vein was similar with that of renal vein and they were joined by lumber vein. CONCLUSION: The variation of renal artery is more common than that of renal vein. The accessory renal arteries are common and usually go toward the upper kidney pole. The variation of renal vessels should be considered before and during a laparoscopic procedure. PMID- 21600176 TI - [Clinical study of laparoscopic rectal surgery without abdominal scar]. AB - OBJECTIVE: To assess the feasibility and safety of laparoscopic rectal surgery without abdominal scar. METHODS: A total of 23 patients of rectal cancer were operated by laparoscopy with the assistance of PPH (procedure for prolapse and hemorrhoids) anal expander and TEM (transanal endoscopic microsurgery) outer shell according to the principle of TME (total mesorectal excision). RESULTS: All operations were successfully accomplished laparoscopically. There was no conversion into an open procedure. The average operative duration was 129 (105 - 211) minutes. The intra-operative blood loss volume was 152 (85 - 420) ml. No immediate or delayed injury of urinary duct and other intra-operative severe complications, such as massive hemorrhage of presacral venous plexus, occurred. There was no pelvic infection or anastomotic stoma fistula during the post operative period. The average follow-up period was 13.4 months. Neither anastomotic stoma recurrence nor Trocar implantation occurred. CONCLUSION: The laparoscopic technique of hybrid NOTES (Natural Orifice Transluminal Endoscopic Surgery), plus PPH/TEM is both feasible and convenient for selective rectal cancer surgery. There is no need for extra abdominal incision. It is recommended for laparoscopic rectal surgery. PMID- 21600177 TI - [Inhibition of airway mucous hypersecretion by azithromycin through matrix metalloproteinase 9]. AB - OBJECTIVE: To investigate the mechanism of azithromycin (AZT) inhibiting the airway mucous hypersecretion through matrix metalloproteinase 9 (MMP9). METHODS: After culturing, the airway epithelial cells of line HBE16 were stimulated with neutrophil elastase (NE) and pretreated with AZT and epidermal growth factor receptor (EGFR) antagonist BIBX1522. Then the cells were divided into 4 groups: control group, NE-stimulated group, AZT-pretreated & NE-stimulated group and BIBX1522-pretreated & NE-stimulated group. The mucin (MUC)5AC mRNA and MMP9 mRNA levels were analyzed by RT-PCR (reverse transcription-polymerase chain reaction). And the MUC5AC protein content in supernatant was detected by ELISA (enzyme linked immunosorbent assay). Gelatin zymogrphy was employed to assay the MMP9 activity. Western blot was used to detect the protein levels of MMP9, prozymogen MMP9 (pro-MMP9), tissue inhibitors of metalloproteinases 1 (TIMP-1), phosphorylated EGFR (p-EGFR) and phosphorylated external-signal regulated kinase (p-ERK). RESULTS: As compared with the control group, the levels of MUC5AC and MMP9 gene transcription (0.83 +/- 0.17, 0.79 +/- 0.16) and protein expression (0.84 +/- 0.15, 0.88 +/- 0.16) in the NE stimulated group were obviously higher than those of the control group (all P < 0.01). And the activity of MMP9 increased (392.33 +/- 18.33, P < 0.01) while the protein level of pro-MMP9 decreased (0.17 +/- 0.10, P < 0.01). But the expression of TIMP-1 showed no significant change. The protein expressions of p-EGFR and p-ERK increased (0.86 +/- 0.23, 0.85 +/- 0.22, both P < 0.01); as compared with the NE-stimulated group, there was a reduction of MUC5AC and MMP9 gene transcription (0.36 +/- 0.15, 0.41 +/- 0.09, both P < 0.01) and protein expression levels (0.30 +/- 0.08, 0.37 +/- 0.14, both P < 0.01) in the AZT-pretreated and NE-stimulated group. The MMP9 activity decreased (295.33 +/- 14.54, P < 0.01), the protein levels of pro MMP9 and TIMP-1 increased (0.46 +/- 0.14, 0.67 +/- 0.17, both P < 0.05), p-ERK protein level decreased (0.40 +/- 0.19, P < 0.01) while the expression of p-EGFR showed no significant decline. As compared with the NE-stimulated group, except for the expressions of MUC5AC mRNA (0.37 +/- 0.14), MMP9 mRNA (0.37 +/- 0.13), p EGFR (0.36 +/- 0.13) and p-ERK (0.37 +/- 0.18) decreasing (all P < 0.01) in BIBX1522-pretreated and NE-stimulated group, the other results had no obvious change. CONCLUSION: AZT may suppress the activity and production of MMP9 in HBE16 cells so as to inhibit the airway mucous hypersecretion. PMID- 21600178 TI - [Rapamycin-mediated interaction of spleen gammadeltaT lymphocytes and lung macrophages in acute lung injury of mice induced by lipopolysaccharide]. AB - OBJECTIVE: To explore the influences of rapamycin (RAPA) upon the cytokine changes of activated spleen gammadeltaT lymphocytes and lung tissue macrophages in acute lung injury of mice induced by lipopolysaccharide (LPS). METHODS: A total of 24 healthy male C57BL/6 mice, 6-8 weeks old, were randomly divided into phosphate buffered saline (PBS), LPS, RAPA and LPS + RAPA groups. Acute lung injury was induced by a single intratracheal instillation of LPS in mice. And spleen gammadeltaT lymphocytes and lung macrophages were purified by immunomagnetic beads at Day 1. The purified spleen gammadeltaT lymphocytes and lung macrophages were adjusted to 10(6) cell/ml. And 24-well plates were used for 4 groups. Each group were further separated with spleen gammadeltaT lymphocytes alone, lung tissue macrophages alone and co-culturing. Supernatant fluid was collected after 24 hours. The expressions of IFN-gamma and TNF-alpha were analyzed by ELISA (enzyme-linked immunosorbent assay). And the expressions of mRNA were analyzed by real-time quantitative PCR (polymerase chain reaction). RESULTS: The total cells numbers and lymphocytes numbers of bronchoalveolar lavage fluid were significantly higher in LPS group than those in PBS and LPS + RAPA groups (P < 0.05). And the level of IFN-gamma was significantly higher in LPS group than that in PBS, RAPA and LPS + RAPA groups by co-culture (P < 0.05). The level of TNF-alpha was significantly higher in LPS group than that in RAPA gand LPS + RAPA groups by co-culture (P < 0.05). However, the mRNA of IFN-gamma was higher in LPS group than that in PBS and RAPA groups (P < 0.05). CONCLUSION: RAPA inhibits the secretion levels of IFN-gamma and TNF-alpha in spleen gammadeltaT lymphocytes and lung tissue macrophages in acute lung injury of mice induced by LPS. PMID- 21600179 TI - [Growth and migration of umbilical cord mesenchymal stem cells on polycarbonate membrane with different pore sizes]. AB - OBJECTIVE: To observe the growth and migration of human umbilical cord mesenchymal stem cells (hUCMSCs) on polycarbonate membrane with different pore sizes and explore the criteria of selecting optimal Transwell insert for indirect co-culture to induce the differentiation of hUCMSCs. METHODS: hUCMSCs were isolated in vitro and then expanded in culture medium. After the treatment of mitomycin C, the cells were seeded on porous membranes of 6-well-dish Transwell inserts with different pore sizes of 0.4, 3.0 and 8.0 um respectively. After culturing for 7 days, the cells were observed and counted on the bottom of each porous membrane. Then the calculation of migration ratio was performed. The growth and migration of hUCMSCs on porous membranes were also examined under scanning electron microscope (SEM). RESULTS: The migration ratios of hUCMSCs on membranes of 0.4, 3.0 and 8.0 um pore sizes were 0, 1.8% and 8.0% respectively. The migration ratio of cells on 0.4 um pore size membrane was statistically different from that of the other two pore size groups (P < 0.01). Under SEM, a small portion of cells were growing on the bottoms of membranes and moving through the pores. But there was no cell movement through 0.4 um pore size membrane. CONCLUSIONS: hUCMSCs can migrate through the polycarbonate membranes of 3.0 um and 8.0 um pore sizes but not through the 0.4 um one. Thus both sides of polycarbonate membrane of 0.4 um pore size may be used for close indirect co culture to induce the differentiation of hUCMSCs. PMID- 21600180 TI - [Inhibition of leflunomide active metabolite A771726 on high glucose-induced podocyte apoptosis]. AB - OBJECTIVE: To explore the therapeutic effects of leflunomide metabolite A771726 on high glucose-induced podocyte injury and understand its mechanism. METHODS: The conditionally immortal human glomerular podocytes were divided into normal glucose group (NG), high glucose group (HG), mannitol group (MA), high glucose with SB202190 (a p38MAPK inhibitor) group and high glucose with active leflunomide metabolite A771726 group. The levels of p38MAPK and p-p38 protein were determined by Western blot. And the rate of podocyte apoptosis was evaluated by flow cytometry. RESULTS: (1) Podocytes with high glucose could activate the p38MAPK signaling pathway. The p-p38 protein expression was significantly elevated. Little activation of the pathways was observed in Groups NG and MA. As compared to HG, the p-p38 protein expression was significantly lowered in SB202190 and A771726 groups. (2) Apoptosis increased in podocytes with high glucose after 24 h. The apoptotic rate of group HG was the most dramatic at 48 h (18.6 +/- 0.7)%. It was significantly higher than those of Groups NG and MA. The group of high glucose with SB202190 and high glucose with active leflunomide metabolite A771726 could reduce the podocyte apoptosis by 26% and 17% respectively versus the HG group. And the difference was statistically significant. CONCLUSION: Leflunomide can inhibit high glucose-induced podocyte apoptosis. And this effect may be involved in its inhibition of activation of p38MAPK. PMID- 21600181 TI - [Expression and tumoricidal activity of a human-mouse chimeric anti-DR5 antibody through a Furin/2A peptide]. AB - OBJECTIVE: To express a full-length human-mouse chimeric anti-DR5 antibody from a single open reading frame with tumoricidal activity to various cancer cells. METHODS: The heavy and light chains of chimeric antibody were joined by the Furin and 2A (F/2A) self-cleavage peptide and cloned into a lentiviral vector of pWPXL. Then the HEK293 cells were infected with the constructed expression vector pWPXL HF2AL. Western blot, enzyme-linked immunosorbent assay (ELISA) and MTS assay were used to detect the chimeric antibody expression, cleavage, binding affinity to the antigen and tumoricidal activity to various tumor cells. RESULTS: The recombinant chimeric antibody was successfully expressed from a single open reading frame in pWPXL-HF2AL construct. And it possessed a similar binding affinity to the parental murine counterpoint and strong tumoricidal activity to various cancer cells. For example, on the concentration of 3 ug/ml, it made the relative cells viability of HCT116, SMMC7721, A549 and U251 down to 20.6% +/- 2.6%, 35.1% +/- 2.7%, 76.1% +/- 6.1% and 15.6% +/- 2.0% respectively. CONCLUSIONS: The human-mouse chimeric anti-DR5 antibody of F/2A peptide is successfully expressed. Possessing a strong tumoricidal activity in various cancer cells, it may provide a novel strategy for cancer biotherapy. PMID- 21600182 TI - Characterization of CuZnSOD model complexes from a redox point of view: redox properties of copper(II) complexes of imidazole containing ligands. AB - The systematic electrochemical studies of the copper complexes of various terminally protected tri-, tetra-, penta- and heptapeptides containing histidine in different location and number in the peptide chain and two histidine derivatives were carried out by cyclic voltammetry. The redox parameters of CuL and CuL2 complexes coordinating exclusively through imidazole nitrogens were determined. For all studied Cu(II) complexes the characteristic redox reactions are quasi-reversible one electron reduction processes. The obtained formal reduction potential values fall into the 200-400 mV potential range supporting the former results that the CuL and CuL2 complexes of these multihistidine peptides are not only structural but also good functional models of the Cu-Zn superoxide dismutase (CuZnSOD) enzyme. These observations are confirmed by the results of SOD activity assay in a representative copper(II)-ligand system. PMID- 21600184 TI - Detection method for quantifying global DNA methylation by fluorescence correlation spectroscopy. AB - A method for quantifying global DNA methylation using fluorescence correlation spectroscopy (FCS) has been established. The single-molecule methylation assay (SMMA) is based on two methodologies. One methodology, FCS, estimates the translational diffusion coefficient of molecules in solution, whereas the other methodology uses the high affinity of methyl-CpG-binding domain protein 2 (MBD2) to bind specifically to methylated DNA. We studied the specific binding rates of fluorescence-labeled MBD2 and methylated DNA from biological samples using the automated FCS system. Using a standard curve with methylated control DNA, we developed the SMMA index to assess the global DNA methylation level of the biological samples. A marked decrease in the SMMA index was observed when human leukemia cell lines (U937 and K562) were cultured with DNA demethylating agents. Our findings clearly indicate the applicability of SMMA as a simple and rapid tool for quantifying global DNA methylation. SMMA may prove useful for genome wide comparative methylation analyses of malignancies and as an indicator of the demethylation effects of epigenetic drugs. PMID- 21600185 TI - An improved nonchromatographic method for the purification of recombinant proteins using elastin-like polypeptide-tagged proteases. AB - Proteins fused to the elastin-like polypeptide (ELP) tag can be selectively separated from crude cell extract without chromatography. To avoid the interference of the ELP tag on properties of the target protein, it is necessary to remove the ELP tag from target protein by protease digestion. Therefore, an additional chromatographic purification step is required to remove the proteases, and this is time- and labor-consuming. Here we demonstrate the utility of the ELP tagged proteases for cleavage of ELP fusion proteins, allowing one-step removal of the cleaved ELP tag and ELP-tagged proteases without chromatography. PMID- 21600183 TI - Effect of transition metal ions on the fluorescence and Taq-catalyzed polymerase chain reaction of tricyclic cytidine analogs. AB - The cytosine analogs 1,3-diaza-2-oxophenothiazine (tC) and 1,3-diaza-2 oxophenoxazine (tCo) stand out among fluorescent bases due to their unquenched fluorescence emission in double-stranded DNA. Recently, we reported a method for the generation of densely tCo-labeled DNA by polymerase chain reaction (PCR) that relied on the use of the extremely thermostable Deep Vent polymerase. We have now developed a protocol that employs the more commonly used Taq polymerase. Supplementing the PCR with Mn(2+) or Co(2+) ions dramatically increased the amount of tCo triphosphate (dtCoTP) incorporated and, thus, enhanced the brightness of the PCR products. The resulting PCR products could be easily detected in gels based on their intrinsic fluorescence. The Mn(2+) ions modulate the PCR by improving the bypass of template tCo and the overall catalytic efficiency. In contrast to the lower fidelity during tCo bypass, Mn(2+) improved the ability of Taq polymerase to distinguish between dtCoTP and dTTP when copying a template dA. Interestingly, Mn(2+) ions hardly affect the fluorescence emission of tC(o), whereas the coordination of Co(2+) ions with the phosphate groups of DNA and nucleotides statically quenches tC(o) fluorescence with small reciprocal Stern-Vollmer constants of 10-300MUM. PMID- 21600187 TI - A modulator domain controlling thermal stability in the Group II chaperonins of Archaea. AB - Archaeal Group II chaperonins (Cpns) are strongly conserved, considering that their growth temperatures range from 23 to 122 degrees C. The C-terminal 15-25 residues are hypervariable, and highly charged in thermophilic species. Our hypothesis is that the C-terminal is a key determinant of stabilization of the Cpn complex. The C-terminus of the Cpn from the hyperthermophile Pyrococcus furiosus was mutated to test this hypothesis. C-terminal deletions and replacement of charged residues resulted in destabilization. The stability of ATPase activity declined in proportion to the reduction in charged residues with Ala or Gly. An EK-rich motif ((528)EKEKEKEGEK5(37)) proved to be a key domain for stabilization at or near 100 degrees C. Mutations "tuned" the Cpn for optimal protein folding at lower optimal temperatures, and Glu substitution was more potent than Lys replacement. Pf Cpn stability was enhanced by Ca(2+), especially in the mutant Cpn lacking C-terminal Lys residues. This suggests that Glu-Glu interactions between C termini might be mediated by Ca(2+). The C-terminal of a Cpn from the psychrophilic archaeon Methanococcoides burtonii was replaced by a domain from the hyperthermophile, resulting in increased thermostability and thermoactivity. We conclude that localized evolutionary variation in the C terminus modulates the temperature range of archaeal Cpns. PMID- 21600186 TI - Functional asymmetry for the active sites of linked 5-aminolevulinate synthase and 8-amino-7-oxononanoate synthase. AB - 5-Aminolevulinate synthase (ALAS) and 8-amino-7-oxononanoate synthase (AONS) are homodimeric members of the alpha-oxoamine synthase family of pyridoxal 5' phosphate (PLP)-dependent enzymes. Previously, linking two ALAS subunits into a single polypeptide chain dimer yielded an enzyme (ALAS/ALAS) with a significantly greater turnover number than that of wild-type ALAS. To examine the contribution of each active site to the enzymatic activity of ALAS/ALAS, the catalytic lysine, which also covalently binds the PLP cofactor, was substituted with alanine in one of the active sites. Albeit the chemical rate for the pre-steady-state burst of ALA formation was identical in both active sites of ALAS/ALAS, the k(cat) values of the variants differed significantly (4.4+/-0.2 vs. 21.6+/-0.7 min(-1)) depending on which of the two active sites harbored the mutation. We propose that the functional asymmetry for the active sites of ALAS/ALAS stems from linking the enzyme subunits and the introduced intermolecular strain alters the protein conformational flexibility and rates of product release. Moreover, active site functional asymmetry extends to chimeric ALAS/AONS proteins, which while having a different oligomeric state, exhibit different rates of product release from the two ALAS and two AONS active sites due to the created intermolecular strain. PMID- 21600188 TI - The Na(+)-translocating F1F0-ATPase from the halophilic, alkalithermophile Natranaerobius thermophilus. AB - Natranaerobius thermophilus is an unusual anaerobic extremophile, it is halophilic and alkalithermophilic; growing optimally at 3.3-3.9M Na(+), pH(50 degrees C) 9.5 and 53 degrees C. The ATPase of N. thermophilus was characterized at the biochemical level to ascertain its role in life under hypersaline, alkaline, thermal conditions. The partially purified enzyme (10-fold purification) displayed the typical subunit pattern for F-type ATPases, with a 5 subunit F(1) portion and 3-subunit-F(O) portion. ATP hydrolysis by the purified ATPase was stimulated almost 4-fold by low concentrations of Na(+) (5mM); hydrolysis activity was inhibited by higher Na(+) concentrations. Partially purified ATPase was alkaliphilic and thermophilic, showing maximal hydrolysis at 47 degrees C and the alkaline pH(50 degrees C) of 9.3. ATP hydrolysis was sensitive to the F-type ATPase inhibitor N,N'-dicylohexylcarbodiimide and exhibited inhibition by both free Mg(2+) and free ATP. ATP synthesis by inverted membrane vesicles proceeded slowly and was driven by a Na(+)-ion gradient that was sensitive to the Na(+)-ionophore monensin. Analysis of the atp operon showed the presence of the Na(+)-binding motif in the c subunit (Q(33), E(66), T(67), T(68), Y(71)), and a complete, untruncated epsilon subunit; suggesting that ATP hydrolysis by the enzyme is regulated. Based on these properties, the F(1)F(O) ATPase of N. thermophilus is a Na(+)-translocating ATPase used primarily for expelling cytoplasmic Na(+) that accumulates inside cells of N. thermophilus during alkaline stress. In support of this theory are the presence of the c subunit Na(+)-binding motif and the low rates of ATP synthesis observed. The complete epsilon subunit is hypothesized to control excessive ATP hydrolysis and preserve intracellular Na(+) needed by electrogenic cation/proton antiporters crucial for cytoplasmic acidification in the obligately alkaliphilic N. thermophilus. PMID- 21600189 TI - Cholesterol attenuates and prevents bilayer damage and breakdown in lipoperoxidized model membranes. A spin labeling EPR study. AB - The stabilizing effect of cholesterol on oxidized membranes has been studied in planar phospholipid bilayers and multilamellar 1-palmitoyl-2-linoleoyl phosphatidylcholine vesicles also containing either 1-palmitoyl-2-glutaroyl phosphatidylcholine or 1-palmitoyl-2-(13-hydroxy-9,11-octadecanedienoyl) phosphatidylcholine oxidized phosphatidylcholine in variable ratio. Lipid peroxidation-dependent membrane alterations in the absence and in the presence of cholesterol were analyzed using Electron Paramagnetic Resonance spectroscopy of the model membranes spin labelled with either cholestane spin label (3-DC) or phosphatidylcholine spin label (5-DSPC). Cholesterol, added to lipid mixtures up to 40% final molar ratio, decreased the inner bilayer disorder as compared to cholesterol-free membranes and strongly reduced bilayer alterations brought about by the two oxidized phosphatidylcholine species. Furthermore, Sepharose 4B gel chromatography and cryo electron microscopy of aqueous suspensions of the lipid mixtures clearly showed that cholesterol is able to counteract the micelle forming tendency of pure 1-palmitoyl-2-glutaroyl-phosphatidylcholine and to sustain multilamellar vesicles formation. It is concluded that membrane cholesterol may exert a beneficial and protective role against bilayer damage caused by oxidized phospholipids formation following reactive oxygen species attack to biomembranes. PMID- 21600190 TI - Conformational changes of beta2-human glycoprotein I and lipid order in lipid protein complexes. AB - We studied the conformation of beta2-human glycoprotein (beta2GPI) in solution and bound to the anionic lipids palmitoyl oleoyl phosphatidylglycerol (POPG), dimiristoyl phosphatidylglycerol (DMPG) and dipalmitoyl phosphatidylglycerol (DPPG) as a function of the temperature. We used the infrared amide I' band to study the protein conformation, and the position of the antisymmetric stretching band of the methylene groups in the lipid hydrocarbon chains to study the lipid order. Lipid-protein complexes were studied in media of low and high ionic strengths. In solution, beta2GPI displayed a conformational pre-transition in the range 47-50 degrees C, characterized by a shift in the band of beta secondary structure, previous to the main unfolding at 64 degrees C. When the protein was bound to the anionic lipid membranes at 25 degrees C, a similar shift as in the pre-transition in solution was observed, together with an increase in the band corresponding to alpha-helix secondary structure. Lipid-protein complexes formed large aggregates within the temperature range 10?60 degrees C. At temperatures above the protein unfolding, the complexes were disrupted to yield vesicles with bound protein. This finding indicated that the native fold was required for the formation of the lipid-protein aggregates. Cycles of heating and cooling showed hysteresis in the formation of aggregates. PMID- 21600191 TI - Effects of a bacterial trehalose lipid on phosphatidylglycerol membranes. AB - Bacterial trehalose lipids are biosurfactants with potential application in the biomedical/healthcare industry due to their interesting biological properties. Given the amphiphilic nature of trehalose lipids, the understanding of the molecular mechanism of their biological action requires that the interaction between biosurfactant and membranes is known. In this study we examine the interactions between a trehalose lipid from Rhodococcus sp. and dimyristoylphosphatidylglycerol membranes by means of differential scanning calorimetry, X-ray diffraction, infrared spectroscopy and fluorescence polarization. We report that there are extensive interactions between trehalose lipid and dimyristoylphosphatidylglycerol involving the perturbation of the thermotropic gel to liquid-crystalline phase transition of the phospholipid, the increase of fluidity of the phosphatidylglycerol acyl chains and dehydration of the interfacial region of the bilayer, and the modulation of the order of the phospholipid bilayer. The observations are interpreted in terms of structural perturbations affecting the function of the membrane that might underline the biological actions of the trehalose lipid. PMID- 21600192 TI - The antifibrotic effects of TGF-beta1 siRNA on hepatic fibrosis in rats. AB - BACKGROUND/AIMS: Hepatic fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSCs), which proliferate during fibrotic liver injury. Transforming growth factor (TGF)-beta1 is the dominant stimulus for extracellular matrix (ECM) production by stellate cells. Our study was designed to investigate the antifibrotic effects of using short interference RNA (siRNA) to target TGF-beta1 in hepatic fibrosis and its mechanism in rats exposed to a high-fat diet and carbon tetrachloride (CCL4). METHODS: A total of 40 healthy, male SD (Sprague-Dawley) rats were randomly divided into five even groups containing of eight rats each: normal group, model group, TGF-beta1 siRNA 0.125mg/kg treatment group, TGF-beta1 siRNA 0.25mg/kg treatment group and TGF beta1 siRNA negative control group (0.25mg/kg). CCL4 and a high-fat diet were used for 8weeks to induce hepatic fibrosis. All the rats were then sacrificed to collect liver tissue samples. A portion of the liver samples were soaked in formalin for Hematoxylin-Eosin staining, classifying the degree of liver fibrosis, and detecting the expression of type I and III collagen and TGF-beta1; the remaining liver samples were stored in liquid nitrogen to be used for detecting TGF-beta1 by Western blotting and for measuring the mRNA expression of type I and III collagen and TGF-beta1 by quantitative real-time polymerase chain reaction. RESULTS: Comparing the TGF-beta1 siRNA 0.25mg/kg treatment group to the model group, the TGF-beta1 siRNA negative control group and the TGF-beta1 siRNA 0.125 mg/kg treatment group showed significantly reduced levels of pathological changes, protein expression and the mRNA expression of TGF-beta1, type I collagen and type III collagen (P<0.01). CONCLUSIONS: Using siRNA to target TGF-beta1 can inhibit the expression of TGF-beta1 and attenuate rat hepatic fibrosis induced by a high-fat diet and CCL4. A possible mechanism is through the down-regulation of TGF-beta1 expression, which could inhibit HSC activation, as well as the proliferation and collagen production of collagen reducing, so that collagen deposition in the liver is reduced. PMID- 21600193 TI - Antitumor effects of a novel benzonaphthofurandione derivative (8e) on the human colon cancer cells in vitro and in vivo through cell cycle arrest accompanied with the modulation of EGFR and mTOR signaling. AB - Benzonaphthofurandione has been considered as an important class of naturally occurring and synthetic compounds having a variety of biological functions. In this study, we evaluated the antitumor effects of 3-[2-(dimethylamino)isopropoxy] 1-hydroxybenzo[b]naphtho[2,3-d]furan-6,11-dione (8e), a novel benzonaphthofurandione derivative, on the growth of colorectal cancer HCT 116 cells both in vitro culture and an in vivo animal model. Compound 8e exhibited the potential growth inhibition of the colon cancer cells in a concentration dependent manner. The anti-proliferative activity of 8e was also associated with the induction of cell cycle arrest in the G(0)/G(1) phase. The 8e-induced cell cycle arrest was well correlated with the suppression of cyclin-dependent kinase 2 (CDK2), CDK4, cyclin D1, cyclin E, c-Myc, and phosphorylated retinoblastoma protein (pRb). The tumor growth in xenograft nude mice bearing HCT 116 cells by compound 8e (10mg/kg) also significantly inhibited without any overt toxicity. In addition, the down-regulation of epidermal growth factor receptor (EGFR), Akt, and mTOR signalings were associated with the anti-proliferative activity of compound 8e in colon cancer cells. Taken together, these findings suggested that cell cycle arrest and modulation of cell signal transduction pathways might be the plausible mechanisms of actions for the anti-proliferative activity of 8e, and thus 8e might be used as an effective chemotherapeutic agent in human colon cancer. PMID- 21600194 TI - The effects of nitrogen-heme-iron coordination on substrate affinities for cytochrome P450 2E1. AB - A descriptor based computational model was developed for cytochrome P450 2E1 (CYP2E1) based on inhibition constants determined for inhibition of chlorzoxazone, or 4-nitrophenol, metabolism. An empirical descriptor for type II binding was developed and tested for a series of CYP2E1 inhibitors. Inhibition constants where measured for 51 different compounds. A fast 2-dimensional predictive model was developed based on 40 compounds, and tested on 8 compounds of diverse structure. The trained model (n=40) had an r(2) value of 0.76 and an RMSE of 0.48. The correlation between the predicted and actual pK(i) values of the test set of compounds not included in the model gives an r(2) value of 0.78. The features that described binding include heme coordination (type II binding), molecular volume, octanol/water partition coefficient, solvent accessible surface area, and the sum of the atomic polarizabilities. The heme coordination parameter assigns an integer between 0 and 6 depending on structure, and is a new descriptor, based on simple quantum chemical calculations with correction for steric effects. The type II binding parameter was found to be important in obtaining a good correlation between predicted and experimental inhibition constants increasing the r(2) value from 0.38 to 0.77. PMID- 21600195 TI - Beneficial role of naringin, a flavanoid on nickel induced nephrotoxicity in rats. AB - This study was conducted to investigate the beneficial role of naringin on nickel induced nephrotoxicity. Nickel (Ni) (20mg/kg body weight (b.w.) was administered intraperitoneally (i.p.) for 20 days. Naringin was administered orally (20, 40 and 80 mg/kg b.w.) with i.p. administration of Ni. Ni administration increased the levels of serum urea, uric acid and creatinine with a significant decrease in creatinine clearance and decreased levels of urea, uric acid and creatinine in urine. The levels of lipid peroxidation markers and nickel concentration in blood and kidney were also increased. While, the activities of enzymic and non-enzymic antioxidants were decreased. Treatment with naringin attenuated the alterations in the renal and urine markers, decreasing lipid peroxidation markers, increasing the antioxidant cascade and decreasing the nickel concentration in blood and kidney. All these changes were supported by histopathological observations. These findings demonstrate that naringin exerts a protective effect against nickel toxicity. PMID- 21600196 TI - Growth factor-dependent branching of the ureteric bud is modulated by selective 6 O sulfation of heparan sulfate. AB - Heparan sulfate proteoglycans (HSPGs) are found in the basement membrane and at the cell-surface where they modulate the binding and activity of a variety of growth factors and other molecules. Most of the functions of HSPGs are mediated by the variable sulfated glycosaminoglycan (GAG) chains attached to a core protein. Sulfation of the GAG chain is key as evidenced by the renal agenesis phenotype in mice deficient in the HS biosynthetic enzyme, heparan sulfate 2-O sulfotransferase (Hs2st; an enzyme which catalyzes the 2-O-sulfation of uronic acids in heparan sulfate). We have recently demonstrated that this phenotype is likely due to a defect in induction of the metanephric mesenchyme (MM), which along with the ureteric bud (UB), is responsible for the mutually inductive interactions in the developing kidney (Shah et al., 2010). Here, we sought to elucidate the role of variable HS sulfation in UB branching morphogenesis, particularly the role of 6-O sulfation. Endogenous HS was localized along the length of the UB suggesting a role in limiting growth factors and other molecules to specific regions of the UB. Treatment of cultures of whole embryonic kidney with variably desulfated heparin compounds indicated a requirement of 6O sulfation in the growth and branching of the UB. In support of this notion, branching morphogenesis of the isolated UB was found to be more sensitive to the HS 6-O sulfation modification when compared to the 2-O sulfation modification. In addition, a variety of known UB branching morphogens (i.e., pleiotrophin, heregulin, FGF1 and GDNF) were found to have a higher affinity for 6-O sulfated heparin providing additional support for the notion that this HS modification is important for robust UB branching morphogenesis. Taken together with earlier studies, these findings suggest a general mechanism for spatio-temporal HS regulation of growth factor activity along the branching UB and in the developing MM and support the view that specific growth factor-HSPG interactions establish morphogen gradients and function as developmental switches during the stages of epithelial organogenesis (Shah et al., 2004). PMID- 21600197 TI - Mesenchymal and mechanical mechanisms of secondary cartilage induction. AB - Secondary cartilage occurs at articulations, sutures, and muscle attachments, and facilitates proper kinetic movement of the skeleton. Secondary cartilage requires mechanical stimulation for its induction and maintenance, and accordingly, its evolutionary presence or absence reflects species-specific variation in functional anatomy. Avians illustrate this point well. In conjunction with their distinct adult mode of feeding via levered straining, duck develop a pronounced secondary cartilage at the insertion (i.e., enthesis) of the mandibular adductor muscles on the lower jaw skeleton. An equivalent cartilage is absent in quail, which peck at their food. We hypothesized that species-specific pattern and a concomitant dissimilarity in the local mechanical environment promote secondary chondrogenesis in the mandibular adductor enthesis of duck versus quail. To test our hypothesis we employed two experimental approaches. First, we transplanted neural crest mesenchyme (NCM) from quail into duck, which produced chimeric "quck" with a jaw complex resembling that of quail, including an absence of enthesis secondary cartilage. Second, we modified the mechanical environment in embryonic duck by paralyzing skeletal muscles, and by blocking the ability of NCM to support mechanotransduction through stretch-activated ion channels. Paralysis inhibited secondary cartilage, as evidenced by changes in histology and expression of genes that affect chondrogenesis, including members of the FGF and BMP pathways. Ion channel inhibition did not alter enthesis secondary cartilage but caused bone to form in place of secondary cartilage at articulations. Thus, our study reveals that enthesis secondary cartilage forms through mechanisms that are distinct from those regulating other secondary cartilage. We conclude that by directing the musculoskeletal patterning and integration of the jaw complex, NCM modulates the mechanical forces and molecular signals necessary to control secondary cartilage formation during development and evolution. PMID- 21600198 TI - Conditional disruption of mouse Klf5 results in defective eyelids with malformed meibomian glands, abnormal cornea and loss of conjunctival goblet cells. AB - Members of the Kruppel-like family of transcription factors regulate diverse developmental processes in various organs. Previously, we have demonstrated the role of Klf4 in the mouse ocular surface. Herein, we determined the role of the structurally related Klf5, using Klf5-conditional null (Klf5CN) mice derived by mating Klf5-LoxP and Le-Cre mice. Klf5 mRNA was detected as early as embryonic day 12 (E12) in the cornea, conjunctiva and eyelids, wherein its expression increased during development. Though the embryonic eye morphogenesis was unaltered in the Klf5CN mice, postnatal maturation was defective, resulting in smaller eyes with swollen eyelids that failed to separate properly. Klf5CN palpebral epidermis was hyperplastic with 7-9 layers of keratinocytes, compared with 2-3 in the wild type (WT). Klf5CN eyelid hair follicles and sebaceous glands were significantly enlarged, and the meibomian glands malformed. Klf5CN lacrimal glands displayed increased vasculature and large number of infiltrating cells. Klf5CN corneas were translucent, thicker with defective epithelial basement membrane and hypercellular stroma. Klf5CN conjunctiva lacked goblet cells, demonstrating that Klf5 is required for conjunctival goblet cell development. The number of Ki67-positive mitotic cells was more than doubled, consistent with the increased number of Klf5CN ocular surface epithelial cells. Co-ablation of Klf4 and Klf5 resulted in a more severe ocular surface phenotype compared with Klf4CN or Klf5CN, demonstrating that Klf4 and Klf5 share few if any, redundant functions. Thus, Klf5CN mice provide a useful model for investigating ocular surface pathologies involving meibomian gland dysfunction, blepharitis, corneal or conjunctival defects. PMID- 21600199 TI - Novel cis-regulatory function in ICR-mediated imprinted repression of H19. AB - Expression of coregulated imprinted genes, H19 and Igf2, is monoallelic and parent-of-origin-dependent. Like most imprinted genes, H19 and Igf2 are regulated by a differentially methylated imprinting control region (ICR). CTCF binding sites and DNA methylation at the ICR have previously been identified as key cis acting elements required for proper H19/Igf2 imprinting. Here, we use mouse models to elucidate further the mechanism of ICR-mediated gene regulation. We specifically address the question of whether sequences outside of CTCF sites at the ICR are required for paternal H19 repression. To this end, we generated two types of mutant ICRs in the mouse: (i) deletion of intervening sequence between CTCF sites (H19(ICR?IVS)), which changes size and CpG content at the ICR; and (ii) CpG depletion outside of CTCF sites (H19(ICR-8nrCG)), which only changes CpG content at the ICR. Individually, both mutant alleles (H19(ICR?IVS) and H19(ICR 8nrCG)) show loss of imprinted repression of paternal H19. Interestingly, this loss of repression does not coincide with a detectable change in methylation at the H19 ICR or promoter. Thus, neither intact CTCF sites nor hypermethylation at the ICR is sufficient for maintaining the fully repressed state of the paternal H19 allele. Our findings demonstrate, for the first time in vivo, that sequence outside of CTCF sites at the ICR is required in cis for ICR-mediated imprinted repression at the H19/Igf2 locus. In addition, these results strongly implicate a novel role of ICR size and CpG density in paternal H19 repression. PMID- 21600201 TI - Quantitative methylation analysis of multiple genes using methylation-sensitive restriction enzyme-based quantitative PCR for the detection of hepatocellular carcinoma. AB - DNA methylation is a promising biomarker for cancer. This study was aimed at investigating the methylation levels of multiple genes in hepatocellular carcinoma (HCC) and to identify a combination of methylation markers that would be useful for the diagnosis of HCC. The methylation status of a panel of nine tumor-associated genes (APC, GSTP1, RASSF1A, CDKN2A, SFRP1, RUNX3, SOCS1, Hint1, and HIC-1) in 8 normal liver tissues and 47 paired HCCs and non-tumorous tissues (NTs) was determined using a modified methylation-sensitive, restriction enzyme based quantitative PCR (MSRE-qPCR) method. The methylation levels of six genes (APC, CDKN2A, GSTP1, RASSF1A, SFRP1 and RUNX3) were significantly higher in HCCs than in adjacent NTs (P<0.05). Although the AUC (area under the curve) for each individual gene was low to moderate (range: 0.576 to 0.835) according to receiver operator characteristic (ROC) curve analysis, the combination analysis of these six genes resulted in an increase of AUC of 0.954 with 85.1% sensitivity, 89.4% specificity, 88.9% positive predictive value, and 85.7% negative predictive value in discriminating HCC tissues from NT tissues. These results indicate that the analysis of a combination of these six methylated genes may be a promising method for the risk assessment and diagnosis of HCC. PMID- 21600200 TI - The inductive role of Wnt-beta-Catenin signaling in the formation of oral apparatus. AB - Proper patterning and growth of oral structures including teeth, tongue, and palate rely on epithelial-mesenchymal interactions involving coordinated regulation of signal transduction. Understanding molecular mechanisms underpinning oral-facial development will provide novel insights into the etiology of common congenital defects such as cleft palate. In this study, we report that ablating Wnt signaling in the oral epithelium blocks the formation of palatal rugae, which are a set of specialized ectodermal appendages serving as Shh signaling centers during development and niches for sensory cells and possibly neural crest related stem cells in adults. Lack of rugae is also associated with retarded anteroposterior extension of the hard palate and precocious mid-line fusion. These data implicate an obligatory role for canonical Wnt signaling in rugae development. Based on this complex phenotype, we propose that the sequential addition of rugae and its morphogen Shh, is intrinsically coupled to the elongation of the hard palate, and is critical for modulating the growth orientation of palatal shelves. In addition, we observe a unique cleft palate phenotype at the anterior end of the secondary palate, which is likely caused by the severely underdeveloped primary palate in these mutants. Last but not least, we also discover that both Wnt and Shh signalings are essential for tongue development. We provide genetic evidence that disruption of either signaling pathway results in severe microglossia. Altogether, we demonstrate a dynamic role for Wnt-beta-Catenin signaling in the development of the oral apparatus. PMID- 21600202 TI - Localization of Epstein-Barr virus to infiltrating lymphocytes in breast carcinomas and not malignant cells. AB - The pathogenesis of breast cancer is unknown. In recent years, a number of studies have implicated a role for Epstein-Barr virus (EBV) in a subset of cases. However, these findings are controversial and others have failed to find any link between the virus and this malignancy. We hypothesized that technical differences and the different type and ethnic origin of the cases may be the cause of the disparities reported. Using a highly sensitive EBER-in situ hybridization and immunohistochemistry, we examined 219 samples (158 malignant and 61 non malignant) from 61 Emirati breast cancer cases to determine if EBV was etiologically associated with Emirati cases and if there was any correlation with other established prognostic factors such as age, histological type, lymph node metastasis, estrogen, progesterone and HER2 expression. We found 47.5% of the cases to be EBV positive, but the virus was localized to occasional infiltrating lymphocytes and not in the malignant cells. EBV lymphocytes were more commonly observed in lymph nodes than in breast tissues, but there was no correlation with malignancy or hormone status. The mean age of our patients was 48years and hormone receptor staining revealed 20% of the cases to be triple negative (ER-/PR /HER2-). We conclude that although EBV can be detected in breast cancer cases, it is not directly associated with the disease. Thus, a PCR-based approach cannot be used to link this ubiquitous virus to the pathogenesis of breast cancer. Furthermore, we do not find any correlation between the presence of EBV in infiltrating lymphocytes and ER, PR, HER2 expression. We believe our findings will help explain some of the controversies relating to the role of EBV in the pathogenesis of breast cancer. PMID- 21600204 TI - Essential residues in the H-NS binding site of Hha, a co-regulator of horizontally acquired genes in Enterobacteria. AB - Proteins of the Hha/YmoA family co-regulate with H-NS the expression of horizontally acquired genes in Enterobacteria. Systematic mutations of conserved acidic residues in Hha have allowed the identification of D48 as an essential residue for H-NS binding and the involvement of E25. Mutations of these residues resulted in deregulation of sensitive genes in vivo. D48 is only partially solvent accessible, yet it defines the functional binding interface between Hha and H-NS confirming that Hha has to undergo a conformational change to bind H-NS. Exposed acidic residues, such as E25, may electrostatically facilitate and direct the approach of Hha to the positively charged region of H-NS enabling the formation of the final complex when D48 becomes accessible by a conformational change of Hha. PMID- 21600203 TI - MicroRNAs in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic and severe autoimmune disease that affects joint tissues, bone, and cartilage. However, the pathogenesis of RA is still unclear. Autoantibodies such as rheumatoid factor and anti-cyclic citrullinated peptide are useful tools for early diagnosis, monitoring disease activity, and predicting prognosis. Recently, many groups have focused their attention on the role of microRNAs in the pathogenesis of RA, as well as a potential biomarker to monitor RA. In fact, the expression of some microRNAs, such as miR-146a, is upregulated in different cell types and tissues in RA patients. MicroRNAs in RA could also be considered as possible future targets for new therapeutic approaches. PMID- 21600205 TI - A polymorphism in IL28B distinguishes exposed, uninfected individuals from spontaneous resolvers of HCV infection. AB - BACKGROUND & AIMS: Polymorphisms in the interleukin-28B (IL28B) gene are associated with outcomes from infection with hepatitis C virus (HCV). However, the role of these polymorphisms in protecting injection drug users who are at high risk for HCV infection but do not have detectable antibodies against HCV or HCV RNA (exposed uninfected) has not been demonstrated. We investigated whether these individuals have the IL28B genotype rs12979860-CC, which protects some individuals against HCV infection. METHODS: Seventy-four exposed uninfected individuals, 89 spontaneous resolvers, and 234 chronically infected individuals were genotyped to determine single nucleotide polymorphisms at IL28B.rs12979860. RESULTS: Exposed, uninfected individuals had a significantly lower frequency of the protective genotype (rs12979860-CC) than anti-HCV-positive spontaneous resolvers (41.9% vs 69.7%, respectively; P=.0005; odds ratio [OR], 0.31; 95% confidence interval [CI]: 0.16-0.60) but a similar frequency to patients who were chronically infected (41.9% vs 43.6%, respectively; P=ns). However, exposed, uninfected individuals had a significantly higher frequency of homozygosity for killer cell immunoglobulin-like receptor 2DL3:group 1 HLA-C (KIR2DL3:HLA-C1) than those with chronic infection (31.1% vs 13.3%, respectively; P=.0008; OR, 2.95; 95% CI: 1.59-5.49). For patients who spontaneously resolved infection, IL28B and KIR:HLA protected, independently, against chronic HCV infection, based on logistic regression and synergy analyses (synergy factor, 1.3; 95% CI: 0.37-4.75; P synergy=.6). CONCLUSIONS: IL28B and KIR2DL3:HLA-C1 are independently associated with spontaneous resolution of viremia following HCV exposure. Resistance to HCV infection in exposed uninfected cases is associated with homozygosity for KIR2DL3:HLA-C1 but not the single nucleotide polymorphism IL28B.rs12979860. Uninfected individuals are therefore a distinct population from patients who spontaneously resolve HCV infection. Distinct, nonsynergistic innate immune mechanisms can determine outcomes of HCV exposure. PMID- 21600206 TI - Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. AB - BACKGROUND & AIMS: The pathogenesis of inflammatory bowel disease (IBD) is believed to involve an altered balance between effector and regulatory T cells. Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor that mediates the toxicity of dioxins, controls T-cell responses. We investigated the role of AhR in inflammation and pathogenesis of IBD in humans and mouse models. METHODS: AhR expression was evaluated in intestinal tissue samples from patients with IBD and controls by real-time polymerase chain reaction (PCR) and flow cytometry. Intestinal lamina propria mononuclear cells (LPMCs) were activated in the presence or absence of the AhR agonist 6-formylindolo(3, 2-b)carbazole (Ficz). Colitis was induced in mice using trinitrobenzene sulfonic acid (TNBS), dextran sulfate sodium (DSS), or T-cell transfer. Mice were given injections of Ficz or the AhR antagonist 2-metyl-2H-pyrazole-3-carboxylic acid; some mice first received injections of a blocking antibody against interleukin (IL)-22. Cytokines were quantified by real-time PCR and flow cytometry. RESULTS: Intestine tissue from patients with IBD expressed significantly less AhR than controls. In LPMCs from patients with IBD, incubation with Ficz reduced levels of interferon gamma (IFN)-gamma and up-regulated IL-22. Mice injected with Ficz were protected against TNBS-, DSS-, and T-cell transfer-induced colitis; they had marked down regulation of inflammatory cytokines and induction of IL-22. Mice given AhR antagonist produced more inflammatory cytokines and less IL-22 and developed a severe colitis. Neutralization of endogenous IL-22 disrupted the protective effect of Ficz on TNBS-induced colitis. CONCLUSIONS: AhR is down-regulated in intestinal tissue of patients with IBD; AhR signaling, via IL-22, inhibits inflammation and colitis in the gastrointestinal tract of mice. AhR-related compounds might be developed to treat patients with IBDs. PMID- 21600207 TI - Nonlinear reduction in risk for colorectal cancer by fruit and vegetable intake based on meta-analysis of prospective studies. AB - BACKGROUND & AIMS: The association between fruit and vegetable intake and colorectal cancer risk has been investigated by many studies but is controversial because of inconsistent results and weak observed associations. We summarized the evidence from cohort studies in categorical, linear, and nonlinear, dose-response meta-analyses. METHODS: We searched PubMed for studies of fruit and vegetable intake and colorectal cancer risk that were published until the end of May 2010. We included 19 prospective studies that reported relative risk estimates and 95% confidence intervals (CIs) of colorectal cancer-associated with fruit and vegetable intake. Random effects models were used to estimate summary relative risks. RESULTS: The summary relative risk for the highest vs the lowest intake was 0.92 (95% CI: 0.86-0.99) for fruit and vegetables combined, 0.90 (95% CI: 0.83-0.98) for fruit, and 0.91 (95% CI: 0.86-0.96) for vegetables (P for heterogeneity=.24, .05, and .54, respectively). The inverse associations appeared to be restricted to colon cancer. In linear dose-response analysis, only intake of vegetables was significantly associated with colorectal cancer risk (summary relative risk=0.98; 95% CI: 0.97-0.99), per 100 g/d. However, significant inverse associations emerged in nonlinear models for fruits (Pnonlinearity<.001) and vegetables (Pnonlinearity=.001). The greatest risk reduction was observed when intake increased from very low levels of intake. There was generally little evidence of heterogeneity in the analyses and there was no evidence of small study bias. CONCLUSIONS: Based on meta-analysis of prospective studies, there is a weak but statistically significant nonlinear inverse association between fruit and vegetable intake and colorectal cancer risk. PMID- 21600209 TI - Effect of inhibitor and activator of ghrelin receptor (GHS-R1a) on porcine ovarian granulosa cell functions. AB - It was previously shown, that ghrelin and its agonistic analogue, ghrelin 1-18, can be a stimulator of ovarian cell functions (promoter of proliferation, inhibitor of apoptosis and stimulator of hormones release). The aim of our studies was to compare the action of two ghrelin analogues - ghrelin 1-18, activator of ghrelin receptors (GHS-R1a), and (D-Lys3)-GHRP-6, its inhibitor, on porcine ovarian granulosa cell functions. Effects of (D-Lys3)-GHRP-6 added at doses of 0, 1, 10 or 100 ng/ml on the expression of markers of proliferation (PCNA, cyclin B1, MAPK/ERK1,2), apoptosis (bax, p53, caspase 3) and release of steroid hormones (progesterone, testosterone, estradiol) were examined. In addition, some effect of ghrelin 1-8 on some of these parameters (expression of MAPK/ERK1,2, bax, p53) were verified. It was shown, that (D-Lys3)-GHRP-6 promotes all markers of granulosa cell proliferation, inhibits all markers of apoptosis and stimulates the release of all three steroid hormones. Similar effects of (D Lys3)-GHRP-6 (inhibitor of GHS-R1a) and ghrelin 1-18 (its stimulator) suggest that the examined effects of these substances on porcine ovaries are not mediated by GHS-R1a. Both chemical analogues could be potentially useful for stimulation of reproductive processes, at least in in vitro conditions. PMID- 21600208 TI - Estrogenic regulation of dopaminergic neurons in the opportunistically breeding zebra finch. AB - Steroid-induced changes in dopaminergic activity underlie many correlations between gonadal hormones and social behaviors. However, the effects of steroid hormones on the various behaviorally relevant dopamine cell groups remain unclear, and ecologically relevant species differences remain virtually unexplored. We examined the effects of estradiol (E2) manipulations on dopamine (DA) neurons of male and female zebra finches (Taeniopygia guttata), focusing on numbers of tyrosine hydroxylase-immunoreactive (TH-ir) cells in the A8-A15 cell groups, and on TH colocalization with Fos, conducted in the early A.M., in order to quantify basal transcriptional activity. TH is the rate-limiting enzyme for catecholamine synthesis, and specifically DA in the A8-A15 cell groups. In contrast to other examined birds and mammals, reducing E2 levels with the aromatase-inhibitor Letrozole failed to alter TH-ir neuron numbers within the ventral tegmental area (VTA; A10), while increasing neuron numbers in the central gray (CG; A11) and caudal midbrain A8 populations. Consistent with findings in other birds, but not mammals, we also found no effects of E2 manipulations (Letrozole or Letrozole plus E2 replacement) on TH-Fos colocalization in any location. In accordance with previous observations in both mammals and birds, E2 treatment decreased the number of TH-ir neurons in the A12 population of the tuberal hypothalamus, a cell group that inhibits the release of prolactin. In general, males and females exhibited similar TH-ir neuron numbers, although males exhibited significantly more TH-ir neurons in the A11 CG population than did females. These results suggest partial variability in E2 regulation of DA across species. PMID- 21600210 TI - Cloning and expression of the translocator protein (18 kDa), voltage-dependent anion channel, and diazepam binding inhibitor in the gonad of largemouth bass (Micropterus salmoides) across the reproductive cycle. AB - Cholesterol transport across the mitochondrial membrane is rate-limiting for steroidogenesis in vertebrates. Previous studies in fish have characterized expression of the steroidogenic acute regulatory protein, however the function and regulation of other genes and proteins involved in piscine cholesterol transport have not been evaluated. In the current study, mRNA sequences of the 18 kDa translocator protein (tspo; formerly peripheral benzodiazepine receptor), voltage-dependent anion channel (vdac), and diazepam binding inhibitor (dbi; also acyl-CoA binding protein) were cloned from largemouth bass. Gonadal expression was examined across reproductive stages to determine if expression is correlated with changes in steroid levels and with indicators of reproductive maturation. In testis, transcript abundance of tspo and dbi increased with reproductive maturation (6- and 23-fold maximal increase, respectively) and expression of tspo and dbi was positively correlated with reproductive stage, gonadosomatic index (GSI), and circulating levels of testosterone. Testis vdac expression was positively correlated with reproductive stage and GSI. In females, gonadal tspo and vdac expression was negatively correlated with GSI and levels of plasma testosterone and 17beta-estradiol. Ovarian dbi expression was not correlated with indicators of reproductive maturation. These studies represent the first investigation of the steroidogenic role of tspo, vdac, and dbi in fish. Findings suggest that cholesterol transport in largemouth bass testis, but not in ovary, may be transcriptionally-regulated, however further investigation will be necessary to fully elucidate the role of these genes in largemouth bass steroidogenesis. PMID- 21600211 TI - Biochemical and in vitro biological significance of natural sequence variation in the ovine leptin gene. AB - The hormone leptin is involved in diverse biological processes, including regulation of food intake, body-weight homeostasis and energy balance. Sequence variation in the bovine leptin gene has been found to be associated with variations in carcass fat content and average daily gain, as well as in milk yield, milk somatic cell count and several traits governing reproduction. We sequenced genomic DNA and cDNA samples of individuals from three divergent sheep breeds and revealed synonymous as well as novel non-synonymous allelic variation at the third exon of the ovine leptin gene (oLEP) as compared to the sequence published at Accession No. U84247 (reference sequence). In addition, two alternatively spliced oLEP transcripts were found in the abdominal fat tissue. The biochemical and the in vitro biological significance of the sequence variation in the oLEP was examined by generating recombinant oLEP-protein variants namely: p.Q28del, p.N78S, p.R84Q, p.P99Q, p.V123L and p.R138Q, carrying the corresponding sequence variation. Surface plasmon resonance experiments revealed, in most cases, reduced affinity of the oLEP protein variants examined, to human leptin-binding domain (hLBD), relative to the reference variant, being 0.75, 0.60, 0.60, 0.89, 0.92 and 1.03, respectively. In competitive binding assays between biotinylated oLEP and the recombinant leptin protein variants, p.N78S and p.R84Q variants exhibited the lowest affinity to hLBD (0.18 and 0.41, respectively) as compared to the reference hormone. We then tested the protein variants' ability to induce proliferation in Baf-3 cells stably expressing the long form of the human leptin receptor: significant differences in proliferative activity were only found for p.N78S (1.8-fold higher) and p.R138Q (4.2-fold lower) relative to the reference oLEP variant. PMID- 21600212 TI - Investigation of the steps involved in the difference of susceptibility of Ephestia kuehniella and Spodoptera littoralis to the Bacillus thuringiensis Vip3Aa16 toxin. AB - BUPM95 is a Bacillus thuringiensis subsp. kurstaki strain producing the Vip3Aa16 toxin with an interesting insecticidal activity against the Lepidopteran larvae Ephestia kuehniella. Study of different steps in the mode of action of this Vegetative Insecticidal Protein on the Mediterranean flour moth (E. kuehniella) was carried out in the aim to investigate the origin of the higher susceptibility of this insect to Vip3Aa16 toxin compared to that of the Egyptian cotton leaf worm Spodoptera littoralis. Using E. kuehniella gut juice, protoxin proteolysis generated a major band corresponding to the active toxin and another band of about 22kDa, whereas the activation of Vip3Aa16 by S. littoralis gut juice proteases generated less amount of the 62kDa active form and three other proteolysis products. As demonstrated by zymogram analysis, the difference in proteolysis products was due to the variability of proteases in the two gut juices larvae. The study of the interaction of E. kuehniella BBMV with biotinylated Vip3Aa16 showed that this toxin bound to a putative receptor of 65kDa compared to the 55 and 100kDa receptors recognized in S. littoralis BBMV. The histopathological observations demonstrated similar damage caused by the toxin in the two larvae midguts. These results demonstrate that the step of activation, mainly, is at the origin of the difference of susceptibility of these two larvae towards B. thuringiensis Vip3Aa16 toxin. PMID- 21600213 TI - Phylogenetic analysis of Nosema ceranae isolated from European and Asian honeybees in Northern Thailand. AB - Nosema ceranae was found to infect four different host species including the European honeybee (A. mellifera) and the Asian honeybees (Apis florea, A. cerana and Apis dorsata) collected from apiaries and forests in Northern Thailand. Significant sequence variation in the polar tube protein (PTP1) gene of N. ceranae was observed with N. ceranae isolates from A. mellifera and A. cerana, they clustered into the same phylogenetic lineage. N. ceranae isolates from A. dorsata and A. florea were grouped into two other distinct clades. This study provides the first elucidation of a genetic relationship among N. ceranae strains isolated from different host species and demonstrates that the N. ceranae PTP gene was shown to be a suitable and reliable marker in revealing genetic relationships within species. PMID- 21600214 TI - AKAPs: the architectural underpinnings of local cAMP signaling. AB - The cAMP-dependent protein kinase A (PKA) is targeted to specific compartments in the cardiac myocyte by A-kinase anchoring proteins (AKAPs), a diverse set of scaffold proteins that have been implicated in the regulation of excitation contraction coupling and cardiac remodeling. AKAPs bind not only PKA, but also a large variety of structural and signaling molecules. In this review, we discuss the basic concepts underlying compartmentation of cAMP and PKA signaling, as well as a few of the individual AKAPs that have been shown to be functionally relevant in the heart. This article is part of a Special Issue entitled "Local Signaling in Myocytes". PMID- 21600215 TI - STAT3/Pim-1 signaling pathway plays a crucial role in endothelial differentiation of cardiac resident Sca-1+ cells both in vitro and in vivo. AB - Cardiac stem cells potentially differentiate into cardiac cells, including cardiomyocytes and endothelial cells (ECs). Previously we demonstrated that STAT3 activation by IL-6 family cytokines, such as leukemia inhibitory factor (LIF), induces the endothelial differentiation of cardiac Sca-1+ cells. In this study, we addressed molecular mechanisms for EC differentiation of Sca-1+ cells. First, DNA array experiments were performed to search for the molecules induced by LIF. Among 134 genes that LIF upregulated by more than 4 fold, we focused on Pim-1 gene transcript, because Pim-1 is associated with the differentiation of some cell lineages. Real time RT-PCR analyses confirmed that LIF stimulation upregulated Pim-1 expression. Adenoviral transfection of dominant negative (dn) STAT3 inhibited LIF-mediated induction of Pim-1, while the overexpression of constitutively active STAT3 upregulated Pim-1 expression, suggesting that STAT3 activation is necessary and sufficient for Pim-1 induction. Moreover, in STAT3 deficient Sca-1+ cells, LIF failed to induce Pim-1 expression and EC differentiation. Importantly, the overexpression of dnPim-1 abrogated the induction of EC markers, indicating Pim kinase activity is indispensable for STAT3-mediated EC differentiation in vitro. Finally, Sca-1+ cells labeled with LacZ were transplanted into post-infarct myocardium and the transdifferentiation was estimated. The overexpression of wild-type STAT3 by adenovirus vector significantly promoted EC differentiation, while STAT3 gene ablation reduced the frequency of differentiating cells in post-infarct myocardium. Furthermore, transplanted Sca-1+ cells overexpressing dnPim-1 showed the reduced frequency of EC differentiation and capillary density. Collectively, Pim-1 kinase is upregulated by STAT3 activation in cardiac Sca-1+ cells and plays a pivotal role in EC differentiation both in vitro and in vivo. PMID- 21600216 TI - Unraveling the secrets of a double life: contractile versus signaling Ca2+ in a cardiac myocyte. AB - No other inorganic molecule known in biology is considered as versatile as Ca(2+). In a vast majority of cell types, Ca(2+) acts as a universal second messenger underlying critical cellular processes varying from gene transcription to cell death. Although the role of Ca(2+) in myocyte contraction has been known for over a century, it was only more recently that this divalent cation has been implicated in mediating reactive signal transduction to promote cardiac hypertrophy. However, it remains unclear how Ca(2+)-dependent signaling pathways are regulated/activated in a cardiac myocyte given the prevailing conditions throughout the cytosol where Ca(2+) concentration oscillates between 100 nM and upwards of 1-2 MUM during each contractile cycle. In this review we will examine three hypotheses put forward to explain how Ca(2+) might still function as a hypertrophic signaling molecule in cardiac myocytes and discuss the current literature that supports each of these views. This article is part of a special issue entitled "Local Signaling in Myocytes." PMID- 21600217 TI - The stalk region of the RecU resolvase is essential for Holliday junction recognition and distortion. AB - The Bacillus subtilis RecU protein has two activities: to recognize, distort, and cleave four-stranded recombination intermediates and to modulate RecA activities. The RecU structure shows a mushroom-like appearance, with a cap and a stalk region. The RuvB interaction and the catalytic residues are located in the cap region of dimeric RecU. We report here that the stalk region is essential not only for RecA modulation but also for Holliday junction (HJ) recognition. Two recU mutants, which map in the stalk region, were isolated and characterized. In vivo, a RecU variant with a Phe81-to-Ala substitution (F81A) was as sensitive to DNA-damaging agents as a null recU strain, and a similar substitution at tyrosine 80 (Y80A) showed an intermediate phenotype. RecUY80A and RecUF81A poorly recognize and distort HJs. RecUY80A cleaves HJs with low efficiency, and RuvB modulates cleavage. At high concentrations, RecUF81A binds to HJs but fails to cleave them. Unlike wild-type RecU, RecUY80A and RecUF81A do not inhibit RecA dATPase and strand-exchange activities. The RecU stalk region is involved in RecA interaction, but once an HJ is bound, RecU fails to modulate RecA activities. Our biochemical study provides a mechanistic basis for the connections between these two mutually exclusive stages (i.e., RecA modulation and HJ resolution) of the recombination reaction. PMID- 21600218 TI - From genes to games: cooperation and cyclic dominance in meiotic drive. AB - Evolutionary change can be described on a genotypic level or a phenotypic level. Evolutionary game theory is typically thought of as a phenotypic approach, although it is frequently argued that it can also be used to describe population genetic evolution. Interpreting the interaction between alleles in a diploid genome as a two player game leads to interesting alternative perspectives on genetic evolution. Here we focus on the case of meiotic drive and illustrate how meiotic drive can be directly and precisely interpreted as a social dilemma, such as the prisoners dilemma or the snowdrift game, in which the drive allele takes more than its fair share. Resistance to meiotic drive can lead to the well understood cyclic dominance found in the rock-paper-scissors game. This perspective is well established for the replicator dynamics, but there is still considerable ground for mutual inspiration between the two fields. For example, evolutionary game theorists can benefit from considering the stochastic evolutionary dynamics arising from finite population size. Population geneticists can benefit from game theoretic tools and perspectives on genetic evolution. PMID- 21600219 TI - Some implications of Scale Relativity theory in avascular stages of growth of solid tumors in the presence of an immune system response. AB - We present a traveling-wave analysis of a reduced mathematical model describing the growth of a solid tumor in the presence of an immune system response in the framework of Scale Relativity theory. Attention is focused upon the attack of tumor cells by tumor-infiltrating cytotoxic lymphocytes (TICLs), in a small multicellular tumor, without necrosis and at some stage prior to (tumor-induced) angiogenesis. For a particular choice of parameters, the underlying system of partial differential equations is able to simulate the well-documented phenomenon of cancer dormancy and propagation of a perturbation in the tumor cell concentration by cnoidal modes, by depicting spatially heterogeneous tumor cell distributions that are characterized by a relatively small total number of tumor cells. This behavior is consistent with several immunomorphological investigations. Moreover, the alteration of certain parameters of the model is enough to induce soliton like modes and soliton packets into the system, which in turn result in tumor invasion in the form of a standard traveling wave. In the same framework of Scale Relativity theory, a very important feature of malignant tumors also results, that even in avascular stages they might propagate and invade healthy tissues, by means of a diffusion on a Newtonian fluid. PMID- 21600220 TI - Apples, oranges, and angles: Comparative kinematic analysis of disparate limbs. AB - Tetrapod limbs exhibit diverse postures and movements during terrestrial locomotion. As with morphological traits, the history of kinematic evolution should be accessible to reconstruction through analysis of limb motion patterns in a phylogenetic framework. However, the angular data comprising most kinematic descriptions appear to suffer from limitations that preclude meaningful comparison among disparate species. Using simple planar models, we discuss how geometric constraints render joint and elevation angles independent of neither morphology, degree of crouch, nor one another during the stance phase of locomotion. The implicit null hypothesis of potential similarity is invalidated because angular data are not viably transferable among limbs of dissimilar proportion and/or degree of crouch. Overlooking or dismissing the effect of constraints on angular parameterization hampers efforts to quantitatively elucidate the evolution of locomotion. We advocate a search for alternative methods of measuring limb movement that can decouple intersegmental coordination from morphology and posture. PMID- 21600221 TI - Non-stationary aging dynamics in ant societies. AB - In recent experiments by Richardson et al. (2010) [Richardson, T.O., Robinson, E.J.H., Christensen, K., Jensen, H.J., Franks, N.R., Sendova-Franks, A.B., 2010. PLoS ONE 5, e9621.] ant motion out of the nest is shown to be a non-stationary process intriguingly similar to the dynamics encountered in physical aging of glassy systems. Specifically, exit events can be described as a Poisson process in logarithmic time, or, for short, a log-Poisson process. Nouvellet et al. (2010) [Nouvellet, P., Bacon, J.P.,Waxman, D., 2010. J. Theor. Biol. 266, 573.] criticized these conclusions and performed new experiments where the exit process could more simply be described by standard Poisson statistics. In their reply Richardson et al. (2011b) [Richardson, T.O., Robinson, E.J.H., Christensen, K., Jensen, J.H., Christensen, K., Jensen, H.J., Franks, N.R., Sendova-Franks, A.B., 2011b. J. Theor. Biol. 269, 356-358.] stressed that the two sets of experiments were performed under very different conditions and claimed that this was the likely source of the discrepancy. Ignoring any technical issues which are part of the above discussion, the focal point of this work is to ascertain whether or not both log-Poisson and Poisson statistics are possible in an ant society under different external conditions. To this end, a model is introduced where interacting ants move in a stochastic fashion from one site to a neighboring site on a finite 2D lattice. The probability of each move is determined by the ensuing changes of a utility function which is a sum of pairwise interactions between ants, weighted by distance. Depending on how the interactions are defined and on a control parameter dubbed 'degree of stochasticity' (DS), the dynamics either quickly converges to a stationary state, where movements are a standard Poisson process, or may enter a non-stationary regime, where exits can be described as suggested by Richardson et al. Other aspects of the model behavior are also discussed, i.e. the time dependence of the average value of the utility function, and the statistics of spatial re-arrangements happening anywhere in the system. Finally, we discuss the role of record events and their statistics in the context of ant societies and suggest the possibility that a transition from non stationary to stationary dynamics can be triggered experimentally. PMID- 21600222 TI - Functionality and metagraph disintegration in boolean networks. AB - We study regulatory networks of N genes giving rise to a vector expression profile v(t) in which each gene is Boolean; either on or off at any time. We require a network to produce a particular time sequence v(t) for t?1,...,T and parameterize the complexity of such a genetic function by its duration T. We establish a number of new results regarding how functional complexity constrains genetic regulatory networks and their evolution. We find that the number of networks which generate a function decreases approximately exponentially with its complexity T and show there is a corresponding weakening of the robustness of those networks to mutations. These results suggest a limit on the functional complexity T of typical networks that is polynomial in N. However, we are also able to prove the existence of a, presumably small, class of networks in which this scales exponentially with N. We demonstrate that an increase in functional complexity T drives what we describe as a metagraph disintegration effect, breaking up the space of networks previously connected by neutral mutations and contrast this with what is found with less restrictive definitions of functionality. Our findings show how functional complexity could be a factor in shaping the evolutionary landscape and how the evolutionary history of a species constrains its future functionality. Finally we extend our analysis to functions with more exotic topologies in expression space, including "stars" and "trees". We quantify how the properties of networks that give rise to these functions differ from those that produce linear functional paths with the same overall duration T. PMID- 21600223 TI - COX-2 expression is correlated with VEGF-C, lymphangiogenesis and lymph node metastasis in human cervical cancer. AB - Lymphangiogenesis has been shown to promote lymph node metastasis in cancers, making it an important target in cancer therapy. Vascular endothelial growth factor (VEGF)-C is upregulated in various tumors/cancers and is one of the most potent growth factors for inducing lymphangiogenesis and promoting lymph node metastasis (LNM). Likewise, cyclooxygenase (COX)-2 plays major roles in carcinogenesis, tumor growth and metastasis via multiple mechanisms including inactivation of host antitumor immunity and promotion of tumor cell migration, tumor cell invasiveness and tumor-associated angiogenesis and lymphangiogenesis. We previously demonstrated an association between COX-2 and VEGF-C in an in vitro model of lung cancer. However, little is known about the regulation of VEGF-C by COX-2 in cervical cancer. In this study, we measured the COX-2 and VEGF-C expressions by immunohistochemistry in 23 LNM-positive and 20 LNM-negative cervical cancer specimens. We then examined the correlations among the expressions and the lymphatic microvessel density (LMVD) and ultrastructural changes to the lymphatic vessel walls by enzyme histochemical staining and electron microscopy. In addition, we used the HeLa cervical cancer cell line to explore the in vitro regulation of VEGF-C by COX-2 and its metabolite, PGE(2), using siRNA-mediated gene silencing and EP receptor blockade. The LNM-positive specimens exhibited significantly higher VEGF-C expression, COX-2 expression and LMVD than the LNM-negative specimens. Furthermore, there were strong correlations between the levels of COX-2 expression and the levels of VEGF-C expression and secretion and a significant positive association between the LMVD and LNM. siRNA mediated knockdown of COX-2 expression inhibited VEGF-C mRNA expression while EP1 and EP4 receptor antagonists reduced the VEGF-C protein level and tyrosine phosphorylation of Src kinase. Moreover, inhibition of Src kinase with the tyrosine kinase inhibitor PP1 attenuated VEGF-C expression. Collectively, our data provide evidence for a clinical association between COX-2 and VEGF-C expressions in cervical cancer. EP1 and EP4 receptors may be involved in the COX 2-mediated regulation of VEGF-C protein and mRNA expressions. Src may be a downstream mediator of EP1 and EP4 receptors. COX-2 inhibition may diminish LNM by suppressing VEGF-C-mediated lymphangiogenesis. PMID- 21600224 TI - Genetics of leukocyte telomere length and its role in atherosclerosis. AB - Humans display a large inter-individual variation in leukocyte telomere length (LTL), which is influenced by heredity, sex, race/ethnicity, paternal age at conception and environmental exposures. LTL dynamics (birth LTL and its age dependent attrition thereafter) mirror telomere dynamics in hematopoietic stem cells (HSCs). LTL at birth is evidently a major determinant of LTL throughout the human lifespan, such that individuals endowed with short (or long) LTL at birth probably have short (or long) LTL later in life. Therefore, the associations of short LTL with atherosclerosis and with diminished survival in the elderly may relate to short birth LTL, accelerated age-dependent LTL attrition, or both. The mechanisms underlying these associations are still not well understood, but they stem in part from genetic factors in control of telomere maintenance and the rate of HSC replication. PMID- 21600225 TI - Review of biological mechanisms and pharmacological treatments of comorbid PTSD and substance use disorder. AB - Posttraumatic stress disorder (PTSD) and alcohol/substance use disorder (A/SUD) are frequently comorbid. Comorbidity is associated with poorer psychological, functional, and treatment outcomes than either disorder alone. This review outlines biological mechanisms that are potentially involved in the development and maintenance of comorbid PTSD and A/SUD including neurotransmitter and hypothalamic-pituitary-adrenal dysregulation, structural differences in the brain, and shared genetic risk factors. The literature regarding pharmacological treatments that have been investigated for comorbid PTSD and A/SUD is also reviewed. Empirical data for each proposed mechanism and pharmacological approach is reviewed with the goal of making recommendations for future research. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. PMID- 21600226 TI - Market mechanisms protect the vulnerable brain. AB - Markets are mechanisms of social exchange, intended to facilitate trading. However, the question remains as to whether markets would help or hurt individuals with decision-makings deficits, as is frequently encountered in the case of cognitive aging. Essential for predicting future gains and losses in monetary and social domains, the striatal nuclei in the brain undergo structural, neurochemical, and functional decline with age. We correlated the efficacy of market mechanisms with dorsal striatal decline in an aging population, by using market based trading in the context of the 2008 U.S. Presidential Elections (primary cycle). Impaired decision-makers displayed higher prediction error (difference between their prediction and actual outcome). Lower in vivo caudate volume was also associated with higher prediction error. Importantly, market based trading protected older adults with lower caudate volume to a greater extent from their own poorly calibrated predictions. Counterintuitive to the traditional public perception of the market as a fickle, risky proposition where vulnerable traders are most surely to be burned, we suggest that market-based mechanisms protect individuals with brain-based decision-making vulnerabilities. PMID- 21600227 TI - Differential neural activity during search of specific and general autobiographical memories elicited by musical cues. AB - Previous neuroimaging studies that have examined autobiographical memory specificity have utilized retrieval cues associated with prior searches of the event, potentially changing the retrieval processes being investigated. In the current study, musical cues were used to naturally elicit memories from multiple levels of specificity (i.e., lifetime period, general event, and event-specific). Sixteen young adults participated in a neuroimaging study in which they retrieved autobiographical memories associated with musical cues. These musical cues led to the retrieval of highly emotional memories that had low levels of prior retrieval. Retrieval of all autobiographical memory levels was associated with activity in regions in the autobiographical memory network, specifically the ventromedial prefrontal cortex, posterior cingulate, and right medial temporal lobe. Owing to the use of music, memories from varying levels of specificity were retrieved, allowing for comparison of event memory and abstract personal knowledge, as well as comparison of specific and general event memory. Dorsolateral and dorsomedial prefrontal regions were engaged during event retrieval relative to personal knowledge retrieval, and retrieval of specific event memories was associated with increased activity in the bilateral medial temporal lobe and dorsomedial prefrontal cortex relative to retrieval of general event memories. These results suggest that the initial search processes for memories of different specificity levels preferentially engage different components of the autobiographical memory network. The potential underlying causes of these neural differences are discussed. PMID- 21600228 TI - Relationships among reproductive morphology, behavior, and testosterone in a natural population of green anole lizards. AB - Laboratory studies of reproductive systems have long supported the idea that neural and/or muscular structures used frequently are often enhanced in size. However, field studies integrating behavioral, morphological, and hormonal data are needed to better understand relationships in natural environments. We examined a natural population of green anole lizards (Anolis carolinensis) to determine whether variation in reproductive morphology both within and between the sexes paralleled differences in courtship and copulatory behaviors and circulating testosterone levels. Display rate in males was positively correlated with the sizes of the cartilage supporting the dewlap (a throat fan used in courtship and aggression) and renal sex segments (portions of the kidney that function similarly to the mammalian prostate), but correlated negatively with seminiferous tubule size. Plasma testosterone in males was negatively correlated with display behavior and was not correlated with any measures of morphology. Females, which display rarely, exhibited no relationships between morphology and frequency of behavior. Comparisons between the sexes show that males have consistently larger courtship and copulation morphologies than females, even when accounting for sex differences in body size. The results not only support the idea of relationships between increased function and enhanced structures, but also show the complexity of mechanistic interactions associated with reproductive behavior in wild animals. PMID- 21600229 TI - Synthesis of novel steroidal 17alpha-triazolyl derivatives via Cu(I)-catalyzed azide-alkyne cycloaddition, and an evaluation of their cytotoxic activity in vitro. AB - Regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition of steroidal 17alpha azides with different terminal alkynes afforded novel 1,4-disubstituted triazolyl derivatives in good yields in both the estrone and the androstane series. The antiproliferative activities of the structurally related triazoles were determined in vitro on three malignant human cell lines (HeLa, MCF7 and A431), with the microculture tetrazolium assay. PMID- 21600230 TI - Interleukins 1alpha and 1beta as regulators of steroidogenesis in human NCI-H295R adrenocortical cells. AB - Inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF alpha) regulate the activity of the hypothalamo-pituitary-adrenal (HPA) axis at several levels. Although hypothalamic CRH secretion may be the primary mechanism by which these cytokines activate the HPA axis, IL-1 expression is increased within the adrenal glands in models for systemic inflammation, and IL-1 may augment adrenal glucocorticoid production. Our aim was to investigate the direct effects of IL-1alpha and IL-1beta on adrenal steroidogenesis and expression of three key steroidogenic genes in human adrenocortical cells using the NCI-H295R cell line as a model. mRNAs encoding receptors for IL-1, TNF-alpha, and leukemia inhibitory factor (LIF) were detectable in the cell line (Affymetrix microarray analysis). Both IL-1alpha and IL-1beta increased cortisol, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate production, and the accumulation of mRNAs for steroidogenic acute regulatory protein (STAR), 17alpha hydroxylase/17,20-lyase (CYP17A1) and 3beta-hydroxysteroid dehydrogenase 2 (HSD3B2) in these cells (P<0.05 for all). Both ILs augmented TNF-alpha- and LIF induced STAR and CYP17A1 mRNA accumulation, and TNF-alpha-induced cortisol production (P<0.05 for all). Both ILs also increased the apoptotic index of the cells (P<0.05), which was efficiently neutralized by their specific antibodies. The IL-induced changes in the STAR, HSD3B2, and CYP17A1 protein levels were not as evident as those in the respective mRNA levels. In conclusion, the combined effect of inflammatory cytokines at the adrenal level in acute or chronic inflammatory states could significantly stimulate glucocorticoid production, and thus explain the observed discrepancy between the cortisol and ACTH concentrations sometimes seen in sepsis and chronic inflammatory states. PMID- 21600231 TI - Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon. AB - Excessive Cl(-) secretion is the driving force for secretory diarrhea. 17beta Estradiol has been shown to inhibit Cl(-) secretion in rat distal colon through a nongenomic pathway. We examined whether 17beta-estradiol inhibits Cl(-) secretion in an animal model of secretory diarrhea and the downstream effectors involved. The effect of 17beta-estradiol on cholera toxin and heat-stable enterotoxin induced Cl(-) secretion in rat colonic mucosal sheets was studied by current voltage clamping. Selective permeabilization of apical or basolateral membranes with amphotericin B or nystatin was used to isolate basolateral K(+) channel and apical Cl(-) channel activity, respectively. 17beta-Estradiol dose-dependently inhibited secretory responses to both toxins with IC(50) values of approximately 1nM. This effect was female-gender specific, with no inhibition observed in male tissues. 17beta-Estradiol responses were insensitive to the pure anti-estrogen ICI 182,720. 17beta-Estradiol exerted its effects downstream of enterotoxin induced production of second messengers (cAMP and cGMP) but was dependent on PKCdelta activation. In nystatin-permeabilized tissues, apical Cl(-) currents were unaffected by 17beta-estradiol treatment while basolateral K(+) current was profoundly inhibited by the hormone. This current was sensitive to the specific KCNQ1 channel inhibitors chromanol 293B and HMR-1556. In conclusion, 17beta estradiol inhibits enterotoxin-induced Cl(-) secretion via a PKCdelta-dependent mechanism involving inhibition of basolateral KCNQ1 channels. These data elucidate mechanisms of 17beta-estradiol inhibition of Cl(-) secretion induced by enterotoxins in intestinal epithelia, which may be relevant for the treatment of diarrheal diseases. PMID- 21600233 TI - The catalytic promiscuity of a microbial 7alpha-hydroxysteroid dehydrogenase. Reduction of non-steroidal carbonyl compounds. AB - A thermostable 7alpha-hydroxysteroid dehydrogenase from Bacteroides fragilis ATCC 25285 was found to catalyze the reduction of various benzaldehyde analogues to their corresponding benzyl alcohols. The enzyme activity was dependent upon the substituent on the benzene ring of the substrates. Benzaldehydes with electron withdrawing substituent usually showed higher activity than those with electron donating groups. Furthermore, this enzyme was tolerant to some organic solvents. These results together with previous studies suggested that 7alpha-hydroxysteroid dehydrogenase from B. fragilis might play multiple functional roles in biosynthesis and metabolism of bile acids, and in the detoxification of xenobiotics containing carbonyl groups in the large intestine. In addition, its broad substrate spectrum offers great potential for finding applications not only in the synthesis of steroidal compounds of pharmaceutical importance, but also for the production of other high-value fine chemicals. PMID- 21600234 TI - Admissible mixing distributions for a general class of mixture survival models with known asymptotics. AB - Statistical analysis of data on the longest living humans leaves room for speculation whether the human force of mortality is actually leveling off. Based on this uncertainty, we study a mixture failure model, introduced by Finkelstein and Esaulova (2006) that generalizes, among others, the proportional hazards and accelerated failure time models. In this paper we first, extend the Abelian theorem of these authors to mixing distributions, whose densities are functions of regular variation. In addition, taking into account the asymptotic behavior of the mixture hazard rate prescribed by this Abelian theorem, we prove three Tauberian-type theorems that describe the class of admissible mixing distributions. We illustrate our findings with examples of popular mixing distributions that are used to model unobserved heterogeneity. PMID- 21600232 TI - Progesterone and estrogen receptor expression and activity in human non-small cell lung cancer. AB - Lung cancer is the most common cause of cancer mortality in male and female patients in the US. Although it is clear that tobacco smoking is a major cause of lung cancer, about half of all women with lung cancer worldwide are never smokers. Despite a declining smoking population, the incidence of non-small cell lung cancer (NSCLC), the predominant form of lung cancer, has reached epidemic proportions particularly in women. Emerging data suggest that factors other than tobacco, namely endogenous and exogenous female sex hormones, have a role in stimulating NSCLC progression. Aromatase, a key enzyme for estrogen biosynthesis, is expressed in NSCLC. Clinical data show that women with high levels of tumor aromatase (and high intratumoral estrogen) have worse survival than those with low aromatase. The present and previous studies also reveal significant expression and activity of estrogen receptors (ERalpha, ERbeta) in both extranuclear and nuclear sites in most NSCLC. We now report further on the expression of progesterone receptor (PR) transcripts and protein in NSCLC. PR transcripts were significantly lower in cancerous as compared to non-malignant tissue. Using immunohistochemistry, expression of PR was observed in the nucleus and/or extranuclear compartments in the majority of human tumor specimens examined. Combinations of estrogen and progestins administered in vitro cooperate in promoting tumor secretion of vascular endothelial growth factor and, consequently, support tumor-associated angiogenesis. Further, dual treatment with estradiol and progestin increased the numbers of putative tumor stem/progenitor cells. Thus, ER- and/or PR-targeted therapies may offer new approaches to manage NSCLC. PMID- 21600235 TI - AHR2 knockdown prevents PAH-mediated cardiac toxicity and XRE- and ARE-associated gene induction in zebrafish (Danio rerio). AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants often present in aquatic systems as complex mixtures. Embryonic fish are sensitive to the developmental toxicity of some PAHs, but the exact mechanisms involved in this toxicity are still unknown. This study explored the role of the aryl hydrocarbon receptor (AHR) in the oxidative stress response of zebrafish to the embryotoxicity of select PAHs. Embryos were exposed to two PAHs, benzo[k]fluoranthene (BkF; a strong AHR agonist) and fluoranthene (FL; a cytochrome P4501A (CYP1A) inhibitor), alone and in combination. CYP1A, CYP1B1, CYP1C1, and redox-responsive genes glutathione s-transferase pi 2 (GSTp2), glutathione peroxidase 1 (GPx1), the glutamate-cysteine ligase catalytic subunit (GCLc), MnSOD and CuZnSOD mRNA expression was examined. CYP1 activity was measured via an in vivo ethoxyresorufin-O-deethlyase (EROD) activity assay, and the area of the pericardium was measured as an index of cardiotoxicity. BkF or FL alone caused no deformities whereas BkF+FL resulted in extreme pericardial effusion. BkF induced CYP activity above controls and co-exposure with FL inhibited this activity. BkF induced expression of all three CYPs, GSTp2, and GCLc. BkF+FL caused greater than additive induction of the three CYPs, GSTp2, GPx1, and GCLc but had no effect on MnSOD or CuZnSOD. AHR2 knockdown protected against the cardiac deformities caused by BkF+FL and significantly inhibited the induction of the CYPs, GSTp2, GPx1, and GCLc after BkF+FL compared to non injected controls. These results further show the protective role of AHR2 knockdown against cardiotoxic PAHs and the role of AHR2 as a mediator of redox responsive gene induction. PMID- 21600236 TI - Comparison of oral toxicological properties of botulinum neurotoxin serotypes A and B. AB - Botulinum neurotoxins (BoNTs) are among the most potent biological toxins for humans. Of the seven known serotypes (A-G) of BoNT, serotypes A, B and E cause most of the foodborne intoxications in humans. BoNTs in nature are associated with non-toxic accessory proteins known as neurotoxin-associated proteins (NAPs), forming large complexes that have been shown to play important roles in oral toxicity. Using mouse intraperitoneal and oral models of botulism, we determined the dose response to both BoNT/B holotoxin and complex toxins, and compared the toxicities of BoNT/B and BoNT/A complexes. Although serotype A and B complexes have similar NAP composition, BoNT/B formed larger-sized complexes, and was approximately 90 times more lethal in mouse oral intoxications than BoNT/A complexes. When normalized by mean lethal dose, mice orally treated with high doses of BoNT/B complex showed a delayed time-to-death when compared with mice treated with BoNT/A complex. Furthermore, we determined the effect of various food matrices on oral toxicity of BoNT/A and BoNT/B complexes. BoNT/B complexes showed lower oral bioavailability in liquid egg matrices when compared to BoNT/A complexes. In summary, our studies revealed several factors that can either enhance or reduce the toxicity and oral bioavailability of BoNTs. Dissecting the complexities of the different BoNT serotypes and their roles in foodborne botulism will lead to a better understanding of toxin biology and aid future food risk assessments. PMID- 21600238 TI - Study of DNA damage via the comet assay and base excision repair activities in rat brain neurons and astrocytes during aging. AB - Earlier we have used biochemical approach to assess the number of single (SSBs) and double (DSBs) strand breaks in brain cellular DNA. However, a quick method to obtain a reliable measure of DNA damage in cells was in need for population studies. Therefore, single cell gel electrophoresis technique (popularly known as "comet" assay) has been standardized using the Trevigen protocol. DNA damage was assessed in isolated neurons and astrocytes from the cortex of young (7 days), adult (6 months) and old (2 years). Marked increase is seen in DNA damage in terms SSBs and DSBs in both types of cells by 6 months of age, which increased further by 2 years of age. The number of 8-oxoguanine DNA glycosylase (OGG1) and uracil DNA glycosylase (UDG) sensitive sites also increased in DNA with age with the simultaneous decrease in OGG1, UDG and AP endonuclease (APE1) activities. Thus the comet assay adapted to our lab conditions has proven to be useful for a quick assessment of DNA damage in a large number of samples that constitute our future studies. PMID- 21600239 TI - Time course of prepulse inhibition disruption induced by dopamine agonists and NMDA antagonists: effects of drug administration regimen. AB - Prepulse inhibition (PPI) of acoustic startle response is impaired in patients with schizophrenia and in animals acutely treated with dopamine agonists and NMDA antagonists. In this study, we investigated the time course of PPI disruption induced by repeated amphetamine, quinpirole, phencyclidine (PCP), and dizocilpine (MK-801) treatment. We focused on how PPI disruption development was influenced by drug administration regimens, comparing a constant versus an escalating dosing regimen. Male Sprague-Dawley rats were repeatedly treated with amphetamine (1.25 5.0 mg/kg, or constant 5.0 mg/kg, sc), PCP (0.50-2.0 mg/kg, or constant 0.5, 1.0 or 2.0 mg/kg, sc), quinpirole (0.03-0.12 mg/kg, or constant 0.12 mg/kg, sc), MK 801 (0.025-0.10 mg/kg, or constant 0.10 mg/kg, sc) or vehicle (saline) and tested for PPI once daily for 6 consecutive days. When amphetamine 5.0 mg/kg or quinpirole 0.12 mg/kg was administrated on a constant dosing schedule, both drugs disrupted PPI upon acute administration, but had no effect after repeated treatment and testing (days 2-5). However, when amphetamine 5.0 mg/kg or quinpirole 0.12 mg/kg was preceded by two lower doses in an escalating dosing regimen, both drugs still disrupted PPI on days 5 and 6 when the constant amphetamine and quinpirole had no effect. For PCP and MK-801, repeated treatment under both regimens produced a stable and persistent disruption of PPI. Startle magnitude increased progressively and dose-dependently under both regimens for all drugs except for quinpirole, which caused a decrease. These results suggest that the drug dosing schedule, rather than the absolute amount of drug that an animal receives, has a greater impact on the development of PPI-disruptive effect of dopamine agonists than NMDA antagonists. Thus, in order to mimic the emerging process of PPI deficit with dopamine agonists, an escalating dosing regimen should be used. PMID- 21600237 TI - Cdk5: mediator of neuronal development, death and the response to DNA damage. AB - In the central nervous system, cyclin-dependent kinase 5 (Cdk5), an unusual member of the Cdk family, is implicated in the regulation of various physiological processes ranging from neuronal survival, migration and differentiation, to synaptogenesis, synaptic plasticity and neurotransmission. Dysregulation of this kinase has been demonstrated to play a critical role in the pathogenic process of neurodegenerative disorders. DNA damage is emerging as an important pathological component in various neurodegenerative conditions. In this review, we discuss the recent progress regarding the regulation and roles of Cdk5 under physiological conditions, and its dysregulation under pathological conditions, especially in neuronal death mediated by DNA damage. PMID- 21600240 TI - A generic real-time TaqMan assay for specific detection of lapinized Chinese vaccines against classical swine fever. AB - Classical swine fever (CSF) is a highly contagious disease, causing severe economic losses in the pig industry worldwide. Vaccination of pigs with lapinized Chinese vaccines is still practised in some regions of the world, where the virus is enzootic, in order to prevent and control the disease. However, a single real time assay that can detect all lapinized Chinese vaccines used widely, namely, Lapinized Philippines Coronel (LPC), Hog Cholera Lapinized virus (HCLV) and the Riems C-strain is still lacking. This study describes a real-time RT-PCR assay, targeting the N(pro) gene region, for specific detection of these lapinized vaccine strains. The assay is highly sensitive, with a detection limit of 10 genome copies per reaction for HCLV and Riems C-strain and highly specific, as more than 100 strains of wild type CSFV representing all major genotypes were not detected. The assay is also highly repeatable: the coefficient of variation of Ct values in three runs was 2.77% for the detection of 10 copies of the vaccine viral RNA. This study provides a potentially useful tool for specific detection of the lapinized Chinese vaccines, HCLV and C-strain, and the differentiation of these vaccines from wild type CSFV. PMID- 21600241 TI - Palindromic-nucleotide substitutions (PNS) of hepatitis C virus genotypes 1 and 5a from South Africa. AB - The HCV stem-loop subdomains III-a, -b and -c have been shown to reflect the characteristics of the virus and identify isolates by genus, genotype and subtype. The aim of this study was to investigate the genotype-specific PNS within the 5'UTR of prevalent HCV genotypes (1 and 5a) found in South Africa. The genotype 5a (N = 35) and genotype 1 sequences (N=20) were from patients presenting with liver disease or haemophilia, respectively. PNS HCV typing characteristics, defined previously, were observed. The PNS method differentiated subtypes 1a and 1c from subtype 1b by the base change at nucleotide position 243. A lack of structural data from the variable loci V1 of the 5'UTR did not allow us to further differentiate the subtypes of 1. A nucleotide change from a thymine (T) to a cytosine (C) at position 183 was found among genotype 5a sequences. This mutation changed the stable U-AA bond to a Y AA bulge at base-pair position 32. There was an insertion of a single adenine (A) at position 207. At present PNS analysis is labour intensive but, with development of further software to aid the computer analysis, it has the potential to provide a rapid, reliable alternative to phylogenetic analysis. PMID- 21600242 TI - Determination of the whole-genome consensus sequence of the prototype DS-1 rotavirus using sequence-independent genome amplification and 454(r) pyrosequencing. AB - The prototype DS-1 rotavirus strain, is characterised by a short electropherotype and G2P[4] serotype specificity. Following sequence-independent genome amplification and 454((r)) pyrosequencing of genomic cDNA, differences between the newly determined consensus sequence and GenBank sequences were observed in 10 of the 11 genome segments. Only the consensus sequence of genome segment 1 was identical to sequences deposited in GenBank. A novel isoleucine at position 397 in a hydrophobic region of VP4 is described. An additional 7 N-terminal amino acids was found in NSP1. For genome segment 10 the first 34 and last 30 nucleotides of the 5' and 3'-terminal ends, respectively, were identified. Genome segment 11 was found to be 821 bp long, which is 148 bp longer than the full length genome segment 11 sequence reported previously. This paper reports the first complete consensus genome sequence for the tissue culture adapted DS-1 strain free from cloning bias and the limitations of Sanger sequencing. Sequence differences in previous publications reporting on DS-1 rotavirus genome segment sequencing, were identified and discussed. PMID- 21600243 TI - Role for purinergic receptors in memory processing in young chicks. AB - The current study used a single trial bead discrimination task for the young chick to ascertain if inhibitors of P2 purinergic receptors would impair memory retention. Suramin and PPADS provided similar retention profiles. Loss of memory retention was evident by 60 min post-training. Both drugs caused persistent memory loss which was still evident 24h post-training. These findings suggest that P2 receptors have a role in memory processing. PMID- 21600244 TI - Food restriction dissociates sexual motivation, sexual performance, and the rewarding consequences of copulation in female Syrian hamsters. AB - Animals can switch their behavioral priorities from ingestive to sex behaviors to optimize reproductive success in environments where energy fluctuates. We hypothesized that energy availability differentially affects the appetitive (motivation), consummatory (performance), and learned (rewarding) components of behavior. In Experiment 1, appetitive and consummatory aspects of sex behavior were dissociated in the majority of female Syrian hamsters restricted to 75% of their ad libitum food intake for between 8 and 11 days. Food restriction significantly inhibited vaginal scent marking, decreased the preference for spending time with male hamsters vs. spending time with food, and increased food hoarding with no significant effect on consummatory behaviors such as the incidence of lordosis or food intake. In Experiments 2 and 3, we attempted to use a similar level of food restriction to dissociate sexual appetite from sexual reward. In hamsters, formation of a conditioned place preference (CPP) for copulatory reward is reflected in increased nucleus accumbens (NAc) neural activation, measured as immunocytochemical staining for c-Fos, the protein product of the immediate-early gene, c-fos. In Experiment 2, neural activation increased 1h after copulation in the NAc, and did not differ significantly between 10-day food-restricted and ad libitum-fed females in any brain area examined. In Experiment 3, females were either food-restricted or fed ad libitum over 8-30 days of conditioning with copulatory stimuli. Food-restricted females showed significantly fewer appetitive behaviors, but no difference in formation of a CPP compared to females fed ad libitum. Together these data are consistent with the idea that mild levels of food restriction that inhibit appetitive behaviors fail to attenuate consummatory behaviors and the rewarding consequences of copulation. Thus, appetitive sex behaviors are, at least partially, neuroanatomically and behaviorally distinct from both consummatory behaviors and copulatory reward. PMID- 21600245 TI - Plasmodium falciparum enolase complements yeast enolase functions and associates with the parasite food vacuole. AB - Plasmodium falciparum enolase (Pfeno) localizes to the cytosol, nucleus, cell membrane and cytoskeletal elements, suggesting multiple non-glycolytic functions for this protein. Our recent observation of association of enolase with the food vacuole (FV) in immuno-gold electron microscopic images of P. falciparum raised the possibility for yet another moonlighting function for this protein. Here we provide additional support for this localization by demonstrating the presence of Pfeno in purified FVs by immunoblotting. To examine the potential functional role of FV-associated Pfeno, we assessed the ability of Pfeno to complement a mutant Saccharomyces cervisiae strain deficient in enolase activity. In this strain (Tetr-Eno2), the enolase 1 gene is deleted and expression of the enolase 2 gene is under the control of a tetracycline repressible promoter. Enolase deficiency in this strain was previously shown to cause growth retardation, vacuolar fragmentation and altered expression of certain vacuolar proteins. Expression of Pfeno in the enolase-deficient yeast strain restored all three phenotypic effects. However, transformation of Tetr-eno2 with an enzymatically active, monomeric mutant form of Pfeno (Delta(5)Pfeno) fully restored cell growth, but only partially rescued the fragmented vacuolar phenotype, suggesting that the dimeric structure of Pfeno is required for the optimal vacuolar functions. Bioinformatic searches revealed the presence of Plasmodium orthologs of several yeast vacuolar proteins that are predicted to form complexes with Pfeno. Together, these observations raise the possibility that association of Pfeno with food vacuole in Plasmodium may have physiological function(s). PMID- 21600246 TI - Differential expression analyses of host genes involved in systemic infection of Tomato leaf curl New Delhi virus (ToLCNDV). AB - Tomato leaf curl viruses (ToLCV) infect tomato plants and eventually cause several phenotypic defects, notably in the leaves in the form of upward curling. The entry of virus triggers plants' basal defense responses which eventually introduce temporal changes in the transcriptome to evade the pathogen attack. In this study, we have identified about 20 tomato ESTs using subtractive hybridization that were induced in tomato leaves upon agro-infection with the constructs bearing the dimers of Tomato leaf curl New Delhi virus (ToLCNDV) DNA-A and DNA-B components. The induced ESTs belonged to the class of genes that play crucial roles in innate immunity, plants metabolism and ethylene signaling. The expression of few of these ESTs was validated by northern blot analysis and two out of six selected genes expressed exclusively in the infected leaf tissues. Besides leaves, the expression status of selected genes was checked in a wide variety of tissues (flower, fruit, stem and root) of both healthy and infected plants by RT-PCR. These results suggest that the flower and fruit tissues, similar to leaves, exhibited induction of most of the genes while the stem and root tissues suffered from down-regulation. Overall, these results indicate that the hosts' transcriptome undergoes considerable changes in response to viral infection. PMID- 21600247 TI - Detection of different variants of Ostreid Herpesvirus 1 in the Pacific oyster, Crassostrea gigas between 2008 and 2010. AB - Since summer 2008, high mortality rates of young Pacific oysters Crassostrea gigas have been recorded in association with the detection of the Ostreid Herpesvirus 1 (OsHV-1). A new variant called MUVar has been recently described, characterized mainly by 12 consecutive deletions followed by one deletion of an adenine in the C region. The purpose of this study is to characterize the genotype (variants or OsHV-1 reference) of 300 positive samples of C. gigas analyzed between July 2008 and July 2010 collected along the French, Jersey, and Irish coasts. Samples were quantified by TaqMan PCR, amplified with conventional PCR, targeting the area of the deletion, and then sequenced. Eighty-seven percent of the samples were characterized and the OsHV-1 MUVar was detected in 257 oyster samples. The genotype OsHV-1 reference was never detected during the 25 months of the present survey. Thirty-eight samples could not be determined and the majority of them had a low viral load. A novel genotype containing only 9 consecutive deletions named OsHV-1 MUVar Delta9 was found in 5 samples. These observations indicate the emergence of different OsHV-1 variants. PMID- 21600248 TI - Intracellular uptake and behavior of two types zinc protoporphyrin (ZnPP) micelles, SMA-ZnPP and PEG-ZnPP as anticancer agents; unique intracellular disintegration of SMA micelles. AB - SMA-ZnPP and PEG-ZnPP are micellar drugs, encapsulating zinc protoporphyrin IX (ZnPP) with styrene maleic acid copolymer (SMA) and covalent conjugate of ZnPP with polyethylene glycol (PEG) respectively. Their intracellular uptake rate and subcellular localization were investigated. We found SMA-ZnPP showed higher and more efficient (about 2.5 times) intracellular uptake rate than PEG-ZnPP, although both SMA-ZnPP and PEG-ZnPP micelles were localized at endoplasmic reticulum (ER) and inhibited the target enzyme heme oxygenase 1 (HO-1) similarly. Both micellar ZnPP were taken up into the tumor cells by endocytosis. Furthermore SMA-ZnPP and PEG-ZnPP were examined for their drug releasing mechanisms. Liberation of ZnPP from the SMA micelle appears to depend on cellular amphiphilic components such as lecithin, while that for PEG-ZnPP depends on hydrolytic cleavage. These results indicate that these micelle formulations make water insoluble ZnPP to water soluble practical anticancer agents. PMID- 21600249 TI - How to screen non-viral gene delivery systems in vitro? AB - Screening of new gene delivery candidates regarding transfection efficiency and toxicity is usually performed by reading out transgene expression levels relative to a reference formulation after in vitro transfection. However, over the years and among different laboratories, this screening has been performed in a variety of cell lines, using a variety of conditions and read-out systems, and by comparison to a variety of reference formulations. This makes a direct comparison of results difficult, if not impossible. Reaching a consensus would enable placing new results into context of previous findings and estimate the overall contribution to the improvement of non-viral gene delivery. In this paper we illustrate the sensitivity of transfection outcomes on testing conditions chosen, and propose a screening protocol with the aim of standardization within the field. PMID- 21600251 TI - Dry powder aerosols of polyethylenimine (PEI)-based gene vectors mediate efficient gene delivery to the lung. AB - Aerosol gene delivery holds great therapeutical potential for many inherited and acquired pulmonary diseases. The physical instability of aqueous suspensions of non-viral vector complexes is a major limitation for their successful application. In this study, we investigated dry powder aerosols as novel gene vector formulations for gene transfer in vitro and murine lungs in vivo. Lyophilization was used to produce dry powder cakes followed by powderization to produce dry powder aerosols. Different sugars, namely lactose, sucrose and trehalose, were tested as lyoprotectants for gene delivery complexes consisting of branched polyethylenimine 25 kDa and plasmid DNA. Biophysical particle characterization demonstrated that lyophilization and powderization in the presence of lyoprotectants were well tolerated. In vitro transfection efficiency remained unaffected by the choice of lyoprotectant and subsequent lyophilization and/or powderization. In vivo screening of powderized samples, by applying the powder with an insufflator, resulted in highest gene expression with lactose as lyoprotectant. Delivering a plasmid coding for murine erythropoietin together with lactose as lyoprotectant resulted in increased blood hematocrit values post application thereby demonstrating the potential of dry powder aerosol as a promising method for pulmonary gene delivery. PMID- 21600250 TI - Anti-tumor activity of liposome encapsulated fluoroorotic acid as a single agent and in combination with liposome irinotecan. AB - To test the hypothesis that co-delivery of synergistic drug combinations in the same liposome provides a better anti-tumor effect than the drugs administered in separate liposomes, fluoroorotic acid (FOA) alone and in combination with irinotecan (IRN) were encapsulated in liposomes and evaluated for their anti tumor activity in the C26 colon carcinoma mouse model. A new chaotropic loading strategy was devised wherein FOA was dissolved in 7 M urea to increase its solubility. This enabled the passive loading of FOA into liposomes at a high concentration. IRN was remote loaded into liposomes that contained the ammonium salt of the multi-valent 1,2,3,4-butanetetracarboxylic acid with a greater than 90% efficiency and at a drug to lipid ratio of 0.2:1. When the two molecules were loaded into the same liposome, FOA was used to remote load IRN. Modulation of the drug/lipid ratio, temperature, and loading time allowed for consistent co encapsulation of FOA+IRN at various molar ratios. The anti-tumor activity of L FOA, L-IRN, L-FOA-IRN (5:1), and the L-FOA+L-IRN mixture (5:1) were examined in the C26 mouse model. The maximum tolerated dose of L-FOA was 10 mg/kg given weekly as compared to 100 mg/kg of the non-encapsulated FOA. Delivering two drugs in the same liposome provided a statistically better anti-tumor effect than delivering the drugs in separate liposomes at the same drug ratio. However, the synergistic activity of the 5:1 ratio of free drugs measured on C26 cells in vitro was not observed in the C26 tumor mouse model. These findings point out the challenges to the design of synergistic treatment protocols based upon results from in vitro cytotoxicity studies. L-FOA at 10 mg/kg as a single agent provided the best anti-tumor efficacy which supports previous suggestions that L-FOA has useful properties as a liposome dependent drug. PMID- 21600252 TI - In vitro human tissue models--moving towards personalized regenerative medicine. AB - The field of tissue engineering is a rapidly growing interdisciplinary field within regenerative medicine involving biology, chemistry, physics, engineering and medical sciences, which focuses on the fabrication of replacement tissues and organs. Another major focus of tissue engineering is the creation of ex vivo manufactured multi-organ test systems, in order to explore fundamental questions of cell, matrix and developmental biology. These ex-vivo manufactured systems can also be used to study drug delivery dynamics. PMID- 21600253 TI - It's who I am and what we eat. Mothers' food-related identities in family food choice. AB - This study aimed to understand mothers' everyday food choices using one type of visual method-participant-driven photo-elicitation (PDPE). The sample consisted of 12 low/moderate income mothers (26-53 years) living in Bryan/College Station, Texas. Each mother completed a photography activity, where she created photographs of her food experience, and an in-depth interview using the mother's photographs. Interview transcripts were analyzed using a grounded theory approach and coded using qualitative data analysis software ATLAS.ti. Mothers emphasized their identities related to food and eating as they described food-related decisions and activities. These identities influenced a mother's food choices for herself and those she made for her children. Analysis revealed that mothers with a more defined health identity made healthier choices for themselves and similar food choices for their children. In addition, they exhibited behaviors that positively influenced their children's food choices. Mothers who struggled to see themselves as healthy indulged with more junk food and indicated feelings of anxiety and guilt; these mothers' food choices were more disconnected from their children's. These findings underscore the importance of understanding how identities related to food and eating can influence food choices. Encouraging mothers to develop and maintain health identities may be one way to improve food and eating habits in families. PMID- 21600254 TI - Losing weight without dieting. Use of commercial foods as meal replacements for lunch produces an extended energy deficit. AB - High-protein liquid meal replacements have proven to be effective in reducing caloric intake and body weight. Recently, substituting high fiber breakfast cereals for the more expensive high-protein drinks has been found to be equally effective to reduce weight. The following study tested the hypothesis that the mechanism responsible for the reduced intake was not the dietary composition of the meal replacement, but the controlled portion sized meals. Seventeen volunteers ate all of their meals and snacks from foods provided by the research unit from Monday to Friday for five consecutive weeks. For the first week, all participants selected their food from a buffet where each food was weighed before and after eating. For the next two weeks, half of the group selected their lunch by choosing one food from a selection of six commercially available portion controlled foods. They could eat as much as they wished at other meals or snacks. For final weeks four and five, the conditions were reversed for the two groups. Consuming the portion controlled lunches resulted in about a 250 kcal reduction in energy intake. More importantly, no sign of caloric compensation was evident across the 10 days of testing, an observation substantiated by a significant loss of body weight. The results suggest that the mere substitution of one smaller portioned meal each day is sufficient to cause reduction in daily energy intake and a significant amount of weight. PMID- 21600255 TI - Cognitive deficits in obese persons with and without binge eating disorder. Investigation using a mental flexibility task. AB - OBJECTIVE: Studies suggest that cognitive deficits and attentional biases play a role in the development and maintenance of obesity and eating disorders. In this study, we simultaneously examine attentional biases, as well as inhibitory control and mental flexibility, which are keys to controlling unwanted behaviors and thoughts in obese patients with and without binge eating disorder. METHODS: 16 obese patients with binge eating disorder and 16 patients without binge eating disorder were compared with 16 normal-weight controls on a "food/body-mental flexibility task", which allows the investigation of inhibitory control, mental flexibility and attention for stimuli related to the body and food. RESULTS: All obese patients made significantly more errors (i.e., pressing a key when a distracter displayed) and more omissions (i.e., not pressing a key when a target displayed) than controls in both food and body sections of the task. Obese participants with binge eating disorder made significantly more errors and omissions than those without binge eating disorder. No difference between groups was found concerning mental flexibility and cognitive biases for food- and body related targets. DISCUSSION: These results suggest that obese patients have a general inhibition problem and difficulty focusing attention, which do not depend on the types of stimuli processed. The results also suggest that these cognitive deficits are more severe in obese patients with binge eating disorder, which indicates that there is a continuum of increasing inhibition and cognitive problems with increasingly disordered eating. These cognitive deficits may contribute to problematic eating behaviors. PMID- 21600256 TI - Physiological role of ghrelin as revealed by the ghrelin and GOAT knockout mice. AB - Ghrelin is a gastric hormone that has been shown to regulate food intake and energy metabolism. One unique feature of ghrelin is that its activity is regulated post transcriptionally by ghrelin O-acyltransferase (GOAT) through the addition of fatty acid to the serine residue in the N terminal region. Despite much biochemical characterization, to date no other proteins have been shown to be specifically octonylated by GOAT, suggesting a unique matching of the acyl transferase for a single ligand, ghrelin. If this is indeed correct, then genetic deletion of ghrelin or GOAT should produce near identical phenotypes and there should be extensive overlap in expression patterns. This review summarizes the similarities and differences in the phenotypes with the genetic deletion of ghrelin and GOAT in the various knockout mouse lines reported to date. While there is considerable overlap in expression pattern between ghrelin and GOAT, the latter does exhibit some unique tissue expression that could suggest that additional peptides may be acylated and await discovery and characterization. PMID- 21600257 TI - Antinociceptive properties of nasal delivery of neurotoxin-loaded nanoparticles coated with polysorbate-80. AB - Neurotoxin-1 (NT) is an analgesic peptide which is endowed an exceptional specificity of action that blocks transmission of the nerve impulse. The aim of this study was to evaluate the potential application of nanoparticles technology as drug carrier system for the nasal delivery of NT. Mice were administered intranasally (i.n.) with NT (NT-P-NP), free NT solution (F-NT) and intravenously (i.v.) with NT (IV-NT) respectively. The NT levels in animal brain and antinociceptive activity of NT were analyzed. The result on brain transport showed that nanoparticles could exert enhanced delivery of NT into the brain significantly after i.n. administration. The results of antinociceptive activity showed that NT-P-NP increased immobility in the open-field test, both phases of formalin test were significantly inhibited by the NT-P-NP and NT-P-NP significantly inhibited the reaction time to thermal stimuli at 60 and 90 min. Both NT-P-NP and IV-NT were able to inhibit constrictions in acetic acid-induced writhing reaction. These data suggest that NT-loaded nanoparticles coated with polysorbate-80 could generate a significant improvement of drug levels in the brain. Intranasal administration of Neurotoxin-1 entrapped in nanoparticles coated with polysorbate-80 is an attractive alternative to intravenous administration. PMID- 21600258 TI - Recent advances in the phylogenetic study of ghrelin. AB - To understand fully the biology of ghrelin, it is important to know the evolutionary history of ghrelin and its receptor. Phylogenetic and comparative genomic studies of mammalian and non-mammalian vertebrates are a useful approach to that end. Ghrelin is a hormone that has apparently evaded natural selection during a long evolutionary history. Surely ghrelin plays crucial physiological roles in living animals. Phylogenetic studies reveal the nature and evolutionary history of this important signaling system. PMID- 21600259 TI - Foxp3(high) and Foxp3(low) Treg cells differentially correlate with T helper 1 and natural killer cells in peripheral blood. AB - Regulatory T (Treg) cells interact with B, natural killer (NK), and dendritic cells in addition to other T cells. In this study, we aimed at determining whether Foxp3(+) T cells and subpopulations have any correlation with other lymphocyte subsets and their functions in a systemic immune environment. Peripheral blood was drawn from 22 nonpregnant healthy women. T, B, and NK cell subpopulations were measured by immunophenotype analysis. Intracellular Foxp3, cytokine expression (tumor necrosis factor-alpha [TNF-alpha], interferon-gamma [IFN-gamma], and interleukin-10 [IL]-10), and NK-cell cytotoxicity were analyzed by flow cytometric analysis. Correlations between Foxp3(+) T cells and other immune variables were analyzed under control of age and menstrual phases. Foxp3(+), Foxp3(low), and CD4(+)Foxp3(+) cells significantly correlated with CD4(+)CD25(+), CD4(+)CD25(dim), and CD4(+)CD25(bright) cells. Foxp3(+), Foxp3(low), and CD4(+)Foxp3(+) cells positively correlated with CD3(+) and CD3(+)CD4(+) T cells, but negatively correlated with CD3(-)CD56(+) and CD3( )CD56(dim) NK cells. CD4(+)Foxp3(high) Treg cells were positively correlated with CD3(+)CD4(+)TNF-alpha(+) (p = 0.014) and negatively correlated with CD3(+)CD8(+)IL-10(+) T cells (p = 0.001). The ratio of type 1/2 cytokine producing CD3(+)CD8(+) cells demonstrated a positive correlation with CD4(+)Foxp3(high) cells (p <= 0.01). CD8(+)Foxp3(+) cells were positively correlated with CD3(+)CD4(+)IL-10(+) cells (p = 0.007) and negatively correlated with CD3(+)CD8(+)TNF-alpha(+) cells (p = 0.008). In conclusion, each Foxp3(+) Treg cell subpopulation has unique immune interaction, which controls particular subsets of lymphocytes. PMID- 21600260 TI - Intranasal c-di-GMP-adjuvanted plant-derived H5 influenza vaccine induces multifunctional Th1 CD4+ cells and strong mucosal and systemic antibody responses in mice. AB - Vaccination is the best available measure of limiting the impact of the next influenza pandemic. Ideally, a candidate pandemic influenza vaccine should be easy to administer and should elicit strong mucosal and systemic immune responses. Production of influenza subunit antigen in transient plant expression systems is an alternative to overcome the bottleneck in vaccine supply during influenza pandemic. Furthermore, a needle-free intranasal influenza vaccine is an attractive approach, which may provide immunity at the portal of virus entry. The present study investigated the detailed humoral and cellular immune responses in mice vaccinated intranasally or intramuscularly with plant-derived influenza H5N1 (A/Anhui/1/05) antigen alone or formulated with bis-(3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP) as adjuvant. The use of c-di-GMP as intramuscular adjuvant did not enhance the immune response to plant-derived influenza H5 antigen. However, intranasal c-di-GMP-adjuvanted vaccine induced strong mucosal and systemic humoral immune responses. Additionally, the intranasal vaccine elicited a balanced Th1/Th2 profile and, most importantly, high frequencies of multifunctional Th1 CD4(+) cells. Our results highlight that c-di-GMP is a promising mucosal adjuvant for pandemic influenza vaccine development. PMID- 21600261 TI - Effects of genistein, apigenin, quercetin, rutin and astilbin on serum uric acid levels and xanthine oxidase activities in normal and hyperuricemic mice. AB - Flavonoids are widely found in plants and many of them possess biological and pharmacological activities. In the present study, we assessed the effects of the flavonoids Genistein, Apigenin, Quercetin, Rutin and Astilbin on xanthine oxidase (XO) activities in vitro, and in serum and the liver. The effects of the flavonoids on serum uric acid levels were also measured in vivo. In vitro studies indicated that the flavonoids tested did not significantly affect XO activity. However, significant increases and decreases in XO activities were observed in vivo. Moreover, serum XO activity was correlated with serum uric acid levels, while no correlation was observed for liver XO activity. The present study showed that serum uric acid levels in mice treated with the flavonoids tested here are higher than control levels. Therefore, the flavonoids tested here are not candidates for replacing Allopurinol as a treatment to reduce serum uric acid levels. PMID- 21600262 TI - Chromene induces apoptosis via caspase-3 activation in human leukemia HL-60 cells. AB - In this study, the potent anti-tumor effects of brown algae on human leukemia HL 60 cells were investigated. The Sargassum siliquastrum extract among the 14 species of brown algae exhibited profound growth inhibitory effect on HL-60 cells in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, therefore, S. siliquastrum was selected for use in further experiments. The highest inhibitory activity of S. siliquastrum on HL-60 cells was detected in the chloroform fraction, and the active compound was identified as a kind of chromene, sargachromanol E (SE). SE treatment showed significant growth inhibitory effects on HL-60 cells in a dose-dependent manner by inducing apoptosis, as evidenced by the formation of apoptotic bodies, fragmented DNA ladder, and the accumulation of DNA in the sub-G(1) phase of cell cycle. SE induced apoptosis was accompanied by downregulation of Bcl-xL, upregulation of Bax, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, z-DEVD-fmk, a caspase-3 inhibitor, significantly inhibited cell cytotoxicity, apoptotic characteristics such as apoptotic bodies, sub-G(1) DNA content, and cleavage of PARP induced by SE. These results suggest that SE exerts its growth inhibitory effects on HL-60 cells through caspase-3-mediated induction of apoptosis. Therefore, SE offers promising chemotherapeuric potential to prevent cancers such as human leukemia. PMID- 21600263 TI - The effects of evening primrose oil on lipid peroxidation induced by subacute aflatoxin exposure in mice. AB - The present study was aimed at the investigation of the antioxidative effect of evening primrose oil in cases of subacute aflatoxin (AF) intoxication induced in mice. For this purpose, forty-eight 6-8-week-old male BALB/c mice, weighing 30-35 g, were used. The animals were allocated to four groups, each comprising of 12 mice, such that one group was maintained as the control group and the other three constituted the trial groups. The mice included in the control group (Group 1) were not subjected to any treatment. Group 2 was administered with 1.5 ml/kg bw/day of evening primrose oil; Group 3 received 1250 MUg/kg bw/day of AF (82.45% AFB(1), 10.65% AFB(2), 4.13% AFG(1) and 2.77% AFG(2)) and Group 4 was given 1250 MUg/kg bw/day of AF plus 1.5 ml/kg bw/day of evening primrose oil using a catheter, for a period of 14 days. At the end of the 14th day, the liver, lungs, kidneys, brain, heart and spleen of the animals included in all groups were extracted. Malondialdehyde (MDA) levels and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidise (GSH-Px) activities were measured in tissue homogenates. In result, it was concluded that, evening primrose oil had a positive effect on aflatoxin-induced lipid peroxidation. PMID- 21600265 TI - Self-organized perturbations enhance class IV behavior and 1/f power spectrum in elementary cellular automata. AB - In this paper, we propose a new class of cellular automata based on the modification of its state space. It is introduced to model a computation which is exposed to an environment. We formalized the computation as extension and projection processes of its state space and resulting misidentifications of the state. This is motivated to embed the role of an environment into the system itself, which naturally induces self-organized internal perturbations rather than the usual external perturbations. Implementing this structure into the elementary cellular automata, we characterized its effect by means of input entropy and power spectral analysis. As a result, the cellular automata with this structure showed robust class IV behavior and a 1/f power spectrum in a wide range of rule space comparative to the notion of the edge of chaos. PMID- 21600264 TI - Iron, zinc and copper in the Alzheimer's disease brain: a quantitative meta analysis. Some insight on the influence of citation bias on scientific opinion. AB - Dysfunctional homeostasis of transition metals is believed to play a role in the pathogenesis of Alzheimer's disease (AD). Although questioned by some, brain copper, zinc, and particularly iron overload are widely accepted features of AD which have led to the hypothesis that oxidative stress generated from aberrant homeostasis of these transition metals might be a pathogenic mechanism behind AD. This meta-analysis compiled and critically assessed available quantitative data on brain iron, zinc and copper levels in AD patients compared to aged controls. The results were very heterogeneous. A series of heavily cited articles from one laboratory reported a large increase in iron in AD neocortex compared to age matched controls (p<0.0001) while seven laboratories failed to reproduce these findings reporting no significant difference between the groups (p=0.76). A more than three-fold citation bias was found to favor outlier studies reporting increases in iron and this bias was particularly prominent among narrative review articles. Additionally, while zinc was not significantly changed in the neocortex (p=0.29), copper was significantly depleted in AD (p=0.0003). In light of these findings, it will be important to re-evaluate the hypothesis that transition metal overload accounts for oxidative injury noted in AD. PMID- 21600266 TI - Increased short latency afferent inhibition after anodal transcranial direct current stimulation. AB - Transcranial direct current stimulation (tDCS), a technique for central neuromodulation, has been recently proposed as possible treatment in several neurological and psychiatric diseases. Although shifts on focal brain excitability have been proposed to explain the clinical effects of tDCS, how tDCS induced functional changes influence cortical interneurones is still largely unknown. The assessment of short latency afferent inhibition (SLAI) of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS), provides the opportunity to test non-invasively interneuronal cholinergic circuits in the human motor cortex. The aim of the present study was to assess whether anodal tDCS can modulate interneuronal circuits involved in SLAI. Resting motor threshold (RMT), amplitude of unconditioned MEPs and SLAI were assessed in the dominant hemisphere of 12 healthy subjects (aged 21-37) before and after anodal tDCS (primary motor cortex, 13min, 1mA). SLAI was assessed delivering electrical conditioning stimuli to the median nerve at the wrist prior to test TMS given at the interstimulus interval (ISI) of 2ms. Whereas RMT and the amplitude of unconditioned MEPs did not change after anodal tDCS, SLAI significantly increased. In conclusion, anodal tDCS-induced effects depend also on the modulation of cortical interneuronal circuits. The enhancement of cortical cholinergic activity assessed by SLAI could be an important mechanism explaining anodal tDCS action in several pathological conditions. PMID- 21600267 TI - Early rehabilitation outcome in patients with middle cerebral artery stroke. AB - Although important data on the prognosis and rehabilitation outcome in stroke patients have been reported, data on functional recovery according to stroke subtypes are limited. This retrospective study aimed to evaluate functional outcome in patients with middle cerebral artery (MCA) stroke-the most common subtype of ischemic stroke. The records of stroke patients that underwent the rehabilitation program at our brain injury rehabilitation service between January 2007 and December 2008 were reviewed, and those with MCA stroke were included in the study. Patient demographic and clinical data, and Barthel Index (BI) and Functional Independence Measure (FIM) scores at admission and discharge were collected. The study included 80 MCA stroke patients with a mean age of 63.54 years. FIM and BI scores improved significantly post rehabilitation (P<0.05). Age was negatively correlated with both BI and FIM scores at admission and discharge. Length of stay was not correlated with improvement in BI or FIM scores during hospitalization. The patients that had <=1 month of inpatient rehabilitation had similar outcomes as those that had >1 month of inpatient rehabilitation (P>0.05). Length of time after stroke onset was not correlated with BI or FIM scores at admission. Regardless of initial functional status, prediction of discharge functional status was misleading. Physiatrists should keep in mind that functional improvement does not always increase with duration of inpatient therapy. PMID- 21600268 TI - In vivo functional brain imaging and a therapeutic trial of L-arginine in MELAS patients. AB - BACKGROUND: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS) is the most common type of mitochondrial disease and is characterized by stroke-like episodes (SEs), myopathy, lactic acidosis, diabetes mellitus, hearing-loss and cardiomyopathy. The causal hypotheses for SEs in MELAS presented to date are angiopathy, cytopathy and neuronal hyperexcitability. L arginine (Arg) has been applied for the therapy in MELAS patients. SCOPE OF REVIEW: We will introduce novel in vivo functional brain imaging techniques such as MRI and PET, and discuss the pathogenesis of SEs in MELAS patients. We will further describe here our clinical experience with L-arg therapy and discuss the dual pharmaceutical effects of this drug on MELAS. MAJOR CONCLUSIONS: Administration of L-arg to MELAS patients has been successful in reducing neurological symptoms due to acute strokes and preventing recurrences of SEs in the chronic phase. L-Arg has dual pharmaceutical effects on both angiopathy and cytopathy in MELAS. GENERAL SIGNIFICANCE: In vivo functional brain imaging promotes a better understanding of the pathogenesis and potential therapies for MELAS patients. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010. PMID- 21600269 TI - Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons. AB - Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane Cl(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. PMID- 21600270 TI - Contribution of astrocyte glycogen stores to progression of spreading depression and related events in hippocampal slices. AB - Spreading depression (SD) is a wave of coordinated cellular depolarization that propagates slowly throughout brain tissue. SD has been associated with migraine aura, and related events have been implicated in the enlargement of some brain injuries. Selective disruption of astrocyte oxidative metabolism has previously been shown to increase the propagation rate of SD in vivo, but it is currently unknown whether astrocyte glycogen stores make significant contributions to the onset or propagation of SD. We examined SD in acutely-prepared murine hippocampal slices, using either localized microinjections of KCl or oxygen and glucose deprivation (OGD) as stimuli. A combination of glycogenolysis inhibitors 1,4 dideoxy-1,4-imino-d-arabinitol (DAB) and 1-deoxynojirimycin (DNJ) increased the propagation rates of both high K(+)-SD and OGD-SD. Consistent with these observations, exposure to l-methionine-dl-sulfoximine (MSO) increased slice glycogen levels and decreased OGD-SD propagation rates. Effects of glycogen depletion were matched by selective inhibition of astrocyte tricarboxylic acid (TCA) cycle activity by fluoroacetate (FA). Prolonged exposure to reduced extracellular glucose (2 mM) has been suggested to deplete slice glycogen stores, but significant modification SD of propagation rate was not observed with this treatment. Furthermore, decreases in OGD-SD latency with this preexposure paradigm appeared to be due to depletion of glucose, rather than glycogen availability. These results suggest that astrocyte glycogen stores contribute to delaying the advancing wavefront of SD, including during the severe metabolic challenge of OGD. Approaches to enhance astrocyte glycogen reserves could be beneficial for delaying or preventing SD in some pathologic conditions. PMID- 21600271 TI - Unimanual and bimanual weight perception of virtual objects with a new multi finger haptic interface. AB - Accurate weight perception is important particularly in tasks where the user has to apply vertical forces to ensure safe landing of a fragile object or precise penetration of a surface with a probe. Moreover, depending on physical properties of objects such as weight and size we may switch between unimanual and bimanual manipulation during a task. Research has shown that bimanual manipulation of real objects results in a misperception of their weight: they tend to feel lighter than similarly heavy objects which are handled with one hand only [8]. Effective simulation of bimanual manipulation with desktop haptic interfaces should be able to replicate this effect of bimanual manipulation on weight perception. Here, we present the MasterFinger-2, a new multi-finger haptic interface allowing bimanual manipulation of virtual objects with precision grip and we conduct weight discrimination experiments to evaluate its capacity to simulate unimanual and bimanual weight. We found that the bimanual 'lighter' bias is also observed with the MasterFinger-2 but the sensitivity to changes of virtual weights deteriorated. PMID- 21600272 TI - The effect of aqueous extract of gross and commercial yerba mate (Ilex paraguariensis) on intra-abdominal and epididymal fat and glucose levels in male Wistar rats. AB - This study analyzed the plasma lipid profile, glucose levels and fat deposits in male rats treated with aqueous extract of gross yerba mate, commercial yerba mate or water. Yerba mate treatment did not change body weight gain and lipid profile. The consumption of gross yerba mate significantly increased blood glucose (6.6 mmol/L) as compared to the water (4.8 mmol/L) and commercial group (5.2 mmol/L) and decreased epididymal and intra-abdominal deposits (10.1mg/g and 23.7 mg/g of weight) as compared to the water (15.4 mg/g and 36.9 mg/g of weight) and commercial group (12.5mg/g and 28 mg/g of weight). The results suggest that gross yerba mate reduces fat more efficiently but produces a greater increase in blood glucose when compared to commercial yerba mate and water groups. PMID- 21600274 TI - Response to a letter to the editor. PMID- 21600273 TI - Increasing oxime efficacy by blood-brain barrier modulation. AB - One of the shortcomings of current treatment of nerve agent poisoning is that oximes hardly penetrate the blood-brain barrier (BBB), whereas nerve agents easily do. Increasing the concentration of oximes in the brain, would therefore provide an attractive approach to improve medical countermeasures. An explanation for limited penetration might be that oximes are substrates for the active P glycoprotein (Pgp) efflux transporter located in the BBB. Using quantitative brain microdialysis in rats, the effect of i.v. injected tariquidar, a non competitive, specific Pgp-inhibitor, on HI-6 levels in blood and brain was investigated. It appeared that tariquidar enhanced HI-6 levels in the brain approximately 2-fold during the first hour after HI-6 administration, whereas plasma levels did not differ between the treatment groups. A subsequent proof-of concept study in rats showed that soman-induced seizures and convulsions were prevented almost completely when they were, in addition to HI-6 and atropine, pretreated with tariquidar. Moreover, twice as much AChE activity was present in their brains as compared to control rats. These results in rats indicate that modulation of the BBB by a drug like tariquidar, which is non-toxic by itself, is of great value in enhancing the efficacy of oximes. PMID- 21600275 TI - The ethanolic extract of Kaempferia parviflora reduces ischaemic injury in rat isolated hearts. AB - AIMS OF THE STUDY: The ethanolic extract of Kaempferia parviflora (KPE) has been reported to contain a range of flavonoids and to enhance endothelial synthesis of NO. We investigated the vascular relaxant, antioxidant and cardioprotective activities of KPE. MATERIALS AND METHODS: Vascular function was assessed in rat aortic rings and superoxide generation determined using lucigenin enhanced chemiluminescence. Ischaemia and reperfusion were induced in rat isolated, perfused hearts. RESULTS: KPE caused vasorelaxation (R(max) 102 +/- 2%), which was partly inhibited by removal of the endothelium (R(max) 91 +/- 1%) or by N(G) nitro-l-arginine (L-NNA, R(max) 83 +/- 3%) or 1H-[1,2,4] oxadiazolo[4,3 a]quinoxaline-1-one (ODQ, R(max) 80 +/- 2%). In addition KPE caused concentration dependent inhibition of the contractile response to exogenous Ca(2+). KPE (10( 3)M) also significantly inhibited superoxide radical generation induced by of xanthine/xanthine oxidase (2.3 +/- 0.4% of control) to a similar extent to the xanthine oxidase inhibitor allopurinol (10(-4)M, 1.6 +/- 0.5%) or by rat isolated aorta in the presence of NADPH (30.0 +/- 6.3% of control) similarly to the NADPH oxidase inhibitor diphenyliodonium (5 * 10(-6)M, 23.1 +/- 5.6%). In the presence of oxidant stress generated by pyrogallol endothelium-dependent relaxation of rat aortic rings was impaired (ACh R(max) control 99 +/- 1%; pyrogallol 44 +/- 5%), an effect that was significantly reduced by KPE (10(-4)M, ACh R(max) 82 +/- 4%). In addition, KPE was found to attenuate the ventricular dysfunction caused by 20 min global ischaemia and 30 min reperfusion (I/R) in rat isolated hearts (dP/dt IR 1016 +/- 242, IR+KPE 2238+/-233 mm Hg/s). CONCLUSION: KPE is an effective vasodilator and antioxidant that is able to prevent myocardial ischaemia reperfusion injury. We suggest that KPE may be useful as an adjunct to thrombolytic therapy in the management of reperfusion injury. PMID- 21600276 TI - Genotoxic and clastogenic activity of saponins extracted from Nauclea bark as assessed by the micronucleus and the comet assays in Chinese Hamster Ovary cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bark extracts of Nauclea latifolia, Nauclea diderrichii, Nauclea pobeguinii and Nauclea vandergutchii are used in traditional medicine in West and South Africa for the treatment of fevers, diarrhea and malaria. AIM OF THE STUDY: To estimate the possible long-term toxicity and genotoxicity of plant extracts (dichloromethane, methanol, water/methanol, water) and saponins. MATERIALS AND METHODS: The clastogenicity of plant extracts and saponins was assessed by the micronucleus assay performed on Chinese Hamster Ovary cells. The DNA-damaging activity of saponin mixture was assessed by the comet assay on Chinese Hamster ovary cells. RESULTS: Hydromethanolic extracts from Nauclea latifolia, Nauclea diderrichii and Nauclea pobeguinii exhibited a significant clastogenic/aneugenic activity without S9 mix. The hydromethanolic extract from Nauclea diderrichii was the most clastogenic/aneugenic fraction with a Minimal Active Concentration (MAC) of 23.1 MUgm L(-1). It was submitted to a separation step leading to six main saponins identified as quinovic acid glycosides (saponins A, D, E, G, J, K). None of the isolated saponins exerted a significant clastogenic/aneugenic activity by the micronucleus assay, however a mixture made with equal quantities of each of the six saponins exhibited a direct genotoxic/clastogenic activity as assessed by both the micronucleus assay and the comet assay on Chinese Hamster Ovary cells. CONCLUSION: Saponins present in the hydromethanolic extracts of Nauclea induced synergistic in vitro DNA-damage and chromosome mutations in mammalian cells. This genotoxic activity was probably due to the capacity of Nauclea saponins to reduce cell defense against oxidative stress through the inhibition of glutathione-S-transferase activity. PMID- 21600278 TI - p38 MAPK activation is required for esculetin-induced inhibition of vascular smooth muscle cells proliferation. AB - The phenolic compound esculetin is known to inhibit the proliferation of vascular smooth muscle cells (VSMC). However, the signaling pathway by which esculetin mediates its molecular effects in VSMC remains to be identified. The present results suggest an unexpected role of the p38 MAPK signaling pathway in esculetin induced inhibition of VSMC growth. Treatment of VSMC with esculetin resulted in significant growth inhibition and G1-phase cell-cycle arrest, which was followed by down-regulation of cyclins and cyclin-dependent kinase (CDK) expression. This G1-phase cell-cycle arrest was due to up-regulation of p21WAF1 expression. In addition, esculetin treatment activated p38 MAPK and ERK1/2. Pretreatment with SB203580, which is a p38 MAPK specific inhibitor, or expression of the dominant negative p38 MAPK (DN p38 MAPK) gene blocked esculetin-induced p38 MAPK activation and p21WAF1 expression. Finally, both the growth inhibition and the down-regulation of CDKs induced by esculetin were suppressed by either SB203580 or the DN p38 MAPK mutant gene. In conclusion, these results demonstrate that activation of p38 MAPK contributes to esculetin-induced p21WAF1 expression in VSMC by decreasing both the cyclin D1/CDK4 and cyclin E/CDK2 complexes. These novel results regarding the molecular mechanism of esculetin action suggest new preventive and therapeutic treatments for atherosclerosis. PMID- 21600277 TI - Aldose reductase pathway contributes to vulnerability of aging myocardium to ischemic injury. AB - Aging men and women display both increased incidence of cardiovascular disease and complications of myocardial infarction and heart failure. We hypothesized that altered glucose metabolism, in particular, flux of glucose via the polyol pathway (PP) may be responsible, in part, for the enhanced vulnerability of aging myocardium to ischemic injury, even in the absence of superimposed disease processes linked to PP flux, such as diabetes. To test our hypothesis, we determined the expression and products of PP enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH) in hearts from Fischer 344 aged (26 months) and young (4 months) rats subjected to global ischemia followed by reperfusion in the presence or absence of blockers of PP and the measures of ischemic injury and functional recovery were determined. Expression and activities of AR and SDH were significantly higher in aged vs. young hearts, and induction of ischemia further increased AR and SDH activity in the aged hearts. Myocardial ischemic injury was significantly greater in aged vs. young hearts, and blockade of AR reduced ischemic injury and improved cardiac functional recovery on reperfusion in aged hearts. These data indicate that innate increases in activity of the PP enzymes augment myocardial vulnerability to I/R injury in aging, and that blockers of PP protect the vulnerable aging hearts. PMID- 21600279 TI - Mutation and copy number detection in human cancers using a custom genotyping assay. AB - Identification of biomarkers for positive and negative predictors of response to cancer therapeutics can help direct clinical strategies. However, challenges with tissue availability and costs are significant limiting factors for diagnostic assays. To address these challenges, we have customized a high-throughput single nucleotide polymorphism genotyping assay with the objective of simultaneously surveying known somatic mutations and copy number alterations for translational studies in cancer. As constructed, this assay can interrogate 376 known somatic mutations and quantify copy number alterations of genes commonly implicated in tumorigenesis or progression. Validation of this assay on a panel of 321 cell lines demonstrates sensitivity to accurately detect mutations, robust accuracy in the presence of infiltrating normal tissue, and the ability to detect both DNA copy number amplifications and deletions. This technology, with its high sensitivity, small DNA requirements, and low costs is an attractive platform for biomarker exploration in cancer. PMID- 21600280 TI - Cloning and identification of two novel NBCe1 splice variants from mouse reproductive tract tissues: a comparative study of NCBT genes. AB - Na(+)-coupled HCO(3)(-) transporters (NCBTs) of the SLC4 family play critical roles in pH regulation as well as transepithelial HCO(3)(-) transport. We systematically examined, in the mouse reproductive tract tissues, the mRNA expression of five NCBTs as well as the five NBCe1 (Slc4a4) variants NBCe1-A through -E, of which NBCe1-D and NBCe1-E are novel. Cloning of NBCe1-D and NBCe1 E, both lacking a 27-nucleotide cassette I, reveals a novel alternative splicing unit in the mouse Slc4a4 gene. Transcripts of Slc4a4 lacking cassette I are expressed in diverse murine tissues as shown by RT-PCR analysis and in diverse tissues of other vertebrate species as shown by blast against GenBank database. Genomic sequence analysis indicates that cassette I of SLC4A4 is conserved in all NCBT genes except for SLC4A5, which presumably lost cassette I during its evolution. Our present study represents an important step towards understanding the molecular physiology of NBCe1, and presumably other NCBTs. PMID- 21600281 TI - DNA methylation as a risk factor in the effects of early life stress. AB - Epigenetic marks (e.g., DNA 5-methylcytosine [5mC] content or CpG methylation) within specific gene regulatory regions have been demonstrated to play diverse roles in stress adaptation and resulting health trajectories following early adversity. Yet the developmental programming of the vast majority of the epigenome has not yet been characterized, and its role in the impact of early stress largely unknown. In the present study, we investigated the relationships among early life stress, whole-epigenome and candidate stress pathway gene (serotonin transporter, 5-HTT) methylation patterns, and adult behavioral stress adaptation in a non-human primate model. Early in life, experimental variable foraging demand (VFD) stress or control conditions were administered to two groups each of 10 female bonnet macaques (Macaca radiata) and their mothers. As adults (3-13 years of age), these females were assessed for behavioral adaptation to stress across four conditions of increasing intensity. Blood DNA 5-HTT 5mC status was determined using sodium bisulfite pyrosequencing and total 5mC content was determined using ELISA. Neither stress reactivity nor DNA methylation differed based on early life stress. However, we found that both greater 5-HTT and whole-genome 5mC was associated with enhanced behavioral stress reactivity following early life stress, but not control conditions. Therefore, regardless of developmental origin, greater DNA methylation conferred a genomic background of "risk" in the context of early stress. We suggest that this may arise from constrained plasticity in gene expression needed for stress adaptation early in development. This risk may have wider implications for psychological and physical stress adaptation and health. PMID- 21600283 TI - Effects of PBN and OKN007 in rodent glioma models assessed by 1H MR spectroscopy. AB - Gliomas, the most common primary brain tumors in adults, have a poor outcome. PBN (alpha-phenyl-tert-butylnitrone) and OKN007 (2,4-disulfophenyl-PBN) are nitrones that have demonstrated beneficial effects in many aging diseases. In this study, we evaluated the anti-tumor effects of PBN and OKN007 in several rodent glioma models (C6, RG2, and GL261) by assessing metabolite alterations with magnetic resonance spectroscopy (MRS). PBN or OKN007 was administered in drinking water before or after tumor formation. MR imaging and single-voxel point-resolved spectroscopy were done to assess tumor morphology and metabolites, after therapy. Major metabolite ratios (choline, N-acetylaspartate, and lipid (methylene or methyl), all compared to creatine), as well as quantification of individual metabolite concentrations, were assessed. Nitrones induced tumor metabolism changes that resulted in restoring major metabolite ratios close to their normal levels, in the glioma regression phase. Nitrone treatment decreased the lipid (methylene)-to-creatine ratio, as well as the estimated concentration of lipid (methylene) significantly. Alterations in lipids can be a useful marker for the evaluation of the efficacy associated with treatment and were found in this study to be related to the reduction of necrosis, but not apoptosis. OKN007 was more effective than PBN when administered after tumor formation in the C6 glioma model. In conclusion, (1)H MRS and conventional MRI are useful methods to assess and follow the response of varied glioma models to anti-tumor treatments. PMID- 21600284 TI - The effect of tamoxifen and raloxifene on estrogen metabolism and endometrial cancer risk. AB - Selective estrogen receptor modulators (SERMs) demonstrate differential endometrial cancer (EC) risk. While tamoxifen (TAM) use increases the risk of endometrial hyperplasia and malignancy, raloxifene (RAL) has neutral effects on the uterus. How TAM increases the risk of EC and why TAM and RAL differentially modulate the risk for EC, however, remain elusive. Here, we tested the hypothesis that TAM increases the risk for EC, at least in part, by enhancing the local estrogen biosynthesis and directing estrogen metabolism towards the formation of genotoxic and hormonally active estrogen metabolites. In addition, the differential effects of TAM and RAL in EC risk are attributed to their differential effect on estrogen metabolism/metabolites. The endometrial cancer cell line (Ishikawa cells) and the nonmalignant immortalized human endometrial glandular cell line (EM1) were used for the study. The profile of estrogen/estrogen metabolites (EM), depurinating estrogen-DNA adducts, and the expression of estrogen-metabolizing enzymes in cells treated with 17beta estradiol (E2) alone or in combination with TAM or RAL were investigated using high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS(2)), ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS), and Western blot analysis, respectively. TAM significantly increased the total EM and enhanced the formation of hormonally active and carcinogenic estrogen metabolites, 4-hydroxestrone (4-OHE1) and 16alpha-hydroxyestrone, with concomitant reduction in the formation of antiestrogenic and anticarcinogenic 2-hydroxyestradiol and 2-methoxyestradiol. Furthermore, TAM increased the formation of depurinating estrogen-DNA adducts 4 OHE1 [2]-1-N7Guanine and 4-OHE1 [2]-1-N3 Adenine. TAM-induced alteration in EM and depurinating DNA adduct formation is associated with altered expression of estrogen metabolizing enzymes CYP1A1, CYP1B1, COMT, NQO1, and SF-1 as revealed by Western blot analysis. In contrast to TAM, RAL has minimal effect on EM, estrogen DNA adduct formation, or estrogen-metabolizing enzymes expression. These data show that TAM perturbs the balance of estrogen-metabolizing enzymes and alters the disposition of estrogen metabolites, which can explain, at least in part, the mechanism for TAM-induced EC. These results also implicate the differential effect of TAM and RAL on estrogen metabolism/metabolites as a potential mechanism for their disparate effects on the endometrium. PMID- 21600285 TI - Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1(G93A) mice model. AB - Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons. To investigate the role of antioxidant defenses in ALS we used knockout mice for the glutamate-cysteine ligase modifier subunit (GCLM-/-), which have a 70-80% reduction in total glutathione. Although GCLM(-/-) mice are viable and fertile, the life span of GCLM(-/-)/hSOD1(G93A) mice decreased in 55% when compared to GCLM(+/+)/hSOD1(G93A) mice. Decreased life span in GCLM(-/-)/hSOD1(G93A) mice was associated to increased oxidative stress, aggravated mitochondrial pathology and increased association of hSOD1 with the mitochondria. Interestingly, when the GCLM(-/-) animals were mated with a different ALS-model which overexpress the experimental mutation hSOD1(H46R/H48Q), no effect was observed in survival of GCLM(-/-)/hSOD1(H46R/H48Q) mice; and little or no mitochondrial pathology was observed. Since a specific disease modifier, such as glutathione deficiency, may affect only certain hSOD1 mutants, these findings contribute to our understanding of the potential difference in the molecular pathways by which different hSOD1 mutants generate disease. PMID- 21600287 TI - Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function. AB - Research over the last few decades has shaped our understanding of the crucial involvement of the N-methyl-D-aspartate receptor (NMDAR) in mediating excitatory synaptic neurotransmission, neuronal development and learning and memory. The complexity of NMDAR modulation has escalated with the knowledge that receptors can traffic between synaptic and extrasynaptic sites, and that location on the plasma membrane profoundly affects the physiological function of NMDARs. Moreover, mechanisms that regulate NMDAR subcellular localization and function, such as protein-protein interactions, phosphorylation, palmitoylation, ubiquitination and receptor proteolytic cleavage, may differ for synaptic and extrasynaptic NMDARs. Recent studies suggest that NMDAR mislocalization is a dominant contributing factor to glutamatergic dysfunction and pathogenesis in neurological disorders such as Huntington's disease, Alzheimer's disease and ischemia. Therapeutic approaches that specifically rectify receptor mislocalization or target resulting downstream apoptotic signaling could be beneficial for preventing disease onset or progression across many disorders that are commonly caused by NMDAR dysfunction. This review will summarize the molecular mechanisms that regulate synaptic and extrasynaptic NMDAR localization in both physiologic and pathogenic states. PMID- 21600286 TI - Regulation of adult neurogenesis by behavior and age in the accessory olfactory bulb. AB - The vomeronasal system (VNS) participates in the detection and processing of pheromonal information related to social and sexual behaviors. Within the VNS, two different populations of sensory neurons, with a distinct pattern of distribution, line the epithelium of the vomeronasal organ (VNO) and give rise to segregated sensory projections to the accessory olfactory bulb (AOB). Apical sensory neurons in the VNO project to the anterior AOB (aAOB), while basal neurons project to the posterior AOB (pAOB). In the AOB, the largest population of neurons are inhibitory, the granule and periglomerular cells (GCs and PGs) and remarkably, these neurons are continuously born and functionally integrated in the adult brain, underscoring their role on olfactory function. Here we show that behaviors mediated by the VNS differentially regulate adult neurogenesis across the anterior-posterior axis of the AOB. We used immunohistochemical labeling of newly born cells under different behavioral conditions in mice. Using a resident intruder aggression paradigm, we found that subordinate mice exhibited increased neurogenesis in the aAOB. In addition, in sexually naive adult females exposed to soiled bedding odorized by adult males, the number of newly born cells was significantly increased in the pAOB; however, neurogenesis was not affected in females exposed to female odors. In addition, we found that at two months of age adult neurogenesis was sexually dimorphic, with male mice exhibiting higher levels of newly born cells than females. Interestingly, adult neurogenesis was greatly reduced with age and this decrease correlated with a decrease in progenitor cells proliferation but not with an increase in cell death in the AOB. These results indicate that the physiological regulation of adult neurogenesis in the AOB by behaviors is both sex and age dependent and suggests an important role of newly born neurons in sex dependent behaviors mediated by the VNS. PMID- 21600288 TI - Purification of proteins containing zinc finger domains using immobilized metal ion affinity chromatography. AB - Heterologous proteins are frequently purified by immobilized metal ion affinity chromatography (IMAC) based on their modification with a hexa-histidine affinity tag (His-tag). The terminal His-tag can, however, alter functional properties of the tagged protein. Numerous strategies for the tag removal have been developed including chemical treatment and insertion of protease target sequences in the protein sequence. Instead of using these approaches, we took an advantage of natural interaction of zinc finger domains with metal ions to purify functionally similar retroviral proteins from two different retroviruses. We found that these proteins exhibited significantly different affinities to the immobilized metal ions, despite that both contain the same type of zinc finger motif (i.e., CCHC). While zinc finger proteins may differ in biochemical properties, the multitude of IMAC platforms should allow relatively simple yet specific method for their isolation in native state. PMID- 21600291 TI - A neural mass model of interconnected regions simulates rhythm propagation observed via TMS-EEG. AB - Knowledge of cortical rhythms represents an important aspect of modern neuroscience, to understand how the brain realizes its functions. Recent data suggest that different regions in the brain may exhibit distinct electroencephalogram (EEG) rhythms when perturbed by Transcranial Magnetic Stimulation (TMS) and that these rhythms can change due to the connectivity among regions. In this context, in silico simulations may help the validation of these hypotheses that would be difficult to be verified in vivo. Neural mass models can be very useful to simulate specific aspects of electrical brain activity and, above all, to analyze and identify the overall frequency content of EEG in a cortical region of interest (ROI). In this work we implemented a model of connectivity among cortical regions to fit the impulse responses in three ROIs recorded during a series of TMS/EEG experiments performed in five subjects and using three different impulse intensities. In particular we investigated Brodmann Area (BA) 19 (occipital lobe), BA 7 (parietal lobe) and BA 6 (frontal lobe). Results show that the model can reproduce the natural rhythms of the three regions quite well, acting on a few internal parameters. Moreover, the model can explain most rhythm changes induced by stimulation of another region, and inter subject variability, by estimating just a few long-range connectivity parameters among ROIs. PMID- 21600289 TI - Purification and functional analysis of protein kinase G-1alpha using a bacterial expression system. AB - 3',5' Cyclic guanosine monophosphate (cGMP)-dependent protein kinase G-1alpha (PKG-1alpha) is an enzyme that is a target of several anti-hypertensive and erectile dysfunction drugs. Binding of cGMP to PKG-1alpha produces a conformational change that leads to enzyme activation. Activated PKG-1alpha performs important roles both in blood vessel vasodilation and in maintaining the smooth muscle cell in a differentiated contractile state. Recombinant PKG-1alpha has been expressed and purified using Sf9-insect cells. However, attempts at purifying full length protein in a soluble and active form in prokaryotes have thus far been unsuccessful. These attempts have been hampered by the lack of proper eukaryotic protein folding machinery in bacteria. In this study, we report the successful expression and purification of PKG-1alpha using a genetically engineered Escherichia coli strain, Rosetta-gami 2(DE3), transduced with full length human PKG-1alpha cDNA containing a C-terminal histidine tag. PKG-1alpha was purified to homogeneity using sequential nickel affinity chromatography, gel filtration and ion exchange MonoQ columns. Protein identity was confirmed by immunoblot analysis. N-terminal sequencing using Edman degradation demonstrated that the purified protein was full length. Analysis of enzyme kinetics, using a nonlinear regression curve, identified that, at constant cGMP levels (10MUM) and varying ATP concentrations, PKG-1alpha had a maximal velocity (V(max)) of 5.02+/ 0.25pmol/min/MUg and a Michaelis-Menten constant (K(m)) of 11.78+/-2.68MUM ATP. Recent studies have suggested that endothelial function can be attenuated by oxidative and/or nitrosative stress but the role of PKG-1alpha under these conditions is unclear. We found that PKG-1alpha enzyme activity was attenuated by exposure to the NO donor, spermine NONOate, hydrogen peroxide, and peroxynitrite but not by superoxide, suggesting that the attenuation of PKG-1alpha activity may be an under-appreciated mechanism underlying the development of endothelial dysfunction in a number of cardiovascular diseases. PMID- 21600290 TI - Feature selection and classification of imbalanced datasets: application to PET images of children with autistic spectrum disorders. AB - Learning with discriminative methods is generally based on minimizing the misclassification of training samples, which may be unsuitable for imbalanced datasets where the recognition might be biased in favor of the most numerous class. This problem can be addressed with a generative approach, which typically requires more parameters to be determined leading to reduced performances in high dimension. In such situations, dimension reduction becomes a crucial issue. We propose a feature selection/classification algorithm based on generative methods in order to predict the clinical status of a highly imbalanced dataset made of PET scans of forty-five low-functioning children with autism spectrum disorders (ASD) and thirteen non-ASD low functioning children. ASDs are typically characterized by impaired social interaction, narrow interests, and repetitive behaviors, with a high variability in expression and severity. The numerous findings revealed by brain imaging studies suggest that ASD is associated with a complex and distributed pattern of abnormalities that makes the identification of a shared and common neuroimaging profile a difficult task. In this context, our goal is to identify the rest functional brain imaging abnormalities pattern associated with ASD and to validate its efficiency in individual classification. The proposed feature selection algorithm detected a characteristic pattern in the ASD group that included a hypoperfusion in the right Superior Temporal Sulcus (STS) and a hyperperfusion in the contralateral postcentral area. Our algorithm allowed for a significantly accurate (88%), sensitive (91%) and specific (77%) prediction of clinical category. For this imbalanced dataset, with only 13 control scans, the proposed generative algorithm outperformed other state-of-the art discriminant methods. The high predictive power of the characteristic pattern, which has been automatically identified on whole brains without any priors, confirms previous findings concerning the role of STS in ASD. This work offers exciting possibilities for early autism detection and/or the evaluation of treatment response in individual patients. PMID- 21600292 TI - Improving the reliability of functional localizers. AB - A critical assumption underlying the practice of functional localization is that the voxels identified by functional localization are essentially the same as those activated in the main experiment for a particular anatomical area. Violations of this assumption bias the resulting analyses and can dramatically increase the likelihood of both Type I and Type II errors. Here we investigated how the amount of data affects the reliability of a set of common functionally defined regions-of-interest (fROIs). Four participants were scanned ten times each to functionally localize extrastriate regions sensitive to visually presented words, objects and faces. A within-subject random-effects analysis was used as the "gold standard" for identifying the fROIs and the results were compared to within-subject, fixed-effect analyses typically used for functional localization. By varying the quantity of data included in the analyses, we empirically assessed the amount needed to ensure reliable identification of the fROIs. The results demonstrated that the most consistent fROIs were based on either stringent statistical thresholding (Z>5.0) of large quantities of data or on lenient thresholding (Z>2.3) of a modest amount of data, with both methods yielding 70-80% overlap between the functional localization results and the "gold standard." Stringent statistical thresholds on typical quantities of localizer data led to the poorest reliability (<20% overlap). These findings suggest that the most reliable and cost-efficient method for functional localization involves collecting a relatively small amount of data (~10 min) and using a lenient statistical threshold to identify all voxels in a given region that are sensitive to the process-of-interest. PMID- 21600294 TI - Influence of skin blood flow on near-infrared spectroscopy signals measured on the forehead during a verbal fluency task. AB - Brain activity during a verbal fluency task (VFT) has been the target of many functional imaging studies. Most studies using near-infrared spectroscopy (NIRS) have reported major activation in the frontal pole, but those using PET or fMRI have not. This led us to hypothesize that changes in the NIRS signals measured in the forehead during VFT were due to changes in skin blood flow. To test this hypothesis, we measured NIRS signals and the Doppler tissue blood flow signals in the foreheads of 50 participants. The measurements were performed while each participant produced words during two 60-s periods with an interval of 100 s. In addition to a conventional optode separation distance of 30 mm (FAR channels), we used a short distance--5mm (NEAR channels)--to measure NIRS signals that originated exclusively from surface tissues. The oxygenated hemoglobin (oxyHb) concentration in the FAR and NEAR channels, as well as the Doppler blood flow signal, increased in a similar manner during the two periods of word production; the signal increase in the first period was twice as high as that in the second period. Accordingly, the mean changes in oxyHb concentration in the FAR channels were correlated closely with the changes in the NEAR channels (R(2) = 0.91) and with the integrated Doppler skin blood flow signal (R(2) = 0.94). Furthermore, task-related NIRS responses disappeared when we blocked skin blood flows by pressing a small area that covered a pair of optodes. Additionally, changes in the FAR channel signals were correlated closely with the magnitude of pulsatile waves in the Doppler signal (R(2) = 0.92), but these signals were not highly correlated with the pulse rate (R(2) = 0.43). These results suggest that a major part of the task-related changes in the oxyHb concentration in the forehead is due to task-related changes in the skin blood flow, which is under different autonomic control than heart rate. PMID- 21600293 TI - Whole brain high-resolution functional imaging at ultra high magnetic fields: an application to the analysis of resting state networks. AB - Whole-brain functional magnetic resonance imaging (fMRI) allows measuring brain dynamics at all brain regions simultaneously and is widely used in research and clinical neuroscience to observe both stimulus-related and spontaneous neural activity. Ultrahigh magnetic fields (7T and above) allow functional imaging with high contrast-to-noise ratios and improved spatial resolution and specificity compared to clinical fields (1.5T and 3T). High-resolution 7T fMRI, however, has been mostly limited to partial brain coverage with previous whole-brain applications sacrificing either the spatial or temporal resolution. Here we present whole-brain high-resolution (1, 1.5 and 2mm isotropic voxels) resting state fMRI at 7T, obtained with parallel imaging technology, without sacrificing temporal resolution or brain coverage, over what is typically achieved at 3T with several fold larger voxel volumes. Using Independent Component Analysis we demonstrate that high resolution images acquired at 7T retain enough sensitivity for the reliable extraction of typical resting state brain networks and illustrate the added value of obtaining both single subject and group maps, using cortex based alignment, of the default-mode network (DMN) with high native resolution. By comparing results between multiple resolutions we show that smaller voxels volumes (1 and 1.5mm isotropic) data result in reduced partial volume effects, permitting separations of detailed spatial features within the DMN patterns as well as a better function to anatomy correspondence. PMID- 21600295 TI - Toward the resolution of an explosive radiation--a multilocus phylogeny of oceanic dolphins (Delphinidae). AB - Oceanic dolphins (Delphinidae) are the product of a rapid radiation that yielded ~36 extant species of small to medium-sized cetaceans that first emerged in the Late Miocene. Although they are a charismatic group of organisms that have become poster children for marine conservation, many phylogenetic relationships within Delphinidae remain elusive due to the slow molecular evolution of the group and the difficulty of resolving short branches from successive cladogenic events. Here I combine existing and newly generated sequences from four mitochondrial (mt) genes and 20 nuclear (nu) genes to reconstruct a well-supported phylogenetic hypothesis for Delphinidae. This study compares maximum-likelihood and Bayesian inference methods of several data sets including mtDNA, combined nuDNA, gene trees of individual nuDNA loci, and concatenated mtDNA+nuDNA. In addition, I contrast these standard phylogenetic analyses with the species tree reconstruction method of Bayesian concordance analysis (BCA). Despite finding discordance between mtDNA and individual nuDNA loci, the concatenated matrix recovers a completely resolved and robustly supported phylogeny that is also broadly congruent with BCA trees. This study strongly supports groupings such as Delphininae, Lissodelphininae, Globicephalinae, Sotalia+Delphininae, Steno+Orcaella+Globicephalinae, and Leucopleurus acutus, Lagenorhynchus albirostris, and Orcinus orca as basal delphinid taxa. PMID- 21600296 TI - Differences in T cell depletion and intestinal mucositis explain inconsistent effects of NOD2/CARD15 polymophisms in SCT. PMID- 21600297 TI - Assessment of acid-base derangements among bonnethead (Sphyrna tiburo), bull (Carcharhinus leucas), and lemon (Negaprion brevirostris) sharks from gillnet and longline capture and handling methods. AB - Blood gasses of wild bonnethead, bull, and lemon sharks were measured with the i STAT clinical analyzer with the CG4+ cartridge immediately after capture; and again immediately prior to release after tagging, handling and morphometric measurements were taken. Relative reference ranges of post-capture status were established. Among species, stress response to capture was similar for all parameters; however, pH declined and lactate concentrations rose over time, indicating continued insult from capture and/or response to additional handling stress. pCO(2) rose faster for S. tiburo than for C. leucas, and lactate concentrations rose faster for S. tiburo than for N. brevirostris. All species caught in gillnets experienced lower pH and higher lactate concentrations than on longlines. Discriminant analysis justified the use of blood gas analysis to assess physiological stress induced by different capture methods. From these results, we recommend 1) that gear be monitored closely and sharks be removed immediately, or suboptimally, that gear is deployed for the shortest soak time possible; 2) longline over gillnet gear; and 3) extra caution with sensitive species (e.g., S. tiburo), which may include the administration of blood buffers and other therapeutics if a shark is beyond the limits of relative reference ranges reported here. PMID- 21600298 TI - Strategies for maintaining Na+ balance in zebrafish (Danio rerio) during prolonged exposure to acidic water. AB - The objective of the present study was to characterize the capacity of zebrafish (Danio rerio) to regulate whole body Na+ levels during exposure to acidic (pH 3.8 4.0) water. Exposure to acidic water significantly affected the mRNA levels of 14 claudin and two occludin isoforms, tight junction proteins thought to be involved in regulating paracellular efflux. Despite these changes, Na+ efflux as well as uptake of polyethylene glycol (PEG), a marker for paracellular pathway, was persistently elevated during the 2-week period of acid exposure, although there was a transient recovery between 12- and 72-h. Pre-exposing fish to acidic water for 2 weeks failed to attenuate the increase in Na+ efflux associated with acute exposure to acidic water of low [Ca2+]. However, during recovery in water of circumneutral pH following exposure to acidic water, normal rates of Na+ efflux were restored within 5h. The rate of Na+ uptake was significantly elevated between 4 and 7 days of exposure to acidic water; the increase was associated with significant increases in maximal Na+ uptake capacity (J(MAX)Na+) and affinity constant (K(M)). These results demonstrate that in acidic water, zebrafish maintain their whole body Na+ balance primarily by regulating Na+ uptake, rather than Na+ efflux. PMID- 21600299 TI - Prostaglandin EP4 receptor enhances BCR-induced apoptosis of immature B cells. AB - Prostaglandin E2 (PGE2) is emerging as an important co-modulator of B cell responses. Using a pharmacological approach, we aimed to delineate the role of PGE2 in B cell receptor (BCR) induced apoptosis of immature B cells. Gene and protein expression analyses showed that, of the four PGE2 receptors subtypes, only EP4 receptor is upregulated upon BCR cross-linking, leading to sensitization of WEHI 231 cells towards PGE2 mediated inhibitory effects. EP4 receptor antagonist ONO-AE3-208, was able to completely revert the observed effects of PGE2. The engagement of EP4 receptor promotes BCR-induced G0/G1 arrest of WEHI 231 cells, resulting in enhanced caspase mediated, BCR-induced apoptosis. We addressed, mechanistically, the interplay between BCR and EP4 receptor signaling components. Prostaglandin1-alcohol (Pge1-OH), a selective EP4 receptor agonist inhibits BCR-induced activation of NF-kappaB by suppression of BCR-induced IkappaBalpha phosphorylation. Disruption of prosurvival pathways is a possible mechanism by which PGE2 enhances BCR-induced apoptosis in immature B lymphocytes. PMID- 21600300 TI - Light-emitting diodes (LED) for domestic lighting: any risks for the eye? AB - Light-emitting diodes (LEDs) are taking an increasing place in the market of domestic lighting because they produce light with low energy consumption. In the EU, by 2016, no traditional incandescent light sources will be available and LEDs may become the major domestic light sources. Due to specific spectral and energetic characteristics of white LEDs as compared to other domestic light sources, some concerns have been raised regarding their safety for human health and particularly potential harmful risks for the eye. To conduct a health risk assessment on systems using LEDs, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES), a public body reporting to the French Ministers for ecology, for health and for employment, has organized a task group. This group consisted physicists, lighting and metrology specialists, retinal biologist and ophthalmologist who have worked together for a year. Part of this work has comprised the evaluation of group risks of different white LEDs commercialized on the French market, according to the standards and found that some of these lights belonged to the group risk 1 or 2. This paper gives a comprehensive analysis of the potential risks of white LEDs, taking into account pre-clinical knowledge as well as epidemiologic studies and reports the French Agency's recommendations to avoid potential retinal hazards. PMID- 21600301 TI - Portfolio management in early stage drug discovery - a traveler's guide through uncharted territory. AB - Portfolio management in drug development has become a best practice in the pharmaceutical industry. By contrast, early on in the value chain - the discovery phase - portfolio management is still in its infancy. Nevertheless, owing to the attrition of R&D projects from phase to phase and the cost of capital involved, these early phases of drug discovery play a significant part for the overall cost of bringing new, innovative drugs to the market. This paper describes various approaches to manage a portfolio of projects in early-stage drug discovery and provides crucial factors that determine the success of such an approach. PMID- 21600302 TI - A review and appraisal of the DNA damage theory of ageing. AB - Given the central role of DNA in life, and how ageing can be seen as the gradual and irreversible breakdown of living systems, the idea that damage to the DNA is the crucial cause of ageing remains a powerful one. DNA damage and mutations of different types clearly accumulate with age in mammalian tissues. Human progeroid syndromes resulting in what appears to be accelerated ageing have been linked to defects in DNA repair or processing, suggesting that elevated levels of DNA damage can accelerate physiological decline and the development of age-related diseases not limited to cancer. Higher DNA damage may trigger cellular signalling pathways, such as apoptosis, that result in a faster depletion of stem cells, which in turn contributes to accelerated ageing. Genetic manipulations of DNA repair pathways in mice further strengthen this view and also indicate that disruption of specific pathways, such as nucleotide excision repair and non homologous end joining, is more strongly associated with premature ageing phenotypes. Delaying ageing in mice by decreasing levels of DNA damage, however, has not been achieved yet, perhaps due to the complexity inherent to DNA repair and DNA damage response pathways. Another open question is whether DNA repair optimization is involved in the evolution of species longevity, and we suggest that the way cells from different organisms respond to DNA damage may be crucial in species differences in ageing. Taken together, the data suggest a major role of DNA damage in the modulation of longevity, possibly through effects on cell dysfunction and loss, although understanding how to modify DNA damage repair and response systems to delay ageing remains a crucial challenge. PMID- 21600303 TI - Biliary-colonic fistula. PMID- 21600304 TI - Hepatitis B genotypes distribution in South Asia and Middle East. PMID- 21600305 TI - Influenza A/H1N1pdm virus in Russian Asia in 2009-2010. AB - In total 3566 blood sera samples were collected in the Russian Far East and Central and Western Siberia in 2009-2010. The presence of antibodies to influenza A/H1N1pdm, seasonal H1N1 and H3N2 influenza viruses in the sera was tested in the hemagglutination inhibition test. 29.5% of samples from the Far East were positive to pandemic influenza, this value for Central and Western Siberia is 2 fold lower (12.8% and 11%, respectively). Fifty-six influenza A/H1N1pdm viruses were isolated during 2009-2010 from samples collected in Central and Western Siberia and the Russian Far East. Molecular and genetic properties of 23 strains were studied. Nucleotide and amino-acid sequences of pandemic influenza virus strains were identical (99% identity or more) to reference strain A/California/04/2009. Sporadic substitutions in antigenic sites were detected but did not change antigenic characteristics of strains. PMID- 21600306 TI - Human impact on genetic diversity of Toxoplasma gondii: example of the anthropized environment from French Guiana. AB - In French Guiana, severe cases of toxoplasmosis in immunocompetent patients are associated with atypical strains of Toxoplasma gondii linked to a wild neotropical rainforest cycle and a higher genetic diversity than usually observed for T. gondii isolates from anthropized environment. This raises the question of the impact of anthropization of the natural environment, on genetic diversity and on the population structure of T. gondii. However, few data are available on strains circulating in the anthropized areas from French Guiana. Seropositive animals originating mainly from anthropized sub-urban areas and punctually from wild environment in French Guiana were analyzed for T. gondii isolation and genotyping. Thirty-three strains were obtained by bioassay in mice and compared with 18 previously reported isolates chiefly originating from the Amazon rainforest. The genotyping analysis performed with 15 microsatellite markers located on 12 different chromosomes revealed a lower genetic diversity in the anthropized environment. Results were analyzed in terms of population structure by clustering methods, Neighbor-joining trees reconstruction based on genetic distances, F(ST,) Mantel's tests and linkage disequilibrium. They clearly showed a genetic differentiation between strains associated to the anthropized environment and those associated to the wild, but with some inbreeding between them. The majority of strains from the anthropized environment were clustered into additional lineages of T. gondii that are common in the Caribbean. In conclusion the two environmental populations "wild" and "anthropized" were genetically well differentiated. The anthropization of the environment seems to be accompanied with a decreased diversity of T. gondii associated with a greater structure of the populations. We detected potential interpenetration and genetic exchanges between these two environmental populations. As a higher pathogenicity in human of "wild" genotypes has been described, the interpenetration of both environments leads to hybridization between strains that may be at risk for human health. PMID- 21600307 TI - Pseudomonas entomophila and Pseudomonas mendocina: potential models for studying the bacterial type VI secretion system. AB - A diversity of molecular translocation mechanisms, including various secretion systems, has been elaborated in host-bacterial interactions. The newly described type VI secretion system (T6SS) appears to be involved in bacterial pathogenesis by acting as a nano-syringe, contributing in translocation of several effector proteins into the eukaryotic host cell cytoplasm. Recent evidences revealed the involvement of T6SS machinery in inter-bacterial interactions. Several Pseudomonas species are found to harbour multiple and well organised T6SS loci, however, their genomic structural similarities as well as phylogenetic divergence suggest an independent evolution. Until now elementary evidence was provided for the presence of T6SS in the genomes of Pseudomonas entomophila (Pen), an aggressive insect pathogen as well as the human opportunistic pathogen Pseudomonas mendocina (Pme). In this report we evidenced by in silico genome mining along with bioinformatic analysis the presence of genes encoding for putative T6SS core components and secreted proteins in the sequenced Pen L48 and Pme ymp, strains and designated their putative promoters, sigma factors binding sites and various regulatory proteins. Moreover, we investigated the phylogenetic relatedness of four T6SS core proteins from these strains with their orthologues from various Pseudomonas species. Our analysis revealed two phylogenetically distinguishable T6SS loci in the genome of Pme that appeared to be highly homologous to Pseudomonas aeruginosa Hcp-Secretion Island-I (HSI-I) and -II. Our findings suggest that Pme could be excellent additional to P. aeruginosa model, for the elucidation of HSI-I and -II biological role(s), avoiding the overlapping activity HSI-III (Lesic et al., 2009), which is missing from Pme's genome. Likewise, our analysis revealed the presence of a unique entire T6SS in Pen genome, which appears to be phylogenetically close to Pme T6SS-II and P. aeruginosa HSI-II. Since Pen lacks the common secretion systems T3SS and T4SS, the single T6SS locus could have an enforced role in the insect-bacterial interactions, providing thus a promising model for studying its biological function. PMID- 21600308 TI - Detection of rabbit haemorrhagic disease virus (RHDV) in nonspecific vertebrate hosts sympatric to the European wild rabbit (Oryctolagus cuniculus). AB - Since its detection in China in 1984, rabbit haemorrhagic disease (RHD) has been the subject of numerous studies. Yet, the evolutionary origin of rabbit haemorrhagic disease virus (RHDV) is still under debate. For example, some aspects related to the epidemiology of the disease are still unknown, such as where the virus is hosted between RHD outbreaks. To detect the presence of RHDV in rabbit-sympatric micromammals, 51 rodents (29 Mus spretus and 22 Apodemus sylvaticus) and 31 rabbits (Oryctolagus cuniculus) from the same location in central Spain were analyzed. In those samples in which the virus was detected, a fragment of the VP60 protein gene from the RHDV capsid was sequenced and the phylogenetic relationships between them and other strains of RHDV in the Iberian Peninsula were analyzed. In total, five viral strains were identified in A. sylvaticus, M. spretus and O. cuniculus. All strains were found to be well supported within the clade of RHDV found in rabbits in the Iberian Peninsula. Moreover, one of the strains was found in all three species under study, which suggests the capability of RHDV to infect other mammals apart from the rabbit which have not yet been investigated. The transmission of the virus is discussed as well as its ecoepidemiological implications. PMID- 21600309 TI - The essential roles of Toll-like receptor signaling pathways in sterile inflammatory diseases. AB - Toll-like receptors (TLRs) form a family of pattern recognition receptors with at least 11 members in human and 13 in mouse. TLRs recognize a wide variety of putative host-derived agonists that have emerged as key mediators of innate immunity. TLR signaling also plays an important role in the activation of the adaptive immune system by inducing pro-inflammatory cytokines and upregulating costimulatory molecules of antigen presenting cells. Inappropriate activation of TLRs by self-components generated by damaged tissues may result in sterile inflammation. This review discusses the contribution of TLR signaling to the initiation and progression of non-infectious inflammatory processes, such as ischemia and reperfusion (I/R) injury, tissue repair and regeneration and autoimmune diseases. The involvement of TLR signaling in the pathogenesis of sterile inflammation-related diseases may provide novel targets for the development of therapeutics. PMID- 21600310 TI - Coupling pathogen recognition to innate immunity through glycan-dependent mechanisms. AB - Innate immune cells have evolved to sense microbial pathogens through pattern recognition receptors (PRRs), which interact with conserved pathogen-associated molecular patterns (PAMPs) to convey microbial information into immune cell signaling and activation events. PRRs also recognize endogenous damage-associated molecular patterns (DAMPs), including alarmins released during microbial invasion, initiation of autoimmune inflammation or tumor growth. In spite of the well-established role of Toll-like receptors (TLRs) in mediating these recognition events, compelling evidence supports a central function for lectin glycan interactions in promoting microbial sensing and evoking immune responses. Here we discuss the role of glycans and lectins (particularly galectins) in mediating microbial recognition and initiation of innate immune responses. Both microbes and host cells are sources of glycan-containing information which is, at least in part, decoded by endogenous glycan-binding proteins or lectins, including C-type lectins, siglecs and galectins. Although C-type lectins and siglecs can recognize microbial glycans when expressed on the cell surface of innate immune cells, galectins mainly function as soluble mediators that bridge microbial or host glycans to amplify or attenuate immune responses. Galectins are widely expressed in host cells and play important roles during different steps of infection such as pathogen recognition, invasion and resolution. In addition, recent studies report the presence of conserved 'galectin-like' domains in certain pathogens including helminths and protistan parasites, suggesting that they could also serve as potential virulence factors that influence the outcome and course of infection. Understanding the role of lectin-glycan interactions and the relevance of PRR or PAMP glycosylation in microbial recognition might contribute to the design of novel prophylactic and therapeutic strategies. PMID- 21600312 TI - Refractory vasculitis. AB - Refractory vasculitis occurs in 4-5% of patients with anti-neutrophil cytoplasmic antibody associated vasculitis (AAV). Differences between therapies used for refractory disease are mostly reflected in the percentages of complete and partial remissions, but also in the number of serious side effects. Rituximab is considered the most safe second line therapy and should be advocated as a first alternative choice for cyclophosphamide in disease induction in refractory AAV. PMID- 21600311 TI - Toll-like receptors in inflammation of the central nervous system. AB - Toll-like receptors (TLRs) belong to pattern-recognition receptor family that could recognize exogenous pathogen-associated molecular patterns and endogenous damage-associated molecular patterns. TLRs play pivotal roles in innate and adaptive immune responses. In this review we summarize the ligands and signal transduction pathways of TLRs and highlight recent progress of the involvement of TLRs in neuroinflammation related disorders, including cerebral ischemia/stroke, brain trauma and hemorrhage, pathogen infection and autoimmune diseases, and explore the potential of TLR signaling as therapeutic targets against these disorders. PMID- 21600313 TI - Refractory disease in systemic lupus erythematosus. AB - There is no definition or guidelines for refractory disease (RD) in Systemic Lupus Erythematosus (SLE). However, new therapies have been tested mainly in refractory patients. The concept, like the disease, is complex and implies deeper knowledge on the disease pathogenesis and patients' subsets. RD is not included in current activity indices of the disease, what raises the question of how are we monitoring its response to new drugs. In this paper, we analyse some concepts considered important for the global definition of RD in SLE and in some specific organ involvements, excluding lupus nephritis. Management issues will be addressed also. Finally, we review therapeutic options in particular subsets of the disease, namely, cutaneous, articular, haematological and neuropsychiatric lupus. Crucial to the management of a patient suspected to be refractory is an accurate diagnosis, assuring that the persistent clinical manifestations are derived primarily from SLE and not from a concomitant or alternative process. Likewise, certainty about the patient compliance with the therapy prescribed is a frequent unrecognized problem that erroneously might lead to a classification of RD. Therapy of RD for SLE, in general and in most particular involvements, is currently based mainly on the clinician's own experience and judgement, with few randomized trials effectively addressing the issue. In such a heterogeneous disease, consideration of approval of drugs for single-organ indications may pave the way for new therapies. Better biomarkers are needed to add accuracy to the currently used activity indices in order to monitor RD and consolidate its definition. Prospective studies directed to RD in the main SLE involvements are needed to improve our understanding on the management of the disease and foster the development of targeted new drugs. PMID- 21600315 TI - Molecular dynamics simulations of the intramolecular proton transfer and carbanion stabilization in the pyridoxal 5'-phosphate dependent enzymes L-dopa decarboxylase and alanine racemase. AB - Molecular dynamics simulations using a combined quantum mechanical and molecular mechanical (QM/MM) potential have been carried out to investigate the internal proton transfer equilibrium of the external aldimine species in l-dopa decarboxylase, and carbanion stabilization by the enzyme cofactor in the active site of alanine racemase. Solvent effects lower the free energy of the O protonated PLP tautomer both in aqueous solution and in the active site, resulting a free energy difference of about -1 kcal/mol relative to the N protonated Schiff base in the enzyme. The external aldimine provides the dominant contribution to lowering the free energy barrier for the spontaneous decarboxylation of l-dopa in water, by a remarkable 16 kcal/mol, while the enzyme l-dopa decarboxylase further lowers the barrier by 8 kcal/mol. Kinetic isotope effects were also determined using a path integral free energy perturbation theory on the primary (13)C and the secondary (2)H substitutions. In the case of alanine racemase, if the pyridine ring is unprotonated as that in the active site, there is destabilizing contribution to the formation of the alpha-carbanion in the gas phase, although when the pyridine ring is protonated the contribution is stabilizing. In aqueous solution and in alanine racemase, the alpha-carbanion is stabilized both when the pyridine ring is protonated and unprotonated. The computational studies illustrated in this article show that combined QM/MM simulations can help provide a deeper understanding of the mechanisms of PLP dependent enzymes. This article is part of a Special Issue entitled: Pyridoxal Phosphate Enzymology. PMID- 21600314 TI - Sensing pulmonary oxidative stress by lung vagal afferents. AB - Oxidative stress in the bronchopulmonary airways can occur through a variety of inflammatory mechanisms and also following the inhalation of environmental pollutants. Oxidative stress causes cellular dysfunction and thus mammals (including humans) have developed mechanisms for detecting oxidative stress, such that defensive behavior and defensive biological mechanisms can be induced to lessen its potential damage. Vagal sensory nerves innervating the airways play a critical role in the detection of the microenvironment in the airways. Oxidative stress and associated compounds activate unmyelinated bronchopulmonary C-fibers, initiating action potentials in these nerves that conduct centrally to evoke unpleasant sensations (e.g. urge to cough, dyspnea, chest-tightness) and to stimulate/modulate reflexes (e.g. cough, bronchoconstriction, respiratory rate, inspiratory drive). This review will summarize the published evidence regarding the mechanisms by which oxidative stress, reactive oxygen species, environmental pollutants and lipid products of peroxidation activate bronchopulmonary C-fibers. Evidence suggests a key role for transient receptor potential ankyrin 1 (TRPA1), although transient receptor potential vanilloid 1 (TRPV1) and purinergic P2X channels may also play a role. Knowledge of these pathways greatly aids our understanding of the role of oxidative stress in health and disease and represents novel therapeutic targets for diseases of the airways. PMID- 21600316 TI - Dynamics of heme in hemoproteins: proton NMR study of myoglobin reconstituted with iron 3-ethyl-2-methylporphyrin. AB - The asymmetric 3-ethyl-2-methylporphyrin iron complex was synthetized and inserted into apomyoglobin. UV-visible spectroscopic studies demonstrated the capacity of iron to coordinate different exogenous axial ligands in ferrous and ferric forms. The position of synthetic heme into the hydrophobic pocket of the reconstituted myoglobin was investigated by ((1))H NMR spectroscopy. In absence of exogenous ligand, signals of the synthetic prosthetic group were not detected, suggesting a rotational disorder of the synthetic porphyrin into the heme pocket. This direct interconversion behavior is favored since site-specific interactions between the poorly substituted heme and protein in the chiral hydrophobic cavity were weak. Complexion of cyanide to the iron allowed to quench partially the heme reorientation and two interconvertible forms, around the meso-Calpha-Cgamma axis, were detected in solution. PMID- 21600317 TI - Protein dynamics: experimental and computational approaches. PMID- 21600318 TI - Local/bulk determinants of conformational stability of exchangeable apolipoproteins. AB - GuHCl-induced denaturation of human plasma apoA-I, apoA-II, apoA-IV, apoE3 and three recombinant apoE isoforms in solution and discoidal complexes with phosphatidylcholine (only plasma proteins) was studied. The protein conformational stability (DeltaG(H(2)O)) and a slope of linear dependence of free energy of unfolding on GuHCl concentration (m-value) were estimated with the three equilibrium schemes. The data for all proteins, except apoA-II, fit with the three-state model, thus evidencing two-domain structure. The predicted folding rate of the four apoE in solution correlated with conformational stability. The dependence disappeared at the inclusion of apoA-I and apoA-IV into analysis and the m-values, adjusted for residue number in helices (m(rh)), differed between those for apoE and apoA-I/apoA-IV. However, the m(rh)-values for six proteins correlated positively with the fractional change in accessible surface area at unfolding for Phe, Lys and Asn, while negatively for Arg, Ala and Gly residues. The difference between the adjusted DeltaG(rh)(H(2)O) values for apolipoproteins in complexes and in solution decreased at the increase of reduced temperature (T(obs)-T(t))/T(t). The induction of intrinsic disorder by arginine residues may be of primary importance in metabolism and function of exchangeable apolipoproteins, while their stability in nascent discoidal HDL is controlled by the physical state of phosphatidylcholine. PMID- 21600319 TI - Outcome of renal transplantation with and without intra-operative diuretics. AB - AIMS: This paper presents an e-survey of current clinical practice of use of intra-operative diuretics during renal transplantation in the United Kingdom and a study to compare outcome of renal transplants carried out with or without intra operative diuretics in our centre. METHODS: An e-mail questionnaire to renal transplant surgeons exploring their practice of renal transplantation with or without intra-operative diuretics, the type of a diuretic/s if used and the relevant doses. An observational study comparing the outcome of renal transplant recipients, group no-diuretics (GND, n = 80) carried out from 2004 to 2008 versus group diuretics (GD n = 69) renal transplant recipients who received intra operative diuretics over a one year period is presented. Outcome measures were incidence of delayed graft function and a comparison of graft survival in both groups. RESULTS: Forty surgeons answered from 18 transplant centres with a response rate of 67%. 13 surgeons do not use diuretics. Mannitol is used by 10/40, Furosemide 6/40 and 11 surgeons use a combination of both. In comparative study there was no significant overall difference in one year graft survival of GD versus GND (N = 65/69, 94% and 75/80, 94% respectively, p = 0.08) and the incidence of delayed graft function was also comparable (16/69, 23% and 21/80, 26% respectively, p = 0.07). The donor characteristics in both groups were comparable. CONCLUSION: The study showed variation in clinical practice on the use of intra-operative diuretics in renal transplantation and it did not demonstrate that the use of diuretics can improve renal graft survival. PMID- 21600320 TI - A de novo 0.57 Mb microdeletion in chromosome 11q13.1 in a patient with speech problems, autistic traits, dysmorphic features and multiple endocrine neoplasia type 1. AB - We report a 21-year-old patient with speech problems, autistic traits, dysmorphic facial features, broad thumbs with short distal phalanges and a pancreatic gastrinoma. Array-CGH demonstrated a 0.57 Mb de novo deletion in chromosome 11q13.1. The deleted region contains several genes which likely contribute to the patient's complex phenotype, including the MEN1 gene. The deletion of the MEN1 gene is causing multiple endocrine neoplasia type 1 (MEN1). The neurodevelopmental phenotype of the patient might be associated with the deletion of the genes NRXN2 and PPP2R5B which have been described to be involved in synaptogenesis and dendritic branching. According to our knowledge, we report for the first time a patient with the combination of a neurodevelopmental phenotype and MEN1 caused by a microdeletion on chromosome 11. PMID- 21600321 TI - An acetylcholinesterase biosensor for determination of low concentrations of Paraoxon and Dichlorvos. AB - The characterization of an economic and ease-to-use carbon paste acetylcholinesterase (AChE) based biosensor to determine the concentration of pesticides Paraoxon and Dichlorvos is discussed. AChE hydrolyses acetylthiocholine (ATCh) in thiocoline (TC) and acetic acid (AA). When AChE is immobilized into a paste carbon working electrode kept at +410 mV vs. Ag/AgCl electrode, the enzyme reaction rate using acetylthiocholine chloride (ATCl) as substrate is monitored as a current intensity. Because Paraoxon and Dichlorvos inhibit the AChE reaction, the decrease of the current intensity, at fixed ATCl concentration, is a measure of their concentration. Linear calibration curves for Paraoxon and Dichlorvos determination have been obtained. The detection limits resulted to be 0.86 ppb and 4.2 ppb for Paraoxon and Dichlorvos, respectively, while the extension of the linear range was up 23 ppb for the former pesticide and up to 33 ppb for the latter. Because the inhibited enzyme can be reactivated when immediately treated with an oxime, the biosensor reactivation has been studied when 1,1'-trimethylene bis 4-formylpyridinium bromide dioxime (TMB-4) and pyridine 2-aldoxime methiodide (2-PAM) were used. TMB-4 resulted more effective. The comparison with the behavior of similar AChE based biosensors is also presented. PMID- 21600322 TI - Sequential application of electron donors and humic acids for the anaerobic bioremediation of chlorinated aliphatic hydrocarbons. AB - In situ anaerobic bioremediation of chlorinated solvents such as perchloroethene (PCE) frequently faces the problem of accumulating toxic, lower chlorinated compounds such as dichloroethene (cis-DCE) and vinyl chloride (VC). In the present study, the efficacy of the sequential application of electron donors, supporting reductive dechlorination, and of humic acids, acting as extracellular electron shuttles facilitating the anaerobic oxidation of recalcitrant intermediates, was explored in microcosm studies. Upon one initial dose of lactose, supplied in a 1000-fold superstoichiometric electron equivalent ratio, PCE was completely converted into cis-DCE within 35 days. Repeated electron donor additions did not entail exhaustive cis-DCE degradation over incubation time (120 days). Although the electron donor was quickly converted into fatty acids, about 30% of added reducing equivalents were recovered as acetate after four months of operation, indicating the inhibition of acetoclastic methanogenesis. In the next step, the substoichiometric addition of anthraquinone-2,6-disulfonate, a humic acid model compound, effected the complete removal of the accumulated cis-DCE within 15 days, probably as a result of the participation of the quinone in the biotic or abiotic anaerobic oxidation of cis-DCE. Cis-DCE degradation was not connected to the accumulation of VC, rendering the proposed two-step treatment an efficient and environmentally compliant remedy for anaerobic groundwater bodies contaminated with chlorinated solvents. PMID- 21600323 TI - CrossWork: software-assisted identification of cross-linked peptides. AB - The increased interest in chemical cross-linking for probing protein structure and interaction has led to a large increase in literature describing new cross linkers and search programs. However, this has not led to a corresponding increase in the analysis of large and complex proteins. A major obstacle is that the new cross-linkers are either not readily available and/or have a low reactivity. In combination with aging search programs that are slow and have low sensitivity, or new search programs that are described but not released, these efforts do little to advance the field of cross-linking. Here we present a method pipeline for chemical cross-linking, using two standard cross-linkers, BS3 and BS2G, combined with our freely available CrossWork search program. By this approach we generate cross-link data sufficient to derive structural information for large and complex proteins. CrossWork searches batches of tandem mass spectrometric data, and identifies cross-linked and non-cross-linked peptides using a standard PC. We tested CrossWork by searching mass-spectrometric datasets of cross-linked complement factor C3 against small (1 protein) and large (1000 proteins) search spaces, and show that the resulting distance constraints agree with the established structures. We further investigated the structure of the multi-domain ERp72, and combined the individual domains of ERp72 into a single structure. PMID- 21600324 TI - Increased fat mass is associated with increased bone size but reduced volumetric density in pre pubertal children. AB - Recent studies have shown that obesity is associated with an increased risk of fracture in both adults and children. It has been suggested that, despite greater bone size, obese individuals may have reduced true volumetric density; however this is difficult to assess using two dimensional techniques such as DXA. We evaluated the relationship between fat mass, and bone size and density, in a population cohort of children in whom DXA and pQCT measurements had been acquired. We recruited 530 children at 6 years old from the Southampton Women's Survey. The children underwent measurement of bone mass at the whole body, lumbar spine and hip, together with body composition, by DXA (Hologic Discovery, Hologic Inc., Bedford, MA, USA). In addition 132 of these children underwent pQCT measurements at the tibia (Stratec XCT2000, Stratec Biomedical Systems, Birkenfeld, Germany). Significant positive associations were observed between total fat mass and both bone area (BA) and bone mineral content (BMC) at the whole body minus head, lumbar spine and hip sites (all p<0.0001). When true volumetric density was assessed using pQCT data from the tibia, fat mass (adjusted for lean mass) was negatively associated with both trabecular and cortical density (beta=-14.6 mg/mm(3) per sd, p=0.003; beta=-7.7 mg/mm(3) per sd, p=0.02 respectively). These results suggest that fat mass is negatively associated with volumetric bone density at 6 years old, independent of lean mass, despite positive associations with bone size. PMID- 21600325 TI - Effects of intermittent parathyroid hormone treatment on osteoprogenitor cells in postmenopausal women. AB - Intermittent parathyroid hormone (PTH) 1-34 treatment stimulates bone formation, but the molecular mechanisms mediating this effect have not been previously studied in humans. Thus, we used magnetic activated cell sorting to isolate hematopoietic lineage negative (lin-)/alkaline phosphatase positive (AP+) osteoprogenitor cells from bone marrow of 20 postmenopausal women treated with PTH (1-34) for 14 days and 19 control subjects. Serum PINP and CTX increased in PTH-treated subjects (by 97% and 30%, respectively, P<0.001). Bone marrow lin /AP+ cells from PTH-treated subjects showed an increase in the RANKL/OPG mRNA ratio (by 7.5-fold, P=0.011) and in the mRNAs for c-fos (a known PTH-responsive gene, by 42%, P=0.035) and VEGF-C (by 57%, P=0.046). Gene Set Enrichment Analysis (GSEA, testing for changes in pre-specified pathways) demonstrated that PTH had no effect on osteoblast proliferation, apoptosis, or differentiation markers. However, PTH treatment resulted in a significant decrease (GSEA P-value, 0.005) in a panel of BMP target genes in the lin-/AP+ cells. Our findings thus identify several future directions for studying mechanisms of PTH action in humans. First, given the increasing evidence that PTH induces angiogenesis, the role of increased VEGF-C production by bone marrow osteoprogenitor cells in mediating this effect and the anabolic response to PTH warrants further study. Second, while the observed inhibition of BMP target gene expression by PTH is not consistent with the anabolic effects of PTH on bone and requires further validation, these data do generate the hypothesis that an inhibition of BMP signaling by PTH may, over time, limit the availability of mature osteoblasts on bone surfaces and thereby contribute to the observed waning of the anabolic response to PTH. PMID- 21600326 TI - Identification of the first deletion in the LRP5 gene in a patient with autosomal dominant osteopetrosis type I. AB - In the last decade, the low-density lipoprotein receptor-related protein 5 (LRP5) gene, coding for a coreceptor in the canonical Wnt signalling pathway, has been shown to play an important role in regulating bone mass and to be involved in the pathogenesis of several bone disorders. Here we describe a patient who presented with a clinical picture of Autosomal Dominant Osteopetrosis type I (ADO I), in whom we could identify the first deletion in the LRP5 gene causing increased bone mass. This mutation caused the in-frame deletion of two amino acids in the fourth blade of the first propeller of the protein, namely the highly conserved glycine at position 171 and the following glutamate residue. In vitro studies suggested that the pathogenic effect of this novel mutation could be due to a decreased inhibition of Wnt signalling by the antagonistic proteins sclerostin and Dickkopf 1, encoded respectively by the SOST and DKK1 genes, in the presence of mutated LRP5. Our results highlight an increasing molecular heterogeneity in LRP5-related bone diseases. PMID- 21600327 TI - [Information, education, psycho-education for bipolar disorders. Yes, we should]. PMID- 21600328 TI - [Drug compliance and health locus of control in schizophrenia]. AB - Schizophrenia is a frequent disorder since it affects about 1% of the general population. Drug compliance, that is to say patients' adherence to their treatment, remains rather poor concerning this disease with, on an average, one patient out of two not complying with his/her medication. Among the factors influencing drug compliance, we focused on patients' beliefs in terms of health control, a concept known as health locus of control. This is a concept that originated from social psychology and derived from the Rotters' original concept of locus of control: it corresponds to the type of connexion established by an individual between subsequent events in the history of his/her disease and internal (personal abilities) or external factors (chance, powerful others). Nowadays, the tridimensional structure of this concept is commonly admitted as being in three dimensions: internality, chance externality and powerful others externality, the latter group being divided between doctors and others. We have assumed that there is a correlation between the degree of drug compliance and the internal and/or doctors' external health locus of control. For this purpose, we have determined the quality of drug compliance by using the Medical Adherence Rating Scale (MARS) and the type of health locus of control by using the Multidimensional Health Locus of Control (MHLC) scale among 65 schizophrenic patients. We have also considered it was important to evaluate patients' insight by using the Amador's scale (Scale of Unawareness of Mental Disorder) because many researchers have established a strong correlation between insight and drug compliance in schizophrenia. Associations between the four dimensions of health locus of control ("internal", "chance external", "others external" and "doctors' external") and drug compliance were assessed by estimating Spearman's rank correlation coefficient (r) and its degree of significance (p). These associations were judged significant at an alpha threshold of 5%, which corresponded to a level of p inferior to 0.05. Our results tend to confirm a statistically significant positive correlation between internal (r=0.25; p=0.043) and/or doctors' external (r=0.27; p=0.027) health locus of control and drug compliance. Conversely, there is no correlation between chance external or others' external health locus of control and drug compliance (p>0.05). This means that the more patients believe that their schizophrenia can be controlled by themselves and/or by doctors, the more they follow their prescriptions. Furthermore, the link between health locus of control and drug compliance appears to be confused by two dimensions of insight, namely awareness of the response to the treatment and perceived need for treatment. An application of these results is that, in the case of patients whose health locus of control is chance or others' external, it can be beneficial to attempt to change their beliefs in order to improve drug compliance. These results hold particular interest in the field of psycho-education and can be directly applied to cognitive therapy for beliefs among stabilized schizophrenic patients. PMID- 21600329 TI - [Early dropout patients in psychiatric psychosocial rehabilitation treatment and their bindings with relational skills, object relation and intensity of psychopathology]. AB - INTRODUCTION: Between 30 and 60% of patients drop-out of institutional psychiatric treatment. There are few studies on this issue and these have not provided a clear understanding of this fact. Although it is a different therapeutic setting, there are many studies on patients' dropout in psychotherapy: the influence of many patient sociodemographic variables such as gender, age, diagnostic, were studied without providing strong and regular links with early dropout. Other, more relational variables (such as object relation and interpersonal functioning), gave stronger results although insufficiently confirmed by different studies. A third kind of variable involves the concrete relationship between patient and therapist (therapeutic alliance, patient's expectations) and provided interesting results (but not easy to use in institutional treatment). AIM: The aim of this study is to provide data to understand patients' institutional dropout in a French psychiatric centre. The latter's aim is psychosocial rehabilitation for schizophrenic and borderline patients. Thirty percent of these dropout during psychosocial treatment. According to the specificities and aims of this psychiatric centre, we hypothesize that there are strong links between relational dimensions (objet relation, interpersonal functioning), subjective evaluation of pathology intensity, and early dropout. POPULATION: Thirty-one subjects; 65% schizophrenic, 23% borderline, 13% other (according to the ICD10 criteria); 71% females; mean age 34 years (min=23; max=55); mean education level=3.4 (2 years of high school university). INCLUSION CRITERIA: to have dropped out before 6 months' of the treatment, or continuing the treatment after 6 months (mean of treatment for all patients=15 months). EXCLUSION CRITERIA: patients present in the service for less than 6 months). METHODOLOGY: At the beginning of the treatment, each patient (informed consent provided) underwent a psychological assessment with: Echelle d'aptitude psychosociale (EAPS) for assessing interactional functioning; SCL90-R for assessing the intensity of psychopathology; TAT (with Social Cognition and Object Relation Scale [SCORS] scales) and Rorschach (with Mutuality Of Autonomy [MOA] scale) for assessing object relations. After 6 months of treatment, each patient was evaluated with a five-point scale (dropout and continuity scale), which assessed the investment in the treatment (criteria: dropout at 3 or 6 months or continuity; according or not to the centre's professionals; level of assiduity). We have correlated this variable with EAPS, SCORS and MOA. In addition, we have calculated statistical relationships between age, gender, diagnostic, education level and early dropout. RESULTS: Correlation was found neither between interactional functioning (EAPS) and dropout nor between object relations (SCORS and MOA) and dropout. Correlations were found between the dropout and intensity of the psychopathology (SCL90-R): the more the patient sees himself suffering, the more he invests the centre and the less he drops out (Spearman R=0.37, P<0.05). No differences were found between the dropout (N=10) and continuity group (N=21) regarding age, gender and diagnostic. However, a correlation was found regarding the education level: the more patients are educated, the more they continue the treatment (R=0.45; P<0.05). CONCLUSION: The dropout (and the continuity of treatment) seems more likely related to concrete variables such as psychological and relational suffering, educational level in this study, than structural psychological variables such as object relation, relational skills, and diagnostic. Other studies are necessary for a better understanding of these drops out. An interesting way should be the study in institution of the therapeutic alliance. PMID- 21600330 TI - [Assessment of targeted clinical audit in suicide attempt]. AB - BACKGROUND: Suicide attempt is a serious condition that is frequent in France. Picardie ranks fifth in France for suicide (418 deaths in 2005 for 1,890,000 inhabitants). Suicide attempt is one of the priorities of the regional public health program. The National Agency for Accreditation and Evaluation in Health (Anaes) has designed targeted clinical audits (TCA) on various conditions to promote this method as the basic tool for quality improvement. AIM: We investigated the contribution of TCA for improving the quality of care of suicide attempt within a regional framework in Picardie. METHODS: TCA were conducted in 12 state hospitals (eight Surgical Medicine and Obstetrics, three specialized in psychiatry, one local) between 2004 and 2006. The standards from the Anaes had 16 criteria in three fields: care on admission (n=10); assessment of family and social environment (n=2); management for after hospital care (n=4). A project manager and a MD certified in health care quality supported the medical (MD certified in acute care and in psychiatry) and nursing staff of the emergency wards. All the wards analyzed 30 patients' files for the first cycle, set up and implemented improvement actions and then performed the second cycle of data collection. RESULTS: All wards fully satisfied the protocol with 30 patients' files per cycle and two cycles. In all wards the teams consisted of physicians (both certified for emergency or psychiatry) and others care providers (nurses, psychologists, social workers, secretary). For the first cycle, three criteria (patient assessment, somatic examination and coordination) met the 100% target for more than half of the wards while three criteria (sociofamily and environmental evaluation, management for after hospital care, monitoring of follow-up) did not conform by more than 50% in more than half of the wards. All wards implemented changes after the first cycle with a total of 29 interventions, each one specifically devoted to improving a particular criterion. Intervention included better coordination and communication, protocol design and reminders, and information tools. The second cycle showed modest and mixed changes. After the interventions only one criteria reached the 100% target in one ward; the degree of conformity decreased in nine cases (with a mean of -23%) and increased in 16 cases (+19%). Globally, three criteria improved by less than 10% while three slightly decreased. DISCUSSION: G. Shaw introduced clinical audits in 1989 to boost a poorly performing system within the "clinical governance" framework, a condition quite different from the French healthcare system in 2005. Therefore, the validation of clinical audit in a different context appeared necessary. Anaes has not yet published the evaluation of this method in a peer reviewed journal. Observed changes are modest and mixed. Moreover, the true impact on care delivery appears limited and one cannot rule out that the observed improvements are in fact related to an improvement in traceability or due to Hawthorne's effect. Quality improvement methods must be evaluated and validated by scientific methods such as for new treatments with clinical research. CONCLUSION: The feasibility of the method was excellent, due to the methodological and technical support, however the method did not significantly improve the quality of care. PMID- 21600331 TI - [Duration of antidepressant drug treatment and its determinants in France]. AB - INTRODUCTION: Practice guidelines recommend maintaining antidepressant treatment for a long duration (at least six months) after symptomatic improvement. In practice, treatment effectiveness is often jeopardized by non-persistence. METHOD: A retrospective cohort study was conducted on a standard sample representative of the members of the French universal health insurance system database, in order to assess antidepressant treatment duration in a real-life setting. 35,053 outpatients who initiated an antidepressant treatment in 2005 2006 were followed up until 2007. Incident antidepressant treatment was defined as no delivery of antidepressant in the six months prior to treatment initiation. Persistence to treatment was defined as antidepressant treatment duration of six months or more. Multivariate analyses were conducted in order to identify characteristics associated with persistence to treatment. RESULTS: Most antidepressant treatments (n = 28,674; 81.8%) lasted for less than six months and more than half for 28 days at most (n = 20,377; 58.1%). Persistence to treatment was associated with older age (OR 1,13; 95% CI 1.11-1.15), female gender (1.22; 1.15-1.30), chronic disease (1.21; 1.13-1.31), not being on welfare (0.67; 0.60 0.74) and coprescription of anxiolytics (0.36; 0.33-0.38), antipsychotics (0.39; 0.35-0.43) or mood-stabilizers (0.45; 0.39-0.53). Prescribers' specialty was also associated with persistence. Treatments prescribed by general practitioners were less likely to be continued than those prescribed by psychiatrists (1.65; 1.47 1.86). CONCLUSION: Non-persistence to antidepressant treatment is very frequent in France. Intervention programs aimed at increasing persistence should target physicians' training and patients' education. PMID- 21600332 TI - [Patients' perception of seclusion in psychiatry: ethical perspectives]. AB - OBJECTIVE: Although seclusion is legally sanctioned in France, its use remains controversial, and debate continues over ethical and therapeutic aspects of the practice. Seclusion continues to be widely used in the management of disturbed behaviour in hospitalized patients. Although recent studies serve to strengthen the link between the use of seclusion and negative patient responses, they are limited in extending our understanding of the seclusion experience. The objective of this work was two-fold: to examine the perceptions and experiences of patients about their seclusion experience and then suggest ways of improving the use of seclusion in relation to an ethical perspective. METHOD: We conducted face-to face semi-structured interviews with inpatients in a French Public Psychiatric Hospital, 3 weeks after their seclusion. They were conducted until no new ideas emerged in the content analysis, comprising 30 patients. Interviews were conducted using an interview guide by a physician. Specific attention was paid to their perceptions of seclusion. This guide was based on the concepts of medical ethics (autonomy, beneficence, non-malfeasance). Interviews were retranscribed and content analysis was performed by two of the authors who were skilled in textual analysis. Data analysis was performed using SPSS 15.0 software. RESULTS: Autonomy was challenged by 50% of interviewed patients. For 70% of patients, there was a lack of information and explanation during the seclusion on therapeutics, practices, procedures, expected length of time in seclusion and behaviours. This can contribute to perception of this process as punishment expressed by the patients. The dominant view of patients was that more effective communication about seclusion was needed. A majority of patients perceived the beneficence of the health professionals even if most of them did not express a benefit from this experience: only 26% believed that seclusion made them calm down and 36% that seclusion helped them to feel and behave better. The level and the quality of the relationship with staff during and following the seclusion experience was a major source of satisfaction for patients and can counter balance their negative perception of seclusion. The non-malfeasance was questioned by patients. The therapeutic value of seclusion was not recognized by a majority of them. Seclusion from the patient's perspective appears to invoke a complex range of feelings that include helplessness (76%), anger (60%), humiliation (60%), depression (50%), and fear (63%). For 60% of patients, the act of placing them in seclusion had a profound negative impact. Seventy-six percent of them considered that seclusion could be prevented. CONCLUSION: Despite advances in our knowledge and understanding of mental illness, seclusion continues, and is likely to continue, as a treatment option for a number of patients. In our study, a certain number of trends were observed. Globally, there is some tension concerning ethical principles. Attention to the specific needs of patients while in seclusion may serve to reduce the punitive connotations linked to the practice. What is needed is a permanent ethical reevaluation of seclusion. For this purpose, healthcare professional staffs may be useful for a truly ethical reflection. The aim is to recognize the patient as the agent of his/her own empowerment through appropriate information. This approach should not only provide the patient with the opportunity to understand why the seclusion occurred, but also some means for overcoming the negative effects of the procedure. PMID- 21600333 TI - [Time processing in the velo-cardio-facial syndrome (22q11) and its link with the caudate nucleus]. AB - INTRODUCTION: Velocardiofacial syndrome (VCFS) is a neurogenetic disorder caused by a microdeletion on chromosome 22q11. Among other cognitive impairments and learning difficulties, affected individuals show difficulties in estimating time intervals (Debbane et al., 2005). Interestingly, neuroimaging studies have found an increased volume of the basal ganglia of people with VCFS (Eliez et al., 2002; Kates et al., 2004; Campbell et al., 2006). Given that the caudate nucleus represents a central component of the cerebral network underlying temporal perception skills, the present report proposes to examine potential relationships between cerebral alteration to the caudate nucleus and time estimation in individuals with VCFS. METHODS: A group of 30 patients with VCFS and 38 age matched healthy individuals participated in time perception and time reproduction tasks. In the time perception task, individuals listened to two sequential stimuli and had to choose the longer of both stimuli by pressing a button. In the time reproduction task, subjects listened to a succession of sounds and once this succession had stopped they had to reproduce the same rhythm with their dominant index. Cerebral MRI images were also obtained for each participant. A manual tracing procedure was performed to measure the basal ganglia volume. RESULTS: Participants with VCFS demonstrated significantly poorer performances during the time perception and time reproduction tasks in comparison to the control participants. Further, increased volume of the caudate nucleus was found in individuals with VCFS. Correlational analyses revealed a significant relationship between the caudate nucleus's volume and the performances obtained in the time perception task for control participants. This correlation was not found for individuals with VCFS. CONCLUSION: The present results suggest that cerebral alterations to the caudate nucleus in VCFS may alter the temporal perception function it sustains. PMID- 21600334 TI - [Switch antidepressants: when? How? Why?]. AB - BACKGROUND: The switch is generally admitted as one of the available options in the event of non-response to an antidepressant treatment, despite uncertainties about its implementation in current practice: what time window before switching? Is it necessary to proceed with a direct or with a gradual switch? Is it necessary to change for a different pharmacotherapeutic class? How to minimize interaction risks? If a treatment fails because of poor compliance due to intolerance, it is possible to remain within the same therapeutic class and select another treatment with a more favourable safety profile for the patient. In the remaining non-response cases, changing therapeutic class is the more logical course and may be slightly more efficacious than the switch within the same class. LITERATURE FINDINGS: A review of the literature shows that it is recommended to wait 4 to 8 weeks before changing treatment if the response is insufficient. However, an early switch is possible in case of non-response at 2-4 weeks. Direct switch is possible and well tolerated in most instances, except for situations implicating a monoamine oxidase inhibitor (MAOI) or a tricyclic antidepressant. Direct switch is easy and, therefore, compliance issues associated with the complexity of treatment tapering can be avoided. DISCUSSION: From the pharmacologic standpoint, the lack of effect on the cytochrome P450 isoenzymes, the absence of active metabolites, and the poor binding to plasmatic proteins are all important elements to be identified in order to minimize the risk of interaction. Current research on physiopathology of depression and mechanisms of action of drugs both support expectations for new perspectives for patients' care. The switch increases the chances for a treatment to be successful with response rates of 20 to 70% in the open-labelled clinical studies. It also has the advantage of minimizing adverse effects compared to polytherapy. CONCLUSION: A great number of depressed patients require more than one treatment protocol to obtain or maintain a response. Switching is part of the therapeutic pattern of depression and is recommended by the French authorities. The available data allow the specification of switch modalities as function of the evolution of the initial treatment. PMID- 21600335 TI - [Evaluation of prescription practices of long acting injectable risperidone in French hospitals]. AB - INTRODUCTION: Atypical antipsychotics or antipsychotics of second generation are still recommended by guidelines for primary use in the treatment of psychotic disorders because of their better neurologic safety and efficacy. However, they require daily dosing, thus compromising their overall efficacy whereas conventional depot neuroleptics provide constant pharmacologic treatment but induce extrapyramidal adverse effects and poor efficacy on negative symptoms. Long acting injectable risperidone (LAIR) is the first long-acting second generation antipsychotic. Registered in October 2003 and launched in March 2005 in France thanks to Kane et al.'s and Fleischhacker et al.'s reference studies, it was supposed to provide the advantages of conventional long acting formulations of antipsychotics over those of an atypical agent. OBJECTIVES AND METHODS: The aims of this study, with the description of the prescription practices of LAIR in naturalistic conditions, were to assess the place of this new drug in psychotic medication, with the efficiency value measured by treatment discontinuation rate and analysis of the reasons for discontinuation, and to assess whether the prescriptions practices are or not in adequacy with guidelines and reglementation. In June 2005, we conducted a one-year naturalistic non randomised open-label study in nine French psychiatric hospitals, members of the PIC network: were included all the patients who received LAIR every 2 weeks, between July 1st 2005 and November 30th 2005. RESULTS: Prescriptions of 216 patients were examined for 1 year. LAIR was used off label for 15% of the patients. Ninety-two percent of patients were hospitalized at the beginning of the treatment while 72% of the treated patients had dropped out one year after the first injection. Regarding the nature of previous antipsychotic treatments prescribed in the last three months before the first injection of LAIR: 31% patients had received a first generation antipsychotic, half of which had received a depot antipsychotic of first generation and 69% had received a second generation antipsychotic, among which half had received oral risperidone. The principal reason noted by the clinicians for starting the new formulation was non observance with anterior treatments. However, oral antipsychotic treatment preceding the first injection was used less than 4 weeks for one third of the patients. When this treatment was oral risperidone, average posology at the first injection was 6.7 +/- 2.4 mg per day; it was 7.4 +/- 2.1 mg per day for the patients who received the higher dose of LAIR (50 mg/2 weeks). So, it seems that some patients were not sufficiently stabilized by their antipsychotic before the beginning of the long acting treatment. The result was a significant rate of treatment discontinuations (53%) in the following year, principally caused by the withdrawal of the patient's consent and an insufficient response to treatment. CONCLUSION: This investigation provided the opportunity to analyze the prescriptions of a new formulation drug in routine clinical practice. It confirms the need for respecting the authorized indications and the recommendations of good use of a drug to avoid the failures of treatment and also the importance of the role of the pharmacist in recalling it to the physicians. PMID- 21600336 TI - [Specialised first-episode psychosis services: a systematic review of the literature]. AB - INTRODUCTION: Schizophrenia and its related disorders are prevalent, disabling and costly. Recent longitudinal studies found that the first two to five years of schizophrenia-spectrum disorders are characterised by symptomatic and functional deterioration. This led to the hypothesis of the existence of a critical period in the treatment of individuals suffering from psychosis: an assertive intervention during the first two to five years of psychosis could improve long term outcomes and prevent the emergence of psychosocial deficits. OBJECTIVES: The objectives of this review are to describe different specialised first-episode psychosis services (FEP) and report their results at different times of follow-up in order to determine what specific approaches they should include, the optimal duration of treatment, and the characteristics of the patients who benefit the most from such programs. METHOD: We systematically reviewed psycINFO and MEDLINE in search of studies dealing with efficacy or efficiency of specialized FEP programs. We only included research that had at least one comparison group and excluded those dealing with primary prevention of psychosis or prodromal interventions. RESULTS: Five, all Scandinavian, programs and their results at different follow-up times are presented. The Parachute project started in 1994 in Sweden with the objectives to use low dosages of antipsychotics (AP), to minimize hospitalisations, to offer specialized individual and familial psychotherapy, and to assure continuity of care during a five-year period. It compared the Parachute study group with a prospective and a historical group. At three years, the Parachute group had spent less days hospitalised (but more days in a crisis home), was associated with a lower percentage of patients receiving disability allowances and had a trend toward better efficiency than the control groups. The Danish National schizophrenia project started in 1997 and included 16 centers that offered a two-year specialised FEP treatment. Patients were randomly assigned to treatment as usual (TU), treatment as usual enriched with support psychodynamic psychotherapy (SPP) and integrated treatment (IT). At the end of the two-year treatment period, patients receiving IT had significantly less positive symptoms, less negative symptoms and better scores in the global assessment scale (GAS) than TU. The Opus project started in 1998 in Denmark. It is a randomised, controlled study comparing a two-year FEP integrated treatment (IT) with standard treatment (ST). After the two-year period, patients were transferred to ST and were assessed at five years (three years after the end of the IT). At the end of the active phase of treatment, patients in IT group had better positive, negative and GAS scores, used lower dosages of AP and used less illicit drugs. At five-years, the only difference between IT and ST groups was that the IT group was associated with more patients living independently. The Open Dialogue project started in 1994 in Finland. It compared conventional treatment (CT) with acute psychosis integrated treatment (API) and Open dialogue approach in acute psychosis treatment (ODAP). At the two-year assessment, API and ODAP groups had less relapses, spent less days hospitalised, used less AP and had better GAS scores than CT. The ODAP group had better scores on the brief psychiatric rating scale than the API group and was associated with fewer patients receiving disability allowances than the CT group. At five-years, there was no difference in the outcomes between API and ODAP, but the authors suggest that the ODAP group was more efficient, because it had similar results as the API group while using less resources. The Soteria Nacka project started in 1990 in Sweden. It compared patients receiving only outpatient specialised FEP treatment (CE) with those receiving outpatient and crisis home specialised FEP treatment (CC). At the five-year assessment, the CC group had better GAS scores than the CE group, but only for patients suffering from a psychosis in the schizophrenia spectrum. Also, less patients in the CC group used AP and when they did, they had lower dosages. The CC group was also associated with more patients working or studying at the end of the five-year follow-up and with significantly more patients in remission compared to the CE group. Finally, the Opus project, Parachute project and Soteria Nacka found that patients suffering from a psychosis in the schizophrenia-spectrum are those who benefit the most from the specialized, comprehensive, FEP-programs. CONCLUSION: The programs specialised in the treatment of FEP show encouraging results mainly during their active phase. This review suggests that a two-year treatment period is not long enough to enable patients to maintain the improvements obtained during the active phase of an integrated treatment. Future studies should aim to determine--the characteristics of the patients that most benefit from--the specific interventions that should be included in and--the ideal duration of treatment of the comprehensive FEP programs. PMID- 21600337 TI - [Differential indications for psychotherapies in borderline personality disorder]. AB - BACKGROUND: Borderline personality disorder (BPD) accounts for 10% of outpatient psychiatric practice. The risk of suicide attempts is high and the psychosocial impairment significant. Different theoretical streams have suggested psychotherapeutical approaches for BPD. OBJECTIVE: to examine the efficacy of psychotherapy for BPD patients on affective symptoms, behavioural outcomes, interpersonal and social functioning, as well as BPD criteria. METHODS: We reviewed the medical literature from 1990 to 2008 on Medline by combining the following keywords "borderline personality disorder" and "psychotherapy" (inclusion criteria). We restricted the analysis to "randomised control trial" or "meta analysis". RESULTS: Of the 39 abstracts that came out from the search, we selected 17 (44%) after applying the exclusion criteria. According to our review, different types of psychotherapies have shown some efficacy on reducing affective symptoms and BPD criteria, as well as improving behavioural outcomes and psychosocial functioning. Dialectical behavioural therapy presents the best documented efficacy, notably on reducing self-mutilating and suicidal behaviours (five randomized controlled trials [RCT]). Mentalization based treatment seems to be efficient on the four types of outcomes, but has been the object of only one RCT. Finally, some evidence suggests that Manual Assisted Cognitive Treatment and Systems Training for Emotional Predictability and Problem Solving are the most cost-effective and easiest to be implemented. CONCLUSION: According to our review, some evidence supports an efficiency of psychotherapies in the management of several features of BPD. It is likely that, depending on the target symptoms, one type of therapy might be more efficient than another. The acceptability of these long-term treatments is however unknown. PMID- 21600338 TI - [Pharmacological management of anxiety in patients suffering from schizophrenia]. AB - INTRODUCTION: Anxiety is a major and frequent symptom of schizophrenia, which is associated with an increased risk of relapse, impaired functioning, lower quality of life and increased incidence of suicide attempts. Despite its clinical relevance, anxiety in schizophrenia remains poorly understood. In the prodromic phase, anxiety indicates a progression towards psychotic decompensation. After a first episode, it is an indicator of relapse. LITERATURE FINDINGS: Two approaches have been used to investigate anxiety in schizophrenia: (i) categorical approach (comorbidity of schizophrenia and anxiety disorders) and (ii) dimensional approach (anxiety as a major symptom of the "dysphoric" dimension). Clinical categorical studies reported an increased frequency of comorbidity between schizophrenia and obsessive-compulsive disorder, panic disorder, social phobia, post-traumatic stress disorder, generalized anxiety disorder, agoraphobia, and specific phobia. The dimensional approach proposes that five different factors contribute to the structure of the Positive and Negative Syndrome Scale (PANSS), with anxiety as a major symptom of the "dysphoria" dimension. Concerning diagnosis, it is unclear whether psychotic and neurotic anxiety differs in nature or intensity. Nevertheless, both are frequently opposed. DISCUSSION: Psychotic anxiety is intense, profound and hermetic. In contrast to neurotic anxiety, it is associated with psychomotor disturbances, such as agitation and sideration. There is no specific tool to evaluate anxiety in schizophrenia. The dimensional approach usually runs an evaluation using items or factors extracted from the most widely-used scales, i.e. PANSS or Brief Psychiatric Rating Scale (BPRS) or from anxiety scales developed in non-schizophrenic populations, such as the Hamilton Anxiety Scale (HAMA). Recently, we developed a specific scale for hetero evaluation (Echelle Anxiete Schizophrenie [EAS scale]). The EAS scale was recently validated and the study of its sensitivity is ongoing. THERAPEUTICAL ISSUES: Several studies have examined the effects of antipsychotics on the anxious/depressive cluster extracted from the PANSS, and some other studies have specifically evaluated the effect of antipsychotics on depressive symptoms using the Montgomery and Asberg Depression Rating Scale (MADRS) and Calgary Depression Scale for Schizophrenia (CDSS), but to our knowledge, no study has reported the effect of antipsychotics or other treatment on anxiety when using a schizophrenia specific scale. There are no specific guideline treatments for anxiety in schizophrenia. Among phenothiazines, cyamemazine is frequently prescribed in France, because of its potent anxiolytic activity and good neurological tolerance. Some authors have suggested a specific treatment with benzodiazepines. However, benzodiazepines should be used with caution, due to undesirable actions such as dependence, rebound and potentiation of certain lateral effects. PMID- 21600339 TI - [Psychotherapeutic management of mental disorders in Madagascar]. PMID- 21600341 TI - Evaluating sleep and sleep disorders in the pediatric primary care setting. AB - Sleep is a vital physiologic function. Asking parents about their children's sleep should be part of every routine physical examination. Evaluating infants requires an understanding of changes in sleep associated with developmental stage. Problems with sleep associations may begin in late infancy and become a major issue for toddlers. Good sleep is crucial for success in learning for all children. Daytime behaviors in children may be symptoms of nighttime problems. Adolescents are often chronically sleep-deprived. Educating parents and their children about the importance of sleep is an important intervention that over time can help children lead happier, more productive lives. PMID- 21600342 TI - Pediatric insomnia. AB - Bedtime struggles, delayed sleep onset, and problematic night wakings are extremely common in the pediatric population, and have a significant impact on quality of life of both children and caregivers. This article reviews the research and clinical nosology of childhood insomnia, prevalence, and etiologic factors in infants, children, and adolescents. Clinical presentation, evaluation, and treatment, both behavioral and pharmacologic, of the most common types of pediatric insomnia are presented. Insomnia in special populations, particularly children with chronic medical, psychiatric, and neurodevelopmental disorders, is discussed. Future directions in childhood insomnia are presented. PMID- 21600343 TI - Update on pediatric sleep-disordered breathing. AB - Pediatric sleep-disordered breathing (SDB) includes an increasingly recognized, highly prevalent, yet still underdiagnosed spectrum of respiratory disorders, the most common and clinically significant of which is obstructive sleep apnea. SDB is linked with significant end-organ dysfunction across various systems, particularly with cardiovascular, neurocognitive, and metabolic consequences. This review summarizes recent advances in understanding of pediatric SDB and discusses the challenges inherent in diagnosing and treating children with SDB. PMID- 21600344 TI - Restless legs syndrome, periodic leg movements, and periodic limb movement disorder in children. AB - The characteristic symptoms of restless legs syndrome (RLS) have been known for hundreds of years and were first reported in medicine in the 1600s. Clinicians must consider potential mimics, comorbid, and associated conditions when evaluating children with RLS symptoms. The traditional differentiation of RLS from periodic limb movement disorder (PLMD) is noted in children as well as adults. Because current pediatric RLS research is sparse, this article provides the most up-to-date evidence-based as well as consensus opinion-based information on the subject of childhood RLS and PLMD. Prevalence, pathophysiology, diagnosis, treatment, and clinical associations are discussed. PMID- 21600345 TI - Circadian rhythm sleep disorders. AB - This article begins with a review of the major central nervous system functional systems that allow for optimal alertness during the waking day, and the rapid initiation and good maintenance of sleep at night. Subsequent sections discuss each of the 6 primary circadian rhythm sleep disorders. Attention is paid to known or suspected pathophysiology, diagnostic criteria and assessment methodology, and treatment options. The article concludes with a discussion of challenges that must be met to improve the recognition and treatment of these quite impactful sleep disorders. PMID- 21600346 TI - Sleep in adolescents: the perfect storm. AB - A reduction in sleep amount from late childhood through the second decade has long been known; however, the weight of current evidence holds that sleep need does not decline across this span. This article will describe how the loss of sleep through adolescence is not driven by lower need for sleep but arises from a convergence of biologic, psychological, and socio-cultural influences. PMID- 21600347 TI - Cognitive, behavioral, and functional consequences of inadequate sleep in children and adolescents. AB - This article summarizes correlational, case-control, quasi-experimental, and experimental studies that have examined whether sleep during childhood and adolescence is related to daytime functioning. Published findings suggest that inadequate sleep quality and/or quantity can cause sleepiness, inattention and, very likely, other cognitive and behavioral deficits that significantly impact children and adolescents in functional settings. This article then integrates findings from longitudinal studies within a developmental psychopathology model. Important questions remain, but evidence supports the integration of sleep screening and interventions into routine clinical care and also supports advocacy for public policy changes to improve the sleep of children and adolescents. PMID- 21600348 TI - A framework for the assessment and treatment of sleep problems in children with attention-deficit/hyperactivity disorder. AB - Children with attention-deficit/hyperactivity disorder (ADHD) have high rates of sleep problems and sleep disorders. It is critical that pediatricians assess for sleep problems during the course of ADHD assessment and when treating children with stimulant medication. Sleep must be considered in the differential diagnosis and in terms of comorbidity with ADHD. The most common sleep problem in children with ADHD is insomnia, and the first line of treatment should be the implementation of behavioral interventions rather than medication. More research is needed to determine if children with ADHD respond to behavioral interventions in a similar manner as typically developing children. PMID- 21600349 TI - Sleep and autism spectrum disorders. AB - Sleep disorders are common in children with autism spectrum disorders and have a significant effect on daytime function and parental stress. The cornerstone of treatment is to establish the cause of the sleep concern, which is often multifactorial. Identifying and treating sleep disorders may result not only in more consolidated sleep, more rapid time to fall asleep, and avoidance of night waking but also favorably affect daytime behavior and parental stress. Targeting effective treatment strategies is dependent on understanding the underlying causes of sleep problems in children with Autism spectrum disorders, therefore further research is paramount. PMID- 21600352 TI - Sleep health education in pediatric community settings: rationale and practical suggestions for incorporating healthy sleep education into pediatric practice. AB - This article offers practical ways to incorporate healthy sleep education into pediatric practice and discusses key questions, barriers, and strategies associated with such efforts. The rationale for incorporating healthy sleep education in pediatric practice settings is presented, and desirable features of sleep education programs that may be implemented in pediatric practice are identified. Potential barriers are reviewed and strategies offered to overcome these barriers, such as developing resources applicable to healthy sleep education and practical information for pediatricians. Key factors regarding effectiveness of such interventional programs and key points relevant to successful healthy sleep education in pediatric practice are highlighted. PMID- 21600350 TI - Sleep problems in children and adolescents with common medical conditions. AB - Untreated sleep disturbances and sleep disorders pose significant adverse daytime consequences and place children at considerable risk for poor health outcomes. Sleep disturbances occur at a greater frequency in children with acute and chronic medical conditions compared with otherwise healthy peers. Sleep disturbances in medically ill children can be associated with sleep disorders, comorbid with acute and chronic conditions, or secondary to underlying disease related mechanisms, treatment regimens, or hospitalization. Clinical management should include a multidisciplinary approach with particular emphasis on routine, regular sleep assessments and prevention of daytime consequences, and promotion of healthy sleep habits and health outcomes. PMID- 21600351 TI - Sleep and obesity in children and adolescents. AB - The purpose of this review is to provide a comprehensive update of epidemiologic studies that have assessed the association between sleep and obesity risk. Data suggest that short sleep is associated with an increased risk for being or becoming overweight/obese or having increased body fat. Late bedtimes are also a risk factor for overweight/obesity. Findings also suggest that changes in eating pathways may lead to increased body fat. Future experimental studies are needed to enhance our understanding of the underlying mechanisms through which sleep may play a role in the development and maintenance of childhood obesity. PMID- 21600353 TI - Cultural issues in children's sleep: a model for clinical practice. AB - Sleep is a human behavior that is driven by biological mechanisms, but also shaped and interpreted by cultural values and beliefs. The large diversity among societies and cultures may indicate that one "optimal cultural standard" for children's sleep behavior does not exist. In pediatric care, the interplay between children's biological as well as socioemotional needs and the cultural norms should be carefully considered and evaluated in the context of sleep complaints and behavioral functioning. Recognizing the culture in which children and their families live may eventually lead to better compliance and higher success rates of treatment interventions. PMID- 21600355 TI - Using NMR spectroscopic methods to determine enantiomeric purity and assign absolute stereochemistry. PMID- 21600356 TI - MRI contrast agents based on dysprosium or holmium. PMID- 21600354 TI - Sleep in the family. AB - Family systems are dynamic, with reciprocal interactions among family members. When children have sleep problems, they often awaken a parent, affecting parent sleep and subsequent parent daytime functioning. Child sleep patterns can also be disrupted by parent cognitions related to the child's sleep, as well as when parents are experiencing external stressors (eg, work or marital problems). This article focuses on sleep in a family context, reviewing the relationship between sleep among children and their parents from infancy to adolescence. Sleep in the family when a child has a chronic illness or development disorder is also reviewed. PMID- 21600357 TI - Long-lived coherences for line-narrowing in high-field NMR. PMID- 21600358 TI - Monoclonal gammopathy of undetermined significance versus smoldering myeloma: is active surveillance enough? PMID- 21600359 TI - Introduction: Supportive care and palliative medicine. PMID- 21600360 TI - The interface between medical oncology and supportive and palliative cancer care. AB - Traditionally, medical oncology has focused on the active period of diagnosis, treatment and follow-up of cancer patients, and palliative medicine, the pre terminal and end-of-life phases. Palliative medicine physicians have particular expertise in communication and symptom control, especially, for example, with pain management. Medical oncologists also have need of excellent communication skills and knowledge of supportive care issues, such as the management of emesis, bone marrow suppression, mucositis, neuropathy, and symptoms created by treatment. This article examines the interface between medical oncology and supportive and palliative care to emphasize how each can benefit from the others. PMID- 21600361 TI - International perspective: outcomes of palliative oncology. AB - Accompanying the ascendance of cancer as a leading cause of death worldwide is a new set of global health priorities focused on palliative care--the relief of symptoms and suffering, optimization of functional status, and quality of life for those with advanced, potentially life-limiting illnesses. In high-income countries, palliative care improves outcomes for patients, caregivers, provider organizations, and health systems. Data are not yet available to demonstrate similar benefits in low- and middle-income countries, where access to even the most basic palliative interventions (eg, opioids for pain management) is inadequate and unevenly distributed. This article describes current global disparities in the availability of palliative care. We make the case for international prioritization of palliative care as a critical strategy for improving outcomes for people with cancer and their caregivers worldwide. PMID- 21600362 TI - Best supportive care: a euphemism for no care or a standard of good care? AB - This article seeks to address the question: Is best supportive care (BSC) in research a euphemism for no care or a standard of good care? The data regarding the ethical and methodological validity of BSC studies are reviewed. Most of the BSC studies published over the past 25 years are really treatment versus no treatment studies represented as BSC studies. By ignoring the best contemporaneous standards of BSC, standardizing practices in multicenter studies, validating participating centers, or documenting treatment delivery, researchers belie the stated intention of studying BSC. Most studies sought to evaluate if there was any benefit of a new anti-tumor treatment versus discontinuation of anti-tumor therapies. Overwhelmingly, and with few exceptions, the impact of BSC practices was not really part of the key research question. To be ethical and methodologically valid, BSC studies must incorporate standards consistent with contemporaneous, proven BSC practice standards. Work is underway to develop widely validated standards of practice for the control arm of best supportive care studies. These can be readily incorporated in to study development and evaluation. PMID- 21600363 TI - Patient-reported outcomes in supportive care. AB - Traditionally, anticancer therapy has focused on eradication of neoplastic tissue, predominantly by invasive and/or toxic treatments. In modern studies, patient-reported outcomes (PROs) have become more common, and give a true picture of toxicity. Increased consideration of subjective patient perspectives of anticancer treatments has allowed a notable shift within supportive oncology. Disparity exists between physician and patient perspectives of symptom severity, despite several common scoring methods. PROs are vital tools in the overall assessment of chronic illnesses, including cancer and associated treatments. Synergistic assessments of objective and subjective observations of symptoms and function are most accurate. PROs include information collected either in a clinic or by a diary system. Patient self-reporting, like any other assessment of health status, is not an absolute measure. Electronic data collection is an increasingly useful way to monitor PROs. Factors that influence quality of life (QOL) are predominantly subjective experiences, and can occur concurrently with pre existing symptoms, which increases symptom burden. There are several validated systems for assessing PROs; some are concerned with specific conditions like mucositis (Oral Mucositis Weekly Questionnaire [OMDQ]), whereas others cover chronic illness in general (Patient-Reported Outcome Measurement Information System [PROMIS]). The PROMIS framework was developed by the National Health Institute (NHI) to standardize self-reported health measurements within chronic illnesses, including pain, fatigue and emotional distress. The general Assessment of Cancer Therapy (FACT-G) scale was developed to assess many different types of cancer; we will discuss use in oral mucositis as a model. There is more to measuring toxicity than the clinician's objective view of the patient experience. There is still much to be done to validate all the necessary PRO tools so that we can competently measure both toxicity and toxicity-reduction strategies. Current systems to assess PROs continue to have a very positive impact on supportive oncology. PMID- 21600364 TI - Geriatric oncology and palliative medicine. AB - People age 65 years and older are the fastest growing segment of the US population. Cancer is one of the leading causes of death in the elderly. Geriatric oncology has developed since most cancer cases are diagnosed in elderly patients and the majority of cancer deaths occur in elderly patients. Little is known on how to best treat elderly patients with cancer and deal with treatment side effects and palliative care. Most recommendations have focused on the need for clinical trials specifically for the elderly with cancer, and a short, easy tool to predict chemotherapy toxicity. The focus of geriatric oncologists has been to integrate geriatric assessment into the care of the elderly cancer patient and find new assessment tools to predict chemotherapy tolerance, toxicity, and outcomes. Understanding the importance of supportive management during antineoplastic treatment and developing an intentional approach to palliative care issues (which are an important part of treating elderly patients with cancer) will help patients complete a full treatment course and maintain quality of life. PMID- 21600365 TI - Supportive care treatment guidelines: value, limitations, and opportunities. AB - Evidence-based guidelines in clinical oncology practice are now prominent, with emphasis on clinical, health outcome and economic perspectives. Given the complexity of cancer management, a multidisciplinary approach is essential. Evidence-based guidelines to address supportive cancer care have merged expert opinion, systematic evaluation of clinical and research data, and meta-analyses of clinical trials. Production of supportive care guidelines by the interdisciplinary team is dependent on sufficient high-quality research studies. Once published, it is essential they be customized at institutional and national levels. Implementation in clinical practice is perhaps the greatest challenge. Optimal management occurs through integration of country-specific issues, including care access, healthcare resources, information technology, and national coordination of healthcare practices. The purpose of this article is to: (1) provide an overview of interdisciplinary cancer management using evidence-based guidelines; (2) delineate the theory and practice of guideline dissemination, utilization and outcome assessment; and (3) recommend future research strategies to maximize guidelines use in clinical practice. PMID- 21600366 TI - Supportive care for children with cancer. AB - In developed countries the survival rate of children with cancer exceeds 75%. Optimal supportive care is necessary to deliver the burdensome treatment protocols. As the intensity of primary treatment has escalated, so have the side effects like myelosuppression and infection. Children who receive aggressive chemotherapy have an approximately 40% chance of experiencing a febrile episode during neutropenia. Patients should be treated with intravenous broad-spectrum antibiotics even if they have been assessed as low risk. There is no proof of the usefulness of special measures concerning food products during neutropenia. In contrast to adults, most children who receive chemotherapy will have a central venous catheter inserted (>= 80-90%). The two most important complications are infections and thrombosis. The Multinational Association of Supportive Care in Cancer (MASCC) guideline in adult oncology is available to prevent and treat nausea and vomiting. In highly emetogenic chemotherapy, the combination of a serotonin receptor antagonist plus a corticosteroid should be used. Pain in children with cancer is mainly therapy- or procedure-related. As in adults, the stepladder of the World Health Organization (WHO) is used as a guideline for adequate treatment of pain. It is of utmost importance that children receive optimal pain management during the initial procedures. Sedation is performed in many different ways. Palliative care starts with information about the incurability of the disease for parents, the patient, and the professionals involved. Children in palliative care for progressive cancer should be at home as much as possible, even in the terminal phase. The organization of health care and the facilities differ at a national level, so the requirements and choices for optimal care vary by country. Palliative care has to be incorporated into the structural base in the training of pediatricians and pediatric nurses. The first goal of palliative care is to reduce distressing symptoms. During the whole period of palliative care stepwise withdrawal and withholding of treatment options are important issues. The multidisciplinary approach should also span the broad field of psychosocial issues covering both the child's and the caregiver's specific psychosocial needs. Continuity of care is also depicted by contacts afterwards during family bereavement. PMID- 21600367 TI - Thinking and talking about life expectancy in incurable cancer. AB - Most patients with incurable cancer want information about the impact cancer will have on their future, and many want specific estimates of the most likely, best case, and worst case scenarios for survival. With improved understanding of life expectancy, patients are better equipped to make appropriate treatment decisions and plans for the future. Although physicians acknowledge that patients with incurable cancer want prognostic information and benefit from this, most struggle to provide it and experience difficulty in making reliable estimates, communicating them, and tailoring the information to the individual patient. In this review we address some of the implications that arise from thinking and talking about life expectancy with people who have incurable cancer, particularly those considering first- or second-line chemotherapy. PMID- 21600368 TI - Cancer rehabilitation. AB - Cancer rehabilitation is the subspecialty of rehabilitation medicine concerned with restoring and maintaining the highest possible level of function, independence, and quality of life to patients at all stages of their cancer diagnosis, including those undergoing potentially curative therapy and those receiving palliative care, as well as cancer survivors. Cancer rehabilitation physicians specialize in the evaluation and treatment of neuromuscular, musculoskeletal, and functional complications of cancer and cancer treatments such as acute and chronic pain, weakness, muscle spasm, myelopathy, radiculopathy, plexopathy, neuropathy, myopathy, deconditioning, contracture, spasticity, lymphedema, amputation, shoulder dysfunction, and gait disorders, among others. Late effects of radiation represents a particular challenge for cancer rehabilitation physicians as radiation fibrosis may affect multiple structures, including the spinal cord, nerve roots, plexus, local nerves, and muscles, as well as their supporting structures. A comprehensive clinical evaluation involving an in-depth working knowledge of neuromuscular and musculoskeletal anatomy and incorporating specialized physical examination maneuvers allows the physiatrist to clarify the specific etiology of pain and functional disorders. A safe and effective rehabilitation program will depend heavily on an accurate diagnosis of the cause of pain or dysfunction. PMID- 21600369 TI - Nonpharmacologic complementary therapies in symptom management for breast cancer survivors. AB - The request and use of nonpharmacologic interventions and complementary and alternative medicine (CAM) in cancer survivors is increasing. Given the large number of breast cancer survivors and the multiple treatment-related symptoms they endure, it is important for physicians to be aware of the evidence supporting nonpharmacologic therapies. Several studies evaluating such interventions have demonstrated improved overall quality of life (QOL). For other symptoms, the literature is limited but growing. We summarize the evidence to support complementary and alternative therapies for the major symptoms in breast cancer survivors. PMID- 21600370 TI - The role of music therapy in palliative medicine and supportive care. AB - This paper is designed to provide an introduction to music therapy in the continuum of cancer care. The value and use of music therapy during diagnosis and treatment, palliation, hospice, actively dying, and bereavement have been well documented. The music therapy process will be identified, research will be shared, and the importance and role of music therapy in palliative medicine and supportive cancer care discussed. Music therapy is invaluable throughout the entire cancer treatment process. PMID- 21600371 TI - The family conference in oncology: benefits for the patient, family, and physician. AB - The family conference (FC) is a forum for communication with both the patient and family to discuss essential information about medical, educational, and psychosocial needs. It ensures appropriate decision-making, which is integral to comprehensive cancer care. Inclusion of the family creates opportunities and challenges. The main opportunities are for the family to share support for the patient and collaborate with the medical team. This can ease adaptation throughout the illness course with better adherence to recommended treatment plans and greater satisfaction with medical care. The challenge is to manage communication to evolve understanding when treatment outcomes are not curative, and to meet the medical information and psychosocial needs of the patient and family. The FC aim is to give the family confidence by: (1) providing a calm discussion and understanding the illness and treatment; (2) offering a sense of safety that patient's goals will be balanced by the impact on the family caregivers; (3) affording the opportunity to connect and sustain each other; (4) sharing hope and mutual empathy; and (5) maintaining self-efficacy to manage their needs. Using the FC to discuss the plan of care and at the same time assisting the family to process the impact of the illness optimizes benefit for the patient, family, and physician. PMID- 21600372 TI - Essential drugs in supportive care. AB - Progress in cancer treatment has brought with it challenges that go beyond cure. Toxicities and morbidity are among the biggest hurdles for a cancer patient to face while hoping for the end of chemotherapy or radiation therapy. Important advances have been made in the science of supportive care to address cancer treatment toxicities and complications. Nausea and vomiting, bone complications, hot flashes, and bone marrow failure are some areas where a huge impact has been made on quality of life and treatment experience. Complications that remain without good remedies await a better understanding of new targets and drugs. PMID- 21600373 TI - Management of the cancer patient with infection and neutropenia. AB - Infections are major causes of morbidity and mortality in cancer. The intensity and duration of immunosuppressive chemotherapy determine the risk. Cancer may be associated with immune defects, in particular hematologic malignancies. Predisposing factors include tumor site, intravenous devices, neutropenia due to underlying disease, mucosal lesions, corticosteroids, monoclonal antibodies, splenic dysfunction, and treatment with chemotherapy or radiation therapy. Bacteremia is documented in approximately 25% of people with febrile neutropenia. The drug choice for empiric therapy is influenced by factors related either to the patient or to the institution. Guidelines and general statements should always take local epidemiology into consideration. The therapeutic hematopoietic growth factors should be reserved for patients with fever and neutropenia and those at high risk for infection-associated complications or poor clinical outcomes. The Multinational Association of Supportive Care in Cancer (MASCC) has developed a Risk Index that predicts the risk of medical complications and outcome. PMID- 21600375 TI - Parenteral nutrition in patients with advanced cancer: merging perspectives from the patient and healthcare provider. AB - The decision to utilize parenteral nutrition in patients with advanced cancer is difficult. There are variable opinions in the literature. Those who routinely care for cancer patients often confront the challenges of discussing these interventions with patients and their families. We review results from previous randomized controlled trials, published guidelines, and recent work that describes the emotional challenges patients and families face as they make such decisions with their healthcare providers. PMID- 21600374 TI - An update on cancer- and chemotherapy-related cognitive dysfunction: current status. AB - The purpose of this review is to summarize the current literature on the effects of cancer treatment-related cognitive difficulties, with a focus on the effects of chemotherapy. Numerous patients have cognitive difficulties during and after cancer treatments and, for some, these effects last years after treatment. We do not yet fully understand which factors increase susceptibility to cognitive difficulties during treatment and which cause persistent problems. We review possible contributors, including genetic and biological factors. Mostly we focus is on cognitive effects of adjuvant chemotherapy for breast cancer; however, cognitive effects of chemotherapy on the elderly and brain tumor patients are also discussed. PMID- 21600376 TI - Palliative radiotherapy--new approaches. AB - Most cancer patients will require radiation therapy some time during their disease. Thirty percent to 50% of all radiation treatments are palliative, either to alleviate symptoms or prophylactic to prevent deterioration of quality of life from local progressive disease. Radiotherapy is a locally effective tool. It typically causes no systemic and mostly mild acute side effects. We will provide an overview of principles, decision-making, and new developments in palliative radiation therapy. PMID- 21600377 TI - Pharmacologic management of cancer-related pain, dyspnea, and nausea. AB - Patients with cancer often face significant distress from their symptoms, especially near the end of life. However, prompt palliation of these symptoms can be complex since symptoms may occur in clusters, may be cancer- or treatment related, and frequently require a multidisciplinary approach to management and a combination of therapeutic regimens. While evidence for many conventional symptom treatments is lacking, an increasing number of randomized clinical trials in palliative oncology means that new treatments will become increasingly evidence based. Herein, we provide a brief overview and update of current and new strategies for the pharmacologic management of cancer-related pain, dyspnea, and nausea, which are three of the most prevalent treatable symptoms in advanced cancer. PMID- 21600378 TI - Methodological challenges in supportive and palliative care cancer research. AB - As a growing medical field, palliative and supportive care should incorporate evidence-based medical practice. The gold standard research method continues to be the randomized clinical trial. This has been pursued with regard to cancer trials focused on cure. It has specific operational and methodological challenges in advanced disease. There are numerous reasons why effective research in palliative and supportive care is difficult. A consensus on the best research strategies and design is lacking. We will discuss the principles of palliative and supportive care research, examine the inherent challenges particularly in randomized controlled trials, and offer some suggestions to overcome them. PMID- 21600379 TI - Introduction: Current and future approaches to chemotherapy in patients with resistant breast cancer. PMID- 21600380 TI - Other options in the treatment of advanced breast cancer. AB - Many cytotoxic therapies are available for patients with metastatic breast cancer, but response rates are low and acquired or de novo resistance is virtually universal. Among the agents that are used in the treatment of pretreated metastatic breast cancer are vinorelbine, gemcitabine, nab-paclitaxel, pemetrexed, platinum salts (eg, cisplatin, carboplatin), pegylated liposomal doxorubicin, etoposide, and irinotecan. Therapies that improve overall survival in patients with anthracycline- and taxane-resistant metastatic breast cancer are needed. PMID- 21600381 TI - Novel agents and future directions for refractory breast cancer. AB - Tumor resistance remains a major clinical challenge. Numerous pathways are under investigation to determine how best to target therapies to specific mutations in tumor biology and circumvent resistance. Agents in development include inhibitors of the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) pathway, such as iniparib, olaparib, and veliparib; the PI3K/Akt/mTOR pathway inhibitor everolimus; and the Src family tyrosine kinase inhibitor dasatinib. Research is ongoing to determine whether patients with specific biochemical attributes, such as the presence of a BRCA1 or BRCA2 mutation, will have a better response to targeted therapy and whether targeted agents act synergistically with chemotherapeutic agents. PMID- 21600382 TI - Approved agents for metastatic breast cancer. AB - The US Food and Drug Administration has approved three agents for treatment of patients with metastatic breast cancer refractory to anthracyclines and taxanes: capecitabine, ixabepilone, and eribulin mesylate. There is no fixed algorithm of therapeutic choices. Median survival remains measured in months, not years. Individual patient performance status, toxicity (to past regimens and any residual toxicity), preferences, and quality of life are factors in determining optimal treatment options for metastatic breast cancer. Ongoing research is seeking to improve outcomes in this patient population. PMID- 21600383 TI - A network meta-analysis of randomized controlled trials of induction treatments in acute myeloid leukemia in the elderly. AB - BACKGROUND: The optimal induction treatment of acute myeloid leukemia (AML) in the clinically and biologically heterogeneous group of elderly patients is not well-defined since direct comparisons between treatments is limited. OBJECTIVE: The aim of this study was to estimate the relative effectiveness of induction treatments in AML elderly patients. METHODS: A network of multiple treatments meta-analysis was performed by combining direct and indirect evidence from published randomized controlled trials (RCTs). The complete remission (CR) was considered as the outcome of interest. We systematically searched PubMed, EMBASE, and Cochrane Library until September 30, 2010, to identify all RCTs published in English that compared diverse induction chemotherapies in elderly AML patients. Our search strategy focused on RCTs that included AML patients >60 years, considering, however, that age stratification was varied between countries and over time and studies were not necessarily designed to compare elderly patients. Regimens were grouped a priori into 42 different types of induction treatment. Prognostic parameters (age, performance status, unfavorable cytogenetics, antecedent malignancy), AML outcomes (median disease-free, overall survival, CR, induction deaths), and myelotoxicity parameters (median duration until neutrophil recovery [>1.0 * 10(9)/L], platelet recovery [>100 * 10(9)/L], hospitalization duration) were evaluated for each induction type. In combining direct and indirect evidence, we calculated the odds ratio (OR) for each therapy relative to the most commonly used combination of standard-dose daunorubicin (30-60 mg/m(2) for 3 days) and standard-dose cytarabine (100 mg/m(2) for 7-10 days) that was set as the reference induction treatment. RESULTS: We identified 65 RCTs (15,110 patients) that described 64 direct comparisons of induction treatments, but only 14 of them showed significant differences in CR after random effects meta analyses. Median age of included patients was 68, 18.0% had secondary AML, 21.1 % had poor performance status, 26.7% displayed unfavorable cytogenetics, and 49.3% finally achieved CR. No significant differences were observed in the recorded induction toxicity parameters among the treatment arms. Through the network meta analysis, the addition of all-trans retinoic acids or lomustine to the combination of idarubicin plus cytarabine showed significantly higher CR rate (OR = 1.93 [1.06-3.49] and 1.76 [1.08-2.88], respectively), whereas no treatment, clofarabine, daunorubicin plus topotecan, and the 2 different schedules of gemtuzumab ozogamicin (at 1, 3, and 5 days and at 1 and 8 days) showed a significantly lower CR rate (OR = 0.01 [0.001-0.19], 0.15 [0.04-0.58], 0.03 [0.002-0.64], 0.06 [0.01-0.51], and 0.05 [0.01-0.32], respectively) than that of the reference induction. Median overall survival showed no difference between treatments (P = 0.150) but was significantly increased during the last 30 years (P < 0.001), presumably reflecting advances in AML management. CONCLUSIONS: Compared with the reference induction, significant differences were found for specific induction regimens, although most compared regimens appeared to have similar efficacy profiles. These results, however, should be interpreted with caution because the network was dominated by indirect comparisons. Data from large RCTs that make direct comparisons between treatments are needed to detect the optimal induction regimen for elderly AML patients. PMID- 21600384 TI - Cost-effectiveness of zoledronic acid in the management of skeletal metastases in patients with lung cancer in France, Germany, Portugal, the Netherlands, and the United kingdom. AB - BACKGROUND: Zoledronic acid (ZOL) significantly reduces the risk of new skeletal related events (SREs) in patients with non-small cell lung cancer (NSCLC) who have bone metastases. OBJECTIVE: The purpose of this study was to assess the cost and cost-effectiveness of ZOL in the management of skeletal metastases in this population across 5 European countries (France, Germany, United Kingdom, Portugal, and the Netherlands) from the perspective of national health care. METHODS: This cost-effectiveness analysis was based on a subset of patients with NSCLC who were enrolled in a Phase III trial of patients with bone metastases secondary to a variety of solid tumors. In this trial, patients were randomized to receive ZOL or placebo every 3 weeks for up to 21 months. Survival, SRE incidence, and number of infusions administered were derived from the clinical trial. Costs of SREs were estimated using hospital Diagnosis Related Group tariffs and published data. Drug, drug administration, and supply costs were obtained from published and internet sources. Quality-adjusted life-years (QALYs) were estimated based on the published utilities and modeled survival and frequency of SREs. Uncertainty surrounding outcomes was addressed via univariate and probabilistic sensitivity analyses. RESULTS: Compared with patients receiving placebo (n = 120), patients receiving ZOL (n = 124) experienced an estimated 0.79 fewer SREs and gained an estimated 0.02 QALYs. ZOL use in patients with NSCLC and bone metastases was associated with a reduction in SRE costs (ranging from ?1547 to ?1893 [2007-2008 ?], depending on the country). After adding drug and drug administration costs, ZOL use resulted in a net savings of ?288 per patient in Germany, ?209 in the United Kingdom, and ?113 in Portugal. In France and the Netherlands, costs increased (?17 and ?178, respectively), but the costs per QALY gained were low (?786 and ?8278, respectively). In univariate sensitivity analyses, the cost per QALY for ZOL versus placebo was <=?50,000 for all scenarios tested. The results were most sensitive to assumptions regarding survival, number of ZOL infusions, and the costs of SREs. The probabilistic sensitivity analysis indicated that ZOL cost <=?50,000 per QALY in 65% to 83% of model simulations (depending on country). However, some degree of uncertainty remained as the 95th percentile of cost per QALY was high. CONCLUSIONS: This analysis is subject to the usual limitations of cost-effectiveness models, which combine assumptions and data from multiple sources. Nevertheless, based on the assumptions used herein, the present model suggests that ZOL increases QALYs and is cost saving and/or cost effective compared with placebo in patients with NSCLC in France, Germany, the United Kingdom, Portugal, and the Netherlands. PMID- 21600385 TI - Pharmacokinetics and tolerability of vandetanib in Chinese patients with solid, malignant tumors: an open-label, phase I, rising multiple-dose study. AB - BACKGROUND: Vandetanib (ZD6474) is an orally available inhibitor of 3 signaling pathways important in tumor progression: vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinase activity. Current development of vandetanib is focused on the treatment of non-small-cell lung cancer and other tumor types, including thyroid cancer. This study was conducted as a requirement for regulatory submission for vandetanib in China. OBJECTIVE: To determine the pharmacokinetics of vandetanib in Chinese patients with advanced, solid, malignant tumors and to compare these with data obtained in Japanese and Western populations. METHODS: Phase I consisted of a nonrandomized, open-label, single-center study conducted in Guangzhou, China. Adult patients (12 per treatment) who had tumors refractory to standard treatments or for whom no appropriate therapies existed received oral vandetanib (100 mg every other day, 100 mg once daily, or 300 mg once daily) until disease progression or discontinuation in the study. The initial cohort was dosed at 100 mg every other day. Once at least 3 patients had received this dose of vandetanib for 28 days without experiencing dose-limiting toxicity, a second cohort at 100 mg once daily was started. Following the same criteria, the third cohort received 300 mg once daily. Pharmacokinetics, tolerability, and tumor response were assessed. The pharmacokinetics of vandetanib in Chinese, Western, and Japanese patients were compared through a combined population pharmacokinetic model. Tolerability was assessed by recording adverse events and monitoring physical examination, body weight, performance status, vital signs, urinalysis, biochemistry, hematology, and 12-lead electrocardiogram. RESULTS: Thirty-six patients were enrolled (age range 21-82 years, 56% male, body mass index range 17.6-33.0 kg/m(2)). Thirty-three of 36 patients (92%) were World Health Organization performance status 0-1. Vandetanib pharmacokinetics were linear over the dose range studied with AUC(ss) for the 300 mg once daily group (38611 ng/h/mL) being 3.6-fold higher than that for the 100 mg once daily group (10826 ng/h/mL). Absorption was relatively slow following a single 100- or 300-mg dose, with T(max) ranging from 2 to 10 hours. Interpatient variability in C(max SS) and AUC(SS) was relatively high, with the coefficient of variation ranging from 29.1% to 40.6%. Vandetanib plasma clearance was slow (7.8-9.2 L/h) and was independent of dose. The most common drug-related adverse events were rash (42%) and diarrhea (39%). No QT(C) prolongation was observed. Hypertension was reported as an adverse event in 3 patients. There were no clinically relevant changes in hematology, urinalysis, or World Health Organization performance status. Elevation of alanine aminotransferase was reported as an adverse event in 1 patient. One patient with medullary thyroid cancer showed a partial tumor response. Population pharmacokinetic analysis suggests that vandetanib pharmacokinetics appear to be comparable in Chinese, Western, and Japanese patients. CONCLUSIONS: The pharmacokinetic properties of vandetanib in these Chinese patients were characterized by low plasma clearance of approximately 8 L/h, a long half-life of approximately 8 to 10 days, and an accumulation of approximately 8-fold to 15-fold on multiple dosing. In these Chinese patients, the pharmacokinetic profile of vandetanib appeared to be comparable with that observed in Japanese and Western populations. Oral doses up to 300 mg once daily appeared to be well tolerated. PMID- 21600386 TI - Iloperidone for the management of adults with schizophrenia. AB - BACKGROUND: Iloperidone is a second-generation antipsychotic drug approved in May 2009 by the US Food and Drug Administration (FDA) for the acute treatment of schizophrenia in adults. It is a piperidinyl-benzisoxazole derivative with mixed serotonin (5HT2A) and D2 dopamine antagonist properties. OBJECTIVE: The purpose of this article was to review the pharmacology, pharmacokinetics, efficacy, safety, and role in treatment for iloperidone in schizophrenia. METHODS: Scientific and clinical data were collected through searches of PubMed, ClinicalTrials.gov, International Pharmaceutical Abstracts, and the FDA, using the search term iloperidone, and limited to English-language articles. Reference lists were reviewed for additional publications. Dates included the beginning of the database through 2010. No limits were placed on study design. RESULTS: In a 4 week Phase III trial, iloperidone 12 mg twice daily lowered the Positive and Negative Syndrome Scale (PANSS) total scores to a significantly greater extent than did placebo (-12 vs -7.1; P < 0.01). The ziprasidone active control also separated from placebo (-12.3 vs -7.1; P < 0.05). A pooled analysis of 3 Phase III trials compared iloperidone in divided doses to placebo. The primary outcome was reduction in PANSS scores. Study 1 included iloperidone 4, 8, or 12 mg/d, haloperidol as an active control, and placebo. The PANSS reduction in the 12 mg/d group was significantly greater at end point versus baseline when compared with placebo (-9.9 vs -4.6; P = 0.047). Study 2 included iloperidone 4 to 8 mg/d or 10 to 16 mg/d, risperidone 4 to 8 mg/d, or placebo. The primary efficacy measure was change from baseline to end point in the Brief Psychiatric Rating Scale (BPRS). Improvement from baseline on all iloperidone doses was significantly greater than with placebo (4-8 mg/d group: -6.2, P = 0.012; 10-16 mg/d group: -7.2, P = 0.001; placebo, -2.5). Study 3 included iloperidone 12 to 16 mg/d, risperidone 6 to 8 mg/d, and placebo. The results on the primary efficacy variable, reduction in the BPRS score, was not significant for the 12 to 16 mg/d group versus placebo (-7.1 vs -5.0; P = 0.09), but was significant for the 20 to 24 mg/d iloperidone group ( 8.6 vs -5.0; P = 0.01) and for the risperidone group (-11.5 vs 5.0; P < 0.001). A 52-week maintenance trial included iloperidone versus haloperidol as an active control. The primary efficacy variable was time to relapse. Comparison of mean time to relapse of the 2 arms showed no significant difference. The most common adverse events (AEs) associated with iloperidone were dizziness (5.1%-23.2%), dry mouth (5.2%-10.4%), somnolence (4%-13%), and dyspepsia (4.8%-7.8%). AEs appeared dose related. Prescribing information recommends a starting dosage of 1 mg twice daily and then titrated over 7 days to reach a target dosage of 12 to 24 mg/d. The titration is necessary to reduce the risk of orthostatic hypotension-related dizziness. CONCLUSIONS: Data support that when titrated slowly to a therapeutic dosage, iloperidone is generally well tolerated, has a favorable safety profile, and is an effective treatment option in patients with schizophrenia. Its place in therapy and performance in a typical patient population remain to be established. Slow initial titration and twice-daily dosing are potential disadvantages. PMID- 21600387 TI - Comparison of preference for NovoPen((r)) 4 with previous insulin pen treatments after 12 weeks in adult patients with type 1 and type 2 diabetes: a multicenter observational study. AB - BACKGROUND: In separate randomized, crossover trials, patients with diabetes reported a preference for durable insulin pen NovoPen((r)) 4 compared with NovoPen 3 and OptiClik((r)). OBJECTIVE: This large post-marketing observational study evaluated treatment satisfaction with NovoPen 4 versus previous treatments, which included NovoPen 3 and other devices, in insulin-treated and insulin-naive patients. METHODS: During regular clinical practice in Canada, Germany, and the Netherlands, health care professionals assigned adult patients with type 1 or type 2 diabetes to treatment with insulin administered via NovoPen 4 after training according to the device's instruction manual. The primary end point was change in treatment satisfaction as determined by the Diabetes Treatment Satisfaction Questionnaire given to patients at the beginning and after 12 weeks of treatment. Two additional questionnaires were used at study end to identify why patients preferred either NovoPen 4 or their previously used insulin devices, which included NovoPen 3 and other devices (eg, HumaPen((r)) Ergo and OptiPen((r)) Pro). Adverse events were also recorded. RESULTS: Two thousand eighteen participants (mean age, 55 years; males, 53%; type 1/type 2 diabetes, 28%/71%; mean duration of disease, 13 years; previously on insulin, 89.8%; insulin-naive, 2.9%) participated. NovoPen 3 was previously used by 1059, HumaPen Ergo by 256, OptiPen Pro by 217, and other devices by 385 patients. Diabetes Treatment Satisfaction Questionnaire scores increased from a mean (SD) baseline of 26.5 (7.2) to 30.5 (5.0) at study end for a median difference of 4.0 (95% CI, 3.5-4.5; Wilcoxon test score: 22.7; P < 0.0001). Over 70% of patients found NovoPen 4 easier to set, read, correct, inject the dose, and change the insulin cartridge than with their previously used device (P < 0.0001). A total of 83.8% rated NovoPen 4 easier to use overall (P < 0.0001). Health care professionals (97.2%) would recommend NovoPen 4 to other patients. No adverse events associated with the device were recorded. CONCLUSIONS: Patients reported a significant preference for NovoPen 4 compared with previous treatment with NovoPen 3 or other insulin device. The high ratings NovoPen 4 received for ease of use and learning could potentially lead to improved acceptance of and compliance with prescribed insulin therapy. Further study is warranted to determine the possible health benefits of using this insulin device. PMID- 21600388 TI - Comparing the efficacy and tolerability of a new daily oral vitamin B12 formulation and intermittent intramuscular vitamin B12 in normalizing low cobalamin levels: a randomized, open-label, parallel-group study. AB - BACKGROUND: Vitamin B(12) deficiency is routinely treated with parenteral dosing and less often with high-dose oral vitamin B(12). Oral vitamin B(12) formulations have low bioavailability in patients with malabsorption and are considered less reliable than parenteral treatments. OBJECTIVE: The objective of this study was to compare the efficacy and safety profile of a new proprietary oral vitamin B(12) formulation (oral B(12)) with intramuscular (IM) vitamin B(12) (IM B(12)) in restoring normal serum B(12) concentrations in patients with low cobalamin levels (<350 pg/mL). METHODS: Patients were recruited from 5 centers and randomly assigned to receive oral B(12) 1000 MUg, taken daily for 90 days, or IM B(12) 1000 MUg, given on study days 1, 3, 7, 10, 14, 21, 30, 60, and 90. The patients were aged >=60 years or aged >=18 years and had gastrointestinal abnormalities or were on a restricted diet. The primary efficacy outcome compared the proportion of patients in each treatment arm in whom cobalamin levels were normalized (>=350 ng/mL) following 60 days of treatment. Secondary objectives included comparing the efficacy of the 2 formulations after 90 days of treatment, assessing time to normalization of B(12) levels, and evaluating the changes in the levels of biomarkers methylmalonic acid (MMA) and homocysteine (HC). The effect on holotranscobalamin II (active B(12)) levels was assessed as an exploratory end point and correlated to serum cobalamin levels in both treatment groups. Blood samples were collected at baseline (day 1) and on days 15, 31, 61, and 91. RESULTS: Fifty patients were recruited. Forty-eight patients (96.0%) completed the study (22 patients [91.7%] in the oral B(12) group and 26 patients [100%] in the IM B(12) group). All patients (100%) in both treatment groups and in both populations had a cobalamin level >=350 pg/mL on day 61 and maintained it on day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance (P < 0.05) for mean percent change from baseline (PCFB) in serum cobalamin levels on day 61 and day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in serum MMA levels on day 61. There was a statistical difference between the IM and oral treatment groups for mean PCFB in serum MMA levels on day 91 (P = 0.033), with lower values in the oral B(12) group. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in plasma HC levels on day 61 and day 91. All patients in each treatment group achieved normalization of serum cobalamin levels by day 15. All patients in both treatment groups and in both populations had plasma holotranscobalamin levels >=40 pmol/L on day 61 and on day 91. No statistical analysis was planned or performed for safety end points, which were reported only descriptively. Most observed adverse effects were considered mild or moderate in intensity. All adverse effects that were considered severe in intensity were also considered by the investigator to be not related to the study drug. CONCLUSIONS: In this selected study population comprising individuals with low cobalamin levels but who otherwise were in good health, patients received oral B(12) (1000 MUg/d) or IM B(12) (1000 MUg in 9 injections over 3 months) for a total of 3 months. Both the oral and IM formulations were effective in restoring normal levels of serum cobalamin in all patients studied (100%). Both formulations used in this study were well tolerated at the dose studied. ClinicalTrials.gov identifier: NCT01312831. PMID- 21600389 TI - Communicating pharmacoeconomic research results to lay audiences. PMID- 21600390 TI - Single-dose, two-way crossover, bioequivalence study of Mycophenolate mofetil 500 mg tablet under fasting conditions in healthy male subjects. AB - BACKGROUND: Mycophenolate mofetil (MMF) is an immunosuppressant indicated for prophylaxis of acute organ transplant rejection. Generic MMF is less costly than the branded product, but European regulatory authorities require bioequivalence studies for the marketing of generics. OBJECTIVES: The aims of the 2 studies reported were to assess the dissolution and bioavailability of a generic (test) and branded (reference) formulation of MMF 500 mg. METHODS: An in vitro analytical dissolution profile test was conducted comparing 500 mg MMF test drug with a reference drug. A separate single-dose, randomized, open-label, 2-way crossover study involving fasting, healthy, adult male volunteers was conducted. Two study periods-1 test drug period and 1 reference drug period-were separated by a 14-day washout period. Blood samples were collected for up to 60 hours after drug administration for the determination of MMF and mycophenolic acid (MPA) pharmacokinetics. Concentrations of the analytes were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method; pharmacokinetic parameters were calculated using noncompartmental analysis; C(max), AUC(0-t), and AUC(0-infinity) were the primary evaluation criteria. Bioequivalence was assumed if the 90% confidence intervals (CIs) for the test/reference ratios of natural logarithm transformed values (obtained using ANOVA) were between 80% and 125%, per European regulations for bioequivalence. Tolerability was monitored throughout the study. RESULTS: The dissolution profiles of the test drug matched those of the reference drug at 4 pH levels. In the bioequivalence study, a total of 126 male subjects were dosed, and 117 subjects completed the study. The 90% CIs for MPA were C(max), 94.13% to 116.46%; AUC(0-t), 98.26% to 102.36%; and AUC(0-infinity), 97.85% to 101.99%. These values met with the European regulatory definition of bioequivalence. Reported adverse events were similar in both the test and reference drugs. CONCLUSIONS: This single-dose study found that the test and reference MMF 500 mg tablets met the European regulatory criteria for assuming bioequivalence in fasting, healthy, male subjects. Both formulations were well tolerated. (Clinical Trials Registry - India [CTRI]: 2011/03/002211). PMID- 21600391 TI - Cell number counts--the fw2.2 and CNR genes and implications for controlling plant fruit and organ size. AB - Two key determinants of plant and organ size are cell number and cell size, and altering either one may affect the plant organ size, but cell number control often plays a predominant role in natural populations. Domesticated crops usually have larger fruit and harvested organ sizes than wild progenitors. Crop yields have increased significantly by breeding, often via heterosis, which is associated with increased plant and organ size primarily achieved by cell number increases. A small class of genes is now known that control plant and organ sizes though cell number or cell size. The fw2.2 gene was found to control a major QTL for tomato fruit size by negatively affecting cell numbers. Orthologs to these fw2.2 genes underlie QTLs for fruit sizes in other species, and their expression can be negatively correlated with increased cell number. In maize decreased or increased expression of the fw2.2 ortholog ZmCNR1, increases or decreases cell number, respectively, thereby affecting maize organ size throughout the plant and thus also whole plant size. Therefore, these genes should now be considered as more general regulators of plant cell number and organ size. The exact molecular function of these transmembrane domain proteins remains unknown, as does any clear relationship to the cell cycle. Because these genes control organ sizes in diverse plants and important crop species, and because they can affect whole plant size, interest arose into how effects of such genes could parallel agronomic crop improvements, in particular that by heterosis, as it also affects cell number. In joining these subjects here in discussion we speculate on how single gene cell number regulation and heterosis may cooperate in crop improvement. PMID- 21600392 TI - Structural analysis in nonsymbiotic hemoglobins: what can we learn from inner cavities? AB - Plants contain three classes of hemoglobins which are not associated with nitrogen fixing bacteria, and have been accordingly termed nonsymbiotic hemoglobins. The function of nonsymbiotic hemoglobins is as yet mostly unknown. A NO dioxygenase activity has been proposed and demonstrated for some of them in vitro. In this context, a sound molecular mechanism that relates the structure with the biological activity is crucial to suggest a given physiological role. Insight into such a mechanism is now facilitated by recent progress made in both experimental and computational techniques. These studies have highlighted a number of key structural features implicated in the function of nonsymbiotic hemoglobins. The bis-histidyl hexacoordination of the heme in both its ferric and ferrous states provides a powerful and general tool to modulate reactivity, protein dynamics, and shape of the cavities. In addition, the specific arrangement of distal cavity residues provides effective protection against autoxidation. Inspection of the static crystal structures available for both liganded and unliganded states seems unsufficient to explain the function of these proteins. Function appears to be intimately linked with protein flexibility, which influences the dynamical behavior of inner cavities, capable of delivering apolar reactants to the reaction site, and removing charged reaction products. In this mini review, we demonstrate how the integration of information derived from experimental assays and computational studies is valuable and can shed light into the linkage between structural plasticity of nonsymbiotic hemoglobins and their biological role. PMID- 21600393 TI - Identification of heterotic loci associated with yield-related traits in Chinese common wild rice (Oryza rufipogon Griff.). AB - Many rice breeding programs have currently reached yield plateaus as a result of limited genetic variability in parental strains. Dongxiang common wild rice (Oryza rufipogon Griff.) is the progenitor of cultivated rice (Oryza sativa L.) and serves as an important gene pool for the genetic improvement of rice cultivars. In this study, heterotic loci (HLs) associated with six yield-related traits were identified in wild and cultivated rice and investigated using a set of 265 introgression lines (ILs) of O. rufipogon Griff. in the background of the Indica high-yielding cultivar Guichao 2 (O. sativa L.). Forty-two HLs were detected by a single point analysis of mid-parent heterosis values from test cross F(1) offspring, and 30 (71.5%) of these HLs showed significantly positive effects, consistent with the superiority shown by the F(1) test cross population in the six yield-related traits under study. Genetic mapping of hsp11, a locus responsible for the number of spikelets per panicle, confirmed the utility of these HLs. The results indicate that favorable HLs capable of improving agronomic traits are available. The identification of HLs between wild rice and cultivated rice could lead to a new strategy for the application of heterosis in rice breeding. PMID- 21600394 TI - Plasma membrane localization of the type I H(+)-PPase AVP1 in sieve element companion cell complexes from Arabidopsis thaliana. AB - Previous literature has shown the presence of a plasma membrane (PM) localized type I H(+)-PPase in sieve elements of Ricinus communis. Unfortunately, the physiological relevance of these findings remains obscure due to the lack of genetic and molecular reagents to study R. communis. The availability of H(+) PPase gain and loss-of-function mutants in Arabidopsis thaliana makes this plant an attractive genetic model to address the question, but data on the PM localization of this H(+)-PPase in A. thaliana are limited to two proteomic approaches. Here we present the first report on the localization of the type I H(+)-PPase AVP1 in sieve element-companion cell complexes (SE-CCc) from A. thaliana. Double epifluorescence and immunogold labeling experiments are consistent with the co-localization of AVP1 and PIP1 (a bona fide PM maker) in PM of SE-CCc from A. thaliana. PMID- 21600395 TI - Changes in the endopolyploidy pattern of different tissues in diploid and tetraploid Phalaenopsis aphrodite subsp. formosana (Orchidaceae). AB - Endopolyploidy is frequently observed during development in plant species. Patterns of endopolyploidy are diverse in the various organs of different plant species. However, little is known about the role of endopolyploidization and its significance in orchids. This study was undertaken to determine the extent of endopolyploidy in different tissues of the diploid and tetraploid genotypes of Phalaenopsis aphrodite subsp. formosana and to examine the factors that contribute to increased ploidy levels. Endopolyploidy occurs in various tissues of diploid and tetraploid orchids, at different developmental stages and under different culture conditions, as determined by flow cytometry. In this study, different patterns of endopolyploidy were observed in parts of the protocorms, leaves, roots and flowers. Endopolyploidy was found in all tissues studied except the pollinia and the tetraploid ovaries. A higher degree of endopolyploidy was observed in mature tissues compared to young tissues, greenhouse-grown plants compared to in vitro plants and diploid plants compared to tetraploid plants. We discuss the relationships between endopolyploidization and several factors related to plant growth, as well as some practical considerations of these findings. PMID- 21600396 TI - Arabidopsis ENHANCER OF SHOOT REGENERATION (ESR)1 and ESR2 regulate in vitro shoot regeneration and their expressions are differentially regulated. AB - The Arabidopsis ENHANCER OF SHOOT REGENERATION (ESR)1 and ESR2 genes are thought to play critical roles in in vitro shoot regeneration. In this study, we investigated the functions and expression patterns of ESR1 and ESR2 during shoot regeneration by using their mutants and promoter-reporter systems. Shoot regeneration efficiencies of esr1 esr2 double mutants from hypocotyl explants decreased drastically; although the effects on shoot regeneration of the esr1 single mutation were much less marked than those of the esr2 single mutation, especially from root explants, their effects were additive. We found that ESR1 was initially expressed 1 day after transfer onto shoot-inducing medium (SIM), compared with 4 days for ESR2 expression. These results suggest that the functions of ESR1 and ESR2 in shoot regeneration are not redundant, even though they encode similar transcription factors and the ESR2 gene substituted with an ESR1 coding region complements the esr2 mutation. We also found that ESR1 expression was localized to a small number of cells in the lateral root meristem (LRM)-like structures, and the ESR1-expressing cells appeared to proliferate to form shoot apical meristem (SAM)-like structures. Thus, ESR1 may be involved in the change of LRM to SAM in tissue culture. PMID- 21600397 TI - Effects of osmotic pretreatments on oxidative stress, antioxidant profiles and cryopreservation of olive somatic embryos. AB - A three-day pretreatment of olive somatic embryos (SE) with 0.75 M sucrose, combined with cryoprotection (0.5M DMSO, 1M sucrose, 0.5M glycerol and 0.009 M proline) and controlled rate cooling, supported regrowth (as 34.6% fresh weight gain) and resumption of embryo development after cryopreservation. Pretreatment with mannitol or sorbitol did not support regrowth. Profiles of sugars, proline, antioxidant enzymes, Reactive oxygen species (ROS), secondary oxidation products and ethylene were constructed for the most successful (0.75 M) pretreatment series. Sucrose was the optimal pretreatment for supporting recovery, it also elevated glutathione reductase (GR) activity compared to controls, whereas superoxide dismutase (SOD), catalase and guaiacol peroxidase activities remained relatively unchanged. Superoxide dismutase activity was higher in SE pretreated with sucrose, compared with those pretreated with polyols; H(2)O(2) was enhanced in SE pretreated with sorbitol and sucrose compared to mannitol. The overall trend for ethylene and OH production revealed their levels were highest in SE pretreated with polyols albeit, for individual treatments this was not always the case. Generally, pretreatments did not significantly change embryo secondary oxidation profiles of ThioBarbituric Acid Reactive Substances (TBARS) and Schiff's bases. In combination these studies suggest oxidative processes may influence regrowth of cryopreserved olive SE and that optimal pretreatments could, in part, increase tolerance by an overall enhancement of endogenous antioxidants (particularly GR), proline and sugars. PMID- 21600398 TI - CIPK7 is involved in cold response by interacting with CBL1 in Arabidopsis thaliana. AB - The family of calcineurin B-like (CBL) proteins is a unique group of Ca(2+) sensors in plants. CBLs relay the calcium signal by interacting with and regulating the family of CBL-interacting protein kinases (CIPKs). Extensive studies have demonstrated that the CBL-CIPK complexes mediate plant responses to a variety of external stresses. However, there are few reports on the CBL-CIPK involved in cold stress responses. In this study, we analyzed expression of CIPK7 and CBL1 in Arabidopsis during cold treatments. Expression of CIPK7 was induced by cold, and CIPK7 interacted with CBL1 in vitro. Moreover, affinity chromatography purification of CIPK7 from Arabidopsis plants using CBL1 suggested that CIPK7 may associate with CBL1 in vivo. Expression of CBL1 was cold inducible, and CBL1 had a role in regulating cold response. By comparing expression patterns of CIPK7 between wild-type and cbl1 mutant plants, we found the induction of CIPK7 by cold stress was influenced by CBL1. This is the first report to demonstrate that CIPK7 may play a role in cold response via its interaction with CBL1. PMID- 21600399 TI - Enrichment of a common wheat genetic map and QTL mapping for fatty acid content in grain. AB - DArT and SSR markers were used to saturate and improve a previous genetic map of RILs derived from the cross Chuan35050 * Shannong483. The new map comprised 719 loci, 561 of which were located on specific chromosomes, giving a total map length of 4008.4 cM; the rest 158 loci were mapped to the most likely intervals. The average chromosome length was 190.9 cM and the marker density was 7.15 cM per marker interval. Among the 719 loci, the majority of marker loci were DArTs (361); the rest included 170 SSRs, 100 EST-SSRs, and 88 other molecular and biochemical loci. QTL mapping for fatty acid content in wheat grain was conducted in this study. Forty QTLs were detected in different environments, with single QTL explaining 3.6-58.1% of the phenotypic variations. These QTLs were distributed on 16 chromosomes. Twenty-two QTLs showed positive additive effects, with Chuan35050 increasing the QTL effects, whereas 18 QTLs were negative with increasing effects from Shannong483. Six sets of co-located QTLs for different traits occurred on chromosomes 1B, 1D, 2D, 5D, and 6B. PMID- 21600401 TI - History of PACS in Asia. AB - First, history of PACS (picture archiving and communication system for medical use) in Japan is described in two parts: in part 1, the early stage of PACS development from 1984 to 2002, and in part 2 the matured stage from 2002 to 2010. PACS in Japan has been developed and installed by local manufacturers by their own technology and demand from domestic hospitals. Part 1 mainly focuses on quantitative growth and part 2 on qualitative change. In part 2, integration of PACS into RIS (radiology information system), HIS (hospital information system), EPR (electronic patient record), teleradiology and IHE (integrating healthcare enterprise) is reported. Interaction with other elements of technology such as moving picture network system and three dimensional display is also discussed. Present situation of main 4 large size hospitals is presented. Second, history of PACS in Korea is reported. Very acute climbing up of filmless PACS diffusion was observed from 1997 to 2000. The reasons for such evolution are described and discussed. Also changes of PACS installation and system integration with other systems such as HIS and role of them in radiological diagnoses in Korea since 2002 are described. Third, history in China is investigated by checking international academic journals in English and described as far as events are logically linked and consistently meaningful. PMID- 21600400 TI - From PACS to the clouds. PMID- 21600402 TI - PACS and diagnostic imaging service delivery--a UK perspective. AB - This review sets out the current position with regard to the implementation of PACS throughout the United Kingdom and the impact this has had on improving patient care. In December 2007 England had implemented full hospital-wide PACS in all hospitals: a major achievement in the relatively short time period of three years. The different approaches used by each country of the UK to achieve full national PACS are described in addition to the current issues with the sharing of images and reports across different healthcare organisations with regard to technical solutions, clinical safety and governance. The review gives insight into the changing methods of service delivery to address increasing demand pressures on diagnostic imaging services and how the national PACS implementation, specifically in England, has made a significant contribution to measures to improve efficiencies. The role of Teleradiology is discussed in the context of supporting local patient services rather than undermining them and the concept of cross-healthcare reporting 'Grids' is described. Finally, in the summary it is recognised that the vast wealth of knowledge accumulated during the national implementations has placed the UK in a strong position to facilitate full national data sharing across all healthcare organisations to improve patient care. PMID- 21600408 TI - The politicization of the wait times issue - and how to rise above it. PMID- 21600440 TI - How can clinical epidemiology better support evidence-based guidelines and policies in low-income countries? PMID- 21600441 TI - Preface. Nerve problems of the lower extremity. PMID- 21600442 TI - Clinical evaluation of neurogenic conditions. PMID- 21600443 TI - Imaging of nerve entrapment in the foot and ankle. AB - Neuropathies can be a cause of chronic foot and ankle pain. The diagnosis can be elusive given the sometimes nonspecific clinical presentation. Although electrodiagnostic studies are primarily relied on for the diagnosis of nerve impairment, imaging is sometimes helpful in helping define the exact site of the entrapment and whether any masses are present. It is critical for the imager to understand the complex anatomy of these nerves and their adjacent structures, to know the most common locations for their entrapments or injury, and to select the proper imaging modality to improve detection of these difficult-to-diagnose clinical conditions. PMID- 21600444 TI - Electrodiagnostic evaluation of lower extremity neurogenic problems. AB - Electrodiagnosis is a powerful tool for evaluating lower extremity disorders that stem from the peripheral nervous system. Electrodiagnostic testing can help differentiate neurogenic versus non-neurogenic causes of complaints such as pain, weakness, and paresthesias. It can help practitioners pinpoint the anatomic location and reveal the underlying pathology in peripheral nerve lesions. This article focuses on the electrodiagnostic evaluation of neurogenic processes that present as foot and ankle symptoms. PMID- 21600445 TI - Nerve problems in the lower extremity. AB - The article provides an overview of management and repair strategies for lower extremity peripheral nerve injuries. It discusses the indications for autografts, nerve conduits, allografts, end-to-side repairs, primary repair, and nerve transfers. The relative pros and cons of each strategy are discussed, providing a broad overview of treatment options for the management of lower extremity nerve injuries. PMID- 21600446 TI - Peripheral nerve entrapments of the lower leg, ankle, and foot. AB - Peripheral nerve entrapments are a relatively rare and heterogeneous group of nerve disorders encompassing a wide variety of etiologies and clinical presentations. These conditions can present significant diagnostic challenges, owing to both the variety of symptoms these patients display, along with the anatomic variation that exists between individuals. Precise knowledge of the anatomic course, the common motor and sensory distributions of each of the peripheral nerves, and judicious use of imaging or electrodiagnostic testing can greatly assist in arriving at a correct diagnosis. In this article, we discuss in detail the anatomy, clinical presentation, diagnosis, and treatment options for peripheral nerve entrapments of the lower extremity involving the sural, saphenous and common, superficial, and deep peroneal nerves. PMID- 21600447 TI - Tarsal tunnel syndrome. AB - Tarsal tunnel syndrome, unlike its similar sounding counterpart in the hand, is a significantly misunderstood clinical entity. Confusion concerning the anatomy involved, the presenting symptomatology, the appropriateness and significance of various diagnostic tests, conservative and surgical management, and, finally, the variability of reported results of surgical intervention attests to the lack of consensus surrounding this condition. The terminology involved in various diagnoses for chronic heel pain is also a hodgepodge of poorly understood entities. PMID- 21600448 TI - The failed tarsal tunnel release. AB - Failed surgical releases of the tarsal tunnel may be due to numerous causes. Many of the failures are due to lack of appreciation of the involved anatomy or inadequate technique. When an insufficient release is done, a revision simply completes the necessary steps. When external scarring is the problem, barrier materials may be used to help protect the nerve after neurolysis. When intrinsic damage is the problem, nerve wrapping, reconstruction, conduits, and nerve stimulators all play a role to restore function or ameliorate pain. PMID- 21600449 TI - The painful neuroma and the use of conduits. AB - Treatment of neuromas in the foot and ankle is evolving. A paucity of studies deals with neuromas in this region; most knowledge comes from hand surgery. A trend toward reconstructive surgery using nerve grafts and conduits for nerves with critical function is being seen. For noncritical nerves, generally accepted treatment is neuroma resection and burial into a tissue bed. A clear knowledge of neural anatomy is paramount, together with correct identification of all the nerves involved in the pain-generation process. More studies dealing with neuromas in this area are needed for evidence-based information. PMID- 21600450 TI - Interdigital neuralgia. AB - Interdigital neuralgia affects a significant number of individuals, with an average age of presentation in the sixth decade and a 4- to 15-fold increased prevalence in women. Historical descriptions date back to the 19th century. Nonoperative treatment with shoe modifications, metatarsal pads, and injections provides relief for most, but long term, 60% to 70% of patients eventually elect to have surgery. Although excision can be performed through a dorsal or plantar approach, we prefer the dorsal incision to prevent scar formation on the plantar aspect of the foot. Satisfactory results are common but not certain with reports of excellent or good ranging from 51% to 93%. PMID- 21600451 TI - Persistent or recurrent interdigital neuromas. AB - Recurrent or persistent symptoms following surgical neurectomy for an interdigital neuroma are quite common, because of incorrect initial diagnosis, true neuroma formation, nerve stump adhesions, accessory nerve branches, or an adjacent web space neuroma. The clinical presentation of a recurrent neuroma is similar to the initial presentation. Recurrent symptoms usually occur within the first 12 months after surgery. The physical examination coupled with diagnostic nerve blocks is critical for diagnosis. Conservative therapy, although not particularly effective in treating true recurrent neuromas, may help to alleviate pain. With proper isolation of the instigating neuroma, revision surgical excision can be effective. PMID- 21600452 TI - Nerve wrapping. AB - Nerve scarring can cause severe pain and dysfunction. Treatment of the scarred nerve frequently yields unpredictable results. A barrier wrap around the scarred nerve could be of benefit in preventing the recurrence of epineural scarring following neurolysis. The barrier would ideally be inert so as to not incite an inflammatory response, and be nondegradable. Veins fulfill both of these objectives. The desirable qualities of a barrier nerve wrap include a substance that decreases nerve scarring, does not constrict and thus compress the nerve, and improves nerve gliding. The primary indication for nerve wrapping is a nerve with adherent scar. PMID- 21600453 TI - Pedicle and free flaps for painful nerve. AB - Treatment of the chronic painful nerve by pedicled or free tissue transfer is a complex surgical procedure, requiring specialized microsurgical training and technique. This procedure is indicated only in patients who have had repeated failure of simpler, conventional procedures. Patients with chronic painful peripheral nerves may be potentially salvaged by external neurolysis and circumferential wrapping of the involved segments of nerve with well-vascularized pedicled or free flaps of fascia, subcutaneous fatty tissue, omentum or muscle, or by the replacement of superficial hypersensitive cutaneous areas and nerves with the same tissues. PMID- 21600454 TI - Diabetic peripheral neuropathy. AB - Diabetic peripheral neuropathy likely affects up to one-third of adults with diabetes. All diabetic patients are likely to develop peripheral neuropathy if they live sufficiently long. Recognition is crucial for initiation of the preventive strategies that have been demonstrated to decrease the potential risk for the development of diabetic foot ulcers, foot infection, Charcot foot, or amputation. The mainstay of current treatment is optimal glucose and hemoglobin A(1C) control. Drug therapy has limited potential for controlling the associated pain. Alternative methods of treatment have thus far demonstrated limited success. PMID- 21600456 TI - Neurosurgery certification in member societies of the World Federation of Neurosurgical Societies: Asia. AB - OBJECTIVE: To objectively compare the complexity and diversity of the certification process in neurological surgery in member societies of the World Federation of Neurosurgical Societies. METHODS: This study centers in continental Asia. We provide here an analysis based on the responses provided to a 13-item survey. The data received were analyzed, and three Regional Complexity Scores (RCS) were designed. To compare national board experience, eligibility requirements for access to the certification process, and the obligatory nature of the examinations, an RCS-Organizational score was created (20 points maximum). To analyze the complexity of the examination, an RCS-Components score was designed (20 points maximum). The sum of both is presented in a Global RCS score. Only those countries that responded to the survey and presented nationwide homogeneity in the conduction of neurosurgery examinations could be included within the scoring system. In addition, a descriptive summary of the certification process per responding society is also provided. RESULTS AND CONCLUSION: On the basis of the data provided by our RCS system, the highest global RCS was achieved by South Korea and Malaysia (21/40 points) followed by the joint examination of Singapore and Hong-Kong (FRCS-Ed) (20/40 points), Japan (17/40 points), the Philippines (15/40 points), and Taiwan (13 points). The experience from these leading countries should be of value to all countries within Asia. PMID- 21600455 TI - Complex regional pain syndrome. AB - Complex regional pain syndrome (CRPS) is a challenging pain condition for doctors and patients, with a natural history characterized by chronicity and relapses that can result in significant disability. CRPS is difficult to diagnose and treat, and requires close follow-up to ensure that progress is being made. Early diagnosis and treatment are required to prevent a long-standing or permanent disability. Clinical features such as spontaneous pain, edema, hyperalgesia, temperature or sudomotor changes, motor function abnormality, and autonomic changes are the hallmark of this disease. The treatment of CRPS remains controversial, and includes medications, physical therapy, regional anesthesia, and neuromodulation. PMID- 21600457 TI - Subspecialties in neurosurgery and its challenges in a developing country. AB - Neurosurgery in developed countries is creating subspecialties. The introduction of such a concept in a developing country like Nepal is discussed. For the steady development of neurosurgery in developing countries, the concept of subspecialization must be introduced. PMID- 21600458 TI - Glioblastoma multiforme tumor stem cells form endothelium. PMID- 21600459 TI - When the clips do not fit. PMID- 21600460 TI - The neurological emergency room: the future is here. PMID- 21600461 TI - Issues and problems associated with neurosurgery in South Korea. PMID- 21600462 TI - Asia and Asian neurosurgery. PMID- 21600463 TI - The Terra Cotta Army of Qin Shi Huang. PMID- 21600464 TI - Kenichiro Sugita (1932-1994): a man of innovation. PMID- 21600465 TI - Professor Keiji Sano: a notable figure in Japanese neurosurgery. PMID- 21600466 TI - Great hospitals of Asia: the University of Tokyo Hospital. PMID- 21600467 TI - Huashan Hospital affiliated to Fudan University: spanning a century of history. AB - Established in 1907, Huashan Hospital affiliated to Fudan University represents in microcosm the growth of modern Chinese medical science and shows its course of development. Over the past 103 years, the hospital has grown from a staff of a dozen to 3103 staff members, covering an area of 37,396 m(2) with 1216 hospital beds. Huashan Hospital has grown into one of the best-known hospitals in China with multiple world-renowned disciplines, including neurosurgery, hand surgery, dermatology, and infectious disease. PMID- 21600468 TI - Neurosurgery center of Beijing Tiantan Hospital, flagship of neurosurgery in China. PMID- 21600469 TI - Great hospitals of Asia: neurosurgery at Prince of Wales Hospital. AB - Prince of Wales Hospital, a 1400-bed regional referral center, was established in 1984 as the primary teaching hospital of the second medical school in Hong Kong at the Chinese University of Hong Kong. The Academic Division of Neurosurgery was given an autonomous status, the support of 40 acute beds, and a well-equipped and well-staffed intensive care unit (ICU), in developing neurosurgery as a distinct surgical specialty. Over this short 26-year history, we have gone through the difficult time of one-man-band neurosurgery, excelled in emergency neurosurgery, and evolved to an era of organized neurosurgical practice, where clinical services, teaching of undergraduate and postgraduate students, and clinical and translational research have been brought up to international standards. PMID- 21600470 TI - Neurosurgery at the National Taiwan University. PMID- 21600471 TI - Long-term results of patients with head injuries treated in different hospitals after the Wenchuan, China, earthquake. AB - OBJECTIVE: To present an overview of mortality, disability, and depression among patients with head injuries admitted to multiple center hospitals after the 2008 Wenchuan earthquake in China. METHODS: A retrospective analysis was done of the medical records of earthquake victims with head traumas admitted to three different area hospitals; analysis included 18 months of follow-up. Demographic data, causes of injury, diagnosis, clinical classification, treatment, and prognosis were reviewed. RESULTS: This analysis included 1299 victims with craniocerebral injuries admitted to eight hospitals in or near the disaster zone. The victims were divided into three main groups. Group A comprised 68 victims treated in the local hospital; all 68 (100%) were hospitalized during the 24 hours after the earthquake, and 38 (55.88%) victims died 18 months later. Group B comprised 600 victims treated in regional hospitals; 264 (44%) were admitted within 72 hours after the earthquake, and 109 (18.17%) died. Group C comprised 631 victims transported to territory hospitals; 39 (6.18%) were dead at 18 months. Among survivors, 409 (31.48%) victims sustained a disability, and 879 (80.35%) have depression. CONCLUSIONS: In the first 72 hours after this major earthquake, the local and regional hospital neurosurgery departments were flooded with numerous victims with craniocerebral injuries. Most of these patients died or were disabled. The territory hospitals with expert neurosurgeons and advanced equipment did not effectively contribute to successful treatment of victims. The mobile hospital played an important role in initial triage and treatment. PMID- 21600472 TI - Great hospitals of Asia: the Department of Neurosurgery at Seoul National University College of Medicine. AB - Established in 1957, the Department of Neurosurgery at Seoul National University College of Medicine is the one of the oldest neurosurgical departments in Korea. The seven past Chairmen (Bo Sung Sim, Kil Soo Choi, Dae Hee Han, Byung-Kyu Cho, Hyun Jib Kim, Hee-Won Jung, and Dong Gyu Kim) have devoted themselves to the development of the department. The current chair, Chun Kee Chung, assumed the position in July 2010. The current department comprises several clinical programs that encompass the entire spectrum of neurosurgical disorders, with 29 specialized faculty members and care teams in three hospitals: Seoul National University Hospital (SNUH), Boramae Medical Center (BMC), and Seoul National University Bundang Hospital (SNUBH). The remarkable growth of the department during the last half century made it possible to perform 5,666 operations (3,299 at SNUH, 411 at BMC and 1,860 at SNUBH) during 2009. A total of 1,201 articles authored by faculty members were published in scientific journals between 1958 and 2009, approximately 32% of which were published in international journals. The department is regarded as the "Mecca" of neurosurgery in Korea because of its outstanding achievement and the many distinguished alumni with leadership roles in the academic field. This article traces the clinical, academic, and scientific development of the department, its present activities, and its future direction. PMID- 21600473 TI - Multimodality treatment of complex cerebral aneurysms, the quest continues. PMID- 21600474 TI - Selecting therapy for complex aneurysms. PMID- 21600475 TI - What is the correct approach to aneurysm management in 2011? PMID- 21600476 TI - Treatment of complex internal carotid artery aneurysms. PMID- 21600477 TI - Surgical bypass for intracranial aneurysms: navigating around a changing paradigm. PMID- 21600478 TI - Commentary on "microporous polysaccharide hemospheres (MPH) for cerebral hemostasis: a preliminary report". PMID- 21600479 TI - Treatment strategy for sphenopetroclival meningiomas. PMID- 21600480 TI - Advantages and disadvantages of surgical approaches to petroclival lesions. PMID- 21600482 TI - Petroclival meningiomas: quo vadis? PMID- 21600481 TI - Combined supratentorial and infratentorial approaches for removal of petroclival meningiomas. PMID- 21600483 TI - Is there still a role for language-Wada testing? PMID- 21600484 TI - Propofol, amobarbital... is it the substance that matters, or the question about the role of the Wada test in brain tumor patients? PMID- 21600485 TI - Toward the application of the hodotopical concept to epilepsy surgery. PMID- 21600486 TI - Seizure-localizing value and functional implications of diffusion-based imaging in epilepsy. PMID- 21600487 TI - Perspectives on "fusion image-based programming after subthalamic nucleus deep brain stimulation". PMID- 21600488 TI - Who needs a hook? PMID- 21600489 TI - Transarticular screws and C1 hooks fixation for os odontoideum with atlantoaxial dislocation. PMID- 21600490 TI - Cervical myelopathy: is it all just one disease? PMID- 21600491 TI - Pathophysiology and surgical strategies in the management of the ossified spinal ligaments. PMID- 21600492 TI - Ossification of the ligamentum flavum (OLF): an increasing cause of cervical myelopathy. PMID- 21600493 TI - Surgery in the DREZ for refractory neuropathic pain after spinal cord/cauda equina injury. PMID- 21600494 TI - Ablative neurosurgical procedure for pain after spinal cord injury. PMID- 21600495 TI - Decompressive craniectomy for severe head injury. PMID- 21600496 TI - Decompressive craniectomy for traumatic brain injury-when and how? PMID- 21600497 TI - Risk-benefit balance of decompressive craniectomy in traumatic brain injury: what's new? PMID- 21600498 TI - The need for WFNS standard simplified guidelines for the management of severe traumatic brain injuries. PMID- 21600499 TI - Principles in case-based aneurysm treatment: approaching complex lesions excluded by International Subarachnoid Aneurysm Trial (ISAT) criteria. AB - OBJECTIVE: To review notable aneurysm cases that required complex decision making from a single institution and to examine available literature when relevant to highlight evidence-based paradigms for treatment of complex aneurysms. METHODS: Case illustrations were used to highlight topics in complex aneurysm treatments. Reviews of the literature were conducted to evaluate the evidence for available treatment models. RESULTS: Current modalities for treating complex aneurysms involve endovascular and microsurgical tools. CONCLUSIONS: Innovations in both arms of the cerebrovascular field will continue to advance the field and provide novel approaches to these complex lesions. PMID- 21600500 TI - Treatment strategies for complex internal carotid artery (ICA) aneurysms: direct ICA sacrifice or combined with extracranial-to-intracranial bypass. AB - OBJECTIVE: Direct surgery for complex internal carotid artery (ICA) aneurysms can be difficult. In certain situations, sacrificing the parent artery is a unique way to obliterate the aneurysm and extracranial-to-intracranial (EC-IC) bypass is indispensable to prevent postoperative cerebral ischemia. This article discusses the indications for direct ICA occlusion, and the strategies, techniques, and outcomes in a series of patients treated for complex ICA aneurysms in a single institution. METHODS: During a 7-year period, 49 patients with complex ICA aneurysms underwent direct ICA sacrifice, or ICA sacrifice combined with EC-IC bypass. The appropriate type of bypass was determined by the results of balloon occlusion test and computed tomographic perfusion. The technique of ICA sacrifice used was selected based on the evaluation of retrograde filling of the aneurysm during balloon occlusion test. RESULTS: Ten patients underwent direct ICA sacrifice and no ischemia-related complications were evident during the 5-12 months of follow-up. A total of 39 patients were treated by ICA sacrifice combined with EC-IC bypass, including 21 cases of superficial temporal artery radial artery-middle cerebral artery and 18 cases of external carotid artery radial artery-middle cerebral artery. ICA sacrifice was achieved in 38 patients by using prolonged occlusion (25 cases) or acute occlusion (13 cases). Five patients presented with minor ischemia after surgery, but four patients recovered completely. Two patients developed brain swelling postoperatively and one developed intracranial hemorrhage, which required evacuation of the hematoma. CONCLUSION: Balloon occlusion test combined with computed tomographic perfusion can be an efficient way to evaluate the compromised cerebrovascular reserve in patients with complex ICA aneurysms after ICA occlusion. In conjunction with EC IC bypass, ICA proximal occlusion or trapping can be an effective treatment strategy. PMID- 21600501 TI - Development of a kit to treat subarachnoid hemorrhage by intrathecal simple urokinase infusion (ITSUKI) therapy: preliminary results in patients with World Federation of Neurological Surgery (WFNS) grade V subarachnoid hemorrhage. AB - OBJECTIVE: To report the effectiveness of intrathecal selective administration of urokinase infusion (ITSUKI) therapy delivered via a special kit (ITSUKit), developed to prevent vasospasm in patients with ruptured aneurysms who had undergone Guglielmi detachable coil (GDC) placement, in patients with World Federation of Neurological Surgery (WFNS) grade V subarachnoid hemorrhage (SAH). METHODS: A study of ITSUKI therapy with or without ventricular drainage enrolled 6 patients with WFNS grade V SAH owing to ruptured intracranial aneurysms who were eligible for coil embolization. The procedures were performed within 48 hours of the occurrence of aneurysmal SAH. The incidence of symptomatic vasospasm and the clinical outcomes based on the Glasgow Outcome Scale (GOS) were assessed at 6 months after SAH onset. RESULTS: All patients underwent complete coil embolization. There were no side effects or adverse reactions attributable to ITSUKI therapy. Symptomatic vasospasm occurred in one patient (16.7%). There were no patients with hydrocephalus. Based on the GOS, one patient had a good outcome, two manifested moderate disability, and three manifested severe disability. CONCLUSIONS: The results showed that the ITSUKit was useful for ITSUKI therapy. Although the combination of coil embolization and ITSUKI therapy did not completely eliminate WFNS grade V SAH, it significantly improved the treatment outcome in some patients. PMID- 21600502 TI - Microporous Polysaccharide Hemospheres (MPH) for cerebral hemostasis: a preliminary report. AB - OBJECTIVE: To report preliminary experience in using Microporous Polysaccharide Hemospheres (MPH; Medafor, Inc, Minneapolis, Minnesota, USA) for cerebral and dural sinus hemostasis. METHODS: Absorbable hemospheres for hemostasis were used in 10 patients (6 men, 4 women, mean age 56.2 years) undergoing cerebral procedures. The indication was corticosubcortical cerebral hemostasis after resection of meningiomas (n = 5) and gliomas (n = 5). In one case, absorbable hemospheres were applied for generalized oozing over the superior sagittal sinus. The surgical technique, time to bleeding control, and associated complications were recorded. RESULTS: Effective hemostasis, defined as cessation of oozing bleeding, was achieved no later than 2 minutes after topical agent application in all patients except two, in whom the hemostatic application was repeated. Mean follow-up was 12 months. No patient developed allergic reactions or systemic complications in association with hemostatic absorbable hemospheres. There was no case of cerebral hematoma, swelling, or infection after surgery. CONCLUSIONS: In this preliminary study, the direct application of absorbable hemospheres helped to control superficial cerebral bleeding, reducing the use of bipolar coagulation and shortening surgical time. Although use of absorbable hemospheres seems to be safe and effective, further investigations and prospective studies with longer follow-up are strongly recommended to arrive at final conclusions. PMID- 21600503 TI - A comparative anatomic study of a modified temporal-occipital transtentorial transpetrosal-ridge approach and a transpetrosal presigmoid approach. AB - OBJECTIVE: To evaluate the anatomic features of a modified temporal-occipital transtentorial transpetrosal-ridge approach versus the conventional approach for surgery of petroclival tumors. METHODS: The conventional transpetrosal presigmoid approach or the modified temporal-occipital transtentorial transpetrosal-ridge approach was performed on different sides of the heads from 10 adult Chinese cadavers to compare incision site, exposure area, and operating space. RESULTS: In the modified approach, only medial and median parts of the petrous ridge were removed. No significant differences in maximal visual angle and operative depth were found between the two approaches (P > 0.05). The modified approach required a much smaller bone window compared with the presigmoid approach. The exposure in the middle of the ventral brainstem in the modified approach was much greater than in the presigmoid approach. The angle required for exposure of the temporal lobe via the ventral medulla oblongata in the modified approach was much smaller than in the presigmoid approach (P < 0.05). CONCLUSIONS: The modified temporal occipital transtentorial transpetrosal-ridge approach is a feasible surgical approach to remove petroclival tumors. PMID- 21600504 TI - Selective propofol injection into the M1 segment of the middle cerebral artery (MCA Wada test) reduces adverse effects and enhances the reliability of the Wada test for determining speech dominance. AB - OBJECT: The Wada test is had been the most reliable for determining speech dominance. Drugs injected into the internal carotid artery, however, may be heterogeneously distributed as the result of asymmetry of the anterior cerebral arteries and the presence of a fetal-type posterior cerebral artery. Variations in drug distribution could occasionally alter consciousness and complicate the evaluation of the test results. We examined selective propofol injection into the M1 segment of the middle cerebral artery (MCA Wada test). METHODS: For the MCA Wada test (17 patients), 7 or 8 mg of propofol was injected via a microcatheter navigated into the M1 segment, and language function was evaluated by patient performing several tasks. The conventional Wada test (internal carotid artery [ICA] Wada test) was performed in four patients (both the ICA and MCA Wada tests were performed in one patient). The efficacy and adverse effects of both procedures were evaluated; all tests were performed by well-trained interventional neuroradiologists. RESULTS: Immediately after propofol injection during the MCA Wada test, patients developed transient contralateral hemiplegia and transient aphasia (in the case of injection on the dominant side). Confusion and other severe adverse effects did not occur during the MCA Wada test, but two of four patients who underwent the ICA Wada test showed altered consciousness that affected the performance of the test. CONCLUSIONS: The MCA Wada test is a feasible and reliable preoperative evaluation, if performed by a trained team of interventional neuroradiologists. PMID- 21600505 TI - Changes in language pathways in patients with temporal lobe epilepsy: diffusion tensor imaging analysis of the uncinate and arcuate fasciculi. AB - OBJECTIVE: The language pathways consist of ventral and dorsal systems connected via the uncinate fasciculus and arcuate fasciculus, respectively. Seizures in medial temporal lobe epilepsy (mTLE) affect both tracts. Previous studies, however, have focused on the arcuate fasciculus to explain the language disturbance in mTLE. In contrast, we compared changes in both the uncinate and arcuate fasciculi using diffusion tensor imaging. METHODS: Thirteen patients with left mTLE and 12 with right mTLE were studied. The Wada test showed left dominance for language in all these patients. Sixteen healthy right-handed subjects were also studied. The mean fractional anisotropy and mean apparent diffusion coefficient with their lateralization index of two fasciculi were compared between hemispheres and between subjects. RESULTS: The mean apparent diffusion coefficient of the arcuate and uncinate fasciculi in both left- and right-mTLE patients increased bilaterally compared with that in healthy subjects. In left mTLE, the fractional anisotropy of the uncinate fasciculus was lower ipsilaterally (P = 0.002) and was significantly lateralized contralaterally (P < 0.001) compared with control subjects, whereas the fractional anisotropy of the arcuate fasciculus showed no lateralization (P = 0.577). In right mTLE, such a difference was not prominent. CONCLUSION: The seizure network affects both arcuate and uncinate fasciculi bilaterally in both left- and right-mTLE patients. The change is most prominent in the left uncinate fasciculus in left mTLE. PMID- 21600506 TI - Fusion image-based programming after subthalamic nucleus deep brain stimulation. AB - OBJECTIVE: To propose fusion image-based programming to adjust patients with advanced Parkinson disease (PD) effectively after subthalamic nucleus (STN) deep brain stimulation (DBS). METHODS: Between January 2007 and July 2008, 38 patients with advanced PD were consecutively treated with STN DBS. The electrode positions and information regarding their contacts with STN were determined via fusion of the images of preoperative magnetic resonance imaging (MRI) and of postoperative computed tomography (CT) obtained 1 month after STN DBS. Postoperative programming was performed using the information of electrode positions based on the fused images. All patients were evaluated with a prospective protocol of the Unified Parkinson Disease Rating Scale (UPDRS), Hoehn and Yahr Staging, Schwab and England Activities of Daily Living (SEADL), levodopa equivalent daily dose (LEDD), short-form-36 health survey (SF-36), and neuropsychological tests before and at 3 months and 6 months after surgery. RESULTS: There was a rapid and significant improvement of motor symptoms, especially tremor and rigidity, after STN stimulation, with low morbidity. Stimulation led to an improvement in the off medication UPDSR III scores of the patients of approximately 55% at 3 months and 6 months after STN DBS. Dyskinesia was significantly improved (74% at 3 months and 95% at 6 months) after STN DBS. In addition, LEDD values decreased to 50% of the level observed before surgery within 1 month after STN DBS. CONCLUSIONS: Programming based on fused images of preoperative MRI and postoperative CT after STN DBS was performed quickly, easily, and efficiently. PMID- 21600507 TI - Depression and coping as predictors of change after deep brain stimulation in Parkinson's disease. AB - BACKGROUND: This study examined changes in motor function and quality of life (QoL) after subthalamic nuclei deep brain stimulation (STN-DBS) in patients with Parkinson disease (PD) and the role of psychosocial predictors on individual changes. METHODS: Forty-one patients with advanced PD (29 men and 12 women; mean age: 62.0 +/- 8.0; disease duration: 14.5 +/- 5.7) completed self-report questionnaires before surgery and at 6 and 12 months after surgery. Psychosocial measures assessed coping strategies (Ways of Coping Checklist-Revised), symptoms of depression (Beck Depression Inventory version II), anxiety (State-Trait Anxiety Inventory), and QoL (Parkinson Disease Questionnaire 39 Items, Medical Outcomes Study 36-Item Short-Form Health Survey). RESULTS: After surgery, motor function (Unified Parkinson Disease Rating Scale III and IV), global QoL (Parkinson Disease Questionnaire 39 Items) and Physical Component Summary of the Medical Outcome Study Short Form 36-items Health Survey improved, whereas the Mental Component Summary tended to deteriorate. Depression and anxiety were stable. Improvements in motor function and QoL were associated with younger age, shorter duration of illness, higher baseline distress (depression and anxiety), and changes in problem-focused coping. Improvements in mental QoL were associated with a less frequent use of coping focused on seeking social support. CONCLUSIONS: STN-DBS is associated with major positive changes in PD affecting motor function and QoL. These changes are related to psychological variables, including emotional distress and coping. A better focus on these individual characteristics is necessary to improve care of patients with PD who undertake STN-DBS. PMID- 21600508 TI - Organotypic human spinal cord slice culture as an alternative to direct transplantation of human bone marrow precursor cells for treating spinal cord injury. AB - OBJECTIVE: To determine the possibility of differentiation of human bone marrow derived mesenchymal precursor cells (BMDMPCs) into neuronal lineage cells using a human spinal cord organotypic slice coculture technique as an alternative to an in vivo human study. METHODS: Human BMDMPCs were stained with PKH-26 dye before transplantation into 12 human spinal cord slices. In the control group, BMDMPCs were embedded into one spinal cord-free six-well plate containing media. The morphologic differentiation of the transplanted BMDMPCs were observed at 0, 3, 7, and 14 days. Neuroglial differentiation was identified with immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Spherical cells were seen in both groups at day 0. On days 7 and 14, cells developed one or two thick, short processes and typical spindle-shaped cells in the control group and three to five thin, long processes and neuron-like cells in the experimental group. Immunohistochemistry showed double-stained cells with PKH-26 dye (positive) and vimentin (positive), PKH-26 (positive) and neuronal nuclei (NeuN) (positive), and PKH-26 (positive) and glial fibrillary acidic protein (GFAP) (positive) in the experimental group only. RT-PCR showed weak expression of tyrosine kinase A, NeuN, beta-tubulin III, and GFAP in the experimental group. CONCLUSIONS: Organotypic human spinal cord slice culture may be a useful method to verify the neuroglial differentiation of human BMDMPCs as an alternative to a direct human study. PMID- 21600509 TI - Transarticular screw and C1 hook fixation for os odontoideum with atlantoaxial dislocation. AB - OBJECTIVE: To introduce a fixation device composed of C1-2 transarticular (TA) screws and C1 hooks and explore its indication and clinical outcome for os odontoideum with atlantoaxial dislocation (AAD). METHODS: From January 2004 to December 2008, 12 patients with os odontoideum (5 men and 7 women, average age 37.7 years [range 14-62 years]) were treated in the authors' hospital. All patients had AAD with local symptoms, and 10 had myelopathy. All patients underwent a posterior atlantoaxial fixation with C1-2 TA screws and C1 hooks. Clinical and radiographic analyses were performed at 3, 6, and 12 months postoperatively and annually thereafter. RESULTS: The follow-up period was 12-66 months (average follow-up period 35.5 months). No neurologic or vascular complications occurred in these cases, and the device was placed well with no loosening or breakage. Plain radiographs and three-dimensional reconstruction of computed tomography (CT) images revealed solid bony fusion with a good alignment of C1 and C2 at 3 months postoperatively. No hardware failure, pseudarthrosis, or instability was noted during the follow-up period. All patients had relief of pain within 3 months, and neurologic symptoms were substantially improved. CONCLUSIONS: When appropriate patients are selected, C1-2 TA screws combined with C1 hooks can be used to treat os odontoideum with AAD effectively with a relatively simple procedure resulting in excellent biomechanical strength and high bone fusion rate. Preoperative planning is crucial for the management of os odontoideum with AAD. PMID- 21600510 TI - Surgical treatments of myelopathy caused by cervical ligamentum flavum ossification. AB - OBJECTIVE: To present a small case series reporting the outcomes of surgical treatment for myelopathy caused by cervical ossification of the ligamentum flavum (OLF). METHODS: The authors assessed 15 cases of myelopathy caused by cervical OLF. Patients were eight women and seven men 37-75 years old (mean age 59.7 years). All patients underwent bilateral laminectomy, and the lesions were removed. The decompression range was confined within the medial sides of the bilateral facets and within the involved segments. Intraoperative specimens were examined histologically to confirm the diagnosis. During the operation, the extent of adherence of the lesions to the dura was recorded. The patients were followed for 3-70 months. Neurofunctional improvements were evaluated with the Japanese Orthopaedic Association (JOA) score. RESULTS: Definite adherences were present in 67.7% of all cases. JOA score showed a 71.5% improvement after operation from a preoperative score of 5-8 (mean 6.4) to a postoperative score of 10-14 (mean 13.5). The operative outcomes were satisfactory without extensive decompression of adjacent segments. CONCLUSIONS: A high rate of adherence to the dura was observed in patients with myelopathy caused by cervical OLF. Bilateral laminectomy and removal of the lesions, without extensive decompression of adjacent segments, provides an optimistic prognosis. PMID- 21600511 TI - A modified microsurgical DREZotomy procedure for refractory neuropathic pain. AB - OBJECTIVE: Control of neuropathic pain secondary to spinal cord injury is difficult; microsurgical DREZotomy (MDT) is the currently preferred treatment modality. According to previous reports, traditional MDT has poor outcomes when addressing diffuse (infralesional), thermal, and continuous pain. Here, we report improvements in surgical outcomes in these neuropathic pain conditions using a modified MDT technique. METHODS: Patients with segmental, mechanical, or intermittent pain underwent MDT using the traditional (Sindou's) technique performed at the indicated cord level based on pain distribution. Patients suffering from diffuse, thermal, or continuous pain underwent a modified MDT procedure in the "lump" and "irritative" zones, as well as another procedure, whereby an attempt was made to cut every injured and fused rootlet. RESULTS: In 38 patients with paraplegic pain resulting from a spinal cord injury occurring within the preceding 7 years, 11 of 15 patients (73%) with a diffuse pain distribution had a good reduction in pain. Thirteen patients (86%) with continuous pain noted good pain relief. In patients with thermal pain, only one patient (20%) demonstrated a good response to the investigational procedure. CONCLUSION: These procedures, including the modified MDT technique, may be helpful in controlling paraplegic pain in patients suffering from diffuse, thermal, or continuous pain. PMID- 21600512 TI - Decompressive craniectomy and early cranioplasty for the management of severe head injury: a prospective multicenter study on 147 patients. AB - OBJECTIVE: In emergency care of patients with severe blunt head injury, uncontrollable high intracranial pressure is one of major causes of morbidity and mortality. The purpose of this study was to evaluate the efficacy of aggressive surgical treatment in managing uncontrollable elevated intracranial pressure coupled with early skull reconstruction. METHODS: This was a prospective study on a series of 147 consecutive patients, managed according to the same protocol by five different neurosurgical units, for severe head injuries (Glasgow coma scale score <=8/15 and high intracranial pressure >25 mm Hg) during a five-year period. All patients received a wide decompressive craniectomy and duroplasty in the acute phase, and a cranioplasty was also performed within 12 weeks (median 6 weeks, range 4-12 weeks). RESULTS: The emergency decompressive surgery was performed within 28 hours (median 16 hours, range 6-28 hours) after sustaining the head injury. The median preoperative Glasgow coma scale score was 6/15 (range 3-8/15). At a mean follow-up of 26 months (range 14-74 months) 14 patients were lost to long-term follow-up, leaving only 133 patients available for the study. The outcome was favorable in 89 (67%, Glasgow outcome score 4 or 5), it was not favorable in 25 (19%, Glasgow outcome score 2 and 3), and 19 patients (14%) died. A younger age (<50 years) and earlier operation (within 9 hours from trauma) had a significant effect on positive outcomes (P < 0.0001 and P < 0.03, respectively). CONCLUSIONS: A prompt aggressive surgery, including a wide decompressive craniectomy coupled with early cranioplasty, could be an effective treatment method to improve the outcome after a severe closed head injury reducing, perhaps, many of the complications related to decompressive craniectomy. PMID- 21600513 TI - Survey of current neurotrauma treatment practice in Japan. AB - BACKGROUND: The Japanese Society of Neurotraumatology announced guidelines for management of severe traumatic brain injury (TBI) in 2000. To evaluate subsequent implementation of these guidelines, we investigated current severe TBI practices in Japan. METHODS: A questionnaire regarding management of severe TBI was sent to each of the 384 Japanese Neurosurgical Society specialist training medical centers and answers were received by mail from 233 centers (60.7%). RESULTS: Of the medical centers, 29% have neurosurgeons in their emergency department. Initial TBI treatment responsibility resided in the Departments of Neurosurgery in 34% of the medical centers, in the emergency department in 29%, and in 36% responsibility is assigned to both departments. Surgery was performed by neurosurgeons in 90% of the centers and postoperative management was assigned to neurosurgeons in 76%. Acute stage magnetic resonance imaging was done in 52% of the centers. An intracranial pressure sensor was inserted in 55%, and jugular venous oxygen saturation was measured in 21%. Hypothermia therapy was performed in 47%, positive normothermia therapy was administered in 76%, and barbiturate therapy was administered in 70%. Of the centers, 94% acknowledged the guidelines but only 72% of the centers implemented protocols that conformed to the guidelines. CONCLUSIONS: Neurosurgeons in Japan are positively involved in management of severe TBI, but few medical centers monitor TBI patients. Many medical centers find it difficult to conform to the guidelines due to lack of neurosurgeons and equipment. These problems can be addressed by consolidation of neurosurgeons into centralized centers and improvement of the medical insurance system. PMID- 21600514 TI - From the editor. Foreword. PMID- 21600516 TI - Clinical perspective: have the results of recent clinical trials of lipid lowering therapies influenced the way we should practice? A Latin American perspective of current issues in clinical lipidology. AB - Traditional tools to evaluate cardiovascular disease risk may underestimate the risk of cardiovascular events. Although reduction of low-density lipoprotein cholesterol (LDL-C) is the mainstay of therapy to mitigate cardiovascular risk from atherosclerosis, noninvasive imaging techniques and biomarkers are now allowing us to identify subclinical atherosclerosis, or high-risk patients, and are providing clinical researchers with new target end points for randomized controlled clinical trials. Current surrogates include carotid intima-media thickness, coronary artery calcification, and high-sensitivity C-reactive protein levels. There is evidence that these biomarkers are useful in clinical practice to improve risk quantification in subjects considered at intermediate risk of coronary events according to clinical risk stratification. Some studies, but not all, have demonstrated achievement of surrogate end points with lipid-lowering therapy in addition to LDL-C reductions. A group of clinical lipidologists from Latin American countries convened to give a perspective on recent clinical trials in clinical lipidology, their designs, and data regarding currently used biomarkers. It was noted that the success of some surrogate end points as possible markers of clinical efficacy has relied heavily on patient selection and trial design. On the basis of current evidence, we believe that correcting elevated LDL-C levels should remain the primary target of therapy for patients with dyslipidemia. The group also agreed that the evidence from recent clinical trials supports the potential role of new biomarkers for the screening and identification of patients at high cardiovascular risk in the absence of overt hyperlipidemia. PMID- 21600517 TI - Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. AB - The familial hypercholesterolemias (FH) are a group of genetic defects resulting in severe elevations of blood cholesterol levels and increased risk of premature coronary heart disease. FH is among the most commonly occurring congenital metabolic disorders. FH is a treatable disease. Aggressive lipid lowering is necessary to achieve the target LDL cholesterol reduction of at least 50% or more. Even greater target LDL cholesterol reductions may be necessary for FH patients who have other CHD risk factors. Despite the prevalence of this disease and the availability of effective treatment options, FH is both underdiagnosed and undertreated, particularly among children. Deficiencies in the diagnosis and treatment of FH indicate the need for greatly increased awareness and understanding of this disease, both on the part of the public and of healthcare practitioners. This document provides recommendations for the screening, diagnosis and treatment of FH in pediatric and adult patients developed by the National Lipid Association Expert Panel on Familial Hypercholesterolemia. This report goes beyond previously published guidelines by providing specific clinical guidance for the primary care clinician and lipid specialist with the goal of improving care of patients with FH and reducing their elevated risk for CHD. PMID- 21600518 TI - Predictors of anterior and posterior wall carotid intima media thickness progression in men and women at moderate risk of coronary heart disease. AB - BACKGROUND: The rate of carotid intima media thickness (CIMT) progression has been widely used in clinical trials as a surrogate marker for subclinical atherosclerosis. OBJECTIVE: The aim of this study was to investigate relationships between coronary heart disease (CHD) risk markers and progression of CIMT in patients at moderate CHD risk. METHODS: Participants included men (45 75 years) and women (55-74 years) in the control arm of a clinical trial. All had at least one major CHD risk factor and baseline posterior wall CIMT 0.7-2.0 mm, without significant stenosis. Posterior (n = 134) and anterior wall (in a subset, n = 72) CIMT were assessed with B-mode ultrasound at baseline and 12 and ~18 months. Fasting lipoprotein lipid, apolipoprotein (Apo), inflammatory, and oxidative stress markers were evaluated. RESULTS: Baseline CIMT was inversely associated (P < .001) with CIMT progression. After adjustment for baseline CIMT, significant predictors of anterior wall CIMT progression in linear regression analyses included glucose (P = .044), high-density lipoprotein cholesterol (HDL C, inverse, P = .006), triglycerides (TG, P = .006), and ratios of total cholesterol (TC)/HDL-C (P = .013), TG/HDL-C (P = .005), and Apo B/HDL-C (P = .021). Posterior wall CIMT progressed on average, whereas anterior wall CIMT regressed (0.0078 vs -0.0164 mm/year, P = .014). Significant baseline CIMT adjusted predictors of posterior wall CIMT progression included TC (P = .028), low-density lipoprotein-C (P = .035), non-HDL-C (P = .004), TG (P = .016), Apo B (P = .005), and ratios of TC/HDL-C (P < .001), TG/HDL-C (P = .015), Apo B/Apo AI (P = .012) and Apo B/HDL-C (P = .004). CONCLUSION: The strongest predictors for CIMT progression in anterior and posterior walls were lower baseline CIMT, increased TG, and elevated ratios, including TC/HDL-C, TG/HDL-C and Apo B/HDL-C. PMID- 21600519 TI - Effects of lecithin: cholesterol acyltransferase genotypes, enzyme levels, and activity on high-density lipoprotein levels. AB - BACKGROUND: Lecithin:cholesterol acyltransferase (LCAT) is one of the key enzymes controlling cholesterol homeostasis and plays a primary role in high-density lipoprotein cholesterol (HDL-C) maturation. OBJECTIVE: The aim of our study was to evaluate the effects of LCAT gene polymorphisms 511C/T (exon4), 4886C/T (rs5923), and 608C/T (rs5922) on LCAT enzyme level, activity, and HDL-C levels. METHODS: The study population was selected from consecutive subjects with low (<35 mg/dL) and high HDL-C levels (>65 mg/dL) seen in our lipid clinic. LCAT polymorphisms were analyzed with a restriction fragment length polymorphism assay. LCAT activity and levels were measured by colorimetric enzymatic and enzyme-linked immunoassay methods, respectively. RESULTS: The 4886C/T polymorphism was the most commonly observed variant of LCAT gene. T-allele frequencies in subjects with low (n = 50) and high (n = 50) HDL-C were 0.54 and 0.37, respectively (P = .019). TT genotype was more common among low HDL-C group (30% vs 14%, P = .05). The effects of LCAT enzyme appeared to depend on the HDL-C level. In subjects with low HDL-C, LCAT enzyme levels correlated positively with body mass index (P < .001, r = 0.544), HDL-C (P = .006, r = 0.404), triglycerides (P = .001, r = 0.487), total cholesterol (P < .001, r = 0.541), and low-density lipoprotein-cholesterol (P = .001, r = 0.477) levels. LCAT activity correlated positively with fasting glucose levels (P = .008, r = 0.390). CONCLUSION: LCAT genotype, enzyme level, and activity modulate HDL-C metabolism, particularly among subjects with low HDL-C levels. PMID- 21600520 TI - Potential effects on clinical management of treatment algorithms on the basis of apolipoprotein-B/A-1 and total/high-density lipoprotein-cholesterol ratios. AB - BACKGROUND: Apolipoprotein-B/A-1 (apoB/A-R) and total/high-density lipoprotein cholesterol ratios (TC/HDL-R) outperform non-high-density lipoprotein-cholesterol (non-HDL-C) suggested by Adult Treatment Panel (ATP) III guidelines for predicting cardiovascular (CV) outcomes. OBJECTIVE: To evaluate the potential effects that implementing our proposed apoB/A-R and TC/HDL-R treatment algorithms would have on clinical management. METHODS: We performed a chart review of all patients referred to the University of Michigan Lipid Clinic from January 2004 to June 2010. ATP III guidelines, including Framingham Risk Scores, were used to determine whether patients met non-HDL-C goals upon referral. Next, we evaluated whether subsequent management would differ if algorithms based upon potential apoB/A-R or TC/HDL-R targets derived from the literature were followed. RESULTS: Among patients (n = 692), mean non-HDL-C, apoB/A-R, and TC/HDL-R were 192.2 +/- 85.8 mg/dL, 0.92 +/- 0.64, and 6.7 +/- 8.0, respectively. Although moderately well correlated with apoB (r = 0.56, P < .01), non-HDL-C was less related to apoB/A-R (r = 0.20, P < .01) and TC/HDL-R (r = 0.39, P < .01). Most low-risk patients (<2 risk factors; n = 207) at non-HDL-C goal (<190 mg/dL) also met apoB/A-R <0.9 (79%) and TC/HDL-R <6.0 (92%) targets. However, a minority of high risk patients (Framingham Risk Score >20%, cardiovascular disease or risk equivalent; n = 307) meeting non-HDL-C goal (<130 mg/dL) achieved targets for apoB/A-R <0.5 (21%) or TC/HDL-C <3.5 (42%). The percentages of intermediate-risk patients meeting both non-HDL-C and ratio goals varied; nonetheless, few met an aggressive apoB/A-R <0.6 (36%-50%) target. CONCLUSIONS: Most high- and many intermediate-risk patients at non-HDL-C goals would require more aggressive treatment to reach the suggested apoB/A-R or TC/HDL-R targets. Whether this strategy yields superior outcomes merits future investigation. PMID- 21600521 TI - The population effects of the global cardiovascular risk model in United States adults: findings from the National Health and Nutrition Surveys, 2005-2006. AB - BACKGROUND: The Framingham Global Cardiovascular Disease (FRS-CVD) risk assessment is a proposed alternative for the assessment of hard coronary heart disease (FRS-CHD) event risk. Beyond heart attack and death, FRS-CVD risk adds the end points of cerebrovascular disease, angina, heart failure, and peripheral vascular disease. OBJECTIVE: We sought to estimate the population impact of using FRS-CVD instead of FRS-CHD risk prediction on U.S. adults. METHODS: We analyzed FRS-CHD and FRS-CVD risk in men age 45-74 and women age 55-74 without cardiovascular disease or diabetes, using the National Health and Nutrition Examination Survey 2005-2006. We stratified the population into 10-year risk categories: low: <6%, moderate >= 6 to <10%, moderate high >= 10 to <20%, and high >= 20% by both risk models, and assessed change in risk category distribution and achievement of lipid goals. RESULTS: We analyzed 1020 subjects who statistically represent approximately 50 million U.S. adults. When the FRS CVD was used, we found that 63% of men and 74% of women increase at least one risk category compared with when the FRS-CHD is used. Overall, the low-risk population decreases from 52% to 16% and the high-risk group increases from 4% to 20%. Of the subjects changing risk categories, 30% will now fail to meet their new corresponding lipid goals. CONCLUSIONS: FRS-CVD end points are more comprehensive, yet the population implications of such a change may be profound. The use of a FRS-CVD risk model significantly increases the intermediate and high risk groups, thus increasing the number of individuals eligible for novel risk assessment tools such as high-sensitivity C-reactive protein, coronary calcium scoring, and more frequent use of pharmacotherapy. PMID- 21600522 TI - Age is positively associated with high-density lipoprotein cholesterol among African Americans in cross-sectional analysis: the Jackson Heart Study. AB - BACKGROUND: African Americans have historically had high high-density lipoprotein cholesterol (HDL-C) compared with other races and ethnicities. OBJECTIVE: We sought to characterize whether there is a cross-sectional association between age and HDL-C in a contemporary community-based study of African Americans. METHODS: Cross-sectional data were modeled by logistic regression for predictors of HDL-C among African Americans, ages 35-74, participating in the baseline examination of a community-based study of cardiovascular disease in Jackson, Mississippi, during 2000-2004. After excluding persons taking lipid-lowering medications, hormone replacement therapy, oral contraceptives, or thyroid replacement, the analytical data set comprised 2420 persons (1370 women, 1050 men). RESULTS: HDL-C had a significant positive association with age after controlling for serum triglycerides, sex, waist circumference, percent dietary calories from carbohydrates, alcohol use, and leisure physical activity. Sex was a significant effect modifier of this relationship, whereby the increase in HDL-C with age was steeper for women than for men. CONCLUSIONS: Cross-sectional analysis found a positive association of HDL-C with age while controlling for triglycerides. Careful evaluation of longitudinal data will be needed to confirm whether this is a true effect of aging, or a cohort or survivor effect. PMID- 21600523 TI - Influence of simvastatin, fenofibrate and/or ezetimibe on correlation of low density lipoprotein and nonhigh-density lipoprotein cholesterol with apolipoprotein B in mixed dyslipidemic patients. AB - OBJECTIVES: Correlations between low-density lipoprotein cholesterol (LDL-C), or nonhigh-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (Apo B) change after statin therapy has been initiated in hypercholesterolemic patients. This post-hoc analysis studied the correlation between these parameters in patients with mixed dyslipidemia before and after receiving lipid-lowering treatment. RESULTS: Data from two randomized, double-blind studies of 1112 patients with mixed dyslipidemia receiving treatment (ezetimibe 10 mg, ezetimibe/simvastatin 10/20 mg, fenofibrate 160 mg, ezetimibe + fenofibrate 10/160 mg, or ezetimibe/simvastatin + fenofibrate 10/20/160 mg) were pooled. Correlation analyses and simple linear regression analyses were performed at baseline in untreated patients and after 12 weeks of treatment in the whole pooled population, the treatment groups, and after stratification by baseline triglyceride levels (150-250, >= 250 mg/dL) within the treatment groups. Both LDL C and non-HDL-C were closely correlated with levels of Apo B at baseline, and these correlations improved after treatment. When using the fitted simple linear regression equations, we found that the on-treatment LDL-C and non-HDL-C levels corresponding to an Apo B of 90, 80, and 70 mg/dL were lower than proposed LDL-C and non-HDL-C treatment targets. For TG >= 250 mg/dL, the corresponding LDL-C was generally lower than that for triglycerides 150-250 mg/dL, except in the cases with fenofibrate in the treatment. CONCLUSION: The results of these analyses suggest that achieving goal-specified levels of Apo B in statin-treated patients with mixed dyslipidemia would require more aggressive LDL-C lowering to achieve the greatest reduction in LDL particle number. PMID- 21600524 TI - A Mediterranean-style low-glycemic-load diet improves variables of metabolic syndrome in women, and addition of a phytochemical-rich medical food enhances benefits on lipoprotein metabolism. AB - BACKGROUND: The high prevalence of metabolic syndrome (MetS) has highlighted the need for effective dietary interventions to combat this growing problem. OBJECTIVE: To assess the impact of a Mediterranean-style low-glycemic-load diet (control arm, n = 44) or the same diet plus a medical food containing phytosterols, soy protein, and extracts from hops and acacia (intervention arm, n = 45) on cardiometabolic risk variables in women with MetS. METHODS: In this 12 week, 2-arm randomized trial, baseline, week 8 and 12, fasting blood samples were drawn to measure plasma lipids, apolipoproteins, and homocysteine. Dietary records were also collected and analyzed. RESULTS: There were decreases in fat and sugar intake (P < .001 for both) and increases in docosahexaenoic acid and eicosapentaenoic acid intake (P < .001 for both) over time, consistent with the prescribed diet. Regarding MetS variables, there were decreases in waist circumference, systolic and diastolic blood pressure, and plasma triglycerides in all subjects (P < .001 for all) with no differences between arms. Plasma low density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein (apo) B, and apo B/apo A1 were reduced over time but to a greater extent in the intervention arm (P < .05 for all), indicating the medical food had a greater effect in altering lipoprotein metabolism. Further, medical food intake was associated with reduced plasma homocysteine (P < .01) compared to the control arm. CONCLUSION: A Mediterranean-style low-glycemic-load diet effectively reduces the variables of MetS. Addition of the medical food results in a less atherogenic lipoprotein profile and lower plasma homocysteine. PMID- 21600525 TI - Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. AB - The familial hypercholesterolemias (FH) are a group of genetic defects resulting in severe elevations of blood cholesterol levels and increased risk of premature coronary heart disease. FH is among the most commonly occurring congenital metabolic disorders. FH is a treatable disease. Aggressive lipid lowering is necessary to achieve the target LDL cholesterol reduction of at least 50% or more. Even greater target LDL cholesterol reductions may be necessary for FH patients who have other CHD risk factors. Despite the prevalence of this disease and the availability of effective treatment options, FH is both underdiagnosed and undertreated, particularly among children. Deficiencies in the diagnosis and treatment of FH indicate the need for greatly increased awareness and understanding of this disease, both on the part of the public and of healthcare practitioners. This document provides recommendations for the screening, diagnosis and treatment of FH in pediatric and adult patients developed by the National Lipid Association Expert Panel on Familial Hypercholesterolemia. This report goes beyond previously published guidelines by providing specific clinical guidance for the primary care clinician and lipid specialist with the goal of improving care of patients with FH and reducing their elevated risk for CHD. PMID- 21600526 TI - Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. PMID- 21600527 TI - Pediatric aspects of familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. PMID- 21600528 TI - Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. PMID- 21600529 TI - Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. PMID- 21600530 TI - Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. PMID- 21600531 TI - Wrist and arm movements of varying difficulties. AB - Although a great deal of experimental attention has been directed at understanding Fitts' law, only a limited number of experiments have attempted to determine if performance differs across effectors for a given movement difficulty. In three experiments reciprocal wrist and arm movements were compared at IDs of 1.5, 3, 4.5 and 6. When absolute movement requirements and visual display were constant, participants' movement times and response characteristics for the arm and wrist were remarkably similar (Experiment 1). However, when amplitude for wrist movements was reduced to 8 degrees and the gain (4*) for the visual display increased participants' movement time, defined on the basis of kinematic markers (movement onset-movement termination), was increasingly shorter relative to arm movements as movement difficulty was increased (Experiment 2). Experiment 3 where the arm was tested at 32 degrees and 8 degrees with the 8 degrees movements provided the same gain (4*) that was used for the 8 degrees wrist movements in Experiment 2, no advantage was observed for the arm at the shorter amplitude. The results are interpreted in terms of the advantages afforded by the increased gain of the visual display, which permitted the wrist, but not the arm, to more effectively preplan and/or correct ongoing movements to achieve the required accuracy demands. It was also noted that while the wrist was more effective during the actual movement production this was accompanied by an offsetting increase in dwell time which presumably is utilized to dissipate the forces accrued during movement production and plan the subsequent movement segment. PMID- 21600532 TI - [Opinion of Spanish dermatologists regarding the use of biologic therapy in patients with moderate to severe psoriasis]. AB - BACKGROUND AND OBJECTIVES: Biologic therapy has represented a major advance in the treatment of moderate to severe psoriasis but its use depends upon the characteristics of the patient and the criteria applied by the dermatologist. The aim of this survey was to determine the criteria employed by dermatologists in the decision to use these drugs. METHODS: A cross-sectional survey was undertaken among Spanish dermatologists with experience in the treatment of moderate to severe psoriasis. The survey comprised 31 items distributed in 5 sections: investigator profile, disease management, treatment of moderate to severe psoriasis, use of biologic drugs, and evaluation of the use of biologic drugs for the treatment of moderate to severe psoriasis. RESULTS: One hundred-ninety dermatologists were included in the study. The study participants reported that 31% of patients receiving treatment for moderate to severe psoriasis are treated with biologic drugs. Of those, 28% require a change in treatment at some point due either to lack of activity or the appearance of side effects. Biologic drugs would be administered as monotherapy in 73% of cases. In between 53% and 59% of cases, biologic drugs would be prescribed as continuous treatments. On a scale of 1 to 5, the most valued pharmacological properties by dermatologists were safety (4.8 points; 95% confidence interval [CI], 4.7-4.9), long-term efficacy (4.6 points [4.5-4.7]), and tolerance (4.5 [4.4-4.6]). CONCLUSIONS: Dermatologists with experience in the use of biologic drugs employ this treatment option in slightly more than a quarter of cases of moderate to severe psoriasis. In their opinion, the choice of biologic drug should be based on, in order of importance, safety, long-term efficacy, and tolerance. PMID- 21600533 TI - Prevalence and impact of coronary artery disease in patients with pulmonary arterial hypertension. AB - The occurrence and impact of coronary artery disease (CAD) among patients with pulmonary arterial hypertension (PAH) are unknown. We aimed to determine the prevalence, clinical correlates, and effect of CAD in patients with PAH. We reviewed the medical records of consecutive patients diagnosed with PAH at a university-based referral center for pulmonary vascular disease from January 1990 to May 2010. The patients systematically underwent right heart catheterization and coronary angiography as a part of their evaluation. The patients with PAH with CAD (defined as >=50% stenosis in >=1 major epicardial coronary artery) were compared to patients without CAD. Among the 162 patients with PAH, the prevalence of CAD was 28.4%. The presence of CAD was associated with older age (66.6 +/- 11.5 vs 49.2 +/- 14.0 years, p <0.001), systemic hypertension, and dyslipidemia. The patients with PAH and CAD had a lower mean pulmonary arterial pressure (44.6 +/- 11.1 vs 49.2 +/- 14.0 mm Hg; p = 0.02) than patients without CAD. During a median follow-up of 36 months, 73 patients died. The presence of CAD was a predictor of all-cause mortality on univariate analysis (hazard ratio 1.97, 95% confidence interval 1.21 to 3.20) but not on multivariate analysis, which identified older age (hazard ratio 1.03, 95% confidence interval 1.01 to 1.05) and right atrial pressure (hazard ratio 1.08, 95% confidence interval 1.03 to 1.14) as the only independent predictors. In conclusion, our study has demonstrated that CAD is common among patients with PAH. CAD prevalence increases with age, dyslipidemia, and hypertension, but we did not detect an independent prognostic effect of CAD on mortality. PMID- 21600534 TI - Relation of early termination of persistent atrial fibrillation by cardioversion or drugs to ablation outcomes. AB - Current ablation consensus documents define persistent atrial fibrillation (AF) as AF lasting >1 week to 1 year or AF requiring cardioversion or pharmacologic conversion in <1 week. These 2 persistent AF subgroups may have different clinical characteristics and ablation outcomes. We compared 179 patients whose persistent AF was always terminated in <1 week by cardioversion/drugs to 244 whose AF actually lasted >1 week to 1 year. Patients with AF termination in <1 week by cardioversion/drugs had smaller left atrial (LA) size (4.1 +/- 0.6 vs 4.5 +/- 0.7 cm, p <0.0001), a longer AF history (7.5 +/- 7.5 vs 6.0 +/- 7.2 years, p = 0.035), more failed drugs (1.6 +/- 1.0 vs 1.3 +/- 1.0, p = 0.004), lower body mass index (28.5 +/- 5.5 vs 30.3 +/- 5.5, p = 0.0008), and fewer cardiomyopathies (3.9% vs 11.1%, p = 0.01). Cox multivariate analysis showed that LA size (p = 0.02), female gender (p = 0.001), and coronary artery disease (p = 0.03) predict ablation failure. There was a linear relation between duration of longest AF episode and LA size (p = 0.0001). Longest AF episode duration was the only factor predicting LA size (p = 0.001). Kaplan-Meier analysis showed more patients with AF termination in <1 week by cardioversion/drugs were free of AF after ablation (p = 0.042) than those whose AF actually lasted >1 week to 1 year. Once AF lasted >1 week, duration up to 1 year did not affect ablation success. In conclusion, patients whose persistent AF is always terminated by drugs/cardioversion in <1 week have different clinical characteristics and better ablation outcomes than patients whose AF persists beyond 1 week. This suggests that maintaining sinus rhythm before ablation is beneficial and that the definition of AF2 may need revision. PMID- 21600535 TI - Association of troponin T, detected with highly sensitive assay, and outcomes in infective endocarditis. AB - Troponin levels have been correlated with adverse outcomes in multiple disease processes, including congestive heart failure, acute coronary syndromes, sepsis, and, in a few small series, infective endocarditis. We hypothesized that a novel measurement of troponin using a highly sensitive assay would correlate with adverse outcomes when prospectively studied in patients with infective endocarditis. At a single center in the International Collaboration on Endocarditis, 42 patients met the inclusion criteria and underwent testing for cardiac troponin T (cTnT) using both a standard and a highly sensitive precommercial assay. The cTnT levels were associated with the prespecified primary composite outcome of death, central nervous system event, and cardiac abscess. Secondary outcomes included the individual components of the composite outcome and the need for cardiac surgery. A receiver operating characteristic curve was derived and used to identify the optimal cutpoint for cTnT using the highly sensitive assay. cTnT was detectable with the highly sensitive assay in 39 (93%) of 42 patients with infective endocarditis and with the standard assay in 25 (56%) of 42 (p <0.05). Of the 42 patients, 15 experienced the composite outcome, 4 died, 9 had a central nervous system event, and 5 had a cardiac abscess. With the hs-cTnT assay, the median cTnT was greater in the patients who experienced the primary outcome (0.12 vs 0.02 ng/ml, p <0.05). According to the receiver operating characteristic curve analysis (area under the curve of 0.74), cTnT levels of >=0.08 ng/ml produced optimal specificity (78%) for the primary outcome. The patients with a cTnT level of >=0.08 ng/ml were more likely to experience the primary outcome (odds ratio 7.0, 95% confidence interval 1.7 to 28.6, p <0.01) and a central nervous system event (odds ratio 9.3, 95% confidence interval 1.3 to 24.1, p = 0.02). In conclusion, cTnT is detectable in 93% of patients with infective endocarditis using a novel highly sensitive assay, with higher levels correlating with poor clinical outcomes. PMID- 21600536 TI - Impact of duration of ischemia on left ventricular diastolic properties following reperfusion for acute myocardial infarction. AB - We sought the correlation between duration of myocardial ischemia and severe left ventricular (LV) diastolic dysfunction (restrictive filling pattern [RFP]) in patients with acute ST-elevation myocardial infarction (STEMI). Duration of ischemia determines infarct size and survival after STEMI. However, the impact of duration of ischemia on LV diastolic function has not been previously studied. Ninety-five consecutive patients with first-ever STEMI underwent transthoracic echocardiography 3 days after primary percutaneous coronary intervention (PCI). RFP was defined as a mitral inflow E/A ratio >2.0 and/or E-wave deceleration time <140 ms. Composite major adverse cardiovascular events (death, reinfarction, heart failure, revascularization) were determined at 12 months. Twenty patients (21%) had RFP on day 3. Symptom-to-reperfusion time in the RFP group was 413 +/- 287 versus 252 +/- 138 minutes in the non-RFP group (p = 0.014). Peak troponin T levels were higher in the RFP group (12.2 +/- 8.4 vs 5.7 +/- 3.6 ng/ml, p = 0.002). Logistic regression identified symptom-to-reperfusion time (hazard ratio 1.02, 95% confidence interval 1.01 to 1.03, p = 0.010) and infarct size by peak troponin T levels (hazard ratio 1.54, 95% confidence interval 1.14 to 2.10, p = 0.005) as independent predictors of RFP. Major adverse cardiovascular events occurred in 10 patients (50%) in the RFP group and 6 patients (8%) in the non-RFP group. On multivariate Cox proportional hazards analysis, RFP was an independent predictor of major adverse cardiovascular events at 12 months (hazard ratio 5.43, 95% confidence interval 1.52 to 19.39, p = 0.001). In conclusion, delayed reperfusion after STEMI was associated with severe LV diastolic dysfunction, which in turn independently predicted adverse long-term outcomes. LV diastolic dysfunction represents a significant pathophysiologic link among duration of myocardial ischemia, infarct size, and outcomes. PMID- 21600537 TI - Usefulness of plasma galectin-3 levels in systolic heart failure to predict renal insufficiency and survival. AB - Galectin-3 plays an important role in fibroblast activation and fibrosis in animal models. Increased galectin-3 levels are associated with poor long-term survival in heart failure (HF). We examined the relation between plasma galectin 3 levels and myocardial indexes of systolic HF. We measured plasma galectin-3 in 133 subjects with chronic HF and 45 with advanced decompensated HF using echocardiographic and hemodynamic evaluations. In the chronic HF cohort, median plasma galectin-3 level was 13.9 ng/ml (interquartile range 12.1 to 16.9). Higher galectin-3 was associated with more advanced age (r = 0.22, p = 0.010), poor renal function (estimated glomerular filtration rate, r = -0.24, p = 0.007; cystatin C, r = 0.38, p <0.0001) and predicted all-cause mortality (hazard ratio 1.86, 95% confidence interval 1.36 to 2.54, p <0.001). In multivariate analysis, galectin-3 remained an independent predictor of all-cause mortality after adjusting for age, estimated glomerular filtration rate, left ventricular (LV) ejection fraction, and mitral early diastolic myocardial relaxation velocity at septal mitral annulus (hazard ratio 1.94, 95% confidence interval 1.30 to 2.91, p = 0.001). However, galectin-3 did not predict the combined end point of all-cause mortality, cardiac transplantation, or HF hospitalization (p >0.05). Furthermore, there were no relations between galectin-3 and LV end-diastolic volume index (r = -0.05, p = 0.61), LV ejection fraction (r = 0.10, p = 0.25), or LV diastolic function (mitral early diastolic myocardial relaxation velocity at septal mitral annulus, r = 0.06, p = 0.52; left atrial volume index, r = 0.08, p = 0.41). In the advanced decompensated HF cohort, we did not observe any relation between galectin-3 and echocardiographic or hemodynamic indexes. In conclusion, high plasma galectin-3 levels were associated with renal insufficiency and poorer survival in patients with chronic systolic HF. However, we did not observe a relation between galectin-3 and echocardiographic or hemodynamic indexes. PMID- 21600538 TI - Relation of clinical, echocardiographic and electrocardiographic features of cardiac amyloidosis to the presence of the transthyretin V122I allele in older African-American men. AB - Previous studies have shown that 3% to 4% of African Americans carry an amyloidogenic allele of the human serum protein transthyretin (TTR V122I). The allele appears to have an absolute anatomic risk for cardiac amyloid deposition after 65 years of age. In this study, a case-control comparison was performed of clinical, echocardiographic, and electrocardiographic characteristics of 23 age at risk carriers of the amyloidogenic allele and 46 age-, gender-, and ethnically matched noncarriers being evaluated for cardiac disease using standard clinical testing. The 2 groups were matched for blood pressure and the cardiac ejection fraction. None of the subjects had a prestudy diagnosis of cardiac amyloidosis. Carriers of the amyloidogenic allele were found to have statistically significant increases in the occurrence of many of the echocardiographic features of cardiac amyloidosis relative to the noncarriers and a higher frequency of congestive heart failure and atrial fibrillation. The observations suggest that TTR V122I represents a substantial risk for clinically significant cardiac amyloidosis in elderly African American men, behaving as an age-dependent autosomal dominant disease-associated allele. The diagnosis is difficult to make but can be suspected in African Americans aged >60 years on the basis of age, echocardiographic evidence of diastolic dysfunction, and interventricular septal thickening, even in the absence of more recently available sophisticated echocardiographic techniques for evaluating long-axis function and cardiac magnetic resonance imaging. Positive results for the amyloidogenic TTR V122I allele support the diagnosis and define the origin of the disease, which can be confirmed by endomyocardial biopsy. PMID- 21600539 TI - Validation of mortality risk stratification models for cardiovascular disease. AB - Risk stratification models are effective tools for the management of cardiovascular diseases. Although several risk scores have been proposed, the relevance and superiority of these predictive models have not been fully validated in an independent and nonclinical trial-based population. We studied 2,472 consecutive patients initially hospitalized in our institution from April 2004 to December 2009. Risk scores were calculated for each patient using 4 risk score models, including the Seattle Heart Failure Model (SHFM), Acute Decompensated Heart Failure National Registry regression model, the American Heart Association Get With The Guidelines-Heart Failure score, and the Association of Health Aging and Body Composition Heart Failure score. The predictive ability for the composite end point, including total death, heart transplantation, and left ventricle assist device implantation, was assessed by calculating the area under the receiver operating characteristic curve for each model. During the follow-up period after admission (median 924.5 days), the combined end point occurred in 295 patients (11.8%), including 27 in-hospital deaths (1.1%). Compared with the other 3 risk score models, the SHFM risk score demonstrated a greater area under the curve for the combined end point at the overall, in-hospital, 30-day, and 1-, 2-, and 3-year follow-up point (0.741 to 0.890). The survival rate predicted by SHFM demonstrated an excellent correlation with the actual survival rate (R(2) = 0.990). In conclusion, these results suggest that the SHFM risk score is the most suitable for the discrimination and calibration of mortality risk stratification in patients with cardiovascular disease. PMID- 21600540 TI - Comparison of medically versus surgically treated acute type a aortic dissection in patients <80 years old versus patients >=80 years old. AB - Although recent progress in emergency surgery has resulted in an increase in the indication for older patients with acute type A aortic dissection (AAD), some patients remain who cannot undergo surgical treatment and little is known about the prognosis of patients with AAD who receive medical treatment, especially in elderly patients. Of the 82 patients with AAD who were admitted to our institution, 48 received medical therapy only. We retrospectively reviewed their clinical data and analyzed the prognostic value of the clinical characteristics in both younger and older patients. The in-hospital and 1-year mortality were significantly lower in the patients who underwent surgical treatment than in those who received medical treatment (6% vs 65%, p <0.001; 8% vs 73%, p <0.001, respectively). Of the patients with medical treatment, the in-hospital and 1-year mortality rate in the younger (<80 years old, n = 27) and older (>=80 years old, n = 21) groups was 70% and 80% and 57% and 65%, respectively. For the younger group, the presence of an open false lumen was significantly associated with in hospital mortality (89% vs 50%, p = 0.044). In contrast, in the older group, a lower serum albumin level (3.4 +/- 0.3 vs 4.0 +/- 0.5 g/dl, p = 0.010) and the incidence of an open false lumen (83% vs 33%, p = 0.032) were significantly associated with in-hospital mortality. In conclusion, in addition to an open false lumen as a risk factor, a lower serum albumin level is an important prognostic factor in older patients with AAD. PMID- 21600541 TI - Usefulness of peripheral vascular function to predict functional health status in patients with Fontan circulation. AB - After the Fontan operation, patients are at a substantial risk of the development of impaired functional health status. Few early markers of suboptimal outcomes have been identified. We sought to assess the association between peripheral vascular function and functional health status in Fontan-palliated patients. Asymptomatic Fontan patients (n = 51) and age- and gender-matched healthy controls (n = 22) underwent endothelial pulse amplitude testing using a noninvasive fingertip peripheral arterial tonometry (PAT) device. Raw data were transformed into the PAT ratio, an established marker of vascular function. Cardiopulmonary exercise testing was performed using the Bruce protocol. In the Fontan cohort, 94% of patients were New York Heart Association functional class I and 88% had a B-type natriuretic peptide level of <50 pg/ml. The baseline pulse amplitude, a measure that reflects the arterial tone at rest, was greater in the Fontan patients than in the controls (median 2.74, interquartile range 1.96 to 4.13 vs median 1.86, interquartile range 1.14 to 2.79, p = 0.03). The PAT ratio, a measure of reactive hyperemia, was lower in Fontan patients (median 0.17, interquartile range -0.04 to 0.44, vs median 0.50, interquartile range 0.27 to 0.74, p = 0.002). The key parameters of exercise performance, including peak oxygen consumption (median 28.8 ml/kg/min, interquartile range 25.6 to 33.2 vs median 45.5 ml/kg/min, interquartile range 41.7 to 49.9, p <0.0001) and peak work (median 192 W, interquartile range 150 to 246 vs median 330, interquartile range 209 to 402 W, p <0.0001), were lower in Fontan patients than in the controls. The PAT ratio correlated with the peak oxygen consumption (r = 0.28, p = 0.02) and peak work (r = 0.26, p = 0.03). In conclusion, in an asymptomatic Fontan population, there is evidence of reduced basal peripheral arterial tone and vasodilator response, suggesting dysfunction of the endothelium-derived nitric oxide pathway. Vasodilator function appears to correlate with exercise performance. PMID- 21600542 TI - Cardiac structure and function in persons 85 years of age. AB - Individuals aged >85 years constitute the world's most rapidly growing age group. Despite the rapid growth of this population and its high incidence of cardiovascular morbidity, normative data concerning cardiac structure and function are limited. The objective of this study was to define cardiac structure and function in an age-homogenous, community-dwelling population of subjects born in 1920 and 1921. Subjects were recruited from the Jerusalem Longitudinal Cohort Study. Echocardiography was performed using a portable echocardiograph at the subject's place of residence. Standard echocardiographic assessment of cardiac structure and function was performed. Four hundred fifty subjects (219 men, 231 women) were enrolled in the study. The cohort exhibited large left atrial volumes (64.6 +/- 26 ml) and high left ventricular (LV) mass indexes (122 +/- 36 g/m(2)) with normal LV volumes. Ejection fractions were preserved (55.3 +/- 10.2%), but tissue Doppler s-wave velocities (lateral 7.8 +/- 2.1 cm/s, septal 6.7 +/- 1.9 cm/s) were reduced. Reduced tissue Doppler e waves (lateral 7.3 +/- 2.2 cm/s, septal 6.2 +/- 2 cm/s) and elevated E/e' ratios (12.2 +/- 4.9) indicated significantly impaired diastolic function. In conclusion, the findings of this study demonstrate a high prevalence of left atrial enlargement, elevated LV mass, evidence of LV systolic dysfunction with preserved ejection fractions, and significant LV diastolic dysfunction in a community-dwelling cohort of 85-year olds. The finding of elevated E/e' ratios in a subset free of known cardiovascular disease should be considered when clinical assessment of LV diastolic dysfunction in this age group is performed. PMID- 21600543 TI - Meta-analysis of randomized controlled trials on effect of angiotensin-converting enzyme inhibitors on cancer risk. AB - The renin-angiotensin system is an important mediator of tumor progression and metastasis. A recent meta-analysis of randomized controlled trials reported an increased risk of cancer with angiotensin receptor blockers. It is unknown whether angiotensin-converting enzyme (ACE) inhibitors may have a similar effect. Our primary objective was to determine the effect of ACE inhibitors on cancer occurrence and cancer death. Our secondary objective was to determine the effect of ACE inhibitors on occurrence of gastrointestinal (GI) cancers given previous concerns of increased risk. Systematic searches of SCOPUS (covering MEDLINE, EMBASE, and other databases) and the Food and Drug Administration official web site were conducted for all randomized controlled trials of ACE inhibitors. Trials with >=1 year of follow-up and enrolling a minimum of 100 patients were included. Fourteen trials reported cancer data in 61,774 patients. This included 10 trials of 59,004 patients providing information on cancer occurrence, 7 trials of 37,515 patients for cancer death, and 5 trials including 23,291 patients for GI cancer. ACE inhibitor therapy did not have an effect on occurrence of cancer (I(2) 0%, risk ratio [RR] 1.01, 95% confidence interval [CI] 0.95 to 1.07, p = 0.78), cancer death (I(2) 0%, RR 1.00, 95% CI 0.88 to 1.13, p = 0.95), or GI cancer (RR 1.09, 95% CI 0.88 to 1.35, p = 0.43). In conclusion, ACE inhibitors did not significantly increase or decrease occurrence of cancer or cancer death. There was also no significant difference in risk of GI cancer. PMID- 21600544 TI - Prognostic value of serial global longitudinal strain measured by two-dimensional speckle tracking echocardiography in patients with ST-segment elevation myocardial infarction. AB - The aim of this study was to determine whether assessment of global longitudinal strain (GLS) before revascularization could predict adverse cardiac events after ST-segment elevation myocardial infarction (STEMI). In addition, the relation between GLS and cardiac biomarkers was investigated. From July 2006 through December 2009, 98 patients with first STEMI underwent conventional and speckle tracking echocardiography at initial presentation and 3 days after primary coronary intervention. Patients were divided into 3 groups according to percent changes of GLS compared to baseline GLS values: group 1, improved GLS >10%; group 2, unchanged GLS from -10% to 10%; and group 3, decreased GLS <-10%. Subsequent complications including all-cause mortality and readmission because of congestive heart failure during a 6-month period of follow-up were prospectively evaluated. After coronary intervention, GLS was improved in 29 patients (30%, group 1), unchanged in 55 patients (56%, group 2), and worsened in 14 patients (14%, group 3). Complications developed in 7 patients (group 1, n = 0, 0%; group 2, n = 2, 28%; group 3, n = 5, 72%, p <0.01). Multivariate Cox analysis showed an independent association of GLS before and after coronary intervention with subsequent complications. Significant correlations were observed between GLS and cardiac biomarkers. In conclusion, GLS assessment before coronary intervention was a good predictor of complications in patients with STEMI comparable to predictions using GLS after intervention at 6-month follow-up. PMID- 21600545 TI - Methodology and pharmacological analysis of effects of uterotonic compounds in human myometrium in vitro. AB - OBJECTIVE: The methodology used to evaluate contractile effects of uterotonic agents in human myometrium in vitro varies. The are no studies evaluating the reliability of these commonly used techniques. STUDY DESIGN: Myometrial strips (n=72) were exposed to 3 known uterotonic agents: oxytocin, U46619, and phenylephrine. The negative log of the molar concentration of the agonist that produces a half-maximal response (pEC50) and maximal response values were obtained, and compared, when either amplitude or mean force was used as indices of contraction. All data were expressed as a percentage of KCl elicited actvity. RESULTS: Using pEC50 measurements, the order of potency was oxytocin greater than U46619 greater than phenylephrine for both indices, whereas the order of maximal response varied between mean force and amplitude. The coefficient of variation was lowest for pEC50 measurements, highest for maximal force estimations, and overall was 10-48% between, and 2-27% within, donor samples. CONCLUSION: These findings support the use of pEC50 measurements for in vitro experiments using uterotonic agents and outline the variability that occurs for such myometrial experiments. PMID- 21600547 TI - Beta-2 adrenoceptor genotype and progress in term and late preterm active labor. AB - OBJECTIVE: We sought to evaluate whether beta-2 adrenoceptor (beta2AR) genotype at a functional polymorphic site encoding for amino acid residue 16 influences rate of cervical dilatation in term and late preterm active labor. STUDY DESIGN: Subjects who underwent vaginal delivery at >=34 weeks' gestational age from May 2006 through August 2007 were identified. Each subject had provided venous blood from which DNA was extracted for beta2AR genotyping. Digital cervical examinations with paired examination times were collected from intrapartum records. Rate of cervical dilatation in active labor was determined using linear regression. Rates were compared between genotype groups. RESULTS: Among 401 subjects with satisfactory genotype and intrapartum data, overall rate of active labor was 0.76+/-0.01 cm/h. When labor was compared by genotype, homozygous Arg/Arg16 subjects progressed at a slower rate (0.64+/-0.03 cm/h) than all other pooled genotypes (0.8+/-0.02 cm/h, P<.001). CONCLUSION: Homozygous beta2AR genotype encoding for Arg/Arg16 was associated with slower progress in active labor. PMID- 21600548 TI - Maternal serum folate species in early pregnancy and lower genital tract inflammatory milieu. AB - OBJECTIVE: We previously reported that elevated antiinflammatory cervical cytokines in early pregnancy were associated with spontaneous preterm birth. Our objective was to explore the relation between serum folate vitamers and the lower genital tract inflammatory milieu. STUDY DESIGN: Pregnant women (n = 417) at <16 weeks' gestation had serum samples that were analyzed for folate species 5 methyltetrahydrofolate, 5-formyltetrahydrofolate, and cervical fluid that was assayed for cytokine concentrations. Patterns in proinflammatory cytokines (interleukin [IL]-1beta, -6, -8, and -10; monocyte chemotactic protein-1) and antiinflammatory cytokines (IL-4, IL-10, IL-13) were identified with factor analysis. RESULTS: After confounder adjustment, maternal serum 5 methyltetrahydrofolate concentrations had a strong negative association with elevated antiinflammatory scores; serum 5-formyltetrahydrofolate concentrations were associated positively with elevated antiinflammatory scores (both P < .05). Maternal folate was not associated with proinflammatory scores. CONCLUSION: Maternal serum folate vitamers are associated with cervical cytokine concentrations, which suggests a possible mechanistic link between folate and preterm birth risk. PMID- 21600549 TI - Predicting the number of women who will undergo incontinence and prolapse surgery, 2010 to 2050. AB - OBJECTIVE: We sought to estimate the number of women who will undergo inpatient and outpatient surgery for stress urinary incontinence (SUI) or pelvic organ prolapse (POP) in the United States from 2010 through 2050. STUDY DESIGN: Using the 2007 Nationwide Inpatient Sample and the 2006 National Survey of Ambulatory Surgery, we calculated the rates for inpatient and outpatient SUI and POP surgery. We applied the surgery rates to the US Census Bureau population projections from 2010 through 2050. RESULTS: The total number of women who will undergo SUI surgery will increase 47.2% from 210,700 in 2010 to 310,050 in 2050. Similarly, the total number of women who will have surgery for prolapse will increase from 166,000 in 2010 to 245,970 in 2050. CONCLUSION: If the surgery rates for pelvic floor disorders remain unchanged, the number of surgeries for urinary incontinence and POP will increase substantially over the next 40 years. PMID- 21600551 TI - Should patients with cytologic high-grade intraepithelial lesions of the cervix be treated without colposcopic-guided biopsy? PMID- 21600550 TI - Progesterone receptor polymorphisms and clinical response to 17-alpha hydroxyprogesterone caproate. AB - OBJECTIVE: Seventeen-alpha-hydroxyprogesterone caproate (17-OHPC) reduces recurrent preterm birth (PTB). We hypothesized that single nucleotide polymorphisms in the human progesterone receptor (PGR) affect response to 17-OHPC in the prevention of recurrent PTB. STUDY DESIGN: We conducted secondary analysis of a study of 17-OHPC vs placebo for recurrent PTB prevention. Twenty PGR gene single nucleotide polymorphisms were studied. Multivariable logistic regression assessed for an interaction between PGR genotype and treatment status in modulating the risk of recurrent PTB. RESULTS: A total of 380 women were included; 253 (66.6%) received 17-OHPC and 127 (33.4%) received placebo. In all, 61.1% of women were African American. Multivariable logistic regression demonstrated significant treatment-genotype interactions (either a beneficial or harmful treatment response) for African Americans delivering<37 weeks' gestation for rs471767 and rs578029, and for Hispanics/Caucasians delivering<37 weeks' gestation for rs500760 and <32 weeks' gestation for rs578029, rs503362, and rs666553. CONCLUSION: The clinical efficacy and safety of 17-OHPC for recurrent PTB prevention may be altered by PGR gene polymorphisms. PMID- 21600552 TI - Impact of using triclosan-antibacterial sutures on incidence of surgical site infection. AB - BACKGROUND: Surgical site infection is a common complication of surgery. Its morbidities range from delayed healing to systemic sepsis. It has impact on the economy and health care resources. METHODS: This study was a prospective, randomized, double-blinded, controlled multicenter study aimed to compare triclosan-coated polyglactin 910 sutures with polyglactin 910 sutures for the reduction of surgical site infections. This article details the results from the Cairo University center. A total of 450 patients who had undergone different surgical procedures were enrolled; 230 were enrolled in the study group and 220 were enrolled in the control group. RESULTS: The study group and the control group were comparable regarding risk factors for surgical site infection. Surgical site infection incidence was 7% in the study group and 15% in the control group (P = .011). The mean extended stay as a result of infection was 3.71 days, with an average cost $91 US per day. CONCLUSIONS: Use of the triclosan coated polyglactin 910 antimicrobial suture lead to reduction of surgical site infection and has an impact on saving health care resources. The triclosan-coated polyglactin 910 antimicrobial suture could save $1,517,727 yearly in this single center. PMID- 21600553 TI - Clinicopathological significance of synchronous carcinoma in colorectal cancer. AB - BACKGROUND: Synchronous colorectal carcinoma has seldom been studied in large series. The study was designed to examine the significance of colorectal synchronous carcinoma in a large cohort of patients. METHODS: The clinicopathological features of 102 patients with synchronous colorectal carcinoma were compared with 1,793 patients with solitary colorectal carcinoma. RESULTS: The prevalence of synchronous colorectal carcinoma was 3.6%. In these patients, 4% had FAP, 6% had hyperplastic polyposis, and 2% had ulcerative colitis. The index carcinoma was more likely to have higher histological grade and T stage than other carcinoma(s) in the same patient. When compared with solitary colorectal carcinoma, synchronous colorectal carcinoma was more often noted in males with coexisting FAP and in proximal location. The 5-year survival rate of patients with synchronous colorectal carcinoma was 53% and was similar to those with solitary colorectal carcinoma. CONCLUSIONS: We examined the clinicopathological features of patients with synchronous colorectal carcinomas in a large cohort of patients. Attention to these features was important for better management of this group of cancer. PMID- 21600554 TI - Repair of large abdominal incisional hernia by reconstructing the midline and use of an onlay of biological material. AB - BACKGROUND: The aim of this study was to determine the feasibility and efficacy of repairing large abdominal incisional hernias by reconstructing the midline using bilateral abdominis rectus muscle sheath (ARS) relaxing incisions and a biological material onlay. METHODS: Between January 2002 and December 2008, 71 patients underwent repair of large incisional hernias at 2 community hospitals. After replacement of hernia sac contents into the peritoneal cavity, a relaxing incision was made in the ARS bilaterally. Then, the midline was closed primarily. The biological material was used as an onlay and sutured to the lateral edges of the relaxed ARS. Main outcome measures were postoperative complications and hernia recurrence. RESULTS: Median defect size was 195 cm(2) (range, 150-420 cm(2)), median surgical time was 125 minutes, and median hospital stay was 6 days. There were no deaths and no wound infections. Wound seroma, the most frequent postoperative complication, occurred in 51 (72%) of the 71 patients. There was 1 (1.4%) recurrence. CONCLUSIONS: In these 71 patients, our technique for repair of large abdominal incisional hernias was safe and effective. PMID- 21600555 TI - Association of 6% hetastarch resuscitation with adverse outcomes in critically ill trauma patients. AB - BACKGROUND: Six percent hetastarch is used as a volume expander but has been associated with poor outcomes. The aim of this study was to evaluate trauma patients resuscitated with hetastarch. METHODS: A retrospective review was performed of adult trauma patients. Demographics, injury severity, laboratory values, outcomes, and hetastarch use were recorded. RESULTS: A total of 2,225 patients were identified, of whom 497 (22%) received hetastarch. There were no differences in age, gender, injury mechanism, lactate, hematocrit, or creatinine. The mean injury severity score was different: 29.7 +/- 12.6 with hetastarch versus 27.5 +/- 12.6 without hetastarch. Acute kidney injury developed in 65 hetastarch patients (13%) and in 131 (8%) without hetastarch (relative risk, 1.73; 95% confidence interval [CI], 1.30-2.28). Hetastarch mortality was 21%, compared with 11% without hetastarch (relative risk, 1.84; 95% CI, 1.48-2.29). Multivariate logistic regression demonstrated hetastarch use (odds ratio, 1.96; 95% CI, 1.49-2.58) as independently significant for death. Hetastarch use was independently significant for renal dysfunction as well (odds ratio, 1.70; 95% CI, 1.22-2.36). CONCLUSIONS: Because of the detrimental association with renal function and mortality, hetastarch should be avoided in the resuscitation of trauma patients. PMID- 21600556 TI - Positive margins after breast-conserving therapy: localization technique or tumor biology? AB - BACKGROUND: The relative contributions of patient and tumor factors versus radiologic localization technique to the rates of inadequate margins of excision in breast-conserving therapy have not been defined. METHODS: Patients undergoing breast-conserving therapy were studied. Margins less than 2 mm from tumor were considered inadequate. RESULTS: Of 539 patients, 31% were guided by palpation and 69% were guided by preoperative radiologic localization. The palpation-guidance patients had larger tumors (P < .0001) and more nodal metastases (P = .0005). The rates of inadequate margins were 10% for palpation-guided patients and 11% for radiologic-localization patients (P = .53). The 3-year rates of local recurrence were .7% for palpation-guided patients and 1.8% for radiologic-guided patients (P = .5). CONCLUSIONS: Patient, tumor, and intraoperative pathologic factors, not just localization device shortcomings, produce inadequate margins of excision in breast-conserving therapy. A reasonable expected rate of inadequate margins owing to patient and tumor factors is 10%. Quality improvement for margin management must focus on intraoperative assessment of margins, especially for patients with identified risk factors, in addition to improving localization technique. PMID- 21600557 TI - Outcome of palliative total gastrectomy for stage IV proximal gastric cancer. AB - BACKGROUND: A few studies have investigated the outcome of palliative total gastrectomy (PTG) in stage IV proximal gastric cancer. In this study, we tried to summarize the outcome of PTG in stage IV proximal gastric cancer. METHODS: Between January 1991 and January 2005, complete clinical data of 197 patients with stage IV proximal gastric cancer undergoing PTG, 642 patients undergoing curative total gastrectomy (CTG), 152 nonsurgical patients, 102 patients undergoing explorative laparotomy, and 78 patients undergoing jejunostomy were enrolled in this study. Survival rates, median survival, complication rates, and mortality were analyzed. RESULTS: The 1-year, 3-year, and 5-year survival rates were 61.3%, 8.9%, and 6.4% in the PTG group, respectively, and 92.3%, 58.5%, and 48.9% in the CTG group, respectively (P < .05). The median survival periods in the PTG, no surgery, laparotomy, and jejunostomy groups were 16.4, 5.5, 4.7, and 5.8 months, respectively. The median survival in the PTG group was significantly longer than that in the other 3 groups (P < .05). The postoperative complication rate and mortality rate were, respectively, 24.3% and 3.0% in the PTG group and 13.5% and 2.3% in the CTG group (P > .05). CONCLUSIONS: PTG for stage IV proximal gastric cancer when compared with no surgery, laparotomy, and jejunostomy is associated with prolonged survival time and improved quality of life. However, despite the feasibility and safety of PTG, patients with stage IV proximal gastric cancer who are suitable for this treatment should be selected, and thoughtful preparation should be made in the perioperative period. PMID- 21600558 TI - Distal pancreatectomy with duct-to-mucosa pancreaticogastrostomy: a novel technique for preventing postoperative pancreatic fistula. AB - BACKGROUND: Management of the pancreatic remnant after distal pancreatectomy remains a clinically relevant problem and a significant clinical challenge. We evaluated the safety and efficacy of duct-to-mucosa pancreaticogastrostomy for preventing pancreatic fistula development after distal pancreatectomy. METHODS: Twenty-one patients underwent distal pancreatectomy using the duct-to-mucosa pancreaticogastrostomy and the clinical data were collected prospectively. Pancreatic fistula was defined and classified according to the international study group definition. RESULTS: The median surgical time was 236 minutes, with a median intraoperative blood loss of 250 mL. Morbidity was 5% and mortality was nil. The postoperative pancreatic fistula rate of clinically relevant grade B or C fistulae was 0%, although the biochemical grade A fistula rate was 29%. Delayed gastric emptying developed in only 1 patient (5%). CONCLUSIONS: Duct-to-mucosa pancreaticogastrostomy may be a safe and effective technique for preventing pancreatic fistula development after distal pancreatectomy when performed by experienced surgeons who are skilled in this technique. PMID- 21600559 TI - Laparo-endoscopic single site cholecystectomy versus standard laparoscopic cholecystectomy: results of a pilot randomized trial. AB - BACKGROUND: In recent years, new devices providing multiple channels have made the performance of laparoscopic cholecystectomy through a single access site not only feasible but much easier. The potential benefits of laparoendoscopic single site (LESS) cholecystectomy may include scarless surgery, reduced postoperative pain, reduced postoperative length of stay, and improved postoperative quality of life. There are no comparative data between LESS cholecystectomy and standard laparoscopic cholecystectomy (LC) available at present with which to quantify these benefits. METHODS: This study was a prospective, randomized, dual institutional pilot trial comparing LESS cholecystectomy with standard LC. The primary end point was postoperative quality of life, measured as length of hospital stay, postoperative pain, cosmetic results, and SF-36 questionnaire scores. Secondary end points included operative time, conversion to standard LC, difficulty of exposure, difficulty of dissection, and complication rate. RESULTS: No significant differences in postoperative lengths of stay were found in the two groups. Postoperative pain evaluation using a visual analogue scale showed significantly better outcomes in the standard LC arm on the same day of surgery (P = .041). No differences in postoperative pain were found at the next visual analogue scale evaluation or in the postoperative administration of pain relieving medications. Cosmetic satisfaction was significantly higher in the LESS group at 1-month follow-up (mean, 94.5 +/- 9.4% vs 86 +/- 22.3%; median, 100% vs 90%; P = .025). Among the 8 scales of the SF-36 assessing patients' physical and mental health, scores on the Role Emotional scale were significantly better in the LESS group (mean, 80.05 +/- 29.42 vs 68.33 +/- 25.31; median, 100 vs 66.67; P < .0001). CONCLUSIONS: In this pilot trial, LESS cholecystectomy resulted in similar lengths of stay and improved cosmetic results and SF-36 Role Emotional scores but performed less well on pain immediately after surgery. A larger multicenter trial is needed to confirm and further investigate these results. PMID- 21600560 TI - Clinically unsuspected papillary microcarcinomas of the thyroid: a common finding with favorable biology? AB - BACKGROUND: The purpose of this study was to describe the incidence and clinical/pathologic characteristics of papillary thyroid microcarcinoma (PMC) in a community hospital setting and to evaluate the frequency and characteristics of these lesions when unsuspected preoperatively. METHODS: A total of 723 patients underwent a partial or total thyroidectomy. A retrospective review was performed. RESULTS: A total of 194 of the 723 patients had a final diagnosis of papillary carcinoma. Ninety-six (49%) of these tumors were PMCs defined as being 1.0 cm or less in diameter. One third (32 of 96) of these lesions were multifocal and 16.7% (16 of 96) were found to have regional lymph node metastases. The majority (58%) of PMCs were found on final pathology and were clinically unsuspected (occult). Multifocality was found in 32.1% (18 of 56) of patients with clinically unsuspected PMC, with nodal metastases in 3.6% (2 of 56). The other 40 patients with PMC had surgeries performed for a clinical reason related to that pathologic lesion. This clinically suspected group was comparably multifocal (35%), but more likely to have cervical lymph node metastasis (35%). Sixty-six percent (37 of 56) diagnosed with a clinically unsuspected PMC underwent a partial thyroidectomy at the initial surgery. CONCLUSIONS: The prevalence of clinically unsuspected PMC in our population undergoing thyroidectomy was 7.7% (56 of 723). In our institution, this is more than half of all PMCs. The incidence of cervical lymph node metastasis in clinically unsuspected PMC was only 3.6% compared with 35% in clinically suspected disease, suggesting that the biological behavior (and possibly treatment) may be different. Long-term follow-up evaluation is needed to better evaluate the significance of these differences. PMID- 21600561 TI - Management of colorectal anastomotic leakage: differences between salvage and anastomotic takedown. AB - BACKGROUND: The aim of this study was to evaluate and compare the morbidity associated with 2 strategies of treatment of colorectal anastomotic leakage: surgical drainage of anastomosis with loop ileostomy versus anastomotic takedown. METHODS: An observational study of patients operated on for ileocolic or colorectal anastomotic leakage between 2001 and 2009. Patients were classified into 2 groups: group 1, salvage of the anastomosis, and group 2, anastomotic takedown. Mortality and morbidity were assessed. Morbidity and mortality of bowel restoration were also evaluated. RESULTS: Thirty-nine patients were included into group 1 and 54 into group 2. Mortality was 15% for group 1 and 37% for group 2 (P = .022). The rate of patients suitable for stoma reversal was 91% for loop ileostomy and 38% for end stoma (P < .001). Morbidity was 18% after loop ileostomy closure and 71% after end stoma reversal (P = .021). Hospitalization was 10 days and 21 days, respectively (P = .009). There was no mortality. CONCLUSIONS: Salvage of anastomosis with loop ileostomy is an effective strategy to control peritoneal sepsis for colorectal anastomotic leakage. PMID- 21600562 TI - The role of surgical treatment in second primary lung cancer. AB - BACKGROUND: This study was designed to assess the treatment of patients in whom a second primary lung cancer developed after the resection of primary lung cancer. METHODS: Between January 1990 and December 2008, 1852 patients underwent complete resection for primary lung cancer in our institution. Of these individuals, patients who had been identified as having a second primary lung cancer by December 2009 were selected for this study using the criteria proposed by Martini and Melamed. RESULTS: Of 1852 patients, a second primary lung cancer developed in 40 (2.2%) during the follow-up period. The overall 5-year and 10-year survival rates after the resection of the first tumor were 78.3% and 39.9%, respectively. The overall 5-year survival rate from the time of detection of the second primary lung cancer was 47.8%, and the 5-year survival rate of the patients who underwent resection of the second tumor was 77.0%. The patients who underwent sublobar resection had comparable overall survival and disease-free survival compared with the patients who underwent anatomic resection. Additionally, the patients who underwent sublobar resection had a better operative outcome. CONCLUSIONS: Surgical resection is feasible and effective in the management of second primary lung cancer, and sublobar resection may be adequate. Long-term surveillance of more than 5 years is essential for early detection to increase the chance of resection of a second primary lung cancer. PMID- 21600563 TI - Obsessive compulsive personality disorder as a predictor of exposure and ritual prevention outcome for obsessive compulsive disorder. AB - Despite elevated rates of obsessive compulsive personality disorder (OCPD) in patients with obsessive compulsive disorder (OCD), no study has specifically examined comorbid OCPD as a predictor of exposure and ritual prevention (EX/RP) outcome. Participants were adult outpatients (n = 49) with primary OCD and a Yale Brown Obsessive Compulsive Scale (YBOCS) total score >= 16 despite a therapeutic serotonin reuptake inhibitor dose for at least 12 weeks prior to entry. Participants received 17 sessions of EX/RP over 8 weeks. OCD severity was assessed with the YBOCS pre- and post-treatment by independent evaluators. At baseline, 34.7% of the OCD sample met criteria for comorbid DSM-IV OCPD, assessed by structured interview. OCPD was tested as a predictor of outcome both as a diagnostic category and as a dimensional score (severity) based on the total number of OCPD symptoms coded as present and clinically significant at baseline. Both OCPD diagnosis and greater OCPD severity predicted worse EX/RP outcome, controlling for baseline OCD severity, Axis I and II comorbidity, prior treatment, quality of life, and gender. When the individual OCPD criteria were tested separately, only perfectionism predicted worse treatment outcome, over and above the previously mentioned covariates. These findings highlight the importance of assessing OCPD and suggest a need to directly address OCPD-related traits, especially perfectionism, in the context of EX/RP to minimize their interference in outcome. PMID- 21600564 TI - Neural correlates of motor-sensory temporal recalibration. AB - The relative timing of a motor-sensory event can be recalibrated after exposure to delayed visual feedback. Here we examined the neural consequences of lag adaptation using event-related potentials (ERPs). Participants tapped their finger on a pad, which triggered a flash either after a short delay (0 ms/50 ms) or a long delay (100 ms/150 ms). Following the exposure phase, they judged the temporal order of a synchronous tap-flash test stimulus. The synchronous flash was more often perceived to occur before the tap after exposure to long than short delays, indicating that the temporal relation between the tap and the flash was realigned. ERPs evoked by the synchronous tap-flash test stimulus showed that adaptation to delayed flashes caused an early attenuation of the visual P1 (85 ms 150 ms), and a later negativity at central electrodes (N450). The P1-attenuation may reflect the unexpected earliness of the test flash, or a violation of "cause before-consequence". The N450 may be due to realignment of the adapted and the actual timing of the tap-flash interval. We conclude that motor-visual temporal recalibration has consequences at early perceptual levels of visual processing and involves a high-level recalibration mechanism. PMID- 21600565 TI - Source localization of late electrocortical positivity during symptom provocation in spider phobia: an sLORETA study. AB - This symptom provocation study on spider phobia investigated sources of late event-related potentials (ERPs) using sLORETA (standardized low resolution brain electromagnetic tomography). Twenty-five phobic female patients and 20 non-phobic controls were confronted with phobia-relevant, generally fear-inducing, disgust inducing and affectively neutral pictures while an electroencephalogram was recorded. Mean amplitudes of ERPs were extracted in the time windows 340-500 ms (P300) and 550-770 ms (late positive potential, LPP). Phobics showed enhanced P300 and LPP amplitudes in response to spider pictures relative to controls. Sources were mainly located in areas engaged in visuo-attentional processing (occipital and parietal regions, ventral visual pathway). Moreover, there were sources in areas which are crucial for emotional processing and the representations of aversive bodily states (cingulate cortex, insula). Further sources were located in premotor areas reflecting the priming of flight behaviour. Our findings are in good accordance with existing brain imaging studies and underline that source localization is a useful alternative for identifying phobia-relevant cortical regions. PMID- 21600566 TI - Sugar-decorated hydroxyapatite: an inorganic material bioactivated with carbohydrates. AB - An efficient method for the direct and covalent decoration of granules of nanostructured apatite with a sample monosaccharide is presented; the hydroxyapatite material was directly functionalised with a short azido-containing spacer arm, to which alpha-propargyl glucopyranoside has been chemoselectively ligated by Huisgen-type cycloaddition. The 'glycosylated' hydroxypatite was characterised by its ability to interact with glucose recognising lectins. PMID- 21600567 TI - Disclosing the distinct interfacial behaviors of structurally and configurationally diverse triazologlycolipids. AB - 1- or 6-Triazologluco- and galactolipid derivatives bearing a lipid chain length of 16 carbons were efficiently constructed via click chemistry. The differentiation in their surface pressure-molecular area (pi-A) isotherms first implies that these structurally and configurationally diverse amphiphiles adopt different distribution manner at air-water interfaces. The Langmuir-Blodgett (LB) films of the synthesized glycoconjugates on mica surface were subsequently prepared and visualized via atomic force microscopy (AFM), which exhibited diverse topographies and possess different contact angles with water. These data further suggest that the structural variation as well as epimeric identity of triazologlycolipids may result in their distinct interfacial behaviors at the air solid interface. Furthermore, the addition of increasing amounts of 1 triazologalactolipid 2 to poly-diacetylene (PDA) was determined to impact the pi A isotherm of the latter, prompting us to further fabricate new colorimetrically detectable mixed-type vesicles containing triazologlycolipids for biochemical studies. PMID- 21600568 TI - Synthesis of lipid II phosphonate analogues. AB - Simple analogues of lipid II were synthesized from 3,4,6-tri-O-acetyl-2-acetamido 2-deoxy-1-thio-beta-D-glucopyranose using conjugate addition onto ethylidene bisphosphonate and subsequent Wadsworth-Horner-Emmons reaction with long chain aliphatic aldehydes. PMID- 21600569 TI - Electrospun nano-fiber mats containing cationic cellulose derivatives and poly (vinyl alcohol) with antibacterial activity. AB - Nano-fibrous mats have been successfully prepared by electrospinning of the blend solutions of cationic cellulose derivatives (PQ-4) and polyvinyl alcohol (PVA). Effects of the blending ratio and applied voltage on the morphology and diameter of the electrospun nano-fibers were investigated. The average diameter of the PQ 4/PVA blend fibers was in the range of 150-250 nm. The electrospinning process became instable and the fiber diameter distribution broadened with increasing PQ 4 content and applied voltage. The antibacterial activity of electrospun PQ-4/PVA blend mats against Gram-negative bacteria Escherichia coli and Gram-positive bacteria Staphylococcus aureus indicated potential for biomedical use. PMID- 21600571 TI - Kiwifruit extracts inhibit cytokine production by lipopolysaccharide-activated macrophages, and intestinal epithelial cells isolated from IL10 gene deficient mice. AB - Inflammatory bowel disease (IBD) is a chronic, inflammatory disorder of the gastrointestinal tract involving an inappropriate immune response to commensal microorganisms in a genetically susceptible host. This study examined the effects of aqueous and ethyl acetate extracts of gold kiwifruit (Actinidia chinensis) or green kiwifruit (Actinidia deliciosa) using in vitro models of IBD. These models comprised primary macrophages and intestinal epithelial cells isolated from C57BL/5J and interleukin-10 gene deficient (Il10(-/-)) mice and RAW 264.7, a murine macrophage-like cell line. All four kiwifruit extracts reduced the activation of these models after lipopolysaccharide stimulation, decreasing nitric oxide and cytokine secretion by both Il10(-/-) and wild-type cells. The ethyl acetate extracts exhibited the highest anti-inflammatory activity, with almost complete suppression of lipopolysaccharide-stimulated macrophage activation. These results suggest that kiwifruit extracts have significant anti inflammatory activity relevant to IBD. We suggest that the Il10(-/-) mouse is a suitable model for further study of these compounds. PMID- 21600570 TI - Psychological stress is associated with altered levels of myeloid-derived suppressor cells in breast cancer patients. AB - Our group has shown in a randomized clinical trial that psychological intervention to reduce stress in patients with stages II and III breast cancer led to enhanced immune function, fewer recurrences and improved overall survival. We hypothesized that patients with high levels of stress would have alterations in myeloid-derived suppressor cells (MDSC) compared to patients with lower stress. PBMC from 16 patients with high stress (n = 8) or with low stress (n = 8) after surgery as measured by the Impact of Event Scale (IES) questionnaire were evaluated for the presence of MDSC. Patients with higher IES scores had significantly elevated salivary cortisol levels (P = 0.013; 13 MUg/dl vs. 9.74 MUg/dl). Levels of IL-1Ralpha were also significantly elevated in the higher IES group (45.09 pg/ml vs. 97.16 pg/ml; P = 0.010). IP 10, G-CSF, and IL-6 were all higher in the high stress group although not to a significant degree. Flow cytometric analysis for CD33+/HLA-DR-neg/CD15+/CD11b+ MDSC revealed increased MDSC in patients with lower IES scores (P = 0.009). CD11b+/CD15+ cells constituted 9.4% of the CD33+/HLA DR-neg cell population in patients with high IES, vs. 27.3% in patients with low IES scores. Additional analyzes of the number of stressful events that affected the patients in addition to their cancer diagnosis revealed that this type of stress measure correlated with elevated levels of MDSC (P = 0.064). These data indicate the existence of a complex relationship between stress and immune function in breast cancer patients. PMID- 21600572 TI - Automatic evaluation of pressure sore status by combining information obtained from high-frequency ultrasound and digital photography. AB - In this study, the different phases of pressure sore generation and healing are investigated through a combined analysis of high-frequency ultrasound (20 MHz) images and digital color photographs. Pressure sores were artificially induced in guinea pigs, and the injured regions were monitored for 21 days (data were obtained on days 3, 7, 14, and 21). Several statistical features of the images were extracted, relating to both the altering pattern of tissue and its superficial appearance. The features were grouped into five independent categories, and each category was used to train a neural network whose outputs were the four days. The outputs of the five classifiers were then fused using a fuzzy integral to provide the final decision. We demonstrate that the suggested method provides a better decision regarding tissue status than using either imaging technique separately. This new approach may be a viable tool for detecting the phases of pressure sore generation and healing in clinical settings. PMID- 21600573 TI - A biologically-based algorithm for companding computerized tomography (CT) images. AB - Computerized Tomography (CT) images are High Dynamic Range (HDR) images of the X ray attenuation coefficients of the body's tissues. The inability to see abnormalities in tissues with marked differences in their X-ray attenuation coefficients, in a single CT window, poses a significant clinical problem in radiology. In order to provide proper contrast, which reveals all the required clinical details within each specifically imaged tissue, a single CT slice must be viewed by a radiologist four times: the first viewing focuses on the lung window; the second viewing focuses on the soft tissues window; the third viewing focuses on the liver window; and the fourth viewing focuses on the bone window. In order to enhance the ability to perform a complete diagnosis, while decreasing diagnostic time, we developed the BACCT (Biologically-based Algorithm for Companding CT images) method. Our algorithm compresses and expands (compands) the HDR CT image into a single, low dynamic range image. Before performing the companding procedure, unique processing is required which involves operations that enhance and stretch the image. The performance of our algorithm has been demonstrated on a large repertoire of CT body images. All the clinically required CT information is exposed in each CT slice in a single image. The algorithm compands the CT images in a fully automatic way. Collaborating radiologists have already tested the results of our algorithmic method, and reported that the images seem to provide all the necessary information. However, clinical tests for statistical reliability are still required. PMID- 21600574 TI - Exposure to moulds and actinomycetes in Alpine farms: a nested environmental study of the PASTURE cohort. AB - Several studies have suggested that children exposed to a farm environment are protected against allergies and asthma. The present work is an environmental study nested within the PASTURE cohort and includes 97 farmers and 74 non-farmers in three regions of the Alpine Arc (Switzerland, France and Germany). The objectives were to determine and compare the fungi and actinomycetes present in farming and non-farming environments (children's bedrooms and cowsheds), and to identify the agricultural practices associated with an increase in airborne fungi and actinomycetes in cowsheds. Air samples were collected by air pump and were analysed by culture and by direct counting of spores on membranes. During their stay in bedrooms, children living on farms were exposed to significantly greater amounts of Absidia spp., Eurotium spp., Cladosporium spp., Penicillium spp. and mesophilic actinomycetes than children who did not live on farms. Depending on the season, the levels of moulds, yeasts and actinomycetes were from 14 to 82 times higher in cowsheds before feeding the cattle than in children's bedrooms, and from 12 to 464 times higher in cowsheds after feeding than in children's bedrooms. Feeding cattle in cowsheds was associated with a significant peak in airborne moulds and actinomycetes, and this peak was higher in winter than in summer. Silage distribution was associated with low amounts of moulds and actinomycetes. Other significant agricultural factors were the type of cowshed, cowshed volume, method of food distribution to cattle and use of fresh grass. An assessment of the microbiological diversity on farms and in children's rooms may help to determine the factors protecting children from asthma and atopic diseases. PMID- 21600575 TI - Massive hematuria with hemodynamic instability--complication of oocyte retrieval. AB - OBJECTIVE: To report a case of pseudoaneurysm causing massive hematuria with hemodynamic instability occurring after oocyte retrieval. DESIGN: Case report. SETTING: Tertiary care infertility clinic. PATIENT(S): A 34-year-old woman with endometriosis undergoing oocyte aspiration for IVF. INTERVENTION(S): Blood transfusion, cystoscopy, and resection and cauterization of pseudoaneurysm. MAIN OUTCOME MEASURE(S): Control of hematuria and hemodynamic stability. RESULT(S): Massive hematuria occurred after oocyte retrieval. Blood transfusion was given. Cystoscopy was done, and a bleeding pseudoaneurysm was seen. It was resected and cauterized. CONCLUSION(S): Pseudoaneurysm after oocyte retrieval has not been reported before. It resulted in massive hematuria causing hemodynamic instability. Immediate resuscitation and cystoscopy should be performed on all patients who present with persistent hematuria after oocyte retrieval. Injury to surrounding structures should always be kept in mind during oocyte retrieval. PMID- 21600576 TI - Serum retinol-binding protein 4, leptin, and plasma asymmetric dimethylarginine levels in obese and nonobese young women with polycystic ovary syndrome. AB - OBJECTIVE: To evaluate retinol-binding protein 4 (RBP4), leptin, and asymmetric dimethylarginine (ADMA) levels in young women with polycystic ovary syndrome (PCOS) and to investigate their relationship with each other and with clinical, metabolic, and hormonal parameters. DESIGN: Clinical study. SETTING: University hospital. PATIENT(S): Fifty-seven young women with PCOS (obese [n = 27] and nonobese [n = 30]) and 27 age-matched healthy controls. INTERVENTION(S): History and physical examination, peripheral venous blood sampling. MAIN OUTCOME MEASURE(S): Asymmetric dimethylarginine, RBP4, leptin, LH, FSH, DHEAS, total T, E(2), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride (TG), and homeostasis model assessment insulin resistance index (HOMA-IR). RESULT(S): Obese women with PCOS had significantly higher HOMA-IR, DHEAS, leptin, RBP4, and ADMA levels. Leptin levels were significantly increased in nonobese subjects with PCOS. Leptin and ADMA levels were positively correlated with HOMA-IR in PCOS. There was no correlation between RBP4 and HOMA-IR. Leptin, RBP4, and ADMA levels are positively correlated in PCOS. CONCLUSION(S): [1] Young obese women with PCOS have increased ADMA, RBP4, and leptin levels, and they are positively correlated with each other. [2] The increased levels of leptin are independent of obesity, and leptin seems to have an association with IR. [3] Levels of RBP4 may not reflect IR in PCOS. PMID- 21600577 TI - New possibilities for the valorization of olive oil by-products. AB - In this contribution, the capabilities of pressurized liquid extraction (PLE) using food-grade solvents, such as water and ethanol, to obtain antioxidant extracts rich on polyphenolic compounds from olive leaves are studied. Different extraction conditions were tested, and the PLE obtained extracts were characterized in vitro according to their antioxidant capacity (using the DPPH radical scavenging and the TEAC assays) and total phenols amounts. The most active extracts were obtained with hot pressurized water at 200 degrees C (EC(50) 18.6 MUg/mL) and liquid ethanol at 150 degrees C (EC(50) 27.4 MUg/mL), attaining at these conditions high extraction yields, around 40 and 30%, respectively. The particular phenolic composition of the obtained extracts was characterized by LC-ESI-MS. Using this method, 25 different phenolic compounds could be tentatively identified, including phenolic acids, secoiridoids, hydroxycinnamic acid derivatives, flavonols and flavones. Among them, hydroxytyrosol, oleuropein and luteolin-glucoside were the main phenolic antioxidants and were quantified on the extracts together with other minor constituents, by means of a UPLC-MS/MS method. Results showed that using water as extracting agent, the amount of phenolic compounds increased with the extraction temperature, being hydroxytyrosol the main phenolic component on the water PLE olive leaves extracts, reaching up to 8.542 mg/g dried extract. On the other hand, oleuropein was the main component on the extracts obtained with ethanol (6.156-2.819 mg/g extract). Results described in this work demonstrate the good possibilities of using PLE as a useful technique for the valorization of by products from the olive oil industry, such as olive leaves. PMID- 21600578 TI - Use of pressure drop profiles to assess the accuracy of Total Pore Blocking measurements of the external porosity of chromatographic columns. AB - By comparing the pressure drop in a column where the meso-pores of the particles have been blocked using the Total Pore Blocking (TPB) method to measure the interstitial volume of the column with that in the same column when the particle meso-pores are fully open, it could be demonstrated in a very sensitive way that the interstitial volume is completely devoid of any significant amount of remaining pore blocking agent in the final phase of a TPB experiment. Monitoring the pressure signal until it returns to its original value can hence be used as a reliable indicator that all blocking agent has been removed from the interstitial void at the end of the flushing period. As a consequence, any small molecular weight dead volume marker that is employed in this phase can explore the full interstitial volume, so that the value of the latter can be measured without being underestimated by the fact that some fractions of the interstitial void would still be occupied by the blocking agent. PMID- 21600579 TI - Novel liquid-liquid-solid microextraction method with molecularly imprinted polymer-coated stainless steel fiber for aqueous sample pretreatment. AB - A novel liquid-liquid-solid microextraction (LLSME) method was developed to overcome the well-known water-compatibility problem of molecularly imprinted polymers (MIPs). The enrichment factors with MIP-LLSME method were within 70-210 for trace chloroacetanilide herbicides under optimized extraction conditions. The method was characterized by simplicity, low solvent-consumption and high selectivity, and it was suitable for the one-step pretreatment of various aqueous samples such as river water and farm water. PMID- 21600580 TI - Salt precipitation and trapped liquid cavitation in micrometric capillary tubes. AB - Laboratory evidence shows that the occurrence of solid salt in soil pores causes drastic changes in the topology of the porous spaces and possibly also in the properties of the occluded liquid. Observations were made on NaCl precipitation in micrometric cylindrical capillary tubes, filled with a 5.5 M NaCl aqueous solution and submitted to drying conditions. Solid plug-shaped NaCl (halite) commonly grows at the two liquid-air interfaces, isolating the inner liquid column. The initially homogeneous porosity of the capillary tube becomes heterogeneous because of these two NaCl plugs, apparently closing the micro system on itself. After three months, we observed cavitation of a vapor bubble in the liquid behind the NaCl plugs. This event demonstrates that the occluded liquid underwent a metastable superheated state, controlled by the capillary state of thin capillary films persisting around the NaCl precipitates. These observations show, first, that salt precipitation can create a heterogeneous porous medium in an initially regular network, thus changing the transfer properties due to isolating significant micro-volumes of liquid. Second, our experiment illustrates that the secondary salt growth drastically modifies the thermo-chemical properties of the occluded liquid and thus its reactive behavior. PMID- 21600581 TI - Charging and stability of anionic latex particles in the presence of linear poly(ethylene imine). AB - Charging properties and colloidal stability of negatively charged polystyrene latex particles were investigated in the presence of linear poly(ethylene imine) (LPEI) of different molecular masses by electrophoresis and dynamic light scattering (DLS). Electrophoretic mobility measurements illustrate that LPEI strongly adsorbs on these particles leading to charge neutralization at isoelectric point (IEP) and charge reversal. Time-resolved DLS experiments indicate that the aggregation of the latex particles is rapid near the IEP and slows down away from this point. Surprisingly, the colloidal stability does not depend on the molecular mass, which indicates that the adsorbed LPEI layer is rather homogeneous. PMID- 21600582 TI - Comparative study on composition, structure, and adsorption behavior of activated carbons derived from different synthetic waste polymers. AB - The composition, structure, and adsorption behavior of activated carbons (ACs) derived from three different types of waste polymers, i.e., tire rubber (TR), polyvinyl chloride (PVC), and polyethyleneterephtalate (PET), by KOH activation were compared. The AC derived from PET exhibited the largest surface area (2831 m(2)/g) and pore volume (1.68 cm(3)/g) due to the homogenous aromatic composition of PET. The AC derived from PVC exhibited relatively lower surface area (2666 m(2)/g) but more narrowed pore size distribution (2-3 nm). The complex composition and high ash content of tire particles resulted in AC product with significantly lower surface area (398.5 m(2)/g) and heterogeneous pore width. Adsorption data of methylene blue (MB) were fitted well by Langmuir equation, indicating monolayer coverage on the ACs. The high oxygen content of PET-derived AC heavily affected its adsorption to MB and iodine. Due to the remarkable surface area and highly mesoporous structures, ACs based on both PET and PVC exhibited much higher adsorption capacities than that of TR and commercial coal based AC (F400). This study demonstrates that the properties of ACs are highly dependent on their starting polymers and the potential of converting synthetic polymer waste into effective adsorbents for environmental remediation and cleanup. PMID- 21600583 TI - Facile synthesis of 3D flowerlike CeO2 microspheres under mild condition with high catalytic performance for CO oxidation. AB - Three-dimensional (3D) hierarchical flowerlike CeO(2) microspheres with 5-8MUm diameter were hydrothermally synthesized by using multiple surfactants at very mild condition (100 degrees C) and characterized by XRD, low-temperature N(2) adsorption, SEM, TEM, TG, FT-IR, and UV-vis spectroscopies. The results show that the flowerlike ceria prepared with the co-surfactant of sodium dodecyl sulfonic and PEG 600 possesses multilevel pore structure and low band gap energy. A possible formation mechanism of flowerlike ceria is that 3D flowerlike microspheres are assembled by 1D nanowires formed through an aggregation of 0D nanoparticles. Based on the unique structure and morphology, the prepared flowerlike CeO(2) exhibits more amount of surface capping oxygen, higher concentrations of Ce(3+) and O vacancy, and more (100) lattice planes, resulting in its higher catalytic activity for CO oxidation than general bulk ceria. Furthermore, photoluminescence property testing shows that flowerlike CeO(2) exhibits the violet blue light emission with a blue shift, because of the quantum size effect, differing from general ceria. PMID- 21600584 TI - Studies on the mixed micelles of alkyltrimethylammonium bromides and butanediyl 1,4-bis(alkyldimethylammonium bromide) dimeric surfactants in the presence and absence of ethylene glycol at different temperatures. AB - Mixed micellization of two cationic dimeric surfactants butanediyl-1,4 bis(alkyldimethylammonium bromide) [C(m)H(2m+1)N(+)(CH(3))(2)-(CH(2))(4) N(+)(CH(3))(2)C(m)H(2m+1),2Br(-)] with their monomeric counterparts alkyltrimethylammonium bromides [C(m)H(2m+1)N(+)(CH(3))(3)Br(-)](m=14 and 16) has been studied at different temperatures (298.15-323.15K) in presence and absence of ethylene glycol (EG) using conductivity data. Steady state fluorescence quenching (SSFQ) measurements were performed to estimate the average aggregation number (N(agg)) of the mixed micelles at 298.15K. The ideal cmc values, experimental and ideal micellar compositions, interaction parameters, activity coefficients of the components, etc. have been evaluated by considering theoretical models of Clint, Rubingh and Rodenas. The analysis reveals that the fraction of the monomeric surfactant in the mixed micelles is higher than the expected ideal micellar mole fraction, and in most of the cases mixed micelles of the studied components become more ideal in the presence of EG. PMID- 21600585 TI - An atomic force microscopy investigation on self-assembled peptide nucleic acid structures on gold(111) surface. AB - Peptide Nucleic Acid (PNA) is an important alternative nucleic acid, which exhibits more effective DNA/RNA detection capabilities compared to DNA. Its potential utility in nucleic acid based detection technologies warrants detail understanding of it's self-assembly behavior on solid substrates, e.g., gold. In the present study, we have applied high-resolution Atomic Force Microscopy (AFM) for obtaining direct visual information on PNA adsorption and formation of a self assembled monolayer of PNA on gold(111) surface. We show from the molecularly resolved AFM data that PNA molecules form a well-defined 1-dimensional molecule by-molecule ordering, over a considerable length scale (few hundred nm), as well as 2-dimensional ordering over a wide area of about 10 MUm*10 MUm, due to parallel positioning of the 1-dimensional ordered arrangements. The way the parameters like PNA concentration, incubation time, incubation temperature and PNA deposition methods can affect the formation of such ordered self-assembled PNA structures has been investigated. Some of the primary observations are that the minimum PNA concentration and incubation time for large scale (10 MUm *10 MUm) 2-dimensional order formation are 0.5 MUM and 4h, respectively. Furthermore, a dense and well-ordered layer over a large area could be better formed in case of immersion method compared to the droplet contact and droplet deposition methods. From the Reflection Absorption Infra Red Spectroscopy (RAIRS) data, indications for PNA concentration-driven reorientation of the PNA backbone towards more upright configuration on gold(111) surface, were obtained. PMID- 21600586 TI - Self-assembly of gold nanoparticles on functional organic molecular crystals. AB - The utilization of metal nanoparticles (NPs) to fabricate metal electrodes under mild conditions is one of the most studied topic in recent years. In this work, colloidal Au NPs were deposited on two isostructural molecular crystals, namely 1,2,3,4-tetrafluoro-7-thiomethyl-acridine (MeSAcr) and 1,2,3,4-tetrafluoro-7 methoxy-acridine (MeOAcr), exposing S atoms and O atoms, respectively, at their largest crystal faces. The depositions were carried out mainly by drop casting under ambient conditions, increasing the contact time from 1 to 120 min, and the samples were then analyzed by atomic force microscopy (AFM) to evaluate the coverage. Thanks to the affinity between S and Au atoms, Au NPs are observed to adhere on the MeSAcr surface within 1-min contact time, whereas at least 1h is required to find NPs on the MeOAcr surface. NP adsorption is also affected by the substrate surface morphology; indeed, step edges represent preferential adsorption sites even in the absence of Au-S interaction. Experiments under different conditions were performed to maximize the coverage on MeSAcr, reaching values up to 13%. AFM equipped with fluid cell was also employed to simultaneously depositing and imaging NPs, achieving a better understanding of the adsorption mechanism. PMID- 21600587 TI - Characterisation of organoclays and adsorption of p-nitrophenol: environmental application. AB - Organoclays were synthesised through ion exchange of a single surfactant for sodium ions, and characterised by a range of method including X-ray diffraction (XRD), BET, X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR), and transmission electron microscopy (TEM). The change in surface properties of montmorillonite and organoclays intercalated with the surfactant, tetradecyltrimethylammonium bromide (TDTMA) were determined using XRD through the change in basal spacing and the expansion occurred by the adsorbed p-nitrophenol. The changes of interlayer spacing were observed in TEM. In addition, the surface measurement such as specific surface area and pore volume was measured and calculated using BET method, this suggested the loaded surfactant is highly important to determine the sorption mechanism onto organoclays. The collected results of XPS provided the chemical composition of montmorillonite and organoclays, and the high-resolution XPS spectra offered the chemical states of prepared organoclays with binding energy. Using TGA and FT-IR, the confirmation of intercalated surfactant was investigated. The collected data from various techniques enable an understanding of the changes in structure and surface properties. This study is of importance to provide mechanisms for the adsorption of organic molecules, especially in contaminated environmental sites and polluted waters. PMID- 21600588 TI - Neural bases of recovery after brain injury. AB - Substantial data have accumulated over the past decade indicating that the adult brain is capable of substantial structural and functional reorganization after stroke. While some limited recovery is known to occur spontaneously, especially within the first month post-stroke, there is currently significant optimism that new interventions based on the modulation of neuroplasticity mechanisms will provide greater functional benefits in a larger population of stroke survivors. To place this information in the context of current thinking about brain plasticity, this review outlines the basic theories of why spontaneous recovery occurs, and introduces important principles to explain the effects of post-stroke behavioral experience on neural plasticity. LEARNING OUTCOMES: Readers will be able to: (a) explain the three classic theories to explain spontaneous recovery after focal brain injury, (b) explain the neurophysiological effects of post injury rehabilitative therapy on functional organization in motor cortex, (c) readers will be able to describe some of the variables that impact the effects of post-stroke behavioral experience on neuroplasticity, and (d) readers will be able to explain some of the current laboratory-based approaches to modifying brain circuits after stroke that might soon be translated to human application. PMID- 21600589 TI - Neural plasticity and neurorehabilitation: teaching the new brain old tricks. AB - Following brain injury or disease there are widespread biochemical, anatomical and physiological changes that result in what might be considered a new, very different brain. This adapted brain is forced to reacquire behaviors lost as a result of the injury or disease and relies on neural plasticity within the residual neural circuits. The same fundamental neural and behavioral signals driving plasticity during learning in the intact brain are engaged during relearning in the damaged/diseased brain. The field of neurorehabilitation is now beginning to capitalize on this body of work to develop neurobiologically informed therapies focused on key behavioral and neural signals driving neural plasticity. Further, how neural plasticity may act to drive different neural strategies underlying functional improvement after brain injury is being revealed. The understanding of the relationship between these different neural strategies, mechanisms of neural plasticity, and changes in behavior may facilitate the development of novel, more effective rehabilitation interventions for treating brain injury and disease. LEARNING OUTCOMES: Readers will be able to: (a) define neural plasticity, (b) understand how learning in the intact and damaged brain can drive neural plasticity, (c) identify the three basic neural strategies mediating functional improvement, and (d) understand how adjuvant therapies have the potential to upregulate plasticity and enhance functional recovery. PMID- 21600590 TI - Intensive two-day cognitive-behavioral intervention decreases cortisol secretion in soldiers suffering from specific phobia to wear protective mask. AB - RESEARCH QUESTIONS: Wearing a protective mask is compulsory for those in professions such as fire-fighters, rescue personnel and soldiers. The phobia to wear a protective mask is considered a specific claustrophobia and may become of major concern during military service. To date, no data are available with respect to the hypothalamus-pituitary-adrenocortical system activity (HPA SA) for both the so-called protective mask phobia (PMP) and its treatment. The aim of the present study was three-fold: 1) to assess HPA SA in soldiers suffering from PMP before and after intensive cognitive-behavioral treatment, 2) to compare these data with controls, and 3) to relate these data to subjective sleep. METHODS: 46 Swiss Army recruits suffering from PMP were enrolled in a two-day intensive treatment course. During initial and final assessments, saliva was sampled to analyse HPA SA via salivary cortisol; saliva samples were also gathered in the morning. For comparison, saliva samples were gathered of 39 Emergency Rescue Service (ERS) recruits. All participants also completed a questionnaire related to sleep and to anxiety. RESULTS: Compared to controls from the ERS, among army recruits suffering from PMP, cortisol secretion was significantly higher during initial and final assessments, and in the morning. Cortisol secretion decreased from initial and final assessment. Subjectively assessed sleep was more impaired in recruits suffering from PMP compared to controls. After cognitive-behavioral treatment, all recruits suffering from PMP were able to wear the protective mask. CONCLUSIONS: Specific phobia about wearing a protective mask is treatable via a two-day intensive course. Treatment success is reflected in modified HPA SA. Methodology and results may be transferred to treat patients suffering from sleep apnea syndrome and presenting high anxiety about wearing continuous positive airway pressure devices. PMID- 21600591 TI - View point: etiology in Parkinson's disease. Dual hit or spreading intoxication. AB - Parkinson's disease is not only a movement disorder: non-motor symptoms such as loss of smell, constipation, depression, cognitive impairment, sleep problems and disturbances of the autonomic nervous system also feature. The etiology is still unknown, although an increasing number of gene-related Parkinsonian syndromes have been identified. It is intriguing to speculate that PD starts by the intake of a toxin, bacteria or virus. This idea stems from the fact that pathological abnormalities such as Lewy neuritis, Lewy bodies and alpha-synuclein accumulation are first found in the enteric nervous system of the gut and in the olfactory bulb. There is increasing evidence that the disease may spread out from the enteric nervous system of the gut via the vagal nerve up to the brain. Here we present data from animal work which supports this assumption. PMID- 21600592 TI - Standardized preoperative corticosteroid treatment in neonates undergoing cardiac surgery: results from a randomized trial. AB - OBJECTIVE: A heightened inflammatory response occurs after cardiac surgery. The perioperative use of glucocorticoids has been advocated as a method to improve postoperative outcomes. Randomized prospective studies to quantify the effect of methylprednisolone on perioperative outcomes in neonatal cardiac surgery have not been performed. We sought to determine whether preoperative methylprednisolone would improve postoperative recovery in neonates requiring cardiac surgery. METHODS: Neonates scheduled for cardiac surgery were randomly assigned to receive either 2-dose (8 hours preoperatively and operatively, n = 39) or single-dose (operatively, n = 37) methylprednisolone (30 mg/kg per dose) in a prospective double-blind trial. The primary outcome was the incidence of low cardiac output syndrome (standardized score) or death 36 hours postoperatively. Secondary outcomes were death at 30 days, interleukin-6 levels, inotropic score, fluid balance, serum creatinine, and intensive care unit and hospital stay. RESULTS: Preoperative plasma levels of the inflammatory cytokine interleukin-6 were reduced by 2-fold (P < .001) in the 2-dose methylprednisolone group, consistent with the anti-inflammatory effects of methylprednisolone. However, the incidence of low cardiac output syndrome was 46% (17/37) in the single-dose and 38% (15/39) in the 2-dose methylprednisolone groups (P = .51). Two-dose methylprednisolone was associated with a higher serum creatinine (0.61 +/- 0.18 mg/dL vs 0.53 +/- 0.12 mg/dL, P = .03) and poorer postoperative diuresis (-96 +/- 49 mL, P = .05). Inotropic requirement, duration of mechanical ventilation, intensive care unit, and hospital stay did not differ between the 2 groups. CONCLUSIONS: Combined preoperative and intraoperative use of glucocorticoids in neonatal cardiac surgery does not favorably affect early clinical outcomes and may exacerbate perioperative renal dysfunction. PMID- 21600593 TI - The utility of automated volumetric growth analysis in a dedicated pulmonary nodule clinic. AB - OBJECTIVE: Our objectives were 3-fold: to define the correlation between automated volumetric and 2-dimensional measurements of pulmonary nodule growth and prospectively; to determine whether volumetric growth analysis represents a useful addition to 2-dimensional measurements; and to evaluate growth rates over time of biopsy-proven lung cancers using automated volumetric software. METHODS: Nodule growth on consecutive 2-dimensional computed tomographic scans was measured, and a decision regarding nodule biopsy was made. Automated volumetric software was then used to determine nodule growth, growth rates obtained from the 2 techniques were correlated, and the decision to perform a biopsy was reassessed. Biopsy-proven lung cancer growth rates were then documented over time. RESULTS: Growth rates measured using volumetric software were highly correlated with 2-dimensional measurements (r = 0.69; P < .00001). This correlation was affected by nodule type (irregular [r = .63] versus smooth [r = 0.84]; P = .02) as well as the interval between scans (<100 days [r = .5] versus >100 days [r = 0.76]; P = .02). The addition of volumetric growth analysis changed the decision to perform a biopsy after only a minority (6.2%) of scan comparisons; however, lung cancer was diagnosed in 43% of these cases. Growth curves for individual cancers were highly variable, with 45% of tumors showing at least 1 period of shrinkage. CONCLUSIONS: Automated volumetric software influences biopsy decisions in only a minority of cases in a dedicated pulmonary nodule clinic, but seems to be useful in detecting lung cancer in this minority. Radiographically determined nodule growth rates, in general, need to be questioned as the sole determinate of the need to perform a biopsy. PMID- 21600594 TI - Pathophysiological studies of overactive bladder and bladder motor dysfunction in a rat model of metabolic syndrome. AB - PURPOSE: We studied bladder motor dysfunction and searched for markers of neurogenic and myogenic alterations among fructose fed rats with or without abnormal voiding behavior. MATERIALS AND METHODS: Female Wistar rats were fed with a fructose rich diet (60%) or a normal diet for 6 months. Based on cystometry and voiding behavior the fructose fed rats were divided into 3 groups, including a group with normal detrusor function with normal micturition frequency, a group with detrusor overactivity with increased micturition frequency and a group with acontractile detrusor with increased micturition frequency. Denuded bladder tissues were obtained to assess in vitro detrusor contractility, postsynaptic receptors, smoothelin, nitrosative products and the intrinsic pathway of apoptosis. RESULTS: Fructose fed rats with abnormal voiding behavior had obvious neurogenic and myogenic alterations, including increased expression of postsynaptic receptors, dysregulation of smoothelin and decreased expression of Bcl-2 with a subsequent increase in apoptotic cells in the bladder stroma, causing decreased carbachol induced contractility. Rats with detrusor overactivity were also insulted by nitrosative stress associated with nitrotyrosine up-regulation in the bladder tissue. Up-regulation of M(2) and M(3) muscarinic receptors, and P2X(1) receptors appeared to be generalized alterations of fructose fed rats and not exclusive to those with detrusor overactivity. CONCLUSIONS: Up-regulation of postsynaptic receptors and dysregulation of smoothelin contribute to overactive bladder symptoms in rats with metabolic syndrome. Nitrosative stress and decreased Bcl-2 expression lead to bladder muscle cell loss via the intrinsic pathway of apoptosis, which may further deteriorate bladder function. PMID- 21600596 TI - A specific gene expression signature characterizes metastatic potential in clear cell renal cell carcinoma. AB - PURPOSE: The discovery of metastasis markers in clear cell renal cell carcinoma is of critical importance to define individual metastatic risk and select patients for new targeted therapies. We identified potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis. MATERIALS AND METHODS: We performed transcriptional profiling of 16 primary metastatic and 18 nonmetastatic clear cell renal cell carcinomas with PIQORTM microarrays. Differentially expressed genes were validated by quantitative real-time polymerase chain reaction. RESULTS: Genes discriminating between metastatic and nonmetastatic tumors were identified at q <0.001 by significance analysis of microarrays. The metastatic signature contained 127 transcripts. In metastatic samples a greater than 4-fold decrease in expression was detected for the genes CD151 and IKBA (t/F statistic p <0.0001) while the genes MMP16, B7-H1, BCL2L2 and FRA2 showed greater than 4-fold increase of expression in metastatic primary tumors (p <0.0001). Quantitative real-time polymerase chain reaction revealed significant differences in expression among all metastatic tumors, including synchronously and metachronously metastasized tumors, and nonmetastatic tumors for FRA2 (p = 0.032) and CD151 (p = 0.005). In addition, the genes B7-H1 (p = 0.040), FRA2 (p = 0.035), CD151 (p = 0.004) and BCL2L2 (p = 0.035) showed significantly higher expression in early metastasized than in nonmetastatic tumor samples. Different B7-H1 (p = 0.002) and BCL2L2 (p = 0.007) expression levels were found in samples with late metastasis compared to those in synchronously metastasized tumors. CONCLUSIONS: We determined a metastatic signature of clear cell renal cell carcinoma by microarray analysis. Our data provide the possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even in a localized situation. PMID- 21600597 TI - Editorial comment. PMID- 21600598 TI - Re: comparative effectiveness of perineal versus retropubic and minimally invasive radical prostatectomy. S. M. Prasad, X. Gu, R. Lavelle, S. R. Lipsitz and J. C. Hu J Urol 2011; 185: 111-115. PMID- 21600599 TI - Evaluation of consistency between physician clinical impression and 3 validated survey instruments for measuring lower urinary tract symptoms in children. AB - PURPOSE: Since many children with lower urinary tract symptoms are treated based on history and physical, it is important to know which symptom survey correlates best with the physician clinical impression. We evaluated 3 tools that have been demonstrated to predict severity of lower urinary tract symptoms, the Dysfunctional Voiding Symptom Score, the Akbal survey and the Nelson survey. Total scores from each survey were compared to clinical impression. MATERIALS AND METHODS: Participants consisted of 36 males and 35 females referred to our pediatric urology center for lower urinary tract symptoms. A total of 37 children 4 to 10 years old completed the Dysfunctional Voiding Symptom Score with the help of their parents, and 34 of these parents completed the Akbal survey. A total of 35 children 11 to 17 years old completed the Nelson survey. Scores from the 3 instruments were compared to the clinical impression of a pediatric urologist using rank correlation (Kendall's tau-b test). RESULTS: Mean total symptom scores were increased relative to physician rating for all 3 surveys. Symptoms reported by younger children using the Dysfunctional Voiding Symptom Score correlated better with physician rating of symptom severity (tau-b 0.43) compared to symptoms reported by parents using the Akbal survey (tau-b 0.41). Older children reporting symptoms using the Nelson survey had the strongest correlation with physician clinical impression (tau-b 0.48). CONCLUSIONS: All 3 surveys were statistically significantly correlated with the physician impression of severity for lower urinary tract symptoms, with the Nelson survey being the most accurate. PMID- 21600601 TI - EPLIN is a negative regulator of prostate cancer growth and invasion. AB - PURPOSE: We investigated the importance of EPLIN, a cytoskeletal associated protein implicated in cancer, in clinical prostate cancer and its role in the PC 3 prostate cancer cell line (ATCCTM). MATERIALS AND METHODS: Full-length human EPLIN cDNA was cloned into a pEF6 expression vector and used to transfect the PC 3 human prostate cancer cell line. Cells over expressing EPLIN were termed PC 3(EPLIN EXP) while wild-type and empty pEF6 vector control cells were designated PC-3(WT) and PC-3(pEF6), respectively. The in vitro and in vivo impact of EPLIN on PC-3 cells was examined using a number of model assays. RESULTS: EPLIN over expression in PC-3 cells resulted in a decrease in the growth rate of this cell line (mean +/- SD 0.6 +/- 0.17 for PC-3(pEF6) cells vs 0.33 +/- 0.01 for PC 3(EPLIN EXP) cells, p <0.01). PC-3(EPLIN EXP) cells were significantly less able to adhere to extracellular matrix than control cells (mean 61.0 +/- 12.4 vs 102.8 +/- 20.7, p = 0.028). Immunofluorescence staining showed an increased staining profile for paxillin in PC-3(EPLIN EXP) cells compared to wild-type cells. CONCLUSIONS: EPLIN over expression in the PC-3 cell line resulted in decreased in vivo and in vitro growth potential together with decreased cell invasiveness and ability to adhere to extracellular matrix, and enhanced paxillin staining. This further highlights the importance of EPLIN in regulating prostate cancer cell growth and aggressiveness, and suggests a possible connection between EPLIN and paxillin. PMID- 21600602 TI - Preclinical study of the novel vascular occluding agent, WST11, for photodynamic therapy of the canine prostate. AB - PURPOSE: Vascular targeted photodynamic therapy with WST09 shows promise for recurrent prostate cancer after radiation but hydrophobicity in aqueous solutions limited application. We tested the safety and efficacy of WST11, a novel water soluble vascular occluding agent, for vascular targeted photodynamic therapy of the dog prostate and compared it to WST09 vascular targeted photodynamic therapy. MATERIALS AND METHODS: Optical fibers were inserted in the prostate and connected to diode lasers. WST11 (Steba Biotech, Cedex, France) at varying doses, including a drug control with no light in 34 dogs, and WST09 (Steba Biotech) (2 mg/kg) in 3 dogs were infused during 10 minutes. Illumination was initiated at 5 or 10 minutes, and lasted up to 33.2 minutes based on laser fluence and delivered energy. Blood was collected for analysis and pharmacokinetics. The end point was at 1 week. RESULTS: No vascular targeted photodynamic therapy associated change was observed in blood pressure or blood test values. Circulating WST11 increased with drug infusion and decreased rapidly during 1 hour to reach undetectable levels by 24 hours. All except 1 dog with bowel intussusception did well after vascular targeted photodynamic therapy with only mild urinary symptoms that resolved within 24 to 48 hours. Lung and liver were normal. Hemorrhage was present in all prostates except controls. This translated into necrosis at a WST11 threshold and within a window of doses at fixed illumination. Necrosis was associated with loss of the vessel endothelial layer. Fluence highly impacted necrosis. WST11 vascular targeted photodynamic therapy was advantageously comparable to WST09 vascular targeted photodynamic therapy, and optimally ablated about 5.0 cm(3) of tissue per lobe and about 10 cm(3) of the whole prostate. CONCLUSIONS: The safety and efficacy of WST11 vascular targeted photodynamic therapy in the dog prostate support clinical applications for prostate cancer and benign prostatic hyperplasia. PMID- 21600603 TI - Effect of ovariectomy on external urethral sphincter activity in anesthetized female rats. AB - PURPOSE: The postmenopausal hypoestrogen condition is associated with various lower urinary tract dysfunctions, including frequency, urgency, stress urinary incontinence and recurrent urinary infection. We determined whether hypoestrogen induced lower urinary tract dysfunction after ovariectomy is also associated with an alteration in external urethral sphincter activity. MATERIALS AND METHODS: Bilateral ovariectomy was performed in female Sprague-Dawley(r) rats and sham operated rats served as controls. Transvesical cystometry and external urethral sphincter electromyogram activity were monitored 4, 6 and 12 weeks after sham operation or bilateral ovariectomy and at 6 weeks in bilaterally ovariectomized rats treated with estrogen. RESULTS: The micturition reflex was elicited in sham operated and bilaterally ovariectomized, urethane anesthetized animals. Post-void residual urine increased and voiding efficiency decreased in rats with 4 to 12 weeks of bilateral ovariectomy. The silent period of external urethral sphincter electromyogram activity was shortened significantly and progressively at increased times after bilateral ovariectomy. These effects were prevented by estradiol treatment. CONCLUSIONS: As evidenced by shortening of the external urethral sphincter electromyogram silent period in ovariectomized rats, the disruption of coordination between the external urethral sphincter and the detrusor muscle could decrease urine outflow and in turn voiding efficiency. Estrogen replacement reverses these changes, suggesting that the central pathways responsible for detrusor-sphincter coordination are modulated by gonadal hormones. PMID- 21600604 TI - Irritation induced bladder overactivity is suppressed by tibial nerve stimulation in cats. AB - PURPOSE: We investigated the effects of tibial nerve stimulation on bladder overactivity induced by acetic acid irritation. MATERIALS AND METHODS: Cystometry was performed in 10 alpha-chloralose anesthetized female cats by infusing saline or acetic acid through a urethral catheter that was secured by a ligature around the urethra. Intravesical infusion of 0.25% acetic acid was used to irritate the bladder and induce bladder overactivity. Multiple cystometrograms were done before, during and after tibial nerve stimulation to determine the inhibitory effect on the micturition reflex. RESULTS: Infusion of 0.25% acetic acid irritated the bladder, induced bladder overactivity and significantly decreased bladder capacity to about 20% of control capacity measured during saline infusion. Tibial nerve stimulation at low (5 Hz) or high (30 Hz) frequency significantly increased bladder capacity to about 40% of saline control capacity when it was applied during acetic acid infusion cystometrogram. Bladder contraction amplitude was smaller during acetic acid irritation than during saline distention due to significantly smaller bladder capacity. Tibial nerve stimulation at 5 Hz increased bladder capacity and bladder contraction amplitude. CONCLUSIONS: Activation of somatic afferents in the tibial nerve of cats can partially reverse the bladder overactivity induced by intravesical administration of a chemical irritant that activates C-fiber afferent nerves. These data are consistent with clinical studies showing that tibial nerve neuromodulation is effective treatment for overactive bladder symptoms. PMID- 21600605 TI - Intravenous sildenafil as a preconditioning drug against hemodynamic consequences of warm ischemia-reperfusion on the kidney. AB - PURPOSE: We designed an experimental model of renal ischemia-reperfusion to evaluate the preemptive effect of intravenous sildenafil according to the dose administered (0.7 vs 1.4 mg/kg) and the time of administration (30 minutes before ischemia or during ischemia). MATERIALS AND METHODS: A total of 20 minipigs were divided into groups of 4 each, including group 1-control, group 2-sildenafil 0.7 mg/kg intravenously 30 minutes before vascular clamping, group 3-sildenafil 0.7 mg/kg intravenously during warm ischemia, group 4-sildenafil 1.4 mg/kg intravenously 30 minutes before vascular clamping and group 5-sildenafil 1.4 mg/kg intravenously during warm ischemia. The ischemia-reperfusion model was applied using laparotomy and right kidney vascular clamping for 30 minutes, followed by unclamping and reperfusion for 45 minutes. Renal vascular flow and systemic mean arterial pressure were recorded for 45 minutes after unclamping. Mean values were compared using Student t test with significance considered at p <0.05. RESULTS: Sildenafil led to a decrease in arterial pressure compared to that in controls, especially at the dose of 1.4 vs 0.7 mg/kg, including 113.77, 109.76, 106.12, 97.41 and 82.85 mm Hg in groups 1 to 5, respectively. Renal vascular flow was significantly higher in groups 2 and 3 than in groups 1, 4 and 5 (112.82 and 111.33 vs 88.25, 87.91 and 84.37 ml per minute, respectively, p = 0.000). CONCLUSIONS: The effect of intravenous sildenafil as a preemptive drug against the hemodynamic effects of renal ischemia-reperfusion is dose dependent. The 0.7 mg/kg dose significantly increased reperfusion renal vascular flow with a small decrease in arterial pressure compared to the 1.4 mg/kg dose. PMID- 21600606 TI - Optimal freeze cycle length for renal cryotherapy. AB - PURPOSE: To our knowledge the optimal freeze cycle length in renal cryotherapy is unknown. Ten-minute time based freeze cycles were compared to temperature based freeze cycles to -20C. MATERIALS AND METHODS: Laparoscopic renal cryotherapy was performed on 16 swine. Time based trials consisted of a double 10-minute freeze separated by a 5-minute thaw. Temperature based trials were double cycles of 1, 5 or 10-minute freeze initiated after 1 of 4 sensors indicated -20C. A 5-minute active thaw was used between freeze cycles. Control trials consisted of cryoneedle placement for 25 minutes without freeze or thaw. Viability staining and histological analysis were done. RESULTS: There was no difference in cellular necrosis between any of the temperature based freeze cycles (p = 0.1). Time based freeze cycles showed more nuclear pyknosis, indicative of necrosis, than the 3 experimental freeze cycles for the renal cortex (p = 0.05) but not for the renal medulla (p = 0.61). Mean time to -20C for freeze cycle 1 was 19 minutes 10 seconds (range 9 to 46 minutes). In 4 of 21 trials (19%) -20C was never attained despite freezing for 25 to 63 minutes. CONCLUSIONS: There was no difference in immediate cellular necrosis among double 1, 5 or 10-minute freeze cycles. Cellular necrosis was evident on histological analysis for trials in which -20C was attained and in freeze cycles based on time alone. With a standard 10-minute cryoablation period most treated parenchyma 1 cm from the probe never attained 20C. Cell death appeared to occur at temperatures warmer than -20C during renal cryotherapy. PMID- 21600608 TI - Re: no good options. J. A. Smith, Jr. J Urol 2011; 185: 8-9. PMID- 21600609 TI - Pneumoperitoneum aggravates renal function in cases of decompensated but not compensated experimental congestive heart failure: role of nitric oxide. AB - PURPOSE: Congestive heart failure is associated with impaired renal function. Previously we noted that increased intra-abdominal pressure (pneumoperitoneum) in normal rats induced renal dysfunction. In this study we investigated the renal effects of pneumoperitoneum in rats with compensated (urinary Na(+) excretion greater than 1,200 MUEq per 24 hours) and decompensated (urinary Na(+) excretion less than 200 MUEq per 24 hours) congestive heart failure, and the possible involvement of nitric oxide in these effects. MATERIALS AND METHODS: After a baseline period rats with congestive heart failure induced by aorto-caval fistula and sham operated controls underwent consecutive intra-abdominal pressures of 7, 10 or 14 mm Hg for 45 minutes each. Urinary flow, urinary Na(+) excretion, glomerular filtration rate, renal plasma flow and urinary nitric oxide metabolites were determined. RESULTS: There were no changes in urinary flow, urinary Na(+) excretion, glomerular filtration rate or renal plasma flow during 7 mm Hg insufflation in controls. However, significant decreases in these parameters were observed during 10 and 14 mm Hg in correlation with intra abdominal pressure. Baseline renal function and hemodynamics were lower in rats with congestive heart failure in correlation with disease severity. Rats with decompensated congestive heart failure that underwent 10 and 14 mm Hg showed aggravated decreases in urinary flow, urinary Na(+) excretion, glomerular filtration rate and renal plasma flow. In contrast, no adverse renal effects were observed in rats with compensated congestive heart failure under identical intra abdominal pressure conditions. Despite unaltered baseline urinary nitric oxide metabolites in the 2 congestive heart failure subgroups, the decompensated group showed decreased urinary nitric oxide metabolites after 14 mm Hg. Finally, rats with compensated congestive heart failure pretreated with the nitric oxide synthase inhibitor L-NAME showed worse renal function in response to pneumoperitoneum. CONCLUSIONS: Decompensated congestive heart failure renders rats susceptible to the adverse renal effects of pneumoperitoneum, a phenomenon that may involve alterations in the renal nitric oxide system. PMID- 21600612 TI - Paraganglioma of the bladder. PMID- 21600613 TI - Re: tonsillectomy does not improve bedwetting: results of a prospective controlled trial. C. M. Kalorin, J. Mouzakes, J. P. Gavin, T. D. Davis, P. Feustel and B. A. Kogan. J Urol 2010; 184: 2527-2531. PMID- 21600614 TI - Re: tumor infiltrated hilar and mediastinal lymph nodes are an independent prognostic factor for decreased survival after pulmonary metastasectomy in patients with renal cell carcinoma. H. Winter, G. Meimarakis, M. K. Angele, M. Hummel, M. Staehler, R. T. Hoffmann, R. A. Hatz and F. Lohe J Urol 2011; 184: 1888-1894. PMID- 21600616 TI - Ductal adenocarcinoma of the prostate. PMID- 21600615 TI - Methodological concerns and quality appraisal of contemporary systematic reviews and meta-analyses in pediatric urology. AB - PURPOSE: The usefulness of systematic reviews and meta-analyses in influencing clinical practice depends on their quality. We sought to analyze the quality of published systematic reviews and meta-analyses in pediatric urology. MATERIALS AND METHODS: We searched PubMed (MEDLINE) and Embase for all systematic reviews and meta-analyses published in the top 5 pediatric urology journals between January 2000 and November 2009. Two reviewers independently selected articles for full text review. Scientific methodological quality was evaluated using the Assessment of Multiple Systematic Reviews 11-item tool. RESULTS: Of 267 initial results 220 articles were excluded because they were surveys, case reports or narrative reviews. Full text evaluation of the remaining 47 articles further excluded 32 series of exclusively adult patients, leaving 15 for final analysis. Seven articles (47%) were published in 2009 (p <0.01). Only 1 review (7%) described a full search strategy and 3 (20%) allowed inclusion of non-English studies. In 8 reviews (53%) selection of studies was performed by 2 reviewers. Five systematic reviews (33%) described some form of quality assessment. Only 5 reviews (33%) described assessment of publication bias, while 8 (53%) checked for heterogeneity among studies. According to AMSTAR criteria, 7 systematic reviews (47%) were considered of less than fair methodological quality, 5 (33%) fair to good quality and 3 (20%) good quality. CONCLUSIONS: Despite a recent increase in the number of systematic reviews and meta-analyses published in pediatric urology journals, almost half of these reviews lack good scientific quality, raising concerns about their role in influencing clinical practice. Efforts should be made to improve the methodological quality of systematic reviews and meta analyses in the pediatric urology literature. PMID- 21600617 TI - Temporal and life history related trends of perfluorochemicals in harbor porpoises from the Danish North Sea. AB - Eighty-five stranded or bycaught harbor porpoises collected from the Danish North Sea between 1980 and 2005 were analyzed for perfluorochemicals in the liver. PFOS was the predominant compound, making up on average 88.9% of the ?PFC, followed by PFOSA (7.8%). PFUnA (1.9%) and PFDA (1.2%) were detected in most samples. PFHxS, PFNA and PFOA were only found in a minority of the samples. We found substantial differences in PFC concentrations among life history stages, the highest concentrations were found in neonates, suckling juveniles and lactating females. Such differences should be considered when PFC levels in wildlife are evaluated. The high concentrations found in young porpoises are of concern as PFCs have known toxic effects on the development of the central nervous system and reproductive organs. Despite efforts to reduce PFC emissions, a decreasing temporal trend of concentrations was not detected for any compound. PFCA concentrations were found to be increasing. PMID- 21600618 TI - Bioindicative potential of shell abnormalities occurring in the clam Macoma balthica (L.) from the Baltic Sea. AB - This study reports the occurrence of shell deformities in the Baltic clam Macoma balthica from the Northern Baltic Sea (Trosa Archipelago, Sweden). The functional significance and the bioindicative potential of observed exoskeleton' anomalies was assessed using a suite of physiological and morphological biomarkers. Analyzed shell deformations (SD) included damages of the dorsal margin visible as shell excavations, destruction of the beak, umbo and hinge ligament and decreased shell' transparency. Deformed clams exhibited worse physiological conditions and increased frequency of micronuclei. Skewed sex ratio towards male domination was observed in all studied populations. Spatial differences in the occurrence of deformed clams are reported, with more than 50% of deformed clams inhabiting polluted locations and 8% the reference station. These results are encouraging for the use of described SDs as initial and cost effective indicators of environmental health. PMID- 21600619 TI - Improving outcomes for patients with depression by enhancing antidepressant therapy with non-pharmacological interventions: a systematic review of reviews. AB - OBJECTIVE: To analyse literature reviews reporting outcomes of non pharmacological interventions directed at improving the treatment of depression. METHODS: A review of English articles was performed in June 2009 using the following databases: PubMed, EMBASE, International Pharmaceutical Abstracts, Web of Science, PsycINFO and the Cochrane Library. Only review articles comparing traditional pharmacotherapy and interventions combining pharmacological and non pharmacological treatments were included. Extraction of articles and quality assessment of included reviews was performed independently by two authors using the AMSTAR score. RESULTS: The articles in the final data set included research on psychotherapeutic, multifaceted and single-component interventions. Single component interventions have failed to demonstrate improved outcome for patients with depression. Collaborative care and additional psychotherapy have been shown to provide more benefits for patients than pharmacotherapy alone. Both approaches have a small effect on short-term treatment, and psychotherapy is the most effective for long-term prognosis in terms of preventing relapse. CONCLUSION: Conclusions regarding the effects of adherence-improving and multifaceted interventions are fairly certain. However, the findings about the impact of combined psychotherapy and pharmacotherapy on the outcomes of depression remain tentative due to the methodological limitations of available reviews. PMID- 21600620 TI - [Imaging signs of ganglioneuroma of the mandible in a seven-year-old girl]. AB - Ganglioneuromas are benign tumors that are rare in children. They are made up of mature ganglion cells, Schwann cells, and connective tissue. The most common sites involved are the posterior mediastinum, retroperitoneum, suprarenal gland, and neck. They rarely involve bone. We present the case of a seven-year-old girl diagnosed with an intraosseous ganglioneuroma in the mandible. She had been treated for a suprarenal neuroblastoma (stage M) five years earlier. Bone scintigraphy and computed tomography of the mandible showed a lesion in the right mandibular ramus. Many osseous lesions can affect the mandible in children and the radiological appearance of most of them is unspecific. We discuss the differential diagnosis and main imaging findings of osseous lesions involving the mandible in children. PMID- 21600621 TI - Cutaneous larva migrans in Hospital Kuala Lumpur, Malaysia: rate of correct diagnosis made by the referring primary care doctors. AB - A retrospective study was undertaken to determine the clinical features of cutaneous larva migrans (CLM) seen in the Department of Dermatology, Hospital Kuala Lumpur (Kuala Lumpur, Malaysia) and to assess the rate of correct diagnosis made by the referring primary care doctors. Clinical records of all 31 patients with CLM seen between January 2006 and June 2010 were retrieved. The majority of patients were male. The mean age was 32.2 years. Pruritus was reported in 83.9% of cases and serpiginous tracts in 100%. The mean lesion count was 4.4 and the mean duration of disease before presentation was 3.1 weeks. The majority of skin lesions were on the buttock and lower extremities. Only 45.2% of patients had the correct diagnosis made by the referring primary care doctors. Older age of patients and lower number of lesions were associated with a higher rate of correct diagnosis. The low rate of correct diagnosis made by the referring primary care doctors to the dermatologists in this study warrants the need for education of not only primary care doctors but also future primary care providers, consisting of medical students, house officers and junior medical officers. PMID- 21600622 TI - Food web connections and the transmission cycles of Trypanosoma cruzi and Trypanosoma evansi (Kinetoplastida, Trypanosomatidae) in the Pantanal Region, Brazil. AB - We examined by parasitological tests (hemocultures and buffy coat) infection by Trypanosoma cruzi and T. evansi in blood samples from Leopardus pardalis, Cerdocyon thous and domestic dogs. Besides, 25 T. cruzi isolates previously derived from feral pigs and small wild mammals were here characterized by miniexon gene and demonstrated to be in the TcI genotype. Herein, we make an overall analysis of the transmission cycle of both trypanosome species in the light of the assemblage of data collected over the last seven years. The carnivore Nasua nasua was confirmed to play a major role in the transmission cycles of both T. cruzi and T. evansi since it was the species that had the higher prevalence and higher parasitemias by both flagellate species. In addition, our results show that both trypanosomatid species may be found throughout the Pantanal landscape, in all forest strata, as shown by the infection of carnivore, arboreal and terrestrial scansorial marsupial species in complex and seasonal transmission cycles. We propose that transmission of T. cruzi and T. evansi in the southern Pantanal region takes place via an intricate ecological trophic network involving generalist and specialist mammal species that are linked through a robust food-web connection. PMID- 21600623 TI - The parvoviral capsid controls an intracellular phase of infection essential for efficient killing of stepwise-transformed human fibroblasts. AB - Members of the rodent subgroup of the genus Parvovirus exhibit lytic replication and spread in many human tumor cells and are therefore attractive candidates for oncolytic virotherapy. However, the significant variation in tumor tropism observed for these viruses remains largely unexplained. We report here that LuIII kills BJ-ELR 'stepwise-transformed' human fibroblasts efficiently, while MVM does not. Using viral chimeras, we mapped this property to the LuIII capsid gene, VP2, which is necessary and sufficient to confer the killer phenotype on MVM. LuIII VP2 facilitates a post-entry, pre-DNA-amplification step early in the life cycle, suggesting the existence of an intracellular moiety whose efficient interaction with the incoming capsid shell is critical to infection. Thus targeting of human cancers of different tissue-type origins will require use of parvoviruses with capsids that effectively make this critical interaction. PMID- 21600624 TI - Canine pneumovirus replicates in mouse lung tissue and elicits inflammatory pathology. AB - Canine pneumovirus (CnPnV) was recently isolated from the respiratory tracts of shelter dogs and shares sequence similarity with the rodent pathogen, pneumonia virus of mice (PVM). We show here that CnPnV replicates in and can elicit local proinflammatory cytokine production and neutrophil recruitment to lung tissue and the airways. In contrast to PVM J3666 infection, fatal CnPnV infections are observed only in response to high titer intranasal inocula (>67 TCID(50) units). Sera from mice that recover from CnPnV infection contain antibodies that cross react with PVM antigens; these mice are protected against lethal PVM infection. Given these findings, it will be intriguing to determine the relative role(s) of CnPnV and PVM in eliciting respiratory symptoms in susceptible canine species. PMID- 21600625 TI - Effect of interferences on the breakthrough of arsenic: rapid small scale column tests. AB - The influences of three important interferences (silica, phosphate, and vanadate) and the effect of different pH levels and initial arsenate concentrations on the breakthrough of arsenic in adsorptive media columns were examined by using the Rapid Small Scale Column Test with a 3 fractional factorial design. Three commercially available adsorbents used for arsenic removal (E33, GFH and Metsorb) were tested. Results indicated that GFH was more susceptible to water quality changes than Metsorb and E33 under conditions tested. GFH also adsorbed more anions than the other two media. The pH was the factor that had the most impact on the performance of the columns, followed by arsenic concentration and silica concentration. Lowering pH from 8.3 to 7.0 resulted in an increase of the mean bed volume treated until 10 MUg/L arsenic breakthrough by 40, 12 and 18 thousands BV treated by GFH, E33 and Metsorb columns, respectively. However, at high silica concentration, lowering pH did not increase the performance of the media. GFH and Metsorb were more sensitive to changes in arsenic concentration at low pH than at high pH. Although vanadium and phosphate were previously reported to reduce arsenic adsorption in batch tests, in column mode with the presence of competitors, their effect was insignificant compared to that of pH, arsenic or silica under the conditions used in this study. PMID- 21600626 TI - Survival of prototype strains of somatic coliphage families in environmental waters and when exposed to UV low-pressure monochromatic radiation or heat. AB - The potential use of specific somatic coliphage taxonomic groups as viral indicators based on their persistence and prevalence in water was investigated. Representative type strains of the 4 major somatic coliphage taxonomic groups were seeded into reagent water and an ambient surface water source of drinking water and the survival of the added phages was measured over 90 days at temperatures of 23-25 and 4 degrees C. Microviridae (type strain PhiX174), Siphoviridae (type strain Lambda), and Myoviridae (type strain T4) viruses were the most persistent in water at the temperatures tested. The Microviridae (type strain PhiX174) and the Siphoviridae (type strain Lambda) were the most resistant viruses to UV radiation and the Myoviridae (type strain T4) and the Microviridae (type strain PhiX174) were the most resistant viruses to heat. Based on their greater persistence in water over time and their relative resistance to heat and/or UV radiation, the Myoviridae (type strain T4), the Microviridae (type strain PhiX174), and the Siphoviridae (type strain Lambda) were the preferred candidate somatic coliphages as fecal indicator viruses in water, with the Microviridae (type strain PhiX174) the most resistant to these conditions overall. PMID- 21600627 TI - Evaluation of surface runoff and road dust as sources of nitrogen using nitrate isotopic composition. AB - Stable nitrogen and oxygen isotope ratios of nitrate (delta(15)N-NO(3) and delta(18)O-NO(3)) have recently been used to identify nitrogen sources in water environments. However, there have been no investigations designed to determine nitrate isotopes in non-point sources in urban areas for evaluating the impact of surface deposits on nitrogen in surface runoff. In this study, we collected rainwater, surface runoff and surface deposits (road dust, roof dust and soil) to evaluate the nitrogen sources in surface runoff using nitrate isotopes. There were no large differences in delta(15)N-NO(3) among rainwater (-0.30/00 to 1.50/00), surface runoff (-2.70/00 to 0.40/00), leachates from road dust ( 5.80/00 to 6.20/00) and soil (-11.50/00 to 0.60/00). In contrast, the delta(18)O NO(3) in surface runoff (28.5-47.90/00) was lower than that in rainwater (62.7 78.60/00), and higher than that in leachates from road dust (6.1-27.60/00) and soil (-1.10/00 to 6.60/00). delta(18)O-NO(3) is a useful indicator for evaluating the NO(3)-N sources in surface runoff. Using this indicator, NO(3)-N from road dust was estimated to account for more than half of the NO(3)-N in surface runoff. This is consistent with a result based on a comparison of their loads per unit surface between rainwater and surface runoff, which also showed that most of the nitrogen in surface runoff was derived from surface deposits. PMID- 21600628 TI - Chitosan/albumin/CaCO3 as mimics for membrane bioreactor fouling: genesis of structural mineralized-EPS-building blocks and cake layer compressibility. AB - Membrane bioreactor biofouling is usually described as an extracellular matrix in which biopolymers, inorganic salts and active microbes co-exist. For that reason, biomineralization (BM) models can be useful to describe the spatial organization and environmental constraints within the referred scenario. BM arguments were utilized as background in order to (1) evaluate CaCO(3) influence on flux decline; pore blocking and cake layer properties (resistance, permeability and compressibility) in a wide range of Chitosan/Bovine serum albumin (BSA) mixtures during step-pressure runs and, (2) perform membrane autopsies in order to explore the genesis of mineralized extracellular building blocks (MEBB) during cake layer build up. Using low molecular weight chitosan (LC) and BSA, 2 L of 5 LC/BSA mixtures (0.25-1.85 ratio) were pumped to an external ultra filtration (UF) membrane (23.5cm(2), hydrophobic, piezoelectric, 100kDa as molecular weight cut off). Eight different pressure steps (40+/-7 to 540+/-21kPa) were applied. Each pressure step was held for 900 s. CaCO(3) was added to LC/BSA mixtures at 0.5, 1.5 and 3mM in order to create MEBB during the filtration tests. Membrane autopsies were performed after the filtration tests using thermo gravimetric, scanning microscopy and specific membrane mass (mgcm(-2)) analyses. Biopolymer CaCO(3) step-pressure filtration created compressible cake layers (with inner voids). The formation of an internal skeleton of MEBB may contribute to irreversible fouling consolidation. A hypothesis for MEBB genesis and development was set forth. PMID- 21600629 TI - Use of fugacity model to analyze temperature-dependent removal of micro contaminants in sewage treatment plants. AB - Effluents from sewage treatment plants (STPs) are known to contain residual micro contaminants including endocrine disrupting chemicals (EDCs) despite the utilization of various removal processes. Temperature alters the efficacy of removal processes; however, experimental measurements of EDC removal at various temperatures are limited. Extrapolation of EDC behavior over a wide temperature range is possible using available physicochemical property data followed by the correction of temperature dependency. A level II fugacity-based STP model was employed by inputting parameters obtained from the literature and estimated by the US EPA's Estimations Programs Interface (EPI) including EPI's BIOWIN for temperature-dependent biodegradation half-lives. EDC removals in a three-stage activated sludge system were modeled under various temperatures and hydraulic retention times (HRTs) for representative compounds of various properties. Sensitivity analysis indicates that temperature plays a significant role in the model outcomes. Increasing temperature considerably enhances the removal of beta estradiol, ethinyestradiol, bisphenol, phenol, and tetrachloroethylene, but not testosterone with the highest biodegradation rate. The shortcomings of BIOWIN were mitigated by the correction of highly temperature-dependent biodegradation rates using the Arrhenius equation. The model predicts well the effects of operating temperature and HRTs on the removal via volatilization, adsorption, and biodegradation. The model also reveals that an impractically long HRT is needed to achieve a high EDC removal. The STP model along with temperature corrections is able to provide some useful insight into the different patterns of STP performance, and useful operational considerations relevant to EDC removal at winter low temperatures. PMID- 21600630 TI - Differences between Arctic and Atlantic fjord systems on bioaccumulation of persistent organic pollutants in zooplankton from Svalbard. AB - Differences in bioaccumulation of persistent organic pollutants (POPs) between fjords characterized by different water masses were investigated by comparing POP concentrations, patterns and bioaccumulation factors (BAFs) in seven species of zooplankton from Liefdefjorden (Arctic water mass) and Kongsfjorden (Atlantic water mass), Svalbard, Norway. No difference in concentrations and patterns of POPs was observed in seawater and POM; however higher concentrations and BAFs for certain POPs were found in species of zooplankton from Kongsfjorden. The same species were sampled in both fjords and the differences in concentrations of POPs and BAFs were most likely due to fjord specific characteristics, such as ice cover and timing of snow/glacier melt. These confounding factors make it difficult to conclude on water mass (Arctic vs. Atlantic) specific differences and further to extrapolate these results to possible climate change effects on accumulation of POPs in zooplankton. The present study suggests that zooplankton do biomagnify POPs, which is important for understanding contaminant uptake and flux in zooplankton, though consciousness regarding the method of evaluation is important. PMID- 21600631 TI - Analysis of vulnerability factors that control nitrate occurrence in natural springs (Osona Region, NE Spain). AB - Nitrate pollution is one of the main concerns of groundwater management in most of the world's agricultural areas. In the Osona region of NE Spain, high concentrations of nitrates have been reported in wells. This study uses the occurrence of this pollutant in natural springs as an indicator of the sub surface dynamics of the water cycle and shows how groundwater quality is affected by crop fertilization, as an approach to determine the aquifer vulnerability. Nitrate concentration and other hydrochemical parameters based on a biannual database are reported for approximately 80 springs for the period 2004-2009. The background concentration of nitrate is first determined to distinguish polluted areas from natural nitrate occurrence. A statistical treatment using logistic regression and ANOVA is then performed to identify the significance of the effect of vulnerability factors such as the geological setting of the springs, land use in recharge areas, sampling periods, and chemical parameters like pH and EC, on groundwater nitrate pollution. The results of the analysis identify a threshold value of 7-8 mg NO(3)(-)/L for nitrate pollution in this area. Logistic regression and ANOVA results show that an increase in EC or a decrease in pH values is linked to the possibility of higher nitrate concentrations in springs. These analyses also show that nitrate pollution is more dependent on land use than the geological setting of springs or sampling periods. Indeed, the specific geological and soil features of the uppermost layers in their recharge areas do not contribute to the buffering of nitrate impacts on aquifers as measured in natural springs. Land use, and particularly fertilization practices, are major factors in groundwater vulnerability. PMID- 21600632 TI - P-selectin ligation induces platelet activation and enhances microaggregate and thrombus formation. AB - INTRODUCTION: Platelet P-selectin is a thrombo-inflammatory molecule involved in platelet activation and aggregation. This may occur via the adhesive function of P-selectin and its potential capacity to trigger intracellular signaling. However, its impact on platelet function remains elusive. This study was therefore designed to investigate the relationship between the signaling potential of platelet P-selectin and its function in platelet physiology. METHODS AND RESULTS: Human and mouse platelets were freshly isolated from whole blood. Platelet activation was assessed using flow cytometry and western blot analysis, while platelet physiological responses were evaluated through aggregation, microaggregate formation and in a thrombosis model in wild-type and P-selectin deficient (CD62P(-/-)) mice. Interaction of P-selectin with its high-affinity ligand, a recombinant soluble form of P-Selectin Glycoprotein Ligand-1 (rPSGL-1), enhances platelet activation, adhesion and microaggregate formation. This augmented platelet microaggregates requires an intact cytoskeleton, but occurs independently of platelet alpha(IIb)beta(3). Thrombus formation and microaggregate were both enhanced by rPSGL-1 in wild-type, but not in CD62P(-/-) mice. In addition, CD62P(-/-) mice exhibited thrombosis abnormalities without an alpha(IIb)beta(3) activation defect. CONCLUSIONS: This study demonstrates that the role of platelet P-selectin is not solely adhesive; its binding to PSGL-1 induces platelet activation that enhances platelet aggregation and thrombus formation. Therefore, targeting platelet P-selectin or its ligand PSGL-1 could provide a potential therapeutic approach in the management of thrombotic disorders. PMID- 21600633 TI - "Zeus" a new oral anticoagulant therapy dosing algorithm: a cohort study. AB - The demand for oral anticoagulant therapy (OAT) has constantly increased during the last ten years with an extended use of computer assistance. Many mathematical algorithms have been projected to suggest doses and time to next visit for patients on OAT. We designed a new algorithm: "Zeus". A "before-after" study was planned to compare the efficacy and safety of this algorithm dosing OAT with manual dosage decided by the same expert physicians according to the target of International Normalized Ratio (INR). The study analysed data of 1876 patients managed with each of the two modalities for eight months, with an interval of two years between them. The aim was to verify the increased quality of therapy by time spent in INR target and efficiency and safety of Zeus algorithm. Time in therapeutic range (TTR) was significantly (p < 0.0001) higher during the algorithm dosing period in comparison with the TTR during manual management period (62.3% vs 50.3%). The number of PT/INR tests above 5 was significantly (p < 0.001) reduced by algorithm suggested prescriptions in comparison with manual those (254 vs 537 times). The anticoagulant drug amount prescribed according to the algorithm suggestions was significantly (p < 0.0001) lower than that of the manual method. The number of clinical events observed in patients during the algorithm management time was significantly (p < 0.05) lower than that in those managed with the manual dosage. This study confirms the clinical utility of the computer-assisted OAT and shows the efficacy and safety of the Zeus algorithm. PMID- 21600634 TI - Past provoking venous thrombosis risk situations on the risk of a recurrent thrombotic event: a cohort study. AB - OBJECTIVE: Strategies that can classify the risk for recurrent venous thrombosis are needed. Some patients may have experienced many risk situations during their life time without developing venous thrombosis (VT), while others may have experienced few of such risk factors and then develop VT idiopathically or after a single provoked risk factor. We hypothesized that those who had 'survived' many risk situations without developing VT would, after a first VT, have a low recurrence risk. METHODS: Brazilian tertiary hospital cohort was followed for an average of 30 months after anticoagulation withdrawal for a first VT. Patients with indication for indefinite anticoagulation were not included. The primary end point was objective recurrent VT. RESULTS: Recurrent VT was recorded in 7% of 378 eligible patients. Patients with a provoked first event and positive past risk situations for VT had an incidence rate of recurrence of 1.16 (95% confidence interval [CI], 0.47-2.39) per 100 patient-years. The incidence rate ratio (IRR) of this subgroup compared to patients with a provoked event without other past risk situations for VT was 1.1 (95% CI, 0.3-4.4). This IRR was 3.3 (95% CI, 1.3 8.7) in patients with an unprovoked event and positive past risk situations and 5.1 (95% CI, 1.6-16.1) in patients with an unprovoked event and no past risk situations. CONCLUSIONS: Asking a patient about past exposure of venous thrombosis risk factors long before the occurrence of a first venous thrombosis occurred, does not provide information to classify patients at lower risk for recurrence of venous thrombosis. PMID- 21600635 TI - Feasibility of a lifestyle intervention for ovarian cancer patients receiving adjuvant chemotherapy. AB - OBJECTIVES: This study aimed to assess the feasibility of a lifestyle intervention for promoting physical activity (PA) and diet quality during adjuvant chemotherapy for ovarian cancer. METHODS: Patients were enrolled post operatively and received PA and nutrition counseling, at every chemotherapy visit for six cycles. Quality of life (QoL) was measured with the Functional Assessment of Cancer Therapy (FACT-G), PA with the Leisure Score Index (LSI), dietary intake with 3-day food records, and symptom severity/distress by the Memorial Symptom Assessment Scale (MSAS). Pedometer step count was collected during chemotherapy cycles. RESULTS: Recruitment was 73% with 27 patients enrolled. Mean [95% confidence interval] change in minutes of PA from cycle #3 to following cycle #6 was 61 min [-3, 120] p=0.063, and from baseline to after cycle #6 was 73 min [ 10, 15]; p=0.082. Mean change in total fruit and vegetable consumption between baseline and during chemotherapy was 0.56 [-0.09, 0.64]; p=0.090. FACT-G increased from 75.4 at baseline to 77.6 during chemotherapy and 83.9 following chemotherapy (p=0.001 for change from baseline to post-chemotherapy). Mean total MSAS score was 20.6 at baseline, 26.6 at cycle #3 and decreased to 17.0 following chemotherapy (p=0.01 comparison of cycle #3 and following chemotherapy). Increased moderate to strenuous PA was correlated with higher physical well-being during chemotherapy (r=0.48, p=0.037). CONCLUSIONS: Lifestyle counseling during adjuvant chemotherapy for ovarian cancer is feasible and may improve PA and diet quality. Randomized controlled trials examining the effects of lifestyle counseling on quality of life and treatment outcomes in ovarian cancer patients are warranted. PMID- 21600636 TI - Management of recurrent endodermal sinus tumor of the ovary associated with pregnancy. PMID- 21600638 TI - Number of sense effects of Chinese disyllabic compounds in the two hemispheres. AB - The current study manipulated the visual field and the number of senses of the first character in Chinese disyllabic compounds to investigate how the related senses (polysemy) of the constituted character in the compounds were represented and processed in the two hemispheres. The ERP results in experiment 1 revealed crossover patterns in the left hemisphere (LH) and the right hemisphere (RH). The sense facilitation in the LH was in favor of the assumption of single-entry representation for senses. However, the patterns in the RH yielded two possible interpretations: (1) the nature of hemispheric processing in dealing with sublexical sense ambiguity; (2) the semantic activation from the separate-entry representation for senses. To clarify these possibilities, experiment 2 was designed to push participants to a deeper level of lexical processing by the word class judgment. The results revealed the sense facilitation effect in the RH. In sum, the current study was in support of the single-entry account for related senses and demonstrated that two hemispheres processed sublexical sense ambiguity in a complementary way. PMID- 21600637 TI - Brain networks associated with sublexical properties of Chinese characters. AB - Cognitive models of reading all assume some division of labor among processing pathways in mapping among print, sound and meaning. Many studies of the neural basis of reading have used task manipulations such as rhyme or synonym judgment to tap these processes independently. Here we take advantage of specific properties of the Chinese writing system to test how differential availability of sublexical information about sound and meaning, as well as the orthographic structure of characters, pseudo-characters and "artificial" control stimuli influence brain activation in the context of the same one-back task. Analyses combine a data-driven approach that identifies temporally coherent patterns of activity over the course of the entire experiment with hypothesis-testing based on the correlation of these patterns with predictors for different stimulus classes. The results reveal a large network of task-related activity. Both the extent of this network and activity in regions commonly observed in studies of Chinese reading are apparently related to task difficulty. Other regions, including temporo-parietal cortex, were sensitive to particular sublexical functional units in mapping among print, sound, and meaning. PMID- 21600639 TI - The use of pediatric early warning scores in the emergency department. PMID- 21600640 TI - Emergency nursing resource: gastric tube placement verification. PMID- 21600641 TI - Emergency nursing resource: family presence during invasive procedures and resuscitation in the emergency department. PMID- 21600642 TI - Emergency Nursing Resource: the use of capnography during procedural sedation/analgesia in the emergency department. PMID- 21600643 TI - Characterization and hydration kinetics of tricalcium silicate cement for use as a dental biomaterial. AB - OBJECTIVES: Investigation and characterization of the replacement of the Portland cement component in mineral trioxide aggregate (MTA) with tricalcium silicate cement which is manufactured using the sol-gel method from pure raw materials. METHODS: Tricalcium silicate and Portland cement were characterized by viewing under the scanning electron microscope (SEM) and surface imaging and elemental analysis with X-ray energy dispersive analysis (EDX), and by X-ray diffraction analysis with Rietveld refinement. In addition the hydration products of the material after 28 days of curing were evaluated by plotting atomic ratio plots from the EDX data. The cement leachate was evaluated for pH and chemical composition by inductively coupled plasma. RESULTS: Portland cement was composed of 68% tricalcium silicate. The tricalcium silicate cement was 99% pure. On hydration both cements produced calcium silicate hydrate and calcium hydroxide. The calcium hydroxide was leached in solution with higher leaching in HBSS. The leaching of calcium hydroxide in solution resulted in an alkaline pH. The reaction of calcium with the phosphorus present in HBSS resulting in the deposition of calcium phosphate on the cement surface. SIGNIFICANCE: Tricalcium silicate could prospectively replace the Portland cement component in MTA. PMID- 21600644 TI - A method for assessing force/work parameters for stickiness of unset resin composites. AB - OBJECTIVES: To evaluate the stickiness of unset resin-composites, at different speeds and temperatures, in terms of maximum probe separation-force (F(max)) and work-of-separation (W(s)). MATERIALS AND METHODS: Eight commercial light-cured resin-composites were selected. Each material was placed in a cylindrical mold (phi=7 mm * 5 mm depth) held at 25 degrees C or 37 degrees C. The maximum force (F(max), N) and work probe separation (W(s), N mm) were measured by using a texture analyzer to register force/displacement. A flat-ended stainless-steel probe (phi=6mm) was mechanically lowered onto and into the surface of the unset sample. When a 'trigger' compressive force of 0.05 N was registered, data acquisition commenced. Descent continued until a compressive force of 1N was reached, which was held constant for 1s. Then the probe was moved vertically upward at constant speed. This was varied over the range 2, 4, 6 and 8mm/s. The tensile force produced on the probe by the sticky resin-composite was plotted against displacement and the maximum value was identified (F(max)). W(s) was obtained as the integrated area. Data was analyzed by multivariate ANOVA and multiple pair wise comparisons was done by using a Tukey post hoc test to establish homogenous subsets (at p=0.05). RESULTS: F(max) and W(s) were taken as potential measures of stickiness. They ranged from 0.47 to 3.68 N and from 0.11 to 2.84 N mm, respectively. Multivariate ANOVA showed a strong interaction of withdrawal speed, temperature and materials on both F(max) and W(s) (p<0.001). CONCLUSION: F(max) and W(s) are useful parameters for characterizing the handling stickiness of resin-composite materials, additional to previously reported stickiness-strain or 'peak-height'. The resin-composites investigated could be differentiated, mostly showing increases in F(max) and W(s) stickiness with increased temperature and probe-withdrawal speed. PMID- 21600645 TI - Gambling disorders. AB - Gambling disorders, including pathological gambling and problem gambling, have received increased attention from clinicians and researchers over the past three decades since gambling opportunities have expanded around the world. This Seminar reviews prevalence, causes and associated features, screening and diagnosis, and treatment approaches. Gambling disorders affect 0.2-5.3% of adults worldwide, although measurement and prevalence varies according to the screening instruments and methods used, and availability and accessibility of gambling opportunities. Several distinct treatment approaches have been favourably evaluated, such as cognitive behavioural and brief treatment models and pharmacological interventions. Although promising, family therapy and support from Gamblers Anonymous are less well empirically supported. Gambling disorders are highly comorbid with other mental health and substance use disorders, and a further understanding is needed of both the causes and treatment implications of this disorder. PMID- 21600646 TI - Electrospun nanofibers as a tool for architecture control in engineered cardiac tissue. AB - This paper presents an in vitro system for cardiac tissue engineering based on cardiomyocytes cultured on electrospun polymethylglutarimide (PMGI) nanofibrous meshes either imprinted on solid substrate or suspended in space. Special care was taken over the ability to control the tissue architecture. The electrospinning process allowed nano-scale diameter PMGI fibers with different positioning density to be collected in a random or in an aligned way that defines the general configuration of the mesh. Micro-imprinted on solid substrate nanofibers guarantee aligned cell growth, when the distance between them is 30 MUm or less. Suspended in 3D space, nanofibers define the overall architecture of the tissue, depending on orientation and positioning density of the nanofibers. As a result, cardiac cells proliferated into contractile tissue filaments, open worked tissue meshes and continuous anisotropic cell sheets. Alignment of the cells was characterized by elongation of the cell shape and orientation of the alpha-actin filaments supported by the FFT data. The advantage of this method is its ability to maintain both three-dimensionality and structural anisotropy. PMID- 21600647 TI - Sustained targeting of Bcr-Abl + leukemia cells by synergistic action of dual drug loaded nanoparticles and its implication for leukemia therapy. AB - Chimeric Bcr-Abl oncoprotein is the molecular hallmark of chronic myeloid leukemia (CML) and hence a lucrative target for therapeutic intervention of CML.However, limited efficacy of current first line treatment for CML calls attention for further development of more efficient strategies. Recently, much attention has been given to nanoparticle (NP) based drug delivery systems loaded with dual drugs to improve current disease therapies by overcoming toxicity and other side effects associated with high doses of single drugs. In the present study, we document to explore an approach to simultaneously deliver two drugs at target sites (i.e. Bcr-Abl oncoprotein) using poly (lactide-co-glycolide) (PLGA) nanoparticles. Preliminary study included screening six different anticancer drugs and their nanoformulations on leukemia cells. Results confirmed superlative antileukemic activity of paclitaxel (especially in formulations) on model cell line K562, but only upon longer exposure. Thus to lower time of action of such a potent drug, different drug combination were experimented taking the advantage of synergistic action of both the drugs. Evaluation at molecular and genetic level helped to identify signaling pathways upstream and downstream of Bcr-Abl, leading to its suppression. Results helped to illustrate dynamic changes primarily involved in inducing apoptotic activities on drug exposure of leukemia cells, thereby facilitating us to integrate different drug combinations in a more specific manner in near future to study CML in clinical settings. PMID- 21600648 TI - C/EBP-alpha and C/EBP-beta-mediated adipogenesis of human mesenchymal stem cells (hMSCs) using PLGA nanoparticles complexed with poly(ethyleneimmine). AB - In this study, to drive efficient adipogenic differentiation, the adipogenic transcription factors C/EBP-alpha and C/EBP-beta fused to green fluorescent protein (GFP) or red fluorescent protein (RFP) were complexed with poly ethyleneimine (PEI) coupled with biodegradable PLGA nanospheres and delivered to human mesenchymal stem cell (hMSC). FACS analysis revealed that the transfection efficiency of C/EBP-alpha, C/EBP-beta, or both genes complexed with PEI-coated PLGA nanospheres was 12.59%, 21.74%, and 28.96% of hMSCs. Expression and localization of C/EBP-alpha and C/EBP-beta were confirmed by Western blotting and confocal laser microscopy. Overexpression of exogenous C/EBP-alpha and C/EBP-beta significantly elevated adipogenic differentiation processes as indicated by RT PCR, real-time PCR, Western blotting, histology, and immunofluorescence microscopy. During adipogenesis, PEI-coupled PLGA nanospheres complexed with C/EBP-alpha and C/EBP-beta greatly increased the adipogenic capability of in vitro cultured cells, as well of in vivo transplanted cells. The expression of genes and proteins specific to adipogenic differentiation in hMSCs was significantly elevated compared to the controls. PMID- 21600649 TI - Suppression of Runx2 protein degradation by fibrous engineered matrix. AB - The fibre structure of engineered matrix that mimic the morphology of type I collagen has exhibited good biological performance for bone regeneration. However, the mechanism by which synthetic fibres promote osteoblast differentiation has yet to be determined. In this study, we demonstrate that fibre structure of an engineered matrix suppresses the degradation of Runx2, a master transcription factor that can turn on to osteoblast differentiation. MC3T3 E1 pre-osteoblasts grown on a fibrous collagen matrix sustained a higher level of Runx2 protein than those on tissue culture dishes or on a collagenase-treated, non-fibrous collagen matrix. The ubiquitin-dependent degradation of Runx2 was profoundly decreased in cells grown on the fibrous collagen matrix. The forced expression of Smurf1, an ubiquitin ligase responsible for Runx2 degradation, abrogated the collagen fibre-induced increase of Runx2. We also prepared a polystyrene fibre matrix, and confirmed that the fibre matrix stabilised the Runx2 protein in MC3T3-E1. Furthermore, we genetically modified C2C12 myoblasts with Runx2, cultured the cells on polystyrene fibre matrix, and observed that the fibre matrix stabilised and sustained exogenous Runx2, which led to the promotion of osteoblast differentiation. Our findings in this study provide evidence that the fibre structure of an engineered matrix contributes to osteoblast differentiation by stabilising the Runx2 protein. PMID- 21600650 TI - Clinical usefulness of plasma specimens for detection of nucleophosmin 1 gene mutations in patients with normal karyotype acute myeloid leukemia. PMID- 21600651 TI - MN1-ETV6 fusion gene arising from MDS with 5q-. PMID- 21600652 TI - Staphylococcus aureus induces IL-1beta expression through the activation of MAP kinases and AP-1, CRE and NF-kappaB transcription factors in the bovine mammary gland epithelial cells. AB - Although mastitis caused by Staphylococcus aureus is a problematic inflammatory disease in lactating cows, the innate immunity to S. aureus in the mammary gland is poorly understood. In the present study, we observed that heat-killed S. aureus (HKS) induced IL-1beta expression at both the mRNA and protein levels in the mammary gland epithelial cell-line, MAC-T. IL-1beta production was suppressed by inhibitors of lipid rafts, ERK, JNK, and p38 kinases. Furthermore, HKS augmented the activities of the AP-1, CRE, and NF-kappaB transcription factors that regulate IL-1beta gene expression. Among staphylococcal cell-wall components with inflammatory potential, Pam2CSK4 (a representative model for diacylated lipoproteins) enhanced IL-1beta mRNA expression, while lipoteichoic acid and peptidoglycan did not. Collectively, we suggest that S. aureus-induced IL-1beta production requires lipid raft formation, activation of MAP kinases, and activation of transcription factors AP-1, CRE, and NF-kappaB. Lipoprotein seems to be a major cell-wall component for the S. aureus-induced IL-1beta production in bovine mammary gland epithelial cells. PMID- 21600653 TI - Mercury pollution in Wuchuan mercury mining area, Guizhou, Southwestern China: the impacts from large scale and artisanal mercury mining. AB - To evaluate the environmental impacts from large scale mercury mining (LSMM) and artisanal mercury mining (AMM), total mercury (THg) and methyl mercury (MeHg) were determined in mine waste, ambient air, stream water and soil samples collected from Wuchuan mercury (Hg) mining area, Guizhou, Southwestern China. Mine wastes from both LSMM and AMM contained high THg concentrations, which are important Hg contamination sources to the local environment. Total gaseous mercury (TGM) concentrations in the ambient air near AMM furnaces were highly elevated, which indicated that AMM retorting is a major source of Hg emission. THg concentrations in the stream water varied from 43 to 2100 ng/L, where the elevated values were mainly found in the vicinity of AMM and mine waste heaps of LSMM. Surface soils were seriously contaminated with Hg, and land using types and organic matter played an important role in accumulation and transportation of Hg in soil. The results indicated heavy Hg contaminations in the study area, which were resulted from both LSMM and AMM. The areas impacted by LSMM were concentrated in the historical mining and smelting facilities, while Hg pollution resulted from AMM can be distributed anywhere in the Hg mining area. PMID- 21600654 TI - Odd-numbered perfluorocarboxylates predominate over perfluorooctanoic acid in serum samples from Japan, Korea and Vietnam. AB - Perfluorooctanoic acid (PFOA) has recently attracted attention as a potential health risk following environmental contamination. However, information detailing exposure to perfluorinated carboxylic acids (PFCAs) other than PFOA is limited. We measured the concentrations of PFCAs (from perfluorohexanoic acid to perfluorotetradecanoic acid) in serum samples obtained from patients in Japan (Sendai, Takayama, Kyoto and Osaka) between 2002 and 2009, Korea (Busan and Seoul) between 1994 and 2008 and Vietnam (Hanoi) in 2007/2008. Total PFCA levels (geometric mean) were increased from 8.9 ng mL(-1) to 10.3 ng mL(-1) in Japan; from 7.0 ng mL(-1) to 9.2 ng mL(-1) in Korea; and were estimated at 4.7 ng mL(-1) in Vietnam. PFCAs of greater length than PFOA were significantly increased in Sendai, Takayama and Kyoto, Japan, and levels of long-chain PFCAs exceeded PFOA levels in serum. Among these PFCAs, perfluoroundecanoic acid (PFUnDA) was the predominant component (28.5%), followed by perfluorononanoic acid (PFNA 17.5%), perfluorodecanoic acid (PFDA 7.9%), perfluorotridecanoic acid (PFTrDA 6.1%) and perfluorododecanoic acid (PFDoDA 1.8%). Odd-numbered PFCAs (PFNA, PFUnDA and PFTrDA) were also observed in Korea and Vietnam and their presence increased significantly in Korea between 1994 and 2007/2008. The proportion of long-chain PFCAs in serum was relatively high compared to reports in Western countries. Further investigations into the sources and exposure routes are needed to predict the future trajectory of these serum PFCA levels. PMID- 21600655 TI - The expression of TIPE1 in murine tissues and human cell lines. AB - Members of the tumor necrosis factor-alpha-induced protein-8 (TNFAIP8 or TIPE) family play important roles in immune homeostasis and cancer. TIPE1 (TNFAIP8-like 1) is a new member of the TIPE family that may regulate cell death. However, due to the lack of a suitable antibody, the nature of cells and tissues that express TIPE1 protein has not been determined. In this study, we generated a highly specific antibody to TIPE1 and examined TIPE1 expression in various murine tissues and human cell lines by immunohistochemistry, reverse transcription real time PCR, and Western blot. We found that TIPE1 protein was detected in a wide variety of tissues in C57BL/6 mice, such as neurons in brain, hepatocytes, germ cells of female and male reproductive organs, muscular tissues, and a variety of cells of the epithelial origin, particularly those with secretory functions. TIPE1 protein was not expressed in mature T or B lymphocytes, but detectable in human B lymphoblast cell line HMy2.CIR and murine T cell line EL4. Furthermore, high levels of TIPE1 mRNA were detected in most human carcinoma cell lines, especially in cells transformed with viral genomes. These results indicate that TIPE1 may perform functions in cell secretion and carcinogenesis, but not in immunity. PMID- 21600656 TI - Complement activation in animal and human pregnancies as a model for immunological recognition. AB - Pregnancy is a most intriguing feature of biology, not at least because of the need to regulate the maternal immune response against fetal antigens. The mammalian embryo expresses paternal antigens foreign to the mother's immune system and thus elicits an immune response that can lead to fetal rejection and bad pregnancy outcomes such as recurrent miscarriages and preeclampsia. More effective strategies to prevent these pregnancy complications should be forthcoming once the underlying pathophysiological mechanisms that are involved in fetal rejection are completely understood. Our goal in writing this review is to discuss the crucial role of the complement system as an effector mechanism in placental and fetal damage that leads to bad pregnancy outcomes. Important information about the role of excessive complement activation and bad pregnancy outcomes was obtained from animal models. That uncontrolled complement activation puts at risk the survival of the fetus was reported in mouse models of recurrent miscarriages and preeclampsia. Interestingly, several observations described in the mouse models were confirmed in humans. Increased circulating levels of complement proteins, and their activation fragments were found in patients with preeclampsia, recurrent miscarriages and intrauterine growth restriction. Studies performed in animals and humans demonstrated the deleterious effect of complement activation on pregnancy outcomes. However, we also described in this article the strategic role of complement component C1q in normal placentation. C1q deserves special consideration for its role in promoting trophoblast invasion of deciduas, a crucial step in normal placental development. In conclusion, in this review we discussed all the available results of basic and clinical studies on the role of the complement system in pregnancy to expand the understanding of the pathophysiology of pregnancy complications. PMID- 21600657 TI - CYP1B1-related anterior segment developmental anomalies novel mutations for infantile glaucoma and von Hippel's ulcer revisited. AB - PURPOSE: To determine the prevalence of CYP1B1 mutations in a cohort of patients with congenital corneal opacification (CCO), infantile glaucoma, or both and to describe a developmental CCO associated with CYP1B1 mutation that may explain von Hippel's original description of an internal ulcer. DESIGN: Retrospective genotyping of a cohort of patients with infantile glaucoma and CCO. PARTICIPANTS: Thirty-three patients with CCO, infantile glaucoma, or both. METHODS: All patients underwent a full clinical evaluation with or without examination under anesthetic including anterior segment photography, ultrasound biomicroscopy (for CCO patients; n = 22), and histopathologic analysis in patients in whom penetrating keratoplasty (PK) was performed (n = 10). Patient DNA and DNA from 50 normal control individuals who had undergone a full ophthalmologic examination were screened for CYP1B1 mutations. MAIN OUTCOME MEASURES: Classification of the developmental corneal opacity phenotype in infantile glaucoma patients with CYP1B1 mutations. RESULTS: Nine distinct pathogenic recessive CYP1B1 mutations were found in 11 patients from 6 unrelated families, including 1 patient with an entire deletion of the CYP1B1 gene. Two of these patients, including the patient with the deletion, had isolated infantile congenital glaucoma with no other abnormalities. No CYP1B1 mutations were found in another 13 patients (7 of whom underwent PK in at least 1 eye) who had CCO with iridocorneal or keratolenticular adhesions (Peters' anomaly types I and II, respectively). Eight further children with CYP1B1 mutations who had CCO from birth and glaucoma underwent successful glaucoma treatment but had persistent diffuse CCO without iridocorneal or keratolenticular adhesions. Three of these underwent bilateral PK, and the histologic results were not consistent with any hitherto recognized congenital corneal dystrophy and showed abnormalities of the central corneal endothelium. CONCLUSIONS: Both severe CCO and isolated infantile glaucoma are associated with CYP1B1 mutations. The severe CCO phenotype reported herein often requires PK and has typical histopathologic changes. The mutations associated with this phenotype have not been reported previously. This phenotype may explain the patient described by Von Hippel in 1897. PMID- 21600658 TI - Intraocular pressure control and long-term visual field loss in the Collaborative Initial Glaucoma Treatment Study. AB - OBJECTIVE: To evaluate the impact of measures of intraocular pressure (IOP) control on progression of visual field (VF) loss during long-term treatment for open-angle glaucoma (OAG). DESIGN: Longitudinal, randomized clinical trial. PARTICIPANTS: We included 607 participants with newly diagnosed OAG. METHODS: Study participants were randomly assigned to initial treatment with medications or trabeculectomy, and underwent examination at 6-month intervals. Standardized testing included Goldmann applanation tonometry and Humphrey 24-2 full threshold VFs. Summary measures of IOP control during follow-up included the maximum, mean, standard deviation (SD), range, proportion less than 16, 18, 20, or 22 mmHg, and whether all IOP values were less than each of these 4 cutpoints. Predictive models for VF outcomes were based on the mean deviation (MD) from VF testing, and were adjusted for age, gender, race, baseline VF loss, treatment, and time. Each summary IOP measure was included as a cumulative, time-dependent variable, and its association with subsequent VF loss was assessed from 3 to 9 years postrandomization. Both linear mixed models, to detect shifts in MD levels, and logistic models, to detect elevated odds of substantial worsening (>=3 dB), were used. MAIN OUTCOME MEASURES: We measured the MD from Humphrey 24-2 full threshold VF tests. RESULTS: The effect of the summary IOP measures differed between the medicine and surgery groups in models that addressed the continuous MD outcome. After adjustment for baseline risk factors, in the medicine group larger values of 3 IOP control measures-maximum IOP (P = 0.0003), SD of IOP (P = 0.0056), and range of IOP (P<0.0001)-were significantly associated with lower (worse) MD over the 3- to 9-year period. No IOP summary measure was significantly associated with MD over time in the surgery group. The same 3 IOP summary measures were also significantly associated with substantial worsening of MD; however, the effects were similar in both treatment groups. In models predicting inadequate IOP control, consistently significant predictors of higher maximum, SD, and range of IOP included black race, higher baseline IOP, and clinical center. CONCLUSIONS: These results support considering more aggressive treatment when undue elevation or variation in IOP measures is observed. PMID- 21600659 TI - High serum bilirubin levels and diabetic retinopathy: the Hisayama Study. AB - PURPOSE: To assess the association between serum total bilirubin levels and diabetic retinopathy prevalence in participants of the Hisayama Study who had diabetes and impaired glucose metabolism. DESIGN: Population-based, cross sectional study. PARTICIPANTS: Of 3119 participants of the Hisayama Study Eye Examinations in 2007, Japan, 1672 aged >=40 years with either diabetes or impaired glucose metabolism (defined by a 75-g oral glucose tolerance test) were enrolled in the present study. METHODS: Diabetic retinopathy was assessed via ophthalmic examination after pupil dilatation. The presence and the severity of diabetic retinopathy were determined by grading of color fundus photographs using the modified Airlie House classification system. Association of diabetic retinopathy with serum bilirubin quartiles was assessed using logistic regression model adjusting for age and known risk factors for diabetic retinopathy. MAIN OUTCOME MEASURES: Prevalent diabetic retinopathy. RESULTS: Diabetic retinopathy was present in 70 of 1672 (4.2%) participants. The prevalence of diabetic retinopathy in persons with the highest bilirubin quartile (>=0.9 mg/dL) was 2.7%, compared with the prevalence of 3.4%, 5.1%, and 5.1% in those with the first (<0.6 mg/dL), second (0.6-0.69 mg/dL), and third quartiles (0.7-0.89 mg/dL). After adjusting for factors known to be associated with diabetic retinopathy, the prevalence was significantly lower among persons with the highest bilirubin quartile compared with those with the lowest quartile (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.09-0.72) or compared with those in the 3 lower quartiles (OR, 0.25; 95% CI, 0.11-0.58). CONCLUSIONS: Elevated serum bilirubin levels may be protective against diabetic retinopathy among persons with either diabetes or impaired glucose metabolism, independent of known risk factors for diabetic retinopathy. PMID- 21600660 TI - Empathy development from 8 to 16 months: early signs of concern for others. AB - The study examined the responses of typically developing infants to the distress of another, prior to and following the transition to the second year. Infants' responses to maternal simulations of distress and to a peer distress videotape were observed from 8 to 16 months, using an accelerated longitudinal design (overall n = 37). Modest levels of affective and cognitive empathy for another in distress were already evident before the second year, and increased gradually (and not always significantly) across the transition to the second year. Prosocial behavior was rare in the first year and increased substantially during the second year. Self-distress reactions were rare overall. Individual differences in cognitive and affective empathy assessed in the first year, particularly at 10-months, predicted the levels of prosocial behavior observed in the second year. No gender differences were found. Theoretical implications and future research directions are discussed. PMID- 21600661 TI - Surface facial electromyography, skin conductance, and self-reported emotional responses to light- and season-relevant stimuli in seasonal affective disorder. AB - BACKGROUND: Learned associations between depressive behavior and environmental stimuli signaling low light availability and winter season may play a role in seasonal affective disorder (SAD). The purpose of this study was to determine whether light and season environmental cues elicit emotional responses that are distinct in individuals with SAD. METHODS: Twenty-four currently depressed SAD participants were compared to 24 demographically-matched controls with no depression history on emotional responses to outdoor scenes captured under two light intensity (i.e., clear, sunny vs. overcast sky) and three season (i.e., summer with green leaves, fall with autumn foliage, and winter with bare trees) conditions. Emotion measures included surface facial electromyography (EMG) activity in the corrugator supercilii and zygomaticus major muscle regions, skin conductance, and self-reported mood state on the Profile of Mood States Depression-Dejection Subscale. RESULTS: Light intensity was a more salient cue than season in determining emotional reactions among SAD participants. Relative to controls, SAD participants displayed more corrugator activity, more frequent significant skin conductance responses (SCR), greater SCR magnitude, and more self-reported depressed mood in response to overcast stimuli and less corrugator activity, lower SCR magnitude, and less self-reported depressed mood in response to sunny stimuli. LIMITATIONS: Study limitations include the single, as opposed to repeated, assessment and the lack of a nonseasonal depression group. CONCLUSIONS: These findings suggest that extreme emotional reactivity to light relevant stimuli may be a correlate of winter depression; and future work should examine its potential onset or maintenance significance. PMID- 21600662 TI - Moderating effect of indoleamine 2,3-dioxygenase (IDO) activation in the association between depressive symptoms and carotid atherosclerosis: evidence from the Young Finns study. AB - BACKGROUND: Depression and inflammation have been suggested to be involved in the atherosclerotic processes, but empirical evidence is mixed. We tested the hypothesis that depressive symptoms are associated with atherosclerosis only when combined with other risk factors, such as inflammation indicated by indoleamine 2,3-dioxygenase (IDO) activation. METHODS: Participants were 544 women and 442 men (aged 24-39 years) who participated in the Young Finns Study medical examinations in 2001 and 2007. At baseline (in 2001), IDO activity (tryptophan and kynurenine ratio) and other biological and behavioral risk factors were assessed and depressive symptoms were determined using a modified 21-item Beck Depression Inventory. Carotid atherosclerosis was measured on the basis of carotid intimamedia thickness (IMT) at baseline and again in 2007. RESULTS: In women, IDO activity moderated the association between depressive symptoms and IMT (p=0.02), so that a longitudinal association between depressive symptoms and IMT was found only in combination with high IDO activity (B=0.21, p=0.009). This association was robust to adjustment for other risk factors except body mass index and lipids which largely removed the association. LIMITATIONS: The results of this study need to be confirmed using larger data sets and studies using clinical cut-off point for depression. CONCLUSIONS: These data suggest that depressive symptoms are associated with preclinical y carotid atherosclerosis only if they are linked to inflammation, and that this association is present only in women. Underlying mechanisms are unknown but probably relate to adiposity. PMID- 21600663 TI - Exploring the relationship between underlying dimensions of posttraumatic stress disorder and depression in a national, trauma-exposed military sample. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) and depression are highly comorbid and intercorrelated. Yet little research has examined the underlying processes explaining their interrelationship. METHOD: In the present survey study, the investigators assessed the combined symptom structure of PTSD and depression symptoms, to examine shared, underlying psychopathological processes. Participants included 740 Canadian military veterans from a national, epidemiological survey, previously deployed on peacekeeping missions and administered the PTSD Checklist and Center for Epidemiological Studies-Depression Scale (CES-D). RESULTS: An eight-factor PTSD/depression model fit adequately. In analyses validating the structure, PTSD's dysphoria factor was more related to depressive affect than to several other PTSD and depression factors. Somatic problems were more related to dysphoria than to other PTSD factors. LIMITATIONS: Only military veterans were sampled, and without the use of structured diagnostic interviews. CONCLUSIONS: Results highlight a set of interrelationships that PTSD's dysphoria factor shares with specific depression factors, shedding light on the underlying psychopathology of PTSD that emphasizes dysphoric mood. PMID- 21600664 TI - The relationship between posttraumatic stress disorder, illness cognitions, defence styles, fatigue severity and psychological well-being in chronic fatigue syndrome. AB - This study investigated, firstly, the rate of posttraumatic stress disorder (PTSD) and the level of psychological well-being amongst people with chronic fatigue syndrome (CFS); and secondly, the extent to which illness cognitions, defence styles and PTSD symptom severity related to fatigue severity and psychological well-being. Seventy-eight participants with a diagnosis of CFS completed the Chalder Fatigue Scale, the General Health Questionnaire-28, the Posttraumatic Stress Diagnostic Scale, the Illness Cognition Questionnaire and the Defence Style Questionnaire. Fifty-nine participants were recruited from the general public to form the non-fatigued control group. CFS participants had significantly higher levels of PTSD symptoms, lower levels of psychological well being and more traumatic life events compared to the non-fatigued controls. Trauma exposure and PTSD severity both predicted CFS status. However, regression analyses demonstrated no significant relationship between PTSD symptoms and fatigue severity or the degree of psychological well-being. 'Helplessness' predicted both physical and mental fatigue and psychological well-being, whilst the 'mature' defence styles predicted fatigue severity only. The results offer support to previous research showing that the rate of traumatic life events and PTSD are significantly higher amongst the CFS population. The lack of relationship between PTSD symptoms and fatigue severity or psychological well being indicates that these processes may operate independently of one another, via different appraisal processes. This study focused on fatigue severity, but it may be that the role of pain in CFS is a key element in the previously reported association between PTSD and CFS. PMID- 21600666 TI - Characterization of monoclonal antibodies against canine P-selectin glycoprotein ligand-1 (PSGL-1). AB - Thirteen different monoclonal antibodies against canine P-selectin glycoprotein ligand-1 (cPSGL-1) were obtained by immunization of rats with cells of a canine lymphoma cell line (Ema). O-sialoglycoprotein endopeptidase treatment of Ema cells showed that all of these antibodies recognized O-glycosylated peptides of canine PSGL-1. Experiments using deletion or point mutants of cPSGL-1 indicated that these antibodies could be categorized into several groups based on their cPSGL-1 recognition characteristics. These anti-cPSGL-1 monoclonal antibodies will be useful for analysis of the canine P-selectin and PSGL-1 system. PMID- 21600667 TI - Molecular structure, bioinformatics analysis, expression and bioactivity of BAFF (TNF13B) in dog (Canis familiaris). AB - B cell activating factor (BAFF), belonging to the tumor necrosis factor (TNF) family, plays an important role in B cell survival, proliferation and differentiation. In the present study, we amplified the cDNA of dog (Canis familiaris) BAFF (designated doBAFF) from spleen by reverse transcription-PCR (RT PCR) and rapid amplification of cDNA ends (RACE) strategies. The open reading frame (ORF) of doBAFF covers 879 bp encoding 292 amino acids, with a 152-aa mature peptide. The soluble mature part of doBAFF (dosBAFF) shares 91.5%, 72.1%, 96.7%, 94.0% and 91.5% identity with the human, mouse, cattle, pig and rabbit counterparts, respectively. The predicted three-dimensional (3D) structural analysis of dosBAFF analyzed by "comparative protein modeling" revealed that it was very similar to its human counterpart. Real-time quantitative PCR analysis revealed that doBAFF was mainly expressed in spleen. Two fusion proteins SUMO dosBAFF and GFP/dosBAFF were efficiently expressed in Escherichia coli BL21 (DE3) and purified using metal chelate affinity chromatography (Ni-NTA). Laser scanning confocal microscopy analysis showed that GFP/dosBAFF could bind to the mouse splenic B-cell. In vitro, SUMO-dosBAFF and GFP/dosBAFF were able to promote the survival/proliferation of dog lymphocytes or mouse splenic B cells with/without anti-IgM. Therefore, BAFF may be a potential immunologic factor for enhancing immunological efficacy in dog. PMID- 21600665 TI - Association of maternal genital and reproductive infections with verbal memory and motor deficits in adult schizophrenia. AB - Maternal exposure to genital and reproductive infections has been associated with schizophrenia in previous studies. Impairments in several neuropsychological functions, including verbal memory, working memory, executive function, and fine motor coordination occur prominently in patients with schizophrenia. The etiologies of these deficits, however, remain largely unknown. We aimed to assess whether prospectively documented maternal exposure to genital/reproductive (G/R) infections was related to these neuropsychological deficits in offspring with schizophrenia and other schizophrenia spectrum disorders. The cases were derived from a population-based birth cohort; all cohort members belonged to a prepaid health plan. Cases were assessed for verbal memory, working memory, executive function, and fine-motor coordination. Compared to unexposed cases, patients exposed to maternal genital/reproductive infection performed more poorly on verbal memory, fine-motor coordination, and working memory. Stratification by race revealed associations between maternal G/R infection and verbal memory and fine-motor coordination for case offspring of African-American mothers, but not for case offspring of White mothers. Significant infection-by-race interactions were also observed. Although independent replications are warranted, maternal G/R infections were associated with verbal memory and motor function deficits in African-American patients with schizophrenia. PMID- 21600668 TI - HIV infection and cocaine use induce endothelial damage and dysfunction in African Americans. AB - BACKGROUND: Clinical and epidemiological evidence suggests that HIV infection and cocaine use are associated with an increased risk of premature atherosclerosis. The underlying mechanisms linking HIV infection and cocaine use with early atherosclerosis remain elusive. METHODS AND RESULTS: Endothelin-1 (ET-1) levels in 360 African American participants in Baltimore, Maryland were measured. Quantile regression analysis was performed to examine the associations between ET 1, HIV infection, cocaine use, and other relevant clinical factors. The median of ET-1 in plasma, (1.05 pg/mL with interquartile range: 0.73, 1.40) for those with HIV infection was significantly higher than values for those without HIV infection (0.74 pg/mL with interquartile range: 0.61, 0.93). The median of ET-1 was markedly higher in chronic cocaine users (0.96 pg/mL with interquartile range: 0.71, 1.36) than that in non-cocaine users (0.72 pg/mL with interquartile range: 0.58, 1.06). Multivariate quantile regression suggested that HIV infection and duration of cocaine use were independently associated with plasma ET-1 levels after controlling for potential confounding factors. CONCLUSIONS: This study may provide insight into the mechanism of premature atherosclerosis in HIV-infected cocaine users and suggest that measurement of ET-1 in plasma can be used as a marker of early atherosclerosis in HIV infected patients and cocaine users. PMID- 21600669 TI - Histopathological correlation of (11)C-choline PET scans for target volume definition in radical prostate radiotherapy. AB - BACKGROUND AND PURPOSE: To evaluate the accuracy of (11)C-choline PET scans in defining dominant intraprostatic lesions (DILs) for radiotherapy target volume definition. MATERIAL AND METHODS: Eight men with prostate cancer who had (11)C choline PET scans prior to radical prostatectomy were studied. Several methods were used to contour the DIL on the PET scans: visual, PET Edge, Region Grow, absolute standardised uptake value (SUV) thresholds and percentage of maximum SUV thresholds. Prostatectomy specimens were sliced in the transverse plane and DILs were delineated on these by a pathologist. These were then compared with the PET scans. The accuracy of correlation was assessed by the Dice similarity coefficient (DSC) and the Youden index. RESULTS: The contouring method resulting in both the highest DSC and the highest Youden index was 60% of the maximum SUV (SUV(60%)), with values of 0.64 and 0.51, respectively. However SUV(60%) was not statistically significantly better than all of the other methods by either measure. CONCLUSIONS: Although not statistically significant, SUV(60%) resulted in the best correlation between (11)C-choline PET and pathology amongst all the methods studied. The degree of correlation shown here is consistent with previous studies that have justified using imaging for DIL radiotherapy target volume definition. PMID- 21600670 TI - Toward enhanced subsurface intervention methods using chaotic advection. AB - Many intervention activities in the terrestrial subsurface involve the need to recover/emplace distributions of scalar quantities (e.g. dissolved phase concentrations or heat) from/in volumes of saturated porous media. These scalars can be targeted by pump-and-treat methods or by amendment technologies. Application examples include in-situ leaching for metals, recovery of dissolved contaminant plumes, or utilizing heat energy in geothermal reservoirs. While conventional pumping methods work reasonably well, costs associated with maintaining pumping schedules are high and improvements in efficiency would be welcome. In this paper we discuss how transient switching of the pressure at different wells can intimately control subsurface flow, generating a range of "programmed" flows with various beneficial characteristics. Some programs produce chaotic flows which accelerate mixing, while others create encapsulating flows which can isolate fluid zones for lengthy periods. In a simplified model of an aquifer subject to balanced pumping, chaotic flow topologies have been predicted theoretically and verified experimentally using Hele-Shaw cells. Here, a survey of the key characteristics of chaotic advection is presented. Mathematical methods are used to show how these characteristics may translate into practical situations involving regional flows and heterogeneity. The results are robust to perturbations, and withstand significant aquifer heterogeneity. It is proposed that chaotic advection may form the basis of new efficient technologies for groundwater interventions. PMID- 21600671 TI - Colonization pressure adjusted by degree of environmental contamination: a better indicator for predicting methicillin-resistant Staphylococcus aureus acquisition. AB - BACKGROUND: Colonization pressure has been confirmed as an important risk factor for methicillin-resistant Staphylococcus aureus (MRSA) acquisition among inpatients, but their precise relationship has not been well investigated. Because MRSA carriers can disperse MRSA into their immediate environment with different abilities, the relationship among colonization pressure, the degree of MRSA contamination in environment surrounding MRSA carriers, and MRSA transmission should be explored to facilitate efficient implementation of infection control measures. METHODS: Active MRSA screening and environmental sampling were performed in a 23-bed emergency ward (EW) and a 7-bed respiratory intensive care unit (RICU) between March 2009 and February 2010. Weekly colonization pressure (WCP) was modified to WCPe (WCP adjusted by degree of environmental contamination). Receiver operating characteristic curve and correlation analyses were used to analyze the accuracy of WCPe in predicting MRSA acquisition and their correlation, respectively. RESULTS: We found that 34.1% (858/2,520) of the immediate environmental sites of MRSA-positive patients were contaminated with MRSA. The areas under the receiver operating characteristic curve of WCPe reached as high as 0.784 (95% confidence interval, 0.659-0.909; P < .01) for the EW and 0.866 (95% confidence interval, 0.766-0.967; P < .01) for the RICU. Spearman's correlation coefficient (r) indicated a positive and significant correlation between WCPe and MRSA acquisition rate in the subsequent weeks for both the EW (r = 0.45; P = .001) and RICU (r = 0.51; P < .001). CONCLUSION: Active MRSA screening combined with targeted environmental contamination monitoring could be a more efficient measure for determining the magnitude of the MRSA reservoir in wards occupied by MRSA carriers. WCPe showed moderate prediction accuracy for both the EW and the RICU, and a threshold WCPe value may be used as a predictor to enhance infection control measures, especially for medical facilities without a sufficient number of single rooms. PMID- 21600672 TI - Management and outcome of a varicella exposure in a neonatal intensive care unit: lessons for the vaccine era. AB - BACKGROUND: Varicella exposure in health care settings poses a threat to susceptible, immunocompromised hosts. We describe the management and outcome of a varicella exposure in a neonatal intensive care unit. METHODS: We reviewed the history of the index case, determination of the exposed cohort, medical management of exposed neonates, and assignment of health care workers based on exposure and immune status. We present the results of serologic testing of health care workers related to their history of varicella disease. RESULTS: Of 427 health care workers assessed at the time of the exposure, 13.1% were seronegative for varicella. Among 180 employees recorded as having a previous history of varicella, 9 were seronegative. A total of 34 infants received prophylaxis with intravenous immune globulin; acyclovir prophylaxis was added for those born at <28 weeks gestational age. The exposed cohort was isolated. No secondary cases of varicella occurred among patients or health care workers. CONCLUSION: Nosocomial varicella exposures require rapid assessment and response, which can be guided by a checklist of actions. Varicella immunity in health care workers cannot be assumed even among those born before 1980; institutional policies should adhere to the 2007 Centers for Disease Control and Prevention's definition of immunity to varicella for health care workers. PMID- 21600673 TI - Digoxin therapy in the elderly: pharmacokinetic considerations in nursing. AB - Digoxin is effective in controlling ventricular rhythm in atrial fibrillation and is used in heart failure when angiotensin converting enzyme inhibitors and diuretics are ineffective. Because use of more than 1 drug is often required with these conditions, pharmacokinetic considerations, including those related to complementary medicine, are important. Increased awareness of drug action in the elderly is important because there is often an increase in body fat and leaner muscle mass as well as changes in organ function, such as that of the kidney, which alters drug activity. Nurses have an important role to play in the safe administration of digoxin. PMID- 21600674 TI - [EAU Guidelines on Urinary Incontinence]. AB - CONTEXT: The first European Association of Urology (EAU) guidelines on incontinence were published in 2001. These guidelines were periodically updated in past years. OBJECTIVE: The aim of this paper is to present a summary of the 2009 update of the EAU guidelines on urinary incontinence (UI). EVIDENCE ACQUISITION: The EAU working panel was part of the 4th International Consultation on Incontinence (ICI) and, with permission of the ICI, extracted the relevant data. The methodology of the 4th ICI was a comprehensive literature review by international experts and consensus formation. In addition, level of evidence was rated according to a modified Oxford system and grades of recommendation were given accordingly. EVIDENCE SUMMARY: A full version of the EAU guidelines on urinary incontinence is available as a printed document (extended and short form) and as a CD-ROM from the EAU office or online from the EAU Web site (http://www.uroweb.org/guidelines/online-guidelines/). The extent and invasiveness of assessment of UI depends on severity and/or complexity of symptoms and clinical signs and is different for men, women, frail older persons, children, and patients with neuropathy. At the level of initial management, basic diagnostic tests are applied to exclude an underlying disease or condition such as urinary tract infection. Treatment is mostly conservative (lifestyle interventions, physiotherapy, physical therapy, pharmacotherapy) and is of an empirical nature. At the level of specialised management (when primary therapy failed, diagnosis is unclear, or symptoms and/or signs are complex/severe),more elaborate assessment is generally required, including imaging, endoscopy, and urodynamics. Treatment options include invasive interventions and surgery. CONCLUSIONS: Treatment options for UI are rapidly expanding. These EAU guidelines provide ratings of the evidence (guided by evidence-based medicine) and graded recommendations for the appropriate assessment and according treatment options and put them into clinical perspective. PMID- 21600675 TI - [Noninvasive mechanical ventilation in severe pneumonia due to H1N1 virus]. AB - OBJECTIVE: The use of noninvasive mechanical ventilation was evaluated in our series of patients admitted to our ICU with pneumonia due to influenza A virus H1N1, assessing the need for intubation, arterial blood gases and clinical improvement, the development of complications and ICU and hospital stay. DESIGN: Retrospective and observational study. SETTING: ICU of Castellon University General Hospital (Castellon, Spain). POPULATION: Patients admitted to ICU with pneumonia due to influenza A virus H1N1 and acute hypoxemic respiratory failure. INTERVENTIONS: Boussignac CPAP, Helmet system and BiPAP Vision((r)) were used. RESULTS: Five of 10 patients with pneumonia and hypoxemia were analyzed, showing 100% effectiveness of noninvasive mechanical ventilation in terms of clinical and arterial blood gas improvement, and avoiding intubation in all cases. There were no patient deaths in ICU or in hospital. The duration (median) of ventilation was 6 (4-11) days, with an ICU stay of 9 (7-11) days. The number of complications was low (except for urinary tract infection due to Pseudomonas aeruginosa), and only the noise produced by CPAP was underscored. There were no infections among the staff. CONCLUSIONS: Based on our results, increased use of noninvasive mechanical ventilation in future epidemics coujld be proposed. PMID- 21600676 TI - [Effects of training in emotional regulation strategies on the well-being of carers of Alzheimer patients]. AB - INTRODUCTION: The present research shows the results of a psychoeducational intervention programme centered on the regulation of the emotion among Alzheimer patients' caregivers. MATERIALS AND METHODS: 52 informal caregivers of Alzheimer's patients participated. These caregivers were distributed into two groups: the experimental group (n = 20) and the control group (n = 32). All the participants were evaluated before and after the intervention programme through the application of different measurement tools measuring variables related to the care giving process; stressors, modulation variables and care giving consequences. RESULTS: In the inter group contrast, the experimental group, when compared with the control condition, obtained higher scores in positive affect, subjective well-being, regulation of emotions, and satisfaction with caregiving. However, the experimental group recorded lower values in perceived stress and negative affect. With reference to the intragroup contrast, the experimental group showed a significant decrease in dysfunctional thoughts and emotional attention. The control group registered higher levels of psychosocial support and lower satisfaction with caregiving. CONCLUSIONS: The training programme, that we both developed and conducted, has contributed to a greater feeling of emotional well-being amongst the its participant caregivers, who now take more adequate care of their emotions and suffer fewer dysfunctional thoughts in relation to caregiving. In future studies, the stability of the results presented in this investigation should be established due to the progressive character of the skills learned during the programme, and the changing needs associated with the caregiving process. PMID- 21600677 TI - Synthesis, activity and pharmacokinetics of novel antibacterial 15-membered ring macrolones. AB - Synthesis, antibacterial activity and pharmacokinetic properties of a novel class of macrolide antibiotics-macrolones-derived from azithromycin, comprising oxygen atom(s) in the linker and either free or esterified quinolone 3-carboxylic group, are reported. Selected compounds showed excellent antibacterial potency towards key erythromycin resistant respiratory pathogens. However, the majority of compounds lacked good bioavailability. The isopropyl ester, compound 35, and a macrolone derivative with an elongated linker 29 showed the best oral bioavailability in rats, both accompanied with an excellent overall microbiology profile addressing inducible and constitutive MLSb as well as efflux mediated macrolide resistance in streptococci, while compound 29 is more potent against staphylococci. PMID- 21600678 TI - Aldol derivatives of Thioxoimidazolidinones as potential anti-prostate cancer agents. AB - The paper discusses the synthesis and stereochemical aspects of the anti aldol products, 3-(substituted phenyl)-5-[(substituted phenyl) hydroxy methyl]-5-methyl 4-oxo-2-thioxoimidazolidines. The stereochemistry observed in the aldol reactions with benzaldehydes was explained by transition state model of the endocyclic (E) enolate formed from the rigid 4-oxo-2-thioxoimidazolidine skeleton. Proton NMR and ROESY spectral analyses were carried out to identify the syn and anti conformations of the aldol diastereomers. Configurations of the enantiomers of the representative anti aldol product 3-(4-chlorophenyl)-5-[(4-chlorophenyl) hydroxy methyl]-5-methyl-4-oxo-2-thioxoimidazolidine was determined by single crystal XRD studies. The compounds were screened in vitro against prostate cancer cell lines, PC-3 and LNCaP and the most potent derivatives were identified. PMID- 21600679 TI - Evaluation of DNA binding, DNA cleavage, protein binding and in vitro cytotoxic activities of bivalent transition metal hydrazone complexes. AB - Divalent Co, Ni and Cu hydrazone complexes containing [N'-(phenyl(pyridine-2 yl)methylidene) benzohydrazide] ligand were synthesised and characterised. Interactions of these complexes with DNA revealed an intercalative mode of binding between them. Further, all the hydrazone chelates showed moderate ability to cleave pUC19 DNA. Synchronous fluorescence spectra proved that the interaction of metal complexes with bovine serum albumin (BSA) resulted in a conformational change of the latter. Assay on the cytotoxicity of the above complexes against HeLa tumor cells and NIH 3T3 normal cells revealed that the complexes are toxic only against tumor cells but not to normal cells. In all the biological assays, the complex with copper ion as the metal center showed enhanced activities than the other two. PMID- 21600680 TI - Site-directed mutagenesis provides insights into the selective binding of trityl derivatives to Plasmodium falciparum dUTPase. AB - We have previously identified a series of triphenylmethane derivatives of deoxyuridine with antimalarial activity in vitro which selectively inhibit Plasmodium falciparum deoxyuridine triphosphate nucleotidohydrolase (PfdUTPase) compared to the human enzyme. The crystal structure of PfdUTPase in complex with one of these inhibitors suggested that the triphenylmethane derivative was selective due to a series of interactions between the trityl group and the side chains of residues Phe(46), Ile(117) and Lys(96) located in a hydrophobic pocket distinct from the phosphate binding site. Here we show by site-directed mutagenesis that the hydrophobic nature of the trityl binding site and in particular aromatic interactions established between the inhibitor and residue Phe(46) contribute significantly to the binding of uracil-based derivatives containing trityl groups in the 5'-position. Thus, changing Phe(46) for alanine resulted in increased K(i) values for all compounds tested. Conversely, substitution of the polar residue Lys(96) for Ala results in smaller K(i) values and an increase in selectivity with regard to human dUTPase. This information will aid in the design of inhibitors with improved activity against the Plasmodium enzyme. PMID- 21600682 TI - RETRACTED: Development of new sensitive diffusive passive samplers for ambient air ozone and ozone concentration in HoChiMinh City. AB - This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21600681 TI - Synthesis and evaluation of mansonone F derivatives as topoisomerase inhibitors. AB - A series of mansonone F (MF) derivatives were designed and synthesized. These compounds were found to be strong inhibitors for topoisomerases, with much more significant inhibition for topoisomerase II rather than topoisomerase I. The best inhibitor showed 20 times stronger anti-topoisomerase II activity than a positive control Etoposide. The cytotoxic activity of these MF derivatives was evaluated against human cancer cell lines CNE-2 and Glc-82, which showed that these compounds were potent antitumor agents. The structure-activity relationships (SARs) study revealed that o-quinone group and pyran ring are important for their cytotoxic activity. PMID- 21600683 TI - How seasonality affects the flow of estrogens and their conjugates in one of Japan's most populous catchments. AB - A detailed study of the free and conjugated estrogen load discharged by the eight major sewage treatment plants into the Yodo River basin, Japan was carried out. Sampling campaigns were focused on the winter and autumn seasons from 2005 to 2008 and the free estrogens estrone(E1), 17beta-estradiol(E2), estriol(E3), 17alpha-ethynylestradiol(EE2) as well as their conjugated (sulfate and glucuronide) forms. For both sewage effluent and river water E2 and E1 concentrations were greatest during the winter period (December-March). This coincides with the period of lowest rainfall and lowest temperatures in Japan. E1 was the dominant estrogenic component in effluent (means of 10-50 ng/L) followed by E2 (means of 0.5-3 ng/L). The estrogen sulfate conjugates were found intermittently in the 0.5-1.7 ng/L concentration range in the sewage effluents. The greatest estrogen exposure was found to be in the Katsura River tributary which exceeded 1 ng/L E2-equivalents during the winter period. PMID- 21600685 TI - Impairments in tactile search following superior parietal damage. AB - The superior parietal cortex is critical for the control of visually guided actions. Research suggests that visual stimuli relevant to actions are preferentially processed when they are in peripersonal space. One recent study demonstrated that visually guided movements towards the body were more impaired in a patient with damage to superior parietal cortex. Whereas past studies have explored disordered movement in optic ataxic patients, there has been less exploration of space perception in terms of search capacity in this population. In addition, there is some debate concerning the relationship between deficits of visuomotor control and impaired attention/perception in optic ataxia. Given that the dorsal stream has been implicated in the spatial processing of stimuli in peripersonal space, and damage to this region is known to cause optic ataxia, we felt that further investigation was warranted. We examined tactile search behavior in the fronto-parallel and radial planes in a patient with right superior parietal damage and optic ataxia. We used a pegboard with removable cylindrical pegs that allowed for the reorganization of targets between trials. To better characterize three-dimensional search behavior, we included both horizontal and vertical search conditions. Results showed that the patient spent more time searching, was more accurate and revisited more targets in right versus left space. Interestingly, the patient spent the majority of her time specifically searching the lower right quadrant of the stimulus array. Further analysis revealed lower target detection rates along the outer borders of the pegboard on all sides. The search pattern observed here is unusual considering that all targets were within arm's reach. The present experiment demonstrates that damage to superior parietal cortex impairs tactile search and biases exploration towards lower right peripersonal space. PMID- 21600684 TI - Opposing amygdala and ventral striatum connectivity during emotion identification. AB - Lesion and electrophysiological studies in animals provide evidence of opposing functions for subcortical nuclei such as the amygdala and ventral striatum, but the implications of these findings for emotion identification in humans remain poorly described. Here we report a high-resolution fMRI study in a sample of 39 healthy subjects who performed a well-characterized emotion identification task. As expected, the amygdala responded to THREAT (angry or fearful) faces more than NON-THREAT (sad or happy) faces. A functional connectivity analysis of the time series from an anatomically defined amygdala seed revealed a strong anticorrelation between the amygdala and the ventral striatum/ventral pallidum, consistent with an opposing role for these regions in during emotion identification. A second functional connectivity analysis (psychophysiological interaction) investigating relative connectivity on THREAT vs. NON-THREAT trials demonstrated that the amygdala had increased connectivity with the orbitofrontal cortex during THREAT trials, whereas the ventral striatum demonstrated increased connectivity with the posterior hippocampus on NON-THREAT trials. These results indicate that activity in the amygdala and ventral striatum may be inversely related, and that both regions may provide opposing affective bias signals during emotion identification. PMID- 21600686 TI - [Pediatric bronchoscopy guidelines]. PMID- 21600687 TI - Early prediction of acute traumatic coagulopathy. AB - INTRODUCTION: The inability to accurately predict acute traumatic coagulopathy (ATC) has been a key factor in the low level of evidence guiding its management. The aim of this study was to develop a tool to accurately identify patients with ATC using pre-hospital variables without the use of pathology or radiological testing. METHODS: Retrospective data from the trauma registry on major trauma patients were used to identify variables independently associated with coagulopathy. These variables were clinically evaluated to develop a scoring system to predict ATC, which was prospectively validated in the same setting. RESULTS: There were 1680 major trauma patients in the derivation dataset, with 151 patients being coagulopathic. Pre-hospital variables independently associated with ATC were entrapment (OR 1.85; 95% CI: 1.12-3.06), temperature (OR 0.60; 95% CI: 0.60-0.72), systolic blood pressure (OR 0.99; 95% CI: 0.98-0.99), abdominal or pelvic content injury (OR 2.0; 95% CI: 1.27-3.12) and pre-hospital chest decompression (OR 4.99; 2.77-8.99). The COAST score was developed, scoring points for entrapment, temperature <35 degrees C, systolic blood pressure < 100 mm Hg, abdominal or pelvic content injury and chest decompression. Prospectively validated using 1225 major trauma patients, a COAST score of >= 3 had a specificity of 96.4% with a sensitivity of 60.0%, with an area under the receiver operating characteristic curve of 0.83 (0.78-0.88). CONCLUSIONS: The COAST score accurately identified a group of patients with ATC using pre-hospital observations. This predictive tool can be used to select patients for inclusion into prospective studies examining management options for ATC. Mortality in these patients is high, potentially improving feasibility of outcome studies. PMID- 21600688 TI - Evaluation of two doses of recombinant human luteinizing hormone supplementation in down-regulated women of advanced reproductive age undergoing follicular stimulation for IVF: a randomized clinical study. AB - OBJECTIVES: To evaluate the effects of mid-follicular recombinant human luteinizing hormone (rhLH) supplementation in down-regulated women of advanced reproductive age undergoing in vitro fertilization (IVF). STUDY DESIGN: This was a prospective, randomized parallel-group study (allocation 1:1) including 187 normogonadotrophic infertile patients aged >= 35 years. Subcutaneous triptorelin was used for pituitary desensitization, and ovarian stimulation was achieved with recombinant human follicle-stimulating hormone (rhFSH) either alone (Group 1) or in combination with rhLH in one of two daily doses: 37.5 IU (Group 2) or 75 IU (Group 3). Ovarian stimulation characteristics and IVF outcome were evaluated. The main outcome was pregnancy rate. RESULTS: A total of 62, 62 and 63 patients were randomized to groups 1, 2 and 3 respectively, and 56, 54 and 55 patients respectively were available for final analysis of the results. Follicular development and oocyte yield were significantly higher in group 1 patients compared with patients in groups 2 and 3. Oocyte maturity and number of oocytes fertilized were also higher in group 1 patients; this difference almost reached statistical significance. No significant difference in implantation and clinical pregnancy rates was found among the three treatment groups. CONCLUSIONS: rhLH supplementation is not a useful tool for patients of advanced reproductive age in ovarian stimulation protocols using an appropriate gonadotrophin-releasing hormone agonist and a step-down regimen of rhFSH. PMID- 21600690 TI - Treatment of vinasse from tequila production using polyglutamic acid. AB - Vinasse, the wastewater from ethanol distillation, is characterised by high levels of organic and inorganic matter, high exit process temperature (ca. 90 degrees C) and low pH (3.0-4.5). In this study, the treatment of tequila vinasse was achieved by a flocculation-coagulation process using poly-gamma-glutamic acid (PGA). Results showed that the use of PGA (250-300 ppm) combined with sodium hypochlorite and sand filtration managed to remove about 70% of the turbidity and reduced chemical oxygen demand (COD) by 79.5% with the extra benefit of colour removal. PGA showed its best flocculating activity at pH 2.5-3.5 and a temperature of 30-55 degrees C. Such a treatment may be a solution for small tequila companies for which other solutions to deal with their vinasse may not be economically affordable. PMID- 21600689 TI - Chemokines and BPH/LUTS. AB - A wealth of published studies indicate that a variety of chemokines are actively secreted by the prostatic microenvironment consequent to disruptions in normal tissue homeostasis due to the aging process or inflammatory responses. The accumulation of senescent stromal fibroblasts, and, possibly, epithelial cells, may serve as potential driving forces behind chemokine secretion in the aging and enlarged human prostate. Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and histological inflammation may also potentially serve as rich sources of chemokine secretion in the prostate. Once bound to their cognate receptors, chemokines can stimulate powerful pro-proliferation signal transduction pathways and thus function as potent growth factors in the development and progression of Benign Prostatic Hyperplasia (BPH) and lower urinary tract symptoms (LUTS). These functions have been amply demonstrated experimentally and particularly point to robust Mitogen Activated Protein Kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling, as well as global transcriptional responses, which mediate chemokine-stimulated cellular proliferative responses. A small body of literature also suggests that chemokine mediated angiogenesis may comprise a contributing factor to BPH/LUTS development and progression. Thus, the observed low-level secretion of multiple chemokines within the aging prostatic microenvironment may promote a concomitant low-level, but cumulative, over-proliferation of both stromal fibroblastic and epithelial cell types associated with increased prostatic volume. Though the accumulated evidence is far from complete and suffers from some rather extensive gaps in knowledge, it argues favorably for the conclusion that chemokines can, and likely do, promote prostatic enlargement and the associated lower urinary tract symptoms, and justifies further investigations examining chemokines as potential therapeutic targets to delay or ablate BPH/LUTS initiation and progression. PMID- 21600691 TI - Aerobic biodegradation of sludge with high hydrocarbon content generated by a Mexican natural gas processing facility. AB - The biodegradation of oil sludge from Mexican sour gas and petrochemical facilities contaminated with a high content of hydrocarbons, 334.7 +/- 7.0 g kg( 1) dry matter (dm), was evaluated. Studies in microcosm systems were carried out in order to determine the capacity of the native microbiota in the sludge to reduce hydrocarbon levels under aerobic conditions. Different carbon/nitrogen/phosphorous (C/N/P) nutrient ratios were tested. The systems were incubated at 30 degrees C and shaken at 100 rpm. Hydrocarbon removals from 32 to 51% were achieved in the assays after 30 days of incubation. The best assay had C/N/P ratio of 100/1.74/0.5. The results of the Microtox((r)) and Ames tests indicated that the original sludge was highly toxic and mutagenic, whereas the best assay gave a final product that did not show toxicity or mutagenicity. PMID- 21600692 TI - Removal of lead compounds from polyvinylchloride in electric wires and cables using cation-exchange resin. AB - Recycling treatment of cable insulation resin generated from electric wires and cables was investigated. Conventional insulation PVC contains a lead component, tribase, as a thermal stabilizer and lead removal is necessary to recycle this PVC as insulation resin. This paper describes a solid surface adsorption method using ion exchange resin to remove the fine lead containing particles from PVC dissolved solution. Low lead concentration in the recovered PVC, complying with the requirements of RoHS, was achieved. PMID- 21600695 TI - Diazinon resistant status in Rhipicephalus (Boophilus) microplus collected from different agro-climatic regions of India. AB - The resistance status of Rhipicephalus (Boophilus) microplus to "Diazinon" was evaluated in 20 locations situated at various agro-climatic regions of India. Adult immersion test (AIT) was optimized using laboratory reared acaricide susceptible IVRI-I strain of R. (B.) microplus and minimum effective concentration of Diazinon was determined as 635.2 ppm. The discriminating dose (DD) was worked out as 1270.4 ppm and was tested on female ticks collected from organized and unorganized farms located at different agro-climatic regions of India. On the basis of the data generated on three variables viz., mortality, egg masses and reproductive index, the resistance level was categorized as I, II, III and IV. The average resistance factor (RF) of 6.1 (level II) was recorded in the ticks collected from the northern sub-temperate trans-gangetic plains while high average RF values of 26.65 (level III) was recorded in the ticks collected from tropical middle-gangetic plains. The tropical middle gangetic plain has a very high density of animal populations where farmers use Diazinon for tick control, for agricultural practices and for mosquito control. Due to the continuous use of OP compounds the environmental load of Diazinon has become high in the area. This is the first experimental data generated on Diazinon resistant status in ticks of India. PMID- 21600693 TI - Nucleotides control the excitability of sensory neurons via two P2Y receptors and a bifurcated signaling cascade. AB - Nucleotides contribute to the sensation of acute and chronic pain, but it remained enigmatic which G protein-coupled nucleotide (P2Y) receptors and associated signaling cascades are involved. To resolve this issue, nucleotides were applied to dorsal root ganglion neurons under current- and voltage-clamp. Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and uridine triphosphate (UTP), but not uridine diphosphate (UDP), depolarized the neurons and enhanced action potential firing in response to current injections. The P2Y(2) receptor preferring agonist 2-thio-UTP was equipotent to UTP in eliciting these effects. The selective P2Y(1) receptor antagonist MRS2179 largely attenuated the excitatory effects of ADP, but left those of 2-thio-UTP unaltered. Thus, the excitatory effects of the nucleotides were mediated by 2 different P2Y receptors, P2Y(1) and P2Y(2). Activation of each of these 2 receptors by either ADP or 2-thio-UTP inhibited currents through K(V)7 channels, on one hand, and facilitated currents through TRPV(1) channels, on the other hand. Both effects were abolished by inhibitors of phospholipase C or Ca(2+)-ATPase and by chelation of intracellular Ca(2+). The facilitation of TRPV(1), but not the inhibition K(V)7 channels, was prevented by a protein kinase C inhibitor. Simultaneous blockage of K(V)7 channels and of TRPV(1) channels prevented nucleotide-induced membrane depolarization and action potential firing. Thus, P2Y(1) and P2Y(2) receptors mediate an excitation of dorsal root ganglion neurons by nucleotides through the inhibition of K(V)7 channels and the facilitation of TRPV(1) channels via a common bifurcated signaling pathway relying on an increase in intracellular Ca(2+) and an activation of protein kinase C, respectively. PMID- 21600696 TI - New techniques for an old disease: sarcoptic mange in the Iberian wolf. AB - Sarcoptic mange, a parasitic skin infection caused by the burrowing mite Sarcoptes scabiei, has been reported in over 100 mammals, including humans. In endangered species, mange causes conservation concerns because it may decimate isolated populations and contribute to extinction. The Iberian Peninsula still maintains one of the largest wolf (Canis lupus) populations in Europe. In Iberia, sarcoptic mange is endemic in red foxes (Vulpes vulpes) and the first confirmed wolf mange cases were recently reported. However, knowledge on S. scabiei in wolves is scarce because of the sampling difficulties inherent to research on scarce species. In order to describe wolf mange epidemiology and to infer conservation implications, this study combined traditional laboratory techniques with the revision of wolf carcass pictures taken by field biologists and original information obtained by camera trapping. A total of 125 necropsies and 8783 camera-trap days allowed insights into wolf mange epidemiology between 2003 and 2010. Living Sarcoptes mites were detected in 19% of the fresh carcasses. Alopecic (delayed) type IV hypersensitive response reactions were observed, while parakeratotic lesions were infrequent. The number of mites isolated per wolf ranged from 1 to 78, and had a negative correlation with the percentage of alopecic skin. No effect by sex on mange prevalence was found. Yearlings showed a lower probability to present mange-compatible lesions than pups or adults. Wolves with mange-compatible lesions had a lower kidney fat index than apparently healthy ones. ELISA testing of 88 sera yielded an antibody prevalence of 20%. Photo-trapping recorded mange-compatible lesions since 2003 with a peak in 2008. The percentage of wolves with mange-compatible lesions registered in camera-traps during 1 year correlated with the percentage of red foxes with lesions in the previous year. This is the first large survey on sarcoptic mange in the Iberian wolf. Necropsy data, with alopecia as the main feature and a slight effect on body condition, and trends derived from camera trapping coincided in showing a rather low prevalence and an apparently stable situation of the disease and its host, suggesting that this parasite is currently not a major threat for this wolf population. However, more information is needed in order to assess the effect of mange on aspects such as pup survival. PMID- 21600698 TI - LPS-stimulated tumor necrosis factor-alpha and interleukin-6 mRNA and cytokine responses following acute psychological stress. AB - The purpose of this study was to examine the effect of acute psychological stress on LPS-stimulated TNF-alpha and IL-6 mRNA expression. Twenty-one healthy male subjects participated in 20 min of acute stress. Blood samples for norepinephrine and LPS-stimulated TNF-alpha and IL-6 cytokines and mRNA were drawn prior to, immediately after and 1-h after stress. Stress-induced increases in anxiety scores, cortisol, plasma norepinephrine, and heart rate demonstrated that the experimental protocol elicited an acute stress response. LPS-stimulated TNF-alpha mRNA decreased significantly immediately post-stress and partially recovered at 1h post-stress, whereas LPS-stimulated IL-6 mRNA exhibited a significant change across time, with an increase immediately after stress and a decrease 1h after stress. Trends in LPS-stimulated TNF-alpha and IL-6 cytokine concentrations followed the patterns of mRNA expression. A negative correlation of body mass index (BMI) and percent change of LPS-stimulated TNF-alpha mRNA was observed immediately post-stress, and BMI positively correlated with percent change of LPS stimulated IL-6 cytokine levels immediately following stress. These findings demonstrated that acute psychological stress affects LPS-stimulated IL-6 and TNF alpha gene expression. These results also indicate that BMI may impact the effects of psychological stress on cytokine responses to immune challenge. Further examination of the effects of stress on synthesis of other cellular cytokines and investigation of the association of BMI and stress responses will provide a more clear representation of the cytokine responses to acute psychological stress. In addition, studies examining the influence of gender on the response of immune cell subsets to acute stress and the possible mediating effect of BMI are warranted. PMID- 21600697 TI - Several stressors fail to reduce adult hippocampal neurogenesis. AB - Neurogenesis in the dentate gyrus of the hippocampus of adult laboratory animals has been widely reported to be vulnerable to many psychological and physical stressors. However, we have found no effects of acute restraint stress, acute or subchronic tailshock stress, or acute, subchronic, or chronic resident-intruder stress on neural progenitor cell (NPC) proliferation, short or long term survival of newborn cells, or brain-derived neurotrophic factor (BDNF) mRNA expression in adult rats. In addition, we did not observe any effect of chronic resident intruder stress on NPC proliferation in adolescent rats. A selectively bred stress-sensitive line was also found to exhibit no alterations in NPC proliferation following tailshock stress, although this line did exhibit a lower proliferation rate under baseline (unstressed) conditions when compared with non selected rats. These results challenge the prevailing hypothesis that any stressor of sufficient intensity and duration has a marked negative impact upon the rate of hippocampal neurogenesis, and suggest that some yet unidentified factors related to stress and experimental conditions are crucial in the regulation of neurogenesis. PMID- 21600699 TI - Transnasal cooling: a Pandora's box of transnasal patho-physiology. AB - The innovative concept of transnasal evaporative cooling for therapeutic hypothermia in cardio-pulmonary-cerebro-resuscitation has therapeutic implications with evidence of rapid and selective brain cooling; however, this author wants to elicit that this concept may hold answers for many physiological phenomena which have not been explored or completely understood up till now. To affirm the physiological role of transnasal cooling, the innovative non-invasive brain temperature monitoring can help the investigators to explore and understand the following transnasal pathophysiological phenomena: (1) understanding correlation of brain temperature and sinus headache secondary to nasal blockade, (2) exploring the therapeutic role of nasal oxygen for prevention of delirium in intubated patients, (3) realizing the impact of controlled enclosed environments on the mood and affect of the inhabitants, (4) understanding the etio pathogenesis of claustrophobia after excluding the confounding factors of morbid obesity, severe cardiopulmonary disease and incapacitating musculoskeletal diseases, (5) exploring the anthropological role of male pattern of moustache, beard and hair loss, and (6) possible development of a coolant moustache as proposed by the author. In summary, transnasal pathophysiology offers many promising lines of fruitful research to explore the non-olfactory physiological functions of nose in human beings. PMID- 21600700 TI - Is a drill-less dental filling possible? AB - Dental caries, a bacterial process that results in the acidic destruction of tooth structure, has historically been managed by the mechanical excavation of diseased tooth structure and then restoration with a synthetic material. The mechanical excavation of the infected site is most commonly achieved by a dental handpiece, or "drill"; this handpiece may induce stress and anxiety in many patients. Alternatively, a drill-less filling will involve the utilization of silver diamine fluoride (38%) to arrest and prevent dental caries, followed by restoration with a bonded filling material to achieve adequate seal at the lesion margins. This is a minimally invasive procedure that addresses both microbial and mechanical issues posed by dental caries. PMID- 21600701 TI - Textural attributes and oxidative stability of pork longissimus muscle injected with marbling-like emulsified lipids. AB - The objective of the study was to create marbling-like fat in lean pork with acceptable oxidative stability through the injection of canola/olive oil substituted emulsions. Pork loins were injected with 5% water as control (CW) or 5% emulsion containing no tocopherols (E) or 0.07% tocopherols (ET) and stored at 2 degrees C in an oxygen-enriched package for up to 3 weeks. Lipid oxidation was totally inhibited in ET pork but increased 3-fold to 0.20mg malonaldehyde/kg in CW and E pork after 3 weeks. ET treatment also had a positive effect on meat red color. Emulsion-containing pork, showing less protein oxidation (carbonyl and disulfide formation), had reduced drip loss and shear force than CW samples (P<0.05). The results indicated that incorporation of antioxidant-containing emulsions could create marbling-like texture in lean pork without compromising oxidative stability. PMID- 21600702 TI - Effect of garlic, onion, and their combination on the quality and sensory characteristics of irradiated raw ground beef. AB - Irradiated raw ground beef had lower a*- and b*-values than nonirradiated ones regardless of garlic or onion treatment at 0 d. Irradiation increased TBARS values of control ground beef, but addition of 0.5% onion or 0.1% garlic+0.5% onion reduced oxidative changes during storage. Addition of garlic or onion greatly increased the amounts of sulfur compounds, but the increase was greater with garlic. With irradiation, the profiles and amounts of S-volatiles in raw ground beef changed significantly. However, the intensity of irradiation aroma in irradiated raw ground beef with garlic or onion was similar to that of the nonirradiated control. This indicated that some of the sulfur compounds unique to garlic or onion interacted with common sulfur compounds detected in irradiated meat and masked or changed the odor characteristics of irradiated raw ground beef. It was concluded that >0.5% onion or <0.01% garlic would be needed to mask or prevent irradiation aroma in irradiated raw ground beef. PMID- 21600703 TI - Malignant mesothelioma of the peritoneum invading the liver and mimicking metastatic carcinoma: a case report. AB - We present a case of malignant mesothelioma of the peritoneum with massive direct invasion to the liver in a 58-year-old Japanese woman. She had no history of asbestos exposure or other malignancies. Abdominal computed tomography revealed one 8-cm intrahepatic mass adjacent to the abdominal wall with peritoneal thickening, multiple smaller nodules in the peritoneal cavity, and intra abdominal lymphadenopathy. Liver biopsy showed a small cluster of atypical cells similar to epithelial neoplasm, which formed a tubulopapillary structure. The tumor cells were positive for calretinin with strong nuclear and cytoplasmic expression together with podoplanin (D2-40) and some cytokeratins, but were negative for hepatocyte paraffin 1 and other adenocarcinoma markers. We confirmed a diffuse peritoneal mesothelioma with direct invasion to the liver. Liver masses with other peritoneal nodules are mostly encountered as metastatic diseases. However, the possibility of mesothelioma should be considered, even in women without an apparent history of asbestos exposure. PMID- 21600704 TI - Helical tomotherapy with simultaneous integrated boost after laparoscopic staging in patients with cervical cancer: analysis of feasibility and early toxicity. AB - PURPOSE: To demonstrate the feasibility and safety of the simultaneous integrated boost technique for dose escalation in combination with helical tomotherapy in patients with cervical cancer. METHODS AND MATERIALS: Forty patients (International Federation of Gynecology and Obstetrics Stage IB1 pN1-IVA) underwent primary chemoradiation with helical tomotherapy. Before therapy, 29/40 patients underwent laparoscopic pelvic and para-aortic lymphadenectomy. In 21%, 31%, and 3% of the patients, pelvic, pelvic and para-aortic, and skip metastases in the para-aortic region could be confirmed. All patients underwent radiation with 1.8-50.4 Gy to the tumor region and the pelvic (para-aortic) lymph node region (planning target volume-A), and a simultaneous boost with 2.12-59.36 Gy to the boost region (planning target volume-B). The boost region was defined using titan clips during laparoscopic staging. In all other patients, standardized borders for the planning target volume-B were defined. High-dose-rate brachytherapy was performed in 39/40 patients. The mean biologic effective dose to the macroscopic tumor ranged from 87.5 to 97.5 Gy. Chemotherapy consisted of weekly cisplatin 40 mg/m(2). Dose-volume histograms and acute gastrointestinal, genitourinary, and hematologic toxicity were evaluated. RESULTS: The mean treatment time was 45 days. The mean doses to the small bowel, rectum, and bladder were 28.5 +/- 6.1 Gy, 47.9 +/- 3.8 Gy, and 48 +/- 3 Gy, respectively. Hematologic toxicity Grade 3 occurred in 20% of patients, diarrhea Grade 2 in 5%, and diarrhea Grade 3 in 2.5%. There was no Grade 3 genitourinary toxicity. All patients underwent curettage 3 months after chemoradiation, which confirmed complete pathologic response in 38/40 patients. CONCLUSIONS: The concept of simultaneous integrated boost for dose escalation in patients with cervical cancer is feasible, with a low rate of acute gastrointestinal and genitourinary toxicity. Whether dose escalation can be translated into improved outcome will be assessed after a longer follow-up time. PMID- 21600705 TI - Pretreatment carbohydrate antigen 19-9 level indicates tumor response, early distant metastasis, overall survival, and therapeutic selection in localized and unresectable pancreatic cancer. AB - PURPOSE: The use of chemoradiotherapy (CRT) for localized and unresectable pancreatic cancer has been disputed because of high probability of distant metastasis. Thus, we analyzed the effect of clinical parameters on tumor response, early distant metastasis within 3 months (DM(3m)), and overall survival to identify an indicator for selecting patients who would benefit from CRT. METHODS AND MATERIALS: This study retrospectively analyzed the data from 84 patients with localized and unresectable pancreatic cancer who underwent CRT between August 2002 and October 2009. Sex, age, tumor size, histological differentiation, N classification, pre- and post-treatment carbohydrate antigen (CA) 19-9 level, and CA 19-9 percent decrease were analyzed to identify risk factors associated with tumor response, DM(3m), and overall survival. RESULTS: For all 84 patients, the median survival time was 12.5 months (range, 2-31.9 months), objective response (complete response or partial response) to CRT was observed in 28 patients (33.3%), and DM(3m) occurred in 24 patients (28.6%). Multivariate analysis showed that pretreatment CA 19-9 level (<=400 vs. >400 U/ml) was significantly associated with tumor response (45.1% vs. 15.2%), DM(3m) (19.6% vs. 42.4%), and median overall survival time (15.1 vs. 9.7 months) (p < 0.05 for all three parameters). CONCLUSION: For patients with localized and unresectable pancreatic cancer, pretreatment CA 19-9 level could be helpful in predicting tumor response, DM(3m), and overall survival and identifying patients who will benefit from CRT. PMID- 21600706 TI - Differential antinociceptive effects of buprenorphine and methadone in the presence of HIV-gp120. AB - BACKGROUND: We showed recently that elevated brain levels of the chemokine stromal cell-derived growth factor-1alpha (SDF-1alpha/CXCL12, a ligand for the human immunodeficiency virus [HIV] co-receptor CXCR4) diminish the antinociceptive effect of morphine, but failed to influence buprenorphine-induced antinociception. AIMS: Because the HIV-1 coat protein, glycoprotein 120 (gp120) T tropic strain, binds to the same receptor as SDF-1alpha/CXCL12, the present experiments were designed to investigate the consequence of administering gp120 to rat brain on buprenorphine-induced antinociception in the 54 degrees C hot plate test. For comparative purposes, the effect of gp120 on an equi antinociceptive dose of methadone was also examined. METHODS: A sterilized stainless-steel C313G guide cannula was implanted into the periaqueductal grey (PAG), a brain region critical for the processing of pain signals, and a primary site of action of many analgesics. Rats were pretreated with gp120, administered into the PAG. RESULTS: The subsequent antinociception associated with methadone was diminished whereas buprenorphine-induced antinociception was unaffected. Buprenorphine thus appears to be a more effective analgesic than methadone in the presence of gp120 in the brain, a condition that is associated with HIV-related pain and infection. PMID- 21600708 TI - Correlates of volunteering among aging Texans: the roles of health indicators, spirituality, and social engagement. AB - OBJECTIVES: This study aimed to identify participant characteristics associated with volunteering among older adults. METHODS: Based on data from the 2008 Aging Texas Well (ATW) Indicators Survey, we examined the degree to which demographic factors, health status, spiritual participation, and community involvement are associated with volunteering among adults aged 60 years or older (n = 525). RESULTS: Rates of volunteering varied by race/ethnicity: non-Hispanic Whites (56.4%), African Americans (51.1%), and Hispanics (43.2%). Bivariate analyses showed that non-Hispanic White older adults were more likely to participate in formal volunteering activities, while their African American and Hispanic counterparts tended to participate in informal volunteering activities. Logistic regression analyses revealed that volunteering was less observed among Hispanics (OR = 0.48, 95% CI 0.29-0.78). Volunteering was more observed among those who reported providing informal care (OR=1.93, 95% CI 1.14-3.28), having very good or excellent mental health (OR = 1.90 and 2.07, 95% CI 1.09-3.32 and 1.20-3.55, respectively), having weekly or daily spiritual participation (OR = 2.15 and 2.35, 95% CI 1.28-3.63 and 1.29-4.28, respectively), perceiving community involvement very important (OR = 2.37, 95% CI 1.55-3.62), and being very satisfied with the community interaction (OR = 1.81, 95% CI 1.15-2.85). CONCLUSIONS: Given the positive associations of mental health, spirituality, and social engagement with volunteering among older adults, system-level efforts to increase the sense of community among older adults and recognize their roles as volunteers will be helpful in recruiting and retaining older volunteers. PMID- 21600709 TI - Effects of a short-term occupational therapy intervention in an acute geriatric unit. A randomized clinical trial. AB - OBJECTIVES: To compare the benefits of a short-term occupational therapy intervention (OTI) when added to the conventional treatment model (CTM) in the functional recovery of patients admitted to an acute geriatric unit (AGU). STUDY DESIGN: Non-pharmacological randomized clinical trial. 400 patients were randomized to OTI (n = 198) or CTM (n = 202) group. Mean age 83.5. Interventions included needs assessment, iatrogenic prevention, retraining in activities of daily living, and instructions for caregivers in three groups of patients defined a priori (cardiopulmonary disease, stroke, other conditions) 5 days a week, 30-45 min a day. MAIN OUTCOME MEASURE: Recovery of >= 10 Barthel index points by discharge. Secondary outcome was the reduction in confusional episodes. RESULTS: The adjusted relative risk (RR) of functional recovery in the OTI group was 1.16 (95%CI 0.91-1.47). In participants with cardiopulmonary disease was 1.57 (95%CI 1.06-2.32), number needed to treat (NNT) 5. Participants with other conditions assigned to OTI had a reduction in acute confusional episodes; RR 0.48 (95% CI 0.26-0.87), NNT 7. CONCLUSIONS: Although overall there were no significant differences, patients with cardiopulmonary disease or non-stroke pathologies admitted to an AGU, may benefit from a short-term OTI. PMID- 21600707 TI - Caffeine choice prospectively predicts positive subjective effects of caffeine and d-amphetamine. AB - BACKGROUND: Individuals vary in their subjective and behavioral response to psychomotor stimulants and these differences may be associated with the likelihood of developing problematic use of these drugs. The present study sought to determine whether individual differences in caffeine choice prospectively predict subjective response to acute doses of caffeine and d-amphetamine. METHODS: In Phase 1, Choosers and Nonchoosers of caffeine were identified using 10 independent choice trials in which subjects repeatedly chose between caffeine (200mg/70 kg) and placebo. Choosers were defined as those who chose caffeine over placebo on >=7 of the 10 trials; Nonchoosers were those who chose placebo on >=7 trials. In Phase 2, Choosers and Nonchoosers were compared in their subjective response to caffeine (100, 200, 400mg/70 kg) and d-amphetamine (5, 10, 20 mg/70 kg). RESULTS: Of the 22 participants completing the study, 11 met criteria for being a caffeine Chooser and 8 were Nonchoosers. In Phase 1, Choosers reported higher ratings of positive (i.e., pleasant) and lower ratings of negative (i.e., unpleasant) effects of caffeine during the sampling sessions. In Phase 2, caffeine Choosers reported more positive subjective effects and fewer negative effects of caffeine and d-amphetamine, particularly at the highest doses examined. CONCLUSIONS: Individual differences in caffeine reinforcement predicted subsequent subjective response to both d-amphetamine and caffeine. This observation may have clinical utility for identifying individuals who are vulnerable to the reinforcing effects of abused psychomotor stimulants. PMID- 21600710 TI - QOL after head and neck reconstruction: evaluation of Japanese patients using SF 36 and GOHAI. AB - OBJECTIVE: To evaluate the health-related quality of life (HRQOL) of Japanese patients with head and neck cancer after treatment. STUDY DESIGN: Cross sectional, descriptive study. PATIENTS AND METHODS: Twenty-nine patients who underwent resection and reconstruction of the head and neck cancer between September 2001 and January 2008 at the National Hospital Organization Tokyo Medical Center completed the Short Form 36 (generic QOL measure) and the General Oral Health Assessment Index (oral-specific QOL measure). RESULTS: The generic QOL of the patients was relatively maintained while oral-specific QOL was impaired compared to the Japanese norms. The patients with musculo-cutaneous flaps and 1y or longer after operation reported significantly lower QOL. CONCLUSION: This is a unique study on Japanese patients with relatively longer time after operation. Further evaluation with increased number of cases and disease-specific QOL scale is required to better understand the QOL of the patients. PMID- 21600711 TI - A new device for delivering drugs into the inner ear: otoendoscope with microcatheter. AB - OBJECTIVES: Intratympanic injection (ITI) of drugs into the inner ear is an attractive way to deliver therapy. However, if the round window membrane (RWM) cannot be visualized, adhesions need to be removed first before ITI can be performed. We developed and tested a novel otoendoscopy device that allows visualization of the RWM for the purpose of ITI. METHODS: Our otoendoscope consists of a catheter channel for delivering drugs and a suction channel. RESULTS: The novel otoendoscope for inner ear drug delivery has a fine needle with catheter, which can be used to remove or perforate round window niche (RWN) mucosal adhesions. The elliptical shape of the otoendoscope effectively captures the field in the light-guided area, resulting in bright images. CONCLUSIONS: Our otoendoscope can be used to apply drugs directly onto the surface of the RWM and to verify the correct placement of an inner ear drug delivery system, ensuring that it is safely in place. PMID- 21600712 TI - Nasal splinting using silicone plates without gauze packing following septoplasty combined with inferior turbinate surgery. AB - OBJECTIVE: Nasal packing after septoplasty is uncomfortable and painful for patients. The aim of this study was to determine the efficacy of nasal splinting using silicone plates to prevent complications and decrease the pain after septoplasty compared with the conventional gauze packing. MATERIALS AND METHODS: Thirty-five adult patients who had undergone septoplasty were included in this study. The patients were allocated into two groups: Group S, silicone plates were used (13 males, 2 females); and Group G, gauze packing smeared with an antibiotic ointment was used (19 males, 1 female). We evaluated and compared the postoperative pain, pain due to postoperative cleaning, nasal bleeding, postnasal drip, body temperature, effect on stay in the hospital, effect on food intake and sleep disturbance using visual analogue scale (VAS) scores. RESULTS: The postoperative pain score in Group S was significantly lower than in Group G on days 1 and 2 after the septoplasty. And the pain due to postoperative cleaning score was significantly lower than in Group G on days 2 and 3 after operation. No statistically significant differences were found between the two groups in regard to nasal bleeding, postnasal drip, body temperature, effect on stay in the hospital, effect on food intake or sleep disturbance. Objective evaluation performed at 4 weeks postoperatively revealed that nasal crusting occurred at a significantly higher incidence in Group G compared with Group S. CONCLUSION: The use of silicone plates in lieu of conventional gauze packing decreased post septoplasty nasal pain and pain due to postoperative cleaning of the nasal cavity. We conclude that nasal splinting using silicone plates after septoplasty is an effective method for managing pain and preventing complications. PMID- 21600713 TI - Neuroprotective effects of recombinant human erythropoietin in the developing brain of rat after lithium-pilocarpine induced status epilepticus. AB - Status epilepticus triggers a mixture of apoptotic and necrotic cell death within the hippocampus. This neuronal loss may result in the development of epilepsy and cognitive deficits. Erythropoietin mediates a number of biological actions within the central nervous system and has been shown to be neuroprotective. In the present study, we investigated the effects of recombinant human erythropoietin on hippocampus of rat after lithium-pilocarpine induced status epilepticus. Twenty one dam reared Wistar male rats, 21-day-old were divided into three groups: control group, lithium-pilocarpine induced status epilepticus and lithium pilocarpine induced status epilepticus and erythropoietin treated group. Erythropoietin treated group received recombinant human erythropoietin 10 U/g intraperitoneally 40 min after pilocarpine injection for 5 days. Rats were sacrificed and brain tissues were collected at 5th day of experiment. Neuronal cell death and apoptosis were evaluated. Histopathological examination showed that erythropoietin significantly decreased neuronal cell death in CA1, CA2, CA3 and dentate gyrus regions of hippocampus. It also diminished apoptosis in the CA1 and dentate gyrus regions of hippocampus. In conclusion, erythropoietin may preserve the number of neurons and decrease apoptosis in model of status epilepticus induced by lithium-pilocarpine. This experimental study suggests that erythropoietin administration may be neuroprotective in status epilepticus. PMID- 21600714 TI - A MECP2 missense mutation within the MBD domain in a Brazilian male with autistic disorder. AB - Point mutations and genomic rearrangements in the MECP2 gene are the major cause of Rett syndrome (RTT), a pervasive developmental disorder affecting almost exclusively females. MECP2 mutations were also identified in patients with autism without RTT. In this study, we present a mutational and gene dosage analysis of the MECP2 in a cohort of 60 Brazilian males with autistic features but not RTT. No duplication or deletion was identified. Sequencing analysis, however, revealed four MECP2 sequence variations. Three of them were previously discussed as non disease causing mutations and one mutation (p.T160S) was novel. It affects a highly conserved amino acid located within the MBD domain, a region of the protein involved in specific recognition and interaction with methylated CpG dinucleotides. The p.T160S variation was not found in the control sample. This mutation may represent a potential genetic factor for autistic phenotype and should be object of further studies. PMID- 21600715 TI - Spinocerebellar ataxias type 27 derived from a disruption of the fibroblast growth factor 14 gene with mimicking phenotype of paroxysmal non-kinesigenic dyskinesia. AB - Many types of spinocerebellar ataxias (SCAs) manifest as progressive disorders with cerebellar involvement. SCA type 27 (SCA27) is a rare type of SCA caused by mutations in the fibroblast growth factor 14 gene (FGF14). FGF14 disruption caused by a de novo reciprocal chromosomal translocation between chromosomes 13 and 21 was identified in a patient with the phenotype of paroxysmal non kinesigenic dyskinesia (PNKD). This indicated genetic heterogeneity of PNKD, since 60% of the patients with PNKD exhibit mutations in another gene responsible for PNKD, the myofibrillogenesis regulator 1 gene (MR-1). We hypothesized that the remaining 40% of patients with PNKD may have FGF14 mutations; therefore, the nucleotide sequences of MR-1 and FGF14 were analyzed in another six patients with PNKD, but no nucleotide alterations were observed in these genes for these patients. Further studies should be conducted on the phenotypic heterogeneity of FGF14 mutations and/or haploinsufficiency in SCA27 and PNKD. PMID- 21600716 TI - Multivariate dependencies between difficult childhood, temperament and antisocial personality disorder in a population of French male prisoners. AB - BACKGROUND: The aim of this study was to contribute to clarification of the relations between antisocial personality disorder (APD) and its potential risk factors in a population of 560 French male prisoners. METHODS: Adverse childhood was assessed as a latent variable determined by several traumatic events. APD (MINI), character and temperament (Cloninger's model), WAIS(r)-III similarities subtest and psychosocial characteristics were assessed by two clinicians. The WAIS(r)-III subtest accounts for verbal and cognitive performance. We used a structural model to determine the weight of the different pathways between adverse childhood and APD. RESULTS: Study confirmed the major and direct role of adverse childhood (standardized coefficient=0.48). An intermediate effect mediated by character (considered as a global variable) and novelty-seeking was also shown, confirming previous results from the literature. CONCLUSION: This study emphasizes the role of adverse childhood in APD, suggesting the potential benefit of early intervention in the prevention of antisocial behaviours. PMID- 21600717 TI - Pulmonary high-resolution computed tomography findings in nephropathia epidemica. AB - PURPOSE: To evaluate lung high-resolution computed tomography (HRCT) findings in patients with Puumala hantavirus-induced nephropathia epidemica (NE), and to determine if these findings correspond to chest radiograph findings. MATERIALS AND METHODS: HRCT findings and clinical course were studied in 13 hospital treated NE patients. Chest radiograph findings were studied in 12 of them. RESULTS: Twelve patients (92%) showed lung parenchymal abnormalities in HRCT, while only 8 had changes in their chest radiography. Atelectasis, pleural effusion, intralobular and interlobular septal thickening were the most common HRCT findings. Ground-glass opacification (GGO) was seen in 4 and hilar and mediastinal lymphadenopathy in 3 patients. Atelectasis and pleural effusion were also mostly seen in chest radiographs, other findings only in HRCT. CONCLUSION: Almost every NE patient showed lung parenchymal abnormalities in HRCT. The most common findings of lung involvement in NE can be defined as accumulation of pleural fluid and atelectasis and intralobular and interlobular septal thickening, most profusely in the lower parts of the lung. As a novel finding, lymphadenopathy was seen in a minority, probably related to capillary leakage and overall fluid overload. Pleural effusion is not the prominent feature in other viral pneumonias, whereas intralobular and interlobular septal thickening are characteristic of other viral pulmonary infections as well. Lung parenchymal findings in HRCT can thus be taken not to be disease-specific in NE and HRCT is useful only for scientific purposes. PMID- 21600718 TI - Rubrimonas shengliensis sp. nov. and Polymorphum gilvum gen. nov., sp. nov., novel members of Alphaproteobacteria from crude oil contaminated saline soil. AB - Four bacterial strains were isolated from a crude oil contaminated saline soil in Shengli Oilfield, China. Strains SL014B-28A2(T) and SL014B-80A1 were most closely related to Rubrimonas cliftonensis OCh 317(T), while strains SL003B-26A1(T) and SL003B-26A2 were most closely related to but readily different from the species in the Pannonibacter-Labrenzia-Roseibium-Stappia cluster. The major fatty acids were C(18:1)omega7c, C(16:0), C(18:0) and 11-Methyl C(18:1)omega7c, and C(18:1)omega7c, 11-Methyl C(18:1)omega7c and C(18:0), respectively, for these two groups of isolates. Q-10 was the predominant ubiquinone. The G+C contents of genomic DNA of the four isolates were 67.9, 69.7, 65.6 and 65.6 mol%. Based on the polyphasic taxonomic characteristics, strains SL014B-28A2(T) and SL014B-80A1 represented a novel species of the genus Rubrimonas, for which the name Rubrimonas shengliensis sp. nov. is proposed, with strain SL014B-28A2(T) (=LMG 26072(T)=CGMCC 1.9170(T)) as the type strain. Isolates SL003B-26A1(T) and SL003B 26A2 represented a novel genus and species of the family Rhodobacteraceae, for which the name Polymorphum gilvum gen. nov., sp. nov. is proposed, with strain SL003B-26A1(T) (=LMG 25793(T)=CGMCC 1.9160(T)) as the type strain. PMID- 21600719 TI - Quantitative determination of daumone in rat plasma by liquid chromatography-mass spectrometry. AB - Daumone, 6-(3,5-dihydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-heptanoic acid is a pheromone secreted by Caenorhabditis elegans, and has been known as a pivotal regulator of chemosensory processes in development and ageing. A quantification method using mass spectrometry was developed for the determination of daumone in rat plasma. After simple protein precipitation with acetonitrile including an internal standard, the analytes were chromatographed on a reversed-phase column and detected by liquid chromatography/tandem mass spectrometry with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for validation of bioanalytical methods. This method was applied to measure the plasma daumone concentrations after a single intravenous administration of daumone in rats. PMID- 21600721 TI - Communication and education about triggers and environmental control strategies during pediatric asthma visits. AB - OBJECTIVE: To determine the extent to which providers, caregivers, and pediatric asthma patients discussed environmental trigger control during primary care visits, and any demographic characteristics associated with having these discussions. METHODS: Children ages 8-16 with persistent asthma and their caregivers were recruited at five pediatric practices in non-urban areas of North Carolina. All of the medical visits were audio-tape recorded. We administered questionnaires to the child's caregiver following the visit. RESULTS: Two hundred and ninety-six patients had useable audio-tape data. Providers typically discussed at least one type of asthma trigger during these visits (86% of visits). The most common discussions were about exercise (70%), the weather/season (42%), and allergies/pollen (35%). Environmental control strategies were discussed less frequently (27% of visits). Providers educated the patient and their caregiver about environmental control strategies during 14% of the visits. CONCLUSION: Although providers frequently discuss some environmental triggers and provide education, there is room for more comprehensive discussions of these issues, which may contribute to decreased asthma exacerbations. PRACTICE IMPLICATIONS: Providers, or alternatively, asthma health educators, should devote more time to discussing environmental asthma triggers and control strategies with pediatric asthma patients and their families, as they are important components of overall asthma control. PMID- 21600720 TI - The early repolarization pattern in the general population: clinical correlates and heritability. AB - OBJECTIVES: This study sought to describe the clinical correlates and heritability of the early repolarization pattern (ERP) in 2 large, population based cohorts. BACKGROUND: There is growing recognition that ERP is associated with adverse outcomes. METHODS: Participants of the Framingham Heart Study (FHS) (N = 3,995) and the Health 2000 Survey (H2K) (N = 5,489) were included. ERP was defined as a J-point elevation >=0.1 mV in >=2 leads in either the inferior (II, III, aVF) or lateral (I, aVL, V(4-6)) territory or both. We tested the association between clinical characteristics and ERP, and estimated sibling recurrence risk. RESULTS: ERP was present in 243 of 3,955 (6.1%) of FHS and 180 of 5,489 (3.3%) of H2K subjects. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of ERP. In the FHS sample, siblings of individuals with ERP had an ERP prevalence of 11.6% (recurrence risk ratio of 1.89). Siblings of individuals with ERP had an increased unadjusted odds of ERP (odds ratio: 2.22, 95% confidence interval: 1.01 to 4.85, p = 0.047). CONCLUSIONS: ERP has strong association with clinical factors and has evidence for a heritable basis in the general population. Further assessment of the genetic determinants of ERP is warranted. PMID- 21600722 TI - Third year medical students perceptions towards learning communication skills: implications for medical education. AB - OBJECTIVE: To analyze students' perceptions towards learning communication skills pre-and-post training in a Communication and Clinical Skills Course (CCSC) at a Portuguese Medical School. METHODS: Content analysis was used to describe and systematically analyze the content written by students (n=215 from a total of 229) in an open-ended survey. In addition, content analysis association rules were used to identify meaning units. RESULTS: Students' pre-training definitions of communication skills were not specific; their post-training definitions were more precise and elaborated. Students perceived communications skills in Medicine as important (61%), but recommended that teaching methodologies (52%) be restructured. There appeared to be no connection between criticism of teaching skills performance and perceptions of the other aspects of the course. CONCLUSION: Students' experiences at CCSC are associated with their perceptions of communications skills learning. Content analysis associations indicated that these perceptions are influenced by context. PRACTICE IMPLICATIONS: Improvement of curricula, teaching and assessment methods, and investment in faculty development are likely to foster positive perceptions towards learning communication skills in these students. PMID- 21600723 TI - The impact of patient-centered communication on patients' decision making and evaluations of physicians: a randomized study using video vignettes. AB - OBJECTIVE: To assess the impact of patient-centered communication (PCC) behaviors on patients' evaluations of physicians and acceptance of clinical recommendations. METHODS: We randomized 248 patients to view video-recorded, standardized vignettes, depicting a cardiologist using a high vs. low degree of PCC while recommending bypass surgery to a patient with angina and 3-vessel coronary artery disease. We compared patients' ratings of the physician and their decision making in response to the physician's recommendation, for high vs. low PCC vignettes. RESULTS: Patients viewing high PCC vignettes rated the video physician more favorably overall (3.01 vs. 2.12, p<0.001) and as more competent (3.22 vs. 2.66, p<0.001) and trustworthy (2.93 vs. 2.28, p<0.001) than those viewing the low PCC version (0-4 range for all scales). Patients viewing the high PCC version more frequently said they would undergo bypass surgery (96% vs. 74%, p<0.001) if they were the patient in the video. CONCLUSION: Patients expressed greater confidence in physicians who used more PCC behaviors, and greater willingness to accept an evidence-based recommendation. PRACTICE IMPLICATIONS: PCC may make physicians more effective in the delivery of evidence-based care. PMID- 21600724 TI - Accepting the unacceptable: medication adherence and different types of action patterns among patients with high blood pressure. AB - OBJECTIVE: To gain deep insight into what it means for patients to live with drug treated hypertension and to understand the implications for the doctors' influence on patients' adherence. METHODS: Group discussions with 43 drug-treated hypertensive patients. Documentary method was used for interpretative analysis. RESULTS: Four basic phenomena were identified (fear, ignorance, reluctance to discuss matters with the doctor, impact of illness experiences), which resulted in different types of action patterns: (1) the assertive actor, (2) the unconscious avoider, and (3) the inconsistent actor. The types of action patterns do not refer to any implications for adherence. The patients' action does not indicate their preferred model of doctor-patient interaction or their acceptance of taking medication. CONCLUSION: Adherence must not be seen as meaningless behaviour, which can simply be learned, but rather as the result of subjective experiences on living with hypertension and the ability to accept the diagnosis and its treatment. PRACTICE IMPLICATIONS: It is premature to initiate therapy straight after the diagnosis, before the patient is prepared to take the tablets. Supporting adherence means to stay in dialogue and to give the time, privacy and patience to enable patients to overcome their inhibitions of asking and to accept the therapy. PMID- 21600725 TI - Distinct adiponectin profiles might contribute to differences in susceptibility to type 2 diabetes in dogs and humans. AB - Dogs develop obesity-associated insulin resistance but not type 2 diabetes mellitus. Low adiponectin is associated with progression to type 2 diabetes in obese humans. The aims of this study were to compare total and high molecular weight (HMW) adiponectin and the ratio of HMW to total adiponectin (S(A)) between dogs and humans and to examine whether total or HMW adiponectin or both are associated with insulin resistance in naturally occurring obese dogs. We compared adiponectin profiles between 10 lean dogs and 10 lean humans and between 6 lean dogs and 6 age- and sex-matched, client-owned obese dogs. Total adiponectin was measured with assays validated in each species. We measured S(A) with velocity centrifugation on sucrose gradients. The effect of total and HMW adiponectin concentrations on MINMOD-estimated insulin sensitivity was assessed with linear regression. Lean dogs had total and HMW adiponectin concentrations three to four times higher than lean humans (total: dogs 32 +/- 5.6 mg/L, humans 10 +/- 1.3 mg/L, P<0.001; HMW: dogs 25 +/- 4.5 mg/L, humans 6 +/- 1.3 mg/L, P<0.001) and a higher S(A) (dogs: 0.78 +/- 0.05; humans: 0.54 +/- 0.08, P = 0.002). Adiponectin concentrations and S(A) were not lower in obese dogs (0.76 +/- 0.05 in both groups; P=1). Total adiponectin, HMW adiponectin, and S(A) were not associated with insulin sensitivity in dogs. We propose that differences in adiponectin profiles between humans and dogs might contribute to the propensity of humans but not dogs to develop type 2 diabetes. Dogs with chronic, naturally occurring obesity do not have selectively reduced HMW adiponectin, and adiponectin does not appear to be important in the development of canine obesity-associated insulin resistance. PMID- 21600726 TI - Prolactin plays a stimulatory role in ovarian follicular development and egg laying in chicken hens. AB - The aim of this study was to show a stimulatory role in ovarian follicle development by prolactin (PRL) in chicken hens. In experiment 1, anti-PRL antibodies were generated in hen plasma by intramuscular administrations of recombinant PRL antigen. Egg laying remained at levels lower (P < 0.05) in the PRL-immunized group than in the BSA-immunized group of hens, whereas development of incubation was depressed in the former but not the latter group. Throughout the experiment, plasma PRL concentrations were lower in the PRL-immunized hens than in non-incubating control hens; LH concentrations were similar between the PRL- and BSA-immunized hens until the end of the experiment when LH was lower in the BSA-immunized hens (P < 0.05). In experiment 2, anti-PRL receptor (PRLR) antibodies were raised in hens with the use of immunizations against recombinant PRLR extracellular domain. Immunization against PRLR initially increased the egg laying rate when measured under the short photoperiod (12 h) but blocked the laying rate increase that occurred in the BSA-immunized control hens when the photoperiod was extended from 12 to 16 h. The development of incubation behavior was not affected by immunization against PRLR nor was plasma PRL or LH concentration. In experiment 3, when the egg-laying rate was depressed in PRL immunization hens, developmental speed of large white follicles was found to be slower than in the BSA-immunized control hens (P < 0.05). These results indicate that immunization against PRL slows down ovarian follicular development and reduces hen egg-laying performance, suggesting that PRL plays a stimulatory role in ovarian follicular development in chicken hens. PMID- 21600728 TI - Effect of acute ethanol and acute allopregnanolone on spatial memory in adolescent and adult rats. AB - The effects of ethanol differ in adolescent and adult rats on a number of measures. The evidence of the effects of ethanol on spatial memory in adolescents and adults is equivocal. Whether adolescents are more or less sensitive to ethanol-induced impairment of spatial memory acquisition remains unclear; with regard to the effects of acute ethanol on spatial memory retrieval there is almost no research looking into any age difference. Thus, we examined the effects of acute ethanol on spatial memory in the Morris Watermaze in adolescents and adults. Allopregnanolone (ALLO) is a modulator of the GABA(A) receptor and has similar behavioral effects as ethanol. We sought to also determine the effects of allopreganolone on spatial memory in adolescent and adults. Male adolescent (post natal [PN]28-30) and adult (PN70-72) rats were trained in the Morris Watermaze for 6 days and acute doses of ethanol (saline, 1.5 and 2.0 g/kg) or ALLO (vehicle, 9 and 18 mg/kg) were administered on Day 7. A probe trial followed on Day 8. As expected, there were dose effects; higher doses of both ethanol and ALLO impaired spatial memory. However, in both the ethanol and ALLO conditions adolescents and adults had similar spatial memory impairments. The current results suggest that ethanol and ALLO both impair hippocampal-dependent spatial memory regardless of age in that once learning has occurred, ethanol or ALLO does not differentially impair the retrieval of spatial memory in adolescents and adults. Given the mixed results on the effect of ethanol on cognition in adolescent rats, additional research is needed to ascertain the factors critical for the reported differential results. PMID- 21600727 TI - GABA transport modulates the ethanol sensitivity of tonic inhibition in the rat dentate gyrus. AB - In recent years, the effect of ethanol on tonic inhibition mediated by extrasynaptic GABA(A) receptors (GABA(A)Rs) has become a topic of intensive investigation and some controversy. The high ethanol sensitivity of extrasynaptic GABA(A) receptors containing the delta subunit combined with the role of tonic inhibition in maintaining the background inhibitory "tone" in hippocampal circuits has suggested that they may play a key role mediating certain behavioral effects of ethanol, including those related to learning and memory. We have found that ethanol disrupts learning and learning-related hippocampal function more potently in adolescent animals than in adults and that ethanol promotes extrasynaptic receptor-mediated GABAergic tonic currents more potently in adolescents than in adults. However, there have been no studies of potential mechanisms that may underlie the enhanced ethanol sensitivity of the tonic current in adolescents. In this study, we recorded GABA(A) receptor-mediated tonic currents in dentate gyrus granule cells in hippocampal slices from adolescent and adult rats. As previously reported, we found that ethanol potentiated the currents more efficaciously in cells from adolescents than in those from adults. We also found that the GAT-1 blocker NO-711 eliminated this developmental difference in ethanol sensitivity. These findings suggest that regulation of ambient GABA by GABA transporters may contribute to the difference in ethanol sensitivity between adolescents and adults. PMID- 21600729 TI - Good morning, doctor Google. PMID- 21600730 TI - Readability of patient-reported outcome questionnaires for use with persons with dysphonia. AB - OBJECTIVES: The purpose of this study was to examine the readability of several published patient-reported outcome (PRO) questionnaires for persons with dysphonia, and to compare the readability results with existing data about average reading levels for English-speaking adults living in the United States. DESIGN: A search was conducted to identify published PRO questionnaires related to dysphonia that are traditionally completed by patients in a self-administered format. METHOD: Reading grade levels were analyzed separately for 12 different voice-related PRO questionnaires using the Flesch Reading Ease, FOG, and FORCAST formulas as computed by a readability calculations software package. Descriptive statistics were also computed across the questionnaires. RESULTS: The results of this study demonstrate that most PRO questionnaires exceeded the fifth- to sixth grade reading levels recommended by health literacy experts regardless of the formula applied. CONCLUSIONS: In the demand for standardization of voice-related quality of life assessment tools, developers should consider readability as another testable construct because poor readability may affect validity, reliability and sensitivity. The voice clinician should consider the average reading level needed to understand a particular PRO questionnaire when administering it to a patient or their proxy. Developers of PRO questionnaires should consider reading level of respondents and include information about this when reporting psychometric data. PMID- 21600731 TI - Adult normative data for the KayPENTAX Phonatory Aerodynamic System Model 6600. AB - OBJECTIVES: The primary purpose of the present study was to establish a preliminary adult normative database for 41 phonatory aerodynamic measures obtained with the KayPENTAX Phonatory Aerodynamic System (PAS) Model 6600 (KayPENTAX Corp, Lincoln Park, NJ). A second purpose was to examine the effect of age and gender on these measures. DESIGN: Prospective data collection across groups. METHOD: A sample of 157 normal speakers (68 males and 89 females) were divided into three age groups (18-39, 40-59, and 60+ years). The PAS protocols of vital capacity, maximum sustained phonation, comfortable sustained phonation, variation in sound pressure level, and voicing efficiency were used to collect 41 phonatory aerodynamic measures. Comfortable pitch and loudness levels were used with each protocol requiring phonation. RESULTS: A statistically significant main effect of age was found for seven measures, and a statistically significant main effect of gender was found for five measures. The remaining 29 measures did not reach statistical significance; however, 13 of these had high observed power. The remaining 16 measures did not reach significance and had low observed power. CONCLUSIONS: Because age- and gender-related changes were found for some measures, one must account for these two variables when assessing phonatory aerodynamics using the PAS Model 6600. The clinical implications of the findings for the assessment and treatment of individuals with voice disorders using the PAS Model 6600 are discussed. PMID- 21600732 TI - Dynamic splinting for the stiff hand after trauma: predictors of contracture resolution. AB - STUDY DESIGN: Prospective cohort. INTRODUCTION: Many variables are believed to influence the success of dynamic splinting, yet their relationship with contracture resolution is unclear. PURPOSE OF THE STUDY: To identify the predictors of outcome with dynamic splinting of the stiff hand after trauma. METHODS: Forty-six participants (56 joints) completed eight weeks of dynamic splinting, and the relationship between 13 clinical variables and outcome was explored. RESULTS: Improvement in passive range of motion, active range of motion (AROM), and torque range of motion averaged 21.8 degrees , 20.0 degrees , and 13.0 degrees , respectively (average daily total end range time, 7.96 hours). Significant predictors included joint stiffness (modified Weeks Test), time since injury, diagnosis, and deficit (flexion/extension). For every degree change in ROM on the modified Weeks Test, AROM improved 1.09 degrees (standard error, 0.2). Test-retest reliability of the modified Weeks Test was high (intraclass correlation coefficient [2, 1]=0.78). CONCLUSIONS: Better progress with dynamic splinting may be expected in joints with less pretreatment stiffness, shorter time since injury (<12 weeks), and in flexion rather than extension deficits. Further research is needed to determine the accuracy with which the modified Weeks Test may predict contracture resolution. LEVEL OF EVIDENCE: 2b. PMID- 21600733 TI - Multi-resolution graph-based analysis of histopathological whole slide images: application to mitotic cell extraction and visualization. AB - In this paper, we present a graph-based multi-resolution approach for mitosis extraction in breast cancer histological whole slide images. The proposed segmentation uses a multi-resolution approach which reproduces the slide examination done by a pathologist. Each resolution level is analyzed with a focus of attention resulting from a coarser resolution level analysis. At each resolution level, a spatial refinement by label regularization is performed to obtain more accurate segmentation around boundaries. The proposed segmentation is fully unsupervised by using domain specific knowledge. PMID- 21600734 TI - Proposal for a 'surgical checklist' for ambulatory oral surgery. AB - The authors propose a new checklist model adapted for ambulatory oral surgery procedures based on the 'surgical checklist' proposed by the WHO. The proposed document contains 18 items divided into two sets: those that must be verified before beginning surgery and those that must be verified after its completion, but prior to the patient's departure from the site where the surgery is performed. A checklist is an easy-to-use tool that requires little time but provides order, logic and systematization taking into account certain basic concepts to increase the level of patient safety. The authors think that the result is a checklist that is easy to complete and ensures that key patient safety-related matters are dealt with in this field of surgery. PMID- 21600735 TI - Psychometric functions for efficient and effective psychophysical testing of sensory function. AB - An efficient test for sensory function has been reported using random order pairs of real and sham stimuli. The constant magnitude of the real stimulus is chosen such that the first error in a patient's forced-choice report on the order of real and sham stimulation, immediately indicates abnormal sensory function. This magnitude just exceeds a critical large percentile of the psychometric function (i.e. the relationship between percentage of detection and stimulus magnitude in healthy subjects). The aim was to determine psychometric functions for one tongue site and six facial sites for adjusting three variants of the real/sham stimulus method (i.e. for light touch, cold sensation and for two-point discrimination). All 150 healthy subjects participated in testing for light touch sensation, 100 subjects additionally participated in testing two-point discrimination and 50 subjects participated additionally in testing cold sensation. The stimulus magnitude was varied using a staircase-limits procedure. Following curve fitting with a Boltzmann function, 90th, 95th or 99th percentiles of the psychometric functions were determined. A set of at least two real/sham tests, one testing the function of large nerve fibres and one for small fibres, allows quick assessment of a patient's disturbed sensory function including its fibre pathology. PMID- 21600736 TI - 3D histology-guided surgery for basal cell carcinoma and squamous cell carcinoma: recurrence rates and clinical outcome. AB - In a prospective study, a large number of patients with basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) underwent surgery using three dimensional (3D) histology and were evaluated with respect to local recurrence. The excised tumours were treated using 3D-histology with a routine paraffin procedure until the surgical margins were clear of tumour. Prospective evaluation of recurrence-free survival and overall survival of 5227 primary BCCs in 3320 patients and 615 invasive primary SCCs in 600 patients was conducted in the form of a letter-based follow-up with feedback from the patients and the referring physicians. The mean follow-up period was 5 years. In the BCC collective, 36 out of 3320 patients developed local recurrence (1%, calculated as a percentage of treated BCCs: 0.7%). In the SCC collective, 20 local recurrences appeared (3%). The recurrence rate for SCCs with desmoplasia was 24%, whilst the recurrence rate for common types of SCC without desmoplasia was 1%. Surgery followed by 3D histology results in very low recurrence rates for BCC and SCC with no additional effort compared with the normal histopathological procedure. PMID- 21600737 TI - Brodmann area analysis of white matter anisotropy and age in schizophrenia. AB - Diffusion tensor and structural MRI images were acquired on ninety-six patients with schizophrenia (69 men and 27 women) between the ages of 18 and 79 (mean=39.83, SD=15.16 DSM-IV diagnosis of schizophrenia according to the Comprehensive Assessment of Symptoms and History). The patients reported a mean age of onset of 23 years (range=13-38, SD=6). Patients were divided into an acute subgroup (duration <=3 years, n=25), and a chronic subgroup (duration >3 years, n=64). Ninety-three mentally normal comparison subjects were recruited; 55 men and 38 women between the ages of 18 and 82 (mean=35.77, SD=18.12). The MRI images were segmented by Brodmann area, and the fractional anisotropy (FA) for the white matter within each Brodmann area was calculated. The FA in white matter was decreased in patients with schizophrenia broadly across the entire brain, but to a greater extent in white matter underneath frontal, temporal and cingulate cortical areas. Both normals and patients with schizophrenia showed a decrease in anisotropy with age but patients with schizophrenia showed a significantly greater rate of decrease in FA in Brodmann area 10 bilaterally, 11 in the left hemisphere and 34 in the right hemisphere. When the effect of age was removed, patients ill more than three years showed lower anisotropy in frontal motor and cingulate white matter in comparison to acute patients ill three years or less, consistent with an ongoing progression of the illness. PMID- 21600738 TI - Angiogenesis and oxidative stress: common mechanisms linking psoriasis with atherosclerosis. AB - Shared angiogenic and oxidative mechanisms underlie the pathophysiology of psoriasis and atherosclerosis. During the pathogenesis of both diseases, stimuli such as injury or local hypoxia trigger the release of pro-angiogenic factors including IL-8, HIF-1alpha, ETS-1, and VEGF. These factors stimulate increased permeability and encourage leukocyte transmigration into areas of inflammation by enhanced expression of cell adhesion molecules. Psoriasis and atherosclerosis also share common enzymatic sources of reactive oxygen species (ROS), and these ROS influence several cellular signaling pathways implicated in the pathogenesis of both diseases. Pharmacologic and genetic therapies that target key factors in these pathways could provide innovative approaches to the management of psoriasis and potentially mitigate the cardiovascular complications suffered by psoriasis patients. PMID- 21600739 TI - N-Acetylglucosamine suppress collagenases activation in ultraviolet B-irradiated human dermal fibroblasts: Involvement of calcium ions and mitogen-activated protein kinases. AB - BACKGROUND: N-Acetylglucosamine (GlcNAc) and its derivates have been utilized in dietary supplements and for therapeutic development due to their unique characteristics. GlcNAc is recognized primarily for its function as a precursor to hyaluronic acid, which plays a significant role in the structure and hydration of the extracellular matrix in skin, in both the epidermis and the dermis. OBJECTIVE: We investigated the protective effects of GlcNAc on immortalized human skin fibroblasts (HS68) against UVB damage. We then explored the inhibitory effects of GlcNAc on UVB-induced collagenases and investigated the molecular mechanism underlying those effects. METHODS: Those effects were assessed by semi quantitative PCR, Western blotting and enzymatic activity assays. RESULTS: GlcNAc increased the viability of, and inhibited ROS production in, HS68 cells exposed to UVB irradiation. Pre-treatment of HS68 cells with GlcNAc inhibited UVB-induced production of the collagenases MMP-1 and MMP-13. Western blot analysis further revealed that GlcNAc markedly suppressed the enhancement of collagen degradation in UVB-exposed HS68 cells. GlcNAc also suppressed UVB-induced activation of c Jun, c-Fos and NF-kappaB and the phosphorylation of MAPKs and PI3K/Akt, upstream modulators of AP-1 and NF-kappaB. Moreover, GlcNAc decreased the UVB-induced influx of Ca(2+) into HS68 cells and the phosphorylation of Ca(2+)/calmodulin dependent kinases (CaMKs). CONCLUSION: The results indicate that GlcNAc inhibited UVB-induced collagenolytic MMP production by interfering with Ca(2+)-dependent Akt and MAPKs/AP-1 and NF-kappaB signaling. They may thus be potentially useful in the prevention and treatment of skin photoaging. PMID- 21600740 TI - Cerebellar and lobar blood flow in schizophrenia: a perfusion weighted imaging study. AB - It is still not clear whether brain hemodynamics plays a role in the functional and structural alterations in schizophrenia, since prior imaging studies showed conflicting findings. In this study we non-invasively explored cerebral and cerebellar lobe perfusion in the largest population of participants with schizophrenia thus far studied with perfusion-weighted imaging (PWI). Forty-seven participants affected by schizophrenia and 29 normal controls were recruited. PWI images were acquired following the intravenous injection of a paramagnetic contrast agent. Regional cerebral blood volume (CBV), blood flow (rCBF), and mean transit time (MTT) were obtained with the block-Circulant Singular Value Decomposition (cSVD) for frontal, temporal, parietal, occipital, and cerebellar lobes, bilaterally. Perfusion parameters were separately obtained for both gray and white matter in each lobe. Subjects with schizophrenia showed no significant differences in perfusion parameters when compared with controls. Interestingly, inverse correlations between age at onset and occipital, frontal and cerebellar MTT and between length of illness and frontal CBV were found. Preserved cerebral and cerebellar perfusion in our chronic population may in part be due to the effects of antipsychotic treatment which may have normalized blood volume and flow. Hypoperfusion in relation to chronicity, particularly in the frontal lobe, has been observed in accordance with earlier studies using positron emission tomography. PMID- 21600741 TI - Preparation and characterization of zinc oxide nanoparticles and their sensor applications for electrochemical monitoring of nucleic acid hybridization. AB - In this study, ZnO nanoparticles (ZNP) of approximately 30 nm in size were synthesized by the hydrothermal method and characterized by X-ray diffraction (XRD), Braun-Emmet-Teller (BET) N2 adsorption analysis and transmission electron microscopy (TEM). ZnO nanoparticles enriched with poly(vinylferrocenium) (PVF+) modified single-use graphite electrodes were then developed for the electrochemical monitoring of nucleic acid hybridization related to the Hepatitis B Virus (HBV). Firstly, the surfaces of polymer modified and polymer-ZnO nanoparticle modified single-use pencil graphite electrodes (PGEs) were characterized using scanning electron microscopy (SEM). The electrochemical behavior of these electrodes was also investigated using differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). Subsequently, the polymer-ZnO nanoparticle modified PGEs were evaluated for the electrochemical detection of DNA based on the changes at the guanine oxidation signals. Various modifications in DNA oligonucleotides and probe concentrations were examined in order to optimize the electrochemical signals that were generated by means of nucleic acid hybridization. After the optimization studies, the sequence selective DNA hybridization was investigated in the case of a complementary amino linked probe (target), or noncomplementary (NC) sequences, or target and mismatch (MM) mixture in the ratio of (1:1). PMID- 21600742 TI - [Childhood cutaneous Abrikossoff tumor]. AB - INTRODUCTION: Granular cell tumor (GCT), also known as Abrikossoff tumor, is a rare and benign neoplasm that more commonly affects the oral cavity in adults. We report here 2 childhood cases of a cutaneous granular cell tumor. CASE REPORTS: An 8- and a 12-year-old girl, with no past medical history, presented with pigmented nodular lesions located, respectively, in the left scapular region and the left iliac crest. Histological examination showed sheets and clusters of infiltrating tumor cells with morphologic and immunohistochemical features consistent with granular cell tumor. In both cases, the lesions were excised with 2-cm margins. The patients are presently being reviewed at 6-month and 2-month intervals to evaluate for recurrence and any malignant transformation. They were in good health with no signs of further tumor development. DISCUSSION: GCT is a relatively uncommon benign neoplasm probably of neural origin derived from Schwann cells. The tongue and buccal mucosa are commonly affected. It develops between the second and sixth decades of life, more frequently among women and blacks. It can also occur in childhood, but this is rare. The cutaneous forms, as in the present observations, are exceptional. Benign granular cell tumours are generally seen as a solitary asymptomatic nodule less than 3 cm in size involving the subcutaneous or submucosal tissues. Histologically, the tumor is not encapsulated but is well circumscribed. The tumor cells may show a degree of infiltration of the surrounding connective tissue. The cells are polygonal, have abundant cytoplasm, are granular and weakly eosinophilic. The nuclei are small, vesicular, and highly chromatic. Mitotic figures are rare. A key element for the histological diagnosis is the expression of S100 protein, neuron specific enolase (NSE), and vimentin on immunohistochemistry. The treatment of choice is a conservative surgical excision of the lesion. However, as the GCT has a poorly defined margin, it is suggested that the tumor should be excised along with portions of adjacent tissue. A low rate of recurrence of the lesion has been reported. CONCLUSION: The specific value of these rare cases is the occurrence in 2 children and the cutaneous location. PMID- 21600743 TI - [Congenital toxoplasmosis due to maternal reinfection during pregnancy]. AB - Reinfection with Toxoplasma gondii is exceptional but can lead to transmission to the fetus when it occurs during pregnancy. We present a case of congenital toxoplasmosis in a young baby born to an immunocompetent mother who had been immunized against toxoplasmosis before pregnancy. The presence of residual IgG specific antibodies does not always mean an absolute protection against a new toxoplasma infection. During the pregnancy, the patient was advised to follow the hygienic and dietary preventive measures even though the previous test results were consistent with past toxoplasma infection. PMID- 21600744 TI - [Kawasaki disease in older children and young adults: 10 years of experience in Marseille, France]. AB - Kawasaki disease is a well-known disease in young children. However, it can also affect older children. The aim of this study was to determine the different characteristics of Kawasaki disease in older children and young adults. This is a descriptive, retrospective, and multicenter study including all cases of Kawasaki disease occurring in children over 8 years and adults hospitalized at children's or adult Hospitals, in Marseille, France, between 1999 and 2009. The clinical, biological, prognostic, and therapeutic data were reviewed for each case. Over a 10-year period, 98 patients were hospitalized for Kawasaki disease. Six cases were aged between 8 years and 1 month and 21 years and 7 months. All patients showed a classic form of the disease with associated organ damage in 5 patients. A cardiac problem was present in 5 cases with 2 patients needing intensive care. The median time to diagnosis and treatment was 11.2 days, with all patients initially diagnosed erroneously. Current treatment guidelines were applied in 2 patients. Kawasaki disease in children over 8 years and adults under 30 years has a worse prognosis than in young children even though clinical features are atypical. It is rarely seen by clinicians in this age group, causing a delay in diagnosis, the main factor of the poor prognosis. The diagnosis of Kawasaki disease must be raised when predisposing factors are present in this group. PMID- 21600745 TI - Conversational case-based reasoning in medical decision making. AB - OBJECTIVES: Balancing the trade-offs between solution quality, problem-solving efficiency, and transparency is an important challenge in medical applications of conversational case-based reasoning (CCBR). For example, test selection in CCBR is often based on strategies in which the absence of a specific hypothesis (e.g., diagnosis) to be confirmed makes it difficult to explain the relevance of test results that users are asked to provide. In this paper, we present an approach to CCBR in medical classification and diagnosis that aims to increase transparency while also providing high levels of accuracy and efficiency. METHODS: We present an algorithm for CCBR called iNN(k) in which feature selection is driven by the goal of confirming a target class and informed by a measure of a feature's discriminating power in favor of the target class. As we demonstrate in a CCBR system called CBR-Confirm, this enables a CCBR system to explain the relevance of any question it asks the user. We evaluate the algorithm's accuracy and efficiency on a selection of datasets related to medicine and health care. RESULTS: The performance of iNN(k) on a given dataset is shown to depend on the value of k and on whether local or global feature selection is used in the algorithm. The combination of these parameters for which iNN(k) is most effective in addressing the trade-off between accuracy and efficiency is identified for each of the selected datasets. For example, only 42% and 51% on average of features in a complete problem description were needed by iNN(k) to provide accuracy levels of 86.5% and 84.3% respectively on the lymphography and SPECT heart datasets from the UCI machine learning repository. CONCLUSION: Our results demonstrate the ability of iNN(k) to provide high levels of accuracy on most of the selected datasets, while often requiring the user to provide only a small subset of the features in a complete problem description, and enabling a CCBR system to explain the relevance of any question it asks the user. PMID- 21600746 TI - The role of embryonic motoneuron transplants to restore the lost motor function of the injured spinal cord. AB - Spinal cord injury or disease result in the loss of critical numbers of spinal motoneurons and consequentially, in severe functional impairment. The most successful way to replace missing motoneurons is the use of embryonic postmitotic motoneuron grafts. This method may also at least partially restore integrity of the injured spinal cord. It has been shown that grafted motoneurons survive, differentiate and integrate into the host cord and many of them are able to reinnervate the denervated muscles. If grafted motoneurons are provided with a conduit (e.g. reimplanted ventral root) the grafted cells are able to extend their axons along the entire length of the peripheral nerves and reach the hind or forelimb muscles and to restore limb locomotion patterns. Grafted motoneurons show excellent survival in motoneuron-depleted adult host cords, but the developing spinal cord appears to provide an unfavourable environment for these motoneurons as they do not survive in immature cords. The long term survival and maturation of the grafted neurons depend on the availability of a nerve conduit and one or more target muscles, independently of whether these are ectopic nerve muscle implants or limb muscles in their original site. Thus, grafted and host motoneurons induce functional recovery in the denervated limb muscles when their axons can grow into an avulsed and reimplanted ventral root and then reach the limb muscles. Following segmental loss of motoneurons induced by partial spinal cord injury, motoneuron-enriched embryonic grafts can be placed into the gap-like hemisection cavity in the cervical spinal cord. Such transplants induce the regeneration of great numbers of host motoneurons possibly by the bridging effect of the grafts. In this case, the regenerating host motoneurons reinnervate their original target muscles while the small graft plays a minimal role in the reinnervation of muscles. These results suggest that reconstruction of the injured spinal cord using an embryonic motoneuron-enriched spinal cord graft is a feasible way to achieve improvement after severe functional motor deficits of the spinal cord. PMID- 21600748 TI - Jaw and hyolingual movements during prey transport in varanid lizards: effects of prey type. AB - The ability to modulate feeding kinematics in response to prey items with different functional properties is likely a prerequisite for most organisms that feed on a variety of food items. Variation in prey properties is expected to reveal variation in feeding function and the functional role of the different phases in a transport cycle. Here we describe the kinematics of prey transport of two varanid species, Varanus niloticus and Varanus ornatus. These species were selected for analysis because of their highly specialised hyolingual system and food transport mechanism (inertial food transport). In these animals, tongue and hyoid movements are expected to make no, or only a minor, contribution to prey transport. We observed statistically significant prey type effects that could be associated with prey properties such as mass, size and mobility. These data show that both species are capable of modulating the kinematics of food transport in response to different prey types. Moreover, not only the kinematics of the jaws were modulated in response to prey characteristics but also the anterior/posterior movements of the tongue and hyoid. This suggests a more important role of the tongue and hyolingual movements in these animals than previously suspected. In contrast, head movements were rather stereotyped and were not modulated in response to changes in prey type. PMID- 21600747 TI - Naturally high plasma glucose levels in mourning doves (Zenaida macroura) do not lead to high levels of reactive oxygen species in the vasculature. AB - Plasma glucose (P(Glu)) concentrations in birds are 1.5-2 times higher than those of mammals of similar body mass. In mammals, sustained elevations of P(Glu) lead to oxidative stress and free radical-mediated scavenging of endogenous vasodilators (e.g., nitric oxide), contributing to elevated blood pressure. Despite the relatively high P(Glu) levels in birds, they appear resistant to the development of oxidative stress in tissues such as the heart, brain and kidneys. To our knowledge no information exists on oxidative stress susceptibility in the resistance vasculature of birds. Therefore, we compared endogenous antioxidant mechanisms in the resistance vasculature of mourning doves (MODO; Zenaida macroura) and rats (Rattus norvegicus). Reactive oxygen species (ROS) were assessed with the fluorescent indicator 7'-dichlorodihydrofluorescein diacetate, acetyl ester in mesenteric arteries from rats and wild-caught MODO. Despite having significantly higher P(Glu) than rats, there were no significant differences in ROS levels between mesenteric arteries from rats or doves. Although superoxide dismutase and catalase activities were lower in the plasma, total antioxidant capacity, uric acid, vitamin E (alpha-tocopherol), and carotenoids (lutein and zeaxanthin) were significantly higher in MODO than in rats. Thus, compared to rats, MODO have multiple circulating antioxidants that may prevent the development of oxidative stress in the vasculature. PMID- 21600749 TI - Health and condition in the adult Weddell seal of McMurdo Sound, Antarctica. AB - Weddell seals (Leptonychotes weddellii) are large-bodied, long-lived mammals that live only in the circumpolar Antarctic. As such, they represent an ideal sentinel species for the impacts of environmental change on polar species. However, longitudinal physiological studies of marine mammals are notoriously difficult due to their largely aquatic lifestyle, such that many baseline indicators of health and condition are not well defined. Fifty known-age, adult seals (9-27 years, 24 males, 26 females) in McMurdo Sound were sampled for mass, total body fat, blubber depth and a suite of blood parameters (21 variables) to assess hydration state, nutritional plane, reproductive hormones (females only), organ function and immune status. Total body mass increased with age, whereas variation in blubber depth was best described by mass and/or sex, with an overall greater blubber thickness in female seals (p<0.001). Ten blood parameters showed a significant effect of one or more model variables, most prominently between the sexes. Serum chemistry suggested that females were better nourished and displayed lower indicators of acute stress compared to males. We noted limited age-related declines that might indicate impaired organ function. Overall, seals demonstrated clinically normal values for large mammals, even at the upper end of the age continuum. Future physiological studies in this species are strongly encouraged to incorporate potential sex effects in experimental design and analysis. PMID- 21600750 TI - Contrasting apoptotic responses of conjugated linoleic acid in the liver of obese Zucker rats fed palm oil or ovine fat. AB - We hypothesized that reducing weight properties of conjugated linoleic acid (CLA) are due to adipocyte apoptosis and that CLA differentially modulates the apoptotic responses in hepatic lipotoxicity from rats fed saturated fat diets. Obese Zucker rats were fed atherogenic diets (2%w/w of cholesterol) formulated with high (15%w/w) saturated fat, from vegetable or animal origin, supplemented or not with 1% of a mixture (1:1) of cis-9, trans-11 and trans-10, cis-12 CLA isomers for 14 weeks. CLA induced no changes on retroperitoneal fat depot weight, which was in line with similar levels of apoptosis. Interestingly, CLA had a contrasting effect on cell death in the liver according to the dietary fat. CLA increased hepatocyte apoptosis, associated with upregulation of Fas protein in rats fed palm oil, compared to rats receiving palm oil alone. However, rats fed ovine fat alone displayed the highest levels of hepatic cell death, which were decreased in rats fed ovine fat plus CLA. This reducing effect of CLA was related to positively restoring endoplasmic reticulum (ER) ATF-6alpha, BiP and CHOP protein levels and increasing phosphorylated c-Jun NH(2)-terminal kinase (JNK) and c-Jun, thus suggesting an adaptive response of cell survival. These findings reinforce the role of CLA as regulator of apoptosis in the liver. Moreover, the dietary fat composition is a key factor in activation of apoptosis. PMID- 21600751 TI - High throughput cellular screens to interrogate the human T and B cell repertoires. AB - There is growing consensus for an urgent need to develop efficient methods to analyze the human T and B cell response in order to understand its regulation, to unravel host-pathogen interactions and to design better vaccines. In this review we will consider different methods that have been developed to analyze human T and B cells and focus in particular on those based on high-throughput cell culture, such as memory B cell immortalization, plasma cell cultures and libraries of naive or memory T cells. These culture-based methods can be used to interrogate with high efficiency the immune repertoires in order to characterize the frequency, function and specificity of naive or memory T cells and to isolate potent and broadly neutralizing monoclonal antibodies. PMID- 21600752 TI - Allergic rhinoconjunctivitis doubles the risk for incident asthma--results from a population study in Helsinki, Finland. AB - OBJECTIVE: To examine the incidence of allergic rhinoconjunctivitis and asthma, and to assess allergic rhinoconjunctivitis as a risk factor for incident asthma, we performed a 11-year follow-up postal survey. METHODS: The original study population was a random population sample of 8000 inhabitants of Helsinki aged 20 69 years in 1996. Participants in the first postal questionnaire survey, 6062 subjects, were invited to this follow-up study, and provided 4302 (78%) answers out of 5484 traced subjects in 2007. RESULTS: Cumulative incidence of asthma from 1996 to 2007 was 4.0% corresponding to an annual incidence rate of 3.7/1000/year. After exclusion of those with asthma medication or physician-diagnosed chronic bronchitis or COPD at baseline in 1996, the cumulative incidence decreased to 3.5% (incidence rate 3.2/1000/year), and further to 2.7% (2.5/1000/year) when also those reporting recurrent wheeze or shortness of breath during the last year in 1996 were omitted from the population at risk. Remission of asthma occurred in 43 subjects and was 16.9% over 11 years. Cumulative 11-year incidence of allergic rhinoconjunctivitis was 16.9% corresponding to 16.8/1000/year, and cumulative remission was 18.1%. Incidence of allergic rhinoconjunctivitis was significantly lower among those who had lived in the countryside or on a farm during the first 5 years of life, but this was not true for asthma. In multivariate analysis, farm living during the first 5 years of life was protective for the development of allergic rhinoconjunctivitis, OR 0.75 (95%CI 0.57-0.99). Allergic rhinoconjunctivitis was a significant independent risk factor for incident asthma, OR 2.15 (95%CI 1.54-3.02). In the cohort, the prevalence of rhinoconjunctivitis increased from 38.0% in 1996 to 40.9% in 2007, physician diagnosed asthma from 6.8% to 9.4%, while current smoking decreased from 31.3% to 23.3%. CONCLUSION: Incidence of allergic rhinoconjunctivitis was higher than in earlier studies, while asthma incidence remained on similar level, both being significantly higher in women. Allergic rhinoconjunctivitis doubled the risk for incident asthma. PMID- 21600753 TI - Estimating national-level syringe availability to injecting drug users and injection coverage: Switzerland, 1996-2006. AB - BACKGROUND: Measuring syringe availability and coverage is essential in the assessment of HIV/AIDS risk reduction policies. Estimates of syringe availability and coverage were produced for the years 1996 and 2006, based on all relevant available national-level aggregated data from published sources. METHODS: We defined availability as the total monthly number of syringes provided by harm reduction system divided by the estimated number of injecting drug users (IDU), and defined coverage as the proportion of injections performed with a new syringe, at national level (total supply over total demand). Estimates of supply of syringes were derived from the national monitoring system, including needle and syringe programmes (NSP), pharmacies, and medically prescribed heroin programmes. Estimates of syringe demand were based on the number of injections performed by IDU derived from surveys of low threshold facilities for drug users (LTF) with NSP combined with the number of IDU. This number was estimated by two methods combining estimates of heroin users (multiple estimation method) and (a) the number of IDU in methadone treatment (MT) (non-injectors) or (b) the proportion of injectors amongst LTF attendees. Central estimates and ranges were obtained for availability and coverage. RESULTS: The estimated number of IDU decreased markedly according to both methods. The MT-based method (from 14,818 to 4809) showed a much greater decrease and smaller size of the IDU population compared to the LTF-based method (from 24,510 to 12,320). Availability and coverage estimates are higher with the MT-based method. For 1996, central estimates of syringe availability were 30.5 and 18.4 per IDU per month; for 2006, they were 76.5 and 29.9. There were 4 central estimates of coverage. For 1996 they ranged from 24.3% to 43.3%, and for 2006, from 50.5% to 134.3%. CONCLUSION: Although 2006 estimates overlap 1996 estimates, the results suggest a shift to improved syringe availability and coverage over time. PMID- 21600754 TI - Multi-criteria GIS-based siting of an incineration plant for municipal solid waste. AB - Siting a municipal solid waste (MSW) incineration plant requires a comprehensive evaluation to identify the best available location(s) that can simultaneously meet the requirements of regulations and minimise economic, environmental, health, and social costs. A spatial multi-criteria evaluation methodology is presented to assess land suitability for a plant siting and applied to Santiago Island of Cape Verde. It combines the analytical hierarchy process (AHP) to estimate the selected evaluation criteria weights with Geographic Information Systems (GIS) for spatial data analysis that avoids the subjectivity of the judgements of decision makers in establishing the influences between some criteria or clusters of criteria. An innovative feature of the method lies in incorporating the environmental impact assessment of the plant operation as a criterion in the decision-making process itself rather than as an a posteriori assessment. Moreover, a two-scale approach is considered. At a global scale an initial screening identifies inter-municipal zones satisfying the decisive requirements (socio-economic, technical and environmental issues, with weights respectively, of 48%, 41% and 11%). A detailed suitability ranking inside the previously identified zones is then performed at a local scale in two phases and includes environmental assessment of the plant operation. Those zones are ranked by combining the non-environmental feasibility of Phase 1 (with a weight of 75%) with the environmental assessment of the plant operation impact of Phase 2 (with a weight of 25%). The reliability and robustness of the presented methodology as a decision supporting tool is assessed through a sensitivity analysis. The results proved the system effectiveness in the ranking process. PMID- 21600755 TI - Energy implications of the thermal recovery of biodegradable municipal waste materials in the United Kingdom. AB - Waste management policies and legislation in many developed countries call for a reduction in the quantity of biodegradable waste landfilled. Anaerobic digestion, combustion and gasification are options for managing biodegradable waste while generating renewable energy. However, very little research has been carried to establish the overall energy balance of the collection, preparation and energy recovery processes for different types of wastes. Without this information, it is impossible to determine the optimum method for managing a particular waste to recover renewable energy. In this study, energy balances were carried out for the thermal processing of food waste, garden waste, wood, waste paper and the non recyclable fraction of municipal waste. For all of these wastes, combustion in dedicated facilities or incineration with the municipal waste stream was the most energy-advantageous option. However, we identified a lack of reliable information on the energy consumed in collecting individual wastes and preparing the wastes for thermal processing. There was also little reliable information on the performance and efficiency of anaerobic digestion and gasification facilities for waste. PMID- 21600756 TI - Advances in ethanol production. AB - Barriers to the commercialization of lignocellulosic ethanol include the development of more robust biocatalysts, reduction of cellulase costs, and high capital cost associated with a complex process. Improvements have been made in all areas during the past two years. Oxidoreductases, transporters, and regulators have been identified that can increase the tolerance of biocatalysts to inhibitors formed during pretreatment. Biocatalysts are being developed that grow under conditions that are optimal for cellulase activity and others have been engineered to produce glycoside hydrolases. Ethanol yields resulting from most current process configurations are similar, approximately 0.21 g ethanol/g dry cellulosic feedstock. Potentially, this can be increased to at least 0.27 g ethanol/g biomass (83 gal/ton) using simpler processes. PMID- 21600757 TI - Regulation and control of metabolic fluxes in microbes. AB - After about ten years of research renaissance in metabolism, the present challenge is to understand how metabolic fluxes are controlled by a complex interplay of overlapping regulatory mechanisms. Reconstruction of various regulatory network topologies is steaming, illustrating that we underestimated the broad importance of post-translational modifications such as enzyme phosphorylation or acetylation for microbial metabolism. With the growing topological knowledge, the functional relevance of these regulatory events becomes an even more pressing need. A major knowledge gap resides in the regulatory network of protein-metabolite interactions, simply because we lacked pertinent methods for systematic analyses - but a start has now been made. Perhaps most dramatic was the conceptual shift in our perception of metabolism from an engine of cellular operation to a generator of input and feedback signals for regulatory circuits that govern many important decisions on cell proliferation, differentiation, death, and naturally metabolism. PMID- 21600758 TI - Recent advances in computational protein design. AB - Proteins are the molecules cells primarily rely on for catalysis, recognition, signaling, defense, locomotion, and structural integrity. Engineering proteins for improved function or new applications is a fast-growing segment of biotechnology and biomedicine. Experimental efforts based on the screening of large mutant libraries have led to many successes but they do not provide quantitative design principles and/or insight into the structural features that underpin the desired function. The computational de novo design of proteins promises to bridge this gap; however, it requires reliable structure prediction, provisions for protein stability, and accurate descriptions of inter-molecule interactions. Studies that successfully meet all these criteria are beginning to emerge including the design of an O(2)-binding protein and a novel enzyme that catalyzes a Diels-Alder reaction. PMID- 21600759 TI - Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). AB - PURPOSE: To compare the efficacy of an extended schedule escalated dose of temozolomide versus standard dose dacarbazine in a large population of patients with stage IV melanoma. PATIENTS AND METHODS: A total of 859 patients were randomised to receive oral temozolomide at 150 mg/m(2)/day for seven consecutive days every 2 weeks or dacarbazine, administered as an intravenous infusion at 1000 mg/m(2)/day on day 1 every 3 weeks. The primary endpoint was overall survival (OS), using an intent-to-treat principle. EudraCT number 2004-000654-23 NCI registration number NCT00005052. RESULTS: Median OS was 9.1 months in the temozolomide arm and 9.4 months in the dacarbazine arm, with a hazard ratio (HR) of 1.00 (95%confidence interval [CI]: 0.86, 1.17; P=0.99). Median progression free survival (PFS) was 2.3 months in the temozolomide arm and 2.2 months in the dacarbazine arm, with a HR of 0.92 (95%CI: 0.80, 1.06; P=0.27). In patients with measurable disease, overall response rate was higher in the temozolomide arm than in the dacarbazine arm (14.5% versus 9.8%, respectively), but the median duration of response was longer for dacarbazine. The extended schedule, escalated dose temozolomide arm showed more toxicity than the standard dose, single agent dacarbazine arm. The most common non-haematological treatment emergent adverse events reported in both treatment arms were nausea, fatigue and vomiting and constipation. CONCLUSION: Extended schedule escalated dose Temozolomide (7 days on 7 days off) is feasible and has an acceptable safety profile, but does not improve OS and PFS in metastatic melanoma when compared to standard dose dacarbazine. PMID- 21600761 TI - Genetic and epigenetic control of UNC5C expression in human renal cell carcinoma. AB - Inappropriate gene silencing and subsequent promiscuous activity define the transformation of many solid tumours including renal cell carcinoma (RCC). Here, we report that UNC5C, one of the Netrin-1 receptors, was frequently inactivated in RCC cell lines and primary tumours. UNC5C protein was expressed in the proximal convoluted tubules of the human kidney, the presumed origin of clear cell RCC (ccRCC) and papillary RCC (pRCC). Compared to paired adjacent non malignant tissues, both UNC5C mRNA and protein expression were significantly down regulated in RCC. Immunohistochemical analysis showed that UNC5C was inactivated in 94.3% of the samples and the loss of UNC5C occurred at the early stage of RCC. Methylation specific PCR showed that UNC5C promoter was methylated in two renal carcinoma cell lines. Pharmacologic demethylation alone or in combination with inhibition of deacetylation dramatically induced UNC5C expression. Furthermore, bisulfite genomic sequencing (BGS) confirmed that dense methylation existed in UNC5C promoter. In paired tumour samples, UNC5C methylation was observed in 12 out of 44 patients (27.3%). Moreover, we analysed the loss of heterozygosity (LOH) of UNC5C in renal cell carcinoma, the LOH was observed in 27 out of 44 patients (61.4%). Finally, restoration of UNC5C expression suppressed the colony formation of renal carcinoma cells. In addition, UNC5C inhibited tumour cell proliferation, migration and enhanced chemosensitivity to cisplatin and etoposide. Therefore, UNC5C acts as a tumour suppressor in RCC and is down regulated in RCC. Loss of heterozygosity and DNA methylation contribute to the inactivation of UNC5C in renal cell carcinoma. PMID- 21600760 TI - Angiotensin system inhibitors and outcome of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective examination. AB - BACKGROUND: Sunitinib is a standard treatment for metastatic renal cell carcinoma. Angiotensin system inhibitors, including angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, are widely used in hypertension, kidney disease and heart failure. Data suggests that they may inhibit tumourigenesis. AIMS: To study the effect of angiotensin system inhibitors on sunitinib treatment outcome in metastatic renal cell carcinoma. METHODS: We performed a retrospective study of an unselected cohort of patients with metastatic renal cell carcinoma who were treated with sunitinib. Patients were divided into angiotensin system inhibitors users (group 1) and non-users (group 2). The effect of angiotensin system inhibitors on objective response, time to disease progression and overall survival, was tested with adjustment for known confounding risk factors through logistic regression model and Cox regression model. RESULTS: Between 2004 and 2010, 127 patients with metastatic renal cell carcinoma were treated with sunitinib, 44 group 1 and 83 group 2. The groups were balanced regarding known clinicopathologic prognostic factors. Objective response was partial response/stable disease 86% versus 72% and progressive disease 14% versus 28% (p=0.07) in group 1 versus 2, respectively. Median progression free survival was 13 versus 6 months (HR 0.537, p=0.0055), and median overall survival 30 versus 23 months (HR 0.688, p=0.21), in favour of group 1. CONCLUSIONS: Angiotensin system inhibitors may improve the outcome of sunitinib treatment in metastatic renal cell carcinoma. This should be investigated prospectively, and if validated applied in clinical practise and clinical trials. PMID- 21600763 TI - Hydrogen production by Rhodopseudomonas palustris WP 3-5 in a serial photobioreactor fed with hydrogen fermentation effluent. AB - In this study, a lab-scale serial photobioreactor composed of three column reactors was constructed and continuously operated to investigate several parameters influencing photohydrogen production when using the synthetic wastewater and the anaerobic hydrogen fermentation effluents as the influents. The results indicated that better hydrogen production rate was obtained when the serial photobioreactor was operated under cellular recycling at a short HRT of 8h. The serial photobioreactor maintained high hydrogen content ca. 80% in the produced gas and 0.4* dilution ratio was the suitable ratio for hydrogen production. When the photobioreactor fed with the real wastewater (Effluent 1) containing 100 mg/L NH4Cl, Column 1 reactor successfully reduced ammonia concentration to about 60 mg/L for cell synthesis, resulting in a steady hydrogen production in the following two column reactors. The average hydrogen production rate was 205 mL-H2/L/d. PMID- 21600762 TI - Antiangiogenic agents and endothelin antagonists in advanced castration resistant prostate cancer. AB - Despite multiple advances in prostate cancer therapy, treatment options for castration resistant disease are very limited. While data from recent studies are encouraging, there is no drug that has significantly improved results of standard chemotherapy. Some of the most consistent results are provided by antiangiogenic agents, showing high response rates and manageable toxicity. We describe some of the main therapeutic angiogenesis inhibitors in metastatic castration resistant prostate cancer. These agents include vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors, antiangiogenic and inmunomodulatory agents and endothelin receptor antagonists. PMID- 21600764 TI - A comparison study on the high-rate co-digestion of sewage sludge and food waste using a temperature-phased anaerobic sequencing batch reactor system. AB - Assessing contemporary anaerobic biotechnologies requires proofs on reliable performance in terms of renewable bioenergy recovery such as methane (CH(4)) production rate, CH(4) yield while removing volatile solid (VS) effectively. This study, therefore, aims to evaluate temperature-phased anaerobic sequencing batch reactor (TPASBR) system that is a promising approach for the sustainable treatment of organic fraction of municipal solid wastes (OFMSW). TPASBR system is compared with a conventional system, mesophilic two-stage anaerobic sequencing batch reactor system, which differs in operating temperature of 1st-stage. Results demonstrate that TPASBR system can obtain 44% VS removal from co substrate of sewage sludge and food waste while producing 1.2m(3)CH(4)/m(3)(system)/d (0.2m(3)CH(4)/kgVS(added)) at organic loading rate of 6.1gVS/L/d through the synergy of sequencing-batch operation, co-digestion, and temperature-phasing. Consequently, the rapid and balanced anaerobic metabolism at thermophilic stage makes TPASBR system to afford high organic loading rate showing superior performance on OFMSW stabilization. PMID- 21600765 TI - Novel diarylheptanoids as inhibitors of TNF-alpha production. AB - Synthesis and anti-inflammatory activity of novel diarylheptanoids [5-hydroxy-1 phenyl-7-(pyridin-3-yl)-heptan-3-ones and 1-phenyl-7-(pyridin-3-yl)hept-4-en-3 ones] as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production is described in the present article. The key reactions involve the formation of a beta-hydroxyketone by the reaction of substituted 4-phenyl butan-2-ones with pyridine-3-carboxaldehyde in presence of LDA and the subsequent dehydration of the same to obtain the alpha,beta-unsaturated ketones. Compounds 4i, 5b, 5d, and 5g significantly inhibit lipopolysaccharide (LPS)-induced TNF-alpha production from human peripheral blood mononuclear cells in a dose-dependent manner. Of note, the in vitro TNF-alpha inhibition potential of 5b and 5d is comparable to that of curcumin (a naturally occurring diarylheptanoid). Most importantly, oral administration of 4i, 5b, 5d, and 5g (each at 100 mg/kg) but not curcumin (at 100 mg/kg) significantly inhibits LPS-induced TNF-alpha production in BALB/c mice. Collectively, our findings indicate that these compounds may have potential therapeutic implications for TNF-alpha-mediated auto-immune/inflammatory disorders. PMID- 21600766 TI - alphavbeta3-Integrin-targeting lanthanide complex: synthesis and evaluation as a tumor-homing luminescent probe. AB - The application of lanthanide complexes in the time-resolved fluorescence imaging of living cells has emerged in the last few decades, providing high-contrast images of cells through detection of the delayed emission. In the present study, we synthesized novel trivalent lanthanide complexes containing the cyclic peptide c(RGDfK) to visualize the alpha(v)beta(3)-integrin-expressing tumor cells. Conjugation of c(RGDfK) with the macrocyclic bipyridine ligand had little effect on the fluorescence properties of the complex, indicating that the coordinated lanthanide ion was well isolated from the peptide. Bright luminescence images of alpha(v)beta(3)-integrin-expressing U87-MG cells were successfully obtained by employing the probes. PMID- 21600767 TI - Synthesis of novel heme-interacting acridone derivatives to prevent free heme mediated protein oxidation and degradation. AB - Heme is an important prosthetic molecule for various hemoproteins and serves important function in living aerobic organisms. But degradation of hemoprotein, for example, hemoglobin during different pathological conditions leads to the release of heme, which is very toxic as it induces oxidative stress and inflammation due to its pro-oxidant nature. Thus, synthesis of compound that will detoxify free heme by interacting with it would be fruitful for the management of heme-induced pathogenesis. Here, we report the synthesis of a novel natural product arborinine and some other acridone derivatives, which interact with free heme. These acridones in vitro block heme-mediated protein oxidation and degradation, markers for heme-induced oxidative stress. PMID- 21600768 TI - alpha-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging. AB - We report that alpha-tocotrienol quinone (ATQ3) is a metabolite of alpha tocotrienol, and that ATQ3 is a potent cellular protectant against oxidative stress and aging. ATQ3 is orally bioavailable, crosses the blood-brain barrier, and has demonstrated clinical response in inherited mitochondrial disease in open label studies. ATQ3 activity is dependent upon reversible 2e-redox-cycling. ATQ3 may represent a broader class of unappreciated dietary-derived phytomolecular redox motifs that digitally encode biochemical data using redox state as a means to sense and transfer information essential for cellular function. PMID- 21600770 TI - Oculopharyngodistal myopathy and acquired noncompaction. PMID- 21600771 TI - The low uptake of breast screening in cities is a major public health issue and may be due to organisational factors: a Census-based record linkage study. AB - BACKGROUND: Cancer screening uptake is generally lower in UK cities but quantifying city-level effects from causes due to population composition that comprise cities is hampered by data limitations. METHODS: A unique data linkage project combining a 2001 Census-based longitudinal study in Northern Ireland with the NHS Breast Screening Program. Validated uptake in the three years following the Census for Belfast Metropolitan Urban Area was compared against the rest of the country with adjustment for cohort attributes defined at Census. RESULTS: Belfast Metropolitan Urban Area contained 34.8% of invited women but a greater proportion who rented their accommodation (40.3%) or who did not have a car (47.1%). After full adjustment for demographic and socio-economic factors, Belfast Metropolitan Urban Area uptake was lower for first and subsequent screen (Odds ratio (OR) 0.72; 95% CIs 0.66, 0.78 and OR 0.58; 95% CIs 0.55, 0.62 respectively). There were no significant interactions between patient characteristics and area of residence indicating that all residents in Belfast Metropolitan Urban Area are equally affected. CONCLUSION: The reduced uptake of screening in cities is a major public health issue; the effects are large and a large proportion of the population are affected, organisational factors appear to be the primary cause. Strategies to correct this imbalance might help reduce inequalities in health. PMID- 21600773 TI - Spatial postural control alterations with chronic ankle instability. AB - Postural control deficits have been identified among individuals with chronic ankle instability (CAI) compared to healthy controls. Although deficits in static balance have previously been reported using center of pressure (COP) and, more recently, time to boundary (TTB) measures, the underlying mechanism behind these deficits warrants further investigation. It is unclear if there are differences in the spatial distribution of COP and TTB minima data points under the foot. Our purpose was to determine if there are differences in the location of the distribution of the COP and the TTB minima data points between groups with and without CAI. Fifty healthy and 61 CAI subjects participated in this case-control study. The subjects performed three successful 10-s trials of quiet single limb stance on a force plate with eyes-open and -closed conditions. Results showed that during eyes-open trials, the CAI group exhibited more COP and TTB minima data points on the anterolateral aspect of the foot compared to controls. With eyes-closed single limb balance, the CAI group demonstrated significantly more COP and TTB minima data points anterior to the horizontal midline of the foot compared to controls. Overall, the CAI group showed a greater anterior displacement of COP and TTB minima during single limb static stance compared to controls. This alteration may result from the CAI subjects adopting a more dorsiflexed position in an effort to keep the ankle in a more stable, closed pack position and limiting the available degrees of freedom in the distal lower extremity. PMID- 21600772 TI - Conversion of mechanical force into TGF-beta-mediated biochemical signals. AB - Mechanical forces influence homeostasis in virtually every tissue [1, 2]. Tendon, constantly exposed to variable mechanical force, is an excellent model in which to study the conversion of mechanical stimuli into a biochemical response [3-5]. Here we show in a mouse model of acute tendon injury and in vitro that physical forces regulate the release of active transforming growth factor (TGF)-beta from the extracellular matrix (ECM). The quantity of active TGF-beta detected in tissue exposed to various levels of tensile loading correlates directly with the extent of physical forces. At physiological levels, mechanical forces maintain, through TGF-beta/Smad2/3-mediated signaling, the expression of Scleraxis (Scx), a transcription factor specific for tenocytes and their progenitors. The gradual and temporary loss of tensile loading causes reversible loss of Scx expression, whereas sudden interruption, such as in transection tendon injury, destabilizes the structural organization of the ECM and leads to excessive release of active TGF-beta and massive tenocyte death, which can be prevented by the TGF-beta type I receptor inhibitor SD208. Our findings demonstrate a critical role for mechanical force in adult tendon homeostasis. Furthermore, this mechanism could translate physical force into biochemical signals in a much broader variety of tissues or systems in the body. PMID- 21600774 TI - Are pathogenic bacteria just looking for food? Metabolism and microbial pathogenesis. AB - It is interesting to speculate that the evolutionary drive for microbes to develop pathogenic characteristics was to access the nutrient resources that animals provided. Animal environments that pathogens colonize have likely driven the evolution of new bacterial characteristics to maximize these new nutritional opportunities. This review focuses on genomic and functional aspects of pathogen metabolism that allow efficient utilization of nutrient resources provided by animals. Similar to genes encoding specific virulence traits, genes encoding metabolic functions have been horizontally acquired by pathogens to provide a selective advantage in host tissues. Selective advantage in host tissues can also be gained by loss of function mutations that alter metabolic capabilities. Greater understanding of bacterial metabolism within host tissues should be important for increased understanding of host-pathogen interactions and the development of future therapeutic strategies. PMID- 21600775 TI - Late spinal metastases from an isolated pineal region germinoma mimicking a schwannoma. AB - A 20-year-old male with a prior history of germinoma presented 8 years after the initial diagnosis with progressive lower back pain. The preoperative diagnosis was schwannoma based on the appearances of a tumor in the lumbosacral region on MRI; however, histologically, a germinoma "drop" metastasis was seen. This report emphasizes the need for long-term follow-up in patients with germinoma. In addition, this patient is unusual in that the preoperative assessment favored schwannoma. PMID- 21600776 TI - Luminescence behavior and Raman characterization of jade from Turkey. AB - Results are presented for the cathodoluminescence (CL), radioluminescence (RL) and thermoluminescence (TL) of jade from Turkey. Jade samples show broad band luminescence from green to red, which, using lifetime-resolved CL, reveals seven overlapping emissions, of which two are dominant. Green emission obtained using spatially resolved CL was associated with Mn(2+) and emission bands centered near at 480 and 530 nm were attributed to (3)P(0)-(3)H(4) and (1)D(2)-(3)H(4) transitions of Pr(3+), respectively. Different shifts of the peak-wavelengths for 326 and 565 nm were observed with varying jade compositions. The incorporation of the larger K ion causes non-linear variations of the cell dimensions and therefore changes in the Fe-O band distance. We suggest that stress of the jade structure can be linked to the luminescence emission at 326 nm. Raman spectra have also been recorded in order to provide an unequivocal identification of the type of jade. The mechanism for the luminescence of the jade is considered. PMID- 21600777 TI - Evaluation of different parameters affecting the liquid scintillation spectrometry measurement of gross alpha and beta index in water samples. AB - Liquid scintillation spectrometry is a fast competitive technique for the simultaneous evaluation of gross alpha and beta indexes. However, the implementation of this technique should not be considered as straightforward, and the pre-concentration methods to decrease the detection limit together with quenching and alpha, and beta crossover corrections should be carefully chosen according to the needs of the laboratory. Both aspects are being approached in this work as to find an easy and robust method for alpha/beta measurement in water samples, taking into account the quenching and alpha/beta crossover interferences effects. Results showed that most of the pre-concentration methods increased the quenching in the measurement, although HNO(3) 0.05 M points to be the best solution for pre-concentration and re-dissolution of the sample as converges into low quenching and maximum recovery. Subsequently, in the measurement of water samples with different conductivities, the analysis of the raw counts to obtain gross alpha and beta indexes was carried out using different approaches to implement quenching and interference corrections. If quenching and salt content in the sample are relatively low, interference and quenching efficiency corrections do not improve the accuracy of the results within the usual precision assumed for a result of gross alpha and beta index (25%). Special attention must be paid when corrections are applied to high quenched or saline samples and when alpha and beta activities values are different in several orders of magnitude. PMID- 21600778 TI - Characterisation of Late Bronze Age large size shield nails by EDXRF, micro-EDXRF and X-ray digital radiography. AB - In the present study six exceptional large size metallic nails, a dagger and a sickle from the Late Bronze Age archaeological site of Figueiredo das Donas (Central Portugal) have been analysed by EDXRF, micro-EDXRF and X-ray digital radiography for the study of material composition and technology of fabrication. The combination of these analytical and examination techniques showed that all artefacts are made of bronze with As, Sb and Pb impurities, and that the nails were most likely manufactured using the casting-on technique. These results reinforce the use of binary bronze by Late Bronze Age in the region, and the incorporation of new fabrication technologies that resulted from ancient spheres of interaction. PMID- 21600779 TI - Site-directed mutagenesis of histidine 69 and glutamic acid 148 alters the ribonuclease activity of pea ABR17 (PR10.4). AB - Pea abscisic acid responsive (ABR17) protein is a member of the pathogenesis related 10 (PR10) family of proteins and its ribonuclease (RNase) activity has been reported previously. In order to investigate the amino acids important for the demonstrated ribonuclease activity of ABR17, site-directed mutants H69L and E148A were generated, expressed in Escherichia coli and purified to homogeneity. These mutations affected RNase activity differently; the H69L mutant exhibited a decreased RNase activity whereas E148A exhibited an elevated activity. A structural model for pea ABR17 has been generated using the three dimensional structure of Lupinus luteus PR10 protein in order to explain the possible effects of the H69L and the E148A mutations on substrate binding and catalysis. PMID- 21600780 TI - Vertical split of the posterior leaflet increases mitral valve area. PMID- 21600781 TI - Endobronchial closure of bronchopleural fistulas with Amplatzer vascular plug. AB - OBJECTIVE: Bronchopulmonary fistula (BPF) is a severe complication following lobectomy or pneumonectomy and is associated with a high rate of morbidity and mortality. We have developed a novel minimally invasive method of central BPF closure using Amplatzer vascular plug (AVP) device that was originally designed for the transcatheter closure of vascular structures in patients with small BPF. METHODS: Patients with BPFs were treated under conscious sedation by bronchoscopic closure of BPFs using AVP. After locating the fistula using bronchography, the self-expanding nitinol made AVP occluder to be delivered under direct bronchoscopic guidance over a loader wire into the fistula followed by bronchography to assure correct device positioning and sealing of the BPF. RESULTS: Six AVPs were placed in five patients, four males and one female, with a mean age of 62.3 years (range: 51-82 years). The underlying disorders and etiologies for BPF development were lobectomy (two patients), pneumonectomy for lung cancer (one patient), lobectomy due to necrotizing pneumonia (one patient), and post-tracheostomy tracheo-pleural fistula (one patient). In all the patients, the bronchoscopic procedure was successful and symptoms related to BPF disappeared following closure by the AVP. The results were maintained over a median follow-up of 9 months (range: 5-34 months). CONCLUSIONS: Endobronchial closure using the AVP is a safe and effective method for treatment of small postoperative BPF. The ease of their implantation by bronchoscopy under conscious sedation adds this novel technique to the armatorium of minimally invasive modalities for the treatment of small BPF. PMID- 21600782 TI - The analysis of intensive care unit length of stay in a competing risk setting. PMID- 21600784 TI - The effect of exercise induced cytokines on insulin stimulated glucose transport in C2C12 cells. AB - Skeletal muscle contractile activity increases the production of the myokines interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-15 (IL-15) and also skeletal muscle glucose transport. Previous work has revealed a role for IL-6 in mediating glucose uptake, while research on the physiological roles of IL-8 and IL-15 is not so abundant. In the present study we investigated the effects of different concentrations and combinations of IL-6, IL-8 and IL-15 on insulin stimulated glucose transport in C2C12 cells. Furthermore, we also measured AMPK Thr172 and Akt Ser473 phosphorylation via Western blotting. Exposure to 20 pg/ml of individual cytokines had no affect on glucose transport while 1 ng/ml enhanced (P<0.05) glucose uptake with IL-6, IL-8 and IL-15, respectively. Moreover, the combinations of IL-8+IL-6 and IL-15+IL-6 at both 20 pg/ml and 1 ng/ml stimulated (P<0.05) glucose transport with IL-8+IL-15 and IL-8+IL-6+IL-15 only increasing (P<0.05) glucose transport at 1 ng/ml, with no affect observed of these combinations at 20 pg/ml. The changes in glucose transport were all associated with an increase (P<0.05) in AMPK Thr172 phosphorylation with no changes in Akt Ser473 phosphorylation. These findings demonstrated that the exercise induced myokines IL-6, IL-8 and IL-15 enhance glucose transport at 1 ng/ml, with changes only seen at 20 pg/ml with certain myokine combinations. Furthermore these changes in insulin stimulated glucose transport were associated with increased AMPK phosphorylation. PMID- 21600783 TI - Pituitary-ovary-spleen axis in ovulation. AB - Leukocytes are rapidly recruited to the preovulatory ovary and play a crucial role as facilitators of ovulation and luteal formation. In this article, recent findings on leukocyte trafficking to the ovary, as well as the physiological role of leukocytes in the ovary, will be summarized and discussed. We then explore the novel hypothesis that the hypothalamus-pituitary-ovary (HPO) axis might include the spleen as a reservoir of leukocytes by summarizing recent reports on this topic, both in the fields of immunology and reproductive biology. PMID- 21600785 TI - Benefits of exercise training on breast cancer progression and inflammation in C3(1)SV40Tag mice. AB - Many observational epidemiologic studies suggest an association between exercise and breast cancer risk. However, the lack of controlled experimental studies that examine this relationship and the mechanisms involved weaken the basis for inferring a causal relationship. Inflammation plays a role in breast cancer progression and exercise has been reported to reduce inflammation; however, the anti-inflammatory effects of exercise in breast cancer have yet to be established. We examined the relationship between exercise training and systemic inflammation in relation to breast cancer progression in C3(1)SV40Tag mice. Female C3(1)SV40Tag mice were assigned to either exercise (Ex) or sedentary (Sed) treatment (n=12-14/group). Beginning at 4 wks of age mice (Ex) were run on a treadmill for 60 min/d (20 m/min and 5% grade), 6 d/wk for a period of 20 wks. Mice were examined weekly for palpable tumors, and tumor number and volume were recorded. At 24 wks of age mice were sacrificed and a more direct measure of tumor number and volume, and spleen weight was recorded. Plasma was analyzed for MCP-1 and IL-6 concentration using ELISA. Ex reduced palpable tumor number at sacrifice (24 wks) by approximately 70% (P<0.05). Tumor volume was also reduced in Ex at 21-23 wks (P<0.05). This reduction in tumor progression by Ex was associated with a reduction in plasma concentration of MCP-1 and IL-6, and spleen weight (P<0.05). These data provide strong support for a beneficial effect of exercise training on tumor progression in the C3(1)SV40Tag mouse model of breast cancer that may be partly mediated by its anti-inflammatory potential. PMID- 21600786 TI - Effect of bone sialoprotein on proliferation and osteodifferentiation of human bone marrow-derived mesenchymal stem cells in vitro. AB - We performed this study to investigate the effects of recombinant human bone sialoprotein (BSP) on the proliferation and osteodifferentiation of human BMSCs(hBMSCs). The hBMSC cultures were divided into 4 groups: control group, 10( 10) M BSP group (BSP group), osteogenic medium group (10 nM dexamethasone, 10 mM beta-glycerophosphate, and 50 mg/L ascorbic acid, OM group) and BSP + OM group (OM plus10(-10) M BSP). Compared with the control group, cell growth of the other three groups slowed down, while fluorescence at the G(0)/G(1) phase increased. After 28 days, in the OM group and the BSP + OM group, the proportion of STRO-1 positive cells decreased by 22.7% and 38.4% and ALP activity increased by 50% and 71.43%, respectively. CD271 mRNA expression decreased while Cbfa1, osteocalcin and osterix mRNA levels increased in the OM and BSP + OM groups, and the mRNA level change was greater in the BSP + OM group. After 28 days, the number of nodules in the BSP + OM group was 112.5% more than that in the OM group, but nodules did not formed in the control or BSP group. We conclude that BSP is capable of inhibiting hBMSCs proliferation and enhancing their osteogenic differentiation and mineralization in the presence of OM. PMID- 21600787 TI - Effect of glenoid deformity on glenoid component placement in primary shoulder arthroplasty. AB - BACKGROUND: Malposition of the glenoid component can result in premature component loosening or instability. This study was designed to test the ability of an experienced shoulder surgeon to position the glenoid component using standard preoperative planning and surgical bone preparation. MATERIALS AND METHODS: Thirteen patients having primary total shoulder arthroplasty were evaluated using 3-dimensional surgical simulator. Ideal version was considered to have version as close to perpendicular to the plane of the scapula, with complete contact of the back side of the component on glenoid bone and maintenance of the center peg of the component within bone. RESULTS: The average retroversion angle was 13 degrees (mean, standard deviation [SD] 12 degrees ), with a range of 1-42 degrees . In 7 of these 13 cases, preoperative glenoid retroversion was greater or equal to 10 degrees . In 3 cases, the component was malpositioned with greater than 10 degrees of ideal version. In cases with less than 10 degrees of preoperative retroversion, the glenoid component was placed within 10 degrees of ideal version in all cases. CONCLUSION: Traditional methods to correct moderate to severe glenoid deformity and place the glenoid component within 5 degrees of the ideal position are not consistent. Optimal glenoid component placement can be achieved when there is minimal bone deformity. Retroversion greater or equal to 20 degrees makes it difficult to place a pegged glenoid component perpendicular to the plane of the scapula by asymmetric reaming without center peg perforation. PMID- 21600788 TI - Comminuted radial head fractures: aspects of current management. PMID- 21600789 TI - Resection arthroplasty of the shoulder as a salvage procedure for deep shoulder infection: does the use of a cement spacer improve outcome? AB - HYPOTHESIS: Resection arthroplasty can be performed for recalcitrant shoulder infection. It is unclear whether a spacer has any benefit. We hypothesized that spacers would increase infection control and improve clinical results. MATERIALS AND METHODS: Twenty-one patients were evaluated retrospectively at a mean follow up of 46.4 months: 11 patients did not receive a spacer (group A), and 10 patients did receive a spacer (group B). Patients were assessed clinically and with radiographs. Patients were scored using the Visual Analog Scale (VAS), Constant-Murley Score (CMS), Simple Shoulder Test, and Disabilities of Arm, Shoulder and Hand. RESULTS: Infection was eradicated in 19 patients without additional surgery. Two patients had elevated C-reactive protein and erythrocyte sedimentation rate and were considered to have low-grade infections. Neither patient received a spacer and had not been revised. Infectious control was not significantly different between group A and group B (P = .48). Fourteen patients found the result good or acceptable. The VAS decreased from 6.5 to 2.6. The CMS increased significantly from 17.8 to 40.4. Active abduction averaged 78.1 degrees and active flexion averaged 85.5 degrees . External rotation was 21.0 degrees . DISCUSSION: No significant difference was shown between group A and group B. Preservation of the tuberosities was identified as a prognosticator for a good result. Unacceptable pain resulted in 5 patients with a spacer undergoing delayed reimplantation of a prosthesis. CONCLUSION: Resection arthroplasty can be offered to patients with long-standing deep shoulder infection that was unresponsive to previous surgical treatment. Control of infection did not differ significantly between the groups. No improvement in outcome was demonstrated with the use of cement spacers. PMID- 21600790 TI - Management of a periprosthetic fracture after humeral head resurfacing total shoulder replacement: a case report. PMID- 21600791 TI - A cadaveric model for suprascapular nerve injury during glenoid component screw insertion in reverse-geometry shoulder arthroplasty. AB - BACKGROUND: Reverse-geometry shoulder replacement requires fixation of a baseplate (called a metaglene) to the glenoid, to which a convex glenosphere is attached. Most systems use screws to achieve this fixation. The suprascapular nerve passes close to the glenoid and is known to be at risk of injury when devices and sutures are inserted into the glenoid. We investigate the risk posed to the suprascapular nerve by placement of metaglene fixation screws. MATERIALS AND METHODS: Ten cadaveric shoulder specimens were used. A metaglene was inserted and fixed by use of 4 screws. The suprascapular nerve was dissected and its branches identified. The screw tips and their proximity to the nerve and branches were identified and recorded. RESULTS: The superior and posterior screws posed the most risk to the suprascapular nerve. The nerve was engaged by the posterior screw on 4 occasions and was within 5 mm of the nerve or a branch of it in 5 others. The superior screw was extraosseous on 4 occasions, making contact with the nerve in 3 of those 4 specimens and being within 2 mm of it in the fourth specimen. CONCLUSION: Metaglene fixation with screws poses a significant risk to the suprascapular nerve. Caution should be used when inserting the posterior and superior screws in particular. Short locking screws may allow adequate fixation while minimizing the risk of neurologic injury. PMID- 21600792 TI - Humeral component revision arthroplasty: outcomes of a split osteotomy technique. AB - BACKGROUND: The purpose of our study was to report results on 13 patients who underwent shoulder revision surgery of a well-fixed cemented humeral component assisted by a longitudinal split osteotomy. Limited data have been published on humeral stem revision using an osteotomy to facilitate removal of a well-fixed humeral component. MATERIALS AND METHODS: Between July 1996 and July 2004, 13 humeral component revisions of well-fixed cemented stems were performed for pain and functional limitation. The patients' preoperative and postoperative function and outcome were evaluated by physical examination, visual analog scale (VAS) for pain, Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons (ASES) score, Short Form-12 (SF-12), and radiographic assessment. RESULTS: At a mean follow-up of 30 months, from preoperatively to postoperatively, the VAS pain score improved from 7.8 to 2.3 (P = .012), the ASES score improved from 19.6 to 58.9 (P < .011), the SST score improved from 1.4 to 4.6 (P < .011), and significant changes were demonstrated on the mental component of the SF-12, with improvement from 49.8 to 59.4 (P < .025). Analysis of range of motion from preoperatively to postoperatively revealed that the mean external rotation improved from 24.4 degrees to 40 degrees (P < .042), and mean forward elevation improved from 60.6 degrees to 89.4 degrees , although this change was not significant (P = .067). There were no iatrogenic fractures. Radiographic follow up demonstrated no evidence of humeral loosening or nonunion. CONCLUSIONS: A longitudinal humeral split osteotomy is a safe and effective technique for revision of a well-fixed humeral stem. PMID- 21600793 TI - Does arthroscopic rotator cuff repair actually heal? Anatomic evaluation with magnetic resonance arthrography at minimum 2 years follow-up. AB - PURPOSE: The goal of this series was to evaluate the clinical and anatomical outcomes of all-arthroscopic rotator cuff tears repair at a mid-term follow-up, using MR arthrography in order to assess tendon-to-bone healing. MATERIALS AND METHODS: This retrospective study included 29 patients (31 shoulders) presenting, according to Cofield classification, a small or moderate-sized supraspinatus full thickness tear with (7/31) or without (24/31) infraspinatus extension. The mean size of the tear was 2.64 +/- 1.61 cm. The Constant score was used for pre- and postoperative clinical evaluation. All tendons were repaired under arthroscopic control. A single row technique was used. Biceps tenotomy and subacromial decompression were systematically performed. All patients operated arm were immobilized in a sling for 4 weeks and full activity was allowed at 6 months. At last follow-up, a rotator cuff MR arthrography was performed by an independent radiologist to evaluate the anatomical status of repair. RESULTS: The mean follow up was 49.4 +/- 17.3 months. Sixteen patients (17 shoulders) had a rotator cuff MR arthrography. Mean Constant score at last follow-up was 82.3 +/- 12.4, with a mean improvement of 24%. Eighty-eight percent of repairs (15/17) showed a small or a large leakage at the MR arthrography. There was no significant correlation between the clinical and anatomical outcomes. CONCLUSION: The interest of this series is to show, at a mid-term follow-up and using an invasive imaging technique, the low rate of tendon-to-bone healing in arthroscopic rotator cuff repair but with a minimal influence on clinical outcome. PMID- 21600794 TI - Do insurance and race represent independent predictors of undergoing total shoulder arthroplasty? A secondary data analysis of 3529 patients. AB - HYPOTHESIS: Race and insurance status are independent predictors of the choice between total shoulder arthroplasty (TSA) and hemiarthroplasty (HA) of the shoulder joint. BACKGROUND: Current literature shows that ethnic and socioeconomic status may influence access to health care. However, no study has demonstrated whether insurance status and race are independent predictors that patients with glenohumeral osteoarthritis will undergo TSA. MATERIALS AND METHODS: Patients with primary International Classification of Diseases, 9th revision, Clinical Modification, procedure codes for TSA and HA were selected from the 1988 to 2007 United States Nationwide Inpatient Sample. Primary predictors were race (Caucasian, African American, Hispanic, other) and insurance status (private, Medicare, Medicaid, other). Multiple logistic regressions were used to determine whether insurance status and race were associated with the choice of procedure for patients presenting with glenohumeral osteoarthritis. RESULTS: The study included data for 3529 patients, of whom 2369 underwent TSA (67.1%) and the remaining 1160 (32.9%) underwent HA. Of patients treated using TSA, 29% were privately insured, 63.2% had Medicare, and 2.5% had Medicaid (P < .001), and 62.1% were Caucasian, 2.5% were African American, 2.46% were Hispanic, and 30.9% had other ethnicities (P < .001). DISCUSSION: Multiple logistic regression analysis found that privately insured patients and Medicare patients did not show statistically different odds of having TSA compared with patients within the Medicaid (reference category) or "other payment" categories, after adjustment for a variety of potential confounders. Caucasian patients also did not show statistically different chances of undergoing TSA compared with African Americans. CONCLUSIONS: We were unable to support statistical evidence that race and insurance status are independent factors associated with the choice of the surgical procedure in patients with glenohumeral osteoarthritis. PMID- 21600795 TI - Outcome of local anconeus flap transfer to cover soft tissue defects over the posterior aspect of the elbow. AB - BACKGROUND: To report the outcome of using local pedicled anconeus flap (LPAF) to cover soft tissue defects over the posterior aspect of the elbow. METHODS: Twenty elbows in 20 patients who had chronic soft tissue defects over the posterior aspect of the elbow that were managed with the use of LPAF were included in this study. The mean soft tissue defect size averaged 4 * 3 cm (range, 2 * 3 cm to 7 * 4 cm). The mean duration of symptoms was 11 months (range, 4-96), and the mean number of debridement and attempt at closure of the wound defect before the flap was performed was 3 (range, 2-7). RESULTS: Wound healing occurred in all elbows at an average 3 weeks (range, 2-5) after surgery. No flap complication either at the time of the surgery or postoperatively was recorded. At the final follow-up that averaged 17 months (range, 15-20) after surgery, there were significant improvements in the subjective elbow value (SEV) and Mayo Elbow Performance Score (MEPS) from average 70% (range, 50-80%) and 74% (range, 65-80%) to an average 95% (80-100%) and 90% (range, 85-100%), respectively (P = .001). All patients had full range of motion of the elbow, and all were satisfied with the surgery and would do it again. CONCLUSION: The LAPF is a reliable flap that could be used to cover chronic soft tissue defect around the posterior aspect of the elbow, with expected wound healing in all patients at an average of 3 weeks after surgery. PMID- 21600796 TI - Simple autonomic seizures and ictal enuresis. AB - Human micturition is physiologically controlled via a complex and finely tuned network of cortical and subcortical regions, hitherto not fully understood. We report the case of a 42-year-old man with juvenile myoclonic epilepsy (JME) and post-traumatic epilepsy. Ictal enuresis was the only manifestation of the de novo post-traumatic simple autonomic seizures. Source analysis of the ictal epileptiform discharges showed activation of the cortical areas surrounding the right inferior frontal sulcus, adjacent to the lesional zone. The case depicted here further endorses recent neuroimaging studies which strongly implicate this cortical region in the regulation and the initiation of the micturition. PMID- 21600798 TI - Transcription factor Smad-independent T helper 17 cell induction by transforming growth factor-beta is mediated by suppression of eomesodermin. AB - Transforming growth factor-beta (TGF-beta) has been shown to be required for Th17 cell differentiation via Smad-independent mechanisms. The molecular mechanism underlying this pathway remains to be clarified, however. We searched for genes regulated by TGF-beta through the Smad-independent pathway by using Smad2 and Smad3 double-deficient T cells and identified the transcription factor Eomesodermin (Eomes), whose expression was suppressed by TGF-beta via the c-Jun N terminal kinase (JNK)-c-Jun signaling pathway. Inhibition of JNK strongly suppressed disease in an in vivo EAE model as well as in vitro Th17 cell induction. Overexpression of Eomes substantially suppressed Th17 cell differentiation, whereas ablation of Eomes expression could substitute for TGF beta in Th17 cell induction in primary T cells. Eomes suppressed Rorc and Il17a promoters by directly binding to the proximal region of these promoters. In conclusion, the suppression of Eomes by TGF-beta via the JNK pathway is an important mechanism for Smad-independent Th17 cell differentiation. PMID- 21600797 TI - Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin 1beta activation and severe autoinflammation in mice. AB - Missense mutations in the C-terminal B30.2 domain of pyrin cause familial Mediterranean fever (FMF), the most common Mendelian autoinflammatory disease. However, it remains controversial as to whether FMF is due to the loss of an inhibitor of inflammation or to the activity of a proinflammatory molecule. We generated both pyrin-deficient mice and "knockin" mice harboring mutant human B30.2 domains. Homozygous knockin, but not pyrin-deficient, mice exhibited spontaneous bone marrow-dependent inflammation similar to but more severe than human FMF. Caspase-1 was constitutively activated in knockin macrophages and active IL-1beta was secreted when stimulated with lipopolysaccharide alone, which is also observed in FMF patients. The inflammatory phenotype of knockin mice was completely ablated by crossing with IL-1 receptor-deficient or adaptor molecule ASC-deficient mice, but not NLRP3-deficient mice. Thus, our data provide evidence for an ASC-dependent NLRP3-independent inflammasome in which gain-of-function pyrin mutations cause autoinflammatory disease. PMID- 21600799 TI - Assessment of optimal target genes for detecting micrometastases in pelvic lymph nodes in patients with prostate cancer undergoing radical prostatectomy by real time reverse transcriptase-polymerase chain reaction. AB - OBJECTIVES: To compare the accuracy to diagnose micrometastases to pelvic lymph nodes (LNs) in patients undergoing radical prostatectomy (RP) by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) targeting several genes specifically expressed in the prostate. MATERIALS AND METHODS: Expression of prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), human kallikrein 2 (hK2), prostate stem cell antigen (PSCA), and differential display code 3 (DD3) in 2215 LNs isolated from 120 patients with localized prostate cancer were assessed by fully quantitative real-time RT-PCR. RESULTS: In addition to pathologically diagnosed LN metastases in 11 patients, real-time RT-PCR targeting PSA, PSMA, hK2, PSCA, and DD3 further identified micrometastases in 23, 29, 31, 15, and 11, respectively. In this series, biochemical recurrence (BR) occurred in 32 patients, of whom 25, 22, 28, 10, and 9 were diagnosed as having micrometastases by real-time RT-PCR targeting PSA, PSMA, hK2, PSCA, and DD3, respectively. Univariate analysis identified pathologic stage, pathologic LN metastases, Gleason score, surgical margin status, and micrometastases detected by real-time RT-PCR targeting PSA, PSMA, hK2, and their combinations as significant predictors for BR-free survival (BRFS), of which only surgical margin status and micrometastases detected by real-time RT-PCR targeting PSA and hK2 appeared to be independently associated with BRFS on multivariate analysis. CONCLUSIONS: Of PSA, PSMA, hK2, PSCA, DD3, and their combinations, combined analysis of PSA and/or hK2 expression in pelvic LNs by real-time RT-PCR could provide findings most precisely predicting BRFS following RP. PMID- 21600801 TI - Comments regarding 'Structure of delay in carotid surgery--an observational study'. PMID- 21600800 TI - Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. AB - OBJECTIVES: We sought to develop a clinical algorithm combining serum PSA with detection of TMPRSS2:ERG fusion and PCA3 in urine collected after digital rectal exam (post-DRE urine) to predict prostate cancer on subsequent biopsy. MATERIALS AND METHODS: Post-DRE urine was collected in 48 consecutive patients before prostate biopsy at 2 centers; quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect PCA3 and TMPRSS2:ERG fusion transcript expression. Serum PSA was measured by clinical assay. The performance of TMPRSS2:ERG fusion, PCA3, and serum PSA as biomarkers predicting prostate cancer at biopsy was measured; a clinically practical algorithm combining serum PSA with TMPRSS2:ERG and PCA3 in post-DRE urine to predict prostate cancer was developed. RESULTS: Post-DRE urine sediment provided informative RNA in 45 patients; prostate cancer was present on subsequent biopsy in 15. TMPRSS2:ERG in post-DRE urine was associated with prostate cancer (OR = 12.02; P < 0.001). PCA3 had the highest sensitivity in predicting prostate cancer diagnosis (93%), whereas TMPRSS2:ERG had the highest specificity (87%). TMPRSS2:ERG had the greatest discriminatory value in predicting prostate cancer (AUC = 0.77 compared with 0.65 for PCA3 and 0.72 for serum PSA alone). Combining serum PSA, PCA3, and TMPRSS2:ERG in a multivariable algorithm optimized for clinical utility improved cancer prediction (AUC = 0.88; specificity = 90% at 80% sensitivity). CONCLUSIONS: A clinical algorithm specifying biopsy for all patients with PSA >= 10 ng/ml, while restricting biopsy among those with PSA <10 ng/ml to only those with detectable PCA3 or TMPRSS2:ERG in post-DRE urine, performed better than the individual biomarkers alone in predicting prostate cancer. PMID- 21600802 TI - Van wyk and grumbach syndrome: an unusual case and review of the literature. AB - BACKGROUND: The syndrome consisting of primary hypothyroidism, precocious puberty, and massive ovarian cysts was termed Van Wyk and Grumbach syndrome in 1960. Little is known about the effect of the cysts on ovarian tumor markers. CASE: A 12-year-old Caucasian female presented with headaches and fatigue. Imaging to evaluate her headaches revealed a pituitary macroadenoma. Soon after her macroadenoma was discovered, she presented to the emergency room with abdominal pain. Imaging at that time revealed massive bilateral ovarian masses with the left measuring 17 * 13 * 8.5 cm and the right measuring 18 * 11 * 10 cm. Ovarian tumor markers were drawn at this time, most of which were highly elevated. Subsequent evaluation revealed extreme hypothyroidism. Given these findings of a pituitary macroadenoma, bilateral ovarian masses, and severe hypothyroidism, the patient was diagnosed with Van Wyk and Grumbach syndrome. We followed the cyst conservatively and the ovaries and tumor markers returned to normal after adequate thyroid replacement. COMMENTS: This case supports conservative treatment as the first-line approach to massive ovarian cysts caused by hypothyroidism. In addition this case shows that tumor markers can be abnormal in the absence of a malignancy in this setting. Before proceeding with surgical evaluation, exclusion of hypothyroidism to exclude this rare but treatable syndrome should be undertaken. The most important diagnostic clue that the cyst may be caused by an endocrine source is the finding of bilateral ovarian cysts rather than one ovary affected as seen in most ovarian malignancies in this age group. PMID- 21600803 TI - Management of children and adolescents with gender dysphoria. PMID- 21600804 TI - Human papillomavirus in infants: transmission, prevalence, and persistence. AB - Human Papillomavirus (HPV) is very common in reproductive age women. It has been demonstrated that this infection can be transmitted from mother to infant. Evidence of HPV infection can be seen in infant and toddlers. A review of the literate was undertaken to examine the manner in which HPV can be transmitted, the rate at which transmission occurs, and if HPV can persist. The manifestations of HPV were also reviewed. It is not clear what effect the quadravalent HPV vaccine, given to mothers will have on HPV infections in infants. PMID- 21600806 TI - Comment on "menstrual disorders in adolescent school girls in Enugu, Nigeria" by Nwankwo et al: does adolescent dysmenorrhea ameliorate after age 20? PMID- 21600805 TI - Diagnosis and treatment of interstitial cystitis in adolescents. AB - Interstitial cystitis (IC), or painful bladder syndrome, is characterized by irritative voiding symptoms and can be a challenging problem that affects children and adolescents. Diagnosis and management in children and adolescents is challenging because of strict diagnostic criteria and the paucity of investigations focusing on this age group, which often can lead to delayed or missed diagnosis. Clinical features suggestive of IC include bladder pain, urgency, frequency, nocturia, and pressure. Symptoms may wax and wane and often are exacerbated by menstruation, intercourse, dietary triggers, and stress. Diagnosis can be made by history, physical exam findings such as suprapubic tenderness, voiding diaries, and exclusion of other etiologies. Some diagnostic tests such as the potassium sensitivity test and cystoscopy are invasive and often impractical in younger patients. Treatment of IC consists of a multimodal approach that should be tailored to the individual needs of the patient. Therapies for younger patients include oral medication, intravesical therapy, cystoscopy with hydrodistention, and conservative measures such as dietary modification. This review of the literature focuses on diagnosing IC in younger patients and on what treatment modalities are appropriate and effective for this age group. PMID- 21600807 TI - Voiding dysfunction: another etiology of vulvovaginitis in young girls. AB - OBJECTIVE: To determine the prevalence of voiding dysfunction (VD) in patients with persistent vulvovaginitis (PVV), and to evaluate the clinical response of PVV in the treatment of VD. PATIENTS AND METHODS: Girls four years or older who consulted for PVV for at least one month and who did not respond to general measures. A physical examination was performed with visual inspection and colposcopy; vaginal samples for culture and vaginoscopy were carried out. On every patient urodynamic studies were performed. Girls who were diagnosed with VD were treated. A pediatric gynecologist did the follow-up; a successful response was considered when inflammatory symptoms and vaginal discharge ceased. RESULTS: Twenty patients were included, mean age 8.6 years (range: 4.6-14 years); 75% prepubertal symptoms lasted for 1.8 years; 19 (95%) had urodynamia, 10 (52.6%) had an overactive bladder, 8 (42.1%) external bladder sphincter dyssynergia, 1 (5.2%) hypotonic bladder, and 13 (65%) showed improvement. CONCLUSION: VD is an important cause when considering the etiology of PVV. PMID- 21600808 TI - Use of emergency contraception by US teens: effect of access on promptness of use and satisfaction. AB - STUDY OBJECTIVE: To examine the effect of policies regarding access to emergency contraception (EC) on teens' promptness of EC use and satisfaction with EC access experience. SETTING: Online survey. PARTICIPANTS: Females, ages 14 to 19, who had engaged in unprotected intercourse at a time when they were aware of EC. MAIN OUTCOME MEASURES: Outcomes included promptness of EC use and satisfaction with EC access experience. Outcomes were compared according to method of obtaining EC and state policies regarding EC access. RESULTS: Surveys were completed by 531 teens from 49 states; 58% were Caucasian and 14% were African American. Only 48% of participants reported ever using EC. Teens who obtained EC without a prescription were more likely to use EC within 24 hours of unprotected intercourse (odds ratio = 2.17; 95% confidence interval: 1.06-4.44). Minors who obtained EC in pharmacist access states were more likely to be satisfied with their EC access experience (odds ratio = 3.05; 95% confidence interval: 1.11-8.35). CONCLUSION: Fewer than half of participants had used EC, despite being aware of EC at the time of unprotected intercourse. Policies allowing minors to access EC without a prescription may increase timely use of EC. PMID- 21600809 TI - Knowledge of HPV in West Virginia high school health students and the effects of an educational tool. AB - STUDY OBJECTIVE: To assess the knowledge of human papillomavirus (HPV) in West Virginia high school students, create an educational DVD that could be used as a supplement to health class, and evaluate whether our intervention increases student knowledge of HPV. DESIGN: Prospective, randomized experimental design with analysis of questionnaire data. SETTING: West Virginia high school health class. PARTICIPANTS: A total of 626 students participated. INTERVENTIONS: HPV educational DVD designed by health care providers. MAIN OUTCOME MEASURES: Three WV counties were chosen for study participation. The study took place in health class during the sexually transmitted infection curriculum. Students were randomized to 2 arms: (1) HPV DVD educational intervention plus health class and (2) health class only. Participants completed a pretest and posttest that involved 11 true and false questions. The changes in test scores were compared between the 2 groups. RESULTS: Overall, posttest scores of those students in the HPV DVD plus health class arm improved significantly more than the posttest scores in the health class only arm (P < .0001). CONCLUSION: The educational HPV DVD we created was shown to be an effective learning tool. This is the first reported study to look at the effects of an educational program created by health care providers on the topic of HPV that would be used in the school setting. We believe this tool can be used to supplement the current health education curriculum in the school system. PMID- 21600810 TI - A retrospective review of the effect of surgeon specialty on the management of 190 benign and malignant pediatric and adolescent adnexal masses. AB - STUDY OBJECTIVE: To investigate the impact of operating surgeon specialty on rates of ovarian preservation, and to explore differences in surgical management when malignant lesions are identified. DESIGN: Retrospective study. SETTING: Education and research hospitals. PARTICIPANTS: Between January 1, 2003 and January 1, 2009, all female patients <= 20 years of age undergoing surgery with pathologically confirmed ovarian or fallopian tube tissues removed were evaluated. INTERVENTIONS: Demographic, operative, and pathologic data were abstracted. MAIN OUTCOME MEASURES: Rates of ovarian preservation with benign lesions, and rates of appropriate surgical staging when malignant lesions were identified. RESULTS: The mean age was 11.9 +/- 4.4 years. Malignant lesions were larger than benign masses, 17.3 +/- 7.1 cm versus 8.8 +/- 7.1 cm respectively (P < .001). Torsion was associated with oophorectomy with a relative risk (RR) of 1.86 and 95% confidence interval (CI) of 1.35-2.57 (P = 0.033). Postmenarchal patients were less likely to undergo ovarian sacrificing procedures (RR 0.62, 95% CI 0.45-0.84, P < .001). The relative risk of incomplete surgical staging with malignant lesions was reduced in the presence of a gynecologic oncologist (RR 0.14, 95% CI 0.02-0.89, P = .003). CONCLUSION: Ovarian conservation should be prioritized in cases with benign lesions, whereas complete and accurate surgical staging is imperative when malignancy is identified. PMID- 21600811 TI - Premenstrual syndrome and dysmenorrhea: urban-rural and multiethnic differences in perception, impacts, and treatment seeking. AB - BACKGROUND: Attitudes toward menarche and menstruation are largely influenced by sociological, cultural, and family environmental factors. Recognizing the influential effects that these factors might have on shaping adolescents' attitudes is crucial in designing a more effective means of transmitting health information. AIMS: This study aimed to gather an in-depth understanding of perceptions, impacts, and treatment seeking on menstruation-related issues from an ethnically mixed group of rural and urban girls. METHODOLOGY: In total, 27 focus group discussions (172 participants) were conducted between November 2008 and April 2009. Participants were adolescent girls aged 13-19 years, recruited from 7 public secondary schools in the Federal Territory of Kuala Lumpur and 4 public secondary schools from the rural districts of Kelantan, in Malaysia. RESULTS: Many participants revealed that they were not given or had not received detailed information about the mechanism or physiology of menstruation prior to its onset. Thus, many described the onset of menarche as shocking, an event for which they were unprepared, and which has had a tremendous impact on their emotions. More positive acceptance of menarche was reported in the urban than with the rural groups. Despite the high prevalence of premenstrual syndrome and dysmenorrhea, participants across urban-rural and ethnic groups perceived the problems as completely normal, hence they relied on self-care methods and did not want to seek professional treatment. More rural girls compared to urban girls were embarrassed to talk to their mothers or consult their physicians regarding menstruation-related problems. CONCLUSION: Menstruation-related education would have a positive impact in improving adolescent girls' knowledge and in nurturing a positive attitude toward menstruation-related matters at home, at school, and in the community. PMID- 21600812 TI - Prevalence of polycystic ovarian syndrome in Indian adolescents. AB - BACKGROUND: PCOS is a common female endocrine disorder with prevalence ranging from 2.2% to 26%. Most reports have studied adult women with age ranged from 18 to 45 years. The aim of this study was to find the prevalence of PCOS in Indian adolescents. METHOD: We prospectively studied 460 girls aged 15 to 18 years from a residential college in Andhra Pradesh, South India, who underwent clinical examination. Out of which 72 girls with oligomenorrhea and/or hirsutism were invited for biochemical, hormonal, and ultrasonographic evaluation for diagnosis of PCOS by Rotterdam criteria. PCOS was defined as the presence of any two of the three features: (1) Oligo/amenorrhea: absence of menstruation for 45 days or more and/or <=8 menses per year. (2) Clinical hyperandrogenism: Modified Ferriman and Gallway (mFG) score of 6 or higher. (3) Polycystic ovaries: presence of >10 cysts, 2-8 mm in diameter, usually combined with increased ovarian volume of >10 cm(3), and an echo-dense stroma in pelvic ultrasound scan. RESULTS: Out of 460 girls, one (0.22%) had oligo/amenorrhea with clinical hyperandrogenism, 29 (6.30%) had oligomenorrhea with polycystic ovaries, one (0.22%) had polycystic ovaries with clinical hyperandrogenism and 11 (2.39%) had oligomenorrhea with polycystic ovaries in the presence of clinical hyperandrogenism. Thus 42 (9.13%) girls satisfied Rotterdam's criteria for PCOS, which increased to 50.46 (10.97%) when imputed data were included. CONCLUSION: Prevalence of PCOS in Indian adolescents is 9.13%.This draws attention to the issue of early diagnosis in adolescent girls. PMID- 21600813 TI - Sleep disturbances in sexual abuse victims: a systematic review. AB - An impressive body of research has investigated whether sexual abuse is associated with sleep disturbances. Across studies there are considerable differences in methods and results. The aim of this paper was to conduct the first systematic review of this area, as well as to clarify existing results and to provide guidelines for future research. We conducted searches in the electronic databases PsycINFO and PubMed up until October 2010 for studies on sleep disturbances in sexually abused samples. Thirty-two studies fulfilled the inclusion criteria (reported empirical data, included sexually abused subjects, employed some form of sleep measurement, English language and published in peer reviewed journals). Across the studies included, sleep disturbances were widespread and more prevalent in sexually abused subjects as compared to in non abused samples. Symptoms reported more frequently by sexually abused samples included nightmare related distress, sleep paralysis, nightly awakenings, restless sleep, and tiredness. Results were divergent with regards to sleep onset difficulties, nightmare frequency, nocturnal activity, sleep efficiency, and concerning the proportion of each sample reporting sleep disturbances as such. Potential sources of these divergences are examined. Several methodological weaknesses were identified in the included studies. In order to overcome limitations, future researchers are advised to use standardized and objective measurements of sleep, follow-up or longitudinal designs, representative population samples, large sample sizes, adequate comparison groups, as well as comparison groups with other trauma experiences. PMID- 21600814 TI - Cortical reorganisation in a preterm born child with unilateral watershed infarction. AB - In this case report we describe the presence of a unilateral watershed infarction in a preterm born infant. Structural imaging in the neonatal period and in adolescence confirmed a typical lesion pattern compatible with watershed infarction in term born infants. Though the resulting parasagittal cleft transected the primary motor cortex, motor function of the affected hand was relatively spared. Functional MRI and transcranial magnetic stimulation revealed an important role for the unaffected hemisphere in motor control of the affected hand, showing once again that early cortical reorganization may lead to a near normal hand function. PMID- 21600815 TI - Neurodevelopmental outcome of post-hemorrhagic ventricular dilatation at 12 and 24 months corrected age with high-threshold therapy. AB - BACKGROUND: The management of post-hemorrhagic hydrocephalus remains a discussion. We describe the neurodevelopmental outcome at the corrected age of 12 and 24 months of infants with PHVD treated with high-threshold therapy. OBJECTIVE: To describe, and compare the neurodevelopmental outcome of a cohort of premature infants with grade III or IV intraventricular hemorrhage with or without development of PHVD. METHODS: Retrospective chart and image review of all IVH grade III and IV infants admitted to the department of Neonatology of the Academic Medical Center, Amsterdam, the Netherlands between January 1999 and December 2006. A standardized neurodevelopmental examination was performed at the corrected ages of 12 and 24 months. RESULTS: In total, 118 cases with IVH were identified. IVH grade III: n = 63, mean gestational age (GA): 28 weeks (SD 2.3), median birth weight (BW): 1130 g (range 908-1460 g); IVH IV: n = 31, mean GA: 28 weeks (SD 2.4), median BW: 1105 g (range 925-1230 g). Grade III and IV cases developed PHVD in 75% versus 42% respectively. Abnormal outcome in IVH III patients mainly occurred in cases with PHVD (12 months: 47% abnormal, 24 months: 64% abnormal). In the IVH IV cases, outcome was comparable with or without PHVD. Developmental delay was more pronounced at 24 months. CONCLUSION: Mainly IVH III cases developed PHVD. Comparing our results with the literature neurodevelopmental outcome was poorer with our high-threshold therapy. PMID- 21600816 TI - Activation of anterior cingulate cortex produces inhibitory effects on noxious mechanical and electrical stimuli-evoked responses in rat spinal WDR neurons. AB - In present study, in vivo electrophysiological techniques were applied to examine the effects of anterior cingulate cortex (ACC) activation on mechanical and electrical stimuli-evoked responses in rat spinal cord wide-dynamic-range (WDR) neurons. We found that bilateral ACC electrical stimulation (100Hz, 20V, 20s) had different effects on neuronal responses to brush, pressure and pinch stimuli (10s). The brush-evoked neuronal responses at baseline, post 1min and post 5min were 60.8+/-15.0, 59.2+/-15.4 and 60.0+/-19.3 spikes/10s, respectively (n=10, P>0.05 vs. baseline). The pressure-evoked neuronal responses at baseline, post 1min and post 5min were 77.8+/-11.9, 38.0+/-7.8 and 45.8+/-7.6 spikes/10s, respectively (n=10, P<0.05 vs. baseline). The pinch-evoked neuronal responses at baseline, post 1min and post 5min were 137.6+/-16.7, 62.6+/-17.5 and 68.8+/-15.0 spikes/10s, respectively (n=10, P<0.05 vs. baseline). Furthermore, ACC stimulation generated distinct effects on the different components of wind-up response. The total numbers of late response (LR) and after-discharge (AD), but not early response (ER), significantly decreased. Collectively, the present study demonstrated that short-term ACC activation could generate long-term inhibitory effects on the responses of WDR neurons to noxious mechanical (pressure and pinch) and electrical stimuli. The results indicated that ACC activation could negatively regulate noxious information ascending from spinal cord with long-term effect, providing potential neuronal substrate for the modulation of ACC activation on nociception. PMID- 21600817 TI - The impact of pain in patients with polyneuropathy. AB - Peripheral neuropathy (PN) is a common impairment which may impact upon quality of life (QoL). Neuropathic pain (NeP) occurs in up to 50% of patients with PN. We hypothesized that disability and impaired quality of life resulting from PN is primarily associated with presence of NeP. Our aim was to determine using prospectively identified PN patients presenting to a tertiary care neuromuscular clinic if presence of NeP (PN+NeP) had greater impact upon QoL than with absence of NeP (PN-NeP). A second aim was to identify if QoL varied based upon etiology of PN. We analyzed neuropathy severity (Toronto Clinical Neuropathy Score (TCSS)), pain quantity and quality (Visual Analogue Scale (VAS) pain score, Brief Pain Inventory (BPI)), QoL and health status measures (EuroQol Instrument 5 Domains (EQ-5D), Medical Outcomes Sleep Study Scale (MOSSS), Hospital Anxiety and Depression Scale (HADS), Short Form 36 Health Survey (SF-36)) and Health Assessment Questionnaire (HAQ) to determine impact of NeP. Although both cohorts were epidemiologically similar and had similar severity of PN, PN+NeP patients had considerably greater impairment for QoL, sleep efficacy, and features of anxiety and depression, leading to substantially greater health care resources utilization when compared to PN-NeP patients. The magnitude of NeP severity was the only explaining variable for increased impact upon QoL measures and diminishing overall wellbeing. Our results confirm that NeP is a primary indicator for worsening QoL and diminished overall wellbeing in PN patients. The etiology of PN did not influence levels of NeP-related compromise of QoL. Further studies are needed to determine optimal methods for management of PN+NeP patients subjected to a significant physiological, psychological and functional burden. PMID- 21600818 TI - Social comparison performance standards, threat, and tolerance for experimentally induced pain. AB - Social modelling experiments have illustrated how upward social comparisons (i.e., observing pain tolerant role models) can facilitate tolerance relative to downward social comparison (i.e., observing pain intolerant alternatives). However, because clinical studies suggest that people prefer to make downward social comparisons with less fortunate others when they are threatened or overwhelmed with pain or illness, it seems plausible that upward social comparisons confer fewer benefits when pain is appraised as threatening. To address this issue, we assessed effects of verbally-presented upward and downward social comparison standards on tolerance for cold pressor pain among 124 Australian adults (44 men, 80 women) primed with either more or less threatening orienting information about task-related pain sensations. As predicted, participants exposed to the lower threat orienting prime and upward comparison performance standard were significantly more pain tolerant than peers in all other conditions. Conversely, the average tolerance time for participants presented with the higher threat orienting prime and upward comparison standard did not differ from that of either downward comparison group. The research highlighted powerful situational influences on tolerance for experimental pain and identified conditions under which verbally-presented upward social comparison standards may facilitate and hinder the capacity to bear pain. PMID- 21600819 TI - Association between prodromal pain and the severity of acute herpes zoster and utilization of health care resources. AB - BACKGROUND: Herpes zoster results from the reactivation of the varicella-zoster virus, which is often accompanied by a prodrome of dermatomal pain. Little is known about the burden of prodromal pain. OBJECTIVES: (1) Describe the frequency, severity and duration of prodromal pain; (2) determine the relationship between prodromal pain and the characteristics of herpes zoster at recruitment and the utilization of health care resources. METHODS: Between 10/2005 and 07/2006, 251 subjects >= 50 years old, seeking care for herpes zoster within 14 days of rash onset, were recruited across Canada. Severity and duration of prodromal pain were measured retrospectively using the Initial Zoster Impact Questionnaire. The burden of prodromal pain was obtained by the product of pain severity and duration. The severity of acute herpes zoster pain was measured using the Zoster Brief Pain Inventory. RESULTS: The majority of participants reported prodromal pain (74%). Mean pain duration and severity were 4.7 days and 6/10, respectively. Subjects aged 61-70 years old were more likely to report prodromal pain (RR=1.14, p-value=0.02). The burden of prodromal pain was greater in subjects not working (p-value=0.02) or immunosuppressed (p-value=0.04). Prodromal pain was associated with more severe acute pain (6.2 vs. 4.3, p-value 0.0001). Compared to subjects who did not report prodromal pain, those with this pain were more likely to receive antivirals (RR=1.18, p-value=0.04) and to visit the emergency room (RR=2.56, p-value=0.04). CONCLUSION: The burden of prodromal pain is significant and should be considered when evaluating the overall benefit of herpes zoster vaccination. PMID- 21600820 TI - Spin relaxation and linear-in-electric-field frequency shift in an arbitrary, time-independent magnetic field. AB - A method is presented to calculate the spin relaxation times T(1), T(2) due to a non-uniform magnetic field, and the linear-in-electric-field precession frequency shift deltaomega(E) when an electric field is present, in the diffusion approximation for spins confined to a rectangular cell. It is found that the rectangular cell geometry admits of a general result for T(1), T(2), and deltaomega(E) in terms of the spatial cosine-transform components of the magnetic field. The result is applied to the case of a permanently-magnetized dipole impurity near the cell. PMID- 21600821 TI - Relative importance of lean mass and fat mass on bone mineral density in a group of Lebanese postmenopausal women. AB - The aim of this study was to determine the relative importance of lean mass and fat mass on bone mineral density (BMD) in a group of Lebanese postmenopausal women. One hundred ten Lebanese postmenopausal women (aged 65-84 yr) participated in this study. Age and years since menopause were recorded. Body weight and height were measured and body mass index (BMI) was calculated. Body composition (lean mass, fat mass, and fat mass percentage) was assessed by dual-energy X-ray absorptiometry (DXA). Bone mineral content (BMC) of the whole body (WB) and BMD of the WB, the lumbar spine (L1-L4), the total hip (TH), the femoral neck (FN), the ultra distal (UD) Radius, and the 1/3 Radius were measured by DXA. The expressions WB BMC/height and WB BMD/height were also used. Weight, BMI, fat mass, and lean mass were positively correlated to WB BMC, WB BMC/height, WB BMD/height, and to WB, L1-L4, TH, FN, UD Radius, and 1/3 Radius BMD. However, using multiple linear regression analyses, fat mass was more strongly correlated to BMC and to BMD values than lean mass after controlling for years since menopause. This study suggests that fat mass is a stronger determinant of BMC and BMD than lean mass in Lebanese postmenopausal women. PMID- 21600822 TI - The assessment of regional skeletal metabolism: studies of osteoporosis treatments using quantitative radionuclide imaging. AB - Studies of bone remodeling using bone biopsy and biochemical markers of bone turnover play an important role in research studies to investigate the effect of new osteoporosis treatments on bone quality. Quantitative radionuclide imaging using either positron emission tomography with fluorine-18 sodium fluoride or gamma camera studies with technetium-99m methylene diphosphonate provides a novel tool for studying bone metabolism that complements conventional methods, such as bone turnover markers (BTMs). Unlike BTMs, which measure the integrated response to treatment across the whole skeleton, radionuclide imaging can distinguish the changes occurring at sites of particular clinical interest, such as the spine or proximal femur. Radionuclide imaging can be used to measure either bone uptake or (if done in conjunction with blood sampling) bone plasma clearance. Although the latter is more complicated to perform, unlike bone uptake, it provides a measurement that is specific to the bone metabolic activity at the measurement site. Treatment with risedronate was found to cause a decrease in bone plasma clearance, whereas treatment with the bone anabolic agent teriparatide caused an increase. Studies of teriparatide are of particular interest because the treatment has different effects at different sites in the skeleton, with a substantially greater response in the flat bone of the skull and cortical bone in the femur compared with the lumbar spine. Future studies should include investigations of osteonecrosis of the jaw and atypical fractures of the femur to examine the associated regional changes in bone metabolism and to throw light on the underlying pathologies. PMID- 21600823 TI - Cross calibration of Hologic QDR2000 and GE lunar prodigy for whole body bone mineral density and body composition measurements. AB - The objective of this study was to undertake an in vivo cross calibration of body composition, whole body bone mineral content (BMC) and bone mineral density (BMD) between a Hologic QDR2000 and a GE Healthcare Lunar Prodigy. Twenty-one subjects attending for routine bone densitometry were recruited to the study (19 female and 2 male, aged 30-79 yr). Phantom cross calibrations were carried out using the Bio-Imaging Variable Composition Phantom (VCP) for percentage fat (%fat) and the Bona Fide Phantom (BFP) for BMD. There was no significant difference in whole body lean body mass between the QDR2000 and the Prodigy. Fat mass (FM) and %fat were significantly higher on the QDR2000. BMC and whole body BMD were significantly higher on Prodigy. As the BMC increased, so did the difference between the 2 instruments. The VCP did not provide an adequate cross calibration of %fat compared with in vivo. The BFP provided a good cross calibration of whole body BMD compared with in vivo. The results suggest that the partitioning of the soft tissue component between lean and fat in the 2 instruments is systematically different. The variation between instruments from the same and different manufacturers reported in the literature varies widely, as does the comparison with criterion methods. This makes it difficult to generalize the results of this study to other centers and it is recommended that each center would have to cross calibrate when changing equipment. PMID- 21600824 TI - Leptin, fat mass, and bone mineral density in healthy pre- and postmenopausal women. AB - The purpose was to examine relationships between age, fat mass, and bone mineral density (BMD) with resting leptin levels in premenopausal and postmenopausal women. Young (aged 18-30 yr, n=30) and estrogen-deficient postmenopausal (aged 55 75 yr, n=43) women were recruited. Total body and segmental fat mass and bone free lean body mass (BFLBM) and total body, lumbar spine, and proximal femur BMD were assessed using dual-energy X-ray absorptiometry. Serum-resting, fasted leptin levels were measured by Immunoradiometric Assay (IRMA), and leptin-to-fat mass ratios were calculated. Young and older women had similar amounts of BFLBM, but older women had greater (p<0.05) amounts of fat mass and 35% higher leptin levels. Age differences in leptin concentrations were no longer significant after controlling for fat mass. Older women had significantly (p<0.05) lower hip BMD values. Age was negatively related (r=-0.29, p<0.05) to leptin:trunk fat ratio. Increases in fat mass, not menopause per se, contributes to higher leptin levels in older women. Relationships between leptin and BMD may be age dependent. PMID- 21600825 TI - Clinical and epidemiological features of human rabies cases in the Philippines: a review from 1987 to 2006. AB - BACKGROUND: Rabies viral infection causes a fatal encephalomyelitis. In humans, classic features include hydrophobia, aerophobia, hypersalivation, agitation, and neurological symptoms. In the Philippines, canine rabies contributes to a significant burden of human disease. METHODS: We retrospectively reviewed the medical records of 1839 patients admitted to San Lazaro Hospital, Manila, Philippines between 1987 and 2006, with a clinical diagnosis of rabies. We used the World Health Organization case definition for clinical rabies, which is defined by the presence of hydrophobia. RESULTS: Male patients outnumbered females by 2.2 to 1 and twice the number of adults were affected compared with children. Most patients were indigent. Dog bites occurred more than cat bites (97.1% vs. 2.9%) and most cases were caused by a single bite (86.2%), compared to multiple bites (8.7%). Bites to the face, head, and neck led to shorter incubation times, yet the incubation period varied, with most cases (42.7%) occurring in the bracket of 91-365 days post-exposure. Clinical symptoms included hydrophobia in all cases, as per our case definition, and aerophobia in 95.5%; only 9.4% had fever, 9.2% exhibited restlessness, and 6.7% exhibited hypersalivation. Localized neurological symptoms included pain (4.1%), numbness (2.6%), and itching (2.3%). None of the patients received appropriate post exposure prophylaxis (PEP). CONCLUSIONS: This study examines the largest cohort of rabies patients reported to-date. Better understanding of clinical disease manifestations may help in salvage efforts to save patients with rabies. Knowledge of epidemiological factors will improve preventative efforts to reduce suffering from rabies. PMID- 21600826 TI - [Giant cell tumors of the distal radius: resection: reconstruction by long avascular fibular graft (a case report)]. AB - Giant cell tumors (GCT) are locally aggressive tumors with a preference for epiphyses and metaphyses of long bones. They represent 5%-10% of all primary bone tumors. They affect mostly young adults between 20 and 40. Their origin remains uncertain. GCT is a purely lytic tumor, recurrent and can even lead to fracture. The distal radius is the third location after the distal femur and proximal tibia. Tumors are benign on histopathology, but "benign" lung metastases can sometimes be seen. Their treatment remains controversial because of the high rate of recurrence; oncological resection of the diseased bone segment with reconstruction reduces the rate of recurrence. Several techniques of resection and reconstruction of the wrist have been proposed. We report a case of giant cell tumor of the distal radius treated by resection and reconstruction by avascular fibular graft to a length of 12cm, and we evaluate the use of this reconstruction to salvage the wrist with this pathology. PMID- 21600827 TI - [Is early cervical cancer screening justified?]. AB - Pap smear screening of women under 25 years old remains controversial. No randomized study exists on this topic. The perception of individual benefit often prevails, although there is no proof of effectiveness and no demonstrated risk benefit ratio. A review of published studies - taking into account epidemiological data, effectiveness of screening of young women, adverse medical outcomes and costs - suggests that there are more arguments against screening before 25 than in favour of it. PMID- 21600828 TI - Adaptive step length estimation algorithm using optimal parameters and movement status awareness. AB - An adaptive step length estimation algorithm operating with optimal parameters and a movement status awareness algorithm are proposed. The proposed algorithm was developed as a means for increasing the accuracy in estimating walking distances. The algorithm was applied to pedestrian navigation system, ubiquitous health monitoring systems, and so forth. The algorithm's optimal parameters were derived after measurement errors were taken into consideration. The movement status awareness algorithm was designed using a walking characteristic called the acceleration variance. After estimating a subject's walking distance using the proposed algorithm, the measured error was 4.8% with respect to actual walking distance. Alternatively, estimating a subject's walking distance without the algorithm yielded an error of 20% with respect to actual walking distance. PMID- 21600829 TI - Global sensitivity analysis of a wave propagation model for arm arteries. AB - Wave propagation models of blood flow and blood pressure in arteries play an important role in cardiovascular research. For application of these models in patient-specific simulations a number of model parameters, that are inherently subject to uncertainties, are required. The goal of this study is to identify with a global sensitivity analysis the model parameters that influence the output the most. The improvement of the measurement accuracy of these parameters has largest consequences for the output statistics. A patient specific model is set up for the major arteries of the arm. In a Monte-Carlo study, 10 model parameters and the input blood volume flow (BVF) waveform are varied randomly within their uncertainty ranges over 3000 runs. The sensitivity in the output for each system parameter was evaluated with the linear Pearson and ranked Spearman correlation coefficients. The results show that model parameter and input BVF uncertainties induce large variations in output variables and that most output variables are significantly influenced by more than one system parameter. Overall, the Young's modulus appears to have the largest influence and arterial length the smallest. Only small differences were obtained between Spearman's and Pearson's tests, suggesting that a high monotonic association given by Spearman's test is associated with a high linear corelation between the inputs and output parameters given by Pearson's test. PMID- 21600830 TI - The effect of compressive deformations on the rate of build-up of oxygen in isolated skeletal muscle cells. AB - In this study we integrated between confocal-based cell-specific finite element (FE) modeling and Virtual Cell (VC) transport simulations in order to determine trends of relationship between externally applied compressive deformations and build-up rates of oxygen in myoblast cells, and to further test how mild culture temperature drops (~3 degrees C) might affect such trends. Geometries of two different cells were used, and each FE cell model was computationally subjected to large compressive deformations. Build-up of oxygen concentrations within the deformed cell shapes over time were calculated using the VC software. We found that the build-up of oxygen in the cells was slightly but consistently hindered when compressive cell deformations were applied. Temperature drops characteristic to ischemic conditions further hinder the oxygen built-up in cells. In a real world condition, a combination of the deformation and temperature factors should be anticipated, and their combined effect might substantially impair cell respiration functions. PMID- 21600831 TI - Cerebellar pathology and essential tremor: did Dr. Purkinje leave any fingerprints? PMID- 21600832 TI - Purkinje cell loss is a characteristic of essential tremor. AB - This paper began as a letter to the editor, commenting on several methodological and conceptual problems with the paper by Rajput et al. [1]. We were asked by the editors to expand the paper to include a more general discussion of the role of the cerebellum in essential tremor (ET). The study of the neuropathological underpinnings of essential tremor (ET) is a relatively new undertaking. The purpose of this paper is three-fold. The first is to comment on methodological problems in a recently-published paper by Rajput et al., the major one being the small sample size of that study, which resulted in a Type II statistical error. Hence, one cannot conclude based on their data that there is no Purkinje cell (PC) loss in ET. Secondly, we comment on conceptual problems with that study, which suggested that PC loss might not be a featured characteristic of ET because it is also found in other disease states. We discuss why this is an erroneous conclusion. Our third purpose is to more broadly discuss the role of the cerebellum in ET, giving consideration to the wealth of clinical and postmortem data that have accumulated over recent years. In this discussion, we make the following points: (1) it is now generally recognized that ET is a disease of cerebellar systems dysfunction, (2) given the nature of the postmortem work, revealing the presence of several types of structural-anatomical changes within the cerebellum and absence of detectable changes in other brain regions, the most empirically-based explanation is that the primary problem in ET is in the cerebellum itself, (3) that the collection of cellular changes in the cerebellum in ET are also present in other cerebellar degenerations should add to rather than detract from the notion that ET is a disease of cerebellar degeneration. PMID- 21600833 TI - Gray matter volume deficits in spinocerebellar ataxia: an optimized voxel based morphometric study. AB - INTRODUCTION: Spinocerebellar ataxias (SCA) are a group of autosomal dominant ataxias with varied clinical phenotypes. However there are no unique distinguishing features on routine neuroimaging among the various genetically defined SCAs. Voxel-based morphometry (VBM) provides an automated unbiased analysis of structural MRI scans and gives a comprehensive assessment of anatomical differences throughout the brain. OBJECTIVES: The aims of this study were to (i) characterize the patterns of atrophy in SCA1, SCA2 and SCA3 using optimized VBM, (ii) demonstrate the characteristic anatomical differences in these genetically distinct SCA subtypes, and (iii) assess the relationship between morphometric measures and the CAG repeat lengths and other attributes of the disease. METHODS: Thirty-one genetically confirmed patients suffering from SCA (SCA1 - 12, SCA2 - 9, and SCA3 - 10) were studied. High resolution T1 weighted 3-Dimensional Magnetic Resonance Images of 31 patients were analyzed using the optimized VBM procedure. RESULTS: In all the three SCAs there was a significant loss of gray matter in both cerebellar hemispheres and vermis. Vermian atrophy was more pronounced in SCA3, while SCA1 and SCA2 had significant white matter atrophy. Pontine white matter atrophy was more pronounced in SCA2. In SCA1, the severity of ataxia strongly correlated with the degree of gray matter atrophy in cerebellar hemispheres. The duration of symptoms and lengths of CAG repeats had no correlation with the degree of atrophy. CONCLUSIONS: This study showed that the different subtypes of SCAs may have morphometric differences in the cerebellum, brainstem and the supratentorial structures. PMID- 21600834 TI - Wilson's disease in consecutive generations of one family. PMID- 21600835 TI - "Walkable by Willpower": resident perceptions of neighbourhood environments. AB - Resident perceptions of neighbourhood walkability, physical activity opportunities, food choice and factors influencing choice of neighbourhood were examined through focus group discussion in higher and lower walkability neighbourhoods. Almost all participants perceived their neighbourhoods as very or reasonably walkable with high food choice. Walking was described as primarily leisure or exercise focused and less frequently as destination or task-oriented. Factors influencing walking and physical activity included connectivity, path quality, weather and traffic. The ability to drive easily was a key factor in neighbourhood choice. Our findings identified important environmental factors perceived by residents as either positively or negatively influencing behaviour related to physical activity and food choice. Future research should examine the relationship between perceived and actual walkability features as well as residential selection. PMID- 21600836 TI - 2D-3D shape reconstruction of the distal femur from stereo X-ray imaging using statistical shape models. AB - Three-dimensional patient specific bone models are required in a range of medical applications, such as pre-operative surgery planning and improved guidance during surgery, modeling and simulation, and in vivo bone motion tracking. Shape reconstruction from a small number of X-ray images is desired as it lowers both the acquisition costs and the radiation dose compared to CT. We propose a method for pose estimation and shape reconstruction of 3D bone surfaces from two (or more) calibrated X-ray images using a statistical shape model (SSM). User interaction is limited to manual initialization of the mean shape. The proposed method combines a 3D distance based objective function with automatic edge selection on a Canny edge map. Landmark-edge correspondences are weighted based on the orientation difference of the projected silhouette and the corresponding image edge. The method was evaluated by rigid pose estimation of ground truth shapes as well as 3D shape estimation using a SSM of the whole femur, from stereo cadaver X-rays, in vivo biplane fluoroscopy image-pairs, and an in vivo biplane fluoroscopic sequence. Ground truth shapes for all experiments were available in the form of CT segmentations. Rigid registration of the ground truth shape to the biplane fluoroscopy achieved sub-millimeter accuracy (0.68mm) measured as root mean squared (RMS) point-to-surface (P2S) distance. The non-rigid reconstruction from the biplane fluoroscopy using the SSM also showed promising results (1.68mm RMS P2S). A feasibility study on one fluoroscopic time series illustrates the potential of the method for motion and shape estimation from fluoroscopic sequences with minimal user interaction. PMID- 21600838 TI - Physiology and metabolism. PMID- 21600839 TI - Spectral studies on Ag8+ ions irradiated LAHCl.H2O and LAHBr.H2O single crystals. AB - L-arginine hydrochloride monohydrate and L-arginine hydrobromide monohydrate single crystals are irradiated by 100 MeV Ag8+ swift heavy ions. The residual gases liberated from the irradiated samples are monitored as a function of ion fluence using quadrupole mass analyzer. The C2H3+, C2H2, N2, CO, HCl and CO2 are the dominant gases liberated. Fourier transform infrared spectra of irradiated crystals explain the breaking of bonds in a localized region of the crystals. The crystallinity of irradiated crystals is analyzed by powder X-ray diffractions. PMID- 21600840 TI - Structural, spectral, optical and dielectric properties of copper and glycine doped LAHCl single crystals. AB - Cu2+ and glycine doped L-arginine monohydrochloride monohydrate (LAHCl) single crystals were grown by slow solvent evaporation technique. The grown single crystals were confirmed by X-ray diffraction study and the interaction of dopants with LAHCl molecule was identified in Fourier transform infrared spectra. The crystalline perfection of pure and doped crystals was analyzed by high resolution X-ray diffraction studies. Vickers microhardness and UV-visible spectroscopy were carried out respectively to study the mechanical stability and optical transmittance of pure and doped LAHCl single crystals. He-Ne laser of wavelength 632.8 nm was used to measure refractive index and birefringence of grown crystals. The second harmonic generation efficiency was also measured for pure and doped LAHCl single crystals using Nd:YAG laser. PMID- 21600837 TI - Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions. AB - Ideal oncology drugs would be curative after a short treatment course if they could eliminate epithelium-originated carcinomas at their non-invasive, pre malignant stages. Such ideal molecules, which are expected to molecularly abrogate all the instrumental mechanisms acquired by migrating cancer stem cells (CSCs) to by-pass tumour suppressor barriers, might already exist. We here illustrate how system biology strategies for repositioning existing FDA-approved drugs may accelerate our therapeutic capacity to eliminate CSC traits in pre invasive intraepithelial neoplasias. First, we describe a signalling network signature that overrides bioenergetics stress- and oncogene-induced senescence (OIS) phenomena in CSCs residing at pre-invasive lesions. Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin ("old drugs") to their recently recognized CSC targets ("new uses") within the network. By discussing the preclinical efficacy of chloroquine and metformin to inhibiting the genesis and self-renewal of CSCs we finally underscore the expected translational impact of the "old drugs-new uses" repurposing strategy to open a new CSC-targeted chemoprevention era. PMID- 21600842 TI - The feasibility of an automated monitoring system to improve nurses' hand hygiene. AB - BACKGROUND: Inadequate hand hygiene (HH) by healthcare staff results in increased rates of hospital acquired infections in healthcare institutions, considerable waste of resources, and negative economic impact for the healthcare system. Toronto Rehabilitation Institute has developed an automated HH monitoring system that detects HH opportunities, generates HH reminding signals when it is necessary and enables hospital management to monitor individual and aggregated HH performance on ongoing basis. OBJECTIVE: To demonstrate that HH improvement is feasible with the proposed technical solution and that technology is acceptable by potential users. METHODS: The technology was installed in four rooms on a nursing unit of a larger complex continuous care hospital. The rooms were selected to make it possible to automatically follow the same nurses for the duration of their entire shift. Eleven nurses were provided with the wearable electronic HH monitors as well as with the instrumented personal wearable alcohol gel dispensers. Stationary gel dispensers installed in the unit were also instrumented with technology. RESULTS: Over 145 h of testing the system automatically recorded a total of 1438 events of entering and leaving monitored rooms and indicated an average of 6.42 HH actions per hour. The baseline observational study indicated 4.2 HH actions per hour. Approximately half of the HH actions recorded by the system were performed using personal wearable alcohol gel dispensers. CONCLUSION: The results obtained when testing the embedded HH monitoring system demonstrated the feasibility of HH improvement and proved that proposed solution merits a larger and longer clinical trial to measure the degree of improvement and the sustainability of that improvement. PMID- 21600841 TI - The experimental and theoretical QM/MM study of interaction of chloridazon herbicide with ds-DNA. AB - We report a multispectroscopic, voltammetric and theoretical hybrid of QM/MM study of the interaction between double-stranded DNA containing both adenine thymine and guanine-cytosine alternating sequences and chloridazon (CHL) herbicide. The electrochemical behavior of CHL was studied by cyclic voltammetry on HMDE, and the interaction of ds-DNA with CHL was investigated by both cathodic differential pulse voltammetry (CDPV) at a hanging mercury drop electrode (HMDE) and anodic differential pulse voltammetry (ADPV) at a glassy carbon electrode (GCE). The constant bonding of CHL-DNA complex that was obtained by UV/vis, CDPV and ADPV was 2.1*10(4), 5.1*10(4) and 2.6*10(4), respectively. The competition fluorescence studies revealed that the CHL quenches the fluorescence of DNA ethidium bromide complex significantly and the apparent Stern-Volmer quenching constant has been estimated to be 1.71*10(4). Thermal denaturation study of DNA with CHL revealed the DeltaTm of 8.0+/-0.2 degrees C. Thermodynamic parameters, i.e., enthalpy (DeltaH), entropy (DeltaS degrees ), and Gibbs free energy (DeltaG) were 98.45 kJ mol(-1), 406.3 J mol(-1) and -22.627 kJ mol(-1), respectively. The ONIOM, based on the hybridization of QM/MM (DFT, 6.31++G(d,p)/UFF) methodology, was also performed using Gaussian 2003 package. The results revealed that the interaction is base sequence dependent, and the CHL has more interaction with ds-DNA via the GC base sequence. The results revealed that CHL may have an interaction with ds-DNA via the intercalation mode. PMID- 21600843 TI - Action of 5 Hz repetitive transcranial magnetic stimulation on sensory, motor and autonomic function in human spinal cord injury. AB - OBJECTIVE: To assess the effectiveness of physiological outcome measures in detecting functional change in the degree of impairment of spinal cord injury (SCI) following repetitive transcranial magnetic stimulation (rTMS) of the sensorimotor cortex. METHODS: Subjects with complete or incomplete cervical (or T1) SCI received real and sham rTMS in a randomised placebo-controlled single blinded cross-over trial. rTMS at sub-threshold intensity for upper-limb muscles was applied (5 Hz, 900 stimuli) on 5 consecutive days. Assessments made before and for 2 weeks after treatment comprised the ASIA (American Spinal Injuries Association) impairment scale (AIS), the Action Research Arm Test (ARAT), a peg board test, electrical perceptual test (EPT), motor evoked potentials, cortical silent period, cardiovascular and sympathetic skin responses. RESULTS: There were no significant differences in AIS outcomes between real and sham rTMS. The ARAT was increased at 1h after real rTMS compared to baseline. Active motor threshold for the most caudally innervated hand muscle was increased at 72 and 120 h compared to baseline. Persistent reductions in EPT to rTMS occurred in two individuals. CONCLUSIONS: Changes in cortical motor threshold measures may accompany functional gains to rTMS in SCI subjects. SIGNIFICANCE: Electrophysiological measures may provide a useful adjunct to ASIA impairment scales. PMID- 21600844 TI - Evidence that the mismatch negativity to pattern violations does not vary with deviant probability. AB - OBJECTIVE: To determine whether the classic inverse relationship between the amplitude of the mismatch negativity (MMN) and deviant probability can be demonstrated to violations of a concrete rule pattern. METHODS: In Experiment 1, oddball and patterned auditory sequences were presented with high (p = 0.16) and rare (p = 0.02) deviant probability. In Experiment 2, a slightly different pattern was presented with high, moderate (p = 0.08), low (p = 0.04), and rare deviant probability. In Experiment 3, deviants in the patterns from Experiments 1 and 2 were actively detected at high and rare probability. RESULTS: In Experiment 1, the amplitude of the MMN varied inversely with deviant probability in both conditions. In Experiment 2, no effect of probability was observed. Experiment 3 supported the hypothesis that high deviant probability causes instability in the memory representation of the standard in the pattern from Experiment 1. CONCLUSIONS: The amplitude of the MMN to concrete pattern violations does not vary with deviant probability. SIGNIFICANCE: The amplitude of the MMN may not vary with deviant probability. Once a stable memory representation is formed for the standard regularities in an auditory sequence, further examples may not strengthen that representation. PMID- 21600845 TI - Physiological and molecular evidence that environmental changes elicit morphological interconversion in the model diatom Phaeodactylum tricornutum. AB - Over the last decades Phaeodactylum tricornutum has become a model to study diatom biology at the molecular level. Cells have the peculiarity to be pleiomorphic and it is thought that this character is triggered by culture conditions, although few quantitative studies have been performed and nothing is known at the molecular level. Our aim was to quantify the effect of growth conditions on cell morphology of different P. tricornutum strains by quantitative microscopy, cellular imaging, and non-targeted transcriptomics. We show that morphotype changes can be regulated by changing culture conditions, depending on the strain, and show a common trend of increased oval cell abundance as a response to stress. Examination of expressed sequence tags (ESTs) from triradiate cells infers the importance of osmoregulation in the maintenance of this morphotype, whereas ESTs derived from oval cells grown in hyposaline and low temperature conditions show a predominance of genes encoding typical components of stress pathways, especially in signaling, cell homeostasis and lipid metabolism. This work contributes to better understand the importance of the unique capability of morphotype conversion in P. tricornutum and its relevance in acclimation to changing environmental conditions. PMID- 21600846 TI - Is it a descending or an ascending artery? PMID- 21600847 TI - Comparison of atrial and brain natriuretic peptide for the assessment of mitral stenosis. AB - BACKGROUND: Accurate evaluation of the functional consequences of mitral stenosis (MS) can be difficult. The aim of this study was to evaluate the relationship between both atrial (ANP) and brain natriuretic peptides (BNP) and symptoms, exercise capacity and echocardiographic measures of MS severity. METHODS: Thirty patients with moderate to severe MS and 14 normal controls underwent clinical assessment, exercise stress echocardiography, measurement of ANP and BNP and two years follow up for clinical events. RESULTS: BNP was higher in MS patients than controls (BNP 58 [IQR 34, 93] vs. 16 [14, 25], p < 0.0001). There was considerable overlap in exercise capacity and echocardiographic severity between asymptomatic and symptomatic patients. An increase in BNP was associated with a larger left atrial area index (r = 0.67, p < 0.0001), reduced mitral valve area (r = -0.38, p = 0.05) and higher resting pulmonary artery pressure (r = 0.47, p = 0.008). Increased BNP predicted lower treadmill exercise capacity (AUC = 0.82 [95% confidence interval 0.67, 0.97], p = 0.004), guideline criteria for intervention (AUC = 0.87 [0.74, 0.99], p = 0.006) and adverse events during follow up (AUC = 0.81 [0.64, 0.99], p = 0.03). Associations for ANP in general were similar but slightly weaker, and ANP did not provide additional predictive information to BNP. CONCLUSION: BNP may improve risk stratification of patients with MS, particularly when symptoms are equivocal. PMID- 21600848 TI - Recordings of consultations are beneficial in the transition from curative to palliative cancer care: a pilot-study in patients with oesophageal or head and neck cancer. AB - PURPOSE: There is reluctance in providing incurable cancer patients with recordings of their consultation. In this pilot-study, we explored the feasibility and utility of providing consultation recordings when patients are told a new diagnosis of non-curable cancer, and the impact of the recordings on quality of life and the openness to discuss cancer-related issues in the family. METHOD: Seventeen patients with a new diagnosis of incurable oesophageal or head and neck cancer were randomized to receive a CD (n = 10) or no CD (n = 7) of their consultation in which the diagnosis was told and the decision to provide only palliative care was discussed. Data were collected before consultation and 1 week and 1 month afterwards. After 1 month, patients allocated to the control group were offered to receiving the CD of their consultation as well. RESULTS: No major technical or procedural problems were encountered. Three-quarters of the patients appreciated receiving the CD, which was listened to by 8/10 patients and by 10/10 others in the CD group. After 1 month, two-thirds of the patients in the control group also asked to receive the CD. We found a trend towards a poorer quality of life but an improved openness to discuss cancer-related issues, in the CD group. CONCLUSION: The provision of a CD recording on the consultation in which the transition from a curative to a palliative care stage was communicated is feasible and was well-received by most cancer patients and their family. These findings require however verification in a study with a larger sample size. PMID- 21600849 TI - Effect of earlier initiation of antiretroviral treatment and increased treatment coverage on HIV-related mortality in China: a national observational cohort study. AB - BACKGROUND: Overall HIV mortality rates in China have not been reported. In this analysis we assess overall mortality in treatment-eligible adults with HIV and attempt to identify risk factors for HIV-related mortality. METHODS: We used data from the national HIV epidemiology and treatment databases to identify individuals aged 15 years or older with HIV who were eligible for highly active antiretroviral therapy between 1985 and 2009. Mortality rates were calculated in terms of person-years, with risk factors determined by Cox proportional hazard regression. Treatment coverage was calculated as the proportion of time that patients who were eligible for treatment received treatment, with risk factors for not receiving treatment identified by use of logistic regression. FINDINGS: Of 323,252 people reported as having HIV in China by the end of 2009, 145,484 (45%) were identified as treatment-eligible and included in this analysis. Median CD4 count was 201 cells per MUL (IQR 71-315) at HIV diagnosis and 194 cells per MUL (73-293) when first declared eligible for treatment. Overall mortality decreased from 39.3 per 100 person-years in 2002 to 14.2 per 100 person-years in 2009, with treatment coverage concomitantly increasing from almost zero to 63.4%. By 2009, mortality was higher and treatment coverage lower in injecting drug users (15.9 deaths per 100 person-years; 42.7% coverage) and those infected sexually (17.5 deaths per 100 person-years; 61.7% coverage), compared with those infected through plasma donation or blood transfusion (6.7 deaths per 100 person years; 80.2% coverage). The two strongest risk factors for HIV-related mortality were not receiving highly active antiretroviral therapy (adjusted hazard ratio 4.35, 95% CI 4.10-4.62) and having a CD4 count of less than 50 cells per MUL when first declared eligible for treatment (7.92, 7.33-8.57). INTERPRETATION: An urgent need exists for earlier HIV diagnosis and better access to treatment for injecting drug users and patients infected with HIV sexually, especially before they become severely immunosuppressed. FUNDING: The National Centre for AIDS/STD Control and Prevention of the Chinese Centre for Disease Control and Prevention. PMID- 21600850 TI - Rationale for pertussis booster vaccination throughout life in Europe. AB - Although the introduction of universal pertussis immunisation in infants has greatly reduced the number of reported cases in infants and young children, disease incidence has been increasing in adolescents and adults in recent years. This changing epidemiological pattern is probably largely attributable to waning immunity after natural infection or vaccination. Furthermore, improved diagnostic testing, active surveillance, changes in disease susceptibility, vaccine characteristics, and increased awareness of the disease might also be contributing factors. Susceptibility to pertussis in adolescents and adults results not only in direct morbidity in these age groups, but also poses a transmission risk to susceptible non-immune infants who are often too young to be vaccinated. Because vaccination schedules vary across Europe, we review the pertussis situation in this region and propose considerations for use of pertussis booster vaccinations at different ages to reduce individual morbidity and transmission from present rates and increase herd protection. PMID- 21600851 TI - HAART for HIV in China--much achieved, more to be done. PMID- 21600852 TI - Protein transduction for tolerance induction. PMID- 21600853 TI - Reduced surgical site infections in patients undergoing posterior spinal stabilization of traumatic injuries using vancomycin powder. AB - BACKGROUND CONTEXT: Despite improvements through the use of prophylactic systemic antibiotics, surgical site infections remain a significant problem in the treatment of traumatic spine injuries. Infection rates as high as 10% have been reported in this population. The impact on patients and cost of treating such infections is profound. Local delivery of antibiotics has been found to be efficacious in animal and human studies as an adjunct to systemic antibiotics in surgical site infection prophylaxis. PURPOSE: To evaluate the efficacy of using vancomycin powder in surgical sites to prevent infections. STUDY DESIGN: Retrospective case review. PATIENT SAMPLE: Patients who underwent posterior spine fusions for traumatic injuries over a 2-year period at a single academic center. OUTCOME MEASURES: Clinical outcome determined was the incidence of either superficial or deep postoperative wound infections. METHODS: A retrospective review of 110 patients with traumatic spine injuries treated with instrumented posterior spine fusions over a 2-year period at a single academic center was performed. One group (control group) received standard systemic prophylaxis only, whereas another (treatment group) received vancomycin powder in the surgical wound in addition to systemic prophylaxis. Patient demographics and perioperative information obtained included history of previous spine surgeries, substance use, diabetes, body mass index, level of injury, presence of neurologic deficit, operative time, and estimated blood loss. Incidence of infection was the primary outcome evaluated. RESULTS: The control (N=54) and treatment groups (N=56) were statistically similar. A statistically significant difference in infection rate was found between the treatment group (0%) and control group (13%, p=.02) without any adverse events. No adverse effects were noted from use of the vancomycin powder. CONCLUSIONS: The use of vancomycin powder in surgical wounds may significantly reduce the incidence of infection in patients with traumatic spine injuries treated with instrumented posterior spine fusion. Applying vancomycin powder to surgical wounds is a promising means of preventing costly and harmful postoperative wound infections in high-risk populations. PMID- 21600854 TI - Angiotensin II type 1 autoantibody induced hypertension during pregnancy is associated with renal endothelial dysfunction. AB - BACKGROUND: Previous investigations suggested that agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) might mediate a hypertensive response through dysregulation of the endothelin-1 system. AT1-AA induced hypertension was attenuated by the AT1 receptor and/or endothelin-1 type A receptor antagonists. OBJECTIVES: This study was undertaken to determine if AT1-AA induced hypertension was associated with renal endothelial dysfunction. METHODS: We compared the vascular reactivity of renal interlobar arteries from normal pregnant control rats and AT1-AA long-term infused pregnant rats in the presence and absence of endothelin type A (ET(A)) receptor antagonism. Renal endothelial function was tested using isolated renal interlobar arteries in a pressure myograph, which were exposed to acetylcholine or sodium nitroprusside. RESULTS: Vasodilatory responses to the endothelial-dependent agonist acetylcholine were impaired in AT1 AA rats (74 [10]%) compared with normal pregnant controls (95 [5]%, P < 0.05). In the presence of ET(A) receptor antagonism, no differences were observed between controls or the AT1-AA treated group with regard to endothelial-dependent (acetylcholine) relaxation. CONCLUSION: AT1-AA induced hypertension during pregnancy was associated with disparate renal endothelial responses to acetylcholine. The difference in renal vascular responses between AT1-AA and normal pregnant rats was abolished by ET(A) receptor blockade. PMID- 21600855 TI - "A case of mobile giant left atrial thrombus which vascularized with coronary arteries in severe mitral valve stenosis," published in Cardiovascular Revascularization Medicine 2010;11(2):71-138. PMID- 21600856 TI - Left anterior descending artery percutaneous coronary intervention from the right radial access via the left internal mammary artery: a case report. AB - BACKGROUND: Trans-radial access in coronary intervention has gained popularity as it grants advantages in patients with higher risk of haemorrhage, especially those with non-cardiac conditions and those treated with oral anticoagulant therapy. CASE REPORT: We report a case of percutaneous coronary intervention (PCI) of the left anterior descending (LAD) artery distal to left internal mammary artery (LIMA) anastomosis from the usually contraindicated right radial approach, in an actively bleeding patient affected by gastric cancer and chronic atrial fibrillation, and with no other available low-risk route. CONCLUSION: LAD trans-LIMA PCI via right radial access can be attempted in selected cases with suitable anatomy. PMID- 21600857 TI - Structural redox control in a 7Fe ferredoxin isolated from Desulfovibrio alaskensis. AB - The redox behaviour of a ferredoxin (Fd) from Desulfovibrio alaskensis was characterized by electrochemistry. The protein was isolated and purified, and showed to be a tetramer containing one [3Fe-4S] and one [4Fe-4S] centre. This ferredoxin has high homology with FdI from Desulfovibrio vulgaris Miyazaki and Hildenborough and FdIII from Desulfovibrio africanus. From differential pulse voltammetry the following signals were identified: [3Fe-4S](+1/0) (E(0')=-158+/ 5mV); [4Fe-4S](+2/+1) (E(0')=-474+/-5mV) and [3Fe-4S](0/-2) (E(0')=-660+/-5mV). The effect of pH on these signals showed that the reduced [3Fe-4S](0) cluster has a pK'(red)(')=5.1+/-0.1, the [4Fe-4S](+2/+1) centre is pH independent, and the [3Fe-4S](0/-2) reduction is accompanied by the binding of two protons. The ability of the [3Fe-4S](0) cluster to be converted into a new [4Fe-4S] cluster was proven. The redox potential of the original [4Fe-4S] centre showed to be dependent on the formation of the new [4Fe-4S] centre, which results in a positive shift (ca. 70mV) of the redox potential of the original centre. Being most [Fe-S] proteins involved in electron transport processes, the electrochemical characterization of their clusters is essential to understand their biological function. Complementary EPR studies were performed. PMID- 21600858 TI - Nucleotide excision repair in chromatin: damage removal at the drop of a HAT. AB - In an earlier review of our understanding of the mechanism of nucleotide excision repair (NER) we examined the process with respect to how it occurs in chromatin [1]. We described how much of our mechanistic understanding of NER was derived from biochemical studies that analysed the repair reaction in DNA substrates not representative of that which exists in the living cell. We pointed out that our efforts to understand how NER operates in chromatin had been hampered in part because of the well-known inhibition of NER that occurs when DNA is assembled into nucleosomes and used as the substrate to examine the repair reaction in vitro. Despite this technical bottleneck, we summarized the biochemical, genetic and cell-based studies which have provided insights into the molecular mechanism of NER in the cellular context. More recently, we revisited the topic of how UV induced DNA damage is repaired in chromatin. In this review we examined the commonly held view that depicts a struggle in which the DNA repair machinery battles to overcome the inhibitory effect of chromatin during the repair process. We suggested that in this interpretation of events, the DNA repair mechanisms might be described as 'tilting at windmills': fighting an imaginary foe [2]. We surmised that this scenario was overly simplistic, and we described an emerging picture in which the DNA repair process and chromatin remodeling were mechanistically linked and were in fact functioning cooperatively to organize the efficient removal of DNA damage from the genome. Here we discuss the latest findings, which contribute to the idea that DNA damage induced changes to chromatin represent an important way in which the DNA repair process is initiated and organized throughout the genome to promote the efficient removal of damage in response to UV radiation. PMID- 21600859 TI - Nucleotide excision repair of DNA: The very early history. AB - This article, taken largely from the book Correcting the Blueprint of Life: An Historical Account of the Discovery of DNA Repair Mechanisms, summarizes the very early history of the discovery of nucleotide excision repair. PMID- 21600860 TI - Modules, modularity and adaptation: Comment on "The emergence of modularity in biological systems" by Dirk M. Lorenz, Alice Jeng, Michael W. Deem. PMID- 21600861 TI - Perceptions of self in 3-5-year-old children: a preliminary investigation into the early emergence of body dissatisfaction. AB - The main objective of this study was to investigate normal weight and overweight preschool children's ability to understand conceptualizations of body image and their association with parental perceptions of their child's body. One hundred and forty-four children aged 3-5 years were interviewed (68 girls and 76 boys) regarding their body image and their satisfaction with such. Parents completed a questionnaire that probed socio-demographic characteristics as well as their perceptions of their child's body image. Results showed that (1) children's misperceptions corresponded to those held by their parents. Specifically, overweight children and their parents underestimated the child's body size. (2) Gender differences in body dissatisfaction were consistently observed and were similar to those seen in adolescents and adults. It was determined that children's inaccuracies were not a result of developmental limits, that is, the participants' inability to understand the concepts measured. PMID- 21600862 TI - Intra-abdominal femoral nerve reconstruction following excision during right hemicolectomy. AB - Iatrogenic femoral nerve injury is an uncommon but recognised complication of abdominal and gynaecological surgery. There have been several reported cases following colorectal surgery which specifically report transient femoral nerve neuropathies with variable but often full recovery. To our knowledge, this is the first documented case of femoral nerve reconstruction after iatrogenic resection during right hemicolectomy. We present a case report of complete femoral nerve transection following abdominal surgery and discuss our management. PMID- 21600863 TI - [How far to promote renal transplantation from living kidney donors?]. PMID- 21600864 TI - Genetic data from 15 STR loci for forensic individual identification and parentage analyses in UK domestic dogs (Canis lupus familiaris). AB - Eighteen STR loci and one sex determination locus present in the Finnzymes Canine 2.1 STR Multiplex Reagent Kit were screened in the UK dog population providing allele frequencies and population genetic parameters necessary for the application of STRs to forensic genetic casework. A total of 375 dogs were genotyped, including representative samples from each of twelve breeds used to evaluate Hardy-Weinberg equilibrium and calculate inter-population pairwise F(ST) values. Three loci were excluded from calculations of average random match probability due to deviations from Hardy-Weinberg Equilibrium or ambiguous genotyping. Random match probability based on fifteen STR loci and one sex locus was subsequently estimated to be 2.8 * 10(-17) for unrelated individuals across breeds. PMID- 21600865 TI - Ultrasound-guided botulinum toxin injections for treatment of drooling. AB - OBJECTIVES: To evaluate the efficacy of treatment of drooling by ultrasound guided botulinum toxin injection of the salivary glands and to determine the optimal modalities of this procedure. PATIENTS AND METHODS: This study is a retrospective review of patients treated for drooling by injection of 100 units of Botox((r)) into the parotid and submaxillary glands between 2002 and 2008. Efficacy was evaluated by a quality of life questionnaire six weeks after the injections. RESULTS: One hundred and eleven injection sessions were performed in 70 patients aged one to 84 years with a beneficial effect in 66% of cases. The most effective protocol was injection of 20 units of botulinum toxin into each submaxillary gland and 30 units of toxin into each parotid gland. CONCLUSION: The treatment of drooling by Botox((r)) injections into salivary glands is effective. The authors propose ultrasound-guided injection of both submaxillary glands and both parotid glands. These injections can be repeated in the case of recurrence of drooling. PMID- 21600866 TI - Primary sinonasal meningioma. AB - INTRODUCTION: Primary meningiomas of the sinonasal tract are rare tumors. Their positive diagnosis is difficult to establish. From one case observation, we report the clinical features, the diagnosis difficulties and the therapeutic modalities of primary meningioma of the sinonasal tract. CASE REPORT: A seventeen year-old girl consulted for a left unilateral nasal obstruction with progressive evolution without episodes of epistaxis, smell disorder or headaches over a year. Physical examination revealed a grayish polypoid tumor in the left nasal fossa. CT scan evidenced an isodense lesion of the left nasal fossa slightly enhanced pushing back the lateral nasal wall without invasion or intracranial connection. Biopsy was in favour of an inverted papilloma. The tumor was resected via endoscopic approach. Pathological examination established the diagnosis of meningothelial menigioma. The prognosis was favourable without recurrence after a six-month follow-up. CONCLUSION: The positive diagnosis of primary sinonasal meningioma is difficult to establish because of their infrequent occurrence in this ectopic site and of their non-specific clinical appearance. The final diagnosis rests on the histological examination. Immunohistochemical studies are helpful to establish the accurate diagnosis. Imaging confirms the primitive nature of these tumors. Prognosis is excellent after complete surgical extirpation without the necessity of adjuvant therapy. PMID- 21600867 TI - Diagnostic challenges of nonalcoholic fatty liver disease (NAFLD) in children of normal weight. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is generally regarded as affecting the overweight or obese. Though previously reported, the notion that NAFLD occurs in the presence of normal body weight (adult BMI<25) is unfamiliar in adults and problematic in children. Normal-body-weight NAFLD accounts for approximately 15% of all NAFLD and may be more prevalent with certain ethnicities. CASE: We describe a case of a child who appeared to have normal-body weight NAFLD, on the basis of typical age of presentation, ultrasonographically evident hepatic steatosis and compatible liver histology, including a NAFLD activity score of 7, but was shown conclusively to have cystic fibrosis. Further we present a clinical strategy for diagnosis of childhood NAFLD, which would discriminate between this patient and actual normal-body-weight NAFLD children in our clinical practice. CONCLUSION: NAFLD requires affirmative diagnostic criteria and should not be merely a diagnosis of exclusion. PMID- 21600869 TI - Amphipathic-Lipid-Packing-Sensor interactions with lipids assessed by atomistic molecular dynamics. AB - The Amphipathic-Lipid-Packing-Sensor (ALPS) motif targets the protein ArfGAP1 to curved membranes during vesicle formation in the Golgi apparatus. ALPS specifically recognizes lipid packing defects due to the positive curvature of budding vesicles. In this work we assessed the microscopic interactions between ALPS and two phospholipid membranes at different degrees of lipid packing by explicit molecular dynamics (MD). Simulations were performed within loosely packed membranes composed of a mixture of dioleoylphosphatidylcholine (DOPC)/dioleoylglycerol (DOG) at a molar ratio 85:15. Some other simulations were performed in pure DOPC for which lipid packing is tighter. We show that the presence of DOG causes packing defects at the phosphate level and thereby modifies some properties of the bilayer. This leads to a higher hydration of the lipid headgroups. When embedded in a membrane with such defects, ALPS displays a higher degree of conformational flexibility than in a more packed membrane. We propose that lipid packing sensing by ALPS may have an entropic origin and that its flexibility is a key feature. PMID- 21600868 TI - Activity restriction and depression in medical patients and their caregivers: a meta-analysis. AB - Depression commonly occurs in conjunction with a variety of medical conditions. In addition, family members who care for patients with medical diagnoses often suffer from depression. Therefore, in addition to treating illnesses, physicians and other healthcare professionals are often faced with managing secondary mental health consequences. We conducted a systematic review and meta-analysis of the association between activity restriction and depression in medical patients and their caregivers. A total of 34 studies (N = 8053) documenting the relationship between activity restriction and depression were identified for the period between January 1980 and June 2010. Effect sizes were calculated as Pearson r correlations using random-effects models. The correlation between activity restriction and depression was positive and of large magnitude (r = 0.39; 95% CI, .34-0.44). Activity restriction was most strongly correlated with depression in medical patients (r = 0.45; 95% CI, 0.42-0.48), followed by caregivers (r = 0.34; 95% CI, 0.28-0.41) and community-dwelling adults (r = 0.28; 95% CI, 0.25-0.31). Activity restriction associated with medical conditions is a significant threat to well-being and quality of life, as well as to the lives of their caregivers. Assessment and treatment of activity restriction may be particularly helpful in preventing depression. PMID- 21600870 TI - Structural and functional analysis of critical amino acids in TMVI of the NHE1 isoform of the Na+/H+ exchanger. AB - The mammalian Na(+)/H(+) exchanger isoform 1 (NHE1) resides on the plasma membrane and exchanges one intracellular H(+) for one extracellular Na(+). It maintains intracellular pH and regulates cell volume, and cell functions including growth and cell differentiation. Previous structural and functional studies on TMVI revealed several amino acids that are potentially pore lining. We examined these and other critical residues by site-directed mutagenesis substituting Asn227->Ala, Asp, Arg; Ile233->Ala; Leu243->Ala; Glu247->Asp, Gln; Glu248->Asp, Gln. Mutant NHE1 proteins were characterized in AP-1 cells, which do not express endogenous NHE1. All the TMVI critical amino acids were highly sensitive to substitution and changes often lead to a dysfunctional protein. Mutations of Asn227->Ala, Asp, Arg; Ile233->Ala; Leu243->Ala; Glu247->Asp; Glu248 >Gln yielded significant reduction in NHE1 activity. Mutants of Asn227 demonstrated defects in protein expression, targeting and activity. Substituting Asn227->Arg and Ile233->Ala decreased the surface localization and expression of NHE1 respectively. The pore lining amino acids Ile233 and Leu243 were both essential for activity. Glu247 was not essential, but the size of the residue at this location was important while the charge on residue Glu248 was more critical to NHE1 function. Limited trypsin digestion on Leu243->Ala and Glu248->Gln revealed that they had increased susceptibility to proteolytic attack, indicating an alteration in protein conformation. Modeling of TMVI with TMXI suggests that these TM segments form part of the critical fold of NHE1 with Ile233 and Leu465 of TMXI forming a critical part of the extracellular facing ion conductance pathway. PMID- 21600871 TI - Spectroscopic analysis of the intrinsic chromophores within small multidrug resistance protein SugE. AB - Small multidrug resistance (SMR) protein family member, SugE, is an integral inner membrane protein that confers host resistance to antiseptic quaternary cation compounds (QCC). SugE studies generally focus on its resistance to limited substrates in comparison to SMR protein EmrE. This study examines the conformational characteristics of SugE protein in two detergents, sodium dodecyl sulphate (SDS) and dodecyl maltoside (DDM), commonly used to study SMR proteins. The influence of cetylpyridinium (CTP) and cetrimide (CET) using SugE aromatic residues (4W, 2Y, 1F) as intrinsic spectroscopic probes was also determined. Organically extracted detergent solubilized Escherichia coli SugE protein was examined by SDS-Tricine PAGE and various spectroscopic techniques. SDS-Tricine PAGE analysis of SugE in either detergent demonstrates the protein predominates as a monomer but also dimerizes in SDS. Far-UV region circular dichroism (CD) analysis determined that the overall alpha-helix content SugE in SDS and DDM was almost identical and unaltered by QCC. Near-UV region CD, fluorescence, and second-derivative ultraviolet absorption (SDUV) indicated that only DDM-SugE promoted hydrophobic environments for its Trp and Tyr residues that were perturbed by QCC addition. This study identified that only the tertiary structure of SugE protein in DDM is altered by QCC. PMID- 21600872 TI - The effect of oxycholesterols on thermo-induced membrane dynamics. AB - The effect of temperature change(s) on the dynamics of giant unilamellar vesicles containing oxidized and non-oxidized cholesterol was investigated and characterized. We have demonstrated that (i) major cholesterol auto-oxidation products, 7beta-hydroxycholesterol (7beta) and 7-ketocholesterol (7keto), rendered vesicles more responsive to temperature changes; (ii) 7keto imparted greater thermo-induced membrane dynamics than 7beta; (iii) 7beta and 7keto vesicles synergistically were more thermo-responsive than the individual oxysterols; (iv) the thermo-responsiveness of 7keto-containing vesicles was equivalent to that of 25 hydroxycholesterol (25OH)-containing vesicles; and (v) we have characterized the observed membrane dynamics. The results provide a new plausible mechanism: oxidative-stressed membranes in conjunction with temperature change induce membrane dynamics. These findings improve the mechanisms reported previously that attributed the induced dynamics solely to membrane oxidation. PMID- 21600873 TI - Identification of Ski as a target for Aurora A kinase. AB - Ski is a negative regulator of the transforming growth factor-beta and other signalling pathways. The absence of SKI in mouse fibroblasts leads to chromosome segregation defects and genomic instability, suggesting a role for Ski during mitosis. At this stage, Ski is phosphorylated but to date little is known about the kinases involved in this process. Here, we show that Aurora A kinase is able to phosphorylate Ski in vitro. In vivo, Aurora A and Ski co-localized at the centrosomes and co-immunoprecipitated. Conversely, a C-terminal truncation mutant of Ski (SkiDelta491-728) lacking a coiled-coil domain, displayed decreased centrosomal localization. This mutant no longer co-immunoprecipitated with Aurora A in vivo, but was still phosphorylated in vitro, indicating that the Ski-Aurora A interaction takes place at the centrosomes. These data identify Ski as a novel target of Aurora A and contribute to an understanding of the role of these proteins in the mitotic process. PMID- 21600874 TI - Steatosis induced by the accumulation of apolipoprotein A-I and elevated ROS levels in H-ras12V transgenic mice contributes to hepatic lesions. AB - Hepatic steatosis is considered to have an important impact on liver tumorigenesis, despite a lack of clear experimental evidence. Histopathological analysis of H-ras12V transgenic mice showed liver lesions on a steatosis background had significantly higher incidence than on a non-steatosis background. Further investigation showed that apolipoprotein A-I was elevated and accumulated around fatty vacuoles. This elevated level of apolipoprotein A-I was coupled with an elevated level of H-ras12V protein and ROS. In conclusion, our results suggest that the expression of H-ras12V oncogene leads to elevated levels of ROS and apolipoprotein A-I that contribute to steatosis. The steatosis, in turn, promotes the development of hepatic lesions induced by H-ras12V oncogene. PMID- 21600875 TI - Downregulation of cPLA2gamma expression inhibits EGF-induced chemotaxis of human breast cancer cells through Akt pathway. AB - Phospholipids play an important role in mediating cell migration. In the present study, we investigated the role of cPLA(2)gamma in chemotaxis of human breast cancer cells. Inhibition of cPLA(2)gamma expression by small interference RNA severely inhibits EGF-induced chemotaxis in a dose-dependent manner in MDA-MB 231, MCF-7, T47D and ZR-75-30 cells. Furthermore, silencing cPLA(2)gamma expression also impaired directional migration, adhesion and invasion in MDA-MB 231 cells. In addition, we investigated the molecular mechanism by which cPLA(2)gamma regulated migration. Knockdown of cPLA(2)gamma suppressed the phosphorylation of Akt at both Thr308 and Ser473. Phosphorylation of PKCzeta, downstream of Akt, was also dampened. Knockdown of cPLA(2)gamma also impaired the phosphorylation of integrin beta1 and cofilin, key regulators of cell adhesion and actin polymerization, respectively. Taken together, our results suggest that cPLA(2)gamma plays an important role in cancer cell chemotaxis. PMID- 21600876 TI - Differential effects of miR-34c-3p and miR-34c-5p on SiHa cells proliferation apoptosis, migration and invasion. AB - MicroRNAs (miRNA) regulate expression of several genes associated with human cancer. Here, we analyzed the function of miR-34c, an effector of p53, in cervical carcinoma cells. Expression of either miR-34c-3p or miR-34c-5p mimics caused inhibition of cell proliferation in the HPV-containing SiHa cells but not in other cervical cells irrespective of tumorigenicity and HPV content. These results suggest that SiHa cells may lack of regulatory mechanisms for miR-34c. Monolayer proliferation results showed that miR-34c-3p produced a more pronounced inhibitory effect although both miRNAs caused inhibition of anchorage independent growth at similar extent. However, ectopic expression of pre-miR-34c-3p, but not pre-miR-34c-5p, caused S-phase arrest in SiHa cells triggering a strong dose dependent apoptosis. A significant inhibition was observed only for miR-34c-3p on SiHa cells migration and invasion, therefore implying alternative regulatory pathways and targets. These results suggest differential tumor suppressor roles for miR-34c-3p and miR-34c-5p and provide new insights in the understanding of miRNA biology. PMID- 21600877 TI - Pilus backbone protein PitB of Streptococcus pneumoniae contains stabilizing intramolecular isopeptide bonds. AB - Streptococcus pneumoniae type 2 pili are recently identified fimbrial structures extending from the bacterial surface and formed by polymers of the structural protein PitB. Intramolecular isopeptide bonds are a characteristic of the related pilus backbone protein Spy0128 of group A streptococci. Based on the identification of conserved residues in PitB, we predicted two intramolecular isopeptide bonds in PitB. Using a combination of tandem mass spectrometry and Edman sequencing, we show that these bonds were formed between Lys(63)-Asn(214) and Lys(243)-Asn(372) in PitB. Mutant proteins lacking the intramolecular isopeptide bonds retained the proteolytic stability observed with the wild type protein. However, absence of these bonds substantially decreased the melting temperature of the PitB-derivatives, indicating a stabilizing function of these bonds in PitB of the pneumococcal type 2 pilus. PMID- 21600878 TI - Inhibition of the Unfolded Protein Response by metformin in renal proximal tubular epithelial cells. AB - Metformin (Met), an AMP-activated protein kinase (AMPK) inducer, is primarily transported by organic cation transporters expressed at the surface of renal proximal tubular epithelial cells. However, the implication of Met in renal function remains poorly understood. Interestingly, AICAR, another AMPK inducer, has been shown to inhibit the Unfolded Protein Response (UPR) generated by tunicamycin in cardiomyocytes in an AMPK-kinase dependent fashion suggesting metformin may also block the UPR. In this work, we have examined the effect of metformin on the expression of UPR-related markers (GRP94 and CHOP) induced by glucosamine (GlcN), 2-deoxyglucose (2-DOG) and tunicamycin (TUNI) in renal proximal tubular epithelial cells and in murine mesangial cells. Met attenuated GRP94 and CHOP expression induced by GlcN and 2-DOG, but not TUNI only in renal epithelial cells, even though the AMPK activation was observed in both renal epithelial and mesangial cells. Met did not require the contribution of its AMPK kinase inducing activity to block UPR markers expression. This report has identified a novel inhibitory function of metformin on UPR, which may have a beneficial impact on kidney homeostatic function. PMID- 21600879 TI - Asperlin induces G2/M arrest through ROS generation and ATM pathway in human cervical carcinoma cells. AB - We exploited the biological activity of an antibiotic agent asperlin isolated from Aspergillus nidulans against human cervical carcinoma cells. We found that asperlin dramatically increased reactive oxygen species (ROS) generation accompanied by a significant reduction in cell proliferation. Cleavage of caspase 3 and PARP and reduction of Bcl-2 could also be detected after asperlin treatment to the cells. An anti-oxidant N-acetyl-L-cysteine (NAC), however, blocked all the apoptotic effects of asperlin. The involvement of oxidative stress in asperlin induced apoptosis could be supported by the findings that ROS- and DNA damage associated G2/M phase arrest and ATM phosphorylation were increased by asperlin. In addition, expression and phosphorylation of cell cycle proteins as well as G2/M phase arrest in response to asperlin were significantly blocked by NAC or an ATM inhibitor KU-55933 pretreatment. Collectively, our study proved for the first time that asperlin could be developed as a potential anti-cancer therapeutics through ROS generation in HeLa cells. PMID- 21600880 TI - Cation permeation through connexin 43 hemichannels is cooperative, competitive and saturable with parameters depending on the permeant species. AB - Kinetics of permeation through connexin 43-EGFP hemichannels (Cx43-EGFP HCs) were evaluated in divalent cation-free solutions, which enhance HC open probability and thus, allow measurements during initial velocity. Three cations that become fluorescent upon binding to intracellular nucleic acids [ethidium (Etd), propidium (Prd) and 4',6-diamidino-2-phenylindole (DAPI)] and Cx43-EGFP or Cx43 wild type HeLa cell transfectants (Cx43-EGFP- and Cx43-WT-HeLa cells, respectively) were used. Levels of Cx43-EGFP at the cell periphery and rate of dye uptake were directly related. The rate of uptake of each dye reached saturation consistent with a facilitated transport mechanism. Before saturation, the relation between rate of uptake and concentration of each dye was sigmoidal with Hill coefficients >1, indicating positive cooperativity of transport at low concentrations. The maximal rate of Etd uptake was not affected by the presence of DAPI and vice versa, but under each condition the apparent affinity constant of the main permeant molecule increased significantly consistent with competitive inhibition or competition for binding sites within the channel. Moreover, Cx43 EGFP and Cx43-WT HCs had similar permeability properties, indicating that EGFP bound to the C-terminal of Cx43 does not significantly alter the permeability of Cx43 HCs to positively charged molecules. Thus, competitive inhibition of permeation through hemichannels might contribute to cellular retention of essential molecules and/or uptake inhibition of toxic compounds. PMID- 21600881 TI - Gastric mucosal injury activates bFGF gene expression and triggers preferential translation of high molecular weight bFGF isoforms through CUG-initiated, non canonical codons. AB - Basic fibroblast growth factor (bFGF or FGF-2) is a pleiotropic growth factor that promotes growth of mesenchymal and epithelial cells, stimulates angiogenesis and neuroprotection. Moreover, exogenous bFGF by stimulating angiogenesis promotes healing of gastroduodenal ulcers and cardiac and brain injury. All these actions were demonstrated in regard to 18kDa bFGF isoform that is secreted by cells via an ER/Golgi-independent pathway and activates FGF receptors. However in some transformed and stressed cells and in some tissues (e.g. brain) the single copy bFGF gene encodes multiple gene products: 18 kDa and also higher molecular weight (HMW) bFGF isoforms: ~21 and ~22 kDa in rodents, and ~22, ~23 and ~24 kDa in humans. The biologic roles of these HMW bFGF isoforms in vivo remain unknown. In this study we demonstrated that in normal, uninjured gastric mucosa, bFGF is almost exclusively expressed as 18kDa isoform translated through a classical AUG (methionine) codon. In contrast, in injured gastric mucosa of rat, bFGF gene is preferentially translated to HMW bFGF isoforms through alternative CUG (leucine) initiation codon. Gastric mucosal injury caused in rats a significant increase in bFGF mRNA at 8 and 24h vs. normal mucosa and a significant increase in bFGF protein at 24-72h, mainly due to increased expression of ~21 and ~22 kDa HMW bFGF isoforms. This is first demonstration that gastric mucosal injury and repair triggers local activation of bFGF gene with preferential translation of HMW bFGF isoforms through a non-canonical CUG codon. This study uncovered CUG-initiated HMW bFGF translation as a novel regulatory mechanism operating in vivo during gastric injury repair. PMID- 21600882 TI - Transcriptional regulation of the Na+/H+ exchanger NHE3 by chronic exposure to angiotensin II in renal epithelial cells. AB - Angiotensin II (Ang II) exerts an acute bimodal effect on proximal tubule NHE3: while low doses stimulate the exchanger, high doses inhibit it. In the present study, we have investigated the chronic effects of Ang II on NHE3 expression and transcriptional regulation. Treatment of a tubular epithelial cell line, OKP, with Ang II 10(-11)M significantly increased NHE protein expression and mRNA levels, without evidence of bimodal effect. No change in mRNA half-life was detected, but transient transfection studies showed a significant increase in NHE3 promoter activity. Binding sites for Sp1/Egr-1 and AP2 transcription factors of the NHE3 proximal promoter were mutated and we observed that the Sp1/Egr-1 binding site integrity is necessary for Ang II stimulatory effects. Inhibition of cytochrome P450, PI3K, PKA and MAPK pathways prevented the Ang II stimulatory effect on the NHE3 promoter activity. Taking all the results together, our data reveal that chronic Ang II treatment exerts a stimulatory effect on NHE3 expression and promoter activity. The Ang II up-regulation of the NHE3 promoter activity appears to involve the Sp1/Egr-1 binding site and the interplay of several intracellular signaling pathways. PMID- 21600883 TI - Osteoblast-enriched membrane protein IFITM5 regulates the association of CD9 with an FKBP11-CD81-FPRP complex and stimulates expression of interferon-induced genes. AB - Osteoblasts are rich in interferon-inducible transmembrane protein 5 (IFITM5), the expression of which peaks around the early mineralization stage. This membrane protein directly associates with FK506 binding protein 11 (FKBP11). To examine the molecular function of IFITM5, we analyzed the protein interaction network around IFITM5-FKBP11. We found that FKBP11 was associated with CD81, which interacts with prostaglandin F2 receptor negative regulator (FPRP) and CD9; cumulatively, these associations result in the formation of a FKBP11-CD81 [FPRP/CD9] complex. However, CD9 dissociated from the complex following expression of Ifitm5, which also led to osteoblast-specific increased expression of 5 interferon-induced genes: bone marrow stromal cell antigen 2 (Bst2), interferon inducible protein 1 (Irgm), interferon-induced protein with tetratricopeptide repeats 3 (Ifit3), b(2)-microglobulin (B2m), and MHC (A.CA/J(H 2K-f) class I antigen gene. Induction of these genes likely resulted from dissociation of CD9 from the FKBP11-CD81-[FPRP/CD9] complex. Cumulatively, these results suggest that IFITM5 is involved not only in bone formation, but also in immune system activity. PMID- 21600884 TI - JWA regulates chronic morphine dependence via the delta opioid receptor. AB - Opioid dependence is correlated with the adaptive changes at the cellular level following chronic opioid use, and believed to be the main cause for the relapse of drug taking behavior of addicts. Despite decades of intensive studies, the underlying mechanisms of morphine dependence are still unclear. Here, we present evidence that JWA was induced by chronic morphine treatment in specific brain regions, and knockdown of JWA expression significantly reduced the withdrawal response to chronic morphine treatment in rats. We further demonstrated that the morphine induced DOR expression, while activation of DARPP-32 and MAP kinase was suppressed by JWA knockdown. Through an in vitro cell model of chronic morphine exposure, we also found that JWA is required for maintaining the stability of DOR via the ubiquitin-proteasome pathway. These observations suggest that JWA is directly involved in the regulation of chronic morphine dependence. PMID- 21600885 TI - Extracellular histone induces plasma hyaluronan-binding protein (factor VII activating protease) activation in vivo. AB - Plasma hyaluronan-binding protein (PHBP), an activator of factor VII and prourokinase, is a serine protease circulating as a single-chain proenzyme (pro PHBP). Pro-PHBP converts to the active two-chain form through autoproteolysis, and effectors that modulate autoactivation can regulate PHBP-mediated processes. Here, we show that histone promotes pro-PHBP autoactivation in vivo. Histone bound to pro-PHBP and promoted intermolecular pro-PHBP binding. Histone-mediated pro-PHBP activation in plasma leads to the formations of bradykinin and PHBP alpha(2)-antiplasmin complex as well as histone degradation. Pro-PHBP activation was observed in the circulation of mice after injection of histone or lipopolysaccharide, which induced septic response accompanying extracellular histone release. Our results suggest pathophysiological relevance of histone dependent pro-PHBP activation in hyperinflammatory process. PMID- 21600886 TI - Oligomerization and toxicity of Abeta fusion proteins. AB - This study has found that the Maltose binding protein Abeta42 fusion protein (MBP Abeta42) forms soluble oligomers while the shorter MBP-Abeta16 fusion and control MBP did not. MBP-Abeta42, but neither MBP-Abeta16 nor control MBP, was toxic in a dose-dependent manner in both yeast and primary cortical neuronal cells. This study demonstrates the potential utility of MBP-Abeta42 as a reagent for drug screening assays in yeast and neuronal cell cultures and as a candidate for further Abeta42 characterization. PMID- 21600887 TI - A cleavable signal peptide enhances cell surface delivery and heterodimerization of Cerulean-tagged angiotensin II AT1 and bradykinin B2 receptor. AB - Heterodimerization of the angiotensin II AT1 receptor with the receptor for the vasodepressor bradykinin, B2R, is known to sensitize the AT1-stimulated response of hypertensive individuals in vivo. To analyze features of that prototypic receptor heterodimer in vitro, we established a new method that uses fluorescence resonance energy transfer (FRET) and applies for the first time AT1-Cerulean as a FRET donor. The Cerulean variant of the green fluorescent protein as donor fluorophore was fused to the C-terminus of AT1, and the enhanced yellow fluorescent protein (EYFP) as acceptor fluorophore was fused to B2R. In contrast to AT1-EGFP, the AT1-Cerulean fusion protein was retained intracellularly. To facilitate cell surface delivery of AT1-Cerulean, a cleavable signal sequence was fused to the receptor's amino terminus. The plasma membrane-localized AT1 Cerulean resembled the native AT1 receptor regarding ligand binding and receptor activation. A high FRET efficiency of 24.7% between membrane-localized AT1 Cerulean and B2R-EYFP was observed with intact, non-stimulated cells. Confocal FRET microscopy further revealed that the AT1/B2 receptor heterodimer was functionally coupled to receptor desensitization mechanisms because activation of the AT1-Cerulean/B2R-EYFP heterodimer with a single agonist triggered the co internalization of AT1/B2R. Receptor co-internalization was sensitive to inhibition of G protein-coupled receptor kinases, GRKs, as evidenced by a GRK specific peptide inhibitor. In agreement with efficient AT1/B2R heterodimerization, confocal FRET imaging of co-enriched receptor proteins immobilized on agarose beads also detected a high FRET efficiency of 24.0%. Taken together confocal FRET imaging revealed efficient heterodimerization of co enriched and cellular AT1/B2R, and GRK-dependent co-internalization of the AT1/B2R heterodimer. PMID- 21600888 TI - Ginsenoside Rb1 and its metabolite compound K inhibit IRAK-1 activation--the key step of inflammation. AB - In the preliminary study, ginsenoside Rb1, a main constituent of the root of Panax ginseng (family Araliaceae), and its metabolite compound K inhibited a key factor of inflammation, nuclear transcription factor kappaB (NF-kappaB) activation, in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. When ginsenoside Rb1 or compound K were orally administered to 2,4,6 trinitrobenzene sulfuric acid (TNBS)-induced colitic mice, these agents inhibited colon shortening, macroscopic score, and colonic thickening. Furthermore, treatment with ginsenoside Rb1 or compound K at 20mg/kg inhibited colonic myeloperoxidase activity by 84% and 88%, respectively, as compared with TNBS alone (p<0.05), and also potently inhibited the expression of tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6, but increased the expression of IL 10. Both ginsenoside Rb1 and compound K blocked the TNBS-induced expressions of COX-2 and iNOS and the activation of NF-kappaB in mice. When ginsenoside Rb1 or compound K was treated in LPS-induced murine peritoneal macrophages, these agents potently inhibited the expression of the proinflammatory cytokines. Ginsenoside Rb1 and compound K also significantly inhibited the activation of interleukin-1 receptor-associated kinase-1 (IRAK-1), IKK-beta, NF-kappaB, and MAP kinases (ERK, JNK, and p-38); however, interaction between LPS and Toll-like receptor-4, IRAK-4 activation and IRAK-2 activation were unaffected. Furthermore, compound K inhibited the production of proinflammatory cytokines more potently than did those of ginsenoside Rb1. On the basis of these findings, ginsenosides, particularly compounds K, could be used to treat inflammatory diseases, such as colitis, by targeting IRAK-1 activation. PMID- 21600889 TI - Nicotinic acetylcholine receptors as therapeutic targets: emerging frontiers in basic research and clinical science--Editorial Comments. PMID- 21600890 TI - Determination of illicit drug cutoff values in a pain patient population. AB - BACKGROUND: When properly selected, cutoff levels minimize the reporting of false negative and false positive test results and allow the laboratory to accurately determine the prevalence of marijuana, cocaine and methamphetamine use. Selecting the ideal cutoff requires the collection of drug excretion data for a large patient population to determine the expected range of drug concentrations. The cutoff can then be set to capture a high percentage of positives at a concentration within the dynamic range of the method. We used quantitative urine drug excretion data to calculate cutoffs needed to best determine the presence of these illicit drugs in urine. METHODS: This study used liquid chromatography tandem mass spectrometry (LC-MS/MS) as the analytical method. The study group was the pain patient population which is well-known to have a significant incidence of use of these illicit drugs. Frequency distributions were plotted for the creatinine normalized and raw data for all positive specimens with values greater than or equal to the method limit of quantitation. A non-parametric 2.5% estimator was applied to each data set to establish the cutoff for each drug. RESULTS: The urinary excretion data for the three drugs studied suggest cutoffs of approximately 30 ng/ml (benzoylecgonine), 10 ng/ml (carboxy-THC), and 50 ng/ml (methamphetamine) to identify 97.5% of the users of these drugs in this population. CONCLUSIONS: Evaluation of urinary excretion data provides an objective method to validate the selection of cutoffs. These data provide additional support for the revised SAMHSA cutoffs which could increase the positivity rates for both benzoylecgonine and methamphetamine by 7%. PMID- 21600891 TI - Active glucagon-like peptide-1 (GLP-1): storage of human plasma and stability over time. PMID- 21600892 TI - A rapid and sensitive chemiluminescence immunoassay based on magnetic particles for squamous cell carcinoma antigen in human serum. AB - BACKGROUND: Because squamous cell carcinoma antigen (SCCa) quantification has demonstrated strong clinical potential, we describe a rapid and highly sensitive magnetic particle-based chemiluminescence immunoassay (CLIA) technique for assaying SCCa in serum. METHODS: Fluorescein isothiocyanate (FITC) and N (aminobutyl)-N-(ethylisoluminol) (ABEI) were used to label 2 different monoclonal antibodies of anti-SCCa. Both of the labeled antibodies combined with SCCa to form a sandwiched immunoreaction that was monitored by chemiluminescence (CL) detection. The magnetic particles (MPs) that were coated with anti-FITC antibody served as both the solid phase and the separator. The relevant variables involved in the CLIA signals were optimized and the parameters of the proposed method were evaluated. RESULTS: The method was linear to 20 ng/ml SCCa with a detection limit of 0.02 ng/ml. The intra-assay imprecision results [mean (CV)] were 1.12 ng/ml (3.81%), 2.58 ng/ml (2.53%) and [6.56 ng/ml (2.24%)]; the inter-assay imprecision results were [1.18 ng/ml (5.26%)], [2.49 ng/ml (4.75%)] and [6.61 ng/ml (4.29%)]. The average recoveries were between 97% and 104%. The relationship between the concentration of diluted SCCa and the dilution ratios gave a linear correlation coefficient of 0.9995. A correlation analysis against an established automated assay generated a slope of 0.9929 and an intercept of 0.0039 ng/ml (r=0.9964). CONCLUSIONS: The proposed method demonstrates an acceptable performance for quantifying serum SCCa and is suitable for the fabrication of a commercial kit with application in the automated CL analyzer. PMID- 21600893 TI - Evaluation of rapid point-of-care creatinine testing in the radiology service of a large academic medical center: impact on clinical operations and patient disposition. AB - BACKGROUND: Measurement of creatinine and calculation of the estimated glomerular filtration rate (eGFR) are widely employed to identify patients with chronic kidney disease who are at risk for contrast induced acute kidney injury and nephrogenic systemic fibrosis. However, patients may present for radiologic studies without a recent creatinine/eGFR necessitating cancelation of the study or performance of the scan without contrast. Both of these approaches are suboptimal. METHODS: We implemented a rapid whole blood point-of-care (POCT) creatinine test (iSTAT, Abbott Point-of-Care) in our radiology department and assessed the impact on clinical operations. RESULTS: Over a 7-month period a total of 3087 creatinine tests were performed. Overall 5.3% of patients presenting for scans (441/month) did not have a recent eGFR. An audit of 1 month of creatinine/eGFR values showed that 74% were normal permitting the scan to be performed without further consideration. Of the abnormal values 74% were performed with contrast and 26% without. Of note 78% of patients with an abnormal eGFR had a normal creatinine value. The cost of the POC test was $10.06 compared to a cost of $5.32 (including phlebotomy) for a creatinine performed in the central laboratory. The added incremental cost for the POC test was therefore $4.74. CONCLUSIONS: Determining the cost effectiveness of the rapid test is extremely challenging because the analysis would need to take many complex factors into consideration including the effect on workflow in the radiology department, the clinical impact of more timely scans, the clinical and financial consequences of performing scans with or without contrast and the impact on revenues complicated by differential reimbursement rates and payor mix. However, given the benefits of the test on radiology operations and on the quality and timeliness of care it appears that the POCT test is cost effective and improves clinical operations. PMID- 21600895 TI - Onecut is a direct neural-specific transcriptional activator of Rx in Ciona intestinalis. AB - Retinal homeobox (Rx) genes play a crucial and conserved role in the development of the anterior neural plate of metazoans. During chordate evolution, they have also acquired a novel function in the control of eye formation and neurogenesis. To characterize the Rx genetic cascade and shed light on the mechanisms that led to the acquisition of this new role in eye development, we studied Rx transcriptional regulation using the ascidian, Ciona intestinalis. Through deletion analysis of the Ci-Rx promoter, we have identified two distinct enhancer elements able to induce Ci-Rx specific expression in the anterior part of the CNS and in the photosensory organ at tailbud and larva stages. Bioinformatic analysis highlighted the presence of two Onecut binding sites contained in these enhancers, so we explored the role of this transcription factor in the regulation of Ci-Rx. By in situ hybridization, we first confirmed that these genes are co expressed in the same cells. Through a series of in vivo and in vitro experiments, we then demonstrated that the two Onecut sites are responsible for enhancer activation in Ci-Rx endogenous territories. We also demonstrated in vivo that Onecut misexpression is able to induce ectopic activation of the Rx promoter. Finally, we demonstrated that Ci-Onecut is able to promote Ci-Rx expression in the sensory vesicle. Together, these results support the conclusion that in Ciona embryogenesis, Ci-Rx expression is under the control of the Onecut transcription factor and that this factor is necessary and sufficient to specifically activate Ci-Rx through two enhancer elements. PMID- 21600894 TI - Pax3 is essential for normal cardiac neural crest morphogenesis but is not required during migration nor outflow tract septation. AB - Systemic loss-of-function studies have demonstrated that Pax3 transcription factor expression is essential for dorsal neural tube, early neural crest and muscle cell lineage morphogenesis. Cardiac neural crest cells participate in both remodeling of the pharyngeal arch arteries and outflow tract septation during heart development, but the lineage specific role of Pax3 in neural crest function has not yet been determined. To gain insight into the requirement of Pax3 within the neural crest, we conditionally deleted Pax3 in both the premigratory and migratory neural crest populations via Wnt1-Cre and Ap2alpha-Cre and via P0-Cre in only the migratory neural crest, and compared these phenotypes to the pulmonary atresia phenotype observed following the systemic loss of Pax3. Surprisingly, using Wnt1-Cre deletion there are no resultant heart defects despite the loss of Pax3 from the premigratory and migratory neural crest. In contrast, earlier premigratory and migratory Ap2alpha-Cre mediated deletion resulted in double outlet right ventricle alignment heart defects. In order to assess the tissue-specific contribution of neural crest to heart development, genetic ablation of neural crest lineage using a Wnt1-Cre-activated diphtheria toxin fragment-A cell-killing system was employed. Significantly, ablation of Wnt1-Cre-expressing neural crest cells resulted in fully penetrant persistent truncus arteriosus malformations. Combined, the data show that Pax3 is essential for early neural crest progenitor formation, but is not required for subsequent cardiac neural crest progeny morphogenesis involving their migration to the heart or septation of the outflow tract. PMID- 21600896 TI - Functional and morphological effects of beta-estradiol in eyes with N-methyl-D Aspartate-induced retinal neurotoxicity in rats. AB - Glutamate-mediated excitotoxicity, mainly induced by N-methyl-d-aspartate (NMDA) receptors, is known to cause retinal ganglion cell death in retinal ischemia, glaucoma, and several other retinal diseases. We evaluated the effects of beta estradiol (E2) against a single intravitreal injection of NMDA using a functional and morphological approach. Male rats were randomly divided into 3 treatment groups: (1) Control; (2) NMDA (intravitreal injection of 5 mM NMDA); and (3) NMDA + E2 (intravitreal injection of 5 mM NMDA and pretreatment with subcutaneous E2 implantation). Seven days after NMDA injection, full-field electroretinograms (ERGs) and quantitative morphological analyses using transverse sections of the retina were conducted. In the NMDA group, full-field ERGs showed reductions in the amplitudes of the negative-scotopic threshold response, rod response b-wave, oscillatory potentials, flicker response second b-wave and cone response b-wave. Morphological evaluations of transverse sections of the retina demonstrated a reduction in the thickness of the inner plexiform layer, increases in the thickness of the outer plexiform and outer nuclear layers, and a loss of cells in the ganglion cell layer. In the NMDA + E2 group, pretreatment with E2 prevented the aggravations in the amplitudes of the ERGs except for oscillatory potential 2 (OP2); however, no morphological differences between the NMDA and NMDA + E2 groups were seen. These findings indicate that E2 can protect retinal function against NMDA-induced neurotoxicity. In addition, these indications suggested that the effect of E2 may have therapeutic benefits in NMDA related diseases, such as retinal ischemia and glaucoma. PMID- 21600897 TI - Inhibition of unfolding and aggregation of lens protein human gamma D crystallin by sodium citrate. AB - Cataract affects 1 in 6 Americans over the age of 40, and represents a global health problem. Mature onset cataract is associated with the aggregation of partially unfolded or damaged proteins in the lens, which accumulate as an individual ages. Currently, surgery is the primary effective treatment for cataract. As an alternative preventive approach, small molecules have been suggested as potential therapeutic agents. In this work, we study the effect of sodium citrate on the stability of Human gammaD Crystallin (HgammaD-Crys), a structural protein of the eye lens, and two cataract-related mutants, L5S HgammaD Crys and I90F HgammaD-Crys. In equilibrium unfolding-refolding studies, the presence of 250 mM sodium citrate increased the transition midpoint of the N terminal domain (N-td) of WT HgammaD-Crys and L5S HgammaD-Crys by 0.3 M GuHCl, the C-terminal domain (C-td) by 0.6 M GuHCl, and the single transition of I90F HgammaD-Crys by 0.4 M GuHCl. In kinetic unfolding reactions, sodium citrate stabilization effect was observed only for the mutant I90F HgammaD-Crys. In the presence of citrate, a kinetic unfolding intermediate of I90F HgammaD-Crys was observed, which was not populated in the absence of citrate. The rates of aggregation were measured using solution turbidity. Sodium citrate demonstrated negligible effect on rate of aggregation of WT HgammaD-Crys, but considerably slowed the rate of aggregation of both L5S HgammaD-Crys and I90F HgammaD-Crys. The presence of sodium citrate dramatically slowed refolding of WT HgammaD-Crys and I90F HgammaD-Crys, but had a significantly smaller effect on the refolding of L5S HgammaD-Crys. The differential stabilizing effect of sodium citrate suggests that the ion is binding to a partially unfolded conformation of the C-td, but a solution-based Hofmeister effect cannot be eliminated as a possible explanation for the effects observed. These results indicate that assessment of potential anti-cataract agents needs to include effects on the unfolding and aggregation pathways, as well as the native state. PMID- 21600898 TI - Insight from genome-wide association studies in rheumatoid arthritis and multiple sclerosis. AB - Autoimmune diseases are caused by multiple genes and environmental effects. In addition, genetic contributions and the number of associated genes differ among different diseases and ethnic populations. Genome-wide association studies (GWAS) on rheumatoid arthritis (RA) and multiple sclerosis (MS) show that these diseases share many genetic factors. Recently, in addition to the major histocompatibility complex (MHC) gene, other genetic loci have been found to be associated with the risk for autoimmune diseases. This review focuses on the search for genetic variants that influence the susceptibility to RA and MS as typical autoimmune diseases and discusses the future of GWAS. PMID- 21600899 TI - Activation of the receptor NKG2D leads to production of Th17 cytokines in CD4+ T cells of patients with Crohn's disease. AB - BACKGROUND & AIMS: The natural killer group 2 member D (NKG2D) is a stimulatory receptor expressed on a subset of mucosal and peripheral CD4+ T cells in patients with Crohn's disease (CD) and other inflammatory diseases. Ligand activation of NKG2D in patients induces CD4+ T cells to release T-helper (Th) 1 cytokines and become cytotoxic. We investigated the Th17 cytokines produced by T cells that express NKG2D in blood and intestinal mucosa samples from patients with CD. METHODS: We isolated CD4+ T cells from peripheral blood and lamina propria samples of patients with CD or ulcerative colitis (UC) and healthy individuals (controls). We analyzed the phenotype and functions of the CD4+NKG2D+ T cells and the cytokines they produce in response to NKG2D stimulation. RESULTS: In patients with CD, CD4+ T cells that express NKG2D produced high levels of interleukin (IL) 17 and IL-22 and expressed high levels of CCR6, the IL-23 receptor, CD161, and RORC (a transcription factor that regulates expression of Th17 cytokines). CD4+ T cells that produced IL-17 expressed high levels of NKG2D and CD161. Costimulation of NKG2D and the T-cell receptor (TCR) significantly increased production of IL 17 and tumor necrosis factor alpha by CD4+ T cells, compared with activation of only the TCR. CD4+NKG2D+ T cells also responded to Th17 polarization. CONCLUSIONS: NKG2D is a functional marker of CD4+ T cells that produce IL-17 in patients with CD, via costimulation of the TCR and NKG2D. Reagents developed to block NKG2D might reduce gastrointestinal inflammation in patients with CD. PMID- 21600900 TI - Involvement of 4E-BP phosphorylation in embryonic development of the silkworm, Bombyx mori. AB - Phosphorylation of the translational repressor 4E-binding protein (4E-BP) plays a critical role in regulating the overall translation levels in cells. In the present study, we investigated 4E-BP phosphorylation of Bombyx mori eggs by an immunoblot analysis of a conserved phospho-specific antibody to 4E-BP and demonstrated its role during embryonic development. When HCl treatment was applied to diapause-destined eggs at 20 h after oviposition, a dramatic increase in the phosphorylation of 4E-BP occurred 5 min after treatment with HCl, and high phosphorylation levels were maintained throughout embryonic stage in HCl-treated eggs compared to those in diapause (control) eggs. When HCl treatment was applied to diapause eggs on day 10 after oviposition, no dramatic activation in 4E-BP phosphorylation occurred, indicating stage-specific effects of HCl treatment. In both non-diapause eggs and eggs whose diapause had been terminated by chilling of diapausing eggs at 5 degrees C for 70 days and then were transferred to 25 degrees C, high phosphorylation levels of 4E-BP were also detected. Moreover, 4E BP phosphorylation dramatically increased when dechorionated eggs were incubated in medium. The addition of rapamycin, a specific inhibitor of mammalian target of rapamycin (TOR) signaling, and LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, but not the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, U0126, dose-dependently inhibited 4E-BP phosphorylation in dechorionated eggs, indicating that PI3K/TOR signaling is an upstream signaling event involved in 4E-BP phosphorylation. Examination of 4E-BP gene expression levels showed no differences between treatments with HCl and water in the first hour after treatment, indicating that changes in phosphorylation of 4E-BP upon HCl treatment are mainly regulated at the post-transcriptional level. In addition, MAPK pathways and glycogen synthase kinase (GSK)-3beta phosphorylation were not significantly affected in the first hour after HCl treatment. These results demonstrate that the rapid phosphorylation of 4E-BP is an early signaling event in embryonic development in the eggs whose diapause initiation was prevented by HCl treatment, thus being involved in the embryonic development of B. mori. PMID- 21600901 TI - Alpha-1 antitrypsin inhibits caspase-1 and protects from acute myocardial ischemia-reperfusion injury. AB - Alpha-1-antitrypsin (AAT) possesses anti-inflammatory and tissue-protective properties. Here, we studied the effects of exogenously administered AAT on caspase-1 activity and on the outcome of ischemia-reperfusion injury (I/R) in a mouse model of acute myocardial infarction (AMI). Adult male mice underwent 30 min of coronary artery ligation followed by reperfusion and were randomly assigned to receive clinical-grade AAT or albumin at reperfusion. Infarct size was evaluated after 1 and 7 days. Caspase-1 activity was measured in homogenates of heart tissue. Left ventricular (LV) end-diastolic diameter (EDD) and end systolic diameter (ESD) were measured and LV fractional shortening (FS) and ejection fraction (EF) were calculated using transthoracic echocardiography. The effect of AAT on caspase-1 activity was determined in cultures of mouse HL-1 cardiomyocytes stimulated with LPS and triggered with nigericin or when HL-1 cells were exposed to simulated ischemia. AAT-treated mice had significantly smaller infarct sizes (-30% day 1 and -55% day 7) compared with mice treated with albumin. AAT treatment resulted in >90% reduction in caspase-1 activity in homogenates of hearts 24h after I/R. Seven days after AMI, AAT-treated mice exhibited a >90% smaller increase in LVEDD and LVESD and smaller reduction in LVEF. The increase in caspase-1 activity in HL-1 cells induced by LPS and nigericin or following exposure to simulated ischemia was reduced by >80% and AAT similarly reduced cell death by >50%. In conclusion, exogenous administration of clinical grade AAT reduces caspase-1 activity in the ischemic myocardium leading to preservation of viable myocardium and prevention of adverse cardiac remodeling. PMID- 21600902 TI - Regulating SR protein phosphorylation through regions outside the kinase domain of SRPK1. AB - SR proteins (splicing factors containing arginine-serine repeats) are essential splicing factors whose phosphorylation by the SR-specific protein kinase (SRPK) family regulates nuclear localization and mRNA processing activity. In addition to an N-terminal extension with unknown function, SRPKs contain a large, nonhomologous spacer insert domain (SID) that bifurcates the kinase domain and anchors the kinase in the cytoplasm through interactions with chaperones. While structures for the kinase domain are now available, constructs that include regions outside this domain have been resistant to crystallographic elucidation. To investigate the conformation of the full-length kinase and the functional role of noncatalytic regions, we performed hydrogen-deuterium exchange and steady state kinetic experiments on SRPK1. Unlike the kinase core, the large SID lacks stable, hydrogen-bonded structure and may provide an intrinsically disordered region for chaperone interactions. Conversely, the N-terminus, which positively regulates SR protein binding, adopts a stable structure when the insert domain is present and stabilizes a docking groove in the large lobe of the kinase domain. The N-terminus and SID equally enhance SR protein turnover by altering the stability of several catalytic loop segments. These studies reveal that SRPK1 uses an N-terminal extension and a large, intrinsically disordered region juxtaposed to a stable structure to facilitate high-affinity SR protein interactions and phosphorylation rates. PMID- 21600903 TI - Rapamycin (sirolimus) protects against hypoxic damage in primary heart cultures via Na+/Ca2+ exchanger activation. AB - AIMS: Rapamycin (sirolimus) is an antibiotic that inhibits protein synthesis through mammalian targeting of rapamycin (mTOR) signaling, and is used as an immunosuppressant in the treatment of organ rejection in transplant recipients. Rapamycin confers preconditioning-like protection against ischemic-reperfusion injury in isolated mouse heart cultures. Our aim was to further define the role of rapamycin in intracellular Ca(2+) homeostasis and to investigate the mechanism by which rapamycin protects cardiomyocytes from hypoxic damage. MAIN METHODS: We demonstrate here that rapamycin protects rat heart cultures from hypoxic reoxygenation (H/R) damage, as revealed by assays of lactate dehydrogenase (LDH) and creatine kinase (CK) leakage to the medium, by MTT (3-[4,5-dimethylthiazol-2 yl]-2,5-diphenyltetrazolium bromide) measurements, and desmin immunostaining. As a result of hypoxia, intracellular calcium levels ([Ca(2+)](i)) were elevated. However, treatment of heart cultures with rapamycin during hypoxia attenuated the increase of [Ca(2+)](i). Rapamycin also attenuated (45)Ca(2+) uptake into the sarcoplasmic reticulum (SR) of skinned heart cultures in a dose- and time dependent manner. KB-R7943, which inhibits the "reverse" mode of Na(+)/Ca(2+) exchanger (NCX), protected heart cultures from H/R damage with or without the addition of rapamycin. Rapamycin decreased [Ca(2+)](i) following its elevation by extracellular Ca(2+) ([Ca(2+)](o)) influx, thapsigargin treatment, or depolarization with KCl. KEY FINDINGS: We suggest that rapamycin induces cardioprotection against hypoxic/reoxygenation damage in primary heart cultures by stimulating NCX to extrude Ca(2+) outside the cardiomyocytes. SIGNIFICANCE: According to our findings, rapamycin preserves Ca(2+) homeostasis and prevents Ca(2+) overload via extrusion of Ca(2+) surplus outside the sarcolemma, thereby protecting the cells from hypoxic stress. PMID- 21600904 TI - piRNAs, transposon silencing, and germline genome integrity. AB - Integrity of the germline genome is essential for the production of viable gametes and successful reproduction. In mammals, the generation of gametes involves extensive epigenetic changes (DNA methylation and histone modification) in conjunction with changes in chromosome structure to ensure flawless progression through meiotic recombination and packaging of the genome into mature gametes. Although epigenetic reprogramming is essential for mammalian reproduction, reprogramming also provides a permissive window for exploitation by transposable elements (TEs), autonomously replicating endogenous elements. Expression and propagation of TEs during the reprogramming period can result in insertional mutagenesis that compromises genome integrity leading to reproductive problems and sporadic inherited diseases in offspring. Recent work has identified the germ cell associated PIWI Interacting RNA (piRNA) pathway in conjunction with the DNA methylation and histone modification machinery in silencing TEs. In this review we will highlight these recent advances in piRNA mediated regulation of TEs in the mouse germline, as well as mention the repercussions of failure to properly regulate TEs. PMID- 21600905 TI - Cortical morphology of visual creativity. AB - BACKGROUND AND OBJECTIVE: The volume of cortical tissue devoted to a function often influences the quality of a person's ability to perform that function. Up to now only white matter correlates of creativity have been reported, and we wanted to learn if the creative visuospatial performance on the figural Torrance Test of Creative Thinking (TTCT) is associated with measurements of cerebral gray matter volume in the regions of the brain that are thought to be important in divergent reasoning and visuospatial processing. METHODS: Eighteen healthy college educated men (mean age=40.78; 15 right-handers) were recruited (via advertisement) as participants. High-resolution MRI scans were acquired on a 1.5T MRI scanner. Voxel-based morphometry regression analyses of TTCT to cortical volume were restrained within the anatomic regions identified. RESULTS: One significant positive focus of association with TTCT emerged within the right parietal lobe gray matter (MNI coordinates: 44, -24, 63; 276 voxels). CONCLUSIONS: Based on theories of parietal lobe function and the requirements of the TTCT, the area observed may be related due to its dominant role in global aspects of attention and visuospatial processing including the capacity for manipulating spatial representations. PMID- 21600906 TI - Hormonal and behavioral responses to stress in lactating and non-lactating female common marmosets (Callithrix jacchus). AB - In several mammalian species, hypothalamic-pituitary-adrenal (HPA) and behavioral responses to stressors are down-regulated in lactating females, possibly preventing stress-induced disruptions of maternal care. Experimental elevations of HPA axis hormones have been found to inhibit maternal behavior in lactating common marmoset monkeys (Callithrix jacchus), raising the question of whether lactating female marmosets also have blunted endogenous responses to stress. Therefore, we compared HPA and behavioral responses to standardized stressors in reproductively experienced female common marmosets that were undergoing ovulatory cycles and that either were (N=7) or were not lactating (N=8). Each marmoset underwent (1) a restraint stressor during the early follicular phase of the ovarian cycle (approximately 5 weeks postpartum for lactating females) and (2) exposure to a simulated hawk predator during the early to mid-luteal phase (approximately 7 weeks postpartum for lactating females). Lactating females were tested in the presence of one of their infants. Blood samples were collected before, during, and immediately after each test for determination of plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations. Both stressors caused significant elevations in plasma ACTH and cortisol levels, and significant decreases in cortisol:ACTH ratios; however, lactating and non-lactating females showed no significant differences in their endocrine or behavioral responses to either stressor, or in baseline ACTH or cortisol levels. These findings suggest that in contrast to several other mammalian species, lactating female marmosets maintain full behavioral and HPA responsiveness to stress, at least in the presence of their infants. PMID- 21600907 TI - Biliary bile acids in birds of the Cotingidae family: taurine-conjugated (24R,25R)-3alpha,7alpha,24-trihydroxy-5beta-cholestan-27-oic acid and two epimers (25R and 25S) of 3alpha,7alpha-dihydroxy-5beta-cholestan-27-oic acid. AB - Three C(27) bile acids were found to be major biliary bile acids in the capuchinbird (Perissocephalus tricolor) and bare-throated bellbird (Procnias nudicollis), both members of the Cotingidae family of the order Passeriformes. The individual bile acids were isolated by preparative RP-HPLC, and their structures were established by RP-HPLC, LC/ESI-MS/MS and NMR as well as by a comparison of their chromatographic properties with those of authentic reference standards of their 12alpha-hydroxy derivatives. The most abundant bile acid present in the capuchinbird bile was the taurine conjugate of C(27) (24R,25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestan-27-oic acid, a diastereomer not previously identified as a natural bile acid. The four diastereomers of taurine conjugated (24xi,25xi)-3alpha,7alpha,24-trihydroxy-5beta-cholestan-27-oic acid could be distinguished by NMR and were resolved by RP-HPLC. The RRT of the diastereomers (with taurocholic acid as 1.0) were found to be increased in the following order: (24R,25R)<(24S,25R)<(24S,25S)<(24R,25S). Two epimers (25R and 25S) of C(27) 3alpha,7alpha-dihydroxy-5beta-cholestan-27-oic acid were also present (as the taurine conjugates) in both bird species. Epimers of the two compounds could be distinguished by their NMR spectra and resolved by RP-HPLC with the (25S)-epimer eluting before the (25R)-epimer. Characterization of the taurine-conjugated (24R,25R)-3alpha,7alpha,24-trihydroxy-5beta-cholestan-27-oic acid and two epimers (25R and 25S) of 3alpha,7alpha-dihydroxy-5beta-cholestan-27 oic acid should facilitate their detection in peroxisomal disease and inborn errors of bile acid biosynthesis. PMID- 21600908 TI - An early single dose of progesterone agonist attenuates endogenous progesterone surge and reduces ovulation rate in immature rat model of induced ovulation. AB - Inhibition of preovulatory synthesis and action of progesterone impairs ovulation in rodents. We evaluated effects of supplementation of exogenous progesterone on human chorionic gonadotropin (hCG)-induced ovulatory response in immature rats. Equine CG-primed mature follicles responded to hCG with induction of immunoreactive steroidogenic acute regulatory protein (StAR) mainly in thecal layers and a transient enhancement in progesterone synthesis peaking at 6h after hCG (hCG6h). A single dose of natural progesterone or a synthetic agonist (MP) at hCG0h both decreased ovulation rates in dose-dependent manners. MP was still effective when treated at hCG4h. Treatment with these agents at hCG0h reduced circulating progesterone and thecal expression of StAR at hCG6h. The treatments further attenuated induction of cyclooxygenase (COX)-2 in mural granulosa cells and ovarian prostaglandin (PG) E(2) level at hCG8h. We also found a significant reduction in bromo-deoxyuridine incorporation by mural granulosa cells. Obtained results show that the early treatment with exogenous progesterone agonist caused attenuated amplitude of endogenous progesterone surge, reduced COX-2/PGE(2) system, dysregulated mitosis of granulosa cells, and decreased oocytes release. We suggest that optimal progesterone synthesis and action are an early critical component of hCG-initiated ovulatory cascade that regulates biochemical function of granulosa cells. PMID- 21600909 TI - Kinetics of the inhibitory interaction of organophosphorus neuropathy inducers and non-inducers in soluble esterases in the avian nervous system. AB - Some published studies suggest that low level exposure to organophosphorus esters (OPs) may cause neurological and neurobehavioral effects at long term exposure. These effects cannot be explained by action on known targets. In this work, the interactions (inhibition, spontaneous reactivation and "ongoing inhibition") of two model OPs (paraoxon, non neuropathy-inducer, and mipafox, neuropathy-inducer) with the chicken brain soluble esterases were evaluated. The best-fitting kinetic model with both inhibitors was compatible with three enzymatic components. The amplitudes (proportions) of the components detected with mipafox were similar to those obtained with paraoxon. These observations confirm the consistency of the results and the model applied and may be considered an external validation. The most sensitive component (Ealpha) for paraoxon (11-23% of activity, I(50) (30 min)=9-11 nM) is also the most sensitive for mipafox (I(50) (30 min)=4 nM). This component is spontaneously reactivated after inhibition with paraoxon. The second sensitive component to paraoxon (Ebeta, 71-84% of activity; I(50) (30 min)=1216 nM) is practically resistant to mipafox. The third component (Egamma, 5-8% of activity) is paraoxon resistant and has I(50) (30 min) of 3.4 MUM with mipafox, similar to NTE (neuropathy target esterase). The role of these esterases remains unknown. Their high sensitivity suggests that they may either play a role in toxicity in low-level long-term exposure of organophosphate compounds or have a protective effect related with the spontaneous reactivation. They will have to be considered in further metabolic and toxicological studies. PMID- 21600910 TI - Purification and characterization of Ts15, the first member of a new alpha-KTX subfamily from the venom of the Brazilian scorpion Tityus serrulatus. AB - Voltage-gated potassium channel toxins (KTxs) are basic short chain peptides comprising 23-43 amino acid residues that can be cross-linked by 3 or 4 disulfide bridges. KTxs are classified into four large families: alpha-, beta-, gamma- and kappa-KTx. These peptides display varying selectivity and affinity for K(v) channel subtypes. In this work, a novel toxin from the Tityus serrulatus venom was isolated, characterized and submitted to a wide electrophysiological screening on 5 different subtypes of Na(V) channels (Na(V)1.4; Na(V)1.5; Na(V)1.6; Na(V)1.8 and DmNa(V)1) and 12 different subtypes of K(V) channels (K(V)1.1 - K(V)1.6; K(V)2.1; K(V)3.1; K(V)4.2; K(V)4.3; Shaker IR and ERG). This novel peptide, named Ts15, has 36 amino acids, is cross-linked by 3 disulfide bridges, has a molecular mass of 3956 Da and pI around 9. Electrophysiological experiments using patch clamp and the two-electrode voltage clamp techniques show that Ts15 preferentially blocks K(V)1.2 and K(V)1.3 channels with an IC50 value of 196 +/- 25 and 508 +/- 67 nM, respectively. No effect on Na(V) channels was observed, at all tested concentrations. Since Ts15 shows low amino acid identity with other known KTxs, it was considered a bona fide novel type of scorpion toxin. Ts15 is the unique member of the new alpha-Ktx21 subfamily and therefore was classified as alpha-Ktx21.1. PMID- 21600911 TI - Nicotine-induced conditioned place preference in adolescent rats. AB - A number of clinical reports have noted that women are more vulnerable to tobacco abuse than men, and adolescent females are especially vulnerable to nicotine addiction. Conditioned place preference (CPP) is a widely used technique for determining the rewarding effects of drugs with abuse potential in animal models. Several studies have reported that nicotine was ineffective in eliciting CPP in rats; while others have observed conditioned place aversion (CPA) rather than preference for nicotine. One recent investigation established CPP in adolescent female rats, however at a reasonably high dose; while a second reported dose dependence of nicotine-induced CPP in male but not female rats. The present study was designed to determine the lowest dose necessary to induce CPP to nicotine in adolescent female rats. Nicotine-induced CPP was obtained at a subcutaneous dose of 0.03 mg/kg (salt content) using a biased conditioning paradigm. Higher doses produced aversion and lower doses provided no rewarding or aversive effects. CPP persisted for at least 3 weeks following conditioning in the absence of further nicotine treatment. In contrast with results from adolescent human females and males, age-matched male rats also evidenced CPP at this very low dose of nicotine. These results indicate that even a low dose of nicotine is reinforcing and addicting in both adolescent male and female rats and brings into question the suggestion that nicotine induces greater addicting capacity in adolescent girls than boys. PMID- 21600912 TI - Rapid delivery of cocaine facilitates acquisition of self-administration in rats: an effect masked by paired stimuli. AB - In general, faster infusions of cocaine are more likely to support behavior related to abuse than are slower infusions. However, some studies of cocaine self administration in rats have failed to support this finding, possibly because the effect was masked by other factors. One such factor may be the pairing of a stimulus with the infusion, a procedure that is known to facilitate acquisition of drug self-administration. We compared fast and slow infusions by allowing groups of rats to acquire cocaine self-administration at a dose of 1mg/kg/infusion, delivered over different durations (1.8 or 100 s). Two groups were trained with either short or long infusions paired with a visual stimulus change (lights off), and two other groups were trained with short or long durations but with no stimulus change. Both groups trained with a paired stimulus acquired cocaine self-administration. With no stimulus change, the rats trained with the 1.8-s infusion acquired cocaine self-administration at a rate comparable to the two groups that were trained with a paired stimulus. However, most rats in the group trained with the 100-s infusion that was not accompanied by a stimulus change failed to acquire cocaine self-administration. The stimulus itself did not support responding. These results indicate that infusing a given dose of cocaine over a longer duration reduces its ability to support self-administration, but drug-paired stimuli can partially mask this effect by enhancing the effectiveness of slow infusions. PMID- 21600913 TI - Acetaminophen modulation of hydrocodone reward in rats. AB - Abuse of prescription opioid analgesics in non-medical context has been on the rise over the past decade. The most commonly abused analgesic in this drug class consists of a combined formulation of hydrocodone and acetaminophen. The present study was aimed to determine the rewarding effects of hydrocodone, acetaminophen, and their combination using the conditioned place preference (CPP) paradigm. Using a 6-day CPP paradigm, rats were paired with hydrocodone (0.5, 1.0 or 5.0 mg/kg) or acetaminophen (50, 100 or 300 mg/kg) to determine whether the drugs given alone would produce a CPP. Rats conditioned with the highest dose of hydrocodone exhibited place preference, whereas rats conditioned with acetaminophen did not demonstrate place preference. In a second experiment, varying doses of hydrocodone and acetaminophen were combined to determine whether acetaminophen would enhance hydrocodone reward. Acetaminophen (100 mg/kg) enhanced the rewarding effects of hydrocodone (1mg/kg), although the effect was unique to this particular dose combination. Higher or lower doses of acetaminophen combined with hydrocodone did not alter hydrocodone CPP. The present findings suggest that acetaminophen has a limited potential of modulating the rewarding properties of hydrocodone in rats. PMID- 21600914 TI - Calorimetric analysis of gelatine-glycosaminoglycans blend system. AB - Gelatine is one of the most valuable natural polymers used for drug delivery applications. Gelatine-GAGs based composite system has been shown to act as good scaffolds for tissue engineering. The objective of the present study is to investigate the calorimetric properties of microporous gelatine-GAGs based blend, which were modified by co-crosslinking with a naturally occurring crosslinking agent genipin. The melting temperature (T(m)), enthalpy change (DeltaH(m)) and heat capacity change (DeltaC(p)) were systematically calculated over the experimentally observed systems using differential scanning calorimeter (DSC). The thermoporometry results suggest that the concentration of the glycosaminoglycans plays an important role in the pore size distribution of the blend matrices. The circular dichroism (CD) spectroscopy study, scanning electron microscopy (SEM) studies provide the valuable information about the structural features of the biodegradable blend that can be utilized for various biomedical applications. The results provide new insights into the thermal stability of blend and suggest potential strategies for its manipulation. PMID- 21600915 TI - Deletion of extra C-terminal segment and its effect on the function and structure of artemin. AB - Artemin acts as a molecular chaperone by protecting Artemia embryos undergoing encystment from damage, caused by heat or other forms of stress. According to the amino acid sequence alignment, although artemin shows a fair amount of homology with ferritin, it also contains an extra C-terminal. Analysis of the C-terminal extension of artemin model in previous studies has shown that there are some favorable interactions between this region and its surrounding cleft. In the current study we tried to investigate the role of this C-terminal in chaperone activity of artemin. This extra C-terminal (39 residues) was deleted and the truncated gene was cloned and expressed in Escherichia coli. According to in vivo chaperone-like activity studies, both full-length and C-terminal truncated artemin conferred thermotolerance on transfected E. coli cells. However, bacteria expressing truncated derivative of artemin was less resistant than those producing native artemin against heat. Moreover, the activity recovery on carbonic anhydrase (CA), as protein substrate, was less in the presence of truncated artemin than that of full-length artemin. The results demonstrated that C-terminal deletion decreases the ability of artemin for chaperone-like activity. Theoretical investigations showed that deletion of artemin C-terminal extension makes substantial structural alterations in a way that structural stability and overall integrity of artemin decrease. PMID- 21600916 TI - Cytocompatibility of electrospun nanofiber tubular scaffolds for small diameter tissue engineering blood vessels. AB - A tubular scaffold was fabricated by using electrospun polymer solution blends of pNSR32 (recombinant spider silk protein), PCL (polycaprolactone) and Gt (gelatin). The physicochemical properties and cytocompatibility of these scaffolds were investigated. Afterwards, the pNSR32/PCL/Gt tubular scaffold (inner diameter=3mm) showed high porosity of 86.2 +/- 2.9%, pore size of 2423 +/- 979nm and average fibre diameter of 166 +/- 85nm. Water uptake and contact angle of the scaffolds reached 112.0 +/- 4.4% and 45.7 +/- 13.7 degrees , respectively. SDRAECs (Sprague Dawley Rat Aortic Endothelial Cells) grew and proliferated well and phenotype could be maintained on the composite scaffolds after they had been cultured on the composite scaffolds for 7 days. Compared with pure PCL scaffolds a greater density of viable cells was seen on the composites, especially the pNSR32/PCL/Gt scaffolds. PMID- 21600917 TI - Thermal and chemical denaturation of the BRCT functional module of human 53BP1. AB - BRCTs are protein-docking modules involved in eukaryotic DNA repair. They are characterized by low sequence homology with generally well-conserved structure organization. In a considerable number of proteins, a pair of BRCT structural repeats occurs, connected with inter-BRCT linkers, variable in length, sequence and structure. Linkers may separate and control the relative position of BRCT domains as well as protect and stabilize the hydrophobic inter-BRCT interface region. Their vital role in protein function has been demonstrated by recent findings associating missense mutations in the inter-repeat linker region of the BRCT domain of BRCA1 (BRCA1-BRCT) to hereditary breast/ovarian cancer. The interaction of 53BP1 with the core domain of the p53 tumor suppressor involves the C-terminal BRCT repeat as well as the inert-BRCT linker of the tandem BRCT domain of 53BP1 (53BP1-BRCT). High-accuracy differential scanning calorimetry (DSC) and circular dichroism (CD) have been employed to characterize the heat induced unfolding of 53BP1-BRCT domain. The calorimetric results provide evidence for unfolding to an intermediate, only partly unfolded state, which, based on the CD results, retains the secondary structural characteristics of the native protein. A direct comparison with the corresponding thermal processes for BRAC1 BRCT and BARD1-BRCT provides evidence that the observed behavior is analogous to BRCA1-BRCT even though the two domains differ substantially in the linker structure. Moreover, chemical denaturation experiments of the untagged 53BP1-BRCT and comparison with BRCA1 and BARD1 BRCTs show that no clear association can be drawn between the structural organization of the inter-BRCT linkers and the overall stability of the BRCT domains. PMID- 21600918 TI - Different approaches of katira gum formulations for colon targeting. AB - The objective of the study is to compare the different formulations prepared by using gum, grafted gum and hydrogel of katira as a carrier for colon-specific drug delivery using in vitro methods with and without enzymes. Katira gum is naturally occurring polysaccharides containing mainly l-rhamnose and d-galactose sugar unit and small percent of d-galactouronic acid. Compared to grafted gum and hydrogel, all proportions of katira gum protect the drug from being released completely in the physiological environment of the stomach and small intestine. In vitro release studies in enzymes (Pectinex Ultra SP-L having galactouronidase activity) have demonstrated the susceptibility of katira gum to the colonic bacterial enzyme (galactouronidase activity from Pectinex Ultra SP-L) with a consequent drug release. It illustrates that katira gum, a natural polysaccharide may be suitable as a carrier for colon targeting. PMID- 21600920 TI - Receptor oligomerization: a pivotal mechanism for regulating chemokine function. AB - Since the first reports on chemokine function, much information has been generated on the implications of these molecules in numerous physiological and pathological processes, as well as on the signaling events activated through their binding to receptors. Despite these extensive studies, no chemokine-related drugs have yet been approved for use in patients with inflammatory or autoimmune diseases. This discrepancy between efforts and results has forced a re-evaluation of the chemokine field. We have explored chemokine receptor conformations at the cell surface and found that, as is the case for other G protein-coupled receptors, chemokine receptors are not isolated entities that are activated following ligand binding; rather, they are found as dimers and/or higher order oligomers at the cell surface, even in the absence of ligands. These complexes form organized arrays that can be modified by receptor expression and ligand levels, indicating that they are dynamic structures. The way in which these receptor complexes are stabilized modulates ligand binding, as well as their pharmacological properties and the signaling events activated. These conformations thus represent a mechanism that increases the broad variety of chemokine functions. Understanding these receptor interactions and their dynamics at the cell surface is thus critical for influencing chemokine function and could open up new possibilities for drug design. PMID- 21600921 TI - A new similarity measure for spike trains: sensitivity to bursts and periods of inhibition. AB - An important problem in neuroscience is that of constructing quantitative measures of the similarity between neural spike trains. These measures can be used, for example, to assess the reliability of the response of a single neuron to repeated stimulus presentations, or to uncover relationships in the firing patterns of multiple neurons in a population. While several similarity measures have been proposed, the extent to which they take into account various biologically important spike train features such as bursts of spikes, or periods of inactivity remains poorly understood. Here we compare these measures using tests specifically designed to assess the sensitivity to bursts and silent periods. In addition, we propose two new measures. The first is designed to detect periods of shared silence between spike trains, while the second is designed to emphasize the presence of common bursts. To assist researchers in determining which measure is best suited to their particular data analysis needs, we also show how these measures can be combined and how their parameters can be determined on the basis of physiologically relevant quantities. PMID- 21600922 TI - Chondroitinase activity can be transduced by a lentiviral vector in vitro and in vivo. AB - The bacterial enzyme chondroitinase ABC (ChABC), which cleaves chondroitin sulfate glycosaminoglycan chains, can degrade inhibitory scar tissue formed following spinal cord injury, thereby promoting axonal growth and regeneration. However, delivering the active enzyme for prolonged periods presents practical limitations. To overcome these problems, we prepared a lentiviral vector (LV) encoding chondroitinase AC (Chase) together with the green fluorescent protein (GFP) reporter (Chase/LV) and demonstrated its expression and enzymatic activity in vitro and in vivo. Neural precursor cells infected with Chase/LV expressed the GFP reporter at levels that increased dramatically with time in culture. Enzymatic activity from the supernatant of the infected cells was demonstrated by dot blot assay using an antibody that recognizes the digested form of CSPG and was compared with the bacterial ChABC enzyme. Chick DRG cultures plated adjacent to the CSPG border and incubated with supernatant from Chase/LV-infected cells showed neurites growing into the CSPG area, a response similar to that after treatment with ChABC. In contrast, in control cultures, the neurites turned to avoid the inhibitory CSPG interface. Degradation of CSPG in these cultures was confirmed by specific CSPG antibodies. A single injection of Chase/LV into the spinal cord resulted in sustained secretion of the enzyme, whose activity was detected for 8 weeks by expression of GFP and evidence of the digested form of CSPG. This study demonstrates the efficacy of the Chase/LV vector and its potential as a therapeutic tool to reduce scar inhibition and promote axonal growth and repair following central nervous system injury. PMID- 21600919 TI - Developmental trajectories during adolescence in males and females: a cross species understanding of underlying brain changes. AB - Adolescence is a transitional period between childhood and adulthood that encompasses vast changes within brain systems that parallel some, but not all, behavioral changes. Elevations in emotional reactivity and reward processing follow an inverted U shape in terms of onset and remission, with the peak occurring during adolescence. However, cognitive processing follows a more linear course of development. This review will focus on changes within key structures and will highlight the relationships between brain changes and behavior, with evidence spanning from functional magnetic resonance imaging (fMRI) in humans to molecular studies of receptor and signaling factors in animals. Adolescent changes in neuronal substrates will be used to understand how typical and atypical behaviors arise during adolescence. We draw upon clinical and preclinical studies to provide a neural framework for defining adolescence and its role in the transition to adulthood. PMID- 21600924 TI - Stress-free microinjections in conscious rats. AB - Microinjections are a major tool in modern neuroscience. Microinjection techniques in conscious animals typically involve four steps: (1) animal adapts to experimental setup; (2) injection system is filled and the microinjector is carefully inserted; (3) a drug solution is injected; (4) 1-2 min later the microinjector is carefully removed. Steps 2 and 4 are difficult to perform in rodents without disturbing the animal. This disruption can cause stress and accompanying tachycardia and hyperthermia - unwanted artifacts in physiological research. To reduce these effects, we altered the traditional approach. Our procedure of microinjection consisted of the following steps: (1) we filled the injection setup and fixed the microinjector in its guide cannula; (2) allowed an animal to adapt to the setup; (3) performed an experiment including microinjection(s); (4) removed the microinjector after the experiment was complete. The key change we incorporated was a 1m long piece of tubing with a small internal diameter; it allowed us to inject nanoliter volumes through the injector which had been placed into the guide cannula in advance. This way we avoided the usual manipulations related to microinjection, and minimized extraneous disturbances to the rat. In this report we describe the details of this technique in conscious rats and provide examples of the effects and the reproducibility of a 100 nL drug injection on cardiovascular function. PMID- 21600923 TI - Sensorimotor behavioral tests for use in a juvenile rat model of traumatic brain injury: assessment of sex differences. AB - Modeling juvenile traumatic brain injury (TBI) in rodents presents several unique challenges compared to adult TBI, one of which is selecting appropriate sensorimotor behavioral tasks that enable the assessment of the extent of injury and recovery over time in developing animals. To address this challenge, we performed a comparison of common sensorimotor tests in Long-Evans rats of various sizes and developmental stages (postnatal days 16-45, 35-190 g). Tests were compared and selected for their developmental appropriateness, scalability for growth, pre-training requirements, and throughput capability. Sex differences in response to TBI were also assessed. Grid walk, automated gait analysis, rotarod, beam walk, spontaneous forelimb elevation test, and measurement of motor activity using the force-plate actometer were evaluated. Grid walk, gait analysis, and rotarod failed to meet one or more of the evaluation criteria. Beam walk, spontaneous forelimb elevation test, and measurement of motor activity using the force-plate actometer satisfied all criteria and were capable of detecting motor abnormalities in rats subjected to controlled cortical impact on postnatal day 17. No sex differences were detected in the acute effects of TBI or functional recovery during the 28 days after injury using these tests. This demonstrates the utility of these tests for the evaluation of sensorimotor function in studies using rat models of pediatric TBI, and suggests that pre-pubertal males and females respond similarly to TBI with respect to sensorimotor outcomes. PMID- 21600926 TI - Single trial classification of magnetoencephalographic recordings using Granger causality. AB - The use of Granger causality (GC) for studying dependencies in neuroimaging data has recently been gaining popularity. Several frameworks exist for applying GC to neurophysiological questions but many rely heavily on specific statistical assumptions regarding autoregressive (AR) models for hypothesis testing. Since it is often difficult to satisfy these assumptions in practical settings, this study proposes an alternative statistical methodology based on the classification of individual trials of data. Instead of testing for significance using statistics based on estimated AR models or prediction errors, hypotheses were tested by determining whether or not individual magnetoencephalography (MEG) recording segments belonging to either of two experimental conditions can be successfully classified using features derived from AR and GC concepts. Using this novel approach, we show that bivariate temporal GC can be used to distinguish button presses based on whether they were experimentally forced or free. Additionally, the methodology was used to determine useful parameter settings for various steps of the analysis and this revealed surprising insight into several aspects of AR and GC analysis which, previously, could not be obtained in a comparable manner. A final mean accuracy of 79.2% was achieved for classifying forced and free button presses for 6 subjects suggesting that classification using GC features is a viable option for studying MEG signals and useful for evaluating the effectiveness of parameter variations in GC analysis. PMID- 21600925 TI - Antibody-enhanced microdialysis collection of CCL2 from rat brain. AB - Chemokine(C-C motif) Ligand 2 (CCL2 or MCP-1) is a signaling protein that is released under various conditions. In this study we demonstrate the first microdialysis collection of CCL2 from rat brain tissue using antibody-enhanced microdialysis. A monoclonal antibody to CCL2 was included in the dialysis perfusion fluid as an affinity agent to enhance the recovery of CCL2 both in vitro and in vivo. In vitro it was found that the use of antibody affinity agent increases the relative recovery of CCL2 from 9.6+/-3.4% to 37.5+/-10.2% and 64.8+/-11.7% (n=10) at flow rates of 2MUL/min and 1MUL/min, respectively. Following the in vitro observation, CCL2 was collected from rat brain with microdialysis sampling using both control and antibody-included perfusion fluids. The in vivo data showed that relative recovery was increased at all but the first time point. This shows that the use of free antibody in the perfusion fluid increases the relative recovery of CCL2 and this enhanced microdialysis method may be applicable to other cytokines. PMID- 21600927 TI - Engagement of IL-1 receptor accessory protein (IL-1RAcP) with the monoclonal antibody AY19 provides co-activating signals and prolongs the CD2-induced proliferation of peripheral blood lymphocytes. AB - IL-1 receptor accessory protein (IL-1RAcP) is the second subunit required to form a functional receptor complex for IL-1alpha and beta, IL-1F6, IL-1F8, IL1-F9 and IL-33. While it does not directly interact with the cytokines, IL-1RAcP is necessary to mediate signal transduction. We previously reported a monoclonal antibody with an unknown specificity, termed AY19, that was capable to induce a significant increase in the size of CFU-GM colonies when added to cultures of human cord blood CD34(+) hematopoietic progenitors. Here we demonstrate that AY19 mAb recognizes IL1-RAcP. We show that this adaptor molecule is significantly present on peripheral blood monocytes and lymphocytes including CD4(+) and CD8(+) T lymphocytes, B and NK cells. Interestingly, its expression is found increased on CD127(low)CD4(+)CD25(high) T cells when compared to CD127(low)CD4(+)CD25(-) T cell subset, suggesting that the level of IL-1RAcP membrane expression could allow to distinguish within CD127(low)CD4(+) T lymphocytes the CD25(high) T regulatory subset from conventional CD25(-) T lymphocytes. Functional studies reveal that addition of AY19 mAb enhances the proliferation of peripheral blood mononuclear cells (PBMC) obtained with mitogenic concentrations of PMA. Interestingly, we found that although AY19 mAb does not increase the optimal PBMC proliferation induced by a mitogenic pair of anti-CD2 mAbs it prolongs their time of proliferation. Thus, these results indicate that the anti-IL-1RAcP mAb AY19 exhibits unique functional properties by triggering co-stimulatory signals in lymphocytes. PMID- 21600928 TI - MCS-18, a novel natural plant product prevents autoimmune diabetes. AB - There is still a vital need for new therapies in order to prevent or treat type I diabetes. In this respect, we report that MCS-18 a novel natural product isolated from the plant Helleborus purpurascens (i.e. Christmas rose) is able to increase diabetes free survival using the NOD-mouse model, which is accompanied with a diminished IFN-gamma secretion of splenocytes. In the animal group which has been treated with MCS-18 during week 8 and week 12 of age 70% of the animals showed a diabetes free survival at week 30, whereas in contrast in the untreated animals less than 10% were free of diabetes. MCS-18 treatment significantly reduced islet T-cell infiltrates as well as the rate of T-cell proliferation. Periinsular infiltrates in the MCS-18 treated animals showed a significantly enhanced number of Foxp3(+) CD25(+) T cells, indicating the increased presence of regulatory T cells. These studies show that MCS-18 exerts an efficient immunosuppressive activity with remarkable potential for the therapy of diseases characterized by pathological over-activation of the immune system. PMID- 21600929 TI - Production and characterization of virus-like particles and the P domain protein of GII.4 norovirus. AB - Noroviruses are an important cause of epidemic acute gastroenteritis in humans. In this study the production and characterization of GII.4 norovirus virus-like particles (VLPs) in insect cells is reported. Furthermore, the expression of corresponding norovirus polyhistidine-tagged P domain protein in Escherichia coli is described. The protruding P domain of the norovirus capsid is known to contain determinants for antibody and receptor binding. Therefore, P domain proteins were studied as an alternative diagnostic tool for evaluating norovirus infection. Analyses by dynamic light scattering and cryo-electron microscopy revealed the presence of intact VLPs with an average diameter of about 40 nm. Immunostaining and ELISA assays using norovirus-specific human sera revealed that VLPs and the P domain are recognized by norovirus-specific antibodies and by their putative receptor. The VLPs and P domain protein are potentially useful in the development of diagnostic and vaccination tools for noroviruses. PMID- 21600930 TI - Comparative detection of rabies RNA by NASBA, real-time PCR and conventional PCR. AB - Five methods for the RNA detection of rabies virus were directly compared in this study. These included conventional nucleic acid sequence-based amplification with electrochemiluminescence (NASBA-ECL) assay, reverse transcription (RT)-heminested (hn) polymerase chain reaction (PCR) and TaqMan real-time RT-PCR using protocols as described previously. The first two methods have been routinely utilised for ante-mortem diagnosis of human rabies in Thailand and other rabies-endemic Asian and African countries. In addition, two real-time NASBA assays based on the use of a NucliSens EasyQ analyser (NASBA-Beacon-EQ) and LightCycler real-time PCR machine (NASBA-Beacon-LC) were studied in parallel. All methods target the N gene, whereas the L gene is used for RT-hnPCR. Using serial dilutions of purified RNA from rabies-infected dog brain tissue to assess sensitivity, all five methods had comparable degrees of sensitivities of detection. However, both real-time NASBA assays had slightly lower sensitivities by 10-fold than the other three assays. This finding was also true (except for TaqMan real-time RT-PCR due to a mismatch between the target and probe sequences) when laboratory-adapted (challenge virus standard-11) virus was used in the assays. Testing on previously NASBA-ECL positive clinical samples from 10 rabies patients (saliva [6] and brain [4]) and 10 rabies-infected dog brain tissues, similar results were obtained among the five methods; real-time NASBA assays yielded false-negative results on 2 saliva samples. None of the assays showed positive results on cerebrospinal fluid specimens of 10 patients without rabies encephalitis. Due to the unavailability of the NASBA-ECL assay, the results show that TaqMan real-time RT PCR and RT-hnPCR can be useful for ante- and post-mortem diagnosis of rabies. PMID- 21600931 TI - Identification of low-molecular weight inhibitors of HIV-1 reverse transcriptase using a cell-based high-throughput screening system. AB - A cell-based drug screening system that utilizes a green fluorescent protein (GFP)-tagged recombinant lentiviral vector has been used to screen a chemical library of 34,000 small molecules for antiretroviral compounds. Thirty-three initial hits were analyzed and four compounds were selected based on their anti human immunodeficiency virus type 1 (HIV-1) activity (EC(50) values ranging from 0.17 to 1.9 MUM) and low cellular toxicity (CC(50) values >50 MUM). The four compounds blocked reverse transcription and were able to inhibit the replication of a panel of different HIV-1 strains, including non-B subtype and viruses resistant to different drug classes. Serial in vitro passages of HIV-1(B-HXB2) in the presence of increasing drug concentrations selected for viruses with reduced susceptibility. Mutations previously associated with resistance to non-nucleoside reverse transcriptase (RT) inhibitors (L100I and Y181C for CBL-17 and CBL-21, respectively) or linked to nucleoside analogue resistance (A62V for CBL-4.0 and CBL-4.1) were identified. Viruses with reduced susceptibility to CBL-17 and CBL 21 but not the ones resistant to CBL-4.0 or CBL-4.1 showed a decrease in replicative fitness. Interestingly, two of the small molecules (CBL-4.0 and CBL 4.1) are indolopyridinones that were previously described as nucleotide-competing RT inhibitors. PMID- 21600933 TI - Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides. AB - Nucleoside 1, with an unusual tricyclic carbohydrate moiety, specifically inhibits HIV-1 replication while being inactive against HIV-2 or other (retro) viruses. In an attempt to increase the inhibitory efficacy against HIV-1, and to further explore the structural features required for anti-HIV-1 activity, different types of modifications have been carried out on this prototype compound. These include substitution of the ethoxy group at the C-4" position by alkoxy groups of different length, branching, conformational freedom or functionalization. In addition, the 4"-ethoxy group has been removed or substituted by other functional groups. The role of the tert-butyldimethylsilyl (TBDMS) group at the 2' position has also been studied by preparing the corresponding 2'-deprotected derivative or by replacing it by other silyl (tert hexyldimethylsilyl) or acyl (acetyl) moieties. Finally, the thymine of the prototype compound has been replaced by N-3-methylthymine, uracil or thiophenyl. Some of these compounds were endowed with a 6- to 7-fold higher selectivity than the prototype 1. The tricyclic nucleosides here described represent a novel type of selective anti HIV-1 inhibitors, targeted at the HIV-1-encoded reverse transcriptase. PMID- 21600932 TI - Activity and the metabolic activation pathway of the potent and selective hepatitis C virus pronucleotide inhibitor PSI-353661. AB - PSI-353661, a phosphoramidate prodrug of 2'-deoxy-2'-fluoro-2'-C-methylguanosine 5'-monophosphate, is a highly active inhibitor of genotype 1a, 1b, and 2a HCV RNA replication in the replicon assay and of genotype 1a and 2a infectious virus replication. PSI-353661 is active against replicons harboring the NS5B S282T or S96T/N142T amino acid alterations that confer decreased susceptibility to nucleoside/tide analogs as well as mutations that confer resistance to non nucleoside inhibitors of NS5B. Replicon clearance studies show that PSI-353661 was able to clear cells of HCV replicon RNA and prevent a rebound in replicon RNA. PSI-353661 showed no toxicity toward bone marrow stem cells or mitochondrial toxicity. The metabolism to the active 5'-triphosphate involves hydrolysis of the carboxyl ester by cathepsin A (Cat A) and carboxylesterase 1 (CES1) followed by a putative nucleophilic attack on the phosphorus by the carboxyl group resulting in the elimination of phenol and the alaninyl phosphate metabolite, PSI-353131. Histidine triad nucleotide-binding protein 1 (Hint 1) then removes the amino acid moiety, which is followed by hydrolysis of the methoxyl group at the O(6) position of the guanine base by adenosine deaminase-like protein 1 (ADAL1) to give 2'-deoxy-2'-fluoro-2'-C-methylguanosine-5'-monophosphate. The monophosphate is phosphorylated to the diphosphate by guanylate kinase. Nucleoside diphosphate kinase is the primary enzyme involved in phosphorylation of the diphosphate to the active triphosphate, PSI-352666. PSI-352666 is equally active against wild type NS5B and NS5B containing the S282T amino acid alteration. PMID- 21600934 TI - Regulation of heparanase by albumin and advanced glycation end products in proximal tubular cells. AB - Diabetic nephropathy is one of the main causes of end-stage renal disease, in which the development of tubular damage depends on factors such as high glucose levels, albuminuria and advanced glycation end-product. In this study, we analyzed the involvement of heparanase, a heparan sulfate glycosidase, in the homeostasis of proximal tubular epithelial cells in the diabetic milieu. In vitro studies were performed on a wild-type and stably heparanase-silenced adult tubular line (HK2) and HEK293. Gene and protein expression analyses were performed in the presence and absence of diabetic mediators. Albumin and advanced glycation end-product, but not high glucose levels, increased heparanase expression in adult tubular cells via the AKT/PI3K signaling pathway. This over expression of heparanase is then responsible for heparan sulfate reduction via its endoglycosidase activity and its capacity to regulate the heparan sulfate proteoglycans core protein. In fact, heparanase regulates the gene expression of syndecan-1, the most abundant heparan sulfate-proteoglycans in tubular cells. We showed that heparanase is a target gene of the diabetic nephropathy mediators albumin and advanced glycation end-product, so it may be relevant to the progression of diabetic nephropathy. It could take part in several processes, e.g. extracellular-matrix remodeling and cell-cell crosstalk, via its heparan sulfate endoglycosidase activity and capacity to regulate the expression of the heparan sulfate-proteoglycan syndecan-1. PMID- 21600935 TI - A chimeric receptor of the insulin-like growth factor receptor type 1 (IGFR1) and a single chain antibody specific to myelin oligodendrocyte glycoprotein activates the IGF1R signalling cascade in CG4 oligodendrocyte progenitors. AB - In order to generate neural stem cells with increased ability to survive after transplantation in brain parenchyma we developed a chimeric receptor (ChR) that binds to myelin oligodendrocyte glycoprotein (MOG) via its ectodomain and activates the insulin-like growth factor receptor type 1 (IGF1R) signalling cascade. Activation of this pro-survival pathway in response to ligand broadly available in the brain might increase neuroregenerative potential of transplanted precursors. The ChR was produced by fusing a MOG-specific single chain antibody with the extracellular boundary of the IGF1R transmembrane segment. The ChR is expressed on the cellular surface, predominantly as a monomer, and is not N glycosylated. To show MOG-dependent functionality of the ChR, neuroblastoma cells B104 expressing this ChR were stimulated with monolayers of cells expressing recombinant MOG. The ChR undergoes MOG-dependent tyrosine phosphorylation and homodimerisation. It promotes insulin and IGF-independent growth of the oligodendrocyte progenitor cell line CG4. The proposed mode of the ChR activation is by MOG-induced dimerisation which promotes kinase domain transphosphorylation, by-passing the requirement of conformation changes known to be important for IGF1R activation. Another ChR, which contains a segment of the beta-chain ectodomain, was produced in an attempt to recapitulate some of these conformational changes, but proved non-functional. PMID- 21600936 TI - Group-specific PCR primers for the phylum Acidobacteria designed based on the comparative analysis of 16S rRNA gene sequences. AB - We performed a comprehensive phylogenetic analysis of the phylum Acidobacteria and developed novel, group-specific PCR primers for Acidobacteria and its class level subgroups. Acidobacterial 16S rRNA gene sequences deposited in the RDP database were used to construct a local database then subsequently analyzed. A total of 556 phylotypes were observed and the majority of the phylotypes belonged to five major subgroups (subgroups 1, 2, 3, 4, and 6), which comprised >80% of the acidobacterial sequences in the RDP database. Phylum-specific and subgroup specific primers were designed from the consensus sequences of the phylotype sequences, and the specificities of the designed primers were evaluated both in silico and empirically for coverage and tolerance. The phylum-specific primer ACIDO, which was designed in this study, showed increased coverage for Acidobacteria, as compared to the previous phylum-specific primer 31F. However, the tolerance of the primer ACIDO for non-target sequences was slightly higher than that of the primer 31F. We also developed subgroup-specific PCR primers for the major subgroups of Acidobacteria, except for subgroup 4. Subgroup-specific primers S1, S2, and S3, which targeted subgroups 1, 2, and 3, respectively, showed high coverage for their target subgroups and low tolerance for non-target sequences. However, the primer S6 targeting subgroup 6 showed a lower specificity in its empirical evaluation than expected from the in silico results. The subgroup-specific primers, as well as the phylum-specific primer designed in this study, will be valuable tools in understanding the phylogenetic diversity and ecological niche of the phylum Acidobacteria and its subgroups. PMID- 21600937 TI - The representation of unattended, segmented sounds: a mismatch negativity (MMN) study. AB - The detection of an irregular, potentially relevant change (deviance) in the regular, unattended acoustic environment is ensured by the automatic deviance detection mechanism. It underlies the formation of a regularity representation and a comparison of an incoming sound with this representation. A mismatch outcome of this comparison evokes the mismatch negativity (MMN) of the event related potential. For unattended pure tones the automatic deviance detection mechanism operates most efficiently for initial sound parts, which is why these are suggested to contribute more to sound representation than later parts. A transient that physically segments the sound can overcome this temporal constraint in sound representation. Whether the resulting individual (initial and terminal) sound segments or the joined two-segments give rise to the regularity representation is addressed here. We took advantage that the MMN attenuation to the second of two successive deviances (deviance-repetition effect) is more pronounced when the deviances belong to the same unit of representation. We measured MMN for two deviances (frequency modulations) within segmented sounds that either occurred within the initial or the terminal segment, or that were split across both segments. Unexpectedly, we did not obtain a deviance-repetition effect. Instead, we obtained a temporal distance effect: With increasing temporal distance from deviance-onset relative to segment-onset the MMN amplitude decreased. Furthermore, this effect did not depend on whether the deviance occurred in the initial or in the terminal segment. Thus, (for the current approach) we suggest that the regularity representation is based on the individual rather than joined segments. PMID- 21600938 TI - Intriguing interplay between feline infectious peritonitis virus and its receptors during entry in primary feline monocytes. AB - Two potential receptors have been described for the feline infectious peritonitis virus (FIPV): feline aminopeptidase N (fAPN) and feline dendritic cell-specific intercellular adhesion molecule grabbing non-integrin (fDC-SIGN). In cell lines, fAPN serves as a receptor for serotype II, but not for serotype I FIPV. The role of fAPN in infection of in vivo target cells, monocytes, is not yet confirmed. Both serotype I and II FIPVs use fDC-SIGN for infection of monocyte-derived cells but how is not known. In this study, the role of fAPN and fDC-SIGN was studied at different stages in FIPV infection of monocytes. First, the effects of blocking the potential receptor(s) were studied for the processes of attachment and infection. Secondly, the level of co-localization of FIPV and the receptors was determined. It was found that FIPV I binding and infection were not affected by blocking fAPN while blocking fDC-SIGN reduced FIPV I binding to 36% and practically completely inhibited infection. Accordingly, 66% of bound FIPV I particles co-localized with fDC-SIGN. Blocking fAPN reduced FIPV II binding by 53% and infection by 80%. Further, 60% of bound FIPV II co-localized with fAPN. fDC-SIGN was not involved in FIPV II binding but infection was reduced with 64% when fDC-SIGN was blocked. In conclusion, FIPV I infection of monocytes depends on fDC-SIGN. Most FIPV I particles already interact with fDC-SIGN at the plasma membrane. For FIPV II, both fAPN and fDC-SIGN are involved in infection with only fAPN playing a receptor role at the plasma membrane. PMID- 21600939 TI - The molecular epidemiology of hepatitis E virus infection. AB - Molecular characterization of various hepatitis E virus (HEV) strains circulating among humans and animals (particularly swine, deer and boars) in different countries has revealed substantial genetic heterogeneity. The distinctive four genotype distribution worldwide of mammalian HEV and varying degrees of genetic relatedness among local strains suggest a long and complex evolution of HEV in different geographic regions. The population expansion likely experienced by mammalian HEV in the second half of the 20th century is consistent with an extensive genetic divergence of HEV strains and high prevalence of HEV infections in many parts of the world, including developed countries. The rate and mechanisms of human-to-human transmission and zoonotic transmission to humans vary geographically, thus contributing to the complexity of HEV molecular evolution. PMID- 21600940 TI - Improving the reach of vaccines to low-resource regions with a needle-free vaccine delivery device and long-term thermostabilization. PMID- 21600941 TI - Cell-penetrating peptides can confer biological function: regulation of inflammatory cytokines in human monocytes by MK2 inhibitor peptides. AB - Cell-penetrating peptides have been used as a method of delivering biologically active peptide for over two decades. In this paper, we covalently attached four different cell-penetrating peptides to a peptide that inhibits a kinase important in inflammation, mitogen-activated protein kinase activated protein kinase 2 (MAPKAP2 or MK2). We evaluated the specificity, toxicity, and functionality of these therapeutics in an in vitro model of inflammation using THP-1 monocytes. When treated with the MK2 peptide inhibitors, activated THP-1 human monocytes challenged with lipopolysaccharide (LPS) showed a decrease in TNF-alpha and IL-6 excretion without apparent toxicity. In addition, western blot analysis revealed decreases in the phosphorylation of heat shock protein 27 (HSP27), a downstream substrate of MK2. These results suggested that our peptides inhibited MK2 activity in vitro and should be investigated further as a potential therapeutic for applications involving inflammation. Furthermore, our results suggested that cell-penetrating peptides can be bioactive. PMID- 21600942 TI - Taste perception and implicit attitude toward sweet related to body mass index and soft drink supplementation. AB - These studies examined the differences in sweet taste perception and implicit attitude toward sweet between normal-weight and overweight/obese adults; and tested the effects of soft drink consumption on sweet taste, explicit preference and implicit attitude toward sweet in normal-weight subjects. In study 1, normal weight (n = 22) and overweight/obese (n = 11) adults were assessed for sweet taste intensity and pleasantness. Implicit attitude toward sweet was assessed by implicit association test (IAT). In study 2, normal-weight, lightly active adults (n = 12) underwent one month soft drink supplementation (~760 ml/day). This increased their daily carbohydrate intake by 2.1 +/- 0.2g/kg body weight. Sweet taste perception, explicit preference and implicit attitudes to sweet were assessed. In both studies salty taste was also assessed as a contrasting perception. Overweight/obese subjects perceived sweet and salty tastes as less intense (-23% and -19%, respectively) and reported higher IAT scores for sweet than normal-weight controls (2.1-fold). The supplementation changed sweet intensity/pleasantness ratings and it increased explicit preference (2.3-fold) for sweet in a subgroup of initial sucrose-dislikers. In conclusion, overweight/obese individuals are more implicitly attracted to sweet. One month of soft drink supplementation changed sweet taste perception of normal-weight subjects. PMID- 21600943 TI - Validation of an instrument to assess toddler feeding practices of Latino mothers. AB - This paper describes qualitative and quantitative aspects of testing a 34-item Toddler-Feeding Questionnaire (TFQ), designed for use in Latino families, and the associations between feeding practices and toddler dietary outcomes. Qualitative methods included review by an expert panel for content validity and cognitive testing of the tool to assess face validity. Quantitative analyses included use of exploratory factor analysis for construct validity; Pearson's correlations for test-retest reliability; Cronbach's alpha (alpha) for internal reliability; and multivariate regression for investigating relationships between feeding practices and toddler diet and anthropometry. Interviews were conducted using a convenience sample of 94 Latino mother and toddler dyads obtained largely through the Supplemental Nutrition Program for Women, Infants and Children (WIC). Data collection included household characteristics, self-reported early-infant feeding practices, the toddler's dietary intake, and anthropometric measurements. Factor analysis suggests the TFQ contains three subscales: indulgent; authoritative; and environmental influences. The TFQ demonstrated acceptable reliability for most measures. As hypothesized, indulgent practices in Latino toddlers were associated with increased energy consumption and higher intakes of total fat, saturated fat, and sweetened beverages. This tool may be useful in future research exploring the relationship of toddler feeding practices to nutritional outcomes in Latino families. PMID- 21600944 TI - Orange-spotted grouper (Epinephelus coioides) orexin: molecular cloning, tissue expression, ontogeny, daily rhythm and regulation of NPY gene expression. AB - Orexin-A and -B, collectively called orexins, are hypothalamic neuropeptides involved in the regulation of food intake, sleep and energy balance. In this study, the full-length cDNA of prepro-orexin was isolated from the hypothalamus of orange-spotted grouper (Epinephelus coioides) using RT-PCR and RACE. The grouper prepro-orexin cDNA is 711 bp in length and encodes a 149-amino acid precursor protein that contains a 46-amino acid signal peptide, a 43-amino acid mature orexin-A peptide, a 27-amino acid mature orexin-B peptide and a 33-amino acid C terminus of unknown function. The tissue distribution and ontogeny of prepro-orexin were examined by quantitative real-time PCR. We found that the prepro-orexin mRNA is widely expressed in brain and peripheral tissues, with abundant expression in the hypothalamus. During the embryonic development, prepro orexin mRNA was first detected in neurula stage embryos, and its expression gradually increased during the remainder of embryogenesis. Our analysis of grouper hypothalamic prepro-orexin expression showed that prepro-orexin mRNA levels were greater in the light phase than in the dark phase and increased significantly at meal-time. Intraperitoneal injection of orexin-A caused a dose related increase in hypothalamus NPY mRNA expression level after 4h. Orexin-A also increased NPY mRNA expression level from static hypothalamic fragments incubation. Our results imply that orexin may be involved in feeding in the orange-spotted grouper and orexin-A is a stimulator of NPY mRNA expression in vivo and in vitro. PMID- 21600945 TI - Cigarette smoke-induced kinin B1 receptor promotes NADPH oxidase activity in cultured human alveolar epithelial cells. AB - Pulmonary inflammation is an important pathological feature of tobacco smoke related lung diseases. Kinin B1 receptor (B1R) is up-regulated in the rat trachea chronically exposed to cigarette-smoke. This study aimed at determining (1) whether exposure to total particulate matter of the cigarette smoke (TPM) can induce B1R in human alveolar epithelial A549 cells, (2) the mechanism of B1R induction, (3) the functionality of de novo synthesized B1R, and (4) the role of B1R in TPM-induced increase of superoxide anion (O2(?-)) level. Results show that A549 cells exposed to 10 MUg/ml TPM increased O2(?-) level along with B1R (protein and mRNA) and IL-1beta mRNA. In contrast, B2R and TNF-alpha mRNA were not affected by TPM. The increasing effect of TPM on O2(?-) level was not significantly affected by the B1R antagonist SSR240612. TPM-increased B1R mRNA was prevented by co-treatments with N-acetyl-l-cysteine (potent antioxidant), diphenyleneiodonium (NADPH oxidase inhibitor), IL-1Ra (interleukin-1R antagonist) and SN-50 (specific inhibitor of NF-kB activation) but not by pentoxifylline (TNF alpha release inhibitor), indomethacin and niflumic acid (COX-1 and -2 inhibitors). Stimulation of B1R with a selective agonist (des-Arg9-BK, 10 MUM; 30 min) increased O2(?-)production which was prevented by apocynin and diphenyleneiodonium (NADPH oxidase inhibitors). Data suggest that the increased expression of B1R by TPM in A549 cells is mediated by oxidative stress, IL-1beta and NF-kB but not by cyclooxygenases or TNF-alpha. The amplification of O2(?-) levels via the activation of B1R-NADPH oxidase may exacerbate pulmonary inflammation and contribute to the chronicity of tobacco smoke-related lung diseases. PMID- 21600946 TI - Disulfide bond prolongs the half-life of therapeutic peptide-GLP-1. AB - The multiple physiological characterization of glucagon-like peptide-1 (GLP-1) makes it a promising drug candidate for the therapy of type 2 diabetes. However, the half-life of GLP-1 is short in vivo due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. This indicates that the stabilization of GLP-1 is critical for its utility in drug development. In this study, we developed a cluster of GLP-1 homodimeric analogs, which fused the mutated GLP-1 monomer by an intra-disulfide bridge. The stabilities of the GLP-1 homodimeric analogs were investigated and the physiological functions of the analogs were compared with those of wild-type GLP-1 in rats and human serum. Single dose glucose tolerance test was performed to investigate the administration frequency which satisfied the efficient glucose regulatory in rats. Multiple dose glucose tolerance tests were employed also to study the long-acting anti-diabetic activity of GLP-1 homodimeric analog. The results indicated that the GLP-1 homodimeric analog (hdGLP1G10C) remarkably raised the biological half-life of GLP 1; also HDGLP1G10C showed better glucose tolerance and higher HbA(1c) reduction than GLP-1 in rodents. Based upon the results in this study, it was suggested that hdGLP1G10C prolonged the stability of GLP-1 and retained the biological activity of GLP-1. The improved physiological characterization of hdGLP1G10C makes it as possible potent anti-diabetic drug in the treatment of type 2 diabetes mellitus. PMID- 21600947 TI - From pancreatic islets to central nervous system, the importance of glutamate dehydrogenase for the control of energy homeostasis. AB - Glutamate dehydrogenase (GDH) is a mitochondrial enzyme linking the Krebs cycle to the multifunctional amino acid glutamate. Thereby, GDH plays a pivotal role between carbohydrate and protein metabolisms, controlling production and consumption of the messenger molecule glutamate in neuroendocrine cells. GDH activity is under the control of several regulators, conferring to this enzyme energy-sensor property. Indeed, GDH directly depends on the provision of the co factor NADH/NAD(+), rendering the enzyme sensitive to the redox status of the cell. Moreover, GDH is allosterically regulated by GTP and ADP. GDH is also regulated by ADP-ribosylation, mediated by a member of the energy-sensor family sirtuins, namely SIRT4. In the brain, GDH ensures the cycling of the neurotransmitter glutamate between neurons and astrocytes. GDH also controls ammonia metabolism and detoxification, mainly in the liver and kidney. In pancreatic beta-cells, the importance of GDH as a key enzyme in the regulation of insulin secretion is now well established. Inhibition of GDH activity decreases insulin release, while activating mutations are associated with a hyperinsulinism syndrome. Although GDH enzyme catalyzes the same reaction in every tissue, its function regarding metabolic homeostasis varies greatly according to specific organs. In this review, we will discuss specificities of GDH regulation in neuroendocrine cells, in particular pancreatic islets and central nervous system. PMID- 21600948 TI - Variable epitope libraries: new vaccine immunogens capable of inducing broad human immunodeficiency virus type 1-neutralizing antibody response. AB - The extreme antigenic variability of human immunodeficiency virus (HIV) leads to immune escape of the virus, representing a major challenge in the design of effective vaccine. We have developed a novel concept for immunogen construction based on introduction of massive mutations within the epitopes targeting antigenically variable pathogens and diseases. Previously, we showed that these immunogens carrying large combinatorial libraries of mutated epitope variants, termed as variable epitope libraries (VELs), induce potent, broad and long lasting CD8+IFN-gamma+ T-cell response. Moreover, we demonstrated that these T cells recognize more than 50% of heavily mutated variants (5 out of 10 amino acid positions were mutated in each epitope variant) of HIV-1 gp120 V3 loop-derived cytotoxic T lymphocyte epitope (RGPGRAFVTI) in mice. The constructed VELs had complexities of 10000 and 12500 individual members, generated as plasmid DNA or as M13 phage display combinatorial libraries, respectively, and with structural composition RGPGXAXXXX or XGXGXAXVXI, where X is any of 20 natural amino acids. Here, we demonstrated that sera from mice immunized with these VELs are capable of neutralizing 5 out of 10 viral isolates from Tier 2 reference panel of subtype B envelope clones, including HIV-1 isolates which are known to be resistant to neutralization by several potent monoclonal antibodies, described previously. These data indicate the feasibility of the application of immunogens based on VEL concept as an alternative approach for the development of molecular vaccines against antigenically variable pathogens. PMID- 21600951 TI - Heat shock protein gp96 enhances humoral and T cell responses, decreases Treg frequency and potentiates the anti-HBV activity in BALB/c and transgenic mice. AB - More than 350 million people worldwide are chronically infected with hepatitis B virus (HBV). Broad repertoire and strong magnitude of HBV-specific T cell responses are thought to play key roles for virus control and clearance. Previous studies together with ours showed that heat shock protein gp96 as adjuvant induces antigen specific T cell responses, yet little is known for its anti-viral properties. Here, we investigated the role of gp96 mediated cellular and humoral immunity in antiviral effects in HBV transgenic mice. Immunization with HBV surface (HBsAg) and core (HBcAg) antigens combined formulation along with gp96 induced robust antiviral T-cell and antibody immunity against HBsAg and HBcAg. Compared with non-immunized control, immunization with gp96 adjuvant vaccine led to decrease of serum HBs level and HBc expression in hepatocyte by 45% and 90% at maximum, respectively, and decreased serum HBV-DNA level to below or close to the detection limit 4 weeks after the last immunization, suggesting the therapeutic effect. A significant enhancement in cellular responses towards HBcAg and increased infiltration of CD8+ T cells in liver of transgenic were observed under treatment with gp96 compared with no treatment (P<0.05 or 0.01). Treatment with gp96 was capable of reducing Tregs by overall 30-40%. The superior immune responses induced with the aid of gp96 correlated with improved antiviral effect by vaccination with HBsAg and HBcAg. We conclude that gp96 may contribute to enhanced antiviral immunity in transgenic mice at least partly by Treg down regulation. HBcAg may act as potent adjuvant for Th1 response. Our study reveals the novel property of gp96 in immune modulation and its potential use for breaking immunotolerance in immunotherapy of chronic HBV infection. PMID- 21600949 TI - A host-restricted viral vector for antigen-specific immunization against Lyme disease pathogen. AB - Newcastle disease virus (NDV) is an avian virus that is attenuated in primates and is a potential vaccine vector for human use. We evaluated NDV as a vector for expressing selected antigens of the Lyme disease pathogen Borrelia burgdorferi. A series of recombinant NDVs were generated that expressed intracellular or extracellular forms of two B. burgdorferi antigens: namely, the basic membrane protein A (BmpA) and the outer surface protein C (OspC). Expression of the intracellular and extracellular forms of these antigens was confirmed in cultured chicken cells. C3H or Balb/C mice that were immunized intranasally with the NDV vectors mounted vigorous serum antibody responses against the NDV vector, but failed to mount a robust response against either the intracellular or extracellular forms of BmpA or OspC. By contrast, a single immunization of hamsters with the NDV vectors via the intranasal, intramuscular, or intraperitoneal route resulted in rapid and rigorous antibody responses against the intracellular or extracellular forms of BmpA and OspC. When groups of hamsters were separately inoculated with various NDV vectors and challenged with B. burgdorferi (10(8)cells/animal), immunization with vector expressing either intracellular or extracellular BmpA was associated with a significant reduction of the pathogen load in the joints. Taken together, our studies highlighted the importance of NDV as vaccine vector that can be used for simple yet effective immunization of hosts against bacterial infections including Lyme disease. PMID- 21600950 TI - Mucosal immunization with liposome-nucleic acid adjuvants generates effective humoral and cellular immunity. AB - Development of effective new mucosal vaccine adjuvants has become a priority with the increase in emerging viral and bacterial pathogens. We previously reported that cationic liposomes complexed with non-coding plasmid DNA (CLDC) were effective parenteral vaccine adjuvants. However, little is known regarding the ability of liposome-nucleic acid complexes to function as mucosal vaccine adjuvants, or the nature of the mucosal immune responses elicited by mucosal liposome-nucleic acid adjuvants. To address these questions, antibody and T cell responses were assessed in mice following intranasal immunization with CLDC adjuvanted vaccines. The effects of CLDC adjuvant on antigen uptake, trafficking, and cytokine responses in the airways and draining lymph nodes were also assessed. We found that mucosal immunization with CLDC-adjuvanted vaccines effectively generated potent mucosal IgA antibody responses, as well as systemic IgG responses. Notably, mucosal immunization with CLDC adjuvant was very effective in generating strong and sustained antigen-specific CD8(+) T cell responses in the airways of mice. Mucosal administration of CLDC vaccines also induced efficient uptake of antigen by DCs within the mediastinal lymph nodes. Finally, a killed bacterial vaccine adjuvanted with CLDC induced significant protection from lethal pulmonary challenge with Burkholderia pseudomallei. These findings suggest that liposome-nucleic acid adjuvants represent a promising new class of mucosal adjuvants for non-replicating vaccines, with notable efficiency at eliciting both humoral and cellular immune responses following intranasal administration. PMID- 21600952 TI - Use of computational tools in the field of food safety. AB - In this article we give an overview of how computational methods are currently used in the field of food safety by national regulatory bodies, international advisory organisations and the food industry. Our results show that currently the majority of stakeholders in the field of food safety do not apply computational methods on a routine basis, mainly because of a lack of in-house expertise. Some organisations, however, are very experienced in their use and have developed specialised in-house approaches. Despite this variable situation, computational tools are widely perceived to be a useful tool to support regulatory assessments and decision making in the field of food safety. Recognized, however, is a widespread need to develop guidance documents and software tools that will promote and harmonise the use of computational methods, together with appropriate training. PMID- 21600953 TI - Butadiene cancer exposure-response modeling: based on workers in the styrene butadiene-rubber industry: total leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. AB - Cox regression is used to estimate exposure-response models (with cumulative 1,3 butadiene (BD) ppm-years as the exposure metric) based on the most recent data and validated exposure estimates from UAB's study of North American workers in the styrene-butadiene-rubber industry. These data are substantially updated from those in USEPA's 2002 risk assessment. The slope for cumulative BD ppm-years is not statistically significantly different than zero for CML, AML, or, when any one of eight exposure covariates is added to the model, for all leukemias combined (total leukemia). For total leukemia, the EC(1/100,000) is approximately 0.15 BD environmental ppm and the corresponding unit risk factor is approximately 0.00007 per BD environmental ppm. The excess risk for CML is approximately 15 fold less than for total leukemia. The maximum likelihood estimates suggest that there is no excess risk for AML from cumulative BD ppm-years. For CLL, the slope is statistically significantly different than zero. The excess risk for CLL is approximately 2.5-fold less than for total leukemia. For both total leukemia and CLL, the slope is not statistically significantly different than zero when the exposure-response modeling is based on the person-years with cumulative BD ppm years less than or equal to 300 ppm-years. PMID- 21600954 TI - Argentinean Andean propolis associated with the medicinal plant Larrea nitida Cav. (Zygophyllaceae). HPLC-MS and GC-MS characterization and antifungal activity. AB - The chemical profile and botanical origin of Andean Argentinian propolis were studied by HPLC-ESI-MS/MS and GC-MS techniques as well as the antifungal activity according to CLSI protocols. Dermatophytes and yeasts tested were strongly inhibited by propolis extracts (MICs between 31.25 and 125 MUg/mL). The main antifungal compounds were: 3'methyl-nordihydroguaiaretic acid (MNDGA) 1, nordihydroguaiaretic acid (NDGA) 2 and a NDGA derivative 3, showing strong activity against Trichophyton mentagrophytes, T. rubrum and Microsporum gypseum (MICs between 15.6 and 31.25 MUg/mL). The lignans 1 and 2 showed activities against clinical isolates of Candidas spp., Cryptococcus spp., T. rubrum and T. mentagrophytes (MICs and MFCs between 31.25 and 62.5 MUg/mL). The lignan and volatile organic compounds (VOCs) profiles from propolis matched with those of exudates of Larrea nitida providing strong evidences on its botanical origin. These results support that Argentinian Andean propolis are a valuable natural product with potential to improve human health. Six compounds (1-6) were isolated from propolis for the first time, while compounds 1 and 3-6 were reported for first time as constituents of L. nitida Cav. PMID- 21600955 TI - Comparison of different exposure assessment methods to estimate the long-term dietary exposure to dioxins and ochratoxin A. AB - Long-term exposures to dioxins (PCCD/F and dioxin-like PCBs) and ochratoxin A were calculated using food consumption data of the European concise database combined with concentration data of the Netherlands (NL) using a deterministic approach. To refine these assessments, exposures were also calculated using three long-term exposure models, observed individual means (OIM), Iowa State University Foods (ISUF), and betabinomial-normal (BBN) models, combined with individual food consumption data of NL. BBN and ISUF correct the variation in long-term exposure for the within-person variation, whereas OIM calculates the mean exposure over the days in the food consumption survey. Exposures obtained with the concise database were highest, and those obtained with OIM higher than with BBN and ISUF. Contribution of the major sources of exposure differed between the concise database and the three models. Given the constraints of the concise database, exposures obtained with this database should be interpreted as a first tier assessment. Preferably, refined assessments using models that correct the variation in long-term exposure for the within-person variation combined with individual food consumption data and national concentration data should be used to assess the long-term exposure. We recommend the use of BBN since it can model exposure distributions that depend on covariates. PMID- 21600956 TI - Sex differences in the neural correlates of emotion: evidence from neuroimaging. AB - Sex differences in emotional processes represent some of the most robust sex stereotypes worldwide. However, empirical support for these stereotypes is lacking, especially from research utilizing objective measures, such as neuroimaging methodologies. We conducted a selective review of functional neuroimaging studies that have empirically tested for sex differences in the association between brain function and emotional processes (including perception, reactivity, regulation and experience). Evidence was found for marked sex differences in the neural mechanisms underlying emotional processes, and in most cases suggested that males and females use different strategies during emotional processing, which may lead to sex differences in the observed (or subjectively reported) emotional process. We discuss how these findings may offer insight into the mechanisms underlying sex differences in emotional behaviors, and outline a number of methodological considerations for future research. Importantly, results suggest that sex differences should not be ignored in research investigating the neurobiology of emotion. PMID- 21600957 TI - COMT and age at onset in mood disorders: a replication and extension study. AB - Our study aims at replicating our previous finding of an association between COMT rs4680 G/A polymorphism and early onset major depression (MD). We included 462 MD, 147 bipolar disorders (BD) subjects and 295 healthy controls. We could partially replicate previous findings. In particular, rs4680 GG+AG genotypes were more represented in the subgroup of early onset MD patients (p=0.04). Additionally, we observed an association between rs737865 alleles and early onset MD (p=0.04). Rs4680 genotype was associated with early onset BD as well (p=0.01). In conclusion, we partially replicated our previous findings confirming a possible influence of COMT variants in MD and BD, particularly in early onset subjects, though not with the same risk genotypes. PMID- 21600958 TI - Deficit of sensorimotor integration in normal aging. AB - Sensorimotor performance declines with normal aging. The present study explored age-related changes in sensorimotor integration by conditioning a supra-threshold transcranial magnetic stimulation pulse with a peripheral nerve shock at different interstimulus intervals. Cortical motor threshold of the abductor pollicis brevis muscle, intracortical inhibition and facilitation were measured. We also assessed the influence of median nerve stimulation on motor cortex excitability at intervals which evoked short- and long-latency afferent inhibition (SAI and LAI, respectively) and afferent-induced facilitation (AIF). We observed a marked decrease of the long latency influence of proprioceptive inputs on M1 excitability in the elderly, with the loss of AIF and LAI. The SAI, motor thresholds and intracortical inhibition and facilitation were not age related. Decreased sensorimotor performance with aging appears to be associated with a decrease in the influence of proprioceptive inputs on motor cortex excitability at longer intervals (probably via higher order cortical areas). PMID- 21600959 TI - Serotonin mediated changes in corticotropin releasing factor mRNA expression and feeding behavior isolated to the hypothalamic paraventricular nuclei. AB - Fenfluramine reduces hunger and promotes body weight loss by increasing central serotonin (5-HT) signaling. More recently, neuropeptides have been linked to the regulation of feeding behavior, metabolism and body weight. To examine possible interactions between 5-HT and neuropeptides in appetite control, fenfluramine (200 nmol/0.5 MUl/side) was administered directly into the hypothalamic paraventricular nuclei (PVN) of male rats. Bilateral fenfluramine produced significant hypophagia and increased expression of PVN corticotropin releasing factor (CRF) mRNA and neuropeptide Y (NPY) mRNA in the arcuate nucleus within the first hour after drug administration. Fenfluramine's effects on feeding behavior and mRNA expression were blocked by PVN injections of a 5-HT(1-2) receptor antagonist, metergoline (15 nmol/0.5 MUl/side). These data suggest that 5-HT neurons targeting hypothalamic paraventricular CRF neurons may participate in an appetite control circuit for reducing food intake. PMID- 21600960 TI - Meningeal/vascular alterations and loss of extracellular matrix in the neurogenic zone of adult BTBR T+ tf/J mice, animal model for autism. AB - Autism spectrum disorders are characterized by impaired social and communication skills and seem to result from altered neural development. We sought to determine whether the anatomy of the meninges and extracellular matrix (ECM) is altered in an animal model of autism, the BTBR T+ tf/J mouse. This mouse displays white matter tract anatomical defects and exhibits several symptoms of autism. Immunofluorescence cytochemistry for laminin, a major ECM marker, was performed on series of coronal sections of the adult BTBR T+ tf/J brain and the anatomy was analyzed in comparison to B6 wild type mice. Laminin immunoreactivity visualized meninges, blood vessels and the subventricular zone (SVZ) stem cell-associated ECM structures, which I have named fractones. All BTBR T+ tf/J mice observed showed the same forebrain defects. The lateral ventricle volume was severely reduced, the falx cerebri elongated, the arteries enlarged and the choroid plexus atrophied. Compared to B6 mice, fractone numbers in BTBR T+ tf/J mice were reduced by a factor three in the SVZ of the anterior portion of the lateral ventricle. This represents the primary neurogenic zone during adulthood. Fractones were reduced by a factor 1.5 in posterior portions of the lateral ventricle. Moreover, fractone size was reduced throughout the lateral ventricle SVZ. These results show hitherto unsuspected alterations in connective tissue/vasculature and associated ECM in the adult BTBR T+ tf/J mouse. The drastic changes of the connective tissue and ECM in the neurogenic zone of the lateral ventricle may contribute to incorrect neurogenesis during developmental and adult stages. PMID- 21600961 TI - Cannabinoid receptor expression and phosphorylation are differentially regulated between male and female cerebellum and brain stem after repeated stress: implication for PTSD and drug abuse. AB - Recent study demonstrated a close relationship between cerebellum atrophy and symptom severity of pediatric maltreatment-related posttraumatic stress disorder (PTSD). It has also been known that females are more vulnerable than males in developing anxiety disorders after exposure to traumatic stress. The mechanisms are unknown. Because cannabinoid receptors (CB1 and CB2) are neuroprotective and highly expressed in the cerebellum, we investigated cerebellar CB expression in stressed rats. Young male and female Sprague-Dawley rats were given 40 unpredictable electric tail-shocks for 2h daily on 3 consecutive days. CB1 and CB2 mRNA and protein levels in rat cerebellum and brain stem were determined using quantitative real-time PCR and Western blot, respectively. Two-way ANOVA revealed significant gender and stress effects on cerebellar CB1 mRNA expression, with females and non-stressed rats exhibiting higher CB1 mRNA levels than the males (3 fold, p<0.01) and stressed rats (30%, p<0.01), respectively. CB1 and CB2 mRNA levels in brain stem were also greater in female rats than males (p<0.01, p<0.05, respectively). Repeated stress increased the level of phosphorylated CB1 receptors, the inactivated CB1, in rat cerebellum (p<0.01), particularly in female rats as revealed by the significant gender * stress interaction. Thus, repeated severe stress caused greater CB1 mRNA suppression and CB1 receptor phosphorylation in female cerebellum that could lead to increased susceptibility to stress-related anxiety disorders including PTSD. PMID- 21600962 TI - ER-stress-inducible Herp, facilitates the degradation of immature nicastrin. AB - BACKGROUND: Herp is an endoplasmic reticulum (ER)-stress-inducible membrane protein harboring an ubiquitin-like domain (ULD). However, its biological functions are not fully understood. Here, we examined the role of Herp in the degradation of gamma-secretase components. METHODS: Effects of ULD-lacking Herp (DeltaUb-Herp) expression on the degradation of gamma-secretase components were analyzed. RESULTS: The cellular expression of DeltaUb-Herp was found to inhibit the degradation of overexpressed immature nicastrin and full-length presenilin. The mechanisms underlying Herp-mediated nicastrin degradation was further analyzed. We found that immature nicastrin accumulates in the ER of DeltaUb-Herp overexpressing cells or Herp-deficient cells more than that in the ER of wild type cells. Further, DeltaUb-Herp expression inhibited nicastrin ubiquitination, suggesting that the ULD of Herp is likely involved in nicastrin ubiquitination. Co-immunoprecipitation study showed that Herp as well as DeltaUb-Herp potentially interacts with nicastrin, mediating nicastrin interaction with p97, which functions in retranslocation of misfolded proteins from the ER to the cytosol. CONCLUSIONS: Thus, Herp is likely involved in degradation of immature nicastrin by facilitating p97-dependent nicastrin retranslocation and ubiquitination. GENERAL SIGNIFICANCE: We suggest that Herp could play a role in the elimination of the excess unassembled components of a multimeric complex. PMID- 21600963 TI - Erythropoietin promotes survival and regeneration of insect neurons in vivo and in vitro. AB - In addition to its function as a regulator of hematopoiesis, the cytokine erythropoietin (Epo) initiates adaptive cellular responses to both moderate environmental challenges and tissue damaging insults in various non-hematopoietic mammalian tissues. Epo's neuroprotective and neuroregenerative functions mediated through janus kinases (JAK)/signal transducers and activators of transcription (STAT) transduction pathways and regulation of Epo and Epo receptor expression in the nervous system by hypoxia inducible factor (HIF) have been documented in a variety of in vitro and in vivo studies and homologs of the human Epo gene are present in fish, amphibians and mammals. The present study reproduces the hallmarks of Epo-mediated mammalian neuroprotection in the grasshopper nervous system. Recombinant human Epo (rhEpo) increases the survival of dissociated grasshopper brain neurons under normoxic and hypoxic conditions and promotes the regeneration of neurites in vitro. In addition, reestablishment of sound source localization after unilateral tympanic nerve crush injury was accelerated and more complete after application of rhEpo, demonstrating in vivo support of auditory receptor cell axon regeneration. Immunoblots of central nervous tissue extracts from mouse, grasshopper, crayfish and leech labeled protein bands of ~38 kDa, fitting to the molecular weight of Epo reported in earlier studies. These results indicate that a ligand/receptor system that shares structural and functional similarities with mammalian Epo and Epo receptor exerts neuroprotective and neuroregenerative effects in insects. With both upstream (HIF system) and downstream (JAK/STAT pathway) elements of the mammalian Epo system being present in insects and other invertebrates, Epo-like signaling involved in tissue protection appears to be an ancient beneficial function shared by vertebrates and invertebrates. PMID- 21600964 TI - Age-related alterations in mitochondrial physiological parameters and nitric oxide production in synaptic and non-synaptic brain cortex mitochondria. AB - Brain aging has been associated with mitochondrial dysfunction and changes in nitric oxide levels. The aim of this study was to evaluate the susceptibility of synaptic and non-synaptic mitochondria to aging-dependent dysfunction. State 3 respiratory rate and respiratory control were 43% and 33% decreased, respectively in brain cortex synaptosomes from 14-month-old animals, as compared with synaptosomes from 3-month-old mice. Respiratory rates were not significantly affected by aging in non-synaptic mitochondrial fractions. Mitochondrial dysfunction was associated with increases of 84% and 38% in H2O2 production rates in brain cortex synaptosomes and non-synaptic mitochondria, respectively, from 14 month-old mice, as compared with young animals. Synaptic mitochondria seem to be more susceptible to calcium insult in 14-month-old mice, as compared with non synaptic mitochondria, as measured by response of both types of fractions to calcium-induced depolarization. With aging, nitric oxide (NO) production was 44% and 27% decreased both in synaptosomal and non-synaptic mitochondrial fractions, respectively. The results of this study suggest that with aging, mitochondrial function at the nerve terminals would be more susceptible to suffer alterations by the constant calcium changes occurring as a consequence of synaptic activity. Non-synaptic mitochondria would be more resistant to age-related dysfunction and oxidative damage. PMID- 21600965 TI - Effects of pioglitazone and retinoic acid in a rotenone model of Parkinson's disease. AB - Parkinson's disease (PD) is a late-onset, progressive and neurodegenerative disorder of unknown etiology. Besides the other therapeutic approaches, new drug options in pharmacotherapy of PD are important. The aim of the present study was to investigate the effects of pioglitazone and retinoic acid, antioxidant and neuroprotective agents, on rotenone-induced model of PD in rats. Adult male Wistar rats (260-373 g) were subjects. Rotenone (2.5mg/kg, sc) was injected to rats for 70 days. At the end of rotenone administration, rats were treated with pioglitazone (10mg/kg, ip) and retinoic acid (1mg/kg, ip) or vehicles for 15 days. Then, rats were tested for evaluation of Parkinson signs by measurement of locomotor activity. In addition, dopamine levels were detected in striatum, hippocampus and hypothalamus in individual groups of control, rotenone and pioglitazone or retinoic acid-treated rats. Rotenone significantly reduced locomotor activity of the rats. It also significantly reduced dopamine levels in striatum and hippocampus, but not hypothalamus. Pioglitazone and retinoic acid reversed in reduction of locomotor activity significantly. Pioglitazone, but not retinoic acid, significantly reversed the reduced striatal dopamine level. Both drugs were ineffective on reduced levels of dopamine in hippocampus. Our results suggest that pioglitazone and retinoic acid have some beneficial effects on rotenone-induced model of PD in rats. Pioglitazone seems to be more effective than retinoic acid. These agents may be helpful for preventing or controlling of some signs of PD. PMID- 21600966 TI - Baicalin attenuates global cerebral ischemia/reperfusion injury in gerbils via anti-oxidative and anti-apoptotic pathways. AB - Baicalin is an important medicinal herb purified from the dry roots of Scutellaria baicalensis Georgi. The present study was undertaken to evaluate the neuroprotective effects of baicalin in gerbils subjected to transient global cerebral ischemic-reperfusion injury. Baicalin at doses of 50, 100 and 200mg/kg was intraperitoneally injected into the gerbils immediately after cerebral ischemia. Seven days after reperfusion, hematoxylin and eosin (HE) staining was performed to analyze hippocampal CA1 pyramidal damage histopathologically. In addition, in order to understand the potential protective mechanism of baicalin, we examined anti-oxidative enzymes, such superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), non-enzymatic scavenger glutathione (GSH) and measured the content of malondialdehyde (MDA) in hippocampus. The mRNA and protein expressions of BDNF were determined in ischemic hippocampus by real-time RT-PCR and Western blot, respectively. Evidence for neuronal apoptosis was detected by real-time RT PCR, Western blot and caspase-3 activity measurement. Histopathological examination showed that the administration of baicalin by the dose of 100 and 200mg/kg significantly attenuated ischemia-induced neuronal cell damage. Reduced level of MDA, obviously elevated activities of SOD and GSH as well as GSH-PX were also found in baicalin-treated groups. Further investigation demonstrated that treatment with baicalin remarkably promoted the expression of BDNF and inhibited the expression of caspase-3 at mRNA and protein levels by real-time RT-PCR and Western blot, respectively. Besides, caspase-3 activity assay also elucidated that the administration of baicalin could significantly suppress caspase-3 in ischemic gerbils hippocampus. Theses findings suggest that baicalin's neuroprotection appears to be associated with its anti-oxidative and anti apoptotic properties in global cerebral ischemia in the gerbils. PMID- 21600967 TI - Tissue distribution and excretion of intravenously administered titanium dioxide nanoparticles. AB - As the biosafety of nanotechnology becomes a growing concern, the in vivo nanotoxicity of nanoparticles (NPs) has been drawn an increasing attention. Titanium dioxide nanoparticles (TiO(2)-NPs) have been developed for versatile use, but the pharmacokinetics of intravenously administered TiO(2)-NPs have not been investigated extensively. In the present study, the rutile-type TiO(2)-NPs with a size about 20nm were labeled with CF680 and (125)I. The labeled TiO(2)-NPs were injected in mice or rats with the concentration of 1mg/ml and the dose of 10mg/kg body weight and their tissue distribution and excretion were investigated by using ex vivo fluorescent imaging, gamma-counter and TEM. The results indicated that the TiO(2)-NPs mainly accumulated in liver and spleen and could be retained for over 30days in these tissues due to the phagocytosis by macrophages. The excretion assay found that the excretory rate of TiO(2)-NPs through urine was higher than that of feces, indicating that renal excretion was the main excretion pathway of TiO(2)-NPs. Overall results of the present study provided important information on distribution and excretion of TiO(2)-NPs in vivo, which would greatly promote the pharmacokinetics and in vivo nanotoxicity research of TiO(2) NPs. PMID- 21600968 TI - Nanostructure formation in aqueous solution of amphiphilic copolymers of 2-(N,N dimethylaminoethyl)methacrylate and alkylacrylate: Characterization, antimicrobial activity, DNA binding, and cytotoxicity studies. AB - Three amphiphilic random copolymers poly(2-(dimethylaminoethyl)methacrylate-co alkylacrylate) (where, alkyl = hexyl, octyl, dodecyl) with 16 mol% hydrophobic substitution were synthesized. Surface tension, viscosity, fluorescence probe, dynamic light scattering (DLS), as well as transmission electron microscopic (TEM) techniques were utilized to investigate self-assembly formation by the hydrophobically modified polymers (HMPs) in pH 5. Formation of hydrophobic domains through inter-polymer chain interaction of the copolymer in dilute solution was confirmed by fluorescence probe studies. Average hydrodynamic diameter of the copolymer aggregates at different polymer concentration was measured by DLS studies. The copolymer with shorter hydrophobic chain exhibits larger hydrodynamic diameter in dilute solution, which decreased with either increase of concentration or increase of hydrophobic chain length. TEM images of the dilute solutions of the copolymers with shorter as well as with longer hydrophobic chain exhibit spherical aggregates of different sizes. The antimicrobial activity of the copolymers was evaluated by measuring the minimum inhibitory concentration value against one Gram-positive bacterium Bacillus subtilis and one Gram-negative bacterium Escherichia coli. The copolymer with the octyl group as pendent hydrophobic chain was found to be more effective in killing these microorganisms. The interaction of the cationic copolymers with calf-thymus DNA was studied by fluorescence quenching method. The polymer-DNA binding was found to be purely electrostatic in nature. The hydrophobes on the polymer backbone were found to have a significant influence on the binding process. Biocompatibility studies of the copolymers in terms of cytotoxicity measurements were finally performed at different concentrations of the HMPs to evaluate their potential application in biomedical fields. PMID- 21600970 TI - Amphiphilic and biodegradable hy-PEI-g-PCL-b-PEG copolymers efficiently mediate transgene expression depending on their graft density. AB - Novel biodegradable amphiphilic copolymers hy-PEI-g-PCL-b-PEG were prepared by grafting PCL-b-PEG chains onto hyper-branched poly(ethylene imine) as non-viral gene delivery vectors. Our investigations focused on the influence of graft densities of PCL-b-PEG chains on physico-chemical properties, DNA complexation and transfection efficiency. We found that the transfection efficiencies of these polymers increased at first towards an optimal graft density (n=3) and then decreased. The buffer-capacity-test showed almost exactly the same tendency as transfection efficiency. Cytotoxicity (MTT-assay) depended on the cooperation of PEG molecular weight and graft density of PCL-b-PEG chains. With increasing the graft density, cytotoxicity, zeta-potential, affinity with DNA, stability of the polyplexes and CMC-values were reduced strongly and regularly. Increasing the excess of polymer over DNA was shown to result in a decrease of the observed particle size to 100-200 nm. PMID- 21600969 TI - Skin photoprotection improvement: synergistic interaction between lipid nanoparticles and organic UV filters. AB - A photoprotective formulation was developed with an increased sunprotection factor (SPF), compared to a conventional nanoemulsion, but having the same concentration of three molecular sunscreens, namely ethylhexyl triazone, bis ethylhexyloxyphenol methoxyphenyl triazine, and ethylhexyl methoxycinnamate. The sunscreen mixture was incorporated into nanostructured lipid carriers (NLCs). The ability of nine different solid lipids to yield stable aqueous NLC suspensions was assessed. After the production by hot high pressure homogenization, the NLC were analyzed in terms of particle size, physical state, particle shape, ultraviolet absorbance and stability. The particle size for all NLC was around 200 nm after production. The NLC suspension with carnauba wax had superior UV absorbance, NLC from bees wax showed similar efficiency as the reference emulsion. The NLC formulations were incorporated into hydrogel formulations and the in vitro SPF was measured. This study demonstrated that approximately 45% higher SPF values could be obtained when the organic UV filters were incorporated into carnauba wax NLC, in comparison to the reference nanoemulsion and bees wax NLC. The data showed that the synergistic effect of NLC and incorporated sunscreens depends not only on the solid state of the lipid but also on its type. PMID- 21600971 TI - Ginsenoside-Rg1 protects podocytes from complement mediated injury. AB - AIM OF THE STUDY: Podocytes injury mediated by complement complex C5b-9 is the main feature of membranous nephropathy (MN). Little work has been done to prove that ginsenoside-Rg1 could inhibit this process. Our study aims to investigate the efficacy of ginsenoside-Rg1 in protecting the podocyte from complement mediated injury. MATERIALS AND METHODS: We chose sublethal C5b-9 induced podocyte injury as the model of MN in vitro. Ginsenoside-Rg1 was given as an intervention. Morphological changes were observed by electron microscope and fluorescence microscope. The production of reactive oxygen species (ROS) was detected by flow cytometry. The expression of the mitogen activated protein kinase (MAPK) including JNK, ERK and P38 was detected by western-blot technique. RESULTS: Ginsenoside-Rg1 could protect foot processes of podocytes, suppress the damage of F-actin, decrease the production of ROS, and inhibit the activation of P38 kinase pathway. CONCLUSION: These results suggest that ginsenoside-Rg1 could protect podocyte from sMAC-induced injury partly because of its antioxidant property and inhibit the activation of P38 kinase pathway. PMID- 21600972 TI - Indigofera suffruticosa Mill as new source of healing agent: involvement of prostaglandin and mucus and heat shock proteins. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Indigofera suffruticosa is specie typical of the "Cerrado" or Brazilian savannah; it is a member of the Fabaceae family - in folkmedicine is used for gastric disorders, infection and inflammation. AIM OF THE STUDY: Ethyl acetate fraction (AcF) and aqueous fraction (AqF) of the methanolic extract of I. suffruticosa leaves were evaluated against acute gastric ulcer. The AcF fraction was selected to assess its activity in ulcer healing and its gastroprotective effects via mucus and gastric secretion. MATERIALS AND METHODS: The gastroprotective action of AcF and AqF fractions were evaluated in a rodent experimental model. The action mechanisms, involvements of the antisecretory action, mucus and prostaglandin production, toxicological and healing activity of the AcF (100mg/kg, p.o.) were evaluated. We also used histological analysis (HE and PAS) and immunohistochemical (PCNA and HSP-70) assays to evaluate the effects of I. suffruticosa. RESULTS: AcF significantly inhibited the gastric mucosal damage caused by ethanol. This effect was statistically significant in 100mg/kg group compared vehicle. AcF did not interfered with gastric secretion, significantly increased the PGE(2) and mucus production (validated in PAS technique). The gastroprotection was attenuated by pretreatment with N-ethylmaleimide, but not L-NAME. In acid-acetic-induced ulcer model AcF accelerated ulcer healing. Immunohistochemistry analysis showed induction of proliferating cell (PCNA) and heat shock protein (HSP 70). CONCLUSIONS: These results showed that AcF acted as gastroprotective agent stimulating prostaglandin, mucus and HSP70. PMID- 21600973 TI - Short- and long-term behavioral effects of exposure to 21%, 40% and 100% oxygen after perinatal hypoxia-ischemia in the rat. AB - Until recently, supplementation with 100% oxygen was standard therapy for newborns who required resuscitation at birth or suffered later hypoxic-ischemic events. Exposure to high concentrations of oxygen, however, may worsen oxidative stress induced by ischemic injury. In this study we investigated the short- and long-term behavioral outcomes in rats that had undergone hypoxic-ischemic brain injury on postnatal day 7, followed by 2h exposure to 21%, 40%, or 100% oxygen, compared to normal controls. There were no differences in the development of walking, head lifting and righting reflexes from postnatal days 9 to 15. Cliff avoidance showed some abnormal responses in the H21 animals. From postnatal days 28 to 56, three tests of sensorimotor coordination were performed weekly: ledged tapered beam, cylinder, and bilateral tactile stimulation. The ledged tapered beam test without prior training of animals was sensitive to injury, but did not distinguish between treatment groups. The cylinder test showed a greater use of the unimpaired limb in female 21% and 40% oxygen groups compared to controls. Performance in both cylinder and the beam tests showed a correlation with the degree of brain injury. The bilateral tactile stimulation test showed that the male 21% oxygen groups had worse sensory asymmetry than male 40% or 100% oxygen groups, but was not statistically significantly different from controls. We thus found a minor benefit to post-hypoxia-ischemic treatment with 100% and 40% oxygen compared to 21% in one test of early motor skills. Our results for long-term sensorimotor behavior, however, showed conflicting results, however, as males treated with 40% or 100% oxygen had less sensory asymmetry (better performance) in the bilateral tactile stimulation test than males treated with 21% oxygen, while females had impaired motor performance in the cylinder test with both 21% and 40% oxygen. PMID- 21600974 TI - Carmustine induces ERK- and JNK-dependent cell death of neuronally-differentiated PC12 cells via generation of reactive oxygen species. AB - Accumulation of reactive oxygen species (ROS) caused by the inhibition of glutathione reductase (GR) has been proposed as one of the mechanisms responsible for carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU)-induced cytotoxicity. Since mitogen-activated protein kinases (MAPKs) are known to mediate ROS dependent cell death in multiple cell types, we examined whether redox-sensitive MAPK activation mediated the carmustine-induced cell death of neuronally differentiated PC12 cells. Carmustine induced a concentration- and time-dependent cell death, which was associated with increased caspase-3 activation, a reduction in GR activity accompanied by a concomitant decrease in reduced glutathione levels, and accumulation of ROS. Carmustine-induced caspase-3 activation and cell death were prevented by pretreatment with anti-oxidants or a reducing agent, indicating that carmustine-induced caspase-3 activation and cell death occur via redox-dependent processes. Carmustine induced phosphorylation of the MAPKs, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. The activation of these kinases was inhibited by pretreatment with N acetyl-L-cysteine (NAC). Although all the MAPKs were activated by carmustine, only the inhibitors of JNK and ERK prevented carmustine-induced cell death and caspase-3 activation. Our data suggest that carmustine-induced neurotoxicity is, at least in part, due to the activation of ROS-dependent JNK and ERK signaling. PMID- 21600975 TI - Effect of interaction between phenolic compounds and copper ion on antioxidant and pro-oxidant activities. AB - Phenolic compounds are widely used in food and cosmetics to prevent undesirable oxidation. On the other hand, phenolic compounds are also strong reducing agents and under in vitro conditions and in the presence of copper ion, they can act as pro-oxidants. In this study, we conducted electron spin resonance (ESR) measurements for the increase in reactive oxygen species (ROS) in relation to their structure and interaction with transition metals. Moreover, the antioxidant activity was assessed with the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, and the pro-oxidant effect of phenolic compounds on DNA damage was assessed by measuring 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is effectively formed during oxidative damage. In conclusion, ortho-dihydroxyl groups that can chelate with Cu(2+) induce the greatest pro-oxidant activity. Moreover, the interaction between phenolic compounds and copper induced to H(2)O(2). The obtained results indicated that ROS participated in oxidative DNA damage induced by phenolic compounds in the presence of Cu(2+). PMID- 21600976 TI - Cellular responses of Prochilodus lineatus hepatocytes after cylindrospermopsin exposure. AB - Cylindrospermopsin is a potent toxicant for eukaryotic cells produced by several cyanobacteria. Recently, primary hepatocyte cultures of Neotropical fish have been established, demonstrating to be a quite efficient in vitro model for cellular toxicology studies. In the current study, a protocol for culture of Prochilodus lineatus hepatocytes was established and utilized to investigate the cellular responses to purified cylindrospermopsin exposure. Hepatocytes were successfully dissociated with dispase, resulting in a cell yield of 6.36 * 10(7)cells g(-1) of liver, viability of 97% and attachment on uncoated culture flasks. For investigation of cylindrospermopsin effects, hepatocytes were dissociated, cultured during 96 h and exposed to three concentrations of the toxin (0.1, 1.0 or 10 MUgl(-1)) for 72 h. Cylindrospermopsin exposure significantly decreased cell viability (0.1 and 1 MUgl(-1)) and multixenobiotic resistance mechanism, MXR (all exposed groups), but increased reactive oxygen/nitrogen species levels (all exposed groups) and lipid peroxidation (10 MUgl(-1)). On the other hand no significant alterations were observed for other biochemical biomarkers as 2GSH/GSSG ratio, protein carbonyl levels and DNA strand breaks or glutathione S-transferase and glucose 6-phosphate dehydrogenase activities. In conclusion, hepatocytes might be made sensitive to cylindrospermopsin, at least in part, due to reduction of xenobiotics and endobiotics efflux capacity by MXR. Additionally, the toxin exposure suggests important issues regarding hepatocytes survival at the lowest cylindrospermopsin concentrations. PMID- 21600977 TI - Radiosensitizing effect of ferulic acid on human cervical carcinoma cells in vitro. AB - Radiotherapy may be effectively combined with plant derived radiosensitizers. Ferulic acid, a naturally occurring phenolic acid, has been reported to have free radical producing properties. In the present study, the radiosensitisation potential of ferulic acid has been tested in two cervical cancer cell lines (HeLa and ME-180) in vitro. Percentage of growth inhibition (MTT assay), colony survival, levels of lipid peroxidation (TBARS, CD and LHP), antioxidant status (SOD, CAT, GPx and GSH), oxidative DNA damage (% tail DNA, tail length, tail moment and Olive tail moment), apoptotic morphological changes (AO/EtBr staining) and intracellular ROS levels (DCFH-DA) were estimated. The present results show that ferulic acid (FA) enhances radiation effects by increasing lipid peroxidative markers in HeLa and ME-180 cells. We observed significant enhancement of ROS levels during ferulic acid plus radiation treatment. FA treatment alone increased intracellular ROS levels indicate its prooxidant nature. Similarly, we observed enhanced oxidative DNA damage and apoptotic morphological changes in FA plus radiation treated cells. The present data suggest radiation sensitizing property of FA in cervical cancer cells. Further investigations warrants to substantiate the present findings. PMID- 21600979 TI - Lipid hydroperoxide-induced and hemoglobin-enhanced oxidative damage to colon cancer cells. AB - Epidemiological studies have indicated that Western diets are related to an increase in a series of malignancies. Among the compounds that are credited for this toxic effect are heme and lipid peroxides. We evaluated the effects of hemoglobin (Hb) and linoleic acid hydroperoxides (LAOOH) on a series of toxicological endpoints, such as cytotoxicity, redox status, lipid peroxidation, and DNA damage. We demonstrated that the preincubation of SW480 cells with Hb and its subsequent exposure to LAOOH (Hb + LAOOH) led to an increase in cell death, DCFH oxidation, malonaldehyde formation, and DNA fragmentation and that these effects were related to the peroxide group and the heme present in Hb. Furthermore, Hb and LAOOH alone exerted a toxic effect on the endpoints assayed only at concentrations higher than 100 MUM. We were also able to show that SW480 cells presented a higher level of the modified DNA bases 8-oxo-7,8-dihydro-2' deoxyguanosine and 1,N(2)-etheno-2'-deoxyguanosine compared to the control. Furthermore, incubations with Hb led to an increase in intracellular iron levels, and this high level of iron correlated with DNA oxidation, as measured as EndoIII and Fpg-sensitive sites. Thus, Hb from either red meat or bowel bleeding could act as an enhancer of fatty acid hydroperoxide genotoxicity, which contributes to the accumulation of DNA lesions in colon cancer cells. PMID- 21600978 TI - A deficit in zinc availability can cause alterations in tubulin thiol redox status in cultured neurons and in the developing fetal rat brain. AB - Zinc (Zn) deficiency during early development can result in multiple brain abnormalities and altered neuronal functions. In rats, a gestational deficit of Zn can affect the fetal brain cytoskeleton and signaling cascades involved in cellular processes that are central to brain development. In this paper, we tested the hypothesis that oxidative stress is involved in Zn deficiency-induced altered tubulin dynamics and the associated dysregulation of transcription factor NF-kappaB. For this purpose, we used two cell culture models (rat cortical neurons, human IMR-32 neuroblastoma cells) and an animal model of Zn deficiency. A low rate of in vitro tubulin polymerization, an increase in tubulin oligomers, and a higher protein cysteine oxidation were observed in the Zn-deficient neuronal cells and in gestation day 19 fetal brains obtained from dams fed marginal-Zn diets throughout pregnancy. These alterations could be prevented by treating the Zn-deficient cells with the reducing agent tris(2 carboxyethyl)phosphine or by the presence of N-acetylcysteine (NAC) and alpha lipoic acid (LA). Consistent with the above, Zn deficiency-induced tubulin mediated alterations in transcription factor NF-kappaB nuclear translocation were prevented by treating IMR-32 cells with LA and NAC. Binding of the NF-kappaB protein p50, dynein, and karyopherin alpha (components of the NF-kappaB transport complex) to beta-tubulin as well as the expression of NF-kappaB-dependent genes (Bcl-2, cyclin D1, and c-myc) was also restored by the addition of LA and NAC to Zn-deficient cells. In conclusion, a deficit in Zn viability could affect early brain development through: (1) an induction of oxidative stress, (2) tubulin oxidation, (3) altered tubulin dynamics, and (4) deregulation of signals (e.g., NF-kappaB) involved in critical developmental events. PMID- 21600980 TI - Nodulation-gene-inducing flavonoids increase overall production of autoinducers and expression of N-acyl homoserine lactone synthesis genes in rhizobia. AB - Legume-nodulating rhizobia use N-acyl homoserine lactones (AHLs) to regulate several physiological traits related to the symbiotic plant-microbe interaction. In this work, we show that Sinorhizobium fredii SMH12, Rhizobium etli ISP42 and Rhizobium sullae IS123, three rhizobial strains with different nodulation ranges, produced a similar pattern of AHL molecules, sharing, in all cases, production of N-octanoyl homoserine lactone and its 3-oxo and/or 3-hydroxy derivatives. Interestingly, production of AHLs was enhanced when these three rhizobia were grown in the presence of their respective nod-gene-inducing flavonoid, while a new molecule, C14-HSL, was produced by S. fredii SMH12 upon genistein induction. In addition, expression of AHL synthesis genes traI from S. fredii SMH12 and cinI and raiI from R. etli ISP42 increased when induced with flavonoids, as demonstrated by qRT-PCR analysis. PMID- 21600981 TI - Heparin stimulates elastogenesis: application to silk-based vascular grafts. AB - With over 500,000 coronary artery bypass grafts (CABG) performed annually in the United States alone, there is a significant clinical need for a small diameter tissue engineered vascular graft. A principle goal in tissue engineering is to develop materials and growth conditions that encourage appropriate recellularization and extracellular matrix formation in vivo. A particular challenge in vascular engineering results from the inability of adult cells to produce elastin, as its expression is developmentally limited. We investigated factors to stimulate elastogenesis in vitro, and found that heparin treatment of adult human vascular smooth muscle cells promoted the formation of elastic fibers. This effect was heparin-specific, and dependent on cell density and growth state. We then applied this information to a silk-based construct, and found that immobilized heparin showed essentially identical biological effects to that of soluble heparin. These findings indicate that heparinized vascular grafts may promote elastin formation and regulate restenosis, in addition to heparin's well-established antithrombotic properties. Given the increase in elastin mRNA level and the increase in extracellular elastin present, our data suggests that there may be multiple levels of elastin regulation that are mediated by heparin treatment. PMID- 21600982 TI - Anti-thyroid cancer properties of a novel isoflavone derivative, 7-(O) carboxymethyl daidzein conjugated to N-t-Boc-hexylenediamine in vitro and in vivo. AB - The incidence of thyroid cancer is up to 3 folds higher in women than in men, suggesting that estrogenic effects may be involved in the pathogenesis of this malignancy. Here, we explore whether or not human thyroid cancer cell growth can be curbed by a novel isoflavone derivative generated in our laboratory, the N-t Boc-hexylenediamine derivative of 7-(O)-carboxymethyl daidzein (cD-tboc). With the exception of the follicular cancer cell line WRO, estrogen receptor (ER)alpha mRNA was only marginally expressed in cell lines derived from papillary (NPA), follicular (MRO), anaplastic thyroid carcinoma (ARO) such that the expression of estrogen receptor (ER) betamRNA was more abundant than that of ERalpha mRNA in these cell types. Estradiol-17beta (E2; 0.03-300nmol/l) per se increased proliferation in all four cell-types. The ERbeta-specific agonist DPN increased [(3)H]-thymidine incorporation in all four thyroid cancer cell lines, whereas the ERalpha-specific agonist PPT increased growth only in NPA and WRO. By contrast, cD-tboc, derived from the weak estrogen daidzein, did not cause cell growth and dose-dependently diminished cell growth in all four cell lines via apoptosis and not necrosis, as detected by the release of histone-DNA fragments. The cytotoxic growth inhibitory effect of cD-tboc in these cells was modulated by E2 and the general caspase inhibitor Z-VAD-FMK, and the magnitude of this salvage was cell type-and dose-dependent. When nude mice carrying ARO thyroid xenografts were treated with cD-tboc, tumor volume decreased significantly, and no apparent toxicity was observed. These results suggest that cD-tboc may be a promising agent for therapy of thyroid carcinoma either alone or in combination with existing cytotoxic drugs. PMID- 21600983 TI - Impact of dopamine to serotonin cell ratio in transplants on behavioral recovery and L-DOPA-induced dyskinesia. AB - Fetal dopamine (DA) cell transplantation has shown to be efficient in reversing behavioral impairments associated with Parkinson's disease. However, the beneficial effects on motor behavior and L-DOPA-induced dyskinesia have varied greatly in between clinical trials and patients within the same trial. Recently, the inclusion of serotonin (5-HT) neurons in the grafted tissue has been suggested to play an important negative role, in particular, on the effect of L DOPA-induced dyskinesia. In the present study we have evaluated the influence of different ratios of DA neurons in relation to 5-HT neurons in the graft on spontaneous motor behavior and L-DOPA-induced dyskinesia in a rat model of Parkinson's disease. We show that using the standard dissection method that gives rise to a DA:5-HT ratio in the graft of 2:1 to 1:2 there is significant and consistent improvement in spontaneous motor behavior and reversal of L-DOPA induced dyskinesia. Increasing the ratio of 5-HT neurons in the graft, to a DA:5 HT ratio of in between 1:3 and 1:10, still induces significant reduction of L DOPA-induced dyskinesia, suggesting that the detrimental effect of 5-HT neurons on L-DOPA-induced dyskinesia is prevented even by small numbers of DA neurons in the graft. Nonetheless, while the post-synaptic responses were normalized following peripheral L-DOPA delivery in animals with low DA:5-HT ratio, we observed a pharmacological indication of hyperactive pre-synaptic response in these animals. These data suggests that 5-HT cells within a graft are neither detrimental nor beneficial for functional effects of DA-rich transplants; however, in absence of sufficient numbers of DA neurons, the 5-HT neurons may induce negative effects following L-DOPA therapy. In summary, our data indicate that for future clinical trials the inclusion of 5-HT neurons in grafted tissue is not critical as long as there are sufficient numbers of DA cells in the graft. PMID- 21600984 TI - Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat. AB - Multiple laboratories have recently demonstrated that long-term dopaminergic transplants form Lewy bodies in patients with Parkinson's disease. Debate has arisen as to whether these Lewy bodies form from the transfer of alpha synuclein from the host to the graft or whether they form from intrinsic responses of the graft from being placed into what was, or became, an inflammatory focus. To test whether the former hypothesis was possible, we grafted fetal rat ventral mesencephalon into the dopamine depleted striatum of rats that had previously received 6-hydroxydopamine lesions. One month after the transplant, rats received viral over expression of human alpha synuclein (AAV2/6-alpha synuclein) or green fluorescent protein (AAV2/6-GFP) into the striatum rostral to the grafts. Care was taken to make sure that the AAV injections were sufficiently distal to the graft so no cells would be directly transfected. All rats were sacrificed five weeks after the virus injections. Double label immunohistochemistry combined with confocal microscopy revealed that a small number of grafted tyrosine hydroxylase (TH) neurons (5.7% +/- 1.5% (mean +/- SEM) of grafted dopamine cells) expressed host derived alpha synuclein but none of the grafted cells expressed host-derived GFP. The alpha synuclein in a few of these cells was misfolded and failed to be digested with proteinase K. These data indicate that it is possible for host derived alpha synuclein to transfer to grafted neurons supporting the concept that this is one possible mechanism by which grafted dopamine neurons form Lewy bodies in Parkinson's disease patients. PMID- 21600986 TI - The adaptor protein Nck2 mediates Slit1-induced changes in cortical neuron morphology. AB - Slits are multifunctional guidance cues, capable of triggering neurite repulsion, extension, or branching, depending on cell type and developmental context. While the Robo family of Slit receptors is a well-established mediator of axon repulsion, a role for Robos in Slit-mediated neurite growth and branching is not well defined, and the signaling molecules that link Robo to the cytoskeletal changes that drive neurite outgrowth are not well characterized in vertebrates. We show that Slit stimulates cortical dendrite branching, and we report that Slit also triggers a robust increase in the length of cortical axons in vitro. Moreover, neurons derived from Robo1; Robo2 deficient mice do not display an increase in neurite length, indicating that endogenous Robos mediate Slit's growth-promoting effects on both axons and dendrites. We also demonstrate that the SH2/SH3 adaptor proteins Nck1 and Nck2 bind to Robo via an atypical SH3 mediated mechanism. Furthermore, we show that only Nck2 is required for the Slit induced changes in cortical neuron morphology in vitro. These findings indicate a specific role for Nck2 in linking Robo activation to the cytoskeleton rearrangements that shape cortical neuron morphology. PMID- 21600987 TI - Thermal precipitation fluorescence assay for protein stability screening. AB - A simple and reliable method of protein stability assessment is desirable for high throughput expression screening of recombinant proteins. Here we described an assay termed thermal precipitation fluorescence (TPF) which can be used to compare thermal stabilities of recombinant protein samples directly from cell lysate supernatants. In this assay, target membrane proteins are expressed as recombinant fusions with a green fluorescence protein tag and solubilized with detergent, and the fluorescence signals are used to report the quantity of the fusion proteins in the soluble fraction of the cell lysate. After applying a heat shock, insoluble protein aggregates are removed by centrifugation. Subsequently, the amount of remaining protein in the supernatant is quantified by in-gel fluorescence analysis and compared to samples without a heat shock treatment. Over 60 recombinant membrane proteins from Escherichia coli were subject to this screening in the presence and absence of a few commonly used detergents, and the results were analyzed. Because no sophisticated protein purification is required, this TPF technique is suitable to high throughput expression screening of recombinant membrane proteins as well as soluble ones and can be used to prioritize target proteins based on their thermal stabilities for subsequent large scale expression and structural studies. PMID- 21600985 TI - Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2 arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats. AB - Dysregulation in signaling of the endocannabinoid 2-arachidonoylglycerol (2-AG) is implicated in hyperresponsiveness to stress. We hypothesized that blockade of monoacylglycerol lipase (MGL), the primary enzyme responsible for 2-AG deactivation in vivo, would produce context-dependent anxiolytic effects in rats. Environmental aversiveness was manipulated by varying illumination of an elevated plus maze. Percentage open arm time and numbers of open and closed arm entries were measured in rats receiving a single intraperitoneal (i.p.) injection of either vehicle, the MGL inhibitor JZL184 (1-8mg/kg), the benzodiazepine diazepam (1mg/kg), the cannabinoid CB(1) receptor antagonist rimonabant (1mg/kg), or JZL184 (8mg/kg) coadministered with rimonabant (1mg/kg). JZL184 (8mg/kg) produced anxiolytic-like effects (i.e., increased percentage open arm time and number of open arm entries) under high, but not low, levels of environmental aversiveness. Diazepam produced anxiolytic effects in either context. Rimonabant blocked the anxiolytic-like effects of JZL184, consistent with mediation by CB(1). Anxiolytic effects of JZL184 were preserved following chronic (8mg/kg per day*6 days) administration. Chronic and acute JZL184 treatment similarly enhanced behavioral sensitivity to an exogenous cannabinoid (WIN55,212-2; 2.5mg/kg i.p.) 24 or 72h following the terminal injection, suggesting a pervasive effect of MGL inhibition on the endocannabinoid system. We attribute our results to alterations in emotion rather than locomotor activity as JZL184 did not alter the number of closed arm entries in the plus maze or produce motor ataxia in the bar test. Our results demonstrate that JZL184 has beneficial, context-dependent effects on anxiety in rats, presumably via inhibition of MGL-mediated hydrolysis of 2-AG. These data warrant further testing of MGL inhibitors to elucidate the functional role of 2 AG in controlling anxiety and stress responsiveness. Our data further implicate a role for 2-AG in the regulation of emotion and validate MGL as a therapeutic target. PMID- 21600988 TI - Molecular architecture of mouse activating NKR-P1 receptors. AB - Receptors belonging to NKR-P1 family and their specific Clr ligands form an alternative missing self recognition system critical in immunity against tumors and viruses, elimination of tumor cells subjected to genotoxic stress, activation of T cell dependent immune response, and hypertension. The three-dimensional structure of the extracellular domain of the mouse natural killer (NK) cell receptor mNKR-P1Aex has been determined by X-ray diffraction. The core of the C type lectin domain (CTLD) is homologous to the other CTLD receptors whereas one quarter of the domain forms an extended loop interacting tightly with a neighboring loop in the crystal. This domain swapping mechanism results in a compact interaction interface. A second dimerization interface resembles the known arrangement of other CTLD NK receptors. A functional dimeric form of the receptor is suggested, with the loop, evolutionarily conserved within this family, proposed to participate in interactions with ligands. PMID- 21600989 TI - Crystal structures of Pseudomonas aeruginosa guanidinobutyrase and guanidinopropionase, members of the ureohydrolase superfamily. AB - Pseudomonas aeruginosa guanidinobutyrase (GbuA) and guanidinopropionase (GpuA) catalyze the hydrolysis of 4-guanidinobutyrate and 3-guanidinopropionate, respectively. They belong to the ureohydrolase superfamily, which includes arginase, agmatinase, proclavaminate amidinohydrolase, and formiminoglutamase. In this study, we have determined the crystal structures of GbuA and GpuA from P. aeruginosa to provide a structural insight into their substrate specificity. Although GbuA and GpuA share a common structural fold of the typical ureohydrolase superfamily, they exhibit significant variations in two active site loops. Mutagenesis of Met161 of GbuA and Tyr157 of GpuA, both of which are located in the active site loop 1 and predicted to be involved in substrate recognition, significantly affected their enzymatic properties, implying their important roles in catalysis. PMID- 21600990 TI - Crystal structures and putative interface of Saccharomyces cerevisiae mitochondrial matrix proteins Mmf1 and Mam33. AB - The yeast Saccharomyces cerevisiae mitochondrial matrix factor Mmf1, a member in the YER057c/Yigf/Uk114 family, participates in isoleucine biosynthesis and mitochondria maintenance. Mmf1 physically interacts with another mitochondrial matrix protein Mam33, which is involved in the sorting of cytochrome b2 to the intermembrane space as well as mitochondrial ribosomal protein synthesis. To elucidate the structural basis for their interaction, we determined the crystal structures of Mmf1 and Mam33 at 1.74 and 2.10 A, respectively. Both Mmf1 and Mam33 adopt a trimeric structure: each subunit of Mmf1 displays a chorismate mutase fold with a six-stranded beta-sheet flanked by two alpha-helices on one side, whereas a subunit of Mam33 consists of a twisted six-stranded beta-sheet surrounded by five alpha-helices. Biochemical assays combined with structure based computational simulation enable us to model a putative complex of Mmf1 Mam33, which consists of one Mam33 trimer and two tandem Mmf1 trimers in a head to-tail manner. The two interfaces between the ring-like trimers are mainly composed of electrostatic interactions mediated by complementary negatively and positively charged patches. These results provided the structural insights into the putative function of Mmf1 during mitochondrial protein synthesis via Mam33, a protein binding to mitochondrial ribosomal proteins. PMID- 21600991 TI - The representation of social interaction in episodic memory: a functional MRI study. AB - The representation of social interaction in episodic memory is a critical factor for the successful navigation of social relationships. In general, it is important to separate episodic memory during social interaction from episodic memory during the self-generation of action events. Different cortical representations have been associated with social interaction vs. self-generated episodic memory. Here we clarified the cortical representation of the effect of context (social vs. solitary) on episodic memory by comparing it with the generation effect (self vs. other) on episodic memory. Each participant learned words while engaged in a sentence generation and a reading task, and subsequently each participant was scanned with functional magnetic resonance imaging (fMRI) while they performed a recognition task using the words that had been learned. The experiment was comprised of four conditions and we looked at two situations that involved a social context and non-social (solitary) context task. In the learning session before entering the MRI, two participants collaborated in a social context either generating (social-contextual self-generation condition: SS) or reading (social-contextual other-generation condition: SO) a sequence of sentences alternately to construct a meaningful story narrative. In the non social context, the participants generated (non-social-contextual self-generation condition: NS) or read (non-social-contextual other-generation condition: NO) a sequence of sentences individually. The stimuli for the recognition session consisted of learned words and novel words. Activation for social context retrieval was identified in the right medial prefrontal cortex (mPFC), and activation for self-generated retrieval was identified in the left mPFC and the left middle cingulate cortex. These results indicate that dissociable regions within the medial prefrontal cortices contribute to the processes involved in the representation of social interaction, including social context and self generation in the retrieval of episodic memory. PMID- 21600992 TI - Physiological correlates of subjective time: evidence for the temporal accumulator hypothesis. AB - Clock-counter models, the most influential cognitive models of temporal computation, have been successful in explaining a large set of behavioral data. However, it remains unclear whether the component operations postulated in these models correspond to any specific biological mechanism. Using stimuli in different sensory modalities and manipulating physical properties known to bias the 'subjective' perception of time (speed for vision and pitch for audition), the present study aimed to highlight brain areas where activity correlates with the 'subjective' perception of time: a time accumulator according to clock counter models. Using functional MRI we found that during the encoding of a temporal interval in the millisecond range (600 and 1000 ms), the hemodynamic response of a few brain regions correlated with the interval reproduction performance. For the visual modality, the activity of the putamen, the mid-insula and the mid-temporal cortex reflected the subjective interval duration, which was biased according to the different speeds of the visual stimuli. This effect was found only when subjects encoded the stimulus duration and was specific for the visual modality, where a significant overestimation of time with increasing speed was observed. These results demonstrate a definite relation between 'subjective time' and brain activity, supporting the hypothesis of a physiological correlate of time 'accumulation'. PMID- 21600993 TI - Electrophysiological effects of semantic context in picture and word naming. AB - Recent language production studies have started to use electrophysiological measures to investigate the time course of word selection processes. An important contribution with respect to this issue comes from studies that have relied on an effect of semantic context in the semantic blocking task. Here we used this task to further establish the empirical pattern associated with the effect of semantic context, and whether the effect arises during output processing. Electrophysiological and reaction time measures were co-registered while participants overtly named picture and word stimuli in the semantic blocking task. The results revealed inhibitory reaction time effects of semantic context for both words and pictures, and a corresponding electrophysiological effect that could not be interpreted in terms of output processes. These data suggest that the electrophysiological effect of semantic context in the semantic blocking task does not reflect output processes, and therefore undermine an interpretation of this effect in terms of word selection. PMID- 21600994 TI - Distortion correction of high b-valued and high angular resolution diffusion images using iterative simulated images. AB - High b-valued diffusion-weighted images (DWI), which were designed to solve fiber crossing problems, are susceptible to many artifacts and distortions. Since DWIs with different diffusion gradients produce dissimilar intensity contrasts, and since the distortion is nonlinear when multiple artifactual sources are intermixed, the mutual information-based affine registration may not be adequate for precise correction of distortions in DWIs, especially for images acquired with high b-values. To overcome these problems, we proposed an iterative image registration technique through which simulated DWIs are generated, driven from a diffusion tensor estimate, as targets for measured DWIs in the registration. Since simulated DWIs have similar intensity profiles to those of measured DWIs and the same geometric profiles as b(0)-images, an iterative procedure enables intensity-based nonlinear registration. As a pre-processing step, we also proposed a motion detection and sub-volume utilization for interleaved volumes. Performance evaluation with high b-valued DWIs for high angular resolution diffusion imaging and diffusion kurtosis imaging showed that the proposed method had a superior advantage over the conventional registration technique. PMID- 21600995 TI - Early time points perfusion imaging: relative time of arrival, maximum derivatives and fractional derivatives. AB - Time of arrival (TOA) of a bolus of contrast agent to the tissue voxel is a reference time point critical for the Early Time Points Perfusion Imaging Method (ET) to make relative cerebral blood flow (rCBF) maps. Due to the low contrast to noise (CNR) condition at TOA, other useful reference time points known as relative time of arrival data points (rTOA) are investigated. Candidate rTOA's include the time to reach the maximum derivative, the maximum second derivative, and the maximum fractional derivative. Each rTOA retains the same relative time distance from TOA for all tissue flow levels provided that ET's basic assumption is met, namely, no contrast agent has a chance to leave the tissue before the time of rTOA. The ET's framework insures that rCBF estimates by different orders of the derivative are theoretically equivalent to each other and monkey perfusion imaging results supported the theory. In rCBF estimation, maximum values of higher order fractional derivatives may be used to replace the maximum derivative which runs a higher risk of violating ET's assumption. Using the maximum values of the derivative of orders ranging from 1 to 1.5 to 2, estimated rCBF results were found to demonstrate a gray-white matter ratio of approximately 3, a number consistent with flow ratio reported in the literature. PMID- 21600996 TI - Monophyly and interrelationships of Snook and Barramundi (Centropomidae sensu Greenwood) and five new markers for fish phylogenetics. AB - Centropomidae as defined by Greenwood (1976) is composed of three genera: Centropomus, Lates, and Psammoperca. But composition and monophyly of this family have been challenged in subsequent morphological studies. In some classifications, Ambassis, Siniperca and Glaucosoma were added to the Centropomidae. In other studies, Lates+Psammoperca were excluded, restricting the family to Centropomus. Recent analyses of DNA sequences did not solve the controversy, mainly due to limited taxonomic or character sampling. The present study is based on DNA sequence data from thirteen genes (one mitochondrial and twelve nuclear markers) for 57 taxa, representative of all relevant species. Five of the nuclear markers are new for fish phylogenetic studies. The monophyly of Centropomidae sensu Greenwood was supported by both maximum likelihood and Bayesian analyses of a concatenated data set (12,888 bp aligned). No support was found for previous morphological hypotheses suggesting that ambassids are closely allied to the Centropomidae. Putative affinities between centropomids and Glaucosoma, Niphon, or Siniperca were strongly rejected by topology tests. In agreement with previous molecular hypotheses, our results place Centropomidae within a group of fishes that includes carangoids (e.g., jacks, remoras, dolphinfish, roosterfish, and cobia), flatfishes, barracudas, archerfishes, billfishes, moonfish, and threadfins. The phylogeny for the extant Centropomidae is ((Lates, Psammoperca), Centropomus). PMID- 21600997 TI - Rooting phylogenies using gene duplications: an empirical example from the bees (Apoidea). AB - The placement of the root node in a phylogeny is fundamental to characterizing evolutionary relationships. The root node of bee phylogeny remains unclear despite considerable previous attention. In order to test alternative hypotheses for the location of the root node in bees, we used the F1 and F2 paralogs of elongation factor 1-alpha (EF-1alpha) to compare the tree topologies that result when using outgroup versus paralogous rooting. Fifty-two taxa representing each of the seven bee families were sequenced for both copies of EF-1alpha. Two datasets were analyzed. In the first (the "concatenated" dataset), the F1 and F2 copies for each species were concatenated and the tree was rooted using appropriate outgroups (sphecid and crabronid wasps). In the second dataset (the "duplicated" dataset), the F1 and F2 copies were aligned to each another and each copy for all taxa were treated as separate terminals. In this dataset, the root was placed between the F1 and F2 copies (e.g., paralog rooting). Bayesian analyses demonstrate that the outgroup rooting approach outperforms paralog rooting, recovering deeper clades and showing stronger support for groups well established by both morphological and other molecular data. Sequence characteristics of the two copies were compared at the amino acid level, but little evidence was found to suggest that one copy is more functionally conserved. Although neither approach yields an unambiguous root to the tree, both approaches strongly indicate that the root of bee phylogeny does not fall near Colletidae, as has been previously proposed. We discuss paralog rooting as a general strategy and why this approach performs relatively poorly with our particular dataset. PMID- 21600998 TI - The cell cycle gene MoCDC15 regulates hyphal growth, asexual development and plant infection in the rice blast pathogen Magnaporthe oryzae. AB - Rice blast, caused by the pathogen Magnaporthe oryzae, is a serious hindrance to rice production and has emerged as an important model for the characterization of molecular mechanisms relevant to pathogenic development in plants. Similar to other pathogenic fungi, conidiation plays a central role in initiation of M.oryzae infection and spread over a large area. However, relatively little is known regarding the molecular mechanisms that underlie conidiation in M. oryzae. To better characterize these mechanisms, we identified a conidiation-defective mutant, ATMT0225B6 (MoCDC15(T-DNA)), in which a T-DNA insertion disrupted a gene that encodes a homolog of fission yeast cdc15, and generated a second strain containing a disruption in the same allele (DeltaMoCDC15(T-DNA)). The cdc15 gene has been shown to act as a coordinator of the cell cycle in yeast. Functional analysis of the MoCDC15(T-DNA) and DeltaMoCDC15(T-DNA) mutants revealed that MoCDC15 is required for conidiation, preinfection development and pathogenicity in M. oryzae. Conidia from these mutants were viable, but failed to adhere to hydrophobic surface, a crucial step required for subsequent pathogenic development. All phenotypic defects observed in mutants were rescued in a strain complemented with wild type MoCDC15. Together, these data indicate that MoCDC15 functions as a coordinator of several biological processes important for pathogenic development in M. oryzae. PMID- 21601000 TI - Small animals models for drug discovery. AB - There has been an explosion of studies of animal models of asthma in the past 20 years. The elucidation of fundamental immunological mechanisms underlying the development of allergy and the complex cytokine and chemokines networks underlying the responses have been substantially unraveled. Translation of findings to human asthma have been slow and hindered by the varied phenotypes that human asthma represents. New areas for expansion of modeling include virally mediated airway inflammation, oxidant stress, and the interactions of stimuli triggering innate immune and adaptive immune responses. PMID- 21601001 TI - The interactive effects of a gradual temperature decrease and long-term food deprivation on cardiac and hepatic blood flows in rainbow trout (Oncorhynchus mykiss). AB - The aim of the present study was to determine the extent to which the fish liver is perfused with blood. Transonic(r) flow probes were therefore implanted around the ventral aorta and hepatic vein(s) to record baseline blood flows in rainbow trout (Oncorhynchus mykiss) previously held under two different feeding regimes (food-deprived or fed to satiation, 8-12 weeks). Fish from both groups were exposed to a gradual temperature decrease (12 degrees C to 5 degrees C) and physical disturbance. Cardiac output (Q), stroke volume (Sv) and hepatic venous blood flow (HVBF) were significantly reduced in food-deprived trout at 12 degrees C. Heart rate was not significantly affected by nutritional status, but was significantly reduced when temperature was decreased to 5 degrees C. Physically disturbing each fish at 12 degrees C and 5 degrees C showed that the performance capacity of the heart was not affected by food deprivation as the capacity to increase Q and Sv was not reduced in the food-deprived group. Overall this study showed that food deprivation in rainbow trout reduced cardiac and hepatic blood flows. However, long-term food deprivation did not affect the capacity of the heart to acutely increase performance. PMID- 21600999 TI - Exploring lung physiology in health and disease with lung slices. AB - The development of therapeutic approaches to treat lung disease requires an understanding of both the normal and disease physiology of the lung. Although traditional experimental approaches only address either organ or cellular physiology, the use of lung slice preparations provides a unique approach to investigate integrated physiology that links the cellular and organ responses. Living lung slices are robust and can be prepared from a variety of species, including humans, and they retain many aspects of the cellular and structural organization of the lung. Functional portions of intrapulmonary airways, arterioles and veins are present within the alveoli parenchyma. The dynamics of macroscopic changes of contraction and relaxation associated with the airways and vessels are readily observed with conventional low-magnification microscopy. The microscopic changes associated with cellular events, that determine the macroscopic responses, can be observed with confocal or two-photon microscopy. To investigate disease processes, lung slices can either be prepared from animal models of disease or animals exposed to disease invoking conditions. Alternatively, the lung slices themselves can be experimentally manipulated. Because of the ability to observe changes in cell physiology and how these responses manifest themselves at the level of the organ, lung slices have become a standard tool for the investigation of lung disease. PMID- 21601003 TI - Amyloid-beta: the seeds of darkness. AB - Whilst the amyloid-beta (Abeta) hypothesis/centric theory continues to evolve, genetic, biochemical and pathological evidence still suggests that Abeta is central to the etiology of Alzheimer's disease (AD). In particular, Abeta oligomers/soluble Abeta, may be an earlier determinant of Alzheimer's disease and better correlative of cognitive impairment. Whilst there are a number of Abeta oligomeric species in existence (making therapeutic and diagnostic biomarker choice cumbersome), their existence is in equilibrium with Abeta-fibrils, the main constituent of cored plaques. Although Alzheimer's disease remains incurable, improvements to Abeta immunotherapies and strategies to target Abeta continue to evolve, with the reliance upon Abeta imaging to shed light on the outcome of therapeutics proving very useful. PMID- 21601002 TI - Inhibition of hematopoietic prostaglandin D synthase improves allergic nasal blockage in guinea pigs. AB - Although it has been suggested that prostaglandin (PG) D(2) is involved in the pathogenesis of allergic rhinitis, whether the inhibition of hematopoietic PGD(2) synthase (H-PGDS) shows beneficial effects on allergic rhinitis has been unclear. We evaluated the effects of a selective H-PGDS inhibitor, TFC-007, on nasal symptoms on Japanese cedar pollen-induced allergic rhinitis of guinea pigs. Sensitized animals were challenged with the pollen once a week. TFC-007 (30mg/kg, p.o.) given once before a challenge almost completely suppressed PGD(2) production in the nasal tissue early and late after the challenge. Although pre treatment did not affect the incidences of sneezing and early phase nasal blockage, late phase nasal blockage was partially but significantly attenuated; however, nasal eosinophilia was not suppressed. In contrast, when TFC-007 was given once 1.5h after the challenge, the late phase response was not affected. Collectively, PGD(2) produced by H-PGDS early after an antigen challenge can participate in the induction of late phase nasal blockage, although the mechanism may be independent of eosinophil infilatration. The strategy for H-PGDS inhibition may be beneficial for allergic rhinitis therapy. PMID- 21601004 TI - An acidic pH environment increases cell death and pro-inflammatory cytokine release in osteoblasts: the involvement of BAX inhibitor-1. AB - BAX Inhibitor-1 (BI-1), a transmembrane protein on the endoplasmic reticulum, has been studied previously in various physio/pathological conditions, but not in bone cells. In this study, using the MG63 osteoblast cell line and osteoblasts differentiated from stem cells, the role of BI-1 was studied. First, expression of BI-1 was confirmed in osteoblasts, as well as osteoclasts, in mouse tibiae bone immunohistochemistry. For evaluation of a recently published property of BI 1, an acidic pH-dependent Ca2+ channel-like effect in osteoblasts, acidic pH associated cell death, and pro-inflammatory cytokine release were examined. In MG63 osteoblasts, acidic pH induced a pH-dependent increase in cell death and ER stress, as determined by elevated expression of GRP78, CHOP, phospho-eIF2alpha, IRE-1alpha, spliced XBP-1, and phospho-JNK. In osteoblasts, mitochondrial Ca2+ also showed a strong pH-dependent increase. BI-1 knock-down using siRNA protected cells against acidic pH, regulating mitochondrial Ca2+ accumulation, possibly via the acidic pH-dependent Ca2+ channel-like effect of BI-1. BI-1 knock-down also resulted in inhibition of acidic pH-induced release of pro-inflammatory cytokines, including IL-1beta, IL-6, and TNF-alpha. In addition, bone marrow stem cells were differentiated into human osteoblasts, which showed increased expression of BI-1 mRNA and protein. In differentiated primary human osteoblasts, acidic pH-associated cell death, mitochondrial Ca2+ accumulation, and pro inflammatory cytokine release were more significant than in non-differentiated stem cells. In summary, endogenous expression of BI-1 is associated with acidic pH-induced Ca2+ release, cell death, and pro-inflammatory cytokine release in human osteoblasts. PMID- 21601005 TI - The impact of pericytes on the blood-brain barrier integrity depends critically on the pericyte differentiation stage. AB - The blood-brain barrier consists of the cerebral microvascular endothelium, pericytes, astrocytes and neurons. In this study we analyzed the differentiation stage dependent influence of primary porcine brain capillary pericytes on the barrier integrity of primary porcine brain capillary endothelial cells. At first, we were able to induce two distinct differentiation stages of the primary pericytes in vitro. TGFbeta treated pericytes expressed more alpha-SMA and actin while desmin, vimentin and nestin expression was decreased when compared to bFGF induced cells. Further analysis of alpha-SMA revealed that most of the pericytes differentiated with TGFbeta expressed functional alpha-SMA while only few cells expressed functional alpha-SMA in the presence of bFGF. In addition the permeability factors VEGF, MMP-2 and MMP-9 were higher secreted by the alpha-SMA positive phenotype indicating a proangiogenic role of this TGFbeta induced pericyte differentiation stage. Higher level of VEGF, MMP-2 and MMP-9 were as well detected in the TGFbeta pretreated pericyte coculture with endothelial cells when compared to the influence of the bFGF pretreated pericytes. The TEER measurement of the barrier integrity of endothelial cells revealed that bFGF induced alpha-SMA negative pericytes stabilize the barrier integrity while alpha SMA positive pericytes differentiated by TGFbeta decrease the barrier integrity. These results together reveal the potential of pericytes to regulate the endothelial barrier integrity in a differentiation stage dependant pathway. PMID- 21601006 TI - Small interfering RNA targeting integrin-linked kinase inhibited the growth and induced apoptosis in human bladder cancer cells. AB - Integrin-linked kinase (ILK), an intracellular serine/threonine kinase, is implicated in cell growth and survival, cell-cycle progression, tumor angiogenesis, and cell apoptosis. Recent studies showed that the expression and activity of ILK increased significantly in many types of solid tumors. However, the exact molecular mechanism of ILK underlie tumor has not been fully ascertained. The purpose of our study was to determine whether knockdown of ILK would inhibit cell growth and induce apoptosis in bladder cancer cells using a plasmid vector based small interfering RNA (siRNA). The experiments showed that knockdown of ILK could remarkably inhibit cell proliferation and growth, regulate cell cycle and induce apoptosis of bladder cancer BIU-87 and EJ cells. We demonstrated that knockdown of ILK inhibited phosphorylation of downstream signaling targets protein kinase B/Akt, glycogen synthase kinase 3-beta (GSK 3beta), and reduced expression of beta-catenin in BIU-87 as well as EJ cells by Western blot and Immunofluorescence analysis. In addition, down-regulation of ILK also could increase expression of Ribonuclease inhibitor (RI), an important acidic cytoplasmic protein with many functions. BALB/C nude mice injected with the BIU-87 cells transfected ILK siRNA showed a significant inhibition of the tumor growth with lighter tumor weight, lower microvessels density and higher apoptosis rate than those in the other two control groups. In conclusion, these results suggest that ILK might be involved in the development of bladder cancer, and could be served as a novel potential therapy target for human bladder cancer. Our study may be of biological and clinical importance. PMID- 21601007 TI - Caveolin-1 overexpression enhances androgen-dependent growth and proliferation in the mouse prostate. AB - Prostate cancer (PCa) continues to be one of the leading causes of cancer-related deaths among American men. The prostate relies upon the androgen receptor (AR) to mediate the effects of androgens on normal growth, a reliance that is maintained during malignant prostate growth. Caveolin-1 (Cav-1), the main structural component of caveolae, has been shown to promote the malignant growth and invasion of prostate tumors. In vitro work has shown that Cav-1 can act as an AR coactivator by enhancing its transciptional activity. However, it is unknown how Cav-1 affects androgen-dependent growth and signaling in vivo. To explore this role, a novel mouse model of Cav-1 overexpression was developed with a hormone insensitive promoter. Cav-1 transgenic (Tg) mice subjected to castration and androgen stimulation display enlarged prostate weights and increased DNA synthesis. Through gene transcript and proteomic profiling, we demonstrate that Cav-1 overexpression favors androgen-regulated responses and enhances processes involved in transcription, cell cycle progression and protein synthesis. Interestingly, Cav-1 overexpression was associated with an increase in the phosphorylation of AR on serine 210, a post-translational modification linked to its activity under androgen-stimulated conditions. In addition, these mice exhibited an increase in the phosphorylation of ribosomal S6 protein on serine 235/236 (pS6), a marker of protein synthesis and a downstream component of the mTOR pathway. Thus, Cav-1 Tg mice could serve as a novel model for studying AR regulated pathways involved in prostate growth and proliferation. PMID- 21601008 TI - Anti-genotoxic activity of Vitis coignetiae Pulliat towards heterocyclic amines and isolation and identification of caftaric acid as an antimutagenic component from the juice. AB - Our study demonstrated that the formation of DNA adducts in liver, lungs, colon and kidneys of mice given a carcinogenic heterocyclic amine, 2-amino-3,8 dimethylimidazo[4,5-f]quinoxaline (MeIQx) or 2-amino-1-methyl-6-phenylimidazo[4,5 b]pyridine (PhIP), in the diet significantly decreased following the administration of the juice of Vitis coignetiae, purple berries from a vine tree. The juice of V. coignetiae significantly inhibited the clastogenicity and mutagenicity of heterocyclic amines in the micronucleus assay and the Ames test, and was an effective inhibitor of the activities of phase I enzymes (cytochrome P450 1A1 and cytochrome P450 1A2) and enhancer of the activities of phase II enzymes (uridine 5'-diphospho-glucuronosyltransferase and glutathione S transferase). We investigated the purification and isolation of an active compound in the juice of V. coignetiae using antimutagenicity as a separation marker. Caftaric acid, a polyphenolic compound, was identified as a component responsible for antimutagenicity in the juice of V. coignetiae towards the carcinogenic heterocyclic amine 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P 2). This is the first report of antimutagenicity of caftaric acid. Caftaric acid was reported as an inhibitor of the protein-protein interactions mediated by the Src-family kinases. The impact of the juice of V. coignetiae and its constituents on tumor initiation and promotion thus warrants further study. PMID- 21601009 TI - Nanomedicine approaches in vascular disease: a review. AB - Nanomedicine approaches have revolutionized the treatment of cancer and vascular diseases, where the limitations of rapid nonspecific clearance, poor biodistribution and harmful side effects associated with direct systemic drug administration can be overcome by packaging the agents within sterically stabilized, long-circulating nanovehicles that can be further surface-modified with ligands to actively target cellular/molecular components of the disease. With significant advancements in genetics, proteomics, cellular and molecular biology and biomaterials engineering, the nanomedicine strategies have become progressively refined regarding the modulation of surface and bulk chemistry of the nanovehicles, control of drug release kinetics, manipulation of nanoconstruct geometry and integration of multiple functionalities on single nanoplatforms. The current review aims to capture the various nanomedicine approaches directed specifically toward vascular diseases during the past two decades. Analysis of the promises and limitations of these approaches will help identify and optimize vascular nanomedicine systems to enhance their efficacy and clinical translation in the future. FROM THE CLINICAL EDITOR: Nanomedicine-based approaches have had a major impact on the treatment and diagnosis of malignancies and vascular diseases. This review discusses various nanomedicine approaches directed specifically toward vascular diseases during the past two decades, highlighting their advantages, limitations and offering new perspectives on future applications. PMID- 21601010 TI - Recruiting and retaining family caregivers to a randomized controlled trial on mindfulness-based stress reduction. AB - Caregivers for a family member with dementia experience chronic long-term stress that may benefit from new complementary therapies such as mindfulness-based stress reduction. Little is known however, about the challenges of recruiting and retaining family caregivers to research on mind-body based complementary therapies. Our pilot study is the first of its kind to successfully recruit caregivers for a family member with dementia to a randomized controlled pilot study of mindfulness-based stress reduction. The study used an array of recruitment strategies and techniques that were tailored to fit the unique features of our recruitment sources and employed retention strategies that placed high value on establishing early and ongoing communication with potential participants. Innovative recruitment methods including conducting outreach to health plan members and generating press coverage were combined with standard methods of community outreach and paid advertising. We were successful in exceeding our recruitment goal and retained 92% of the study participants at post intervention (2 months) and 90% at 6 months. Recruitment and retention for family caregiver interventions employing mind-body based complementary therapies can be successful despite many challenges. Barriers include cultural perceptions about the use and benefit of complementary therapies, cultural differences with how the role of family caregiver is perceived, the use of group-based designs requiring significant time commitment by participants, and travel and respite care needs for busy family caregivers. PMID- 21601011 TI - International human subject research: taking stock in the wake of the Guatemala affair. AB - The recent unearthing of a US-funded study wherein unknowing Guatemalans were exposed to syphilis, gonorrhea, or chancroid sent shock waves throughout the scientific community. Prompted by this revelation, the Presidential Commission for the Study of Bioethical Issues has been convened to determine if current "standards adequately guard the health and well-being of participants in scientific studies supported by the Federal Government." This communication revisits the statutory and regulatory framework undergirding federally sponsored human subject research and explores its continued relevance in a rapidly globalizing enterprise. The emerging patterns are daunting and disconcerting. Over half of all clinical trials registered with ClinicalTrials.gov (http://clinicaltrials.gov/) (>100,000) are presently conducted in 145 (often poorly resourced) nations under the jurisdiction of over 2000 international IRBs. Review of the operational characteristics of the Office of Human Research Protection, the relevant oversight authority, reveals it to be underfunded and understaffed and thus unable to discharge its rapidly globalizing responsibilities. A review of federally sponsored human subject research by the Presidential Commission-now underway-could not be timelier. PMID- 21601012 TI - Molecular characterization and phylogenetic analysis of full-genome HBV subgenotype D3 sequences from Serbia. AB - Hepatitis B virus (HBV) is classified into 8 genotypes with distinct geographical distribution. Genotype D (HBV/D) has the widest distribution area and is comprised of 7 subgenotypes. Subgenotypes D1, D2 and D3 appear worldwide, while D4-D7 have a more restricted distribution. Within the Mediterranean area, HBV/D and subgenotype D3 are the most prevalent. The purpose of this study was to characterize the full genome of Serbian HBV/D3 isolates by comparison and phylogenetic analysis with HBV/D3 sequences (66 samples) found in GeneBank/DDBJ databases from different parts of the world. Isolates were obtained from three patients diagnosed with chronic hepatitis B (HBsAg+). All three isolates have two very rare nucleotide substitutions, A929T and T150A, which indicate the same ancestor. Phylogenetic analysis of HBV/D3 genome sequences throughout the world follows an ethno-geographical origin of isolates with rare exceptions, which could be explained by human travelling and migration. The geographically close but ethnically different Serbian and Italian isolates clustered in the same subnode, and on a common branch with strains from Northern Canada. To test the apparently close HBV phylogenetic relationship between completely separated patients from Serbia and Northern Canada we analyzed in depth a 440 bp region of the HBsAg from Canadian (n=73) and Serbian (n=70) isolates. The constructed parsimony tree revealed that strains from Serbia and Northern Canada fell along the same branch which indicates independent evolution within regions of each country. Considering that HBsAg sequence has limited variability for phylogenetic analyses, our hypothesis needs further confirmation with more HBV complete genome sequences. PMID- 21601013 TI - SP-A1, SP-A2 and SP-D gene polymorphisms in severe acute respiratory syncytial infection in Chilean infants. AB - Respiratory syncytial virus (RSV) is the principal pathogen that causes acute lower respiratory tract infection (ALRI) in infants. Severe RSV-ALRI has been associated with the host genetic susceptibility. To assess whether severe RSV disease in infants is associated with certain single nucleotide polymorphism (SNP) into the gene of SP-A1, SP-A2 and SP-D, a prospective study was performed among blood donors and RSV-infected infants aged 600-fold. Efficient amplification of nucleic acid was achieved with as few as three copies of the DNA template. This system may be useful for the development of novel lab-on-a-chip devices and shows promise for single-molecule amplification in droplet assays, with potential applications in nanobiotechnology, nanomedicine, and clinical molecular diagnostics. PMID- 21601026 TI - Determination of antioxidant additives in foodstuffs by direct measurement of gold nanoparticle formation using resonance light scattering detection. AB - The capability of antioxidant compounds to reduce gold(III) to gold nanoparticles has been kinetically studied in the presence of cetyltrimethylammonium bromide using stopped-flow mixing technique and resonance light scattering as detection system. This study has given rise to a simple and rapid method for the determination of several synthetic and natural antioxidants used as additives in foodstuff samples. The formation of AuNPs was monitored by measuring the initial reaction-rate of the system in about 5s, using an integration time of 0.1s. Dynamic ranges of the calibration graphs and detection limits, obtained with standard solutions of the analytes, were (MUmolL-1): gallic acid (0.04-0.59, 0.01), propyl gallate (0.04-1.41, 0.01), octyl gallate (0.03-0.35, 0.08), dodecyl gallate (0.02-0.30, 0.007), butylated hydroxyanisol (0.07-0.39, 0.009), butylated hydroxytoluene (0.04-0.32, 0.01), ascorbic acid (0.11-1.72, 0.03) and sodium citrate (0.07-1.29, 0.02). The regression coefficients were higher than 0.994 in all instances. The precision of the method, expressed as RSD%, was established at two concentration levels of each analyte, with values ranging between 0.6 and 4.8%. The practical usefulness of the developed method was demonstrated by the determination of several antioxidant additives in foodstuff samples, which were extracted, appropriately diluted and assayed, obtaining recoveries between 95.4 and 99.5%. The results obtained were validated using two reference methods. PMID- 21601027 TI - Ionic liquids in solid-phase microextraction: a review. AB - Solid-phase microextraction (SPME) has undergone a surge in popularity within the field of analytical chemistry in the past two decades since its introduction. Owing to its nature of extraction, SPME has become widely known as a quick and cost-effective sample preparation technique. Although SPME has demonstrated extraordinary versatility in sampling capabilities, the technique continues to experience a tremendous growth in innovation. Presently, increasing efforts have been directed towards the engineering of novel sorbent material in order to expand the applicability of SPME for a wider range of analytes and matrices. This review highlights the application of ionic liquids (ILs) and polymeric ionic liquids (PILs) as innovative sorbent materials for SPME. Characterized by their unique physico-chemical properties, these compounds can be structurally-designed to selectively extract target analytes based on unique molecular interactions. To examine the advantages of IL and PIL-based sorbent coatings in SPME, the field is reviewed by gathering available experimental data and exploring the sensitivity, linear calibration range, as well as detection limits for a variety of target analytes in the methods that have been developed. PMID- 21601028 TI - Novel electrochemical sensor for the selective recognition of chlorogenic acid. AB - In this study, a novel sensitive molecularly imprinted electrochemical sensor was constructed for the selective detection of chlorogenic acid (CGA) by deposition of a molecularly imprinted siloxane (MIS) film, prepared by sol-gel process, onto Au bare electrode surface. Initially, a (3-mercaptopropyl)siloxane layer (MSL) was formed on the Au bare surface, followed by a siloxane layer obtained from the acid-catalyzed hydrolysis/condensation of a solution constituted by tetraethoxysilane (TEOS), phenyltriethoxysilane (PTEOS), 3 (aminopropyl)trimethoxysilane (APTMS) and CGA, as a molecular template. After the GCA extraction the MIS imprinted film was electrochemically characterized using differential pulse voltammetry (DPV). The MIS/Au sensor was tested in a solution of the CGA template and other similar molecules. This electrode displayed excellent selectivity towards CGA when compared with structurally similar molecules. Under optimized experimental conditions, the peak current response of the sensor for CGA was linear from 5.0 * 10(-7)mol L(-1) to 1.4 * 10(-5)mol L( 1), and the detection limit was 1.48 * 10(-7)mol L(-1). The MIS/Au sensor was successfully applied for the determination of CGA in coffee and tea samples. PMID- 21601030 TI - CMK-3 nanoporous carbon as a new fiber coating for solid-phase microextraction coupled to gas chromatography-mass spectrometry. AB - CMK-3 nanoporous carbon was prepared and characterized as a highly porous fiber coating, with a highly ordered carbon framework, for solid-phase microextraction (SPME). The nanomaterial was immobilized onto platinum, stainless steel and copper metal wires for preparation of new SPME fibers. The copper-CMK-3 fiber showed superior properties and therefore was applied for extraction of some phenolic compounds in combination with GC-MS. For optimization of the extraction conditions, a simplex optimization method was used. The selected conditions were: sample volume 13 ml, extraction temperature 56 degrees C, extraction time 7 min, ultrasonic time 5.5 min, pH 5 and salt concentration 8.9%. The selected fiber showed some selectivity towards the polar phenolic compounds and its extraction efficiency was better than a commercial PDMS fiber. Linear calibration curves with correlation coefficients better than 0.99 and detection limits in the range from 0.002 to 0.068 MUg mL(-1) were obtained for the fiber. No significant change was observed in the extraction efficiency of the new SPME fiber over at least 40 extractions. The fiber was successfully used for the determination of phenolic compounds in natural water samples. PMID- 21601029 TI - Characterization of Hg(II) binding with different length phytochelatins using liquid chromatography and amperometric detection. AB - A simple and rapid methodology is optimised to analyse mixtures of different phytochelatins (PC(n), n=2-5) with Hg(II) by HPLC with amperometric detection as a first step towards the analysis of extracts of plants stressed with Hg(II). The separation was achieved in a C(18) column with a mobile phase of 0.1% trifluoroacetic acid (TFA) in water and 0.1% TFA in acetonitrile using gradient elution. Electrochemical detection with glassy carbon electrode and UV-vis detection were used in series. This methodology can clearly distinguish between the free peptides and their complexes and permits to study the evolution of the different complexes formed and predicts the possible interactions between the long chain phytochelatin complexes. ESI-MS is used as a complementary technique to find out the stoichiometries of such long chain phytochelatin complexes. PMID- 21601031 TI - Development and characterization of molecularly imprinted polymers for the selective enrichment of podophyllotoxin from traditional Chinese medicines. AB - In the present work, microwave heating initiated precipitation polymerization was developed to prepare podophyllotoxin (PPT) molecularly imprinted polymers (MIPs), resulting in much shorter polymerization time and better particle morphology. Prior to the polymerization, ultraviolet and FTIR spectroscopy were used to study the interactions between PPT and the functional monomers. The synthesized parameters were respectively optimized and the optimal conditions for the efficient adsorption property were template: PPT, 1 mmol; functional monomer: acrylamide, 6 mmol; bi-crosslinker: ethylene glycol dimethacrylate, 20 mmol and divinylbenzene, 20 mmol; porogen: acetonitrile, 40 mL; initiator: azobisisobutyronitrile, 0.01mol L-1; polymerization temperature: 60 degrees C. FTIR spectroscopy, SEM and thermal analysis were used to characterize the MIPs. The results of the equilibrium rebinding experiments and the competitive adsorption experiments showed that these imprinted polymers exhibited good adsorption ability for the PPT. Scatchard analysis illustrated that two and one types of binding sites were generated in the MIPs and non-imprinted polymers (NIPs), respectively. Using the prepared MIPs as the solid phase extraction (SPE) sorbent, PPT was extracted selectively and efficiently from Dysosma versipellis, Sinopodophyllum hexandrum and Diphylleia sinensis. The regression equation was y=5.873*106x+17075.659 with the correlation coefficient of 0.9994 in the concentration range of 0.005-0.4 mg mL-1. After washing and eluting the SPE column with methanol and MeOH/acetic acid solution (v/v, 9:1), the limits of detection were 0.12-0.18 MUg mL-1 and their recoveries were in the range of 89.5 91.1% with all RSDs lower than 3.7. PMID- 21601032 TI - Rotating disk sorbent extraction for pre-concentration of chromogenic organic compounds and direct determination by solid phase spectrophotometry. AB - A novel and very simple microextraction approach for pre-concentration and direct solid phase spectrophotometric measurement has been developed for the determination of chromogenic analytes. The model analyte to assess this approach was the chromophore malachite green (MG). The analyte was extracted from water samples onto a small rotating disk made of Teflon containing a sorbent phase of polydimethylsiloxane (PDMS) on one of its surfaces. We refer to the extraction procedure as rotating disk sorptive extraction (RDSE). After extraction, the sorbent phase with the concentrated analyte was separated from the Teflon disk and used directly for MG determination by solid phase spectrophotometry at 624 nm, without the necessity of a desorption step. Chemical and extraction variables such as concentration of sodium sulfate, pH, disk rotational velocity, extraction time, and temperature were studied in order to establish the best conditions for extraction. Under optimum conditions, the extraction of MG was carried out in 18 min and 90 min, for sample volumes of 100mL or 1000 mL, respectively. The detection limit, based on three times the standard deviation of the blank phase (3sigma(b)), was 1.4 MUg L-1 and the repeatability, expressed as relative standard deviation (RSD), for 20 MUg L-1 MG was 8.1%. This study also applied the method to real samples, obtaining quantitative recovery (mean recovery of 99.3%). The PDMS phases could be reused after desorbing the MG into methanol for 3h. Replacement of the PDMS film onto the disk is very easy and low cost. PMID- 21601033 TI - Identification and quantification of glucosamine in rabbit cartilage and correlation with plasma levels by high performance liquid chromatography electrospray ionization-tandem mass spectrometry. AB - A new HPLC-ESI-MS/MS method for the determination of glucosamine (2-amino-2-deoxy d-glucose) in rabbit cartilage was developed and optimized. Glucosamine was extracted from cartilage by cryogenic grinding followed by protein precipitation with trichloroacetic acid. The HPLC separation was achieved with a polymer-based amino column using a mobile phase composed of 10mM ammonium acetate (pH 7.5) acetonitrile (20:80%, v/v) at 0.3 mL min flow rate. d-[1-(13)C]Glucosamine was used as internal standard. Selective detection was performed by tandem mass spectrometry with electrospray source, operating in positive ionization mode and in multiple reaction monitoring acquisition (m/z 180->72 and 181->73 for glucosamine and internal standard, respectively). Limit of quantification was 0.045 ng injected, corresponding to 0.25 MUg g-1 in cartilage. Linearity was obtained up to 20 MUg g-1 (R(2)>0.991). Precision values (%R.S.D.) were <10%. Accuracy (% bias) ranged from -6.0% to 12%. Mean recoveries obtained at 3 concentration levels were higher than 81% (%R.S.D.<=8%). The method was applied to measure glucosamine levels in rabbit cartilage and plasma after single oral administration of glucosamine sulfate at a dose of 98 mg kg-1(n=6). Glucosamine was present in cartilage in physiological condition before the treatment. After dosing, mean concentration of cartilage glucosamine significantly increased from 461 to 1040 ng g-1. Cartilage glucosamine levels resulted to be well correlated with plasma concentrations, which therefore are useful to predict the target cartilage concentration and its pharmacological activity. PMID- 21601034 TI - A highly sensitive and rapid organophosphate biosensor based on enhancement of CdS-decorated graphene nanocomposite. AB - This work reports a rapid and sensitive organophosphates (OPs) amperometric biosensor based on acetylcholinesterase (AChE) immobilized on CdS-decorated graphene (CdS-G) nanocomposite. The as-prepared biosensor shows high affinity to acetylthiocholine (ATCl) with a Michaelis-Menten constant (K(m)) value of 0.24 mM. A rapid inhibition time (2 min) is obtained due to the integration of the CdS G nanocomposite. Based on the inhibition of OPs on the enzymatic activity of the immobilized AChE, and used carbaryl as the model compound, the resulting biosensor exhibits excellent performance for OPs detection including good reproducibility, acceptable stability, and a reliable linear relationship between the inhibition and log[carbaryl] from 2 ng mL-1 up to 2 MUg mL-1 with a detection limit of 0.7 ng mL-1,which provides a new promising tool for analysis of enzyme inhibitors. PMID- 21601036 TI - Gold nanoparticle-fluorophore complex for conditionally fluorescing signal mediator. AB - Fluorescent contrast agents with high specificity and sensitivity are valuable for accurate disease detection and diagnosis. Spherical gold nanoparticles (GNPs) can be smartly utilized for developing highly effective agents. The strong electromagnetic (plasmon) field on their surface can be very effective in influencing the electrons of fluorophores and, thus, manipulating the fluorescence output (i.e., either quenching or enhancement). Fluorescence quenching can be used for negative sensing, or for conditional de-quenching to increase the specificity. Fluorescence enhancement allows sensing to be more sensitive. The level of fluorescence alteration depends on the GNP size, the excitation and emission wavelengths and quantum yield of the fluorophore, and the distance between the GNP and the fluorophore. To understand the mechanisms of the fluorescence change by GNP, we have theoretically analyzed the parameters involved in the fluorescence alteration for commonly used fluorophores, with an emphasis on quenching. The results showed that the fluorescence of fluorophores with the excitation (Ex) and emission (Ex) wavelengths close to the GNP resonance peak tended to be significantly quenched by GNPs. For those fluorophores emitting fluorescence in red or near infrared, to achieve quenching, the distance between GNP and the fluorophore was required to be very short. In general, a shorter distance resulted in more quenching. Bigger GNPs require a shorter distance to achieve the same level of quenching. The fluorescence of a fluorophore with a lower quantum yield (especially the one with emission in far-red or near infrared) is more difficult to be quenched by GNPs (requires very short distance). Instead, it can be enhanced. Based on the theoretical study, we have developed a near-infrared contrast agent, i.e., Cypate conjugated GNP via a short peptide spacer. Normally the fluorescence of Cypate was quenched. The spacer has a motif of a substrate for urokinase type plasminogen activator (uPA; cancer secreting enzyme). This contrast agent emits fluorescence only in the presence of uPA, where the uPA cleaves the spacer. This design can be used in characterization of the cancer type and also in diagnosing other diseases with signature enzymes. PMID- 21601035 TI - Chitosan coated carbon fiber microelectrode for selective in vivo detection of neurotransmitters in live zebrafish embryos. AB - We report the development of a chitosan modified carbon fiber microelectrode for in vivo detection of serotonin. We find that chitosan has the ability to reject physiological levels of ascorbic acid interferences and facilitate selective and sensitive detection of in vivo levels of serotonin, a common catecholamine neurotransmitter. Presence of chitosan on the microelectrode surface was investigated using scanning electron microscopy (SEM) and cyclic voltammetry (CV). The electrode was characterized using differential pulse voltammetry (DPV). A detection limit of 1.6 nM serotonin with a sensitivity of 5.12 nA/MUM, a linear range from 2 to 100 nM and a reproducibility of 6.5% for n=6 electrodes were obtained. Chitosan modified microelectrodes selectively measure serotonin in presence of physiological levels of ascorbic acid. In vivo measurements were performed to measure concentration of serotonin in the live embryonic zebrafish intestine. The sensor quantifies in vivo intestinal levels of serotonin while successfully rejecting ascorbic acid interferences. We demonstrate that chitosan can be used as an effective coating to reject ascorbic acid interferences at carbon fiber microelectrodes, as an alternative to Nafion, and that chitosan modified microelectrodes are reliable tools for in vivo monitoring of changes in neurotransmitter levels. PMID- 21601037 TI - Development of an on-column affinity smart polymer gel glucose sensor. AB - An on-column affinity smart polymer gel glucose sensor was developed as a non enzymatic glucose sensor. A copolymer of 3-acrylamidophenylboronic acid and acrylamide, the so called "smart polymer", was synthesized in situ in a 5 cm long capillary tube with a detection window to provide the on-column detection. The optical density of this semitransparent affinity smart polymer gel, coated inside the tube, decreased with increasing glucose concentration and was detected using a UV-vis detector at 500 nm. The capillary tube was incorporated into a flow injection system. Under optimum conditions, a linear dynamic range of 0.5-16.0mM with a limit of detection of 0.5mM (S/N >= 3) was obtained. A single coated affinity smart polymer gel had good stability for up to 250 consecutive injections with relative standard deviation of less than 5%. The analysis time for each injection was 6 min. Ten glucose samples prepared in distilled water were analyzed by the developed method and the results compared well with those obtained from the conventional dinitrosalicylic acid (DNS) method (P>0.05). Real urine samples with known glucose levels were analyzed and the developed sensor provided comparable results to those from the normal strip test technique. Acceptable percentage recoveries, ranging from 88 +/- 2% to 103 +/- 4% from the spiked urine sample, were obtained. PMID- 21601038 TI - Research advances in rabies. Preface. PMID- 21601039 TI - Rabies virus transcription and replication. AB - Rabies virus (RABV) is a negative-stranded RNA virus. Its genome is tightly encapsidated by the viral nucleoprotein (N) and this RNA-N complex is the template for transcription and replication by the viral RNA-dependent RNA polymerase (L) and its cofactor, the phosphoprotein (P). We present molecular, structural, and cellular aspects of RABV transcription and replication. We first summarize the characteristics and molecular biology of both RNA synthesis processes. We then discuss biochemical and structural data on the viral proteins (N, P, and L) and their interactions with regard to their role in viral transcription and replication. Finally, we review evidence that rabies viral transcription and replication take place in cytoplasmic inclusion bodies formed in RABV-infected cells and discuss the role of this cellular compartmentalization. PMID- 21601040 TI - Rabies virus assembly and budding. AB - Rabies virus (RABV) and other negative-strand RNA viruses are the causes of serious diseases in humans and animals worldwide. Assembly and budding are important late events in the replication cycles of these negative-strand RNA viruses that have received much attention in the past decade. Indeed, important insights into the molecular mechanisms by which rhabdoviral proteins usurp and/or interact with host proteins to promote efficient virion assembly and egress has greatly enhanced our understanding of the budding process. Assembly/budding of rhabdoviruses is driven largely by the matrix (M) protein. RABV M protein contains a late budding domain that mediates the recruitment of host proteins linked to the vacuolar protein sorting pathway of the cell to facilitate virus cell separation. This chapter summarizes our current knowledge of the roles that both RABV M protein and interacting host proteins play during the budding process. PMID- 21601041 TI - Evasive strategies in rabies virus infection. AB - Rabies virus (RABV) is a strictly neurotropic virus that slowly propagates in the nervous system (NS) of the infected host from the site of entry (usually due to a bite) up to the site of exit (salivary glands). Successful achievement of the virus cycle relies on the preservation of the neuronal network. Once RABV has entered the NS, its progression is not interrupted either by destruction of the infected neurons or by the immune response, which are major host mechanisms for combating viral infection. RABV has developed two main mechanisms to escape the host defenses: (1) its ability to kill protective migrating T cells and (2) its ability to sneak into the NS without triggering apoptosis of the infected neurons and preserving the integrity of neurites. PMID- 21601042 TI - Rabies virus clearance from the central nervous system. AB - Rabies, a neurological disease associated with replication in central nervous system (CNS) tissues of any of a number of rabies viruses endemic in nature, is generally fatal. Prophylactic medical intervention is immune mediated and directed at preventing the spread of the virus from a peripheral site of exposure to the CNS. While individuals rarely develop immune responses capable of clearing the virus from CNS tissues, a variety of laboratory-attenuated rabies viruses are readily cleared from the CNS tissues in animal models. By comparing immune responses to wild-type and attenuated rabies viruses in these models, we have discovered that the latter induce processes required for immune effector infiltration into CNS tissues that are absent from lethal infections. Predominant among these are activities of cells of the neurovascular unit (NVU) that promote an interaction with circulating immune cells. In the absence of this interaction, the specialized barrier function of the NVU remains intact and circulating virus specific immune effectors are largely excluded from infected CNS tissues. Studies of mixed infections with wild-type and attenuated rabies viruses reveal that wild type rabies viruses fail to trigger, rather than inhibit, the interactions between immune cells and the NVU required for virus clearance from the CNS. These studies provide insights into how immune effectors with the capacity to clear the virus may be delivered into CNS tissues to contain a wild-type rabies virus infection. However, to apply immunotherapeutic strategies beyond the initial stages of CNS infection, further insights into the fate of the infected cells during virus clearance are needed. PMID- 21601043 TI - Role of chemokines in rabies pathogenesis and protection. AB - Chemokines are a family of structurally related proteins that are expressed by almost all types of nucleated cells and mediate leukocyte activation and/or chemotactic activities. The role of chemokines in rabies pathogenesis and protection has only recently been investigated. Expression of chemokines is induced by infection with laboratory-adapted, but not street, rabies viruses (RABVs), and it has been hypothesized that expression of chemokines is one of the mechanisms by which RABV is attenuated. To further define the role of chemokines in rabies pathogenesis and protection, chemokine genes such as MIP-1alpha, RANTES, IP-10, and macrophage-derived chemokine (MDC) have been cloned into RABV genome. It has been found that recombinant RABVs expressing RANTES or IP-10 induce high and persistent expression of these chemokines, resulting in massive infiltration of inflammatory cells into the central nervous system (CNS) and development of diseases and death in the mouse model. However, recombinant RABVs expressing MIP-1alpha, MDC, as well as GM-CSF further attenuate RABV by inducing a transient expression of chemokines, infiltration of inflammatory cells, enhancement of blood-brain barrier (BBB) permeability. Yet, these recombinant RABVs show increased adaptive immune responses by recruiting/activating dendritic cells, T and B cells in the periphery as well as in the CNS. Further, direct administration of these recombinant RABVs into the CNS can prevent mice from developing rabies days after infection with street RABV. All these studies together suggest that chemokines are both protective and pathogenic in RABV infections. Those with protective roles could be exploited for development of future RABV vaccines or therapeutic agents. PMID- 21601044 TI - Interferon in rabies virus infection. AB - Rabies is among the longest known and most dangerous and feared infectious diseases for humans and animals and still is responsible for tenth of thousands of human deaths per year. The rabies virus (RABV) is a rather atypical member of the Rhabdoviridae family as it has completely adapted during evolution to warm blooded hosts and is directly transmitted between them, whereas most other rhabdoviruses are transmitted by insect vectors. The virus is also unique with respect to its extremely broad host species range and a very narrow host organ range, namely its strict neurotropism. It is becoming increasingly clear that the host innate immune system, particularly the type I interferon system, and the viral counteractions profoundly shape this virus-host relationship. In the past few years, exciting new insight was obtained on how viruses are sensed by innate immune receptors, how the downstream signaling networks for activation of interferon are working, and how viruses can interfere with the system. While RABV 5'-triphosphate RNAs were identified as the major pathogen-associated molecular pattern sensed by cytoplasmic RIG-I-like receptors (RLR), the RABV phosphoprotein (P) has emerged as a potent multifunctional antagonist able to counteract the signaling cascades leading to transcriptional activation of interferon genes as well as interferon signaling pathways, thereby limiting expression of antiviral and immune-stimulatory genes. PMID- 21601045 TI - The role of toll-like receptors in the induction of immune responses during rabies virus infection. AB - The host response to infection generally begins with interactions between pathogen-associated molecular patterns common to a variety of infectious agents and reciprocal pattern-recognition receptors (PRRs) expressed by cells of the innate immune system. The innate responses triggered by these interactions contribute to the early, innate control of infection as well as the induction of pathogen-specific adaptive immunity. The outcome of infection with wild-type rabies virus is particularly dependent upon the rapid induction of innate and adaptive immune mechanisms that can prevent the virus from reaching central nervous system (CNS) tissues, where it can evade immune clearance. However, laboratory strains that reach the CNS can be cleared, and this has evidently occurred in individuals with rabies. Therefore, PRRs may be active in the periphery and the CNS during rabies virus infection, possibly depending upon the nature of the infecting virus. To investigate these possibilities, we first examined the outcome of infection with attenuated rabies virus in mice lacking MyD88, an adaptor protein that is used to activate the transcription factor NF kappaB by a number of PRRs including all of the Toll-like receptors (TLRs) except for TLR3. Finding that attenuated rabies virus mediates lethal disease in the absence of MyD88, we then examined the effects of the deletion of receptors using MyD88 including TLRs 2, 4, 7, and 9 as well as IL-1-receptor 1, and IFN alphabetaR on infection. Only mice lacking TLR7 exhibited a phenotype, with mortality intermediate between MyD88(-/-) and control mice with deficits in both the development of peripheral immunity and rabies virus clearance from the CNS. PMID- 21601046 TI - Role of oxidative stress in rabies virus infection. AB - Recent studies in an experimental model of rabies indicated that there are major structural changes in the brain involving neuronal processes that are associated with severe clinical disease. Cultured adult mouse dorsal root ganglion (DRG) neurons are a good in vitro model for studying the mechanisms involved in rabies virus-induced degeneration of neurites (axons) because, unlike other neuronal cell types, these neurons are fairly permissive to rabies virus infection. DRG neurons infected with the challenge virus standard-11 (CVS) strain of rabies virus show axonal swellings and immunostaining for 4-hydroxy-2-nonenal (4-HNE), indicating evidence of lipid peroxidation associated with oxidative stress, and also reduced axonal growth in comparison with mock-infected DRG neurons. Treatment with the antioxidant N-acetyl cysteine prevented the reduction in axonal outgrowth that occurred with CVS infection. The axonal swellings with 4 HNE-labeled puncta were found to be associated with aggregations of actively respiring mitochondria. We postulate that rabies virus infection likely induces mitochondrial dysfunction resulting in oxidative stress and degenerative changes involving neuronal processes. This mitochondrial dysfunction may be the result of either direct or indirect effects of the virus on the mitochondrial electron transport chain or it may occur through other mechanisms. Further investigations are needed to gain a better understanding of the basic mechanisms involved in the oxidative damage associated with rabies virus infection. This information may prove helpful in the design of future therapeutic effects for this dreaded ancient disease. PMID- 21601047 TI - Rabies virus as a research tool and viral vaccine vector. AB - Until recently, single-stranded negative sense RNA viruses (ssNSVs) were one of only a few important human viral pathogens, which could not be created from cDNA. The inability to manipulate their genomes hindered their detailed genetic analysis. A key paper from Conzelmann's laboratory in 1994 changed this with the publication of a method to recover rabies virus (RABV) from cDNA. This discovery not only dramatically changed the broader field of ssNSV biology but also opened a whole new avenue for studying RABV pathogenicity, developing novel RABV vaccines as well a new generation of RABV-based vaccine vectors, and creating research tools important in neuroscience such as neuronal tracing. PMID- 21601048 TI - Rabies virus as a transneuronal tracer of neuronal connections. AB - Powerful transneuronal tracing technologies exploit the ability of some neurotropic viruses to travel across neuronal pathways and to function as self amplifying markers. Rabies virus is the only viral tracer that is entirely specific, as it propagates exclusively between connected neurons by strictly unidirectional (retrograde) transneuronal transfer, allowing for the stepwise identification of neuronal connections of progressively higher order. Transneuronal tracing studies in primates and rodent models prior to the development of clinical disease have provided valuable information on rabies pathogenesis. We have shown that rabies virus propagation occurs at chemical synapses but not via gap junctions or cell-to-cell spread. Infected neurons remain viable, as they can express their neurotransmitters and cotransport other tracers. Axonal transport occurs at high speed, and all populations of the same synaptic order are infected simultaneously regardless of their neurotransmitters, synaptic strength, and distance, showing that rabies virus receptors are ubiquitously distributed within the CNS. Conversely, in the peripheral nervous system, rabies virus receptors are present only on motor endplates and motor axons, since uptake and transneuronal transmission to the CNS occur exclusively via the motor route, while sensory and autonomic endings are not infected. Infection of sensory and autonomic ganglia requires longer incubation times, as it reflects centrifugal propagation from the CNS to the periphery, via polysynaptic connections from sensory and autonomic neurons to the initially infected motoneurons. Virus is recovered from end organs only after the development of rabies because anterograde spread to end organs is likely mediated by passive diffusion, rather than active transport mechanisms. PMID- 21601049 TI - Molecular phylogenetics of the lyssaviruses--insights from a coalescent approach. AB - Technical improvements over the past 2 decades have enormously facilitated the generation of nucleotide sequence data for lyssavirus collections. These databases are amenable to methods of phylogenetic analysis, which attempt to define the taxonomic structure of this genus and predict the evolutionary relationships of current circulating strains. Coupled with a range of mathematical tools to explore the appropriateness of nucleotide substitution models and test for positive selection, the evolutionary process is being explored in detail. Despite the potential for high viral mutation levels, the operation of purifying selection appears to effectively constrain lyssavirus evolution. The recent development of coalescent theory has provided additional approaches to data analysis whereby the time frame of emergence of viral lineages can be most reliably estimated. Such studies suggest that all currently circulating rabies viruses have emerged within the past 1500 years. Moreover, through the capability of analyzing viral population dynamics and determining patterns of population size variation, coalescent approaches can provide insight into the demographics of viral outbreaks. Whereas human-assisted movement of reservoir host species has clearly facilitated transfer of rabies between continents, topographical landscape features significantly influence the rate and extent of contiguous disease spread. Together with empirical studies on virus diversity, the application of coalescent approaches will help to better understand lyssavirus emergence, evolution, and spread. In particular, such methods are presently facilitating exploration of the factors operating to limit the ability of lyssaviruses to establish new persistent virus-host associations and ultimately control the emergence of new species of this genus. PMID- 21601050 TI - Bats and lyssaviruses. AB - Numerous bat species have been identified as important reservoirs of zoonotic viral pathogens. Rabies and rabies-related viruses constitute one of the most important viral zoonoses and pose a significant threat to public health across the globe. Whereas rabies virus (RABV) appears to be restricted to bats of the New World, related lyssavirus species have not been detected in the Americas and have only been detected in bat populations across Africa, Eurasia, and Australia. Currently, 11 distinct species of lyssavirus have been identified, 10 of which have been isolated from bat species and all of which appear to be able to cause encephalitis consistent with that seen with RABV infection of humans. In contrast, whereas lyssaviruses are apparently able to cause clinical disease in bats, it appears that these lyssaviruses may also be able to circulate within bat populations in the absence of clinical disease. This feature of these highly encephalitic viruses, alongside many other aspects of lyssavirus infection in bats, is poorly understood. Here, we review what is known of the complex relationship between bats and lyssaviruses, detailing both natural and experimental infections of these viruses in both chiropteran and nonchiropteran models. We also discuss potential mechanisms of virus excretion, transmission both to conspecifics and spill-over of virus into nonvolant species, and mechanisms of maintenance within bat populations. Importantly, we review the significance of neutralizing antibodies reported within bat populations and discuss the potential mechanisms by which highly neurovirulent viruses such as the lyssaviruses are able to infect bat species in the absence of clinical disease. PMID- 21601051 TI - Postexposure prophylaxis for rabies in resource-limited/poor countries. AB - Human rabies is essentially a fatal disease once clinical signs develop. Rabies postexposure prophylaxis (PEP) consists of thorough wound care in combination with administration of rabies immunoglobulin and rabies vaccine. This is highly effective in rabies prevention if carried out diligently. Preexposure rabies prophylaxis simplifies PEP in the event of an exposure by eliminating the need for immunoglobulin. Shortened and more convenient and economical PEP regimens are being developed with promising results. They reduce the cost of PEP as well as travel expenses for the often very poor patients. The intradermal PEP regimen can now reduce the vaccine cost by ~60-70%. Although PEP in humans can prevent death, controlling the canine vector by sustained vaccination remains the mainstay of rabies elimination. PMID- 21601052 TI - Neuroimaging in rabies. AB - Rabies remains a virtually incurable disease once symptoms develop. Neuroimaging studies demonstrate lesions in the different parts of the neuroaxis, even before brain symptoms are evident. These abnormalities have been detailed in both rabies virus-infected humans and dogs with magnetic resonance imaging (MRI). MRI disturbances were similar in both forms (furious or paralytic) in human rabies; however, they were more pronounced in paralytic than in furious rabies virus infected dogs in which examination was done early in the disease course. Abnormalities were not confined only to neuronal structures of hippocampus, hypothalamus, basal ganglia, and brain stem but also extended to white matter. The blood-brain barrier (BBB) has been clearly shown to be intact during the time rabies virus-infected patients and dogs remained conscious, whereas leakage was demonstrated as soon as they became comatose. Although the location of MRI abnormalities can help diagnosing rabies, the intensities of signals are usually not very distinct and sometimes not recognizable. Newer techniques and protocols have been developed and utilized, such as diffusion-weighted imaging and diffusion tensor imaging, and the latter provides both qualitative and quantitative data. These techniques have been applied to normal and rabies virus infected dogs to construct fractional anisotropy and mean diffusivity maps. Results showed clear-cut evidence of BBB intactness with absence of vasogenic brain edema and preservation of most neuronal structures and tracts except at the level of brainstem in paralytic rabies-infected dogs. Neuroimaging is one of the most useful tools for the in vivo study of central nervous system infections. PMID- 21601053 TI - Rabies virus infection and microRNAs. AB - Endogenous RNA-silencing mechanisms have been shown to play a role in regulating viral and host processes during the course of infection. Such interactive processes may involve host cellular and/or viral-encoded microRNAs (miRNAs). Rabies is unique not only in terms of its invariably fatal course once disease signs develop, but it also has a variable incubation period (eclipse phase). It has been recently shown that cells or tissues of different origin have their own specific miRNAs that, in theory, may impact on viral transcription and replication. This may possibly explain, in part, why rabies virus remains dormant at the inoculation site in rabies patients for long periods. Owing to the RNA interference (RNAi) technology, it has been possible to introduce exogenously designed artificial short interfering RNAs (siRNAs) and miRNAs into virus infected cells for therapeutic purposes. Successful attempts in using RNAi for prevention and treatment of DNA and RNA virus infections both in vitro and in vivo experiments have been reported. The fact that rabies remains incurable has stimulated the development of the therapeutic RNAi strategy. We describe herein preliminary evidence that cellular miRNA may play a role in suppressing viral replication, explaining the eclipse phase, and that artificially designed multitargeting miRNA can successfully inhibit rabies virus transcription and replication in vitro. PMID- 21601054 TI - Design of future rabies biologics and antiviral drugs. AB - In recent years, no major paradigm shifts have occurred in the utilization of new products for the prevention and control of rabies. Development of new cost effective rabies biologics and antiviral drugs is critical in continuing to prevent and reduce disease. Current rabies vaccines are highly effective but have developed largely based on technical improvements in the vaccine industry. In the future, alternative approaches for improved vaccines, including novel avirulent rabies virus (RABV) vectors, should be pursued. Any rabies vaccine that is effective without the need for rabies immune globulin (RIG) will contribute fundamentally to disease prevention by reducing the cost and complexity of postexposure prophylaxis (PEP). The lack of high quality, affordable RIG is a continuing problem. Virus-specific monoclonal antibodies (mAbs) will soon fulfill the PEP requirement for passive immunity, currently met with RIG. Several relevant strategies for mAb production, including use of transgenic mice, humanization of mouse mAbs, and generation of human immune libraries, are underway. As a result of successful PEP and pre-exposure prophylaxis in developed countries, until recently, no significant focused efforts have been devoted to RABV-specific antiviral agents. To date, combination therapy including broad spectrum antiviral agents has been successful in only one case, and reports of antiviral activity are often conflicting. Current antiviral strategies target either the nucleoprotein or phosphoprotein, but drugs targeting the viral polymerase should be considered. Considering the lag from creation of new concepts to experimental development and clinical trials, many years will likely elapse between today's ideas and tomorrow's practices. PMID- 21601055 TI - Therapy of human rabies. AB - Preventive therapy for rabies, including wound cleansing and active and passive immunization after a recognized exposure, is highly efficacious. Unfortunately, there is no established therapy that is effective for patients who develop rabies encephalomyelitis. There have been several survivors from rabies and all but one received rabies vaccine prior to the onset of clinical illness. Aggressive approaches to therapy of human rabies may be appropriate in certain situations. There is no scientific rationale for the use of therapeutic coma, and there are many reports of failures using this approach. Therapeutic coma should be abandoned for the therapy of rabies. New approaches such as therapeutic hypothermia should be evaluated, in combination with other therapeutic agents. More basic research is needed on the mechanisms involved in rabies pathogenesis, which will hopefully facilitate the development of new therapeutic approaches in the future for this ancient disease. PMID- 21601056 TI - Mathematical models for rabies. AB - Rabies virus and its associated host-pathogen population dynamics have proven a remarkable model system for developing mathematical models of infectious disease emergence and spread. Beginning with simple susceptible-infectious-removed (SIR) compartment models of fox rabies emergence and spread across Western Europe, mathematical models have now been developed to incorporate dynamics across heterogeneous landscapes, host demographic variation, and environmental stochasticity. Model structures range from systems of ordinary differential equations (ODEs) to stochastic agent-based computational simulations. We have reviewed the variety of mathematical approaches now available for analyzing dynamics in different host populations; most notably rabies virus spread in raccoon hosts. PMID- 21601057 TI - Evolution of wildlife rabies control tactics. AB - The development of tactics for the control of rabies in wildlife species has evolved dramatically during the past few decades in part due to research advances. Historically, rabies control measures primarily involved the culling of target species. However, contemporary advances in the research and development of oral rabies vaccines and delivery systems for wildlife have now made it feasible to treat rabies outbreaks over thousands of square kilometers of habitat. Systems have been developed to control rabies in several of the primary wildlife vectors such as raccoon dogs, red foxes, and raccoons, and rabies has been eliminated from many jurisdictions. However, future research is needed to develop cost effective and efficacious methods to control rabies in species such as striped skunks as well as in nonterrestrial vectors such as bats. As well, cost-effective rabies management techniques need to be adopted by developing nations so that wildlife rabies control is a realistic and achievable goal globally. PMID- 21601058 TI - Understanding effects of barriers on the spread and control of rabies. AB - This chapter reviews the evidence for the impact of natural and anthropogenic barriers on the spread of rabies using evidence mainly drawn from the epidemics of fox and raccoon variant rabies virus over the past 60 years in North America. Those barriers have both directed and inhibited the spread of rabies and, at a regional scale, have been integrated with rabies control efforts in North America. Few studies have been done, however, to examine how the texture (grain) and configuration of the habitat at finer scales affect rabies control, particularly the massive oral vaccination campaigns in operation along the Atlantic coast and southeastern Canada (Ontario, Quebec, New Brunswick). To explore these questions, the authors used stochastic simulation. The model of choice was the Ontario Rabies Model (ORM) adapted for use on the high performance computing resources network in Quebec (RQCHP-Reseau quebecois de calcul de haute performance; http://rqchp.qc.ca). The combination of the ORM and RQCHP allowed us to run many thousands of experiments to explore interactions between nine landscape grain/configuration combinations and vaccination barriers with varying widths and immunity levels. Our results show that breaches of vaccine barriers increase as the grain size of the landscape increases and as the landscape becomes more structured. We caution that mid levels of vaccination can be counterproductive resulting in rabies persistence rather than control. We also note that our model/computing system has the flexibility and capacity to explore a wide range of questions pertinent to improving the efficacy of rabies control. PMID- 21601059 TI - Rabies research in resource-poor countries. AB - Many cost-benefit/effective rabies research projects need to be carried out in less-developed canine-endemic regions. Among these are educational approaches directed at the public and governments. They would address effective primary wound care, availability, and proper use of vaccines and immunoglobulins, better reporting of rabies, final elimination of dangerous nerve tissue-derived vaccines, and the recognition that rabies is still expanding its geographic range. Such efforts could also reduce deaths in victims who had received no or less than adequate postexposure prophylaxis. There is a need for new technology in canine population control and sustainable vaccination. We have virtually no workable plans on how to control bat rabies, particularly that from hematophagous bats. Preexposure vaccination of villagers in vampire rabies-endemic regions may be one temporary solution. Current efforts to reduce further the time required and vaccine dose required for effective postexposure vaccination need to be encouraged. We still have incomplete understanding of the transport channels from inoculation site to rabies virus antibody generating cells. The minimum antigen dose required to achieve a consistently protective and lasting immune response has been established for intramuscular vaccine administration, but is only estimated for intradermal use. Greater knowledge may have clinical benefits, particularly in the application of intradermal reduced dose vaccination methods. Curing human rabies is still an unattained goal that challenges new innovative researchers. PMID- 21601060 TI - Neuro-ophthalmology. Preface. PMID- 21601061 TI - Anatomy and physiology of the afferent visual system. AB - The efficient organization of the human afferent visual system meets enormous computational challenges. Once visual information is received by the eye, the signal is relayed by the retina, optic nerve, chiasm, tracts, lateral geniculate nucleus, and optic radiations to the striate cortex and extrastriate association cortices for final visual processing. At each stage, the functional organization of these circuits is derived from their anatomical and structural relationships. In the retina, photoreceptors convert photons of light to an electrochemical signal that is relayed to retinal ganglion cells. Ganglion cell axons course through the optic nerve, and their partial decussation in the chiasm brings together corresponding inputs from each eye. Some inputs follow pathways to mediate pupil light reflexes and circadian rhythms. However, the majority of inputs arrive at the lateral geniculate nucleus, which relays visual information via second-order neurons that course through the optic radiations to arrive in striate cortex. Feedback mechanisms from higher cortical areas shape the neuronal responses in early visual areas, supporting coherent visual perception. Detailed knowledge of the anatomy of the afferent visual system, in combination with skilled examination, allows precise localization of neuropathological processes and guides effective diagnosis and management of neuro-ophthalmic disorders. PMID- 21601062 TI - The anatomy and physiology of the ocular motor system. AB - Accurate diagnosis of abnormal eye movements depends upon knowledge of the purpose, properties, and neural substrate of distinct functional classes of eye movement. Here, we summarize current concepts of the anatomy of eye movement control. Our approach is bottom-up, starting with the extraocular muscles and their innervation by the cranial nerves. Second, we summarize the neural circuits in the pons underlying horizontal gaze control, and the midbrain connections that coordinate vertical and torsional movements. Third, the role of the cerebellum in governing and optimizing eye movements is presented. Fourth, each area of cerebral cortex contributing to eye movements is discussed. Last, descending projections from cerebral cortex, including basal ganglionic circuits that govern different components of gaze, and the superior colliculus, are summarized. At each stage of this review, the anatomical scheme is used to predict the effects of lesions on the control of eye movements, providing clinical-anatomical correlation. PMID- 21601063 TI - The neuro-ophthalmological examination. AB - The neuro-ophthalmological examination constitutes one of the most refined and exact components of the clinical examination, often allowing precise diagnosis and formulation of a treatment plan even within the compass of the first visit. This chapter briefly highlights important features in the neuro-ophthalmological history and then presents detailed information on the important components of a comprehensive neuro-ophthalmological examination. Covered examination topics include visual acuity, visual field testing, color vision, external eye exam, pupils, ophthalmoscopy, and eye movements. The final section discusses ancillary tests that supplement the bedside neuro-ophthalmological examination, including formal visual field analysis, electroretinography, fluorescein angiography, ocular coherence tomography, visual-evoked potentials, neuroimaging, and quantitative eye movement recordings. PMID- 21601064 TI - Retinal disorders. AB - The retina represents part of the central nervous system (CNS). After modifying the neural signal, the axon of the last neuron enters the optic nerve and leaves the eye. In most cases of retinal disease leading to visual loss, the diagnosis will be made by an ophthalmologist after examining the ocular fundus. Some retinal disorders, however, might not be detectable at the time of examination. Those patients will be referred to a neurologist for "unexplained visual loss" when suspecting a lesion behind the optic nerve. Moreover, knowledge of potential retinal abnormalities is useful for the neurologist when seeing patients with CNS disease, which can manifest itself also in the retina. This chapter aims to give an overview about retinal disorders causing no or only few retinal abnormalities, those associated with neurological diseases, as well as the most important retinal diseases involving the tissues of the ocular fundus (vitreous body, retina, pigment epithelium, and the choroid). The most frequently used examination techniques and diagnostic tools are described. Tumors, vascular disease, especially diabetic retinopathy, age-related macular degeneration, chorioretinal inflammatory and toxic disorders, paraneoplastic retinopathies, inherited retinal dystrophies, and retinal involvement in CNS disease such as phakomatoses and multiple sclerosis are discussed. PMID- 21601065 TI - Abnormalities of the optic disc. AB - The optic disc represents the anterior end of the optic nerve, the most forward extension of the central nervous system (CNS). The optic disc gives a rare glimpse into the CNS. Hence, diseases of the CNS are often manifested on fundus examination. Abnormalities of the optic disc may reflect eye disease (such as glaucoma), problems in development (as in various syndromes), or CNS disease (such as increased intracranial pressure). Each optic nerve is composed of about 1.2 million axons deriving from the retinal ganglion cells of one eye. Optic atrophy is a morphological sequela reflecting the loss of many or all of these axons. Myriad diseases such as hereditary, metabolic, tumor, and increased intracranial pressure can lead to optic atrophy. Some diseases, such as optic disc drusen, intracranial masses, orbital tumors, ischemic optic neuropathies, inflammations, and infiltrations, can produce optic disc edema before leading to optic atrophy. A number of new imaging modalities, such as optical coherence tomography (OCT), quantitate the thickness of the peripapillary retinal nerve fiber layer as an indirect measure of axonal loss or swelling. OCT can therefore be used to quantitate pathology or the response to therapy in various generalized CNS conditions, such as multiple sclerosis. PMID- 21601066 TI - Lesions of the optic nerve. AB - As experts on the central nervous system, neurologists are expected to be familiar with the many conditions that can result in visual loss arising from lesions of the optic nerve. The optic nerves are unique central nervous system structures in terms of surrounding anatomy, size, location, and blood supply; therefore, they are uniquely vulnerable to every pathological process that can affect the central and peripheral nervous systems, including inflammation, ischemia, compression, infiltration, toxic or hereditary metabolic dysfunction, trauma, and mechanical damage. This chapter highlights the importance of being able to identify the historical and clinical features that will enable neurologists to narrow down the broad differential diagnosis of optic nerve lesions. Distinguishing an optic neuropathy on the basis of history and clinical examination alone, however, can be difficult, especially when bilateral optic neuropathies are present. Specific ancillary tests, especially new imaging modalities, help further localization and differential diagnosis. PMID- 21601067 TI - The optic chiasm. AB - In the first part of this chapter the anatomy and vascular supply of the chiasm are recounted, and the visual symptoms that may arise in chiasmal disease are noted. The neuro-ophthalmic signs, including the pattern of visual field defects, appearance of the optic disc, and various uncommon clinical accompaniments, are described. The second part deals with a comprehensive list of disease processes that may directly or indirectly affect the chiasm. These are divided into inflammatory disorders, including sarcoidosis, multiple sclerosis, and idiopathic chiasmitis; infective disorders, including tuberculosis; and a large section on tumors, including pituitary adenomas, cysts, and choristomas, malignant disorders, including germ cell tumors and glioma, and meningioma; and finally vascular disorders and compression due to hydrocephalus. In each case the clinical features and management of the disorder are noted, as well as the prognosis for visual improvement following treatment. PMID- 21601068 TI - Disorders of the optic tract, radiation, and occipital lobe. AB - Disorders of the optic tract, lateral geniculate nucleus, optic radiation, and occipital lobe - collectively called the retrochiasmal visual pathways - are commonly encountered in neurological practice, and may result from a number of causes. The major visual morbidity of retrochiasmal disease is the homonymous visual field defect, which is found in approximately 8% of stroke patients. A homonymous visual field defect may have profound legal, occupational, and financial consequences for patients, with many patients unable to read, drive, or return to work after sustaining retrochiasmal damage. Some homonymous hemianopias may improve, usually within days of a cerebral infarction, but remain stable after 3 months. Although treatment options are limited to those of the underlying cause, appropriate counseling and low-vision rehabilitation may be helpful. PMID- 21601069 TI - Disorders of higher visual processing. AB - A significant proportion of human cortex is involved in visual processing. Cerebral regions beyond striate cortex show specialization for specific stimulus properties: damage to these regions leads to syndromes that also reflect this specialization. These syndromes can be grouped into two broad categories. In the ventral group, there is damage to medial occipitotemporal structures that participate in object identification and recognition. This can result in a variety of syndromes, including achromatopsia, general visual object agnosia, or more selective object recognition deficits such as prosopagnosia, alexia, and certain forms of topographagnosia, such as landmark agnosia. In the second, dorsal group, there is damage to lateral occipitoparietal structures that participate in visuospatial processing and localization. Patients with such damage may have akinetopsia (impaired motion processing), various components of Balint syndrome, or astereopsis. Finally, it is also possible to find patients in whom residual visual processing is evident despite damage to the geniculostriate pathway; this blindsight may reflect residual function of either subcortical structures, such as the superior colliculus, or alternate afferent routes to surviving extrastriate cortex. PMID- 21601070 TI - Rehabilitative techniques. AB - This chapter deals with neuro-ophthalmological diseases at different levels of the afferent visual pathways with special regard to visual field defects, their functional impact, and their rehabilitation. The nature of these impairments and their significance for activities of daily living can be quite varied; an exact assessment of the residual function is required to determine specific rehabilitation approaches. Rehabilitation aims to compensate for the visual deficits by means of specific training and visual aids. Visual field defects in the center cause reading disability. Preconditions for reading are a sufficient size of the reading visual field or perceptual span and sufficient resolution of the retinal area used for reading. In central scotoma, as in macular or optic nerve disease, reading ability can be regained by eccentric fixation plus text magnification. In hemianopia, reading depends on the amount of sparing in the center, the side of the defect, and adaptive strategies. Field defects in the periphery cause orientation and mobility problems. In constricted fields, tactile training with a cane is indicated; in hemianopia, explorative saccadic training is effective. With the appropriate technique, rehabilitation can be very successful, and quality of life can be regained in most patients. PMID- 21601071 TI - Infranuclear ocular motor disorders. AB - This chapter covers the very large number of possible disorders that can affect the three ocular motor nerves, the neuromuscular junction, or the extraocular muscles. Conditions affecting the nerves are discussed under two major headings: those in which the site of damage can be anatomically localized (e.g., fascicular lesions and lesions occurring in the subarachnoid space, the cavernous sinus, the superior orbital fissure, or the orbit) and those in which the site of the lesion is either nonspecific or variable (e.g., vascular lesions, tumors, "ophthalmoplegic migraine," and congenital disorders). Specific comments on the diagnosis and management of disorders of each of the three nerves follow. Ocular motor synkineses (including Duane's retraction syndrome and aberrant regeneration) and disorders resulting in paroxysms of excess activity (e.g., neuromyotonia) are then covered, followed by myasthenia gravis and other disorders that affect the neuromuscular junction. A final section discusses disorders of the extraocular muscles themselves, including thyroid disease, orbital myositis, mitochondrial disease, and the muscular dystrophies. PMID- 21601072 TI - Nuclear, internuclear, and supranuclear ocular motor disorders. AB - In the brainstem, lateral and vertical eye movements are controlled by separate structures, the former mainly in the pons and the latter in the midbrain. The abducens nucleus (VI) in the pons controls all ipsilateral eye movements, i.e., ipsilateral saccades as well as the horizontal vestibulo-ocular reflex (VOR). This nucleus contains the abduction motoneurons, but also the internuclear neurons involved in adduction, passing through the contralateral medial longitudinal fasciculus (MLF) before relaying in the third-nerve nucleus in the midbrain. Lesions affecting the abducens nucleus result in complete ipsilateral eye movement paralysis, and lesions damaging the MLF result in internuclear ophthalmoplegia, whereas an association of these two lesions leads to the "one and-a-half" syndrome. Ipsilateral saccades are controlled by the ipsilateral paramedian pontine reticular formation located close to the sixth nucleus, whereas the ipsilateral VOR is controlled by the contralateral medial vestibular nucleus. Vertical eye movements are controlled by the third- and fourth-nerve nuclei in the midbrain. A lesion unilaterally affecting the third-nerve nucleus results in an ipsilateral third-nerve paralysis and a contralateral upgaze paralysis because of the decussation of the superior rectus motoneurons, at the level of the third-nerve nuclei. Vertical saccades are controlled by the rostral interstitial nucleus of the MLF (riMLF) located close to the third-nerve nucleus. Downward and upward saccade paralysis results from bilateral riMLF damage whereas upgaze paralysis usually results from a unilateral lesion affecting the region of the posterior commissure, suggesting that the suprareticular control of these two types of vertical saccade is distinct. PMID- 21601073 TI - Nystagmus and saccadic intrusions. AB - We review current concepts of nystagmus and saccadic oscillations, applying a pathophysiological approach. We begin by discussing how nystagmus may arise when the mechanisms that normally hold gaze steady are impaired. We then describe the clinical and laboratory evaluation of patients with ocular oscillations. Next, we systematically review the features of nystagmus arising from peripheral and central vestibular disorders, nystagmus due to an abnormal gaze-holding mechanism (neural integrator), and nystagmus occurring when vision is compromised. We then discuss forms of nystagmus for which the pathogenesis is not well understood, including acquired pendular nystagmus and congenital forms of nystagmus. We then summarize the spectrum of saccadic disorders that disrupt steady gaze, from intrusions to flutter and opsoclonus. Finally, we review current treatment options for nystagmus and saccadic oscillations, including drugs, surgery, and optical methods. Examples of each type of nystagmus are provided in the form of figures. PMID- 21601074 TI - Disorders of higher gaze control. AB - The neural centers in the cerebral hemispheres, both cortex and basal ganglia, involved in the generation of saccadic and smooth pursuit eye movements have been well delineated in terms of their location and function. For the generation of saccades these include the frontal eye fields, the supplementary eye field, and the intraparietal sulcus, and in the basal ganglia the caudate nucleus and the substantia nigra, pars compacta. The generation of pursuit eye movements involves the middle temporal (area V5) and medial superior temporal areas and the frontal eye field. These centers and their connections are disturbed not only in acute and chronic lesions such as cerebral infarction, but also in a wide variety of neurodegenerative diseases. In certain of these conditions, such as patients with cortical dementias and basal ganglia disorders, correct interpretation of the resulting eye movement abnormalities can contribute to differentiating between a range of differential diagnoses. PMID- 21601075 TI - Normal and abnormal lid function. AB - This chapter on lid function is comprised of two primary sections, the first on normal eyelid anatomy, neurological innervation, and physiology, and the second on abnormal eyelid function in disease states. The eyelids serve several important ocular functions, the primary objectives of which are protection of the anterior globe from injury and maintenance of the ocular tear film. Typical eyelid behaviors to perform these functions include blinking (voluntary, spontaneous, or reflexive), voluntary eye closure (gentle or forced), partial lid lowering during squinting, normal lid retraction during emotional states such as surprise or fear (startle reflex), and coordination of lid movements with vertical eye movements for maximal eye protection. Detailed description of the neurological innervation patterns and neurophysiology of each of these lid behaviors is provided. Abnormal lid function is divided by conditions resulting in excessive lid closure (cerebral ptosis, apraxia of lid opening, blepharospasm, oculomotor palsy, Horner's syndrome, myasthenia gravis, and mechanical) and those resulting in excessive lid opening (midbrain lid retraction, facial nerve palsy, and lid retraction due to orbital disease). PMID- 21601076 TI - Disorders of the pupil. AB - Pupil size is determined by the interaction of the parasympathetic and the sympathetic nervous system. The parasympathetic system conducts the light reaction with its major center in the dorsal midbrain. The sympathetic nervous system acts either directly on the dilator muscle (peripherally) or centrally by inhibiting the Edinger-Westphal nucleus. Psychosensory reactions are transmitted via the sympathetic system. The afferent input of the light reflex system in humans is characteristically wired, allowing a detailed analysis of a lesion of the afferent input. Even in humans a subgroup of ganglion cells containing melansopsin plays an important role as a light sensor for the pupillary system. To diagnose normal pupillary function, pupils need to be isocoric and react bilaterally equally to light. Anisocoria indicates a problem of the efferent pupillary pathway. Pupillary disorders may involve the afferent pathways (relative afferent pupillary defect) or the efferent pathways. Physiological anisocoria is a harmless condition that has to be distinguished from Horner's syndrome. In this case pharmacological testing with cocaine eye-drops is helpful. Disorders of the parasympathetic system will impair the light response. They include dorsal midbrain syndrome, third-nerve palsy, and tonic pupil. Tonic pupils are mainly idiopathic and do not need imaging. Disorders of the iris, including application of cholinergic agents, need also to be considered in impaired pupillary light reaction. PMID- 21601077 TI - Neuro-ophthalmology of orbital disease. AB - In this chapter the presentation and management of common orbital diseases are discussed. An accurate clinical history and assessment are essential, with computed tomography being the imaging of choice. Magnetic resonance imaging provides detail of intrinsic optic nerve disease and orbital apical or intracranial pathology, and ultrasonography is valuable in assessing anterior orbital masses, in particular vascular lesions. Inflammatory lesions require a tissue biopsy before immunosuppression is instituted. Exceptions to this principle are scleritis, myositis, thyroid eye disease, and characteristic orbital apex syndrome, in which delay in immune suppression may jeopardize visual outcome. The term "orbital pseudotumor" is now obsolete. The management of active thyroid eye disease includes immunosuppression and low-dose orbital radiotherapy. Urgent orbital decompression is indicated in the presence of nonresponsive optic neuropathy, and inactive disease is managed by decompression for exophthalmos, and correction of muscle imbalance and lid retraction. Subacute lacrimal gland inflammation, unresponsive to a few weeks of nonsteroidal treatment, may be due to underlying carcinoma and a specialist opinion should be sought without delay. Pleomorphic adenoma, with typical features on imaging, should always be excised intact to avoid subsequent pervasive malignant disease. PMID- 21601078 TI - Functional neuro-ophthalmology. AB - Patients with physical signs and symptoms for which no adequate organic cause can be found may receive any one of a large range of diagnostic labels, including functional illness, functional overlay, hysteria, hysterical overlay, conversion reaction, psychophysiological reaction, somatization reaction, hypochondriasis, invalid reaction, neurasthenia, psychogenic reaction, psychosomatic illness, malingering, and Munchausen syndrome. In this chapter, we describe both common and uncommon "functional" ocular symptoms and signs, including visual loss in one or both eyes, constricted visual fields and other field defects, various types of ocular motor dysfunction, including disorders of ocular motility and alignment, disorders of pupillary size and reactivity, and abnormalities of eyelid position and function. We also discuss and illustrate the methods by which the nonorganic nature of these manifestations can be determined. In many cases simple techniques performed in the clinic are sufficient to establish a diagnosis of nonorganic ocular disease, whereas in other cases ancillary studies such as electrophysiological testing may be necessary. The chapter also describes the appropriate approach that the physician should take when dealing with a patient who has proven functional ocular signs and symptoms. PMID- 21601079 TI - Synthetic biology, Part A. Preface. PMID- 21601080 TI - Sequence-specificity and energy landscapes of DNA-binding molecules. AB - A central goal of biology is to understand how transcription factors target and regulate specific genes and networks to control cell fate and function. An equally important goal of synthetic biology, chemical biology, and personalized medicine is to devise molecules that can regulate genes and networks in a programmable manner. To achieve these goals, it is necessary to chart the sequence specificity of natural and engineered DNA-binding molecules. Cognate site identification (CSI) is now achieved via unbiased, high-throughput platforms that interrogate an entire sequence space bound by typical DNA-binding molecules. Analysis of these comprehensive specificity profiles is facilitated through the use of sequence-specificity landscapes (SSLs). SSLs reveal new modes of sequence cognition and overcome the limitations of current approaches that yield amalgamated "consensus" motifs. The landscapes also reveal the impact of nonconserved flanking sequences on binding to cognate sites. SSLs also serve as comprehensive binding energy landscapes that provide insights into the energetic thresholds at which natural and engineered molecules function within cells. Furthermore, applying the CSI binding data to genomic sequence (genomescapes) provides a powerful tool for identification of potential in vivo binding sites of a given DNA ligand, and can provide insight into differential regulation of gene networks. These tools can be directly applied to the design and development of synthetic therapeutic molecules and to expand our knowledge of the basic principles of molecular recognition. PMID- 21601081 TI - Promoter reliability in modular transcriptional networks. AB - Synthetic biologists engineer systems with desired properties from simple and well-characterized biological parts. Among the most popular and versatile parts are tunable promoters and the transcription factors (TFs) that regulate them. Individual TFs can transduce physical or chemical signals to regulate gene expression; networks of TFs regulating each other's expression can filter signals, reduce noise, store memories, and oscillate. However, the biochemical parameters that describe TF-promoter interactions are often context dependent, making it challenging to build systems that reliably achieve specific outcomes. Here, we explore this problem using plasmid-borne transcriptional networks in Escherichia coli. We demonstrate that the expression properties of a positive feedback module quantitatively and qualitatively change when this module is embedded within the context of a larger network, where the original TF is used to drive new outputs. A mathematical model suggests this might be due in part to the sequestration of the TF by additional copies of its cognate promoter. The parameters describing TF-promoter interactions (the Hill coefficient and half saturation constant) can vary depending on promoter copy number. This problem is acute for plasmid-borne systems where promoter concentrations exceed the TF promoter equilibrium constant. In this regime, we advocate the use of operator buffers: passive multimeric stretches of TF-binding sites that insulate promoter properties from context. If such buffers are included in a standard host chassis, promoters once characterized can be reliably integrated into larger networks. PMID- 21601082 TI - The analysis of ChIP-Seq data. AB - Chromatin immunoprecipitation coupled with ultra-high-throug put parallel DNA sequencing (ChIP-seq) is an effective technology for the investigation of genome wide protein-DNA interactions. Examples of applications include the studies of RNA polymerases transcription, transcriptional regulation, and histone modifications. The technology provides accurate and high-resolution mapping of the protein-DNA binding loci that are important in the understanding of many processes in development and diseases. Since the introduction of ChIP-seq experiments in 2007, many statistical and computational methods have been developed to support the analysis of the massive datasets from these experiments. However, because of the complex, multistaged analysis workflow, it is still difficult for an experimental investigator to conduct the analysis of his or her own ChIP-seq data. In this chapter, we review the basic design of ChIP-seq experiments and provide an in-depth tutorial on how to prepare, to preprocess, and to analyze ChIP-seq datasets. The tutorial is based on a revised version of our software package CisGenome, which was designed to encompass most standard tasks in ChIP-seq data analysis. Relevant statistical and computational issues will be highlighted, discussed, and illustrated by means of real data examples. PMID- 21601084 TI - Orthogonal gene expression in Escherichia coli. AB - Here, we describe a route orthogonal gene expression which combines orthogonal transcription and translation using library-based selections. We show how orthogonal gene expression can be used to create a minimal orthogonal ribosome and describe how to create orthogonal transcription-translation feed forward loops that introduce tailored information processing delays into gene expression. PMID- 21601083 TI - Using DNA microarrays to assay part function. AB - In recent years, the capability of synthetic biology to design large genetic circuits has dramatically increased due to rapid advances in DNA synthesis technology and development of tools for large-scale assembly of DNA fragments. Large genetic circuits require more components (parts), especially regulators such as transcription factors, sigma factors, and viral RNA polymerases to provide increased regulatory capability, and also devices such as sensors, receivers, and signaling molecules. All these parts may have a potential impact upon the host that needs to be considered when designing and fabricating circuits. DNA microarrays are a well-established technique for global monitoring of gene expression and therefore are an ideal tool for systematically assessing the impact of expressing parts of genetic circuits in host cells. Knowledge of part impact on the host enables the user to design circuits from libraries of parts taking into account their potential impact and also to possibly modify the host to better tolerate stresses induced by the engineered circuit. In this chapter, we present the complete methodology of performing microarrays from choice of array platform, experimental design, preparing samples for array hybridization, and associated data analysis including preprocessing, normalization, clustering, identifying significantly differentially expressed genes, and interpreting the data based on known biology. With these methodologies, we also include lists of bioinformatic resources and tools for performing data analysis. The aim of this chapter is to provide the reader with the information necessary to be able to systematically catalog the impact of genetic parts on the host and also to optimize the operation of fully engineered genetic circuits. PMID- 21601085 TI - Directed evolution of promoters and tandem gene arrays for customizing RNA synthesis rates and regulation. AB - Manipulating RNA synthesis rates is a primary method the cell uses to adjust its physiological state. Therefore to design synthetic genetic networks and circuits, precise control of RNA synthesis rates is of the utmost importance. Often, however, a native promoter does not exist that has the precise characteristics required for a given application. Here, we describe two methods to change the rates and regulation of RNA synthesis in cells to create RNA synthesis of a desired specification. First, error-prone PCR is discussed for diversifying the properties of native promoters, that is, changing the rate of synthesis in constitutive promoters and the induction properties for an inducible promoter. Specifically, we describe techniques for generating diversified promoter libraries of the constitutive promoters P(L)tetO-1 in Escherichia coli and TEF1 in Saccharomyces cerevisiae as well as the inducible, oxygen-repressed promoter DAN1 in S. cerevisiae. Beyond generating promoter libraries, we discuss techniques to quantify the parameters of each new promoter. Promoter characteristics for each promoter in hand, the designer can then pick and choose the promoters needed for the specific genetic circuit described in silico. Second, Chemically Induced Chromosomal Evolution (CIChE) is presented as an alternative method to finely adjust RNA synthesis rates in E. coli by variation of gene cassette copy numbers in tandem gene arrays. Both techniques result in precisely defined RNA synthesis and should be of great utility in synthetic biology. PMID- 21601086 TI - Design and connection of robust genetic circuits. AB - Phenotypic robustness is a highly sought after goal for synthetic biology. There are many well-studied examples of robust systems in biology, and for the advancement of synthetic biology, particularly in performance-critical applications, fundamental understanding of how robustness is both achieved and maintained is very important. A synthetic circuit may fail to behave as expected for a multitude of reasons, and since many of these failures are difficult to predict a priori, a better understanding of a circuit's behavior as well as its possible failures are needed. In this chapter, we outline work that has been done in developing design principles for robust synthetic circuits, as well as sharing our experiences designing and constructing gene circuits. PMID- 21601087 TI - Engineering RNAi circuits. AB - Engineered "computing" biological networks are a generalization of endogenous regulatory pathways. They are intended to generate novel biological responses based on preprogrammed processing of multiple molecular signals. We have recently introduced an approach to constructing complex signal processing networks in mammalian cells using RNA interference (RNAi) as the underlying regulatory mechanism. The approach is modular and the circuits contain sensory, computational, and actuation modules. In the sensory module, various molecular signals are transduced into RNAi-compatible effectors such as small interfering RNA, or microRNA. In the computational module, multiple small RNA (sRNA) effectors converge on the small number of output constructs. Here, we describe experimental methods utilized in circuit construction with the focus on the computational module. We emphasize the steps involved in the design of large sRNA sets required for such circuits. PMID- 21601088 TI - From SELEX to cell dual selections for synthetic riboswitches. AB - Synthetic riboswitches have emerged as useful tools for controlling gene expression to reprogram cellular behavior. However, advancing beyond proof-of principle experiments requires the ability to quickly generate new synthetic riboswitches from RNA libraries. In this chapter, we provide a step-by-step overview of the process of obtaining synthetic riboswitches for use in Escherichia coli, starting from a randomized RNA library. PMID- 21601089 TI - Using noisy gene expression mediated by engineered adenovirus to probe signaling dynamics in mammalian cells. AB - Perturbations from environmental, genetic, and pharmacological sources can generate heterogeneous biological responses, even in genetically identical cells. Although these differences have important consequences on cell physiology and survival, they are often subsumed in measurements that average over the population. Here, we describe in detail how variability in adenoviral-mediated gene expression provides an effective means to map dose responses of signaling pathways. Cell-cell variability is inherent in gene delivery methods used in cell biology, which makes this approach adaptable to many existing experimental systems. We also discuss strategies to quantify biologically relevant inputs and outputs. PMID- 21601090 TI - De novo design and construction of an inducible gene expression system in mammalian cells. AB - Inducible expression systems represent the founding technology for the emergence of synthetic biology in mammalian cells. The core molecules in these systems are bacterial regulator proteins that bind to or dissociate from a cognate DNA operator sequence in response to an exogenous stimulus like a small-molecule inducer. In this chapter, we describe a generic protocol of how bacterial regulator proteins can be applied to the design, construction, and optimization of an inducible expression system in mammalian cells. By choosing regulator proteins with an appropriate small-molecule inducer, this protocol provides a straightforward approach for establishing biosensors, cell-to-cell communication systems, or tools to control gene expression in vivo. PMID- 21601091 TI - BioBuilding using banana-scented bacteria to teach synthetic biology. AB - Student interest in synthetic biology is detectable and growing. Each year teenagers from around the world participate in iGEM, a summer long synthetic biology competition. As part of their iGEM experience, undergraduates design and construct novel living systems using standardized biological parts. One engineering feat was accomplished by the 2006 MIT iGEM team, who modified the normally putrid smell of bacteria so that the cells generated pleasant scents, such as wintergreen and banana. We have taken advantage of their project as well as other iGEM successes to develop a teaching curriculum for high schools and colleges. The curriculum includes four hands-on activities and two classroom assignments. We envision these activities either complementing existing instruction, for example in an advanced placement biology lab, or replacing some outdated, cookbook lab classes that are often used as gateways to undergraduate research opportunities. The activities we have developed also introduce engineering and technology concepts that are often overlooked in the already over stuffed high school and college curricula. To ease their adoption, the activities include teacher materials, such as annotated instructions, grading rubrics, and animated resources. Here, we detail the student and teacher materials for performing the banana-scented bacteria lab, called "Eau that Smell." Other free teaching materials similar to the content here can be accessed through BioBuilder.org. PMID- 21601092 TI - Use of fluorescence microscopy to analyze genetic circuit dynamics. AB - The physiological processes and programs of cells are not typically determined by single genes, but are governed by the patterns of interactions between genes and proteins [Alon, U. (2007). An Introduction To Systems Biology: Design Principles of Biological Circuits. Chapman & Hall/CRC, Boca Raton.]. These interactions are commonly referred to as genetic circuits, and the pattern of these interactions is called the circuit's architecture [Sprinzak, D. and Elowitz, M.B. (2005). Reconstruction of genetic circuits. Nature438(7067), 443-448.]. Genetic circuits control diverse cellular processes, and each process requires specific dynamic behaviors to properly function. Biochemical evidence aids in the identification of interactions between genes and proteins, but the spatiotemporal dynamics of these interactions are more difficult to probe using conventional techniques. Fluorescence time-lapse microscopy is a powerful tool in the study of genetic circuit dynamics, allowing the measurement of circuit dynamics in single cells [Suel, G.M., et al. (2007). Tunability and noise dependence in differentiation dynamics. Science315(5819), 1716-1719.]. Uncovering the dynamics of genetic circuits allows verification of mathematical models of genetic circuits and aids in the design of forward experiments. By enabling the study of relationships between circuit architecture and dynamic behavior, fluorescence time-lapse microscopy opens new frontiers in synthetic biology, allowing for the alteration of genetic circuits to achieve novel behaviors [Cagatay, T., et al. (2009). Architecture-dependent noise discriminates functionally analogous differentiation circuits. Cell139(3), 512-522.], and even the generation of completely synthetic, purpose built genetic circuits [Elowitz, M.B. and Leibler, S. (2000). A synthetic oscillatory network of transcriptional regulators. Nature403(6767), 335-338.]. Perhaps more importantly, determination of genetic circuit dynamics can reveal the concepts and principles underlying the biological functions they regulate. PMID- 21601093 TI - Microfluidics for synthetic biology: from design to execution. AB - With the expanding interest in cellular responses to dynamic environments, microfluidic devices have become important experimental platforms for biological research. Microfluidic "microchemostat" devices enable precise environmental control while capturing high quality, single-cell gene expression data. For studies of population heterogeneity and gene expression noise, these abilities are crucial. Here, we describe the necessary steps for experimental microfluidics using devices created in our lab as examples. First, we discuss the rational design of microchemostats and the tools available to predict their performance. We carefully analyze the critical parts of an example device, focusing on the most important part of any microchemostat: the cell trap. Next, we present a method for generating on-chip dynamic environments using an integrated fluidic junction coupled to linear actuators. Our system relies on the simple modulation of hydrostatic pressure to alter the mixing ratio between two source reservoirs and we detail the software and hardware behind it. To expand the throughput of microchemostat experiments, we describe how to build larger, parallel versions of simpler devices. To analyze the large amounts of data, we discuss methods for automated cell tracking, focusing on the special problems presented by Saccharomyces cerevisiae cells. The manufacturing of microchemostats is described in complete detail: from the photolithographic processing of the wafer to the final bonding of the PDMS chip to glass coverslip. Finally, the procedures for conducting Escherichia coli and S. cerevisiae microchemostat experiments are addressed. PMID- 21601094 TI - Plate-based assays for light-regulated gene expression systems. AB - Light sensing proteins can be used to control living cells with exquisite precision. We have recently constructed a set of bacterial light sensors and used them to pattern gene expression across lawns of Escherichia coli with images of green and red light. The sensors can be expressed in a single cell and controlled independently by applying different light wavelengths. Both sensors also demonstrate continuous input-output behavior, where the magnitude of gene expression is proportional to the intensity of light applied. This combination of features allows complex patterns of gene expression to be programmed across an otherwise homogeneous cell population. The red light sensor has also been connected to a cell-cell communication system and several genetic logic circuits in order to program the bacterial lawn to behave as a distributed computer that performs the image-processing task of edge detection. Here, we will describe protocols for working with these systems in the laboratory. PMID- 21601095 TI - Spatiotemporal control of small GTPases with light using the LOV domain. AB - Signaling networks in living systems are coordinated through subcellular compartmentalization and precise timing of activation. These spatiotemporal aspects ensure the fidelity of signaling while contributing to the diversity and specificity of downstream events. This is studied through development of molecular tools that generate localized and precisely timed protein activity in living systems. To study the molecular events responsible for cytoskeletal changes in real time, we generated versions of Rho family GTPases whose interactions with downstream effectors is controlled by light. GTPases were grafted to the phototropin LOV (light, oxygen, or voltage) domain (Huala, E., Oeller, P. W., Liscum, E., Han, I., Larsen, E., and Briggs, W. R. (1997). Arabidopsis NPH1: A protein kinase with a putative redox-sensing domain. Science278, 2120-2123.) via an alpha helix on the LOV C-terminus (Wu, Y. I., Frey, D., Lungu, O. I., Jaehrig, A., Schlichting, I., Kuhlman, B., and Hahn, K. M. (2009). A genetically encoded photoactivatable Rac controls the motility of living cells. Nature461, 104-108.). The LOV domain sterically blocked the GTPase active site until it was irradiated. Exposure to 400-500nm light caused unwinding of the helix linking the LOV domain to the GTPase, relieving steric inhibition. The change was reversible and repeatable, and the protein could be returned to its inactive state simply by turning off the light. The LOV domain incorporates a flavin as the active chromophore. This naturally occurring molecule is incorporated simply upon expression of the LOV fusion in cells or animals, permitting ready control of GTPase function in different systems. In cultured single cells, light-activated Rac leads to membrane ruffling, protrusion, and migration. In collectively migrating border cells in the Drosophila ovary, focal activation of photoactivatable Rac (PA-Rac) in a single cell is sufficient to redirect the entire group. PA-Rac in a single cell also rescues the phenotype caused by loss of endogenous guidance receptor signaling in the whole group. These findings demonstrate that cells within the border cell cluster communicate and are guided collectively. Here, we describe optimization and application of PA Rac using detailed examples that we hope will help others apply the approach to different proteins and in a variety of different cells, tissues, and organisms. PMID- 21601096 TI - Light control of plasma membrane recruitment using the Phy-PIF system. AB - The ability to control the activity of intracellular signaling processes in live cells would be an extraordinarily powerful tool. Ideally, such an intracellular input would be (i) genetically encoded, (ii) able to be turned on and off in defined temporal or spatial patterns, (iii) fast to switch between on and off states, and (iv) orthogonal to other cellular processes. The light-gated interaction between fragments of two plant proteins--termed Phy and PIF- satisfies each of these constraints. In this system, Phy can be switched between two conformations using red and infrared light, while PIF only binds one of these states. This chapter describes known constraints for designing genetic constructs using Phy and PIF and provides protocols for expressing these constructs in mammalian cells, purifying the small molecule chromophore required for the system's light responsivity, and measuring light-gated binding by microscopy. PMID- 21601098 TI - Metabolic pathway flux enhancement by synthetic protein scaffolding. AB - Spatial control over enzyme organization presents a promising posttranslational strategy for improving metabolic flux. Directly tethering enzyme polypeptides has had inconsistent success. Use of a separate scaffold molecule, built from modular protein-protein interaction domains, provides designable control over enzyme assembly parameters, including stoichiometry, as well as providing scalability for multiple enzymes. Thus, metabolic flux can be optimized by expression of these scaffolds in vivo. It is important to note that exploration of the use of synthetic scaffolds for improving metabolic flux is in its early stages. Accordingly, in this chapter, we describe efforts to date, hypotheses for scaffold function, and parameters to consider for application to new pathways. PMID- 21601097 TI - Synthetic physiology strategies for adapting tools from nature for genetically targeted control of fast biological processes. AB - The life and operation of cells involve many physiological processes that take place over fast timescales of milliseconds to minutes. Genetically encoded technologies for driving or suppressing specific fast physiological processes in intact cells, perhaps embedded within intact tissues in living organisms, are critical for the ability to understand how these physiological processes contribute to emergent cellular and organismal functions and behaviors. Such "synthetic physiology" tools are often incredibly complex molecular machines, in part because they must operate at high speeds, without causing side effects. We here explore how synthetic physiology molecules can be identified and deployed in cells, and how the physiology of these molecules in cellular contexts can be assessed and optimized. For concreteness, we discuss these methods in the context of the "optogenetic" light-gated ion channels and pumps that we have developed over the past few years as synthetic physiology tools and widely disseminated for use in neuroscience for probing the role of specific brain cell types in neural computations, behaviors, and pathologies. We anticipate that some of the insights revealed here may be of general value for the field of synthetic physiology, as they raise issues that will be of importance for the development and use of high performance, high-speed, side-effect free physiological control tools in heterologous expression systems. PMID- 21601099 TI - A synthetic iterative pathway for ketoacid elongation. AB - Iterative formation of nonpolymeric carbon-carbon bonds has been employed by organisms to synthesize fatty acids, polyketides, and isoprenoids. In these biosynthetic schemes, same reaction cycles are used iteratively for functional modifications that result in the increase in carbon-chain length. This principle has been used in the design of a synthetic module for 2-ketoacid elongation. The system utilizes the Escherichia coli enzymes LeuABCD, which were engineered to accept bulkier nonnatural substrates, and was able to extend the chain length iteratively. The success in achieving a diverse range of 2-ketoacids and alcohols from this module via engineering of the 2-isopropylmalate synthase and ketoacid decarboxylase demonstrates the plasticity of LeuABCD and its feasibility for iterative carbon-chain elongations. In addition, this strategy illustrates a principle of designing novel metabolic modules for nonpolymeric carbon-chain elongation, which is essential in the synthesis of nonnative metabolites in microorganisms. PMID- 21601100 TI - Synthetic biology in Streptomyces bacteria. AB - Actinomycete bacteria of the genus Streptomyces are major producers of bioactive compounds for the biotechnology industry. They are the source of most clinically used antibiotics, as well as of several widely used drugs against common diseases, including cancer . Genome sequencing has revealed that the potential of Streptomyces species for the production of valuable secondary metabolites is even larger than previously realized. Accessing this rich genomic resource to discover new compounds by activating "cryptic" pathways is an interesting challenge for synthetic biology. This approach is facilitated by the inherent natural modularity of secondary metabolite biosynthetic pathways, at the level of individual enzymes (such as modular polyketide synthases), but also of gene cassettes/operons and entire biosynthetic gene clusters. It also benefits from a long tradition of molecular biology in Streptomyces, which provides a number of specific tools, ranging from cloning vectors to inducible promoters and translational control elements. In this chapter, we first provide an overview of the synthetic biology challenges in Streptomyces and then present the existing toolbox of molecular methods that can be employed in this organism. PMID- 21601101 TI - Methods for engineering sulfate reducing bacteria of the genus Desulfovibrio. AB - Sulfate reducing bacteria (SRB) are physiologically important given their nearly ubiquitous presence and have important applications in the areas of bioremediation and bioenergy. This chapter provides details on the steps used for homologous-recombination mediated chromosomal manipulation of Desulfovibrio vulgaris Hildenborough, a well-studied sulfate reducer. More specifically, we focus on the implementation of a "parts" based approach for suicide vector assembly, important aspects of anaerobic culturing, choices for antibiotic selection, electroporation-based DNA transformation, as well as tools for screening and verifying genetically modified constructs. These methods, which in principle may be extended to other SRB, are applicable for functional genomics investigations, as well as metabolic engineering manipulations. PMID- 21601102 TI - Modification of the genome of Rhodobacter sphaeroides and construction of synthetic operons. AB - The alpha-proteobacterium Rhodobacter sphaeroides is an exemplary model organism for the creation and study of novel protein expression systems, especially membrane protein complexes that harvest light energy to yield electrical energy. Advantages of this organism include a sequenced genome, tools for genetic engineering, a well-characterized metabolism, and a large membrane surface area when grown under hypoxic or anoxic conditions. This chapter provides a framework for the utilization of R. sphaeroides as a model organism for membrane protein expression, highlighting key advantages and shortcomings. Procedures covered in this chapter include the creation of chromosomal gene deletions, disruptions, and replacements, as well as the construction of a synthetic operon using a model promoter to induce expression of modified photosynthetic reaction center proteins for structural and functional analysis. PMID- 21601103 TI - Synthetic biology in cyanobacteria engineering and analyzing novel functions. AB - Cyanobacteria are the only prokaryotes capable of using sunlight as their energy, water as an electron donor, and air as a source of carbon and, for some nitrogen fixing strains, nitrogen. Compared to algae and plants, cyanobacteria are much easier to genetically engineer, and many of the standard biological parts available for Synthetic Biology applications in Escherichia coli can also be used in cyanobacteria. However, characterization of such parts in cyanobacteria reveals differences in performance when compared to E. coli, emphasizing the importance of detailed characterization in the cellular context of a biological chassis. Furthermore, cyanobacteria possess special characteristics (e.g., multiple copies of their chromosomes, high content of photosynthetically active proteins in the thylakoids, the presence of exopolysaccharides and extracellular glycolipids, and the existence of a circadian rhythm) that have to be taken into account when genetically engineering them. With this chapter, the synthetic biologist is given an overview of existing biological parts, tools and protocols for the genetic engineering, and molecular analysis of cyanobacteria for Synthetic Biology applications. PMID- 21601104 TI - Developing a synthetic signal transduction system in plants. AB - One area of focus in the emerging field of plant synthetic biology is the manipulation of systems involved in sensing and response to environmental signals. Sensing and responding to signals, including ligands, typically involves biological signal transduction. Plants use a wide variety of signaling systems to sense and respond to their environment. One of these systems, a histidine kinase (HK) based signaling system, lends itself to manipulation using the tools of synthetic biology. Both plants and bacteria use HKs to relay signals, which in bacteria can involve as few as two proteins (two-component systems or TCS). HK proteins are evolutionarily conserved between plants and bacteria and plant HK components have been shown to be functional in bacteria. We found that this conservation also applies to bacterial HK components which can function in plants. This conservation of function led us to hypothesize that synthetic HK signaling components can be designed and rapidly tested in bacteria. These novel HK signaling components form the foundation for a synthetic signaling system in plants, but typically require modifications such as codon optimization and proper targeting to allow optimal function. We describe the process and methodology of producing a synthetic signal transduction system in plants. We discovered that the bacterial response regulator (RR) PhoB shows HK-dependent nuclear translocation in planta. Using this discovery, we engineered a partial synthetic pathway in which a synthetic promoter (PlantPho) is activated using a plant adapted PhoB (PhoB-VP64) and the endogenous HK-based cytokinin signaling pathway. Building on this work, we adapted an input or sensing system based on bacterial chemotactic binding proteins and HKs, resulting in a complete eukaryotic signal transduction system. Input to our eukaryotic signal transduction system is provided by a periplasmic binding protein (PBP), ribose-binding protein (RBP). RBP interacts with the membrane-localized chemotactic receptor Trg. PBPs like RBP have been computationally redesigned to bind small ligands, such as the explosive 2,4,6-trinitrotoluene (TNT). A fusion between the chemotactic receptor Trg and the HK, PhoR, enables signal transduction via PhoB, which undergoes nuclear translocation in response to phosphorylation, resulting in transcriptional activation of an output gene under control of a synthetic plant promoter. Collectively, these components produce a novel ligand-responsive signal transduction system in plants and provide a means to engineer a eukaryotic synthetic signaling system. PMID- 21601105 TI - Lentiviral vectors to study stochastic noise in gene expression. AB - Lentiviral vectors are vehicles for gene delivery that were originally derived from the human immunodeficiency virus type-1 (HIV-1) lentivirus. These vectors are defective for replication, and thus considered relatively safe, but are capable of stably integrating into the genomic DNA of a broad range of dividing and nondividing mammalian cell types. The ability to stably integrate at semi random genomic positions make lentiviral vectors a unique and ideal tool for studying stochastic variation in gene expression. Here, we describe the experimental and mathematical methods for using lentiviral vectors to study stochastic noise in gene expression. PMID- 21601106 TI - More than a biomarker: CA125 may contribute to ovarian cancer pathogenesis. PMID- 21601107 TI - Advances in cervical cancer treatment. PMID- 21601109 TI - Pierre Masson (1880-1957). PMID- 21601110 TI - [The use of virtual slides in the daily practice of a pathology laboratory]. AB - INTRODUCTION: We describe a first experiment in routine use of a virtual slides system within a pathology practice whose technical facilities are not located on the same geographical site as pathologists. MATERIAL AND METHODS: The samples to be analyzed were biopsies, tissues, and cytology preparations in liquid environment. They were processed through technical facilities using a slide scanner. The process is monitored by the company specialised in e@pathology solutions (CCITI) http://www.e@pathologie facility. RESULTS: From November 2008 to September 2009, 611 patient files have been processed, i.e. 1183 slides have been digitalized without selective criteria. The average digitalization time per slide was 30 seconds to 2 minutes for biopsies and 7 minutes for tissues and smears. The record of the areas examined confirms that the whole slide has been visualized. The time and space constraints were reduced in case a second reading is requested. Less than 1% of the slides had to be re-digitalized. The reports were standardized with pre-defined questions/answers or bible code. The average time for processing a file is 3 to 5 minutes. DISCUSSION: The http://www.e@pathologie facility simplifies routine second advice requests and allows the control of operating costs through the mutualisation of technical facilities of several laboratories while preserving their independence. CONCLUSION: The online virtual slide system must go beyond the experimental stage whilst remaining in perfect accord with the users needs and economic realities. It will also make it possible to enrich the patient's medical follow-up digital file. PMID- 21601111 TI - [HER2 and gastric cancer. Recommendations for clinical practice in 2011]. AB - Trastuzumab in combination with capecitabine or 5-fluorouracil and cisplatin has been approved by the European Medicines Agency (EMEA) for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry [IHC] 3+ or IHC 2+/ fluorescence in situ hybridization [FISH]-positive or IHC 2+/ silver in situ hybridization [SISH]-positive) metastatic adenocarcinoma of the stomach or gastro-esophageal (GE) junction. HER2 testing in gastric cancer (GC) differs from testing in breast cancer (BC) due to major differences in the tumor biology; as the disease is progressing rapidely, we recommend to test every GC at diagnosis and to offer a rapid testing (less than five days) in the metastatic setting. IHC should be the initial testing methodology and FISH or SISH should be used to retest IHC 2+ samples. As GC more frequently shows incomplete membrane staining and focal staining for HER2, HER2 testing guidelines have been adapted from BC protocols. The scoring system is slightly different in respect to the characteristics of GC. For in situ hybridization, SISH should be used in order to identify heterogeneous staining with a higher accuracy than FISH. Enrollment in training and quality assurance programs is highly recommended. In case of negativity on biopsy, it is recommended to retest for HER2, when possible, on surgical specimens and/or metastasis. This will ensure accurate and consistent HER2 testing results, which will allow the appropriate selection of patients eligible for treatment with trastuzumab. PMID- 21601112 TI - [The new WHO classification of digestive neuroendocrine tumors]. AB - A new classification of digestive neuroendocrine neoplasms has been formulated in the 2010 revision of the WHO classification of digestive tumors. The principles of this new classification are different from those used in the previous one and the terminology is quite novel. Five main categories are recognized: neuroendocrine tumor G1; neuroendocrine tumor G2; neuroendocrine carcinoma, small cell type; neuroendocrine carcinoma, large cell type; mixed adenoneuroendocrine carcinoma (a new term for mixed tumors). This new classification will change the habits of the clinicians, familiar with the previous classification, which formed the basis for deciding the therapeutic strategy and the type of patient management. Attention must be paid when establishing the concordance between the new classification and the previous one and when reclassifying a previously diagnosed case, now under follow-up. Recommendations are proposed for the redaction of the pathological reports in this period of transition. PMID- 21601113 TI - [A rare cause of sudden cardiac failure: histiocytoid cardiomyopathy]. AB - Histiocytoid cardiomyopathy is a rare disease which occurs predominantly in the first two years of life, with a female preponderance. We report the cases of two girls (11 and 15-month-old) which were respectively referred to our institution for ventricular tachycardia and ventricular fibrillation without prodroma. Etiologic findings only showed mild cardiomyopathy. Autopsy and histologic examination led to the diagnosis of histiocytoid cardiomyopathy. Furthermore, in the first observation, agenesis of the corpus callosum was found. PMID- 21601114 TI - [Uterine leiomyoma with massive lymphoid infiltration: case report]. AB - Uterine leiomyoma with massive lymphoid infiltration is a rare and unusual pathological finding; only 20 cases have been reported in the literature. We report a case of this unusual lesion in a 35-year-old woman who underwent a myomectomy. On gross examination, the tumor was of white color and firm consistency. Histological sections showed interlacing bundles of spindle shaped cells of low density with moderate to severe lymphocytic infiltrate associated to lymphoid follicles and few plasma cells. Immunohistochemically, the diffusely infiltrating lymphoid cells were predominantly of T cell phenotype. The interspersed spindle shaped cells were positive with alpha smooth muscle actin, desmin and h-caldesmon. The cause of this unusual lesion is not clear, but the recognition of its distinct histological features is important to avoid possible confusion with differential diagnosis including malignant lymphoma, inflammatory pseudotumor and pyomyoma. PMID- 21601115 TI - [Polypoid PEComa: case report and literature review]. AB - PEComa group is a heterogeneous group of rare mesenchymal tumors supposed to derive from perivascular cells and characterized by a coexpression of myogenic and melanocytic markers. We describe an 11-year-old female patient presenting a 2 cm ulcerated rectal polyp, exteriorized by anus, which was totally resected. Morphologically, this tumour was composed of cells arranged in nests or large cords separated by fibrous stroma, with abundant clear cytoplasms and with round regular small nuclei without atypia. There was no necrotic area and mitotic activity was very low. Immunohistochemically, the tumours cells stained for HMB45. Only 17 cases have been reported in literature and this case is the 18th. Here, we present a literature review focusing on both malignancy criteria and differential diagnosis. PMID- 21601116 TI - [A rare scrotal lesion with disputed aetiology]. PMID- 21601117 TI - [Breast metastasis of ileal endocrine carcinoma]. PMID- 21601118 TI - [A rare cause of renal graft dysfunction]. PMID- 21601119 TI - [A rare testicular tumor]. PMID- 21601120 TI - [Unusual mucosal changes in a severe colitis]. PMID- 21601121 TI - [A not very catholic nodule]. PMID- 21601122 TI - Humbling snapshots. PMID- 21601123 TI - Quiz page June 2011. Profound metabolic acidosis and abdominal pain in a diabetic patient on long-term hemodialysis. PMID- 21601124 TI - Predicting development of CKD in the general population--early days in a rapidly evolving field. PMID- 21601125 TI - Percutaneous kidney biopsy: "the needle and the damage done"? PMID- 21601126 TI - Hypertension and autosomal dominant polycystic kidney disease. PMID- 21601127 TI - Improving incident fistula rates: a process of care issue. PMID- 21601129 TI - Intra-abdominal pressure can be estimated inexpensively by the sagittal abdominal diameter. PMID- 21601130 TI - Antifibrinolytic use during cardiac and hepatic surgery makes tubular proteinuria based early biomarkers poor tools to diagnose perioperative acute kidney injury. PMID- 21601132 TI - Sublingual immunotherapy is safe in children, but the challenge is how to increase its efficiency? PMID- 21601133 TI - Recent perspectives on the global epidemiology of childhood eczema. AB - The International Study of Asthma and Allergies in Childhood (ISAAC) is the largest epidemiological study ever performed and the only truly global allergy study. This review summarises the childhood eczema-related findings from ISAAC and discusses how these fit into our current understanding of eczema aetiology, with particular emphasis on worldwide time trends in eczema prevalence, climatic and dietary risk factors, breastfeeding, the role of skin barrier impairment and allergic sensitisation. PMID- 21601134 TI - Noninvasive assessment of atherosclerosis in apolipoprotein-e knockout mice by ultrasound biomicroscopy. AB - Intima media thickness is a marker for human atherosclerosis. This study aimed to validate the hypothesis that atherosclerosis progression in vivo in mice can be visualized noninvasively using high-resolution ultrasound biomicroscopy (UBM), and to study the association between UBM characteristics and plasma lipids in the apolipoprotein-E knockout (ApoE-/-) mouse model. Four age groups of male ApoE-/- mice were used as atherosclerotic models, with age-matched male C57BL/6 mice used as controls. Plaque thickness and area measured by UBM correlated with histologic measurements (r = 0.81, r = 0.70, respectively; p < 0.001). Serum total cholesterol, low density lipoprotein cholesterol and triglycerides were higher in the ApoE-/- groups compared with controls (p < 0.01). Plaque thickness was correlated with total cholesterol (r = 0.505, p < 0.001). High-resolution UBM provides a noninvasive, accurate means of detecting atherosclerosis progression in vivo in mice and can detect changes in the early stage of atherosclerosis. PMID- 21601135 TI - Validation of dynamic contrast-enhanced ultrasound in rodent kidneys as an absolute quantitative method for measuring blood perfusion. AB - Contrast-enhanced ultrasound (CEUS) has demonstrated utility in the monitoring of blood flow in tissues, organs and tumors. However, current CEUS methods typically provide only relative image-derived measurements, rather than quantitative values of blood flow in milliliters/minute per gram of tissue. In this study, CEUS derived parameters of blood flow are compared with absolute measurements of blood flow in rodent kidneys. Additionally, the effects of contrast agent infusion rate and transducer orientation on image-derived perfusion measurements are assessed. Both wash-in curve and time-to-refill algorithms are examined. Data illustrate that for all conditions, image-derived flow measurements were well-correlated with transit-time flow probe measurements (R > 0.9). However, we report differences in the sensitivity to flow across different transducer orientations as well as the contrast analysis algorithm utilized. Results also indicate that there exists a range of contrast agent flow rates for which image-derived estimates are consistent. PMID- 21601137 TI - Nonspherical shape oscillations of coated microbubbles in contact with a wall. AB - In this experimental study, the nonspherical and translational behavior of individual coated microbubbles of different sizes, in contact with a 20-MUm thickness cellulose wall, are observed and categorized systematically. Images from two orthogonally positioned microscopes are merged and then recorded with an ultra-fast framing camera. Large nonspherical deformations were found with 2.25 MHz frequency ultrasound pulses having driving pressures from 80 to 325 kPa. A parametric model combining potential flow theory with a viscous boundary layer at the wall is developed and used to calculate stresses from the optically recorded microbubble oscillations. Peak shear stress of up to 300 kPa and normal stresses of up to 1 MPa are estimated when microbubbles are insonifed with a 2.25 MHz pulse at 325 kPa. The clinical relevance of these results is discussed. PMID- 21601136 TI - Real-time passive acoustic monitoring of HIFU-induced tissue damage. AB - Thermal ablation by high-intensity focused ultrasound (HIFU) shows great promise as a noninvasive cancer therapy. This work proposes a novel method of real-time HIFU treatment monitoring that uses the passively monitored acoustic signal emanating from the focus during HIFU exposure. We performed 212 exposures in seven freshly excised ox livers using 1.067-MHz HIFU at a 95% duty cycle for a range of insonation durations and acoustic intensities. Acoustic emissions were recorded using a 15-MHz passive detector aligned confocally and coaxially with the HIFU transducer. Lesion presence and size were ascertained by slicing the tissue in the transverse and axial focal planes post exposure. Our results demonstrate that successful formation of HIFU lesions in ex vivo ox liver is highly correlated with the presence of pronounced dips in the magnitude of the received signal at integer harmonics of the insonation frequency. A detector based on this observation predicted lesioning with >80% accuracy in regimes that were very likely to create lesions (>=60 J of energy) and had an error rate of <6% for exposures that were too short to cause lesioning (<=1 s long). The overall sensitivity and specificity of the detector were 75.6% and 74.2%, respectively. The proposed detector could therefore provide a low-cost means of effectively monitoring clinical HIFU treatments passively and in real time. PMID- 21601138 TI - Assessment of ultrasound monitor image display performance. AB - The display monitor on an ultrasound scanner is used to make primary diagnoses. In this study, 31 ultrasound systems were assessed against current American Association of Physicists in Medicine (AAPM) display standards. Measurements of peak levels (L(max) and L(min)) were generated. Ambient light, L(amb) (cd/m(2)) and room illuminance, L(x) (Lux) were measured. Luminance ratio was calculated (LR' = (L(max)+L(amb))/(L(min)+L(amb))). Initially, only 8/31 systems (26%) passed all the criteria. After adjustment, a further 7/31 (23%) passed making a total of 15/31 passes (48%). A total of 16/31 (52%) were considered overall fails: three due to poor room lighting, 14 due to poor monitor performance. Considering errors this could be as low as 6/31 (19%). Although further work is required to confirm the applicability of these results, it is of concern that three-quarters of ultrasound scanners could be suboptimally adjusted with 19%-55% unable to pass the AAPM criteria. The impact of this on clinical practice is unknown but there is clearly a need to review display quality assurance on ultrasound scanners. PMID- 21601139 TI - Wave simulation in biologic media based on the Kelvin-Voigt fractional-derivative stress-strain relation. AB - The acoustic behavior of biologic media can be described more realistically using a stress-strain relation based on fractional time derivatives of the strain, since the fractional exponent is an additional fitting parameter. We consider a generalization of the Kelvin-Voigt rheology to the case of rational orders of differentiation, the so-called Kelvin-Voigt fractional-derivative (KVFD) constitutive equation, and introduce a novel modeling method to solve the wave equation by means of the Grunwald-Letnikov approximation and the staggered Fourier pseudospectral method to compute the spatial derivatives. The algorithm can handle complex geometries and general material-property variability. We verify the results by comparison with the analytical solution obtained for wave propagation in homogeneous media. Moreover, we illustrate the use of the algorithm by simulation of wave propagation in normal and cancerous breast tissue. PMID- 21601140 TI - Adoption of CONSORT statements for randomized control trials published in the Journal of Pediatric Nursing. PMID- 21601141 TI - Comparison of temporal artery to rectal temperature measurements in children up to 24 months. AB - This descriptive study compared temporal artery (TA) and rectal temperature measurements, patient comfort during temperature measurements, and nursing time required to obtain temperature measurements. Study participants (n = 40) included children 0-24 months old with fever higher than 38 degrees C, admitted to a freestanding children's hospital in the Midwest. Statistical analysis of 450 paired TA and rectal temperature measurements revealed a 0.776 correlation, mean difference of 0.03 degrees C, and 94.7% of measurements differing by less than 1.0 degrees C. Patient comfort, measured via the Face, Legs, Activity, Cry, Consolability Scale, was enhanced with TA thermometry compared to rectal. TA thermometry resulted in an 87% savings of nursing time. PMID- 21601142 TI - Differences on psychosocial outcomes between male and female caregivers of children with life-limiting illnesses. AB - This secondary analysis of data examined the psychosocial outcomes of meaning in caregiving, self-esteem, optimism, burden, depression, spirituality, and posttraumatic growth in 273 parents caring for children with life-limiting illnesses to (a) determine if there were gender differences and (b) identify gender-specific correlations among these outcomes. Findings suggest that significant gender differences exist. Women reported higher average scores compared with men for meaning in caregiving, depression, burden, and posttraumatic growth and lower average scores for optimism. Correlations also revealed some significant differences. Health care professionals need to be aware of gender differences and tailor their interventions appropriately. PMID- 21601143 TI - Caregiver self-report of children's use of the sippy cup among children 1 to 4 years of age. AB - PURPOSE: This research examined the prevalence of the use of the sippy cup, as compared to the baby bottle, among children 1 to 4 years of age. METHOD: Using a population-based telephone surveillance survey in Ontario, caregivers of children 1 to 4 years of age were asked about their child's use of the sippy cup/baby bottle from the Rapid Risk Factor Surveillance System Module: Early Childhood Tooth Decay. RESULTS: Most caregivers reported that children 1 to 4 years of age were currently using the sippy cup (69.7%), with the proportion increasing to 94.4% when including children with past use of the sippy cup. Younger children were significantly more likely to use the sippy cup, and 10.8% of children 4 years of age continued to use the baby bottle. Diluted fruit juice was the most frequently used liquid in the sippy cup (58.2%). Most of the caregivers did not report the use of the sippy cup at night. CONCLUSION: Caregivers need education as to potential increases in exposure to sugared/acidic liquids through the use of the sippy cup. Future research is needed to understand the extensive and prolonged use of the sippy cup/baby bottle by young children. PMID- 21601144 TI - Parental support in neonatal intensive care units: a cross-cultural comparison between New Zealand and Japan. AB - This is a cross-cultural comparative study involving both quantitative and qualitative data analyses. This study examines sources of parental stress in the two neonatal intensive care units (NICUs) located in New Zealand and Japan and explores how cultural norms of NICU care environments influence parental stress related experiences and nursing support. The three main sources of data collection were the following: a NICU staff interview, parental interview, and parental questionnaire survey, the PSS: NICU. Thirty-one pairs of parents in each NICU (N = 121) participated in this study. The differences between the two NICUs in terms of the NICU care environment and sources of parental stress within the NICU contexts were identified, highlighting NICU characteristics associated with the sources of stress in the two NICUs. Recognition of the norms of NICU care environments that may hinder parent-staff communication is an important element of NICU nursing practice. PMID- 21601145 TI - Predictors of unprotected intercourse for female adolescents measured at their request for a pregnancy test. AB - The purpose of this study was to identify predictors of unprotected intercourse in a sample of female adolescents requesting pregnancy testing. A survey was completed by 305 adolescents at a clinic visit. The dependent variable, unprotected sexual intercourse, was measured by self-reported frequency of condom use. Significant variables in the final regression model predicting condom nonuse included current partner's age, frequency of sexual activity, race, age at menarche, time dating, resiliency, reproductive knowledge, and fertility fear. Fertility fears were identified as a possible motivator for unprotected intercourse, an important finding for health care professionals providing care to adolescents. PMID- 21601146 TI - Enhancing the pediatric undergraduate nursing curriculum through simulation. AB - Pediatric nursing courses have been affected by the increasingly limited amount of clinical placements and experiences for students. Securing clinical sites that provide well-rounded experiences in a limited amount of time is difficult. In addition, "teachable moments" can be lost on a busy unit due to variables outside of the control of the clinical faculty member, leading to a less than positive learning experience for students. A pediatric simulation curriculum was developed for the clinical rotation. This allowed students to begin their clinical experience better prepared and broadened their overall clinical experiences in a limited amount of time. PMID- 21601147 TI - The "white plague" and color: children, race, and tuberculosis in Virginia 1900 1935. AB - Drawing on a wealth of primary documents, this historical research describes nurses' efforts regarding early 20th century pediatric tuberculosis care in Virginia. Virginia nurses played a leadership role in designing a template for children's care. Ultimately, however, their legacy is a mixed one. They helped forge a system funded by a complicated, poorly coordinated, race- and class-based mix of public and private support that is now delivered through an idiosyncratic web of community, state, and federal programs. However, they also took courageous action, and their efforts improved the lives of many children. By so doing, they helped invent pediatric nursing. PMID- 21601148 TI - Self-concept in children and adolescents with attention deficit hyperactivity disorder. AB - Children with attention deficit hyperactivity disorder (ADHD) struggle with behavioral symptoms, yet little research has provided information about how behavioral symptoms impact their self-concept, especially in terms of gender, age, and ethnicity. Data were collected from 145 children and adolescents with ADHD and their mothers. African Americans, Hispanic Americans, and Caucasians were nearly equally represented in the sample, with approximately one third each. The Child Behavior Checklist was used to assess ADHD symptom severity, and Piers- Harris Children's Self-Concept Scale was used to measure self-concept. Older ages and more internalizing behavior problems predicted lower self-concept. There were no significant differences between ethnic groups on behavior problem and self concept scores, although post hoc analyses revealed a trend for Caucasian children with ADHD to have lower self-concept scores than those of African American or Hispanic children. The findings indicate that there is a need to assess self-concept in children and adolescents with ADHD, especially those who are older and have comorbid conditions of anxiety and depression. PMID- 21601149 TI - Nursing strategies to reduce the incidence of early childhood caries in culturally diverse populations. AB - In the United States, early childhood caries (ECC) is a major unmet health care need adversely affecting the overall health of young children from diverse ethnic populations. Nurses who work in the newborn nursery, pediatrics, public, and community health centers have a unique opportunity to positively influence a change in this epidemic of ECC. Guided by Leininger's theory of cultural care, these authors describe ways to implement a comprehensive culturally sensitive oral health education program for parents of newborns and infants. Interventions based on the best available evidence for oral health education, a culturally sensitive caries risk assessment, recommendations for fluoride varnish treatments, and ways for parents to establish a dental home for the infant by 12 months old are presented. PMID- 21601150 TI - Letter to the editor by Butler in response to "obesity and cholesterol in Japanese, French, and U.S. Children". PMID- 21601151 TI - Response to H1N1 Influenza Outbreak. PMID- 21601152 TI - Evaluating the application of knowledge: the use of restraints. PMID- 21601153 TI - New food allergy guidelines. PMID- 21601154 TI - The scope of pediatric nursing: the interplay of developmental and psychosocial needs with the demands of illness. PMID- 21601155 TI - Balancing the benefits and risks of new drugs for MS. PMID- 21601156 TI - Decompressive craniectomy in diffuse traumatic brain injury. PMID- 21601157 TI - Fluoxetine and motor recovery after ischaemic stroke. PMID- 21601158 TI - Fluoxetine and motor recovery after ischaemic stroke. PMID- 21601160 TI - Jeffrey Cohen: covering clinical trials of MS from all angles. PMID- 21601161 TI - Lifeline. Bas Bloem. PMID- 21601162 TI - Atypical presentations of acute cerebrovascular syndromes. AB - Correct diagnosis of acute stroke is of paramount importance to clinicians to enable selection of correct treatments and to ensure prevention of acute complications, including recurrent stroke. Timely diagnosis can be difficult in some cases because patients with acute stroke can present with atypical or uncommon symptoms that suggest another cause altogether. Publications on these patients suggest that the following strategies could help to reduce misdiagnosis. First, clinicians should suspect stroke in any patient with abrupt onset of neurological symptoms. Second, clinicians should be aware that some patients will initially present with various uncommon and atypical stroke symptoms. Third, a complete and systematic neurological examination should be routinely done in patients presenting with acute neurological symptoms because this might shed light on the true nature of the problem. Finally, clinicians should be aware that even with the most sophisticated neuroimaging tests, stroke might be missed in the early hours after the event. PMID- 21601163 TI - Primary angiitis of the CNS. AB - Meaningful progress in our understanding and clinical approach to primary angiitis of the CNS (PACNS) has been made in the past three decades. Increased recognition of PACNS and general advances in diagnosis of neurological disorders have led to an aggressive diagnostic approach and a proliferation of case reports providing enriched clinical and pathological descriptions. We have witnessed major advances not only in the diagnosis of PACNS but in the recognition of its mimics. Epidemiological, clinical, neuroradiagnostic, and laboratory findings have enhanced our diagnostic accuracy and recognition of PACNS mimics, however, many challenges to our understanding and management of the disease in children and adults remain. PMID- 21601164 TI - Development of biomarkers for Huntington's disease. AB - Huntington's disease is an autosomal dominant, progressive neurodegenerative disorder, for which there is no disease-modifying treatment. By use of predictive genetic testing, it is possible to identify individuals who carry the gene defect before the onset of symptoms, providing a window of opportunity for intervention aimed at preventing or delaying disease onset. However, without robust and practical measures of disease progression (ie, biomarkers), the efficacy of therapeutic interventions in this premanifest Huntington's disease population cannot be readily assessed. Current progress in the development of biomarkers might enable evaluation of disease progression in individuals at the premanifest stage of the disease; these biomarkers could be useful in defining endpoints in clinical trials in this population. Clinical, cognitive, neuroimaging, and biochemical biomarkers are being investigated for their potential in clinical use and their value in the development of future treatments for patients with Huntington's disease. PMID- 21601165 TI - Rapid control of a hospital-wide outbreak caused by extensively drug-resistant OXA-72-producing Acinetobacter baumannii. AB - Extensively drug-resistant Acinetobacter baumannii (XDRAb) emerges as an important pathogen of health care-associated infections and outbreaks worldwide. During January and February 2006, there was a hospital-wide outbreak of XDRAb at a medical center in Taiwan. Without limiting the usage of carbapenems or the closure of any ward, this outbreak was effectively controlled. We investigated the molecular epidemiology and reported the infection control experiences. XDRAb is defined as A baumannii that is resistant to multiple antibiotics but susceptible to tigecycline and polymyxin B. During the outbreak, the clinical and environmental XDRAb isolates were collected and studied by antimicrobial susceptibility testing, pulsed-field gel electrophoresis, and polymerase chain reaction for Verona integron-encoded metallo-beta-lactamases, imipenemases, and oxacillinases (OXA). Our measures to control the outbreak included private room isolation of patients until there were three successive negative cultures, reinforcement of contact precautions, daily environmental cleansing with room dedicated cleaning tools and sodium hypochlorite, and careful auditing of adherence. During the outbreak, 32 clinical XDRAb isolates came from 13 patients who were hospitalized in four intensive care units and three wards. Most (7 of 13, 53.8%) cases were associated with a surgical intensive care unit. The results from pulsed-field gel electrophoresis study indicated that all isolates were of one genotype. All 32 isolates harbored ISAba1-bla(OxA-51-like) and bla(OxA-72) genes. After this outbreak till August 2010, further incidences of XDRAb were sporadic cases of XDRAb with different clones and did not reach the level of outbreak. To our knowledge, this is the first reported hospital-wide outbreak caused by OXA-72 carbapenemase-producing A baumannii in the Asia-Pacific region, with successful and sustained control. Although the source or vehicle of the outbreak was not identified, our results suggest that a hospital-wide outbreak can be successfully managed with strict infection control measures, and that the limitation of the use of carbapenems and closure of wards may not be necessary. PMID- 21601166 TI - Reappraisal of heart rate variability in acute ischemic stroke. AB - Cardiac autonomic dysfunction is a common complication after acute ischemic stroke (IS). Prior investigators have emphasized that infarction of brain stem or hemispheres with insular involvement is related to this dysfunction and may predict poor clinical outcome. From the viewpoint of stroke physicians, however, all stroke patients, particularly large-artery atherosclerosis (LAA) should be monitored for possible cardiac complications after acute IS. This study aimed to investigate cardiac autonomic impaction in patients with acute IS and to make the comparison between LAA and small-vessel occlusion (SVO) subtypes. Of the 126 acute IS patients prospectively enrolled in this study, 32 had LAA, 56 had SVO, and 38 had undetermined etiology according to the Trial of Org 10172 in Acute Stroke Treatment criteria. Cardiac autonomic function of all patients was assessed by measuring heart rate variability (HRV). The low- and high-frequency components of HRV in all stroke patients were significantly lower than those of control subjects after comparing multivariable models, including additional adjustments for age, gender, and all risk factors. There were no significant differences on HRV between LAA and SVO although post hoc comparisons showed that stroke patients of SVO had increased sympathetic modulation and reduced vagal activity. In conclusion, in acute IS patients, both LAA and SVO are predisposed to have cardiac autonomic dysfunction, manifesting as abnormalities in HRV, whether in hemispheric or brain stem lesions. Stroke patients of SVO are at higher risks of cardiac abnormalities, which might suggest an early cardiac dysfunction because of long-term hypertension. The HF component of HRV thought to be for vagal control might be a cardinal marker for predicting cardiac autonomic dysfunction after acute IS. Short-term HRV spectral analysis is a convenient approach for stroke clinicians to assess autonomic function in acute stroke. Long term follow-up for HRV and clinical outcome relative to LAA and SVO stroke subtypes is warranted, particularly when an abnormal HRV is found at admission. PMID- 21601167 TI - Use of high-dose nandrolone aggravates septic shock in a mouse model. AB - Nandrolone, an anabolic-androgenic steroid, is widely misused by athletes who wish to rapidly increase muscle mass and performance. An increasing number of reports have indicated that nandrolone may affect and modulate the immune system. This study aimed to investigate the effects of nandrolone on septic shock-caused immune responses and the cellular mechanism of action using a sepsis murine model. Before septic shock induction, BALB/c mice were given a high dose of nandrolone or peanut oil only. After septic shock induction, mice were sacrificed at different time points. Their blood and tissue specimens were analyzed. It was found that the high-dose nandrolone group had significantly increased mortality compared with the control group (p<0.001). The serum malondialdehyde level was significantly increased in the high-dose group compared with the control group. Animals administered a high dose of nandrolone had significantly increased hepatic tumor necrosis factor-alpha or splenic interferon-gamma at 0 and 6 hours. In lung tissue, insulin-like growth factor-1, insulin-like growth factor binding proteins (IGFBPs) and insulin-like growth factor-1 receptor, and IGFBP1 and IGFBP2 mRNA expression were increased in the high-dose nandrolone group at 6 hours. Nandrolone abuse may hasten the death of patients with septic shock and may aggravate septic shock in mice. PMID- 21601168 TI - Problem-based learning: developing resilience in nursing students. AB - A society needs mature and confident nurse practitioners, who are able to think analytically and flexibly, recognize needs for further preparation, and willing to engage in self-development. Concern is raised regarding how educators will build the capacity of resilient students with a knowledge base and a minimum set of skills in responding to various issues and for engaging in self-reflection. Drawing on the framework of nursing competencies and global standards for the education of professional nurses, resilient students may contribute through their social competence, problem-solving ability, sense of purpose, and persistence in the process to achieve the goal of the project. Educators should know how to build the resilient attribute in students by encouraging them to engage in self reflection. This article discusses four areas that help students build resilience from project-based learning of a small group: the impact of problem-based learning at clinical practice, project/problem-based learning, resilient nursing student, and developing nursing students' resilience. Self-assessment to check the promoting skills for teaching in a problem-based learning program helps the faculty holding the empowerment to encourage or support the students to face the challenge within the small team. PMID- 21601169 TI - Ogilvie's syndrome-related right colon perforation after cesarean section: a case series. AB - The objective of this article is to discuss and report three cases of right colon perforation secondary to postcesarean Ogilvie's syndrome (OS; colonic pseudo obstruction) requiring right hemicolectomy. We retrospectively reviewed the case notes of three patients who underwent caesarean section and postoperatively developed OS. OS is an uncommon problem in patients undergoing caesarean section. Abdominal X-ray and water-soluble contrast enema are the main diagnostic modalities. Drip-suck therapy along with endoscopic or pharmacological decompression should be performed in early stages. In a significant percentage of patients, diagnosis is delayed resulting in bowel ischemia and perforation requiring surgical resection and adding significant mortality/morbidity. We recommend our obstetric colleagues to involve surgical team in earlier stages to avoid surgery-related mortality and morbidity. We also advocate general surgeons to be aware of OS in patients after caesarean section and recommend a stepwise systematic approach toward the diagnosis and management of OS. PMID- 21601170 TI - Mixed-type paratesticular rhabdomyosarcoma--a case report. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue tumor of childhood; about 80% of cases occur before the age of 21 with the remaining 20% evenly spread throughout the remaining decades. A primary paratesticular site is considered to have a good prognosis in comparison with other RMS sites. Histologically, any subtype of RMS, including alveolar, pleomorphic, embryonal, and mixed type, may occur in the paratesticular region, but only a relatively small number of cases are mixed and this variant has a poor prognosis. We report a case of paratesticular RMS (mixed embryonal and alveolar type) in a 16-year-old boy. PMID- 21601171 TI - Delayed superficial femoral artery pseudoaneurysm following distal femoral shaft fracture: a case report. AB - A 69-year-old man presented with an expanding tissue mass over the medial aspect of his left thigh 6 weeks after a fracture of the distal femur shaft. Imaging studies confirmed a rare traumatic pseudoaneurysm of the superficial femoral artery. For the massive hematoma and persistent exsanguinating hemorrhage, staged interventions were taken. First, the pseudoaneurysm was hemodynamically isolated with an endovascular stent-graft placement. Subsequent surgical exploration and aneurysmectomy were performed later for the evacuation of the formed hematoma and the relief of the resultant compressive symptoms. Because traumatic pseudoaneurysm can have an insidious onset and delayed presentation, surgeons should consider the possible complication even after initial fracture fixation. PMID- 21601172 TI - Aortobronchial fistula after esophagectomy for esophageal cancer -- a very rare complication. AB - Most aorto-respiratory fistulas are related to aortic pathology or procedures, but fistula formation after esophageal resection has never been reported in the literature. We are now reporting a case of hemoptysis that occurred after esophagectomy for locally advanced esophageal cancer. Aortobronchial fistula was detected by computed tomography scan. The patient was finally saved by emergency surgery-Dacron graft interposition of the descending thoracic aorta. There was no malignant cell in the postoperative specimen of the fistula. The erosion of the ligaclips (Johnson & Johnson) might be responsible for the aortobronchial fistula formation. For esophageal surgery, avoidance of trauma to aortic wall and careful using of ligaclips are important to circumvent this complication. PMID- 21601173 TI - [Psoriasis and obesity: a review and practical recommendations]. AB - Epidemiological studies have shown that patients with psoriasis have a higher risk of developing certain metabolic disorders, particularly obesity. Psoriasis and obesity are linked through a common pathophysiological mechanism of chronic low-grade inflammation. Not only is obesity associated with a higher incidence of psoriasis and greater severity, but it also affects response to treatment. The dermatologic management of these patients must therefore take their overall metabolic situation into consideration. We present a review of the recent literature on this subject and practical recommendations on the management of this group of patients, including relevant additional tests and advice on diet and a healthy lifestyle. PMID- 21601174 TI - A revised root for the human Y chromosomal phylogenetic tree: the origin of patrilineal diversity in Africa. AB - To shed light on the structure of the basal backbone of the human Y chromosome phylogeny, we sequenced about 200 kb of the male-specific region of the human Y chromosome (MSY) from each of seven Y chromosomes belonging to clades A1, A2, A3, and BT. We detected 146 biallelic variant sites through this analysis. We used these variants to construct a patrilineal tree, without taking into account any previously reported information regarding the phylogenetic relationships among the seven Y chromosomes here analyzed. There are several key changes at the basal nodes as compared with the most recent reference Y chromosome tree. A different position of the root was determined, with important implications for the origin of human Y chromosome diversity. An estimate of 142 KY was obtained for the coalescence time of the revised MSY tree, which is earlier than that obtained in previous studies and easier to reconcile with plausible scenarios of modern human origin. The number of deep branchings leading to African-specific clades has doubled, further strengthening the MSY-based evidence for a modern human origin in the African continent. An analysis of 2204 African DNA samples showed that the deepest clades of the revised MSY phylogeny are currently found in central and northwest Africa, opening new perspectives on early human presence in the continent. PMID- 21601175 TI - Surveillance testing for metastasis from primary uveal melanoma and effect on patient survival. AB - PURPOSE: To evaluate the quality of evidence about effectiveness of regular periodic surveillance testing for metastasis in patients with primary uveal melanoma (PUM) following treatment of the primary tumor in prolonging survival. DESIGN: Literature review and personal perspective of the authors. METHODS: Identification and analysis of peer-reviewed articles on human PUM published between 1980 and 2009 that reported on "screening," "surveillance," or "systemic follow-up evaluation" for metastasis in patients with PUM following treatment of primary tumor. RESULTS: Of 4222 identified articles, only 31 were considered satisfactory for inclusion in this study. Satisfactory articles reported levels of specific biomarkers when metastasis was first confirmed (14), percentage of patients with abnormal results on surveillance testing (13), values of diagnostic markers (eg, sensitivity, specificity) associated with evaluated components of a surveillance regimen (7), survival time after first detection of metastasis from primary uveal melanoma (7), total survival time after initial diagnosis or initial treatment of primary uveal melanoma (3), percentage of patients whose metastatic tumors were detected by presymptomatic testing (5), surveillance regimens employed by different groups (1), and relationship with generally accepted clinical and histopathologic prognostic factors for primary uveal melanoma metastasis (1). However, none of these articles reported survival times of comparable subgroups of patients in which regular periodic surveillance for metastasis vs no surveillance was performed. CONCLUSION: Available evidence from the peer-reviewed literature does not provide any compelling evidence of survival benefit for any regimen or frequency of surveillance for metastasis relative to no such testing. In view of this, advisability of periodic surveillance for metastasis in routine clinical practice must be questioned. PMID- 21601176 TI - A comparative analysis of video-assisted mediastinoscopy and conventional mediastinoscopy. AB - BACKGROUND: The objective of this study was to compare outcomes of video-assisted mediastinoscopic lymph node biopsy in patients with non-small cell lung cancer (NSCLC) with outcomes of conventional mediastinoscopic lymph node biopsy in this same patient population. METHODS: All mediastinoscopies at one medical center from January 2008 to December 2009 were analyzed. Numbers of lymph nodes dissected, stations biopsied, remnant lymph nodes when major lung resection was performed after mediastinoscopic lymph node biopsy, and complications were recorded. RESULTS: Of 521 mediastinoscopies, 222 were in the conventional mediastinoscopic lymph node biopsy group (CM group) and 299 were in the video assisted mediastinoscopic lymph node biopsy group (VAM group). Eleven complications (2.11%) occurred, with more occurring in the CM group (3.6%) than in the VAM group (1.6%; p=0.030). The total number of dissected nodes was higher in the VAM group (mean, 8.53+/-5.8) than in the CM group (mean, 7.13+/-4.9; p=0.004), and there was no statistically significant difference between the average number of stations sampled in the CM group (2.98+/-0.7) and in the VAM group (3.06+/-0.75; p=not significant). The number of remnant lymph nodes when major lung surgery was performed after mediastinoscopy was lower in the VAM group (mean, 5.05+/-4.5) than in the CM group (mean, 7.67+/-6.5; p<0.001). CONCLUSIONS: This study found that video-assisted mediastinoscopic lymph node biopsy had fewer complications than did the conventional method. More lymph nodes were examined and fewer lymph nodes remained after mediastinoscopy by video-assisted mediastinoscopy (VAM) than by conventional mediastinoscopy. PMID- 21601178 TI - Structure of type 3Gn coaggregation receptor polysaccharide from Streptococcus cristatus LS4. AB - The presence of a novel coaggregation receptor polysaccharide (RPS) on the dental plaque isolate Streptococcus cristatus LS4 was suggested by this strain's antigenic and coaggregation properties. Examination of RPS isolated from strain LS4 by a combination of 2-dimensional and pseudo 3-dimensional single quantum heteronuclear NMR methods that included detection of (13)C chemical shifts at high resolution revealed the following repeat unit structure: ->6)-beta-d-Galf-(1 >6)-beta-d-GalpNAc-(1->3)-alpha-d-Galp-(1->P->6)-alpha-d-Galp-(1->3)-beta-L-Rhap (1->4)-beta-d-Glcp-(1->. The identification of this polysaccharide as RPS3Gn, a new structural type, was established by the alpha-d-Galp-containing epitope of RPS serotype 3 and Gn recognition motif (i.e., beta-d-GalpNAc (1->3)-alpha-d Galp) for coaggregation with other bacteria. PMID- 21601177 TI - Brain morphology at entry into treatment for alcohol dependence is related to relapse propensity. AB - BACKGROUND: We examined whether any differences in brain volumes at entry into alcohol dependence treatment differentiate subsequent Abstainers from Relapsers. METHODS: Individuals in alcohol dependence treatment (n = 75) underwent magnetic resonance imaging approximately 6 +/- 4 days after their last alcoholic drink, and 40 age-matched nonsmoking light drinkers (LD) were studied as control subjects. At follow-up 7.8 +/- 2.6 months later, 23 alcoholics (31%) had abstained from drinking and 52 (69%) had relapsed. Deformation morphometry compared Relapsers, Abstainers, and LD. RESULTS: Compared with LD, future Abstainers had smaller brain tissue volumes in the left amygdala, hippocampal head, and entorhinal cortex and bilaterally in the thalamus and adjacent subcortical white matter (WM) and had larger volume in the left lateral orbitofrontal region. Compared with LD, future Relapsers had smaller brain tissue volumes in the right middle temporal, occipital, and superior frontal WM. Compared with future Abstainers, future Relapsers had smaller tissue volumes primarily in bilateral orbitofrontal cortex and surrounding WM. Results were virtually unaffected after controlling for common comorbidities. CONCLUSIONS: At entry into alcohol dependence treatment, the brain structure of future Relapsers differs from that of future Abstainers. Future Relapsers have smaller brain volumes in regions of the mesocorticolimbic reward system that are critically involved in impulse control, emotional regulation, craving, and evaluation and anticipation of stimulus salience and hedonics. Structural abnormalities of this circuitry might confer greater risk for resumption of hazardous drinking after treatment and might contribute to the definition of a neurobiological relapse risk profile in alcohol dependence. PMID- 21601179 TI - Structural analyses of the core oligosaccharide from the lipopolysaccharide of bovine and ovine strains of Mannheimia haemolytica serotype 2. AB - Previous structural studies in our laboratory on lipopolysaccharide derived core oligosaccharide had identified a conserved inner core structure in several strains of the veterinary pathogens Mannheimia haemolytica, Actinobacillus pleuropneumoniae and Pasteurella multocida. In this study we describe the elucidation of the core oligosaccharide structure of two strains from M. haemolytica serotype 2. Structural information was established by a combination of monosaccharide and methylation analyses, NMR spectroscopy and mass spectrometry. The following structure for the core oligosaccharide was determined on the basis of the combined data from these experiments: [carbohydrate structure: see text]. The structural analyses revealed that the conserved inner core structure was maintained in this serotype, with only the terminal beta galactose residue of serotype 1 absent. PMID- 21601181 TI - Efficient conversion of d-glucose into d-sorbitol over MCM-41 supported Ru catalyst prepared by a formaldehyde reduction process. AB - Ru/MCM-41 catalyst prepared by an impregnation-formaldehyde reduction method showed higher catalytic activity and sorbitol selectivity than other catalysts in the hydrogenation of glucose. SEM and XRD indicated the partial surface properties of Ru/MCM-41. Moreover, Ru dispersion and Ru surface area of Ru/MCM-41 were determined by pulse chemisorption, and the result further proved that Ru/MCM 41 had higher catalytic activity. A catalyst recycling experiment demonstrated that Ru/MCM-41 was a better catalyst and it could be reused three or four times. A speculated mechanism was proposed to illustrate the detailed process of d glucose hydrogenation to produce sorbitol. PMID- 21601180 TI - Synthesis and antigenicity of BBGL-2 glycolipids of Borrelia burgdorferi, the causative agent of Lyme disease. AB - Borrelia burgdorferi is the etiological agent for Lyme disease (LD), the most common vector borne disease in the United States. There is no human vaccine against LD currently available. Our approach to a vaccine is based on its surface exposed glycolipids. One group of these glycolipids termed BBGL-2 consists of 1,2 di-O-acyl-3-O-(alpha-d-galactopyranosyl)-sn-glycerol congeners having palmitic, oleic, stearic, linoleic, and myristic acids. In order to delineate the immunodominant region(s) of the BBGL-2 components, we embarked on a synthetic project to provide available structurally defined, homogeneous analogs of BBGL-2 that might help identify the best vaccine candidate. The antigenicity of the synthetic glycolipids was examined by dot-blot analysis using mice sera obtained by immunization with killed B. burgdorferi cells, with native BBGL-2 in complete Freund's adjuvant, as well as sera obtained from patients with Lyme disease. We found that the presence of two acyl groups in the glycerol moiety was essential for antigenicity. At least one of these groups must be an oleoyl moiety. Neither the anomeric configuration of the galactose nor the configuration of the glycerol at C-2 was a decisive factor. Based on these findings we designed an 'unnatural' BBGL-2 analog having the structure 3-O-(beta-d-galactopyranosyl)-1,2-di-O-oleoyl dl-glycerol which is easier and less expensive to synthesize than the other BBGL 2 congeners prepared in this study. This substance proved to be antigenic and is considered a candidate vaccine for Lyme disease. PMID- 21601182 TI - Some observations on the reductive ring opening of 4,6-O-benzylidene acetals of hexopyranosides with the borane trimethylamine-aluminium chloride reagent. AB - Reductive ring openings of 3-O-benzoyl-4,6-O-benzylidene-D-glucopyranosides with BH(3).NMe(3)-AlCl(3) are accompanied by side reactions, such as debenzoylation and reduction of the benzoate to benzyl ether. This phenomenon was rationalized by aluminium chelate formation between the O-4 acetal and the benzoyl carbonyl group oxygens. It was also shown that these side reactions can be eliminated by using BH(3).THF as the reducing agent. PMID- 21601183 TI - Don't be a clot: a radiologist's guide to haemostasis including novel antiplatelet and anticoagulant therapies. AB - Normal haemostasis relies on the complex interactions of the coagulation cascade, platelets, and the endothelium. In this review, the roles of each of these elements are described as well as common causes for their derangement. Haemostasis may be manipulated via pharmacological means and in recent years there has been a significant increase in the number of agents available for influencing haemostatic mechanisms. It is essential that radiologists are aware of these mechanisms and drugs if they are to perform image-guided procedures safely. In addition to describing the relevant pathways and drugs, practical tips are provided. PMID- 21601184 TI - Diffusion-weighted imaging in characterization of cystic pancreatic lesions. AB - AIM: To evaluate whether apparent diffusion coefficient (ADC) measurements from diffusion-weighted imaging (DWI) can characterize or predict the malignant potential of cystic pancreatic lesions. MATERIALS AND METHODS: Retrospective review of the magnetic resonance imaging (MRI) database over a 2-year period revealed 136 patients with cystic pancreatic lesions. Patients with DWI studies and histological confirmation of cystic mass were included. In patients with known pancreatitis, lesions with amylase content of >1000 IU/l that resolved on subsequent scans were included as pseudocysts. ADC of cystic lesions was measured by two independent reviewers. These values were then compared to categorize these lesions as benign or malignant using conventional MRI sequences. RESULTS: Seventy lesions were analysed: adenocarcinoma (n=4), intraductal papillary mucinous neoplasm (IPMN; n=28), mucinous cystic neoplasm (MCN; n=9), serous cystadenoma (n=16), and pseudocysts (n=13). There was no difference between ADC values of malignant and non-malignant lesions (p=0.06), between mucinous and serous tumours (p=0.12), or between IPMN and MCN (p=0.42). ADC values for low-grade IPMN were significantly higher than those for high-grade or invasive IPMN (p=0.03). CONCLUSION: ADC values may be helpful in deciding the malignant potential of IPMN. However, they are not useful in differentiating malignant from benign lesions or for characterizing cystic pancreatic lesions. PMID- 21601185 TI - SASAgent: an agent based architecture for search, retrieval and composition of scientific models. AB - Scientific computing is a multidisciplinary field that goes beyond the use of computer as machine where researchers write simple texts, presentations or store analysis and results of their experiments. Because of the huge hardware/software resources invested in experiments and simulations, this new approach to scientific computing currently adopted by research groups is well represented by e-Science. This work aims to propose a new architecture based on intelligent agents to search, recover and compose simulation models, generated in the context of research projects related to biological domain. The SASAgent architecture is described as a multi-tier, comprising three main modules, where CelO ontology satisfies requirements put by e-science projects mainly represented by the semantic knowledge base. Preliminary results suggest that the proposed architecture is promising to achieve requirements found in e-Science projects, considering mainly the biological domain. PMID- 21601186 TI - EEG-based functional networks in schizophrenia. AB - Schizophrenia is often considered as a dysconnection syndrome in which, abnormal interactions between large-scale functional brain networks result in cognitive and perceptual deficits. In this article we apply the graph theoretic measures to brain functional networks based on the resting EEGs of fourteen schizophrenic patients in comparison with those of fourteen matched control subjects. The networks were extracted from common-average-referenced EEG time-series through partial and unpartial cross-correlation methods. Unpartial correlation detects functional connectivity based on direct and/or indirect links, while partial correlation allows one to ignore indirect links. We quantified the network properties with the graph metrics, including mall-worldness, vulnerability, modularity, assortativity, and synchronizability. The schizophrenic patients showed method-specific and frequency-specific changes especially pronounced for modularity, assortativity, and synchronizability measures. However, the differences between schizophrenia patients and normal controls in terms of graph theory metrics were stronger for the unpartial correlation method. PMID- 21601187 TI - Interactions between motor imagery and pain. Comment on Raffin et al. (2012). PMID- 21601189 TI - [AIDS in the Community of Madrid: analysis by place of birth]. PMID- 21601188 TI - Associations between brominated flame retardants in human milk and thyroid stimulating hormone (TSH) in neonates. AB - BACKGROUND: Brominated flame retardants (BFRs) have been in widespread use in a vast array of consumer products since the 1970s. The metabolites of some BFRs show a structural similarity to thyroid hormones and experimental animal studies have confirmed that they may interfere with thyroid hormone homeostasis. A major concern has been whether intrauterine exposure to BFRs may disturb thyroid homeostasis since the fetal brain is particularly susceptible to alterations in thyroid hormones. However, few reports on newborns have been published to date. OBJECTIVES: To evaluate the association between BFRs and neonatal thyroid stimulating hormone (TSH). METHODS: We studied six polybrominated diphenyl ethers (PBDEs) measured in milk samples from 239 women who were part of the "Norwegian Human Milk Study" (HUMIS), 2003-2006. Hexabromocyclododecane (HBCD) and BDE-209 were measured in a subset of the women (193 and 46 milk samples, respectively). The milk was sampled at a median of 33 days after delivery. TSH was measured in babies three days after delivery as part of the routine national screening program for early detection of congenital hypothyroidism. Additional information was obtained through the Medical Birth Registry and questionnaires to the mothers. RESULTS: The PBDE concentrations in human milk in Norway were comparable to concentrations reported from other European countries and Asia, but not the US and Canada where levels are approximately one order of higher magnitude. We observed no statistically significant associations between BDE-47, 99, 153, 154, 209 and HBCD in human milk and TSH in models adjusted for possible confounders and other environmental toxicants including polychlorinated biphenyls (PCBs). CONCLUSIONS: We did not observe an association between TSH and exposure to HBCD and PBDEs within the exposure levels observed. PMID- 21601190 TI - Increased expression of endothelin-1 and its receptors in varicocele: an immunohistochemical study. AB - We hypothesized that diminished endothelin 1 (ET-1) expression at the spermatic vein wall level might be responsible for the development of varicocele. However, immunohistochemical evaluation of spermatic and control vein samples from 55 patients with varicocele showed overexpression of ET-1 and its receptors ETA and ETB in varicose veins. PMID- 21601191 TI - Genome-wide identification of micro-ribonucleic acids associated with human endometrial receptivity in natural and stimulated cycles by deep sequencing. AB - OBJECTIVE: To identify microRNAs (miRNAs) associated with endometrial receptivity. DESIGN: Observational study. SETTING: Medical center. PATIENT(S): Healthy, regularly cycling women undergoing IVF treatment. INTERVENTION(S): Gonadotropin stimulation and endometrial biopsy. MAIN OUTCOME MEASURE(S): Quantification of miRNA expression profiles by deep sequencing. RESULT(S): The miRNA expression profiles in human endometrium on days LH+2 and LH+7 (LH = 0 is the day of the LH surge) in natural cycles as well as on days hCG+4 and hCG+7 (hCG = 0 is the day of hCG injection) in stimulated cycles were determined by deep sequencing. In natural cycles, there were 20 significantly changed miRNAs in human endometrium on LH+7 compared with LH+2. These miRNAs were predicted to target a large set of genes with different functions, including cell cycle, transport, cell adhesion, cell death, and metabolism. In stimulated cycles, 22 miRNAs were significantly dysregulated on hCG+7 in comparison with LH+7, 11 of which exhibited putative estrogen response elements or P response elements in the promoters. Additionally, unsupervised hierarchical clustering analysis demonstrated that the miRNA expression profile on hCG+4 was similar to that on LH+7, suggesting that ovarian stimulation may alter the window of endometrial receptivity. CONCLUSION(S): MiRNAs may be novel biomarkers for human endometrial receptivity and may help optimize the protocol for IVF treatment. PMID- 21601192 TI - A single nucleotide polymorphism in a miR-1302 binding site in CGA increases the risk of idiopathic male infertility. AB - OBJECTIVE: To explore the possible association between single nucleotide polymorphisms (SNPs) in the miRNA-binding sites of spermatogenesis-related genes and idiopathic infertility in humans. DESIGN: Prospective study. SETTING: Research laboratory of a university hospital. PATIENT(S): A total of 494 patients with azoospermia or severe oligozoospermia and 357 fertile controls were included in our study. INTERVENTION(S): The 3' untranslated region sequences of 140 candidate genes for male infertility were analyzed using specialized algorithms including Pictar, miRanda, Targetscan, and RNAhybrid and 39 SNPs located at putative miRNA-binding sites were identified. The possible association of 6 putatively functional SNPs and male infertility was explored further with the use of case-control studies. The function of SNPs significantly associated with male infertility was analyzed by dual luciferase assay. MAIN OUTCOME MEASURE(S): Significantly associated SNPs and their influence on gene expression. RESULT(S): Two SNPs from two genes (rs6631 of CGA and rs2303846 of CPEB1) were found to be associated with idiopathic male infertility. Functionally, the substitution of A by T in rs6631 results in decreased binding affinity of miR-1302 and overexpression of CGA in vitro. CONCLUSION(S): Our results reveal for the first time that SNPs residing in miRNA-binding sites of CGA could influence expression of CGA and elevate the risk of spermatogenesis impairment. PMID- 21601193 TI - Random-start gonadotropin-releasing hormone (GnRH) antagonist-treated cycles with GnRH agonist trigger for fertility preservation. AB - OBJECTIVE: To describe our experience with random-start IVF with the use of GnRH agonist for final oocyte maturation, to reduce the risk of ovarian hyperstimulation syndrome. DESIGN: Case series. SETTING: University-based center for reproductive endocrinology and infertility. PATIENT(S): Patients with a new diagnosis of cancer who presented with a narrow time frame for IVF before initiating cancer therapy. INTERVENTION(S): Random-start GnRH antagonist cycles with GnRH agonist trigger for final oocyte maturation. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved, fertilization rate, rates of ovarian hyperstimulation syndrome. RESULTS: Cycles were started in the late follicular or luteal phase, and the duration of controlled ovarian hyperstimulation ranged between 8-13 days. A total of 14-40 oocytes were retrieved and 5-20 embryos cryopreserved for each patient. CONCLUSION(S): Random-start IVF is a reasonable option for fertility preservation in those cancer patients for whom the treatment window may be narrow. In addition, the use of a GnRH agonist for final oocyte maturation may decrease the potential risk of ovarian hyperstimulation syndrome. PMID- 21601195 TI - Normal pregnancy after outpatient tubouterine implantation in patient with Adiana sterilization. AB - OBJECTIVE: To demonstrate the feasibility of outpatient correction of Adiana proximal tubal occlusion by surgical implantation of the fallopian tubes. DESIGN: Case study. SETTING: Outpatient surgical center. PATIENT(S): A 36-year-old woman with a history of bilateral proximal tubal occlusion secondary to Adiana sterilization who desired surgical correction and natural conception. INTERVENTION(S): Outpatient surgical correction of proximal Adiana tubal occlusion by use of a minilaparotomy to perform bilateral tubouterine implantation. MAIN OUTCOME MEASURE(S): Natural conception of pregnancy. RESULT(S): The patient underwent a successful outpatient bilateral tubouterine implantation to correct Adiana sterilization. The procedure was performed through a minilaparotomy abdominal incision by use of a posterior transfundal uterine incision to implant the isthmic sections of each tube into the uterine cavity. The patient's postoperative course was uncomplicated. Natural conceptions occurred at 6 and 9 months after surgery. The first pregnancy was of unknown location and aborted spontaneously. The second pregnancy was uncomplicated and was delivered at 39 weeks' gestation by elective cesarean delivery. CONCLUSION(S): Adiana hysteroscopic tubal occlusion can be surgically corrected in an outpatient setting through tubouterine implantation and this surgical technique can provide patients with an alternative to in vitro fertilization. PMID- 21601196 TI - Interleukin-17F increases the secretion of interleukin-8 and the expression of cyclooxygenase 2 in endometriosis. AB - OBJECTIVE: To examine the effects of interleukin (IL)-17F on the secretion of IL 8 and the gene expression of cyclooxygenase 2 (COX2) in endometriotic stromal cells. DESIGN: In vitro experimental study using human samples. SETTING: University hospital. PATIENT(S): Endometriotic tissues were obtained from women with ovarian endometriomas undergoing laparoscopic surgery. INTERVENTION(S): Endometriotic stromal cells (ESCs) were cultured with IL-17F. MAIN OUTCOME MEASURE(S): Concentrations of IL-8 were measured by a specific ELISA, and messenger RNA levels of IL-8 and COX2 were measured by real-time reverse transcription-polymerase chain reaction (PCR). RESULT(S): IL-17F increased the secretion of IL-8 from ESCs, and the effect was inhibited by antibodies for IL-17 receptor A and IL-17 receptor C. Tumor necrosis factor alpha (TNF-alpha) synergistically enhanced IL-17F-induced increase in IL-8 secretion from ESCs. The IL-17F increased the gene expression of IL-8 and COX2 in ESCs. CONCLUSION(S): These findings suggest that IL-17F may stimulate the development of endometriosis by up-regulation of IL-8 and COX2. PMID- 21601197 TI - In vitro viability and secretory capacity of human luteinized granulosa cells after gonadotropin-releasing hormone agonist trigger of oocyte maturation. AB - OBJECTIVE: To evaluate viability of luteinized granulosa cells obtained from patients triggered with either GnRH agonist or hCG and to assess the secretion of steroids and vascular endothelial growth factor (VEGF) by cultured luteinized granulosa cells in the presence or absence of hCG. DESIGN: Prospective, randomized controlled trial. SETTING: University-based fertility center. PATIENT(S): A subset of patients who underwent a randomized trial involving GnRH agonist trigger after GnRH antagonist protocol vs. hCG trigger after pituitary suppression with GnRH agonist protocol. INTERVENTION(S): In vitro fertilization cycles. MAIN OUTCOME MEASURE(S): Proportion of apoptosis; basal and hCG-induced secretion of E(2), P, and VEGF by luteinized granulosa cells; follicular-fluid VEGF and luteal-phase serum E(2), P, and plasma VEGF concentrations. RESULT(S): There were no differences in the proportion of granulosa/luteal cell apoptosis, follicular-fluid or luteal-phase plasma VEGF concentration, or basal culture media E(2), P, and VEGF concentrations between the two groups. Addition of hCG to the culture media significantly increased the P concentration in both groups, but there were no changes in E(2) or VEGF concentrations. Serum E(2) levels were lower at 5 and 9 days after GnRH agonist compared with hCG trigger. CONCLUSION(S): The granulosa/luteal cells obtained on the day of oocyte retrieval after GnRH agonist trigger are still viable and have the capacity to respond to hCG by increasing the secretion of steroids. PMID- 21601198 TI - An alternative treatment option in tubal ectopic pregnancies with fetal heartbeat: aspiration of the embryo followed by single-dose methotrexate administration. AB - OBJECTIVE: To present 13 cases of unruptured tubal ectopic pregnancies successfully treated with ultrasound-guided aspiration and local and systemic methotrexate (MTX) administration. DESIGN: Case series. SETTING: University hospital. PATIENT(S): Thirteen women with an unruptured tubal ectopic pregnancy. INTERVENTION(S): Transvaginal ultrasound-guided aspiration of the tubal ectopic pregnancy followed by MTX administration into the gestational sac (half of the calculated total dose of 25 mg/m(2)) and intramuscular injection (the remaining half of the calculated total dose of 25 mg/m(2)). MAIN OUTCOME MEASURE(S): Recovery of the patients, successful conservative treatment of the tubal ectopic pregnancies with preservation of the fallopian tubes. RESULT(S): Twelve (92%) of 13 women were successfully aborted, without need for salpingectomy or salpingostomy. CONCLUSION(S): Transvaginal ultrasound-guided aspiration of fetus followed by local and systemic methotrexate administration can be safely used to treat unruptured tubal ectopic pregnancies. PMID- 21601199 TI - Which surgery should be the first-line uterine-sparing procedure to control severe postpartum hemorrhage? PMID- 21601200 TI - Second-generation colon capsule endoscopy compared with colonoscopy. AB - BACKGROUND: Colon capsule endoscopy (CCE) represents a noninvasive technology that allows visualization of the colon without requiring sedation and air insufflation. A second-generation colon capsule endoscopy system (PillCam Colon 2) (CCE-2) was developed to increase sensitivity for colorectal polyp detection compared with the first-generation system. OBJECTIVE: To assess the feasibility, accuracy, and safety of CCE-2 in a head-to-head comparison with colonoscopy. DESIGN AND SETTING: Prospective, multicenter trial including 8 European sites. PATIENTS: This study involved 117 patients (mean age 60 years). Data from 109 patients were analyzed. INTERVENTION: CCE-2 was prospectively compared with conventional colonoscopy as the criterion standard for the detection of colorectal polyps that are >=6 mm or masses in a cohort of patients at average or increased risk of colorectal neoplasia. Colonoscopy was independently performed within 10 hours after capsule ingestion or on the next day. MAIN OUTCOME MEASUREMENTS: CCE-2 sensitivity and specificity for detecting patients with polyps >=6 mm and >=10 mm were assessed. Capsule-positive but colonoscopy negative cases were counted as false positive. Capsule excretion rate, level of bowel preparation, and rate of adverse events also were assessed. RESULTS: Per patient CCE-2 sensitivity for polyps >=6 mm and >=10 mm was 84% and 88%, with specificities of 64% and 95%, respectively. All 3 invasive carcinomas were detected by CCE-2. The capsule excretion rate was 88% within 10 hours. Overall colon cleanliness for CCE-2 was adequate in 81% of patients. LIMITATIONS: Not unblinding the CCE-2 results at colonoscopy; heterogenous patient population; nonconsecutive patients. CONCLUSION: In this European, multicenter study, CCE-2 appeared to have a high sensitivity for the detection of clinically relevant polypoid lesions, and it might be considered an adequate tool for colorectal imaging. PMID- 21601202 TI - Conflict of interest vs. competition of interest in orthopaedic surgery. PMID- 21601201 TI - Adherence to biopsy guidelines increases celiac disease diagnosis. AB - BACKGROUND: Celiac disease (CD) is common but underdiagnosed in the United States. A proposed quality guideline recommends that >=4 specimens be submitted during duodenal biopsy. The degree of adherence to this recommendation in clinical practice is unknown. OBJECTIVE: To measure the number of specimens submitted during duodenal biopsy among patients throughout the United States and to determine the incremental diagnostic yield of adherence to the recommended number of specimens. DESIGN: Retrospective cohort study. PATIENTS: This study involved 132,352 patients without known CD who underwent duodenal biopsy. INTERVENTION: Duodenal biopsy. MAIN OUTCOME MEASUREMENTS: Duodenal biopsy specimens were submitted to a pathology laboratory operating in 43 states in the United States. We used multivariate logistic regression to identify factors associated with submitting >=4 specimens. We also compared the prevalence of newly diagnosed CD in biopsies with >=4 specimens with that in biopsies with <4 specimens. RESULTS: Of the 132,352 patients who underwent biopsy (67% women, mean age 52.9 years), >=4 specimens were submitted in 45,995 cases (35%). A modest increase in the proportion of biopsies with >=4 specimens occurred after this guideline was proposed in 2006 (odds ratio for 2009 vs 2006, 1.51; 95% confidence interval, 1.22-1.88), but the rate of adherence in 2009 remained low at 37%. Among patients in whom the indication was malabsorption/suspected CD (n = 3261), adherence to this standard was only 39.5%. The probability of a new diagnosis of CD was increased when >=4 specimens were submitted (1.8% vs 0.7%; P < .0001). LIMITATIONS: Retrospective analysis lacking clinical follow-up. The guideline publication occurred during the study period, possibly influencing clinical practice and confounding results. CONCLUSION: Although this proposed standard remains a subject of debate, adherence to submitting >=4 specimens is low in the United States. Adherence yields a diagnosis rate of 1.8%, a small absolute increase but a doubling of the diagnosis rate of CD. Efforts to increase adherence are warranted. PMID- 21601203 TI - Biomechanical effect of bone cement augmentation on rotational stability and pull out strength of the Proximal Femur Nail AntirotationTM. AB - INTRODUCTION: After surgical treatment of osteoporotic hip fractures, complications such as implant cut-out are reported to be high and implant failure often is associated with poor bone quality. As augmentation is reported to enhance implant anchorage, the aim of our study was to investigate the effect of bone cement augmentation on the rotational stability and the pull-out resistance of the Proximal Femur Nail AntirotationTM (PFNa) blade. MATERIALS AND METHODS: A total of 18 fresh-frozen femoral heads (mean age 68 years, standard deviation (SD) 8.2) were scanned with quantitative computed tomography (qCT) for bone mineral density (BMD) measurements and instrumented with a PFNa blade. Nine specimens were augmented with a mean volume of 4.4 ml Traumacem V+. After cement consolidation, the blade was rotated for 60 degrees for the rotational test. Subsequently, the blade was extracted from the specimens. Force, torque, displacement and angle were recorded constantly. RESULTS: In the rotational test, the mean maximum torque in the augmented group (17.2 Nm, SD 5.0) was significantly higher (p=0.017) than in the non-augmented group (11.7 Nm, SD 3.5). The pull-out test also yielded a significant difference (p=0.047) between the augmented (maximum pullout force: 2315.2N, SD 1060.6) and the non-augmented group (1180.4N, SD 1171.4). DISCUSSION: Augmentation of femoral heads yielded a significantly superior rotational stability, as well as an enhanced pull-out resistance, compared to the non-augmented state. However, the higher the BMD of the specimens, the lower was the effect of augmentation on the rotational stability. Therefore, augmentation can be a good clinical tool to enhance implant anchorage in osteoporotic bone. PMID- 21601205 TI - Welcome intrusions: an interpretive phenomenological study of TB nurses' relational work. AB - BACKGROUND: Nurse-client relationships are valued in descriptions of public health practice and require consideration as work involving knowledge, skill, and personal engagement. Even so, in public health, they are largely taken-for granted, particularly in the area of tuberculosis (TB). Instead, TB nursing is often structured by a population focus, which at times challenges individually focused relationship ideals. PURPOSE AND DESIGN: This paper describes an interpretive phenomenological study which was undertaken to understand the nature of TB nurses' relational work. METHODS: Data were collected over an eight month period through observations of usual nurse-client visits and semi-structured interviews. SETTING AND PARTICIPANTS: The study took place in the TB program of a public health department of a large multicultural Canadian city with nine nurses and 24 clients. RESULTS: The phrase 'welcome intrusions' represents the nature of relational work and along with three key themes, 'getting through the door', 'doing TB but more than that', and 'beyond a professional', speaks to the central tension in this relational work: balancing its dual surveillance-care focus. CONCLUSIONS: Together these themes emphasize the importance of nurses' skill of involvement in two key domains of TB nursing practice: providing comfort and being watchful. PMID- 21601204 TI - Community-based participatory research (CBPR) approach to study children's health in China: experiences and reflections. AB - BACKGROUND: Community-based participatory research principles have been successfully applied to public health research in U.S. settings. While there is a long history of collaboration between government and communities in China, to date, community-based participatory research has not been used in children's environmental health studies. METHOD: This article describes how community-based participatory research principles were applied by an international research group to the China Jintan Child Cohort Study, a longitudinal study of malnutrition and lead exposure on cognitive and neurobehavioral development. Challenges emerged and lessons learned from implementing the study were discussed and recommendations were presented. CONCLUSION: We conclude that the community-based participatory research model can be applied in conducting and promoting environmental health research in China and researchers should be prepared for special challenges and cultural constraints in the implementation of the research in regards to human subject regulations, information dissemination, and culture. PMID- 21601206 TI - Combined atherogenic effects of celiac disease and type 1 diabetes mellitus. AB - OBJECTIVE: Previous studies have shown a high cardiovascular risk in patients with autoimmune diseases, such as type 1 diabetes mellitus (T1DM). Conversely, few data are available about patients with celiac disease (CD). The aim of our study was to assess carotid intima-media thickness (c-IMT), in patients with T1DM, CD or both (T1DM+CD) as compared with age- and sex-matched healthy individuals (H). METHODS: We enrolled 120 patients, 30 with T1DM, 30 with CD, 30 with T1DM+CD and 30 H. Clinical, metabolic and anthropometric data were collected. All T1DM patients were on insulin while all CD patients were on a gluten-free diet. c-IMT was evaluated by high frequency linear digital ultrasound. RESULTS: c-IMT was significantly greater in patients with T1DM+CD than in patients with T1DM or CD (P<0.001 for both), while no difference was found between T1DM and CD. Moreover, c-IMT was greater in CD than in H (P<0.001). Glycemic control and disease duration were similar between T1DM+CD and T1DM. Lipid and anthropometric parameters were similar among groups. Furthermore, in a pooled multivariate analysis, only age and disease type were significantly correlated with c-IMT (P<0.001 for both). CONCLUSION: Our study demonstrates that celiac patients have greater c-IMT as compared with healthy individuals. Thus, non-invasive monitoring of c-IMT in CD might be useful in preventing cardiovascular disease. Moreover, patients with T1DM+CD show more severe subclinical atherosclerosis as compared with those presenting T1DM or CD only, suggesting that the association of these autoimmune diseases might accelerate the atherosclerotic process. PMID- 21601207 TI - Targeting therapeutics to the vascular wall in atherosclerosis--carrier size matters. AB - OBJECTIVE: Vascular-targeted imaging and drug delivery systems are promising for the treatment of atherosclerosis due to the vast involvement of endothelium in the initiation and growth of plaque. Herein, we investigated the role of particle size in dictating the ability of vascular-targeted spherical particles to interact with the vascular wall (VW) from pulsatile and recirculating human blood flow relevant in atherosclerosis. METHODS: In vitro parallel plate flow chambers (PPFC) with straight or vertical step channel were used to examine the localization and binding efficiency of inflammation-targeted polymeric spheres sized from 0.2 to 5 MUm to inflamed endothelium from disturbed reconstituted and whole blood flow. Apolipoprotein deficient mice were used to study particle localization and binding to plaque in vivo. RESULTS: The efficiency of particle binding in disturbed reconstituted blood flow increases as spherical diameter increases from 500 nm to 5 MUm. No significant difference was observed between adhesion of 200 nm and 500 nm spheres. Binding efficiency for all particle size was enhanced in disturbed whole blood flow except adhesion of 5 MUm in pulsatile whole blood. The adhesion trend in the in vivo model confirmed the binding pattern observed in in vitro assays. CONCLUSIONS: The presented data shows that the binding efficiency of vascular-targeted drug carriers in blood flow is a function of particle size, wall shear rate, flow type, blood composition and ligand characteristics. Overall, the presented results suggest that micron-sized spherical particles (2 MUm), not nanospheres, are optimal for vascular-targeted drug delivery applications in medium to large vessel relevant in atherosclerosis. PMID- 21601208 TI - Genetic variation in ABCA1 and risk of cardiovascular disease. PMID- 21601209 TI - Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models. AB - OBJECTIVE: Polyphenols such as quercetin may exert several beneficial effects, including those resulting from anti-inflammatory activities, but their impact on cardiovascular health is debated. We investigated the effect of quercetin on cardiovascular risk markers including human C-reactive protein (CRP) and on atherosclerosis using transgenic humanized models of cardiovascular disease. METHODS: After evaluating its anti-oxidative and anti-inflammatory effects in cultured human cells, quercetin (0.1%, w/w in diet) was given to human CRP transgenic mice, a humanized inflammation model, and ApoE*3Leiden transgenic mice, a humanized atherosclerosis model. Sodium salicylate was used as an anti inflammatory reference. RESULTS: In cultured human endothelial cells, quercetin protected against H(2)O(2)-induced lipid peroxidation and reduced the cytokine induced cell-surface expression of VCAM-1 and E-selectin. Quercetin also reduced the transcriptional activity of NFkappaB in human hepatocytes. In human CRP transgenic mice (quercetin plasma concentration: 12.9 +/- 1.3 MUM), quercetin quenched IL1beta-induced CRP expression, as did sodium salicylate. In ApoE*3Leiden mice, quercetin (plasma concentration: 19.3 +/- 8.3 MUM) significantly attenuated atherosclerosis by 40% (sodium salicylate by 86%). Quercetin did not affect atherogenic plasma lipids or lipoproteins but it significantly lowered the circulating inflammatory risk factors SAA and fibrinogen. Combined histological and microarray analysis of aortas revealed that quercetin affected vascular cell proliferation thereby reducing atherosclerotic lesion growth. Quercetin also reduced the gene expression of specific factors implicated in local vascular inflammation including IL-1R, Ccl8, IKK, and STAT3. CONCLUSION: Quercetin reduces the expression of human CRP and cardiovascular risk factors (SAA, fibrinogen) in mice in vivo. These systemic effects together with local anti-proliferative and anti-inflammatory effects in the aorta may contribute to the attenuation of atherosclerosis. PMID- 21601210 TI - Knee kinematics and kinetics during shuttle run cutting: comparison of the assessments performed with and without the point cluster technique. AB - The differences between the assessments performed with and without the point cluster technique (PCT) for knee joint motions during the high-risk movements associated with non-contact anterior cruciate ligament (ACL) injuries have not been reported. This study aims to examine the differences between PCT and non-PCT assessments for knee joint angles and moments during shuttle run cutting. Fourteen high school athletes performed a maximal effort shuttle run cutting task. Motion data were collected by an 8-camera motion analysis system at 200 Hz, and ground reaction force data were recorded using a force plate at 1000 Hz. In both PCT and non-PCT approaches, the knee joint angles were calculated using Euler angle rotations, and the knee joint moments were obtained by solving the Newton-Euler equations using an inverse dynamics technique. For the extension/flexion angle, good agreement was measured between PCT and non-PCT assessments. The abduction angle obtained in the non-PCT assessment was smaller than that obtained with the PCT. An internal rotation angle was obtained in the PCT assessment, whereas a small external rotation angle was obtained in the non PCT assessment. For the knee joint moments, good agreement between PCT and non PCT assessments was observed for all the components. The differences in the knee joint angles were attributed in part to the differences in the position of the medial femoral epicondyle. The results suggest that the ACL injury risk during shuttle run cutting is estimated lower in the non-PCT assessment than in the PCT assessment. PMID- 21601211 TI - Wave front migration of endothelial cells in a bone-implant interface. AB - The neo-vascularization of the host site is crucial for the primary fixation and the long-term stability of the bone-implant interface. Our aim was to investigate the progression of endothelial cell population in the first weeks of healing. We proposed a theoretical reactive model to study the role of initial conditions, random motility, haptotaxis and chemotaxis in interactions with fibronectin factors and transforming angiogenic factors. The application of governing equations concerned a canine experimental implant and numerical experiments based upon statistical designs of experiments supported the discussion. We found that chemotaxis due to transforming angiogenic factors was attracting endothelial cells present into the host bone. Haptotaxis conditioned by fibronectin factors favored cells adhesion to the host bone. The combination of diffusive and reactive effects nourished the wave front migration of endothelial cells from the host bone towards the implant. Angiogenesis goes together with new-formed bone formation in clinics, so the similarity of distribution patterns of mineralized tissue observed in-vivo and the spatio-temporal concentration of endothelial cells predicted by the model, tended to support the reliability of our theoretical approach. PMID- 21601212 TI - Preparation of magnetic polymer material with phosphate group and its application to the enrichment of phosphopeptides. AB - As one of the most important post-translational modifications (PTM), reversible phosphorylation of protein is involved in many cellular processes. Enrichment and separation of phosphopeptides have become essential for large-scale identification of protein phosphorylation by mass spectrometry. In this work, five magnetic polymer materials with different numbers of phosphate groups were fabricated using a simple polymeric method and their abilities to enrich phosphopeptides were investigated. Our results showed that the enrichment efficiency is closely related to the number of phosphate groups attached to magnetic polymer sorbent. Under optimized condition (3% trifluoroacetic acid and 80% acetonitrile), magnetic polymer-particles with appropriate proportion of phosphate groups (Fe(3)O(4)@p(VPA-EDMA-1)-Zr(4+)) showed high performance for extracting phosphopeptides from complex peptides mixture of standard protein digestion. In this regard, a total of 988 unique phosphopeptides were successfully identified from proteolytic digestion of HeLa cell extracts by employing magnetic polymer-particles combined with nano-RPLC-MS/MS analysis. PMID- 21601213 TI - Dispersive liquid-liquid microextraction based on solidification of floating organic droplet followed by high-performance liquid chromatography with ultraviolet detection and liquid chromatography-tandem mass spectrometry for the determination of triclosan and 2,4-dichlorophenol in water samples. AB - A novel, simple and efficient dispersive liquid-liquid microextraction based on solidification of floating organic droplet (DLLME-SFO) technique coupled with high-performance liquid chromatography with ultraviolet detection (HPLC-UV) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for the determination of triclosan and its degradation product 2,4-dichlorophenol in real water samples. The extraction solvent used in this work is of low density, low volatility, low toxicity and proper melting point around room temperature. The extractant droplets can be collected easily by solidifying it at a lower temperature. Parameters that affect the extraction efficiency, including type and volume of extraction solvent and dispersive solvent, salt effect, pH and extraction time, were investigated and optimized in a 5 mL sample system by HPLC UV. Under the optimum conditions (extraction solvent: 12 MUL of 1-dodecanol; dispersive solvent: 300 of MUL acetonitrile; sample pH: 6.0; extraction time: 1 min), the limits of detection (LODs) of the pretreatment method combined with LC MS/MS were in the range of 0.002-0.02 MUg L(-1) which are lower than or comparable with other reported approaches applied to the determination of the same compounds. Wide linearities, good precisions and satisfactory relative recoveries were also obtained. The proposed technique was successfully applied to determine triclosan and 2,4-dichlorophenol in real water samples. PMID- 21601214 TI - Developing a self-assembled monolayer microarray to study stem cell differentiation. AB - We have developed a novel strategy to generate self-assembled monolayer microarray (SAMs-Array) of alkanethiolates on gold surfaces for the study of human mesenchymal stem cells (hMSCs) differentiation. Electroactive alkanethiols were microarray-printed in varying densities to probe the chemical effects on stem cell differentiation. Cyclic voltammetry (CV) was used for the precise determination of the amount of alkanethiol molecules transferred and SAMs formed on the microarray. We can also control the oxidative and reductive state of each molecule displayed to cells by CV. Based on this SAMs-Array technology, we generated a platform for potential high-throughput screening of various surface chemistry effects on cell behaviors for future applications in biomaterials and tissue engineering. PMID- 21601215 TI - Characteristics of aggregation in aqueous solutions of dialkylpyrrolidinium bromides. AB - Three pyrrolidinium-based ionic liquids-N-dodecyl-N-methylpyrrolidinium bromide, N-butyl-N-octylpyrrolidinium bromide, and N-butyl-N-dodecylpyrrolodinium bromide were synthesized and characterized by their decomposition temperatures (T(d)) measured by thermogravimetric analysis, and by their melting point (T(m)), glass transition (T(g)) and crystallization temperatures (T(cryst)) determined by differential scanning calorimetry. Their self-aggregation properties in aqueous solution were studied and their behavior is compared with that of analogous conventional cationic surfactants, namely tetra-alkylammonium bromide salts. The critical micellar concentration, cmcs were obtained by isothermal titration calorimetry (ITC); which were further validated by measurements of interfacial tension, fluorescence and NMR spectroscopy. Enthalpies of micellization were measured at three different temperatures using ITC. The Taylor dispersion method and DOSY NMR were used to determine diffusion coefficients of the ionic liquid surfactants in aqueous solution at 298.15K. Several correlations between structural features of the surfactant species, such as the number and size of their alkyl chains, and the thermodynamic quantities of micellization-expressed by experimental values of cmc, counter-ion binding fraction, Delta(mic)G degrees , Delta(mic) degrees , and Delta(mic)S degrees -are established. We could interpret the different contributions of the two alkyl side chains to the aggregation properties in terms of the balance of interactions in homogeneous and micellar phases, contributing to understanding the aggregation behavior of ionic liquids in water and the parallel between these systems and traditional ionic surfactants. PMID- 21601216 TI - Preparation of poly(methyl methacrylate) grafted hydroxyapatite nanoparticles via reverse ATRP. AB - Surface-initiated reverse atom transfer radical polymerization (reverse ATRP) technical was successfully employed to modify hydroxyapatite (HAP) nanoparticles with poly(methyl methacrylate) (PMMA). The peroxide initiator moiety for reverse ATRP was covalently attached to the HAP surface through the surface hydroxyl groups. Reverse ATRP of methyl methacrylate (MMA) from the initiator functionalized HAP was carried out, and the end bromide groups of grafted PMMA initiated ATRP of MMA subsequently. Fourier transformation infrared (FTIR) spectroscopy, thermal gravimetric analysis (TGA) and transmission electron microscopy (TEM) were employed to confirm the grafting and to characterize the nanoparticle structure. The grafted PMMA gave HAP nanoparticles excellent dispersibility in MMA monomer. As the amount of grafted PMMA increased, the dispersibility of surface-grafted HAP and the compressive strength of HAP/PMMA composites were improved. PMID- 21601217 TI - Interaction of naproxen amphiphilic derivatives with biomembrane models evaluated by differential scanning calorimetry and Langmuir-Blodgett studies. AB - Anti-inflammatory drugs represent a potential new strategy for the treatment of Alzheimer's disease (AD). The ability to cross the blood-brain barrier and to reach brain tissues is a critical point for these drugs and is strictly related to their lipophilicity. Naproxen (NAP) is a non-steroidal anti-inflammatory drug (NSAIDs) under active investigation for AD. To improve its lipophilic character, NAP was conjugated through a diethylamine spacer (EDA) to lipoamino acids (LAA), alpha-amino acids containing a long alkyl side chain, to obtain the NAP-EDA-LAA10 and NAP-EDA-LAA14 prodrugs. The interaction of NAP and prodrugs with dimyristoylphosphatidylcholine phospholipids, forming either multilamellar vesicles or monolayers (at the air/water interface) and used as biomembrane models, was studied by differential scanning calorimetry and Langmuir-Blodgett techniques. Experimental data showed that NAP conjugation with LAA residues was able to enhance the drug interaction with such biomembrane models. PMID- 21601218 TI - Categorical perception of emotional facial expressions in preschoolers. AB - Adults perceive emotional facial expressions categorically. In this study, we explored categorical perception in 3.5-year-olds by creating a morphed continuum of emotional faces and tested preschoolers' discrimination and identification of them. In the discrimination task, participants indicated whether two examples from the continuum "felt the same" or "felt different." In the identification task, images were presented individually and participants were asked to label the emotion displayed on the face (e.g., "Does she look happy or sad?"). Results suggest that 3.5-year-olds have the same category boundary as adults. They were more likely to report that the image pairs felt "different" at the image pair that crossed the category boundary. These results suggest that 3.5-year-olds perceive happy and sad emotional facial expressions categorically as adults do. Categorizing emotional expressions is advantageous for children if it allows them to use social information faster and more efficiently. PMID- 21601219 TI - Patterns of continuous positive airway pressure adherence during the first 3 months of treatment in children. AB - OBJECTIVE: To determine predictors of continuous airway pressure (CPAP) adherence in children. STUDY DESIGN: Analysis of CPAP usage data for children between 2004 and 2008. RESULTS: During the study period, 32 children were prescribed CPAP; 2 failed to accept the mask, and 30 (mean +/- SD age 9.1 +/- 5.3 years) were included in further analysis. In the first 2 to 3 months of treatment, average (+/- SD) CPAP use was 4.7 +/- 2.7 hours/night. Hours of use were not affected by age, sex, baseline obstructive apnea-hypopnea index, intellectual disability, or socioeconomic status (P > .05). Of the children, 10 (33%) used CPAP for one hour or more on more than 6 nights per week and were defined as consistent users. Consistent users treated with CPAP for significantly longer on nights of use than intermittent users (7.2 +/- 2.0 hours vs 4.7 +/- 2.4 hours, P = .008). The hours of use differed between the two groups after the second night of treatment (P < .05), and this difference persisted for the first 3 months of therapy. CONCLUSIONS: Children who attempted to use CPAP at least 6 nights a week were treated with CPAP for a longer time on the nights of use. Usage in the first week of treatment predicted longer term use over 2 to 3 months. Monitoring adherence in the first week of treatment and intervening in cases of low adherence may improve long-term CPAP use. PMID- 21601220 TI - Preemptive gastrostomy tube placement after Norwood operation. AB - OBJECTIVE: Because infants undergoing a Norwood operation have poor interstage weight gain, we hypothesized that preemptive gastrostomy tube (GT) placement would result in earlier discharge, improved growth, and higher survival to stage 2. STUDY DESIGN: Records of 74 neonates who underwent a Norwood operation were reviewed until stage 2 palliation. The patients were divided into conventional (n = 43) and preemptive GT groups (n = 31). Data included demographics, cardiac surgery, feeding strategy, length of hospitalization, and mortality. RESULTS: Transplant-free survival to stage 2 was significantly higher in the preemptive group, but there were no significant differences in survival to discharge after stage 1, length of hospitalization, and weight-for-age z-score at discharge and at stage 2 palliation. In the conventional group, 27 of 43 underwent GT placement, all via laparotomy, 23 with Nissen fundoplication. In the preemptive group, all underwent GT placement (21 laparoscopic, 10 laparotomy), 7 with Nissen fundoplication. A second gastric intervention was performed in 11 of 21 with laparoscopic GT (7 conversion to gastrojejunostomy tube, 4 Nissen fundoplication). CONCLUSION: Preemptive GT placement is associated with improved survival to stage 2 after a Norwood operation but not with shorter hospitalization or better growth. A thorough gastrointestinal evaluation must be performed before GT placement to avoid additional surgery. PMID- 21601222 TI - Identifying risk factors for renal failure and myocardial infarction following colorectal surgery. AB - BACKGROUND: The development of acute renal failure and myocardial infarction (MI) following colectomy prolongs recovery and is associated with worse outcomes. The purpose of this study is to identify perioperative factors that predispose patients to an adverse cardiac or renal complication. MATERIALS AND METHODS: We conducted a retrospective review of colectomies from 2001 to 2009. Patients were evaluated based upon the electronic inpatient record and followed to determine the incidence of acute renal failure (creatinine elevation over 50% of baseline) and myocardial injury. RESULTS: A total of 339 inpatient records were reviewed, of which 134 were female (40%) and 205 male (60%). The mean age was 61.96 +/- 16.2 years with 39.5% right hemicolectomies, 22.7% sigmoidectomy, 13.9% Left hemicolectomy, 11.5% total abdominal colectomy, and 6.2% for ileocectomy and transverse colectomy. Within the cohort, 13.9% had baseline renal insufficiency (Cr > 1.4), 7.1% sustained anastomotic leak, 23.9% required postoperative intubation, 15% sustained postoperative sepsis, 11.2% postoperative MI, and 5% clinically significant acidosis. Excluding patients with an anastomotic leak, postoperative intubation, and sepsis, we found that the need for blood product transfusion was associated with postoperative acute renal failure (OR= 7.15 [2.4 20.7]). Preoperative creatinine > 1.5, limited functional capacity, and preoperative systolic blood pressure < 90 mm Hg were all associated with increased MI rates (OR= 15.7 [3.6-66.8], 9.5 [2.1-42.2], 12.0 [5.523-26.072], and 40.6 [1.7-968], respectively). CONCLUSION: This study demonstrates that several potentially modifiable preoperative and intraoperative factors exist that predispose patients to postoperative cardiac and renal dysfunction in the absence of major surgical complications. PMID- 21601221 TI - Clinicopathologic characteristics and surgical outcomes of hepatocellular carcinoma with portal vein tumor thrombosis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) has a high predilection for portal vein invasion. Furthermore, the treatment of HCC with portal vein tumor thrombosis (PVTT) is controversial. The objective of this study was to investigate clinicopathologic characteristics and surgical outcomes of HCC patients with PVTT. METHODS: The clinicopathologic data and surgical outcomes of 88 patients HCC with PVTT and 211 patients without PVTT who underwent surgery were retrospectively reviewed. The risk factors and the prognosis of HCC patients with PVTT were determined. RESULTS: Cirrhosis, serum alkaline phosphatase (ALP) > 100 IU/L, tumor size > 8 cm, incomplete tumor capsule, and adjacent organ invasion were risk factors for PVTT in HCC on multivariate analysis. Furthermore, HCC patients with PVTT received more major hepatectomies, had more intraoperative blood loss and greater blood transfusion requirements, and higher incidence of postoperative mortality compared with HCC patients without PVTT. The median overall survival of HCC patients with PVTT after surgery was 9 mo, with the 1-, 2 , and 3-y overall survival rates of 31.1%, 18.3%, and 15.2 %, respectively. AFP level, adjacent organ invasion, and PVTT location predicted overall survival of HCC patients with PVTT. CONCLUSIONS: High serum ALP level, cirrhosis, large tumor, incomplete tumor capsule and adjacent organ invasion are predictors of PVTT in HCC. Surgery is a valid therapy for selected HCC patients with PVTT. PMID- 21601223 TI - Pathophysiologic difference between frostbite and burn injury and implications for therapy. PMID- 21601224 TI - Clinical, electrophysiological and pathological findings of a patient with CMT2 due to the p.Ala738Val mitofusin 2 mutation. AB - Mutations in the gene encoding mitofusin 2 (MFN2) are responsible of about 20% of Charcot-Marie-Tooth disease type 2 (CMT2) case. A great variability exists among CMT2A concerning severity and associated clinical features. Generally patients with an early onset CMT2A disclose a severe phenotype while the cases with a late onset present a more benign clinical course. We describe clinical, electrophysiological and pathological findings of a patient with a mild CMT2A due to the c.2213C>T, p.Ala738Val MFN2 mutation. This mutation has been already described to be only associated with an early onset and moderately severe CMT2A phenotype. PMID- 21601225 TI - A newborn with Pierre Robin sequence after preconceptional mitoxantrone exposure of a female with multiple sclerosis. AB - Multiple sclerosis is a common disease of young adults in which accidental and unplanned pregnancies under disease modifying or immunosuppressive therapies may occur. The experience with mitoxantrone (MIX) especially in the first trimenon is very limited, until now only one case of a pregnant woman with MS who was exposed to MIX in early pregnancy and delivered a growth restricted but healthy child was published. We report a case of a secondary progressive MS patient who was exposed periconceptionally to MIX and delivered a child with Pierre Robin Sequence (PRS), a syndrome with the main features of glossoptosis, micrognathia, and palate clefts. PRS is a very rare defect and therefore a causal relation with MIX seems possible. PMID- 21601226 TI - Impacts of a fuel oil spill on seagrass meadows in a subtropical port, Gladstone, Australia--the value of long-term marine habitat monitoring in high risk areas. AB - We used an established seagrass monitoring programme to examine the short and longer-term impacts of an oil spill event on intertidal seagrass meadows. Results for potentially impacted seagrass areas were compared with existing monitoring data and with control seagrass meadows located outside of the oil spill area. Seagrass meadows were not significantly affected by the oil spill. Declines in seagrass biomass and area 1month post-spill were consistent between control and impact meadows. Eight months post-spill, seagrass density and area increased to be within historical ranges. The declines in seagrass meadows were likely attributable to natural seasonal variation and a combination of climatic and anthropogenic impacts. The lack of impact from the oil spill was due to several mitigating factors rather than a lack of toxic effects to seagrasses. The study demonstrates the value of long-term monitoring of critical habitats in high risk areas to effectively assess impacts. PMID- 21601227 TI - Oxidative stress markers in canine atopic dermatitis. AB - There are no data in the veterinary literature relating to oxidative stress in canine atopic dermatitis (CAD). The study aimed to determine levels of oxidative stress markers, plasma malondialdehyde (MDA), total antioxidant capacity (TAC), whole blood glutathione peroxidase (GPX) and erythrocyte superoxide dismutase (SOD), in 15 CAD patients and 17 healthy dogs. A correlation between CADESI (Canine Atopic Dermatitis Extent and Severity Index) score and MDA was also determined. Significantly higher plasma MDA levels were found in patients than in healthy dogs. The significant, highly positive correlation determined between CADESI score and MDA in the patient group indicates an association between the severity of CAD and the extent of oxidative damage to membrane lipids. There were no significant differences in TAC, GPX and SOD between patients and healthy dogs. Our findings suggest that oxidative stress with increased lipid peroxidation could be involved in the pathogenesis of atopic dermatitis in dogs. PMID- 21601228 TI - Classification of clinical consequences of scorpion stings: consensus development. AB - The objective of our consensus process was to develop a unique classification of the natural history of scorpion stings and their clinical signs and symptoms. The technique used was an adapted Delphi approach completed by a nominal group meeting. Researchers included in a study received a questionnaire in which we listed all terms used in published studies to characterize clinical consequences of scorpion stings and all signs and symptoms belonging to each class. For each term, experts had to judge the relevance for classifying clinical consequences of scorpion stings and state whether they agreed with the terminology; they could also propose new terms or classes. For each sign or symptom, they had to choose in which class it belonged and also propose if any other sign or symptom should be added. Sixteen researchers participated. Consensus was reached to include four classes: local manifestations; minor systemic manifestations; major systemic manifestations; lethal envenomation. Signs and symptoms associated with each class were defined. A second Delphi round is planned to define indicators to follow the epidemiological situation within and across countries and to develop recommendations for an optimal management of scorpion envenomations. These consensus-based tools should facilitate development of international clinical studies. PMID- 21601229 TI - Characterisation and evaluation of antiviral recombinant peptides based on the heptad repeat regions of NDV and IBV fusion glycoproteins. AB - Mixed virus infections can cause livestock losses that are more devastating than those caused by single virus infections. Newcastle disease virus (NDV) and infectious bronchitis virus (IBV), serious threats to the poultry industry, can give rise to complex mixed infections that hinder diagnosis and prevention. In this study, we show that newly designed peptides, which are based on the heptad repeat (HR) region of the fusion glycoproteins from NDV and IBV, have more potent antiviral activity than the mother HR peptides. Plaque formation and chicken embryo infectivity assays confirmed these results. The novel peptides completely inhibited single virus infections and mixed infections caused by NDV and IBV. Furthermore, we assessed cell toxicity and possible targets for the peptides, thereby strengthening the notion that HR2 is an attractive site for therapeutic intervention. These results suggest the possibility of designing a relatively broad-spectrum class of antiviral peptides that can reduce the effects of mixed infections. PMID- 21601230 TI - Ion channel activity of HIV-1 Vpu is dispensable for counteraction of CD317. AB - While the C-terminal domain of HIV-1 Vpu is critical for CD4 degradation, the transmembrane domain (TM) mediates ion channel activity, enhances virus release and is essential for counteracting CD317/Bst-2/Tetherin. Here we analyzed whether the ion channel activity of Vpu is required to antagonize CD317-mediated restriction of virion release. We examined TM-mutants of three conserved residues: the S23A mutation, which was previously shown to abrogate ion channel function, did not affect Vpu mediated augmentation of virus release. In contrast, the A14N and A18N mutation did not affect ion channel activity of Vpu, but substantially reduced its ability to support virus release and to down-regulate CD317 from the cell surface. Altogether, our data suggest that not the ion channel activity of Vpu, but its ability to remove CD317 from the cell surface is required to augment HIV-1 release. PMID- 21601231 TI - Identification of interaction domains within the UL37 tegument protein of herpes simplex virus type 1. AB - Herpes simplex virus type 1 (HSV-1) UL37 is a 1123 amino acid tegument protein that self-associates and binds to the tegument protein UL36 (VP1/2). Studies were undertaken to identify regions of UL37 involved in these protein-protein interactions. Coimmunoprecipitation assays showed that residues within the carboxy-terminal half of UL37, amino acids 568-1123, are important for interaction with UL36. Coimmunoprecipitation assays also revealed that amino acids 1-300 and 568-1123 of UL37 are capable of self-association. UL37 appears to self-associate only under conditions when UL36 is not present or is present in low amounts, suggesting UL36 and UL37 may compete for binding. Transfection infection experiments were performed to identify domains of UL37 that complement the UL37 deletion virus, K?UL37. The carboxy-terminal region of UL37 (residues 568-1123) partially rescues the K?UL37 infection. These results suggest the C terminus of UL37 may contribute to its essential functional role within the virus infected cell. PMID- 21601232 TI - The Autographa californica multiple nucleopolyhedrovirus lef-5 gene is required for productive infection. AB - To examine the role of the AcMNPV lef-5 gene in the context of the infection cycle, we generated an AcMNPV lef-5 knockout virus (vAc(lef5ko)) and a complementing cell line that supports viral replication. We examined AcMNPV DNA replication, early and late gene expression, and production of infectious viral progeny in the absence of lef-5. While early gene expression and DNA replication were not reduced by the lef-5 knockout, expression of a late reporter was disrupted and representative late transcripts were dramatically reduced. Progeny virus production was not detected after transfection of Sf9 cells with the lef-5 knockout bacmid, but was rescued by insertion of an egfp- or myc-tagged lef-5 gene into the vAc(lef5ko) genome. An egfp-tagged lef-5 gene from SeMNPV was used to generate a stable Sf9 cell line that supported replication of the vAc(lef5ko) virus. The LEF-5 protein was also found to co-localize with IE-1 in infected cell nuclei. PMID- 21601233 TI - Dissolution and sorption of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and 2,4,6-trinitrotoluene (TNT) residues from detonated mineral surfaces. AB - Composition B (Comp B) is a commonly used military formulation composed of the toxic explosive compounds 2,4,6-trinitrotoluene (TNT), and hexahydro-1,3,5 trinitro-1,3,5-triazine (RDX). Numerous studies of the temporal fate of explosive compounds in soils, surface water and laboratory batch reactors have been conducted. However, most of these investigations relied on the application of explosive compounds to the media via aqueous addition and thus these studies do not provide information on the real world loading of explosive residues during detonation events. To address this we investigated the dissolution and sorption of TNT and RDX from Comp B residues loaded to pure mineral phases through controlled detonation. Mineral phases included nontronite, vermiculite, biotite and Ottawa sand (quartz with minor calcite). High Performance Liquid Chromatography and Attenuated Total Reflectance Fourier Transform Infrared spectroscopy were used to investigate the dissolution and sorption of TNT and RDX residues loaded onto the mineral surfaces. Detonation resulted in heterogeneous loading of TNT and RDX onto the mineral surfaces. Explosive compound residues dissolved rapidly (within 9 h) in all samples but maximum concentrations for TNT and RDX were not consistent over time due to precipitation from solution, sorption onto mineral surfaces, and/or chemical reactions between explosive compounds and mineral surfaces. We provide a conceptual model of the physical and chemical processes governing the fate of explosive compound residues in soil minerals controlled by sorption-desorption processes. PMID- 21601234 TI - Insights into the structural and conformational requirements of polybrominated diphenyl ethers and metabolites as potential estrogens based on molecular docking. AB - PBDEs and their metabolites are of concern due to their increasing concentrations in the environment and their toxic effects. Knowledge about the toxicological mechanisms of PBDEs and metabolites is urgently needed for further screening. The objective of the present study was to explore the structural and conformational requirements of PBDE compounds as human estrogen receptor alpha (hERalpha) agonists, and further screened out hERalpha agonists from PBDE compounds. Molecular docking and postdocking analysis were adopted to attain the aim. The obtained results revealed that PBDEs can be primarily screened for their estrogenicity using score values, hydrogen bonds interaction with amino acid residues Glu353 and/or Arg394 might be important for HO-PBDEs' estrogenicity. For most MeO-PBDEs, hydrophobic interaction might be the key factor affecting their estrogenic activity. The current study suggested that molecular docking and postdocking analysis can serve as an efficient pre-screening technique for identifying potential estrogens. PMID- 21601235 TI - Suitability of different salt marsh plants for petroleum hydrocarbons remediation. AB - The suitability of the salt-marsh species Halimione portulacoides, Scirpus maritimus, Juncus maritimus and an association of the last two for remediation of petroleum hydrocarbons (PHC) in soil was investigated. An outdoor laboratory experiment (microcosm-scale) was carried out using contaminated soil collected in a refinery, as a complement of another study carried out in the refinery environment (mesocosm-scale). Soil samples with old contamination (mainly crude oil) and with a mixture of the old and recent (turbine oil) contamination were tested. Studies in both micro- and mesocosm-scale provided results coherent in substance. The presence of S. maritimus caused removal of old contamination which was refractory to natural attenuation (after 7months of exposure, efficiency was 13% when only old contamination was present and 40% when the soil also contained recent contamination). H. portulacoides (only included in the microcosm-scale study) revealed also potentiality for PHC remediation, although with less efficiency than S. maritimus. Degradation of recent contamination was also faster in the presence of plants (after 7months: 100% in the presence of S. maritimus vs. 63% in its absence). As these species are common in salt marsh areas in Atlantic coast of Europe, it is probable they will be also useful for recovering coast sediments. In contrast, J. maritimus and association did not reveal capability to remove PHC from soil, the presence of J. maritimus inhibiting the capability of S. maritimus. PMID- 21601236 TI - Adsorption behavior of 17alpha-ethynylestradiol onto soils followed by fluorescence spectral deconvolution. AB - In this study, a simple and rapid procedure for monitoring adsorption of 17alpha ethynylestradiol (EE2) onto soil samples was developed. The used method is based on a multiwavelength fluorescence spectral deconvolution (FSD) where the emission fluorescence spectrum of a sample is considered as a linear combination of emission spectra, named reference spectra. The combination of the reference spectra allows the restitution of the shape of the emission spectrum of any unknown sample. This approach was applied to follow EE2 adsorption onto four soil samples and is an easy and low cost alternative. Adsorption experimental data showed a good fit with the Hill equation, mathematically equivalent to the Langmuir-Freundlich model assuming that the adsorption is a cooperative process influenced by adsorbate-adsorbate interactions. Molecular modelling studies clearly support the "co-operative adsorption" model, showing that after the adsorption of the first layer of EE2 molecules onto the soil, at least one more layer of EE2 is adsorbed, due to interactions established with the first adsorbed layer. Notwithstanding, packing a third row would imply interactions between two EE2 molecules that differ from the ones verified in the lowest energy structure, which also explains the plateau achieved in the adsorption curve. PMID- 21601237 TI - Observations of ozone and carbon monoxide at Mei-Feng mountain site (2269 m a.s.l.) in Central Taiwan: seasonal variations and influence of Asian continental outflow. AB - Continuous measurements of ozone (O(3)) and carbon monoxide (CO) were carried out at Mei-Feng (24.05 degrees N, 120.10 degrees E, 2269 m above sea level), a remote mountain site in central Taiwan, to investigate the influence of long-range transported air pollution on O(3) and CO variations in the subtropical Pacific region. Data collected from March 2009 to September 2010 revealed average mixing ratios of 37+/-14 ppb for O(3) and 188+/-82 ppb for CO at this remote site. Diurnal variations for both O(3) and CO were observed as well in all seasons. The higher levels for O(3) and CO in the afternoon were attributed to transport of boundary layer pollution to the site during daytime upslope flow. Monthly means of both O(3) and CO showed maxima in spring and in the continental air masses from Southeast Asia, coastal China, and Korea/Japan. On the contrary, the lower O(3) and CO levels found in summer were due to the marine air masses originating from the Philippine Sea and Pacific Ocean. The relationship between O(3) and CO was analyzed, using nighttime data to minimize any local influence. The results showed a fairly good correlation between O(3) and CO from March to September. The contribution of CO from the Asian outflow reached a maximum in spring (88 ppb) and had a minimum in summer (27 ppb). The photochemical buildup of O(3) resulting from anthropogenic emissions in continental Asia was estimated to be 15 ppb in spring, while its production was insignificant, with an average of 4 ppb, in summer. A positive correlation between O(3) and CO plus high ozone levels in springtime suggested that the enhancements of O(3) were likely due to O(3) which was photochemically produced over this region. PMID- 21601238 TI - Blood lead level and its relationship to certain essential elements in the children aged 0 to 14 years from Beijing, China. AB - OBJECTIVE: To investigate blood lead level and its relationship to copper, zinc, calcium, magnesium and iron in the children aged 0 to 14 years old from Beijing, China. METHODS: We classified 3181 children into one of the four groups: Group A (n=783, <1 year old); Group B (n=1538, 1-3 years old); Group C (n=443, 3-7 years old); and, Group D (n=417, 7-14 years old). All these metal elements were determined by atomic absorption spectrometry. RESULTS: The blood lead level was 0.207+/-0.105 MUmol/L. There was a significant gender difference for zinc (P<0.05) in Group C, and there was also a significant gender difference for copper (P<0.05) and lead (P<0.05) in Group D. Controlling for gender and age, we observed that there was a negative correlation of lead with zinc (r=-0.052, P<0.01), magnesium (r=-0.042, P<0.05) and iron (r=-0.031, P<0.05), respectively. Furthermore, in the children aged 1-7 years old, we also found there was a negative linear correlation of lead with zinc, magnesium and iron, respectively (P<0.01). CONCLUSION: Blood lead level in children from Beijing was markedly decreased. And deficiency of zinc, magnesium and iron is related to the elevated blood lead level in the children aged 1-7 years. PMID- 21601239 TI - Mercury (Hg) burden in children: the impact of dental amalgam. AB - The risks and benefits of using mercury (Hg) in dental amalgam have long been debated. This study was designed to estimate Hg body burden and its association with dental amalgam fillings in 182 children (ages: 5-15 years) living in Taif City. Hg was measured in urine (UHg), hair (HHg) and toenails (NHg) by the Atomic Absorption Spectrophotometer with Vapor Generator Accessory system. Urinary Hg levels were calculated as both micrograms per gram creatinine (MUg/g creatinine) and micrograms per liter (MUg/L). We found that children with amalgam fillings (N=106) had significantly higher UHg-C levels than children without (N=76), with means of 3.763 MUg/g creatinine versus 3.457 MUg/g creatinine, respectively (P=0.019). The results were similar for UHg (P=0.01). A similar pattern was also seen for HHg, with means of 0.614 MUg/g (N=97) for children with amalgam versus 0.242 MUg/g (N=74) for those without amalgam fillings (P=0). Although the mean NHg was higher in children without amalgam (0.222 MUg/g, N=61) versus those with (0.163 MUg/g, N=101), the relationship was not significant (P=0.069). After adjusting for many confounders, the multiple logistic regression model revealed that the levels of UHg-C and HHg were 2.047 and 5.396 times higher, respectively, in children with dental amalgam compared to those without (P<0.01). In contrast, a significant inverse relationship was seen between NHg levels and dental amalgam fillings (P=0.003). Despite the controversy surrounding the health impact of dental amalgam, this study showed some evidence that amalgam-associated Hg exposure might be related with symptoms of oral health, such as aphthous ulcer, white patches, and a burning-mouth sensation. Further studies are needed to reproduce these findings. The present study showed that significant numbers of children with or without amalgam had Hg levels exceeding the acceptable reference limits. The detrimental neurobehavioral and/or nephrotoxic effects of such an increased Hg on children should be a cause of concern, and further investigation is warranted. Our results are alarming and indicate an urgent need for biomonitoring and assessment of exposure. Changes in dental practices involving amalgam, especially for children, are highly recommended in order to avoid unnecessary exposure to Hg. PMID- 21601240 TI - Increased number of circulating endothelial cells and plasma markers of endothelial damage in chronic cocaine users. AB - BACKGROUND: Cocaine use has been related with the development of accelerated atherosclerosis and with an increased risk of cardiac and cerebrovascular events, such as myocardial infarction, sudden cardiac death, and ischemic stroke. The underlying mechanisms leading to these complications are not fully understood, although thrombus formation and altered vascular function are prominent findings. OBJECTIVES: Our aim was to evaluate markers of endothelial dysfunction in chronic cocaine consumers before and after drug withdrawal. PATIENTS/METHODS: We determined circulating endothelial cells (CECs) and plasma levels of stromal cell derived factor-1 (SDF-1), monocyte chemotactic protein-1(MCP-1), soluble intracellular adhesion molecule (sICAM), high-sensitivity C reactive protein (hsCRP) and endothelin-1(ET-1), in DSM-IV cocaine addicts at baseline and after one month of cocaine abstinence. RESULTS: Cocaine users showed a strikingly higher numbers of CEC (62.35 +/- 18.4 vs 8.25 +/- 13.8 CEC/mL) and significantly elevated plasma levels for all the markers evaluated as compared to the control group. After cocaine withdrawal, patients improved SDF-1, ET-1, hsCRP and sICAM levels. However, CEC number and MCP-1 plasma levels remained significantly elevated. All the results were adjusted for blood levels of cholesterol and triglycerides and for smoking habit. CONCLUSIONS: Our results demonstrated that chronic cocaine consumption alters several functions of the endothelium towards a pro-thrombotic condition and that some of those functions remain abnormal even after short-term drug withdrawal. These observations support the notion that endothelial dysfunction may play a key role in the pathogenesis of ischemic vascular disease observed in cocaine abusers. PMID- 21601241 TI - The split-leg modified lateral position for percutaneous renal surgery and optimal retrograde access to the upper urinary tract. AB - OBJECTIVES: To present our experience with percutaneous nephrolithotomy (PCNL) in the split-leg modified lateral position. MATERIAL AND METHOD: The patient is placed with the thorax in the lateral position and the pelvis in an oblique position. Then the lower limbs are split and bent in the lowest position. Initial placement of a retrograde ureteral catheter, tract formation, stone fragmentation and retrieval, and optional extra procedures were accomplished with the patient in the same position. RESULTS: PCNL in the split-leg modified lateral position resulted in decreased operating room time, less manipulation of the anesthetized patient, and maintaining the sterility of the retrograde ureteral catheter. In addition, it allowed simultaneous antegrade and retrograde endoscopic approach to the upper urinary tract. Ureteral catheter placement, PCNL, and associated procedures were possible in all patients. Adjunct procedures were internal urethrotomy, transurethral resection of the prostate, rigid and flexible ureteroscopy, and endopyelotomy or endopyeloplasty. CONCLUSIONS: Performing PCNL in the split-leg modified lateral position has several advantages for the patient and the urologist, with greater versatility of stone manipulation along the entire urinary tract. PMID- 21601242 TI - Staged male urethroplasty transferring megalourethra tissue as free graft dorsal inlay to proximal urethral atresia in VACTERL association. AB - Megalourethra is a rare spectrum of urologic malformations of penile corporal structures frequently associated with multiple congenital anomalies, such as prune belly syndrome or vertebral, anorectal, cardiac, trachea-esophageal, renal, and limb (VACTERL association) defects. A 6-year-old boy with VACTERL association and proximal urethral atresia with distal fusiform megalourethra underwent staged reconstruction, including appendicovesicostomy, perineal urethrostomy, and first stage urethroplasty with a dorsal inlay free graft of megalourethra tissue to the proximal urethral atretic region, followed by second-stage urethroplasty. At 2.6 years of follow-up, he was continent, voids per urethra without postvoid residual urine volume, and no longer performs clean intermittent catheterization by way of the appendicovesicostomy. PMID- 21601243 TI - Dynamic real-time microscopy of the urinary tract using confocal laser endomicroscopy. AB - OBJECTIVES: To develop the diagnostic criteria for benign and neoplastic conditions of the urinary tract using probe-based confocal laser endomicroscopy (pCLE), a new technology for dynamic, in vivo imaging with micron-scale resolution. The suggested diagnostic criteria will formulate a guide for pCLE image interpretation in urology. METHODS: Patients scheduled for transurethral resection of bladder tumor (TURBT) or nephrectomy were recruited. After white light cystoscopy (WLC), fluorescein was administered as contrast. Different areas of the urinary tract were imaged with pCLE via direct contact between the confocal probe and the area of interest. Confocal images were subsequently compared with standard hematoxylin and eosin analysis. RESULTS: pCLE images were collected from 66 participants, including 2 patients who underwent nephrectomy. We identified key features associated with different anatomic landmarks of the urinary tract, including the kidney, ureter, bladder, prostate, and urethra. In vivo pCLE of the bladder demonstrated distinct differences between normal mucosa and neoplastic tissue. Using mosaicing, a post hoc image-processing algorithm, individual image frames were juxtaposed to form wide-angle views to better evaluate tissue microarchitecture. CONCLUSIONS: In contrast to standard pathologic analysis of fixed tissue with hematoxylin and eosin, pCLE provides real time microscopy of the urinary tract to enable dynamic interrogation of benign and neoplastic tissues in vivo. The diagnostic criteria developed in this study will facilitate adaptation of pCLE for use in conjunction with WLC to expedite diagnosis of urinary tract pathology, particularly bladder cancer. PMID- 21601244 TI - Metabolic syndrome, urine pH, and time-dependent risk of nephrolithiasis in Korean men without hypertension and diabetes. AB - OBJECTIVE: To examine the independent effect of metabolic syndrome (MS) on nephrolithiasis (NL) even with changes in MS status over time. METHODS: From 2002 2003, 3872 men who were reexamined annually or biannually until 2009 were enrolled in the analysis and observed for development of NL. The examination included anthropometric measurements, biochemical measurement, and kidney ultrasonography (US). A standard Cox proportional hazards model and a time dependent Cox model were used to calculate the adjusted hazard ratio in the NL model. RESULTS: After adjusting for age, baseline glomerular filtration rate, and uric acid level, MS at baseline was associated with a significantly increased risk of NL (HR, 1.771; 95% confidence interval, 1.157-2.711). MS over time as a time-dependent variable also predicted the development of NL (HR, 1.678; 95% CI, 1.151-2.447) after adjusted baseline covariate. After adjustment for potential confounding factors, there was a significant stepwise increase in risk of NL, with each additional MS trait compared with those with no traits of MS at baseline and follow-up. As the numbers of MS traits at baseline and follow-up increased, the urine pH of participants at baseline and follow-up decreased significantly (P <.01). The prevalence of NL in participants with continual MS (6.6%) was higher than those with resolved MS, and continual MS was an independent factor to predict NL. CONCLUSION: Our findings suggest that MS is significantly associated with increased risk of developing urine acidification, even with changes in status of MS observed during follow-up. PMID- 21601245 TI - Female covered urethral duplication with urogenital sinus. AB - We report a covered urethral duplication in a girl presenting prenatally with an enlarged fluid-filled vulvar cyst, genital duplication, and urogenital sinus revealed by fetal magnetic resonance imaging (MRI) and serial ultrasounds. Physical examination revealed an enlarged vulvar mass covering the clitoris, a single orifice, and normally sited anus. Congenital adrenal hyperplasia was ruled out at birth. MRI in addition showed an accessory duct between the sinus and the urine-filled vulvar pouch with a bifid clitoris. A total urogenital sinus mobilization with resection of the accessory urethra and vulvoplasty was performed with uneventful follow-up. PMID- 21601246 TI - Testosterone relaxes human internal spermatic vein through potassium channel opening action. AB - OBJECTIVES: To investigate the relation of testosterone-induced relaxation with smooth muscle K+ channels in human internal spermatic veins. Testosterone induces relaxation in human isolated internal spermatic veins, and this effect decreases in high-grade varicocele (recently reported). METHODS: The responses of isolated internal spermatic veins from patients with varicocele were recorded isometrically using a force displacement transducer. After contracting the venous rings with 45 mM KCl, relaxation with testosterone (0.1-300 MUM) was recorded in the absence or presence of large conductance calcium-activated K+ channel and the voltage-sensitive K+ channel inhibitor tetraethylammonium, adenosine triphosphate sensitive K+ channel inhibitor glibenclamide, voltage-dependent inward rectifier K+ channel inhibitor barium chloride, and voltage-sensitive K+ channel inhibitor 4-aminopyridine. RESULTS: Testosterone induced relaxation in human isolated internal spermatic veins in the absence of inhibitors (maximal effect 52.88+/ 6.72, n=24). Although tetraethylammonium, barium chloride, and 4-aminopyridine did not alter the testosterone-induced relaxant responses, GLI inhibited these responses. CONCLUSIONS: These results have demonstrated that testosterone induces relaxation in human isolated internal spermatic veins of patients with varicocele by way of adenosine triphosphate-sensitive K+ channels. PMID- 21601247 TI - Treatment of debilitating cremasteric synkinesia with intracremasteric botulinum A toxin injections. AB - OBJECTIVE: To describe the surgical technique of botulinum-A toxin injection into the cremasteric muscles of a 26-year-old male with bilateral cremasteric muscle spasms causing significant pain and limitation of activity. This pain has been refractory to multiple previous therapies, including inguinal nerve blocks and bilateral orchidopexies with cremasteric muscle lysis. Multiple imaging modalities revealed no obvious pathology for this significant bilateral pain. Genitourinary examination revealed hyper-retractile testes with changes consistent with bilateral orchidopexies and was otherwise normal. MATERIAL AND METHODS: The patient has undergone 3 outpatient staged injections of botulinum-A toxin into the bilateral cremasteric muscles after spermatic cord block with 1% lidocaine. One hundred units of botulinum-A toxin mixed into 10 mL of sterile normal saline were used for each injection staged 6 weeks apart. RESULTS: The patient tolerated all injections without apparent side effects. After the first injection into his left side, his baseline pain scores were reduced from 8 out of 10 to 3 out of 10 on a standard 10-point pain scale. He reported maximal efficacy 2 weeks after each injection, with dissipation over 4-6 weeks. After 2 left-sided and 1 right-sided injections, his baseline pain was 2 to 4 of 10, equal bilaterally, and he was back to rigorous activity with some limitations. CONCLUSION: Direct injection of botulinum-A toxin into the cremasteric muscle is a viable treatment option for the rare patient with debilitating and painful cremasteric spasms refractory to other therapies. PMID- 21601249 TI - Improving lymph node yield in retroperitoneal lymph node dissection using fluorescent molecular imaging: a novel method of localizing lymph nodes in Guinea pig model. AB - OBJECTIVES: To propose that fluorescent molecular imaging has utility in specifically identifying the lymph nodes, thereby enabling more definitive lymph node visualization and dissection. Retroperitoneal lymph node dissection (RPLND) is an invasive procedure with significant morbidity. A minimally invasive approach would be of great clinical benefit but has been limited by the extensive perivascular dissection required to remove all lymphatic tissue. Directed lymph node visualization would allow a limited dissection, making a laparoscopic approach more feasible. METHODS: Ten male Hartley guinea pigs underwent nonsurvival RPLND, 5 with the protease activatable in vivo fluorescent molecular imaging agent, ProSense and 5 without image guidance (control). ProSense was administered 24 hours before surgery and detected 24 hours later using a photodynamic detector. In group 1, RPLND was first performed without molecular imaging followed by image-guided lymph node dissection for residual nodes. In group 2, the near infrared detector was used initially for lymph node excision followed by traditionally unassisted extraction of the residual lymph nodes. The lymph nodes were extracted, counted, and sent for histopathologic analysis. RESULTS: With the assistance of molecular imaging, no additional lymph nodes were identified after complete dissection, and all tissue identified by ProSense was confirmed by histopathologic analysis to be lymph nodes. Without molecular imaging, all lymph nodes were not identified, and in 2 instances, the tissue was incorrectly thought to be lymphatic tissue. CONCLUSIONS: Molecular image-guided RPLND is a promising technique to improve in vivo, live visualization and dissection of lymph nodes and has the potential for application in improving the diagnosis and treatment of other urologic malignancies. PMID- 21601250 TI - A prospective, randomized controlled study comparing lidocaine and tramadol in periprostatic nerve blockage for transrectal ultrasound-guided prostate biopsy. AB - OBJECTIVES: To assess the efficacy of tramadol and lidocaine in reducing pain using the periprostatic nerve block technique with a spinal needle, guided by transrectal ultrasound (TRUS) before the biopsy application. METHODS: Of the 112 eligible candidates who were asked to participate in the study, 90 agreed and provided informed consent. These 90 men were randomized into 3 groups. Group 1 (n = 30) received lidocaine, group 2 (n = 29) received tramadol, and group 3 (n = 31) received saline solution. Within 10 minutes of biopsy procedure completion, the patients were presented with visual pain scales and asked to rate the pain. The patients also asked whether they would be to return for this procedure if it became medically necessary. RESULTS: The postprocedural mean pain scores of lidocaine, tramadol, and placebo groups were found to be 1.73, 2.89, and 4.32, respectively. The mean pain scores were significantly lower in both the lidocaine and the tramadol groups compared with the placebo group (P <.001). In addition, statistically significant differences were found among the 3 groups regarding how willing they would be to return for the procedure if necessary. CONCLUSIONS: In this study, we showed that the local anesthetic effect of tramadol in decreasing pain in periprostatic nerve block during TRUS-guided biopsy. The use of tramadol for pain relief in transrectal ultrasound-guided prostate biopsy is a practical, effective, and comfortable method compared with the results of the control group. PMID- 21601251 TI - Another component of the pelvic plexus that innervates the penis in the rat. AB - OBJECTIVES: To determine whether the small plexus located at the base of the penis, consisting of nerves arising from the major pelvic ganglion, connecting with the sensory branch of the pudendal nerve, contains postganglionic neurons innervating the erectile tissue and urethra of the penis. METHODS: A total of 22 adult male Wistar rats 3-4 months of age (weight 250-350 g) were used. The features, distribution, and topography of the small plexus were determined by gross anatomy and histologic studies (Masson's trichrome and Nissl stain). Postganglionic neurons were traced with horseradish peroxidase-wheat germ agglutinin injected in the cavernosum, spongiosum corpora, and penile urethra. RESULTS: The small plexus located at the base of the penis has ganglia containing cells with large nuclei. The cells were stained with the Nissl technique confirming they are neurons. The neurons were positively labeled with horseradish peroxidase-wheat germ agglutinin after the tracer was injected in the penile structures. CONCLUSIONS: In the male rat, the small plexus located at the base of the penis contains postganglionic neurons innervating the penile structures. These neurons can contribute to the regulation of the sexual and urinary function of the genitourinary tract. Because the rat is the main laboratory animal used in urologic studies, it is important to consider, when designing experiments or discussing results, that in addition to the major pelvic ganglion, other postganglionic neurons of the penis are provided by the small plexus. The small plexus could be named the minor pelvic ganglia and considered a component of the pelvic plexus. PMID- 21601248 TI - Solifenacin as add-on therapy for overactive bladder symptoms in men treated for lower urinary tract symptoms--ASSIST, randomized controlled study. AB - OBJECTIVES: To assess the efficacy and safety of solifenacin add-on therapy to tamsulosin in lower urinary tract symptoms (LUTS) men with residual overactive bladder (OAB) symptoms despite tamsulosin monotherapy. METHODS: In this randomized, multicenter, double-blind study, male LUTS patients aged>=50 years with urgency episodes/24 hours>=2 and micturitions/24 hours>=8 were randomized to 3 groups: 12-weeks tamsulosin plus placebo (TAM+PBO), tamsulosin plus solifenacin 2.5 mg (TAM+SOL), and tamsulosin plus solifenacin 5 mg (TAM+SOL). Changes from baseline to end of treatment in the number of urgency episodes/24 hours (primary endpoint), micturitions, nocturia, urgency incontinence episodes, International Prostate Symptom Scores (IPSS), and Overactive Bladder Symptom Score (OABSS) were compared between the TAM+SOL groups and TAM+PBO. Safety was assessed on adverse events, postvoid residual volume, and maximal urinary flow rate (Qmax.). RESULTS: Six-hundred thirty-eight men were randomized. Urgency was reduced by 2.2 and 2.4 episodes in the TAM+SOL 2.5 and 5 mg groups, respectively. The TAM+SOL 5 mg group showed significant improvement compared with TAM+PBO (-2.4 vs -1.9, P=.049). The number of micturitions in both TAM+SOL groups were significantly reduced compared with TAM+PBO (both P<.001). IPSS storage symptom score and OABSS significantly improved in both TAM+SOL groups compared with TAM+PBO. Changes in IPSS voiding symptom score and Qmax. were similar in all groups. Four patients (1.9%) in the TAM+SOL 5 mg group had urinary retention, but all recovered after catheterization. CONCLUSIONS: In male LUTS patients with residual OAB symptoms despite tamsulosin monotherapy, TAM+SOL showed efficacy on urgency, which represents OAB symptoms and was well tolerated. PMID- 21601252 TI - Predictors for negative ureteroscopy in the management of upper urinary tract stone disease. AB - OBJECTIVE: To identify factors predictive of negative ureteroscopy (URS). Although computed tomography (CT) scans are sensitive in assessing upper tract calculi, there is increased effort to limit CT radiation exposure. On occasion, patients undergo URS and it is discovered that the stone has already passed. METHODS: Retrospective chart review was conducted on all URS cases for renal and ureteral stones performed by a single surgeon from August 2003 to May 2008. Renal units were examined separately and excluded for stone size >10 mm, staged procedures, and previously placed ureteral stents. Negative URS cases were compared with those where stones were identified for differences in stone size, location, presence of preoperative pain, time interval since CT, presence of hydronephrosis, and use of medical expulsive therapy (MET). RESULTS: Two-hundred fifty-six cases were identified. Twenty-five of 256 renal units (9.8%) did not have stones upon direct visualization. Stone size (P < .001) and stone location (P = .043) were significantly associated with outcome on univariate analysis. On multivariate analysis, only stone size was significant (P < .001). CONCLUSION: Negative URS occurred in almost 10% of cases, with reasonable chance of spontaneous stone passage. Our data support smaller stone size and distal location as predictive of negative URS as opposed to preoperative pain, presence of hydronephrosis, and use of MET. Time interval since CT was not predictive. Rate of negative ureteroscopy is not insignificant, thus patients with small, distal stones who elect to undergo URS should be counseled regarding negative URS with an alternative being repeat imaging. PMID- 21601253 TI - Effect of age on transitional cell carcinoma of the upper urinary tract: presentation, treatment, and outcomes. AB - OBJECTIVES: To determine the effect of age on the disease characteristics, treatment administered, and disease-specific survival (DSS) for patients with upper tract urothelial carcinoma. The effect of advancing age on the disease extent and survival has not been well delineated in patients with upper tract urothelial carcinoma. METHODS: Using the Surveillance, Epidemiology, and End Results database from the National Cancer Institute, we identified patients diagnosed with UTUC from 1984 to 2004. The data were analyzed for age (40-49, 50 59, 60-69, 70-79, and >=80 years), sex, race, disease extent, treatment type, and cause of death. Relationships among age, clinicopathologic features, and treatment were tabulated. The effect of age on overall and DSS were calculated using Cox proportional hazards ratio analyses. RESULTS: The final cohort consisted of 12 639 patients. Advancing age was associated with greater T stage and grade at presentation. Of those 40-49 years old, 41% presented with invasive tumors (T2-T4) compared with 50% of octogenarians. Poor or undifferentiated tumors increased in frequency from 42% among those 40-49 years old to 59% among those>=80 years old. Extirpative surgery was less likely among those with Stage T1 or less disease (88.3% vs 92.8%). Octogenarians were less likely to have undergone extirpative surgery than those 40-49 years old (86% vs 95%). Despite adjustments for T stage, grade, and treatment, DSS (hazard ratio 2.64) worsened with increasing age. CONCLUSIONS: With advancing age, we found a corresponding increase in stage and grade at presentation. After adjustment for stage, grade, and treatment type, older patients still had worse DSS. PMID- 21601254 TI - Urologist compliance with AUA best practice guidelines for benign prostatic hyperplasia in Medicare population. AB - OBJECTIVES: To improve benign prostatic hyperplasia (BPH) care, the American Urological Association created the best practice guidelines for BPH management. We evaluated the trends in use of BPH-related evaluative tests and the extent to which urologists comply with the guidelines for these evaluative tests. METHODS: From a 5% random sample of Medicare claims from 1999 to 2007, we created a cohort of 10,248 patients with new visits for BPH to 748 urologists. The trends in use of BPH-related testing were determined. After classifying urologists by compliance with the best practice guidelines, the models were fit to determine the differences in the use of BPH-related testing among urologists. Additional models were used to define the extent to which individual BPH-related tests influenced guideline compliance. RESULTS: The use of most BPH testing increased with time (P<.001) except for prostate-specific antigen (declined; P<.001) and ultrasonography (P=.416). Northeastern and Midwestern urologists were more likely to be in the lowest compliance group compared with Southern and Western urologists (29%, 27%, 13%, and 19%, respectively; P=.01). The testing associated with high guideline compliance included urinalysis and prostate-specific antigen measurement (P<.01 for both). Prostate ultrasonography (P=.03), cystoscopy (P<.01), uroflow (P<.01), and postvoid residual urine volume determination (P=.02) were associated with low guideline compliance. Urodynamics, postvoid residual urine volume, cytology, serum creatinine, and upper tract imaging were not strongly associated with guideline compliance. CONCLUSIONS: Despite the American Urological Association guidelines for BPH care, wide variations in the evaluation and treatment were seen. Improving guideline adherence and reducing variation could improve BPH care quality. PMID- 21601255 TI - Postprostatectomy established stress urinary incontinence treated with duloxetine. AB - OBJECTIVES: To evaluate the efficacy of duloxetine to treat stress urinary incontinence, 1 of the most frequent complications after radical prostatectomy. Conservative measures and surgery are well-established treatments. However, drug treatment could be an intermediate option. METHODS: All patients had >1 year of follow-up after radical prostatectomy to avoid interfering with the natural recovery period (established stress urinary incontinence). Continence was measured by the average daily use of pads and the International Consultation on Incontinence Questionnaire-short form. In Spain, it is necessary to proceed with off-label use formality, and all patients were informed and agreed. The initial dose of duloxetine was 30 mg once daily and was increased to 60 mg/d. Drug treatment was maintained for 9 months. RESULTS: From June 2006 to July 2007, 68 patients were included. The median age was 68 years (range 52-79). The median duration of duloxetine treatment was 5.56 months (range 1-18). A statistically significant decrease in the International Consultation on Incontinence Questionnaire-Urinary Incontinence-short form (from 13 to 9; P < .001) and the average number of pads/d (from 2 to 1; P < .001) was observed between the initial and 3-month visit. At the end of the follow-up period, 74% and 57% of the patients had a reduced International Consultation on Incontinence Questionnaire Urinary Incontinence-short form score and a decrease in the number of pads used daily, respectively. Of the 68 patients, 32 (47%) presented with some side effects and 17 patients stopped the treatment because of adverse effects (25%). CONCLUSIONS: Our results suggest that duloxetine is a possible alternative treatment of postprostatectomy established stress urinary incontinence. The continence improvement results were mild and conditioned in part by the frequency of the side effects. Provided that duloxetine does not preclude later continence surgery and the benefits are observed at the first visit, we believe it can be a treatment option for selected patients. PMID- 21601256 TI - Male susceptibility to hepatic damage in acute uremia in rats. AB - OBJECTIVE: To evaluate the role of gender in hepatic oxidative stress response and production of inflammatory cytokines in acute uremia after bilateral nephrectomy. Published studies indicate that the severity of tissue damage in kidney, brain, or heart injury may differ according to gender. We recently demonstrated that acute renal failure after kidney injury or bilateral nephrectomy activates oxidative stress and causes damage to the liver. METHODS: Male and female rats were subjected to bilateral nephrectomy and euthanized four hours later. Serum and liver tissues were collected and analyzed. To ascertain the role of testosterone and estrogen in hepatic oxidative stress, castration was carried out 15 days before bilateral nephrectomy. In some groups, animals were administrated 17-beta-estradiol or vehicle for 2 weeks before bilateral nephrectomy. RESULTS: Hepatic oxidative stress was significantly pronounced in male rats as determined by increase in malondialdehyde (MDA) levels and decrease in total glutathione (GSH) contents. An increase in proinflammatory cytokine concentration was seen in male rats, whereas the antiinflammatory cytokine level was more elevated in females. Castration reduced hepatic oxidative stress and proinflammatory cytokine concentration, whereas exogenous estradiol after castration did not have an additional effect on these parameters. CONCLUSIONS: There is a gender difference with regard to the severity of hepatic oxidative stress and inflammatory response in acute uremia after bilateral nephrectomy, with female rats displaying significant protection relative to male rats. We suggest that sex hormones could play an important role in the severity of remote tissue damage in acute kidney failure. PMID- 21601257 TI - Emergency ureteroscopic removal of ureteral calculi after first colic attack: is there any advantage? AB - OBJECTIVE: To comparatively evaluate the efficacy of ureteroscopic stone treatment immediately after the first colic attack and in an electively planned manner. METHODS: A total of 145 patients underwent semirigid ureteroscopic removal of obstructive ureteral calculi using 2 different approaches (group 1, 69 patients, and group 2, 76 patients). The 69 patients in group 1 were treated with appropriate medical therapy for a period of >=7 days for colic pain and subsequently underwent either semirigid ureteroscopy or pneumatic lithotripsy in a planned manner. The 76 patients in group 2 underwent semirigid ureteroscopy after the first colic attack. The stone-free status, auxiliary procedures, and complications were evaluated between the 2 groups using the Mann-Whitney U test; for qualitative data, Fisher's exact test was used. RESULTS: Of the 145 patients who underwent semirigid ureteroscopy, the mean stone size was 11.80+/-3.95 mm and 8.32+/-2.08 mm in the 2 groups. No patient experienced a major complication during or after the procedure. The stone-free rate was 87% and 90.7% in groups 1 and 2, respectively. The mean readmission rate to the emergency department for the management of a colic attack was 3.03+/-2.84 in group 1; no patient in group 2 required readmission. CONCLUSION: Ureteroscopic stone removal immediately after the first colic attack in the cases of obstructive ureteral stones proved to be safe and effective. It has the main advantage of offering both immediate stone fragmentation and the relief of acute onset colic pain causing extreme discomfort. PMID- 21601258 TI - Loss of EpCAM expression in breast cancer derived serum exosomes: role of proteolytic cleavage. AB - OBJECTIVE: Cancer cells in the body release soluble and membranous factors that manipulate the tumor environment to facilitate growth and survival. Recent years have provided evidence that small microvesicles that are termed exosomes may play a pivotal role in this process. Exosomes are membrane vesicles with a size of 40 100 nm that are released by both tumor and normal cells and can be found in various body fluids. Tumor-derived exosomes carry functional proteins, mRNAs, and miRNAs and could serve as novel platform for tumor diagnosis and prognosis. However, marker proteins that allow enrichment of tumor-derived exosomes over normal exosomes are less well defined. METHODS: We used Western blot analysis and antibody coupled magnetic beads to characterize CD24 and EpCAM as markers for exosomes. We investigated ovarian carcinoma ascites, pleural effusions and serum of breast carcinoma patients. As non-tumor derived control we used exosomes from ascites of liver cirrhosis patients. RESULTS: Exosomes could be isolated from all body fluids and contained marker proteins as well as miRNAs. We observed that CD24 and EpCAM were selectively present on ascites exosomes of tumor patients and copurified together on anti-EpCAM or anti-CD24 magnetic beads. In breast cancer patients CD24 was present but EpCAM was absent from serum exosomes. Instead, the intact EpCAM ectodomain was recovered in a soluble form. We provide evidence that EpCAM can be cleaved from exosomes via serum metalloproteinase(s). CONCLUSION: Loss of EpCAM on serum exosomes may hamper enrichment by immune-affinity isolation. We suggest that CD24 could be an additional marker for the enrichment of tumor-derived exosomes from blood. PMID- 21601259 TI - Lung dendritic cells induce T(H)17 cells that produce T(H)2 cytokines, express GATA-3, and promote airway inflammation. AB - BACKGROUND: Dendritic cells (DCs) are crucial to shape the adaptive immune response. Extensive in vitro manipulation reprograms T(H)2 and T(H)17 cell lines into T(H)1 cells, leading to the concept of CD4(+) T(H) cell subset plasticity. The conversion of memory T(H)17 cells into T(H)2 cells or vice versa remains to be clarified. OBJECTIVE: We examined the localization of T(H)17/T(H)2 cells in vivo, their cellular origin (T(H)2 vs T(H)17), and the underlying mechanisms that drive the generation of these double T(H) producers. METHODS: Antigen-loaded bone marrow-derived DCs (ovalbumin-DCs) were repeatedly administered locally (intratracheally) or systemically (intravenously) to naive mice to elicit chronic airway inflammation. Inflamed lungs and mediastinal lymph nodes were examined for the presence of IL-17(+)IL-13(+)IL-4(+)CD4(+) T cells that coexpressed retinoic acid receptor-related orphan receptor gammat and GATA-3 (T(H)17/T(H)2). RESULTS: We show that repetitive administration of inflammatory ovalbumin-DCs, locally or systemically, promoted the development of antigen-specific T(H)17/T(H)2 cells in lungs and mediastinal lymph nodes. Immunized mice had IgE-independent and steroid resistant airway inflammation with a mixed neutrophil and eosinophil infiltration of the bronchoalveolar lavage fluid. Airway inflammatory signal regulatory protein alpha-positive DCs reprogrammed in vitro-generated T(H)17 but not T(H)2 cells, as well as lung effector T(H) cells, into T(H)17/T(H)2 cells. CONCLUSION: We demonstrate the existence of T(H)17/T(H)2 cells that express GATA-3 in inflamed tissues and their T(H)17 origin. We further propose that repeated immunization with inflammatory DCs prevails on the route of DC administration to drive T(H)17/T(H)2-associated chronic lung inflammation. PMID- 21601260 TI - Functional FCGR2B gene variants influence intravenous immunoglobulin response in patients with Kawasaki disease. PMID- 21601261 TI - Effects of prostaglandin administration on ovarian follicular dynamics, conception, prolificacy, and fecundity in sheep. AB - Two experiments were conducted to determine the effects of prostaglandin administration on ovarian follicular dynamics, conception, prolificacy, and fecundity in sheep. During the breeding season, multiparous Corriedale ewes were randomly allocated to two groups: 1) PG group (n = 15 and n = 135 in Experiments I and II, respectively): synchronized with two injections of DL-Cloprostenol (125 MUg) given 7 d apart, and inseminated at a fixed time (Day 0), 48 h after the second injection; and 2) Control group (n = 15 and n = 73 in Experiments I and II): ewes in spontaneous estrus inseminated at detected estrus. Ewes received 100 * 10(6) sperm by intrauterine AI. Ultrasonography was used to evaluate growth of the ovulatory follicle, ovulation rate (OR), conception rate, and prolificacy on Days 30 and 60. Ewes from the group PG had a larger (4.8 +/- 0.5 mm, mean +/- SEM; P < 0.05) ovulatory follicle that grew faster (1.2 +/- 0.3 mm/d, P = 0.08), and a lower OR (1.37 +/- 0.1, P < 0.05), compared to ewes from the Control group (3.9 +/- 0.2 mm, 0.7 +/- 0.2 mm/d, and 1.61 +/- 0.1 respectively). Plasma progesterone concentrations from Days -6 to 1 were lower in the PG group (P < 0.05), but plasma estradiol concentrations were similar between groups (P > 0.05). Progesterone concentrations were similar between groups during the early luteal phase and on Days 12 and 17 (P > 0.05). The embryo recovery rate (Day 7) tended to be lower in the PG group (39 vs 64%, P = 0.08), but embryo quality did not differ between groups. Conception, prolificacy and fecundity, were lower in the PG than in the Control group (P < 0.05). Cumulative reproductive losses were similar between groups, but more twins were lost in the PG group (P < 0.05). We concluded that in ewes synchronized with PGF(2alpha) given twice, 7 d apart, lower reproductive performance was associated with an environment dominated by lower progesterone concentrations that stimulated the preovulatory follicle to grow faster and become larger; this was associated with lower rates of ovulation, conception, prolificacy, and fecundity. PMID- 21601263 TI - In vitro maturation and artificial activation of donkey oocytes. AB - Three media were evaluated for their ability to support in vitro maturation of donkey (Equus asinus) oocytes and their development after parthenogenetic activation. The basal medium for Medium 1 (M1) and Medium 2 (M2) was M199 and DMEM/F12 respectively, whereas, Medium 3 (M3) consisted of equal parts (v/v) of M199 and DMEM/F12. All three media were supplemented with 10% (v/v) fetal calf serum, 0.01 units/mL porcine FSH, 0.01 units/mL equine LH, 200 ng/mL insulin-like growth factor 1(IGF-I), 10 MUl/mL insulin-transferrin-selenium (ITS), 0.1 mg/mL taurine, 0.1 mg/mL L-cysteine, 0.05 mg/mL L-glutamine, 0.11 mg/mL sodium pyruvate, and 25 mg/mL gentamycin. There were no significant differences among the three maturation media for oocyte maturation. Maturation rate of donkey oocytes in M1 was 53% for compact (Cp) cumulus-oocyte complexes and 75% for expanded (Ex) cumulus-oocyte complexes; in M2 these were 55 and 77%, respectively; and in M3, 58 and 75%. The percentage of cleaved parthenotes and 4- or 8-cell embryos were not significantly different for oocytes matured in the various media (61 and 24% for M1; 66 and 32% for M2; and 67 and 33% for M3). Oocytes matured in M3 tended to yield a higher rate of advanced embryo development (morula) than oocytes matured in M1 (22 vs 9%; P = 0.07). In conclusion, donkey oocytes were matured and parthenogenetically activated in vitro, using methods similar to those used in the horse. PMID- 21601262 TI - Influence of lameness on follicular growth, ovulation, reproductive hormone concentrations and estrus behavior in dairy cows. AB - The objective of this study was to examine the effect of a chronic stressor, lameness, on reproductive parameters. Seventy cows 30-80 days post-partum were scored for lameness and follicular phases synchronized with GnRH followed seven days later by prostaglandin (PG). Fifteen Lame animals did not respond to GnRH ovarian stimulation. Milk progesterone for 5 days prior to PG was lower in the remaining Lame cows than Healthy herdmates. Fewer Lame cows ovulated (26/37 versus 17/18; P = 0.04) and the interval from PG to ovulation was shorter in Lame cows. In Subset 1 (20 animals), the LH pulse frequency was similar in ovulating animals (Lame and Healthy) but lower in Lame non-ovulators. An LH surge always preceded ovulation but lameness did not affect the interval from PG to LH surge onset or LH surge concentrations. Before the LH surge, estradiol was lower in non ovulating cows compared to those that ovulated and estradiol concentrations were positively correlated with LH pulse frequency. In Subset 2 (45 cows), Lame ovulating cows had a less intense estrus than Healthy cows, although Lame cows began estrus and stood-to-be-mounted earlier than Healthy cows. In conclusion, we have identified several parameters to explain poor fertility in some chronically stressed animals. From 30 to 80 days post-partum, there was a graded effect that ranged from 29% Lame cows with absence of ovarian activity, whereas another 21% Lame cows failed to express estrus or ovulate a low estrogenic follicle; in 50% cows, many reproductive parameters were unaffected by lameness. PMID- 21601264 TI - Use of polarized light microscopy in porcine reproductive technologies. AB - The meiotic spindle in the oocyte is composed of microtubules and plays an important role during chromosome alignment and separation at meiosis. Polarized light microscopy (PLM) could be useful for a non-invasive evaluation of the meiotic spindle and may allow removal of nuclear structures without fluorochrome staining and ultraviolet exposure. In this study, PLM was used to assess its potential application in porcine reproductive technologies. The objectives of the present study were to assess the efficiency of PLM to detect microtubule polymerized protein in in vitro-matured porcine oocytes; to examine its effects on the oocyte developmental competence; to select oocytes based on the presence of the meiotic spindle detected by PLM; and to assess the efficiency oocyte enucleation assisted with PLM. In the first experiment, the presence of microtubule-polymerized protein was assessed and confirmed in oocytes (n = 117) by immunostaining and chromatin detection. In the second experiment, oocytes (n = 160) were exposed or not (controls) to PLM for 10 minutes, and then parthenogenetically activated and cultured in vitro. In the third experiment, development competence of oocytes with a positive or negative signal to PLM was analyzed after in vitro fertilization. Finally, oocytes (n = 54) were enucleated using PLM as a tool to remove the meiotic spindle. A positive PLM signal was detected in 98.2 % of the oocytes, which strongly correlated (r = 1; p < 0.0001) with the presence of microtubule-polymerized protein as confirmed by immunostaining. Oocytes exposed to PLM did not differ significantly from controls on cleavage, total blastocyst, expanded blastocyst rates and total cell numbers. The percentage of oocytes at the MII stage and blastocyst formation rate in the negative PLM group significantly differed from control and PLM positive groups. Overall efficiency of spindle removal using the PLM-Oosight system was 92.6%. These results suggest that polarized light microscopy is an efficient system to detect microtubule-polymerized protein in in vitro-matured porcine oocytes and does not exert detrimental effects on porcine oocyte developmental competence. Selecting oocytes by the presence of a PLM signal provides limited improvement on IVF results. Finally, PLM appears as an efficient method to enucleate porcine oocytes. PMID- 21601265 TI - In vivo tissue sampling of embryonic resorption sites using ultrasound guided biopsy. AB - In the polytocous European brown hare (Lepus europaeus) more than 23% of all successful implantations undergo embryonic resorption. The objective of the study was to establish a minimally invasive ultrasound guided biopsy technique to collect embryonic resorption tissue in vivo. The sampled material was genetically analysed to determine paternity and the sex of the embryo. Female hares were either mated or artificially inseminated and pregnancy was confirmed by ultrasound on day six post ovulation. Subsequent embryonic development was ultrasonographically monitored on a regular basis to detect embryos undergoing resorption. Cell material of the resorption site was collected under ultrasonographic control via transabdominal biopsy of the placenta or aspiration of resorption fluid. To avoid breathing movements during the biopsy, the animals were intubated and a short apnoea was evoked by assisted ventilation. The presence of embryonic cells in the biopsy material was confirmed by microsatellite analysis in 11 of the fluid samples (n = 28) and six of the placental samples (n = 8). The lower success rate in the fluid samples was attributed to the abundance of maternal cells which was confirmed by the analysis of fluid sample smears. Male sex of the embryos undergoing resorption was detected by SRY analysis for ten of the fluid samples and for one of the placental samples. The two biopsy techniques did not have any negative impact on the prenatal development of the healthy siblings nor did it influence the future breeding performance of the females that were biopsied. PMID- 21601266 TI - Artificial insemination with cryopreserved sperm from feline epididymides stored at 4 degrees C. AB - Recovering and storing sperm from the epididymides of males of rare felidae is useful for preserving the species. The objective of the present study was to determine pregnancy rates following artificial insemination (AI) of frozen-thawed epididymal sperm, which were cryopreserved following low-temperature storage of the epididymides. In this study, these sperm were used for unilateral intrauterine AI (UIUAI) or unilateral intratubal AI (UITAI) using 40 * 10(6) and 10 * 10(6) sperm, respectively. The caudal epididymides of 17 cats were stored at 4 degrees C for 24 h after castration. Artificial insemination of seven female cats was performed on Days 3 or 4 (start of estrus = Day 1) by UIUAI, 20 h after injection of 100 IU hCG to induce ovulation. Furthermore, UITAI at 24 h (UITAI 24) or 30 h (UITAI-30) after hCG were also done (five cats per group). It was noteworthy that AI by UIUAI and UITAI-24 was performed before ovulation, whereas AI by UITAI-30 was performed after ovulation. Pregnancy rates were 28.6% (2/7) by UIUAI, 80% (4/5) by UITAI-24, and 20% (1/5) by UITAI-30. Litter size was one or two by UIUAI, and one to four by UITAI. Spontaneous abortion occurred on Days 25 30 of pregnancy in one of the two female cats pregnant following UIUAI, and in two of five female cats pregnant following UITAI. Based on the high pregnancy rate obtained with 10 * 10(6) sperm in the UITAI-24 group (AI performed before ovulation), we concluded that this was the most appropriate method for AI with frozen-thawed epididymal sperm after initial low-temperature storage of epididymides. PMID- 21601267 TI - Hormonal and antimicrobial therapy in theriogenology practice: currently approved drugs in the USA and possible future directions. AB - Hormonal and antimicrobial therapies are essential to regulate and maintain healthy reproduction in domestic animals. The appropriate and legal use of these compounds is ultimately the responsibility of the veterinarian and other users, with a primary mission to directly protect and promote the health of animals, and indirectly the health of people. The appropriate use of these products is defined by the Federal Food, Drug, and Cosmetic Act, 21 United States of America S 301 et seq and implementing regulations in the Code of Federal Regulations. In the past, use of a drug in an animal for an unapproved use violated this Act. However, passage of the Animal Medicinal Drug Use Clarification Act 1994 legalized the extra-label use of certain animal and human drugs in veterinary practice for treating diseases. This manuscript reviews currently approved hormonal and antimicrobial drugs for use in theriogenology. Considering the ever increasing knowledge in the area of veterinary reproduction, particularly in the treatment and control of reproduction using antimicrobials and hormones, it would be beneficial to widen the therapeutic options in these categories. The potential for widening the therapeutic options is also discussed in this review, by providing a non-exhaustive but essential list of potential new drugs for use in clinical animal reproduction (theriogenology). PMID- 21601268 TI - Dynamics of zonula occludens-2 expression during preimplantation embryonic development in the hamster. AB - The objective was to study the expression of zonula occludens-2, a tight junction protein, during preimplantation hamster embryonic development, to predict its possible localization, source, and roles in trophectoderm differentiation and blastocyst formation in this species. Comparison of zonula occludens-2 expression pattern between the hamster and mouse preimplantation embryos from the zygote up to the blastocyst stage was also an objective of this study. Zonula occludens-2 localization was noted in nuclei of blastomeres in all stages of hamster and mouse embryonic development. Compared to mice, where zonula occludens-2 was first localized in the interblastomere membrane at the morula stage, hamster embryos had membranous zonula occludens-2 localization from the 2-cell stage onwards. Based on combined results of immunolocalization study in parthenogenic embryos and ovarian and epididymal sections, and quantitative PCR done in oocytes and all developmental stages of preimplantation embryos, perhaps there was a carry-over of zonula occludens-2 proteins or mRNA from the dam to the embryo. Based on these findings, we inferred that maternally derived zonula occludens-2 was involved in nuclear functions, as well as differentiation of blastomeres and blastocoel formation during preimplantation embryonic development in the hamster. PMID- 21601269 TI - Conserved ram seminal plasma proteins bind to the sperm membrane and repair cryopreservation damage. AB - Whole seminal plasma (SP) enhances the function and fertility of frozen/thawed ram sperm. The objective of the current study was to investigate whether SP proteins capable of binding to molecules from the sperm plasma membrane were conserved among ram breeds, and whether these proteins were sufficient to overcome cryopreservation-induced reductions in sperm quality. Whole ram SP, obtained from rams of various breeds, improved progressive motility of frozen/thawed sperm at all times evaluated (P < 0.05); however, it did not improve total motility (15 min, P = 0.480; 30 min, P = 0.764; and 45 min, P = 0.795). To identify SP proteins responsible for this effect, a new method was developed to retain SP proteins that bound specifically to the sperm membrane by immobilization of sperm membrane proteins. These proteins specifically bound to the sperm surface, especially the acrosomal region. Lactotransferrin, epididymal secretory protein E1, Synaptosomal-associated protein 29, and RSVP-20 were identified (mass spectrometry) in this fraction. The retained SP proteins fraction repaired ultrastructural damage of frozen/thawed sperm and, with the addition of fructose, significantly improved motility of frozen/thawed sperm. We concluded that SP proteins that bound to the sperm membrane were conserved among ram breeds, and that when added to frozen/thawed semen (along with an energy source), they repaired ram sperm damage and enhanced sperm motility. PMID- 21601270 TI - Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. AB - BACKGROUND: Repeated periods of stimulation of the spinal cord and training increased the ability to control movement in animal models of spinal cord injury. We hypothesised that tonic epidural spinal cord stimulation can modulate spinal circuitry in human beings into a physiological state that enables sensory input from standing and stepping movements to serve as a source of neural control to undertake these tasks. METHODS: A 23-year-old man who had paraplegia from a C7-T1 subluxation as a result of a motor vehicle accident in July 2006, presented with complete loss of clinically detectable voluntary motor function and partial preservation of sensation below the T1 cord segment. After 170 locomotor training sessions over 26 months, a 16-electrode array was surgically placed on the dura (L1-S1 cord segments) in December 2009, to allow for chronic electrical stimulation. Spinal cord stimulation was done during sessions that lasted up to 250 min. We did 29 experiments and tested several stimulation combinations and parameters with the aim of the patient achieving standing and stepping. FINDINGS: Epidural stimulation enabled the man to achieve full weight-bearing standing with assistance provided only for balance for 4.25 min. The patient achieved this standing during stimulation using parameters identified as specific for standing while providing bilateral load-bearing proprioceptive input. We also noted locomotor-like patterns when stimulation parameters were optimised for stepping. Additionally, 7 months after implantation, the patient recovered supraspinal control of some leg movements, but only during epidural stimulation. INTERPRETATION: Task-specific training with epidural stimulation might reactivate previously silent spared neural circuits or promote plasticity. These interventions could be a viable clinical approach for functional recovery after severe paralysis. FUNDING: National Institutes of Health and Christopher and Dana Reeve Foundation. PMID- 21601271 TI - The remaining smallpox stocks: the healthiest outcome. PMID- 21601272 TI - Spinal cord injury: time to move. PMID- 21601273 TI - Cutaneous larva migrans. PMID- 21601274 TI - Extended release of high molecular weight hydroxypropyl methylcellulose from molecularly imprinted, extended wear silicone hydrogel contact lenses. AB - Symptoms of contact lenses induced dry eye (CLIDE) are typically treated through application of macromolecular re-wetting agents via eye drops. Therapeutic soft contact lenses can be formulated to alleviate CLIDE symptoms by slowly releasing comfort agent from the lens. In this paper, we present an extended wear silicone hydrogel contact lens with extended, controllable release of 120 kDa hydroxypropyl methylcellulose (HPMC) using a molecular imprinting strategy. A commercial silicone hydrogel lens was tailored to release approximately 1000 MUg of HPMC over a period of up to 60 days in a constant manner at a rate of 16 MUg/day under physiological flowrates, releasing over the entire range of continuous wear. Release rates could be significantly varied by the imprinting effect and functional monomer to template ratio (M/T) with M/T values 0, 0.2, 2.8, 3.4 corresponding to HPMC release durations of 10, 13, 23, and 53 days, respectively. Lenses had high optical quality and adequate mechanical properties for contact lens use. This work highlights the potential of imprinting in the design and engineering of silicone hydrogel lenses to release macromolecules for the duration of wear, which may lead to decreased CLIDE symptoms and more comfortable contact lenses. PMID- 21601275 TI - Platelet inhibition and endothelial cell adhesion on elastin-like polypeptide surface modified materials. AB - Platelet adhesion and activation are important early markers of biomaterial blood compatibility, while surfaces that promote enhanced endothelial cell adhesion and eNOS expression are strategic targets for long term vascular graft applications. Materials surface modified with fluorinated surface modifiers, containing peptides inspired from elastin cross-linking domains, have been used for the cross-linking of elastin-like polypeptide 4 (ELP4) macromolecules onto polyurethane surfaces. In the present study, ELP4 modified polyurethanes were evaluated in vitro to assess platelet adhesion, microparticle formation and bulk platelet activation following blood-material interactions. Reduced platelet adhesion and bulk platelet activation were observed following contact between reconstituted human blood and the ELP4 materials, relative to the uncoated base polyurethane controls. ELP4 modified materials also promoted endothelial cell adhesion and retention over a period of one week and showed that the endothelial cells exhibited an organized actin cytoskeleton and enhanced endothelial nitric oxide synthase (eNOS) expression relative to the control surfaces. These results indicate that polyurethane elastomers modified with ELP4 covalently bound to fluorinated surface modifiers provide a promising approach for endowing synthetic elastomers with both reduced blood platelet activation properties and enhanced endothelial cell adhesion for potential use in vascular graft applications. PMID- 21601276 TI - Stacking of aligned cell sheets for layer-by-layer control of complex tissue structure. AB - Children suffering from congenital heart defects (CHD) often require vascular reconstruction. Pediatric patients would greatly benefit from a cell-based tissue engineered vascular patch (TEVP) that has potential for growth. As artery structure and function are intimately linked, mimicking native tissue organization is an important design consideration. In this study, we cultured human mesenchymal stem cell on patterned thermo-responsive substrates. Cell alignment improved over time up to 2 wk in culture when sheets were ready for harvest. We then used cell sheets as "functional units" to build complex tissue structures that mimic native vascular smooth muscle cell organization in the medial layer of the artery. Cell sheets could be stacked using a gelatin stamp such that individual sheets in the construct were well aligned with each other (mimic of circumferential orientation) or at angles with respect to each other (mimic of herringbone structure). Controlling tissue organization layer-by-layer will be a powerful approach to building tissues with well defined and complex structure. PMID- 21601277 TI - Potential of 3-D tissue constructs engineered from bovine chondrocytes/silk fibroin-chitosan for in vitro cartilage tissue engineering. AB - The use of cell-scaffold constructs is a promising tissue engineering approach to repair cartilage defects and to study cartilaginous tissue formation. In this study, silk fibroin/chitosan blended scaffolds were fabricated and studied for cartilage tissue engineering. Silk fibroin served as a substrate for cell adhesion and proliferation while chitosan has a structure similar to that of glycosaminoglycans, and shows promise for cartilage repair. We compared the formation of cartilaginous tissue in silk fibroin/chitosan blended scaffolds seeded with bovine chondrocytes and cultured in vitro for 2 weeks. The constructs were analyzed for cell viability, histology, extracellular matrix components glycosaminoglycan and collagen types I and II, and biomechanical properties. Silk fibroin/chitosan scaffolds supported cell attachment and growth, and chondrogenic phenotype as indicated by Alcian Blue histochemistry and relative expression of type II versus type I collagen. Glycosaminoglycan and collagen accumulated in all the scaffolds and was highest in the silk fibroin/chitosan (1:1) blended scaffolds. Static and dynamic stiffness at high frequencies was higher in cell seeded constructs than non-seeded controls. The results suggest that silk/chitosan scaffolds may be a useful alternative to synthetic cell scaffolds for cartilage tissue engineering. PMID- 21601278 TI - Highly stable carbon nanotube doped poly(3,4-ethylenedioxythiophene) for chronic neural stimulation. AB - The function and longevity of implantable microelectrodes for chronic neural stimulation depends heavily on the electrode materials, which need to present high charge injection capability and high stability. While conducting polymers have been coated on neural microelectrodes and shown promising properties for chronic stimulation, their practical applications have been limited due to unsatisfying stability. Here, poly(3,4-ethylenedioxythiophene) (PEDOT) doped with pure carbon nanotubes (CNTs) was electrochemically deposited on Pt microelectrodes to evaluate its properties for chronic stimulation. The PEDOT/CNT coated microelectrodes demonstrated much lower impedance than the bare Pt, and the PEDOT/CNT film exhibited excellent stability. For both acute and chronic stimulation tests, there is no significant increase in the impedance of the PEDOT/CNT coated microelectrodes, and none of the PEDOT/CNT films show any cracks or delamination, which have been the limitation for many conducting polymer coatings on neural electrodes. The charge injection limit of the Pt microelectrode was significantly increased to 2.5 mC/cm(2) with the PEDOT/CNT coating. Further in vitro experiments also showed that the PEDOT/CNT coatings are non-toxic and support the growth of neurons. It is expected that this highly stable PEDOT/CNT composite may serve as excellent new material for neural electrodes. PMID- 21601279 TI - Aggregation-enhanced fluorescence in PEGylated phospholipid nanomicelles for in vivo imaging. AB - We report polymeric nanomicelles doped with organic fluorophores (StCN, (Z)-2,3 bis[4-(N-4-(diphenylamino)styryl)phenyl]-acrylonitrile), which have the property of aggregation-enhanced fluorescence. The fluorescent nanomicelles have two unique features: (1) They give much brighter fluorescence emission than mono fluorophores. (2) The nanomicelles with amphiphilic copolymers [e.g., phospholipids-PEG (polyethylene glycol)] make the encapsulated fluorophores more stable in various bio-environments and easy for further conjugation with bio molecules. After chemical and optical characterization, these fluorescent nanomicelles are utilized as efficient optical probes for in vivo sentinel lymph node (SLN) mapping of mice. The StCN-encapsulated nanomicelles, as well as their bioconjugates with arginine-glycine-aspartic acid (RGD) peptides, are used to target subcutaneously xenografted tumors in mice, and in vivo fluorescence images demonstrate the potential to use PEGylated phospholipid nanomicelles with aggregation-enhanced fluorescence as bright nanoprobes for in vivo diagnosis of tumors. PMID- 21601280 TI - Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis. AB - A variety of stimuli utilize an increase of cytosolic free Ca(2+) concentration as a second messenger to transmit signals, through Ca(2+) release from the endoplasmic reticulum or opening of plasma membrane Ca(2+) channels. Mitochondria contribute to the tight spatiotemporal control of this process by accumulating Ca(2+), thus shaping the return of cytosolic Ca(2+) to resting levels. The rise of mitochondrial matrix free Ca(2+) concentration stimulates oxidative metabolism; yet, in the presence of a variety of sensitizing factors of pathophysiological relevance, the matrix Ca(2+) increase can also lead to opening of the permeability transition pore (PTP), a high conductance inner membrane channel. While transient openings may serve the purpose of providing a fast Ca(2+) release mechanism, persistent PTP opening is followed by deregulated release of matrix Ca(2+), termination of oxidative phosphorylation, matrix swelling with inner membrane unfolding and eventually outer membrane rupture with release of apoptogenic proteins and cell death. Thus, a rise in mitochondrial Ca(2+) can convey both apoptotic and necrotic death signals by inducing opening of the PTP. Understanding the signalling networks that govern changes in mitochondrial free Ca(2+) concentration, their interplay with Ca(2+) signalling in other subcellular compartments, and regulation of PTP has important implications in the fine comprehension of the main biological routines of the cell and in disease pathogenesis. PMID- 21601281 TI - Being bullied in childhood and disruptive behaviors in the medical setting in adulthood. PMID- 21601282 TI - Concentration and potential health risk of heavy metals in market vegetables in Chongqing, China. AB - Concentration and daily intake (DI) of heavy metals (Pb, Zn, Mn, Cu, Cd and Cr) in market vegetables in Chongqing of China are investigated and their potential health risk for local consumers is simultaneously evaluated by calculating the target hazard quotient (THQ). The results showed that the measured Pb and Cd concentrations exceeded the safety limits given by FAO/WHO and Chinese regulations, indicating serious contamination of market vegetables by these metals. As respective DI values for Pb, Mn and Cd were also above the international guideline bases, health risk to the consumers is obvious. The individual THQ for Pb and Cd in pakchoi and Cd in mustard, and the combined THQ for all metals in each vegetable species excluding cos lettuce were above the threshold 1.0, implying the obviously adverse effect on health. Therefore, attention should be paid particularly to the potential hazardous exposure to vegetable heavy metals, especially for Pb and Cd, over a lifetime for people in Chongqing. PMID- 21601283 TI - Systematic review of pentachlorophenol occurrence in the environment and in humans in China: not a negligible health risk due to the re-emergence of schistosomiasis. AB - Pentachlorophenol (PCP) has been widely used for killing snails in areas of China where schistosomiasis is epidemic. With the re-emergence of schistosomiasis, the warranted production and consumption of PCP has inevitably resulted in persistent environmental contamination by it and its impurities, polychlorinated dibenzo-p dioxins and dibenzofurans (PCDD/Fs). This study aimed to evaluate the contamination status and human burden of PCP and its impurities (PCDD/Fs) in China, considering the previous epidemic and re-emergence of schistosomiasis. We searched studies relevant to PCP occurrence in the environment and in humans in China. Data on snail elimination areas were included to estimate PCP consumption. Relevant publications were analyzed to distinguish PCDD/Fs contamination from PCP usage. PCP contamination was detected ubiquitously in various environmental media and in human samples; environmental levels were generally low, with the exception of some hot spots. In schistosomiasis-epidemic areas, there were significantly higher PCP levels in the environment and in humans than in control areas. Spatial disparities indicated the consistency between serious schistosomiasis epidemic areas and hot spots of PCP contamination. The data suggest an increased trend in PCP contamination of the environment. Specific PCDD/Fs contamination from PCP usage existed even at low environmental levels. The occurrence of PCP in the environment and in humans positively correlated with the epidemic of schistosomiasis. Thyroid-disrupting effects and cancer risk caused by PCP and PCDD/Fs even at low environmental levels in China's schistosomiasis-epidemic areas are of concern. PMID- 21601284 TI - The clustering and transmission dynamics of pandemic influenza A (H1N1) 2009 cases in Hong Kong. AB - OBJECTIVES: Human influenza A (H1N1) 2009 has caused severe epidemics in many countries, but its dynamics in spatial and temporal contexts have so far been poorly appreciated. METHODS: A total of 24,414 laboratory confirmed human influenza A (H1N1) 2009 cases reported from May to September 2009 in Hong Kong were evaluated, using a Geographic Information System (GIS)-based approach. Spatio-temporal clustering was assessed after dividing Hong Kong into 4 geographic sectors, 18 districts and 500 m * 500 m cells. Global Moran's I, Local Moran's I and SaTScanTM were used in the exploration. RESULTS: Spatio-temporal clusters first appeared on Hong Kong Island at week 3, alongside multiple foci suggestive of infection nidus introduced from abroad. The clusters grew rapidly and became confluent in urban areas, lasting till week 22. Separately, local clusters emerged in the North representing second or third generation infections, which died down over a relatively short period of time. CONCLUSION: Heterogeneity of spatio-temporal clustering of H1N1 was demonstrated during the epidemic, despite the small area of the territory of Hong Kong. The dynamics could have been shaped by population mobility at a local level. The application of GIS in epidemiology studies can add value to standard surveillance activities. PMID- 21601285 TI - 16S rDNA sequencing of valve tissue improves microbiological diagnosis in surgically treated patients with infective endocarditis. AB - OBJECTIVES: The aim was to evaluate 16S rDNA sequencing in heart valves in patients with infective endocarditis undergoing surgery. METHODS: Fifty-seven patients with infective endocarditis were examined in this prospective study by analysing heart valves with 16S rDNA sequencing and culturing methods and comparing the results to blood cultures. As controls, heart valves from 61 patients without any signs of endocarditis were examined. RESULTS: All together 77% of the endocarditis patients were positive for 16S rDNA, 84% had positive blood cultures and 23% had positive cultures from heart valves, whereas only 16% of the cultures from heart valves were concordant with results from blood cultures or 16S rDNA. Concordant results between 16S rDNA sequencing and blood cultures were found in 75% patients. All controls were negative for 16S rDNA. In 4 out of 9 patients with negative blood cultures, the aetiology was established by 16S rDNA alone, i.e. viridans group streptococci. CONCLUSION: In this Swedish study, 16S rDNA sequencing of valve material was shown to be a valuable addition in blood culture-negative cases. The value of heart valve culture was low. Molecular diagnosis using 16S rDNA sequencing should be recommended in patients undergoing valve replacement for infective endocarditis. PMID- 21601286 TI - Suicide and suicide attempts in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). AB - BACKGROUND: The current report describes individuals with bipolar disorder who attempted or completed suicide while participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. METHODS: Baseline and course features of individuals with suicide events are described. RESULTS: Among the 4360 people with bipolar disorder enrolled, 182 individuals made 270 prospectively observed suicidal acts, including 8 completed suicides. This represents a suicide rate of .014 per 100 person years in STEP-BD, which included frequent clinical visits, evidence based care, and standardized assessment at each patient contact. Approximately 1/3 of those who attempted suicide had more than one attempt during study participation. Those who completed suicide tended to do so early in study participation, and half of them did so on their first attempt. LIMITATIONS: While this study is limited to description of individuals and precipitants of completed suicides and attempts in STEP-BD, further analyses are planned to explore risk factors and potential interventions for prevention of suicidal acts in persons with bipolar disorder. CONCLUSIONS: Persons with bipolar disorder are at high risk for suicide. Overall rates of suicide events in STEP-BD were lower than expected, suggesting that the combination of frequent clinical visits (i.e., access to care), standardized assessment, and evidence-based treatment were helpful in this population. PMID- 21601287 TI - Randomized comparison of selective serotonin reuptake inhibitor (escitalopram) monotherapy and antidepressant combination pharmacotherapy for major depressive disorder with melancholic features: a CO-MED report. AB - BACKGROUND: The clinical effects of antidepressant combinations vs. monotherapy as initial treatment for major depression with melancholic features (MDD-MF) are unknown. METHODS: Outpatients with chronic or recurrent major depression (MDD) were randomized to initial treatment with escitalopram+placebo (the MONO condition), bupropion-sustained release+escitalopram, or venlafaxine-extended release+mirtazapine (the COMB conditions) in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial. Secondary data analyses were conducted to compare demographic and clinical characteristics, and contrast clinical responses according to drug treatment, in patients with MDD-MF (n=124) and non-melancholic MDD (n=481). RESULTS: While numerically lower, remission rates in MDD-MF did not differ significantly from those with non-melancholic MDD either at 12 (33.1% vs. 41.0%, aOR 1.16, p=0.58) or 28 (39.5% vs. 46.8%, aOR=1.02, p=0.93) weeks of treatment. Remission rates did not differ significantly between combination and monotherapy groups in either MDD-MF or non-melancholic MDD patients at either time point. Similar conclusions were reached for response rates, premature study discontinuation, and self-rated depression symptom severity. LIMITATIONS: This is a secondary analysis of data from the CO-MED trial, which was not designed to address differential treatment response in melancholic and non-melancholic MDD. CONCLUSIONS: We found no evidence of differential remission or response rates to antidepressant combination or monotherapy between melancholic/non-melancholic MDD patients, or according to antidepressant treatment group, after 12 and 28 weeks. Melancholic features may not be a valid predictor of more favorable response to antidepressant combination therapy as initial treatment. PMID- 21601288 TI - Psychometric value of the Center for Epidemiologic Studies Depression (CES-D) scale for screening of depressive symptoms in Armenian population. AB - BACKGROUND: This study examined the psychometric value of the Center for Epidemiologic Studies Depression Scale (CES-D) translated for use with an Armenian population. METHODS: Using data obtained from a country-wide health survey of 2310 households involving female and male respondents aged 18 and over, we investigated the response pattern to the CES-D items, the factor structure, internal consistency, inter-item correlations of the total scale and its negatively and positively formulated subscales. We used logistic regression analysis to relate the constructs measured by the CES-D and its subscales to known determinants of depression. RESULTS: Armenian respondents of both genders significantly suppressed their positive emotions, thus over-endorsing positively formulated (reverse-coded) items, therefore producing artificially high depression scores. Factor analysis of the scale yielded a three-factor structure (combined Depressed/Somatic, Positive Affect, and Interpersonal). The Positive Affect factor correlated weakly with the other two factors, and its inclusion reduced the internal consistency of the whole scale. Unlike the 16-item subscale of negatively formulated items, Positive Affect was not related to several known determinants of depression and did not reflect known depression-specific differences between genders. The set of determinants of Positive Affect included mainly lifestyle and attitudinal variables. LIMITATIONS: This study did not assess the concurrent and discriminate validity of the Armenian CES-D. CONCLUSIONS: For Armenians, the construct measured by the four Positive Affect items of CES-D is not related to depressive symptoms as measured by the other items. It introduces ethnical/cultural response bias in CES-D score and reduces the cross-cultural comparability of the latter. PMID- 21601289 TI - Damage to the right dorsal anterior cingulate cortex induces panic disorder. AB - Brain imaging studies suggest that panic disorder (PD) is mediated by several brain regions, including the anterior cingulate cortex (ACC). In the present report we describe a patient who experienced a panic attack during awake surgery (case 1) and another patient who developed PD after surgery and radiotherapy (case 2). In case 1, the patient experienced repeated panic attacks when the tumor at the upper border of right dorsal ACC was removed during awake surgery. In case 2, the patient developed PD at six months after surgery and Cyberknife radiotherapy. MRI examination revealed that the dorsal ACC size was reduced at six months after surgery and that the dorsal ACC was absent at two years after surgery, possibly due to radiotherapy-induced damage by radiotherapy. Profile of mood states (POMS) testing characterized the presence of tension-anxiety as the common abnormal symptom in cases 1 and 2. In conclusion, these results suggest that damage to the right dorsal ACC can induce PD and that this structure likely plays a pathophysiologic role in PD. PMID- 21601290 TI - Association between the TPH1 A218C polymorphism and risk of mood disorders and alcohol dependence: evidence from the current studies. AB - BACKGROUND: Several studies have assessed the association between genetic polymorphisms of tryptophan hydroxylase (TPH1) and risk of mood disorders and alcohol dependence, with controversial results. Our aim was to assess the association of TPH1 A218C polymorphism (rs1800532) with mood disorders, including major depressive disorder and bipolar disorder, and alcohol dependence by using meta-analysis. METHODS: Data were collected from the related literatures published until November 25, 2010 from MEDLINE, EMBASE and ISI Web of Science databases, and meta-analysis stratified by ethnicity was performed in either fixed or random effect model as appropriate by using Stata Statistical Package (version 10.0). RESULTS: Twenty-seven individual studies were included in the current study, among which, there were 9 studies for bipolar disorder, with 1951 cases and 2161 controls, 14 studies for major depressive disorder, with 2340 cases and 3204 controls, and 4 studies for alcohol dependence, with 601 cases and 711 controls. We found that in Caucasian population, the TPH1 218AA genotype was significantly associated with increased bipolar disorder risk (recessive comparison: OR, 1.42; Bonferroni-adjusted P=0.006; homozygote comparison: OR, 1.63; Bonferroni-adjusted P=0.072), and elevated alcohol dependence risk (recessive comparison: OR, 1.83; Bonferroni-adjusted P=0.012), while the association was not significant in Asian population. Moreover, the A218C polymorphism did not appear to have any effect on major depressive disorder risk either in Caucasians or in Asians. CONCLUSION: The TPH1 A218C polymorphism is a potential biomarker for bipolar disorder and alcohol dependence risk in Caucasian population. PMID- 21601291 TI - Age-specific 3-month cumulative incidence of postpartum depression: the Hamamatsu Birth Cohort (HBC) Study. AB - BACKGROUND: The prevalence of postpartum depression (PPD) in the general population has been reported to be 10% to 15% worldwide. However, the relevance of age of the parturients to the emergence of PPD has not been well documented. To address this, we estimated the age-specific 3-month cumulative incidence of PPD using the Hamamatsu Birth Cohort for Mothers and Children (HBC). METHODS: Women with PPD were defined as those scoring 9 points or higher using the Edinburgh Postnatal Depression Scale 3 months after childbirth. RESULTS: Among 675 participating parturients, 100 women were found to have PPD; the cumulative incidence of PPD over the 3 months after childbirth was 14.8%. The age-specific estimates were 20.8% for <25 years, 14.2% for 25 to 29 years, 11.5% for 30 to 34 years, and 17.9% for >= 35 years. In the logistic regression analysis, the increased OR for having PPD among parturients aged >= 35 years was 1.7, which remained significant after controlling for age of partner, parity, and household income. LIMITATIONS: Although the sample was representative, the sample size was modest. CONCLUSION: The cumulative incidence of PPD was significantly different across age groups, with the highest estimates in the advanced age band. The heightened estimate was not accounted for by the age of the partner, parity, or annual household income. PMID- 21601292 TI - Receptor targets for antidepressant therapy in bipolar disorder: an overview. AB - The treatment of bipolar depression is one of the most challenging issues in contemporary psychiatry. Currently only quetiapine and the olanzapine-fluoxetine combination are officially approved by the FDA against this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain relatively elusive. We performed a complete and systematic review to identify agents with definite positive or negative results concerning efficacy followed by a second systematic review to identify the pharmacodynamic properties of these agents. The comparison of properties suggests that the stronger predictors for antidepressant efficacy in bipolar depression were norepinephrine alpha-1, dopamine D1 and histamine antagonism, followed by 5 HT2A, muscarinic and dopamine D2 and D3 antagonism and eventually by norepinephrine reuptake inhibition and 5HT-1A agonism. Serotonin reuptake which constitutes the cornerstone in unipolar depression treatment does not seem to play a significant role for bipolar depression. Our exhaustive review is compatible with a complex model with multiple levels of interaction between the major neurotransmitter systems without a single target being either necessary or sufficient to elicit the antidepressant effect in bipolar depression. PMID- 21601294 TI - In situ characterization of the granulomatous immune response with time in nonhealing lesional skin of Leishmania braziliensis-infected rhesus macaques (Macaca mulatta). AB - We have recently introduced a macaque (Macaca mulatta) model of Leishmania braziliensis-induced self-healing cutaneous leishmaniasis in which the T cell mediated inflammatory response effectively promotes parasite clearance and granuloma resolution. Here we show that macaques infected with a highly pathogenic L. braziliensis strain displayed longstanding granulomatous lesions which lasted until the end of the observation period (52 weeks). Immunoperoxidase staining of representative tissue sections indicated that distinct cell populations (CD3, CD4, CD8, CD20, Foxp3, CD20, CD68, HLA-DR, CCL2, and CXCL-10) change uniformly during infection, suggesting that the same components of the local immune response are working in unison. This model also confirmed that granuloma formation is orchestrated by diverse inflammatory mediators that are important for T helper type 1 (Th1) cell development and macrophage effector functions. Cytometry analysis of ex vivo granuloma-derived leukocytes revealed accumulation of distinct functional subsets of effector and regulatory T cells into the inflamed skin. We provide evidence that local interleukin (IL)-10 production by both Foxp3(+) and Foxp3(-) CD4(+) T subsets is likely important in promoting lesional granuloma maintenance. Further studying the immune suppression mechanisms that induces granulomas in L. braziliensis-infected macaques may reveal new opportunities for therapeutic control of this important human disease. PMID- 21601293 TI - Delayed sleep phase syndrome is related to seasonal affective disorder. AB - BACKGROUND: Both delayed sleep phase syndrome (DSPS) and seasonal affective disorder (SAD) may manifest similar delayed circadian phase problems. However, the relationships and co-morbidity between the two conditions have not been fully studied. The authors examined the comorbidity between DSPS and SAD. METHODS: We recruited a case series of 327 DSPS and 331 controls with normal sleep, roughly matched for age, gender, and ancestry. Both DSPS and controls completed extensive questionnaires about sleep, the morningness-eveningness trait, depression, mania, seasonality of symptoms, etc. RESULTS: The prevalences of SAD and subsyndromal SAD (S-SAD) were higher in DSPS compared to controls (chi(2)=12.65, p=0.002). DSPS were 3.3 times more likely to report SAD (odds ratio, 3.34; 95% CI, 1.41 7.93) compared to controls as defined by the Seasonal Pattern Assessment Questionnaire (SPAQ). Correspondingly, DSPS showed significantly higher seasonality scores compared to controls in mood, appetite, and energy level subscores and the global seasonality score (t=3.12, t=0.002; t=2.04, p=0.041; t=2.64, p=0.008; and t=2.15, p=0.032, respectively). Weight fluctuation during seasons and winter-summer sleep length differences were also significantly higher in DSPS than controls (t=5.16, p<0.001 and t=2.64, p=0.009, respectively). SAD and S-SAD reported significantly higher eveningness, higher depression self ratings, and more previous mania symptoms compared to non-seasonal subjects regardless of whether they were DSPS or controls. CONCLUSIONS: These cases suggested that DSPS is partially comorbid with SAD. These data support the hypothesis that DSPS and SAD may share a pathophysiological mechanism causing delayed circadian phase. PMID- 21601295 TI - Twin study on transplacental-acquired antibodies and attention deficit/hyperactivity disorder--a pilot study. AB - OBJECTIVE: We hypothesize that maternal transplacentally acquired antibodies may cause Attention Deficit/Hyperactivity Disorder (ADHD) symptoms years after birth, and tested the hypothesis in twins discordant for ADHD symptoms. METHOD: In a pre screened sample of 7793 same sex twin pair's (4-18 years) questionnaire data on hyperactivity and inattention was collected. Blood samples taken 5 days after birth from 190 ADHD-score discordant pairs (15% MZ) were analyzed for antibodies. RESULTS: Pneumococcus Polysaccaride 14 (PnPs14) was present in the ADHD high scoring twin more often than in the lower scoring twin (P=0.04). CONCLUSION: Although the study provides no strong support for the hypothesis, infection or immunological factors may be one among several causes of ADHD. The genetic control obtained in a twin design may reduce the exposure contrast and a larger sample is needed to further explore the role of PnPs14 in the etiology of ADHD. PMID- 21601296 TI - Secondary prevention in coronary artery disease. Achieved goals and possibilities for improvements. AB - AIM: To describe presence of risk indicators of recurrence 6 months after hospitalisation due to coronary artery disease at a university clinic. METHODS: The presence of risk indicators, including tobacco use, lipid levels, blood pressure and glucometabolic status, including 24-hour blood pressure monitoring and an oral glucose-tolerance test, was analysed. RESULTS: Of 1465 patients who were screened, 402 took part in the survey (50% previous myocardial infarction and 50% angina pectoris). Mean age was 64 years (range 40-85 years) and 23% were women. Present medications were: lipid lowering drugs (statins; 94%), beta blockers (85%), aspirin or warfarin (100%) and ACE-inhibitors or angiotensin II blockers (66%). Values above target levels recommended in guidelines were: a) low density lipoprotein (LDL) in 40%; b) mean blood pressure (day or night) in 38% and c) smoking in 13%. Of all patients, 66% had at least one risk factor (LDL or blood pressure above target levels or current smoking). An abnormal glucose tolerance test was found in 59% of patients without known diabetes. If no history of diabetes, 85% had either LDL or blood pressure above target levels, current smoking or an abnormal glucose-tolerance test. However, with treatment intensification to patients with elevated risk factors 56% reached target levels for blood pressure and 79% reached target levels for LDL. CONCLUSION: Six months after hospitalisation due to coronary artery disease, despite the high use of medication aimed at prophylaxis against recurrence, the majority were either above target levels for LDL or blood pressure or continued to smoke. PMID- 21601297 TI - Advances in farm animal transgenesis. AB - The first transgenic livestock were produced in 1985 by microinjection of foreign DNA into zygotic pronuclei. This was the method of choice for more than 20 years, but more efficient protocols are now available, including somatic cell nuclear transfer and lentiviral transgenesis. Typical applications include carcass composition, lactational performance and wool production, as well as enhanced disease resistance and reduced environmental impact. Transgenic farm animal production for biomedical applications has found broad acceptance. In 2006 the European Medicines Agency (EMA) approved commercialization of the first recombinant pharmaceutical protein, antithrombin, produced in the mammary gland of transgenic goats. As the genome sequencing projects for various farm animal species are completed, it has become feasible to perform precise genetic modifications employing the emerging tools of lentiviral vectors, small interfering ribonucleic acids, meganucleases, zinc finger nucleases and transposons. We anticipate that genetic modification of farm animals will be instrumental in meeting global challenges in agricultural production and will open new horizons in biomedicine. PMID- 21601298 TI - Risk assessment in animal welfare - especially referring to animal transport. AB - The increasing awareness of animal welfare in public and science induces a need for objective evaluation. Particularly animal welfare during transport is discussed due to the variable transport conditions in Europe. Therefore an objective evaluation of animal transport is relevant and the first attempts to develop animal welfare risk assessment guidelines for animal transport are made. A report of the development of a guideline on animal welfare risk assessment during animal transport (Dalla Villa et al., 2009) bases on other recent reports and guidelines of animal welfare risk assessment published by EFSA (2009) and adapts the method to animal transport condition. For the implementation of a model for quantitative risk assessment, transport conditions were defined to develop multiple scenarios. Hazard identification was prepared for each scenario and for three selected scenarios a complete risk assessment was performed. Within the exemplary risk assessment potential hazards were initially identified and furthermore hazard description and exposure assessment were evaluated by expert opinion which resulted in risk characterisation. Within risk characterisation of each hazard, magnitude and risk estimate were calculated to afford an individual ranking of these values in order to obtain a graphical illustration of the ten highest estimated risks. PMID- 21601299 TI - Economics of individualization in comparative effectiveness research and a basis for a patient-centered health care. AB - The United States aspires to use information from comparative effectiveness research (CER) to reduce waste and contain costs without instituting a formal rationing mechanism or compromising patient or physician autonomy with regard to treatment choices. With such ambitious goals, traditional combinations of research designs and analytical methods used in CER may lead to disappointing results. In this paper, I study how alternate regimes of comparative effectiveness information help shape the marginal benefits (demand) curve in the population and how such perceived demand curves impact decision-making at the individual patient level and welfare at the societal level. I highlight the need to individualize comparative effectiveness research in order to generate the true (normative) demand curve for treatments. I discuss methodological principles that guide research designs for such studies. Using an example of the comparative effect of substance abuse treatments on crime, I use novel econometric methods to salvage individualized information from an existing dataset. PMID- 21601300 TI - Descending control to the nonparetic limb degrades the cyclic activity of paretic leg muscles. AB - During anti-phased locomotor tasks such as cycling or walking, hemiparetic phasing of muscle activity is characterized by inappropriate early onset of activity for some paretic muscles and prolonged activity in others. Pedaling with the paretic limb alone reduces inappropriate prolonged activity, suggesting a combined influence of contralesional voluntary commands and movement-related sensory feedback. Five different non-target leg movement state conditions were performed by 15 subjects post-stroke and 15 nonimpaired controls while they pedaled with the target leg and EMG was recorded bilaterally. Voluntary engagement of the non-lesioned motor system increased prolonged paretic vastus medialis (VM) activity and increased phase-advanced rectus femoris (RF) activity. We suggest bilateral descending commands are primarily responsible for the inappropriate activity in the paretic VM during anti-phase pedaling, and contribute to the dysfunctional motor output in the paretic RF. Findings from controls suggest that even an undamaged motor system can contribute to this phenomenon. PMID- 21601301 TI - Hierarchical control in redundant and non-redundant postural tasks. AB - Prior studies of postural coordination have shown inconsistencies between hip ankle coordination in redundant and non-redundant coordination tasks as well as predictions of the HKB model. These inconsistencies were investigated by testing the hypothesis that there are different hierarchical control structures for redundant (multiple potential task solutions) and non-redundant (a single task solution) coordination tasks (Bernstein, 1996). The transfer between a non redundant postural tracking task and a redundant scanning task consisting of 16 hip-ankle relative phase patterns from 0 degrees to 337.5 degrees was investigated. The results showed that the transfer between the tasks was transitory, negative and occurred only from the non-redundant to the redundant task. This finding supports the hypothesis that inconsistencies between redundant and non-redundant coordination dynamics may be due to a hierarchical relation between control structures for the performance of these types of tasks. PMID- 21601302 TI - Chemical composition, cytotoxicity effect and antimicrobial activity of Ceratonia siliqua essential oil with preservative effects against Listeria inoculated in minced beef meat. AB - The present study describes the phytochemical profile and the protective effects of Ceratonia siliqua pods essential oil (CsEO), a food and medicinal plant widely distributed in Tunisia. Twenty five different components were identified in the CsEO. Among them, the major detected components were: Nonadecane, Heneicosane , Naphthalene, 1,2-Benzenedicarboxylic acid dibutylester, Heptadecane, Hexadecanoic acid, Octadecanoic acid, 1,2-Benzenedicarboxylic acid, Phenyl ethyl tiglate, Eicosene, Farnesol 3, Camphor, Nerolidol and n-Eicosane. The antimicrobial activity of CsEO was evaluated against a panel of 13 bacteria and 8 fungal strains using agar diffusion and broth microdilution methods. Results have shown that CsEO exhibited moderate to strong antimicrobial activity against the tested species. In addition, the inhibitory effect of this CsEO was evaluated in vivo against a foodborne pathogens Listeria monocytogenes, experimentally inoculated in minced beef meat (2*10(2) CFU/g of meat) amended with different concentrations of the CsEO and stored at 7 degrees C for 10 days. The antibacterial activity of CsEO in minced beef meat was clearly evident and its presence led to a strong inhibitory effect against the pathogens at 7 degrees C. On the other hand, the cytotoxic effects of the essential oil against two tumoral human cell lines HeLa and MCF-7 were examined by MTT assay. The CsEO showed an inhibition of both cell lines with significantly stronger activity against HeLa cells. The IC(50) values were 210 and 800 MUg/ml for HeLa and MCF-7 cells, respectively. Overall, results presented here suggest that the EO of C. siliqua possesses antimicrobial and cytotoxic properties, and is therefore a potential source of active ingredients for food and pharmaceutical industry. PMID- 21601303 TI - Optimization of scheduling patient appointments in clinics using a novel modelling technique of patient arrival. AB - This paper re-visits the question of mapping a probability distribution to patient unpunctuality in appointment-driven outpatient clinics, with reference to published empirical arrival data. This data indicates the possibility of interesting aberrations such as local modes and near-modes, asymmetry and peakedness. We examine the form of some published data on patient unpunctuality, and propose a mixed distribution which we call "F3" to provide a richer representation of shape such as in the shoulders of the distribution. The adequacy of this model is assessed in a worked example referencing a classical study, where a comparison is made of F3 against the normal and Pearson VII distributions with reference to summary statistics, graphical probability plots (P-P and Q-Q), a range of goodness of fitness criteria. Under this patient arrival setting, 2P method is proposed for optimal patient interval setting to minimize waiting time of both patient and the doctor and this 2P method is validated with a tentative simulation example. This study argues that frequency distribution of patient unpunctuality shows asymmetry in shape which is resulted from various types of arrival behaviours. Consequently optimal appointment intervals of scheduled patients, which minimize the total waiting time of patients and the doctor is highly related to patient unpunctuality patterns and this makes the optimal appointment intervals for various patient unpunctualities predictable. PMID- 21601304 TI - The balance between the expressions of hASH1 and HES1 differs between large cell neuroendocrine carcinoma and small cell carcinoma of the lung. AB - To clarify the biological differences between small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), we investigated the expression of two bHLH type transcription factors, human achaete-scute homolog 1 (hASH1) and hairy/enhancer of split 1 (HES1), which positively and negatively regulate the neuroendocrine differentiation of respiratory epithelial cells, respectively. Eighty-eight formalin-fixed and paraffin-embedded pulmonary carcinomas (32 SCLC, 32 LCNEC, 14 adenocarcinomas, and 10 squamous cell carcinomas) and 14 SCLC and 1 LCNEC derived cell lines were used. hASH1 and HES1 mRNA were detected using a highly sensitive in situ hybridization method with digoxigenin-labeled cRNA probes and biotinylated tyramide. The staining results were scored from 0 to 12 by multiplying the staining intensity by the percentage of positive tumor cells. The mean staining score of hASH1 mRNA was significantly higher in SCLC than in LCNEC (p<0.01); conversely, that of HES1 mRNA was lower in SCLC than in LCNEC (p<0.01). These findings reveal that SCLC more strongly expresses the neuroendocrine phenotype, while LCNEC shows characteristics more similar to the ciliated epithelium phenotype, suggesting that the biological characteristics of these two tumors are different. PMID- 21601305 TI - Tumor-associated macrophages provide a suitable microenvironment for non-small lung cancer invasion and progression. AB - OBJECTIVE: It remains largely unknown whether tumor-associated macrophages (TAMs) are involved in invasion and metastasis of human lung cancer. The aim of our study was to obtain an accurate overview of the broad range of changes occurring in monocytes that develop into TAMs, and the roles of TAMs during the progression of non-small cell lung cancer. METHODS: TAM was isolated from 98 primary lung cancer tissues by short term cultivation in serum-free medium. The mRNA expression levels of 9 genes, including EGF, Cathepsin K, Cathepsin S, COX-2, MMP 9, PDGF, uPA, VEGFA, HGF, were evaluated by real-time PCR in 98 NSCLC. The relationships between those gene expression levels and clinicopathological features were investigated. The effects of conditioned medium from TAMs on the invasive properties of different lung cancer cell lines were measured using Transwell chambers. RESULTS: We successfully achieved up to 95% purity of TAM, derived from 98 primary lung cancer tissues. TAM expressed high levels of Cathepsin K, COX-2, MMP-9, PDGF-B, uPA, VEGFA, and HGF. Phenotypic expression on TAMs, like MMP9, was shown to be correlated with disease progression by analyzing lung cancer tissues. Conditioned medium from TAM significantly increased cell migration and invasion in SPC-A1 cells, H460 cells and A549 cells. Anti-uPA and anti-MMP-9, but not anti-VEGF monoclonal antibodies, can inhibit TAM-induced invasion. The increase of invasiveness in the lung cancer cell lines was also correlated with their gelatinase activity, through MMP9. CONCLUSIONS: Short-term culture in serum free medium is an effective way to isolate TAM in NSCLC. The results of this study also demonstrated that those up-regulated genes in TAMs contributed to suitable microenvironments for lung cancer invasion and metastasis. These findings may be useful in developing novel therapeutic strategies to prevent lung cancer progression. PMID- 21601306 TI - A proposed unified framework for biological invasions. AB - There has been a dramatic growth in research on biological invasions over the past 20 years, but a mature understanding of the field has been hampered because invasion biologists concerned with different taxa and different environments have largely adopted different model frameworks for the invasion process, resulting in a confusing range of concepts, terms and definitions. In this review, we propose a unified framework for biological invasions that reconciles and integrates the key features of the most commonly used invasion frameworks into a single conceptual model that can be applied to all human-mediated invasions. The unified framework combines previous stage-based and barrier models, and provides a terminology and categorisation for populations at different points in the invasion process. PMID- 21601307 TI - Can YKL-40 be a new inflammatory biomarker in cardiovascular disease? AB - Coronary artery disease is the most common background of death in western countries. Medical therapies and revisualization by percutaneous coronary intervention or coronary by-pass surgery have reduced the mortality significantly. However, many of the treated patients still have angina or heart failure symptoms, many hospitalisations and a poor prognosis. Therefore, there is need for identifying new biomarkers, which alone or in combination with other risk markers are useful in monitoring treatment and as prognostic markers for future cardiovascular events in patients with ischemic heart disease. The inflammatory biomarker YKL-40 has recently been found elevated in patients with both acute and stable chronic cardiovascular diseases. Therefore, YKL-40 could potentially be a new useful biomarker of disease severity, prognosis and survival in patients with ischemic heart disease. The review will present published information about YKL40 in cardiac patients and discuss whether YKL-40 could be used for monitoring the therapies and for prognostic evaluations in patients with cardiovascular disease. PMID- 21601308 TI - A synthetic peptide homologous to IL-10 functional domain induces monocyte differentiation to TGF-beta+ tolerogenic dendritic cells. AB - We have previously demonstrated that IT9302, a nonameric peptide homologous to the C-terminal domain of human IL-10, mimics several effects of the cytokine including down-regulation of the antigen presentation machinery and increased sensitivity of tumor cells to NK-mediated lysis. In the present report, we have explored a potential therapeutic utility for IT9302 related to the ex vivo production of tolerogenic dendritic cells (DCs). Our results indicate that IT9302 impedes human monocyte response to differentiation factors and reduces antigen presentation and co-stimulatory capacity by DCs. Additionally, peptide-treated DCs show impaired capacity to stimulate T-cell proliferation and IFN-gamma production. IT9302 exerts its effect through mechanisms, in part, distinct from IL-10, involving STAT3 inactivation and NF-kappaB intracellular pathway. IT9302 treated DCs display increased expression of membrane-associated TGF-beta, linked to a more effective induction of foxp3+ regulatory T cells. These results illustrate for the first time that a short synthetic peptide can promote monocytes differentiation to tolerogenic DCs with therapeutic potential for the treatment of autoimmune and transplantation-related immunopathologic disease. PMID- 21601309 TI - Interaction between oxidative stress and chemokines: possible pathogenic role in systemic lupus erythematosus and rheumatoid arthritis. AB - Imbalance oxidative stress and chemokines are considered as a universal factors involved in the development of various clinical features seen in the patients with SLE and arthritis. To evaluate the interaction between oxidative stress and chemokines and their relationship with disease activity in SLE and RA patients, oxidative/anti-oxidant profiles and chemokines were assessed. Oxidant and anti oxidant enzymes were measured in the plasma and the levels of chemokines; MCP 1/CCL2, RANTES/CCL5, MIP-1beta/CCL-4 and IP-10/CXCL-10 were evaluated in the serum by an enzyme-linked immunosorbent assay (ELISA). A significant increase in the level of lipid peroxidation was found in SLE and RA patients and positively associated with disease activity. The activities of anti-oxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and anti oxidant molecule GSH were significantly reduced in both diseases. Strong positive associations were found between MDA with RANTES/CCL5 and MIP-1beta/CCL4 than MCP 1/CCL-2 in SLE patients while a sturdy connotation was seen with MIP-1beta/CCL4 and MCP-1/CCL-2 in RA patients. The anti-oxidant molecule GSH shows a negative association with serum levels of MCP-1/CCL-2, RANTES/CCL5 and IP-10/CXCL-10 in SLE patients and with MCP-1/CCL-2 and RANTES/CCL5 in RA patients. A low level of GSH and high level of RANTES/CCL5 were associated with lupus nephritis patients. These results indicates that excessive production of ROS disturbs redox status and can modulate the expression of inflammatory chemokines leading to inflammatory processes, exacerbating inflammation and affecting tissue damage in autoimmune diseases, as exemplified by their strong association with disease activity. PMID- 21601310 TI - Pompholyx and eczematous reactions associated with intravenous immunoglobulin therapy. AB - INTRODUCTION: Intravenous immunoglobulin (IVIG) is used to treat many inflammatory and autoimmune disorders and although generally well tolerated, cutaneous side effects occur. OBJECTIVE: We reviewed reports of pompholyx and eczematous reactions associated with IVIG. METHODS: A literature search was performed using the PubMed and MEDLINE databases with the search terms "intravenous immunoglobulin pompholyx," "intravenous immunoglobulin eczema," "intravenous immunoglobulin cutaneous adverse effects," "intravenous immunoglobulin cutaneous effects," "intravenous immunoglobulin skin effects," and "intravenous immunoglobulin adverse effects." Relevant English-language articles or articles in other languages cited in English-language articles were included. RESULTS: We identified 64 cases of eczematous reactions associated with IVIG therapy, including a patient treated on our inpatient consult service. In reported cases, the majority of patients (62.5%) had pompholyx alone or a combination of pompholyx on the hands or feet and two or fewer additional body surfaces involved. The majority of reported cases (75%) experienced the eczematous reaction after their first IVIG treatment. Neurologic conditions were the most common (85.9%) diseases for which IVIG was used. Most patients responded well to topical steroids or did not require treatment. LIMITATIONS: Some reported cases had insufficient descriptions to be included in this review. A literature review may underestimate the frequency of eczematous reactions to IVIG because these reactions are often limited and may not be reported. CONCLUSIONS: With the use of IVIG increasing, it is important for dermatologists to recognize this cutaneous side effect of IVIG. PMID- 21601311 TI - Adverse effects of propranolol when used in the treatment of hemangiomas: a case series of 28 infants. AB - BACKGROUND: Infantile hemangioma (IH) is a frequently encountered tumor with a potentially complicated course. Recently, propranolol was discovered to be an effective treatment option. OBJECTIVE: To describe the effects and side effects of propranolol treatment in 28 children with (complicated) IH. METHODS: A protocol for treatment of IH with propranolol was designed and implemented. Propranolol was administered to 28 children (21 girls and 7 boys, mean age at onset of treatment: 8.8 months). RESULTS: All 28 patients had a good response. In two patients, systemic corticosteroid therapy was tapered successfully after propranolol was initiated. Propranolol was also an effective treatment for hemangiomas in 4 patients older than 1 year of age. Side effects that needed intervention and/or close monitoring were not dose dependent and included symptomatic hypoglycemia (n = 2; 1 patient also taking prednisone), hypotension (n = 16, of which 1 is symptomatic), and bronchial hyperreactivity (n = 3). Restless sleep (n = 8), constipation (n = 3) and cold extremities (n = 3) were observed. LIMITATIONS: Clinical studies are necessary to evaluate the incidence of side effects of propranolol treatment of IH. CONCLUSIONS: Propranolol appears to be an effective treatment option for IH even in the nonproliferative phase and after the first year of life. Potentially harmful adverse effects include hypoglycemia, bronchospasm, and hypotension. PMID- 21601312 TI - The performance limits of traditional triage. PMID- 21601313 TI - Dry skin in older adults. AB - Dry skin is a common problem in the older individual due to physiological changes of the aging process as well as chronic health conditions. Dry skin can worsen if management is inappropriate or lacking. Nursing management of dry skin in the elderly is comprehensive including applying topical products to replenish lipids and reduce water loss, maintaining or increasing fluid intake, limiting sun exposure, and reducing symptoms of chronic illnesses. PMID- 21601314 TI - Vascular inflammation in cerebral small vessel disease. AB - Cerebral small vessel disease (CSVD) is considered to be caused by an increased permeability of the blood-brain barrier and results in enlargement of Virchow Robin spaces (VRs), white matter lesions, brain microbleeds, and lacunar infarcts. The increased permeability of the blood-brain barrier may relate to endothelial cell activation and activated monocytes/macrophages. Therefore, we hypothesized that plasma markers of endothelial activation (adhesion molecules) and monocyte/macrophage activation (neopterin) relate to CSVD manifestations. In 163 first-ever lacunar stroke patients and 183 essential hypertensive patients, we assessed CSVD manifestations on brain magnetic resonance imaging (MRI) and levels of C-reactive protein (CRP), neopterin, as well as circulating soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin, sP-selectin). Neopterin, sICAM 1 and sVCAM-1 levels were higher in patients with extensive CSVD manifestations than in those without (p < 0.01). Neopterin levels independently related to higher numbers of enlarged Virchow Robin spaces (p < 0.001). An inflammatory process with activated monocytes/macrophages may play a role in the increased permeability of the blood brain barrier in patients with CSVD. PMID- 21601315 TI - Prolonged coenzyme Q10 treatment in Down syndrome patients: effect on DNA oxidation. AB - Oxidative stress is known to play a relevant role in Down syndrome (DS) and its effects are documented from embryonic life. Oxidative DNA damage has been shown to be significantly elevated in Down syndrome patients, and this has been indicated as an early event promoting neurodegeneration and Alzheimer type dementia. The aim of this study was to investigate the efficacy of coenzyme Q(10) (CoQ(10)) in delaying the effect of oxidative damage in these patients. In our previous study we demonstrated a mild protective effect of CoQ(10) on DNA, although the treatment was unable to modify the overall extent of oxidative damage at the patient level. Possible limitations of the previous study were: time of treatment (6 months) or spectrum of DNA lesions detected. In order to overcome these limitations we planned a continuation of the trial aimed at evaluating the effects of CoQ(10) following a prolonged treatment. Our results highlight an age-specific reduction in the percentage of cells showing the highest amount of oxidized bases, indicating a potential role of CoQ(10) in modulating DNA repair mechanisms. PMID- 21601316 TI - [Diagnostic sequence of MRI and PET/CT in a case of bone metastases by hypopharyngeal squamous cell carcinoma]. PMID- 21601317 TI - Synthesis and structural investigation of some pyrimido[5,4-c]quinolin-4(3H)-one derivatives with a long-chain arylpiperazine moiety as potent 5-HT(1A/2A) and 5 HT(7) receptor ligands. AB - A series of new pyrimido[5,4-c]quinolin-4(3H)-ones with variable length of the spacer between amide and 4-arylpiperazine moiety were prepared to further explore the role of a terminal portion in the serotonergic activity. The majority of compounds demonstrated high in vitro affinity for 5-HT(1A) receptor, and moderate to-low affinity for 5-HT(2A) and 5-HT(7) receptors. X-ray analysis, two dimensional NMR, conformational studies and docking into the 5-HT(1A) receptor model were conducted to investigate conformational preferences of selected 5 HT(1A) receptor ligands in different environments. The extended conformation of tetramethylene derivatives was found in a solid state, in DMSO (for a protonated form) and as a global energy minimum during conformational analysis in simulated water environment. Ligand geometry in top-scored complexes, obtained by docking to a set of 100 receptor models, were either fully extended or with central spacer torsion in synclinal conformation. PMID- 21601318 TI - [Nasosinusal and cervical sarcoidosis: a case series of three patients and literature review]. AB - INTRODUCTION: Sinonasal sarcoidosis is difficult to treat. Infliximab seems to be useful in the treatment of sarcoidosis of the upper respiratory tract. CASE SERIES: We report three cases of sinonasal sarcoidosis in two women of 36 and 42 year-old and in a 64-year-old man. Resistance or dependence to corticosteroids and absence of efficacy of methotrexate therapy in one patient led to administer anti-TNFalpha therapy with infliximab. Outcome was favourable on sarcoid lesions but treatment was discontinued because of infectious complications and worsening of sarcoid chest involvement. CONCLUSION: This case series suggests that infliximab might be useful for the treatment of sarcoidosis with sinonasal involvement. PMID- 21601319 TI - Prospective multicentre randomised controlled trial of early enteral nutrition for patients undergoing major upper gastrointestinal surgical resection. AB - BACKGROUND & AIMS: The evidence in support of Early Enteral Nutrition (EEN) after upper gastrointestinal surgery is inconclusive. The aim of this study was to determine if EEN improved clinical outcomes and shortened length of hospital stay. METHODS: Open, prospective multicentre randomised controlled trial within a regional UK Cancer Network. One hundred and twenty-one patients with suspected operable upper gastrointestinal cancer (54 oesophageal, 38 gastric, 29 pancreatic) were studied. Patients were randomised to receive EEN (n = 64) or Control management postoperatively (nil by mouth and IV fluid, n = 57). Analysis was based on intention-to-treat and the primary outcome measure was length of hospital stay. RESULTS: Operative morbidity was less common after EEN (32.8%) than Control management (50.9%, p = 0.044), due to fewer wound infections (p = 0.017), chest infections (p = 0.036) and anastomotic leaks (p = 0.055). Median length of hospital stay was 16 days (IQ = 9) after EEN compared with 19 (IQ = 11) days after Control management (p = 0.023). CONCLUSIONS: EEN was associated with significantly shortened length of hospital stay and improved clinical outcomes. These findings reinforce the potential benefit of early oral nutrition in principle and as championed within enhanced recovery after surgery programmes, and such strategies deserve further research in the arena of upper GI surgery. PMID- 21601320 TI - Background and anthropogenic radionuclide derived dose rates to freshwater ecosystem: nuclear power plant cooling pond: reference organisms. AB - The radiological assessment of non-human biota to demonstrate protection is now accepted by a number of international and national bodies. Therefore, it is necessary to develop a scientific basis to assess and evaluate exposure of biota to ionizing radiation. Radionuclides from the Ignalina Nuclear Power Plant (Lithuania) were discharged into Lake Druksiai cooling pond. Additional radionuclide migration and recharge to this lake from a hypothetical near surface, low-level radioactive waste disposal, to be situated 1.5 km from the lake, had been simulated using RESRAD-OFFSITE code. This paper uses ERICA Integrated Approach with associated tools and databases to compare the radiological dose to freshwater reference organisms. Based on these data, it can be concluded that background dose rates to non-human biota in Lake Druksiai far exceed those attributable to anthropogenic radionuclides. With respect the fishery and corresponding annual committed effective human dose as a result of this fish consumption Lake Druksiai continues to be a high-productivity water body with intensive angling and possible commercial fishing. PMID- 21601321 TI - The International Confederation of Midwives essential competencies for basic midwifery practice. an update study: 2009-2010. AB - OBJECTIVE: a 2-year study was conducted to update the core competencies for basic midwifery practice, first delineated by the International Confederation of Midwives in 2002. A competency domain related to abortion-related care services was newly developed. DESIGN: a modified Delphi survey process was conducted in two phases: a pilot item affirmation study, and a global field survey. SETTING: a global survey conducted in 90 countries. PARTICIPANTS: midwifery educators or clinicians associated with midwifery education schools and programmes located in any of the ICM member association countries. Additional participants represented the fields of nursing, medicine, and midwifery regulatory authorities. A total of 232 individuals from 63 member association and five non-member countries responded to one or both of the surveys. The achieved sample represented 42% of member association countries, which was less than the 51% target. However, the sample was proportionally representative of ICM's nine global regions. MEASUREMENTS: survey respondents expressed an opinion whether to retain or to delete any of 255 statements of midwifery knowledge, skill, or professional behaviour. They also indicated whether the item should be a basic (core) item of midwifery knowledge or skill that would be included as mandatory content in a programme of midwifery pre-service education, or whether the item could be added to the fund of knowledge or acquired as an additional skill by those who would need or wish to include the item within the scope of their clinical practice. FINDINGS: a majority consensus of .85 was required to accept the item without further deliberation. An expert panel made final decisions in all instances where consensus was not achieved. The panel also amended the wording of selected items, or added new items based on feedback received from survey respondents. The final document contains 268 items organised within seven competency domains. PMID- 21601322 TI - Midwives on the move: comparing the requirements for practice and integration contexts for internationally educated midwives in Canada with the U.S., U.K. and Australia. AB - Midwives have long been internationally mobile, but there has been relatively little attention paid to the requirements that internationally educated midwives (IEMs) must meet to practice and become integrated into the health-care systems of their destination country. This paper examines from a comparative perspective the policy context and integration procedures that IEMs must follow in order to practice in Canada and how this compares with the U.S., the U.K., and Australia. The data upon which this paper is based are largely derived from an analysis of documents and websites for key organisations involved in the integration process supplemented with interviews with key informants influential in the assessment and integration of IEMs. What these data reveal is that the challenges for IEMs derive in large part from the differences in entry to practice requirements midwifery and nursing training in three of the cases, baccalaureate training in one. Another critical factor is whether bridging or adaptation programmes are available (rarely in the U.S.), and whether they focus more on orientation objectives (as they do in the U.K. and Australia) or also the upgrading of skills (as they do in Canada) critical for IEM professional integration. These different approaches to the integration of IEMs have important implications for the 'brain drain' and 'brain waste' of much needed midwifery skills in both source and destination countries. PMID- 21601323 TI - Experiences of teenage pregnancy among Xhosa families. AB - OBJECTIVES: to explore and describe the experiences of teenage pregnancy among Xhosa families, and, depending on the results of the study, to recommend a strategy to assist midwives to enhance pregnancy outcomes. DESIGN: a qualitative, explorative, descriptive, phenomenological and contextual research design. In depth face-to-face interviews were performed to collect data. PARTICIPANTS: 10 pregnant teenagers, eight mothers, two fathers, seven grandmothers and three grandfathers from the same families were interviewed independently and privately. FINDINGS: pregnant teenagers experienced emotional turmoil as they strived to cope with their pregnancy, and experienced a change in their relationships with significant others due to expectations that were not met and role confusion which led to crisis. Parents experienced overwhelming emotions due to the unexpected pregnancy of their child, and loss of control as the pregnancy could not be reversed. Grandparents of pregnant teenagers experienced the pregnancy as a family disturbance, and acknowledged that healing should take place in the family. KEY CONCLUSIONS: teenage pregnancy was experienced differently by different generations within the same family, but all the experiences culminated in anger that hampered the necessary parental support for the pregnant teenager. Lack of support during pregnancy can easily affected the well-being of the unborn child, as teenagers are not supervised and experience acute emotional stress. Intervention by a midwife could help to relieve the teenager's stress and optimise the pregnancy outcome. PMID- 21601324 TI - Monitoring and evaluation of skilled birth attendance: a proposed new framework. AB - BACKGROUND: The maternal mortality ratio (MMR) and proportion of births attended by skilled attendants are the two indicators selected to measure progress towards the achievement of MDG five. By the year 2015, the international community aims to have achieved a 75% reduction in MMR and 90% coverage of women having a skilled attendant at birth. In spite of the importance of this indicator, there is little consistency in how this is monitored and evaluated. This paper provides a review of the literature on the approaches and conceptual frameworks for evaluating progress with skilled birth attendance (SBA). The applicability of current frameworks is reviewed and a new simplified framework for monitoring and evaluation of SBA is proposed. METHODS: We searched electronic databases, internet, publications and databases of organisations. We hand searched reference lists of key papers, using search terms such as skilled attend*, maternal health, maternal mortality, midwi*, health professional, impact*, monitor* and evaluat*. FINDINGS: there were 44 potentially relevant articles from PUBMED, three from Scopus, seven from WHO, two from UNFPA, one obtained via hand search and one via personal communication. A total of 27 publications were found to be relevant after a review of their abstracts. Of these, 17 were on SBA and maternal mortality, and 10 were on monitoring and evaluation of SBA. Of the publications on monitoring and evaluation of SBA, two studies assessed global coverage of SBA, eight studies evaluated specific programmes and three of these had a 'conceptual framework'. CONCLUSIONS: No standard framework to evaluate progress made in ensuring increased coverage with skilled birth attendance currently exists. There are three published conceptual frameworks, each of which has valuable and workable components as well as limitations. A simplified systems approach to the Monitoring and Evaluation of SBA using structure, process and outcome criteria is proposed. PMID- 21601325 TI - GFR estimating equations in a multiethnic Asian population. AB - BACKGROUND: Clinical practice guidelines recommend using equations for estimating glomerular filtration rate (GFR) in chronic kidney disease (CKD) management and research. The MDRD (Modification of Diet in Renal Disease) Study and CKD-EPI (CKD Epidemiology Collaboration) equations originally were derived from a North American population and had an ethnic coefficient adjustment for African Americans. A Chinese coefficient for the MDRD Study equation subsequently was determined, but this has not been externally validated. We compared the accuracy of the equations, evaluated the ethnic coefficients, and assessed the equations for disease staging in a multiethnic Asian population with CKD. STUDY DESIGN: A diagnostic test study comparing the Asian coefficient (and subgroups)-modified MDRD Study and CKD-EPI equations and a cross-sectional study assessing disease staging. SETTING & PARTICIPANTS: 232 outpatients (52% men; 40.5% Chinese, 32% Malay, and 27.5% Indian/other) with stable CKD. INDEX TEST: Asian and ethnicity based modifications of the MDRD Study and CKD-EPI equations. REFERENCE TEST: Measured GFR using 3-sample plasma clearance of technetium-99m diethylenetriaminepentaacetic acid ((99m)Tc-DTPA), calculated using the slope intercept method, with body surface area normalization (du Bois) and Brochner Mortensen correction. RESULTS: Overall, the CKD-EPI equation is more accurate than the MDRD Study equation throughout the GFR range, with improved bias (median difference of estimated GFR - measured GFR) and root mean square error (P <0.001). CKD-EPI versus MDRD Study equation: bias, 1.1 +/- 13.8 vs -1.0 +/- 15.2 mL/min/1.73 m(2); precision, 12.1 vs 12.2 mL/min/1.73 m(2). Ethnic coefficients did not improve estimates of GFR significantly. The correctness of staging was improved using the CKD-EPI equation. LIMITATIONS: All participants had CKD, but few were of European descent. The reference GFR technique was different from the original studies. CONCLUSIONS: The CKD-EPI is more accurate than the MDRD Study equation, particularly at higher GFRs. Therefore, we recommend adopting the CKD EPI equation without ethnic adjustment for estimating GFR in multiethnic Asian patients with CKD. PMID- 21601326 TI - Noninvasive and direct measures of kidney size in kidney donors. AB - BACKGROUND: Kidney size is important for clinical assessment of kidney disease. This study was performed to determine the usefulness of radiologic methods for predicting direct measurements of kidney size. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: 139 living kidney donors were enrolled. INDEX TEST: Body mass index, body surface area, and total-body water were estimated from body height and weight. Kidney lengths were estimated using ultrasound sonography (US) and computed tomography (CT), and kidney volumes were estimated from CT scans using the ellipsoid and voxel-count methods. REFERENCE TEST: Kidney length and weight were measured directly after donor nephrectomy. RESULTS: Mean measured kidney length and weight were 11.5 +/- 0.9 cm and 188.5 +/- 33.5 g, respectively. All body indexes correlated with measured size of the left kidney; the highest correlation was between body weight and measured kidney weight (gamma = 0.54; P < 0.001). The difference between measured and estimated lengths was greater for US than for CT (-1.1 +/- 0.9 cm for US [P < 0.001] vs -0.7 +/- 0.7 cm for CT [P < 0.001]). Bland-Altman analysis showed that limits of agreement between CT estimates and measured kidney length (-0.62 to 2.75 cm) were narrower than those between US estimates and measured kidney length (-0.78 to 2.15 cm). Correlation coefficients between radiologic estimates and measured kidney weight were 0.41 and 0.49 for US and CT estimates of kidney length and 0.72 and 0.79 for volume estimates using the ellipsoid and voxel-count methods, respectively (all P < 0.01). LIMITATIONS: No direct measurement of kidney volume. CONCLUSIONS: CT estimation of kidney length is more accurate than US estimation, and CT estimation of kidney volume using the voxel-count method is most useful to predict kidney weight. PMID- 21601327 TI - Association of waist circumference and body mass index with all-cause mortality in CKD: The REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study. AB - BACKGROUND: Obesity management requires understanding the mortality risks associated with different adiposity measures. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 5,805 adults with body mass index (BMI) >=18.5 kg/m(2) and stages 1-4 chronic kidney disease, defined as a spot urine albumin-creatinine ratio >=30 mg/g and/or estimated glomerular filtration rate <60 mL/min/1.73 m(2), enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. PREDICTOR: BMI categorized as 18.5-24.9, 25.0-29.9, 30.0-34.9, 35.0-39.9, and >=40 kg/m(2) and waist circumference categorized as <80, 80-87.9, 88-97.9, 98 107.9, and >=108 cm in women and <94, 94-101.9, 102-111.9, 112-121.9, and >=122 cm in men. OUTCOMES: All-cause mortality. MEASUREMENTS: BMI and waist circumference were measured using a standardized protocol during the home visit. RESULTS: 686 (11.8%) deaths occurred during a median follow-up of 4 years. Compared with the referent BMI category of 25-29.9 kg/m(2), HRs for mortality were 1.27 (95% CI, 0.96-1.69) for BMI <25 kg/m(2) and 0.84 (95% CI, 0.62-1.13), 0.81 (95% CI, 0.52-1.26), and 0.95 (95% CI, 0.54-1.65) for BMI categories 30 34.9, 35-39.9, and >=40 kg/m(2) after adjustment for covariates including waist circumference, respectively. In contrast, after adjustment for covariates including BMI, higher mortality rates were noted for all waist circumference categories compared with the referent (<80 cm in women and <94 cm in men), with HRs of 1.04 (95% CI, 0.77-1.41) for waist circumference of 80-87.9 cm in women and 94-101.9 cm in men, 1.29 (95% CI, 0.92-1.81) for waist circumference of 88 97.9 cm in women and 102-111.9 cm in men, 1.72 (95% CI, 1.12-2.62) for waist circumference of 98-107.9 cm in women and 112-121.9 cm in men, and 2.09 (95% CI, 1.26-3.46) for waist circumference >=108 cm in women and >=122 cm in men. LIMITATIONS: BMI and waist circumference measured at baseline only. CONCLUSIONS: Waist circumference should be considered in conjunction with BMI when assessing mortality risk associated with obesity in adults with chronic kidney disease. PMID- 21601328 TI - Association of educational attainment with chronic disease and mortality: the Kidney Early Evaluation Program (KEEP). AB - BACKGROUND: Recent reports have suggested a close relationship between education and health, including mortality, in the United States. STUDY DESIGN: Observational cohort. SETTING & PARTICIPANTS: We studied 61,457 participants enrolled in a national health screening initiative, the National Kidney Foundation's Kidney Early Evaluation Program (KEEP). PREDICTOR: Self-reported educational attainment. OUTCOMES: Chronic diseases (hypertension, diabetes, cardiovascular disease, reduced kidney function, and albuminuria) and mortality. MEASUREMENTS: We evaluated cross-sectional associations between self-reported educational attainment with the chronic diseases listed using logistic regression models adjusted for demographics, access to care, behaviors, and comorbid conditions. The association of educational attainment with survival was determined using multivariable Cox proportional hazards regression. RESULTS: Higher educational attainment was associated with a lower prevalence of each of the chronic conditions listed. In multivariable models, compared with persons not completing high school, college graduates had a lower risk of each chronic condition, ranging from 11% lower odds of decreased kidney function to 37% lower odds of cardiovascular disease. During a mean follow-up of 3.9 (median, 3.7) years, 2,384 (4%) deaths occurred. In the fully adjusted Cox model, those who had completed college had 24% lower mortality compared with participants who had completed at least some high school. LIMITATIONS: Lack of income data does not allow us to disentangle the independent effects of education from income. CONCLUSIONS: In this diverse contemporary cohort, higher educational attainment was associated independently with a lower prevalence of chronic diseases and short-term mortality in all age and race/ethnicity groups. PMID- 21601329 TI - Automatic adaptive system dialysis for hemodialysis-associated hypotension and intolerance: a noncontrolled multicenter trial. AB - BACKGROUND: Hemodialysis is complicated by a high incidence of intradialytic hypotension and disequilibrium symptoms caused by hypovolemia and a decrease in extracellular osmolarity. Automatic adaptive system dialysis (AASD) is a proprietary dialysis system that provides automated elaboration of dialysate and ultrafiltration profiles based on the prescribed decrease in body weight and sodium content. STUDY DESIGN: A noncontrolled (single arm), multicenter, prospective, clinical trial. SETTING & PARTICIPANTS: 55 patients with intradialytic hypotension or disequilibrium syndrome in 15 dialysis units were studied over a 1-month interval using standard treatment (642 sessions) followed by 6 months using AASD (2,376 sessions). INTERVENTION: AASD (bicarbonate dialysis with dialysate sodium concentration and ultrafiltration rate profiles determined by the automated procedure). OUTCOMES: Primary and major secondary outcomes were the frequency of intradialytic hypotension and symptoms (hypotensive events, headache, nausea, vomiting, and cramps), respectively. RESULTS: More stable intradialytic systolic and diastolic blood pressures with lower heart rate were found using AASD compared with standard treatment. Sessions complicated by hypotension decreased from 58.7% +/- 7.3% to 0.9% +/- 0.6% (P < 0.001). The incidence of other disequilibrium syndrome symptoms was lower in patients receiving AASD. There were no differences in end-session body weight, interdialytic weight gain, or presession natremia between the standard and AASD treatment periods. LIMITATIONS: A noncontrolled (single arm) study, no crossover from AASD to standard treatment. CONCLUSIONS: This study shows the long-term clinical efficacy of AASD for intradialytic hypotension and disequilibrium symptoms in a large number of patients and dialysis sessions. PMID- 21601330 TI - Cystatin C in prediction of acute kidney injury: a systemic review and meta analysis. AB - BACKGROUND: Cystatin C (CysC) has been proposed as a filtration marker for the early detection of acute kidney injury (AKI); however, a wide range of its predictive accuracy has been reported. STUDY DESIGN: Meta-analysis of diagnostic test studies. SETTING & POPULATION: Various clinical settings of AKI, including patients after cardiac surgery, pediatric patients, and critically ill patients. SELECTION CRITERIA: Computerized search of PubMed, Current Contents, CINAHL, and EMBASE from inception until November 15, 2010, was performed to identify potentially relevant articles. Inclusion criteria were studies investigating the diagnostic accuracy of CysC level to predict AKI. There were no language restrictions in the search. INDEX TESTS: Increasing or increased serum CysC level or urinary CysC excretion. REFERENCE TESTS: The outcome was the development of AKI, primarily based on serum creatinine level (definition varied across studies). RESULTS: We analyzed data from 19 studies and 11 countries involving 3,336 patients. Of these studies, 13 could be included in the meta-analysis. Across all settings, the diagnostic OR for serum CysC level to predict AKI was 27.7 (95% CI, 12.8-59.8), with sensitivity and specificity of 0.86 and 0.82, respectively. The area under the receiver operating characteristic curve (AUROC) of serum CysC levelto predict AKI was 0.87 (95% CI, 0.81-0.93). In an analysis excluding studies that did not clearly define the measurement time point, early serum CysC (within 24 hours after renal insult or intensive care unit admission) remained of diagnostic value. For the diagnostic value of urinary CysC excretion, the diagnostic OR was 3.10 (95% CI, 2.00-4.81), with sensitivity and specificity of0.61 and 0.67, respectively. TheAUROC of urinary CysC excretion to predict AKI was 0.67 (95% CI, 0.63-0.71) [corrected]. LIMITATIONS: Variation in criteria for definitions of index and reference tests, absence of measured glomerular filtration rate in most studies. CONCLUSION: Serum CysC appears to be a good biomarker in the prediction of AKI, whereas urinary CysC excretion has only moderate diagnostic value. PMID- 21601331 TI - When enough is enough: the nephrologist's responsibility in ordering dialysis treatments. AB - For more than 20 years, nephrologists have been reporting that they are increasingly being expected to dialyze patients whom they believe may receive little benefit from dialysis therapy. During this time, there has been substantial research about the outcomes of patients of differing ages and comorbid conditions requiring dialysis and the development of clinical practice guidelines for dialysis decision making based on research evidence, ethics, and the law. The importance of palliative medicine to the care of the patient throughout the continuum of kidney disease also has been recognized, and its application has been described. This article summarizes these advances and provides an approach for decision making and treatment for patients who are not likely to benefit from dialysis therapy. PMID- 21601332 TI - Successful simultaneous liver-kidney transplant in an adult with atypical hemolytic uremic syndrome associated with a mutation in complement factor H. AB - Atypical hemolytic uremic syndrome was diagnosed in a 62-year-old man. Sequencing of the CFH gene, which encodes complement factor H, revealed a heterozygous adenine to guanine mutation at nucleotide 3550 of the complementary DNA, leading to a predicted substitution of alanine for threonine at amino acid position 1184 in the protein (c.3550A>G, p.Thr1184Ala). Three years later, he received a simultaneous liver-kidney transplant with plasmapheresis and intratransplant plasma infusion. The postoperative course was complicated by an anastomotic biliary stricture that was treated successfully using endoscopic stenting. One year later, he has excellent function of both transplants, emphasizing that simultaneous liver-kidney transplant is a valuable treatment option in the management of adult patients with atypical hemolytic uremic syndrome. PMID- 21601334 TI - Identification of urologic complications after kidney transplant. AB - Urologic complications after kidney transplant are important causes of morbidity, hospitalization, and transplant loss. We report 2 cases of clinically unsuspected urine extravasation after kidney transplant that were diagnosed accurately using SPECT/CT (single-photon emission computed tomography/computed tomography) radionuclide renal scan and corrected using surgery. These cases emphasize the value of dynamic radionuclide renal scan using SPECT/CT in the detection of urologic complications. PMID- 21601333 TI - Relapsing and recurrent peritoneal dialysis-associated peritonitis: a multicenter registry study. AB - BACKGROUND: The causes, predictors, treatment, and outcomes of relapsed and recurrent peritoneal dialysis (PD)-associated peritonitis are poorly understood. STUDY DESIGN: Observational cohort study using Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry data. SETTING & PARTICIPANTS: All Australian PD patients between October 1, 2003, and December 31, 2007, with first episodes of peritonitis. PREDICTORS: Demographic, clinical, and facility variables and type of peritonitis; relapse (same organism or culture-negative episode occurring within 4 weeks of completion of therapy of a prior episode or 5 weeks if vancomycin used); recurrence (different organism occurring within 4 weeks of completion of therapy of a prior episode or 5 weeks if vancomycin used); control (first peritonitis episode without relapse or recurrence). OUTCOMES & MEASUREMENTS: Hospitalization, catheter removal, hemodialysis therapy transfer, death. RESULTS: Of 6,024 PD patients studied, first episodes of relapsed, recurrent, and control peritonitis occurred in 356, 165, and 2,021 patients, respectively. Coagulase-negative staphylococci and Staphylococcus aureus accounted for 48% of relapsing peritonitis (adjusted OR, 1.26 [95% CI, 0.94-1.70] and 1.54 [95% CI, 1.08-2.19], respectively), but were much less likely to be isolated in recurrent peritonitis. Recurrent peritonitis was associated more frequently with fungi (13%; OR, 2.16; 95% CI, 1.12-4.17). The empirical antimicrobial approaches to relapsing and recurrent peritonitis were similar and their subsequent clinical outcomes were comparable. Compared with uncomplicated peritonitis, relapsed and recurrent peritonitis were associated with higher rates of catheter removal (22% vs 30% vs 37%, respectively; P < 0.001) and permanent hemodialysis therapy transfer (20% vs 25% vs 32%; P < 0.001), but similar rates of hospitalization (73% vs 70% vs 70%) and death (2.8% vs 2.0% vs 1.2%). LIMITATIONS: Limited covariate adjustment. Residual confounding and coding bias could not be excluded. CONCLUSIONS: Relapsed and recurrent peritonitis are caused by different spectra of micro-organisms, but are not readily clinically distinguishable at presentation. Empirical treatment with broad-spectrum antibiotics and subsequent adjustment according to antimicrobial susceptibilities results in similar clinical outcomes, albeit with appreciably higher rates of catheter removal and hemodialysis therapy transfer than for uncomplicated peritonitis. PMID- 21601335 TI - Serum albumin as a predictor of mortality in peritoneal dialysis: comparisons with hemodialysis. AB - BACKGROUND: Serum albumin level predicts mortality in dialysis patients and is used to assess their health status and the quality of delivered care. Whether the threshold level of serum albumin at which mortality risk increases in peritoneal dialysis (PD) patients is the same as for hemodialysis (HD) patients has not been studied. STUDY DESIGN: Observational cohort study of dialysis patients undertaken to determine the survival-predictability of serum albumin level in PD patients and compare it with that in HD patients. SETTING & PARTICIPANTS: 130,052 dialysis patients (PD, 12,171; HD, 117,851) who received treatment in any of the 580 dialysis units owned by DaVita Inc between July 1, 2001, through June 30, 2006, followed up through June 30, 2007. PREDICTOR: Baseline and time-averaged serum albumin level (assayed using bromcresol green) and change in serum albumin level over 6 months. OUTCOME MEASURES: All-cause, cardiovascular, and infection-related mortality. RESULTS: PD patients with baseline serum albumin level <3.0 g/dL had a more than 3-fold higher adjusted risk of all-cause and cardiovascular mortality and 3.4-fold higher risk of infection-related mortality (reference group: serum albumin, 4.00-4.19 g/dL). Adjusted all-cause mortality was significantly lower in PD patients with a >=0.3-g/dL increase in serum albumin level over 6 months and significantly higher in those for whom it decreased by >=0.2 g/dL (reference group: serum albumin change, +0.1 to -0.1 g/dL). A significant increase in death risk was evident for HD patients with serum albumin level <4.0 g/dL, but at <3.8 g/dL for PD patients. For each albumin category, overall death risk for PD patients was lower than for HD patients (reference group: HD patients with serum albumin of 4.00-4.19 g/dL). LIMITATIONS: Study can identify associations only without attribution of causality and residual confounding cannot be excluded. CONCLUSIONS: Serum albumin predicts all-cause, cardiovascular, and infection related mortality in both PD and HD patients. However, the threshold at which risk of death increases varies by dialysis modality, and this difference should be considered by agencies or organizations that set quality standards. PMID- 21601337 TI - Encapsulating Peritoneal Sclerosis Complicated by an Intra-abdominal Abscess. AB - We present a case of a 68-year-old woman who developed encapsulating peritoneal sclerosis (EPS) with an intra-abdominal abscess. The patient was referred to our hospital with abdominal pain, nausea, and vomiting. She had end-stage kidney disease secondary to diabetes mellitus that had been treated with continuous ambulatory peritoneal dialysis for 9 years. EPS had been diagnosed 1 year ago, and she had been treated with prednisone daily. On presentation, a computed tomographic scan showed a calcified peritoneum and intra-abdominal abscess, and surgery showed that the abscess was caused by a bowel perforation. The perforated bowel could not be sutured or resected because of the presence of fibrotic tissue and peritoneal calcification. She was treated with bowel rest with total parenteral nutrition, as well as general antibiotic therapy and drainage for 8 months. However, the site of perforation did not heal, and she died of septic shock. Because treatment of EPS complicated by bowel perforation is very difficult, it is necessary to diagnose and treat the early stages of EPS to prevent bowel perforation. Imaging techniques are important in making an early diagnosis and successfully managing EPS. PMID- 21601336 TI - Presurgical serum cystatin C and risk of acute kidney injury after cardiac surgery. AB - BACKGROUND: Acute kidney injury (AKI) after cardiac surgery is associated with poor outcomes, but is challenging to predict from information available before surgery. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: The TRIBE-AKI (Translational Research Investigating Biomarker Endpoints in Acute Kidney Injury) Consortium enrolled 1,147 adults undergoing cardiac surgery at 6 hospitals from 2007-2009; participants were selected for high AKI risk. PREDICTORS: Presurgical values for cystatin C, creatinine, and creatinine-based estimated glomerular filtration rate (eGFR) were categorized into quintiles and grouped as "best" (quintiles 1-2), "intermediate" (quintiles 3-4), and "worst" (quintile 5) kidney function. OUTCOMES: The primary outcome was AKI Network (AKIN) stage 1 or higher; >=0.3 mg/dL or 50% increase in creatinine level. MEASUREMENTS: Analyses were adjusted for characteristics used clinically for presurgical risk stratification. RESULTS: Average age was 71 +/- 10 years (mean +/- standard deviation); serum creatinine, 1.1 +/- 0.3 mg/dL; eGFR-Cr, 74 +/- 9 mL/min/1.73 m(2); and cystatin C, 0.9 +/- 0.3 mg/L. 407 (36%) participants developed AKI during hospitalization. Adjusted odds ratios for intermediate and worst kidney function by cystatin C were 1.9 (95% CI, 1.4-2.7) and 4.8 (95% CI, 2.9-7.7) compared with 1.2 (95% CI, 0.9-1.7) and 1.8 (95% CI, 1.2-2.6) for creatinine and 1.0 (95% CI, 0.7-1.4) and 1.7 (95% CI, 1.1-2.3) for eGFR-Cr categories, respectively. After adjustment for clinical predictors, the C statistic to predict AKI was 0.70 without kidney markers, 0.69 with creatinine, and 0.72 with cystatin C. Cystatin C also substantially improved AKI risk classification compared with creatinine, based on a net reclassification index of 0.21 (P < 0.001). LIMITATIONS: The ability of these kidney biomarkers to predict risk of dialysis-requiring AKI or death could not be assessed reliably in our study because of a small number of patients with either outcome. CONCLUSIONS: Presurgical cystatin C is better than creatinine or creatinine-based eGFR at forecasting the risk of AKI after cardiac surgery. PMID- 21601338 TI - PET-MRI fusion in head-and-neck oncology: current status and implications for hybrid PET/MRI. AB - PURPOSE: To review the current status and clinical effect of PET-MRI image fusion in the staging of head-and-neck cancer and to show its implications for imaging with future hybrid PET/MRI scanners. MATERIALS AND METHODS: We reviewed the current literature in order to provide an overview of the potential of the combination of the anatomic and functional imaging capabilities of magnetic resonance imaging (MRI) and of the potential for molecular and metabolic imaging with Positron emission tomography (PET). The research question was whether these image devices might be of synergistic value. RESULTS: PET with [18F] fluorodeoxyglucose has shown promising results for the assessment of lymph node involvement in cancer, the identification of distant metastasis and synchronous and metachronous tumors, and the evaluation of tumor recurrence or carcinoma of an unknown primary. For morphologic imaging, MRI has several advantages compared with computed tomography in the head-and-neck area. This is mainly because of the superior soft tissue contrast and fewer artifacts from dental implants. Moreover, MRI allows functional imaging, such as the assessment of perfusion with dynamic contrast-enhanced MRI. The published data indicate that image fusion should be beneficial in the case of the recurrence of oromaxillofacial cancer and in the evaluation of potential metastatic lymph nodes. However, retrospective image fusion is technically demanding in the head-and-neck area, mainly because of the varied patient positions used for the various scanners and the anatomic complexity of this region. CONCLUSIONS: Combined PET/MRI scanners might overcome the above-named problems. Both sequential and fully integrated PET/MRI scanners are now available in selected departments, and future studies will show whether hybrid PET/MRI is of greater clinical value than PET/CT and retrospective image fusion techniques. PMID- 21601339 TI - Tracheotomy in the unprotected airway. AB - PURPOSE: Although rare, there are many circumstances in which a secure airway is needed urgently. A newly developed technique is presented for quick and efficient performance of this procedure. PATIENTS AND METHODS: All patients who had tracheotomies performed at a tertiary referral center from January 1, 2004, through December 31, 2008, were found by querying the admission database. Three hundred twenty-seven separate procedures performed in 325 patients were identified. Urgent tracheotomies were distinguished from elective and emergent tracheotomies by reading operative reports and excluding elective and emergent procedures. Elective procedures were defined as performed in patients with a secure airway (with an endotracheal tube or laryngeal mask airway). Urgent tracheotomies were defined as having an intact, unprotected airway. Emergent procedures were performed in a patient with complete airway obstruction. RESULTS: Twenty instances of urgent, awake tracheotomies were found in 19 patients, resulting in an incidence of 20 of 327 tracheotomies (6.1%) in 19 of 325 patients (5.8%). CONCLUSIONS: Tracheotomy is an alternative to cricothyroidotomy as a surgical airway in patients with deteriorating respiratory status who cannot be safely intubated by nonsurgical means. PMID- 21601340 TI - Deidentification of facial images using composites. AB - PURPOSE: Maxillofacial surgeons rely on photography for education and documentation. Photographs of the face, unlike those of other body regions, are readily identifiable. Traditional methods of facial image deidentification decrease educational quality or fail to adequately conceal identity. In the present study, a method that uses blended facial composites to deidentify original facial images was developed. This method allows significant components of the original face to be visualized while concealing its identity. MATERIALS AND METHODS: The method was used to develop 20 different composite facial images that were viewed by student subjects. Ten of these images contained at least one third of a face that was familiar to the subjects. Subjects viewed the composite faces twice--first unaware that the faces were composites, and then primed to the presence of composites. Subjects later rated the efficacy of this method for image deidentification. RESULTS: When unaware that they were viewing composite images, no subjects recognized the familiar faces within the composites or rated them as familiar (0/120 total views, 0%). When later primed to the potential presence of familiar faces within composites, the identification rate increased significantly (74/120, 62%; P < .001). Results were similar no matter which portion of the familiar face (upper, 67%; mid, 54%; lower, 67%) was present. Subjects rated all composites as clinically realistic patient images. They also rated composites as more effective at deidentification than traditional methods. CONCLUSION: The use of composites appears to be a promising concept for facial image deidentification. Further larger-scale studies are needed to validate these findings. PMID- 21601341 TI - Prevalence of comorbid obstructive sleep apnea and metabolic syndrome: syndrome Z and maxillofacial surgery implications. AB - PURPOSE: To determine the prevalence of the recently identified syndrome Z (SZ), which is the co-occurrence of obstructive sleep apnea (OSA; hypoxia, systemic and pulmonary hypertension, nocturnal arrhythmias) and metabolic syndrome (MetS; increased abdominal girth, hypertriglyceridemia, decreased high-density lipoprotein, hypertension, increased fasting glucose), which places the surgical patient at heightened risk of perioperative complications (myocardial infarction, stroke, pneumonia, wound infection). MATERIALS AND METHODS: Electronic medical records of 296 male veterans were assessed for the presence of SZ using the American Academy of Sleep Medicine definition of OSA and a modified Adult Treatment Panel III definition of MetS, where obesity was defined by a body mass index of at least 30 kg/m(2) rather than by waist circumference. RESULTS: SZ was diagnosed in 59% of patients. These individuals commonly exhibited severe OSA and least commonly mild OSA. The more severe the OSA, the more likely (60%) that patients manifested moderate (4 risk markers) or severe (5 risk markers) MetS. Furthermore, with increasing apnea-hypopnea index values, the more severe were the MetS elements. CONCLUSIONS: The results of this study demonstrate the high prevalence rate of MetS in patients with OSA seeking treatment. Given the risk of perioperative complications, it is suggested that all patients scheduled for maxillofacial surgical procedures to treat OSA be evaluated for SZ. PMID- 21601343 TI - [The validity and sensitivity to change of the Spanish self-administered version of the chronic respiratory questionnaire (CRQ-SAS)]. AB - INTRODUCTION: The interviewer-administered chronic respiratory questionnaire (CRQ IA) is widely used and has demonstrated excellent properties for measuring health related quality of life (HRQL) in patients with chronic obstructive pulmonary disease (COPD). However, the self-administered version (CRQ-SAS) in Spanish has not been validated. The aim of this trial was to evaluate the validity and the sensitivity of the Spanish version of the CRQ-SAS in patients with COPD. MATERIAL AND METHODS: We randomized 40 patients with COPD (33 treated with pulmonary rehabilitation and 7 with liquid oxygen therapy) to one of the two methods of administration of CRQ (SAS vs. IA) both before and 8 weeks after the treatment. In addition, patients completed the SF-36 questionnaire, pulmonary function tests, and six-minute walk test. RESULTS: The CRQ-SAS demonstrated good longitudinal construct validity on all domains with a range of correlations, for the change scores, between 0.46 (P=.05) and 0.71 (P=.01). Regarding sensitivity to change, we observed a minimal clinically significant change in most domains (fatigue 0.71 [P=.02], emotional factor 0.62 [P=.04], control of the disease 0.83 [P=.06]). CONCLUSIONS: The Spanish version of CRQ-SAS is valid for evaluating HRQL in COPD patients. The correlations of the CRQ-SAS with other tools provide construct validity and show good sensitivity to change. PMID- 21601344 TI - The impact of backboard size and orientation on sternum-to-spine compression depth and compression stiffness in a manikin study of CPR using two mattress types. AB - OBJECTIVES: To explore how backboard orientation and size impact chest compressions during cardiopulmonary resuscitation (CPR). METHODS: Experiments were conducted on a full-body CPR training manikin using a custom-built simulator. Two backboards of different sizes were tested in longitudinal (head to toe) and latitudinal (side to side) directions to assess the impact of size and orientation on chest compressions during CPR. The net sternum-to-spine displacement, combined mattress and sternal displacement as well as the axial reaction force were measured during each test. RESULTS: The difference in net compression depth between the larger and smaller backboards ranged between 0.08+/ 0.30 cm and 1.47+/-0.13 cm, while the difference in back support stiffness varied between 103.7+/-211 N/cm and 688.1+/-180.3 N/cm. The difference in net compression depth between the longitudinal and latitudinal backboard orientations ranged from 0.07+/-0.32 cm to 0.34+/-0.18 cm, while for the back support stiffness the difference was between 13.4+/-50.0 N/cm and 592.2+/-211.0 N/cm. CONCLUSIONS: The effect of backboard size on chest compression (CC) performance during CPR was found to be significant with the larger backboard producing deeper chest compressions and higher back support stiffness than the smaller backboard. The impact of backboard orientation was found to depend on the size of the backboard and type of mattress used. Clinicians should be aware that although a smaller backboard may be easier for rescuers to manipulate, it does not provide as effective back support or produce as deep chest compressions as a larger backboard. PMID- 21601342 TI - Bone regeneration and docking site healing after bone transport distraction osteogenesis in the canine mandible. AB - PURPOSE: Bone transport distraction osteogenesis provides a promising alternative to traditional grafting techniques. However, existing bone transport distraction osteogenesis devices have many limitations. The purpose of this research was to test a new device, the mandibular bone transport reconstruction plate, in an animal model with comparable mandible size to humans and to histologically and mechanically examine the regenerate bone. MATERIALS AND METHODS: Eleven adult foxhounds were divided into an unreconstructed control group of 5 animals and an experimental group of 6 animals. In each animal, a 34-mm segmental defect was created in the mandible. The defect was reconstructed with a bone transport reconstruction plate. Histologic and biomechanical characteristics of the regenerate and unrepaired defect were analyzed and compared with bone on the contralateral side of the mandible after 4 weeks of consolidation. RESULTS: The reconstructed defect was bridged with new bone, with little bone in the control defect. Regenerate density and microhardness were 22.3% and 42.6%, respectively, lower than the contralateral normal bone. Likewise, the anisotropy of the experimental group was statistically lower than in the contralateral bone. Half the experimental animals showed nonunion at the docking site. CONCLUSION: The device was very stable and easy to install and activate. After 1 month of consolidation, the defect was bridged with new bone, with evidence of active bone formation. Regenerate bone was less mature than the control bone. Studies are underway to identify when the regenerate properties compare with normal bone and to identify methods to augment bone union at the docking site. PMID- 21601345 TI - Flight ventilation and Boyle-Mariotte law. PMID- 21601346 TI - The relationship between the structures of periphery ligands and the DNA binding mode of [Ru(II)(1,10-phenanthroline)(L1L2)dipyrido[3,2-a:2',3'-c]phenazine](n+) (L1=Cl or pyridine and L2=pyridine, n=1,2). AB - The binding modes of the [Ru(II)(1,10-phenanthroline)(L(1)L(2)) dipyrido[3,2 a:2',3'-c]phenazine](2+) {[Ru(phen)(py) Cl dppz](+) (L(1)=Cl, L(2)=pyridine) and ([Ru(phen)(py)(2)dppz](2+) (L(1)=L(2)=pyridine)} to native DNA is compared to that of the [Ru(II)(1,10-phenanthroline)(2)dipyrido[3,2-a:2',3'-c]phenazine](2+) complex ([Ru(phen)(2)dppz](2+)) by various spectroscopic and hydrodynamic methods including electric absorption, linear dichroism (LD), fluorescence spectroscopy, and viscometric titration. All measured properties, including red-shift and hypochromism in the dppz absorption band, nearly perpendicular molecular plane of the dppz ligand with respect to the local DNA helix axis, prohibition of the ethidium binding, the light switch effect and binding stoichiometry, increase in the viscosity upon binding to DNA, increase in the melting temperature are in agreement with classical intercalation of dppz ligand of the [Ru(phen)(2)dppz](2+) complex, in which both phenanthroline ligand anchored to the DNA phosphate groups by electrostatic interaction. [Ru(phen)(py)(2) dppz](2+) and [Ru(phen)(py) Cl dppz](+) complexes had one of the phenanthroline ligand replaced by either two pyridine ligands or one pyridine plus a chlorine ion. They exhibited similar protection from water molecules, interaction with DNA bases, and occupying site that is common with ethidium. The dppz ligand of these two Ru(II) complex were greatly tilted relative to the DNA helix axis, suggesting that the dppz ligand resides inside the DNA and is not perpendicular relative to the DNA helix axis. These observation suggest that anchoring the [Ru(phen)(2)dppz](2+)complex by both phenanthroline is essential for the dppz ligand to be classically intercalated between DNA base-pairs. PMID- 21601347 TI - Interactions of the DNA polymerase X from African Swine Fever Virus with the ssDNA. Properties of the total DNA-binding site and the strong DNA-binding subsite. AB - Interactions of the polymerase X from the African Swine Fever Virus with the ssDNA have been studied, using quantitative fluorescence titration and fluorescence resonance energy transfer techniques. The primary DNA-binding subsite of the enzyme, independent of the DNA conformation, is located on the C terminal domain. Association of the bound DNA with the catalytic N-terminal domain finalizes the engagement of the total DNA-binding site of the enzyme and induces a large topological change in the structure of the bound ssDNA. The free energy of binding includes a conformational transition of the protein. Large positive enthalpy changes accompanying the ASFV pol X-ssDNA association indicate that conformational changes of the complex are induced by the engagement of the N terminal domain. The enthalpy changes are offset by large entropy changes accompanying the DNA binding to the C-terminal domain and the total DNA-binding site, predominantly resulting from the release of water molecules. PMID- 21601349 TI - Introduction to the mini-series on epigenetics. PMID- 21601348 TI - Eukaryotic initiation factor 6 (eif6) overexpression affects eye development in Xenopus laevis. AB - The translation initiation factor eif6 has been implicated as a regulator of ribosome assembly, selective mRNA translation and apoptosis. Many of these activities depend upon the phosphorylation of eif6 serine 235 by PKC. Previous data showed that eif6 binds to the 60S ribosomal subunit when unphosphorylated, inhibiting assembly with the 40S subunit. Phosphorylation of Ser235 releases eif6 from the 60S subunit and allows assembly. eif6 acts as an anti-apoptotic factor via regulation of the bcl2/bax balance and acts selectively upstream of bcl2. This activity also depends upon phosphorylation of eif6 Ser235. One of the consequences of eif6 overexpression in Xenopus embryos is aberrant eye development. Here we evaluate the eye phenotype and show that it is transient. We show that the whole eye, particularly the retina layers, of the embryos injected with eif6-encoding mRNA recover by stage 42. Embryos over-expressing eif6 have normal expression of anterior- and brain-specific markers, indicating that outside the eye field, other neural regions appear unaffected by the eif6 injection. No eye defect was detected when morpholinos were used to reduce eif6 protein synthesis. We tested how two known pathways of eif6 function with respect to alteration of eye development. We found that injection of bcl2 did not produce the eye phenotype and eif6-bax co-injection did not rescue the eye defect, suggesting that the eye phenotype is not bearing on the anti-apoptotic role played by eif6 is not linked to its role as an anti-apoptotic factor. We also determined that PKC-dependant phosphorylation of Ser235 in eif6 is not required to produce defective eye development. These results indicate that the aberrant eye phenotype, produced by eif6 overexpression, is not directly linked to the PKC regulated effects of eif6 on translation and ribosomal subunit interaction or on eif6 anti-apoptotic properties. PMID- 21601350 TI - Is research keeping up with changes in landscape policy? A review of the literature. AB - Several innovative directions for landscape policy development and implementation have emerged over recent years. These include: (i) an expansion of scope to include all landscape aspects and landscape types, (ii) an increased emphasis on public participation, (iii) a focus on designing measures appropriate for different contexts and scales, and (iv) encouraging support for capacity building. In this paper, we evaluate the extent to which these policy directions are reflected in the practice of academic landscape research. We evaluate all research papers published in three leading landscape journals over six years, as well as published research papers relating directly to the European Landscape Convention. The latter, which was adopted in 2000, establishes a framework for landscape protection, planning and management in Europe and is to date the only international legal instrument of its kind. Results indicate that whilst policy innovations do not appear to be a major stimulus for academic research, studies nevertheless address a range of landscape aspects, types and scales (albeit with a slight bias towards bio-physical landscape aspects). However, geographical representativeness of research is weak and dominated by the United States and northern/western Europe, and research capacity likewise appears to be unevenly distributed. Landscape research is also limited in the extent to which it involves stakeholders or develops innovative methods for doing so, notwithstanding that this remains a key challenge for policy-makers. Results point to the potential for landscape research to address areas (topical and geographical) which have received little attention to date, as well as suggesting mutual benefits of stronger links between policy and academia. PMID- 21601354 TI - Transsphenoidal surgery assisted by a new guidance device: results of a series of 747 cases. AB - OBJECTIVE: The objective of this study is to report the efficacy and safety of microsurgical transsphenoidal surgery using a frame for sella guidance in a series of patients with untreated pituitary adenoma. METHODS: In this study, seven hundred and forty-seven patients undergoing transsphenoidal resection of a pituitary adenoma involving use of the frame were included. Follow-up of twelve to one hundred months was performed in all patients. RESULTS: During the procedures using the frame, pituitary adenomas were fully exposed, and no cavernous sinus haemorrhage due to anteroposterior displacement or internal carotid artery lesion due to right-and-left deviation occurred. The duration of the surgical procedure ranged from 28 min to 87 min with a mean of 44 min. The most frequent tumour type was prolactin-secreting adenoma (32.4%), followed by clinically non-functioning adenoma (NFPA) (28.5%), growth hormone-secreting adenoma (25.0%), and adrenocorticotropin-secreting adenoma (13.7%). Normalisation of visual defects occurred in 226 (42.2%) of the 535 patients with visual disturbances. Normalisation of hormone occurred in 458 of 551 patients with endocrine-active tumour in the follow-up period. Two patients died as a consequence of surgery. CONCLUSION: The endonasal transsphenoidal technique is a safe, quick, and effective approach to pituitary adenomas. Our guidance frame allows the surgeon to open and close the wound rapidly, which avoids trajectory deviation and shortens the duration of the surgical procedure. PMID- 21601352 TI - Disease-specific survival of men with prostate cancer detected during the screening interval: results of the European randomized study of screening for prostate cancer-Rotterdam after 11 years of follow-up. AB - BACKGROUND: In a screening program, interval cancers are cancers diagnosed between two screening visits. OBJECTIVE: To assess the disease-specific survival (DSS) of men with prostate cancer (PCa) detected during the screening interval. DESIGN, SETTING, AND PARTICIPANTS: Within the European Randomized Study of Screening for Prostate Cancer section Rotterdam, 42 376 men identified from population registries (55-74 yr of age) were randomized to a screening or control arm. The median follow-up was 11 yr. INTERVENTION: Men with prostate-specific antigen >= 3.0 ng/ml were recommended to undergo lateralized sextant biopsy. The screening interval was 4 yr. MEASUREMENTS: The disease-specific mortality of men with interval cancers was compared with that of men with PCa in the control arm; the secondary end point was overall mortality. An independent committee determined the causes of death. RESULTS AND LIMITATIONS: In the screening arm, 139 men were diagnosed with interval cancer of whom 8 died of the disease. In the control arm, the corresponding numbers were 1149 and 128, respectively. When comparing men with interval cancer to men with PCa in the control arm, no statistically significant difference in disease-specific mortality (hazard ratio [HR]:1.12; 95% confidence interval [CI], 0.53-2.36; p = 0.77) and overall mortality (HR: 0.98; 95% CI, 0.68-1.38; p = 0.90) was found, adjusted for age, prognostic factors, and treatment modality. The follow-up is too limited to address the difference in DSS stratified for screening interval. CONCLUSIONS: In the setting of population-based PCa screening at 4-yr intervals, the DSS of men with interval cancer seems to be similar to that of men with PCa in the control arm. Given that interval cancers contribute significantly to PCa mortality, further benefit in DSS in the screening arm may be achieved by decreasing the occurrence of interval cancer. However, the balance between mortality reduction and overdiagnosis should be preserved. TRIAL REGISTRATION: ISRCTN49127736. PMID- 21601355 TI - Comparative in vitro cytotoxicity study of carbon nanotubes and titania nanostructures on human lung epithelial cells. AB - The aim of this study is to assess in vitro cytotoxic effects of titania nanostructures and carbon nanotubes (CNTs) by exposing A549 lung epithelial cell line to these materials. Titania nanotubes (TiNTs) were grown by hydrothermal treatment of TiO(2) nanoparticles, followed by annealing them at 400 degrees C. The titania nanostructures obtained on annealing (mixture of nanotubes and nanorods) were hollow and open ended, containing 3-5 layers of titania sheets, with an internal diameter ~3-5 nm and external diameter ~8-10 nm, and a specific surface area of 265 m(2)/g. As-supplied single walled (SWCNTs) and microwave plasma enhanced chemical vapour deposition (MPCVD) grown multi walled carbon nanotubes (MWCNTs) were used in this study. The lengths and diameters of the SWCNTs were 5-10nm and 0.5-3 nm respectively. The lengths and diameters of the MWCNTs were 25-30 MUm and 10-30 nm respectively. The cell viability was evaluated using the MTT (3-(4,-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium) assay. No significant cytotoxic effects of titania nanostructures were observed over a period of a week of testing time, while the presence of CNTs in some cases demonstrated significant cytotoxic effects. Finally, possible reason of cytotoxicity is discussed in the light of microstructures of materials. PMID- 21601356 TI - In-situ remediation of acid mine drainage using a permeable reactive barrier in Aznalcollar (Sw Spain). AB - Following on the accident occurred in Aznalcollar in 1998, whereby a huge amount of acid mine drainage and heavy metal-bearing pyritic sludge was released to the Agrio river valley with the subsequent contamination of groundwater, a subsurface permeable reactive barrier (PRB) was installed to mitigate the long-term impacts by the spillage. The PRB material consisted of a mixture of limestone and vegetal compost. A particular characteristic of the Agrio aquifer is its high water flow velocity (0.5-1 m/d), which may pose difficulties in its remediation using PRB technology. The present study reports the 36-month performance of the PRB. Vertical differences in water velocity were observed within the PRB, with the deeper part being slower and more effective in neutralizing pH and removing heavy metals (Zn, Al, Cu). On the other hand, partial sulfate removal appeard to be restricted to the bottom of the PRB, but with no apparent influence on downgradient water quality. The results are finally compared with the other four reported existing PRBs for AMD worldwide. PMID- 21601357 TI - Application of accelerated carbonation on MSW combustion APC residues for metal immobilization and CO2 sequestration. AB - The present study focuses on the application of an aqueous phase accelerated carbonation treatment on air pollution control (APC) residues from municipal solid waste combustion, aimed at assessing its influence on the environmental behaviour of the residue under concern, as well as the potential of the process in terms of sequestration of the CO2. APC residues are considered hazardous waste and must be treated before final disposal in order to achieve the immobilization/mobilization of critical contaminants such as heavy metals as well as mobilization of soluble salts. The treatment applied proved to be effective in reducing the mobility of Pb, Zn, Cr, Cu and Mo, the optimum final pH for the carbonated APC residues being in a range of 10-10.5, whilst a mobilization effect was noticed for Sb and no effect was assessed for chlorides. The effect of carbonation treatment on the contaminant release was further evaluated by means of a sequential extraction procedure, indicating that the distribution of contaminants on water soluble, exchangeable and carbonate fraction was modified after treatment. The CO2 sequestration potential assessed for the APC residues showed that the carbonation technology could be a technically viable option in order to reduce emissions from WtE plants. PMID- 21601358 TI - Fast kinetic and efficient removal of As(V) from aqueous solution using anion exchange resins. AB - Glycidyl methacrylate/methelenebisacrylamide resin with immobilized tetraethylenepentamine ligand was prepared. This pentamine containing resin was transformed to two anion exchange resins through treatment by glycidyl trimethylammonium chloride to give (RI) or hydrochloric acid giving (RII). The resins were used to adsorb As(V) at different experimental conditions using batch and column methods. Kinetics and thermodynamic properties as well as the mechanism of interaction between As(V) and resin active sites were discussed. The maximum adsorption capacities of As(V) on RI and RII were found to be 1.83 and 1.12 mmol/g, respectively. The regeneration and the durability of the loaded resin towards the successive reuse were also investigated. PMID- 21601359 TI - Speciation of arsenic in rice and estimation of daily intake of different arsenic species by Brazilians through rice consumption. AB - Rice is an important source of essential elements. However, rice may also contain toxic elements such as arsenic. Therefore, in the present study, the concentration of total arsenic and five main chemical species of arsenic (As(3+), As(5+), DMA, MMA and AsB) were evaluated in 44 different rice samples (white, parboiled white, brown, parboiled brown, parboiled organic and organic white) from different Brazilian regions using high-performance liquid chromatography hyphenated to inductively coupled plasma mass spectrometry (HPLC-ICP-MS). The mean level of total arsenic was 222.8 ng g(-1) and the daily intake of inorganic arsenic (the most toxic form) from rice consumption was estimated as 10% of the Provisional Tolerable Daily Intake (PTDI) with a daily ingestion of 88 g of rice. Inorganic arsenic (As(3+), As(5+)) and dimethylarsinic acid (DMA) are the predominant forms in all samples. The percentages of species were 38.7; 39.7; 3.7 and 17.8% for DMA, As(3+), MMA and As(5+), respectively. Moreover, rice samples harvested in the state of Rio Grande do Sul presented more fractions of inorganic arsenic than rice in Minas Gerais or Goias, which could lead to different risks of arsenic exposure. PMID- 21601360 TI - Consequence of chitosan treating on the adsorption of humic acid by granular activated carbon. AB - In this work, equilibrium and kinetic adsorption of humic acid (HA) onto chitosan treated granular activated carbon (MGAC) has been investigated and compared to the granular activated carbon (GAC). The adsorption equilibrium data showed that adsorption behaviour of HA could be described reasonably well by Langmuir adsorption isotherm for GAC and Freundlich adsorption isotherm for MGAC. It was shown that pre-adsorption of chitosan onto the surface of GAC improved the adsorption capacity of HA changing the predominant adsorption mechanism. Monolayer capacities for the adsorption of HA onto GAC and MGAC were calculated 55.8 mg/g and 71.4 mg/g, respectively. Kinetic studies showed that film diffusion and intra-particle diffusion were simultaneously operating during the adsorption process for MGAC. PMID- 21601361 TI - Effect of illite and birnessite on thallium retention and bioavailability in contaminated soils. AB - The influence of illite and birnessite (delta-MnO(2)) amendments on the retention and bioavailability of Tl in contaminated soils was investigated. The efficiency of both phases was evaluated using Tl uptake by white mustard (Sinapis alba L.), sequential extraction and sorption experiments. The obtained data demonstrate that the application of birnessite can effectively transform Tl from the labile (easily mobilizable) fraction to its reducible form, thus lowering Tl bioavailability in soil and subsequent accumulation by plants. The Mn oxide added to the soils reduced substantially Tl uptake; Tl levels in the plants decreased by up to 50%, compared to the non-amended soil. The effect of illite on the immobilization and uptake of Tl was less pronounced, and in the carbonate-rich Leptosol has not been proved at all, suggesting the importance of bulk soil mineralogy and nature of the soil sorption complex on the behavior of this amendment. Therefore, the general applicability of illite for Tl stabilization in soils seems to be limited and strongly dependent on soil composition. In contrast, the use of birnessite like soil additive might be an efficient and environment-friendly solution for soil systems contaminated with Tl. PMID- 21601362 TI - Statins, vitamin D, and neuropathic pain. PMID- 21601364 TI - Transcriptional regulation by DNA methylation. AB - Epigenetic mechanisms synergize with genetic alterations in modulating gene expression patterns in cancer cells. While epigenetic alterations are reversible genetic modifications are not. This has raised the attention of many groups to focus on a better understanding of the molecular mechanisms that underlie the establishment of altered DNA methylation, histone modifications patterns and miRNA expression. The improved understanding of these mechanisms we will in turn allow us to improve the strategies that can be used for epigenetic therapies. In this review we will discuss and summarize briefly our current knowledge of epigenetic alterations in leukemias and will turn our attention to a concrete example of epigenetic deregulation of CCAAT/enhancer-binding protein alpha (C/EBPalpha), a key regulator for granulocytic differentiation of common myeloid progenitor cells in order to highlight the cooperativity of genetic and epigenetic mechanisms acting on this gene during the process of leukemogenesis. PMID- 21601367 TI - Evaluating the vascularity of intestinal anastomoses--can narrow band imaging play a role? AB - A variety of factors are critical for the success of bowel anastomoses. The most crucial patient factor is adequate vascularity of the bowel ends which are to be anastomosed. Currently, intraoperative features such as healthy looking bleeding edges of the bowel are considered to be signs of adequate vascular supply. However, once the anastomosis is performed, external appearances may not be reliable. In order to improve evaluation of the bowel as well as the anastomosis, our group has adopted the routine use of post-anastomosis intraoperative colonoscopy. Intraoperative colonoscopy provides vital information regarding the integrity of the anastomosis (leak testing) and also visualizes the mucosa of the bowel. Narrow Band Imaging (NBI) is a novel real-time imaging technique which is an integral component of many modern colonoscopes. We hypothesize that NBI assessment of vascularity at the time of intestinal anastomosis can improve safety and reduce the risks of anastomotic complications following surgery. PMID- 21601365 TI - Poorer self-rated health is associated with elevated inflammatory markers among older adults. AB - OBJECTIVE: Self-rated health is a strong independent predictor of mortality after accounting for objective health status, behavioral risk factors, and sociodemographic characteristics. However, mechanisms underlying this association are largely unexplained. Inflammation has been associated with increased risk of morbidity and mortality in the elderly. The current study aimed to: (1) examine associations between self-rated health and serum inflammatory markers in older adults; (2) examine the relative strength of these associations for self-rated health versus self-rated change in recent health; (3) examine components of self rated health that may underlie the association between inflammation and global self-rated health. METHODS: Self-rated health, as measured by the RAND health survey, and serum interleukin (IL)-6 and C-reactive protein (CRP) were assessed among 250 generally healthy older adults (185 women, 65 men; average age=63.8+/ 13.7 years). RESULTS: A series of linear regression analyses demonstrated that poorer self-rated health was significantly associated with higher IL-6 and CRP. These relationships remained after controlling for age, body mass index, gender, and objective health conditions. These associations also remained after controlling for depressive symptoms, neuroticism, perceived change in health over the past year, and health behaviors (smoking, sleep quality, and physical activity). Analyses of RAND component measures demonstrated that poorer physical functioning was significantly associated with IL-6; the relationship between global self-rated health and both IL-6 and CRP remained after accounting for perceived physical functioning. CONCLUSIONS: Poorer self-rated health is associated with elevated serum inflammatory markers among generally healthy older adults. The relationship of self-rated health with inflammatory markers is not secondary to depressive symptoms, neuroticism, or recent changes in perceived health. Subjective ratings of health provide important clinical information regarding inflammatory status, beyond traditional objective risk factors, even among generally healthy individuals. PMID- 21601368 TI - ACI and MACI procedures for cartilage repair utilise mesenchymal stem cells rather than chondrocytes. PMID- 21601366 TI - Cortisol suppression by dexamethasone reduces exaggerated fear responses in posttraumatic stress disorder. AB - PTSD symptoms are associated with heightened fear responses in laboratory fear conditioning paradigms. This study examined the effects of dexamethasone administration on hypothalamic-pituitary-adrenal (HPA) function and fear potentiated startle (FPS) in trauma-exposed individuals with and without PTSD. We used an established fear discrimination procedure, in which one visual stimulus (CS+, danger cue) was paired with aversive airblasts to the throat (unconditioned stimulus, US), and another stimulus (CS-, safety cue) was presented without airblasts. In addition to FPS, the dexamethasone suppression test (DST) was performed. The study sample (N=100) was recruited from a highly traumatized civilian population in Atlanta, GA. Half of the subjects (n=54, 16 PTSD, 38 controls) underwent conditioning at baseline and the other half (n=46, 17 PTSD, 29 controls) after DST, in a cross-sectional design. We found a significant interaction effect of diagnostic group and dexamethasone treatment. Under baseline conditions, subjects with PTSD showed more than twice as much fear potentiated startle to the danger cue compared to traumatized controls, F(1,53)=8.08, p=0.006. However, there was no group difference in subjects tested after dexamethasone suppression. Furthermore, there was a significant treatment effect in PTSD subjects but not in controls, with dexamethasone reducing fear potentiated startle to the CS+, F(1,32)=4.00, p=0.05. There was also a positive correlation between PTSD subjects' FPS and cortisol levels, r=0.46, p=0.01. These results suggest that transient suppression of HPA function via dexamethasone suppression may reduce exaggerated fear in patients with PTSD. PMID- 21601369 TI - Fibrin glue coating of the surgical surfaces may facilitate formation of a successful bleb in trabeculectomy surgery. AB - Trabeculectomy is commonly conducted when medical therapy fails to control intraocular pressure (IOP). The success of trabeculectomy for the treatment of glaucoma depends on the wound-healing response at the subconjunctival filtering bleb site. Postoperative scar formation is a serious problem in this surgery. Current strategies to counteract scarring include local antimetabolite treatment, which is associated with severe side effects, limiting its application. Therefore, additional means to safely modulate wound healing are desirable. In ophthalmic surgery, fibrin glue is used mainly for sealing and hemostatics purpose. Fibrin glue coating of tenon face of conjunctiva, scleral surface, reverse face of scleral flap and scleral bed with insoluble fibrin glue can halt both ooze bleeding and vascular leakage. By retarding the first step of wound healing, less postoperative inflammation may occur. Additionally aqueous humor flows through a fibrin glue coated interface. Therefore, we hypothesize that fibrin glue coating of the surgical surfaces in trabeculectomy surgery may yield less subconjunctival fibrosis and more successful bleb. To the best of our knowledge, no basic research has yet been performed regarding fibrin glue coating for halting the vascular leakage and easing the aqueous drainage into subconjunctival space in glaucoma surgery. PMID- 21601370 TI - A new choice for the treatment of epilepsy: electrical auricula-vagus stimulation. AB - Preliminary reports have suggested that chronic, intermittent electrical stimulation of the cervical vagus nerve (VNS) is an effective treatment for patients who suffered from medically refractory epilepsy. But the traditional VNS is an invasive and implantable procedure that will bring some injury to the patient. Anatomic studies have confirmed the existence of auricular branch of the vagus nerve-Arnold nerve. The Arnold nerve mainly consists of afferent fibers and the superficial sites of the Arnold nerve are optimal for electrical stimulation. We hypothesized that electrical auricula-vagus-stimulation could be a new choice for the treatment of epilepsy. PMID- 21601371 TI - A comprehensive analysis of cardiac dose in balloon-based high-dose-rate brachytherapy for left-sided breast cancer. AB - PURPOSE: To investigate radiation dose to the heart in 60 patients with left sided breast cancer who were treated with balloon-based high-dose-rate brachytherapy using MammoSite or Contura applicators. METHODS AND MATERIALS: We studied 60 consecutive women with breast cancer who were treated with 34 Gy in 10 twice-daily fractions using MammoSite (n = 37) or Contura (n = 23) applicators. The whole heart and the left and right ventricles were retrospectively delineated, and dose-volume histograms were analyzed. Multiple dosimetrics were reported, such as mean dose (D(mean)); relative volume receiving 1.7, 5, 10, and 20 Gy (V1.7, V5, V10, and V20, respectively); dose to 1 cc (D(1cc)); and maximum point dose (D(max)). Biologic metrics, biologically effective dose and generalized equivalent uniform dose were computed. The impact of lumpectomy cavity location on cardiac dose was investigated. RESULTS: The average +/- standard deviation of D(mean) was 2.45 +/- 0.94 Gy (range, 0.56-4.68) and 3.29 +/ 1.28 Gy (range, 0.77-6.35) for the heart and the ventricles, respectively. The average whole heart V5 and V10 values were 10.2% and 1.3%, respectively, and the heart D(max) was >20 Gy in 7 of 60 (11.7%) patients and >25 Gy in 3 of 60 (5%) patients. No cardiac tissue received >=30 Gy. The V1.7, V5, V10, V20, and D(mean) values were all higher for the ventricles than for the whole heart. For balloons located in the upper inner quadrant of the breast, the average whole heart D(mean) was highest. The D(mean), biologically effective dose, and generalized equivalent uniform dose values for heart and ventricles decreased with increasing minimal distance from the surface of the balloon. CONCLUSIONS: On the basis of these comprehensive cardiac dosimetric data, we recommend that cardiac dose be routinely reported and kept as low as possible in balloon-based high-dose-rate brachytherapy treatment planning for patients with left-sided breast cancer so the correlation with future cardiac toxicity data can be investigated. PMID- 21601372 TI - Phase II study evaluating the addition of cetuximab to the concurrent delivery of weekly carboplatin, paclitaxel, and daily radiotherapy for patients with locally advanced squamous cell carcinomas of the head and neck. AB - PURPOSE: To report the mature data of a prospective Phase II trial designed to evaluate the efficacy of an epidermal growth factor receptor inhibitor cetuximab (CTX) added to the concurrent therapy of weekly paclitaxel/carboplatin (PC) and daily radiation therapy (RT). METHODS AND MATERIALS: From 2005 to 2009, a total of 43 patients were enrolled in the study. The median follow-up was 31 months (range, 9-59 months). All patients had Stage III/IV disease at presentation, and 67% had oropharyngeal primaries. The weekly IV dose schedules were CTX 250 mg/m(2) (400 mg/m(2) IV loading dose 1 week before RT), paclitaxel 40 mg/m(2), and carboplatin AUC 2. RT was given at 1.8 Gy per day to 70.2 Gy. Intensity modulated RT was used in 70% of cases. RESULTS: All patients completed the planned RT dose, 74% without any treatment breaks. The planned CTX and PC cycles were completed in 70% (91% with at least seven of planned nine cycles) and 56% (93% with at least seven of planned eight cycles) of patients, respectively. Toxicity included Grade 3 mucositis (79%), rash (9%), leucopenia (19%), neutropenia (19%), and RT dermatitis (16%). The complete response (CR) rate at the completion of therapy was 84%. The estimated 3-year local regional control rate was 72%. Six patients with an initial CR subsequently experienced a local recurrence, 10 patients experienced distant progression. The median overall survival and disease-free survivals have not been reached. The 3-year actuarial overall survival and disease-free survival were 59% and 58%, respectively. CONCLUSIONS: The addition of CTX to weekly PC and daily RT was well tolerated and resulted in encouraging local control and survival rates. PMID- 21601373 TI - Dynamic contrast-enhanced magnetic resonance imaging as a predictor of outcome in head-and-neck squamous cell carcinoma patients with nodal metastases. AB - PURPOSE: Dynamic contrast-enhanced MRI (DCE-MRI) can provide information regarding tumor perfusion and permeability and has shown prognostic value in certain tumors types. The goal of this study was to assess the prognostic value of pretreatment DCE-MRI in head and neck squamous cell carcinoma (HNSCC) patients with nodal disease undergoing chemoradiation therapy or surgery. METHODS AND MATERIALS: Seventy-four patients with histologically proven squamous cell carcinoma and neck nodal metastases were eligible for the study. Pretreatment DCE MRI was performed on a 1.5T MRI. Clinical follow-up was a minimum of 12 months. DCE-MRI data were analyzed using the Tofts model. DCE-MRI parameters were related to treatment outcome (progression-free survival [PFS] and overall survival [OS]). Patients were grouped as no evidence of disease (NED), alive with disease (AWD), dead with disease (DOD), or dead of other causes (DOC). Prognostic significance was assessed using the log-rank test for single variables and Cox proportional hazards regression for combinations of variables. RESULTS: At last clinical follow-up, for Stage III, all 12 patients were NED. For Stage IV, 43 patients were NED, 4 were AWD, 11 were DOD, and 4 were DOC. K(trans) is volume transfer constant. In a stepwise Cox regression, skewness of K(trans) (volume transfer constant) was the strongest predictor for Stage IV patients (PFS and OS: p <0.001). CONCLUSION: Our study shows that skewness of K(trans) was the strongest predictor of PFS and OS in Stage IV HNSCC patients with nodal disease. This study suggests an important role for pretreatment DCE-MRI parameter K(trans) as a predictor of outcome in these patients. PMID- 21601374 TI - Sequencing of local therapy affects the pattern of treatment failure and survival in children with atypical teratoid rhabdoid tumors of the central nervous system. AB - PURPOSE: To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT). METHODS AND MATERIALS: Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated. RESULTS: Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45-16.87 years) were enrolled into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% +/- 9%; progression-free survival was 33.2% +/- 10%; and OS was 53.5% +/- 10%. Children receiving delayed RT (>=1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT. CONCLUSIONS: Delayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed. PMID- 21601375 TI - Concurrent chemoradiotherapy followed by consolidation chemotherapy with bi weekly docetaxel and carboplatin for stage III unresectable, non-small-cell lung cancer: clinical application of a protocol used in a previous phase II study. AB - PURPOSE: To assess the clinical applicability of a protocol evaluated in a previously reported phase II study of concurrent chemoradiotherapy followed by consolidation chemotherapy with bi-weekly docetaxel and carboplatin in patients with stage III, unresectable, non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Between January 2000 and March 2006, 116 previously untreated patients with histologically proven, stage III NSCLC were treated with concurrent chemoradiotherapy. Radiation therapy was administered in 2-Gy daily fractions to a total dose of 60 Gy in combination with docetaxel, 30 mg/m(2), and carboplatin at an area under the curve value of 3 every 2 weeks during and after radiation therapy. RESULTS: The median survival time for the entire group was 25.5 months. The actuarial 2-year and 5-year overall survival rates were 53% and 31%, respectively. The 3-year cause-specific survival rate was 60% in patients with stage IIIA disease, whereas it was 35% in patients with stage IIIB disease (p = 0.007). The actuarial 2-year and 5-year local control rates were 62% and 55%, respectively. Acute hematologic toxicities of Grade >=3 severity were observed in 20.7% of patients, while radiation pneumonitis and esophagitis of Grade >=3 severity were observed in 2.6% and 1.7% of patients, respectively. CONCLUSIONS: The feasibility of the protocol used in the previous phase II study was reconfirmed in this series, and excellent treatment results were achieved. PMID- 21601376 TI - Toxicity of gamma knife radiosurgery in the treatment of intracranial tumors in patients with collagen vascular diseases or multiple sclerosis. AB - PURPOSE: To assess toxicity in patients with either a collagen vascular disease (CVD) or multiple sclerosis (MS) treated with intracranial radiosurgery. METHODS AND MATERIALS: Between January 2004 and April 2009, 6 patients with MS and 14 patients with a CVD were treated with Gamma Knife radiosurgery (GKRS) for intracranial tumors. Treated lesions included 15 total brain metastases in 7 patients, 11 benign brain tumors, 1 low grade glioma, and 1 cavernous malformation. Toxicities were graded by the Radiation Therapy Oncology Group Acute/Late Radiation Morbidity Scoring Criteria. "Rare toxicities" were characterized as those reported in the scientific literature at an incidence of <5%. RESULTS: Median follow-up time was 16 months. Median dose to the tumor margin was 13.0 Gy (range, 12-21 Gy). Median size of tumor was 5.0 cm(3) (range, 0.14-7.8 cm(3)). Of the 14 patients with CVD, none experienced a Grade 3 or 4 toxicity or a toxicity characterized as rare. Of the 6 patients with MS, 3 experienced rare toxicities, and two of these were Grade 3 toxicities. Rare complications included a patient experiencing both communicating hydrocephalus and facial nerve palsy, as well as 2 additional patients with motor cranial nerve palsy. High-grade toxicities included the patient with an acoustic neuroma requiring ventriculoperitoneal shunt placement for obstructive hydrocephalus, and 1 patient with a facial nerve schwannoma who experienced permanent facial nerve palsy. Interval between radiosurgery and high-grade toxicities ranged from 1 week to 4 months. CONCLUSIONS: Our series suggests that patients with MS who receive GKRS may be at increased risk of rare and high-grade treatment-related toxicity. Given the time course of toxicity, treatment-related edema or demyelination represent potential mechanisms. PMID- 21601378 TI - Early-stage young breast cancer patients: impact of local treatment on survival. AB - PURPOSE: In young women, breast-conserving therapy (BCT), i.e., lumpectomy followed by radiotherapy, has been associated with an increased risk of local recurrence. Still, there is insufficient evidence that BCT impairs survival. The aim of our study was to compare the effect of BCT with mastectomy on overall survival (OS) in young women with early-stage breast cancer. METHODS AND MATERIALS: From two Dutch regional population-based cancer registries (covering 6.2 million inhabitants) 1,453 women <40 years with pathologically T1N0-1M0 breast cancer were selected. Cox regression survival analysis was used to study the effect of local treatment (BCT vs. mastectomy) stratified for nodal stage on survival and corrected for tumor size, age, period of diagnosis, and use of adjuvant systemic therapy. RESULTS: With a median follow-up of 9.6 years, 10-year OS was 83% after BCT and 78% after mastectomy, respectively (unadjusted hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.09-1.72). In N0-patients, 10 year OS was 84% after BCT and 81% after mastectomy and local treatment was not associated with differences in OS (HR 1.19; 95% CI, 0.89-1.58; p = 0.25). Within the N1-patient group, OS was better after BCT compared with mastectomy, 79% vs. 71% at 10 years (HR 1.91; 95% CI, 1.28-2.84; p = 0.001) and in patients treated with adjuvant hormonal therapy (HR 0.34; 95% CI, 0.18-0.66; p = 0.001). CONCLUSIONS: In this large population-based cohort of early-stage young breast cancer patients, 10-year OS was not impaired after BCT compared with mastectomy. Patients with 1 to 3 positive lymph nodes had better prognosis after BCT than after mastectomy. PMID- 21601377 TI - Basal subtype of invasive breast cancer is associated with a higher risk of true recurrence after conventional breast-conserving therapy. AB - PURPOSE: To determine whether breast cancer subtype is associated with patterns of ipsilateral breast tumor recurrence (IBTR), either true recurrence (TR) or elsewhere local recurrence (ELR), among women with pT1-T2 invasive breast cancer (IBC) who receive breast-conserving therapy (BCT). METHODS AND MATERIALS: From Jan 1998 to Dec 2003, 1,223 women with pT1-T2N0-3 IBC were treated with BCT (lumpectomy plus whole-breast radiation). Ninety percent of patients received adjuvant systemic therapy, but none received trastuzumab. Biologic cancer subtypes were approximated by determining estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), and human epidermal growth factor receptor 2-positive (HER-2+) expression, classified as luminal A (ER+ or PR+ and HER-2 negative [HER-2-]), luminal B (ER+ or PR+ and HER-2+), HER-2 (ER- and PR- and HER 2+), and basal (ER- and PR- and HER-2- ) subtypes. Imaging, pathology, and operative reports were reviewed by two physicians independently, including an attending breast radiologist. Readers were blinded to subtype and outcome. TR was defined as IBTR within the same quadrant and within 3 cm of the primary tumor. All others were defined as ELR. RESULTS: At a median follow-up of 70 months, 24 patients developed IBTR (5-year cumulative incidence of 1.6%), including 15 TR and 9 ELR patients. At 5 years, basal (4.4%) and HER-2 (9%) subtypes had a significantly higher incidence of TR than luminal B (1.2%) and luminal A (0.2%) subtypes (p < 0.0001). On multivariate analysis, basal subtype (hazard ratio [HR], 4.8, p = 0.01), younger age at diagnosis (HR, 0.97; p = 0.05), and increasing tumor size (HR, 2.1; p = 0.04) were independent predictors of TR. Only younger age (HR, 0.95; p = 0.01) significantly predicted for ELR. CONCLUSIONS: Basal and HER-2 subtypes are significantly associated with higher rates of TR among women with pT1-T2 IBC after BCT. Younger age predicts for both TR and ELR. Strategies to reduce TR in basal breast cancers, such as increased boost doses, concomitant radiation and chemotherapy, or targeted therapy agents, should be explored. PMID- 21601379 TI - Substance-related traffic-risk behaviors among college students. AB - AIMS: Drunk driving is a major public health concern, but drugged driving has received little attention. This study examines drugged driving and riding with a drugged driver in a college student sample, in terms of prevalence, age-related trends, race/sex differences, overlap with drunk driving, and risk for alcohol and marijuana dependence. METHODS: Students (N=1194) ages 19-22 were interviewed annually for 3 years about past-year frequency of drugged driving, riding with a drugged/drunk driver, drunk driving, access to a car, and alcohol/drug dependence. Annual follow-up rates were excellent (88-91%). Repeated measures analyses were conducted using generalized estimating equations (GEE). RESULTS: One in six (17%(wt)) 19-year-olds with access to a car drove drugged in the past year; prevalence remained stable through age 22. Drugged driving was more prevalent among males (p<.001) and whites (p<.01). Riding with a drugged driver varied by race and sex (overall prevalence 28%(wt) at age 19), was stable from age 19 to 21, and decreased by age 22 (p<.05). Annually, half of drugged drivers also drove drunk (ranges between 47% and 60%). Both drugged and drunk driving were independently associated with increased risk for alcohol dependence, holding constant age, sex, and race. Drunk driving did not add to the risk for marijuana dependence in the context of drugged driving. CONCLUSIONS: The prevalence of drugged driving is similar to drunk driving among college students. Both are strongly associated with underlying alcohol and drug dependence. Prevention and treatment implications are discussed. PMID- 21601380 TI - The social context of homeless men's substance use. AB - BACKGROUND: Homeless men may be at particular risk for the negative health effects of substance use. This cross-sectional study investigates the individual and personal network risk factors associated with substance use in this vulnerable population. METHODS: Participants were a representative probability sample of 305 heterosexually active homeless men interviewed from meal programs in the Skid Row region of Los Angeles, CA. Interviews assessed individual, personal network, and substance use characteristics. Logistic regression examined individual and personal network predictors of the three most prevalent substances. RESULTS: In the past 6 months, the three most prevalent substances were marijuana (56%), crack (40%), and alcohol to intoxication (38%). The mental health status of homeless men was associated with substance use, with PTSD more common among those who used crack. Riskier networks (comprised of a larger proportion of drug users) were associated with marijuana use, and normative social ties (family, employed and school/work contacts) were associated with a decreased likelihood of crack use. CONCLUSIONS: Mental health problems and riskier personal networks are associated with homeless men's substance use. These findings underscore the importance of interventions that focus on improving mental health, mitigating the drug-using norms of personal networks, and helping men to maintain contact with normative, low-risk alters. Mental health care and peer-based, network interventions to reduce substance use should be a priority for heterosexually active homeless men. PMID- 21601381 TI - Immunoproteomic analysis of the antibody response obtained in Nile tilapia following vaccination with a Streptococcus iniae vaccine. AB - Streptococcus iniae is one of the most economically important Gram-positive pathogens in cultured fish species worldwide. The USDA-ARS Aquatic Animal Health Research Unit developed a modified (contains concentrated culture supernatant) S. iniae bacterin that has been demonstrated to be efficacious, and protection is mediated by specific anti-S. iniae antibodies. Although effective, the specific vaccine components important for efficacy are not known. In the present study, an immunoproteomic approach was utilized to identify whole-cell lysate proteins of S. iniae that stimulated specific antibody production in Nile tilapia (Oreochromis niloticus) following vaccination. Groups of tilapia were vaccinated by intraperitoneal injection with the modified S. iniae bacterin or were mock vaccinated, and at 30 d post-vaccination sera samples were obtained from individual fish. Vaccination of tilapia with the S. iniae vaccine stimulated significantly elevated specific antibody responses against proteins of the bacterium and passive immunization of tilapia with this serum demonstrated the antibodies were highly protective. Whole-cell lysate proteins of S. iniae were separated by 2D-PAGE and were probed with a pooled serum sample from vaccinated tilapia. A total of eleven unique immunogenic proteins were positively identified by mass spectrometry. Based on research conducted on homologous proteins in other Streptococcus spp., antibodies specific for three of the identified proteins, enolase, glyceraldehyde-3-phosphate dehydrogenase, and fructose-bisphosphate aldolase, are likely involved in protection from streptococcosis caused by S. iniae. PMID- 21601382 TI - Intraspecific sequence variation in 16S rRNA gene of Ureaplasma diversum isolates. AB - Ureaplasma diversum infection in bulls may result in seminal vesiculitis, balanoposthitis and alterations in spermatozoids. In cows, it can cause placentitis, fetal alveolitis, abortion and the birth of weak calves. U. diversum ATCC 49782 (serogroups A), ATCC 49783 (serogroup C) and 34 field isolates were used for this study. These microorganisms were submitted to Polymerase Chain Reaction for 16S gene sequence determination using Taq High Fidelity and the products were purified and bi-directionally sequenced. Using the sequence obtained, a fragment containing four hypervariable regions was selected and nucleotide polymorphisms were identified based on their position within the 16S rRNA gene. Forty-four single nucleotide polymorphisms (SNP) were detected. The genotypic variability of the 16S rRNA gene of U. diversum isolates shows that the taxonomy classification of these organisms is likely much more complex than previously described and that 16S rRNA gene sequencing may be used to suggest an epidemiologic pattern of different origin strains. PMID- 21601383 TI - The response of luteinizing hormone secretion to photoperiod is modified by the level of nutrition in female Mediterranean goats. AB - This paper reports the influence of nutrition on the photoperiodic control of luteinizing hormone (LH) secretion in female Mediterranean goats (i.e., goats from the Mediterranean area in general). Ovariectomized, oestradiol-treated goats were subjected to two consecutive intervals of 3 months of long days followed by 3 months of short days (group LDSD, N=20), or vice versa (group SDLD, N=20). The LDSD and SDLD does were also randomly assigned to one of two nutrition groups that received either 1.1 (H group, N=10) or 0.7 (L group, N=10) times their maintenance requirements. Live weight and body condition score were determined weekly and LH concentrations twice per week. To establish the pulsatility of secretion of LH, three periods of intensive sampling were undertaken. Melatonin was determined after a period of 45 short or long days. All photoperiod/nutrition groups showed large variations in LH concentrations according to photoperiod, with nutrition having a significant effect (P<0.001). The mean time between the shift from long to short days and the stimulation of LH secretion, and between the shift from short to long days and the inhibition of LH secretion, was different in each nutrition group (at least P<0.05). No differences were seen in the frequency of LH pulses between the nutrition groups, but differences between sampling periods were observed (P<0.001). Melatonin secretion was not affected by food supply. These results confirm: (1) that Mediterranean female goats are sensitive to photoperiod, (2) that this environmental cue may control the timing of pituitary activity under natural conditions, and (3) suggest that nutrition plays an important role in the effect of photoperiod on LH secretion. PMID- 21601385 TI - Production and health assessment of second-generation cloned Holstein cows derived by somatic cell nuclear transfer. AB - In this study we evaluated cloning efficiency of second-generation (G2) cloned Holstein cows derived from ear fibroblasts of a first-generation (G1) cloned cow, and assessed their health status in terms of physical, growth and reproductive parameters. Compared with G1 cloning, G2 cloning showed a slight decrease on blastocyst rate of reconstructed embryos (30.2+/-5.8% vs. 28.5+/-7.2%, p>0.05), while the quality of its blastocysts reduced significantly (Grade 1 and Grade 2, 21.1+/-4.1% vs. 17.1+/-5.7%, p<0.05). After embryo transfer (ET), both pregnancy rate to term and calving rate of G2 cloning were approximately half of G1 cloning (5.8% vs. 10.7%; 3.9% vs. 8.6%, p>0.05). Six G2 cloned cows were delivered, and three of them survived. G2 cloned calves displayed symptoms of being overweight at birth and tachycardia in the first week after birth. During the first 12 months, the growth of G2 cloned calves was similar to control calves derived from artificial insemination (AI). Furthermore, the interindividual variation of growth within the G2 clonal family was smaller except at birth and at two months of age. Interestingly, although G2 cloned cows reached puberty 45 days later in comparison with control cows derived from AI, they were all pregnant by AI, and gave birth to healthy calves. This suggests that their reproductive performance was not affected by late puberty. In summary, our results showed that although cloning efficiency of G2 was lower than that of G1, the surviving G2 clones appeared physically healthy and were fertile. PMID- 21601384 TI - Undiluted or extended storage of ram epididymal spermatozoa as alternatives to refrigerating the whole epididymes. AB - The effect of storage procedure at 5 degrees C on the quality of ram spermatozoa from the cauda epididymis was analyzed. Two strategies were tested at 0, 24, 48 and 72h post-mortem: (1) spermatozoa held in the epididymal fluid and stored either in the cauda epididymis (In-EPID) or in vitro (Ex-EPID), (2) epididymal spermatozoa extended in three media at 320, 370 and 420 mOsm/kg (D320, D370, D420). Analyzed parameters were: osmolality, pH, motility, acrosomal status and viability. In experiment 1, osmolality of the In-EPID samples, but not in Ex EPID, increased with post-mortem time. Motility of In-EPID spermatozoa in samples, after 24h post-mortem, was higher compared to the Ex-EPID samples, although differences decreased at 48 and 72h. In experiment 2, total (TM) and progressive motility (PM) were not significantly affected by storage time for D320 and In-EPID samples. However, the motility of D370 and D420 samples significantly decreased with time. TM and PM of D320 were significantly higher than D370 and D420 at 72h. At 24h, sperm viability was higher for In-EPID (80.7+/ 3.4%) than for the extended samples (44.8+/-2.9%, 37.7+/-3.9% and 48.6+/-6.0% for D320, D370 and D420, respectively), which also decreased faster with time. At 24h, the percentage of damaged acrosomes was low and similar for the four methods of storage, but damaged acrosomes increased with time for D320 and D370. Storing the spermatozoa in the epididymis is a good strategy for maintaining sperm quality in ram, at least for 48h. The D320 extender preserve motility of epididymal spermatozoa but does not protect the status of the acrosome. PMID- 21601386 TI - Expression of genes for oestrogen and progesterone receptors in the cervix of anoestrous ewes treated with gonadotrophin releasing hormone with or without progesterone priming. AB - The aim was to determine the oestrogens receptor alpha (ERalpha) mRNA and the binding capacity of oestrogens (ER) and progesterone receptor (PR) in the cervix of anoestrous ewes treated with gonadotrophin-releasing hormone (GnRH) with or without progesterone (P) priming, at the expected time of induced ovulation and early luteal phase. In Experiment 1, ewes were treated with P for 10 days (n=4), with nine micro-doses of GnRH followed by a GnRH bolus injection (n=4), or with P plus GnRH treatments (n=3), and tissues were harvested either without treatment (n=4), when P was removed, or 24h after the GnRH bolus injection. In Experiment 2, ewes were treated with the same GnRH or P plus GnRH treatments and tissues were harvested on Day 1 (n=12) or Day 5 (n=10) after the GnRH bolus injection. In the cranial cervix, the P treatment decreased and the GnRH treatment (after P treatment) increased the ERalpha mRNA, ER and PR concentrations (P<0.002). The ERalpha mRNA and ER concentrations were greater on Day 1, than on Day 5 in P plus GnRH treated ewes (P<0.0005). In the caudal cervix, lesser ERalpha mRNA, ER and PR concentrations than cranial cervix were found (P<0.0001). In conclusion, the ERalpha transcriptional activity and ER and PR binding capacity were strongly influenced by P and/or GnRH treatments in the cranial cervix, while the steroid receptors binding capacity remained unchanged in the caudal cervix of anoestrous ewes at the expected time of induced ovulation and early luteal phase. PMID- 21601387 TI - The analysis of substituted cathinones. Part 1: chemical analysis of 2-, 3- and 4 methylmethcathinone. AB - The ring substituted methyl isomers of methcathinone, 2-, 3- and 4 methylmethcathinone were analysed. The 2- and 3-isomers were synthesized. The 4 methylmethcathinone isomer is also known as mephedrone and has been widely studied. We present GCMS, NMR and IR data for the three isomers. We show that the three isomers can be separated by GCMS and that the IR spectra for the three compounds can be used to distinguish between them. A seized sample was analysed and it was found to contain 4-methylmethcathinone and benzocaine. PMID- 21601388 TI - Evaluation of two immunoassay procedures for drug testing in hair samples. AB - A preliminary initial enzyme-linked immunosorbent assay (LUCIO-Direct ELISA kit) and a preliminary DRI enzyme immunoassay were evaluated for drug detection in head hair with respect to lowered cutoff values recommended in Germany for the control of abstinence in cases of re-granting of drivers' licences. Following drug classes were included: cannabinoids, opiates, cocaine like substances, amphetamine, methamphetamine (and methylenedioxyamphetamines), methadone, and benzodiazepines. 759 analyses were performed using LUCIO-Direct ELISA kits and 936 analyses using DRI enzyme immunoassay tests. Sample size for each drug group and immunoassay test reached from 74 to 178. The LUCIO-Direct ELISA kit revealed a sensitivity of 91% for amphetamine up to 98% for methadone (methamphetamine 92%, cocaine 94%, opiates 94%, benzodiazepines 96%) and values of specificity of 72% for methadone up to 89% for amphetamine and benzodiazepines. The test was not useful for a preliminary screening for tetrahydrocannabinol (sensitivity of 65%) in consideration of a suggested cutoff of 0.02 ng/mg. The DRI enzyme immunoassay test was only useful for morphine and cocaine testing at low recommended new cutoff values (0.1 ng/mg) revealing sensitivities of 94% and 99%, respectively. PMID- 21601389 TI - Larval-mass effect: Characterisation of heat emission by necrophageous blowflies (Diptera: Calliphoridae) larval aggregates. AB - Numerous Calliphoridae species larvae are necrophageous and develop on animal cadavers. During the feeding stages, a strong gregarious behaviour leads to the formation of large larval masses, allowing larvae to share digestive fluids. Furthermore, a mass of larvae emits heat, resulting in a local increase of temperature. Differences greater than 20 degrees C between ambient and larval mass temperatures have already been observed, and the temperature of the mass can reach 50 degrees C. Thus, larvae could benefit from this increased local temperature to speed up their development. This study focuses on the dynamic and characterisation of heat emission by Lucilia sericata (Diptera: Calliphoridae) (Meigen, 1826) larval masses. Experiments were performed under controlled conditions using several ambient temperatures and different numbers of larvae. Results indicate that heat emission depends on the instar and is strongly affected by available amount of food. Furthermore, according to the experimental data, the heat emission is also relative to the weight of the larval mass, the larvae number and the local temperature. These results also demonstrate that optimum ambient-temperature values ranging between 22 degrees C and 25 degrees C produce maximal heat-emission per larva. Furthermore, a feedback loop, involving heat exchanges and physiological and behavioural thermoregulation processes, appears inside aggregates. In the context of forensic cases and post-mortem interval (PMI) estimation, these results indicate that heat emission can occur even with "small" masses if they are composed of high number of second stage larvae. Furthermore, particular attention should be paid on cases involving L. sericata larvae at ambient temperature ranging from 22 degrees C to 25 degrees C, which appears to maximise the heat-emission process. PMID- 21601390 TI - An immunohistochemical study of sinonasal hemangiopericytoma. AB - We present herein the imaging and pathological features of a 28-year-old male with a sinonasal hemangiopericytoma-like tumor occupying the left nasal meatus. At the initial visit, a nasal polyp was suspected, but, as the patient was bleeding readily, an angiomatoid lesion was also regarded as a possible diagnosis. Based on a thorough histopathological analysis, a sinonasal hemangiopericytoma-like tumor was diagnosed. Hematoxylin and eosin staining also showed a mild degree of nuclear pleomorphism and a slight increase in mitotic activity, and immunohistochemical studies using anti-CD34, MIB-1, and Vimentin antibodies were useful for distinguishing the hemangiopericytoma-like tumor from true hemangiopericytoma and a solitary fibrous tumor. PMID- 21601391 TI - Reversible cochlear disorders with normal vestibular functions in three cases with Wegener's granulomatosis. AB - Patients with Wegener's granulomatosis (WG) often suffer from hearing loss, but its precise mechanisms have not been well understood. We experienced 3 WG cases whose initial symptoms were bilateral progressive mixed (both conductive and sensorineural) hearing loss, followed by systemic symptoms one year later. They were diagnosed as WG based on positive serology of anti-neutrophil cytoplasmic antibodies (ANCAs) and pathologic findings of affected lesions in addition to systemic symptoms. Although they were different in the type of ANCAs and systemic lesions, all showed considerably reversible cochlear disorders with normal vestibular functions. Moreover, their initial otologic manifestations shared same characteristic features, (1) thick ear drums with pulsatile serous intratympanic effusion, (2) poor speech discrimination ability, and (3) steroid-dependent changes of hearing levels (HLs). They exhibited no significant vestibular abnormalities in chair vestibule-ocular reflex (VOR) testing and cold air caloric tests even when they had severe hearing loss. On the basis of these results, we hypothesized that vasculitis of stria vascularis which generates endocochlear potential might cause these reversible cochlear-specific dysfunctions. PMID- 21601392 TI - Hearing aids reduce overestimation in pre-fitting self-assessment. AB - OBJECTIVE: When asking about hearing disability, the self-reported answers are not always equivalent to those of their family and neighbors. It is often experienced that family and neighbors indicate more severe hearing disability. Hearing difficulty itself may prevent hearing impaired subjects from understanding the degree of their own hearing disability. If their hearing impairment interferes with self-assessment of unaided hearing ability, it may change after a non-hearing aid user begins using hearing aids. METHODS: Thirty four adults who had almost no experience with using hearing aids participated in this study. Unaided hearing disability was assessed with visual analog scale (VAS) and ten 5-point category scales. The assessment was performed not only by the subject (pre-fitting self-assessment) but also by his/her family members, presumed to be understanding persons regarding the degree of his/her hearing disability (family-assessment). For evaluating the effect of amplification on self-assessment, re-assessment was performed more than three months later (post fitting self-assessment). The overestimation in the pre-fitting self-assessment and the effect of amplification were investigated in comparison to the family- and post-fitting self-assessments. RESULTS: The pre-fitting self-, family- and post-fitting self-VAS values for total hearing abilities were 50.5+/-15.6, 45.1+/ 14.7 and 34.3+/-18.8, respectively. The pre-fitting self-VAS value was significantly higher than the family- and post-fitting self-VAS values (p<0.05 and p<0.01, respectively). For the 5-point category scale, the pre-fitting self assessment was better than the family- and post-fitting self-assessments. Significant differences were observed in 1 and 2 situations, as compared with the family- and post-fitting self-assessments, respectively. These findings suggest the involvement of overestimation in pre-fitting self-assessment and its reduction after amplification with hearing aids. Although the pre-fitting self- and the family-VAS values were independent of the results of audiometric tests, the post-fitting self-VAS value was significantly related to the pure tone threshold and maximum speech recognition score (p<0.05). Regarding the changes in self-VAS values after amplification, the higher the pre-fitting self-VAS value, the larger the decrease in the self-VAS value. Thus, amplification with hearing aids may reduce overestimation and change self-assessment to reflect the audiometric assessments. CONCLUSION: The pre-fitting self-assessment of hearing disability involves over estimation which is exacerbated by hearing difficulty. A high pre-fitting VAS value may reflect a large overestimation in hearing ability. This overestimation can be improved by the amplification with hearing aids. PMID- 21601393 TI - Hearing loss in bullous myringitis. AB - OBJECTIVE: To evaluate the incidence of sensorineural and mixed hearing loss in patients with bullous myringitis. METHODS: Prospective observational study was conducted in a tertiary care medical center.Patients diagnosed as having bullous myringitis in our medical center between 2007 and 2009, underwent pure-tone audiometry upon presentation and were treated according to physicians' preferences RESULTS: Bullous myringitis was diagnosed in 43 patients (16 males, 27 females) with a mean age of 30.9 years (range 15-92). Thirty-six (83.7%) had unilateral infection (24 right, 12 left), and 7 (16.3%) had bilateral involvement. The most common type of hearing loss was mixed, detected in 24 patients (55.8%) and involving 27 of the 50 affected ears (54%). Seven patients (16.3%) had a conductive hearing loss, involving 9 ears (18%). Three patients (6.9%) presented with sensorineural hearing loss involving 5 ears (10%). The mean air-bone gap was 20.6+/-8.8dB. Down-slope audiometry was noted in 68.7% of the affected ears, followed by a U-shaped curve (25%). The sensorineural component mainly involved the high frequencies and the hearing loss ranged from slight to severe. CONCLUSION: The results of the present study demonstrate a high incidence of mixed or sensorineural hearing loss in bullous myringitis patients, and emphasize the need for routine early audiometric evaluation and appropriate follow up for individuals diagnosed as having bullous myringitis. PMID- 21601395 TI - Tinnitus retraining therapy using portable music players. AB - OBJECTIVE: We aimed to perform acoustic analysis of environmental sounds used in sound therapy for tinnitus retraining therapy (TRT) and to evaluate the efficacy of TRT performed by using a portable music player (PMP) with recorded environmental sounds as the sound generator. METHODS: Acoustic analysis of environmental sounds was performed using a sound analyzer. The subjects were 23 patients with chronic tinnitus. Patients who had bilateral hearing loss and required hearing assistance were fitted with hearing aids (HAs). Patients with normal hearing or unilateral hearing loss were fitted with a tinnitus control instrument (TCI) or a PMP. The patients were divided into the PMP group, TCI group, and HA group. All subjects underwent audiometric evaluations prior to TRT and completed the tinnitus handicap inventory (THI). The THI scores were evaluated before treatment and 1 month, 3 months, 6 months, and 12 months after treatment. RESULTS: The sound spectrogram of the murmur of a stream showed a wide frequency band with a constant strength, whereas that of a wave sound showed a wide-frequency band with variable strength. The THI score clearly decreased after 1 month, and this decrease tended to continue over 12 months. The TRT efficacy ratios in the PMP group, TCI group, and HA group at 12 months after treatment were 71%, 67%, and 70%, respectively. CONCLUSIONS: TRT using a PMP had efficacy similar to those of TCI and HA. The murmur of a stream was one of the most effective sounds in TRT. TRT using a PMP as the sound generator can provide the most cost-effective treatment option for tinnitus patients. PMID- 21601394 TI - Evaluation of the effect of methylprednisolone and N-acetylcystein on anastomotic degeneration and regeneraton of the facial nerve. AB - OBJECTIVES: This study was aimed to determine the effects of methylprednisolone and N-acetylcystein on nerve healing in facial nerve anastomosis. METHODS: Thirty rabbits were randomly divided into 3 groups: Group I: control group received no medication; Group II: 50mg/kg/day N-acetylcystein administered group; Group III, 1mg/kg/day Methylprednisolone administered group. All rabbits underwent the same standard surgical procedure. A 1mm segment was resected from the facial nerve and the free ends were anastomosed. The drugs were administered for two months twice a day. At the end of the second month, the anastomosed regions were dissected and examined under electron and light microscopy. RESULTS: Best nerve regeneration was observed in the N-acetylcystein and the control groups, respectively, whereas the weakest regeneration was determined in the methylprednisolone group. In the N acetylcystein group, due to Schwann cell and glial cell proliferation, the increased regeneration rate was significantly higher compared to that of the methylprednisolone group. In the methylprednisolone group, no significant regeneration was observed despite the presence of degenerative signs of significant axonal withdrawal and an increase in the number of myelin debris. CONCLUSION: In the present study, we demonstrated that methylprednisolone had no beneficial effect in nerve regeneration after facial nerve anastomosis. It further caused increased degeneration. On the contrary, N-acetylcystein administration significantly increased the extent of regeneration, whereas it decreased the extent of degeneration compared to the control and the methylprednisolone groups. PMID- 21601396 TI - Effect of prehydration on nasal mucociliary clearance in low relative humidity. AB - OBJECTIVE: Nasal mucociliary clearance, which plays an important role in defending the respiratory system, tends to decrease under conditions of low relative humidity (RH). The purpose of this randomized cross-over study was to investigate the preventive effect of prehydration on nasal mucociliary clearance under low RH conditions. METHODS: Fourteen young healthy subjects were assigned to three interventions: prehydration (6ml/kg body weight) using water (W), prehydration using a carbohydrate-electrolyte beverage (CE), and control conditions (Cont) with no prehydration. For each intervention trial, subjects sat for 4h in an environmental chamber (23 degrees C, 10% RH). Nasal mucociliary clearance was measured by the saccharin transit time (ST). Furthermore, a dry sensation of the mucosa, urine volume, and body weight were measured at the baseline, 2h and 4h after entering the environmental chamber, respectively. RESULTS: ST was prolonged under the Cont conditions after entering the environmental chamber. Prehydration with CE led to a significantly lower ST compared to the Cont pretreatment at 2h, whereas the W trial showed no significance difference in comparison to the Cont values. CONCLUSION: These results suggest that prehydration with a carbohydrate-electrolyte beverage is therefore beneficial for maintaining better nasal mucociliary clearance at least for 2h under low RH conditions. PMID- 21601397 TI - Molecular genetic epidemiology of age-related hearing impairment. AB - Genetic epidemiology focuses on the genetic determinants in the etiology of disease among populations and seeks to elucidate the role of genetic factors and their interaction with environmental factors in disease occurrence. In recent years, genetic epidemiological research has become more focused on complex diseases, and human genome analysis technology has made remarkable advances. Age related hearing impairment (ARHI) is a complex trait, which results from a multitude of confounding intrinsic and extrinsic factors. Although the number of genetic investigations of ARHI is increasing at a surprising rate, the etiology of ARHI is not firmly established. In this article, we review (1) the methodological strategies used to analyze genetic factors that contribute to human ARHI, (2) several representative investigations, and (3) specific genetic risk factors for human ARHI identified in previous work. PMID- 21601398 TI - Expression of myelin basic protein in the human auditory nerve - an immunohistochemical and comparative study. AB - OBJECTIVE: The aim of this study is to analyse the expression and distribution of myelin basic protein (MBP or Myelin A1 protein) in the human spiral ganglion and auditory nerve. MATERIALS AND METHODS: Cryostat sections were made from freshly fixed human cochlear specimens removed at surgery in patients with life threatening petro-clival meningiomas compressing the brain stem. The sections were subjected to immunohistochemistry using antibodies against MBP, S-100 and Tubulin. The immunoreaction was documented using laser confocal microscopy. RESULTS: Type I spiral ganglion nerve somata (SGN) were surrounded by so-called "satellite glial cells" (SGCs) that lacked expression of MBP consistent with earlier light and electron microscopic findings indicating that these cells are non-myelinating. S-100 labeling showed that the SGCs form a continuous network in the apical region. CONCLUSIONS: The pattern of myelination in human spiral ganglion is different from that in other species' spiral ganglion. The striking differences in myelin outline should be investigated further in combination with its influence on signal coding and preservation properties in man. PMID- 21601399 TI - [Intracardiac thrombosis in Behcet disease: clinical presentation and outcome of three cases]. AB - BACKGROUND: Behcet's disease is recognized as a multisystem disorder that affects mainly young adults in Mediterranean, Middle Eastern, and Far Eastern countries. The diagnosis is very difficult because there is no laboratory test. Clinical features - such as orogenital aphtae, ocular and skin lesions, arthritis, and neurologic, gastrointestinal, vascular, and pulmonary symptoms - are helpful for diagnosis. Various cardiovascular manifestations, such as pancarditis, acute myocardial infarction, conduction system disturbances, and valvular diseases, have been reported but are rare. Intracardiac thrombus formation, as seen in our patients, is exceptional even among cardiovascular cases of Behcet's. OBSERVATIONS: We report three cases of intracardiac thrombosis among 204 patients followed for Behcet's disease within our unit over a period of 7 years. We report outcomes after corticosteroid, cyclophosphamide, and oral anticoagulant therapy. DISCUSSION: Cardiovascular involvement has been reported in 7 % to 29 % of patients with Behcet's syndrome. Intracardiac thrombosis is extremely rare and the right heart is the most common site of involvement. The first symptoms and signs of the disease frequently precede systemic organ manifestations. CONCLUSION: Diagnosis of Behcet's disease might be considered if a patient presents with a mass in the right-sided cardiac chambers, even in the absence of the characteristic clinical features of the condition. This is particularly applicable if the patient is a young male from the Mediterranean basin or the Middle East. We suggest that the treatment could include colchicine, anticoagulant therapy, and corticosteroids and discuss immunosuppressive therapy. PMID- 21601400 TI - Role of high resolution contrast-enhanced magnetic resonance angiography (HR CeMRA) in management of arterial complications of the renal transplant. AB - INTRODUCTION: Transplant renal artery (RA) stenosis (TRAS) is the most frequent posttransplantation vascular complication. Contrast enhanced magnetic resonance (CeMRA) angiography has been established as the preferred imaging technique for the evaluation of TRAS because it does not require the use of iodinated contrast material and does not expose the patient to ionizing radiation. Digital subtraction angiography (DSA) is the gold standard in the evaluation of arterial tree of the renal allograft. AIM OF THE WORK: This study was carried out to assess the accuracy of CeMRA in the detection of arterial complications after renal transplantation. PATIENTS AND METHODS: Thirty renal transplant patients with suspected arterial complications in which both CeMRA and DSA were performed were included in the study. The HR CeMRA shows 93.7% sensitivity, 80% specificity, 88.2% positive predictive value, 88.9% negative predictive value and 88.5% accuracy. CONCLUSION: HR CeMRA is an accurate reliable tool in the assessment of arterial complications after renal transplantation. It may replace DSA as a diagnostic modality with reservation of interventional techniques for endovascular treatment of suitable cases. PMID- 21601401 TI - To evaluate the efficacy of ultrasonography compared to clinical diagnosis, radiography and histopathological findings in the diagnosis of maxillofacial swellings. AB - AIM: To evaluate the efficacy of Ultrasonography compared to clinical diagnosis, radiography and histopathological findings in the diagnosis of maxillofacial swellings. MATERIAL AND METHODS: The study was conducted on forty-five patients with maxillofacial swellings. The clinical diagnosis, radiographic diagnosis and ultrasonographic diagnosis were made which was compared to the histopathological diagnosis. The maxillofacial swellings included cystic lesions, benign swellings, malignant swellings, lymphadenopathies and abscesses and space infections. RESULTS: The diagnostic accuracy and contingency coefficient was evaluated considering histopathology as gold standard. The diagnostic accuracy of ultrasound was found to be 92.30% in the diagnosis of cystic lesions, 87.5% in benign tumors, 81.8% in malignant tumors, 100% in lymphadenopathies and 90% in space infections and abscesses. The contingency coefficient of 0.934 was obtained when ultrasonography was compared to the histopathology, which was highly significant. Similar significant results were obtained comparing ultrasonography with clinical diagnosis (0.895) and radiographic diagnosis (0.889). CONCLUSION: Ultrasonography provides accurate imaging of the head and neck region and provides information about the nature of the lesion, its extent, and relationship with the surrounding structures. As the conventional and digital radiography enable the diagnosis of the presence of the disease, but do not give any indication of its nature. So, together with clinical and histopathological examinations, real time ultrasound imaging works out as a valuable adjunct in the diagnosis of orofacial swellings. PMID- 21601402 TI - Safety and feasibility in highly concentrated contrast material power injections for CT-perfusion studies of the brain using central venous catheters. AB - INTRODUCTION: CT perfusion studies play an important role in the early detection as well as in therapy monitoring of vasospasm after subarachnoid hemorrhage. High flow injections via central venous catheters are not recommended but may sometimes be the only possibility to obtain high-quality images. MATERIALS AND METHODS: We retrospectively analyzed our data for CT perfusions performed with power injection of contrast material with an iodine concentration of 400mg/ml via the distal 16G lumen of the Arrow three and five lumen central venous catheter with preset flow rates of 5ml/s. RESULTS: 104 examinations with central venous catheters were evaluated (67 with five lumen and 37 with three lumen). No complications were observed. Mean flow rates were 4.4+/-0.5ml/s using the three lumen catheter and 4.6+/-0.6ml/s using the five lumen catheter respectively. The mean injection pressure measured by the power injector was 200.7+/-17.5psi for the three lumen central venous catheter and 194.5+/-6.5psi for the five lumen catheter, respectively. CONCLUSION: Following a strict safety protocol there were no complications associated with power injections of contrast material containing 400mg iodine/ml with preset flow rates up to 5ml/s via the distal 16G lumen of the Arrow multi-lumen central venous catheter. However, since power-injections are off-label use with Arrow central venous catheters, this procedure cannot be recommended until potential safety hazards have been ruled out by the manufacturer. PMID- 21601403 TI - Measurements and detection of abdominal aortic aneurysm growth: Accuracy and reproducibility of a segmentation software. AB - PURPOSE: To validate the reproducibility and accuracy of a software dedicated to measure abdominal aortic aneurysm (AAA) diameter, volume and growth over time. MATERIALS AND METHODS: A software enabling AAA segmentation, diameter and volume measurement on computed tomography angiography (CTA) was tested. Validation was conducted in 28 patients with an AAA having 2 consecutive CTA examinations. The segmentation was performed twice by a senior radiologist and once by 3 medical students on all 56 CTAs. Intra and inter-observer reproducibility of D-max and volumes values were calculated by intraclass correlation coefficient (ICC). Systematic errors were evaluated by Bland-Altman analysis. Differences in D-max and volume growth were compared with paired Student's t-tests. RESULTS: Mean D max and volume were 49.6+/-6.2mm and 117.2+/-36.2ml for baseline and 53.6+/-7.9mm and 139.6+/-56.3ml for follow-up studies. Volume growth (17.3%) was higher than D max progression (8.0%) between baseline and follow-up examinations (p<.0001). For the senior radiologist, intra-observer ICC of D-max and volume measurements were respectively estimated at 0.997 (>=0.991) and 1.000 (>=0.999). Overall inter observer ICC of D-max and volume measurements were respectively estimated at 0.995 (0.990-0.997) and 0.999 (>0.999). Bland-Altman analysis showed excellent inter-reader agreement with a repeatability coefficient <3mm for D-max, <7% for relative D-max growth, <6ml for volume and <6% for relative volume growth. CONCLUSION: Software AAA volume measurements were more sensitive than AAA D-max to detect AAA growth while providing an equivalent and high reproducibility. PMID- 21601404 TI - Non-Gaussian diffusion imaging: a brief practical review. AB - The departure from purely mono-exponential decay of the signal, as observed from brain tissue following a diffusion-sensitized sequence, has prompted the search for alternative models to characterize these unconventional water diffusion dynamics. Several approaches have been proposed in the last few years. While multi-exponential models have been applied to characterize brain tissue, several unresolved controversies about the interpretations of the results have motivated the search for alternative models that do not rely on the Gaussian diffusion hypothesis. In this brief review, diffusional kurtosis imaging (DKI) and anomalous diffusion imaging (ADI) techniques are addressed and compared with diffusion tensor imaging. Theoretical and experimental issues are briefly described to allow readers to understand similarities, differences and limitations of these two non-Gaussian models. However, since the ultimate goal is to improve specificity, sensitivity and spatial localization of diffusion MRI for the detection of brain diseases, special attention will be paid on the clinical feasibility of the proposed techniques as well as on the context of brain pathology investigations. PMID- 21601405 TI - Magnetization transfer using inversion recovery during off-resonance irradiation. AB - Estimation of magnetization transfer (MT) parameters in vivo can be compromised by an inability to drive the magnetization to a steady state using allowable levels of radiofrequency (RF) irradiation, due to safety concerns (tissue heating and specific absorption rate (SAR)). Rather than increasing the RF duration or amplitude, here we propose to circumvent the SAR limitation by sampling the formation of the steady state in separate measurements made with the magnetization initially along the -z and +z axis of the laboratory frame, i.e. with or without an on-resonance inversion pulse prior to the off-resonance irradiation. Results from human brain imaging demonstrate that this choice provides a tremendous benefit in the fitting procedure used to estimate MT parameters. The resulting parametric maps are characterized by notably increased tissue specificity as compared to those obtained with the standard MT acquisition in which magnetization is initially along the +z axis only. PMID- 21601406 TI - MRI measurements of CO2 hydrate dissociation rate in a porous medium. AB - After obtaining experimental data of CO(2) hydrate formation and dissociation in a porous medium using magnetic resonance imaging (MRI), the purpose of this study was to analyze the different dissociation rate of CO(2) hydrate using two heating rates. Images were obtained by using a fast spin-echo sequence, and the field of view was set to 40*40*40 mm. The vessel pressure was monitored during hydrate formation and dissociation, which was used to compare with MRI mean intensity. The result indicated that the MRI could visualize hydrate formation and dissociation, and the MRI mean intensity of water was in good agreement with the vessel pressure changes. The hydrate formation and dissociation rates were also quantified using the MRI mean intensity of water. The experimental results showed that the higher heating rate caused the rapid hydrate dissociation. PMID- 21601407 TI - GC-MS method for the simultaneous determination of beta-blockers, flavonoids, isoflavones and their metabolites in human urine. AB - A sensitive and selective method based on gas chromatography hyphenated to mass spectrometry (GC-MS) for the screening of 23 different compounds including beta blockers, flavonoids, isoflavones and metabolites in human urine sample was developed and validated. The present paper reports, for the first time, the method for the simultaneous determination of beta-blockers, isoflavones, flavonoids and metabolites in human urine samples. When flavonoids are ingested in combination with drugs that have a narrow therapeutic range, interactions between flavonoids and drugs should be investigated. Substances of interest were extracted from urine samples by solid-phase extraction (SPE) employing a mixture of tert-butyl methyl ether:methanol:formic acid (4.5:4.5:1; v/v/v) as a mobile phase and Oasis HLB (Waters) as a stationary phase. Before extraction, urine samples were incubated with beta-glucuronidase/sulfatase in order to achieve enzymatic hydrolysis. Before GC-MS analysis the analytes had to be derivatized with N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) into their trimethylsilyl derivatives by incubating for 60 min at 60 degrees C. Statistical central composite design and response surface analysis were used to optimize the derivatization reagent. These multivariate procedures were efficient in determining the optimal separation condition, using peak areas as responses. The calibration curves were indicative of high linearity (r2 >= 0.9992) in the range of interest for each analyte. LODs (S/N=3) ranged between 0.6 and 9.7 ng/ml. Intra-day and inter-day precision (CV, %) was less than 4.96%, accuracy between 0.01 and 4.98% and recovery was found in the range from 70.20 to 99.55%. The developed method can be applied to the routine determination of examined compounds' concentrations in human urine. Moreover the method is suitable for detecting pharmaceutical compounds containing beta-blockers, isoflavones and flavonoids in urine after administration to humans. PMID- 21601408 TI - Quantification of reduced and oxidized thiols in mouse serum by column-switching hydrophilic interaction chromatography coupled with mass spectrometry. AB - An automated online solid-phase extraction method for the determination of the reduced and oxidized forms of thiols in mouse serum was developed and validated. Analysis was performed with column-switching hydrophilic interaction chromatography coupled with mass spectrometry (CS-HILIC-MS). The proposed CS HILIC-MS method enabled the simultaneous determination of reduced and oxidized thiols in mouse serum samples. In addition, interference from endogenous compounds was removed by means of the column-switching technique. We also compared the effects of derivatization before and after preparing serum from blood samples and found that it was necessary to perform the derivatization immediately before preparing serum from blood samples. We investigated the role of thiol compounds in lipopolysaccharide (LPS)-induced acute inflammation in vivo. Serum glutathione disulfide and cystine levels were significantly decreased at 4h after LPS treatment. Our method is expected to be useful for the assessment of the roles of reduced and oxidized glutathione in the oxidative state. PMID- 21601409 TI - A comparison of the safety of olanzapine and haloperidol in combination with benzodiazepines in emergency department patients with acute agitation. AB - BACKGROUND: Pharmacologic management of the agitated emergency department patient is controversial. The combination of olanzapine + benzodiazepines is not recommended by the manufacturer, but a recent report suggested harm only if the patient was intoxicated. Whether this is also true for haloperidol + benzodiazepines is not known. OBJECTIVES: The measurement of vital signs and ethanol levels in patients who received haloperidol with or without benzodiazepines was compared to a previous analysis of patients who received olanzapine with or without benzodiazepines. METHODS: This is a structured retrospective chart review of patients who received parenteral haloperidol or parental olanzapine either with or without benzodiazepines. RESULTS: There were 96 patients (71 haloperidol, 25 olanzapine) who met inclusion criteria. No patient in the olanzapine + benzodiazepine group had hypotension, although one patient in the olanzapine-only group did (6.7%); 2 patients in the haloperidol + benzodiazepines group (5.1%) and 2 patients in the haloperidol-only group (6.3%) had hypotension. In alcohol-negative (ETOH-) patients, neither olanzapine alone nor olanzapine + benzodiazepines was associated with decreased oxygen saturations. In ETOH+ patients, olanzapine alone was not associated with decreased oxygen saturations, but olanzapine + benzodiazepines were associated with lower oxygen saturations than haloperidol + benzodiazepines. CONCLUSIONS: In this sample, olanzapine alone or with a benzodiazepine was not associated with more hypotension than haloperidol. However, olanzapine + benzodiazepines were associated with lower oxygen saturations than haloperidol + benzodiazepines in ETOH+ but not ETOH- patients. In patients with known alcohol ingestion, haloperidol, haloperidol + benzodiazepines, or olanzapine alone may be better choices for treatment of agitation. PMID- 21601410 TI - [Assessment of the French surgical checklist: the experience of 17 French cancer centres]. AB - INTRODUCTION: The use of WHO checklist has been associated to a decrease of complication incidence and mortality. This control is mandatory since January the 1st 2010. Evaluation of the quality of documentation is important and includes filling rate, which is a reflexion of participant adhesion and analysis of the circumstances where the team answers "no" during the control. METHODS: This study concerned 17 among 20 French cancer centres. Percentage of documented checklist, exhaustivity of the answers in each checklist and "no" answers have been compared during two periods: January 2010 and October 2010. RESULTS: Rate of filled document is satisfactory and stable during the two periods (95.5% versus 95.8%). Exhaustivity was slightly better during the second period (64 and 68%, P=0,039). Nevertheless, variability between centres was large; one centre improved and four centres worsened their scores. Rate of "no" answers was low and increased during the second period (1.5% in January 1.9% in October P<0.001). They mainly concerned antibiotic administration and at a lesser degree bleeding risk, the name of the procedure, equipment problem to be addressed and postoperative management. DISCUSSION: There is a large discrepancy between centres and for a given centre in reporting quality. Significant progress should be expected using target improvement. This approach implies multiple critical analysis of checklist content in each hospital and in multicentre enquiries. PMID- 21601411 TI - [The surgical safety list: are you aware of having such therapeutic effectiveness without side effects?]. PMID- 21601412 TI - [Check-list "Patient Safety" in the operating room: one year experience of 40,000 surgical procedures at the university hospital of Nice]. AB - OBJECTIVES: The implementation of the check-list "Safe surgery saves live" (CL) has proven effective to reduce morbidity and perioperative mortality. Since 1st January 2010 it is a requirement of the HAS as part of the process of certification of hospitals. The CL has been established on all the operating rooms of our hospital after the onset of a near accident. METHODS: The CL has been computerized to facilitate its adoption by professionals. An internal benchmarking was immediately implemented to allow each surgical specialty to benchmark themselves with other teams. We conducted an audit concerning the CL and periodic assessments in order to learn more precisely concerning the expectations and feelings of medical and nursing teams. RESULTS: Nearly 40 000 CL were collected in the patient record. The completeness of information of some items seems to reflect the difficulty for professionals to realize the difference between traceability and information sharing within the team on the implementation of a protocol. This audit has confirmed the difficulty in sharing information orally. CONCLUSIONS: The CL is involved in developing a safety culture in the operating room and led to the establishment of a risk mapping in the operating room and the recovery room and participation in the program error prevention procedure and surgical site through international program "High 5s" whose purpose is to improve the safety of care. PMID- 21601413 TI - [Urinary continence following radical prostatectomy: comparison of open, laparoscopic, and robotic approaches]. AB - AIM: To compare urinary continence following radical prostatectomy (RP) between open (Op), laparoscopic (Lap), and robotic (Ro) approaches. METHOD: Urinary continence of the first 59 patients operated by Ro RP between May 2008 and August 2009 was evaluated by self-questionnaires. Results were compared to those obtained in 2006 using the same questionnaire from patients operated by Lap RP or Op RP in the same institution. Patients treated by radiotherapy were excluded from the analysis. RESULTS: Fifty-one of the 59 operated by RP Ro answered the questionnaire. Op and Lap groups included 82 and 100 patients respectively. No significant difference was observed between the three groups in terms of age, body mass index, preoperative PSA, prostate gland weight, and TNM stage on pathology. Overall incontinence rate was 8%, 32%, and 21% for Ro, Lap, and Op RP, respectively. Median duration to recover continence after surgery was three weeks in the Ro group, versus eight weeks in the two other groups. CONCLUSION: In our experience, patients operated by a Ro approach had a lower risk of incontinence and a shorter duration to recover continence compared to those operated by Op and Lap RP. Our previous experience of laparoscopy might explain these findings. Evaluation of overall functional and oncological results is necessary before concluding to a possible superiority of Ro RP. PMID- 21601414 TI - [Hot topics in cardiovascular diseases in 2011]. PMID- 21601415 TI - Unexpected failure of highly cross-linked polyethylene acetabular liner. AB - Highly cross-linked polyethylene (HXPE) in total hip arthroplasty has been shown to decrease wear rate compared with conventional liner. However, it has some disadvantages in that the mechanical properties cause early failure of the implant. This case report presents an unexpected failure of total hip arthroplasty in a 72-year-old woman that occurred at 20 months postsurgery. Operative findings revealed fracture of superior rim at locking groove of liner. We concluded that the failure was caused by decreased mechanical properties of highly cross-linked polyethylene, less thickness of polyethylene, more vertical cup, and use of large femoral head. PMID- 21601416 TI - Real-time polymerase chain reaction test to discriminate between contamination and intraocular infection after cataract surgery. AB - PURPOSE: To determine the usefulness of real-time polymerase chain reaction (PCR) assays in the diagnosis of postoperative bacterial endophthalmitis in clinically diagnosed infectious cases and to test for bacterial DNA in control samples collected from noninfected eyes. SETTING: Federal University of Sao Paulo, Brazil. DESIGN: Evaluation of diagnostic test or technology. METHODS: This study comprised patients with clinically diagnosed infectious endophthalmitis after cataract surgery and vitreous samples (from noninflamed eyes obtained through vitrectomy) and aqueous samples (at end of phacoemulsification) from control patients at a single university setting. Universal and gram-specific real-time PCR, Gram staining, and culture were performed. Sensitivity and cycle thresholds were determined. Clinical and microbiologic data were also assessed. RESULTS: The study evaluated 11 patients with infectious endophthalmitis (9 vitreous and 7 aqueous samples), 12 control vitreous samples, and 50 control aqueous samples. Gram and culture identified 80% and 75%, respectively, of patients with infectious endophthalmitis. Real-time PCR assays were positive in 91% of patients with a clinical diagnosis of endophthalmitis using aqueous samples, vitreous samples, or both. None of the 12 vitreous controls were positive by PCR. Two aqueous control samples were positive by real-time PCR. The cycle threshold cutoff value was 36 for universal PCR (sensitivity 93.8%; specificity 100%) and 38 for gram-specific PCR (sensitivity 93.8%; specificity 100%). Gram-positive microorganisms prevailed, and visual acuity varied according to the causative bacteria. CONCLUSIONS: Real-time PCR provided fast and accurate diagnosis of bacterial endophthalmitis. As a quantitative technique, it may be useful in distinguishing between contamination and infection based on the cycle thresholds value. PMID- 21601417 TI - New phacoemulsification tip with a grooved, threaded-tip construction. AB - PURPOSE: To visually compare ultrasonic tip vibrations between a phaco tip with internal grooves (threaded tip) and a standard phaco tip during continuous-mode ultrasound (US) using ultra-high-speed digital video imaging. SETTING: Watanabe Eye Clinic, Hyogo, Japan. DESIGN: Experimental study. METHODS: The threaded tip was constructed by creating grooves inside a standard phaco tip using a screw. An ultra-high-speed digital video camera was used to record the image during continuous-mode US. Samples used in the test chamber during phacoemulsification included a piece of chestnut as a representative human lens sample and actual human lens fragments. RESULTS: Ultra-high-speed digital images showed that the threaded tip created a larger amount of cavitation than the standard phaco tip during US oscillation. Phacoemulsification of the sample using the standard phaco tip produced a chattering motion, making it difficult to maintain a steady tip position. The threaded tip produced little chattering motion, making it relatively easy to maintain a steady tip position. Once a piece of sample was gripped by the threaded tip, it was shaved and aspirated into the threaded tip without chattering motion. The mean effective phacoemulsification time (EPT) of the threaded tip was significantly shorter than that of the normal phaco tip (6.0 seconds +/- 1.9 [SD] versus 15.4 +/- 1.3 seconds; P=.002). CONCLUSIONS: The threaded tip created larger amounts of cavitation and had strong destructive and holding power. This threaded construction is simple to produce and appears to be very effective for phacoemulsification. PMID- 21601418 TI - Comparison of a monocular pupillometer and the pupillometry function of a binocular free-viewing autorefractor. AB - PURPOSE: To compare a binocular free-viewing autorefractor pupillometer (WAM 5500 Binocular Accommodation Instrument) and a monocular occlusion pupillometer (Neuroptics pupillometer). SETTING: Department of Ophthalmology and Visual Sciences, Texas Tech University Health Sciences Center, Lubbock, Texas, USA. DESIGN: Evaluation of diagnostic test or technology. METHODS: Normal subjects were tested under 1 lux and 7 lux ambient illumination with controlled distance fixation. The monocular occlusion pupillometer and free-viewing autorefractor pupillometer test order and eye test order were randomized. Devices were compared using Bland-Altman plots. Effects of eye test order and device test order were analyzed. The number of outliers (ie, difference >= 0.5 mm between devices) was tabulated. RESULTS: The mean device difference (monocular pupillometer minus binocular pupillometer) was +0.51 mm +/- 0.36 (SD) (range -0.20 to +1.50 mm) in right eyes and +0.27 +/- 0.31 mm (SD) (range -0.30 to +1.00 mm) in left eyes at 1 lux and +0.26 +/- 0.28 mm (range -0.30 to +0.90 mm) and +0.21 +/- 0.24 mm (range 0.80 to +0.40 mm), respectively, at 7 lux. The outlier frequency (N = 49) at 1 lux was 23 (47%) in right eyes and 7 (14%) in left eyes and at 7 lux, 11 (22%) and 10 (20%), respectively. At all age decades, the free-viewing autorefractor underestimated dark-adapted pupil diameter. Eye test order and device order did not cause unidirectional bias. CONCLUSIONS: The free-viewing pupillometer frequently disagreed with the monocular occlusion pupillometer by more than 0.5 mm. Testing the first eye with the monocular pupillometer did not induce sustained pupillary constriction that might bias results in the second eye. PMID- 21601419 TI - Influence of different acrylic intraocular lens materials on optical quality of vision in pseudophakic eyes. AB - PURPOSE: To analyze the effect of hydrophobic and hydrophilic acrylic intraocular lens (IOL) material on the optical quality in pseudophakic eyes with a clear posterior capsule and assess in vitro forward light scatter of these IOLs. SETTING: St. Thomas' Hospital, London, United Kingdom. DESIGN: Comparative case series. METHODS: Eyes with a hydrophobic or hydrophilic acrylic IOL and a clear posterior capsule within the central 4.0 mm at least 3 months postoperatively were identified from 2 ongoing studies. Data on 100% and 9% logMAR corrected distance visual acuities (CDVA) and total eye aberrations with a 4.0 mm pupil were collected. The 10% and 50% point-spread function (PSF) values of double-pass measurements were collected. In vitro forward light scattering was analyzed for the IOL models using a standardized laboratory technique. RESULTS: Twenty-eight eyes had hydrophilic IOLs, and 43 had hydrophobic IOLs. There was no significant difference in IOL power, postoperative spherical equivalent, or 100% logMAR CDVA between hydrophilic IOLs and hydrophobic acrylic IOLs. Nine percent logMAR CDVA (P=.000), 10% PSF (P=.005), 50% PSF (P=.008), and Zernike polynomial 4 (P=.000) were significantly different between the IOL groups. Although in vitro forward scatter levels were low in both groups, hydrophilic IOLs had more forward scatter. CONCLUSIONS: Hydrophobic acrylic IOLs gave better low contrast visual acuity. Even within the acrylic subgroup, the optical quality varied significantly. The IOL material is an important factor influencing the optical quality of vision with different acrylic IOLs. PMID- 21601420 TI - Assisting people with multiple disabilities by actively keeping the head in an upright position with a Nintendo Wii Remote Controller through the control of an environmental stimulation. AB - The latest researches have adopted software technology by applying the Nintendo Wii Remote Controller to the correction of hyperactive limb behavior. This study extended Wii Remote Controller functionality for improper head position (posture) correction (i.e. actively adjusting abnormal head posture) to assess whether two people with multiple disabilities would be able to actively keep the upright head position by controlling their favorite stimulation using a Wii Remote Controller with a newly developed active head position correcting program (AHPCP). The study was performed according to an ABAB design, in which A represented the baseline and B represented intervention phases. Results showed that both participants significantly increased their time duration of maintaining upright head position (TDMUHP) to obtain the desired environmental stimulation during the intervention phases. Practical and developmental implications of the findings were discussed. PMID- 21601421 TI - Right ventricular myocardial systolic and diastolic dysfunction in heart failure with normal left ventricular ejection fraction. AB - OBJECTIVE: We hypothesized that in patients with heart failure with normal left ventricular (LV) ejection fraction (HFNEF), the same fibrotic processes that affect the subendocardial layer of the LV could also alter the subendocardial fibers of the right ventricle (RV). Consequently, these alterations and to a lesser extent chronically elevated pulmonary arterial pressures would lead to both systolic and diastolic subendocardial dysfunction of the RV (i.e., impaired RV longitudinal systolic and diastolic function) in patients with HFNEF. METHODS: Patients with HFNEF and a control group consisting of asymptomatic patients with LV diastolic dysfunction (asymptomatic LVDD) matched by age, gender, and LV ejection fraction were studied by two-dimensional speckle-tracking echocardiography. RESULTS: A total of 565 patients were included (201 with HFNEF and 364 with asymptomatic LVDD). RV longitudinal diastolic (RV global longitudinal early-diastolic strain rate [RV-SRe]) and systolic (RV global longitudinal systolic strain [RV-Strain]) function were significantly more impaired in patients with HFNEF than in patients with asymptomatic LVDD (HFNEF: RV-Strain -14.41% +/- 3.80% and RV-SRe 0.86 +/- 0.33 s(-1); asymptomatic LVDD: RV Strain -16.90% +/- 4.28% and RV-SRe 1.02 +/- 0.34 s(-1); all P < .0001). On multiple regression analysis, LV global longitudinal systolic strain was the most important independent predictor of RV longitudinal systolic and diastolic function, in contrast with pulmonary arterial systolic pressure, which was weakly related to these functions. Furthermore, in patients with HFNEF the subendocardial function of both the LV and RV were significantly impaired in similar proportions. In that regard, in patients with HFNEF the prevalences of RV longitudinal systolic and diastolic dysfunction were 75% and 48%, whereas the rates of LV longitudinal systolic and diastolic dysfunction were 80% and 60%, respectively. In addition, patients with both systolic and diastolic longitudinal dysfunction of the RV presented worse New York Heart Association functional class. CONCLUSION: In patients with HFNEF, RV subendocardial systolic and diastolic dysfunction are common and possibly associated with the same fibrotic processes that affect the subendocardial layer of the LV and to a lesser extent with RV pressure overload. Furthermore, our findings suggest that RV longitudinal systolic and diastolic dysfunction could contribute to the symptomatology of patients with HFNEF. PMID- 21601423 TI - A description of a process to calibrate the Morse fall scale in a long-term care home. AB - The purpose of this article is to describe the process of calibrating the Morse Fall Scale in a Canadian long-term care home as one aspect of a complex fall prevention program. The authors propose that the implementation of a calibration process of a fall risk assessment tool enables care providers to identify residents at greatest risk for falling. The authors further suggest that the ability to identify those residents most likely to experience a fall facilitates tailoring of fall prevention strategies for these individuals at greatest risk. PMID- 21601422 TI - Automated coronary artery tree extraction in coronary CT angiography using a multiscale enhancement and dynamic balloon tracking (MSCAR-DBT) method. AB - RATIONAL AND OBJECTIVES: To evaluate our prototype method for segmentation and tracking of the coronary arterial tree, which is the foundation for a computer aided detection (CADe) system to be developed to assist radiologists in detecting non-calcified plaques in coronary CT angiography (cCTA) scans. MATERIALS AND METHODS: The heart region was first extracted by a morphological operation and an adaptive thresholding method based on expectation-maximization (EM) estimation. The vascular structures within the heart region were enhanced and segmented using a multiscale coronary response (MSCAR) method that combined 3D multiscale filtering, analysis of the eigenvalues of Hessian matrices and EM estimation segmentation. After the segmentation of vascular structures, the coronary arteries were tracked by a 3D dynamic balloon tracking (DBT) method. The DBT method started at two manually identified seed points located at the origins of the left and right coronary arteries (LCA and RCA) for extraction of the arterial trees. The coronary arterial trees of a data set containing 20 ECG-gated contrast enhanced cCTA scans were extracted by our MSCAR-DBT method and a clinical GE Advantage workstation. Two experienced thoracic radiologists visually examined the coronary arteries on the original cCTA scans and the rendered volume of segmented vessels to count the untracked false-negative (FN) segments and false positives (FPs) for both methods. RESULTS: For the visible coronary arterial segments in the 20 cases, the radiologists identified that 25 segments were missed by our MSCAR-DBT method, ranging from 0 to 5 FN segments in individual cases, and that 55 artery segments were missed by the GE software, ranging from 0 to 7 FN segments in individual cases. 19 and 15 FPs were identified in our and the GE coronary trees, ranging from 0 to 4 FPs for both methods in individual cases, respectively. CONCLUSION: The preliminary study demonstrates the feasibility of our MSCAR-DBT method for segmentation and tracking coronary artery trees. The results indicated that both our method and GE software can extract coronary artery trees reasonably well and the performance of our method is superior to that of GE software in this small data set. Further studies are underway to develop methods for improvement of the segmentation and tracking accuracy. PMID- 21601424 TI - Implants in the pterygoid region: a systematic review of the literature. AB - This systematic review aimed to identify clinical studies on the short-term and long-term survival of implants placed in the pterygoid region. A structured literature search was conducted using PubMed, Scopus and Cochrane databases. Relevant studies were selected according to predetermined inclusion and exclusion criteria. Data from the final included studies could only be extracted for calculating interval survival rate (ISR) and cumulative survival rate (CSR) of implants for different time intervals. The initial database search yielded 693 titles. After filtering, 32 abstracts were selected culminating in 17 full text articles. Three additional articles were added through a hand search to obtain a total of 20 articles. Application of exclusion criteria led to elimination of 11 articles. Pooled data from the final 9 articles showed a first year ISR of 92%. The CSR over a 10 year period, largely due to data from one study was 91%. The minimum follow-up period reported in various studies was less than a year. There is insufficient data about failures that occurred beyond the first year interval, making it difficult to draw conclusions about long-term survival of these implants. More studies with longer follow-up periods involving adequate number of pterygoid implants are needed. PMID- 21601425 TI - Occult prostate cancer detected by hyoid bone metastasis after resection of thyroglossal duct cyst. AB - Metastatic carcinoma involving the hyoid bone has rarely been mentioned in the literature. The most frequent malignant lesion involving the hyoid bone metastasized from the larynx, followed by the vallecula and pyriform sinus. The authors report a unique case of occult prostate cancer that presented with an anterior midline neck mass diagnosed as a thyroglossal duct cyst. Two foci of metastatic carcinoma lesions in the hyoid bone were detected after Sistrunk's operation and occult prostate cancer was confirmed by immunohistochemical staining of prostate-specific antigen. Prostate cancer with metastasis to hyoid bone has not been described previously in the literature. The authors report this case which raises important pathological considerations for diagnosis. The unique presentation also reiterates the importance of prostate cancer bone metastasis. PMID- 21601426 TI - The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy. AB - Lamotrigine (LTG) which has a widespread use in epilepsy treatment as an antiepileptic agent is metabolized by UDP-glucuronosyl transferase (UGT) enzymes. In this study, single nucleotide polymorphisms, P24T and L48V, of the UGT1A4 enzyme have been investigated in a Turkish population of patients with epilepsy (n=131) by comparing serum levels of LTG of wild type and polymorphic subjects. High performance liquid chromatography (HPLC) was used to measure serum concentrations of LTG. The P24T and L48V polymorphisms of the UGT1A4 enzyme were analyzed with a matrix assisted laser desorption-time of flight (MALDI-TOF) mass spectrometry method. The frequencies of the heterozygous alleles for L48V or P24T polymorphisms were 22.4% and 3.8%, respectively. L48V polymorphism was found to decrease the serum concentration of LTG in patients on monotherapy or polytherapy. The LTG levels of non smoking monotherapy patients were 52% lower for the L48V polymorphism than for wild type alleles. Also the LTG levels were significantly lower for non smoking or smoking polymorphic alleles than for normal. The high frequency of the L48V polymorphism detected in the Turkish population indicates that LTG dose adjustments in patients with the UGT1A4 L48V polymorphic enzyme should be taken into account. PMID- 21601427 TI - The long-term retention of zonisamide in a large cohort of people with epilepsy at a tertiary referral centre. AB - Zonisamide (ZNS) is an antiepileptic drug (AED) with multiple putative mechanisms of action. It is chemically unrelated to other AEDs. It has been available in Japan since 1989 but was only licensed in Europe in 2005. Its efficacy and tolerability have been shown in several randomised controlled trials, but large studies on long-term performance in Western clinical practice are scarce. We assessed a large cohort of consecutive people who started ZNS at a tertiary epilepsy referral centre, from June 2005 to July 2009. Forty-six percent of the 417 people included were still taking ZNS at last follow-up, with an estimated retention rate at three years of 30%. Almost one third of the population reported a period of improvement in terms of seizure reduction of at least six months duration whilst on ZNS. Sixteen people became seizure free for at least six months and seven of these were seizure free for one year or more. Adverse events occurred in 58%, frequently CNS-related. People on three or more AEDs and people starting zonisamide at 25mg daily rather than 50mg or more, were more likely to discontinue ZNS. Retention rates for ZNS were similar to those previously reported, and comparable to lamotrigine, topiramate, pregabalin, higher than gabapentin, and lower than levetiracetam. PMID- 21601428 TI - EEG functional connectivity of the intrahemispheric cortico-cortical network of idiopathic generalized epilepsy. AB - AIMS: Intrahemispheric, cortico-cortical EEG functional connectivity (fC) was investigated in untreated patients with idiopathic generalized epilepsy (IGE) in this explorative study. PATIENTS AND METHODS: Group comparison was carried out between 19, drug-naive IGE patients and 19, matched healthy persons. 90*2s of 19 channels waking, interictal background EEG signal (without epileptiform potentials) were processed to the LORETA (low resolution electromagnetic tomography) software to compute current source density for 2394 voxels representing parcels of the cerebral cortex for 25 very narrow bands of 1Hz bandwidth (VNBs) from 1 to 25Hz. EEG fC was investigated among the already localized sources. Pearson correlation coefficients (R) were computed among the 33 regions of interest (ROI) within the left and within the right hemisphere, separately. Group differences were computed by means of t-statistics. Corrected p<0.05 differences were accepted as statistically significant. MAIN RESULTS: (1) The anatomical patterns of the fC differences showed great frequency-dependency. (2) Hemispheric asymmetry was prominent within most VNBs. (3) Decreased fC in the IGE group was found across all VNBs in the 1-6Hz frequency range as compared to mixed patterns comprising both increased and decreased fC at >6Hz frequencies. (4) In the 5-25Hz range, decreased fC dominated in the anterior, increased fC in the posterior parts of the cortex. (5) The results delineated an anterior and a posterior network. DISCUSSION: (1) Decreased fC in the 1-6Hz band might indicate some relationship to yet hidden structure network abnormalities. (2) The anatomical patterns of fC indicate frequency-dependent, pathological coupling and decoupling processes in the interictal state. (3) The two networks might help to understand seizure liability and seizure precipitation in IGE. SIGNIFICANCE: This is the first study to explore EEG fC in the interictal condition of IGE patients. The importance of EEG frequencies in evaluating fC in IGE was demonstrated and starting points for further research were given. PMID- 21601429 TI - Development of a recovery manual for suicidal patients with schizophrenia. PMID- 21601430 TI - A recurrent p. A353V mutation in DKC1 responsible for different phenotypes of dyskeratosis congenita in a Chinese family. PMID- 21601431 TI - Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence. AB - Research in the area of herbal psychopharmacology has increased markedly over the past decades. To date however, a comprehensive review of herbal antidepressant, anxiolytic and hypnotic psychopharmacology and applications in depression, anxiety and insomnia has been absent. A search of MEDLINE (PubMed), CINAHL, PsycINFO, and the Cochrane Library databases was conducted (up to February 21st 2011) on commonly used psychotropic herbal medicines. A review of the literature was conducted to ascertain mechanisms of action of these botanicals, in addition to a systematic review of controlled clinical trials for treatment of mood, anxiety and sleep disorders, which are common comorbid psychiatric disorders. Specific emphasis was given to emerging phytomedicines. Analysis of evidence levels was conducted, as were effect sizes (Cohen's d) where data were available. Results provided evidence of a range of neurochemical, endocrinological, and epigenetic effects for 21 individual phytomedicines, which are detailed in this paper. Sixty six controlled studies were located involving eleven phytomedicines. Several of these provide a high level of evidence, such as Hypericum perforatum for major depression, and Piper methysticum for anxiety disorders. Several human clinical trials provide preliminary positive evidence of antidepressant effects (Echium amoenum, Crocus sativus, and Rhodiola rosea) and anxiolytic activity (Matricaria recutita, Ginkgo biloba, Passiflora incanata, E. amoenum, and Scutellaria lateriflora). Caution should however be taken when interpreting the results as many studies have not been replicated. Several herbal medicines with in vitro and in vivo evidence are currently unexplored in human studies, and along with use of emerging genetic technologies "herbomics", are areas of potential future research. PMID- 21601432 TI - Does physical activity influence semantic memory activation in amnestic mild cognitive impairment? AB - The effect of physical activity (PA) on functional brain activation for semantic memory in amnestic mild cognitive impairment (aMCI) was examined using event related functional magnetic resonance imaging during fame discrimination. Significantly greater semantic memory activation occurred in the left caudate of High- versus Low-PA patients, (P=0.03), suggesting PA may enhance memory-related caudate activation in aMCI. PMID- 21601434 TI - Fronto-striatal underactivation during interference inhibition and attention allocation in grown up children with attention deficit/hyperactivity disorder and persistent symptoms. AB - Attention deficit hyperactivity disorder (ADHD) in medication-naive children has been associated with reduced activation in inferior/medial prefrontal, striatal and parieto-temporal cortices during inhibitory control and attention allocation. Functional magnetic resonance imaging (fMRI) studies in adult ADHD, however, have been inconsistent and confounded by medication-history and the need for a retrospective diagnosis of childhood ADHD. We used fMRI combined with a Simon task that measured interference inhibition and controlled for and co-measured attention allocation to compare brain function in 11 medication-naive adults with persistent inattentive/hyperactive behaviours, followed up from childhood ADHD, and 15 age-matched controls. Despite comparable task performance, patients showed reduced activation compared to controls in left orbital/medial frontal cortex and striatum during interference inhibition and in left lateral inferior/dorsolateral prefrontal cortex during attention allocation. Whole-brain regression analyses within patients showed a negative correlation between symptom severity and fronto striatal, temporo-parietal and cerebellar brain activation. The findings demonstrate that the typical fronto-striatal dysfunction observed in children with ADHD during interference inhibition and attention allocation is also observed in adults grown up from childhood ADHD with persistent symptoms. Furthermore, they show that functional deficits in adult ADHD are not related to chronic stimulant medication given that this sample was medication-naive. PMID- 21601435 TI - A simple method for analyzing 51V solid-state NMR spectra of complex systems. AB - Five vanadium complexes as models for biological systems were investigated using (51)V-MAS-NMR spectroscopy. All spectra show an uncommon line shape, which can be attributed to a shorter relaxation time of the satellite transition in contrast to the central one. A method for the reliable analysis of such kind of spectra is presented for the first time and the most important NMR parameters of the investigated complexes (quadrupolar coupling constant C(Q), asymmetry of the EFG tensor eta(Q), isotropic chemical shift delta(iso), chemical shift anisotropy delta(sigma) and asymmetry of the CSA tensor eta(sigma)) are presented. These results are of particular importance with respect to the analysis of the (51)V MAS-NMR spectra of vanadium moieties in biological matrices such as vanadium chloroperoxidase, which show hitherto unexplained low intensity of the satellite sideband pattern. PMID- 21601433 TI - Atypical modulation of medial prefrontal cortex to self-referential comments in generalized social phobia. AB - Generalized social phobia (GSP) involves the fear of being negatively evaluated. Previous work suggests that self-referentiality, mediated by the medial prefrontal cortex (MFPC), plays an important role in the disorder. However, it is not clear whether this anomalous MPFC response to self-related information in patients with GSP concerns an increased representation of their own or others' opinions. In this article, we examine whether GSP is associated with increased response to own (1st person) or other individuals' (2nd person) opinions relative to healthy individuals. Unmedicated individuals with GSP (n=15) and age-, IQ-, and gender-matched comparison individuals (n=15) read 1st (e.g., I'm ugly), and 2nd (e.g., You're ugly) person viewpoint comments during functional magnetic resonance imaging. We observed significant group-by-viewpoint interactions within the ventral MPFC. Whereas the healthy comparison individuals showed significantly increased (or less decreased) BOLD responses to 1st relative to 2nd person viewpoints, the patients showed significantly increased responses to 2nd relative to 1st person viewpoints. The reduced BOLD responses to 1st person viewpoint comments shown by the patients correlated significantly with severity of social anxiety symptom severity. These results underscore the importance of dysfunctional self-referential processing and MPFC in GSP. We believe that these data reflect a reorganization of self-referential reasoning in the disorder with a self-concept perhaps atypically related to the view of others. PMID- 21601436 TI - Framework and extra-framework aluminium in wet ion exchanged Fe-ZSM5 and the effect of steam during the decomposition of N2O. AB - The role of extra-framework and framework aluminium in wet-ion exchanged Fe-ZSM5 has been studied using (29)Si NMR and (27)Al triple quantum magic angle spinning (3QMAS) NMR. A series of samples were studied, the parent material, the wet ion exchanged Fe-ZSM5 and Fe-ZSM5 that has been used in the decomposition of N(2)O with varying reaction conditions. Various framework and extra-framework aluminium species have been identified. It was found that cationic Fe species prefer to replace the Bronsted acid protons in their charge balancing role at those aluminium sites associated with the largest quadrupolar product. The framework aluminium atoms that pertain to the smaller quadrupolar product, which are either charge balanced by extra-framework aluminium or a proton, are much less prone to exchange. In the catalytic decomposition of N(2)O it seemed that water present in small amounts enhances the catalytic activity. However, water also decreases the long term stability and performance by dealuminating the zeolite framework. With a high amount of water present, Fe-ZSM5 was destabilised and catalytically inferior. PMID- 21601437 TI - Adsorption of Cr(VI) on ureolytic mixed culture from biocatalytic calcification reactor. AB - Ca-rich water and wastewater have caused problems in water use, wastewater reuse and the operations of reactors treating Ca-rich wastewater. Nowadays, reuse of wastewaters is fast gaining importance as water sources have been polluted. Therefore, the concept of biocatalytic calcification reactors (BCR) based on urea hydrolysis, pH increase and calcite production has been studied to remove Ca from wastewaters. This biological process produces significant amounts of waste sludge. In the present study, Cr(VI) adsorption on the ureolytic mixed culture (UMC) waste by-product from BCR was investigated to evaluate its potential for metal removal. The biosorption process was investigated using equilibrium batch tests and the data were fit to the Langmuir, Freundlich and Temkin isotherm models. The Cr(VI) ion concentration dependence of sorption (1-100 mg/L) could be fit to the Langmuir isotherm model. Monolayer adsorption capacity, qm (mg/g), of the adsorbent was 8.67 and the Langmuir constant b (L/mg) was 0.881. Based on the obtained results, the waste UMC appears to be a potential biosorbent for the removal of Cr(VI) from wastewater, although its adsorptive capacity is lower than those of other biosorbents. PMID- 21601438 TI - The effect of maternal omega-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation during pregnancy and/or lactation on body fat mass in the offspring: a systematic review of animal studies. AB - Dietary n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) reduce adipogenesis and lipogenesis in adult rodents, but it is not clear whether an increased n-3 LCPUFA supply during the perinatal period influences body fat mass in the offspring. This systematic review aimed to evaluate the existing evidence from animal studies, which have addressed this question. Medline was searched for relevant articles. Studies were included if they involved maternal n-3 PUFA or LCPUFA supplementation and measured fat mass in the offspring. The design and quality of each study was assessed. Only four animal studies met our inclusion criteria. Three studies reported a lower fat mass in offspring of n-3 LCPUFA supplemented dams, however only one of these studies confined the intervention to the perinatal period. The dose of n-3 PUFA, the nature of the control treatment, the approaches used and outcomes assessed differed between studies. This review highlights the paucity of robust animal data as to the effect of increased n-3 LCPUFA exposure during the perinatal period alone, on body fat mass in the offspring and calls for further studies. PMID- 21601439 TI - Dietary ratio of n-6 to n-3 polyunsaturated fatty acids and periodontal disease in community-based older Japanese: a 3-year follow-up study. AB - The longitudinal relationship between dietary n-6 to n-3 PUFAs ratio and periodontal disease in 235 Japanese subjects for whom data were available for the years 2003-2006 was investigated. PUFAs intake was assessed at baseline with a brief-type self-administered diet history questionnaire. Full-mouth periodontal status, measured as the clinical attachment level (CAL), was recorded at baseline and once a year for 3 years. The number of teeth with a change in the loss of CAL >=3 mm at any site over a year was calculated as 'periodontal disease events'. Poisson regression analysis was conducted, with dietary n-6 to n-3 PUFAs ratio as the main predictor, to estimate its influence on periodontal disease events. A high dietary n-6 to n-3 PUFAs ratio was significantly associated with greater number of periodontal disease events. The findings suggest the dietary n-6 to n-3 PUFAs ratio is associated with periodontal disease among older Japanese. PMID- 21601440 TI - Waste management, energy production, healthcare: Amazing similarities. PMID- 21601441 TI - High-sensitivity electrochemical enzyme-linked assay on a microfluidic interdigitated microelectrode. AB - A novel enzyme-linked DNA hybridization assay on an interdigitated array (IDA) microelectrode integrated into a microfluidic channel is demonstrated with sub-nM detection limit. To improve the detection limit as compared to conventional electrochemical biosensors, a recyclable redox product, 4-aminophenol (PAP) is used with an IDA microelectrode. The IDA has a modest and easily fabricated inter digit spacing of 10 MUm, yet we were able to demonstrate 97% recycling efficiency of PAP due to the integration in a microfluidic channel. With a 70 nL sample volume, the characterized detection limit for PAP of 1.0 * 10-10 M is achieved, with a linear dynamic range that extends from 1.0 * 10-9 to 1.0 * 10-5 M. This detection limit, which is the lowest reported detection limit for PAP, is due to the increased sensitivity provided by the sample confinement in the microfluidic channel, as well as the increased repeatability due to perfectly static flow in the microchannel and an additional anti-fouling step in the protocol. DNA sequence detection is achieved through a hybridization sandwich of an immobilized complementary probe, the target DNA sequence, and a second complementary probe labeled with beta-galactosidase (beta-GAL); the beta-GAL converts its substrate, 4-aminophenyl-d-galactopyranoside (PAPG), into PAP. In this report we present the lowest reported observed detection limit (1.0 * 10-10 M) for an enzyme-linked DNA hybridization assay using an IDA microelectrode and a redox signaling paradigm. Thus, we have demonstrated highly sensitive detection of a targeted DNA sequence using a low-cost easily fabricated electrochemical biosensor integrated into a microfluidic channel. PMID- 21601442 TI - Microflow Cytometer for optical analysis of phytoplankton. AB - Analysis of the intrinsic fluorescence profiles of individual marine algae can be used in general classification of organisms based on cell size and fluorescence properties. We describe the design and fabrication of a Microflow Cytometer on a chip for characterization of phytoplankton. The Microflow Cytometer measured distinct side scatter and fluorescence properties of Synechococcus sp., Nitzschia d., and Thalassiosira p.; measurements were confirmed using the benchtop Accuri C6 flow cytometer. The Microflow Cytometer proved sensitive enough to detect and characterize picoplankton with diameter approximately 1 MUm and larger phytoplankton of up to 80 MUm in length. The wide range in size discrimination coupled with detection of intrinsic fluorescent pigments suggests that this Microflow Cytometer will be able to distinguish different populations of phytoplankton on unmanned underwater vehicles. PMID- 21601443 TI - Microbial chemical factories: recent advances in pathway engineering for synthesis of value added chemicals. AB - The dwindling nature of petroleum and other fossil reserves has provided impetus towards microbial synthesis of fuels and value added chemicals from biomass derived sugars as a renewable resource. Microbes have naturally evolved enzymes and pathways that can convert biomass into hundreds of unique chemical structures, a property that can be effectively exploited for their engineering into Microbial Chemical Factories (MCFs). De novo pathway engineering facilitates expansion of the repertoire of microbially synthesized compounds beyond natural products. In this review, we visit some recent successes in such novel pathway engineering and optimization, with particular emphasis on the selection and engineering of pathway enzymes and balancing of their accessory cofactors. PMID- 21601444 TI - Examination of microbial fuel cell start-up times with domestic wastewater and additional amendments. AB - Rapid startup of microbial fuel cells (MFCs) and other bioreactors is desirable when treating wastewaters. The startup time with unamended wastewater (118 h) was similar to that obtained by adding acetate or fumarate (110-115 h), and less than that with glucose (181 h) or Fe(III) (353 h). Initial current production took longer when phosphate buffer was added, with startup times increasing with concentration from 149 h (25 mM) to 251 h (50 mM) and 526 h (100 mM). Microbial communities that developed in the reactors contained Betaproteobacteria, Acetoanaerobium noterae, and Chlorobium sp. Anode biomass densities ranged from 200 to 600 MUg/cm(2) for all amendments except Fe(SH) (1650 MUg/cm(2)). Wastewater produced 91 mW/m(2), with the other MFCs producing 50 mW/m(2) (fumarate) to 103mW/m(2) (Fe(III)) when amendments were removed. These experiments show that wastewater alone is sufficient to acclimate the reactor without the need for additional chemical amendments. PMID- 21601445 TI - Utilization of residues from agro-forest industries in the production of high value bacterial cellulose. AB - Bacterial cellulose (BC), a very peculiar form of cellulose, is gaining considerable importance due to its unique properties. In this study, several residues, from agro-forestry industries, namely grape skins aqueous extract, cheese whey, crude glycerol and sulfite pulping liquor were evaluated as economic carbon and nutrient sources for the production of BC. The most relevant BC amounts attained with the residues from the wine and pulp industries were 0.6 and 0.3 g/L, respectively, followed by biodiesel crude residue and cheese whey with productions of about, 0.1 g/L after 96 h of incubation. Preliminary results on the addition of other nutrient sources (yeast extract, nitrogen and phosphate) to the residues-based culture media indicated that, in general, these BC productions could be increased by ~200% and ~100% for the crude glycerol and grape skins, respectively, after the addition organic or inorganic nitrogen. PMID- 21601446 TI - Microbial community structure and dynamics in a mixotrophic nitrogen removal process using recycled spent caustic under different loading conditions. AB - A laboratory-scale Bardenpho process was established to investigate the proper nitrogen loading rate (NLR) when modified spent caustic (MSC) is applied as electron donor and alkalinity source for denitrification. MSC injection induced autotrophic nitrogen removal with sulfur as electron donor and heterotrophic denitrification. The nitrogen removal rate (NRR) did not increase proportionally to NLR. Based on the total nitrogen concentration in the effluent observed in the trials with MSC, the NLR in the influent should not exceed 0.15 kg N/m(3)d in order to satisfy water quality regulations. Microbial communities in the anoxic reactors were characterized by pyrosequencing of 16S rRNA gene sequences amplified by the polymerase chain reaction of DNA extracted from sludge samples. Microbial diversity was lower as MSC dosage was increased, and the injection of MSC caused an increase in SOB belonging to the genus Thiobacillus which is responsible for denitrification using sulfur. PMID- 21601447 TI - Ionic liquid-mediated extraction of lipids from algal biomass. AB - Lipids from algal biomass were extracted using mixtures of ionic liquids (ILs) and methanol, and fatty acid profiles of the extracted lipids were characterized in this work. Mixtures of ILs and methanol successfully dissolved biomass leaving lipids insoluble. The total contents of lipids extracted from commercial and cultivated Chlorella vulgaris were 10.6% and 11.1%, respectively, by the conventional Bligh and Dyer's method, while a mixture of [Bmim][CF(3)SO(3)] and methanol extracted 12.5% and 19.0% of the lipids, respectively. Multi-parameter regression by the linear solvation energy relationship showed that dipolarity/polarizability and hydrogen bond acidity of ILs are more important than their hydrogen bond basicity for effectively extracting lipids from algal biomass. Fatty acid profiles of the lipids extracted using IL-methanol mixtures showed that C16:0, C16:1, C18:2, and C18:3 fatty acids were dominant. This suggests that the lipids extracted from C. vulgaris can be used as a source of biodiesel production. PMID- 21601448 TI - Lipophilicity of acidic compounds: impact of ion pair partitioning on drug design. AB - In drug discovery projects the ability to show a relationship between a compound's molecular structure and its pharmacokinetic, in vivo efficacy, or toxicity profile is paramount for the design of better analogues. To aid this understanding the measurement of distribution coefficients at some physiologically relevant pH, for example, log D(7.4), is common practice as they are used as a key descriptor in mathematical models for predicting various biological parameters. Evidence is presented that under typical experimental conditions ion pair partitioning can contribute greatly to log D(7.4) results for acidic compounds; if this is ignored it may compromise data analysis within drug discovery projects where the modulation of lipophilicity is a primary design strategy. The work herein focuses on acidic compounds and reflects the experience of AstraZeneca R&D Charnwood (AZ) where ion pair partitioning contributions can be minimized by the routine measurement of log D(5.5) data. The magnitude of ion pair partitioning contributions to the log D(7.4) measurements of 24 acidic drugs are investigated, and the risks to drug discovery projects that ignore such contributions are discussed. The superiority of measured lipophilicity data over calculated data for a set of AZ proprietary acidic compounds is also presented. PMID- 21601449 TI - Ketonethiosemicarbazones: structure-activity relationships for their melanogenesis inhibition. AB - A series of 2-(1-phenylalkylidene)hydrazinecarbothioamides 2, 2-(1 phenylalkyl)hydrazinecarbothioamides 3, 2-(3,4-dihydronaphthalen-1(2H) ylidene)hydrazinecarbothioamide (4), and 2-(1-(thiophen-2 yl)ethylidene)hydrazinecarbothioamide (5) were synthesized for their melanogenesis inhibition in melanoma B16 cells. The SAR of these ketonethiosemicarbazones revealed that the benzylidene hydrogen in aldehydethiosemicarbazones 1 can be replaced by hydrophobic moiety and substitutions with alkyl group for the terminal amino hydrogen of ketonethiosemicarbazones improved the activity appreciably. In addition, the double bond in thiosemicarbazones is an important factor for the increment of hydrophobicity. Thus hydrophobic ketonethiosemicarbazones are excellent inhibitors of melanogenesis like aldehydethiosemicarbazones. PMID- 21601450 TI - Novel, potent, and orally bioavailable phosphinic acid inhibitors of the hepatitis C virus NS3 protease. AB - A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conformationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described. PMID- 21601451 TI - Covalent stabilization of a small molecule-RNA complex. AB - We demonstrate covalent bond formation between an RNA aptamer containing a cysteamine-tethered nucleobase and helix-threading peptides (HTPs) containing alpha-bromoacetamide N-termini. The reaction is high yielding and inhibited by a DNA strand Watson-Crick complementary to the aptamer sequence indicating covalent reaction is dependent on the high affinity HTP-binding site present in the folded aptamer. These results are important for future structural studies of HTP-RNA complexes and methods for the discovery of new high affinity analogs via covalent tethering strategies. PMID- 21601452 TI - Tetrazine-trans-cyclooctene ligation for the rapid construction of integrin alphavbeta3 targeted PET tracer based on a cyclic RGD peptide. AB - Labeling biomolecules with (18)F is usually done through coupling with prosthetic groups, which generally requires several time-consuming radiosynthetic steps resulting in low labeling yield. Recently, the tetrazine-trans-cyclooctene ligation has been introduced as a method of bioconjugation that proceeds with fast reaction rates without need for catalysis. Herein, we report the development of an extremely fast and efficient method for generating (18)F labeled probes based on the tetrazine-trans-cyclooctene ligation. Starting with only 30 MUg (78 MUM) of a tetrazine-RGD conjugate and 2 mCi (5 MUM) of (18)F-trans-cyclooctene, the (18)F labeled RGD peptide could be obtained in more than 90% yield within five minutes. The (18)F labeled RGD peptide demonstrated prominent tumor uptake in vivo. The receptor specificity was confirmed by blocking experiments. These results successfully demonstrate that the tetrazine-trans-cyclooctene ligation serves as an efficient labeling method for PET probe construction. PMID- 21601453 TI - Isotope-coded chemical reporter and acid-cleavable affinity reagents for monitoring protein sulfenic acids. AB - We have developed an approach that allows relative quantification of protein sulfenic acids using a pair of light and heavy isotope labled probes, DAz-2 and d(6)-DAz-2. In conjunction with a new complementary acid-cleavable linker, Yn ACL, we demonstrate that tagged peptides are successfully labeled, enriched, and fully characterized by LC-MS/MS analysis. Overall, this method can be applied to map sites of cysteine oxidation and compare protein sulfenylation in normal and disease states. PMID- 21601454 TI - Identification and optimisation of novel sulfonamide, selective vasopressin V1B receptor antagonists. AB - The synthesis and preliminary structure-activity relationships (SAR) of a novel class of vasopressin V(1B) receptor antagonists are described. Hit compound 5, identified via high throughput screening of the corporate collection, showed good activity in a V(1B) binding assay (K(i) 63 nM) but did not possess the lead-like physicochemical properties typically required in a hit compound. A 'deletion approach' on the HTS hit 5 was performed, with the focus on improvement of physicochemical properties, yielding the selective V(1B) antagonist 9f (K(i) 190 nM), with improved druglike characteristics. PMID- 21601455 TI - Synthesis, cytotoxic activities and cell cycle arrest profiles of naphtho[2,1 alpha]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione glycosides. AB - Naphtho[2,1-alpha]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione (NPCD) is known to be a very potent and selective cyclin D1-CDK4 inhibitors and could induce strong G1 phase arrest in breast tumor cell lines. In this work, the synthesis of five NPCD glycosides and their cytotoxic activities against eight tumor cell lines are presented, as well as the investigation of their cell cycle arrest profiles. The results showed that the introduction of a sugar moiety onto NPCD did not affect much of their cytotoxic activities, while the subtle structure of the sugar moiety affected the underlying mechanism strongly. In addition, NPCD showed distinct cell-cycle arrest profiles in BxPC3 prostate cells and MCF-7 breast cells, while NPCD glycosides shared similar cell cycle arrest profiles in MCF-7 and BxPC3 cells, which also indicated that not only the indolocarbazole framework as well known before but the sugar moiety can have a profound impact on the mechanism of action for these types of compounds. PMID- 21601456 TI - Enzymatic synthesis of a 6-sialyl lactose analogue using a pH-responsive water soluble polymer support. AB - The Letter describes a strategy for the enzymatic synthesis of glycans based on a pH-responsive water-soluble polymer. In neutral condition, the polymer is water soluble and convenient for in-solution enzymatic synthesis, whereas in acidic condition (pH lower than 4.0), the polymer disconnects with the product and becomes insoluble, which can be easily removed. A 6-Sialyl lactose analogue was synthesized as a model reaction using this approach. PMID- 21601457 TI - Part 1: N-alkylated glycines as potent alpha2delta ligands. AB - A new series of glycine-derived ligands of the alpha(2)delta subunit of voltage gated calcium channels is described. Several novel compounds (7) based on (6) were prepared that possessed a potency <100 nM in the alpha(2)delta binding assay. PMID- 21601458 TI - Impact of immediate breast reconstruction on breast cancer recurrence and survival. AB - The practise of Immediate Breast Reconstruction (IBR) following mastectomy for primary breast cancer is being increasingly adopted. Here the impact of IBR on disease progression and survival was assessed following treatment for invasive breast cancer. 1697 consecutive patients received surgical treatment for operable primary breast cancer between January 1996 and December 2007. Overall, 691 (41%) received mastectomy of whom 136 (20%) underwent IBR (82 Latissimus Dorsi, 54 Subpectoral). The effect of IBR on overall survival, local and distant recurrence was analysed in all patients studied and also separately within subgroups defined by Nottingham Prognostic Index (NPI) scores. The median follow up of patients studied was 55 months (range 16-148). There was no difference between IBR and mastectomy alone in survival (p=0.176), time to distant metastasis (p=0.783) or local recurrence (p=0.505), either overall or within Nottingham Prognostic groups. PMID- 21601459 TI - To repress or not to repress: this is the guardian's question. AB - p53 is possibly the most central tumor suppressor gene of our cells, integrating stress signals to activate a transcriptional program responsible for maintaining cellular homeostasis. Many of the downstream effects of p53 are a consequence of its activity as a transcription factor, resulting in the induction of multiple target genes. In addition to gene activation, however, gene repression is an essential part of the p53 cellular response. Despite extensive research efforts towards the elucidation of p53 functions, the molecular mechanisms and biological consequences of gene repression by p53 have not been studied extensively. We review our current knowledge of the mechanisms and biological consequences of p53 repression, with special attention to recently discovered mechanisms of repression that involve non-coding RNA molecules, an emerging aspect of regulation in the p53 cellular network. PMID- 21601460 TI - Strategies of stepping over obstacles: The effects of long-term exercise in older adults. AB - BACKGROUND: Stepping over obstacles challenges stability and is a leading cause of falls in older adult populations. As walking and Tai Chi (TC) exercise have been suggested practices for older adults for fall prevention, the purpose of this study was to evaluate the obstacle-crossing strategies of long-term TC practitioners and exercise walkers. METHODS: Thirty healthy older women (average age: 65.7 years) with either TC (n=15) experience (average experience: 8.2 years) or walking exercise (n=15; average experience: 8.8 years) participated in this study. We used three trial conditions: (1) normal walking, (2) crossing a 15cm (20% of leg length) obstacle, and (3) crossing a 23cm (30% of leg length) to assess obstacle-crossing strategy. Sagittal plane obstacle-crossing kinematic parameters and plantar pressures were used to evaluate the obstaclecrossing strategy. A MANOVA assessed differences between groups. RESULTS: Individuals with a TC background crossed the obstacle significantly faster with a significantly longer step relative to the exercise walkers. Plantar pressure profiles between the two groups also differed. Exercise walkers showed greater plantar pressure in the forefoot; TC practitioners demonstrated greater medial heel plantar pressure during obstacle-crossing. CONCLUSIONS: Our results suggest that obstacle-crossing strategies were affected by the type of longterm exercise. The strategies each group used had important attributes that affect stability during obstacle crossing. Future studies are needed to understand how obstacle-crossing strategies are adopted and how exercise may influence the strategy used. PMID- 21601461 TI - A new cerebral hemorrhage model in cynomolgus macaques created by injection of autologous anticoagulated blood into the brain. AB - The aim of this study was to establish and validate a clinically relevant model of intracerebral hemorrhage (ICH) via injection of autologous blood into the brains of cynomolgus macaques (Macaca fascicularis). Eight male cynomolgus macaques received 1.5 mL of fresh anticoagulated autologous femoral artery blood into the inner side of the claustrum near the right basal ganglia under stereotactic guidance. Animals were evaluated with MRI and positron emission tomography (PET) scanning before and 24 hours after surgery and once per week thereafter. A neurological deficit scale was used to assess the animals on days 1, 2, 3, 7, 14, 21, and 28 after surgery. Animals showed focal neurological signs corresponding to the MRI-located hematoma. The behavioral impairment progressively ameliorated over time, but never fully resolved. The hematoma was absorbed over time but was still present 4 weeks after surgery, with persistent metabolic deficit detected using PET scanning. Histological examinations confirmed the in vivo findings. This ICH model in a non-human primate mimics human ICH in the basal ganglia and may be useful for assessing the safety and efficacy of neuroprotective agents. PMID- 21601462 TI - Leg alignment and tibial slope after minimal invasive total knee arthroplasty: a prospective, randomized radiological study of intramedullary versus extramedullary tibial instrumentation. AB - The purpose of the study was analysis of leg alignment and tibial slope comparing intramedullary versus extramedullary tibial instrumentation in the Genesis II MIS TKA (Smith & Nephew, Memphis, USA). A prospective randomized study was performed according to the CONSORT guidelines. All patients (56 patients) for MIS-TKA were included, if the pre-operative standing long leg X-ray demonstrated the tibia eligible for use of both intra- and extramedullary MIS tibial instrumentation. Randomization was performed by envelope selecting intra- or extramedullary tibia MIS instrumentation. All patients were operated by, or under supervision of, one experienced knee surgeon (RJ). Measurements of leg alignment and tibial slope were made on standardized long leg standing X-rays and lateral knee X-rays performed pre-operatively and 4-12 months post-surgery. Leg alignment was defined as being within or outside the range of 3 degrees varus-valgus on the mechanical leg. The tibial slope was compared pre- and post-surgery. In the present study, there was no difference in leg alignment after MIS-TKA comparing intramedullary versus extramedullary tibial instrumentation. Restoration of tibial slope was significantly better with use of the extramedullary tibial instrumentation. PMID- 21601463 TI - Significant enhancement in radical-scavenging activity of curcuminoids conferred by acetoxy substituent at the central methylene carbon. AB - For a compound to be a radical-trapping antioxidant, the antioxidant-derived radical must be sufficiently inert to molecular oxygen as this would generate harmful chain-propagating peroxyl radicals. Curcumin has a unique structure with phenolic hydroxyl group as well as beta-diketone moiety in the same molecule, both of which are able to donate electrons to free radicals. However, due to the reactivity toward molecular oxygen, the carbon-centered radical derived from beta diketone moiety do not serve as radical-trapping antioxidants. In this study, we reasoned that stabilization of the carbon-centered radical through substitution with an electron-withdrawing group would enhance the radical-scavenging antioxidative activity of the resulting curcuminoids. Thus, various substituents (methyl, allyl, methoxy, xanthate, and acetoxy) covering broad spectrum of the polar substituent effect were introduced to the central methylene position of both phenolic and non-phenolic curcuminoids. With the free phenolic hydroxyl groups present, the methylene-substituent did not exert significant effect on the antioxidant activity of the curcuminoids (EC(50)=23.2-30.3 MUM) with the exception of the acetoxy-substituted derivative (EC(50)=8.7 MUM) which showed more potent activity than curcumin (EC(50)=22.6 MUM). When substituted to the non phenolic curcumin scaffold, however, the methylene-substituent enhanced antioxidant activity of the otherwise inactive curcuminoids in the increasing order of methyl=80 years) Australian patients undergoing isolated aortic valve replacement. METHODS: Data obtained prospectively between June 2001 and December 2009 by the Australasian Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database Program were retrospectively analysed. Isolated aortic valve replacement was performed in 2791 patients; of these, 531 (19%) were at least 80 years old (group 1). The patient characteristics, morbidity and short term mortality of these patients were compared with those of patients who were <80 years old (group 2). The long-term outcomes in elderly patients were compared with the age-adjusted Australian population. RESULTS: Group 1 patients were more likely to be female (58.6% vs 38.0%, p<0.001) and presented more often with co morbidities including hypertension, cerebrovascular disease and peripheral vascular disease (all p<0.05). The 30-day mortality rate was not independently higher in group 1 patients (4.0% vs 2.0%, p=0.144). Group 1 patients had an independently increased risk of complications including new renal failure (11.7% vs 4.2%, p<0.001), prolonged (>=24 h) ventilation (12.4% vs 7.2%, p=0.003), gastrointestinal complications (3.0% vs 1.3%, p=0.012) and had a longer mean length of intensive care unit stay (64 h vs 47 h, p<0.001). The 5-year survival post-aortic valve replacement was 72%, which is comparable to that of the age matched Australian population. CONCLUSION: Conventional aortic valve replacement in elderly patients achieves excellent outcomes with long-term survival comparable to that of an age-adjusted Australian population. In an era of percutaneous aortic valve implantation, it should still be regarded as the gold standard in the management of aortic stenosis. PMID- 21601471 TI - Microbiology specimens obtained at the time of surgical lung biopsy for interstitial lung disease: clinical yield and cost analysis. AB - OBJECTIVES: In efforts to obtain complete results, current practice in surgical lung biopsy (LB) for interstitial lung disease (ILD) recommends sending lung tissue samples for bacterial, mycobacterial, fungal, and viral cultures. This study assesses the value of this practice by evaluating the microbiology findings obtained from LB for ILD and their associated costs. METHODS: A total of 296 consecutive patients (140 women, 156 men, median age=61 years) underwent LB for ILD from 2002 to 2009. All had lung tissue sent for microbiology examination. Microbiology results and resultant changes in patient management were analyzed retrospectively. A cost analysis was performed based upon nominal hospital charges adjusted on current inflation rates. Cost data included cultures, stains, smears, direct fluorescent antibody studies, and microbiologist consulting fees. RESULTS: As many as 25 patients (8.4%) underwent open LB and 271 (91.6%) underwent thoracoscopic LB. A total of 592 specimens were assessed (range 1-4 per patient). The most common pathologic diagnoses were idiopathic pulmonary fibrosis in 122 (41.2%), cryptogenic organizing pneumonia in 31 (10.5%), and respiratory bronchiolitis ILD in 16 (5.4%). Microbiology testing was negative in 174 patients (58.8%). A total of 118 of 122 (96.7%) positive results were clinically considered to be contaminants and resulted in no change in clinical management. The most common contaminants were Propionibacterium acnes (38 patients; 31%) and Penicillium fungus (16 patients; 13%). In only four patients (1.4%), the organism cultured (Nocardia one, Histoplasma one, and Aspergillus fumigatus two) resulted in a change in clinical management. The cost of microbiology studies per specimen was $984 (?709), with a total cost for the study cohort being $582,000 (?420,000). CONCLUSIONS: The yield and impact on clinical management of microbiology specimens from LB for ILD is very low. Its routine use in LB is questionable. We suggest it should be limited to those cases of ILD with a high suspicion of infection. Substantial cost savings are possible with this change in clinical practice. PMID- 21601472 TI - Ablation of paroxysmal atrial fibrillation during coronary artery bypass grafting: 12 months' follow-up through implantable loop recorder. AB - OBJECTIVES: The study aimed to identify responders to atrial fibrillation (AF) ablation, through continuous subcutaneous monitoring in patients with paroxysmal atrial fibrillation (PAF), who underwent epicardial pulmonary vein isolation (PVI) concomitantly with coronary artery bypass grafting (CABG). METHODS: Seventy two patients aged 61.6+/-4.7 years with PAF underwent epicardial PVI with bipolar radiofrequency during CABG. Conduction block was confirmed by pacing. At the end of the procedure, the implantable loop recorder (ILR) for continuous monitoring was implanted in all patients. Follow-up data were collected through the ILR telemetry. Patients with an AF burden (AF%)<0.5% were considered AF free (responders). Patients with AF%>0.5% were classified as non-responders. The AF episodes stored by the implanted device were visually inspected by the investigators to confirm the arrhythmia. The data were collected each month during 1-year follow-up. RESULTS: No procedure-related complications occurred either for ablation or for the monitoring device. At the first post-ablation follow-up (1 month) during the blanking period, 37 patients (51%) were AF free, that is, with AF%<0.5%. At the end of the blanking period (3rd follow-up), 44 (61%) patients were AF free. At 12 months' follow-up, 52 (72%) patients were AF free. Among 20 (28%) patients with AF recurrence, six (30%) patients were completely asymptomatic. There were no ischaemic strokes during the 1-year follow up. CONCLUSION: Concomitant AF ablation during CABG is effective in the treatment of AF, as assessed through 1 year of continuous monitoring. Use of subcutaneous monitors is safe and accurate for AF detection, clinically relevant in identifying responders and non-responders and managing the medical therapies accordingly. PMID- 21601473 TI - Double-lumen tube intubation systematic verification with fiberoptic bronchoscopy: between what who should do and what we can do. PMID- 21601474 TI - Role of chemotherapy in the management of vulvar carcinoma. AB - The aim of this review is to evaluate the use of chemotherapy (CT) in the treatment of squamous vulvar cancer. Since the 90s there was a continuous evolution in the therapeutic approach to this tumour. Although primary surgery is now considered the most effective approach, there are advanced diseases in which surgery may compromise anatomical structures causing severe mutilation. These are the reasons why CHT, with or without concomitant radiotherapy RT, started to be strongly recommended as neoadjuvant strategy. Chemotherapeutic agents have also been used alone as adjuvant treatment or in association with RT, by exploiting the radiosensitizing effect of these drugs. There are few data about the use of CHT as palliative treatment but recent studies point to the use of target therapy. In conclusion, clinical data and the evidence of chemo-sensitivity in vulvar squamous cell carcinoma open new possibilities to future research in this field. PMID- 21601475 TI - Circulating chemokine (CXC motif) ligand (CXCL)9 is increased in aggressive chronic autoimmune thyroiditis, in association with CXCL10. AB - Chemokine (CXC motif) ligand (CXCL)9 (CXCL9) has been shown to be involved in autoimmune thyroid disorders, however no data are present about CXCL9 circulating levels in chronic autoimmune thyroiditis (AT) vs controls. Serum CXCL9 (and for comparison CXCL10) has been measured in patients with AT vs normal control and nontoxic multinodular goiter, and this parameter has been related to the clinical phenotype. For this study we selected 189 consecutive patients with newly diagnosed AT, 63 euthyroid controls, 30 patients with nontoxic multinodular goiter. The three groups were similar in gender distribution and age; 26% of AT patients had subclinical hypothyroidism. Serum CXCL9 was significantly higher in AT (148+/-110 pg/mL) than in controls (71+/-34 pg/mL) or patients with multinodular goiter (87+/-35 pg/mL) (p<0.0001). Among AT patients, CXCL9 levels were significantly higher in patients older than 50 years, those with a hypoechoic ultrasonographic pattern or with hypothyroidism. Also CXCL10 was confirmed to be associated with AT, overall in presence of hypothyroidism. In a multiple linear regression model of CXCL9 (ln[pg/mL]) vs age, thyroid volume, TSH, AbTg, AbTPO, hypoechoic pattern, the presence of hypervascularity, and CXCL10 (ln[pg/mL]), only TSH and CXCL10 (ln[pg/mL]) were significantly related to serum CXCL9 levels. We show that circulating CXCL9 is increased in patients with aggressive thyroiditis and hypothyroidism. A strong relation between circulating CXCL9 and CXCL10 has been first shown, underlining the importance of a T helper 1 immune attack in the initiation of AT. PMID- 21601476 TI - Food impaction after expandable metal stent placement: experience in 1,360 patients with esophageal and upper gastrointestinal tract obstruction. AB - PURPOSE: To retrospectively evaluate the incidence, predictive factors, and interventional management of food impaction after expandable metallic stent placement in patients with obstruction of the esophagus or upper gastrointestinal tract caused by benign or malignant disease. MATERIALS AND METHODS: Between March 1993 and March 2010, 1,360 patients (1,029 men, 331 women; age range, 21-89 y; mean age, 61 y) underwent fluoroscopically guided stent placement for dysphagia caused by esophageal or gastrointestinal tract strictures. Five types of covered expandable metal stents were used, including four types of esophageal stents (types A-D) and one type of gastroduodenal stent (type E), with types A, B, C, D, and E stents used in 180, 60, 90, 432, and 598 patients, respectively. Multivariate analysis was performed to evaluate factors predictive of food impaction. RESULTS: Food impaction occurred in 41 of 1,360 patients (3.0%). The food impaction rates for types A, B, C, D, and E stents were 0.6%, 1.7%, 1.1%, 3.2%, and 4.0%, respectively. Multivariate analysis showed that stent length was an independent predictor of food impaction (odds ratio, 0.839; P = .012). Of the 41 patients with food impaction, 23 underwent endoscopic management, 12 underwent fluoroscopically guided management, and six did not require management because impacted food spontaneously passed through the stent. CONCLUSIONS: The overall food impaction rate was 3.0%, with multiple logistic regression analysis showing that shorter stent length was the only significant predictor of food impaction. Food impaction can be managed by endoscopic or fluoroscopically guided removal or placement of a second stent. PMID- 21601477 TI - State-of-the-art mechanical ventilation. PMID- 21601478 TI - Introspecting a conscious decision or the consciousness of a decision? PMID- 21601480 TI - Psychological and quality of life changes in patients using GLP-1 analogues. AB - AIMS: Using psychological and quality of life assessment tools, we prospectively studied changes in health-related quality of life and emotional well-being in patients who had commenced GLP-1 analogue therapy (exenatide) and compared them with new insulin starters. METHODS: Two matched groups of patients with type 2 diabetes who had suboptimal glycaemic control on oral medication were assessed using a battery of well-validated psychological and quality of life tests at baseline, prior to commencement of treatment and then again after 6 months of continuous therapy, along with body mass index (BMI) and hemoglobin A1c (HbA1c) measurements. RESULTS: In the exenatide-treated patient group (n=71), treatment satisfaction was greater (P<.05), as was the well-being score, at 6 months (P<.05), and the Hospital Anxiety and Depression Scale scores were significantly reduced (P<.05) when compared with the insulin-treated group (n=67). This was also found to be independent of changes in BMI in an analysis of covariance calculation. The effect size (using Cohen's d) of these changes was however relatively small. CONCLUSIONS: Although exenatide and insulin appear to have similar efficacy for the treatment of type 2 diabetes mellitus, there are several differences between them that could influence outcomes from a patient's perspective. Exenatide affects both physiological and psychological parameters. 'Well-being' generally tends to improve in exenatide-treated patients and could be used as an adjunctive therapy for depression in the context of diabetes. A larger study is required to confirm these interesting findings. PMID- 21601479 TI - Multiple HbA1c targets and insulin analogues in type 2 diabetes: a systematic review. AB - PROBLEM: Insulin analogues are increasingly used in patients with type 2 diabetes. We performed a systematic review of randomized controlled trials (RCTs) to assess the role of insulin analogues to reach different hemoglobin A1c (HbA1c) targets (from 6.5% to 8%) in type 2 diabetic patients. METHODS: RCTs involving insulin regimens (basal, prandial, biphasic, and basal-bolus) with insulin analogues in type 2 diabetes were identified through electronic searches (MEDLINE, EMBASE, CINAHL, and The Cochrane Library) through August 2010. We included any study arm of RCTs if they were at least 12 weeks in duration, and reported HbA1c as an outcome and the proportion of diabetic patients reaching the HbA1c target of <7%. The proportion of patients with HbA1c <6.5%, <7.0%, <7.5%, and <8.0% was estimated using mean and standard deviation of HbA1c at the end of treatment. RESULTS: We identified 53 RCTs, with 92 arms, and 32,689 patients. The proportion of patients at target was highest with the basal-bolus regimen, and ranged from 27.8% (95% CI, 22.2-34%) for the HbA1c target <6.5% to 88% (CI 83 92%) for the HbA1c target <8%. Biphasic insulin regimen ranked second at any HbA1c target, while prandial and basal regimens alternated across different HbA1c targets. CONCLUSIONS: At any HbA1c target, basal-bolus insulin regimens with insulin analogues obtained the best results, which may be useful for detailing the best treatment effect in individual patients. PMID- 21601482 TI - Depression among adults with diabetes in Jordan: risk factors and relationship to blood sugar control. AB - OBJECTIVES: The aims of this study were to estimate the prevalence of undiagnosed depression among adults with diabetes mellitus in Jordan and to determine the factors that may indicate the presence of depression and to examine the relationship between depression and blood sugar control among Jordanian subjects with diabetes. METHODS: A systemic random sample of 649 type 1 and type 2 diabetic patients aged 18-75 years was selected during the period from July 2009 to January 2010. A prestructured questionnaire was used for collecting the information about sociodemographic data and clinical characteristics. Depression was evaluated using the Patients' Health Questionnaire-8 (PHQ-8). A PHQ-8 score >=10 has been recommended as a cutoff point for depression. Self-care management behaviors and barrier to adherence were collected. Weights and heights were measured. Glycated hemoglobin was abstracted from each patient directly after the interview. RESULT: Of the 649, 128 (19.7) have depression according to the PHQ-8 scores. According to the multivariate analysis, females are more likely to develop depression than males with [odds ratio (OR), 1.91; P=001] and low educated people versus educated people (OR, 3.09; P<=.002). Being on insulin treatment also has a significant association with depression (OR, 3.31; P=.001). Not following eating plans as recommended by dietitians, lacking self-monitoring blood glucose and increased barriers to adherence scale scores were also associated with depression among the subjects with diabetes. CONCLUSION: The prevalence of depression among Jordanian subjects with type 1 and type 2 diabetes is high compared with some developed countries. This was associated with gender, educational level, insulin treatment, low self-management behaviors and increased barriers to adherence. This result shows the urgent need to include the routine screening of depression during outpatient visit, which might help prevention, early detection and management of depression. PMID- 21601481 TI - Anemia normalization in patients with type 2 diabetes and chronic kidney disease: results of the NEPHRODIAB2 randomized trial. AB - STATEMENTS OF THE PROBLEM: Correction of anemia in type 2 diabetes (T2DM) patients with chronic kidney disease stages 3-4 may slow the decline of kidney function but may increase cardiovascular risk through higher hematocrit. The NEPHRODIAB2 study was designed to assess efficacy and safety of complete hemoglobin (Hb) normalization in these patients. METHODS: We randomly assigned 89 T2DM patients with an estimated glomerular filtration rate (eGFR; abbreviated 175 Modification of Diet in Renal Disease formula) of 25 to 60 ml/min per 1.73 m(2) and moderate anemia (Hb, 100-129 g/l) to a target Hb value in subnormal range (110-129g/l, group 1, n=43) or normal range (130-149 g/l, group 2, n=46). The primary end point was eGFR decline after 2 years of follow-up. Secondary end points included iron and erythropoietin dosage, quality of life (Medical Outcomes Study 36-item Short-Form Health Survey scores) and adverse events. RESULTS: Six months after randomization, the mean Hb levels were <120 g/l in group 1 and >130 g/l in group 2 (P<.05 at 6, 12, 18 and 24 months). Blood pressure, 24-h proteinuria and HbA1c did not differ during follow-up (P>.05). Two-year declines in eGFR were -8.7+/-12.2 in group 1 and -5.1+/-7.8 ml/min per 1.73 m(2) in group 2 (P=.29). Mean weekly use of erythropoietin was 7.8+/-11.6 MUg in group 1 and 30.1+/-33.6 MUg in group 2 (P<.0001). There was no significant difference regarding Medical Outcomes Study 36-item Short-Form Health Survey score change or adverse event occurrence. CONCLUSIONS: In this trial, normalization of Hb level in T2DM patients with chronic kidney disease was safe but did not significantly slow renal function decline and increased treatment cost due to erythropoietin use. PMID- 21601483 TI - Insulin resistance and hypertension in patients with type 1 diabetes. AB - AIM: The aims of this study were to determine the prevalence of hypertension in type 1 diabetes patients and to analyze its relationship with insulin resistance and other associated factors. DESIGN AND METHODS: A cross-sectional study on 291 patients with type 1 immune-mediated diabetes managed at two outpatient endocrinology clinics was performed. All participants were Caucasian, 18 years or older with type 1 diabetes duration of more than 6 months, who had completed the study protocol. Hypertension was defined as blood pressure >=130/80 mmHg or use of antihypertensive medication, excluding angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers when used as treatment for micro- or macroalbuminuria. RESULTS: Hypertension was found in 87 [29.9% (95% confidence interval, or CI): 24.6%-35.2%] patients with type 1 diabetes. Hypertensive patients presented older age, male predominance, higher body mass index and overweight/obesity prevalence, and longer diabetes duration compared with normotensive patients. Insulin sensitivity quantified by estimated glucose disposal rate (eGDR) was lower in patients with hypertension compared with normotensives (5.2+/-1.4 vs. 9.1+/-1.2 mg kg(-1) min(-1), P<.001) and showed a negative correlation with systolic blood pressure level (r=-0.612, P<.01). In multivariate logistic regression analysis, eGDR, besides nephropathy, emerged significantly and independently associated with hypertension. An increment of 1 unit in insulin sensitivity assessed by eGDR was associated with a 5.7% decrease in hypertension prevalence (95% CI: 0.018-0.175) and the absence of nephropathy with an 88.2% decrease (95% CI: 0.15-0.92). CONCLUSIONS: Hypertension was present in approximately one third of patients with type 1 diabetes, especially in men, those with microangiopathy, overweight or obesity, older age and longer diabetes duration. Hypertension prevalence increased in parallel to the degree of renal impairment and was inversely related to insulin sensitivity. PMID- 21601484 TI - Osteonecrosis of the distal tibia after a pronation external rotation ankle fracture: literature review and management. AB - Posttraumatic osteonecrosis of the distal tibia is a rare but recognized complication of Weber C ankle fractures. To our knowledge, we report the first documented case managed with early percutaneous drilling of the defect. The patient noticed an improvement in symptoms, and magnetic resonance imaging confirmed resolution of the avascular area. The previously reported complication of secondary periarticular collapse and subsequent osteoarthritis was avoided. We advocate that a high index of suspicion, early detection, and drilling can encourage neovascularisation and prevent secondary joint destruction. PMID- 21601485 TI - Endoscopic excision of symptomatic nonunion of anterior calcaneal process. AB - Most fractures of the anterior process of the calcaneus are successfully treated with cast immobilization. Large fragments might be amenable to open reduction and internal fixation. The correct initial diagnosis and treatment are important, particularly if the fracture fragment is large. An improper initial diagnosis will lead to painful nonunion requiring surgical intervention. We present a case of symptomatic nonunion of the anterior calcaneal process that was successfully treated by endoscopic resection of the fragment. The adjacent structures can be examined arthroscopically for concomitant lesions and treated accordingly. PMID- 21601486 TI - Ray reduction of the foot in the treatment of macrodactyly and review of the literature. AB - Macrodactyly of the foot is a rare disorder characterized by enlargement of the soft tissue and osseous elements of the foot that impedes the development of normal function and gait. Despite the morbidity associated with this condition, many surgeons are reluctant to perform surgical reduction. In the present report, we describe 3 pediatric patients with pedal macrodactyly, who underwent surgical correction consisting of amputation of the most enlarged ray, reduction of the adjacent rays, and ray transposition, combined with debulking of soft tissues. All 3 patients subsequently developed a normal gait and were able to wear normal, or minimally adjusted, shoes. We advocate early surgical treatment of macrodactyly of the foot to enhance the development of normal function and gait. PMID- 21601487 TI - The impact of an acute care emergency surgical service on timely surgical decision-making and emergency department overcrowding. AB - BACKGROUND: This study evaluated how implementation of an acute care emergency surgery service (ACCESS) affected key determinants of emergency department (ED) length of stay, and particularly, surgical decision time. Also, we analyzed how ACCESS affected ED overcrowding. STUDY DESIGN: We conducted a before and after study of all ED patients referred to ACCESS from January 1, 2007 to June 30, 2009. ACCESS was implemented on July 1, 2008. The primary outcome was surgical decision time; the secondary outcome was a measure of overall ED overcrowding: "time-to-stretcher" for all ED patients. The control groups were patients referred to internal medicine or urology. Patients with appendicitis were studied in order to analyze the impact on patient outcomes and to determine barriers to efficient ED patient flow. RESULTS: Of 2,510 patients, 1,448 patients were pre ACCESS, and 1,062 were after ACCESS implementation. Implementation of ACCESS was associated with a 15% reduction in surgical decision time (12.6 hours vs 10.8 hours, p < 0.01). During the same period, there were no significant changes in decision time for our control groups. Also, the mean time-to-stretcher for all ED patients decreased by 20%. In patients with appendicitis, we found that patient flow could be further improved by a timely request for surgical consultation and expedited imaging. Finally, we found that patients with nonperforated appendicitis with a fecalith on CT imaging were more likely to suffer perforation while waiting for surgery. CONCLUSIONS: ACCESS reduced surgical decision time for surgical patients. Also, ACCESS improved overall ED crowding, as measured by time to-stretcher for ED patients. Further improvements could be made by improving time to imaging. Patients referred for nonperforated appendicitis with a fecalith on CT should have expedited surgery. PMID- 21601488 TI - Survival after resection for invasive intraductal papillary mucinous neoplasm and for pancreatic adenocarcinoma: a multi-institutional comparison according to American Joint Committee on Cancer Stage. AB - BACKGROUND: Survival after resection for invasive intraductal papillary mucinous neoplasm (inv-IPMN) is superior to pancreatic ductal adenocarcinoma (PDAC). This difference may be explained by earlier presentation of inv-IPMN. We hypothesized that inv-IPMN has survival comparable with PDAC after resection when matched by stage. STUDY DESIGN: From 1999 to 2009, 113 patients underwent resection for inv IPMN at 2 large academic institutions. These data were compared with 845 patients during the same period undergoing resection for PDAC. Demographics, pathology, and overall survival (OS) were compared according to current American Joint Committee on Cancer stage. RESULTS: Mean age with inv-IPMN and PDAC was 68 and 65 years, respectively. Follow-up was 33 and 24 months for inv-IPMN and PDAC, respectively. Median OS was 32 months for inv-IPMN and 17 months in PDAC (p < 0.001). Median OS in lymph node-negative inv-IPMN was 41 months and 24 months in PDAC (p = 0.003), with the greatest absolute difference in stage Ia patients with OS of 80 and 50 months in inv-IPMN and PDAC, respectively (p = 0.03). In node positive patients, OS was 20 months in inv-IPMN and 15 months in PDAC (p = 0.06). Of inv-IPMN, 24% was colloid versus 75% of tubular subtype; 37(85%) of node positive inv-IPMN were tubular subtype. Median OS was 23 and 127 months for tubular and colloid subtypes, respectively (p < 0.001). CONCLUSIONS: When matched by stage, inv-IPMN has superior survival after resection compared with PDAC. This disparity is greatest in node-negative and least in node-positive disease. These findings suggest the behaviors of inv-IPMN and PDAC, although different, converge with advancing American Joint Committee on Cancer stage because of a greater proportion of tubular subtype. PMID- 21601489 TI - Fine needle aspiration of the thyroid: correlation with final histopathology in a surgical series of 797 patients. AB - BACKGROUND: Fine needle aspiration (FNA) is accepted as the diagnostic procedure of choice in the management of patients with thyroid nodules. Follicular/Hurthle cell neoplasms have traditionally been grouped under the category of indeterminate FNA results. This study examined the experience with FNA in a large cohort of patients undergoing thyroidectomy before adoption of the Bethesda system for reporting thyroid cytopathology (BSTC) at a single academic medical center. STUDY DESIGN: A retrospective review of prospectively collected data of 797 consecutive patients with dominant nodules >1 cm who underwent FNA and thyroidectomy from 2003 to 2009 was performed. Patients were categorized into groups based on FNA results: malignant, benign, indeterminate, and nondiagnostic. The indeterminate group had FNA results that included follicular neoplasm, Hurthle cell neoplasm, and suspicion of papillary thyroid cancer. FNA results were compared with final histopathology after thyroidectomy. RESULTS: FNA results included 147 (18%) positive for malignancy, 255 (32%) benign, 358 (45%) indeterminate, and 37 (5%) nondiagnostic. The overall malignancy rate on final histopathology was 369 of 797 (46%). Overall, there was a false positive rate of 2% and false negative rate of 8.6%. Among the 358 indeterminate FNA results, carcinoma was found in 81 (36%) of 223 follicular neoplasms, 18 (36%) of 50 Hurthle cell neoplasms, and 78 (92%) of 85 that were suspicious for papillary thyroid cancer. When FNA was nondiagnostic, cancer was present in 9 of 37 (24%). Among 39 patients with benign FNA who had cancer on final histopathology, 22 of 255 (8.6%) had cancer in the index thyroid nodule, and 81% of cancers were >1 cm. CONCLUSIONS: Patients with FNA and dominant nodules >1 cm, who underwent thyroidectomy, had an overall rate of thyroid malignancy of 46%. There was a cancer prevalence of 8.6% in patients with benign FNA results referred for surgical resection. Despite not yet implementing the BSTC at this medical center, the majority of thyroidectomies were adequately performed for indeterminate FNAs with underlying malignancy. PMID- 21601490 TI - Lymph node ratio: a proposed refinement of current axillary staging in breast cancer patients. AB - BACKGROUND: The optimal method for classifying lymph node (LN) status in breast cancer patients is unknown. We sought to determine if LN ratio (LNR) improves axillary staging. STUDY DESIGN: Kentucky Cancer Registry data (1996 to 2007) were used to compare LN categorization schemas. Overall survival (OS) was evaluated using the Kaplan-Meier method and log rank tests. Schemas included: LN positive (+) vs negative (-) disease, current American Joint Committee on Cancer (AJCC) staging (0 vs 1 to 3 vs 4 to 9 vs >=10 LN+), and LNR 0 vs 0.01 to 0.20 vs 0.21 to 0.65 vs >0.65 (LN- vs low, intermediate, and high risk LN+ groups). RESULTS: There were 1,436 patients who had complete LN evaluation data: 880 (61.3%) were LN- and 556 (39.6%) were LN+; 309 (21.5%) had 1 to 3 positive LNs, 138 (9.6%) had 4 to 9 positive LNs, and 109 (7.6%) had 10 or more positive LNs. For LN+ patients, the median number of positive LNs was 3; median LNR was 0.23. The median follow-up was 65 months. LN status was associated with 5-year OS (91.3% and 73.3% for LN- and LN+ groups, respectively, p < 0.001). Increasing AJCC pN stage was associated with worse OS (5-year OS 80.5%, 75.3%, and 49.8% for pN1 to N3, respectively, p < 0.001). LNR was also associated with OS (5-year OS of 83.1%, 72.7%, and 52.7% for the low, intermediate, and high risk LN+ groups, respectively, p < 0.001). In subgroup analyses of patients in the 1 to 3 and 4 to 9 LN+ groups, OS was statistically associated with LNR (p = 0.021 and p = 0.016, respectively). On multivariable survival analysis, LNR was associated with OS, independent of AJCC categorization, p = 0.003. CONCLUSIONS: LNR was associated with OS, regardless of AJCC LN categories. PMID- 21601491 TI - Surgical site infection and analytic morphometric assessment of body composition in patients undergoing midline laparotomy. AB - BACKGROUND: Obesity is a known risk factor for surgical site infection (SSI). Our hypothesis is that morphometric measures of midline subcutaneous fat will be associated with increased risk of SSI and will predict SSI better than conventional measures of obesity. STUDY DESIGN: We identified 655 patients who underwent midline laparotomy (2006 to 2009) using the Michigan Surgical Quality Collaborative database. Using novel, semiautomated analytic morphometric techniques, the thickness of subcutaneous fat along the linea alba was measured between T12 and L4. To adjust for variations in patient size, subcutaneous fat was normalized to the distance between the vertebrae and anterior skin. Logistic regression analyses were used to identify factors independently associated with the incidence of SSI. RESULTS: Overall, SSIs were observed in 12.5% (n = 82) of the population. Logistic regression revealed that patients with increased subcutaneous fat had significantly greater odds of developing a superficial incisional SSI (odds ratio [OR] = 1.76 per 10% increase, 95% CI 1.10 to 2.83, p = 0.019). Smoking, steroid use, American Society of Anesthesiologists (ASA) classification, and incision-to-close operative time were also significant independent risk factors for superficial incisional SSI. When comparing subcutaneous fat and body mass index (BMI) as the only model variables, subcutaneous fat significantly improved model predictions of superficial incisional SSI (area under the receiver operating characteristic curve [AUC] 0.60, p = 0.023); BMI did not (AUC 0.52, p = 0.73). CONCLUSIONS: Abdominal subcutaneous fat is an independent predictor of superficial incisional SSI after midline laparotomy. Novel morphometric measures may improve risk stratification and help elucidate the pathophysiology of surgical complications. PMID- 21601494 TI - The role of sensory input of the chorda tympani nerve and the number of fungiform papillae in burning mouth syndrome. AB - OBJECTIVE: The aim of this study was to evaluate patients suffering from burning mouth syndrome (BMS) and control subjects by means of sensory testing and fungiform papillae count. STUDY DESIGN: The left and right anterior two-thirds of the tongue of of 25 BMS subjects and 20 healthy control subjects were evaluated for electric taste and electric detection threshold. The number of fungiform papillae/cm(2) was evaluated by using close-up digital photography. RESULTS: The electric taste/tingling detection threshold ratio was significantly higher in BMS compared with control subjects (P = .041). No difference was found between the number of fungiform papillae/cm(2) in the BMS compared with the control subjects (P = .277). Patients suffering from BMS for a prolonged period of time presented with a significantly elevated electric taste/tingling detection threshold ratio (P = .031). CONCLUSIONS: BMS may be a neurodegenerative process with chorda tympani nerve hypofunction potentially playing a role in the pathophysiology of this disorder. PMID- 21601492 TI - The impact of age on quality measure adherence in colon cancer. AB - BACKGROUND: Recently lymph node yield (LNY) has been endorsed as a quality measure of colon cancer resection adequacy. It is unclear whether this measure is relevant to all ages. We hypothesized that total lymph node yield (LNY) is negatively correlated with increasing age and overall survival (OS). STUDY DESIGN: The Surveillance, Epidemiology and End Results (SEER) database was queried for all nonmetastatic colon cancer patients diagnosed from 1992 to 2004 (n = 101,767), grouped by age (<40, 41 to 45, 46 to 50, and in 5-year increments until 86+ years). Proportions of patients meeting the 12 LNY minimum criterion were determined in each age group and analyzed with multivariate linear regression adjusting for demographics and American Joint Committee on Cancer (AJCC) 6(th) Edition stage. OS comparisons in each age category were based on the guideline of 12 LNY. RESULTS: Mean LNY decreased with increasing age (18.7 vs 11.4 nodes/patient, youngest vs oldest group, p < 0.001). The proportion of patients meeting the 12 LNY criterion also declined with each incremental age group (61.9% vs 35.2% compliance, youngest vs oldest, p < 0.001). Multivariate regression demonstrated a negative effect of each additional year in age and log (LNY) with coefficient of -0.003 (95% CI -0.003 to -0.002). When stratified by age and nodal yield using the 12 LNY criterion, OS was lower for all age groups in stage II colon cancer with less than 12 LNY, and each age group over 60 years with less than 12 LNY for stage III colon cancer (p < 0.05). CONCLUSIONS: Every attempt to adhere to proper oncologic principles should be made at the time of colon cancer resection regardless of age. The prognostic significance of the 12 LN minimum criterion should be applied even to elderly colon cancer patients. PMID- 21601495 TI - A screening test for capsaicin-stimulated salivary flow using filter paper: a study for diagnosis of hyposalivation with a complaint of dry mouth. AB - OBJECTIVE: The purpose of this study was to develop a simple screening technique for diagnosis of hyposalivation with dry mouth by estimation of capsaicin stimulated salivary flow using filter paper. STUDY DESIGN: An assay system comprising 5 spots containing starch and potassium iodide on filter paper incorporating or without capsaicin and a coloring reagent was designed. We investigated whether the number of colored spots using the filter paper incorporating capsaicin could distinguish between healthy subjects and subjects with hyposalivation and dry mouth. RESULTS: In the healthy group (>200 MUL/min; n = 33), the capsaicin-stimulated salivary flow significantly increased as compared with the resting salivary flow, from 1.2 +/- 1.4 to 2.9 +/- 1.3 colored spots (P < .05). In contrast, the hyposalivation group with dry mouth (<100 MUL/min; n = 32) hardly changed (4.4 +/- 1.0 vs 4.9 +/- 0.2), except for 3 subjects who had considerable elevated secretion on capsaicin stimulation. CONCLUSION: By measuring resting and stimulated salivary flows, this method should be useful for evaluating retained functional ability of salivary glands and screening of hyposalivation with dry mouth. PMID- 21601496 TI - Risk of laryngeal edema and facial swellings after tooth extraction in patients with hereditary angioedema with and without prophylaxis with C1 inhibitor concentrate: a retrospective study. AB - OBJECTIVE: Tooth extractions may trigger clinical symptoms of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH). The aim of this study was to determine how many tooth extractions were followed by symptoms of HAE-C1-INH in patients with and without preoperative short-term prophylaxis with C1 inhibitor concentrate. STUDY DESIGN: Tooth extractions and clinical symptoms of HAE-C1-INH were determined from clinical record files of 171 patients with HAE-C1 INH. RESULTS: Facial swelling or potentially life-threatening laryngeal edema, or both, occurred in 124/577 tooth extractions (21.5%) without prophylaxis. Similar symptoms occurred in a fewer proportion of patients undergoing extractions (16/128; 12.5%) after short-term prophylaxis with C1 inhibitor concentrate. The graded dose-response relationship was significant at P < .05. CONCLUSIONS: Short term prophylaxis with C1 inhibitor concentrate significantly reduces the risk of HAE-C1-INH symptoms after tooth extraction. In some patients, however, facial swellings and laryngeal edema symptoms may occur despite prophylaxis. PMID- 21601498 TI - Raymond Greene: physician, mountaineer, and raconteur. AB - C. Raymond Greene (1901-1982) was a man of many talents. After graduating from medical school in 1927, he spent a decade in general practice. He subsequently became heavily involved in the emerging specialty of endocrinology and went on to gain considerable recognition in the treatment of thyroid disorders before eventually becoming involved in the world of medical publishing. Aside from Greene's mainstream vocational and intellectual pursuits, from boyhood he nurtured a passionate interest in mountaineering--first in his native Great Britain, and then the European Alps, and ultimately in the high Himalayas. His involvement in landmark climbs, such as the successful Kamet venture in 1931 and Everest attempt in 1933, earned him a place in the pantheon of Himalayan explorers and mountaineers and stimulated Green's interest in high altitude physiology and medicine. He made notable additions to the literature on this subject in publications such as Nature and Journal of Physiology. Apart from his remarkable life achievements in the areas of medicine, mountaineering, and publishing, Greene was perhaps best remembered by those close to him (and by contemporary readers who are devotees of his writing) as a peerless storyteller with a sardonic sense of irony. PMID- 21601497 TI - Expression and significance of Cyr61 in distant metastasis cells of human primary salivary adenoid cystic carcinoma. AB - OBJECTIVE: The objective of this study was to examine the expression of cysteine rich protein 61 (Cyr61) in the distant metastatic tumor cells of human primary salivary adenoid cystic carcinoma (SACC) and its relationship with tumor angiogensis and metastasis. STUDY DESIGN: The experimental group comprised 35 paraffin-embedded tumor specimens of distant metastasis from primary SACC, with their corresponding primary tumor tissues and matched normal salivary gland tissues used as the control groups. Immunohistochemical staining was used to detect the expression of Cyr61 and vascular endothelial growth factor in the experimental and control groups. Vascular endothelial cells were highlighted by the anti-CD34 antibody, and the Weidner method was used to quantify microvessel density (MVD). RESULTS: Cyr61 was overexpressed in distant metastatic tumor cells of primary SACC. Positive expression of Cyr61 and vascular endothelial growth factor (VEGF) progressively increased in normal salivary gland tissues, primary tumor tissues, and tumor tissues of distant metastasis (P < .05). Compared with primary tumor tissues, Cyr61 expression and VEGF expression showed significant increase in tumor tissues of distant metastasis (P < .05). Cyr61 expression significantly correlated with VEGF expression and MVD (P < .05). CONCLUSIONS: Cyr61 appeared to have a significant association with tumor angiogenesis and metastasis in SACC and may be an important target in tumor antiangiogenesis therapy. PMID- 21601499 TI - Is there a link between mild sleep disordered breathing and psychiatric and psychosomatic disorders? PMID- 21601500 TI - Effects of palmitoylethanolamide on the cutaneous allergic inflammatory response in Ascaris hypersensitive Beagle dogs. AB - Palmitoylethanolamide (PEA) is an endogenous lipid mediator with anti inflammatory and anti-hyperalgesic properties. The main objective of the present study was to evaluate the effects of PEA on the cutaneous allergic inflammatory reaction induced by different immunological and non-immunological stimuli in hypersensitive dogs. Six spontaneously Ascaris hypersensitive Beagle dogs were challenged with intradermal injections of Ascaris suum extract, substance P and anti-canine IgE, before and after a single oral administration of PEA at doses of 3, 10 and 30 mg/kg. A significant reduction in wheal area induced by both antigen and anti-canine IgE challenge was observed after PEA administration. No significant differences were observed between the two higher doses studied, suggesting that the 10 mg/kg dose had exerted the maximum inhibitory effect. When blood levels of PEA were compared with the effects at different times, an evident correlation was obtained. However, the anti-inflammatory effects of PEA were more long-lasting than their plasma concentrations. The intradermal injection of substance P did not reveal any skin reaction (wheal or erythema formation) at any of the concentrations tested. In conclusion, PEA might constitute a new therapeutic strategy for the treatment of allergic inflammatory skin diseases in companion animals. PMID- 21601501 TI - ApoER2 and VLDLR in the developing human telencephalon. AB - The Reelin-Dab1 signaling pathway plays a crucial role in regulating the migration and position of cortical neurons during the development of the cerebral cortex. Mutation in Reelin may result in severe developmental disorders such as autosomal recessive lissencephaly. Apolipoprotein E receptor type-2 (ApoER2) and very low-density lipoprotein receptor (VLDLR) are canonical receptors of Reelin, through which extracellular Reelin activates the intracellular adapter, Disabled1(Dab1), and subsequently interacts with other molecules. Although it is widely accepted that ApoER2 and VLDLR are indispensable components of the Reelin signaling pathway, little is known of their expression pattern in the laminated developing human brain. Here, we collected 18 cases of human fetal brains of 6-18 gestational weeks (GW) old and examined the expression of ApoER2 and VLDLR in the their telencephalon using immunocytochemical staining. We found that both receptors were absent in the preplate (PP) and the earliest stage of the cortical plate (CP). In later stages of CP development, ApoER2 was expressed earlier than VLDLR in the migrating neurons. Thus, the Reelin-Dab1 signaling pathway may not be involved in the formation of the preplate and deep layers of the CP. Instead, the pathway may act on neurons that are destined to form the more superficial layers of the CP. In addition, the pathway required ApoER2 only rather than both ApoER2 and VLDLR at the initiation of activity. PMID- 21601502 TI - Constitutive induction of pro-inflammatory and chemotactic cytokines in cystathionine beta-synthase deficient homocystinuria. AB - Cystathionine beta-synthase (CBS) deficient homocystinuria (HCU) is an inherited metabolic defect that if untreated, typically results in cognitive impairment, connective tissue disturbances, atherosclerosis and thromboembolic disease. In recent years, chronic inappropriate expression of the inflammatory response has emerged as a major driving force of both thrombosis and atherosclerotic lesion development. We report here a characterization of the abnormalities in cytokine expression induced in both a mouse model of HCU and human subjects with the disease in the presence and absence of homocysteine lowering therapy. HCU mice exhibited highly significant induction of the pro-inflammatory cytokines Il 1alpha, Il-1beta and TNF-alpha. Similarly, in untreated/poorly compliant human subjects with HCU we observed constitutive induction of multiple pro-inflammatory cytokines (IL-1alpha, IL-6, TNF-alpha, Il-17 and IL-12(p70)) and chemotactic chemokines (fractalkine, MIP-1alpha and MIP-1beta) compared to normal controls. These HCU patients also exhibited significant induction of IL-9, TGF-alpha and G CSF. The expression levels of anti-inflammatory cytokines were unaffected in both HCU mice and human subjects with the disease. In the human subjects, homocysteine lowering therapy was associated with either normalization or significant reduction of all of the pro-inflammatory cytokines and chemokines investigated. We conclude that HCU is a disease of chronic inflammation and that aberrant cytokine expression has the potential to contribute to multiple aspects of pathogenesis. Our findings indicate that anti-inflammatory strategies could serve as a useful adjuvant therapy for this disease. PMID- 21601503 TI - Not all cystic leukoencephalopathies are "vanishing white matter". PMID- 21601504 TI - Risk factors for community-acquired pneumonia with influenza A/H1N1 in southern Israel. AB - OBJECTIVES: To determine the risk factors for community-acquired pneumonia (CAP) with influenza A/H1N1 flu in our region. METHODS: Adult patients with CAP from July 2009 to February 2010 who were screened for influenza A/H1N1 were identified retrospectively. This was a retrospective case-control study. Cases had CAP with influenza A/H1N1 and controls had CAP without influenza A/H1N1. Patient files were reviewed for demographics, clinical characteristics, treatment, and outcome. RESULTS: Three hundred and eight patients with CAP were identified: 107 cases and 201 controls. For cases vs. controls there were significant differences in the following: median age (40 (range 18-82) vs. 56 (range 18-89) years; p<0.001), female gender (63.6% vs. 44.3%; p<0.05), Bedouin Arab origin (41.1% vs. 26.4%; p<0.05), pyrexia (97.6% vs. 88.5%; p<0.01), cough (96.3% vs. 75%; p<0.05), admission to the intensive care unit (18.7% vs. 10.6%; p<0.05), and CURB-65 score >= 3 (2.8% vs. 11.4%; p<0.05). Laboratory values including white blood cell (WBC) and platelet counts were lower in cases than in controls, whereas creatine phosphokinase and lactate dehydrogenase levels were higher (p<0.01). By logistic regression models, young age, Bedouin origin, and lower WBC and platelet counts were independent risk factors for the acquisition of CAP with influenza A/H1N1. CONCLUSIONS: In our region CAP with influenza A/H1N1 occurred in younger females of Bedouin Arab origin with less co-morbidity. No difference in mortality was found. We believe that inequalities in socioeconomic conditions could explain our findings. PMID- 21601505 TI - Multi-parametric evaluation of sit-to-stand and stand-to-sit transitions in elderly people. AB - The aim of this study was to extract multi-parametric measures characterizing different features of sit-to-stand (Si-St) and stand-to-sit (St-Si) transitions in older persons, using a single inertial sensor attached to the chest. Investigated parameters were transition's duration, range of trunk tilt, smoothness of transition pattern assessed by its fractal dimension, and trunk movement's dynamic described by local wavelet energy. A measurement protocol with a Si-St followed by a St-Si postural transition was performed by two groups of participants: the first group (N=79) included Frail Elderly subjects admitted to a post-acute rehabilitation facility and the second group (N=27) were healthy community-dwelling elderly persons. Subjects were also evaluated with Tinetti's POMA scale. Compared to Healthy Elderly persons, frail group at baseline had significantly longer Si-St (3.85+/-1.04 vs. 2.60+/-0.32, p=0.001) and St-Si (4.08+/-1.21 vs. 2.81+/-0.36, p=0.001) transition's duration. Frail older persons also had significantly decreased smoothness of Si-St transition pattern (1.36+/ 0.07 vs. 1.21+/-0.05, p=0.001) and dynamic of trunk movement. Measurements after three weeks of rehabilitation in frail older persons showed that smoothness of transition pattern had the highest improvement effect size (0.4) and discriminative performance. These results demonstrate the potential interest of such parameters to distinguish older subjects with different functional and health conditions. PMID- 21601507 TI - Frontal pole function: what is specifically human? PMID- 21601506 TI - An African-American family with dystonia. AB - The genetic cause of late-onset focal and segmental dystonia remains unknown in most individuals. Recently, mutations in Thanatos-associated protein domain containing, apoptosis associated protein 1 (THAP1) have been described in DYT6 dystonia and associated with some cases of familial and sporadic late-onset dystonia in Caucasians. We are not aware of any previous descriptions of familial dystonia in African-Americans or reports of THAP1 mutations in African-Americans. Herein, we characterize an African-American (AA) kindred with late-onset primary dystonia, clinically and genetically. The clinical phenotype included cervical, laryngeal and hand-forearm dystonia. Symptoms were severe and disabling for several family members, whereas others only displayed mild signs. There were no accompanying motor or cognitive signs. In this kindred, age of onset ranged from 45 to 50 years and onset was frequently sudden, with symptoms developing within weeks or months. DYT1 was excluded as the cause of dystonia in this kindred. The entire genomic region of THAP1, including non-coding regions, was sequenced. We identified 13 sequence variants in THAP1, although none co-segregated with dystonia. A novel THAP1 variant (c.-237-3G>T/A) was found in 3/84 AA dystonia patient alleles and 3/212 AA control alleles, but not in 5870 Caucasian alleles. In summary, although previously unreported, familial primary dystonia does occur in African-Americans. Genetic analysis of the entire genomic region of THAP1 revealed a novel variant that was specific for African-Americans. Therefore, genetic testing for dystonia and future studies of candidate genes must take genetic background into consideration. PMID- 21601508 TI - Contact lens wear and the goblet cells of the human conjunctiva-A review. AB - PURPOSE: To review the reported effects of contact lens wear on the goblet cells of the human conjunctiva. METHODS: A literature search was undertaken to identify reports on the conjunctival health after contact lens wear, principally as assessed using the conjunctival impression cytology (CIC) technique in which cells are examined ex vivo, after fixation and staining. Details of technique, data on duration of contact lens wear and then CIC outcome in terms of goblet cell density (GCD) were extracted. RESULTS: Of 24 reports identified, 22 examined the bulbar conjunctiva and 2 examined the tarsal conjunctiva. A decrease in GCD was considered, directly or indirectly, to be a consequence of contact lens wear in 18 of the studies, but there was no obvious overall relationship between duration of lens wear and the GCD changes. Conversely, four reports indicated an increase in GCD or goblet cell-related mucins. Two reports concluded that there was no change in goblet cells or their mucin, a result however that is consistent with a recent conclusion that no statistically significant change in GCD was detectable in contact lens wearers assessed by in vivo imaging of the human conjunctiva by confocal microscopy. CONCLUSIONS: The majority of published studies have concluded that contact lens wear results in a decrease in goblet cells in the conjunctiva. While there are reports that draw a very different conclusion, it should be noted that there has been limited consistency in technique or the method of reporting the results across the various studies. PMID- 21601509 TI - The oncogenic PIM kinase family regulates drug resistance through multiple mechanisms. AB - Resistance to chemotherapeutic drugs is a significant clinical problem for the treatment of cancer patients and has been linked to the activation of survival pathways and expression of multidrug efflux transporters. Thus inhibition of these survival pathways or efflux transporter expression may increase the efficacy of drug treatment. Here we review the role of the oncogenic PIM kinase family in regulating important proliferation and survival pathways in cancer cells and the involvement of PIM kinases in the expression and activity of MDR-1 and BCRP, two of the most important drug efflux transporters. PIM kinases are over expressed in various types of tumors and regulate the activation of signaling pathways that are important for tumor cell proliferation, survival and expression of drug efflux proteins. This makes PIM kinases attractive targets for the development of anti-cancer chemotherapeutic drugs. Focussing mainly on solid tumors, we provide an update on the literature describing the tumorigenic functions of PIM kinases. Also we provide an overview of the development of selective small molecule PIM kinase inhibitors. Because of the intense effort by pharmaceutical companies and academia it is reasonable to expect that PIM kinase inhibitors will enter the clinic in the foreseeable future. We therefore finish this review with a discussion on the most efficient application of these PIM inhibitors. This includes a consideration of which tumor type is the most appropriate target for treatment, how to select the patient population that stands to gain the most from treatment with PIM inhibitors, which molecular markers are suitable to follow the course of treatment and whether PIM kinase inhibitors should be used as monotherapy or in combination with other cytotoxic agents. PMID- 21601510 TI - Metagenomic exploration of antibiotic resistance in soil. AB - The ongoing development of metagenomic approaches is providing the means to explore antibiotic resistance in nature and address questions that could not be answered previously with conventional culture-based strategies. The number of available environmental metagenomic sequence datasets is rapidly expanding and henceforth offer the ability to gain a more comprehensive understanding of antibiotic resistance at the global scale. Although there is now evidence that the environment constitutes a vast reservoir of antibiotic resistance gene determinants (ARGDs) and that the majority of ARGDs acquired by human pathogens may have an environmental origin, a better understanding of their diversity, prevalence and ecological significance may help predict the emergence and spreading of newly acquired resistances. Recent applications of metagenomic approaches to the study of ARGDs in natural environments such as soil should help overcome challenges concerning expanding antibiotic resistances. PMID- 21601512 TI - Raman spectroscopy of stercorite H(NH4)Na(PO4).4H2O--a cave mineral from Petrogale Cave, Madura, Eucla, Western Australia. AB - Raman spectroscopy complimented with infrared spectroscopy has been used to characterise the mineral stercorite H(NH4)Na(PO4).4H2O. The mineral stercorite originated from the Petrogale Cave, Madura, Eucla, Western Australia. This cave is one of many caves in the Nullarbor Plain in the South of Western Australia. These caves have been in existence for eons of time and have been dated at more than 550 million years old. The mineral is formed by the reaction of bat guano chemicals on calcite substrates. A single Raman band at 920 cm(-1) defines the presence of phosphate in the mineral. Antisymmetric stretching bands are observed in the infrared spectrum at 1052, 1097, 1135 and 1173 cm(-1). Raman spectroscopy shows the mineral is based upon the phosphate anion and not the hydrogen phosphate anion. Raman and infrared bands are found and assigned to PO4(3-), H2O, OH and NH stretching vibrations. The detection of stercorite by Raman spectroscopy shows that the mineral can be readily determined; as such the application of a portable Raman spectrometer in a 'cave' situation enables the detection of minerals, some of which may remain to be identified. PMID- 21601511 TI - A combined experimental and theoretical quantum chemical studies on 4 morpholinecarboxaldehyde. AB - Extensive spectroscopic investigations have been carried out by recording the Fourier transform infrared (FTIR) and FT-Raman spectra and carrying out the theoretical quantum chemical studies on 4-morpholinecarboxaldehyde (4MC). From the ab initio and DFT analysis using HF, B3LYP and B3PW91 methods with 6-31G(d,p) and 6-311G++(d,p) basis sets the energies, structural, thermodynamical and vibrational characteristics of the compound were determined. The energy difference between the chair equatorial and chair axial conformers of 4MC have been calculated by density functional theory (DFT) method. The optimised geometrical parameters, theoretical wavenumbers and thermodynamic properties of the molecule were compared with the experimental values. The effect of carbonyl group on the characteristic frequencies of the morpholine ring has been analysed. The mixing of the fundamental modes with the help of potential energy distribution (PED) through normal co-ordinate analysis has been discussed. PMID- 21601513 TI - Effect of pain and pain expectation on primary motor cortex excitability. AB - OBJECTIVE: The study aimed to test whether pain and pain expectation affect corticospinal excitability. METHODS: Transcranial magnetic stimulation was used to measure corticospinal excitability among 15 subjects in five experimental conditions in which thermic stimulations were applied to the hand: (1) neutral stimulus; (2) actual heat; (3) actual pain; (4) expected heat; and (5) expected pain. Motor-evoked potentials were recorded in two intrinsic hand muscles. RESULTS: A significant difference was found between experimental conditions for both muscles (p<0.005). Contrast analysis showed that actual pain led to a significant corticospinal inhibition compared with both neutral and actual heat conditions, whereas no effect was observed during pain expectation. CONCLUSIONS: Our results suggest that acute pain (low-to-moderate intensity (~3/10)) does elicit motor inhibition but that its expectation does not. SIGNIFICANCE: The fact that low and short-lasting pain can induce motor inhibition suggests that even moderate pain might interfere with optimal motor function in patients with both pain and motor deficits. PMID- 21601514 TI - Evidence of different spinal pathways for the warmth evoked potentials. AB - OBJECTIVE: To investigate the presence of multiple spinothalamic pathways for warmth in the human spinal cord. METHODS: Laser evoked potentials to C-fiber stimulation (C-LEPs) were recorded in 15 healthy subjects after warmth stimulation of the dorsal midline at C5, T2, T6, and T10 vertebral levels. This method allowed us to calculate the spinal conduction velocity (CV) in two different ways: (1) the reciprocal of the slope of the regression line was obtained from the latencies of the different C-LEP components, and (2) the distance between C5 and T10 was divided by the latency difference of the responses at the two sites. In particular, we considered the C-N1 potential, generated in the second somatosensory (SII) area, and the late C-P2 response, generated in the anterior cingulate cortex (ACC). RESULTS: The calculated CV of the spinal fibers generating the C-N1 potential (around 2.5m/s) was significantly different (p<0.01) from the one of the pathway producing the P2 response (around 1.4m/s). CONCLUSIONS: Our results suggest that the C-N1 and the C-P2 components are generated by two parallel spinal pathways. SIGNIFICANCE: Warmth sensation is subserved by parallel spinothalamic pathways, one probably reaching the SII area, the other the ACC. PMID- 21601515 TI - Magnetic separation of cells from developing embryoid bodies using magnetite cationic liposomes. AB - Embryoid bodies resemble post-implantation egg-cylinder stage embryos and are used to differentiate embryonic stem cells in vitro. In this study, we enriched mouse vasa homolog-positive germ cells from embryoid bodies after 8d of differentiation using a magnetic separation method with magnetite cationic liposomes. PMID- 21601516 TI - Identification and characterization of genes involved in glutathione production in yeast. AB - Glutathione is a major peptide protecting cells against oxidative stress. To study the cellular processes affecting intracellular glutathione production, we screened Saccharomyces cerevisiae mutant collections and identified new eight yeast deletion mutants that produced more than 1.2-fold higher levels of intracellular glutathione: chc1, cst6, ddc1, def1, pep12, rts1, ubp6, and yih1. Furthermore, overexpression of the DEF1 and CYS4 genes led to a higher production of glutathione, similar to overexpression of GSH1. A multiplier effect on activation of glutathione synthesis was observed by a combination of overexpression of GSH1 and deletion of one of the eight genes. Metabolome analysis of the def1, pep12, and ubp6 deletion mutant, and DEF1-overexpressing strains showed that levels of intracellular methionine and oxidized glutathione were higher than in the control strains, suggesting that methionine biosynthesis was activated and the oxidative stress response was increased in these glutathione-overproductive strains. Moreover, overexpression of GSH1, CYS4, and DEF1 also increased glutathione production in Candida utilis. Taken together, these results will significantly contribute to more effective industrial production of glutathione using yeasts. PMID- 21601517 TI - Firm wheat-germ cell-free system with extended vector usage for high-throughput protein screening. AB - The wheat germ cell-free system is composed out of five basic steps, growth of Escherichia coli harboring plasmid, first colony-PCR, second PCR, transcription, and translation. Improvements of culture medium, colony based PCR, and modifications within the split primer set of the second PCR amplify both DNA and RNA levels. This yields more than 5 times increase in protein amount for pEU originated templates. Especially, for the low PCR-amplifiable vectors with pET origin, it leads to 30 fold higher product amount in translation. This broadens the range of usable vectors, overcoming the existing cell-free system limitations for high-throughput protein screening. Noteworthily, the system successfully maintains translation by S-30 cell-free extract below 30 OD. In conclusion, this improved firm cell-free system reduces cost and enables robotic automation and high-throughput thermodynamic analysis, especially for proteins that are difficult to be expressed. PMID- 21601518 TI - Effects of cultural medium and conditions on the proliferation and hypoglycemic activity of Saccharomyces pastorianus no. 54. AB - A yeast strain of Saccharomyces pastorianus no. 54 with hypoglycemic activity was isolated from soils of a winery. The aims of this study were first to investigate the effects of the cultivation conditions on proliferation and hypoglycemic activity of this yeast using the assay model of the differentiated 3T3-L1 adipocytes, and then, to confirm in vivo the hypoglycemic activity of cultured yeast by oral administration in streptozotocin (STZ)-induced diabetic mice. Among 7 diluted fruit juice samples the diluted strawberry juice (1.74 g/L reducing sugar content) was chosen as the basal medium. After investigation of the effects of addition of various substances, including 1% of 5 different sugars and glycerol, 0.1% of 6 nitrogen-containing substances, and 1 ppm of 7 growth factors, the diluted strawberry juice added with 1% glucose, 0.1% yeast extract and 1 ppm aspartic acid was optimized at 20 degrees C with initial pH value of 6.0 for cultivating S. pastorianus no. 54 in flask. The scale-up system of a 5-L fermentor was further established by using the same medium with initial pH 6.0 and being incubated at 20 degrees C with an aeration rate of 1.2 vvm for 96 h. The hypoglycemic activity of yeast cells cultivated in fermentor was 3.11 times of that in flask. Oral administration of the cultured yeast at a dosage of 130 mg/kg body weight/day for 6 days could significantly reduce the plasma glucose content in STZ-induced diabetic mice and keep their body weights in the normal range. PMID- 21601519 TI - Dissection of the factors driving the placebo effect in hypnotic treatment of depressed insomniacs. AB - OBJECTIVES: Our prior work has shown that there is improvement in self-reported sleep in persons receiving placebo in hypnotic clinical trials. We examined the components of the "placebo response" in a hypnotic clinical trial. METHODS: This was an exploratory analysis of a randomized, double-blind clinical trial of eszopiclone versus placebo in the treatment of persons with depression and insomnia who were also receiving fluoxetine at a clinic of a teaching hospital. Sixty adults with both depression and insomnia symptoms, who were free of significant primary sleep disorders, received open-label fluoxetine for 9weeks. Patients were further randomized 1:1 to receive either masked eszopiclone 3mg or placebo at bedtime after the first week of fluoxetine. We examined the respective contributions of three factors associated with the "placebo effect": (1) regression to the mean, (2) expectancy, and (3) social desirability. RESULTS: There was evidence for regression to the mean for the continuous measurement of the Insomnia Severity Index (ISI) and the Hamilton Depression Rating Scale. There was evidence for expectancy in self-reported Wake After Sleep Onset, continuous measurement of ISI, and dichotomous remission/non-remitter measurement of ISI. There was evidence of social desirability affecting self-reported Total Sleep Time. CONCLUSIONS: Factors that have been associated with the "placebo effect" are operating in hypnotic clinical trials. However, the role of each factor differs depending upon which self-reported variable is being considered. The findings have implications for clinical trial design in insomnia. PMID- 21601520 TI - Normative values of polysomnographic parameters in childhood and adolescence: quantitative sleep parameters. AB - OBJECTIVE: To provide normative values for sleep macroarchitecture of healthy children aged 1-18 years using the AASM sleep scoring criteria, assessing the effects of gender, age, and Tanner pubertal stage. METHODS: One-night polysomnography was performed at subjects' habitual bedtimes in 16 laboratories on 209 healthy German children. RESULTS: Normal values of sleep macrostructure show significant age dependencies (p<0.05). Increasing with age: awakening index, R latency (RL), sleep efficiency (SE) (total sleep time (TST)/sleep period time (SPT)) and SE (TST/time in bed), stage N2, mean sleep cycle duration, number of stage shifts. Decreasing with age: TST, SPT, wake after sleep onset, stage N3, stage R, movement time (MT), number of sleep cycles. The following sleep parameters show a dependency on Tanner stages as well as corresponding age (p<0.05):TST, SPT, awakening index, R latency, stage N2, stage N3, MT, number of sleep cycles, mean sleep cycle duration. No gender dependencies were found. CONCLUSION: The given study, considering AASM rules, shows the development of sleep in normal children ages 1-18. Subject selection criteria and other factors influencing sleep as well AASM guideline modifications including scoring arousals in N2 and scoring MT as a measure of sleep fragmentation are discussed. PMID- 21601521 TI - Inactivation of a macronuclear intra-S-phase checkpoint in Tetrahymena thermophila with caffeine affects the integrity of the micronuclear genome. AB - Aphidicolin (APH), an inhibitor of DNA polymerase alpha, arrested cell divisions in Tetrahymena thermophila. Surprisingly, low concentrations of APH induced an increase of macronuclear DNA content and cell size in non-dividing cells. In spite of the cell size increase, most proliferation of basal bodies, ciliogenesis and development of new oral primordia were prevented by the APH treatment. The division arrest induced by APH was partly overridden by caffeine (CAF) treatment, which caused the fragmentation ("pulverization") of the chromosomes in G2 micronuclei. Somatic progeny of dividers with pulverized micronuclei (APH+CAF strains) contained aneuploid and amicronucleate cells. The amicronucleate cells, after losing their oral structures and most of their cilia, and undergoing progressive disorganization of cortical structures, assumed an irregular shape ("crinkled") and were nonviable. "Crinkled" cells were not formed after APH + CAF treatment of the amicronuclear BI3840 strain, which contains some mic-specific sequences in its macronucleus. Most of the APH +CAF strains had a typical "*"- like conjugation phenotype: they did not produce pronuclei, but received them unilaterally from their mates and retained old macronuclei. However, 4 among 100 APH+CAF clones induced arrest at meiotic metaphase I in their wt mates. It is likely that the origin of such clones was enhanced by chromosome pulverization. PMID- 21601523 TI - Do nurses risk underestimating the problems of patients with frontal lobe neoplasms? AB - PURPOSE: Although the profile of the problems and risks associated with cancer patients has expanded over the past few years, and so has our available knowledge on the concordance between patients and nurses, there is a lack of evidence concerning neurosurgical patients. In comparison with patients who have neoplasm located in other lobes, those with frontal lobe cancer can suffer from personality changes, disinhibition, apathy, and higher-order attentional difficulties. Such behavior may give rise to a stigma, and consequently, pose a risk to have their problems misunderstood by caregivers, and be at greater risk than they are perceived to be. OBJECTIVE: To explore the risk of nurses underestimating the problems of patients who were operated on for frontal neoplasm, compared to patients suffering from neoplasms located in other cerebral lobes. METHODS: A prospective study was undertaken in 2008 in Italy. Patients admitted to the hospital with brain neoplasm were eligible for the study. For each patient with a frontal lobe neoplasm, a corresponding patient with a cerebral neoplasm located in either the temporal, parietal or occipital lobes was also included. Nurses working in the units involved and providing care to these patients were also included. On the afternoon of the 2nd postoperative day, the researcher interviewed both the patients, and the registered nurses (RNs) responsible for the patients' care, in regards to pain intensity, dependence in activities of daily living, anxiety and depression, and fear of falling, as each was perceived by patients and nurses. The level of concordance between the patients' and nurses' responses was calculated. RESULTS: Forty-six patients were considered (mean age 53.5 years); 23 had surgery for a frontal brain neoplasm and 23 for brain neoplasms located in either the temporal, parietal, or occipital areas. Overall, patients operated on for frontal lobe neoplasms had much of the same risks of underestimation of their problems, as patients with other cerebral neoplasms. CONCLUSIONS: Patients with frontal lobe neoplasms seemed, overall, to run the same risk of their problems being underestimated as patients with cerebral neoplasms located at other sites. Neurosurgical nurses tended to overestimate patients' problems, particularly in cases with neoplasms not located in the frontal lobe. This unexpected finding needs to be addressed with further research, and might warrant a different approach to caring for patients with frontal lobe neoplasms, whose problems are overestimated less, so that they might receive less supportive care. PMID- 21601522 TI - Studies on galactofuranose-containing glycostructures of the pathogenic mold Aspergillus fumigatus. AB - Galactofuranose is a hexose that is exclusively found in microbes and in particular in certain pathogenic species. In the mold Aspergillus fumigatus, it is the characteristic constituent of the cell wall component galactomannan. Detection of this carbohydrate is currently a widespread method used for diagnosis of systemic A. fumigatus infections. In this study, we raised and characterized 2 monoclonal antibodies that specifically react with galactofuranose-containing glycostructures. We investigated the distribution of surface-accessible galactomannan on different A. fumigatus morphotypes. We provide evidence that the antibodies recognize distinct antigens and are suitable to detect A. fumigatus hyphae in immunohistology. A mutant that is impaired in synthesis of galactofuranose stimulated a normal cytokine response in murine macrophages, which argues against galactomannan being a relevant PAMP, at least in mice. Purified galactomannan-specific monoclonal IgM L10-1 failed to inhibit the hyphal growth under in vitro conditions, but L10-1 binding to hyphae led to an enhanced deposition of the complement protein C1q. However, administration of purified L10-1 antibodies prior to infection was not able to protect mice. In conclusion, we have found no evidence for galactomannan being a relevant A. fumigatus PAMP and describe 2 novel galactomannan antibodies that might be valuable tools for the diagnosis of A. fumigatus infections and further analysis of the biological significance of galactomannan. PMID- 21601524 TI - Art, archetypes and alchemy: images of self following treatment for breast cancer. AB - PURPOSE: The loss or alteration of a breast poses a threat to a woman's selfhood, particularly those aspects that embrace feminine identity such as sexuality and caring. The use of art as a vehicle for recreating a sense of self after breast cancer surgery framed the study that generated the stories reported here. A team of nurse-researchers and professional artists entered into a collaborative partnership aimed at creating life-like prototypes of the torsos of two breast cancer survivors. METHOD: The authors sought to understand participants' experiences of healing through the narratives of their breast cancer journeys and their experiences of creating art through the use of their bodies. The participants consented to having interviews and casting sessions audio-taped. The authors used thematic analysis to explore the narratives. RESULTS: The authors present excerpts of stories and comment on how participants articulated the feminine archetype in the form of the Greek goddesses Hestia, Artemis, and Aphrodite. The authors explore the transformative nature of participants' experiences. CONCLUSION: The emergence of the goddess archetypes in participants' narratives was an unanticipated result of the study. The authors invite readers to contemplate these anecdotes and embark on their own quest for deeper knowledge of breast cancer experiences. PMID- 21601525 TI - Exploration of the family's role and strengths after a young woman is diagnosed with breast cancer: views of women and their families. AB - PURPOSE: This exploratory descriptive study examined the role and strengths of the family when supporting the younger woman (<50 years) after a diagnosis of breast cancer. The perspectives of women and family members were sought. METHOD: Participants were recruited from oncology outpatient units in Australia. Semi structured interviews guided by the Family Resiliency Framework were undertaken with 14 young women with breast cancer and 11 family members who reflected on the roles of family. Transcripts were analysed individually and in family groupings. RESULTS: Women with breast cancer and their family members experienced a range of emotions during the treatment period. Roles within the family changed as members responded to their circumstances. Analysis of interview transcripts identified the following primary themes; 'just being there', 'paradox of help' and 'buffer from society'. A secondary theme related to support, specifically 'the changing role of support for family members', highlighting the strengths and experiences of family. CONCLUSION: Recognition needs to be given to the complexity of changing roles experienced by young women with breast cancer and their families. Young women with breast cancer require unique forms of support because of the nature of their experience. Family roles were shaped through a shared sense of commitment and open communication amongst members. Families may demonstrate a range of strengths but are also vulnerable during this stressful period. Health professionals need to be aware of the possible needs of families, assess their adaptation to changing circumstances, and intervene through the provision of information, and counselling to enhance coping. PMID- 21601526 TI - Biochemical and imaging surveillance in germline TP53 mutation carriers with Li Fraumeni syndrome: a prospective observational study. AB - BACKGROUND: Individuals with Li-Fraumeni syndrome have a high lifetime risk of developing cancer. We assessed the feasibility and potential clinical effect of a comprehensive surveillance protocol in asymptomatic TP53 mutation carriers in families with this syndrome. METHODS: We implemented a clinical surveillance protocol, using frequent biochemical and imaging studies, for asymptomatic TP53 mutation carriers on Jan 1, 2004, and did a prospective observational study of members of eight families with Li-Fraumeni syndrome who either chose to undergo surveillance or chose not to undergo surveillance. The primary outcome measure was detection of new cancers. The secondary outcome measure was overall survival. FINDINGS: As of Nov 1, 2010, 33 TP53 mutation carriers were identified, 18 of whom underwent surveillance. The surveillance protocol detected ten asymptomatic tumours in seven patients, including small, high-grade tumours and low-grade or premalignant tumours. All seven mutation carriers were alive after a median follow-up of 24 months (IQR 22-65 months). 12 high-grade, high-stage tumours developed in 10 individuals in the non-surveillance group, two of whom (20%) were alive at the end of follow-up (p=0.0417 for comparison with survival in the surveillance group). 3-year overall survival was 100% in the surveillance group and 21% (95% CI 4-48%) in the non-surveillance group (p=0.0155). INTERPRETATION: Our findings show the feasibility of a clinical surveillance protocol for the detection of asymptomatic neoplasms in individuals with germline TP53 mutations. This strategy offers a management option for affected individuals, and its benefits lend support to the use of early genetic testing of at-risk individuals and families. FUNDING: Canadian Cancer Society Research Institute, Canadian Institutes of Health Research, SickKids Foundation, and Soccer for Hope. PMID- 21601528 TI - Role-playing in the problem-based learning class. AB - Learning and teaching have been conceptualized and executed in many styles, such as self-learning, peer learning, and interaction between the learner and mentor. Today, openness to alternative ideas and embracing innovative approaches in nursing education are encouraged in order to meet students' learning interests and needs, and to address ever-changing healthcare requests. Problem-based learning has been widely adopted in nursing education, with various positive effects on students' learning, such as motivated learning, team work, problem solving skills and critical thinking. Role-plays have been demonstrated as an effective learning strategy that includes an active and experiential feature that facilitates students' autonomy in their health-related learning. However, there is a lack of discussion of whether and how role-play can be used in problem-based learning (PBL). This paper shows the development of a classroom-based innovation using role-play in the PBL class for higher diploma year-one nurse students (a total of 20 students, five per group). This paper consists of five sections: a) the literature on PBL and nurse education, and role-plays as the innovation; b) the PBL case scenario with the illustration of the two role-play scripts, c) student evaluation on role-play in the PBL class; d) discussions on both achievements and limitations of this innovation, and e) the conclusion. It is hoped that this paper will be an example to other nurse educators who are keen on exploring interactive and student-driven learning and teaching strategies in the PBL class. PMID- 21601527 TI - Student attitudes and educational support in caring for older people--a review of literature. AB - The ageing population is currently one of the main issues facing UK healthcare systems. Nurses of the future will be faced with the task of caring for this elderly population. Meanwhile, care standards and government policies have emphasized the need for preparing students to care for the older people. Preparing nursing students to meet the care needs of an expanding ageing population is a challenge for nursing education. Moreover, caring for older people are often not seen by students as an attractive option, a perception that exerts a considerable influence on the values that inform their future professional practice. This paper examines the literature related to the students' perceptions of caring for older people and suggests the need for specific curricular content, teaching and a structured approach to the educational preparation and support of students for their practice experience. If students are provided with the relevant preparation and support, they can engage in enriched learning experiences, deliver quality care and develop positive attitudes in caring for older people in their professional practice. PMID- 21601530 TI - In-vitro assessment of platelet function. AB - Platelets (PLTs), play a key role in hemostasis, clot stability and retraction as well as in vascular repair and anti-microbial host defense. Upon vessel wall damage, PLTs undergo a highly regulated set including adhesion, spreading, aggregation, release reactions as well as exposure of procoagulant surfaces to rapidly form a hemostatic plug that occludes the site of damage. When PLT function is impaired, the bleeding risk increases, but (hyperreactive) PLTs are also involved in many pathophysiological events like thrombosis, vessel constriction, atherogenesis, tumor growth and metastasis, inflammation including atherosclerosis and the subsequent formation of arterial thrombi resulting in stroke and myocardial infarction. While hereditary PLT function disorders are very rare, acquired PLT function abnormalities occur in the course of many diseases and can be associated with many drugs, i.e., non-steroidal anti inflammatorics, antibiotics or heparin. Therefore, apart from disease diagnosis, severity, and prognosis, assessment of PLT function also serves for identifying the efficacy of anti-PLT therapy and PLT hyperfunction as a possible predictor for thromboembolic events. Since PLTs undergo a lot of measurable changes during storage ex-vivo, one effort of transfusion medicine is the quality monitoring of PLT concentrates (PCs), but also the detection of donors with PLT dysfunction and the determination of patients in which PLT transfusions are effective. The majority of PLT tests focus only on PLT functions involved directly in hemostasis including adhesion/aggregation, coagulation, and clot retraction. Traditional tests, almost complex, time-consuming, and poorly specified, are meanwhile enriched by more user friendly and easy-to-use point-of-care tests on fully automated instruments within whole blood without the requirement of sample processing. These tests help identifying surgical patients at increased risk of post-operative bleeding or with resistance to anti-PLT therapy, therefore at increased risk of thromboembolism. However, up to now, no study shows real outcome benefits by including these tests into the disease management. To date, no function test is suitable to address all distinct steps of PLT activation or reliably predict PLT behavior in vivo following transfusion. PMID- 21601529 TI - Fatty acyl-AMP ligases and polyketide synthases are unique enzymes of lipid biosynthetic machinery in Mycobacterium tuberculosis. AB - The cell envelope of Mycobacterium tuberculosis (Mtb) possesses a repertoire of unusual lipids that are believed to play an important role in pathogenesis. In this review, we specifically focus on computational, biochemical and structural studies in lipid biosynthesis that have established functional role of polyketide synthases (PKSs) and fatty acyl-AMP ligases (FAALs). Mechanistic and structural studies with FAALs suggest that this group of proteins may have evolved from omnipresent fatty acyl-CoA ligases (FACLs). FAALs activate fatty acids as acyl adenylates and transfer them on to the PKSs which then produce unusual acyl chains that are the components of mycobacterial lipids. FAALs are a newly discovered family of enzymes; whereas involvement of PKSs in lipid metabolism was not known prior to their discovery in Mtb. Since Mtb genome contains multiple homologs of FAALs and PKSs and owing to the conserved reaction mechanism and overlapping substrate specificity; there is tempting opportunity to develop 'systemic drugs' against these enzymes as anti-tuberculosis agents. PMID- 21601531 TI - The impact of type D personality and high-sensitivity C-reactive protein on health-related quality of life in patients with atrial fibrillation. AB - BACKGROUND: Anxiety or depressive symptoms are known to be predictors of impaired health-related quality of life (HRQoL). However, little research has focused on the impact of type D personality as chronic psychological distress on HRQoL in atrial fibrillation (AF) patients. Increased high-sensitivity C-reactive protein (hsCRP) is likely to be associated with anxiety or depressive symptoms, whereas the relation of hsCRP to Type D personality was unexplored, and the impact of hsCRP on HRQoL was undetermined in AF patients. AIM: To determine whether type D personality and hsCRP are independently associated with impaired HRQoL. METHODS: A cross-sectional study design was used among a total of 114 patients with chronic AF. Patients underwent measurements of serum levels of hsCRP. Type D personality, anxiety and depressive symptoms, and HRQoL were assessed by the type D scale, the hospital anxiety and depression scale, and the short-form medical outcomes survey, respectively. Hierarchical linear regression was used to determine the impact of Type D personality and hsCRP on HRQoL. RESULTS: Thirty two percent of patients had Type D personality. Patients with type D personality had higher hsCRP than those with non-type D personality (1.4 +/- 1.9 vs. 0.6 +/- 2.2, p = 0.046). In hierarchical linear regression, type D personality (beta = - 0.28; p = 0.005) and hsCRP (beta = -0.21; p = 0.034) were independently associated with HRQoL controlling for clinical risk factors, anxiety, and depression symptoms. CONCLUSIONS: Type D personality and hsCRP are independent predictors of impaired HRQoL. Clinicians need to pay attention to patients with Type D personality and monitor serum levels of hsCRP to prevent impaired HRQoL in AF patient. PMID- 21601532 TI - Development and preliminary testing of a scale to assess pain-related fear in children and adolescents. AB - It is assumed that pain-related fear, a present response to an immediate danger or threat such as pain, plays a significant role in the experience of pediatric pain. However, there are no measures to adequately measure this construct in children and adolescents. The purpose of this study was to develop and test the psychometric properties of a scale to assess pain-related fear to be used with Catalan-speaking children and adolescents between 7- and 16-years-old. We initially developed a list of items that reflected the physiological, cognitive, and behavioral components of pain-related fear components. We also queried an international group of experts, and interviewed children and adolescents. After pilot testing the initial version with a sample of 10 children, we administered the questionnaire to a sample of schoolchildren (n = 273) and children from medical clinics (n = 164) through individual interviews. Additional information was also collected during the interview to study the psychometric properties of the scale. Ten days after the initial interview, participating schoolchildren were requested to answer the questionnaire again. Item analysis and exploratory factor analysis with data from the school sample produced 2 meaningful factors (namely, Fearful thoughts and Fearful physical feelings and behaviors). Findings also showed that the Pediatric Pain Fear Scale (total scale and the 2 subscales) was both reliable and valid. This scale could help researchers to gain a better understanding about the role of pain-related fear in children and adolescents and support clinical decision-making. PERSPECTIVE: This article presents a new measure of fear associated with pain in children and adolescents. This measure could potentially help researchers to gain a better understanding about the role of pain-related fear in children and adolescents and support clinical decision making. PMID- 21601533 TI - Real-world practice patterns, health-care utilization, and costs in patients with low back pain: the long road to guideline-concordant care. AB - BACKGROUND CONTEXT: Treatment guidelines suggest that most acute low back pain (LBP) episodes substantially improve within a few weeks and that immediate use of imaging and aggressive therapies should be avoided. PURPOSE: Assess the actual practice patterns of imaging, noninvasive therapy, medication use, and surgery in patients with LBP, and compare their costs to those of matched controls without LBP. STUDY DESIGN: A retrospective analysis of claims data from 40 self-insured employers in the United States. PATIENT SAMPLE: The study sample included 211,551 patients, aged 18 to 64 years, with one LBP diagnosis or more (per Healthcare Effectiveness Data and Information Set specification) during 2004 to 2006, identified from a claims database. Patients had continuous eligibility for 12 months or more after their index LBP diagnosis (study period), for 6 months or more before their index diagnosis (baseline period), and no other LBP diagnosis during the baseline period. Patients with LBP were matched to a random cohort of patients without LBP by age, gender, employment status, and index year. OUTCOMES MEASURES: Physiological measures (eg, imaging and diagnostic tests), functional measures (eg, pharmacologic and nonpharmacologic treatment for LBP, health-care resource use), and direct (medical and prescription drug) and indirect (disability and medically related absenteeism) costs were assessed within the year after the LBP diagnosis. METHODS: Univariate analyses described treatment patterns and compared baseline characteristics and study period costs. RESULTS: Patients with LBP had significantly higher rates of baseline comorbidities and resource use compared with controls. Of patients with LBP, 41.6% had imaging mean (median) [standard deviation] 34.3 (0) [78.6] days after the LBP diagnosis. Most patients with LBP (69.4%) used medications starting 51.9 (8) [86.2] days after the diagnosis. Opioids were commonly prescribed early (41.6% of patients; after 82.8 (25) [105.9] days). Of patients with LBP, 2.05% had surgery during the study period. Patients with LBP were likely to have chiropractic treatment first, followed by pharmacotherapy with muscle relaxants and nonsteroidal anti inflammatory drugs. Except for less surgery, these findings also held for patients with only nonspecific LBP. Patients with LBP had higher mean direct costs compared with controls ($7,211 vs. $2,382, respectively; p<.0001), with surgery patients having mean direct costs of $33,931. CONCLUSIONS: Contrary to clinical guidelines, many patients with LBP start incurring significant resource use and associated expenses soon after the index diagnosis. Achieving guideline concordant care will require substantial changes in LBP practice patterns. PMID- 21601534 TI - Quality control of endometriosis data starts with careful reading of the full paper. Reply. PMID- 21601535 TI - Ddc1 checkpoint protein and DNA polymerase E interact with nick-containing DNA repair intermediate in cell free extracts of Saccharomyces cerevisiae. AB - To characterize proteins that interact with base excision/single-strand interruption repair DNA intermediates in cell free extracts of Saccharomyces cerevisiae, we used a combination of photoaffinity labeling with the protein identification by MALDI-TOF-MS peptide mapping. Photoreactive analogue of dCTP, namely exo-N-[4-(4-azido-2,3,5,6,-tetrafluorobenzylidenehydrazinocarbonyl) butylcarbamoyl]-2'-deoxycytidine-5'-triphosphate, and [(32)P]-labeled DNA duplex containing one nucleotide gap were used to generate nick-containing DNA with a photoreactive dCMP residue at the 3'-margin of the nick. This photoreactive DNA derivative was incubated with the yeast cell extract and after UV irradiation a number of proteins were labeled. Two of the crosslinked proteins were identified as the catalytic subunit of DNA polymerase E and Ddc1 checkpoint protein. Labeling of DNA polymerase E catalytic subunit with the nick-containing DNA repair intermediate indicates that the DNA polymerase is involved in the DNA repair synthesis in yeast, at least at DNA single-strand interruptions. Crosslinking of Ddc1 to DNA nicks took place independently of the other components of checkpoint clamp, Mec3 and Rad17, suggesting that the protein alone is able to recognize DNA single-strand breaks. Indeed, purified GST-tagged Ddc1 protein was efficiently crosslinked to nick-containing DNA. The interaction of Ddc1 with DNA nicks may provide a link between the DNA damage checkpoint and DNA base excision/single-strand breaks repair pathways in yeast. In addition, we found that absence of Ddc1 protein greatly influences the overall pattern of other proteins crosslinked to DNA nick. We suggested that this last effect of Ddc1 is at least partially due to its capacity to prevent proteolytic degradation of the DNA-protein adducts. PMID- 21601536 TI - DNA polymerases and repair synthesis in NER in human cells. AB - The late steps of nucleotide excision repair, following incisions to remove the damaged section of DNA, comprise repair synthesis and ligation. In vitro and in vivo studies have shown the size of the repaired patch to be about 30 nucleotides. In vitro studies implicated the replicative polymerases in repair synthesis, but recent in vivo data have shown that several DNA polymerases and ligases are involved in these steps in human cells. PMID- 21601537 TI - Identification of novel mammalian phospholipids containing threonine, aspartate, and glutamate as the base moiety. AB - In this study, we showed the occurrence of phosphatidyl-L-threonine (PThr), phosphatidyl-L-aspartate (PAsp), and phosphatidyl-L-glutamate (PGlu) in rat brain. Analyses using an HPLC-ESI-MS and an amino acid analyzer showed the presence of L-threonine, L-aspartate, and L-glutamate in the acid-hydrolysates of phospholipids from porcine cerebrum, rat cerebrum, and rat liver. Results of ESI MS/MS analyses with neutral loss scanning and product ion scanning suggest the presence of PThr-(18:0, 18:1), PThr-(18:0, 22:6), PAsp-(18:0, 18:1), PAsp-(18:0, 22:6), PGlu-(18:0, 18:1), and PGlu-(18:0, 22:6) in rat brain. This is the first study to identify 2 novel phospholipids, PAsp and PGlu, with a carboxylate phosphate anhydride bond, in living organisms. PMID- 21601538 TI - Determination of nifedipine in human plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study. AB - A fast, sensitive and selective ultra performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method was developed for the determination of nifedipine in human plasma. Nitrendipine was used as the internal standard. The sample preparation employed liquid-liquid extraction with a mixture of n-hexane diethyl ether (1:3, v/v). Chromatographic separation was performed on an ACQUITY UPLCTM BEH C(18) column. The mobile phase was composed of acetonitrile-10 mmol/L ammonium acetate (75:25, v/v) with a flow rate of 0.20 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source. A high throughput was achieved with a run time of 1.4 min per sample. The linear calibration curves were obtained in the concentration range of 0.104-52.0 ng/mL (r(2)>= 0.99) with a lower limit of quantification (LLOQ) of 0.104 ng/mL. The intra- and inter-day precision (relative standard deviation, RSD) values were below 15% and the accuracy (relative error, RE) was -4.0% to 6.2% at three quality control levels. The method was fully validated and successfully applied to a clinical pharmacokinetic study of nifedipine sustained-release tablet in healthy male volunteers. PMID- 21601539 TI - Altered glycosylation and expression of plasma alpha-1-acid glycoprotein and haptoglobin in rheumatoid arthritis. AB - Altered glycosylation patterns in plasma proteins are found to be associated with the pathogenesis of various malignancies and autoimmune disorders. Our previous studies demonstrated the occurrence of some differentially glycosylated plasma proteins in rheumatoid arthritis (RA) patients. The current study was conducted to evaluate the alterations in expression and glycosylation of major acute phase proteins from wheat germ agglutinin enriched RA patients' plasma. Immunoblotting studies revealed a significant enhancement in the plasma levels of alpha-1 acid glycoprotein (AGP) and haptoglobin (Hp) in RA patients with respect to healthy controls. Monosaccharide analysis by high performance anion exchange chromatography with pulse amperometric detection showed significant variations in the relative percentage of galactose, glucosamine and mannose in AGP and of mannose in Hp in RA patients. Altered patterns of mannosylation in AGP and Hp were also established by enzyme linked immunosorbent assay and Western blotting using Concanavalin-A lectin. These results could give information for understanding the disease pathogenesis and may provide an insight into the development and progression of the disease. PMID- 21601540 TI - Reaction pathway of tryptophanase-catalyzed L-tryptophan synthesis from D-serine. AB - Tryptophanase, L-tryptophan indole-lyase with extremely absolute stereospecificity, can change the stereospecificity in concentrated diammonium hydrogenphosphate solution. While tryptophanase is not inert to D-serine in the absence of diammonium hydrogenphosphate, it can undergo L-tryptophan synthesis from D-serine along with indole in the presence of it. It has been well known that tryptophanase synthesizes L-tryptophan from L-serine through a beta substitution mechanism of the ping-pong type. However, a metabolic pathway of L tryptophan synthesis from D-serine has remained unclear. The present study aims to elucidate it. Diammonium hydrogenphosphate plays a role in the emergence of catalytic activity on D-serine. The salt gives tryptophanase a small conformational change, which makes it possible to catalyze D-serine. Tryptophanase-bound D-serine produces L-tryptophan synthesis by beta-replacement reaction via the enzyme-bound aminoacrylate intermediate. Our result will be valuable in studying the origin of homochirality. PMID- 21601541 TI - Towards a neural basis of processing musical semantics. AB - Processing of meaning is critical for language perception, and therefore the majority of research on meaning processing has focused on the semantic, lexical, conceptual, and propositional processing of language. However, music is another a means of communication, and meaning also emerges from the interpretation of musical information. This article provides a framework for the investigation of the processing of musical meaning, and reviews neuroscience studies investigating this issue. These studies reveal two neural correlates of meaning processing, the N400 and the N5 (which are both components of the event-related electric brain potential). Here I argue that the N400 can be elicited by musical stimuli due to the processing of extra-musical meaning, whereas the N5 can be elicited due to the processing of intra-musical meaning. Notably, whereas the N400 can be elicited by both linguistic and musical stimuli, the N5 has so far only been observed for the processing of meaning in music. Thus, knowledge about both the N400 and the N5 can advance our understanding of how the human brain processes meaning information. PMID- 21601542 TI - Liver transplantation for the treatment of nodular regenerative hyperplasia. AB - BACKGROUND: Nodular regenerative hyperplasia (NRH) is the leading cause of non cirrhotic portal hypertension in Western countries. Although some patients are successfully managed medically or with shunting procedures, others require liver transplantation. The aim of this review was to assess the overall results obtained with liver transplantation and to better define its role in this setting. METHODS: Systematic review of all published studies on liver transplantation for NRH without language restrictions, in Medline, Embase and Cochrane Library databases through March 2010. RESULTS: 17 studies including a total of 73 patients were identified; 47 (64.3%) were excluded due to lacking inclusion criteria or clinical data and 26 (35.7%) were analysed. Before liver transplantation, the most frequent clinical presentation was gastroesophageal bleeding (65.3%) followed by ascites (61.5%), hepatic encephalopathy (30.7%) and liver failure (11.5%). The mean follow-up reported after liver transplantation was 30.6+/-27.6 months and patient and graft survival rate was 78.3%. Only one case reported a NRH recurrence 7 years after liver transplantation (LT). CONCLUSIONS: Although there are no hard data supporting the role of liver transplantation in symptomatic NRH, onset of severe portal hypertension in this setting may represent a valid indication. PMID- 21601543 TI - Emergence of uncommon emm types of Streptococcus pyogenes among adult patients in southern Taiwan. AB - BACKGROUND: Streptococcus pyogenes isolated from adult patients during a 12-year period in southern Taiwan were analyzed to estimate the distribution of emm types and their correlation with disease manifestations and patient age. METHODS: Three hundred thirty-four invasive and noninvasive isolates collected from patients older than 20 years between 1997 and 2008 at National Cheng Kung University Hospital were included for emm typing. A correlation between emm type, disease manifestations, and patient ages was analyzed. RESULTS: The nine most prevalent types were emm11, emm12, emm4, emm1, Sp9458/VT8, emm81, emm106, emm13, and emm75. Formerly rare emm types, including emm11, emm81, and emm102, emerged dramatically after 2004 in southern Taiwan. Type emm11 was significantly associated with both superficial infections and cellulitis. In addition, types emm13, emm81, and emm106 were more prevalent in patients older than 50 years and significantly associated with specific invasive disease manifestation. CONCLUSION: These results suggest new emm types (emm11, emm81, and emm102) of S pyogenes were introduced into the adult population in southern Taiwan after 2004. The rarely reported emm types, including emm13, emm81, and emm106, caused invasive diseases more often in adult patients. PMID- 21601545 TI - [Facial paralysis associated with herpes simplex-induced erythema multiform]. PMID- 21601544 TI - Caffeic acid phenethyl ester suppresses eotaxin secretion and nuclear p-STAT6 in human lung fibroblast cells. AB - BACKGROUND: Caffeic acid phenethyl ester (CAPE), an active component of propolis, has been proven to have anti-inflammatory and antiallergic properties. We have investigated the activity of CAPE in regulating cytokine-induced eotaxin production and its related signal protein, signal transducer and activator of transcription 6 (STAT6), in human lung fibroblast. METHODS: The CCD-11Lu human lung fibroblast cell line was used as an in vitro model. Cells were pretreated with CAPE followed by stimulation with interleukin-4 and tumor necrosis factor alpha. The levels of eotaxin in cultured supernatants were measured by enzyme linked immunosorbent assay. The amounts of STAT6 and phosphorylated STAT6 in cellular nuclear protein extracts were determined by Western blot analysis. STAT6 DNA binding activities were detected by electrophoretic mobility shift assay. RESULTS: Pretreated CCD-11Lu cells with noncytotoxic doses (0.1-10 MUM) of CAPE inhibited the production of eotaxin under stimulation of interleukin-4 (10 ng/mL) and tumor necrosis factor alpha (10 ng/mL). CAPE pretreatment also decreased the amount of phosphorylated STAT6 and the STAT6 DNA binding complexes in nuclear extracts. CONCLUSION: CAPE inhibited the production of eotaxin protein in stimulated human lung fibroblast cells in a dose-dependent manner. This activity is, at least, through STAT6 inhibition. We suggest that CAPE is a promising agent in controlling eotaxin secretion and subsequent eosinophils influx and may therefore have a potential role to play in treating allergic airway disease. PMID- 21601546 TI - [Urine infection as a sign of a pelvic abscess]. PMID- 21601547 TI - Emotion regulation moderates relationships between body image concerns and psychological symptomatology. AB - The study investigated the moderating role of emotion regulation (ER) in relationships between body image concerns and psychological symptomatology. A community sample of 533 boys and girls (11-20 years) completed measures assessing body image thoughts and feelings, domain-specific and general ER strategies, drive for thinness, and bulimic, depressive and anxiety symptoms. Results indicated that ER moderated relationships between body image concerns and both bulimic and depressive symptoms, but not relationships between body image concerns and drive for thinness or anxiety symptoms. Adolescents who reported frequent body image concerns were more likely to have higher levels of bulimic symptoms if they tended to use avoidance and internal dysfunctional ER strategies. Furthermore, adolescents who reported frequent body image concerns were more likely to have higher levels of depressive symptoms if they used positive rational acceptance and internal functional strategies infrequently. Implications of the findings for prevention and intervention are discussed. PMID- 21601548 TI - Clinical profile of diabetes in the young seen between 1992 and 2009 at a specialist diabetes centre in south India. AB - AIM: To describe the trends and clinical profile of young diabetic patients (YD) attending a tertiary diabetes centre in south India. METHODS: We reviewed medical records of 2630 YD patients (age at onset <=25 years) registered between 1992 and 2009. Patients were classified as type 1 diabetes (T1DM), type 2 diabetes (T2DM) gestational diabetes mellitus (GDM) and other types. Retinopathy was assessed initially by direct and indirect ophthalmoscopy and later by retinal photography, nephropathy if urine protein excretion was >500 mg/day, neuropathy if vibration perception threshold on biothesiometry was >=20 V. RESULTS: The percentage of YD patients rose from 0.55% in 1992 to 2.5% in 2009 (trend chi square, 15.1, p<0.001). Of the 2630 YD subjects registered, 1135 (43.2%) had T1DM, 1262 (48.0%) had T2DM, 118 (4.5%) had GDM and 115 (4.4%) other types. T1DM patients were younger, had lower body mass index, waist circumference, systolic and diastolic blood pressures, and less family history of diabetes compared to T2DM (p<0.001 for each). Retinopathy was seen in 71.9% and 77.3% nephropathy in 22.1% and 12.1% and neuropathy in 34.5% and 21.4% of T2DM and T1DM respectively in those with >=15 years duration of diabetes. CONCLUSIONS: The percentage of YD in south India is increasing, predominantly due to early onset T2DM. PMID- 21601549 TI - [Tunnelled internal jugular vein catheters with taurolidine lock: an acceptable challenge to arterio-venous fistula in 70 years old haemodialyzed patients: a prospective pilot study]. AB - Arteriovenous fistula (AVF) is still in 2010 the gold standard of vascular(2) access in haemodialysis (HD) patients. Nevertheless it may be difficult to obtain and/or to use AVF in elderly. With this prospective randomised pilot study, we compare two strategies of vascular access in 70 years old or more new HD patients. AVF were compared to tunnelled jugular vein catheters (TIJC) with taurolidine as bacterial lock solution. Results were as follow: [table: see text] The responses with the visual analogic scale of comfort was 8/10 for TIJC and 5/10 with AVF * P<0.05. In five TIJC patients, heparin was added with success to taurolidine because of partial clotting of catheters. Albuminemia was significantly lower in AVF failure patients compared to AVF success patients (24.8g/L vs 31.1g/L). This pilot study allows to conclude that TIJC is an acceptable challenge to AVF in haemodialysed patients of 70 years or more in a two years long use. PMID- 21601551 TI - Patient satisfaction and functional results with the bone-anchored hearing aid (BAHA). AB - OBJECTIVES: To assess patient satisfaction with bone-anchored hearing aids (BAHA) and the role of preoperative audiometric testing. PATIENTS AND METHODS: A telephone satisfaction survey was conducted on all patients implanted between June 1, 2005 and February 1, 2008. Patients with unilateral total deafness underwent preoperative audiometric tests in quiet and in noise and stereoaudiometry with and without BAHA. Patients with a conductive hearing loss underwent preoperative audiometric tests in quiet and in noise and real-life testing at home using a headband. A standardized satisfaction questionnaire derived from the Entific BAHA questionnaire was used. RESULTS: Twenty-two out of 26 patients responded to the questionnaire. Ten patients were implanted for conductive hearing loss (CHL) and 12 for unilateral total deafness (UTD). Mean follow-up was 19 months in the UTD group and 21 months in the CHL group. Sixty seven percent of UTD and 80% of CHL patients reported improved quality of life. The BAHA was worn for more than 4hours per day by 83% of UTD and 100% of CHL patients, and at least 5 days per week by 67% of UTD and 80% of CHL patients. CONCLUSION: BAHAs provided real benefit in all situations for CHL patients. In UTD, its benefit basically related to noisy environments. In UTD, satisfaction on preoperative stereoaudiometric testing in noise with and without BAHA was predictive of postimplantation satisfaction. In response to the question "Would you do it again?", 81% of patients answered "Yes". PMID- 21601552 TI - What is inverse-geometry CT? AB - Inverse-geometry computed tomography (IGCT) systems are being developed to provide improved volumetric imaging. In conventional multislice CT systems, x rays are emitted from a small area and irradiate a large-area detector. In an IGCT system, x-ray sources are distributed over a large area, with each beam irradiating a small-area detector. Therefore, in the inverse geometry, a series of narrow x-ray beams are switched on and off while the gantry rotates. In conventional CT geometry, cone-beam and scatter artifacts increase with the imaged volume thickness. An inverse geometry may be less susceptible to scatter effects, because only a fraction of the field of view is irradiated at one time. The distributed source in the inverse geometry potentially improves sampling, leading to reduced cone-beam artifacts. In the inverse geometry, the tube current may be adjusted separately for each source location, which potentially reduces dose. Multiple IGCT prototypes have been constructed and tested on phantoms. A gantry-based IGCT system with one-second gantry rotation was developed, and images of phantoms and small animals were successfully acquired. Clinical feasibility with acceptable noise levels and scan times has not yet been shown. Overall, results from prototype systems suggest that the inverse geometry will enable imaging of a thick volume (~16 cm) while potentially reducing cone-beam artifacts, scatter effects, and radiation dose. The magnitude of these benefits will depend on the specific IGCT implementation and need to be quantified relative to comparable multislice scanners. PMID- 21601553 TI - Interventions for alcohol-related offending by women: a systematic review. AB - Treatment programmes specifically for women offenders are under-developed. A systematic review of studies that could inform interventions for alcohol-related offending by women is reported. Three questions were addressed: 1) What is the most up to date knowledge of 'what works' with females who commit alcohol-related offences? 2) What are the identifiable risk-needs factors for non-alcohol dependent women who commit offences involving alcohol misuse? 3) Are there differences between male and female alcohol-related offending? Four studies addressed the effectiveness of psychosocial interventions; three addressed identifiable risk-needs; and 19 addressed differences between male and female offenders' alcohol-related offending. Heterogeneity of these studies precluded meta-analyses, and so a narrative synthesis method was used. There is insufficient evidence to answer the question of what treatment works with women who commit alcohol-related offences. Drunk-driving is most widely studied, and women offenders appear to have more psychosocial problems than men. Alcohol increases the likelihood of violence for both men and women, and, while the mechanisms whereby alcohol increases the likelihood of violence are likely the same in men and women, the effect may be moderated by gender-associated issues. Again, women offenders appear to have more psychosocial problems than men. Implications for developing interventions are discussed. PMID- 21601555 TI - Optimization of pyrosequencing reads by superior successive incorporation efficiency of improved 2'-deoxyadenosine-5'-triphosphate analogs. AB - Conventional pyrosequencing using 2'-deoxyadenosine-5'-O-(1-thiotriphosphate) (dATPalphaS) is problematic due to the high cost of the substrate (dATPalphaS) and deterioration in the accuracy of incorporation to read through poly(T) regions. One reason for these problems is that dATPalphaS has a sulfur on the alpha-phosphate and also has isomers (Sp and Rp). To solve these problems, 11 nucleotide substrates, which could replace dATPalphaS in pyrosequencing, were newly synthesized. All substrates were modified on the seventh or eighth position of the adenine base from normal dATP. We found that the substrate that had an ethenyl-linked modified group on the seventh position of the adenine base had low activity in the luciferase reaction and high incorporation efficiency with the thymine base. One substrate in particular had 10-fold better incorporation efficiency than dATPalphaS. The new nucleotide substrate satisfied all conditions as a replacement of dATPalphaS. PMID- 21601554 TI - The pharmacological inhibition of sterol biosynthesis in Leishmania is counteracted by enhancement of LDL endocytosis. AB - Leishmania parasites, despite being able to synthesize their own sterols, acquire and accumulate significant amounts of cholesterol through low density lipoprotein (LDL) particle endocytosis. The role of this system in Leishmania amazonensis promastigotes under pharmacological pressure by sterol biosynthesis inhibitors (SBIs) was investigated. First, thin layer chromatography demonstrated that L. amazonensis promastigotes, in response to ergosterol biosynthesis inhibition by treatment with 4.0 and 6.0 MUM ketoconazole or miconazole, accumulate up to two times more cholesterol than controls. The treatment of promastigotes with ketoconazole and simvastatin, two SBIs with non-related mechanisms of action, showed that both drugs induce increases in (125)I-LDL endocytosis in a dose dependent manner, indicating that the accumulation of exogenous cholesterol is due to the enhancement of LDL uptake. Finally, it was demonstrated that L. amazonensis promastigotes were rendered more susceptible to treatment with SBIs (ketoconazole, miconazole, simvastatin and terbinafine) in the absence of exogenous cholesterol sources, with a reduction of the IC50s of about 50% in three of the four tested drugs. These results show that the exogenous cholesterol uptake system in L. amazonensis plays a role as a compensatory mechanism in response to the presence of SBIs, suggesting that it may be a potential pharmacological target. PMID- 21601556 TI - Stabilization of hypoxia-inducible factor-1alpha in buffer containing cobalt chloride for Western blot analysis. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) is a widely studied protein with significant biomedical impact. Care is needed to stabilize HIF-1alpha protein during sample preparation for Western blot analysis due to its rapid degradation in the presence of oxygen. Enzyme inhibitor cocktails can be complex and expensive. We present a protease inhibitor-free buffer, containing cobalt chloride, which is effective at stabilizing HIF-1alpha, while being inexpensive, straightforward, and convenient, and has potential for widespread application. PMID- 21601557 TI - Electroporation for three commonly used yeast strains for two-hybrid screening experiments. AB - The efficiency of transformation by electroporation has been known to be compromised by strain dependency. A high efficiency protocol is still lacking for distinct two-hybrid yeast strains of diverse genetic features. Here, we used 0.5 M lithium acetate (LiAc) and 50 mM Tris-HCl with 5 mM EDTA (pH 7.5), i.e., fivefold the standard concentrations, and voltage at 1.0 to develop a protocol which, for the first time, is able to effect an average efficiency of 1.84*10(6)transformants/MUg DNA for three commonly used yeast strains committed to two-hybrid screening experiments. PMID- 21601558 TI - Simple cloning strategy using GFPuv gene as positive/negative indicator. AB - Because construction of expression vectors is the first requisite in the functional analysis of genes, development of simple cloning systems is a major requirement during the postgenomic era. In the current study, we developed cloning vectors for gain- or loss-of-function studies by using the GFPuv gene as a positive/negative indicator of cloning. These vectors allow us to easily detect correct clones and obtain expression vectors from a simple procedure by means of the combined use of the GFPuv gene and a type IIS restriction enzyme. PMID- 21601559 TI - Detection of protease activities by flash chronopotentiometry using a reversible polycation-sensitive polymeric membrane electrode. AB - A novel electrochemical method, termed flash chronopotentiometry (FCP), is used to develop a rapid and sensitive method for detecting protease activities. In this method, an appropriate current pulse is applied across a polycation selective polymer membrane to induce a strong flux of the polycationic peptides from the sample phase into the organic membrane of the electrode. During this current pulse, the cell potential (EMF) is monitored continuously, and is a function of the polypeptide concentration. The imposed current causes a local depletion of the polypeptide at the sample/membrane interface, which yields a drastic potential change in the observed chronopotentiogram at a characteristic time, called the transition time (tau). For a given magnitude of current, the square root of tau is directly proportional to the concentration of the polypeptide. Proteases cleave polypeptides into smaller fragments that are not favorably extracted into the membrane of the sensor. Therefore, a decrease in the transition time is observed during the proteolysis process. The degree of change in the transition time can be correlated to protease activity. To demonstrate this approach, the activities of trypsin and alpha-chymotrypsin are detected using protamine and synthetic polycationic oligopeptides that possess specific cleavage sites that are recognized by these proteases. PMID- 21601560 TI - Evidence for an inhibitory LIM domain in a rat brain agmatinase-like protein. AB - We recently cloned a rat brain agmatinase-like protein (ALP) whose amino acid sequence greatly differs from other agmatinases and exhibits a LIM-like domain close to its carboxyl terminus. The protein was immunohistochemically detected in the hypothalamic region and hippocampal astrocytes and neurons. We now show that truncated species, lacking the LIM-type domain, retains the dimeric structure of the wild-type protein but exhibits a 10-fold increased k(cat), a 3-fold decreased K(m) value for agmatine and altered intrinsic tryptophan fluorescent properties. As expected for a LIM protein, zinc was detected only in the wild-type ALP (~2 Zn(2+)/monomer). Our proposal is that the LIM domain functions as an autoinhibitory entity and that inhibition is reversed by interaction of the domain with some yet undefined brain protein. PMID- 21601561 TI - Sorafenib induces apoptotic cell death in human non-small cell lung cancer cells by down-regulating mammalian target of rapamycin (mTOR)-dependent survivin expression. AB - Sorafenib, a multikinase inhibitor, is emerging as a promising targeted agent that may possess antitumor activity against a broad range of cancers. The mechanism by which sorafenib induces lung cancer cell death and apoptosis, however, is not understood. In the present study, we provide evidence that sorafenib acts through inhibition of mammalian target of rapamycin (mTOR) to down regulate survivin and promote apoptotic cell death in human non-small cell lung cancer (NSCLC) cells. Sorafenib induced ATF4-mediated Redd1 expression, leading to mTOR inhibition-the upstream signal for down-regulation of survivin. Overexpression of survivin reduced sorafenib-induced apoptosis, whereas silencing survivin using small interfering RNA (siRNA) enhanced it, supporting the interpretation that down-regulation of survivin is involved in sorafenib-induced cell death in human NSCLC cells. Furthermore, sorafenib abolished the induction of survivin that normally accompanies IGF-1-stimulated mTOR activation. We further found that Redd1-induced mTOR down-regulation and ATF4/CHOP-induced expression of the TRAIL receptor DR5 associated with sorafenib treatment helped sensitize cells to TRAIL-induced apoptosis. Our study suggests that sorafenib mediates apoptotic cell death in human NSCLC cells through Redd1-induced inhibition of mTOR and subsequent down-regulation of survivin, events that are associated with sensitization to TRAIL-induced apoptotic cell death. PMID- 21601562 TI - Endocannabinoids inhibit release of nerve growth factor by inflammation-activated mast cells. AB - Nerve growth factor (NGF) is a pleiotropic member of the neurotrophin family. Beside its neuronal effects, NGF plays a role in various processes, including angiogenesis. Mast cells release NGF and are among elements contributing to angiogenesis, a process regulated by arrays of factors, including the inhibitory cannabinoids. The possible inhibitory role of cannabinoids on mast cell-related NGF mitogenic effect on endothelial cells was then investigated. Human mastocytic cells HMC-1, challenged with PMA to yield release of NGF, were preincubated with the endocannabinoid PEA. Then, conditioned media were added to HUVEC cultures. PMA-activated HMC-1 cells released substantial amounts of NGF, whereas PEA inhibited PMA-induced NGF release. HUVEC proliferation increased after treatment with media from activated HMC-1 cells, while was reduced with media from HMC-1 cells treated with PEA. To characterize receptors mediating such effects of PEA, RT-PCR and western blot analysis were performed on HMC-1 cells. None of the two cannabinoid CB1 and CB2 receptors was expressed by HMC-1 cells, which on the other hand expressed the orphan receptor GPR55. PEA was ineffective in inhibiting NGF release from HMC-1 cells treated with PMA and transfected with positive GPR55 RNAi, whereas it induced significant reduction of NGF in cells transfected with the corresponding negative control RNAi. Results indicate that NGF released from inflammatory mast cells induces angiogenesis. Cannabinoids attenuate such pro angiogenic effects of NGF. Finally, cannabinoids could be considered for antiangiogenic treatment in disorders characterized by prominent inflammation. PMID- 21601563 TI - Isotope dilution ultra performance liquid chromatography-tandem mass spectrometry method for simultaneous measurement of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3 and 3-epi-25-hydroxyvitamin D3 in human serum. AB - BACKGROUND: An ultra performance liquid chromatography-tandem mass spectrometry method with calibration traceable to NIST SRM was developed and validated to measure concentrations of 25-hydroxyvitamin D(2) (25OHD(2)), 25-hydroxyvitamin D(3) (25OHD(3)) and the C-3 epimer of 25OHD(3) (epi-25OHD(3)) in human serum. METHODS: Tri- and hexa-deuterated internal standards were added to serum (100 MUl) to monitor recovery. Liquid-liquid extraction was used to extract the hexane soluble materials. Calibration solutions [8-100 nmol/L 25OHD(2,) 12-150 nmol/L 25OHD(3), and 4-50 nmol/L epi-25OHD(3)] prepared in phosphate-buffered saline containing 4% albumin were similarly processed. Using a pentafluorophenyl column (2.1*100 mm) and isocratic methanol/water (72/28, v/v) flowing at 0.4 ml/min, run time was 14 min per sample; 25OHD(3) and epi-25OHD(3) were baseline separated. Atmospheric pressure chemical ionization in the positive ion mode with selected reaction monitoring captured the following transitions: 25OHD(2), m/z 395.3>377.3 (209.1 qualifier); (epi-)25OHD(3), m/z 383.3>365.3 (105.1 qualifier); d(3) 25OHD(2), m/z 398.3>380.3; and d(6)-25OHD(3), m/z 389.3>371.3. RESULTS: Recovery averaged >=98%. Total imprecision was <=10% when concentrations were >=20 nmol/l. Bias averaged <5%. Detection limits were <5 nmol/l. Median (nmol/l) 25OHD(2), 25OHD(3) and epi-25OHD(3) were quantitated in 98 blood donors (=20 years assessed in the Third Korea National Health and Nutrition Examination Survey (2005). Dyslipidemia was defined according to the National Cholesterol Education Program Adult Treatment Panel III. RESULTS: The prevalence of dyslipidemia was higher in men than in women. The odds ratios (95% confidence interval) of dyslipidemia associated with current smoking were 1.35 (0.98-1.85) in men and 1.92 (1.19-3.10) in women (p for interaction with gender <0.001). After stratification by components of dyslipidemia, women smokers showed higher odds ratios of having high triglyceride and low high-density lipoprotein cholesterol than men smokers. The association between current heavy-smoking (>=20 pack-years) and dyslipidemia was stronger in women than in men. CONCLUSIONS: The association between smoking and dyslipidemia was significantly different between men and women. Women smokers might be more susceptible to develop dyslipidemia than men smokers. PMID- 21601565 TI - Quantitative analysis of glycation patterns in human serum albumin using 16O/18O labeling and MALDI-TOF MS. AB - BACKGROUND: The glycation of human serum albumin (HSA) during diabetes can affect the ability of this protein to bind drugs and small solutes in blood. This study describes the use of (16)O/(18)O-labeling and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to compare the levels of modification that occur throughout HSA under various glycation conditions in vitro. These quantitative studies build on a recent report that has identified the early and advanced glycation products that are formed on such samples of HSA. METHODS: Glycated HSA samples were prepared by incubating 42 g/l HSA with 0 to 15 mmol/l glucose at pH 7.4 and 37 degrees C for up to 5 weeks. A control HSA sample was digested in (16)O-enriched water and glycated HSA samples were digested in the presence of (18)O-enriched water. These 2 types of samples were then mixed and the amounts of (16)O- vs. (18)O-labeled peptides were measured to determine the levels of modification that were occurring throughout HSA. RESULTS: The largest levels of modification occurred in residues 101-119, 1-10 or 42-51, 87 100, 360-372, 521-531, and 275-286 of HSA after 2 weeks of glycation, and in residues 21-41, 1-10 or 42-51, 521-531, 82-93, and 146-160 after 5 weeks of glycation. Some of these regions contained the N-terminus, K199, K439, and K525, which have been previously identified as major glycation sites on HSA. The glycation pattern of HSA was dominated by early glycation products (e.g., fructosyl-lysine) after a reaction period of 2 weeks for mildly glycated HSA, while advanced glycation end products became more prominent at longer reaction times. CONCLUSIONS: The time course of the observed modifications indicated that the pattern of glycation products changed as HSA was incubated over longer periods of time with glucose. Several regions found to have significant levels of modification were at or near the major drug binding regions on HSA. These results explain why the interaction of some drugs with HSA has been observed to vary with the level of glycation for this protein. PMID- 21601566 TI - Evaluation of salivary melatonin measurements for Dim Light Melatonin Onset calculations in patients with possible sleep-wake rhythm disorders. AB - BACKGROUND: Dim Light Melatonin Onset (DLMO) can be calculated within a 5-point partial melatonin curve in saliva collected at home. We retrospectively analyzed the patient melatonin measurements sample size of the year 2008 to evaluate these DLMO calculations and studied the correlation between diary or polysomnography (PSG) sleep onset and DLMO. METHODS: Patients completed an online questionnaire. If this questionnaire pointed to a possible Delayed Sleep Phase Disorder (DSPD), saliva collection devices were sent to the patient. Collection occurred at 5 consecutive hours. Melatonin concentration was measured with a radioimmunoassay and DLMO was defined as the time at which the melatonin concentration in saliva reaches 4 pg/mL. Sleep onset time was retrieved from an online one-week sleep diary and/or one-night PSG. RESULTS: A total of 1848 diagnostic 5-point curves were obtained. DLMO could be determined in 76.2% (n=1408). DLMO significantly differed between different age groups and increased with age. Pearson correlations (r) between DLMO and sleep onset measured with PSG or with a diary were 0.514 (p=<0.001, n=54) and 0.653 (p=0.002, n=20) respectively. CONCLUSION: DLMO can be reliably measured in saliva that is conveniently collected at home. DLMO correlates moderately with sleep onset. PMID- 21601567 TI - A study of pre-analytical variables in clinical biochemistry laboratory. AB - OBJECTIVES: Pre-analytical error decisively influences the total error and consequently the diagnostic accuracy. The following were the objectives for the study: 1. To detect the percent of pre-analytical errors in clinical biochemistry laboratory. 2. To categorize these pre-analytical errors. 3. To formulate corrective measures to be taken to avoid such errors. DESIGN AND METHODS: Study period was for 3 months with documenting the frequency and type of pre-analytical errors occurring in the venous samples. RESULT: Average pre-analytical errors were 44.7% per day. Improper request, incorrect timing of sample, wrong tube collection and in-vitro hemolysis of samples amounted to the major proportion of errors. CONCLUSION: Pre-analytical errors occurring in each laboratory have to be checked. Such errors are not inevitable and can be avoided with a diligent application of quality control, continuing education and effective collection systems to ensure total quality patient care. PMID- 21601568 TI - Reference ranges for serum S100B protein during the first three years of life. AB - OBJECTIVE: Clinical and diagnostic management of traumatic brain injuries is problematic in young children. To facilitate this management, we describe blood reference ranges for the well established biomarker S100B in children younger than 3 years. DESIGN AND METHODS: Serum S100B concentrations were determined by electro-chemiluminescence immunoassay in a population of 186 healthy children aged 0-3 years. RESULTS: Four age groups emerged, i.e. 0-3, 4-9, 10-24 and 25-36 months. We also found an interesting inverse correlation with head circumference. CONCLUSION: This study provides useful serum S100B values from the largest cohort of healthy children aged 0-3 years old. PMID- 21601569 TI - Oxidative DNA damage in early pregnancy and risk of gestational diabetes mellitus: A pilot study. AB - OBJECTIVES: To examine the association of maternal early pregnancy oxidative stress with risk of gestational diabetes mellitus (GDM). DESIGN AND METHODS: A pilot prospective, nested case-control study was conducted. Study participants were recruited before 20weeks gestation. Maternal urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of systemic oxidative DNA damage and repair, was measured using competitive immunoassays. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (95%CI). RESULTS: Elevations in early pregnancy urinary 8-OHdG concentrations were associated with increased GDM risk. After adjusting for confounders, the OR for extreme quartiles (>=8.01 vs. <4.23ng/mg creatinine) of 8-OHdG was 3.79 (95%CI 1.03-14.00). The risk for GDM was highest for overweight women with urine 8-OHdG concentrations >=8.01ng/mg creatinine (OR=5.36, 95%CI 1.33-21.55) when compared with lean women who had 8 OHdG concentrations <8.01ng/mg creatinine. CONCLUSIONS: Elevated urine 8-OHdG concentrations in early pregnancy appear to be associated with increased GDM risk. PMID- 21601570 TI - Nav1.7 accumulates and co-localizes with phosphorylated ERK1/2 within transected axons in early experimental neuromas. AB - Peripheral nerve injury can result in formation of a neuroma, which is often associated with heightened sensitivity to normally innocuous stimuli as well as spontaneous dysesthesia and pain. The onset and persistence of neuropathic pain have been linked to spontaneous ectopic electrogenesis in axons within neuromas, suggesting an involvement of voltage-gated sodium channels. Sodium channel isoforms Na(V)1.3, Na(V)1.7 and Na(V)1.8 have been shown to accumulate in chronic painful human neuromas, while, to date, only Na(V)1.3 has been reported to accumulate within experimental neuromas. Although recent evidence strongly support a major contribution for Na(V)1.7 in nociception, the expression of Na(V)1.7 in injured axons within acute neuromas has not been studied. The current study examined whether Na(V)1.7 accumulates in experimental rat neuromas. We further investigated whether activated (phosphorylated) mitogen-activated protein (MAP) kinase ERK1/2, which is known to modulate Na(V)1.7 properties, is co localized with Na(V)1.7 within axons in neuromas. We demonstrate increased levels of Na(V)1.7 in experimental rat sciatic nerve neuromas, 2weeks after nerve ligation and transaction. We further show elevated levels of phosphorylated ERK1/2 within individual neuroma axons that exhibit Na(V)1.7 accumulation. These results extend previous descriptions of sodium channel and MAP kinase accumulation within experimental and human neuromas, and suggest that targeted blockade of Na(V)1.7 or ERK1/2 may provide a strategy for amelioration of chronic pain that often follows nerve injury and formation of neuromas. PMID- 21601571 TI - Valine 1532 of human BRC repeat 4 plays an important role in the interaction between BRCA2 and RAD51. AB - The breast cancer susceptibility protein BRCA2 is essential for recombinational DNA repair. BRCA2 specifically binds to RAD51 via eight BRC repeat motifs and delivers RAD51 to double-stranded DNA breaks. In this study, a mammalian two hybrid assay and competitive ELISA showed that the interaction between BRC repeat 4 (BRC4) and RAD51 was strengthened by the substitution of a single BRC4 amino acid from valine to isoleucine (V1532I). However, the cancer-associated V1532F mutant exhibited very weak interaction with RAD51. This study used a comparative analysis of BRC4 between animal species to identify V1532 as an important residue that interacts with RAD51. PMID- 21601572 TI - Tyrphostin analogs are GPR35 agonists. AB - GPR35 is an orphan G protein-coupled receptor that is not well-characterized. Here we employ dynamic mass redistribution (DMR) assays to discover new GPR35 agonists. DMR assays identified tyrphostin analogs as GPR35 agonists, which were confirmed with receptor internalization, Tango beta-arrestin translocation, and extracellular-signal-regulated kinase phosphorylation assays. These agonists provide pharmacological tools to study the biology and function of GPR35. PMID- 21601573 TI - The selection and characterization of antibodies to minichromosome maintenance proteins that highlight cervical dysplasia. AB - BACKGROUND: Screening efforts using the Papanicolaou test have significantly reduced the incidence of cervical cancer in countries with an active screening program. However, this test does not accurately identify all abnormal cases. Significant effort has been expended investigating molecular markers that could improve the sensitivity and specificity of detection of high-grade disease. In this study, we describe the selection and characterization of a set of antibodies to the minichromosome maintenance proteins MCM6 and MCM7 that highlight cervical disease in an immunoassay. METHODS: Antibodies to MCM6 or MCM7 proteins were identified from hybridoma clones screened against tissue microarrays containing different grades of diseased cervical tissue along with normal controls. We determined epitopes by western blotting against nested truncations of either the MCM6 or MCM7 proteins fused to GFP protein. We also determined specificity by western blotting against a panel of major MCM proteins (MCM2-MCM8). Affinity to recombinant antigen and epitope-only peptides was determined using solution-phase binding and determination of free antibody concentration by ELISA. Optimization studies resulted in the selection of antibodies specific to MCM6 and MCM7 for use in immunocytochemistry (ICC) with cervical cytology samples. RESULTS: Four antibodies were identified that demonstrated strong nuclear staining of abnormal cervical epithelial cells in immunohistochemistry (IHC) of cervical biopsies with minimal background staining of normal cervical tissues. Of these four antibody clones, 2E6.7 (MCM7) and 9D4.3 (MCM6) were chosen for further study. Linear epitopes of at most 12 amino acids were identified and verified by binding to epitope-only peptides. Affinities of at least 4*10(-9) M were determined for these two antibodies and both were found to be specific for their respective antigens by western blotting. Clones 9D4.3 and 2E6.7 were also determined to stain abnormal cells in high-grade squamous intraepithelial lesion cytology samples, with minimal background staining of normal cells. CONCLUSION: In this study, we present a method for selecting antibodies that perform well in IHC and ICC applications and characterize two antibodies generated by this method that effectively stain abnormal cells in cervical cancer tissue and cervical cytology samples. PMID- 21601574 TI - Mitochondrial aminoacyl-tRNA synthetase single-nucleotide polymorphisms that lead to defects in refolding but not aminoacylation. AB - Defects in organellar translation are the underlying cause of a number of mitochondrial diseases, including diabetes, deafness, encephalopathy, and other mitochondrial myopathies. The most common causes of these diseases are mutations in mitochondria-encoded tRNAs. It has recently become apparent that mutations in nuclear-encoded components of the mitochondrial translation machinery, such as aminoacyl-tRNA synthetases (aaRSs), can also lead to disease. In some cases, mutations can be directly linked to losses in enzymatic activity; however, for many, their effect is unknown. To investigate how aaRS mutations impact function without changing enzymatic activity, we chose nonsynonymous single-nucleotide polymorphisms (nsSNPs) that encode residues distal from the active site of human mitochondrial phenylalanyl-tRNA synthetase. The phenylalanyl-tRNA synthetase variants S57C and N280S both displayed wild-type aminoacylation activity and stability with respect to their free energies of unfolding, but were less stable at low pH. Mitochondrial proteins undergo partial unfolding/refolding during import, and both S57C and N280S variants retained less activity than wild type after refolding, consistent with their reduced stability at low pH. To examine possible defects in protein folding in other aaRS nsSNPs, we compared the refolding of the human mitochondrial leucyl-tRNA synthetase variant H324Q to that of wild type. The H324Q variant had normal activity prior to unfolding, but displayed a refolding defect resulting in reduced aminoacylation compared to wild type after renaturation. These data show that nsSNPs can impact mitochondrial translation by changing a biophysical property of a protein (in this case refolding) without affecting the corresponding enzymatic activity. PMID- 21601575 TI - Electron microscopy and 3D reconstruction of F-actin decorated with cardiac myosin-binding protein C (cMyBP-C). AB - Myosin-binding protein C (MyBP-C) is an ~130-kDa rod-shaped protein of the thick (myosin containing) filaments of vertebrate striated muscle. It is composed of 10 or 11 globular 10-kDa domains from the immunoglobulin and fibronectin type III families and an additional MyBP-C-specific motif. The cardiac isoform cMyBP-C plays a key role in the phosphorylation-dependent enhancement of cardiac function that occurs upon beta-adrenergic stimulation, and mutations in MyBP-C cause skeletal muscle and heart diseases. In addition to binding to myosin, MyBP-C can also bind to actin via its N-terminal end, potentially modulating contraction in a novel way via this thick-thin filament bridge. To understand the structural basis of actin binding, we have used negative stain electron microscopy and three dimensional reconstruction to study the structure of F-actin decorated with bacterially expressed N-terminal cMyBP-C fragments. Clear decoration was obtained under a variety of salt conditions varying from 25 to 180 mM KCl concentration. Three-dimensional helical reconstructions, carried out at the 180-mM KCl level to minimize nonspecific binding, showed MyBP-C density over a broad portion of the periphery of subdomain 1 of actin and extending tangentially from its surface in the direction of actin's pointed end. Molecular fitting with an atomic structure of a MyBP-C Ig domain suggested that most of the N-terminal domains may be well ordered on actin. The location of binding was such that it could modulate tropomyosin position and would interfere with myosin head binding to actin. PMID- 21601576 TI - Structural analysis of a putative aminoglycoside N-acetyltransferase from Bacillus anthracis. AB - For the last decade, worldwide efforts for the treatment of anthrax infection have focused on developing effective vaccines. Patients that are already infected are still treated traditionally using different types of standard antimicrobial agents. The most popular are antibiotics such as tetracyclines and fluoroquinolones. While aminoglycosides appear to be less effective antimicrobial agents than other antibiotics, synthetic aminoglycosides have been shown to act as potent inhibitors of anthrax lethal factor and may have potential application as antitoxins. Here, we present a structural analysis of the BA2930 protein, a putative aminoglycoside acetyltransferase, which may be a component of the bacterium's aminoglycoside resistance mechanism. The determined structures revealed details of a fold characteristic only for one other protein structure in the Protein Data Bank, namely, YokD from Bacillus subtilis. Both BA2930 and YokD are members of the Antibiotic_NAT superfamily (PF02522). Sequential and structural analyses showed that residues conserved throughout the Antibiotic_NAT superfamily are responsible for the binding of the cofactor acetyl coenzyme A. The interaction of BA2930 with cofactors was characterized by both crystallographic and binding studies. PMID- 21601578 TI - Studies on the reaction of nitric oxide with the hypoxia-inducible factor prolyl hydroxylase domain 2 (EGLN1). AB - The hypoxic response in animals is mediated via the transcription factor hypoxia inducible factor (HIF). An oxygen-sensing component of the HIF system is provided by Fe(II) and 2-oxoglutarate-dependent oxygenases that catalyse the posttranslational hydroxylation of the HIF-alpha subunit. It is proposed that the activity of the HIF hydroxylases can be regulated by their reaction with nitric oxide. We describe biochemical and biophysical studies on the reaction of prolyl hydroxylase domain-containing enzyme (PHD) isoform 2 (EGLN1) with nitric oxide and a nitric oxide transfer reagent. The combined results reveal the potential for the catalytic domain of PHD2 to react with nitric oxide both at its Fe(II) and at cysteine residues. Although the biological significance is unclear, the results suggest that the reaction of PHD2 with nitric oxide has the potential to be complex and are consistent with proposals based on cellular studies that nitric oxide may regulate the hypoxic response by direct reaction with the HIF hydroxylases. PMID- 21601577 TI - Escherichia coli Fpg glycosylase is nonrendundant and required for the rapid global repair of oxidized purine and pyrimidine damage in vivo. AB - Endonuclease (Endo) III and formamidopyrimidine-N-glycosylase (Fpg) are two of the predominant DNA glycosylases in Escherichia coli that remove oxidative base damage. In cell extracts and purified form, Endo III is generally more active toward oxidized pyrimidines, while Fpg is more active towards oxidized purines. However, the substrate specificities of these enzymes partially overlap in vitro. Less is known about the relative contribution of these enzymes in restoring the genomic template following oxidative damage. In this study, we examined how efficiently Endo III and Fpg repair their oxidative substrates in vivo following treatment with hydrogen peroxide. We found that Fpg was nonredundant and required to rapidly remove its substrate lesions on the chromosome. In addition, Fpg also repaired a significant portion of the lesions recognized by Endo III, suggesting that it plays a prominent role in the global repair of both purine damage and pyrimidine damage in vivo. By comparison, Endo III did not affect the repair rate of Fpg substrates and was only responsible for repairing a subset of its own substrate lesions in vivo. The absence of Endo VIII or nucleotide excision repair did not significantly affect the global repair of either Fpg or Endo III substrates in vivo. Surprisingly, replication recovered after oxidative DNA damage in all mutants examined, even when lesions persisted in the DNA, suggesting the presence of an efficient mechanism to process or overcome oxidative damage encountered during replication. PMID- 21601579 TI - Acetylcholine chloride as a potential source of variability in the study of cutaneous vascular function in man. AB - INTRODUCTION: Laser-Doppler flowmetry (LDF) coupled with acetylcholine chloride (ACh) iontophoresis is increasingly recognized as a reliable non-invasive method to study the endothelial function. However, ACh-vasodilation measurement appears highly variable possibly due to the ACh pharmacological properties itself. These problems may be partially overcome by using methacholine chloride (MCh), a more stable synthetic agonist of muscarinic receptors, instead of ACh. Therefore, we first studied the correlation between the two drugs and then the effects of (1) spatial variability (inter-site measurements), (2) temporal variability (inter day measurements), (3) intra-day variability (morning versus evening), and (4) age on the variability of both ACh-vasodilation and MCh-vasodilation. METHODS: The endothelium-dependent vasodilation response to simultaneous iontophoretic applications (4 doses of 10s at 0.1mA with 2min of current-free interval) of ACh (11mM) or MCh (10mM) was studied on the forearm of 40 healthy subjects (36 males, median 28yr, range 21-59yr). The percent change in perfusion (CVCpeak) from baseline and the area under the curve (CVC(AUC)) during iontophoresis were assessed. Inter-site, inter-day and intra-day coefficients of variation (CV) were studied for each drug as well as correlations between drugs and age. RESULTS: A linear relationship was found between ACh- and MCh-CVCpeak (r2=0.75, p=0.01) and between ACh- and MCh-CVC(AUC) (r2=0.55, p=0.02). MCh inter-site CV for both CVCpeak (12.2%) and CVC(AUC) (13.8%) was significantly lower than ACh inter-site CV for CVCpeak (15.5%) and CVC(AUC) (15.3%), respectively. MCh inter-day CV for CVCpeak (17.2%) and CVC(AUC) (14.6%) was significantly lower than ACh inter-day CV for CVCpeak (19.7%) and ACh CVC(AUC) (21.2%). For ACh and MCh, the CVCpeak and CVC(AUC) were higher at 16:00pm than at 11:00am (p<0.05 for all). Finally, both ACh- and MCh-CVCpeak exhibited a logarithmic decrease with age (r2=0.61, p<0.01 and r2=0.58, p<0.01). CONCLUSION: Although both drugs exhibited circadian and age variability, MCh exhibited less inter-site and interday variabilities than did ACh for the evaluation of cutaneous endothelium-dependent vasodilation. These findings should be taken into account in studies of cutaneous vascular function by iontophoresis coupled with laser Doppler flowmetry. PMID- 21601580 TI - HapMap-based study of a region encompassing ERCC1 and ERCC2 related to lung cancer susceptibility in a Chinese population. AB - DNA repair genes play a crucial role in carcinogenesis. The paper aims to explore if common variants in ERCC1 are involved in lung cancer susceptibility. A Chinese case-control study included 339 lung cancer cases and 358 controls using five haplotype-tagging SNPs (htSNPs) (rs3212980, rs3212964, rs3212961, rs11615 and rs2298881) from the HapMap database, capturing 95% of the common haplotypic diversity of ERCC1. A combined analysis of eleven htSNPs covering ERCC2 and ERCC1 was performed. No significant association between individual htSNPs and lung cancer susceptibility was observed. There were interactions between rs3212961 and rs2298881and smoking duration (P=0.03 and P=0.01, respectively). Thus, the variant alleles of rs3212961 [OR (95% CI)=1.81(1.03-3.17), P=0.04] and rs2298881 [OR (95% CI)=2.16(1.26-3.70), P=0.005] were associated with risk of lung cancer among long-term smokers (>20 years) but not among never smokers and short-term smokers. No significant associations with lung cancer susceptibility were observed for global or individual haplotypes defined by five htSNPs of ERCC1. A highly differential distribution of haplotypes based on eleven htSNPs covering ERCC2 and ERCC1 were found (global test P=4.3*10(-5)). After Bonferroni correction, haplotypeER2+1-1 [OR (95% CI)=3.63 (1.39-9.47), P=0.005, marginally] and haplotypeER2+1-8 [OR (95% CI)=4.46 (2.03-9.79), P=5.6*10(-5), strongly] were associated with increased risk of lung cancer. The diplotype analysis with haplotypeER2+1-8 was also statistically significant (P<0.001). Haplotype analysis of pathological subtypes revealed that htSNPs of both genes may mainly influence the risk of lung adenocarcinoma. Strong linkage disequilibrium exist in two regions encompassing ERCC2 and ERCC1. These data suggest that common genetic variations in ERCC1 may influence increased risk of smoking-related lung cancer and one of the causative effectors may locate around or within ERCC2. PMID- 21601581 TI - Inhibition of ERK phosphorylation by substance P N-terminal fragment decreases capsaicin-induced nociceptive response. AB - Previous research has demonstrated that substance P N-terminal fragments produced by the action of several different enzymes in the spinal cord could reduce nociception when injected intrathecally (i.t.) into mice. The present study examined the possible involvement of spinal extracellular signal-regulated protein kinase (ERK), a mitogen-activated protein kinase (MAPK), in i.t. substance P (1-7)-induced antinociception as assayed by the capsaicin test. The i.t. injection of substance P (1-7) (20-80 nmol) into mice resulted in a dose dependent attenuation of paw-licking/biting behavior induced by intraplantar injection of capsaicin, which was reversed by co-injection of [D-Pro(2), D Phe(7)]substance P (1-7), a D-isomer and antagonist of substance P (1-7). In Western blot analysis, intraplantar injection of capsaicin (400 and 1600 ng/paw) produced an increase of ERK phosphorylation in the dorsal spinal cord, whereas expression of p38 and c-Jun N-terminal kinase (JNK) phosphorylation was unchanged by capsaicin treatment. In parallel to the behavioral results, i.t. substance P (1-7) inhibited capsaicin-induced ERK phosphorylation, which was reversed by [D Pro(2), D-Phe(7)]substance P (1-7), a substance P (1-7) antagonist. Both nociceptive behavioral response and spinal ERK activation induced by intraplantar capsaicin were reduced by U0126, an upstream inhibitor of ERK phosphorylation. Taken together, these findings suggest that the activation of ERK, but not p38 and JNK MAPKs in the spinal cord, contributes to intraplantar capsaicin-induced nociception, and that blocking ERK activation via substance P (1-7) binding sites may provide significant antinociception at the spinal cord level. PMID- 21601582 TI - Age differences in callosal contributions to cognitive processes. AB - In many cases bilateral cortical activation in older adults has been associated with better task performance, suggesting that a greater reliance on interhemispheric interactions aids performance. Interhemispheric communication is primarily mediated via the corpus callosum (CC), however with advancing age the anterior half of the CC undergoes significant atrophy. Here we determine whether there are age differences in the relationship between cross-sectional area of the CC and performance on cognitive tests of psychomotor processing speed and working memory. We found that older adults had significantly smaller callosal area in the anterior and mid-body of the CC than young adults. Furthermore, older adults with larger size in these callosal areas performed better on assessments of working memory and processing speed. Our results indicate that older adults with larger size of the anterior half of the CC exhibit better cognitive function, although their performance was still poorer than young adults with similar CC size. Thus, while the capability for interhemispheric interactions, as inferred from callosal size, may provide performance benefits for older adults, this capacity alone does not assure protection from general performance decline. PMID- 21601584 TI - Handedness in preterm born children: a systematic review and a meta-analysis. AB - It has been proposed that left and/or non-right handedness (NRH) is over represented in children with a history of preterm birth because such births are associated with a greater incidence of insult to the brain. We report an approximate two-fold increase in left and/or non-right handedness based on a systematic search of the literature from 1980 to September 2010 for English language articles reporting handedness status in preterm children compared with fullterm controls either as a main focus of the study or as a secondary finding. In total, thirty articles met the inclusion criteria. However, there was a great variation between the included studies in terms of objectives, population characteristics, sample size and methodologies used. While the majority of studies reported a higher incidence of NRH in preterm than fullterm children, this was not a consistent finding. A quality assessment was made to explore the differences in overall study quality and handedness assessment methodology between studies. A random-effects model meta-analysis was then performed to estimate the accumulated effect of preterm birth on handedness (18 studies; 1947 cases and 8170 controls). Preterm children displayed a significantly higher occurrence of NRH than fullterm children (odds ratio [OR]: 2.12; 95% confidence interval [CI]: 1.59-2.78). Sources of heterogeneity were investigated by supplementary meta-analyses considering studies with high or low overall and handedness assessment quality. Publication bias was assessed by Egger's test of the intercept and Duvall and Tweedie's trim-and-fill method. The outcomes of these procedures did not jeopardize the overall finding of reliably increased OR for NRH in preterm children. The present review suggests that a preterm birth is indeed associated with a greater than two-fold likelihood of NRH. Several studies also explored the relationship between handedness and neuropsychological functioning (cognition mainly) with an array of methods. Although not without disagreement, this association was found to be concordant. Studying handedness in preterm children, therefore, is a potentially important index of hemispheric organization and cognitive and sensory-motor functions following neurodevelopmental disturbance. PMID- 21601583 TI - Impaired holistic processing in congenital prosopagnosia. AB - It has long been argued that face processing requires disproportionate reliance on holistic or configural processing, relative to that required for non-face object recognition, and that a disruption of such holistic processing may be causally implicated in prosopagnosia. Previously, we demonstrated that individuals with congenital prosopagnosia (CP) did not show the normal face inversion effect (better performance for upright compared to inverted faces) and evinced a local (rather than the normal global) bias in a compound letter global/local (GL) task, supporting the claim of disrupted holistic processing in prosopagnosia. Here, we investigate further the nature of holistic processing impairments in CP, first by confirming, in a large sample of CP individuals, the absence of the normal face inversion effect and the presence of the local bias on the GL task, and, second, by employing the composite face paradigm, often regarded as the gold standard for measuring holistic face processing. In this last task, we show that, in contrast with controls, the CP group perform equivalently with aligned and misaligned faces and was impervious to (the normal) interference from the task-irrelevant bottom part of faces. Interestingly, the extent of the local bias evident in the composite task is correlated with the abnormality of performance on diagnostic face processing tasks. Furthermore, there is a significant correlation between the magnitude of the local bias in the GL and performance on the composite task. These results provide further evidence for impaired holistic processing in CP and, moreover, corroborate the critical role of this type of processing for intact face recognition. PMID- 21601585 TI - The anatomic basis of the right face-selective N170 IN acquired prosopagnosia: a combined ERP/fMRI study. AB - The N170 waveform is larger over posterior temporal cortex when healthy subjects view faces than when they view other objects. Source analyses have produced mixed results regarding whether this effect originates in the fusiform face area (FFA), lateral occipital cortex, or superior temporal sulcus (STS), components of the core face network. In a complementary approach, we assessed the face-selectivity of the right N170 in five patients with acquired prosopagnosia, who also underwent structural and functional magnetic resonance imaging. We used a non parametric bootstrap procedure to perform single-subject analyses, which reliably confirmed N170 face-selectivity in each of 10 control subjects. Anterior temporal lesions that spared the core face network did not affect the face-selectivity of the N170. A face-selective N170 was also present in another subject who had lost only the right FFA. However, face-selectivity was absent in two patients with lesions that eliminated the occipital face area (OFA) and FFA, sparing only the STS. Thus while the right FFA is not necessary for the face-selectivity of the N170, neither is the STS sufficient. We conclude that the face-selective N170 in prosopagnosia requires residual function of at least two components of the core face-processing network. PMID- 21601586 TI - Exposure of Jurkat cells to bis (tri-n-butyltin) oxide (TBTO) induces transcriptomics changes indicative for ER- and oxidative stress, T cell activation and apoptosis. AB - Tributyltin oxide (TBTO) is an organotin compound that is widely used as a biocide in agriculture and as an antifouling agent in paints. TBTO is toxic for many cell types, particularly immune cells. The present study aimed to identify the effects of TBTO on the human T lymphocyte cell line Jurkat. Cells were treated with 0.2 and 0.5MUM TBTO for 3, 6, 12 and 24h and then subjected to whole genome gene expression microarray analysis. The biological interpretation of the gene expression profiles revealed that endoplasmic reticulum (ER) stress is among the earliest effects of TBTO. Simultaneously or shortly thereafter, oxidative stress, activation of NFKB and NFAT, T cell activation, and apoptosis are induced. The effects of TBTO on genes involved in ER stress, NFAT pathway, T cell activation and apoptosis were confirmed by qRT-PCR. Activation and nuclear translocation of NFATC1 and the oxidative stress response proteins NRF2 and KEAP1 were confirmed by immunocytology. Taking advantage of previously published microarray data, we demonstrated that the induction of ER stress, oxidative stress, T cell activation and apoptosis by TBTO is not unique for Jurkat cells but does also occur in mouse thymocytes both ex vivo and in vivo and rat thymocytes ex vivo. We propose that the induction of ER stress leading to a T cell activation response is a major factor in the higher sensitivity of immune cells above other types of cells for TBTO. PMID- 21601587 TI - Association between environmental exposure to pesticides and neurodegenerative diseases. AB - Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population. PMID- 21601589 TI - A comparative study of the effects of venoms from five rear-fanged snake species on the growth of Leishmania major: identification of a protein with inhibitory activity against the parasite. AB - Leishmania parasites of several species cause cutaneous and visceral disease to millions of people worldwide, and treatment for this vector-borne protozoan parasite typically involves administration of highly toxic antimonial drugs. Snake venoms are one of the most concentrated enzyme sources in nature, displaying a broad range of biological effects, and several drugs now used in humans were derived from venoms. In this study, we compared the effects of the venoms of the South American rear-fanged snakes Philodryas baroni (PbV), Philodryas olfersii olfersii (PooV) and Philodryas patagoniensis (PpV), and the North American rear-fanged snakes Hypsiglena torquata texana (HttV) and Trimorphodon biscutatus lambda (TblV), on the growth of Leishmania major, a causative agent of cutaneous leishmaniasis. Different concentrations of each venom were incubated with the log-phase promastigote stage of L. major. TblV showed significant anti-leishmanial activity (IC50 of 108.6 MUg/mL) at its highest concentrations; however, it induced parasite proliferation at intermediate concentrations. PpV was not very active in decreasing the parasitic growth, and a high final concentration (1.7 mg/mL) was necessary to inhibit proliferation by only 51.5% +/- 3.6%. PbV, PooV and HttV, at final concentrations of 562, 524 and 438 MUg/mL respectively, had no significant effect on L. major growth. The phospholipase A2 of TblV (trimorphin) was isolated and assayed as for crude venom, and it also exhibited dose-dependent biphasic effects on the parasite culture, with potent cytotoxicity at higher concentrations (IC50 of 0.25 MUM; 3.6 MUg/mL) and stimulation of proliferation at very low concentrations. Anti-leishmanial activity of TblV appears to be solely due to the action of trimorphin. This is the first report of anti-leishmanial activity of rear-fanged snake venoms, and these results suggest novel possibilities for discovering new protein-based drugs that might be used as possible agents against leishmaniasis as well as tools to study the biology of Leishmania parasites. PMID- 21601588 TI - Oxidative stress in MeHg-induced neurotoxicity. AB - Methylmercury (MeHg) is an environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. Although the molecular mechanisms mediating MeHg-induced neurotoxicity are not completely understood, several lines of evidence indicate that oxidative stress represents a critical event related to the neurotoxic effects elicited by this toxicant. The objective of this review is to summarize and discuss data from experimental and epidemiological studies that have been important in clarifying the molecular events which mediate MeHg-induced oxidative damage and, consequently, toxicity. Although unanswered questions remain, the electrophilic properties of MeHg and its ability to oxidize thiols have been reported to play decisive roles to the oxidative consequences observed after MeHg exposure. However, a close examination of the relationship between low levels of MeHg necessary to induce oxidative stress and the high amounts of sulfhydryl-containing antioxidants in mammalian cells (e.g., glutathione) have led to the hypothesis that nucleophilic groups with extremely high affinities for MeHg (e.g., selenols) might represent primary targets in MeHg-induced oxidative stress. Indeed, the inhibition of antioxidant selenoproteins during MeHg poisoning in experimental animals has corroborated this hypothesis. The levels of different reactive species (superoxide anion, hydrogen peroxide and nitric oxide) have been reported to be increased in MeHg exposed systems, and the mechanisms concerning these increments seem to involve a complex sequence of cascading molecular events, such as mitochondrial dysfunction, excitotoxicity, intracellular calcium dyshomeostasis and decreased antioxidant capacity. This review also discusses potential therapeutic strategies to counteract MeHg-induced toxicity and oxidative stress, emphasizing the use of organic selenocompounds, which generally present higher affinity for MeHg when compared to the classically studied agents. PMID- 21601590 TI - Acute hypoglycemia decreases central retinal function in the human eye. AB - The goal of this pilot study was to assess the effects of acute hypoglycemia on retinal function and contrast sensitivity in individuals with and without diabetes. Hyperinsulinemic hypoglycemic and euglycemic clamp procedures were performed in subjects without diabetes (n=7) and with controlled type 1 diabetes (n=5). Mean age was 28 years, and none had retinal disease. During euglycemia (glucose 95-110 mg/dl) and acute hypoglycemia (glucose 50-55 mg/dl), contrast sensitivity was measured and spatial retinal responses were recorded with multifocal electroretinograms (mfERG), a rapid technique for mapping sensitivity from the foveal, macular and peripheral areas of the retina. During hypoglycemia, retinal responses (mfERG P1 wave) were decreased in both type 1 diabetes subjects and subjects without diabetes. The dominant effect was in the amplitude of the responses in the central macular retina, not in their temporal properties. Responses from the central region, central 10(0), were on average 1.8-fold lower than those from the periphery for both groups. All diabetes subjects and 3/7 without diabetes reported central scotoma. Decreases in mfERG amplitude were accompanied by decreases in contrast sensitivity. These changes were immediately reversed with the restoration of euglycemia. Overall, this study demonstrates that the acute effects of hypoglycemia in the human eye predominantly involve central vision, and these visual effects originate, at least in part, in the retina. The association between low blood glucose levels and impaired central vision underscores the importance of avoiding when possible and promptly treating hypoglycemia, particularly in individuals with diabetes. PMID- 21601591 TI - Primary school interventions to promote fruit and vegetable consumption: a systematic review and meta-analysis. AB - OBJECTIVE: The consumption of fruits and vegetables (FV) may contribute to the prevention of many diseases. However, children at school age do not eat an enough amount of those foods. We have systematically reviewed the literature to assess the effectiveness of school interventions for promoting the consumption of FV. METHODS: We performed a search in MEDLINE, EMBASE, CINAHL and CENTRAL. We pooled results and stratified the analysis according to type of intervention and study design. RESULTS: Nineteen cluster studies were included. Most studies did not describe randomization method and did not take the cluster's effect into account. Pooled results of two randomized controlled trials (RCTs) of computer-based interventions showed effectiveness in improving consumption of FV [Standardized Mean Difference (SMD) 0.33 (95% CI 0.16, 0.50)]. No significant differences were found in pooled analysis of seven RCTs of multicomponent interventions or pooling results of two RCTs evaluating free/subsidized FV interventions. CONCLUSIONS: Meta-analysis shows that computer-based interventions were effective in increasing FV consumption. Multicomponent interventions and free/subsidized FV interventions were not effective. Improvements in methodology are needed in future cluster studies. Although these results are preliminary, computer-based interventions could be considered in schools, given that they are effective and cheaper than other alternatives. PMID- 21601592 TI - Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy. AB - Cardiovascular disease is the biggest killer globally and the principal contributing factor to the pathology is atherosclerosis; a chronic, inflammatory disorder characterized by lipid and cholesterol accumulation and the development of fibrotic plaques within the walls of large and medium arteries. Macrophages are fundamental to the immune response directed to the site of inflammation and their normal, protective function is harnessed, detrimentally, in atherosclerosis. Macrophages contribute to plaque development by internalizing native and modified lipoproteins to convert them into cholesterol-rich foam cells. Foam cells not only help to bridge the innate and adaptive immune response to atherosclerosis but also accumulate to create fatty streaks, which help shape the architecture of advanced plaques. Foam cell formation involves the disruption of normal macrophage cholesterol metabolism, which is governed by a homeostatic mechanism that controls the uptake, intracellular metabolism, and efflux of cholesterol. It has emerged over the last 20 years that an array of cytokines, including interferon-gamma, transforming growth factor-beta1, interleukin-1beta, and interleukin-10, are able to manipulate these processes. Foam cell targeting, anti-inflammatory therapies, such as agonists of nuclear receptors and statins, are known to regulate the actions of pro- and anti-atherogenic cytokines indirectly of their primary pharmacological function. A clear understanding of macrophage foam cell biology will hopefully enable novel foam cell targeting therapies to be developed for use in the clinical intervention of atherosclerosis. PMID- 21601593 TI - Inhibition of the replication of grass carp reovirus in CIK cells with plasmid transcribed shRNAs. AB - Two DNA constructs targeting the grass carp reovirus (GCRV) RNA dependent RNA polymerase (RdRp) gene and outer capsid protein (OCP) gene that were each 64 bp in length were synthesized chemically and cloned into pSilencer2.1-U6 neo plasmid, named pSi-RdRp1286 and pSi-OCP117, respectively. After transfection of pSi-RdRp1286 and pSi-OCP117 plasmids into CIK cells, the inhibition of GCRV replication in the cells were detected by observing cytopathic effect (CPE), quantitating virus titers (TCID(50)/mL) and real-time quantitative RT-PCR analysis of viral RdRp and OCP genes. Five days after the cells were challenged with GCRV, both pSi-RdRp1286 and pSi-OCP117 reduced the viral titers by 5.47 lgTCID(50)/mL and 4.37 lgTCID(50)/mL, respectively. Compared to the positive control, CPE induced by GCRV in transfected cells was delayed and significantly less. Furthermore, the real-time quantitative RT-PCR analysis of the viral RdRp gene and OCP gene showed that the targeted gene expression were reduced by 89% and 73%, respectively. These results proved that the plasmid-transcribed shRNAs could inhibit effectively GCRV replication in CIK cells. These shRNAs provide potential tools for inhibiting GCRV infection and replication both in vitro and in vivo. PMID- 21601594 TI - An improved HAdV-41 E1B55K-expressing 293 cell line for packaging fastidious adenovirus. AB - Human adenovirus type 41 (HAdV-41) is difficult to cultivate under laboratory conditions. Tripartite leader sequence (TPL) of HAdV-41 was cloned, inserted into eukaryotic expression plasmid, and used to establish a HAdV-41 E1B55K-transduced cell line (293TE7). HAdV-41 E1B55K was expressed more abundantly in 293TE7 than in 293E12, an HAdV-41 E1B55K-expressing cell line developed previously. After being infected with E1-deleted HAdV-41 vector (HAdV-41-GFP), 293TE7 synthesized more viral genomic DNA and structural proteins, which led ultimately to a significant increase of the yield of progeny viruses. Typically, 293TE7 produced progeny viruses 3-15 times more than 293E12 did, depending on the amount of seed viruses and culture time. These data demonstrated that 293TE7 was an effective packaging cell line, and implied its application for wild-type HAdV-41 isolation, HAdV-41 virological study and recombinant HAdV-41 construction. PMID- 21601595 TI - Maternal voluntary drinking in C57BL/6J mice: advancing a model for fetal alcohol spectrum disorders. AB - Fetal alcohol spectrum disorders (FASD) remain the most common preventable cause of behavioural abnormalities and cognitive deficits, yet little is known about the biological mechanisms involved in FASD pathology. Maternal voluntary ethanol consumption in mice may be a useful model for establishing the biological basis of moderate ethanol exposure phenotypes, which make up the majority of FASD cases. We have employed a two-bottle choice paradigm of maternal ethanol consumption throughout gestation and the early postnatal period in C57BL/6J mice. We assessed the efficacy of this model to produce a range of FASD-relevant phenotypes and evaluated gene expression changes in the adult offspring. Results showed stable maternal consumption and lack of maternal care differences between ethanol-consuming and water-only dams. Ethanol-exposed offspring showed delays in neonatal reflex and coordination development. Further, ethanol-exposed adolescent mice showed decreased activity in a novel environment that appeared to be the result of novelty-induced anxiety, and acquisition learning deficits. Evaluation of the neurotransmitter-associated genes Gabra6, Glra1, and Grin2c revealed significant down-regulation of Glra1 and Grin2c in the brains of ethanol-exposed young adult males. These results suggest that this model is able to produce a range of behavioural phenotypes consistent with prenatal ethanol exposure and may be used to evaluate resulting long-term genetic changes. Given the range of genetic resources available for inbred mouse strains, the model described here may prove to be a useful tool in evaluating the molecular basis of FASD. PMID- 21601596 TI - Acidic NAADP-releasable Ca(2+) compartments in the megakaryoblastic cell line MEG01. AB - BACKGROUND: A novel family of intracellular Ca(2+)-release channels termed two pore channels (TPCs) has been presented as the receptors of NAADP (nicotinic acid adenine dinucleotide phosphate), the most potent Ca(2+) mobilizing intracellular messenger. TPCs have been shown to be exclusively localized to the endolysosomal system mediating NAADP-evoked Ca(2+) release from the acidic compartments. OBJECTIVES: The present study is aimed to investigate NAADP-mediated Ca(2+) release from intracellular stores in the megakaryoblastic cell line MEG01. METHODS: Changes in cytosolic and intraluminal free Ca(2+) concentrations were registered by fluorimetry using fura-2 and fura-ff, respectively; TPC expression was detected by PCR. RESULTS: Treatment of MEG01 cells with the H(+)/K(+) ionophore nigericin or the V-type H(+)-ATPase selective inhibitor bafilomycin A1 revealed the presence of acidic Ca(2+) stores in these cells, sensitive to the SERCA inhibitor 2,5-di-(tert-butyl)-1,4-hydroquinone (TBHQ). NAADP releases Ca(2+) from acidic lysosomal-like Ca(2+) stores in MEG01 cells probably mediated by the activation of TPC1 and TPC2 as demonstrated by TPC1 and TPC2 expression silencing and overexpression. Ca(2+) efflux from the acidic lysosomal-like Ca(2+) stores or the endoplasmic reticulum (ER) results in ryanodine-sensitive activation of Ca(2+)-induced Ca(2+) release (CICR) from the complementary Ca(2+) compartment. CONCLUSION: Our results show for the first time NAADP-evoked Ca(2+) release from acidic compartments through the activation of TPC1 and TPC2, and CICR, in a megakaryoblastic cell line. PMID- 21601597 TI - Within plant distribution of Potato Virus Y in hairy nightshade (Solanum sarrachoides): an inoculum source affecting PVY aphid transmission. AB - Potato virus Y (PVY) is vectored by several potato-colonizing and non-colonizing aphid species in a non-persistent manner and has a wide host range. It occurs naturally in several plant families. Myzus persicae and Macrosiphum euphorbiae are the most efficient potato-colonizing aphid vectors of PVY. Rhopalosiphum padi, a cereal aphid that migrates in large numbers through potato fields during the middle of the growing season, does not colonize potato plants but can transmit PVY. Hairy nightshade, Solanum sarrachoides, a prevalent annual solanaceous weed in the Pacific Northwest (PNW) of the United States, is an alternative host for PVY and a preferred host for M. persicae and M. euphorbiae. Hence, hairy nightshade plants might play an important role as an inoculum source in the epidemiology of PVY. We looked at titre accumulation and distribution of PVY(O), PVY(N:O) and PVY(NTN) in S. sarrachoides and potato after aphid inoculation with M. persicae and studied the transmission of PVY(O) and PVY(NTN), by M. persicae, M. euphorbiae and R. padi from hairy nightshade to potato plants. Virus titre at different positions on the plant was similar in S. sarrachoides and potato plants with strains PVY(O) and PVY(N:O). Titres of PVY(NTN) were similar in S. sarrachoides and potato but differences in titre were observed at different positions within the plant depending on the plant phenology. Percentage transmission of PVY(NTN) by M. persicae and M. euphorbiae was twice as high (46 and 34%, respectively) from hairy nightshade to potato than from potato to potato (20 and 14%). Percentage transmission of PVY(O) by M. persicae and M. euphorbiae was not affected by the inoculum source. No effect of the inoculum source was observed in the transmission of either PVY strain by R. padi. These results show that hairy nightshade may be an equal or better virus reservoir than potato and thus, important in the epidemiology of PVY. PMID- 21601598 TI - Individualizing hepatitis B infection prophylaxis in liver transplant recipients. PMID- 21601599 TI - Chronic hepatitis C genotype 2 and 3: are we ready for personalized medicine? PMID- 21601600 TI - Targeted therapy of liver fibrosis/cirrhosis and its complications. PMID- 21601601 TI - TAK1: Another mesh in the NF-kappaB - JNK controlled network causing hepatocellular carcinoma. AB - The MAP3-kinase TGF-beta-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signaling pathways. Here, we report that conditional ablation of TAK1 in liver parenchymal cells (hepatocytes and cholangiocytes) causes hepatocyte dysplasia and early-onset of hepatocarcinogenesis, coinciding with biliary ductopenia and cholestasis. TAK1-mediated cancer suppression is exerted through activating NF-kappaB in response to tumor necrosis factor (TNF) and through preventing Caspase-3-dependent hepatocyte and cholangiocyte apoptosis. Moreover, TAK1 suppresses a procarcinogenic and pronecrotic pathway, which depends on NF-kappaB-independent functions of the I kappaB-kinase (IKK)-subunit NF-kappaB essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-kappaB-independent function of NEMO in parenchymal liver cells. PMID- 21601602 TI - Nanodrug particles and nanoformulations for drug delivery. PMID- 21601603 TI - New strategy for drug development with exploratory IND studies: scientific basis and future directions. PMID- 21601604 TI - Central and peripheral effects of ghrelin on energy balance, food intake and lipid metabolism in teleost fish. AB - Ghrelin was first identified and characterized from rat stomach as an endogenous ligand for the growth hormone secretagogue receptor. Ghrelin and its receptor system are present not only in peripheral tissues such as stomach and intestine, but also in the central nervous system of mammals. Interestingly, administration of ghrelin induces an orexigenic effect and also modifies locomotor activity, suggesting its involvement in feeding control and the regulation of energy balance, in addition to the regulation of growth hormone release. Information about ghrelin in non-mammals, such as teleost fish, has also been increasing, and important data have been obtained. An understanding of the evolutionary background of the energy regulation system and the central and peripheral roles of ghrelin in teleost fish could provide indications as to their roles in mammals, particularly humans. In this review, we overview the central and peripheral effects of ghrelin on energy balance, locomotor activity, and lipid metabolism in teleost fish. PMID- 21601605 TI - Student utilization of a university 2009 H1N1 vaccination clinic. AB - The 2009 H1N1 influenza resulted in widespread outbreaks on college campuses. Once sufficient quantity of vaccine became available, many universities held vaccination clinics for students. We sought to examine factors associated with participation in an on-campus vaccination effort. A self-administered questionnaire was completed by students in January 2010. Our results suggest a high degree of awareness of the 2009 H1N1 virus among students. The odds of being vaccinated were higher for students who believed the H1N1 virus was a greater public health threat and for students who had friends and family that were vaccinated after controlling for sex, ethnicity, age, and living conditions. PMID- 21601606 TI - "Wait and see" vaccinating behaviour during a pandemic: a game theoretic analysis. AB - During the 2009 H1N1 pandemic, many individuals did not seek vaccination immediately but rather decided to "wait and see" until further information was available on vaccination costs. This behaviour implies two sources of strategic interaction: as more individuals become vaccinated, both the perceived vaccination cost and the probability that susceptible individuals become infected decline. Here we analyze the outcome of these two strategic interactions by combining game theory with a disease transmission model during an outbreak of a novel influenza strain. The model exhibits a "wait and see" Nash equilibrium strategy, with vaccine delayers relying on herd immunity and vaccine safety information generated by early vaccinators. This strategic behaviour causes the timing of the epidemic peak to be strongly conserved across a broad range of plausible transmission rates, in contrast to models without such adaptive behaviour. The model exhibits not only feedback mechanisms but also a feed forward mechanism: a high initial perceived vaccination cost perpetuates high perceived vaccine costs (and lower vaccine coverage) throughout the remainder of the outbreak. This suggests that any effect of risk communication at the start of a pandemic outbreak will be amplified compared to the same amount of risk communication effort distributed throughout the outbreak. PMID- 21601607 TI - Characterizing non-constant relative potency. AB - Relative potency plays an important role in toxicology. Estimates of relative potency are used to rank chemicals by their effects, to calculate equivalent doses of test chemicals compared to a standard, and to weight contributions of constituent chemicals when evaluating mixtures. Typically relative potency is characterized by a constant dilution factor, even when non-similar dose-response curves indicate that constancy is inappropriate. Improperly regarding relative potency as constant may distort conclusions and potentially mislead investigators or policymakers. We consider a more general approach that allows relative potency to vary as a function of dose, response, or response quantile. Distinct functions can be defined, each generalizing different but equivalent descriptions of constant relative potency. When two chemicals have identical response limits, these functions all carry fundamentally equivalent information; otherwise, relative potency as a function of response quantile is distinct and embodies a modified definition of relative potency. Which definition is preferable depends on whether one views any differences in response limits as intrinsic to the chemicals or as extrinsic, arising from idiosyncrasies of data sources. We illustrate these ideas with constructed examples and real data. Relative potency functions offer a unified and principled description of relative potency for non similar dose-response curves. PMID- 21601608 TI - Vulnerability factors in anxiety: Strain and sex differences in the use of signals associated with non-threat during the acquisition and extinction of active-avoidance behavior. AB - Rats that exhibit a behaviorally inhibited temperament acquire active-avoidance behaviors quicker, and extinguish them slower, than normal outbred rats. Here we explored the contribution of stimuli that signal periods of non-threat (i.e. safety signals) in the process of acquiring active-avoidance behavior. Utilizing a discrete lever-press escape-avoidance protocol, outbred Sprague-Dawley (SD) rats and inbred, behaviorally inhibited, Wistar-Kyoto (WKY) rats were tested under conditions where a flashing light was either presented or not during periods of non-threat (the inter-trial interval, ITI). For males, we found the absence of the ITI-signal slowed the acquisition of avoidance behavior selectively in WKY rats. However, extinction of the avoidance behavior was not influenced by training with or without the ITI-signal; WKY males extinguished slower than SD males. For females, the presence of the ITI-signal did not affect acquisition in either strain. However, after training with the ITI-signal, females of both strains extinguished quicker in its absence than in its presence. In order to determine if facilitated acquisition of avoidance learning in male WKY rats was due to a paradigm-independent influence of the visual stimulus used as ITI-signal upon associative learning, we conducted eyeblink conditioning in the presence or absence of a similar visual stimulus. No differences in acquisition, as a function of this visual stimulus, were observed within the male WKY rats, but, as was observed in avoidance learning, male WKY rats extinguished slower than male SD rats. Thus, avoidance susceptibility for male WKY rats may be tied both to the presence of non-threat signals as well as a resistance to extinguish Pavlovian-conditioned associations. Female susceptibility to resist extinguishing avoidant behavior is discussed with respect to the possible role of stimuli serving as occasion setters for threat contexts. PMID- 21601611 TI - Mitochondrial defects and cytotoxicity by antimycin A on cultured osteoblastic MC3T3-E1 cells. AB - Antimycin A (AMA), which inhibits complex III of the electron transport system, has been used as a reactive oxygen species (ROS) generator in biological systems. We investigated the effects of AMA on various parameters related to mitochondrial function in osteoblastic MC3T3-E1 cells. Here, we show that AMA-induced cell death was accompanied by the loss of ATP, complex I and IV activities, and mitochondrial membrane potential. Moreover, AMA stimulated oxidative stress and induced cytochrome c release from mitochondria in osteoblasts. Our data support AMA-induced death in osteoblasts via a mitochondria-dependent pathway. These biochemical changes in mitochondria were effectively prevented upon pre-treatment with ROS scavengers, indicating that ROS plays a critical role as an upstream controller in the AMA-induced cell dysfunction. PMID- 21601609 TI - Inhibition of phospholipase A2 in rat brain modifies different membrane fluidity parameters in opposite ways. AB - Fluidity is an important neuronal membrane property and it is influenced by the concentration of polyunsaturated fatty acids (PUFAs) in membrane phospholipids. Phospholipase A(2) (PLA(2)) is a key enzyme in membrane phospholipid metabolism, generating free PUFAs. In Alzheimer disease (AD), reduced PLA(2) activity, specifically of calcium-dependent cytosolic PLA(2) (cPLA(2)) and calcium independent intracellular PLA(2) (iPLA(2)), and phospholipid metabolism was reported in the frontal cortex and hippocampus. This study investigated the effects of in vivo infusion of the dual cPLA(2) and iPLA(2) inhibitor MAFP into rat brain on PLA(2) activity and membrane fluidity parameters in the postmortem frontal cortex and dorsal hippocampus. PLA(2) activity was measured by radioenzymatic assay and membrane fluidity was determined by fluorescence anisotropy technique using three different probes: DPH, TMA-DPH, and pyrene. MAFP significantly inhibited PLA(2) activity, reduced the flexibility of fatty acyl chains (indicated by increased DPH anisotropy), increased the fluidity in the lipid-water interface (indicated by decreased TMA-DPH anisotropy), and increased the lipid lateral diffusion in the hydrocarbon core (represented by pyrene excimer formation) of membranes in both brain areas. The findings suggest that reduced cPLA(2) and iPLA(2) activities in AD brain might contribute to the cognitive impairment, in part, through alterations in membrane fluidity parameters. PMID- 21601610 TI - Expression of Ca2+-dependent activator protein for secretion 2 is increased in the brains of schizophrenic patients. AB - Ca(2+)-dependent activator protein for secretion 2 (CADPS2), a secretory granule associate protein, mediates monoamine transmission and the release of neurotrophins including brain-derived neurotrophic factor (BDNF) which have been implicated in psychiatric disorders. Furthermore, the expression of CADPS2deltaExon3, a defective splice variant of CADPS2, has been reported to be associated with autism. Based on these observations, we examined whether expression levels of CADPS2 and CADPS2deltaExon3 are altered in psychiatric disorders. Quantitative polymerase chain reaction analysis was performed for postmortem frontal cortex tissues (BA6) from 15 individuals with schizophrenia, 15 with bipolar disorder, 15 with major depression, and 15 controls (Stanley neuropathology consortium). The mean CADPS2 expression levels normalized to human glyceraldehyde-3phosphate dehydrogenase (GAPDH) or TATA-box binding protein levels was found to be significantly increased in the brains of the schizophrenia group, compared to the control group. On the other hand, the ratio of CADPS2deltaExon3 to total CADPS2 was similar in the 4 diagnostic groups. We then analyzed CADPS2 expression in blood samples from 121 patients with schizophrenia and 318 healthy controls; however, there was no significant difference between the two groups. Chronic risperidone treatment did not alter the expression of CADPS2 in frontal cortex of mice. The observed increase in the expression of CADPS2 may be related to the impaired synaptic function in schizophrenia. PMID- 21601612 TI - Comparative study on antioxidant activity of different varieties of commonly consumed legumes in India. AB - Legumes are rich source of proteins, dietary fiber, micronutrients and bioactive phytochemicals. Thirty different varieties of commonly consumed legumes in India, were screened for phenolic content and antioxidant activity using, radical scavenging [(1,1-diphenyl-2-picryl-hydrazyl (DPPH.) and 2,2'-azino-bis (3 ethylbenz-thiazoline-6-sulfonic acid, (ABTS.+], Ferric Reducing Antioxidant Power (FRAP) and metal ion (Fe2+) chelation assays. Legumes varied largely in their antioxidant activity. Horse gram, common beans, cowpea (brown and red) and fenugreek showed high DPPH. radical scavenging activity (>400 units/g), while lablab bean (cream and white), chickpea (cream and green), butter bean and pea (white and green) showed low antioxidant activity (<125 units/g). Green gram, black gram, pigeon pea, lentils, cowpea (white) and common bean (maroon) showed intermediate activity. Similar trend was observed when the activity was assessed with ABTS.+ and FRAP assays. Thus most of the varieties having light color seed coat, except soybean exhibited low antioxidant activity. While legumes having dark color seed coat did not always possessed high antioxidant activity (e.g. moth bean, black pea, black gram, lentils). Antioxidant activity showed positive correlation (r2>0.95) with phenolic contents, in DPPH., ABTS.+ and FRAP assays, whereas poor correlation (r2=0.297) was observed between Fe2+ chelating activity of the legumes and phenolic contents. PMID- 21601613 TI - Dysregulation of immune responses in an allergic mouse model following low-level toluene exposure. AB - To investigate the effect of low-level toluene inhalation on immune regulation in an allergic mouse model, C3H/HeN mice were exposed to 0, 5, 50, or 500ppm of toluene for 6h/day, 5 days/week for 3 or 6 weeks. For allergic mouse model, half of the mice in each group were immunized with ovalbumin (OVA). Allergic mice exposed to toluene for 3 weeks did not exhibit any changes in their plasma, lung or spleen samples. Although exposure to toluene alone for 6 weeks did not increase the number of inflammatory cells in bronchoalveolar lavage (BAL) fluid, coexposure to 50ppm toluene and OVA increased the number of BAL cells. Histological changes and increased amounts of fibronectin were observed in the lungs of OVA-immunized, 50-ppm-toluene-exposed mice. Exposure to 500ppm significantly increased the expressions of transcription factors STAT3, STAT4 and STAT5a mRNAs in spleen. In spleens from the allergic mouse model, the expressions of STAT3, STAT4, STAT5a, STAT6, GATA3 and Foxp3 mRNAs were significantly enhanced following exposure to 50ppm toluene for 6 weeks, but the expression of T-bet mRNA was not increased. Regarding the Th1/Th2 balance, the expressions of IL-4 and IL 12 mRNAs were enhanced in the spleens of toluene-exposed mice. Total IgG1 antibody production in the plasma was significantly increased in the 50-ppm toluene-exposed allergic mouse model. These results indicate that low-level toluene exposure might dysregulate the allergic responses to OVA in C3H/HeN mice. PMID- 21601614 TI - Development of Alzheimer-disease neuroimaging-biomarkers using mouse models with amyloid-precursor protein-transgene expression. AB - There are important recent developments in Alzheimer's disease (AD) translational research, especially with respect to the imaging of amyloid pathology in vivo using MRI and PET technologies. Here we exploit the most widely used transgenic mouse models of amyloid pathology in order to relate the imaging findings to our knowledge about the histopathological phenotype of these models. The development of new diagnostic criteria of AD necessitates the use of biological markers to diagnose AD even in the absence of overt dementia or early symptomatic mild cognitive impairment. The validity of the diagnosis will depend on the availability of an in vivo marker to reflect underlying neurobiological changes of AD. Transgenic models with essential features of AD pathology and mechanisms provide a test setting for the development and evaluation of new biological imaging markers. Among the best established imaging markers of amyloid pathology in transgenic animals are high-field MRI of brain atrophy, proton spectroscopy of neurochemical changes, high-field MRI of amyloid plaque load, and in vivo plaque imaging using radio-labelled ligands with PET. We discuss the implications of the findings as well as the methodological limitations and the specific requirements of these technologies. We furthermore outline future directions of transgene imaging research. Transgene imaging is an emerging area of translational research that implies strong multi- and interdisciplinary collaborations. It will become ever more valuable with the introduction of new diagnostic standards and novel treatment approaches which will require valid and reliable biological markers to improve the diagnosis and early treatment of AD patients. PMID- 21601616 TI - c-Fos expression in neurons projecting from the preoptic and lateral hypothalamic areas to the ventrolateral periaqueductal gray in relation to sleep states. AB - The ventrolateral division of the periaqueductal gray (vlPAG) and the adjacent deep mesencephalic reticular nucleus have been implicated in the control of sleep. The preoptic hypothalamus, which contains populations of sleep-active neurons, is an important source of afferents to the vlPAG. The perifornical lateral hypothalamus (LH) contains populations of wake-active neurons and also projects strongly to the vlPAG. We examined nonREM and REM sleep-dependent expression of c-Fos protein in preoptic-vlPAG and LH-vlPAG projection neurons identified by retrograde labeling with Fluorogold (FG). Separate groups of rats (n=5) were subjected to 3 h total sleep deprivation (TSD) followed by 1 h recovery sleep (RS), or to 3 h of selective REM sleep deprivation (RSD) followed by RS. A third group of rats (n=5) was subjected to TSD without opportunity for RS (awake group). In the median preoptic nucleus (MnPN), the percentage of FG+ neurons that were also Fos+ was higher in TSD-RS animals compared to both RSD-RS rats and awake rats. There were significant correlations between time spent in deep nonREM sleep during the 1 h prior to sacrifice across groups and the percentage of double-labeled cells in MnPN and ventrolateral preoptic area (VLPO). There were no significant correlations between percentage of double labeled neurons and time spent in REM sleep for any of the preoptic nuclei examined. In the LH, percentage of double-labeled neurons was highest in awake rats, intermediate in TSD-RS rats and lowest in the RSD-RS group. These results suggest that neurons projecting from MnPN and VLPO to the vlPAG are activated during nonREM sleep and support the hypothesis that preoptic neurons provide inhibitory input to vlPAG during sleep. Suppression of excitatory input to the vlPAG from the LH during sleep may have a permissive effect on REM sleep generation. PMID- 21601617 TI - Bisindole alkaloids and secoiridoids from Alstonia macrophylla Wall. ex G. Don. AB - The ethanolic extract from stems of a Thai medicinal plant, Alstonia macrophylla Wall. ex G. Don (Apocynaceae) showed a significant inhibitory effect on acetylcholinesterase (AChE) determined by using Ellman assay. Four compounds i.e., a bisindole alkaloid, macralstonine (1), a new bisindole alkaloid, thungfaine (2), a secoiridoid glycoside, sweroside (3) and a new secoiridoid glycoside, naresuanoside (4) were isolated. Compound 4 showed moderate AChE and butyrylcholinesterase (BChE) inhibitory effects. Interestingly, compound 4 inhibited cell growth on human androgen-sensitive prostate cancer cell line (LNCaP) but no effect on viability of human foreskin fibroblast cells (HF). PMID- 21601618 TI - Temporal discounting and heart rate reactivity to stress. AB - Temporal discounting is the reduction of the value of a reinforcer as a function of increasing delay to its presentation. Impulsive individuals discount delayed consequences more rapidly than self-controlled individuals, and impulsivity has been related to substance abuse, gambling, and other problem behaviors. A growing body of literature has identified biological correlates of impulsivity, though little research to date has examined relations between delay discounting and markers of poor health (e.g., cardiovascular reactivity to stress). We evaluated the relation between one aspect of impulsivity, measured using a computerized temporal discounting task, and heart rate reactivity, measured as a change in heart rate from rest during a serial subtraction task. A linear regression showed that individuals who were more reactive to stress responded more impulsively (i.e., discounted delayed reinforcers more rapidly). When results were stratified by gender, the effect was observed for females, but not for males. This finding supports previous research on gender differences in cardiovascular reactivity and suggests that this type of reactivity may be an important correlate of impulsive behavior. PMID- 21601615 TI - Activity-regulated genes as mediators of neural circuit plasticity. AB - Modifications of neuronal circuits allow the brain to adapt and change with experience. This plasticity manifests during development and throughout life, and can be remarkably long lasting. Evidence has linked activity-regulated gene expression to the long-term structural and electrophysiological adaptations that take place during developmental critical periods, learning and memory, and alterations to sensory map representations in the adult. In all these cases, the cellular response to neuronal activity integrates multiple tightly coordinated mechanisms to precisely orchestrate long-lasting, functional and structural changes in brain circuits. Experience-dependent plasticity is triggered when neuronal excitation activates cellular signaling pathways from the synapse to the nucleus that initiate new programs of gene expression. The protein products of activity-regulated genes then work via a diverse array of cellular mechanisms to modify neuronal functional properties. Synaptic strengthening or weakening can reweight existing circuit connections, while structural changes including synapse addition and elimination create new connections. Posttranscriptional regulatory mechanisms, often also dependent on activity, further modulate activity-regulated gene transcript and protein function. Thus, activity-regulated genes implement varied forms of structural and functional plasticity to fine-tune brain circuit wiring. PMID- 21601619 TI - Influence of escalating alternative reinforcer values on cigarette choice. AB - The availability of alternative reinforcers reduces drug taking. Escalating alternative reinforcer values have been used to initiate and maintain abstinence from drug use. A reset in reinforcer value has been added to the schedule of alternative reinforcer presentation to discourage relapse. The purpose of this preliminary study was to test the influence of escalating and escalating and resetting alternative reinforcer value on cigarette choice in the human laboratory. Fourteen daily cigarette smokers completed this experiment, which required one practice and three experimental sessions. During each experimental session, subjects made six choices between smoking a cigarette and receiving money, available under Constant, Escalating or Escalating and Resetting conditions. The total number of cigarettes chosen and puffs taken, but not the maximum consecutive number of cigarettes choices, was decreased in the Escalating condition relative to the Constant condition. The maximum number of consecutive cigarettes chosen was decreased in the Escalating and Resetting condition relative to the Constant condition. The proportion of money earned was increased in the Escalating condition relative to the Constant and Escalating and Resetting conditions. These initial findings indicate that whereas an escalating alternative reinforcer schedule reduces cigarette smoking overall, an escalating and resetting alternative reinforcer schedule may reduce repeated cigarette smoking (i.e., relapse). PMID- 21601620 TI - Investigation of the 1758G>C and 2880A>G variants within the NCOA3 gene in a breast cancer affected Australian population. AB - NCOA3 is a known low to moderate-risk breast cancer susceptibility gene, amplified in 5-10% and over expressed in about 60% of breast tumours. Additionally, this over expression is associated with Tamoxifen resistance and poor prognosis. Previously, two variants of NCOA3, 1758G>C and 2880A>G have been associated with breast cancer in two independent populations. Here we assessed the influence of the two NCOA3 variants on breast cancer risk by genotyping an Australian case-control study population. 172 cases and 178 controls were successfully genotyped for the 1758G>C variant and 186 cases and 182 controls were successfully genotyped for the 2880A>G variant using high-resolution melt analysis (HRM). The genotypes of the 1758G>C variant were validated by sequencing. chi(2) tests were performed to determine if significant differences exist in the genotype and allele frequencies between the cases and controls. chi(2) analysis returned no statistically significant difference (p>0.05) for genotype frequencies between cases and controls for 1758G>C (chi(2)=0.97, p=0.6158) or 2880A>G (chi(2)=2.09, p=0.3516). Similarly, no statistical difference was observed for allele frequencies for 1758G>C (chi(2)=0.07, p=0.7867) or 2880A>G (chi(2)=0.04, p=0.8365). Haplotype analysis of the two SNPs also showed no difference between the cases and the controls (p=0.9585). Our findings in an Australian Caucasian population composed of breast cancer sufferers and an age matched control population did not support the findings of previous studies demonstrating that these markers play a significant role in breast cancer susceptibility. Here, no significant difference was detected between breast cancer patients and healthy matched controls by either the genotype or allele frequencies for the investigated variants (all p >= 0.05). While an association of the two variants and breast cancer was not detected in our case-control study population, exploring these variants in a larger population of the same kind may obtain results in concordance with previous studies. Given the importance of NCOA3 and its involvement in biological processes involved in breast cancer and the possible implications variants of the gene could have on the response to Tamoxifen therapy, NCOA3 remains a candidate for further investigations. PMID- 21601621 TI - An investigation into silk fibroin conformation in composite materials intended for drug delivery. AB - Regenerated silk fibroin (SF) is a promising biomaterial to design drug delivery systems. To guarantee satisfactory prolonged release of loaded drugs, the native beta-sheet conformation of SF is generally induced by a final curing which can determine instability of the loaded drug. This work aimed to investigate the influence on SF conformation of the addition of hydrophilic polymers, namely poloxamer 188 (PEO), a range of poly(ethylenglycol) (PEG)and poly(vinyl pyrrolidone) (PVP) and drying conditions, namely spray-drying or evaporation at 60 degrees C. DSC data on spray-dried products indicated that SF in composite materials was in the random coil conformation. ATR-FTIR spectroscopy with Fourier self-deconvolution of the amide I band revealed that SF in spray dried products was partially organized in the beta-sheet structure only in presence of PEG4000. Both DSC and ATR-FTIR spectra registered on composite materials obtained by the slowest evaporation method indicated that all hydrophilic polymers favoured the beta-sheet conformation. This feature was attributed to the formation of H-bonds with the tyrosine residues of the semicrystalline region in SF. In conclusion, this approach to prepare of SF/hydrophilic polymer composites at slow evaporation rate leads to water insoluble materials which could be used in the development of drug delivery systems. PMID- 21601622 TI - Cholesterol implications in plasmid DNA electrotransfer: Evidence for the involvement of endocytotic pathways. AB - The delivery of therapeutic molecules such as plasmid DNA in cells and tissues by means of electric fields holds great promise for anticancer treatment. To allow for their therapeutic action, the molecules have first to traverse the cell membrane. The mechanisms by which the electrotransferred pDNA interacts with and crosses the plasma membrane are not yet fully explained. The aim of this study is to unravel the role of cholesterol during gene electrotransfer in cells. We performed cholesterol depletion experiments and measured its effects on various steps of the electroporation process. The first two steps consisting of electropermeabilization of the plasma membrane and of pDNA interaction with it were not affected by cholesterol depletion. In contrast, gene expression decreased. Colocalization studies with endocytotic markers showed that pDNA is endocytosed with concomitant clathrin- and caveolin/raft-mediated endocytosis. Cholesterol might be involved in the pDNA translocation through the plasma membrane. This is the first direct experimental evidence of the occurrence of endocytosis in gene electrotransfer. PMID- 21601623 TI - Comparison of mesoporous silicon and non-ordered mesoporous silica materials as drug carriers for itraconazole. AB - Mesoporous materials have an ability to enhance dissolution properties of poorly soluble drugs. In this study, different mesoporous silicon (thermally oxidized and thermally carbonized) and non-ordered mesoporous silica (Syloid AL-1 and 244) microparticles were compared as drug carriers for a hydrophobic drug, itraconazole (ITZ). Different surface chemistries pore volumes, surface areas, and particle sizes were selected to evaluate the structural effect of the particles on the drug loading degree and on the dissolution behavior of the drug at pH 1.2. The results showed that the loaded ITZ was apparently in amorphous form, and that the loading process did not change the chemical structure/morphology of the particles' surface. Incorporation of ITZ in both microparticles enhanced the solubility and dissolution rate of the drug, compared to the pure crystalline drug. Importantly, the physicochemical properties of the particles and the loading procedure were shown to have an effect on the drug loading efficiency and drug release kinetics. After storage under stressed conditions (3 months at 40 degrees C and 70% RH), the loaded silica gel particles showed practically similar dissolution profiles as before the storage. This was not the case with the loaded mesoporous silicon particles due to the almost complete chemical degradation of ITZ after storage. PMID- 21601624 TI - Drug release characteristics from nanoclay hybrids and their dispersions in organic polymers. AB - This study establishes and compares structure-property-processing relationships on three drug delivery systems containing an anionic active pharmaceutical ingredient (API) in the following excipient carriers: (a) an inorganic anionic nanoclay, (b) pH responsive acrylic polymers, and (c) combinations thereof. The effects of the excipients on the APIs dissolution rate were studied from their release profile in simulated body fluids (SBFs) with different pH. In the API nanoclay system, calcination of the clay followed by its reconstitution in an API solution was successfully used to intercalate the API in its amorphous state in the clay. As a result, the API showed increased apparent solubility vs. its crystalline form with its release mechanism from the clay being predominantly diffusion controlled and depending on the pH of the SBFs. In melt mixed ternary polymer systems containing the above hybrids, as a result of an additional diffusional step due to presence of nanoplatelets, the API showed a more controlled release vs. polymer systems that contained only API. By comparison to the low pH SBF, the ternary system in the pH 7.4 SBF showed a reduced diffusion contribution due to the presence of clay platelets, the latter unaffected by the high pH value. Reasonable agreement was found with predictions from literature diffusion/erosion models. It is confirmed that hot melt mixing offers opportunities to produce systems with enhanced API apparent solubility. The presence of nanoclays can also increase the API's apparent solubility and affect its release in a controlled manner. PMID- 21601625 TI - Determination of the scale of segregation of low dose tablets using hyperspectral imaging. AB - In this work, near infrared (NIR) hyperspectral imaging was used to quantify the spatial distribution of drug in tablets containing tolmetin sodium dihydrate. Hyperspectral data cubes were generated by imaging the same spatial region of a sample while illuminated by a laser at a different wavelength for each image. Images were generated for wavelengths ranging from 1100 to 2200 nm. Ten tablets with concentrations ranging from 0.0 to 10.0% w/w tolmetin were imaged, and the scales of segregation were calculated for the tablets. Lactose anhydrous was used as the diluent, and all mixtures contained 0.5% magnesium stearate as a lubricant. This research has shown hyperspectral imaging to be viable tool for quantifying segregation of low dose drugs in tablets. PMID- 21601626 TI - PosintroTM-HBsAg, a modified ISCOM including HBsAg, induces strong cellular and humoral responses. AB - To improve the hepatitis B vaccines on the market new adjuvant systems have to substitute aluminium. In this study the hepatitis B surface antigen (HBsAg) was incorporated into a novel adjuvant system, the PosintroTM, a modification of the traditional immune stimulatory complexes (ISCOMs). This new HBsAg vaccine formulation, PosintroTM-HBsAg, was compared to two commercial hepatitis B vaccines including aluminium or monophosphoryl lipid A (MPL) and the two adjuvant systems MF59 and QS21 in their efficiency to prime both cellular and humoral immune responses. The PosintroTM-HBsAg induced the strongest humoral response with high titers of HBsAg specific antibody, high number of antigen specific B cells and a strong T helper 1 (Th1) antibody profile when compared to the other adjuvant formulations. The PosintroTM-HBsAg was also a strong inducer of cellular immune responses with induction of delayed type hypersensitivity (DTH) reaction and CD4(+) T-cell proliferation. In addition, PosintroTM-HBsAg was the only vaccine tested that also induced a strong cytotoxic T lymphocyte (CTL) response, with high levels of antigen specific CD8 T-cells secreting IFN-gamma mediating cytolytic activity. The results demonstrate that this novel experimental vaccine formulation, the PosintroTM-HBsAg, is strongly immunogenic and can induce both class I and class II responses in experimental animals. This shows promise both for the protection against hepatitis B virus infection and as a potential therapeutic vaccine. PMID- 21601628 TI - Heat shock protein 90 and its cochaperone, p23, are markedly increased in the aged gerbil hippocampus. AB - In the present study, we compared HSP90 and its co-chaperone, p23, immunoreactivity and their protein levels in the hippocampus between adult (postnatal month 6) and aged (postnatal month 24) gerbils using immunohistochemistry and western blot analysis. HSP90 immunoreactivity was markedly increased in pyramidal cells in the hippocampus proper and in polymorphic cells in the dentate gyrus of the aged group compared to the adult group. p23 immunoreactivity was slightly increased in pyramidal cells of the hippocampus proper and in granule cells of the dentate gyrus in the aged group. In addition, HSP90 and p23 protein levels in the aged hippocampus were much higher than the adult hippocampus. These results indicate that HSP90 and p23 immunoreactivity and protein levels in the hippocampus are distinctively increased in the aged gerbils compared to the adult gerbils. PMID- 21601627 TI - Zinc-pectinate beads as an in vivo self-assembling system for pulsatile drug delivery. AB - Zinc-pectinate beads are interesting drug carriers for oral delivery. In order to investigate their in vitro and in vivo release behaviour, ionotropic gelation was used to entrap theophylline into calcium- or zinc-pectinate beads. Beads were investigated in vitro for their particle properties, especially the release kinetic in different media, and their in vivo pharmacokinetic parameters were tested in rats. Particle size varied between 1.8 and 2.8mm and encapsulation rates between 27 and 30% for Ca- and Zn-pectinate beads, respectively. While Ca pectinate beads revealed a relative fast disintegration, drug release profiles from Zn-pectinate beads were very much release medium-dependent. Especially, in the presence of phosphate ions, the release from Zn-pectinate beads was blocked at 20% and 40% of the total drug load when tested in phosphate buffer or simulated colonic medium. In vivo Zn-pectinate beads (t(max): 12.0 +/- 0.1h) led to a significant lag time for the theophylline absorption compared to Ca pectinate (t(max): 6.0 +/- 2.8h) or free theophylline (t(max): 2.5 +/- 2.1h). This delayed release was attributed to the formation of a zinc phosphate coating in vitro and in vivo inducing the retention of theophylline release. Zn-pectinate beads exhibit interesting properties due to its potential as pulsatile delivery system induced by the in situ formation of Zn phosphate, while Ca-pectinate was found to be of limited suitability for controlled release of theophylline. PMID- 21601629 TI - Decreased myeloperoxidase expressing cells in the aged rat brain after excitotoxic damage. AB - Brain aging is associated to several morphological and functional alterations that influence the evolution and outcome of CNS damage. Acute brain injury such as an excitotoxic insult induces initial tissue damage followed by associated inflammation and oxidative stress, partly attributed to neutrophil recruitment and the expression of oxidative enzymes such as myeloperoxidase (MPO), among others. However, to date, very few studies have focused on how age can influence neutrophil infiltration after acute brain damage. Therefore, to evaluate the age dependent pattern of neutrophil cell infiltration following an excitotoxic injury, intrastriatal injection of N-methyl-d-aspartate was performed in young and aged male Wistar rats. Animals were sacrificed at different times between 12h post-lesion (hpl) to 14 days post-lesion (dpl). Cryostat sections were processed for myeloperoxidase (MPO) immunohistochemistry, and double labeling for either neuronal cells (NeuN), astrocytes (GFAP), perivascular macrophages (ED-2), or microglia/macrophages (tomato lectin histochemistry). Our observations showed that MPO + cells were observed in the injured striatum from 12 hpl (when maximum values were found) until 7 dpl, when cell density was strongly diminished. However, at all survival times analyzed, the overall density of MPO + cells was lower in the aged versus the adult injured striatum. MPO + cells were mainly identified as neutrophils (especially at 12 hpl and 1 dpl), but it should be noted that MPO + neurons and microglia/macrophages were also found. MPO + neurons were most commonly observed at 12 hpl and reduced in the aged. MPO + microglia/macrophages were the main population expressing MPO from 3 dpl, when density was also reduced in aged subjects. These results point to neutrophil infiltration as another important factor contributing to the different responses of the adult and aged brain to damage, highlighting the need of using aged animals for the study of acute age-related brain insults. PMID- 21601630 TI - Recent advances in biotechnological production of 2-phenylethanol. AB - 2-Phenylethanol (2-PE) is an important aromatic alcohol with a rose-like fragrance. It has been widely applied in the cosmetic, perfume, and food industries and is mainly produced by chemical synthesis. An alternative method for the production of natural flavors and fragrances is the microbial transformation process, which is attracting increasing attention because it is an environmentally friendly process and the products are considered "natural". The production of 2-PE from L-phenylalanine by biotransformation is possible through the Ehrlich pathway and considerable progress has been made in the development of this process. The present report reviews recent advances in biotechnological production of 2-PE, with emphasis on the strategies used to increase production and the applications of in situ product removal techniques. Future research should focus on product scale-up and product recovery processes for the industrialization of microbial processes. PMID- 21601631 TI - Luteolin induced G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells. AB - In this study, we investigated the underlying molecular mechanism for the potent cell cycle inhibition and pro-apoptotic effect of luteolin (2-(3,4 dihydroxyphenyl)-5,7-dihydroxy-4-chromenone) on human non-small-cell lung carcinoma cell line A549. MTT assay showed that luteolin had obvious cytotoxicity on A549 with IC(50) of 40.2 MUM at 48 h. Pro-apoptotic effect of luteolin on A549 cells was demonstrated by Hoechst 33258 staining assay and annexin V-FITC/PI double staining analysis. A great quantity of apoptotic cells and increasing G2 phase cells were observed by flow cytometry. Western blotting assay revealed that luteolin activated JNK, increased Bax, promoted procaspase-9 cleavage and activated caspase-3 at last. Assay using TNFalpha, an active agent of NF-kappaB, showed that pretreatment of A549 cells with luteolin could inhibit TNFalpha induced trans-nuclear of NF-kappaB. In summary, luteolin displayed a significant cytotoxic effect through cell cycle arrest and apoptosis induction in A549 cells. Pro-apoptotic effect was implemented via activating JNK and inhibiting translocation of NF-kappaB (p65). These results suggested that luteolin might have therapeutic potential against NSCLC. PMID- 21601632 TI - Genotoxicity of the copper antineoplastic coordination complexes casiopeinas. AB - Casiopeinas is the generic name of a group of coordination complexes with a central copper atom bound to organic ligands, designed to be an alternative to cancer therapy. Indeed, some of these compounds can reduce implanted tumors in mice. Casiopeinas were expressly designed to interact with the genetic material, so the aim of the present work is to determine if these compounds have genotoxic activity. The results indicate that casiopeinas produce DNA fragmentation and base oxidation and suggest that their mode of action is related to reactive oxygen species (ROS) generation after copper reduction. PMID- 21601633 TI - Is the amphibian X. laevis WEC a good alternative method to rodent WEC teratogenicity assay? The example of the three triazole derivative fungicides Triadimefon, Tebuconazole, Cyproconazole. AB - The aim of the present work is the assessment of teratogenic effects of three triazole-derived fungicides (Triadimefon, FON, Tebuconazole, TEBU, Cyproconazole, CYPRO) on rat and Xenopus laevis embryos cultured in vitro. Rat embryos, exposed to FON 31.25-250MUM, CYPRO 31.25-62.5MUM and to TEBU 62.5-250MUM, showed specific malformations (fusions) at the level of the first and second branchial arches, with a concentration-dependent increase of severity of malformative pictures. After immunostaining, the ectomesenchyme has been identified as the target tissue. X. laevis larvae showed, at the same concentrations, specific malformations at the level of cartilaginous element derived from the first and second branchial arch ectomesenchyme. This work indicates the three tested triazoles as teratogenic both in rodents and in amphibian, inducing ectomesenchymal abnormalities, and suggests, at least for this class of molecules, the X. laevis method as adequate alternative model for teratogenic screening. PMID- 21601634 TI - Characterization and expression of a novel cystatin gene from Schistosoma japonicum. AB - Cystatins are a family of cysteine protease inhibitors that play a crucial role in the immune evasion from their host and in the adaptation to host defence. Here, we isolated a full-length cDNA sequence inferred to encode a novel cystatin gene from a blood fluke, Schistosoma japonicum. The cDNA, designated SjCystatin, comprised an open reading frame (ORF) of 306 bp, and encoded 101 amino acids with a predicted molecular weight of 11.3 kDa. This predicted protein shared a significant degree of sequence identity with the type I cystatin (stefin) of Schistosoma mansoni and Homo sapiens. These proteins exhibited a typical cystatin topology, including the absence of disulfide bonds and three conserved catalytic motifs, Gly at the N-terminus (Gly(6)), Gln-X-Val-X-Gly motif (Q(49)VVAG(53)) and an LP pair at the C-terminus (L(76)P(77)). The SjCystatin gene spanned 376 bp and contained three exons. The positions of two introns were conserved between the cystatin genes of trematodes and their vertebrate hosts. Reverse transcription polymerase chain reaction confirmed the transcription of SjCystatin in the egg, schistosomula and adult stages of S. japonicum. The encoding ORF region was cloned into pET-28a (+) prokaryotic expression vector. After purification, the recombinant protein SjCystatin (recSjCystatin), expressed in Escherichia coli, was used to immunize animals and produce its specific polyclonal antibody. Western blot analysis revealed that the native SjCystatin was expressed in the egg and adult stages. The enzyme activity assay of the recSjCystatin showed that it inhibited the proteolytic activity of papain. SjCystatin protein was mainly localized on the miracidium within eggs. Immunohistochemistry revealed that SjCystatin mainly localized in the epithelial cells lining the gut as well as the tegument on the surface of adult worms. The conserved genomic DNA structure among cystatin homologues of trematode and their vertebrate host emphasized the characteristics of compatibility between parasites and their hosts. This study provides the first insight into the gene and protein of S. japonicum cystatin and a basis for a further understanding the functions of this gene. PMID- 21601635 TI - N-hydroxyethyl-4-aza-didehydropodophyllotoxin derivatives as potential antitumor agents. AB - Three different series of N-hydroxyethyl aza-podophyllotoxin derivatives containing (i) a five-membered methylenedioxy ring (7a-f), (ii) a five-membered ring with no heteroatom (8a-f) or (iii) a six membered ethylenedioxy ring (9a-f) as ring A were synthesized using a convenient one-pot multi-component reaction. Further variation on ring E was done by decorating it with methoxy and hydroxy groups at different positions. Calculation of logP values of these compounds indicates them to be better soluble than corresponding non-hydroxy derivatives. These novel aza-podophyllotoxin derivatives were screened for their cytostatic and cytotoxic activities on National Cancer Institute's 60 human tumor cell lines to study the structure activity relationship. The overall anticancer activity of these compounds was in the order of 8a-f>9a-f>7a-f. Furthermore, the compounds having 3'-methoxy and 3',4',5'-trimethoxy substitution at ring E were the most active within the series. The cytotoxicity of all the active compounds was low, while their antiproliferative (or cytostatic) activity was high, providing a wide therapeutic window for their potential application as anticancer drugs. PMID- 21601636 TI - Reduced postsynaptic GABAA receptor number and enhanced gaboxadol induced change in holding currents in Purkinje cells of the dystrophin-deficient mdx mouse. AB - Duchenne muscular dystrophy (DMD) is caused by the absence of a functional transcript of the protein dystrophin. DMD is associated with a range of cognitive deficits that are thought to result from a lack of the protein dystrophin in brain structures involved in cognitive functions. The CNS involvement extends to an impairment of cognitive abilities, with many DMD boys having significant reduction in IQ. In the cerebellum, dystrophin is normally localized at the postsynaptic membrane of GABAergic synapses on Purkinje cells. Here, we investigate the effect of an absence of dystrophin on the number of GABA(A) channels located at the synapse in cerebellar Purkinje cells of the dystrophin deficient mdx mouse. Whole-cell patch-clamp recordings of spontaneous miniature inhibitory postsynaptic currents (mIPSCs) were performed in cerebellar slices from mdx and littermate control mice. Our results showed that the number of receptors at GABAergic synapses in the cerebellar Purkinje cell was significantly reduced in mdx mice (38.38 +/- 2.95) compared to littermate controls (53.03 +/- 4.11). Furthermore, when gaboxadol was added to the bath, the change in holding current in mdx mice was significantly enhanced (65.01 +/- 5.89pA) compared to littermate controls (37.36 +/- 3.82pA). The single channel unitary conductance and the rise and decay time of mIPSCs were not significantly different in these two groups of mice, indicating that those GABA(A) channels located at the postsynaptic sites in the mdx mice function normally. CONCLUSION: There is a reduction in the number of functional receptors localized at GABAergic synapses in the cerebellar Purkinje cells of dystrophin-deficient mdx mice and an increase in a gaboxadol induced holding current, which is evidence for an increase in extrasynaptic GABA(A) receptors in mdx mice. We hypothesize that the absence of dystrophin, from mdx Purkinje cells, reduces the number of post-synaptic GABA(A) receptors and as a result there is an increase in extrasynaptic receptors. If similar changes occur in the CNS in boys with DMD, it will impact on the function of neural networks and may contribute to some of the motor, behavioral and cognitive impairment apparent in many boys with DMD. PMID- 21601637 TI - Edwardsiella tarda DnaJ is a virulence-associated molecular chaperone with immunoprotective potential. AB - Members of the DnaJ/Hsp40 family play an important role in protein homeostasis by regulating the activity of DnaK/Hsp70. In this study, we examined the activity and function of the DnaJ from Edwardsiella tarda, a serious fish pathogen that can also infect humans and birds. In silico analysis indicated that E. tarda DnaJ contains structural features, i.e. the J domain, the glycine/phenylalanine-rich region, and the zinc-finger domain, that are conserved among Type I Hsp40. Purified recombinant DnaJ was able to stimulate the ATPase activity of DnaK. Pull down assay indicated that DnaJ could interact specifically with DnaK. Mutation of the conserved HPD site in the J domain completely abolished the DnaK-stimulating effect of DnaJ. To examine the functional importance of DnaJ, a dnaJ-defective mutant was constructed. Compared to the wild type, the dnaJ mutant (i) was retarded in growth and more sensitive to H2O2-induced oxidative damage, (ii) dramatically reduced in general bacterial virulence and in blood dissemination capacity, and (iii) significantly weakened in the ability to block macrophage activation and to survive within macrophages. Furthermore, when used as a subunit vaccine, purified recombinant DnaJ induced protective immunity in Japanese flounder (Paralichthys olivaceus). Taken together, these results indicate that DnaJ plays an important role in the pathogenesis of E. tarda probably by functioning as a DnaK partner and that DnaJ, with its immunoprotective property, may be useful in the control of E. tarda infection in aquaculture. PMID- 21601638 TI - Genetic diversity in the social amoeba Dictyostelium discoideum: population differentiation and cryptic species. AB - The social amoeba Dictyostelium discoideum is a commonly used model organism for the study of social evolution, multicellularity, and cell biology. But the boundaries and structure of the species have not been explored. The lack of morphological traits to distinguish D. discoideum makes even knowing whether a given clone is D. discoideum a challenge. We address this with a phylogeny of a widespread collection of clones from a range of locations and including clones identified previously as potential cryptic species. We sequenced portions of nuclear ribosomal DNA and mitochondrial DNA, analyzing approximately 5500 and 2500 base pairs from the two regions respectively. We compared these sequences to known reference sequences for both D. discoideum and other closely related Dictyostelium species to create Bayesian and neighbor-joining phylogenetic trees representing the evolutionary relationships among the clones. We identified 51 unique D. discoideum concatenated sequences based on the combined mitochondrial and ribosomal sequence data. We also identified four unique D. citrinum concatenated sequences, three of which were previously classified as D. discoideum clones. Our analysis of the data revealed that all D. discoideum clones form a monophyletic group, but there are several well-supported subclades and pronounced genetic differentiation among locations (F(ST)=0.242, P=0.011), suggesting the presence of geographic or other barriers between populations. Our results reveal the need for further investigation into potential tropical cryptic species. PMID- 21601640 TI - Incidence and prognostic value of eosinophilia in chronic graft-versus-host disease after nonmyeloablative hematopoietic cell transplantation. AB - Data from a number of cohorts indicate that eosinophilia (Eo) could be associated with better outcomes following allogeneic hematopoietic cell transplant (HCT). However, little is known about its significance and prognostic value in chronic graft-versus-host disease (cGVHD) after nonmyeloablative (NMA) transplantation. Data were collected from 170 patients who underwent HCT using the same preparative regimen and GVHD prophylaxis. Donors were 6/6 HLA-matched siblings and stem cell source was peripheral blood. An eosinophil count of >=0.5 * 10(9)/L was defined as Eo. Patients were transplanted mainly for lymphoproliferative disorders. Median age and follow-up were 54 years and 58 months, respectively. Incidents of grade II-IV acute GVHD (aGVHD) and cGVHD were 8.2% and 81.2%. Median time from HCT to cGVHD diagnosis was 142 days. Organs involved were: mouth in 80% of patients, skin in 75%, liver in 57%, eyes in 37%, gut in 14%, lungs in 5%, others in 5%. Eo was found in 44% of patients at diagnosis of cGVHD (range: 0.5 4.4 * 10(9)/L). Median time between first appearance of Eo and diagnosis of cGVHD was 4.5 days. We found no correlation between organ involvement and Eo but a lower prevalence of Eo in cGVHD associated with thrombocytopenia (P = .023). Nevertheless, we observed no association among Eo and overall survival (OS), relapse incidence, or nonrelapse mortality (NRM) in the overall cohort, nor in subsets of patients with multiple myeloma and follicular non-Hodgkin lymphoma. Although Eo is observed frequently in cGVHD following NMA transplantation, we report no correlation beween Eo and outcome. PMID- 21601639 TI - Anti-HLA antibodies in double umbilical cord blood transplantation. AB - Recent registry data suggest that host-versus-graft alloreactions mediated by anti-donor HLA antibodies in recipients of adult allogeneic hematopoietic stem cells or single-unit umbilical cord blood (UCB) contribute to the risk of graft failure. The present study evaluated the impact of anti-HLA antibodies on engraftment and unit predominance in 126 double-UCB (dUCB) recipients. Eighteen dUCB recipients were identified with at least 1 of 2 UCB units recognized by anti HLA antibodies directed against donor-directed HLA-specific antibodies (DSAs). Overall, 9 of 12 patients who had DSAs against 1 of the 2 UCB units composing the graft and 5 of 6 patients who had DSAs against both units engrafted. The cumulative incidence of engraftment was similar in patients with and without DSAs (83% vs 78%). Thus, our data do not support a negative effect of anti-HLA antibodies on engraftment, at least in the setting of cyclosporine and mycophenolate mofetil and the conditioning regimens used at the University of Minnesota, and argue against routine screening for use in graft selection before dUCB transplantation. Further studies are needed to fully understand the value of anti-HLA antibody testing in dUCB graft selection and its impact on transplantation outcomes. PMID- 21601641 TI - Prognostic significance of FDG-PET in relapsed or refractory classical Hodgkin lymphoma treated with standard salvage chemotherapy and autologous stem cell transplantation. AB - Positron emission tomography using [(18)F]fluorodeoxyglucose (FDG-PET) has emerged as the standard response assessment tool in frontline therapy for classical Hodgkin lymphoma (cHL). The ability of FDG-PET to predict outcomes in patients with relapsed cHL treated with modern standard salvage chemotherapy and autologous stem cell transplantation (ASCT) remains uncertain. Forty-six patients with relapsed/refractory cHL treated from 2001 to 2007 with standard salvage/ASCT therapy had FDG-PET available for blinded review. The results of pre-ASCT FDG-PET interpreted by the international harmonization project (IHP) criteria were compared with published prognostic models for prediction of event-free survival (EFS) and overall survival (OS). Overall, 3-year EFS was 62% and OS was 78%, with a median follow-up of 38 months. Pre-ASCT FDG-PET response significantly predicted 3-year EFS in FDG-PET-negative (82%) versus FDG-PET-positive (41%) patients (P = .02). A trend was observed for 3-year OS comparing FDG-PET-negative (91%) versus -positive (64%) patients (P = .08). Multivariate analysis demonstrated the independent prognostic significance of pre-ASCT FDG-PET for EFS with a hazard ratio (HR) of 3.2 (confidence interval [CI] 1.1-9.0, P = .03). Pre ASCT FDG-PET scans predict EFS in patients with relapsed cHL patients treated with modern salvage/ASCT therapy and warrant prospective evaluation. PMID- 21601642 TI - Fludarabine, antithymocyte globulin, and very low-dose busulfan for reduced intensity conditioning before allogeneic stem cell transplantation in patients with lymphoid malignancies. AB - This retrospective report compared the results of a reduced-intensity conditioning (RIC) regimen including fludarabine (Flu), and very low-dose oral busulfan (BU) (4 mg/kg total dose) in combination with antithymocyte globulin (ATG) (Flu/ATG/BU) to the classical Flu and low-dose total body irradiation (TBI) (2 Gy) regimen (Flu/TBI) in patients with lymphoid malignancies. With a median follow-up of 42 months, the cumulative incidence of transplant-related mortality (TRM) was 22% in the Flu/ATG/BU group versus 41% in the Flu/TBI group (P = .09). Grade 3-4 acute graft-versus-host disease (aGVHD) and extensive chronic GVHD (cGVHD) incidents were 15% versus 44% (P = .006), and 12% versus 58% (P = .0003), in the Flu/ATG/BU group versus the Flu/TBI group, respectively. The Kaplan-Meier estimate of overall survival (OS) at 2 years was comparable between both groups (71%; 95% confidence interval [CI] 58%-86%, in the Flu/ATG/BU group vs 60%; 95% CI 44%-83%, in the Flu/TBI group, P = .20). The estimate of progression-free survival (PFS) was 63% (95% CI 50%-80%) in the Flu/ATG/BU group versus 52% (95% CI, 36%-76%) in the Flu/TBI group (P = .18), suggesting that reduced-intensity conditioning (RIC) based on Flu, very low-dose BU, and ATG has the potential to induce long-term remissions in patients with lymphoid malignancies. PMID- 21601643 TI - A 971-bp insertion in the rns gene is associated with mitochondrial hypovirulence in a strain of Cryphonectria parasitica isolated from nature. AB - In the chestnut-blight fungus Cryphonectria parasitica, cytoplasmically transmissible hypovirulence phenotypes frequently are elicited by double-stranded RNA (dsRNA) virus infections. However, some strains manifest cytoplasmically transmissible hypovirulence traits without containing any mycovirus. In this study, we describe an altered form of mtDNA that is associated with hypovirulence and senescence in a virus-free strain of C. parasitica, KFC9, which was obtained from nature and has an elevated level of cyanide-resistant respiration. In this strain, a 971-bp DNA element, named InC9, has been inserted into the first exon of the mitochondrial small-subunit ribosomal RNA (rns) gene. Sequence analysis indicates that InC9 is a type A1 group II intron that lacks a maturase-encoding ORF. RT-PCR analyses showed that the InC9 sequence is spliced inefficiently from the rRNA precursor. The KFC9 strain had very low amounts of mitochondrial ribosomes relative to virulent strains, thus most likely is deficient in mitochondrial protein synthesis and lacks at least some of the components of the cyanide-sensitive, cytochrome-mediated respiratory pathway. The attenuated virulence trait and the splicing-defective intron are transferred asexually and concordantly by hyphal contact from hypovirulent donor strains to virulent recipients, confirming that InC9 causes hypovirulence. PMID- 21601644 TI - Analysis of the Fusarium graminearum species complex from wheat, barley and maize in South Africa provides evidence of species-specific differences in host preference. AB - Species identity and trichothecene toxin potential of 560 members of the Fusarium graminearum species complex (FGSC) collected from diseased wheat, barley and maize in South Africa was determined using a microsphere-based multilocus genotyping assay. Although three trichothecene types (3-ADON, 15-ADON and NIV) were represented among these isolates, strains with the 15-ADON type predominated on all three hosts. A significant difference, however, was identified in the composition of FGSC pathogens associated with Gibberella ear rot (GER) of maize as compared to Fusarium head blight (FHB) of wheat or barley (P<0.001). F. graminearum accounted for more than 85% of the FGSC isolates associated with FHB of wheat and barley (N=425), and was also the dominant species among isolates from maize roots (N=35). However, with the exception of a single isolate identified as an interspecific hybrid between Fusariumboothii and F. graminearum, GER of maize (N=100) was exclusively associated with F. boothii. The predominance of F. graminearum among FHB isolates, and the near exclusivity of F. boothii among GER isolates, was observed across all cultivars, collection dates, and provinces sampled. Because these results suggest a difference in host preference among species of the FGSC, we hypothesize that F. graminearum may be less well adapted to infect maize ears than other members of the FGSC. PMID- 21601645 TI - Phr1p, a glycosylphosphatidylinsitol-anchored beta(1,3)-glucanosyltransferase critical for hyphal wall formation, localizes to the apical growth sites and septa in Candida albicans. AB - Cell wall biogenesis is a dynamic process relying on the coordinated activity of several extracellular enzymes. PHR1 is a pH-regulated gene of Candida albicans encoding a glycosylphosphatidylinositol-anchored beta(1,3)-glucanosyltransferase of family GH72 which acts as a cell wall remodelling enzyme and is crucial for morphogenesis and virulence. In order to explore the function of Phr1p, we obtained a green fluorescent protein (GFP) fusion to determine its localization. During induction of vegetative growth, Phr1p-GFP was concentrated in the plasma membrane of the growing bud, in the mother-bud neck, and in the septum. Phr1p-GFP was recovered in the detergent-resistant membranes indicating its association with the lipid rafts as the wild type Phr1p. Upon induction of hyphal growth, Phr1p-GFP highly concentrated at the apex of the germ tubes and progressively distributed along the lateral sides of the hyphae. Phr1p-GFP also labelled the hyphal septa, where it colocalized with chitin. Localization to the hyphal septa was perturbed in nocodazole-treated cells, whereas inhibition of actin polymerization hindered the apical localization. Electron Microscopy analysis of the hyphal wall ultrastructure of a PHR1 null mutant showed loss of compactness and irregular organization of the surface layer. These observations indicate that Phr1p plays a crucial role in hyphal wall formation, a highly regulated process on which morphogenesis and virulence rely. PMID- 21601646 TI - The physiological response of the Caribbean reef shark (Carcharhinus perezi) to longline capture. AB - Longline fishing is the most common elasmobranch capture method around the world, yet the physiological consequences of this technique are poorly understood. To quantify the sub-lethal effects of longline capture in the commonly exploited Caribbean reef shark (Carcharhinus perezi), 37 individuals were captured using standard, mid-water longlines. Hook timers provided hooking duration to the nearest minute. Once sharks were landed, blood samples were taken and used to measure a suite of physiological parameters. Control data were obtained by sampling an additional three unrestrained Caribbean reef sharks underwater at an established shark feeding site. The greatest level of physiological disruption occurred after 120-180min of hooking, whereas sharks exposed to minimal and maximal hook durations exhibited the least disturbed blood chemistry. Significant relationships were established between hooking duration and blood pH, pCO(2), lactate, glucose, plasma calcium and plasma potassium. Longline capture appears more benign than other methods assessed to date, causing a shift in the stress response from acute at the onset of capture to a sub-acute regime as the capture event progresses, apparently facilitating a degree of physiological recovery. Continued investigation into the physiological response of elasmobranchs to longline capture is vital for the effective management of such fisheries. PMID- 21601647 TI - cDNA cloning and bacterial expression of an endo-beta-1,4-mannanase, AkMan, from Aplysia kurodai. AB - Previously we isolated an endo-beta-1,4-mannanase (EC 3.2.1.78), AkMan, from the digestive fluid of a common sea hare Aplysia kurodai and demonstrated that this enzyme had a broad pH optimum spanning 4.0 to 7.5 and an appreciably high heat stability in this pH range (Zahura et al., Comp. Biochem. Physiol., B157, 137-148 (2010)). In the present study, we cloned the cDNA encoding AkMan and constructed a bacterial expression system for this enzyme to enrich information about the primary structure and the characteristic properties of this enzyme. cDNA fragments encoding AkMan were amplified by PCR followed by 5'- and 3'-RACE PCRs from the A. kurodai hepatopancreas cDNA using degenerated primers designed on the basis of partial amino-acid sequences of AkMan. The cDNA including entire translational region of AkMan consisted of 1392bp and encoded 369 amino-acid residues. The N-terminal region of 17 residues of the deduced sequence except for the initiation Met was regarded as the signal peptide of AkMan and the mature enzyme region was considered to comprise 351 residues with a calculated molecular mass of 39961.96Da. Comparison of the primary structure of AkMan with other beta 1,4-mannanases indicated that AkMan belongs to the subfamily 10 of glycosyl hydrolase-family-5 (GHF5). Phylogenetic analysis for the GHF5 beta-1,4-mannanases indicated that AkMan together with other molluscan beta-1,4-mannanases formed an independent clade of the subfamily 10 in the phylogenetic tree. The recombinant AkMan (recAkMan) was expressed with an Escherichia coli BL21(DE3)-pCold1 expression system as an N-terminal hexahistidine-tagged protein and purified by Ni-NTA affinity chromatography. The recAkMan showed the broad pH optimum in acidic pH range as did native AkMan; however, heat stability of recAkMan was considerably lower than that of native enzyme. This may indicate that the stability of AkMan is derived from an appropriate folding and/or some posttranslational modifications in Aplysia cells. PMID- 21601648 TI - Harnessing yeast subcellular compartments for the production of plant terpenoids. AB - The biologically and commercially important terpenoids are a large and diverse class of natural products that are targets of metabolic engineering. However, in the context of metabolic engineering, the otherwise well-documented spatial subcellular arrangement of metabolic enzyme complexes has been largely overlooked. To boost production of plant sesquiterpenes in yeast, we enhanced flux in the mevalonic acid pathway toward farnesyl diphosphate (FDP) accumulation, and evaluated the possibility of harnessing the mitochondria as an alternative to the cytosol for metabolic engineering. Overall, we achieved 8- and 20-fold improvement in the production of valencene and amorphadiene, respectively, in yeast co-engineered with a truncated and deregulated HMG1, mitochondrion-targeted heterologous FDP synthase and a mitochondrion-targeted sesquiterpene synthase, i.e. valencene or amorphadiene synthase. The prospect of harnessing different subcellular compartments opens new and intriguing possibilities for the metabolic engineering of pathways leading to valuable natural compounds. PMID- 21601649 TI - In vivo intra-luteal implants of prostaglandin (PG) E(1) or E(2) (PGE(1), PGE(2)) prevent luteolysis in cows. I. Luteal weight, circulating progesterone, mRNA for luteal luteinizing hormone (LH) receptor, and occupied and unoccupied luteal receptors for LH. AB - Previously, it was reported that chronic intra-uterine infusion of PGE(1) or PGE(2) every four hours inhibited luteolysis in ewes. However, estradiol-17beta or PGE(2) given intra-uterine every 8h did not inhibit luteolysis in heifers, but infusion of estradiol+PGE(2) inhibited luteolysis in heifers. The objective of this experiment was to determine whether and how intra-luteal implants containing PGE(1) or PGE(2) prevent luteolysis in Angus or Brahman cows. On day-13 post estrus, Angus cows received no intra-luteal implant and corpora lutea were retrieved or Angus and Brahman cows received intra-luteal silastic implants containing Vehicle, PGE(1), or PGE(2) and corpora lutea were retrieved on day-19. Coccygeal blood was collected daily for analysis for progesterone. Breed did not influence the effect of PGE(1) or PGE(2) on luteal mRNA for LH receptors or unoccupied or occupied luteal LH receptors did not differ (P>0.05) so the data were pooled. Luteal weights of Vehicle-treated Angus or Brahman cows from days-13 19 were lower (P<0.05) than those treated with intra-luteal implants containing PGE(1) or PGE(2). Day-13 Angus luteal weights were heavier (P<0.05) than Vehicle treated Angus cows on day-19 and luteal weights of day-13 corpora lutea were similar (P>0.05) to Angus cows on day-19 treated with intra-luteal implants containing PGE(1) or PGE(2). Profiles of circulating progesterone in Angus or Brahman cows treated with intra-luteal implants containing PGE(1) or PGE(2) differed (P<0.05) from controls, but profiles of progesterone did not differ (P>0.05) between breeds or between cows treated with intra-luteal implants containing PGE(1) or PGE(2). Intra-luteal implants containing PGE(1) or PGE(2) prevented (P<0.05) loss of luteal mRNA for LH receptors and unoccupied or occupied receptors for LH compared to controls. It is concluded that PGE(1) or PGE(2) alone delays luteolysis regardless of breed. We also conclude that either PGE(1) or PGE(2) prevented luteolysis in cows by up-regulating expression of mRNA for LH receptors and by preventing loss of unoccupied and occupied LH receptors in luteal tissue. PMID- 21601650 TI - PLK1 as an oncology target: current status and future potential. AB - The Polo-like kinases (PLKs) have been investigated as oncology targets for several years; however, only recently have potent inhibitors been described. Here, we report on progress in the clinical validation of the PLKs as antitumor drug targets as well as recent understanding gained regarding their synergistic roles in the context of other molecular defects occurring in tumors. Also relevant to the development of PLK inhibitors as therapeutics are the putative roles of other members of this family as tumor suppressors. The resulting potential drawbacks of non-isoform selective compounds are presented. As an alternative approach to achieving PLK1 specificity, we discuss prospects for developing small molecule inhibitors of the crucial regulatory and subcellular targeting domain containing the Polo-boxes. PMID- 21601651 TI - DNA demethylases: a new epigenetic frontier in drug discovery. AB - DNA methylation is one of the most extensively studied, and one of the most stable, of all epigenetic modifications. Two drugs that target DNA methyltransferase enzymes are licensed for clinical use in oncology but relatively little attention has focused on the enzymatic pathways by which DNA methylation can be reversed. Recent breakthroughs have identified at least two classes of enzymes that can achieve functional reversal. This review discusses the significance of DNA demethylation in a range of human diseases, the candidate proteins that mediate the demethylation and the opportunities and challenges in targeting these candidates to develop new therapeutics. PMID- 21601652 TI - Molecular clinical safety intelligence: a system for bridging clinically focused safety knowledge to early-stage drug discovery - the GSK experience. AB - Drug toxicity is a major cause of late-stage product attrition. During lead identification and optimization phases little information is typically available about which molecules might have safety concerns. A system was built linking chemistry, preclinical and human safety information, enabling scientists to lever safety knowledge across multiple disciplines. The system consists of a data warehouse with chemical structures and chemical and biological properties for ~80000 compounds and tools to access and analyze clinical data, toxicology, in vitro pharmacology and drug metabolism data. Tapping into this safety knowledge enables rapid clinically focused risk assessments of drug candidates. Use of this strategy adds value to the drug discovery process at GSK via efficient triage of compounds based on their potential for toxicity. PMID- 21601653 TI - Genetic and functional studies of phosphatidyl-inositol 4-kinase type IIIalpha. AB - Phosphatidylinositol 4-kinase type IIIa (PI4KIIIalpha) is one of four mammalian PI 4-kinases that catalyzes the first committed step in polyphosphoinositide synthesis. PI4KIIIalpha has been linked to regulation of ER exit sites and to the synthesis of plasma membrane phosphoinositides and recent studies have also revealed its importance in replication of the Hepatitis C virus in liver. Two isoforms of the mammalian PI4KIIIalpha have been described and annotated in GenBank: a larger, ~230kDa (isoform 2) and a shorter splice variant containing only the ~97kDa C-terminus that includes the catalytic domain (isoform 1). However, Northern analysis of human tissues and cancer cells showed only a single transcript of ~7.5kb with the exception of the proerythroleukemia line K562, which contained significantly higher level of the 7.5kb transcript along with smaller ones of 2.4, 3.5 and 4.2kb size. Bioinformatic analysis also confirmed the high copy number of PI4KIIIalpha transcript in K562 cells along with several genes located in the same region in Chr22, including two pseudogenes that cover most exons coding for isoform 1, consistent with chromosome amplification. A panel of polyclonal antibodies raised against peptides within the C-terminal half of PI4KIIIalpha failed to detect the shorter isoform 1 either in COS-7 cells or K562 cells. Moreover, expression of a cDNA encoding isoform 1 yielded a protein of ~97kDa that showed no catalytic activity and failed to rescue hepatitis C virus replication. These data draw attention to PI4KIIIalpha as one of the genes found in Chr22q11, a region affected by chromosomal instability, but do not substantiate the existence of a functionally relevant short form of PI4KIIIalpha. PMID- 21601654 TI - Wireless capsule endoscopy fragmentation in a patient with Crohn's disease. PMID- 21601655 TI - Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis. AB - Cellular microvesicles and nanovesicles (exosomes) are involved in many disease processes and have major potential as biomarkers. However, developments in this area are constrained by limitations in the technology available for their measurement. Here we report on the use of fluorescence nanoparticle tracking analysis (NTA) to rapidly size and phenotype cellular vesicles. In this system vesicles are visualized by light scattering using a light microscope. A video is taken, and the NTA software tracks the brownian motion of individual vesicles and calculates their size and total concentration. Using human placental vesicles and plasma, we have demonstrated that NTA can measure cellular vesicles as small as ~ 50 nm and is far more sensitive than conventional flow cytometry (lower limit ~ 300 nm). By combining NTA with fluorescence measurement we have demonstrated that vesicles can be labeled with specific antibody-conjugated quantum dots, allowing their phenotype to be determined. FROM THE CLINICAL EDITOR: The authors of this study utilized fluorescence nanoparticle tracking analysis (NTA) to rapidly size and phenotype cellular vesicles, demonstrating that NTA is far more sensitive than conventional flow cytometry. PMID- 21601656 TI - Expression of Crip2, a LIM-domain-only protein, in the mouse cardiovascular system under physiological and pathological conditions. AB - LIM domain-containing proteins mediate protein-protein interactions and play regulatory roles in various physiopathological processes. The mRNA of Crip2, a LIM-only gene, has been detected abundantly in developing and adult hearts but its cell-type specific expression profile has not been well characterized. In this study, we showed that Crip2 is highly expressed in the myocardium, moderately expressed in the endocardium and absent from the epicardium of the developing mouse heart. Interestingly, Crip2 expression is present in the endocardial cells that line both endocardial cushions, whereas it is markedly reduced in the cushion mesenchymes during valve leaflet formation. In the developing vascular system, Crip2 is detected in the endothelial cells of both blood and lymphatic vessels. Consistent with the expression pattern observed in embryos, Crip2 is also highly expressed in the myocardium, endocardium and coronary vascular endothelial cells of the adult heart. In the cardiomyocytes, Crip2 is colocalized with cardiac troponin T in the thin-filaments of sarcomeres. Nonetheless, experimental studies revealed that the expression level of Crip2 is not altered in the isoproterenol (ISO) induced hypertrophic heart. Moreover, Crip2 is detected in endothelial cells of the neovasculature during wound healing and tumor growth. The persistence of Crip2 expression in cardiovascular tissues implies that Crip2 might exert an important impact on the cardiovascular development, maintenance and homeostasis. PMID- 21601657 TI - Refractory disease in autoimmune diseases. AB - Refractory disease (RD) definition has different meanings but it is dynamic, according to knowledge and the availability of new drugs. It should be differentiated from severe disease and damage definitions and it must take into account duration of adequate therapy and compliance of the patient. It can be related to inadequate or inefficacious treatment or to pathogenesis. RD definition has multiple implications to clinical guidelines and to the use of off label drugs. It should not be regarded as lost cases and prospective studies, registries and clinical trials should be planned. PMID- 21601658 TI - Contributions of vascular inflammation in the brainstem for neurogenic hypertension. AB - Essential hypertension is idiopathic although it is accepted as a complex polygenic trait with underlying genetic components, which remain unknown. Our supposition is that primary hypertension involves activation of the sympathetic nervous system. One pivotal region controlling arterial pressure set point is nucleus tractus solitarii (NTS). We recently identified that pro-inflammatory molecules, such as junctional adhesion molecule-1, were over expressed in endothelial cells of the microvasculature supplying the NTS in an animal model of human hypertension (the spontaneously hypertensive rat: SHR) compared to normotensive Wistar Kyoto (WKY) rats. We have also shown endogenous leukocyte accumulation inside capillaries within the NTS of SHR but not WKY rats. Despite the inflammatory state in the NTS of SHR, transcripts of some inflammatory molecules such as chemokine (C-C motif) ligand 5 (Ccl5), and its receptors, chemokine (C-C motif) receptor 1 and 3 were down-regulated in the NTS of SHR compared to WKY rats. This may be compensatory to avoid further strong inflammatory activity. More importantly, we found that down-regulation of Ccl5 in the NTS of SHR may be pro-hypertensive since microinjection of Ccl5 into the NTS of SHR decreased arterial pressure but was less effective in WKY rats. Leukocyte accumulation of the NTS microvasculature may also induce an increase in vascular resistance and hypoperfusion within the NTS; the latter may trigger release of pro-inflammatory molecules which via paracrine signaling may affect central neural cardiovascular activity conducive to neurogenic hypertension. All told, we suggest that vascular inflammation within the brainstem contributes to neurogenic hypertension by multiple pathways. PMID- 21601659 TI - Hypoxic ventilatory response of adult rats and mice after developmental hyperoxia. AB - Chronic postnatal hyperoxia attenuates the hypoxic ventilatory response (HVR) of rats. To determine whether the ability to detect deficits in the HVR depends on the degree of hypoxia, we assessed the HVR at several levels of hypoxia in adult rats reared in 60% O(2) for the first two postnatal weeks. Hyperoxia-treated rats exhibited smaller increases in ventilation than control rats at 12% O(2) (30+/-8 vs. 53+/-4% baseline, mean+/-SEM; P=0.02) but not at 10% O(2) (83+/-11 vs. 96+/ 14% baseline; P=0.47). Interestingly, 10% O(2) was used as the test gas in the only study to assess HVR in mice exposed to developmental hyperoxia, and that study reported normal HVR (Dauger et al., Chest 123 (2003), 530-538). Therefore, we assessed the HVR at 12.5% O(2) in adult mice reared in 60% O(2) for the first two postnatal weeks. Hyperoxia-treated mice exhibited smaller increases in ventilation (28+/-7 vs. 58+/-8% baseline; P<0.01) and smaller carotid bodies than control mice. We conclude that hyperoxia impairs the HVR in both rats and mice, but this effect is most evident at moderate levels of hypoxia. PMID- 21601660 TI - Synthesis, characterization and in vitro drug release of magnetic N-benzyl-O carboxymethylchitosan nanoparticles loaded with indomethacin. AB - Magnetic N-benzyl-O-carboxymethylchitosan nanoparticles were synthesized through incorporation and in situ methods and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, and magnetization measurements. Indomethacin was incorporated into the nanoparticles via the solvent evaporation method. The indomethacin-loaded magnetic nanoparticles were characterized by the same techniques, and also by transmission electron microscopy. The nanoparticles containing the polymer showed a drug loading efficiency of between 60.8% and 74.8%, and the magnetic properties were not significantly affected by incorporation of the drug. The in vitro drug release study was carried out in simulated body fluid, pH 7.4 at 37 degrees C. The profiles showed an initial fast release, which became slower as time progressed. The percentage of drug released after 5 h was between 60% and 90%, and the best fitting mathematical model for drug release was the Korsmeyer-Peppas model, indicating a Fickian diffusion mechanism. PMID- 21601661 TI - Protective effects of COX-2 inhibitor on titanium-particle-induced inflammatory osteolysis via the down-regulation of RANK/RANKL. AB - Particle-wear-induced inflammatory osteolysis remains a major problem for the long-term success of total joint arthroplasty. Previous studies have demonstrated that cyclooxygenase-2 (COX-2) is expressed abundantly in the tissue around a failed implant. However, the role of COX-2 in the development of particle-wear induced osteoclastogenesis remains unclear. The aim of the study was to test the hypothesis that Dynastat, a COX-2 inhibitor, ameliorates particle-wear-induced inflammatory osteoclastogenesis through the down-regulation of the receptor activators of nuclear factor-kappaB (RANK) and nuclear factor-kappaB ligand (RANKL) expression in a murine osteolysis model. Titanium (Ti) particles were introduced into established air pouches in BALB/c mice, followed by the implantation of calvaria bone from syngeneic littermates. Dynastat was given to mice intraperitoneally 2 days before the introduction of Ti particles and maintained until the mice were sacrificed. Pouch tissues were collected 14 days after Ti inoculation for molecular and histological analysis. The results showed that Dynastat has more impact on Ti-particle-induced prostaglandin E(2) expression and less on the expression of interleukin-1beta and tumor necrosis factor-alpha. Dynastat inhibited Ti-particle-induced osteoclastogenesis by reducing the gene activation of RANK and RANKL, and diminishing the RANKL expression in Ti-particle-charged pouches. Dynastat markedly reduced the number of tartrate-resistant acid-phosphatase-positive cells in pouch tissues stimulated by Ti particles. In conclusion, this study provides evidence that Dynastat can markedly inhibit Ti-particle-induced osteoclastogenesis by the down-regulation of RANK/RANKL in a murine air pouch model, and is a promising therapeutic candidate for the treatment of inflammatory osteolysis induced by wear particles. PMID- 21601662 TI - Soft tissue response to titanium dioxide nanotube modified implants. AB - Titanium is widely used clinically, yet little is known regarding the effects of modifying its three-dimensional surface geometry at the nanoscale level. In this project we have explored the in vivo response in terms of nitric oxide scavenging and fibrotic capsule formation to nano-modified titanium implant surfaces. We compared titanium dioxide (TiO(2)) nanotubes with 100 nm diameters fabricated by electrochemical anodization with TiO(2) control surfaces. Significantly lower nitric oxide was observed for the nanostructured surface in solution, suggesting that nanotubes break down nitric oxide. To evaluate the soft tissue response in vivo TiO(2) nanotube and TiO(2) control implants were placed in the rat abdominal wall for 1 and 6 weeks. A reduced fibrotic capsule thickness was observed for the nanotube surfaces for both time points. Significantly lower nitric oxide activity, measured as the presence of nitrotyrosine (P<0.05), was observed on the nanotube surface after 1 week, indicating that the reactive nitrogen species interaction is of importance. The differences observed between the titanium surfaces may be due to the catalytic properties of TiO(2), which are increased by the nanotube structure. These findings may be significant for the interaction between titanium implants in soft tissue as well as bone tissue and provide a mechanism by which to improve future clinical implants. PMID- 21601663 TI - Recurrence of food bolus impaction of the oesophagus: a retrospective observational study. AB - BACKGROUND: Most cases of oesophageal food bolus impactions (FB) are one-off events, but recurrence is recognised. The aims of this study are to establish the recurrence rate of food bolus impaction and to identify features associated with recurrence. METHODS: Clinical records of all FB cases were reviewed and the following information was recorded (patient identifier, age, gender, dates of admission, history of oesophageal pathologies). Results of investigations were also recorded (contrast swallow, endoscopies, oesophageal manometry and pH studies). Cases were coded according to the most common oesophageal pathologies. RESULTS: 99 patients fulfilled inclusion criteria and consisted of 65 males and 34 females. Recurrence was noted in 9 patients who did not demonstrate any significant difference compared with cases suffering a single episode of FB in terms of age (Median 61 years IQR 49-79 years, Mann-Whitney U test 374.5, p = 0.71) or gender (recurrences in 3/34 females and 6/65 males, Pearson chi-square test 0.004, p = 0.99). 86 patients had investigations performed. Logistic regression demonstrated that hiatus hernia was the only oesophageal pathology demonstrating statistical significance in its association with FB recurrence (odds ratio 4.77 95% CI 1.15-19.82, p = 0.032). All other variables (oesophageal pathologies, age and gender of patients) were not statistically significant (p > 0.35). CONCLUSION: The rate of recurrence of FB in our study group was 9%. Hiatus hernia was the only oesophageal pathology associated with recurrence of FB. It is not possible to draw any conclusions regarding the role of hiatus hernia in the causation of recurrence of FB. PMID- 21601664 TI - There is no pimping at Harvard. AB - As I slowly close the door on this part of my career--but keeping the peephole open--I feel that the timing is perfect, that it's time for a new generation to have their influence. PMID- 21601665 TI - Other nonstress influences can alter salivary alpha-amylase activity. AB - Clearly, more research is required to fully evaluate the impact of stress on both fertile and infertile women, and discovery of a biomarker that correlates well with psychosocial stress would be a great advantage to researchers. This article is a first step toward that goal, but it may be premature to assign these findings to stress alone. PMID- 21601666 TI - Ethical application of Shared Risk programs in assisted reproductive technology. AB - Shared Risk programs require adherence to core principles: transparency, patient autonomy, and appropriate medical care. These programs improve utilization of and perseverance with fertility treatment, receiving strong patient endorsements. PMID- 21601667 TI - Heterotopic pregnancy in a cross border oocyte donation patient: the importance of cooperation between centers. AB - OBJECTIVE: To report a case of tubal heterotopic pregnancy after oocyte donation in a cross border patient. DESIGN: Case report. SETTING: Private University Clinic, Spain, and Public University Hospital, Italy. PATIENT(S): A woman with a tubal heterotopic pregnancy after oocyte donation. INTERVENTION(S): Oocyte donation and ET (Spain), laparoscopic removal of the tubal heterotopic pregnancy (Italy). MAIN OUTCOME MEASURE(S): Diagnosis and treatment of the heterotopic pregnancy. RESULT(S): Laparoscopic treatment of the heterotopic pregnancy resulting in a single ongoing intrauterine pregnancy. CONCLUSION(S): Cross border reproductive care is increasing in Europe. When patients go back to their respective countries of origin they may not inform their doctors about having undergone fertility treatments abroad. This can lead to a delayed diagnosis in case of complications arising after treatment or during pregnancy. It is of vital importance that clinicians are aware of this possibility to speed up the diagnosis and treatment of potentially fatal situations such as the one described in the present case report. PMID- 21601669 TI - [From the Editorial board]. PMID- 21601668 TI - Middle cerebral artery thrombosis after IVF and ovarian hyperstimulation: a case report. AB - OBJECTIVE: To report a rare case of left middle cerebral artery thrombosis in a patient after controlled ovarian hyperstimulation and IVF. DESIGN: Case report. SETTING: University-affiliated teaching hospital. PATIENT(S): A 30-year-old woman who had undergone in vitro fertilization and subsequently developed left middle cerebral artery thrombosis. INTERVENTION(S): Ovulation induction with gonadotropins, IVF-ET, sodium ozagrel injection, and mannitol and albumin administration. MAIN OUTCOME MEASURE(S): Outcome of treatment. RESULT(S): The patient survived with some neurologic sequelae. CONCLUSION(S): Prevention of ovarian hyperstimulation syndrome is key to reducing incidence of thrombosis. Be aware of any neurologic symptoms after IVF-ET. Immediate and correct therapy should be given after thrombosis is suspected. PMID- 21601671 TI - DNA-binding specificity prediction with FoldX. AB - With the advent of Synthetic Biology, a field between basic science and applied engineering, new computational tools are needed to help scientists reach their goal, their design, optimizing resources. In this chapter, we present a simple and powerful method to either know the DNA specificity of a wild-type protein or design new specificities by using the protein design algorithm FoldX. The only basic requirement is having a good resolution structure of the complex. Protein DNA interaction design may aid the development of new parts designed to be orthogonal, decoupled, and precise in its target. Further, it could help to fine tune the systems in terms of specificity, discrimination, and binding constants. In the age of newly developed devices and invented systems, computer-aided engineering promises to be an invaluable tool. PMID- 21601672 TI - The ribosome binding site calculator. AB - The Ribosome Binding Site (RBS) Calculator is a design method for predicting and controlling translation initiation and protein expression in bacteria. The method can predict the rate of translation initiation for every start codon in an mRNA transcript. The method may also optimize a synthetic RBS sequence to achieve a targeted translation initiation rate. Using the RBS Calculator, a protein coding sequence's translation rate may be rationally controlled across a 100,000+ fold range. We begin by providing an overview of the potential biotechnology applications of the RBS Calculator, including the optimization of synthetic metabolic pathways and genetic circuits. We then detail the definitions, methodologies, and algorithms behind the RBS Calculator's thermodynamic model and optimization method. Finally, we outline a protocol for precisely measuring steady-state fluorescent protein expression levels. These methods and protocols provide a clear explanation of the RBS Calculator and its uses. PMID- 21601673 TI - Designing genes for successful protein expression. AB - DNA sequences are now far more readily available in silico than as physical DNA. De novo gene synthesis is an increasingly cost-effective method for building genetic constructs, and effectively removes the constraint of basing constructs on extant sequences. This allows scientists and engineers to experimentally test their hypotheses relating sequence to function. Molecular biologists, and now synthetic biologists, are characterizing and cataloging genetic elements with specific functions, aiming to combine them to perform complex functions. However, the most common purpose of synthetic genes is for the expression of an encoded protein. The huge number of different proteins makes it impossible to characterize and catalog each functional gene. Instead, it is necessary to abstract design principles from experimental data: data that can be generated by making predictions followed by synthesizing sequences to test those predictions. Because of the degeneracy of the genetic code, design of gene sequences to encode proteins is a high-dimensional problem, so there is no single simple formula to guarantee success. Nevertheless, there are several straightforward steps that can be taken to greatly increase the probability that a designed sequence will result in expression of the encoded protein. In this chapter, we discuss gene sequence parameters that are important for protein expression. We also describe algorithms for optimizing these parameters, and troubleshooting procedures that can be helpful when initial attempts fail. Finally, we show how many of these methods can be accomplished using the synthetic biology software tool Gene Designer. PMID- 21601674 TI - Application of metabolic flux analysis in metabolic engineering. AB - Metabolic flux analysis (MFA) is an important analytical technique to quantify intracellular metabolic fluxes as a consequence of all catalytic and transcriptional interactions. In systems metabolic engineering, MFA has played important role to understand cellular physiology under particular conditions and predict its metabolic capability after genetic or environmental perturbations. Two methods using optimization procedure, 13C-based flux analysis and constraints based flux analysis, have been used generally on the basis of stoichiometry of metabolic reactions and mass balances around intracellular metabolites under pseudo-steady state assumption. Practically, MFA has been applied to generate new knowledge on the biological system, analyze cellular physiology system-wide, and consequently design metabolic engineering strategies at a systems-level. In this chapter, we study the basic principle of MFA (more particularly constraints-based flux analysis), inspect the characteristics of several in silico algorithms developed for system-wide analysis of cellular metabolic fluxes, and discuss their applications. PMID- 21601675 TI - Developer's and user's guide to Clotho v2.0 A software platform for the creation of synthetic biological systems. AB - To design the complex systems that synthetic biologists propose to create, software tools must be developed. Critical to success is the enablement of collaboration across our community such that individual tools that perform specific tasks combine with other tools to provide multiplicative benefits. This will require standardization of the form of the data that exists within the field (Parts, Strains, measurements, etc.), a software environment that enables communication between tools, and a sharing mechanism for distributing the tools. Additionally, this data model must describe the data in a sufficiently rigorous and validated form such that meaningful layers of abstraction can be built upon the base. Herein, we describe a software platform called "Clotho" which provides such a data model, and the plugin and sharing mechanisms needed for a rich tool environment. This document provides a tutorial for users of Clotho and information for software developers who wish to contribute new tools (known as "Apps") to it. PMID- 21601677 TI - The Eugene language for synthetic biology. AB - Synthetic biological systems are currently created by an ad hoc, iterative process of design, simulation, and assembly. These systems would greatly benefit from the introduction of a more formalized and rigorous specification of the desired system components as well as constraints on their composition. In order to do so, the creation of robust and efficient design flows and tools is imperative. We present a human readable language (Eugene) which allows for both the specification of synthetic biological designs based on biological parts as well as providing a very expressive constraint system to drive the creation of composite devices from collection of parts. This chapter provides an overview of the language primitives as well as instructions on installation and use of Eugene v0.03b. PMID- 21601676 TI - SynBioSS-aided design of synthetic biological constructs. AB - We present walkthrough examples of using SynBioSS to design, model, and simulate synthetic gene regulatory networks. SynBioSS stands for Synthetic Biology Software Suite, a platform that is publicly available with Open Licenses at www.synbioss.org. An important aim of computational synthetic biology is the development of a mathematical modeling formalism that is applicable to a wide variety of simple synthetic biological constructs. SynBioSS-based modeling of biomolecular ensembles that interact away from the thermodynamic limit and not necessarily at steady state affords for a theoretical framework that is generally applicable to known synthetic biological systems, such as bistable switches, AND gates, and oscillators. Here, we discuss how SynBioSS creates links between DNA sequences and targeted dynamic phenotypes of these simple systems. PMID- 21601678 TI - A step-by-step introduction to rule-based design of synthetic genetic constructs using GenoCAD. AB - GenoCAD is an open source web-based system that provides a streamlined, rule driven process for designing genetic sequences. GenoCAD provides a graphical interface that allows users to design sequences consistent with formalized design strategies specific to a domain, organization, or project. Design strategies include limited sets of user-defined parts and rules indicating how these parts are to be combined in genetic constructs. In addition to reducing design time to minutes, GenoCAD improves the quality and reliability of the finished sequence by ensuring that the designs follow established rules of sequence construction. GenoCAD.org is a publicly available instance of GenoCAD that can be found at www.genocad.org. The source code and latest build are available from SourceForge to allow advanced users to install and customize GenoCAD for their unique needs. This chapter focuses primarily on how the GenoCAD tools can be used to organize genetic parts into customized personal libraries, then how these libraries can be used to design sequences. In addition, GenoCAD's parts management system and search capabilities are described in detail. Instructions are provided for installing a local instance of GenoCAD on a server. Some of the future enhancements of this rapidly evolving suite of applications are briefly described. PMID- 21601679 TI - Methods for open innovation on a genome-design platform associating scientific, commercial, and educational communities in synthetic biology. AB - Synthetic biology requires both engineering efficiency and compliance with safety guidelines and ethics. Focusing on the rational construction of biological systems based on engineering principles, synthetic biology depends on a genome design platform to explore the combinations of multiple biological components or BIO bricks for quickly producing innovative devices. This chapter explains the differences among various platform models and details a methodology for promoting open innovation within the scope of the statutory exemption of patent laws. The detailed platform adopts a centralized evaluation model (CEM), computer-aided design (CAD) bricks, and a freemium model. It is also important for the platform to support the legal aspects of copyrights as well as patent and safety guidelines because intellectual work including DNA sequences designed rationally by human intelligence is basically copyrightable. An informational platform with high traceability, transparency, auditability, and security is required for copyright proof, safety compliance, and incentive management for open innovation in synthetic biology. GenoCon, which we have organized and explained here, is a competition-styled, open-innovation method involving worldwide participants from scientific, commercial, and educational communities that aims to improve the designs of genomic sequences that confer a desired function on an organism. Using only a Web browser, a participating contributor proposes a design expressed with CAD bricks that generate a relevant DNA sequence, which is then experimentally and intensively evaluated by the GenoCon organizers. The CAD bricks that comprise programs and databases as a Semantic Web are developed, executed, shared, reused, and well stocked on the secure Semantic Web platform called the Scientists' Networking System or SciNetS/SciNeS, based on which a CEM research center for synthetic biology and open innovation should be established. PMID- 21601680 TI - Recursive construction and error correction of DNA molecules and libraries from synthetic and natural DNA. AB - Making error-free, custom DNA assemblies from potentially faulty building blocks is a fundamental challenge in synthetic biology. Here, we show how recursion can be used to address this challenge using a recursive procedure that constructs error-free DNA molecules and their libraries from error-prone synthetic oligonucleotides and naturally existing DNA. Specifically, we describe how divide and conquer (D&C), the quintessential recursive problem-solving technique, is applied in silico to divide target DNA sequences into overlapping, albeit error prone, oligonucleotides, and how recursive construction is applied in vitro to combine them to form error-prone DNA molecules. To correct DNA sequence errors, error-free fragments of these molecules are then identified, extracted, and used as new, typically longer and more accurate, inputs to another iteration of the recursive construction procedure; the entire process repeats until an error-free target molecule is formed. The method allows combining synthetic and natural DNA fragments into error-free designer DNA libraries, thus providing a foundation for the design and construction of complex synthetic DNA assemblies. PMID- 21601681 TI - Industrial scale gene synthesis. AB - The most recent developments in the area of deep DNA sequencing and downstream quantitative and functional analysis are rapidly adding a new dimension to understanding biochemical pathways and metabolic interdependencies. These increasing insights pave the way to designing new strategies that address public needs, including environmental applications and therapeutic inventions, or novel cell factories for sustainable and reconcilable energy or chemicals sources. Adding yet another level is building upon nonnaturally occurring networks and pathways. Recent developments in synthetic biology have created economic and reliable options for designing and synthesizing genes, operons, and eventually complete genomes. Meanwhile, high-throughput design and synthesis of extremely comprehensive DNA sequences have evolved into an enabling technology already indispensable in various life science sectors today. Here, we describe the industrial perspective of modern gene synthesis and its relationship with synthetic biology. Gene synthesis contributed significantly to the emergence of synthetic biology by not only providing the genetic material in high quality and quantity but also enabling its assembly, according to engineering design principles, in a standardized format. Synthetic biology on the other hand, added the need for assembling complex circuits and large complexes, thus fostering the development of appropriate methods and expanding the scope of applications. Synthetic biology has also stimulated interdisciplinary collaboration as well as integration of the broader public by addressing socioeconomic, philosophical, ethical, political, and legal opportunities and concerns. The demand-driven technological achievements of gene synthesis and the implemented processes are exemplified by an industrial setting of large-scale gene synthesis, describing production from order to delivery. PMID- 21601682 TI - Gene synthesis: methods and applications. AB - DNA synthesis techniques and technologies are quickly becoming a cornerstone of modern molecular biology and play a pivotal role in the field of synthetic biology. The ability to synthesize whole genes, novel genetic pathways, and even entire genomes is no longer the dream it was 30 years ago. Using little more than a thermocycler, commercially synthesized oligonucleotides, and DNA polymerases, a standard molecular biology laboratory can synthesize several kilobase pairs of synthetic DNA in a week using existing techniques. Herein, we review the techniques used in the generation of synthetic DNA, from the chemical synthesis of oligonucleotides to their assembly into long, custom sequences. Software and websites to facilitate the execution of these approaches are explored, and applications of DNA synthesis techniques to gene expression and synthetic biology are discussed. Finally, an example of automated gene synthesis from our own laboratory is provided. PMID- 21601683 TI - Assembly of BioBrick standard biological parts using three antibiotic assembly. AB - An underlying goal of synthetic biology is to make the process of engineering biological systems easier and more reliable. In support of this goal, we developed BioBrick assembly standard 10 to enable the construction of systems from standardized genetic parts. The BioBrick standard underpins the distributed efforts by the synthetic biology research community to develop a collection of more than 6000 standard genetic parts available from the Registry of Standard Biological Parts. Here, we describe the three antibiotic assembly method for physical composition of BioBrick parts and provide step-by-step protocols. The method relies on a combination of positive and negative selection to eliminate time- and labor-intensive steps such as column cleanup and agarose gel purification of DNA during part assembly. PMID- 21601684 TI - Genetic assembly tools for synthetic biology. AB - With the completion of myriad genome sequencing projects, genetic bioengineering has expanded into many applications including the integrated analysis of complex pathways, the construction of new biological parts and the redesign of existing, natural biological systems. All these areas require the precise and concerted assembly of multiple DNA fragments of various sizes, including chromosomes, and the fine-tuning of gene expression levels and protein activity. Current commercial cloning products are not robust enough to support the assembly of very large or very small genetic elements or a combination of both. In addition, current strategies are not flexible enough to allow further modifications to the original design without having to undergo complicated cloning strategies. Here, we present a set of protocols that allow the seamless, simultaneous, flexible, and highly efficient assembly of genetic material, designed for a wide size dynamic range (10s to 100,000s base pairs). The assembly can be performed either in vitro or within the living cells and the DNA fragments may or may not share homology at their ends. A novel site-directed mutagenesis approach enhanced by in vitro recombineering is also presented. PMID- 21601685 TI - Enzymatic assembly of overlapping DNA fragments. AB - Three methods for assembling multiple, overlapping DNA molecules are described. Each method shares the same basic approach: (i) an exonuclease removes nucleotides from the ends of double-stranded (ds) DNA molecules, exposing complementary single-stranded (ss) DNA overhangs that are specifically annealed; (ii) the ssDNA gaps of the joined molecules are filled in by DNA polymerase, and the nicks are covalently sealed by DNA ligase. The first method employs the 3' exonuclease activity of T4 DNA polymerase (T4 pol), Taq DNA polymerase (Taq pol), and Taq DNA ligase (Taq lig) in a two-step thermocycled reaction. The second method uses 3'-exonuclease III (ExoIII), antibody-bound Taq pol, and Taq lig in a one-step thermocycled reaction. The third method employs 5'-T5 exonuclease, Phusion(r) DNA polymerase, and Taq lig in a one-step isothermal reaction and can be used to assemble both ssDNA and dsDNA. These assembly methods can be used to seamlessly construct synthetic and natural genes, genetic pathways, and entire genomes and could be very useful for molecular engineering tools. PMID- 21601686 TI - Automated assembly of standard biological parts. AB - The primary bottleneck in synthetic biology research today is the construction of physical DNAs, a process that is often expensive, time-consuming, and riddled with cloning difficulties associated with the uniqueness of each DNA sequence. We have developed a series of biological and computational tools that lower existing barriers to automation and scaling to enable affordable, fast, and accurate construction of large DNA sets. Here we provide detailed protocols for high throughput, automated assembly of BglBrick standard biological parts using iterative 2ab reactions. We have implemented these protocols on a minimal hardware platform consisting of a Biomek 3000 liquid handling robot, a benchtop centrifuge and a plate thermocycler, with additional support from a software tool called AssemblyManager. This methodology enables parallel assembly of several hundred large error-free DNAs with a 96+% success rate. PMID- 21601687 TI - MEGAWHOP cloning: a method of creating random mutagenesis libraries via megaprimer PCR of whole plasmids. AB - MEGAWHOP allows for the cloning of DNA fragments into a vector and is used for conventional restriction digestion/ligation-based procedures. In MEGAWHOP, the DNA fragment to be cloned is used as a set of complementary primers that replace a homologous region in a template vector through whole-plasmid PCR. After synthesis of a nicked circular plasmid, the mixture is treated with DpnI, a dam methylated DNA-specific restriction enzyme, to digest the template plasmid. The DpnI-treated mixture is then introduced into competent Escherichia coli cells to yield plasmids carrying replaced insert fragments. Plasmids produced by the MEGAWHOP method are virtually free of contamination by species without any inserts or with multiple inserts, and also the parent. Because the fragment is usually long enough to not interfere with hybridization to the template, various types of fragments can be used with mutations at any site (either known or unknown, random, or specific). By using fragments having homologous sequences at the ends (e.g., adaptor sequence), MEGAWHOP can also be used to recombine nonhomologous sequences mediated by the adaptors, allowing rapid creation of novel constructs and chimeric genes. PMID- 21601688 TI - Multiplexed genome engineering and genotyping methods applications for synthetic biology and metabolic engineering. AB - Engineering at the scale of whole genomes requires fundamentally new molecular biology tools. Recent advances in recombineering using synthetic oligonucleotides enable the rapid generation of mutants at high efficiency and specificity and can be implemented at the genome scale. With these techniques, libraries of mutants can be generated, from which individuals with functionally useful phenotypes can be isolated. Furthermore, populations of cells can be evolved in situ by directed evolution using complex pools of oligonucleotides. Here, we discuss ways to utilize these multiplexed genome engineering methods, with special emphasis on experimental design and implementation. PMID- 21601689 TI - Construction and manipulation of giant DNA by a genome vector. AB - Since the entire sequence of a number of genome came into determination, current studies are gradually focusing on unveiling global networks of gene products, RNA, protein, and metabolites that support real-life activities. Our understanding of whole gene networks will be brought about by use of not only a few recombinant genes but also more number of genes at a time, or the genome. Genomes should be likely handled freely; however, there exist certain barriers in handling between genes and genomes. They are intrinsic fragility of giant DNA in test tube and the size limit of conventional cloning vector systems relying on prevailing cloning host Escherichia coli. A eubacterium, Bacillus subtilis has been offered as a replacement for particular large DNA or genomes, relying on inherent ability to take up DNA given outside and integrate it into its own genome via homologous recombination. The Bacillus GenoMe (BGM) vector derived from the 4,200-kbp genome of B. subtilis 168 has been demonstrated to accommodate fairly large DNAs and is highlighted by the successful stable cloning of a whole 3,500-kbp genome of the nonpathogenic, unicellular photosynthetic bacterium Synechocystis and any sequence-known DNAs. In the chapter, highlighted are clear differences in cloning concept and actual manipulation from other conventional ones, focusing methodological aspects as plainly as possible. We may also indicate that B. subtilis provides other opportunities for assembly of a large number of DNA fragments, in unbelievably high efficiency. The new workhorse described here exhibits technical breakthroughs leading to the new concept for designing the desired genomes even from scratch. The novel system not only offers unprecedented opportunities for addressing important contemporary issues in biotechnology, but also gives rise to new ideas of thinking among versatile field of biology. PMID- 21601690 TI - Mapping E. coli RNA polymerase and associated transcription factors and identifying promoters genome-wide. AB - The ability to examine gene regulation in living cells has been greatly enabled by the development of chromatin immunoprecipitation (ChIP) methodology. ChIP captures a snapshot of protein-DNA interactions in vivo and has been used to study interactions in bacteria, yeast, and mammalian cell culture. ChIP conditions vary depending upon the organism and the nature of the DNA-binding proteins under study. Here, we describe a customized ChIP protocol to examine the genome-wide distribution of a mobile DNA-binding enzyme, Escherichia coli RNA Polymerase (RNAP) as well as the factors that dynamically associate with RNAP during different stages of transcription. We describe new data analysis methods for determining the association of a broadly distributed DNA-binding complex. Further, we describe our approach of combining small molecules and antibiotics that perturb specific cellular events with ChIP and genomic platforms to dissect mechanisms of gene regulation in vivo. The chemical genomic methods can be leveraged to map natural and cryptic promoters and transcription units, annotate genomes, and reveal coupling between different processes in regulation of genes. This approach provides the framework for engineering gene networks and controlling biological output in a desired manner. PMID- 21601691 TI - HIV treatment as prevention--it works. PMID- 21601692 TI - A top-down approach to diabetes. PMID- 21601693 TI - It happened to me: responses to the Stillbirths Series. PMID- 21601694 TI - Do we need oncology trials tailored for the elderly or frail? PMID- 21601696 TI - Paulo Buss--a leader of public health and health policy in Brazil. PMID- 21601697 TI - Sonia Fleury--promoting social inclusion for better health in Brazil. PMID- 21601698 TI - Treatment of mild persistent asthma in children. PMID- 21601699 TI - Treatment of mild persistent asthma in children. PMID- 21601700 TI - Treatment of mild persistent asthma in children. PMID- 21601702 TI - Health research--Europe's future. PMID- 21601703 TI - Lessons from the Netherlands for the health and social care bill. PMID- 21601704 TI - A deserving role for the National Center for Advancing Translational Sciences. PMID- 21601706 TI - Cholera in Haiti: please do not forget zinc. PMID- 21601707 TI - Violence against Chinese health-care workers. PMID- 21601708 TI - Joined-up thinking in reduction of cardiovascular risk. PMID- 21601709 TI - Violence against Chinese health-care workers. PMID- 21601710 TI - HIV counselling and testing in South African schools. PMID- 21601711 TI - An accidental mass. PMID- 21601712 TI - Comments on "Desvenlafaxine as a possible cause of acquired hemophilia". PMID- 21601714 TI - The impact of unemployment on utilization of psychiatric emergency services. PMID- 21601715 TI - Comments on "Hyponatremia-induced change in mood mimicking late-onset bipolar disorder". PMID- 21601716 TI - Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis of 25 years of research. AB - OBJECTIVE: A meta-analysis of over 25 years of research into the relationship between post-myocardial infarction (MI) depression and cardiac prognosis was conducted to investigate changes in this association over time and to investigate subgroup effects. METHOD: A systematic literature search was performed (Medline, Embase and PsycINFO; 1975-2011) without language restrictions. Studies investigating the impact of post-MI depression on cardiovascular outcome, defined as all-cause mortality, cardiac mortality and cardiac events within 24 months after the index MI, were identified. Depression had to be assessed within 3 months after MI using established instruments. Pooled odds ratios (ORs) were calculated using a random effects model. RESULTS: A total of 29 studies were identified, resulting in 41 comparisons. Follow-up (on average 16 months) was described for 16,889 MI patients. Post-MI depression was associated with an increased risk of all-cause mortality [(OR), 2.25; 95% confidence interval [CI], 1.73-2.93; P<.001], cardiac mortality (OR, 2.71; 95% CI, 1.68-4.36; P<.001) and cardiac events (OR, 1.59; 95% CI, 1.37-1.85; P<.001). ORs proved robust in subgroup analyses but declined over the years for cardiac events. CONCLUSIONS: Post-MI depression is associated with a 1.6- to 2.7-fold increased risk of impaired outcomes within 24 months. This association has been relatively stable over the past 25 years. PMID- 21601717 TI - Prevalence of depressive symptoms in patients with chronic obstructive pulmonary disease: a systematic review, meta-analysis and meta-regression. AB - OBJECTIVE: This meta-analysis was aimed to evaluate the differences in aggregated prevalence of depressive symptoms among people with chronic obstructive pulmonary disease (COPD) as compared to controls without COPD and to determine underlying moderators to explain potential heterogeneity of prevalence. METHODS: A meta analysis of published work was performed using the random effect model. A total of eight studies were identified. We calculated the differences in prevalence proportion of depressive symptoms in patients with COPD versus controls. Meta regression and subgroup analysis were performed to identify factors that may contribute to heterogeneity. RESULTS: The prevalence proportion of depressive symptoms was found to be significantly higher (pooled odds ratio: 2.81; 95% CI: 1.69-4.66) among 39587 individuals with COPD as compared to 39,431 controls (24.6%, 95% CI: 20.0-28.6% vs. 11.7%, 95% CI: 9-15.1%). Meta-regression was conducted to account for the heterogeneity of the prevalence proportion, but moderators like mean age, gender, mean FEV(1) and proportion of current smokers among COPD patients were nonsignificant and could not explain heterogeneity in prevalence of depressive symptoms. Subgroup analyses showed no significant differences based on different methods of assessment of depressive symptoms and countries sampled. CONCLUSION: This meta-analytical review identified higher prevalence of depressive symptoms among COPD patients, and meta-regression showed that demographic and clinical factors were not the determinants of heterogeneity in prevalence of depressive symptoms. PMID- 21601718 TI - Depressive vulnerabilities predict depression status and trajectories of depression over 1 year in persons with acute coronary syndrome. AB - OBJECTIVE: Depression is prevalent in patients hospitalized with acute coronary syndrome (ACS). We determined whether theoretical vulnerabilities for depression (interpersonal life events, reinforcing events, cognitive distortions, Type D personality) predicted depression, or depression trajectories, post hospitalization. METHODS: We followed 375 ACS patients who completed depression scales during hospital admission and at least once during three follow-up intervals over 1 year (949 observations). Questionnaires assessing vulnerabilities were completed at baseline. Logistic regression for panel/longitudinal data predicted depression status during follow-up. Latent class analysis determined depression trajectories. Multinomial logistic regression modeled the relationship between vulnerabilities and trajectories. RESULTS: Vulnerabilities predicted depression status over time in univariate and multivariate analysis, even when controlling for baseline depression. Proportions in each depression trajectory category were as follows: persistent (15%), subthreshold (37%), never depressed (48%). Vulnerabilities independently predicted each of these trajectories, with effect sizes significantly highest for the persistent depression group. CONCLUSIONS: Self-reported vulnerabilities - stressful life events, reduced reinforcing events, cognitive distortions, personality - measured during hospitalization can identify those at risk for depression post-ACS and especially those with persistent depressive episodes. Interventions should focus on these vulnerabilities. PMID- 21601719 TI - Prevalence of liver disease in veterans with bipolar disorder or schizophrenia. AB - OBJECTIVE: To assess the prevalence of three liver diseases [hepatitis C virus (HCV), nonalcoholic fatty liver disease and alcohol-induced cirrhosis] in patients (veterans) with/without schizophrenia/schizoaffective disorder and bipolar disorder. METHODS: A retrospective electronic chart review of Veterans Integrated Services Network 20 facilities from January 1, 2001 to December 21, 2006 selected patients to one of two groups: schizophrenia/schizoaffective disorder or bipolar disorder. Patients in both groups were compared with veterans in an equal-sized random sample from the same data set of veterans without psychiatric diagnoses. Logistic regression models evaluated risk for overall liver diseases as well as HCV, nonalcoholic fatty liver disease and alcoholic induced cirrhosis. RESULTS: Patients with schizophrenia (n=6521) had a higher prevalence of liver disease [22.4% versus 3.2%; odds ratio (OR)=8.73]; HCV (16.5% versus 1.9%; OR=10.21); and alcohol-related cirrhosis (1.6% versus 0.4%; OR=4.09) than matched controls. Patients with bipolar disorder (n=5319) had a higher prevalence of liver disease (21.5% versus 3.5%; OR=7.58); HCV (15.5% versus 2.1%; OR=8.60); and alcohol-related cirrhosis (1.6% versus 0.4%; OR=3.82) than matched controls. Risk factors for liver disease in patients with schizophrenia (versus matched controls) included diabetes (OR=1.29), hypertension (OR=1.27), HIV (OR=3.54), substance use disorder (SUD) (OR=2.28), alcohol use disorder (OR=3.05) and schizophrenia (OR=2.74). Risk factors for development of liver disease for patients with bipolar disorder: diabetes (OR=1.40), HIV (OR=3.66), SUD (OR=2.68), alcohol use disorder (OR=3.22) and bipolar disorder (OR=2.27). CONCLUSIONS: This study in veterans shows that the presence of mental illness and its comorbidities represents a significant risk factor for the diagnosis of liver disease, including HCV and alcohol-related cirrhosis. PMID- 21601720 TI - Multimorbidity and depression treatment. AB - OBJECTIVES: We compare treatment for depression among individuals with multiple chronic physical conditions to those with single chronic physical condition, after controlling for demographic, socioeconomic, access to care and the number of outpatient visits. METHODS: Using a cross-sectional study design, we analyzed data on 1,376 adults age above 21 years, with depression and at least one chronic physical condition in the following clusters: cardiometabolic (diabetes or heart disease or hypertension), respiratory (chronic obstructive pulmonary disease or asthma) and musculoskeletal (arthritis or osteoporosis) from the 2007 Medical Expenditure Panel Survey for depression treatment. RESULTS: Overall, 56.2% used antidepressants, 21.4% had psychotherapy and 22.5% reported no depression treatment. After adjusting for factors, there were no statistically significant differences in the likelihood of type of depression treatment. CONCLUSION: Individuals with multiple conditions are as likely as those with single condition to report treatment for depression perhaps due to increased contact with the health care system. Our findings suggest that competing demands due to multiple chronic conditions may not affect depression treatment. PMID- 21601721 TI - Prevalence and associated factors of psychological distress among Korean cancer patients. AB - OBJECTIVES: This study primarily aimed to investigate the prevalence and associated factors of psychological distress among Korean cancer patients. Its secondary objective was to classify mental illnesses among cancer patients with significant psychological distress. METHODS: We administered the Modified Distress Thermometer (MDT), Hospital Anxiety and Depression Scale (HADS), and Center for Epidemiologic Studies-Depression Scale (CES-D) to consecutive, newly diagnosed cancer patients and conducted subsequent psychiatric interviews. A multiple logistic regression produced a discriminate profile of individuals with psychological distress. RESULTS: Among 295 participants, 85 (28.8%) were identified as patients with psychological distress. Female gender [odds ratio (OR)=1.97], low educational level (OR=2.25) and low performance status (OR=4.10) were significantly associated with this condition. Among the 38 patients with psychological distress who received psychiatric assessment, the most common mental illness was adjustment disorder (n=23, 69.7%). CONCLUSION: The results of this study showed that approximately one-third of the cancer patients suffered from psychological distress. We recommend that physicians focus on the psychological status of female cancer patients with low levels of education and poor performance status. PMID- 21601722 TI - Oral health of psychiatric inpatients: a survey of central Taiwan hospitals. AB - OBJECTIVE: The objective was to investigate the status of oral health and its determinants in a group of psychiatric inpatients in central Taiwan. METHOD: A cross-sectional study of the oral health of psychiatric inpatients (n=200) in three hospitals in central Taiwan was carried out during a half-year period. Demographic data and data on oral health habits, dental visit frequency, treatment fear and dental health knowledge were collected. Oral health was determined by the Decayed/Missing/Filled Teeth (DMFT) index, Community Periodontal Index (CPI), Plaque Index and Gingival Index. RESULTS: In terms of prevalence of caries, the mean DMFT score for all patients was 14.9 +/- 8.8 (S.D.), which was significantly worse than that in the general population. The CPI showed that only 10% of patients were periodontally healthy, 9.5% had bleeding, 31% had calculus and 49.5% had periodontal pockets. Increasing age, treatment anxiety, neglect of tooth-brushing and chronic ward inpatients were predictive factors for poor periodontal health. The self-awareness of poor oral health was inadequate and the treatment needs were huge in psychiatric inpatients. CONCLUSION: The oral health of psychiatric inpatients was poor compared with the general population and was generally ignored by the patients themselves. The phenomenon is universal, occurring in both Western and Eastern countries. PMID- 21601723 TI - Quality of psychiatric care in the general hospital: referrer perceptions of an inpatient liaison psychiatry service. AB - AIMS: To explore the experience of senior staff on acute medical wards using an established inpatient liaison psychiatry service and obtain their views on clinically relevant performance measures. METHODS: Semistructured face-to-face interviews with consultants and senior nurses were taped, transcribed and analyzed manually using the framework method of analysis. RESULTS: Twenty-five referrers were interviewed. Four key themes were identified - benefits of the liaison service, potential areas of improvement, indices of service performance such as speed and quality of response and expanded substance misuse service. Respondents felt the liaison service benefited patients, staff and service delivery in the general hospital. Medical consultants wanted stepped management plans devised by consultant liaison psychiatrists. Senior nurses, who perceived themselves as frontline crisis managers, valued on-the-spot input on patient management. CONCLUSIONS: Consultants and senior nurses differed in their expectations of liaison psychiatry. Referrers valued speed of response and regarded time from referral to definitive management plan as a key performance indicator for benchmarking services. PMID- 21601724 TI - OB CARES--The Obstetric Clinics and Resources Study: providers' perceptions of addressing perinatal depression--a qualitative study. AB - OBJECTIVE: We conducted a qualitative study to understand how prenatal care providers perceive influences on their delivery of perinatal depression care. Given that depression screening protocols were in place at the clinics where we sampled providers, we hypothesized that clinic- and system-level factors such as resources, training opportunities and coordination would be dominant in influencing provider decisions. METHODS: We conducted semistructured interviews with 20 prenatal care providers from six obstetric clinics. We performed a thematic analysis, including within-case and cross-case comparisons, and built a conceptual model of provider decision making from the data. RESULTS: Although depression screening protocols were in place at our study clinics, we found that decisions to address perinatal depression were largely made at the level of the individual provider and were undefined on a clinic level, resulting in highly variable practice patterns. In addition, while providers acknowledged externally derived influences, such as logistical resources and coordination of care, they spoke of internally derived influences, including familiarity with consultants, personal engagement styles and perceptions of role identity, as more directly relevant to their decision making. CONCLUSION: Our results highlight the pivotal role of internal factors in decisions to deliver perinatal depression care. Future interventions in obstetric settings should target the intrinsic motivations of providers. PMID- 21601725 TI - Toward a more comprehensive assessment of depression remission: the Remission Evaluation and Mood Inventory Tool (REMIT). AB - OBJECTIVE: Depression remission continues to be defined in terms of resolution of the Diagnostic and Statistical Manual of Mental Disorders criteria symptoms. However, it may be useful to assess additional symptoms as part of a more complete evaluation of remission. We sought to develop an adjunct self-report measure that can be used with commonly used depression measures when assessing remission. METHODS: Secondary data analysis and expert input were used to develop candidate items that were evaluated cross-sectionally in 1003 primary care clinician-identified depressed patients from two practice-based research networks. Multivariable regression analysis, with self-assessed recovery as the dependent variable, identified five symptoms that contributed significantly beyond the Patient Health Questionnaire (PHQ)-8. Further analysis was performed in selected subsamples. RESULTS: Emotional control, contentedness, future seeming dark, ability to bounce back and happiness yielded an 11% increase in R(2) beyond 60% yielded by the PHQ-8. The summed Remission Evaluation and Mood Inventory Tool (REMIT) 5 items have a mean=9.6 (S.D.=4.5), range 0-20 and reliability of 0.86. Subsample analysis showed incremental R(2) ranging from 9% in men to 15% in African-Americans. CONCLUSION: Depression remission is a multidimensional concept that includes important nondepressive symptom dimensions. These important dimensions can be measured using a self-report instrument feasible for routine primary care. Pending longitudinal validation, REMIT5 is a promising tool for depression management. PMID- 21601726 TI - Psychiatric emergency "surge capacity" following acts of terrorism and mass violence with high media impact: what is required? AB - OBJECTIVE: Adequate preparedness for acts of terrorism and mass violence requires a thorough understanding of the postdisaster mental health needs of all exposed groups, including those watching such events from a distance. This study examined emergency psychiatric treatment-seeking patterns following media exposure to four national terrorist or mass casualty events. METHOD: An event was selected for study if (a) it precipitated local front-page headlines for >5 consecutive days and (b) emergency service psychiatrists identified it as specifically precipitating help-seeking in the study hospital. Four events qualified: the Oklahoma City bombing (1995), the Columbine High School (1999) and Wedgewood Baptist Church (1999) shootings and the terrorist attacks of September 11, 2001. Time-series analyses were used to correct for autocorrelation in visit patterns during the postdisaster week, and equivalent time periods from years before and after each event were used as control years. RESULTS: Overall, disaster week census did not differ significantly from predisaster weeks, although 3-day nonsignificant decreases in visit rate were observed following each disaster. Treatment-seeking for anxiety-related issues showed a nonsignificant increase following each disaster, which became significant in the "all disaster" model (t=5.17; P=.006). Intensity of media coverage did not impact rate of help-seeking in any analysis. CONCLUSIONS: Although these sentinel US disasters varied in scope, method, geographic proximity to the study site, perpetrator characteristics, public response, sequelae and degree of media coverage, the extent to which they impacted emergency department treatment-seeking was minimal. Geographically distant mass violence and disaster events of the type and scope studied here may require only minimal mental health "surge capacity" in the days following the event. PMID- 21601727 TI - Factors associated with referral to mental health services among suicide attempters visiting emergency centers of general hospitals in Korea: does history of suicide attempts predict referral? AB - OBJECTIVE: This study examined whether a history of past suicide attempts was a critical factor for referral to mental health services among suicide attempters visiting emergency centers of general hospitals in Korea. METHOD: In this cross sectional study, a resident of emergency medicine at each emergency center interviewed 310 suicide attempters visiting five tertiary general hospitals located in Seoul, using standardized questionnaires, during 7 months in 2007. We examined associations between suicide attempt history and referral to mental health services via multiple logistic regressions. RESULTS: Subjects' rate of referral to mental health services was 47.3%. When we controlled for participant age, time of arrival at the emergency center, psychiatric treatment history, use of alcohol, suicide attempt lethality and subjective expectation to suicide attempts, past suicide attempts did not predict referral to mental health services (odds ratio=1.74; 95% confidence interval .88-3.43). CONCLUSION: Psychiatric interventions for suicide reattempters visiting emergency centers are important for preventing suicide, but providers have not considered suicide attempt history as a critical factor for referral to mental health services. Therefore, we suggest that more effort is needed to systemize psychiatric interventions for suicide reattempters at emergency centers in Korea. PMID- 21601728 TI - Secondary mania associated with enterococcal meningitis in an elderly patient. AB - Primary mania is associated with bipolar disorder, whereas secondary mania may result from many etiologies, including metabolic, pharmacological and neurological causes. Strong evidence has shown that, in older adults, new onset mania is more likely associated with an underlying cause, suggesting that late onset mania is often secondary [Bipolar Disord. 2004;6(5):343-67]. Cryptococcal meningitis has been reported to induce secondary mania [Gen Hosp Psychiatry. 2005;27(4):301-3]. Here, we present a 75-year-old female patient who developed mania as a symptom of enterococcal meningitis. To our knowledge, this is the first report describing secondary mania in a case of enterococcal meningitis. PMID- 21601729 TI - Post-stroke mania precipitated by withdrawal of antidepressant in an elderly patient with chronic major depression. AB - Post-stroke mania is a rare neuropsychiatric complication that is observed in less than 1% cases of stroke and is less common than depression. Growing evidence suggests that it may be associated with the specific regions of the brain, preexisting subcortical atrophy, a family history of mood disorders, and chronic vascular burden. However, the development of bipolar disorder after stroke is uncommon in a patient with chronic major depression. In this report, we present the case of an elderly woman with depression and chronic vascular burden; she experienced her first episode of mania after a lacunar infarct on the right side and the withdrawal of antidepressant therapy. PMID- 21601731 TI - Neuroleptic malignant syndrome associated with bromocriptine withdrawal in Parkinson's disease--a case report. AB - A 74-year-old man had 15-year history of Parkinson's disease and received bromocriptine monotherapy for 3 years. We present the first case report of neuroleptic malignant syndrome associated with the withdrawal of bromocriptine. The symptoms were alleviated by adequate replenishment of intravenous fluid, temperature reduction and replacement of bromocriptine. Clinicians need to be aware of this potential complication and that a thorough history of current medications is crucial to its identification. PMID- 21601730 TI - A case of mania due to cryptococcal meningitis, successfully treated with adjunctive olanzapine, in a patient with acquired immunodeficiency syndrome. AB - We report on the case of a patient with acquired immune deficiency syndrome- and Cryptococcus neoformans meningitis-related mania in which olanzapine was successfully used adjunctively and transiently to antifungal therapy. PMID- 21601732 TI - Serotonin syndrome associated with polypharmacy in the elderly. AB - The increasing use of serotonergic agents, alone and in combination, across multiple disciplines, makes it likely that the prevalence of serotonin syndrome will rise. Caution should be used, especially in the elderly, to avoid unnecessary and potentially harmful polypharmacy. We describe a case of serotonin syndrome in a 79-year-old man taking mirtazapine, venlafaxine and quetiapine. As this case illustrates, serotonin syndrome can be caused by combinations of direct serotonin agonists (e.g., serotonergic antidepressants) and indirect serotonin agonists (e.g., atypical antipsychotics). PMID- 21601733 TI - Multiple intracerebral hemorrhages in an elderly patient after adding quetiapine to a stable warfarin regimen. AB - The efficacy of antipsychotics in patients with dementia exhibiting psychiatric symptoms has been overshadowed by safety concerns in recent years. Evidence suggests that the long-term use of antipsychotics in older adults is associated with a greater risk of cerebrovascular adverse events than accrues with short term use (less than 30 days) [J Clin Psychiatry. 2010;71(6):689-98]. Here, we present an elderly male patient with dementia who developed multiple intracerebral hemorrhages (ICHs) 3 days after the addition of quetiapine to his stable warfarin regimen. To our knowledge, this is the second case of possible interaction between quetiapine and warfarin. We suggest mechanisms that may account for the patient's clinical presentation and highlight that combining treatment with quetiapine and warfarin may cause serious complications in patients with risk factors for ICH. PMID- 21601734 TI - Panic-attack-induced transient leukocytosis in a healthy male: a case report. AB - The lifetime prevalence of panic attacks is 28.3% in American adults 18 years and older. The age of onset of panic attack extends throughout adulthood; however, it typically develops in early adulthood, with median age of onset of 22 years [Kessler R.C., Chiu W.T., Jin R., Ruscio A.M., Shear K., Walters E.E. The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2006 Apr;63(4):415-24.]. As reported in our case, panic attacks could induce transient leukocytosis in healthy adults. If practitioners recognize this association, expensive investigations and extensive hospital stays may be prevented, although prudent practice would likely still require some type of investigations. PMID- 21601735 TI - A case of catatonia due to posterior reversible encephalopathy syndrome treated successfully with antihypertensives and adjunctive olanzapine. AB - Catatonia is a distinct neuropsychiatric syndrome with prominent motor manifestations. Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic syndrome usually precipitated by malignant hypertension. Given the overlapping neuropathology in both syndromes, we present a case of catatonia precipitated by PRES, with full resolution of the former after successful treatment of the latter. PMID- 21601736 TI - Psychoses as the presenting manifestation of Creutzfeldt-Jakob disease in an elderly male. AB - The differential diagnosis of acute psychosis includes delirium, dementia and primary psychiatric disorders. A comprehensive medical evaluation is crucial to make the proper diagnosis. We report the case of a healthy elderly man who presents with acute psychosis. We describe our diagnostic evaluation based on the patient's history and physical examination, which identified Creutzfeldt-Jakob disease. Avoiding diagnostic error in patients who face such a rapidly progressive and catastrophic illness is paramount. PMID- 21601737 TI - Acute Charles Bonnet syndrome secondary to eye patching. AB - OBJECTIVE: The aim of this study was to report a case of Charles Bonnet syndrome secondary to eye patching following eyelid reconstruction with an unusually acute onset. METHOD: An observational case report was conducted. RESULTS: The patient reported complex visual hallucinations that started less than 10 minutes after patching of her right eye (the left eye had poor vision from previous trauma). The patch was removed after 2 days, and the hallucinations gradually stopped over the subsequent 2 days. CONCLUSION: This case of Charles Bonnet syndrome describes an unusually acute onset of hallucinations and is only the second reported case following eye patching. Eye patching is commonly used in a number of situations, and it is important to be aware of this association, as the diagnosis of Charles Bonnet syndrome is often overlooked. PMID- 21601738 TI - A case of obsessive-compulsive disorder by proxy. AB - Obsessive-compulsive disorder is a frequent psychiatric disorder with a lifetime prevalence rate of 2%-3 % (Sadock, B.J. & Kaplan, H.I. (Eds.). Kaplan and Sadock's synopsis of psychiatry: behavioral sciences/clinical psychiatry, 9th ed. Lippincott, Williams & Wilkins. 2003). Patients almost always carry out compulsions to minimize their anxiety/distress associated with the obsessions. Repeated thoughts about contamination represent one of the most common obsessions (American Psychiatric Association. Obsessive-compulsive disorder. In: Diagnostic and statistical manual of mental disorders (4th ed., text revision). Washington, DC: American Psychiatric Association; 2000). In this report, we describe an interesting case of a 58-year-old lady who substituted her husband for her to perform the compulsive behaviors. PMID- 21601739 TI - Seventh International Workshop on Reproductive Immunology, Immunological Tolerance and Immunology of Preeclampsia, Tioman Island, Malaysia. Preface. PMID- 21601740 TI - Preface: the role of the veterinarian in hospice and palliative care. PMID- 21601741 TI - In the shadow of a rainbow: the history of animal hospice. AB - This article outlines the young history of animal hospice by first focusing on the history of human hospice, with special emphasis on the last 200 years. It then examines similarities between the two, showing how human hospice has informed its animal counterpart and defined it as specialized comfort care benefiting terminally ill companion animals in their home setting as well as a unique journey wherein the caregiver understands that quality of death is as important as quality of life. The article includes a bibliography and two specialized reading lists-on human hospice and on the growing field of animal hospice. PMID- 21601743 TI - Pet hospice and palliative care protocols. AB - Starting a palliative or hospice care plan as soon as possible after a pet qualifies allows for better care of the pet and the family. The process is made more efficient by applying the 5-step strategy for comprehensive palliative and hospice care. The veterinarian and staff can immediately begin applying the philosophy of palliative and hospice care by following this protocol and be sure that no area of care is being neglected. PMID- 21601742 TI - Delivery systems of veterinary hospice and palliative care. AB - There is great flexibility in how palliative medicine and hospice care can be delivered to pet owners. The veterinarian needs to develop a plan based on the professional's individual preferences. Variations in the services that are offered, the location of where the services are delivered, and the composition of the professional team will vary with the veterinarians preferences. Marketing and legal issues must be addressed when considering to offer palliative and hospice care. An organizational worksheet is provided at the end of this article to help with planning. PMID- 21601744 TI - Quality-of-life assessment techniques for veterinarians. AB - The revised veterinary oath commits the profession to the prevention and relief of animal suffering. There is a professional obligation to properly assess quality of life (QoL) and confront the issues that ruin it, such as undiagnosed suffering. There are no clinical studies in the arena of QoL assessment at the end of life for pets. This author developed a user-friendly QoL scale to help make proper assessments and decisions along the way to the conclusion of a terminal patient's life. This article discusses decision aids and establishes commonsense techniques to assess a pet's QoL. PMID- 21601745 TI - Pain management for veterinary palliative care and hospice patients. AB - When negotiating the challenges of end-of-life care for animal patients with clients, veterinary health care providers must continually engage in ongoing evaluation of the pet's quality of life, as well as assessing the client's quality of life to ensure that the best decisions possible are made. By combining regular physical evaluations, including careful palpation to unmask pain, with open and honest dialog with the client about the pet's day-to-day reality, the partnership of pet owner and veterinary health care team can accept the challenge of anticipating, preventing, finding, and relieving pain in the veterinary palliative care and hospice patient. PMID- 21601746 TI - Assessment and treatment of nonpain conditions in life-limiting disease. AB - The "Pawspice" philosophy, which the author introduced at the 2000 American Veterinary Medical Association meeting, focuses on symptom management along with a kinder, gentler, or modified approach to standard therapy. Many veterinarians have preconceived bias or ingrained beliefs about aging, serious illness, multiple comorbidities, and cancer, which may cause a negative or dismissive approach toward palliative treatment, especially in geriatric pets. Veterinarians and their v-teams must overcome this insensitive attitude about life-limiting disease. This article describes assessment, treatment, and home management of some nonpainful life-limiting diseases, including cancer and age-related decline of vital functions in the Pawspice setting. PMID- 21601747 TI - Clinical signs and management of anxiety, sleeplessness, and cognitive dysfunction in the senior pet. AB - Physical signs of old age may be obvious, but mental and cognitive changes require more careful observation. Changes in behavior may represent the earliest indications of medical problems, or disorders of the central nervous system, and these may be bidirectional. Cognitive dysfunction syndrome is underdiagnosed and affects a substantial portion of aged companion animals. This article describes potential treatment regimens to address age-related behavioral problems, as well as a framework for investigating differential diagnoses. Early identification of changes in behavior is essential for the adequate treatment and management of medical and behavioral problems, and for monitoring outcomes. PMID- 21601748 TI - The role of physical medicine and rehabilitation for patients in palliative and hospice care. AB - Veterinary patients in palliative and hospice care have progressive and often degenerative diseases that can cause pain as well as loss of function and decreased quality of life. These patients can often benefit from the application of physical medicine and rehabilitation techniques to maximize comfort and function. Physical medicine and rehabilitation are most effective as adjuncts to pharmacologic pain management. Physical medicine and rehabilitation can decrease the doses of analgesics required to keep these patients comfortable. The blend of physical and pharmacologic medicine allows an optimum balance between maximum comfort and maximum mentation. PMID- 21601749 TI - Managing mobility challenges in palliative and hospice care patients. AB - Some pet owners may have more difficulty managing a pet's mobility challenges than any other disorder. This problem is especially frustrating because the pet is often otherwise healthy. The decline in mobility is also connected to many disease processes, such as the neuropathies seen in poorly regulated diabetes and the weakness associated with degenerative myelopathy. As death nears, a decline in mobility toward becoming recumbent or moribund is expected. The progression of the mobility disorder will vary according to the disease process. As the pet's mobility declines, the burden of care will increase. This article addresses how to care for pets with mobility changes. PMID- 21601750 TI - Comfort, hygiene, and safety in veterinary palliative care and hospice. AB - Hygiene, comfort, and safety during pet palliative care and hospice are usually straightforward. The veterinary health care team must coordinate care to ensure that the pet and the family are fully informed and engaged in the process. End-of life issues, euthanasia, and death are typically not everyday concerns for the pet owner. Pet owners and veterinary patients rely on the veterinary health care team to help create the structure within which the pet will die. The veterinary team can give the family-pet unit the gift of structure and multifaceted comfort. The veterinary profession must take seriously this unique niche of care. PMID- 21601751 TI - A veterinarian's role in helping pet owners with decision making. AB - End-of-life care frequently requires owners and veterinarians to make decisions of monumental consequences while feeling they sorely lack essential information. This feeling can be distressing to owners and veterinarians and lead to strains in their relationship. This article illustrates an approach to end-of-life decision making that offers the greatest benefit to the animal, the owner, the veterinarian, the veterinary practice, and, ultimately, the veterinary profession. The article introduces issues and concepts that underlie all companion animal end-of-life decision making-the human-animal bond, quality of life, and veterinarians' nonmedical helping roles-and discusses major end-of-life decisions. PMID- 21601752 TI - Ten tips for veterinarians dealing with terminally ill patients. AB - This article discusses tips for veterinarians dealing with terminally ill patients. These tips include veterinarians taking care of themselves physically, mentally, and spiritually and exploring beliefs about pets dying. This article also addresses veterinarians' relationships to pets and owners and their role as facilitator; studying the ethics of end-of-life-treatment; referring owners to other specialists; and taking care of staff. PMID- 21601753 TI - Euthanasia, moral stress, and chronic illness in veterinary medicine. AB - Euthanasia is a double-edged sword in veterinary medicine. It is a powerful and ultimately the most powerful tool for ending the pain and suffering. Demand for its use for client convenience is morally reprehensible and creates major moral stress for ethically conscious practitioners. But equally reprehensible and stressful to veterinarians is the failure to use it when an animal faces only misery, pain, distress, and suffering. Finding the correct path through this minefield may well be the most important ethical task facing the conscientious veterinarian. PMID- 21601754 TI - Legal concerns with providing hospice and palliative care. AB - Most veterinary hospice services are provided in the pet owner's home. Recognized standards of care have not yet been established in this emerging field. This article explores the legal implications surrounding the provision of veterinary hospice care in the United States; and provides veterinarians with the legal information necessary to determine whether and how to prepare for offering palliative and hospice care services. The legal issues that may arise in the context of veterinary hospice are largely duplicative of those that arise in the course of other types of small animal veterinary practice. PMID- 21601755 TI - A case report: veterinary palliative care and hospice for a west highland terrier with transitional cell carcinoma. AB - In providing palliative care and hospice in a veterinary outpatient primary care setting it is important to manage all aspects of the patient's needs as well as the primary disease process, and to understand that veterinary palliative care and hospice do not require a special degree or board certification. They only require compassion for the terminally ill patient and the human family members, a commitment to keeping patients united with their families for as long as they are comfortable, and a willingness to keep a comprehensive perspective on the patient's changing needs as death nears. PMID- 21601756 TI - A case report: Pawspice for a visla with splenic lymphoma. AB - This author's experience in oncology proposes "Pawspice," a new concept that offers early supportive care for pets with life-limiting disease, embracing palliative care and standard care. Pawspice offers compassionate and comprehensive symptom relief at diagnosis while addressing life-limiting diseases. The concept of Pawspice is to maintain quality of life with palliative care that improves the patient's debilitating conditions by 30% to 50%, while simultaneously administering standard care via gentle chemotherapy modified for low toxicity. This combination makes Pawspice different than palliative care (pain and symptom relief) or hospice (intense comfort care that precedes imminent death), which prevail in most conventional thinking. PMID- 21601757 TI - A case report: caring for a golden retriever with nasal cancer. AB - This article is a case report of a veterinarian caring for a golden retriever with nasal cancer. It addresses the 5-step strategy for comprehensive palliative and hospice care protocol, which organizes examinations, consultations, and conversations with clients. The case report presents diagnosis, treatment, and euthanasia. PMID- 21601759 TI - Cool flow--the microcirculation in cardiac arrest patients treated with therapeutic hypothermia. PMID- 21601760 TI - [An outstanding tool of communication for our specialty!]. PMID- 21601768 TI - Acute heart failure: lessons learned so far. AB - Acute heart failure (AHF) affects nearly every Canadian with heart failure (HF) at least once. Despite several attempts, no medical therapies have been shown to improve the natural history of AHF. In addition, the place of diagnosis of AHF is increasingly made in the outpatient setting. In this view, AHF is a moving target, and from recent registry data and from clinical trials, 5 critical lessons regarding the syndrome of AHF emerge: (1) The period of clinical instability preceding AHF may be much longer than previously thought. (2) Refinement of tools used to aid the early and accurate diagnosis of AHF will impact patient outcomes. (3) Standard supportive care of patients with AHF includes early use of diuretics with frequent reassessment in nearly all patients and supplemental vasodilators and oxygen therapy in selected cases. (4) Patients who survive presentation of AHF continue to suffer high rates of re-presentation, death, and rehospitalization following discharge from either hospital or emergency department. (5) Interventions shown to improve patient outcomes for AHF to date are related to process of care rather than new medications or devices. This report reviews the recent literature regarding the presentation, diagnosis, management, and prognosis of AHF. Areas of future research priority are indicated and guidelines for improving treatment are provided. AHF is an important clinical area that has not been as intensively studied as chronic HF; it presents both important needs and exciting opportunities for research and innovation. PMID- 21601769 TI - New and emerging drugs and device therapies for chronic heart failure in patients with systolic ventricular dysfunction. AB - Chronic heart failure remains a common end product of cardiovascular diseases and, despite significant advances in therapy, continues to be accompanied by significant morbidity and mortality. Attenuation of neurohumoral overactivation with blockers of the renin-angiotensin-aldosterone system and beta-blockers has improved outcome and helped reverse or halt disease progression in many patients; however, despite this, morbidity and mortality have remained elevated, and only marginal advances have occurred over the last few years. How best to combine these various agents continue to be tested but, apart from the addition of aldosterone receptor blockers and reduction of heart rate with ivabradine, advances have been few. Implantable defibrillators and cardiac resynchronization devices have proved to be very beneficial, and the limits of their use are presently still being tested. How best to handle atrial fibrillation in patients with heart failure remains unanswered, but for now, rate control appears to be appropriate in many patients. Surgical ventricular restoration of the left ventricle has not proved to generally be useful, and although the role of coronary artery bypass graft surgery (CABG) is well established in some patients, its use in others is being reevaluated. The use of biomarkers in patients with heart failure has stimulated great interest; however, much work remains before its full potential can be realized. As the complexity of the use of pharmacogenomics in clinical practice becomes clearer, research in the area is intensifying, but much work remains to be done before its use can be clearly outlined in patients with heart failure. PMID- 21601770 TI - Diastolic heart failure: progress, treatment challenges, and prevention. AB - Diastolic heart failure (DHF) is an important entity, the significance of which is increasingly recognized. This report examines the available evidence regarding the role, significance, and mechanisms of DHF. Epidemiologic studies have documented the rising burden of DHF, and experimental data are revealing the unique mechanisms distinguishing it from systolic heart failure. Despite controversies on the definition of DHF, or heart failure with preserved ejection fraction, standardized clinical criteria with supplementary imaging and structural data have identified DHF as a distinct pathophysiological entity. The mechanisms underlying DHF include abnormal matrix dynamics, altered myocyte cytoskeleton, and impaired active relaxation. The commonly held belief that survival of patients with DHF is better than that of patients with systolic heart failure has been challenged by updated data. The heterogeneous etiologies or risk factors for the condition include aging, diabetes, hypertension, and ischemia, making a common diagnostic or treatment pathway difficult. Novel therapeutic targets that address the pathophysiology of this disease are under consideration, although there are no proven therapies for DHF to date. Exacerbating factors include volume and sodium indiscretion, arrhythmias, ischemia, and comorbidities. Strategies to ameliorate or to obviate these precipitating factors are most effective in preventing DHF and its exacerbations. Meanwhile, prevention of DHF through appropriate and aggressive risk factor identification and management must remain the cornerstone of clinical intervention. PMID- 21601771 TI - Assessment of left ventricular diastolic function: the power, possibilities, and pitfalls of echocardiographic imaging techniques. AB - Abnormal diastolic function portends a poor prognosis regardless of any associated systolic dysfunction. There is controversy regarding the precision with which diagnosis of diastolic dysfunction can be made non-invasively. Clinical studies show that non-invasive evaluation of the severity of diastolic function predicts the risk of cardiac death and heart failure whereas invasive monitoring of intracardiac pressures is not proven to be better than clinical judgement in guiding patient management. The traditional paradigm of centreing the classification of diastolic function on transmitral and transpulmonic flow may no longer be adequate considering the availability of less volume dependent measures of diastolic function. Mitral inflow-based diastolic function assessment is traditionally graded as "normal", "abnormal relaxation", "pseudonormal", and "restrictive filling pattern". However, the transition between various levels of abnormal LV filling pressure is dynamic and related to the ambient heart rate and preload. This dynamic transition makes accurate depiction of severity using just one snapshot of imaging, or single parameters in isolation problematic. Furthermore the prognosis associated with pseudonormal and restrictive filling patterns are comparable. A better understanding of the physiology of diastole highlights the relevance of the cardiac substrate in the genesis of diastolic dysfunction. The availability of newer diagnostic tools such as tissue Doppler imaging has informed the need to assess all components of diastolic function within the context of predisposing or consequential morphological substrates. A new prognosis-centred paradigm implies that diastolic function need only be stratified into "normal", "mildly abnormal" (compensated dysfunction), or "severely abnormal" (uncompensated diastolic dysfunction) categories. PMID- 21601772 TI - The 2011 Canadian Cardiovascular Society heart failure management guidelines update: focus on sleep apnea, renal dysfunction, mechanical circulatory support, and palliative care. AB - The 2011 Canadian Cardiovascular Society Heart Failure (HF) Guidelines Focused Update reviews the recently published clinical trials that will potentially impact on management. Also reviewed is the less studied but clinically important area of sleep apnea. Finally, patients with advanced HF represent a group of patients who pose major difficulties to clinicians. Advanced HF therefore is examined from the perspectives of HF complicated by renal failure, the role of palliative care, and the role of mechanical circulatory support (MCS). All of these topics are reviewed from a perspective of practical applications. Important new studies have demonstrated in less symptomatic HF patients that cardiac resynchronization therapy will be of benefit. As well, aldosterone receptor antagonists can be used with benefit in less symptomatic HF patients. The important role of palliative care and the need to address end-of-life issues in advanced HF are emphasized. Physicians need to be aware of the possibility of sleep apnea complicating the course of HF and the role of a sleep study for the proper assessment and management of the conditon. Patients with either acute severe or chronic advanced HF with otherwise good life expectancy should be referred to a cardiac centre capable of providing MCS. Furthermore, patients awaiting heart transplantation who deteriorate or are otherwise not likely to survive until a donor organ is found should be referred for MCS. PMID- 21601773 TI - The relationship between left and right pericardial pressures in humans: an intraoperative study. AB - BACKGROUND: The purpose of this study was to show the similarity between the pericardial constraint over the right and left ventricles of humans at various levels of central venous pressure (CVP) using flat Silastic balloons in the pericardial space during elective cardiac surgery. METHODS: Six subjects (aged 19 76 years) were instrumented with flat, liquid-containing Silastic balloons in the pericardial space during elective cardiac surgery. No subject had valvular disease or right ventricular (RV) hypertrophy. These balloons were positioned to lie over the RV and left ventricular (LV) free walls to measure RV and LV pericardial pressure (P(prv) and P(plv), respectively). Volume loading was achieved by an intravenous infusion of 1 to 2 L of Ringer's lactate or normal saline. Depending on the patient's status during the operative procedure, the mean CVP was increased by 5-10 mm Hg from the baseline postinduction levels. RV and LV pericardial pressures were measured continuously throughout the volume loading. RESULTS: The pooled data from all subjects demonstrate that RV pericardial pressure is equal to LV pericardial pressure over central venous pressures ranging from 4 to 18 mm Hg and that the RV late-diastolic (pre-a-wave) cavitary pressure (P(rv)) correlates with LV pericardial pressure. CONCLUSIONS: Changes in LV pericardial pressure are approximately equal to changes in RV pericardial pressure and RV late-diastolic (pre-a-wave) cavitary pressure is a good predictor of LV pericardial pressure. PMID- 21601767 TI - Targeted gene therapy for the treatment of heart failure. AB - Chronic heart failure is one of the leading causes of morbidity and mortality in Western countries and is a major financial burden to the health care system. Pharmacologic treatment and implanting devices are the predominant therapeutic approaches. They improve survival and have offered significant improvement in patient quality of life, but they fall short of producing an authentic remedy. Cardiac gene therapy, the introduction of genetic material to the heart, offers great promise in filling this void. In-depth knowledge of the underlying mechanisms of heart failure is, obviously, a prerequisite to achieve this aim. Extensive research in the past decades, supported by numerous methodological breakthroughs, such as transgenic animal model development, has led to a better understanding of the cardiovascular diseases and, inadvertently, to the identification of several candidate genes. Of the genes that can be targeted for gene transfer, calcium cycling proteins are prominent, as abnormalities in calcium handling are key determinants of heart failure. A major impediment, however, has been the development of a safe, yet efficient, delivery system. Nonviral vectors have been used extensively in clinical trials, but they fail to produce significant gene expression. Viral vectors, especially adenoviral, on the other hand, can produce high levels of expression, at the expense of safety. Adeno-associated viral vectors have emerged in recent years as promising myocardial gene delivery vehicles. They can sustain gene expression at a therapeutic level and maintain it over extended periods of time, even for years, and, most important, without a safety risk. PMID- 21601774 TI - Successful weaning and explantation of the Heartmate II left ventricular assist device. AB - BACKGROUND: Ventricular assist devices (VADs) are used in cases of heart failure refractory to medical therapy. Most VADs are used as a bridge to heart transplantation; however, in certain cases, myocardial function recovers and VADs can be explanted after the patient is weaned. The objectives of this study were to describe patients who required Heartmate II VAD insertion, followed by myocardial recovery and explanation in a quaternary heart centre. METHODS: Patients who had a VAD explanted were identified in the mechanical support institutional database and their outcomes were analyzed. Clinical examinations, biochemical markers, and serial echocardiograms were used to demonstrate myocardial recovery. RESULTS: Seventeen patients had a Heartmate II VAD inserted between 2008 and 2010. Four patients underwent successful weaning and subsequent VAD explantation. Etiology of decompensated heart failure was idiopathic dilated cardiomyopathy (n = 1), ischemic (n = 1), or myocarditis (n = 2). Mean age was 35.3 years. Patients were supported for 213 days (range 70-293 days) and were in New York Heart Association class I in the community before explantation. The devices were explanted via a minimally invasive approach, without cardiopulmonary bypass. All patients survived explantation and were discharged alive from hospital after an average of 5.7 +/- 1.5 days post pump explantation. No adverse events were reported after explantation. Only one patient required allogenic blood transfusion after the procedure. CONCLUSIONS: Patients requiring VAD support for myocardial failure can undergo significant reverse remodelling. Explantation can lead to optimal outcome with minimal morbidity. Methods for assessment of reverse remodelling, weaning protocol, and optimal timing of explantation remain under evaluation. PMID- 21601775 TI - Wave propagation and reflection in the canine aorta: analysis using a reservoir wave approach. AB - BACKGROUND: Our objective was to demonstrate wave propagation and reflection in the canine aorta. Recently we proposed that aortic pressure is the instantaneous sum of wave-related or "excess" pressure and reservoir or windkessel pressure. Accordingly, in this research we calculated reservoir pressure and subtracted it from measured pressure to identify the change in pressure due to forward- or backward-travelling waves. METHODS: In 8 anesthetized dogs, excess pressures were calculated from pressure and flow measurements at 4 locations along the aorta; wave intensity analysis was employed to identify wavefronts and the type of waves. RESULTS: We found that forward compression and decompression waves generated by the left ventricle are reflected, first, from a negative or "open end" reflection site near the renal arteries (32.0 +/- 0.8 cm [SEM] from the aortic root) and, second, from a positive site in the femoral arteries (65.3 +/- 2.8 cm or 54.9 +/- 2.1 cm, based on 2 alternative extrapolation techniques). CONCLUSIONS: Aortic wave propagation and reflection can be demonstrated clearly and directly by wave intensity analysis after volume-related changes-changes in reservoir or windkessel pressure-in aortic pressure are accounted for. PMID- 21601777 TI - Critical left main coronary artery stenosis identified by colour Doppler screening during pre-exercise stress echocardiogram. PMID- 21601776 TI - Prevalence and treatment patterns of lower extremity peripheral arterial disease among patients at risk in ambulatory health settings. AB - BACKGROUND: Lower extremity peripheral arterial disease (PAD) is underdiagnosed and undertreated in Canada, although data are limited. We sought to measure PAD prevalence and treatment patterns in ambulatory settings. METHODS: Five trained undergraduate pharmacy students screened subjects > 50 years of age in 10 community pharmacies and 4 physician offices in northern and central Alberta. We assessed cardiovascular risk factors, cardiovascular disease (CVD), and use of evidence-based therapies; administered the Edinburgh Claudication Questionnaire; and measured the ankle-brachial index (ABI). Patients with definite claudication but ABI > 0.90, or patients with ABI > 1.30 were referred to the study vascular medicine physician for further assessment. PAD was defined as an ABI <= 0.90 at the initial community screening or an exercise ABI of <= 0.90 and 20% lower than the resting ABI, or toe-brachial index of <= 0.70. RESULTS: We recruited 361 patients (65.1 +/- 9.5 years old, 55% female, 85% white) between July 1 and November 30, 2008. Sixteen subjects had PAD (prevalence 4.4%; 95% confidence interval [CI], 2.3-6.5), and all were previously unaware that they had PAD. Nine patients (2.5%) had PAD only, 7 (1.9%) had both PAD and CVD, 87 (24%) had CVD only, and 259 (72%) had neither PAD nor CVD. Use of antiplatelet agents (44%), angiotensin blockade (56%), or statins (44%) was low in patients with newly diagnosed PAD and without other CVD. CONCLUSIONS: About 1 in 20 ambulatory persons > 50 years of age screened had PAD. All cases of PAD that we found were previously undiagnosed, and there was a large treatment gap for those without concomitant CVD. PMID- 21601778 TI - Eosinophilic endomyocarditis: an unusual cause of heart failure in a young patient. PMID- 21601779 TI - Women's issues in gastroenterology. Preface. PMID- 21601780 TI - Treatment of irritable bowel syndrome in women. AB - Irritable bowel syndrome (IBS) is a complex clinical process with multiple pathophysiologic mechanisms. There has recently been a shift in the treatment of patients with severe IBS symptoms to disease-modifying therapies as opposed to symptomatic treatment. Because pathophysiologic differences exist between men and women, so does the efficacy of treatment options. These differences could further explain gender-related differences in disease prevalence and treatment response. A brief discussion of the definition, epidemiology, and diagnostic criteria of IBS is followed by a comprehensive review of the current treatment choices and potential future therapeutic options of IBS in women. PMID- 21601781 TI - When to reconsider the diagnosis of irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a highly prevalent disorder characterized by nonspecific symptoms that can mimic other common medical conditions. A careful history and physical examination may reveal clues that suggest a coexisting or alternative diagnosis, such as small intestinal bacterial overgrowth or celiac disease (CD). Testing for bacterial overgrowth has limitations, but emerging data suggest that antibiotics may be of some benefit in patients with IBS with diarrhea and bloating. CD seems to have a higher prevalence in patients with IBS. Some patients with IBS may have symptomatic improvement on gluten-restricted diets, without histologic or serologic evidence of CD. PMID- 21601783 TI - Liver disease in pregnancy. AB - This article briefly discusses gestational physiologic changes and thereafter reviews liver diseases during pregnancy, which are divided into 3 main categories. The first category includes conditions that are unique to pregnancy and generally resolve with the termination of pregnancy, the second category includes liver diseases that are not unique to the pregnant population but occur commonly or are severely affected by pregnancy, and the third category includes diseases that occur coincidentally with pregnancy and in patients with underlying chronic liver disease, with cirrhosis, or after liver transplant who become pregnant. PMID- 21601784 TI - Hepatitis B in pregnancy: challenges and treatment. AB - Hepatitis B virus (HBV) during pregnancy presents unique management challenges. Varying aspects of care must be considered, including the effects of HBV on maternal and fetal health, effects of pregnancy on the course of HBV infection, treatment of HBV during and after pregnancy, and prevention of perinatal infection. Antiretroviral therapy has not been associated with increased risk of birth defects or toxicity, but despite studies designed to elucidate the drug efficacy and safety in affected individuals and the developing fetus, recommendations are inconclusive. Clinicians and patients must make individualized decisions after carefully evaluating the risks and benefits summarized in this article. PMID- 21601785 TI - Primary biliary cirrhosis. AB - Primary biliary cirrhosis is a chronic autoimmune inflammatory disease of the liver with a striking female preponderance. It has an insidious onset and typically affects middle-aged women. The disease manifests gradually with symptoms of fatigue, pruritis, and increased alkaline phosphatase levels on laboratory evaluation. The hallmark of the disease is the circulating antimitochondrial antibody. Histology is characterized by inflammation of the bile ducts, destruction of cholangiocytes, and subsequent cholestasis, progressing to biliary cirrhosis. The standard treatment for primary biliary cirrhosis is ursodeoxycholic acid, which improves survival, but the disease can still lead to cirrhosis and liver failure over decades. PMID- 21601782 TI - Nausea and vomiting of pregnancy. AB - Nausea and vomiting are common experiences in pregnancy, affecting 70% to 80% of all pregnant women. Various metabolic and neuromuscular factors have been implicated in the pathogenesis of nausea and vomiting of pregnancy (NVP) and hyperemesis gravidarum (HG), an entity distinct from NVP. However, their exact cause is unknown. Consequently, treatment of NVP and HG can be difficult, as neither the optimal targets for treatment nor the full effects of potential treatments on the developing fetus are known. This article reviews the epidemiology, pathology, diagnosis, outcomes, and treatment of NVP and HG. PMID- 21601786 TI - Special considerations for women with IBD. AB - Inflammatory bowel diseases (IBD), namely Crohn disease (CD) and ulcerative colitis (UC), are common in Western society. Because at least half of the patients suffering from these diseases are women, it is important that physicians are aware of their gender-specific needs. There are multiple important concerns for women with UC and CD including issues of body image and sexuality, menstruation, contraception, screening for cervical cancer, matters related to menopause and hormone replacement therapy, osteoporosis, and the overlap seen between IBS and IBD. In this article, we have addressed these important, non pregnancy-related issues faced by women with IBD. PMID- 21601787 TI - Inflammatory bowel disease in pregnancy. AB - Crohn disease and ulcerative colitis commonly affect women in their childbearing years. Fortunately, advances in the field of inflammatory bowel disease have made successful pregnancy outcomes a reality for many women. These advances have led to family planning as a common discussion between gastroenterologists and inflammatory bowel disease patients. Common discussion topics are fertility, conception, medication safety, pregnancy, delivery, and breastfeeding although there are limited available data. Education and patient awareness have become vital factors in successful pregnancy outcomes. PMID- 21601788 TI - Issues related to colorectal cancer and colorectal cancer screening practices in women. AB - Studies have shown that colorectal cancer (CRC) incidence is equal between men and women. However, several studies have demonstrated lower adenoma detection rates in women than in men. Many questions arise about differences in adenomas, CRC, and screening practices between men and women: should screening be the same for both sexes, are there differences in risk factors in the formation of colon cancer, should special groups of women be screened differently from the general population, are colonoscopies tolerated differently in women and why, and what determines if a woman will undergo colonoscopy? This article reviews these issues. PMID- 21601789 TI - A global perspective on gastrointestinal diseases. AB - Common gastrointestinal diseases often exhibit geographic, cultural, and gender variations. Diseases previously less common in certain areas of the world have shown a recent increase in prevalence. Industrialization has traditionally been noted as a major cause for this epidemiologic evolution. However, environmental factors such as diet, hygiene, and exposure to infections may play a major role. Moreover, the way one disease presents in a certain location may vary significantly from the way it manifests in another culture or location. This article discusses global variations of inflammatory bowel disease, Helicobacter pylori, irritable bowel disease, fecal incontinence, hepatitis B, and hepatocellular cancer. PMID- 21601790 TI - The challenges of being a female gastroenterologist. AB - Women have started to enter gastroenterology (GI) in significant numbers over the past 5 years, although they are still underrepresented compared with the proportion of female graduating medical students. This underrepresentation is most likely caused by the culture of GI where female students and residents have felt undervalued and unwelcome. This type of discrimination is difficult to fight because it is behind the scenes. However, with increasing female role models in GI, this underrepresentation will likely change in the coming years. PMID- 21601791 TI - Gastrointestinal issues in the older female patient. AB - As the body ages, it undergoes a multitude of changes. Some of these changes are visible, whereas others are not and may be elicited during the patient encounter. Some gastrointestinal issues may be more common in the elderly population and possibly in older women. These issues range from motility disorders, such as fecal incontinence and constipation, to changes in neuropeptide function and its effect on the anorexia of aging. This article comprehensively reviews gastrointestinal issues that commonly afflict the elderly female population. PMID- 21601792 TI - Childhood trauma and cognitive function in first-episode affective and non affective psychosis. AB - BACKGROUND: A history of childhood trauma is reportedly more prevalent in people suffering from psychosis than in the general population. Childhood trauma has also been linked to cognitive abnormalities in adulthood, and cognitive abnormalities, in turn, are one of the key clinical features of psychosis. Therefore, this study investigated whether there was a relationship between childhood trauma and cognitive function in patients with first-episode psychosis. The potential impact of diagnosis (schizophrenia or affective psychosis) and gender on this association was also examined. METHODS: Data were available for 138 first-episode psychosis patients and 138 geographically-matched controls recruited from a catchment area based organisation. History of childhood trauma was obtained using the Childhood Experience of Care and Abuse Questionnaire. Cognitive function was assessed through a comprehensive and standardised neuropsychological test battery. RESULTS: A history of childhood trauma was associated with worse cognitive performances, predominantly in affective psychoses, and in male patients. No association between a history of childhood trauma and cognition was found amongst female patients, or female controls. CONCLUSIONS: The results need replication, but underline the necessity of investigating biological and psychosocial mechanisms underlying these subjects' sensitivity to the negative effect of childhood stress. PMID- 21601793 TI - Lymphoid tissue inducer cells. PMID- 21601794 TI - Septins. PMID- 21601795 TI - Cell size: chromosomes get slapped by a midzone ruler. AB - Spatial and temporal coordination of mitotic events has been generally attributed to the coincidental outcome of increasing cyclin-dependent kinase activity. A recent study reports that mitotic events and structures previously considered to be independently controlled are capable of trans-regulation to ensure genomic integrity. PMID- 21601796 TI - Perceptual learning: visual function improved by LTP/LTD-like stimulation. AB - A new behavioral training approach has been found significantly to improve visual function; the results further attest to the high degree of plasticity in sensory systems. PMID- 21601797 TI - Chloroplast signaling: retrograde regulation revelations. AB - Developing chloroplasts are able to communicate their status to the nucleus and regulate expression of genes whose products are needed for photosynthesis. Heme is revealed to be a signaling molecule for this retrograde communication. PMID- 21601798 TI - Memory formation: filling in the gaps in flies. AB - Research in Drosophila has many advantages for the study of complex behavior. Two studies identify a new role for chemical and electrical signaling in the anterior paired lateral neurons during memory formation. PMID- 21601799 TI - Organelle dynamics: a tale of fusing nucleoli. AB - Recent experiments on nucleoli suggest that their dynamic behavior is liquid-like with common fusion events and that the surrounding actin plays an active role in these dynamics. PMID- 21601800 TI - Notch signaling: a role in sleep and stress. AB - The molecular pathways regulating sleep remain poorly understood. Studies in this issue demonstrate a role for Notch signaling in sleep regulation as well as stress response in both Caenorhabditis elegans and Drosophila. PMID- 21601801 TI - Evolutionary genetics: evolution with foresight. AB - Evolution has no foresight, but produces ad hoc solutions by tinkering with available variation. A new study demonstrates how evolution nevertheless prepares organisms for the future by increasing their evolvability. PMID- 21601802 TI - Circadian rhythms: lost in post-translation. AB - Multiple studies question the necessity of transcription/translation feedback loops for the generation of circadian rhythms. New data emphasize the necessity of proteasomal degradation for circadian rhythmicity in transcriptionally competent cells. PMID- 21601803 TI - Synaptic growth: dancing with adducin. AB - Manipulations of the actin-capping protein adducin in Drosophila and mammalian neurons provide new insights into the mechanisms linking structural changes to synaptic plasticity and learning. Adducin regulates synaptic remodeling, providing a molecular switch that controls synaptic growth versus disassembly during plasticity. PMID- 21601804 TI - Side effects of doxycycline in adolescents treated for pelvic inflammatory disease. PMID- 21601806 TI - Dermatology for pediatric/adolescent gynecology. PMID- 21601807 TI - Vulvodynia in adolescence: childhood vulvar pain syndromes. AB - BACKGROUND: Children, adolescents and young women represent a unique group of patients with vulvodynia. STUDY OBJECTIVE: To define and characterize vulvodynia, diagnostic criteria, causes and pathophysiology, propose treatment modalities, emphasizing its prevalence in young children, adolescents and young women less than 25 years of age. DESIGN: Medline review of the literature on vulvar pain disorders, using the key word vulvodynia, from the years 1995 to 2010, comparing characteristics in children, adolescents and young women ages 25 years and less to older adult women. SETTING: MEDLINE review of current literature from 1995 to 2010. PARTICIPANTS: None INTERVENTIONS: There were no interventions during this literature review. MAIN OUTCOME MEASURES: A synthesis of cases of vulvodynia in these populations and the specific characteristics and recommendations in these age groups. RESULTS: Childhood vulvar pain is usually found to have a cause. Pain characteristics in this group are similar to adults. In adolescents and young reproductive age women, vulvar pain is associated with sexual intercourse or early tampon use. The psychological component of vulvar pain is limited due to small numbers of patients available for review. Treatment modalities and recommendations are based on limited data. CONCLUSIONS: Women with vulvodynia vary in ages from 16 to 80 years with the majority between the ages of 20 to 50 years. Young women in their teens and early twenties are at the greatest risk of developing vulvodynia. Vulvar pain disorders are important in these groups because early pain syndromes may affect future development of body image, self esteem, and attitudes toward sexual behavior and functioning. PMID- 21601808 TI - Congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia (CAH) due to P450c21 (21-hydroxylase deficiency) is a common autosomal recessive disorder. This disorder is due to mutations in the CYP21A2 gene which is located at chromosome 6p21. The clinical features reflect the magnitude of the loss of function mutations. Individuals with complete loss of function mutations usually present in the neonatal period. The clinical features of individuals with mild loss of function mutations are predominantly due to androgen excess rather than adrenal insufficiency leading to an ascertainment bias favoring diagnosis in females. Treatment goals include normal linear growth velocity and "on-time" puberty in affected children. For adolescent and adult women, treatment goals include regularization of menses, prevention of progression of hirsutism, and fertility. This article will review key aspects regarding pathophysiology, diagnosis, and treatment of CAH. PMID- 21601809 TI - The exotic animal respiratory system. PMID- 21601810 TI - Disorders of the respiratory system in pet and ornamental fish. AB - The respiratory organ of fish is the gill. In addition to respiration, the gills also perform functions of acid-base regulation, osmoregulation, and excretion of nitrogenous compounds. Because of their intimate association with the environment, the gills are often the primary target organ of pollutants, poor water quality, infectious disease agents, and noninfectious problems, making examination of the gills essential to the complete examination of sick individual fish and fish populations. The degree of response of the gill tissue depends on type, severity, and degree of injury and functional changes will precede morphologic changes. Antemortem tests and water quality testing can, and should, be performed on clinically affected fish whenever possible. PMID- 21601811 TI - Respiratory medicine of reptiles. AB - Noninfectious and infectious causes have been implicated in the development of respiratory tract disease in reptiles. Treatment modalities in reptiles have to account for species differences in response to therapeutic agents as well as interpretation of diagnostic findings. Data on effective drugs and dosages for the treatment of respiratory diseases are often lacking in reptiles. Recently, advances have been made on the application of advanced imaging modalities, especially computed tomography for the diagnosis and treatment monitoring of reptiles. This article describes common infectious and noninfectious causes of respiratory disease in reptiles, including diagnostic and therapeutic regimen. PMID- 21601812 TI - The chelonian respiratory system. AB - This article reviews anatomy, physiology, diagnostic techniques, and specific disease syndromes of the chelonian respiratory system. Respiratory disease is common in chelonians and is a cause of significant morbidity and mortality in these animals. Mycoplasma, herpesvirus, and iridovirus are reviewed in depth. PMID- 21601813 TI - Avian respiratory distress: etiology, diagnosis, and treatment. AB - Respiratory distress is usually a life-threatening emergency in any species and this is particularly important in avian species because of their unique anatomy and physiology. In the emergency room, observation of breathing patterns, respiratory sounds, and a brief physical examination are the most important tools for the diagnosis and treatment of respiratory distress in avian patients. These tools will help the clinician localize the lesion. This discussion focuses on the 5 anatomic divisions of the respiratory system and provides clinically important anatomic and physiologic principles and diagnosis and treatment protocols for the common diseases occurring in each part. PMID- 21601814 TI - Rabbit respiratory system: clinical anatomy, physiology and disease. AB - Rabbits are obligate nose breathers due to their epiglottis positioned rostrally to the soft palate. Any obstruction within the nasal cavity will produce a respiratory wheeze with increased respiratory effort. Respiratory diseases are a major cause of morbidity and mortality in rabbits. This article focuses on these diseases and their causative pathogens. PMID- 21601815 TI - Hedgehogs and sugar gliders: respiratory anatomy, physiology, and disease. AB - This article discusses the respiratory anatomy, physiology, and disease of African pygmy hedgehogs (Atelerix albiventris) and sugar gliders (Petaurus breviceps), two species commonly seen in exotic animal practice. Where appropriate, information from closely related species is mentioned because cross susceptibility is likely and because these additional species may also be encountered in practice. Other body systems and processes are discussed insofar as they relate to or affect respiratory function. Although some topics, such as special senses, hibernation, or vocalization, may seem out of place, in each case the information relates back to respiration in some important way. PMID- 21601816 TI - A review of respiratory system anatomy, physiology, and disease in the mouse, rat, hamster, and gerbil. AB - The purpose of this article is to provide for practitioners a comprehensive overview of respiratory diseases, both infectious and noninfectious, in the mouse, rat, hamster, and gerbil. The information presented will also be useful for veterinarians pursuing board certification. Anatomy and physiology are briefly addressed, as those two facets alone could encompass an entire article for these species. PMID- 21601817 TI - Respiratory system anatomy, physiology, and disease: Guinea pigs and chinchillas. AB - Respiratory diseases are common in guinea pigs and chinchillas. There are multifactorial causes of respiratory involvement in these species of rodents, from infectious (bacterial, viral, and fungal) to neoplastic causes. Toxicoses and diseases affecting other systems may also induce respiratory signs. Knowledge of biology, including husbandry, nutritional requirements, and behavior, are important clues for the clinician to determine the role these issues may play in the development, progression, and prognosis of respiratory clinical cases in rodents. Current approaches in the diagnosis and therapy for respiratory disease in small mammals warrant more research concerning response-to-treatment reports. PMID- 21601818 TI - Ferret respiratory system: clinical anatomy, physiology, and disease. AB - The upper and lower respiratory tracts of ferrets have several similarities to humans, and therefore have been used as a research model for respiratory function. This article describes the clinical anatomy and physiology, and common respiratory diseases of the ferret. PMID- 21601819 TI - Diagnostic imaging of the respiratory system in exotic companion mammals. AB - The level of care for smaller companion mammals has increased significantly during the past few years. Today, exotic companion mammals are acknowledged as a specific area of zoologic medicine. Owner demands for a higher level of care is increasing dramatically. Because most of these patients are small (less than 2 kg), this represents a great challenge, in particular for the field of diagnostic imaging. This article reviews the 5 main diagnostic imaging modalities currently available for investigation of the respiratory system of exotic companion mammals: radiography, ultrasonography, endoscopy, computed tomography, and magnetic resonance. PMID- 21601820 TI - Magnetic fluid hyperthermia: focus on superparamagnetic iron oxide nanoparticles. AB - Due to their unique magnetic properties, excellent biocompatibility as well as multi-purpose biomedical potential (e.g., applications in cancer therapy and general drug delivery), superparamagnetic iron oxide nanoparticles (SPIONs) are attracting increasing attention in both pharmaceutical and industrial communities. The precise control of the physiochemical properties of these magnetic systems is crucial for hyperthermia applications, as the induced heat is highly dependent on these properties. In this review, the limitations and recent advances in the development of superparamagnetic iron oxide nanoparticles for hyperthermia are presented. PMID- 21601821 TI - Outcomes of hospitalized patients with non-acute coronary syndrome and elevated cardiac troponin level. AB - OBJECTIVE: Cardiac troponin levels help risk-stratify patients presenting with an acute coronary syndrome. Although cardiac troponin levels may be elevated in patients presenting with non-acute coronary syndrome conditions, specific diagnoses and long-term outcomes within that cohort are unclear. METHODS: By using the Veterans Affairs centralized databases, we identified all hospitalized patients in 2006 who had a troponin assay obtained during their initial reference hospitalization. On the basis of the diagnostic codes of the International Classification of Diseases, 9th Revision, primary diagnoses were categorized as acute coronary syndrome or non-acute coronary syndrome conditions. RESULTS: Of a total of 21,668 patients with an elevated troponin level who were discharged from the hospital, 12,400 (57.2%) had a non-acute coronary syndrome condition. Among that cohort, the most common diagnostic category involved the cardiovascular system, and congestive heart failure (N=1661) and chronic coronary artery disease (N=1648) accounted for the major classifications. At 1 year after hospital discharge, mortality in patients with a non-acute coronary syndrome condition was 22.8% and was higher than in the acute coronary syndrome cohort (odds ratio 1.39; 95% confidence interval, 1.30-1.49). Despite the high prevalence of cardiovascular diseases in patients with a non-acute coronary syndrome diagnosis, use of cardiac imaging within 90 days of hospitalization was low compared with that in patients with acute coronary syndrome (odds ratio 0.25; 95% confidence interval, 0.23-0.27). CONCLUSIONS: Hospitalized patients with an elevated troponin level more often have a primary diagnosis that is not an acute coronary syndrome. Their long-term survival is poor and justifies novel diagnostic or therapeutic strategy-based studies to target the highest risk subsets before hospital discharge. PMID- 21601822 TI - Comparing chronic pain between fibrin sealant and suture fixation for bilayer polypropylene mesh inguinal hernioplasty: a randomized clinical trial. AB - BACKGROUND: The aim of this study was to compare the postoperative pain, complications, and recurrence after bilayer polypropylene mesh inguinal hernioplasty using fibrin sealant versus sutures for fixation. METHODS: Patients were assigned randomly to either a mesh fixed with suture group (n = 26) or a mesh fixed with fibrin sealant group (n = 30). Postoperative pain was evaluated with a visual analogue scale at days 1 and 7, and the first, third, and sixth month postoperatively. Complications and hernia recurrence were recorded. RESULTS: At each time point after surgery, visual analogue scale pain scores in the fibrin sealant group were lower but there was no statistically significant difference. There were no differences in complications or hernia recurrence between the 2 groups. CONCLUSIONS: Fibrin sealant is associated with similar rates of complications and recurrence as mesh fixation with sutures. There was no statistical difference in pain 6 months postoperatively between the 2 groups. PMID- 21601823 TI - Is the length of follow-up evaluation in published reports on the treatment of infrainguinal occlusive disease decreasing? AB - BACKGROUND: There is increasing pressure for the rapid development and implementation of new techniques and procedures. This study examined whether or not there has been a trend toward increasingly short follow-up times for studies evaluating the treatment of lower-extremity occlusive disease. METHODS: A search was performed of PubMed using the term "femoropopliteal occlusive disease" from 1976 to 2006. Reports describing the open and/or endovascular treatment of femoropopliteal occlusive disease were classified according to the number of patients, method of treatment, and follow-up time. RESULTS: A total of 103 of the 435 reports met the inclusion criteria. Average follow-up times from 1976 to 1986 were a mean of 43.3 months and a median of 38.8 months, from 1986 to 1996 were a mean of 32.4 months and a median of 16.9 months, from 1996 to 2006 were a mean of 22.6 months and a median of 16.5 months. CONCLUSIONS: The number of reports on femoropopliteal occlusive disease treatment has increased. The length of follow up period was 2- to 3-fold longer for reports on open procedures compared with those on endovascular procedures. Whether length of follow-up evaluation and reporting intervals should be standardized warrants further investigation. PMID- 21601824 TI - Treatment of small-bowel fistulae in the open abdomen with topical negative pressure therapy. AB - BACKGROUND: An open abdomen (OA) can result from surgical management of trauma, severe peritonitis, abdominal compartment syndrome, and other abdominal emergencies. Enteroatmospheric fistulae (EAF) occur in 25% of patients with an OA and are associated with high mortality. METHODS: We report our experience with topical negative pressure (TNP) therapy in the management of EAF in an OA using the VAC (vacuum asisted closure) device (KCI Medical, San Antonio, TX). Nine patients with 17 EAF in an OA were treated with topical TNP therapy from January 2006 to January 2009. Surgery with enterectomy and abdominal closure was planned 6 to 10 weeks later. RESULTS: Three EAF closed spontaneously. The median time from the onset of fistulization to elective surgical management was 51 days. No additional fistulae occurred during VAC therapy. One patient with a short bowel died as a result of persistent leakage after surgery. CONCLUSIONS: Although previously considered a contraindication to TNP therapy, EAF can be managed successfully with TNP therapy. Surgical closure of EAFs is possible after several weeks. PMID- 21601825 TI - Bariatric surgery using a network and teleconferencing to serve remote patients in the Veterans Administration Health Care System: feasibility and results. AB - BACKGROUND: Previously, Midwestern veteran patients had limited bariatric surgery access because they lived long distances from a bariatric surgery center (BSC). The creation and outcomes of a network to increase bariatric surgery access and patient satisfaction with teleconsultation are discussed. METHODS: Several referring Midwestern Veterans Affairs Medical Centers (VAMCs) performed pre- and postoperative management and were linked by teleconferencing and a computerized patient record system to a single BSC. RESULTS: Twenty-eight high-risk patients (older, male) residing an average distance of 324.5 miles from the BSC underwent gastric bypass. Eighty-two percent used teleconferencing for the initial surgical consultation with excellent patient satisfaction saving at least 19,000 miles and 69 travel days. Surgical outcomes were equivalent and follow-up was excellent (96.6%) compared with non-Veterans Affairs patients. CONCLUSIONS: A cooperative network using teleconference and computerized records facilitated bariatric surgery in high-risk, remotely located VA patients with high patient satisfaction and without compromising surgical outcomes. PMID- 21601826 TI - The role of antibiotic prophylaxis in totally implantable venous access device placement: results of a single-center prospective randomized trial. AB - BACKGROUND: This study evaluated whether prophylactic treatment with a cefazolin could prevent infections in patients who had a surgically inserted totally implantable venous access device (TIVAD). METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled trial comparing wound infection rates in 404 patients (203 received prophylactic cefazolin, 201 received a placebo) undergoing TIVAD insertion. Infections were evaluated 3, 7, 14, and 30 days after discharge and outcomes were compared and analyzed. RESULTS: Groups were well matched for all preoperative variables studied, including comorbid conditions. Superficial surgical site infection developed in 5 patients (2.5%) from the antibiotic group and 6 (3%) from the placebo group (P = .75). One from each group developed deep surgical site infection. Both patients were readmitted and underwent repeated debridement, which eventually resulted in port loss in 1 patient. CONCLUSIONS: We do not recommend the use of prophylactic antibiotics in TIVAD insertion because they will not decrease the already low rate of postoperative infectious complications. Registration number NCT00867295 (http://www.clinicaltrials.gov). PMID- 21601827 TI - The C-reactive protein-to-prealbumin ratio predicts fistula closure. AB - BACKGROUND: The purpose of this study was to evaluate the predictability of fistula closure using the ratio of C-reactive protein to prealbumin (C:P ratio). METHODS: A database of 89 patients with gastrointestinal fistulas (1994-2009) was created based on the records of our Nutrition Support Services Team. All patients had weekly blood work including C-reactive protein level, prealbumin level, and albumin level. Forty-three fistulas were managed without surgery for 6 weeks or more; of these, 29 closed. RESULTS: The median C:P ratio for those fistulas that remained open after 6 weeks of conservative management differed significantly from those that closed (.10 vs .35; P < .001). For patients with a C:P ratio of .25 or less, fistula closure occurred in 87.0% (95% confidence interval, 74.0 94.3), whereas for patients with a ratio of greater than 1.0, no fistulas closed. CONCLUSION: Our results suggest that the C:P ratio is a predictor of fistula closure. PMID- 21601828 TI - Female sex as an independent predictor of morbidity and survival after isolated coronary artery bypass grafting. AB - BACKGROUND: This study sought to determine whether female sex was an independent risk factor for combined in-hospital morbidity, mortality, and long-term survival after coronary artery bypass grafting (CABG). METHODS: Data were collected prospectively for 1,114 (23.5%) women and 3,628 (76.5%) men operated on between January 1, 1996 and December 31, 2004 with median follow-up of 7.9 years (interquartile range 3.55 to 10.5). The combined morbidity end point was defined as in-hospital renal failure, stroke, ventilation for more than 24 hours, deep sternal wound infection, reoperation, myocardial infarction (MI), and mortality less than 30 days after discharge. The long-term all-cause and cardiac mortality outcomes were analyzed using multivariate proportional hazard regression. RESULTS: Females were older, with lower body surface area, and generally had more significant comorbid conditions than did males (p<0.05). Female sex was associated with increased odds of the combined morbidity end point (adjusted odds ratio [OR]=1.29; 95% confidence interval, 1.04 to 1.59, p=0.02). There were 868 deaths (18.3% of total sample) during the follow-up period, and 305 deaths (n=305 [35.1%] of deaths) were deemed to be of cardiac causes. In adjusted survival models, female sex was associated with cardiac mortality (hazard ratio [HR]=1.28; 95% confidence interval, 0.96 to 1.73; p=0.10) but not with all-cause mortality (HR=0.92; 95% confidence interval, 0.77 to 1.11; p=0.38). CONCLUSIONS: Female sex was associated with early combined morbidity and long-term cardiac mortality but not long-term all-cause mortality. A greater proportion of concomitant risk factors characterize female patients undergoing CABG. PMID- 21601829 TI - Fate of functional mitral regurgitation and predictors of persistent mitral regurgitation after isolated aortic valve replacement. AB - BACKGROUND: There are no clear guidelines in regard to optimal management of functional mitral regurgitation (MR) in patients undergoing aortic valve replacement (AVR). This study evaluated changes in functional MR and determined predictors of persistent MR after isolated AVR. METHODS: We retrospectively reviewed 118 consecutive patients with functional MR at the time of isolated AVR from January 2000 to December 2009. We collected preoperative and postoperative echocardiographic data to determine the degree of change in MR after AVR. Patients were divided into those without (n=71) and those with persistent MR (n=42). Late follow-up echocardiography was completed in 95% (113/118) of patients. The mean follow-up duration was 56.7+/-35.3 months. RESULTS: Mitral regurgitation improved in 72% (81/113), was unchanged in 25% (28/113), and worsened in 3% (4/113) of patients. There were no differences in 10-year survival rates among groups based on preoperative MR status (grade I, 93.1%; grade II, 85.4%; grade III, 80%; p=0.432). However, there was a significant difference in postoperative survival between patients without and with persistent MR (93.1% versus 77.8% respectively, p=0.036). Predictors of persistent MR by univariate analysis included higher left ventricular ejection fraction (LVEF), higher right ventricular (RV) systolic pressure, decreased left ventricular end systolic dimension (LVESD), and decreased left ventricular end diastolic dimension (LVEDD). In multivariate analysis, only RV systolic pressure was identified as an independent risk factor predicting persistent MR (p=0.035; odds ratio [OR], 1.037; confidence interval [CI], 1.003 to 1.072). CONCLUSIONS: Functional MR improved in most patients after AVR alone. Postoperative persistent MR affects long-term survival in functional MR. Preoperative RV systolic pressure is an independent risk factor predicting persistent MR. PMID- 21601830 TI - Comparison of three strategies of trunk support during asymmetric two-handed reach in standing. AB - No trunk support (NTS) was compared to a lower trunk support (LTS) of leaning against a worktable and a dynamic upper trunk support (UTS) using postural kinematics, trunk extensor muscle activity and subjective rating of both comfort and effort. Ten females completed 3 repetitions where they lifted 0 and 5 kg load from a symmetrical position at hip-height to a 45 degrees asymmetric position at: i) hip-height and ii) shoulder-height. Human motion capture showed trunk flexion decreased by 12 degrees +/- 10 with trunk support with hip-height reach. The table blocked axial rotation of the pelvis which was compensated by an additional 8 degrees +/- 6 rotation of the thoracic segment. Surface EMG of the lumbar erector spinae, contralateral to reach, showed the UTS to be almost twice as effective as the LTS with shoulder-height reach with a 30% +/- 18 reduction. With hip-height reach, UTS resulted in a smaller reduction equal to 23% +/- 27 while the LTS had no effect. Further investigation is needed to determine optimal performance parameters for trunk support with complex, dynamic trunk postures and whether altered kinematics arising from LTS have higher risk of upper back discomfort. PMID- 21601831 TI - Vigilance for threat interacts with amygdala responses to subliminal threat cues in specific phobia. AB - BACKGROUND: The amygdala has been strongly implicated in the processing of threat relevant information in specific phobia. However, there is an ongoing debate as to whether the amygdala may also be engaged outside of conscious stimulus awareness. Furthermore, considering that sustained vigilance for threat constitutes a crucial characteristic of specific phobias, we hypothesized a possible role of this symptom in modulating amygdala sensitivity to disorder relevant cues. Using event-related functional magnetic resonance imaging, we examined responses of the amygdala to subliminal and supraliminal phobogenic stimuli in spider-phobic subjects and whether these responses might be specifically associated with disorder-related hypervigilance. METHODS: Eighteen female spider-phobic subjects and 18 healthy female control subjects were exposed to pictures of spiders and phobia-irrelevant objects, presented briefly during two backward-masking conditions used to manipulate stimulus awareness. Brain activation data were analyzed as a function of subjects' perceptual performance on each single trial and were tested for correlations with different components of the phobic symptomatology, such as vigilance, as assessed by self-report scales. RESULTS: Compared with control subjects, phobic participants showed stronger responses of both amygdalae to consciously perceived spiders versus nonspider targets, whereas during unconscious stimulus processing, enhanced activation was only apparent in the right amygdala. Moreover, the intensity of disorder-related vigilance was positively correlated with right amygdala activation specifically during the subliminal condition. CONCLUSIONS: These findings provide evidence for unconscious threat processing in specific phobia, with the magnitude of amygdala responses specifically potentiated by sustained hypervigilance for threat. Aberrations in this vigilance system may be critically involved in anxiety disorders. PMID- 21601833 TI - Two-week administration of the combined serotonin-noradrenaline reuptake inhibitor duloxetine augments functioning of mesolimbic incentive processing circuits. AB - BACKGROUND: Anhedonia and lack of motivation are core symptoms of major depressive disorder (MDD). Neuroimaging studies in MDD patients have shown reductions in reward-related activity in terminal regions of the mesolimbic dopamine (DA) system, such as the ventral striatum. Monoamines have been implicated in both mesolimbic incentive processing and the mechanism of action of antidepressant drugs. However, not much is known about antidepressant effects on mesolimbic incentive processing in humans, which might be related to the effects on anhedonia. METHODS: To investigate the short-term effects of antidepressants on reward-related activity in the ventral striatum, we investigated the effect of the combined serotonin-norepinephrine reuptake inhibitor duloxetine. Healthy volunteers underwent functional magnetic resonance imaging in a randomized, double-blind, placebo-controlled, crossover study. After taking duloxetine (60 mg once a day) or placebo for 14 days, participants completed a monetary incentive delay task that activates the ventral striatum during reward anticipation. RESULTS: Our results (n = 19) show enhanced ventral striatal responses after duloxetine administration compared with placebo. Moreover, this increase in ventral striatal activity was positively correlated with duloxetine plasma levels. CONCLUSIONS: This is the first study to demonstrate that antidepressants augment neural activity in mesolimbic DA incentive processing circuits in healthy volunteers. These effects are likely caused by the increase in monoamine neurotransmission in the ventral striatum. Our findings suggest that antidepressants may alleviate anhedonia by stimulating incentive processing. PMID- 21601832 TI - Functional differentiation of posterior superior temporal sulcus in autism: a functional connectivity magnetic resonance imaging study. AB - BACKGROUND: Socio-communicative impairments are salient features of autism spectrum disorder (ASD). Abnormal development of posterior superior temporal sulcus (pSTS)--a key processing area for language, biological motion, and social context--could play a role in these deficits. METHODS: Functional connectivity magnetic resonance imaging was used to examine the synchronization of low frequency blood oxygen level-dependent fluctuations during continuous performance on a visual search task. Twenty-one children and adolescents with ASD and 26 typically developing individuals-matched on age and IQ-participated in the study. Three subregions of pSTS were delineated with a data-driven approach, and differentiation of pSTS was examined by comparing the connectivity of each subregion. RESULTS: In typically developing individuals, differentiation of networks was positively associated with age and anatomical maturation (cortical thinning in pSTS, greater white matter volume). In the ASD group, differentiation of pSTS connectivity was significantly reduced, and correlations with anatomical measures were weak or absent. Moreover, pSTS differentiation was inversely correlated with autism symptom severity. CONCLUSIONS: Atypical maturation of pSTS suggests altered trajectories for functional segregation and integration of networks in ASD, potentially related to impaired cognitive and sensorimotor development. Furthermore, our findings provide a novel explanation for atypically increased connectivity in ASD that has been observed in some functional connectivity magnetic resonance imaging studies. PMID- 21601834 TI - The neural basis of familial risk and temperamental variation in individuals at high risk of bipolar disorder. AB - BACKGROUND: Bipolar disorder is a highly heritable psychiatric disorder characterized by episodic elevation or depression of mood. Bipolar disorder is associated with structural and functional brain abnormalities but it is unclear whether these are present in relatives of affected individuals and if they are associated with subclinical symptoms or traits associated with the disorder. METHODS: Functional magnetic resonance imaging scans were conducted on 93 unrelated relatives of bipolar disorder patients and 70 healthy comparison subjects performing the Hayling sentence completion paradigm. Examination of comparison subjects versus high-risk individuals was followed by assessments of associations with depression scores and measures of cyclothymic temperament. RESULTS: Examination of comparison subjects versus high-risk subjects revealed increased activation in the high-risk group in the left amygdala. No interaction effects were observed between the groups for scores of depression or cyclothymia and activation in any region. Significant associations were found across the groups with depression ratings and activation in the ventral striatum and with cyclothymia and activation in ventral prefrontal regions, however no interaction effects were observed between the groups. CONCLUSIONS: Differences in activation in the left amygdala in those at familial risk may represent a heritable endophenotype of bipolar disorder. Activation in striatal and ventral prefrontal regions may, in contrast, represent a distinct biological basis of subclinical features of the illness regardless of the presence of familial risk. PMID- 21601835 TI - A new method for the quantification of chitin and chitosan in edible mushrooms. AB - Along with beta-glucans, chitin is the dominant component of the fungal cell wall. Chitosan, the deacetylated form of chitin, has found quite a number of biomedical and biotechnological applications recently. Mushroom chitin could be an important source for chitosan production. A direct determination of chitin and chitosan in mushrooms is of expedient interest. In this paper, a new method for the quantification of chitin and chitosan is described. This method is based on the specific reaction between polyiodide anions and chitosan and on measuring the optical density of the insoluble polyiodide-chitosan complex. After deacetylation, chitin can also be quantified. The specificity of the reaction is used to quantify the polymers in the presence of complex matrices. With this new spot assay, the chitin content of mycelia and fruiting bodies from several basidiomycetes and an ascomycete were analysed. The presented method could also be used for the determination in other samples as well. The chitin content of the analysed species varies between 0.4 and 9.8 g chitin per 100 g of dry mass. Chitosan could not be detected in our mushroom samples, indicating that the glucosamine units are mostly acetylated. PMID- 21601836 TI - Effects of synthetic retinoid Am80 on iodide-induced autoimmune thyroiditis in nonobese diabetic mice. AB - We examined whether a synthetic retinoid Am80 prevented the development of autoimmune thyroiditis in iodide-treated nonobese diabetic mice, an animal model of Hashimoto's thyroiditis (HT). Am80 (0, 0.1 or 1 mg/kg/day) was orally administered in feed during the 8-week iodide treatment. While iodide ingestion effectively induced thyroiditis, Am80 administration failed to interfere with thyroiditis development and serum anti-thyroglobulin antibody levels regardless of the dose of the retinoid. Splenic T cell numbers, splenocyte proliferation and interferon-gamma production were decreased in the Am80-treated mice. Our data suggest that Am80 is not a candidate for use in the prevention of HT. PMID- 21601838 TI - [Safe extraction of an intrapulmonary foreign body after a penetrating thoracic trauma: vascular control and primary suture is the treatment of choice]. PMID- 21601839 TI - When ignorance is no excuse: Different roles for intent across moral domains. AB - A key factor in legal and moral judgments is intent. Intent differentiates, for instance, murder from manslaughter. Is this true for all moral judgments? People deliver moral judgments of many kinds of actions, including harmful actions (e.g., assault) and purity violations (e.g., incest, consuming taboo substances). We show that intent is a key factor for moral judgments of harm, but less of a factor for purity violations. Based on the agent's innocent intent, participants judged accidental harms less morally wrong than accidental incest; based on the agent's guilty intent, participants judged failed attempts to harm more morally wrong than failed attempts to commit incest. These patterns were specific to moral judgments versus judgments of the agent's control, knowledge, or intent, the action's overall emotional salience, or participants' ratings of disgust. The current results therefore reveal distinct cognitive signatures of distinct moral domains, and may inform the distinct functional roles of moral norms. PMID- 21601837 TI - Dendritic cell maturation occurs through the inhibition of GSK-3beta. AB - Dendritic cell (DC) maturation results in changes in antigen processing and presentation, governing the fate of adaptive immunity. Understanding the intracellular signaling pathways governing DC maturation is therefore critical. In this study, we observed that the kinase, GSK-3beta, is present in its active form in resting immature DCs isolated from the spleen and bone marrow of mice. Induction of DC maturation using GM-CSF, IL-4 and TNF-alpha resulted in GSK-3beta inhibition, as reflected by increased phosphorylation of Serine 9 on the kinase, and concomitant stabilization of its substrate, beta-catenin. Treatment of immature DCs with a GSK-3beta inhibitor increased cell surface expression of CD80, CD86 and CD40 on DCs, enhancing their ability to present antigen and activating IL-2 secretion by T cells. GSK-3beta inhibition also parallels dendritic cell maturation in vivo. Our results show that GSK-3beta signaling controls DC maturation and suggest that this kinase could be manipulated to modulate adaptive immunity. PMID- 21601840 TI - Fully automated tumor segmentation based on improved fuzzy connectedness algorithm in brain MR images. AB - Uncontrollable and unlimited cell growth leads to tumor genesis in the brain. If brain tumors are not diagnosed early and cured properly, they could cause permanent brain damage or even death to patients. As in all methods of treatments, any information about tumor position and size is important for successful treatment; hence, finding an accurate and a fully automated method to give information to physicians is necessary. A fully automatic and accurate method for tumor region detection and segmentation in brain magnetic resonance (MR) images is suggested. The presented approach is an improved fuzzy connectedness (FC) algorithm based on a scale in which the seed point is selected automatically. This algorithm is independent of the tumor type in terms of its pixels intensity. Tumor segmentation evaluation results based on similarity criteria (similarity index (SI), overlap fraction (OF), and extra fraction (EF) are 92.89%, 91.75%, and 3.95%, respectively) indicate a higher performance of the proposed approach compared to the conventional methods, especially in MR images, in tumor regions with low contrast. Thus, the suggested method is useful for increasing the ability of automatic estimation of tumor size and position in brain tissues, which provides more accurate investigation of the required surgery, chemotherapy, and radiotherapy procedures. PMID- 21601841 TI - Classification and retrieval on macroinvertebrate image databases. AB - Aquatic ecosystems are continuously threatened by a growing number of human induced changes. Macroinvertebrate biomonitoring is particularly efficient in pinpointing the cause-effect structure between slow and subtle changes and their detrimental consequences in aquatic ecosystems. The greatest obstacle to implementing efficient biomonitoring is currently the cost-intensive human expert taxonomic identification of samples. While there is evidence that automated recognition techniques can match human taxa identification accuracy at greatly reduced costs, so far the development of automated identification techniques for aquatic organisms has been minimal. In this paper, we focus on advancing classification and data retrieval that are instrumental when processing large macroinvertebrate image datasets. To accomplish this for routine biomonitoring, in this paper we shall investigate the feasibility of automated river macroinvertebrate classification and retrieval with high precision. Besides the state-of-the-art classifiers such as Support Vector Machines (SVMs) and Bayesian Classifiers (BCs), the focus is particularly drawn on feed-forward artificial neural networks (ANNs), namely multilayer perceptrons (MLPs) and radial basis function networks (RBFNs). Since both ANN types have been proclaimed superior by different investigations even for the same benchmark problems, we shall first show that the main reason for this ambiguity lies in the static and rather poor comparison methodologies applied in most earlier works. Especially the most common drawback occurs due to the limited evaluation of the ANN performances over just one or few network architecture(s). Therefore, in this study, an extensive evaluation of each classifier performance over an ANN architecture space is performed. The best classifier among all, which is trained over a dataset of river macroinvertebrate specimens, is then used in the MUVIS framework for the efficient search and retrieval of particular macroinvertebrate peculiars. Classification and retrieval results present high accuracy and can match an experts' ability for taxonomic identification. PMID- 21601842 TI - Action-based language: a theory of language acquisition, comprehension, and production. AB - Evolution and the brain have done a marvelous job solving many tricky problems in action control, including problems of learning, hierarchical control over serial behavior, continuous recalibration, and fluency in the face of slow feedback. Given that evolution tends to be conservative, it should not be surprising that these solutions are exploited to solve other tricky problems, such as the design of a communication system. We propose that a mechanism of motor control, paired controller/predictor models, has been exploited for language learning, comprehension, and production. Our account addresses the development of grammatical regularities and perspective, as well as how linguistic symbols become meaningful through grounding in perception, action, and emotional systems. PMID- 21601843 TI - Relationship between blood manganese and blood pressure in the Korean general population according to KNHANES 2008. AB - INTRODUCTION: We present data on the association of manganese (Mn) level with hypertension in a representative sample of the adult Korean population who participated in the Korean National Health and Nutrition Examination Survey (KNHANES) 2008. METHODS: This study was based on the data obtained by KNHANES 2008, which was conducted for three years (2007-2009) using a rolling sampling design involving a complex, stratified, multistage, probability-cluster survey of a representative sample of the noninstitutionalized civilian population of South Korea. RESULTS: Multiple regression analysis after controlling for covariates, including gender, age, regional area, education level, smoking, drinking status, hemoglobin, and serum creatinine, showed that the beta coefficients of log blood Mn were 3.514, 1.878, and 2.517 for diastolic blood pressure, and 3.593, 2.449, and 2.440 for systolic blood pressure in female, male, and all participants, respectively. Multiple regression analysis including three other blood metals, lead, mercury, and cadmium, revealed no significant effects of the three metals on blood pressure and showed no effect on the association between blood Mn and blood pressure. In addition, doubling the blood Mn increased the risk of hypertension 1.828, 1.573, and 1.567 fold in women, men, and all participants, respectively, after adjustment for covariates. The addition of blood lead, mercury, and cadmium as covariates did not affect the association between blood Mn and the prevalence of hypertension. CONCLUSION: Blood Mn level was associated with an increased risk of hypertension in a representative sample of the Korean adult population. PMID- 21601844 TI - The effect of prenatal perfluorinated chemicals exposures on pediatric atopy. AB - BACKGROUND: The role of perfluorinated compounds (PFCs) in the immune system and allergic diseases is not well-known. This study examined the effects of pre-natal exposure to PFCs on immunoglobulin E (IgE) levels and atopic dermatitis (AD). METHODS: In Taiwan Birth Panel cohort study, newborns with cord blood and peri natal factors (i.e. birth body weight, weeks of gestation, and type of delivery) gathered at birth were evaluated. At the age of 2 years, information on the development of AD, environmental exposures, and serum total IgE were collected. The AD and non-AD children were compared for the concentration of cord blood serum PFCs measured by Ultra-performance liquid chromatography/triple-quadrupole mass (UPLC-MS/MS). Correlations among cord blood IgE, serum total IgE at 2 years of age, and cord blood PFC levels were made. RESULTS: Of 244 children who completed the follow-up and specimen collections, 43 (17.6%) developed AD. Concentrations of cord blood serum perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS) were median (range) 1.71 (0.75-17.40), 5.50 (0.11-48.36), 2.30 (0.38 63.87), and 0.035 (0.035-0.420)ng/mL, respectively. PFOA and PFOS levels positively correlated with cord blood IgE levels (per ln-unit: beta=0.134 KU/l, p=0.047 for PFOA; beta=0.161 KU/l, p=0.017 for PFOS). Analyses stratified by gender revealed that PFOA and PFOS levels positively correlated with cord blood IgE levels only in boys (per ln-unit: beta=0.206 KU/l, p=0.025 for PFOA; beta=0.175 KU/l, p=0.053 for PFOS). When dividing cord blood serum PFCs into quartiles in the fully adjusted models, AD had no significant association with PFOS. CONCLUSIONS: Pre-natal PFOA and PFOS exposures positively correlated with cord blood IgE levels. PMID- 21601845 TI - Extreme air pollution events from bushfires and dust storms and their association with mortality in Sydney, Australia 1994-2007. AB - INTRODUCTION: Extreme air pollution events due to bushfire smoke and dust storms are expected to increase as a consequence of climate change, yet little has been published about their population health impacts. We examined the association between air pollution events and mortality in Sydney from 1997 to 2004. METHODS: Events were defined as days for which the 24h city-wide concentration of PM(10) exceeded the 99th percentile. All events were researched and categorised as being caused by either smoke or dust. We used a time-stratified case-crossover design with conditional logistic regression modelling adjusted for influenza epidemics, same day and lagged temperature and humidity. Reported odds ratios (OR) and 95% confidence intervals are for mortality on event days compared with non-event days. The contribution of elevated average temperatures to mortality during smoke events was explored. RESULTS: There were 52 event days, 48 attributable to bushfire smoke, six to dust and two affected by both. Smoke events were associated with a 5% increase in non-accidental mortality at a lag of 1 day OR (95% confidence interval (CI)) 1.05 (95%CI: 1.00-1.10). When same day temperature was removed from the model, additional same day associations were observed with non-accidental mortality OR 1.05 (95%CI: 1.00-1.09), and with cardiovascular mortality OR (95%CI) 1.10 (95%CI: 1.00-1.20). Dust events were associated with a 15% increase in non-accidental mortality at a lag of 3 days, OR (95%CI) 1.16 (95%CI: 1.03-1.30). CONCLUSIONS: The magnitude and temporal patterns of association with mortality were different for smoke and dust events. Public health advisories during bushfire smoke pollution episodes should include advice about hot weather in addition to air pollution. PMID- 21601846 TI - The impact of the learning curve on adhesion formation in a laparoscopic mouse model. AB - OBJECTIVE: To evaluate the impact of surgeon training on adhesion formation in a laparoscopic mouse model. Laparoscopic surgery and bowel manipulation was demonstrated to enhance postoperative adhesion formation. DESIGN: Prospective randomized, controlled trial. SETTING: University laboratory research center. ANIMAL(S): 200 BALB/c and 200 Swiss female mice. INTERVENTION(S): Adhesions were induced by opposing bipolar lesions and 60 minutes of pneumoperitoneum. Each surgeon operated on 80 mice (40 Swiss and 40 BALB/c), the only variable thus being his/her increasing experience. Some surgeons were already experienced gynecologists, others were starting their training. MAIN OUTCOME MEASURE(S): End points were the duration of surgery while performing the lesions. The adhesion formation was scored quantitatively (proportion and total) and qualitatively (extent, type, and tenacity) after 7 days. RESULT(S): With training, duration of surgery and adhesion formation decreased exponentially for all surgeons, whether experienced or not. Experienced surgeons had initially a shorter duration of surgery, less adhesion formation, and less de novo adhesions than inexperienced surgeons. CONCLUSION(S): These data suggest that laparoscopic skills improve with training, leading to a decrease in the duration of surgery and formation of adhesions. Therefore completion of a standardized learning curve should be mandatory when initiating adhesion formation studies both in laboratory or clinical setting. PMID- 21601847 TI - Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome with pituitary apoplexy. AB - After hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome was diagnosed in a 35-year-old woman at 39 weeks' gestation, magnetic resonance imaging and hormone examination revealed pituitary apoplexy with panhypopituitarism and diabetes insipidus. Evaluation of pituitary function should be considered in patients with HELLP syndrome. PMID- 21601848 TI - Cri du chat syndrome after preimplantation genetic diagnosis for reciprocal translocation. AB - OBJECTIVE: To report the first case of cri du chat syndrome after preimplantation genetic diagnosis (PGD) for reciprocal translocation. DESIGN: Case report. SETTING: In vitro fertilization center in a university affiliated hospital. PATIENT(S): A woman carrying a t(11;22)(q23;q11.2) translocation. INTERVENTION(S): Preimplantation genetic diagnosis was performed, and the woman became pregnant. MAIN OUTCOME MEASURE(S): Successful PGD for reciprocal translocation and diagnosis of Cri du chat syndrome for the baby. RESULT(S): A male baby was born at 36 weeks' gestation. However, the baby presented with a high-pitched, cat-like cry. Cytogenetic study revealed a rare case of cri du chat syndrome associated with t(11;22)(q23;q11.2) translocation. CONCLUSION(S): Chromosomal abnormalities, including the rare cru du chat syndrome, may occur after fluorescent in situ hybridization-based preimplantation genetic diagnosis. PMID- 21601849 TI - Androgen pretreatment in poor responders undergoing controlled ovarian stimulation and in vitro fertilization treatment. PMID- 21601850 TI - Does a woman's educational attainment influence in vitro fertilization outcomes? AB - The association between educational level and cycle outcomes was quantified by applying multivariable logistic and linear regression within a prospective cohort of 2,569 women commencing their first in vitro fertilization (IVF) cycle. Although a woman's educational attainment was not associated with the likelihood of implantation failure, chemical pregnancy, spontaneous abortion, or live birth, the odds of cycle cancellation before egg retrieval were 40% lower among those with an college degree and 48% lower among those with graduate school attendance compared with women who had no college degree, suggesting that educational attainment is inversely associated with the likelihood of cycle cancellation. PMID- 21601852 TI - Prophylactic antibiotics for simple hand lacerations: time for a clinical trial? AB - BACKGROUND: Simple hand lacerations (not involving bones, tendons, nerves, or vessels) are a common emergency department (ED) complaint. Whilst the practices of irrigation, debridement, foreign body removal, and suture repair are well accepted, the use of prophylactic antibiotics is not. Without evidenced-based guidelines, practice is left to physician preference. OBJECTIVES: The aim of this study was to assess the need for, and the feasibility to perform, a randomised controlled trial to evaluate the role of prophylactic antibiotics in simple hand lacerations. METHODS: The study was done in three phases: (1) estimation of the national ED burden of simple hand lacerations and the use of antibiotic prophylaxis; (2) assessment of indications for antibiotic prophylaxis and (3) investigation of patient willingness to enrol in a randomised controlled trial and their preferred outcomes from simple hand lacerations. For Phase 1, we analysed the 2007 National Hospital Ambulatory Medical Care Survey. For Phase 2, we surveyed ED physicians in three urban teaching institutions (two in Brooklyn, NY and one in Washington, DC). For Phase 3, we surveyed ED patients at the same three institutions. RESULTS: Phase 1: out of 116.8 million ED visits nationally in 2007, 1.8 million (1.6%) were due to simple hand lacerations, of which 1.3 million (71%) required repair. Of those repaired, 27% (95% CI, 19-35%) were prescribed prophylactic antibiotics, most commonly cephalexin (73%). Phase 2: out of 108 providers surveyed, 69 (64%) responded. 16% (95% CI, 9-27%) reported prescribing prophylactic antibiotics routinely, most commonly cephalexin (84%, 95% CI, 67-93%). The degree of contamination was the most important factor (91%, 95% CI, 82-96%) in the physicians' decision to prescribe antibiotics. Phase 3: of the 490 patients surveyed, 64% (95% CI, 60-68%) expressed interest in participating in a study to evaluate the use of prophylactic antibiotics. Their primary concern was prevention of infection (77%, 95% CI, 73-81%). CONCLUSION: Simple hand lacerations represent a substantial number of ED visits in the United States. Absence of clear guidelines, disparity in physician practice, and patient interest in infection prevention all support performing a prospective randomised controlled trial to establish the role of antibiotic prophylaxis in simple hand lacerations. PMID- 21601853 TI - A 2-year experience, management and outcome of 200 clavicle fractures. AB - INTRODUCTION: Clavicle fractures can cause pain and functional impairment if not managed appropriately. This article evaluates the prevalence of clavicular fractures, estimates the number of cases requiring operative treatment, evaluates whether removal of implant is a frequent necessity and compares the final functional outcome of the operative and non-operative groups. PATIENTS AND METHODS: Between November 2005 and November 2007, patients with clavicular fractures were eligible for participation. Patients below 18 years of age and those with pathological fractures were excluded. Demographic details, mechanism of injury, operative versus non-operative treatment, radiographic classification (Allman system), complications, implant removal and functional outcome using the University of California, Los Angeles (UCLA) shoulder-rating score were documented and analysed. RESULTS: Out of 16,280 fractures that presented to our University Teaching Hospitals, 200 (1.23%) met the inclusion criteria. As many as 20 patients were lost due to natural attrition. A total of 159 (88.3%) patients were treated non-operatively and 21 (11.7%) patients were operated upon, over half of them for symptomatic non-union. All clavicles united postoperatively. Eighty-one conservatively managed undisplaced medial, middle and lateral end fractures had excellent mean UCLA shoulder scores. A statistical significance in UCLA scores (p<0.05) was noted between the operative and non-operative patient groups in mid-shaft fractures. There was no statistical difference between the operative and non-operative groups in lateral-end fractures. A total of 42.9% required removal of metal implant due to soft tissue irritation with complete resolution of symptoms. CONCLUSION: The incidence of clavicle fractures was 1.23%. A small number of patients (11.7%) required operative treatment. We recommend surgical management of symptomatic non-union and removal of metal implant for hardware-related irritation. PMID- 21601854 TI - Weight and pressure ulcer occurrence: a secondary data analysis. AB - BACKGROUND: Prolonged external mechanical loads lead to compression, tension and shear of the skin and underlying tissues leading to pressure ulcers. Underweight seems to be associated with high pressure ulcer risk but the distinct relation between overweight and pressure ulcer development is uncertain. Anatomical and physiological differences of typical pressure ulcer points are often neglected. OBJECTIVES: (1) Is there a relationship between BMI and superficial (category 2) and deep (category 3/4) pressure ulcers on the trunk? (2) Is there a relationship between BMI and superficial (category 2) and deep (category 3/4) pressure ulcers at the heels? DESIGN: Secondary data analysis of ten pressure ulcer prevalence surveys in Germany. Comparison of proportions of pressure ulcer patients according to the 12 BMI groups provided by the WHO considering superficial and deep pressure ulcers and different anatomic locations. SETTING AND SAMPLE: Hospital patients (n=50,446). Median age was 68 (IQR 55-78) years and the proportion of female patients was 55.4%. RESULTS: The overall proportion of patients with at least one pressure ulcer at the trunk was 2.0% (99% CI 1.8-2.2) for category 2 and 0.9% (99% CI 0.8-1.0) for category 3/4 pressure ulcers. Trunk pressure ulcer proportions were significantly higher in thin individuals than in normal weight and obese patients. The overall proportion of patients with at least one heel pressure ulcer was 0.6% (99% CI 0.5-0.7) for category 2 and 0.6% (99% CI 0.5-0.7) for category 3/4. With one exception there were no statistically significant differences between BMI groups. CONCLUSIONS: Irrespective of the degree of mobility and activity thin patients are at higher risk for pressure ulcers at the sacrum, ischial tuberosity, trochanter and shoulder than normal weight and obese patients. Heel pressure ulcers seem to be unrelated to the BMI level, indicating that the BMI is not a predictor for heel PU development. These results also support the assumption that the etiology and pathogenetic mechanisms of trunk and heel PU development might be partially different. Pressure ulcer risk models might need to be redesigned because distinct risk factors only apply to distinct anatomic locations. PMID- 21601855 TI - Nurse-administered procedural sedation and analgesia in the cardiac catheter laboratory: an integrative review. AB - OBJECTIVES: To identify and appraise the literature concerning nurse-administered procedural sedation and analgesia in the cardiac catheter laboratory. DESIGN AND DATA SOURCES: An integrative review method was chosen for this study. MEDLINE and CINAHL databases as well as The Cochrane Database of Systematic Reviews and the Joanna Briggs Institute were searched. Nineteen research articles and three clinical guidelines were identified. RESULTS: The authors of each study reported nurse-administered sedation in the CCL is safe due to the low incidence of complications. However, a higher percentage of deeply sedated patients were reported to experience complications than moderately sedated patients. To confound this issue, one clinical guideline permits deep sedation without an anaesthetist present, while others recommend against it. All clinical guidelines recommend nurses are educated about sedation concepts. Other findings focus on pain and discomfort and the cost-savings of nurse-administered sedation, which are associated with forgoing anaesthetic services. CONCLUSIONS: Practice is varied due to limitations in the evidence and inconsistent clinical practice guidelines. Therefore, recommendations for research and practice have been made. Research topics include determining how and in which circumstances capnography can be used in the CCL, discerning the economic impact of sedation-related complications and developing a set of objectives for nursing education about sedation. For practice, if deep sedation is administered without an anaesthetist present, it is essential nurses are adequately trained and have access to vital equipment such as capnography to monitor ventilation because deeply sedated patients are more likely to experience complications related to sedation. These initiatives will go some way to ensuring patients receiving nurse-administered procedural sedation and analgesia for a procedure in the cardiac catheter laboratory are cared for using consistent, safe and evidence-based practices. PMID- 21601856 TI - Myocardial infarction with angiographically normal coronary arteries. AB - Myocardial Infarction with Normal Coronary Arteries (MINCA) is an important subgroup of myocardial infarction with a frequency of at least 3-4% of all myocardial infarctions. The interest and awareness of MINCA have increased recently due to the frequent use of coronary angiography, the description of Takotsubo stress cardiomyopathy and new sensitive troponin assays. Since myocarditis may mimic myocardial infarction it is essential to exclude this in patients with myocardial infarction with angiographically normal coronary arteries. Cardiac magnetic resonance imaging is a cornerstone not only to establish the diagnosis but also an important tool in the search for different causes of myocardial damage. In the future, atherosclerotic burden, hemostatic function, characterization of stressors and inflammation will be important targets for research in this group of patients. PMID- 21601857 TI - A systematic review of randomized controlled trials: Walking versus alternative exercise prescription as treatment for intermittent claudication. AB - OBJECTIVE: There is a subset of older adults with peripheral arterial disease (PAD) who are unable to complete current walking exercise therapy guidelines due to the severity of claudication, presence of foot pathology, arthritis and/or other co-morbidities. Our aim was to therefore systematically review the evidence for the effectiveness of all forms of exercise on claudication in PAD, and subsequently compare walking to alternative modes. METHODS: An electronic search of the literature was performed from earliest record until March 2011 using a variety of electronic databases. To be included trials must have been a randomized controlled trial of an exercise intervention for adults with intermittent claudication and have reported at least one claudication parameter such as initial (ICT/D) and/or absolute claudication time or distance (ACT/D) measured via a treadmill protocol. Assessment of study quality was performed using a modified version of the Physiotherapy Evidence Database Scale (PEDro). Mean difference and relative effect sizes (ESs) were calculated and adjusted via Hedges' bias-corrected for small sample sizes. RESULTS: Thirty-six trials reported on walking distance in PAD: 32 aerobic (including 20 walking); 4 progressive resistance training (PRT) or graduated weight lifting exercise. In total 1644 subjects (73% male) were studied (1183 underwent exercise training); with few over 75. Most modes and intensities of exercise, irrespective of pain level, significantly improved walking capability (ACD/T Relative ES range 0.5 3.53). However, overall quality of the trials was only modest with on average 6 of the 11 PEDro quality criteria being present (mean 5.8 +/- 1.3), and on average sample sizes were small (mean 44 +/- 51). CONCLUSIONS: Modes of aerobic exercise other than walking appear equally beneficial for claudication and the benefits of PRT and upper body exercise appear promising, but little data are published on these modalities. Additional studies of high quality are required to validate these alternative prescriptions and their efficacy relative to walking. PMID- 21601858 TI - Labedipinedilol-A prevents lysophosphatidylcholine-induced vascular smooth muscle cell death through reducing reactive oxygen species production and anti apoptosis. AB - OBJECTIVE: Labedipinedilol-A, a novel calcium antagonist, has been previously demonstrated to have pleiotropic protective effects in the cardiovascular system. This study aimed to investigate its cytoprotective effects in rat vascular smooth muscle cells (VSMCs) treated with lysophosphatidylcholine (lysoPC), a key lipid component mediating atherogenesis. METHODS AND RESULTS: VSMCs were incubated with lysoPC with or without labedipinedilol-A pretreatment to determine its effects on lysoPC-induced cell death, Ca(2+) influx, oxidative stress, MAPK signaling and apoptosis. Labedipinedilol-A attenuated lysoPC-induced cell death and Ca(2+) influx. It also reduced reactive oxygen species (ROS) production evoked by lysoPC and down-regulated expressions of NAD(P)H oxidase subunits, Nox1 and Rac1. Moreover, it inhibited lysoPC-induced phosphorylation of MAPK including ERK1/2, JNK, and p38. It mitigated the dissipation of mitochondrial transmembrane potential induced by lysoPC. Lastly, labedipinedilol-A inhibited lysoPC-induced apoptosis with attenuation of caspase-3/-9 activations and modulation of Bax/Bcl 2 protein expressions. CONCLUSION: Labedipinedilol-A can suppress lysoPC-induced VSMCs death via reducing ROS production and anti-apoptosis. These protective effects are potentially mediated through the inhibition of Ca(2+) influx, down regulation of the NAD(P)H oxidase subunits (Nox1/Rac1) and MAPK signaling, and attenuation of mitochondrial depolarization. Thus, labedipinedilol-A may have a valuable role in the preventing atherosclerosis associated with hyperlipidemia. PMID- 21601859 TI - Entrapment of adult fingers between window glass and seal entry of a motor vehicle side door: an experimental study for investigation of the force at the subjective pain threshold. AB - In modern motor vehicles with automatic power windows, a potential hazard exists for jam events of fingers between the window glass and seal entry. This study determined entrapment forces acting on adult fingers at the subjective maximum pain threshold during entrapment in such windows. The length and the girth of the proximal and distal interphalangeal joints of the triphalangeal fingers of the right hands of 109 participants (60 men, 49 women) were measured; the diameter was calculated from girth, which was assumed to be circular. The automatic power window system of a motor vehicle side door was changed to a mechanical system. During entrapment the force distributed across the four proximal interphalangeal joints (PIPs), and separately on the proximal interphalangeal (iPIP) and then the distal interphalangeal (iDIP) joints of the index finger was measured using a customized force sensor. The maximum bearable entrapment force was 97.2 +/- 51.8 N for the PIPs, 43.4 +/- 19.9 N for the iPIP, and 36.9 +/- 17.8 N for the iDIP. The positive correlation between finger diameter and maximum entrapment force was significant. Particularly with regard to the risk to children's fingers, the 100 N statutory boundary value for closing force of electronic power windows should be reduced. PMID- 21601860 TI - Estimation of stride length in level walking using an inertial measurement unit attached to the foot: a validation of the zero velocity assumption during stance. AB - In a variety of applications, inertial sensors are used to estimate spatial parameters by double integrating over time their coordinate acceleration components. In human movement applications, the drift inherent to the accelerometer signals is often reduced by exploiting the cyclical nature of gait and under the hypothesis that the velocity of the sensor is zero at some point in stance. In this study, the validity of the latter hypothesis was investigated by determining the minimum velocity of progression of selected points of the foot and shank during the stance phase of the gait cycle while walking at three different speeds on level ground. The errors affecting the accuracy of the stride length estimation resulting from assuming a zero velocity at the beginning of the integration interval were evaluated on twenty healthy subjects. Results showed that the minimum velocity of the selected points on the foot and shank increased as gait speed increased. Whereas the average minimum velocity of the foot locations was lower than 0.011 m/s, the velocity of the shank locations were up to 0.049 m/s corresponding to a percent error of the stride length equal to 3.3%. The preferable foot locations for an inertial sensor resulted to be the calcaneus and the lateral aspect of the rearfoot. In estimating the stride length, the hypothesis that the velocity of the sensor can be set to zero sometimes during stance is acceptable only if the sensor is attached to the foot. PMID- 21601861 TI - Sex-specific differences in gait patterns of healthy older adults: results from the Baltimore Longitudinal Study of Aging. AB - The effects of normal aging and orthopedic conditions on gait patterns during customary walking have been extensively investigated. Empirical evidence supports the notion that sex differences exist in the gait patterns of young adults but it is unclear as to whether sex differences exist in older adults. The aim of this study was to investigate sex-specific differences in gait among older adults. Study participants were 336 adults (50-96 years; 162 women) enrolled in the Baltimore Longitudinal Study of Aging (BLSA) who completed walking tasks at self selected speed without assistance. After adjusting for significant covariates, women walked with higher cadence (p=0.01) and shorter stride length (p=0.006) compared to men, while gait speed was not significantly related to sex. Women also had less hip range of motion (ROM; p=0.004) and greater ankle ROM (p<0.001) in the sagittal-plane, and greater hip ROM (p=0.004) in the frontal-plane. Hip absorptive mechanical work expenditure (MWE) of the women was greater in the sagittal-plane (p<0.001) and lower in the frontal-plane (p<0.001), compared to men. In summary, women's gait is characterized by greater ankle ROM than men while men tend to have greater hip ROM than women. Characterizing unique gait patterns of women and men with aging may be beneficial for detecting the early stages of gait abnormalities that may lead to pathology. PMID- 21601862 TI - Simultaneous separation and determination of 16 testosterone and nandrolone esters in equine plasma using ultra high performance liquid chromatography-tandem mass spectrometry for doping control. AB - The potential for using testosterone and nandrolone esters in racehorses to boost the biological concentrations of these steroids and enhance athletic performance is very compelling and should be seriously considered in formulating regulatory policies for doping control. In order to regulate the use of these esters in racehorses, a sensitive and validated method is needed. In this paper, we report such a method for simultaneous separation, screening, quantification and confirmation of 16 testosterone and nandrolone esters in equine plasma by ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Analytes were extracted from equine plasma by liquid-liquid extraction using a mixture of methyl tert-butyl ether and ethyl acetate (50:50, v/v) and separated on a sub-2 micron C(18) column. Detection of analytes was achieved on a triple quadrupole mass spectrometer by positive electrospray ionization mode with selected reaction monitoring (SRM). Mobile phase comprised 2 mM ammonium formate and methanol. Deuterium-labeled testosterone enanthate and testosterone undecanoate were used as dual-internal standards for quantification. Limits of detection (LOD) and quantification (LOQ) were 25-100 pg/mL and 100-200 pg/mL, respectively. The linear dynamic range of quantification was 100-10,000 pg/mL. For confirmation of the presence of these analytes in equine plasma, matching of the retention time with mass spectrometric ion ratios from MS/MS product ions was used. The limit of confirmation (LOC) was 100-500 pg/mL. The method is sensitive, robust, selective and reliably reproducible. PMID- 21601863 TI - Coupling of acetonitrile deproteinization and salting-out extraction with acetonitrile stacking in chiral capillary electrophoresis for the determination of warfarin enantiomers. AB - Concurrent sample clean-up and enhancement in detection sensitivity for chiral capillary electrophoresis was demonstrated based on the coupling of salting-out extraction with acetonitrile stacking and the use of dimethyl-beta-cyclodextrin as the chiral selector for the sensitive and enantioselective separation of warfarin enantiomers in urine samples. By optimizing the pH of salting-out extraction, warfarin enantiomers can be efficiently extracted from the aqueous sample solution into a smaller volume organic solvent (acetonitrile) phase. The pressure injection of the enriched acetonitrile phase (containing ca. 1% NaCl) into the CE capillary at 10% capillary volume resulted in additional concentration of the warfarin enantiomers. The limit of detection for both warfarin enantiomers was as low as 1.5 ng/mL in urine sample. Our results show that the novel strategy offers improved sensitivity compared to conventional CE analysis, reaching a combined enrichment factor higher than 1000. Calibration curves of warfarin enantiomers in urine samples were found to be linear between 10 and 1000 ng/mL, and intra- and inter-day precision (N=9) for both warfarin enantiomers in terms of migration time and peak area were found to be within the range of 0.1-0.8% and 1.0-6.7%, respectively. The recovery of warfarin enantiomers from urine was ca. 90%. PMID- 21601864 TI - Synthesis of Fe3O4@poly(methylmethacrylate-co-divinylbenzene) magnetic porous microspheres and their application in the separation of phenol from aqueous solutions. AB - A simple strategy to fabricate magnetic porous microspheres of Fe(3)O(4)@poly(methylmethacrylate-co-divinylbenzene) was demonstrated. The magnetic microspheres, consisting of polymer-coated iron oxide nanoparticles, were synthesized by the modified suspension polymerization of methacrylate and divinylbenzene in the presence of a magnetic fluid. The morphology and the properties of the magnetic porous microspheres were examined by scanning electron microscopy, transmission electron microscopy, superconducting quantum interference device, Fourier transform infrared spectroscopy, thermogravimetry, and X-ray powder diffraction. The pore size distribution and the specific surface area of the microspheres were measured by nitrogen sorption and mercury porosimetry technique. As predicted from the previous knowledge, the magnetic porous microspheres possessed a high specific surface area using n-hexane as a porogen. It was further found that the amounts of divinylbenzene and methacrylate, the ratio of porogens, and the dosage of ferrofluids affect the specific surface area of the microspheres. Furthermore, the microspheres were applied to remove phenol from aqueous solutions. The results showed that the microspheres had a high adsorption capacity for phenol and a high separation efficiency due to their porous structure, polar groups, and superparamagnetic characteristic. PMID- 21601865 TI - The aggregation of Tyr-Phe dipeptide and Val-Tyr-Val tripeptide in aqueous solution and in the presence of SDS and PEO-PPO-PEO triblock copolymer: fluorescence spectroscopic studies. AB - The micelle formation of Tyr-Phe dipeptide and Val-Tyr-Val tripeptide has been studied for the first time. The aggregation numbers were determined for both the peptides in aqueous solution and in the presence of SDS and PEO-PPO-PEO triblock copolymer additive environments. The results obtained by steady state and time resolved fluorescence spectroscopic techniques are in good agreement with each other. The higher value of aggregation number confirms the formation of mixed micelles. The fluorescence lifetime of tyrosine in various micellar and mixed micellar systems were also determined. The decreased lifetime values with the quencher suggested the dynamic nature of the quenching process. However, the possibility of static quenching cannot be ruled out. The accessibility of DPC quencher was found to be more in dipeptide than tripeptide. PMID- 21601866 TI - Roles of head group architecture and side chain length on colorimetric response of polydiacetylene vesicles to temperature, ethanol and pH. AB - In this contribution, we report the relationship between molecular structures of polydiacetylene (PDA) vesicles, fabricated by using three monomers, 10,12 tricosadiynoic acid (TCDA), 10,12-pentacosadiynoic acid (PCDA) and N-(2 aminoethyl)pentacosa-10,12-diynamide (AEPCDA), and their color-transition behaviors. The modification of side chain length and head group of the PDA vesicles strongly affects the colorimetric response to temperature, ethanol and pH. A shorter side chain of poly(TCDA) yields weaker inter- and intra-chain dispersion interactions in the bilayers compared to the system of poly(PCDA), which in turn results in a faster color transition upon exposure to all stimuli. A change of head group in poly(AEPCDA) slightly reduces the transition temperature. Interestingly, the colorimetric response of poly(AEPCDA) vesicles to the addition of ethanol is found to occur in a two-step fashion while the response of poly(PCDA) vesicles takes place in a one-step process. The amount of ethanol required for inducing complete color-transition of poly(AEPCDA) vesicles is also much higher, about 87% v/v. The increase of pH to ~9 and ~10 causes a color-transition of poly(TCDA) and poly(PCDA) vesicles, respectively. The poly(AEPCDA) vesicles, on the other hand, change color upon decreasing pH to ~0. The colorimetric response also occurs in a multi-step fashion. These discrepancies are attributed to the architecture of surface layers of poly(AEPCDA), constituting amine and amide groups separated by ethyl linkers. PMID- 21601867 TI - Synthesis and characterization of novel thermo-responsive F68 block copolymers with cell-adhesive RGD peptide. AB - Thermosensitive poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymer, Pluronic F68, containing a hydrophobic unit, oligo-(lactic acid)(oligo-LA) or oligo-caprolactone (oligo-CL), 2-META and RGD as side groups was successfully synthesized and characterized by (1)H NMR, FTIR, and elemental analysis. Their aqueous solution displayed special gel-sol-gel phase transition behavior with increasing temperature from 10 to 70 degrees C, when the polymer concentration was above critical micelle concentration (CMC). The gel-sol phase diagram was investigated using tube inversion method, rheological measurement, and dynamic light scattering. Based on these results, the gelation properties of modified F68 were affected by several factors such as the composition of the substituents, chain length of oligo L-LA or oligo epsilon-CL, and the concentration of the polymer solutions. The unique phase transition behavior with temperature was observed by modified F68 triblock copolymer, composed of the PPO blocks core and the PEO blocks shell in aqueous solution. This phenomenon was elucidated using (1)H NMR data; the alteration of hydrophobic interaction and chain mobility led to the formation of transparent gel, coexistence of gel-sol, and opaque gel. These hydrogels may be useful in drug delivery and tissue engineering. PMID- 21601868 TI - Predictors of spoken language learning. AB - We report two sets of experiments showing that the large individual variability in language learning success in adults can be attributed to neurophysiological, neuroanatomical, cognitive, and perceptual factors. In the first set of experiments, native English-speaking adults learned to incorporate lexically meaningfully pitch patterns in words. We found those who were successful to have higher activation in bilateral auditory cortex, larger volume in Heschl's Gyrus, and more accurate pitch pattern perception. All of these measures were performed before training began. In the second set of experiments, native English-speaking adults learned a phonological grammatical system governing the formation of words of an artificial language. Again, neurophysiological, neuroanatomical, and cognitive factors predicted to an extent how well these adults learned. Taken together, these experiments suggest that neural and behavioral factors can be used to predict spoken language learning. These predictors can inform the redesign of existing training paradigms to maximize learning for learners with different learning profiles. LEARNING OUTCOMES: Readers will be able to: (a) understand the linguistic concepts of lexical tone and phonological grammar, (b) identify the brain regions associated with learning lexical tone and phonological grammar, and (c) identify the cognitive predictors for successful learning of a tone language and phonological rules. PMID- 21601869 TI - Behavioral and neurophysiological correlates of striatal dopamine depletion: a rodent model of Parkinson's disease. AB - Both limb and cranial motor functions are adversely impacted by Parkinson's disease (PD). While current pharmacological and surgical interventions are effective in alleviating general limb motor symptoms of PD, they have failed to provide significant benefit for cranial motor functions. This suggests that the neuropathologies mediating limb and cranial motor impairments in PD may differ. Animal models provide a mechanism by which the potential neural dysfunctions underlying these different motor impairments may be characterized. Central goals to our laboratory have been to (a) determine the differential responses of cranial motor and limb motor function to striatal dopamine depletion and (b) determine the differential effects of striatal dopamine depletion on the integrity of cranial motor and limb motor neural circuits. This paper details the use of a comprehensive battery of limb and cranial motor behavioral tasks and the application of intracortical microstimulation to assess corticospinal and corticobulbar circuits in a rodent model of PD. Our work suggests that striatal dopamine depletion does differentially affect cranial and limb motor function and corticospinal and corticobulbar circuits. Further, we propose that cranial motor impairments in PD may be mediated by pathology both within and outside nigrostriatal dopamine system. LEARNING OUTCOMES: Readers will be able to (a) describe a set of motor tests used to assess limb motor and cranial motor function in an animal model of Parkinson's disease, (b) understand the application of intracortical microstimulation to assess corticospinal and corticobulbar circuits, (c) describe the differential effects of dopamine depletion on limb motor and cranial motor function in a rodent model of PD, and (d) understand the potential role of dysfunction outside the nigrostriatal system mediating cranial motor impairments in Parkinson's disease. PMID- 21601870 TI - Lymphoplasmacytic endotheliitis and anterior uveitis in sheep infected experimentally with rift valley fever virus. AB - Lymphoplasmacytic endotheliitis and anterior uveitis was diagnosed in four lambs infected experimentally with field isolates of Rift Valley fever virus (RVFV). Formalin-fixed and paraffin wax-embedded tissue from these animals was investigated by histopathology and quantitative real time reverse transcriptase polymerase chain reaction. To our knowledge, this is the first pathological description of this ocular manifestation of RVFV infection in ruminants, although these lesions have been described in man. PMID- 21601871 TI - Systemic herpesvirus and morbillivirus co-infection in a striped dolphin (Stenella coeruleoalba). AB - During 2007 a dolphin morbillivirus epizootic affected the western Mediterranean and several striped dolphins (Stenella coeruleoalba) stranded on the Catalonian coasts. One of those animals had severe lymphoid depletion, necrosis and syncytial formation in lymph nodes and spleen, with large basophilic nuclear inclusions compatible with herpesvirus detected by immunohistochemical and ultrastructural examination. Non-suppurative encephalitis with associated morbillivirus antigen and morbillivirus antigen within alveolar macrophages were also observed. A pan-herpesvirus nested polymerase chain reaction amplified a sequence virtually identical to two cetacean herpesvirus sequences previously identified in systemic infections in an Atlantic Cuvier's beaked whale (Ziphius cavirostris) and in a Mediterranean striped dolphin. The herpesviral infection was probably secondary to the immunosuppression caused by the morbillivirus. To our knowledge, this is the first report of a cetacean co-infected by dolphin morbillivirus and herpesvirus with evidence of lesions attributable to both viruses. PMID- 21601872 TI - Immunohistochemical detection of COX-2 in feline and canine actinic keratoses and cutaneous squamous cell carcinoma. AB - Cyclooxygenase-2 (COX-2) overexpression and its causal role in epidermal carcinogenesis have been demonstrated in human actinic keratoses (AK) and cutaneous squamous cell carcinoma (SCC). The aim of this study was to determine immunohistochemically the level of expression of COX-2 in feline and canine AK (n=18), SCC (n=36) and inflammatory dermatoses (n=24). COX-2 immunoreactivity was detected in all feline and canine SCC. In all specimens, labelled basal and suprabasal neoplastic keratinocytes were localized within and below areas of superficial erosion or ulceration and only scattered deeper tumour cells were positively labelled. In most cases, positive immunoreactivity of keratinocytes was associated with the presence of granulocytes. COX-2 expression was detected in 3/9 canine and 4/9 feline cases of AK and in only one case was associated with inflammation. Inflammatory dermatoses were characterized by positively labelled epidermal and follicular basal and suprabasal keratinocytes that were always associated with granulocyte exocytosis. These results indicate that further study of the effect of using COX-2 inhibitors in the management and prevention of feline and canine cutaneous SCC is warranted. The association between inflammatory cells and COX-2 expressing epidermal cells opens a new line of research regarding the role of COX-2 in SCC oncogenesis. Moreover, further studies should investigate the role of COX-2 in the pathogenesis and management of AK in animals. PMID- 21601873 TI - Pyogranulomatous pleuropneumonia and mediastinitis in ferrets (Mustela putorius furo) associated with Pseudomonas luteola Infection. AB - Between 2008 and 2009, three pet ferrets from different sources presented with acute episode of dyspnoea. Cytological examination of pleural exudates revealed severe purulent inflammation with abundant clusters of rod-shaped microorganisms with a clear surrounding halo. Treatment was ineffective and the ferrets died 2-5 days later. Two ferrets were subjected to necropsy examination, which revealed pyothorax, mediastinal lymphadenopathy and multiple white nodules (1-2mm) in the lungs. Microscopical examination showed multifocal necrotizing-pyogranulomatous pleuropneumonia and lymphadenitis with aggregates of encapsulated microorganisms, some of which were positively stained by periodic acid-Schiff and alcian blue. In situ hybridization for Pneumocystis spp., Ziehl-Neelsen staining and immunohistochemistry for distemper, coronavirus and influenza antigen were negative in all cases. Electron microscopically, the bacteria were 2-3 MUm long with a thick electron-lucent capsule. Microbiology from one ferret yielded a pure culture of gram-negative bacteria identified phenotypically as Pseudomonas luteola. This speciation was later confirmed by 16S RNA gene amplification. PMID- 21601875 TI - Poor resident-attending intraoperative communication may compromise patient safety. AB - BACKGROUND: Prior research suggests that hierarchy in medicine may impact communication and patient safety. This study examined the factors that influence surgical trainees in expressing their opinion in the operating room and the consequences this might have on patient safety. METHODS: An anonymous survey of general surgery, gynecology, and orthopedic surgery residents and attendings was conducted at a teaching institution in 2010. Separate surveys were used for attendings and for trainees consisting of 26 and 27 questions, respectively, with 17 questions in common. The surveys assessed whether the surgical hierarchy interfered with the residents voicing concerns about patient safety. Survey data was compiled, and chi2, Fisher exact tests, and the Wilcoxon rank sum test were used depending on the normality of the data. RESULTS: Thirty-eight trainees and 23 attendings participated in the survey; 74%-78% of trainees and attendings recalled an incident where the trainee spoke up and prevented an adverse event. While all attendings reported that they encourage residents to question their intraoperative decision making, only 55% of residents agreed (P<0.01). Residents indicated that they were more likely to voice their opinion with some attendings than with others based on their personality. Both groups agreed that the hierarchical structure of general surgical residency is necessary. CONCLUSION: Our findings indicate that resident attending intraoperative communication can prevent adverse patient events. Trainees often feel impaired in voicing their concerns to their attendings. Strategies that improve resident attending communication intraoperatively are needed as they are likely to enhance patient safety. PMID- 21601876 TI - Survival outcomes of pediatric intestinal failure patients: analysis of factors contributing to improved survival over the past two decades. AB - BACKGROUND: Intestinal failure (IF) is associated with significant and life threatening complications. Recent studies suggest that treatments for IF in the pediatric population are improving over time. Based on this, we examined whether pediatric IF survival rates have improved in our patient population over the past two decades, and secondarily examined which aspects of patient care contributed to changes in survival. METHODS: We conducted a retrospective chart review of all pediatric patients with IF at our children's hospital from 1990 through 2009. Cox regression analyses were used to determine change in survival rates over time (5 y cohorts), and we examined multiple covariates to determine their potential influence on survival rates over time. RESULTS: A significant improvement in survival of 171 children with IF was noted over the past two decades. Children with an onset of IF in the 1990-1994 cohort had significantly decreased survival compared with children in all subsequent cohorts (P = 0.011). The only intervention that was identified between this time period and future periods was the establishment of a comprehensive intestinal failure clinical care team. While the latter three cohorts were not significantly different, progressively increased survival was noted. Ability to wean off parenteral nutrition (PN) and small bowel length greater than 10% of the expected length were significantly associated with improved survival over this time period (P < 0.01). Other tested covariates, including the more recent use of ethanol lock therapy (to prevent catheter sepsis) and lipid reduction strategies (to treat PN-associated cholestasis) failed to show a significant impact on improved survival. CONCLUSIONS: Despite a striking improvement in survival of children with IF over the past two decades, the only identified intervention that significantly impacted survival was establishment of a comprehensive care team. These findings emphasize the need for multi-disciplinary efforts to care for such complex and challenging children. PMID- 21601877 TI - A novel CT volume index score correlates with outcomes in polytrauma patients with pulmonary contusion. AB - BACKGROUND: Exact quantification of pulmonary contusion by computed tomography (CT) may help trauma surgeons identify high-risk populations. We hypothesized that the size of pulmonary contusions, measured accurately, will predict outcomes. Our specific aims were to (1) precisely quantify pulmonary contusion size using pixel analysis, (2) correlate contusion size with outcomes, and (3) determine the threshold contusion size portending complications. METHODS: Thoracic CTs of 106 consecutive polytrauma patients with pulmonary contusion were evaluated at a university-based urban trauma center. A novel CT volume index (CTVI) score was calculated based on the ratio of affected lung to total lung [slices of lung on CT * affected pixel region/lung pixel region * 0.45 (left side) + slices of lung on CT * affected pixel region/lung pixel region * 0.55 (right side)]. Multivariate analysis correlated CTVI and patient predictors' impact on outcomes. RESULTS: Of 106 polytrauma patients (mean ISS = 28 +/- 1.2, AIS chest = 3.5 +/- 0.1), 39 developed complications (acute respiratory distress syndrome [ARDS], pneumonia, and/or death). Mean CTVI was significantly higher in the group with complications (0.28 +/- 0.03 versus 17 +/- 0.02, P = 0.01). By multivariate analysis, CTVI predicted longer ICU LOS (R(2) = 0.84, P < 0.01). A receiver operating curve (ROC) analysis identified a CTVI threshold score of 0.2 (AUC 0.67, P < 0.01) for developing pneumonia, ARDS or death. Patients with CTVI scores of 0.2 or more had longer hospitalization, longer ICU LOS, more ventilator days, and developed pneumonia (P < 0.01). CONCLUSIONS: Higher CTVI scores predicted prolonged ICU LOS across all sizes of pulmonary contusion. Pulmonary contusion volumes greater than 20% of total lung volume specifically identifies patients at risk for developing complications. PMID- 21601878 TI - Monocyte deactivation correlates with injury severity score, but not with heme oxygenase-1 levels in trauma patients. AB - Traumatic injury induces a local and systemic release of pro-inflammatory cytokines, acute phase proteins, hormones, and other inflammatory mediators. The excessive release of these mediators plays an important role in the pathogenesis of shock. In parallel to this pro-inflammatory response, there is a regulatory response characterized by the release of anti-inflammatory mediators, which is thought to represent the host's attempt to restore immunological equilibrium. Studies in septic patients have suggested the compensatory anti-inflammatory response may result in an "immunodeficient state" that leaves the host susceptible to further infectious insults. A key feature of the anti-inflammatory state in septic patients is a change in the responsiveness of monocytes that has been termed "monocyte deactivation." This is supported by data that link monocyte deactivation to increased mortality in septic patients. Monocytes with reduced HLA-DR expression have been described in trauma patients. We collected blood from 25 severely injured patients and evaluated peripheral blood mononuclear cells (PBMC) for HLA-DR expression and TNF-alpha response to LPS stimulation as markers of monocyte deactivation. Levels of intracellular HO-1 were determined in each patient, as HO-1 has been implicated in monocyte deactivation in patients with severe systemic inflammatory response syndrome (SIRS). HLA-DR expression correlated inversely with Injury Severity Scores and TNF-alpha response to LPS stimulation, but failed to correlate with HO-1 levels in these patients. HLA-DR expression was decreased in normal monocytes stimulated with patient plasma, but this treatment had no effect on HO-1 levels. These results suggest monocyte deactivation in trauma patients is unlikely to be mediated by HO-1. PMID- 21601879 TI - Gene pathway analysis of hepatocellular carcinoma genomic expression datasets. AB - BACKGROUND: Genomic analyses of cancer rarely show significant overlap in reported significant genes from one study to the next. We posit that viewing transcriptomic data from the broader view of gene pathways and biologic processes will yield a more coherent and meaningful understanding compared with analyzing lists of individual genes. MATERIALS AND METHODS: To this end, we collected publicly available data from hepatocellular carcinoma (HCC) gene expression studies and collectively analyzed them using ANOVA, Gene Set Enrichment Analysis, and gene pathway analyses. RESULTS: The degree of pathway and function overlap was very high between datasets compared with individual gene overlap. Analysis of pathways shared among all the datasets showed that processes such as cell proliferation, cell cycle control, and apoptosis were highly represented in the HCC samples, and liver-specific processes such as lipid synthesis, coagulation protein synthesis, and drug metabolism were present in normal liver cells. Specific gene networks known to be important in HCC, such as WNT, PCNA, TGF, and TP53, are present in the study. CONCLUSIONS: We describe a generalizable method to combine multiple genomic datasets generated from diverse experimental platforms and study populations into an intuitive and biologically meaningful format. This approach allows the delineation of biologic processes of clinical significance that can predict important endpoints such as survival and tumor recurrence. PMID- 21601880 TI - Assessing residents in surgical ethics: we do it a lot; we only know a little. AB - BACKGROUND: PGY-1 year of surgical residency brings together many persons of disparate experiences and educational backgrounds, including their exposure to ethics. We hypothesized that surgical PGY-1s would have a similar exposure to ethical scenarios but lack the confidence in practice and understanding of ethical principles compared with more senior residents. MATERIALS AND METHODS: Surgical residents were invited to resident-initiated surgical ethics workshops utilizing a standardized text. Here a survey and multiple choice tests were administered to participants. The survey determined prior exposure to ethics curricula, the frequency of exposure to various ethics topics, and their comfort with these scenarios. A multiple choice test then quantified the knowledge base of participating residents. The results were collected and compared between surgical PGY-1s and more senior residents. RESULTS: Eighteen PGY-1s and 12 senior residents completed this curriculum. Resident exposure to ethical concepts was common. Resident confidence in these topics was ranked moderate or higher for both groups. Despite frequent clinical exposure and strong confidence in their skills of addressing these topics, performance on the test was poor, with an average score of 59% for PGY-1s and 47% for more senior residents (P=0.03). CONCLUSIONS: Despite clinical exposure to and confidence in their management of ethical topics, their knowledge base was poor and worse for more senior residents. Given the overall interest in a formal ethics curriculum and the knowledge deficit demonstrated, educational intervention and professional ethics support should be provided for surgical residents even with the current educational time constraints. PMID- 21601881 TI - Anti-CA19-9 diabody as a PET imaging probe for pancreas cancer. AB - BACKGROUND: Intact antibodies are poor imaging agents due to a long serum half life (10-20 d) preventing adequate contrast between the tumor and surrounding blood. Smaller engineered antibody fragments overcome this problem by exhibiting shorter serum half-lives (4-20 h).The diabody (55 kDa) is the smallest antibody fragment, which retains the bivalency of the intact antibody. Our goal was to develop and characterize the anti-CA19-9 diabody fragment and determine its ability to provide antigen specific imaging of pancreas cancer. METHODS: The diabody DNA construct was created by isolation of the variable region genes of the intact anti-CA19-9 antibody. Diabody expression was carried out in NS0 cells and purified using HPLC from supernatant. Specific antigen binding was confirmed with flow cytometry and immunofluorescence. Radiolabeled diabody was injected into mice harboring an antigen positive xenograft (BxPC3 or Capan-2) and a negative xenograft (MiaPaca-2). MicroCT and MicroPET were performed at successive time intervals after injection. Radioactivity was measured in blood and tumor to provide objective confirmation of the microPET images. RESULTS: Immunofluorescence and flow cytometry showed specific binding of the anti-CA19-9 diabody. Pancreas xenograft imaging of BxPC3/MiaPaca-2 and Capan-2/MiaPaca-2 models with the anti-CA19-9 diabody demonstrated an average tumor:blood ratio of 5.0 and 2.0, respectively, and an average positive:negative tumor ratio of 11 and 6, respectively. With respect to the tumor:blood ratio, these data indicate five times and two times more radioactivity in the tumor than in the blood yielding adequate contrast between tumor tissue and background (i.e., blood) to create the representative microPET images. CONCLUSIONS: We successfully engineered a functional diabody against CA19-9, a tumor antigen present on the vast majority of pancreas cancers. Additionally, we demonstrate high contrast antigen specific microPET imaging of pancreas cancer in xenograft models. PMID- 21601882 TI - CD133(-) cells, derived from a single human colon cancer cell line, are more resistant to 5-fluorouracil (FU) than CD133(+) cells, dependent on the beta1 integrin signaling. AB - BACKGROUND AND AIM: Recently, the cancer stem cells (CSCs) theory has been proposed, and CD133 has been suggested as a potential marker of CSCs in various cancer types. In the present study, we aimed evaluate CD133 as a potential marker of colorectal CSCs and, for this purpose, isolated CD133(+) and CD133(-) cells from a single colorectal cancer cell line, and compared their features, especially related to the tumor-forming and differentiation abilities, and the sensitivity to chemotherapy. METHODS AND RESULTS: CD133(+) cells had higher in vivo tumor-forming ability than CD133(-) cells, and in culture, they progressively differentiated into CD133(-) cells, but not vice-versa. On the other hand, CD133(-) cells were more resistant to 5-fluorouracil (FU) treatment than CD133(+) cells, and it was found to be dependent on the higher expression of beta1-integrins, and consequently, higher ability to bind collagen. Disruption of the beta1-integrin function abrogated the chemoresistance. CONCLUSION: From the present results, we concluded that colorectal cancer CD133(+) cells, although showing some features of CSCs, are not more resistant to 5-FU than CD133(-) cells. Therefore, definite conclusions can not be drawn yet, but it is strongly suggestive that CD133 should not be used as a single CSC marker of colorectal cancer. PMID- 21601883 TI - TLR2 and TLR4 up-regulation and colonization of the ileal mucosa by Clostridiaceae spp. in chronic/relapsing pouchitis. AB - BACKGROUND: Chronic pouchitis, which can lead to pouch failure, occurs in approximately 5% of patients after restorative proctocolectomy for ulcerative colitis (UC). This work examined the interplay between the microbiota adherent to the ileal pouch mucosa and the mucosal immune system in chronic/relapsing pouchitis. PATIENTS AND METHODS: Thirty-two consecutive patients attending our surgical gastroenterological department following restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for UC were considered eligible candidates for this study. Biopsy samples of bacteria adherent to the mucosa were collected. TLR4 and TLR2 mucosal expression was measured by Real Time RT-PCR. Serum and mucosal IL-1beta, IL-6, and TNF-alpha levels were assessed using immunometric assays. Fecal lactoferrin concentrations were determined by quantitative ELISA. After a median follow-up of 23 months (IQR 20-24 months) each patient underwent a global assessment of their clinical condition and disease activity status. RESULTS: Six patients were diagnosed with relapsing/chronic pouchitis during the follow-up period. Mucosal TLR2 and TLR4 expression was higher in the chronic/relapsing pouchitis group than in the no or only one episode of pouchitis group (P = 0.036 and P = 0.016, respectively). The number of colony forming units (CFU) of mucosa-associated Clostridiaceae spp. was higher in the former than in the latter group (P = 0.031). Clostridiaceae were associated to a significant risk of chronic/relapsing pouchitis [OR: 14 (95% CI 0.887 224.021), P = 0.045]. CONCLUSION: Chronic/relapsing pouchitis is associated to higher mucosal TLR2 and TLR4 expression. Mucosal colonization by Clostridiaceae spp seems to play a role in the pathogenesis of chronic/relapsing pouchitis. PMID- 21601884 TI - Pre-hospital intubation is associated with increased mortality after traumatic brain injury. AB - BACKGROUND: Early endotracheal intubation in patients sustaining moderate to severe traumatic brain injury (TBI) is considered the standard of care. Yet the benefit of pre-hospital intubation (PHI) in patients with TBI is questionable. The purpose of this study was to investigate the relationship between pre hospital endotracheal intubation and mortality in patients with isolated moderate to severe TBI. METHODS: The Los Angeles County Trauma System Database was queried for all patients > 14 y of age with isolated moderate to severe TBI admitted between 2005 and 2009. The study population was then stratified into two groups: those patients requiring intubation in the field (PHI group) and those patients with delayed airway management (No-PHI group). Demographic characteristics and outcomes were compared between groups. Multivariate analysis was used to determine the relationship between pre-hospital endotracheal intubation and mortality. RESULTS: A total of 2549 patients were analyzed and then stratified into the two groups: PHI and No-PHI. There was a significant difference noted in overall mortality (90.2% versus 12.4%), with the PHI group being more likely to succumb to their injuries. After adjusting for possible confounding factors, multivariable logistic regression analysis demonstrated that PHI was independently associated with increased mortality (AOR 5, 95% CI: 1.7-13.7, P = 0.004). CONCLUSIONS: Pre-hospital endotracheal intubation in isolated, moderate to severe TBI patients is associated with a nearly 5-fold increase in mortality. Further prospective studies are required to establish guidelines for optimal pre hospital management of this critically injured patient population. PMID- 21601885 TI - An experimental study on the effect of safflower yellow on tendon injury-repair in chickens. AB - BACKGROUND: The present study sought to investigate pathologic changes in tendon, expression of basic fibroblast growth factor (bFGF) and collagen type I, and effects of safflower yellow (SY) on the process of tendon injury-repair. MATERIALS AND METHODS: A tendon injury-repair model was used, and stereology, biomechanics, and immunohistochemistry were employed to assess the benefits of local application of SY for the repair. In this model, the flexor digitorum profundus muscle tendon of the third digit was transected bilaterally, and the transected ends sutured. Data were analyzed with SPSS ver. 10.0 software (SPSS Inc., Chicago, IL). RESULTS: The adhesion to surrounding tissues and tensile strength gradually increased after the injury and repair in control (no-SY) tendons, and were significantly greater by the sixth wk than any other time. In the SY tendons, adhesion was significantly lower, and tensile strength significantly higher than in no-SY tendons at the same post-injury-suture time points. An inflammatory reaction was observed in the injury-repair areas of the tendon by the end of first wk post-injury-suture, and reached its peak by the end of second wk. The inflammatory reaction was significantly less in SY tendons than in controls. Immunostaining for bFGF occurred in the tendon injury-repair areas by the end of first wk, and the number of bFGF positive cells reached a peak by the end of second wk, with a greater abundance in SY than control tendons from the second to sixth wk. Expression of collagen type I protein was observed in the injury-repair areas as well, coincident with bFGF, and was remarkably higher in SY than in controls. CONCLUSIONS: Tendon adhesion and tensile strength increased with time post-injury-suture repair, as did expression of bFGF and collagen type I protein in the injured area. SY enhanced expression of bFGF and collagen type I protein, enhanced the tensile strength of the injured tendon, and alleviated the injured tendon adhesion and inflammatory reaction. The results indicated that SY promoted the repair of injured tendon by up-regulating expression of bFGF and collagen type I protein. PMID- 21601886 TI - MMP-3 (5A/6A) polymorphism does not influence human smooth muscle cell invasion. AB - BACKGROUND: Stromelysin (MMP-3) is an important regulator of vascular smooth muscle cell (SMC) invasion, a key contributor to saphenous vein (SV) bypass graft failure. The 5A allele of the common -1612 MMP-3 5A/6A promoter polymorphism reportedly confers increased promoter activity, MMP-3 tissue expression, and susceptibility to a number of vascular pathologies. The aim of this study was to determine whether the MMP-3 5A/6A polymorphism directly influences endogenous MMP 3 expression levels and, consequently, cell invasion, in SV-derived SMC cultured from patients with different genotypes. MATERIAL AND METHODS: Genotyping of 226 patients revealed -1612 MMP-3 5A/6A genotype frequencies of 20.8% 5A/5A, 52.7% 5A/6A, and 26.5% 6A/6A. Using a standardized, controlled protocol, we investigated cytokine- and growth factor-induced MMP-3 expression (real-time polymerase chain reaction [RT-PCR], ELISA) and SV-SMC invasion (Boyden chamber with Matrigel barrier) using cultured SV-SMC from patients with different MMP-3 genotypes. RESULTS: Despite observing a strong correlation between MMP-3 mRNA levels and MMP-3 protein secretion, no significant differences were apparent in MMP-3 expression levels or cell invasion between cells with different MMP-3 5A/6A genotypes. CONCLUSIONS: Our data suggest that the MMP-3 5A/6A promoter polymorphism in isolation does not influence levels of MMP-3 secretion or cellular invasion in human SV-SMC. PMID- 21601888 TI - Early life child exposure and the risk of multiple sclerosis: a population based study. AB - The precise aetiology of multiple sclerosis (MS) is yet to be conclusively determined, but both genes and environment and interactions thereof are important. It has been suggested that early life child exposure influences MS susceptibility. Here, in a population-based cohort, we investigated whether infant day care attendance influences the subsequent risk to develop MS. We identified 379 MS index cases and 101 spousal controls, all of whom were a single child (i.e. they had no biological sibs, half-sibs, step-sibs, adopted sibs) from the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). Frequency of infant day care attendance was compared for index cases and controls and the results were not statistically significant. Exposure to other infants during early childhood thus does not appear to be a risk factor for MS. PMID- 21601887 TI - Role of neutrophils and macrophages in the pathogenesis of necrotizing enterocolitis caused by Cronobacter sakazakii. AB - BACKGROUND: Cronobacter sakazakii (CS) is a highly virulent gram-negative opportunistic pathogen that has been implicated in clinical outbreaks of necrotizing enterocolitis (NEC). The role of mucosal immune cells in CS infection is not well understood. In this study, we sought to elucidate the role of neutrophils (polymorphonuclear leukocytes; PMNs) and macrophages in the pathogenesis of NEC induced by CS using a novel newborn mouse model. MATERIALS AND METHODS: PMNs and macrophages were depleted in newborn mice using Gr-1 antibody and carrageenan, respectively, and then infected with 10(3) CFU of CS. The development of NEC in these mice was assessed by a pathologist based on the morphologic changes in the intestine. Cytokine production was determined in the serum and intestinal homogenates of infected mice by enzyme-linked immunosorbent assay (ELISA). Inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production was determined by flow cytometry and Greiss method, respectively. RESULTS: Depletion of PMNs and macrophages in newborn mice led to increased recruitment of dendritic cells (DCs) in the intestine compared with wild-type mice upon infection with CS. PMN- and macrophage-depleted mice showed increased bacterial load, production of pro-inflammatory cytokines, iNOS expression, and NO production in the intestines in comparison to wild-type mice fed with CS. In addition, depletion of PMNs and macrophages prior to infection in mice resulted in severe inflammation, villus destruction, and enhanced enterocyte apoptosis in the intestines compared with CS-infected wild-type mice. CONCLUSIONS: Our data suggest that depletion of PMNs and macrophages from the lamina propria (LP) exacerbates experimental NEC, indicating that both of these immunocytes play an important role in the clearance of CS during the initial stages of infection. The increased mucosal cytokine response and NO production in the absence of these immunocytes may be responsible for the observed increase in mucosal injury. Understanding how CS manipulates these cells, employing novel mouse model of NEC reported in this study, will provide significant insights for the development of novel therapeutic and preventive strategies to combat NEC. PMID- 21601889 TI - Neurofilament stoichiometry simulations during neurodegeneration suggest a remarkable self-sufficient and stable in vivo protein structure. AB - BACKGROUND: Neurofilaments (Nfs) are protein biomarkers of neurodegeneration in human disease. There is in vivo evidence of changes of the Nf stoichiometry in the cerebrospinal fluid (CSF) of patients. The protein-structural implications of these findings are not known but may be assessed indirectly using simulations studies. METHODS: Monte Carlo simulations were performed using a coarse-grained model of a Nf brush. Based on the published in vivo CSF data the tested Nf stoichiometries (NfL:NfM:NfH) were 16:11:4 for multiple system atrophy (MSA), 24:5:2 for relapsing remitting multiple sclerosis (RRMS), and 30:0:1 for clinically isolated syndromes (CIS). Simulations were performed in a wide range of ionic strength (1 mM-100 mM) for dephosphorylated and phosphorylated NF isoforms. RESULTS: At lower ionic strengths (1 mM, 10 mM), NfM is the main determinant for the radius of gyration (R(g)) ranging from ~15 nm in the dephosphorylated state at 10 mM ionic strength to ~27 nm at 1mM ionic strength if fully phosphorylated. At high ionic strength (100mM) NfH becomes the main determinant with R(g) of 14.8+/-0.2 nm if dephosphorylated and 15+/-0.2 nm if phosphorylated. There was no significant difference in the structures of the three Nf sidearms for MSA, RRMS or CIS. CONCLUSION: Large changes of the in vivo Nf stoichiometry have only little effect on the simulated structure of Nf sidearms independent of phosphorylation and ionic strength. This suggests that the axonal cytoskeleton is remarkably stable, possibly relying on NfL which forms a dense brush around the Nf backbone and virtually excludes NfM and NfH from the core region, such that the dropout of NfM and NfH can be dealt with structurally. PMID- 21601890 TI - [Differences in the predictive values of the FRAXTM tool between the Spanish and United Kingdom population and considerations about the intervention threshold]. PMID- 21601891 TI - [Non-melanoma skin cancer: incidence time trends analysis in Girona, Spain, 1994 2007]. AB - BACKGROUND AND OBJECTIVE: We aimed to assess the population-based incidence trends of non-melanoma skin cancer (NMSC): squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). PATIENTS AND METHOD: From January 1994 to December 2007, 9,247 patients diagnosed with NMSC were recruited in the population-based Cancer Registry of Girona. Incidence rates were calculated with age-adjusted according to the Word standard population (WASR) by a direct method and reported as number of new cases per 100,000 person-year. To evaluate incidence trends by age group we used specific rates for these groups (45-64, > 64 years). We excluded patients younger than 45 years. Joinpoint method was used to estimate the average annual percentage change (AAPC) for the whole study period according to histologic and age groups. RESULTS: Age-adjusted incidence was 55.74 per 10(5) person-year; it was higher in males (67.13) than in females (46.9). Age-adjusted incidence for BCC was higher compared with the incidence for SCC (44.56 and 11.18 respectively). Age-adjusted incidence rate for NMSC for both sexes increased from 48.53 (1994-95) to 60.54 (2004-05) with an AAPC of 2.30%, which was higher in females (2.65%) than in males (1.99%). CONCLUSIONS: There has been a significant increase in the incidence of NMSC in our area, particularly evident for SCC, and it is more important in patients older than 64 years and in females. PMID- 21601892 TI - [Patients with clinical criteria for Lynch syndrome with and without mutations in DNA repair genes (MLH1 and MSH2). A challenge for the clinician]. AB - BACKGROUND AND OBJECTIVES: The objective was to study the clinicopathologic characteristics of patients diagnosed of colorectal cancer (CRC) with clinical criteria for Lynch syndrome, in our region, in order to assess and improve the care of them and their families in the Genetic Counseling Unit of our hospital. PATIENTS AND METHODS: This was an observational, transversal retrospective study. The studied sample was made up of all the patients with clinical criteria for Lynch syndrome, who underwent a molecular analysis test in the Genetic Counseling Unit of Salamanca, during the period 2004-2009. We included patient and tumor related variables and the presence or absence of mutations in MLH1 and MSH2. RESULTS: A total of 76 patients were included in the analysis. Fifteen of them carried a mutation either in MLH1 or in MSH2. The mean age at diagnosis of colorectal cancer was 51.2 and 54.3 years in the group with and without mutation respectively, with a similar gender distribution in both groups. A wide phenotypic heterogeneity was found in the sample. CONCLUSIONS: Lynch syndrome is an entity difficult to categorize from a clinical point of view. Therefore, it is important to be alert for a better management of these patients and their families. PMID- 21601893 TI - [Validity of the CKD-EPI equation to estimate the creatinine clearance in patients admitted to Intensive Care]. PMID- 21601894 TI - The genus Dracunculus--a source of triacylglycerols containing odd-numbered omega phenyl fatty acids. AB - Reversed phase liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (RP-HPLC/MS-APCI) was used to identify and quantify triacylglycerols (TAGs) having odd-numbered omega-phenylalkanoic acids from seeds of the flower plant Dracunculus vulgaris, and TAGs from the bacterium Rhodococcus erythropolis prepared by precursor directed biosynthesis from phenylalanine and having the corresponding even-numbered omega-phenylalkanoic acids. Model compounds, which are not commercially available, were prepared by organic synthesis and this allowed us to extend the number of identified natural TAGs to nearly 140 molecular species. Both synthetic and natural compounds containing omega-phenylalkanoic acids were found to have antioxidant and free radical scavenging properties. PMID- 21601895 TI - Antiviral isoindolone derivatives from an endophytic fungus Emericella sp. associated with Aegiceras corniculatum. AB - Chemical investigation of the endophytic fungus Emericella sp. (HK-ZJ) isolated from the mangrove plant Aegiceras corniculatum led to isolation of six isoindolones derivatives termed as emerimidine A and B and emeriphenolicins A and D, and six previously reported compounds named aspernidine A and B, austin, austinol, dehydroaustin, and acetoxydehydroaustin, respectively. Their structures were elucidated on the basis of NMR spectroscopic evidence while the anti influenza A viral (H1N1) activities of eight compounds were also evaluated using the cytopathic effect (CPE) inhibition assay. PMID- 21601896 TI - Antiprotozoal and antiangiogenic saponins from Apodytes dimidiata. AB - Bioassay-guided isolation was performed on the leaves of Apodytes dimidiata E. Mey. Ex Arn. (Icacinaceae), based on previously demonstrated activity against Leishmania. Six saponins never isolated from nature before were elucidated with LC-MS/MS, GC-MS and 1D and 2D NMR. The compounds apodytine A-F are responsible at least in part for the antiprotozoal activity, but also possess haemolytic activity and display antiangiogenic activity in the rat aorta ring assay, an effect which may be due to a non-selective toxicity. PMID- 21601897 TI - Iridoid glycosides and glycosidic constituents from Eriophyton wallichii Benth. AB - C9-iridoid glycosides, wallichiisides A-C, and four dimers, wallichiisides D-G, together with 13 known glycosidic compounds, were isolated from whole plants of Eriophyton wallichii Benth. Their structures were elucidated by spectroscopic methods and comparison with literature values. Four of these compounds showed moderate DPPH free radical scavenging activity. PMID- 21601898 TI - Metabolic fingerprinting reveals differences between shoots of wild and cultivated carrot (Daucus carota L.) and suggests maternal inheritance or wild trait dominance in hybrids. AB - Differences between the metabolic content of cultivars and their related wild species not only have implications for breeding and food quality, but also for the increasingly studied area of crop to wild introgression. Wild and cultivated western carrots belong to the same outcrossing species and hybridize under natural conditions. The metabolic fingerprinting of Dutch wild carrot and of western orange carrot cultivar shoots using (1)H NMR showed only quantitative differences in chemical content, indicating relatively low divergence after domestication. Main differences reside in the primary metabolite content and in the concentrations of chlorogenic acid and feruloyl quinic acid in the shoots of the different carrot types. Wild*cultivar hybrids cannot be distinguished from wild plants based on the metabolome, suggesting maternal, maternal environment, or dominance effects, and indicating high hybrid fitness in wild conditions. Considering these similarities, introgression is a real possibility in carrots, but understanding its consequences would require further studies using backcrosses in a multiple environments. PMID- 21601899 TI - [Nutritional factors and oral cancers]. AB - The number of new oral cancers in France has been estimated at 7000 cases for 2005, 75% of these cancers affecting male patients. International expert groups met by the International Agency for research on Cancer (IARC), or the World Cancer Research Fund (WCRF) associated to the American Institute for Cancer Research (AICR) have identified two factors which can modify the risk of oral cancers. Alcoholic beverages increase the risk of cancer and are classified as carcinogen for humans by IARC (level of evidence qualified as convincing by WCRF and AICR). Fruits and vegetables decrease the risk of cancer (level of evidence qualified as probable by WCRF and AICR). For other nutritional factors, the data are too limited to draw any conclusion. We present the major epidemiologic and mechanistic results of these evaluations, completed by results from recent studies. In addition to actions targeting other risk factors such as tobacco, reducing alcohol intake and increasing the consumption of fruits and vegetables can contribute to the prevention of oral cancers. PMID- 21601900 TI - [Epidemiology of oral cavity cancers in France]. AB - INTRODUCTION: We had for objective to describe the updated epidemiology of oral cancers in France. MATERIAL AND METHODS: Estimates made from data collected from various French cancer institutions. The distribution by topography, histology, regions, mean age, and specific incidence rates were calculated from the collected data. The survival data was taken from the Francim network studies. RESULTS: Approximately 7000 oral cavity cancers were diagnosed in France in 2005. In 2007, 1746 people died of that cancer. Standardized (world population) incidence rates are respectively, in men and women, 12.3 and 3.0 cases per 100,000 person-years. These cancers have significantly decreased in men: the standardized incidence rate decreased by 43.2% between 1980 and 2005. Among women, the trend is reversed with an increased incidence of 51.7% over the same period. CONCLUSION: In France, the incidence of oral cavity cancers has been strongly decreasing in men and strongly increasing in women. This trend should be compared to the frequency of the main risk factors: alcohol and tobacco. PMID- 21601901 TI - Effect of annual mass administration of diethylcarbamazine and albendazole on bancroftian filariasis in five villages in south India. AB - Annual mass drug administration (MDA) is the recommended strategy for lymphatic filariasis (LF) elimination. We assessed the effect of six rounds of mass administration of diethylcarbamazine (DEC) and albendazole (ALB) on microfilaria (Mf) prevalence and intensity and vector infection and infectivity rates and circulating filarial antigenaemia (CFA) in a group of five villages in south India, endemic for Culex-transmitted bancroftian filariasis. During different rounds of MDA, 60-70% of the eligible population (>15 kg body weight) was treated. The MDA reduced the Mf prevalence from 8.10% (CI 6.18-10.01) to 1.01% (CI 0.31-1.71) (P<0.05) and geometric mean intensity of Mf from 0.31 (CI 0.22 0.40) to 0.02 (CI 0.00-0.04) (P<0.05), equivalent to a fall of 86% and 94% respectively. The vector infection and infectivity rates declined from 13.11% (CI 11.52-14.70) to 0.78% (CI 0.16-1.40) (P<0.05) and 1.04% (CI 0.56-1.52) to 0.13% (CI 0.00-0.39) (P<0.05), respectively. Four out of the five villages recorded <0.5% Mf prevalence and 0% vector infection rate. Circulating filarial antigenaemia (CFA) fell by 86% in the total population and 100% in 1-10 year old children. One of the five villages, which showed the highest baseline vector infection rate, showed >1.0% Mf rate. The results suggest that six rounds of mass administration of DEC and ALB, with 60-70% treatment coverage, is likely to achieve total interruption of transmission and elimination of LF in the majority of villages. PMID- 21601902 TI - Vitreous substitutes: a comprehensive review. AB - Vitreoretinal disorders constitute a significant portion of treatable ocular disease. Advances in vitreoretinal surgery have included the development and characterization of suitable substitutes for the vitreous. Air, balanced salt solutions, perfluorocarbons, expansile gases, and silicone oil serve integral roles in modern vitreoretinal surgery. Vitreous substitutes vary widely in their properties, serve different clinical functions, and present different shortcomings. Permanent vitreous replacement has been attempted with collagen, hyaluronic acid, hydroxypropylmethylcellulose, and natural hydrogel polymers. None, however, have proven to be clinically viable. A long-term vitreous substitute remains to be found, and recent research suggests promise in the area of synthetic polymers. Here we review the currently available vitreous substitutes, as well those in the experimental phase. We classify these compounds based on their functionality, composition, and properties. We also discuss the clinical use, advantages, and shortcomings of the various substitutes. In addition we define the ideal vitreous substitute and highlight the need for a permanent substitute with long-term viability and compatibility. Finally, we attempt to define the future role of biomaterials research and the various functions they may serve in the area of vitreous substitutes. PMID- 21601903 TI - Retinal vein occlusion: beyond the acute event. AB - Retinal vein occlusion is a major cause of vision loss. We provide an overview of the clinical features, pathogenesis, natural history, and management of both branch retinal vein occlusion and central retinal vein occlusion. Several recent multicenter randomized clinical trials have been completed which have changed the approach to this disorder. Management of retinal vein occlusions can be directed at the underlying etiology or the resulting sequelae. Options include surgical intervention, laser photocoagulation, intravitreal pharmacotherapy, and sustained drug delivery devices. PMID- 21601904 TI - The effect of primary treatment and flow regime on clogging development in horizontal subsurface flow constructed wetlands: An experimental evaluation. AB - The effect of both the type of primary treatment (hydrolitic up-flow sludge blanket (HUSB) reactor and conventional settling) and the flow regime (batch and continuous) on clogging development in subsurface flow constructed wetlands (SSF CWs) was studied. Clogging indicators (such as accumulated solids, hydraulic conductivity and drainable porosity) were determined in an experimental plant with three treatment lines. Correlations were encountered between the solids accumulated and both saturated hydraulic conductivity and drainable porosity reduction over time (74.5% and 89.2% of correlation, respectively). SSF CW implemented with a HUSB reactor accumulated ca. 30% lower sludge (1.9 kg DM/m(2)) than a system with a settler (2.5-2.8 kg DM/m(2)). However, no significant differences were recorded among treatment lines concerning hydraulic parameters (such as hydraulic conductivity or porosity). Root system development contributed to clogging. Accordingly, planted wetlands showed between 30% and 40% and 10% lower hydraulic conductivity and porosity reduction, respectively, than non planted wetlands. PMID- 21601905 TI - Effects of bioaugmentation on indigenous PCB dechlorinating activity in sediment microcosms. AB - Bioaugmentation is an attractive mechanism for reducing recalcitrant pollutants in sediments, especially if this technology could be applied in situ. To examine the potential effectiveness of a bioaugmentation strategy for PCB contamination, PCB dehalorespiring populations were inoculated into Baltimore Harbor sediment microcosms. A culture containing the two most predominant indigenous PCB dehalorespiring microorganisms and a culture containing a strain with a rare ortho dechlorination activity and a non-indigenous strain that attacks double flanked chlorines, were inoculated into sediment microcosms amended with 2,2',3,5,5',6-hexachlorobiphenyl (PCB 151) and Aroclor 1260. Although we observed a similar reduction in the concentration of PCB 151 in all microcosms at day 300, a reduced lag time for dechlorination activity was observed only in the bioaugmented microcosms and the pattern of dechlorination was altered depending on the initial combination of microorganisms added. Dechlorination of Aroclor 1260 was most extensive when dehalorespiring microorganisms were added to sediment. Overall numbers of dehalorespiring microorganisms in both bioaugmented and non-bioaugmented microcosms increased 100- and 1000-fold with PCB 151 and Aroclor 1260, respectively, and they were sustained for the full 300 days of the experiments. The ability of bioaugmentation to redirect dechlorination reactions in the sediment microcosms indicates that the inoculated PCB dehalorespiring microorganisms effectively competed with the indigenous microbial populations and cooperatively enhanced or altered the specific pathways of PCB dechlorination. These observations indicate that bioaugmentation with PCB dehalorespiring microorganisms is a potentially tractable approach for in situ treatment of PCB impacted sites. PMID- 21601906 TI - Impact of heavy metal pollution on the hemogram and serum biochemistry of the Libyan jird, Meriones libycus. AB - The stress profiles of the hemogram and serum biochemistry were determined in the context of heavy metal (Cd, Cu, Hg, Ni and Pb) exposure in the wild libyan jird, Meriones libycus, from one of Riyadh's polluted areas versus a reference site. Coupling the pronounced drop in platelets (PLT) (28%) and mean platelet volume (MPV) (17%) with the insignificant responses of other red blood cell indices, suggests bone marrow suppression that is characterized by thrombocytopenia as an initial abnormality. The species-specific stress leukogram for M. libycus is expressed by leukocytosis (66%), monocytosis (40%), lymphocytosis (23%) with eosinopenia (81%) and neutropenia (42%). Hyperglycemia (50%), hyper-low-density lipoproteinemia (38%), hypocortisolism (85%) and hypotriglyceridemia (55%) depicted serum biochemistry profile. In polluted jirds, the elevated activities of pseudocholinesterase (PChE) and serum marker enzymes (alanine aminotransferase ALT, aspartate aminotransferase AST and creatine kinase CK) strongly suggest functional damage of the liver and/or heart. A potential role of PChE in low density lipoprotein (LDL) metabolism is implied in the joint rise of both indices and in the recognized relationship between PChE and lipid metabolites. While increased utilization in lipid metabolism and energy synthesis could rationalize the inhibition of the normal patterns of triglycerides and lactate dehydrogenase (LDH), the inhibited activities of LDH could additionally be attributed to its hormetic behavior towards low and high metal concentrations. The overall findings presented here documented the relevance of M. libycus in biomonitoring and predicting the risk imposed on human populations living in polluted areas. PMID- 21601907 TI - Toxicity assessment of a common laundry detergent using the freshwater flagellate Euglena gracilis. AB - Synthetic detergents are among the commonly used chemicals in everyday life. Detergents, reaching aquatic environments through domestic and municipal wastewater, can cause many different effects in aquatic organisms. The present study was aimed at the toxicity evaluation of a commonly used laundry detergent, Ariel, using the freshwater flagellate Euglena gracilis as a biotest organism. Different parameters of the flagellate like motility, swimming velocity, cell shape, gravitactic orientation, photosynthesis and concentration of light harvesting pigments were used as end points for the toxicity assessment. No Observed Effect Concentration (NOEC) and EC(50) values were calculated for the end point parameters at four different incubation times, i.e. 0, 6, 24 and 72 h. After 72 h incubation, swimming velocity of the cells was found to be the most sensitive parameter giving NOEC and EC(50) values of 10.8 and 34 mg L(-1), respectively. After 72 h exposure to the detergent, chlorophyll a and total carotenoids were significantly decreased in cultures treated with Ariel at concentrations of 50 mg L(-1) and above while chlorophyll b significantly decreased at concentrations above 750 mg L(-1). The maximum inhibitory effect on the quantum yield of photosystem II was observed after 24 h exposure and thereafter a recovery trend was observed. Motility, gravitaxis and cell shape were strongly impaired immediately upon exposure to the detergent, but with increasing exposure time these parameters showed acclimatization to the stress and thus the NOEC values obtained after 72 h were higher than those immediately after exposure. PMID- 21601908 TI - Assessment of oral bioaccessibility of arsenic in playground soil in Madrid (Spain): a three-method comparison and implications for risk assessment. AB - Three methodologies to assess As bioaccessibility were evaluated using playground soil collected from 16 playgrounds in Madrid, Spain: two (Simplified Bioaccessibility Extraction Test: SBET, and hydrochloric acid-extraction: HCl) assess gastric-only bioaccessibility and the third (Physiologically Based Extraction Test: PBET) evaluates mouth-gastric-intestinal bioaccessibility. Aqua regia-extractable (pseudo total) As contents, which are routinely employed in risk assessments, were used as the reference to establish the following percentages of bioaccessibility: SBET-63.1; HCl-51.8; PBET-41.6, the highest values associated with the gastric-only extractions. For Madrid playground soils- characterised by a very uniform, weakly alkaline pH, and low Fe oxide and organic matter contents--the statistical analysis of the results indicates that, in contrast with other studies, the highest percentage of As in the samples was bound to carbonates and/or present as calcium arsenate. As opposed to the As bound to Fe oxides, this As is readily released in the gastric environment as the carbonate matrix is decomposed and calcium arsenate is dissolved, but some of it is subsequently sequestered in unavailable forms as the pH is raised to 5.5 to mimic intestinal conditions. The HCl extraction can be used as a simple and reliable (i.e. low residual standard error) proxy for the more expensive, time consuming, and error-prone PBET methodology. The HCl method would essentially halve the estimate of carcinogenic risk for children playing in Madrid playground soils, providing a more representative value of associated risk than the pseudo total concentrations used at present. PMID- 21601909 TI - Phenol depletion by thermally activated peroxydisulfate at 70 degrees C. AB - The ability of thermal activated peroxydisulfate (PS) of mineralizing phenol at 70 degrees C from contaminated waters is investigated. Phenol in concentrations of 10(-4) to 5*10(-4)M is quantitatively depleted by 5*10(-3) to 10(-2)M activated PS in 15 min of reaction. However, mineralization of the organic carbon is not observed. Instead, an insoluble phenol polymer-type product is formed. A reaction mechanism including the formation of phenoxyl radicals and validated by computer simulations is proposed. High molecular weight phenolic products are formed by phenoxyl radical H-abstraction reactions. This is not the case for the room temperature degradation of phenol by sulfate radicals where sulfate addition to the aromatic ring mainly leads to the generation of hydroxycyclohexadienyl radicals leading to hydroxybenzenes and oxidized open chain products. Therefore, a change in the reaction mechanism is observed with increasing temperature, and thermal activation of PS at 70 degrees C does not lead to the mineralization of phenol. Thus PS activation at 70 degrees C may be considered a potential method to reduce the load of phenol in polluted waters by polymerization. PMID- 21601910 TI - Chemical extraction of arsenic from contaminated soil under subcritical conditions. AB - In this research, we investigated a chemical extraction process, under subcritical conditions, for arsenic (As)-contaminated soil in the vicinity of an abandoned smelting plant in South Korea. The total concentration of As in soil was 75.5 mg/kg, 68% of which was As(+III). X-ray photoelectron spectroscopy analysis showed that the possible As(+III)-bearing compounds in the soil were As(2)O(3) and R-AsOOH. At 20 degrees C, 100 mM of NaOH could extract 26% of the As from the soil samples. In contrast, 100 mM of ethylenediaminetetraacetic acid (EDTA) and citric acid showed less than 10% extraction efficiency. However, as the temperature increased to 250 and 300 degrees C, extraction efficiencies increased to 75-91% and 94-103%, respectively, regardless of the extraction reagent used. Control experiments with subcritical water at 300 degrees C showed complete extraction of As from the soil. Arsenic species in the solution extracted at 300 degrees C indicated that subcritical water oxidation may be involved in the dissolution of As(+III)-bearing minerals under given conditions. Our results suggest that subcritical water extraction/oxidation is a promising option for effective disposal of As-contaminated soil. PMID- 21601911 TI - Follow-up outcomes for a large cohort of US women with negative imaged liquid based cytology findings and positive high risk human papillomavirus test results. AB - OBJECTIVE: This study aimed to follow a large group of US women with negative computer-imaged liquid-based cytology (LBC) and positive high risk (hr) HPV DNA results. METHODS: Negative LBC and positive hrHPV cases were identified between July 1, 2005 and December 31, 2009. Cytologic and histopathologic follow-up results, repeat HPV results, and prior history were analyzed. RESULTS: 1099 Patients with negative LBC and positive hrHPV results were identified. Eight hundred sixty-nine had repeat Pap or histopathologic follow-up results. Average age was 41.2 years. Average follow-up was 23.2 months. Two hundred ninety of 869 had colposcopic examination and biopsies, including 33 diagnostic excisional procedures and 10 hysterectomies. Cervical intraepithelial neoplasia (CIN) 1 and low-grade squamous intraepithelial lesions (CIN1/LSIL) and more severe lesions (CIN1/LSIL+) were detected in 211 of 689 (24.3%). CIN2+ was diagnosed in 21 (2.4%) (1 VAIN3, 2 adenocarcinoma in situ, 1 invasive cervical adenocarcinoma). Six hundred six had repeat HPV tests and 200 had multiple repeat HPV tests. More LSIL/CIN1+ was identified with repeat positive HPV results than with repeat negative HPV results (P<0.001). LSIL/CIN1+ was detected more often with a history of LSIL/CIN1+ than with a history of negative Paps (P<0.001). Eight of 105 (7.6%) cytology-negative HPV-positive patients tested positive for HPV 16 and/or HPV 18. CONCLUSION: This is the largest study documenting follow-up on US cytology negative hrHPV-positive patients screened with now widely utilized FDA-cleared methods of ciLBC and hrHPV testing. Of 869 patients followed for an average of almost 2 years, 20 cases of high grade intraepithelial neoplasia (2.3%) and one case of endocervical adenocarcinoma were detected. 90.5%(190/210) of intraepithelial neoplasias detected during follow-up were CIN1. PMID- 21601912 TI - Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers. AB - OBJECTIVES: Currently, pegylated liposomal doxorubicin (PLD) is regarded as one of the standard treatment options in recurrent ovarian cancers (ROC). Bevacizumab has shown significant antitumor activity for ROC in single-agent or in combination with cytotoxic agents. We have conducted a preliminary study to investigate effects of combination of bevacizumab and PLD for heavily pretreated patients with ROC. METHODS: Thirty patients with ROC were treated with combination therapy with weekly bevacizumab and PLD, 2 mg/kg of continuous weekly bevacizumab and 10 mg/m(2) of PLD (3 weeks on, 1 week off). The treatment was continued until development of disease progression, or unmanageable adverse effects. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and Gynecologic Cancer Intergroup (GCIG) CA125 response criteria. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. RESULTS: Overall response rate was 33%, and clinical benefit rate (CR+PD+SD) was 73%. Median progression-free survival was 6 months (range: 2-20 months), and a 6-months progression-free survival was 47%. Any hematological toxicities more than grade 3 were not observed. Two cases developed non-hematologic toxicities more than grade 2; a case with grade 3 hand-foot syndrome, another with grade 3 gastrointestinal perforation (GIP). The case with GIP was conservatively treated and recovered after 2 months, and there was no case with treatment-related death. CONCLUSION: The present investigation suggested that combination therapy with bevacizumab and PLD was active and well tolerated for patients with ROC. We recommend the regimen be evaluated in further clinical studies. PMID- 21601913 TI - Dietary baked milk accelerates the resolution of cow's milk allergy in children. AB - BACKGROUND: The majority (approximately 75%) of children with cow's milk allergy tolerate extensively heated (baked) milk products. Long-term effects of inclusion of dietary baked milk have not been reported. OBJECTIVE: We report on the outcomes of children who incorporated baked milk products into their diets. METHODS: Children evaluated for tolerance to baked milk (muffin) underwent sequential food challenges to baked cheese (pizza) followed by unheated milk. Immunologic parameters were measured at challenge visits. The comparison group was matched to active subjects (by using age, sex, and baseline milk-specific IgE levels) to evaluate the natural history of development of tolerance. RESULTS: Over a median of 37 months (range, 8-75 months), 88 children underwent challenges at varying intervals (range, 6-54 months). Among 65 subjects initially tolerant to baked milk, 39 (60%) now tolerate unheated milk, 18 (28%) tolerate baked milk/baked cheese, and 8 (12%) chose to avoid milk strictly. Among the baked milk reactive subgroup (n = 23), 2 (9%) tolerate unheated milk, and 3 (13%) tolerate baked milk/baked cheese, whereas the majority (78%) avoid milk strictly. Subjects who were initially tolerant to baked milk were 28 times more likely to become unheated milk tolerant compared with baked milk-reactive subjects (P < .001). Subjects who incorporated dietary baked milk were 16 times more likely than the comparison group to become unheated milk tolerant (P < .001). Median casein IgG(4) levels in the baked milk-tolerant group increased significantly (P < .001); median milk IgE values did not change significantly. CONCLUSIONS: Tolerance of baked milk is a marker of transient IgE-mediated cow's milk allergy, whereas reactivity to baked milk portends a more persistent phenotype. The addition of baked milk to the diet of children tolerating such foods appears to accelerate the development of unheated milk tolerance compared with strict avoidance. PMID- 21601914 TI - Effect of low density lipoproteins in extender on freezability and fertility of buffalo (Bubalus bubalis) bull semen. AB - This study was designed to determine whether low-density lipoporoteins (LDLs) extracted from egg yolk in extender improve the freezability and fertility of buffalo bull semen. Semen from three Nili-Ravi buffalo bulls was diluted at 37 degrees C with tris-citric acid extender (50 * 10(6) motile spermatozoa mL(-1)) containing LDLs 2.5%, 5%, 10%, and 15% extracted from egg yolk and extender containing 20% egg yolk was kept as control. Diluted semen was cooled to 4 degrees C in 2 h, equilibrated at 4 degrees C for 4 h, filled in 0.5 mL French straws, and kept on liquid nitrogen vapors for 10 min. Straws were then plunged and stored in liquid nitrogen (-196 degrees C). Sperm motility (visually; %), plasma membrane integrity (%; with supravital hypo-osmotic swelling test), and viability (%; with dual staining test using Trypan-blue Giemsa) were assessed at post-dilution, pre-freezing and post-thawing. At post-dilution and pre-freezing, sperm progressive motility, plasma membrane integrity and viability was similar (P > 0.05) in extender containing 10% LDLs or the control. However, at post-thaw the aforementioned parameters were higher (P < 0.05) in extender containing 10% LDLs compared with the control and other experimental extenders. The fertility rate of inseminations performed were higher (P < 0.05) with extender containing 10% LDLs than the control. It was concluded that LDLs (10%) in extender improved the freezability and fertility of buffalo bull spermatozoa. PMID- 21601915 TI - Treatment of sperm with extracellular adenosine 5'-triphosphate improves the in vitro fertility rate of inbred and genetically modified mice with low fertility. AB - In vitro fertilization (IVF) is one of the most important techniques used for assisted reproduction in mouse colony management. As with natural mating, where mice have varying fertility indices, fertility rates of genetically modified (GM) [transgenic (Tg), knock out (KO) and congenic (Cg)] mice are influenced by their genetic background. Lines of GM mice that have poor fertility have a concomitant poor IVF outcome. Treatment of mouse sperm with extracellular adenosine 5' triphosphate (ATPe) enhanced in vitro fertilization rates in outbred and hybrid mice. The objective of this study was to analyze the effects of using extracellular adenosine 5'-triphosphate-treated sperm for IVF of inbred wild type, and genetically modified mouse lines, for which standard IVF did not work well. The IVF was performed using the GM mice on C57BL/10SnJ, C57BL/6J, BALB/cJ and NFS/N background strains and wild type (WT) mice such as C57BL/6N, BALB/cAnN, and B6129SF1 strains. Oocytes from superovulated females were fertilized in vitro with sperm from the same background strain, and either treated or not treated with ATPe. The ATPe treatment enhanced IVF outcome in most of the GM and some WT strains, as indicated by the percentage of embryos that progressed to the two cell stage. There was no marked difference between ATPe treated and control groups for the development rate of two-cell embryos to blastocysts in culture, or in the number of pups born after transfer of two-cell embryos into recipient females. The observed improvement of the IVF results following ATPe treatment of transgenic and KO mouse sperm were a potential solution for improving the outcome of assisted reproduction techniques used for rederivation or for gamete banking. PMID- 21601916 TI - Genital lesions in male red fronted gazelles (Gazella rufifrons) experimentally infected with Trypanosoma brucei and the effect of melarsamine hydrochloride (Cymelarsan(r)) and diminazene aceturate (Berenil(r)) in its treatment. AB - Thirty red fronted gazelles (Gazella rufifrons) were used to assess the genital lesions associated with trypanosomosis and the efficacy of melarsamine hydrochloride (Cymelarsan(r)) and diminazene aceturate (Berenil(r)) in the treatment of the condition. The animals were divided into 6 equal groups (A-F). Animals in groups A-E were infected with Trypanosoma brucei, and later treated on day 8 post infection (p.i.) with either melarsamine hydrochloride (Cymelarsan(r)) at 0.3 mg/kg (Group A) and 0.6 mg/kg (Group B) or diminazene aceturate (Berenil(r)) at 3.5 mg/kg (Group C) and 7.0 mg/kg (Group D). Animals in group E remained untreated while group F served as healthy controls. Parasitaemia was established by day 8 p.i. in all infected groups and eliminated by day 16 following treatment on day 8 p.i. with melarsamine hydrochloride (Cymelarsan(r)) (Groups A and B) or diminazene aceturate (Berenil(r)) (Group D). On the other hand, diminazene aceturate treatment (Berenil(r)) on day 8 p.i. at 3.5 mg/kg (Group C) caused a temporary disappearance of parasites from the circulation by day 16 p.i. but there was a relapse parasitaemia on day 44 with a peak count of 500 +/- 2.79 * 10(3) parasites/MUL of blood by day 52 p.i. In the infected/untreated group (E), parasitaemia fluctuated but attained the same peak as Group C by day 52 p.i. Increase in body temperatures (40.5 +/- 3.16 - 42.8 +/- 3.25 degrees C) occurred during the first wave of parasitaemia but declined to pre-infection values from day 28 p.i. in Groups A, B and D. In Groups C and E, there was a second wave of parasitaemia (P < 0.05) with peak counts of 42.4 +/- 0.81 * 10(3)/MUL and 41.8 +/- 0.80 * 10(3)/MUL respectively by day 52 p.i. A significant (P < 0.05) decline in packed cell volume was also noted by day 52 p.i. The major clinical signs observed in Groups C and E were pyrexia, inappetance, emaciation, anaemia, dullness, starry hair coat, pallor of buccal and ocular mucous membranes. Similarly, in Groups C and E, the testicles appeared oedematous and painful to touch with degenerative changes, morphological sperm abnormalities and oligospermia with 2.0% and 0% sperm reserves respectively. Sperm reserve was 100% in Groups A, B and D. It is therefore, concluded that trypanosomosis can cause serious infertility in male red fronted gazelles and that early treatments with melarsamine hydrochloride (Cymelarsan(r)) at 0.3 and 0.6 mg/kg body weight or diminazene aceturate (Berenil(r)) at 7.0 mg/kg body weight may prevent such effects. PMID- 21601917 TI - Two-dimensional polyacrylamide gel electrophoresis of equine seminal plasma proteins and their relation with semen freezability. AB - The objective was to evaluate protein profiles of equine seminal plasma using two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and to determine whether any of these proteins were related to semen freezability. Seminal plasma was collected from 10 stallions, of high and low semen freezability, housed at the State Stud of Lower Saxony, and routinely used in AI programs. Twenty-five protein spots were identified from the two-dimensional gel (12%), seven of which were present in all samples (all proteins were identified by MALDI-MS). Matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been used to generate ion images of samples in one or more mass-to-charge (m/z) values, providing the capability of mapping specific molecules to two-dimensional coordinates of the original sample. Of the 25 proteins identified, two spots had greater relative content (P < 0.05) in seminal plasma samples collected from stallions with high semen freezability: spot 5 (80-85 kDa, isoelectric point [pI] 7.54), identified as CRISP-3; and spot 45 (18.2 kDa, pI 5.0-5.2), identified as HSP-2. Conversely, protein content was greater (P < 0.05) in seminal plasma samples from stallions with low semen freezability: spot 7 (75.4 kDa, pI 6.9 7.4), identified as lactoferrin; spot 15 (26.7 kDa, pI 5.51), identified as kallikrein; spot 25 (25 kDa, pI 7.54), identified as CRISP-3; and spot 35 (13.9 kDa, pI 3.8-4.2), identified as HSP-1. In conclusion, there were differences in the seminal plasma protein profile from stallions with high and low semen freezability. Furthermore, CRISP-3 and HSP-2 were potential seminal plasma markers of high semen freezability. PMID- 21601918 TI - Relationships between cytology, bacteriology and vaginal discharge scores and reproductive performance in dairy cattle. AB - The objective was to compare three diagnostic approaches for intrauterine infection and inflammation: scoring of vaginal contents; quantification of percentage of nucleated cells that were polymorphonuclear leukocytes (PMN) following endometrial cytology; and intra-uterine bacteriology. Dairy cows (n = 303) were examined twice, Days 28 (D28) and 42 (D42), where Day 0 = day of calving. Associations between gross vaginal inflammation scores, uterine cytology, and bacteriology, and subsequent reproductive performance were examined using multivariable models. There was fair agreement at D28 (Kappa = 0.29), but only slight agreement at D42 (Kappa < 0.15), between PMN% and gross vaginal inflammation score. Cows were categorized as having PMN% in the highest quartile (H), or not (L), at both D28 and D42; therefore, cows were categorized as PMNLL, PMNLH, PMNHL, or PMNHH. Cows in the highest PMN% quartile at both time periods were slower to conceive (P < 0.001) than those in all other quartiles (mean +/- SEM 32.2 +/- 2.3, 37.0 +/- 5.3, 40.8 +/- 4.1, and 55.3 +/- 7.3 d from start of breeding to conception for PMNLL, PMNLH, PMNHL, and PMNHH PMN% cows, respectively). Milk yield was greater (P = 0.001) in cows in the lower quartiles for PMN% at D28 and D42 (i.e., PMNLL) than those in the PMNHH and PMNHL categories, with PMNLH intermediate (P = 0.001). We concluded that PMN% was a better predictor of reproductive performance than either intra-uterine bacteriology or gross vaginal inflammation score. Cows in the highest quartile for PMN% at both D28 and D42 had lower pregnancy rates, took longer to conceive, and had a lower milk yield than those in the lower PMN% categories. PMID- 21601919 TI - Petroleum-related hydrocarbons in deep and subsurface sediments from South Western Barents Sea. AB - Subsurface sediments from a pockmark area in South-Western Barents Sea have been earlier found to contain elevated levels of petroleum-related polycyclic aromatic hydrocarbons. This work describes a comprehensive analysis of various biomarkers, including the highly source-specific hopanes, in a 4.5 m long gravity core from the same area, together with subsurface sediment samples from other areas in the region without pockmarks present ("background samples"). A clear difference between the pockmark gravity core and the background sediment cores was found, both with regard to genesis and the level of transformation of organic matter. A number of indicator parameters, such as methylphenanthrene index (MPI-1), point towards a significantly higher maturity of hydrocarbons in the pockmark core throughout its length as compared to the other sampled locations. Higher contents of microbial hopanoids (hopenes) may indicate the former presence of petroleum. These findings confirm the hypothesis of a natural hydrocarbon source in the deeper strata present in the studied location with pockmarks. PMID- 21601920 TI - In vivo distribution, pharmacokinetics, and toxicity of aqueous synthesized cadmium-containing quantum dots. AB - Fluorescent II-IV Quantum dots (QDs) have demonstrated to be highly promising biological probes for various biological and biomedical applications due to their many attractive merits, such as robust photostabilty, strong photoluminescence, and size-tunable fluorescence. Along with wide ranging bioapplications, concerns about their biosafety have attracted increasingly intensive attentions. In comparison to full investigation of in vitro toxicity, there has been only scanty information regarding in vivo toxicity of the QDs. Particularly, while in vivo toxicity of organic synthesized QDs (orQDs) have been investigated recently, there exist no comprehensive studies concerning in vivo behavior of aqueous synthesized QDs (aqQDs) up to present. Herein, we investigate short- and long term in vivo biodistribution, pharmacokinetics, and toxicity of the aqQDs. Particularly, the aqQDs are initially accumulated in liver after short-time (0.5 4 h) post-injection, and then are increasingly absorbed by kidney during long time (15-80 days) blood circulation. Moreover, obviously size-dependent biodistribution is observed: aqQDs with larger sizes are more quickly accumulated in the spleen. Furthermore, histological and biochemical analysis, and body weight measurement demonstrate that there is no overt toxicity of aqQDs in mice even at long-time exposure time. Our studies provide invaluable information for the design and development of aqQDs for biological and biomedical applications. PMID- 21601921 TI - Encapsulation of curcumin in self-assembling peptide hydrogels as injectable drug delivery vehicles. AB - Curcumin, a hydrophobic polyphenol, is an extract of turmeric root with antioxidant, anti-inflammatory and anti-tumorigenic properties. Its lack of water solubility and relatively low bioavailability set major limitations for its therapeutic use. In this study, a self-assembling peptide hydrogel is demonstrated to be an effective vehicle for the localized delivery of curcumin over sustained periods of time. The curcumin-hydrogel is prepared in-situ where curcumin encapsulation within the hydrogel network is accomplished concurrently with peptide self-assembly. Physical and in vitro biological studies were used to demonstrate the effectiveness of curcumin-loaded beta-hairpin hydrogels as injectable agents for localized curcumin delivery. Notably, rheological characterization of the curcumin-loaded hydrogel before and after shear flow have indicated solid-like properties even at high curcumin payloads. In vitro experiments with a medulloblastoma cell line confirm that the encapsulation of the curcumin within the hydrogel does not have an adverse effect on its bioactivity. Most importantly, the rate of curcumin release and its consequent therapeutic efficacy can be conveniently modulated as a function of the concentration of the MAX8 peptide. PMID- 21601922 TI - Organophosphate pesticide exposure and perinatal outcomes in Shanghai, China. AB - Although pesticide use is widespread in China, little is known about levels of exposure to organophosphate pesticides in the population and its potential adverse health effects. We investigated levels of organophosphate exposure in pregnant women and the association between organophosphate exposure and perinatal outcomes in Shanghai, China, by enrolling 187 healthy pregnant women between September 2006 and January 2007. Pesticide exposure was assessed by a questionnaire administered to the mothers in the hospital after delivery as well as by analyses of maternal urinary nonspecific metabolites of organophosphate pesticides (dimethyl and diethyl phosphates). Information on birth weight and length was collected from medical records. Geometric means of metabolites were 25.75 MUg/L for dimethylphosphate (DMP); 11.99 MUg/L for dimethylthiophosphate (DMTP); 9.03 MUg/L for diethylphosphate (DEP); and 9.45 MUg/L for diethyldithiophosphate (DETP). We found that a log unit increase in urinary DEP was associated with a decrease in gestational duration in girls by 1.79 weeks. [beta(adjusted)=-1.79 weeks per log(10) unit increase; 95% confidence interval (CI), -2.82 to -0.76; p=0.001]. These data suggest that high pesticide level might adversely affect duration of gestation although this association was not present among boys. No associations for any of the organophosphate exposure measures were present for birth weight and length, suggesting that organophosphate pesticides may have no effects on fetal growth. Given that maternal urine pesticide levels in Shanghai were much higher than those reported in developed countries, more studies on the effects of in utero organophosphate exposure on fetal growth and child neurodevelopment are warranted. PMID- 21601924 TI - Pro-inflammatory type-1 and anti-inflammatory type-2 macrophages differentially modulate cell survival and invasion of human bladder carcinoma T24 cells. AB - Findings from numerous studies suggest that inflammation is likely to have an important role in bladder carcinogenesis and cancer disease progression. While macrophages (Mphis) constitute a major inflammatory component of the stroma of human bladder carcinoma, the regulatory role of such inflammatory leukocytes in tumor cell survival and invasion remains elusive. Human urothelial bladder cancer (UBC) T24 cells and monocyte-derived macrophages were used to study the relative contribution of pro-inflammatory type-1 (Mphi-1) and anti-inflammatory type-2 (Mphi-2) macrophages in the regulation of UBC cell behaviour. Cell-to-cell studies indicated that the number of viable cells were considerable higher in T24 cell/Mphi-2 cocultures but lower in T24 cell/Mphi-1 cocultures when compared to cultures of T24 cells alone. Mphi-1-derived factors inhibit T24 cell growth but fail to induce caspase-3-mediated apoptosis. Mphi-2-derived factors have the ability to suppress the inhibitory effect of Mphi-1-derived factors on T24 cell growth. Exogenous interleukin (IL)-10 reverse Mphi-1-mediated arrest growth in T24 cell/Mphi-1 cell cocultures. Further analyses showed that Mphi-1-derived factors induced tumor necrosis factor (TNF)-alpha gene expression, promoted cellular invasiveness and increased phosphoinositide 3-kinase (PI 3-K)/Akt signaling pathway activity in T24 cells. Inhibition of PI 3-K activation in T24 cells or blockade of TNFalpha receptor in T24 cell/Mphi-1 cell cocultures decreased cellular invasiveness but did not affect T24 cell viability. Based on these observations, we propose that similar functional interactions between UBC cells and infiltrating macrophages can take place in vivo and influence tumor cell survival and invasion during bladder cancer progression. PMID- 21601925 TI - Risk factors for pandemic H1N1 2009 infection in healthcare personnel of four general hospitals. AB - To characterize an outbreak of pandemic H1N1 2009 among healthcare personnel (HCP), we conducted a cross-sectional survey of HCP who had worked in four general hospitals during the outbreak. More than one-quarter of responding HCP (27.6%) had influenza-like illness (ILI) during the outbreak. The estimated infection rate of pandemic H1N1 2009 was 9.1% in the study of HCP. Independent risk factors for ILI were female gender, <40 years of age, the presence of chronic diseases associated with influenza complications, having family members with ILI or pandemic H1N1 2009, and working in influenza outpatient, influenza inpatient, non-influenza outpatient or emergency departments. During the outbreak of pandemic H1N1 2009, HCP frequently had ILI or the influenza infection. The development of the influenza infection in HCP was associated with some of their baseline characteristics, occupational risk factors, and non-occupational ones during the outbreak. PMID- 21601923 TI - Dense deposit disease. AB - Dense deposit disease (DDD) is an orphan disease that primarily affects children and young adults without sexual predilection. Studies of its pathophysiology have shown conclusively that it is caused by fluid-phase dysregulation of the alternative pathway of complement, however the role played by genetics and autoantibodies like C3 nephritic factors must be more thoroughly defined if we are to make an impact in the clinical management of this disease. There are currently no mechanism-directed therapies to offer affected patients, half of whom progress to end stage renal failure disease within 10 years of diagnosis. Transplant recipients face the dim prospect of disease recurrence in their allografts, half of which ultimately fail. More detailed genetic and complement studies of DDD patients may make it possible to identify protective factors prognostic for naive kidney and transplant survival, or conversely risk factors associated with progression to renal failure and allograft loss. The pathophysiology of DDD suggests that a number of different treatments warrant consideration. As advances are made in these areas, there will be a need to increase healthcare provider awareness of DDD by making resources available to clinicians to optimize care for DDD patients. PMID- 21601926 TI - Emotional and physiological responses to normative and idiographic positive stimuli in bipolar disorder. AB - BACKGROUND: Few studies have examined differences in emotional responding among distinct types of positive stimuli. This is important to understand both for individuals characterized by extreme positive mood (i.e., bipolar disorder) and healthy adults. METHODS: Using a multi-method within-subjects design, the current study examined physiological, behavioral, and self-reported responses to normative (film) and idiographic (memory) happy stimuli in bipolar (BD; n=25) and healthy control groups (CTL; n=23). RESULTS: For both groups, the happy films were associated with greater self-reported and behavioral displays of positive emotion compared to the happy memory. Furthermore, the BD group displayed greater cardiac vagal tone - a putative marker of positive emotion - across both the film and memory. CONCLUSION: Normative stimuli were more potent elicitors of positive emotion compared to idiographic stimuli. The study provided further evidence for cardiac vagal tone as a potential biomarker of extreme positive emotion in BD. PMID- 21601927 TI - Facial emotion perception in depression and bipolar disorder: a quantitative review. AB - A considerable body of literature has reported on emotion perception deficits and the relevance of these impairments in persons with depression and bipolar disorder. Fifty-one studies published between 1981-February 2009 were examined regarding emotion perception abilities between patient and control groups, and potential methodological, demographic and clinical moderators. Studies were identified through a computerized literature search of the MEDLINE, PsychINFO, and PubMed databases. The Meta-analysis Of Observational Studies in Epidemiology (MOOSE) standard (Stroup et al., 2000) was followed in the extraction of relevant studies and data. Data on emotion perception, methodology, demographic and clinical characteristics were compiled and analyzed using Comprehensive Meta Analysis version 2.0 (Biostat, 2005). The meta-analysis revealed a moderate deficit in emotion perception in both bipolar disorder and major depressive disorder, irrespective of task type, diagnosis, age of onset/duration of illness, sex, and hospitalization status. Several factors that moderated the observed impairment include self-reported depression, age at time of testing, and years of education. Emotion perception impairment in bipolar disorder and major depressive disorder represents a moderate and stable deficit that appears to be moderated by a limited number of demographic and clinical factors. PMID- 21601928 TI - Lower limb muscle strength (LLMS): why sedentary life should never start? A review. AB - Aging coincides with a decline in LLMS. Preserving LLMS may be considered a very important determinant of functional independence in the elderly. To maintain LLMS the question arises whether habitual physical activities (HPA) can prevent a decline in LLMS. This review aims to determine the relationship between HPA throughout life and LLMS above age 50. Using relevant databases and keywords, 70 studies that met the inclusion criteria were reviewed and where possible, a meta analysis was performed. The main findings are: (1) the present level of HPA is positively related to LLMS; (2) HPA in the past has little effect on present LLMS; (3) HPA involving endurance have less influence on LLMS compared to HPA involving strength; (4) people with a stable habitually physically active life are able to delay a decline in LLMS. In conclusion, to obtain a high amount of LLMS during aging, it is important to achieve and maintain a high level of HPA with mainly muscle-strengthening activities. PMID- 21601930 TI - Changes of psychical and physical conditions in the elderly after a four-year follow-up. AB - The elderly show a loss of both the intellectual functions and of motion ability. This happens also without particular pathologies; possible tests to highlight this loss are the Mini Mental State Examination (MMSE), and the Functional Reach (FR)-test. During 2004-2005 winter 50 healthy subjects were analyzed; the subjects were divided into three age-groups: from 55 to 64 years; from 65 to 74 years; over 75 years of age. The test results showed a significant decline of MMSE and FR from the first group to the other two groups, a same behavior of male and female subjects, a greater decline of physical characteristics compared to psychic characteristics. During 2008-2009 winter several subjects (34 of 50) were again analyzed, and a more accurate facility was used to measure the FR. The aim of the new test has been the exam of the cognitive conditions and of the physical performances after the 4 year follow-up. The results of the new tests confirm the previous results, both with regard to the decline of the psychophysical characteristics from the first age-group to the others but the decrease is not as significant as the previous, and with regard to the greater physical decline. What is surprising is that the decline of both the psychic and the physical characteristics concerns only the first age-group, not the other two. Maybe healthy subjects, without particular pathologies reach a stabilization of the above-mentioned characteristics; some hypothesis is given to explain what happens. PMID- 21601929 TI - Urinary incontinence (UI) and new psychological distress among community dwelling older adults. AB - This study aimed at determining whether UI is associated with increased risk for the onset of psychological distress. This was a population based longitudinal survey of adults aged 50 and older who did not report psychological distress in 1993 and for whom complete data were available. Participants were classified as having UI if they reported uncontrolled urine loss within 12 months of the 1993 interview. Condition-specific functional loss secondary to UI was assessed by questions on participants' ability to engage in certain activities due to UI. Psychological distress was assessed using the General Health Questionnaire (GHQ) in 2004. The continuing participants were living in East Baltimore, Maryland in 1981. Persons with UI in 1993 were more likely to experience new psychological distress in 2004 than were persons without UI in 1993 adjusting for potentially influential covariates (relative odds (RO)=2.18, 95% confidence interval (CI)=1.19-4.01). Persons with condition-specific functional loss secondary to UI were more likely to experience new psychological distress than were persons without UI adjusting for potentially influential covariates (RO=7.57, 95%CI=2.92 19.62). We conclude that UI, especially when associated with condition-specific functional loss, predicted the onset of psychological distress among community dwelling older adults. PMID- 21601931 TI - Caregiver burden associated with behavioral and psychological symptoms of dementia (BPSD) in Taiwanese elderly. AB - The purpose of this study was to investigate caregiver burden associated with BPSD in Taiwanese people. The study had a cross-sectional design. Eighty-eight patients with dementia and 88 caregivers who visited the memory clinic of a medical center from January 2007 to December 2007 were recruited. The BPSD were assessed using the neuropsychiatric inventory (NPI); caregiver burden was evaluated using the NPI caregiver distress scale (NPI-D). Demographic data on the patients and caregivers along with patients' cognitive functions and clinical dementia ratings were collected. In addition to descriptive statistics, we analyzed the relationship between each parameter and caregiver burden using binary correlation. The results showed a statistically significant positive correlation between the total NPI-D score and the total NPI score (r=0.898, p<0.001). For individual BPSD, delusions had the highest mean NPI-D score, followed by agitation/aggression, anxiety, irritability/lability, and dysphoria/depression. The symptom frequency of anxiety, delusions, and agitation/aggression showed a statistically significant positive correlation with caregiver's NPI-D score. These findings suggest that improvement of treatments for delusions, agitation/aggression, anxiety, irritability/lability, and dysphoria/depression among dementia patients may reduce caregiver burden. PMID- 21601932 TI - Quantification of collateral artery growth by automated fluorescent microsphere perfusion. AB - BACKGROUND: Since their introduction, genetically modified mice have become more and more important to examine molecular mechanisms involved in vascular growth. Today the gold standard for measuring vessel conductivity is to directly assess in vivo perfusion. However, this usually becomes more complicated the smaller the animal, especially due to the need for extensive instrumentation and requirement of maximal vasodilation. METHODS: We developed an automated system that allows pressure-controlled in vivo perfusion of small animals with differently labeled fluorescent microspheres. RESULTS: Besides precise operation of the system (mean pressures divergence 0.08%), automation of small animal microsphere perfusion is reliable and highly accurate in mice with and without femoral artery occlusion. In sham-operated control mice, which did not undergo femoral occlusion, highly reproducible measurements of hind limb perfusion (right vs. left=1.03 +/- 0.037) could be assessed. In mice after unilateral femoral artery occlusion, mean perfusion ratios of the automated method (ratio occluded vs. non-occluded hind limb=0.598 +/- 0.046) were comparable to the manual approach (0.561 +/- 0.062). However, inter-individual variances were significantly smaller with the automated system. CONCLUSION: We describe here a novel and innovative technical approach for pressure-controlled fluid handling specifically designed for microsphere perfusion measurements in small animals. PMID- 21601933 TI - Consensus-based reporting standards for diagnostic test accuracy studies for paratuberculosis in ruminants. AB - The Standards for Reporting of Diagnostic Accuracy (STARD) statement (www.stard statement.org) was developed to encourage complete and transparent reporting of key elements of test accuracy studies in human medicine. The statement was motivated by widespread evidence of bias in test accuracy studies and the finding that incomplete or absent reporting of items in the STARD checklist was associated with overly optimistic estimates of test performance characteristics. Although STARD principles apply broadly, specific guidelines do not exist to account for unique considerations in livestock studies such as herd tests, potential use of experimental challenge studies, a more diverse group of testing purposes and sampling designs, and the widespread lack of an ante-mortem reference standard with high sensitivity and specificity. The objective of the present study was to develop a modified version of STARD relevant to paratuberculosis (Johne's disease) in ruminants. Examples and elaborations for each of the 25 items were developed by a panel of experts using a consensus-based approach to explain the items and underlying concepts. The new guidelines, termed STRADAS-paraTB (Standards for Reporting of Animal Diagnostic Accuracy Studies for paratuberculosis), should facilitate improved quality of reporting of the design, conduct and results of paratuberculosis test accuracy studies which were identified as "poor" in a review published in 2008 in Veterinary Microbiology. PMID- 21601934 TI - Introduction and uptake of new medical technologies in the Australian health care system: a qualitative study. AB - OBJECTIVE: The aim of this study was to explore the views and perceptions of stakeholders about the current national health technology assessment process conducted by the Medical Services Advisory Committee (MSAC) and its role in the uptake and diffusion of new medical technologies in Australia. METHODS: Data collection occurred over a nine month period (August 2008-April 2009). Twenty in depth, semi-structured interviews were conducted with individuals from four stakeholders groups: (i) MSAC members and evaluators, (ii) academic and health technology assessment experts, (iii) medical industry representatives and (iv) medical specialists. Interviews were digitally recorded, transcribed verbatim and coded using a constant comparative method. RESULTS: Respondents expressed a consensus opinion that the MSAC process is generally fair and transparent, and has been increasingly so over time. The process was described as "flexible" and "intuitive" yet also "idiosyncratic" due to the nature of the technologies being appraised. Approval by MSAC was generally reported to be increasingly important once a technology becomes more widely used. While successful MSAC approval was felt to be important for widespread distribution of a new technology, it was viewed more as a "facilitator of the uptake of new technologies" as opposed to a primary "driver" of technology uptake. Instead, other factors were identified as providing the actual impetus for the uptake of new technologies, with MSAC approval and reimbursement eventually helping facilitate more widespread diffusion. CONCLUSIONS: MSAC's decision making process is perceived as fair but with room for improvement. Its role in the uptake and diffusion of new medical technologies in Australia is limited. MSAC does not act as a barrier to significant market penetration of new procedures and medical technologies. However reimbursement is a trigger for increased use. PMID- 21601936 TI - Column study of Cr(VI) removal by cationic hydrogel for in-situ remediation of contaminated groundwater and soil. AB - Column experiments were conducted for examining the effectiveness of the cationic hydrogel on Cr(VI) removal from groundwater and soil. For in-situ groundwater remediation, the effects of background anions, humic acid (HA) and pH were studied. Cr(VI) has a higher preference for being adsorbed onto the cationic hydrogel than sulphate, bicarbonate ions and HA. However, the adsorbed HA reduced the Cr(VI) removal capacity of the cationic hydrogel, especially after regeneration of the adsorbents, probably due to the blockage of adsorption sites. The Cr(VI) removal was slightly influenced by the groundwater pH that could be attributed to Cr(VI) speciation. The 6-cycle regeneration and reusability study shows that the effectiveness of the cationic hydrogel remained almost unchanged. On average, 93% of the adsorbed Cr(VI) was recovered in each cycle and concentrated Cr(VI) solution was obtained after regeneration. For in-situ soil remediation, the flushing water pH had an insignificant effect on the release of Cr(VI) from the soils. Multiple-pulse flushing increased the removal of Cr(VI) from the soils. In contrast, more flushing water and longer operation may be required to achieve the same removal level by continuous flushing. PMID- 21601937 TI - CXCL12 expression within the CNS contributes to the resistance against experimental autoimmune encephalomyelitis in Albino Oxford rats. AB - Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis, a chronic inflammatory and demyelinating disease of the CNS. Albino Oxford (AO) rats are resistant to the induction of EAE, while the disease can be readily induced in Dark Agouti (DA) rats. Here we investigated a potential contribution of the CNS milieu in the limitation of the encephalitogenic autoimmune response. EAE was induced by immunization of the respective rat strains with spinal cord homogenate emulsified in complete Freund's adjuvant. AO rats did not exhibit clinical signs after immunization while DA rats developed severe neurologic deficits. Infiltration of immune cells into spinal cords (SC) was evident in both strains 12-14 days after the immunization. EAE lesions of AO rats contained substantially lower numbers of CD4+ T cells and CD11b+ cells compared to those in DA rats. This went together with lower levels of interferon (IFN)-gamma and interleukin (IL)-17 in the cells isolated from SC. We found a dramatic increase of CXCL12 expression in SC tissue and microvessels of AO rats, whereas DA rats markedly decreased the expression of this chemokine within their CNS. Administration of the CXCL12 antagonist AMD3100 to a substrain of AO rats that developed a weak EAE led to earlier onset and exacerbation of the disease. These results suggest a role of CXCL12 in down-regulating autoimmune processes in AO rats during EAE. Therapeutic modulation of CXCL12 could be a promising strategy for the treatment of CNS autoimmunity. PMID- 21601935 TI - Functional consequences of bidirectional promoters. AB - Several studies have shown that promoters of protein-coding genes are origins of pervasive non-coding RNA transcription and can initiate transcription in both directions. However, only recently have researchers begun to elucidate the functional implications of this bidirectionality and non-coding RNA production. Increasing evidence indicates that non-coding transcription at promoters influences the expression of protein-coding genes, revealing a new layer of transcriptional regulation. This regulation acts at multiple levels, from modifying local chromatin to enabling regional signal spreading and more distal regulation. Moreover, the bidirectional activity of a promoter is regulated at multiple points during transcription, giving rise to diverse types of transcripts. PMID- 21601938 TI - Widespread distribution of HLA-DR-expressing cells in macroscopically undiseased intima of the human aorta: a possible role in surveillance and maintenance of vascular homeostasis. AB - The architectonics and cell composition of the human large arteries are not sufficiently understood. The present study is the first to undertake an analysis of the distribution and quantities of HLA-DR-expressing cells in grossly undiseased human intima using immunohistochemical and immunofluorescent analysis, complemented by the advantages of confocal microscopy. The study revealed a widespread distribution of HLA-DR-expressing cells throughout the intimal space where the cells were integrated into continuous networks via long cell processes. Numbers of HLA-DR+ cells were found to be significantly larger in the middle third of the intima than in the superficial and deep intimal portions. We speculate that a widespread distribution of HLA-DR-expressing cells in the intima of normal human aorta might play a role in the surveillance and maintenance of vascular homeostasis. PMID- 21601939 TI - rhIL-12 as adjuvant augments lung cell cytokine responses to pneumococcal whole cell antigen. AB - Conjugate pneumococcal vaccines offer suboptimal protection against mucosal infections and are restricted in serotype and geographical coverage. New protein based vaccines using conserved pneumococcal antigens and better mucosal adjuvant technology are urgently needed. Interleukin-12 (IL-12) has shown efficacy as a pneumococcal protein vaccine adjuvant in murine models of pneumococcal infection. Systemic administration of recombinant human (rh) IL-12 to humans, however, has been associated with adverse clinical and laboratory side effects. Inhaled forms of IL-12 have improved the safety profiles in humans, as suggested by animal models. Here we evaluated rhIL-12 as an adjuvant on ex vivo human BAL cells when stimulated with pneumococcal whole cells. We show that co-incubation of ex vivo human BAL cells with pneumococcal whole cell antigen (WCA) and a low dose of rhIL 12 (2 ng) can elevate TNF production compared to treatment with WCA (p=0.06) or rhIL-12 (p=0.03) alone. The production of IFNgamma was also increased but not in an antigen specific manner, suggesting perhaps a predominant Th(1) response. Our data suggest that 100-200-fold lower doses of inhaled rhIL-12 than those previously tested for systemic use may be adequate in a phase 1 study and commend further evaluation of rhIL-12 as a potential mucosal adjuvant in human vaccine studies. PMID- 21601940 TI - Epithelial cells modulate genes associated with NF kappa B activation in co cultured human macrophages. AB - Macrophages located in airways and the alveolar space are continually exposed to different signals from the respiratory mucosa. In this respect, epithelial cells represent an important source of cytokines and mediators modulating the state of activation and/or differentiation of mononuclear phagocytes. Many of the proinflammatory genes induced in macrophages during immune and immunopathological reactions are regulated by transcription factor NF kappa B. The aim of our study was to characterize changes in the expression of genes associated with NF kappa B activation and signalling in THP-1 human macrophages co-cultured with A549 respiratory epithelial cells. At least 4-fold upregulation of mRNA level was found in 29 of 84 tested genes including genes for multiple cytokines and chemokines, membrane antigens and receptors, and molecules associated with NF kappa B signalling. The mRNA induction was confirmed at the level of protein expression by evaluating the release of IL-6 and IL-8 and by ICAM-1 expression. Blocking of one NFkappaB subunit by p65 siRNA inhibited the production of IL-6 in both cell types while IL-8 release from THP-1 cells did not seem to be affected. We conclude from our data that unstimulated respiratory epithelial cells regulate genes associated with NF kappa B dependent immune responses in human macrophages and that these interactions may play a key role in immediate responses in the respiratory mucosa. PMID- 21601941 TI - Effects of Plasmodium berghei on thymus: high levels of apoptosis and premature egress of CD4(+)CD8(+) thymocytes in experimentally infected mice. AB - We have previously showed alterations in the thymus during experimental infection with Plasmodium berghei, the causative agent of Malaria. Such alterations comprised histological changes with loss of delimitation between cortical and medullar regions, a profound atrophy with depletion of CD4(+)CD8(+) double positive (DP) thymocytes, and severe changes in the expression of cell migration related molecules, belonging to the extracellular matrix and chemokine protein families. Taken together, these considerations prompted us to evaluate if the acute thymic atrophy observed during Plasmodium infection was correlated with increased apoptotic levels of thymocytes or with their premature emigration to the periphery. Our results confirmed that the marked reduction of the thymus weight in infected animals was accompanied by histological alterations, which included a very large number of cells showing nuclear condensation and karyorrhectic changes surrounded by histiocytes suggesting increased levels of apoptosis. This was confirmed by immunohistochemistry and flow cytometry techniques. In order to verify if an accelerated emigration of thymic cells to the peripheral lymphoid organs was also occurring we analyzed the spleen and mesenteric lymph nodes from control and infected mice. No significant differences were found in the spleen, but were seen after 14 days of infection between control and infected mice in the mesenteric lymph nodes. The main alteration was the presence of double negative (CD4(-)CD8(-)) and double positive (CD4(+)CD8(+)) cells. We concluded that both apoptosis of thymocytes and premature egress of immature cells take place during infection. Additional studies will be necessary to verify how such alterations might influence the systemic immune response to the parasite. PMID- 21601942 TI - Mycobacteria-induced anaemia revisited: a molecular approach reveals the involvement of NRAMP1 and lipocalin-2, but not of hepcidin. AB - Anaemia is a frequent complication of chronic infectious diseases but the exact mechanisms by which it develops remain to be clarified. In the present work, we used a mouse model of mycobacterial infection to study molecular alterations of iron metabolism induced by infection. We show that four weeks after infection with Mycobacterium avium BALB/c mice exhibited a moderate anaemia, which was not accompanied by an increase on hepatic hepcidin mRNA expression. Instead, infected mice presented increased mRNA expression of ferroportin (Slc40a1), ceruloplasmin (Cp), hemopexin (Hpx), heme-oxygenase-1 (Hmox1) and lipocalin-2 (Lcn2). Both the anaemia and the mRNA expression changes of iron-related genes were largely absent in C.D2 mice which bear a functional allele of the Nramp1 gene. Data presented in this work suggest that anaemia due to a chronic mycobacterial infection may develop in the absence of elevated hepcidin expression, is influenced by Nramp1 and may involve lipocalin-2. PMID- 21601943 TI - Toll-like receptor cross-talk in human monocytes regulates CC-chemokine production, antigen uptake and immune cell recruitment. AB - Chemokines production in monocytes/macrophages is crucial in modulating immune responses generated through Toll-like receptor (TLR)-mediated recognition of microbes. During microbial onset, multiple pathogen-associated structures can be present at infection sites, and simultaneously trigger different TLRs. We report here that TLR3, TLR4 and TLR8 engagement induce CCL1, CCL2 and CCL4 production in freshly isolated monocytes. While differentiating cells maintain the capacity to secrete CCL2 and CCL4, CCL1 is no longer induced at later differentiation stages. Although different pairs of TLR agonists have been described to synergistically induce cytokine production in different cell types, agonist combinations cooperate in reducing CCL1 and CCL2, but not CCL4 secretion in freshly isolated monocytes, and fail to rescue CCL1 production at later differentiation stages. The effects of single, but not combined, TLR engagement on chemokine expression mostly occur at transcriptional level, and are IL-10 independent. Conversely, inhibition of CCL1 secretion upon combined TLR engagement is partially rescued by blocking IL-23. A different chemotactic activity of monocyte-conditioned medium on blood mononuclear cells as well as antigen uptake capacity of TLR agonist activated monocytes parallel the regulated production of chemokines. Overall, these findings indicate that simultaneous engagement of TLRs may lead to different patterns of chemokine expression depending on cellular differentiation state, chemokine, and TLR agonist combination. These different responses may be relevant for the distinct but complementary functions of monocytes and macrophages in the immune response, and may have important implications for the therapeutic manipulation of the innate immune system. PMID- 21601944 TI - D-Psicose induces upregulation of defense-related genes and resistance in rice against bacterial blight. AB - We examined rice responses to a rare sugar, d-psicose. Rice growth was inhibited by d-psicose but not by common sugars. Microarray analysis revealed that d psicose treatment caused an upregulation of many defense-related genes in rice, and dose-dependent upregulation of these genes was confirmed by quantitative reverse-transcription polymerase chain reaction. The level of upregulation of defense-related genes by d-psicose was low compared with that by d-allose, which is another rare sugar known to confer induction of resistance to rice bacterial blight in rice. Treatment with d-psicose conferred resistance to bacterial blight in rice in a dose-dependent manner, and the results indicate that d-psicose might be a candidate plant activator for reducing disease development in rice. PMID- 21601945 TI - Regulation of plant primary metabolism. PMID- 21601946 TI - An appraisal of oral retinoids in the treatment of pachyonychia congenita. AB - BACKGROUND: Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused by mutations in keratin genes KRT6A/B, KRT16, or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Available studies assessing oral retinoid treatment for PC are limited to a few case reports. OBJECTIVE: We sought to assess overall effectiveness, adverse effects, and patient perspective in patients with PC receiving oral retinoids. METHODS: In a questionnaire-based retrospective cross-sectional survey of 30 patient with PC assessing oral retinoids (10-50 mg/d for 1-240 months), we determined the clinical score, satisfaction score, visual analog pain scale, and adverse effects. RESULTS: In 50% of patients there was thinning of hyperkeratoses (average improvement 1.6 on a scale from -3 to +3) (95% confidence interval 1.2 1.9, P < .001). In all, 14% observed amelioration of their pachyonychia; 79% did not experience any nail change. The self-reported overall satisfaction score with oral retinoid treatment was 2 or greater in 50% of the patients (mean 4.5 on a scale of 1-10). Although 33% reported decreased and 27% increased plantar pain with treatment, 40% did not notice any pain change. All patients experienced adverse effects, and 83% reported to have discontinued medication. Risk/benefit analysis favored lower retinoid doses (<=25 mg/d) over a longer time period (>5 months), compared with higher doses (>25 mg/d) for a shorter time (<=5 months). LIMITATIONS: The retrospective, cross-sectional study design is prone to a recall bias. CONCLUSION: Oral retinoids are effective in some patients with PC. However, many patients discontinued medication because adverse effects outweighed the benefits. Careful dose titration is warranted in patients informed about potential adverse effects. PMID- 21601947 TI - Miliary and agminated-type primary cutaneous follicle center lymphoma: report of 18 cases. AB - BACKGROUND: Primary cutaneous follicle center lymphoma (PCFCL) presents usually with reddish nodules, plaques, and tumors on the head and neck area, particularly the scalp, and on the back. OBJECTIVE: We sought to describe a peculiar clinical variant of PCFCL. METHODS: We report a series of 18 patients (male:female = 7:11; median age 52 years; mean age 50.8 years; age range 27-75 years) with a clinical variant of PCFCL characterized clinically by multiple, miliary, or agminated papules predominantly on the head and neck. RESULTS: All patients presented with multiple erythematous, firm papules arranged in a manner that resembled millet seeds or collected together in small clusters. Lesions were located on the entire face in one patient (5.6%), the forehead in 8 (44.4%), the cheeks in 3 (16.7%), the preauricular region in two (11.1%), and multiple regions on the head and neck area in 3 (16.7%). The last patient had miliary papules on the entire face, back, upper aspect of arms, and scattered on the front of the chest. The initial diagnosis was never cutaneous lymphoma, and all patients had been treated unsuccessfully for different skin conditions including mainly rosacea, lupus miliaris disseminatus faciei, and persistent arthropod bite reaction. Microscopic examination confirmed the diagnosis of PCFCL in all patients. LIMITATIONS: Small number of cases and retrospective study are limitations. CONCLUSIONS: This peculiar clinical presentation of PCFCL is unusual and represents a pitfall in the clinical diagnosis. Dermatologists should be aware of this variant of PCFCL so as to treat patients timely and properly. PMID- 21601948 TI - Clinical severity does not reliably predict quality of life in women with alopecia areata, telogen effluvium, or androgenic alopecia. AB - BACKGROUND: Hair loss may significantly impact an individual's self-image, and studies indicate that patients with both clinically apparent and clinically imperceptible hair loss may have significantly decreased quality of life (QoL). Moreover, clinical severity of hair loss does not necessarily predict impact on QoL. OBJECTIVE: The aim of this study was to assess QoL in patients (n = 104) with alopecia areata, telogen effluvium, and androgenic alopecia, and to compare QoL with hair loss severity (HLS) as independently rated by both patient and dermatologist. METHODS: Questionnaires and clinical assessment tools were used to assess HLS, and QoL was measured by completion of Skindex-16. RESULTS: Overall, patients rated their hair loss as more severe than the dermatologist, and the patient's HLS rating more strongly correlated with QoL than the dermatologist's rating. Clinical assessment of HLS did not reliably predict the patient's QoL, nor did it predict the patient's perception of HLS. LIMITATIONS: A convenience sample was recruited from a referral clinic and Skindex-16 has not been validated for use in women's alopecia disorders. CONCLUSION: These findings indicate dermatologists should address these psychosocial and QoL issues when treating patients with alopecia. PMID- 21601949 TI - Disinfection of meticillin-resistant Staphylococcus aureus and Staphylococcus epidermidis biofilms using a remote non-thermal gas plasma. AB - The effective disinfection of hospital surfaces is recognised as an important factor in preventing hospital-acquired infections. The purpose of this study was to quantify the disinfection rate of a novel gas plasma system on clinically relevant biofilms. Clinical isolates of Staphylococcus epidermidis and meticillin resistant Staphylococcus aureus (MRSA) were grown as biofilms on glass surfaces and tested in a disinfection container remote from the plasma source. The strains used in this study were known to produce substantial quantities of biofilm and average log10 counts were 9.0 and 9.1 cfu/cm(2) for S. epidermidis and MRSA respectively. Counts were reduced by between 4 and 4.5 log10 after 1h of exposure for MRSA and S. epidermidis respectively. More prolonged treatment in the case of MRSA biofilms resulted in a 5.5 log10 reduction after 90 min. Biofilm samples were also placed in medical device packaging bags and similar rates of disinfection were observed. PMID- 21601950 TI - Tetanus vaccination coverage among nurses in Greece. PMID- 21601951 TI - Hepatitis B vaccination coverage levels among nurses in Greece. PMID- 21601952 TI - Frail older persons' experiences of interinstitutional relocation. AB - This study examined the effects and experiences of an interinstitutional relocation on older persons' quality of life, wellbeing, and perceived person centeredness. A pre-test/post-test mixed method design, with an equivalent reference group, was used to examine relationships between variables and to explore personal meaning. Results indicate a significantly larger deterioration in perceived person centeredness among those cognitively intact residents that moved compared to the non-movers. Interviews with moving residents revealed that the relocation was experienced as uncontrollable, un-affectable, and uncertain. However, no significant relocation effects were found from the proxy ratings of the cognitively impaired residents. Nursing interventions that involve, inform, and prepare older persons prior to interinstitutional relocation to enhance their sense of control of the move might minimize adverse relocation effects. Further research is needed on the effects of interinstitutional relocations, which procedures that should be used, as well as effects of preparatory interventions. PMID- 21601953 TI - Behavioral and cellular markers of olfactory aging and their response to enrichment. AB - Aging of olfactory function (discrimination and short-term memory) was studied in 2, 10, and 23-month-old mice. We also addressed the issue of the responsiveness of the aging system to olfactory experience-dependent plasticity by submitting mice of different ages to an enrichment paradigm, and assessed neurogenesis in the olfactory bulb and the status of the noradrenergic system, 2 effectors of enrichment. Discrimination ability and its response to enrichment were essentially preserved with aging. In contrast, memory and its improvement by enrichment were altered at 10 and 23 months. Regarding neurogenesis, we found less proliferation of progenitors at 10 months and then lower neuronal differentiation and survival at 23 months. Furthermore, enrichment did not improve neurogenesis beyond the age of 2 months. Noradrenergic markers and their response to enrichment were altered at 23 months in line with memory performance. Aging thus differentially affected olfactory discrimination and memory abilities and their responsiveness to enrichment. Bulbar neurogenesis was an early target of aging whose decline could contribute to age-dependent memory impairments. PMID- 21601955 TI - [Prostate cancer: the revolution of the fusion genes]. AB - BACKGROUND: TMPRSS2-ETS fusion gene rearrangements constitute a very common and specific alteration in prostate cancer cells. These genetic alterations lead the overexpression of ETS genes which encode the E26 family of transcription factors involved in cell proliferation. Of this family, the ERG oncogene is overexpressed in almost 50% of prostate cancer cases. EVIDENCE SYNTHESIS: TMPRSS2-ERG overexpresses ERG through an androgen-mediated response. Structurally, the rearrangement is due to interstitial deletion and to a lesser extent to reciprocal translocation and plays a key role in cellular metabolism. Almost all fusion gene transcripts produce a truncated ERG protein and the presence of a specific isoform of this gene suggests the clonality of the tumor; hence, metastasis shares the fusion gene status of their primary lesion. Although the prognostic implications of TMPRSS2-ERG have not been fully elucidated, they constitutes a field of great diagnostic potential and, therefore, the development of techniques to identify and to analyze the presence and characteristics of this gene in a non-invasive fashion deserves great interest in this area. Currently, there is evidence supporting the hypothesis that the presence of fusion gene differentiates two molecular groups within prostate cancer with a differential behaviour making the fusion gene a potential therapeutic target. In this regard, the use of anti-HDAC (trichostatin), antagonists of estrogen receptor alpha and abiraterone acetate have shown promising results. CONCLUSIONS: This review describes the great potential offered by the investigation of fusion genes in PC and the need for further studies. PMID- 21601956 TI - [Quality of life and burden of carers of patients with acquired brain injury]. AB - INTRODUCTION: The health impact of acquired brain injury (ABI) is not only apparent in the patient, but also in the loss of health related quality of life (HRQol) of their carers. The objectives of this study were to measure the loss of HRQol as well as the burden of the carers of patients with ABI. MATERIAL AND METHODS: A retrospective study was conducted with 76 carers of patients with ABI. A questionnaire was used to collect information on the sociodemographic aspects, carer burden (Zarit Scale) and the HRQol (EuroQol Questionnaire) of the carers. A multiple linear regression model was constructed to analyse the effect of the different variables. RESULTS: The carers were predominantly women over 50 years, retired or dedicated to domestic tasks and who cared for their husband or one of their parents. One third showed a high risk of claudication. The mean HRQol obtained with the EuroQol went from a similar score to that of the general population (0.9) in the group without burden, to 0.67 in the group with risk of claudication. The regression models explained the burden better than the loss in quality of life. CONCLUSIONS: Carers of patients with brain injury suffer a significant loss in HRQol compared to the general population. The deterioration arises from the mental dimensions and depends on the level of burden. PMID- 21601957 TI - [Senile osteoporosis: an update]. AB - Knowledge of the mechanisms underlying the development of osteoporosis in the elderly has advanced greatly in the past few years. After an initial sudden loss of bone mineral mass in the peri-menopausal period there follows a more progressive and gradual loss that has also been seen in men. This initial drop in bone mass is due to a significant increase in bone resorption. There is also a significant reduction in bone formation with age that is mainly due to osteoblastogenesis in the bone marrow passing to a second plane, transferring its main role to adipogenesis. In this article, the latest evidence on the pathophysiology of senile osteoporosis is reviewed, highlighting the mechanisms of action of available treatments. Potential future treatments are also considered, which include new therapeutic approaches based on the pathophysiology of osteoporosis in the elderly, mainly on the potential reversibility of the adipogenesis. PMID- 21601954 TI - Genetic players in multiple system atrophy: unfolding the nature of the beast. AB - Multiple system atrophy (MSA) is a fatal oligodendrogliopathy characterized by prominent alpha-synuclein inclusions resulting in a neuronal multisystem degeneration. Until recently MSA was widely conceived as a nongenetic disorder. However, during the last years a few postmortem verified Mendelian pedigrees have been reported consistent with monogenic disease in rare cases of MSA. Further, within the last 2 decades several genes have been associated with an increased risk of MSA, first and foremost the SNCA gene coding for alpha-synuclein. Moreover, genes involved in oxidative stress, mitochondrial dysfunction, inflammatory processes, as well as parkinsonism- and ataxia-related genes have been implicated as susceptibility factors. In this review, we discuss the emerging evidence in favor of genetic players in MSA. PMID- 21601958 TI - [Repetition stroke as onset of giant cell arteritis]. PMID- 21601959 TI - [Hand grip strength: can this be a prognostic factor for mortality in palliative care patients?]. AB - OBJECTIVE: To determine whether hand grip strength (HGS) is a prognostic factor for mortality in a palliative care unit (PCU), using two variables: A1: The HP on admission; A2: The progression of the HGS in the first 12days of admission. MATERIAL AND METHODS: A prospective, observational and comparative study of patients with advanced cancer admitted consecutively over a 4 month period into a PCU. A series of 4 determinations of HGS were made using a JAMAR((r)) 5030J1 dynamometer. A total of 78 patients fulfilled the inclusion criteria, of which 61 (78.2%) agreed to take part. RESULTS: Objective A1: Of the 61 enrolled patients, the survivors (n=25) differed by -1.8 (Standard Deviation (SD) 0.8) from the reference values for age and gender, and for those that died (n=36) it was -1.9 (1.1) (P=.6). A survival analysis was performed with this sample. The sample was subdivided into those who were > -2 SD (n=34) and those < -2 SD (n=27) (P=.3). Those patients who managed 4 determinations (n=49) were included in objective A2. At discharge there were 26 deaths and 23 alive. There were no statistically significant differences between the determinations. Only the comparison between the difference between the 4th and 1st determination in the two groups showed a significant result (P=.01). CONCLUSIONS: The HGS measured at admission, as well as in the first 12days, was not a prognostic factor for mortality in the sample studied. PMID- 21601960 TI - [Atypical presentation of pyometra in an elderly woman]. PMID- 21601961 TI - [Digestive intolerance in an elderly patient due to compression of giant liver cyst]. PMID- 21601962 TI - [Factors related to polypharmacy in the non-institutionalised elderly. Analysis of the subsample of the national survey of health 2006 for the elderly in Castile Leon]. AB - BACKGROUND: The increase in chronic and degenerative diseases in the elderly leads to increased and multiple drug usage, which in turn leads to problems associated with adverse reactions and drug interactions. MATERIAL AND METHODS: We analysed the subsample of the National Health Survey 2006, for adults over 65 living in Castile-Leon (n=458). Using a logistic regression model and correlation analysis the variables having more influence on polypharmacy were evaluated. RESULTS: A total of 86% of those interviewed claimed to be taking drugs and 93.9% had a chronic illness. The most common health problems included arthrosis, arthritis or rheumatism (53.5%) and hypertension (48.3%), and most frequently used drugs were hypotensives (45%), pain medications (37.1%) and those for rheumatism (21.4%). Both the mean number of illnesses suffered and the drugs consumed are significantly higher in those who claimed to have, "or or fair health, used the health services, had impaired eyesight and hearing, dependent for personal care and domestic tasks, and mobility (P<.05). The variables associated with polypharmacy are three or more chronic diseases (OR=18.3), regular-poor self perceived health (OR=3.4) and females (OR=1.9). CONCLUSIONS: Given the magnitude of the problem it would be appropriate to include a review of the medications in health examinations of the elderly, particularly in women older than 75 years, with regular or self-perceived poor health and who have 3 or more diseases. PMID- 21601963 TI - [(99m)Tc-MIBI SPECT in the study of brain lymphoma]. PMID- 21601964 TI - Synthesis of 2,4-diaryl chromenopyridines and evaluation of their topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship. AB - Designed and synthesized were a series of 5H-chromeno[4,3-b]pyridines with substitution at 2- and 4-positions with various 5- or 6-membered heteroaromatics as antitumor agents. They were evaluated for topoisomerase I and II inhibitory activities as well as cytotoxicities against several human cancer cell lines. Structure-activity relationship study showed that 2-furyl or 2-thienyl at 2- or 4 position of central pyridine is crucial in displaying topo I or II inhibitory activity and cytotoxicity. PMID- 21601965 TI - [Weight loss and dyspnea in a 46-year-old woman]. PMID- 21601966 TI - Factors associated with depressive symptoms among postpartum mothers in a rural district in Uganda. AB - OBJECTIVE: across Africa the prevalence of postpartum depression is a major health problem affecting mothers, their infants and families. The purpose of this study was to explore the factors associated with postpartum depressive symptoms (PDS) among women living in a rural Ugandan district. DESIGN: descriptive correlation design. SETTING: Young-Child's Clinic of a public hospital, providing postpartum care services to approximately 450 women and their babies per month in a rural district of Uganda. PARTICIPANTS: 202 postpartum women who have lived in the rural district both during pregnancy and postpartum period following birth of the current infant of age <=12 weeks. MEASUREMENTS: PDS were measured using the Edinburgh Postnatal Depression Scale (EPDS). FINDINGS: participants' mean age and number of children were 24+/-4.33 years and 2.85+/-1.26 children, respectively. Majority of participants were married (61%), delivered the current infant by normal vaginal delivery (91%) at a health facility (86%) and experienced no complications (80%). The mean EPDS score for the sample was 9.5+/-0.18 and 43% of the participants were found to have PDS (scores >=10). Statistically significant relationships were found between PDS and factors such as number of female sexual partners the husband has (r=0. 28, p<=0.01); current problems in marriage (r=0.22, p<=0.01), participant's parity (r=-0.24, p<=0.05), infant's ability to breast feed (r=0.28, p<=0.05) and husband support during the postpartum period (r=0. 20, p<=0.05). CONCLUSION: male partners of postpartum women are a major source of factors associated with PDS in rural areas. IMPLICATION FOR PRACTICE: midwifery practitioners in rural settings should emphasise psychosocial assessment and male involvement in postpartum care to increase opportunities of identifying mothers at risk of PDS and implementation of interventions targeting men. PMID- 21601967 TI - Global gene expression profile induced by the UV-filter 2-ethyl-hexyl-4 trimethoxycinnamate (EHMC) in zebrafish (Danio rerio). AB - Residues of the UV-filter 2-ethyl-hexyl-4-trimethoxycinnamate (EHMC) are ubiquitously found in aquatic biota but potential adverse effects in fish are fairly unknown. To identify molecular effects and modes of action of EHMC we applied a gene expression profiling in zebrafish using whole genome microarrays. Transcriptome analysis and validation of targeted genes were performed after 14 days of exposure of male zebrafish. Concentrations of 2.2 MUg/L and 890 MUg/L EHMC lead to alteration of 1096 and 1137 transcripts, respectively, belonging to many pathways. Genes involved in lipid metabolism and estrogenic pathway (vtg1), lipid biosynthesis (ptgds), vitamin A metabolic process (rbp2a), DNA damage and apoptosis (gadd45b), and regulation of cell growth (igfbp1a) were investigated by qRT-PCR analysis in whole body, liver, brain and testis. The analysis showed tissue-specific gene profiles and revealed that EHMC slightly affects the transcription of genes involved in hormonal pathways including vtg1, esr1, esr2b, ar, cyp19b and hsd17beta3. PMID- 21601968 TI - Fate and effects of anthropogenic chemicals in mangrove ecosystems: a review. AB - The scientific literature for fate and effects of non-nutrient contaminant concentrations is skewed for reports describing sediment contamination and bioaccumulation for trace metals. Concentrations for at least 22 trace metals have been reported in mangrove sediments. Some concentrations exceed sediment quality guidelines suggesting adverse effects. Bioaccumulation results are available for at least 11 trace metals, 12 mangrove tissues, 33 mangrove species and 53 species of mangrove-habitat biota. Results are specific to species, tissues, life stage, and season and accumulated concentrations and bioconcentration factors are usually low. Toxicity tests have been conducted with 12 mangrove species and 8 species of mangrove-related fauna. As many as 39 effect parameters, most sublethal, have been monitored during the usual 3 to 6 month test durations. Generalizations and extrapolations for toxicity between species and chemicals are restricted by data scarcity and lack of experimental consistency. This hinders chemical risk assessments and validation of effects based criteria. PMID- 21601969 TI - Modeling vehicle emissions in different types of Chinese cities: importance of vehicle fleet and local features. AB - We propose a method to simulate vehicle emissions in Chinese cities of different sizes and development stages. Twenty two cities are examined in this study. The target year is 2007. Among the cities, the vehicle emission factors were remarkably different (the highest is 50-90% higher than the lowest) owing to their distinct local features and vehicle technology levels, and the major contributors to total vehicle emissions were also different. A substantial increase in vehicle emissions is foreseeable unless stronger measures are implemented because the benefit of current policies can be quickly offset by the vehicle growth. Major efforts should be focused on all cities, especially developing cities where the requirements are lenient. This work aims a better understanding of vehicle emissions in all types of Chinese cities. The proposed method could benefit national emission inventory studies in improving accuracy and help in designing national and local policies for vehicle emission control. PMID- 21601970 TI - Making a difference: the construction of ethnicity in HIV and STI epidemiological research by the Dutch National Institute for Public Health and the Environment. AB - Biomedical and public health researchers and practitioners routinely record and comment on ethnicity: however, the use of this category is often vague and without explicit statement on what ethnicity is or how it correlates to health disparities. Presented here is an inquiry into the case of ethnicity in HIV/STI research in the Netherlands. This paper considers the construction and operationalization of the concept ethnicity in HIV/STI epidemiological research in the Netherlands. The concept ethnicity is followed as it is defined, measured, categorized, communicated and constructed in the annual national HIV/STI surveillance report of the Dutch National Institute for Public Health and the Environment (RIVM) and as this construction co-evolves in society through the Dutch media, politics and prevention practice. The epidemiological work of the RIVM on HIV/STI in The Netherlands has resulted in the materialization of a distinct ethnic construction, the high risk sexual ethnic other, presumed, not only to be at heightened risk for HIV, but also to spread HIV in the Netherlands through promiscuity and absent safe sex practices. This construct is shown to be perpetually self-validating as it informs methodological choices, such that, behavioural studies almost always establish ethnic behavioural differences. The construct and related ethnic rhetoric also allow for the extrapolation of "findings" within a specific ethnic group regarding a specific STI to all groups considered ethnic minorities and so a categorical ethnic minority problem group is constructed within Dutch society. This imagery is disseminated through newspaper articles and dialogue in the Dutch House of Representative and HIV/STI prevention practice, through which the construct is reaffirmed and ascribed scientific and social validity. Knowledge of ethnic minorities' high-risk status and their sexual practices that lead to this become common, and so the construct is further operationalized in government budget planning and subsequent research programmes. PMID- 21601971 TI - [Respiratory disease registries in Spain: fundamentals and organization]. AB - This present paper describes the general characteristics, objectives and organizational aspects of the respiratory disease registries in Spain with the aim to report their activities and increase their diffusion. The document compiles information on the following registries: the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency, Spanish Registry of Bronchiectasis, International Registry of Thromboembolic Disease, Spanish Registry of Occupational Diseases, Spanish Registry of Pulmonary Artery Hypertension, Registry of Pleural Mesothelioma, Spanish Registry of Tuberculosis and Spanish Multi-center Study of Neuroendocrine Pulmonary Tumors. Our paper provides information on each of the registries cited. Each registry has compiled specific clinical information providing data in real situations, and completes the results obtained from clinical assays. Said information has been published both in national as well as international publications and has lead to the creation of various guidelines. Therefore, the activities of the professionals involved in the registries have spread the knowledge about the diseases studied, promoting the exchange of information among workgroups. PMID- 21601972 TI - [Use of an explanted pacemaker connected to a regular screw-in lead for temporary pacing]. PMID- 21601974 TI - [Use of amplatzer(r) device for closure of bronchopleural fistulas, a hybrid procedure using bronchoscopy and radiology]. PMID- 21601973 TI - [Effects of raloxifene on endothelial function and hemostasis in women with ischemic heart disease]. AB - INTRODUCTION AND OBJECTIVES: Modulation of vascular tone is one of the most relevant estrogen effects. A beneficial effect on endothelial function in postmenopausal women has also been proposed for the selective estrogen receptor modulator raloxifene. However, its effects in women with established cardiovascular disease have not been fully elucidated. In addition, recent trials have generated controversy regarding thromboembolic risk with raloxifene use. The aim of the study was to assess the effect of raloxifene on: a) endothelial function and b) coagulation and fibrinolysis pathways. METHODS: The MERCED trial was a prospective, randomized clinical trial. Thirty-three postmenopausal women with ischemic heart disease were enrolled in the study. Raloxifene treatment was administered for a 3-month period, according to a double-blind crossover design. Assessment of vascular function and biologic parameters related to coagulation pathways were conducted at various pre-established time-points. RESULTS: Flow mediated dilatation was severely impaired in the study population, and raloxifene had no effect on endothelial function. Treatment with raloxifene was associated to decreased levels of fibrinogen (3.41 [3.11-3.74] vs. 3.69 [3.40-4.00], P<.05); prothrombin fragments F(1+2) (0.93 [0.77-1.12] vs. 0.94 [0.78-1.15], P<.05); and plasmin/antiplasmin complexes (211 [166-267] vs. 242 [199-295], P<.01). CONCLUSIONS: The present study provides evidence that in postmenopausal women with demonstrated endothelial dysfunction and ischemic heart disease, mid-term treatment with raloxifene does not affect endothelial function. In the MERCED trial, no increased thrombotic risk was observed, but a decreased thrombotic and fibrinolytic activity was observed with raloxifene. Further studies are required to determine whether thrombotic risk is associated with specific clinical characteristics or subgroups of postmenopausal women with cardiovascular disease. Full English text available from: www.revespcardiol.org. PMID- 21601975 TI - [Endovascular diagnosis and palliative treatment of a pulmonary artery angiosarcoma]. PMID- 21601976 TI - [Caseous calcification of the mitral annulus, a rare echocardiographic finding]. AB - Caseous calcification of mitral annulus, also known as caseoma, is a rare echocardiographic finding. Because it often presents asymptomatically, the diagnosis is usually incidental. The condition arises due to caseous degeneration in the internal material of the mitral annulus calcification. On echocardiography, the calcification is a round mass with a central echolucent area, typically located at the base of the posterior leaflet, and can be mistaken for cardiac tumors or abscesses. We describe 3 patients with the condition, one of whom required surgical removal of the mass to obtain a definitive diagnosis. PMID- 21601977 TI - [Simultaneous percutaneous closure of patent foramen ovale and left atrial appendage]. PMID- 21601978 TI - Clinical analysis of ovarian pregnancy: a report of 49 cases. AB - OBJECTIVE: To clinically analyze cases of ectopic ovarian pregnancy and to generate data regarding the evaluation and management of suspected ectopic ovarian pregnancies. STUDY DESIGN: We retrospectively analyzed 49 ovarian pregnancies that were surgically treated at Cheil General Hospital and Women's Healthcare Center between January 1996 and December 2009. We analyzed patient age, parity, symptoms, risk factors, preoperative diagnosis, and ovarian pregnancy type. RESULTS: During the study period, the incidence of ovarian pregnancy was 1.59% of all ectopic pregnancies (49/3081); 45/49 (91.8%) were primary ovarian pregnancies. At the time of diagnosis, mean age was 30.7 years (SD: +/- 4.4 years) and mean parity was 0.63 (SD: +/- 0.8). The most common presenting symptoms were abdominal pain (42.9%) and vaginal bleeding (28.6%). The most common sonographic findings were fluid surrounding the ovarian pregnancy and ovarian enlargement. In regard to surgical treatment, ovarian wedge resection was most often performed (85.7% of cases), followed by oophorectomy (8.2% of cases). The most common risk factors were endometriosis (16 patients) and a history of abdominal surgery (19 patients). CONCLUSIONS: Ovarian pregnancies are extremely rare and difficult to diagnose both pre- and intra-operatively. Our data may assist surgeons in understanding the clinical presentation of ovarian pregnancy and in counseling patients. Larger studies are warranted to gather more data on this rare form of ectopic pregnancy. PMID- 21601979 TI - Effectiveness of the association micronized N-Palmitoylethanolamine (PEA) transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study. AB - OBJECTIVE: Aim of our study was to evaluate the effectiveness of the association between N-Palmitoylethanolamine and transpolydatin in the management of chronic pelvic pain related to EMS. STUDY DESIGN: This was a randomized, double-blind, parallel-group, placebo-controlled clinical trial involving 61 subjects, submitted to a first line laparoscopic conservative surgery, who were randomized into 3 groups receiving: group A (n=21) the association N-Palmitoylethanolamine transpolydatin 400 mg + 40 mg twice a day for 3 months; group B (n=20) the placebo for 3 months; group C (n=20) a single course of Celecoxib 200mg twice a day for 7 consecutive days. Assessments of the severity of pelvic endometriosis (pelvic pain, dysmenorrhoea and dyspareunia) were recorded before and after treatment on a questionnaire and a 10-point VAS. Differences between groups were verified with Kruskal-Wallis ANOVA for non-parametric multiple comparisons. RESULTS: A marked decrease in dysmenorrhoea, dyspareunia and pelvic pain was observed in all groups, and the association between N-Palmitoylethanolamine and transpolydatin resulted to be more effective than placebo (P<.001). Additionally, the treatment with Celecoxib resulted in a decrease in pelvic pain more effective either than the association N-Palmitoylethanolamine and transpolydatin or placebo. CONCLUSION: These preliminary results show that the association between micronized N-Palmitoylethanolamine and transpolydatin is effective in the management of pelvic pain related to endometriosis after laparoscopy. Additionally, this association seems to be safe, shows an optimal control of pain and can be used in patients who are unable to receive other therapies. PMID- 21601980 TI - Retziusscopy: a minimal invasive technique for the treatment of retropubic hematomas after TVT procedure. AB - OBJECTIVES: Retropubic hematomas are rare but typical complications during or after the tension-free vaginal tape (TVT) procedure. We investigated the possibility of treating these hematomas with retziusscopy, as an update of a previous study by our group. STUDY DESIGN: Over a 10-year period the clinical course of all 685 consecutive patients undergoing the tension-free vaginal tape procedure (TVT, Gynecare) was prospectively recorded, including management strategies for clinically relevant hematomas. We report on 10 patients with hematoma and our following surgical management. RESULTS: In twenty-eight patients (4.1%) a symptomatic retropubic hematoma developed. In 10 cases (1.5%) volume exceeded 250 mL (range 250-1000 mL). These patients required surgical intervention because of moderate or severe symptoms. In the first case we performed open laparotomy, whereas in the following cases the hematomas could be successfully drained by retziusscopy. CONCLUSIONS: In cases of large masses, intervention may be necessary because of significant discomfort. This can usually be achieved by a minimally invasive retziusscopy. PMID- 21601981 TI - Ovarian stromal hyperplasia and hyperthecosis: an unusual case of post-menopausal hirsutism. PMID- 21601982 TI - The contemporary concept of significant versus insignificant prostate cancer. AB - CONTEXT: The notion of insignificant prostate cancer (Ins-PCa) has progressively emerged in the past two decades. The clinical relevance of such a definition was based on the fact that low-grade, small-volume, and organ-confined prostate cancer (PCa) may be indolent and unlikely to progress to biologic significance in the absence of treatment. OBJECTIVE: To review the definition of Ins-PCa, its incidence, and the clinical impact of Ins-PCa on the contemporary management of PCa. EVIDENCE ACQUISITION: A review of the literature was performed using the Medline, Scopus, and Web of Science databases with no restriction on language up to September 2010. The literature search used the following terms: insignificant, indolent, minute, microfocal, minimal, low volume, low risk, and prostate cancer. EVIDENCE SYNTHESIS: The most commonly used criteria to define Ins-PCa are based on the pathologic assessment of the radical prostatectomy specimen: (1) Gleason score <= 6 without Gleason pattern 4 or 5, (2) organ-confined disease, and (3) tumour volume<0.5 cm(3). Several preoperative criteria and prognostication tools for predicting Ins-PCa have been suggested. Nomograms are best placed to estimate the risk of progression on an individualised basis, but a substantial proportion of men with a high probability of harbouring Ins-PCa are at risk for pathologic understaging and/or undergrading. Thus, there is an ongoing need for identifying novel and more accurate predictors of Ins-PCa to improve the distinction between insignificant versus significant disease and thus to promote the adequate management of PCa patients at low risk for progression. CONCLUSIONS: The exciting challenge of obtaining the pretreatment diagnostic tools that can really distinguish insignificant from significant PCa should be one of the main objectives of urologists in the following years to decrease the risk of overtreatment of Ins-PCa. PMID- 21601983 TI - Mesenchymal stem cells promote mammary cancer cell migration in vitro via the CXCR2 receptor. AB - Bone metastasis is a common event during breast cancer progression. Recently, mesenchymal stem cells (MSCs) have been implicated in the metastasis of primary mammary cancer. Given that bone is the native environment for MSCs, we hypothesized MSCs facilitate the homing of circulating mammary cancer cells to the bone. To test this hypothesis, we examined in vitro whether bone derived MSCs from FVB mice could influence the migration of syngeneic murine mammary cancer cell lines derived from the polyoma virus middle-T (PyMT) model of mammary gland tumorigenesis. Our data show that conditioned media derived from MSCs significantly enhanced the migration of PyMT mammary cancer cell lines. Analysis of conditioned media using a cytokine array revealed the presence of numerous cytokines in the MSC conditioned media, most notably, the murine orthologs of CXCL1 and CXCL5 that are cognate ligands of the CXCR2 receptor. Further investigation identified that: (1) CXCL1, CXCL5 and CXCR2 mRNA and protein were expressed by the MSCs and PyMT cell lines and; (2) neutralizing antibodies to CXCL1, CXCL5 and CXCR2 or a CXCR2 small molecule inhibitor (SB265610) significantly abrogated the migratory effect of the MSC conditioned media on the PyMT cells. Therefore, in vitro evidence demonstrates that bone derived MSCs play a role in the migration of mammary cancer cells, a conclusion that has potential implications for breast to bone metastasis in vivo. PMID- 21601984 TI - p53 protein accumulation, iodine-unstained lesions, and alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotypes in Japanese alcoholic men with esophageal dysplasia. AB - Inactive heterozygous aldehyde dehydrogenase-2 (ALDH2(*)1/(*)2) and less-active alcohol dehydrogenase-1B (ADH1B(*)1/(*)1) increase the risk of esophageal cancer in East Asian drinkers, and esophageal cancer multiplicity is strongly associated with ALDH2(*)1/(*)2. p53 alterations are key molecular events in multifocal carcinogenesis in the esophagus. We studied 260 esophageal-cancer free Japanese alcoholics with esophageal dysplasia diagnosed by biopsy of distinct iodine unstained lesions (DIULs) >=5mm. The degree of p53 protein accumulation was positively associated with the degree of atypia (p<0.0001) and size (p=0.040) of DIULs and with the presence of multiple DIULs (p=0.070), but not with ALDH2(*)1/(*)2 or ADH1B(*)1/(*)1. PMID- 21601985 TI - Estrogen promotes benzo[a]pyrene-induced lung carcinogenesis through oxidative stress damage and cytochrome c-mediated caspase-3 activation pathways in female mice. AB - Estrogen may contribute to the development of smoking-induced lung cancer in women. To test this hypothesis, an mouse model was used to investigate the effects of 17 beta-estradiol (E2) on benzo[a]pyrene (B[a]P)-induced lung carcinogenesis. We found that B[a]P could cause oxidative stress damage, upregulate mitochondrial cytochrome-c and caspase-3 expression, induce lung carcinogenesis in female mice, E2 promoted these effects of B[a]P while tamoxifen (TAM) inhibited this effects of E2. We conclude that E2 can promote the tumorigenic effects of B[a]P in female mice, and oxidative stress damage and activation of cytochrome-c-mediated caspase-3 pathway may be involved in this process. PMID- 21601988 TI - Molecular characterization and prevalence of cystic echinococcosis in slaughtered water buffaloes in Turkey. AB - The present study was carried out between March 2006 and June 2010. During the study nine abattoirs were visited and 166 water buffalo internal organs were examined in Black Sea Region of Turkey. It was found that 10.24% buffaloes were infected with cystic echinococcosis (CE). The rate of CE found as 3.77% in males and 21.66% in females, 37.93% in older and 4.38% in young animals. The degree of prevalence according to age and sex was statistically significant (p<0.05). CE was observed 29.41% only in liver, 47.06% only in lungs and 23.53% in both liver and lungs. Therefore, the lungs were the predominant sites of the CE in buffaloes. Molecular identification on nine isolates, based on mitochondrial cox1 sequencing analyses, revealed that six cysts belonged to G1 genotype (domestic sheep strain) while 3 samples showed variant genotypes of Echinococcus granulosus complex G1-G2-G3. Two of them showed a thymine in position 52, like G2 strain, but the rest of sequences were completely identical to strain G1; also one specimen showed a single nucleotide change compared to strain G1 (C122T). PMID- 21601986 TI - Associations between recreational exercise and chronic pain in the general population: evidence from the HUNT 3 study. AB - The evidence for an association between leisure-time physical activity and prevalence of pain is insufficient. This study investigated associations between frequency, duration, and intensity of recreational exercise and chronic pain in a cross-sectional survey of the adult population of a Norwegian county (the Nord Trondelag Health Study; HUNT 3). Of the 94,194 invited to participate, complete data were obtained from 46,533 participants. Separate analyses were performed for the working-age population (20-64 years) and the older population (65 years or more). When defined as pain lasting longer than 6 months, and of at least moderate intensity during the past month, the overall prevalence of chronic pain was 29%. We found that increased frequency, duration, and intensity of exercise were associated with less chronic pain in analyses adjusted for age, education, and smoking. For those aged 20-64 years, the prevalence of chronic pain was 10 12% lower for those exercising 1-3 times a week for at least 30 minutes duration or of moderate intensity, relative to those not exercising. Dependent on the load of exercise, the prevalence of chronic pain was 21-38% lower among older women who exercised, relative to those not exercising. Similar, but somewhat weaker, associations were seen for older men. This study shows consistent and linear associations between frequency, duration, and intensity of recreational exercise and chronic pain for the older population, and associations without an apparent linear shape for the working-age population. PMID- 21601989 TI - A possible mechanism of transfer of memories from the hippocampus to the cortex. AB - The mechanism of time-dependent transfer of memories from the hippocampus to the cortex associated with the memory consolidation process still remains unknown. By visualizing memory as the virtual sensation of sensory stimuli, it has become possible to conceptualize memory as an integral of semblances induced at the postsynapses in the absence of the activation of their corresponding presynapses. This is hypothesized to be possible during memory retrieval by the re-activation of functional LINKs formed between the postsynapses during learning. On occasions of repetition of learning, related learning and unrelated learning, stimulation of the sensory receptor pairs used in the original learning event activates new hippocampal neurons incorporated in the circuitry and induces formation of new functional LINKs in the cortex. Since the virtual sensory units of semblances provide provisions for the formation of similar net semblance from different sets of postsynapses of origin both independently and cumulatively, locations of their formation appear transferable. When semblances from the cortex alone become sufficient to contribute to a specific memory, after a certain period of time from the initial learning, removal of the hippocampus gives an impression of (an apparent) transfer of memories from the hippocampus to the cortex. PMID- 21601990 TI - Personality traits of aggression-submissiveness and perfectionism associate with ABO blood groups through catecholamine activities. AB - Personality trait research has shown associations with many genes, prominently those of the catecholamine metabolism such as dopamine beta hydroxylase (DBH), catechol-O-methyltransferase (COMT), and monoamine oxidase A (MAOA). Because DBH gene is in linkage disequilibrium with ABO gene, there is reason to think that other catecholamine genes using the same substrate as DBH may also have associations with ABO blood groups, and this paper demonstrates how this may be so. Reasons include similarities in hapmap population frequency distributions, similarities in illness risks between ABO blood groups and DBH activities as well as between ABO blood groups and COMT activities and between ABO blood groups and MAOA activities. If ABO blood groups can be demonstrated to associate with all these catecholamine genes, then the catecholamine personality trait research can be applied to ABO blood groups and tested for confirmation. ABO blood typing is widely available and affords ability to test this hypothesis and thus confirm the possible joint association of personality traits of aggression-submissiveness and perfectionism to catecholamine genes and to ABO blood groups. Clinical applications and implications are discussed. PMID- 21601991 TI - Periodontal disease as a risk factor for cardiovascular disease: suggestion of a further link in systemic lupus erythematosus. AB - Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Due to either infection or disease activity, elevated levels of inflammatory markers and up-regulation of the autoimmune process can contribute to the development of atherosclerosis in SLE patients. Periodontal diseases are among the most prevalent chronic infections in humans and are characterized by pathogen-induced oral inflammatory disease affecting the supporting tissues of teeth. Several cytokines capable of inducing systemic effects are produced during the course of this infection. The presence of these cytokines can be verified by changes in the levels of C reactive protein (CRP). Periodontal disease is a well-known risk factor for atherosclerosis. The potential for beneficial prevention of CVD events through the use of periodontal treatment has been previously recommended. This review reinforces the hypothesis that periodontal infection could be a risk factor for CVD in patients diagnosed with SLE, and suggests that by reducing the progression of this oral infection, levels of inflammatory markers common to both diseases (SLE and periodontal disease) would likely decrease. PMID- 21601992 TI - Balanced polymorphism: a survival advantage in celiac disease. PMID- 21601993 TI - Vibration-enhanced posture stabilization achieved by tactile supplementation: may blind individuals get extra benefits? AB - Diminished balance ability poses a serious health risk due to the increased likelihood of falling, and impaired postural stability is significantly associated with blindness and poor vision. Noise stimulation (by improving the detection of sub-threshold somatosensory information) and tactile supplementation (i.e., additional haptic information provided by an external contact surface) have been shown to improve the performance of the postural control system. Moreover, vibratory noise added to the source of tactile supplementation (e.g., applied to a surface that the fingertip touches) has been shown to enhance balance stability more effectively than tactile supplementation alone. In view of the above findings, in addition to the well established consensus that blind subjects show superior abilities in the use of tactile information, we hypothesized that blind subjects may take extra benefits from the vibratory noise added to the tactile supplementation and hence show greater improvements in postural stability than those observed for sighted subjects. If confirmed, this hypothesis may lay the foundation for the development of noise-based assistive devices (e.g., canes, walking sticks) for improving somatosensation and hence prevent falls in blind individuals. PMID- 21601994 TI - Maternal dietary protein induces opposite myofiber type transition in Meishan pigs at weaning and finishing stages. AB - To describe the effects of maternal dietary protein level on offspring skeletal muscle fiber plasticity, 14 Meishan sows were fed on either low-protein (LP) or high-protein (HP) diets throughout gestation and lactation, and the myofiber characteristics of the offspring were observed both at weaning and finishing. Body weight, as well as the longissimus dorsi (LD) and psoas major (PM) muscle weights were significantly higher (P<0.05) in HP piglets at weaning with increased myofiber cross-sectional area and higher expression of myosin heavy chain (MyHC) IIb mRNA and MyHC II protein in LD and IIx mRNA in PM. A conversed transition towards higher proportion of type I fibers in LD, together with decreased MyHC II protein and MyHC IIb mRNA in both LD and PM, was observed at finishing stage in HP group. Although the slaughter weight and meat quality were not affected, the fast-to-slow shift in myofiber types was detected at slaughter. PMID- 21601995 TI - Peripheral blood lymphocyte depletion after hepatic arterial 90Yttrium microsphere therapy for hepatocellular carcinoma. AB - PURPOSE: The short- and long-term effects of (90)Yttrium microspheres therapy for hepatocellular carcinoma (HCC) on peripheral blood lymphocytes are unknown and were therefore examined. METHODS AND MATERIALS: Ninety-two HCC patients were enrolled in a (90)Yttrium therapy study and routine blood counts were examined as part of standard clinical monitoring. RESULTS: We found an early, profound, and prolonged lymphopenia. In a subsequent cohort of 25 additional HCC patients, prospective flow cytometric immune-monitoring analysis was performed to identify specific changes on distinct lymphocyte subsets (i.e., CD3, CD4, CD8 T, and CD19 B lymphocytes) and NK cells absolute numbers, in addition to the granulocytes and platelets subsets. We found that the pretreatment lymphocyte subset absolute numbers (with the exception of NK cells) had a tendency to be lower compared with healthy control values, but no significant differences were detected between groups. Posttherapy follow-up revealed that overall, all lymphocyte subsets, except for NK cells, were significantly (>50% from pretherapy values), promptly (as early as 24 h) and persistently (up to 30 months) depleted post-(90)Yttrium microspheres therapy. In contrast, granulocytes increased rapidly (24 h) to compensate for lymphocyte depletion, and remained increased at 1-year after therapy. We further stratified patients into two groups, according to survival at 1 year. We found that lack of recovery of CD19, CD3, CD8, and especially CD4 T cells was linked to poor patient survival. No fungal or bacterial infections were noted during the 30-month follow-up period. CONCLUSIONS: The results show that lymphocytes (and not granulocytes, platelets, or NK cells) are sensitive to hepatic arterial (90)Yttrium without associated clinical toxicity, and lack of lymphocyte recovery (possibly leading to dysregulation of adaptive cellular immunity) posttherapy indicates poor survival. PMID- 21601996 TI - Typical brachial neuritis (Parsonage-Turner syndrome) with hourglass-like constrictions in the affected nerves. AB - PURPOSE: To report on 5 patients who had acute brachial neuritis (Parsonage Turner syndrome) with hourglass-like constriction in the affected nerves. METHODS: We retrospectively reviewed 5 patients who were treated in our department from December 2003 to December 2008. Acute, intense pain around the shoulder girdle and upper arm was the first symptom and was followed by muscle weakness and atrophy. Clinical and EMG examinations showed involvement of 2 or more nerves in the affected extremity. Those severely affected nerves that had no response to conservative treatment were explored, and an hourglass-like constriction was identified. Neurolysis was performed at the sites of constrictions in 2 radial nerves and 1 median nerve. The constricted portion was resected, and direct coaptation was performed in 1 radial nerve and 1 musculocutaneous nerve. The constricted portion was resected, and nerve graft was performed in 2 radial nerves and 1 median nerve. RESULTS: All patients were followed up for 24 to 84 months after surgery. Of 3 nerves treated with external neurolysis, all attained full recovery. Of 2 nerves treated with resection and neurorrhaphy, 1 attained full recovery, and the other had an incomplete recovery. Of 3 nerves treated with resection and nerve graft, 1 (4-cm nerve graft) attained full recovery, and 2 (4-cm and 13-cm nerve graft, respectively) had incomplete recovery. CONCLUSIONS: The site of nerve lesion of brachial neuritis was not necessarily within the brachial plexus. Our finding of hourglass-like constrictions in individual peripheral nerves suggest that multifocal involvement of terminal branch lesions may underlie the complex patterns of paralysis often encountered clinically. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 21601997 TI - Congenital upper limb deficiencies and associated malformations in Finland: a population-based study. AB - PURPOSE: To calculate the national incidence of upper limb deficiencies and associated infant mortality in children in Finland using the International Federation of Societies for Surgery of the Hand (IFSSH) classification. Radial ray deficiency, ulnar ray deficiency, central ray deficiency, transverse arrest, phocomelia, undergrowth, and constriction band syndrome with skeletal defects were evaluated. METHODS: We reviewed upper limb deficiencies among all 753,342 births in Finland during 1993 to 2005 reported to the Finnish Register of Congenital Malformations. Classification of these upper limb deficiencies was done according to a modified IFSSH system. We calculated incidence, gender and side distributions, frequency of associated anomalies, and infant mortality rates in different subtypes of the deficiencies. Familial occurrence of congenital upper limb defects was recorded. RESULTS: A total of 419 cases (234 male, 185 female) of upper limb deficiencies were identified. The national incidence of upper limb deficiencies was 5.56 per 10,000 births and 5.25 per 10,000 live births. The most common upper limb abnormality was radial ray deficiency (138), followed by subgroups of undergrowth (91), upper limb defects due to constriction band syndrome (51), central ray deficiency (41), and ulnar ray deficiency (33). Perinatal mortality was 14%. Infant mortality among children with upper limb deficiencies was 137 per 1,000 live births, compared with an overall infant mortality of 3.7 per 1,000 live births in Finland. Additional birth defects were found in 60% of these children. Prevalence of upper limb defects in relatives of the census population was 2% (11 of 419). CONCLUSIONS: The national incidence of upper limb deficiencies is 5.25 per 10,000 live births. Congenital upper limb deficiencies are associated with additional birth defects in two thirds of cases. These children, especially children with radial ray deficiency, have a high perinatal mortality rate. When divided into subgroups using IFSSH classification, differences emerge in both associated anomalies and mortality. PMID- 21601998 TI - NR2B subunit of NMDA receptor at nucleus accumbens is involved in morphine rewarding effect by siRNA study. AB - BACKGROUND: Chronic use of morphine causes rewarding effects and behavioral sensitization, which may lead to the development of craving for morphine. A number of studies indicate that the NMDA receptors may be involved in these effects, especially the NR2B-containing NMDA receptors. It is also well recognized that the nucleus accumbens (NAc) and the ventral tegmental area (VTA) are involved in drug addiction, including morphine addiction. AIMS: In this study, we further investigate the role of the NR2B subunit of NMDA receptors at NAc or VTA in morphine rewarding effects and behavioral sensitization. METHODS AND RESULTS: The siRNA against the NR2B subunit of NMDA receptors was locally injected to decrease the expression of NR2B at NAc or posterior VTA in male Sprague-Dawley (S.D.) rats in the present study. The rats were then treated with morphine chronically. A conditioned place preference (CPP) test was used to examine the rewarding effect, and locomotor activity was measured to determine the behavioral sensitization induced by chronic morphine treatment. Results showed that morphine-induced rewarding behavior but not behavioral sensitization was abolished when the NR2B subunit of NMDA receptors at the NAc were significantly decreased. The dopamine turnover rate was not altered by the decrease of NR2B subunit at NAc. CONCLUSION: These findings suggest that the NR2B subunit of NMDA receptors at the NAc is involved in morphine-induced rewarding effect and may not be through directly interacting with dopamine neurons. PMID- 21601999 TI - Phylogenetic analysis of Foot-and-Mouth Disease Virus type O circulating in the Andean region of South America during 2002-2008. AB - At present, Foot-and-Mouth Disease (FMD) has been successfully controlled in most territories of South America, where only Ecuador and Venezuela remain as endemic countries. In this context, the precise characterization of circulating viruses is of utmost importance. This work describes the first molecular epidemiology study performed with the complete VP(1)-coding region of 114 field isolates of FMD virus (FMDV) type O, collected in the Andean countries mainly during 2002 2008. Sequences were aligned and compared to isolates responsible for emergencies in the Southern Cone of the continent between the years 2000 and 2006, and to other representative type O viruses worldwide. The results showed that FMD type O viruses isolated in South America and analyzed up to date are placed in 11 different lineages within the Euro SA topotype. Five of these lineages included viruses circulating in Ecuador and Venezuela during 2002-2008. The last emergencies reported in already-free areas in the Andean region, showed close relationships with viruses circulating in these endemic countries. Andean lineages showed a clear separation from the unique lineage containing viruses responsible for the emergencies in the Southern Cone, reflecting the different livestock circuits and providing evidence that support the ecosystem dynamics in the region. A wide geographical dissemination of the same strain in short time intervals has been observed, pointing to animal movements as the most significant risk parameter. This fact, together with an important generation of viral variants in areas under weak control strategies, reinforce the need of stronger official controls, as well as for establishing multinational cooperative measures in the border areas. PMID- 21602000 TI - Development of a technique for evaluating temporal parameters of sucking in breastfeeding preterm newborns. AB - AIMS: The aim of the current study was to developed and test the reliability of a technique for measuring temporal parameters of sucking in breastfeeding infants. METHODS: The technique was developed using a cohort of 11 term and 12 preterm infants, and subsequently evaluated using a cohort of 43 preterm infants. Measurements related to sucking pressure in the term and preterm infants were acquired. The signals were recorded for 5 min, saved on a computer, and stored for analysis. For purposes of analysis, the minute with the highest quality signal was chosen. Signal analysis was performed by two researchers, and inter- and intra-observer agreement was assessed. The newborns in the sample had different gestational ages. RESULTS: A technique was developed for the analysis of temporal parameters of sucking during breastfeeding and evaluated in 43 preterm infants with different gestational ages for the following variables: number of bursts per minute, number of sucks per burst, sucking rate, pause rate, and duration of pauses. The intra-observer agreement was 0.85 and the inter observer agreement was 0.85. CONCLUSIONS: The technique that was developed and validated proved capable of measuring temporal parameters of sucking in breastfeeding newborns. PMID- 21602001 TI - Oesophageal adenocarcinoma: the new epidemic in men? AB - The last decades have witnessed an unprecedented rise in the incidence of oesophageal adenocarcinoma. This rise has mainly affected men, and current male to-female sex ratio estimates range from 7-10 to 1. Major risk factors for oesophageal adenocarcinoma are gastro-oesophageal reflux disease and obesity, especially in combination. The prevalence of these risk factors has increased during the last decades, but there does not seem to be a marked differential distribution among men and women. However, reflux among men is more often associated with erosive reflux disease than it is among women. There is also evidence that male-type obesity, with a prominent abdominal distribution of fat, confers a greater risk increase for oesophageal adenocarcinoma than the female equivalent. Due to the marked male predominance and the finding that women tend to develop specialized intestinal metaplasia (Barrett's oesophagus) and adenocarcinoma at a later age than men, interest has been directed towards a potential aetiological role of reproductive factors and sex hormones. Breastfeeding has been found to be a protective factor for the development of adenocarcinoma, while no association has hitherto been established with other reproductive factors. Taken together, the male predominance in the incidence of oesophageal adenocarcinoma may partly be explained by the differential effect of the major risk factors reflux disease and obesity, but the mechanisms whereby this occurs need to be elucidated. Moreover, the association with breastfeeding indicates a need for extensive epidemiological studies to clarify a possible role of sex hormonal influence in the aetiology of oesophageal adenocarcinoma. PMID- 21602002 TI - Stroke, obesity and gender: a review of the literature. AB - Cerebrovascular disease constitutes one of the main causes of morbidity, disability and mortality worldwide. Obesity, a major health problem reaching global epidemic proportions, is also associated with morbidity and mortality. The present review provides an update on the current knowledge regarding the association of gender and obesity with stroke prevalence and outcome. We also discuss the areas that future research needs to point towards. In general, gender differences in relation to stroke are increasingly being recognized and evaluated. Age-specific stroke incidence is generally higher in men, except in the elderly. Women are treated less frequently with intravenous thrombolysis compared with men stroke patients and the two genders seem to respond differently to aspirin and statins. Regarding obesity, although it is a well-known predictor of cardiovascular disease, there is a growing body of evidence revealing the presence of an inverse relationship between obesity and outcome in patients with stroke or established cardiovascular disease, the so-called obesity paradox. Further research is warranted on these important topics, as human population is continuously aging and becoming more obese. In this context, the causes of gender differences in stroke prevalence and outcome and the obesity-stroke paradox should be further investigated in future studies. PMID- 21602003 TI - Decomposition and insect succession of clothed and unclothed carcasses in Western Australia. AB - The effect of clothing on carcass decomposition and patterns of insect succession onto remains were investigated in two separate years during autumn in Western Australia. The progression of decomposition differed between clothed and unclothed carcasses in both years of the study. The presence of clothing markedly prolonged the wet decay stage in both years with larval feeding occurring across the moist skin surface underneath clothing, as well as within and under the carcasses. Ambient temperatures were higher in the second year of the study and corresponded to marginally faster rates of decay throughout decomposition. Within years, insect arrival and oviposition were largely consistent between clothed and unclothed carcasses with a few notable exceptions. The green blow fly, Lucilia sericata Meigen (Diptera: Calliphoridae) oviposited one day earlier on clothed than unclothed carcasses in both years of the study. The black carrion fly, Australophyra rostrata Robineau-Desvoidy, (Diptera: Muscidae) colonised clothed carcasses in two distinct waves of succession but only one wave of ovipoistion was observed on unclothed carcasses in either year. Correspondingly, clothed carcasses supported larval feeding by A. rostrata for a longer duration than unclothed carcasses. Finally, dipteran larval masses were more widely distributed across the carcass surface and were present for a longer period of time on clothed carcasses than on unclothed carcasses in both years. Forensically relevant data detailing the seasonal pattern of insect succession onto clothed and unclothed decomposing remains in Western Australia are reported. PMID- 21602004 TI - Getting in touch--3D printing in forensic imaging. AB - With the increasing use of medical imaging in forensics, as well as the technological advances in rapid prototyping, we suggest combining these techniques to generate displays of forensic findings. We used computed tomography (CT), CT angiography, magnetic resonance imaging (MRI) and surface scanning with photogrammetry in conjunction with segmentation techniques to generate 3D polygon meshes. Based on these data sets, a 3D printer created colored models of the anatomical structures. Using this technique, we could create models of bone fractures, vessels, cardiac infarctions, ruptured organs as well as bitemark wounds. The final models are anatomically accurate, fully colored representations of bones, vessels and soft tissue, and they demonstrate radiologically visible pathologies. The models are more easily understood by laypersons than volume rendering or 2D reconstructions. Therefore, they are suitable for presentations in courtrooms and for educational purposes. PMID- 21602005 TI - 3D analysis of spontaneous upbeat nystagmus in a patient with astrocytoma in cerebellum. AB - AIMS: We report the case of a 58-year-old female patient who consulted our Department complaining of positional vertigo and showing spontaneous upbeat nystagmus (UBN) in darkness. METHOD: We analyzed her UBN three-dimensionally. The MRI scan revealed the astrocytoma in the left cerebellum involving the cerebellar vermis. RESULT: Three-dimensional analysis showed a spontaneous UBN rotating around the intra-aural axis in the pitch plane. CONCLUSION: Since the cerebellar vermis is known to plays an inhibitory role on the central vertical vestibule ocular reflex (VOR), the present results suggest that the spontaneous UBN in darkness observed in this patient was induced by an imbalance of central vertical VOR tone. PMID- 21602006 TI - Sleep problems in physically disabled children and burden on caregivers. AB - AIM: The present study was implemented to investigate relationships between sleep problems in physically disabled children and sleep quality and perceived burden of caregivers. METHODS: Subjects comprised 100 caregivers of disabled children, including 96 mothers, 2 fathers and 2 grandmothers. Questionnaires included demographic data for children and caregivers, sleep problems of children, and sleep quality (Pittsburgh sleep quality index (PSQI)) and perceived burden on caregivers (Japanese version of the Zarit Burden Interview (J-ZBI)). The sleep problems of children were evaluated according to the following five categories: "Problems initiating and maintaining sleep"; "Problems with sleep-related breathing"; "Problems with excessive somnolence"; "Problems with circadian rhythm"; and "Problems with sleep-related movement". RESULTS: The children comprised 66 boys and 34 girls (age range, 1-17 years). Of these, 65 children could not sit up and 35 could. A total of 88 children were found to have one or more categories of sleep problems. The most common sleep problem was "Problems initiating and maintaining sleep" (64.8%), followed by "Problems with sleep related movement" (59.1%). J-ZBI was significantly higher in caregivers of children with "Problems initiating and maintaining sleep". PSQI scores were significantly higher in caregivers of children with "Problems with sleep-related breathing" and "Problems with circadian rhythm". A significant correlation was identified between perceived J-ZBI and PSQI of the caregiver. CONCLUSIONS: Increased focus on the sleep problems of disabled children is needed, particularly in relation to the sleep quality and perceived burden of caregivers. PMID- 21602007 TI - [Linezolid use in an intensive care unit]. PMID- 21602008 TI - Incidental adrenal lesions: Accuracy of quadriphasic contrast enhanced computed tomography in distinguishing adenomas from nonadenomas. AB - PURPOSE: To evaluate the accuracy in distinguishing adrenal adenomas from nonadenomas by means of quadriphasic CT exam, including unenhanced (UE), arterial enhanced (AE), portal enhanced (PE) and 5-min delayed enhanced (DE) CT scans. METHODS: This retrospective study had institutional review board approval; the need for informed consent was waived. From September 2007 to September 2009, 104 adrenal masses were evaluated in 87 patients (49 M, 38 F, mean age 58.4 years) undergoing UE, AE (35-s delay), PE (80-s delay) and DE (5-min delay) CT scans. The mean adrenal attenuation during all imaging phases was measured by two readers. The accuracy values of absolute unenhanced attenuation (UE), absolute wash-out (AWO), relative percentage wash-out (RPWO) and percentage enhancement wash-out (PEW) were assessed by using receiver operator curves (ROC) analysis. The overall accuracy of the quadriphasic protocol and other triphasic protocols were evaluated. A value of p<=0.05 was considered significant. RESULTS: The accuracy in characterizing adrenal lesions was 86.5% (90/104) for UE attenuation (<=10 HU threshold), 90.1% (82/91) for RPWO (>=30% threshold), 85.7% (78/91) for AWO (>=12 HU threshold) and 83.5% (76/91) for PEW (>=30% threshold), respectively. Quadriphasic CT (accuracy 97.1%, 101/104) performed better than triphasic CT including only AE scan (efficiency 90.0%, 94/104; p=0.011) and triphasic CT including only PE scan (efficiency 96.1%, 100/104; p=0.025). CONCLUSION: Quadriphasic CT protocol including 5-min DE scan may be used to characterize incidentally detected adrenal masses. RPWO represented the best wash out parameter for characterizing adrenal lesions. PMID- 21602009 TI - Identification of metabolites of crude and processed Fructus Corni in rats by microdialysis sampling coupled with electrospray ionization linear quadrupole ion trap mass spectrometry. AB - A microdialysis (MD) sampling coupled with electrospray ionization linear quadrupole ion trap mass spectrometry (LTQ-MS(n)) method has been developed for rapid and sensitive analysis of rat microdialysate metabolite profile of Fructus Corni, a well-known Traditional Chinese Medicine (TCM). The purified samples were separated by a reversed-phase HPLC with C18 column under a gradient elution. Parent compounds and metabolites of crude and processed Fructus Corni of Jiu Zheng Pin (JZP, JZP is produced after steaming the crude drug pre-steeped in wine) were detected by the on-line MS(n) detector in negative scan model. The identification of the metabolites and their structural elucidation were performed by comparing the changes in molecular mass and defining sites of biotransformation based on the accurate MS(n) spectral information of diagnostic fragment ions. In this work, we used such strategies for the identification of the parent compounds and metabolites of crude and processed Fructus Corni in rats, and seven parent compounds and three new metabolites of Fructus Corni were found in rats for the first time. This study provides important structural information regarding to the metabolism of crude Fructus Corni and its JZP. Furthermore, this work also demonstrated the possibilities of using microdialysis sampling coupled with LC-MS(n) approach for identification of bioactive compounds from TCM in vivo. PMID- 21602010 TI - Development and validation of motivational messages to improve prescription medication adherence for patients with chronic health problems. AB - OBJECTIVE: Poor adherence with prescription medications is a serious problem in health care, especially true for patients with chronic diseases. Previous strategies to promote adherence have generally not resulted in long-term improvements. This research program is designed to improve on past intervention strategies by developing evidence-based and theoretically grounded communication interventions to promote increased adherence. METHODS: Phase 1 of this research program used qualitative methods to examine the uncertainties and concerns that influence medication adherence, identify messages for addressing these concerns, and develop refined motivational messages for promoting medication adherence. Phase 2 of this research program experimentally assessed chronic disease patients' evaluations of the refined motivational messages. RESULTS: Phase 1 qualitative research indicated that patient concerns about their need for the prescribed medication (commitment) was the primary adherence issue, followed by concerns about side effects and the safety of prescription medications, and concerns about the medication costs. These three key issues were translated into draft motivational messages which were evaluated, validated, and refined. Phase 2 experimental research showed that exposure to motivational messages increased consumers' intention to adhere with medication recommendations. CONCLUSION: Follow-up intervention research is warranted to test the use of these motivational messages to promote medication adherence. PRACTICE IMPLICATIONS: Pharmacies and pharmacists have the potential to perform a central role in providing consumers with the relevant information they need to make responsible decisions that lead to increased adherence with prescription medication recommendations. PMID- 21602011 TI - Chronic lower leg swelling caused by isolated popliteal venous entrapment. AB - Isolated popliteal vein entrapment is a rare pathologic condition. Mimicking any venous pathology, a high degree of suspicion is mandatory for diagnosis. We describe a case of a 50-year-old woman, suffering from excessive swelling and heaviness of her left leg for more than 15 years. The ascending venography at functional positions of the feet demonstrated the entrapment. A rich collateral venous network appeared in the popliteal area at plantar foot's flexion. Surgical division of a wide soleus aponeurosis decompressed the vein. At the 2-year follow up, the patient remains free of recurrence. PMID- 21602012 TI - Electromagnetic thermotherapy using fine needles for hepatoma treatment. AB - BACKGROUND AND AIMS: Hepatocellular carcinoma can be treated with heat-based therapies, especially radiofrequency ablation (RFA). However, RFA has limited efficacy and is quite expensive. We designed a new system using fine needles combined with an alternating magnetic field to generate hyperthermia for the treatment of hepatocellular carcinoma in a rat hepatoma model. Our aims are to assess the efficacy of our method and determine survival up to 30 days. METHODS: An N1-S1 cell line was inoculated into the livers of Sprague-Dawley rats, generating tumors after 14 days. The animals were randomized into 5 groups and treated after laparotomy either with normal saline (group I), iron oxide nanoparticles (group II), fine needles (group III), fine needles and iron oxide nanoparticles combined (group IV) or self-designed two-part needles placed under ultrasonographic guidance percutaneously (group V). Every rat was placed in an alternating magnetic field. The temperature in the treatment area was maintained between 55 and 60 degrees C. At day 30 after treatment, tumor volumes and mortality were assessed and histology samples were studied. RESULTS: Tumor volumes were significantly reduced and survival rate was prolonged in groups III, IV and V versus groups I and II (P < 0.05). On pathological examination, groups III, IV and V presented obvious necrosis, apoptosis, calcifications and inflammatory changes in the treatment area. CONCLUSION: Our study demonstrates that hyperthermia generated by fine stainless-steel needles combined with an alternating magnetic field effectively inhibits hepatoma growth in rats and prolongs their survival. Further, this method can be applied percutaneously under ultrasonographic guidance. PMID- 21602013 TI - [Severe facial trauma: control of the upper airway?]. AB - This is the case report of a 16-year-old male who suffered major facial trauma in a road traffic accident (unhelmeted scooter rider against signpost). During prehospital care, he was stable and awake. He was admitted to the emergency room of our university hospital and rapidly transferred, in a sitting position and breathing spontaneously, to the operating room for emergent surgical tracheostomy under local anaesthesia and sedation. This procedure turned out to be difficult (sitting position, patient uncooperative) and ventilatory compromise led us to intubate the patient without difficulties: indeed, supraphysiological mouth aperture (due to multifocal mandible fractures) and presence of supraglottic bubbling under spontaneous ventilation facilitated intubation in spite of major oropharyngeal bleeding. This allowed rapid restoration of adequate ventilation and tracheostomy was performed under standard conditions without further problems. This case report confirms the superiority of orotracheal intubation under light sedation over emergent tracheostomy in this type of situation, as stated under the SFAR guidelines. PMID- 21602014 TI - [Does pulmonary contusion expose to the risk of Streptococcus pneumoniae infections? Results of an experimental study]. AB - OBJECTIVE: To create a reliable and reproducible model of pulmonary contusion (PC) in rats in order to evaluate the influence of PC on bacterial lung proliferation. STUDY DESIGN: Experimental. ANIMALS: Male albino CD rats. METHODS: Animals were anesthetized and a PC was performed using a spring-loaded metal bar. The existence of an isolated right PC was confirmed by macroscopic, histological and radiological analysis. This model was used to compare four randomized groups of animals. These were either injured or only anesthetized and inoculated with a pneumococcal solution concentrated in 2 or 4 log(CFU/mL). The animals' lungs were collected for microbiological culture at 24 hours. The bacterial count evolution per gram of lung was the primary endpoint. RESULTS: Twelve rats were needed to validate the model, 84 to determine the morbidity and mortality and its reproducibility and 66 to assess the intra-pulmonary bacterial proliferation. The PC obtained was unilateral and isolated in 95% of cases. Mortality rate was 43%. For a low initial inoculum concentration (2 log [CFU/mL]), there is bacterial overgrowth in the PC group versus the no-PC group (P=0.0017). This difference was not found when the inoculum was more concentrated. CONCLUSION: This experimental model is reliable and reproducible. The initially high mortality seems to decrease with the experience of operators. The CP significantly increases intra pulmonary bacterial proliferation when the inoculation is low. A high inoculum neutralizes the effect of CP. These results suggest that enhanced prevention of micro-inhalation could be beneficial in cases of CP. PMID- 21602015 TI - [Upper digestive endoscopy in children with laryngeal mask evaluate with 200 patients]. PMID- 21602016 TI - [Microcirculatory dysfunction after cardiac surgery: Interest of NIRS technology with two case reports]. AB - Near infrared spectroscopy (NIRS) seems to be an interesting technology to study microcirculatory dysfunction. These alterations have been described after cardiac surgery under cardiopulmonary bypass. We report two case study reports with monitoring of StO(2) and reperfusion slope after an ischemic challenge. These two parameters are early altered notably in case of cardiac dysfunction (decrease of StO(2) and reperfusion slope). We discuss the interest of microcirculatory measurement in this context. PMID- 21602017 TI - [Hyperlactatemia as a complication of renal embolization in a blunt trauma patient]. PMID- 21602019 TI - [Oral morphine and acute pain management after caesarean section]. PMID- 21602018 TI - [Measure of preoperative anxiety and need for information with six issues]. AB - INTRODUCTION: A questionnaire for self-assessment, the Amsterdam Preoperative Anxiety and Information Scale (APAIS) translated into French has been compared to a background questionnaire to validate their use as screening tool and assessment of anxiety and information needs of patients. PATIENTS AND METHOD: An epidemiological study was conducted anonymously. Patients completed a questionnaire comprising a French version of APAIS and Spielberger Anxiety Inventory (STAI). A study of correlation between scores for each questionnaire was conducted. A high level of anxiety was investigated. RESULTS: So 1800 questionnaires were distributed, 1504 were usable. The first 100 questionnaires have confirmed the internal validity of the questionnaire APAIS. The following questionnaires in 1404 accounted 49.7% of men 55.7 +/- 15.7 years old and 50.2% of women 50.8 +/- 15.2 years old. The correlation coefficient (r) between STAI state and appeasement was of 0.675 (P<0.001). A score higher than 10/20 by APAIS corresponded to 73% of patients with high anxiety by Spielberger's inventory. No correlation was found between the STAI state and the need for information (r=0.252; P<0.001). CONCLUSION: APAIS, in its French version, assesses anxiety and information needs of patients. This questionnaire has metrological capabilities and ease of execution that make it a screening tool for use in anesthesia consultation. A score above 10 out of 20 reflects a high level of anxiety. PMID- 21602020 TI - The Ras signaling pathway mediates cetuximab resistance in nasopharyngeal carcinoma. AB - This work aimed to investigate the role of the Ras signaling pathway in cetuximab resistance in human nasopharyngeal carcinoma (hNPC). An hNPC 5-8F cell line was induced by stepwise exposure to increasing doses of cetuximab. Western blot was conducted to detect protein levels. Our results are as follows: cetuximab resistant hNPC 5-8F/Erbitux cell lines were successfully developed. After treatment with cetuximab for 3 and 5 d, the RI was 1.2 and 1.1, respectively. Compared with the 5-8F cells, the protein expression levels of H-ras, JNK/P-JNK, P-ERK1/2, p38/P-p38, P-AKT, NF-kappaB p65/P-NF-kappaB p65 and c-fos were significantly increased in the 5-8F/Erbitux cells (P=0.000 for all); however, the protein expression levels of ERK1/2 and c-jun/P-c-jun were significantly decreased (P=0.000 for all) and AKT protein expression showed no significant change (P=0.176). After the 5-8F/Erbitux cells were transfected with H-ras shRNA, H-ras protein expression was significantly decreased (P=0.000) and cetuximab sensitivity improved. In contrast, in the 5-8F/Erbitux+siH-ras cells, protein expression levels of P-ERK1/2, P-JNK, P-AKT and NF-kappaB p65/P-NF-kappaB p65 were significantly decreased (P=0.000 for all). Additionally, protein expression levels of JNK, ERK1/2, p38/P-p38 and c-jun/P-c-jun were significantly increased (P=0.000 for all), but protein expression levels of AKT and c-fos did not change significantly (P=0.061 and P=0.068, respectively). In conclusion, the activation of the H-ras/ERK1/2, H-ras/JNK and PI3K-AKT signaling pathways is closely associated with cetuximab resistance in 5-8F/Erbitux cells. NF-kappaB is activated in 5-8F/Erbitux cells without activation of c-jun. PMID- 21602021 TI - Synthesis of 4-aminoquinoline analogues and their platinum(II) complexes as new antileishmanial and antitubercular agents. AB - A series of 4-amino-7-chloroquinoline derivatives were synthesized by the reaction of 4,7-dichloro-quinoline with the corresponding diamine and then with propargyl bromide. In addition, platinum(II) complexes were obtained by reacting some of the organic derivatives with K(2)PtCl(4). Several of the synthesized compounds displayed antituberculosis activities. Compound 3 was 47.5 times more active than amphotericin B against Leishmania chagasi (IC(50)=0.04 MUg/mL). Compounds 5, 6, 7, 9, 10, 11 and 13 presented promising results against Mycobacterium tuberculosis, with MIC values ranging from 12.5 to 15.6 MUg/mL, comparable to the "first and second line" drugs used to treat tuberculosis. PMID- 21602022 TI - Management options for total knee arthroplasty in osteoarthritic knees with extra articular tibial stress fractures: a 5-year experience. AB - Difficult primary knees are fairly common in Asian countries, and tibial stress fractures in deformed osteoarthritic knees add to the challenge. Management options are ill-defined because of limited experience; for 5 years, 8 osteoarthritic knees with extra-articular tibial stress fractures ranging from unicortical stress lesions to frankly mobile fractures were managed by total knee arthroplasty. At mean 42.25 months follow-up, average Knee Society Score improved from 23.62 to 80.87; and average functional score improved from 18.75 to 67.75. All 8 fractures united; 1 (plate plus stem extender) had wound breakdown and delayed union. We present our learning experience with single-stage modular total knee arthroplasty using stem extenders or plates; with proper planning and additional use of image intensifier, these unique cases can reliably be managed with satisfactory outcomes. PMID- 21602023 TI - Health state utility in patients with osteoarthritis of the hip and total hip arthroplasty. AB - Understanding patients' perceived health status, as measured by health state utility, is important when evaluating the societal impact of hip osteoarthritis (OA) and total hip arthroplasty (THA). The purpose of this study was to measure health state utility in patients with hip OA and THA. A total of 231 patients from 2 institutions were enrolled into 1 of 6 cohorts: chronic hip OA, successful and failed primary THA, successful and failed revision THA, and infected THA. Average health state utilities were calculated using the time-trade-off method. Health state utilities were highest for primary THA (0.96) and lowest for infected THA (0.46). Our data demonstrate that THA results in substantial improvement in perceived health status in patients with chronic hip OA. However, health state utility is significantly worse after revision THA than primary THA, and failed primary or revision THA results in substantially reduced health state utility, similar to or worse than chronic OA. PMID- 21602024 TI - Do patients return to work after hip arthroplasty surgery. AB - Improvements in total hip arthroplasty implant design and advances in bearing materials, including modern surface arthroplasty, have resulted in these procedures being performed in younger and more active patients. There is limited information in the literature to provide to patients, employers, and insurance companies about returning to work after hip arthroplasty surgery. We conducted a multicenter telephone survey on 943 patients younger than 60 years with a University of California, Los Angeles, activity score of 6 or higher (regularly participates in moderate activities) who underwent hip arthroplasty surgery between 2005 and 2007 at a minimum of 1 year after surgery. We found that most young, active patients employed before surgery can expect to return to work (90.4%), with the vast majority returning to their preoperative occupation, and very few (2.3%) were limited in their ability to return to work because of their operative hip. PMID- 21602025 TI - Little clinical advantage of modified Watson-Jones approach over modified mini incision direct lateral approach in primary total hip arthroplasty. AB - This study compared the clinical outcomes of total hip arthroplasty using a minimally invasive anterolateral approach with a muscle-sparing technique (modified Watson-Jones approach) and the modified mini-incision direct lateral approach. We randomly assigned 102 patients to the muscle-sparing group (n = 52) or the mini-incision direct lateral group (n = 50). Muscle strength recovery of hip abduction at 6 weeks after surgery was better, and creatine kinase level at 1 day after surgery was lower in the muscle-sparing group than in the mini-incision direct lateral group (P < .01). However, there was no difference in the Harris hip score, pain visual analog scale, the Western Ontario and McMaster Universities Osteoarthritis Index, and Medical Outcomes Study Short Form 36 score between the 2 groups throughout the 1-year study period. PMID- 21602026 TI - Distal fixation of proximally coated tapered stems may predispose to a failure of osteointegration. AB - Despite excellent long-term results of proximally coated tapered wedge femoral stems in noncemented total hip arthroplasty, we have consistently observed a minority fail to achieve osteointegration. We retrospectively reviewed 320 consecutive total hip arthroplasties performed by a single surgeon using a single stem over a 4-year period. Clinical and radiographic parameters were analyzed for risk factors predisposing to a failure of osteointegration, defined as a progressive circumferential radiolucency around the proximal porous coating on both anteroposterior and lateral radiographs. Fifteen stems (4.7%) failed to osteointegrate; 3 underwent femoral revision for persistent thigh pain, whereas the remainder expressed varying degrees of symptomatology. Risk factors associated with failure of osteointegration were male sex, a smaller canal-flare index, larger stem size, and greater canal fill at the mid- and distal-thirds of the stem. Awareness of variability in proximal femoral morphology and problems caused by distal fixation with a proximally coated implant may help avoid this uncommon but potentially serious complication. PMID- 21602027 TI - School refusal and anxiety in adolescence: non-randomized trial of a developmentally sensitive cognitive behavioral therapy. AB - The main objectives were to evaluate efficacy and acceptability of a developmentally sensitive cognitive behavioral therapy for anxiety-based school refusal in adolescence. Twenty school-refusing adolescents meeting DSM-IV anxiety disorder criteria participated in a non-randomized trial, together with parents and school staff. Outcome was assessed at post-treatment and 2-month follow-up. Treated adolescents showed significant and maintained improvements across primary outcome variables (school attendance; school-related fear; anxiety), with medium to large effect sizes. Half of the adolescents were free of any anxiety disorder at follow-up. Additional improvements were observed across secondary outcome variables (depression; overall functioning; adolescent and parent self-efficacy). The treatment was rated as acceptable by adolescents, parents, and school staff, which may help explain the very low attrition rate. Social anxiety disorder was the most common disorder among adolescents still meeting anxiety disorder criteria at follow-up. Treatment modifications to improve efficacy for school refusing adolescents presenting with social anxiety disorder are suggested. PMID- 21602028 TI - Is autologous platelet concentrate beneficial for post-extraction socket healing? A systematic review. AB - The aim of this systematic review was to assess if the use of autologous platelet concentrates may be beneficial to the healing of extraction sockets. Medline, Embase and Cochrane Central Register of Controlled Trials were searched using a combination of specific search terms. Hand searching of the relevant journals and of the bibliographies of reviews was also performed. Prospective comparative studies evaluating the effect of a platelet concentrate on fresh extraction sockets were included. Outcome variables related to hard and soft tissue healing, aesthetics and postoperative discomfort were considered. A methodological study quality assessment was made. The initial search yielded 425 articles, eight were finally included. 207 tooth extractions (104 tests and 103 controls) in 115 patients were evaluated. The articles provided a broad range of variable outcomes to assess the regenerative potential of platelet concentrate and its possible benefits to the treatment. Favourable effects on hard and soft tissue healing and postoperative discomfort reduction were often reported. A large heterogeneity was found regarding study design, sample size, surgical techniques and methods for preparing platelet concentrates. Standardization of experimental design is needed in order to detect the true effect of platelet concentrates in regenerative procedures of extraction sockets. PMID- 21602029 TI - A simple method to expand the joint space for TMJ surgery. AB - When performing open surgery for internal derangement of the temporomandibular joint, it is essential to expand the joint spaces to access the lesions and perform various procedures. This paper presents a simple method to achieve this goal. PMID- 21602030 TI - Persistent psychosis following the use of Spice. PMID- 21602031 TI - Insights into theory of mind in schizophrenia: the impact of cognitive impairment. AB - The ability to mentalize and attribute beliefs, intentions and desires to others has been found by the vast majority of studies to be impaired in patients with schizophrenia. However, it is not yet clear if this deficit in Theory of Mind (ToM) is independent of their also well established deficits in basic cognitive functioning. In the present study, we sought to clarify the above relationship by exploring patients' ToM impairment after controlling for their putative cognitive deficits. We examined 36 patients with schizophrenia and 30 healthy matched controls on first and second order tasks of ToM and on commonly used neuropsychological tests. Patients performed poorly on ToM tasks even after controlling for their cognitive deficits, particularly on second order ToM. The present findings contribute to the understanding of the mechanism of ToM, suggesting that ToM deficits are core characteristics in schizophrenia and relatively independent of patients' cognitive impairment. PMID- 21602032 TI - Transgenic rescue of desmoglein 3 null mice with desmoglein 1 to develop a syngeneic mouse model for pemphigus vulgaris. AB - BACKGROUND: An active disease mouse model of pemphigus vulgaris (PV) was developed using the adoptive transfer of splenocytes from Dsg3(-/-) mice with a mixed C57BL/6J (B6) and 129/Sv genetic background into B6-Rag2(-/-) mice. Further immunological investigation is needed to resolve the genetic mismatch between host and recipient mice. The B6-Dsg3(-/-) mice did not grow old enough to provide splenocytes, probably due to severe oral erosions, with resulting inhibition of food intake. OBJECTIVE: To rescue the B6-Dsg3(-/-) mice and to produce syngeneic PV model mice. METHODS: Transgenic expression of mouse Dsg1 was attempted to compensate for the genetic loss of Dsg3 using the keratin 5 promoter. We evaluated the compensatory ability of Dsg1 in vivo by comparing Dsg1(wt/wt), Dsg1(tg/wt), and Dsg1(tg/tg) mice. We generated a PV model via the adoptive transfer of B6-Dsg1(tg/tg)Dsg3(-/-) splenocytes to B6-Rag2(-/-) mice. RESULTS: Dsg1(tg/tg) and Dsg1(tg/wt) mice expressed ectopic Dsg1 on keratinocyte cell surfaces in the lower layers of the epidermis, oral epithelium, and telogen hair follicles. Ectopic Dsg1 blocked the pathogenic effects of AK23 anti-Dsg3 mAb, and improved the body weight loss, telogen hair loss, and survival rate dose dependently. While the B6-Dsg1(wt/wt)Dsg3(-/-) mice died by week 2, over 80% of the B6-Dsg1(tg/tg)Dsg3(-/-) mice survived at week 6. Furthermore, the syngeneic PV model mice showed the characteristic phenotype, including stable anti-Dsg3 antibody production and suprabasilar acantholysis on histology. CONCLUSION: Transgenic expression of Dsg1 rescued the severe B6-Dsg3(-/-) phenotype and provided a syngeneic mouse model of PV, which may be a valuable tool for clarifying immunological mechanisms in autoimmunity and tolerance of Dsg3. PMID- 21602033 TI - A melanocortin receptor 1 and 5 antagonist inhibits sebaceous gland differentiation and the production of sebum-specific lipids. AB - BACKGROUND: The melanocortin receptor-5 (MC5R) is present in human sebaceous glands, where it is expressed in differentiated sebocytes only. The targeted disruption of MC5R in mice resulted in reduced sebaceous lipid production and a severe defect in water repulsion. OBJECTIVE: To investigate the physiological function of MC5R in human sebaceous glands. METHODS: A novel MC1R and MC5R antagonist (JNJ-10229570) was used to treat primary human sebaceous cells or human skins grafted onto severe combined immunodeficient (SCID) mice. Transcription profiling, lipid analyses, and histological and immunohistochemical staining were used to analyze the effect of MC5R inhibition on sebaceous gland differentiation and sebum production. RESULTS: JNJ-10229570 dose dependently inhibited the production of sebaceous lipids in cultured primary human sebocytes. Topical treatment with JNJ-10229570 of human skins transplanted onto SCID mice resulted in a marked decrease in sebum-specific lipid production, sebaceous gland's size and the expression of the sebaceous differentiation marker epithelial-membrane antigen (EMA). Treatment with flutamide, a known inhibitor of sebum production, gave similar results, validating the human skin/SCID mouse experimental system for sebaceous secretion studies. CONCLUSION: Our data suggest that antagonists of MC1R and MC5R could be effective sebum suppressive agents and might have a potential for the treatment of acne and other sebaceous gland pathologies. PMID- 21602034 TI - Negative symptoms and psychosocial functioning in schizophrenia: neglected but important targets for treatment. AB - BACKGROUND: Many patients with schizophrenia suffer from poor social functioning, with high levels of unemployment being one particular consequence. Negative symptoms tend to persist during periods of clinical stability and may have a detrimental effect on function. This paper aims to investigate the relationship between negative symptoms and ability to function. METHODS: The EGOFORS study measured negative symptoms in 295 schizophrenia patients in 11 European sites using the PANSS Negative Subscale and assessment scales for psychosocial function: Global Assessment of Functioning (GAF), Personal and Social Performance (PSP), Quality of Life Scale (QLS), Functional Remission of General Schizophrenia (FROGS), Psychosocial Remission in Schizophrenia (PSRS) and Subjective Wellbeing under Neuroleptics (SWN). The relationships between the PANSS Negative Subscale and the functional scales were investigated, adjusting for differences between study sites. Being in work, duration of illness, age of onset and number of years of education were also investigated for a relationship with function. RESULTS: There were strong, statistically significant correlations between PANSS Negative Subscale and all of the function scales (95% confidence intervals for the correlation coefficients: PSRS 0.77-0.91; FROGS 0.74-0.89; QLS 0.74-0.92; GAF 0.64-0.78; PSP 0.63-0.80) except the SWN. All of the functional scales except SWN were at least moderately related to one another. All of the items in each of the PANSS Negative Subscale and the function scales contributed to the relationships between them. Better functioning correlated strongly with participants being in work. CONCLUSION: This study shows a strong and significant relationship between negative symptoms and psychosocial functioning. Given the impact of negative symptoms on psychosocial function, much more emphasis should be placed on developing effective treatments for negative symptoms, given that most patients with schizophrenia now live in community settings and require to function adequately to support their quality of life. PMID- 21602035 TI - Dynamics in space and time of four testate amoebae (Difflugia spp.) co-existing in the zooplankton of a reservoir in southern China. AB - We studied a long time series of the dynamics in space and time of four species of Difflugia (thecamoebae) that co-exist in the pelagic plankton of Liuxihe Reservoir, an oligo-mesotrophic impoundment in southern China, during 8-9 months ("summer" form March to November), and retreat to the benthos during the rest of the year ("winter"). We discuss the reasons for the winter retreat, and suggest that predator evasion may be involved, although temperature-linked physiological effects (like the rate of gas bubble production) appear more probable. Clear diel vertical migration of Difflugia was not observed, but patchiness was common. We found no evident lake edge-effects in the spatial pattern either, but the abundances were strongly influenced by trophic conditions and increased by up to one order of magnitude in the upstream, eutrophic sections of the reservoir. PMID- 21602036 TI - A population-based study of prostate cancer chemotherapy. AB - The use of chemotherapy in the treatment of prostate cancer is a relatively recent development, with no published data on the patterns of care in the UK. We carried out a population-based study to assess variation in the use of prostate cancer chemotherapy over time in a UK cancer network. PMID- 21602037 TI - The effect of DHEA treatment on the oxidative stress and myocardial fibrosis induced by Keshan disease pathogenic factors. AB - Oxidative stress induced by the combined deficiencies of selenium (Se) and vitamin E (VE) is considered the basic factor of Keshan disease (KD). Dehydroepiandrosterone (DHEA) is a naturally occurring adrenal androgen that has antioxidant properties. We found that a Se- and VE-deficient diet induced KD lesions in rats, while 0.05, 0.125, and 0.25 g/kg DHEA caused a concentration dependent inhibition in the development of oxidative stress and extracellular matrix (ECM) deposition in the left ventricles of the Se- and VE-deficient rats. In addition, DHEA counteracted activation of NFkappaB as well as the subsequent increase in TGFbeta-1 and CTGF induced by the Se- and VE-deficient diet. These studies suggested that DHEA prevents oxidative stress and might be useful in treating Se and VE deficiency-related KD. These effects were based on its antioxidant effects and ECM deposition inhibition in left ventricles. PMID- 21602038 TI - Magnetic microparticle-based multiplexed DNA detection with biobarcoded quantum dot probes. AB - We have developed a new analytical method to detect multiple DNA simultaneously based on the biobarcoded CdSe/ZnS quantum dot (QD) and magnetic microparticle (MMP). It was demonstrated by using oligonucleotide sequences of 64 bases associated with human papillomavirus 16 and 18 L1 genes (HPV-16 and HPV-18) as model systems. This analytical system involves three types of probes, a MMP probe and two streptavidin-modified QD probes. The MMPs are functionalized with HPV-16 and HPV-18 captures DNA to form MMP probes. The QDs are conjugated with HPV-16 or HPV-18 probe DNA along with FAM- or Rox-labeled random DNA to form HPV-16 and HPV 18 QD probes, respectively. A one-step hybridization reaction was performed by mixing the MMP probes, HPV-16 and HPV-18 target DNA (T-16 and T-18), HPV-16 and HPV-18 QD probes. Afterwards, the hybrid-conjugated microparticles were separated by a magnet and heated to remove the MMPs. Finally, the detections of T-16 and T 18 were done by measuring fluorescence signals of FAM and Rox, respectively. Under the optimum conditions, the fluorescence intensity exhibited a good linear dependence on target DNA concentration in the range from 8 * 10-11 to 8 * 10-9 M. The detection limit of T-16 is up to 7 * 10-11 M (3sigma), and that of T-18 is 6 * 10-11 M. Compared with other biobarcode assay methods, the proposed method that QDs were used as the solid support has some advantages including shorter preparation time of QD probes, faster binding kinetics and shorter analytical time. Besides, it is simple and accurate. PMID- 21602039 TI - The MOXFQ patient-reported questionnaire: assessment of data quality, reliability and validity in relation to foot and ankle surgery. AB - Previously validated for hallux valgus surgery, the Manchester-Oxford Foot Questionnaire (MOXFQ) is here evaluated for use with different regions of the foot and ankle. The study recruited 671 consecutive patients (87.8% of those eligible), mean age 52.8 years, 64% female, who completed the MOXFQ and SF-36 general health survey before foot or ankle surgery. Surgeons completed the American Orthopaedic Foot & Ankle Society (AOFAS) scales and indicated that the patients' main regions for surgery were: Hallux 210 (31.3%), Lesser toes 119 (17.7%), Mid foot 22 (3.3%), Ankle/hind foot 311 (46.3%), Multiple/whole foot 9 (1.3%). Individual MOXFQ items were assessed in terms of response rate and floor/ceiling effects, with the validity of the three MOXFQ scales (Walking/standing, Pain, and Social interaction) being assessed in terms of item total correlations, internal and test-retest reliability, and construct validity. MOXFQ item response rates were high (all >98%). Cronbach's alphas of >0.7 confirmed internal consistency of all three scales. Test-retest ICCs were all >=0.89. Correlations of >0.4 obtained with related SF-36 and AOFAS scales supported a priori hypotheses. Good measurement properties are confirmed for the MOXFQ in the context of baseline assessment of patients receiving surgery for a variety of foot or ankle problems. PMID- 21602040 TI - Failure of neuraxial anaesthesia in a patient with Velocardiofacial syndrome. AB - Velocardiofacial or 22q11 deletion syndrome is a genetic condition caused by deletion 22q11, the deletion of a small segment of the long arm of chromosome 22. To our knowledge this is the first case report of a woman with Velocardiofacial syndrome presenting in late pregnancy for caesarean delivery. She had undergone a Tetralogy of Fallot repair as an infant and had residual pulmonary regurgitation. In addition examination revealed micrognathia and scoliosis. Neuraxial anaesthesia was unsuccessful and subsequent conversion to general anaesthesia was necessary despite concerns regarding her facial abnormalities, pulmonary regurgitation and mild intellectual impairment. PMID- 21602041 TI - Biological treatment of refinery spent caustics under halo-alkaline conditions. AB - The present research demonstrates the biological treatment of refinery sulfidic spent caustics in a continuously fed system under halo-alkaline conditions (i.e. pH 9.5; Na(+)= 0.8M). Experiments were performed in identical gas-lift bioreactors operated under aerobic conditions (80-90% saturation) at 35 degrees C. Sulfide loading rates up to 27 mmol L(-1)day(-1) were successfully applied at a HRT of 3.5 days. Sulfide was completely converted into sulfate by the haloalkaliphilic sulfide-oxidizing bacteria belonging to the genus Thioalkalivibrio. Influent benzene concentrations ranged from 100 to 600 MUM. At steady state, benzene was removed by 93% due to high stripping efficiencies and biodegradation. Microbial community analysis revealed the presence of haloalkaliphilic heterotrophic bacteria belonging to the genera Marinobacter, Halomonas and Idiomarina which might have been involved in the observed benzene removal. The work shows the potential of halo-alkaliphilic bacteria in mitigating environmental problems caused by alkaline waste. PMID- 21602042 TI - Effect of culture conditions on producing and uptake hydrogen flux of biohydrogen fermentation by metabolic flux analysis method. AB - In this work, metabolic flux analysis (MFA) method was used to estimate the effects of the culture conditions on both the producing and uptake hydrogen flux inside the cell of Klebsiella pneumoniae ECU-15. The results indicated that higher temperature could reduce the amount of the uptake hydrogen and enhance the hydrogen production from the NADH pathway. Moreover, both the producing hydrogen flux from formate and the uptake hydrogen flux were attained to the maximum at pH 7.0-7.5. The producing hydrogen flux was higher at 5g/L initial glucose than that of the other concentrations, and the uptake hydrogen flux showed the minimum value under the same condition. The apparent hydrogen generation was caused by the combined action of producing hydrogenase, uptake hydrogenase and bidirectional hydrogenase. These results were helpful to deeply understand the mechanism of the biohydrogen evolving process and establish the suitable molecular strategies for improving hydrogen production. PMID- 21602043 TI - Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors. AB - Novel triazoloquinazolines have been found as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity studies improved the initial micromolar potency which was found in the lead compound by a 100-fold identifying 5-(1H benzoimidazol-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[1,5-c]quinazoline, 42 (PDE10A IC(50)=12 nM) as the most potent compound from the series. Two X-ray structures revealed novel binding modes to the catalytic site of the PDE10A enzyme. PMID- 21602044 TI - Methyl-monofluorination of ibuprofen selectively increases its inhibitory activity toward cyclooxygenase-1 leading to enhanced analgesic activity and reduced gastric damage in vivo. AB - Newly developed monofluoromethylation reaction provided access to various bioactive molecules with an interesting monofluoromethyl unit. An iridium catalyzed asymmetric version was employed for large-scale methyl-monofluorination of widely used nonsteroidal anti-inflammatory drug ibuprofen (the active S isoform). The methyl-monofluorinated ibuprofen was found to selectively inhibit cyclooxygenase-1 over cyclooxygenase-2 and surprisingly, the compound, with almost equal pharmacokinetic profile, was shown to increase analgesic activity and diminish gastric damage in animal models comparing to the parent drug ibuprofen. Therefore, methyl-monofluorination could be a useful strategy for improving efficacy and safety profile of drugs from the 'profen' family. PMID- 21602045 TI - Conformational selection mechanism governs oxygen ligation to H-NOX proteins. AB - H-NOX proteins are at present the only structural models available for the study of the ligand binding affinity and selectivity of soluble guanylate cyclase, the physiological receptor of nitric oxide. The oxy complex and resting state structures of two bacterial H-NOX proteins of markedly different oxygen affinity, but of quite similar sequence, were studied by molecular dynamics simulations at 300 K and 400 K. Unexpectedly, the different O(2) affinity was found to be reflected in differences of the resting states structures. A conformation containing a pre-formed oxygen-binding cage is the most populated in the resting state equilibrium ensemble of the only successful O(2) binder, Tt H-NOX at 300 K, suggesting that conformational selection governs the interaction. PMID- 21602046 TI - 172nd ENMC International Workshop: dysferlinopathies 29-31 January 2010, Naarden, The Netherlands. PMID- 21602047 TI - Percentage height of center of mass is associated with the risk of falls among elderly women: A case-control study. AB - Falls are a serious health problem for aged people, causing social and economic burden. Despite being an important determinant of balance, the positioning of the center of mass (COM) has not been evaluated as a risk factor for falls. This study examined the association between the percentage height of COM (%COM) and the risk of falls in the elderly. Healthy women aged 60 years and older were consecutively selected in a case-control study. Forty-eight individuals classified as "fallers" (having suffered two or more falls in the previous year) were the cases while 48 age and weight-matched women with one fall or no falls in the previous year were the controls ("non-fallers"). Body composition and bone mineral density (BMD) by DXA, 30-second chair stand test, abdominal circumference, Berg's balance scale and %COM using the reaction board method were evaluated in all participants. Body composition parameters were not significantly different between groups. Spine and hip BMD tended to be lower in the fallers, but the difference was significant only at the femoral neck (0.80+/-0.10g/cm(2) versus 0.87+/-0.76g/cm(2); p<0.01). Berg's balance scale scores were lower among fallers than non-fallers (p<0.05). Percentage height of COM was significantly higher among fallers (p<0.001) and this was associated with a higher number of fractures (p<0.05). Percentage height of COM is significantly higher in the elderly with frequent falls. Further work is needed in order to determine the value of board reaction measurements in a clinical setting to identify patients at high risk. PMID- 21602048 TI - Syntheses of cellotriose and cellotetraose analogues as transition state mimics for mechanistic studies of cellulases. AB - Cellotriose and cellotetraose analogues carrying cyclohexene rings were developed as molecular probes which are expected to mimic the transition state conformation of hydrolysis by cellulases. The cyclohexene ring was placed at the pyranose ring being expected to locate the -1 subsite of the enzyme. In order to evaluate these probes, sulfur derivatives of cellotriose and cellotetraose were also synthesized as the enzyme tolerant analogues which mimic the stable conformations of the natural cellulose. The binding assays using differential scanning calorimetry revealed that introduction of the cyclohexene ring is effective to the complexation with an endoglucanase, NCE5 from Humicola insolens. PMID- 21602049 TI - 18F -PEG-biotin: Precursor (boroaryl-PEG-biotin) synthesis, 18F -labelling and an in-vitro assessment of its binding with NeutravidinTM-trastuzumab pre-treated cells. AB - In terms of nuclear decay 18F is the most ideal PET nuclide but its short t(1/2) precludes its use for directly labelling whole antibodies due to their long blood residence times. Pre-targeted imaging using affinity systems such as NeutravidinTM-biotin facilitates the application of short-lived nuclides by their attachment to biotin for imaging cell surface proteins targeted with NeutravidinTM-conjugated antibodies. METHODS: Boroaryl functionalised biotin was prepared with a PEG linker and radiolabelled by incubation with 18F in acidified aqueous solution. Cells expressing high (SKBr3), medium (MDA-MB-453) and low (MDA MB-468) levels of HER-2 were pre-incubated with NeutravidinTM-conjugated trastuzumab, washed, and then incubated with 18F -PEG-biotin. RESULTS: The 18F fluorination of boroaryl-PEG-biotin was much more efficient than reported for other versions of boroaryl-biotin. The novel 18F -PEG-biotin was demonstrated to bind to HER-2-expressing cells in-vitro pre-incubated with NeutravidinTM conjugated trastuzumab. CONCLUSION: Biotin can be functionalised with boroaryl and readily 18F -radiolabelled in aqueous solution and will bind to cells pre incubated with NeutravidinTM-antibody conjugates. PMID- 21602050 TI - Lung biopsies for interstitial lung disease: the limits of the traditional methods of microbiological identification. PMID- 21602051 TI - Non-melanoma skin cancers in elderly patients. AB - Non-melanoma skin cancers are a common reality worldwide. The principal cause that determines the occurrence of these diseases is the exposition of the sun, which principally causes an alteration in the immune system. Therefore, it is possible that other forms of innate or acquired alterations of the immune system could favor the occurrence of non-melanoma skin cancers. For example, several studies have demonstrated that immunosenescence creates an immunosuppressive state that encourages the development of malignances, and new discoveries have noted the importance of T cells and in particular of T regulatory cells (Treg) and T receptor CD28 in this mechanism. Similar results are obtained analyzing the effect of immunosuppressive drugs. The importance of the immune system and its alteration in the genesis of non-melanoma skin cancers is fundamental for the creation of a new therapeutic and less invasive approach. PMID- 21602052 TI - Dentoalveolar infections. AB - Dentoalveolar infections represent a wide spectrum of conditions, from simple localized abscesses to deep neck space infections. The initial assessment of the patient with a dentoalveolar infection requires considerable clinical skill and experience, and determines the need for further airway management or emergent surgical therapy. Knowledge of head and neck fascial space anatomy is essential in diagnosing, understanding spread, and surgically managing these infections. Oral and maxillofacial surgeons must make use of their wide spectrum of clinical skill and knowledge to effectively evaluate and treat patients with dentoalveolar infections. PMID- 21602053 TI - Towards a serotonin-dependent leptin roadmap in the brain. AB - Leptin exerts control over energy metabolism, reproduction and bone mass accrual, raising the question does leptin act through a common neuronal circuit to mediate these effects? Historically, the hypothalamus has been viewed as the site for leptin signaling in the brain. Recent genetic studies, however, indicate that these physiological functions, notably the regulation of appetite and bone mass accrual by leptin, take place for the most part through inhibition of serotonin (5-hydroxytryptamine) synthesis and release by brainstem neurons. Here, we review how these findings have redefined the roadmap of leptin signaling in the brain. This has led to proof-of-principle studies showing that selective inhibition of the leptin-serotonin axis is a viable therapeutic approach to treat appetite disorders. PMID- 21602055 TI - Preconception health of low socioeconomic status women: assessing knowledge and behaviors. AB - INTRODUCTION: The stalled U.S. infant mortality rate and persistent disparities in adverse pregnancy outcomes may be addressed by optimizing a woman's health throughout her childbearing years. This study examines women's knowledge and behaviors related to preconception risk factors in two community health centers serving lower income, racially diverse populations. METHODS: A survey was administered among a convenience sample of women ages 18 to 44 years (n = 340). Questions focused on health behaviors and conditions, knowledge of risk factors, and recommendations of health care providers. Outcomes include the prevalence of risk factors and correlations between the presence of a risk factor and either a respondent's knowledge or a health care provider's recommendation. Data were analyzed for total respondents and two subgroups: Black, non-Hispanic and Hispanic. RESULTS: Despite strong knowledge of risk factors in the preconception period, high-risk behaviors and conditions existed: 63% of women overweight or obese, 20% drinking alcohol, and 42% taking a multivitamin. Significant differences in risk factors were noted between Black, non-Hispanic and Hispanic respondents. Overweight/obesity (t = 3.0; p < .05) and alcohol use (chi2 = 9.2; p < .05) were higher among Black, non-Hispanics, whereas Hispanic women had lower rates of multivitamin use (chi2 = 11.1; p < .05). The majority of respondents recall being spoken to by a health care provider about pregnancy-related risks. Most risk factors were not influenced by provider's recommendations, including multivitamin use, drinking alcohol, and smoking. However, birth control use was correlated with a provider's recommendation (chi2 = 7.6; p < .05). Correlations between the presence of risk factors and respondent's knowledge existed for immunizations (chi2 = 9.6; p < .05), but not for multivitamin use, drinking alcohol, or smoking. CONCLUSION: Our study identified behaviors amenable to change. Knowledge alone or a doctor's recommendation are not enough to change those behaviors. Innovative programs and support systems are required to encourage women to adopt healthy behaviors throughout the childbearing years. PMID- 21602057 TI - Prognosis of cryptogenic ischemic stroke: a prospective single-center study in Chile. AB - Approximately 25%-40% of ischemic strokes are considered of unknown cause (ie, cryptogenic). The available information on associated risk factors, functional outcome, and recurrence of this subtype of stroke is limited, especially for the Chilean population. We conducted a prospective cohort study of 380 patients aged >= 18 years admitted consecutively to a stroke unit with demonstrated ischemic stroke. The stroke subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment criteria. The modified Rankin Scale score and Barthel Index were used to assess functional outcome. The Kaplan-Meier product-limit method and Cox proportional hazards regression analysis were used to identify predictors of recurrent stroke during the follow-up period (mean, 2.1 years). Cryptogenic stroke (CS) was diagnosed in 76 patients (20%), 55.2% of them male, with a mean age of 62 +/- 17 years. CS was the third most common stroke subtype after the large-artery disease (29%) and cardioembolic (24.4%) subtypes. After adjustment for age and sex, no vascular risk factors or laboratory parameters assessed at the time of admission were found to be predictive of CS. The CS subtype had the lowest rate of stroke recurrence at the end of the follow-up period (n = 4; 2.5% per year; odds ratio, 0.32; 95% confidence interval, 0.11 0.91; P = .022), a favorable functional outcome (mean modified Rankin Scale score, 2; mean Barthel Index, 77), and no increase in mortality risk (odds ratio, 0.73; 95% confidence interval, 0.29-1.77; P = .48). Our findings demonstrate that patients with no definite etiology identified after an extensive workup are at lower risk of recurrence and more likely to have a favorable outcome. No risk factors distinguish CS from other stroke subtypes in our study population. PMID- 21602054 TI - T cells expanded in presence of IL-15 exhibit increased antioxidant capacity and innate effector molecules. AB - Persistence of effector cytotoxic T lymphocytes (CTLs) during an immunological response is critical for successfully controlling a viral infection or tumor growth. Various cytokines are known to play an important part in regulating the immune response. The IL-2 family of cytokines that includes IL-2 and IL-15 are known to function as growth and survival factors for antigen-experienced T cells. IL-2 and IL-15 possess similar properties, including the ability to induce T cell proliferation. Whereas long-term IL-2 exposure has been shown to promote apoptosis and limit CD8(+) memory T cell survival and proliferation, it is widely believed that IL-15 can inhibit apoptosis and helps maintain a memory CD8(+) T cell population. However, mechanisms for superior outcomes for IL-15 as compared to IL-2 are still under investigation. Our data shows that human T cells cultured in the presence of IL-15 exhibit increased expression of anti-oxidant molecules glutathione reductase (GSR), thioredoxin reductase 1 (TXNDR1), peroxiredoxin (PRDX) and superoxide dismutase (SOD). An increased expression of cell-surface thiols, intracellular glutathione, and thioredoxins was also noted in IL-15 cultured T cells. Additionally, IL-15 cultured T cells showed an increase in cytolytic effector molecules. Apart from increased level of Granzyme A and Granzyme B, IL-15 cultured T cells exhibited increased accumulation of reactive oxygen (ROS) and reactive nitrogen species (RNS) as compared to IL-2 cultured T cells. Overall, this study suggests that T cells cultured in IL-15 show increased persistence not only due to levels of anti-apoptotic proteins, but also due to increased anti-oxidant levels, which is complimented by increased cytolytic effector functions. PMID- 21602058 TI - Excluding aortic dissection before thrombolysis in patients with ischemic stroke has been insufficiently advised. PMID- 21602059 TI - Echocardiographic assessment of hypertensive left ventricular hypertrophy in patients with acute ischemic stroke or transient ischemic attack. AB - BACKGROUND: Hypertensive left ventricular hypertrophy (HLVH) is a major risk factor for cardiovascular morbidity, mortality, and stroke. However, little is known about the importance of transthoracic echocardiography (TTE) in the assessment of HLVH in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA). METHODS: We studied 203 consecutive patients admitted to our hospital with AIS or TIA and who were referred for TTE over the last 4 years. We included 102 (50.2%) lacunar strokes, 76 (37.1%) nonlacunar strokes, and 25 (12.3%) TIAs. The mean age was 68.9 years (standard deviation +/- 11) and 128 patients were male (63.1%). RESULTS: Hypertension was the most common risk factor (131 patients; 64.5%). HLVH was seen in 86 cases (42.3%), in 51.9% of patients with previous hypertension, and in 25% of patients without known hypertension. We found that neither stroke subtype nor any previous risk factor, with the exception of hypertension (P = .0001), were associated with HLVH. Patients with HLVH were younger (67 v 71 yrs; P = .013) and more frequently women (50.6% v 37.5%; P = .078). At discharge, patients with HLVH were more likely to receive antihypertensive treatment (97% v 80%; P = .009) and a higher average number of antihypertensive drugs (2.2 v 1.4; P = .0001). CONCLUSIONS: HLVH was common in patients with AIS or TIA. These individuals had an increased risk of stroke and needed a more intensive therapy. TTE should be carried out in all AIS and TIA patients in order to optimize the management of these patients. PMID- 21602060 TI - On the role of imagery in event-based prospective memory. AB - The role of imagery in encoding event-based prospective memories has yet to be fully clarified. Herein, it is argued that imagery augments a cue-to-context association that supports event-based prospective memory performance. By this account, imagery encoding not only improves prospective memory performance but also reduces interference to intention-related information that occurs outside of context. In the current study, when lure words occurred outside of the appropriate responding context, the use of imagery encoding strategies resulted in less interference when compared with a standard event-based intention condition. This difference was eliminated when participants were not given a specific context to associate their intention (i.e., lures occurred within the appropriate responding context). These results support a cue-to-context association account of how imagery operates in certain event-based prospective memory tasks. PMID- 21602061 TI - Schizophrenia, dissociation, and consciousness. AB - Current thinking suggests that dissociation could be a significant comorbid diagnosis in a proportion of schizophrenic patients with a history of trauma. This potentially may explain the term "schizophrenia" in its original definition by Bleuler, as influenced by his clinical experience and personal view. Additionally, recent findings suggest a partial overlap between dissociative symptoms and the positive symptoms of schizophrenia, which could be explained by inhibitory deficits. In this context, the process of dissociation could serve as an important conceptual framework for understanding schizophrenia, which is supported by current neuroimaging studies and research of corollary discharges. These data indicate that the original conception of "split mind" may be relevant in an updated context. Finally, recent data suggest that the phenomenal aspects of dissociation and conscious disintegration could be related to underlying disruptions of connectivity patterns and neural integration. PMID- 21602062 TI - Propionibacterium acnes infection of the elbow. PMID- 21602063 TI - Essex-Lopresti lesion associated with an impacted radial neck fracture: interest of ulnar shortening in the secondary management of sequelae. PMID- 21602064 TI - Progressive osteolysis of the radius after distal biceps tendon repair with the bioabsorbable screw. AB - BACKGROUND: Several complications have been reported with the use of the PLLA (poly-L-Lactide) bioabsorbable screw in orthopedic surgery. The hypothesis was that the use of a bioabsorbable screw in distal biceps tenodesis results in significant osteolysis of the radial bone. The correlation between osteolysis and functional and clinical outcomes was also studied. METHODS: All consecutive patients who underwent anatomic repair of the distal biceps tendon with a bioabsorbable screw were included. From the x-ray taken immediately after the surgery, the ratio between the volume of the bone tunnel and the volume of the radius bone section was measured. This relation was calculated at different follow-up periods to obtain the percentage of tunnel enlargement over time. Complications, as well as functional and clinical outcomes, were also assessed. Mayo Elbow Performance Score (MEPS), the quick-Disability Arm Shoulder Hand (DASH), and the Short-Form 12 (SF-12) were used. RESULTS: Nineteen consecutive patients were available for follow-up. The average initial relative volume occupied by the screw tunnel was 49% of the bone section and increased to 61% at the last follow-up at an average of 22 months (range, 3-62 months). Eight of the 19 patients presented postoperative complications. There was only 1 case of complete bone filling of the tunnel, which was observed at a 5-year and 2-months follow-up. There was no significant correlation between the volume of bone resorption and functional and clinical outcomes. DISCUSSION: No correlation was found between the volume of bone tunnel and the functional outcome. However, the results indicate that the use of a bioabsorbable screw in distal biceps tendon repair results in significant bone osteolysis. PMID- 21602065 TI - Humeral fracture following subpectoral biceps tenodesis in 2 active, healthy patients. PMID- 21602066 TI - Shoulder arthroplasty in patients with dwarfism: a report of 2 cases. PMID- 21602067 TI - Bristow-Latarjet and Bankart: a comparative study of shoulder stabilization in 185 shoulders during a seventeen-year follow-up. AB - BACKGROUND: In 2 Swedish hospitals, 88 consecutive shoulders underwent Bankart repair (B), and 97 consecutive shoulders underwent Bristow-Latarjet repair (B-L) for traumatic anterior recurrent instability. MATERIALS AND METHODS: Mean age at surgery was 28 years (B-L group) and 27 years (B group). All shoulders had a follow-up by letter or telephone after a mean of 17 years (range, 13-22 years). The patients answered a questionnaire and completed the Western Ontario Shoulder Index (WOSI), Disability of Arm Shoulder and Hand (DASH), and SSV (Simple Shoulder Value) assessments. RESULTS: Recurrance resulted revision surgery in 1 shoulder in the B-L group and in 5 shoulders in the B group (P = .08). Redislocation or subluxation after the index operation occurred in 13 of 97 B-L shoulders and in 25 of 87 of B shoulders (after excluding 1 patient with arthroplasty because of arthropathy, P = .017). Of the 96 Bristow shoulders, 94 patients were very satisfied/satisfied compared with 71 of 80 in the B series (P = .01). Mean WOSI score was 88 for B-L shoulders and 79 for B shoulders (P = .002). B-L shoulders also scored better on the DASH (P = .002) and SSV (P = .007). Patients had 11 degrees loss of subjectively measured outward rotation with the arm at the side after B-L repair compared with 19 degrees after Bankart (P = .012). The original Bankart, with tunnels through the glenoid rim, had less redislocation(s) or subluxation(s) than shoulders done with anchors (P = .048). CONCLUSIONS: Results were better after the Bristow-Latarjet repair than after Bankart repairs done with anchors with respect to postoperative stability and subjective evaluation. Shoulders with original Bankart repair also seemed to be more stable than shoulders repaired with anchors. PMID- 21602068 TI - EASY-GOING deconvolution: combining accurate simulation and evolutionary algorithms for fast deconvolution of solid-state quadrupolar NMR spectra. AB - A fast and accurate fit program is presented for deconvolution of one-dimensional solid-state quadrupolar NMR spectra of powdered materials. Computational costs of the synthesis of theoretical spectra are reduced by the use of libraries containing simulated time/frequency domain data. These libraries are calculated once and with the use of second-party simulation software readily available in the NMR community, to ensure a maximum flexibility and accuracy with respect to experimental conditions. EASY-GOING deconvolution (EGdeconv) is equipped with evolutionary algorithms that provide robust many-parameter fitting and offers efficient parallellised computing. The program supports quantification of relative chemical site abundances and (dis)order in the solid-state by incorporation of (extended) Czjzek and order parameter models. To illustrate EGdeconv's current capabilities, we provide three case studies. Given the program's simple concept it allows a straightforward extension to include other NMR interactions. The program is available as is for 64-bit Linux operating systems. PMID- 21602069 TI - Structural determinants of the alpha2 adrenoceptor subtype selectivity. AB - Alpha2-adrenergic receptor (alpha2-AR) subtypes, acting mainly on the central nervous and cardiovascular systems, represent important targets for drug design, confirmed by the high number of studies published so far. Presently, only a few alpha2-AR subtype selective compounds are known. Using homology modeling and ligand docking, the present study analyzes the similarities and differences between binding sites, and between extracellular loops of the three subtypes of alpha2-ARs. Several alpha2-AR subtype selective ligands were docked into the active sites of the three alpha2-AR subtypes, key interactions between ligands and receptors were mapped, and the predicted results were compared with the available experimental data. Binding site analysis reveals a strong identity between important amino acid residues in each receptor, the very few differences being the key toward modulating selectivity of alpha2-AR ligands. The observed differences between binding site residues provide an excellent starting point for virtual screening of chemical databases, in order to identify potentially selective ligands for alpha2-ARs. PMID- 21602070 TI - The chondrotoxicity of local anaesthetics: any clinical impact? PMID- 21602071 TI - Paravertebral mass in a patient with hemoglobin C disease. PMID- 21602072 TI - An unusual association between erosive hand osteoarthritis and morphea. PMID- 21602073 TI - Evaluation of the risk factors for acute occupational hand injuries. AB - OBJECTIVES: To evaluate the effect of demographic and occupational factors on the severity of the acute occupational hand injuries. METHODS: Patients with acute hand injuries presenting to the emergency department of the Ege university hospital between 01.08.2008 and 27.02.2009 were included. A questionnaire investigating demographic and occupational factors of the patients and their injuries was filled out for each patient. Modified Hand Injury Severity Score (MHISS) was used to assess the severity of the injury. RESULTS: A total of 144 subjects were included. Forty-three patients had occupational hand injuries. Age at injury, occupation, and main earning status did not alter the MHISS score significantly. Also, the mechanism of injury, occupational experience, timing of the injury, glove use, safety training did not have a significant effect on the injury severity. The injury pattern was found to have a statistically significant effect on the MHISS score. CONCLUSION: The potentially modifiable factors such as the working conditions, safety training and use of gloves are important in the etiology of occupational acute hand injury. Most probably, in this study the size of the sample was not large enough to be able to demonstrate any relation between these and the injury severity. However, attempts to modify these factors by various strategies may reduce the incidence of acute hand injury at work. Precautions and widespread educational programs can prevent occupational acute hand injury. PMID- 21602074 TI - [New treatment of advanced Kienbock disease: replacement of lunate with costochondral autograft]. AB - Treatment of advanced Kienbock's disease (Lichtmann IV) is commonly proximal row carpectomy or partial arthrodesis. The purpose of this study is to evaluate a more conservative treatment of advanced Kienbock's disease for young people: replacement of the lunate with a costochondral autograft. Between 2007 and 2009, four patients of mean age 40 years (32-51) were operated by two surgeons using this technique. This is a prospective study with a final follow-up by an independent operator. Mean follow-up was 27 months (6-36). Surgery is in two stages: excision of lunate and replacement with costochondral autograft taken from the ninth rib. Patients were evaluated with DASH and Cooney scores, pain, satisfaction, mobility and strength. Results show disappearance of pain at rest and during daily activities for all patients and a mean DASH of 6. Flexion extension was 108 degrees and grip strength 83% compared with the opposite side. Radiological evaluation showed no disease evolution. No complication was noted. Functional improvement was significant with good results compared to conventional techniques. Alternative techniques have been proposed for the replacement of the lunate, each with its specific problems. Lunate replacement by a costochondral graft is possible because studies showed vitality of this free graft up to five years. It also allows subsequent surgery. The absence of carpal collapse and good functional results are encouraging but the follow up is short. A long-term study is needed to confirm findings. PMID- 21602075 TI - Arthroscopic dorsal capsuloplasty in chronic scapholunate ligament tears: a new procedure; preliminary report. AB - We report our preliminary results of arthroscopic dorsal capsuloplasty for chronic scapholunate lesions to obviate the need for an open exposure of the wrist capsule. Twenty-two consecutive patients with scapholunate ligament tears underwent an arthroscopically-assisted dorsal capsuloplasty with or without percutaneous pinning. The mean age of subjects was 36 years (range, 27 to 55 years). The mean preoperative delay was 9 months (range 3 to 24 months). Criteria for surgery were persistent pain over the dorsal radial wrist in the scapholunate region and a positive finding on performing Watson's test. All patients were reviewed at a mean follow-up of 13 months (range, 7 to 19 months). The range of motion was recovered with a slight limitation in flexion in only four cases. The average grip strength attained was 96% of the contralateral side. The results in terms of pain were excellent. The seven high level athletes resumed practice at the same level as prior to the injury. A longer follow-up is necessary to confirm these encouraging preliminary results. PMID- 21602076 TI - Relationship between thumb laxity and trapezium kinematics. AB - OBJECTIVES: To investigate the relationship between thumb laxity (passive mobility), shape of the trapezium and trapezial mobility relative to the second metacarpal. METHODS: Sixty normal volunteers were assessed for the amount of thumb laxity by measuring the shortest distance of the thumb nail to the radius when the thumb was forcefully approximated to the forearm with the wrist in flexion. The inclination of the distal surface of the trapezium (angle beta) and the mobility of the trapezium relative to the II metacarpal (Deltaangle alpha) were assessed using dynamic X-rays in maximal radial and ulnar deviation. RESULTS: There was no statistical correlation between thumb laxity and shape of the trapezium (angle beta). However, trapezium mobility (Deltaangle alpha) and thumb laxity were strongly correlated (P=0.018), with the more lax individuals registering higher trapezium mobility. CONCLUSION: This investigation does not support the concept of thumb hypermobility being associated to a trapezium with more pronounced inclination of its distal articular surface. However, it has been found that the higher the thumb mobility, the more the trapezium tilts under load. PMID- 21602077 TI - [Chorio-amnionitis: clinical and biological aspects--medicolegal implications]. AB - The authors present fetal and maternal risks in chorio-amnionitis diseases. Major fetal risk is the increase of the rate of cerebral palsy which is growing to five. The protocol of 2011 is presented for the prevention and treatment of chorio-amnionitis in premature rupture of the membranes in relation with gestational age. A French statistical survey, period 2001 to 2006, indicates maternal risks of chorio-amnionitis. Medicolegal implications of the chorio amnionitis diseases emphasize the importance of placental investigations and bacteriological tests. PMID- 21602078 TI - [Biomechanical characteristics of human fetal membranes. Preterm fetal membranes are stronger than term fetal membranes]. AB - The purpose of this study was to determine the biomechanical characteristics of human fetal membranes (FM) throughout gestation. Biomechanical properties were determined for 115 FM of 23-41 weeks gestation using our previously described methodology. The areas of membrane immediately adjacent to the strongest and weakest tested spots were sampled for histomorphometric analysis. Clinical data on the patients whose FM were examined were also collected. FM less than 28 weeks gestation were associated with higher incidence of abruption and chorioamnionitis. Topographically FM at all gestations had heterogeneous biomechanical characteristics over their surfaces with distinct weak areas. The most premature membranes were the strongest. FM strength represented by rupture force and work to rupture decreased with increasing gestation in both weak and strong regions of FM. This decrease in FM strength was most dramatic at more than 38 weeks gestation. The FM component amnion-chorion sublayers were thinner in the weak areas compared to strong areas. Compared to term FM, preterm FM are stronger but have similar heterogeneous weak and strong areas. Following a gradual increase in FM weakness with increasing gestation, there is a major drop-off at term 38 weeks gestation. The FM weak areas are thinner than the stronger areas. Whether the difference in thickness is enough to account for the strength differences is unknown. PMID- 21602079 TI - [Biochemistry of fetal membranes rupture]. AB - Fetal membranes, amnion and chorion, line up the amniotic cavity and are essential for its integrity towards normal term of pregnancy. They consist of a pluristratified structure whose composition assures their cohesion and elasticity. They firstly function in retaining the fluctuant amniotic fluid in a half-rigid cavity. Their elastic limit depends on the organization of the extracellular matrix and firstly on the collagen type it contains. The compact layer of the amnion, responsible for the elastic limit, contains mainly type I collagen, organized in lattice; this allows elongation or spreading. Underneath, the spongy layer, principally of collagen III, is organized in a loose mesh, enriched in hydrated proteoglycans, which allows the absorption of the shocks and the sliding of the amnion on the chorion. The cascade of events leading to the membrane rupture displays: (i) membranes distension with elasticity loss, (ii) separation of the chorion from the amnion, (iii) chorion fracture, (iv) amnion distension which produces an hernia, (v) amnion rupture. The rupture mechanism was long thought to be a consequence of uterine contractions. However, the observation before labour of a zone of altered morphology, with biochemical variations (modifications of metalloprotease activity and of proteoglycans, apoptosis...) associated with focal physical weakness in the region overlying the cervix suggests programming of the rupture before parturition. A better understanding of the biochemical mechanisms of membranes rupture will provide new insights into how to anticipate and to intervene in the case of risk of premature rupture. PMID- 21602080 TI - [Key points for the analysis of a scientific paper: searching for biases in a clinical trial]. PMID- 21602081 TI - [Against the routinely hysteroscopic metroplasty for septate uterus]. PMID- 21602082 TI - [Quality control of first trimester ultrasonography for Down syndrome screening: more questions than answers]. PMID- 21602083 TI - [Residentship in obstetrics and gynaecology in Nantes]. PMID- 21602084 TI - [Favourable outcome after fetoscopic laser surgery for twin-twin transfusion syndrome: experience of an emerging centre]. AB - OBJECTIVES: Our objective was to report perinatal outcome during the first three years of an emerging centre for laser photocoagulation in twin-twin transfusion syndrome (TTTS) and to compare with outcome observed earlier in the same centre when management consisted in recurrent amniodrainage. PATIENTS AND METHODS: We conducted a single centre retrospective study. We compared perinatal outcome of 19 consecutive cases of mid trimester TTTS managed by amniodrainage over a 10 year period with 49 cases of TTTS managed by laser photocoagulation over a 3-year period. RESULTS: Laser photocoagulation increased survival rate at birth (P=0.02) and at postnatal day 28 (P=0.01). Neurologic and cardiologic complications did not differ significantly (P=0.5 and P=0.3 respectively). We observed a significant increase in survival of the donor after laser coagulation at birth (P=0.04). DISCUSSION AND CONCLUSION: Our study demonstrated better outcome after laser photocoagulation. Early results of an emerging centre appeared comparable to those of more experienced centres. PMID- 21602085 TI - [Basic advances and clinical practice in the rupture of fetal membranes]. PMID- 21602086 TI - [Systematic section of uterine septum: pros and cons]. PMID- 21602087 TI - [Periodontal diseases and preterm birth: a pilot study]. AB - The aim of this work is to determine periodontal disease's prevalence in preterm delivery (before 37 weeks of gestation) and find a significant association between preterm birth and periodontal diseases. Periodontal status was determined. Status and severity were noted and correlated to term of delivery. Fifty-two patients were included in the study. Periodontal disease's prevalence was 33% for gingivitis and 44% for periodontitis. No significant correlation was found (P=0.41). Periodontal disease's prevalence is agreed with literature review. The different opinion are largely discussed. Methodological harmonization of periodontal definitions is needed to increase study's power. PMID- 21602088 TI - [Post-residentship: setting up]. PMID- 21602090 TI - An e-caring chair for physiological signal measurement and recording. AB - There is an increasing awareness among the populace of the need for regular health check-up to detect diseases in their early stages and thereby administer treatments in a timely fashion. However, commercially available physiological signal monitoring devices, which may offer clues on the onset of diseases, are time-consuming, far from user friendly and limited in their applications. We design an e-caring chair that combines six modular physiological signal measurement instruments into a single unit, enabling users to simultaneously measure the blood pressure, body temperature, heart rate, height, weight and body fat percentage, and display the results and simple diagnoses in real time. The e caring chair further allows for easy integration of additional physiological signal measuring devices, speedy measurements and long term monitoring of any trends that may emerge, making it easier for users to be alerted to physiological changes in the body without the need to enlist assistance from medical personnel. In this paper, we describe how this e-caring chair can be placed in several different environments for different purposes. PMID- 21602089 TI - [External cephalic version: 1 year study in a level 3 maternity]. AB - PATIENTS AND METHODS: Observational and retrospective study, from February 1, 2007 until February 29, 2008. All fetal versions cases in the Edouard-Herriot hospital's maternity have been studied. RESULTS: Seventy-eight cases were recorded: 19 were successful (24.4%) and 59 unsuccessful. Eighty-four per cent of fetus with success were born by vaginal delivery, and 16% by cesarean section. After unsuccessfully version, 11 women (19%) have vaginal delivery (nine breech presentations). There were no differences in the version's result in front of parity, gestational age, operator, placental location and amniotic fluid index. DISCUSSION AND CONCLUSION: Low success rate seems to be related to inadapted tocolytic. A follow-up study concerning the type of tocolyse would be interesting to bring to light a possible improvement. The small number of cases not having allowed to obtain significant results, study with large scale would be also necessary before envisaging a modification of the service protocol. PMID- 21602091 TI - Acquired progressive ataxia and palatal tremor: importance of MRI evidence of hemosiderin deposition and vascular malformations. AB - Oculopalatal tremor is frequently accompanied by progressive ataxia. In symptomatic oculopalatal tremor the ataxia frequently is delayed in onset. Progressive ataxia is a defining clinical feature of superficial siderosis. We report 5 cases with palatal tremor and ataxia. Four cases had evidence of intraparenchymal hemosiderin deposition on T2-gradient-echo imaging. Three cases had a brainstem vascular malformation. In two cases the hemosiderin deposition was likely due to prior trauma. The significance of these associations and possible similarities between ataxia related to superficial siderosis and ataxia and intraparenchymal hemosiderin is discussed. PMID- 21602093 TI - Found in translation: applications of protein and peptide molecular diversity. PMID- 21602092 TI - Innate immunity in rice. AB - Advances in studies of rice innate immunity have led to the identification and characterization of host sensors encoding receptor kinases that perceive conserved microbial signatures. Receptor kinases that carry the non-orginine aspartate domain, are highly expanded in rice (Oryza sativa) compared with Arabidopsis (Arabidopsis thaliana). Researchers have also identified a diverse array of microbial effectors from bacterial and fungal pathogens that triggers immune responses upon perception. These include effectors that indirectly target host Nucleotide binding site/Leucine rich repeat proteins and transcription activator-like effectors that directly bind promoters of host genes. Here we review the recognition and signaling events that govern rice innate immunity. PMID- 21602094 TI - Validity of the FACT-H&N (v 4.0) among Malaysian oral cancer patients. AB - To assess the cross-sectional construct validity of the Malay-translated and cross-culturally adapted FACT-H&N (v 4.0) for discriminative use in a sample of Malaysian oral cancer patients. A cross-sectional study of adults newly diagnosed with oral cancer. HRQOL data were collected using the FACT-H&N (v 4.0), a global question and a supplementary set of eight questions ('MAQ') obtained earlier in pilot work. Of the 76 participants (61.8% female; 23.7% younger than 50), most (96.1%) had oral squamous cell carcinoma; two-thirds were in Stages III or IV. At baseline, patients' mean FACT summary (FACT-G, FACT-H&N, FACT-H&N TOI, and FHNSI) and subscale (pwb, swb, ewb, fwb, and hnsc) scores were towards the higher end of the range. Equal proportions (36.8%) rated their overall HRQOL as 'good' or 'average'; fewer than one-quarter rated it as 'poor', and only two as 'very good'. All six FACT summary and most subscales had moderate-to-good internal consistency. For all summary scales, those with 'very poor/poor' self-rated HRQOL differed significantly from the 'good/very good' group. All FACT summary scales correlated strongly (r>0.75). Summary scales showed convergent validity (r>0.90) but little discriminant validity. The discriminant validity of the FHNSI improved with the addition of the MAQ. The FACT-H&N summary scales and most subscales demonstrated acceptable cross-sectional construct validity, reliability and discriminative ability, and thus appear appropriate for further use among Malaysian oral cancer patients. PMID- 21602095 TI - Prediction of outcome of patients with oral squamous cell carcinoma using vascular invasion and the strongly positive expression of vascular endothelial growth factors. AB - Vascular invasion and lymph node metastasis have been used as histopathological prognosticators of cancers including oral squamous cell carcinoma (OSCC). In addition to metastatic potential via blood vessels, tumor-induced angiogenesis might also be associated with prognosis. However, the efficacy of combined evaluation of vascular invasion and angiogenesis-associated molecules for the prognosis of OSCC remains obscure. This is also the case in lymph node metastasis and lymphovasculogenesis-associated molecules. The aim of this study was to examine factors related to prognosis to improve the accuracy of prognostic prediction of OSCC using vasculogenesis-associated markers. Ninety specimens of patients from 1991 to 2002 with previously untreated OSCC, who underwent either biopsy or surgery, were histopathologically and immunohistochemically analyzed using antibodies for vascular endothelial growth factor (VEGF)-A, VEGF-C, cyclooxygenase (COX)-2 and Midkine. The ninety cases were composed of 72 well differentiated, 12 moderately differentiated and 6 poorly differentiated OSCC. Efficient models of prognostic prediction were evaluated by extensive statistical analyses. The presence of vascular invasion or lymph node metastasis was confirmed to be significantly associated with poor prognosis in the univariate analysis. Multivariate logic regression analysis suggested that patients with the strongly positive expression of either VEGF-A or VEGF-C had a significant association with poor prognosis even in patients without vascular invasion and in early-stage patients. Neither COX-2 nor Midkine contributed to predict the prognosis of the patients. The strongly positive expression of VEGF-A or VEGF-C was suggested to reinforce the histopathological diagnosis of vascular invasion and improve the accuracy and efficacy of prognostic prediction of OSCC. PMID- 21602096 TI - EMT: new signals from the invasive front. PMID- 21602097 TI - Archaeal diversity and community development in deep-sea hydrothermal vents. AB - Over the past 35 years, researchers have explored deep-sea hydrothermal vent environments around the globe and studied a number of archaea, their unique metabolic and physiological properties, and their vast phylogenetic diversity. Although the pace of discovery of new archaeal taxa, phylotypes and phenotypes in deep-sea hydrothermal vents has slowed recently, bioinformatics and interdisciplinary geochemistry-microbiology approaches are providing new information on the diversity and community composition of archaea living in deep sea vents. Recent investigations have revealed that archaea could have originated and dispersed from ancestral communities endemic to hydrothermal vents into other biomes on Earth, and the community structure and productivity of chemolithotrophic archaea are controlled primarily by variations in the geochemical composition of hydrothermal fluids. PMID- 21602098 TI - Growth and characterization of organic material 2-methylamino-5 chlorobenzophenone single crystal by modified vertical Bridgman technique. AB - The organic material 2-methylamino-5-chlorobenzophenone single crystal has been grown by modified vertical Bridgman technique using the single wall ampoule with nano translation. The grown crystal was confirmed by single crystal and powder X ray diffraction analyses. Fourier transform infrared analysis was used to identify the functional groups present in the grown crystal. High resolution X ray diffraction studies show the crystalline perfection of the grown crystal. The optical property of the grown crystal was analyzed by UV-vis-NIR and photoluminescence spectral studies. The thermal behavior of the grown crystal was analyzed by thermogravimetric and differential thermal analyses. The dielectric measurements of the grown crystal were carried out with different frequencies and temperatures and the results indicate an increase in dielectric and conductivity parameters with the increase of temperature at all frequencies. The microhardness measurements were performed to analyze the mechanical property of the grown crystal. PMID- 21602099 TI - Lipase-catalyzed synthesis of hydrophobically modified dextrans: activity and regioselectivity of lipase from Candida rugosa. AB - Vinyl decanoate-modified dextran macromolecules (DexT40-VD) were synthesized in dimethyl sulfoxide at 50 degrees C using lipase AY from Candida rugosa for catalyzing transesterification between polysaccharide and vinyl fatty esters. The extent of dextran modification (quantified by the molar ratio of attached alkyl tails to sugar repeat units) with native-, pH-adjusted-, 18-crown-6 ether pretreated pH-adjusted-, and stepwise addition of pretreated lipase AY yielded <3%, 49%, 64% and 96% modified dextran respectively. Lipase AY accelerated the transesterification of DexT40 from 2- to 63-fold higher than the non-catalyzed system. This procedure was extended to other acyl donors showing that modification pattern exhibited regioselectivity depending on acyl donor structure. Regioselectivity equaled between 2- and 3-OH with saturated fatty acyl donors. The 2-OH was favored for unsaturated fatty acyl donors, while sterically hindered acyl donors oriented modification toward 3-OH position. DexT40-VD at 96% modification was a water-insoluble polymer forming 150nm diameter nanoparticles in water which can be used as drug carrier systems. PMID- 21602100 TI - Ovalopodium desertum n. sp. and the phylogenetic relationships of Cochliopodiidae (Amoebozoa). AB - An amoeba isolated from a weakly saline semi-desert pond in Kazakhstan (Central Asia) resembles a small Cochliopodium in the light microscope, but has a dorsal fibrous cell coat without scales. Thus it can be identified morphologically as a new species of Ovalopodium Sawyer, 1980, and it is herein named O. desertum. Phylogenetic analysis of the SSU rRNA gene sequences of the new species and four Cochliopodium spp. sequenced additionally shows that Ovalopodium desertum is a sister clade to a robustly monophyletic Cochliopodium. The close relationship between Ovalopodium and Cochliopodium is also confirmed by the analysis of SSU rRNA secondary structure showing the specific helices in the region V5 in all species of both genera. Analysis of actin gene sequences fails to resolve the position of Ovalopodium but demonstrates that Parvamoeba Rogerson, 1993 is probably related to Cochliopodium. The position of Cochliopodiidae within Amoebozoa remains unresolved, despite our efforts to resolve it using broader taxonomic sampling of Amoebozoa, testing alternative tree topologies and removing the fast-evolving sites. Among sequenced genera, Parvamoeba and Endostelium Olive et al., 1984 are probable relatives to Cochliopodiidae. Molecular trees weakly support an inclusion of the family in Flabellinia (Discosea), but more phylogenomic data are necessary to test this hypothesis. PMID- 21602101 TI - Soil respiration, climate change and the role of microbial communities. PMID- 21602102 TI - Custom formed orthoses in cycling. AB - To assess the effects of currently used prescribed in-shoe custom foot orthoses (CFOs) on a number of biomechanical variables during the power phase of cycling, including: hip adduction, knee abduction and tibial internal rotation. Before and after cross-over study recording subjects' biomechanical variables with and without their CFOs. Twelve competitive cyclists, currently using prescribed in shoe CFOs, performed two exercise bouts on a stationary trainer, with 3 dimensional data recorded on an 8 camera Vicon Mx system. 2-way ANOVA statistical analysis of Null vs Orthotic condition, and left leg vs right leg. No systematic effects from the CFOs were seen. A trend towards reduced tibial internal rotation range of movement was found (P<0.072). Significant subject-specific effects from the CFOs were seen (P<0.05). Three distinct patterns of knee movement were observed. All subjects had significant left to right leg differences. CFOs do not produce systematic effects on cycling biomechanics. Significant subject-specific biomechanical effects can be produced by CFOs utilizing rearfoot and/or forefoot wedges. An individualised approach to orthotic prescription, and attention to the forefoot-rearfoot relationship, is recommended. PMID- 21602103 TI - Marked reduction of effective radiation dose in patients undergoing CT coronary angiography using prospective ECG gating. AB - Coronary CT angiography (CCTA) is a rapidly evolving technology which can characterise and image sub clinical atherosclerotic plaque and visualise anatomy and quantitate stenosis. Concern about radiation exposure has limited the uptake of this technology. The aim of this study was to review the radiation dose data in 2298 consecutive patients referred to a single centre in an Australian outpatient setting over 27 months using all available radiation dose reduction strategies. Prospective ECG gating ("step and shoot") was used preferentially in 2025 patients with a mean effective dose of 3.39 +/- 1.84 mSv (range 0.86-12.6 mSv). For clinical reasons only 273 patients required retrospective ECG gating, mean dose 19.21 +/- 5.58 mSv (range 2.4-34.9 mSv) resulting in an 85.7% reduction in dose for the majority of patients with the low dose technique. In conclusion, most patients referred for routine CCTA can be studied with a radiation dose comparable to invasive X-ray angiography and less than radionuclide myocardial perfusion imaging. PMID- 21602104 TI - Using brown adipose tissue to treat obesity - the central issue. AB - Current therapeutic strategies are proving inadequate to deal with growing obesity rates because of the inherent resistance of the human body to weight loss. The activation of human brown adipose tissue (BAT) represents an opportunity to increase energy expenditure and weight loss alongside improved lipid and glucose homeostasis. Research into the regulation of BAT has made increasing the thermogenic capacity of an individual to treat metabolic disease a plausible strategy, despite thermogenesis being under tight central nervous system control. Previous therapies targeted at the sympathetic nervous system have had deleterious effects because of a lack of organ specificity, but advances in our understanding of central BAT regulatory systems might open up better strategies to specifically stimulate BAT in obese individuals to aid weight reduction. PMID- 21602105 TI - Heart rate variability during two sequential mountaineering expeditions. AB - This study was undertaken to assess the duration of altitude acclimatization retention in individuals after initial exposure to a maximum altitude of 5360 m during a mountaineering expedition. Spectral heart rate variability analysis accompanied by an assessment of acute mountain sickness using the Lake Louise Scoring System was performed during two sequential mountaineering expeditions to altitudes of 5360 m and 5642 m, with a period of 30 days between each expedition. Subjects displayed varying degrees of alterations in heart rate variability during the initial expedition, which indicated differing degrees of dysadaptation and stress development. Their Lake Louise Scores accounted for the presence of acute mountain sickness throughout the trip. During the subsequent expedition, the subjects' heart rate variability measures were within the normal range, and there were no signs of acute mountain sickness. All three subjects who underwent step-by-step exposure to altitudes of 5360 m displayed differing degrees of alterations in heart rate variability in conjunction with differing degrees of acute mountain sickness. All subjects also developed acclimatization to hypoxic conditions at this altitude, which was preserved for 30 days, and was sufficient to prevent them from showing any significant alterations in heart rate variability when re-exposed to the same altitude. PMID- 21602106 TI - Anorgasmia with gabapentin may be common in older patients. AB - BACKGROUND: Gabapentin is commonly used to treat neuropathic pain, seizures, and bipolar disease in older and elderly patients. It is preferred for its well tolerated side effect profile. Anorgasmia with gabapentin use is reported, with most cases in young patients. CASE SUMMARY: This report describes 4 older patients who experienced anorgasmia while taking gabapentin. Of 15 patients initiated on gabapentin in 18 months, 3 male patients aged 73, 76, and 78 years experienced dose-dependent anorgasmia. A fourth case, a 59-year-old female patient, was noted in another clinic. Orgasm returned when gabapentin was reduced or stopped. Although this is not a blinded study, anorgasmia in 3 of 15 patients newly initiated on gabapentin (3 of 11 in those aged >50 years) seems to represent a much higher incidence than the originally reported <1% in epilepsy clinical trials. Outside of erectile dysfunction, clinicians rarely ask older patients about sexual function. CONCLUSION: Gabapentin-associated anorgasmia may be more common in older patients and appears to be dose dependent. PMID- 21602107 TI - Interactions among sex, ethnicity, religion, and gender role expectations of pain. AB - BACKGROUND: Sex, gender, ethnicity, and religion are powerful factors that may affect pain experience. Recently, gender role expectations of pain (GREP) were suggested to account for some of the differences in pain perception between men and women. However, the interaction between GREP and ethnicity and religion was not examined. This interaction was studied with regard to pain sensitivity, pain endurance, and willingness to report pain. OBJECTIVE: Our objective was to study the interaction among GREP, sex, and ethno-religious belonging. METHOD: Participants (548 healthy men and women) of 3 different ethno-religious groups (341 Jews, 105 Muslim-Arabs, 102 Christian-Arabs) completed the GREP questionnaire; pain sensitivity, pain endurance, and willingness to report pain were analyzed. RESULTS: Men of all 3 ethno-religious groups perceived themselves and other men as less sensitive and less willing to report pain than typical women. Women of all 3 ethno-religious groups perceived themselves and other women as more sensitive and more willing to report pain than men. Ethno-religious differences were observed in the attitudes towards typical men and women, with Christian men and women exhibiting stronger stereotypical views regarding pain sensitivity and pain endurance. CONCLUSIONS: Individual's perceptions of pain regarding one's self compared with the same or opposite sex were similar regardless of ethno-religious belonging and were related to sex. However, attitudes on pain of typical men and women seemed to be influenced by ethno religious belonging. This differential effect of ethno-religion on GREP with relation to sex suggests that these factors should be considered when pain perception is evaluated. PMID- 21602109 TI - Preparation of highly pure daidzin on oligo-beta-cyclodextrin-Sepharose HP and investigation of chromatographic behavior of isoflavones by molecular docking. AB - A novel method using column chromatography on oligo-beta-cyclodextrin-Sepharose HP for the preparation of high purity daidzin from crude soybean samples was proposed in this work. The isoflavone of daidzin in sample A and B was purified under the optimum mobile phase composed of methanol/acetic acid/water=20.0/8.0/72.0 (v/v/v) at a flow-rate of 1.0 mL/min in one-step operation with a purity of 97.2% and 98.1%, a recovery of 95.3% and 96.3% respectively. The target products in isolated fraction were detected and characterized by HPLC analysis and ESI-MS spectrum. Preparative separation with sample-load of up to 2.42 mg/mL medium gave satisfactory results for daidzin with the purities over 97% and recoveries approximately 90%. Molecular docking simulations were utilized to help demonstrate the inclusion complexation between beta-cyclodextrin and the isoflavones in samples through inclusion geometries and calculations of the binding energies. The prediction of the elution orders with AUTODOCK and SURFLEX-DOCK were validated by the chromatographic results. PMID- 21602108 TI - Mind the gap: keeping UV lesions in check. AB - Cells respond to genotoxic insults by triggering a DNA damage checkpoint surveillance mechanism and by activating repair pathways. Recent findings indicate that the two processes are more related than originally thought. Here we discuss the mechanisms involved in responding to UV-induced lesions in different phases of the cell cycle and summarize the most recent data in a model where Nucleotide Excision Repair (NER) and exonucleolytic activities act in sequence leading to checkpoint activation in non replicating cells. The critical trigger is likely represented by problematic intermediates that cannot be completely or efficiently repaired by NER. In S phase cells, on the other hand, the replicative polymerases, blocked by bulky UV lesions, re-initiate DNA synthesis downstream of the lesions, leaving behind a ssDNA tract. If these gaps are not rapidly refilled, checkpoint kinases will be activated. PMID- 21602110 TI - Hookworm infection in a healthy adult that manifested as severe eosinphilia and diarrhea. AB - A 54-year-old male was admitted because of having suffered from progressive watery diarrhea for 12 days. He had no history of diabetes mellitus, hypertension, heart disease, organ transplantation, or malignancy. After admission, he still complained of diarrhea despite medical treatment. The laboratory examination showed leukocytosis with eosinophilia and a stool examination by the concentration method was negative four times. When a sigmoidoscopy was performed as a part of an explorative survey, a single protruding mass consisting if a moving adult hookworm was found. The fifth stool examination by the concentration method identified hookworm ova. The patient was treated with oral mebendazole 100 mg twice a day for 3 days. The diarrhea and eosinophilia subsided after this treatment. PMID- 21602111 TI - Risk factors and outcomes of cytomegalovirus viremia in cancer patients: a study from a medical center in northern Taiwan. AB - BACKGROUND: Cytomegalovirus (CMV) is a pathogen and can cause life-threatening infection in the patients with malignancies. This study was conducted to investigate the risk factors and outcomes of CMV viremia in patients with malignancies. METHODS: Data were collected with retrospective analysis from adults suffering from CMV viremia with underlying malignancies. A total of 107 patients were enrolled in a tertiary medical center in northern Taiwan from March 2008 to December 2009. RESULTS: Among the 107 patients who suffered with CMV viremia with an overall mortality rate of 56.1% (60/107), 75 patients (70.1%) had solid organ malignancies and 32 (29.9%) had hematological malignancies. Mechanical ventilation (p=0.048), leukocytosis (p=0.004), and lack of appropriate early treatment (p=0.011) were independent predisposing factors associated with higher mortality rate. CONCLUSIONS: CMV viremia predicts high mortality rate in cancer patients, especially in those with mechanical ventilation, leukocytosis, and lack of appropriate early treatment. Appropriate early antiviral therapy is recommended to improve outcomes. PMID- 21602112 TI - [Paediatric obesities: from childhood to adolescence]. AB - Obesity, as in every western country, is currently the most prevalent chronic disease in childhood in Spain. This has led to obesity being one of the most common consultations in general paediatrics and, particularly, in paediatric endocrinology. Furthermore, obesity associated comorbidities are increasing in prevalence in children and adolescents. It is widely accepted that this increase in the prevalence of obesity is derived from an imbalance between energy intake and expenditure, associated to the lifestyle in western countries. However, there is increasing evidence of the role of individual and familial genetic background in the risk of developing obesity. The pathophysiological basis of the mechanisms responsible for the control of appetite and energy expenditure are being discovered on the basis of the increasing known cases of human monogenic, syndromic and endocrine obesity. Thus it is no longer appropriate to talk about obesity but rather about "obesities", as their pathophysiological bases differ and they require different diagnostic and management approaches. In 2011, the paediatrician must be aware of this issue and focus the clinical history and physical examination towards these specific clinical sign and symptoms, to better manage the available diagnostic and therapeutic resources when faced with a child with obesity. PMID- 21602113 TI - Tetanus prophylaxis in the management of patients with acute wounds. PMID- 21602114 TI - Chondral repair of the knee joint using mosaicplasty. AB - Mosaicplasty grafting is performed by transferring one or more cylindral osteochondral autografts from a low weight-bearing area of the knee towards the defective site, usually the femoral condyle. Numerous biomechanical, histological, animal and clinical studies have evaluated the different technical aspects of this procedure. The preoperative work-up encompasses an evaluation of functional disturbances, alignment, knee stability and imaging (CT arthrography or MRI with cartilage sequences). The surgical procedure includes harvesting the grafts by mini-arthrotomy of the medial or lateral trochlea and a stage for arthroscopic graft insertion. The ICRS classification is used to describe the defect (area, depth, location) before and then after debridement. A few, large diameter grafts are harvested from the trochlea across from the defect. The graft plugs are transplanted by press-fit, flush with the cartilage, along a convergent plane in recipient sockets of exactly the same depth. Each stage, harvesting, drilling and insertion is repeated until all the full-thickness gap region has been covered. Postoperative movement is free but weight-bearing is delayed for 2 to 4 weeks. Mosaicplasty is indicated in young patients (under 50), with symptomatic chondral or osteochondral defects of less than 3 cm in the weight bearing part of the femoral condyle. Pre-osteoarthritis is an absolute contraindictation for this procedure. Any misalignment (of more than 5 degrees ) or sagittal instability is treated simultaneously. This is a difficult and demanding procedure. PMID- 21602115 TI - The well-differentiated liposarcoma of the hypopharynx. AB - INTRODUCTION: The aim of this article is to describe the clinical, radiological, and therapeutic aspects of well-differentiated liposarcomas of the hypopharynx. CASE PRESENTATION: We report the case of a 34-year-old woman seen for dysphonia and dyspnea. The nasal endoscopy found a well-delimited ovoid tumefaction, attached at the right lateral wall of the hypopharynx. The diagnosis of a well differentiated liposarcoma was made based on the histopathology of the surgical specimen. DISCUSSION/CONCLUSION: The incidence of well-differentiated liposarcoma of the head and neck is extremely low. The imaging is not specific. Wide surgical resection is sufficient. Histopathological review confirms the diagnosis. PMID- 21602116 TI - Influence of the major connector in a maxillary denture on phonetic function. AB - PURPOSE: The purpose of this study was to investigate the influence of the major connector in a maxillary denture. METHODS: Eight patients with sound dentition were recruited in this study. The experimental connectors were fabricated with Co Cr. Two positional designs were used: one was the middle type (M), and the other was the anterior and posterior type (AP). The six sounds, /shi/, /hi/, /chi/, /ki/, /ri/, and /ni/, were chosen as the test sounds. Using a speech recognition system, the intelligibility, change and duration of the test sounds were evaluated under three conditions: without connector (WO.C), with the M-type connector (W.M), and with the AP-type connector (W.AP). RESULTS: The intelligibility in WO.C and W.AP was 86.9 +/- 17.4% and 57.1 +/- 30.1% for /shi/, 79.2 +/- 19.7% and 70.5 +/- 27.0% for /hi/, 74.7 +/- 14.6% and 43.6 +/- 24.3% for /chi/, 54.4 +/- 16.5% and 23.2 +/- 17.8% for /ki/, 85.2 +/- 15.9% and 55.1 +/- 30.6% for /ri/, and 76.9 +/- 26.9% and 50.2 +/- 31.3% for /ni/. Significant differences were recognized between WO.C and W.AP in /shi/, /chi/, /ki/ and /ri/(P<0.01). The intelligibility in W.M was higher than that in W.AP in all test sounds. As for incorrect labels, significant differences were recognized in the appearance ratio of /hi/ as the incorrect label in the test sound /shi/ (P<0.05). There were significant differences in some incorrect labels of /hi/ and /chi/. As for duration of consonant part, there was no significant difference in each test sound. CONCLUSION: It was indicated that the middle type of the major connector would be recommended from a viewpoint of phonetic function. PMID- 21602117 TI - [Liver X receptor agonist T0901317 inhibits TGF-beta1-induced alpha-SMA expression in normal human lung fibroblasts]. AB - OBJECTIVE: To investigate the effect of liver X receptor agonist T0901317 on transforming growth factor-beta1 (TGF-beta1)-induced expression of alpha-smooth muscle actin (alpha-SMA) in normal human lung fibroblasts. METHODS: Primary normal human lung fibroblast isolated from the lung specimens of lung cancer patients by explant culture technique were identified with immunostaining for vimentin and keratin. The cells in passages 4 to 10 were treated with T0901317 and/or TGF-beta1, and RT-PCR, Western blotting and immunofluorescence assay were used to detect alpha-SMA expression in the fibroblasts. RESULTS: Lung fibroblast expressed vimentin but not keratin. The results of RT-PCR, Western blotting and immunofluorescence assay all showed that normal human lung fibroblasts constitutively expressed alpha-SMA under baseline condition, and TGF-beta1 at 5 ng/ml induced a significant upregulation of alpha-SMA both at the mRNA and protein levels. Liver X receptor agonist T0901317 (5 ug/ml) significantly inhibited TGF-beta1-induced upregulation of alpha-SMA expression. CONCLUSION: Liver X receptor agonist T0901317 can inhibit the upregulation of alpha-SMA in normal human lung fibroblasts induced by TGF-beta1, suggesting the potential value of liver X receptor agonist in the treatment of lung fibrosis. PMID- 21602118 TI - Patient outcome and prognostic factors of renal cell carcinoma in clinical stage T(1-3)N(1-2)M(0): a single-institution analysis. AB - OBJECTIVE: To report our data of patients with clinical stage T(1-3)N(1-2)M(0) renal cell carcinoma (RCC) and explore the biological behavior of this malignancy. METHODS: A total of 531 patients with no distant metastatic RCC underwent open radical nephrectomy at our institution between 1988 and 2008, among whom 42 patients with histological nodal metastases had successful surgical tumor resection. The clinical data and outcomes of the 42 patients were analyzed. RESULTS: Of those 42 patients, 19.0% had T1, 21.4% had T2, and 59.5% had T3 stage tumors; 42.9% had N1 and 57.1% had N2 stage tumors. Tumor recurred in 30 (71.4%) patients after the surgery, and death occurred in 26 (61.9%) cases at the last follow-up; among the recurrent cases, 83.3% (25/30) had multiple metastases at the initial recurrence. The median cancer-specific survival (CSS) and disease free survival (DFS) was 23 and 11 months in these cases, respectively. Multivariate analysis demonstrated that Fuhrman grade (P=0.005), N stage (P=0.014) and T stage (P=0.037) were the independent predictors of CSS; Eastern Cooperative Oncology Group (ECOG) performance status (PS) (P=0.002), tumor size (P=0.007), Fuhrman grade (P=0.009) and N stage (P=0.019) were the independent predictors of DFS. CONCLUSION: Patients with T(1-3)N(1-2)M(0) RCC have poor prognosis. N stage is an independent predictor of both CSS and DFS, suggesting that extended lymph node dissection should be performed when suspicious enlarged nodal disease is found during surgery. PMID- 21602119 TI - [Study of a new zebrafish mutant defective in primitive myelopoiesis]. AB - OBJECTIVE: To perform phenotypic identification and characteristic analysis of a new zebrafish mutant 1276 defective in primitive myelopoiesis. METHODS: The AB strain male zebrafish were mutagenized with N-ethyl N-nitrosourea (ENU) to induce mutations in the spermatogonial cells, and the mutations were transmitted to the offsprings. The F3 embryos were screened by neutral red staining for identifying the mutants defective in primitive myelopoiesis. One of the myeloid mutants 1276 was further studied by cytochemistry and whole mount in stiu hybridization (WISH) with different lineage markers. RESULTS: A total of 2140 mutagenized genomes from the 1296 F2 families were analyzed, and 12 mutants were identified to show abnormal signal by neutral red staining. In the primitive hematopoiesis stage, the mutant 1276 showed the absence of neutral red staining-positive cells in the whole body. The expression of microglia marker apoe was totally lost in the head of the mutant, and the expression of the macrophage marker l-plastin was slightly decreased in the head and remained normal in the ventral dorsal aorta region, but the granulocytes and erythrocytes developed normally. in the definitive hematopoiesis stage, the mutant 1276 still showed abnormal macrophages as found in the primitive hematopoiesis stage, but the granulocytes, erythrocytes and lymphocytes appeared normal. CONCLUSION: The zebrafish mutant 1276 shows abnormalities in the function, development and migration of the macrophages in the primitive hematopoiesis stage, which can not be compensated in the definitive hematopoiesis stage. PMID- 21602120 TI - [Selection and identification of specific-binding peptides for cancer stem cell surface marker CD133]. AB - OBJECTIVE: To select the peptides that specifically bind human cancer stem cell surface marker CD133 from the Ph.D.-7>(TM) phage peptide library. METHODS: With a biotinylated extracellular fragment of human cancer stem cell surface marker CD133 as the target protein, the CD133 high-affinity peptides were screened from the phage peptide library by liquid phase panning. The clones with high-binding force with human CD133 were then identified by sandwich ELISA and their single stranded DNA was extracted to test the specificity by competitive ELISA. The amino acid sequences of the selected peptides derived from the phage DNA sequences were synthesized after sequence alignment analysis, and their capacity of binding with colorectal carcinoma cells was assessed by immunofluorescence technique. RESULTS: After 4 rounds of liquid phase selection, the phages capable of specific binding with human CD133 were effectively enriched, with an enrichment ratio of 388 times compared to that at the fourth and first rounds. Thirteen out of the 20 clones from the fourth round of panning were identified as positive clones, among which 11 had identical amino acid sequence of TISWPPR, and 2 had the sequence of STTKLAL, and the former sequence showed a stronger binding specificity to CD133. CONCLUSION: We have successfully obtained a peptide that specifically binds human CD133 from the Ph.D.-7(TM) phage peptide library, demonstrating the feasibility of screening small molecule high-affinity polypeptides from phage peptide library by liquid-phase panning. PMID- 21602121 TI - [Genetic fingerprinting of human lung squamous cancer with lymphatic metastasis]. AB - OBJECTIVE: To identify the differentially expressed genes related to lymphatic metastasis of lung squamous cell carcinoma. METHODS: Specimens of primary lung squamous cancer tissues and regional lymph nodes were obtained from 10 patients undergoing complete surgical resection of the tumor. The samples were classified into 3 groups, namely the primary tumor with lymphatic metastasis (TxN+, n=5), primary tumor without lymphatic metastasis (TxN-, n=5) and matched tumor cells from the metastatic lymph nodes (N+, n=5). The total RNA extracted from the laser microdissected primary tumor or metastatic nodes was labeled and hybridized with the microarray containing 6 000 known human genes or ESTs. Data analysis was performed using GeneSpring(TM) 6.2 software. Immunohistochemical staining was used to detect the expression of CCL20 in the specimens. RESULTS: A total of 37 genes showed differential expressions between TxN+ and TxN- tissues, among which 8 genes were upregulated and 29 were downregulated in TxN+ group. No genes, however, showed distinct differential expressions between N+ and TxN+ tissues. The expression of CCL20 was significantly higher in TxN- than in TxN+ tissues (P<0.05). CONCLUSION: The acquisition of the metastatic phenotype may occur early in the development of lung squamous cancer. The gene expression signature of lung squamous cell carcinoma is valuable to elucidate the molecular mechanisms regarding lymphatic metastasis of the malignancy, and may provide important clues for exploring novel therapeutic targets. PMID- 21602122 TI - [Ca(2+) is an important mediator of nanosecond steep pulse-induced apoptosis in human ovarian cancer SKOV3 cells]. AB - OBJECTIVE: To explore the role of Ca(2+) in nanosecond steep pulse (NSP)-induced apoptosis of human ovarian carcinoma cell line SKOV3 in vitro. METHODS: The early apoptotic rate of SKOV3 cells treated with NSP was detected by Annexin V/PI double staining and flow cytometry. MTT assay was used to detect the viability of the cells pretreated with BAPTA-AM (0, 25, 50 and 100 umol/L) chelation for 1 h to increase the intracellular free Ca(2+) prior to NSP exposure, and the cell morphological changes and caspase 12 expression were detected using Hoechst 33342 staining and Western blotting, respectively. RESULTS: Flow cytometry showed that NSP induced early apoptosis of SKOV3 cells, and the optimal effect was achieved with the treatment parameter configuration of field strength of 90 kV/cm, pulse width of 100 ns, frequency of 1 Hz, and exposure time of 30 s. The highest early apoptotic rate and necrosis rate was (60.31?5.67)% and (1.35?0.39)%, respectively. Pretreatment with BAPTA-AM chelation prior to NSP exposure significantly increased the cell viability (P<0.05), and resulted also in lowered apoptosis rate and decreased expression of caspase 12 (P<0.05). CONCLUSION: NSP can induce apoptosis in SKOV3 cells. Increased intracellular free Ca(2+) functions as an important mediator in NSP-induced cell apoptosis, which may also involve Ca(2+)-mediated endo- plasmic reticulum pathway. PMID- 21602123 TI - [Impact of elevated basal follicle-stimulating hormone on the quantity and quality of oocytes and embryos and pregnancy outcomes in young women]. AB - OBJECTIVE: To evaluate the effect of elevated basal follicle-stimulating hormone (FSH) on both the quantity and quality of oocytes and embryos and the clinical outcomes of pregnancy in women under 35 years of age. METHODS: A retrospective analysis was conducted for inspecting 294 in vitro fertilization-embryo transfer (IVF-ET) cycles in women under 35 years of age. According to the basal FSH levels, the women were divided into groups A, B, and C with basal FSH of 10 14.99, 15-19.99 and >=20 IU/L, respectively, to compare the average number of oocytes retrieved, morphologies of the oocytes and embryos, and clinical outcomes of pregnancy. RESULTS: Group A showed greater average numbers of oocytes collected, total embryos and good-quality embryos with a lower gonadotrophin dose required to achieve follicular maturity than groups B and C. The 3 groups showed no significant differences in the percentage of metaphase II oocytes, optimal embryos-blastomere number, normal fertilization rate, cleavage rate, good-quality embryo rate, implantation rate, pregnancy rates, live birth rate or miscarriage rate, but the pregnancy rates and live birth rate tended to decrease in women with basal FSH >=15 U/L. CONCLUSION: In women below 35 years of age, an elevated serum FSH (especially one >=15 U/L) indicates diminished ovarian reserve and reduced numbers of oocyte and embryo but not poor oocyte or embryos quality, and good clinical pregnancy rate can still be expected. PMID- 21602124 TI - [Adiponectin decreases insulin receptor substrate-1 phosphorylation in the liver of OLETF rats possibly through nuclear factor-kappaB signaling pathway]. AB - OBJECTIVE: To investigate the effect of adiponectin (APN) on the insulin pathway in the liver of OLETF rats and explore its molecular mechanism. METHODS: Twenty male OLETF rats and 10 male LETO rats were sacrificed at 8 and 32 weeks of age to examine the fasting blood glucose, serum insulin, adiponectin and blood lipid profiles. The APN, phosphotyrosine of insulin receptor substrate-1 (IRS-1), IKKbeta and nuclear-kappaB (NF-kappaB) in the liver tissue were determined using ELISA, Western blotting or immunohistochemistry. RESULTS: The plasma adiponectin level in OLETF rats was significantly lower than that of LETO rats since 8 weeks of age (P<0.01). At 32 weeks of age, the blood lipid levels of OLETF rats increased significantly (P<0.05) with inverse correlations to plasma adiponectin (P<0.01). The liver APN, py-IRS-1, IKKbeta and NF-kappaB levels in OLETF rats differed significantly from those of LETO rats at both 8 and 32 weeks. At 32 weeks of age, the APN level of both rats were correlated to the levels of NF kappaB and py-IRS-1 (P<0.01). CONCLUSION: APN may decrease tyrosine phosphorylation of IRS-1 via the IKK/NFkappaB pathway and inhibit insulin signaling pathway in the liver, which contributes to hyperlipidemia, hyperglycemia and development of type 2 diabetes. PMID- 21602125 TI - [Effect of ecdysterone on the proliferation of human umbilical cord mesenchymal stem cells in vitro]. AB - OBJECTIVE: To investigate the effect of ecdysterone on the proliferation of human umbilical cord mesenchymal stem cells (hUCMSCs) in vitro. METHODS: hUCMSCs isolated by enzyme digestion from human umbilical cord tissues were cultured and identified for the surface antigens using fluorescence-activated cell sorting (FACS). The cells were treated with ecdysterone at the concentrations of 0, 25, 50, 100, 150, and 200 ug/ml, and the changes in the cell proliferation were detected using MTT assay. RESULTS: The third-passage hUCMSCs were positive for CD29 and CD105 and negative for CD34 and CD45 as shown by flow cytometry. Treatment with ecdysterone resulted in significantly increased cell proliferation as compared to the control cells (P<0.05), but no significant differences were found in cells treated with 100, 150, and 200 ug/ml ecdysterone (P>0.05). The growth curves of the cells also demonstrated the definite effect of ecdysterone in promoting the proliferation of hUCMSCs. CONCLUSION: Ecdysterone can promote the proliferation of hUCMSCs in vitro with the optimal concentration of 100 ug/ml, suggesting its potential value in the enrichment of mesenchymal stem cells. PMID- 21602126 TI - [Association of CCR5, CCR2 and SDF1 gene polymorphisms with HIV-1 infection in Chinese population: a meta-analysis]. AB - OBJECTIVE: To explore the association of CCR5delta32, CCR2-64I and SDFl-3 A gene polymorphisms with HIV-1-infection in Chinese population. METHODS: A meta analysis was performed to identify case-control studies of CCR5delta32, CCR2-64I and SDFl-3 A polymorphisms from the literatures. RESULTS: Fourteen studies of CCR5delta32 were found, involving a total of 1607 cases and 1632 controls. Compared with the wild-type homozygote wt/wt, the pooled odds ratios (95%CI) of wt/mt, mt/mt, and wt/mt+mt/mt genotypes of CCR5delta32 gene polymorphisms were 1.156 (0.808, 1.654), 0.997 (0.198, 5.022), and 1.149 (0.808, 1.634), respectively. Twelve studies of CCR2-64I were identified, including 1415 cases and 1239 controls. Compared with the wild-type homozygote wt/wt, the pooled odds ratios (95%CI) of wt/mt, mt/mt, and wt/mt+mt/mt genotypes of CCR2-64I gene polymorphisms were 1.005 (0.844, 1.197), 1.191 (0.808, 1.754), and 1.028 (0.870, 1.214), respectively. Ten studies of SDFl-3 A were found, involving 1179 cases and 1003 controls. Compared with the wild-type homozygote wt/wt, the pooled odds ratios (95%CI) of wt/mt, mt/mt, and wt/mt + mt/mt genotypes of SDF1-3 A gene polymorphisms were 1.010 (0.830, 1.228), 1.188 (0.860, 1.643), and 1.038 (0.861, 1.250). CONCLUSION: CCR5delta32, CCR2-64I and SDFl-3 A gene polymorphisms do not show strong correlations to HIV-1-infection in Chinese population. These 3 genes may not have protective effect against HIV-1 infection in Chinese population, suggesting the susceptibility of Chinese population to the infection. PMID- 21602127 TI - [Differential expression of the anti-oncogene ARHI between patients with and without endometriosis]. AB - OBJECTIVE: To investigate the expression of the anti-oncogene ARHI in the endometriotic tissue and explore its clinical significance. METHODS: A semiquantitative analysis of the expression of ARHI mRNA and protein in the ectopic and eutopic endometrium of women with endometriosis was conducted using RT-PCR and Western blotting in comparison with that in the endometrium of women without endometriosis. Immunohistochemistry and in situ hybridization were performed for semi qualitative analysis and localization of ARHI expression. RESULTS: The expression levels of ARHI mRNA and protein differed significantly between the groups. ARHI was expressed at significantly higher levels in ectopic endometrium than in eutopic and normal endometrium (P<0.005), but showed no significant difference between the latter two tissues (Pgt;0.05). The positivity rate ARHI DNA was 97.3% in the endometrium of women without endometriosis, 100% in the ectopic endometrium and 93.8% in the eutopic endometrium of women with endometriosis. immunohistochemistry showed an ARHI positivity of 93.2% in the endometrium of women without endometriosis, 100% in the ectopic endometrium and 92.3% in the eutopic endometrium of women with endometriosis. The expression patterns of ARHI DNA and protein were consistent. Immunohistochemistry in 5 cases of malignant endometriosis showed negative ARHI expression in 4 cases and weak positivity in 1 case. CONCLUSION: ARHI expressions are present in the endometrium and up-regulated in ectopic endometrium, whereas in the ectopic endometrium of patients with malignant endometriosis its expression is often negative, suggesting a role of ARHI in infertility and tumorigenesis of endometriosis. PMID- 21602128 TI - [Cisplatin induces drug resistance in human esophageal squamous carcinoma cell line EC109 by decreasing CTR1 protein expression]. AB - OBJECTIVE: To investigate the mechanism of the development of cisplatin resistance in a human esophageal squamous carcinoma cell line. METHODS: The cytotoxicity of cisplatin in the cisplatin-resistant resistant cell line EC109/CDDP and its parental cell line EC109 was measured by MTT assay. Whole-cell cisplatin accumulation and Pt-DNA adduct formation were determined by inductively coupled plasma mass spectrometry (ICP-MS). Western blotting was used to investigate the protein expression of full length PARP, cleaved PARP, and copper transporter 1 (CTR1). RESULTS: EC109/CDDP cells was more resistant to cisplatin induced cytotoxicity and apoptosis than EC109 cells. Compared with EC109 cells, EC109/CDDP cells exhibited less cisplatin accumulation and Pt-DNA adduct formation with also decreased CTR1 protein expression. CONCLUSION: Cisplatin induces drug resistant phenotype by decreasing the protein level of CTR1, which controls cell accumulation and cytotoxic effect of cisplatin. PMID- 21602130 TI - [Development of an amplified luminescent proximity homogeneous immunoassay kit for detecting human hepatitis B virus e antibody]. AB - OBJECTIVE: To develop an amplified luminescent proximity homogeneous immunoassay (AlphaLISA) kit for the detection of human hepatitis B virus e antibody (HBeAb). METHODS: The neutralizing and competitive inhibition method was used to develop the AlphaLISA kit for detection of serum HBeAb. RESULTS: The working range of the kit was 0.003-16 NCU/ml with a sensitivity up to 0.003 NCU/ml. The intra- and inter-assay coefficient of variation was 5.3% and 6.8%, respectively. The kit showed no cross-reaction with HBcAb, and comparison of the detection results with those of a commercially available Elecsys HBeAb kit (Roche) for 136 samples showed a correlation coefficient of 0.961. CONCLUSION: The AlphaLISA kit for HBeAb detection meets the clinical requirements for detection HBeAb in human serum. PMID- 21602129 TI - [Application of intraoperative magnetic resonance imaging and functional neuronavigation in microsurgery for lesions near language-related brain regions]. AB - OBJECTIVE: To explore the clinical value of intraoperative magnetic resonance imaging (MRI) and functional neuronavigation in the preservation of the language function during microsurgery for lesions near language-related brain regions. METHODS: Sixty-one right-handed patients underwent microsurgical resection of the lesions near the language-related brain regions with the assistance of intraoperative MRI and blood oxygen level- and diffusion tensor imaging-based functional neuronavigation. The patients were divided into 2 groups according to the location of the lesions, namely group A with lesions near the left posterior inferior frontal gyrus and group B with lesions near the left posterior superior temporal gyrus. The aphasia quotient (AQ) of all patients were obtained using Western Aphasia Battery (WAB) before and 2 weeks after the operation. RESULTS: In the 33 patients with a normal AQ score (>=93.8) before the operation, the AQ score underwent no significant changes after the operation (P>0.05). Twenty-eight patients had lowered AQ scores (<93.8) preoperatively, which were improved significantly after the operation (P<0.01). At 2 weeks after the operation, the language function worsened in 14 patients (23.0%), and only 2 (3.2%) showed a persistent language deficit at 6 months. Of the 61 patients, radical resection of the lesions was achieved in 41 and subtotal resection in 20 patients. The variation of AQ scores after the operation was not found to correlate to the degree of lesion resection, and the patients in group A showed a greater AQ variation than those in group B. CONCLUSIONS: Intraoperative MRI and functional neuronavigation can well demonstrate the structural relations between the lesions, the cortical areas and the fasciculi related to language functions, thus helping to better preserve the language function during microsurgical lesion resection in patients with lesions near language-related brain regions. PMID- 21602131 TI - [Effect of ultrasound on osteoprotegerin and receptor activator nuclear factor kappaB ligand expression during root resorption in rats]. AB - OBJECTIVE: To evaluate the effect of pulsed ultrasound on the expressions of osteoprotegerin (OPG) and receptor activator nuclear factor kappaB ligand (RANKL) during root resorption in a mouse model of orthodontic tooth movement. METHODS: Thirty-two male Wistar rats (6-8 weeks old) were randomly assigned into 4 equal groups, including the blank control group, two ultrasound exposure groups with daily local LIPUS stimulation (100 and 150 MW/cm(2)) for 10 days during mechanical loading, and the control group with mechanical loading but not LIPUS exposure. Nickel-titanium closed-coil springs were used to generate 100 g mesial force for 10 days to move the maxillary right first molars. The expression of OPG and RANKL proteins at the compression sites was detected by immunohistochemistry. RESULTS: Ultrasound stimulation significantly up-regulated the expression of OPG and down-regulated RANKL expression (P<0.05). The expressions of OPG and RANKL showed significant differences between the two ultrasound exposure groups (P<0.05). CONCLUSION: Ultrasound stimulation might be useful to protect against root resorption and accelerate its repair by regulating the expressions of OPG and RANKL. PMID- 21602132 TI - [Effect of allogenic adipose-derived stem cell transplantation on bone mass in rats with glucocorticoid-induced osteoporosis]. AB - OBJECTIVE: To investigate the effects of systemic transplantation of allogenic adipose-derived stem cells (ADSCs), the main undifferentiated cells in the supporting-storing system based on the fasciology hypothesis, on the bone mineral density (BMD) and histomorphometry in rats with glucocorticoid-induced osteoporosis (GIOP) rats, and explore a new therapeutic approach for osteoporosis. METHODS: Forty female adult Wistar rats were randomized equally into blank control group (A), model group (B), control treatment group (C) and treatment group (D). In groups B, C, and D, osteoporosis was induced by injection of prednisolone (8 mg/kg) via the tail vein 3 times a week for 12 consecutive weeks. After successful establishment of osteoporosis, allogenic ADSCs (3*10(6)/ml) were transplanted via the tail vein. The BMD at the L3-L5 levels and of the right femurs were detected, and the histomorphometry of the right tibias was analyzed in all the rats. RESULTS: After prednisolone injection, the BMD of L3-L5 vertebrae and the right femurs, the percent trabecular area, trabecular thickness and trabecular number of the right tibias were all obviously lowered while the trabecular separation and osteoclast number increased in group B as compared to those in group A (P<0.05). Four weeks after ADSC transplantation, all these indices were significantly improved in group D, showing significant differences from those in group B (P<0.05) and also group C. CONCLUSION: Transplantation of allogenic ADSCs can restore the BMD and bone histomorphometric properties of rats with GIOP, and may serve as a potential treatment for GIOP. These results also provide partial experimental evidence supporting the hypothesis of fasciaology. PMID- 21602133 TI - [GenoType MTBDRplus assay for rapid detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis in Sichuan]. AB - OBJECTIVE: To explore the molecular and epidemic characteristics of rifampin (RFP) and isoniazid (INH) resistance of mycobacterium tuberculosis (MTB) in Sichuan. METHODS: GenoType reg; MTBDRplus Assay GTplus was used to examine 68 clinical isolates of MTB and 105 clinical specimens for mutations in rpoB, katG and inhA genes related to RFP and INH resistance. RESULTS: Of the 151 valid tests obtained, 44 (29.14%) and 26 (17.22%) showed drug resistance and multidrug resistance, respectively. Resistance to RFP and INH was found in 21.85% (33/151) and 24.50% (37/151) of the samples, respectively. The most prevalent mutations were rpoB S531L, katG S315T1 and inhA C-15T. The multidrug resistance rate in the sputum specimens was significantly higher than that in the non-respiratory samples (19.35% vs 7.41%). CONCLUSION: Drug-resistant, especially multidrug resistant tuberculosis is highly prevalent in Sichuan. The multidrug-resistant bacteria most frequently show rpoB S531L combined with katG S315T1 mutations, suggesting the necessity of developing rapid clinical identification methods for drug-resistant MTB to control the spread of the resistant strains. PMID- 21602134 TI - [Effect of mesenchymal stem cell transplantation on immunological injury of the ovary in mice]. AB - OBJECTIVE: To investigate the effect of mesenchymal stem cell (MSC) transplantation in repairing ovarian injury in mice sensitized with porcine ovarian proteins. METHODS: Wild-type female mice with ICR background (6-8 weeks old) were divided randomly into groups A, B and C (n=12). In groups B and C, the mice were treated with the total protein extract from porcine ovary to induce immunological injury of the ovary, while those in group A received no treatment. MSCs-derived from GFP transgenic mice were transplanted into the mice of group C, and equal volume of PBS was injected intraperitoneally in mice of the other two groups. PCR was used to detect GFP gene in the genomic DNA of the ovaries to assess MSCs homing in the ovary, and the reparative effect of MSCs on ovarian injury was evaluated using HE staining and TUNEL analysis. RESULTS: After transplantation, the MSCs could reach the injured ovaries to promote the repair of the ovarian injury, resulting also in reduced apoptosis of the granulosa cells (GCs) in the injured ovaries. CONCLUSION: MSCs transplantation can promote the recovery of the immunological injury of the ovary in mice, the mechanism of which may involve reduced apoptosis of the GCs. PMID- 21602135 TI - [Expression of leptin and leptin receptor in hepatocellular carcinoma and the clinicopathological significance]. AB - OBJECTIVE: To investigate the expressions of leptin and leptin receptor in hepatocellular carcinoma (HCC) and explore the clinicopathological significance. METHODS: The expressions of leptin and leptin receptor were examined by immunohistochemistry in 81 HCC patients undergoing curative tumor resection. The correlations between the expression of two biomarkers and the clinicopathological factors were analyzed. RESULTS: The overexpression rate of leptin and leptin receptor in HCC was 56.8% and 35.8%, respectively. No significant correlation was observed between their overexpression (r=0.236, P=0.034). Leptin receptor overexpression was significantly correlated to the tumor size and TNM stage (P<0.05), but not to age, body mass index, alpha-fetoprotein, hepatitis B surface antigen status, tumor grade, vascular invasion, or liver cirrhosis (P>=0.05). Leptin overexpression showed no significant correlations to the above clinicopathological factors (P>=0.05). CONCLUSION: Leptin receptor overexpression may have an inhibitory effect on hepatocellular carcinoma. The expression status of leptin receptor decides the action of leptin and leptin receptor after their binding. PMID- 21602136 TI - [Microsurgical treatment of complicated tethered cord resulting from mixed lipoma in a 12-year-old patient: a case report]. AB - OBJECTIVE: A 12-year-old boy was admitted for complaint of progressive urination disorder for over 2 years. Physical examination found dysesthesia in the perineal region and disappearance of anal reflex with anal relaxation and a spinal cleft in the sacrococcygeal region. Lumbosacral magnetic resonance imaging MRI showed a low-set of the spinal cord, tethered cord, spina bifida of sacral vertebrae, and meningocele combined with lipoma inside and outside of the spinal canal. Ultrasonography displayed a significantly increased residual urine volume. The diagnosis of tethered-cord syndrome resulting from mixed lipoma was thus established. During the microsurgery, the adhesions between the spinal cord, coccygeal nerve and lipoma were released with a laser scalpel, and the lipoma inside and outside of the spinal canal was excised, after which the dural defect was repaired. The patient recovered smoothly, and the urinary function was normal at the follow-up 6 months after the surgery. Spinal cord lipoma can be classified into 2 types based on the integrity of the dura mater, and in this case, a combined dural defect was found. A definite diagnosis can be derived from the clinical manifestations and MRI findings. Microsurgery remains the currently only effective treatment, and a favorable prognosis can be expected after an early surgical intervention, especially before the functional lesion of the spinal cord. The integrity of the local dura mater considerably affects the outcome of the treatment, and dural defect often leads to surgical difficulty and poor results. The key to a successful operation lies in a full release of the adhesion and avoidance of injury to the conus medullaris and cauda equina. A reoperation in case of recurrence should be carefully evaluated for its benefits. PMID- 21602137 TI - [Embolization combined with endovascular stenting for treatment of intracranial pseudoaneurysms]. AB - OBJECTIVE: To evaluate the therapeutic effect of embolization combined with endovascular stenting in the for treatment of intracranial pseudoaneurysms. METHODS: Seventeen patients with intracranial pseudoaneurysms received endovascular treatment with coil placement, NBCA glue embolization and endovascular stenting, and the therapeutic effect was evaluated according to the findings in immediate postoperative and follow-up angiography. RESULTS: Fatal aneurysm rupture occurred in 1 case during embolization, and the surgical procedures were carried out smoothly in the remaining 16 cases. The aneurysm cavity dense coil packing ratio was 50% in coil embolization group and 42.9% in stent-assisted coil embolization group. In the follow-up for 3 months to 2 years, 2 patients in coil embolization group experienced pseudoaneurysm recurrence and were managed successfully with additional embolization with coils and stent. Aneurysms were not found postoperatively in stent-assisted coil embolization group. CONCLUSION: Embolization combined with endovascular stenting is a safe and effective treatment of intracranial pseudoaneurysms with minimized risk of recurrence. PMID- 21602138 TI - [Connective tissue growth factor mediates high glucose-induced down-regulation of podocalyxin expression in mouse podocytes]. AB - OBJECTIVE: To detect the effect of connective tissue growth factor (CTGF) on podocalyxin expression in mouse podocytes exposed to high glucose in vitro and explore the possible pathway involved. METHODS: The expression vector carrying a small interfering RNA (siRNA) targeting CTGF was transfected into mouse podocytes cultured in the presence of 1 g/L glucose (normal control), 4.5 g/L glucose (high glucose group), 1 g/L glucose + 3.5 g/L mannitol (iso-osmolar control group). The changes in the protein expression levels of podocalyxin, CTGF and ERK1/2 in the cells in response to the treatments were investigated using Western blotting. RESULTS: High glucose exposure for 24 and 48 h resulted in significantly decreased expression of podocalyxin and increased CTGF in the podocytes (P<0.05). Phosphorylation of ERK1/2 occurred as early as 30 min after the exposure, and the activation was maintained till 24 h. Transfection of the cells with siRNA targeting CTGF significantly inhibited these changes. CONCLUSION: CTGF is an important mediator of high glucose-induced podocyte damage and decreases the protein level of podocalyxin by the ERK1/2 pathway. CTGF-specific siRNA can alleviate high glucose-induced podocyte injury, suggesting its potential value in treatment of diabetic nephropathy. PMID- 21602139 TI - [Therapeutic effect of photodynamic treatment for psoriasis vulgaris in guinea pigs]. AB - OBJECTIVE: To observe the efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) for treating psoriasis vulgaris in guinea pigs. METHODS: Experimental psoriasis vulgaris was induced in guinea pigs by application of 5% propranolol on the ear skin. After dressing of the skin lesion with 20% ALA solution for 4 h, the lesions were irradiated with a semiconductor laser at the wavelength of 635 nm and energy density of 12 J/cm(2). The guinea pigs were divided into control group, ALA only group, light only group, single ALA-PDT treatment group and twice ALA-PDT treatment group. In each group, gross observation and biopsy of the skin lesions was conducted on days 7, 14, 21 and 28 after the treatment. RESULTS: In terms of gross observation of the lesion, epidermal thickness and proliferating cell nuclear antigen (PCNA) expression, ALA-PDT treatment showed obvious therapeutic effect on the skin lesion, and two treatment sessions resulted in better effect than a single session. CONCLUSION: ALA-PDT can cure psoriasis vulgaris lesions characterized by abnormal epidermal proliferation in guinea pigs, and multiple treatment sessions can achieve better effects. PMID- 21602140 TI - [Isolation and identification of stem cells derived from human exfoliated deciduous teeth by magnetic activated cell sorting]. AB - OBJECTIVE: To isolate stem cells from human exfoliated deciduous teeth (SHEDs) and identify their phenotypes and multi-lineage differentiation potential. METHODS: Human pulp tissue from exfoliated deciduous teeth were dissected and digested to obtain the single cell suspension. The SHEDs selected by magnetic activated cell sorting system (MACS) were identified by examination of the cell morphology and growth in vitro and detection of the expressions of the cell markers. Osteogenic and adipogenic induction was performed to test the multi lineage differentiation potential of the cells. RESULTS: SHEDs were successfully isolated from human exfoliated deciduous teeth. SHEDs showed a lower growth rate than dental pulp cells and displayed high expressions of CD29 and CD105 but low expressions of CD34 and CD45 as shown by flow cytometry. Experiments of in vitro induction demonstrated a strong potential of the STRO-1+ SHEDs for osteogenic and adipogenic differentiation. CONCLUSION: Immunomagnetic bead selection can be used to isolate and purify SHEDs, and the STRO-1+ SHEDs show the characteristics of stem cells with multipotent differentiation potentials. PMID- 21602141 TI - [Expression of CD133 in the bone marrow of patients with myelodysplastic syndrome and its clinical significance]. AB - OBJECTIVE: To investigate the expression of CD133 in the bone marrow of patients with myelodysplastic syndrome (MDS) and explore its clinical significance. METHODS: The expression of CD133 and CD34/CD38 in the bone marrow was detected using flow cytometry in 31 cases of refractory anemia with excess blasts (RAEB), 10 cases of refractory cytopenia with multilineage dysplasia (RCMD) and 11 cases of aplastic anemia (AA). RESULTS: The percentage of CD133-expressing cells was 6.75% in patients with RAEB, significantly higher than that in patients with RCMD (1.41%) and AA (2.70%) (P<0.05); the percentage of CD133-positive cells were similar between the latter two patient groups (P>0.05). The percentage of CD34(+)/CD38- cells was similar in the 3 groups (P>0.05), all lower than 1%. CONCLUSIONS: Advanced MDS patients are characterized by an increase of CD133 expressing cells, suggesting the value of CD133 in the diagnosis of RAEB. CD34(+)/CD38- cells do not show a significant value in the diagnosis of MDS. PMID- 21602142 TI - [Familial and sporadic distal myopathy with rimmed vacuoles: comparison of the clinical, pathological, laboratory test and follow-up data]. AB - OBJECTIVE: To compare the clinical, pathological, laboratory test and follow-up data between familial and sporadic patients with distal myopathy with rimmed vacuoles (DMRV) and discuss the characteristics of this disorder in Chinese population. METHODS: The clinical and pathological features, laboratory data and follow-up results of 33 sporadic and 4 familial cases of pathologically confirmed DMRV were summarized and compared retrospectively. RESULTS: The patients age, onset age, or disease duration showed no significant difference between sporadic and familial cases; the onset pattern and affected muscle groups were also similar, but the sporadic cases showed more frequent dysmorphic features than the familial cases. The patients showed mild to moderate elevation of the muscle enzymes by one to three folds, and the familial patients had more significant elevation than the sporadic ones. No correlation was found between the disease duration and the level of muscle enzymes. The pathological findings were similar between the cases, and Gomori staining showed rimmed vacuoles and inclusion bodies without inflammatory cell infiltration. Follow-up results of 29 cases showed no significant difference between the two groups. The disease was slowly progressive and severely affected the quality of life of the patients, but did not produce obvious effect on the life expectancy. CONCLUSION: The clinical, pathological and laboratory data of Chinese DMRV patients are basically similar to those of Japanese cases. Sporadic cases tend to show more dysmorphic features than the familial ones, and occasional sporadic cases have early disease onset in early childhood. PMID- 21602143 TI - [Small interfering RNA-mediated OCT4 gene silencing inhibits the proliferation and induces apoptosis of pancreatic cancer cell line PANC1]. AB - OBJECTIVE: To observe the effects of small interfering RNA (siRNA)-mediated silencing of octamer binding factor 4 (OCT4) gene on the proliferation and apoptosis of pancreatic carcinoma cell line PANC1 in vitro. METHODS: Chemically synthesized siRNA against human OCT4 was transfected into PANC1 cells via Lipofectamine(TM)2000. The expression of OCT4 mRNA in the cells was detected using RT-PCR, and the protein expressions of OCT4 and PARP were assayed using Western blotting. The changes in the cell proliferation were evaluated using CCK8 method. Flow cytometry was used to detect the apoptosis of the transfected cells. RESULTS: siRNA transfection significantly suppressed the expression of OCT4 gene, which activated the expression of PARP in PANC1 cells (P<0.05). CCK8 method demonstrated a significant inhibition of cell proliferation by OCT4 siRNA transfection, which also resulted in significantly increased apoptotic rate of the cells (P<0.05). CONCLUSION: siRNA-mediated OCT4 gene silencing can inhibit the proliferation and induce apoptosis of pancreatic carcinoma PANC1 cells, and this study provides a basis for further functional study of OCT4 gene. PMID- 21602144 TI - [Application of three-dimensional laser scanning-based maxillofacial soft tissue reconstruction in orthodontic treatment]. AB - OBJECTIVE: To establish a convenient and rapid method for constructing a digital model of the maxillofacial soft tissue based on three-dimensional laser surface scanning to allow direct and accurate observation of the soft tissue changes in the course of orthodontic treatment. METHODS: The point cloud data of three dimensional laser scanning of the maxillofacial region were acquired from a healthy woman with Angle Class I occlusion, who maintained a horizontal Frankfort plane during scanning with the scanner placed at a distance of 80 cm. The scanning was repeated twice after wearing the dental cast for an Angle Class I occlusion. The three-dimensional digital model of the maxillofacial soft tissue was constructed based on the point cloud using GeoMagic10.0 software. RESULTS: The high-resolution three-dimensional model of the maxillofacial soft tissue reconstructed allowed accurate observation of the distinct facial anatomical landmarks and represented directly the soft tissue changes in the process of orthodontic treatment by merging the models. Using the analytic tool provided by the software, this model also allowed direct quantitative measurement of the nasolabial angle and the distances from the esthetic plane to the upper lip, labral inferior, and mentolabial sulcus, which were 111.86 degrees , -3.57 mm, 2.54 mm, and 3.95 mm before orthodontic treatment as compared to 114.31 degrees , -2.73 mm, -1.06 mm, and 3.46 mm during treatment, and 116.53 degrees , -0.15 mm, 0.64 mm, and 3.11 mm after the treatment, respectively. CONCLUSION: Three dimensional laser surface scanning enables accurate and rapid construction of the digital model of the facial soft tissues, which may provide valuable assistance in orthodontic treatment. PMID- 21602145 TI - [Relation between insulin resistance and insulin receptor gene methylation in the endometrium of patients with polycystic ovary syndrome]. AB - OBJECTIVE: To study the relationship between insulin resistance and methylation of insulin receptor (INSR) gene in the endometrium of women with polycystic ovary syndrome (PCOS). METHODS: Based on the HOMA index, 35 patients with PCOS were divided into insulin resistant group (IR group, n=18) and non-resistant group (NIR group, n=18). The patients age, serum estriol, testosterone, FSH and LH, fasting insulin and fasting blood glucose were compared between the two groups. The endometrial samples were obtained from the patients to examine DNA methylation status of INSR gene in the endometrial cells using methylation specific PCR. RESULTS: The BMI, WHR, fasting glucose, fasting insulin, and HOMA index differed significantly between the two groups (P<0.05). PCR analysis showed partial methylation in the promoter region of INSR gene in 13 samples in IR group and 11 samples in NIR group, without detection of full methylation of the INSR gene in either group. The methylation status showed no significant difference between the two groups (P=0.328). CONCLUSION: Partial methylation of the INSR gene occurs in the endometria of PCOS patients, but this study does not provide a strong evidence supporting the relationship between insulin resistance and INSR gene methylation in women with PCOS. PMID- 21602146 TI - [Inhibitory effect of apatinib on HL-60 cell proliferation and its mechanism]. AB - OBJECTIVE: To investigate the effect of apatinib, a small-molecule vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, on the proliferation of human acute myeloid leukemia HL-60 cells and explore the possible mechanism. METHODS: MTT assay was used to assess the cytotoxicity of apatinib in HL-60 cells. The apoptosis and cell cycle changes of the cells in response to apatinib treatment were analyzed by flow cytometry, and Western blotting was used to assay P-Akt and P-Erk1/2 expressions in the cells. RESULTS: Apatinib significantly inhibited the proliferation of HL-60 cells in vitro with an IC(50) of 4.96?0.32 umol/L. Apatinib treatment significantly increased the apoptotic rate of the cells in a dose-dependent manner, but produced no significant effect on the cell cycle (P>0.05). Western blotting showed that the expressions of P-Akt and P-Erk1/2 decreased in HL-60 cells after a 48-h apatinib treatment. CONCLUSION: Apatinib inhibits the proliferation of HL-60 cells by inducing cell apoptosis probably through the mechanism of inhibiting the expressions of the Akt/Erk1/2 signal transduction pathway. PMID- 21602147 TI - [Synthesis and antitumor activities of pyrimidines]. AB - OBJECTIVE: To synthesize cyclin-dependent kinase (CDKs) inhibitors and assay their antitumor activities. METHODS: A series of pyrimidines containing different arylamino and 1-(methylsulfonyl)piperidin moieties were designed by combining the segments 1-(methylsulfonyl)piperidin and pyrimidine heterocycles according to the super-position principle of the reinforcement of biological activities. RESULTS: Their structures were characterized by MS and 1H NMR spectra and all the synthesized compounds were screened for their antimicrobial activity with MTT assay. CONCLUSION: The preliminary bioassay showed that compound 3 b displayed good antitumor activity (IC(50)=13.6 umol/L). The preliminary structure activity relationship analysis of these analogues suggest that the steric factor may have important impact on the anti-tumor activity. PMID- 21602148 TI - [Urinary level of tissue factor and its procoagulant activity in patients with type 2 diabetes]. AB - OBJECTIVE: To examine the urinary level of tissue factor (uTF) and its procoagulant activity (PCA) in patients with diabetes mellitus, and explore the relationship between uTF and renal damage in diabetes mellitus. METHODS: Eighty six patients with type 2 diabetes mellitus were divided into 3 groups according to urine albumin excretion (UACR), namely normal albuminuria group, microalbuminuria group and macroalbuminuria group. The levels of uTF, PCA, blood urea nitrogen (BUN), serum creatinine (CRE), serum cystatin C (CYSC), glycohemoglobin A1c (HbA1c), and high-sensitivity C-reactive protein (hs-CRP) were measured in all the patients and 21 healthy controls. RESULTS: Compared with normal control, the diabetic patients showed significantly increased levels of uTF and PCA. The urinary TF-PCA was positively correlated to BUN, CYSC, CRE, UACR, fasting glucose and hs-CRP, but not to uTF; only hs-CRP, UACR were positively correlated to uTF. CONCLUSION: uTF is probably implicated in the development and progression of diabetic nephropathy. PMID- 21602149 TI - [Factors affecting the prognosis of invasive pulmonary fungal infections after kidney transplantation: analysis of the ten-year single-center data]. AB - OBJECTIVE: To investigate the factors affecting the prognosis of invasive pulmonary fungal infection (IPFI) in patients after kidney transplantation. METHODS: This retrospective study involved 80 concurrent patients with IPFI after receiving kidney transplantation in Zhujiang Hospital from January 1, 2000 to April 1, 2010. Fourteen factors including age, gender, pathogens, body temperature on day 5, renal insufficiency, mechanical ventilation, and clinical pulmonary infection score (CPIS) on day 5 were analyzed by univariate analysis and multivariate Logistic regression analysis to identify the factors related to the prognosis. RESULTS: Univariate analysis showed that a normal body temperature on day 5 of antifungal treatment (P=0.024), fasting high blood glucose (P=0.001), renal insufficiency (P=0.002), malnutrition (P=0.018), time of infection after transplantation (P=0.046), low CPIS on day 5 (P=0.000) and mechanical ventilation (P=0.000) all affected the prognosis of the patients. Logistic regression analysis showed that renal insufficiency (OR=18.096), mechanical ventilation (OR=130.7) and low CPIS on day 5 (OR=0.011) were independent prognostic factors, among which the low CPIS on day 5 was a protective factor. CONCLUSION: Timely and adequate empirical therapy and renal replacement therapy, along with adjusted anti-fungal therapy protocol according to the CPIS score on day 5, may improve the prognosis of IPFI after kidney transplantation. PMID- 21602150 TI - [Clinical features of women with idiopathic premature ovarian failure]. AB - OBJECTIVE: To summarize the clinical features of idiopathic premature ovarian failure (POF) and explore the early diagnosis and intervention. METHODS: A retrospective study was conducted in 39 women with idiopathic POF treated between February, 2009 and January, 2010. The clinical data of the patients including the menstrual feature, POF incidence, vaginal ultrasound and pregnancy outcomes were investigated. RESULTS: One patient had primary amenorrhea and 38 had secondary amenorrhea with an average duration of amenorrhea of 5.82 years. Abrupt cessation occurred after 1-2 menstruations following the menarche in 2 cases (5.1%) and without identifiable preceding signs in 9 cases (23%). The mean uterine and ovarian volume was significantly smaller in POF group than in the control group. Antral follicle count (AFC) was also significantly lower in POF group. Vaginal ultrasound detected at least one ovary in 89.7% and follicular activity in 79.5% of the POF patients. Evidence of ovulation was found in 12 patients, and spontaneous pregnancy occurred in 2 patients with a pregnancy rate of 5.1%. CONCLUSION: Patients with menstrual disturbance, polymenorrhea and oligomenorrhea are at risk of developing POF, in which case regular detection of the mean uterine volume, ovarian volume and AFC by vaginal ultrasound may help in early POF detection. Close monitoring can be necessary in the course of hormone replacement therapy, and timely intervention with assisted reproductive techniques may increase the chance of pregnancy. PMID- 21602151 TI - [Effect of L-838,417 on pain behavior in a rat model of trigeminal neuralgia]. AB - OBJECTIVE: To investigate the effect of L-838,417 on the results of behavioral test in rats with experimentally induced trigeminal neuralgia. METHODS: Male SD rats were randomized into model group (n=34), sham-operated group (n=30) and control group (n=6). Thirty rats with trigeminal neuralgia induced by chronic constriction injury of the infraorbital nerve below the zygomatic bone were randomly divided into 5 equal groups for treatment with 1.0 mg/kg L-838,417 (L1 group), 10.0 mg/kg L-838,417 (L10 group), 5 mg/kg morphine (M group), 3 mg/kg diazepam (D group), or normal saline (NS group). The pain threshold of the tentacles pad to von-Frey filament stimulation was measured in the rats before and at 1, 2, 3, 4, 5 h after the treatments. The sedative effect of L-838,417 was evaluated by recording the position scores and righting reflex scores, and the drug tolerance was also evaluated. RESULTS: Nine days after the operation, the pain threshold of the rats in the model group was significantly decreased compared with that before operation and that of the sham group (P<0.01). The threshold of L1 and L10 groups were both significantly increased 1 h after L 838,417 administration (P<0.01). The rats in the NS, L1, and L10 groups did not show unusual posture or righting reflex. In L1 and L10 groups, L838,417 did not show attenuated efficacy after prolonged use (10 days). CONCLUSION: L-838,417 can effectively improve hyperalgesia in rats with trigeminal neuralgia without causing sedation, motor impairment, or drug tolerance. PMID- 21602152 TI - [Development of an immunochromatographic strip test for rapid detection of Vibrio vulnificus]. AB - OBJECTIVE: To establish a rapid strip test for detection of Vibrio vulnificus. METHOD: Anti-Vibrio vulnificus polyclonal antibodies were obtained from the rabbits immunized with Vibrio vulnificus (ATCC27562). Colloidal gold was prepared through reducing HAuCl(4).4H(2)O by sodium citrate and conjugated with the polyclonal antibodies as the detecting reagent. The polyclonal antibodies and sheep anti-rabbit immunoglobulins were separately coated onto the same nitrocellulose membrane for sample detection and quality-control, respectively. The nitrocellulose membrane, gold conjugate pad, sample pad, filter paper and absorbent pad were assembled to prepare the strips. The detection specificity and sensitivity of this strip were evaluated. RESULTS: The strip test for detecting Vibrio vulnificus yielded results in 20 to 30 min. The detection sensitivity of the test was 2*10(6) CFU/ml. The strip showed no cross-reaction with other bacterial strains. The strips remained stable after preservation at 4 degrees celsius; for 4 months. CONCLUSION: With a high specificity and sensitivity, this strip test is applicable in the detection of Vibrio vulnificus. PMID- 21602153 TI - [Minimally invasive percutaneous nephrolithotomy under ultrasound and X-ray guidance for treatment of complicated renal calculi]. AB - OBJECTIVE: To evaluate the therapeutic effect of minimally invasive percutaneous nephrolithotomy (MPCNL) under ultrasonic and X-ray guidance in the treatment of complicated renal calculi. METHODS: A retrospective analysis was conducted among 36 patients undergoing MPCNL under ultrasonic and X-ray guidance for complicated renal calculi. The general clinical data, stone size, operative time, blood loss, complications and stone clearance rate were analyzed. RESULTS: Double working channel was established accurately under ultrasonic and X-ray guidance in the 36 cases. The stone clearance rate in one treatment session was 80.56%, with an average operation time of 100 min and a mean hospital stay of 13.5 days (13-15 days) after operation. A second lithotripsy was performed in 5 cases and no residual renal calculi were found 1 month after the operation. Sixteen out of the 18 patients with preoperative elevation of serum creatinine recovered normal creatinine level after the operation. CONCLUSION: MPCNL under ultrasonic and X ray guidance is safe and effective for treatment of complicated renal calculi and is associated with few postoperative complications. PMID- 21602154 TI - [Protective effects of penehyclidine hydrochloride against acute renal injury induced by hemorrhagic shock and lipopolysaccharides in rats]. AB - OBJECTIVE: To investigate the effect of penehyclidine hydrochloride (PHC) in a rat model of renal injury induced by hemorrhagic shock and lipopolysaccharides (LPS). METHODS: Forty-five healthy Wistar rats were randomized into sham operated group, model group, and 3 penehyclidine hydrochloride (PHC) dose (1, 2 and 3 mg/kg) groups (PHC1, PHC2, and PHC3 groups, respectively). The arterial blood samples were collected to determine the concentrations of serum tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), interleukin-1 (IL-1), urine creatinine (Cr) and blood urine nitrogen (BUN), and the renal tissues were collected to measure the expressions of ICAM-1 and nuclear factor-kappaB (NF kappaB) and observe the pathological changes. RESULTS: TNF-alpha, IL-8, IL-1, Cr, BUN, ICAM-1 and NF-kappaB in the 3 PHC groups were significantly lower than those in the model group (P<0.05). TNF-alpha, IL-8, IL-1, Cr and BUN were significantly lower in PHC1 (P<0.05) than in the PHC2 and PHC3 groups, and ICAM-1 and NF-kappaB were similar between 3 PHC groups (P>0.05). Compared with the model group, the 3 PHC groups showed lessened pathological changes in the renal tubules. CONCLUSION: PHC has protective effects against renal injury induced by hemorrhagic-endotoxin shock in rats, and treatment with 1 mg/kg PHC produces the most significant protective effect. PMID- 21602155 TI - [Human umbilical cord mesenchymal stem cells with adenovirus-mediated interleukin 12 gene transduction inhibits the growth of ovarian carcinoma cells both in vitro and in vivo]. AB - OBJECTIVE: To study the inhibitory effect of human umbilical cord mesenchymal stem cells (UC-MSCs) infected by a adenoviral vector containing interleukin 12 (IL-12) gene on the proliferation of ovarian carcinoma SKOV3 in vitro and the growth of tumor explants in nude mice. METHODS: Cultured human UC-MSCs were infected with the recombinant adenovirus vector harboring IL-12 gene to establish the IL-12-expressing cell line AdIL-12-MSCs. Western blotting and RT-PCR were used to detect IL-12 expressions in AdIL-12-MSCs at the protein and mRNA levels, respectively. ELISA were used to detect IL-12 content in the supernatant of AdIL 12-MSCs, whose effect on the proliferation and apoptosis of ovarian carcinoma SKOV3 cells was evaluated with MTT assay and flow cytometry, respectively. In a nude mouse model bearing subcutaneous SKOV3 tumor explants, AdIL-12-MSCs were infused via the tail vein and the inhibitory effect on the tumor growth was observed. RESULTS: The exogenous IL-12 gene was successfully transduced into UC MSCs by the recombinant adenovirus vector, resulting in efficient IL-12 expression in the cell at both the protein and mRNA levels. The supernatant of AdIL-12-MSCs significantly inhibited the proliferation of SKOV3 cells and induced cellular apoptosis in vitro as compared with UC-MSC supernatant. In the tumor bearing nude mouse model, the transplantation of AdIL-12-MSCs significantly inhibited the growth of SKOV3 tumor explants (P<0.05). CONCLUSION: Human UC-MSCs with IL-12 gene transduction, which express IL-12 at protein and mRNA levels, can inhibit the proliferation and induce apoptosis of ovarian carcinoma SKOV3 cells in vitro, and suppress the growth of ovarian cancer explants in nude mice. PMID- 21602156 TI - [Risk factors for anastomotic leakage after anterior resection for rectal cancer]. AB - OBJECTIVE: To identify the risk factors associated with anastomotic leakage following an anterior resection for rectal cancer. METHODS: Between June, 1999 and June, 2009, 628 patients underwent anterior resection for rectal cancer. A retrospective study of the cases was performed to identify the risk factors for anastomotic leakage following the resection. RESULTS: The overall incidence rate of anatomic leak was 8.6% (54/628) in these patients. A low albumin level (less than 35 g/L), diabetes, absence of a protective stoma, a distance less than 7 cm from the tumor to the anal edge, and a tumor diameter over 5 cm were identified as the risk factors for anastomotic leakage after anterior resection. CONCLUSION: For patients at a high risk for anastomotic leakage, a protective stoma can significantly decrease the rate of clinical leaks and subsequent reoperation after low anterior resection for rectal cancer. PMID- 21602157 TI - [Pullout test in expansive unilateral open-door laminoplasty of the cervical spine with OsteoMed M3 plate and screws: the screw orientation matters]. AB - OBJECTIVE: To study the impact of screw orientation on the pullout strength of OsteoMed M3 titanium screws in expansive unilateral open-door laminoplasty of the cervical spine. METHODS: Six fresh human cervical spine specimens were randomly numbered and OsteoMed M3 plate and screws were used for an expansive unilateral open-door laminoplasty. The screws were inserted in the lateral mass at different extraversion angles (0 degrees , 30 degrees and 45 degrees ). The maximum pullout strength was tested on the ElectroForce material testing machine. RESULTS: The maximum pullout strength was 81.60?7.33 N, 150.05?15.57 N, and 160.08?17.77 N in extraversion angle 0 degrees , 30 degrees , and 45 degrees groups, respectively. The maximum pullout strength was significantly less in extraversion angle 0 degrees group than in 30 degrees and 45 degrees groups (P<0.05), but similar in the latter two groups. CONCLUSION: The pullout strength of the screws inserted at an extraversion angle over 30 degrees provides stronger fixation than an angle of 0 degrees in the unilateral open-door laminoplasty using OsteoMed M3 titanium plate and screws. PMID- 21602158 TI - [Expression of Oct-4 transcription factor in squamous cell skin carcinoma and seborrheic keratosis]. AB - OBJECTIVE: To detect the expression of stem cell transcription factor Oct-4 in squamous cell carcinoma (SCC) and seborrheic keratosis (SK) and its association with cancer stem cells. METHODS: Immunohistochemistry was used to detect Oct-4 expression in 35 SCC cases, 21 SK cases and 15 normal control skin tissues. RESULTS: Oct-4 expression was negative in normal skin and showed a significant difference between SCC and SK tissues (P<0.05). CONCLUSION: The Oct-4-positive cells in SCC and SK are probably tumor stem cells. Oct-4 expression may provide an important evidence for isolation and identification of human SCC and SK stem cells. PMID- 21602159 TI - [Outcomes of surgeries for acute cervical spinal cord injury without cervical spine fracture or dislocation in young and middle-aged patients]. AB - OBJECTIVE: To study the outcomes of surgeries for acute central cervical spinal cord injury without cervical spine fracture or dislocation in young and middle aged patients. METHODS: The clinical data of 58 young and middle-aged patients with acute central cervical spinal cord injury treated in our hospital between August 2005 and August 2009 were analyzed retrospectively. Of these patients, 33 (24 males and 9 females) received surgical treatment and 25 (17 males and 8 females) had conservative therapy. The ASIA grade and ASIA motor and sensory score were used for evaluation at admission and at 14 days and 1 year after the treatment. The neurological symptoms and treatment outcomes in the two groups were evaluated. RESULTS: The proportion of patients with ASIA grade D-E and the ASIA motor and sensory scores were all significantly higher in the surgical group than in the non-surgical treatment group (P<0.05). CONCLUSION: For young and middle-aged patients with central cervical spinal cord injury, immediate surgery can relieve the pressure on the injured spinal cord and improve the micro circulation to promote functional recovery of the spinal cord. PMID- 21602160 TI - Cultural context is crucial in suicide research and prevention. PMID- 21602162 TI - Impact of withdrawal of the analgesic Co-proxamol on nonfatal self-poisoning in the UK. AB - BACKGROUND: In early 2005 the UK Committee on Safety of Medicines (CSM) announced gradual withdrawal of the analgesic co-proxamol because of its adverse benefit/safety ratio, especially its use for intentional and accidental fatal poisoning. Prescriptions of co-proxamol were reduced in the 3-year withdrawal phase (2005 to 2007) following the CSM announcement. AIMS: To assess the impact of the CSM announcement in January 2005 to withdraw co-proxamol on nonfatal self poisoning with co-proxamol and other analgesics. METHODS: Interrupted time series analysis of general hospital presentations for nonfatal self-poisoning (five hospitals in three centers in England), comparing the 3-year withdrawal period 2005-2007 with 2000-2004. RESULTS: A marked reduction in the number of episodes of nonfatal self-poisoning episodes involving co-proxamol was found following the CSM announcement (an estimated 62% over the period 2005 to 2007 compared to 2000 to 2004). There was no evidence of an increase in nonfatal self-poisoning episodes involving other analgesics (co-codamol, codeine, co-dydramol, dihydrocodeine, and tramadol) in relation to the CSM announcement over the same period, nor a change in the number of all episodes of self-poisoning. LIMITATIONS: Data were from three centers only. CONCLUSIONS: The impact of the policy appears to have reduced nonfatal self-poisoning with co-proxamol without significant substitution with other analgesics. This finding is in keeping with that for suicide. PMID- 21602164 TI - The therapist's reaction to a patient's suicide: results of a survey and implicationsfor health care professionals'well-being. AB - BACKGROUND: A substantial proportion of therapists experience the loss of a patient to suicide at some point during their professional life. AIMS: To assess (1) the impact of a patient's suicide on therapists distress and well-being over time, (2) which factors contribute to the reaction, and (3) which subgroup might need special interventions in the aftermath of suicide. METHODS: A 63-item questionnaire was sent to all 185 Psychiatric Clinics at General Hospitals in Germany. The emotional reaction of therapists to patient's suicide was measured immediately, after 2 weeks, and after 6 months. RESULTS: Three out of ten therapists suffer from severe distress after a patients' suicide. The item "overall distress" immediately after the suicide predicts emotional reactions and changes in behavior. The emotional responses immediately after the suicide explained 43.5% of the variance of total distress in a regression analysis. LIMITATIONS: The retrospective nature of the study is its primary limitation. CONCLUSIONS: Our data suggest that identifying the severely distressed subgroup could be done using a visual analog scale for overall distress. As a consequence, more specific and intensified help could be provided to these professionals. PMID- 21602163 TI - A systematic review of elderly suicide prevention programs. AB - BACKGROUND: Suicide rates are highest among the elderly, yet research on suicide prevention in old age remains a much-neglected area. AIMS: We carried out a systematic review to examine the results of interventions aimed at suicidal elderly persons and to identify successful strategies and areas needing further exploration. METHODS: Searches through various electronic databases yielded 19 studies with an empirical evaluation of a suicide prevention or intervention program designed especially for adults aged 60 years and older. RESULTS: Most studies were centered on the reduction of risk factors (depression screening and treatment, and decreasing isolation), but when gender was considered, programs were mostly efficient for women. The empirical evaluations of programs attending to the needs of high-risk older adults seemed positive; most studies showed a reduction in the level of suicidal ideation of patients or in the suicide rate of the participating communities. However, not all studies used measures of suicidality to evaluate the outcome of the intervention, and rarely did they aim at improving protective factors. CONCLUSIONS: Innovative strategies should improve resilience and positive aging, engage family and community gatekeepers, use telecommunications to reach vulnerable older adult, and evaluate the effects of means restriction and physicians education on elderly suicide. PMID- 21602166 TI - Are caregivers adherent to their own medications? AB - OBJECTIVE: To explore caregiver adherence to chronic medications and predictors of appropriate medication use. DESIGN: Descriptive, nonexperimental, cross sectional study. SETTING: United States in May 2009. PARTICIPANTS: 2,000 adults randomly selected from a large national consumer panel. INTERVENTION: Web-based survey of community pharmacy patients. MAIN OUTCOME MEASURE: Self-reported medication adherence. RESULTS: 21% of those invited (3,775) responded to the survey invitation. Of the 2,000 individuals who were eligible to participate, 38% described themselves as caregivers. Among caregivers, 45% agreed that they were more likely to forget their own medications than medications for their caregivees. Caregivers were 10% more likely to forget to take their medications, 11% more likely to stop taking medications if they felt well, and 13% more likely to forget to refill their medications than noncare-givers (P < 0.001 for all). In fully adjusted models, caregivers had 36% greater odds (95% CI 0.52-0.79) of reporting that they were nonadherent compared with noncare-givers and increased medication use among caregivees was associated with worse adherence among caregivers (P < 0.05). CONCLUSION: Medication nonadherence was common in this population, and caregivers were more likely to report poor medication adherence than noncaregivers. Considering that caregivers often engage health professionals, physicians and pharmacists may choose to screen for caregiving status. Pharmacists are uniquely positioned to intervene to enhance appropriate medication adherence. PMID- 21602167 TI - Theme: non-traumatic subarachnoid haemorrhages. PMID- 21602168 TI - Liquid ecstasy intoxication: clinical features of 505 consecutive emergency department patients. AB - BACKGROUND: To describe the epidemiological profile and clinical manifestations of liquid ecstasy (GHB) poisonings. METHODS: All cases of GHB poisoning or overdose admitted to the Emergency Department (ED) of the Hospital Clinic (Barcelona) between 2000 and 2007 were recorded. RESULTS: A total of 505 patients (mean age 24.7 years, 68% men) were included. Most patients were brought to the hospital by ambulance (98%), during the weekend (89%) and during the early morning (75%). Symptoms began in a public place in 97%. Reduced consciousness was the most important clinical manifestation: 72% of patients had a Glasgow Coma Score of <= 12. 76% of patients had consumed other drugs: ethanol (64%), amphetamines and derivates (30%), cocaine (28%), ketamine (11%), cannabis (9%) and others (5%). Treatment was required in 26% of cases and an antidote was administered in 35 cases with no response. There were no deaths. The combined GHB group had a longer time to complete recovery of consciousness (71 +/- 40 vs 59 +/ 40 min, p < 0.001) and a higher percentage of patients with severely reduced consciousness at ED arrival (54% vs 37%, p = 0.01), need for treatment (29% vs 16%, p < 0.01) and need for mechanical ventilation (3% vs 0%, p < 0.05) compared with the pure GHB group. CONCLUSIONS: GHB intoxication leading to reduced consciousness is a frequent reason for ED admission, above all in young people and in the early morning at the weekend. Symptoms are more severe in patients who have taken GHB in combination with other substances of abuse. PMID- 21602169 TI - Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. Bet 1: The effectiveness of oral terbutaline in treatment of priapism. PMID- 21602171 TI - Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 2: Intraosseous access and drug administration in adult cardiac arrest. PMID- 21602172 TI - Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 3: Central line insertion in deranged clotting. PMID- 21602174 TI - Zebrafish as a model to study cardiac development and human cardiac disease. AB - Over the last decade, the zebrafish has entered the field of cardiovascular research as a new model organism. This is largely due to a number of highly successful small- and large-scale forward genetic screens, which have led to the identification of zebrafish mutants with cardiovascular defects. Genetic mapping and identification of the affected genes have resulted in novel insights into the molecular regulation of vertebrate cardiac development. More recently, the zebrafish has become an attractive model to study the effect of genetic variations identified in patients with cardiovascular defects by candidate gene or whole-genome-association studies. Thanks to an almost entirely sequenced genome and high conservation of gene function compared with humans, the zebrafish has proved highly informative to express and study human disease-related gene variants, providing novel insights into human cardiovascular disease mechanisms, and highlighting the suitability of the zebrafish as an excellent model to study human cardiovascular diseases. In this review, I discuss recent discoveries in the field of cardiac development and specific cases in which the zebrafish has been used to model human congenital and acquired cardiac diseases. PMID- 21602175 TI - Generation and characterization of peptide mimotopes specific for anti ErbB-2 monoclonal antibodies. AB - The erbb-2 gene receptor is often over-expressed in human cancer and its overexpression is accompanied by worse prognosis. Targeting erbb-2 gene with antibodies is an effective approach to curtail the progression of erbb-2 gene expressing cancer types. Two monoclonal antibodies, L-26 and N-12, previously generated in our laboratory, have shown effective tumor inhibition in mice, especially when used in combination. Here, we describe novel peptide mimics of erbb-2 gene protein epitopes, also called mimotopes, that were selected from a constraint random 12-mer peptide phage library, specific for the antibodies L-26 and N-12. Initial sequencing analyses revealed little sequence conservation among the peptide mimotopes, and no sequence homology with the erbb-2 gene protein. However, computational analyses of the two groups of peptides, specific for L-26 and N-12, suggested different epitopes on the erbb-2 gene extracellular domain. In vitro assays showed that the phage displayed peptide mimotopes were specific to their respective antibodies. Selected cyclic peptide mimotopes, but not their corresponding linear equivalents, were able to inhibit binding of the antibodies L-26 and N-12 to the surface of erbb-2 gene-expressing cancer cells in a concentration-dependent manner. In line with this observation, phage-displayed cyclic peptides successfully competed in vitro with recombinant erbb-2 gene protein for binding to their respective antibodies L-26 or N-12. Consistent with the antibody inhibition experiments, we detected specific anti-erbb-2 gene antibodies following vaccination with KLH-coupled cyclic peptides but not with multiple antigenic linear peptides. Potentially, the selected peptides could serve as a starting point for the development of a vaccine against erbb-2 gene over-expressing cancer. PMID- 21602176 TI - Recombination activation gene-2-deficient blastocyst complementation analysis reveals an essential role for nuclear factor I-A transcription factor in T-cell activation. AB - Nuclear factor I (NFI)-A is a member of the NFI family of transcription factors implicated in regulation of granulocyte differentiation. However, its role in the lymphoid lineage is not known. NFI-A deficiency results in perinatal lethality, thus precluding analysis of the role of NFI-A in lymphocyte development and function. Using recombination activation gene-2-deficient (RAG-2(-/-)) blastocysts and embryonic stem cells with homozygous NFI-A gene deletion, we show an essential role for NFI-A in T-cell activation. NFI-A(-/-)->RAG-2(-/-) chimeric mice had normal distributions of CD4(-)CD8(-) double negative, CD4(+)CD8(+) double positive, CD4(+)CD8(-) and CD4(-)CD8(+)-single positive cells in the thymus and CD4(+)CD8(-) and CD4(-)CD8(+) cells in spleen and lymph nodes. However, NFI-A(-/-)->RAG-2(-)(/)(-) mice had severely reduced thymus size and hypocellularity. The decrease in thymocytes and peripheral T cells in NFI-A(-/-) >RAG-2(-/-) chimeric mice is attributed to proliferative defects associated with decreased blast transformation, CD69 expression and DNA synthesis in response to T antigen receptor stimulation. Interestingly, NFI-A-null T cells showed increased levels of c-myc transcription that is inhibited in response to antigen receptor-mediated activation. These studies demonstrate for the first time a requirement for the NFI-A transcription factor in antigen receptor-induced T-cell activation events. PMID- 21602177 TI - Specific expression of PAD4 and citrullinated proteins in lung cancer is not associated with anti-CCP antibody production. AB - Anti-citrullinated protein antibodies (ACPAs), produced against citrullinated proteins, are diagnostic and prognostic markers of rheumatoid arthritis (RA). The underlying mechanism that explains the connection of smoking, citrullination [catalyzed by peptidyl arginine deiminases (PADs)] and ACPAs is still unclarified in RA. Thus, we searched for a non-arthritic model in which an increased cell death allows the formation of autoantibodies. Data supporting that lung cancer might be a good candidate are as follows: (i) smoking plays a role in its pathogenesis, (ii) the disease is frequently accompanied by paraneoplastic syndrome, (iii) smoking increases citrullination in the lung, (iv) various types of malignancies are associated with increased citrullination and (v) lung cancer tissue shows similarities with RA synovium. Serum PAD4, rheumatoid factor (RF) and ACPA levels were measured in 42 lung cancer patients; expression of cytokeratin 7 (CK7), PAD4 and citrullinated proteins was visualized in 113 lung cancer tissues. All parameters were analyzed in correlation with smoking history. None of the patients had polyarthritis or autoimmune disease. Significantly increased RF levels were associated with higher PAD4 levels in smoker lung cancer patients compared with non-smokers. Both PAD4 and citrullination immunostaining strongly correlated with that of CK7 in lung cancer, however, did not differ according to smoking history. Two of 30 smoker lung cancer patients had high anti cyclic citrullinated peptide levels. In conclusion, PAD4 and citrullination may be helpful in distinguishing lung cancer from healthy tissue. Smoking, abnormal serum PAD4 and RF levels may not be sufficient for the production of ACPAs and development of autoimmunity. PMID- 21602178 TI - An integrative functional genomic and gene expression approach revealed SORBS2 as a putative tumour suppressor gene involved in cervical carcinogenesis. AB - Human papillomavirus (HPV) types 16 and 18 are known to play a major role in cervical carcinogenesis. However, additional genetic alterations are required for the development and progression of cervical cancer. Our aim was to identify genes which are consistently down-regulated in cervical cancers (CxCa) and which are likely to contribute to malignant transformation. Microarray analyses of RNA from high-grade cervical precancers (CIN2/3) and CxCa were performed to screen for putative tumour suppressor genes (TSG) in predefined regions on chromosomes 4 and 10. Validation of the candidate genes was done by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in 16 normal cervical tissues, 14 CIN2/3 and 16 CxCa. The two most promising genes, SORBS2 and CALML5, were expressed ectopically in various cell lines in order to analyse their functional activity. Reconstitution of SORBS2 expression resulted in a significant reduction in cell proliferation, colony formation and anchorage-independent growth in CaSki, HPKII and HaCaT cells, whereby anchorage-independent growth could only be investigated for CaSki cells. SORBS2 had no effect on cell migration. In contrast, reconstitution of CALML5 expression did not influence the phenotype of all cell lines tested. None of the genes could induce senescence or apoptosis. Our results underline a possible role of SORBS2 as a TSG in cervical carcinogenesis. PMID- 21602179 TI - The value of the WISC-IV Digit Span subtest in detecting noncredible performance during pediatric neuropsychological examinations. AB - In adult populations, research on methodologies to identify negative response bias has grown exponentially in the last two decades. Far less work has focused on methods appropriate for children. Although several recent studies have demonstrated the appropriateness of using stand-alone symptom validity tests with younger populations, a near absence of pediatric work has investigated embedded validity indicators. The present study examined the classification value of several scores derived from the WISC-IV Digit Span subtest. The sample consisted of 274 clinically referred mild traumatic brain injury patients aged 8 through 16 years. Fourteen percent of the participants failed both the Medical Symptom Validity Test and Test of Memory Malingering, which was used as the criterion for noncredible effort. For age-corrected scaled scores, a score of <=5 resulted in the optimal cut-score, yielding sensitivity of 51% and specificity of 96%. For Reliable Digit Span, the optimal cut-score was <=6, with sensitivity of 51% and specificity of 92%. Although only moderately sensitive, Digit Span scores are likely to have good utility in identifying noncredible performance in relatively high-functioning older children and adolescents. Indeed, classification statistics produced in this pediatric sample compare favorably with those produced in many real-world adult patients. PMID- 21602180 TI - Quercetin reduces cisplatin nephrotoxicity in rats without compromising its anti tumour activity. AB - BACKGROUND: Nephrotoxicity is the major limitation for the clinical use of cisplatin as an anti-tumoural drug. Our aim was to investigate the protective effect of quercetin on cisplatin nephrotoxicity in a rat tumour model in vivo and to examine the mechanisms of renal protection. METHODS: Breast adenocarcinoma (13762 Mat B-III) cells were inoculated subcutaneously in male Fischer rats and 7 days later, the rats were administered daily with quercetin [50 mg/kg/day, intraperitoneally (i.p.)] or vehicle. Four days after that, the rats were given a single dose of cisplatin (4 mg/kg, i.p.) or vehicle. Tumour growth and renal function were monitored throughout the experiment. Two or 6 days after cisplatin administration, the rats were killed and the kidneys and tumours were removed to examine renal function and toxicity markers in both tissues. RESULTS: In the kidney, cisplatin treatment induced: (i) a decrease in renal blood flow and glomerular filtration rate, (ii) tubular necrosis/apoptosis, (iii) increased lipid peroxidation and decreased endogenous antioxidant systems, (iv) increased expression of inflammation markers and (v) increased activity of the apoptosis executioner caspase-3. Cisplatin effectively reduced tumour size and weight. CONCLUSIONS: Co-treatment with quercetin partially prevented all the renal effects of cisplatin, whereas it did not impair its anti-tumour activity. In conclusion, in a model of tumour-bearing rats, quercetin prevents the nephrotoxic effect of cisplatin without affecting its anti-tumour activity. PMID- 21602181 TI - Steroid-related osteonecrosis--an update. PMID- 21602182 TI - Renal involvement in a large cohort of Chinese patients with Castleman disease. AB - BACKGROUND: The association of kidney disease with Castleman disease (CD) is uncommon. To date, most studies have been based on single-case reports. Here, we describe renal involvement in CD in a large Chinese cohort. METHODS: Seventy-six CD patients were identified in one clinical center. Clinical and pathological characteristics of patients with renal involvement were described, which were also compared with cases identified through a systematic literature review. RESULTS: Nineteen patients (25%) exhibited renal involvement. Patients with multicentric clinical type (59 versus 0%) or plasma cell (PC)/mixed cellularity histological variant (61.5 versus 6%) were more likely to have renal involvement (P < 0.001). Proteinuria (with 7/19 reaching nephrotic range) and acute renal failure (12/19, 63%) were the main clinical presentations. Kidney biopsy revealed various glomerular diseases (10/11) and interstitial nephritis (1/11), while with 'thrombotic microangiopathy-like' lesions were the most common pathological characteristics (6/11, 55%). This contrasted significantly with the literature in which amyloidosis was the most reported. Renal outcomes responded well to chemotherapy. Nine (9/12, 75%) patients with acute renal failure recovered completely, one recovered partially. Overall, only three (3/19, 16%) patients progressed to end-stage kidney disease. Renal involvement did not influence survival rate (log-rank test, P = 0.73) in the follow-up. CONCLUSIONS: CD with multicentric type and PC or mixed cellularity variant are often associated with renal complications. Thrombotic microangiopathy-like lesions are the most common pathological characteristics. Chemotherapy can reverse kidney damage in most cases. PMID- 21602183 TI - Insulin resistance and left ventricular hypertrophy in end-stage renal disease: association between the ENPP1 gene and left ventricular concentric remodelling. AB - BACKGROUND: Left ventricular hypertrophy (LVH) and insulin resistance (IR) are frequent complications of end-stage renal disease (ESRD). The ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) gene, whose variability has been repeatedly associated with IR, codes for a membrane glycoprotein which inhibits insulin-receptor signalling. METHODS: We investigated the relationship of ENPP1 variability, as indicated by 10 single nucleotide polymorphisms (SNPs) representative of the gene haploblock structure, with left ventricular mass and geometry (by echocardiography) in an ethnically homogeneous series of 238 Caucasian ESRD patients. RESULTS: ENPP1 rs1974201 and rs9402349 polymorphisms were coherently associated (P ranging from 0.04 to 0.005) with indicators of left ventricular (LV) myocardial hypertrophy (mean wall thickness) and concentric remodelling (relative wall thickness and LV mass-to-volume ratio) but unrelated with the cavitary component of the LV (left ventricular end-diastolic volume). As compared to individuals carrying the alternative genotypes, the risk of LV concentric remodelling was approximately doubled in major allele homozygous for rs1974201 [odds ratio (OR) of GG versus GC + CC: 2.31, 95% confidence interval (CI): 1.30-4.12, P = 0.004] and rs9402349 (OR of AA versus AC + CC: 1.91, 95% CI: 1.02-3.56, P = 0.04) polymorphisms. CONCLUSIONS: Coherent associations exists between echocardiographic parameters of LV myocardial hypertrophy and concentric remodelling and ENPP1 variability in ESRD patients. These data support the hypothesis that IR is a relevant factor in the pathogenesis of myocardiopathy in this population. PMID- 21602184 TI - Detection of anti-ESA antibodies in human samples from PRCA and non-PRCA patients: an immunoassay platform comparison. AB - BACKGROUND: The immunological methods for detecting antibodies to erythropoiesis stimulating agents (ESAs) differ in assay sensitivity. However, this parameter, routinely determined in clinical assays using a high-affinity non-human polyclonal antibody, gives a one-dimensional assessment of antibody detection. We compare three widely used immunological methods and evaluate the ability of each to detect mature human antibodies and human antibodies characteristic of an early immune response. METHODS: The detection of anti-ESA antibodies was compared between a radioimmunoprecipitation (RIP) assay, an electrochemiluminescence (ECL) bridging enzyme-linked immunosorbent assay and a surface plasmon resonance (SPR) based immunoassay. All three methods were validated for sensitivity, specificity and precision. Specimens from clinical studies or post market testing were categorized as pure red cell aplasia (PRCA) or non-PRCA and then analyzed in each method. RESULTS: Among the antibody-mediated PRCA samples, which contain high affinity neutralizing antibodies, there was strong correlation between all methods. The results from non-PRCA sample analysis show high correlation between RIP and ECL methods; however, differences between the SPR immunoassay and the ECL and RIP were demonstrated. The samples that scored positive in the SPR immunoassay and negative by RIP and ECL were characterized to be of low antibody concentration, contained a high percentage of rapidly dissociating antibodies, or were antibodies of the IgM isotype. CONCLUSIONS: All three immunological methods are appropriate for detection of antibodies associated with antibody-mediated PRCA. However, the SPR immunoassay platform detected an early, low affinity IgG and IgM antibody response as well as detected and characterized a pathogenic antibody response associated with antibody-mediated PRCA. PMID- 21602185 TI - Periodontal disease is associated with metabolic syndrome in hemodialysis patients. AB - BACKGROUND: Periodontitis and metabolic syndrome are highly prevalent in hemodialysis (HD) patients but little information is available on their association. Thus, this study aimed to assess the association between these two conditions in a HD cohort. METHODS: Data from 253 HD patients were analyzed. The association of periodontitis, gingival inflammation and dental plaque burden with metabolic syndrome and its individual component conditions were evaluated. Adjustments for age, gender, socioeconomic status, comorbidity and smoking status were considered. RESULTS: The prevalence of metabolic syndrome was 65.1% among individuals (n = 149) with moderate-severe periodontitis, 54.5% among individuals (n = 55) with mild periodontitis and 36.7% among individuals (n = 49) without periodontitis. After adjustment of confounders, patients with moderate-severe periodontitis were 2.736 [95% confidence interval (CI), 1.293-5.790] times more likely to develop metabolic syndrome than were those without periodontitis. In addition, the odds ratio for metabolic syndrome was 1.561 (95% CI, 1.121-2.166) per score of gingival inflammation severity and 1.724 (95% CI, 1.135-12.615) per score of dental plaque burden. CONCLUSIONS: Moderate-severe periodontitis is associated with metabolic syndrome in HD patients. Whether improved oral health reduces the risk of metabolic syndrome is worth determining through further studies. PMID- 21602186 TI - Statins and resistance to erythropoiesis-stimulating agents: are the two associated? PMID- 21602187 TI - Epigenetic mechanisms of mouse interstrain variability in genotoxicity of the environmental toxicant 1,3-butadiene. AB - 1,3-Butadiene (BD) is a common environmental contaminant classified as "carcinogenic to humans." Formation of BD-induced DNA adducts plays a major role in its carcinogenicity. BD is also an epigenotoxic agent (i.e., it affects DNA and histone methylation in the liver). We used a panel of genetically diverse inbred mice (NOD/LtJ, CAST/EiJ, A/J, WSB/EiJ, PWK/PhJ, C57BL/6J, and 129S1/SvImJ) to assess whether BD-induced genotoxic and epigenotoxic events may be subject to interstrain differences. Mice (male, 7 weeks) were exposed via inhalation to 0 or 625 ppm BD for 6 h/day and 5 days/week for 2 weeks and liver BD-DNA adducts, epigenetic alterations, and liver toxicity were assessed. N-7-(2,3,4 trihydroxybut-1-yl)-guanine adducts were detected in all strains after exposure, yet BD-induced DNA damage in CAST/EiJ mice was two to three times lower. Epigenetic effects of BD were most prominent in C57BL/6J mice where loss of global DNA methylation and loss of trimethylation of histone H3 lysine 9, histone H3 lysine 27, and histone H4 lysine 20, accompanied by dysregulation of liver gene expression indicative of hepatotoxicity, were found. Interestingly, we observed an increase in histone methylation in the absence of changes in gene expression and DNA methylation in CAST/EiJ strain. We hypothesized that mitigated genotoxicity of BD in CAST/EiJ mice may be due to chromatin condensation. Indeed, we show that in response to BD exposure, chromatin condensation occurs in CAST/EiJ, whereas the opposite effect is observed in C57BL/6J mice. These findings demonstrate that interstrain susceptibility to genotoxicity by a well known environmental carcinogen may be due to strain-specific epigenetic events in response to the exposure. PMID- 21602188 TI - Predictive toxicology of cobalt nanoparticles and ions: comparative in vitro study of different cellular models using methods of knowledge discovery from data. AB - The toxicological effects of cobalt nanoparticles (Co-NPs) aggregates were examined and compared with those of cobalt ions (Co-ions) using six different cell lines representing lung, liver, kidney, intestine, and the immune system. Dose-response curves were studied in the concentration range of 0.05-1.0 mM, employing 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide test, neutral red, and Alamar blue as end point assays following exposures for 48 and 72 h. Data analysis and predictive modeling of the obtained data sets were executed by employing a decision tree model (J48), where training and validation were carried out by an iterative process. It was established, as expected, that concentration is the highest rank parameter. This is because concentration parameter provides the highest information gain with respect to toxicity. The second-rank parameter emerged to be either the compound type (Co-ions or Co-NPs) or the cell model, depending on the concentration range. The third and the lowest rank in the model was exposure duration. The hierarchy of cell sensitivity toward cobalt ions was found to obey the following sequence of cell lines: A549 > MDCK > NCIH441 > Caco-2 > HepG2 > dendritic cells (DCs), with A549 being the most sensitive cell line and primary DCs were the least sensitive ones. However, a different hierarchy pattern emerged for Co-NPs: A549 = MDCK = NCIH441 = Caco-2 > DCs > HepG2. The overall findings are in line with the hypothesis that the toxic effects of aggregated cobalt NPs are mainly due to cobalt ion dissolution from the aggregated NPs. PMID- 21602189 TI - Transmembrane transport of microcystin to Danio rerio zygotes: insights into the developmental toxicity of environmental contaminants. AB - Microcystins (MCs) produced by cyanobacteria and their continuing "blooms" are a worldwide problem owing to the toxicity of microcystin-LR (MC-LR) to plants and animals. In the present study, we investigated membrane transport of MC-LR and its toxic effects on zebrafish embryos using fragmentation of embryos, scanning electron microscope (SEM), fluorescence microscopy, and toxic exposure tests. At a concentration < 0.04 mmol/l, MC-LR was predominantly adsorbed on outer membrane surface of embryos according to Langmuir isotherm. The absorption characteristics of MC-LR within the range from 0.05 to 0.4 mmol/l conformed to Freundlich isotherm model. At concentrations > 0.50 mmol/l MC-LR directly entered the cytoplasm via partition. Thinning and disruption of membranes was confirmed using SEM and fluorescence morphological observations. Exposure to different concentrations of MC-LR resulted in differences in membrane transport and toxicity characteristics. At low concentrations, more than 75% of the adsorbed MC LR accumulated on the outer membrane surface and resulted in axial malformation, tail curving, and tail twisting. Increasing the concentration of MC-LR to between 0.05 and 0.4 mmol/l improved membrane transport and it was evident in cytoplasm of embryos, resulting in serious pericardial edema, hatching gland edema, hemagglutination, hemorrhage, and vacuolization. At > 0.50 mmol/l, more than 70% of the adsorbed MC-LR entered the cytoplasm and this was lethal to the embryos. The current research outlines a new method and mechanism for the transmembrane transport of large molecular weight organic compounds and could be important for studies concerning molecular toxicology. PMID- 21602190 TI - Involvement of microRNAs in dioxin-induced liver damage in the mouse. AB - MicroRNA (miRNA) is a class of small RNA that functions as a negative regulator of gene expression. Human and mouse genomes encode over 1400 and 700 miRNAs, respectively, and most of the cellular pathways are considered to be modulated by miRNAs. However, the pathophysiological role of miRNAs is still largely unknown. Thus, we investigated the possible involvement of miRNAs in the toxic responses to xenobiotic chemicals. Here, we searched for miRNAs responsible for inducing liver damage in mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and found that miR-101a and miR-122 are differentially downregulated by TCDD in a time-dependent manner. Because miRNA exerts multiple actions by repressing its target genes, we quantified the target genes of miR-101a, such as cyclooxygenase 2 (COX-2), enhancer of zeste homolog 2, and cFos, and found the upregulation of these genes, which suggests that miR-101a downregulates the expressions of these genes in the mouse liver. A COX-2 selective inhibitor, NS-398, suppressed the onset of TCDD-induced liver damage. In conclusion, this study demonstrated that TCDD dysregulates the expression of miR101a and miR122 and that COX-2, a target gene of miR101a, plays a significant role in liver damage in mice exposed to TCDD. PMID- 21602191 TI - The interplay of the aryl hydrocarbon receptor and beta-catenin alters both AhR dependent transcription and Wnt/beta-catenin signaling in liver progenitors. AB - beta-catenin is a key integrator of cadherin-mediated cell-cell adhesion and transcriptional regulation through the Wnt/beta-catenin pathway, which plays an important role in liver biology. Using a model of contact-inhibited liver progenitor cells, we examined the interactions of Wnt/beta-catenin signaling with the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, which mediates the toxicity of dioxin-like compounds, including their effects on development and hepatocarcinogenesis. We found that AhR and Wnt/beta-catenin cooperated in the induction of AhR transcriptional targets, such as Cyp1a1 and Cyp1b1. However, simultaneously, the activation of AhR led to a decrease of dephosphorylated active beta-catenin pool, as well as to hypophosphorylation of Dishevelled, participating in regulation of Wnt signaling. A sustained AhR activation by its model ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), led to a downregulation of a number of Wnt/beta-catenin pathway target genes. TCDD also induced a switch in cytokeratin expression, where downregulation of cytokeratins 14 and 19 was accompanied with an increased cytokeratin 8 expression. Together with a downregulation of additional markers associated with stem-like phenotype, this indicated that the AhR activation interfered with differentiation of liver progenitors. The downregulation of beta-catenin was also related to a reduced cell adhesion, disruption of E-cadherin-mediated cell-cell junctions and an increased G1-S transition in liver progenitor cell line. In conclusion, although beta-catenin augmented the expression of selected AhR target genes, the persistent AhR activation may lead to downregulation of Wnt/beta catenin signaling, thus altering differentiation and/or proliferative status of liver progenitor cells. PMID- 21602192 TI - Arsenite exposure downregulates EAAT1/GLAST transporter expression in glial cells. AB - Chronic exposure to inorganic arsenic severely damages the central nervous system (CNS). Glutamate (GLU) is the major excitatory amino acid and is highly neurotoxic when levels in the synaptic cleft are not properly regulated by a family of Na+-dependent excitatory amino acid transporters. Within the cerebellum, the activity of the Bergmann glia Na+-dependent GLU/aspartate transporter (GLAST) excitatory amino acid transporter 1 (EAAT1/GLAST) accounts for more than 90% of GLU uptake. Because exposure to the metalloid arsenite results in CNS toxicity, we examined whether EAAT1/GLAST constitutes a molecular target. To this end, primary cultures of chick cerebellar Bergmann glial cells were exposed to sodium arsenite for 24 h, and EAAT1/GLAST activity was evaluated via 3H-D-aspartate uptake. A sharp decrease in GLU transport was observed, and kinetic studies revealed protein kinase A, protein kinase C, and p38 mitogen activated protein kinase-dependent decreases in K(M) and V(max) concomitant with diminished chglast transcription. To gain insight into the molecular mechanisms involved in these phenomena, we investigated the generation of reactive oxidative species and the lipid peroxidative damage caused by arsenite exposure. None of these responses were found, although we did observe an increase in nuclear factor (erythroid-derived 2)-like 2 DNA-binding activity correlated with a rise in total glutathione levels. Our results clearly suggest that EAAT1/GLAST is a molecular target of arsenite and support the critical involvement of glial cells in brain function and dysfunction. PMID- 21602193 TI - Blood gene expression profiling detects silica exposure and toxicity. AB - Blood gene expression profiling was investigated as a minimally invasive surrogate approach to detect silica exposure and resulting pulmonary toxicity. Rats were exposed by inhalation to crystalline silica (15 mg/m3, 6 h/day, 5 days), and pulmonary damage and blood gene expression profiles were determined after latency periods (0-16 weeks). Silica exposure resulted in pulmonary toxicity as evidenced by histological and biochemical changes in the lungs. The number of significantly differentially expressed genes in the blood, identified by microarray analysis, correlated with the severity of silica-induced pulmonary toxicity. Functional analysis of the differentially expressed genes identified activation of inflammatory response as the major biological signal. Induction of pulmonary inflammation, as suggested by the blood gene expression data, was supported by significant increases in the number of macrophages and infiltrating neutrophils as well as the activity of pro-inflammatory chemokines observed in the lungs of the silica-exposed rats. A gene expression signature developed using the blood gene expression data predicted the exposure of rats to lower, minimally toxic and nontoxic concentrations of silica. Taken together, our findings suggest the potential application of peripheral blood gene expression profiling as a minimally invasive surrogate approach to detect pulmonary toxicity induced by silica in the rat. However, further research is required to determine the potential application of our findings specifically to monitor human exposure to silica and the resulting pulmonary effects. PMID- 21602194 TI - Geographic variation: a view from the hospital sector. AB - Efforts to characterize geographic variation in health care utilization and spending have focused on patterns observed with Medicare data. The authors analyzed the Healthcare Cost and Utilization Project national all-payer data for inpatient stays to assess variation in hospitalizations by age groups and, consequently, to understand how utilization of the Medicare population may differ from the population of other payers. The authors found that the correlation between inpatient discharges and costs per capita for the Medicare-eligible population over 65 and younger age groups increased from moderate to strong with age. These findings suggest examining Medicare inpatient data alone may provide a useful but not comprehensive understanding how hospital utilization and costs vary for the total population. PMID- 21602196 TI - Longitudinal analysis of market factors associated with provision of peritoneal dialysis services. AB - Despite the appeal of peritoneal dialysis (PD) among patients, payers, and providers, its use in the United States has been limited and declining. Prior research has found that patient factors explain little variation in PD utilization, and little is known about the contribution of dialysis facility factors. The authors examined market factors associated with the provision of PD services in dialysis facilities between 1995 and 2003. Less than half of dialysis facilities offered PD. PD provision was not explained by disease trends or patient characteristics commonly associated with PD use. Facilities were more likely to offer PD in less competitive and less spatially concentrated markets. PD services may not be available to all patients who would benefit from it and there may be insufficient demand, economics of scale, or incentives for facilities to provide PD. These findings warrant further investigation on dialysis facilities' provision of a preferred, potentially beneficial, and cost effective therapy. PMID- 21602195 TI - Structural estimates of treatment effects on outcomes using retrospective data: an application to ductal carcinoma in situ. AB - Analysis of observational cohort data is subject to bias from unobservable risk selection. The authors compared econometric models and treatment effectiveness estimates using the linked Surveillance, Epidemiology, and End Results (SEER) Medicare claims data for women diagnosed with ductal carcinoma in situ. Treatment effectiveness estimates for mastectomy and breast-conserving surgery (BCS) with or without radiotherapy were compared using three different models: simultaneous equations model, discrete-time survival model with unobserved heterogeneity (frailty), and proportional hazards model. Overall trends in disease-free survival (DFS), or time to first subsequent breast event, by treatment are similar regardless of the model, with mastectomy yielding the highest DFS over 8 years of follow-up, followed by BCS with radiotherapy, and then BCS alone. Absolute rates and direction of bias varied substantially by treatment strategy. DFS was underestimated by single-equation and frailty models compared with the simultaneous-equations model and randomized controlled trial results for BCS with radiotherapy and overestimated for BCS alone. PMID- 21602197 TI - Medicare's payment policy for hospital-acquired conditions: perspectives of administrators from safety net hospitals. AB - In 2008, Medicare implemented a policy limiting reimbursement to hospitals for treating avoidable hospital-acquired conditions (HACs). Although the policy will expand nationally to Medicaid programs in 2011, little is known about the impact on safety net hospitals. The authors conducted interviews with 60 chief quality officers and 55 chief financial officers from safety net hospitals to explore the impact of Medicare's HACs policy during its first year. Despite the predicted small financial impact, the authors found that the policy gained the attention of hospital leaders and many governing boards. Although the policy reportedly provided additional motivation to reduce HACs, few hospitals implemented new care practices and instead focused on documenting conditions that are present for patients on admission. The findings also illustrate the need for Centers for Medicare & Medicaid Services to provide more guidance to the industry when this type of policy is introduced. PMID- 21602198 TI - Implementing small group health insurance reform: the HEALTHpact plan of Rhode Island. AB - This study analyzes administrative impediments to enrollment in HEALTHpact, a high-deductible plan with premiums capped at 10% of the average Rhode Island wage. HEALTHpact includes an opportunity for enrollees to reduce their deductibles from $5,000 ($10,000 for a family) to $750 ($1,500 for a family) if they engage in prespecified wellness behaviors. A stakeholder panel was convened to develop guidelines for insurers, which, in turn, were required to develop products satisfying those guidelines. Implementation was examined using stakeholder interviews and archival documents. Results indicate that since no funds were allocated for education and monitoring, there was little opportunity to promote "bottom up" demand or to oversee insurers. They also indicate that both insurers and brokers adopted strategies that inhibited take-up. Providing the resources necessary for effective government oversight and outreach will be critical to small group market reform nationally. So too will be promoting broker and insurer buy-in. PMID- 21602199 TI - The sexual assault of undergraduate women at historically Black colleges and universities (HBCUs). AB - Although research has shown that undergraduate women are at high risk for experiencing sexual assault, little research has been conducted with undergraduate women who are attending a historically Black college or university (HBCU). The purpose of this research is to document the prevalence of different types of sexual assault among undergraduate women at HBCUs and make comparisons to data collected from undergraduate women at non-HBCUs. Data on sexual assault victimization were collected from 3,951 undergraduate women at HBCUs using a cross-sectional, web-based survey. These data are compared to data collected from 5,446 undergraduate women at non-HBCUs using the same research methods. Findings indicate that approximately 9.7% of undergraduate women at HBCUs report experiencing a completed sexual assault since entering college. This rate is considerably lower than the comparable rate obtained from undergraduate women at non-HBCUs (13.7%). This difference seems to be associated with differences in alcohol-use frequency. Perhaps undergraduate women at HBCUs drink alcohol much less frequently and are thus less likely to be sexually assaulted when they are incapacitated and unable to provide consent. Alcohol use frequency, while controlling for other factors, seems to have an independent association with the likelihood of an undergraduate woman being sexually assaulted. Implications for the creation and delivery of sexual assault risk reduction and prevention policies and programs are discussed. PMID- 21602200 TI - Prevalence and correlates of elder mistreatment in South Carolina: the South Carolina elder mistreatment study. AB - The purposes of this study were to (a) derive prevalence estimates for elder mistreatment (emotional, physical, sexual, neglectful, and financial mistreatment of older adults [age 60 +]) in a randomly selected sample of South Carolinians; (b) examine correlates (i.e., potential risk factors) of mistreatment; and (c) examine incident characteristics of mistreatment events. Random Digit Dialing (RDD) was used to derive a representative sample in terms of age and gender; computer-assisted telephone interviewing was used to standardize collection of demographic, correlate, and mistreatment data. Prevalence estimates and mistreatment correlates were obtained and subjected to logistic regression. A total of 902 participants provided data. Prevalence for mistreatment types (since age 60) were 12.9% emotional, 2.1% physical, 0.3% sexual, 5.4% potential neglect, and 6.6% financial exploitation by family member. The most consistent correlates of mistreatment across abuse types were low social support and needing assistance with daily living activities. One in 10 participants reported either emotional, physical, sexual, or neglectful mistreatment within the past year, and 2 in 10 reported mistreatment since age 60. Across categories, the most consistent correlate of mistreatment was low social support, representing an area toward which preventive intervention may be directed with significant public health implications. PMID- 21602201 TI - The role of adolescent physical abuse in adult intimate partner violence. AB - This study's primary aims were to examine whether a sample of young adults, aged 23 to 31, who had been documented as physically abused by their parent(s) during adolescence would be more likely to aggress, both physically and verbally, against their intimate partners compared with nonabused young adults and whether abuse history was (along with other risk factors) a significant predictor of intimate partner physical and emotional violence perpetration or victimization. In this longitudinal study, 67 abused and 78 nonabused adults (of an original sample of 198 adolescents) completed the Modified Conflict Tactics Scale and the Jealousy and Emotional Control Scales. Nonabused comparison adolescents were matched for age, gender, and community income. As adults, participants with abuse histories had significantly higher rates of intimate partner physical violence and verbal aggression than did comparison participants. Multivariate logistic regressions indicated that adults with histories of physical abuse were more than twice as likely to be physically violent and almost six times more likely to be verbally aggressive to their intimate partners than were comparison participants. Having had an alcohol use disorder, being married to or living with a partner, and perceiving one's partner as controlling were also significantly associated with physical violence. Jealousy and feeling controlled by one's partner were also significant predictors of verbal aggression. These findings underscore the importance of preventing adolescent abuse as a means of decreasing the incidence of intimate partner physical violence in adulthood. PMID- 21602203 TI - Adult sexual assault survivors' experiences with sexual assault nurse examiners (SANEs). AB - Sexual assault survivors often feel traumatized by the care received in traditional hospital emergency departments. To address these problems, Sexual Assault Nurse Examiner (SANE) programs were created to provide comprehensive medical care, crisis intervention, and forensic services. However, there is limited research on the actual experiences and emotional impact of sexual assault survivors who seek treatment from SANEs. This qualitative study examined twenty rape survivors' experiences with forensic nurse examiners of a Midwestern SANE program. Findings suggest that SANEs provided survivors with care and compassion, clear explanations, and choices. Taken together, these positive experiences were perceived as "humanizing". However, some survivors perceived forensic nurses as hurtful when they were not provided with choices, explanation, and/or acted cold and distant. Implications for future research on SANE care and practice are discussed. PMID- 21602202 TI - Is knowledge power? The effects of a victimology course on victim blaming. AB - The current study examines the impact of a victimology course on students' perceptions of the blameworthiness of crime victims and knowledge of victimization issues. Victim-blaming attitudes among college students enrolled in a victimology course were compared with students enrolled in other courses. Results from a pretest and posttest suggest that the victimology students were significantly less likely to blame victims and these students also gained significantly more knowledge over time compared with the students who did not enroll in the course. Results from the multivariate analysis indicate that less knowledge over time and a higher propensity to blame victims at the beginning of the semester predicted more victim-blaming attitudes on the posttest. Overall, the findings suggest that knowledge of victimology significantly affects students' propensity to blame victims of crime. PMID- 21602204 TI - Victimization, posttraumatic stress disorder symptomatology, and later nonsuicidal self-harm in a birth cohort. AB - This longitudinal population-based study examined pathways to nonsuicidal self harm (NSSH) in relation to childhood sexual abuse (CSA), assault victimization in early adulthood, posttraumatic stress disorder symptomatology (PTSD), and other mental disorders. At age 21, 476 men and 455 women completed interviews on assault victimization, PTSD, and other mental disorders. At age 26, they completed independent interviews on self-harm and childhood sexual abuse (CSA). Multivariate logistic regression analyses were conducted to determine predictors for NSSH at age 26. For men, anxiety and depressive disorders at age 21 were the only significant predictors of NSSH at age 26. For women, victimization, PTSD, and other anxiety disorders at age 21 all significantly predicted NSSH. CSA predicted later NSSH only indirectly, by increasing the risk of anxiety disorders among men and of assault victimization among women. In conclusion, pathways to nonsuicidal self-harm differed by sex. For women there were direct links with assault victimization and PTSD in early adulthood, whereas for men only internalizing disorders predicted future NSSH. PMID- 21602205 TI - Gender differences in intended escalatory tendencies among marital partners. AB - This study addresses the intended escalatory tendency in eight hypothetical situations in which the provocator's identity (partner or stranger, male or female) and the provocation form (verbal or physical aggression) were manipulated. The research question is "how does the identity of the provocator and the form of his or her provocation affect the participant's intended escalation level, and does the gender of the participant affect differences in intended escalation level?" The research sample consisted of 208 Israeli couples. The main finding is that women's intended response to their male partner is more escalatory than men's intended response to their female partner. Results also show that women's escalation is the most severe to partner provocation and the least severe to male strangers' provocation. Men's escalation is the most severe to provocation by male strangers and the least severe to their partner's provocation. Findings indicate that men's intention to escalate decreases as their partner's provocation becomes more severe. The severity of provocation has little effect on women's inten-tion to escalate. Such results are consistent with social role theory and sexual selection theory that maintain that status enhancement is more important for men than for women, and is more important for men than risk reduction is, whereas the opposite is true for women. PMID- 21602206 TI - Interpersonal violence as social construction: the potentially undermining role of claims making and advocacy statistics. AB - The relationship between empirical research inquiry and advocacy efforts is complex and seldom addressed in the interpersonal violence literature. In this article, we first examine how social conditions come to be seen as social problems, using a social constructionist perspective. Next, we focus specifically on the problem of interpersonal violence as viewed through a social constructionist lens, highlighting the many ways in which advocacy has influenced public perceptions of interpersonal violence as a social problem. Finally, this article considers some of the consequences that may result from exaggerated or misleading claims, especially when they are made by social scientists who are presumably engaged in an objective discussion of a problem. These consequences include generating skepticism toward the social sciences, feeding a backlash movement, and diverting attention away from the most severe forms of interpersonal violence. Contrary to the goals of many advocates, some of these consequences may be detrimental to the very social problems they hope to alleviate. PMID- 21602207 TI - Intergenerational child abuse and coping. AB - Many studies have investigated the consequences of child sexual abuse (CSA) but few have examined the intergenerational effects of poly- victimization and maladaptive coping. The purpose of this investigation was to examine patterns of maltreatment and maladaptive coping among second-generation CSA survivors. It is hypothesized that: (a) maternal CSA history would be associated with a higher incidence of poly-victimization and maladaptive coping and (b) experiencing more forms of abuse would mediate the relation between maternal CSA history and maladaptive coping behaviors. The method used was a chart review of 139 sexually abused females aged 12 to 17, examining maternal abuse history, maladaptive coping behaviors, and child maltreatment. The results showed that poly victimization differed as a function of maternal CSA history but maladaptive coping did not. Experiencing more types of abuse was associated with both self injurious behaviors and substance use. In conclusion, results support the hypothesis that second generation CSA survivors are more likely to experience poly-victimization. Future research should address how intergenerational patterns of abuse might affect presenting symptomatology and treatment outcome. PMID- 21602208 TI - Effects of childhood adversity on bullying and cruelty to animals in the United States: findings from a national sample. AB - This study examined effects of type of and cumulative burden of childhood adversities on bullying and cruelty to animals in the United States. Data were derived from Waves I and II of the National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative sample of U.S. adults. Structured psychiatric interviews were completed by trained lay interviewers between 2001 2002 and 2003-2004. Although the effects of childhood adversity diminished with the inclusion of confounding variables, several adversities remained significant. For bullying, these included being made to do chores that were too difficult or dangerous, threatening to hit or throw something, pushing, shoving, slapping, or hitting, and hitting that left bruises, marks, or injuries. With respect to cruelty to animals, swearing and saying hurtful things, having a parent or other adult living within the home that went to jail or prison, and adult/other person fondling/touching in a sexual way were significant. The final models indicated that the cumulative burden of childhood adversities had strong effects on the increased likelihood of bullying behavior but not cruelty to animals. PMID- 21602209 TI - Unwanted sex among young adults in the United States: the role of physical disability and cognitive performance. AB - This study examined associations between unwanted sexual experiences and both physical disability and cognitive performance in a nationally representative sample of young adults. We used data from 11,878 participants (ages 26-32) in Waves I, III, and IV of the National Longitudinal Study of Adolescent Health (Add Health). Logistic regressions determined associations between physical disability and level of cognitive performance (using a modified Peabody Picture Vocabulary Test) and the odds of experiencing physically forced and nonphysically coerced sex. Approximately 24% of females and 4% of males reported unwanted sexual experiences. Compared to respondents without disabilities, females with a physical disability had greater odds of experiencing forced sex (OR = 1.49; 95% CI [1.06, 2.08]), whereas males with a physical disability had greater odds of coerced sex (OR = 1.90; 95% CI [1.02, 3.52]). Compared to those with average cognitive performance scores, females with scores above 110 had slightly higher odds of coerced sex (OR = 1.20; 95% CI [1.03-1.41]). Further research on pathways underlying these associations is needed to inform prevention efforts. PMID- 21602210 TI - The correlation of childhood physical abuse history and later abuse in a group of Turkish population. AB - Domestic violence is passed from one generation to the next, and it affects not only the victim but also the psychological states of the witnesses, and especially the psychosocial development of children. Studies have reported that those who have been the victim of or witnessing violence during their childhood will use violence to a greater extent as adults in their own families. This research examines the relationships between a history of childhood physical abuse, likelihood of psychiatric diagnoses, and potential for being a perpetrator of childhood physical abuse in adulthood among women who received psychiatric treatment and in the healthy population from Turkey. Estimates of the prevalence of childhood physical abuse vary depending on definition and setting. The frequency of witnessing and undergoing physical abuse within the family during childhood is much higher in the psychiatrically disordered group than the healthy controls. Childhood physical abuse history is one of the major risk factors for being an abuser in adulthood. The best indicator of physically abusing one's own children was found to be as physical abuse during the childhood period rather than psychiatric diagnosis. There is a large body of research indicating that adults who have been abused as children are more likely to abuse their own children than adults without this history. This is an important study from the point of view that consequences of violence can span generations. Further studies with different risk factor and populations will help to identify different dimensions of the problem. PMID- 21602211 TI - Posttraumatic anger, recalled peritraumatic emotions, and PTSD in victims of violent crime. AB - A mixed cross-sectional and longitudinal design was employed to explore the association between posttraumatic anger and posttraumatic stress disorder (PTSD; symptoms) in victims of civilian violence. It was speculated that this relationship is mainly due to concurrent recalled peritraumatic emotions. Such emotions may be interpreted to result from anger-rooted threat perceptions and to share similarities with posttraumatic intrusion symptoms. In addition, predictors of PTSD maintenance were investigated. Cross-sectional data indicated that posttraumatic anger and several indices of PTSD were highly interconnected. Recalled peritraumatic emotions partly accounted for the relation between posttraumatic anger and posttraumatic intrusions (n = 177). Only posttraumatic intrusions were associated with PTSD symptom persistence at follow-up (n = 56). Findings were discussed in light of study limitations and directions for future research. PMID- 21602212 TI - Role of zonadhesin during sperm-egg interaction: a species-specific acrosomal molecule with multiple functions. AB - Sperm-zona adhesion is an essential event in mammalian fertilization, failure of which causes sterility. However, the molecular mechanisms involved in this process are still poorly understood. It has been suggested by few laboratories studying gamete interaction that acrosomal molecules are implicated in sperm-zona pellucida adhesion prior to the acrosome reaction (AR). Zonadhesin, a sperm specific protein located in the acrosome is critically involved in zona binding. Here we describe the cellular and molecular interaction of zonadhesin during fertilization and also discuss its role in species-specific gamete interaction- an intriguing question in biology. We propose a model in which sperm could transiently expose acrosomal molecules that adhere to the zona independently of the AR in a 'kiss and run' mechanism. This could be a valuable framework for further investigations and a detailed understanding of the molecular events during gamete adhesion is likely to provide new approaches for the design of more effective male contraceptives and better diagnostic methods for sperm dysfunction. PMID- 21602214 TI - Selection of hyperadherent mutants in Pseudomonas putida biofilms. AB - A number of genetic determinants required for bacterial colonization of solid surfaces and biofilm formation have been identified in different micro-organisms. There are fewer accounts of mutations that favour the transition to a sessile mode of life. Here we report the isolation of random transposon Pseudomonas putida KT2440 mutants showing increased biofilm formation, and the detailed characterization of one of them. This mutant exhibits a complex phenotype, including altered colony morphology, increased production of extracellular polymeric substances and enhanced swarming motility, along with the formation of denser and more complex biofilms than the parental strain. Sequence analysis revealed that the pleiotropic phenotype exhibited by the mutant resulted from the accumulation of two mutations: a transposon insertion, which disrupted a predicted outer membrane lipoprotein, and a point mutation in lapG, a gene involved in the turnover of the large adhesin LapA. The contribution of each alteration to the phenotype and the possibility that prolonged sessile growth results in the selection of hyperadherent mutants are discussed. PMID- 21602213 TI - BgaA acts as an adhesin to mediate attachment of some pneumococcal strains to human epithelial cells. AB - Streptococcus pneumoniae colonization of the respiratory tract is an essential precursor for pneumococcal disease. To colonize efficiently, bacteria must adhere to the epithelial-cell surface. S. pneumoniae possesses surface-associated exoglycosidases that are capable of sequentially deglycosylating human glycans. Two exoglycosidases, neuraminidase (NanA) and beta-galactosidase (BgaA), have previously been shown to contribute to S. pneumoniae adherence to human epithelial cells, as deletion of either of these genes results in reduced adherence. It has been suggested that these enzymes may modulate adherence by cleaving sugars to reveal a receptor on host cells. Pretreatment of epithelial cells with exogenous neuraminidase restores the adherence of a nanA mutant, whereas pretreatment with beta-galactosidase does not restore the adherence of a bgaA mutant. These data suggest that BgaA may not function to reveal a receptor, and implicate an alternative role for BgaA in adherence. Here we demonstrate that beta-galactosidase activity is not required for BgaA-mediated adherence. Addition of recombinant BgaA (rBgaA) to adherence assays and pretreatment of epithelial cells with rBgaA both significantly reduced the level of adherence of the parental strain, but not the BgaA mutant. One possible explanation of these data is that BgaA is acting as an adhesin and that rBgaA is binding to the receptor, preventing bacterial binding. A bead-binding assay demonstrated that BgaA can bind directly to human epithelial cells, supporting the hypothesis that BgaA is an adhesin. Preliminary characterization of the epithelial-cell receptor suggests that it is a glycan in the context of a glycosphingolipid. To further establish the relevance of this adherence mechanism, we demonstrated that BgaA-mediated adherence contributed to adherence of a recent clinical isolate to primary human epithelial cells. Together, these data suggest a novel role for BgaA as an adhesin and suggest that this mechanism could contribute to adherence of at least some pneumococcal strains in vivo. PMID- 21602216 TI - Hyphal induction in the human fungal pathogen Candida albicans reveals a characteristic wall protein profile. AB - The ability of Candida albicans to switch from yeast to hyphal growth is essential for its virulence. The walls and especially the covalently attached wall proteins are involved in the primary host-pathogen interactions. Three hyphal induction methods were compared, based on fetal calf serum, the amino sugar N-acetylglucosamine (GlcNAc) and the mammalian cell culture medium Iscove's modified Dulbecco's medium (IMDM). GlcNAc and IMDM were preferred, allowing stable hyphal growth over a prolonged period without significant reversion to yeast growth and with high biomass yields. We employed Fourier transform-MS combined with a (15)N-metabolically labelled reference culture as internal standard for relative quantification of changes in the wall proteome upon hyphal induction. A total of 21 wall proteins were quantified. Our induction methods triggered a similar response characterized by (i) a category of wall proteins showing strongly increased incorporation levels (Als3, Hwp2, Hyr1, Plb5 and Sod5), (ii) another category with strongly decreased levels (Rhd3, Sod4 and Ywp1) and (iii) a third one enriched for carbohydrate-active enzymes (including Cht2, Crh11, Mp65, Pga4, Phr1, Phr2 and Utr2) and showing only a limited response. This is, to our knowledge, the first systematic, quantitative analysis of the changes in the wall proteome of C. albicans upon hyphal induction. Finally, we propose new wall-protein-derived candidates for vaccine development. PMID- 21602215 TI - Helicobacter pylori perceives the quorum-sensing molecule AI-2 as a chemorepellent via the chemoreceptor TlpB. AB - Helicobacter pylori moves in response to environmental chemical cues using a chemotaxis two-component signal-transduction system. Autoinducer-2 (AI-2) is a quorum-sensing signal produced by the LuxS protein that accumulates in the bacterial environment in a density-dependent manner. We showed previously that a H. pylori luxS mutant was defective in motility on soft agar plates. Here we report that deletion of the luxS gene resulted in swimming behaviour with a reduced frequency of stops as compared to the wild-type strain. Stopping frequency was restored to wild-type levels by genetic complementation of the luxS mutation or by addition of synthetic 4,5-dihydroxy-2,3-pentanedione (DPD), which cyclizes to form AI-2. Synthetic DPD also increased the frequency of stops in wild-type H. pylori, similar to the behaviour induced by the known chemorepellent HCl. We found that whereas mutants lacking the chemoreceptor genes tlpA, tlpC or tlpD responded to an exogenous source of synthetic DPD, the chemoreceptor mutant tlpB was non-responsive to a gradient or uniform distribution of the chemical. Furthermore, a double mutant lacking both tlpB and luxS exhibited chemotactic behaviour similar to the tlpB single mutant, whereas a double mutant lacking both tlpB and the chemotransduction gene cheA behaved like a nonchemotactic cheA single mutant, supporting the model that tlpB functions in a signalling pathway downstream of luxS and upstream of cheA. We conclude that H. pylori perceives LuxS-produced AI-2 as a chemorepellent via the chemoreceptor TlpB. PMID- 21602217 TI - Identification of a novel subgroup of uncultured gammaproteobacterial glycogen accumulating organisms in enhanced biological phosphorus removal sludge. AB - The presence of glycogen-accumulating organisms (GAO) has been hypothesized to be a cause of deterioration in enhanced biological phosphorus removal (EBPR) processes due to their abilities to out-compete polyphosphate-accumulating organisms (PAO). Based on 16S rRNA gene sequences, new members of uncultured gammaproteobacterial GAO (GB) were identified from sludge samples of a lab-scale sequencing batch reactor used for EBPR. The new GB formed a phylogenetic lineage (GB8) clearly distinct from the previously reported seven GB subgroups. Because the new GB8 members were not targeted by the known fluorescence in situ hybridization (FISH) oligonucleotide probes, a GB8-specific FISH probe (GB429) and a new FISH probe (GB742) targeting all eight GB subgroups were designed, and the phenotypic properties of the new GB8 members were investigated. FISH and microautoradiography approaches showed that GB429-targeted cells (GB8) were large coccobacilli (2-4 um in size) with the ability to take up acetate under anaerobic conditions, but unable to accumulate polyphosphate under the subsequent aerobic conditions, consistent with in situ phenotypes of GB. FISH analyses on several sludge samples showed that members of GB8 were commonly detected as the majority of GB in lab- and full-scale EBPR processes. In conclusion, this study showed that members of GB8 could be a subgroup of GB with an important role in EBPR deterioration. Designs of FISH probes which hybridize with broader GB subgroups at different hierarchical levels will contribute to studies of the distributions and ecophysiologies of GB in lab- or full-scale EBPR plants. PMID- 21602219 TI - Identification of the in vitro target of an iron-responsive AraC-like protein from Neisseria meningitidis that is in a regulatory cascade with Fur. AB - In this study we characterized a genetic locus that is predicted to encode one of the three AraC-like regulators of Neisseria meningitidis, a homologue of MpeR of Neisseria gonorrhoeae which is specific to the pathogenic Neisseria species. Previous microarray studies have suggested that this gene is a member of the Fur regulon. In strain MC58, it is a pseudogene (annotated as two ORFs, NMB1879 and NMB1878) containing a frameshift mutation which we show is common to all strains tested belonging to the ST-32 hypervirulent clonal complex. Using primer extension and S1 nuclease protection assays, we mapped two promoters in the upstream intergenic region: the mpeR promoter and the NMB1880 promoter. The latter promoter drives transcription of the divergent upstream locus, which is predicted to encode a high-affinity iron uptake system. We demonstrated that both promoters are induced during iron limitation and that this regulation is also mediated by the Fur regulator. DNA-binding studies with the purified MpeR protein revealed that it binds to a region directly upstream of the NMB1880 divergent promoter, suggesting a role in its regulation. Mutants of N. meningitidis strains lacking MpeR or overexpressing MpeR showed no significant differences in expression of the P(NMB1880) promoter, nor did global transcriptional profiling of an MpeR knockout identify any deregulated genes, suggesting that the MpeR protein is inactive under the conditions used in these experiments. The presence of MpeR in a regulatory cascade downstream of the Fur master iron regulator implicates it as being expressed in the iron-limiting environment of the host, where it may in turn regulate a group of genes, including the divergent iron transport locus, in response to signals important for infection. PMID- 21602218 TI - Regulation of D-alanylation of lipoteichoic acid in Streptococcus gordonii. AB - d-Alanyl esters on lipoteichoic acid (LTA) are involved in adhesion, biofilm formation, resistance to cationic antimicrobial peptides, and immune stimulation. There is evidence that bacteria can modulate the level of d-alanyl esters on LTA in response to challenge, but the mechanism of regulation appears to be different among bacteria. In this study, expression of the dlt operon responsible for d alanylation of LTA was examined in the commensal bacterium Streptococcus gordonii. dlt expression was assessed using the dlt promoter-lacZ reporter gene assay, LTA d-alanine content measurements and dlt mRNA quantification. The results showed that dlt expression was growth phase-dependent, with the greatest expression at the mid-exponential phase of growth. In contrast to Staphylococcus aureus, dlt expression in Strep. gordonii was not affected by the exogenous addition of Mg(2+) or K(+). Interestingly, dlt expression was upregulated under acidic conditions or when cells were stressed with polymyxin B, indicating that cell envelope stress may be a signal for dlt expression. In view of these results, mutants defective in the cell envelope stress LiaSR two-component regulatory system were constructed. The liaS and liaR mutants showed an increase in dlt expression over the parent strain at neutral pH. The mutants failed to respond to low pH and polymyxin B stress; dlt expression remained the same in the presence or absence of these stresses. These results suggest that dlt expression in Strep. gordonii is regulated by the LiaSR regulatory system in response to environmental signals such as pH and polymyxin B. The regulation appears to be complex, involving both repression and activation mechanisms. PMID- 21602220 TI - Single-cell analysis in situ in a Bacillus subtilis swarming community identifies distinct spatially separated subpopulations differentially expressing hag (flagellin), including specialized swarmers. AB - The non-domesticated Bacillus subtilis strain 3610 displays, over a wide range of humidity, hyper-branched, dendritic, swarming-like migration on a minimal agar medium. At high (70 %) humidity, the laboratory strain 168 sfp+ (producing surfactin) behaves very similarly, although this strain carries a frameshift mutation in swrA, which another group has shown under their conditions (which include low humidity) is essential for swarming. We reconcile these different results by demonstrating that, while swrA is essential for dendritic migration at low humidity (30-40 %), it is dispensable at high humidity. Dendritic migration (flagella- and surfactin-dependent) of strains 168 sfp+ swrA and 3610 involves elongation of dendrites for several hours as a monolayer of cells in a thin fluid film. This enabled us to determine in situ the spatiotemporal pattern of expression of some key players in migration as dendrites develop, using gfp transcriptional fusions for hag (encoding flagellin), comA (regulation of surfactin synthesis) as well as eps (exopolysaccharide synthesis). Quantitative (single-cell) analysis of hag expression in situ revealed three spatially separated subpopulations or cell types: (i) networks of chains arising early in the mother colony (MC), expressing eps but not hag; (ii) largely immobile cells in dendrite stems expressing intermediate levels of hag; and (iii) a subpopulation of cells with several distinctive features, including very low comA expression but hyper-expression of hag (and flagella). These specialized cells emerge from the MC to spearhead the terminal 1 mm of dendrite tips as swirling and streaming packs, a major characteristic of swarming migration. We discuss a model for this swarming process, emphasizing the importance of population density and of the complementary roles of packs of swarmers driving dendrite extension, while non-mobile cells in the stems extend dendrites by multiplication. PMID- 21602221 TI - The components of helping relationships with professionals in psychiatry: users' perspective. AB - BACKGROUND: The quality of the relationship between professional and user is one of the important factors in the recovery process. However, more knowledge is needed concerning the components of helping relationships and characteristics of the helping professional. The aim of this study was to explore users' experiences of helping relationships with professionals. DATA AND METHODS: This was a grounded theory analysis of 71 qualitative interviews to explore users' experience of helping relationships and their components, in psychiatric care in Sweden. DISCUSSION: Within the three main categories - interpersonal continuity, emotional climate and social interaction - two core themes were found that described vital components of helping relationships: a non-stigmatizing attitude on the part of the professionals and their willingness to do something beyond established routines. CONCLUSIONS: The focus in psychiatric treatment research needs to be broadened. In addition to research on the outcome of particular methods and interventions, the common factors also need to be investigated, above all, what is the effect of the quality of the relationship between user and professional. Greater attention needs to be paid, as well, to how helping respective obstructive relationships in psychiatric services arise, are maintained or are modified. PMID- 21602222 TI - Unemployment and mental health--who is (not) affected? AB - BACKGROUND: The aim of this study is first, to investigate the association between periods of unemployment and mental distress, adjusting for previous health status, and second, to study differences and similarities between groups defined by age, sex, family situation, socioeconomic position and work environment. METHODS: The analyses are based on a cohort of participants in Stockholm county council's Public Health Survey 2002 with a follow-up in 2007. Selected from the initial cohort are respondents 20-59 years who were employed at T1 and had no unemployment in 2001-02. Logistic regression is used and differences between groups are expressed as odds ratios. Interaction analyses are also performed. RESULTS: Initial odds ratios of 1.84 in the group with 1 year of unemployment or more compared to the reference group with no unemployment is reduced to 1.52 after adjustment for prior mental and somatic health. Analyses show that the impact of unemployment in this sample is stronger for men, those working overtime, those with high social support or low control at their previous job, self-employed and those with low occupational class or low previous wage. Regarding family situation, unemployment is least associated with mental distress among individuals living in couples without children. CONCLUSION: Results show an independent effect of unemployment on mental distress, but this effect varies between groups. Both proposed theories: role loss and differential susceptibility, receive some support. Since all interaction analyses are insignificant, results should be interpreted with caution. PMID- 21602223 TI - Changes in healthy food habits after transition to old age retirement. AB - BACKGROUND: Retirement is one of the major transitions in the life course. However, it is poorly understood how health behaviours, such as food habits, might change after retirement. This study aimed to examine whether healthy food habits change after the transition to old age retirement and whether socio demographic or health-related factors explain the association between retirement, being continuously employed and healthy food habits at follow-up. METHODS: The data were derived from the Helsinki Health Study cohort on the staff of the City of Helsinki, Finland. The baseline questionnaire survey data were collected in 2000-02 and the follow-up in 2007. We included only participants who were aged 55 60 years at baseline and entered old age retirement during the follow-up (n = 1156, 76% women) or remained continuously employed (n = 1269, 79% women). Food habits from a food frequency questionnaire included eight items formed according to the Finnish and Nordic dietary recommendations. Logistic regression models were fitted to examine the associations between retirement, being continuously employed and healthy food habits at follow-up. RESULTS: Healthy food habits increased more among retired women than those continuously employed (P = 0.03). At follow-up retired women had healthier food habits than continuously employed women after adjusting for baseline food habits [OR = 1.36 (1.12-1.65)]. Among men, healthy food habits were unassociated with retirement. CONCLUSION: Transition to old age retirement is likely to have beneficial effects on food habits among women. This helps prevent major diseases and supports better public health among ageing people. PMID- 21602225 TI - Non-communicable diseases--neglected diseases in global health work? PMID- 21602224 TI - Mortality from circulatory diseases by specific country of birth across six European countries: test of concept. AB - BACKGROUND: Important differences in cardiovascular disease (CVD) mortality by country of birth have been shown within European countries. We now focus on CVD mortality by specific country of birth across European countries. METHODS: For Denmark, England and Wales, France, The Netherlands, Scotland and Sweden mortality information on circulatory disease, and the subcategories of ischaemic heart disease, and cerebrovascular disease, was analysed by country of birth. Information on population was obtained from census data or population registers. Directly age-standardized rates per 100 000 were estimated by sex for each country of birth group using the WHO World Standard population 2000-25 structure. For differences in the results, at least one of the two 95% confidence intervals did not overlap. RESULTS: Circulatory mortality was similar across countries for men born in India (355.7 in England and Wales, 372.8 in Scotland and 244.5 in Sweden). For other country of birth groups-China, Pakistan, Poland, Turkey and Yugoslavia-there were substantial between-country differences. For example, men born in Poland had a rate of 630.0 in Denmark and 499.3 in England and Wales and 153.5 in France; and men born in Turkey had a rate of 439.4 in Denmark and 231.4 in The Netherlands. A similar pattern was seen in women, e.g. Poland born women had a rate of 264.9 in Denmark, 126.4 in England and Wales and 54.4 in France. The patterns were similar for ischaemic heart disease mortality and cerebrovascular disease mortality. CONCLUSION: Cross-country comparisons are feasible and the resulting findings are interesting. They merit public health consideration. PMID- 21602226 TI - When the official drug policy failed: self-organization of the people to defend public health interest. PMID- 21602227 TI - Patient information under the EU patients' rights Directive. PMID- 21602228 TI - The quality and safety paradox in the patients' rights Directive. PMID- 21602229 TI - Common features of melamine-associated urinary stones: a summary of available information based on biochemical and ultrasonographic evidence. PMID- 21602230 TI - Oxidative stress in children with severe malaria. AB - Fifty cases of severe malaria were studied for their oxidant and antioxidant status. Severe anemia (54%) was the most common presentation followed by hyperpyrexia, cerebral malaria and jaundice. Plasma malondialdehyde, protein carbonyl, nitrite, ascorbic acid and copper levels were significantly raised in cases as compared with controls (p < 0.001). Plasma ceruloplasmin, glutathione and superoxide dismutase levels were significantly decreased in children with severe malaria (p < 0.001). Plasma zinc was increased in cases but difference is not statistically significant. Significantly decreased level of nitrites and increased value of glutathione was found in patients with hemoglobinuria and jaundice, respectively. The significantly elevated malondialdehyde and protein carbonyl levels reflect the increased oxidative stress, whereas decreased levels of glutathione and superoxide dismutase point toward utilization of the antioxidants in severe malaria. Thus, changes in oxidants and antioxidants observed suggest the production of reactive oxygen species and their possible role in pathogenesis of severe malaria. PMID- 21602233 TI - Reliability of AcuGraph system for measuring skin conductance at acupoints. AB - OBJECTIVE: There are many commercially available instruments for measuring electrical conductance, but there is little information about their reliability. The aim of this study was to quantify measurement variability and assess reliability of the AcuGraph system-a commonly used electrodermal screening device. METHODS: Four experiments were conducted to measure variability in electrical conductance readings obtained by the AcuGraph system. The first involved measuring known resistors. The second measured non-human organic matter. The third was a test-retest assessment of the Yuan-Source and Jing-Well points in 30 healthy volunteers who were measured by a single operator. The fourth was an interoperator reliability evaluation of seven acupuncturists at the Yuan-Source and Jing-Well acupoints on four individuals at two time points. RESULTS: Against known resistors, the AcuGraph had an average coefficient of variability (CV) of 1.8% between operators and test-retests. On non-human organic material the AcuGraph had an average CV of 0.9% and 2.8%. When a single operator tested 30 participants, the average reliability for the Yuan-Source points was 0.86 and 0.76 for Jing-Well points with a CV of 23.2% and 25.9% respectively. The average CV for the seven acupuncturists was 24.5% on Yuan-Source points and 23.7% on Jing Well points. CONCLUSIONS: The AcuGraph measures known resistors and organic matter accurately and reliably. Skin conductance at acupoints recorded by one operator was also reliable. There was less consistency in electrodermal recordings obtained by seven different operators. Operator training and technical improvements to the AcuGraph may improve consistency among operators. PMID- 21602234 TI - Otorrhoea. PMID- 21602235 TI - Government may give "range" of scenarios in pandemics rather than "worst case" predictions only. PMID- 21602236 TI - Spanish government approves draft bill regulating terminal care. PMID- 21602237 TI - New network hopes to define role of health systems in controlling infectious diseases. PMID- 21602241 TI - Israel's health maintenance organisations will have to publish their performance data. PMID- 21602242 TI - Outbreak of measles in France shows no signs of abating. PMID- 21602243 TI - People with HIV in China are routinely denied medical treatment. PMID- 21602245 TI - Health bill should include commitment to promote medical research, say research leaders. PMID- 21602246 TI - I can't get my husband to go and have a colonoscopy: gender and screening for colorectal cancer. AB - It is anticipated that a colorectal cancer (CRC) screening programme will be introduced in New Zealand making it the first screening programme in this country to include both males and females. In-depth interviews were carried out with 80 participants (53 females and 27 males) about their knowledge and attitudes to screening programmes in general, as well as their understanding and perceptions of CRC screening in particular. The study highlighted the perceived marginalization of men's health with a sense that women had advocated for, and therefore monopolized, screening while men's health had been left unattended. There were also perceptions of women's responsibility for ensuring men's access to health services. There are arguments that such perceptions disempower or 'infantalize' men which have no long term benefits. While health is perceived as being a feminine matter, it may be difficult to encourage men to engage in preventative behaviours, such as taking up the offer of screening. This article also highlights the heterogeneity of men, where different performances of masculinities were presented. A stereotypical 'staunch' or 'macho image' discourse was evident in some of the interviews where much emphasis was on maintaining and controlling bodily boundaries. Letting the barrier of embodied 'staunchness' down to access health services is a threat to identity. What is required for successful implementation of the CRC screening programme is a normalization of men's health help-seeking, taking into account the fact that men are not homogenous. Studies in relation to men's health need to attend to cultural diversity which is likely to present a challenge to individualism. Critical studies of men would be enhanced by more engagement with the work of black male scholars. PMID- 21602247 TI - The rise of cancer in urban India: Cultural understandings, structural inequalities and the emergence of the clinic. AB - Cancer services in India have evolved and expanded significantly in recent years, with a surge in the availability of biomedical oncological treatment facilities for certain cohorts of the Indian population in urban areas. Despite significant and sustained economic development in many areas of India, major issues persist in the delivery of cancer care, even in the context of relatively prosperous urban populations. This article explores the dilemmas evident in Indian cancer care as perceived by a group of Indian oncology clinicians. Specifically, the interviews focused on their perspectives on the key challenges facing cancer patients, particularly in relation to help-seeking and access to care. The main concerns that emerged in the interviews were: (a) practical constraint (i.e. access and treatment); (b) cultural values (i.e. communication, stigma and the clinic); and (c) structural conditions (i.e. inequalities related to place, gender and class). We unpack these as important elements of cancer care in contemporary India, and present Farmer's notion of structural violence, among other concepts, as potentially useful for understanding some facets of this social problem. We conclude that without a greater understanding of social and cultural issues shaping cancer care in India, little progress will be made in coping with a disease that is set to become a major burden within an increasingly prosperous and ageing population. PMID- 21602248 TI - Beyond the caveman: rethinking masculinity in relation to men's help-seeking. AB - Statistically, men make less use of health-care services than women. This has been interpreted as the result of the 'hegemonic' masculine code in which 'real' men are understood to be physically fit, uninterested in their health and self reliant. However, less attention has been paid to understanding how hegemonic masculinity intersects with the wider western socio-cultural contexts of men's help-seeking, particularly the valorization of health as a form of social achievement. This article presents the results of interviews with 14 higher socio economic status (SES) men to uncover their 'interpretive repertoires' in relation to health and illness, help-seeking and masculinity. Although many interviewees drew on the stereotype of the 'Neanderthal Man' who avoids the doctors to explain help-seeking by men 'in general', they constructed their own experiences of help seeking in terms of being responsible, problem-solving and in control. It is argued that the framing of help-seeking in terms of 'taking action' chimes with an increasingly pro-active 'expert patient' approach within western health-care. This conceptual reconstruction of the dominant masculine code in relation to help seeking, from 'Neanderthal Man' to 'Action Man', may lead to greater gender equality in terms of accessing health-care. However, it has the potential to exacerbate social inequalities between men from different SES groups. PMID- 21602249 TI - The pursuit of medical knowledge and the potential consequences of the hidden curriculum. AB - This study explores how preclinical medical students experience particular elements of their training, specifically their pursuit for medical knowledge and how this may impact their attributes as well as their relations with those outside of the realm of medicine. Ten first-year and 10 second-year students of a US medical school were interviewed regarding their experiences with and perceptions of their medical training. The students reported a cognitive and emotional distance from non-medical students that appears to be accentuated not only by their strenuous academic responsibilities but also elements of the hidden curriculum nested within medical training. Furthermore, students discuss experiencing disapproval, mistrust, and negative judgment toward laypersons thereby suggesting that this distancing may lend to deleterious effects on students' ability and willingness to connect with others. A Parsonian lens is utilized to examine the notion of a 'Knowledge Gap' as well as aspects of the hidden curriculum in medical education and their role in professionalizing medical students. PMID- 21602250 TI - Healthcare experiences of families affected by Huntington disease: need for improved care. AB - OBJECTIVES: To explore the healthcare experiences of families affected by Huntington disease (HD), a fatal neurodegenerative genetic disorder, and elicit their suggestions for improvement in the quality of care provided to them. METHODS: 24 semi-structured interviews were completed with members of families affected by HD in Eastern Canada. The sample was chosen to reflect a wide range of experiences with HD (e.g. patients, caregivers, family members at risk, but asymptomatic). RESULTS: Complex needs for healthcare services and emotional supports were found. Participants expressed frustration at the lack of knowledge about HD displayed by their family physicians. They described numerous difficulties accessing appropriate healthcare and other supports, and anticipated access difficulties in the future. Participants offered several suggestions to improve the quality of care to their families, including better education of healthcare professionals about the complex nature of HD and the provision of regular follow-up support. DISCUSSION: Health service planners and policy makers must recognize that HD is a debilitating, complicated illness requiring a high degree of care. Sustained follow-up support from knowledgeable healthcare professionals is required from the initial discovery of HD in the family, throughout a lengthy disease trajectory that normally ends with institutionalization. PMID- 21602251 TI - A glass-reinforced hydroxyapatite and surgical-grade calcium sulfate for bone regeneration: In vivo biological behavior in a sheep model. AB - A glass-reinforced hydroxyapatite (HA) composite (Bonelike(r)) was developed for bone grafting. This biomaterial is composed of a modified HA matrix with alpha- and beta-tricalcium phosphate secondary phases, resulting in higher solubility than single HA type of materials. Several in vitro and in vivo studies demonstrated that Bonelike(r) has a highly bioactive behavior, which was also confirmed by employing granular forms of this biomaterial in orthopedics and dental applications. However, a fast consolidation vehicle was needed to promote the fixation of Bonelike(r) granules if applied in larger defects or in unstable sites. Surgical-grade calcium sulfate (CS), which is widely recognized as a well tolerated and inexpensive bone graft material, was the chosen vehicle to improve the handling characteristics of Bonelike(r) as it can be used in the form of a powder that is mixed with a liquid to form a paste that sets in situ. After application in non-critical monocortical defects in sheep, histological, and scanning electron microscopy evaluations demonstrated that Bonelike(r) associated to CS functioned as a very satisfactory scaffold for bone regeneration as it achieved synchronization of the ingrowing bone with biomaterial resorption and subsequent preservation of the bone graft initial volume. Therefore, our results indicate that CS is an effective vehicle for Bonelike(r) granules as it facilitates their application and does not interfere with their proven highly osteoconductive properties. In the opposite way, the incorporation of Bonelike(r) improves the bone regeneration capabilities of CS. PMID- 21602252 TI - Pharmacomechanical thrombolysis of acute and chronic symptomatic deep vein thrombosis: a systematic review of literature. AB - Pharmacomechanical thrombolysis (PMT) is an emerging treatment option for symptomatic deep vein thrombosis (DVT). This may obviate the need for systemic or catheter-directed thrombolysis. PubMed, EMBASE, and Cochrane database search of PMT in acute and chronic symptomatic DVT was undertaken. Baseline demographic and clinical characteristics, procedural details, DVT characteristics, and procedural and clinical outcomes are presented. A total of 8 case series (n = 2528; 1998 2009) qualified for inclusion. Lower extremity symptomatic DVTs constituted the majority of the cases (>80%). Both acute (<14 days) and chronic (>14 days) DVTs were included. Procedural success was 59% to 100% and catheter-directed thrombolysis was used as an adjunct in 16% to 53%. No deaths or major bleeding complications were reported. Pharmacomechanical thrombolysis leads to the immediate resolution of clinical symptoms of DVT in the majority of patients. Pharmacomechanical thrombolysis may be a safe and novel method, when appropriate expertise and resources are available, for the treatment of symptomatic acute and chronic DVT. PMID- 21602253 TI - Association of endothelial nitric oxide synthase gene variant (G894T) with coronary artery disease in Western Iran. AB - There are conflicting reports about the association of endothelial nitric oxide synthase (eNOS) gene polymorphism and the risk of coronary artery disease (CAD). To determine the frequency of eNOS G894T variant and to find the possible association between this polymorphism with CAD we studied 207 unrelated patients with total CAD (with and without diabetes) and 92 controls. The eNOS variants were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The presence of GT + TT genotype was associated with 2.1 fold (P = .006), 2.29-fold (P = .006), and 1.93-fold (P = .032) increased risk of CAD in total CAD, CAD with diabetes, and in CAD without diabetes patients, respectively. The presence of T allele of eNOS increased the risk of CAD 2.15 fold (P = .001). The levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) tended to be higher in patients carrier for T allele compared to those with G allele. The results of present study revealed that eNOS G894T polymorphism is associated with increased risk of CAD in our population. PMID- 21602254 TI - Adiponectin and sE-selectin concentrations in relation to inflammation in obese type 2 diabetic patients with coronary heart disease. AB - Adipose tissue can release proinflammatory mediators, namely C-reactive protein (CRP), interleukin 1beta (IL-1beta), and monocyte chemotactic protein 1 (MCP-1), contributing to vascular injury and insulin resistance (IR). Other mediators namely, adiponectin and nitric oxide (NO) are protective. We enrolled type 2 diabetes mellitus (T2DM) obese male patients without coronary heart disease ([CHD] group II, n = 25) and T2DM obese patients with CHD (group III, n = 25). They were compared with 20 age- and body mass index (BMI)-matched nondiabetic control males (group I). Fasting blood glucose (FBG), glycated hemoglobin (HbA(1c)%), lipids, insulin, malondialdehyde ([MDA]; lipid peroxidation product), NO, high-sensitivity CRP (hsCRP), IL-1beta, MCP-1, adiponectin as well as sE selectin concentration were significantly different in patients with T2DM and CHD compared with patients without CHD and nondiabetic controls (P = .01). There was a significant negative correlation between adiponectin and E-selectin (P = .0001). Adipose tissue in T2DM obese patients may contribute to the pathogenesis of CHD. PMID- 21602255 TI - Glomerular filtration rate estimated by the CKD-EPI formula is a powerful predictor of in-hospital adverse clinical outcomes after an acute coronary syndrome. AB - The prognostic value of admission estimated glomerular filtration rate (eGFR) calculated by the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for cardiovascular adverse outcomes in acute coronary syndrome (ACS) was explored. Baseline eGFR was classified as no renal dysfunction (>90 mL/min per 1.73 m(2)), borderline (90-60.1 mL/min per 1.73 m(2)), moderate (60-30.1 mL/min per 1.73 m(2)), or severe (<=30 mL/min per 1.73 m(2)) renal dysfunction. Of the 5034 patients, 3415 (67.8%) had eGFR <90. Compared to patients with an eGFR >=60 mL/min per 1.73 m(2), patients with <60 mL/min per 1.73 m(2) were less likely to be treated with beta-blockers, angiotensin-converting enzyme inhibitors, or statins, or to undergo percutaneous coronary interventions. Lower eGFR showed a stepwise association with significantly worse adverse in-hospital outcomes. The adjusted odds ratio of in-hospital death with an eGFR <30 mL/min per 1.73 m(2) was 3.1 (95% confidence interval 1.1-8.4, P = .0324), compared with an eGFR >90 mL/min per 1.73 m(2). Estimated glomerular filtration rate calculated by the new CKD-EPI is an independent predictor of major adverse cardiac outcomes in patients with ACS. PMID- 21602256 TI - Angiogenin and hemoxygenase in pregnancy: influence of hypertension. AB - The pathophysiology of hypertension and preeclampsia involves angiogenesis and endothelial damage/dysfunction, as shown by abnormal growth factors (vascular endothelial growth factor [VEGF], and its receptor sFlt-1) and von Willebrand factor (vWf) in the plasma. Angiogenin and hemoxygenase are abnormal in hypertension and angiogenesis but data on pregnancy are scant. We hypothesized altered angiogenin and hemoxygenase in 38 hypertensive pregnant women (HTPW) compared to 38 normotensive pregnant women (NTPW) and 50 nonpregnant controls (NonPCs). Plasma markers were measured by enzyme-linked immunosorbent assay (ELISA). Hypertensive pregnant women had lower VEGF than NonPCs (P < .01), vWf was raised in both pregnant groups (P < .01), but sFlt-1 was no different. Both angiogenin and hemoxygenase were lower in NTPW compared to NonPCs (both p<0.02). In both pregnancy groups, angiogenin correlated with vWf (r > .33, P < .05), but in NonPCs this was not significant (r = .13, P = .367). These changes may reflect differences in endothelial cell physiology and pathology in the hypertension in pregnancy. PMID- 21602257 TI - Prevalence of abdominal wall hernia in participants with abdominal aortic aneurysm versus peripheral arterial disease--a population-based study. AB - Small studies suggest an association between abdominal aortic aneurysms (AAAs) and hernias, possibly related to connective tissue weakness. We evaluated the association between AAA and abdominal wall hernia (AWH), using peripheral arterial disease (PAD) patients as controls, in Olmsted County, Minnesota. In a retrospective cohort study we queried the electronic medical records for the diagnosis of AAA. The resulting data were then queried for prevalence of AWH. The same set of queries was repeated for PAD. Occurrence of AWH in the 2 groups was compared using the chi-square test. Of the 187 151 patient records queried, 939 had AAA and 3465 had PAD. Abdominal wall hernia occurred in 157 (16.7%) patients with AAA and in 343 (9.9%) patients with PAD. Abdominal wall hernia was 1.7 times more prevalent in those with AAA versus PAD (P < .0001). A history of hernia may prompt screening for AAA in some patients. PMID- 21602258 TI - Relationship between plasma inflammatory markers and platelet aggregation in patients with clopidogrel resistance after angioplasty. AB - We evaluated the relationship between plasma inflammation markers and clopidogrel resistance in patients after stent implantation. The plasma levels of C-reactive protein (CRP), P-selectin, platelet soluble CD40 ligand (sCD40L), interleukin 6 (IL-6) and platelet aggregation were measured in 352 patients undergoing percutaneous coronary intervention (PCI) at baseline and after 6 months. The plasma levels of CRP, P-selectin, sCD40L, IL-6 was higher in 65 (18.5%) patients with clopidogrel resistance than in those with normal responsiveness at 6 months after PCI. There was a significant positive correlation between soluble CD40L levels and platelet aggregation (r = .28, P < .05). Diabetes (DM) and sCD40L level were independent predictors for unresponsiveness after stent implantation according to stepwise multivariate analyses. The hazard ratio (HR) for sCD40L level was 3.02 (95% CI = 1.28 to 3.25; P = .036) and for DM 2.53 (95% CI = 1.28 to 6.55, P = .03). We conclude that sCD40L and DM may influence clopidogrel resistance. PMID- 21602259 TI - The changes in plasma retinol-binding protein 4 levels are associated with those of the apolipoprotein B-containing lipoproteins during dietary and drug treatment. AB - We investigated the association between retinol-binding protein 4 (RBP(4)) and apolipoprotein B (ApoB)-containing lipoproteins. Obese or overweight, hypertriglyceridemic patients underwent the following interventions for 3 months: (1) Diet (n = 20), (2) Diet + fenofibrate (n = 18), (3) Diet + rimonabant (n = 8). Circulating RBP4 decreased during dietary treatment. The percentage change in RBP(4) was positively correlated with the percentage changes in very-low density lipoprotein cholesterol (r = .570, P = .02), low-density lipoprotein cholesterol ([LDL-C]; r = .605, P = .01), ApoB (r = .705, P = .007), and small dense LDL-C ([sdLDL-C]; r = .872, P < .001). The percentage change in RBP4 was the best predictor of the percentage changes in sdLDL-C and ApoB. Rimonabant treatment reduced RBP4, whereas fenofibrate increased RBP4 during the first month of therapy followed by a subsequent decrease. In conclusion, RBP4 may significantly influence the metabolic pathways responsible for changes in ApoB lipoprotein subspecies, thus RBP4 may be associated with cardiovascular disease risk. PMID- 21602260 TI - Lack of association of tumor-associated macrophages with clinical outcome in patients with classical Hodgkin's lymphoma. AB - BACKGROUND: A recent study demonstrated that an increased number of CD68+ macrophages were correlated with primary treatment failure, shortened progression free survival (PFS) and disease-specific survival (DSS) in patients with classical Hodgkin's lymphoma (cHL). PATIENTS AND METHODS: The aim of the present study was to verify the relationship between the number of CD68+ and CD163+ macrophages with clinical outcomes in a cohort of 265 well-characterized patients with cHL treated uniformly with the standard doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy regimen. Two pairs of hematopathologists carried out independent pathological evaluations of tissue microarray slides. RESULTS: There were no associations between clinical characteristics and the expression of CD68 or CD163. However, higher levels of CD68 and CD163 expression were correlated with the presence of Epstein-Barr virus-positive Hodgkin tumor cells (P = 0.01 and 0.037, respectively). The expression of CD68 or CD163 was not associated with either the PFS or the DSS. CONCLUSION: CD68 and CD163 expression require further evaluation before their use can be recommended for prognostic stratification of patients with cHL. PMID- 21602261 TI - Control of gene expression by modulated self-assembly. AB - Numerous transcription factors self-assemble into different order oligomeric species in a way that is actively regulated by the cell. Until now, no general functional role has been identified for this widespread process. Here, we capture the effects of modulated self-assembly in gene expression with a novel quantitative framework. We show that this mechanism provides precision and flexibility, two seemingly antagonistic properties, to the sensing of diverse cellular signals by systems that share common elements present in transcription factors like p53, NF-kappaB, STATs, Oct and RXR. Applied to the nuclear hormone receptor RXR, this framework accurately reproduces a broad range of classical, previously unexplained, sets of gene expression data and corroborates the existence of a precise functional regime with flexible properties that can be controlled both at a genome-wide scale and at the individual promoter level. PMID- 21602262 TI - Inferring transcription factor complexes from ChIP-seq data. AB - Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) allows researchers to determine the genome-wide binding locations of individual transcription factors (TFs) at high resolution. This information can be interrogated to study various aspects of TF behaviour, including the mechanisms that control TF binding. Physical interaction between TFs comprises one important aspect of TF binding in eukaryotes, mediating tissue-specific gene expression. We have developed an algorithm, spaced motif analysis (SpaMo), which is able to infer physical interactions between the given TF and TFs bound at neighbouring sites at the DNA interface. The algorithm predicts TF interactions in half of the ChIP-seq data sets we test, with the majority of these predictions supported by direct evidence from the literature or evidence of homodimerization. High resolution motif spacing information obtained by this method can facilitate an improved understanding of individual TF complex structures. SpaMo can assist researchers in extracting maximum information relating to binding mechanisms from their TF ChIP-seq data. SpaMo is available for download and interactive use as part of the MEME Suite (http://meme.nbcr.net). PMID- 21602264 TI - miRvestigator: web application to identify miRNAs responsible for co-regulated gene expression patterns discovered through transcriptome profiling. AB - Transcriptome profiling studies have produced staggering numbers of gene co expression signatures for a variety of biological systems. A significant fraction of these signatures will be partially or fully explained by miRNA-mediated targeted transcript degradation. miRvestigator takes as input lists of co expressed genes from Caenorhabditis elegans, Drosophila melanogaster, G. gallus, Homo sapiens, Mus musculus or Rattus norvegicus and identifies the specific miRNAs that are likely to bind to 3' un-translated region (UTR) sequences to mediate the observed co-regulation. The novelty of our approach is the miRvestigator hidden Markov model (HMM) algorithm which systematically computes a similarity P-value for each unique miRNA seed sequence from the miRNA database miRBase to an overrepresented sequence motif identified within the 3'-UTR of the query genes. We have made this miRNA discovery tool accessible to the community by integrating our HMM algorithm with a proven algorithm for de novo discovery of miRNA seed sequences and wrapping these algorithms into a user-friendly interface. Additionally, the miRvestigator web server also produces a list of putative miRNA binding sites within 3'-UTRs of the query transcripts to facilitate the design of validation experiments. The miRvestigator is freely available at http://mirvestigator.systemsbiology.net. PMID- 21602263 TI - A rapid, inexpensive yeast-based dual-fluorescence assay of programmed--1 ribosomal frameshifting for high-throughput screening. AB - Programmed -1 ribosomal frameshifting (-1 PRF) is a mechanism that directs elongating ribosomes to shift-reading frame by 1 base in the 5' direction that is utilized by many RNA viruses. Importantly, rates of -1 PRF are fine-tuned by viruses, including Retroviruses, Coronaviruses, Flavivriuses and in two endogenous viruses of the yeast Saccharomyces cerevisiae, to deliver the correct ratios of different viral proteins for efficient replication. Thus, -1 PRF presents a novel target for antiviral therapeutics. The underlying molecular mechanism of -1 PRF is conserved from yeast to mammals, enabling yeast to be used as a logical platform for high-throughput screens. Our understanding of the strengths and pitfalls of assays to monitor -1 PRF have evolved since the initial discovery of -1 PRF. These include controlling for the effects of drugs on protein expression and mRNA stability, as well as minimizing costs and the requirement for multiple processing steps. Here we describe the development of an automated yeast-based dual fluorescence assay of -1 PRF that provides a rapid, inexpensive automated pipeline to screen for compounds that alter rates of -1 PRF which will help to pave the way toward the discovery and development of novel antiviral therapeutics. PMID- 21602265 TI - Design principles for bifunctional targeted oligonucleotide enhancers of splicing. AB - Controlling the patterns of splicing of specific genes is an important goal in the development of new therapies. We have shown that the splicing of a refractory exon, SMN2 exon 7, could be increased in fibroblasts derived from patients with spinal muscular atrophy by using bifunctional targeted oligonucleotide enhancers of splicing (TOES) oligonucleotides that anneal to the exon and contain a 'tail' of enhancer sequences that recruit activating proteins. We show here that there are striking agreements between the effects of oligonucleotides on splicing in vitro and on both splicing and SMN2 protein expression in patient-derived fibroblasts, indicating that the effects on splicing are the major determinant of success. Increased exon inclusion depends on the number, sequence and chemistry of the motifs that bind the activator protein SRSF1, but it is not improved by increasing the strength of annealing to the target site. The optimal oligonucleotide increases protein levels in transfected fibroblasts by a mean value of 2.6-fold (maximum 4.6-fold), and after two rounds of transfection the effect lasted for a month. Oligonucleotides targeted to the upstream exon (exon 6 in SMN) are also effective. We conclude that TOES oligonucleotides are highly effective reagents for restoring the splicing of refractory exons and can act across long introns. PMID- 21602266 TI - CLICK--topology-independent comparison of biomolecular 3D structures. AB - Our server, CLICK: http://mspc.bii.a-star.edu.sg/click, is capable of superimposing the 3D structures of any pair of biomolecules (proteins, DNA, RNA, etc.). The server makes use of the Cartesian coordinates of the molecules with the option of using other structural features such as secondary structure, solvent accessible surface area and residue depth to guide the alignment. CLICK first looks for cliques of points (3-7 residues) that are structurally similar in the pair of structures to be aligned. Using these local similarities, a one-to one equivalence is charted between the residues of the two structures. A least square fit then superimposes the two structures. Our method is especially powerful in establishing protein relationships by detecting similarities in structural subdomains, domains and topological variants. CLICK has been extensively benchmarked and compared with other popular methods for protein and RNA structural alignments. In most cases, CLICK alignments were statistically significantly better in terms of structure overlap. The method also recognizes conformational changes that may have occurred in structural domains or subdomains in one structure with respect to the other. For this purpose, the server produces complementary alignments to maximize the extent of detectable similarity. Various examples showcase the utility of our web server. PMID- 21602267 TI - PINTA: a web server for network-based gene prioritization from expression data. AB - PINTA (available at http://www.esat.kuleuven.be/pinta/; this web site is free and open to all users and there is no login requirement) is a web resource for the prioritization of candidate genes based on the differential expression of their neighborhood in a genome-wide protein-protein interaction network. Our strategy is meant for biological and medical researchers aiming at identifying novel disease genes using disease specific expression data. PINTA supports both candidate gene prioritization (starting from a user defined set of candidate genes) as well as genome-wide gene prioritization and is available for five species (human, mouse, rat, worm and yeast). As input data, PINTA only requires disease specific expression data, whereas various platforms (e.g. Affymetrix) are supported. As a result, PINTA computes a gene ranking and presents the results as a table that can easily be browsed and downloaded by the user. PMID- 21602268 TI - Adenine and guanine recognition of stop codon is mediated by different N domain conformations of translation termination factor eRF1. AB - Positioning of release factor eRF1 toward adenines and the ribose-phosphate backbone of the UAAA stop signal in the ribosomal decoding site was studied using messenger RNA (mRNA) analogs containing stop signal UAA/UAAA and a photoactivatable cross-linker at definite locations. The human eRF1 peptides cross-linked to these analogs were identified. Cross-linkers on the adenines at the 2nd, 3rd or 4th position modified eRF1 near the conserved YxCxxxF loop (positions 125-131 in the N domain), but cross-linker at the 4th position mainly modified the tripeptide 26-AAR-28. This tripeptide cross-linked also with derivatized 3'-phosphate of UAA, while the same cross-linker at the 3'-phosphate of UAAA modified both the 26-28 and 67-73 fragments. A comparison of the results with those obtained earlier with mRNA analogs bearing a similar cross-linker at the guanines indicates that positioning of eRF1 toward adenines and guanines of stop signals in the 80S termination complex is different. Molecular modeling of eRF1 in the 80S termination complex showed that eRF1 fragments neighboring guanines and adenines of stop signals are compatible with different N domain conformations of eRF1. These conformations vary by positioning of stop signal purines toward the universally conserved dipeptide 31-GT-32, which neighbors guanines but is oriented more distantly from adenines. PMID- 21602269 TI - CENTDIST: discovery of co-associated factors by motif distribution. AB - Transcription factors (TFs) do not function alone but work together with other TFs (called co-TFs) in a combinatorial fashion to precisely control the transcription of target genes. Mining co-TFs is thus important to understand the mechanism of transcriptional regulation. Although existing methods can identify co-TFs, their accuracy depends heavily on the chosen background model and other parameters such as the enrichment window size and the PWM score cut-off. In this study, we have developed a novel web-based co-motif scanning program called CENTDIST (http://compbio.ddns.comp.nus.edu.sg/~chipseq/centdist/). In comparison to current co-motif scanning programs, CENTDIST does not require the input of any user-specific parameters and background information. Instead, CENTDIST automatically determines the best set of parameters and ranks co-TF motifs based on their distribution around ChIP-seq peaks. We tested CENTDIST on 14 ChIP-seq data sets and found CENTDIST is more accurate than existing methods. In particular, we applied CENTDIST on an Androgen Receptor (AR) ChIP-seq data set from a prostate cancer cell line and correctly predicted all known co-TFs (eight TFs) of AR in the top 20 hits as well as discovering AP4 as a novel co-TF of AR (which was missed by existing methods). Taken together, CENTDIST, which exploits the imbalanced nature of co-TF binding, is a user-friendly, parameter-less and powerful predictive web-based program for understanding the mechanism of transcriptional co-regulation. PMID- 21602270 TI - Impaired cognition in rats with cortical dysplasia: additional impact of early life seizures. AB - One of the most common and serious co-morbidities in patients with epilepsy is cognitive impairment. While early-life seizures are considered a major cause for cognitive impairment, it is not known whether it is the seizures, the underlying neurological substrate or a combination that has the largest impact on eventual learning and memory. Teasing out the effects of seizures from pre-existing neurological disorder is critical in developing therapeutic strategies. We therefore investigated the additional cognitive effects of seizures on rodents with malformations of cortical development induced with methylazoxymethanol acetate. Pregnant rats were injected with saline or methylazoxymethanol acetate at embryonic Day 15 or 17 to induce differing malformation severity. From the day of birth to 9 days of age, half the pups received 50 flurothyl-induced seizures. All rats underwent testing in the Morris water maze to test spatial memory at 25 days of age (immediate post-weaning) or during adolescence at 45 days of age. Post-weaning rats had severe spatial cognitive deficits in the water maze and seizures worsened performance. In contrast, in animals tested during adolescence, there was no longer an additional adverse effect of seizures. We also investigated whether the severity of the structural abnormality and seizures impacted brain weight, cortical thickness, hippocampal area and cell dispersion area. The mean brain weight in control animals was greater than in rats exposed to methylazoxymethanol acetate at embryonic Day 17, which was greater than rats exposed to methylazoxymethanol acetate at embryonic Day 15. Rats exposed to methylazoxymethanol acetate at embryonic Day 15 had a thinner cortical mantle compared with rats exposed at embryonic Day 17 and control animals. The hippocampal area was similar in rats exposed at embryonic Days 15 and 17 but was smaller compared with controls. Methylazoxymethanol at embryonic Day 17 caused dispersion of the CA1-4 cell layers in the hippocampus, whereas methylazoxymethanol at embryonic Day 15 caused focal nodules in or above the CA1 layer, but the CA1-4 layers were intact and similar to control. Early-life seizures did not have a significant impact on any of these parameters. These observations indicate that the major factor responsible for the cognitive impairment in the rats with cortical dysplasia was the underlying brain substrate, not seizures. These findings have significant implications for the understanding of cognitive impairments in childhood epilepsy and suggest that early aggressive therapy of seizures alone may not be an adequate strategy for minimizing cognitive effects. PMID- 21602271 TI - Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression. AB - OBJECTIVE: MicroRNAs (miRNAs) regulate the expression of genes involved in immune activation. A study was undertaken to characterise the miRNA signature and identify novel genes involved in the regulation of immune responses in systemic lupus erythematosus (SLE). METHODS: The expression of 365 miRNAs in peripheral blood mononuclear cells of patients with SLE and healthy controls was analysed using TaqMan Low Density Arrays. The results were validated by quantitative real time PCR and potential target genes were identified using prediction analysis software. The effect of miR-21 on T cell function was assessed by transfection with antago-miR-21 or pre-miR-21. RESULTS: A 27-miRNA signature was identified in patients with SLE; 19 miRNAs correlated with disease activity. Eight miRNAs were deregulated specifically in T cells and four miRNAs in B cells. miR-21 was upregulated and strongly correlated with SLE disease activity (r(2)=0.92). Compared with controls, CD4 T lymphocytes from patients with SLE had higher basal and activation-induced miR-21 expression. Silencing of miR-21 reversed the activated phenotype of T cells from patients with SLE--namely, enhanced proliferation, interleukin 10 production, CD40L expression and their capacity to drive B cell maturation into Ig-secreting CD19+CD38(hi)IgD-(plasma cells. Overexpression of mMiR-21 in normal T cells led to acquisition of an activated phenotype. Investigation of putative gene- targets showed that PDCD4 (a selective protein translation inhibitor) was suppressed by miR-21 and its expression was decreased in active SLE. CONCLUSIONS: miRNAs represent potential biomarkers in SLE as their expression reflects underlying pathogenic processes and correlates with disease activity. Upregulated miR-21 affects PDCD4 expression and regulates aberrant T cell responses in human SLE. PMID- 21602272 TI - Regulation of adipocyte differentiation by the zinc finger protein ZNF638. AB - Zinc finger proteins constitute the largest family of transcription regulators in eukaryotes. These factors are involved in diverse processes in many tissues, including development and differentiation. We report here the characterization of the zinc finger protein ZNF638 as a novel regulator of adipogenesis. ZNF638 is induced early during adipocyte differentiation. Ectopic expression of ZNF638 increases adipogenesis in vitro, whereas its knockdown inhibits differentiation and decreases the expression of adipocyte-specific genes. ZNF638 physically interacts and transcriptionally cooperates with CCAAT/enhancer-binding protein (C/EBP) beta and C/EBPdelta. This interaction leads to the expression of peroxisome proliferator-activated receptor gamma, which is the key regulator of adipocyte differentiation. In summary, ZNF638 is a novel and early regulator of adipogenesis that works as a transcription cofactor of C/EBPs. PMID- 21602273 TI - Interplay between flavodiiron proteins and photorespiration in Synechocystis sp. PCC 6803. AB - Flavodiiron (Flv) proteins are involved in detoxification of O(2) and NO in anaerobic bacteria and archaea. Cyanobacterial Flv proteins, on the contrary, function in oxygenic environment and possess an extra NAD(P)H:flavin oxidoreductase module. Synechocystis sp. PCC 6803 has four genes (sll1521, sll0219, sll0550, and sll0217) encoding Flv proteins (Flv1, Flv2, Flv3, and Flv4). Previous in vitro studies with recombinant Flv3 protein from Synechocystis provided evidence that it functions as a NAD(P)H:oxygen oxidoreductase, and subsequent in vivo studies with Synechocystis confirmed the role of Flv1 and Flv3 proteins in the Mehler reaction (photoreduction of O(2) to H(2)O). Interestingly, homologous proteins to Flv1 and Flv3 can be found also in green algae, mosses, and Selaginella. Here, we addressed the function of Flv1 and Flv3 in Synechocystis using the Deltaflv1, Deltaflv3, and Deltaflv1/Deltaflv3 mutants and applying inorganic carbon (C(i))-deprivation conditions. We propose that only the Flv1/Flv3 heterodimer form is functional in the Mehler reaction in vivo. (18)O(2) labeling was used to discriminate between O(2) evolution in photosynthetic water splitting and O(2) consumption. In wild type, ~20% of electrons originated from water was targeted to O(2) under air level CO(2) conditions but increased up to 60% in severe limitation of C(i). Gas exchange experiments with Deltaflv1, Deltaflv3, and Deltaflv1/Deltaflv3 mutants demonstrated that a considerable amount of electrons in these mutants is directed to photorespiration under C(i) deprivation. This assumption is in line with increased transcript abundance of photorespiratory genes and accumulation of photorespiratory intermediates in the WT and to a higher extent in mutant cells under C(i) deprivation. PMID- 21602275 TI - The N-terminal domain of NPC1L1 protein binds cholesterol and plays essential roles in cholesterol uptake. AB - Niemann-Pick C1-like 1 (NPC1L1) is a multitransmembrane protein playing a crucial role in dietary and biliary cholesterol absorption. Cholesterol promotes the formation and endocytosis of NPC1L1-flotillin-cholesterol membrane microdomains, which is an early step in cholesterol uptake. How cholesterol is sensed in this step is unknown. Here, we find that the N-terminal domain (NTD) of NPC1L1 binds cholesterol. Mutation of residue Leu-216 in NPC1L1-NTD eliminates cholesterol binding, decreases the formation of NPC1L1-flotillin-cholesterol membrane microdomains, and prevents NPC1L1-mediated cholesterol uptake in culture cells and mice livers. NPC1L1-NTD specifically binds cholesterol but not plant sterols, which may account for the selective cholesterol absorption in intestine. Furthermore, 25- or 27-hydroxycholesterol competes with cholesterol to bind NPC1L1-NTD and inhibits the cholesterol induced endocytosis of NPC1L1. Together, these results demonstrate that plasma membrane-localized NPC1L1 binds exogenous cholesterol via its NTD, and facilitates the formation of NPC1L1-flotillin cholesterol membrane microdomains that are then internalized into cells through the clathrin-AP2 pathway. Our study uncovers the mechanism of cholesterol sensing by NPC1L1 and proposes a mechanism for selective cholesterol absorption. PMID- 21602274 TI - Activation of AMP-activated protein kinase is essential for lysophosphatidic acid induced cell migration in ovarian cancer cells. AB - Lysophosphatidic acid (LPA) is a bioactive phospholipid that affects various biological functions, such as cell proliferation, migration, and survival, through LPA receptors. Among them, the motility of cancer cells is an especially important activity for invasion and metastasis. Recently, AMP-activated protein kinase (AMPK), an energy-sensing kinase, was shown to regulate cell migration. However, the specific role of AMPK in cancer cell migration is unknown. The present study investigated whether LPA could induce AMPK activation and whether this process was associated with cell migration in ovarian cancer cells. We found that LPA led to a striking increase in AMPK phosphorylation in pathways involving the phospholipase C-beta3 (PLC-beta3) and calcium/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) in SKOV3 ovarian cancer cells. siRNA-mediated knockdown of AMPKalpha1, PLC-beta3, or (CaMKKbeta) impaired the stimulatory effects of LPA on cell migration. Furthermore, we found that knockdown of AMPKalpha1 abrogated LPA-induced activation of the small GTPase RhoA and ezrin/radixin/moesin proteins regulating membrane dynamics as membrane cytoskeleton linkers. In ovarian cancer xenograft models, knockdown of AMPK significantly decreased peritoneal dissemination and lung metastasis. Taken together, our results suggest that activation of AMPK by LPA induces cell migration through the signaling pathway to cytoskeletal dynamics and increases tumor metastasis in ovarian cancer. PMID- 21602276 TI - A rice phenolic efflux transporter is essential for solubilizing precipitated apoplasmic iron in the plant stele. AB - Iron deficiency is one of the major agricultural problems, as 30% of the arable land of the world is too alkaline for optimal crop production, rendering plants short of available iron despite its abundance. To take up apoplasmic precipitated iron, plants secrete phenolics such as protocatechuic acid (PCA) and caffeic acid. The molecular pathways and genes of iron uptake strategies are already characterized, whereas the molecular mechanisms of phenolics synthesis and secretion have not been clarified, and no phenolics efflux transporters have been identified in plants yet. Here we describe the identification of a phenolics efflux transporter in rice. We identified a cadmium-accumulating rice mutant in which the amount of PCA and caffeic acid in the xylem sap was dramatically reduced and hence named it phenolics efflux zero 1 (pez1). PEZ1 localized to the plasma membrane and transported PCA when expressed in Xenopus laevis oocytes. PEZ1 localized mainly in the stele of roots. In the roots of pez1, precipitated apoplasmic iron increased. The growth of PEZ1 overexpression lines was severely restricted, and these lines accumulated more iron as a result of the high solubilization of precipitated apoplasmic iron in the stele. We show that PEZ1 is responsible for an increase of PCA concentration in the xylem sap and is essential for the utilization of apoplasmic precipitated iron in the stele. PMID- 21602277 TI - Zinc inactivates melastatin transient receptor potential 2 channels via the outer pore. AB - Zinc ion (Zn(2+)) is an endogenous allosteric modulator that regulates the activity of a wide variety of ion channels in a reversible and concentration dependent fashion. Here we used patch clamp recording to study the effects of Zn(2+) on the melastatin transient receptor potential 2 (TRPM2) channel. Zn(2+) inhibited the human (h) TRPM2 channel currents, and the steady-state inhibition was largely not reversed upon washout and concentration-independent in the range of 30-1000 MUM, suggesting that Zn(2+) induces channel inactivation. Zn(2+) inactivated the channels fully when they conducted inward currents, but only by half when they passed outward currents, indicating profound influence of the permeant ion on Zn(2+) inactivation. Alanine substitution scanning mutagenesis of 20 Zn(2+)-interacting candidate residues in the outer pore region of the hTRPM2 channel showed that mutation of Lys(952) in the extracellular end of the fifth transmembrane segment and Asp(1002) in the large turret strongly attenuated or abolished Zn(2+) inactivation, and mutation of several other residues dramatically changed the inactivation kinetics. The mouse (m) TRPM2 channels were also inactivated by Zn(2+), but the kinetics were remarkably slower. Reciprocal mutation of His(995) in the hTRPM2 channel and the equivalent Gln(992) in the mTRPM2 channel completely swapped the kinetics, but no such opposing effects resulted from exchanging another pair of species-specific residues, Arg(961)/Ser(958). We conclude from these results that Zn(2+) inactivates the TRPM2 channels and that residues in the outer pore are critical determinants of the inactivation. PMID- 21602278 TI - Clustering and activity tuning of Kv1 channels in myelinated hippocampal axons. AB - Precise localization of axonal ion channels is crucial for proper electrical and chemical functions of axons. In myelinated axons, Kv1 (Shaker) voltage-gated potassium (Kv) channels are clustered in the juxtaparanodal regions flanking the node of Ranvier. The clustering can be disrupted by deletion of various proteins in mice, including contactin-associated protein-like 2 (Caspr2) and transient axonal glycoprotein-1 (TAG-1), a glycosylphosphatidylinositol-anchored cell adhesion molecule. However, the mechanism and function of Kv1 juxtaparanodal clustering remain unclear. Here, using a new myelin coculture of hippocampal neurons and oligodendrocytes, we report that tyrosine phosphorylation plays a critical role in TAG-1-mediated clustering of axonal Kv1.2 channels. In the coculture, myelin specifically ensheathed axons but not dendrites of hippocampal neurons and clustered endogenous axonal Kv1.2 into internodes. The trans homophilic interaction of TAG-1 was sufficient to position Kv1.2 clusters on axonal membranes in a neuron/HEK293 coculture. Mutating a tyrosine residue (Tyr458) in the Kv1.2 C terminus or blocking tyrosine phosphorylation disrupted myelin- and TAG-1-mediated clustering of axonal Kv1.2. Furthermore, Kv1.2 voltage dependence and activation threshold were reduced by TAG-1 coexpression. This effect was eliminated by the Tyr458 mutation or by cholesterol depletion. Taken together, our studies suggest that myelin regulates both trafficking and activity of Kv1 channels along hippocampal axons through TAG-1. PMID- 21602279 TI - Random mutagenesis of the proton-coupled folate transporter (SLC46A1), clustering of mutations, and the bases for associated losses of function. AB - Loss-of-function mutations in the proton-coupled folate transporter (PCFT, SLC46A1) result in the autosomal recessive disorder, hereditary folate malabsorption (HFM). Identification and characterization of HFM mutations provide a wealth of information on the structure-function relationship of this transporter. In the current study, PCR-based random mutagenesis was employed to generate unbiased loss-of-function mutations of PCFT, simulating the spectrum of alterations that might occur in the human disorder. A total of 26 mutations were generated and 4 were identical to HFM mutations. Eleven were base deletion or insertion mutations that led to a frameshift and, along with similar HFM mutations, are predominantly localized to two narrow regions of the pcft gene at the 5'-end. Base substitution mutations identified in the current study and HFM patients were largely distributed across the pcft gene. Elimination of the ATG initiation codon by a one-base substitution (G > A) did not result in a complete lack of translation at the same codon consistent with rare non-ATG translation initiation. Among six missense mutants evaluated, three mutant PCFTs were not detected at the plasma membrane, one mutation resulted in decreased binding to folate substrate, and one had a reduced rate of conformational change associated with substrate translocation. The remaining PCFT mutant had defects in both processes. These results broaden understanding of the regions of the pcft gene prone to base insertion and deletion and inform further approaches to the analysis of the structure-function of PCFT. PMID- 21602280 TI - Impaired infectivity of ritonavir-resistant HIV is rescued by heat shock protein 90AB1. AB - Certain ritonavir resistance mutations impair HIV infectivity through incomplete Gag processing by the mutant viral protease. Analysis of the mutant virus phenotype indicates that accumulation of capsid-spacer peptide 1 precursor protein in virus particles impairs HIV infectivity and that the protease mutant virus is arrested during the early postentry stage of HIV infection before proviral DNA synthesis. However, activation of the target cell can rescue this defect, implying that specific host factors expressed in activated cells can compensate for the defect in ritonavir-resistant HIV. This ability to rescue impaired HIV replication presented a unique opportunity to identify host factors involved in postentry HIV replication, and we designed a functional genetic screen so that expression of a given host factor extracted from activated T cells would lead directly to its discovery by rescuing mutant virus replication in nonactivated T cells. We identified the cellular heat shock protein 90 kDa alpha (cytosolic), class B member 1 (HSP90AB1) as a host factor that can rescue impaired replication of ritonavir-resistant HIV. Moreover, we show that pharmacologic inhibition of HSP90AB1 with 17-(allylamino)-17 demethoxygeldanamycin (tanespimycin) has potent in vitro anti-HIV activity and that ritonavir-resistant HIV is hypersensitive to the drug. These results suggest a possible role for HSP90AB1 in postentry HIV replication and may provide an attractive target for therapeutic intervention. PMID- 21602283 TI - Structural underpinnings of prion protein conversion. PMID- 21602281 TI - Identification of the PDZ3 domain of the adaptor protein PDZK1 as a second, physiologically functional binding site for the C terminus of the high density lipoprotein receptor scavenger receptor class B type I. AB - The normal expression, cell surface localization, and function of the murine high density lipoprotein receptor scavenger receptor class B type I (SR-BI) in hepatocytes in vivo, and thus normal lipoprotein metabolism, depend on its four PDZ domain (PDZ1-PDZ4) containing cytoplasmic adaptor protein PDZK1. Previous studies showed that the C terminus of SR-BI ("target peptide") binds directly to PDZ1 and influences hepatic SR-BI protein expression. Unexpectedly an inactivating mutation in PDZ1 (Tyr(20) -> Ala) only partially, rather than completely, suppresses the ability of PDZK1 to control hepatic SR-BI. We used isothermal titration calorimetry to show that PDZ3, but not PDZ2 or PDZ4, can also bind the target peptide (K(d) = 37.0 MUm), albeit with ~10-fold lower affinity than PDZ1. This binding is abrogated by a Tyr(253) -> Ala substitution. Comparison of the 1.5-A resolution crystal structure of PDZ3 with its bound target peptide ((505)QEAKL(509)) to that of peptide-bound PDZ1 indicated fewer target peptide stabilizing atomic interactions (hydrogen bonds and hydrophobic interactions) in PDZ3. A double (Tyr(20) -> Ala (PDZ1) + Tyr(253) -> Ala (PDZ3)) substitution abrogated all target peptide binding to PDZK1. In vivo hepatic expression of a singly substituted (Tyr(253) -> Ala (PDZ3)) PDZK1 transgene (Tg) was able to correct all of the SR-BI-related defects in PDZK1 knock-out mice, whereas the doubly substituted [Tyr(20) -> Ala (PDZ1) + Tyr(253) -> Ala (PDZ3)]Tg was unable to correct these defects. Thus, we conclude that PDZK1-mediated control of hepatic SR-BI requires direct binding of the SR-BI C terminus to either the PDZ1 or PDZ3 domains, and that binding to both domains simultaneously is not required for PDZK1 control of hepatic SR-BI. PMID- 21602285 TI - Two conflicting NHE1 model structures: compatibility with experimental data and implications for the transport mechanism. PMID- 21602286 TI - The importance of cardiovascular disease for mortality in patients with COPD: a prognostic cohort study. AB - BACKGROUND: Cardiovascular diseases are the major cause of mortality in patients with chronic obstructive pulmonary disease (COPD), however, are rarely considered in prediction models in patients with COPD. OBJECTIVE: To quantify the effect of cardiovascular determinants on mortality in patients with a GP's diagnosis of COPD. METHODS: Four hundred and five patients aged >=65 years with a diagnosis of COPD (244 with COPD by spirometry) were followed up for an average period of 4.2 (SD 1.4) years. Cox proportional hazard regression analyses with bootstrapping techniques were performed to identify independent predictors of all-cause mortality. RESULTS: In multivariable analysis, all-cause mortality was best predicted by age [hazard ratio (HR) 1.05 [95% confidence interval (CI): 1.01 1.10] per year of age], angina pectoris on history taking [HR 2.32 (95% CI: 1.50 3.58)], airflow obstruction [HR 1.02 (95% CI: 1.01-1.03) per percentage decrease in level of forced expiratory volume in one second (FEV(1)) as % predicted] and C reactive protein [HR 1.04 (95% CI: 1.02-1.05] per milligram per millilitre increase), respectively. The final model had a C statistic of 0.78 (95% CI: 0.72 0.83) after bootstrapping, and the calibration of the model was very good. The model performed similarly in the subgroup of 244 patients with COPD according to the GOLD criteria (post-dilatory FEV(1)/forced vital capacity < 0.70). CONCLUSIONS: Physicians should consider ischaemic heart disease in the clinical evaluation of any patient with a GP's diagnosis of COPD. Angina pectoris on history taking is a strong predictor of all-cause mortality in these patients and should be treated adequately to improve prognosis. PMID- 21602287 TI - The impact of research in primary care and family medicine: the Thomson Reuters Web of Science Subject Category 'Primary Health Care'. PMID- 21602289 TI - Ethnicity and cardiovascular disease. PMID- 21602290 TI - An Arabidopsis E3 ligase, SHOOT GRAVITROPISM9, modulates the interaction between statoliths and F-actin in gravity sensing. AB - Higher plants use the sedimentation of amyloplasts in statocytes as statolith to sense the direction of gravity during gravitropism. In Arabidopsis thaliana inflorescence stem statocyte, amyloplasts are in complex movement; some show jumping-like saltatory movement and some tend to sediment toward the gravity direction. Here, we report that a RING-type E3 ligase SHOOT GRAVITROPISM9 (SGR9) localized to amyloplasts modulates amyloplast dynamics. In the sgr9 mutant, which exhibits reduced gravitropism, amyloplasts did not sediment but exhibited increased saltatory movement. Amyloplasts sometimes formed a cluster that is abnormally entangled with actin filaments (AFs) in sgr9. By contrast, in the fiz1 mutant, an ACT8 semidominant mutant that induces fragmentation of AFs, amyloplasts, lost saltatory movement and sedimented with nearly statically. Both treatment with Latrunculin B, an inhibitor of AF polymerization, and the fiz1 mutation rescued the gravitropic defect of sgr9. In addition, fiz1 decreased saltatory movement and induced amyloplast sedimentation even in sgr9. Our results suggest that amyloplasts are in equilibrium between sedimentation and saltatory movement in wild-type endodermal cells. Furthermore, this equilibrium is the result of the interaction between amyloplasts and AFs modulated by the SGR9. SGR9 may promote detachment of amyloplasts from AFs, allowing the amyloplasts to sediment in the AFs-dependent equilibrium of amyloplast dynamics. PMID- 21602291 TI - cis- and trans-Regulation of miR163 and target genes confers natural variation of secondary metabolites in two Arabidopsis species and their allopolyploids. AB - MicroRNAs (miRNAs) play essential roles in plant and animal development, but the cause and effect of miRNA expression divergence between closely related species and in interspecific hybrids or allopolyploids are unknown. Here, we show differential regulation of a miR163-mediated pathway in allotetraploids and their progenitors, Arabidopsis thaliana and Arabidopsis arenosa. miR163 is a recently evolved miRNA in A. thaliana and highly expressed in A. thaliana, but its expression was undetectable in A. arenosa and repressed in resynthesized allotetraploids. Repression of A. arenosa MIR163 (Aa MIR163) is caused by a weak cis-acting promoter and putative trans-acting repressor(s) present in A. arenosa and allotetraploids. Moreover, ectopic Aa MIR163 precursors were processed more efficiently in A. thaliana than in resynthesized allotetraploids, suggesting a role of posttranscriptional regulation in mature miR163 abundance. Target genes of miR163 encode a family of small molecule methyltransferases involved in secondary metabolite biosynthetic pathways that are inducible by a fungal elicitor, alamethicin. Loss of miR163 or overexpression of miR163 in mir163 mutant plants alters target transcript and secondary metabolite profiles. We suggest that cis- and trans-regulation of miRNA and other genes provides a molecular basis for natural variation of biochemical and metabolic pathways that are important to growth vigor and stress responses in Arabidopsis-related species and allopolyploids. PMID- 21602292 TI - The influence of nurse staffing levels on quality of care in nursing homes. AB - OBJECTIVE: This study examines the relationship between increasing certified nursing assistants (CNAs) and licensed nurse staffing ratios and deficiencies in Florida nursing homes over a 4-year period. METHODS: Data from Florida staffing reports and the Online Survey Certification and Reporting database examine the relationship among staffing levels and deficiency citations for 663 Florida nursing homes between 2002 and 2005. Using a generalized estimating equation approach in SAS Proc Genmod, we estimate the relationship between CNA and licensed nursing staff, and facilities' total deficiency score and quality of care deficiency scores-calculated using the Centers for Medicare and Medicaid Services' Nursing Home Compare Five-Star Quality Rating System, which accounts for the complexity of the scope and severity of the cittions. RESULTS: Our results confirmed that higher CNA staffing levels were predictors of lower total deficiency scores and quality of care deficiency scores after controlling for facility characteristics. CONCLUSION: With a large sample size, repeated measure design, and advanced methods, we have found a relationship between CNA staffing and nursing home quality. PMID- 21602293 TI - alpha-Adrenergic effects on low-frequency oscillations in blood pressure and R-R intervals during sympathetic activation. AB - The present study was designed to address the contribution of alpha-adrenergic modulation to the genesis of low-frequency (LF; 0.04-0.15 Hz) oscillations in R-R interval (RRi), blood pressure (BP) and muscle sympathetic nerve activity (MSNA) during different sympathetic stimuli. Blood pressure and RRi were measured continuously in 12 healthy subjects during 5 min periods each of lower body negative pressure (LBNP; -40 mmHg), static handgrip exercise (HG; 20% of maximal force) and postexercise forearm circulatory occlusion (PECO) with and without alpha-adrenergic blockade by phentolamine. Muscle sympathetic nerve activity was recorded in five subjects during LBNP and in six subjects during HG and PECO. Low frequency powers and median frequencies of BP, RRi and MSNA were calculated from power spectra. Low-frequency power during LBNP was lower with phentolamine versus without for both BP and RRi oscillations (1.6 +/- 0.6 versus 1.2 +/- 0.7 ln mmHg(2), P = 0.049; and 6.9 +/- 0.8 versus 5.4 +/- 0.9 ln ms(2), P = 0.001, respectively). In contrast, the LBNP with phentolamine increased the power of high-frequency oscillations (0.15-0.4 Hz) in BP and MSNA (P < 0.01 for both), which was not observed during saline infusion. Phentolamine also blunted the increases in the LBNP-induced increase in frequency of LF oscillations in BP and RRi. Phentolamine decreased the LF power of RRi during HG (P = 0.015) but induced no other changes in LF powers or frequencies during HG. Phentolamine resulted in decreased frequency of LF oscillations in RRi (P = 0.004) during PECO, and a similar tendency was observed in BP and MSNA. The power of LF oscillation in MSNA did not change during any intervention. We conclude that alpha-adrenergic modulation contributes to LF oscillations in BP and RRi during baroreceptor unloading (LBNP) but not during static exercise. Also, alpha-adrenergic modulation partly explains the shift to a higher frequency of LF oscillations during baroreceptor unloading and muscle metaboreflex activation. PMID- 21602294 TI - Uraemic serum induces dysfunction of vascular endothelial cells: role of ubiquitin-proteasome pathway. AB - The ubiquitin-proteasome pathway (UPP) has been indicated to contribute to dysfunction of endothelial cells (ECs). Nevertheless, the relationship between UPP and vascular complications of uraemia remains unknown. We aimed to determine whether the UPP is activated in vascular ECs when cultured with uraemic serum, and to examine the role of the UPP on dysfunction of ECs in uraemia. Rabbit aortic endothelial cells (RAECs) were cultured with normal serum or different concentrations of uraemic serum. The expression of the ubiquitin-activating enzyme (E1), an indicator of the UPP, was detected by real-time RT-PCR and Western blot; proteasome activity was determined by fluorescence spectrophotometry; and nuclear factor-kappaB (NF-kappaB) activity and expression, as well as tumour necrosis factor-alpha (TNF-alpha) expression, were also detected. We found that the expression of E1 and the activities of three kinds of proteasomes were increased significantly in RAECs after incubation with uraemic serum. Proliferation of RAECs was increased significantly by incubation with 3 15% uraemic serum but decreased markedly when incubated with uraemic serum above 15% (increased apoptosis). Incubation of RAECs with uraemic serum induced increased NF-B DNA-binding activity and nuclear translocation of NF-kappaB, decreased nitric oxide production and increased expression of TNF-alpha, which is the final effector of inflammatory activation of cells. All of these responses in RAECs were suppressed by the specific proteasome inhibitor, MG132. The inhibition of inflammatory responses by MG132 was further supported by a parallel experiment with pyrrolidine dithiocarbamate, a specific inhibitor of kappaNF-B. These findings suggest that the UPP was activated in RAECs by administration of uraemic serum, and played a pivotal role in the dysfunction of vascular ECs, such as inflammatory activation. PMID- 21602295 TI - Changes in the control of skin blood flow with exercise training: where do cutaneous vascular adaptations fit in? AB - Heat is the most abundant byproduct of cellular metabolism. As such, dynamic exercise in which a significant percentage of muscle mass is engaged generates thermoregulatory demands that are met in part by increases in skin blood flow. Increased skin blood flow during exercise adds to the demands on cardiac output and confers additional circulatory strain beyond that associated with perfusion of active muscle alone. Endurance exercise training results in a number of physiological adaptations which ultimately reduce circulatory strain and shift thermoregulatory control of skin blood flow to higher levels of blood flow for a given core temperature. In addition, exercise training induces peripheral vascular adaptations within the cutaneous microvasculature indicative of enhanced endothelium-dependent vasomotor function. However, it is not currently clear how (or if) these local vascular adaptations contribute to the beneficial changes in thermoregulatory control of skin blood flow following exercise training. The purpose of this Hot Topic Review is to synthesize the literature pertaining to exercise training-mediated changes in cutaneous microvascular reactivity and thermoregulatory control of skin blood flow. In addition, we address mechanisms driving changes in cutaneous microvascular reactivity and thermoregulatory control of skin blood flow, and pose the question: what (if any) is the functional role of increased cutaneous microvascular reactivity following exercise training? PMID- 21602296 TI - Baroreflex control of renal sympathetic nerve activity and heart rate in near term fetal sheep. AB - Late preterm infants, born between 34 and 36 weeks gestation, have significantly higher morbidity than neonates born at full term, which may be partly related to reduced sensitivity of the arterial baroreflex. The present study assessed baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in near-term fetal sheep at 123 +/- 1 days gestation. At this age, although fetuses are not fully mature in some respects (term is 147 days), sleep-state cycling is established [between high-voltage, low-frequency (HV) and low-voltage, high-frequency (LV) sleep], and neural myelination is similar to the term human infant. Fetal sheep were instrumented to record blood pressure (BP), HR (n = 15) and RSNA (n = 5). Blood pressure was manipulated using vasoactive drugs, phenylephrine and sodium nitroprusside. In both HV and LV sleep, phenylephrine was associated with increased arterial BP and decreased HR. In HV sleep, phenylephrine was associated with a fall in RSNA, from 124 +/- 14 to 58 +/- 11% (P < 0.05), but no significant change in RSNA in LV sleep. In contrast, the fall in BP after sodium nitroprusside was associated with a significant increase in HR during LV but not HV sleep, and there was no significant effect of hypotension on RSNA. These data demonstrate that in near-term fetal sheep baroreflex activity is only partly active and is highly modulated by sleep state. Critically, there was no RSNA response to marked hypotension; this finding has implications for the ability of the late preterm fetus to adapt to low BP. PMID- 21602297 TI - Angiotensin II-induced dilated cardiomyopathy in Balb/c but not C57BL/6J mice. AB - Balb/c mice, which are T-helper lymphocyte 2 (Th2) responders, are highly susceptible to infectious and non-infectious heart diseases, whereas C57BL/6 mice (Th1 responders) are not. Angiotensin II (Ang II) is not only a vasopressor but also a pro-inflammatory factor that leads to cardiac hypertrophy, fibrosis and dysfunction. We hypothesized that Ang II exacerbates cardiac damage in Balb/c but not in C57BL/6 mice even though both strains have a similar level of hypertension. Twelve-week-old male C57BL/6J and Balb/c mice received either vehicle or Ang II (1.4 mg kg(-1) day(-1), s.c. via osmotic minipump) for 8 weeks. At baseline, Balb/c mice exhibited the following: (1) a lower heart rate; (2) an enlarged left ventricular chamber; (3) a lower ejection fraction and shortening fraction; and (4) twice the left ventricular collagen deposition of age-matched C57BL/6J mice. Angiotensin II raised systolic blood pressure (to ~150 mmHg) and induced cardiomyocyte hypertrophy in a similar manner in both strains. While C57BL/6J mice developed compensatory concentric hypertrophy and fibrosis in response to Ang II, Balb/c mice demonstrated severe left ventricular chamber dilatation, wall thinning and fibrosis, leading to congestive heart failure as evidenced by dramatically decreased ejection fraction and lung congestion (significant increase in lung weight), which are both characteristic of dilated cardiomyopathy. Our study suggests that the Th phenotype plays an active role in cardiac remodelling and function both in basal conditions and in hypertension. Angiotensin II-induced dilated cardiomyopathy in Balb/c mice is an ideal animal model for studying the impact of the adaptive immune system on cardiac remodelling and function and for testing strategies to prevent or treat hypertension-associated heart failure. PMID- 21602299 TI - Curcumin sensitizes acute promyelocytic leukemia cells to unfolded protein response-induced apoptosis by blocking the loss of misfolded N-CoR protein. AB - Acute promyelocytic leukemia (APL) is characterized by accumulation of apoptosis resistant immature promyelocytic cells in the bone marrow and peripheral blood. We have shown that endoplasmic reticulum (ER)-associated degradation (ERAD) and protease-mediated degradation of misfolded nuclear receptor corepressor (N-CoR) confer resistance to unfolded protein response (UPR)-induced apoptosis in APL. These findings suggest that therapeutic inhibition of N-CoR misfolding or degradation may promote growth arrest in APL cells by sensitizing them to UPR induced apoptosis. On the basis of this hypothesis, we tested the effects of several known protein conformation-modifying agents on the growth and survival of APL cells and identified curcumin, a natural component of turmeric, as a potent growth inhibitor of APL cells. Curcumin selectively inhibited the growth and promoted apoptosis in both primary and secondary leukemic cells derived from APL. The curcumin-induced apoptosis of APL cells was triggered by an amplification of ER stress, possibly from the accumulation of misfolded N-CoR protein in the ER. Curcumin promoted this net accumulation of aberrantly phosphorylated misfolded N CoR protein by blocking its ERAD and protease-mediated degradation, which then led to the activation of UPR-induced apoptosis in APL cells. The activation of UPR by curcumin was manifested by phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and eukaryotic translation initiation factor 2 alpha (eIF2alpha), and upregulation of C/EBP homologous protein (CHOP) and GADD34, the principal mediators of proapoptotic UPR. These findings identify the therapeutic potential of curcumin in APL and further establish the rationale of misfolded N-CoR protein as an attractive molecular target in APL. PMID- 21602300 TI - Age-specific differences in influenza A epidemic curves: do children drive the spread of influenza epidemics? AB - There is accumulating evidence suggesting that children may drive the spread of influenza epidemics. The objective of this study was to quantify the lead time by age using laboratory-confirmed cases of influenza A for the 1995/1996-2005/2006 seasons from Canadian communities and laboratory-confirmed hospital admissions for the H1N1/2009 pandemic strain. With alignment of the epidemic curves locally before aggregation of cases, slight age-specific differences in the timing of infection became apparent. For seasonal influenza, both the 10-19- and 20-29-year age groups peaked 1 week earlier than other age groups, while during the fall wave of the 2009 pandemic, infections peaked earlier among only the 10-19-year age group. In the H3N2 seasons, infections occurred an average of 3.9 (95% confidence interval: 1.7, 6.1) days earlier in the 20-29-year age group than for youth aged 10-19 years, while during the fall pandemic wave, the 10-19-year age group had a statistically significant lead of 3 days compared with both younger children aged 4-9 years and adults aged 20-29 years (P < 0.0001). This analysis casts doubt on the hypothesis that younger school-age children actually lead influenza epidemic waves. PMID- 21602298 TI - Adaptation and visual coding. AB - Visual coding is a highly dynamic process and continuously adapting to the current viewing context. The perceptual changes that result from adaptation to recently viewed stimuli remain a powerful and popular tool for analyzing sensory mechanisms and plasticity. Over the last decade, the footprints of this adaptation have been tracked to both higher and lower levels of the visual pathway and over a wider range of timescales, revealing that visual processing is much more adaptable than previously thought. This work has also revealed that the pattern of aftereffects is similar across many stimulus dimensions, pointing to common coding principles in which adaptation plays a central role. However, why visual coding adapts has yet to be fully answered. PMID- 21602301 TI - Covariate selection in high-dimensional propensity score analyses of treatment effects in small samples. AB - To reduce bias by residual confounding in nonrandomized database studies, the high-dimensional propensity score (hd-PS) algorithm selects and adjusts for previously unmeasured confounders. The authors evaluated whether hd-PS maintains its capabilities in small cohorts that have few exposed patients or few outcome events. In 4 North American pharmacoepidemiologic cohort studies between 1995 and 2005, the authors repeatedly sampled the data to yield increasingly smaller cohorts. They identified potential confounders in each sample and estimated both an hd-PS that included 0-500 covariates and treatment effects adjusted by decile of hd-PS. For sensitivity analyses, they altered the variable selection process to use zero-cell correction and, separately, to use only the variables' exposure association. With >50 exposed patients with an outcome event, hd-PS-adjusted point estimates in the small cohorts were similar to the full-cohort values. With 25-50 exposed events, both sensitivity analyses yielded estimates closer to those obtained in the full data set. Point estimates generally did not change as compared with the full data set when selecting >300 covariates for the hd-PS. In these data, using zero-cell correction or exposure-based covariate selection allowed hd-PS to function robustly with few events. hd-PS is a flexible analytical tool for nonrandomized research across a range of study sizes and event frequencies. PMID- 21602302 TI - The C-terminal end of the Trypanosoma brucei editing deaminase plays a critical role in tRNA binding. AB - Adenosine to inosine editing at the wobble position allows decoding of multiple codons by a single tRNA. This reaction is catalyzed by adenosine deaminases acting on tRNA (ADATs) and is essential for viability. In bacteria, the anticodon specific enzyme is a homodimer that recognizes a single tRNA substrate (tRNA(Arg)(ACG)) and can efficiently deaminate short anticodon stem-loop mimics of this tRNA in vitro. The eukaryal enzyme is composed of two nonidentical subunits, ADAT2 and ADAT3, which upon heterodimerization, recognize seven to eight different tRNAs as substrates, depending on the organism, and require a full-length tRNA for activity. Although crystallographic data have provided clues to why the bacterial deaminase can utilize short substrates, residues that provide substrate binding and recognition with the eukaryotic enzymes are not currently known. In the present study, we have used a combination of mutagenesis, binding studies, and kinetic analysis to explore the contribution of individual residues in Trypanosoma brucei ADAT2 (TbADAT2) to tRNA recognition. We show that deletion of the last 10 amino acids at the C terminus of TbADAT2 abolishes tRNA binding. In addition, single alanine replacements of a string of positively charged amino acids (KRKRK) lead to binding defects that correlate with losses in enzyme activity. This region, which we have termed the KR-domain, provides a first glance at key residues involved in tRNA binding by eukaryotic tRNA editing deaminases. PMID- 21602303 TI - Differentiating analogous tRNA methyltransferases by fragments of the methyl donor. AB - Bacterial TrmD and eukaryotic-archaeal Trm5 form a pair of analogous tRNA methyltransferase that catalyze methyl transfer from S-adenosyl methionine (AdoMet) to N(1) of G37, using catalytic motifs that share no sequence or structural homology. Here we show that natural and synthetic analogs of AdoMet are unable to distinguish TrmD from Trm5. Instead, fragments of AdoMet, adenosine and methionine, are selectively inhibitory of TrmD rather than Trm5. Detailed structural information of the two enzymes in complex with adenosine reveals how Trm5 escapes targeting by adopting an altered structure, whereas TrmD is trapped by targeting due to its rigid structure that stably accommodates the fragment. Free energy analysis exposes energetic disparities between the two enzymes in how they approach the binding of AdoMet versus fragments and provides insights into the design of inhibitors selective for TrmD. PMID- 21602304 TI - piRNA profiling during specific stages of mouse spermatogenesis. AB - PIWI-interacting RNAs (piRNAs) are a class of small RNAs abundantly expressed in animal gonads. piRNAs that map to retrotransposons are generated by a "ping-pong" amplification loop to suppress the activity of retrotransposons. However, the biogenesis and function of other categories of piRNAs have yet to be investigated. In this study, we first profiled the expression of small RNAs in type A spermatogonia, pachytene spermatocytes, and round spermatids by deep sequencing. We then focused on the computational analysis of the potential piRNAs generated in the present study as well as other published sets. piRNAs mapping to retrotransposons, mRNAs, and intergenic regions had different length distributions and were differentially regulated in spermatogenesis. piRNA generating mRNAs (PRMRs), whose expression positively correlated with their piRNA products, constituted one-third of the protein-coding genes and were evolutionarily conserved and enriched with splicing isoforms and antisense transcripts. PRMRs with piRNAs preferentially mapped to CDSs and 3' UTRs partitioned into three clusters differentially expressed during spermatogenesis and enriched with unique sets of functional annotation terms related to housekeeping activities as well as spermatogenesis-specific processes. Intergenic piRNAs were divided into 2992 clusters probably representing novel transcriptional units that have not been reported. The transcripts of a large number of genes involved in spermatogenesis are the precursors of piRNAs, and these genes are intricately regulated by alternative splicing and antisense transcripts. piRNAs, whose regulatory role in gene expression awaits to be identified, are clearly products of a novel regulatory process that needs to be defined. PMID- 21602305 TI - A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. AB - To map the genetics of gene expression in metabolically relevant tissues and investigate the diversity of expression SNPs (eSNPs) in multiple tissues from the same individual, we collected four tissues from approximately 1000 patients undergoing Roux-en-Y gastric bypass (RYGB) and clinical traits associated with their weight loss and co-morbidities. We then performed high-throughput genotyping and gene expression profiling and carried out a genome-wide association analyses for more than 100,000 gene expression traits representing four metabolically relevant tissues: liver, omental adipose, subcutaneous adipose, and stomach. We successfully identified 24,531 eSNPs corresponding to about 10,000 distinct genes. This represents the greatest number of eSNPs identified to our knowledge by any study to date and the first study to identify eSNPs from stomach tissue. We then demonstrate how these eSNPs provide a high quality disease map for each tissue in morbidly obese patients to not only inform genetic associations identified in this cohort, but in previously published genome-wide association studies as well. These data can aid in elucidating the key networks associated with morbid obesity, response to RYGB, and disease as a whole. PMID- 21602306 TI - The relationship between risk of hospitalization for schizophrenia, SES, and cognitive functioning. AB - Although most studies find low socioeconomic status (SES) to be associated with prevalence of schizophrenia, incidence studies do not generally support this, and some even report an inverse association. The objective of the current historical prospective study was to examine the relationship between SES, cognitive functioning, and risk of hospitalization for schizophrenia in a population-based sample of Israeli adolescents. Subjects were 811 487 adolescents, assessed by the Israeli military draft board for socio-demographic factors and cognitive functioning. Data on later hospitalization for schizophrenia were obtained from a population-based hospitalization registry. Findings indicated that when simply examining SES and schizophrenia, lower SES was associated with greater risk of hospitalization for schizophrenia (Hazard Ratio [HR] = 1.193, 95% CI = 1.091 1.303). When dividing the cohort into low, average, and high cognitive functioning, SES did not influence the risk for schizophrenia among individuals with high and average cognitive functioning, whereas among individuals with low cognitive functioning, high SES was found to slightly increase the risk for schizophrenia (HR = 1.21, 95% CI = 1.03-1.42). One possible explanation for this finding might be that among individuals from low socioeconomic backgrounds, low IQ may reflect decreased opportunities related to SES, whereas among individuals from high SES backgrounds, low IQ might reflect risk for later psychopathology. PMID- 21602307 TI - Understanding suboptimal human papillomavirus vaccine uptake among ethnic minority girls. AB - BACKGROUND: The introduction of human papillomavirus (HPV) vaccines represents a breakthrough in the primary prevention of cervical cancer. However, little is known about vaccination uptake and correlates among low-income, ethnic minority, and immigrant populations in the U.S. who may benefit most from the vaccine. METHODS: Telephone interviews (N = 490) were conducted in six languages between January and November 2009 among mothers of vaccine-eligible girls (ages 9-18) using the Los Angeles County Department of Public Health, Office of Women's Health service referral hotline. HPV and vaccine awareness, knowledge, beliefs, barriers, and daughter's vaccine receipt were assessed. RESULTS: The sample consisted of low-income, uninsured, ethnic minority, and immigrant women. Only 29% of daughters initiated the vaccine and 11% received all three doses. No ethnic differences were observed in initiation or completion rates. Ethnic differences were observed in HPV awareness, perceived risk, and other vaccine related beliefs. The strongest predictor of initiation was vaccine awareness (OR = 12.00). Daughter's age and reporting a younger acceptable age for vaccination were positively associated with initiation. Mothers of unvaccinated girls reported lacking information about the vaccine to make a decision (66%) and not knowing where they could obtain the vaccine (74%). CONCLUSION: Vaccination rates in this sample were lower than state and national estimates, and were associated with low levels of vaccine awareness. Interventions, including culturally targeted messaging, may be helpful for enhancing HPV-vaccine knowledge, modifying vaccine-related beliefs and increasing uptake. IMPACT: Our findings provide valuable guidance for developing interventions to address suboptimal HPV vaccination in high-risk groups. PMID- 21602308 TI - Racial differences in colorectal cancer incidence and mortality in the Women's Health Initiative. AB - BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates are higher in African-Americans as compared with other racial/ethnic groups. The women's health initiative (WHI) study sample was used to determine whether differences in CRC risk factors explain racial/ethnic differences in incidence and mortality. METHODS: The WHI is a longitudinal study of postmenopausal women recruited from 40 centers. Baseline questionnaires were used to collect sociodemographic and health status information. All CRC diagnoses were centrally adjudicated. Cox regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for invasive CRC by race/ethnicity. RESULTS: The study sample included 131,481 (83.7%) White, 14,323 (9.1%) African-American, 6,362 (4.1%) Hispanic, 694 (0.4%) Native American and 4,148 (2.6%) Asian/Pacific Islanders. After a mean follow-up of 10.8 years (SD 2.9), CRC incidence was the highest in African-Americans (annualized rate = 0.14%), followed by Whites and Native Americans (0.12% each), Asian/Pacific Islanders (0.10%), and Hispanics (0.08%). After adjustment for age and trial assignment, Hispanics had a lower risk compared with Whites, HR 0.73 (95% CI: 0.54-0.97) (P = 0.03), and African Americans had a marginally greater risk, HR 1.16 (95% CI: 0.99-1.34), P = 0.06. Multivariable adjustment attenuated the difference in incidence between African Americans and Whites (HR 0.99, 95% CI: 0.82-1.20), while strengthening the lower HR for Hispanics (HR 0.68, 95% CI: 0.48-0.97). CONCLUSIONS: African American/White differences in CRC risk are likely due to sociodemographic/cultural factors other than race. IMPACT: A number of modifiable exposures could be a focus for reducing CRC risk in African-Americans. PMID- 21602309 TI - Inactivation of tautomerase activity of macrophage migration inhibitory factor by sulforaphane: a potential biomarker for anti-inflammatory intervention. AB - BACKGROUND: Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine with keto-enol tautomerase activity, rises rapidly in response to inflammation and is elevated in many chronic diseases. Isothiocyanates, such as sulforaphane from broccoli, are very potent inactivators of MIF tautomerase activity. A simple rapid method for determining this activity in tissues and body fluids may therefore be valuable for assessing severity of inflammation and efficacy of intervention. METHODS: Existing spectrophotometric assays of MIF, based on conversion of methyl L-dopachrome to methyl 5,6-dihydroxyindole-2 carboxylate and associated loss of absorption at 475 nm, lack sensitivity. Assay sensitivity and efficiency were markedly improved by reducing the nonenzymatic rate, by lowering pH to 6.2, replacing phosphate (which catalyzes the reaction) with Bis-Tris buffer, and converting to a microtiter plate format. RESULTS: A structure-potency study of MIF tautomerase inactivation by isothiocyanates showed that sulforaphane, benzyl, n-hexyl, and phenethyl isothiocyanates were especially potent. MIF tautomerase could be readily quantified in human urine concentrated by ultrafiltration. This activity comprised: (i) a heat-labile, sulforaphane inactivated macromolecular fraction (presumably MIF) that was concentrated during ultrafiltration; (ii) a flow-through fraction, with constant activity during filtration, that was heat stable and insensitive to sulforaphane. Administration of the sulforaphane precursor glucoraphanin to human volunteers almost completely abolished urinary tautomerase activity, which recovered over many hours. CONCLUSION: A simple, rapid, quantitative MIF tautomerase assay has been developed as a potential biomarker for assessing inflammatory severity and effectiveness of intervention. IMPACT: An improved assay for measuring MIF tautomerase activity and its applications are described. PMID- 21602311 TI - A single dose mass balance study of the Hedgehog pathway inhibitor vismodegib (GDC-0449) in humans using accelerator mass spectrometry. AB - Vismodegib (GDC-0449), a small-molecule Hedgehog pathway inhibitor, was well tolerated in patients with solid tumors and showed promising efficacy in advanced basal cell carcinoma in a Phase I trial. The purpose of the study presented here was to determine routes of elimination and the extent of vismodegib metabolism, including assessment and identification of metabolites in plasma, urine, and feces. Six healthy female subjects of nonchildbearing potential were enrolled; each received a single 30-ml oral suspension containing 150 mg of vismodegib with 6.5 MUg of [(14)C]vismodegib to yield a radioactivity dose of approximately 37 kBq (1000 nCi). Plasma, urine, and feces samples were collected over 56 days to permit sample collection for up to 5 elimination half-lives. Nonradioactive vismodegib was measured in plasma using liquid chromatographic-tandem mass spectrometry, and total radioactivity in plasma, urine, and feces was measured using accelerator mass spectrometry. Vismodegib was slowly eliminated by a combination of metabolism and excretion of parent drug, most of which was recovered in feces. The estimated excretion of the administered dose was 86.6% on average, with 82.2 and 4.43% recovered in feces and urine, respectively. Vismodegib was predominant in plasma, with concentrations representing >98% of the total circulating drug-related components. Metabolic pathways of vismodegib in humans included oxidation, glucuronidation, and uncommon pyridine ring cleavage. We conclude that vismodegib and any associated metabolic products are mainly eliminated through feces after oral administration in healthy volunteers. PMID- 21602310 TI - A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort Study. AB - BACKGROUND: Human papillomavirus (HPV) DNA testing is more sensitive than cytology for detection of cervical intraepithelial neoplasia grade 3 and cancer (>=CIN3). Adding HPV testing to cytology is recommended for women >=30 but long term prospective studies of HPV testing are rare. METHODS: Beginning in 1989 1990, ~20,000 women in a prepaid health maintenance organization (median age = 34) were followed passively by recommended annual cytology. We tested archived cervicovaginal lavage specimens collected at enrollment, primarily by MY09-MY11 PCR-based methods, for carcinogenic HPV types. We calculated positive and negative predictive values for the entire study period, and Kaplan-Meier estimates of cumulative probability for >=CIN3, up to 18 years of follow-up. RESULTS: We observed 47 cases of invasive cervical cancer during the study period, and 156 cases of CIN3. Predictive values and Kaplan-Meier analyses yielded the same conclusions. In women 30 and older, the reassurance against >=CIN3 following a single negative HPV test was long-lasting (cumulative probability = 0.7% during follow-up). In this age group, a single HPV test (positive vs. negative, hazard ratio of 8.5, 95% CI = 4.8-15.1) provided greater long-term risk stratification than a single cytologic result (abnormal vs. normal, HR = 2.9, 95% CI = 1.2-6.6). The risk for >=CIN3 was higher for HPV16 than for the average of the other carcinogenic types (hazard ratio = 2.7). CONCLUSION AND IMPACT: The data from this cohort study show the long-term predictive value of HPV testing, particularly in women >=30, and a possible role for distinguishing particularly carcinogenic types like HPV16. PMID- 21602312 TI - Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells. AB - Glucocorticoids (Gcs) are commonly used to treat patients suffering from a wide range of cancers. Their main therapeutic role is based on Gc receptor (GR) mediated mechanisms that trigger cell death but this varies depending on the cancer type. This review aims to provide an overview of the mechanisms of Gc induced cell death and more importantly the changes in GR that lead to resistance to Gc treatment in cancer. The three main cancer types, which are susceptible to Gc resistance and therefore loss of Gc-induced apoptotic effects, are acute lymphoblastic leukaemia, osteosarcoma and small-cell lung carcinoma. A common theme is the loss of GR function and/or a downregulation of GR expression which leads to failure of the cell death-inducing effects of Gcs. Loss of GR function is attributed to mutations in the GR gene, and in some cases a dominant-negative effect on any functional GR still present. The downregulation of GR expression can be due to decreased GR promoter activation, increased GR promoter methylation or increased expression of alternative splice isoforms of GR that have decreased transcriptional activity. Understanding the mechanisms behind Gc-triggered apoptosis and the resistance to it in these cancer types will help in further refining treatment regimens for patients and will decrease the chance of relapse caused by Gc-resistant cancer phenotypes. PMID- 21602314 TI - Anti-Mullerian hormone confirms the novel classification of female functional androgenization including polycystic ovary syndrome. AB - OBJECTIVE: Functional androgenization (FA) can be divided into five groups corresponding to the predominant organ pathology as recently shown by our group: functional cutaneous androgenization (FCA, skin) and FA syndrome (FAS) I (ovary, lean individual), II (adrenal gland), III (ovary, fat tissue, pancreas, and hyperinsulinemia), and IV (residual FA dysfunctions). Group-specific clusters are based on primary variables such as LH, testosterone, DHEAS, sex hormone-binding globulin (SHBG), body mass index (BMI), glucose, insulin, and enlarged polyfollicular ovaries. Because anti-Mullerian hormone (AMH) positively correlates with the antral follicle count, its relevance as an additional primary variable for classifying FA was investigated. DESIGN: In this study, 178 patients with FA were consecutively enrolled and classified into the five FA groups as described earlier and 30 women with regular menstrual cycles served as control. METHODS: Primary variables and serum AMH were analyzed in the early follicular phase. RESULTS: FA patients showed significantly elevated AMH levels (11.1+/-6.7 ng/ml) versus control (3.0+/-2.0 ng/ml; P<.0001). AMH was significantly increased in groups FAS I (15.6+/-5.8 ng/ml) and FAS III (11.6+/-6.6 ng/ml) compared with groups FCA (7.0+/-3.8 ng/ml), FAS II (5.05+/-3.0 ng/ml), and FAS IV (6.9+/-4.6 ng/ml) and correlated positively (P<.0001) with LH (r=0.538) and testosterone (r=0.368). In regression and multivariate analyses, AMH was not dependent on SHBG, DHEAS, BMI, glucose, or insulin. In receiver operating characteristic analysis, 9.21 ng/ml AMH showed 90% specificity with 71.2% sensitivity for the diagnosis of the two ovarian FA groups, FAS I and III. CONCLUSION: AMH confirms the novel stratification system and constitutes a useful primary variable in the algorithm of FA classification. PMID- 21602313 TI - Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet. AB - OBJECTIVE: Short-term energy deprivation reduces leptin concentrations and alters the levels of circulating hormones of the hypothalamic-pituitary-peripheral axis in lean subjects. Whether the reduction in leptin concentration during long-term weight loss in obese individuals is linked to the same neuroendocrine changes seen in lean, leptin-sensitive subjects remains to be fully clarified. METHODS: In this study, 24 overweight and obese adults (16 women and eight men; body mass index (BMI): 27.5-38.0 kg/m(2)) were prescribed a hypocaloric diet (-500 kcal/day) and were randomized to receive recombinant methionyl leptin (n=18, metreleptin, 10 mg/day self-injected s.c.) or placebo (n=6, same volume and time as metreleptin) for 6 months. RESULTS: Metreleptin administration did not affect weight loss beyond that induced by hypocaloric diet alone (P for interaction=0.341) but increased the serum concentrations of total leptin by six- to eight-fold (P<0.001) and led to the generation of anti-leptin antibodies. Despite free leptin concentration (P for interaction=0.041) increasing from 9+/-1 ng/ml at baseline to 43+/-15 and 36+/-12 ng/ml at 3 and 6 months, respectively, changes in circulating hormones of the thyroid and IGF axes at 3 and 6 months were not significantly different in the placebo- and metreleptin-treated groups. CONCLUSIONS: Leptin does not likely mediate changes in neuroendocrine function in response to weight loss induced by a mild hypocaloric diet in overweight and obese subjects. PMID- 21602315 TI - Adrenal vein sampling using rapid cortisol assays in primary aldosteronism is useful in centers with low success rates. AB - OBJECTIVE: Adrenal vein sampling (AVS) is considered the gold standard in the differential diagnosis of primary aldosteronism (PA), but success rates vary between centers. We hypothesized that rapid (intraprocedure) cortisol measurement can improve performance in a center with initially low AVS success rate. DESIGN: We analyzed 46 patients with confirmed PA studied between 2008 and 2010. Forty seven PA patients studied between 2004 and 2008 identified by retrospective chart review served as controls. All patients were treated at a single tertiary care university hospital. METHODS: Starting in 2008, rapid cortisol assays (RCA) were performed in all patients during the AVS procedure. A cortisol gradient of >=2.0 between adrenal vein and a femoral vein sample was used as success criterion. Up to two repeat samples were drawn if adrenal vein cortisol was below this threshold. Results During the control period 26 of 47 AVS were successful (55%). After introduction of RCA, 39 out of 46 AVS (85%) were successful (P=0.003). In 21 of the 46 cases (46%) a resampling was necessary. The increase in overall success was due to an increase in successful right AVS (85 vs 62% before introduction of RCA; P=0.02) and a training effect (P=0.024 for trend). CONCLUSION: RCA during AVS are useful in centers with an initially low AVS success rate. PMID- 21602316 TI - Sexual desire in female-to-male transsexual persons: exploration of the role of testosterone administration. AB - OBJECTIVE: To describe sexual desire in female-to-male transsexual persons post sex reassignment surgery (SRS). The associations between serum androgen levels and sexual desire are examined. DESIGN: Single center cross-sectional study. METHODS: Forty-five female-to-male transsexual persons post SRS completed a standardized questionnaire assessing sexual desire (Sexual Desire Inventory). In addition, participants were asked questions on sexual desire before starting hormone treatment and having SRS. Serum levels of testosterone, LH and sex hormone-binding globulin were measured on fasting morning serum samples. RESULTS: In retrospect, 73.9% of the participants reported an increase in sexual desire after hormone treatment and SRS. Solitary sexual desire scores were significantly correlated with frequency of masturbation (r=0.835; P<0.001), whereas frequency of sexual intercourse with a partner was not. No direct associations were found between testosterone and solitary or dyadic sexual desire. However, ANOVA showed an independent effect of LH on solitary sexual desire (P<0.001). Post hoc analysis revealed that female-to-male transsexual persons with elevated levels of LH, indicating suboptimal testosterone therapy, reported significantly lower solitary sexual desire levels (than those with low LH levels; P=0.007). Suppressed LH levels were also associated with having a higher need for sexual activities (P=0.009) and a higher frequency of excessive sexual desire (P=0.007). CONCLUSION: Most female-to-male transsexual persons report on a marked increase in sexual desire after testosterone treatment and SRS. No direct associations between levels of testosterone and solitary or dyadic sexual desire were found. However, measures of sexual desire were inversely associated with LH levels. PMID- 21602317 TI - Cancer risk in hyperprolactinemia patients: a population-based cohort study. AB - OBJECTIVE: Experimental evidence indicates that prolactin might play a role in tumorigenesis of several human cancers, but data on cancer risk in hyperprolactinemia patients are sparse. The aim of this study was to investigate cancer risk in hyperprolactinemia patients. Design A population-based matched cohort study in Sweden. METHODS: The hyperprolactinemia cohort consisted of patients hospitalized for hyperprolactinemia from 1987 to 1995 identified in the National Patient Register (n=585) and a hospital cohort of prolactinoma patients at Karolinska University Hospital (n=384). For each patient, ten matched individuals were identified via the Register of Population. Cancer occurrence was ascertained via the Swedish Cancer Registry. Hazard ratios (HRs) were estimated by Cox proportional hazards regression. RESULTS: Seventy-three malignant tumors were identified in the hyperprolactinemia patients and 660 tumors in the comparison group (HR 1.31; 95% confidence interval (CI): 1.02-1.68), mainly attributed to an increased risk of upper gastrointestinal cancer in both males and females (HR 3.69; 95% CI: 1.70-8.03) and hematopoietic cancer in females (HR 3.51; 95% CI: 1.06-11.6). Twelve breast cancers occurred in the female patients, corresponding to an HR of 1.09 (95% CI: 0.60-1.99). Prostate cancer risk in hyperprolactinemia men was reduced (HR 0.40; 95% CI: 0.16-0.99). CONCLUSIONS: An increased overall cancer risk was found in hyperprolactinemia patients, but no increased risk of breast cancer in women and a reduced risk of prostate cancer in men. These findings warrant further investigations and to be confirmed in larger studies but may indicate the importance of an active treatment strategy and follow-up of hyperprolactinemia patients. PMID- 21602318 TI - The Endocrine Society's Clinical Practice Guideline on endocrine and nutritional management of the post-bariatric surgery patient: commentary from a European Perspective. AB - Bariatric and metabolic surgery is experiencing a noteworthy increase worldwide in recent years, but protocols and consensus published in the past decade have not yet established clear evidence-based clinical recommendations. The Endocrine Society, with the participation of the European Society of Endocrinology, has promoted the creation of an expert panel to propose a clinical practice guideline for postoperative management of patients, candidates to bariatric surgery, that places a particular emphasis on evidence-based medical aspects. The main arguments reflected in those recommendations are set out in this article and are subject to analysis and discussion from the specific viewpoint of the current European experience. PMID- 21602319 TI - Phosphodiesterases in endocrine physiology and disease. AB - The cAMP-protein kinase A pathway plays a central role in the development and physiology of endocrine tissues. cAMP mediates the intracellular effects of numerous peptide hormones. Various cellular and molecular alterations of the cAMP signaling pathway have been observed in endocrine diseases. Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP levels. Indeed, PDEs are the only known mechanism for inactivation of cAMP by catalysis to 5'-AMP. It has been suggested that disruption of PDEs could also have a role in the pathogenesis of many endocrine diseases. This review summarizes the most recent advances concerning the role of the PDEs in the physiopathology of endocrine diseases. The potential significance of this knowledge can be easily envisaged by the development of drugs targeting specific PDEs. PMID- 21602320 TI - Independence of first- and second-order memories in newborn rabbits. AB - The mammary pheromone promotes the acquisition of novel odorants (CS1) in newborn rabbits. Here, experiments pinpoint that CS1 becomes able to support neonatal learning of other odorants (CS2). We therefore evaluated whether these first- and second-order memories remained dependent after reactivation. Amnesia induced after CS2 recall selectively blocked this memory, when recall and amnesia of CS1 left the souvenir of CS2 safe; this finding partially differed from results obtained in adult mammals. Thus, in this model of neonatal appetitive odor learning, second-order memory seems to depend on first-order memory for its formation but not for its maintenance. PMID- 21602321 TI - Interactions between brainstem noradrenergic neurons and the nucleus accumbens shell in modulating memory for emotionally arousing events. AB - The nucleus accumbens shell (NAC) receives axons containing dopamine-beta hydroxylase that originate from brainstem neurons in the nucleus of the solitary tract (NTS). Recent findings show that memory enhancement produced by stimulating NTS neurons after learning may involve interactions with the NAC. However, it is unclear whether these mnemonic effects are mediated by norepinephrine (NE) release from NTS terminals onto NAC neurons. The present studies approached this question by examining the contribution of NAC alpha-noradrenergic receptors in mediating this effect and assessed whether glutamatergic activation of the NTS alters NE concentrations in the NAC. Rats were trained for 6 d to drink from a water spout located at the end of an inhibitory avoidance chamber. On day 7, a 0.35-mA footshock was initiated once the rat approached the spout and remained active until it escaped into the neutral compartment. Blockade of alpha noradrenergic receptors in the NAC with phentolamine (0.5 ug/0.5 uL) attenuated memory enhancement produced by glutamatergic (50 ng/0.5 uL) infusion on NTS neurons (P < 0.01). Experiment 2 used in vivo microdialysis to assess whether glutamate activation of NTS alters NAC NE concentrations. NE levels were unchanged by NTS infusion of phosphate-buffered saline (PBS) or low dose glutamate (50 ng/0.5 uL) but elevated significantly (P < 0.05) by combining the same dose with the footshock (0.35 mA, 2 sec) given in Study 1 or infusion of (100 ng/0.5 uL) glutamate alone. Findings demonstrate that NE released from NTS terminals enhances representations in memory by acting on alpha-noradrenergic receptors within the NAC. PMID- 21602322 TI - Effects of flow and colony morphology on the thermal boundary layer of corals. AB - The thermal microenvironment of corals and the thermal effects of changing flow and radiation are critical to understanding heat-induced coral bleaching, a stress response resulting from the destruction of the symbiosis between corals and their photosynthetic microalgae. Temperature microsensor measurements at the surface of illuminated stony corals with uneven surface topography (Leptastrea purpurea and Platygyra sinensis) revealed millimetre-scale variations in surface temperature and thermal boundary layer (TBL) that may help understand the patchy nature of coral bleaching within single colonies. The effect of water flow on the thermal microenvironment was investigated in hemispherical and branching corals (Porites lobata and Stylophora pistillata, respectively) in a flow chamber experiment. For both coral types, the thickness of the TBL decreased exponentially from 2.5 mm at quasi-stagnant flow (0.3 cm s(-1)), to 1 mm at 5 cm s(-1), with an exponent approximately 0.5 consistent with predictions from the heat transfer theory for simple geometrical objects and typical of laminar boundary layer processes. Measurements of mass transfer across the diffusive boundary layer using O(2) microelectrodes revealed a greater exponent for mass transfer when compared with heat transfer, indicating that heat and mass transfer at the surface of corals are not exactly analogous processes. PMID- 21602324 TI - Analgesic use and its effect on male reproduction. PMID- 21602323 TI - Developing rice with high yield under phosphorus deficiency: Pup1 sequence to application. AB - The major quantitative trait locus (QTL) Phosphorus uptake1 (Pup1) confers tolerance of phosphorus deficiency in soil and is currently one of the most promising QTLs for the development of tolerant rice (Oryza sativa) varieties. To facilitate targeted introgression of Pup1 into intolerant varieties, the gene models predicted in the Pup1 region in the donor variety Kasalath were used to develop gene-based molecular markers that are evenly distributed over the fine mapped 278-kb QTL region. To validate the gene models and optimize the markers, gene expression analyses and partial allelic sequencing were conducted. The markers were tested in more than 80 diverse rice accessions revealing three main groups with different Pup1 allele constitution. Accessions with tolerant (group I) and intolerant (group III) Pup1 alleles were distinguished from genotypes with Kasalath alleles at some of the analyzed loci (partial Pup1; group II). A germplasm survey additionally confirmed earlier data showing that Pup1 is largely absent from irrigated rice varieties but conserved in varieties and breeding lines adapted to drought-prone environments. A core set of Pup1 markers has been defined, and sequence polymorphisms suitable for single-nucleotide polymorphism marker development for high-throughput genotyping were identified. Following a marker-assisted backcrossing approach, Pup1 was introgressed into two irrigated rice varieties and three Indonesian upland varieties. First phenotypic evaluations of the introgression lines suggest that Pup1 is effective in different genetic backgrounds and environments and that it has the potential to significantly enhance grain yield under field conditions. PMID- 21602325 TI - Complete genome sequence of Gallibacterium anatis strain UMN179, isolated from a laying hen with peritonitis. AB - Gallibacterium anatis is a member of the normal flora of avian hosts and an important causative agent of peritonitis and salpingitis in laying hens. Here we report the availability of the first completed G. anatis genome sequence of strain UMN179, isolated from an Iowa laying hen with peritonitis. PMID- 21602326 TI - The xnp1 P2-like tail synthesis gene cluster encodes xenorhabdicin and is required for interspecies competition. AB - Xenorhabdus nematophila, the mutualistic bacterium of the nematode Steinernema carpocapsae, produces the R-type bacteriocin called xenorhabdicin, which is thought to confer a competitive advantage for growth in the insect host. We have identified a P2-like tail synthesis gene cluster (xnp1) that is required for xenorhabdicin production. The xnp1 genes were expressed constitutively during growth and were induced by mitomycin C. Deletion of either the sheath (xnpS1) or fiber (xnpH1) genes eliminated xenorhabdicin production. Production of R-type bacteriocins in a host organism had not been shown previously. We show that xenorhabdicin is produced in the hemocoel of insects infected with the wild type but not with the DeltaxnpS1 deletion strain. Xenorhabdicin prepared from the wild type strain killed the potential competitor Photorhabdus luminescens TT01. P. luminescens was eliminated during coculture with wild-type X. nematophila but not with the DeltaxnpS1 strain. Furthermore, P. luminescens inhibited reproduction of S. carpocapsae in insect larvae, while coinjection with wild-type X. nematophila, but not the DeltaxnpS1, strain restored normal reproduction, demonstrating that xenorhabdicin was required for killing P. luminescens and protecting the nematode partner. Xenorhabdicin killed X. nematophila from Steinernema anatoliense, demonstrating for the first time that it possesses intraspecies activity. In addition, activity was variable against diverse strains of Xenorhabdus and Photorhabdus and was not correlated with phylogenetic distance. These findings are discussed in the context of the role of xenorhabdicin in the life cycle of the mutualistic bacterium X. nematophila. PMID- 21602327 TI - Genome sequence of strain IMCC2047, a novel marine member of the Gammaproteobacteria. AB - Strain IMCC2047 was isolated from the Yellow Sea using dilution-to-extinction culturing. The strain was shown to occupy a distinct phylogenetic position within the Gammaproteobacteria. Here we present the genome sequence of strain IMCC2047, which harbors genes for various metabolic pathways, including proteorhodopsin and ribulose bisphosphate carboxylase. PMID- 21602328 TI - Genome sequence of the Enterobacter mori type strain, LMG 25706, a pathogenic bacterium of Morus alba L. AB - Enterobacter mori is a plant-pathogenic enterobacterium responsible for the bacterial wilt of Morus alba L. Here we present the draft genome sequence of the type strain, LMG 25706. To the best of our knowledge, this is the first genome sequence of a plant-pathogenic bacterium in the genus Enterobacter. PMID- 21602329 TI - Hfq is required for optimal nitrate assimilation in the Cyanobacterium Anabaena sp. strain PCC 7120. AB - Hfq is an RNA binding protein involved in posttranscriptional regulation of gene expression in bacteria. It acts by binding to regulatory small RNAs (sRNAs), which confer specificity for the regulation. Recently, orthologues of the Hfq protein were annotated in cyanobacterial genomes, although its capacity to regulate gene expression by interacting with sRNAs has not been yet demonstrated. Anabaena sp. strain PCC 7120 is a filamentous cyanobacterium that, in the absence of combined nitrogen, is able to fix atmospheric nitrogen by differentiating specialized cells called heterocysts. We have generated an hfq knockout mutant of Anabaena sp. PCC 7120. Deletion of this gene results in differentiation of heterocysts in the presence of nitrate, suggesting a defect in nitrate assimilation. We show that hfq mutant cells are affected in transport and use of nitrate and nitrite. An analysis of the expression of several genes in the nir operon, encoding different elements of the nitrate assimilation pathway, demonstrates a downregulation of their transcription in mutant cells. We also observed that genes ntcB and cnaT, involved in the regulation of the nir operon, show a lower expression in cells lacking Hfq. Finally, when hfq was reintroduced in the mutant, heterocyst differentiation was no longer observed in the presence of nitrate. Therefore, our results indicate that the RNA chaperone Hfq is involved in the regulation of the nir operon, although the mechanism for this regulation is still unknown. PMID- 21602330 TI - Genome sequence of lineage III Listeria monocytogenes strain HCC23. AB - More than 98% of reported human listeriosis cases are caused by Listeria monocytogenes serotypes within lineages I and II. Serotypes within lineage III (4a and 4c) are commonly isolated from environmental and food specimens. We report the first complete genome sequence of a lineage III isolate, HCC23, which will be used for comparative analysis. PMID- 21602331 TI - Genome sequence of Lactococcus garvieae UNIUD074, isolated in Italy from a lactococcosis outbreak. AB - Lactococcus garvieae is the etiological agent of lactococcosis disease, affecting many cultured fish species worldwide. In addition, this bacterium is currently considered a potential zoonotic microorganism since it is known to cause several opportunistic human infections. Here we present the draft genome sequence of the L. garvieae strain UNIUD074. PMID- 21602332 TI - Genome sequence of Escherichia coli AA86, isolated from cow feces. AB - Escherichia coli AA86 (=KACC 15541) is an enteric bacterium that was isolated from a sample of healthy cow feces. Its genome sequence revealed that it is most closely related to the human fecal strain E. coli SE15 and could be classified under E. coli phylogenetic group B2. Here, we report the genome sequence of E. coli AA86, consisting of 3 contigs and 2 plasmids. PMID- 21602333 TI - Broad-spectrum biofilm inhibition by Kingella kingae exopolysaccharide. AB - Cell-free extracts prepared from Kingella kingae colony biofilms were found to inhibit biofilm formation by Aggregatibacter actinomycetemcomitans, Klebsiella pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Candida albicans, and K. kingae. The extracts evidently inhibited biofilm formation by modifying the physicochemical properties of the cell surface, the biofilm matrix, and the substrate. Chemical and biochemical analyses indicated that the biofilm inhibition activity in the K. kingae extract was due to polysaccharide. Structural analyses showed that the extract contained two major polysaccharides. One was a linear polysaccharide with the structure ->6)-alpha-d-GlcNAcp-(1->5) beta-d-OclAp-(2->, which was identical to a capsular polysaccharide produced by Actinobacillus pleuropneumoniae serotype 5. The second was a novel linear polysaccharide, designated PAM galactan, with the structure ->3)-beta-d-Galf-(1 >6)-beta-d-Galf-(1->. Purified PAM galactan exhibited broad-spectrum biofilm inhibition activity. A cluster of three K. kingae genes encoding UDP galactopyranose mutase (ugm) and two putative galactofuranosyl transferases was sufficient for the synthesis of PAM galactan in Escherichia coli. PAM galactan is one of a growing number of bacterial polysaccharides that exhibit antibiofilm activity. The biological roles and potential technological applications of these molecules remain unknown. PMID- 21602334 TI - Genome sequence of strain IMCC1989, a novel member of the marine gammaproteobacteria. AB - Strain IMCC1989 is a novel member of the oligotrophic marine Gammaproteobacteria (OMG) group and is closely related with a symbiont group of the genera Teredinibacter and "Candidatus Endobugula." Here we present the genome sequence of strain IMCC1989, which was isolated from the Yellow Sea by using dilution-to extinction culturing. PMID- 21602335 TI - Role of dihydrolipoamide dehydrogenase in regulation of raffinose transport in Streptococcus pneumoniae. AB - Streptococcus pneumoniae strains lacking the enzyme dihydrolipoamide dehydrogenase (DLDH) show markedly reduced ability to grow on raffinose and stachyose as sole carbon sources. Import of these sugars occurs through the previously characterized raffinose ATP-binding cassette (ABC) transport system, encoded by the raf operon, that lacks the necessary ATP-binding protein. In this study, we identified the raffinose ATP-binding protein RafK and showed that it was directly involved in raffinose and stachyose import. RafK carries a C terminal regulatory domain present in a subset of ATP-binding proteins that has been involved in both direct regulation of transporter activity (inducer exclusion) and transcription of transporter genes. Pneumococci lacking RafK showed a 50- to 80-fold reduction in expression of the raf operon genes aga (alpha-galactosidase) and rafEFG (raffinose substrate binding and permease genes), and both glucose and sucrose inhibited raffinose uptake through inducer exclusion. Like RafK, the presence of DLDH also activated the expression of raf operon genes, as DLDH-negative pneumococci showed a significantly decreased expression of aga and rafEFG, but DLDH did not regulate rafK or the putative regulatory genes rafR and rafS. DLDH also bound directly to RafK both in vitro and in vivo, indicating the possibility that DLDH regulates raffinose transport by a direct interaction with the regulatory domain of the transporter. Finally, although not as attenuated as DLDH-negative bacteria, pneumococci lacking RafK were significantly outcompeted by wild-type bacteria in colonization experiments of murine lung and nasopharynx, indicating a role for raffinose and stachyose transport in vivo. PMID- 21602336 TI - Complete genome sequence of the haloalkaliphilic, hydrogen-producing bacterium Halanaerobium hydrogeniformans. AB - Halanaerobium hydrogenoformans is an alkaliphilic bacterium capable of biohydrogen production at pH 11 and 7% (wt/vol) salt. We present the 2.6-Mb genome sequence to provide insights into its physiology and potential for bioenergy applications. PMID- 21602337 TI - Deciphering the electron transport pathway for graphene oxide reduction by Shewanella oneidensis MR-1. AB - We determined that graphene oxide reduction by Shewanella oneidensis MR-1 requires the Mtr respiratory pathway by analyzing a range of mutants lacking these proteins. Electron shuttling compounds increased the graphene oxide reduction rate 3- to 5-fold. These results may help facilitate the use of bacteria for large-scale graphene production. PMID- 21602338 TI - Genome sequence of Sphingomonas sp. S17, isolated from an alkaline, hyperarsenic, and hypersaline volcano-associated lake at high altitude in the Argentinean Puna. AB - The high-altitude Andean lakes (HAAL) in the Argentinean Puna-high Andes region represent an almost unexplored ecosystem exposed to extreme conditions (high UV irradiation, hypersalinity, drastic temperature changes, desiccation, and high pH). Here we present the first genome sequence, a Sphingomonas sp., isolated from this extreme environment. PMID- 21602339 TI - Flagellar glycosylation in Burkholderia pseudomallei and Burkholderia thailandensis. AB - Glycosylation of proteins is known to impart novel physical properties and biological roles to proteins from both eukaryotes and prokaryotes. In this study, gel-based glycoproteomics were used to identify glycoproteins of the potential biothreat agent Burkholderia pseudomallei and the closely related but nonpathogenic B. thailandensis. Top-down and bottom-up mass spectrometry (MS) analyses identified that the flagellin proteins of both species were posttranslationally modified by novel glycans. Analysis of proteins from two strains of each species demonstrated that B. pseudomallei flagellin proteins were modified with a glycan with a mass of 291 Da, while B. thailandensis flagellin protein was modified with related glycans with a mass of 300 or 342 Da. Structural characterization of the B. thailandensis carbohydrate moiety suggests that it is an acetylated hexuronic acid. In addition, we have identified through mutagenesis a gene from the lipopolysaccharide (LPS) O-antigen biosynthetic cluster which is involved in flagellar glycosylation, and inactivation of this gene eliminates flagellar glycosylation and motility in B. pseudomallei. This is the first report to conclusively demonstrate the presence of a carbohydrate covalently linked to a protein in B. pseudomallei and B. thailandensis, and it suggests new avenues to explore in order to examine the marked differences in virulence between these two species. PMID- 21602340 TI - S-adenosylmethionine-binding properties of a bacterial phospholipid N methyltransferase. AB - The presence of the membrane lipid phosphatidylcholine (PC) in the bacterial membrane is critically important for many host-microbe interactions. The phospholipid N-methyltransferase PmtA from the plant pathogen Agrobacterium tumefaciens catalyzes the formation of PC by a three-step methylation of phosphatidylethanolamine via monomethylphosphatidylethanolamine and dimethylphosphatidylethanolamine. The methyl group is provided by S adenosylmethionine (SAM), which is converted to S-adenosylhomocysteine (SAH) during transmethylation. Despite the biological importance of bacterial phospholipid N-methyltransferases, little is known about amino acids critical for binding to SAM or phospholipids and catalysis. Alanine substitutions in the predicted SAM-binding residues E58, G60, G62, and E84 in A. tumefaciens PmtA dramatically reduced SAM-binding and enzyme activity. Homology modeling of PmtA satisfactorily explained the mutational results. The enzyme is predicted to exhibit a consensus topology of the SAM-binding fold consistent with cofactor interaction as seen with most structurally characterized SAM-methyltransferases. Nuclear magnetic resonance (NMR) titration experiments and (14)C-SAM-binding studies revealed binding constants for SAM and SAH in the low micromolar range. Our study provides first insights into structural features and SAM binding of a bacterial phospholipid N-methyltransferase. PMID- 21602341 TI - Modulation of Rho-dependent transcription termination in Escherichia coli by the H-NS family of proteins. AB - Nascent transcripts in Escherichia coli that fail to be simultaneously translated are subject to a factor-dependent mechanism of termination (also termed a polarity) that involves the proteins Rho and NusG. In this study, we found that overexpression of YdgT suppressed the polarity relief phenotypes and restored the efficiency of termination in rho or nusG mutants. YdgT and Hha belong to the H-NS and StpA family of proteins that repress a large number of genes in Gram-negative bacteria. Variants of H-NS defective in one or the other of its two dimerization domains, but not those defective in DNA binding alone, also conferred a similar suppression phenotype in rho and nusG mutants. YdgT overexpression was associated with derepression of proU, a prototypical H-NS-silenced locus. Polarity relief conferred by rho or nusG was unaffected in a derivative completely deficient for both H-NS and StpA, although the suppression effects of YdgT or the oligomerization-defective H-NS variants were abolished in this background. Transcription elongation rates in vivo were unaffected in any of the suppressor bearing strains. Finally, the polarity defects of rho and nusG mutants were exacerbated by Hha and YdgT deficiency. A model is proposed that invokes a novel role for the polymeric architectural scaffold formed on DNA by H-NS and StpA independent of the gene-silencing functions of these nucleoid proteins, in modulating Rho-dependent transcription termination such that interruption of the scaffold (as obtained by expression either of the H-NS oligomerization variants or of YdgT) is associated with improved termination efficiency in the rho and nusG mutants. PMID- 21602342 TI - Characterization of peptide chain length and constituency requirements for YejABEF-mediated uptake of microcin C analogues. AB - Microcin C (McC), a natural antibacterial compound consisting of a heptapeptide attached to a modified adenosine, is actively taken up by the YejABEF transporter, after which it is processed by cellular aminopeptidases, releasing the nonhydrolyzable aminoacyl adenylate, an inhibitor of aspartyl-tRNA synthetase. McC analogues with variable length of the peptide moiety were synthesized and evaluated in order to characterize the substrate preferences of the YejABEF transporter. It was shown that a minimal peptide chain length of 6 amino acids and the presence of an N-terminal formyl-methionyl-arginyl sequence are required for transport. PMID- 21602343 TI - Identification of ten Anabaena sp. genes that under aerobic conditions are required for growth on dinitrogen but not for growth on fixed nitrogen. AB - Heterocysts are specialized cells required for aerobic fixation of dinitrogen by certain filamentous cyanobacteria. Numerous genes involved in the differentiation and function of heterocysts in Anabaena sp. strain PCC 7120 have been identified by mutagenizing and screening for mutants that require fixed nitrogen for growth in the presence of oxygen. We have verified that 10 Anabaena sp. genes, all1338, all1591, alr1728, all3278, all3520, all3582, all3850, all4019, alr4311, and all4388, identified initially by transposon mutagenesis, are such genes by complementing or reconstructing the original mutation and by determining whether the mutant phenotype might be due to a polar effect of the transposon. Elucidation of the roles of these genes should enhance understanding of heterocyst biology. PMID- 21602344 TI - Comparative genomics of the dormancy regulons in mycobacteria. AB - In response to stresses, Mycobacterium cells become dormant. This process is regulated by the DosR transcription factor. In Mycobacterium tuberculosis, the dormancy regulon is well characterized and contains the dosR gene itself and dosS and dosT genes encoding DosR kinases, nitroreductases (acg; Rv3131), diacylglycerol acyltransferase (DGAT) (Rv3130c), and many universal stress proteins (USPs). In this study, we apply comparative genomic analysis to characterize the DosR regulons in nine Mycobacterium genomes, Rhodococcus sp. RHA1, Nocardia farcinica, and Saccharopolyspora erythraea. The regulons are highly labile, containing eight core gene groups (regulators, kinases, USPs, DGATs, nitroreductases, ferredoxins, heat shock proteins, and the orthologs of the predicted kinase [Rv2004c] from M. tuberculosis) and 10 additional genes with more restricted taxonomic distribution that are mostly involved in anaerobic respiration. The largest regulon is observed in M. marinum and the smallest in M. abscessus. Analysis of large gene families encoding USPs, nitroreductases, and DGATs demonstrates a mosaic distribution of regulated and nonregulated members, suggesting frequent acquisition and loss of DosR-binding sites. PMID- 21602345 TI - Characterization of DNA binding sites of the ComE response regulator from Streptococcus mutans. AB - In Streptococcus mutans, both competence and bacteriocin production are controlled by ComC and the ComED two-component signal transduction system. Recent studies of S. mutans suggested that purified ComE binds to two 11-bp direct repeats in the nlmC-comC promoter region, where ComE activates nlmC and represses comC. In this work, quantitative binding studies and DNase I footprinting analysis were performed to calculate the equilibrium dissociation constant and further characterize the binding site of ComE. We found that ComE protects sequences inclusive of both direct repeats, has an equilibrium dissociation constant in the nanomolar range, and binds to these two direct repeats cooperatively. Furthermore, similar direct repeats were found upstream of cslAB, comED, comX, ftf, vicRKX, gtfD, gtfB, gtfC, and gbpB. Quantitative binding studies were performed on each of these sequences and showed that only cslAB has a similar specificity and high affinity for ComE as that seen with the upstream region of comC. A mutational analysis of the binding sequences showed that ComE does not require both repeats to bind DNA with high affinity, suggesting that single site sequences in the genome may be targets for ComE-mediated regulation. Based on the mutational analysis and DNase I footprinting analysis, we propose a consensus ComE binding site, TCBTAAAYSGT. PMID- 21602346 TI - Whole genome sequences of four Brucella strains. AB - Brucella melitensis and Brucella suis are intracellular pathogens of livestock and humans. Here we report four genome sequences, those of the virulent strain B. melitensis M28-12 and vaccine strains B. melitensis M5 and M111 and B. suis S2, which show different virulences and pathogenicities, which will help to design a more effective brucellosis vaccine. PMID- 21602347 TI - Age of inoculum strongly influences persister frequency and can mask effects of mutations implicated in altered persistence. AB - The majority of cells transferred from stationary-phase culture into fresh medium resume growth quickly, while a few remain in a nongrowing state for longer. These temporarily nonproliferating bacteria are tolerant of several bactericidal antibiotics and constitute a main source of persisters. Several genes have been shown to influence the frequency of persisters in Escherichia coli, although the exact mechanism underlying persister formation is unknown. This study demonstrates that the frequency of persisters is highly dependent on the age of the inoculum and the medium in which it has been grown. The hipA7 mutant had 1,000 times more persisters than the wild type when inocula were sampled from younger stationary-phase cultures. When started after a long stationary phase, the two displayed equal and elevated persister frequencies. The lower persister frequencies of glpD, dnaJ, and surA knockout strains were increased to the level of the wild type when inocula aged. The mqsR and phoU deletions showed decreased persister levels only when the inocula were from aged cultures, while sucB and ygfA deletions had decreased persister levels irrespective of the age of the inocula. A dependency on culture conditions underlines the notion that during screening for mutants with altered persister frequencies, the exact experimental details are of great importance. Unlike ampicillin and norfloxacin, which always leave a fraction of bacteria alive, amikacin killed all cells in the growth resumption experiment. It was concluded that the frequency of persisters depends on the conditions of inoculum cultivation, particularly its age, and the choice of antibiotic. PMID- 21602348 TI - Regulon of the N-acetylglucosamine utilization regulator NagR in Bacillus subtilis. AB - N-Acetylglucosamine (GlcNAc) is the most abundant carbon-nitrogen biocompound on earth and has been shown to be an important source of nutrients for both catabolic and anabolic purposes in Bacillus species. In this work we show that the GntR family regulator YvoA of Bacillus subtilis serves as a negative transcriptional regulator of GlcNAc catabolism gene expression. YvoA represses transcription by binding a 16-bp sequence upstream of nagP encoding the GlcNAc specific EIIBC component of the sugar phosphotransferase system involved in GlcNAc transport and phosphorylation, as well as another very similar 16-bp sequence upstream of the nagAB-yvoA locus, wherein nagA codes for N acetylglucosamine-6-phosphate deacetylase and nagB codes for the glucosamine-6 phosphate (GlcN-6-P) deaminase. In vitro experiments demonstrated that GlcN-6-P acts as an inhibitor of YvoA DNA-binding activity, as occurs for its Streptomyces ortholog, DasR. Interestingly, we observed that the expression of nag genes was still activated upon addition of GlcNAc in a DeltayvoA mutant background, suggesting the existence of an auxiliary transcriptional control instance. Initial computational prediction of the YvoA regulon showed a distribution of YvoA binding sites limited to nag genes and therefore suggests renaming YvoA to NagR, for N-acetylglucosamine utilization regulator. Whole-transcriptome studies showed significant repercussions of nagR deletion for several major B. subtilis regulators, probably indirectly due to an excess of the crucial molecules acetate, ammonia, and fructose-6-phosphate, resulting from complete hydrolysis of GlcNAc. We discuss a model deduced from NagR-mediated gene expression, which highlights clear connections with pathways for GlcNAc-containing polymer biosynthesis and adaptation to growth under oxygen limitation. PMID- 21602349 TI - Characterization of a novel heat shock protein (Hsp22.5) involved in the pathogenesis of Mycobacterium tuberculosis. AB - Tuberculosis is a worldwide health problem, given that one-third of the world's population is currently infected with Mycobacterium tuberculosis. Understanding the regulation of virulence on the molecular level will provide a better understanding of how M. tuberculosis can establish chronic infection. Using in vivo microarray analysis (IVMA), we previously identified a group of genes that are activated in BALB/c mouse lungs compared to in vitro cultures, including the rv0990c gene. Our analysis indicated that this gene is a member of the heat shock regulon and was activated under other stress conditions, including survival in macrophages or during the late phase of chronic tuberculosis in the murine lungs. Deletion of rv0990c from the genome of M. tuberculosis strain H37Rv affected the transcriptional profiles of many genes (n = 382) and operons involved in mycobacterial survival, including the dormancy regulon, ATP synthesis, respiration, protein synthesis, and lipid metabolism. Comparison of the proteomes of the mutant to those of the wild-type strain further confirmed the differential expression of 15 proteins, especially those involved in the heat shock response (e.g., DnaK and GrpE). Finally, the rv0990c mutant strain showed survival equivalent to that of the isogenic wild-type strain during active tuberculosis in guinea pigs, despite showing significant attenuation in BALB/c mice during the chronic phase of the disease. Overall, we suggest that rv0990c encodes a heat shock protein that plays an important role in mycobacterial virulence. Hence, we renamed rv0990c heat shock protein 22.5 (hsp22.5), reflecting its molecular mass. PMID- 21602350 TI - Characterization of the periplasmic region of PomB, a Na+-driven flagellar stator protein in Vibrio alginolyticus. AB - The stator proteins PomA and PomB form a complex that couples Na(+) influx to torque generation in the polar flagellar motor of Vibrio alginolyticus. This stator complex is anchored to an appropriate place around the rotor through a putative peptidoglycan-binding (PGB) domain in the periplasmic region of PomB (PomB(C)). To investigate the function of PomB(C), a series of N-terminally truncated and in-frame mutants with deletions between the transmembrane (TM) segment and the PGB domain of PomB was constructed. A PomB(C) fragment consisting of residues 135 to 315 (PomB(C5) formed a stable homodimer and significantly inhibited the motility of wild-type cells when overexpressed in the periplasm. A fragment with an in-frame deletion (PomB(DeltaL)) of up to 80 residues retained function, and its overexpression with PomA impaired cell growth. This inhibitory effect was suppressed by a mutation at the functionally critical Asp (D24N) in the TM segment of PomB, suggesting that a high level of Na(+) influx through the mutant stator causes the growth impairment. The overproduction of functional PomA/PomB(DeltaL) stators also reduced the motile fractions of the cells. That effect could be slightly relieved by a mutation (L168P) in the putative N terminal alpha-helix that connects to the PGB domain without affecting the growth inhibition, suggesting that a conformational change of the region including the PGB domain affects stator assembly. Our results reveal common features of the periplasmic region of PomB/MotB and demonstrate that a flexible linker that contains a "plug" segment is important for the control of Na(+) influx through the stator complex as well as for stator assembly. PMID- 21602351 TI - Functional significance of an evolutionarily conserved alanine (GCA) resume codon in tmRNA in Escherichia coli. AB - Occasionally, ribosomes stall on mRNAs prior to the completion of the polypeptide chain. In Escherichia coli and other eubacteria, tmRNA-mediated trans-translation is a major mechanism that recycles the stalled ribosomes. The tmRNA possesses a tRNA-like domain and a short mRNA region encoding a short peptide (ANDENYALAA in E. coli) followed by a termination codon. The first amino acid (Ala) of this peptide encoded by the resume codon (GCN) is highly conserved in tmRNAs in different species. However, reasons for the high evolutionary conservation of the resume codon identity have remained unclear. In this study, we show that changing the E. coli tmRNA resume codon to other efficiently translatable codons retains efficient functioning of the tmRNA. However, when the resume codon was replaced with the low-usage codons, its function was adversely affected. Interestingly, expression of tRNAs decoding the low-usage codon from plasmid-borne gene copies restored efficient utilization of tmRNA. We discuss why in E. coli, the GCA (Ala) is one of the best codons and why all codons in the short mRNA of the tmRNA are decoded by the abundant tRNAs. PMID- 21602352 TI - Antiparallel and interlinked control of cellular iron levels by the Irr and RirA regulators of Agrobacterium tumefaciens. AB - The plant pathogen Agrobacterium tumefaciens encodes predicted iron-responsive regulators, Irr and RirA, that function in several other bacteria to control the response to environmental iron levels. Deletion mutations of irr and rirA, alone and in combination, were evaluated for their impact on cellular iron response. Growth was severely diminished in the Deltairr mutant under iron-limiting conditions, but reversed to wild-type levels in an Deltairr DeltarirA mutant. The level of uncomplexed iron in the Deltairr mutant was decreased, whereas the DeltarirA mutant exhibited elevated iron levels. Sensitivity of the Deltairr and DeltarirA mutants to iron-activated antimicrobial compounds generally reflected their uncomplexed-iron levels. Expression of genes that encode iron uptake systems was decreased in the Deltairr mutant, whereas that of iron utilization genes was increased. Irr function required a trihistidine repeat likely to mediate interactions with heme. Iron uptake genes were derepressed in the DeltarirA mutant. In the Deltairr DeltarirA mutant, iron uptake and utilization genes were derepressed, roughly combining the phenotypes of the single mutants. Siderophore production was elevated in the rirA mutant, but most strongly regulated by an RirA-controlled sigma factor. Expression of rirA itself was regulated by Irr, RirA, and iron availability, in contrast to irr expression, which was relatively stable in the different mutants. These studies suggest that in A. tumefaciens, the Irr protein is most active under low-iron conditions, inhibiting iron utilization and activating iron acquisition, while the RirA protein is active under high-iron conditions, repressing iron uptake. PMID- 21602353 TI - Structure of Burkholderia cepacia UDP-glucose dehydrogenase (UGD) BceC and role of Tyr10 in final hydrolysis of UGD thioester intermediate. AB - Members of the Burkholderia cepacia complex (BCC) are serious respiratory pathogens in immunocompromised individuals and in patients with cystic fibrosis (CF). They are exceptionally resistant to many antimicrobial agents and have the capacity to spread between patients, leading to a decline in lung function and necrotizing pneumonia. BCC members often express a mucoid phenotype associated with the secretion of the exopolysaccharide (EPS) cepacian. There is much evidence supporting the fact that cepacian is a major virulence factor of BCC. UDP-glucose dehydrogenase (UGD) is responsible for the NAD-dependent 2-fold oxidation of UDP-glucose (UDP-Glc) to UDP-glucuronic acid (UDP-GlcA), which is a key step in cepacian biosynthesis. Here, we report the structure of BceC, determined at 1.75-A resolution. Mutagenic studies were performed on the active sites of UGDs, and together with the crystallographic structures, they elucidate the molecular mechanism of this family of sugar nucleotide-modifying enzymes. Superposition with the structures of human and other bacterial UGDs showed an active site with high structural homology. This family contains a strictly conserved tyrosine residue (Y10 in BceC; shown in italics) within the glycine rich motif (GXGYXG) of its N-terminal Rossmann-like domain. We constructed several BceC Y10 mutants, revealing only residual dehydrogenase activity and thus highlighting the importance of this conserved residue in the catalytic activity of BceC. Based on the literature of the UGD/GMD nucleotide sugar 6-dehydrogenase family and the kinetic and structural data we obtained for BceC, we determined Y10 as a key catalytic residue in a UGD rate-determining step, the final hydrolysis of the enzymatic thioester intermediate. PMID- 21602354 TI - Phenazine-1-carboxylic acid promotes bacterial biofilm development via ferrous iron acquisition. AB - The opportunistic pathogen Pseudomonas aeruginosa forms biofilms, which render it more resistant to antimicrobial agents. Levels of iron in excess of what is required for planktonic growth have been shown to promote biofilm formation, and therapies that interfere with ferric iron [Fe(III)] uptake combined with antibiotics may help treat P. aeruginosa infections. However, use of these therapies presumes that iron is in the Fe(III) state in the context of infection. Here we report the ability of phenazine-1-carboxylic acid (PCA), a common phenazine made by all phenazine-producing pseudomonads, to help P. aeruginosa alleviate Fe(III) limitation by reducing Fe(III) to ferrous iron [Fe(II)]. In the presence of PCA, a P. aeruginosa mutant lacking the ability to produce the siderophores pyoverdine and pyochelin can still develop into a biofilm. As has been previously reported (P. K. Singh, M. R. Parsek, E. P. Greenberg, and M. J. Welsh, Nature 417:552-555, 2002), biofilm formation by the wild type is blocked by subinhibitory concentrations of the Fe(III)-binding innate-immunity protein conalbumin, but here we show that this blockage can be rescued by PCA. FeoB, an Fe(II) uptake protein, is required for PCA to enable this rescue. Unlike PCA, the phenazine pyocyanin (PYO) can facilitate biofilm formation via an iron independent pathway. While siderophore-mediated Fe(III) uptake is undoubtedly important at early stages of infection, these results suggest that at later stages of infection, PCA present in infected tissues may shift the redox equilibrium between Fe(III) and Fe(II), thereby making iron more bioavailable. PMID- 21602355 TI - Compromised factor-dependent transcription termination in a nusA mutant of Escherichia coli: spectrum of termination efficiencies generated by perturbations of Rho, NusG, NusA, and H-NS family proteins. AB - The proteins NusA and NusG, which are essential for the viability of wild-type Escherichia coli, participate in various postinitiation steps of transcription including elongation, antitermination, and termination. NusG is required, along with the essential Rho protein, for factor-dependent transcription termination (also referred to as polarity), but the role of NusA is less clear, with conflicting reports that it both promotes and inhibits the process. In this study, we found that a recessive missense nusA mutant [nusA(R258C)] exhibits a transcription termination-defective (that is, polarity-relieved) phenotype, much like missense mutants in rho or nusG, but is unaffected for either the rate of transcription elongation or antitermination in lambda phage. Various combinations of the rho, nusG, and nusA mutations were synthetically lethal, and the lethality was suppressed by expression of the N-terminal half of nucleoid protein H-NS. Our results suggest that NusA function is indeed needed for factor-dependent transcription termination and that an entire spectrum of termination efficiencies can be generated by perturbations of the Rho, NusG, NusA, and H-NS family of proteins, with the corresponding phenotypes extending from polarity through polarity relief to lethality. PMID- 21602356 TI - Significance of the glutamate-139 residue of the V-type Na+-ATPase NtpK subunit in catalytic turnover linked with salt tolerance of Enterococcus hirae. AB - A Glu139Asp mutant of the NtpK subunit (kE139D) of Enterococcus hirae vacuolar type ATPase (V-ATPase) lost tolerance to sodium but not to lithium at pH 10. Purified kE139D V-ATPase retained relatively high specific activity and affinity for the lithium ion compared to the sodium ion. The kE139 residue of V-ATPase is indispensable for its enzymatic activity that is linked with the salt tolerance of enterococci. PMID- 21602357 TI - Complete genome sequence of hyperthermophilic Pyrococcus sp. strain NA2, isolated from a deep-sea hydrothermal vent area. AB - Pyrococcus sp. strain NA2, isolated from a deep-sea hydrothermal vent sample, is a novel marine hyperthermophilic archaeon that grows optimally at 93 degrees C. The complete genome sequence of the strain contains all the genes for the tricarboxylic acid cycle except for succinate dehydrogenase/fumarate reductase, but the genome does not encode proteins involved in polysaccharide utilization. PMID- 21602358 TI - Comparative genomics of 28 Salmonella enterica isolates: evidence for CRISPR mediated adaptive sublineage evolution. AB - Despite extensive surveillance, food-borne Salmonella enterica infections continue to be a significant burden on public health systems worldwide. As the S. enterica species comprises sublineages that differ greatly in antigenic representation, virulence, and antimicrobial resistance phenotypes, a better understanding of the species' evolution is critical for the prediction and prevention of future outbreaks. The roles that virulence and resistance phenotype acquisition, exchange, and loss play in the evolution of S. enterica sublineages, which to a certain extent are represented by serotypes, remains mostly uncharacterized. Here, we compare 17 newly sequenced and phenotypically characterized nontyphoidal S. enterica strains to 11 previously sequenced S. enterica genomes to carry out the most comprehensive comparative analysis of this species so far. These phenotypic and genotypic data comparisons in the phylogenetic species context suggest that the evolution of known S. enterica sublineages is mediated mostly by two mechanisms, (i) the loss of coding sequences with known metabolic functions, which leads to functional reduction, and (ii) the acquisition of horizontally transferred phage and plasmid DNA, which provides virulence and resistance functions and leads to increasing specialization. Matches between S. enterica clustered regularly interspaced short palindromic repeats (CRISPR), part of a defense mechanism against invading plasmid and phage DNA, and plasmid and prophage regions suggest that CRISPR mediated immunity could control short-term phenotype changes and mediate long term sublineage evolution. CRISPR analysis could therefore be critical in assessing the evolutionary potential of S. enterica sublineages and aid in the prediction and prevention of future S. enterica outbreaks. PMID- 21602359 TI - Substitutions in the presumed sensing domain of the Bacillus subtilis stressosome affect its basal output but not response to environmental signals. AB - The stressosome is a multiprotein, 1.8-MDa icosahedral complex that transmits diverse environmental signals to activate the general stress response of Bacillus subtilis. The way in which it senses these cues and the pathway of signal propagation within the stressosome itself are poorly understood. The stressosome core consists of four members of the RsbR coantagonist family together with the RsbS antagonist; its cryo-electron microscopy (cryoEM) image suggests that the N terminal domains of the RsbR proteins form homodimers positioned to act as sensors on the stressosome surface. Here we probe the role of the N-terminal domain of the prototype coantagonist RsbRA by making structure-based amino acid substitutions in potential interaction surfaces. To unmask the phenotypes caused by single-copy rsbRA mutations, we constructed strains lacking the other three members of the RsbR coantagonist family and assayed system output using a reporter fusion. Effects of five individual alanine substitutions in the prominent dimer groove did not match predictions from an earlier in vitro assay, indicating that the in vivo assay was necessary to assess their influence on signaling. Additional substitutions expected to negatively affect domain dimerization had substantial impact, whereas those that sampled other prominent surface features had no consequence. Notably, even mutations resulting in significantly altered phenotypes raised the basal level of system output only in unstressed cells and had little effect on the magnitude of subsequent stress signaling. Our results provide evidence that the N-terminal domain of the RsbRA coantagonist affects stressosome function but offer no direct support for the hypothesis that it is a signal sensor. PMID- 21602360 TI - Tropicibacter multivorans sp. nov., an aerobic alphaproteobacterium isolated from surface seawater. AB - Strain MD5T, an aerobic marine alphaproteobacterium, was isolated from Mediterranean seawater at Malvarrosa beach, Valencia, Spain. The strain was characterized in a polyphasic study and was placed phylogenetically within the Roseobacter clade in the family Rhodobacteraceae. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain MD5T is related to Tropicibacter naphthalenivorans C02T, Phaeobacter inhibens T5T, P. gallaeciensis BS107T and P. daeponensis TF-218T, with 96.9, 96.2, 96.1 and 96.1 % sequence similarity, respectively. Phylogenetic analyses also showed that strain MD5T forms a stable clade only with T. naphthalenivorans C02T. Strain MD5T requires Na+ plus a divalent cation (either Mg2+ or Ca2+) to grow, does not reduce nitrate to nitrite and uses a large number of carbohydrates as sole carbon sources. It is positive for beta-galactosidase and urease activities and aesculin hydrolysis. Enzyme activities displayed in the API ZYM strip were alkaline phosphatase, leucine arylamidase, acid phosphatase and alpha-glucosidase. Major cellular fatty acids were summed feature 8 (C18:1omega7c and/or C18:1omega6c; 70.9 %) and C16:0 (8.2 %). The results of physiological and biochemical tests allowed clear phenotypic differentiation of this isolate from the only described species of the genus Tropicibacter. It is evident from the genotypic and phenotypic data obtained that the strain should be classified in a novel species in the genus Tropicibacter. The name Tropicibacter multivorans sp. nov. is proposed, with the type strain MD5T (=CECT 7557T=KCTC 23350T). PMID- 21602361 TI - Kazachstania bromeliacearum sp. nov., a yeast species from water tanks of bromeliads. AB - Cultures of a novel nutritionally specialized, fermentative yeast species were isolated from 34 water tanks of five bromeliad species, two mangrove sediment samples and one swamp water sample in Rio de Janeiro, Brazil. Sequence analysis of the D1/D2 domains of the large subunit of the rRNA gene showed that the novel species belongs to the genus Kazachstania. The novel species differs from Kazachstania martiniae by 11 substitutions and 2 gaps in the sequence of the domains D1/D2 of the LSU rRNA gene. The name Kazachstania bromeliacearum sp. nov. is proposed for the novel species. The type strain is IMUFRJ 51496T (=CBS 7996T=DBVPG 6864T=UFMG BR-174T). PMID- 21602362 TI - Marivita hallyeonensis sp. nov., isolated from seawater, reclassification of Gaetbulicola byunsanensis as Marivita byunsanensis comb. nov. and emended description of the genus Marivita Hwang et al. 2009. AB - A Gram-stain-negative, non-motile, non-spore-forming, aerobic, rod-shaped bacterial strain, designated DPG-28T, was isolated from seawater on the southern coast of Korea. Strain DPG-28T grew optimally at 30 degrees C and in the presence of 2 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain DPG-28T formed a coherent cluster with members of the genera Marivita and Gaetbulicola, with which it exhibited sequence similarity values of 97.8-98.5 %. The DNA G+C content of strain DPG-28T was 65.1 mol%. The predominant ubiquinone of strain DPG-28T was ubiquinone-10 (Q-10), consistent with data for the genera Marivita and Gaetbulicola. The cellular fatty acid profiles of strain DPG-28T and the type strains of Marivita cryptomonadis, Marivita litorea and Gaetbulicola byunsanensis were essentially similar in that the common predominant fatty acid was C18:1omega7c. Major polar lipids found in strain DPG-28T and the type strains of M. cryptomonadis, M. litorea and G. byunsanensis were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine and an unidentified aminolipid. From these data, it is proposed that Gaetbulicola byunsanensis be reclassified as a member of the genus Marivita, for which the name Marivita byunsanensis comb. nov. is proposed, with the type strain SMK-114T (=CCUG 57612T=KCTC 22632T), and that strain DPG-28T be classified in the genus Marivita. Differential phenotypic properties and genetic distinctiveness of strain DPG-28T demonstrated that this strain is distinguishable from M. cryptomonadis, M. litorea and G. byunsanensis. On the basis of the data presented, strain DPG-28T is considered to represent a novel species of the genus Marivita, for which the name Marivita hallyeonensis sp. nov. is proposed. The type strain is DPG-28T (=KCTC 23421T=CCUG 60522T). An emended description of the genus Marivita is also provided. PMID- 21602363 TI - Mucilaginibacter polysacchareus sp. nov., an exopolysaccharide-producing bacterial species isolated from the rhizoplane of the herb Angelica sinensis. AB - Three exopolysaccharide-producing bacteria, designated strains DRP28(T), DRP29 and DRP31, were isolated from the rhizoplane of Angelica sinensis from the Geumsan, Republic of Korea. Cells were straight rods, Gram reaction-negative, aerobic, non-motile, and catalase- and oxidase- positive. Flexirubin-type pigments were absent. Phylogenetic analysis of the 16S rRNA gene indicated that these bacteria belong to the genus Mucilaginibacter in the phylum Bacteroidetes. 16S rRNA gene sequence similarities to strains of recognized species of the genus Mucilaginibacter were 93.8-97.4%. The major fatty acids were iso-C(15:0) and summed feature 3 (C(16:1)omega7c and/or iso-C(15:0) 2-OH). The strains contained MK-7 as the major isoprenoid quinone. Strains DRP28(T), DRP29 and DRP31 formed a single, distinct genomospecies with DNA G+C contents of 41.9-42.7 mol% and DNA hybridization values of 82.6-86.8%; the strains exhibited DNA-DNA hybridization values of only 20.4-41.3% with related species of the genus Mucilaginibacter. On the basis of evidence presented in this study, strains DRP28(T), DRP29 and DRP31 were considered to represent a novel species of the genus Mucilaginibacter, for which the name Mucilaginibacter polysacchareus sp. nov. is proposed. The type strain is DRP28(T) (=KACC 15075(T) =NBRC 107757(T)). PMID- 21602364 TI - Description of Anaerobaculum hydrogeniformans sp. nov., an anaerobe that produces hydrogen from glucose, and emended description of the genus Anaerobaculum. AB - A novel anaerobic, moderately thermophilic, NaCl-requiring fermentative bacterium, strain OS1T, was isolated from oil production water collected from Alaska, USA. Cells were Gram-negative, non-motile, non-spore-forming rods (1.7 2.7*0.4-0.5 um). The G+C content of the genomic DNA of strain OS1T was 46.6 mol%. The optimum temperature, pH and NaCl concentration for growth of strain OS1T were 55 degrees C, pH 7 and 10 g l(-1), respectively. The bacterium fermented D fructose, D-glucose, maltose, D-mannose, alpha-ketoglutarate, L-glutamate, malonate, pyruvate, L-tartrate, L-asparagine, Casamino acids, L-cysteine, L histidine, L-leucine, L-phenylalanine, L-serine, L-threonine, L-valine, inositol, inulin, tryptone and yeast extract. When grown on D-glucose, 3.86 mol hydrogen and 1.4 mol acetate were produced per mol substrate. Thiosulfate, sulfur and L cystine were reduced to sulfide, and crotonate was reduced to butyrate with glucose as the electron donor. 16S rRNA gene sequence analysis indicated that strain OS1T was related to Anaerobaculum thermoterrenum (99.7 % similarity to the type strain), a member of the phylum Synergistetes. DNA-DNA hybridization between strain OS1T and A. thermoterrenum DSM 13490T yielded 68 % relatedness. Unlike A. thermoterrenum, strain OS1T fermented malonate, maltose, tryptone, L-leucine and L-phenylalanine, but not citrate, fumarate, lactate, L-malate, glycerol, pectin or starch. The major cellular fatty acid of strain OS1T was iso-C15:0 (91 % of the total). Strain OS1T also contained iso-C13:0 3-OH (3 %), which was absent from A. thermoterrenum, and iso-C13:0 (2 %), which was absent from Anaerobaculum mobile. On the basis of these results, strain OS1T represents a novel species of the genus Anaerobaculum, for which the name Anaerobaculum hydrogeniformans sp. nov. is proposed. The type strain is OS1T (=DSM 22491T=ATCC BAA-1850T). An emended description of the genus Anaerobaculum is also given. PMID- 21602365 TI - Monitoring the wet-heat inactivation dynamics of single spores of Bacillus species by using Raman tweezers, differential interference contrast microscopy, and nucleic acid dye fluorescence microscopy. AB - Dynamic processes during wet-heat treatment of individual spores of Bacillus cereus, Bacillus megaterium, and Bacillus subtilis at 80 to 90 degrees C were investigated using dual-trap Raman spectroscopy, differential interference contrast (DIC) microscopy, and nucleic acid stain (SYTO 16) fluorescence microscopy. During spore wet-heat treatment, while the spores' 1:1 chelate of Ca(2+) with dipicolinic acid (CaDPA) was released rapidly at a highly variable time T(lag), the levels of spore nucleic acids remained nearly unchanged, and the T(lag) times for individual spores from the same preparation were increased somewhat as spore levels of CaDPA increased. The brightness of the spores' DIC image decreased by ~50% in parallel with CaDPA release, and there was no spore cortex hydrolysis observed. The lateral diameters of the spores' DIC image and SYTO 16 fluorescence image also decreased in parallel with CaDPA release. The SYTO 16 fluorescence intensity began to increase during wet-heat treatment at a time before T(lag) and reached maximum at a time slightly later than T(release). However, the fluorescence intensities of wet-heat-inactivated spores were ~15 fold lower than those of nutrient-germinated spores, and this low SYTO 16 fluorescence intensity may be due in part to the low permeability of the dormant spores' inner membranes to SYTO 16 and in part to nucleic acid denaturation during the wet-heat treatment. PMID- 21602366 TI - Influence of the drilling mud formulation process on the bacterial communities in thermogenic natural gas wells of the Barnett Shale. AB - The Barnett Shale in north central Texas contains natural gas generated by high temperatures (120 to 150 degrees C) during the Mississippian Period (300 to 350 million years ago). In spite of the thermogenic origin of this gas, biogenic sulfide production and microbiologically induced corrosion have been observed at several natural gas wells in this formation. It was hypothesized that microorganisms in drilling muds were responsible for these deleterious effects. Here we collected drilling water and drilling mud samples from seven wells in the Barnett Shale during the drilling process. Using quantitative real-time PCR and microbial enumerations, we show that the addition of mud components to drilling water increased total bacterial numbers, as well as the numbers of culturable aerobic heterotrophs, acid producers, and sulfate reducers. The addition of sterile drilling muds to microcosms that contained drilling water stimulated sulfide production. Pyrosequencing-based phylogenetic surveys of the microbial communities in drilling waters and drilling muds showed a marked transition from typical freshwater communities to less diverse communities dominated by Firmicutes and Gammaproteobacteria. The community shifts observed reflected changes in temperature, pH, oxygen availability, and concentrations of sulfate, sulfonate, and carbon additives associated with the mud formulation process. Finally, several of the phylotypes observed in drilling muds belonged to lineages that were thought to be indigenous to marine and terrestrial fossil fuel formations. Our results suggest a possible alternative exogenous origin of such phylotypes via enrichment and introduction to oil and natural gas reservoirs during the drilling process. PMID- 21602367 TI - Goose-type lysozyme inhibitor (PliG) enhances survival of Escherichia coli in goose egg albumen. AB - The goose-type lysozyme inhibitor PliG enhances the survival of Escherichia coli in goose but not in chicken egg white, which contains goose- and chicken-type lysozymes, respectively. These results indicate that both the type of host lysozyme and the type of bacterial lysozyme inhibitor may affect bacterium-host interactions. PMID- 21602368 TI - Secretion of anti-Plasmodium effector proteins from a natural Pantoea agglomerans isolate by using PelB and HlyA secretion signals. AB - The insect-vectored disease malaria is a major world health problem. New control strategies are needed to supplement the current use of insecticides and medications. A genetic approach can be used to inhibit development of malaria parasites (Plasmodium spp.) in the mosquito host. We hypothesized that Pantoea agglomerans, a bacterial symbiont of Anopheles mosquitoes, could be engineered to express and secrete anti-Plasmodium effector proteins, a strategy termed paratransgenesis. To this end, plasmids that include the pelB or hlyA secretion signals from the genes of related species (pectate lyase from Erwinia carotovora and hemolysin A from Escherichia coli, respectively) were created and tested for their efficacy in secreting known anti-Plasmodium effector proteins (SM1, anti Pbs21, and PLA2) in P. agglomerans and E. coli. P. agglomerans successfully secreted HlyA fusions of anti-Pbs21 and PLA2, and these strains are under evaluation for anti-Plasmodium activity in infected mosquitoes. Varied expression and/or secretion of the effector proteins was observed, suggesting that the individual characteristics of a particular effector may require empirical testing of several secretion signals. Importantly, those strains that secreted efficiently grew as well as wild-type strains under laboratory conditions and, thus, may be expected to be competitive with the native microbiota in the environment of the mosquito midgut. PMID- 21602369 TI - Validation of internal controls for extraction and amplification of nucleic acids from enteric viruses in water samples. AB - Inhibitors that reduce viral nucleic acid extraction efficiency and interfere with cDNA synthesis and/or polymerase activity affect the molecular detection of viruses in aquatic environments. To overcome these significant problems, we developed a methodology for assessing nucleic acid yields and DNA amplification efficiencies for environmental water samples. This involved adding particles of adenovirus type 5 and murine norovirus and newly developed primer-sharing controls, which are amplified with the same primer pairs and result in the same amplicon sizes as the targets, to these samples. We found that nucleic acid loss during the extraction process, rather than reverse transcription-PCR (RT-PCR) inhibition, more significantly attributed to underestimation of the presence of viral genomes in the environmental water samples tested in this study. Our success rate for satisfactorily amplifying viral RNAs and DNAs by RT-PCR was higher than that for obtaining adequate nucleic acid preparations. We found that inhibitory properties were greatest when we used larger sample volumes. A magnetic silica bead-based RNA extraction method effectively removed inhibitors that interfere with viral nucleic acid extraction and RT-PCR. To our knowledge, this is the first study to assess the inhibitory properties of environmental water samples by using both control virus particles and primer-sharing controls. PMID- 21602370 TI - Responses of Escherichia coli, Listeria monocytogenes, and Staphylococcus aureus to simulated food processing treatments, determined using fluorescence-activated cell sorting and plate counting. AB - Three common food pathogenic microorganisms were exposed to treatments simulating those used in food processing. Treated cell suspensions were then analyzed for reduction in growth by plate counting. Flow cytometry (FCM) and fluorescence activated cell sorting (FACS) were carried out on treated cells stained for membrane integrity (Syto 9/propidium iodide) or the presence of membrane potential [DiOC2(3)]. For each microbial species, representative cells from various subpopulations detected by FCM were sorted onto selective and nonselective agar and evaluated for growth and recovery rates. In general, treatments giving rise to the highest reductions in counts also had the greatest effects on cell membrane integrity and membrane potential. Overall, treatments that impacted cell membrane permeability did not necessarily have a comparable effect on membrane potential. In addition, some bacterial species with extensively damaged membranes, as detected by FCM, appeared to be able to replicate and grow after sorting. Growth of sorted cells from various subpopulations was not always reflected in plate counts, and in some cases the staining protocol may have rendered cells unculturable. Optimized FCM protocols generated a greater insight into the extent of the heterogeneous bacterial population responses to food control measures than did plate counts. This study underlined the requirement to use FACS to relate various cytometric profiles generated by various staining protocols with the ability of cells to grow on microbial agar plates. Such information is a prerequisite for more-widespread adoption of FCM as a routine microbiological analytical technique. PMID- 21602371 TI - Shedding light on selenium biomineralization: proteins associated with bionanominerals. AB - Selenium-reducing microorganisms produce elemental selenium nanoparticles with particular physicochemical properties due to an associated organic fraction. This study identified high-affinity proteins associated with such bionanominerals and with nonbiogenic elemental selenium. Proteins with an anticipated functional role in selenium reduction, such as a metalloid reductase, were found to be associated with nanoparticles formed by one selenium respirer, Sulfurospirillum barnesii. PMID- 21602372 TI - Preferential feeding by the ciliates Chilodonella and Tetrahymena spp. and effects of these protozoa on bacterial biofilm structure and composition. AB - Protozoa are important components of microbial food webs, but protozoan feeding preferences and their effects in the context of bacterial biofilms are not well understood. The feeding interactions of two contrasting ciliates, the free swimming filter feeder Tetrahymena sp. and the surface-associated predator Chilodonella sp., were investigated using biofilm-forming bacteria genetically modified to express fluorescent proteins. According to microscopy, both ciliates readily consumed cells from both Pseudomonas costantinii and Serratia plymuthica biofilms. When offered a choice between spatially separated biofilms, each ciliate showed a preference for P. costantinii biofilms. Experiments with bacterial cell extracts indicated that both ciliates used dissolved chemical cues to locate biofilms. Chilodonella sp. evidently used bacterial chemical cues as a basis for preferential feeding decisions, but it was unclear whether Tetrahymena sp. did also. Confocal microscopy of live biofilms revealed that Tetrahymena sp. had a major impact on biofilm morphology, forming holes and channels throughout S. plymuthica biofilms and reducing P. costantinii biofilms to isolated, grazing resistant microcolonies. Grazing by Chilodonella sp. resulted in the development of less-defined trails through S. plymuthica biofilms and caused P. costantinii biofilms to become homogeneous scatterings of cells. It was not clear whether the observed feeding preferences for spatially separated P. costantinii biofilms over S. plymuthica biofilms resulted in selective targeting of P. costantinii cells in mixed biofilms. Grazing of mixed biofilms resulted in the depletion of both types of bacteria, with Tetrahymena sp. having a larger impact than Chilodonella sp., and effects similar to those seen in grazed single-species biofilms. PMID- 21602373 TI - Inhibition of the NF-kappaB pathway in human intestinal epithelial cells by commensal Streptococcus salivarius. AB - Streptococcus salivarius exhibited an anti-inflammatory effect on intestinal epithelial cells (IECs) and monocytes. Strains were screened using a reporter clone, HT-29/kB-luc-E, induced by tumor necrosis factor alpha (TNF-alpha). Supernatant from each strain downregulated NF-kappaB activation. The two most efficient strains produced an active metabolite (<3 kDa) which was able to downregulate the secretion of the proinflammatory chemokine interleukin-8 (IL-8). PMID- 21602374 TI - Small-molecule inhibition of choline catabolism in Pseudomonas aeruginosa and other aerobic choline-catabolizing bacteria. AB - Choline is abundant in association with eukaryotes and plays roles in osmoprotection, thermoprotection, and membrane biosynthesis in many bacteria. Aerobic catabolism of choline is widespread among soil proteobacteria, particularly those associated with eukaryotes. Catabolism of choline as a carbon, nitrogen, and/or energy source may play important roles in association with eukaryotes, including pathogenesis, symbioses, and nutrient cycling. We sought to generate choline analogues to study bacterial choline catabolism in vitro and in situ. Here we report the characterization of a choline analogue, propargylcholine, which inhibits choline catabolism at the level of Dgc enzyme catalyzed dimethylglycine demethylation in Pseudomonas aeruginosa. We used genetic analyses and 13C nuclear magnetic resonance to demonstrate that propargylcholine is catabolized to its inhibitory form, propargylmethylglycine. Chemically synthesized propargylmethylglycine was also an inhibitor of growth on choline. Bioinformatic analysis suggests that there are genes encoding DgcA homologues in a variety of proteobacteria. We examined the broader utility of propargylcholine and propargylmethylglycine by assessing growth of other members of the proteobacteria that are known to grow on choline and possess putative DgcA homologues. Propargylcholine showed utility as a growth inhibitor in P. aeruginosa but did not inhibit growth in other proteobacteria tested. In contrast, propargylmethylglycine was able to inhibit choline-dependent growth in all tested proteobacteria, including Pseudomonas mendocina, Pseudomonas fluorescens, Pseudomonas putida, Burkholderia cepacia, Burkholderia ambifaria, and Sinorhizobium meliloti. We predict that chemical inhibitors of choline catabolism will be useful for studying this pathway in clinical and environmental isolates and could be a useful tool to study proteobacterial choline catabolism in situ. PMID- 21602375 TI - Selective quantification of viable Escherichia coli bacteria in biosolids by quantitative PCR with propidium monoazide modification. AB - Quantitative differentiation of live cells in biosolids samples, without the use of culturing-based approaches, is highly critical from a public health risk perspective, as recent studies have shown significant regrowth and reactivation of indicator organisms. Persistence of DNA in the environment after cell death in the range of days to weeks limits the application of DNA-based approaches as a measure of live cell density. Using selective nucleic acid intercalating dyes like ethidium monoazide (EMA) and propidium monoazide (PMA) is one of the alternative approaches to detecting and quantifying viable cells by quantitative PCR. These compounds have the ability to penetrate only into dead cells with compromised membrane integrity and intercalate with DNA via their photoinducible azide groups and in turn inhibit DNA amplification during PCRs. PMA has been successfully used in different studies and microorganisms, but it has not been evaluated sufficiently for complex environmental samples such as biosolids. In this study, experiments were performed with Escherichia coli ATCC 25922 as the model organism and the uidA gene as the target sequence using real-time PCR via the absolute quantification method. Experiments with the known quantities of live and dead cell mixtures showed that PMA treatment inhibits PCR amplification from dead cells with over 99% efficiency. The results also indicated that PMA-modified quantitative PCR could be successfully applied to biosolids when the total suspended solids (TSS) concentration is at or below 2,000 mg.liter(-1). PMID- 21602376 TI - Dehydrogenase GRD1 represents a novel component of the cellulase regulon in Trichoderma reesei (Hypocrea jecorina). AB - Trichoderma reesei (Hypocrea jecorina) is nowadays the most important industrial producer of cellulase and hemicellulase enzymes, which are used for pretreatment of cellulosic biomass for biofuel production. In this study, we introduce a novel component, GRD1 (glucose-ribitol dehydrogenase 1), which shows enzymatic activity on cellobiose and positively influences cellulase gene transcription, expression, and extracellular endo-1,4-beta-D-glucanase activity. grd1 is differentially transcribed upon growth on cellulose and the induction of cellulase gene expression by sophorose. The transcription of grd1 is coregulated with that of cel7a (cbh1) under inducing conditions. GRD1 is further involved in carbon source utilization on several carbon sources, such as those involved in lactose and D galactose catabolism, in several cases in a light-dependent manner. We conclude that GRD1 represents a novel enhancer of cellulase gene expression, which by coregulation with the major cellulase may act via optimization of inducing mechanisms. PMID- 21602377 TI - Thalassospira sp. isolated from the oligotrophic eastern Mediterranean Sea exhibits chemotaxis toward inorganic phosphate during starvation. AB - The eastern Mediterranean Sea represents an ultraoligotrophic environment where soluble phosphate limits the growth of bacterioplankton. Correspondingly, genes coding for high-affinity phosphate uptake systems and for organophosphonate utilization are highly prevalent in the plankton metagenome. Chemotaxis toward inorganic phosphate constitutes an alternative strategy to cope with phosphate limitation, but so far has only been demonstrated for two bacterial pathogens and an archaeon, and not in any free-living planktonic bacterium. In the present study, bacteria affiliated with the genus Thalassospira were found to constitute a regular, low-abundance member of the bacterioplankton that can be detected throughout the water column of the eastern Mediterranean Sea. A representative (strain EM) was isolated in pure culture and exhibited a strong positive chemotaxis toward inorganic phosphate that was induced exclusively in phosphate starved cultures. Phosphate-depleted cells were 2-fold larger than in exponentially growing cultures, and 43% of the cells retained their motility even during prolonged starvation over 10 days. In addition, Thalassospira sp. strain EM was chemotactically attracted by complex substrates (yeast extract and peptone), amino acids, and 2-aminoethylphosphonate but not by sugar monomers. Similarly to the isolate from the eastern Mediterranean, chemotaxis toward phosphate was observed in starved cultures of the other two available isolates of the genus, T. lucentensis DSM 14000T and T. profundimaris WP0211T. Although Thalassospira sp. represents only up to 1.2% of the total bacterioplankton community in the water column of the eastern Mediterranean Sea, its chemotactic behavior potentially leads to an acceleration of nutrient cycling and may also explain the persistence of marine copiotrophs in this extremely nutrient-limited environment. PMID- 21602378 TI - Phylogenetic and functional analysis of Aspergillus fumigatus MGTC, a fungal protein homologous to a bacterial virulence factor. AB - MgtC is important for the survival of several bacterial pathogens in macrophages and for growth under magnesium limitation. Among eukaryotes, a gene homologous to mgtC was found only in the pathogenic fungus Aspergillus fumigatus. Our data show that the A. fumigatus MgtC (AfuMgtC) protein does not have the same function as the bacterial MgtC proteins. PMID- 21602379 TI - Meta-analysis and functional validation of nutritional requirements of solventogenic Clostridia growing under butanol stress conditions and coutilization of D-glucose and D-xylose. AB - Recent advances in systems biology, omics, and computational studies allow us to carry out data mining for improving biofuel production bioprocesses. Of particular interest are bioprocesses that center on microbial capabilities to biotransform both the hexose and pentose fractions present in crop residues. This called for a systematic exploration of the components of the media to obtain higher-density cultures and more-productive fermentation operations than are currently found. By using a meta-analysis approach of the transcriptional responses to butanol stress, we identified the nutritional requirements of solvent-tolerant strain Clostridium beijerinckii SA-1 (ATCC 35702). The nutritional requirements identified were later validated using the chemostat pulse-and-shift technique. C. beijerinckii SA-1 was cultivated in a two-stage single-feed-stream continuous production system to test the proposed validated medium formulation, and the coutilization of D-glucose and D-xylose was evaluated by taking advantage of the well-known ability of solventogenic clostridia to utilize a large variety of carbon sources such as mono-, oligo-, and polysaccharides containing pentose and hexose sugars. Our results indicated that C. beijerinckii SA-1 was able to coferment hexose/pentose sugar mixtures in the absence of a glucose repression effect. In addition, our analysis suggests that the solvent and acid resistance mechanisms found in this strain are differentially regulated compared to strain NRRL B-527 and are outlined as the basis of the analysis toward optimizing butanol production. PMID- 21602380 TI - Development of a real-time PCR assay for detection and quantification of Rhizobium leguminosarum bacteria and discrimination between different biovars in zinc-contaminated soil. AB - Primers were designed to target 16S rRNA and nodD genes of Rhizobium leguminosarum from DNA extracted from two different soil types contaminated with Zn applied in sewage sludge. Numbers of rhizobia estimated using 16S rRNA gene copy number showed higher abundance than those estimated by both nodD and the most-probable-number (MPN) enumeration method using a plant trap host. Both 16S rRNA gene copies and the MPN rhizobia declined with increased levels of Zn contamination, as did the abundance of the functional gene nodD, providing compelling evidence of a toxic effect of Zn on R. leguminosarum populations in the soil. Regression analysis suggested the total Zn concentration in soil as a better predictor of rhizobial numbers than both NH4NO3-extractable and soil solution Zn. R. leguminosarum bv. viciae nodD gene copies were generally less sensitive to Zn than R. leguminosarum bv. trifolii nodD. The latter were generally below detection limits at Zn levels of >250 mg kg(-1). Although there were differences in the actual numbers estimated by each approach, the response to Zn was broadly similar across all methods. These differences were likely to result from the fact that the molecular approaches assess the potential for nodulation while the MPN approach assesses actual nodulation. The results demonstrate that the use of targeted gene probes for assessing environmental perturbations of indigenous soil rhizobial populations may be more sensitive than the conventional plant bioassay and MPN methods. PMID- 21602381 TI - Spatiotemporal changes in the structure and composition of a less-abundant bacterial phylum (Planctomycetes) in two perialpine lakes. AB - We used fingerprinting and cloning-sequencing to study the spatiotemporal dynamics and diversity of Planctomycetes in two perialpine lakes with contrasting environmental conditions. Planctomycetes, which are less-abundant bacteria in freshwater ecosystems, appeared to be structured in the same way as the entire bacterial community in these ecosystems. They were more diversified and displayed fewer temporal variations in the hypolimnia than in the epilimnia. Like the more abundant bacterial groups in aquatic systems, Planctomycetes communities seem to be composed of a very small number of abundant and widespread operational taxonomic units (OTUs) and a large number of OTUs that are present at low abundance. This indicates that the concept of "abundant or core" and "rare" bacterial phylotypes could also be applied to less-abundant freshwater bacterial phyla. The richness and diversity of Planctomycetes were mainly driven by pH and were similar in both of the lakes studied, whereas the composition of the Planctomycetes community seemed to be determined by a combination of factors including temperature, pH, and nutrients. The relative abundances of the dominant OTUs varied over time and were differently associated with abiotic factors. Our findings demonstrate that less-abundant bacterial phyla, such as Planctomycetes, can display strong spatial and seasonal variations linked to environmental conditions and suggest that their functional role in the lakes studied might be attributable mainly to a small number of phylotypes and vary over space and time in the water column. PMID- 21602382 TI - Selection pressure required for long-term persistence of blaCMY-2-positive IncA/C plasmids. AB - Multidrug resistance blaCMY-2 plasmids that confer resistance to expanded spectrum cephalosporins have been found in multiple bacterial species collected from different hosts worldwide. The widespread distribution of blaCMY-2 plasmids may be driven by antibiotic use that selects for the dissemination and persistence of these plasmids. Alternatively, these plasmids may persist and spread in bacterial populations in the absence of selection pressure if a balance exists among conjugative transfer, segregation loss during cell division, and fitness cost to the host. We conducted a series of experiments (both in vivo and in vitro) to study these mechanisms for three blaCMY-2 plasmids, peH4H, pAR060302, and pAM04528. Results of filter mating experiments showed that the conjugation efficiency of blaCMY-2 plasmids is variable, from <10(-7) for pAM04528 and peH4H to ~10(-3) for pAR060302. Neither peH4H nor pAM04528 was transferred from Escherichia coli strain DH10B, but peH4H was apparently mobilized by the coresident trimethoprim resistance-encoding plasmid pTmpR. Competition studies showed that carriage of blaCMY-2 plasmids imposed a measurable fitness cost on the host bacteria both in vitro (0.095 to 0.25) and in vivo (dairy calf model). Long-term passage experiments in the absence of antibiotics demonstrated that plasmids with limited antibiotic resistance phenotypes arose, but eventually drug-sensitive, plasmid-free clones dominated the populations. Given that plasmid decay or loss is inevitable, we infer that some level of selection is required for the long-term persistence of blaCMY-2 plasmids in bacterial populations. PMID- 21602383 TI - Engineering Escherichia coli BL21(DE3) derivative strains to minimize E. coli protein contamination after purification by immobilized metal affinity chromatography. AB - Recombinant His-tagged proteins expressed in Escherichia coli and purified by immobilized metal affinity chromatography (IMAC) are commonly coeluted with native E. coli proteins, especially if the recombinant protein is expressed at a low level. The E. coli contaminants display high affinity to divalent nickel or cobalt ions, mainly due to the presence of clustered histidine residues or biologically relevant metal binding sites. To improve the final purity of expressed His-tagged protein, we engineered E. coli BL21(DE3) expression strains in which the most recurring contaminants are either expressed with an alternative tag or mutated to decrease their affinity to divalent cations. The current study presents the design, engineering, and characterization of two E. coli BL21(DE3) derivatives, NiCo21(DE3) and NiCo22(DE3), which express the endogenous proteins SlyD, Can, ArnA, and (optionally) AceE fused at their C terminus to a chitin binding domain (CBD) and the protein GlmS, with six surface histidines replaced by alanines. We show that each E. coli CBD-tagged protein remains active and can be efficiently eliminated from an IMAC elution fraction using a chitin column flowthrough step, while the modification of GlmS results in loss of affinity for nickel-containing resin. The "NiCo" strains uniquely complement existing methods for improving the purity of recombinant His-tagged protein. PMID- 21602384 TI - Disruption of a type II endonuclease (TDE0911) enables Treponema denticola ATCC 35405 to accept an unmethylated shuttle vector. AB - The oral spirochete Treponema denticola is associated with human periodontal disease. T. denticola ATCC 35405 and ATCC 33520 are two routinely used laboratory strains. Compared to T. denticola ATCC 33520, ATCC 35405 is more virulent but less accessible to genetic manipulations. For instance, the shuttle vectors of ATCC 33520 cannot be transformed into strain ATCC 35405. The lack of a shuttle vector has been a barrier to study the biology and virulence of T. denticola ATCC 35405. In this report, we hypothesize that T. denticola ATCC 35405 may have a unique DNA restriction-modification (R-M) system that prevents it from accepting the shuttle vectors of ATCC 33520 (e.g., the shuttle plasmid pBFC). To test this hypothesis, DNA restriction digestion, PCR, and Southern blot analyses were conducted to identify the differences between the R-M systems of these two strains. DNA restriction digestion analysis of these strains showed that only the cell extract from ATCC 35405 was able to digest pBFC. Consistently, PCR and Southern blot analyses revealed that the genome of T. denticola ATCC 35405 encodes three type II endonucleases that are absent in ATCC 33520. Among these three endonucleases, TDE0911 was predicted to cleave unmethylated double-stranded DNA and to be most likely responsible for the cleavage of unmethylated pBFC. In agreement with this prediction, the mutant of TDE0911 failed to cleave unmethylated pBFC plasmid, and it could accept the unmethylated shuttle vector. The study described here provides us with a new tool and strategy to genetically manipulate T. denticola, in particular ATCC 35405, and other strains that may carry similar endonucleases. PMID- 21602385 TI - FadD19 of Rhodococcus rhodochrous DSM43269, a steroid-coenzyme A ligase essential for degradation of C-24 branched sterol side chains. AB - The actinobacterial cholesterol catabolic gene cluster contains a subset of genes that encode beta-oxidation enzymes with a putative role in sterol side chain degradation. We investigated the physiological roles of several genes, i.e., fadD17, fadD19, fadE26, fadE27, and ro04690DSM43269, by gene inactivation studies in mutant strain RG32 of Rhodococcus rhodochrous DSM43269. Mutant strain RG32 is devoid of 3-ketosteroid 9alpha-hydroxylase (KSH) activity and was constructed following the identification, cloning, and sequential inactivation of five kshA gene homologs in strain DSM43269. We show that mutant strain RG32 is fully blocked in steroid ring degradation but capable of selective sterol side chain degradation. Except for RG32DeltafadD19, none of the mutants constructed in RG32 revealed an aberrant phenotype on sterol side chain degradation compared to parent strain RG32. Deletion of fadD19 in strain RG32 completely blocked side chain degradation of C-24 branched sterols but interestingly not that of cholesterol. The additional inactivation of fadD17 in mutant RG32DeltafadD19 also did not affect cholesterol side chain degradation. Heterologously expressed FadD19DSM43269 nevertheless was active toward steroid-C26-oic acid substrates. Our data identified FadD19 as a steroid-coenzyme A (CoA) ligase with an essential in vivo role in the degradation of the side chains of C-24 branched-chain sterols. This paper reports the identification and characterization of a CoA ligase with an in vivo role in sterol side chain degradation. The high similarity (67%) between the FadD19(DSM43269) and FadD19H37Rv enzymes further suggests that FadD19H37Rv has an in vivo role in sterol metabolism of Mycobacterium tuberculosis H37Rv. PMID- 21602387 TI - Aeration controls the reduction and methylation of tellurium by the aerobic, tellurite-resistant marine yeast Rhodotorula mucilaginosa. AB - We previously described a marine, tellurite-resistant strain of the yeast Rhodotorula mucilaginosa that both precipitates intracellular Te0 and volatilizes methylated Te compounds when grown in the presence of the oxyanion tellurite. The uses of microbes as a "green" route for the production of Te0-containing nanostructures and for the remediation of Te-oxyanion wastes have great potential, and so a more thorough understanding of this process is required. Here, Te precipitation and volatilization catalyzed by R. mucilaginosa were examined in continuously aerated and sealed (low oxygen concentration) batch cultures. Continuous aeration was found to strongly promote Te volatilization while inhibiting Te0 precipitation. This differs from the results in sealed batch cultures, for which tellurite reduction to Te0 was found to be very efficient. We show also that volatile Te species may be degraded rapidly in medium and converted to the particulate form by biological activity. Further experiments revealed that Te0 precipitates produced by R. mucilaginosa can be further transformed to volatile and dissolved Te species. However, it was not clearly determined whether Te0 is a required intermediate for Te volatilization. Based on these results, we conclude that low oxygen concentrations will be the most efficient for production of Te0 nanoparticles while limiting the production of toxic volatile Te species, although the production of these compounds may never be completely eliminated. PMID- 21602386 TI - Culture-independent analysis of bacterial fuel contamination provides insight into the level of concordance with the standard industry practice of aerobic cultivation. AB - Bacterial diversity in contaminated fuels has not been systematically investigated using cultivation-independent methods. The fuel industry relies on phenotypic cultivation-based contaminant identification, which may lack accuracy and neglect difficult-to-culture taxa. By the use of industry practice aerobic cultivation, 16S rRNA gene sequencing, and strain genotyping, a collection of 152 unique contaminant isolates from 54 fuel samples was assembled, and a dominance of Pseudomonas (21%), Burkholderia (7%), and Bacillus (7%) was demonstrated. Denaturing gradient gel electrophoresis (DGGE) of 15 samples revealed Proteobacteria and Firmicutes to be the most abundant phyla. When 16S rRNA V6 gene pyrosequencing of four selected fuel samples (indicated by "JW") was performed, Betaproteobacteria (42.8%) and Gammaproteobacteria (30.6%) formed the largest proportion of reads; the most abundant genera were Marinobacter (15.4%; JW57), Achromobacter (41.6%; JW63), Burkholderia (80.7%; JW76), and Halomonas (66.2%; JW78), all of which were also observed by DGGE. However, the Clostridia (38.5%) and Deltaproteobacteria (11.1%) identified by pyrosequencing in sample JW57 were not observed by DGGE or aerobic culture. Genotyping revealed three instances where identical strains were found: (i) a Pseudomonas sp. strain recovered from 2 different diesel fuel tanks at a single industrial site; (ii) a Mangroveibacter sp. strain isolated from 3 biodiesel tanks at a single refinery site; and (iii) a Burkholderia vietnamiensis strain present in two unrelated automotive diesel samples. Overall, aerobic cultivation of fuel contaminants recovered isolates broadly representative of the phyla and classes present but lacked accuracy by overrepresenting members of certain groups such as Pseudomonas. PMID- 21602388 TI - Functional characterization of a mucus-specific LPXTG surface adhesin from probiotic Lactobacillus rhamnosus GG. AB - In spite of the wealth of clinical evidence supporting the health benefits of Lactobacillus rhamnosus GG in humans, there is still a lack of understanding of the molecular mechanisms behind its probiosis. Current knowledge suggests that the health-promoting effects of this probiotic strain might be partly dependent on its persistence in the intestine and adhesion to mucosal surfaces. Moreover, L. rhamnosus GG contains mucus-binding pili that might also explain the occupation of its ecological niche as a comparatively less stringent allochthonous intestine-dwelling bacterium. To uncover additional surface proteins involved in mucosal adhesion, we investigated the adherence properties of the only predicted protein (LGG_02337) in L. rhamnosus GG that exhibits homology with a known mucus-binding domain. We cloned a recombinant form of the gene for this putative mucus adhesin and established that the purified protein readily adheres to human intestinal mucus. We also showed that this mucus adhesin is visibly distributed throughout the cell surface and participates in the adhesive interaction between L. rhamnosus GG and mucus, although less prominently than the mucus-binding pili in this strain. Based on primary structural comparisons, we concluded that the current annotation of the LGG_02337 protein likely does not accurately reflect its predicted properties, and we propose that this mucus-specific adhesin be called the mucus-binding factor (MBF). Finally, we interpret our results to mean that L. rhamnosus GG MBF, as an active mucus specific surface adhesin with a presumed ancillary involvement in pilus-mediated mucosal adhesion, plays a part in the adherent mechanisms during intestinal colonization by this probiotic. PMID- 21602389 TI - Effect of Lactobacillus fermentum on beta2 toxin production by Clostridium perfringens. AB - Clostridium perfringens, although a member of the normal gut flora, is also an important cause of intestinal disease in animals and, to a lesser extent, in humans. Disease is associated with the production of one or more toxins, and little is known about environmental influences on the production of these toxins. One of the health-promoting effects of lactic acid bacteria (LAB) is the establishment and maintenance of a low pH in the intestine since an acidic environment inhibits the growth of many potentially harmful bacteria. Here, the effect of the LAB Lactobacillus fermentum on beta2 toxin production by C. perfringens is described. Coculturing of C. perfringens with L. fermentum showed that under in vitro conditions, L. fermentum was capable of silencing beta2 toxin production by C. perfringens without influencing bacterial viability. The reduction in toxin production was shown to be most likely a result of the decline in pH. Quantitative PCR showed that the reduction in beta2 toxin production was due to a decrease in cpb2 mRNA. These results suggest that in the intestine, the production of beta2 toxin by C. perfringens might be regulated by other members of the normal intestinal flora. PMID- 21602390 TI - Lectin microarray reveals binding profiles of Lactobacillus casei strains in a comprehensive analysis of bacterial cell wall polysaccharides. AB - We previously showed a pivotal role of the polysaccharide (PS) moiety in the cell wall of the Lactobacillus casei strain Shirota (YIT 9029) as a possible immune modulator (E. Yasuda M. Serata, and T. Sako, Appl. Environ. Microbiol. 74:4746 4755, 2008). To distinguish PS structures on the bacterial cell surface of individual strains in relation to their activities, it would be useful to have a rapid and high-throughput methodology. Recently, a new technique called lectin microarray was developed for rapid profiling of glycosylation in eukaryotic polymers and cell surfaces. Here, we report on the development of a simple and sensitive method based on this technology for direct analysis of intact bacterial cell surface glycomes. The method involves labeling bacterial cells with SYTOX Orange before incubation with the lectin microarray. After washing, bound cells are directly detected using an evanescent-field fluorescence scanner in a liquid phase. Using this method, we compared the cell surface glycomes from 16 different strains of L. casei. The patterns of lectin-binding affinity of most strains were found to be unique. There appears to be two types of lectin-binding profiles: the first is characterized by a few lectins, and the other is characterized by multiple lectins with different specificities. We also showed a dramatic change in the lectin-binding profile of a YIT 9029 derivative with a mutation in the cps1C gene, encoding a putative glycosyltransferase. In conclusion, the developed technique provided a novel strategy for rapid profiling and, more importantly, differentiating numerous bacterial strains with relevance to the biological functions of PS. PMID- 21602391 TI - Lichenicidin biosynthesis in Escherichia coli: licFGEHI immunity genes are not essential for lantibiotic production or self-protection. AB - This study demonstrated, for the first time, that immunity genes licFGEHI are not essential for self-protection and production of the two-component lantibiotic lichenicidin in the Gram-negative heterologous host Escherichia coli BLic5. Additionally, it was experimentally demonstrated that lichenicidin lantibiotics are active against the E. coli imp4213 strain, a mutant strain possessing a permeable outer membrane. PMID- 21602392 TI - Patchwork assembly of nag-like nitroarene dioxygenase genes and the 3 chlorocatechol degradation cluster for evolution of the 2-chloronitrobenzene catabolism pathway in Pseudomonas stutzeri ZWLR2-1. AB - Pseudomonas stutzeri ZWLR2-1 utilizes 2-chloronitrobenzene (2CNB) as a sole source of carbon, nitrogen, and energy. To identify genes involved in this pathway, a 16.2-kb DNA fragment containing putative 2CNB dioxygenase genes was cloned and sequenced. Of the products from the 19 open reading frames that resulted from this fragment, CnbAc and CnbAd exhibited striking identities to the respective alpha and beta subunits of the Nag-like ring-hydroxylating dioxygenases involved in the metabolism of nitrotoluene, nitrobenzene, and naphthalene. The encoding genes were also flanked by two copies of insertion sequence IS6100. CnbAa and CnbAb are similar to the ferredoxin reductase and ferredoxin for anthranilate 1,2-dioxygenase from Burkholderia cepacia DBO1. Escherichia coli cells expressing cnbAaAbAcAd converted 2CNB to 3-chlorocatechol with concomitant nitrite release. Cell extracts of E. coli/pCNBC exhibited chlorocatechol 1,2-dioxygenase activity. The cnbCDEF gene cluster, homologous to a 3-chlorocatechol degradation cluster in Sphingomonas sp. strain TFD44, probably contains all of the genes necessary for the conversion of 3-chlorocatechol to 3 oxoadipate. The patchwork-like structure of this catabolic cluster suggests that the cnb cluster for 2CNB degradation evolved by recruiting two catabolic clusters encoding a nitroarene dioxygenase and a chlorocatechol degradation pathway. This provides another example to help elucidate the bacterial evolution of catabolic pathways in response to xenobiotic chemicals. PMID- 21602393 TI - Shewanella oneidensis MR-1 sensory box protein involved in aerobic and anoxic growth. AB - Although little is known of potential function for conserved signaling proteins, it is hypothesized that such proteins play important roles to coordinate cellular responses to environmental stimuli. In order to elucidate the function of a putative sensory box protein (PAS domains) in Shewanella oneidensis MR-1, the physiological role of SO3389 was characterized. The predicted open reading frame (ORF) encodes a putative sensory box protein that has PAS, GGDEF, and EAL domains, and an in-frame deletion mutant was constructed (DeltaSO3389) with approximately 95% of the ORF deleted. Under aerated conditions, wild-type and mutant cultures had similar growth rates, but the mutant culture had a lower growth rate under static, aerobic conditions. Oxygen consumption rates were lower for mutant cultures (1.5-fold), and wild-type cultures also maintained lower dissolved oxygen concentrations under aerated growth conditions. When transferred to anoxic conditions, the mutant did not grow with fumarate, iron(III), or dimethyl sulfoxide (DMSO) as electron acceptors. Biochemical assays demonstrated the expression of different c-type cytochromes as well as decreased fumarate reductase activity in the mutant transferred to anoxic growth conditions. Transcriptomic studies showed the inability of the mutant to up-express and down express genes, including c-type cytochromes (e.g., SO4047/SO4048, SO3285/SO3286), reductases (e.g., SO0768, SO1427), and potential regulators (e.g., SO1329). The complemented strain was able to grow when transferred from aerobic to anoxic growth conditions with the tested electron acceptors. The modeled structure for the SO3389 PAS domains was highly similar to the crystal structures of FAD binding PAS domains that are known O2/redox sensors. Based on physiological, genomic, and bioinformatic results, we suggest that the sensory box protein, SO3389, is an O2/redox sensor that is involved in optimization of aerobic growth and transitions to anoxia in S. oneidensis MR-1. PMID- 21602395 TI - Impact of medicated feed on the development of antimicrobial resistance in bacteria at integrated pig-fish farms in Vietnam. AB - Integrated livestock-fish aquaculture utilizes animal excreta, urine, and feed leftovers as pond fertilizers to enhance the growth of plankton and other microorganisms eaten by the fish. However, antimicrobial-resistant bacteria may be transferred and develop in the pond due to selective pressure from antimicrobials present in animal feed, urine, and feces. In an experimental pig fish farm located in periurban Hanoi, Vietnam, nine piglets were provided feed containing 5 MUg of tetracycline (TET)/kg pig weight/day and 0.45 MUg of enrofloxacin (ENR)/kg pig weight/day during the second and fourth (last) months of the experiment. The aim of this study was to determine the association between the provision of pig feed with antimicrobials and the development of antimicrobial resistance, as measured in a total of 520 Escherichia coli and 634 Enterococcus strains isolated from pig manure and water-sediment pond samples. MIC values for nalidixic acid (NAL) and ENR showed that E. coli and Enterococcus spp. overall exhibited significant higher frequencies of resistance toward NAL and ENR during the 2 months when pigs were administered feed with antimicrobials, with frequencies reaching 60 to 80% in both water-sediment and manure samples. TET resistance for both indicators was high (>80%) throughout the study period, which indicates that TET-resistant E. coli and Enterococcus spp. were present in the piglets before the initiation of the experiment. PCR-based identification showed similar relative occurrences of Enterococcus faecium, Enterococcus faecalis, and other Enterococcus spp. in the water-sediment and manure samples, suggesting that Enterococcus spp. isolated in the ponds originated mainly from the pig manure. The development of antimicrobial resistance in integrated animal husbandry-fish farms and possible transfers and the impact of such resistance on food safety and human health should be further assessed. PMID- 21602394 TI - Planktonic versus biofilm catabolic communities: importance of the biofilm for species selection and pesticide degradation. AB - Chloropropham-degrading cultures were obtained from sludge and soil samples by using two different enrichment techniques: (i) planktonic enrichments in shaken liquid medium and (ii) biofilm enrichments on two types of solid matrixes (plastic chips and gravel). Denaturing gradient gel electrophoresis fingerprinting showed that planktonic and biofilm cultures had a different community composition depending on the presence and type of added solid matrix during enrichment. This was reflected in the unique chloropropham-degrading species that could be isolated from the different cultures. Planktonic and biofilm cultures also differed in chloropropham-degrading activity. With biofilm cultures, slower chloropropham removal was observed, but with less build-up of the toxic intermediate 3-chloroaniline. Disruption of the biofilm architecture resulted in degradation characteristics shifting toward those of the free suspensions, indicating the importance of a well-established biofilm structure for good performance. These results show that biofilm-mediated enrichment techniques can be used to select for pollutant-degrading microorganisms that like to proliferate in a biofilm and that cannot be isolated using conventional shaken liquid procedures. Furthermore, the influence of the biofilm architecture on the pesticide degradation characteristics suggests that for bioaugmentation the use of biofilm catabolic communities might be a proficient alternative to using planktonic freely suspended cultures. PMID- 21602396 TI - Combined application of PCR-based functional assays for the detection of aromatic compound-degrading anaerobes. AB - To explore the reliability of assays that detect aromatic-compound-degrading anaerobes, a combination of three functional-gene-targeting assays was applied to microcosms from benzene-contaminated aquifers. Results of the assays were consistent and suggest that species related to the genera Azoarcus and Geobacter dominated benzene degradation at the individual sites. PMID- 21602397 TI - Development of a Streptomyces venezuelae-based combinatorial biosynthetic system for the production of glycosylated derivatives of doxorubicin and its biosynthetic intermediates. AB - Doxorubicin, one of the most widely used anticancer drugs, is composed of a tetracyclic polyketide aglycone and l-daunosamine as a deoxysugar moiety, which acts as an important determinant of its biological activity. This is exemplified by the fewer side effects of semisynthetic epirubicin (4'-epi-doxorubicin). An efficient combinatorial biosynthetic system that can convert the exogenous aglycone epsilon-rhodomycinone into diverse glycosylated derivatives of doxorubicin or its biosynthetic intermediates, rhodomycin D and daunorubicin, was developed through the use of Streptomyces venezuelae mutants carrying plasmids that direct the biosynthesis of different nucleotide deoxysugars and their transfer onto aglycone, as well as the postglycosylation modifications. This system improved epirubicin production from epsilon-rhodomycinone by selecting a substrate flexible glycosyltransferase, AknS, which was able to transfer the unnatural sugar donors and a TDP-4-ketohexose reductase, AvrE, which efficiently supported the biosynthesis of TDP-4-epi-l-daunosamine. Furthermore, a range of doxorubicin analogs containing diverse deoxysugar moieties, seven of which are novel rhodomycin D derivatives, were generated. This provides new insights into the functions of deoxysugar biosynthetic enzymes and demonstrates the potential of the S. venezuelae-based combinatorial biosynthetic system as a simple biological tool for modifying structurally complex sugar moieties attached to anthracyclines as an alternative to chemical syntheses for improving anticancer agents. PMID- 21602398 TI - Cellular response of the amoeba Acanthamoeba castellanii to chlorine, chlorine dioxide, and monochloramine treatments. AB - Acanthamoeba castellanii is a free-living amoebae commonly found in water systems. Free-living amoebae might be pathogenic but are also known to bear phagocytosis-resistant bacteria, protecting these bacteria from water treatments. The mode of action of these treatments is poorly understood, particularly on amoebae. It is important to examine the action of these treatments on amoebae in order to improve them. The cellular response to chlorine, chlorine dioxide, and monochloramine was tested on A. castellanii trophozoites. Doses of disinfectants leading to up to a 3-log reduction were compared by flow cytometry and electron microscopy. Chlorine treatment led to size reduction, permeabilization, and retraction of pseudopods. In addition, treatment with chlorine dioxide led to a vacuolization of the cytoplasm. Monochloramine had a dose-dependent effect. At the highest doses monochloramine treatment resulted in almost no changes in cell size and permeability, as shown by flow cytometry, but the cell surface became smooth and dense, as seen by electron microscopy. We show that these disinfectants globally induced size reduction, membrane permeabilization, and morphological modifications but that they have a different mode of action on A. castellanii. PMID- 21602400 TI - Licensing regime to govern wild animal welfare in circuses. PMID- 21602402 TI - Hard work pays off at Royal wedding. PMID- 21602406 TI - Survey suggests decline in pet vaccination levels. PMID- 21602407 TI - Raising awareness of zoonoses. PMID- 21602409 TI - Canine atopy - inside out, or outside in? PMID- 21602410 TI - Control of foot-and-mouth disease. PMID- 21602411 TI - Tail docking of dairy cattle in the UK. PMID- 21602412 TI - Distribution category for oral copper supplements for sheep. PMID- 21602413 TI - Survey of vets employed in industry. PMID- 21602414 TI - Use of darting guns and administration of sedatives. PMID- 21602415 TI - Recruitment of temporary veterinary inspectors in FMD emergencies. PMID- 21602416 TI - Recruitment of temporary veterinary inspectors in FMD emergencies. PMID- 21602417 TI - Naked-neck chickens. PMID- 21602418 TI - Is it safe to perform coronary angiography during acute endocarditis? AB - A best evidence topic was written according to a structured protocol. The question addressed was 'Is it safe to perform coronary angiography (CA) in acute endocarditis?' Three hundred and ninety-seven papers were found using the reported search, of which six represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes, key results and limitations of these papers are tabulated. One of the papers is a case report, which reported a fatal vegetation embolism from an infected aortic valve into the left main coronary artery 14 h after angiography. The remaining five papers are cohort studies. Four of these studies were performed between 1970 and 1980 before the era of echocardiography and were aimed at quantifying the severity of valvular regurgitation. No embolic complications or dislodgement of vegetations occurred in any of the five studies (186 patients). Guidelines published by the European Society of Cardiology (ESC) in 2009 recommended CA in the context of infective endocarditis (IE) for men >40 years old, postmenopausal women, and patients with at least one cardiovascular risk factor or a history of coronary artery disease. Exceptions include patients with large aortic vegetations which may be dislodged during catheterisation, and when emergency surgery is necessary - 1) native aortic or mitral IE with severe acute regurgitation or valve obstruction, or prosthetic valve IE with severe prosthetic dysfunction (dehiscence or obstruction) causing refractory pulmonary oedema or cardiogenic shock; 2) native aortic, mitral, or prosthetic valve IE with fistula into a cardiac chamber or pericardium causing refractory pulmonary oedema or shock. This is reiterated by the guidelines on the management of valvular heart disease published by the ESC in 2007. From the findings of the six papers, it can be concluded that coronary angiography can be performed safely in IE and should be performed if deemed necessary, unless the patients are haemodynamically unstable requiring emergency surgery, or have large vegetations of the aortic valve. This is consistent with the ESC guidelines. PMID- 21602419 TI - Does the nerve of Kuntz exist? AB - A best evidence topic was written according to a structured protocol. The question addressed was, in what proportion of patients is the nerve of Kuntz identifiable? A total of 55 papers were found using the reported search, of which six represented the best evidence to answer the clinical question. The authors, date, journal, study type, population, main outcome measures and results are tabulated. The nerve of Kuntz was originally described in 1927 as being a connection from the second intercostal nerve to the first thoracic ventral ramus. Controversy exists as to whether it is present universally and thus whether it should be identified during thoracoscopic sympathectomy. The six studies highlighted involved dissection of the upper thoracic sympathetic chain of adult cadavers with descriptions of the anatomical variations. A study by Cho et al. [Cho HM, Lee DY, Sung SW. Anatomical variations of rami communicants in the upper thoracic sympathetic trunk. Eur J Cardiothorac Surg 2005;27:320-324] suggested that anatomical variation was more common at T2 compared to T3 and T4, of which 60% corresponded to the original description of the nerve of Kuntz. A similar prevalence was found by Marhold and colleagues [Marhold F, Izay B, Zacherl J, Tschabitscher M, Neumayer C. Thoracoscopic and anatomic landmarks of Kuntz's nerve: implications for sympathetic surgery. Ann Thorac Surg 2008;86:1653-1658], who also suggested that open dissection led to significantly easier identification of this anatomy than thoracoscopy. The same authors frequently found that the nerve of Kuntz was associated with a superior intercostal vein located parallel to it, meaning that these subpleural veins may act as an anatomical landmark. In four of the papers where cadavers where dissected bilaterally, variations in the anatomy of the sympathetic chain were not always symmetrical. We conclude that most patients will have some form of variation in the anatomy of their T2 ganglion, which often corresponds to the original description of the nerve of Kuntz. The appreciation of this variation may be more difficult during thoracoscopy as compared to open anatomic dissection. PMID- 21602420 TI - Intrathoracic application of a vacuum-assisted closure device in managing pleural space infection after lung resection: is it an option? AB - Empyema after lung resection is a challenging condition to manage and is associated with a high mortality. Intrathoracic application of a vacuum-assisted closure (VAC) device is recently introduced as an adjunct in the management of this condition. A best evidence topic was constructed to address whether this approach is effective in successful chest closure and reducing hospital stay. Twenty-three papers were found using the reported search, of which nine papers were identified that provided the best evidence to answer the question. All papers were retrospective and included a total of 69 patients treated with intrathoracic VAC. There was only one cohort study and the rest were either case series or case reports. In a cohort of 19 patients reported by Palmen et al. the average duration of an open window thoracostomy in a group of patients with VAC (n=11) was 39 +/- 17 days and in those without VAC (n=8) was 933 +/- 1422 days. Median length of VAC treatment was 22 days (range 6-66 days) in a series of 28 patients reported by Saadi et al. Some authors excluded patients with a bronchopleural fistula (BPF) from VAC treatment. However, Groetzner et al. have safely used VAC in patients with BPF after covering the bronchus stump with an intrathoracic muscle flap. The mediastinum and the bronchus can be covered using a polyvinyl-alcohol foam. Polyurethane foam is commonly used to fill the intrathoracic cavity up to the superficial wound. The suggested starting level of negative pressure is as low as -25 mmHg to -75 mmHg depending on the presence or absence of signs of mediastinal traction; this negative pressure can gradually be increased to -125 mmHg over time. The recommended interval between VAC changes is two to five days. Accumulated evidence in this article, although limited, suggests that VAC, as an adjunct to the standard treatment, can potentially alleviate the morbidity and decrease hospital stay in patients with empyema after lung resection. VAC can reduce inpatient length of treatment and can make the condition manageable in an outpatient setting. These results are yet to be proven by larger studies and clinical trials. PMID- 21602421 TI - Stress and primary headache in adolescents: do those with migraine but not tension-type headache experience increased stress? PMID- 21602422 TI - Morning headache in habitual snorers: frequency, characteristics, predictors and impacts. AB - OBJECTIVES: Morning headache has been considered as an accompanying symptom of obstructive sleep apnoea syndrome (OSAS). However the frequency, characteristics, predictors and impacts of morning headache in habitual snorers are not well defined. METHODS: We studied consecutive patients with habitual snoring in a sleep laboratory using polysomnography. All patients were interviewed by a physician regarding the presence or absence of morning headache, migraine and insomnia. Each patient completed the Short Form-36 health survey (SF-36) and the Hospital Anxiety and Depression Scale (HADS). Morning headache was defined as headache on awakening >=1 day/week for >=6 months. RESULTS: Of the 268 participants with habitual snoring, 63 (23.5%) had morning headache and 184 (69%) had OSAS. Patients with morning headache reported lower scores in all eight domains of the SF-36 than those without (difference: 10.6 to 29.7 points, all p <= 0.005). The independent predictors of morning headache were migraine (adjusted odds ratio (AOR) 6.3), insomnia (AOR 4.2), psychological distress (HADS >= 8) (AOR 3.9) and OSAS (AOR 2.6). Morning headache in 12 patients (19%) fulfilled the criteria for migraine attacks. CONCLUSIONS: Morning headache was common in habitual snorers and associated with a pervasive impairment of health-related quality of life. Migrainous features were not uncommon. Not only OSAS, but migraine, insomnia and psychological distress were also important predictors for morning headache, even in snoring patients. PMID- 21602423 TI - Involvement of matrix metalloproteinase-mediated proteolysis of neural cell adhesion molecule in the development of cerebral ischemic neuronal damage. AB - Neural cell adhesion molecule (NCAM) is a membrane protein abundantly expressed in the central nervous system. Recently, it has been reported that dysfunction of NCAM is linked to human brain disorders. Furthermore, NCAM is one of the proteolysis targets of matrix metalloproteinase (MMP), whose activation is implicated in neuronal damage. The aim of this study was to elucidate the involvement of MMP-mediated proteolysis of NCAM in the development of ischemic neuronal damage. Male ddY and MMP-9 knockout (KO) C57BL/6J mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). In MCAO model mice, development of infarction and behavioral abnormality were clearly observed on days 1 and 3 after MCAO. Protein levels of MMP-2 and MMP-9 were significantly increased on days 1 and 3 after MCAO. In addition, full-length NCAM (180 kDa) was significantly decreased, but its metabolite levels increased on day 1 by ischemic stress per se. NCAM small interfering RNA significantly increased the neuronal damage induced by MCAO. MMP inhibition or MMP-9 gene KO attenuated the infarction, behavioral abnormalities, and decrease of NCAM (180 kDa) observed after MCAO in mice. The present findings clearly suggest that MMP-2/MMP-9 mediated NCAM proteolysis is implicated in the exacerbation of ischemic neuronal damage. PMID- 21602424 TI - Intermediate-conductance Ca2+-activated K+ channel, KCa3.1, as a novel therapeutic target for benign prostatic hyperplasia. AB - Recently, a new experimental stromal hyperplasia animal model corresponding to clinical benign prostatic hyperplasia (BPH) was established. The main objective of this study was to elucidate the roles of the intermediate-conductance Ca(2+) activated K(+) channel (K(Ca)3.1) in the implanted urogenital sinus (UGS) of stromal hyperplasia BPH model rats. Using DNA microarray, real-time polymerase chain reaction, Western blot, and/or immunohistochemical analyses, we identified the expression of K(Ca)3.1 and its transcriptional regulators in implanted UGS of BPH model rats and prostate needle-biopsy samples and surgical prostate specimens of BPH patients. We also examined the in vivo effects of a K(Ca)3.1 blocker, 1 [(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), on the proliferation index of implanted UGS by measurement of UGS weights and proliferating cell nuclear antigen immunostaining. K(Ca)3.1 genes and proteins were highly expressed in implanted UGS rather than in the normal host prostate. In the implanted UGS, the gene expressions of two transcriptional regulators of K(Ca)3.1, repressor element 1-silencing transcription factor and c-Jun, were significantly down- and up-regulated, and the regulations were correlated negatively or positively with K(Ca)3.1 expression, respectively. Positive signals of K(Ca)3.1 proteins were detected exclusively in stromal cells, whereas they were scarcely immunolocalized to basal cells of the epithelium in implanted UGS. In vivo treatment with TRAM-34 significantly suppressed the increase in implanted UGS weights compared with the decrease in stromal cell components. Moreover, significant levels of K(Ca)3.1 expression were observed in human BPH samples. K(Ca)3.1 blockers may be a novel treatment option for patients suffering from BPH. PMID- 21602425 TI - Glucose absorption in gestational diabetes mellitus during an oral glucose tolerance test. AB - OBJECTIVE: Women with gestational diabetes mellitus (GDM) show reduced insulin sensitivity and markedly elevated glucose excursions. After delivery, GDM mostly reverts to normal glucose tolerance (NGT), although leaving an increased risk of type 2 diabetes. Because gastrointestinal function changes during pregnancy causing vomiting, constipation, or reduced motility, we thought that gut glucose absorption in GDM or pregnancy might be altered to affect circulating glucose excursions. RESEARCH DESIGN AND METHODS: By undergoing 180-min oral glucose tolerance tests (OGTTs), pregnant women with GDM (GDMpreg; n=15, BMI=32+/-2 kg/m2, aged 33+/-1 years) were compared with NGT women (NGTpreg; n=7, BMI=28+/-1 kg/m2, aged 34+/-2 years), matching for major anthropometric characteristics (each P>0.2). After delivery (6-7 months later), both groups were studied the same way. We computed and mathematically modeled gut glucose absorption from insulin-mediated glucose disappearance and endogenous glucose production (EGP). Whole-body insulin sensitivity was calculated using the Clamp-like Index. RESULTS: GDMpreg showed 16-25% higher plasma glucose concentrations (P<0.04) during the final 2 h of OGTT, similar EGP, but lower (P<0.01) insulin sensitivity (2.7+/-0.2 mg.kg(-1).min(-1) vs. NGTpreg: 4.5+/-0.8 mg.kg(-1).min(-1)). In GDMpreg, gut glucose absorption rates were <=52% lower from 30 to 120 min (P<0.03 vs. conditions after delivery or NGTpreg). In contrast, glucose absorption rates in NGTpreg were comparable during and after pregnancy. None of the studied women developed diabetes after delivery. CONCLUSIONS: In GDMpreg, OGTT gut glucose absorption is markedly lower during hyperglycemia, whereas both glycemia and glucose absorption in NGTpreg are comparable between pregnant and postpartum states. Thus, hyperglycemia in GDM does not seem to result from too rapid or increased glucose absorption. PMID- 21602426 TI - Type 2 diabetes and the risk of renal cell cancer in women. AB - OBJECTIVE: Type 2 diabetes is associated with increased risks of several types of cancer; however, its relationship to renal cell cancer remains unclear. RESEARCH DESIGN AND METHODS: A total of 118,177 women aged 30 to 55 years at baseline (1976) were followed up through 2008 in the Nurses' Health Study. Self-reports of physician-diagnosed diabetes were collected at baseline and updated biennially. Hazard ratios (HRs) were calculated using Cox proportional hazards models with adjustment for age, BMI, hypertension, smoking, and parity. RESULTS: During 32 years of follow-up (3,531,170 person-years), 16,819 cases of type 2 diabetes and 330 cases of pathology-confirmed incident renal cell cancer were documented. After multivariate adjustment, type 2 diabetes was significantly associated with an increased risk of renal cell cancer (HR 1.60 [95% CI 1.19-2.17]). These associations were consistent across different strata of BMI, smoking, and hypertension (Pinteraction>=0.32). The risk of renal cell cancer increased with an increasing number of comorbidities, including obesity, hypertension, and type 2 diabetes (Ptrend<0.001). When compared with women without any comorbidity, women who had all three conditions had a HR of 4.13 (2.76-6.18) for renal cell cancer. CONCLUSIONS: Type 2 diabetes is independently associated with an increased risk of renal cell cancer in women. In addition, comorbidity of obesity, hypertension, and type 2 diabetes substantially elevates the risk of renal cell cancer. PMID- 21602427 TI - Long-term and recent progress in blood pressure levels among U.S. adults with diagnosed diabetes, 1988-2008. AB - OBJECTIVE: To examine whether there were long-term (between 1988-1994 and 2001 2008) and recent (between 2001-2004 and 2005-2008) changes in blood pressure (BP) levels among U.S. adults with diagnosed diabetes. RESEARCH DESIGN AND METHODS: Using data from National Health and Nutrition Examination Surveys (NHANES), we examined changes in BP distributions, mean BPs, and proportion with BP<140/90 mmHg. RESULTS: Between 1988-1994 and 2001-2008, for adults with diabetes, mean BPs decreased from 135/72 mmHg to 131/69 mmHg (P<0.01) and the proportion with BP<140/90 mmHg increased from 64 to 69% (P=0.01). Although hypertension prevalence increased, hypertension awareness, treatment, and control improved. However, there was no evidence of improvement for adults 20-44 years old. Between 2001-2004 and 2005-2008, there were no significant changes in BP levels. CONCLUSIONS: BP levels among adults with diabetes improved between 1988-1994 and 2001-2008, but the progress stalled between 2001-2004 and 2005-2008. The lack of improvement among young adults is concerning. PMID- 21602428 TI - Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype. AB - OBJECTIVE: To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation. RESEARCH DESIGN AND METHODS: The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA1c during childhood and adolescence of <=7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes. RESULTS: WSD was diagnosed earlier than type 1 diabetes (5.4+/-3.8 vs. 7.9+/-4.2 years; P<0.001) with a lower prevalence of ketoacidosis (7 vs. 20%; P=0.049). Mean duration of remission in WSD was 2.3+/-2.4 vs. 1.6+/ 2.1 in type 1 diabetes (NS). Severe hypoglycemia occurred in 37 vs. 7.9% (P<0.001). Neurologic disease progression was faster in the WSD group with a mean HbA1c>7.5% (P=0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P=0.028). CONCLUSIONS: Endoplasmic reticulum stress-mediated decline of beta cells in WSD occurs earlier in life than autoimmune-mediated beta-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease. PMID- 21602429 TI - Physical activity, high-sensitivity C-reactive protein, and total and cardiovascular disease mortality in type 2 diabetes. AB - OBJECTIVE: Physical activity reduces high-sensitivity C-reactive protein (hs CRP), cardiovascular disease (CVD), and total mortality in type 2 diabetic patients. However, it is not known whether the effects of physical activity on mortality depend on the levels of hs-CRP in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We prospectively followed-up on 569 type 2 diabetic patients, aged 45-64 years, who were free of CVD at baseline. Participants were stratified according to the level of hs-CRP (<1.0, 1.0-3.0, or >3.0 mg/L) and the degree of physical activity (0-4 metabolic equivalent tasks [METs] or >4 METs). The Cox proportional hazards model was used to estimate the joint association between physical activity and hs-CRP levels and the risk of mortality. RESULTS: During an 18-year follow-up, 356 patients died, 217 of whom died of CVD. Those who were physically more active had significantly reduced total, CVD and coronary heart disease (CHD) mortality among patients with elevated hs-CRP levels (>3 mg/L). These findings persisted in multivariable analyses. However, in patients with an hs-CRP level<1 mg/L or between 1 and 3 mg/L, there was no statistically significant relationship between physical activity and CVD or CHD mortality. CONCLUSIONS: Physical activity reduces total, CVD, and CHD mortality in type 2 diabetic patients with elevated hs-CRP levels. This suggests that the anti inflammatory effect of physical activity may counteract increased CVD and CHD morbidity and mortality associated with high CRP levels. PMID- 21602430 TI - Metformin and exercise in type 2 diabetes: examining treatment modality interactions. AB - OBJECTIVE: To determine the effect of metformin on the acute metabolic response to submaximal exercise, the effect of exercise on plasma metformin concentrations, and the interaction between metformin and exercise on the subsequent response to a standardized meal. RESEARCH DESIGN AND METHODS: Ten participants with type 2 diabetes were recruited for this randomized crossover study. Metformin or placebo was given for 28 days, followed by the alternate condition for 28 days. On the last 2 days of each condition, participants were assessed during a nonexercise and a subsequent exercise day. Exercise took place in the morning and involved a total of 35 min performed at three different submaximal intensities. RESULTS: Metformin increased heart rate and plasma lactate during exercise (both P<=0.01) but lowered respiratory exchange ratio (P=0.03) without affecting total energy expenditure, which suggests increased fat oxidation. Metformin plasma concentrations were greater at several, but not all, time points on the exercise day compared with the nonexercise day. The glycemic response to a standardized meal was reduced by metformin, but the reduction was attenuated when exercise was added (metformin*exercise interaction, P=0.05). Glucagon levels were highest in the combined exercise and metformin condition. CONCLUSIONS: This study reveals several ways by which metformin and exercise therapies can affect each other. By increasing heart rate, metformin could lead to the prescription of lower exercise workloads. Furthermore, under the tested conditions, exercise interfered with the glucose-lowering effect of metformin. PMID- 21602431 TI - Obesity and type 2 diabetes: what can be unified and what needs to be individualized? AB - OBJECTIVE: This report examines what is known about the relationship between obesity and type 2 diabetes and how future research in these areas might be directed to benefit prevention, interventions, and overall patient care. RESEARCH DESIGN AND METHODS: An international working group of 32 experts in the pathophysiology, genetics, clinical trials, and clinical care of obesity and/or type 2 diabetes participated in a conference held on 6-7 January 2011 and cosponsored by The Endocrine Society, the American Diabetes Association, and the European Association for the Study of Diabetes. A writing group comprising eight participants subsequently prepared this summary and recommendations. Participants reviewed and discussed published literature and their own unpublished data. RESULTS: The writing group unanimously supported the summary and recommendations as representing the working group's majority or unanimous opinions. CONCLUSIONS: The major questions linking obesity to type 2 diabetes that need to be addressed by combined basic, clinical, and population-based scientific approaches include the following: 1) Why do not all patients with obesity develop type 2 diabetes? 2) Through what mechanisms do obesity and insulin resistance contribute to beta cell decompensation, and if/when obesity prevention ensues, how much reduction in type 2 diabetes incidence will follow? 3) How does the duration of type 2 diabetes relate to the benefits of weight reduction by lifestyle, weight-loss drugs, and/or bariatric surgery on beta-cell function and glycemia? 4) What is necessary for regulatory approval of medications and possibly surgical approaches for preventing type 2 diabetes in patients with obesity? Improved understanding of how obesity relates to type 2 diabetes may help advance effective and cost effective interventions for both conditions, including more tailored therapy. To expedite this process, we recommend further investigation into the pathogenesis of these coexistent conditions and innovative approaches to their pharmacological and surgical management. PMID- 21602432 TI - Human tumor cells killed by anthracyclines induce a tumor-specific immune response. AB - Immunogenic cell death is characterized by the early surface exposure of chaperones including calreticulin and HSPs, which affect dendritic cell (DC) maturation and the uptake and presentation of tumor antigens. It has also been shown that it is characterized by the late release of high mobility group box 1 (HMGB1), which acts through Toll-like receptor 4 (TLR4) and augments the presentation of antigens from dying tumor cells to DCs. Most of the data on immunogenic tumor cell death were obtained using mouse models. In this study, we investigated the capacity of clinically used chemotherapeutics to induce immunogenic cell death in human tumor cell lines and primary tumor cells. We found that only anthracyclines induced a rapid translocation of calreticulin, HSP70, and HSP90 to the cell surface and the release of HMGB1 12 hours after the treatment. The interaction of immature DCs with immunogenic tumor cells led to an increased tumor cell uptake and induces moderate phenotypic maturation of DCs. Killed tumor cell-loaded DCs efficiently stimulated tumor-specific IFN-gamma producing T cells. DCs pulsed with killed immunogenic tumor cells also induced significantly lower numbers of regulatory T cells than those pulsed with nonimmunogenic tumor cells. These data indicate that human prostate cancer, ovarian cancer, and acute lymphoblastic leukemia cells share the key features of immunogenic cell death with mice tumor cells. These data also identify anthracyclines as anticancer drugs capable of inducing immunogenic cell death in sensitive human tumor cells. PMID- 21602433 TI - CD8+ T cells regulate bone tumor burden independent of osteoclast resorption. AB - Blockade of osteoclast (OC) activity efficiently decreases tumor burden as well as associated bone erosion in immune-compromised animals bearing human osteolytic cancers. In this study, we showed that modulation of antitumor T-cell responses alters tumor growth in bone, regardless of OC status, by using genetic and pharmacologic models. PLCgamma2(-/-) mice, with dysfunctional OCs and impaired dendritic cell (DC)-mediated T-cell activation, had increased bone tumor burden despite protection from bone loss. In contrast, Lyn(-/-) mice, with more numerous OCs and a hyperactive myeloid population leading to increased T-cell responses, had reduced tumor growth in bone despite enhanced osteolysis. The unexpected tumor/bone phenotype observed in PLCgamma2(-/-) and Lyn(-/-) mice was transplantable, suggesting the involvement of an immune component. Consistent with this hypothesis, T-cell activation diminished skeletal metastasis whereas T cell depletion enhanced it, even in the presence of zoledronic acid, a potent antiresorptive agent. Importantly, injection of antigen-specific wild-type cytotoxic CD8(+) T cells in PLCgamma2(-/-) mice or CD8(+) T-cell depletion in Lyn(-/-) mice normalized tumor growth in bone. Our findings show the important contribution of CD8(+) T cells in the regulation of bone metastases regardless of OC status, thus including T cells as critical regulators of tumor growth in bone. PMID- 21602434 TI - Combination of PI3K/mTOR inhibitors: antitumor activity and molecular correlates. AB - The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway is a major target for cancer therapy. As a strategy to induce the maximal inhibition of this pathway in cancer cells, we combined allosteric mTOR inhibitors (rapamycin and RAD001) with a dual PI3K/mTOR kinase inhibitor (PI-103). Both in vitro and in vivo, the combination exhibited more activity than single agents in human ovarian and prostate cancer cells that harbor alterations in the pathway. At the molecular level, combined inhibition of mTOR prevented the rebound activation of Akt that is seen after treatment with rapamycin and its analogues and caused more sustained inhibition of Akt phosphorylation. Furthermore, the combination strongly inhibited the expression of PI3K/Akt/mTOR downstream proteins. In particular, it showed greater activity than the single agents in inhibiting the phosphorylation of 4EBP1, both in vitro and in vivo, resulting in selective inhibition of CAP-dependent translation. A proteomic approach was used to confirm the identification of c-Myc as the key regulator for the reduction in downstream proteins affected by the combined inhibition of mTOR. In conclusion, the combination of a catalytic and an allosteric inhibitor of mTOR shows greater activity, without a concomitant increase in toxicity, than either drug alone, and this may have therapeutic implications for inhibiting this pathway in the clinical setting. PMID- 21602435 TI - Cultivating the professional virtues in medical training and practice. PMID- 21602436 TI - Collective wisdom: recommended texts to encourage wisdom in trainees. PMID- 21602437 TI - Transitioning to academic psychiatry while maintaining balance: working smarter, not harder. PMID- 21602438 TI - Professional boundaries in the era of the Internet. AB - OBJECTIVE: The era of the Internet presents new dilemmas in educating psychiatrists about professional boundaries. The objective of this overview is to clarify those dilemmas and offer recommendations for dealing with them. METHOD: The characteristics of social networking sites, blogs, and search engines are reviewed with a specific focus on their potential to present problems of professional boundaries for psychiatrists. RESULTS: The professional boundary questions that have arisen in the expanded world of online communication can be subdivided into three areas: ethical concerns, professionalism issues, and clinical dilemmas. Only the first category involves true boundary problems as normally defined. CONCLUSIONS: The expansion of the Internet has redefined traditional areas of privacy and anonymity in the clinical setting. Guidelines are proposed to manage the alteration of professional boundaries, as well as issues of professionalism and clinical work, that have arisen from the complexities of cyberspace. The author discusses implications for residency training. PMID- 21602440 TI - Psychiatric residents' needs for education about informed consent, principles of ethics and professionalism, and caring for vulnerable populations: results of a multisite survey. AB - OBJECTIVE: The authors examined psychiatric residents' perceived needs for education in informed consent, principles of ethics and professionalism, and treating vulnerable populations. METHOD: A written survey was distributed to psychiatric residents (N=249) at seven U.S. residency programs in 2005. The survey contained 149 questions in 10 content domains, 6 questions regarding personal ethics experiences during training, and 5 demographic questions. Here, the authors report responses to items regarding informed consent, professional principles, and care of vulnerable populations. RESULTS: A total of 151 psychiatric residents responded to the survey (61% overall response rate). On a scale of 1: Much Less, to 5: Same, to 9: Much More Education Desired, psychiatric residents indicated that 9 topics relating to informed consent, 10 issues surrounding professional principles, and 25 topics relating to care of vulnerable populations should receive more educational attention than currently provided. No topics were rated as needing less education. Higher ratings of the need for additional educational attention were associated with more reported ethical conflicts encountered during training. CONCLUSION: Psychiatric residents at seven diverse U.S. training programs expressed the need for greater educational attention to issues around informed consent, ethical and professional principles, and treating vulnerable populations. These findings reflect the ongoing need for educators to devote curricular attention to these areas so that trainees can incorporate such knowledge effectively into their daily clinical practice in an always-complex, highly fragmented medical care environment. PMID- 21602439 TI - Results of a multisite survey of U.S. psychiatry residents on education in professionalism and ethics. AB - OBJECTIVE: The authors assess the perspectives of psychiatry residents about the goals of receiving education in professionalism and ethics, how topics should be taught, and on what ethical principles the curriculum should be based. METHOD: A written survey was sent to psychiatry residents (N=249) at seven U.S. residency programs in Spring 2005. The survey was based on an instrument originally developed at the University of New Mexico, consisting of 149 questions in 10 content domains, with 6 questions regarding ethics experiences during training and 5 demographic questions. RESULTS: A total of 151 psychiatry residents (61%) returned usable responses to our survey. Residents reported receiving a moderate amount of ethics training during medical school (mean: 5.20; scale: 1: None to 9: Very Much) and some ethics training during residency (mean: 4.60). Residents endorsed moderate to moderately-strong agreement with all 11 goals of medical education in professionalism and ethics (means: 5.29 to 7.49; scale: 1: Strongly Disagree to 9: Strongly Agree). Respondents were more likely to endorse the value of clinically- and expert-oriented learning methods over web-based educational approaches. CONCLUSION: U.S. psychiatry residents endorse a range of goals for education in professionalism and ethics. At the same time, they prefer that these topics be taught in clinically relevant ways and through expert instruction. The value of web-based approaches warrants further investigation. PMID- 21602441 TI - Survey of the importance of professional behaviors among medical students, residents, and attending physicians. AB - OBJECTIVE: The authors compared the importance of items related to professional behavior among medical students rotating through their psychiatry clerkship, psychiatry residents, and attending psychiatrists. METHOD: The authors sent an electronic survey with 43 items (rated on the scale 1: Not at All Important; to 5: Very Important) to medical students, psychiatry residents, and attending psychiatrists at one academic center. RESULTS: Medical students rated several items in the categories Personal Characteristics and Interactions With Patients significantly less important than did residents and attending psychiatrists. Both medical students and attending psychiatrists rated the category Social Responsibility significantly less important than did residents. CONCLUSION: All three groups surveyed rated the majority of items as Important or Very Important, indicating that they value professional behavior. Resident physicians had the highest mean score in every category measured. Overall, medical students rated most items related to professionalism as less important than the two other groups surveyed. PMID- 21602442 TI - What medical students say about psychiatry: results of a reflection exercise. AB - OBJECTIVE: The author describes the results of a reflection exercise for psychiatry clerkship students. METHOD: The author performed a qualitative analysis on 100 "reflection" papers written by medical students in their psychiatry clerkship and identified the most prominent thematic content. RESULTS: The most common thematic content involved social issues in psychiatry, the reality of mental illness, the role of trauma, difficulties forming alliances with patients, the efficacy of interventions, the power of empathic connection, and students' personal identifications. CONCLUSION: Reflection exercises can foster students' awareness of their preexisting attitudes toward mental illness and the evolution of their views during training. Educators can use reflection exercises to better appreciate their students' concerns and target curriculum content toward specific issues. PMID- 21602443 TI - Factors influencing consent to having videotaped mental health sessions. AB - OBJECTIVE: The authors critically reviewed the literature regarding factors influencing consent to having videotaped mental health sessions. METHODS: The authors searched the literature in PubMed, PsycINFO, Google Scholar, and Web of Science from the mid-1950s through February 2009. RESULTS: The authors identified 27 studies, of which 19 (73%) examined general practice. Only 4 (15%) were in mental health. Most patients agree to be videotaped when asked. Those who did not consent tended to be female and younger, with previous psychiatric history or psychological distress. The data are mixed about whether psychiatric patients felt inhibited in videotaped sessions. CONCLUSION: The mental health literature in this area is limited and dated. Implications for practice are drawn inferentially from the general-practice literature. Recommendations for increasing the consent rate include building a relationship with patients before asking them for videotaping and, when asking, explaining the educational value and specific purpose of the recording. PMID- 21602444 TI - A framework for understanding media depictions of mental illness. PMID- 21602447 TI - Number and brightness image analysis reveals ATF-induced dimerization kinetics of uPAR in the cell membrane. AB - We studied the molecular forms of the GPI-anchored urokinase plasminogen activator receptor (uPAR-mEGFP) in the human embryo kidney (HEK293) cell membrane and demonstrated that the binding of the amino-terminal fragment (ATF) of urokinase plasminogen activator is sufficient to induce the dimerization of the receptor. We followed the association kinetics and determined precisely the dimeric stoichiometry of uPAR-mEGFP complexes by applying number and brightness (N&B) image analysis. N&B is a novel fluctuation-based approach for measuring the molecular brightness of fluorophores in an image time sequence in live cells. Because N&B is very sensitive to long-term temporal fluctuations and photobleaching, we have introduced a filtering protocol that corrects for these important sources of error. Critical experimental parameters in N&B analysis are illustrated and analyzed by simulation studies. Control experiments are based on mEGFP-GPI, mEGFP-mEGFP-GPI, and mCherry-GPI, expressed in HEK293. This work provides a first direct demonstration of the dimerization of uPAR in live cells. We also provide the first methodological guide on N&B to discern minor changes in molecular composition such as those due to dimerization events, which are involved in fundamental cell signaling mechanisms. PMID- 21602446 TI - Synthetic liposomes are protective from bleomycin-induced lung toxicity. AB - Idiopathic pulmonary fibrosis is a devastating disease characterized by a progressive, irreversible, and ultimately lethal form of lung fibrosis. Except for lung transplantation, no effective treatment options currently exist. The bleomycin animal model is one of the best studied models of lung injury and fibrosis. A previous study using mouse tumor models observed that liposome encapsulated bleomycin exhibited reduced lung toxicity. Therefore, we hypothesized that airway delivery of synthetic phosphatidylcholine-containing liposomes alone would protect mice from bleomycin-induced lung toxicity. C57BL/6 mice were administered uncharged multilamellar liposomes (100 MUl) or PBS vehicle on day 0 by airway delivery. Bleomycin (3.33 U/kg) or saline vehicle was then given intratracheally on day 1 followed by four additional separate doses of liposomes on days 4, 8, 12, and 16. Fluorescent images of liposomes labeled with 1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate confirmed effective and widespread delivery of liposomes to the lower respiratory tract as well as uptake primarily by alveolar macrophages and to a lesser extent by type II alveolar epithelial cells. Results at day 22, 3 wk after bleomycin treatment, showed that airway delivery of liposomes before and after intratracheal administration of bleomycin significantly reduced bleomycin-induced lung toxicity as evidenced by less body weight loss, chronic lung inflammation, and fibrosis as well as improved lung compliance compared with controls. These data indicate that airway-delivered synthetic liposomes represent a novel treatment strategy to reduce the lung toxicity associated with bleomycin in a mouse model. PMID- 21602448 TI - Activation of nuclear factor-kappaB following muscle eccentric contractions in humans is localized primarily to skeletal muscle-residing pericytes. AB - Limited data exist on the molecular mechanisms that govern skeletal muscle regeneration in humans. This study characterized the early molecular alterations in humans to eccentric contractions (ECs), a stimulus known to induce a muscle regenerative response. Thirty-five subjects completed 100 ECs of the knee extensors with 1 leg, and muscle biopsies were taken from both legs 3 h post-EC. The sample from the non-EC leg served as the control. We first conducted a well powered transcriptomic screen and network analysis. Our screen identified significant changes in several transcripts with functions relating to inflammation, cell growth, and proliferation. Network analysis then identified the transcription factor NF-kappaB as a key molecular element affected by ECs. A transcription factor ELISA, using nuclear extracts from EC and control muscle samples, showed a 1.6-fold increase in NF-kappaB DNA binding activity following ECs. Immunohistochemical experiments localized the majority of NF-kappaB-positive nuclei to cells in the interstitium, which stained positive for the pericyte markers NG2 proteoglycan and alkaline phosphatase. Our results provide the first evidence of NF-kappaB activation in human muscle following ECs and suggest a novel role for muscle residing pericytes in the early adaptive response to ECs. PMID- 21602449 TI - Relaxin causes selective outward remodeling of brain parenchymal arterioles via activation of peroxisome proliferator-activated receptor-gamma. AB - Brain parenchymal arterioles (PAs), but not pial arteries, undergo hypotrophic outward remodeling during pregnancy that involves peroxisome proliferator activated receptor-gamma (PPARgamma) activation. Relaxin, a peptide hormone produced during pregnancy, is involved in systemic and renal artery remodeling and activates PPARgamma in vitro. Thus, we hypothesized that relaxin is involved in the selective outward remodeling of PAs through a PPARgamma-dependent mechanism. Nonpregnant rats were treated with relaxin (4 MUg/h, osmotic minipump), relaxin plus PPARgamma inhibitor GW9662 (10 mg/kg/d), or vehicle for 10 d. Vascular function and structure were compared in isolated and pressurized middle cerebral arteries (MCAs) and PAs taken from the same animals. Relaxin treatment increased serum relaxin to the level of pregnancy (54 ng/ml) and increased passive wall thickness (hypertrophy; 70 +/- 5 vs. 54 +/- 4 MUm in vehicle; P<0.05) and inner diameter (outward remodeling; 10.6 +/- 0.5 vs. 8.0 +/- 0.6 MUm in vehicle; P<0.05) in PAs, but not in MCAs. This hypertrophic outward remodeling was prevented by GW9662 that had diameters (57 +/- 3 MUm) and wall thickness (8.6 +/- 1.0 MUm) similar to vehicle. GW9662 also prevented relaxin induced changes in PPARgamma target gene expression. These results suggest that relaxin produced during pregnancy may be partly responsible for selective remodeling of PAs during pregnancy through a mechanism involving PPARgamma PMID- 21602451 TI - Cerebral glucose and lactate consumption during cerebral activation by physical activity in humans. AB - At rest, the brain takes up oxygen and carbohydrate at an ~6:1 ratio. Exercise increases systemic lactate availability reducing this to as little as 1.7:1 despite a ~20% increase in cerebral metabolic rate for oxygen (CMRo2), thus indicating a disproportionate increase of carbohydrate metabolism. Underlining mechanisms and metabolic fate for the augmented lactate uptake are unknown. This meta-analysis examines whether adrenergic activation explains the increased lactate uptake, cerebral lactate release following cerebral activation compensates for the extra carbohydrate uptake during exercise, and cerebral lactate uptake spares glucose as fuel. Ten studies (n=96) measuring arteriovenous differences for lactate, glucose, and oxygen and cerebral blood flow were included. Cerebral lactate uptake increased during brain activation by whole-body exercise compared to the resting state. Unlike glucose, lactate uptake is proportional to its arterial concentration but is unaffected by sympathetic activity. Following exercise, significant cerebral lactate released as arterial lactate levels decreased, which may balance the surplus lactate uptake in the brain during physical activity in the long term. Finally, cerebral glucose uptake was reduced by ~25% in relation to CMRo2 when cerebral lactate uptake increased, suggesting, in part, preferential lactate consumption during activation. This meta-analysis favors the notion that cerebral lactate uptake is mainly passively governed by its availability, but when lactate is available, lactate supplements glucose and supports an increase in cerebral energy metabolism in an activity dependent manner. PMID- 21602450 TI - Analysis of promoters and expression-targeted gene therapy optimization based on doubling time and transfectability. AB - Genes under the control of the cyclooxygenase-2 (Cox-2), human epidermal growth factor receptor 2 (Her-2), and survivin promoters were constructed and delivered to murine and human carcinoma cells. It was found that (P)Cox-2-driven reporter expression was strong and correlated well with endogenous Cox-2 levels, while (P)Her-2 and (P)survivin yielded poor results, consistent with the three distinct expression mechanisms used by cancer cells to overexpress the endogenous versions of the selected genes. The (P)Cox-2 was then used to drive the expression of caspase genes both in vitro and in vivo to bring about targeted apoptosis of carcinoma cells successfully. The results led to the following conclusions. 1) When selecting a promoter/enhancer for expression-targeted gene delivery, it is not enough to perform a microarray on some tumor tissue and select the control element associated with the greatest amount of gene up-regulation vs. normal controls. The mechanism of expression for the particular gene should be taken into account to prevent lengthy and costly research trials. 2) When overexpression is due to activator binding, a predictive model based on endogenous gene expression levels, overall cell transfectability, and cell doubling rates can be used to predict expression-targeted gene delivery outcomes with significant accuracy. PMID- 21602452 TI - Patient information page from The Hormone Foundation. Patient guide to growth hormone deficiency in adults. PMID- 21602453 TI - Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. AB - OBJECTIVE: The aim was to update The Endocrine Society Clinical Practice Guideline on Evaluation and Treatment of Adult Growth Hormone Deficiency (GHD) previously published in 2006. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes. CONCLUSIONS: GHD can persist from childhood or be newly acquired. Confirmation through stimulation testing is usually required unless there is a proven genetic/structural lesion persistent from childhood. GH therapy offers benefits in body composition, exercise capacity, skeletal integrity, and quality of life measures and is most likely to benefit those patients who have more severe GHD. The risks associated with GH treatment are low. GH dosing regimens should be individualized. The final decision to treat adults with GHD requires thoughtful clinical judgment with a careful evaluation of the benefits and risks specific to the individual. PMID- 21602455 TI - A giant primary hemangioma of the thyroid gland. PMID- 21602454 TI - Approach to the girl with early onset of pubic hair. AB - Premature pubarche, or the development of pubic hair before the age of 8 in girls or 9 in boys, is most commonly caused by premature adrenarche. Adrenarche is the maturation of the adrenal zona reticularis in both boys and girls, resulting in the development of pubic hair, axillary hair, and adult apocrine body odor. Although originally thought to be a benign variant of normal development, premature adrenarche has been associated with insulin resistance and the later development of metabolic syndrome and polycystic ovary syndrome. Although further studies are needed to confirm these relationships, the case presented herein argues for periodic assessment of children at risk. Indeed, recognition of these associations may allow for early preventive measures. PMID- 21602456 TI - A rare localization of a neuroendocrine tumor. PMID- 21602457 TI - Obesity and type 2 diabetes: what can be unified and what needs to be individualized? AB - OBJECTIVE: This report examines what is known about the relationship between obesity and type 2 diabetes and how future research in these areas might be directed to benefit prevention, interventions, and overall patient care. RESEARCH DESIGN AND METHODS: An international working group of 32 experts in the pathophysiology, genetics, clinical trials, and clinical care of obesity and/or type 2 diabetes participated in a conference held on 6-7 January 2011 and cosponsored by The Endocrine Society, the American Diabetes Association, and the European Association for the Study of Diabetes. A writing group comprising eight participants subsequently prepared this summary and recommendations. Participants reviewed and discussed published literature and their own unpublished data. RESULTS: The writing group unanimously supported the summary and recommendations as representing the working group's majority or unanimous opinions. CONCLUSIONS: The major questions linking obesity to type 2 diabetes that need to be addressed by combined basic, clinical, and population-based scientific approaches include the following: 1) Why do not all patients with obesity develop type 2 diabetes? 2) Through what mechanisms do obesity and insulin resistance contribute to beta cell decompensation, and if/when obesity prevention ensues, how much reduction in type 2 diabetes incidence will follow? 3) How does the duration of type 2 diabetes relate to the benefits of weight reduction by lifestyle, weight-loss drugs, and/or bariatric surgery on beta-cell function and glycemia? 4) What is necessary for regulatory approval of medications and possibly surgical approaches for preventing type 2 diabetes in patients with obesity? Improved understanding of how obesity relates to type 2 diabetes may help advance effective and cost effective interventions for both conditions, including more tailored therapy. To expedite this process, we recommend further investigation into the pathogenesis of these coexistent conditions and innovative approaches to their pharmacological and surgical management. PMID- 21602458 TI - Selecting weight loss surgery based on HDL genotype--are we there yet? At the brink of "personalized surgery". PMID- 21602459 TI - Long-acting growth hormone for replacement therapy. PMID- 21602460 TI - The continuing health burden of congenital hypothyroidism in the era of neonatal screening. PMID- 21602461 TI - Endogenous 3-iodothyronamine (T1AM): more than we bargained for. PMID- 21602465 TI - Aortic stiffness in vivo in hypertensive rat via echo-tracking: analysis of the pulsatile distension waveform. AB - Large-artery stiffening is a major risk factor in aging and hypertension. Elevated blood pressure (BP) and vascular wall properties participate in arterial stiffening; we aimed to evaluate their respective role by combining echo-tracking and the spontaneously hypertensive rats (SHR) treated with low doses of a nitric oxide synthase inhibitor, shown to have arterial stiffening. Normotensive [Wistar Kyoto (WKY)], SHR, and SHR treated for 2 wk with N(G)-nitro-L-arginine methyl ester (SHRLN) were anesthetized; BP and distension (pulsatile displacement) of the aortic walls with the ArtLab echo-tracking device were measured. Stiffness index increased in SHRLN vs. SHR; compliance, distensibility, and the slopes and area of the distension-pressure loop curve decreased. The pulsatile distension and pressure waveforms were strongly altered in SHRLN. Maximal values were decreased and increased, respectively, and the waveform kinetics also differed. Thus the area under the curve adjusted to heart rate (AUC/ms) was calculated. Acute BP reductions were induced by diltiazem in SHR and SHRLN, to levels similar to those of WKY. In SHR, compliance, distensibility, stiffness index, and the ascending slope of the distension-pressure loop reached the values of WKY, whereas they were only partially improved in SHRLN. Aortic distension (maximal value and AUC/ms) and the area of the distension-pressure loop were improved in SHR, but not in SHRLN. These data confirm the aortic stiffening induced by nitric oxide reduction in SHR. They show that the ArtLab system analyzes aortic stiffness in rats, and that the aortic pulsatile distension waveform is a parameter strongly dependent on the vascular wall properties. PMID- 21602466 TI - An association between vasomotion and oxygen extraction. AB - Vasomotion is defined as a spontaneous local oscillation in vascular tone whose function is unclear but may have a beneficial effect on tissue oxygenation. Optical reflectance spectroscopy and laser Doppler fluximetry provide unique insights into the possible mechanisms of vasomotion in the cutaneous microcirculation through the simultaneous measurement of changes in concentration of oxyhemoglobin ([HbO(2)]), deoxyhemoglobin ([Hb]), and mean blood saturation (S(mb)O(2)) along with blood volume and flux. The effect of vasomotion at frequencies <0.02 Hz attributed to endothelial activity was studied in the dorsal forearm skin of 24 healthy males. Fourier analysis identified periodic fluctuations in S(mb)O(2) in 19 out of 24 subjects, predominantly where skin temperatures were >29.3 degrees C (X(2) = 6.19, P < 0.02). A consistent minimum threshold in S(mb)O(2) (mean: 39.4%, range: 24.0-50.6%) was seen to precede a sudden transient surge in flux, inducing a fast rise in S(mb)O(2). The integral increase in flux correlated with the integral increase in [HbO(2)] (Pearson's correlation r(2) = 0.50, P < 0.001) and with little change in blood volume suggests vasodilation upstream, responding to a low S(mb)O(2) downstream. This transient surge in flux was followed by a sustained period where blood volume and flux remained relatively constant and a steady decrease in [HbO(2)] and equal and opposite increase in [Hb] was considered to provide a measure of oxygen extraction. A measure of this oxygen extraction has been approximated by the mean half-life of the decay in S(mb)O(2) during this period. A comparison of the mean half-life in the 8 normal subjects [body mass index (BMI) <26.0 kg/m(2)] of 12.2 s and the 11 obese subjects (BMI >29.5 kg/m(2)) of 18.8 s was statistically significant (Mann Whitney, P < 0.004). The S(mb)O(2) fluctuated spontaneously in this saw tooth manner by an average of 9.0% (range 4.0-16.2%) from mean S(mb)O(2) values ranging from 30 to 52%. These observations support the hypothesis that red blood cells may act as sensors of local tissue hypoxia, through the oxygenation status of the hemoglobin, and initiate improved local perfusion to the tissue through hypoxic vasodilation. PMID- 21602467 TI - Prior exposure to oxidized low-density lipoprotein limits apoptosis in subsequent generations of endothelial cells by altering promoter methylation. AB - Oxidized LDL (ox-LDL) plays a critical role in atherogenesis, including apoptosis. As hypercholesterolemia causes epigenetic changes resulting in long term phenotypic consequences, we hypothesized that repeated and continuous exposure to ox-LDL may alter the pattern of apoptosis in human umbilical vein endothelial cells (HUVECs). We also analyzed global and promoter-specific methylation of apoptosis-related genes. As expected, ox-LDL evoked a dose dependent increase in apoptosis in the first passage HUVECs that was completely abrogated by lectin-like ox-LDL receptor (LOX-1)-neutralizing antibody. Ox-LDL induced apoptosis was associated with upregulation of proapoptotic LOX-1, ANXA5, BAX, and CASP3 and inhibition of antiapoptotic BCL2 and cIAP-1 genes accompanied with reciprocal changes in the methylation of promoter regions of these genes. Subsequent passages of cells displayed attenuated apoptotic response to repeat ox LDL challenge with blunted gene expression and exaggerated methylation of LOX-1, BAX, ANXA5, and CASP3 genes (all P < 0.05 vs. first exposure to ox-LDL). Treatment of cells with LOX-1 antibody before initial ox-LDL treatment prevented both gene-specific promoter methylation and expression changes and reduction of apoptotic response to repeat ox-LDL challenge. Based on these data, we conclude that exposure of HUVECs to ox-LDL induces epigenetic changes leading to resistance to apoptosis in subsequent generations and that this effect may be related to the LOX-1-mediated increase in DNA methylation. PMID- 21602468 TI - Inducible nitric oxide synthase provides protection against injury-induced thrombosis in female mice. AB - Nitric oxide (NO) is an important vasoactive molecule produced by three NO synthase (NOS) enzymes: neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS). While eNOS contributes to blood vessel dilation that protects against the development of hypertension, iNOS has been primarily implicated as a disease promoting isoform during atherogenesis. Despite this, iNOS may play a physiological role via the modulation of cyclooxygenase and thromboregulatory eicosanoid production. Herein, we examined the role of iNOS in a murine model of thrombosis. Blood flow was measured in carotid arteries of male and female wild type (WT) and iNOS-deficient mice following ferric chloride-induced thrombosis. Female WT mice were more resistant to thrombotic occlusion than male counterparts but became more susceptible upon iNOS deletion. In contrast, male mice (with and without iNOS deletion) were equally susceptible to thrombosis. Deletion of iNOS was not associated with a change in the balance of thromboxane A(2) (TxA(2)) or antithrombotic prostacyclin (PGI(2)). Compared with male counterparts, female WT mice exhibited increased urinary nitrite and nitrate levels and enhanced ex vivo induction of iNOS in hearts and aortas. Our findings suggest that iNOS-derived NO in female WT mice may attenuate the effects of vascular injury. Thus, although iNOS is detrimental during atherogenesis, physiological iNOS levels may contribute to providing protection against thrombotic occlusion, a phenomenon that may be enhanced in female mice. PMID- 21602469 TI - Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. AB - There is strong evidence showing that aging is associated with vascular oxidative stress, which has been causally linked to the development of cardiovascular diseases. NF-E2-related factor-2 (Nrf2) is a transcription factor, which is activated by reactive oxygen species in the vasculature of young animals leading to the upregulation of various antioxidant genes. The present study was designed to elucidate age-related changes in the homeostatic role of Nrf2-driven free radical detoxification mechanisms in the vasculature. We found that in the aorta of Fischer 344 * Brown Norway rats, aging results in a progressive increase in O(2)(.-) production, and downregulates protein and mRNA expression of Nrf2, which is associated with a decreased nuclear Nrf2 activity and a decrease in the Nrf2 target genes NAD(P)H:quinone oxidoreductase 1, gamma-glutamylcysteine synthetase, and heme oxygenase-1. There was an inverse relationship between vascular expression of Nrf2 target genes and age-related increases in the expression of the NF-kappaB target genes ICAM-1 and IL-6, which was significant by regression analysis. In cultured aorta segments of young (3 mo old) rats treatment with H(2)O(2) and high glucose significantly increases nuclear translocation of Nrf2 and upregulates the expression of Nrf2 target genes. In contrast, in cultured aorta segments of aged (24 mo old) rats, the induction of Nrf2-dependent responses by H(2)O(2) and high glucose are blunted. High glucose-induced vascular oxidative stress was more severe in aortas of aged rats, as shown by the significantly increased H(2)O(2) production in these vessels, compared with responses obtained in aortas from young rats. Moreover, we found that aging progressively increases vascular sensitivity to the proapoptotic effects of H(2)O(2) and high glucose treatments. Taken together, aging is associated with Nrf2 dysfunction in the vasculature, which likely exacerbates age-related cellular oxidative stress and increases sensitivity of aged vessels to oxidative stress-induced cellular damage. PMID- 21602471 TI - Angiotensin-converting enzyme inhibition augments the expression of rat elastase 2, an angiotensin II-forming enzyme. AB - Mounting evidence suggest that tissue levels of angiotensin (ANG) II are maintained in animals submitted to chronic angiotensin-converting enzyme (ACE) inhibitor treatment. We examined the expression levels of transcripts for elastase-2, a chymostatin-sensitive serine protease identified as the alternative pathway for ANG II generation from ANG I in the rat vascular tissue and the relative role of ACE-dependent and -independent pathways in generating ANG II in the rat isolated carotid artery rings of spontaneously hypertensive rats (SHR) and Wistar normotensive rats (WNR) treated with enalapril for 7 days. Enalapril treatment decreased blood pressure of SHR only and resulted in significantly more elastase-2 mRNA expression in carotid artery of both enalapril-treated WNR and SHR. Captopril induced a comparable rightward shift of concentration-response curves to ANG I in vehicle and enalapril-treated rats, although this effect was of lesser magnitude in SHR group. Chymostatin induced a rightward shift of the dose response to ANG I in vehicle-treated and a decrease in maximal effect of 22% in enalapril-treated WNR group. Maximal response induced by ANG I was remarkably reduced by chymostatin in enalapril-treated SHR carotid artery (by 80%) compared with controls (by 23%). Our data show that chronic ACE inhibition was associated with augmented functional role of non-ACE pathway in generating ANG II and increased elastase-2 gene expression, suggesting that this protease may contribute as an alternative pathway for ANG II generation when ACE is inhibited in the rat vascular tissue. PMID- 21602470 TI - Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice. AB - Type 2 diabetes (T2D) is a leading risk factor for a variety of cardiovascular diseases including coronary heart disease and atherosclerosis. Exercise training (ET) has a beneficial effect on these disorders, but the basis for this effect is not fully understood. This study was designed to investigate whether the ET abates endothelial dysfunction in the aorta in T2D. Heterozygous controls (m Lepr(db)) and type 2 diabetic mice (db/db; Lepr(db)) were either exercise entrained by forced treadmill exercise or remained sedentary for 10 wk. Ex vivo functional assessment of aortic rings showed that ET restored acetylcholine induced endothelial-dependent vasodilation of diabetic mice. Although the protein expression of endothelial nitric oxide synthase did not increase, ET reduced both IFN-gamma and superoxide production by inhibiting gp91(phox) protein levels. In addition, ET increased the expression of adiponectin (APN) and the antioxidant enzyme, SOD-1. To investigate whether these beneficial effects of ET are APN dependent, we used adiponectin knockout (APNKO) mice. Indeed, impaired endothelial-dependent vasodilation occurred in APNKO mice, suggesting that APN plays a central role in prevention of endothelial dysfunction. APNKO mice also showed increased protein expression of IFN-gamma, gp91(phox), and nitrotyrosine but protein expression of SOD-1 and -3 were comparable between wild-type and APNKO. These findings in the aorta imply that APN suppresses inflammation and oxidative stress in the aorta, but not SOD-1 and -3. Thus ET improves endothelial function in the aorta in T2D via both APN-dependent and independent pathways. This improvement is due to the effects of ET in inhibiting inflammation and oxidative stress (APN-dependent) as well as in improving antioxidant enzyme (APN independent) performance in T2D. PMID- 21602472 TI - SPARC mediates early extracellular matrix remodeling following myocardial infarction. AB - Secreted protein, acidic, and rich in cysteine (SPARC) is a matricellular protein that functions in the extracellular processing of newly synthesized collagen. Collagen deposition to form a scar is a key event following a myocardial infarction (MI). Because the roles of SPARC in the early post-MI setting have not been defined, we examined age-matched wild-type (WT; n=22) and SPARC-deficient (null; n=25) mice at day 3 post-MI. Day 0 WT (n=28) and null (n=20) mice served as controls. Infarct size was 52 +/- 2% for WT and 47 +/- 2% for SPARC null (P=NS), indicating that the MI injury was comparable in the two groups. By echocardiography, WT mice increased end-diastolic volumes from 45 +/- 2 to 83 +/- 5 MUl (P < 0.05). SPARC null mice also increased end-diastolic volumes but to a lesser extent than WT (39 +/- 3 to 63 +/- 5 MUl; P < 0.05 vs. day 0 controls and vs. WT day 3 MI). Ejection fraction fell post-MI in WT mice from 57 +/- 2 to 19 +/- 1%. The decrease in ejection fraction was attenuated in the absence of SPARC (65 +/- 2 to 28 +/- 2%). Fibroblasts isolated from SPARC null left ventricle (LV) showed differences in the expression of 22 genes encoding extracellular matrix and adhesion molecule genes, including fibronectin, connective tissue growth factor (CTGF; CCN2), matrix metalloproteinase-3 (MMP-3), and tissue inhibitor of metalloproteinase-2 (TIMP-2). The change in fibroblast gene expression levels was mirrored in tissue protein extracts for fibronectin, CTGF, and MMP-3 but not TIMP 2. Combined, the results of this study indicate that SPARC deletion preserves LV function at day 3 post-MI but may be detrimental for the long-term response due to impaired fibroblast activation. PMID- 21602474 TI - Evaluation of muscle metaboreflex function through graded reduction in forearm blood flow during rhythmic handgrip exercise in humans. AB - Hypoperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex. Our aim was to determine the muscle metaboreflex threshold and gain in humans by creating an open-loop relationship between active muscle blood flow and hemodynamic responses during a rhythmic handgrip exercise. Eleven healthy subjects performed the exercise at 5 or 15% of maximal voluntary contraction (MVC) in random order. During the exercise, forearm blood flow (FBF), which was continuously measured using Doppler ultrasound, was reduced in five steps by manipulating the inner pressure of an occlusion cuff on the upper arm. The FBF at each level was maintained for 3 min. The initial reductions in FBF elicited no hemodynamic changes, but once FBF fell below a threshold, mean arterial blood pressure (MAP) and heart rate (HR) increased and total vascular conductance (TVC) decreased in a linear manner. The threshold FBF during the 15% MVC trial was significantly higher than during the 5% MVC trial. The gain was then estimated as the slope of the relationship between the hemodynamic responses and FBFs below the threshold. The gains for the MAP and TVC responses did not differ between workloads, but the gain for the HR response was greater in the 15% MVC trial. Our findings thus indicate that increasing the workload shifts the threshold for the muscle metaboreflex to higher blood flows without changing the gain of the reflex for the MAP and TVC responses, whereas it enhances the gain for the HR response. PMID- 21602473 TI - Epoxyeicosatrienoic acid-dependent cerebral vasodilation evoked by metabotropic glutamate receptor activation in vivo. AB - Group I metabotropic glutamate receptors (mGluR) on astrocytes have been shown to participate in cerebral vasodilation to neuronal activation in brain slices. Pharmacological stimulation of mGluR in brain slices can produce arteriolar constriction or dilation depending on the initial degree of vascular tone. Here, we examined whether pharmacological stimulation of mGluR in vivo increases cerebral blood flow. A 1-mM solution of the group I mGluR agonist (S)-3,5 dihydroxyphenylglycine (DHPG) superfused at 5 MUl/min over the cortical surface of anesthetized rats produced a 30 +/- 2% (+/-SE) increase in blood flow measured by laser-Doppler flowmetry after 15-20 min. The response was completely blocked by superfusion of group I mGluR antagonists and attenuated by superfusion of an epoxyeicosatrienoic acid (EET) antagonist (5 +/- 4%), an EET synthesis inhibitor (11 +/- 3%), and a cyclooxygenase-2 inhibitor (15 +/- 3%). The peak blood flow response was not significantly affected by administration of inhibitors of cyclooxygenase-1, neuronal nitric oxide synthase, heme oxygenase, adenosine A(2B) receptors, or an inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE). The blood flow response gradually waned following 30-60 min of DHPG superfusion. This loss of the flow response was attenuated by a 20-HETE synthesis inhibitor and was prevented by superfusion of an inhibitor of epoxide hydrolase, which hydrolyzes EETs. These results indicate that pharmacological stimulation of mGluR in vivo increases cerebral blood flow and that the response depends on the release of EETs and a metabolite of cyclooxygenase-2. Epoxide hydrolase activity and 20-HETE synthesis limit the duration of the response to prolonged mGluR activation. PMID- 21602475 TI - Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake. AB - The AMP-activated protein kinase (AMPK) is known to increase cardiac insulin sensitivity on glucose uptake. AMPK also inhibits the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K) pathway. Once activated by insulin, mTOR/p70S6K phosphorylates insulin receptor substrate-1 (IRS-1) on serine residues, resulting in its inhibition and reduction of insulin signaling. AMPK was postulated to act on insulin by inhibiting this mTOR/p70S6K-mediated negative feedback loop. We tested this hypothesis in cardiomyocytes. The stimulation of glucose uptake by AMPK activators and insulin correlated with AMPK and protein kinase B (PKB/Akt) activation, respectively. Both treatments induced the phosphorylation of Akt substrate 160 (AS160) known to control glucose uptake. Together, insulin and AMPK activators acted synergistically to induce PKB/Akt overactivation, AS160 overphosphorylation, and glucose uptake overstimulation. This correlated with p70S6K inhibition and with a decrease in serine phosphorylation of IRS-1, indicating the inhibition of the negative feedback loop. We used the mTOR inhibitor rapamycin to confirm these results. Mimicking AMPK activators in the presence of insulin, rapamycin inhibited p70S6K and reduced IRS-1 phosphorylation on serine, resulting in the overphosphorylation of PKB/Akt and AS160. However, rapamycin did not enhance the insulin-induced stimulation of glucose uptake. In conclusion, although the insulin-sensitizing effect of AMPK on PKB/Akt is explained by the inhibition of the insulin-induced negative feedback loop, its effect on glucose uptake is independent of this mechanism. This disconnection revealed that the PKB/Akt/AS160 pathway does not seem to be the rate-limiting step in the control of glucose uptake under insulin treatment. PMID- 21602476 TI - Allosteric modulation of the M3 muscarinic receptor by amiodarone and N ethylamiodarone: application of the four-ligand allosteric two-state model. AB - We have reported previously that amiodarone interacts with muscarinic receptors via a novel allosteric site. This study presents mechanistic details on the nature of that interaction. Amiodarone enhanced the maximal level of agonist stimulated release of arachidonic acid (AA) from Chinese hamster ovary cells that expressed M3 muscarinic receptors; this enhancement was observed for acetylcholine and for the partial agonist pilocarpine. A similar effect of amiodarone was observed when pilocarpine was used to stimulate inositol phosphate (IP) metabolism, but not when acetylcholine was used. Subsequent studies showed that the IP response exhibited a much larger receptor reserve than the AA response, and reduction of that reserve by receptor alkylation unmasked amiodarone's enhancement of the maximal IP response to acetylcholine. Modulating the receptor reserve also revealed acetylcholine's greater affinity (K(A)) for the conformation of the receptor that mediates the AA response. The amiodarone analog N-ethylamiodarone (NEA) did not alter maximal agonist response but merely reduced agonist potency (that is, it appeared to be an antagonist). However, the action of NEA could be clearly distinguished from the action of the orthosteric antagonist NMS. Demonstration of this point was facilitated by an elaboration of Hall's allosteric two-state model; this new model represents a system composed of two ligands that compete with each other at the orthosteric site and two ligands that compete with each other at the allosteric site. In conclusion, amiodarone competes with NEA at a novel, extracellular, allosteric site to enhance the maximal stimulation evoked by acetylcholine and pilocarpine in two different responses. PMID- 21602477 TI - Endothelial keratoplasty without stripping the Descemet's membrane. PMID- 21602478 TI - Prevalence of diabetic macular oedema and related health and social care resource use in England. AB - AIMS: To address the absence from the public health ophthalmology literature of age- and sex-specific prevalence and related resource use for diabetic macular oedema (DMO) in England, UK. METHODS: Calculation of age- and sex-specific rates from primary source clinical data, and application to the demographic structure of England to estimate the number of cases affected by DMO. A public health commissioner and provider of social care perspective was adopted in a standard cost of illness study. RESULTS: The number of people with diabetes in England in 2010 was estimated at 2,342,951 of which 2,334,550 were aged >= 12 years. An estimated 166,325 (7.12%) had DMO in one or both eyes, and of these, 64,725 individuals had clinically significant DMO reducing the visual acuity to poorer than 6/6 in at least one eye. The overall health and social care costs in 2010, on the pathway from screening to rehabilitation and care in the home, are estimated at L116,296,038. CONCLUSIONS: The outcomes of this study should alert public health commissioners and clinical providers to the burden of DMO. The methods employed should also encourage the use of clinical ophthalmic data at the interface between local population and hospital-based recording systems. PMID- 21602479 TI - Effects of glaucoma medications and preservatives on cultured human trabecular meshwork and non-pigmented ciliary epithelial cell lines. AB - AIMS: We investigated the potential cytotoxicity of various topical ophthalmic glaucoma formulations containing different preservatives in cultured human trabecular meshwork (TM) and non-pigmented ciliary epithelial (NPCE) cell lines. METHODS: We tested 0.004% travoprost preserved with either 0.015% benzalkonium chloride (BAK), sofZia or 0.001% Polyquad (PQ); and 0.005% latanoprost preserved with 0.020% BAK. We also tested a range of BAK concentrations in balanced salt solution (BSS). TM cells were treated for 10 min at 37 degrees C with solutions diluted 1:10 to mimic the reduced penetration of topical preparations to the anterior chamber. Viability was determined by the uptake of the fluorescent vital dye calcein-AM (n = 6). RESULTS: BAK solutions (diluted 1:10) demonstrated a dose dependent reduction in cell viability in both cell types (TM and NPCE). With a 1:10 dilution of 0.020% BAK, there were significantly more living NPCE cells (89 +/- 6%) than TM cells (57 +/- 6%; p < 0.001). In TM cells, travoprost + BAK had statistically fewer live cells (83 +/- 5%) than both travoprost + sofZia (97 +/- 5%) and travoprost + PQ (97 +/- 6%; p < 0.05). Compared with BSS-treated NPCE cells, travoprost had statistically fewer live cells (p < 0.05) when preserved with BAK (85 +/- 16%), sofZia (91 +/- 6%) or PQ (94 +/- 2%). CONCLUSIONS: These results demonstrate that substitution of BAK from topical ophthalmic drugs results in greater viability of cultured TM cells, the cells involved in the conventional outflow pathway. Cultured NPCE, responsible for aqueous inflow, appear more resilient to BAK. PMID- 21602480 TI - Delayed diagnosis of oculopharyngeal muscular dystrophy in Scotland. AB - INTRODUCTION: Oculopharyngeal muscular dystrophy (OPMD) presents with progressive ptosis, dysphagia and limb girdle weakness, and is caused by expansion of a trinucleotide tandem repeat within the gene encoding poly-(A) binding protein 2. AIM: To review the clinical manifestations of all genetically confirmed patients with OPMD in Scotland identified since 2002, and to estimate the delay between symptom onset and diagnosis. Method Retrospective case note review. RESULTS: The authors identified 17 patients. The commonest first symptom was ptosis at about the age of 60 years. Three to 20 years elapsed from the onset of ptosis to OPMD diagnosis. In 14 (82%) patients, dysphagia had developed by the time of diagnosis, and four (24%) out of these 14 patients with dysphagia had undergone a decade of investigation and treatment for pharyngeal problems. Thirteen patients (77%) also had symptoms of limb girdle muscle weakness. Every patient had a first degree relative with ptosis. CONCLUSIONS: OPMD could have been diagnosed earlier in every patient in this case series. Greater awareness of OPMD among ophthalmologists, gastroenterologists and otolaryngologists may lead to earlier diagnosis, improved management and avoidance of unnecessary investigations. PMID- 21602481 TI - CATT: Into the eye of a tiger. PMID- 21602483 TI - Ccr4 promotes resolution of the endoplasmic reticulum stress response during host temperature adaptation in Cryptococcus neoformans. AB - Adaptation to host temperature is a prerequisite for any pathogen capable of causing deep infection in humans. Our previous studies demonstrated that a Cryptococcus neoformans ccr4Delta mutant lacking the major deadenylase involved in regulated mRNA decay was defective in host temperature adaptation and therefore virulence. In this study, the ccr4Delta mutant was found to exhibit characteristics of chronic unfolded-protein response (UPR) engagement in both the gene expression profile and phenotype. We demonstrate that host temperature adaptation in C. neoformans is accompanied by transient induction of the endoplasmic reticulum (ER) stress response and that Ccr4-dependent posttranscriptional gene regulation contributes to resolution of ER stress during host temperature adaptation. PMID- 21602484 TI - The polyketide MPBD initiates the SDF-1 signaling cascade that coordinates terminal differentiation in Dictyostelium. AB - Dictyostelium uses a wide array of chemical signals to coordinate differentiation as it switches from a unicellular to a multicellular organism. MPBD, the product of the polyketide synthase encoded by stlA, regulates stalk and spore differentiation by rapidly stimulating the release of the phosphopeptide SDF-1. By analyzing specific mutants affected in MPBD or SDF-1 production, we delineated a signal transduction cascade through the membrane receptor CrlA coupled to Galpha1, leading to the inhibition of GskA so that the precursor of SDF-1 is released. It is then processed by the extracellular protease of TagB on prestalk cells. SDF-1 apparently acts through the adenylyl cyclase ACG to activate the cyclic AMP (cAMP)-dependent protein kinase A (PKA) and trigger the production of more SDF-1. This signaling cascade shows similarities to the SDF-2 signaling pathway, which acts later to induce rapid spore encapsulation. PMID- 21602485 TI - Development and application of a cellular, gain-of-signal, bioluminescent reporter screen for inhibitors of type II secretion in Pseudomonas aeruginosa and Burkholderia pseudomallei. AB - The type II secretion (T2S) system in gram-negative bacteria comprises the Sec and Tat pathways for translocating proteins into the periplasm and an outer membrane secretin for transporting proteins into the extracellular space. To discover Sec/Tat/T2S pathway inhibitors as potential new therapeutics, the authors used a Pseudomonas aeruginosa bioluminescent reporter strain responsive to SecA depletion and inhibition to screen compound libraries and characterize the hits. The reporter strain placed a luxCDABE operon under regulation of a SecA depletion-responsive upregulated promoter in a secA deletion background complemented with an ectopic lac-regulated secA copy. Bioluminescence was indirectly proportional to the isopropyl-beta-D-thiogalactopyranoside concentration and stimulated by azide, a known SecA ATPase inhibitor. A total of 96 compounds (0.1% of 73,000) were detected as primary hits due to stimulation of luminescence with a z score >=5. Direct secretion assays of the nine most potent hits, representing five chemical scaffolds, revealed that they do not inhibit SecA-mediated secretion of beta-lactamase into the periplasm but do inhibit T2S mediated extracellular secretion of elastase with IC(50) values from 5 to 25 uM. In addition, seven of the nine compounds also inhibited the T2S-mediated extracellular secretion of phospholipase C by P. aeruginosa and protease activity by Burkholderia pseudomallei. PMID- 21602486 TI - A high-throughput assay for modulators of NNT activity in permeabilized yeast cells. AB - Nicotinamide nucleotide transhydrogenase (NNT) mutant mice show glucose intolerance with impaired insulin secretion during glucose tolerance tests. Uncoupling of the beta cell mitochondrial metabolism due to such mutations makes NNT a novel target for therapeutics in the treatment of pathologies such as type 2 diabetes. The authors propose that increasing NNT activity would help reduce deleterious buildup of reactive oxygen species in the inner mitochondrial matrix. They have expressed human Nnt cDNA for the first time in Saccharomyces cerevisiae, and transhydrogenase activity in mitochondria isolated from these cells is six times greater than is seen in wild-type mitochondria. The same mitochondria have partially uncoupled respiration, and the cells have slower growth rates compared to cells that do not express NNT. The authors have used NNT's role as a redox-driven proton pump to develop a robust fluorimetric assay in permeabilized yeast. Screening in parallel a library of known pharmacologically active compounds (National Institute of Neurological Disorders and Stroke collection) against NNT +/- cells, they demonstrate a robust and reproducible assay suitable for expansion into larger and more diverse compound sets. The identification of NNT activators may help in the elucidation of the role of NNT in mammalian cells and assessing its potential as a therapeutic target for insulin secretion disorders. PMID- 21602487 TI - A framework for addressing structural uncertainty in decision models. AB - Decision analytic models used for health technology assessment are subject to uncertainties. These uncertainties can be quantified probabilistically, by placing distributions on model parameters and simulating from these to generate estimates of cost-effectiveness. However, many uncertain model choices, often termed structural assumptions, are usually only explored informally by presenting estimates of cost-effectiveness under alternative scenarios. The authors show how 2 recent research proposals represent parts of a framework to formally account for all common structural uncertainties. First, the model is expanded to include parameters that encompass all possible structural choices. Uncertainty can then arise because these parameters are estimated imprecisely from data, for example, a treatment effect of doubtful significance. Uncertainty can also arise if there are no relevant data. If there are relevant data, uncertainty can be addressed by averaging expected costs and effects generated from probabilistic analysis of the models with and without the parameter. The weights used for averaging are related to the predictive ability of each model, assessed against the data. If there are no data, additional parameters can often be informed by eliciting expert beliefs as probability distributions. These ideas are illustrated in decision models for antiplatelet therapies for vascular disease and new biologic drugs for the treatment of active psoriatic arthritis. PMID- 21602488 TI - Divergent intentions to use antibiotic guidelines: a theory of planned behavior survey. AB - BACKGROUND: To improve physicians' antimicrobial practice, it is important to identify barriers to and facilitators of guideline adherence and assess their relative importance. The theory of planned behavior permits such assessment and has been previously used for evaluating antibiotic use. According to this theory, guideline use is fueled by 3 factors: attitude, subjective norm (perceived social pressure regarding guidelines), and perceived behavioral control (PBC; perceived ability to follow the guideline). The authors aim to explore factors affecting guideline use in their hospital. METHODS: Starting from their earlier observations, the authors constructed a questionnaire based on the theory of planned behavior, with an additional measure of habit strength. After pilot testing, the survey was distributed among physicians in a major teaching hospital. RESULTS: Of 393 contacted physicians, 195 completed questionnaires were received (50.5% corrected response rate). Using multivariate analysis, the overall intention toward using antibiotic guidelines was not very predictable (model R (2) = .134). Habit strength (relative weight = .391) and PBC (relative weight = .354) were the principal significant predictors. A moderator effect of respondents' position (staff member v. resident) was found, with staff members' intention being significantly influenced only by habit strength and residents' intention by PBC. Regarding previously identified barriers, education on antibiotics and guidelines was rated unsatisfactory. CONCLUSIONS: These divergent origins of influence on guideline adherence point to different approaches for improvement. As habits strongly influence staff members, methods that focus on changing habits (e.g., automated decision support systems) are possible interventions. As residents' intention seems to be guided mainly by external influences and experienced control, this may make feedback, convenient guideline formats, and guideline familiarization more suitable. PMID- 21602489 TI - Self-management of Type 1 Diabetes Across Adolescence. AB - PURPOSE: The purpose of this study was to examine differences in self-management behaviors (Collaboration with Parents, Diabetes Care Activities, Diabetes Problem Solving, Diabetes Communication, and Goals) between early, middle, and late adolescence. The role of regimen and gender as covariates in self-management behaviors was also examined. METHODS: This was a secondary analysis with a cross sectional descriptive survey design. A sample of 504 participants ages 13 to 21 years from the Self-Management of Diabetes-Adolescent instrument development study were analyzed to determine self-management behaviors in early, middle, and late adolescence. This study was partially guided by the Self and Family Management Framework. This framework contains broad conceptual areas that are thought to pose a risk to or have a protective influence on self-management and family management behaviors and associated outcomes. RESULTS: Significant findings included a decline between early, middle, and late adolescence in the Collaboration with Parents scale as well as an increase between early and late adolescence on the Diabetes Problem Solving scale. Regimen was a significant covariate for Collaboration with Parents, Diabetes Care Activities, and Diabetes Problem Solving, and gender was a significant covariate for Diabetes Care Activities and Diabetes Communication. CONCLUSIONS: Clinicians should consider the influence of adolescent stage and development on self-management when educating adolescents. Youth and their families should be educated to consider the implications that regimen will have on daily self-management when making treatment decisions. Furthermore, gender variations can necessitate different educational approaches to meet different needs. Future research should identify other variables that can influence self-management at different points across adolescence. PMID- 21602490 TI - Human lung hydrolases delineate Mycobacterium tuberculosis-macrophage interactions and the capacity to control infection. AB - Pulmonary surfactant contains homeostatic and antimicrobial hydrolases. When Mycobacterium tuberculosis is initially deposited in the terminal bronchioles and alveoli, as well as following release from lysed macrophages, bacilli are in intimate contact with these lung surfactant hydrolases. We identified and measured several hydrolases in human alveolar lining fluid and lung tissue that, at their physiological concentrations, dramatically modified the M. tuberculosis cell envelope. Independent of their action time (15 min to 12 h), the effects of the hydrolases on the M. tuberculosis cell envelope resulted in a significant decrease (60-80%) in M. tuberculosis association with, and intracellular growth of the bacteria within, human macrophages. The cell envelope-modifying effects of the hydrolases also led to altered M. tuberculosis intracellular trafficking and induced a protective proinflammatory response to infection. These findings add a new concept to our understanding of M. tuberculosis-macrophage interactions (i.e., the impact of lung surfactant hydrolases on M. tuberculosis infection). PMID- 21602493 TI - Inflammatory cytokines IL-32 and IL-17 have common signaling intermediates despite differential dependence on TNF-receptor 1. AB - Cytokines IL-32 and IL-17 are emerging as critical players in the pathophysiology of immune-mediated chronic inflammatory diseases. It has been speculated that the molecular mechanisms governing IL-32- and IL-17-mediated cellular responses are differentially dependent on the TNF pathway. In this study, kinome analysis demonstrated that following stimulation with cytokine IL-32, but not IL-17, there was increased phosphorylation of a peptide target corresponding to TNF-R1. Consistent with this observation, blocking TNF-R1 resulted in a suppression of IL 32-induced downstream responses, indicating that IL-32-mediated activity may be dependent on TNF-R1. In contrast, blocking TNF-R1 did not affect IL-17-induced downstream responses. Kinome analysis also implicated p300 (transcriptional coactivator) and death-associated protein kinase-1 (DAPK-1) as signaling intermediates for both IL-32 and IL-17. Phosphorylation of p300 and DAPK-1 upon stimulation with either IL-32 or IL-17 was confirmed by immunoblots. The presence of common targets was supported by results demonstrating similar downstream responses induced in the presence of IL-32 and IL-17, such as transcriptional responses and the direct activation of NF-kappaB. Furthermore, knockdown of p300 and DAPK-1 altered downstream responses induced by IL-32 and IL-17, and impacted certain cellular responses induced by TNF-alpha and IL-1beta. We hypothesize that p300 and DAPK-1 represent nodes where the inflammatory networks of IL-32 and IL 17 overlap, and that these proteins would affect both TNF-R1-dependent and independent pathways. Therefore, p300 and DAPK-1 are viable potential therapeutic targets for chronic inflammatory diseases. PMID- 21602492 TI - beta2-glycoprotein I and protection from anti-SSA/Ro60-associated cardiac manifestations of neonatal lupus. AB - One mechanism to molecularly explain the strong association of maternal anti-Ro60 Abs with cardiac disease in neonatal lupus (NL) is that these Abs initiate injury by binding to apoptotic cardiomyocytes in the fetal heart. Previous studies have demonstrated that beta(2)-glycoprotein I (beta(2)GPI) interacts with Ro60 on the surface of apoptotic Jurkat cells and prevents binding of anti-Ro60 IgG. Accordingly, the current study was initiated to test two complementary hypotheses, as follows: 1) competition between beta(2)GPI and maternal anti-Ro60 Abs for binding apoptotic induced surface-translocated Ro60 occurs on human fetal cardiomyocytes; and 2) circulating levels of beta(2)GPI influence injury in anti Ro60-exposed fetuses. Initial flow cytometry experiments conducted on apoptotic human fetal cardiomyocytes demonstrated dose-dependent binding of beta(2)GPI. In competitive inhibition experiments, beta(2)GPI prevented opsonization of apoptotic cardiomyocytes by maternal anti-Ro60 IgG. ELISA was used to quantify beta(2)GPI in umbilical cord blood from 97 neonates exposed to anti-Ro60 Abs, 53 with cardiac NL and 44 with no cardiac disease. beta(2)GPI levels were significantly lower in neonates with cardiac NL. Plasmin-mediated cleavage of beta(2)GPI prevented binding to Ro60 and promoted the formation of pathogenic anti-Ro60 IgG-apoptotic cardiomyocyte complexes. In aggregate these data suggest that intact beta(2)GPI in the fetal circulation may be a novel cardioprotective factor in anti-Ro60-exposed pregnancies. PMID- 21602494 TI - Tight control of STAT5 activity determines human CD34-derived interstitial dendritic cell and langerhans cell development. AB - Despite the crucial function of dendritic cells (DC) in immunity, the molecular mechanisms regulating human DC development remain poorly defined. STAT5 regulates various hematopoietic lineages and is activated by GM-CSF, a critical cytokine in DC development. In this study, we investigated the role of STAT5 during differentiation of human CD34(+) hematopoietic progenitors into precursor DC (pre DC) and their subsequent differentiation toward interstitial DC and Langerhans cells. Inhibiting STAT5 activity by dominant-negative STAT5 promoted Langerhans cell commitment of hematopoietic progenitors but resulted in loss of pre interstitial DC development, showing subset-specific regulation. Increasing the low endogenous STAT5 activity by ectopic STAT5 activation downregulated expression of the critical DC transcription factor PU.1 and abrogated commitment to either DC lineage. In contrast, high STAT5 activity was beneficial in already committed pre-DC: terminal DC differentiation was associated with increased endogenous STAT5 phosphorylation levels, JAK2-STAT5 inhibition reduced terminal DC differentiation, and conditional STAT5 activation in pre-DC improved development of BDCA-1(+), DC-SIGN(+), and Langerin(+) DC with normal maturation and T cell stimulation. These data show that STAT5 critically regulates human DC development, with specific requirements for the level of STAT5 activation at distinct differentiation stages. By regulating STAT5 activity, cytokines present at specific locations and under different pathophysiological conditions can determine the fate of DC precursors. PMID- 21602491 TI - FIZZ2/RELM-beta induction and role in pulmonary fibrosis. AB - Found in inflammatory zone (FIZZ) 2, also known as resistin-like molecule (RELM) beta, belongs to a novel cysteine-rich secreted protein family named FIZZ/RELM. Its function is unclear, but a closely related family member, FIZZ1, has profibrotic activities. The human ortholog of rodent FIZZ1 has not been identified, but human FIZZ2 has significant sequence homology to both rodent FIZZ2 (59%) and FIZZ1 (50%). Given the greater homology to rodent FIZZ2, analyzing the role of FIZZ2 in a rodent model of bleomycin-induced pulmonary fibrosis would be of greater potential relevance to human fibrotic lung disease. The results showed that FIZZ2 was highly induced in lungs of rodents with bleomycin-induced pulmonary fibrosis and of human patients with idiopathic pulmonary fibrosis. FIZZ2 expression was induced in rodent and human lung epithelial cells by Th2 cytokines, which was mediated via STAT6 signaling. The FIZZ2 induction in murine lungs was found to be essential for pulmonary fibrosis, as FIZZ2 deficiency significantly suppressed pulmonary fibrosis and associated enhanced extracellular matrix and cytokine gene expression. In vitro analysis indicated that FIZZ2 could stimulate type I collagen and alpha-smooth muscle actin expression in lung fibroblasts. Furthermore, FIZZ2 was shown to have chemoattractant activity for bone marrow (BM) cells, especially BM-derived CD11c(+) dendritic cells. Notably, lung recruitment of BM-derived cells was impaired in FIZZ2 knockout mice. These findings suggest that FIZZ2 is a Th2 associated multifunctional mediator with potentially important roles in the pathogenesis of fibrotic lung diseases. PMID- 21602495 TI - IL-10 Prevents apoptosis of brain endothelium during bacteremia. AB - IL-10-deficient mice infected with the relapsing fever bacterium Borrelia turicatae rapidly succumb to a brain hemorrhage if they are unable to clear peak bacteremia. In this study, we investigated the protective role of IL-10 during relapsing-remitting bacteremia and explored the molecular events involved in the protection of brain endothelium by IL-10. Brain endothelial injury was measured with cytotoxicity and diverse apoptotic assays, whereas the signaling pathway analysis was done by quantitative PCR array. The results showed that severe endothelial cell injury leading to hemorrhage in the brain and other organs occurred in IL-10-deficient mice during relapsing-remitting infection. Human brain microvascular endothelial cells (HBMEC) produced abundant proinflammatory mediators upon exposure to whole bacteria or purified bacterial lipoprotein but did not produce any detectable IL-10. Whole bacteria and purified outer membrane lipoprotein rapidly killed HBMEC by apoptosis in a time- and concentration dependent manner. Exogenous IL-10 protected HBMEC from apoptosis. HBMEC apoptosis during exposure to a low number of bacteria was associated with downregulation of TNF and TNFAIP3 and upregulation of BAX. In contrast, HBMEC apoptosis during exposure to high concentrations of purified outer membrane lipoprotein was associated with marked upregulation of FAS, FAS ligand, and the adaptor molecules RIPK1 and CFLAR. Exogenous IL-10 reversed all the apoptotic signaling changes induced by whole bacteria or its purified lipoprotein. The results indicate that prominent brain endothelial cell apoptosis occurs during relapsing-remitting bacteremia in the absence of IL-10 and point to a prominent role for bacterial lipoprotein-mediated activation of FAS and caspase-3 in this process. PMID- 21602496 TI - TLR2 mediates the innate response of retinal Muller glia to Staphylococcus aureus. AB - Muller cells, the principal glia of the retina, play several key roles in normal and various retinal diseases. To date, their direct involvement in retinal innate defense against bacterial pathogens has not been investigated. In this article, we show that Muller cells express TLR2, a key sensor implicated in recognizing Gram-positive bacteria. We found that intravitreal injection of TLR2 agonist Pam3Cys and Staphylococcus aureus activated Muller glia in C57BL/6 mouse retina. Similarly, Pam3Cys or S. aureus elicited the expression of TLR2 and activated the NF-kappaB and p38 MAPK signaling cascade. Concomitant with the activation of signaling pathways, transcriptional expression and secretion of various proinflammatory cytokines (IL-6, TNF-alpha, and IL-1beta), chemokines (IL-8), and antimicrobial peptide (LL-37) were also induced in Muller glia. Importantly, the culture media derived from TLR2-activated Muller glia exhibited robust bactericidal activity against S. aureus. Furthermore, use of neutralizing Ab, small interfering RNA, and pharmacological inhibitors revealed that Muller glial innate response to S. aureus is mediated via the TLR2-NF-kappaB axis. Collectively, this study for the first time, to our knowledge, establishes that the retinal Muller glia senses pathogens via TLR2 and contributes directly to retinal innate defense via production of inflammatory mediators and antimicrobial peptides. PMID- 21602497 TI - Sparse low-order interaction network underlies a highly correlated and learnable neural population code. AB - Information is carried in the brain by the joint activity patterns of large groups of neurons. Understanding the structure and function of population neural codes is challenging because of the exponential number of possible activity patterns and dependencies among neurons. We report here that for groups of ~100 retinal neurons responding to natural stimuli, pairwise-based models, which were highly accurate for small networks, are no longer sufficient. We show that because of the sparse nature of the neural code, the higher-order interactions can be easily learned using a novel model and that a very sparse low-order interaction network underlies the code of large populations of neurons. Additionally, we show that the interaction network is organized in a hierarchical and modular manner, which hints at scalability. Our results suggest that learnability may be a key feature of the neural code. PMID- 21602498 TI - Expanded methyl-sensitive cut counting reveals hypomethylation as an epigenetic state that highlights functional sequences of the genome. AB - Methyl-sensitive cut counting (MSCC) with the HpaII methylation-sensitive restriction enzyme is a cost-effective method to pinpoint unmethylated CpGs at single base-pair resolution. However, it has the drawback of addressing only CpGs in the context of the CCGG site, leaving out the remainder of the possible 16 XCGX tetranucleotides in which CpGs are found. We expanded MSCC to include three additional enzymes to address a total of 5 of the 16 XCGX combinations. This allowed us to survey methylation at about one-third of all a mammalian genome's CpGs. Applied to mouse liver DNA, we correctly confirmed data reported with other methods showing hypomethylation to be concentrated at promoters and in CpG islands (CGIs), with gene bodies and intergenic regions being mostly methylated. Grouping unmethylated CpGs, characterized by high MSCC scores (7% false discovery rate), we found a large number of unmethylated regions not qualifying as CGIs located in intergenic and intronic regions, which are highly enriched in functional DNA sequences (open regulatory annotation database) as well as in noncoding yet highly conserved mammalian sequences thought to be important but with as yet unknown function. About 50% of MSCC-defined unmethylated regions do not overlap algorithm-defined CGIs and offer a novel search space in which new functionalities of DNA may be found in health and disease. PMID- 21602499 TI - Science to practice: Can T1rho imaging be used to diagnose and assess the severity of hepatic fibrosis? PMID- 21602500 TI - Vertebroplasty and the placebo response. PMID- 21602501 TI - Rethinking peer review: what aviation can teach radiology about performance improvement. PMID- 21602503 TI - MR imaging of multiple sclerosis. AB - Owing to its ability to depict the pathologic features of multiple sclerosis (MS) in exquisite detail, conventional magnetic resonance (MR) imaging has become an established tool in the diagnosis of this disease and in monitoring its evolution. MR imaging has been formally included in the diagnostic work-up of patients who present with a clinically isolated syndrome suggestive of MS, and ad hoc diagnostic criteria have been proposed and are updated on a regular basis. In patients with established MS and in those participating in treatment trials, examinations performed with conventional MR pulse sequences provide objective measures to monitor disease activity and progression; however, they have a limited prognostic role. This has driven the application of newer MR imaging technologies, including higher-field-strength MR units, to estimate overall MS burden and mechanisms of recovery in patients at different stages of the disease. These techniques have allowed in vivo assessment of the heterogeneity of MS pathologic features in focal lesions and in normal-appearing tissues. More recently, some of the finer details of MS, including macrophage infiltration and abnormal iron deposition, have become quantifiable with MR imaging. The utility of these modern MR techniques in clinical trial monitoring and in the assessment of the individual patient's response to treatment still need to be evaluated. PMID- 21602505 TI - Case 170: Pericardial fat necrosis. PMID- 21602506 TI - More attention should be given to the risk from CT in the emergency department. PMID- 21602507 TI - Rectal use of gadopentetate dimeglumine for anastomotic leak evaluation in patients with sensitivity to iodinated contrast media. PMID- 21602508 TI - Pancreatic metastases can have radiologic characteristics similar to small solid pseudopapillary tumors. PMID- 21602502 TI - Transcatheter intraarterial therapies: rationale and overview. AB - Transcatheter intraarterial therapies have proved valuable in the battle against primary and secondary hepatic malignancies. The unique aspects of all such therapies are their reduced toxicity profiles and highly effective tumor responses. These unique characteristics coupled with their minimally invasive nature provide an attractive therapeutic option in patients who may have previously had few alternatives. The concept of all catheter-based intraarterial therapies is to selectively deliver anticancer treatment to tumor(s). These therapies, which include transarterial embolization, intraarterial chemoinfusion, transarterial chemoembolization with or without drug-eluting beads, and radioembolization with use of yttrium 90, inflict lethal insult to tumors while preserving normal hepatic parenchyma. This is possible because hepatic neoplasms preferentially derive their blood supply from an arterial source while the majority of noncancerous liver is supplied by the portal vein. As part of the interventional oncology review series, in this article we describe the rationale behind each of these transcatheter therapies and provide a review of the existing medical literature. PMID- 21602509 TI - A bayesian mixture model for comparative spectral count data in shotgun proteomics. AB - Recent developments in mass-spectrometry-based shotgun proteomics, especially methods using spectral counting, have enabled large-scale identification and differential profiling of complex proteomes. Most such proteomic studies are interested in identifying proteins, the abundance of which is different under various conditions. Several quantitative methods have recently been proposed and implemented for this purpose. Building on some techniques that are now widely accepted in the microarray literature, we developed and implemented a new method using a Bayesian model to calculate posterior probabilities of differential abundance for thousands of proteins in a given experiment simultaneously. Our Bayesian model is shown to deliver uniformly superior performance when compared with several existing methods. PMID- 21602510 TI - GProX, a user-friendly platform for bioinformatics analysis and visualization of quantitative proteomics data. AB - Recent technological advances have made it possible to identify and quantify thousands of proteins in a single proteomics experiment. As a result of these developments, the analysis of data has become the bottleneck of proteomics experiment. To provide the proteomics community with a user-friendly platform for comprehensive analysis, inspection and visualization of quantitative proteomics data we developed the Graphical Proteomics Data Explorer (GProX)(1). The program requires no special bioinformatics training, as all functions of GProX are accessible within its graphical user-friendly interface which will be intuitive to most users. Basic features facilitate the uncomplicated management and organization of large data sets and complex experimental setups as well as the inspection and graphical plotting of quantitative data. These are complemented by readily available high-level analysis options such as database querying, clustering based on abundance ratios, feature enrichment tests for e.g. GO terms and pathway analysis tools. A number of plotting options for visualization of quantitative proteomics data is available and most analysis functions in GProX create customizable high quality graphical displays in both vector and bitmap formats. The generic import requirements allow data originating from essentially all mass spectrometry platforms, quantitation strategies and software to be analyzed in the program. GProX represents a powerful approach to proteomics data analysis providing proteomics experimenters with a toolbox for bioinformatics analysis of quantitative proteomics data. The program is released as open-source and can be freely downloaded from the project webpage at http://gprox.sourceforge.net. PMID- 21602511 TI - Suppression of FoxO1 activity by long-chain fatty acyl analogs. AB - OBJECTIVE: Overactivity of the Forkhead transcription factor FoxO1 promotes diabetic hyperglycemia, dyslipidemia, and acute-phase response, whereas suppression of FoxO1 activity by insulin may alleviate diabetes. The reported efficacy of long-chain fatty acyl (LCFA) analogs of the MEDICA series in activating AMP-activated protein kinase (AMPK) and in treating animal models of diabesity may indicate suppression of FoxO1 activity. RESEARCH DESIGN AND METHODS: The insulin-sensitizing and anti-inflammatory efficacy of a MEDICA analog has been verified in guinea pig and in human C-reactive protein (hCRP) transgenic mice, respectively. Suppression of FoxO1 transcriptional activity has been verified in the context of FoxO1- and STAT3-responsive genes and compared with suppression of FoxO1 activity by insulin and metformin. RESULTS: Treatment with MEDICA analog resulted in total body sensitization to insulin, suppression of lipopolysaccharide-induced hCRP and interleukin-6-induced acute phase reactants and robust decrease in FoxO1 transcriptional activity and in coactivation of STAT3. Suppression of FoxO1 activity was accounted for by its nuclear export by MEDICA-activated AMPK, complemented by inhibition of nuclear FoxO1 transcriptional activity by MEDICA-induced C/EBPbeta isoforms. Similarly, insulin treatment resulted in nuclear exclusion of FoxO1 and further suppression of its nuclear activity by insulin-induced C/EBPbeta isoforms. In contrast, FoxO1 suppression by metformin was essentially accounted for by its nuclear export by metformin-activated AMPK. CONCLUSIONS: Suppression of FoxO1 activity by MEDICA analogs may partly account for their antidiabetic anti-inflammatory efficacy. FoxO1 suppression by LCFA analogs may provide a molecular rational for the beneficial efficacy of carbohydrate-restricted ketogenic diets in treating diabetes. PMID- 21602512 TI - Impaired insulin secretion and enhanced insulin sensitivity in cholecystokinin deficient mice. AB - OBJECTIVE: Cholecystokinin (CCK) is released in response to lipid intake and stimulates insulin secretion. We hypothesized that CCK deficiency would alter the regulation of insulin secretion and glucose homeostasis. RESEARCH DESIGN AND METHODS: We used quantitative magnetic resonance imaging to determine body composition and studied plasma glucose and insulin secretion of CCK gene knockout (CCK-KO) mice and their wild-type controls using intraperitoneal glucose and arginine infusions. The area of anti-insulin staining in pancreatic islets was measured by immunohistochemistry. Insulin sensitivity was assessed with euglycemic-hyperinsulemic clamps. RESULTS: CCK-KO mice fed a low-fat diet had a reduced acute insulin response to glucose but a normal response to arginine and normal glucose tolerance, associated with a trend toward greater insulin sensitivity. However, when fed a high-fat diet (HFD) for 10 weeks, CCK-KO mice developed glucose intolerance despite increased insulin sensitivity that was associated with low insulin secretion in response to both glucose and arginine. The deficiency of insulin secretion in CCK-KO mice was not associated with changes in beta-cell or islet size. CONCLUSIONS: CCK is involved in regulating insulin secretion and glucose tolerance in mice eating an HFD. The impaired insulin response to intraperitoneal stimuli that do not typically elicit CCK release suggests that this hormone has chronic effects on beta-cell adaptation to diet in addition to acute incretin actions. PMID- 21602513 TI - The soluble CTLA-4 splice variant protects from type 1 diabetes and potentiates regulatory T-cell function. AB - OBJECTIVE: CTLA4 gene variation associates with multiple autoimmune disorders, including type 1 diabetes. The CTLA4 susceptibility allele was found to generate decreased levels of mRNA encoding soluble CTLA-4 (sCTLA-4) relative to the full length isoform, the functional consequence of which is as yet unknown. In this study, we investigated the contribution of sCTLA-4 to immune regulation with the aim to elucidate the functional basis of the disease association of CTLA4. RESEARCH DESIGN AND METHODS: To model the disease-associated splicing variation of CTLA4, we generated NOD mice in which sCTLA-4 mRNA is silenced by RNA interference. RESULTS: We found that loss of sCTLA-4 impairs the function of regulatory T (Treg) cells. This functional defect could be attributed, at least in part, to the failure of sCTLA-4 knockdown (KD) Treg cells to downregulate dendritic cell costimulation. sCTLA-4 KD Treg cells, in contrast with wild-type Treg cells, failed to inhibit colitis induced by transfer of CD4(+)CD45RB(hi) cells into NOD.SCID animals. Furthermore, diminished sCTLA-4 expression accelerated the onset of autoimmune diabetes in transgenic mice. CONCLUSIONS: Our results demonstrate that sCTLA-4 participates in immune regulation by potentiating the function of Treg cells. The functional outcome of silencing this splice variant in the NOD model provides an explanation for the association of CTLA4 variation with autoimmunity. Lower sCTLA-4 expression from the susceptibility allele may directly affect the suppressive capacity of Treg cells and thereby modulate disease risk. Our unprecedented approach establishes the feasibility of modeling splicing variations relevant to autoimmunity. PMID- 21602514 TI - Comparison of dorsocervical with abdominal subcutaneous adipose tissue in patients with and without antiretroviral therapy-associated lipodystrophy. AB - OBJECTIVE: Combination antiretroviral therapy (cART) is associated with lipodystrophy, i.e., loss of subcutaneous adipose tissue in the abdomen, limbs, and face and its accumulation intra-abdominally. No fat is lost dorsocervically and it can even accumulate in this region (buffalo hump). It is unknown how preserved dorsocervical fat differs from abdominal subcutaneous fat in HIV-1 infected cART-treated patients with (cART+LD+) and without (cART+LD-) lipodystrophy. RESEARCH DESIGN AND METHODS: We used histology, microarray, PCR, and magnetic resonance imaging to compare dorsocervical and abdominal subcutaneous adipose tissue in cART+LD+ (n=21) and cART+LD- (n=11). RESULTS: Albeit dorsocervical adipose tissue in cART+LD+ seems spared from lipoatrophy, its mitochondrial DNA (mtDNA; copies/cell) content was significantly lower (by 62%) than that of the corresponding tissue in cART+LD-. Expression of CD68 mRNA, a marker of macrophages, and numerous inflammatory genes in microarray were significantly lower in dorsocervical versus abdominal subcutaneous adipose tissue. Genes with the greatest difference in expression between the two depots were those involved in regulation of transcription and regionalization (homeobox genes), irrespective of lipodystrophy status. There was negligible mRNA expression of uncoupling protein 1, a gene characteristic of brown adipose tissue, in either depot. CONCLUSIONS: Because mtDNA is depleted even in the nonatrophic dorsocervical adipose tissue, it is unlikely that the cause of lipoatrophy is loss of mtDNA. Dorsocervical adipose tissue is less inflamed than lipoatrophic adipose tissue. It does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal subcutaneous adipose tissue is in expression of homeobox genes. PMID- 21602515 TI - Metabolic remodeling of human skeletal myocytes by cocultured adipocytes depends on the lipolytic state of the system. AB - OBJECTIVE: Adipocyte infiltration of the musculoskeletal system is well recognized as a hallmark of aging, obesity, and type 2 diabetes. Intermuscular adipocytes might serve as a benign storage site for surplus lipid or play a role in disrupting energy homeostasis as a result of dysregulated lipolysis or secretion of proinflammatory cytokines. This investigation sought to understand the net impact of local adipocytes on skeletal myocyte metabolism. RESEARCH DESIGN AND METHODS: Interactions between these two tissues were modeled using a coculture system composed of primary human adipocytes and human skeletal myotubes derived from lean or obese donors. Metabolic analysis of myocytes was performed after coculture with lipolytically silent or activated adipocytes and included transcript and metabolite profiling along with assessment of substrate selection and insulin action. RESULTS: Cocultured adipocytes increased myotube mRNA expression of genes involved in oxidative metabolism, regardless of the donor and degree of lipolytic activity. Adipocytes in the basal state sequestered free fatty acids, thereby forcing neighboring myotubes to rely more heavily on glucose fuel. Under this condition, insulin action was enhanced in myotubes from lean but not obese donors. In contrast, when exposed to lipolytically active adipocytes, cocultured myotubes shifted substrate use in favor of fatty acids, which was accompanied by intracellular accumulation of triacylglycerol and even-chain acylcarnitines, decreased glucose oxidation, and modest attenuation of insulin signaling. CONCLUSIONS: The effects of cocultured adipocytes on myocyte substrate selection and insulin action depended on the metabolic state of the system. These findings are relevant to understanding the metabolic consequences of intermuscular adipogenesis. PMID- 21602516 TI - Genital and extra-genital warts increase the risk of asymptomatic genital human papillomavirus infection in men. AB - OBJECTIVES: To evaluate the relationship of warts in different parts of the body and the risk of asymptomatic genital human papillomavirus (HPV) infection in men. METHODS: We examined the relationship of self-reported genital and extra-genital warts with the subsequent acquisition of asymptomatic genital HPV infection in a cohort of 331 adult men. Participants were followed at 2-month intervals for up to 4 years. Past and current presence of warts was queried at study entry. At each visit, the external genitals were sampled for HPV DNA testing. RESULTS: Men who reported a history of genital warts, including current warts, were at increased risk of acquisition of asymptomatic HPV infection of the penis glans/corona, penis shaft and scrotum. The magnitude of these associations was greatest for HPV 6/11 infection. History of warts on the fingers, arms and trunk of the body was also associated with increased risk of genital HPV infection. Current presence of warts on the fingers and trunk specifically increased the risk of acquisition of HPV types not typically found on the genitals. CONCLUSIONS: Men with a history of warts on the genitals, fingers, arms and trunk may be at increased risk for acquisition of new genital HPV infections. Warts may provide an efficient reservoir for the transmission of virions to the genitals through auto-inoculation. The potential for the spread of HPV throughout the body through auto-inoculation has important implications for prevention and control of HPV infection. PMID- 21602517 TI - The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers. AB - Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neoplasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose ruxolitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) and erythromycin (a moderate CYP3A4 inhibitor) increased total ruxolitinib plasma exposure (AUC(0-infinity)) by 91% and 27%, respectively, and ruxolitinib PD, as measured by the inhibition of interleukin (IL)-6-stimulated STAT3 phosphorylation in whole blood, was generally consistent with the PK observed. Pretreatment with rifampin, a potent CYP3A4 inducer, decreased ruxolitinib AUC(0-infinity) by 71% while resulting in only a 10% decrease in the overall PD activity. This apparent PK/PD discrepancy may be explained, in part, by an increase in the relative abundance of ruxolitinib active metabolites with the rifampin coadministration. The collective PK/PD data suggest that starting doses of ruxolitinib should be reduced by 50% if coadministered with a potent CYP3A4 inhibitor, whereas adjustments in ruxolitinib starting doses may not be needed when coadministered with inducers or mild/moderate inhibitors of CYP3A4. All study doses of ruxolitinib were generally safe and well tolerated when given alone and in combination with ketoconazole, erythromycin, or rifampin. PMID- 21602518 TI - Biliary excretion of imatinib and its active metabolite CGP74588 during severe hepatic dysfunction. PMID- 21602519 TI - Varespladib inhibits secretory phospholipase A2 in bronchoalveolar lavage of different types of neonatal lung injury. AB - Secretory phospholipase A2 (sPLA2), which links surfactant catabolism and lung inflammation, is associated with lung stiffness, surfactant dysfunction, and degree of respiratory support in acute respiratory distress syndrome and in some forms of neonatal lung injury. Varespladib potently inhibits sPLA2 in animal models. The authors investigate varespladib ex vivo efficacy in different forms of neonatal lung injury. Bronchoalveolar lavage fluid was obtained from 40 neonates affected by hyaline membrane disease, infections, or meconium aspiration and divided in 4 aliquots added with increasing varespladib or saline. sPLA2 activity, proteins, and albumin were measured. Dilution was corrected with the urea ratio. Varespladib was also tested in vitro against pancreatic sPLA2 mixed with different albumin concentration. Varespladib was able to inhibit sPLA2 in the types of neonatal lung injury investigated. sPLA2 activity was reduced in hyaline membrane disease (P < .0001), infections (P = .003), and meconium aspiration (P = .04) using 40 uM varespladib; 10 uM was able to lower enzyme activity (P = .001), with an IC(50) of 87 uM. An inverse relationship existed between protein level and activity reduction (r = 0.5; P = .029). The activity reduction/protein ratio tended to be higher in hyaline membrane disease. Varespladib efficacy was higher in vitro than in lavage fluids obtained from neonates (P < .001). PMID- 21602520 TI - A review of lumbar spinal instrumentation: evidence and controversy. AB - Disability secondary to disorders of the spine is a significant problem worldwide. In the USA, there has been a recent surge in the costs associated with caring for spinal pathology; from 1997 to 2005, there was a growth of 65% in healthcare expenditures on spinal disease, totalling $86 billion in 2005. Increasingly, there has been media and public scrutiny over the rapid rise in the volume of procedures with spinal instrumentation; some have suggested that this rise has been fuelled by non-medical drivers such as the financial incentives involved with the use of instrumentation; others suggest that innovation in spine technology and devices has led to improved options for the treatment of spine pathology.In this context, we conducted a review of the literature to assess the use of instrumentation in lumbar procedures and its relationship to successful fusion and patient outcome. Our review suggests that there is data supporting the thesis that lumbar instrumentation improves rates of fusion. However, there is no consistent correlation between increased rates of fusion and improved patient outcomes. PMID- 21602521 TI - Impact of contrast-induced acute kidney injury with transient or persistent renal dysfunction on long-term outcomes of patients with acute myocardial infarction undergoing percutaneous coronary intervention. AB - OBJECTIVE: To investigate the long-term prognostic implications of contrast induced acute kidney injury (CI-AKI) with transient or persistent renal dysfunction in acute myocardial infarction (AMI) patients undergoing percutaneous coronary intervention (PCI). DESIGN: A retrospective observational registry study. SETTING: Clinical follow-up after PCI. Patients and methods A total of 1041 PCI-treated AMI patients from the Infarction Prognosis Study registry. CI AKI was defined as an increase in serum creatinine (>25% or >0.5 mg/dl (>44.2 MUmol/l)) within 2 days after PCI. Main outcome measures Two-year cumulative event rate of all-cause death or renal failure requiring dialysis. RESULTS: CI AKI was observed in 148 patients (14.2%). Patients with CI-AKI had a higher rate of death or dialysis (25.4% vs. 6.3%, p<0.001) at 2 years compared with patients without CI-AKI. CI-AKI was an important independent predictor of death or dialysis (HR 2.76, 95% CI 1.61 to 4.73, p<0.001) Persistent renal dysfunction after CI-AKI was documented in 68 patients (45.9%). Patients with transient renal dysfunction showed a lower 2-year event rate of death or dialysis compared with those with persistent renal dysfunction (17.9% vs. 34.1%, p=0.013); however, they showed a higher event rate compared with those without CI-AKI (17.9% vs. 6.3%, p<0.001). CONCLUSION: Transient and persistent renal dysfunction after CI-AKI was associated with increased short and long-term mortality and morbidity in AMI patients treated by PCI. Better preventive strategies are needed to improve clinical outcomes in AMI patients at high risk of developing CI-AKI. PMID- 21602522 TI - Performance of the 2010 European Society of Cardiology criteria for ECG interpretation in athletes. AB - BACKGROUND: The European Society of Cardiology (ESC) recently published revised criteria for ECG interpretation in the athlete. OBJECTIVE: To examine the performance of the 2010 ESC ECG criteria in a population of athletes undergoing preparticipation cardiovascular disease screening. METHODS: University athletes (n=508) underwent routine medical history/physical examination and ECG before athletic participation. Transthoracic echocardiography (TTE) was also performed on each participant to detect or exclude cardiac findings with relevance to sport participation. Screening test statistics were calculated to determine the performance of the 2010 ESC criteria, and the performance of the 2010 criteria was compared with the 2005 criteria. RESULTS: Application of the 2010 ESC criteria, compared with the 2005 criteria, reduced the number of participants with abnormal ECG findings from 83/508 (16.3%) to 49/508 (9.6%). The reduction in the number of abnormal ECGs was driven by the reclassification of participants with isolated QRS voltage criteria for left ventricular hypertrophy from abnormal to normal. Of the 49 participants with abnormal ECGs, 14/49 (29%) had a single ECG abnormality and 35/49 (71%) had two or more abnormalities. The use of the 2010 criteria was associated with improved specificity (reduction in the false positive rate) and preserved sensitivity when compared with the 2005 criteria. CONCLUSION: Application of the 2010 ESC criteria for ECG interpretation in the athlete improves the accuracy of an ECG-inclusive preparticipation screening strategy by reducing the rate of false positive ECGs. PMID- 21602523 TI - Impact of prosthesis--patient mismatch after mitral valve replacement: a multicentre analysis of early outcomes and mid-term survival. AB - BACKGROUND: Prosthesis-patient mismatch (PPM) is characterised by the effects of inadequate prosthesis size relative to body surface area (BSA). It is uncertain whether PPM after mitral valve replacement impacts upon clinical outcome. This was examined in an Australian population. METHODS: From 2001 to 2009, 1006 mechanical and bioprosthetic mitral valves were implanted across 10 institutions. Effective orifice areas (EOA) were obtained from a literature review of in vivo echocardiographic data. Absent, moderate and severe PPM was defined as an indexed EOA (EOA/BSA) of >1.20 cm(2)/m(2), >0.90 to <=1.20 cm(2)/m(2) and <=0.9 cm(2)/m(2), respectively. Early outcomes and 7-year survival were compared between these three groups. RESULTS: PPM was absent in 34%, moderate in 53% and severe in 13% of patients. Patients with PPM were more likely to be male (42% vs 52% vs 62%, p<0.0001) and obese (14% vs 20% vs 56%, p<0.0001). Postoperatively there was similar 30-day mortality (5% vs 5% vs 6%, p=0.83) and early any mortality/morbidity (24% vs 27% vs 29%, p=0.40). Seven-year survival was similar between groups (72+/-4.1% vs 76+/-3.2% vs 69+/-10.3%, p=0.76). PPM did not predict adverse events after logistic and Cox regressions with and without propensity score adjustment. Subgroup analyses of those with isolated mitral valve surgery, patients with preoperative congestive heart failure and non-obese patients failed to show an association between PPM and mid-term mortality. CONCLUSIONS: Overall, PPM was not associated with poorer early outcomes or mid term survival. Oversizing valves may be technically hazardous and do not yield superior outcomes. Easier implantation by appropriate sizing appears justified. PMID- 21602524 TI - A unique proteomic profile on surface IgM ligation in unmutated chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course with 2 extreme subsets: indolent, ZAP70(-) and mutated immunoglobulin heavy chain gene (M-CLL); and aggressive, ZAP70(+) and unmutated immunoglobulin heavy chain (UM-CLL). Given the long-term suspicion of antigenic stimulation as a primum movens in the disease, the role of the B-cell receptor has been extensively studied in various experimental settings; albeit scarcely in a comparative dynamic proteomic approach. Here we use a quantitative 2-dimensional fluorescence difference gel electrophoresis technology to compare 48 proteomic profiles of the 2 CLL subsets before and after anti-IgM ligation. Differentially expressed proteins were subsequently identified by mass spectrometry. We show that unstimulated M- and UM-CLL cells display distinct proteomic profiles. Furthermore, anti-IgM stimulation induces a specific proteomic response, more pronounced in the more aggressive CLL. Statistical analyses demonstrate several significant protein variations according to stimulation conditions. Finally, we identify an intermediate form of M-CLL cells, with an indolent profile (ZAP70(-)) but sharing aggressive proteomic profiles alike UM-CLL cells. Collectively, this first quantitative and dynamic proteome analysis of CLL further dissects the complex molecular pathway after B-cell receptor stimulation and depicts distinct proteomic profiles, which could lead to novel molecular stratification of the disease. PMID- 21602525 TI - Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells. AB - Although many literature data are available on the role of Notch signaling in T cell acute lymphoblastic leukemia (ALL) biology, the importance of this molecular pathway in the development of B-lineage ALL (B-ALL) cells in the BM microenvironment is unknown so far. In this study, we used anti-Notch molecules neutralizing Abs and gamma-secretase inhibitor (GSI) XII to investigate the role of the Notch signaling pathway in the promotion of human B-ALL cell survival in presence of stromal cell support. The treatment with combinations of anti-Notch molecule neutralizing Abs resulted in the decrease of B-ALL cell survival, either cultured alone or cocultured in presence of stromal cells from normal donors and B-ALL patients. Interestingly, the inhibition of Notch-3 and -4 or Jagged-1/-2 and DLL-1 resulted in a dramatic increase of apoptotic B-ALL cells by 3 days, similar to what is obtained by blocking all Notch signaling with the GSI XII. Our data suggest that the stromal cell-mediated antiapoptotic effect on B- ALL cells is mediated by Notch-3 and -4 or Jagged-1/-2 and DLL-1 in a synergistic manner. PMID- 21602526 TI - Modulation of TGF-beta signaling by endoglin in murine hemangioblast development and primitive hematopoiesis. AB - Endoglin (Eng), an accessory receptor for the transforming growth factor beta (TGF-beta) superfamily, is required for proper hemangioblast and primitive hematopoietic development. However the mechanism by which endoglin functions at this early developmental stage is currently unknown. Transcriptional analyses of differentiating eng(-/-) and eng(+/+) ES cells revealed that lack of endoglin leads to profound reductions in the levels of key hematopoietic regulators, including Scl, Lmo2, and Gata2. We also detected lower levels of phosphorylated Smad1 (pSmad1), a downstream target signaling molecule associated with the TGF beta pathway. Using doxycycline-inducible ES cell lines, we interrogated the TGF beta signaling pathway by expressing activated forms of ALK-1 and ALK-5, type I receptors for TGF-beta. Our results indicate that ALK-1 signaling promotes hemangioblast development and hematopoiesis, as evidenced by colony assays, gene expression and FACS analyses, whereas signaling by ALK-5 leads to the opposite effect, inhibition of hemangioblast and hematopoietic development. In Eng(-/-) ES cells, ALK-1 rescued both the defective hemangioblast development, and primitive erythropoiesis, indicating that ALK-1 signaling can compensate for the absence of endoglin. We propose that endoglin regulates primitive hematopoiesis by modulating the activity of the Smad1/5 signaling pathway in early stages of development. PMID- 21602527 TI - Circulating microRNAs let-7a and miR-16 predict progression-free survival and overall survival in patients with myelodysplastic syndrome. AB - Circulating microRNAs (miRNAs) are potential biomarkers for cancer. We examined plasma levels of 2 miRNAs, let-7a and miR-16, in 50 patients with myelodysplastic syndrome (MDS) and 76 healthy persons using quantitative real-time PCR. Circulating levels of both miRNAs were similar among healthy controls but were significantly lower in MDS patients (P = .001 and P < .001, respectively). The distributions of these 2 miRNA levels were bimodal in MDS patients, and these levels were significantly associated with their progression-free survival and overall survival (both P < .001 for let-7a; P < .001 and P = .001 for miR-16). This association persisted even after patients were stratified according to the International Prognostic Scoring System. Multivariate analysis revealed that let 7a level was a strong independent predictor for overall survival in this patient cohort. These findings suggest that let-7a and miR-16 plasma levels can serve as noninvasive prognostic markers in MDS patients. PMID- 21602528 TI - SALL4 is a robust stimulator for the expansion of hematopoietic stem cells. AB - HSCs are rare cells that have the unique ability to self-renew and differentiate into cells of all hematopoietic lineages. The lack of donors and current inability to rapidly and efficiently expand HSCs are roadblocks in the development of successful cell therapies. Thus, the challenge of ex vivo human HSC expansion remains a fertile and critically important area of investigation. Here, we show that either SALL4A- or SALL4B-transduced human HSCs obtained from the mobilized peripheral blood are capable of rapid and efficient expansion ex vivo by >10 000-fold for both CD34(+)/CD38(-) and CD34(+)/CD38(+) cells in the presence of appropriate cytokines. We found that these cells retained hematopoietic precursor cell immunophenotypes and morphology as well as normal in vitro or vivo potential for differentiation. The SALL4-mediated expansion was associated with enhanced stem cell engraftment and long-term repopulation capacity in vivo. Also, we demonstrated that constitutive expression of SALL4 inhibited granulocytic differentiation and permitted expansion of undifferentiated cells in 32D myeloid progenitors. Furthermore, a TAT-SALL4B fusion rapidly expanded CD34(+) cells, and it is thus feasible to translate this study into the clinical setting. Our findings provide a new avenue for investigating mechanisms of stem cell self-renewal and achieving clinically significant expansion of human HSCs. PMID- 21602529 TI - Thiopurines prevent advanced colorectal neoplasia in patients with inflammatory bowel disease. AB - BACKGROUND AND AIMS: Previous studies have suggested a chemopreventive effect of 5-aminosalicylic acid (5-ASA) therapy in patients with inflammatory bowel disease (IBD). This effect has not been reported in IBD patients using thiopurines. We investigated the association between thiopurine or 5-ASA use and the risk of advanced neoplasia (AN), including high-grade dysplasia and colorectal cancer, in a large cohort of patients with IBD in the Netherlands. METHODS: PALGA, the nationwide network and registry of histo- and cytopathology in The Netherlands was linked to an anonymised computerised database of a Dutch health insurance company to identify patients with IBD with or without AN. Pharmaceutical data, including type and duration of medication use, were collected between January 2001 and December 2009. Cox proportional hazard regression analysis was used to calculate risk of AN in patients with and without thiopurine or 5-ASA use. RESULTS: A total of 2578 patients with IBD were included. Of these, 973 patients (38%) used 5-ASA, 314 (12%) thiopurines, 456 (18%) both 5-ASA and thiopurines and 835 (32%) none of these drugs. Twenty-eight patients (1%) developed AN during 16,289 person-years of follow-up. Of these, 11 patients (39%) had used 5-ASA, two (7%) thiopurines and one (4%) both drugs. Thiopurine use was associated with a significantly decreased risk of developing AN (adjusted HR 0.10, 95% CI 0.01 to 0.75). 5-ASA therapy also had a protective effect on developing AN, but this was not statistically significant (adjusted HR 0.56, 95% CI 0.22 to 1.40). CONCLUSION: Thiopurine use protects IBD patients against the development of AN. The effect of 5-ASA appeared to be less pronounced. PMID- 21602530 TI - Coronary artery disease and cardiovascular outcomes in patients with non alcoholic fatty liver disease. AB - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is associated with cardiovascular risk. The aim of this study was to determine the role of fatty liver in predicting coronary artery disease and clinical outcomes in patients undergoing coronary angiogram. METHODS: This was a prospective cohort study carried out in a University hospital. Consecutive patients who underwent coronary angiogram had ultrasound screening for fatty liver. Significant cardiovascular disease was defined as >=50% stenosis in at least one coronary artery. The primary outcome was a composite end point comprising cardiovascular deaths, non-fatal myocardial infarction and the need for further coronary intervention during prospective follow-up. RESULTS: Among 612 recruited patients, 356 (58.2%) had fatty liver by ultrasonography, 318 (52.0%) had elevated serum alanine aminotransferase and 465 (76.0%) had significant coronary artery disease. Coronary artery disease occurred in 84.6% of patients with fatty liver and 64.1% of those without fatty liver (p<0.001). After adjusting for demographic and metabolic factors, fatty liver (adjusted OR 2.31; 95% CI 1.46 to 3.64) and alanine aminotransferase level (adjusted OR 1.01; 95% CI 1.00 to 1.02) remained independently associated with coronary artery disease. At a mean follow-up of 87+/-22 weeks, 30 (10.0%) patients with fatty liver and 18 (11.0%) patients without fatty liver reached the composite clinical end point (p=0.79). CONCLUSIONS: In patients with clinical indications for coronary angiogram, fatty liver is associated with coronary artery disease independently of other metabolic factors. However, fatty liver cannot predict cardiovascular mortality and morbidity in patients with established coronary artery disease. PMID- 21602531 TI - The relevance of symptom association analysis in GORD patients undergoing anti reflux surgery. PMID- 21602533 TI - Airway inflammation in atopic patients: a comparison of the upper and lower airways. AB - OBJECTIVE: The purpose of this study was to understand and assess the inflammatory response within the upper and lower airways in patients suffering from both asthma and allergic rhinitis. Study Design. Cross-sectional study. Setting. A laboratory-based study of patients with allergic rhinitis and asthma. SUBJECTS AND METHODS: Glycol methacrylate resin-embedded specimens from 10 patients with allergic rhinitis and asthma taken from the nose and bronchi were assessed by immunohistochemistry. Monoclonal antibodies directed against specific cell markers for mast cells (AA1), eosinophils (EG2), neutrophils (NOE), and lymphocytes (CD3(+), CD4(+), CD8(+)) were studied. Cells were counted blind (as cells/mm(2)) in the submucosal matrix. Mann-Whitney U test was used for analyses. P values of .05 or lower were considered statistically significant. RESULTS: There was a significant increase in CD4(+) (P = .05) and CD8(+) cell counts (P = .001) in the lower airway compared to the upper airway. There were no differences between the 2 groups in the number of neutrophils, mast cells, eosinophils, and the CD3(+) cell counts. CONCLUSION: The upper and lower airways have parallel inflammation with possible bidirectional extension of inflammation in patients suffering from asthma and allergic rhinitis. There is increased lymphocytic infiltration in the lower airway, suggesting a possible preponderance for development and maintenance of allergic disease in the lower airway. PMID- 21602532 TI - Type 2 diabetes risk variants and colorectal cancer risk: the Multiethnic Cohort and PAGE studies. AB - BACKGROUND: Diabetes has been positively associated with the risk of colorectal cancer. This study investigated whether recently established risk variants for diabetes also have effects on colorectal cancer. METHODS: 19 single nucleotide repeats (SNPs) associated with type 2 diabetes in genome-wide association studies were tested in a case-control study of 2011 colorectal cancer cases and 6049 controls nested in the Multiethnic Cohort study as part of the Population Architecture using Genomics and Epidemiology (PAGE) initiative. ORs and 95% CIs were estimated by unconditional logistic regression to evaluate the association between SNPs and colorectal cancer risk, adjusting for age, sex and race/ethnicity. Permutation testing was conducted to correct for multiple hypothesis testing. RESULTS: Four type 2 diabetes SNPs were associated with colorectal cancer risk: rs7578597 (THADA), rs864745 (JAZF1), rs5219 (KCNJ11) and rs7961581 (TSPAN8, LGR5). The strongest association was for the rs7578597 (THADA) Thr1187Ala missense polymorphism (P(trend)=0.004 adjusted for multiple testing), with the high risk allele for colorectal cancer being the low risk allele for diabetes. Similar patterns of associations were seen with further adjustment for diabetes status and body mass index. The association of diabetes status with colorectal cancer risk was somewhat weakened after adjustment for these SNPs. CONCLUSION: The findings suggest that diabetes risk variants also influence colorectal cancer susceptibility, possibly through mechanisms different from those for diabetes. PMID- 21602534 TI - Giant nasal mass causing feeding difficulty in tuberous sclerosis. PMID- 21602535 TI - Superior canal dehiscence effect on hearing thresholds: animal model. AB - OBJECTIVE: Superior semicircular dehiscence syndrome is associated with vestibular symptoms and an air-bone gap component in the audiogram, apparently caused by the creation of a pathological bony "third window" in the superior semicircular canal. The aim of this study was to evaluate changes in auditory air and bone-conduction thresholds to low- and high-frequency stimuli in an animal model of a bony fenestration facing the aerated mastoid cavity. STUDY DESIGN: Anatomic, audiological. SETTING: Tertiary university-affiliated medical center. ANIMALS: A small hole was drilled in the bony apical portion of the superior semicircular canal facing the mastoid bulla/cavity, with preservation of the membranous labyrinth, in 5 adult-size fat sand rats. MAIN OUTCOME MEASURES: Auditory brain stem responses to clicks and 1-kHz tone bursts delivered by air and bone conduction before surgery, after opening the bulla, and after fenestration. RESULTS: After fenestration, a significant air-bone gap was measured in response to clicks (mean +/- standard deviation, 37 +/- 5.8 dB) and bursts (mean +/- standard deviation, 34 +/- 14.5 dB). The gap was attributable solely to the significant deterioration in air-conduction thresholds, in the absence of a significant change in bone conduction thresholds. The pattern of auditory brain response changes closely resembled that reported for middle ear dysfunction, namely, an increase in absolute latency of waves I, III, and V without significant alterations in interpeak latency differences. CONCLUSIONS: Bony fenestration of the superior semicircular canal toward an aerated cavity in a rodent model mimics the auditory loss pattern of patients with superior semicircular dehiscence syndrome. The dehiscent membrane accounts for the auditory changes. PMID- 21602536 TI - Reduction in hospital admissions for acute coronary syndrome after the successful implementation of 100% smoke-free legislation in Argentina: a comparison with partial smoking restrictions. AB - BACKGROUND: Several studies have shown a decrease in acute coronary syndrome (ACS) admissions after the implementation of 100% smoke-free legislation. However, no studies have been conducted in developing countries. METHODS: We conducted a time series analysis of ACS hospital admissions in Santa Fe province and Buenos Aires city, Argentina. In 2006, Santa Fe implemented a 100% smoke-free law and Buenos Aires implemented a partial law with designated smoking areas and exceptions. Age-standardised ACS admissions rates were compared before and after the implementation of the laws in each district. Smoking prevalence, compliance with legislation and exposure to secondhand smoke (SHS) was also assessed in both districts. RESULTS: In Santa Fe an immediate decrease in ACS admissions was observed after implementation (-2.5 admissions per 100,000, p=0.03; 13% reduction), compared with no change in Buenos Aires city (rate ratio Santa Fe vs Buenos Aires: 0.74, 95% CI 0.63 to 0.86, p<=0.001). In Santa Fe, the immediate effect was followed by a persistent decrease in admissions due to ACS (-0.26 admissions per 100,000 per month). Smoking prevalence did not change significantly in either district during the same period. In both districts, there was a reduction in self-reported SHS exposure, with a trend towards lower exposure in Santa Fe province. No other comprehensive tobacco control interventions were implemented during the study period. CONCLUSIONS: A 100% smoke free law was more effective than a partial restriction law in reducing ACS admissions. An immediate effect was followed by a sustained decrease in ACS admissions. Smoke-free initiatives can be also effective in decreasing acute coronary events in developing countries. PMID- 21602537 TI - Carcinogenic tobacco-specific N-nitrosamines in US cigarettes: three decades of remarkable neglect by the tobacco industry. AB - BACKGROUND: Modification of tobacco curing methods and other changes in cigarette manufacturing techniques could substantially reduce the levels of tobacco specific nitrosamines (TSNA), a group of potent carcinogens, in cigarette smoke. In 1999, two major US cigarette manufacturers stated their intent to move towards using tobaccos low in TSNA. There is no information available on current TSNA levels in tobacco of various cigarettes available in the US, particularly in the newer varieties introduced over the past decade. METHODS: Seventeen brands of cigarettes were purchased in April of 2010 from retail stores in Minnesota. TSNA levels were measured in the tobacco filler and smoke of these cigarettes. RESULTS: In all brands, the sum of two potent carcinogenic TSNA--4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone and N'-nitrosonornicotine--in cigarette filler averaged 2.54 (+/- 1.05) MUg/g tobacco. This value is virtually identical to the sum of these two carcinogens reported for the tobacco of a US filtered cigarette in 1979. TSNA levels in smoke positively correlated with those in tobacco filler of the same cigarettes. CONCLUSION: We found no indication that any meaningful attempt was made to reduce or at least control TSNA levels in the new varieties of the popular brands Marlboro and Camel introduced over the last decade. In light of the recently granted regulatory authority to the FDA over tobacco products, regulation of TSNA levels in cigarette tobacco should be strongly considered to reduce the levels of these potent carcinogens in cigarette smoke. PMID- 21602538 TI - Association between cleaning-related chemicals and work-related asthma and asthma symptoms among healthcare professionals. AB - OBJECTIVES: Work-related asthma (WRA) is an important public health problem affecting one quarter of adults with asthma. Although cleaning substances are routinely used in hospitals, few studies have addressed their potential adverse respiratory health effects on healthcare professionals (HCPs). This study attempts to identify relationship between work-related exposure to cleaning related chemicals and development of WRA among HCPs. METHODS: Of 5600 HCPs surveyed, 3650 responded to a validated questionnaire about their occupation, asthma diagnosis, variability of asthma symptoms at and away from work, and exposure to individual cleaning substances. Workplace asthma was defined as a categorical variable with four mutually exclusive categories: work-related asthma symptoms (WRAS), work-exacerbated asthma (WEA), occupational asthma (OA) and none. Multivariable logistic regression analysis was used to evaluate the association between self-reported use of cleaning substances and asthma outcomes among HCPs. RESULTS: Prevalences of WRAS, WEA and OA were 3.3%, 1.1% and 0.8%, respectively. The prevalence estimates were generally higher among female than male HCPs. The odds of WRAS and WEA increased in a dose-dependent manner for exposure in the longest job to cleaning agents and disinfectants/sterilants, respectively. For exposure in any job, the odds of WRAS were significantly elevated for both factor 1 (bleach, cleaners/abrasives, toilet cleaners, detergents and ammonia) and factor 2 (glutaraldehyde/ortho-phtaldehyde, chloramines and ethylene oxide). Significantly elevated odds of WEA were observed for exposure to bleach, factor 2 and formalin/formaldehyde. Exposure to chloramines was significantly associated with an almost fivefold elevated odds of OA. CONCLUSIONS: HCPs are at risk of developing WRA from exposure to cleaning substances. PMID- 21602539 TI - The effectiveness of two active interventions compared to self-care advice in employees with non-acute low back symptoms: a randomised, controlled trial with a 4-year follow-up in the occupational health setting. AB - OBJECTIVE: Evaluate the effectiveness of two active interventions, aimed at secondary prevention of low back pain (LBP), in occupational health. METHODS: We performed a survey of LBP (n=2480; response rate 71%) and randomized 143 employees (66% males, 45 years) with LBP over 34 mm on VAS into Rehabilitation (n=43), Exercise (n=43) or self-care (n=40) groups. Primary outcomes were LBP, physical impairment (PI) and health-related quality of life (HRQoL) for two years and sickness absence (SA) days during four years (LBP specific, total). RESULTS: Compared to self-care, exercise reduced LBP at 12 months (mean difference (MD) 12 mm; 95% CI -21 to -2) and improved HRQoL at 12 and 24 months (0.03; 0.00 to 0.05), but did not reduce PI. The MDs of SA days in four years were -17 (-70 to 35, total) and -15 (-47 to 13, LBP specific). Exercise reduced the probability of LBP specific SA during the third and fourth year. Compared to self-care, Rehabilitation reduced LBP at 3 months (-10 mm; -19 to -1) and 6 months (-10 mm; 20 to - 1), but was not effective in HRQoL or PI. The MDs of SA days in four years were -41 (-93 to 8; total) and 5 (-30 to 47; LBP specific). Rehabilitation reduced the probability of total SA during first and second year and amount of total SA days in the fourth year. CONCLUSIONS: Among employees with relatively mild LBP, both interventions reduced pain, but the effects on SA and PI were minor. Exercise improved HRQoL. The effect sizes were rather small. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00908102. PMID- 21602540 TI - Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. AB - BACKGROUND: The effect of inhaled corticosteroids (ICS) on fracture risk in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to evaluate the association between ICS and fractures in COPD. METHODS: MEDLINE, EMBASE, regulatory documents and company registries were searched up to August 2010. Randomised controlled trials (RCTs) of budesonide or fluticasone versus control treatment for COPD (>=24 weeks duration) and controlled observational studies reporting on fracture risk with ICS exposure vs no exposure in COPD were included. Peto OR meta-analysis was used for fracture risk from RCTs while ORs from observational studies were pooled using the fixed effect inverse variance method. Dose-response analysis was conducted using variance-weighted least squares regression in the observational studies. Heterogeneity was assessed using the I(2) statistic. RESULTS: Sixteen RCTs (14 fluticasone, 2 budesonide) with 17,513 participants, and seven observational studies (n=69,000 participants) were included in the meta-analysis. ICSs were associated with a significantly increased risk of fractures (Peto OR 1.27; 95% CI 1.01 to 1.58; p=0.04; I(2)=0%) in the RCTs. In the observational studies, ICS exposure was associated with a significantly increased risk of fractures (OR 1.21; 95% CI 1.12 to 1.32; p<0.001; I(2)=37%), with each 500 MUg increase in beclomethasone dose equivalents associated with a 9% increased risk of fractures, OR 1.09 (95% CI 1.06 to 1.12; p<0.001). CONCLUSION: Among patients with COPD, long-term exposure to fluticasone and budesonide is consistently associated with a modest but statistically significant increased likelihood of fractures. PMID- 21602541 TI - Effectiveness of home respiratory polygraphy for the diagnosis of sleep apnoea and hypopnoea syndrome. AB - INTRODUCTION: Home respiratory polygraphy (HRP) may be a cost-effective alternative to polysomnography for the diagnosis of sleep apnoea-hypopnoea syndrome (SAHS), but stronger evidence is needed. Normally, patients transport HRP equipment from the hospital to home and back, which may create difficulties for some patients. OBJECTIVES: To determine both the diagnostic efficacy and cost of HRP (with and without a transportation service moving the device and telematic transmission of data) in a large sample compared with in-hospital polysomnography. METHODS: Patients suspected of having SAHS were included in a multicentre study (eight hospitals). They were assigned to home and hospital protocols in random order. Receiver operating characteristic curves were constructed for manual respiratory polygraphy scoring protocol and different polysomnographic cut-off points. Diagnostic efficacies for several polysomnographic cut-off points were explored and costs for two equally effective alternatives were calculated. RESULTS: Of 366 randomised patients, 348 completed the protocol. The best receiver operating characteristic curve was obtained with a polysomnographic cut-off of the apnoea-hypopnoea index (AHI)>=5. The sensitive HRP AHI cut-off point (<5) had a sensitivity of 96%, a specificity of 57% and a negative likelihood ratio (LR) of 0.07; the specific cut-off (>10) had a sensitivity of 87%, a specificity of 86% and a positive LR of 6.25. The cost of HRP was half that of polysomnography. Telematic transmission costs were similar if the patients' costs were taken in to account. CONCLUSION: HRP is an alternative to polysomnography in patients with suspected SAHS. Telematic procedures may help patients with limited mobility and those who live a long way from the sleep centre. PMID- 21602543 TI - Asthma protection with bacteria--science or fiction? PMID- 21602542 TI - Associations between fluctuations in lung function and asthma control in two populations with differing asthma severity. AB - BACKGROUND: Lung function is a major criterion used to assess asthma control. Fluctuation analyses can account for lung function history over time, and may provide an additional dimension to characterise control. The relationships between mean and fluctuations in lung function with asthma control, exacerbation and quality of life were studied in two independent data sets. METHODS: Data from 132 adults with mild to moderate asthma and 159 adults with severe asthma were analysed separately. Fluctuations in twice-daily peak expiratory flow (PEF) over 6 months were measured by alpha, representing the strength of correlation with past lung function and potentially asthma stability. alpha and mean percentage predicted PEF (%predPEF) were plotted with and compared between patients grouped by asthma control defined by recent GINA (Global Initiative for Asthma) guidelines, the Asthma Control Questionnaire score, exacerbations and Asthma Quality of Life Questionnaire score. Associations of alpha and %predPEF with these outcomes were examined using multiple regression analyses. RESULTS: Both alpha and %predPEF differed with and were significantly associated with GINA defined asthma control in both the mild to moderate and severe asthma groups. Only alpha was related to whether or not exacerbations occurred in mild to moderate asthma, while %predPEF was more significantly related than alpha in severe asthma. In those with severe asthma, only %predPEF was significantly related to Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. CONCLUSION: Lung function history quantified by fluctuation analysis provides additional information to mean lung function, and may help characterise the current state of asthma control. It may also potentially aid in phenotyping clinical asthma. PMID- 21602546 TI - Regulation of epithelial-mesenchymal transition by homeobox gene DLX4 in JEG-3 trophoblast cells: a role in preeclampsia. AB - The pathogenesis of preeclampsia is unclear but is thought to be related to shallow trophoblast invasion. An invasive phenotype is acquired by trophoblasts through the process of epithelial-mesenchymal transition (EMT). We proposed that EMT in trophoblasts is deregulated in preeclampsia. The homeobox gene DLX4 plays an important role in epithelial-mesenchymal interactions during embryonic and placental development. To elucidate the role of DLX4 in trophoblast EMT and preeclampsia, we investigated the expression of DLX4 in preeclampsia-affected placentas and the effect of DLX4 on EMT in trophoblast-derived JEG-3 cells. DLX4 expression was downregulated in preeclampsia-affected placentas and hypoxic JEG-3 cells. Knockdown of DLX4 by RNA interference (RNAi) inhibited the motility and invasion ability of JEG-3 cells, decreased the expression of E-cadherin, and upregulated the expression of the E-cadherin repressor Snail. Our findings suggest that decreased expression of DLX4 leads to the pathogenesis of preeclampsia by inhibiting EMT in trophoblasts and provides new insight into the pathophysiological mechanism of preeclampsia. PMID- 21602548 TI - Retraction. PMID- 21602547 TI - Glucocorticoid regulation of placental breast cancer resistance protein (Bcrp1) in the mouse. AB - Placental breast cancer resistance protein (Bcrp1; encoded by the Abcg2 gene) limits maternal-fetal transplacental transfer of numerous endogenous and exogenous substrates; however, the regulation of placental Abcg2 and Bcrp1 and is not well understood. Placental Abcg2 messenger RNA (mRNA) levels decrease with advancing gestation in the mouse, and this corresponds to increasing levels of maternal and fetal plasma glucocorticoid. Glucocorticoids, including dexamethasone (DEX), downregulate Bcrp1 expression and function in both breast cancer cell lines and the blood-brain barrier in vitro; whether this occurs in the placenta is not known. The potential regulatory role of synthetic glucocorticoids on placental Bcrp1 is of interest, given that approximately 10% of pregnant women are treated with synthetic glucocorticoid for threatened preterm labor. We hypothesized that (1) exposure of pregnant mice to DEX will downregulate placental Abcg2 mRNA and Bcrp1 protein, and (2) results in increased fetal accumulation of [(3)H]mitoxantrone. Pregnant mice were treated with DEX (low-dose: 0.1 mg/kg or high-dose: 1 mg/kg) or vehicle (saline) from embryonic day (E) E9.5 to E15.5 or E12.5 to E18.5. In placentae derived from female fetuses, high-dose DEX significantly downregulated Abcg2 mRNA expression on E15.5 (P < .05) and significantly inhibited Bcrp1 function (P < .05). Similarly, high dose DEX significantly inhibited Bcrp1 function in the placentae derived from male fetuses (P < .05). In conclusion, there is a dose-dependent regulatory effect of synthetic glucocorticoid on placental Abcg2 mRNA and Bcrp1 function in vivo. Further, it appears that, at the level of Abcg2 gene expression, the female derived placentae are more susceptible to the effects of DEX than male placentae. PMID- 21602549 TI - Diagnosis of heart failure with preserved ejection fraction: which parameters and diagnostic strategies are more valuable? AB - AIMS: There are no unified criteria for diagnosing heart failure with preserved ejection fraction (HFpEF). The aim of this study was to evaluate the present main diagnostic criteria and to discover which parameters and strategies are more valuable. METHODS AND RESULTS: Echocardiographic data and plasma N-terminal pro brain natriuretic peptide levels were assessed in a derivation cohort (n= 236) and a validation cohort (n= 98). Both cohorts included normal controls, patients with hypertensive heart disease without heart failure and patients with HFpEF. In the derivation cohort, the ratio of early mitral inflow velocity to tissue Doppler velocity at lateral mitral annulus (lateral E/e'>=12), left atrial volume index (LAVI>=34 mL/m(2)), and the difference between duration of reversed pulmonary vein atrial systole flow and duration of mitral A wave flow (Ard-Ad>30 ms) had the greatest diagnostic value among all the single parameters. A brief strategy that consisted of either: (i) lateral E/e'>=12; or (ii) 12>lateral E/e'>=8, with either LAVI>=34 mL/m(2) or Ard-Ad>30 ms, provided good diagnostic accuracy for identifying diastolic dysfunction in HFpEF, with a sensitivity of 77% and specificity of 81%. These observations were confirmed in the validation cohort. CONCLUSION: Echocardiographic parameters including lateral E/e', LAVI, and Ard-Ad have the greatest value in diagnosing HFpEF. A brief strategy that included these three parameters had great diagnostic value and would be simple to use in clinic practice. PMID- 21602550 TI - Comparative analysis of the therapeutic effects of long-acting and short-acting loop diuretics in the treatment of chronic heart failure using (123)I metaiodobenzylguanidine scintigraphy. AB - AIMS: Loop diuretics are essential for the treatment of chronic heart failure (CHF) but short-acting diuretics are reported to induce sympathetic nervous system (SNS) activation. This study was performed to compare therapeutic effects of two loop diuretics, long-acting azosemide and short-acting furosemide, using (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy. METHODS AND RESULTS: Twenty-two patients with New York Heart Association class II-III heart failure and left ventricular dysfunction, who required treatment with a loop diuretic, were included. In this crossover study, 11 patients were randomized to azosemide treatment first and the remaining 11 patients to furosemide. Treatments were administered for 6 months and then patients were crossed over to the second treatment. (123)I-MIBG scintigraphy was performed before and 6 months after the start of treatment with each loop diuretic. Early and delayed images were obtained 20 min and 4 h after administration of (123)I-MIBG, respectively; and the heart/mediastinum (H/M) ratio and washout rate (WR) were measured. In addition, left ventricular ejection fraction (LVEF), levels of brain natriuretic peptide (BNP), and norepinephrine were measured before and 6 months after the start of treatment. No differences were observed between the two groups in terms of concomitant medication, cause of heart failure, H/M ratio, WR, BNP, norepinephrine, or LVEF. The azosemide group exhibited a significant increase in delayed image H/M ratio, and a significant decrease in WR and norepinephrine after the final administration compared with the furosemide group. CONCLUSION: This study indicates that azosemide suppresses SNS activation compared with furosemide in patients with CHF, suggesting that long-acting loop diuretics may have more beneficial effects on the prognosis of CHF. PMID- 21602552 TI - Interactions of mefloquine with praziquantel in the Schistosoma mansoni mouse model and in vitro. AB - OBJECTIVES: Mefloquine has interesting antischistosomal properties, hence it might be an attractive partner drug for combination treatment with praziquantel. The aim of this study was to evaluate activities of mefloquine/praziquantel combinations against Schistosoma mansoni in vitro and in vivo. METHODS: Dose response relationships were established following exposure of adult S. mansoni to mefloquine, praziquantel and fixed dose combinations of mefloquine/praziquantel in vitro. S. mansoni-infected mice were treated orally with selected doses of single drugs and drug combinations 7 weeks post-infection. RESULTS: We calculated in vitro LC(50) values of 0.024 and 1.9 MUg/mL for praziquantel and mefloquine, respectively. Mefloquine/praziquantel combinations showed synergistic effects, with combination index (CI) values <1 when adult S. mansoni were simultaneously incubated with both drugs in vitro. Reduced viabilities were also observed when schistosomes were first exposed to mefloquine followed by praziquantel in vitro. ED(50)s of 62 mg/kg and 172 mg/kg were determined for mefloquine and praziquantel against adult S. mansoni in vivo, respectively. Combinations of praziquantel (50 or 100 mg/kg) followed the next day by mefloquine (50 or 100 mg/kg) treatment revealed only moderate total worm burden reductions of 47.8%-54.7%. On the other hand, when both drugs (100 mg/kg each) were either given simultaneously or mefloquine was given prior to praziquantel, high total and female worm burden reductions of 86.0%-93.1% were observed. For the later treatment regimen, synergistic effects (CI < 1) were calculated when mefloquine and praziquantel were combined using a fixed dose ratio based on their ED(50)s. CONCLUSIONS: Combinations of mefloquine and praziquantel may have clinical utility in the treatment of schistosomiasis. PMID- 21602551 TI - Effectiveness of tuberculosis chemotherapy correlates with resistance to Mycobacterium tuberculosis infection in animal models. AB - OBJECTIVES: It is widely believed that persistent Mycobacterium tuberculosis inhabits necrotic lung granulomas in humans and that the microenvironmental conditions encountered therein render the bacilli phenotypically tolerant to antibiotics, accounting for the long duration required for successful treatment of tuberculosis (TB). To validate this belief, we directly compared the activity of rifampicin/isoniazid/pyrazinamide (RHZ) against chronic TB infection in guinea pigs, which exhibit caseous granulomas histologically resembling human caseous foci, and in mice, which lack necrotic granulomas. METHODS: Guinea pigs and mice were aerosol-infected with M. tuberculosis CDC1551 and twice weekly treatment with RHZ was started 4 weeks later. Culture-positive relapse was assessed in subgroups of guinea pigs after 3 months and 4 months of treatment. RESULTS: All guinea pig lungs exhibited histological evidence of granulomas with central caseation, while mouse lungs exhibited cellular lesions at the initiation of antibiotic treatment. Guinea pig lungs became culture-negative after 2 months of RHZ given twice weekly at human-equivalent doses. Relapse rates in guinea pigs were 0% (0/10) both after 3 months and 4 months of treatment. In contrast, all mouse lungs remained culture-positive after 4 months of equivalent RHZ exposures. CONCLUSIONS: Caseous necrosis does not reduce the sterilizing activity of the standard antituberculosis regimen of RHZ. Our findings have important implications for the use of alternative animal models in testing novel TB drug regimens and for modelling M. tuberculosis persistence. PMID- 21602553 TI - Feature-based attention involuntarily and simultaneously improves visual performance across locations. AB - Selective attention can selectively increase sensitivity to particular visual features in order to prioritize behaviorally relevant stimuli. Moreover, neural responses to attended feature values are boosted even at ignored locations. We provide behavioral evidence for involuntary and simultaneous effects of this "global" feature-based attention on visual performance. Observers were cued to attend to dots moving in a particular direction at one location (the primary task), while discriminating which of two groups of moving dots on the other side of the screen contained coherent motion (the secondary task). An analogous experiment tested selective attention to orientation. The secondary tasks did not require observers to discriminate or selectively attend to the particular feature values present. Nonetheless, sensitivity was highest when the direction or orientation happened to match the one cued in the primary task. By comparing performance to a neutral condition, we revealed more enhancement of attended feature values than suppression of others. PMID- 21602554 TI - Optimal inference explains the perceptual coherence of visual motion stimuli. AB - The local spatiotemporal pattern of light on the retina is often consistent with a single translational velocity which may also be interpreted as a superposition of spatial patterns translating with different velocities. Human perception reflects such interpretations, as can be demonstrated using stimuli constructed from a superposition of two drifting gratings. Depending on a variety of parameters, these stimuli may be perceived as a coherently moving plaid pattern or as two transparent gratings moving in different directions. Here, we propose a quantitative model that explains how and why such interpretations are selected. An observer's percept corresponds to the most probable interpretation of noisy measurements of local image motion, based on separate prior beliefs about the speed and singularity of visual motion. This model accounts for human perceptual interpretations across a broad range of angles and speeds. With optimized parameters, its components are consistent with previous results in motion perception. PMID- 21602555 TI - No more top-heavy bias: infants and adults prefer upright faces but not top-heavy geometric or face-like patterns. AB - A non-specific "top-heavy" configuration bias has been proposed to explain neonatal face preference (F. Simion, E. Valenza, V. Macchi Cassia, C. Turati, & C. Umilta, 2002). Using an eye tracker (Tobii T60), we investigated whether the top-heavy bias is still present in 3- to 5.5-month-old infants and in adults as a comparison group. Each infant and adult viewed three classes of stimuli: simple geometric patterns, face-like figures, and photographs of faces. Using area of interest analyses on fixation duration, we computed a top-heavy bias index (a number between -1 and 1) for each individual. Our results showed that the indices for the geometric and face-like patterns were about zero in infants, indicating no consistent bias for the "top-heavy" configuration. In adults, the indices for the geometric and face-like patterns were also close to zero except for the T shaped figure and the ones that had higher rating on facedness. Moreover, the indices for photographs of faces were positive in both infants and adults, indicating significant preferences for upright natural faces over inverted ones. Taken together, we found no evidence for the top-heavy configuration bias in both infants and adults. The absence of top-heavy bias plus a clear preference for photographed upright faces in infants seem to suggest an early cognitive specialization process toward face representation. PMID- 21602556 TI - Compensation for equiluminant color motion during smooth pursuit eye movement. AB - Motion perception is compromised at equiluminance. Because previous investigations have been primarily carried out under fixation conditions, it remains unknown whether and how equiluminant color motion comes into play in the velocity compensation for retinal image motion due to smooth pursuit eye movement. We measured the retinal image velocity required to reach subjective stationarity for a horizontally drifting sinusoidal grating in the presence of horizontal smooth pursuit. The grating was defined by luminance or chromatic modulation. When the subjective stationarity of the color motion was shifted toward environmental stationarity, compared with the subjective stationarity of luminance motion, that of color motion was farther from retinal stationarity, indicating that a slowing of color motion occurred before this factor contributed to the process by which retinal motion was integrated with a biological estimate of eye velocity during pursuit. The gain in the estimate of eye velocity per se was unchanged irrespective of whether the stimulus was defined by luminance or by color. Indeed, the subjective reduction in the speed of color motion during fixation was accounted for by the same amount of deterioration in speed. From these results, we conclude that the motion deterioration at equiluminance takes place prior to the velocity comparison. PMID- 21602557 TI - Dependence of the retinal Ganglion cell's responses on local textures of natural scenes. AB - An important property of natural images contributing to a retinal ganglion cell's (RGC) responses is the temporal modulation of mean intensity (contrast) in the receptive field (RF) center. However, these responses exhibit a significant amount of variability. This variability could arise in part from responses to the spatial intensity variation of the natural images in the RF center, i.e., their local intensity distribution or their local visual texture. We tested five predictions derived from this hypothesis: First, responses tend to increase with the variance of the local visual texture of natural images. Second, the skewed distribution of intensities in natural images leads to asymmetric responses to their onset and offset to and from a gray background of the same mean intensity. Third, repeating this experiment with the negative of natural images inverts the asymmetry. Fourth, performing an intensity histogram equalization of the images eliminates the asymmetry. Fifth, RGCs' responses increase with the spatial contrast of artificial plaids. The hypothesis passed all five tests, which indicate that responses to natural images increase with the variance of their visual texture. To account for this texture sensitivity, we propose a model in which the RFs of most RGCs of the rabbit have multiple nonlinear subunits. PMID- 21602558 TI - Attentional oblique effect when judging simultaneity. AB - We extended the investigation of the oblique effect in two novel ways: from stimulus-driven vision to visual attention and from space to time. Participants fixated the center of briefly flashed displays that contained a temporally varying Gabor stimulus in each of the four peripheral quadrants. Across trial blocks, we manipulated which two of the four peripheral stimuli were to be selected for a simultaneity judgment. Simultaneity judgments were significantly worse for obliquely (diagonally) attended targets than for cardinally (horizontally or vertically) attended targets, despite identical retinal stimulation across all attentional conditions. The impairment in judging the simultaneity of obliquely attended targets occurred between and within lateral hemifields, despite significantly greater temporal acuity for the left hemifield. The oblique effect in simultaneity judgments disappeared when the same targets were presented without temporally varying stimuli at distractor locations-a finding that implicates selective attention. Intriguingly, the oblique effect in excluding stimuli at distractor locations also disappeared when participants viewed the original displays but attended to spatial frequency rather than to simultaneity. These findings raise the possibility of different spatial integration windows when attending to spatial versus temporal features, even when those features are co-presented in space and time. PMID- 21602559 TI - Conifer expansion reduces the competitive ability and herbivore defense of aspen by modifying light environment and soil chemistry. AB - Disturbance patterns strongly influence plant community structure. What remains less clear, particularly at a mechanistic level, is how changes in disturbance cycles alter successional outcomes in plant communities. There is evidence that fire suppression is resulting in longer fire return intervals in subalpine forests and that these lengthened intervals increase competitive interactions between aspen and conifer species. We conducted a field and greenhouse study to compare photosynthesis, growth and defense responses of quaking aspen and subalpine fir regeneration under light reductions and shifts in soil chemistry that occur as conifers increase in dominance. The studies demonstrated that aspen regeneration was substantially more sensitive to light and soil resource limitations than that of subalpine fir. For aspen, light reductions and/or shifts in soil chemistry limited height growth, biomass gain, photosynthesis and the production of defense compounds (phenolic glycosides and condensed tannins). Biomass gain and phenolic glycoside concentrations were co-limited by light reduction and changes in soil chemistry. In contrast, subalpine fir seedlings tended to be more tolerant of low light conditions and showed no sensitivity to changes in soil chemistry. Unlike aspen, subalpine fir increased its root to shoot ratio on conifer soils, which may partially explain its maintenance of growth and defense. The results suggest that increasing dominance of conifers in subalpine forests alters light conditions and soil chemistry in a way that places greater physiological and growth constraints on aspen than subalpine fir, with a likely outcome being more successful recruitment of conifers and losses in aspen cover. PMID- 21602560 TI - Candidate gene association analysis of acute lymphoblastic leukemia identifies new susceptibility locus at 11p15 (LMO1). AB - To determine the contribution of susceptibility loci in explaining the genetic basis of acute lymphoblastic leukemia (ALL), we genotyped 29 high-potential candidate genes with 672 tagged single-nucleotide polymorphisms (SNPs) in a sample (163 cases and 251 healthy controls) of Caucasian children. Fifty SNPs in 15 genes were significantly associated with ALL risk at the P < 0.05 level. After correction for multiple testing, rs442264 within the LIM domain only 1 (LMO1) gene at 11p15 remained significant [odds ratio (OR) = 1.90, P = 3 * 10(-5)]. In addition, a major haplotype within LMO1 comprising 14 SNPs with individual risk associations was found to significantly increase ALL risk (OR = 1.79, P = 0.0006). A stratified analysis on subtype indicated that risk associations of LMO1 variants are significant in children with precursor B-cell leukemia. These data show that genetic variants within LMO1 are associated with ALL and identify this gene as a strong candidate for precursor B-cell leukemogenesis. PMID- 21602561 TI - Navigating adaptive challenges in quality improvement. PMID- 21602562 TI - Lessons learnt from incidents reported by postgraduate trainees in Dutch general practice. A prospective cohort study. AB - BACKGROUND: There is an inherent tension between allowing trainees in general practice (GP) to feel comfortable to report and learn from errors in a blame-free environment while still assuring high-quality and safe patient care. Unfortunately, little is known about the types and potential severity of incidents that may confront GP trainees. Furthermore, incident reporting by resident trainees is hindered by their concern that such transparency might result in more negative performance evaluations. OBJECTIVE: To explore the number and nature of incidents that were reported by GP trainees and to determine whether there were differences between the reporters and non-reporters based on their performance evaluations. DESIGN: Prospective cohort study. METHODS: Confidential and voluntary incident reporting was implemented in GP vocational training of the University Medical Center Utrecht, the Netherlands. Seventy-nine GP trainees were asked to report incidents over 6 months. Mixed methods were used to analyse the data. RESULTS: 24 trainees reported a total of 44 incidents. 23 incidents concerned the work process and 17 concerned problems with diagnosis or therapy. Three-quarters (34/44) of incidents were determined to be not specifically related to the inexperience of the GP trainees. While actual patient harm was determined to be minimal or absent in two-thirds of incidents (29/44), the potential for moderate, major, or catastrophic harm was 89% (39/44). Trainees performing best on their performance assessment in the domain of clinical expertise reported incidents more often (43% vs 18%, p<0.03) than those who performed at a lower level. CONCLUSIONS: GP trainees rated highly by their faculty voluntarily reported incidents in the delivery of clinical care when given a safe, blame-free, and confidential reporting process. Most incidents were not found to be directly related to the inexperience of the trainee, but were caused by failing organisational processes in the healthcare delivery system. Moreover, the trainees who tended to report these incidents were those whose performance was highly evaluated in the domain of clinical expertise. PMID- 21602563 TI - A novel GC-MS method in urinary estrogen analysis from postmenopausal women with osteoporosis. AB - Estrogen metabolites play important roles in the development of female-related disorders and homeostasis of the bone. To improve detectability, a validated gas chromatography-mass spectrometry (GC-MS) method was conducted with two-phase extractive ethoxycarbonlyation (EOC) and subsequent pentafluoropropionyl (PFP) derivatization was introduced. The resulting samples were separated through a high-temperature MXT-1 column within an 8 min run and were detected in the selected ion monitoring (SIM) mode. The optimized analytical conditions led to good separation with a symmetric peak shape for 19 estrogens as their EOC-PFP derivatives. The limit of quantification (LOQ) was from 0.02 to ~0.1 ng/ml for most estrogens analyzed, except for 2-hydroxyestriol (0.5 ng/ml). The devised method was found to be linear (r2 > 0.995) in the range from the LOQ to 40 ng/ml, whereas the precision (% CV) and accuracy (% bias) ranged from 1.4 to 10.5% and from 91.4 to 108.5%, respectively. The good sensitivity and selectivity of this method even allowed quantification of the estrogen metabolites in urine samples obtained from the postmenopausal female patients with osteoporosis. The present technique can be useful for clinical diagnosis as well as to better understand the pathogenesis of estrogen-related disorders in low-level quantification. PMID- 21602564 TI - Rehabilitation after autologous chondrocyte implantation for isolated cartilage defects of the knee. AB - Autologous chondrocyte implantation for treatment of isolated cartilage defects of the knee has become well established. Although various publications report technical modifications, clinical results, and cell-related issues, little is known about appropriate and optimal rehabilitation after autologous chondrocyte implantation. This article reviews the literature on rehabilitation after autologous chondrocyte implantation and presents a rehabilitation protocol that has been developed considering the best available evidence and has been successfully used for several years in a large number of patients who underwent autologous chondrocyte implantation for cartilage defects of the knee. PMID- 21602565 TI - One-year follow-up of platelet-rich plasma treatment in chronic Achilles tendinopathy: a double-blind randomized placebo-controlled trial. AB - BACKGROUND: Achilles tendinopathy is a common disease among both athletes and in the general population in which the use of platelet-rich plasma has recently been increasing. Good evidence for the use of this autologous product in tendinopathy is limited, and data on longer-term results are lacking. PURPOSE: To study the effects of a platelet-rich plasma injection in patients with chronic midportion Achilles tendinopathy at 1-year follow-up. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Fifty-four patients, aged 18 to 70 years, with chronic tendinopathy 2 to 7 cm proximal to the Achilles tendon insertion were randomized to receive either a blinded injection containing platelet-rich plasma or saline (placebo group) in addition to an eccentric training program. The main outcome was the validated Victorian Institute of Sports Assessment Achilles score. Patient satisfaction was recorded and ultrasound examination performed at baseline and follow-up. RESULTS: The mean Victorian Institute of Sports Assessment-Achilles score improved in both the platelet-rich plasma group and the placebo group after 1 year. There was no significant difference in increase between both groups (adjusted between-group difference, 5.5; 95% confidence interval, -4.9 to 15.8, P = .292). In both groups, 59% of the patients were satisfied with the received treatment. Ultrasonographic tendon structure improved significantly in both groups but was not significantly different between groups (adjusted between-group difference, 1.2%; 95% confidence interval, -4.1 to 6.6, P = .647). CONCLUSION: This randomized controlled trial showed no clinical and ultrasonographic superiority of platelet-rich plasma injection over a placebo injection in chronic Achilles tendinopathy at 1 year combined with an eccentric training program. PMID- 21602566 TI - Measurements of tibiofemoral kinematics during soft and stiff drop landings using biplane fluoroscopy. AB - BACKGROUND: Previous laboratory studies of landing have defined landing techniques in terms of soft or stiff landings according to the degree of maximal knee flexion angle attained during the landing phase and the relative magnitude of the ground-reaction force. Current anterior cruciate ligament injury prevention programs are instructing athletes to land softly to avoid excessive strain on the anterior cruciate ligament. PURPOSE: This study was undertaken to measure, describe, and compare tibiofemoral rotations and translations of soft and stiff landings in healthy individuals using biplane fluoroscopy. STUDY DESIGN: Controlled laboratory study. METHODS: The in vivo, lower extremity, 3 dimensional knee kinematics of 16 healthy adults (6 male and 10 female) instructed to land softly and stiffly in different trials were collected in biplane fluoroscopy as they performed the landing from a height of 40 cm. RESULTS: Average and maximum relative anterior tibial translation (average, 2.8 +/- 1.2 mm vs 3.0 +/- 1.4 mm; maximum, 4.7 +/- 1.6 mm vs 4.4 +/- 0.8 mm), internal/external rotation (average, 3.7 degrees +/- 5.1 degrees vs 2.7 degrees +/- 4.3 degrees ; maximum, 5.6 degrees +/- 5.5 degrees vs 4.9 degrees +/- 4.7 degrees ), and varus/valgus (average, 0.2 degrees +/- 1.2 degrees vs 0.2 degrees +/- 1.0 degrees ; maximum, 1.7 degrees +/- 1.2 degrees vs 1.6 degrees +/- 0.9 degrees ) were all similar between soft and stiff landings, respectively. The peak vertical ground-reaction force was significantly larger for stiff landings than for soft landings (2.60 +/- 1.32 body weight vs 1.63 +/- 0.73; P < .001). The knee flexion angle total range of motion from the minimum angle at contact to the maximum angle at peak knee flexion was significantly greater for soft landings than for stiff (55.4 degrees +/- 8.8 degrees vs 36.8 degrees +/- 11.1 degrees ; P < .01). CONCLUSION: Stiff landings, as defined by significantly lower knee flexion angles and significantly greater peak ground-reaction forces, do not result in larger amounts of anterior tibial translation or knee rotation in either varus/valgus or internal/external rotation in healthy individuals. CLINICAL RELEVANCE: In healthy knees, the musculature and soft tissues of the knee are able to maintain translations and rotations within a small, safe range during controlled landing tasks of differing demand. The knee kinematics of this healthy population will serve as a comparison for injured knees in future studies. It should be stressed that because the authors did not compare how the loads were distributed over the soft tissues of the knee between the 2 landing styles, the larger ground-reaction forces and more extended knee position observed during stiff landings should still be considered dangerous to the anterior cruciate ligament and other structures of the lower extremities, particularly in competitive settings where movements are often unanticipated. PMID- 21602567 TI - Anatomic single- and double-bundle anterior cruciate ligament reconstruction, part 2: clinical application of surgical technique. AB - The anterior cruciate ligament has been and is of great interest to scientists and orthopaedic surgeons worldwide. Anterior cruciate ligament reconstruction was initially performed using an open approach. When the approach changed from open to arthroscopic reconstruction, a 2- and, later, 1-incision technique was applied. With time, researchers found that traditional arthroscopic single-bundle reconstruction did not fully restore rotational stability of the knee joint and a more anatomic approach to reconstruct the anterior cruciate ligament has been proposed. Anatomic anterior cruciate ligament reconstruction intends to replicate normal anatomy, restore normal kinematics, and protect long-term knee health. Although double-bundle anterior cruciate ligament reconstruction has been shown to result in better rotational stability in both biomechanical and clinical studies, it is vital to differentiate between anatomic and double-bundle anterior cruciate ligament reconstruction. The latter is merely a step closer to reproducing the native anatomy of the anterior cruciate ligament; however, it can still be done nonanatomically. To evaluate the potential benefits of reconstructing the anterior cruciate ligament in an anatomic fashion, accurate, precise, and reliable outcome measures are needed. These include, for example, T2 magnetic resonance imaging mapping of cartilage and quantification of graft healing on magnetic resonance imaging. Furthermore, there is a need for a consensus on which patient-reported outcome measures should be used to facilitate homogeneous reporting of outcomes. PMID- 21602568 TI - Molecular mechanism of selective recruitment of Syk kinases by the membrane antigen-receptor complex. AB - ZAP-70 and Syk are essential tyrosine kinases in intracellular immunological signaling. Both contain an inhibitory SH2 domain tandem, which assembles onto the catalytic domain. Upon binding to doubly phosphorylated ITAM motifs on activated antigen receptors, the arrangement of the SH2 domains changes. From available structures, this event is not obviously conducive to dissociation of the autoinhibited complex, yet it ultimately translates into kinase activation through a mechanism not yet understood. We present a comprehensive theoretical study of this molecular mechanism, using atomic resolution simulations and free energy calculations, totaling >10 MUs of simulation time. Through these, we dissect the microscopic mechanism coupling stepwise ITAM engagement and SH2 tandem structural change and reveal key differences between ZAP-70 and Syk. Importantly, we show that a subtle conformational bias in the inter-SH2 connector causes ITAM to bind preferentially to kinase-dissociated tandems. We thus propose that phosphorylated antigen receptors selectively recruit kinases that are uninhibited and that the resulting population shift in the membrane vicinity sustains signal transduction. PMID- 21602569 TI - Probing conformational rescue induced by a chemical corrector of F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutant. AB - Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that cause loss of function of the CFTR channel on the apical surface of epithelial cells. The major CF-causing mutation, F508del CFTR, is misfolded, retained in the endoplasmic reticulum, and degraded. Small molecule corrector compounds have been identified using high throughput screens, which partially rescue the trafficking defect of F508del-CFTR, allowing a fraction of the mutant protein to escape endoplasmic reticulum retention and traffic to the plasma membrane, where it exhibits partial function as a cAMP regulated chloride channel. A subset of such corrector compounds binds directly to the mutant protein, prompting the hypothesis that they rescue the biosynthetic defect by inducing improved protein conformation. We tested this hypothesis directly by evaluating the consequences of a corrector compound on the conformation of each nucleotide binding domain (NBD) in the context of the full length mutant protein in limited proteolytic digest studies. Interestingly, we found that VRT-325 was capable of partially restoring compactness in NBD1. However, VRT-325 had no detectable effect on the conformation of the second half of the molecule. In comparison, ablation of the di-arginine sequence, R(553)XR(555) (F508del-KXK-CFTR), modified protease susceptibility of NBD1, NBD2, and the full-length protein. Singly, each intervention led to a partial correction of the processing defect. Together, these interventions restored processing of F508del-CFTR to near wild type. Importantly, however, a defect in NBD1 conformation persisted, as did a defect in channel activation after the combined interventions. Importantly, this defect in channel activation can be fully corrected by the addition of the potentiator, VX-770. PMID- 21602570 TI - Protein structural modularity and robustness are associated with evolvability. AB - Theory suggests that biological modularity and robustness allow for maintenance of fitness under mutational change, and when this change is adaptive, for evolvability. Empirical demonstrations that these traits promote evolvability in nature remain scant however. This is in part because modularity, robustness, and evolvability are difficult to define and measure in real biological systems. Here, we address whether structural modularity and/or robustness confer evolvability at the level of proteins by looking for associations between indices of protein structural modularity, structural robustness, and evolvability. We propose a novel index for protein structural modularity: the number of regular secondary structure elements (helices and strands) divided by the number of residues in the structure. We index protein evolvability as the proportion of sites with evidence of being under positive selection multiplied by the average rate of adaptive evolution at these sites, and we measure this as an average over a phylogeny of 25 mammalian species. We use contact density as an index of protein designability, and thus, structural robustness. We find that protein evolvability is positively associated with structural modularity as well as structural robustness and that the effect of structural modularity on evolvability is independent of the structural robustness index. We interpret these associations to be the result of reduced constraints on amino acid substitutions in highly modular and robust protein structures, which results in faster adaptation through natural selection. PMID- 21602571 TI - Structural and content diversity of mitochondrial genome in beet: a comparative genomic analysis. AB - Despite their monophyletic origin, mitochondrial (mt) genomes of plants and animals have developed contrasted evolutionary paths over time. Animal mt genomes are generally small, compact, and exhibit high mutation rates, whereas plant mt genomes exhibit low mutation rates, little compactness, larger sizes, and highly rearranged structures. We present the (nearly) whole sequences of five new mt genomes in the Beta genus: four from Beta vulgaris and one from B. macrocarpa, a sister species belonging to the same Beta section. We pooled our results with two previously sequenced genomes of B. vulgaris and studied genome diversity at the species level with an emphasis on cytoplasmic male-sterilizing (CMS) genomes. We showed that, contrary to what was previously assumed, all three CMS genomes belong to a single sterile lineage. In addition, the CMSs seem to have undergone an acceleration of the rates of substitution and rearrangement. This study suggests that male sterility emergence might have been favored by faster rates of evolution, unless CMS itself caused faster evolution. PMID- 21602572 TI - Increased polymorphism near low-complexity sequences across the genomes of Plasmodium falciparum isolates. AB - Low-complexity regions (LCRs) within proteins sequences are often considered to evolve neutrally even though recent studies reported evidence for selection acting on some of them. Because of their widespread distribution among eukaryotes genomes and the potential deleterious effect of expansion/contraction of some of them in humans, low-complexity sequences are of major interest and numerous studies have attempted to describe their dynamic between genomes as well as the factors correlated to their variation and to assess their selective value. However, due to the scarcity of individual genomes within a species, most of the analyses so far have been performed at the species level with the implicit assumption that the variation both in composition and size within species is too small relative to the between-species divergence to affect the conclusions of the analysis. Here we used the available genomes of 14 Plasmodium falciparum isolates to assess the relationship between low-complexity sequence variation and factors such as nucleotide polymorphism across strains, sequence composition, and protein expression. We report that more than half of the 7,711 low-complexity sequences found within aligned coding sequences are variable in size among strains. Across strains, we observed an increasing density of polymorphic sites toward the LCR boundaries. This observation strongly suggests the joint effects of lowered selective constraints on low-complexity sequences and a mutagenic effect of these simple sequences. PMID- 21602573 TI - An exploration in health education of an integrated theoretical basis for sexuality education pedagogies for young people. AB - In Health Education, much sexuality education appears to have little evidence of an acknowledged theoretical basis for its knowledge and skills' teaching and learning. The Health Education teacher can frequently be at a loss to decipher what theoretical principles could or should permeate sexuality education curricula, which may be both detracting and distracting from the educational process. This paper explores and analyses a suggested selection of sexuality education pedagogies integrating the theoretical framework of Anderson and Krathwohl and Gardner's Inter-personal Intelligence theories. In response to the earlier maturation of girls and boys, and the concomitant need for better and earlier sexuality education, pedagogies relevant for three age groups, elementary/primary school (7-9 years), middle school (10-12 years) and high school (13-15 years), are identified and analysed as appropriate for these students' cognitive abilities. The integration of these two educational theories has implications for Health Education practitioners, whereby this approach may be useful to assist sexuality educators in identifying and anchoring pedagogies in a more theoretical and structured approach. Providing theoretical starting points, and directions to achieve students' learning goals, may enhance the quality of Health teachers' conceptualizing and planning for implementing quality sexuality education knowledge and skills' teaching and learning. PMID- 21602574 TI - Dyssynchrony, contractile function, and response to cardiac resynchronization therapy. AB - BACKGROUND: Despite benefits of cardiac resynchronization therapy (CRT) in patients with severe but less symptomatic heart failure, approximately 30% of patients do not fully respond to treatment. We hypothesized that a combined assessment of left ventricular (LV) dyssynchrony and contractile function by strain-based imaging would identify patients who would most benefit from CRT. METHODS AND RESULTS: We studied 1077 patients with New York Heart Association class I/II, LV ejection fraction <=30% and QRS width >=130 ms enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial with sufficient echocardiographic image quality for cardiac deformation analysis (implantable cardioverter-defibrillator [ICD], n=416; CRT, n=661). Patients were assigned to CRT plus an ICD or to ICD alone in 3:2 random assignment. We assessed the degree to which baseline echocardiographic assessments of dyssynchrony, measured as the standard deviation of time-to-peak transverse strain over 12 segments, contractile function, measured as global longitudinal strain, or both predicted the effect of treatment on the primary outcome of death or heart failure. With 213 primary events occurring over a mean of 2.4 years, the benefit of CRT plus an ICD relative to ICD alone was greatest in patients with mild to moderate dyssynchrony (time-to-peak transverse strain standard deviation, 142 to 230 ms) and greater baseline contractile function (global longitudinal strain <=-8.7%). Overall, those patients with mild to moderate dyssynchrony and those with best contractile function at baseline demonstrated the greatest benefit from CRT (adjusted hazards ratio, 0.20; 95% confidence interval, 0.09 to 0.44). Dyssynchrony and global longitudinal strain predicted response to CRT independent of each other, QRS width, LV ejection fraction, and presence versus absence of left bundle-branch block, although the observed benefit remained greatest in patients with left bundle-branch block. CONCLUSIONS: Both mechanical dyssynchrony and contractile function are important independent correlates of benefit from CRT. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271. PMID- 21602575 TI - Test-retest reliability of two attention tests in schizophrenia. AB - The Symbol Digit Modalities Test (SDMT) and Digit Vigilance Test (DVT), both well recommended attention tests for schizophrenia, are measures of switching and sustained attention, respectively. The purpose of this study was to investigate the test-retest reliability of the two attention tests in schizophrenia. A rater administered both tests on 147 participants with schizophrenia twice at a 1-week interval. Test-retest reliability was determined through the calculation of the intra-class correlation (ICC) coefficient. We also carried out the Bland-Altman analysis, which include a scatter plot of the differences between test and retest against their mean. System biases were evaluated by use of a paired t-test. The ICC for the SDMT was 0.87 and that for the DVT was 0.83. The limits of agreement (LOAs) of the SDMT and DVT were 11.5 to -9.9 correct responses and 156.3 to 249.2 s, respectively. The mean difference scores of the SDMT and DVT were 1.5 (4.7% of the first session mean; p= .002) and -46.4 (7.6% of the first session mean; p< .001). The ICCs show that the SDMT and DVT are stable measures across assessment in different sessions in schizophrenia. However, the paired t-test indicates a practice effect, and the LOAs show large variations. Thus, the SDMT and DVT are reliable for a group of subjects but limited for individual subjects with schizophrenia in 1-week interval clinical trials. PMID- 21602577 TI - Hip dislocation in spina bifida: when is surgery required and what type of surgery should be performed? AB - Children with spina bifida develop a wide variety of congenital and acquired hip joint deformities. Among these are contractures, subluxation or dislocation. This paper will review both the overall orthopedic care of a spina bifida patient with hip problems and provide a focused review of surgery management of hip deformities. Special emphasis is placed on the indications and contraindications to surgery based on a literature review and the author's personal experience. PMID- 21602578 TI - Surgical treatment of spastic hip dislocation--to treat or not to treat?--My personal experience. AB - Patients with infantile cerebral palsy often develop a typical adduction-, internal rotation- and flexion contracture of the hip, caused by a central disturbance of muscle tone coordination. This deviation leads, when verticalisation and weight-bearing of the child is absent or insufficient, to coxa valga and spastic hip dislocation. In order to prevent or correct this faulty form, soft tissue release operations or bony joint reconstructive procedures of the proximal femur and acetabular roof or, in severely impaired patients, palliative measures can be performed. The indication must be judged critically, especially in patients with total body involvement. In this paper special procedures, performed for a number of years at the Orthopedic Poliklinik of the University of Munich and the Spastiker-Zentrum (Integrationszentrum fur Cerebralparesen ICP) Munchen ("Munich approach") are described, and the important role of surgery is discussed as part of a comprehensive rehabilitation program in patients with cerebral palsy, including sometimes also the decision, not to perform surgery. PMID- 21602576 TI - Pyruvate:ferredoxin oxidoreductase and thioredoxin reductase are involved in 5 nitroimidazole activation while flavin metabolism is linked to 5-nitroimidazole resistance in Giardia lamblia. AB - OBJECTIVES: The mechanism of action of, and resistance to, metronidazole in the anaerobic (or micro-aerotolerant) protozoan parasite Giardia lamblia has long been associated with the reduction of ferredoxin (Fd) by the enzyme pyruvate:ferredoxin oxidoreductase (PFOR) and the subsequent activation of metronidazole by Fd to toxic radical species. Resistance to metronidazole has been associated with down-regulation of PFOR and Fd. The aim of this study was to determine whether the PFOR/Fd couple is the only pathway involved in metronidazole activation in Giardia. METHODS: PFOR and Fd activities were measured in extracts of highly metronidazole-resistant (MTR(r)) lines and activities of recombinant G. lamblia thioredoxin reductase (GlTrxR) and NADPH oxidase were assessed for their involvement in metronidazole activation and resistance. RESULTS: We demonstrated that several lines of highly MTR(r) G. lamblia have fully functional PFOR and Fd indicating that PFOR/Fd-independent mechanisms are involved in metronidazole activation and resistance in these cells. Flavin-dependent GlTrxR, like TrxR of other anaerobic protozoa, reduces 5 nitroimidazole compounds including metronidazole, although expression of TrxR is not decreased in MTR(r) Giardia. However, reduction of flavins is suppressed in highly MTR(r) cells, as evidenced by as much as an 80% decrease in NADPH oxidase flavin mononucleotide reduction activity. This suppression is consistent with generalized impaired flavin metabolism in highly MTR(r) Trichomonas vaginalis. CONCLUSIONS: These data add to the mounting evidence against the dogma that PFOR/Fd is the only couple with a low enough redox potential to reduce metronidazole in anaerobes and point to the multi-factorial nature of metronidazole resistance. PMID- 21602579 TI - Current experience in the treatment of neurogenic deformities of the hip joint in patients with myelomeningocoele. AB - BACKGROUND: The purpose of this study is to present the current approach to and an evaluation of the results of treatment of neurogenic deformities of the hip joints in children with myelomeningocoele (MMC). MATERIAL AND METHODS: The study population consisted of 210 patients with MMC admitted to the Department of Pediatric Orthopaedics and Traumatology in Poznan in the years 1970-2008. The study involved 131 hips (85 patients). The duration of follow-up was 1 to 38 years (mean 17.3 years). The clinical status of patients and treatment results were evaluated with regard to the assignment of the patient to one of 6 groups according to the modified Sharrard and Parsch classification. Radiographic evaluation included the femoral neck angle, anteversion angle, acetabular index, head-acetabular coefficient, centre-edge angle, focusing angle, and Labaziewicz distance angle. The operative treatment in Groups I-II consisted of correction of contractures. In Group III, we performed open reduction of the dislocation or subluxation, Mustard iliopsoas transfer, intertrochanteric femoral osteotomy and Dega's transiliac osteotomy, or shelf procedure. In Group IV patients, we corrected subluxations or dislocations. RESULTS: Surgery in patients from Groups I-II was associated with a high rate of recurrence. In Group III patients, we achieved good joint stability. The transferred iliopsoas muscle was active in 70% of the patients and 65% of the patients in this group became ambulant. More beneficial functional effects were observed after operative treatment in patients from Group IV. CONCLUSIONS: In Groups I-II recurrence of the deformity was often observed. In patients from Groups III-IV, good functional outcomes were noted after comprehensive surgical treatment. PMID- 21602580 TI - Classification of patients with myelodysplasia according to the level of neurosegmental lesion as a basis of motor function assessment. AB - The purpose of this article is to present the current principles of comprehensive assessment and treatment of patients with myelomeningocele. We present the connection between the level of neurosegmental lesion according to modified Sharrard's classification and functional abilities of the patient. We describe lower limbs deformity typically associated with neurosegmental lesions of spina bifida at different levels (I to VI). The classification of neurosegmental lesion levels is based on an evaluation of muscle strength of individual muscle groups according to the Lovett scale. PMID- 21602581 TI - Two-stage surgery in the treatment of spastic hip dislocation--comparison between early and late results of open reduction and derotation-varus femoral osteotomy combined with Dega pelvic osteotomy preceded by soft tissue release. AB - BACKGROUND: Authors present and compare early and late results of treatment of spastic hip dislocation in cerebral palsy patients. MATERIAL AND METHODS: We analyzed a group of 77 patients (109 hips) with hip joint dislocation (MP>80%). The patients were divided into two groups: <3 years of follow-up vs. > 3 years of follow-up. The first group thus included 64 hips (47 patients) with mean follow up duration of 2.2 years (range 1.1-3), and the second group had 45 hips (30 patients) with mean follow-up duration of 4.8 years (range 3.2-10.2). The hips were evaluated clinically and radiographically. The relation of the femoral head to the acetabulum was described as the Acetabular Index (AI) and Reimers' migration percentage (MP). RESULTS: In Group I, AI improved from 32.2 degrees (17 degrees -50 degrees ) to 22.2 degrees (6 degrees -45 degrees ), MP improved from 98.9% (82%-100%) to 15.9% (0%- 100%). In Group II, AI improved from 28.9 degrees (10 degrees -62 degrees ) to 19.4 degrees (3 degrees -50 degrees ). The changes in AI and MP were statistically significant. Group I demonstrated a reduction in the flexion contracture from 21.1 degrees (0 degrees -50 degrees ) to 10.7 degrees (0 degrees -30 degrees ), an increase in abduction from 19.5 degrees (0 degrees -60 degrees ) to 29.9 degrees (0 degrees -60 degrees ), and a decrease in the popliteal angle from 52.0 degrees (0 degrees -100 degrees ) to 34.2 degrees (0 degrees -85 degrees ). Group II showed a reduction in the flexion contracture from 24.6 degrees (0 degrees -60 degrees ) to 12.6 degrees (0 degrees -40 degrees ), an increase in abduction from 17.3 degrees (-25 degrees 80 degrees ) to 26.1 degrees (-15 degrees -80 degrees ), and a decrease in the popliteal angle from 61.4 degrees (0 degrees -120 degrees ) to 40.7 degrees (10 degrees -100 degrees ). These improvements were statistically significant. CONCLUSION: Open reduction of the hip joint combined with derotation-varus femoral osteotomy and Dega pelvic osteotomy is a very effective treatment in spastic hip joint dislocation. We observed no statistically significant deterioration of results between the groups. PMID- 21602582 TI - Evaluation of adductor myotomy versus adductor transfer to ischiadic tuber in the treatment of spastic hip in cerebral palsy. AB - BACKGROUND: The muscle imbalance associated with the spastic type of infantile cerebral palsy may result in subluxations or dislocations of the hip. The aim of the study was to compare the clinical and radiological results of myotomy of the hip adductor muscles versus adductor transfer to the ischiadic tuber in the prevention of hip subluxation and dislocation in infantile cerebral palsy. MATERIAL AND METHODS: The study involved 36 ambulant children with spastic diparetic CP treated at our Department in the years 1987-2002. Group I consisted of 21 children (41 hip joints) who underwent myotomy of the adductor longus, adductor brevis and gracilis muscles. Mean age at the time of surgery was 10 years (3 to 17 years). Group II consisted of 15 children (28 hip joints) who underwent transfer of the tendons of the adductor muscles to the ischiadic tuber. Mean age at the time of surgery in this group was 8 years (3 to 16 years). The mean duration of hospital stay was 6 days in Group I and 9 days in Group II. Rehabilitation was carried out for an average of 3 months in Group I and 4 months in Group II. RESULTS: The follow-up examination showed improvement in the hip range of motion in both groups and no radiographic differences. CONCLUSIONS: Adductor myotomy is superior to adductor transfer because of easier surgical technique, shorter duration of hospital stay and no need to immobilize the hip. PMID- 21602583 TI - Unilateral and bilateral neurogenic dislocation of the hip joint--which deformity is more difficult to treat? AB - BACKGROUND: Authors present and compare the results of treatment of spastic hip dislocation in a group of patients with unilateral or bilateral dislocation. MATERIAL AND METHODS: We analyzed a group of 77 patients (109 hips) with a dislocated hip joint (MP>80%). The patients were divided into Group 1 (47 hip joints, 47 patients) with unilateral dislocation and Group 2 (62 hips, 31 patients) with bilateral dislocation. The mean duration of follow-up was 2.5 years (range 1.2-7.5) in Group 1 and 3.4 years (1.2-10.2) in Group 2. The hips were evaluated clinically and radiographically in the pre- and post-operative period. The relation of the femoral head to the acetabulum was described as the Acetabular Index (AI) and Reimers' migration percentage (MP). The Pelvic Femoral Angle (PFA) was used to measure the degree of windblown deformity. RESULTS: There were three cases of post-operative redislocation (MP>80%) and four cases of severe subluxation (MP>50%) in Group 1 compared to no dislocations in Group 2. In Group 1, AI improved from 31.3 degrees (20 degrees -50 degrees ) to 22.7 degrees (3 degrees -50 degrees ) and MP improved from 98.8% (85%-100%) to 23.4% (0% 100%). In Group 2, AI improved from 30.5 degrees (10 degrees -62 degrees ) to 19.9 degrees (4 degrees -40 degrees ) and MP improved from 98.8% (82%-100%) to 9.6% (0%-60%). In Group 1, PFA before surgery was -10.3 degrees (-40 degrees to 10 degrees ) for the dislocated side and 6.6 degrees (-16 degrees to 55 degrees ) for the non-dislocated side and after surgery it was -5.7 degrees (-46 to 45) for the treated side and 5.6 degrees (-18 degrees to 45 degrees ) for the untreated side. In Group 2, PFA was -3.1 degrees (-22 degrees to 9 degrees ) before surgery and -0.15 degrees (-18 degrees to 25 degrees ) after surgery. We found improved ranges of motion for the movements investigated. CONCLUSION: The clinical and radiological results of operative treatment presented in this paper allow for the conclusion that patients with unilateral dislocations run a higher risk of redislocation, subluxation, and windblown deformity. PMID- 21602584 TI - Changes in the hip migration percentage and motor function in patients with cerebral palsy treated surgically by multilevel soft tissue release--preliminary report. AB - BACKGROUND: Disturbed muscle balance secondary to upper motor neuron damage in the course of infantile cerebral palsy (ICP) leads to the development of progressive morphological changes in joints, especially the hip. We analysed changes in Reimers' index (hip migration percentage - MP), and functional ability in CP children after multilevel soft tissue release. MATERIAL AND METHODS: We studied 22 patients with cerebral palsy following one-stage multilevel soft tissue release. The children were examined twice: one day before the surgery and at least 6 months (a mean of 9 months) after the procedure. Hip stability was evaluated radiographically using Reimers' index. Post-operative functional changes were analysed with the Gross Motor Function Measure-88 scale (GMFM-88). RESULTS: Reimers' index decreased post-operatively in 20 right and 18 left hips and increased in 2 right and 4 left hips. Functional ability according to the GMFM scale increased in 17 children (by a mean of 7.1%), did not change in 3 patients with near-maximum pre-operative scores, and worsened in 2 patients. CONCLUSIONS: Our study showed that, when performed for appropriate indications, multilevel soft tissue release surgery can improve hip stability and functional ability in CP children. PMID- 21602585 TI - Effectiveness of two methods of treatment of the spastic hip in CP children. AB - BACKGROUND: Authors analysed the post-operative course of the hip joints in ICP children following two types of surgery. MATERIAL AND METHODS: We analysed 50 children with CP (100 hips) treated in our department between 1999-2004 whose radiological records were complete. The children were divided into 2 groups of those following open adductor tenotomy and those treated according to Gob's method, i.e. by release of the flexion-adduction hip contracture. Hip joint stability was compared radiologically with the Reimers index. Consecutive radiographs were obtained at least 6 months apart and at least two radiographs were obtained in each patient. RESULTS: In the first group, the Reimers index improved in 56 hips (70%), deteriorated in 14 hips (17.5%), and did not change in 10 hips (12.5%). In the second group, the index improved in 6 hips (30%), deteriorated in 4 hips (20%), and did not change in 10 hips (50%). CONCLUSIONS: 1. Open adductor tenotomy may be an effective treatment for hip joint instability in cerebrally palsied children. 2. Continual monitoring of the Reimers index is a prerequisite for predicting the natural history of the spastic hip. PMID- 21602586 TI - Basic mechanisms of antiepileptic drugs and their pharmacokinetic/pharmacodynamic interactions: an update. AB - This article aims to summarize the current views of AED action and the promising new targets for the pharmacotherapy of epilepsy. In the first section of this paper, a neurobiological basis of epilepsy treatment and brief pharmacological characteristics of classical and new AEDs will be presented. In the second part, the results of experimental studies that have combined AEDs with similar or different mechanisms of action will be discussed. PMID- 21602587 TI - Pharmocoepigenetics: a new approach to predicting individual drug responses and targeting new drugs. AB - Epigenetics is the study of heritable changes in genes and gene expression that do not involve DNA nucleotide sequences. Epigenetic modifications include DNA methylation, several forms of histone modifications, and microRNA expression. Because of its dynamic nature, epigenetics provides a link between the genome and the environment and fills the gap between DNA and proteins. Advances in epigenetics and epigenomics (the study of epigenetics on a genome-wide basis) have influenced pharmacology, leading to the development of a new specialty, pharmacoepigenetics, the study of the epigenetic basis for variations in drug response. Many genes encoding enzymes, drug transporters, nuclear receptors, and drug targets are under epigenetic control. This review describes the known epigenetic regulation of drug-metabolizing enzymes and other proteins that might affect drug response and compounds that modify the epigenetic status. PMID- 21602588 TI - Natural and synthetic acridines/acridones as antitumor agents: their biological activities and methods of synthesis. AB - Acridine derivatives constitute a class of compounds that are being intensively studied as potential anticancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is limited or even excluded because of side effects. Numerous synthetic methods are focused on the preparation of target acridine skeletons or modifications of naturally occurring compounds, such as acridone alkaloids, that exhibit promising anticancer activities. They have been examined in vitro and in vivo to test their importance for cancer treatment and to establish the mechanism of action at both the molecular and cellular level, which is necessary for the optimization of their properties so that they are suitable in chemotherapy. In this article, we review natural and synthetic acridine/acridone analogs, their application as anticancer drugs and methods for their preparation. PMID- 21602589 TI - Therapeutic potential of the biscoclaurine alkaloid, cepharanthine, for a range of clinical conditions. AB - Cepharanthine (CEP) is a naturally occurring alkaloid extracted from the plant Stephania cepharantha Hayata. It has been widely used in Japan for more than 40 years to treat a wide variety of acute and chronic diseases. CEP inhibits tumor necrosis factor (TNF)-alpha-mediated NFkappaB stimulation, plasma membrane lipid peroxidation and platelet aggregation and suppresses cytokine production. It has also been shown to scavenge free radicals and to have a protective effect against some of the responses mediated by pro-inflammatory cytokines such as TNF-alpha, interleukin (IL)-1beta and IL6. CEP has successfully been used to treat a diverse range of medical conditions, including radiation-induced leukopenia, idiopathic thrombocytopenic purpura, alopecia areata, alopecia pityrodes, venomous snakebites, xerostomia, sarcoidosis, refractory anemia and various cancer-related conditions. No safety issues have been observed with CEP, and side effects are very rarely reported. PMID- 21602590 TI - Functional changes in transcriptomes of the prefrontal cortex and hippocampus in a mouse model of anxiety. AB - Anxiety is a multi-etiology disorder influenced by both genetic background and environment. To study the impact of a genetic predisposition, we developed a novel mouse model of anxiety using a combination of crossbreeding and behavioral selection. Comparison of the transcriptomes from the prefrontal cortex and hippocampus of anxious and control mice revealed that the numbers of significantly up- and down-regulated genes were modest, comprising approximately 2% of the tested genes. Functional analysis of the significantly altered gene sets showed that functional groups such as nervous system development, behavior, glial cell differentiation and synaptic transmission were significantly enriched among the up-regulated genes, whereas functional groups such as potassium ion transport, Wnt signaling and neuropeptidergic signaling were significantly enriched among the down-regulated genes. Many of the identified genes and functional groups have been previously linked to the molecular biology of anxiety, while several others, such as transthyretin, vasoactive intestinal polypeptide and various potassium ion channels, are novel or not as well described in this context. Supporting the gene expression data, we also found increased excitability in the hippocampi of anxious mice, which can be a phenotypic result of decreased potassium channel density. Our transcriptome screen showed that the initiation and/or effect of anxiety involve multiple pathways and cellular processes. The identified novel genes and pathways could be involved in the molecular pathogenesis of anxiety and provide potential targets for further drug development. PMID- 21602591 TI - Effects of bupropion on the reinstatement of nicotine-induced conditioned place preference by drug priming in rats. AB - Nicotine is one of the most widely consumed psychoactive drugs, and its consumption is currently associated with other drugs of abuse, such as opioids. The aim of the present study was to evaluate the efficacy of the atypical antidepressant drug bupropion (5, 10 and 20 mg/kg, ip) in blocking the reinstatement of nicotine-induced conditioned place preference (CPP) provoked by nicotine and morphine. It was shown that nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.175 mg/kg, ip, free base, three drug sessions). Once established, nicotine-induced CPP was extinguished by repeated testing. Following this extinction phase, the reinstatement of CPP was investigated. Nicotine-experienced rats were challenged with nicotine (0.175 mg/kg, ip) or morphine (10 mg/kg, ip). These priming injections of both drugs induced a marked preference for the compartment previously paired with nicotine. Our results demonstrated that bupropion (10 and 20 mg/kg) attenuated the nicotine-induced reinstatement of nicotine-conditioned response. Moreover, bupropion (5 and 10 mg/kg) diminished the morphine-induced reinstatement of nicotine-conditioned response. The results of our studies suggest that bupropion may offer an interesting approach to the relapse-prevention pharmacotherapy of addiction, including nicotinism and polydrug abuse. PMID- 21602592 TI - Concomitant use of carbamazepine and olanzapine and the effect on some behavioral functions in rats. AB - As shown in clinical studies, combinations of first generation normothymics (carbamazepine - CBZ) with atypical neuroleptics (olanzapine - OLA) lead to improvements in approximately half of patients treated for relapses of bipolar affective disease. Our previous studies have shown OLA to have an antidepressant effect when administered at a dose of 0.5 mg/kg only upon single administration; the effect did not last throughout chronic administration, whereas CBZ administered at a dose of 30 mg/kg showed an antidepressant effect only after 7 days of administration. As shown in our previous studies, both OLA and CBZ improve memory in rats but only after chronic administration. The improved antidepressant effect of many drugs, including OLA and CBZ used in combined therapy - as observed in our clinic - as well as confirmed evidence of OLA's and CBZ's positive effects on cognitive functions in humans and animals substantiated commencement of research on defining the effect of combined administration of OLA and CBZ on sedation (tested in a locomotor activity test), antidepressant effect (Porsolt test) and spatial memory (Morris test) in animals. The tests were performed on male Wistar rats. It was found that in combined administration of CBZ and OLA for 7 and 14 days, OLA would completely prevent the CBZ's sedative effect. With combined administration of CBZ and OLA, both as a single dose and after prolonged treatment for 7 days, a significant reduction in immobility time was observed. Combined administration of CBZ and OLA did not improve memory in rats that received these drugs in a single dose, whereas statistically significant differences were observed in the chronic experiments. It can be assumed that the observed effects of combined administration of CBZ and OLA may be due to the pharmacokinetic interactions, but further studies are necessary to confirm these assumptions. PMID- 21602593 TI - Increases in beta-amyloid protein in the hippocampus caused by diabetic metabolic disorder are blocked by minocycline through inhibition of NF-kappaB pathway activation. AB - Activation of the NF-kappaB pathway plays an important role in the pathophysiology of Alzheimer's disease (AD), and blocking NF-kappaB pathway activation has been shown to attenuate cognitive impairment. Diabetic metabolic disorder contributes to beta-amyloid protein (Abeta) generation. The goal of this study was to determine the effect of minocycline on Abeta generation and the NF kappaB pathway in the hippocampus of diabetic rats and to elucidate the neuroprotective mechanisms of minocycline for the treatment of diabetic metabolic disorder. The diabetic rat model was established using a high-fat diet and an intraperitoneal injection of streptozocin (STZ). Behavioral tests showed that the capacity of learning and memory was significantly lower in diabetic rats. The levels of NF-kappaB, COX-2, iNOS, IL-1beta and TNF-alpha after the STZ injection were significantly increased in the hippocampus. Significant increases in Abeta, BACE1, NF-kappaB, COX-2, iNOS, IL-1beta and TNF-alpha were found in diabetic rats. The levels of Abeta, NF-kappaB, COX-2, iNOS, IL-1beta and TNF-alpha were significantly decreased after minocycline administration; however, minocycline had no effect on BACE1 expression. In sum, diabetes contributes to the activation of the NF-kappaB pathway and upregulates BACE1 and Abeta. Minocycline downregulates Abeta in the hippocampus by inhibiting NF-kappaB pathway activation. PMID- 21602594 TI - Immunosuppressant cytoprotection correlates with HMGB1 suppression in primary astrocyte cultures exposed to combined oxygen-glucose deprivation. AB - The protective potential of immunosuppressants has been reported in many experimental models of ischemia both in vivo and in vitro, suggesting a novel therapeutic application of these drugs. Because high-mobility group box 1 (HMGB1) protein has recently been reported to be involved in ischemic brain injury, the purpose of the present study was to determine whether treatment with immunosuppressants could decrease the expression and release of HMGB1 in astrocytes exposed to simulated ischemic conditions (combined oxygen-glucose deprivation, OGD). We also investigated whether immunosuppressive drugs could attenuate necrosis in astrocyte cultures exposed to OGD. Finally, we studied the influence of immunosuppressants on the expression of NFkappaB, inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Cells were treated with cyclosporine A, FK506 and rapamycin (all drugs at concentrations of 0.1, 1 and 10 MUM). Our study provides evidence that immunosuppressants decrease the expression and release of HMGB1 in ischemic astrocytes. Our data suggest that HMGB1 release may be partly an active process triggered by oxidative stress because the antioxidant N-acetylcysteine (NAC) clearly attenuated HMGB1 expression and release. Furthermore, we show that the immunosuppressants, at the same concentrations that significantly suppressed HMGB1 expression and release, were also able to prevent the necrosis of ischemic astrocytes and inhibit the expression of inflammatory mediators (NFkappa, iNOS and COX-2). These results provide further information about the cytoprotective mechanisms of immunosuppressants on ischemic astrocytes, especially in relation to the pathophysiology of ischemic brain injury. It appears that the protective effects of immunosuppressants can be mediated in part by the suppressing the expression and release of HMGB1 in astrocytes, which leads to the attenuation of ischemia induced necrosis and neuroinflammation. PMID- 21602595 TI - Kinetic studies of the effects of Temodal and quercetin on astrocytoma cells. AB - The aim of the present study was to investigate the kinetics of the effects exerted by Temodal and quercetin on the survival of the human astrocytoma MOGGCCM cell line. Our results indicate that quercetin was toxic and induced necrosis, whereas Temodal induced autophagy-mediated cell death most effectively. The amount of cell death directly correlated with drug concentration and length of exposure. During combined administration of both drugs, Temodal attenuated the cytotoxic effects of quercetin. Combinations of both drugs were effective in inducing programmed cell death, but the type of cell death was concentration dependent. Co-administration of Temodal (100 MUM) with a low quercetin concentration (5 MUM) resulted in a very significant induction of autophagy; however, after treatment with quercetin at a higher concentration (30 MUM), apoptosis became the primary mechanism of cell death. The sequence of drug administration was also important. The highest number of dead cells was observed after simultaneous administration of both drugs or after pre-incubation with Temodal followed by treatment with quercetin. Apoptosis was identified through activation of the mitochondrial pathway including cleavage of caspase-3 and release of cytochrome c. Autophagy was identified through increased levels of LC3II. Our results indicate that Temodal and quercetin are synergistic inducers of programmed cell death, better together than applied separately. This drug combination appears to be a potent and promising therapeutic relevant to the treatment of gliomas. PMID- 21602596 TI - Effects of norepinephrine on the electrical activities of pain-related neurons in the rat nucleus accumbens. AB - This study examined the effects of norepinephrine (NE) and phentolamine on the electrical activities of pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the nucleus accumbens (NAc) of Wistar rats. Trains of electric pulses applied to the right sciatic nerve were used to provide noxious stimulation, and the discharges of PENs and PINs were recorded using a glass microelectrode. Our results revealed that in response to noxious stimulation, NE decreases the evoked discharge frequency of PENs and increases the evoked discharge frequency of PINs in the NAc of healthy rats, whereas phentolamine produced opposite responses. These results demonstrate that NE is involved in the modulation of nociceptive information transmission in the NAc. PMID- 21602597 TI - Interaction between histamine and morphine at the level of the hippocampus in the formalin-induced orofacial pain in rats. AB - The present study explored the interaction between histaminergic and opioidergic systems at the level of the hippocampus in modulation of orofacial pain by intra hippocampal microinjections of histamine, pyrilamine (an antagonist of histamine H(1) receptors), ranitidine (an antagonist of histamine H(2) receptors), morphine (an opioid receptor agonist) and naloxone (an opioid receptor antagonist) in separate and combined treatments. Orofacial pain was induced by subcutaneous (sc) injection of formalin (50 MUl, 1%) in the upper lip region and the time spent face rubbing was recorded in 3 min blocks for 45 min. Formalin (sc) produced a marked biphasic (first phase: 0-3 min, second phase: 15-33 min) pain response. Histamine and morphine suppressed both phases of pain. Histamine increased morphine-induced antinociception. Pyrilamine and ranitidine had no effects when used alone, whereas pretreatments with pyrilamine and ranitidine prevented histamine- and morphine-induced antinociceptive effects. Naloxone alone non significantly increased pain intensity and inhibited the antinociceptive effects of morphine and histamine. The results of the present study indicate that at the level of the hippocampus, histamine through its H(1) and H(2) receptors, mediates orofacial region pain. Moreover, morphine via a naloxone-reversible mechanism produces analgesia. In addition, both histamine H(1) and H(2) receptors, as well as opioid receptors may be involved in the interaction between histamine and morphine in producing analgesia. PMID- 21602598 TI - Synergism between dexketoprofen and meloxicam in an orofacial formalin test was not modified by opioid antagonists. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs for the management of acute and chronic pain. The role of the opioid system in the synergism between NSAIDs is not well characterized. Mice were injected with a 5% formalin solution (20 MUl) into the upper right lip to perform an orofacial formalin test. The isobolographic method was used to determine the interaction between dexketoprofen, which is the (S)-(+) enantiomer of ketoprofen, and meloxicam co-administration. Additionally, the non-selective, opioid antagonist naltrexone, the selective delta opioid receptor (DOP) antagonist naltrindole and the selective kappa opioid receptor (KOP) antagonist norbinaltorphimine were used to assess the opioid effects on this interaction. Intraperitoneal administration of dexketoprofen or meloxicam induced dose dependent antinociception with different phase I and phase II potencies in the orofacial formalin test. Meloxicam displayed similar potencies (ED(50)) in phase I (7.20 mg/kg) and phase II (8.60 mg/kg). Dexketoprofen was more potent in phase I (19.96 mg/kg) than in phase II (50.90 mg/kg). The interactions between dexketoprofen and meloxicam were synergistic in both phases. This was determined based on the fixed ratios (1:1) of their ED(50) values, which were determined by isobolographic analysis. Furthermore, this antinociceptive activity does not seem to be modulated by opioid receptor blockers because they did not induce changes in the nature of this interaction. This finding may be relevant with regards to NSAID multi-modal analgesia where an opioid antagonist must be used. PMID- 21602599 TI - Impact of fluoxetine on liver damage in rats. AB - Fluoxetine (Flux) is a fluorine-containing drug that selectively inhibits serotonin reuptake. It is widely prescribed as a treatment for depression disorders. Hepatic side effects have been reported during Flux therapy. These reports led us to investigate the involvement of oxidative stress mechanisms in liver injury caused by Flux. It has been shown that exposure to fluoride (F(-)) induces excessive production of free radicals and affects the antioxidant defense system. Based on this knowledge, we examined the F(-) concentration in serum and urine during administration of Flux. In our study, the effects of one month of Flux treatment on lipid and protein peroxidation, the concentration of uric acid in the liver and the activity of transaminases and transferases in the serum were investigated in rats. Eighteen adult male Wistar rats were divided into three equal groups of six animals each: (I) controls who drank tap water and received 1 ml of tap water intragastrically; (II) animals that received 8 mg Flux/kg bw/day intragastrically; and (III) animals that received 24 mg Flux/kg bw/day intragastrically. Flux treatment increased of the levels of carbonyl groups, thiobarbituric acid reactive species (TBARS) and the uric acid content in the liver. The activities of alanine transaminase (ALT), aspartate transaminase (AST) and glutathione-S transferase (GST) increased in the serum of the treated groups. The Flux levels in the plasma of the treated rats increased significantly in a dose-dependent manner. We observed no changes in the concentration of fluoride in either the serum or the urine of treated rats compared to the control group. In conclusion, our study indicates that Flux induces liver damage and mediates free radical reactions. Our data also indicate that Flux does not release F(-) during metabolism and does not affect physiological levels of F(-) in the serum or urine. PMID- 21602600 TI - Vasopressor and heart rate responses to systemic administration of bombesin in anesthetized rats. AB - The aim of the present study was to investigate the effects of aortic depressor nerve (ADN) transection, supranodosal vagi denervation (NG vagi cut) and adrenergic receptor blocker treatment on the cardiovascular responses evoked by systemic injection of bombesin. The cardiovascular effects were studied in spontaneously breathing rats that were (i) bilaterally, midcervically vagotomized (MC vagi cut) and subjected to section of the aortic depressor nerves, (ii) midcervically vagotomized and subsequently vagotomized at the supranodosal level or (iii) midcervically vagotomized before and after pharmacological blockade of alpha- or beta-adrenergic receptors with phentolamine and propranolol, respectively. An intravenous bolus of bombesin (10 MUg/kg) in midcervically vagotomized and ADN denervated animals increased mean arterial blood pressure (MAP) and heart rate (HR). An approximate 20% increase in blood pressure occurred immediately following bombesin injection and lasted for 2-3 min. Augmentation of the heart rate occurred 30-60 s after the bombesin challenge and persisted for more than 10 min. After section of the supranodosal vagi, bombesin failed to induce an increase in heart rate. Blockade of alpha-adrenergic receptors with an intravenous dose of phentolamine significantly reduced post-bombesin hypertension. These results indicate that bombesin-evoked increases in blood pressure do not require aortic depressor nerves and supranodosal vagi and are presumably mediated by the activation of peripheral alpha-adrenergic receptors. Bombesin-induced tachycardia was dependent on an intact supranodose pathway and was amplified by activation of beta-adrenoceptors. PMID- 21602601 TI - Antiarrhythmic and hypotensive activities of 1-[2-hydroxy-3-(4-phenyl-1 piperazinyl)propyl]-pyrrolidin-2-one (MG-1(R,S)) and its enantiomers. AB - The compound MG-1(R,S), (1-[2-hydroxy-3(4-phenyl-1-piperazinyl)propyl]-pyrrolidin 2-one, and its enantiomers were tested for electrocardiographic, antiarrhythmic and hypotensive activities. The racemic mixture (MG-1(R,S)) and its S-enantiomer significantly decreased systolic and diastolic blood pressure and possessed antiarrhythmic activity. The S-enantiomer displayed the greatest effect. The R enantiomer did not show antiarrhythmic or hypotensive activity. The results suggest that the antiarrhythmic and hypotensive effects of these compounds are related to their adrenolytic properties. PMID- 21602602 TI - Modified C-reactive protein interacts with platelet glycoprotein Ibalpha. AB - Herein, we investigated the possible mechanisms by which recombinant modified CRP(m(r)CRP) modulates blood platelet function. Modified CRP could activate blood platelets and stimulate their adhesion and aggregation in the absence of any other physiological stimuli. Preincubation of isolated blood platelets with m(r)CRP at a concentration as low as 2 MUg/ml resulted in significant platelet degranulation (fraction of CD62-positive platelets increased 2-fold, p < 0.0002), and at concentrations of 20 MUg/ml and 100 MUg/ml, increased exposure of the platelet procoagulant surface was observed (expression of annexin V-positive platelets increased to 5.7 +/- 1.0% and 10.4 +/- 2.2%, respectively, p < 0.03, vs. 2.9 +/- 0.2% in control). Furthermore, m(r)CRP (100 MUg/ml) strongly augmented spontaneous and ADP-induced fibrinogen binding to platelets (p < 0.05), platelet adhesion to fibrinogen and platelet aggregation. Using the BiacoreTM surface plasmon resonance technique and glycoprotein Ibalpha (GPIbalpha) immobilized on the sensor surface, we demonstrated direct binding between platelet GPIbalpha and m(r)CRP. Binding of m(r)CRP to GPIbalpha and C1q was also observed by ELISA, irrespective of the immobilized ligand. These outcomes strongly support a role of the GPIb-IX-V complex in the interactions of m(r)CRP with blood platelets. PMID- 21602603 TI - Structure-cardiovascular activity relationships in a group of new 8-alkylamino 1,3-dimethyl-7-(2-hydroxy-3-aminopropyl)-3,7-dihydro-1H-purine-2,6-diones. AB - On the basis of our earlier studies in a group of 7,8-disubstituted derivatives of 1,3-dimetyl-3,7-dihydropurine-2,6-dione, a series of new 8-alkylamino-1,3 dimethyl-7-(2-hydroxy-3-aminopropyl)-3,7-dihydropurine-2,6-diones (8-15) were synthesized and tested for their electrocardiographic, antiarrhythmic and hypotensive activity and for alpha(1)- and alpha(2)-adrenoreceptor affinities. Among the new derivatives, compounds with the 7-[2-hydroxy-3-(4-phenylpiperazine) propyl] substituent (9-11) displayed prophylactic antiarrhythmic activity in epinephrine-induced arrhythmia. Analogue 10 with the 8-(2-morpholin-4-yl) ethylamino group was the most active (ED(50) = 3.9 mg/kg and TI = 59.8), which may indicate that this substituent is preferably important for the antiarrhythmic effect. Only compound 11 with the 8-(2-diethylamino)-ethylamino group significantly decreased the systolic (20.4-28.1%) and diastolic (23.4-33.2%) pressure, but this effect lasted for only 1-5 min. The pharmacologically active compounds 9-11 with the phenylpiperazine moiety showed affinity for alpha(1) receptors (K(i) = 0.143-0.383 MUM), but the other compounds were almost (12-15) or completely (8) inactive at this site. Compounds 9-11 and 13-15 displayed moderate to low affinity for alpha(2)-receptors (K(i) = 0.36-2.7 MUM). PMID- 21602604 TI - Insulin suppresses the expression and function of breast cancer resistance protein in primary cultures of rat brain microvessel endothelial cells. AB - The aim of this study was to investigate the role of insulin in the regulation of breast cancer resistance protein (BCRP) function and expression using primary cultured rat brain microvessel endothelial cells (rBMECs) as an in vitro model of the blood brain barrier (BBB). The prazosin uptake assay and western blot analysis were used to assess the function and expression of BCRP, respectively. It was noted that the uptake of prazosin by rBMECs was time-, concentration- and temperature-dependent. The BCRP inhibitors novobiocin and imatinib mesylate significantly increased the uptake of prazosin by the cells in a concentration dependent manner. The cells were also incubated with sera from diabetic rats for 72 h, serving as a diabetic in vitro model. We found that the uptake of prazosin by rBMECs incubated in the diabetic rat sera was 39.8% of that in normal rat sera, and insulin treatment reversed this decrease. Further results showed that insulin down-regulated the function and expression of BCRP in rBMECs in a concentration-dependent manner. Treatment with an antibody against the insulin receptor abolished the down-regulation of BCRP function and expression that was induced by insulin. These results indicate that insulin suppressed the function and expression of BCRPs in rBMEC primary cultures. PMID- 21602605 TI - Protective effects of endothelin-A receptor antagonist BQ123 against LPS-induced oxidative stress in lungs. AB - The aim of this study was to assess whether endothelin-A receptor (ET(A)-R) blocker, BQ123, influences lung edema, lipid peroxidation TBARS), hydrogen peroxide (H(2)O(2)), TNF-alpha concentration or the glutathione redox system in the lung homogenates obtained from LPS-induced endotoxic shock rats. The study was performed on male Wistar rats (n = 6 per group) divided into groups: (1) saline, (2) LPS (15 mg/kg)-saline, (3) BQ123 (0.5 mg/kg)-LPS, (4) BQ123 (1 mg/kg) LPS. The ET(A)-R antagonist was injected intravenously 30 min before LPS administration. Five hours after saline or LPS administration, animals were sacrificed and lungs were isolated for indices of lung edema, oxidative stress and TNF-alpha concentration. Injection of LPS alone resulted in lung edema development and a marked increase in TNF-alpha (p < 0.02), TBARS (p < 0.02), and H(2)O(2) (p < 0.01) concentrations as well as a depletion of total glutathione (p < 0.01). Administration of BQ123 (1 mg/kg), before LPS challenge, led to a significant reduction in TNF-alpha and H(2)O(2) concentrations (p < 0.05) and elevation of both total glutathione and the GSH/GSSG ratio (p < 0.05). However, it did not prevent LPS-induced TBARS increase and lung edema formation. Interestingly, a lower dose of BQ123 was much more effective in decreasing H(2)O(2), TBARS, as well as TNF-alpha levels (p < 0.02, p < 0.05, p < 0.05, respectively). That dose was also effective in prevention of lung edema development (p < 0.01). Taken together, the obtained results indicate that BQ123 is highly effective in decreasing LPS-induced oxidative stress in lungs. Moreover, the dose of 0.5 mg/kg of the antagonist showed to be more effective in decreasing free radical generation and lung edema in endotoxemic rats. PMID- 21602606 TI - Estimation of the action of three different mechlorethamine doses on biochemical parameters during experimentally induced pleuritis in rats. AB - Nitrogranulogen (NTG) may modify the character of inflammatory reactions. These modifications are a result of cytotoxic and mutagenic effects. NTG has high affinity to DNA and causes disorders in the synthesis of acute phase proteins (e.g., haptoglobin, transferrin, fibrinogen, and complement protein C3). Our previous studies have shown that small doses of NTG can enhance immunological defense reactions in the organism. The aim of the current studies was to determine how different NTG doses cause changes in the values of biochemical parameters in pleuritis-induced rats. The animals were randomized into five groups: Group I - control group; Group II - IP (induced pleuritis) group; Group III - NTG5 group; Group IV - NTG50 group; Group V - NTG600 group. Blood was collected from all groups of animals at 24, 48, and 72 h after the initiation of the carrageenin-induced inflammatory reaction. These investigations revealed that a dose of 5 MUg NTG/kg b.w. (body weight) can change the character of the inflammation. Our studies also show that a dose of 600 MUg NTG/kg b.w. causes a rapid decrease in the level of C3 at the 72 h of the experiment (after 3 applications every 24 h), which indicates a cytotoxic action of such a large NTG dose. NTG used at doses of 50 and 600 MUg/kg b.w. causes the opposite metabolism of albumins and other serum proteins. Our studies show that the different doses of NTG have distinct effects on the inflammatory reaction. PMID- 21602607 TI - Antiulcerative effect of dexmedetomidine on indomethacin-induced gastric ulcer in rats. AB - A gastroprotective effect occurs when alpha(2) receptors are innervated. The dextro isomer of medetomidine, dexmedetomidine, is a highly selective alpha(2) adrenoreceptor agonist. The aim of this study was to investigate whether dexmedetomidine has an antiulcerative effect and to show whether the antiulcer mechanism of dexmedetomidine is linked with oxidant/antioxidant parameters. The antiulcerative effect of dexmedetomidine was studied in an indomethacin-induced ulcer model, and some oxidant/antioxidant parameters were measured in these gastric tissues. Whereas the average ulcerous areas for the groups that received 10, 25, 50, and 100 MUg/kg dexmedetomidine doses were 29 +/- 4.2, 8 +/- 2.1, 0 +/ 0 and 0 +/- 0 mm(2), respectively, the ulcerous area was 52.1 +/- 4.5 mm(2) in the indomethacin control group and 0.5 +/- 0.2 mm(2) in the famotidine group. In conclusion, the alpha(2)-adrenoreceptor agonist dexmedetomidine showed a significant antiulcerative effect in rat gastric tissue at all doses. This antiulcerative effect is stronger with increasing dosage; at the 50 and 100 MUg/kg doses, no ulcerous areas were observed. In light of these results, we conclude that there is a correlation between antiulcer mechanisms and alpha(2) receptor activation. In rats given dexmedetomidine, all of the investigated antioxidant parameters increased, except for catalase (CAT). Conversely, aside from myeloperoxidase (MPO), all oxidant parameters decreased. Therefore, oxidant/antioxidant parameters play a role in the antiulcer mechanism of dexmedetomidine. PMID- 21602608 TI - Epigallocatechin gallate accelerates healing of indomethacin-induced stomach ulcers in mice. AB - Management of the gastric toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) remains a crucial problem because the commercially available drugs have side effects and are often expensive. Therefore, we examined the potential of the green tea-derived polyphenol epigallocatechin gallate (EGCG) to treat indomethacin-induced stomach ulcers in mice. Administration of indomethacin (18 mg/kg, po) to mice induced ulceration in the glandular portion of the gastric mucosa, accompanied by increased lipid peroxidation (LPO) and protein oxidation and reductions in thiol defense, mucin, cyclooxygenase (COX) expression and prostaglandin (PG) synthesis in the gastric tissues. Daily oral administration of EGCG (2 mg/kg) or omeprazole (3 mg/kg) for 3 days produced similar (~ 72-75%, p < 0.001) beneficial effects on the acute gastric ulceration. Treatment with the test samples partially reversed all the adverse oxidative effects of indomethacin. In addition, EGCG, but not omeprazole, enhanced expression of the COX isoforms and PG synthesis. The results suggest that the non-toxic and inexpensive tea polyphenol EGCG may be an excellent candidate for further evaluation as a potent anti-ulcer drug. PMID- 21602609 TI - Chronic unpredictable stress-induced reduction in the hippocampal brain-derived neurotrophic factor (BDNF) gene expression is antagonized by zinc treatment. AB - Preclinical data indicate the antidepressant activity of zinc and the involvement of the brain-derived neurotrophic factor (BDNF) in this mechanism. The present study investigates the effect of chronic (16 days) combined treatment with zinc (15 mg/kg zinc hydroaspartate) and imipramine (5 mg/kg) in chronic unpredictable stress (CUS) on the BDNF mRNA level in the rat brain. Moreover, serum zinc concentrations were also assessed. CUS induced a significant reduction in the BDNF mRNA level in the hippocampus by 21% but had no effect in the frontal cortex. Repeated treatment with zinc induced a significant increase in the BDNF mRNA level in the hippocampus in the unstressed animals by 12% and as in the chronically stressed animals by 14%, compared to the appropriate controls. Imipramine treatment did not affect this factor. However, combined treatment of zinc and imipramine induced a 12% elevation of the BDNF mRNA level in the stressed but not in the unstressed rats. CUS induced a 19% reduction in the serum zinc concentration, whereas combined treatment of zinc and imipramine reduced this concentration by 24% in the unstressed and increased it (by 20%) in the stressed animals. These results indicate that: 1) CUS induces a reduction in the BDNF gene expression with a concomitant diminution of serum zinc concentration and 2) the CUS-induced reduction in the BDNF gene expression is antagonized by chronic treatment with zinc. PMID- 21602610 TI - Sphingosine-1-phosphate augments agonist-mediated contraction in the bronchial smooth muscles of mice. AB - The effects of sphingosine-1-phosphate (S1P) on bronchial smooth muscle (BSM) contractility were investigated in naive mice. S1P had no effect on the basal tone of the isolated BSM tissues. However, in the presence of S1P (10(-6) M), the BSM contractions induced by acetylcholine (ACh) and endothelin-1 (ET-1) were significantly augmented: both the ACh and ET-1 concentration-response curves were significantly shifted to the left. In contrast, the pretreatment with S1P had no effect on the contractions induced by high K(+) depolarization. It is thus possible that S1P augments BSM contraction induced by the activation of G protein coupled receptors. PMID- 21602611 TI - Effect of kynurenic acid on the viability of probiotics in vitro. AB - Probiotics are bacteria that are commercially available as dietary supplements. One of the important properties of probiotics is their ability to survive in the intestine. Recent evidence has identified kynurenic acid (KYNA) as a bactericidal constituent of intestinal fluid. These data led us to study the influence of KYNA on the viability of selected probiotics. We found that KYNA supported the growth of bacteria in the probiotics Acidolac (Lactobacillus acidophilus, Bifidobacterium) and Lakcid Forte (Lactobacillus rhamnosus) or retarded the growth of bacteria from the Acidolac, BioGaia (Lactobacillus reuteri Protectis), Dicoflor (Lactobacillus rhamnosus GG), Lacium (Lactobacillus plantarum) and Trilac (Lactobacillus acidophilus, Lactobacillus delbrueckii subsp. bulgaricus, Bifidobacterium animalis subsp. lactis) probiotics depending on its concentration. KYNA did not affect the viability of bacteria from the probiotic Linex (Lactobacillus acidophilus LA-5, Bifidobacterium animalis subsp. lactis BB 12). Our results suggest a potential role of KYNA in the regulation of bacterial growth in the digestive system. PMID- 21602612 TI - Peptide inhibitors against influenza virus. AB - Influenza A virus is a particularly problematic virus because of its ability to cause high levels of morbidity on a global scale within a remarkably short period of time. It also has the potential to kill very large numbers of people as occurred in the Spanish influenza pandemic in 1918. Options for antiviral therapy are limited because of the paucity of available drugs and the rapid mutation rate of the virus leading to the emergence of drug-resistant strains. The current H1N1 pandemic and potential threats posed by other strains highlight the need to develop novel therapeutic and prophylactic strategies. Here, we summarize the current state and recent developments of peptide-based inhibitors of influenza A virus. PMID- 21602613 TI - Structural basis for a new mechanism of inhibition of HIV-1 integrase identified by fragment screening and structure-based design. AB - BACKGROUND: HIV-1 integrase is a clinically validated therapeutic target for the treatment of HIV-1 infection, with one approved therapeutic currently on the market. This enzyme represents an attractive target for the development of new inhibitors to HIV-1 that are effective against the current resistance mutations. METHODS: A fragment-based screening method employing surface plasmon resonance and NMR was initially used to detect interactions between integrase and fragments. The binding sites of the fragments were elucidated by crystallography and the structural information used to design and synthesize improved ligands. RESULTS: The location of binding of fragments to the catalytic core of integrase was found to be in a previously undescribed binding site, adjacent to the mobile loop. Enzyme assays confirmed that formation of enzyme-fragment complexes inhibits the catalytic activity of integrase and the structural data was utilized to further develop these fragments into more potent novel enzyme inhibitors. CONCLUSIONS: We have defined a new site in integrase as a valid region for the structure-based design of allosteric integrase inhibitors. Using a structure based design process we have improved the activity of the initial fragments 45 fold. PMID- 21602614 TI - Aprotinin, a protease inhibitor, suppresses proteolytic activation of pandemic H1N1v influenza virus. AB - BACKGROUND: The recent emergence of pandemic influenza virus H1N1v stresses the need for the development of new anti-influenza drugs. METHODS: Host proteases responsible for viral haemagglutinin (HA) cleavage are attractive targets for such drugs. Aprotinin, a natural 58-amino-acid polypeptide from bovine lungs, was chosen for this purpose because it is a drug already approved for human use as an antiprotease compound to treat pancreatitis and bleeding, and because it inhibits a wide spectrum of serine proteases, some of which are involved in influenza virus activation. RESULTS: First, we show that HA of pandemic H1N1v was intensively cleaved and activated in different host systems (human tracheo bronchial epithelium, human intestinal Caco-2 cells and chicken embryonated eggs). Second, aprotinin inhibited HA cleavage and replication of pandemic influenza virus H1N1v in all host systems, including human tracheo-bronchial epithelium. Third, aprotinin did not induce any apparent toxic side effects in these hosts. CONCLUSIONS: Aprotinin can be considered a promising drug against the novel H1N1v pandemic influenza virus. PMID- 21602615 TI - Fabrication and manipulation of solid-state SiO2 nano-gears on a gold surface. AB - A process is presented to fabricate solid-state nano-gears down to a 60 nm outer diameter with six teeth, where the 350 nm diameter ones already have 24 teeth. The small gears are free to move on a polycrystalline gold surface. The gears can be manipulated one by one, using an atomic force microscope (AFM) tip, to construct a train of gears where mechanical motion can be transmitted from one gear to another by mastering the surface friction. This is a first step on the way to bridge the fabrication gap between microfabricated and molecule gears. PMID- 21602616 TI - Rapid turnaround scanning probe nanolithography. AB - Scanning probe nanolithography (SPL) has demonstrated its potential in a variety of applications like 3D nanopatterning, 'direct development' lithography, dip-pen deposition or patterning of self-assembled monolayers. One of the main issues holding back SPL has been the limited throughput for patterning and imaging. Here we present a complete lithography and metrology system based on thermomechanical writing into organic resists. Metrology is carried out using a thermoelectric topography sensing method. More specifically, we demonstrate a system with a patterning pixel clock of 500 kHz, 20 mm s(-1) linear scan speed, a positioning accuracy of 10 nm, a read-back frequency bandwidth of 100, 000 line-pairs s(-1) and a turnaround time from patterning to qualifying metrology of 1 min. Thus, we demonstrate a nanolithography system capable of implementing rapid turnaround. PMID- 21602617 TI - Enriching PMMA nanospheres with adjustable charges as novel templates for multicolored dye@PMMA nanocomposites. AB - Multicolored fluorescent dye loaded PMMA nanospheres were synthesized by the electrostatic adsorption of dye molecules on the charged PMMA nanospheres, whose charges were adjusted by choosing different initiators. The charged PMMA nanospheres have a wider capacity and advantage for combining the charged dyes. The fluorescent dye@PMMA composite nanospheres possess the advantages of higher brightness, longer lifetime and stronger resistance to photobleaching relative to dye molecules. Dye leakage remained lower than 5% over one week. These fluorescent nanospheres have been used in biological labels in cell imaging. They can easily stain blood cancer cells without further surface modification. PMID- 21602618 TI - Fabrication of a nanostructure thermal property measurement platform. AB - Measurements of the electrical and thermal transport properties of one dimensional nanostructures (e.g. nanotubes and nanowires) are typically obtained without detailed knowledge of the specimen's atomic-scale structure or defects. To address this deficiency, we have developed a microfabricated, chip-based characterization platform that enables both transmission electron microscopy (TEM) of the atomic structure and defects as well as measurement of the thermal transport properties of individual nanostructures. The platform features a suspended heater line that physically contacts the center of a suspended nanostructure/nanowire that was placed using in situ scanning electron microscope nanomanipulators. Suspension of the nanostructure across a through-hole enables TEM characterization of the atomic and defect structure (dislocations, stacking faults, etc) of the test sample. This paper explains, in detail, the processing steps involved in creating this thermal property measurement platform. As a model study, we report the use of this platform to measure the thermal conductivity and defect structure of a GaN nanowire. PMID- 21602619 TI - Endocrinology and Art. Dwarf entertainers in the Roman Empire. PMID- 21602620 TI - Improving immunogenicity, efficacy and safety of vaccines through innovation in clinical assay development and trial design: the Phacilitate Vaccine Forum, Washington D.C. 2011. AB - The 9th Annual Vaccine Forum organized by Phacilitate in Washington D.C. 2011 brought together 50+ senior level speakers and over 400 participants representing all the key stakeholders concerning vaccines. The main focus of the meeting was to define priorities in the global vaccines sector from funding to manufacturing and evaluation of vaccine efficacy. A special session was devoted to improving immunogenicity, efficacy and safety of vaccines through innovation in clinical assay development and trial design. The current regulatory approach to clinical assay specification, validation and standardization that enable more direct comparisons of efficacy between trials was illustrated by the success in meningococcal vaccine development. The industry approach to validation strategies was exemplified by a new serologic test used on the diagnostic of pneumococcal pneumonia. The application of the Animal Rule to bridge clinical and non-clinical studies in botulism has allowed significant progress in developing one of the first vaccines to seek approval under the FDA Animal Efficacy Rule. An example of pushing the boundaries in the correlation of immunological responses and efficacy points was represented by a recent cell-based influenza vaccine for which the same correlates of protection apply as for the traditional, egg-based flue vaccine. In the field of HIV phase 2b studies are underway, based on promising results obtained with some vaccine candidates. The conclusion of this session was that creativity in vaccine design and evaluation is beneficial and can lead to innovative new vaccine designs as well as to validated assays to assess vaccine efficacy. PMID- 21602621 TI - How will diagnostics create new opportunities for prophylactic and therapeutic vaccines?: 2011 Phacilitate Vaccine Forum, Washington DC Day 2, afternoon plenary session-January 25, 2011. AB - The Phacilitate Vaccine Forum in Washington DC (Jan 24-26, 2011) brought together vaccine stakeholders from industry, government and non-government organizations to discuss broad current issues covering the spectrum of vaccine policy, funding, research and clinical development, manufacturing, regulatory, and post marketing safety and surveillance. While the conference is held annually and the topics generally discussed reflect the emerging trends, case studies, and best practices of current interest to the vaccine industry, this year's meeting had a new plenary session focusing on the intersection of diagnostics and vaccine development. The session was chaired by Dr. Una Ryan (President and CEO, Diagnostics for All) with the provocative title "How will diagnostics create new opportunitites for prophylactic and therapeutic vaccines?" and was followed by a panel discussion amongst industry leaders discussing the key diagnostic applications gaining interest in the vaccine industry. A common theme running through the session was the increasingly significant role of companion diagnostics and immune monitoring to facilitate and accelerate vaccine development. Indeed the recent examples from pneumococcal and meningococcal vaccine development where the developers and regulatory agencies have considered the use of diagnostic assays and immune markers to assess efficacy of the candidate vaccines in regards to licensure strategies for expanding the serotypes covered, can be considered as breakthrough events for the diagnostics developers. As such the meeting and the session was timely in presenting current progress and for soliciting a convergence of opinions amongst the vaccine industry and the regulatory agencies. PMID- 21602622 TI - Promoting professional development through poster presentations. AB - Poster presentations are commonplace at regional and national nursing conferences, although the development of a poster remains an intimidating task for many staff nurses. The author describes the staff development department's role in implementing in-house poster presentation sessions. Nursing staff are provided support and assistance in presenting posters to their colleagues at yearly sessions. The result has been increased comfort and experience with poster creation, participation in professional development activities, and dissemination of nursing practice innovation. PMID- 21602623 TI - Willingness and preferences of nurses related to learning with technology. AB - To what extent are nurses willing to learn with technology-enhanced tools, such as online education, podcasts, webcasts, mobile learning, and realistic simulations? What factors influence their willingness? This article includes a description of a mixed methodology study that addressed these questions. Nurses of all ages indicated a willingness to learn with a variety of technological tools. Primary determinants of willingness were associated with ease of use, familiarity, convenience, and perceived benefit. PMID- 21602625 TI - Basic life support instructor training: comparison of instructor-led and self guided training. AB - In this randomized trial, the authors compared the instructional quality of instructor candidates trained in instructional methods through an Internet-based versus a traditional classroom-led version of the American Heart Association Core Instructor Course. The self-guided, Internet-based group had significantly higher posttest scores than did the traditional instructor-led group (although not when adjusted for pretest scores). The Internet-based group scores changed from 54% to 67%, exceeding the a priori definition of 8% as a minimally practically significant improvement (instructor-led group scores changed from 49% to 53%). The Internet-based course appeared to be a suitable alternative to the traditional course. PMID- 21602626 TI - Time is the new currency in membership organizations. PMID- 21602627 TI - Professional development research literature from 1996 to 2006: an integrative review. AB - An integrative review of the professional development research literature, spanning the years 1996 to 2006, was conducted by the National Nurses in Staff Development Organization Research Committee at the request of the organization's Board of Directors. Rigorous research criteria were used to evaluate 949 publications. Results determined that 8 studies met the research criteria. Outcomes are reported and recommendations are suggested for advancement of research in the field. PMID- 21602628 TI - Implementing a virtual journal club in a clinical nursing setting. AB - Healthcare practice is increasingly focused on delivering care that is based on published research evidence. Staff development nurses can institute journal clubs to teach nursing staff critical appraisal of research articles and ways to translate research findings into clinical practice. Unfortunately, attending meetings regularly is often a challenge for nurses, and relatively few have the knowledge and expertise to adequately critique research articles. One way to bridge the limitations of accessibility and limited research expertise of journal club members is to establish a virtual journal club. This article describes one hospital's experience with developing a virtual journal club. PMID- 21602629 TI - An educational program to promote positive communication and collaboration between nurses and medical staff. AB - An educational program was implemented for nurses and medical residents to improve communication and collaboration. It has been noted that communication and collaboration between members of the healthcare team improve patient outcomes and job satisfaction among nurses. In this article, the program is outlined and outcomes are presented. PMID- 21602630 TI - Implementing handoff communication. AB - Healthcare systems are seeking assistance from other well-known industries for a solution to issues related to handoff communication, the system for relaying patient information from one caregiver to another. Although the handoff should provide accurate information about a patient's care, treatment, services, and condition, inconsistencies in communication among practitioners exist. This lack of consistent messages prompted staff development nurses in a community hospital to introduce the SBAR process (situation, background, assessment, and recommendation) as the standard for handoff communication to reduce errors and improve patient safety. PMID- 21602631 TI - Critical thinking: Reported enhancers and barriers by nurses in long-term care: implications for staff development. AB - Nursing acknowledges critical thinking as an important guide to clinical decision making. Agreement on how to define, teach, and evaluate this skill is lacking. The purpose of this study was to evaluate critical thinking in practice using a survey that asked nurses to evaluate work-related factors that enhance or pose barriers to the use of critical thinking in practice. Results indicated that enhancers and barriers to practice included teamwork, staffing patterns, and staff and administrator support. A relationship with patients was the most satisfying factor, whereas paperwork was the least. Staff development educators must consider the work environment aspects that affect performance and create the life long learning needed for increased competency in practice. PMID- 21602632 TI - Effectiveness of a fall awareness and education program in acute care. AB - The impact of a patient fall can have serious consequences for the patient, the family, and the healthcare institution. More than half of patient falls are considered preventable. This article reflects the outcomes of a quasi experimental study to determine the effectiveness of a fall awareness and education program in an acute care setting. Staff development educators working in acute care settings may find the strategies useful in addressing the issue of falls in their own institutions. PMID- 21602633 TI - Emergency code color standardization: implementation without traumatization. AB - An emergency code call for a life-threatening cardiovascular emergency may be identified differently between facilities. Nurses and physicians who work secondary jobs or for temporary agencies may find themselves in the position of misunderstanding emergency code calls. The miscommunication of an emergency could easily result in a life-threatening situation for patients and staff. Therefore, the need for standardization is crucial. This article describes an entertaining education plan to assist with implementing standardization facility wide. PMID- 21602634 TI - Successful orientation of new employees: please engage me! PMID- 21602636 TI - What is "meaningful use" when it comes to electronic health records? PMID- 21602637 TI - An open letter to the US Food and Drug Administration regarding the value of electroconvulsive therapy. PMID- 21602638 TI - Intraictal cessation of electroencephalographic activity during electroconvulsive therapy. AB - There have been a few reports of intraictal cessation of electroencephalographic (EEG) activity during electroconvulsive therapy. We present a case of a gentleman with recurrent severe major depressive disorder, who had a "start-stop-start" phenomenon of EEG activity during his electroconvulsive therapy treatment. This brief intraictal arrest of activity demonstrates the importance of continued EEG monitoring to confirm the postictal termination phase. PMID- 21602639 TI - Mirtazapine relieves post-electroconvulsive therapy headaches and nausea: a case series and review of the literature. AB - Headaches and nausea are the 2 most common adverse effects of electroconvulsive therapy (ECT). These adverse effects have been frequently reported in the postictal period and make it difficult for the patient to continue with the following ECTs. Mirtazapine is an antidepressant with a mechanism that involves activating serotonin (5-HT1) receptors. This mechanism has been hypothesized to be the underlying therapeutic effects for depression and anxiety. In addition, mirtazapine possesses antagonistic effects on the postsynaptic serotonin 5-HT2 and 5-HT3 receptors. The pharmacological actions are hypothesized to be related to its treatment effects of headaches and nausea. Here, we report a case series of patients developing post-ECT headaches and nausea, and the concomitant administration of mirtazapine successfully relieved the ECT-associated adverse effects. This case series suggest that mirtazapine may be an optional treatment for ECT-induced headaches and nausea. PMID- 21602640 TI - Response to Dr Wiwanitkit's letter to the editor. PMID- 21602641 TI - Electroconvulsive therapy in depression. PMID- 21602643 TI - Commentary on Kratz et Al "seizure in a nonpredisposed individual induced by single-pulse transcranial magnetic stimulation". PMID- 21602644 TI - Reply to the letter to the editor "response to Kratz et Al, seizure in a nonpredisposed individual induced by single-pulse transcranial magnetic stimulation". PMID- 21602645 TI - Biochemical and endocrine responses to impact and collision during elite Rugby League match play. AB - The purpose of this study was to investigate the relationship between the prematch and short-term postmatch biochemical and endocrine responses to the intensity, number, and distribution of impacts associated with collisions during elite Rugby League match play. Seventeen elite male Rugby League players each provided blood and saliva samples 24 hours prematch, 30 minutes prematch, 30 minutes postmatch, and then at 24-hour intervals for a period of 5 days postmatch to determine plasma creatine kinase concentration ([CK]) and salivary cortisol concentration ([sCort]). The intensity, number, and distribution of impact forces experienced by players during match play were recorded using portable global positioning systems (GPSs). The change in the dependent variables at each sample collection time was compared to 24 hours prematch and 30-minute prematch measures. The [CK] and [sCort] increased significantly (p < 0.05) during match play. Significant correlations (p < 0.05) were observed between the number of hit ups and peak [CK] 24 hours postmatch, 48 hours postmatch, and 72 hours postmatch (p < 0.05). The number of impacts recorded in zone 5 (8.1-10.0G) and zone 6 (>10.1G) during match play was significantly correlated (p < 0.05) to [CK] 30 minutes postmatch, 24 hours post, 48 hours post, and 72 hours postmatch. The GPS was able to provide data on the intensity, number, and distribution of impacts resulting from collisions during match play. Elite Rugby League match play resulted in significant skeletal muscle damage and was highly dependent on the number of heavy collisions >8.1G. [CK] remained elevated 120 hours postmatch identifying that at least 5 days modified activity is required to achieve full recovery after elite Rugby League match play. PMID- 21602646 TI - Crossmodal session rating of perceived exertion response at low and moderate intensities. AB - Session rating of perceived exertion (SRPE) permits global effort estimations after an exercise bout and has shown promise for evaluating training load. However, factors mediating SRPE are not well understood. The purpose of this study was to compare SRPE between cycling and treadmill exercise at low and moderate intensities. In a counterbalanced order, male subjects (n = 7) completed a VO2max trial on a cycle ergometer and a motor-driven treadmill. Then, participants completed trials at 50 and 75% mode-specific VO2max on a cycle ergometer (BK75, BK50) and a treadmill (TM75, TM50) to achieve ~ 400-kcal energy expenditure per trial. Acute RPE (i.e., during exercise) at 5 minutes, midway, and test termination were recorded with SRPE (20-minutes postexercise) expressed as overall (SRPEO), legs (SRPEL), and breathing also recorded were heart rate (HR) and change in rectal temperature (DeltaTrec). Significance was accepted at p <= 0.05. Repeated-measures analysis of variance revealed significantly greater SRPE for higher intensities within each mode. Crossmodal comparisons also show a higher SRPE at moderate (75% VO2max) intensities [SRPEO] = BK75: 7.6 +/- 1.0, TM75: 6.9 +/- 1.3) vs. lower (50% VO2max) intensities (BK50: 4.6 +/- 1.4, TM50: 4.6 +/- 1.1). Within modes, SRPE corresponded well with DeltaTrec and HR. Acute RPE was linked with intensity and drifted upward across time. Results indicated that overall and differentiated SRPEs are magnified with exercise intensity with the corresponding disruption in internal environment potentially mediating subjective responses. From a practical application standpoint, SRPE provides a subjective assessment for immediate evaluation of daily training. Results indicate that, when using SRPE to monitor training, consideration should be given to responses across differing exercise modes. PMID- 21602647 TI - Alternating consecutive maximum contractions as a test of muscle function. AB - Although regularly used, the standard strength test (SST) is known to have several shortcomings, such as being based only on sustained maximum forces, and on a relatively large number of trials that expose the tested muscle to rapid fatigue. The purpose of this study was to evaluate alternating consecutive maximum contractions (ACMCs) as a test of the muscle function through its comparison with SST. Twenty-four participants performed both the externally paced isometric ACMC (i.e., series of consecutive maximum force exertions in 2 directions) and SST of the knee extensor and flexor muscle. The derived variables of both tests included the knee extensor and flexor peak forces (PFs) and their maximum rates of development. Movement speed and muscle power output were also assessed through standard maximum performance tests. Both ACMC and SST revealed on average high intratrial (intraclass correlation coefficient [ICC] > 0.80) and moderate-to-high test-retest reliability (ICC > 0.60), and significant (p < 0.05) positive relationships among the PFs and their rates of development of the tested muscles. The variables of both tests also suggested on average moderate correlations with the maximum performance tests. Finally, ACMC variables revealed relatively stable values across a wide range of frequencies including the 'self selected' one. Although some properties of ACMC could be similar to SST, the important comparative advantages of ACMC could be relatively low and transitional maximum forces exerted, and fewer trials needed for testing 2 antagonistic muscles. Although further research is needed, particularly concerning the external validity and generalizability, we conclude that the ACMC represents a test of muscle function that could be applied either as an alternative or complementary test to SST. PMID- 21602648 TI - Strength training's chronic effects on muscle architecture parameters of different arm sites. AB - Strength training generates alterations in muscle geometry, which can be monitored by imaging techniques as, for example, the ultrasound (US) technique. There is no consensus about the homogeneity of hypertrophy in different muscle sites. Therefore, the purpose of this study was to compare the muscle thickness (MT) and pennation angle (PA) in 3 different sites (50, 60, and 70% of arm length) of the biceps brachii and triceps brachii after 12 weeks of strength training. Forty-nine healthy untrained men were divided into 2 groups: Training Group ([TG, n = 40] 29.90 +/- 1.72 years; 79.53 +/- 11.84 kg; 173 +/- 0.6 cm) and Control Group (n = 9 25.89 +/- 3.59 years; 73.96 +/- 9.86 kg; 171 +/- 6 cm). The TG underwent a strength training program during 12 weeks, which included exercises such as a free-weight bench press, machine lat pull-down, triceps extension in lat pull-down, and standing free-weight biceps curl with a straight bar. A US apparatus was used to measure the PA and MT at the 3 sites. The maximal voluntary isometric contraction (MVC) test was conducted for each muscle group. After 12 weeks of training, a significant difference was observed between MT in biceps brachii, with an improvement of 12% in the proximal site, whereas the distal site increased by only 4.7% (p < 0.05). For the long head of the triceps brachii, the MT and PA at the 3 sites presented significant increases, but no significant variation was observed among them, probably because of the pennated fiber arrangement. The MVC increased significantly for both muscle groups. The results indicated that the strength training program was efficient in promoting hypertrophy in both muscles, but with dissimilar responses of the pennated and fusiform muscle architecture at different arm sites. PMID- 21602650 TI - Hemodynamic signals of mixed messages during a social exchange. AB - This study used functional magnetic resonance imaging to characterize hemodynamic activation patterns recruited when the participants viewed mixed social communicative messages during a common interpersonal exchange. Mixed messages were defined as conflicting sequences of biological motion and facial affect signals that are unexpected within a particular social context (e.g. observing the reception of a gift). Across four social vignettes, valenced facial expressions were crossed with rejecting and accepting gestures in a virtual avatar responding to presentation of a gift from the participant. The results indicate that conflicting facial affect and gesture activated superior temporal sulcus, a region implicated in expectancy violations, as well as inferior frontal gyrus and putamen. Scenarios conveying rejection differentially activated the insula and putamen, regions implicated in embodied cognition, and motivated learning, as well as frontoparietal cortex. Characterizing how meaning is inferred from integration of conflicting nonverbal communicative cues is essential to understand nuances and complexities of human exchange. PMID- 21602651 TI - Spatiotemporal differences in vascular permeability after ischaemic brain damage. AB - To study spatiotemporal differences in vascular permeability, we histologically analysed tracer extravasation, neovessels and reactive astrocytes in a mouse ischaemic brain damage model. On day 1 after damage induction, the extravasation was not associated with the distribution of neovessels or reactive astrocytes. On day 7, the extravasation was limited within the infarct region in which neovessels, but not reactive astrocytes, were observed. However, the extravasation was not observed at peri-infarct region in which both neovessels and reactive astrocytes were observed, suggesting that neovessels had high permeability and reactive astrocytes prevented the extravasation from neovessels. Furthermore, the extravasation was denser in the regions near the surface than in those further in the infarct region, suggesting a spatial heterogeneity in neovascular permeability. PMID- 21602652 TI - Pax6 regulates the epidermal growth factor-responsive neural stem cells of the subventricular zone. AB - Neural stem/progenitor cells transit from fibroblast growth factor-responsive to epidermal growth factor (EGF)-responsive stem cells in the subventricular zone (SVZ). Here, we provide evidences that Pax6 plays a crucial role in the regulation of the EGF-responsive stem cell pool of the SVZ. Using Pax6 homozygous mutant mice (E18.5d), we found that the neurospheres were formed less than that from the wild-type mice, and the expression of EGF receptor in these neurospheres is downregulated very much. The amount of EGF-responsive cells in the mutant dorsal cortex SVZ (E18.5d) was also decreased from 16.8 (wild) to 4.5% (mutant), by flow cytometry method. Immunostaining of the cortex showed a downregulation of EGF receptor expression. All these results suggest that Pax6 regulate the EGF responsive stem cells in the SVZ. PMID- 21602654 TI - Award papers reveal a remarkable state. PMID- 21602657 TI - Choline acetyltransferase 2384G>a polymorphism and the risk of Alzheimer disease. AB - The potential association between choline acetyltransferase (CHAT) polymorphism and the risk of Alzheimer disease (AD) has been controversial. We examined the main effect of CHAT polymorphism and its interaction with apolipoprotein E (APOE) polymorphism in the development of AD in a well-powered elderly Korean sample. We analyzed CHAT 2384G>A polymorphism and APOE polymorphism among 736 Korean patients with probable AD and 1386 nondemented Korean controls. We tested the association between AD and CHAT genotype using a logistic regression model. In addition, we used generalized multifactor dimensionality reduction to investigate the interaction between CHAT and APOE with regard to the risk of AD. The CHAT A allele was associated with AD risk in a dose-dependent manner (odds ratio=1.40, 95% confidence interval=1.06-1.85, P=0.018 for heterozygotes; and odds ratio=3.92, 95% confidence interval=1.78-8.58, P=0.001 for homozygotes). The generalized multifactor dimensionality reduction approach identified a significant gene-gene interaction between CHAT and APOE (Balanced accuracy score=0.647, P=0.001). The CHAT A/A genotype was associated with earlier onset of AD (F=5.070, df=2, P=0.007). The CHAT A allele was associated with AD risk in a dose-dependent manner, and its interaction with the APOE epsilon4 allele was significant with regard to the development of AD. The CHAT A allele was also associated with earlier onset and possibly accelerated progression of AD. PMID- 21602658 TI - Chromophobe renal cell carcinoma: a clinicopathologic study of 203 tumors in 200 patients with primary resection at a single institution. AB - Despite multiple studies, many clinicopathologic issues about chromophobe renal cell carcinoma (RCC) remain contentious; for example, its biological behavior whether better or similar to papillary RCC, the incidence of sarcomatoid features, and whether pathologic features such as necrosis, nuclear grade, and tumor stage predict worse outcome. We studied 203 consecutive primary chromophobe RCCs resected at our institution in an attempt to answer these and other questions. The tumors showed significant progressive decrease in size and stage (P=0.047 and 0.001) from 1980 to 2000. Five patients had metastasis at presentation, and further disease-specific events (recurrence/metastasis/death due to disease) occurred in 8 more. Only 4 of 203 tumors had sarcomatoid features. Over median follow-up of 6.1 years (range, 0.1 to 18 y), 5-year and 10 year disease-specific events occurred in 3.7% (95% CI, 1.5%, 7.4%) and 6.4% (95% CI, 2.7%, 12.2%) patients. Outcomes showed significant association with tumor size, small-vessel invasion, sarcomatoid features, and microscopic necrosis (P<=0.05 each). pT stage or nodal metastasis tended to show some association, without reaching statistical significance (P=0.05 and 0.06, respectively). A modified tumor grading scheme, somewhat similar to that proposed recently, mitotic index, cytologic eosinophilia, and architecture, were not significantly associated with outcome. In conclusion, sarcomatoid differentiation is quite uncommon in chromophobe RCC. Tumor size, small-vessel invasion, sarcomatoid differentiation, and microscopic necrosis are the only features that are significantly associated with adverse outcome. On the basis of this long follow up on a large number of cases, chromophobes seem to have better clinical outcomes than those reported for clear cell and papillary RCCs. PMID- 21602659 TI - Duplicated muscularis mucosae invasion has similar risk of lymph node metastasis and recurrence-free survival as intramucosal esophageal adenocarcinoma. AB - Duplicated muscularis mucosae (MM) in early esophageal adenocarcinoma (EAC) can cause overstaging of the disease on endoscopic ultrasound and pathology specimens. No study has determined the correlation between lymph node metastasis and invasion in the space between duplicated MM in pathologic tumor stage (pT) 1 EAC. Hematoxylin and eosin-stained slides from surgically resected pT1 EAC (n=99) were reviewed for tumor configuration, grade, level of invasion (lamina propria/inner MM, space between duplicated MM, and submucosa), quantitative depth of invasion in millimeter, and lymphovascular invasion (LVI). These pathologic characteristics were correlated with lymph node status and recurrence-free survival (RFS). All specimens had duplicated MM with thick-walled blood vessels. Tumor differentiation was well in 37, moderate in 47, and poor in 15 specimens. EAC invaded the lamina propria/inner MM in 28 cases, duplicated MM space in 41 cases, and submucosa in 30 cases. LVI was identified in 23 tumors. Eleven patients had lymph node metastasis. Quantitative depth of invasion as a continuous variable (P=0.002), poorly differentiated histology (P=0.028), presence of LVI (P=0.001), and submucosal invasion versus duplicated MM/lamina propria invasion (P=0.02) were associated with increased risk of lymph node metastasis and shorter RFS by univariate analysis. By multivariate analysis, LVI was an independent predictor of lymph node status and RFS. EAC invasion into the space between duplicated MM confers a similar risk of lymph node metastasis and recurrence as those of intramucosal EAC, and LVI is the best predictor of lymph node status and RFS in pT1 EAC. PMID- 21602660 TI - MUC2 is a highly specific marker of goblet cell metaplasia in the distal esophagus and gastroesophageal junction. AB - Currently, the American College of Gastroenterology requires identification of goblet cells in mucosal biopsies from the esophagus to diagnose Barrett esophagus (BE). Identification of goblet cells in mucosal biopsies is fraught with limitations such as sampling and interpretation error. One previous study by our group suggested that MUC2 expression in esophageal nongoblet columnar cells represents a late biochemical reaction in the conversion of mucinous columnar cells to goblet cells in BE. We conducted this study to evaluate the prevalence, sensitivity, and specificity of MUC2 positivity in nongoblet columnar epithelium for detection of goblet cells in the distal esophagus and gastroesophageal junction (GEJ) region. We also sought to identify associations between MUC2 positivity and clinical and endoscopic risk factors for BE. This analysis utilized mucosal biopsies of the distal esophagus or GEJ from 100 patients who participated in a community clinic-based study of patients with chronic gastroesophageal reflux disease evaluated prospectively in the western part of Washington state. We randomly selected 50 patients who had columnar epithelium with goblet cells, representing the study group and 50 patients without goblet cells, representing the comparison group. Immunohistochemistry for MUC2 was performed on samples in a blinded manner without knowledge of the clinical or endoscopic features of the patients. The presence of staining was noted in both goblet and nongoblet epithelium, both close to and distant from the mucosa with goblet cells, when the latter were present. All study patients showed MUC2 positivity in goblet cells. MUC2 was present in nongoblet columnar epithelium in 78% of study patients with goblet cells, but in only 4% of controls without goblet cells (P<0.0001) (sensitivity, 78%; specificity, 96% for goblet cell metaplasia). MUC2 was significantly more common in nongoblet columnar cells close to, rather than distant from, the mucosa with goblet cells (P<0.00001). Finally, MUC2 was significantly associated with endoscopic evidence of columnar metaplasia in the distal esophagus, and with known risk factors for BE, such as older age, white race, frequent heartburn, and elevated body mass index. We conclude that goblet cells likely develop from a field of MUC2-positive mucinous columnar cells, and as such, MUC2 represents a late event in the development of goblet cells. MUC2 staining in nongoblet columnar cells is a reasonably sensitive and highly specific marker for goblet cells in the distal esophagus and GEJ, and its presence is predictive of endoscopic columnar metaplasia of the esophagus, even in patients without goblet cells. PMID- 21602661 TI - Evaluation of a gene expression microarray-based assay to determine tissue type of origin on a diverse set of 49 malignancies. AB - The Tissue of Origin Frozen (TOO-FRZ) assay from Pathwork Diagnostics has been cleared by the Food and Drug Administration as a diagnostic study for malignancies of unknown primary. The goal of this study was to evaluate the performance of TOO-FRZ on a diverse collection of malignancies. We collected a diverse set of 49 malignancies. We classified each case into 1 of 4 groups: common morphology from a tissue type included in the TOO-FRZ assay (n=29), uncommon morphology from a tissue type included in the TOO-FRZ assay (n=10), tumor from a tissue type not included in the TOO-FRZ assay (n=3), and malignancies of unknown primary (n=7). We found strong diagnostic performance for common morphologies from tissue types on the TOO-FRZ [overall accuracy=26 of 29 (90%, 95% CI, 73% to 97%)], with perfect performance in all tissue types except gastric (0 of 2) and pancreatic (1 of 2) tissues. There was a significant decline in performance for uncommon morphologies from tissue types included in the TOO FRZ assay [6 of 10 (60%) cases with an indeterminate result, 1 of 10 (10%) cases with an incorrect prediction, and 3 of 10 (30%) with a correct prediction] and for tumors from tissue types not included in the assay (incorrect prediction in 2 of 3 cases). For the 7 malignancies of unknown primary in our study set, the TOO FRZ provided a likely clinically useful result in only 2 of 7 cases. These results provide an insight into the strengths and limitations of this molecular assay for the surgical pathologist, and our findings suggest future directions for research in this area. PMID- 21602662 TI - Pregabalin suppresses spinal neuronal hyperexcitability and visceral hypersensitivity in the absence of peripheral pathophysiology. AB - BACKGROUND: Opioid-induced hyperalgesia is recognized in the laboratory and the clinic, generating central hyperexcitability in the absence of peripheral pathology. We investigated pregabalin, indicated for neuropathic pain, and ondansetron, a drug that disrupts descending serotonergic processing in the central nervous system, on spinal neuronal hyperexcitability and visceral hypersensitivity in a rat model of opioid-induced hyperalgesia. METHODS: Male Sprague-Dawley rats (180-200 g) were implanted with osmotic mini-pumps filled with morphine (90 MUg . MUl-1 . h-1) or saline (0.9% w/v). On days 7-10 in isoflurane anesthetized animals, we evaluated the effects of (1) systemic pregabalin on spinal neuronal and visceromotor responses, and (2) spinal ondansetron on dorsal horn neuronal response. Messenger ribonucleic acid concentrations of alpha2delta-1, 5HT3A, and MU-opioid receptor in the dorsal root ganglia of all animals were analyzed. RESULTS: In morphine-treated animals, evoked spinal neuronal responses were enhanced to a subset of thermal and mechanical stimuli. This activity was attenuated by pregabalin (by at least 71%) and ondansetron (37%); the visceromotor response to a subset of colorectal distension pressures was attenuated by pregabalin (52.8%; n = 8 for all measures, P < 0.05). Messenger ribonucleic acid concentrations were unchanged. CONCLUSIONS: The inhibitory action of pregabalin in opioid-induced hyperalgesia animals is neither neuropathy-dependent nor reliant on up-regulation of the alpha2delta-1 subunit of voltage-gated calcium channels-mechanisms proposed as being essential for pregabalin's efficacy in neuropathy. In opioid-induced hyperalgesia, which extends to colonic distension, a serotonergic facilitatory system may be up regulated, creating an environment that is permissive for pregabalin-mediated analgesia without peripheral pathology. PMID- 21602664 TI - Study of D2-40 immunoexpression of the spindle cell areas of a metaplastic basal cell carcinoma (sarcomatoid basal cell carcinoma). AB - Sarcomatoid basal cell carcinoma (BCC) is rare. In the literature, data on the prognosis of such a variant is somewhat contradictory. D2-40 immunoexpression has been shown to have prognostic connotations in carcinomas of organs other than the skin. However, although D2-40 immunoexpression has been investigated in "common" (nonsarcomatoid) BCC, it has not yet been studied in the spindle cell component of a sarcomatoid BCC. We present a sarcomatoid BCC on the neck of an 87-year-old man that has grown rapidly over the last few months. The sarcomatoid component of the tumor expressed several types of cytokeratins, such as AE1/AE3, CK 5/6, 34betaE12, and CAM 5.2. It was also positive for p63 and for D2-40 in a diffuse pattern. PMID- 21602665 TI - Lymphocyte-rich renal cell carcinoma: an unusual histomorphologic manifestation of a tumor that is not part of lynch syndrome. AB - Lynch syndrome (LS) is characterized by familial clustering of early cancer development in various organs. One of the histologic characteristics of carcinomas associated with LS is prominent intratumoral and peritumoral lymphocytes. The relationship between LS and the rare lymphocyte-rich clear cell renal cell carcinoma (CRCC) has been not been studied. We compared lymphocyte rich CRCC (N=15) with CRCC with no or minimal lymphoid infiltration, occurring in young (<40 y of age) patients (N=15) and in a control group of older (>62 y of age) patients (N=5) with CRCC having conventional histologic features. All cases were analyzed histologically and immunohistochemically using antibodies against the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2. The mutational status of the Von Hippel-Lindau (VHL) gene was analyzed successfully in 25 cases. We found no case with complete absence of immunoreactivity for the MMR proteins/ enzymes studied in any of the groups. Hence, none of the RCCs with heavy lymphocytic infiltration displayed complete absence of protein expression of any of the MMR enzymes. We found mutation of the VHL gene in 2 of 8 tumors from group A, in 4 of 12 tumors from group B, and no mutation in the control group C. We conclude that this rare subset of renal neoplasms is not part of the spectrum of tumors seen in LS. The results of the VHL gene analysis are in concordance with published data on sporadic CRCCs. PMID- 21602663 TI - Antagonism of nerve growth factor-TrkA signaling and the relief of pain. AB - Nerve growth factor (NGF) was originally discovered as a neurotrophic factor essential for the survival of sensory and sympathetic neurons during development. However, in the adult NGF has been found to play an important role in nociceptor sensitization after tissue injury. The authors outline mechanisms by which NGF activation of its cognate receptor, tropomyosin-related kinase A receptor, regulates a host of ion channels, receptors, and signaling molecules to enhance acute and chronic pain. The authors also document that peripherally restricted antagonism of NGF-tropomyosin-related kinase A receptor signaling is effective for controlling human pain while appearing to maintain normal nociceptor function. Understanding whether there are any unexpected adverse events and how humans may change their behavior and use of the injured/degenerating tissue after significant pain relief without sedation will be required to fully appreciate the patient populations that may benefit from these therapies targeting NGF. PMID- 21602666 TI - The prognostic value of the immunohistochemical expression and mutational pattern of the key mediator of Wnt signaling: beta-catenin in Tunisian patients with colorectal carcinoma. AB - Beta-catenin plays a critical role with E-cadherin in cell-cell adhesion and is also a key molecule of the highly conserved Wnt signaling pathway that regulates cell proliferation and differentiation. Abrogation of this pathway is implicated in the carcinogenesis of several malignancies, especially colorectal cancer. The objective of this study was to determine the prognostic value of beta-catenin/E cadherin complex in Tunisian patients with colorectal cancer. Matched primary tumors from 150 patients with sporadic colorectal adenocarcinomas were stained for beta-catenin and E-cadherin by using immunohistochemistry. Deletion of exon 3 of CTNNB1 gene was performed by polymerase chain reaction. Our results showed that beta-catenin and E-cadherin expressions were related inversely to tumor differentiation. Furthermore, the nuclear expression of beta-catenin was considerably increased in advanced colorectal adenocarcinomas and was highly associated with shorter survival of patients. Deletion of exon 3 of CTNNB1 was identified in 2 cases by using polymerase chain reaction and was significantly related to tumor invasion and aberrant expression of E-cadherin. The major finding of this study is that activation of beta-catenin gene by deletions involving exon 3 may be considered as an advanced event in colorectal tumorigenesis in Tunisian patients, in contrast to some worldwide studies. Moreover, disruption of beta-catenin/E-cadherin complex may be considered as a dependent predictor of disease outcome. PMID- 21602667 TI - Blocking endogenous peroxidases in immunohistochemistry: a mandatory, yet also subtle measure. PMID- 21602668 TI - Dual stain immunohistochemical localization of p16INK4A and ki-67: a synergistic approach to identify clinically significant cervical mucosal lesions. AB - BACKGROUND: The primary goal of this study was to assess the clinical utility of a multiplexed immunohistochemical method using colocalization of p16 and Ki-67 in identifying high-grade cervical mucosal lesions. DESIGN: The study included formalin-fixed cervical biopsy specimens, representative of 297 diagnostic regions. They were subjected to 2 colors immunohistochemical staining for p16 and Ki-67 using an EnVision polymer-based method. The chromogens used were of DAB brown for the detection of p16 and alkaline phosphatase blue for Ki-67. Histologic regions were scored positive for either marker based on the detection of p16 or Ki-67 in >10% of the cells of interest. RESULT: Positive test results with colocalization of p16/Ki-67 were found in 20 of 40 cases of cervical intraepithelial neoplasia 1 (n=40) and in all cases of cervical intraepithelial neoplasia 2/3 (n=32), squamous cell carcinoma (n=11), adenocarcinoma in situ (n=10), and invasive adenocarcinoma (n=8). Colocalization of p16/Ki-67 was also detected in few cells in 1 of 19 sections with tuboendometrial metaplasia but was not detected in normal squamous mucosa (n=78), normal endocervical mucosa (n=76), immature squamous metaplasia (n=13), or in microglandular hyperplasia (n=9). CONCLUSIONS: The p16 and Ki-67 are coexpressed in virtually 100% of cases of high grade squamous and glandular lesions, but they are rarely coexpressed in normal tissues or in benign lesions of the squamous and glandular mucosa. Thus, multiplexed colocalization of p16 and Ki-67 is a practical and potentially powerful diagnostic approach to enhance the accuracy of cervical histopathologic diagnosis. PMID- 21602670 TI - The Impella 2.5 and 5.0 devices for ST-elevation myocardial infarction patients presenting with severe and profound cardiogenic shock: the Academic Medical Center intensive care unit experience. AB - OBJECTIVE: Cardiogenic shock remains an important therapeutic challenge, with high in-hospital mortality rates. Mechanical circulatory support may be beneficial in these patients. Since the efficacy of the intra-aortic balloon pump seems limited, new percutaneously placed mechanical left ventricular support devices, such as the Impella system, have been developed for this purpose. Our current purpose was to describe our experience with the Impella system in patients with ST-elevation myocardial infarction presenting in profound cardiogenic shock, who were admitted to our intensive care unit for mechanical ventilation. METHODS: From January 2004 through August 2010, a total of 34 ST elevation myocardial infarction patients with profound cardiogenic shock were admitted to our intensive care unit and treated with either the Impella 2.5 or the Impella 5.0 device. Baseline and follow-up characteristics were collected retrospectively. MEASUREMENTS AND MAIN RESULTS: Within the study cohort, 25 patients initially received treatment with the Impella 2.5, whereas nine patients received immediate Impella 5.0 support. Eight out of 25 patients in the Impella 2.5 group were upgraded to 5.0 support. After 48 hrs, 14 of 25 patients in the 2.5 group were alive, five of whom had been upgraded. In the 5.0 group, eight out of nine patients were alive. After 30 days, six of 25 patients in the 2.5 group were alive, three of whom had been upgraded. In the 5.0 group, three of nine patients were alive at 30 days. CONCLUSIONS: In ST-elevation myocardial infarction patients with severe and profound cardiogenic shock, our initial experience suggests improved survival in patients who received immediate Impella 5.0 treatment, as well as in patients who were upgraded from 2.5 to 5.0 support, when compared to patients who received only Impella 2.5 support. PMID- 21602669 TI - Suppression of the stem cell antigen-1 response and granulocyte lineage expansion by alcohol during septicemia. AB - OBJECTIVE: Granulocytopenia frequently occurs in alcohol abusers with severe bacterial infection, which strongly correlates with poor clinical outcome. Knowledge of the molecular mechanisms underlying the granulopoietic response to bacterial infection remains limited. This study investigated the involvement of stem cell antigen-1 expression by granulocyte lineage-committed progenitors in the granulopoietic response to septicemia and how alcohol affected this response. DESIGN: : Laboratory investigation. SETTING: University laboratory. SUBJECTS: Male Balb/c mice. INTERVENTIONS: Thirty mins after intraperitoneal injection of alcohol (20% ethanol in saline at 5 g of ethanol/kg) or saline, mice received an intravenous Escherichia coli challenge. MEASUREMENTS AND MAIN RESULTS: E. coli septicemia activated stem cell antigen-1 expression by marrow immature granulocyte differentiation antigen-1 precursors which correlated with an increase in proliferation, granulocyte macrophage colony-forming unit production, and expansion of this granulopoietic precursor cell pool. Acute alcohol treatment suppressed stem cell antigen-1 activation and inhibited the infection-induced increases in proliferation, granulocyte macrophage colony-forming unit production, and expansion the of immature granulocyte differentiation antigen-1 precursor cell population. Consequently, recovery of the marrow mature granulocyte differentiation antigen-1 cell population after E. coli challenge was impaired. Stem cell antigen-1 was induced in sorted granulocyte differentiation antigen-1, stem cell antigen-1' cells by lipopolysaccharide-stimulated C-Jun kinase activation that was also inhibited by alcohol. Furthermore, stem cell antigen-1 knockout mice failed to expand the marrow immature granulocyte differentiation antigen-1 cell pool and demonstrated fewer newly produced granulocytes in the circulation after the E. coli challenge. CONCLUSIONS: Alcohol suppresses the stem cell antigen-1 response in granulocyte lineage-committed precursors and restricts granulocyte production during septicemia, which may serve as a novel mechanism underlying impaired host defense in alcohol abusers. PMID- 21602671 TI - Treatment of acute coronary syndrome: Part 1: Non-ST-segment acute coronary syndrome. AB - OBJECTIVE: Acute coronary syndrome is a common cause of morbidity and mortality, both in the United States and worldwide. The goal of this review is to familiarize clinicians with recent information regarding the diagnosis and treatment of acute coronary syndrome. DATA SOURCES: PubMed search and review of the relevant medical literature. SUMMARY: Acute coronary syndrome encompasses three clinical diagnoses: unstable angina, non-ST-segment elevation myocardial infarction), and ST-segment elevation myocardial infarction. The definition, pathophysiology, clinical presentation, diagnosis, and treatment of unstable angina/non-ST-segment elevation myocardial infarction are reviewed here. Diagnosing unstable angina/non-ST-segment elevation myocardial infarction is a significant challenge in critically ill patients not initially suspected of having acute coronary syndrome (i.e., noncardiac intensive care unit patients), and diagnostic and treatment strategies for these patients have not been clearly established. CONCLUSIONS: Patients with acute coronary syndrome benefit from intensive medical therapy, including antianginal, antiplatelet, antithrombotic, and statin agents. Depending on their risk for future cardiovascular events as well as their risk of bleeding complications, patients may benefit from either an early invasive treatment strategy, in which routine coronary revascularization is performed, or a conservative strategy, in which revascularization is reserved for patients with recurrent or provocable cardiac ischemia. PMID- 21602672 TI - The anaesthetic management of caesarean section in the interventional radiology suite. AB - PURPOSE OF REVIEW: Interventional radiology has been used in the last decade for the management of major obstetric haemorrhage particularly when the placenta is pathologically adherent (accreta) or for postpartum haemorrhage when a bleeding vessel is suspected. This review describes the radiological, obstetric and anaesthetic interventions which are often carried out in the radiology suite. RECENT FINDINGS: The incidence of placenta accreta is increasing as the caesarean section rate rises. Pre-delivery diagnosis has been facilitated by the use of ultrasound and magnetic resonance imaging. The use of interventional radiology for elective caesarean sections with suspected placenta accreta is mainly restricted to larger centres and the evidence base for its use is currently weak. The actual location of the surgery remains controversial. Some centres with expertise perform the caesarean section in the radiology suite with obstetric, anaesthetic and neonatal teams in attendance. Robust communication is essential, especially when working in sites remote to the usual place of care. SUMMARY: This review describes the management of patients who are amenable to prophylactic or emergency radiological intervention for obstetric haemorrhage in the radiology suite. Controversy surrounds the optimum place for surgery and the most suitable mode of anaesthesia in these patients. PMID- 21602673 TI - Anesthetic management of transcatheter aortic valve implantation. AB - PURPOSE OF REVIEW: The revolution in transcatheter aortic valve implantation (TAVI) for the treatment of aortic stenosis has been well described by the large number of randomized trials, registries, and single and multicenter experiences published during 2010-2011. The aim of this review is to describe the challenges of the anesthetic management related to TAVI. RECENT FINDINGS: Recent data show that TAVI is clinically effective in patients with inoperable aortic stenosis when compared with standard therapy. It can be accomplished in high-risk patients with favorable outcomes compared with surgery as predicted by standard estimates of mortality and is associated with functional and hemodynamic improvement. Currently, TAVI is targeted at high-risk patients, but may be extended to lower risk groups in the near future. Outstanding questions concerning TAVI are related to its long-term durability and to procedural complications. SUMMARY: Preprocedural, multidisciplinary assessment of the patient is essential prior to TAVI and should include a full anesthetic evaluation, consideration of patient comorbidities, and determination of technical feasibility. The role of scoring systems for risk prediction requires further scrutiny. Multidevice/multiple access approaches allow for treatment of a wide range of patients. Anesthetic techniques and supportive measures vary depending on procedural concerns, patient comorbidity, and severe, often unstable cardiac disease. Echocardiography is fundamental to preoperative evaluation, procedure guidance, and assessment of complications. Planned bailout strategies should be discussed with all members of the medical team. Postoperative standardized monitoring and management protocols are essential. PMID- 21602674 TI - Anesthesiologists and remote locations. PMID- 21602675 TI - Sedation and anesthesia for the pediatric patient undergoing radiation therapy. AB - PURPOSE OF REVIEW: Radiation oncology is a cornerstone in the treatment of cancer in children. Although painless, there is a requirement for the child to lie still by themselves in the radiation treatment room, for multiple daily or twice daily treatments for up to 6 weeks. Anesthesia or sedation is usually necessary to achieve this in younger children. This review provides a brief update of the latest developments in radiation oncology and describes the current best practice in anesthesia for these children. RECENT FINDINGS: Advances in radiation therapy and the newer modality of proton beam therapy have enabled radiation oncologists to target tumors more successfully, while avoiding damage to normal tissues. Anesthesiologists are increasingly being asked to provide sedation or anesthesia to ensure a completely immobile patient during radiation therapy. SUMMARY: In the vast majority of cases, total intravenous anesthesia or sedation using propofol ensures that the child remains immobile, whilst maintaining spontaneous respiration, an unobstructed airway, and cardiovascular stability. PMID- 21602676 TI - Lymphadenectomy in ovarian cancer: standard of care or unnecessary risk. AB - PURPOSE OF REVIEW: The clinical significance of lymphadenectomy in ovarian cancer is controversial. In early ovarian cancer (EOC), it is the extent of the procedure that is the main focus of debate. In advanced disease [advanced ovarian cancer (AOC)], the issue is whether or not lymphadenectomy independently impacts survival. This review summarizes the current standard of care as it relates to the role of lymphadenectomy in ovarian cancer. RECENT FINDINGS: Lymphadenectomy in EOC is a diagnostic procedure in as much as it is an integral and mandatory part of a complete surgical staging. The required extent of the procedure, however, remains uncertain. It has been suggested that at least 10 nodes from different, predefined retroperitoneal sites should be the minimum number removed. Lymphadenectomy in AOC is of potential therapeutic value. The only published randomized clinical trial (RCT) showed no overall survival benefit after radical/systematic lymphadenectomy, although there was an impact on 6-month disease-free survival. Conversely, retrospective studies, a meta-analysis and a re-analysis of three RCTs in AOC do suggest an overall survival benefit for radical/systematic lymphadenectomy. SUMMARY: This review concludes with the recommendation that lymphadenectomy in EOC is a mandatory part of surgical staging and that a minimum of 10 nodes should be harvested from different retroperitoneal sites. In AOC, lymphadenectomy can be considered when intraperitoneal cytoreduction has been complete or when there are bulky nodes. PMID- 21602677 TI - Imaging cervical cancer: recent advances and future directions. AB - PURPOSE OF REVIEW: There has been considerable progress in the imaging of cervical cancer over the last 5 years. In countries with access to cross sectional imaging resources, technical advances have enabled a range of imaging techniques to become increasingly employed and established in the detection, staging and treatment planning of cervical cancer and for identifying disease recurrence. This review highlights these developments and summarizes recent significant articles. RECENT FINDINGS: Functional imaging techniques provide information on tumour biology by probing characteristics of tumour vascularity, cellularity and metabolism which critically contribute to decision making and stratification for management options. Particularly, functional MRI techniques have improved accuracy of disease staging and detection of recurrence. PET computed tomography is useful in lymph node staging and targeted radiotracers are increasingly exploited as potential biomarkers of treatment response. SUMMARY: Improvements in hardware, software and contrast agents are revolutionizing the role of imaging in cervical cancer. Once standardized and validated, the techniques should enable individualized patient treatment and optimization of outcome. PMID- 21602678 TI - New therapies in pediatric dermatology. AB - PURPOSE OF REVIEW: There have been many new developments in therapeutic modalities for the treatment of pediatric dermatological diseases in the past year. Advances in the treatment of atopic dermatitis, psoriasis, infantile hemangiomas and dystrophic epidermolysis bullosa will be discussed. The following review will update the reader on these exciting new possibilities for patient care and future directions for research to improve the lives of children suffering from skin diseases. RECENT FINDINGS: This review will discuss recent articles describing the use of topical tacrolimus for maintenance of remission in atopic dermatitis, utility of nurse educators in atopic dermatitis, safety and efficacy of etanercept for the treatment of psoriasis in children, narrow band ultraviolet B phototherapy for atopic dermatitis and psoriasis, use of topical timolol for infantile hemangiomas and bone marrow transplantation for dystrophic epidermolysis bullosa. SUMMARY: There are many new interesting, potentially useful therapeutic modalities emerging in pediatric dermatology. New treatments for atopic dermatitis, psoriasis, infantile hemangiomas and dystrophic epidermolysis bullosa are reviewed. PMID- 21602679 TI - Supraclavicular swelling in hypothyroidism. AB - Hypothyroidism can have a variety of presentations. We report here a case of acquired hypothyroidism in a pediatric patient who first presented with bilateral supraclavicular swelling. Hypothyroidism and its presenting signs and symptoms are discussed with a focus on the less common findings that can be associated with hypothyroidism in children. PMID- 21602680 TI - Youth, risks, and chronic illness. PMID- 21602681 TI - Caring for teens with chronic illness: risky business? AB - PURPOSE OF REVIEW: With advances in medicine, more children with chronic illness are reaching adolescence and young adulthood. Research has shown that this group is not immune to the behavioral risks endorsed by healthy adolescents. Recent literature exploring the etiology of risk behaviors and their impact on chronic illness is presented. RECENT FINDINGS: Risk taking may be the result of differential maturation of two distinct parts of the adolescent brain. Risk taking can be considered normal in adolescents with chronic illness, but there is some evidence that chronic illness affects normal psychosocial development. Moreover, evidence supports that chronic illness can lead to disparities in risk education and assessment because of disease focused management rather than a more comprehensive approach. SUMMARY: Youth living with chronic illnesses face unique challenges in accomplishing the developmental tasks of adolescence. These challenges include risk behaviors, which jeopardize current and future health. The reasons for risk taking are multifactorial and require providers to make the adolescent and not the illness the center of management. More research is needed on how to improve developmentally appropriate and relevant interventions to aid in safe passage into adulthood. PMID- 21602682 TI - Natriuretic peptides in children: physiology and clinical utility. AB - PURPOSE OF REVIEW: This article reviews the genetics, biochemistry, and physiology of the natriuretic polypeptide family and their receptors; their roles in cardiac, bone, and lipid metabolism in children; and pharmacological agents that utilize the natriuretic polypeptide system. RECENT FINDINGS: Clinically, measurements of circulating levels of the natriuretic polypeptides are useful diagnostic and prognostic markers of cardiovascular disease in children. The natriuretic polypeptides also play an important role in growth and body composition. Therapeutic application of the natriuretic polypeptide system may provide new treatments for cardiac, renal, bone, and metabolic disease in children. SUMMARY: The natriuretic polypeptide system has promising clinical utility in the care of pediatric patients with cardiac, renal, bone, and metabolic disease. PMID- 21602683 TI - Austerity, poverty, resilience, and the future of mental health services for children and adolescents. PMID- 21602684 TI - The role of latent internalizing and externalizing predispositions in accounting for the development of comorbidity among common mental disorders. AB - PURPOSE OF REVIEW: Although numerous studies have examined the latent structure of internalizing and externalizing mental disorders, the effects of this structure in predicting the development of comorbidity have remained unexamined until recently. RECENT FINDINGS: A novel approach to study the effects of latent internalizing and externalizing predispositions to the development of comorbidity was used to analyze data from 14 countries in the WHO World Mental Health Survey Initiative. Pervasive significant positive associations were found between temporally primary and secondary internalizing and externalizing disorders in survival analyses, with time-lagged associations consistently stronger within domains than between domains. The vast majority of these associations were explained by latent internalizing and externalizing variables. Specific phobia and obsessive compulsive disorder were the most important internalizing components and hyperactivity disorder and oppositional-defiant disorder the most important externalizing components. Several intriguing residual time-lagged associations remained significant, though, even after controlling latent predispositions. SUMMARY: The latent variable model suggests that common causal pathways account for most comorbidity among internalizing-externalizing disorders. These pathways should be the focus of future research on the development of comorbidity, although isolation of consistent residual time-lagged associations between certain pairs of primary-secondary disorders is also important in pointing the way to subsequent focused study. PMID- 21602685 TI - Psychiatric epidemiological surveys in China 1960-2010: how real is the increase of mental disorders? AB - PURPOSE OF REVIEW: Community psychiatric epidemiological surveys over the last five decades have revealed a dramatic increase in the prevalence of mental disorders in China. This article summarizes the main surveys and attempts to interpret the increase of prevalence from a methodological perspective. RECENT FINDINGS: Regional and national surveys conducted in China during 1960-1990 focused on severe mental disorders and revealed very low and stable rates of disorders. By contrast, those performed in the last decade, whether psychiatrists or lay interviewers were used, have shown much higher and more 'reliable' rates comparable to those found in high-income countries. This is especially so for depression and anxiety disorders. SUMMARY: Given the sociopolitical turmoil that had previously plagued people in China, the dramatic rise in prevalence estimates of mental disorders in recent years cannot be simply interpreted as a substantive deterioration of mental health following rapid social change. Global and local factors that shape research methodology aimed at showing that mental disorders are common may play an important role in the dramatic increase. Future research in China should move beyond descriptive epidemiology. It should also address policy relevant issues in view of the limited resources available for mental health interventions. PMID- 21602686 TI - Complementary medicine for children and young people who have attention deficit hyperactivity disorder. AB - PURPOSE OF REVIEW: Despite effectiveness of medication in treating children and young people who have attention deficit hyperactivity disorder (ADHD), concerns about the effects of medication on children's developing brains, adverse side effects, possibility of long-term use, and compliance issues have all contributed to the continuing search for alternative therapies. This article reviews the latest scientific evidence of the effectiveness and safety of these treatments in ADHD. RECENT FINDINGS: Although there is evidence from a large randomized controlled study that neurofeedback has positive effects on reducing children's symptoms of ADHD, most recent randomized controlled trials have generally yielded negative results. Some positive results exist from a pilot study of repetitive transcranial magnetic stimulation. However, the sample size was far too small to enable any conclusions to be drawn about the evidence. Findings from the recent randomized controlled trials of supplements of essential fatty acids in children who have ADHD clearly demonstrated lack of superiority compared with placebo. SUMMARY: Notwithstanding efforts made to increase the scientific rigor of previous studies, more recent studies have generally been unsuccessful in demonstrating adequate treatment effects of complementary medicine on children who have ADHD. Currently, there is no proof that complementary medicine provides a better alternative for children who have ADHD than treatments that are currently available within multimodal therapy. PMID- 21602687 TI - Colorectal cancer screening in patients with ulcerative and Crohn's colitis with use of colonoscopy, chromoendoscopy and confocal endomicroscopy. AB - BACKGROUND: Patients with ulcerative colitis and Crohn's colitis have increased risk of colorectal cancer. Current screening endoscopy protocols based on white light endoscopy (WLE) and random biopsies are laborious and of uncertain sensitivity. Novel endoscopic techniques include chromoendoscopy (CE) and confocal laser endomicroscopy (CLE). AIM: The aim was to compare WLE and CE for the detection of intraepithelial neoplasia (IEN). Furthermore, we analysed the sensitivity and specificity of CE and CLE for the diagnosis of IEN. METHODS: The cohort consisted of 30 patients examined by WLE, CE with 0.4% indigocarmine, and by a CLE system Pentax EC-3870CIFK during one examination. Additional 15 patients were examined by conventional protocol only. Random biopsies and biopsies from all suspicious lesions were taken. We compared the number of IENs detected by WLE and CE and analysed the predictive values of CE and CLE for the histology diagnosis. RESULTS: There were 1584 random biopsies (35.2 per patient) taken. There were 78 targeted biopsies (1.7 per patient) taken in 24 of 45 patients examined by WLE and an additional 36 biopsies in 16 of 30 patients examined by CE (1.17 additional per patient). There were no IENs found on random biopsies versus six low-grade or high-grade IENs in four patients (two detected by WLE, four additional by CE) from targeted biopsies, P=0.02. A total of 100 suspicious lesions were detected and analysed by CE and histology. CLE could not examine 32 of 100 lesions (two of 30 flat vs. 30 of 70 pedunculated lesions, P=0.0002, odds ratio 10.5). The sensitivity of CE/CLE for low-grade or high-grade IEN was 100/100%, the specificity 96.8/98.4%, positive predictive value was 62.5/66.7% and negative predictive value was 100/100%. CONCLUSION: Targeted biopsies are superior to random biopsies in the screening of IEN in patients with inflammatory bowel disease. CE increases the diagnostic yield of WLE. In our study CLE did not provide additional clinical benefits. PMID- 21602688 TI - Spontaneous bacterial peritonitis secondary to Streptococcus bovis in a patient with chronic chylous ascites. AB - Spontaneous bacterial peritonitis (SBP) is a common complication of cirrhosis and ascites, and is predominantly caused by enteric organisms. Streptococcus bovis is a rare etiology of SBP that was first reported in 1994. Since then, few prior reports of SBP secondary to S. bovis have been observed in patients with underlying cirrhosis or hepatitis. We now present a case of SBP caused by S. bovis in the setting of chronic chylous ascites in a patient with no known liver pathology. PMID- 21602689 TI - Safety of infliximab in 10 years of clinical practice. AB - Assessment of the long-term safety of anti-tumour necrosis factor therapies is vital for the safe treatment of inflammatory bowel disease, a disease affecting a young cohort of patients. AIMS: The aim of this retrospective study was to assess the safety and long-term outcome of infliximab use in clinical practice in our institution on an intention to treat basis over the 10-year period from December 1998 to 31 December 2008. METHODS: All cases receiving infliximab for ulcerative colitis or Crohn's disease over a 10-year period were identified from hospital pharmacy records. The study was based on a single centre cohort, with an unselected patient group. RESULTS: A total of 271 patients were identified as receiving infliximab for either Crohn's disease or ulcerative colitis over the 10 year study period. In total, 2169 infusions were given to the patient cohort. Fifty adverse events led to discontinuation of infliximab therapy in 47 cases. Two patients stopped due to neurological complications. There were six malignancies diagnosed within the cohort during the study period. Four of these were diagnosed while the individual was receiving Infliximab and two occurred at an interval of 21-52 months post their final infliximab infusion. A total of five deaths (1.5%) were observed during the study period. CONCLUSION: Infliximab therapy seems to be safe and efficacious in the long term. Although the development of malignancy remains a concern, we have not seen an increased risk of serious infection within our cohort. PMID- 21602690 TI - Management of chronic hepatitis B. AB - Chronic hepatitis B continues to be a major global health burden. It accounts for a substantial impact on health care resources and finances in many parts of the world including Europe. Natural history and disease spectrum are varied, depending on when and how the infection is acquired. The chronic infective state increases patients' risk of progression to liver cirrhosis or hepatocellular carcinoma. Several treatment options are currently available, but their use depends on the stage of the patient's infection, which is influenced by both host and viral factors. The ultimate goals in hepatitis B treatment are to prevent disease progression, hepatic decompensation, hepatocellular carcinoma, and death. Patients with decompensated liver cirrhosis should be referred to specialized transplant centers in a timely manner. PMID- 21602691 TI - Committee report: Considerations and recommendations for national guidance regarding the retention and use of residual dried blood spot specimens after newborn screening. AB - Newborn screening programs are state based with variable policies. Guidance regarding the retention, storage, and use of portions of newborn screening dried blood spots that remain after screening (residual specimens) was first published in 1996. Since then, newborn screening programs have paid increased attention to specimen storage and usage issues. Standard residual specimen uses include quality assurance and program evaluation, treatment efficacy, test refinement, and result verification. In all cases, privacy and security are primary concerns. In general, two distinct state practices regarding the storage and use of residual newborn screening specimens exist: (1) short-term storage (<3 years), primarily for standard program uses and (2) long-term storage (>18 years), for standard program uses and possible important public health research uses. Recently, there have been concerns in some consumer communities regarding both the potential uses of residual specimens and patient (newborn and family) privacy. To assist in policy improvements that can protect the individual's privacy and allow for important public health uses of residual newborn screening specimens, the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children has developed recommendations (with requested action by the Secretary where applicable). This report presents the Committee's recommendations and reviews the pertinent associated issues. PMID- 21602692 TI - Antiretroviral therapy and tuberculosis: what's the connection and what's the way forward? PMID- 21602693 TI - Decreasing HIV transmission through breastfeeding: moving from evidence to practice. PMID- 21602695 TI - Antiretroviral drugs for preventing mother-to-child transmission of HIV: a review of potential effects on HIV-exposed but uninfected children. AB - The provision of antiretroviral drugs for the prevention of mother-to-child HIV transmission has been rising sharply in low- and middle-income countries. Changes to the World Health Organization guidelines support further extension of these programs. The result will be a greatly expanded population of HIV-exposed but uninfected children with substantial exposure to antiretroviral drugs, both in utero and while breastfeeding. There are limited data on possible toxicities in this burgeoning population, and the large number of confounding factors limits any conclusions. Although the evidence on birth defects and mitochondrial toxicity remains equivocal, considerable data link protease inhibitors to preterm delivery and low birth-weight. Transient hematologic toxicities are also likely. The drug impact later in life is an open question. Larger and longer cohort studies are necessary to properly balance the risks and benefits of large-scale infant exposure to antiretroviral agents. PMID- 21602694 TI - Elevated CD8 counts during HAART are associated with HIV virologic treatment failure. AB - OBJECTIVE: To evaluate whether elevated CD8 counts are associated with increased risk of virologic treatment failure in HIV-infected individuals. DESIGN: Retrospective cohort study. METHODS: US Military HIV Natural History Study participants who initiated highly active antiretroviral therapy (HAART) in 1996 2008 had 6- and 12-month post-HAART HIV RNA <400 copies per milliliter, >= 2 subsequent HIV viral loads and a baseline CD8 count were eligible (n = 817). Baseline was 12 months after the start of HAART, virologic failure (VF) was defined as confirmed HIV RNA >= 400 copies per milliliter, and CD8 counts >= 1200 cells per cubic millimeter were considered elevated. Cox models were used to examine the effect of baseline and time-updated CD8 counts on VF. RESULTS: There were 216 failures for a rate of 5.6 per 100 person-years [95% confidence interval (CI): 4.9 to 6.4]. Among those initiating HAART in 2000-2008, the participants with elevated baseline CD8 counts had significantly greater risk of VF compared with those with baseline CD8 counts <= 600 cells per cubic millimeter [hazard ratio (HR) = 2.68, 95% CI: 1.13 to 6.35]. The participants with elevated CD8 counts at >20% of previous 6-month follow-up visits had a greater risk of failure at the current visit than those who did not (HR = 1.53, 95% CI: 1.14 to 2.06). Those with CD8 counts that increased after the start of HAART had a greater risk of failure than those with CD8 counts that decreased or remained the same (HR = 1.59, 95% CI: 1.19 to 2.13). CONCLUSIONS: Initial or serial elevated CD8 counts while on HAART or an increase in CD8 counts from HAART initiation may be early warnings for future treatment failure. PMID- 21602696 TI - Effect of nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy on dysglycemia and insulin sensitivity in South African HIV-infected patients. AB - BACKGROUND: Data on the prevalence of the complications of antiretroviral therapy (ART) (diabetes, central fat accumulation, peripheral fat wasting, and dyslipidemia) in sub-Saharan Africa are sparse. We examined the prevalence and associated risk factors of dysglycemia and insulin sensitivity in HIV-infected South Africans. METHODS: HIV-infected patients, on nonnucleoside reverse transcriptase inhibitor-based ART or ART-naive, had oral glucose tolerance tests and clinical anthropometry. Insulin sensitivity and beta-cell function were assessed. RESULTS: The prevalence of dysglycemia in 406 ART-naive patients and 443 patients on ART was 25.7% and 21.9% (P = 0.193), respectively. Dysglycemic patients on ART had a similar body mass index (P = 0.440), greater waist circumference (P = 0.047), and smaller calf skinfold thickness (P = 0.015) than dysglycemic ART-naive patients but no difference in beta-cell function or insulin sensitivity. Normoglycemic patients on ART had a greater body mass index (P = 0.0009), waist circumference (P = 0.0001), and abdominal skinfold thickness (P = 0.040), similar calf skinfold thickness (P = 0.079), and reduced beta-cell function [lower insulinogenic index (P = 0.027) and oral disposition index (D(o), P = 0.020)] compared with normoglycemic ART-naive patients. In multivariate analysis, older age [odds ratio (OR): 1.04, 95% confidence interval (CI): 1.02 to 1.06], male gender (OR: 1.96, 95% CI: 1.28 to 2.99), higher CD4 count (OR: 1.0, 95% CI: 1.00 to 1.02) and use of efavirenz (OR: 1.70, 95% CI: 1.19 to 2.45) were associated with dysglycemia. CONCLUSIONS: The prevalence of dysglycemia in ART naive and ART patients was similar. Peripheral fat wasting was more common in dysglycemic patients on ART. The association of efavirenz with dysglycemia is important because first-line ART regimens in the developing world include nonnucleoside reverse transcriptase inhibitors, and increasingly, efavirenz is selected because of its perceived lower toxicity than nevirapine. PMID- 21602697 TI - Mortality among antiretroviral-eligible patients in an urban public clinic. AB - BACKGROUND: Advances in antiretroviral therapy (ART) over the last decade have improved clinical outcomes for people living with human immunodeficiency virus (HIV), but whether these improvements are experienced by disadvantaged urban populations is less clear. METHODS: We evaluated mortality among a clinical cohort in a public safety-net HIV specialty clinic in San Francisco, California. RESULTS: Among 1651 ART-eligible patients attending an urban US HIV clinic, 4 year mortality was 10.0% in 2000-2004 and 11.0% in 2005-2009. Despite universal ART availability, only 72 (42%) of 172 patients who died, compared with 69% of survivors, ever achieved an HIV viral load, 400 copies per cubic millimeter. The leading causes of death were acquired immunodeficiency syndrome (56%), violence/overdose (16%), and pulmonary disease (6%). CONCLUSIONS: Disadvantaged subpopulations in the developed world can experience high mortality rates despite accessing specialty HIV clinical services with full ART availability. New strategies are needed to improve the outcomes in these populations. PMID- 21602698 TI - Clinical management and follow-up of hypercholesterolemia among perinatally HIV infected children enrolled in the PACTG 219C study. AB - BACKGROUND: Hypercholesterolemia is common in perinatally HIV-infected (HIV+) children, but little is known about the clinical course and management in this population. METHODS: We studied HIV+ children in a multisite prospective cohort study (Pediatric AIDS Clinical Trials Group 219C) and considered follow-up for 2 years after development of hypercholesterolemia. We estimated the time and factors associated with resolution of hypercholesterolemia and described changes in antiretroviral regimen and use of lipid-lowering medications. We defined incident hypercholesterolemia as entry total cholesterol (cholesterol) <220 mg/dL and 2 subsequent consecutive cholesterol >= 220 mg/dL and defined resolution of hypercholesterolemia as 2 consecutive cholesterol <200 mg/dL after incident hypercholesterolemia. RESULTS: Among 240 incident hypercholesterolemia cases, 81 (34%) had resolution to normal cholesterol within 2 years of follow-up (median follow-up = 1.9 years). The median age of cases was 10.3 years with 54% non Hispanic black and 53% male. Resolution to normal cholesterol was more likely in children who changed antiretroviral regimen (adjusted hazard ratio = 2.37, 95% confidence interval: 1.45 to 3.88) and who were 13 years and older (aHR = 2.39, 95% confidence interval: 1.33 to 4.27). Types of regimen changes varied greatly, and 15 children began statins. CONCLUSION: The majority of children who develop hypercholesterolemia maintain elevated levels over time, potentially placing them at risk for premature cardiovascular morbidity. PMID- 21602699 TI - CD4+ T-cell counts and plasma HIV-1 RNA levels beyond 5 years of highly active antiretroviral therapy. AB - BACKGROUND: The heterogeneity of CD4 T-cell counts and HIV-1 RNA at 5-12 years after the initiation of highly active antiretroviral therapy (HAART) remains largely uncharacterized. METHODS: In the Multicenter AIDS Cohort Study, 614 men who initiated HAART contributed data 5-12 years subsequently. Multivariate regression was used to evaluate the predictors of CD4 counts and HIV-1 RNA levels. RESULTS: At 5 to 12 years post-HAART, the median CD4 T-cell count was 586 (interquartile range, 421-791) cells per microliter and 78% of the HIV-1 RNA measurements were undetectable. Higher CD4 T-cell counts 5-12 years post HAART were predicted by higher CD4 T-cell counts and higher total lymphocyte count pre HAART, lack of hepatitis B or C virus coinfections, and greater CD4 T-cell change and suppressed HIV-1 RNA in the first 5 years after starting HAART. Men who were 50 years and older with 351-500 CD4 cells per microliter at HAART initiation had adjusted mean CD4 T-cell count of 643 cells per microliter at 10-12 years post HAART, which was similar to the adjusted mean CD4 T-cell count (670 cells/MUL, P = 0.45) in this period for younger men starting HAART with lower CD4 T-cell counts. HIV-1 RNA suppression in the first 5 years post HAART predicted subsequent viral suppression. CONCLUSIONS: Immunological and virological responses in the first 5 years post HAART predicted subsequent CD4 T-cell counts and HIV-1 RNA levels. The association between age and subsequent CD4 T-cell count supports incorporating age in the guidelines for use of HAART. PMID- 21602700 TI - Clinical competencies for burn rehabilitation therapists. AB - Nationally agreed-upon standards for competence are needed for burn physical and occupational rehabilitation therapists (BRTs) to define what constitutes safe and competent burn rehabilitation practice. Currently, consensus regarding the knowledge and skill components needed for the training and evaluation of BRT job performance is lacking. The Rehabilitation Committee of the American Burn Association used a staged, multimethod approach and input from more than 25 experts in the burn rehabilitation community to develop competency standards for BRTs. The result was the "Burn Rehabilitation Therapist Competency Tool" (BRTCT) that defines competency domains required of BRTs to provide physical and occupational therapy to patients with burn injury during their initial acute hospitalization and rehabilitation. This article describes the staged development and validation of the BRTCT. The component parts of the tool itself are presented, and the recommendations for assessment of competence are discussed. The BRTCT provides a common framework and language for expectations of performance in burn rehabilitation. Development of the BRTCT is a critical step in the ongoing process of promoting professional development and consistent practice standards in burn rehabilitation. PMID- 21602701 TI - Intraductal papillary mucinous neoplasm and acute pancreatitis. AB - Intraductal papillary mucinous neoplasms (IPMNs) are cystic pancreatic tumors that arise from the pancreatic ducts and are increasingly reported worldwide. Both benign and malignant tumors of the pancreas are thought to contribute to recurrent pancreatitis possibly by pancreatic duct obstruction, and IPMNs contribute to a major share of this burden. The rate of acute pancreatitis (AP) in IPMN patients in the largest published surgical series has varied from 12% to 67%. IPMN may be categorized into 3 forms on the basis of the areas of involvement: main pancreatic duct (MD-IPMN), side branch (SB-IPMN), or combined. Both MD-IPMN and SB-IPMN may be the cause of pancreatitis. The risk of AP seems to be similar with both main duct IPMN and SB-IPMN, although data are controversial. AP in IPMN patients is not severe and often recurs without treatment. The rate of AP does not seem to differ among benign and malignant IPMNs, and the correlation between the malignant potential and the occurrence of AP is ill defined. AP seems to occur more often in patients with IPMN that in those with usual pancreatic adenocarcinoma possibly because of obstruction of the main duct by thick, abundant mucus secretion. Although the Sendai guidelines recommend surgical resection in patients with SB-IPMN with AP, data are controversial. Moreover, in patients with an episode of pancreatitis, the finding of pancreatic cysts is often attributed to pseudocysts or fluid collections that make the diagnosis of IPMN less suspicious. Future longitudinal and prospective studies to understand the natural history of AP in patients with IPMN are required to better manage patients with recurrent AP in the setting of IPMN. PMID- 21602702 TI - Hepatic lipid peroxidation and cytochrome P-450 2E1 in pediatric nonalcoholic fatty liver disease and its subtypes. AB - GOAL: To compare hepatic lipid peroxidation and cytochrome P-450 2E1 (CYP2E1) protein content in liver biopsies from children with nonalcoholic fatty liver disease (NAFLD) and 2 control groups. BACKGROUND: Elevated hepatic lipid peroxidation resulting from increased hepatic CYP2E1 enzyme activity is involved in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) in adults, but studies in children are lacking. STUDY: Liver biopsies from 59 children with NAFLD (49 with NASH), 10 children with normal liver histology, and 9 children with mild chronic hepatitis C (HCV) infection were examined. Hepatic malondialdehyde (a measure of lipid peroxidation) levels and CYP2E1 protein content were quantitated, as a percentage of the total area, by immunohistochemical staining of liver biopsy material followed by digital image quantitation. RESULTS: Lipid peroxidation was significantly greater in NAFLD liver biopsies (46.7 +/- 20.8%) compared with biopsies from children with normal liver histology (7.6 +/- 9.4%; P<0.001) or HCV infection (7.7 +/- 7.6%; P<0.001). However, hepatic CYP2E1 expression was not different across the NAFLD, normal liver histology, and HCV groups (60.7 +/- 8.7%, 53.5 +/- 10.7%, and 60.0 +/- 11.9%, respectively; P=0.116). Among children with NAFLD, lipid peroxidation and CYP2E1 protein content did not differ between biopsies with and without NASH. Body mass index was independently associated with hepatic lipid peroxidation levels (r=0.549; P<0.001). CONCLUSIONS: Hepatic lipid peroxidation is increased in children with NAFLD but this is not related to hepatic CYP2E1 expression. No difference in lipid peroxidation in pediatric NAFLD versus NASH argues against a role in disease progression. PMID- 21602703 TI - Endoscopically assisted water perfusion esophageal manometry with minimal sedation: technique, indications, and implication on the clinical management. AB - GOALS: To demonstrate feasibility and clinical utility of endoscopically assisted manometry (EAM). BACKGROUND: Esophageal manometry performed without sedation is the standard for assessment of esophageal motility. However, some patients cannot tolerate the procedure with intranasal intubation. We have accumulated experience performing EAM with minimal sedation on patients who cannot tolerate standard esophageal manometry. STUDY: We report our single center experience of EAM in adult patients. Patient records were analyzed retrospectively. PROCEDURE PROTOCOL: Upper endoscopy is performed with minimal sedation to place a guide wire, over which a water perfusion manometry catheter is introduced and standard manometry protocol performed. RESULTS: From 2007 to 2009, 51 patients underwent EAM, 41 (80.4%) for failed transnasal esophageal manometry and 10 (19.6%) for Zencker diverticulum, achalasia, or neurologic disease. Five patients could not tolerate the procedure despite sedation. No early or late complications were recorded and 100% of the completed procedures were diagnostic: 15 (32.6%) patients had a normal study, 13 (28.3%) were diagnosed with achalasia, 12 (26.1%) patients had low lower esophageal sphincter pressure, 10 (21.7%) patients showed ineffective esophageal motility, 3 (6.5%) patients had hypertensive lower esophageal sphincter, and 1 (2.2%) patient had nutcracker esophagus. Completed procedures resulted in treatment for achalasia (33.3%), medication changes (33.3%), completion of preoperative assessment for antireflux surgery (27.7%), or no impact clinical management (11.1%). EAM had a direct clinical impact on 89% of patients. CONCLUSIONS: EAM is a safe, reliable, and feasible technique providing objective diagnostic information that directly impacted clinical management in many problematic patients where the standard procedure failed. PMID- 21602704 TI - Patient involvement in healthcare is associated with higher rates of surveillance for hepatocellular carcinoma. AB - BACKGROUND: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but earlier studies suggest that it is used less than one-third of the time. Patient factors associated with surveillance rates are incompletely understood. GOALS: The aims of our study were to determine HCC surveillance rates in a tertiary-care center and to identify patient predictors of receiving surveillance. STUDY: Patients with Child A or B cirrhosis seen in the University of Michigan liver clinics between October 2008 and March 2009 were enrolled to complete a self-administered survey. Surveillance rates and clinical data were extracted from the patient electronic medical record. RESULTS: Of the 160 patients enrolled, 74.4% had HCC surveillance performed in the past year. On multivariate analysis, predictors of receiving surveillance included male sex (odds ratio 7.1, 95% confidence interval, 1.2-43.2) and patient involvement in their care (odds ratio 3.4, 95% confidence interval, 1.5-7.9). Patients expressed high levels of concern regarding HCC, desired more information from their physicians, and wanted to be more involved in their care. CONCLUSIONS: HCC surveillance rates in a tertiary-care center were significantly higher than earlier reported rates. Direct patient involvement in decisions regarding HCC surveillance may help to improve surveillance rates. PMID- 21602706 TI - Development of a resident training module for systematic optic disc evaluation in glaucoma. AB - PURPOSE: To determine the impact on ophthalmology residents of a training module to teach systematic optic disc (disc) evaluation. METHODS: A training module for disc evaluation was developed consisting of: (1) a computer-based evaluation course with 100 illustrative disc photographs featuring normal and glaucomatous discs; (2) 2 different disc photograph test sets to be completed before and after taking the course; and (3) a 1-page checklist emphasizing 8 areas of disc evaluation to guide the residents through the test sets. Each area required identification of 2 to 3 key features pertinent to glaucoma. Points were assigned to each correctly answered item on the checklist by ophthalmology residents of 2 training programs. Residents were also asked to evaluate the disc according to a glaucoma scale. Main outcome measures included precourse and postcourse checklist scores and disc glaucoma evaluation scores. RESULTS: Twenty-eight residents from 2 training programs completed the training module. Mean checklist scores improved significantly after taking the evaluation course across all residents and in residents who had 2 years of ophthalmology residency experience (P = 0.019, 0.017, respectively). Precourse disc glaucoma evaluation score increased 4% to 6% per year of ophthalmology residency training (P = 0.023, R = 0.1838). One program had a higher mean postcourse disc glaucoma evaluation score than another (P = 0.038). CONCLUSIONS: A systematic disc evaluation module for resident training may improve disc evaluation, provide an objective method to assess the resident's learning experience, monitor the progress and identify areas of weakness of training, and compare results among groups of residents across different residency programs. PMID- 21602705 TI - Five-year outcomes of eyes with glaucoma drainage device and penetrating keratoplasty. AB - PURPOSE: To investigate intraocular pressure (IOP) control and corneal graft survival rates in eyes with glaucoma drainage device (GDD) implantation and penetrating keratoplasty (PK) and 5 years of follow-up data. DESIGN: Retrospective review. METHODS: We performed a review of records of all patients who underwent both GDD placement and PK at our institution between January 1, 1988 and December 31, 2003. Twenty-eight eyes of 27 patients were studied. Glaucoma outcome was assessed by postoperative IOP, number of glaucoma medications, and need for further glaucoma surgery. Corneal grafts were assessed for clarity. RESULTS: All eyes had GDD placement in the anterior chamber. The mean pre-GDD IOP was 28.8 +/- 10.3 mm Hg on a mean of 2.6 +/- 0.8 glaucoma medications. At 5-year follow-up, the mean IOP was 13.0 +/- 5.9 mm Hg on a mean of 0.9 +/- 1.0 glaucoma medications. GDD implantation successfully controlled glaucoma in 96%, 86%, 79%, 75%, and 71% of eyes at 1, 2, 3, 4, and 5 years, respectively. Grafts remained clear in 96%, 82%, 75%, 57%, and 54% of eyes at 1, 2, 3, 4, and 5 years, respectively. Failure of glaucoma outcome or graft survival was associated with prior intraocular surgeries. CONCLUSIONS: Our data suggests that GDD placement can provide glaucoma control in a high percentage (71%) of eyes with PK even at 5 years. Furthermore, the success of PK in eyes with GDD remains reasonable (54%) at 5 years. IOP control and graft survival rates are comparable with earlier published studies with shorter follow-up or tube placement in the vitreous cavity. PMID- 21602707 TI - 24-hour intraocular pressure fluctuation monitoring using an ocular telemetry Sensor: tolerability and functionality in healthy subjects. AB - PURPOSE: To evaluate the tolerability, comfort, and reliability of the signal transmission of an ocular Sensor used for 24-hour intraocular pressure fluctuation monitoring in humans. PATIENTS AND METHODS: In this uncontrolled open trial involving 10 healthy volunteers, an 8.7-mm radius prototype ocular telemetry Sensor (SENSIMED Triggerfish, Lausanne, Switzerland) and an orbital bandage containing a loop antenna were applied and connected to a portable recorder after full eye examination. Best-corrected visual acuity and position, surface wetting ability, and mobility of the Sensor were assessed after 5 and 30 minutes, 4, 12, and 24 hours. Subjective wearing comfort was scored and activities documented in a logbook. After Sensor removal, a full eye examination was repeated and the recorded signal analyzed. RESULTS: The comfort score was high and did not fluctuate significantly over time. The mobility of the Sensor was limited across follow-up visits and its surface wetting ability remained good. Best-corrected visual acuity was significantly reduced during Sensor wear and immediately after its removal (from 1.07 before, to 0.85 after, P value 0.008). Three subjects developed a mild, transient corneal abrasion. In all but 1 participant, we obtained usable data of a telemetric signal recording with sufficient sensitivity to depict ocular pulsation. CONCLUSIONS: This 24-hour trial has encouraging results on the tolerability and functionality of the ocular telemetric Sensor for intraocular pressure fluctuation monitoring. Further studies with different Sensor radii conducted on a larger study population are needed to improve comfort, precision, and interpretation of the telemetric signal. PMID- 21602708 TI - Longitudinal changes in anterior chamber configuration in eyes with open-angle glaucoma and associated factors. AB - PURPOSE: To investigate longitudinal changes in anterior chamber depth (ACD) and anterior chamber angle (ACA) and the associated factors in patients with primary open-angle glaucoma using the scanning peripheral ACD analyzer. METHODS: The scanning peripheral ACD analyzer evaluated ACD by numeric grade (ACDG 1 to 12) and ACA twice in 2003 and 2008. The exclusion criteria were as follows: history of laser or incisional surgery, other ocular diseases that may affect visual field, visual acuity less than 20/30, and treatment with pilocarpine ophthalmic solution. Patients with pseudophakic eye were used as control. RESULTS: One hundred fifty-seven patients with glaucoma and 26 patients with pseudophakic eye were subjected to the analysis. ACDG and ACA of patients with glaucoma were significantly decreased from 7.2+/-2.3 to 6.5+/-2.1 (P<0.001) and from 34.2+/ 12.6 to 28.1+/-10.3 degrees (P<0.0001), respectively, whereas patients with cataract surgery showed no significant changes in ACDG and ACA. The change in ACD was greater at the peripheral region than at the central region. The decrease in ACDG was significantly associated with deep initial ACDG and wide ACA. Patients having shallow ACDG and narrow ACA showed more rapid deterioration of visual field than those having deep ACDG and wide ACA. CONCLUSIONS: ACDG and ACA decreased with age, and initial ACDG and ACA were related to the progression of open-angle glaucoma. PMID- 21602709 TI - The role of antihypertensive therapy in reducing vascular complications of type 2 diabetes. Findings from the DIabetic REtinopathy Candesartan Trials-Protect 2 study. AB - BACKGROUND: Recent trials question previously accepted low blood pressure targets in type 2 diabetes to reduce complication risk. We explored this question in the DIabetic REtinopathy Candesartan Trials-Protect 2 clinical trial. METHODS: A total of 1905 normoalbuminuric participants with type 2 diabetes and mild moderate retinopathy were randomized to candesartan or placebo. Participants were normotensive [untreated, blood pressure (BP) < 130/85 mmHg] or treated hypertensive [(62%), BP < 160/90 mmHg]. The effects of candesartan on microvascular and macrovascular endpoints alone and in combination were analysed, including subgroup analyses by baseline hypertension status. RESULTS: Mean age was 57 +/- 8 years, 50% were men, mean diabetes duration was 9 +/- 5 years and baseline HbA1c was 8.2 +/- 1.6%. Mean randomization BP was 123/75 mmHg in the normotensive, and 139/79 mmHg in the treated hypertensive subgroups. During the median 4.7-year follow-up, achieved systolic pressure on candesartan was 128 mmHg in baseline normotensive individuals, and 136 mmHg in treated hypertensive patients. Candesartan reduced combined macrovascular and microvascular complication risk; the age and baseline SBP overall adjusted hazard ratio for candesartan vs. placebo was 0.85 [95% confidence interval (CI) 0.72-0.99], P = 0.040, reflecting hazard ratios of 0.86 (0.66-1.13) for baseline normotensive individuals and 0.83 (0.68-1.02) for hypertensive patients. Hazard ratios were 0.87 (0.74-1.04) for microvascular and 0.84 (0.57-1.25) for macrovascular complications, when analysed separately. However, an interaction (P = 0.06) between hypertensive [hazard ratio 0.67 (0.42-1.07)] and normotensive (1.45, 0.71 2.94) subgroups was observed for macrovascular events. CONCLUSION: Candesartan modestly reduces vascular complication risk in treated hypertensive diabetic individuals at low risk of cardiovascular disease. Separate analyses of microvascular and macrovascular events suggest that candesartan may not reduce macrovascular events in normotensive persons with type 2 diabetes. PMID- 21602710 TI - Cardiovascular consequences of extreme prematurity: the EPICure study. AB - OBJECTIVES: The long-term consequences of extreme prematurity are becoming increasingly important, given recent improvements in neonatal intensive care. The aim of the current study was to examine the cardiovascular consequences of extreme prematurity in 11-year-olds born at or before 25 completed weeks of gestation. METHODS: Age and sex-matched classmates were recruited as controls. Information concerning perinatal and maternal history was collected, and current anthropometric characteristics were measured in 219 children born extremely preterm and 153 classmates. A subset of the extremely preterm children (n = 68) and classmates (n = 90) then underwent detailed haemodynamic investigations, including measurement of supine blood pressure (BP), aortic pulse wave velocity (aPWV, a measure of aortic stiffness) and augmentation index (AIx, a measure of arterial pressure wave reflections). RESULTS: Seated brachial systolic and diastolic BP were not different between extremely preterm children and classmates (P = 0.3 for both), although there was a small, significant elevation in supine mean and diastolic BP in the extremely preterm children (P < 0.05 for both). Arterial pressure wave reflections were significantly elevated in the extremely preterm children (P < 0.001) and this persisted after adjusting for confounding variables. However, aortic stiffness was not different between the groups (P = 0.1). CONCLUSIONS: These data suggest that extreme prematurity is associated with altered arterial haemodynamics in children, not evident from the examination of brachial BP alone. Moreover, the smaller, preresistance and resistance vessels rather than large elastic arteries appear to be most affected. Children born extremely preterm may be at increased future cardiovascular risk. PMID- 21602711 TI - Olmesartan ameliorates peripheral nerve dysfunction in Zucker diabetic fatty rats. AB - OBJECTIVE: Angiotensin (ANG) II type 1 receptor (AT1R) blockers have neuroprotective effects against neuronal lesions. The present study examines whether the AT1R blocker olmesartan improves peripheral nerve dysfunction in rats with type 2 diabetes. METHODS: Fourteen-week-old male type 2 diabetic Zucker diabetic fatty (ZDF) rats were orally administered with olmesartan (6 mg/kg per day; n = 7) or not treated (n = 7) and then followed up for nine weeks. Age matched and sex-matched nondiabetic lean rats served as controls (n = 7). RESULTS: Olmesartan for 9 weeks did not influence blood glucose and A1c levels that were higher in untreated ZDF (U-ZDF) rats than in control rats. In U-ZDF rats, myelinated fiber density and myelin areas of myelinated fibers in peroneal nerves significantly increased and decreased, respectively, and the intraepidermal nerve fiber density (IENFD) of footpad skin tended to decrease. The U-ZDF rats developed mechanical hyperalgesia, thermal hypoalgesia and slower sensory and motor nerve conduction in the sciatic-tibial nerves. Olmesartan increased myelin areas and IENFD and ameliorated sensory nerve conduction deficits. These beneficial effects of olmesartan were associated with ANG II and insulin receptor upregulation in sensory neurons as well as deactivation of Erk1/2 in sciatic nerves. CONCLUSION: Olmesartan appears to improve the structure and function of small and large nerves and upregulate ANG II and insulin receptors in sensory neurons of rats with type 2 diabetes. PMID- 21602712 TI - Dysregulation of renal transient receptor potential melastatin 6/7 but not paracellin-1 in aldosterone-induced hypertension and kidney damage in a model of hereditary hypomagnesemia. AB - RATIONALE: Hyperaldosteronism, important in hypertension, is associated with electrolyte alterations, including hypomagnesemia, through unknown mechanisms. OBJECTIVE: To test whether aldosterone influences renal Mg(2+) transporters, (transient receptor potential melastatin (TRPM) 6, TRPM7, paracellin-1) leading to hypomagnesemia, hypertension and target organ damage and whether in a background of magnesium deficiency, this is exaggerated. METHODS AND RESULTS: Aldosterone effects in mice selectively bred for high-normal (MgH) or low (MgL) intracellular Mg(2+) were studied. Male MgH and MgL mice received aldosterone (350 MUg/kg per day, 3 weeks). SBP was elevated in MgL. Aldosterone increased blood pressure and albuminuria and increased urinary Mg(2+) concentration in MgH and MgL, with greater effects in MgL. Activity of renal TRPM6 and TRPM7 was lower in vehicle-treated MgL than MgH. Aldosterone increased activity of TRPM6 in MgH and inhibited activity in MgL. TRPM7 and paracellin-1 were unaffected by aldosterone. Aldosterone-induced albuminuria in MgL was associated with increased renal fibrosis, increased oxidative stress, activation of mitogen-activated protein kinases and nuclear factor-NF-kappaB and podocyte injury. Mg(2+) supplementation (0.75% Mg(2+)) in aldosterone-treated MgL normalized plasma Mg(2+), increased TRPM6 activity and ameliorated hypertension and renal injury. Hence, in a model of inherited hypomagnesemia, TRPM6 and TRPM7, but not paracellin-1, are downregulated. Aldosterone further decreased TRPM6 activity in hypomagnesemic mice, a phenomenon associated with hypertension and kidney damage. Such effects were prevented by Mg(2+) supplementation. CONCLUSION: Amplified target organ damage in aldosterone-induced hypertension in hypomagnesemic conditions is associated with dysfunctional Mg(2+)-sensitive renal TRPM6 channels. Novel mechanisms for renal effects of aldosterone and insights into putative beneficial actions of Mg(2+), particularly in hyperaldosteronism, are identified. PMID- 21602713 TI - Effect of nebivolol vs. hydrochlorothiazide on the walking capacity in hypertensive patients with intermittent claudication. AB - AIMS: Whereas product labels of beta blockers list peripheral arterial disease (PAD) as a contraindication, current PAD guidelines state otherwise. We aimed to evaluate the clinical efficacy and safety of the beta(1) selective blocker nebivolol in hypertensive patients with PAD. METHODS AND RESULTS: This multicentre, prospective, double-blind, active controlled, parallel-group study compared once-daily treatment with nebivolol (Neb) 5 mg vs. hydrochlorothiazide (HCTZ) 25 mg, in hypertensive patients with Fontaine stage II (intermittent claudication). The primary endpoint was the initial claudication distance (ICD) during treadmill exercise after 24-week treatment in the per protocol population, using a noninferiority statistical approach. A total of 177 patients (mean age was 66.3 +/- 9.2 years, 76.7% men) were randomized to study treatment and 127 completed the study; the intent-to-treat (ITT) analysis was performed on 163 patients, the per protocol analysis on 127 patients. Both drugs lowered blood pressure significantly. After 24-week treatment, ICD increased in the Neb group in the ITT population by 28.3% (95% CI 15.6-41.0) vs. in the HCTZ group by 26.5% (14.4-38.5), and in the per protocol population in the Neb group by 26.4% (13.4 39.4) vs. in the HCTZ group by 32.1% (18.4-45.7). Thus, noninferiority of Neb could neither be confirmed nor rejected. An increase of absolute claudication distance (ACD, mean percentage increase after 24 weeks on Neb 15.8 +/- 33.2 vs. on HCTZ 20.2 +/- 46.6) was observed without statistical differences between groups. Ankle-brachial index (ABI) increased slightly in both groups. Generally, both treatments were well tolerated. CONCLUSION: The increases in ICD, ACD and ABI with nebivolol suggest that this medication does not have negative effects on hypertensive patients with symptomatic PAD, and can be used for treatment of hypertension in these patients at high cardiovascular risk without reducing the walking ability. PMID- 21602715 TI - Detection of neurosurgical intraoperative brisk blood loss with stroke volume variation. PMID- 21602714 TI - alpha-Kinase 2 is a novel candidate gene for inherited hypertension in Dahl rats. AB - OBJECTIVES: The interval harboring a quantitative trait locus for blood pressure (BP), C18QTL3, contains beta-2 adrenergic receptor (Adrb2) and neural precursor cell expressed, developmentally downregulated 4-like (Nedd4l) genes. None of the other genes in the C18QTL3-residing interval is known to affect BP. The identification of C18QTL3 might uncover a brand new gene that could prosper into a novel diagnostic and/or therapeutic target for essential hypertension, if neither Adrb2 nor Nedd4l could be upheld as candidate genes. METHODS: Congenic fine resolution was combined with gene analyses. RESULTS: The gene encoding alpha kinase 2 (Alpk2) contains a three base-pair deletion and multiple nonconserved mutations in its coding region in Dahl salt-sensitive (DSS) rats. In contrast, the gastrin-releasing peptide gene (Grp) possesses two nonconserved mutations, designated as single nucleotide polymorphisms 1 and 2 (i.e. SNP1 and SNP2), but could not be supported as a candidate gene because the C18S.L14 congenic strain displayed a homozygous DSS genotype at both SNP1 and SNP2. Furthermore, Adrb2 and Nedd4l could not account for the BP-diminishing effect of Lewis alleles in C18S.L14, as their DSS alleles bear functionally identical domains as those of Lewis, and no evidence of differential expression and splicing was evident. No significant nucleotide variations were found in 13 other genes closely linked to Alpk2. CONCLUSION: Alpk2 emerged as a strong candidate gene for C18QTL3. The present study is the first to implicate Alpk2 in the genetics of polygenic hypertension and paves the way for novel gene discovery. PMID- 21602717 TI - Body composition changes in preterm infants following hospital discharge: comparison with term infants. AB - BACKGROUND AND OBJECTIVES: Infants experiencing catch-up growth devote a greater proportion of their energy to fat deposition, potentially at the expense of gains in lean body mass. The objective of the present study was to compare the body composition of preterm and term infants after hospital discharge and to determine the effect of gestational age (GA), birth size, nutrition, and illness on growth in fat-free mass (FFM) after hospitalization. PATIENTS AND METHODS: Anthropometric measurements and body composition testing via air displacement plethysmography were performed on 26 appropriate-for-gestational-age (AGA) preterm (mean GA 31.5 +/- 2.7 weeks) and 97 AGA term (mean GA 39.8 +/- 1.0 weeks) infants at term corrected age (CA) and at 3 to 4 months CA. RESULTS: At term CA, preterm infants had lower FFM (3.0 vs 3.3 kg, P = 0.001), higher percentage of body fat (18.7% vs 15.2%, P < 0.0001), lower weight (P =0.04), and shorter length (P = 0.001) than term infants. By 3 to 4 months CA, weight, length, percentage of body fat, and FFM were similar in the 2 groups. GA, inpatient nutrition, and illness were associated with FFM at 4 months CA in the preterm infants (P < 0.05). CONCLUSIONS: Markedly lower FFM and higher adiposity were observed in preterm infants at term CA, but these differences had lessened and were no longer statistically significant at 3 to 4 months CA. Although early nutrition was associated with growth trajectories in the hospital, the continuing influence of early illness on postdischarge growth suggests that nonnutritional factors (eg, disturbances in the growth hormone axis) also may affect body composition trajectories of preterm infants. PMID- 21602718 TI - Efficacy of hydroxyurea in providing transfusion independence in beta thalassemia. AB - BACKGROUND: Packed red blood cell (PRC) transfusion with iron chelation is the mainstay of treatment for beta-thalassemia major. This prospective interventional trial serves as a follow up to our similar earlier study that evaluated the efficacy and safety of hydroxyurea (HU) in minimizing PRC transfusions in patients with beta-thalassemia major. METHODS: One hundred fifty-two patients with beta-thalassemia major received HU at a mean dose of 16 mg/kg/d. The results were analyzed at the end of 24 months. Transfusion requirement during the 6 months preceding the study was considered as the control. RESULTS: One hundred forty-six of 152 patients were evaluated after 24 months of follow up; 6 patients were either lost to follow-up or withdrew consent. Grade 1 myelosuppression was observed in 4 patients and diarrhea in 2 patients. Sixty children (41%) did not require any transfusion after using HU; 57 patients (39%) showed partial response with greater than 50% reduction in PRC transfusion; and 29 patients (20%) were nonresponders with less than 50% reduction in PRC transfusion. The mean volume of PRC transfused was reduced for all patients. CONCLUSIONS: HU was found to be safe in patients with beta-thalassemia major, and resulted in the reduction of transfusion requirement and in an increase in the interval between transfusions. PMID- 21602719 TI - Plasma homocysteine levels, methylene tetrahydrofolate reductase polymorphisms, and the risk of thromboembolism in children. AB - INTRODUCTION: Hyperhomocystenemia (HHcy) is a risk factor for thrombosis in adults. Polymorphisms in methylene tetrahydrofolate reductase (MTHFR) enzyme may cause HHcy. Data on their role in pediatric thromboembolism (TE) are sparse. MATERIALS AND METHODS: Charts of patients from 1989 to 2007, with documented TE, were reviewed. Homocysteine (Hcy) levels were defined both as per the adult normal range and the age-specific normal ranges from literature. RESULTS: A total of 141 patients (67 females, 74 males) were identified. With age-specific normal ranges for Hcy, 15 patients were found to have HHcy: 6 had CT, 9 patients had CC, and none had TT MTHFR genotype. When adult normal range was used, HHcy (>12 MUmol/L) was seen in 7 patients: 4 had CT and 3 had the CC genotype. Again, none had TT genotype. In addition, the mean Hcy levels were unaffected by sex and ethnicities, but universal folic acid supplementation (post 1996) lowered the mean. CONCLUSIONS: (1) Age-specific ranges for Hcy should be used in pediatrics for accurate diagnosis of HHcy. (2) MTHFR C677T polymorphism is not a risk factor in pediatric TE. (3) Folic acid supplementation could play a role in lowering the prevalence of HHcy. PMID- 21602720 TI - Inferior vena cava filters in children: our experience and suggested guidelines. AB - Although use of inferior vena cava (IVC) filters for prophylaxis against pulmonary embolism (PE) is well reported in adults, long-term studies in children are lacking. We performed retrospective review of imaging and clinical database of IVC filters for the last 12 years. Thirty-five patients (mean age: 15.5 y) underwent filter placement and/or retrieval. Indications for placement were contraindication to anticoagulation with known deep venous thrombosis (DVT) (18) or high risk of venous thromboembolism (5), recurrent DVT despite anticoagulation (1), and prophylaxis before endovascular thrombolysis (8). All filter placements were technically successful without any complications. Filter retrieval was successful in 15 of 19 attempted (79%) at a mean of 42 days. Two complications occurred during retrieval: IVC stenosis successfully treated with angioplasty and contained IVC perforation. Endothelialization of filter prevented retrieval in 4 patients. Mean follow-up was 29.3 months. No patients had IVC thrombosis, breakthrough pulmonary embolism, filter fracture, or embolism. Two patients had recurrent DVT. Our results indicate that IVC filters can be successfully placed and retrieved in children with minimal procedural complications; follow-up demonstrates acceptable complication rate owing to presence of filters. Prophylactic IVC filter placement may be considered before endovascular thrombolysis for lower extremity DVT. Retrievable filters should be used in children for appropriate indications. PMID- 21602721 TI - Childhood hemangiopericytoma: review of St Jude Children's Research Hospital. AB - BACKGROUND: Hemangiopericytoma (HPC) is a heterogeneous, highly vascularized malignant soft-tissue neoplasm with 2 different clinical presentations: adult type and infantile-type HPC. Intracranial HPC represents a special subtype with a high proclivity toward recurrence and metastasis. METHODS: The authors have reviewed the clinical features, response to treatment, and outcomes of 17 patients with HPC treated at St Jude Children's Research Hospital from 1962 to 2009. RESULTS: At diagnosis, 11 patients were older than 1 year (subgroup A) and 6 patients were younger than 1 year (subgroup B). Subgroup A: median age at diagnosis 13.5 years, (range, 4 to 20 y). Primary sites were intracranial (n=5), thigh (n=3), calf (n=1), foot (n=1), and scalp (n=1). One patient who presented with a thigh HPC had metastatic disease at diagnosis, and 3 patients with head location had unresectable tumors. Two patients with thigh location experienced objective responses to chemotherapy. Six patients died of disease progression, 4 of them had an intracranial location. The remaining 5 children are alive at follow-up of 12 to 32 years. Subgroup B: median age at diagnosis 0.5 months (range, 0 to 3 mo). Primary sites were thigh (n=2), calf (n=1), perianal (n=1), forearm (n=1), and lung (n=1). Three patients with limb location had unresectable disease at diagnosis, 2 of them experienced excellent responses to neoadjuvant chemotherapy and 1 did not show any response to chemotherapy and a staged resection was performed. All 6 infants are alive without evidence of disease at follow-up of 2 to 27 years. CONCLUSIONS: Infantile HPC is characterized by a better clinical behavior than the adult type, which requires an aggressive multimodality therapy. Chemoresponsiveness and spontaneous regression have been reported in children younger than 1 year, suggesting that a more conservative surgical approach should be used. Intracranial HPC is considered as an aggressive tumor because of its propensity for recurrence and metastasis. PMID- 21602722 TI - Excellent local control and survival after intraoperative and external beam radiotherapy for pediatric solid tumors: long-term follow-up of the Mayo Clinic experience. AB - Use of external beam radiotherapy (EBRT) for pediatric solid malignancies is generally limited by the tolerance of normal tissue in developing organs. Intraoperative electron radiotherapy (IOERT) allows a more focal delivery of radiation dose because vital organs can be displaced and avoided during treatment. From February 1983 to July 2003, 20 children underwent IOERT for treatment of locally advanced or recurrent malignancies of the extremity or abdominopelvic area. All patients underwent EBRT and received IOERT doses of 7.5 to 25 Gy with 6-MeV to 15-MeV electrons. At a median follow-up of 11.6 years (range, 2.1 to 25.5 y), 13 patients (65%) were alive and without evidence of disease. Patients who underwent gross total resection had better local control (88% vs. 67%) and survival (71% vs. 33%) than patients for whom the resection was not achieved. Among 7 patients, 11 grade 3 toxicity events were reported. No grade >3 toxicities or second malignancies were observed during follow-up. Use of IOERT in combination with surgery and EBRT in management of pediatric solid malignancies provides excellent local control with reasonable toxicity. IOERT should be considered as an integral part of a multimodality regimen for pediatric solid malignancies, especially for patients with abdominopelvic malignancies. PMID- 21602723 TI - Growing up with sickle cell disease: a pilot study of a transition program for adolescents with sickle cell disease. AB - We implemented the Duke Sickle Cell Disease (SCD) Transition Program for adolescents with SCD and investigated the knowledge about SCD; concerns and emotions about transitioning; and the initial impact of the Transition Program. Thirty-three adolescents participated in the initial study. Gaps in knowledge included ethnicities affected by SCD and inheritance of SCD. Adolescents were primarily concerned about transferring to a new medical team. There was a mix of both positive and negative emotions that varied over time. Overall, we have identified educational gaps and concerns and emotions about transitioning, which we will address through the Duke SCD Transition Program. PMID- 21602724 TI - Vancomycin-resistant Enterococcus faecium bacteremia successfully treated with high-dose ampicillin-sulbactam in a pediatric patient after hematopoietic stem cell transplantation. PMID- 21602725 TI - Use of positron emission tomography in the evaluation of diffuse intrinsic brainstem gliomas in children. AB - BACKGROUND: Diffuse intrinsic brainstem gliomas (DIBSGs) in children remain difficult tumors to treat and have a very poor prognosis. Intensifying both chemotherapy and radiation programs have been attempted without success. Positron emission tomography (PET) has been used to differentiate benign from malignant tumors and may predict outcome. OBJECTIVES: To determine whether PET can characterize a specific metabolic pattern of DIBSGs and correlate this with patient survival. METHODS: We conducted a retrospective review of patients with DIBSGs and PET scans at diagnosis. Data for 18[F] fluorodeoxyglucose (FDG) and 11C-methionine (CMET) PET scans were collected. Treatment and survival were reviewed. RESULTS: We identified 30 patients with DIBSGs, 25 of whom had FDG and/or CMET PET scans. Scans showed both focal and generalized metabolic activity, and the patterns showed no correlation with survival. Patients with both FDG and CMET positive scans had a mean survival of 380 days, whereas those negative for both isotopes had a mean survival of 446 days. CONCLUSIONS: There was no specific PET pattern identified in this DIBSG cohort but a trend toward improved survival was noted with absence of FDG and CMET metabolism. Metabolically active areas may suggest potential sites for biopsy. We believe that biopsy is essential for improving therapy for this patient population. PMID- 21602726 TI - A rare case of ectopic recurrence of a craniopharyngioma diagnosed 17 years after initial presentation. AB - Ectopic recurrence of craniopharyngioma 17 years after initial diagnosis is exceedingly rare in pediatric neuro-oncology. Only 23 cases of ectopic recurrence in children with craniopharyngioma are described in the literature with a median time to recurrence of 3 years. We describe a patient diagnosed at 5 years of age, presenting with neck pain and ataxia 17 years after diagnosis. Her original follow-up care was fragmented and included surveillance imaging for 10 years after surgery and endocrine management of panhypopituitarism. Rare, extremely late relapse of this tumor highlights the importance of extended multidisciplinary follow-up care that includes neuro-oncologists in a late effects/survivorship program. PMID- 21602727 TI - Intraspinal epidermoid tumor of the cauda equina region: seven cases and a review of the literature. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To investigate the clinical features and surgical outcomes of patients with intraspinal epidermoid tumor of the cauda equina region. SUMMARY OF BACKGROUND DATA: Intraspinal epidermoid tumor of the cauda equina region is very rare, and the majority of the existing literature of this condition comprises case reports with a few case series. METHODS: The clinical features and surgical outcomes of 7 patients (2 males, 5 females; age range, 4-66 y) with intraspinal epidermoid tumor of the cauda equina region were retrospectively studied, and a literature review was performed. All patients complained of neurologic symptoms and underwent microscope-assisted surgery. The mean duration of postoperative follow-up was 126 months (range, 52 209 mo). RESULTS: Antecedent lumbar puncture had been performed on 3 patients, and 4 cases thought to be of congenital origin without a past history of lumbar puncture had no associated anomalies, such as spina bifida or dermal sinus. Postoperatively, complications occurred in 3 patients concerning cauda equina symptom. Two patients (29%) had tumor recurrence, diagnosed 1 and 13 years after surgery, respectively. Immediately after additional surgery for tumor recurrence, both patients had severe paresis of the hemilateral foot. CONCLUSIONS: Complete removal without tear of the tumor was difficult in our case series, because the capsule of the tumor was thin and often adhered to the cauda equina nerve roots or dura mater. However, total resection of the capsule is important, because patients with epidermoid tumor are at risk for recurrence. On the other hand, aggressive resection of the capsule adhering to the neural elements can cause a high rate of neurological complications postoperatively, especially after surgery for tumor recurrence. PMID- 21602728 TI - Assessment of pedicle screw placement accuracy, procedure time, and radiation exposure using a miniature robotic guidance system. AB - STUDY DESIGN: Controlled, cadaveric implantation trial. OBJECTIVE: To evaluate the effect of a robotic guidance system on screw placement accuracy, amount of radiation exposure, and length of procedure time during percutaneous pedicle screw implantation. SUMMARY OF BACKGROUND DATA: Pedicle screws are associated with low complication rates, and several computer-assisted image guidance systems exist that facilitate accurate screw placement. However, these systems may represent substantial radiation exposure risk to patients and surgeons. METHODS: We implanted 234 pedicle screws in 12 cadavers (study group: 15 surgeons, 197 screws, and 10 specimens; control group: 2 surgeons, 37 screws, and 2 specimens). We measured procedure time, fluoroscopy time, and radiation exposure and evaluated screw placement accuracy with computed tomography scans. To evaluate the learning curve, we compared measurements with those of an experienced robotic guidance user through the 2-sample (heteroscedastic), 1-tail t test (P< 0.05). RESULTS: Relative to control, the study group had fewer screw placement deviations (average, 2.6+/-0.7 mm vs. 1.1+/-0.4 mm; P<0.0001), fewer pedicle wall breaches of 4 mm or greater (average, 5.4% vs. 1.5%), lower surgeon radiation exposure (average, 136 mrem vs. 4.2 mrem), lower fluoroscopy time per screw (average, 33.0 s vs. 0.9 s), and shorter procedure time (average, 1.98 h vs. 1.23 h). Use of robotic guidance increased the accuracy of percutaneous pedicle screw placement by 58%, thereby reducing the risk of neurologic injury (as measured by breaches >4 mm), new-user radiation exposure (by 98.2%), and procedure time (by 36%). CONCLUSIONS: The advantages associated with a robotic guidance system may make the surgeon more at ease about offering minimally invasive or percutaneous surgical options to patients and more comfortable about implementing pedicle based fixation in general. This advanced technology may also allow inclusion of patients with complicated anatomic deformities, who are often excluded from pedicle screw-based surgery options. PMID- 21602729 TI - Making do. PMID- 21602730 TI - Screening for hyperopia in infants using the PowerRefractor. AB - PURPOSE: To determine the proportion of infants in a pediatric medical practice who have high levels of hyperopia in addition to evaluating the ability of the PowerRefractor (PR) [with and without accessory +4.50 diopter (D) spectacles] compared with cycloplegic retinoscopy to detect highly hyperopic refractive errors. METHODS: The cycloplegic refractive error (2 drops tropicamide 1% given 5 min apart) of 200 normal birth weight infants was measured by retinoscopy and the Plusoptix PR. If initial readings were >= +2.00 D, PR measurement was repeated with accessory +4.50 D spectacles to extend its operating range. Examinations were conducted during well-baby visits at 2 months of age at the office of a local pediatrician group practice. RESULTS: Of the 200 infants, 7.5% had a spherical equivalent refractive error of +5.00 D or more in both eyes. The use of +4.50 D accessory glasses during PowerRefraction significantly improved the ability to detect higher levels of hyperopia. Areas under receiver operating characteristic curves that were 0.69 to 0.51 when no glasses were worn improved to 0.87 to 0.98 when the glasses were worn (cutpoints between +3.50 and +5.00 D by retinoscopy). Significant underestimation of higher levels of hyperopia by the PR compared with retinoscopy was eliminated when +4.50 D accessory glasses were worn. CONCLUSIONS: Accessory +4.50 diopter sphere spectacles appeared to successfully extend the operating range of the PR with cycloplegia, allowing for detection of high levels of hyperopia that occurred in a large proportion of 2 month old infants with adequate sensitivity and specificity compared with cycloplegic retinoscopy. PMID- 21602731 TI - A comprehensive comparison of central corneal thickness measurement. AB - PURPOSE: To assess the repeatability and reproducibility of central corneal thickness (CCT) measurements by high-resolution rotating Scheimpflug imaging (Pentacam, Oculus) and Fourier-domain optical coherence tomography (RTvue-100, Optovue) after laser in situ keratomileusis (LASIK) and to compare the agreement with ultrasound pachymetry (USP). METHODS: Forty-seven eyes of 47 patients after LASIK were included in the study. The first examiner took two successive Pentacam and RTvue CCT measurements, and this was repeated once again by the second examiner to assess intraobserver and interobserver repeatability and reproducibility. After performing non-contact examinations, the corneas were measured by USP to compare the level of agreement among the three devices. RESULTS: All Pentacamcenter, Pentacamapex, Pentacamthinnest, and RTvue CCT measurements demonstrated high intraobserver repeatability, with respective precision (1.96 within-subject standard deviation) and intraclass correlation coefficients of 7.52, 7.43, 7.55, and 3.81 MUm and 0.985, 0.986, 0.986, and 0.997; interobserver repeatability results were similar. All coefficients of variation were low: <1% for all measures. Compared with Pentacam and USP measurements, the RTvue measurement significantly underestimated CCT by a mean of 10.52 to 15.28 MUm (p < 0.001) and 9.17 MUm (p < 0.001), respectively. The agreement of USP with Pentacam and RTvue by Bland-Altman analysis spanned over 30 MUm. The agreement of Pentacam with RTvue spanned approximate 20 MUm. CONCLUSIONS: Both Pentacam imaging and RTvue Fourier-domain optical coherence tomography provide reliable and interchangeable measurement of CCT in post-LASIK corneas. However, they cannot be considered to be clinically interchangeable with USP. PMID- 21602732 TI - Risk factors for interruption to soft contact lens wear in children and young adults. AB - PURPOSE: The purpose of this study was to describe age and other risk factors for ocular events that interrupt soft contact lens (SCL) wear in youth. METHODS: A retrospective chart review of SCL wearers aged 8 to 33 years at the first observed visit was conducted at six academic eye care centers in North America. Data were extracted from all visits during the observation period (>3 years). Clinical records that documented conditions resulting in an interruption of SCL wear "events" were scanned, masked for age and SCL parameters, and then adjudicated to consensus diagnosis. Generalized estimating equations were used to examine the effect of selected covariates, including age, on the risk of an event. RESULTS: Chart review of 3549 SCL wearers yielded 522 events among 426 wearers (12%). The risk of an event increased from ages 8 to 18 years, showed modest increases between ages 19 and 25 years, and then began to decline after age 25 years. New lens wearers (<1 year) were less likely to experience events (p = 0.001). Lens replacement schedule and material were also predictive of interruptions to SCL wear with the lowest risk in daily replacement and hydrogel lens wearers (both p < 0.0001). CONCLUSIONS: These results suggest that the risk of events that interrupt SCL wear peaks in late adolescence and early adulthood and reflects risk factors identified in prospective contact lens studies. Relative to older teens and young adults, patients younger than 14 years presented with significantly fewer events resulting in interrupted lens wear. PMID- 21602733 TI - Influence of protein deposition on bacterial adhesion to contact lenses. AB - PURPOSE: The aim of the study is to determine the adhesion of Gram positive and Gram negative bacteria onto conventional hydrogel (CH) and silicone hydrogel (SH) contact lens materials with and without lysozyme, lactoferrin, and albumin coating. METHODS: Four lens types (three SH-balafilcon A, lotrafilcon B, and senofilcon A; one CH-etafilcon A) were coated with lysozyme, lactoferrin, or albumin (uncoated lenses acted as controls) and then incubated in Staphylococcus aureus (Saur 31) or either of two strains of Pseudomonas aeruginosa (Paer 6294 and 6206) for 24 h at 37 degrees C. The total counts of the adhered bacteria were determined using the H-thymidine method and viable counts by counting the number of colony-forming units on agar media. RESULTS: All three strains adhered significantly lower to uncoated etafilcon A lenses compared with uncoated SH lenses (p < 0.05). Lysozyme coating on all four lens types increased binding (total and viable counts) of Saur 31 (p < 0.05). However, lysozyme coating did not influence P. aeruginosa adhesion (p > 0.05). Lactoferrin coating on lenses increased binding (total and viable counts) of Saur 31 (p < 0.05). Lactoferrin coated lenses showed significantly higher total counts (p < 0.05) but significantly lower viable counts (p < 0.05) of adhered P. aeruginosa strains. There was a significant difference between the total and viable counts (p < 0.05) that were bound to lactoferrin-coated lenses. Albumin coating of lenses increased binding (total and viable counts) of all three strains (p < 0.05). CONCLUSIONS: Lysozyme deposited on contact lenses does not possess antibacterial activity against certain bacterial strains, whereas lactoferrin possess an antibacterial effect against strains of P. aeruginosa. PMID- 21602734 TI - Negative predictive value of positron emission tomography/computed tomography in patients with a clinical suspicion of pancreatic cancer. AB - OBJECTIVES: The aim of this study was to determine the negative predictive value of positron emission tomography (PET)/computed tomography (CT) in patients with lesions suggestive of pancreatic cancer. METHODS: A retrospective review from January 2005 to August 2008 of all patients who underwent a PET/CT to evaluate a lesion suggestive of pancreatic cancer based on prior imaging. One hundred eighty four patients underwent PET/CT, of which 60 patients had a negative PET scan. Of these 60 patients, 56 patients (30 women, 26 men) had endoscopic ultrasound guided fine-needle aspiration or surgical pathology for clinical correlation. The Fisher exact test was used for statistical analysis. RESULTS: The negative predictive value of PET/CT was 75%. Eighteen patients had a benign lesion, 24 patients had a premalignant lesion, and 14 patients had a malignant lesion. In the cystic group, 72.4% of the PET/CT-negative lesions were premalignant compared with the solid group that was only 5.9%. This was in contrast to the solid group, where 64.7% was malignant versus 6.9% in the cystic group. Two of 14 patients with malignancy had metastatic disease. CONCLUSIONS: The negative predictive value of PET/CT in pancreatic lesions suggestive of pancreatic cancer was 75%. A negative PET/CT does not exclude pancreatic cancer, and further workup of these PET-negative lesions is warranted. PMID- 21602735 TI - Patient preferences after endoscopic ultrasound with fine needle aspiration (EUS FNA) diagnosis of pancreas cancer: rapid communication valued over long-term relationships. AB - BACKGROUND: Endoscopic ultrasound with fine needle aspiration (EUS-FNA) is used for the diagnosis of pancreatic malignancy. However, there are limited data as to patient preferences regarding the delivery of cancer diagnoses. OBJECTIVE: This study aimed to assess if patients had met the endosonographer before their EUS, their suspicion of having cancer, and whether they would like the cytology results given to them by their referring physician (with whom they had a previous relationship) or the endosonographer. This question was also asked with respect to the timing of receiving cytology results. METHODS: A total of 131 patients with a suspected solid pancreatic mass undergoing EUS-FNA at 2 tertiary referral centers were prospectively enrolled and completed a preprocedure questionnaire. RESULTS: One hundred twenty patients (92%) had not met the endosonographer before their EUS-FNA, and only 37 patients (28%) thought they had a pancreatic malignancy. Of the 131 patients, 89 (68%) stated that they wanted to hear results from the endosonographer (P = 0.0001) and 100 patients (76%) chose to hear results as soon as possible from the endosonographer (P = 0.001). CONCLUSIONS: Our data highlight the importance of the endosonographer's role in the delivery of cancer diagnoses and that patients value expediency of reporting results over long-term physician relationships. PMID- 21602736 TI - Evidence of an intracellular angiotensin-generating system and non-AT1, non-AT2 binding site in a human pancreatic cell line. AB - OBJECTIVES: To assess the presence of a local angiotensin-generating systems (LAGS) and its participation in tumor growth in the human pancreatic cancer derived cell line Capan-1. METHODS: Capan-1 cells were cultured in Dulbecco modified Eagle medium, and angiotensin I was assayed by radioimmunoassay and angiotensin II and vascular endothelial growth factor were assayed by enzyme linked immunosorbent assay in the supernatant. Immunohistochemistry and reverse transcription-polymerase chain reaction were performed for the expression of AT1 and AT2 receptors. Angiotensin II binding assays and blockade were studied. RESULTS: High levels of both angiotensins I and II were found in Capan-1 cells, although neither angiotensin I nor angiotensin II was detected in the cell culture supernatant. Reverse transcription-polymerase chain reaction and immunocytochemistry revealed that Capan-1 cells do not express AT1 and AT2 receptors; however, specific binding to the cell membrane was identified for angiotensin II. Neither exogenous angiotensin II nor Dup753 (specific AT1 receptor blocker) affected Capan-1 cells' proliferation or vascular endothelial growth factor secretion. CONCLUSIONS: Detection of both angiotensin I and angiotensin II along with specific binding of angiotensin II in Capan-1 cells provides evidence of the existence of a LAGS that operates in an intracrine manner. Intracellular angiotensin II may play a role in the aggressiveness of pancreatic cancer and is a possible target for therapeutic agents. PMID- 21602737 TI - Pancreatic ultrastructural enhancement due to telmisartan plus sitagliptin treatment in diet-induced obese C57BL/6 mice. AB - OBJECTIVE: We sought to evaluate the effects of telmisartan, sitagliptin, or their combination on pancreatic ultrastructural alterations in high-fat-fed C57BL/6 mice. METHODS: Three-month-old C57BL/6 mice were fed with standard chow (SC, 10% lipids) or high-fat diet (HF, 60% lipids) during 10 weeks to induce obesity and its comorbidities. After this period, treatment began (lasted 6 weeks), and the HF group was divided into 4 subgroups: untreated HF, HF plus telmisartan (5 mg/kg per day), HF plus sitagliptin (1.1 g/kg per day), and HF plus telmisartan plus sitagliptin. Drugs were mixed with diet. Biochemical analyses, radioimmunoassay, immunofluorescence, stereology, and transmission electron microscopy were performed to assess pancreatic remodeling. RESULTS: Overweight, hyperinsulinemia, hyperglycemia, and dyslipidemia were found in the HF group, but these outcomes were controlled by the different treatments. Untreated HF animals also showed alterations concerning distribution of alpha/beta cell followed by large and numerous lipid droplets within pancreas. Telmisartan and sitagliptin as monotherapy alleviated these findings, and a complete reversal of pancreatic steatosis was observed after treating with the combination of the 2 drugs. CONCLUSIONS: AT1 receptor blockade, partial peroxisome proliferator-activated receptor gamma activation, and extended incretin action emerge as feasible strategies to control pancreatic steatosis and avoid progression of pancreatic diseases due to lipotoxicity. PMID- 21602738 TI - Leukotriene B4 mediates inflammation via TRPV1 in duct obstruction-induced pancreatitis in rats. AB - OBJECTIVES: We tested the hypothesis that leukotriene B4 (LTB4) mediates pancreatic inflammation in rats via activation of the transient receptor potential vanilloid 1 (TRPV1). METHODS: Leukotriene B4 or a vehicle was administered to adult rats via celiac axis injection after pretreatment with the TRPV1 antagonist, capsazepine, or vehicle, and the severity of subsequent pancreatitis was assessed by measuring pancreatic edema, myeloperoxidase (MPO) activity, and histological grading. In a second experiment, acute pancreatitis was induced by common pancreaticobiliary duct ligation. Six hours after surgery, pancreatic tissue levels of LTB4 were determined by enzyme-linked immunosorbent assay. Also, the effects of inhibition of LTB4 biosynthesis by pretreatment with the 5-lipoxygenase-activating peptide inhibitor, MK-886, were determined. RESULTS: Celiac axis administration of LTB4 significantly increased pancreatic edema and MPO activity, and produced histological evidence of pancreatic edema, neutrophil infiltration, and necrosis. Capsazepine pretreatment significantly reduced all inflammatory parameters in LTB4-induced pancreatitis. Pancreatic tissue levels of LTB4 were significantly elevated in rats that underwent common pancreaticobiliary duct ligation compared with control rats. MK-886 pretreatment significantly inhibited pancreatic edema, histological damage, and pancreatic MPO concentrations. CONCLUSIONS: Common pancreaticobiliary duct obstruction causes an increase in pancreatic LTB4 concentrations that in turn mediates activation of TRPV1 resulting in acute pancreatitis. PMID- 21602740 TI - An epistemological dilemma: is ertapenem adequate to treat severe infections in critically ill patients? PMID- 21602746 TI - Why, when and how to propose noninvasive ventilation in cystic fibrosis? AB - Cystic fibrosis (CF) lung disease is characterized by progressive airflow obstruction, due to mucus plugging and inflammation within the bronchial walls, and destruction of the lung parenchyma secondary to bronchiectasis. These alterations result in an increase of the work of breathing, leading to alveolar hypoventilation predominantly during sleep, exercise and acute respiratory exacerbations. Noninvasive positive pressure ventilation (NPPV) has been shown to unload the respiratory muscles in patients with CF, which increases alveolar ventilation and improves gas exchange. NPPV has been shown to reduce oxygen desaturation during sleep, exercise and chest physiotherapy and may facilitate the recovery of a severe hypercapnic respiratory exacerbation. Several ventilatory modes may be used in cystic fibrosis patients but the most physiological mode is pressure support. However, validated criteria to start NPPV as well as data on long term outcome, notably in terms of improved survival and quality of life, are lacking and should be assessed in the future. PMID- 21602748 TI - Extracorporeal carbon dioxyde removal for additional pulmonary resection after pneumonectomy. AB - Additional pulmonary surgery in a previously pneumonectomized patient requires apnea during surgical manipulation of the surviving lung. We report on a novel approach to manage the intraoperative apnea period, combining apneic oxygenation and minimally invasive, low flow extracorporeal CO2 removal. A 69-year-old man previously submitted to left pneumonectomy was scheduled for wedge resection of a single right upper lobe lesion. During the intraoperative apnea period, oxygenation was maintained through apneic oxygenation with continuous positive airway pressure (CPAP) of 5 cmH2O and inspiratory oxygen fraction (FiO2) of 1 and respiratory acidosis was prevented through extracorporeal CO2 removal, performed with the Decap(r) system (Hemodec, Salerno, Italy), a veno!venous pump-driven extracorporeal circuit including a neonatal membrane lung. The extracorporeal circuit was connected to the right femoral vein, accessed via a 14 Fr double lumen catheter. The blood flow through the circuit was 350 mL/min and the sweep flow of oxygen through the membrane lung was 8 L/min. The intraoperative apnea period lasted 13 minutes. Our approach allowed maintaining normocapnia (PaCO2 38,5 and 40 mmHg before and at the end of the apnea period, respectively), preserving oxygenation (P/F ratio 378, 191, 198 and 200 after 3, 6, 9 and 12 min of apnea, respectively). Our report suggests that the minimally invasive CO2 removal associated with apneic oxygenation is an useful technique for managing anesthesiological situations requiring moderate apnea periods. PMID- 21602750 TI - The use of the Foley Airway Stylet Tool(r) to guide tracheal intubations through an intubating laryngeal mask airway. AB - BACKGROUND: Blind insertion of endotracheal tubes through the intubating laryngeal mask airway (ILMA) is unsuccessful in almost 50% of cases on the first attempt, with an overall success rate of approximately 90%. We used a portable fiber optic device (Foley Airway Stylet Tool(r) FAST) to detect the reasons for failed intubations and tested its use in facilitating endotracheal tube placement. METHODS: Thirty patients without anticipated intubation difficulties participated in the study. The fiber optic device was fastened with its tip at the end of the endotracheal tube, and both instruments were advanced through the previously inserted ILMA past the lifting bar. The view was scored in the following manner: I, full view of laryngeal inlet; II, partial vocal cords, arytenoids, epiglottis; III, epiglottis; IV, no laryngeal structures identifiable. The ILMA was adjusted for the best obtainable view, which was scored, and the endotracheal tube was inserted. RESULTS: The initial laryngeal view was I in four patients, II in eighteen patients, III in one patient and IV in seven patients. The best view after corrective maneuvers was I in twenty-seven patients, II in two patients and IV in one patient. First attempt tracheal intubations were successful in twenty-seven (90%) patients; two patients required a second attempt. CONCLUSION: A grade II view or worse indicated misalignment of the ILMA with the glottis. An endotracheal tube inserted blindly through the misaligned ILMA will impinge on and potentially damage laryngeal structures. The use of a portable fiber optic device can help reduce the failure rate of endotracheal intubations by utilizing ILMA in emergent situations. PMID- 21602751 TI - Glucose response during craniotomy: propofol-remifentanil versus isoflurane remifentanil. AB - BACKGROUND: Major surgery is associated with a stress response. The aim of this study was to compare the effects of isoflurane or propofol, both supplemented with remifentanil, on the glucose, cortisol and insulin-based stress responses prospectively. METHODS: Forty patients undergoing craniotomy randomly received either 1% isoflurane (Group I, N.=20) or propofol 6 mg kg h(-1) (Group P, N.=20) during remifentanil-based (0.125 MUg kg min(-1)) anesthesia. Blood glucose was recorded preoperatively, after induction, intubation and pin placement, before and after skin incision, craniotomy, dura incision, 15th, 30th, 60th, 90th, 120th, 150th, 180th min post-dura incision, following dura and skin closure, extubation and at the 1st and 24th postoperative hours. Insulin and cortisol were measured preoperatively, after intubation, dura incision, at the 60th min, extubation and at the 1st and 24th hour postoperatively. The glucose/insulin ratio and glycemic stress index were calculated after all the measurements were obtained. RESULTS: Patient characteristics were comparable in both groups. Blood glucose significantly decreased after induction in comparison to the baseline value in both groups. Blood glucose was significantly higher in Group I than Group P before skin incision, after craniotomy and dura incision and at all measurement time points after the 60th minute following dura incision. There was a significant alteration with time in insulin values in both groups and the insulin values at the 60th min were significantly lower in Group I than in Group P. There was not any difference in the inter-group analysis of cortisol; however, there was a significant change over time in the insulin values in both groups. There was no difference in the intra-group glucose/insulin ratio, however, there was a significant difference between groups at the 60th min and at extubation. The Glycemic Stress Index was comparable between groups (Group I vs. Group P: 2.48+/-1.15 vs. 2.15+/-0.86, P=0.465). CONCLUSION: Isoflurane and propofol, both combined with remifentanil, provided clinically comparable cortisol and insulin responses to surgery in craniotomy operations, whereas propofol attenuated the increase in plasma blood glucose. PMID- 21602752 TI - Strategies for diagnosis and treatment of iatrogenic tracheal ruptures. AB - BACKGROUND: Management of tracheal ruptures in critically ill patients is challenging. Conservative treatment has been described, but in mechanically ventilated patients with distal tracheal ruptures surgical repair might be inevitable. Strategies for diagnosis and treatment of tracheal ruptures and handling of mechanical ventilation remain to be clarified. Our aim was to comprise a structured diagnostic and treatment protocol for patients suspicious of tracheal injury, including detailed principles of mechanical ventilation and specific indications for conservative or surgical treatment. METHODS: Patients with tracheal ruptures were compared in accordance to the need of mechanical ventilation and to indication for surgical repair. In patients suffering from tracheal ruptures affecting the whole tracheal wall and with protrusion of mediastinal structures into the lumen surgery was indicated. We compared ventilatory, hemodynamic and clinical parameters between the different patient groups. We report our structured approach in diagnostics and treatment of tracheal ruptures and place special emphasis on respiratory management. RESULTS: Seventeen patients with tracheal rupture were identified. In 8 patients surgical repair was performed 1.8+/-1.5 days after diagnosis. Previous to surgery, ventilation parameters improved significantly: plateau pressure decreased, percentage of assisted spontaneous breathing increased and compliance improved. Conservative treatment was successful in long-term ventilated patients (13.7+/-8 days) even when suffering from distal lesions. CONCLUSION: Invasiveness of mechanical ventilation and obstruction of tracheal lumen might indicate conservative or surgical treatment strategies in long-term ventilated patients suffering from iatrogenic tracheal rupture. Indications for surgical repair remain to be further clarified. PMID- 21602755 TI - Pain, postdural puncture headache, nausea, and pruritus after cesarean delivery: a survey of prophylaxis and treatment. AB - BACKGROUND: The need for a cesarean delivery may interfere negatively with the overall experience of childbirth. Several factors related to anesthesiological management such as postoperative pain and discomfort, nausea and pruritus, and postdural puncture headache (PDPH), may lead to dissatisfaction and have a negative impact on early mobilization and a new mother's ability to care for her newborn baby. Optimal prophylaxis and treatment decrease these complications, increase satisfaction, and prevent chronic pain. This survey determined how prophylaxis and treatment of pain, PDPH, nausea, and pruritus after cesarean section (CS) is managed. METHODS: A questionnaire was sent to 709 departments of anesthesiology serving an obstetric unit in Germany. The questionnaire asked about different aspects of pain management, the management of accidental dural puncture (ADP), and treatment of PDPH. Further we asked about therapy and prophylaxis of nausea and pruritus in the peripartal setting. RESULTS: In all, 360 questionnaires (50.8%) were returned; 346 were complete and analyzed (accounting for 330000 births per year). Paracetamol (77.5%) and piritramide (85.6%) are the most common analgesics used. If epidural catheters were used for anesthesia for CS, 47.7% were used for postoperative pain therapy. However, 92.7% of the departments removed catheters in less than 24 hours after delivery. In case of an ADP most departments (69.9%) repeated puncture, 2.6% placed catheters intrathecally. Median blood volume for an epidural blood patch was 10ml. CONCLUSION: Apart from conservative treatment of PDPH, prophylaxis and treatment of pain after cesarean delivery, PDPH, nausea, and pruritus varied widely, indicating the need for the qualitative evaluation of overall management. PMID- 21602759 TI - A comparison of high intensity aerobic exercise and passive modalities for the treatment of workers with chronic low back pain: a randomized, controlled trial. AB - BACKGROUND: In recent years, disability due to chronic low back pain (LBP) has steadily increased in all industrialized countries. In the treatment of chronic LBP, the objectives are to reduce pain, to improve function and minimize avoiding behavior. Exercise therapy is a management strategy that is widely used as a treatment for LBP. AIM: The aim of this study was to investigate the effects of high- intensity aerobic exercise on pain, disability, anxiety or depression in people with chronic LBP. DESIGN: This was a randomized controlled trial SETTING: Institute of Occupational Medicine, Department of Physical Medicine and Rehabilitation - Outpatient Ward POPULATION: Kosovo power plant workers. METHODS: Participants with chronic low back pain, excluding those with "red flag" criteria were assigned randomly to one of the two treatment groups: an aerobic exercise group (N.=50), and an passive modalities group (N.=51). Data on low back pain intensity (visual analogue scale), disability (Oswestry Low Back Pain Disability Questionnaire), fingertip-to-floor distance, and psychosocial factors (Hospital Anxiety and Depression Scale) were collected at baseline and after 12-weeks follow-up points. RESULTS: At 12-week follow-up, significant improvements in pain intensity and disability had occurred in the exercise group. We have verified significant improvements in comparison with basic values in pain intensity (6 +/- 2.6 vs. 2 +/- 1.7, diff. of mean=3.9, P < 0.001), disability (31 +/- 17.4 vs. 15.8 +/- 12.7, diff. of mean=15.2, P<0.001), anxiety and depression (21.1 +/- 8.2 vs. 14 +/- 6.7, diff. of mean=7.1, P < 0.001), and fingertip- to-floor distance (27.8 +/- -9.1 vs. 14.2 +/- -5.7, P<0.001). Whereas, differences in average pain, disability, anxiety and depression and fingertip-to-floor distance are not significant in the control group. CONCLUSION: High intensity aerobic exercise reduces pain, disability and psychological strain in patients with chronic low back pain. CLINICAL REHABILITATION IMPACT: This research is important for the fact that High Intensity Aerobic Exercise Programs are not so exploited in the current available literature for the treatment of LBP. Therefore, this is another modest contribution which can reinforce the need for more frequent use of High Intensity Aerobic Exercise Programs in the treatment of LBP. PMID- 21602761 TI - Rehabilitation outcomes of stroke patients treated with multi-modal endovascular reperfusion therapy. AB - AIM: The aim of this study was to investigate the influence of multi-modal endovascular reperfusion therapy (MMRT) on functional outcomes following rehabilitation. METHODS: Data from 14 MMRT-treated patients were analyzed and compared to MMRT-ineligible, age and stroke severity-matched patients treated at the same Neurological and Rehabilitation departments. Neurological evaluation was assessed with the NIH stroke scale (NIHSS). Activity of daily living was measured using the FIMTM instrument. Functional outcome was measured using the modified Rankin scale (mRS). RESULTS: The baseline characteristics of both groups were similar. NIHSS scores were lower in the MMRT group and they had slightly better functional and rehabilitation scores on admission to rehabilitation. At the end of rehabilitation, more MMRT-treated patients reached functional independence (mRS<=2; 50% vs. 7% respectively P=0.03). FIM scores were also higher in the MMRT group (mean score 93.3 vs. 87.7, respectively) but the difference did not reach significance. The delta in FIM and NIHSS scores obtained during rehabilitation did not significantly differ between the groups. MMRT remained a significant modifier of good outcome after regression analysis (OR 21.5 95% CI 1.1-410). CONCLUSION: MMRT-treated patients have better chances of attaining independence after rehabilitation therapy. However, the additional improvements gained while in active rehabilitation were independent of reperfusion status. PMID- 21602762 TI - Mosquito diversity in the Chilika lake area, Orissa, India. AB - Twenty-two species of mosquitoes belonging to six genera (Anopheles, Aedeomyia, Aedes, Armigeres, Culex and Mansonia) were collected from eight villages in and around the Chilika lake area, Khurda and Puri Districts from 2006-2007. Greater numbers of the culicines (65.59%) were collected from the area, as compared with the anophelines (34.4%). Mansonia indiana and Mansonia dives were reported for the first time from the area. The values of the species richness (S), Shannon Index (H), and Shanon evenness (Es) between anophelines and culicines were 10, 12; 0.89, 1.85; 0.38, 0.74, respectively. Based on biostatistical analysis, the culicines were more diverse than anophelines in the study area. PMID- 21602763 TI - High dose of N-acetylcysteine increase H2O2 and MDA levels and decrease GSH level of HUVECs exposed with malaria serum. AB - Dysfunction of endothelial cells in severe malaria may result from excessive activation of tumor necrosis factor (TNF)-alpha which leads to an increase in production of reactive oxygen species (ROS) and decrease of antioxidant level of endothelial cells. To investigate the effect of N-acetylcysteine (NAC) on hydrogen peroxide (H2O2), malondialdehyde (MDA) and glutathione (GSH) levels produced by endothelial cells exposed with serum of malaria falciparum patient, an in vitro model of human umbilical vein endothelial cells (HUVECs) culture was used. Sample groups were normal HUVECs (group A), HUVECs that was exposed with malaria serum without any treatment (group B), HUVECs that were exposed with malaria serum and treated with NAC 2 MUM (group C), HUVECs that were exposed with malaria serum and treated with NAC 4 MUM (group D), and HUVECs that were exposed with malaria serum and treated with NAC 8 MUM (group E). The level of MDA was measured by thio-barbituric acid reaction assay and H2O2 level was measured by NWLSS Hydrogen Peroxyde/Peroxydase Assay kit. The level of GSH was determined by using NWLSS Glutathione Assay kit. The level of H2O2 and MDA decreased after administration of low dose of NAC. Unfortunately, increased H2O2 and MDA levels were found on HUVECs treated with high dose of NAC (8 MUM). There was a positive correlation between NAC dose and H2O2 level (r= 0,603) and between NAC dose and MDA level (r= 0,721). A significant decreased level of GSH was found on HUVECs treated with high dose of NAC (p = 0,023). It can be concluded that the use of high dose of NAC as supportive therapy in severe malaria infection must be taken carefully. PMID- 21602764 TI - Isolation of Campylobacter and Salmonella from houseflies (Musca domestica) in a university campus and a poultry farm in Selangor, Malaysia. AB - Insects, in particular house flies and cockroaches, have been shown to be associated with the spread of pathogens in livestock farms and in human disease outbreaks: among these pathogens are salmonellae and campylobacters. A total of 60 flies were caught in three locations: an animal teaching facility and a cafeteria in a university campus, and a poultry farm. Five percent (5%) and 13.3% of flies sampled were found to carry Campylobacter and Salmonella, respectively. PMID- 21602765 TI - Simultaneous detection of methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa by multiplex PCR. AB - A PCR-based assay that can simultaneously detect and differentiate five different types of nosocomial bacterial pathogens was developed. Six pairs of selected primers targeting femA (132 bp) and mecA (310 bp) of methicillin-resistant Staphylococcus aureus, gltA (722 bp) of Acinetobacter baumannii, phoA (903 bp) of Escherichia coli, mdh (364 bp) of Klebsiella pneumoniae and oprL (504 bp) of Pseudomonas aeruginosa were used in this study. The conditions were optimized for the multiplex PCR to ensure specific amplification of the selected targets. Sensitivity and specificity tests were also carried out using a blind test approach on 50 bacterial cultures and resulted in 100% for both positive and negative predictive values. PMID- 21602767 TI - Prevalence and molecular characterization of Cryptosporidium in schoolchildren from department of Rio San Juan (Nicaragua). AB - A cross-sectional study of cryptosporidiosis was carried out in Nicaragua. The prevalence of Cryptosporidium infection was determined in 272 (110 boys and 162 girls) schoolchildren, aged between 4 to 15 years from department of Rio San Juan. The total percentage obtained for Cryptosporidium (35.7%) was one of the highest reported so far. Cryptosporidium appeared in 94.8% of multiparasitism cases. No significant statistical differences were detected in the cryptosporidiosis prevalence between loose/watery (22.2%) and soft/formed (36.7%) stool samples. No significant age and sex differences were observed. This is the first report to identify Cryptosporidium in Nicaragua at species level, providing a preliminary molecular characterization of all positive samples, such as Cryptosporidium parvum (genotype 2). The high prevalence of C. parvum suggests that animals may be potential sources of infection for human cryptosporidiosis, although C. parvum infections may have originated from humans themselves. The human health problem caused by Cryptosporidium in this region may be related to the poor human hygiene/sanitation and contamination of the environment, food, or water supplies. Continuous exposure to the parasite could have been protective against development of symptoms in the children examined. PMID- 21602766 TI - Epidemiology of giardiasis and genotypic characterization of Giardia duodenalis in preschool children of a rural community, central Thailand. AB - A cross-sectional study was conducted to determine the prevalence and risk factors of Giardia duodenalis infection in 189 preschool children at Sanamchaiket District, Chachoengsao Province, central Thailand in February 2007. Stool specimens were examined for the presence of Giardia using simple wet preparation and PBS-ethyl acetate concentration technique. The prevalence of G. duodenalis in preschool children was 5.8%. Using PCR-RFLP analysis of the glutamate dehydrogenase gene (gdh), genotypes of G. duodenalis revealed assemblage AII (3, 30.0%), BIII (1, 10.0%), and BIV (6, 60.0%). Using multivariate analysis, children who kept cat(s) at home were at 5.1 times (95% CI; 1.3- 20.3) greater risk of acquiring giardiasis. This study possibly represents the information supporting the potential zoonotic transmission of G. duodenalis between cats and preschool children. Unfortunately, in this study, we did not determine G. duodenalis infection in cats, so further studies in cats should be performed to confirm this postulation. PMID- 21602768 TI - Ovitrap surveillance of the dengue vectors, Aedes (Stegomyia) aegypti (L.) and Aedes (Stegomyia) albopictus Skuse in selected areas in Bentong, Pahang, Malaysia. AB - Ovitrap surveillance was conducted in methodically selected areas in Bentong, Pahang, Malaysia from June 2008 till December 2009 in order to identify insular sites with stable Aedes aegypti population. Eleven sites were surveyed in Bentong district, Pahang, and one of these locations (N3o33' E101o54') was found to have an ovitrap index of Ae. aegypti and Aedes albopictus ranging from 8%-47% and 37% 78% respectively, indicating that this site could be a high-risk area for dengue outbreak. Ae. aegypti larvae were found in both indoor and outdoor ovitraps (p>0.05) while significant difference between the populations of Ae. albopictus larvae from indoors and outdoors was observed (p<0.01). Data collected in this study could provide important entomological information for designing an effective integrated vector control programme to combat Aedes mosquitoes in this area. PMID- 21602769 TI - Capsular serotyping of Pasteurella multocida from various animal hosts - a comparison of phenotypic and genotypic methods. AB - One hundred and fourteen strains of Pasteurella multocida were isolated from different domestic animals species (cattle, buffalo, sheep, goat, pig, rabbit, dog, cat), avian species (chicken, duck, turkey) and wild animals (deer, tiger, orang utan, marmoset). The serogroups of P. multocida were determined by both conventional capsular serotyping and a multiplex PCR assay targeting specific capsular genes. Based on the conventional serotyping method, the 114 strains of P. multocida were subtyped into 55 species-specific (untypeable strains) P. multocida, 15 serogroup A, 23 serogroup B and 21 serogroup D. Based on the multiplex PCR assay on the specific capsular genes associated with each serogroup, the 114 strains were further divided to 22 species-specific P. multocida (KMT1 - 460 bp), 53 serogroup A (A - 1,044 bp), 33 serogroup B (B - 760 bp) and 6 serogroup D (D - 657 bp). No serogroup E (511 bp) or F (851 bp) was detected among the Malaysian P. multocida. PCR-based typing was more discriminative and could further subtype the previously untypeable strains. Overall, there was a significant and positive correlation between both methods in serogrouping P. multocida (r = 0.7935; p<0.4893). Various serogroups of P. multocida were present among the livestock with 75% of the strains belonging to serogroups A or B. PCR serotyping was therefore a highly species-specific, sensitive and robust method for detection and differentiation of P. multocida serogroups compared to conventional serotyping. To the best of our knowledge, this is the first report from Malaysia of the application of a PCR to rapidly define the species-specific P. multocida and its serogroups as an important zoonotic pathogen in Malaysia. PMID- 21602770 TI - Strongyloides stercoralis induced bilateral blood stained pleural effusion in patient with recurrent Non-Hodgkin lymphoma. AB - Infections and malignancies are common causes of pleural effusion. Among infectious causes, hyperinfection syndrome of Strongyloides stercoralis may occur in immunosuppressive patient. A 62-year-old man, known case of Non-Hodgkin lymphoma (NHL) was presented with recurrent NHL stage IV and had undergone salvage chemotherapy. Patient subsequently developed pneumonia with bilateral pleural effusion and ascites. We reported rhabditiform larvae of S. stercoralis in pleural fluid of both lungs without infiltration by lymphoma cells. Stool for microscopic examination also revealed rhabditiform larvae of S. stercoralis. This patient was a known case of NHL receiving chemotherapy resulting in immunosuppression state. Although S. stercoralis infection is not very common compared to other parasitic infections, it is common in immunosuppressive patients and may present with hyperinfection. Therefore, awareness of this parasite should be kept in mind in immunosuppressive patients. PMID- 21602771 TI - Haemoprotozoa of cattle in Northern Kerala, India. AB - A cross-sectional study was conducted using 150 blood samples collected from apparently normal / healthy crossbred cattle of Northern Kerala, South India, for detection of haemoprotozoan infections using staining techniques (Giemsa and Acridine Orange) and specific PCR. Theileria like piroplasms and Babesia bigemina were the only protozoan organisms detected in blood smears. Polymerase chain reaction using specific primers revealed amplification of products specific for Trypanosoma evansi (34.6%), Theileria sp. other than T. annulata (16%) and B. bigemina (0.6%). The higher prevalence rate of Trypanosoma evansi indicated that the subclinical parasitism can be due to higher prevalence of tabanid flies. The study also revealed the presence of a theilerial piroplasm other than T. annulata in North Kerala, which needs further investigation. PMID- 21602772 TI - Effect of construction of an irrigation canal on malaria situation in two primary health centres of Dhenkanal district of Orissa, India. AB - To assess the impact of irrigation canals on malaria transmission, a study was conducted in Dhenkanal district of Orissa, India. The district is situated in the central part of Orissa and hyperendemic area for malaria. A canal system is being constructed for irrigation in the district, which passes through Parjang and Analabereni Primary Health Centres (PHC), endemic for malaria. The water has been released only up to Parjang (Canal with water -CWW) area during the end of 2004 and construction work is still going on in Analabereni PHC (Canal under construction-CUC). Retrospective clinical data (2001-2008) collected from health services from two study sites showed average Slide Positivity Rate (SPR) before release of water (2001-2004) was 9.25% and 18.04% in CWW and CUC areas, respectively. After release of water (2005-2008) the SPR was 5.77% and 10.19%, in CWW and CUC areas, respectively. The average Annual Parasite Incidence (API) was 7.66 and 22.67 in CWW and CUC areas before the release of water and 5.32 and 12.28 after release of water, respectively. A point fever survey was conducted in 2009 which revealed the presence of Plasmodium falciparum (Pf) and P. vivax (Pv) in both study areas. The survey found SPR of 18.82% and 24.54%, and Pf percentages of 75% and 85%, in CWW and CUC areas, respectively. The present study revealed the presence of two malaria vectors, Anopheles culicifacies and Anopheles annularis in the area. Vector Per Man Hour Density was 2.38 in CWW and 2.69 in CUC for An. culicifacies and 1.46 and 1.54 for An. annularis respectively. The sporozoites rates were found to be 3.6 and 3.8 for CWW and CUC, respectively. The present study reveals that, the construction of canal system did not increase the malaria prevalence during post water release period - implying that the malaria control programme was effective although still more intensive situation specific vectors control programme need to be continued simultaneously so that malaria transmission can be curtailed. PMID- 21602773 TI - Screening of parasitic and IHHNV infections in wild giant freshwater prawn Macrobrachium rosenbergii from Rejang River at Kuching, Sarawak. AB - A preliminary survey of parasitic and infectious hypodermal and haematopoietic necrosis virus (IHHNV) infections in giant freshwater prawn from the Damak Sea of Rejang River, Kuching, Sarawak was conducted. Symptoms of black spots/patches on the rostrum, carapace, pleopods or telson were observed in most of the 107 samples collected. Parasitic examination revealed sessiline peritrichs such as (Zoothamnium sp.), nematode larvae, gregarine stage and cocoon of leech with prevalences of 1.2%, 1.2%, 5% and 17% respectively. Under histopathological examination, changes like accumulation of hemocytes around hepatopancreatic tubules due to vibriosis, basophilic intranuclear inclusions in the epithelium and E-cell of hepatopancreatic tubules as a result of HPV were seen through the section. No positive infection of IHHNV was detected in 78 samples. As such, the wild giant freshwater prawns in Damak Sea of Rejang River in Kuching are IHHNV free though infections of parvo-like virus and bacteria were seen in histopathology. PMID- 21602774 TI - Genetic diversity among Schistosoma mansoni population in the western region of Saudi Arabia. AB - Schistosomiasis is an important parasitic disease that infects humans. Among the main species of schistosomes infecting humans are Schistosoma mansoni and Schistosoma haematobium. The accurate diagnosis of these parasitic infections will improve the success of disease control and management. Many studies proved that Schistosoma exhibit variations not only among species, but also among strains and between males and females, other than the obvious sexual characteristics associated with variations in the levels of infectivity, pathogenicity and immunogenicity. Our study on genetic diversity among populations of Schistosoma in Saudi Arabia gave a clear picture about this population and subsequently the method for controlling the parasites. From the examination of 40 collected samples of stools and urine, all urine samples were shown to be negative for the presence of Schistosoma eggs. On the other hand all stools samples were positive. Eggs were extracted from 20 faecal samples. Worms from each stool sample were collected, through completing the life cycle in white mice. The worms from each sample were collected and used for genetic diversity studies. Using three different primers, RAPD-PCR banding patterns showed that samples collected from Jeddah cluster together away from the rest of samples. Also, samples collected from Taif and Abha did not show any correlation between geographical location and DNA banding patterns. PMID- 21602775 TI - Prevalence and chemo-therapeutical investigations of gastrointestinal nematodes in domestic pigeons in Lahore, Pakistan. AB - The prevalence of gastrointestinal nematodes was studied in 143 (80 male and 63 female) domestic pigeons. Faecal samples were collected to determine the gastrointestinal nematodes of domestic pigeons through qualitative and quantitative faecal examinations. A total of 48 (male 33 and 25 female) naturally infected domestic pigeons were divided into G1 (albendzdole) and G2 (fenbendazole) treatment-groups along with one control group (C). The overall prevalence of gastrointestinal nematodes was 40.5% (58/143) in domestic pigeons. Likewise, the prevalence of gastrointestinal nematodes in males and females was found 41.3% (33/58) and 39.7% (25/58) respectively. The overall prevalence of Capillaria obsignata and Ascaridia columbae was found to be 67.2% and 32.8%, respectively. The prevalence of C. obsignata and A. columbae in males was 72.7% (24/33) and 27.8% (9/33) and in females was 60% (15/25) and 40% (10/25), respectively. There was no significant sex related difference seen in the prevalence of C. obsignata (p>0.56) and A. columbae (p>0.40) in domestic pigeons, respectively. The overall efficacy of albendazole and fenbendazole was calculated to be 66% and 71%. A remarkable significant difference (p<0.05) was observed in eggs per gram before and after treatment in both G1 and G2 treated-groups. The efficacy of fenbendazole was found to be more significant (p<0.02) than albendazole. PMID- 21602776 TI - Insecticide resistance and synergism of three field-collected strains of the German cockroach Blattella germanica (L.) (Dictyoptera: Blattellidae) from hospitals in Kermanshah, Iran. AB - The development of insecticide resistance in the German cockroach, Blattella germanica (L.) is a serious problem in controlling this medically important household pest. The insecticide resistance status in three hospital-collected strains of the German cockroach using four commonly used insecticides from different classes (permethrin, cypermethrin, bendiocarb and chlorpyrifos) was detected by topical bioassay method and preliminary information on possible involvement of monooxygenases in permethrin resistant strains employing synergist piperonyl butoxide (PBO) was obtained. For each insecticide, four to six concentrations resulting in >0% and <100% mortality were used. Three to six replicates of 10 cockroaches per concentration were conducted. For synergism studies, 100 MUg PBO per gram body weight of cockroach as the maximum sublethal dose was administered to the first abdominal segment 1 h before insecticide treatment. The differences between LD50 (MUg/g) values were considered statistically significant only when the 95% confidence intervals did not overlap. The resistance ratio and synergism ratio were calculated for each insecticide. All three hospital-collected strains of the German cockroach showed different levels of resistance to permethrin and cypermethrin based on resistance ratios compared with SUS strain. Permethrin and cypermethrin resistance ratios ranged from 11.61 to 17.64 and 11.45 to 26.45 at LD50 levels, respectively. Low to moderate levels of bendiocarb resistance and low level of chlorpyrifos resistance were also observed in the hospital-collected strains under study. The synergist piperonyl butoxide (PBO) significantly enhanced the toxicity of permethrin to all strains with different degrees of synergist ratio, 2.45-, 1.87-, 2.51- and 2.38 fold, suggesting monooxygenase involvement in permethrin resistance. PMID- 21602777 TI - Plasmodium berghei induces apoptotic changes in splenic and peripheral blood cells. AB - Intracellular parasites manipulate host cell apoptosis in different ways either to increase their life span within infected cells or to spread infection. The present data provided information on the cellular changes taking place in spleen and peripheral blood during Plasmodium berghei-infection and indicated apoptosis mediated host immune response during infection. Our results suggested a significant change in cellular composition and absolute number of white blood cells in spleen and peripheral blood of P. berghei-infected Balb/c mice. Plasmodium berghei-infection was associated with marked increase in percentage of apoptotic mononuclear cells compared to polymorphonuclear white blood cells. PMID- 21602778 TI - Cryptosporidiosis and its potential risk factors in children and calves in Babol, north of Iran. AB - This study was carried out during April-August 2009 to determine the prevalence of Cryptosporidium spp. and its potential risk factors in children and calves in Babol, north of Iran. A total of 150 faecal samples were taken directly from the rectums of calves which were no more than two months old. Information about age, breeding conditions, consistency of faeces (as diarrhoeic or normal) and contact with human were recorded. At the same time, 150 stool samples were taken from children aged one month to 6 years old in Amir Kola children hospital (Babol, north of Iran). All samples were stained with modified Ziehl-Neelsen's acid-fast and Auramine O techniques to detect for the presence of Cryptosporidium oocysts. Results revealed that the prevalence of Cryptosporidium in children and calves were 16% and 7.33% (Auramine O stain), and 10.67% and 4% (Modified Acid-fast stain), respectively. The prevalence of the infection according to age groups and consistency of faeces were found to be statistically significant with Auramine O stain. The prevalence of infection in urban and rural children was similar, but prevalence of Cryptosporidium was more in calves with native breeding. The young calves and children and type of animal breeding represent important risk factors for transmission of cryptosporidiosis. Moreover, there was no relationship between infection of Cryptosporidium in children and calves. Our finding revealed that clinical cryptosporidiosis cases exist in north of Iran and the most important infection route for Cryptosporidium spp. is anthroponotic transmission. PMID- 21602779 TI - In vitro and in vivo anticandidal activity of Swietenia mahogani methanolic seed extract. AB - Swietenia mahogani crude methanolic (SMCM) seed extract was investigated for the antifungal activity against Candida albicans which has not been evaluated previously. The antifungal activity was evaluated against C. albicans via disk diffusion, minimum inhibition concentration (MIC), scanning electron microscope (SEM), transmission electron microscope (TEM) and time killing profile. The MIC value of SMCM seed extract is 12.5 mg/ml. The SEM and TEM findings showed there is morphological changes and cytological destruction of C. albicans at the MIC value. Animal model was used to evaluate the in vivo antifungal activity of SMCM seed extract. The colony forming unit (CFU) were calculated per gram of kidney sample and per ml of blood sample respectively for control, curative and ketaconazole treated groups. There was significant reduction for the CFU/ml of blood and CFU/g of kidney. This indicated that the extract was observed to be effective against C. albicans in vitro and in vivo conditions. PMID- 21602780 TI - Rabbit anti-rabies immunoglobulins production and evaluation. AB - Due to the disadvantages of human and equine rabies immunoglobulin, it is necessary to develop a substitute for HRIG and ERIG, especially for those people living in the developing countries. Because of higher affinity and lower immunogenicity of rabbit's immunoglobulins, anti-rabies immunoglobulins specific to rabies virus were produced in rabbits as a bioreactor, and had been characterized by ELISA, affinity assay, immunofluorescence assay (IFA), immunocytochemistry, rapid fluorescent focus inhibition test (RFFIT). ELISA, affinity assay and IFA showed that rabbit RIG (RRIG) bound specifically to rabies virions. RFFIT result showed that RRIG has neutralization activity. This result was confirmed in vivo in a Kunming mouse challenge model and the protection rate of the treatment with RRIG was higher (25%) than that offered by HRIG when mice were challenged with a lethal RV dose. Our results demonstrate that RRIG is safe and efficacious as a candidate drug to replace rabies immunoglobulin in post exposure prophylaxis. PMID- 21602781 TI - Environmental surveillance and molecular characterization of Legionella in tropical Singapore. AB - Legionnaires' disease is often acquired by inhalation of legionellae from a contaminated environmental source. In recent years, Singapore has seen an increase in the use of aerosol-generating fixtures such as mist fans and spa pools. Poorly maintained and designed water fixtures could pose a public health threat to the community. In this study, we provided an update on the prevalence of Legionella in mist fans (N=28), household water heaters with storage tanks (N=19) and instantaneous heaters (N=30); and extended the survey to spa pools (N=29) and aerosol-generating fixtures in nursing homes (N=116). The prevalence of Legionella were 21.1% in water heaters with storage tanks, 24.1% in spa pools, 14.2% in mist fans and 3.3% in instantaneous heaters. Legionella was not detected in nursing homes. A total of 37 isolates were subjected to molecular characterization using Sequence-Based Typing (SBT) protocol from the European Working Group on Legionella Infections (EWGLI). This is the first study on the use of SBT protocol on environmental strains isolated from tropical South East Asia. The Legionella flora was very heterogenous. The overall diversity of the allelic profile was found to be 0.970 (95% CI 0.946 - 0.994). All known STs of our isolates have been associated with clinical cases in EWGLI database. The phylogenetic analysis showed that our novel environmental isolates were clustered with clinical STs that were previously reported in Europe, Japan, United Kingdom and United States etc. (in EWGLI database), suggesting that Legionella found in the environment of Singapore may potentially cause human disease. PMID- 21602782 TI - Development and evaluation of flow through assay for detection of antibodies against porcine cysticercosis. AB - A flow through assay (FTA) was developed on cellulose acetate membrane for the serodiagnosis of porcine cysticercosis using cyst fluid (CFA) and whole cyst antigens (WCA) of Taenia solium metacestode. The assay consisted of antigen of T. solium metacestode coated onto membrane, mounted on a flow-through test device to provide assay capture matrix. The optimum concentration of coating antigen was 250 ng. The protein A colloidal gold conjugate served as antigen-antibody detecting reagent. A total of 225 serum samples were tested using two antigens. Results were better with CFA (96.0% sensitivity; 96.0% specificity) compared to WCA (92.0% sensitivity; 96.0% specificity). The test was also compared with enzyme-linked immunosorbent assay. The ELISA showed 96 per cent sensitivity with both the antigens whereas; the specificity was 96 and 92 per cent with CFA and WCA respectively. The sensitivity and specificity of flow through assay agrees closely with those of the ELISA. The cross-reaction was observed in one out of eight hydatidosis positive pigs (12.5%) with CFA by both the assays. The highest diagnostic accuracy (96%) was obtained with CFA-FTA and CFA-ELISA. For its high sensitivity and sporadic cross-reactions, CFA-FTA appears to be suitable for practical use at field level without instrumentation. PMID- 21602783 TI - Determination of toxinotypes of environmental Clostridium perfringens by Polymerase Chain Reaction. AB - Toxinotype of Clostridium perfringens (CP) isolates collected from the Bernam River, Selangor River and Tengi Canal between April 2007 and January 2008 were determined by Polymerase Chain Reaction (PCR) using published primers. All the 147 isolates were toxinotype Type A, harbouring the alpha toxin gene. In addition, 5 of the isolates also had the enterotoxin (CPE) gene. PMID- 21602784 TI - Anti-Candida activity and biofilm inhibitory effects of secreted products of tropical environmental yeasts. AB - This study describes the killer phenotypes of tropical environmental yeasts and the inhibition effects of the culture filtrates on the biofilm of Candida albicans. A total of 26 (10.5%) of 258 yeast isolates obtained from an environmental sampling study demonstrated killer activity to Candida species. The killer yeasts were identified as species belonging to the genus Aureobasidium, Pseudozyma, Ustilago and Candida based on sequence analysis of the ITS1-5.8S-ITS2 region of the yeasts. Pseudozyma showed the broadest killing effects against sensitive strains of Candida. New species of Ustilago and Pseudozyma demonstrating killer phenotypes were identified in this study. Interestingly, more than 50% reduction in the metabolic activity of Candida albicans biofilm was noted after exposure to the culture filtrates of the nine killer yeasts. Purification and characterization of toxin and metabolites are essential for understanding the yeast killing effects. PMID- 21602785 TI - Updated distribution records for Anopheles vagus (Diptera: Culicidae) in the Republic of Philippines, and considerations regarding its secondary vector roles in Southeast Asia. AB - Distribution records for Anopheles (Cellia) vagus in the Republic of the Philippines were updated, including recent collection and museum records from Luzon and Visayas Provinces. Larval habitats (e.g. rice paddies, irrigation and drainage ditches), associated species, and the vector potential of this species were also noted. PMID- 21602786 TI - Strongyloides stercoralis in common vegetables and herbs in Kota Bharu, Kelantan, Malaysia. AB - Transmission of soil-transmitted helminthes infection is by faecal oral route, and is influenced by food preference. Kelantanese love to consume ulam which are raw vegetables and herbs. Some of the herbs grow on grounds with high humidity and are abundant near drainage areas, these are also places with higher likelihood of harbouring viable parasite ova. The aim of this study was to determine the prevalence of soiltransmitted helminthes in vegetables, herbs and fruits found in our local setting. The results by microscopy showed that there was no helminthes ovum or protozoan parasite in the samples. However, Strongyloides stercoralis rhabdatiform larvae were identified in water samples used to wash pegaga, kesum and water spinach, and the number of larvae observed were 152, 9 and 16 respectively. Analysis by real-time PCR confirmed the microscopic observation of this helminth. This study highlighted that vegetables and herbs are likely sources of Strongyloides stercoralis infection in Kota Bharu, Kelantan. Thus vegetable sellers as well as the food handlers are the two important groups who are at high risk of acquiring the infection. PMID- 21602787 TI - Nephrocystins and MKS proteins interact with IFT particle and facilitate transport of selected ciliary cargos. AB - Cilia are required for the development and function of many organs. Efficient transport of protein cargo along ciliary axoneme is necessary to sustain these processes. Despite its importance, the mode of interaction between the intraflagellar ciliary transport (IFT) mechanism and its cargo proteins remains poorly understood. Our studies demonstrate that IFT particle components, and a Meckel-Gruber syndrome 1 (MKS1)-related, B9 domain protein, B9d2, bind each other and contribute to the ciliary localization of Inversin (Nephrocystin 2). B9d2, Inversin, and Nephrocystin 5 support, in turn, the transport of a cargo protein, Opsin, but not another photoreceptor ciliary transmembrane protein, Peripherin. Interestingly, the components of this mechanism also contribute to the formation of planar cell polarity in mechanosensory epithelia. These studies reveal a molecular mechanism that mediates the transport of selected ciliary cargos and is of fundamental importance for the differentiation and survival of sensory cells. PMID- 21602788 TI - The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. AB - The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin-dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone-dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach. PMID- 21602789 TI - RNA polymerase II kinetics in polo polyadenylation signal selection. AB - Regulated alternative polyadenylation is an important feature of gene expression, but how gene transcription rate affects this process remains to be investigated. polo is a cell-cycle gene that uses two poly(A) signals in the 3' untranslated region (UTR) to produce alternative messenger RNAs that differ in their 3'UTR length. Using a mutant Drosophila strain that has a lower transcriptional elongation rate, we show that transcription kinetics can determine alternative poly(A) site selection. The physiological consequences of incorrect polo poly(A) site choice are of vital importance; transgenic flies lacking the distal poly(A) signal cannot produce the longer transcript and die at the pupa stage due to a failure in the proliferation of the precursor cells of the abdomen, the histoblasts. This is due to the low translation efficiency of the shorter transcript produced by proximal poly(A) site usage. Our results show that correct polo poly(A) site selection functions to provide the correct levels of protein expression necessary for histoblast proliferation, and that the kinetics of RNA polymerase II have an important role in the mechanism of alternative polyadenylation. PMID- 21602790 TI - Reprogramming the genetic code. PMID- 21602791 TI - SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors. AB - Endocytic sorting of signalling receptors between recycling and degradative pathways is a key cellular process controlling the surface complement of receptors and, accordingly, the cell's ability to respond to specific extracellular stimuli. The beta2 adrenergic receptor (beta2AR) is a prototypical seven-transmembrane signalling receptor that recycles rapidly and efficiently to the plasma membrane after ligand-induced endocytosis. beta2AR recycling is dependent on the receptor's carboxy-terminal PDZ ligand and Rab4. This active sorting process is required for functional resensitization of beta2AR-mediated signalling. Here we show that sequence-directed sorting occurs at the level of entry into retromer tubules and that retromer tubules are associated with Rab4. Furthermore, we show that sorting nexin 27 (SNX27) serves as an essential adaptor protein linking beta2ARs to the retromer tubule. SNX27 does not seem to directly interact with the retromer core complex, but does interact with the retromer associated Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex. The present results identify a role for retromer in endocytic trafficking of signalling receptors, in regulating a receptor-linked signalling pathway, and in mediating direct endosome-to-plasma membrane traffic. PMID- 21602792 TI - Subcellular spatial regulation of canonical Wnt signalling at the primary cilium. AB - Mechanisms of signal transduction regulation remain a fundamental question in a variety of biological processes and diseases. Previous evidence indicates that the primary cilium can act as a signalling hub, but its exact role in many of the described pathways has remained elusive. Here, we investigate the mechanism of cilia-mediated regulation of the canonical Wnt pathway. We found that primary cilia dampen canonical Wnt signalling through a spatial mechanism involving compartmentalization of signalling components. The cilium, through regulated intraflagellar transport, diverts Jouberin (Jbn), a ciliopathy protein and context-specific Wnt pathway regulator, away from the nucleus and limits beta catenin nuclear entry. This repressive regulation does not silence the pathway, but instead maintains a discrete range of Wnt responsiveness; cells without cilia have potentiated Wnt responses, whereas cells with multiple cilia have inhibited responses. Furthermore, we show that this regulation occurs during embryonic development and is disrupted in cancer cell proliferation. Together these data explain a spatial mechanism of Wnt signalling regulation that may provide insight into ciliary regulation of other signalling pathways. PMID- 21602793 TI - The bidirectional depolymerizer MCAK generates force by disassembling both microtubule ends. AB - During cell division the replicated chromosomes are segregated precisely towards the spindle poles. Although many cellular processes involving motility require ATP-fuelled force generation by motor proteins, most models of the chromosome movement invoke the release of energy stored at strained (owing to GTP hydrolysis) plus ends of microtubules. This energy is converted into chromosome movement through passive couplers, whereas the role of molecular motors is limited to the regulation of microtubule dynamics. Here we report, that the microtubule-depolymerizing activity of MCAK (mitotic centromere-associated kinesin), the founding member of the kinesin-13 family, is accompanied by the generation of significant tension-remarkably, at both microtubule ends. An MCAK decorated bead strongly attaches to the microtubule side, but readily slides along it in either direction under weak external loads and tightly captures and disassembles both microtubule ends. We show that the depolymerization force increases with the number of interacting MCAK molecules and is ~1 pN per motor. These results provide a simple model for the generation of driving force and the regulation of chromosome segregation by the activity of MCAK at both kinetochores and spindle poles through a 'side-sliding, end-catching' mechanism. PMID- 21602794 TI - LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. AB - We identify LSD1 (lysine-specific demethylase 1; also known as KDM1A and AOF2) as a key histone modifier that participates in the maintenance of pluripotency through the regulation of bivalent domains, a chromatin environment present at the regulatory regions of developmental genes that contains both H3K4 di/trimethylation and H3K27 trimethylation marks. LSD1 occupies the promoters of a subset of developmental genes that contain bivalent domains and are co-occupied by OCT4 and NANOG in human embryonic stem cells, where it controls the levels of H3K4 methylation through its demethylase activity. Thus, LSD1 has a role in maintaining the silencing of several developmental genes in human embryonic stem cells by regulating the critical balance between H3K4 and H3K27 methylation at their regulatory regions. PMID- 21602795 TI - Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway. AB - Multiciliated cells lining the surface of some vertebrate epithelia are essential for various physiological processes, such as airway cleansing. However, the mechanisms governing motile cilia biosynthesis remain poorly elucidated. We identify miR-449 microRNAs as evolutionarily conserved key regulators of vertebrate multiciliogenesis. In human airway epithelium and Xenopus laevis embryonic epidermis, miR-449 microRNAs strongly accumulated in multiciliated cells. In both models, we show that miR-449 microRNAs promote centriole multiplication and multiciliogenesis by directly repressing the Delta/Notch pathway. We established Notch1 and its ligand Delta-like 1(DLL1) as miR-449 bona fide targets. Human DLL1 and NOTCH1 protein levels were lower in multiciliated cells than in surrounding cells, decreased after miR-449 overexpression and increased after miR-449 inhibition. In frog, miR-449 silencing led to increased Dll1 expression. Consistently, overexpression of Dll1 mRNA lacking miR-449 target sites repressed multiciliogenesis, whereas both Dll1 and Notch1 knockdown rescued multiciliogenesis in miR-449-deficient cells. Antisense-mediated protection of miR-449-binding sites of endogenous human Notch1 or frog Dll1 strongly repressed multiciliogenesis. Our results unravel a conserved mechanism whereby Notch signalling must undergo miR-449-mediated inhibition to permit differentiation of ciliated cell progenitors. PMID- 21602796 TI - Semaphorin 3A induces CaV2.3 channel-dependent conversion of axons to dendrites. AB - Polarized neurites (axons and dendrites) form the functional circuitry of the nervous system. Secreted guidance cues often control the polarity of neuron migration and neurite outgrowth by regulating ion channels. Here, we show that secreted semaphorin 3A (Sema3A) induces the neurite identity of Xenopus spinal commissural interneurons (xSCINs) by activating Ca(V)2.3 channels (Ca(V)2.3). Sema3A treatment converted the identity of axons of cultured xSCINs to that of dendrites by recruiting functional Ca(V)2.3. Inhibition of Sema3A signalling prevented both the expression of Ca(V)2.3 and acquisition of the dendrite identity, and inhibition of Ca(V)2.3 function resulted in multiple axon-like neurites of xSCINs in the spinal cord. Furthermore, Sema3A-triggered cGMP production and PKG activity induced, respectively, the expression of functional Ca(V)2.3 and the dendrite identity. These results reveal a mechanism by which a guidance cue controls the identity of neurites during nervous system development. PMID- 21602797 TI - Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. AB - A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 * 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 * 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder. PMID- 21602798 TI - Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21. AB - In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 * 10(-13)). The frequency of the risk allele is ~5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations. PMID- 21602799 TI - High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays. AB - Heterogeneity in cell populations poses a major obstacle to understanding complex biological processes. Here we present a microfluidic platform containing thousands of nanoliter-scale chambers suitable for live-cell imaging studies of clonal cultures of nonadherent cells with precise control of the conditions, capabilities for in situ immunostaining and recovery of viable cells. We show that this platform mimics conventional cultures in reproducing the responses of various types of primitive mouse hematopoietic cells with retention of their functional properties, as demonstrated by subsequent in vitro and in vivo (transplantation) assays of recovered cells. The automated medium exchange of this system made it possible to define when Steel factor stimulation is first required by adult hematopoietic stem cells in vitro as the point of exit from quiescence. This technology will offer many new avenues to interrogate otherwise inaccessible mechanisms governing mammalian cell growth and fate decisions. PMID- 21602800 TI - A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cells. AB - Cellular immunity has an inherent high level of functional heterogeneity. Capturing the full spectrum of these functions requires analysis of large numbers of effector molecules from single cells. We report a microfluidic platform designed for highly multiplexed (more than ten proteins), reliable, sample efficient (~1 * 10(4) cells) and quantitative measurements of secreted proteins from single cells. We validated the platform by assessment of multiple inflammatory cytokines from lipopolysaccharide (LPS)-stimulated human macrophages and comparison to standard immunotechnologies. We applied the platform toward the ex vivo quantification of T cell polyfunctional diversity via the simultaneous measurement of a dozen effector molecules secreted from tumor antigen-specific cytotoxic T lymphocytes (CTLs) that were actively responding to tumor and compared against a cohort of healthy donor controls. We observed profound, yet focused, functional heterogeneity in active tumor antigen-specific CTLs, with the major functional phenotypes quantitatively identified. The platform represents a new and informative tool for immune monitoring and clinical assessment. PMID- 21602801 TI - Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems. AB - Mammalian peptidoglycan recognition proteins (PGRPs), similar to antimicrobial lectins, bind the bacterial cell wall and kill bacteria through an unknown mechanism. We show that PGRPs enter the Gram-positive cell wall at the site of daughter cell separation during cell division. In Bacillus subtilis, PGRPs activate the CssR-CssS two-component system that detects and disposes of misfolded proteins that are usually exported out of bacterial cells. This activation results in membrane depolarization, cessation of intracellular peptidoglycan, protein, RNA and DNA synthesis, and production of hydroxyl radicals, which are responsible for bacterial death. PGRPs also bind the outer membrane of Escherichia coli and activate the functionally homologous CpxA-CpxR two-component system, which kills the bacteria. We exclude other potential bactericidal mechanisms, including inhibition of extracellular peptidoglycan synthesis, hydrolysis of peptidoglycan and membrane permeabilization. Thus, we reveal a previously unknown mechanism by which innate immunity proteins that bind the cell wall or outer membrane exploit the bacterial stress defense response to kill bacteria. PMID- 21602802 TI - Lrp5 functions in bone to regulate bone mass. AB - The human skeleton is affected by mutations in low-density lipoprotein receptor related protein 5 (LRP5). To understand how LRP5 influences bone properties, we generated mice with osteocyte-specific expression of inducible Lrp5 mutations that cause high and low bone mass phenotypes in humans. We found that bone properties in these mice were comparable to bone properties in mice with inherited mutations. We also induced an Lrp5 mutation in cells that form the appendicular skeleton but not in cells that form the axial skeleton; we observed that bone properties were altered in the limb but not in the spine. These data indicate that Lrp5 signaling functions locally, and they suggest that increasing LRP5 signaling in mature bone cells may be a strategy for treating human disorders associated with low bone mass, such as osteoporosis. PMID- 21602803 TI - Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death. AB - Glutamate acting on N-methyl-D-aspartate (NMDA) receptors induces neuronal injury following stroke, through activation of poly(ADP-ribose) polymerase-1 (PARP-1) and generation of the death molecule poly(ADP-ribose) (PAR) polymer. Here we identify Iduna, a previously undescribed NMDA receptor-induced survival protein that is neuroprotective against glutamate NMDA receptor-mediated excitotoxicity both in vitro and in vivo and against stroke through interfering with PAR polymer induced cell death (parthanatos). Iduna's protective effects are independent and downstream of PARP-1 activity. Iduna is a PAR polymer-binding protein, and mutation at the PAR polymer binding site abolishes the PAR binding activity of Iduna and attenuates its protective actions. Iduna is protective in vivo against NMDA-induced excitotoxicity and middle cerebral artery occlusion-induced stroke in mice. To our knowledge, these results define Iduna as the first known endogenous inhibitor of parthanatos. Interfering with PAR polymer signaling could be a new therapeutic strategy for the treatment of neurologic disorders. PMID- 21602804 TI - Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer. AB - Therapies targeting estrogen receptor alpha (ERalpha, encoded by ESR1) have transformed the treatment of breast cancer. However, large numbers of women relapse, highlighting the need for the discovery of new regulatory targets modulating ERalpha pathways. An siRNA screen identified kinases whose silencing alters the estrogen response including those previously implicated in regulating ERalpha activity (such as mitogen-activated protein kinase and AKT). Among the most potent regulators was lemur tyrosine kinase-3 (LMTK3), for which a role has not previously been assigned. In contrast to other modulators of ERalpha activity, LMTK3 seems to have been subject to Darwinian positive selection, a noteworthy result given the unique susceptibility of humans to ERalpha+ breast cancer. LMTK3 acts by decreasing the activity of protein kinase C (PKC) and the phosphorylation of AKT (Ser473), thereby increasing binding of forkhead box O3 (FOXO3) to the ESR1 promoter. LMTK3 phosphorylated ERalpha, protecting it from proteasomal degradation in vitro. Silencing of LMTK3 reduced tumor volume in an orthotopic mouse model and abrogated proliferation of ERalpha+ but not ERalpha- cells, indicative of its role in ERalpha activity. In human cancers, LMTK3 abundance and intronic polymorphisms were significantly associated with disease free and overall survival and predicted response to endocrine therapies. These findings yield insights into the natural history of breast cancer in humans and reveal LMTK3 as a new therapeutic target. PMID- 21602805 TI - Autoantigen discovery with a synthetic human peptidome. AB - Immune responses targeting self-proteins (autoantigens) can lead to a variety of autoimmune diseases. Identification of these antigens is important for both diagnostic and therapeutic reasons. However, current approaches to characterize autoantigens have, in most cases, met only with limited success. Here we present a synthetic representation of the complete human proteome, the T7 peptidome phage display library (T7-Pep), and demonstrate its application to autoantigen discovery. T7-Pep is composed of >413,000 36-residue, overlapping peptides that cover all open reading frames in the human genome, and can be analyzed using high throughput DNA sequencing. We developed a phage immunoprecipitation sequencing (PhIP-Seq) methodology to identify known and previously unreported autoantibodies contained in the spinal fluid of three individuals with paraneoplastic neurological syndromes. We also show how T7-Pep can be used more generally to identify peptide-protein interactions, suggesting the broader utility of our approach for proteomic research. PMID- 21602806 TI - Specification of transplantable astroglial subtypes from human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) have been differentiated efficiently to neuronal cell types. However, directed differentiation of hPSCs to astrocytes and astroglial subtypes remains elusive. In this study, hPSCs were directed to nearly uniform populations of immature astrocytes (>90% S100beta(+) and GFAP(+)) in large quantities. The immature human astrocytes exhibit similar gene expression patterns as primary astrocytes, display functional properties such as glutamate uptake and promotion of synaptogenesis, and become mature astrocytes by forming connections with blood vessels after transplantation into the mouse brain. Furthermore, hPSC-derived neuroepithelia, patterned to rostral-caudal and dorsal ventral identities with the same morphogens used for neuronal subtype specification, generate immature astrocytes that express distinct homeodomain transcription factors and display phenotypic differences of different astroglial subtypes. These human astroglial progenitors and immature astrocytes will be useful for studying astrocytes in brain development and function, understanding the roles of astrocytes in disease processes and developing novel treatments for neurological disorders. PMID- 21602807 TI - Local elastic properties of a metallic glass. AB - The nature of non-crystalline materials causes the local potential energy of a cluster of atoms or molecules to vary significantly in space. Different configurations of an ensemble of atoms in a metallic glass lead therefore to a distribution of elastic constants which also changes in space. This is totally different to their crystalline counterparts, where a long-range order exists in space and therefore a much more unified elastic modulus is expected. Using atomic force acoustic microscopy, we present data which show that the local so-called indentation modulus M indeed exhibits a wide distribution on a scale below 10 nm in amorphous PdCuSi, with DeltaM/M~30%. About 10(4) atoms are probed in an individual measurement. Crystallized PdCuSi shows a variation that is 10-30 times smaller and which is determined by the resolution of the microscope and by the polycrystalline structure of the material. PMID- 21602808 TI - Collective cell guidance by cooperative intercellular forces. AB - Cells comprising a tissue migrate as part of a collective. How collective processes are coordinated over large multi-cellular assemblies has remained unclear, however, because mechanical stresses exerted at cell-cell junctions have not been accessible experimentally. We report here maps of these stresses within and between cells comprising a monolayer. Within the cell sheet there arise unanticipated fluctuations of mechanical stress that are severe, emerge spontaneously, and ripple across the monolayer. Within that stress landscape, local cellular migrations follow local orientations of maximal principal stress. Migrations of both endothelial and epithelial monolayers conform to this behaviour, as do breast cancer cell lines before but not after the epithelial mesenchymal transition. Collective migration in these diverse systems is seen to be governed by a simple but unifying physiological principle: neighbouring cells join forces to transmit appreciable normal stress across the cell-cell junction, but migrate along orientations of minimal intercellular shear stress. PMID- 21602809 TI - Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages. AB - Endotoxin tolerance, a key mechanism for suppressing excessive inflammatory cytokine production, is induced by prior exposure of macrophages to Toll-like receptor (TLR) ligands. Induction of cross-tolerance to endotoxin by endogenous cytokines has not been investigated. Here we show that prior exposure to tumor necrosis factor (TNF) induced a tolerant state in macrophages, with less cytokine production after challenge with lipopolysaccharide (LPS) and protection from LPS induced death. TNF-induced cross-tolerization was mediated by suppression of LPS induced signaling and chromatin remodeling. TNF-induced cross-tolerance was dependent on the kinase GSK3, which suppressed chromatin accessibility and promoted rapid termination of signaling via the transcription factor NF-kappaB by augmenting negative feedback by the signaling inhibitors A20 and IkappaBalpha. Our results demonstrate an unexpected homeostatic function for TNF and a GSK3 mediated mechanism for the prevention of prolonged and excessive inflammation. PMID- 21602810 TI - A cascade of protein kinase C isozymes promotes cytoskeletal polarization in T cells. AB - Polarization of the T cell microtubule-organizing center (MTOC) toward the antigen-presenting cell (APC) is driven by the accumulation of diacylglycerol (DAG) at the immunological synapse (IS). The mechanisms that couple DAG to the MTOC are not known. By single-cell photoactivation of the T cell antigen receptor (TCR), we found that three distinct isoforms of protein kinase C (PKC) were recruited by DAG to the IS in two steps. PKC-E and PKC-eta accumulated first in a broad region of membrane, whereas PKC-theta arrived later in a smaller zone. Functional experiments indicated that PKC-theta was required for MTOC reorientation and that PKC-E and PKC-eta operated redundantly to promote the recruitment of PKC-theta and subsequent polarization responses. Our results establish a previously uncharacterized role for PKC proteins in T cell polarity. PMID- 21602811 TI - Structure and mechanism of the diterpene cyclase ent-copalyl diphosphate synthase. AB - The structure of ent-copalyl diphosphate synthase reveals three alpha-helical domains (alpha, beta and gamma), as also observed in the related diterpene cyclase taxadiene synthase. However, active sites are located at the interface of the betagamma domains in ent-copalyl diphosphate synthase but exclusively in the alpha domain of taxadiene synthase. Modular domain architecture in plant diterpene cyclases enables the evolution of alternative active sites and chemical strategies for catalyzing isoprenoid cyclization reactions. PMID- 21602812 TI - Metabolic engineering of Escherichia coli for direct production of 1,4 butanediol. AB - 1,4-Butanediol (BDO) is an important commodity chemical used to manufacture over 2.5 million tons annually of valuable polymers, and it is currently produced exclusively through feedstocks derived from oil and natural gas. Herein we report what are to our knowledge the first direct biocatalytic routes to BDO from renewable carbohydrate feedstocks, leading to a strain of Escherichia coli capable of producing 18 g l(-1) of this highly reduced, non-natural chemical. A pathway-identification algorithm elucidated multiple pathways for the biosynthesis of BDO from common metabolic intermediates. Guided by a genome-scale metabolic model, we engineered the E. coli host to enhance anaerobic operation of the oxidative tricarboxylic acid cycle, thereby generating reducing power to drive the BDO pathway. The organism produced BDO from glucose, xylose, sucrose and biomass-derived mixed sugar streams. This work demonstrates a systems-based metabolic engineering approach to strain design and development that can enable new bioprocesses for commodity chemicals that are not naturally produced by living cells. PMID- 21602813 TI - Discovery of superconductivity in KTaO3 by electrostatic carrier doping. AB - Superconductivity at interfaces has been investigated since the first demonstration of electric-field-tunable superconductivity in ultrathin films in 1960(1). So far, research on interface superconductivity has focused on materials that are known to be superconductors in bulk. Here, we show that electrostatic carrier doping can induce superconductivity in KTaO(3), a material in which superconductivity has not been observed before. Taking advantage of the large capacitance of the self-organized electric double layer that forms at the interface between an ionic liquid and KTaO(3) (ref. 12), we achieve a charge carrier density that is an order of magnitude larger than the density that can be achieved with conventional chemical doping. Superconductivity emerges in KTaO(3) at 50 mK for two-dimensional carrier densities in the range 2.3 * 10(14) to 3.7 * 10(14) cm(-2). The present result clearly shows that electrostatic carrier doping can lead to new states of matter at nanoscale interfaces. PMID- 21602814 TI - Spin-orbit-driven ferromagnetic resonance. AB - Ferromagnetic resonance is the most widely used technique for characterizing ferromagnetic materials. However, its use is generally restricted to wafer-scale samples or specific micro-magnetic devices, such as spin valves, which have a spatially varying magnetization profile and where ferromagnetic resonance can be induced by an alternating current owing to angular momentum transfer. Here we introduce a form of ferromagnetic resonance in which an electric current oscillating at microwave frequencies is used to create an effective magnetic field in the magnetic material being probed, which makes it possible to characterize individual nanoscale samples with uniform magnetization profiles. The technique takes advantage of the microscopic non-collinearity of individual electron spins arising from spin-orbit coupling and bulk or structural inversion asymmetry in the band structure of the sample. We characterize lithographically patterned (Ga,Mn)As and (Ga,Mn)(As,P) nanoscale bars, including broadband measurements of resonant damping as a function of frequency, and measurements of anisotropy as a function of bar width and strain. In addition, vector magnetometry on the driving fields reveals contributions with the symmetry of both the Dresselhaus and Rashba spin-orbit interactions. PMID- 21602815 TI - Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel-Lindau gene and hypoxia-inducible factor pathway-related proteins. AB - Over the past few years several investigators have independently described unique low-grade renal epithelial neoplasms with clear cytoplasm, focal to diffuse papillary architecture, and occasional leiomyomatous stromal metaplasia that are not currently recognized in the World Health Organization classification of renal tumors. These tumors have been referred to by a variety of names including clear cell papillary renal cell carcinoma and recently "clear-cell tubulopapillary renal cell carcinoma". On the basis of the available data, such tumors are positive for cytokeratin 7 (CK7) and carbonic anhydrase IX (CA9), while being negative for CD10, alpha-methylacyl-CoA racemase (AMACR), and TFE3. These tumors reportedly lack trisomies of chromosomes 7 and 17, deletions of 3p25, von Hippel Lindau (VHL) gene mutations, and VHL promoter hypermethylation. Herein, we report on nine cases of this tumor emphasizing detailed studies of the VHL gene and hypoxia-inducible factor (HIF) pathway. Molecular studies performed included VHL mutational analysis, copy number changes assessed using single-nucleotide polymorphism arrays, and qRT-PCR for VHL mRNA expression. Immunohistochemical stains for markers of HIF pathway activation (HIF-1alpha, CA9, and glucose transporter-1 (GLUT-1)) as well as other relevant markers (CK7, CD10, AMACR, and TFE3) were performed. None of our tumors harbored VHL gene mutations, losses of chromosomal region 3p25, or trisomies of chromosomes 7 or 17. VHL mRNA was overexpressed in our tumors relative to normal renal tissue and clear-cell renal cell carcinoma. All cases showed strong co-expression of CK7, HIF-1alpha, GLUT-1, and CA9. No expression of TFE3, CD10, or AMACR was seen. The morphological, immunophenotypic, and molecular features of these unique low-grade tumors are sufficiently distinct to allow separation from other renal cell carcinoma subtypes. The co-expression of CA9, HIF-1alpha, and GLUT-1 in the absence of VHL gene alterations in clear-cell papillary renal cell carcinoma suggests activation of the HIF pathway by non-VHL-dependent mechanisms. PMID- 21602816 TI - All atypia diagnosed at stereotactic vacuum-assisted breast biopsy do not need surgical excision. AB - The necessity of excision is debatable when atypia are diagnosed at stereotactic vacuum-assisted breast biopsy (microbiopsy). Among the 287 surgical excisions performed at Institut Bergonie from 1999 to 2009, we selected a case-control study group of 151 excisions; 52 involving all the diagnosed cancers and 99 randomly selected among the 235 excisions without cancer, following atypical microbiopsy (24 flat epithelial atypia; 50 atypical ductal hyperplasia; 14 lobular neoplasia; 63 mixed lesions). Mammographical calcification (type, extension, complete removal) and histological criteria of epithelial atypia (type, number of foci, size/extension), topography and microcalcification extension at microbiopsy were compared according to the presence or absence of cancer at excision. Factors associated with cancer at excision were Breast Imaging Reporting and Data System (BI-RADS5) lesions, large and/or multiple foci of mammographical calcifications, histological type, number, size and extension of atypical foci. Flat epithelial atypia alone was never associated with cancer at excision. BI-RADS5, atypical ductal hyperplasia (alone or predominant) and >3 foci of atypia were identified as independent pejorative factors. There was never any cancer at excision when these pejorative factors were absent (n=31). Presence of one (n=59), two (n=23) or three (n=14) factors was associated with cancer in 24, 15 and 13 cases with an odds ratio=5.8 (95% CI: 3-11.2) for each additional factor. We recommend that mammographical data and histological characteristics be taken into account in the decision-making process after diagnosis of atypia on microbiopsy. With experienced senologists and strict histological criteria, some patients could be spared surgery resulting in significant patient, financial and time advantages. PMID- 21602817 TI - Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions. AB - Cathepsin K is a protease whose expression is driven by microphthalmia transcription factor (MITF) in osteoclasts. TFE3 and TFEB are members of the same transcription factor subfamily as MITF and all three have overlapping transcriptional targets. We have shown that all t(6;11) renal cell carcinomas, which harbor an Alpha-TFEB gene fusion, as well as a subset of the Xp11 translocation renal carcinomas, which harbor various TFE3 gene fusions, express cathepsin K, while no other common renal carcinoma does. We have hypothesized that overexpression of TFEB or certain TFE3 fusion proteins function like MITF in these neoplasms, and thus activate cathepsin K expression. However, the expression of cathepsin K in specific genetic subtypes of Xp11 translocation carcinomas, as well as alveolar soft part sarcoma, which harbors the same ASPSCR1 TFE3 gene fusion as some Xp11 translocation carcinomas, has not been addressed. We performed immunohistochemistry for cathepsin K on 14 genetically confirmed t(X;1)(p11;q21) carcinomas, harboring the PRCC-TFE3 gene fusion; eight genetically confirmed t(X;17)(p11;q25) carcinomas, harboring the ASPSCR1-TFE3 gene fusion; and 18 alveolar soft part sarcomas (12 genetically confirmed), harboring the identical ASPSCR1-TFE3 gene fusion. All 18 alveolar soft part sarcomas expressed cathepsin K. In contrast, all eight ASPSCR1-TFE3 carcinomas were completely negative for cathepsin K. However, 12 of 14 PRCC-TFE3 carcinomas expressed cathepsin K. Expression of cathepsin K distinguishes alveolar soft part sarcoma from the ASPSCR1-TFE3 carcinoma, harboring the same gene fusion. The latter can be useful diagnostically, especially when alveolar soft part sarcoma presents in an unusual site (such as bone) or with clear cell morphology, which raises the differential diagnosis of metastatic ASPSCR1-TFE3 renal cell carcinoma. The difference in expression of cathepsin K between the PRCC-TFE3 and ASPSCR1-TFE3 carcinomas, together with the observed clinical differences between these subtypes of Xp11 translocation carcinomas, suggests the possibility of functional differences between these two related fusion proteins. PMID- 21602818 TI - Structure of the ATP synthase catalytic complex (F(1)) from Escherichia coli in an autoinhibited conformation. AB - ATP synthase is a membrane-bound rotary motor enzyme that is critical for cellular energy metabolism in all kingdoms of life. Despite conservation of its basic structure and function, autoinhibition by one of its rotary stalk subunits occurs in bacteria and chloroplasts but not in mitochondria. The crystal structure of the ATP synthase catalytic complex (F(1)) from Escherichia coli described here reveals the structural basis for this inhibition. The C-terminal domain of subunit E adopts a heretofore unknown, highly extended conformation that inserts deeply into the central cavity of the enzyme and engages both rotor and stator subunits in extensive contacts that are incompatible with functional rotation. As a result, the three catalytic subunits are stabilized in a set of conformations and rotational positions distinct from previous F(1) structures. PMID- 21602819 TI - X-ray structure of a functional full-length dynein motor domain. AB - Dyneins are large microtubule-based motors that power a wide variety of cellular processes. Here we report a 4.5-A X-ray crystallographic analysis of the entire functional motor domain of cytoplasmic dynein with ADP from Dictyostelium discoideum, which has revealed the detailed architecture of the functional units required for motor activity, including the ATP-hydrolyzing ring, the long coiled coil microtubule-binding stalk and the force-generating rod-like linker. We discovered a Y-shaped protrusion composed of two long coiled coils-the stalk and the newly identified 'strut'. This structure supports our model in which the strut coiled coil actively contributes to communication between the primary ATPase site in the ring and the microtubule-binding site at the tip of the stalk coiled coil. Our work also provides insight into how the two motor domains are arranged and how they interact with each other in a functional dimer form of cytoplasmic dynein. PMID- 21602820 TI - Genome-wide CTCF distribution in vertebrates defines equivalent sites that aid the identification of disease-associated genes. AB - Many genomic alterations associated with human diseases localize in noncoding regulatory elements located far from the promoters they regulate, making it challenging to link noncoding mutations or risk-associated variants with target genes. The range of action of a given set of enhancers is thought to be defined by insulator elements bound by the 11 zinc-finger nuclear factor CCCTC-binding protein (CTCF). Here we analyzed the genomic distribution of CTCF in various human, mouse and chicken cell types, demonstrating the existence of evolutionarily conserved CTCF-bound sites beyond mammals. These sites preferentially flank transcription factor-encoding genes, often associated with human diseases, and function as enhancer blockers in vivo, suggesting that they act as evolutionarily invariant gene boundaries. We then applied this concept to predict and functionally demonstrate that the polymorphic variants associated with multiple sclerosis located within the EVI5 gene impinge on the adjacent gene GFI1. PMID- 21602821 TI - A differentially amplified motion in the ear for near-threshold sound detection. AB - The ear is a remarkably sensitive pressure fluctuation detector. In guinea pigs, behavioral measurements indicate a minimum detectable sound pressure of ~20 MUPa at 16 kHz. Such faint sounds produce 0.1-nm basilar membrane displacements, a distance smaller than conformational transitions in ion channels. It seems that noise within the auditory system would swamp such tiny motions, making weak sounds imperceptible. Here we propose a new mechanism contributing to a resolution of this problem and validate it through direct measurement. We hypothesized that vibration at the apical side of hair cells is enhanced compared with that at the commonly measured basilar membrane side. Using in vivo optical coherence tomography, we demonstrated that apical-side vibrations peaked at a higher frequency, had different timing and were enhanced compared with those at the basilar membrane. These effects depend nonlinearly on the stimulus sound pressure level. The timing difference and enhancement of vibrations are important for explaining how the noise problem is circumvented. PMID- 21602822 TI - The SK2-long isoform directs synaptic localization and function of SK2-containing channels. AB - SK2-containing channels are expressed in the postsynaptic density (PSD) of dendritic spines on mouse hippocampal area CA1 pyramidal neurons and influence synaptic responses, plasticity and learning. The Sk2 gene (also known as Kcnn2) encodes two isoforms that differ only in the length of their N-terminal domains. SK2-long (SK2-L) and SK2-short (SK2-S) are coexpressed in CA1 pyramidal neurons and likely form heteromeric channels. In mice lacking SK2-L (SK2-S only mice), SK2-S-containing channels were expressed in the extrasynaptic membrane, but were excluded from the PSD. The SK channel contribution to excitatory postsynaptic potentials was absent in SK2-S only mice and was restored by SK2-L re-expression. Blocking SK channels increased the amount of long-term potentiation induced in area CA1 in slices from wild-type mice but had no effect in slices from SK2-S only mice. Furthermore, SK2-S only mice outperformed wild-type mice in the novel object recognition task. These results indicate that SK2-L directs synaptic SK2 containing channel expression and is important for normal synaptic signaling, plasticity and learning. PMID- 21602823 TI - Forces between clustered stereocilia minimize friction in the ear on a subnanometre scale. AB - The detection of sound begins when energy derived from an acoustic stimulus deflects the hair bundles on top of hair cells. As hair bundles move, the viscous friction between stereocilia and the surrounding liquid poses a fundamental physical challenge to the ear's high sensitivity and sharp frequency selectivity. Part of the solution to this problem lies in the active process that uses energy for frequency-selective sound amplification. Here we demonstrate that a complementary part of the solution involves the fluid-structure interaction between the liquid within the hair bundle and the stereocilia. Using force measurement on a dynamically scaled model, finite-element analysis, analytical estimation of hydrodynamic forces, stochastic simulation and high-resolution interferometric measurement of hair bundles, we characterize the origin and magnitude of the forces between individual stereocilia during small hair-bundle deflections. We find that the close apposition of stereocilia effectively immobilizes the liquid between them, which reduces the drag and suppresses the relative squeezing but not the sliding mode of stereociliary motion. The obliquely oriented tip links couple the mechanotransduction channels to this least dissipative coherent mode, whereas the elastic horizontal top connectors that stabilize the structure further reduce the drag. As measured from the distortion products associated with channel gating at physiological stimulation amplitudes of tens of nanometres, the balance of viscous and elastic forces in a hair bundle permits a relative mode of motion between adjacent stereocilia that encompasses only a fraction of a nanometre. A combination of high-resolution experiments and detailed numerical modelling of fluid-structure interactions reveals the physical principles behind the basic structural features of hair bundles and shows quantitatively how these organelles are adapted to the needs of sensitive mechanotransduction. PMID- 21602825 TI - Tunable pKa values and the basis of opposite charge selectivities in nicotinic type receptors. AB - Among ion channels, only the nicotinic-receptor superfamily has evolved to generate both cation- and anion-selective members. Although other, structurally unrelated, neurotransmitter-gated cation channels exist, no other type of neurotransmitter-gated anion channel, and thus no other source of fast synaptic inhibitory signals, has been described so far. In addition to the seemingly straightforward electrostatic effect of the presence (in the cation-selective members) or absence (in the anion-selective ones) of a ring of pore-facing carboxylates, mutational studies have identified other features of the amino-acid sequence near the intracellular end of the pore-lining transmembrane segments (M2) that are also required to achieve the high charge selectivity shown by native channels. However, the mechanism underlying this more subtle effect has remained elusive and a subject of speculation. Here we show, using single-channel electrophysiological recordings to estimate the protonation state of native ionizable side chains, that anion-selective-type sequences favour whereas cation selective-type sequences prevent the protonation of the conserved, buried basic residues at the intracellular entrance of the pore (the M2 0' position). We conclude that the previously unrecognized tunable charge state of the 0' ring of buried basic side chains is an essential feature of these channels' versatile charge-selectivity filter. PMID- 21602824 TI - Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. AB - Live vaccines have long been known to trigger far more vigorous immune responses than their killed counterparts. This has been attributed to the ability of live microorganisms to replicate and express specialized virulence factors that facilitate invasion and infection of their hosts. However, protective immunization can often be achieved with a single injection of live, but not dead, attenuated microorganisms stripped of their virulence factors. Pathogen associated molecular patterns (PAMPs), which are detected by the immune system, are present in both live and killed vaccines, indicating that certain poorly characterized aspects of live microorganisms, not incorporated in dead vaccines, are particularly effective at inducing protective immunity. Here we show that the mammalian innate immune system can directly sense microbial viability through detection of a special class of viability-associated PAMPs (vita-PAMPs). We identify prokaryotic messenger RNA as a vita-PAMP present only in viable bacteria, the recognition of which elicits a unique innate response and a robust adaptive antibody response. Notably, the innate response evoked by viability and prokaryotic mRNA was thus far considered to be reserved for pathogenic bacteria, but we show that even non-pathogenic bacteria in sterile tissues can trigger similar responses, provided that they are alive. Thus, the immune system actively gauges the infectious risk by searching PAMPs for signatures of microbial life and thus infectivity. Detection of vita-PAMPs triggers a state of alert not warranted for dead bacteria. Vaccine formulations that incorporate vita-PAMPs could thus combine the superior protection of live vaccines with the safety of dead vaccines. PMID- 21602826 TI - Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. AB - The differentiation of patient-derived induced pluripotent stem cells (iPSCs) to committed fates such as neurons, muscle and liver is a powerful approach for understanding key parameters of human development and disease. Whether undifferentiated iPSCs themselves can be used to probe disease mechanisms is uncertain. Dyskeratosis congenita is characterized by defective maintenance of blood, pulmonary tissue and epidermal tissues and is caused by mutations in genes controlling telomere homeostasis. Short telomeres, a hallmark of dyskeratosis congenita, impair tissue stem cell function in mouse models, indicating that a tissue stem cell defect may underlie the pathophysiology of dyskeratosis congenita. Here we show that even in the undifferentiated state, iPSCs from dyskeratosis congenita patients harbour the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1) in X-linked dyskeratosis congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of dyskeratosis congenita caused by mutations in TCAB1 (also known as WRAP53), telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, because telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in dyskeratosis congenita patients. These findings in iPSCs from dyskeratosis congenita patients reveal that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell culture-based system for the development of targeted therapeutics. PMID- 21602828 TI - Consequences of combat stress on brain functioning. PMID- 21602827 TI - Determinants of nucleosome organization in primary human cells. AB - Nucleosomes are the basic packaging units of chromatin, modulating accessibility of regulatory proteins to DNA and thus influencing eukaryotic gene regulation. Elaborate chromatin remodelling mechanisms have evolved that govern nucleosome organization at promoters, regulatory elements, and other functional regions in the genome. Analyses of chromatin landscape have uncovered a variety of mechanisms, including DNA sequence preferences, that can influence nucleosome positions. To identify major determinants of nucleosome organization in the human genome, we used deep sequencing to map nucleosome positions in three primary human cell types and in vitro. A majority of the genome showed substantial flexibility of nucleosome positions, whereas a small fraction showed reproducibly positioned nucleosomes. Certain sites that position in vitro can anchor the formation of nucleosomal arrays that have cell type-specific spacing in vivo. Our results unveil an interplay of sequence-based nucleosome preferences and non nucleosomal factors in determining nucleosome organization within mammalian cells. PMID- 21602829 TI - Discovering imaging endophenotypes for major depression. AB - Psychiatry research lacks an in-depth understanding of mood disorders phenotypes, leading to limited success of genetics studies of major depressive disorder (MDD). The dramatic progress in safe and affordable magnetic resonance-based imaging methods has the potential to identify subtle abnormalities of neural structures, connectivity and function in mood disordered subjects. This review paper presents strategies to improve the phenotypic definition of MDD by proposing imaging endophenotypes derived from magnetic resonance spectroscopy measures, such as cortical gamma-amino butyric acid (GABA) and glutamate/glutamine concentrations, and from measures of resting-state activity and functional connectivity. The proposed endophenotypes are discussed regarding specificity, mood state-independence, heritability, familiarity, clinical relevance and possible associations with candidate genes. By improving phenotypic definitions, the discovery of new imaging endophenotypes will increase the power of candidate gene and genome-wide associations studies. It will also help to develop and evaluate novel therapeutic treatments and enable clinicians to apply individually tailored therapeutic approaches. Finally, improvements of the phenotypic definition of MDD based on neuroimaging measures will contribute to a new classification system of mood disorders based on etiology and pathophysiology. PMID- 21602830 TI - PSA velocity may not be of value in prostate cancer detection. PMID- 21602831 TI - Prostate-specific antigen (PSA) screening: has the pendulum swung too far? PMID- 21602832 TI - Role of the tumor-associated trypsin inhibitor SPINK1 in cancer development. PMID- 21602833 TI - An open, comparative, multicentre clinical study of combined oral therapy with sildenafil and doxazosin GITS for treating Chinese patients with erectile dysfunction and lower urinary tract symptoms secondary to benign prostatic hyperplasia. AB - This study sought to investigate the clinical efficacy and safety of combined oral therapy with sildenafil and doxazosin GITS compared to sildenafil monotherapy in treating Chinese patients with erectile dysfunction (ED) and lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH/LUTS). The trial was conducted in hospitals in Beijing, Shanghai, Changsha, Wuhan and Guangzhou, five major cities in China. A total of 250 patients diagnosed with ED and BPH/LUTS aged 50-75 years, and who had International Index of Erection Function-5 (IIEF-5) scores <=21 and International Prostate Symptom Score (IPSS) >=10 points, were enrolled and randomly divided into Group A (168 cases; doxazosin GITS 4 mg once daily plus sildenafil 25-100 mg on demand) and Group B (82 cases; sildenafil 25-100 mg on demand). Efficacies were evaluated by IIEF-5 and IPSS scores and a quality of life (QoL) questionnaire, and adverse effects were evaluated during the treatment period. There were no statistically significant differences in mean age, and IIEF-5, IPSS and QoL scores pre treatment between the two groups. After treatment, IIEF-5, IPSS and QoL scores were significantly improved in Group A, while only IIEF-5 scores were significantly improved in Group B compared with pre-treatment. There were no significant differences in side effects between the two groups. The results indicated that combined therapy with sildenafil and doxazosin GITS for the treatment of ED and BPH/LUTS is safe and effective compared to sildenafil monotherapy. PMID- 21602834 TI - Current paradigms and evolving concepts in metastatic castration-resistant prostate cancer. AB - Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents (sipuleucel-T, cabazitaxel and abiraterone) with distinct mechanisms of action. Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that more recent trials with older agents have also shown improved survival and discuss potential non therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC. PMID- 21602836 TI - CFTR chloride channel as a molecular target of anthraquinone compounds in herbal laxatives. AB - AIM: To clarify whether CFTR is a molecular target of intestinal fluid secretion caused by the anthraquinone compounds from laxative herbal plants. METHODS: A cell-based fluorescent assay to measure I(-) influx through CFTR chloride channel. A short-circuit current assay to measure transcellular Cl(-) current across single layer FRT cells and freshly isolated colon mucosa. A closed loop experiment to measure colon fluid secretion in vivo. RESULTS: Anthraquinone compounds rhein, aloe-emodin and 1,8-dihydroxyanthraquinone (DHAN) stimulated I( ) influx through CFTR chloride channel in a dose-dependent manner in the presence of physiological concentration of cAMP. In the short-circuit current assay, the three compound enhanced Cl(-) currents in epithelia formed by CFTR-expressing FRT cells with EC(50) values of 73 +/- 1.4, 56 +/- 1.7, and 50 +/- 0.5 MUmol/L, respectively, and Rhein also enhanced Cl(-) current in freshly isolated rat colonic mucosa with a similar potency. These effects were completely reversed by the CFTR selective blocker CFTR(inh)-172. In in vivo closed loop experiments, rhein 2 mmol/L stimulated colonic fluid accumulation that was largely blocked by CFTR(inh)-172. The anthraquinone compounds did not elevate cAMP level in cultured FRT cells and rat colonic mucosa, suggesting a direct effect on CFTR activity. CONCLUSION: Natural anthraquinone compounds in vegetable laxative drugs are CFTR potentiators that stimulated colonic chloride and fluid secretion. Thus CFTR chloride channel is a molecular target of vegetable laxative drugs. PMID- 21602837 TI - Association of serum omentin-1 levels with coronary artery disease. AB - AIM: Omentin-1, a novel adipokine expressed in visceral adipose tissue, is negatively correlated with insulin resistance and obesity. Decreased omentin-1 expression has been found in many chronic inflammatory diseases. However, the role of omentin-1 in coronary artery disease (CAD) has not been elucidated. The aim of the present study was to determine whether serum concentration of omentin 1 was independently associated with CAD. METHODS: One hundred and fifty five patients with CAD were divided into two groups: acute coronary syndrome (ACS) and stable angina pectoris (SAP). A total of 52 healthy participants served as controls. Serum concentrations of omentin-1 and interleukin-6 (IL-6) were measured using ELISA. The association of omentin-1 with CAD and cardiovascular disease risk factors was evaluated. RESULTS: Serum omentin-1 levels were lower in patients with ACS or SAP compared with controls (ACS, 113.08+/-61.43 ng/mL; SAP, 155.41+/-66.89 ng/mL; control, 254.00+/-72.9 ng/mL; P<0.01). Patients with ACS also had lower serum concentrations of omentin-1 compared with patients with SAP (P<0.01). Serum concentration of omentin-1 was negatively correlated with body mass index (r=-0.17, P<0.05) and serum IL-6 concentration (r=-0.19, P<0.05). Furthermore, multiple logistic regression analysis showed that serum omentin-1 concentrations were independently correlated with CAD. CONCLUSION: The findings suggest that serum concentrations of omentin-1 are related to CAD. PMID- 21602835 TI - Current understanding of K ATP channels in neonatal diseases: focus on insulin secretion disorders. AB - ATP-sensitive potassium (K(ATP)) channels are cell metabolic sensors that couple cell metabolic status to electric activity, thus regulating many cellular functions. In pancreatic beta cells, K(ATP) channels modulate insulin secretion in response to fluctuations in plasma glucose level, and play an important role in glucose homeostasis. Recent studies show that gain-of-function and loss-of function mutations in K(ATP) channel subunits cause neonatal diabetes mellitus and congenital hyperinsulinism respectively. These findings lead to significant changes in the diagnosis and treatment for neonatal insulin secretion disorders. This review describes the physiological and pathophysiological functions of K(ATP) channels in glucose homeostasis, their specific roles in neonatal diabetes mellitus and congenital hyperinsulinism, as well as future perspectives of K(ATP) channels in neonatal diseases. PMID- 21602839 TI - Maternal-fetal fluid balance and aquaporins: from molecule to physiology. AB - Maternal-fetal fluid balance is critical during pregnancy, and amniotic fluid is essential for fetal growth and development. The placenta plays a key role in a successful pregnancy as the interface between the mother and her fetus. Aquaporins (AQPs) form specific water channels that allow the rapid transcellular movement of water in response to osmotic/hydrostatic pressure gradients. AQPs expression in the placenta and fetal membranes may play important roles in the maternal-fetal fluid balance. PMID- 21602838 TI - The ClC-3 chloride channels in cardiovascular disease. AB - ClC-3 is a member of the ClC voltage-gated chloride (Cl(-)) channel superfamily. Recent studies have demonstrated the abundant expression and pleiotropy of ClC-3 in cardiac atrial and ventricular myocytes, vascular smooth muscle cells, and endothelial cells. ClC-3 Cl(-) channels can be activated by increase in cell volume, direct stretch of beta1-integrin through focal adhesion kinase and many active molecules or growth factors including angiotensin II and endothelin-1 mediated signaling pathways, Ca(2+)/calmodulin-dependent protein kinase II and reactive oxygen species. ClC-3 may function as a key component of the volume regulated Cl(-) channels, a superoxide anion transport and/or NADPH oxidase interaction partner, and a regulator of many other transporters. ClC-3 has been implicated in the regulation of electrical activity, cell volume, proliferation, differentiation, migration, apoptosis and intracellular pH. This review will highlight the major findings and recent advances in the study of ClC-3 Cl(-) channels in the cardiovascular system and discuss their important roles in cardiac and vascular remodeling during hypertension, myocardial hypertrophy, ischemia/reperfusion, and heart failure. PMID- 21602841 TI - Expression and function of aquaporins in peripheral nervous system. AB - The expression and role of the aquaporin (AQP) family water channels in the peripheral nervous system was less investigated. Since 2004, however, significant progress has been made in the immunolocalization, regulation and function of AQPs in the peripheral nervous system. These studies showed selective localization of three AQPs (AQP1, AQP2, and AQP4) in dorsal root ganglion neurons, enteric neurons and glial cells, periodontal Ruffini endings, trigeminal ganglion neurons and vomeronasal sensory neurons. Functional characterization in transgenic knockout mouse model revealed important role of AQP1 in pain perception. This review will summarize the progress in this field and discuss possible involvement of AQPs in peripheral neuropathies and their potential as novel drug targets. PMID- 21602840 TI - Antcin A, a steroid-like compound from Antrodia camphorata, exerts anti inflammatory effect via mimicking glucocorticoids. AB - AIM: To determine the active ingredient of Niuchangchih (Antrodia camphorata) responsible for its anti-inflammatory effects and the relevant molecular mechanisms. METHODS: Five major antcins (A, B, C, H, and K) were isolated from fruiting bodies of Niuchangchih. Structural similarity between the antcins and 2 glucocorticoids (cortisone and dexamethasone) was compared. After incubation with each compound, the cytosolic glucocorticoid receptor (GR) was examined for its migration into the nucleus. Mo lecular docking was performed to model the tertiary structure of GR associated with antcins. RESULTS: Incubation with cortisone, dexamethasone or antcin A (but not antcins B, C, H, and K) led to the migration of glucocorticoid receptor into the nucleus. The minimal concentration of antcin A, cortisone and dexamethasone to induce nuclear migration of glucocorticoid receptor was 10, 1, and 0.1 mol/L, respectively. The results are in agreement with the simulated binding affinity scores of these three ligands docking to the glucocorticoid receptor. Molecular modeling indicates that C-7 of antcin A or glucocorticoids is exposed to a hydrophobic region in the binding cavity of the glucocorticoid receptor, and the attachment of a hydrophilic group to C-7 of the other four antcins presumably results in their being expelled when docking to the cavity. CONCLUSION: The anti-inflammatory effect of Niuchangchih is, at least, partly attributed to antcin A that mimics glucocorticoids and triggers translocation of glucocorticoid receptor into nucleus to initiate the suppressing inflammation. PMID- 21602842 TI - Pregnant phenotype in aquaporin 8-deficient mice. AB - AIM: Aquaporin 8 (AQP8) is expressed within the female reproductive system but its physiological function reminds to be elucidated. This study investigates the role of AQP8 during pregnancy using AQP8-knockout (AQP8-KO) mice. METHODS: Homozygous AQP8-KO mice were mated, and the conception rate was recorded. AQP8-KO pregnant mice or their offspring were divided into 5 subgroups according to fetal gestational day (7, 13, 16, 18 GD) and newborn. Wild type C57 pregnant mice served as the control group. The number of pregnant mice, total embryos and atrophic embryos, as well as fetal weight, placental weight and placental area were recorded for each subgroup. The amount of amniotic fluid in each sac at 13, 16, and 18 GD was calculated. Statistical significance was determined by analysis of variance of factorial design and chi-square tests. RESULTS: Conception rates did not differ significantly between AQP8-KO and wild type mice. AQP8-KO pregnant mice had a significantly higher number of embryos compared to wild type controls. Fetal/neonatal weight was also significantly greater in the AQP8-KO group compared to age-matched wild type controls. The amount of amniotic fluid was greater in AQP8-KO pregnant mice than wild type controls, although the FM/AFA (fetal weight/amniotic fluid amount) did not differ. While AQP8-KO placental weight was significantly larger than wild type controls, there was no evidence of placental pathology in either group. CONCLUSION: The results suggest that AQP8 deficiency plays an important role in pregnancy outcome. PMID- 21602843 TI - No association between polymorphisms and haplotypes of COL1A1 and COL1A2 genes and osteoporotic fracture in postmenopausal Chinese women. AB - AIM: To study whether genetic polymorphisms of COL1A1 and COL1A2 genes affected the onset of fracture in postmenopausal Chinese women. METHODS: SNPs in COL1A1 and COL1A2 genes were identified via direct sequencing in 32 unrelated postmenopausal Chinese women. Ten SNPs were genotyped in 1252 postmenopausal Chinese women. The associations were examined using both single-SNP and haplotype tests using logistic regression. RESULTS: Twenty four (4 novel) and 28 (7 novel) SNPs were identified in COL1A1 and COL1A2 gene, respectively. The distribution frequencies of 2 SNPs in COL1A1 (rs2075554 and rs2586494) and 3 SNPs in COL1A2 (rs42517, rs1801182, and rs42524) were significantly different from those documented for the European Caucasian population. No significant difference was observed between fracture and control groups with respect to allele frequency or genotype distribution in 9 selected SNPs and haplotype. No significant association was found between fragility fracture and each SNP or haplotype. The results remained the same after additional corrections for other risk factors such as weight, height, and bone mineral density. CONCLUSION: Our results show no association between common genetic variations of COL1A1 and COL1A2 genes and fracture, suggesting the complex genetic background of osteoporotic fractures. PMID- 21602844 TI - MLK4 has negative effect on TLR4 signaling. AB - The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of proinflammatory cytokines such as tumor-necrosis factor-alpha (TNF-alpha). The TNF production is mediated by a series of signaling events and subsequent transcriptional and post-transcriptional activation of the TNF gene. Termination of TLR-mediated cellular signaling is also important for a proper immunoresponse, since sustained cytokine expression can result in immune disorders. Here we identified that mixed-lineage kinase (MLK) 4 is a TLR4-interacting protein. Unlike previously characterized MLK group members, MLK4 cannot act as a mitogen activated protein kinase kinase kinase (MAP3K) to mediate c-Jun N-terminal kinase (JNK), p38 or extracellular signal-regulated kinase (ERK) activation. Rather, MLK4 appears to be able to inhibit lipopolysaccharide (LPS)-induced activation of the JNK or ERK pathways, but does not have effect on LPS-induced p38 or NF-kappaB activation. The LPS-induced TNF production in MLK4 knockdown and overexpression cells were also increased and reduced, respectively. These data demonstrate that MLK4 is a negative regulator of TLR4 signaling. PMID- 21602846 TI - Neolexia. PMID- 21602845 TI - Construction of a Der p2-transgenic plant for the alleviation of airway inflammation. AB - In clinical therapy, the amount of antigen administered to achieve oral tolerance for allergic diseases is large, and the cost is a major consideration. In this study, we used tobacco plants to develop a large-scale protein production system for allergen-specific immunotherapy, and we investigated the mechanisms of oral tolerance induced by a transgenic plant-derived antigen. We used plants (tobacco leaves) transgenic for the Dermatophagoides pteronyssinus 2 (Der p2) antigen to produce Der p2. Mice received total protein extract from Der p2 orally once per day over 6 days (days 0-2 and days 6-8). Mice were also sensitized and challenged with yeast-derived recombinant Der p2 (rDer p2), after which the mice were examined for airway hyper-responsiveness and airway inflammation. After sensitization and challenge with rDer p2, mice that were fed with total protein extracted from transgenic plants showed decreases in serum Der p2-specific IgE and IgG1 titers, decreased IL-5 and eotaxin levels in bronchial alveolar lavage fluid, and eosinophil infiltration in the airway. In addition, hyper responsiveness was also decreased in mice that were fed with total protein extracted from transgenic plants, and CD4(+)CD25(+)Foxp3(+) regulatory T cells were significantly increased in mediastinal and mesenteric lymph nodes. Furthermore, splenocytes isolated from transgenic plant protein-fed mice exhibited decreased proliferation and increased IL-10 secretion after stimulation with rDer p2. The data here suggest that allergen-expressing transgenic plants could be used for therapeutic purposes for allergic diseases. PMID- 21602850 TI - Natural product synthesis: making nematodes nervous. PMID- 21602851 TI - Photochemistry: scrambled by the sun? PMID- 21602852 TI - Conjugated polymers: watching polymers dance. PMID- 21602853 TI - Molecular magnetism: uranium memory. PMID- 21602854 TI - Microfluidics: pensioning off pipettes. PMID- 21602855 TI - Metal-organic frameworks: a porous maze. PMID- 21602857 TI - A microdroplet dilutor for high-throughput screening. AB - Pipetting and dilution are universal processes used in chemical and biological laboratories to assay and experiment. In microfluidics such operations are equally in demand, but difficult to implement. Recently, droplet-based microfluidics has emerged as an exciting new platform for high-throughput experimentation. However, it is challenging to vary the concentration of droplets rapidly and controllably. To this end, we developed a dilution module for high throughput screening using droplet-based microfluidics. Briefly, a nanolitre sized sample droplet of defined concentration is trapped within a microfluidic chamber. Through a process of droplet merging, mixing and re-splitting, this droplet is combined with a series of smaller buffer droplets to generate a sequence of output droplets that define a digital concentration gradient. Importantly, the formed droplets can be merged with other reagent droplets to enable rapid chemical and biological screens. As a proof of concept, we used the dilutor to perform a high-throughput homogeneous DNA-binding assay using only nanolitres of sample. PMID- 21602856 TI - Blueprinting macromolecular electronics. AB - Recently, by mastering either top-down or bottom-up approaches, tailor-made macromolecular nano-objects with semiconducting properties have been fabricated. These engineered nanostructures for organic electronics are based on conjugated systems predominantly made up of sp2-hybridized carbon, such as graphene nanoribbons. Here, we describe developments in a selection of these nanofabrication techniques, which include graphene carving, stimulus-induced synthesis of conjugated polymers and surface-assisted synthesis. We also assess their potential to reproduce chemically and spatially precise molecular arrangements, that is, molecular blueprints. In a broad context, the engineering of a molecular blueprint represents the fabrication of an integrated all-organic macromolecular electronic circuit. In this Perspective, we suggest chemical routes, as well as convergent on-surface synthesis and microfabrication approaches, for the ultimate goal of bringing the field closer to technology. PMID- 21602858 TI - Near-threshold H/D exchange in CD3CHO photodissociation. AB - Measuring the isotopic abundance of hydrogen versus deuterium atoms is a key method for interrogating reaction pathways in chemistry. H/D 'scrambling' is the intramolecular rearrangement of labile isotopes of hydrogen atoms and when it occurs through unanticipated pathways can complicate the interpretation of such experiments. Here, we investigate H/D scrambling in acetaldehyde at the energetic threshold for breaking the formyl C-H bond and reveal an unexpected unimolecular mechanism. Laser photolysis experiments of CD3CHO show that up to 17% of the products have undergone H/D exchange to give CD2H + DCO. Transition-state theory calculations reveal that the dominant mechanism involves four sequential H- or D shifts to form CD2HCDO, which then undergoes conventional C-C bond cleavage. At the lowest energy the molecule undergoes an average of 20 H- or D-shifts before products are formed, evincing significant scrambling of H and D atoms. Analogous photochemically induced isomerizations and isotope scrambling are probably important in both atmospheric chemistry and combustion reactions. PMID- 21602859 TI - Synthesis of conolidine, a potent non-opioid analgesic for tonic and persistent pain. AB - Management of chronic pain continues to represent an area of great unmet biomedical need. Although opioid analgesics are typically embraced as the mainstay of pharmaceutical interventions in this area, they suffer from substantial liabilities that include addiction and tolerance, as well as depression of breathing, nausea and chronic constipation. Because of their suboptimal therapeutic profile, the search for non-opioid analgesics to replace these well-established therapeutics is an important pursuit. Conolidine is a rare C5-nor stemmadenine natural product recently isolated from the stem bark of Tabernaemontana divaricata (a tropical flowering plant used in traditional Chinese, Ayurvedic and Thai medicine). Although structurally related alkaloids have been described as opioid analgesics, no therapeutically relevant properties of conolidine have previously been reported. Here, we describe the first de novo synthetic pathway to this exceptionally rare C5-nor stemmadenine natural product, the first asymmetric synthesis of any member of this natural product class, and the discovery that (+/-)-, (+)- and (-)-conolidine are potent and efficacious non opioid analgesics in an in vivo model of tonic and persistent pain. PMID- 21602860 TI - A delocalized arene-bridged diuranium single-molecule magnet. AB - Single-molecule magnets (SMMs) are compounds that, below a blocking temperature, exhibit stable magnetization purely of molecular origin, and not caused by long range ordering of magnetic moments in the bulk. They thus show promise for applications such as data storage of ultra-high density. The stability of the magnetization increases with increasing ground-state spin and magnetic anisotropy. Transition-metal SMMs typically possess high-spin ground states, but insufficient magnetic anisotropies. Lanthanide SMMs exhibit large magnetic anisotropies, but building high-spin ground states is difficult because they tend to form ionic bonds that limit magnetic exchange coupling. In contrast, the significant covalent bonding and large spin-orbit contributions associated with uranium are particularly attractive for the development of improved SMMs. Here we report a delocalized arene-bridged diuranium SMM. This study demonstrates that arene-bridged polyuranium clusters can exhibit SMM behaviour without relying on the superexchange coupling of spins. This approach may lead to increased blocking temperatures. PMID- 21602861 TI - Water-oxidation catalysis by manganese in a geochemical-like cycle. AB - Water oxidation in all oxygenic photosynthetic organisms is catalysed by the Mn4CaO4 cluster of Photosystem II. This cluster has inspired the development of synthetic manganese catalysts for solar energy production. A photoelectrochemical device, made by impregnating a synthetic tetranuclear-manganese cluster into a Nafion matrix, has been shown to achieve efficient water oxidation catalysis. We report here in situ X-ray absorption spectroscopy and transmission electron microscopy studies that demonstrate that this cluster dissociates into Mn(II) compounds in the Nafion, which are then reoxidized to form dispersed nanoparticles of a disordered Mn(III/IV)-oxide phase. Cycling between the photoreduced product and this mineral-like solid is responsible for the observed photochemical water-oxidation catalysis. The original manganese cluster serves only as a precursor to the catalytically active material. The behaviour of Mn in Nafion therefore parallels its broader biogeochemistry, which is also dominated by cycles of oxidation into solid Mn(III/IV) oxides followed by photoreduction to Mn2+. PMID- 21602862 TI - Visible-light-enhanced catalytic oxidation reactions on plasmonic silver nanostructures. AB - Catalysis plays a critical role in chemical conversion, energy production and pollution mitigation. High activation barriers associated with rate-limiting elementary steps require most commercial heterogeneous catalytic reactions to be run at relatively high temperatures, which compromises energy efficiency and the long-term stability of the catalyst. Here we show that plasmonic nanostructures of silver can concurrently use low-intensity visible light (on the order of solar intensity) and thermal energy to drive catalytic oxidation reactions--such as ethylene epoxidation, CO oxidation, and NH3 oxidation--at lower temperatures than their conventional counterparts that use only thermal stimulus. Based on kinetic isotope experiments and density functional calculations, we postulate that excited plasmons on the silver surface act to populate O2 antibonding orbitals and so form a transient negative-ion state, which thereby facilitates the rate limiting O2-dissociation reaction. The results could assist the design of catalytic processes that are more energy efficient and robust than current processes. PMID- 21602863 TI - Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst. AB - Single-step constructions of molecules with multiple quaternary carbon stereocentres are rare. The spirooxindole structural motif is common to a range of bioactive compounds; however, asymmetric synthesis of this motif is complicated due to the presence of multiple chiral centres. The development of organocatalytic cascade reactions has proven to be valuable for the construction of several chiral centres in one step. Here, we describe a newly designed organocatalytic asymmetric domino Michael-aldol reaction between 3-substituted oxindoles and methyleneindolinones that affords complex bispirooxindoles. This reaction was catalysed by a novel multifunctional organocatalyst that contains tertiary and primary amines and thiourea moieties to activate substrates simultaneously, providing extraordinary levels of stereocontrol over four stereocentres, three of which are quaternary carbon stereocentres. This new methodology provides facile access to a range of multisubstituted bispirocyclooxindole derivatives, and should be useful in medicinal chemistry and diversity-oriented syntheses of this intriguing class of compounds. PMID- 21602864 TI - Core@shell bimetallic nanoparticle synthesis via anion coordination. AB - Core@shell structured bimetallic nanoparticles are currently of immense interest due to their unique electronic, optical and catalytic properties. However, their synthesis is non-trivial. We report a new supramolecular route for the synthesis of core@shell nanoparticles, based on an anion coordination protocol--the first to function by binding the shell metal to the surface of the pre-formed primary metal core before reduction. The resultant gold/palladium and platinum/palladium core@shell nanoparticles have been characterized by aberration-corrected scanning transmission electron microscopy (as well as other techniques), giving striking atomic-resolution images of the core@shell architecture, and the unique catalytic properties of the structured nanoparticles have been demonstrated in a remarkable improvement of the selective production of industrially valuable chloroaniline from chloronitrobenzene. PMID- 21602865 TI - Total synthesis of solanoeclepin A. AB - Cyst nematodes are troublesome parasites that live on, and destroy, a range of important host vegetable plants. Damage caused by the potato cyst nematode has now been reported in over 50 countries. One approach to eliminating the problem is to stimulate early hatching of the nematodes, but key hatching stimuli are not naturally available in sufficient quantities to do so. Here, we report the first chemical synthesis of solanoeclepin A, the key hatch-stimulating substance for potato cyst nematode. The crucial steps in our synthesis are an intramolecular cyclization reaction for construction of the highly strained tricyclo[5.2.1.01'6]decane skeleton (DEF ring system) and an intramolecular Diels Alder reaction of a furan derivative for the synthesis of the ABC carbon framework. The present synthesis has the potential to contribute to addressing one of the critical food issues of the twenty-first century. PMID- 21602866 TI - The effect of gold loading and particle size on photocatalytic hydrogen production from ethanol over Au/TiO2 nanoparticles. AB - Catalytic hydrogen production from renewables is a promising method for providing energy carriers in the near future. Photocatalysts capable of promoting this reaction are often composed of noble metal nanoparticles deposited on a semiconductor. The most promising semiconductor at present is TiO2. The successful design of these catalysts relies on a thorough understanding of the role of the noble metal particle size and the TiO2 polymorph. Here we demonstrate that Au particles in the size range 3-30 nm on TiO2 are very active in hydrogen production from ethanol. It was found that Au particles of similar size on anatase nanoparticles delivered a rate two orders of magnitude higher than that recorded for Au on rutile nanoparticles. Surprisingly, it was also found that Au particle size does not affect the photoreaction rate over the 3-12 nm range. The high hydrogen yield observed makes these catalysts promising materials for solar conversion. PMID- 21602868 TI - Cobalt close-up. PMID- 21602869 TI - Budgeting for the long run. PMID- 21602871 TI - Organic thermoelectrics: green energy from a blue polymer. PMID- 21602872 TI - Colloidal self-assembly: designed to yield. PMID- 21602873 TI - Material witness: smart tipping. PMID- 21602874 TI - Cell mechanics: moving under peer pressure. PMID- 21602875 TI - Active gels: motors keep dynamics steady. PMID- 21602876 TI - Graphene: pushing the boundaries. PMID- 21602879 TI - Twist2 contributes to breast cancer progression by promoting an epithelial mesenchymal transition and cancer stem-like cell self-renewal. AB - The epithelial to mesenchymal transition (EMT) is a highly conserved cellular programme that has an important role in normal embryogenesis and in cancer invasion and metastasis. We report here that Twist2, a tissue-specific basic helix-loop-helix transcription factor, is overexpressed in human breast cancers and lymph node metastases. In mammary epithelial cells and breast cancer cells, ectopic overexpression of Twist2 results in morphological transformation, downregulation of epithelial markers and upregulation of mesenchymal markers. Moreover, Twist2 enhances the cell migration and colony-forming abilities of mammary epithelial cells and breast cancer cells in vitro and promotes tumour growth in vivo. Ectopic expression of Twist2 in mammary epithelial cells and breast cancer cells increases the size and number of their CD44(high)/CD24(low) stem-like cell sub-populations, promotes the expression of stem cell markers and enhances the self-renewal capabilities of stem-like cells. In addition, exogenous expression of Twist2 leads to constitutive activation of STAT3 (signal transducer and activator of transcription 3) and downregulation of E-cadherin. Thus, the overexpression of Twist2 may contribute to breast cancer progression by activating the EMT programme and enhancing the self-renewal of cancer stem-like cells. PMID- 21602880 TI - Integrin-linked kinase: not so 'pseudo' after all. AB - Integrin-linked kinase (ILK) is a highly evolutionarily conserved intracellular protein that was originally identified as an integrin-interacting protein, and extensive genetic and biochemical studies have shown that ILK expression is vital during both embryonic development and tissue homeostasis. At the cellular and tissue levels, ILK regulates signaling pathways for cell adhesion-mediated cell survival (anoikis), apoptosis, proliferation and mitosis, migration, invasion, and vascularization and tumor angiogenesis. ILK also has central roles in cardiac and smooth-muscle contractility, and ILK dysregulation causes cardiomyopathies in humans. ILK protein levels are increased in several human cancers and often the expression level predicts poor patient outcome. Abundant evidence has accumulated suggesting that, of the diverse functions of ILK, some may require kinase activity whereas others depend on protein-protein interactions and are, therefore, independent of kinase activity. However, the past several years have seen an ongoing debate about whether ILK indeed functions as a protein serine/threonine kinase. This debate centers on the atypical protein kinase domain of ILK, which lacks some amino-acid residues thought to be essential for phosphotransferase activity. However, similar deficiencies are present in the catalytic domains of other kinases now known to possess protein kinase activity. Numerous studies have shown that ILK phosphorylates peptide substrates in vitro, corresponding to ILK-mediated phosphorylations in intact cells, and a recent report characterizing in vitro phosphotransferase activity of highly purified, full-length ILK, accompanied by detailed enzyme kinetic analyses, shows that, at least in vitro, ILK is a bona fide protein kinase. However, several genetic studies suggest that, not all biological functions of ILK require kinase activity, and that it can function as an adaptor/scaffold protein. Here, we review evidence for and against ILK being an active kinase, and provide a framework for strategies to further analyze the kinase and adaptor functions of ILK in different cellular contexts. PMID- 21602882 TI - HIPK2 phosphorylates DeltaNp63alpha and promotes its degradation in response to DNA damage. AB - Homeodomain-interacting protein kinase 2 (HIPK2) is an emerging player in cell response to genotoxic agents that senses damage intensity and contributes to the cell's choice between cell cycle arrest and apoptosis. Phosphorylation of p53 at S46, an apoptosis-specific p53 posttranslational modification, is the most characterized HIPK2 function in response to lethal doses of ultraviolet (UV), ionizing radiation or different anticancer drugs, such as cisplatin, roscovitine and doxorubicin (DOX). Indeed, like p53, HIPK2 has been shown to contribute to the effectiveness of these treatments. Interestingly, p53-independent mechanisms of HIPK2-induced apoptosis were described for UV and tumor growth factor-beta treatments; however, it is unknown whether these mechanisms are relevant for the responses to anticancer drugs. Because of the importance of the so-called 'p53 independent apoptosis and drug response' in human cancer chemotherapy, we asked whether p53-independent factor(s) might be involved in HIPK2-mediated chemosensitivity. Here, we show that HIPK2 depletion by RNA interference induces resistance to different anticancer drugs even in p53-null cells, suggesting the involvement of HIPK2 targets other than p53 in response to chemotherapy. In particular, we found that HIPK2 phosphorylates and promotes proteasomal degradation of DeltaNp63alpha, a prosurvival DeltaN isoform of the p53 family member, p63. Indeed, effective cell response to different genotoxic agents was shown to require phosphorylation-induced proteasomal degradation of DeltaNp63alpha. In DOX-treated cells, we show that HIPK2 depletion interferes with DeltaNp63alpha degradation, and expression of a HIPK2-resistant DeltaNp63alpha-Delta390 mutant induces chemoresistance. We identify T397 as the DeltaNp63alpha residue phosphorylated by HIPK2, and show that the non phosphorylatable DeltaNp63alpha-T397A mutant is not degraded in the face of either HIPK2 overexpression or DOX treatment. These results indicate DeltaNp63alpha as a novel target of HIPK2 in response to genotoxic drugs. PMID- 21602881 TI - RasGRP3, a Ras activator, contributes to signaling and the tumorigenic phenotype in human melanoma. AB - RasGRP3, an activator for H-Ras, R-Ras and Ras-associated protein-1/2, has emerged as an important mediator of signaling downstream from receptor coupled phosphoinositide turnover in B and T cells. Here, we report that RasGRP3 showed a high level of expression in multiple human melanoma cell lines as well as in a subset of human melanoma tissue samples. Suppression of endogenous RasGRP3 expression in these melanoma cell lines reduced Ras-GTP formation as well as c Met expression and Akt phosphorylation downstream from hepatocyte growth factor (HGF) or epidermal growth factor (EGF) stimulation. RasGRP3 suppression also inhibited cell proliferation and reduced both colony formation in soft agar and xenograft tumor growth in immunodeficient mice, demonstrating the importance of RasGRP3 for the transformed phenotype of the melanoma cells. Reciprocally, overexpression of RasGRP3 in human primary melanocytes altered cellular morphology, markedly enhanced cell proliferation and rendered the cells tumorigenic in a mouse xenograft model. Suppression of RasGRP3 expression in these cells inhibited downstream RasGRP3 responses and suppressed cell growth, confirming the functional role of RasGRP3 in the altered behavior of these cells. The identification of the role of RasGRP3 in melanoma highlights its importance, as a Ras activator, in the phosphoinositide signaling pathway in human melanoma and provides a new potential therapeutic target. PMID- 21602883 TI - Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression. AB - Aging is thought to negatively affect multiple cellular processes including the ability to maintain chromosome stability. Chromosome instability (CIN) is a common property of cancer cells and may be a contributing factor to cellular transformation. The types of DNA aberrations that arise during aging before tumor development and that contribute to tumorigenesis are currently unclear. Mdm2, a key regulator of the p53 tumor suppressor and modulator of DNA break repair, is frequently overexpressed in malignancies and contributes to CIN. To determine the relationship between aging and CIN and the role of Mdm2, precancerous wild-type C57Bl/6 and littermate-matched Mdm2 transgenic mice at various ages were evaluated. Metaphase analyses of wild-type cells showed a direct correlation between age and increased chromosome and chromatid breaks, chromosome fusions and aneuploidy, but the frequency of polyploidy remained stable over time. Elevated levels of Mdm2 in precancerous mice increased both the numerical and the structural chromosomal abnormalities observed. Chromosome and chromatid breaks, chromosome fusions, aneuploidy and polyploidy were increased in older Mdm2 transgenic mice compared with wild-type littermates. Unexpectedly, chromosome fusions, aneuploidy and polyploidy rates in Mdm2 transgenic mice, but not chromosome and chromatid breaks, showed cooperation between Mdm2 overexpression and age. Notably, Mdm2 overexpression promoted gains in one or more chromosomes with age, while it did not affect the rate of chromosome loss. Therefore, aging increased specific forms of genomic instability, and elevated Mdm2 expression cooperated with aging to increase the likelihood of gaining certain chromosomal abnormalities of the kind thought to lead to cancer development. PMID- 21602884 TI - Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo. AB - Ionizing radiation is a genotoxic agent and human carcinogen. Recent work has questioned long-held dogmas by showing that cancer-associated genetic alterations occur in cells and tissues not directly exposed to radiation, questioning the robustness of the current system of radiation risk assessment. In vitro, diverse mechanisms involving secreted soluble factors, gap junction intercellular communication (GJIC) and oxidative metabolism are proposed to mediate these indirect effects. In vivo, the mechanisms behind long-range 'bystander' responses remain largely unknown. Here, we investigate the role of GJIC in propagating radiation stress signals in vivo, and in mediating radiation-associated bystander tumorigenesis in mouse central nervous system using a mouse model in which intercellular communication is downregulated by targeted deletion of the connexin43 (Cx43) gene. We show that GJIC is critical for transmission of oncogenic radiation damage to the non-targeted cerebellum, and that a mechanism involving adenosine triphosphate release and upregulation of Cx43, the major GJIC constituent, regulates transduction of oncogenic damage to unirradiated tissues in vivo. Our data provide a novel hypothesis for transduction of distant bystander effects and suggest that the highly branched nervous system, similar to the vascular network, has an important role. PMID- 21602886 TI - Uncommitted precursor cells might contribute to increased incidence of embryonal rhabdomyosarcoma in heterozygous Patched1-mutant mice. AB - Embryonal rhabdomyosarcoma (ERMS) is a tumor of the skeletal muscle in children and is frequently initiated by heterozygous germline mutations in the Hedgehog (Hh) receptor Patched1 (Ptch), both in humans and mice. Using a conditional knock out strategy in Ptch(flox/+) mice, we demonstrate that early embryonic stages are more susceptible to ERMS development than later stages and that cells normally not committed to undergo myogenesis at this stage represent the major source of ERMS. We found that deletion of a single copy of the Ptch allele at E9.5 using the ubiquitously active Rosa26CreERT2 resulted in a tumor incidence of 88% but reached only 44% and 12% when the Ptch allele was inactivated at E11.5 and E13.5, respectively. Induction of the Ptch mutation at E9.5 did also significantly shorten ERMS-free survival and increased tumor multiplicity compared with tumor induction at E11.5 and E13.5. Interestingly, we observed a more that 10-fold reduction of ERMS incidence when the Ptch mutation was specifically introduced in Myf5-expressing cells, which is the myogenic factor expressed in all muscle cells at E9.5. We conclude that Myf5-negative cells are more susceptible to ERMS development than Myf5-positive embryonic precursors. As the propensity to undergo tumorigenic transformation declined with age, concomitant with the increase of stably committed muscle cells, it seems likely that the Ptch mutation favors tumor formation in progenitor cells, which have not yet acquired a muscle cell fate. PMID- 21602885 TI - Expression of BARHL1 in medulloblastoma is associated with prolonged survival in mice and humans. AB - Medulloblastoma is the most common malignant brain tumor in childhood, and development of targeted therapies is highly desired. Although the molecular mechanisms of malignant transformation are not fully understood, it is known that medulloblastomas may arise from cerebellar granule neuron precursors. The homeodomain transcription factor Barhl1 is known to regulate migration and survival of granule cell precursors, but its functional role in medulloblastoma is unknown. We show here that the expression of BARHL1 is significantly upregulated during human cerebellar development and in human medulloblastoma samples as compared with the normal adult cerebellum. We also detected high levels of Barhl1 expression in medulloblastomas of Math1-cre:SmoM2 mice, a mouse model for Sonic hedgehog-associated medulloblastomas that we developed previously. To investigate Barhl1 function in vivo during tumor development, we generated Barhl1(-/-)Math1-cre:SmoM2 mice. Interestingly, tumors that developed in these mice displayed increased mitotic activity and decreased neuronal differentiation. Moreover, survival of these mice was significantly decreased. Similarly, low expression of BARHL1 in human medulloblastoma cases was associated with a less favorable prognosis for patients. These results suggest that the expression of Barhl1 decelerates tumor growth both in human and in murine medulloblastomas and should be further investigated with respect to potential implications for individualized therapeutic strategies. PMID- 21602887 TI - PAX8 promotes tumor cell growth by transcriptionally regulating E2F1 and stabilizing RB protein. AB - The retinoblastoma protein (RB)-E2F1 pathway has a central role in regulating the cell cycle. Several PAX proteins (tissue-specific developmental regulators), including PAX8, interact with the RB protein, and thus regulate the cell cycle directly or indirectly. Here, we report that PAX8 expression is frequent in renal cell carcinoma, bladder, ovarian and thyroid cancer cell lines, and that silencing of PAX8 in cancer cell lines leads to a striking reduction in the expression of E2F1 and its target genes, as well as a proteasome-dependent destabilization of RB protein, with the RB1 mRNA level remaining unaffected. Cancer cells expressing PAX8 undergo a G(1)/S arrest and eventually senesce following PAX8 silencing. We demonstrate that PAX8 transcriptionally regulates the E2F1 promoter directly, and E2F1 transcription is enhanced after RB depletion. RB is recruited to the PAX8-binding site, and is involved in PAX8 mediated E2F1 transcription in cancer cells. Therefore, our results suggest that, in cancer, frequent and persistent expression of PAX8 is required for cell growth control through transcriptional activation of E2F1 expression and upregulation of the RB-E2F1 pathway. PMID- 21602888 TI - Inactivation of the von Hippel-Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer. AB - A human endogenous retrovirus type E (HERV-E) was recently found to be selectively expressed in most renal cell carcinomas (RCCs). Importantly, antigens derived from this provirus are immunogenic, stimulating cytotoxic T cells that kill RCC cells in vitro and in vivo. Here, we show HERV-E expression is restricted to the clear cell subtype of RCC (ccRCC) characterized by an inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene with subsequent stabilization of hypoxia-inducible transcription factors (HIFs)-1alpha and 2alpha. HERV-E expression in ccRCC linearly correlated with HIF-2alpha levels and could be silenced in tumor cells by either transfection of normal VHL or small interfering RNA inhibition of HIF-2alpha. Using chromatin immunoprecipitation, we demonstrated that HIF-2alpha can serve as transcriptional factor for HERV-E by binding with HIF response element (HRE) localized in the proviral 5' long terminal repeat (LTR). Remarkably, the LTR was found to be hypomethylated only in HERV-E-expressing ccRCC while other tumors and normal tissues possessed a hypermethylated LTR preventing proviral expression. Taken altogether, these findings provide the first evidence that inactivation of a tumor suppressor gene can result in aberrant proviral expression in a human tumor and give insights needed for translational research aimed at boosting human immunity against antigenic components of this HERV-E. PMID- 21602889 TI - The exonuclease activity of hPMC2 is required for transcriptional regulation of the QR gene and repair of estrogen-induced abasic sites. AB - We have previously reported that the expression of antioxidative stress enzymes is upregulated by trans-hydroxytamoxifen (TOT) in breast epithelial cell lines providing protection against estrogen-induced DNA damage. This regulation involves Estrogen Receptor beta (ERbeta) recruitment to the Electrophile Response Element (EpRE) and a novel protein, human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2). We have also demonstrated that ERbeta and hPMC2 are required for TOT-dependent recruitment of poly (ADP-ribose) polymerase 1 (PARP-1) and Topoisomerase IIbeta (Topo IIbeta) to the EpRE. Sequence analysis reveals that the C-terminus of hPMC2 encodes a putative exonuclease domain. Using in vitro kinetic assays, we found that hPMC2 is a 3'-5' non-processive exonuclease that degrades both single-stranded and double-stranded substrates. Mutation of two conserved carboxylate residues drastically reduced the exonuclease activity of hPMC2, indicating the relative importance of the catalytic residues. Western blot analysis of breast cancer cell lines for Quinone Reductase (QR) levels revealed that the intrinsic exonuclease activity of hPMC2 was required for TOT induced QR upregulation. Chromatin immunoprecipitation (ChIP) assays also indicated that hPMC2 was involved in the formation of strand breaks observed with TOT treatment and is specific for the EpRE-containing region of the QR gene. We also determined that the transcription factor NF-E2-related factor-2 (Nrf2) is involved in the specificity of hPMC2 for the EpRE. In addition, we determined that the catalytic activity of hPMC2 is required for repair of abasic sites that result from estrogen-induced DNA damage. Thus, our study provides a mechanistic basis for transcriptional regulation by hPMC2 and provides novel insights into its role in cancer prevention. PMID- 21602890 TI - Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1alpha mediated by the PTEN/PI3K/Akt pathway. AB - Mel-18 has been implicated in several processes in tumor progression, in which the Akt pathway is involved as an important key molecular event. However, the function of Mel-18 in human cancers has not been fully established yet. Here, we examined the effect of Mel-18 on tumor angiogenesis in human breast cancer, and found that Mel-18 was a novel regulator of HIF-1alpha. Mel-18 negatively regulated the HIF-1alpha expression and its target gene VEGF transcription during both normoxia and hypoxia. We demonstrated that Mel-18 regulated the HIF-1alpha expression and activity via the PI3K/Akt pathway. Loss of Mel-18 downregulated Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, consequently activating the PI3K/Akt/MDM2 pathway, and leading to an increase of HIF-1alpha protein level. Mel-18 modulated the HIF-1alpha transcriptional activity via regulating the cytoplasmic retention of FOXO3a, a downstream effector of Akt, and recruitment of HIF-1alpha/CBP complex to the VEGF promoter. Furthermore, our data shows that Mel-18 blocked tumor angiogenesis both in vitro and in vivo. Mel-18 overexpression inhibited in vitro tube formation in human umbilical endothelial cells (HUVECs). Xenografts in NOD/SCID mice derived from stably Mel-18 knocked down MCF7 human breast cancer cells showed increased tumor volume, microvessel density, and phospho-Akt and HIF-1alpha expression levels. In conclusion, our findings provide that Mel-18 is a novel regulator of tumor angiogenesis through regulating HIF-1alpha and its target VEGF expressions mediated by the PTEN/PI3K/Akt pathway, suggesting a new tumor-suppressive role of Mel-18 in human breast cancer. PMID- 21602891 TI - Phosphorylation of Crk on tyrosine 251 in the RT loop of the SH3C domain promotes Abl kinase transactivation. AB - Here, we report the identification and characterization of a novel tyrosine phosphorylation site in the carboxy-terminal Src Homology 3 (SH3) (SH3C) domain of the Crk adaptor protein. Y251 is located in the highly conserved RT loop structure of the SH3C, a region of Crk involved in the allosteric regulation of the Abl kinase. Exploiting kinase assays to show that Y251 is phosphorylated by Abl in vitro, we generated affinity-purified antisera against phosphorylated Y251 in Crk and showed that Abl induces phosphorylation at Y251 in vivo, and that the kinetics of phosphorylation at Y251 and the negative regulatory Y221 site in vitro are similar. Y251 on endogenous Crk was robustly phosphorylated in chronic myelogenous leukemia cell lines and in A431 and MDA-MB-468 cells stimulated with epidermal growth factor. Using streptavidin-biotin pull downs and unbiased high throughput Src Homology 2 (SH2) profiling approaches, we found that a pY251 phosphopeptide binds specifically to a subset of SH2 domains, including Abl and Arg SH2, and that binding of pY251 to Abl SH2 induces transactivation of Abl 1b. Finally, the Y251F Crk mutant significantly abrogates Abl transactivation in vitro and in vivo. These studies point to a yet unrealized positive regulatory role resulting from tyrosine phosphorylation of Crk, and identify a novel mechanism by which an adaptor protein activates a non-receptor tyrosine kinase by SH2 domain displacement. PMID- 21602892 TI - Nucleocytoplasmic localization of p70 S6K1, but not of its isoforms p85 and p31, is regulated by TSC2/mTOR. AB - The tuberous sclerosis complex gene 2 (TSC2)/mammalian target of rapamycin (mTOR) pathway controls many cellular functions via phosphorylation of ribosomal protein S6 kinases (S6Ks). Alternative splicing and translation generate three S6K1 proteins. Although nuclear and cytoplasmic S6K targets are known, the nucleocytoplasmic localization of the S6K1 proteins has not been comparatively elucidated so far. We show that in primary fibroblasts p85 S6K1 is cytoplasmic, p70 can be found in both compartments and p31 is exclusively nuclear. As already known for p70 and p85, our data suggest that p31 is also a target of mTOR mediated phosphorylation. Blocking mTOR kinase activity via rapamycin and its activation in TSC2(-/-) cells and via TSC2 small interfering RNAs revealed that it regulates the localization of p70, but not of p85 and p31. The mTOR-dependent phosphorylation of p70 S6K1 at T389 is essential for its nuclear localization and exclusively hyperphosphorylated p70 S6K1 can be found in the nucleus. We further demonstrate this mTOR-controlled p70 S6K1 localization to be growth factor dependent. During the cell-cycle phosphorylation and nuclear localization of p70 S6K1 occur in mid G1 phase. We report that the different S6K1 proteins exhibit different nucleocytoplasmic localizations and that the TSC2/mTOR cascade not only regulates p70 S6K1 activity, but also its localization. These findings provide new important insights into the temporal and spatial dynamics of TSC2/mTOR/S6K regulation. PMID- 21602893 TI - Integrative mRNA profiling comparing cultured primary cells with clinical samples reveals PLK1 and C20orf20 as therapeutic targets in cutaneous squamous cell carcinoma. AB - Identifying therapeutic targets for cancer treatment relies on consistent changes within particular types or sub-types of malignancy. The ability to define either consistent changes or sub-types of malignancy is often masked by tumor heterogeneity. To elucidate therapeutic targets in cutaneous squamous cell carcinoma (cSCC), the most frequent skin neoplasm with malignant potential, we have developed an integrated approach to gene expression profiling beginning with primary keratinocytes in culture. Candidate drivers of cSCC development were derived by first defining a set of in vitro cancer genes and then comparing their expression in a range of clinical data sets containing normal skin, cSCC and the benign hyper-proliferative condition psoriasis. A small interfering RNA (siRNA) screen of the resulting 21 upregulated genes has yielded targets capable of reducing xenograft tumor volume in vivo. Small-molecule inhibitors for one target, Polo-like kinase-1 (PLK1), are already in clinical trials for other malignancies, and our data show efficacy in cSCC. Another target, C20orf20, is identified as being overexpressed in cSCC, and siRNA-mediated knockdown induces apoptosis in vitro and reduces tumor growth in vivo. Thus, our approach has shown established and uncharacterized drivers of tumorigenesis with potent efficacy as therapeutic targets for the treatment of cSCC. PMID- 21602895 TI - Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum. AB - Heterozygous Patched1 (Ptc1(+/-)) mice are prone to medulloblastoma (MB), and exposure of newborn mice to ionizing radiation dramatically increases the frequency and shortens the latency of MB. In Ptc1(+/-) mice, MB is characterized by loss of the normal remaining Ptc1 allele, suggesting that genome rearrangements may be key events in MB development. Recent evidence indicates that brain tumors may be linked to defects in DNA-damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints, apoptosis and DNA repair result in MB in mice. Non-homologous end joining (NHEJ) and homologous recombination (HR) contribute to genome stability, and deficiencies in either pathway predispose to genome rearrangements. To test the role of defective HR or NHEJ in tumorigenesis, control and irradiated Ptc1(+/ ) mice with two, one or no functional Rad54 or DNA-protein kinase catalytic subunit (DNA-PKcs) alleles were monitored for MB development. We also examined the effect of Rad54 or DNA-PKcs deletion on the processing of endogenous and radiation-induced double-strand breaks (DSBs) in neural precursors of the developing cerebellum, the cells of origin of MB. We found that, although HR and NHEJ collaborate in protecting cells from DNA damage and apoptosis, they have opposite roles in MB tumorigenesis. In fact, although Rad54 deficiency increased both spontaneous and radiation-induced MB development, DNA-PKcs disruption suppressed MB tumorigenesis. Together, our data provide the first evidence that Rad54-mediated HR in vivo is important for suppressing tumorigenesis by maintaining genomic stability. PMID- 21602894 TI - IRX1 influences peritoneal spreading and metastasis via inhibiting BDKRB2 dependent neovascularization on gastric cancer. AB - The overexpression of IRX1 gene correlates with the growth arrest in gastric cancer. Furthermore, overexpression of IRX1 gene suppresses peritoneal spreading and long distance metastasis. To explore the precise mechanisms, we investigated whether restoring IRX1 expression affects the angiogenesis or vasculogenic mimicry (VM). Human umbilical vein endothelial cells (HUVECs) and chick embryo and SGC-7901 gastric cancer cells were used for angiogenesis and VM analysis. Small interfering RNA was used for analyzing the function of BDKRB2, a downstream target gene of IRX1. As results, the remarkable suppression on peritoneal spreading and pulmonary metastasis of SGC-7901 cells by IRX1 transfectant correlates to reduced angiogenesis as well as VM formation. Using the supernatant from SGC-7901/IRX1 cells, we found a strong inhibiting effect on angiogenesis both in vitro and in chick embryo. SGC-7901/IRX1 cells revealed strong inhibiting effect on VM formation too. By gene-specific RNA interference for BDKRB2, or its effector PAK1, we got an effective inhibition on tube formation, cell proliferation, cell migration and invasion in vitro. In conclusion, enforcing IRX1 expression effectively suppresses peritoneal spreading and pulmonary metastasis via anti-angiogenesis and anti-VM mechanisms, in addition to previously found cell growth and invasion. BDKRB2 and its downstream effector might be potential targets for anti-cancer strategy. PMID- 21602896 TI - Epithelial cells in PBSC grafts: source of donor-type epithelial cells after allogeneic transplantation? PMID- 21602897 TI - A double cure: Omenn syndrome and beta thalassaemia successfully treated with mismatched unrelated donor transplantation. PMID- 21602898 TI - Quality of life in patients before and after haematopoietic stem cell transplantation measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire QLQ-C30. AB - The EORTC Quality of Life Core Questionnaire QLQ-C30 is widely used, but no reference values are available for patients receiving HSCT. We retrieved data for 38 samples from 33 papers in English and German that provided evaluable information on QLQ-C30 scores (mean, s.d.) covering about 2800 patients. Results are presented as a table that provides reference data that allow QLQ-C30 scores at different points during the disease trajectory to be put in context. With respect to their central tendency and their variance, scores vary over time. Quality of life is lowest during inpatient time. About 1 year after HSCT, the pre transplant level is reached. Physical functioning is the scale reaching the highest level of all scales. Fatigue, dyspnoea and insomnia are symptoms that remain at an elevated level and should thus be considered as persisting problems after HSCT. For the interpretation of differences between scores, a very conservative recommendation would be to set the s.d. at 30 points. Doing so, one could be quite sure of having found a clinically significant change if the difference of two scores exceeds 15 points. Differences below 5 points should be interpreted with caution. PMID- 21602899 TI - Tandem chemo-mobilization followed by high-dose melphalan and carmustine with single autologous hematopoietic cell transplantation for multiple myeloma. AB - Single autologous hematopoietic cell transplant (AHCT) with high-dose melphalan prolongs survival in patients with multiple myeloma but is not curative. We conducted a study of intensive single AHCT using tandem chemo-mobilization with CY and etoposide followed by high-dose conditioning with melphalan 200 mg/m(2) plus carmustine 15 mg/kg. One hundred and eighteen patients in first consolidation (CON1) and 58 patients in relapse (REL) were transplanted using this intensified approach. Disease response improved from 32% very good PR (VGPR)+CR pre-mobilization to 76% VGPR+CR post transplant in CON1. With a median follow-up of 4.7 years, the median EFS was 2.8 years, and the median OS was 5.1 years in CON1. OS from time of transplant was significantly shorter for REL (3.4 years) compared with CON1 (5.1 years; P=0.02). However, OS from time of diagnosis was similar in REL (6.1 years) and CON1 (6.0 years; P=0.80). The 100-day non relapse mortality in the CON1 and REL groups was 0% and 7%, respectively. In summary, intensified single AHCT with tandem chemo-mobilization and augmented high-dose therapy is feasible in multiple myeloma and leads to high-quality response rates. PMID- 21602900 TI - Reduced-intensity hematopoietic cell transplantation in older patients with AML/MDS: umbilical cord blood is a feasible option for patients without HLA matched sibling donors. AB - Umbilical cord blood (UCB) has increased access to hematopoietic cell transplantation (HCT) for patients without HLA-matched sibling donors (MSD). We compared outcomes of HCT using MSD (N=38) or UCB (N=60) among older patients (age >= 55 years) with AML or myelodysplastic syndromes (MDS). All patients received a reduced intensity regimen consisting of CY, fludarabine and 200 cGy TBI. Median age at HCT was 63 years for MSD and 61 years for UCB recipients. Among UCB recipients, 95% received two UCB units and 88% received 1-2 locus HLA-mismatched units to optimize cell dose. OS at 3-years was 37% for MSD and 31% for UCB recipients (P=0.21). On multivariate analysis, donor source (MSD vs UCB) did not impact risks of OS, leukemia-free survival and relapse or treatment-related mortality. UCB is feasible as an alternative donor source for reduced-intensity conditioning HCT among older patients with AML and MDS who do not have a suitable MSD. PMID- 21602901 TI - Successful treatment of metastatic retinoblastoma with high-dose chemotherapy and autologous stem cell rescue in South America. AB - High-dose chemotherapy (HDC) followed by autologous stem cell rescue (ASCR) is the only curative treatment for metastatic retinoblastoma, but its feasibility in developing countries is unknown. We report 11 consecutive children (six unilateral) treated in three South-American middle-income countries with HDC ASCR. One patient had metastatic retinoblastoma at diagnosis and the remaining ones had a metastatic relapse. Metastatic sites included BM=6, bone=4, orbit=5 and central nervous system (CNS)=4. All patients received induction with conventional chemotherapy achieving CR at a median of 5.7 months from the diagnosis of metastasis. Conditioning regimens included carboplatin and etoposide with thiotepa in six or with CY in four or melphalan in one patient. All patients engrafted after G-CSF-mobilized peripheral blood ASCR and no toxic deaths occurred. Two children received post-ASCR CNS radiotherapy. Seven children have disease-free survival (median follow-up 39 months). CNS relapse, isolated (n=3) or with systemic relapse (n=1), occurring at a median of 7 months after ASCT was the most common event. In the same period, five children with metastatic retinoblastoma did not qualify for HDC-ASCR and died. We conclude that HDC-ASCR is a feasible and effective treatment for children with metastatic retinoblastoma in middle-income countries. PMID- 21602903 TI - Cytoskeleton: RhoC invades cofilin's space. PMID- 21602905 TI - Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis. AB - Skeletal muscle is the dominant organ system in locomotion and energy metabolism. Postnatal muscle grows and adapts largely by remodelling pre-existing fibres, whereas embryonic muscle grows by the proliferation of myogenic cells. Recently, the genetic hierarchies of the myogenic transcription factors that control vertebrate muscle development - by myoblast proliferation, migration, fusion and functional adaptation into fast-twitch and slow-twitch fibres - have become clearer. The transcriptional mechanisms controlling postnatal hypertrophic growth, remodelling and functional differentiation redeploy myogenic factors in concert with serum response factor (SRF), JUNB and forkhead box protein O3A (FOXO3A). It has also emerged that there is extensive post-transcriptional regulation by microRNAs in development and postnatal remodelling. PMID- 21602906 TI - Keeping mRNPs in check during assembly and nuclear export. AB - The cell nucleus is an intricate organelle that coordinates multiple activities that are associated with DNA replication and gene expression. In all eukaryotes, it stores the genetic information and the machineries that control the production of mature and export-competent messenger ribonucleoproteins (mRNPs), a multistep process that is regulated in a spatial and temporal manner. Recent studies suggest that post-translational modifications play a part in coordinating the co transcriptional assembly, remodelling and export of mRNP complexes through nuclear pores, adding a new level of regulation to the process of gene expression. PMID- 21602907 TI - Turing's next steps: the mechanochemical basis of morphogenesis. AB - Nearly 60 years ago, Alan Turing showed theoretically how two chemical species, termed morphogens, diffusing and reacting with each other can generate spatial patterns. Diffusion plays a crucial part in transporting chemical signals through space to establish the length scale of the pattern. When coupled to chemical reactions, mechanical processes - forces and flows generated by motor proteins - can also define length scales and provide a mechanochemical basis for morphogenesis. forces and flows generated by motor proteins - can also define length scales and provide a mechanochemical basis for morphogenesis. PMID- 21602908 TI - High cleavage efficiency of a 2A peptide derived from porcine teschovirus-1 in human cell lines, zebrafish and mice. AB - When expression of more than one gene is required in cells, bicistronic or multicistronic expression vectors have been used. Among various strategies employed to construct bicistronic or multicistronic vectors, an internal ribosomal entry site (IRES) has been widely used. Due to the large size and difference in expression levels between genes before and after IRES, however, a new strategy was required to replace IRES. A self-cleaving 2A peptide could be a good candidate to replace IRES because of its small size and high cleavage efficiency between genes upstream and downstream of the 2A peptide. Despite the advantages of the 2A peptides, its use is not widespread because (i) there are no publicly available cloning vectors harboring a 2A peptide gene and (ii) comprehensive comparison of cleavage efficiency among various 2A peptides reported to date has not been performed in different contexts. Here, we generated four expression plasmids each harboring different 2A peptides derived from the foot-and-mouth disease virus, equine rhinitis A virus, Thosea asigna virus and porcine teschovirus-1, respectively, and evaluated their cleavage efficiency in three commonly used human cell lines, zebrafish embryos and adult mice. Western blotting and confocal microscopic analyses revealed that among the four 2As, the one derived from porcine teschovirus-1 (P2A) has the highest cleavage efficiency in all the contexts examined. We anticipate that the 2A-harboring cloning vectors we generated and the highest efficiency of the P2A peptide we demonstrated would help biomedical researchers easily adopt the 2A technology when bicistronic or multicistronic expression is required. PMID- 21602909 TI - Lactate Effectively Covers Energy Demands during Neuronal Network Activity in Neonatal Hippocampal Slices. AB - Although numerous experimental data indicate that lactate is efficiently used for energy by the mature brain, the direct measurements of energy metabolism parameters during neuronal network activity in early postnatal development have not been performed. Therefore, the role of lactate in the energy metabolism of neurons at this age remains unclear. In this study, we monitored field potentials and contents of oxygen and NAD(P)H in correlation with oxidative metabolism during intense network activity in the CA1 hippocampal region of neonatal brain slices. We show that in the presence of glucose, lactate is effectively utilized as an energy substrate, causing an augmentation of oxidative metabolism. Moreover, in the absence of glucose lactate is fully capable of maintaining synaptic function. Therefore, during network activity in neonatal slices, lactate can be an efficient energy substrate capable of sustaining and enhancing aerobic energy metabolism. PMID- 21602911 TI - Must Family/Carers Look after Strangers? Post-DBS Identity Changes and Related Conflicts Of Interest. PMID- 21602912 TI - Morphological analysis of activity-reduced adult-born neurons in the mouse olfactory bulb. AB - Adult-born neurons (ABNs) are added to the olfactory bulb (OB) throughout life in rodents. While many factors have been identified as regulating the survival and integration of ABNs into existing circuitry, the understanding of how these factors affect ABN morphology and connectivity is limited. Here we compare how cell intrinsic [small interfering RNA (siRNA) knock-down of voltage gated sodium channels Na(V)1.1-1.3] and circuit level (naris occlusion) reductions in activity affect ABN morphology during integration into the OB. We found that both manipulations reduce the number of dendritic spines (and thus likely the number of reciprocal synaptic connections) formed with the surrounding circuitry and inhibited dendritic ramification of ABNs. Further, we identified regions of ABN apical dendrites where the largest and most significant decreases occur following siRNA knock-down or naris occlusion. In siRNA knock-down cells, reduction of spines is observed in proximal regions of the apical dendrite. This suggests that distal regions of the dendrite may remain active independent of Na(V)1.1-1.3 channel expression, perhaps facilitated by activation of T-type calcium channels and NMDA receptors. By contrast, circuit level reduction of activity by naris occlusion resulted in a global depression of spine number. Together, these results indicate that ABNs retain the ability to develop their typical overall morphological features regardless of experienced activity, and activity modulates the number and location of formed connections. PMID- 21602910 TI - Exercise-induced cognitive plasticity, implications for mild cognitive impairment and Alzheimer's disease. AB - Lifestyle factors such as intellectual stimulation, cognitive and social engagement, nutrition, and various types of exercise appear to reduce the risk for common age-associated disorders such as Alzheimer's disease (AD) and vascular dementia. In fact, many studies have suggested that promoting physical activity can have a protective effect against cognitive deterioration later in life. Slowing or a deterioration of walking speed is associated with a poor performance in tests assessing psychomotor speed and verbal fluency in elderly individuals. Fitness training influences a wide range of cognitive processes, and the largest positive impact observed is for executive (a.k.a. frontal lobe) functions. Studies show that exercise improves additional cognitive functions such as tasks mediated by the hippocampus, and result in major changes in plasticity in the hippocampus. Interestingly, this exercise-induced plasticity is also pronounced in APOE epsilon4 carriers who express a risk factor for late-onset AD that may modulate the effect of treatments. Based on AD staging by Braak and Braak (1991) and Braak et al. (1993) we propose that the effects of exercise occur in two temporo-spatial continua of events. The "inward" continuum from isocortex (neocortex) to entorhinal cortex/hippocampus for amyloidosis and a reciprocal "outward" continuum for neurofibrillary alterations. The exercise-induced hypertrophy of the hippocampus at the core of these continua is evaluated in terms of potential for prevention to stave off neuronal degeneration. Exercise induced production of growth factors such as the brain-derived neurotrophic factor (BDNF) has been shown to enhance neurogenesis and to play a key role in positive cognitive effects. Insulin-like growth factor (IGF-1) may mediate the exercise-induced response to exercise on BDNF, neurogenesis, and cognitive performance. It is also postulated to regulate brain amyloid beta (Abeta) levels by increased clearance via the choroid plexus. Growth factors, specifically fibroblast growth factor and IGF-1 receptors and/or their downstream signaling pathways may interact with the Klotho gene which functions as an aging suppressor gene. Neurons may not be the only cells affected by exercise. Glia (astrocytes and microglia), neurovascular units and the Fourth Element may also be affected in a differential fashion by the AD process. Analyses of these factors, as suggested by the multi-dimensional matrix approach, are needed to improve our understanding of this complex multi-factorial process, which is increasingly relevant to conquering the escalating and intersecting world-wide epidemics of dementia, diabetes, and sarcopenia that threaten the global healthcare system. Physical activity and interventions aimed at enhancing and/or mimicking the effects of exercise are likely to play a significant role in mitigating these epidemics, together with the embryonic efforts to develop cognitive rehabilitation for neurodegenerative disorders. PMID- 21602913 TI - Effect of portfolio assessment on student learning in prenatal training for midwives. AB - The tendency to use portfolios for evaluation has been developed with the aim of optimizing the culture of assessment. The present study was carried out to determine the effect of using portfolios as an evaluation method on midwifery students' learning and satisfaction in prenatal practical training. In this prospective cohort study, all midwifery students in semester four (n=40), were randomly allocated to portfolio and routine evaluation groups. Based on their educational goals, the portfolio groups prepared packages which consisted of a complete report of the history, physical examinations, and methods of patient management (as evaluated by a checklist) for women who visited a prenatal clinic. During the last day of their course, a posttest, clinical exam, and student satisfaction form were completed. The two groups' mean age, mean pretest scores, and their prerequisite course that they should have taken in the previous semester were similar. The mean difference in the pre and post test scores for the two groups' knowledge and comprehension levels did not differ significantly (P>0.05). The average scores on questions in Bloom's taxonomy 2 and 3 of the portfolio group were significantly greater than those of the routine evaluation group (P=0.002, P=0.03, respectively). The mean of the two groups' clinical exam scores was significantly different. The portfolio group's mean scores on generating diagnostic and therapeutic solutions and the ability to apply theory in practice were higher than those of the routine group. Overall, students' satisfaction scores in the two evaluation methods were relatively similar. Portfolio evaluation provides the opportunity for more learning by increasing the student's participation in the learning process and helping them to apply theory in practice. PMID- 21602914 TI - A study on Korean nursing students' educational outcomes. AB - The purpose of this study was to describe outcome indicators of nursing education including critical thinking, professionalism, leadership, and communication and to evaluate differences among nursing programs and academic years. A descriptive research design was employed. A total of 454 students from four year baccalaureate (BS) nursing programs and two three-year associate degree (AD) programs consented to complete self-administered questionnaires. The variables were critical thinking, professionalism, leadership and communication. Descriptive statistics, chi(2)-test, t-tests, ANOVA, and the Tukey test were utilized for the data analysis. All the mean scores of the variables were above average for the test instruments utilized. Among the BS students, those in the upper classes tended to attain higher scores, but this tendency was not identified in AD students. There were significant differences between BS students and AD students for the mean scores of leadership and communication. These findings suggested the need for further research to define properties of nursing educational outcomes, and to develop standardized instruments for research replication and verification. PMID- 21602915 TI - Basal Ganglia preferentially encode context dependent choice in a two-armed bandit task. AB - Decision is a self-generated phenomenon, which is hard to track with standard time averaging methods, such as peri-event time histograms (PETHs), used in behaving animals. Reasons include variability in duration of events within a task and uneven reaction time of animals. We have developed a temporal normalization method where PETHs were juxtaposed all along task events and compared between neurons. We applied this method to neurons recorded in striatum and GPi of behaving monkeys involved in a choice task. We observed a significantly higher homogeneity of neuron activity profile distributions in GPi than in striatum. Focusing on the period of the task during which the decision was taken, we showed that approximately one quarter of all recorded neurons exhibited tuning functions. These so-called coding neurons had average firing rates that varied as a function of the value of both presented cues, a combination here referred to as context, and/or value of the chosen cue. The tuning functions were used to build a simple maximum likelihood estimation model, which revealed that (i) GPi neurons are more efficient at encoding both choice and context than striatal neurons and (ii) context prediction rates were higher than those for choice. Furthermore, the mutual information between choice or context values and decision period average firing rate was higher in GPi than in striatum. Considered together, these results suggest a convergence process of the global information flow between striatum and GPi, preferentially involving context encoding, which could be used by the network to perform decision-making. PMID- 21602916 TI - Widespread increases in malondialdehyde immunoreactivity in dopamine-rich and dopamine-poor regions of rat brain following multiple, high doses of methamphetamine. AB - Treatment with multiple high doses of methamphetamine (METH) can induce oxidative damage, including dopamine (DA)-mediated reactive oxygen species (ROS) formation, which may contribute to the neurotoxic damage of monoamine neurons and long-term depletion of DA in the caudate putamen (CPu) and substantia nigra pars compacta (SNpc). Malondialdehyde (MDA), a product of lipid peroxidation by ROS, is commonly used as a marker of oxidative damage and treatment with multiple high doses of METH increases MDA reactivity in the CPu of humans and experimental animals. Recent data indicate that MDA itself may contribute to the destruction of DA neurons, as MDA causes the accumulation of toxic intermediates of DA metabolism via its chemical modification of the enzymes necessary for the breakdown of DA. However, it has been shown that in human METH abusers there is also increased MDA reactivity in the frontal cortex, which receives relatively fewer DA afferents than the CPu. These data suggest that METH may induce neuronal damage regardless of the regional density of DA or origin of DA input. The goal of the current study was to examine the modification of proteins by MDA in the DA rich nigrostriatal and mesoaccumbal systems, as well as the less DA-dense cortex and hippocampus following a neurotoxic regimen of METH treatment. Animals were treated with METH (10 mg/kg) every 2 h for 6 h, sacrificed 1 week later, and examined using immunocytochemistry for changes in MDA-adducted proteins. Multiple, high doses of METH significantly increased MDA immunoreactivity (MDA ir) in the CPu, SNpc, cortex, and hippocampus. Multiple METH administration also increased MDA-ir in the ventral tegmental area and nucleus accumbens. Our data indicate that multiple METH treatment can induce persistent and widespread neuronal damage that may not necessarily be limited to the nigrostriatal DA system. PMID- 21602917 TI - Preferential localization of human origins of DNA replication at the 5'-ends of expressed genes and at evolutionarily conserved DNA sequences. AB - BACKGROUND: Replication of mammalian genomes requires the activation of thousands of origins which are both spatially and temporally regulated by as yet unknown mechanisms. At the most fundamental level, our knowledge about the distribution pattern of origins in each of the chromosomes, among different cell types, and whether the physiological state of the cells alters this distribution is at present very limited. METHODOLOGY/PRINCIPAL FINDINGS: We have used standard lambda-exonuclease resistant nascent DNA preparations in the size range of 0.7 1.5 kb obtained from the breast cancer cell line MCF-7 hybridized to a custom tiling array containing 50-60 nt probes evenly distributed among genic and non genic regions covering about 1% of the human genome. A similar DNA preparation was used for high-throughput DNA sequencing. Array experiments were also performed with DNA obtained from BT-474 and H520 cell lines. By determining the sites showing nascent DNA enrichment, we have localized several thousand origins of DNA replication. Our major findings are: (a) both array and DNA sequencing assay methods produced essentially the same origin distribution profile; (b) origin distribution is largely conserved (>70%) in all cell lines tested; (c) origins are enriched at the 5'ends of expressed genes and at evolutionarily conserved intergenic sequences; and (d) ChIP on chip experiments in MCF-7 showed an enrichment of H3K4Me3 and RNA Polymerase II chromatin binding sites at origins of DNA replication. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the program for origin activation is largely conserved among different cell types. Also, our work supports recent studies connecting transcription initiation with replication, and in addition suggests that evolutionarily conserved intergenic sequences have the potential to participate in origin selection. Overall, our observations suggest that replication origin selection is a stochastic process significantly dependent upon local accessibility to replication factors. PMID- 21602918 TI - Recurrent chromosomal copy number alterations in sporadic chordomas. AB - The molecular events in chordoma pathogenesis have not been fully delineated, particularly with respect to copy number changes. Understanding copy number alterations in chordoma may reveal critical disease mechanisms that could be exploited for tumor classification and therapy. We report the copy number analysis of 21 sporadic chordomas using array comparative genomic hybridization (CGH). Recurrent copy changes were further evaluated with immunohistochemistry, methylation specific PCR, and quantitative real-time PCR. Similar to previous findings, large copy number losses, involving chromosomes 1p, 3, 4, 9, 10, 13, 14, and 18, were more common than copy number gains. Loss of CDKN2A with or without loss of CDKN2B on 9p21.3 was observed in 16/20 (80%) unique cases of which six (30%) showed homozygous deletions ranging from 76 kilobases to 4.7 megabases. One copy loss of the 10q23.31 region which encodes PTEN was found in 16/20 (80%) cases. Loss of CDKN2A and PTEN expression in the majority of cases was not attributed to promoter methylation. Our sporadic chordoma cases did not show hotspot point mutations in some common cancer gene targets. Moreover, most of these sporadic tumors are not associated with T (brachyury) duplication or amplification. Deficiency of CDKN2A and PTEN expression, although shared across many other different types of tumors, likely represents a key aspect of chordoma pathogenesis. Sporadic chordomas may rely on mechanisms other than copy number gain if they indeed exploit T/brachyury for proliferation. PMID- 21602919 TI - A comprehensive analysis of gene expression changes provoked by bacterial and fungal infection in C. elegans. AB - While Caenorhabditis elegans specifically responds to infection by the up regulation of certain genes, distinct pathogens trigger the expression of a common set of genes. We applied new methods to conduct a comprehensive and comparative study of the transcriptional response of C. elegans to bacterial and fungal infection. Using tiling arrays and/or RNA-sequencing, we have characterized the genome-wide transcriptional changes that underlie the host's response to infection by three bacterial (Serratia marcescens, Enterococcus faecalis and otorhabdus luminescens) and two fungal pathogens (Drechmeria coniospora and Harposporium sp.). We developed a flexible tool, the WormBase Converter (available at http://wormbasemanager.sourceforge.net/), to allow cross study comparisons. The new data sets provided more extensive lists of differentially regulated genes than previous studies. Annotation analysis confirmed that genes commonly up-regulated by bacterial infections are related to stress responses. We found substantial overlaps between the genes regulated upon intestinal infection by the bacterial pathogens and Harposporium, and between those regulated by Harposporium and D. coniospora, which infects the epidermis. Among the fungus-regulated genes, there was a significant bias towards genes that are evolving rapidly and potentially encode small proteins. The results obtained using new methods reveal that the response to infection in C. elegans is determined by the nature of the pathogen, the site of infection and the physiological imbalance provoked by infection. They form the basis for future functional dissection of innate immune signaling. Finally, we also propose alternative methods to identify differentially regulated genes that take into account the greater variability in lowly expressed genes. PMID- 21602920 TI - Large scale homing in honeybees. AB - Honeybee foragers frequently fly several kilometres to and from vital resources, and communicate those locations to their nest mates by a symbolic dance language. Research has shown that they achieve this feat by memorizing landmarks and the skyline panorama, using the sun and polarized skylight as compasses and by integrating their outbound flight paths. In order to investigate the capacity of the honeybees' homing abilities, we artificially displaced foragers to novel release spots at various distances up to 13 km in the four cardinal directions. Returning bees were individually registered by a radio frequency identification (RFID) system at the hive entrance. We found that homing rate, homing speed and the maximum homing distance depend on the release direction. Bees released in the east were more likely to find their way back home, and returned faster than bees released in any other direction, due to the familiarity of global landmarks seen from the hive. Our findings suggest that such large scale homing is facilitated by global landmarks acting as beacons, and possibly the entire skyline panorama. PMID- 21602921 TI - Gitools: analysis and visualisation of genomic data using interactive heat-maps. AB - Intuitive visualization of data and results is very important in genomics, especially when many conditions are to be analyzed and compared. Heat-maps have proven very useful for the representation of biological data. Here we present Gitools (http://www.gitools.org), an open-source tool to perform analyses and visualize data and results as interactive heat-maps. Gitools contains data import systems from several sources (i.e. IntOGen, Biomart, KEGG, Gene Ontology), which facilitate the integration of novel data with previous knowledge. PMID- 21602922 TI - Chronic ethanol consumption in rats produces opioid antinociceptive tolerance through inhibition of mu opioid receptor endocytosis. AB - It is well known that the mu-opioid receptor (MOR) plays an important role in the rewarding properties of ethanol. However, it is less clear how chronic ethanol consumption affects MOR signaling. Here, we demonstrate that rats with prolonged voluntary ethanol consumption develop antinociceptive tolerance to opioids. Signaling through the MOR is controlled at many levels, including via the process of endocytosis. Importantly, agonists at the MOR that promote receptor endocytosis, such as the endogenous peptides enkephalin and beta-endorphin, show a reduced propensity to promote antinociceptive tolerance than do agonists, like morphine, which do not promote receptor endocytosis. These observations led us to examine whether chronic ethanol consumption produced opioid tolerance by interfering with MOR endocytosis. Indeed, here we show that chronic ethanol consumption inhibits the endocytosis of MOR in response to opioid peptide. This loss of endocytosis was accompanied by a dramatic decrease in G protein coupled receptor kinase 2 (GRK2) protein levels after chronic drinking, suggesting that loss of this component of the trafficking machinery could be a mechanism by which endocytosis is lost. We also found that MOR coupling to G-protein was decreased in ethanol-drinking rats, providing a functional explanation for loss of opioid antinociception. Together, these results suggest that chronic ethanol drinking alters the ability of MOR to endocytose in response to opioid peptides, and consequently, promotes tolerance to the effects of opioids. PMID- 21602923 TI - Optimized purification of a heterodimeric ABC transporter in a highly stable form amenable to 2-D crystallization. AB - Optimized protocols for achieving high-yield expression, purification and reconstitution of membrane proteins are required to study their structure and function. We previously reported high-level expression in Escherichia coli of active BmrC and BmrD proteins from Bacillus subtilis, previously named YheI and YheH. These proteins are half-transporters which belong to the ABC (ATP-Binding Cassette) superfamily and associate in vivo to form a functional transporter able to efflux drugs. In this report, high-yield purification and functional reconstitution were achieved for the heterodimer BmrC/BmrD. In contrast to other detergents more efficient for solubilizing the transporter, dodecyl-beta-D maltoside (DDM) maintained it in a drug-sensitive and vanadate-sensitive ATPase competent state after purification by affinity chromatography. High amounts of pure proteins were obtained which were shown either by analytical ultracentrifugation or gel filtration to form a monodisperse heterodimer in solution, which was notably stable for more than one month at 4 degrees C. Functional reconstitution using different lipid compositions induced an 8-fold increase of the ATPase activity (k(cat)~5 s(-1)). We further validated that the quality of the purified BmrC/BmrD heterodimer is suitable for structural analyses, as its reconstitution at high protein densities led to the formation of 2-D crystals. Electron microscopy of negatively stained crystals allowed the calculation of a projection map at 20 A resolution revealing that BmrC/BmrD might assemble into oligomers in a lipidic environment. PMID- 21602924 TI - Functional impairment of central memory CD4 T cells is a potential early prognostic marker for changing viral load in SHIV-infected rhesus macaques. AB - In HIV infection there is a paucity of literature about the degree of immune dysfunction to potentially correlate and/or predict disease progression relative to CD4(+) T cells count or viral load. We assessed functional characteristics of memory T cells subsets as potential prognostic markers for changing viral loads and/or disease progression using the SHIV-infected rhesus macaque model. Relative to long-term non-progressors with low/undetectable viral loads, those with chronic plasma viremia, but clinically healthy, exhibited significantly lower numbers and functional impairment of CD4(+) T cells, but not CD8(+) T cells, in terms of IL-2 production by central memory subset in response to PMA and ionomycine (PMA+I) stimulation. Highly viremic animals showed impaired cytokine production by all T cells subsets. These results suggest that functional impairment of CD4(+) T cells in general, and of central memory subset in particular, may be a potential indicator/predictor of chronic infection with immune dysfunction, which could be assayed relatively easily using non-specific PMA+I stimulation. PMID- 21602925 TI - Analysis of transcriptional regulatory pathways of photoreceptor genes by expression profiling of the Otx2-deficient retina. AB - In the vertebrate retina, the Otx2 transcription factor plays a crucial role in the cell fate determination of both rod and cone photoreceptors. We previously reported that Otx2 conditional knockout (CKO) mice exhibited a total absence of rods and cones in the retina due to their cell fate conversion to amacrine-like cells. In order to investigate the entire transcriptome of the Otx2 CKO retina, we compared expression profile of Otx2 CKO and wild-type retinas at P1 and P12 using microarray. We observed that expression of 101- and 1049-probe sets significantly decreased in the Otx2 CKO retina at P1 and P12, respectively, whereas, expression of 3- and 4149-probe sets increased at P1 and P12, respectively. We found that expression of genes encoding transcription factors involved in photoreceptor development, including Crx, Nrl, Nr2e3, Esrrb, and NeuroD, was markedly down-regulated in the Otx2 CKO at both P1 and P12. Furthermore, we identified three human retinal disease loci mapped in close proximity to certain down-regulated genes in the Otx2 CKO retina including Ccdc126, Tnfsf13 and Pitpnm1, suggesting that these genes are possibly responsible for these diseases. These transcriptome data sets of the Otx2 CKO retina provide a resource on developing rods and cones to further understand the molecular mechanisms underlying photoreceptor development, function and disease. PMID- 21602926 TI - Muc5b is the major polymeric mucin in mucus from thoroughbred horses with and without airway mucus accumulation. AB - Mucus accumulation is a feature of inflammatory airway disease in the horse and has been associated with reduced performance in racehorses. In this study, we have analysed the two major airways gel-forming mucins Muc5b and Muc5ac in respect of their site of synthesis, their biochemical properties, and their amounts in mucus from healthy horses and from horses with signs of airway mucus accumulation. Polyclonal antisera directed against equine Muc5b and Muc5ac were raised and characterised. Immunohistochemical staining of normal equine trachea showed that Muc5ac and Muc5b are produced by cells in the submucosal glands, as well as surface epithelial goblet cells. Western blotting after agarose gel electrophoresis of airway mucus from healthy horses, and horses with mucus accumulation, was used to determine the amounts of these two mucins in tracheal wash samples. The results showed that in healthy horses Muc5b was the predominant mucin with small amounts of Muc5ac. The amounts of Muc5b and Muc5ac were both dramatically increased in samples collected from horses with high mucus scores as determined visually at the time of endoscopy and that this increase also correlated with increase number of bacteria present in the sample. The change in amount of Muc5b and Muc5ac indicates that Muc5b remains the most abundant mucin in mucus. In summary, we have developed mucin specific polyclonal antibodies, which have allowed us to show that there is a significant increase in Muc5b and Muc5ac in mucus accumulated in equine airways and these increases correlated with the numbers of bacteria. PMID- 21602927 TI - Comparative methods for association studies: a case study on metabolite variation in a Brassica rapa core collection. AB - BACKGROUND: Association mapping is a statistical approach combining phenotypic traits and genetic diversity in natural populations with the goal of correlating the variation present at phenotypic and allelic levels. It is essential to separate the true effect of genetic variation from other confounding factors, such as adaptation to different uses and geographical locations. The rapid availability of large datasets makes it necessary to explore statistical methods that can be computationally less intensive and more flexible for data exploration. METHODOLOGY/PRINCIPAL FINDINGS: A core collection of 168 Brassica rapa accessions of different morphotypes and origins was explored to find genetic association between markers and metabolites: tocopherols, carotenoids, chlorophylls and folate. A widely used linear model with modifications to account for population structure and kinship was followed for association mapping. In addition, a machine learning algorithm called Random Forest (RF) was used as a comparison. Comparison of results across methods resulted in the selection of a set of significant markers as promising candidates for further work. This set of markers associated to the metabolites can potentially be applied for the selection of genotypes with elevated levels of these metabolites. CONCLUSIONS/SIGNIFICANCE: The incorporation of the kinship correction into the association model did not reduce the number of significantly associated markers. However incorporation of the STRUCTURE correction (Q matrix) in the linear regression model greatly reduced the number of significantly associated markers. Additionally, our results demonstrate that RF is an interesting complementary method with added value in association studies in plants, which is illustrated by the overlap in markers identified using RF and a linear mixed model with correction for kinship and population structure. Several markers that were selected in RF and in the models with correction for kinship, but not for population structure, were also identified as QTLs in two bi-parental DH populations. PMID- 21602928 TI - UV-deprived coloration reduces success in mate acquisition in male sand lizards (Lacerta agilis). AB - BACKGROUND: Recent work on animal signals has revealed a wide occurrence of UV signals in tetrapods, in particular birds, but also in lizards (and perhaps other Squamate reptiles). Our previous work on the Swedish sand lizard (Lacerta agilis) has verified, both in correlative selection analyses in the wild and with laboratory and field experiments, the importance of the green 'badge' on the body sides of adult males for securing mating opportunities, probably mostly through deterring rival males rather than attracting females. The role of UV in communication has, however, never been examined. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that when measured immediately after spring skin shedding, there is also signaling in the UV. By UV-depriving the signal (reflectance) with sun block chemicals fixated with permeable, harmless spray dressing, we show that males in the control group (spray dressing only) had significantly higher success in mate acquisition than UV-deprived males. CONCLUSIONS/SIGNIFICANCE: These results suggest that at least two colour traits in sand lizards, badge area and UV, contribute to rival deterrence and/or female choice on UV characters, which elevates success in mate acquisition in UV intact male sand lizards. PMID- 21602929 TI - Added value of deep sequencing relative to population sequencing in heavily pre treated HIV-1-infected subjects. AB - OBJECTIVE: To explore the potential of deep HIV-1 sequencing for adding clinically relevant information relative to viral population sequencing in heavily pre-treated HIV-1-infected subjects. METHODS: In a proof-of-concept study, deep sequencing was compared to population sequencing in HIV-1-infected individuals with previous triple-class virological failure who also developed virologic failure to deep salvage therapy including, at least, darunavir, tipranavir, etravirine or raltegravir. Viral susceptibility was inferred before salvage therapy initiation and at virological failure using deep and population sequencing genotypes interpreted with the HIVdb, Rega and ANRS algorithms. The threshold level for mutant detection with deep sequencing was 1%. RESULTS: 7 subjects with previous exposure to a median of 15 antiretrovirals during a median of 13 years were included. Deep salvage therapy included darunavir, tipranavir, etravirine or raltegravir in 4, 2, 2 and 5 subjects, respectively. Self-reported treatment adherence was adequate in 4 and partial in 2; one individual underwent treatment interruption during follow-up. Deep sequencing detected all mutations found by population sequencing and identified additional resistance mutations in all but one individual, predominantly after virological failure to deep salvage therapy. Additional genotypic information led to consistent decreases in predicted susceptibility to etravirine, efavirenz, nucleoside reverse transcriptase inhibitors and indinavir in 2, 1, 2 and 1 subject, respectively. Deep sequencing data did not consistently modify the susceptibility predictions achieved with population sequencing for darunavir, tipranavir or raltegravir. CONCLUSIONS: In this subset of heavily pre-treated individuals, deep sequencing improved the assessment of genotypic resistance to etravirine, but did not consistently provide additional information on darunavir, tipranavir or raltegravir susceptibility. These data may inform the design of future studies addressing the clinical value of minority drug-resistant variants in treatment experienced subjects. PMID- 21602930 TI - Detection of variants in 15 genes in 87 unrelated Chinese patients with Leber congenital amaurosis. AB - BACKGROUND: Leber congenital amaurosis (LCA) is the earliest onset and most severe form of hereditary retinal dystrophy. So far, full spectrum of variations in the 15 genes known to cause LCA has not been systemically evaluated in East Asians. Therefore, we performed comprehensive detection of variants in these 15 genes in 87 unrelated Han Chinese patients with LCA. METHODOLOGY/PRINCIPAL FINDINGS: The 51 most frequently mutated exons and introns in the 15 genes were selected for an initial scan using cycle sequencing. All the remaining exons in 11 of the 15 genes were subsequently sequenced. Fifty-three different variants were identified in 44 of the 87 patients (50.6%), involving 78 of the 88 alleles (11 homozygous and 56 heterozygous variants). Of the 53 variants, 35 (66%) were novel pathogenic mutations. In these Chinese patients, variants in GUCY2D are the most common cause of LCA (16.1% cases), followed by CRB1 (11.5%), RPGRIP1 (8%), RPE65 (5.7%), SPATA7 (4.6%), CEP290 (4.6%), CRX (3.4%), LCA5 (2.3%), MERTK (2.3%), AIPL1 (1.1%), and RDH12 (1.1%). This differs from the variation spectrum described in other populations. An initial scan of 55 of 215 PCR amplicons, including 214 exons and 1 intron, detected 83.3% (65/78) of the mutant alleles ultimately found in these 87 patients. In addition, sequencing only 9 exons would detect over 50% of the identified variants and require less than 5% of the labor and cost of comprehensive sequencing for all exons. CONCLUSIONS/SIGNIFICANCE: Our results suggest that specific difference in the variation spectrum found in LCA patients from the Han Chinese and other populations are related by ethnicity. Sequencing exons in order of decreasing risk is a cost-effective way to identify causative mutations responsible for LCA, especially in the context of genetic counseling for individual patients in a clinical setting. PMID- 21602931 TI - Attitudinal and demographic predictors of measles-mumps-rubella vaccine (MMR) uptake during the UK catch-up campaign 2008-09: cross-sectional survey. AB - BACKGROUND AND OBJECTIVE: Continued suboptimal measles-mumps-rubella (MMR) vaccine uptake has re-established measles epidemic risk, prompting a UK catch-up campaign in 2008-09 for children who missed MMR doses at scheduled age. Predictors of vaccine uptake during catch-ups are poorly understood, however evidence from routine schedule uptake suggests demographics and attitudes may be central. This work explored this hypothesis using a robust evidence-based measure. DESIGN: Cross-sectional self-administered questionnaire with objective behavioural outcome. SETTING AND PARTICIPANTS: 365 UK parents, whose children were aged 5-18 years and had received <2 MMR doses before the 2008-09 UK catch-up started. MAIN OUTCOME MEASURES: Parents' attitudes and demographics, parent reported receipt of invitation to receive catch-up MMR dose(s), and catch-up MMR uptake according to child's medical record (receipt of MMR doses during year 1 of the catch-up). RESULTS: Perceived social desirability/benefit of MMR uptake (OR = 1.76, 95% CI = 1.09-2.87) and younger child age (OR = 0.78, 95% CI = 0.68-0.89) were the only independent predictors of catch-up MMR uptake in the sample overall. Uptake predictors differed by whether the child had received 0 MMR doses or 1 MMR dose before the catch-up. Receipt of catch-up invitation predicted uptake only in the 0 dose group (OR = 3.45, 95% CI = 1.18-10.05), whilst perceived social desirability/benefit of MMR uptake predicted uptake only in the 1 dose group (OR = 9.61, 95% CI = 2.57-35.97). Attitudes and demographics explained only 28% of MMR uptake in the 0 dose group compared with 61% in the 1 dose group. CONCLUSIONS: Catch-up MMR invitations may effectively move children from 0 to 1 MMR doses (unimmunised to partially immunised), whilst attitudinal interventions highlighting social benefits of MMR may effectively move children from 1 to 2 MMR doses (partially to fully immunised). Older children may be best targeted through school-based programmes. A formal evaluation element should be incorporated into future catch-up campaigns to inform their continuing improvement. PMID- 21602932 TI - Downregulation of FIP200 induces apoptosis of glioblastoma cells and microvascular endothelial cells by enhancing Pyk2 activity. AB - The expression of focal adhesion kinase family interacting protein of 200-kDa (FIP200) in normal brain is limited to some neurons and glial cells. On immunohistochemical analysis of biopsies of glioblastoma tumors, we detected FIP200 in the tumor cells, tumor-associated endothelial cells, and occasional glial cells. Human glioblastoma tumor cell lines and immortalized human astrocytes cultured in complete media also expressed FIP200 as did primary human brain microvessel endothelial cells (MvEC), which proliferate in culture and resemble reactive endothelial cells. Downregulation of endogenous expression of FIP200 using small interfering RNA resulted in induction of apoptosis in the human glioblastoma tumor cells, immortalized human astrocytes, and primary human brain MvEC. It has been shown by other investigators using cells from other tissues that FIP200 can interact directly with, and inhibit, proline-rich tyrosine kinase 2 (Pyk2) and focal adhesion kinase (FAK). In the human glioblastoma tumor cells, immortalized human astrocytes, and primary human brain MvEC, we found that downregulation of FIP200 increased the activity of Pyk2 without increasing its expression, but did not affect the activity or expression of FAK. Coimmunoprecipitation and colocalization studies indicated that the endogenous FIP200 was largely associated with Pyk2, rather than FAK, in the glioblastoma tumor cells and brain MvEC. Moreover, the pro-apoptotic effect of FIP200 downregulation was inhibited significantly by a TAT-Pyk2-fusion protein containing the Pyk2 autophosphorylation site in these cells. In summary, downregulation of endogenous FIP200 protein in glioblastoma tumor cells, astrocytes, and brain MvECs promotes apoptosis, most likely due to the removal of a direct interaction of FIP200 with Pyk2 that inhibits Pyk2 activation, suggesting that FIP200 expression may be required for the survival of all three cell types found in glioblastoma tumors. PMID- 21602934 TI - Excessive biologic response to IFNbeta is associated with poor treatment response in patients with multiple sclerosis. AB - BACKGROUND: Interferon-beta (IFNbeta) is used to inhibit disease activity in multiple sclerosis (MS), but its mechanisms of action are incompletely understood, individual treatment response varies, and biological markers predicting response to treatment have yet to be identified. METHODS: The relationship between the molecular response to IFNbeta and treatment response was determined in 85 patients using a longitudinal design in which treatment effect was categorized by brain magnetic resonance imaging as good (n = 70) or poor response (n = 15). Molecular response was quantified using a customized cDNA macroarray assay for 166 IFN-regulated genes (IRGs). RESULTS: The molecular response to IFNbeta differed significantly between patients in the pattern and number of regulated genes. The molecular response was strikingly stable for individuals for as long as 24 months, however, suggesting an individual 'IFN response fingerprint'. Unexpectedly, patients with poor response showed an exaggerated molecular response. IRG induction ratios demonstrated an exaggerated molecular response at both the first and 6-month IFNbeta injections. CONCLUSION: MS patients exhibit individually unique but temporally stable biological responses to IFNbeta. Poor treatment response is not explained by the duration of biological effects or the specific genes induced. Rather, individuals with poor treatment response have a generally exaggerated biological response to type 1 IFN injections. We hypothesize that the molecular response to type I IFN identifies a pathogenetically distinct subset of MS patients whose disease is driven in part by innate immunity. The findings suggest a strategy for biologically based, rational use of IFNbeta for individual MS patients. PMID- 21602933 TI - Cumulative inflammatory load is associated with short leukocyte telomere length in the Health, Aging and Body Composition Study. AB - BACKGROUND: Leukocyte telomere length (LTL) is an emerging marker of biological age. Chronic inflammatory activity is commonly proposed as a promoter of biological aging in general, and of leukocyte telomere shortening in particular. In addition, senescent cells with critically short telomeres produce pro inflammatory factors. However, in spite of the proposed causal links between inflammatory activity and LTL, there is little clinical evidence in support of their covariation and interaction. METHODOLOGY/PRINCIPAL FINDINGS: To address this issue, we examined if individuals with high levels of the systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha) and C-reactive protein (CRP) had increased odds for short LTL. Our sample included 1,962 high-functioning adults who participated in the Health, Aging and Body Composition Study (age range: 70-79 years). Logistic regression analyses indicated that individuals with high levels of either IL-6 or TNF-alpha had significantly higher odds for short LTL. Furthermore, individuals with high levels of both IL-6 and TNF-alpha had significantly higher odds for short LTL compared with those who had neither high (OR = 0.52, CI = 0.37-0.72), only IL-6 high (OR = 0.57, CI = 0.39-0.83) or only TNF-alpha high (OR = 0.67, CI = 0.46 0.99), adjusting for a wide variety of established risk factors and potential confounds. In contrast, CRP was not associated with LTL. CONCLUSIONS/SIGNIFICANCE: Results suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-alpha, is associated with increased odds for short LTL. In contrast, high levels of CRP were not accompanied by short LTL in this cohort of older adults. These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population. PMID- 21602935 TI - Cell pattern in adult human corneal endothelium. AB - A review of the current data on the cell density of normal adult human endothelial cells was carried out in order to establish some common parameters appearing in the different considered populations. From the analysis of cell growth patterns, it is inferred that the cell aging rate is similar for each of the different considered populations. Also, the morphology, the cell distribution and the tendency to hexagonallity are studied. The results are consistent with the hypothesis that this phenomenon is analogous with cell behavior in other structures such as dry foams and grains in polycrystalline materials. Therefore, its driving force may be controlled by the surface tension and the mobility of the boundaries. PMID- 21602938 TI - An open access mandate for the National Institutes of Health. PMID- 21602936 TI - CD133 positive embryonal rhabdomyosarcoma stem-like cell population is enriched in rhabdospheres. AB - Cancer stem cells (CSCs) have been identified in a number of solid tumors, but not yet in rhabdomyosarcoma (RMS), the most frequently occurring soft tissue tumor in childhood. Hence, the aim of this study was to identify and characterize a CSC population in RMS using a functional approach. We found that embryonal rhabdomyosarcoma (eRMS) cell lines can form rhabdomyosarcoma spheres (short rhabdospheres) in stem cell medium containing defined growth factors over several passages. Using an orthotopic xenograft model, we demonstrate that a 100 fold less sphere cells result in faster tumor growth compared to the adherent population suggesting that CSCs were enriched in the sphere population. Furthermore, stem cell genes such as oct4, nanog, c-myc, pax3 and sox2 are significantly upregulated in rhabdospheres which can be differentiated into multiple lineages such as adipocytes, myocytes and neuronal cells. Surprisingly, gene expression profiles indicate that rhabdospheres show more similarities with neuronal than with hematopoietic or mesenchymal stem cells. Analysis of these profiles identified the known CSC marker CD133 as one of the genes upregulated in rhabdospheres, both on RNA and protein levels. CD133(+) sorted cells were subsequently shown to be more tumorigenic and more resistant to commonly used chemotherapeutics. Using a tissue microarray (TMA) of eRMS patients, we found that high expression of CD133 correlates with poor overall survival. Hence, CD133 could be a prognostic marker for eRMS. These experiments indicate that a CD133(+) CSC population can be enriched from eRMS which might help to develop novel targeted therapies against this pediatric tumor. PMID- 21602937 TI - Insulin versus an oral antidiabetic agent as add-on therapy in type 2 diabetes after failure of an oral antidiabetic regimen: a meta-analysis. AB - BACKGROUND: Although evidence-based guidelines for the treatment of type 2 diabetes mellitus provide clear recommendations for initial therapy, evidence on an optimal treatment strategy after secondary failure is unclear. PURPOSE: To compare the efficacy of add-on therapy using basal insulin versus an additional oral antidiabetic agent in patients with type 2 diabetes and secondary failure. DATA SOURCES: We searched the following electronic databases from inception until June 2007: MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials; Web of Science; Scopus; CINAHL; International Pharmaceutical Abstracts; Academic OneFile; PASCAL; Global Health Database; LILACS; HealthSTAR; PubMed. Reference lists of potentially relevant articles and clinical trial databases were searched, pharmaceutical manufacturers were contacted, and grey literature sources were sought. STUDY SELECTION: Randomized controlled trials (RCTs) involving subjects with type 2 diabetes with secondary failure who were randomly assigned to receive additional basal insulin therapy (insulin glargine, detemir, or NPH [neutral protamine Hagedorn]) versus another oral antidiabetic agent from any class. DATA EXTRACTION: Two reviewers independently screened articles, extracted data and assessed methodological quality. Our primary outcome was glycemic control measured by change in glycosylated hemoglobin (Hb(A1C)) and the proportion of subjects achieving a Hb(A1C) value of <= 7%. DATA SYNTHESIS: To compare overall efficacy between the 2 treatment strategies, change in Hb(A1C) was pooled across studies using a random-effects model and weighted mean difference (WMD). Eleven RCTs, involving 757 participants with a median age of 56 and a median known duration of diabetes of 11 years, were included in our analysis. Insulin treatment demonstrated a small but statistically significant improvement in Hb(A1C) compared with the use of an additional oral agent as add on therapy (WMD -0.17; 95% CI [confidence interval] -0.33 to -0.02). LIMITATIONS: The use of surrogate outcomes and the short duration of the trials makes it impossible to gain information on long-term patient-oriented outcomes. The overall quality of the studies was low, primarily in view of inadequate blinding. CONCLUSIONS: Although add-on therapy using injected insulin shows a slight benefit over an additional oral antidiabetic agent, our results indicate that basal insulin therapy and the use of an oral agent as add-on therapy produce comparable results. Non-therapeutic differences must be considered in the choice of treatment strategies. More high-quality studies with adequate safety data using more aggressive insulin titrations are needed. PMID- 21602939 TI - Protecting academic freedom. PMID- 21602940 TI - How well do Canadian media outlets convey medical treatment information?: Initial findings from a year and a half of media monitoring by Media Doctor Canada. PMID- 21602941 TI - EQUATOR: reporting guidelines for health research. PMID- 21602942 TI - Building capacity to address emerging problems in developing countries: intentional self-poisoning and pesticides. PMID- 21602944 TI - Finding healing hands: the global health workforce shortage. PMID- 21602943 TI - Email security in clinical practice: ensuring patient confidentiality. PMID- 21602945 TI - Retention of provisionally licensed international medical graduates: a historical cohort study of general and family physicians in Newfoundland and Labrador. AB - BACKGROUND: To alleviate the shortage of primary care physicians in rural communities, the Canadian province of Newfoundland and Labrador (NL) introduced provisional licensure for international medical graduates (IMGs), allowing them to practise in under-served communities while completing licensing requirements. Although provisional licensing has been seen as a needed recruitment strategy, little is known about its impact on physician retention. To assess the relationship between provincial retention time and type of initial practice licence, we compared the retention of: (1) IMGs who began practice with a provisional licence; (2) fully licensed Memorial University medical graduates (MMGs); and (3) fully licensed medical graduates from other Canadian medical schools (CMGs). METHODS: Using administrative data from the NL College of Physicians and Surgeons, the 2004 Scott's Medical Database, and the Memorial University postgraduate database, we identified family physicians/general practitioners (FPs/GPs) who began their practice in NL in the period 1997-2000 and determined where they were in 2004. We used Cox regression to examine differences in retention among these 3 groups of physicians. RESULTS: There were 42 MMGs, 38 CMGs and 77 IMGs in our sample. The median time for IMGs to qualify for full licensure was 15 months. Twenty-one physicians (13.4%) stayed in NL after beginning their practice (35.7% MMGs, 5.3% CMGs, 5.2% IMGs; p < 0.000). The median retention time was 25 months (MMGs, 39 months; CMGs, 22 months; IMGs, 22 months; p < 0.000). After controlling for Certificant of the College of Family Physicians status, CMGs (hazard ratio [HR] = 2.15; 95% confidence interval [CI] 1.29-3.60) and IMGs (HR = 2.03; 95% CI 1.26-3.27) were more likely to leave NL than MMGs. CONCLUSIONS: Provisional licensing accounts for the largest proportion of new primary care physicians in NL but does not lead to long-term retention of IMGs. However, IMG retention is no worse than the retention of CMGs. PMID- 21602946 TI - Open science, open access and open source software at Open Medicine. PMID- 21602947 TI - Determining medical fitness to drive: physicians need support. PMID- 21602948 TI - The window-mirror: a new model of the patient-physician relationship. PMID- 21602949 TI - Toward a definition of pharmaceutical innovation. AB - ONGOING DEBATES IN THE PHARMACEUTICAL SECTOR ABOUT INTELLECTUAL PROPERTY, PRICING AND REIMBURSEMENT, AND PUBLIC RESEARCH INVESTMENTS HAVE A COMMON DENOMINATOR: the pursuit of innovation. However, there is little clarity about what constitutes a true pharmaceutical innovation, and as a result there is confusion about what kind of new products should be pursued, protected and encouraged through health policy and clinical practice. If the concept of pharmaceutical innovation can be clarified, then it may become easier for health policy-makers and practitioners to evaluate, adopt and procure products in ways that appropriately recognize, encourage and give priority to truly valuable pharmaceutical innovations. PMID- 21602951 TI - Public reporting of the hospital standardized mortality ratio (HSMR): implications for the Canadian approach to safety and quality in health care. PMID- 21602950 TI - Mandatory reporting by physicians of patients potentially unfit to drive. AB - BACKGROUND: One strategy for the prevention of motor vehicle crashes is physician reporting of medically unfit drivers to vehicle licensing authorities, as mandated by law in Ontario, Canada. We studied drivers involved in life threatening crashes who required hospital admission to determine how many had previously been seen and reported by a physician in the community. METHODS: We identified consecutive drivers involved in a crash who were admitted to Canada's largest trauma centre between 30 June 1996 and 30 June 2001 to assess the prevalence of 3 chronic medical conditions reportable to vehicle licensing authorities (alcohol abuse, cardiac disease, and neurological disorders). We then conducted a case series analysis of linked health and transportation databases to determine how many drivers had previously been seen and reported by a physician in the community. RESULTS: A total of 1,605 injured drivers were identified, of whom 37% had a reportable condition (95% confidence interval [CI] 35-39). Those with a reportable condition had made a total of 20,505 previous visits to 2,332 physicians during the five years before the crash. The majority of patients with a reportable condition (85%, 95% CI 82-88) had seen a physician in the year before the crash but few (3%, 95% CI 2-4) had been reported to licensing authorities. Alcohol abuse was the most common underlying reportable condition (prevalent in 72% of trauma patients with a reportable condition) and the least common reason for a previous report (reported in 2% of those with a reportable condition). INTERPRETATION: Unsafe drivers often visit physicians and yet are rarely reported to licensing authorities even under mandatory reporting laws for preventive medical reporting. PMID- 21602952 TI - Frequency and predictors of tablet splitting in statin prescriptions: a population-based analysis. AB - BACKGROUND: The price per milligram for most statin medications decreases at higher strengths, which provides an economic incentive to split tablets. We sought to determine the frequency with which statin tablets are split, and to evaluate factors associated with this practice. METHODS: We obtained prescription claims data for statins from the BC Ministry of Health for the period Jan. 1, 1996, to Dec. 31, 2006. We estimated the number of tablets per day, based on the ratio of the number of tablets to days-supply in each prescription, to estimate the frequency with which splitting occurred with each statin. We used multivariable logistic regression to assess patient and physician characteristics and the level of public drug plan coverage associated with tablet splitting. To estimate related cost savings, we used information on drug costs and quantities of dispensed statins reported by pharmacies. RESULTS: During the 11-year study period, we estimated that tablet splitting occurred in 2.6% of 7.2 million statin prescriptions. There was an increasing trend in the practice over time, to 4.5% of prescriptions in 2006. Lovastatin was the only scored tablet and was the most likely to be split, followed by rosuvastatin and atorvastatin. Fifty percent of the prescriptions in which tablet splitting occurred were prescribed by only 7.9% of the routine statin prescribers (i.e., > 10 statin prescriptions over the study period). Specialists were less likely than general practitioners to prescribe statins that were subsequently split (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.40-0.46). Statin prescriptions that were fully covered by the public drug plan were half as likely as those with no such coverage to involve tablet splitting (OR 0.48, 95% CI 0.44-0.92). Having no public drug coverage, having a low annual household income and being female were patient factors found to be positively associated with tablet splitting. In 2006, the cost savings associated with tablet splitting was $2.3 million. INTERPRETATION: The frequency of tablet splitting in statin prescriptions in British Columbia was low but increased over time. It varied between patients, physicians and different levels of insurance coverage. In the final study year, 94.5% of the statin prescriptions were dispensed at strengths for which a tablet of twice the strength was available and could have been split, which suggests a potentially enormous cost savings. PMID- 21602953 TI - Validity of self-reported height and weight for measuring prevalence of obesity. AB - OBJECTIVES: To examine the validity of self-reported body mass index (BMI) in estimating the prevalence of obesity in the Canadian population, and to suggest a model for predicting actual BMI from self-reported data. METHODS: This analysis is based on 1131 participants with both self-reported and measured height and weight from the Canadian Community Health Survey, Cycle 2.2 dataset. We estimated the prevalence of obesity as well as the mean and standard deviation (SD) of BMI according to sex, age group, and measured weight classification. Multiple regression analysis was used to build a model to assess the relation between actual BMI and variables of age, sex, and self-reported BMI. RESULTS: The overall prevalence of obesity was 23.0% based on measured BMI, and 15.6% based on self reported BMI. Estimated mean (SD) for self-reported and measured BMI were 25.8 (4.8) and 26.9 (5.0) kg/m(2), respectively. Only 74.3% of obese men and 56.2% of obese women were correctly classified as obese on the basis of self-reported measures. Females and heavier respondents showed more BMI under-reporting than others. CONCLUSIONS: To estimate overweight and obesity in etiological and disease relationship studies, the use of measured height and weight in BMI estimation is preferable to the use of self-reported values. However, if self reported height and weight are used in population studies, our proposed model can be used to reliably predict the actual BMI with a narrow 95% confidence interval. PMID- 21602954 TI - Catholic bioethical perspectives on Ontario's HPV vaccination. PMID- 21602955 TI - No budget, no worries: Free and open source publishing software in biomedical publishing. PMID- 21602956 TI - Ethical considerations of publication planning in the pharmaceutical industry. PMID- 21602957 TI - Leaders or followers? It's time for health faculty to open up. PMID- 21602958 TI - Income-related inequities: Cross-sectional analyses of the use of medicare services in British Columbia in 1992 and 2002. AB - BACKGROUND: The primary demonstration of the principle of income-related equity in Canada is the provision of health care services based on need rather than ability to pay. Despite this principle, Canada, along with other OECD countries, exhibits income-related variations in the use of health care services. This paper extends previous analyses to include surgical day care, assesses changes in income-related equity between 1992 and 2002 in British Columbia and tests the feasibility of using administrative data for general equity analyses. METHODS: Data derive from the BC Linked Health Database and from a custom tabulation of income tax filer data provided by Statistics Canada. Cross-sectional analyses measure inequity in the probability and conditional use of services using concentration indices, which summarize health care services use for individuals ranked by income, after standardization for age, sex, region of residence and need for health care services. RESULTS: Small but systematic relationships were found between income and use of health care services for all types of services, with the exception of visits to general practitioners (GPs). Lower income is associated with greater conditional use of GPs and greater use of acute inpatient care. Higher income is associated with the greater use of specialist and surgical day care services; the latter inequity was found to grow substantially over time. CONCLUSIONS: Deviations from equity deserve further investigation, especially because the use of day care surgery is continually expanding. For example, an understanding of the reasons for differential admission rates to acute and day surgery might provide insight as to whether community-based services could help shift some acute care use among lower income groups to surgical day care. It is possible to use administrative data to monitor income-related equity, and future research should take advantage of this possibility. PMID- 21602959 TI - Physiological weight loss in the breastfed neonate: a systematic review. AB - BACKGROUND: Healthy, full-term, exclusively breastfed infants are expected to lose weight in the first days following birth. There are conflicting opinions about what constitutes a normal neonatal weight loss, and about when interventions such as supplemental feedings should be considered. OBJECTIVE: To establish the reference weight loss for the first 2 weeks following birth by conducting a systematic review of studies reporting birth weights of exclusively breastfed neonates. METHODS: We searched 5 electronic databases from June 2006 to June 2007: the Cochrane Database of Systematic Reviews; MEDLINE (from 1950); CINAHL (from 1982); EMBASE (from 1980); and Ovid HealthSTAR (from 1999). We included primary research studies with weight loss data for healthy, full-term, exclusively breastfed neonates in the first 2 weeks following birth. RESULTS: Eleven studies met the inclusion criteria. Definitions, types of measurements, and reporting styles varied among studies. In most studies, daily weights were not measured and measurements did not continue for 2 weeks. Mean weight loss ranged from 5.7% to 6.6%, with standard deviations around 2%. Median percentage weight loss ranged from 3.2 to 8.3, with the majority around 6%. The majority of infants in these 11 studies regained their birth weight within the first 2 weeks postpartum. The second and third days following birth appear to be the days of maximum weight loss. DISCUSSION: Methods used to report weight loss were inconsistent, using either an average of single lowest weights or a combination of weight losses. The 7% maximum allowable weight loss recommended in 4 clinical practice guidelines appears to be based on mean weight loss and does not account for standard deviation. Further research is needed to understand the causes of neonatal weight loss and its implications for morbidity and mortality. PMID- 21602960 TI - The clinical usefulness of the sentinel lymph node in rectal cancer: do we believe it? PMID- 21602961 TI - Long-term Oncologic Outcomes of Laparoscopic Resection for Colorectal Cancer. PMID- 21602962 TI - Pruritus ani. AB - Pruritus ani is an unpleasant cutaneous sensation that induces the desire to scratch the skin around the anal orifice. It may start insidiously and appears in 1% to 5% of the population. It is classified as primary (idiopathic) pruritus ani when no cause can be found. However, as 25% to 75% of cases have co-existing pathology, a detailed history and examination are necessary. The goal of treatment is asymptomatic, intact, dry, clean perianal skin with reversal of morphological changes. The management of pruritus ani is directed towards the underlying cause. If the diagnosis is idiopathic pruritus ani, the patients can still be managed with great success by eliminating of irritants and scratching, by giving general advice regarding hygiene and lifestyle modification and by using active treatment measures. PMID- 21602963 TI - Conventional Linear versus Purse-string Skin Closure after Loop Ileostomy Reversal: Comparison of Wound Infection Rates and Operative Outcomes. AB - PURPOSE: Wound infection after an ileostomy reversal is a common problem. To reduce wound-related complications, purse-string skin closure was introduced as an alternative to conventional linear skin closure. This study is designed to compare wound infection rates and operative outcomes between linear and purse string skin closure after a loop ileostomy reversal. METHODS: Between December 2002 and October 2010, a total of 48 consecutive patients undergoing a loop ileostomy reversal were enrolled. Outcomes were compared between linear skin closure (group L, n = 30) and purse string closure (group P, n = 18). The operative technique for linear skin closure consisted of an elliptical incision around the stoma, with mobilization, and anastomosis of the ileum. The rectus fascia was repaired with interrupted sutures. Skin closure was performed with vertical mattress interrupted sutures. Purse-string skin closure consisted of a circumstomal incision around the ileostomy using the same procedures as used for the ileum. Fascial closure was identical to linear closure, but the circumstomal skin incision was approximated using a purse-string subcuticular suture (2-0 Polysorb). RESULTS: Between group L and P, there were no differences of age, gender, body mass index, and American Society of Anesthesiologists (ASA) scores. Original indication for ileostomy was 23 cases of malignancy (76.7%) in group L, and 13 cases of malignancy (77.2%) in group P. The median time duration from ileostomy to reversal was 4.0 months (range, 0.6 to 55.7 months) in group L and 4.1 months (range, 2.2 to 43.9 months) in group P. The median operative time was 103 minutes (range, 45 to 260 minutes) in group L and 100 minutes (range, 30 to 185 minutes) in group P. The median hospital stay was 11 days (range, 5 to 4 days) in group L and 7 days (range, 4 to 14 days) in group P (P < 0.001). Wound infection was found in 5 cases (16.7%) in group L and in one case (5.6%) in group L (P = 0.26). CONCLUSION: Based on this study, purse-string skin closure after a loop ileostomy reversal showed comparable outcomes, in terms of wound infection rates, to those of linear skin closure. Thus, purse-string skin closure could be a good alternative to the conventional linear closure. PMID- 21602964 TI - Long-term Outcomes of Laparoscopic Surgery for Colorectal Cancer. AB - PURPOSE: The long-term results of a laparoscopic resection for colorectal cancer have been reported in several studies, but reports on the results of laparoscopic surgery for rectal cancer are limited. We investigated the long-term outcomes, including the five-year overall survival, disease-free survival and recurrence rate, after a laparoscopic resection for colorectal cancer. METHODS: Using prospectively collected data on 303 patients with colorectal cancer who underwent a laparoscopic resection between January 2001, and December 2003, we analyzed sex, age, stage, complications, hospital stay, mean operation time and blood loss. The overall survival rate, disease-free survival rate and recurrence rate were investigated for 271 patients who could be followed for more than three years. RESULTS: Tumor-node-metastasis (TNM) stage I cancer was present in 55 patients (18.1%), stage II in 116 patients (38.3%), stage III in 110 patients (36.3%), and stage IV in 22 patients (7.3%). The mean operative time was 200 minutes (range, 100 to 535 minutes), and the mean blood loss was 97 mL (range, 20 to 1,200 mL). The mean hospital stay was 11 days and the mean follow-up period was 54 months. The mean numbers of resected lymph nodes were 26 and 21 in the colon and the rectum, respectively, and the mean distal margins were 10 and 3 cm. The overall morbidity rate was 26.1%. The local recurrence rates were 2.2% and 4.4% in the colon and the rectum, respectively, and the distant recurrence rates were 7.8% and 22.5%. The five-year overall survival rates were 86.1% in the colon (stage I, 100%; stage II, 97.6%; stage III, 77.5%; stage IV, 16.7%) and 68.8% in the rectum (stage I, 90.2%; stage II, 84.0%; stage III, 57.6; stage IV, 13.3%). The five-year disease-free survival rates were 89.8% in the colon (stage I, 100%; stage II, 97.7%; stage III, 74.2%) and 74.5% in the rectum (stage I, 90.0%; stage II, 83.9%; stage III, 59.2%). CONCLUSION: Laparoscopic surgery for colorectal cancer is a good alternative method to open surgery with tolerable oncologic long term results. PMID- 21602965 TI - Impact on Prognosis of Lymph Node Micrometastasis and Isolated Tumor Cells in Stage II Colorectal Cancer. AB - PURPOSE: Even though the importance of micrometastases (MMS) and isolated tumor cells (ITC) has been brought up by many physicians, its impact on the prognosis in stage II colorectal cancer is uncertain. In this research, we tried to investigate the clinical features of MMS and ITC and to prove any correlation with prognosis. METHODS: The research pool was 124 colorectal cancer patients who underwent a curative resection from April 2005 to November 2009. A total of 2,379 lymph nodes (LNs) were examined, and all retrieved LNs were evaluated by immunohistochemical staining with anti-cytokeratin antibody panel. Clinicopathologic parameters and survival rates were compared based on the presence of MMS or ITC and on the micrometastatic lymph node ratio (mmLNR), which is defined as the number of micrometastatic LNs divided by the number of retrieved LNs. RESULTS: Out of 124 patients (26.6%) 33 were found to have MMS or ITC. There were no significant differences in clinicopathologic features, such as gender, tumor location and size, depth of invasion, histologic grade, except for age (P = 0.04). The three-year disease-free survival rate for the MMS or ITC positive group was 85.7%, and that for MMS and ITC negative group was 92.8% (P = 0.209). The three-year disease-free survival rate for the mmLNR > 0.25 group was 73.3%, and that for the mmLNR <= 0.25 group was 92.9% (P = 0.03). CONCLUSION: The presence of MMS or ITC was not closely correlated to the prognosis. However, mmLNR is thought to be a valuable marker of prognosis in cases of stage II colorectal cancer. PMID- 21602966 TI - Relationship between Metabolic Syndrome and MTHFR Polymorphism in Colorectal Cancer. AB - PURPOSE: There have been studies on the relations between metabolic syndrome and colorectal cancer or on the relations between methylenetetrahydrofolate reductase (MTHFR) polymorphism and colorectal cancer, but reports on the relationship between metabolic syndrome, MTHFR polymorphism and colorectal cancer all together are rare. The aim of this study is to find the interrelation between metabolic syndrome and MTHFR polymorphism in colorectal cancer. METHODS: This study investigated 255 colorectal cancer patients (cancer group) who underwent surgery in our hospital from March 2003 to December 2008 and compared those patients to 488 healthy patients (control group). The diagnostic criterion for metabolic syndrome was based on the National Cholesterol Education Program-Adult Treatment Panel III (NCEP ATP III), and the MTHFR 677 polymorphism was analyzed. RESULTS: When colorectal cancer patients and patients in the control group were classified as MTHFR 677 subtypes, there was no difference between the two groups: CC 87 (34.1%), CT 134 (52.6%), and TT 34 (13.3%) for the cancer group and CC 145 (32.4%), CT 238 (53.1%), and TT 65 (14.5%) for the control group. Distributions of MTHFR 677C/T genotype and allele frequencies in the individuals with and without metabolic syndrome in the cancer group showed no differences. Moreover, we could find no differences in distributions of MTHFR 677C/T genotypes in the clinical and the biomedical variables of individuals with and without metabolic syndrome in the cancer group. CONCLUSION: Our results show no relation between metabolic syndrome and MTHFR polymorphism in colorectal cancer. However, a further prospective study, based on a precise diagnostic criterion for metabolic syndrome, is needed. PMID- 21602967 TI - The Feasibility of an Ex-vivo Sentinel Lymph Mapping Using Preoperative Radioisotope Injection in Cases of Extraperitoneal Rectal Cancer. AB - PURPOSE: The purpose of this research was to evaluate the feasibility of sentinel lymph node (SLN) mapping involving transanal injection with an ex-vivo mapping in patients with rectal cancer. METHODS: Between April 2007 and December 2009, 20 consecutive patients with T1-3, N0-1 clinical stage rectal cancer preoperatively underwent a SLN procedure using submucosal (99m)Tc-phytate injection. All the patients underwent a total mesorectal excision. After the standard surgical resection, all specimens were identified on lymphoscintigraphy, and bench work was done to pick up the sentinel node basin. All the lymph nodes (non-SLNs and SLNs) were examined using conventional hematoxylin and eosin staining and immunohistochemistry with anti-cytokeratin antibodies. RESULTS: SLNs were identified from 19 of 20 patients with rectal cancer. The total number of sentinel nodes retrieved from the surgical specimens was 29, and the mean number per patient was 1.6 (range, 0 to 4). In three patients, the SLN was the only positive lymph node. There was one false-negative case with a sensitivity of 88.8% and two upstaged cases (20.0%). The SLN samples from rectal cancer are mainly localized in the pararectal region, but aberrant nodes receive direct drainage from the rectal cancer. On planar lymphoscintigraphy, 15.7% of all patients had aberrant lymphatic drainage to the sigmoid mesenteric or sigmoid lymph node station. CONCLUSION: In conclusion, the intraoperative transanal injection for ex-vivo SLN navigation is a safe, feasible surgical modality in patients with rectal cancer. Large studies are warranted to determine the clinical significance of the SLN concept and micrometastasis in rectal cancer. PMID- 21602968 TI - Multiple Presacral Teratomas in an 18-year-old Girl: A Case Report. AB - Although the sacrococcygeal area is the most common site for a teratoma in infants, it is a rare site for a teratoma in older patients. Most of the teratomas found in this area in adults are single mass, but in a few cases, multiple masses have been reported. The author reports on the case of an 18-year old female patient with 3 presacral teratomas. The tumors were surgically removed via a transabdominal approach and were pathologically diagnosed as mature cystic teratomas. This case report indicates that an adult presacral teratoma can appear as multiple tumors, although it is very unusual. PMID- 21602969 TI - A case of colovesical fistula induced by sigmoid diverticulitis. AB - Colonic diverticulosis has continuously increased, noticeably left-sided diseases, in Korea. A colovesical fistula is an uncommon complication of diverticulitis, and its most common cause is diverticular disease. Confirmation of its presence generally depends on clinical findings, such as pneumaturia and fecaluria. The primary aim of a diagnostic workup is not to observe the fistular tract itself but to find the etiology of the disease so that an appropriate therapy can be initiated. We present here the case of a 79-year-old man complaining of pneumaturia and fecaluria. On abdomen and pelvis CT, the patient was diagnosed as having a colovesical fistula due to sigmoid diverticulitis. After division of the adhesion between the sigmoid colon and the bladder, the defect of the bladder wall was repaired by simple closure. The colonic defect was treated with a segmental resection, including the rectosigmoid junction. The patient is doing well at 6 months after the operation and shows no evidence of recurrence of the fistula. PMID- 21602970 TI - Adult Intussusception due to Cecal Lymphangioma: A Case Report. AB - We present a rare case of adult intussusception due to cecal lymphangioma. A 30 year-old female was admitted to our hospital with abdominal pain and a palpatable mass on the right lower quadrant. Preoperative radiologic studies by ultrasound and computed tomography showed ileocolic intussusception with a multiseptated cystic tumor as a leading point on the cecum. An ileocecectomy was performed, and the postoperative course was uneventful. Histopathology showed a cecal lymphangioma. Although endoscopic polypectomy or endoscopic mucosal resection is recommended for pedunculated or semi-pedunculated colonic lymphangiomas less than 2 cm in size, it is proper to treat large or symptomatic colonic lymphangiomas with limited a bowel resection or a tumor resection. PMID- 21602971 TI - Ephedrine and hypothermia- old drug, new use? PMID- 21602972 TI - The uncalibrated pulse contour cardiac output during off-pump coronary bypass surgery: performance in patients with a low cardiac output status and a reduced left ventricular function. AB - BACKGROUND: We compared the continuous cardiac index measured by the FloTrac/VigileoTM system (FCI) to that measured by a pulmonary artery catheter (CCI) with emphasis on the accuracy of the FCI in patients with a decreased left ventricular ejection fraction (LVEF) and a low cardiac output status during off pump coronary bypass surgery (OPCAB). We also assessed the influence of several factors affecting the pulse contour, such as the mean arterial pressure (MAP), the systemic vascular resistance index (SVRI) and the use of norepinephrine. METHODS: Fifty patients who were undergoing OPCAB (30 patients with a LVEF >= 40%, 20 patients with a LVEF < 40%) were enrolled. The FCI and CCI were measured and we performed a Bland-Altman analysis. Subgroup analyses were done according to the LVEF (< 40%), the CCI (<= 2.4 L/min/m), the MAP (60-80 mmHg), the SVRI (1,600-2,600 dyne/s/cm(5)/m(2)) and the use of norepinephrine. RESULTS: The FCI was reliable at all the time points of measurement with an overall bias and limit of agreement of -0.07 and 0.67 L/min/m(2), respectively, resulting in a percentage error of 26.9%. The percentage errors in the patients with a decreased LVEF and in a low cardiac output status were 28.2% and 22.3%, respectively. However, the percentage error in the 91 data pairs outside the normal range of the SVRI was 40.2%. CONCLUSIONS: The cardiac output measured by the FloTrac/VigileoTM system was reliable even in patients with a decreased LVEF and in a low cardiac output status during OPCAB. Acceptable agreement was also noted during the period of heart displacement and grafting of the obtuse marginalis branch. PMID- 21602973 TI - Comparison of the ease of laryngeal mask airway ProSeal insertion and the fiberoptic scoring according to the head position and the presence of a difficult airway. AB - BACKGROUND: The sniffing position is recommended for conventional laryngeal mask airway (LMA) insertion. However, there has been a high success rate of LMA insertion with the head in the neutral position. The effect of a difficult airway on the ease of LMA insertion is not clear. In this study, we compared the ease of LMA ProSealTM (PLMA) insertion and the fiberoptic scoring according to the head position and the presence of a difficult airway. METHODS: After obtaining informed consent from the subjects, we enrolled 144 adult patients (age range: 18 65) with an ASA physical status 1 or 2. After evaluation of the airway, all the patients were grouped into the EA (easy airway) group (n = 68) and the DA (difficult airway) group (n = 76). According to the head position, each group was divided into the EA-SE (extension) group (n = 35), the EA-SN (sniffing) group (n = 33), the DA-SE group (n = 39) and the DA-SN group (n = 37). The success rate and insertion time at the first attempt were evaluated. The position of the PLMA was fiberoptically scored from the mask aperture of the airway tube in the original head position. After the head position was changed to the sniffing and neutral positions in the SE and SN group, respectively, the position of PLMA was re-evaluated fiberoptically. RESULTS: The success rate and insertion time at the first attempt and the fiberoptic score showed no significant difference among the groups. After head position was changed, there were no significant changes in the fiberopitc scores. CONCLUSIONS: A difficult airway and the head position had no influence on the ease of PLMA insertion and the fiberopic score. Therefore, the head position can be selected according to the individual patient's situation. PMID- 21602974 TI - The effect of ephedrine on intraoperative hypothermia. AB - BACKGROUND: Prevention of intraoperative hypothermia has become a standard of operative care. Since ephedrine has a thermogenic effect and it is frequently used to treat hypotension during anesthesia, this study was designed to determine the effect of ephedrine on intraoperative hypothermia of patients who are undergoing spine surgery. METHODS: Twenty-four patients were randomly divided to receive an ephedrine (the ephedrine group, n = 12) or normal saline (the control group, n = 12) infusion for 2 h. The esophageal temperature (the core temperature), the index finger temperature (the peripheral temperature) and the hemodynamic variables such as the mean blood pressure and heart rate were measured every 15 minutes after the intubation. RESULTS: At the end of the study period, the esophageal temperature and hemodynamic variables were significantly decreased in the control group, whereas those in the ephedrine group were stably maintained. The index finger temperature was significantly lower in the ephedrine group compared to that in the control group, suggesting the prevention of core-to peripheral redistribution of the heat as the cause of temperature maintenance. CONCLUSIONS: An intraoperative infusion of ephedrine minimized the decrease of the core temperature and it stably maintained the hemodynamic variables during spine surgery with the patient under general anesthesia. PMID- 21602975 TI - A comparison between caudal block versus splash block for postoperative analgesia following inguinal herniorrhaphy in children. AB - BACKGROUND: We wanted to determine the postoperative analgesic efficacy of preincisional caudal epidural block versus instillation (splash block) following inguinal herniorrhaphy in children. METHODS: THIRTY CHILDREN (AGE RANGE: 1-7 years) who were scheduled to undergo inguinal herniorrhaphy were divided into 2 groups: the caudal block group and the splash block group with 15 children in each group. Tracheal intubation was performed. Fifteen children received caudal block with 1.0 ml/kg of 0.25% ropivacaine (Group 1). Caudal block was performed using the loss of resistance method via the sacral hiatus. Fifteen children in Group 2 received local instillation (splash block) in the surgical site with up to 0.4 ml/kg of 0.25% ropivacaine. The patients were observed for 90 minutes in the postanesthesia care unit and then they were transferred to the ward. The pain scores were taken 4 times. We assessed pain using the Faces pain scores. RESULTS: There were no significant differences between the groups regarding the pain scores at 10, 30 and 60 minutes upon entering the postanesthesia care unit. The pain scores of Group 1 were slightly lower at the last evaluation point when compared to that of Group 2. One patient in Group 1 required supplemental postoperative intravenous (IV) tramadol, while all the other patients in both groups did not require supplemental IV tramadol. The intraoperative requirement for sevoflurane was decreased in Group 1 as compared to that of Group 2. There were no major complications related to either type of block. CONCLUSIONS: We conclude that a splash block can have a similar analgesic effect as that of a caudal block for the postoperative herniorrhaphy pain of children. PMID- 21602976 TI - Analysis of expert consultation referrals for anesthesia-related issues (December 2008-July 2010): KSA legislation committee report. AB - BACKGROUND: Since 2009, database construction of anesthesia-related adverse events has been initiated through the legislation committee of the Korean Society of Anesthesiologists (KSA), based on expert consultation referrals provided by police departments, civil courts, and criminal courts. METHODS: This study was a retrospective descriptive analysis of expert consultation referrals on surgical anesthesia-related cases between December 2008 and July 2010. RESULTS: During the given period, 46 surgical anesthesia-related cases were referred to the KSA legislation committee for expert consultation. Because six cases were excluded due to insufficient data, 40 cases were included in the final analysis. Of 40 cases, 29 (72.5%) resulted in death. Respiratory events were most common in both surviving/disabled and dead patients (36.4 vs. 51.7%, respectively; P > 0.05). Overall, respiratory depression due to the drugs used for monitored anesthesia care (MAC) was the most common specific mechanism (25%), in which all but one case (profound brain damage) resulted in death. In all of these cases, surgeons or physicians provided MAC without the help of anesthesiologists. CONCLUSIONS: Overall, the most common damaging mechanism was related to respiratory depression due to sedatives or anesthetics used for MAC. Almost all MAC injury cases are believed to be preventable with the use of additional or better monitoring and an effective response to initial physiological derangement. Thus, it is essential to establish practical MAC guidelines and adhere to these guidelines strictly to reduce the occurrence of severe anesthesia-related adverse outcomes. PMID- 21602977 TI - Suction conditions for minimizing the production of free hemoglobin during blood salvage using an autotransfusion apparatus. AB - BACKGROUND: Three kinds of conditions should be considered to reduce free hemoglobin production using an autologous cell salvage device. They are the negative suction pressure, the size of suction tip, and the air contact during suction. We want to examine which condition is the most important factor to produce free hemoglobin. METHODS: One pack of red blood cell and one pack of fresh frozen plasma with the same blood type were mixed. They were aspirated based on the two suction pressure (-150 mmHg or -300 mmHg), three sizes of suction tips, and the two conditions of air contact, in which the suction tip was located in the surface of blood or in the middle of the blood. Seven ml sized EDTA tube was used to collect 5 ml blood. All the procedure repeated ten times. Free hemoglobin, total hemoglobin, and hematocrit were measured. Hemolysis ratio was calculated with following formula. Hemolysis ratio = (new free hemoglobin production) * (100-hematocrit) / (total hemoglobin). RESULTS: Free hemoglobin production and hemolysis ratio were increased when the suction tip was positioned in the surface than when it was in the middle of the blood. The pressure of negative suction and three kinds of the suction tips did not influence the production of free hemoglobin nor the hemolysis ratio. CONCLUSIONS: The air contact is the most important factor to reduce hemolysis using autologous cell salvage device. Suction pressure or suction tip diameter have little influence to produce hemolysis. PMID- 21602978 TI - The diabetes-induced functional and distributional changes of the alpha 1 adrenoceptor of the abdominal aorta and distal mesenteric artery from streptozotocin-induced diabetic rats. AB - BACKGROUND: The aim of this study was to evaluate the effect of diabetes on the function and distribution of vascular alpha(1)-adrenoceptors in the abdominal aorta and distal mesenteric artery from streptozotocin (STZ)-induced diabetic rats at the level of the alpha(1)-adrenoceptor subtypes. METHODS: Diabetes was induced by a single intravenous injection of STZ (60 mg/kg) in 8 week-old male Sprague-Dawley rats (n = 11). Age-matched normal rats (n = 14) were used as a control group. Four weeks after STZ injection, the tilting-induced change of the mean arterial pressure was recorded. The alpha(1)-adrenoceptor subtypes mediating the contractions of the distal mesenteric artery and abdominal aorta were investigated using the agonist phenylephrine and subtype-selective antagonists that included prazocin, 5-methylurapidil and BMY 7378. The expressions of the alpha(1)-adrenoceptor subtypes of each artery were examined by immunofluorescence staining using the subtype selective antibodies. RESULTS: The recovery of the mean arterial pressure was delayed after positional change in the diabetic rats. Compared with that of the normal rats, the contractile response to phenylephrine was increased in the abdominal aortas and it was decreased in the distal mesenteric arteries in the diabetic rats. In addition, compared with the normal rats, the fluorescent intensity of all the alpha(1)-adrenoceptor subtypes was increased in the abdominal aortas and it was decreased in the mesenteric arteries of the diabetic rats. CONCLUSIONS: Diabetes increased the contractility of the abdominal aorta in response to phenylephrine, yet diabetes decreased that of the mesenteric arteries in the STZ-induced diabetic rats. Those results are mainly based on the overall change of the alpha(1)-adrenoceptor, and not on the change of the specific alpha(1)-adrenoceptor subtypes. PMID- 21602979 TI - Bladder perforation during laparoscopy detected by gaseous distention of the urinary bag -A report of two cases-. AB - Bladder perforation during laparoscopy is a recognized, uncommon complication. We present two cases of bladder perforation during laparoscopic gynecologic operations that were detected by gaseous distention of the urinary bag. Bladder perforation occurred through laparoscopic division of adhesion. One bladder perforation was repaired laparoscopically, and the other case was repaired by laparotomy during the same general anesthesia. In this report, we present evidence that monitoring a gas-distended urinary bag during a laparoscopic procedure can help detect intraoperative bladder perforation. PMID- 21602980 TI - Tracheal laceration during intubation of a double-lumen tube and intraoperative fiberoptic bronchoscopic evaluation through an LMA in the lateral position -A case report-. AB - A 76-year-old, 148-cm woman was scheduled for right upper lobectomy. A 32 Fr left sided double lumen tube was placed using a conventional technique. Despite several attempts under fiberoptic bronchoscope-guidance, we could not locate the double lumen tube properly. We thus decided to proceed with the bronchial tube in the right mainstem bronchus. During surgery, 8-cm-long laceration was noted on the posterolateral side of the trachea. To check the possibility of laceration of the proximal trachea, the double lumen tube was changed to an LMA for use as a conduit for fiberoptic bronchoscopic evaluation in the lateral position. A plain endotracheal tube with the cuff modified and collapsed was re-intubated after evaluation. And then she was transferred to SICU. PMID- 21602981 TI - Severe hypotension and water intoxication developed after an accidental oxytocin overdose in a morbidly obese patient undergoing cesarean section -A case report-. AB - We present a 32-year-old, extremely obese, pregnant woman who developed severe hypotension and water intoxication after an accidental injection of large bolus of oxytocin during cesarean section under general anesthesia. The patient was initially thought to have an amniotic fluid embolism because of the abrupt hemodynamic changes developed immediately after fetal delivery and lack of recognition of medication error. It is highly recommended that careful attention should be paid not only to the possibility of hemodynamic deterioration and water intoxication if oxytocin is given rapidly in excessive doses, but to the confirmation of the proper use of the drug before it is injected. PMID- 21602982 TI - Postanesthetic torsade de pointes in a patient with unrecognized long QT syndrome -A case report-. AB - Torsade de pointes (TdP) is a devastating form of polymorphic ventricular arrhythmia associated with corrected QT (QTc) interval prolongation. TdP usually terminates spontaneously but frequently recurs and may degenerate to ventricular fibrillation. The present report describes a case of TdP in a patient being transferred to the postanesthetic care unit following an emergency laparoscopic appendectomy. The patient had undergone open heart surgery 1 week before. Retrospective electrocardiogram analysis revealed the patient had QTc and Tpeak Tend interval prolongation that had gone unrecognized. We believe TdP may have been induced by accentuation of sympathetic nervous system during emergence from general anesthesia. PMID- 21602983 TI - Occipital nerve stimulation in a patient with an intractable chronic headache -A case report-. AB - Occipital nerve stimulation (ONS) is a form of peripheral nerve stimulation used to treat refractory headaches. The trial of ONS was carried with the midline incision C1-2 level, inserted electrical lead subcutaneously to oblique and cephalad direction followed by trajectory of blunt dissection. We used 8 pole electrical lead to cover lesser occipital nerve, greater occipital nerve, third occipital nerve and great auricular nerve. We anchored the lead at the midline insertion site after confirming the stimulation of the patient. And then we looped and tightened the lead loosely, connected the lead and the extension under right supraspinatus muscle region. After 1 week trial period, we performed the permanent implantation of occipital nerve stimulator. We inserted internal pulse generator under a pocket located at right infraclavicular region. The VAS score dropped from 8/10 to 1-2/10. No serious complications were detected during 1 month follow-up. PMID- 21602984 TI - The stance of Jehovah's Witnesses on the use blood and Hospital Liaison Committee. PMID- 21602985 TI - Nocturnal gastroesophageal reflux: assessment and clinical implications. PMID- 21602986 TI - Disturbed sleep and disturbed bowel functions: implications for constipation in healthy individuals. PMID- 21602987 TI - Noncardiac chest pain: epidemiology, natural course and pathogenesis. AB - Noncardiac chest pain is defined as recurrent chest pain that is indistinguishable from ischemic heart pain after a reasonable workup has excluded a cardiac cause. Noncardiac chest pain is a prevalent disorder resulting in high healthcare utilization and significant work absenteeism. However, despite its chronic nature, noncardiac chest pain has no impact on patients' mortality. The main underlying mechanisms include gastroesophageal reflux, esophageal dysmotility and esophageal hypersensitivity. Gastroesophageal reflux disease is likely the most common cause of noncardiac chest pain. Esophageal dysmotility affects only the minority of noncardiac chest pain patients. Esophageal hypersensitivity may be present in non-GERD-related noncardiac chest pain patients regardless if esophageal dysmotility is present or absent. Psychological co-morbidities such as panic disorder, anxiety, and depression are also common in noncardiac chest pain patients and often modulate patients' perception of disease severity. PMID- 21602988 TI - What is the difference between Helicobacter pylori-associated dyspepsia and functional dyspepsia? AB - Advances in basic and clinical research have revealed that Helicobacter pylori (H. pylori) infection plays an important role in the development of gastroduodenal dysmotility and hypersensitivity, as also in dyspepsia symptoms. In addition, recent studies have proposed an inflammation-immunological model for the pathogenesis of functional dyspepsia. Since H. pylori is the major microbe that provokes a gastroduodenal inflammatory response, it should not be overlooked when considering the pathophysiology of dyspepsia symptoms. In fact, population based studies have demonstrated that H. pylori is detected more frequently in dyspepsia patients. However, although many clinical studies tried to reveal the association of H. pylori infection with gastric motility dysfunction or hypersensitivity, the results have been conflicting. On the other hand, many etiological features were revealed for the development of H. pylori-associated dyspepsia, such as abnormal ghrelin or leptic secretion, altered expression of muscle-specific microRNAs, and duodenal inflammatory cell infiltration. In addition, therapeutic strategy for H. pylori-associated dyspepsia would be different from H. pylori-negative functional dyspepsia. This review focuses the issue of whether H. pylori-associated dyspepsia should be considered as a different disease entity from functional dyspepsia. PMID- 21602989 TI - Biopsychosocial model of irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a common chronic disorder seen in gastroenterology and primary care practice. It is characterized by recurrent abdominal pain or discomfort associated with disturbed bowel function. It is a heterogeneous disorder with varying treatments, and in this regard physicians sometimes struggle with finding the optimal approach to management of patients with IBS. This disorder induces high health care costs and variably reduces health-related quality of life. IBS is in the class of functional gastrointestinal disorders, and results from dysregulation of central and enteric nervous system interactions. Psychosocial factors are closely related to their gut physiology, associated cognitions, symptom manifestations and illness behavior. Therefore, it is important for the physician to recognize the psychosocial issues of patients with IBS and in addition to build a good patient physician relationship in order to optimize treatment. This review focuses on the interaction between psychological and physiological factors associated with IBS by using a biopsychosocial model. In this article, we describe (1) the predisposing psychological features seen in early life; (2) the psychological factors associated with life stress, the symptom presentation, and their associated coping patterns; (3) gut pathophysiology with emphasis on disturbances in motility, visceral hypersensitivity and brain-gut interactions; and finally (4) the clinical outcomes and effective treatments including psychotherapeutic methods. PMID- 21602991 TI - Nocturnal gastroesophageal reflux revisited by impedance-pH monitoring. AB - BACKGROUND/AIMS: Impedance-pH monitoring allows detailed characterization of gastroesophageal reflux and esophageal activity associated with reflux. We assessed the characteristics of nocturnal reflux and esophageal activity preceding and following reflux. METHODS: Impedance-pH tracings from 11 healthy subjects and 76 patients with gastroesophageal reflux disease off acid suppressive therapy were analyzed. Characteristics of nocturnal supine reflux, time distribution and esophageal activity seen on impedance at 2 minute intervals preceding and following reflux were described. RESULTS: Patients had more nocturnal reflux events than healthy subjects (8 [4-12] vs 2 [1-5], P = 0.002), with lower proportion of weakly acidic reflux (57% [35-78] vs 80% [60-100], P = 0.044). Nocturnal reflux was mainly liquid (80%) and reached the proximal esophagus more often in patients (6% vs 0%, P = 0.047). Acid reflux predominated in the first 2 hours (66%) and weakly acidic reflux in the last 3 hours (70%) of the night. Most nocturnal reflux was preceded by aboral flows and cleared by short lasting volume clearance. In patients, prolonged chemical clearance was associated with less esophageal activity. CONCLUSIONS: Nocturnal weakly acidic reflux is as common as acid reflux in patients with gastroesophageal reflux disease, and predominates later in the night. Impedance-pH can predict prolonged chemical clearance after nocturnal acid reflux. PMID- 21602990 TI - Microflora modulation of motility. AB - That gastrointestinal motility can influence the gut microbiota has been known for decades and the clinical consequences of impaired motility, in terms of the bacterial population of the small intestine, amply illustrated by the syndrome of small intestinal bacterial overgrowth which so commonly accompanies diffuse intestinal motility disorders. As the importance of the microbiota to homeostasis in health and to a variety of disease states is increasingly appreciated and as the full diversity and biology of this "hidden organ" have been revealed by molecular methodologies, the true nature of the interaction between the microbiota and motility is being re-examined and the complexity of this relationship exposed. In health, as well as in disease states, this is a truly bi directional relationship: not only can gut motor patterns influence the microbiota but changes in the microbiota can exert profound influences on gut sensori-motor function. PMID- 21602992 TI - Yield of combined impedance-pH monitoring for refractory reflux symptoms in clinical practice. AB - BACKGROUND/AIMS: In patients with gastroesophageal reflux disease, persistent symptoms on proton pump inhibitor (PPI) therapy may be due to residual acid or non-acid reflux. Combined impedance-pH has been suggested to be superior to pH alone in the management of refractory patients to PPI. The utility of implementation of this technique in every day clinical practice is still unknown. The aim of this study was to investigate the outcomes of patients studied with combined impedance-pH and to evaluate the yield of additional impedance monitoring over pH alone in patients with persistent gastroesophageal reflux disease symptoms. METHODS: Seventy-one patients (31 men; mean age, 49.1 +/- 15.5 years) on PPI therapy underwent combined impedance-pH for persistent typical (76%) or atypical (49%) symptoms. RESULTS: During impedance-pH study, 44 (62%) patients reported symptoms. A positive symptom index (SI) was found in 21 (48%) patients: 8 (18.2%) had a positive SI for acid reflux, 9 (20.5%) for non-acid reflux and 4 (9.1%) for mixed reflux. Addition of impedance allowed association between reflux and symptoms in 20.5% of patients who would have been missed by pH study alone. Heartburn was the most prevalent symptom associated with acid reflux, whereas regurgitation and ear, nose and throat symptoms were associated with non-acid reflux. CONCLUSIONS: The use of combined impedance-pH monitoring substantially increased the diagnostic yield compared to pH alone. With SI analysis, 20.5% of patients received a diagnosis that could not have been achieved with pH testing alone. PMID- 21602993 TI - The value of Carlsson-dent questionnaire in diagnosis of gastroesophageal reflux disease in area with low prevalence of gastroesophageal reflux disease. AB - BACKGROUND/AIMS: Symptom-based diagnosis for gastroesophageal reflux disease (GERD) has been accepted in the population with high prevalence. Carlsson-Dent questionnaire (CDQ) is a standardized symptom-based diagnosis tool for GERD. The value of this tool in the population with low prevalence is unknown. The aim of this study was to determine CDQ performance for diagnosis of GERD in Thai population with low prevalence versus endoscopy or 24 hour pH monitoring. METHODS: Patients with dyspepsia by Rome II criteria were recruited. All patients completed a Thai version of CDQ and underwent endoscopic examination. Those without esophagitis or peptic ulcer and positive CDQ score took pH monitoring. RESULTS: One hundred patients (68 female) with mean age +/- SD of 45.6 +/- 12.4 years were recruited. Six with Los Angeles grade A esophagitis had negative CDQ score. In 44 with positive CDQ score, 3 had Los Angeles grade B esophagitis and 41 had pH monitoring done with 8 having positive test. The GERD diagnosis by CDQ was confirmed in 11 of 44 patients (25%). CDQ detected 11 out of 17 GERD detected by endoscopy and pH monitoring and the sensitivity of CDQ was 64%. CONCLUSIONS: CDQ diagnosed more GERD in Thai population with low prevalence compared with endoscopy and pH monitoring. This may be due to some patients with functional heartburn were picked up by CDQ and some patients with GERD were not detected by endoscopy and pH monitoring. PMID- 21602994 TI - Genetic evaluation of ALADIN gene in early-onset achalasia and alacrima patients. AB - BACKGROUND/AIMS: ALADIN gene has been known to cause achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. A considerable proportion of achalasia patients has been known to show alacrima (decreased secretion of tear). However, the genetic mechanism between achalasia and alacrima has not been defined yet. We postulated that ALADIN gene may be involved in the occurrence of early-onset achalasia; thus, we investigated the correlation of ALADIN gene in early-onset achalasia patients. METHODS: From 1989 to 2007, patients who were diagnosed as primary achalasia before age 35 were enrolled. All of the enrolled patients were asked for (1) blood sampling for DNA, (2) Shirmer test and (3) dysphagia questionnaires. RESULTS: The ALADIN gene in exon 1, 2, 10, 11 and 12 from 19 patients was investigated (M:F = 12:7). The mean age of patients at diagnosis was 27 +/- 5 (15-35) years old. Eight out of 19 (42%) showed alacrima by the positive Shirmer test. In spite of thorough exam in the genetic study, there was no definite abnormal genetic finding in this study. CONCLUSIONS: A considerable number of achalasia patients showed alacrima. Due to the limitation of this study, it is difficult to conclude that early-onset achalasia may have significant correlations with the ALADIN gene. PMID- 21602996 TI - Impact of sleep dysfunction on anorectal motility in healthy humans. AB - BACKGROUND/AIMS: Sleep dysfunction is associated with altered gastrointestinal function and subsequently exacerbations of gastrointestinal problems. We aimed to investigate whether sleep dysfunction would influence anorectal motility as determined by anorectal manometry. The effect of anxiety on anorectal motility was also determined. METHODS: A total of 24 healthy volunteers underwent anorectal manometry. The anorectal parameters included resting and squeeze sphincter pressure, sensory thresholds in response to balloon distension, sphincter length, rectal compliance, and rectoanal inhibitory reflex. Sleep dysfunction was subjectively assessed by using Pittsburgh Sleep Quality Index (PSQI). Anxiety was assessed by the application of the State-Trait Anxiety Inventory questionnaire. RESULTS: There were sixteen subjects without sleep dysfunction (7 women; mean age, 22 years) and eight subjects with sleep dysfunction (2 women; mean age, 22 years). There was no group difference in the volume threshold for rectoanal inhibitory reflux, rectal compliance or sphincter length (P = NS). Anal sphincter pressure did not differ between the groups (P = NS). The rectal sensitivity for different levels of stimulation did not differ between the groups (P = NS). Sleep quality as determined by PSQI correlated with rectal compliance (r = 0.66, P = 0.007). Although there was no differences in any manometric parameters between subjects with and without anxiety, the anxiety score correlated with rectal compliance (r = 0.57, P = 0.003). CONCLUSIONS: Despite a positive association between rectal compliance and the level of subjective sleep or anxiety, sleep dysfunction did not apparently affect most of anorectal function in healthy subjects, nor did anxiety. PMID- 21602995 TI - Change of gastric emptying with chewing gum: evaluation using a continuous real time C breath test (BreathID system). AB - BACKGROUND/AIMS: There are few reports on the correlation between chewing gum and the gastrointestinal functions. But previous report showed use of chewing gum to be an effective method for controlling gastrointestinal symptoms. The aim of this study was to determine the correlation between chewing gum and gastric emptying using the continuous real time (13)C breath test (BreathID system). METHODS: Ten healthy male volunteers participated in this randomized, 2-way crossover study. The subjects fasted overnight and were randomly assigned to chewing gum (Xylish, 2-3/1 tablet) for an hour following intake of a test meal (200 kcal/200 mL) or intake of the test meal alone. Gastric emptying was monitored for 4 hours after administration of the test meal by the (13)C-acetic acid breath test performed continually using the BreathID system. RESULTS: No significant differences in the calculated parameters, namely, T(1/2) (median, 111.82 vs 109.26 minutes; P = 0.575), T(lag) (median, 53.28 vs 56.53 minutes; P = 0.333), gastric emptying coefficient (median, 3.58 vs 3.65; P = 0.285), regression-estimated constant beta (median, 1.85 vs 1.80; P = 0.575) and regression-estimated constant kappa (median, 0.61 vs 0.62; P = 0.959) were observed between the test meal alone group and the test meal and chewing gum group. CONCLUSIONS: This study showed that chewing gum had no effect on the rate of gastric emptying. Therefore, since chewing gum did not enhance the speed of gastric emptying, it may ameliorate gastrointestinal symptoms through other mechanisms, such as saliva and autonomic nervous system. PMID- 21602997 TI - Slow transit constipation associated with excess methane production and its improvement following rifaximin therapy: a case report. AB - Constipation, a common problem in gastroenterology practice, may result from slow colonic transit. Therapeutic options for slow transit constipations are limited. Excessive methane production by the methanogenic gut flora, which is more often found in patients with constipation, slows colonic transit. Thus, reduction in methane production with antibiotic treatment directed against methanogenic flora of the gut may accelerate colonic transit resulting in improvement in constipation. However, there is not much data to prove this hypothesis. We, therefore, report a patient with slow transit constipation associated with high methane production both in fasting state and after ingestion of glucose, whose constipation improved after treatment with non-absorbable antibiotic, rifaximin, which reduced breath methane values. PMID- 21602998 TI - How to interpret gastric emptying scintigraphy. AB - Gastric emptying scintigraphy has long been the standard method for measuring gastric motility. Various methodologies for this study have been used including meal composition, patient positioning, instrumentation, frequency of data acquisition, study length and quantitative method. For accurate quantification, it is not important which method is in use, except that the methodology should always be the same and normal values need to be derived and validated for that methodology. PMID- 21602999 TI - Varicella zoster cranial polyneuropathy presenting with Dysphagia, esophagitis and gastroparesis. PMID- 21603000 TI - A 44-year-old female with Dysphagia presenting a thin muscle thickness on high frequency intraluminal ultrasound. PMID- 21603001 TI - Weak peristalsis in esophageal pressure topography: classification and association with Dysphagia (am j gastroenterol 2011;106:349-356). PMID- 21603002 TI - Could down-regulation of muscle-specific MircoRNAs provoke functional dyspepsia in helicobacter pylori-infected stomach? (Gastroenterology 2011;140:189-198). PMID- 21603003 TI - Is the intestinal gas associated with the development of right colonic diverticula?: author's reply. PMID- 21603004 TI - Can achalasia subtyping by high-resolution manometry predict the therapeutic outcome of pneumatic balloon dilatation? PMID- 21603005 TI - Can achalasia subtyping by high-resolution manometry predict the therapeutic outcome of pneumatic balloon dilatation?: author's reply. PMID- 21603006 TI - Is there true gender difference of irritable bowel syndrome in Asia? PMID- 21603007 TI - Is there true gender difference of irritable bowel syndrome in Asia?: author's reply. PMID- 21603008 TI - Early life Conditions and Trends in Mortality at Later Life: Is There any Relationship? PMID- 21603009 TI - Dynamics in Cardiometabolic Risk among Turkish Adults: Similarities to that in Iranians? AB - Based on 20 years experiences of follow-up of the Turkish Adult Risk Factor (TARF) study, this review summarizes the distribution of risk factors among Turks which is dominated by components of the metabolic syndrome (MetS), especially abdominal obesity and atherogenic dyslipidemia. The adoption of a 95 cm cutoff for male abdominal circumference was crucial in the understanding of cardiometabolic risk factors. The prevalence of MetS, type-2 diabetes and coronary heart disease (CHD) are high, alike in Iranians. The TARF study demonstrated that low-grade systemic inflammation and oxidative stress are major determinants of cardiometabolic risk in the population at large, and involves the female sex to a greater extent than the male. As a result, impaired anti inflammatory and atheroprotective function developed in middle-aged and elderly obese individuals emerging as dysfunction of apolipoprotein A-I and HDL particles. This dysfunction is currently a major driver cardiometabolic risk in Turkish adults leading to substantial excess diabetes and CHD. Separate algorithms for diabetes and CHD were derived that improved the risk prediction of these diseases.The author strongly suspects that such dynamics in the development of diabetes and CHD exist in Western adults prone to impaired glucose tolerance, and evidence is accumulating regarding general Iranian adults. These issues posing a vast threat on public cardiometabolic health will have to be recognized with the purpose of not delaying implementation of measures for the modification of cardiometabolic risk, especially in women. PMID- 21603010 TI - Review of cost-effectiveness analysis of medical treatment for myocardial infarction. AB - OBJECTIVES: Myocardial infarction (MI) is a leading cause of death in both the industrialized and developing countries globally. The economic evaluation of MI is undertaken to rationale the allocation of scarce healthcare resource. The objective is to review cost-effectiveness analysis of MI with medications. METHODS: WE SEARCHED PUBMED USING THE KEY WORDS: "cost effectiveness analysis"and "myocardial infarction" After applying the selection criteria, eight articles were selected for the present study. RESULTS: Out of eight articles, five had studied thrombolytic agents. All of these papers clearly explain the costs and benefits of different drugs for MI. ICER was assessed in six out of the eight articles to compare the costs and health effects between alternative medications. ICER was expressed in different effect units. CONCLUSIONS: This study found that various medications including thrombolytic agents, ACEI and heparin are administered to treat MI in many countries. It is also found that five of eight studies focus on thrombolytic therapies. It implies that thrombolytic is generally very cost effective for MI to the whole society. PMID- 21603011 TI - Epigenetically reprogramming of human embryonic stem cells by 3-deazaneplanocin a and sodium butyrate. AB - OBJECTIVES: Infertility affects about 6.1 million women aged 15-44 in the United States. The leading cause of infertility in women is quantitative and qualitative defects in human germ-cell development (these sentences are not mentioned in introduction so it is not correct to mention in abstract, you can omit). Human embryonic stem cell (hESC) lines are derived from the inner cell mass (ICM) of developing blastocysts and have a broad clinical potential. hESCs have been classified into three classes based on their epigenetic state. The goal of this study was to epigenetically reprogram Class II and Class III cell lines to Class I (naive state), and to in vitro differentiation of potent hESCs to primordial germ cells (PGCs). METHODS: Recent evidence suggests that 3-deazaneplanocin A (DZNep) is a global histone methylation inhibitor which selectively inhibits trimethylation of lysine 27 on histone H3K27, and it is an epigenetic therapeutic for cancer. The characteristics of DZNep lead us to hypothesize that it is a good candidate to epigenetically reprogram hESCs to the Class I. Additionally, we used sodium butyrate (NaBu) shown in previous studies to up-regulate the expression of germ cell specific markers (these sentences should be come in introduction). RESULTS: We used these two drugs to produce epigenetically stable hESC lines. hESC lines are an appropriate system for disease modeling and understanding developmental stages, therefore producing stable stem cell lines may have an outstanding impact in different research fields such as preventive medicine. CONCLUSIONS: X-Chromosome inactivation has been used as a tool to follow the reprogramming process. We have used immunostaining and western blot as methods to follow this reprogramming qualitatively and quantitatively. PMID- 21603012 TI - A six months follow-up on children less than 6 years old in contact with smear positive tuberculosis patients, varamin city, tehran, iran. AB - OBJECTIVES: Current international guidelines recommend 6-9 months of Isoniazid (INH) preventive chemotherapy to prevent the development of active tuberculosis in children exposed to smear positive tuberculosis (TB) patients. The aim of the present study was to evaluate the adherence to a six-month of supervised INH prophylaxis program and outcome in children with household exposure to an adult pulmonary tuberculosis index case in Varamin city, Tehran, Iran. METHODS: This cross sectional study was conducted among household contacts in Varamin city, between 1997- 1998. All children <6 years old with a household contact with an adult pulmonary tuberculosis index case were screened for tuberculosis and given supervised INH preventive chemotherapy once active tuberculosis was excluded as planned. Adherence and outcome were monitored. RESULTS: In total, 31 index cases and 128 household contact cases were identified; 23 (18%) children <6 years old experienced household exposure, who were fully evaluated. two children were treated for active tuberculosis and 15 (12%) children received preventive chemotherapy. All children completed 6 months of supervised INH prophylaxis with normal clinical examination in 3 and 6 months after beginning INH prophylaxis. No side effects (peripheral neuropathy or liver damage) were reported or observed within this study. CONCLUSIONS: Strategy of six months of supervised INH chemoprophylaxis is successful, particularly in children who are at a high risk to progress to disease following exposure. PMID- 21603013 TI - Converting three general-cognitive function scales into persian and assessment of their validity and reliability. AB - OBJECTIVES: Glasgow Outcome Scale Extended (GOSE), Galveston Amnesia and orientation Test (GOAT) and Disability Rating Scale (DRS) are three popular outcome measure tools used principally in traumatic brain injury (TBI) patients. We conducted this study to provide a Farsi version of these outcome scales for use in Iran. METHODS: Following a comprehensive literature review, Farsi transcripts were prepared by "forward-backward" translation and reviewed by subject experts. After a pretest on a few patients, the final versions were obtained. 38 patients with closed head injury were interviewed simultaneously by two interviewers. Main statistics used to assess validity and reliability included "Factor analysis" for construct validity, Cronbach's alpha for internal consistency, and Pearson Correlation and Kappa Coefficient for inter-rater agreement. RESULTS: Factor analysis for Farsi-GOAT (FGOAT) revealed 5 independent factors with a total distribution variance of 80.2%. For Farsi-DRS (FDRS), 3 independent factors were found with a 92.3% variance. The Cronbach's alpha (95% confidence interval) was 0.84 (0.763- 0.919) and 0.91 (0.901-0.919) for FGOAT and FDRS, respectively. Pearson Correlation between total scores of two raters was 0.98 and 0.97 for FGOAT and FDRS, in order. Kappa coefficient (95% CI) between outcome rankings of raters was 0.73 (0.618-0.852) and 0.68 (0.594-0.770) for FGOAT and FDRS, respectively. As for Farsi-GOSE scale, Kappa value was 0.4 (0.285 0.507) for 8-level outcome ranking and improved to 0.7 (0.585-0.817) for 5-level scale. We found a good correlation between FDRS and FGOSE predicted prognoses (Spearman's rho= 0.74, 95% CI: 0.676-0.802). CONCLUSIONS: FDRS and FGOAT had appropriate validity and reliability. The 8-level outcome FGOSE scale disclosed a low inter-rater agreement, but a suitable observer agreement was achieved when the 5-level outcome was applied. PMID- 21603014 TI - A gap between policy and practice: a case study on maternal mortality reports, kerman, iran. AB - OBJECTIVES: Maternal mortality, a preventable tragedy, is an indicator of development, poverty and democracy. Therefore, prevention of maternal deaths is one of the main goals in many countries. Iran is one of the developing countries which aim to reduce maternal mortality through introduction of a new policy at national level. This study aimed to explore the extent to which this policy is practiced at peripheral levels. METHODS: The data were collected through interviews with relevant people, observation, and review of the documents. RESULTS: The results showed that there is a gap between policy and practice which can be explained by inadequate training programs, inadequate collaboration, lack of guidelines and instigation of a specific investigation into maternal deaths. CONCLUSIONS: This study suggests a number of considerations such as an initiative to collaborate, developing a guideline and presenting training programs before such policies are launched. PMID- 21603015 TI - Effects of apple consumption on lipid profile of hyperlipidemic and overweight men. AB - OBJECTIVES: Fruits and vegetables may be beneficial on lipid profile of hyperlipidemic subjects. The present study was aimed to verify the effect of golden delicious apple on Lipid Profile in hyperlipidemic and overweight men. METHODS: Forty six hyperlipidemic and overweight men were randomly divided into two groups. Intervention group received 300g golden delicious apple per day for 8 weeks. Control group had the regular dietary regimen for the same period of time. Blood samples were analyzed for serum triglycerides (TG), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), very low density lipoprotein-cholesterol (VLDL), apolipoprotein B (Apo B), lipoprotein a (Lp a) and LDL/HDL ratio at baseline and after intervention. RESULTS: Total polyphenols and fibers were 485 mg/kg and 4.03 g/100g in fresh apple respectively. After 8 weeks, significant statistical differences were observed considering the TG and VLDL levels between two groups, but no significant differences were observed regarding TC, LDL-C, HDL-C, Apo (B), Lp (a) and LDL/HDL ratio. CONCLUSIONS: Consumption of Golden delicious apple may be increased serum TG and VLDL in hyperlipidemic and overweight men. We need more studies to assay the effect of apple consumption on serum TC, LDL-C, HDL-C, Apo (B), Lp (a) and LDL/HDL ratio. PMID- 21603016 TI - Stomach cancer mortality in the future: where are we going? PMID- 21603017 TI - Do we transfer health research results to people? PMID- 21603018 TI - EUS-FNA for the Diagnosis of Retroperitoneal Primitive Neuroectodermal Tumor. AB - Primitive neuroectodermal tumor (PNET) is a rare "small round blue cell tumor" that is diagnosed by open biopsy or percutaneous biopsy of the lesion under radiologic guidance. In this case report, we present a novel approach to the diagnosis of a retroperitoneal PNET by endoscopic ultrasound- (EUS-) guided fine needle aspiration (FNA). A 35-year-old man presented with the history of left sided flank pain and swelling of 3-weeks duration. Computerized tomography (CT) scan of his abdomen revealed a 12.8 * 13 * 12.5 cm cystic and solid mass arising from the retroperitoneum and displacing the third and fourth portions of the duodenum. He underwent EUS which revealed a well-circumscribed heterogeneous mass abutting the inferior portion of the stomach. EUS-FNA of the mass revealed malignant cells consistent with primitive neuroectodermal tumor (PNET)/Ewing's sarcoma. EUS-guided FNA is an appropriate technique for diagnosing retroperitoneal PNET/Ewing's sarcoma. PMID- 21603019 TI - Two cases of appendiceal intussusception: a rare diagnostic pitfall in colonoscopy. AB - Partially or completely invaginated appendix mistaken for a polyp during colonoscopy and leading to intussusception is a rare situation. This paper describes our experience with two cases of appendiceal intussusception. In the first case, there was no underlying ileocecal abnormality, and, in the second case, histologic examination of the resected appendix and cecum revealed widespread foci of angiodysplasia, and this was thought to be the basis for the intussusception. The authors present reviews of the literature concerning clinical features and associated conditions and emphasize that failure to recognize this condition may result in unexpected complications such as consequent peritonitis in case of endoscopic removal. PMID- 21603020 TI - Capsule endoscopy in patients with cardiac pacemakers, implantable cardioverter defibrillators, and left heart devices: a review of the current literature. AB - Background and Study Aims. Capsule endoscopy is an established tool for investigation of the small intestine. Because of limited clinical experience in patients with cardiac devices, the Food and Drug Administration and the manufacturer recommended not to use capsule endoscopy in these patients. The vast majority of investigations did not reveal any interference between capsule endoscopy and cardiac devices. Methods. Studies investigating interference between CE and cardiac devices were analysed. For the review we considered studies published in English or German and indexed in Medline, as well as highly relevant abstracts. Results. In vitro and in vivo studies mainly revealed no interference between capsule endoscopy and cardiac devices. Technical data of capsule endoscopy (Given Imaging) reveal that interference with cardiac pacemakers and implantable cardioverter defibrillator is impossible. Telemetry can interfere with CE video. Conclusion. The clinical use of capsule endoscopy (Given Imaging) is unproblematic in patients with cardiac pacemakers. PMID- 21603021 TI - Total Colonic Expulsion with Part of Small Bowel per Vaginum due to Low-Flow Phenomenon and NOMI: A Case Report. AB - Introduction. Intestinal ischaemia is a devastating disease process that could lead to bowel gangrene and death if either not diagnosed early or left untreated; death is usually caused by irreversible shock, intestinal necrosis, or septicaemia. It is usually seen in elderly patients with atherosclerotic disease. The course of bowel ischaemia may affect variable lengths of the intestine and it is not unusual for the condition to be followed by uneventful recovery. Case presentation. We are reporting an unusually rare case where an elderly patient passed an extraordinarily long segment of bowel, including rectum, the whole of the large bowel, and part of the small bowel, through anus following an episode of nonobstructive mesenteric ischaemia (NOMI) complicating myocardial infarction. To our knowledge, there are only eight cases reported in the literature where the condition was diagnosed upon the passage of short segments of the large bowel particularly of the rectosigmoid segment through the anus. Conclusion. Physician should keep a high level of suspicion in order to prevent it or at least recognise it early on and offer adequate management and hence reducing morbidity and mortality. PMID- 21603022 TI - Cat scratch colon. AB - Over the past few years, we have read several publications regarding the term "cat scratch colon." This neologism was developed to define some bright red linear markings seen in the colonic mucosa that resemble scratches made by a cat. We would like to communicate a recent case attended at our institution. PMID- 21603023 TI - Training the trainees in radiation oncology with telemedicine as a tool in a developing country: a two-year audit. AB - Purpose. The estimated new cancer patient load in the Indian state of Uttar Pradesh is 0.1-0.12 million per year. Approximately two thirds of these require treatment by a radiation oncologist. Radiation oncologists: cancer patient ratio in this state is 1 : 2000 as compared to the recommended 1 : 250. This problem is compounded by the poor infrastructure of radiation oncology departments in the state which is suboptimal for teaching, training of resident doctors, and treatment in most barring a few departments. To bridge some gap in the sociodemographics stated above and enhancement of training of residents, we submitted a project for establishment of a telemedicine facility in our department to the Department of Science and Technology, Government of India. We present the design, implementation, and a two-year audit of our tele-education activities. Materials and Methods. After the sanction of the project, we established telemedicine linkage with another medical institute in the city located 25 kms away in 2007. After implementation of the project, academic sessions designed for trainee residents in our department were shared with the remote end. A record of these activities and a feedback of the activities were audited at the end of 2 years of implementation of this project. Results. Regular videoconferencing sessions comprising of lectures on clinical oncology, medical physics, and radiobiology were held. Feedback from the users revealed satisfaction with the content of the academic sessions for the purpose of MD training. Conclusions. Distance education in radiation oncology is an important tool for training of the trainee residents. PMID- 21603024 TI - Referral to an electronic screening and brief alcohol intervention in primary health care in sweden: impact of staff referral to the computer. AB - The aim of this paper was to evaluate whether primary health care staff's referral of patients to perform an electronic screening and brief intervention (e SBI) for alcohol use had a greater impact on change in alcohol consumption after 3 month, compared to patients who performed the test on their own initiative. Staff-referred responders reported reduced weekly alcohol consumption with an average decrease of 8.4 grams. In contrast, self-referred responders reported an average increase in weekly alcohol consumption of 2.4 grams. Staff-referred responders reported a 49% reduction of average number of heavy episodic drinking (HED) occasions per month. The corresponding reduction for self-referred responders was 62%. The differences between staff- and self-referred patient groups in the number who moved from risky drinking to nonrisky drinking at the followup were not statistically significant. Our results indicate that standalone computers with touchscreens that provide e-SBIs for risky drinking have the same effect on drinking behaviour in both staff-referred patients and self-referred patients. PMID- 21603025 TI - High-Resolution Melting (HRM) Analysis of the Cu/Zn Superoxide Dismutase (SOD1) Gene in Japanese Sporadic Amyotrophic Lateral Sclerosis (SALS) Patients. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, and the majority of ALS are sporadic (SALS). Recently, several causative genes for familial ALS (FALS) were identified, but the cause of the SALS is still unknown. This time, we aimed to identify the genetic background of SALS. First, we applied the new sensitive screening methods: high-resolution melting (HRM) analysis. HRM analysis detected 18 out of 19 known SOD1 gene mutations (94.7% sensitivity). Next, we screened SOD1, three novel mutations (C6Y, Q22H, and S134T) were identified in our own 184 SALS cases (1.63% prevalence), and four mutations in another 255 SALS cases (1.56% prevalence) registered from all over Japan. The patients with SOD1 mutations suggested a relatively young onset and limb involvement at onset. The HRM analysis is a sensitive and easy screening method; we will use this method for screening other ALS causative genes and revealing the genetic background of SALS. PMID- 21603026 TI - Brief review of the role of glycogen synthase kinase-3beta in amyotrophic lateral sclerosis. AB - Glycogen synthase kinase-3beta (GSK-3beta) is known to affect a diverse range of biological functions controlling gene expression, cellular architecture, and apoptosis. GSK-3beta has recently been identified as one of the important pathogenic mechanisms in motor neuronal death related to amyotrophic lateral sclerosis (ALS). Therefore, the development of methods to control GSK-3beta could be helpful in postponing the symptom progression of ALS. Here we discuss the known roles of GSK-3beta in motor neuronal cell death in ALS and the possibility of employing GSK-3beta modulators as a new therapeutic strategy. PMID- 21603027 TI - Mechanisms of neuroprotection by protein disulphide isomerase in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterised by the progressive loss of motor neurons, leading to paralysis and death within several years of onset. Although protein misfolding is a key feature of ALS, the upstream triggers of disease remain elusive. Recently, endoplasmic reticulum (ER) stress was identified as an early and central feature in ALS disease models as well as in human patient tissues, indicating that ER stress could be an important process in disease pathogenesis. One important chaperone induced by ER stress is protein disulphide isomerase (PDI), which is both upregulated and posttranslationally inhibited by S-nitrosylation in ALS. In this paper, we present evidence from studies of genetics, model organisms, and patient tissues which indicate an active role for PDI and ER stress in ALS disease processes. PMID- 21603028 TI - SOD1 Transcriptional and Posttranscriptional Regulation and Its Potential Implications in ALS. AB - Copper-zinc superoxide dismutase (SOD1) is a detoxifying enzyme localized in the cytosol, nucleus, peroxisomes, and mitochondria. The discovery that mutations in SOD1 gene cause a subset of familial amyotrophic lateral sclerosis (FALS) has attracted great attention, and studies to date have been mainly focused on discovering mutations in the coding region and investigation at protein level. Considering that changes in SOD1 mRNA levels have been associated with sporadic ALS (SALS), a molecular understanding of the processes involved in the regulation of SOD1 gene expression could not only unravel novel regulatory pathways that may govern cellular phenotypes and changes in diseases but also might reveal therapeutic targets and treatments. This review seeks to provide an overview of SOD1 gene structure and of the processes through which SOD1 transcription is controlled. Furthermore, we emphasize the importance to focus future researches on investigating posttranscriptional mechanisms and their relevance to ALS. PMID- 21603029 TI - Communication Support for People with ALS. AB - Almost all people with amyotrophic lateral sclerosis (ALS) experience a motor speech disorder, such as dysarthria, as the disease progresses. At some point, 80 to 95% of people with ALS are unable to meet their daily communication needs using natural speech. Unfortunately, once intelligibility begins to decrease, speech performance often deteriorates so rapidly that there is little time to implement an appropriate augmentative and alternative communication (AAC) intervention; therefore, appropriate timing of referral for AAC assessment and intervention continues to be a most important clinical decision-making issue. AAC acceptance and use have increased considerably during the past decade. Many people use AAC until within a few weeks of their deaths. PMID- 21603031 TI - Asymptomatic primary biliary cirrhosis is not associated with increased frequency of cardiovascular disease. AB - AIM: To estimate the prevalence of cardiovascular events in Primary biliary cirrhosis (PBC) and to determine whether this risk is higher within specific subgroups of patients with PBC. METHODS: We included 180 patients with PBC (cases) and 151 patients seen for HCV infection (controls). Medical records were reviewed and statistical analyses were performed as appropriate. RESULTS: When compared to controls, PBC patients were older, leaner and had higher serum levels of total cholesterol, high density lipoprotein and low density cholesterol. There were more females in the PBC group (91.7% vs 43%, P < 0.001). More control subjects had smoked than the PBC patients (63.6% vs 35%, P < 0.001). The prevalence of hypertension, diabetes, coronary artery disease and stroke was similar between the two groups. Seven percent of controls and 10% of cases developed any type of cardiovascular disease (P = 0.3). Only 36.7% were asymptomatic at diagnosis. Three cardiovascular events were documented among asymptomatic patients (4.5%) and fifteen among symptomatic patients (13.2%; P = 0.06). Among PBC patients with fatigue, 10 (13.5%) had a cardiovascular event compared to 7 (6.7%) among patients without fatigue (P = 0.1). CONCLUSION: Asymptomatic PBC patients do not have a greater frequency of cardiovascular disease; nor do patients suffering with fatigue. PMID- 21603030 TI - Infections in liver transplant recipients. AB - Liver transplantation is a standard life-saving procedure for the treatment of many end-stage liver diseases. The success of this procedure may be limited by infectious complications. In this article, we review the contemporary state of infectious complications during the post-operative period, with particular emphasis on those that occur most commonly during the first 6 mo after liver transplantation. Bacteria, and less commonly Candida infections, remain the predominant pathogens during the immediate post-operative period, especially during the first month, and infections caused by drug-resistant strains are emerging. Infections caused by cytomegalovirus and Aspergillus sp. present clinically during the "opportunistic" period characterized by intense immunosuppression. As newer potent immunosuppressive therapies with the major aim of reducing allograft rejection are developed, one potential adverse effect is an increase in certain infections. Hence, it is essential for liver transplant centers to have an effective approach to prevention that is based on predicted infection risk, local antimicrobial resistance patterns, and surveillance. A better understanding of the common and most important infectious complications is anticipated to lead to improvements in quality of life and survival of liver transplant recipients. PMID- 21603032 TI - Emerging role of bioflavonoids in gastroenterology: Especially their effects on intestinal neoplasia. AB - Flavonoids, secondary plant products which could be essential for normal physiology in humans and animals, may be the vitamins of the next century. Flavonoids belong to the polyphenols and possess antioxidative, anti inflammatory, antimutagenic and anticarcinogenic properties. Among the various flavonoid species, tea flavonoids such as apigenin (from camomile) and epigallocatechin gallate (EGCG from green tea) can be used for the prevention of intestinal neoplasia, especially for adenoma and cancer prevention in the gastrointestinal tract. Numerous experimental studies with molecular and biological end points support the therapeutic efficacy of bioflavonoids. Clinical studies with cohorts and case-control trials suggest that flavonoids are effective in tertiary bioprevention but, as yet, there are no controlled randomized clinical trials. Flavonoids can inhibit inflammatory pathways and could be useful for chronic inflammatory bowel diseases. Flavonoid deficiency syndromes could be therapeutic targets in the future. PMID- 21603033 TI - Pedunculated gastric tube interposition in an esophageal cancer patient with prepyloric adenocarcinoma. AB - Gastric carcinoma is one of the malignancies that are most frequently associated with esophageal carcinoma. We describe herein our device for advanced esophageal cancer associated with early gastric cancer in the antrum. A 57-year-old man presenting with dysphagia and upper abdominal pain was admitted to our hospital. Preoperative examinations revealed locally advanced squamous cell carcinoma (SCC) of the middle thoracic esophagus (T3N0M0 Stage IIA) and mucosal signet-ring cell carcinoma of the gastric antrum (T1N0M0 Stage IA). Although the gastric tumor appeared to be an intramucosal carcinoma, its margin was obscure, so endoscopic en-bloc resection was considered inadequate. We chose surgical resection of the gastric tumor as well as the esophageal SCC after neoadjuvant chemotherapy with 5 fluorouracil and cisplatin for advanced esophageal cancer. Following transthoracic esophagectomy with three-field lymph node dissection, the gastric carcinoma was removed by gastric antrectomy, which preserved the right gastroepiploic vessels, and a pedunculated short gastric tube was used as the esophageal substitute. Twenty-eight months after the surgery, the patient is well with no evidence of cancer recurrence. Because it minimizes surgical stress and organ sacrifice, gastric tube interposition is a potentially useful technique for esophageal cancer associated with localized early gastric cancer. PMID- 21603034 TI - Management of complications following endoscopic submucosal dissection for gastric cancer. AB - Endoscopic treatment should be considered for early gastric cancer (EGC) and gastric precancerous lesions. Endoscopic submucosal dissection (ESD) was developed for en bloc removal of a large gastric neoplasm and has been developed following improvements in electrical equipment for hemostasis and dissection and with advances in various knives, hemostatic forceps and endoscopic equipment. ESD is currently the treatment of choice for precancerous lesions or EGC showing mucosal invasion. Hemorrhage and perforation are major complications of ESD for EGC. We describe the complication of ESD procedures in gastric lesions for endoscopists who are relatively inexperienced in ESD and who may lack optimal access to ESD education and facilities. PMID- 21603035 TI - Assessment of gastroesophageal reflux disease by serodiagnosis of Helicobacter pylori-related chronic gastritis stage. AB - AIM: To evaluate the association of Helicobacter pylori (H.pylori)-related chronic gastritis stage with upper gastrointestinal symptoms and gastroesophageal reflux disease (GERD). METHODS: Subjects underwent upper gastrointestinal endoscopy, a questionnaire using a frequency scale for symptoms of GERD (FSSG), and measurements of serum H.pylori-antibody and pepsinogen (PG) levels. They were classified into the following 4 groups in terms of H.pylori-related chronic gastritis stage: Group A (n = 219), H.pylori(-)PG(-); Group B (n = 310), H.pylori(+)PG(-); Group C (n = 279), H.pylori(+)PG(+); and Group D (n = 17), H.pylori(-)PG(+). RESULTS: Reflux esophagitis occurred in 30.6% of Group A, 14.5% of Group B, 6.8% of Group C, and 0% of Group D (P < 0.001). Scores for acid reflux symptoms decreased significantly with chronic gastritis stage (from Group A to D) (P < 0.05), while scores for dysmotility symptoms did not differ significantly. The prevalence of non-erosive reflux disease (NERD) did not differ among groups. However, in subjects with GERD, the prevalence of NERD tended to increase with chronic gastritis stage (P = 0.081). CONCLUSION: Acid reflux symptoms and the prevalence of reflux esophagitis can be assessed by measuring both serum H.pylori-antibody and PG levels. PMID- 21603036 TI - Double balloon enteroscopy to retrieve an accidentally swallowed dental reamer deep in the jejunum. AB - Accidentally swallowed foreign objects are not uncommon but difficult to manage without complications. We describe the case of a 68 year old man who accidentally a swallowed sharp-pointed dental reamer that had reached deep in his jejunum. Double balloon enteroscopic retrieval was performed with polypectomy snare but the reamer was entangled in the wire loop of the snare and penetrated the jejunal wall. After releasing the reamer by pushing and pulling the snare for approximately 30 min, the reamer was retrieved with biopsy forceps. This is the first report of double balloon enteroscopic removal of a dental reamer. Furthermore, this is a novel case with regard to decision making in situations when sharp objects are swallowed. PMID- 21603037 TI - Trust in Nanotechnology? On Trust as Analytical Tool in Social Research on Emerging Technologies. AB - Trust has become an important aspect of evaluating the relationship between lay public and technology implementation. Experiences have shown that a focus on trust provides a richer understanding of reasons for backlashes of technology in society than a mere focus of public understanding of risks and science communication. Therefore, trust is also widely used as a key concept for understanding and predicting trust or distrust in emerging technologies. But whereas trust broadens the scope for understanding established technologies with well-defined questions and controversies, it easily fails to do so with emerging technologies, where there are no shared questions, a lack of public familiarity with the technology in question, and a restricted understanding amongst social researchers as to where distrust is likely to arise and how and under which form the technology will actually be implemented. Rather contrary, 'trust' might sometimes even direct social research into fixed structures that makes it even more difficult for social research to provide socially robust knowledge. This article therefore suggests that if trust is to maintain its important role in evaluating emerging technologies, the approach has to be widened and initially focus not on people's motivations for trust, but rather the object of trust it self, as to predicting how and where distrust might appear, how the object is established as an object of trust, and how it is established in relation with the public. PMID- 21603038 TI - Centre and Periphery of Nano-A Norwegian Context. AB - This work describes the nano field in Norway as currently emerging in the dynamics between two forms of nano research activities described along a centre periphery axis. 1) There are strategic research initiatives committed to redeem the envisioned potential of the field by means of social and material reorganisation of existing research activities. This activity is seen as central as it is one of our premises that the standard circulating nano vision implies such a work of reorganisation. The fact that nano is often taken as a paradigmatic example of the shift from Mode-1 to Mode-2 research, supports this assumption. 2) In parallel to this activity, a wide variety of research projects pursuing nano strategies are being funded. We regard such research activity as peripheral in so far as the activity is not marked by being committed to the circulating nano vision, as may often be the case. In the process of reorganising, this article argues, the research activity at the periphery provides a crucial arena for discussing and validating what is to be achieved through the work of reorganisation that takes place at the centre. Our analysis is informed by two Norwegian cases. We examine a major nano research initiative at a Norwegian university as a centre and a research project utilising nanoparticles in fish vaccines as a periphery. PMID- 21603039 TI - Conversations About Responsible Nanoresearch. AB - There is currently a strong focus on responsible research in relation to the development of nanoscience and nanotechnology. This study presents a series of conversations with nanoresearchers, with the 'European Commission recommendation on a code of conduct for responsible nanosciences and nanotechnologies research' (EC-CoC) as its point of departure. Six types of reactions to the document are developed, illustrating the diversity existing within the scientific community in responses towards this kind of new approaches to governance. Three broad notions of responsible nanoresearch are presented. The article concludes by arguing that while the suggestion put forward in the EC-CoC brings the concept of responsible nanoresearch a long way, one crucial element is to be wanted, namely responsible nanoresearch as increased awareness of moral choices. PMID- 21603040 TI - Mapping Uncertainties in the Upstream: The Case of PLGA Nanoparticles in Salmon Vaccines. AB - The diversity of nanotechnologies and of the governance challenges that their applications raise calls for exploration and learning across different cases. We present an Upstream Oversight Assessment (UOA) of expected benefits and potential harms of nanoparticles made of a synthetic polymer (PLGA) to improve vaccines for farmed salmon. Suggested by Jennifer Kuzma and colleagues, an UOA may help identify and prioritise research needs, and it may support evaluations of the adequacy of relevant existing regulatory frameworks. In this work, the UOA approach is modified and supported with elements from the uncertainty analysis framework developed by Warren Walker and colleagues. Empirically, we draw on relevant available published literature and insights generated in an ongoing nanoparticle salmon vaccine project, in which one of the authors participates. Nanotechnologies have not previously been encountered in the regulatory context of fish vaccines, which in part raises unique challenges due to prospective large scale vaccine use in semi-open aquatic systems. Strengthened through cooperation between ELSA and technology researchers we found the UOA useful for an early mapping of benefits and concerns, and for identifying areas in need of further research prior to a nanoparticle based salmon vaccine is developed and taken into use. We consider our approach to represent one among several complementing initiatives that seek to contribute to early stage evaluations of possible negative side effects, broadly conceived, in order to facilitate a more robust nanotechnology development. PMID- 21603041 TI - Trust as Glue in Nanotechnology Governance Networks. AB - This paper reflects on the change of relations among participants in nanotechnology governance through their participation in governance processes such as stakeholder dialogues. I show that policymaking in practice-that is, the practice of coming and working together in such stakeholder dialogues-has the potential for two-fold performative effects: it can contribute to the development of trust and mutual responsibility on the part of the involved actors, and it may bring about effects on the formation of boundaries of what is sayable and thinkable in nanotechnology governance. Three vignettes about the work of the German NanoKommission indicate the development of new relations of trust, recognition and mutual responsibility among actors. It is concluded that governance in practice can assemble new collectives in which relations of trust are the glue holding the complex structure together. While such a consensus-based progress may be favourable for smooth technology development, it can be considered problematic if evaluated against the ideals of deliberative democracy, which often form the premises on which public engagement is based. Stakeholder forums were set in place with the intention of including various actors, but this is Janus-faced: if a dialogue becomes encapsulated in new governance networks, new exclusions can arise. For example, a policing of which information is released to a wider audience can occur. PMID- 21603042 TI - Trustworthy Nanotechnology: Risk, Engagement and Responsibility. PMID- 21603043 TI - Precaution or Integrated Responsibility Approach to Nanovaccines in Fish Farming? A Critical Appraisal of the UNESCO Precautionary Principle. AB - Nanoparticles have multifaceted advantages in drug administration as vaccine delivery and hence hold promises for improving protection of farmed fish against diseases caused by pathogens. However, there are concerns that the benefits associated with distribution of nanoparticles may also be accompanied with risks to the environment and health. The complexity of the natural and social systems involved implies that the information acquired in quantified risk assessments may be inadequate for evidence-based decisions. One controversial strategy for dealing with this kind of uncertainty is the precautionary principle. A few years ago, an UNESCO expert group suggested a new approach for implementation of the principle. Here we compare the UNESCO principle with earlier versions and explore the advantages and disadvantages by employing the UNESCO version to the use of PLGA nanoparticles for delivery of vaccines in aquaculture. Finally, we discuss whether a combined scientific and ethical analysis that involves the concept of responsibility will enable approaches that can provide a supplement to the precautionary principle as basis for decision-making in areas of scientific uncertainty, such as the application of nanoparticles in the vaccination of farmed fish. PMID- 21603044 TI - Medical research and social media: Can wikis be used as a publishing platform in medicine? PMID- 21603045 TI - Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. PMID- 21603046 TI - Assuming our global responsibility: improving working conditions for health care workers globally. PMID- 21603047 TI - Comparison of tiered formularies and reference pricing policies: a systematic review. AB - OBJECTIVES: To synthesize methodologically comparable evidence from the published literature regarding the outcomes of tiered formularies and therapeutic reference pricing of prescription drugs. METHODS: We searched the following electronic databases: ABI/Inform, CINAHL, Clinical Evidence, Digital Dissertations & Theses, Evidence-Based Medicine Reviews (which incorporates ACP Journal Club, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, Database of Abstracts of Reviews of Effectiveness, Health Technology Assessments and NHS Economic Evaluation Database), EconLit, EMBASE, International Pharmaceutical Abstracts, MEDLINE, PAIS International and PAIS Archive, and the Web of Science. We also searched the reference lists of relevant articles and several grey literature sources. We sought English-language studies published from 1986 to 2007 that examined the effects of either therapeutic reference pricing or tiered formularies, reported on outcomes relevant to patient care and cost-effectiveness, and employed quantitative study designs that included concurrent or historical comparison groups. We abstracted and assessed potentially appropriate articles using a modified version of the data abstraction form developed by the Cochrane Effective Practice and Organisation of Care Group. RESULTS: From an initial list of 2964 citations, 12 citations (representing 11 studies) were deemed eligible for inclusion in our review: 3 studies (reported in 4 articles) of reference pricing and 8 studies of tiered formularies. The introduction of reference pricing was associated with reduced plan spending, switching to preferred medicines, reduced overall drug utilization and short-term increases in the use of physician services. Reference pricing was not associated with adverse health impacts. The introduction of tiered formularies was associated with reduced plan expenditures, greater patient costs and increased rates of non-compliance with prescribed drug therapy. From the data available, we were unable to examine the hypothesis that tiered formulary policies result in greater use of physician services and potentially worse health outcomes. CONCLUSION: The available evidence does not clearly differentiate between reference pricing and tiered formularies in terms of policy outcomes. Reference pricing appears to have a slight evidentiary advantage, given that patients' health outcomes under tiered formularies have not been well studied and that tiered formularies are associated with increased rates of medicine discontinuation. PMID- 21603048 TI - Medi-wiki worries? PMID- 21603050 TI - Prescription drug insurance and unmet need for health care: a cross-sectional analysis. AB - BACKGROUND: Despite Canada's universal health insurance coverage, many Canadians still report an unmet need for health care. I investigated whether not having prescription drug insurance increases the likelihood of reporting an unmet need for health care. I hypothesized that people without prescription drug insurance would be more likely than those with insurance to report an unmet health care need. METHODS: I included 31 630 people in Ontario 64 years of age or younger who had participated in the Canadian Community Health Survey Cycle 3.1. Multivariate logistic regression models were used to obtain an adjusted odds ratio (OR) for the association between having prescription drug insurance and reporting an unmet need for health care in the past 12 months, adjusting for age, sex, socio economic status, health status and having a regular medical doctor. The reasons for reporting an unmet need for care were stratified into reasons related or not related to prescription drug insurance. Three separate multivariate logistic regressions were performed to obtain an adjusted OR for the association between prescription drug insurance and unmet need based on the reasons for reporting unmet need. RESULTS: Not having prescription drug insurance that covers all or part of prescription medication costs increased the likelihood of reporting an unmet need for health care services (adjusted OR 1.27, 95% confidence interval [CI] 1.16-1.39). Not having such insurance significantly increased the likelihood of reporting an unmet need for health care for reasons that were related to prescription drug insurance (adjusted OR 2.21, 95% CI 1.80-2.71). This relation was not significant when the analysis was restricted to people who reported unmet need for health care for reasons that did not relate to prescription drug insurance (adjusted OR 1.12, 95% CI 1.00-1.23). CONCLUSIONS: These results suggest an association between a lack of prescription drug coverage and reporting an unmet need for health care. This association warrants further investigation. PMID- 21603049 TI - Health promotion activity in primary care: performance of models and associated factors. AB - BACKGROUND: Lifestyle behaviours have significant health and economic consequences. Primary care providers play an important role in promoting healthy behaviours. We compared the performance of primary care models in delivering health promotion and identified practice factors associated with its delivery. METHODS: Surveys were conducted in 137 randomly selected primary care practices in 4 primary care models in Ontario, Canada: 35 community health centres, 35 fee for-service practices, 35 family health networks and 32 health service organizations. A total of 4861 adult patients who were visiting their family practice participated in the study. Qualitative nested case studies were also conducted at 2 practices per model. A 7-item question was used to evaluate health promotion. The main outcome was whether at least 1 of the 7 health promotion items was discussed at the survey visit. Multilevel logistic regressions were used to compare the models and determine performance-related practice factors. RESULTS: The rate of health promotion was significantly higher in community health centres than in the other models (the unadjusted difference ranged between 8% and 13%). This finding persisted after controlling for patient and family physician profiles. Factors independently positively associated with health promotion were as follows: reason for visit (for a general checkup: adjusted odds ratio [AOR] 3.34, 95% confidence interval [CI] 2.81-3.97; for care for a chronic disease: AOR 2.03, 95% CI 1.69-2.43), patients having and seeing their own provider (for those not: AOR 0.58, 95% CI 0.43-0.78), number of nurses in the practice (AOR 1.07, 95% CI 1.02-1.12), percentage of female family physicians (AOR 1.38, 95% CI 1.15-1.66), smaller physician panel size (AOR 0.92, 95% CI 0.85 1.01) and longer booking interval (AOR 1.03, 95% CI 1.01-1.04). Providers in interdisciplinary practices viewed health promotion as an integral part of primary care, whereas other providers emphasized the role of relational continuity in effective health promotion. CONCLUSION: We have identified several attributes associated with health promotion delivery. These results may assist practice managers and policy-makers in modifying practice attributes to improve health promotion in primary care. PMID- 21603051 TI - The Comparison of Models of Primary Care in Ontario (COMP-PC) study: methodology of a multifaceted cross-sectional practice-based study. AB - BACKGROUND: Many industrialized nations have initiated reforms in the organization and delivery of primary care. In Ontario, Canada, salaried and capitation models have been introduced in an attempt to address the deficiencies of the traditional fee-for-service model. The Ontario setting therefore provides an opportunity to compare these funding models within a region that is largely homogeneous with respect to other factors that influence care delivery. We sought to compare the performance of the models across a broad array of dimensions and to understand the underlying practice factors associated with superior performance. We report on the methodology grounding this work. METHODS: Between 2004 and 2006 we conducted a cross-sectional mixed-methods study of the fee-for service model, including family health groups, family health networks, community health centres and health service organizations. The study was guided by a conceptual framework for primary care organizations. Performance across a large number of primary care attributes was evaluated through surveys and chart abstractions. Nested case studies generated qualitative provider and patient data from 2 sites per model along with insights from key informants and policy-makers familiar with all models. RESULTS: The study recruited 137 practices. We conducted 363 provider surveys and 5361 patient surveys, and we performed 4108 chart audits. We also conducted interviews with 40 family physicians, 6 nurse practitioners, 24 patients and 8 decision-makers. The practice recruitment rate was 45%; it was lowest in fee-for-service practices (23%) and in family health networks (37%). A comparison with all Ontario practices in these models using health administrative data demonstrated that our sample was adequately representative. The patient participation (82%) and survey scale completion (93%) rates were high. CONCLUSIONS: This article details our approach to performing a comprehensive evaluation of primary care models and may be a useful resource for researchers interested in primary care evaluation. PMID- 21603052 TI - Papanicolaou test utilization and frequency of screening opportunities among women diagnosed with cervical cancer. AB - BACKGROUND: Although the importance of Papanicolaou (Pap) smear test screening in reducing the incidence of cervical cancer is well established, in 1994-95 one in 4 women in Manitoba aged 18 to 69 years reported never having had a Pap test or not having had a Pap test in the last 3 years. The objectives of this study were to examine the screening history of women in Manitoba diagnosed with invasive cervical cancer and to explore whether opportunities for screening were missed. METHODS: In this case-control study women aged 18 years and older who resided in Manitoba and were diagnosed with invasive cervical cancer between 1989 and 2001 were each matched by age and area of residence to 5 controls, (N = 4009). Conditional logistic regression analyses were used to examine the association between Pap test utilization and the likelihood of diagnosis with invasive cervical cancer. Generalized linear models using the negative binomial distribution were used to assess the association between cancer status and rates of prior Pap testing and of opportunities to be screened. Logistic generalized estimating equation models were used for the analysis of physician characteristics. RESULTS: Forty-six percent of women in Manitoba diagnosed with invasive cervical cancer and 67% of the control group had received a Pap test in the 5 years before the case's diagnosis. After adjustment for age, income and residence, the rate of Pap testing was significantly higher in the control group (rate ratio [RR] = 1.57, 95% confidence interval [CI] 1.44-1.73). Conversely, when cervical cancer was the outcome, women who had not had Pap tests were more likely to be diagnosed with invasive cervical cancer (odds ratio [OR] = 2.77, 95% CI 2.30-3.30) than women who did have a Pap test. Although women diagnosed with invasive cervical cancer had fewer Pap tests, they had had as many opportunities to be screened as controls (RR = 1.04, 95% CI 0.96-1.12). Compared with urban family physicians, rural family physicians were less likely to provide Pap tests (OR = 0.68, 95% CI 0.58-0.80) and specialists were more likely to provide Pap tests (OR = 1.70, 95% CI 1.30-2.22). CONCLUSIONS: Women who were diagnosed with invasive cervical cancer in the province of Manitoba, Canada, had fewer Pap tests but the same frequency of opportunities to be screened as matched controls. These results reinforce the need to educate women about cervical cancer screening and the importance of receiving Pap tests. PMID- 21603053 TI - Synthesis of C1-C20 and C21-C40 fragments of tetrafibricin. AB - Efficient syntheses of suitably functionalized top and bottom fragments of tetrafibricin are described. The bottom fragment is prepared by two consecutive Kocienski-Julia couplings, while the top fragment synthesis features a dithiane alkylation and a Horner-Wadsworth-Emmons reaction. PMID- 21603054 TI - ON THE GENERALISED FANT EQUATION. AB - An analysis is made of the fluid-structure interactions involved in the production of voiced speech. It is usual to avoid time consuming numerical simulations of the aeroacoustics of the vocal tract and glottis by the introduction of Fant's 'reduced complexity' equation for the glottis volume velocity Q (G. Fant, Acoustic Theory of Speech Production, Mouton, The Hague 1960). A systematic derivation is given of Fant's equation based on the nominally exact equations of aerodynamic sound. This can be done with a degree of approximation that depends only on the accuracy with which the time-varying flow geometry and surface-acoustic boundary conditions can be specified, and replaces Fant's original 'lumped element' heuristic approach. The method determines all of the effective 'source terms' governing Q. It is illustrated by consideration of a simplified model of the vocal system involving a self-sustaining single-mass model of the vocal folds, that uses free streamline theory to account for surface friction and flow separation within the glottis. Identification is made of a new source term associated with the unsteady vocal fold drag produced by their oscillatory motion transverse to the mean flow. PMID- 21603055 TI - Revised Reinforcement Sensitivity Theory and Laboratory Assessment of BIS and BAS in Children. AB - There is considerable interest in Gray's reinforcement sensitivity theory. However, few measures of the behavioral approach (BAS) and inhibition systems (BIS) exist for children. Moreover, the theory was substantially revised a decade ago and measurement instruments are still largely based on the old theory. Our aim was to revise questionnaire and laboratory assessments of BIS and BAS for children. Performance on the Point Scoring Reaction Time Task for Children Revised (PSRTT-CR) conformed to theoretical expectations. Caregiver reports of BIS and BAS were associated with corresponding PSRTT-CR indices, suggesting cross method convergent and discriminant validity. There was convergence with physiological correlates of BAS, but not physiological correlates of BIS. Overall, our revised measures represent promising instruments of children's BIS and BAS. PMID- 21603056 TI - Stability of Phosphonic Self Assembled Monolayers (SAMs) on Cobalt Chromium (Co Cr) Alloy under Oxidative conditions. AB - Cobalt Chromium (Co-Cr) alloys has been widely used in the biomedical arena for cardiovascular, orthopedic and dental applications. Surface modification of the alloy allows us to tailor the interfacial properties to address critical challenges of Co-Cr alloy in medical applications. Self assembled monolayers (SAMs) of Octadecylphosphonic acid (ODPA) have been used to form thin films on the oxide layer of the Co-Cr alloy surface by solution deposition technique. The SAMs formed were investigated for their stability to oxidative conditions of ambient laboratory environment over periods of 1, 3, 7 and 14 days. The samples were then characterized for their stability using X-ray Photoelectron Spectroscopy (XPS), Atomic Force Microscopy (AFM) and Contact Angle Measurements. Detailed high energy XPS elemental scans confirmed the presence of the phosphonic monolayer after oxidative exposure which suggested that the SAMs were firmly attached to the oxide layer of Co-Cr alloy. AFM images gave topographical data of the surface and showed islands of SAMs on Co-Cr alloy surface, before and after SAM formation and also over the duration of the oxidative exposure. Contact angle measurements confirmed the hydrophobicity of the surface over 14 days. Thus the SAMs were found to be stable for the duration of the study. These SAMs could be subsequently tailored by modifying the terminal functional groups and could be used for various potential biomedical applications such as drug delivery, biocompatibility and tissue integration. PMID- 21603058 TI - A one-year longitudinal study of English and Japanese vowel production by Japanese adults and children in an English-speaking setting. AB - The effect of age of acquisition on first- and second-language vowel production was investigated. Eight English vowels were produced by Native Japanese (NJ) adults and children as well as by age-matched Native English (NE) adults and children. Productions were recorded shortly after the NJ participants' arrival in the USA and then one year later. In agreement with previous investigations [Aoyama, et al., J. Phon. 32, 233-250 (2004)], children were able to learn more, leading to higher accuracy than adults in a year's time. Based on the spectral quality and duration comparisons, NJ adults had more accurate production at Time 1, but showed no improvement over time. The NJ children's productions, however, showed significant differences from the NE children's for English "new" vowels /i/, /epsilon/, /alpha/, /v/ and /upsilon/ at Time 1, but produced all eight vowels in a native-like manner at Time 2. An examination of NJ speakers' productions of Japanese /i/, /a/, /u/ over time revealed significant changes for the NJ Child Group only. Japanese /i/ and /a/ showed changes in production that can be related to second language (L2) learning. The results suggest that L2 vowel production is affected importantly by age of acquisition and that there is a dynamic interaction, whereby the first and second language vowels affect each other. PMID- 21603059 TI - First-time DWI offenders are at risk of recidivating regardless of sanctions imposed. AB - OBJECTIVE: Research demonstrates that punitive approaches to DWI employed by the judiciary have failed to significantly reduce recidivism. However, little is known about the deterrent effects of administrative and diversion sanctions. We examine whether such sanctions deter first-time DWI offenders. METHODS: We grouped combinations of administrative, judicial, and diversion sanctions routinely employed in the state of Maryland for processing drivers arrested for DWI into one of eight mutually exclusive disposition sequences. We applied this classification to Maryland drivers who had been licensed in the state and had precisely one DWI on their record prior to January 1, 1999. We then used a proportional hazards model to estimate the probability of remaining free of a new DWI during a 6-year period (January 1, 1999 - December 31, 2004) as a function of the disposition of the index violation, and of selected factors that could affect that probability. RESULTS: Drivers with a prior DWI were at relatively high risk of recidivating regardless of how they were sanctioned. Those who received administrative and alternative sanctions had a risk of recidivating similar to that of drivers who were convicted. CONCLUSION: All dispositions sequences, not just convictions, indicate that first-time DWI offenders are at high risk of recidivating. PMID- 21603060 TI - Treatment Effects for Common Outcomes of Child Sexual Abuse: A Current Meta Analysis. AB - The present meta-analysis examined the effects of psychosocial treatments at reducing deleterious outcomes of sexual abuse. The meta-analysis included a total of 35 published and unpublished studies written in English, focusing on youth under the age of 18, and evaluating the effectiveness of treatments for the most common negative outcomes of sexual abuse: PTSD symptoms, externalizing problems, and internalizing problems. Results revealed medium effect sizes for PTSD symptoms, externalizing problems, and internalizing problems following treatment for sexual abuse. This study also examined the potential moderating effects of treatment (e.g., modality, duration, inclusion of caregiver) and participant (e.g., age, gender, ethnicity) characteristics. Results indicated that longer interventions were associated with greater treatment gains while group and individual treatments were equally effective. These findings shed new light on treatment effectiveness and provide useful information regarding the conditions under which treatment may be most effective. Future directions for research in this area are discussed. PMID- 21603061 TI - Longitudinal Modeling of Adolescents' Activity Involvement, Problem Peer Associations, and Youth Smoking. AB - Longitudinal associations among different types of organized activity involvement, problem peer associations, and cigarette smoking were examined in a sample of 1,040 adolescents (mean age = 15.62 at baseline, 16.89 at 15-month assessment, 17.59 at 24 months) enriched for smoking experimentation (83% had tried smoking). A structural equation model tested longitudinal paths between three categories of involvement (team sports, school clubs and activities, and religious activities, measured at baseline and 15 months), problem peer associations (baseline and 15 months), and cigarette smoking behavior (baseline and 24 months). Multi-group analyses indicated pathways differed by type of activity and adolescent gender. Boys' baseline team sports and religious involvement predicted lower levels of smoking at 24 months via continued activity involvement at 15 months. Girls' involvement in school clubs and activities and religious activities indirectly predicted lower levels of smoking at 24 months via reduced exposure to problem peers at 15 months. PMID- 21603062 TI - The Impact of Children's Social Adjustment on Academic Outcomes. AB - This study tested whether social adjustment added to the prediction of academic outcomes above and beyond prior academic functioning. School records and peer-, teacher-, and self-report measures were collected for 1,255 third grade children in the fall and spring of the school year. Social acceptance by and aggression with peers were included as measures of social adjustment. Academic outcomes included math and reading GPA, classroom behavior, academic self-esteem, and absenteeism. As expected, support for the causal model was found where both forms of social adjustment contributed independently to the prediction of each area of academic adjustment. Gender differences in the patterns of results were present, particularly for the impact of aggression on academic adjustment. Discussion focuses on the implications for social-emotional literacy programs to prevent negative academic outcomes. PMID- 21603057 TI - Mammalian diseases of phosphatidylinositol transfer proteins and their homologs. AB - Inositol and phosphoinositide signaling pathways represent major regulatory systems in eukaryotes. The physiological importance of these pathways is amply demonstrated by the variety of diseases that involve derangements in individual steps in inositide and phosphoinositide production and degradation. These diseases include numerous cancers, lipodystrophies and neurological syndromes. Phosphatidylinositol transfer proteins (PITPs) are emerging as fascinating regulators of phosphoinositide metabolism. Recent advances identify PITPs (and PITP-like proteins) to be coincidence detectors, which spatially and temporally coordinate the activities of diverse aspects of the cellular lipid metabolome with phosphoinositide signaling. These insights are providing new ideas regarding mechanisms of inherited mammalian diseases associated with derangements in the activities of PITPs and PITP-like proteins. PMID- 21603063 TI - Alcohol, Drug and Sexual Risk Behavior Correlates of Recent Transactional Sex Among Female Black South African Drug Users. AB - Transactional sex among black South African women has become a mode of economic survival putting them at higher risk for HIV and other infectious disease. In order to inform HIV interventions, drug and sexual risk behavior correlates of recent transactional sex among a descriptive epidemiological, cross-sectional sample of 189, black, South African women in Pretoria were examined using log binomial regression. Prevalence of HIV seropositivity was extremely high among non-transactional sex workers (47.1%) and transactional sex workers (54.6%), albeit not significantly different. Adjusted regression results indicated that the probability of transactional sex was greater for drug using women who tested positive for cocaine use (Adjusted Prevalence Ratio (APR)=1.3, 95% CI=1.1, 1.5) and knew of anyone who died of AIDS (APR =1.5, 95% CI 1.1, 2.1). The probability of transactional sex was lower for female drug users who reported greater education (APR =0.6, 95% CI= 0.4, 0.8), condom use in their first sexual encounter (APR =0.7, 95% CI=0.6, 1.0) or reported a recent steady sexual partnership (APR =0.8, 95% CI=0.7, 0.9). Drug use-related interventions for female transactional sex workers may need to focus on methods for the reduction of not only drug use, especially cocaine use, but also the reduction of sexual risk behaviors. PMID- 21603065 TI - Optimizing Gold Nanoparticle Cluster Configurations (n <= 7) for Array Applications. AB - Nanoparticle cluster arrays (NCAs) are novel electromagnetic materials whose properties depend on the size and shape of the constituent nanoparticle clusters. A rational design of NCAs with defined optical properties requires a thorough understanding of the geometry dependent optical response of the building blocks. Herein, we systematically investigate the near- and far-field responses of clusters of closely packed 60 nm gold nanoparticles (n <= 7) as a function of size and cluster geometry through a combination of experimental spectroscopy and generalized Mie Theory calculations. From all of the investigated cluster configurations, nanoparticle trimers with D(3h) geometry and heptamers in D(6h) geometry stand out due to their polarization insensitive responses and high electric (E-) field intensity enhancement, making them building blocks of choice in this size range. The near-field intensity maximum of the D(6h) heptamer is red shifted with regard to the D(3h) trimer by 125 nm, which confirms the possibility of a rational tuning of the near-field response in NCAs through the choice of the constituent nanoparticle clusters. For the nanoparticle trimer we investigate the influence of the cluster geometry on the optical response in detail and map near- and far-field spectra associated with the transition of the cluster configuration from D(3h) into D(infinityh). PMID- 21603064 TI - Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block. AB - Most prostate cancers (PCa) are critically reliant on functional androgen receptor (AR) signaling. At its onset, PCa is androgen-dependent and although temporarily halted by surgically or pharmacologically blocking the AR (androgen ablation), the disease ultimately recurs as an aggressive, fatal castration resistant prostate cancer (CRPC). FDA-approved treatments like docetaxel, a chemotherapeutic agent, and Provenge, a cancer vaccine, extend survival by a scant 3 and 4 months, respectively. It is clear that more effective drugs targeting CRPC are urgently needed. The ErbB family (EGFR/ErbB1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) of receptor tyrosine kinases (RTKs) have long been implicated in PCa initiation and progression, but inhibitors of ErbB1 and ErbB2 (prototypic family members) fared poorly in PCa clinical trials. Recent research suggests that another family member ErbB3 abets emergence of the castration resistant phenotype. Considerable efforts are being directed towards understanding ErbB3-mediated molecular mechanisms of castration resistance and searching for novel ways of inhibiting ErbB3 activity via rational drug design. Antibody-based therapy that prevents ligand binding to ErbB3 appears promising and fully-humanized antibodies that inhibit ligand-induced phosphorylation of ErbB3 are currently in early development. Small molecule tyrosine kinase inhibitors are also being vigorously pursued, as are siRNA-based approaches and combination treatment strategies- the simultaneous suppression of ErbB3 and its signaling partners or downstream effectors - with the primary purpose of undermining the resiliency of ErbB3-mediated signal transduction. This review summarizes the existing literature and reinforces the importance of ErbB3 as a therapeutic target in the clinical management of prostate cancer. PMID- 21603066 TI - Solution of the nonlinear elasticity imaging inverse problem: The incompressible case. AB - We have recently developed and tested an efficient algorithm for solving the nonlinear inverse elasticity problem for a compressible hyperelastic material. The data for this problem are the quasi-static deformation fields within the solid measured at two distinct overall strain levels. The main ingredients of our algorithm are a gradient based quasi-Newton minimization strategy, the use of adjoint equations and a novel strategy for continuation in the material parameters. In this paper we present several extensions to this algorithm. First, we extend it to incompressible media thereby extending its applicability to tissues which are nearly incompressible under slow deformation. We achieve this by solving the forward problem using a residual-based, stabilized, mixed finite element formulation which circumvents the Ladyzenskaya-Babuska-Brezzi condition. Second, we demonstrate how the recovery of the spatial distribution of the nonlinear parameter can be improved either by preconditioning the system of equations for the material parameters, or by splitting the problem into two distinct steps. Finally, we present a new strain energy density function with an exponential stress-strain behavior that yields a deviatoric stress tensor, thereby simplifying the interpretation of pressure when compared with other exponential functions. We test the overall approach by solving for the spatial distribution of material parameters from noisy, synthetic deformation fields. PMID- 21603067 TI - Bioenergetics, mitochondria, and cardiac myocyte differentiation. AB - Cardiac metabolism is finely tuned, and disruption of myocardial bioenergetics can be clinically devastating. Many cardiomyopathies that present early in life are due to disruption of the maturation of these metabolic pathways. However, this bioenergetic maturation begins well before birth, when the embryonic heart is first beginning to beat, and continues into the mature animal. Thus, the changes in energy production seen after birth are actually part of a continuum that coincides with the structural and functional changes that occur as the cardiac myocyte differentiates and the heart undergoes morphogenesis. Therefore, although bioenergetics and mitochondrial biology have not been studied in great detail in the developing heart, bioenergetic maturation should be considered an important component of normal myocyte differentiation.Although events occurring after birth will be discussed, this review will focus on the changes in bioenergetics and mitochondrial biology that coincide with myocyte differentiation and cardiac morphogenesis. The relationship of these changes to the etiology and presentation of cardiomyopathies will be used as a starting point for this discussion. Then, after reviewing cardiac development and mitochondrial biology, the published data on bioenergetics and mitochondrial structure and function in the developing heart will be presented. Finally, the case will be made that mitochondria may be critical regulators of cardiac myocyte differentiation and cardiac development. PMID- 21603068 TI - A 20-channel coil for improved magnetic resonance imaging of the optic nerve. PMID- 21603069 TI - Multi-technique Characterization of Self-assembled Carboxylic Acid Terminated Alkanethiol Monolayers on Nanoparticle and Flat Gold Surfaces. AB - Gold nanoparticles (AuNPs) with 14, 25 and 40nm diameters were functionalized with different chain length (C6, C8, C11 and C16) carboxylic acid terminated alkanethiol self-assembled monolayers (COOH-SAMs). X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were used to examine the changes in surface chemistry as both AuNP diameter and SAM chain length were varied. COOH-SAMs on flat gold surfaces were also examined and compared to the COOH-SAM on AuNP results. For a given surface, as the COOH SAM chain length increased the XPS C/Au atomic ratio increased due to an increased number of carbon atoms per molecule in the overlayer and an increased attenuation of the Au substrate signal. For the C16 COOH-SAMs, as the size of AuNPs decreased the XPS C/Au atomic ratio and the apparent SAM thickness increased due to the increased curvature of the smaller AuNPs. The C16 COOH-SAMs on the flat Au had the lowest XPS C/Au atomic ratio and apparent SAM thickness of any C16 COOH-SAM covered Au surface. The effective take-off angles of the COOH SAMs were also calculated by comparing the apparent thickness of COOH-SAMs with literature values. The effective take-off angle for C16 COOH-SAM on 14nm, 25nm and 40nm diameter AuNPs and flat Au were found to be 57 degrees , 53 degrees , 51 degrees and 39 degrees , respectively, for data acquired in a mode that collects a wide range of photoelectron take-off angles. The effective take-off angle for C16 COOH-SAM on 14nm AuNP and flat Au decreased to 52 degrees and 0 degrees , respectively, for data acquired in a mode that collects a narrow range of photoelectron take-off angles. The ToF-SIMS results showed similar changes in surface chemistry with COOH-SAM chain length and AuNP size. For example, the ratio of the sum of the C(1-4)H(x)O(y) positive ion intensities to the sum of the Au-containing positive ions intensities increased with decreasing AuNP size and increasing COOH-SAM chain length. Fourier transform IR spectroscopy in the attenuated total reflectance mode (FTIR-ATR) was used to characterize the crystallinity of the COOH-SAMs. The CH(2) stretching frequencies decreased with increasing COOH-SAM chain length on flat Au. The C16 COOH-SAM on the 14nm AuNPs exhibited a crystalline-like CH(2) stretching frequency. The size, size distribution, shapes and solution stability of AuNPs were investigated with transmission electron microscopy (TEM) and UV/VIS spectroscopy. As the average diameter of the AuNPs decreased the size distribution became narrower and the shape became more spherical. PMID- 21603070 TI - Probing the Chemical Stability of Mixed Ferrites: Implications for MR Contrast Agent Design. AB - Nanomaterials with mixed composition, in particular magnetic spinel ferrites, are emerging as efficient contrast agents for magnetic resonance imaging (MRI). Many factors, including size, composition, atomic structure, and surface properties are crucial in the design of such nanoparticle-based probes due to their influence on the magnetic properties. Silica-coated iron oxide (IO-SiO(2)) and cobalt ferrite (CoIO-SiO(2)) nanoparticles were synthesized using standard high temperature thermal decomposition and base-catalyzed water-in-oil microemulsion techniques. Under neutral aqueous conditions, it was found that 50-75% of the cobalt content in the CoIO-SiO(2) nanoparticles leached out of the core structure. Leaching caused a 7.2-fold increase in longitudinal relaxivity and an increase in the saturation magnetization from ~48 emu/g core to ~65 emu/g core. X ray absorption fine structure studies confirmed that the atomic structure of the ferrite core was altered following leaching, while TEM and DLS confirmed that the morphology and size of the nanoparticle remained unchanged. The CoIO-SiO(2) nanoparticles converted from a partially inverted spinel cation arrangement (unleached state) to an inverse spinel arrangement (leached state). The control IO-SiO(2) nanoparticles remained stable with no change in structure and negligible changes in magnetic behavior. This detailed analysis highlights how important understanding the properties of nanomaterials is in the development of reliable agents for diagnostic and therapeutic applications. PMID- 21603071 TI - Spatial Memory Performance Associated with Measures of Immune Function in Elderly Female Rhesus Macaques. AB - We recently reported that in aged female rhesus macaques, spatial learning and memory correlates with circadian sleep-wake measures and hippocampal muscarinic type 1 (M(1)) receptor binding. To investigate if spatial memory also correlates with measures of immune function, we now assessed the magnitude of the adaptive immune response to vaccination in the same old female rhesus macaques. Cognitively characterized animals were classified as good spatial performers (GSP) or poor spatial performers (PSP) based on performance in the Spatial Foodport maze. The GSP group had higher frequency of CD8, but not CD4, interferon gamma (IFN-gamma) producing cells following vaccination compared to the PSP group, suggesting a stronger CD8 T cell response in the GSP group. In addition, the number of CD-8 IFN-gamma positive cells correlated with measures of sleep quality. Interestingly, the PSP group had a significantly higher antibody titer compared to the GSP group, and antibody titer negatively correlated with day-time activity. Thus, in aged female rhesus macaques, superior cognitive performance is correlated with a more robust CD8 T cell response but a reduced antibody response to vaccination. PMID- 21603073 TI - Genomic analysis of high altitude adaptation: innovations and implications. PMID- 21603074 TI - Maternity Leave in Taiwan. AB - Using the first nationally representative birth cohort study in Taiwan, this paper examines the role that maternity leave policy in Taiwan plays in the timing of mothers returning to work after giving birth, as well as the extent to which this timing is linked to the amount of time mothers spend with their children and their use of breast milk versus formula. We found that the time when mothers returned to work coincided with the duration of guaranteed leave. In particular, mothers with a labor pension plan resumed work significantly earlier than mothers with no pension plan, and mothers with no pension plan returned to work significantly later than those with pension plans. The short leave of absence guaranteed under existing policies translated into mothers spending less time with their children and being more likely to exclusively use formula by 6 months after birth. In contrast, mothers who resumed work later than 6 months after birth were more likely to have not worked before birth or to have quit their jobs during pregnancy. Implications and recommendations for parental leave policy in Taiwan are discussed. PMID- 21603075 TI - Ensemble and Single Molecule Studies on the Use of Metallic Nanostructures to Enhance the Intrinsic Emission of Enzyme Cofactors. AB - We present a strategy for enhancing the intrinsic emission of the enzyme cofactors flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) and nicotinamide adenine dinucleotide (NADH). Ensemble studies show that silver island films (SIFs) are the optimal metal enhanced fluorescence (MEF) substrates for flavins and gave emission enhancements of over 10-fold for both FAD and FMN. A reduction in the lifetime of FAD and FMN on SIFs was also observed. Thermally evaporated aluminum films on quartz slides were found to be the optimal MEF substrate for NADH and gave a 5-fold increase in the emission intensity of NADH. We present finite-difference time-domain (FDTD) calculations that compute the enhancement in the radiated power emitting from an excited state dipole emitting in the wavelength range of NADH in close proximity to an aluminum nanoparticle, and a dipole emitting in the emission wavelength of flavins next to a silver nanoparticle. These calculations confirm that aluminum serves as the optimal MEF substrate for NADH and silver was the optimal MEF substrate for flavins. This is because the plasmon resonance properties of aluminum lie in the UV-blue regime and that of silver lie in the visible region. We also present the results of single molecule studies on FMN which show SIFs can both significantly enhance the intrinsic emission from single FMN molecules, significantly reduce their lifetimes and also significantly reduce FMN blinking. This is the first report of the observation of MEF from cofactors both at the ensemble and single molecule level. We hope this study will serve as a platform to encourage the future use of metallic nanostructures to study cofactors using their intrinsic fluorescence to directly monitor enzyme binding reactions without the need of extrinsic labeling of the molecules. PMID- 21603076 TI - Using Individual-oriented Relationship Education to Prevent Family Violence. AB - Relationship aggression has negative effects on adults, children, and on our society that cannot be overstated. In this paper, we first outline the benefits of using relationship education programs that are delivered to individuals (rather than couples) in preventing relationship aggression and co-occurring relationship aggression toward children. Next, we briefly review one such program, Within My Reach, and related research on its effectiveness in preventing relationship aggression. Implications of this research for future research, clinical practice, and policy are also discussed. PMID- 21603077 TI - Repetitive mechanical stretch increases extracellular collagenase activity in vaginal fibroblasts. AB - OBJECTIVES: The objectives were 1) to determine whether human vaginal fibroblasts are mechanosensitive and 2) to study the impact of mechanical stretch on these cells in the presence and absence of hormones. METHODS: Fibroblasts obtained from biopsies of full thickness vagina of 3 women were cyclically biaxially stretched at a magnitude of 8 and 16% for 72 hours with or without 17-beta-estradiol plus progesterone. Culture media was collected and total collagenase activity was measured in duplicate using a fluorogenic substrate degradation assay. Data were analyzed at the 0.05 level of significance using Student t-test. RESULTS: Cells remained 90% viable throughout the experiments. Relative to the controls, hormonal treatment alone decreased collagenase activity (P=0.008). In the presence of mechanical stretch and in the absence of hormones, collagenase activity was increased (8% elongation, P=0.04; 16% elongation, P=0.001, respectively). The increase in collagenase activity was linearly correlated with magnitude (P<0.001). In the presence of hormones, the increase in enzyme activity by mechanical stretch was suppressed to baseline control levels (P=0.46). There was no difference in suppression by hormones by magnitude (P=0.48). CONCLUSIONS: Vaginal connective tissue fibroblasts are mechanosensitive with increased collagenase activity in the presence of stretch. This degradative behavior is inhibited in the presence of hormones. The data provide a mechanism by which events that induce vaginal stretch may lead to progression of pelvic organ prolapse, particularly, in the absence of hormones. Further studies are needed to determine whether these events lead to tissue with inferior mechanical properties. PMID- 21603078 TI - An insult-inducible vector system activated by hypoxia and oxidative stress for neuronal gene therapy. AB - Gene therapy has demonstrated the protective potential of a variety of genes against stroke. However, conventional gene therapy vectors are limited due to the inability to temporally control their expression, which can sometimes lead to deleterious side effects. Thus, an inducible vector that can be temporally controlled and activated by the insult itself would be advantageous. Using hypoxia responsive elements (HRE) and antioxidant responsive elements (ARE), we have constructed an insult-inducible vector activated by hypoxia and reactive oxygen species (ROS). In COS7 cells, the inducible ARE-HRE-luciferase vectors are highly activated by oxygen deprivation, hydrogen peroxide treatment, and the ROS induced transcription factor NF-E2-related factor 2 (Nrf2). Using a defective herpes virus, the neuroprotective potential of this inducible vector was tested by over-expressing the transcription factor Nrf2. In primary cortical cultures, expression of the inducible ARE-HRE-Nrf2 protects against oxygen glucose deprivation, similar to that afforded by the constitutively expressed Nrf2. This ARE+HRE vector system is advantageous in that it allows the expression of a transgene to be activated not only during hypoxia but also maintained after reperfusion, thus prolonging the transgene expression during an ischemic insult. This insult-inducible vector system will be a valuable gene therapy tool for activating therapeutic/protective genes in cerebrovascular diseases. PMID- 21603079 TI - Phase I Clinical Trials in Patients >=80. AB - Phase I clinical trials play a crucial role in development of therapeutics for cancer patients. During phase I clinical trials common toxicities are delineated, dose limiting toxicities (DLT) are determined and a dose for phase II studies is recommended. However, reviews of the phase I population indicate a younger group of participants with a median age of 50-55. No data exists on the performance of octogenarians on phase I trials. Concerns for enrollment of this patient population, relates to presence of comorbidities and possibly altered pharmacokinetics in the setting of unknown potential toxicities. We present herein the largest review of octogenarians on phase I trials. Twenty-two octogenarian patients with a median age of 83 were enrolled on phase I clinical trials. More than 50% of them were chemotherapy-naive most likely indicative of the fact that treating physicians believed standard therapy to be potentially toxic to this population. These 22 patients were otherwise matched in terms of performance status and other parameters to a control group of participants < 80. This includes a similar number of cycles administered. Patients >=80 had a 3 fold higher rate of achieving DLT (p=0.06) compared to the control group enrolled at the same dose level. The toxicities observed include cardiovascular, gastrointestinal and infectious complications. Three patients were enrolled on molecular targeted treatments with no significant toxicities. We conclude that enrollment of patients >=80 on phase I trials of chemotherapy agents is most likely associated with higher risk of DLT. PMID- 21603080 TI - Mitochondrial dysfunction during sepsis: still more questions than answers. PMID- 21603082 TI - TCAT Analysis of Capillary Pressure in Non-equilibrium, Two-fluid-phase, Porous Medium Systems. AB - Standard models of flow of two immiscible fluids in a porous medium make use of an expression for the dependence of capillary pressure on the saturation of a fluid phase. Data to support the mathematical expression is most often obtained through a sequence of equilibrium experiments. In addition to such expressions being hysteretic, recent experimental and theoretical studies have suggested that the equilibrium functional forms obtained may be inadequate for modeling dynamic systems. This situation has led to efforts to express relaxation of a system to an equilibrium capillary pressure in relation to the rate of change of saturation. Here, based on insights gained from the thermodynamically constrained averaging theory (TCAT) we propose that dynamic processes are related to changes in interfacial area between phases as well as saturation. A more complete formulation of capillary pressure dynamics is presented leading to an equation that is suitable for experimental study. PMID- 21603081 TI - Novel Methods of Enhanced Retention in and Rapid, Targeted Release from Liposomes. AB - Liposomes are single bilayer capsules with distinct interior compartments in which hydrophilic drugs, imaging agents, diagnostics, etc. can be sequestered from the exterior environment. The polar parts of the individual lipids face the water compartments, while the hydrophobic parts of the lipid provide a barrier in which hydrophilic or charged molecules are poorly soluble. Hydrophobic molecules can be dissolved within the bilayer. The bilayers are typically from 3 - 6 nm thick and the liposome can range from about 50 nm - 50 microns in diameter. The question asked in this review is if any one bilayer, regardless of its composition, can provide the extended drug retention, long lifetime in the circulation, active targeting to specific tissues and rapid and controllable drug release at the site of interest. As an alternative, we review methods of self assembling multicompartment lipid structures that provide enhanced drug retention in physiological environments. We also review methods of externally targeting and triggering drug release via the near infrared heating of gold nanoshells attached to or encapsulated within bilayer vesicles. PMID- 21603084 TI - SOLVING PDES IN COMPLEX GEOMETRIES: A DIFFUSE DOMAIN APPROACH. AB - We extend previous work and present a general approach for solving partial differential equations in complex, stationary, or moving geometries with Dirichlet, Neumann, and Robin boundary conditions. Using an implicit representation of the geometry through an auxilliary phase field function, which replaces the sharp boundary of the domain with a diffuse layer (e.g. diffuse domain), the equation is reformulated on a larger regular domain. The resulting partial differential equation is of the same order as the original equation, with additional lower order terms to approximate the boundary conditions. The reformulated equation can be solved by standard numerical techniques. We use the method of matched asymptotic expansions to show that solutions of the re formulated equations converge to those of the original equations. We provide numerical simulations which confirm this analysis. We also present applications of the method to growing domains and complex three-dimensional structures and we discuss applications to cell biology and heteroepitaxy. PMID- 21603083 TI - Consistent DNA hypermethylation patterns in laryngeal papillomas. AB - INTRODUCTION: This study examined the contribution of promoter hypermethylation to the pathogenesis of respiratory papillomatosis (RP), including recurrences (RRP) and progression to squamous cell carcinoma (SSC). MATERIALS AND METHODS: A retrospective cohort of 25 laryngeal papilloma cases included 21 RRP, two of which progressed to SCC. Aberrant methylation status was determined using the multi-gene (22 tumor suppressor genes) methylation-specific multiplex ligation dependent probe amplification assay and confirmed using methylation specific PCR. RESULTS: Twenty genes had altered DNA methylation in 22 of 25 cases. Aberrant methylation of CDKN2B and TIMP3 was most frequent. Promoter hypermethylation of BRCA2, APC, CDKN2A and CDKN2B was detected in 2 RRP cases with subsequent progression to SCC. Of the 25 cases, 22 were positive for HPV-6, 2 for HPV-11 and 1 for HPV-16 and 33. CONCLUSIONS: Consistent aberrant methylation of multiple tumor suppressor genes contributes to the pathogenesis of laryngeal papillomas. Persistent aberrant DNA methylation events in 2 RRP cases that progressed to cancer indicate an epigenetic monoclonal progression continuum to SCC. PMID- 21603085 TI - Decisions and Dilemmas in Everyday Life: Daily Use of Wheelchairs by Individuals with Spinal Cord Injury and the Impact on Pressure Ulcer Risk. AB - Individuals with spinal cord injury (SCI) use wheelchairs for mobility and for full participation in their daily activities. The use of wheelchairs, however, can increase the risk of pressure ulcers. This study focused on wheelchair users' perceptions of the interplay between their wheeled mobility and the development of pressure ulcers by performing a secondary analysis of data gathered during a 2 year ethnographic study of 20 community-dwelling adults with SCI. Data from a subset of these individuals are described; each of these stories contains a pressure ulcer risk episode related to wheeled mobility or cushion use. Identified risk episodes were associated with wheelchair selection, wheelchair adjustment, habituation to new equipment, lifestyle choices, and challenging life contexts. Examples highlighted the crucial relationship between individuals' minute-to-minute decision-making and pressure ulcer risk. PMID- 21603086 TI - A Wire Crossed-Loop-Resonator for Rapid Scan EPR. AB - A crossed-loop (orthogonal mode) resonator (CLR) was constructed of fine wire to achieve design goals for rapid scan in vivo EPR imaging at VHF frequencies (in practice, near 250 MHz). This application requires the resonator to have a very open design to facilitate access to the animal for physiological support during the image acquisition. The rapid scan experiment uses large amplitude magnetic field scans, and sufficiently large resonator and detection bandwidths to record the rapidly-changing signal response. Rapid-scan EPR is sensitive to RF/microwave source noise and to baseline changes that are coherent with the field scan. The sensitivity to source noise is a primary incentive for using a CLR to isolate the detected signal from the RF source noise. Isolation from source noise of 44 and 47 dB was achieved in two resonator designs. Prior results showed that eddy currents contribute to background problems in rapid scan EPR, so the CLR design had to minimize conducting metal components. Using fine (AWG 38) wire for the resonators decreased eddy currents and lowered the resonator Q, thus providing larger resonator bandwidth. Mechanical resonances at specific scan frequencies are a major contributor to rapid scan backgrounds. PMID- 21603087 TI - COSMIC INHERITANCE RULES: IMPLICATIONS FOR HEALTH CARE AND SCIENCE. AB - Countering the trend in specialization, we advocate the trans-disciplinary monitoring of blood pressure and heart rate for signatures of environmental cyclic and other variabilities in space as well as terrestrial weather on the one hand, and for surveillance of personal and societal health on the other hand. New rules (if confirmed novel laws) emerge as we recognize our inheritance from the cosmos of cycles that constitute and characterize life and align them with inheritance from parents. In so doing, we happen to follow the endeavors of Gregor Mendel, who recognized the segregation and independent assortment of what became known as genes. Circadians, rhythms with periods, tau, between 20 and 28 hours, and cycles with frequencies that are higher (ultradian) or lower (infradian) than circadian, are genetically anchored. An accumulating long list of very important but aeolian (nonstationary) infradian cycles, characterizing the incidence patterns of sudden cardiac death, suicide and terrorism, with drastically different taus, constitutes the nonphotic (corpuscular emission from the sun, heliogeomagnetics, ultraviolet flux, gravitation) Cornelissen-series. PMID- 21603088 TI - Achieving High Performance with FPGA-Based Computing. AB - Numerous application areas, including bioinformatics and computational biology, demand increasing amounts of processing capability. In many cases, the computation cores and data types are suited to field-programmable gate arrays. The challenge is identifying the design techniques that can extract high performance potential from the FPGA fabric. PMID- 21603089 TI - Decision-oriented multi-outcome modeling for anesthesia patients. AB - Anesthesia drugs have impact on multiple outcomes of an anesthesia patient. Most typical outcomes include anesthesia depth, blood pressures, heart rates, etc. Traditional diagnosis and control in anesthesia focus on a one-drug-one-outcome scenario. This paper studies the problem of real-time modeling for monitoring, diagnosing, and predicting multiple outcomes of anesthesia patients. It is shown that consideration of multiple outcomes is necessary and beneficial for anesthesia managements. Due to limited real-time data, real-time modeling in multi-outcome modeling requires low-complexity model strucrtures. This paper introduces a method of decision-oriented modeling that significantly reduces the complexity of the problem. The method employs simplified and combined model functions in a Wiener structure to contain model complexity. The ideas of drug impact prediction and reachable sets are introduced for utility of the models in diagnosis, outcome prediction, and decision assistance. Clinical data are used to evaluate the effectiveness of the method. PMID- 21603090 TI - GlycomicsDB - A Data Integration Platform for Glycans and their Strucutres. AB - Glycomics is a discipline of biology that deals with the structure and function of glycans (or carbohydrates). Analytical techniques such as mass spectrometry (MS) and nuclear magnetic resonance (NMR) are having a significant impact on the field of glycomics. However, effective progress in glycomics research requires collaboration between laboratories to share experimental data, structural information of glycans, and simulation results. Herein we report the development of a web-based data management system that can incorporate large volumes of data from disparate sources and organize them into a uniform format for users to store and access. This system enables participating laboratories to set up a shared data repository which members of interdisciplinary teams can access. The system is able to manage and share raw MS data and structural information of glycans.The database is available at http://www.glycomics.bcf.ku.edu. PMID- 21603091 TI - Model-based prediction of the patient-specific response to adrenaline. AB - A model for the cardiovascular and circulatory systems has previously been validated in simulated cardiac and circulatory disease states. It has also been shown to accurately capture the main hemodynamic trends in porcine models of pulmonary embolism and PEEP (positive end-expiratory pressure) titrations at different volemic levels. In this research, the existing model and parameter identification process are used to study the effect of different adrenaline doses in healthy and critically ill patient populations, and to develop a means of predicting the hemodynamic response to adrenaline. The hemodynamic effects on arterial blood pressures and stroke volume (cardiac index) are simulated in the model and adrenaline-specific parameters are identified. The dose dependent changes in these parameters are then related to adrenaline dose using data from studies published in the literature. These relationships are then used to predict the future, patient-specific response to a change in dose or over time periods from 1-12 hours. The results are compared to data from 3 published adrenaline dosing studies comprising a total of 37 data sets. Absolute percentage errors for the identified model are within 10% when re-simulated and compared to clinical data for all cases. All identified parameter trends match clinically expected changes. Absolute percentage errors for the predicted hemodynamic responses (N=15) are also within 10% when re-simulated and compared to clinical data. Clinically accurate prediction of the effect of inotropic circulatory support drugs, such as adrenaline, offers significant potential for this type of model based application. Overall, this work represents a further clinical, proof of concept, of the underlying fundamental mathematical model, methods and approach, as well as providing a template for using the model in clinical titration of adrenaline in a decision support role in critical care. They are thus a further justification in support of upcoming human clinical trials to validate this model. PMID- 21603092 TI - Synthesis and structural characterization of rhenium(I) tricarbonyl complexes with the bidentate ligands o-(diphenylphosphino)benzaldehyde (P?O) and o [(diphenylphosphino)benzylidene]analine (P?N). AB - A series of rhenium(I) tricarbonyl complexes with bidentate P,O donor ligand o (diphenylphosphino)benzaldehyde (P?O) and its Schiff base P,N donor ligand o [diphenylphosphino)benzylidene]analine (P?N) have been synthesized and structurally characterized. All the complexes of the type [ReX(CO)(3)(LL)] (where LL = P?O, P?N) reveal a distorted octahedral structure with the three carbonyl ligands arranged in the facial fashion. Crystal data for 1, C(22)H(15)ClO(4)PRe.1/2C(6)H(14): triclinic, P1, a=8.7430(4), b=9.5767(4), c=13.9449(6) A, alpha=93.651(1), beta=101.265(1), gamma=93.048(1); V=1140.20(9) A(3), Z=2.2, C(22)H(15)BrO(4)Pre: monoclinic, C2/c, a=31.6800(16), b=8.8880(4), c=18.4517(9) A, beta=124.990(1); V=4256.4(4) A(3), Z=8. 3, C(28)H(20)ClNO(3)Pre: monoclinic, C2/c, a=22.675(4), b=8.803(2), c=28.218(5) A, beta=100.192(3); V=5543.5(16) A(3), Z=8.4, C(28)H(20)BrNO(3)Pre: monoclinic, C2/c, a=23.035(1), b=8.7561(4), c=28.269(1) A, beta=100.811(1); V=5600.4(5) A(3), Z=8. PMID- 21603093 TI - Detection of human hematopoietic stem cell engraftment in the livers of adult immunodeficient mice by an optimized flow cytometric method. AB - Immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG) mice are a valuable resource to study human hematopoietic stem cells. Prolonged multilineage hematopoiesis indicates stem cell engraftment and generally is measured by flow cytometry. In this study, we took advantage of the multi-parameter detection afforded by modern flow cytometers to optimize detection of human hematopoiesis in NSG mice. Antigens widely expressed by mouse or human cells were evaluated as markers to distinguish mixtures of these cells to optimize and test the limits of chimerism detection. The bone marrow, spleen, and liver of NSG mice transplanted with human hematopoietic cells were analyzed for evidence of engraftment.Mouse bone marrow cells were best marked for exclusion by staining with a combination of CD45, TER-119, and anti-H-2K(d) monoclonal antibodies, whereas live human cells were most accurately identified by elimination of cell doublets and positive staining for CD59. Human stem cells (CD34(++)CD133(+)CD38(low)) and progenitors were detected in the bone marrow and liver, but not in the spleen. An unusual pattern of myeloid antigen expression was detected in the bone marrow and CD3(+)CD4(+)CD8(+) T-cells were detected in the spleen. We concluded that multicolor flow cytometric analysis that clearly distinguishes mouse and human cells offers accurate detection of human chimerism in NSG mice. Human hematopoiesis can be detected in the bone marrow and liver of NSG mice with T lymphopoiesis, possibly occurring in the spleen. PMID- 21603094 TI - Management of upper respiratory tract infections in children. AB - Upper respiratory tract infection (URTI) occurs commonly in both children and adults and is a major cause of mild morbidity. It has a high cost to society, being responsible for absenteeism from school and work and unnecessary medical care, and is occasionally associated with serious sequelae. URTIs are usually caused by several families of virus; these are the rhinovirus, coronavirus, parainfluenza, respiratory syncytial virus (RSV), adenovirus, human metapneumovirus, influenza, enterovirus and the recently discovered bocavirus. This review will mainly focus on the rhinovirus, where significant advances have been made in understanding the epidemiology, natural history and relationship with other pathogens. PMID- 21603095 TI - An Adaptable XML Based Approach for Scientific Data Management and Integration. AB - Increased complexity of scientific research poses new challenges to scientific data management. Meanwhile, scientific collaboration is becoming increasing important, which relies on integrating and sharing data from distributed institutions. We develop SciPort, a Web-based platform on supporting scientific data management and integration based on a central server based distributed architecture, where researchers can easily collect, publish, and share their complex scientific data across multi-institutions. SciPort provides an XML based general approach to model complex scientific data by representing them as XML documents. The documents capture not only hierarchical structured data, but also images and raw data through references. In addition, SciPort provides an XML based hierarchical organization of the overall data space to make it convenient for quick browsing. To provide generalization, schemas and hierarchies are customizable with XML-based definitions, thus it is possible to quickly adapt the system to different applications. While each institution can manage documents on a Local SciPort Server independently, selected documents can be published to a Central Server to form a global view of shared data across all sites. By storing documents in a native XML database, SciPort provides high schema extensibility and supports comprehensive queries through XQuery. By providing a unified and effective means for data modeling, data access and customization with XML, SciPort provides a flexible and powerful platform for sharing scientific data for scientific research communities, and has been successfully used in both biomedical research and clinical trials. PMID- 21603096 TI - Towards Building High Performance Medical Image Management System for Clinical Trials. AB - Medical image based biomarkers are being established for therapeutic cancer clinical trials, where image assessment is among the essential tasks. Large scale image assessment is often performed by a large group of experts by retrieving images from a centralized image repository to workstations to markup and annotate images. In such environment, it is critical to provide a high performance image management system that supports efficient concurrent image retrievals in a distributed environment. There are several major challenges: high throughput of large scale image data over the Internet from the server for multiple concurrent client users, efficient communication protocols for transporting data, and effective management of versioning of data for audit trails. We study the major bottlenecks for such a system, propose and evaluate a solution by using a hybrid image storage with solid state drives and hard disk drives, RESTful Web Services based protocols for exchanging image data, and a database based versioning scheme for efficient archive of image revision history. Our experiments show promising results of our methods, and our work provides a guideline for building enterprise level high performance medical image management systems. PMID- 21603097 TI - A Study of Students' Learning Styles, Discipline Attitudes and Knowledge Acquisition in Technology-Enhanced Probability and Statistics Education. AB - Many modern technological advances have direct impact on the format, style and efficacy of delivery and consumption of educational content. For example, various novel communication and information technology tools and resources enable efficient, timely, interactive and graphical demonstrations of diverse scientific concepts. In this manuscript, we report on a meta-study of 3 controlled experiments of using the Statistics Online Computational Resources in probability and statistics courses. Web-accessible SOCR applets, demonstrations, simulations and virtual experiments were used in different courses as treatment and compared to matched control classes utilizing traditional pedagogical approaches. Qualitative and quantitative data we collected for all courses included Felder Silverman-Soloman index of learning styles, background assessment, pre and post surveys of attitude towards the subject, end-point satisfaction survey, and varieties of quiz, laboratory and test scores. Our findings indicate that students' learning styles and attitudes towards a discipline may be important confounds of their final quantitative performance. The observed positive effects of integrating information technology with established pedagogical techniques may be valid across disciplines within the broader spectrum courses in the science education curriculum. The two critical components of improving science education via blended instruction include instructor training, and development of appropriate activities, simulations and interactive resources. PMID- 21603098 TI - The Contribution of DOPA to Substrate-Peptide Adhesion and Internal Cohesion of Mussel-Inspired Synthetic Peptide Films. AB - Mussels use a variety of 3, 4-dihydroxyphenyl-l-alanine (DOPA) rich proteins specifically tailored to adhering to wet surfaces. Synthetic polypeptide analogues of adhesive mussel foot proteins (specifically mfp-3) are used to study the role of DOPA in adhesion. The mussel-inspired peptide is a random copolymer of DOPA and N(5) -(2-hydroxyethyl)-l-glutamine synthesized with DOPA concentrations of 0-27 mol% and molecular weights of 5.9-7.1 kDa. Thin films (3-5 nm thick) of the mussel-inspired peptide are used in the surface forces apparatus (SFA) to measure the force-distance profiles and adhesion and cohesion energies of the films in an acetate buffer. The adhesion energies of the mussel-inspired peptide films to mica and TiO(2) surfaces increase with DOPA concentration. The adhesion energy to mica is 0.09 MUJ m(-2) mol(DOPA) (-1) and does not depend on contact time or load. The adhesion energy to TiO(2) is 0.29 MUJ m(-2) mol(DOPA) ( 1) for short contact times and increases to 0.51 MUJ m(-2) mol(DOPA) (-1) for contact times >60 min in a way suggestive of a phase transition within the film. Oxidation of DOPA to the quinone form, either by addition of periodate or by increasing the pH, increases the thickness and reduces the cohesion of the films. Adding thiol containing polymers between the oxidized films recovers some of the cohesion strength. Comparison of the mussel-inspired peptide films to previous studies on mfp-3 thin films show that the strong adhesion and cohesion in mfp-3 films can be attributed to DOPA groups favorably oriented within or at the interface of these films. PMID- 21603100 TI - Molecular data and ploidal levels indicate several putative allopolyploidization events in the genus Potentilla (Rosaceae). AB - Several naturally occurring hybrids in Potentilla (Rosaceae) have been reported, but no molecular evidence has so far been available to test these hypotheses of hybridization. We have compared a nuclear and a chloroplast gene tree to identify topological incongruences that may indicate hybridization events in the genus. Furthermore, the monophyly and phylogenetic position of the proposed segregated genera Argentina, Ivesia and Horkelia have been tested. The systematic signal from the two morphological characters, style- and anther shape, has also been investigated by ancestral state reconstruction, to elucidate how well these characters concur with the results of the molecular phylogenies. Six major clades, Anserina, Alba, Fragarioides, Reptans, ivesioid and Argentea, have been identified within genus Potentilla. Horkelia, Ivesia and Horkeliella (the ivesioid clade), form a monophyletic group nested within Potentilla. Furthermore, the origin of the proposed segregated genus Argentina (the Anserina clade) is uncertain but not in conflict with a new generic status of the group. We also found style morphology to be an informative character that reflects the phylogenetic relationships within Potentilla. Five well-supported incongruences were found between the nuclear and the chloroplast phylogenies, and three of these involved polyploid taxa. However, further investigations, using low copy molecular markers, are required to infer the phylogeny of these species and to test the hypothesis of hybrid origin. PMID- 21603101 TI - Chronic constrictive pericarditis in association with end-stage renal disease. AB - Pericardial involvement in end-stage renal disease (ESRD) is manifested most commonly as acute uremic or dialysis pericarditis and infrequently as chronic constrictive pericarditis (CCP). We report a 27-year-old patient with a history of uncontrolled hypertension, end-stage-renal disease on hemodialysis, who presented with recurrent ascites, dyspnea, and hypotension. After diagnosis with CCP, a partial pericardiectomy was performed; however, the patient did not improve and a salvage total pericardiectomy soon followed. He continued to decompensate and expired following a terminal extubation. No definitive cause of constrictive pericarditis was found. Nonetheless, we surmise it may have developed secondary to his end-stage renal disease. A literature review revealed end-stage kidney disease as a relatively uncommon cause of CCP; only a few other such associations have thus far been reported. PMID- 21603099 TI - Imaging of brain dopamine pathways: implications for understanding obesity. AB - Obesity is typically associated with abnormal eating behaviors. Brain imaging studies in humans implicate the involvement of dopamine (DA)-modulated circuits in pathologic eating behavior(s). Food cues increase striatal extracellular DA, providing evidence for the involvement of DA in the nonhedonic motivational properties of food. Food cues also increase metabolism in the orbitofrontal cortex indicating the association of this region with the motivation for food consumption. Similar to drug-addicted subjects, striatal DA D2 receptor availability is reduced in obese subjects, which may predispose obese subjects to seek food as a means to temporarily compensate for understimulated reward circuits. Decreased DA D2 receptors in the obese subjects are also associated with decreased metabolism in prefrontal regions involved in inhibitory control, which may underlie their inability to control food intake. Gastric stimulation in obese subjects activates cortical and limbic regions involved with self-control, motivation, and memory. These brain regions are also activated during drug craving in drug-addicted subjects. Obese subjects have increased metabolism in the somatosensory cortex, which suggests an enhanced sensitivity to the sensory properties of food. The reduction in DA D2 receptors in obese subjects coupled with the enhanced sensitivity to food palatability could make food their most salient reinforcer putting them at risk for compulsive eating and obesity. The results from these studies suggest that multiple but similar brain circuits are disrupted in obesity and drug addiction and suggest that strategies aimed at improving DA function might be beneficial in the treatment and prevention of obesity. PMID- 21603102 TI - Calcium mass balances in bicarbonate hemodialysis. AB - Dialysate calcium (Ca) concentration should be viewed as part of the integrated therapeutic regimen to control renal osteodystrophy and maintain normal mineral metabolism. The goals of this integrated approach are to keep the patient in a mild positive Ca mass balance (CaMB), to maintain normal serum Ca levels, to control plasma parathyroid hormone values to two to three times above normal levels, and to avoid soft-tissue calcifications. Thus, a correct net CaMB during hemodialysis (HD) is crucial in the treatment of renal osteodystrophy. Very few studies have been published which measured CaMBs in bicarbonate HD. This is mainly due to the technical difficulties in achieving an accurate measurement of CaMBs owing to the need for the collection of the total spent dialysate or of a proportional aliquot of it. Whereas no doubt exists about the fact that an inlet dialysate Ca concentration (CaD) of 1.75 mmol/L leads to a positive CaMB, more controversial is this issue, when dealing with a CaD of 1.50 mmol/L and, even more, when dealing with a CaD of 1.25 mmol/L. Another important issue is the appropriate CaD in long-hour slow-flow nocturnal HD. Finally, which CaMB should we study: ionized CaMB or total CaMB? This issue is largely discussed in the review. PMID- 21603103 TI - Potential use of stem cells for kidney regeneration. AB - Significant advances have been made in stem cell research over the past decade. A number of nonhematopoietic sources of stem cells (or progenitor cells) have been identified, including endothelial stem cells and neural stem cells. These discoveries have been a major step toward the use of stem cells for potential clinical applications of organ regeneration. Accordingly, kidney regeneration is currently gaining considerable attention to replace kidney dialysis as the ultimate therapeutic strategy for renal failure. However, due to anatomic complications, the kidney is believed to be the hardest organ to regenerate; it is virtually impossible to imagine such a complicated organ being completely rebuilt from pluripotent stem cells by gene or chemical manipulation. Nevertheless, several groups are taking on this big challenge. In this manuscript, current advances in renal stem cell research are reviewed and their usefulness for kidney regeneration discussed. We also reviewed the current knowledge of the emerging field of renal stem cell biology. PMID- 21603104 TI - Caring for Patients with CRF: Rewards and Benefits. AB - Patients with CRF usually progress through different stages before they reach ESRD and require special medical, social and psychological care and support during the pre-ESRD and following renal replacement therapy (RRT). Early referral of patients with CRF has the advantage of receiving adequate management and regular followup, with significant reduction in cardiovascular morbidity and mortality, attending an education program, prepared psychologically, participate in the decision of type of RRT, preemptive kidney transplantation, early creation of dialysis access, and adequate training in selected modality of RRT. During the early stages of commencement of RRT, psychological support and social care with rehabilitation program are mandatory. The degree of involvement and interaction must be individualized according to the needs of patient and type of RRT. A multidisciplinary team is crucial for implementation of a variety of strategies to help staff intervene more effectively in meeting the care needs of CRF patients. PMID- 21603105 TI - Cardiorenal syndromes and sepsis. AB - The cardiorenal syndrome is a clinical and pathophysiological entity defined as the concomitant presence of renal and cardiovascular dysfunction. In patients with severe sepsis and septic shock, acute cardiovascular, and renal derangements are common, that is, the septic cardiorenal syndrome. The aim of this paper is to describe the pathophysiology and clinical features of septic cardiorenal syndrome in light of the actual clinical and experimental evidence. In particular, the importance of systemic and intrarenal endothelial dysfunction, alterations of kidney perfusion, and myocardial function, organ "crosstalk" and ubiquitous inflammatory injury have been extensively reviewed in light of their role in cardiorenal syndrome etiology. Treatment includes early and targeted optimization of hemodynamics to reverse systemic hypotension and restore urinary output. In case of persistent renal impairment, renal replacement therapy may be used to remove cytokines and restore renal function. PMID- 21603106 TI - Hyponatremia and congestive heart failure: a marker of increased mortality and a target for therapy. AB - Heart failure is one of the most common chronic medical conditions in the developed world. It is characterized by neurohormonal activation of multiple systems that can lead to clinical deterioration and significant morbidity and mortality. In this regard, hyponatremia is due to inappropriate and continued vasopressin activity despite hypoosmolality and volume overload. Hyponatremia is also due to diuretic use in an attempt to manage volume overload. When hyponatremia occurs, it is a marker of heart failure severity and identifies patients with increased mortality. The recent introduction of specific vasopressin-receptor antagonists offers a targeted pharmacological approach to these pathophysiological derangements. Thus far, clinical trials with vasopressin receptor antagonists have demonstrated an increase in free-water excretion, improvement in serum sodium, modest improvements in dyspnea but no improvement in mortality. Continued clinical trials with these agents are needed to determine their specific role in the treatment of both chronic and decompensated heart failure. PMID- 21603108 TI - PyMC: Bayesian Stochastic Modelling in Python. AB - This user guide describes a Python package, PyMC, that allows users to efficiently code a probabilistic model and draw samples from its posterior distribution using Markov chain Monte Carlo techniques. PMID- 21603107 TI - Stepwise increasing and decreasing fluid shear stresses differentially regulate the functions of osteoblasts. AB - It is well accepted that osteoblasts respond to fluid shear stress (FSS) depending on the loading magnitude, rate, and temporal profiles. Although in vivo observations demonstrated that bone mineral density changes as the training intensity gradually increases/decreases, whether osteoblasts perceive such slow temporal changes in the strength of stimulation remains unclear. In this study, we hypothesized that osteoblasts can detect and respond differentially to the temporal gradients of FSS. In specific, we hypothesized that when the temporal FSS gradient is high enough, i) the increasing FSS inhibits the osteoblastic potential in supporting osteoclastogenesis and enhances the osteoblastic anabolic responses; ii) on the other hand, the deceasing FSS would have opposite effects on osteoclastogenesis and anabolic responses. To test the hypotheses, stepwise varying FSS was applied on primary osteoblasts and osteogenic and resorption markers were analyzed. The cells were subjected to FSS increasing from 5, 10, to 15 or decreasing from 15, 10, to 5 dyn/cm(2) at a step of 5 dyn/cm(2) for either 6 or 12 hours. In a subset experiment, the cells were stimulated with stepwise increasing or decreasing FSS at a higher step (10 dyn/cm(2)) for 12 hours. Our results showed that, with the step of 5 dyn/cm(2), the stepwise increasing FSS inhibited the osteoclastogenesis with a 3- to 4-fold decrease in RANKL/OPG gene expression versus static controls, while the stepwise decreasing FSS increased RANKL/OPG ratio by 2- to 2.5-fold versus static controls. Both increasing and decreasing FSS enhanced alkaline phosphatase expression and calcium deposition by 1.0- to 1.8 fold versus static controls. For a higher FSS temporal gradient (three steps of 10 dyn/cm(2) over 12 hour stimulation), the increasing FSS enhanced the expression of alkaline phosphatase expression and calcium deposition by 1.3 fold, while the decreasing FSS slightly inhibited them by -10% compared with static controls. Taken together, our results suggested that osteoblasts can detect the slow temporal gradients of FSS and respond differentially in a dose dependent manner, which may account for the observed bone mineral density changes in response to the gradual increasing/decreasing exercise in vivo. The stepwise FSS can be a useful model to study bone cell responses to long-term mechanical usage or disuse. These studies will complement the short-term studies and provide additional clinically relevant insights on bone adaptation. PMID- 21603109 TI - Renal replacement therapy in austere environments. AB - Myoglobinuric renal failure is the classically described acute renal event occurring in disaster environments-commonly after an earthquake-which most tests the ingenuity and flexibility of local and regional nephrology resources. In recent decades, several nephrology organizations have developed response teams and planning protocols to address disaster events, largely focusing on patients at risk for, or with, acute kidney injury (AKI). In this paper we briefly review the epidemiology and outcomes of patients with dialysis-requiring AKI after such events, while providing greater focus on the management of the end-stage renal disease population after a disaster which incapacitates a pre-existing nephrologic infrastructure (if it existed at all). "Austere" dialysis, as such, is defined as the provision of renal replacement therapy in any setting in which traditional, first-world therapies and resources are limited, incapacitated, or nonexistent. PMID- 21603110 TI - Citrate anticoagulation for continuous renal replacement therapy in critically ill patients: success and limits. AB - Citrate anticoagulation has risen in interest so it is now a real alternative to heparin in the ICUs practice. Citrate provides a regional anticoagulation virtually restricted to extracorporeal circuit, where it acts by chelating ionized calcium. This issue is particularly true in patients ongoing CRRT, when the "continuous" systemic anticoagulation treatment is per se a relevant risk of bleeding. When compared with heparin most of studies with citrate reported a longer circuit survival, a lower rate of bleeding complications, and transfused packed red cell requirements. As anticoagulant for CRRT, the infusion of citrate is prolonged and it could potentially have some adverse effects. When citrate is metabolized to bicarbonate, metabolic alkalosis may occur, or for impaired metabolism citrate accumulation leads to acidosis. However, large studies with dedicated machines have indeed demonstrated that citrate anticoagulation is well tolerated, safe, and an easy to handle even in septic shock critically ill patients. PMID- 21603111 TI - Pseudohyperkalemia in patients with chronic lymphocytic leukemia. AB - Pseudohyperkalemia occurs occasionally in patients with extreme leukocytosis. Increased white blood cell fragility coupled with mechanical stress is felt to be causal. Serum and plasma potassium levels have been both associated with pseudohyperkalemia. Whole blood potassium determination will usually verify the correct diagnosis. It is important to diagnose this condition early so that patients are not inappropriately treated. Two patients with chronic lymphocytic leukemia and extreme leukocytosis are presented, one with pseudohyperkalemia and one with probable pseudohyperkalemia, and diagnostic considerations are discussed. PMID- 21603112 TI - Endothelial progenitor cells in acute ischemic kidney injury: strategies for increasing the cells' renoprotective competence. AB - Acute ischemic kidney injury is the most frequent cause of acute renal failure in daily clinical practice. It has become increasingly recognized that microvascular endothelial cell dysfunction (ED) in peritubular capillaries inhibits the process of postischemic renal reperfusion. ED can serve as therapeutic target in the management of acute ischemic kidney injury. Postischemic reflow can be restored by systemic administration of either mature endothelial cells or of endothelial progenitor cells. Endothelial progenitor cells EPCs can be cultured from the peripheral circulation of humans and different animals. The cells act vasoprotectively by direct and indirect mechanisms. The protective effects of EPCs in acute ischemic kidney injury can be stimulated by preincubating the cells with different agonistic mediators. This paper summarizes the currently available data on strategies to improve the renoprotective activity of EPCs in acute ischemic kidney injury. PMID- 21603113 TI - Longitudinal Associations Between Husbands' and Wives' Depressive Symptoms. AB - Although concordance between husbands' and wives' mental health problems is often reported, questions remain about the nature of these relations. Extending research in this area, this study examined dynamic-longitudinal pathways among husbands' and wives' depressive symptoms and marital satisfaction as a moderator of associations. Participants were 296 heterosexual couples. Husbands and wives reported on their depressive symptoms and marital satisfaction. Results from dynamic bivariate latent difference score analyses indicated unidirectional longitudinal coupling such that higher levels of husbands' depressive symptoms predicted subsequent elevations in wives' depressive symptoms over time. This relation was stronger among couples reporting marital distress as compared to couples reporting higher marital satisfaction. The findings underscore the importance of considering one's spouses' depressive symptoms in treatment efforts. PMID- 21603114 TI - TOO SICK TO START: ENTREPRENEUR'S HEALTH AND BUSINESS ENTRY IN TOWNSHIPS AROUND DURBAN, SOUTH AFRICA. AB - Unlike large firms with management teams, small businesses are usually run by one key person, the owner-entrepreneur, who bears almost all of the risks and makes almost all of the decisions related to the business. Because the owner entrepreneur also embodies most of the firm-specific knowledge capital, health of the owner-entrepreneur is an important factor in the production process. Following a cohort of respondents in townships around Durban, South Africa, over a three-year period, we examined the relationship between an individual's physical health and the decision to start a business. Our results suggest that respondents who were recent business entrants were in better health than respondents who did not start new businesses. Moreover, respondents without a business at the beginning of the study who later opened businesses during the three-year study interval were significantly more likely to have better baseline health than those respondents who never started a new business. Hence, good health among entrepreneurs seems to be an important prerequisite to small business entry. PMID- 21603115 TI - Marital Conflict and Children's Emotional Security in the Context of Parental Depression. AB - Evidence has emerged for emotional security as an explanatory variable linking marital conflict to children's adjustment. Further evidence suggests parental psychopathology is a key factor in child development. To advance understanding of the pathways by which these family risk factors impact children's development, the mediational role of emotional security for children with parents who have potentially clinical levels of depression compared to children whose parents have lower levels of symptomatology was examined (i.e., moderated mediation). Participants included 297 families assessed annually for 3 years. Paternal depression moderated pathways, such that marital conflict was associated with greater child emotional insecurity 2 years later in the context of paternal depression. Testing alternative pathways, emotional insecurity mediated relations between maternal depression and externalizing problems. PMID- 21603117 TI - Arterial stiffness and dialysis calcium concentration. AB - Arterial stiffness is the major determinant of isolated systolic hypertension and increased pulse pressure. Aortic stiffness is also associated with increased cardiovascular morbidity and mortality in patients with chronic kidney disease, hypertension, and general population. Hemodynamically, arterial stiffness results in earlier aortic pulse wave reflection leading to increased cardiac workload and decreased myocardial perfusion. Although the clinical consequence of aortic stiffness has been clearly established, its pathophysiology in various clinical conditions still remains poorly understood. The aim of the present paper is to review the studies that have looked at the impact of dialysis calcium concentration on arterial stiffness. Overall, the results of small short-term studies suggest that higher dialysis calcium is associated with a transient but significant increase in arterial stiffness. This calcium dependant increase in arterial stiffness is potentially explained by increased vascular smooth muscle tone of the conduit arteries and is not solely explained by changes in mean blood pressure. However, the optimal DCa remains to be determined, and long term studies are required to evaluate its impact on the progression of arterial stiffness. PMID- 21603116 TI - Thermodynamic analysis of the structure-function relationship in the total DNA binding site of enzyme-DNA complexes. AB - Both helicases and polymerases perform their activities when bound to the nucleic acids, that is, the enzymes possess a nucleic acid-binding site. Functional complexity of the helicase or the polymerase action is reflected in the intricate structure of the total nucleic acid-binding site, which allows the enzymes to control and change their nucleic acid affinities during the catalysis. Understanding the fundamental aspects of the functional heterogeneity of the total nucleic acid-binding site of a polymerase or helicase can be achieved through quantitative thermodynamic analysis of the enzyme binding to the nucleic acids oligomers, which differ in their length. Such an analysis allows the experimenter to assess the presence of areas with strong and weak affinity for the nucleic acid, that is, the presence of the strong and the weak nucleic acid binding subsites, determine the number of the nucleotide occlude by each subsite, and estimate their intrinsic free energies of interactions. PMID- 21603118 TI - Diagnostic Workup for Disorders of Bone and Mineral Metabolism in Patients with Chronic Kidney Disease in the Era of KDIGO Guidelines. AB - KDIGO (KIDNEY DISEASE: Improving Global Outcomes) is an international nonprofit organization devoted to "improve the care and outcomes of kidney disease patients worldwide through promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines." The mineral and bone disorder (MBD) in patients with chronic kidney disease (CKD) has been the first area of interest of KDIGO international initiative. KDIGO guidelines on CKD-MBD were published in 2009 with the intent to modify the previous KDOQI guidelines that had failed to consistently change the global outcome of CKD patients. After the publication of KDOQI guidelines for bone metabolism and disease in 2003, a large number of observational data emerged in literature linking disordered mineral metabolism with adverse clinical outcomes. Notwithstanding this large body of observational data, a paucity of evidence from high-quality clinical trials was available for the development of KDIGO guidelines. Herein, a summary will be provided of the most important findings of KDIGO guidelines regarding the diagnostic workup and clinical monitoring of CKD MBD patients. PMID- 21603119 TI - Cardiovascular and Renal Links along the Cardiorenal Continuum. AB - The cardiorenal syndrome includes the widely known relationship between kidney function and cardiovascular disease. A large number of patients have various degrees of heart and kidney dysfunction worldwide, both in developed and developing countries. Disorders affecting one of them mostly involve the other. Such interactions represent the pathogenesis for a clinical condition called cardiorenal syndrome. Renal and cardiovascular disease shares similar etiologic risk factors. The majority of vascular events are caused by accelerated atherosclerosis. Moreover, cardiovascular events rarely occur in patients without underlying disease; rather, they typically take place as the final stage of a pathophysiological process that results in progressive vascular damage, including vital organ damage, specifically the kidney and the heart if these factors are uncontrolled. Chronic kidney disease is a novel risk factor included at this stage that accelerates both vascular and cardiac damage. PMID- 21603120 TI - Strong Narrow-Band Luminescence from Silicon-Vacancy Color Centers in Spatially Localized Sub-10 nm Nanodiamond. AB - Discrete nanodiamond particles of 500 nm and 6 nm average size were seeded onto silicon substrates and plasma treated using chemical vapor deposition to create silicon-vacancy color centers. The resulting narrow-band room temperature photoluminescence is intense, and readily observed even for weakly agglomerated sub-10 nm size diamond. This is in contrast to the well-studied nitrogen-vacancy center in diamond which has luminescence properties that are strongly dependant on particle size, with low probability for incorporation of centers in sub-10 nm crystals. We suggest the silicon-vacancy center to be a viable alternative to nitrogen-vacancy defects for use as a biomarker in the clinically-relevant sub-10 nm size regime, for which nitrogen defect-related luminescent activity and stability is reportedly poor. PMID- 21603121 TI - Proteomic characterization of non-small cell lung cancer in a comprehensive translational thoracic oncology database. AB - BACKGROUND: In recent years, there has been tremendous growth and interest in translational research, particularly in cancer biology. This area of study clearly establishes the connection between laboratory experimentation and practical human application. Though it is common for laboratory and clinical data regarding patient specimens to be maintained separately, the storage of such heterogeneous data in one database offers many benefits as it may facilitate more rapid accession of data and provide researchers access to greater numbers of tissue samples. DESCRIPTION: The Thoracic Oncology Program Database Project was developed to serve as a repository for well-annotated cancer specimen, clinical, genomic, and proteomic data obtained from tumor tissue studies. The TOPDP is not merely a library-it is a dynamic tool that may be used for data mining and exploratory analysis. Using the example of non-small cell lung cancer cases within the database, this study will demonstrate how clinical data may be combined with proteomic analyses of patient tissue samples in determining the functional relevance of protein over and under expression in this disease. Clinical data for 1323 patients with non-small cell lung cancer has been captured to date. Proteomic studies have been performed on tissue samples from 105 of these patients. These tissues have been analyzed for the expression of 33 different protein biomarkers using tissue microarrays. The expression of 15 potential biomarkers was found to be significantly higher in tumor versus matched normal tissue. Proteins belonging to the receptor tyrosine kinase family were particularly likely to be over expressed in tumor tissues. There was no difference in protein expression across various histologies or stages of non small cell lung cancer. Though not differentially expressed between tumor and non tumor tissues, the over expression of the glucocorticoid receptor (GR) was associated improved overall survival. However, this finding is preliminary and warrants further investigation. CONCLUSION: Though the database project is still under development, the application of such a database has the potential to enhance our understanding of cancer biology and will help researchers to identify targets to modify the course of thoracic malignancies. PMID- 21603122 TI - Optofluidic waveguides: II. Fabrication and structures. AB - We review fabrication methods and common structures for optofluidic waveguides, defined as structures capable of optical confinement and transmission through fluid filled cores. Cited structures include those based on total internal reflection, metallic coatings, and interference based confinement. Configurations include optical fibers and waveguides fabricated on flat substrates (integrated waveguides). Some examples of optofluidic waveguides that are included in this review are Photonic Crystal Fibers (PCFs) and two-dimensional photonic crystal arrays, Bragg fibers and waveguides, and Anti Resonant Reflecting Optical Waveguides (ARROWs). An emphasis is placed on integrated ARROWs fabricated using a thin-film deposition process, which illustrates how optofluidic waveguides can be combined with other microfluidic elements in the creation of lab-on-a-chip devices. PMID- 21603123 TI - Spatial variation of volatile organic compounds in a "Hot Spot" for air pollution. AB - The spatial variations of volatile organic compounds (VOCs) were characterized in the Village of Waterfront South neighborhood (WFS), a "hot spot" for air toxics in Camden, NJ. This was accomplished by conducting "spatial saturation sampling" for 11 VOCs using 3500 OVM passive samplers at 22 sites in WFS and 16 sites in Copewood/Davis Streets (CDS) neighborhood, an urban reference area located ~1000 m east of the WFS. Sampling durations were 24 and 48 h. For all 3 sampling campaigns (2 in summer and 1 in winter), the spatial variations and median concentrations of toluene, ethylbenzene, and xylenes (TEX) were found significantly higher (p < 0.05) in WFS than in CDS, where the spatial distributions of these compounds were relatively uniform. The highest concentrations of methyl tert-butyl ether (MTBE) (maximum of 159 MUg m(-3)) were always found at one site close to a car scrapping facility in WFS during each sampling campaign. The spatial variation of benzene in WFS was found to be marginally higher (p = 0.057) than in CDS during one sampling campaign, but similar in the other two sampling periods. The results obtained from the analyses of correlation among all species and the proximity of sampling site to source indicated that local stationary sources in WFS have significant impact on MTBE and BTEX air pollution in WFS, and both mobile sources and some of the stationary sources in WFS contributed to the ambient levels of these species measured in CDS. The homogenous spatial distributions (%RSD < 24%) and low concentrations of chloroform (0.02-0.23 MUg m(-3)) and carbon tetrachloride (0.45-0.51 MUg m(-3)) indicated no significant local sources in the study areas. Further, results showed that the sampling at the fixed monitoring site may under- or over-estimate air pollutant levels in a "hot spot" area, suggesting that the "spatial saturation sampling" is necessary for conducting accurate assessment of air pollution and personal exposure in a community with a high density of sources. PMID- 21603124 TI - Multiply robust inference for statistical interactions. AB - A primary focus of an increasing number of scientific studies is to determine whether two exposures interact in the effect that they produce on an outcome of interest. Interaction is commonly assessed by fitting regression models in which the linear predictor includes the product between those exposures. When the main interest lies in the interaction, this approach is not entirely satisfactory because it is prone to (possibly severe) bias when the main exposure effects or the association between outcome and extraneous factors are misspecified. In this article, we therefore consider conditional mean models with identity or log link which postulate the statistical interaction in terms of a finite-dimensional parameter, but which are otherwise unspecified. We show that estimation of the interaction parameter is often not feasible in this model because it would require nonparametric estimation of auxiliary conditional expectations given high dimensional variables. We thus consider 'multiply robust estimation' under a union model that assumes at least one of several working submodels holds. Our approach is novel in that it makes use of information on the joint distribution of the exposures conditional on the extraneous factors in making inferences about the interaction parameter of interest. In the special case of a randomized trial or a family-based genetic study in which the joint exposure distribution is known by design or by Mendelian inheritance, the resulting multiply robust procedure leads to asymptotically distribution-free tests of the null hypothesis of no interaction on an additive scale. We illustrate the methods via simulation and the analysis of a randomized follow-up study. PMID- 21603125 TI - Lexical and Post-Lexical Complexity Effects on Eye Movements in Reading. AB - The current study investigated how a post-lexical complexity manipulation followed by a lexical complexity manipulation affects eye movements during reading. Both manipulations caused disruption in all measures on the manipulated words, but the patterns of spill-over differed. Critically, the effects of the two kinds of manipulations did not interact, and there was no evidence that post lexical processing difficulty delayed lexical processing on the next word (c.f. Henderson & Ferreira, 1990). This suggests that post-lexical processing of one word and lexical processing of the next can proceed independently and likely in parallel. This finding is consistent with the assumptions of the E-Z Reader model of eye movement control in reading (Reichle, Warren, & McConnell, 2009). PMID- 21603126 TI - Ruthenium Olefin Metathesis Catalysts Bearing Carbohydrate-Based N-Heterocyclic Carbenes. AB - Ru-based olefin metathesis catalysts containing carbohydrate-derived NHCs from glucose and galactose were synthesized and characterized by NMR spectroscopy. 2D NMR spectroscopy revealed the presence of Ru-C (benzylidene) rotamers at RT and the rate of rotation was measured using magnetization transfer and VT-NMR spectroscopy. The catalysts were found to be effective at ring-opening metathesis polymerization (ROMP), ring closing metathesis (RCM), cross metathesis (CM), and asymmetric ring opening cross metathesis (AROCM) and showed surprising selectivity in both CM and AROCM. PMID- 21603127 TI - Out of sync? Demographic and other social science research on health conditions in developing countries. AB - In this paper, we present a framework for considering whether the marginal social benefits of demographic and social science research on various health conditions in developing countries are likely to be relatively high. Based on this framework, we argue that the relative current and future predicted prevalence of burdens of different health/disease conditions, as measured by disability adjusted life years (DALYs), provide a fairly accurate reflection of some important factors related to the relative marginal social benefits of demographic and social science research on different health conditions. World Health Organization (WHO) DALYs projections for 2005-30 are compared with (a) demographic and other social science studies on health in developing countries during 1990-2005, and (b) presentations made at the Population Association of America annual meetings during the same time period. These comparisons suggest that recent demographic and social science research on health in developing countries has focused too much on HIV/AIDS, and too little on non-communicable diseases. PMID- 21603128 TI - Photon emission from massive projectile impacts on solids. AB - First evidence of photon emission from individual impacts of massive gold projectiles on solids for a number of projectile-target combinations is reported. Photon emission from individual impacts of massive Au(n) (+q) (1 <= n <= 400; q = 1-4) projectiles with impact energies in the range of 28-136 keV occurs in less than 10 ns after the projectile impact. Experimental observations show an increase in the photon yield from individual impacts with the projectile size and velocity. Concurrently with the photon emission, electron emission from the impact area has been observed below the kinetic emission threshold and under unlikely conditions for potential electron emission. We interpret the puzzling electron emission and correlated luminescence observation as evidence of the electronic excitation resulting from the high-energy density deposited by massive cluster projectiles during the impact. PMID- 21603129 TI - Study of the Generalized MTF and DQE for a New Microangiographic System. AB - We study the properties of a new microangiographic system, consisting of a Region of Interest (ROI) microangiographic detector, x-ray source, and patient. The study was performed under conditions intended for clinical procedures such as neurological diagnostic angiograms as well as treatments of intracranial aneurysms, and vessel-stenoses. The study was performed in two steps; first a uniform head equivalent phantom was used as a "filter". This allowed us to study the properties of the detector alone, under clinically relevant x-ray spectra. We report the detector MTF, NPS, NEQ, and DQE for beam energies ranging from 60 100kVp and for different detector entrance exposures. For the second step, the phantom was placed adjacent to the detector, allowing scatter to enter the detector and new measurements were obtained for the same beam energies and detector entrance exposures. Different radiation field sizes were studied, and the effects of different scatter amounts were investigated. The spatial distribution of scatter was studied using the edge-spread method and a generalized system MTF was obtained by combining the scatter MTF weighted by the scatter fraction with the detector MTF and focal spot unsharpness due to magnification. The NPS combined with the generalized MTF gave the generalized system NEQ and DQE. The generalized NEQ and the ideal object detectability were used to calculate the Dose Area Product to the patient for 75% object detection probability. This was used as a system optimization method. PMID- 21603130 TI - The Role of Phospholipase A(2)-derived Mediators in Obesity. AB - Obesity has become an epidemic and its prevalence is increasing exponentially. A great deal of focus has been given to understanding the molecular processes that regulate obesity. The characterization of phospholipase A(2)s, especially adipose specific PLA(2), have lead to a proposed role of their downstream products in the progression of obesity and obesity related disorders. This review summarizes recent developments in the role of PLA(2) and their downstream effects in the development of metabolic disorders. PMID- 21603131 TI - Screening and Referral for Postpartum Depression among Low-Income Women: A Qualitative Perspective from Community Health Workers. AB - Postpartum depression is a serious and common psychiatric illness. Mothers living in poverty are more likely to be depressed and have greater barriers to accessing treatment than the general population. Mental health utilization is particularly limited for women with postpartum depression and low-income, minority women. As part of an academic-community partnership, focus groups were utilized to examine staff practices, barriers, and facilitators in mental health referrals for women with depression within a community nonprofit agency serving low-income pregnant and postpartum women. The focus groups were analyzed through content analyses and NVIVO-8. Three focus groups with 16 community health workers were conducted. Six themes were identified: (1) screening and referral, (2) facilitators to referral, (3) barriers to referral, (4) culture and language, (5) life events, and (6) support. The study identified several barriers and facilitators for referring postpartum women with depression to mental health services. PMID- 21603133 TI - Ghrelin Protects against the Detrimental Consequences of Porphyromonas gingivalis Induced Akt Inactivation through S-Nitrosylation on Salivary Mucin Synthesis. AB - Disturbances in nitric oxide synthase isozyme system and the impairment in salivary mucin synthesis are well-recognized features associated with oral mucosal inflammatory responses to periodontopathic bacterium, P. gingivalis. In this study, using rat sublingual gland acinar cells, we report that P. gingivalis LPS-induced impairment in mucin synthesis and associated suppression in Akt kinase activity were accompanied by a decrease in constitutive nitric oxide synthase (cNOS) activity and an induction in inducible nitric oxide synthase (iNOS) expression. The LPS effect on Akt inactivation was manifested in the kinase S-nitrosylation and a decrease in its phosphorylation at Ser(473). Further, we demonstrate that a peptide hormone, ghrelin, countered the LPS induced impairment in mucin synthesis. This effect of ghrelin was reflected in the suppression of iNOS and the increase in Akt activation, associated with the loss in S-nitrosylation and the increase in phosphorylation, as well as cNOS activation through phosphorylation. Our findings suggest that induction in iNOS expression by P. gingivalis-LPS leads to Akt kinase inactivation through S nitrosylation that detrimentally impacts cNOS activation through phosphorylation as well as mucin synthesis. We also show that the countering effect of ghrelin on P. gingivalis-induced impairment in mucin synthesis is associated with Akt activation through phosphorylation. PMID- 21603134 TI - Acute arterial thrombosis after covered stent exclusion of bleeding mycotic pseudoaneurysm: treatment using catheter-directed thrombolysis. AB - Conventional absolute contraindications to catheter-directed thrombolysis include active or recent hemorrhage and the presence of local vascular infection, both of which increase the risk of procedure-related complications such as bleeding and systemic sepsis. For this reason, lytic therapy of arterial thromboembolism under these circumstances is generally precluded. Herein, we describe a unique case of safe catheter-directed lysis of an acutely thrombosed iliac artery following covered stent placement for treatment of an actively bleeding infected pseudoaneurysm. Our management approach is discussed. PMID- 21603135 TI - The effects of parathyroid hormone applied at different regimes on the trochanteric region of the femur in ovariectomized rat model of osteoporosis. AB - This study aims to investigate the effects of two application frequencies of parathyroid hormone on the trochanteric region of rat femur. Forty-three-month old female Sprague-Dawley rats were divided into 4 groups (n = 10/group). Three groups were ovariectomized, and 8 weeks later they were administered the following treatments (5 weeks): soy-free diet (OVX), subcutaneously injected PTH (0.040 mg/kg) 5 days a week (PTH 5x/w), subcutaneously injected PTH (0.040 mg/kg) every 2 days (PTH e2d), and a sham group. The values of the biomechanical and histomorphometric parameters showed higher results in 5x/w animals in comparison to the OVX and PTH 2ed groups. The ratio between bone diameter/marrow diameter (B.Dm/Ma.Dm) in subtrochanteric cross sections did not show any significant differences between PTH 5x/w and PTH e2d. The increased bone formation rate was observed under PTH treatment in both groups mainly at the endosteal side. The endosteum seems here to be one of the targets of PTH with an accelerate bone formation and a pronounced filling-in of intracortical cavities with higher intensity for the PTH 5x/w in comparison to PTH e2d rats. PMID- 21603132 TI - Models for LRRK2-Linked Parkinsonism. AB - Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD is not fully understood, but it appears to involve both genetic susceptibility and environmental factors. Treatment for PD that prevents neuronal death progression in the dopaminergic system and abnormal protein deposition in the brain is not yet available. Recently, mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified to cause autosomal dominant late-onset PD and contribute to sporadic PD. Here, we review the recent models for LRRK2-linked Parkinsonism and their utility in studying LRRK2 neurobiology, pathogenesis, and potential therapeutics. PMID- 21603136 TI - Testosterone increases: sodium reabsorption, blood pressure, and renal pathology in female spontaneously hypertensive rats on a high sodium diet. AB - Estrogen (E) and testosterone (T) are important in the sexually dimorphic pattern of blood pressure (BP) development. The goal was to examine the effects of endogenous E and exogenous T in the development of hypertension in female spontaneously hypertensive rats (SHR) on a high sodium diet. Female SHR (N = 27, 5-week) were divided into four groups: (1) control (n = 8), (2) ovariectomized (OVX, n = 26), (3) testosterone implants with intact ovaries (T, n = 6), and (4) ovariectomized + testosterone implants (OVX+T, n = 7). T was given immediately after OVX and replaced every two weeks and they were fed a 3% NaCl diet. BP was measured weekly and plasma norepinephrine (NE) analyzed by HPLC. OVX+T females exhibited the greatest elevation in BP (190 +/- 4.0 mmHg) compared to controls at 15 weeks of age (140 +/- 3.4 mmHg, P < .001) and a pattern of hypertension development similar to that of male SHR. Females with T treatment showed evidence of glomerulosclerosis. In conclusion, T accelerated the development of hypertension similar to the BP pattern observed in males; the presence of ovaries attenuated the T induced increase in BP; T increased renal sodium reabsorption, and T increased glomerulosclerosis. PMID- 21603137 TI - Depressive symptoms and psychosocial functioning in preadolescent children. AB - The current study was designed to determine the percentage of children "at-risk" of depression or evidencing clinical levels of depression. In addition, the study examined how the "at-risk" and the clinical groups differed from children who demonstrated no depressive symptoms on positive and negative affect, four aspects of self-concept, and peer ratings of popularity. Respondents were 510 children (270 boys 240 girls) who ranged in age from 7 to 13 years (mean = 9.39). The results demonstrated that 23% of children were either in the "at-risk" or clinical range of depression. Children in both the clinical and the "at-risk" range demonstrated higher negative affect but lower positive affect and lower self-concepts than children in the normal range. However, children's peers only differentiated between the "clinical" and "normal" groups. It is harder for peers, and other informants such as teachers and parents, to detect the problems of children with elevated depressive symptoms but who do not meet the diagnostic criteria. It is important to implement intervention programs for children who evidence depression symptoms, as well as "at-risk" children. "At-risk" children with elevated levels of depressive symptoms may be more disadvantaged, as their problems are less likely to be detected and treated. PMID- 21603138 TI - Unusual paraneoplastic syndrome accompanies neuroendocrine tumours of the pancreas. AB - Neuroendocrine tumours comprise a small percentage of pancreatic neoplasia (10%) (1). Diagnosis of neuroendocrine tumours is difficult, especially if the tumours are small and nonfunctional. CT scans, MRI, and nuclear scans are sufficiently sensitive assessment tools for tumours with diameters of at least 2 cm; otherwise, the sensitivity and specificity of these techniques is less than 50% (2). Myasthenia gravis (MG) is a heterogeneous neuromuscular junction disorder that is primarily caused when antibodies form against the acetylcholine receptors (Ab-AchR). MG can develop in conjunction with neoplasia, making MG a paraneoplastic disease. In those cases, MG is most commonly associated with thymomas and less frequently associated with extrathymic malignancies. The mechanism underlying this paraneoplastic syndrome has been hypothesized to involve an autoimmune response against the tumour cells (3). No published reports have linked malignant pancreatic diseases with MG. Here, we report the case of a young woman, negative for Ab-AchR, with a neuroendocrine tumour in the pancreatic head, who experienced a complete resolution of her MG-like syndrome after surgical enucleation of the tumour. PMID- 21603139 TI - Cord blood-derived hematopoietic stem/progenitor cells: current challenges in engraftment, infection, and ex vivo expansion. AB - Umbilical cord blood has served as an alternative to bone marrow for hematopoietic transplantation since the late 1980s. Numerous clinical studies have proven the efficacy of umbilical cord blood. Moreover, the possible immaturity of cells in umbilical cord blood gives more options to recipients with HLA mismatch and allows for the use of umbilical cord blood from unrelated donors. However, morbidity and mortality rates associated with hematopoietic malignancies still remain relatively high, even after cord blood transplantation. Infections and relapse are the major causes of death after cord blood transplantation in patients with hematopoietic diseases. Recently, new strategies have been introduced to improve these major problems. Establishing better protocols for simple isolation of primitive cells and ex vivo expansion will also be very important. In this short review, we discuss several recent promising findings related to the technical improvement of cord blood transplantation. PMID- 21603141 TI - Clinical characteristics of patients with isolated calf vein thrombosis in a large teaching hospital. AB - Objective. To identify the clinical characteristics of a patient population newly diagnosed with acute isolated calf deep venous thrombosis (ICDVT) by duplex ultrasound scan (DUS). Methods. A retrospective review of the records of 100 consecutive patients diagnosed with ICDVT by DUS was conducted. Results. Patients (59% male) were predominantly Caucasian (86%) and inpatients (69%) with an average age of 53 years. The most frequent risk factors were malignancy (22%), immobility (18%), and previous DVT (13%). Thrombus was present in named tibial veins in 58% and muscular branches in 42%. The peroneal vein was most frequently involved (39/117, 33%) followed by the gastrocnemius veins (29/117, 22%) and muscular calf tributaries (14%). Conclusions. Our patient population with ICDVT was predominantly symptomatic, in-patient cohort with a high incidence of risk factors such as malignancy, immobility, previous DVT, trauma, and postoperative status. Partial or complete resolution was documented by DUS in 53%. PMID- 21603140 TI - Bone health in patients with multiple sclerosis. AB - Multiple sclerosis (MS) is a gait disorder characterized by acute episodes of neurological defects leading to progressive disability. Patients with MS have multiple risk factors for osteoporotic fractures, such as progressive immobilization, long-term glucocorticoids (GCs) treatment or vitamin D deficiency. The duration of motor disability appears to be a major contributor to the reduction of bone strength. The long term immobilization causes a marked imbalance between bone formation and resorption with depressed bone formation and a marked disruption of mechanosensory network of tightly connected osteocytes due to increase of osteocyte apoptosis. Patients with higher level of disability have also higher risk of falls that combined with a bone loss increases the frequency of bone fractures. There are currently no recommendations how to best prevent and treat osteoporosis in patients with MS. However, devastating effect of immobilization on the skeleton in patients with MS underscores the importance of adequate mechanical stimuli for maintaining the bone structure and its mechanical competence. The physical as well as pharmacological interventions which can counteract the bone remodeling imbalance, particularly osteocyte apoptosis, will be promising for prevention and treatment of osteoporosis in patients with MS. PMID- 21603142 TI - Antidepressant-resistant depression and antidepressant-associated suicidal behaviour: the role of underlying bipolarity. AB - The complex relationship between the use of antidepressants and suicidal behaviour is one of the hottest topics of our contemporary psychiatry. Based on the literature, this paper summarizes the author's view on antidepressant resistant depression and antidepressant-associated suicidal behaviour. Antidepressant-resistance, antidepressant-induced worsening of depression, antidepressant-associated (hypo)manic switches, mixed depressive episode, and antidepressant-associated suicidality among depressed patients are relatively most frequent in bipolar/bipolar spectrum depression and in children and adolescents. As early age at onset of major depressive episode and mixed depression are powerful clinical markers of bipolarity and the manic component of bipolar disorder (and possible its biological background) shows a declining tendency with age antidepressant-resistance/worsening, antidepressant-induced (hypo)manic switches and "suicide-inducing" potential of antidepressants seem to be related to the underlying bipolarity. PMID- 21603144 TI - Osteoporosis Knowledge, Self-Efficacy, and Beliefs among College Students in the USA and China. AB - This study investigated differences in osteoporosis knowledge, self-efficacy, and health beliefs among Chinese and American college students. Information obtained will be used in developing osteoporosis prevention programs for younger adults. Methods. Chinese (n = 409) and US (n = 408) college students completed the Osteoporosis Health Belief, Self-Efficacy, and Knowledge Tests. Results. Differences were seen in osteoporosis knowledge (M(us) = 14.52, M(Chinese) = 11.82), exercise knowledge (M(us) = 8.16, M(Chinese) = 9.04), calcium knowledge (M(us) = 8.47, M(Chinese) = 9.73), perceptions of exercise benefits (M(us) = 24.07, M(Chinese) = 21.09), calcium benefits (M(us) = 23.17, M(Chinese) = 18.36), exercise barriers (M(us) = 11.75, M(Chinese) = 14.96), calcium barriers (M(us) = 13.04, M(Chinese) = 15), and exercise self-efficacy (M(us) = 73.71, M(Chinese) = 63.81). Conclusion. US college students know more about osteoporosis and its risk factors; however, there are similarities in perception of risk between US and Chinese students. Chinese students perceive greater barriers to reducing their risk through exercise and dietary calcium intake. PMID- 21603143 TI - Cardiac differentiation of pluripotent stem cells. AB - The ability of human pluripotent stem cells to differentiate towards the cardiac lineage has attracted significant interest, initially with a strong focus on regenerative medicine. The ultimate goal to repair the heart by cardiomyocyte replacement has, however, proven challenging. Human cardiac differentiation has been difficult to control, but methods are improving, and the process, to a certain extent, can be manipulated and directed. The stem cell-derived cardiomyocytes described to date exhibit rather immature functional and structural characteristics compared to adult cardiomyocytes. Thus, a future challenge will be to develop strategies to reach a higher degree of cardiomyocyte maturation in vitro, to isolate cardiomyocytes from the heterogeneous pool of differentiating cells, as well as to guide the differentiation into the desired subtype, that is, ventricular, atrial, and pacemaker cells. In this paper, we will discuss the strategies for the generation of cardiomyocytes from pluripotent stem cells and their characteristics, as well as highlight some applications for the cells. PMID- 21603145 TI - Spontaneous supraceliac isolated abdominal aortic dissection sparing major visceral and renal vessels and presenting as chronic limb ischemia. AB - Aortic dissections that originate from isolated tears in the abdominal aorta are uncommon. Rarer still are cases of isolated abdominal aortic dissections arising in suprarenal locations, as most appear from infrarenal intimal defects. We present a quite unusual case of a spontaneous supraceliac isolated abdominal aortic dissection sparing the renal and mesenteric arteries and manifesting as chronic rather than acute limb ischemia. The atypical presentation of this case led to repeated misdiagnosis with consequent loss of part of the patient's limb. Better illustration of the natural history of this ill-defined pathology is needed to aid understanding and improve patient care. PMID- 21603146 TI - The role of glucose, serum, and three-dimensional cell culture on the metabolism of bone marrow-derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have become a critical addition to all facets of tissue engineering. While most in vitro research has focused on their behavior in two-dimensional culture, relatively little is known about the cells' behavior in three-dimensional culture, especially with regard to their metabolic state. To evaluate MSC metabolism during twodimensional culture, murine bone marrow-derived MSCs were cultured for one week using twelve different medium compositions, varying in both glucose and fetal bovine serum (FBS) concentrations. The results indicate that glucose concentration was the more important factor in sustaining cell growth and viability. To evaluate metabolic state during three-dimensional culture, MSCs were cultured for one week using two different medium compositions and two different concentrations of collagen gel matrix. The medium compositions only varied in glucose concentration. The results indicate that glucose and extracellular matrix were significant factors in the metabolic response of the cells. However, cells cultured in low density collagen exhibited considerable cell death, likely because of physical contraction of the collagen hydrogel which was not observed in the higher density collagen. These findings will be useful to the development of in vitro cell culture models that properly mimic in vivo physiological processes. PMID- 21603147 TI - Bisphosphonates and atypical fractures of femur. AB - Bisphosphonates are the most widely prescribed medicines for the treatment of osteoporosis and have generally been regarded as well-tolerated and safe drugs. Since 2005, there have been numerous case reports about atypical fractures of the femur linked to long-term treatment of osteoporosis with bisphosphonates. Some attempts to characterize pathophysiology and epidemiology of these fractures have been published as well. However, as the American Society for Bone and Mineral Research (ASBMR) concluded in their task force report, the subject warrants further studies. PMID- 21603148 TI - "Humanized" stem cell culture techniques: the animal serum controversy. AB - Cellular therapy is reaching a pinnacle with an understanding of the potential of human mesenchymal stem cells (hMSCs) to regenerate damaged tissue in the body. The limited numbers of these hMSCs in currently identified sources, like bone marrow, adipose tissue, and so forth, bring forth the need for their in vitro culture/expansion. However, the extensive usage of supplements containing xenogeneic components in the expansion-media might pose a risk to the post transplantation safety of patients. This warrants the necessity to identify and develop chemically defined or "humanized" supplements which would make in vitro cultured/processed cells relatively safer for transplantation in regenerative medicine. In this paper, we outline the various caveats associated with conventionally used supplements of xenogenic origin and also portray the possible alternatives/additives which could one day herald the dawn of a new era in the translation of in vitro cultured cells to therapeutic interventions. PMID- 21603149 TI - Risk factors and options to improve engraftment in unrelated cord blood transplantation. AB - Use of umbilical unrelated cord-blood (UCB) cells as an alternative source of hematopoietic cell transplantation has been widely used mainly for patients lacking an HLA-matched donor. UCB present many advantages over bone marrow or mobilized peripheral blood from volunteer donors, such as rapid availability, absence of risk for the donor, and decreased incidence of acute graft-versus-host disease. However, a significant clinical problem is delayed engraftment that is directly correlated with the number of hematopoietic stem cells in a cord-blood unit. The identification of prognostic factors associated with engraftment that can be easily modified (e.g., strategies for donor choice) and the development of new approaches including use of multiple donors, intrabone injection of UCB, ex vivo expansion, and cotransplantation with accessory cells are of crucial importance in order to circumvent the problem of delayed engraftment after UCB transplantation. Those approaches may increase the quality and availability of UCB for transplantation. PMID- 21603152 TI - Computing Models for FPGA-Based Accelerators. AB - Field-programmable gate arrays are widely considered as accelerators for compute intensive applications. A critical phase of FPGA application development is finding and mapping to the appropriate computing model. FPGA computing enables models with highly flexible fine-grained parallelism and associative operations such as broadcast and collective response. Several case studies demonstrate the effectiveness of using these computing models in developing FPGA applications for molecular modeling. PMID- 21603151 TI - Vitamin C-induced oxalate nephropathy. AB - Although a multitude of syndromes have been thoroughly described as a result of vitamin deficiencies, over consumption of such substances may also be quite dangerous. Intratubular crystallization of calcium oxalate as a result of hyperoxaluria can cause acute renal failure. This type of renal failure is known as oxalate nephropathy. Hyperoxaluria occurs as a result of inherited enzymatic deficiencies known as primary hyperoxaluria or from exogenous sources known as secondary hyperoxaluria. Extensive literature has reported and explained the mechanism of increased absorption of oxalate in malabsorptive syndromes leading to renal injury. However, other causes of secondary hyperoxaluria may also take place either via direct dietary consumption of oxalate rich products or via other substances which may metabolize into oxalate within the body. Vitamin C is metabolized to oxalate. Oral or parenteral administration of this vitamin has been used in multiple settings such as an alternative treatment of malignancy or as an immune booster. This article presents a clinical case in which ingestion of high amounts of vitamin C lead to oxalate nephropathy. This article further reviews other previously published cases in order to illustrate and highlight the potential renal harm this vitamin poses if consumed in excessive amounts. PMID- 21603150 TI - From prostate to bone: key players in prostate cancer bone metastasis. AB - Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules including specific chemokines and their receptors, are distinct in nature and function, yet play intricate and significant roles in prostate cancer bone metastasis. Examining the impact of these facets of bone metastasis in vivo remains a significant challenge, as animal models that mimic the natural history and malignant progression clinical prostate cancer are rare. The goals of this article are to discuss (1) characteristics of bone that most likely render it a favorable environment for prostate tumor cell growth, (2) chemokine signaling that is critical in the recruitment and migration of prostate cancer cells to the bone, and (3) current animal models utilized in studying prostate cancer bone metastasis. Further research is necessary to elucidate the mechanisms underlying the extravasation of disseminated prostate cancer cells into the bone and to provide a better understanding of the basis of cancer cell survival within the bone microenvironment. The development of animal models that recapitulate more closely the human clinical scenario of prostate cancer will greatly benefit the generation of better therapies. PMID- 21603153 TI - The benefits and protective effects of behavioural treatment for dysgraphia in a case of primary progressive aphasia. AB - BACKGROUND: Spoken and written language difficulties are the predominant symptoms in the progressive neurodegenerative disease referred to as primary progressive aphasia (PPA). There has been very little research on the effectiveness of intervention on spoken language impairments in this context and none directed specifically at progressive written language impairment. AIMS: To examine the effectiveness of behavioural intervention for dysgraphia in a case of primary progressive aphasia. METHODS #ENTITYSTARTX00026; PROCEDURES: We carried out a longitudinal single-case study that allowed us to examine the effectiveness of a non-intensive spell-study-spell intervention procedure. We did so by comparing performance on four sets of words: trained, repeated, homework, and control words at five evaluations: baseline, during intervention, after the intervention, and at 6- and 12-month follow-up. OUTCOMES #ENTITYSTARTX00026; RESULTS: We find that: (1) at the end of the intervention, Trained words show a small but statistically significant improvement relative to baseline and an advantage in accuracy over Control, Homework, and Repeated word sets. (2) All word sets exhibited a decline in accuracy from the end of treatment to the 6-month follow up evaluation, consistent with the degenerative nature of the illness. Nonetheless, accuracy on Trained words continued to be superior to that of Control words and not statistically different from pre-intervention baseline levels. (3) Repeated testing and practice at home yielded modest numerical advantages relative to Control words; but these differences were, for many comparisons, not statistically significant. (4) At 12 months post-intervention, all words sets had significantly declined relative to pre-intervention baselines and performance on the four sets was comparable. CONCLUSIONS: This investigation documents-for the first time-that behavioural intervention can provide both immediate and short-term benefits for dysgraphia in the context of primary progressive aphasia. PMID- 21603154 TI - Accent trumps race in guiding children's social preferences. AB - A series of experiments investigated the effect of speakers' language, accent, and race on children's social preferences. When presented with photographs and voice recordings of novel children, 5-year-old children chose to be friends with native speakers of their native language rather than foreign-language or foreign accented speakers. These preferences were not exclusively due to the intelligibility of the speech, as children found the accented speech to be comprehensible, and did not make social distinctions between foreign-accented and foreign-language speakers. Finally, children chose same-race children as friends when the target children were silent, but they chose other-race children with a native accent when accent was pitted against race. A control experiment provided evidence that children's privileging of accent over race was not due to the relative familiarity of each dimension. The results, discussed in an evolutionary framework, suggest that children preferentially evaluate others along dimensions that distinguished social groups in prehistoric human societies. PMID- 21603156 TI - Risk of Disclosure, Perceptions of Risk, and Concerns about Privacy and Confidentiality as Factors in Survey Participation. AB - This article reports on a web-based vignette experiment investigating how likely subjects would be to participate in surveys varying in topic sensitivity and risk of disclosure. A total of 3,672 participants each responded to a series of eight vignettes, along with a variety of background questions, concerns about confidentiality, trust in various institutions, and the like.Vignettes were randomly assigned to respondents, such that each respondent was exposed to four levels of disclosure risk for each level of topic sensitivity (high versus low). Half the sample was assigned to receive a confidentiality statement for all eight vignettes, while the other half received no mention of confidentiality in the vignettes. The order of presentation of vignettes was randomized for each respondent.Respondents were also asked for their subjective perceptions of risk, harm, and social as well as personal benefits for one of the eight vignettes. Adding these questions permits us to examine how objective risk information presented by the researcher relates to the subjective perception of risk by the participant, and to assess the importance of both for their willingness to participate in the surveys described.Under conditions resembling those of real surveys, objective risk information does not affect willingness to participate. On the other hand, topic sensitivity does have such effects, as do general attitudes toward privacy and survey organizations as well as subjective perceptions of risk, harm, and benefits. We discuss the limitations and implications of these findings. PMID- 21603155 TI - Management of the kidney transplant patient with chronic hepatitis C infection. AB - Chronic Hepatitis C (HCV) infection is an important cause of morbidity and mortality in patients with end-stage renal disease. Renal transplantation confers a survival advantage in HCV-infected patients. Renal transplant candidates with serologic evidence of HCV infection should undergo a liver biopsy to assess for fibrosis and cirrhosis. Patients with Metavir fibrosis score <=3 and compensated cirrhosis should be evaluated for interferon-based therapy. Achievement of sustained virological response (SVR) may reduce the risks for both posttransplantation hepatic and extrahepatic complications such as de novo or recurrent glomerulonephritis associated with HCV. Patients who cannot achieve SVR and have no live kidney donor may be considered for HCV-positive kidneys. Interferon should be avoided after kidney transplant except for treatment of life threatening liver injury, such as fibrosing cholestatic hepatitis. Early detection, prevention, and treatment of complications due to chronic HCV infection may improve the outcomes of kidney transplant recipients with chronic HCV infection. PMID- 21603157 TI - Loss, Psychosis, and Chronic Suicidality in a Korean American Immigrant Man: Integration of Cultural Formulation Model and Multicultural Case Conceptualization. AB - Culture shapes the nature, experience, and expression of psychopathology and help seeking behavior across ethnically diverse groups. Although the study of psychopathology among Asian Americans has advanced, clinicians remain in need of culturally appropriate tools for the assessment and diagnosis of severe mental disorders including psychotic symptoms among Asian Americans. In this article, we present a brief overview of two culturally relevant conceptual tools: a) the Cultural Formulation Model, and b) the Multicultural Case Conceptualization approach. We use a case scenario to illustrate the integration of these two approaches in providing culturally responsive clinical conceptualization, assessment and treatment of a Korean American immigrant suffering from prominent psychiatric symptoms. We intend this discussion to engender further empirical work to advance our knowledge of the manifestation and experience of severe mental illness including psychotic disorders among Asian Americans, and contribute to culturally competent prevention and intervention of chronic and persistent mental illness within this group. PMID- 21603158 TI - The Effect of Paricalcitol on Vascular Calcification and Cardiovascular Disease in Uremia: Beyond PTH Control. AB - Secondary hyperparathyroidism is a systemic disorder that associates with bone and cardiovascular disease, including arterial calcification. Treatment with calcitriol, the active form of vitamin D, reduces parathyroid hormone levels, but may result in elevations in serum calcium and phosphorus, increasing the risk of vascular calcification in dialysis patients. New vitamin D receptor activators (VDRAs) have been developed and investigated with the rationale to treat high serum PTH levels, with a reduced risk of hypercalcemia and hyperphosphatemia. Paricalcitol is a selective VDRA that suppresses PTH secretion with minimal increases on serum calcium and phosphate. Moreover, paricalcitol prevents vascular calcification in experimental models of renal failure, compared with calcitriol. PMID- 21603159 TI - Clinical Significance of FGF-23 in Patients with CKD. AB - FGF23 is a bone-derived hormone that plays an important role in the regulation of phosphate and 1,25-dihydroxy vitamin D metabolism. FGF23 principally acts in the kidney to induce urinary phosphate excretion and suppress 1,25-dihydroxyvitamin D synthesis in the presence of FGF receptor 1 (FGFR1) and its coreceptor Klotho. In patients with chronic kidney disease (CKD), circulating FGF23 levels are progressively increased to compensate for persistent phosphate retention, but this results in reduced renal production of 1,25-dihydroxyvitamin D and leads to hypersecretion of parathyroid hormone. Furthermore, FGF23 is associated with vascular dysfunction, atherosclerosis, and left ventricular hypertrophy. This paper summarizes the role of FGF23 in the pathogenesis of mineral, bone, and cadiovascular disorders in CKD. PMID- 21603160 TI - Correction of iron deficiency in the cardiorenal syndrome. AB - Impaired energy metabolism is a feature of Congestive Heart Failure (CHF). Iron deficiency has been shown to reduce energy production in the cell in animals and humans. Iron deficiency is common in both Chronic Kidney Disease (CKD) and in CHF. Recent studies suggest that iron deficiency is an independent risk factor for mortality in CHF. Studies of correction of the anemia with intravenous (IV) iron in both CKD and CHF have shown an improvement in the anemia and, in some cases, in the renal function as well. Some CHF studies of correction of the iron deficiency have shown an improvement in cardiac function and structure as well as in exercise capacity and quality of life. This occurred independent of whether or not they had anemia, suggesting that the iron deficiency itself may be independently contributing to the worsening of the CHF and CKD. If future long term studies confirm the safety and efficacy of IV iron in the treatment of iron deficiency in CKD and CHF, this will become a new addition to the therapeutic armamentarium of the cardiorenal syndrome, and parameters of iron deficiency will become part of the routine measurements performed in both CKD and CHF whether or not the patient is anemic. PMID- 21603162 TI - Nanoprodrugs of NSAIDs: Preparation and Characterization of Flufenamic Acid Nanoprodrugs. AB - We demonstrated that hydrophobic derivatives of the nonsteroidal anti inflammatory drug (NSAID)flufenamic acid (FA), can be formed into stable nanometer-sized prodrugs (nanoprodrugs) that inhibit the growth of glioma cells, suggesting their potential application as anticancer agent. We synthesized highly hydrophobic monomeric and dimeric prodrugs of FA via esterification and prepared nanoprodrugs using spontaneous emulsification mechanism. The nanoprodrugs were in the size range of 120 to 140 nm and physicochemically stable upon long-term storage as aqueous suspension, which is attributed to the strong hydrophobic interaction between prodrug molecules. Importantly, despite the highly hydrophobic nature and water insolubility, nanoprodrugs could be readily activated into the parent drug by porcine liver esterase, presenting a potential new strategy for novel NSAID prodrug design. The nanoprodrug inhibited the growth of U87-MG glioma cells with IC(50) of 20 MUM, whereas FA showed IC(50) of 100 MUM, suggesting that more efficient drug delivery was achieved with nanoprodrugs. PMID- 21603164 TI - Thyroid tuberculosis: a case series and a review of the literature. AB - Objective. Tuberculosis of the thyroid gland is a very rare disease. The incidence of extrapulmonary tuberculosis has been showing a progressive increase in the recent years. We present three cases of primary thyroid tuberculosis. Methods. Two cases were diagnosed on the basis of fine-needle aspiration cytology (FNAC), as they presented with thyroid nodule. The third case was diagnosed on histopathology as the patient underwent total thyroidectomy for the left-side nodule which was a follicular lesion on FNAC. Tuberculosis was diagnosed on the other lobe. Results. All three patients were given antituberculous treatment for nine months, and their nodular lesions completely resolved after treatment. Conclusion. Although rare the, thyroid tuberculosis should be kept in mind in the differential diagnosis of thyroid masses, even in patient with no history and symptom of tuberculosis disease elsewhere. PMID- 21603163 TI - Allergic bronchopulmonary aspergillosis in asthma and cystic fibrosis. AB - Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity lung disease in response to Aspergillus fumigatus that affects asthmatic and cystic fibrosis (CF) patients. Sensitization to A. fumigatus is common in both atopic asthmatic and CF patients, yet only 1-2% of asthmatic and 7-9% of CF patients develop ABPA. ABPA is characterized by wheezing and pulmonary infiltrates which may lead to pulmonary fibrosis and/or bronchiectasis. The inflammatory response is characterized by Th2 responses to Aspergillus allergens, increased serum IgE and eosinophilia. A number of genetic risks have recently been identified in the development of ABPA. These include HLA-DR and HLA-DQ, IL-4 receptor alpha chain (IL-4RA) polymorphisms, IL-10-1082GA promoter polymorphisms, surfactant protein A2 (SP-A2) polymorphisms, and cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations. The studies indicate that ABPA patients are genetically at risk to develop skewed and heightened Th2 responses to A. fumigatus antigens. These genetic risk studies and their consequences of elevated biologic markers may aid in identifying asthmatic and CF patients who are at risk to the development of ABPA. Furthermore, these studies suggest that immune modulation with medications such as anti-IgE, anti-IL-4 and/or IL-13 monoclonal antibodies may be helpful in the treatment of ABPA. PMID- 21603161 TI - Exogenous control of the expression of Group I CD1 molecules competent for presentation of microbial nonpeptide antigens to human T lymphocytes. AB - Group I CD1 (CD1a, CD1b, and CD1c) glycoproteins expressed on immature and mature dendritic cells present nonpeptide antigens (i.e., lipid or glycolipid molecules mainly of microbial origin) to T cells. Cytotoxic CD1-restricted T lymphocytes recognizing mycobacterial lipid antigens were found in tuberculosis patients. However, thanks to a complex interplay between mycobacteria and CD1 system, M. tuberculosis possesses a successful tactic based, at least in part, on CD1 downregulation to evade CD1-dependent immunity. On the ground of these findings, it is reasonable to hypothesize that modulation of CD1 protein expression by chemical, biological, or infectious agents could influence host's immune reactivity against M. tuberculosis-associated lipids, possibly affecting antitubercular resistance. This scenario prompted us to perform a detailed analysis of the literature concerning the effect of external agents on Group I CD1 expression in order to obtain valuable information on the possible strategies to be adopted for driving properly CD1-dependent immune functions in human pathology and in particular, in human tuberculosis. PMID- 21603165 TI - Review of allergic and photoallergic contact dermatitis from an ingredient in a medicament vehicle consisting of a compress, poultice, plaster, and tape. AB - The topical application of a medicament vehicle consisting of a compress, poultice, plaster, and tape containing a nonsteroidal anti-inflammatory drug or methyl salicylate is prevalent in Japan. The method is effective for conveying ingredients to the muscles via the skin for the relief of muscular pain. However, an ingredient in the occlusive vehicle can cause allergic and photoallergic contact dermatitis. We summarize cases reported over the past decade and discuss the current strategy for diminishing the risk of allergic and photoallergic contact dermatitis. PMID- 21603166 TI - Pediatric stroke: clinical findings and radiological approach. AB - This paper focuses on radiological approach in pediatric stroke including both ischemic stroke (Arterial Ischemic Stroke and Cerebral Sinovenous Thrombosis) and hemorrhagic stroke. Etiopathology and main clinical findings are examined as well. Magnetic Resonance Imaging could be considered as the first-choice diagnostic exam, offering a complete diagnostic set of information both in the discrimination between ischemic/hemorrhagic stroke and in the identification of underlying causes. In addition, Magnetic Resonance vascular techniques supply further information about cerebral arterial and venous circulation. Computed Tomography, for its limits and radiation exposure, should be used only when Magnetic Resonance is not available and on unstable patients. PMID- 21603168 TI - Occupational asthma in antibiotic manufacturing workers: case reports and systematic review. AB - Background. The risks of occupational asthma (OA) from antibiotics are uncertain. We report 4 new cases and a systematic review of the literature. Methods. Cases were identified through a specialist clinic, each underwent specific provocation testing (SPT). We subsequently reviewed the published literature. Results. The patients were employed in the manufacture of antibiotics; penicillins were implicated in three cases, in the fourth erythromycin, not previously reported to cause OA. In two, there was evidence of specific IgE sensitisation. At SPT each developed a late asthmatic reaction and increased bronchial hyperresponsiveness. 36 case reports have been previously published, 26 (citing penicillins or cephalosporins). Seven cross-sectional workplace-based surveys found prevalences of 5-8%. Conclusions. OA in antibiotic manufacturers may be more common than is generally recognised. Its pathogenesis remains unclear; immunological tests are of uncertain value and potential cases require confirmation with SPT. Further study of its frequency, mechanisms, and diagnosis is required. PMID- 21603167 TI - Recent advances in molecular diagnosis of thyroid cancer. AB - Recent molecular studies have described a number of abnormalities associated with the progression and dedifferentiation of thyroid carcinoma. These distinct molecular events are often associated with specific stages of tumor development. In particular, remarkable advances have occurred in several major biological areas of thyroid cancer, including the molecular alterations for the loss of radioiodine avidity of thyroid cancer, the pathogenic role of the MAP kinase and PI3K/Akt pathways and their related genetic alterations, and the aberrant methylation of functionally important genes in thyroid tumorigenesis and pathogenesis. Recognition of these features is crucial to the management of patients with thyroid cancer. Novel treatments are being designed based on our enhanced understanding of this disease process. PMID- 21603169 TI - Comparison of the Effectiveness of Three Methods of Recanalization in a Model of the Middle Cerebral Artery: Thrombus Aspiration via a 4F Catheter, Thrombus Aspiration via the GP Thromboaspiration Device, and Mechanical Thrombectomy Using the Solitaire Thrombectomy Device. AB - Introduction. This paper compares different approaches to recanalization in a model of the middle cerebral artery (MCA). Methods. An occlusive thrombus (lamb's blood) was introduced into the MCA of a model of the cerebral circulation perfused with Hartmann's solution (80 pulsations/min, mean pressure 90 mm Hg). Three methods of clot retrieval were tested: thrombus aspiration via a 4F catheter (n = 26), thrombus aspiration via the GP thrombus aspiration device (GPTAD) (n = 30), and mechanical thrombectomy via the Solitaire Device (n = 30). Results. Recanalization rate was similar for all 3 approaches (62%, 77%, and 85%). Time to recanalization was faster with aspiration devices (41 SD 42 s for 4F and 61 SD 21 s for GPTAD) than with the Solitaire (197 SD 64 s P < .05 Kruksal Wallis). Clot fragmentation was the same in the Solitaire (23%) and the GPTAD (23%), but higher with the 4F (53%, P < .05). Conclusion. In this model, thrombus aspiration was faster than mechanical thrombectomy, and similarly effective at recanalization. These results should be confirmed in vivo. PMID- 21603170 TI - A Patient with Postpartum Hypopituitarism (Sheehan's Syndrome) Developed Postpartum Autoimmune Thyroiditis (Transient Thyrotoxicosis and Hypothyroidism): A Case Report and Review of the Literature. AB - A 36-year-old woman with postpartum hypopituitarism (Sheehan's syndrome: SS) developed postpartum autoimmune thyroiditis (PPAT). She delivered a baby by Caesarean section (620 mL blood loss). At 1 month post partum, she developed thyrotoxicosis due to painless thyroiditis (autoimmune destructive thyroiditis). She was positive for antithyroid antibodies. Postpartum and hypoadrenalism induced exacerbation of autoimmune thyroiditis caused the thyrotoxicosis due to autoimmune destructive thyroiditis. ACTH was undetectable. She had ACTH deficiency and secondary hypoadrenalism. Hydrocortisone was started. At 6 months post partum, she was referred to us with hypothyroidism. Thyroxine was administered. She had thyrotoxicosis at 1-2 months post partum and then hypothyroidism. She was diagnosed with PPAT. She had hypopituitarism, ACTH deficiency (secondary hypoadrenalism), low prolactin with agalactia, and low LH with failure to resume regular menses. She had empty sella on MRI. She was diagnosed with SS. Three cases with SS have been reported to develop PPAT. Postpartum immunological rebounds and hypoadrenalism-induced immunological alterations (or a combination of the two) might have been responsible for the PPAT. PMID- 21603171 TI - A case of severe bronchial asthma controlled with tacrolimus. AB - Background. The control of severe bronchial asthma, such as corticosteroid resistant asthma, is difficult. It is also possible that immunosuppressive agents would be effective for bronchial asthma. Case Summary. A 55-year-old Japanese female presented with severe bronchial asthma controlled with tacrolimus. She had been diagnosed with bronchial asthma during childhood. Her asthma worsened, and a chest radiograph showed atelectasis of the left lung. Bronchoscopy revealed the left main bronchus to be obstructed with viscous sputum consisting of 82% neutrophils and no eosinophils. The atelectasis did not improve with corticosteroid treatment, but was ameliorated by administration of tacrolimus. Discussion. This patient had severe asthma due to neutrophilic inflammation of the airways. Tacrolimus is effective for treating severe asthma, for example, in corticosteroid-resistant cases. PMID- 21603172 TI - Invariant NKT Cell Lines Derived from the NOD.H2 Mouse Enhance Autoimmune Thyroiditis. AB - To study the role of invariant Natural Killer T cell ( iNKT) cells in autoimmune thyroiditis, we derived two iNKT cell lines from the spleens of NOD. H2(h4) mice, a strain that develops spontaneous autoimmune thyroiditis exacerbated by excess dietary iodine. The two lines were CD1d-restricted and expressed CD4(+), DX5(+), and the Valpha4Jalpha281 gene segment, of the T-cell receptor alpha locus. Upon stimulation with alpha-galactosyl-ceramide (alpha-GalCer), both lines rapidly produced IL-2, IL-4, IFN-gamma, IL-10, and TNF-alpha. Strikingly, a similar cytokine response was also induced by thyroglobulin, one of the most abundant protein in the thyroid gland and a major autoantigen in human autoimmune thyroiditis. Transfer of the iNKT cell lines to syngeneic hosts enhanced autoimmune thyroiditis. Intraperitoneal injections of alpha-GalCer in iodine primed mice also induced thyroid disease. This paper reports for the first time that iNKT cells respond to thyroglobulin and enhance autoimmune thyroiditis in iodine fed NOD.H2(h4) mice. PMID- 21603173 TI - A review of the impact of occupational contact dermatitis on quality of life. AB - Occupational contact dermatitis (OCD) is the most common occupational skin disease in many countries. We reviewed the current evidence on how OCD impacts on quality of life (QoL). The three commonly used QoL questionnaires in OCD were the Short-Form Health Survey (SF-36), the Dermatology Life Quality Index (DLQI), and the Skindex. Despite the availability of a variety of validated QoL instruments, none of them is specific to OCD or entirely adequate in capturing the impact of OCD on QoL. Nonetheless, the results of this paper do suggest a significant impact. Use of QoL measures in clinical settings will provide patients with an opportunity to express their concerns and assist clinicians to evaluate the effectiveness of management beyond the clinical outcomes. This paper also highlights the lack of a disease-specific QOL instrument and the importance of developing a validated measure to assess QOL in OCD, enabling comparison across countries and occupational groups. PMID- 21603174 TI - Barriers of thrombolysis therapy in developing countries. AB - The developing world carries the highest burden of stroke mortality and stroke related disability. The number of stroke patients receiving r-tPA in the developing world is extremely low. Prehospital delay, financial constraints, and lack of infrastructure are main barriers of thrombolysis therapy in developing countries. Until a cheaper thrombolytic agent and the proper infrastructure for utilization of thrombolytic therapy is available, developing countries should focus on primary and secondary stroke prevention strategies. However, governments and health systems of developing countries should efforts exerb for promotion of their infrastructure of stroke care. PMID- 21603175 TI - Comprehensive CT Evaluation in Acute Ischemic Stroke: Impact on Diagnosis and Treatment Decisions. AB - Background. With modern CT imaging a comprehensive overview of cerebral macro- and microcirculation can be obtained within minutes in acute ischemic stroke. This opens for patient stratification and individualized treatment. Methods. Four patients with acute ischemic stroke of different aetiologies and/or treatments were chosen for illustration of the comprehensive CT protocol and its value in subsequent treatment decisions. The patients were clinically evaluated according to the NIHSS-scale, examined with the comprehensive CT protocol including both CT angiography and CT perfusion, and followed up by MRI. Results. The comprehensive CT examination protocol increased the examination time but did not delay treatment initiation. In some cases CT angiography revealed the cause of stroke while CT perfusion located and graded the perfusion defect with reasonable accuracy, confirmed by follow-up MR-diffusion. In the presented cases findings of the comprehensive CT examination influenced the treatment strategy. Conclusions. The comprehensive CT examination is a fast and safe method allowing accurate diagnosis and making way for individualized treatment in acute ischemic stroke. PMID- 21603176 TI - Case of "slow" stroke from carotid artery occlusion treated by delayed but cautious endovascular intervention. AB - In a challenging case of carotid occlusion with slowly evolving stroke, we used brain imaging to facilitate endovascular revascularization resulting in the relief of the patient's symptoms. Patients with carotid occlusion and continued neurological worsening or fluctuations present enormous treatment challenges. These patients may present "slow" strokes with subacute infarcts that present significant challenges and risks during attempts at revascularization of the occluded artery. We present such a case in which we used multimodal imaging techniques, including MR-perfusion, to facilitate endovascular revascularization. Our approach of delayed but cautious intra-arterial thrombolytic therapy, guided by brain imaging, and followed by stent placement across the residual stenosis, enabled revascularization of the occluded artery without overt in-hospital complications. PMID- 21603177 TI - Lipopolysaccharide animal models for Parkinson's disease. AB - Lipopolysaccharide (LPS), an endotoxin from Gram-negative bacteria, acts as a potent stimulator of microglia and has been used to study the inflammatory process in the pathogenesis of Parkinson's disease (PD) and anti-inflammatory therapy for PD treatment. Here, we review the growing body of literature on both in vitro and in vivo LPS PD models. Primary cell cultures from mesencephalic tissue were exposed to LPS in vitro; LPS was stereotaxically injected into the substantia nigra, striatum, or globus pallidus of brain or injected into the peritoneal cavity of the animal in vivo. In conclusion, the LPS PD models are summarized as (1) local and direct LPS treatment and (2) systemic LPS treatment. Mechanisms underlying the PD models are investigated and indicated that LPS induces microglial activation to release a variety of neurotoxic factors, and damaged neurons may trigger reactive microgliosis, which lead to progressive dopaminergic neurodegeneration. PMID- 21603179 TI - Association rule based similarity measures for the clustering of gene expression data. AB - In life threatening diseases, such as cancer, where the effective diagnosis includes annotation, early detection, distinction, and prediction, data mining and statistical approaches offer the promise for precise, accurate, and functionally robust analysis of gene expression data. The computational extraction of derived patterns from microarray gene expression is a non-trivial task that involves sophisticated algorithm design and analysis for specific domain discovery. In this paper, we have proposed a formal approach for feature extraction by first applying feature selection heuristics based on the statistical impurity measures, the Gini Index, Max Minority, and the Twoing Rule and obtaining the top 100-400 genes. We then analyze the associative dependencies between the genes and assign weights to the genes based on their degree of participation in the rules. Consequently, we present a weighted Jaccard and vector cosine similarity measure to compute the similarity between the discovered rules. Finally, we group the rules by applying hierarchical clustering. To demonstrate the usability and efficiency of the concept of our technique, we applied it to three publicly available, multiclass cancer gene expression datasets and performed a biomedical literature search to support the effectiveness of our results. PMID- 21603178 TI - Peripheral inflammation increases the damage in animal models of nigrostriatal dopaminergic neurodegeneration: possible implication in Parkinson's disease incidence. AB - Inflammatory processes described in Parkinson's disease (PD) and its animal models appear to be important in the progression of the pathogenesis, or even a triggering factor. Here we review that peripheral inflammation enhances the degeneration of the nigrostriatal dopaminergic system induced by different insults; different peripheral inflammations have been used, such as IL-1beta and the ulcerative colitis model, as well as insults to the dopaminergic system such as 6-hydroxydopamine or lipopolysaccharide. In all cases, an increased loss of dopaminergic neurons was described; inflammation in the substantia nigra increased, displaying a great activation of microglia along with an increase in the production of cytokines such as IL-1beta and TNF-alpha. Increased permeability or disruption of the BBB, with overexpression of the ICAM-1 adhesion molecule and infiltration of circulating monocytes into the substantia nigra, is also involved, since the depletion of circulating monocytes prevents the effects of peripheral inflammation. Data are reviewed in relation to epidemiological studies of PD. PMID- 21603180 TI - DoctorEye: A clinically driven multifunctional platform, for accurate processing of tumors in medical images. AB - This paper presents a novel, open access interactive platform for 3D medical image analysis, simulation and visualization, focusing in oncology images. The platform was developed through constant interaction and feedback from expert clinicians integrating a thorough analysis of their requirements while having an ultimate goal of assisting in accurately delineating tumors. It allows clinicians not only to work with a large number of 3D tomographic datasets but also to efficiently annotate multiple regions of interest in the same session. Manual and semi-automatic segmentation techniques combined with integrated correction tools assist in the quick and refined delineation of tumors while different users can add different components related to oncology such as tumor growth and simulation algorithms for improving therapy planning. The platform has been tested by different users and over large number of heterogeneous tomographic datasets to ensure stability, usability, extensibility and robustness with promising results. AVAILABILITY: the platform, a manual and tutorial videos are available at: http://biomodeling.ics.forth.gr. it is free to use under the GNU General Public License. PMID- 21603181 TI - Pharmacological modulation of dopamine receptor D2-mediated transmission alters the metabolic phenotype of diet induced obese and diet resistant C57Bl6 mice. AB - High fat feeding induces a variety of obese and lean phenotypes in inbred rodents. Compared to Diet Resistant (DR) rodents, Diet Induced Obese (DIO) rodents are insulin resistant and have a reduced dopamine receptor D2 (DRD2) mediated tone. We hypothesized that this differing dopaminergic tone contributes to the distinct metabolic profiles of these animals. C57Bl6 mice were classified as DIO or DR based on their weight gain during 10 weeks of high fat feeding. Subsequently DIO mice were treated with the DRD2 agonist bromocriptine and DR mice with the DRD2 antagonist haloperidol for 2 weeks. Compared to DR mice, the bodyweight of DIO mice was higher and their insulin sensitivity decreased. Haloperidol treatment reduced the voluntary activity and energy expenditure of DR mice and induced insulin resistance in these mice. Conversely, bromocriptine treatment tended to reduce bodyweight and voluntary activity, and reinforce insulin action in DIO mice. These results show that DRD2 activation partly redirects high fat diet induced metabolic anomalies in obesity-prone mice. Conversely, blocking DRD2 induces an adverse metabolic profile in mice that are inherently resistant to the deleterious effects of high fat food. This suggests that dopaminergic neurotransmission is involved in the control of metabolic phenotype. PMID- 21603183 TI - The identification of insulin saturation effects during the dynamic insulin sensitivity test. AB - BACKGROUND: Many insulin sensitivity (SI) tests identify a sensitivity metric that is proportional to the total available insulin and measured glucose disposal despite general acceptance that insulin action is saturable. Accounting for insulin action saturation may aid inter-participant and/or inter-test comparisons of insulin efficiency, and model-based glycaemic regulation. METHOD: Eighteen subjects participated in 46 dynamic insulin sensitivity tests (DIST, low-dose 40 50 minute insulin-modified IVGTT). The data was used to identify and compare SI metrics from three models: a proportional model (SI(L)), a saturable model (SI(S )and Q50) and a model similar to the Minimal Model (SG and SI(G)). The three models are compared using inter-trial parameter repeatability, and fit to data. RESULTS: The single variable proportional model produced the metric with least intra-subject variation: 13.8% vs 40.1%/55.6%, (SI(S)/I50) for the saturable model and 15.8%/88.2% (SI(G)/SG) for the third model. The average plasma insulin concentration at half maximum action (I50) was 139.3 mU.L-1, which is comparable to studies which use more robust stepped EIC protocols. CONCLUSIONS: The saturation model and method presented enables a reasonable estimation of an overall patient-specific saturation threshold, which is a unique result for a test of such low dose and duration. The detection of previously published population trends and significant bias above noise suggests that the model and method successfully detects actual saturation signals. Furthermore, the saturation model allowed closer fits to the clinical data than the other models, and the saturation parameter showed a moderate distinction between NGT and IFG T2DM subgroups. However, the proposed model did not provide metrics of sufficient resolution to enable confidence in the method for either SI metric comparisons across dynamic tests or for glycamic control. PMID- 21603182 TI - Optimizing a rodent model of Parkinson's disease for exploring the effects and mechanisms of deep brain stimulation. AB - Deep brain stimulation (DBS) has become a treatment for a growing number of neurological and psychiatric disorders, especially for therapy-refractory Parkinson's disease (PD). However, not all of the symptoms of PD are sufficiently improved in all patients, and side effects may occur. Further progress depends on a deeper insight into the mechanisms of action of DBS in the context of disturbed brain circuits. For this, optimized animal models have to be developed. We review not only charge transfer mechanisms at the electrode/tissue interface and strategies to increase the stimulation's energy-efficiency but also the electrochemical, electrophysiological, biochemical and functional effects of DBS. We introduce a hemi-Parkinsonian rat model for long-term experiments with chronically instrumented rats carrying a backpack stimulator and implanted platinum/iridium electrodes. This model is suitable for (1) elucidating the electrochemical processes at the electrode/tissue interface, (2) analyzing the molecular, cellular and behavioral stimulation effects, (3) testing new target regions for DBS, (4) screening for potential neuroprotective DBS effects, and (5) improving the efficacy and safety of the method. An outlook is given on further developments of experimental DBS, including the use of transgenic animals and the testing of closed-loop systems for the direct on-demand application of electric stimulation. PMID- 21603184 TI - Dopamine-induced nonmotor symptoms of Parkinson's disease. AB - Nonmotor symptoms of Parkinson's disease (PD) may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS) is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease. PMID- 21603185 TI - Do somatic mitochondrial DNA mutations contribute to Parkinson's disease? AB - A great deal of evidence supports a role for mitochondrial dysfunction in the pathogenesis of Parkinson's disease (PD), although the origin of the mitochondrial dysfunction in PD remains unclear. Expression of mitochondrial DNA (mtDNA) from PD patients in "cybrid" cell lines recapitulates the mitochondrial defect, implicating a role for mtDNA mutations, but the specific mutations responsible for the mitochondrial dysfunction in PD have been difficult to identify. Somatic mtDNA point mutations and deletions accumulate with age and reach high levels in substantia nigra (SN) neurons. Mutations in mitochondrial DNA polymerase gamma (POLG) that lead to the accumulation of mtDNA mutations are associated with a premature aging phenotype in "mutator" mice, although overt parkinsonism has not been reported in these mice, and with parkinsonism in humans. Together these data support, but do not yet prove, the hypothesis that the accumulation of somatic mtDNA mutations in SN neurons contribute to the pathogenesis of PD. PMID- 21603186 TI - Do PPAR-Gamma Agonists Have a Future in Parkinson's Disease Therapy? AB - Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor (PPAR) gamma agonists commonly used as insulin-sensitizing drugs for the treatment of type 2 diabetes. In the last decade, PPAR-gamma agonists have received increasing attention for their neuroprotective properties displayed in a variety of neurodegenerative diseases, including Parkinson's disease (PD), likely related to the anti-infammatory activity of these compounds. Recent studies indicate that neuroinflammation, specifically reactive microglia, plays important roles in PD pathogenesis. Moreover, after the discovery of infiltrating activated Limphocytes in the substantia nigra (SN) of PD patients, most recent research supports a role of immune-mediated mechanisms in the pathological process leading to chronic neuroinflammation and dopaminergic degeneration. PPAR-gamma are highly expressed in cells of both central and peripheral immune systems, playing a pivotal role in microglial activation as well as in monocytes and T cells differentiation, in which they act as key regulators of immune responses. Here, we review preclinical evidences of PPAR-gamma-induced neuroprotection in experimental PD models and highlight relative anti-inflammatory mechanisms involving either central or peripheral immunomodulatory activity. Specific targeting of immune functions contributing to neuroinflammation either directly (central) or indirectly (peripheral) may represent a novel therapeutic approach for disease modifying therapies in PD. PMID- 21603187 TI - Diversity in the regulation of autophagy and mitophagy: lessons from Parkinson's disease. AB - Selective mitochondrial degradation through autophagy (mitophagy) has emerged as an important homeostatic mechanism in a variety of organisms and contexts. Complete clearance of mitochondria can be observed during normal maturation of certain mammalian cell types, and during certain forms of neuronal cell death. In recent years, autophagy dysregulation has been implicated in toxin-injured dopaminergic neurons as well as in major genetic models of Parkinson's disease (PD), including alpha-synuclein, leucine-rich repeat kinase 2 (LRRK2), parkin, PTEN-induced kinase 1 (PINK1), and DJ-1. Indeed, PINK1-parkin interactions may form the basis of a mechanism by which dissipation of the inner mitochondrial membrane potential can trigger selective mitochondrial targeting for autophagy. Multiple signals are likely to exist, however, depending upon the trigger for mitophagy. Similarly, the regulation of basal or injury-induced autophagy does not always follow canonical pathways described for nutrient deprivation. Implications of this regulatory diversity are discussed in the context of neuronal function and survival. Further studies are needed to address whether alterations in autophagy regulation play a directly injurious role in PD pathogenesis, or if the observed changes reflect impaired, appropriate, or excessive autophagic responses to other forms of cellular injury. PMID- 21603188 TI - Idiopathic REM Sleep Behavior Disorder: Implications for the Pathogenesis of Lewy Body Diseases. AB - Objectives. Both results of the odor identification and cardiac (123)I metaiodobenzylguanidine accumulation have been investigated for their potential to enhance the detection of pathogenesis resembling that of Lewy body-related alpha-synucleinopathies in patients clinically diagnosed as having idiopathic REM sleep behavior disorder. Methods. We performed both the Odor Stick Identification Test for Japanese and (123)I-metaiodobenzylguanidine scintigraphy in 30 patients with idiopathic REM sleep behavior disorder, 38 patients with Parkinson's disease, and 20 control subjects. Results. In idiopathic REM sleep behavior disorder, reduced odor identification score and an early or delayed heart to mediastinum ratio on (123)I-metaiodobenzylguanidine were almost as severe as in Parkinson's disease patients. Delayed cardiac (123)I-metaiodobenzylguanidine uptake was even more severe in the idiopathic REM sleep behavior disorder group than in the Parkinson's disease group. Conclusions. Reduced cardiac (123)I metaiodobenzylguanidine uptake, which is independent of parkinsonism, may be more closely associated with idiopathic REM sleep behavior disorder than olfactory impairment. PMID- 21603189 TI - Autonomic disorders in multiple sclerosis. AB - Multiple sclerosis is an inflammatory disease leading to disseminated lesions of the central nervous system resulting in both somatomotor and autonomic disturbances. These involve the central centers of the autonomic nervous system, as well as the automatic control and pathway systems. All autonomic functions may be disordered individually or in combined form. There is no other disease with a clinical picture so multifaceted. Besides cardiovascular dysfunctions disorders of bladder and rectum have become apparent. Somatomotor and autonomic disturbances occur with similar frequency; however the focused exam often heavily favors somatomotor symptoms. Autonomic disturbances should primarily be taken into account on history taking and clinical examination. Individual diagnosis and treatment is a secondary feature. Impairments of the autonomic nervous systems in multiple sclerosis are frequently overlooked. PMID- 21603190 TI - The immunomodulatory effects of albumin in vitro and in vivo. AB - Albumin appears to have proinflammatory effects in vitro. We hypothesized that albumin would induce a state of tolerance to subsequent administration of lipopolysaccharide (LPS) in vitro and in vivo. RAW264.7 and primary peritoneal macrophages were treated with increasing doses of bovine serum albumin (BSA) and harvested for NF-kappaB luciferase reporter assay or TNF-alpha ELISA. In separate experiments, RAW264.7 cells were preconditioned with 1 mg/mL BSA for 18 h prior to LPS (10 MUg/mL) treatment and harvested for NF-kappaB luciferase reporter assay or TNF-alpha ELISA. Finally, C57Bl/6 mice were preconditioned with albumin via intraperitoneal administration 18 h prior to a lethal dose of LPS (60 mg/kg body wt). Blood was collected at 6 h after LPS administration for TNF-alpha ELISA. Albumin produced a dose-dependent and TLR-4-dependent increase in NF kappaB activation and TNF-alpha gene expression in vitro. Albumin preconditioning abrogated the LPS-mediated increase in NF-kappaB activation and TNF-alpha gene expression in vitro and in vivo. The clinical significance of these findings remains to be elucidated. PMID- 21603191 TI - Adherence to antibiotic prophylaxis in children with vesicoureteral reflux. AB - Vesicoureteral reflux (VUR) affects approximately 1% of children and may predispose a child with a bladder infection to develop pyelonephritis and renal scarring. To prevent these potential sequelae, one accepted treatment option for VUR includes low-dose continuous antibiotic prophylaxis (CAP) to maintain urine sterility until the condition resolves. Despite the widespread use of CAP, little data exists regarding adherence to long-term antibiotic therapy. Not only will poor adherence to CAP potentially preclude the intended benefit, but also nonadherence with antibiotic regimens may carry untoward effects including unnecessary treatment changes for presumed antibiotic failure, emergence of resistant organisms, and compromised clinical trial outcomes. We present an overview of medication adherence in children with VUR, discuss possible consequences of nonadherence to antibiotic prophylaxis, and suggest ways to improve adherence. We raise awareness of issues related to nonadherence relevant to healthcare providers, investigators, and the community. PMID- 21603192 TI - Adaptive immune responses in primary cutaneous sarcoidosis. AB - Sarcoidosis is a multisystemic inflammatory disorder with cutaneous lesions present in about one-quarter of the patients. Cutaneous lesions have been classified as specific and nonspecific, depending on the presence of nonnecrotizing epithelial cell granulomas on histologic studies. The development and progression of specific cutaneous sarcoidosis involves a complex interaction between cells of the adaptive immune systems, notably T-lymphocytes and dendritic cells. In this paper, we will discuss the role of T-cells and skin dendritic cells in the development of primary cutaneous sarcoidosis and comment on the potential antigenic stimuli that may account for the development of the immunological response. We will further explore the contributions of selected cytokines to the immunopathological process. The knowledge of the adaptive immunological mechanisms operative in cutaneous sarcoidosis may subsequently be useful for identifying prevention and treatment strategies of systemic sarcoidosis. PMID- 21603193 TI - Outcome of glansectomy and skin grafting in the management of penile cancer. AB - Purpose. To report outcome data for patients with penile cancer treated surgically with glansectomy and skin grafting. Materials and Methods. We retrospectively reviewed data on all patients undergoing surgical management of penile cancer by a single surgeon between 1998 and 2008. Outcomes in patients who underwent glansectomy and skin grafting were analysed. Results. Between 1998 and 2008 a total of 25 patients with a mean age 60 (39-83) underwent glansectomy and skin grafting. Six patients had carcinoma in situ (CIS); the stage in the remaining patients ranged from T1G1 to T3G3. Mean followup for patients was 28 months (range 6-66). Disease specific survival was 92% with 2 patients who had positive nodes at lymph node dissection developing groin recurrence. One patient developed a local recurrence requiring a partial penectomy. Conclusions. Penile preserving surgery with glansectomy and skin grafting is a successful technique with minimal complications for local control of penile carcinoma arising on the glans. Careful followup to exclude local recurrence is required. PMID- 21603194 TI - Possible roles of ectophosphatases in host-parasite interactions. AB - The interaction and survival of pathogens in hostile environments and in confrontation with host immune responses are important mechanisms for the establishment of infection. Ectophosphatases are enzymes localized at the plasma membrane of cells, and their active sites face the external medium rather than the cytoplasm. Once activated, these enzymes are able to hydrolyze phosphorylated substrates in the extracellular milieu. Several studies demonstrated the presence of surface-located ecto-phosphatases in a vast number of pathogenic organisms, including bacteria, protozoa, and fungi. Little is known about the role of ecto phosphatases in host-pathogen interactions. The present paper provides an overview of recent findings related to the virulence induced by these surface molecules in protozoa and fungi. PMID- 21603195 TI - Drug nanoparticle formulation using ascorbic Acid derivatives. AB - Drug nanoparticle formulation using ascorbic acid derivatives and its therapeutic uses have recently been introduced. Hydrophilic ascorbic acid derivatives such as ascorbyl glycoside have been used not only as antioxidants but also as food and pharmaceutical excipients. In addition to drug solubilization, drug nanoparticle formation was observed using ascorbyl glycoside. Hydrophobic ascorbic acid derivatives such as ascorbyl mono- and di-n-alkyl fatty acid derivatives are used either as drugs or carrier components. Ascorbyl n-alkyl fatty acid derivatives have been formulated as antioxidants or anticancer drugs for nanoparticle formulations such as micelles, microemulsions, and liposomes. ASC-P vesicles called aspasomes are submicron-sized particles that can encapsulate hydrophilic drugs. Several transdermal and injectable formulations of ascorbyl n-alkyl fatty acid derivatives were used, including ascorbyl palmitate. PMID- 21603197 TI - Cancer stem cells. PMID- 21603196 TI - Gonadotropin-dependent precocious puberty: neoplastic causes and endocrine considerations. AB - Premature activation of the hypothalamic-pituitary-gonadal (HPG) axis manifests as gonadotropin-dependent precocious puberty. The mechanisms behind HPG activation are complex and a clear etiology for early activation is often not elucidated. Though collectively uncommon, the neoplastic and developmental causes of gonadotropin-dependent precocious puberty are very important to consider, as a delay in diagnosis may lead to adverse patient outcomes. The intent of the current paper is to review the neoplastic and developmental causes of gonadotropin-dependent precocious puberty. We discuss the common CNS lesions and human chorionic gonadotropin-secreting tumors that cause sexual precocity, review the relationship between therapeutic radiation and gonadotropin-dependent precocious puberty, and finally, provide an overview of the therapies available for height preservation in this unique patient population. PMID- 21603198 TI - Prolactin may not play a role in primary antiphospholipid (Hughes') syndrome. AB - The relationship between prolactin (PRL) and the immune system has been demonstrated in the last two decades and has opened new windows in the field of immunoendocrinology. However, there are scarce reports about PRL in primary antiphospholipid syndrome (pAPS). The objective of this study was to evaluate PRL levels in patients with pAPS compared to healthy controls and to investigate their possible clinical associations. Fifty-five pAPS patients according to Sapporo criteria were age- and sex-matched with 41 healthy subjects. Individuals with secondary causes of hyperprolactinemia (HPRL) were excluded; demographic, biometric, and clinical data, PRL levels, antiphospholipid antibodies, inflammatory markers, and other routine laboratory findings were analyzed. PRL levels were similar between pAPS and healthy controls (8.94 +/- 7.02 versus 8.71 +/- 6.73 ng/mL, P = .876). Nine percent of the pAPS patients and 12.1% of the control subjects presented HPRL (P = .740). Comparison between the pAPS patients with hyper- and normoprolactinemia revealed no significant differences related to anthropometrics, clinical manifestations, medications, smoking, and antiphospholipid antibodies (P > .05). This study showed that HPRL does not seem to play a role in clinical manifestations of the pAPS, differently from other autoimmune rheumatic diseases. PMID- 21603199 TI - Effects of a flexibility and relaxation programme, walking, and nordic walking on Parkinson's disease. AB - Symptoms of Parkinson's disease (PD) progress despite optimized medical treatment. The present study investigated the effects of a flexibility and relaxation programme, walking, and Nordic walking (NW) on walking speed, stride length, stride length variability, Parkinson-specific disability (UPDRS), and health-related quality of life (PDQ 39). 90 PD patients were randomly allocated to the 3 treatment groups. Patients participated in a 6-month study with 3 exercise sessions per week, each lasting 70 min. Assessment after completion of the training showed that pain was reduced in all groups, and balance and health related quality of life were improved. Furthermore, walking, and Nordic walking improved stride length, gait variability, maximal walking speed, exercise capacity at submaximal level, and PD disease-specific disability on the UPDRS in addition. Nordic walking was superior to the flexibility and relaxation programme and walking in improving postural stability, stride length, gait pattern and gait variability. No significant injuries occurred during the training. All patients of the Nordic walking group continued Nordic walking after completing the study. PMID- 21603200 TI - Effects of Environmental Temperature on the Dynamics of Ichthyophoniasis in Juvenile Pacific Herring (Clupea pallasii). AB - The effects of temperature and infection by Ichthyophonus were examined in juvenile Pacific herring (Clupea pallasii) maintained under simulated overwinter fasting conditions. In addition to defining parameters for a herring bioenergetics model (discussed in Vollenweider et al. this issue), these experiments provided new insights into factors influencing the infectivity and virulence of the parasite Ichthyophonus. In groups of fish with established disease, temperature variation had little effect on disease outcome. Ichthyophonus mortality outpaced that resulting from starvation alone. In newly infected fish, temperature variation significantly changed the mortality patterns related to disease. Both elevated and lowered temperatures suppressed disease related mortality relative to ambient treatments. When parasite exposure dose decreased, an inverse relationship between infection prevalence and temperature was detected. These findings suggest interplay between temperature optima for parasite growth and host immune function and have implications for our understanding of how Ichthyophonus infections are established in wild fish populations. PMID- 21603201 TI - Management of Bladder Cancer following Solid Organ Transplantation. AB - Objective. Present our experience managing bladder cancer following liver and renal transplantation. Methods. Single institution retrospective review of patients diagnosed with bladder urothelial carcinoma (BUC) following solid organ transplantation between January 1992 and December 2007. Results. Of the 2,925 renal and 2,761 liver transplant recipients reviewed, we identified eleven patients (0.2%) following transplant diagnosed with BUC. Two patients with low grade T1 TCC were managed by TURBT. Three patients with CIS and one patient with T1 low grade BUC were treated by TURBT and adjuvant BCG. All four are alive and free of recurrence at a mean follow-up of 51 +/- 22 months. One patient with T1 high grade BUC underwent radical cystectomy and remains disease free with a follow-up of 98 months. Muscle invasive TCC was diagnosed in four patients at a median of 3.6 years following transplantation. Two patients are recurrence free at 24 and 36 months following radical cystectomy. Urinary diversion and palliative XRT were performed in one patient with un-resectable disease. Conclusions. Bladder cancer is uncommon following renal and liver transplantation, but it can be managed successfully with local and/or extirpative therapy. The use of intravesical BCG is possible in select immunosuppressed patients. PMID- 21603202 TI - Local gene delivery system by bubble liposomes and ultrasound exposure into joint synovium. AB - Recently, we have developed novel polyethylene glycol modified liposomes (bubble liposomes; BL) entrapping an ultrasound (US) imaging gas, which can work as a gene delivery tool with US exposure. In this study, we investigated the usefulness of US-mediated gene transfer systems with BL into synoviocytes in vitro and joint synovium in vivo. Highly efficient gene transfer could be achieved in the cultured primary synoviocytes transfected with the combination of BL and US exposure, compared to treatment with plasmid DNA (pDNA) alone, pDNA plus BL, or pDNA plus US. When BL was injected into the knee joints of mice, and US exposure was applied transcutaneously to the injection site, highly efficient gene expression could be observed in the knee joint transfected with the combination of BL and US exposure, compared to treatment with pDNA alone, pDNA plus BL, or pDNA plus US. The localized and prolonged gene expression was also shown by an in vivo luciferase imaging system. Thus, this local gene delivery system into joint synovium using the combination of BL and US exposure may be an effective means for gene therapy in joint disorders. PMID- 21603203 TI - Limited Weight Loss or Simply No Weight Gain following Lifestyle-Only Intervention Tends to Redistribute Body Fat, to Decrease Lipid Concentrations, and to Improve Parameters of Insulin Sensitivity in Obese Children. AB - Objectives. To investigate whether lifestyle-only intervention in obese children who maintain or lose a modest amount of weight redistributes parameters of body composition and reverses metabolic abnormalities. Study Design. Clinical, anthropometric, and metabolic parameters were assessed in 111 overweight or obese children (CA of 11.3 +/- 2.8 years; 63 females and 48 males), during 8 months of lifestyle intervention. Patients maintained or lost weight (1-5%) (group A; n: 72) or gained weight (group B). Results. Group A patients presented with a decrease in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (P < .005 and P < .05, resp.), BMI (P < .0001), z-score BMI (P < .0001), waist circumference (P < .0001), fat mass (P < .005), LDL-C (P < .05), Tg/HDL-C ratio (P < .05), fasting and postprandial insulin (P < .005), and HOMA (P < .005), while HDL-C (P < .05) and QUICKI increased (P < .005). Conversely, group B patients had an increase in BMI (P < .0001), waist circumference (P < .005), SBP (P < .005), and in QUICKI (P < .005), while fat mass (P < .05), fasting insulin (P < .05), and HOMA (P < .05) decreased. Lean mass, DBP, lipid concentrations, fasting and postprandial glucose, postprandial insulin, and ultrasensitive C reactive protein (CRP) remained stable. Conclusions. Obese children who maintain or lose a modest amount of weight following lifestyle-only intervention tend to redistribute their body fat, decrease blood pressure and lipid levels, and to improve parameters of insulin sensitivity. PMID- 21603206 TI - Hypothalamic Obesity following Craniopharyngioma Surgery: Results of a Pilot Trial of Combined Diazoxide and Metformin Therapy. AB - Objective. To assess the effect of combined diazoxide-metformin therapy in obese adolescents treated for craniopharyngioma. Design. A prospective open-label 6 month pilot treatment trial in 9 obese subjects with craniopharyngioma. Diazoxide (2 mg/kg divided b.i.d., maximum 200 mg/day) and metformin (1000 mg b.i.d.). Whole body insulin sensitivity index (WBISI) and area-under-the-curve insulin (AUC(ins)) were calculated. Results. Seven subjects completed: 4M/3F, mean +/- SD age 15.4 +/- 2.9 years, weight 99.7 +/- 26.3 kg, BMI 35.5 +/- 5.6 kg/m(2), and BMI SDS 2.3 +/- 0.3. Two were withdrawn due to vomiting and peripheral edema. Of participants completing the study, the mean +/- SD weight gain, BMI, and BMI SDS during the 6 months were reduced compared to the 6 months prestudy (+1.2 +/- 5.9 versus +9.5 +/- 2.7 kg, P = .004; -0.3 +/- 2.3 versus +2.2 +/- 1.5 kg/m(2), P = .04; -0.04 +/- 0.15 versus +0.11 +/- 0.08, P = .021, resp.). AUC(ins) correlated with weight loss (r = 0.82, P = .02) and BMI decrease (r = 0.96, P = .009). Conclusion. Combined diazoxide-metformin therapy was associated with reduced weight gain in patients with hypothalamic obesity. AUC(ins) at study commencement predicted effectiveness of the treatment. PMID- 21603205 TI - Malaria Vaccine Development: Are Bacterial Flagellin Fusion Proteins the Bridge between Mouse and Humans? AB - In the past 25 years, the development of an effective malaria vaccine has become one of the biggest riddles in the biomedical sciences. Experimental data using animal infection models demonstrated that it is possible to induce protective immunity against different stages of malaria parasites. Nonetheless, the vast body of knowledge has generated disappointments when submitted to clinical conditions and presently a single antigen formulation has progressed to the point where it may be translated into a human vaccine. In parallel, new means to increase the protective effects of antigens in general have been pursued and depicted, such as the use of bacterial flagellins as carriers/adjuvants. Flagellins activate pathways in the innate immune system of both mice and humans. The recent report of the first Phase I clinical trial of a vaccine containing a Salmonella flagellin as carrier/adjuvant may fuel the use of these proteins in vaccine formulations. Herein, we review the studies on the use of recombinant flagellins as vaccine adjuvants with malarial antigens in the light of the current state of the art of malaria vaccine development. The available information indicates that bacterial flagellins should be seriously considered for malaria vaccine formulations to the development of effective human vaccines. PMID- 21603204 TI - Mechanisms that regulate peripheral immune responses to control organ-specific autoimmunity. AB - The immune system must balance the need to maintain a diverse repertoire of lymphocytes to be able to fight infection with the need to maintain tolerance to self-proteins. The immune system places strict regulation over the ability of T cells to produce the major T cell growth factor interleukin 2 as this cytokine can influence a variety of immune outcomes. T cells require the delivery of two signals, one through the antigen receptor and a second through the costimulatory receptor CD28. The immune system uses a variety of E3 ubiquitin ligases to target signaling proteins that function downstream of the TCR and CD28 receptors. Mutations in these E3 ligases can lead to a breakdown in immune tolerance and development of autoimmunity. This paper will examine the role of a range of E3 ubiquitin ligases and signaling pathways that influence the development of T-cell effector responses and the development of organ-specific autoimmune diseases such as type 1 diabetes. PMID- 21603207 TI - A rare cause of scrotal swelling: transitional cell carcinoma of the bladder presenting as a testicular metastasis. AB - A 72-year-old Caucasian male who presented with haematuria in July of 2000 was found to have a large left-sided bladder tumour. He underwent a transurethral resection of the tumour and surveillance program. In October 2008 he underwent a transurethral resection of the prostate (TURP). Histology of the prostatic chippings showed poorly differentiated TCC with prostatic invasion. A CT of his chest abdomen and pelvis revealed no lymph node involvement or metastatic spread. He therefore underwent a cystoprostato-urethrectomy with ileal conduit formation, in December 2008. In May 2010 the decision was made to perform a left inguinal orchidectomy as he presented with a craggy mass of his left testis, and there were clinical concerns that this was a tumour. Histology revealed that the left testis had been wholly replaced by a tumour. Taking into account his previous urological history, the features of this tumour are consistent with metastatic TCC, which is very rare. PMID- 21603209 TI - Preparation and Characterization of Stealth Archaeosomes Based on a Synthetic PEGylated Archaeal Tetraether Lipid. AB - The present studies were focused on the formation and characterization of sterically stabilized archaeosomes made from a synthetic PEGylated archaeal lipid. In a first step, a synthetic archaeal tetraether bipolar lipid was functionalized with a poly(ethylene glycol), PEG, and (PEG(45)-Tetraether) with the aim of coating the archaeosome surface with a sterically stabilizing hydrophilic polymer. In a second step, Egg-PC/PEG(45)-Tetraether (90/10 wt%) archaeosomes were prepared, and their physicochemical characteristics were determined by dynamic light scattering (size, polydispersity), cryo-TEM (morphology), and by high-performance thin layer chromatography (lipid composition), in comparison with standard Egg-PC/PEG(45)-DSPE formulations. Further, a fluorescent dye, the carboxyfluorescein, was encapsulated into the prepared archaeosomes in order to evaluate the potential of such nanostructures as drug carriers. Release studies have shown that the stability of Egg-PC/PEG(45) Tetraether-based archaeosomes is significantly higher at 37 degrees C than the one of Egg-PC/PEG(45)-DSPE-based liposomes, as evidenced by the slower release of the dye encapsulated into PEGylated archaeosomes. This enhanced stability could be related to the membrane spanning properties of the archaeal bipolar lipid as already described with natural or synthetic tetraether lipids. PMID- 21603208 TI - Anti-IL-6 receptor antibody causes less promotion of tuberculosis infection than anti-TNF-alpha antibody in mice. AB - Objective. Our aim was to investigate the effects of IL-6 blockade on the progression of Mycobacterium tuberculosis (TB) and compare them with those of TNF alpha blockade in mice. Methods. Mice were intravenously infected with TB and injected with antibodies. Survival was monitored and histological and immunological studies were carried out. Results. All anti-IL-6R Ab-treated mice and 8 of 10 control mice survived until sacrificed 224 days after TB challenge, whereas anti-TNF-alpha Ab-treated mice all died between 120 and 181 days. Anti-IL 6R Ab-treated mice exhibited no significant differences in TB CFU in organs, including the lungs, and no deterioration in histopathology compared to control mice at 4 weeks. In contrast, anti-TNF-alpha Ab-treated mice exhibited increased TB CFU and greater progression of histopathological findings in organs than control mice. Spleen cells from anti-TNF-alpha Ab-treated mice had decreased antigen-specific response in IFN-gamma release and proliferation assays. The results in anti-IL-6R Ab-treated mice suggest that spleen cell responses were decreased to a lesser degree. Similar results were obtained in IL-6 knockout (KO) mice, compared with TNF receptor 1 (TNFR1) KO and TNFR1/IL-6 double KO (DKO) mice. Conclusion. IL-6R blockade promotes the progression of TB infection in mice far less than TNF-alpha blockade. PMID- 21603210 TI - Unveiling Stability Criteria of DNA-Carbon Nanotubes Constructs by Scanning Tunneling Microscopy and Computational Modeling. AB - We present a combined approach that relies on computational simulations and scanning tunneling microscopy (STM) measurements to reveal morphological properties and stability criteria of carbon nanotube-DNA (CNT-DNA) constructs. Application of STM allows direct observation of very stable CNT-DNA hybrid structures with the well-defined DNA wrapping angle of 63.4 degrees and a coiling period of 3.3 nm. Using force field simulations, we determine how the DNA CNT binding energy depends on the sequence and binding geometry of a single strand DNA. This dependence allows us to quantitatively characterize the stability of a hybrid structure with an optimal pi-stacking between DNA nucleotides and the tube surface and better interpret STM data. Our simulations clearly demonstrate the existence of a very stable DNA binding geometry for (6,5) CNT as evidenced by the presence of a well-defined minimum in the binding energy as a function of an angle between DNA strand and the nanotube chiral vector. This novel approach demonstrates the feasibility of CNT-DNA geometry studies with subnanometer resolution and paves the way towards complete characterization of the structural and electronic properties of drug-delivering systems based on DNA CNT hybrids as a function of DNA sequence and a nanotube chirality. PMID- 21603211 TI - Unmasking of Partial Diabetes Insipidus during Stress but Not Maintenance Dosing of Glucocorticoids in an Infant with Septo-Optic Dysplasia. AB - Background. It is well acknowledged that glucocorticoid (GC) replacement can unmask diabetes insipidus (DI) in subjects with hypopituitarism. Objective. To increase the awareness and monitoring for transient and symptomatic DI in children with partial hypopituitarism during periods in which increased GC needs are required. Methods/Case. A 2-month-old female infant with septo-optic dysplasia (SOD; on thyroid and maintenance GC replacement therapy at 8 mg/m(2)/day) developed transient DI during 2 separate episodes of stress (one hypothermia, one febrile) when stress dosing of GC (25 mg/m(2)/day) was instituted. Conclusion. Children not diagnosed with DI during initial evaluation for hypopituitarism may benefit from rescreening of serum sodium levels during acute periods of stress that demand "stress" GC dosing. This will permit treatment and/or increased vigilance for ensuing permanent DI. PMID- 21603212 TI - Endoscopic bulking materials for the treatment of vesicoureteral reflux: a review of our 20 years of experience and review of the literature. AB - Purpose. We reviewed our 20 years of experience and the current literature regarding the long-term outcome of endoscopic treatment of vesicoureteric reflux (VUR) using the different tissue bulking substances with a special emphasis on the long-term efficacy. Material and Methods. Our own experience and the current literature on the long-term results after endoscopic treatment using various bulking agents were reviewed. Results. Short-term data following endoscopic treatment of VUR is similar to the various substances and comparable in the majority of the series to the success rate following open surgery. Recently, a relatively high recurrence rate was noticed especially with the use of dextranomer hyaluronic acid (Dx/HA) as a tissue augmenting material which raises the need for further search for alternative substances. Conclusions. Unfortunately, there is a significant shortage of evidence-based literature on the long-term followup after endoscopic correction of reflux with various substances. No doubt, there is a high recurrence rate during long-term followup after Dx/HA injection, and there is probably lack of proper evaluation regarding the long-term efficacy of other bulking materials. These facts demand long-term close observation and long-term studies beyond the routine protocols following endoscopic treatment of VUR and the correct parental counseling upon the endoscopic correction. PMID- 21603214 TI - Encapsulation of Protein-Polysaccharide HIP Complex in Polymeric Nanoparticles. AB - The objective of the present study is to formulate and characterize a nanoparticulate-based formulation of a macromolecule in a hydrophobic ion pairing (HIP) complex form. So far, HIP complexation approach has been studied only for proteins with molecular weight of 10-20 kDa. Hence, we have selected bovine serum albumin (BSA) having higher molecular weight (66.3 kDa) as a model protein and dextran sulphate (DS) as a complexing polymer to generate HIP complex. We have prepared and optimized the HIP complex formation process of BSA with DS. Ionic interactions between basic amino acids of BSA with sulphate groups of DS were confirmed by FTIR analysis. Further, nanoparticles were prepared and characterized with respect to size and surface morphology. We observed significant entrapment of BSA in nanoparticles prepared with minimal amounts of PLGA polymer. Finally, results of circular dichroism and intrinsic fluorescence assay have clearly indicated that HIP complexation and method of nanoparticle preparation did not alter the secondary and tertiary structures of BSA. PMID- 21603213 TI - Innate immune recognition of Mycobacterium tuberculosis. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a major health problem, with 10 million new cases diagnosed each year. Innate immunity plays an important role in the host defense against M. tuberculosis, and the first step in this process is recognition of MTB by cells of the innate immune system. Several classes of pattern recognition receptors (PPRs) are involved in the recognition of M. tuberculosis, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nod-like receptors (NLRs). Among the TLR family, TLR2, TLR4, and TLR9 and their adaptor molecule MyD88 play the most prominent roles in the initiation of the immune response against tuberculosis. In addition to TLRs, other PRRs such as NOD2, Dectin-1, Mannose receptor, and DC-SIGN are also involved in the recognition of M. tuberculosis. Human epidemiological studies revealed that genetic variation in genes encoding for PRRs and downstream signaling products influence disease susceptibility, severity, and outcome. More insight into PRRs and the recognition of mycobacteria, combined with immunogenetic studies in TB patients, does not only lead to a better understanding of the pathogenesis of tuberculosis but also may contribute to the design of novel immunotherapeutic strategies. PMID- 21603215 TI - The role of lymph node fine-needle aspiration in penile cancer in the sentinel node era. AB - Penile squamous cell carcinoma (SCC) is an uncommon condition in Western countries. Inguinal lymph nodes dissection can be curative in 20%-60% of node positive patients. However, there is a high complication rates from the dissection, thus accurate diagnosis of inguinal lymph nodes metastasis is required. Current non invasive methods to detect lymph nodes metastasis are unreliable. Dynamic Sentinel Node Biopsy (DNSB), ultrasonography (US), and fine needle aspiration (FNA) cytology were proposed to in an attempt to detect sentinel lymph node (SLN). Despite the initial high rate of false negative results, recent DSNB showed improved survival compared to wait and see policy as well as reduced mortality compared to prophylactic inguinal lymphadenectomy. In addition, the US guided FNA shown 100% of specificity in detecting clinically occult lymph nodes metastasis. We proposed an algorithm for management of lymph nodes in penile cancer and suggest that FNA with US guidance should be performed in all high risk patients and that therapeutic dissection should be performed if findings are positive. PMID- 21603216 TI - Newborn mice vaccination with BCG.HIVA222 + MVA.HIVA enhances HIV-1-specific immune responses: influence of age and immunization routes. AB - We have evaluated the influence of age and immunization routes for induction of HIV-1- and M. tuberculosis-specific immune responses after neonatal (7 days old) and adult (7 weeks old) BALB/c mice immunization with BCG.HIVA(222) prime and MVA.HIVA boost. The specific HIV-1 cellular immune responses were analyzed in spleen cells. The body weight of the newborn mice was weekly recorded. The frequencies of HIV-specific CD8(+) T cells producing IFN-gamma were higher in adult mice vaccinated intradermally and lower in adult and newborn mice vaccinated subcutaneously. In all cases the IFN-gamma production was significantly higher when mice were primed with BCG.HIVA(222) compared with BCGwt. When the HIV-specific CTL activity was assessed, the frequencies of specific killing were higher in newborn mice than in adults. The prime-boost vaccination regimen which includes BCG.HIVA(222) and MVA.HIVA was safe when inoculated to newborn mice. The administration of BCG.HIVA(222) to newborn mice is safe and immunogenic and increased the HIV-specific responses induced by MVA.HIVA vaccine. It might be a good model for infant HIV and Tuberculosis bivalent vaccine. PMID- 21603217 TI - Clinical feature of men who benefit from dose escalation of naftopidil for lower urinary tract symptoms: a prospective study. AB - Objectives. To examine the feature of men who benefit from dose escalation of naftopidil for lower urinary tract symptoms (LUTSs). Methods. Based on the IPSS, men reporting LUTS were prospectively studied using 50 mg/day of naftopidil for the first 4 weeks; satisfied patients continued its 50 mg/day (n = 11), and those reporting unsatisfactory improvement received its 75 mg/day (n = 35) for the next 4 weeks. Results. The 75 mg group showed improvement in the total IPSS and QOL score in a dose-dependent manner (at 4 weeks: P < .001, at 4 weeks versus 8 weeks: P < .05). In the 50 mg group, both scores reduced at 4 weeks, thereafter unchanged. The baseline slow stream score alone was higher in the 75 mg group (P = .013). The rate of change in the QOL score during the initial 4 weeks (DeltaQOL) and Deltanocturia was smaller in the 75 mg group (P < .05). Conclusions. Men with high slow stream score and unsatisfactory improvement in nocturia may benefit from dose escalation of naftopidil. PMID- 21603218 TI - Transplantation of porcine hepatocytes cultured with polylactic Acid-o carboxymethylated chitosan nanoparticles promotes liver regeneration in acute liver failure rats. AB - In this study, free porcine hepatocytes suspension (Group A), porcine hepatocytes embedded in collagen gel (Group B), porcine hepatocytes cultured with PLA-O-CMC nanoparticles and embedded in collagen gel (Group C), and PLA-O-CMC nanoparticles alone (Group D) were transplanted into peritoneal cavity of ALF rats, respectively. The result showed that plasma HGF levels were elevated post transplantation with a peak at 12 hr. The rats in Group C showed highest plasma HGF levels at 2, 6, 12, 24 and 36 hr post-transplantation and lowest HGF level at 48 hr. Plasma VEGF levels were elevated at 48 hr post-transplantation with a peak at 72 hr. The rats in Group C showed highest plasma HGF levels at 48, 72, and 96 hr post-transplantation. The liver functions in Group C were recovered most rapidly. Compared with Group B, Group C had significant high liver Kiel 67 antigen labeling index (Ki-67 LI) at day 1 post-HTx (P < .05). Ki-67 LI in groups B and C was higher than that in groups A and D at days 5 and 7 post-HTx. In conclusion, intraperitoneal transplantation of porcine hepatocytes cultured with PLA-O-CMC nanoparticles and embedded in collagen gel can promote significantly liver regeneration in ALF rats. PMID- 21603219 TI - The M. tuberculosis phosphate-binding lipoproteins PstS1 and PstS3 induce Th1 and Th17 responses that are not associated with protection against M. tuberculosis infection. AB - The M. tuberculosis phosphate-binding transporter lipoproteins PstS1 and PstS3 were good immunogens inducing CD8(+) T-cell activation and both Th1 and Th17 immunity in mice. However, this antigen-specific immunity, even when amplified by administration of the protein with the adjuvant LTK63 or by the DNA priming/protein boosting regimen, was not able to contain M. tuberculosis replication in the lungs of infected mice. The lack of protection might be ascribed with the scarce/absent capacity of PstS1/PstS3 antigens to modulate the IFN-gamma response elicited by M. tuberculosis infection during which, however, PstS1-specific IL-17 secreting cells were generated in both unvaccinated and BCG vaccinated mice. In spite of a lack of protection by PstS1/PstS3 immunizations, our results do show that PstS1 is able to induce IL-17 response upon M. tuberculosis infection which is of interest in the study of anti-M. tuberculosis immunity and as potential immunomodulator in combined vaccines. PMID- 21603220 TI - Enhanced Transport Capabilities via Nanotechnologies: Impacting Bioefficacy, Controlled Release Strategies, and Novel Chaperones. AB - Emerging nanotechnologies have, and will continue to have, a major impact on the pharmaceutical industry. Their influence on a drug's life cycle, inception to delivery, is rapidly expanding. As the industry moves more aggressively toward continuous manufacturing modes, utilizing Process Analytical Technology (PAT) and Process Intensification (PI) concepts, the critical role of transport phenomena becomes elucidated. The ability to transfer energy, mass, and momentum with directed purposeful outcomes is a worthwhile endeavor in establishing higher production rates more economically. Furthermore, the ability to obtain desired drug properties, such as size, habit, and morphology, through novel manufacturing strategies permits unique formulation control for optimum delivery methodologies. Bottom-up processing to obtain nano-sized crystals is an excellent example. Formulation and delivery are intimately coupled in improving bio-efficacy at reduced loading and/or better controlled release capabilities, minimizing side affects and providing improved therapeutic interventions. Innovative nanotechnology applications, such as simultaneous targeting, imaging and delivery to tumors, are now possible through use of novel chaperones. Other examples include nanoparticles attachment to T-cells, release from novel hydrogel implants, and functionalized encapsulants. Difficult tasks such as drug delivery to the brain via the blood brain barrier and/or the cerebrospinal fluid are now easier to accomplish. PMID- 21603221 TI - Social and Health Factors Associated with Physical Activity among Kuwaiti College Students. AB - Our aim was to explore the social and health factors that are associated with the level of physical activity among Kuwaiti college students. A random sample of 787 students (48% males and 52% females) was chosen and weight and height were measured to obtain body mass index (BMI, kg/m(2)). Associated social and health factors were obtained using a questionnaire. Those reporting being physically inactive numbered 354 and the remaining 433 were active. Obesity among males was 13% and was 10.5% among females. The social and health factors that were found to be significantly associated with physical activity among the students were gender (P < .001), marital status (P < .05), BMI category (obese or nonobese) (P < .05), last dental and health checkup (P < .01), desiring a higher degree (P < .001), and countries preferred for visiting (P < .01). Males significantly exceeded females in the practice of physical activity. In conclusion, behavioural modifications, intervention studies, and health education touting the benefits of being physically active should be instituted to increase the practice of sports and other physical activities in order to control and decrease obesity-related morbidity and mortality. PMID- 21603222 TI - Enzymatic Synthesis of Isopropyl Acetate by Immobilized Bacillus cereus Lipase in Organic Medium. AB - Selective production of fragrance fatty acid ester from isopropanol and acetic acid has been achieved using silica-immobilized lipase of Bacillus cereus MTCC 8372. A purified thermoalkalophilic extracellular lipase was immobilized by adsorption onto the silica. The effects of various parameters like molar ratio of substrates (isopropanol and acetic acid; 25 to 100 mM), concentration of biocatalyst (25-125 mg/mL), reaction time, reaction temperature, organic solvents, molecular sieves, and initial water activity were studied for optimal ester synthesis. Under optimized conditions, 66.0 mM of isopropyl acetate was produced when isopropanol and acetic acid were used at 100 mM: 75 mM in 9 h at 55 degrees C in n-heptane under continuous shaking (160 rpm) using bound lipase (25 mg). Addition of molecular sieves (3 A * 1.5 mm) resulted in a marked increase in ester synthesis (73.0 mM). Ester synthesis was enhanced by water activity associated with pre-equilibrated saturated salt solution of LiCl. The immobilized lipase retained more than 50% of its activity after the 6th cycle of reuse. PMID- 21603224 TI - ADIPOQ Gene Variants Associated with Susceptibility to Obesity and Low Serum Adiponectin Levels in Healthy Koreans. AB - OBJECTIVES: This study aimed to measure the association between the adiponectin, C1Q and collagen domain-containing (ADIPOQ) gene variants and obesity in Koreans. METHODS: Three single nucleotide polymorphisms located in the ADIPOQ gene were genotyped in a population-based cross-sectional study of 986 healthy Koreans. Three different case-control groups (i.e. G1, G2, and G3) were defined according to body mass index (BMI) and serum adiponectin levels. Allelic and genotypic associations of this gene with obesity were measured using multivariate logistic regression analyses in each group. RESULTS: The G allele of -11377C>G, a polymorphism located in the promoter region of the ADIPOQ gene (odds ratio (OR), 1.48; 95% confidence interval, 1.13-1.94) and most haplotypes including this allele significantly increased the risk for obesity. However, the OR decreased from 3.98 (G1 group) to 2.90 (G2 group) and 2.30 (G3 group) when a less strict definition of obesity was used. Most haplotypes, including this allele, significantly increased the risk of obesity. The statistical evidence from the GG genotype of -11377C>G (OR, 3.98) and the GT/GT diplotype composed of -11377G>C and +45T>G (OR, 5.20) confirmed the contribution of the G allele toward a predisposition for obesity. CONCLUSION: These results suggest the contribution of the ADIPOQ gene toward susceptibility to obesity in healthy Koreans. The high risk genotypes and haplotypes identified here may provide more information for identifying individuals who are at risk of obesity. PMID- 21603223 TI - Enolase: a key player in the metabolism and a probable virulence factor of trypanosomatid parasites-perspectives for its use as a therapeutic target. AB - Glycolysis and glyconeogenesis play crucial roles in the ATP supply and synthesis of glycoconjugates, important for the viability and virulence, respectively, of the human-pathogenic stages of Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. These pathways are, therefore, candidate targets for antiparasite drugs. The glycolytic/gluconeogenic enzyme enolase is generally highly conserved, with similar overall fold and identical catalytic residues in all organisms. Nonetheless, potentially important differences exist between the trypanosomatid and host enzymes, with three unique, reactive residues close to the active site of the former that might be exploited for the development of new drugs. In addition, enolase is found both in the secretome and in association with the surface of Leishmania spp. where it probably functions as plasminogen receptor, playing a role in the parasite's invasiveness and virulence, a function possibly also present in the other trypanosomatids. This location and possible function of enolase offer additional perspectives for both drug discovery and vaccination. PMID- 21603225 TI - Ussing's "Little Chamber": 60 Years+ Old and Counting. PMID- 21603226 TI - In vivo monitoring of adult neurogenesis in health and disease. AB - Adult neurogenesis, i.e., the generation of new neurons in the adult brain, presents an enormous potential for regenerative therapies of the central nervous system. While 5-bromo-2'-deoxyuridine labeling and subsequent histology or immunohistochemistry for cell-type-specific markers is still the gold standard in studies of neurogenesis, novel techniques, and tools for in vivo imaging of neurogenesis have been recently developed and successfully applied. Here, we review the latest progress on these developments, in particular in the area of magnetic resonance imaging (MRI) and optical imaging. In vivo in situ labeling of neural progenitor cells (NPCs) with micron-sized iron oxide particles enables longitudinal visualization of endogenous progenitor cell migration by MRI. The possibility of genetic labeling for cellular MRI was demonstrated by using the iron storage protein ferritin as the MR reporter-gene. However, reliable and consistent results using ferritin imaging for monitoring endogenous progenitor cell migration have not yet been reported. In contrast, genetic labeling of NPCs with a fluorescent or bioluminescent reporter has led to the development of some powerful tools for in vivo imaging of neurogenesis. Here, two strategies, i.e., viral labeling of stem/progenitor cells and transgenic approaches, have been used. In addition, the use of specific promoters for neuronal progenitor cells such as doublecortin increases the neurogenesis-specificity of the labeling. Naturally, the ultimate challenge will be to develop neurogenesis imaging methods applicable in humans. Therefore, we certainly need to consider other modalities such as positron emission tomography and proton magnetic resonance spectroscopy ((1)H-MRS), which have already been implemented for both animals and humans. Further improvements of sensitivity and neurogenesis-specificity are nevertheless required for all imaging techniques currently available. PMID- 21603227 TI - Testing multi-alternative decision models with non-stationary evidence. AB - Recent research has investigated the process of integrating perceptual evidence toward a decision, converging on a number of sequential sampling choice models, such as variants of race and diffusion models and the non-linear leaky competing accumulator (LCA) model. Here we study extensions of these models to multi alternative choice, considering how well they can account for data from a psychophysical experiment in which the evidence supporting each of the alternatives changes dynamically during the trial, in a way that creates temporal correlations. We find that participants exhibit a tendency to choose an alternative whose evidence profile is temporally anti-correlated with (or dissimilar from) that of other alternatives. This advantage of the anti correlated alternative is well accounted for in the LCA, and provides constraints that challenge several other models of multi-alternative choice. PMID- 21603228 TI - Dopaminergic Balance between Reward Maximization and Policy Complexity. AB - Previous reinforcement-learning models of the basal ganglia network have highlighted the role of dopamine in encoding the mismatch between prediction and reality. Far less attention has been paid to the computational goals and algorithms of the main-axis (actor). Here, we construct a top-down model of the basal ganglia with emphasis on the role of dopamine as both a reinforcement learning signal and as a pseudo-temperature signal controlling the general level of basal ganglia excitability and motor vigilance of the acting agent. We argue that the basal ganglia endow the thalamic-cortical networks with the optimal dynamic tradeoff between two constraints: minimizing the policy complexity (cost) and maximizing the expected future reward (gain). We show that this multi dimensional optimization processes results in an experience-modulated version of the softmax behavioral policy. Thus, as in classical softmax behavioral policies, probability of actions are selected according to their estimated values and the pseudo-temperature, but in addition also vary according to the frequency of previous choices of these actions. We conclude that the computational goal of the basal ganglia is not to maximize cumulative (positive and negative) reward. Rather, the basal ganglia aim at optimization of independent gain and cost functions. Unlike previously suggested single-variable maximization processes, this multi-dimensional optimization process leads naturally to a softmax-like behavioral policy. We suggest that beyond its role in the modulation of the efficacy of the cortico-striatal synapses, dopamine directly affects striatal excitability and thus provides a pseudo-temperature signal that modulates the tradeoff between gain and cost. The resulting experience and dopamine modulated softmax policy can then serve as a theoretical framework to account for the broad range of behaviors and clinical states governed by the basal ganglia and dopamine systems. PMID- 21603229 TI - Extracellular Calcium-Sensing Receptor Inhibition of Intestinal EpithelialTNF Signaling Requires CaSR-Mediated Wnt5a/Ror2 Interaction. AB - Tumor necrosis factor alpha (TNFalpha) and its receptor TNFR1 play a central role in the development of colitis-associated colon cancer. To understand a role for the extracellular calcium-sensing receptor (CaSR) and its non-canonical Wnt mediators, Wnt5a/Ror2, we used reductionistic systems. We added lipopolysaccharide (LPS) to mouse peritoneal macrophages, RAW264.7 cells, a murine macrophage cell line, and 18Co colonic myofibroblasts, to stimulate TNFalpha secretion and then activated endogenous CaSR. CaSR activation inhibited TNFalpha secretion, which in RAW264.7 cells knockdown of CaSR by short interfering RNA (siRNA) duplex reversed. LPS-stimulated NFkappaB promoter activity in RAW264.7 cells was inhibited by CaSR activation with Ca(2+) or other polyvalent CaSR agonists. Reducing CaSR expression with siRNA duplex prevented this inhibition. Following LPS addition to CaSR-HEK cells or RAW264.7 macrophages, CaSR stimulation deneddylated Cullin1. Wnt5a added to HT-29 cells which overexpressed Ror2 or T84 monolayers treated with 3 mM Ca(2+) reduced TNFR1 protein expression ~70%. TNFalpha/INFgamma addition to high resistance T84 monolayers reduced transepithelial resistance 50% within 4 h. CaSR activation (3 mM Ca(2+)) together with rhWnt5a (200 ng/ml) prevented this reduction while Wnt3a addition had no effect. LPS-stimulated TNFalpha secretion from RAW264.7 cells was not effected by rhWnt5a but increased 10-fold by Wnt3a. Together our results suggest that following LPS challenge, CaSR activation will inhibit NFkappaB activity and reduce TNFalpha secretion from macrophages and stroma while Wnt5a/Ror2 engagement on intestinal epithelia reduces TNFR1 expression, allowing TNFalpha signaling to be titrated. Our results also suggest that canonical Wnt signaling may enhance TLR4 stimulation of TNFalpha secretion from murine macrophages. PMID- 21603230 TI - Design of a flow-through voltammetric sensor based on an antimony-modified silver electrode for determining lithol rubine B in cosmetics. AB - Lithol Rubine B (LRB; the disodium salt of 3-hydroxy-4-[(4-methyl-2-sulfophenyl) azo]-2-naphthalenecarboxylic acid) was detected using high-performance liquid chromatography with an electrochemical (antimony film on silver) detector (HPLC ECD). For direct current (DC) mode, with the current at a constant potential, and measurements with suitable experimental parameters, a linear concentration from 0.125 to 1.80 MUg/mL was found. The detection limit of our method was approximately 2.0 ng/mL. An antimony-modified silver detector was used to demonstrate that LRB is electrochemically reduced in acidic media and to analyze commercial cosmetics to determine their LRB content. Findings using HPLC-ECD and HPLC with an ultraviolet detector were comparable. PMID- 21603232 TI - Cytokines in systemic lupus erythematosus. PMID- 21603231 TI - Safety and tolerability of antiretrovirals during pregnancy. AB - Combination antiretroviral therapy (CART) dramatically decreases mother-to-child HIV-1 transmission (MTCT), but maternal adverse events are not infrequent. A review of 117 locally followed pregnancies revealed 7 grade >= 3 AEs possibly related to antiretrovirals, including 2 hematologic, 3 hepatic, and 2 obstetric cholestasis cases. A fetal demise was attributed to obstetric cholestasis, but no maternal deaths occurred. The drugs possibly associated with these AE were zidovudine, nelfinavir, lopinavir/ritonavir, and indinavir. AE or intolerability required discontinuation/substitution of nevirapine in 16% of the users, zidovudine in 10%, nelfinavir in 9%, lopinavir/ritonavir in 1%, but epivir and stavudine in none. In conclusion, nevirapine, zidovudine, and nelfinavir had the highest frequency of AE and/or the lowest tolerability during pregnancy. Although nevirapine and nelfinavir are infrequently used in pregnancy at present, zidovudine is included in most MTCT preventative regimens. Our data emphasize the need to revise the treatment recommendations for pregnant women to include safer and better-tolerated drugs. PMID- 21603233 TI - HSV serologic testing for pregnant women: willingness to be tested and factors affecting testing. AB - OBJECTIVE: This prospective study was undertaken to evaluate pregnant women's willingness to undergo HSV type-specific serologic testing and factors affecting willingness in an obstetrics/gynecology ambulatory unit. METHODS: At prenatal Visit 1, pregnant women (n = 303) with no history of HSV-2 were tested for HSV 1/HSV-2 before and after they received counseling on genital and neonatal herpes. RESULTS: In both the Unwilling Subgroup and the group that changed from being willing to being unwilling, the most common reasons for choosing not to be tested were not being at risk for genital herpes, being tested is too personal, and concern about what will be done with the results. Of the 134 participants in the Willing/Tested Subgroup, 27 (20%) were HSV-2 seropositive and 81 (60%) were HSV-1 seropositive. Conclusions. These results support the feasibility of HSV serologic testing and counseling in pregnant women. PMID- 21603234 TI - Antidiabetic Activities of Abutilon indicum (L.) Sweet Are Mediated by Enhancement of Adipocyte Differentiation and Activation of the GLUT1 Promoter. AB - Abutilon indicum (L.) Sweet is an Asian phytomedicine traditionally used to treat several disorders, including diabetes mellitus. However, molecular mechanisms supporting the antidiabetic effect of A. indicum L. remain unknown. The aim of this study was to evaluate whether extract of A. indicum L. improves insulin sensitivity. First, we observed the antidiabetic activity of aqueous extract of the entire plant (leaves, twigs and roots) of A. indicum L. on postprandial plasma glucose in diabetic rats. The subsequent experiments revealed that butanol fractions of the extract bind to PPARgamma and activate 3T3-L1 differentiation. To measure glucose uptake enhanced by insulin-like activity, we used rat diaphragm incubated with various concentrations of the crude extract and found that the extract enhances glucose consumption in the incubated solution. Our data also indicate that the crude extract and the fractions (water and butanol) did not affect the activity of kinases involved in Akt and GSK-3beta pathways; however, the reporter assay showed that the crude extract could activate glucose transporter 1 (GLUT1) promoter activity. These results suggest that the extract from A. indicum L. may be beneficial for reducing insulin resistance through its potency in regulating adipocyte differentiation through PPARgamma agonist activity, and increasing glucose utilization via GLUT1. PMID- 21603235 TI - The Role of CT-Based Attenuation Correction and Collimator Blurring Correction in Striatal Spect Quantification. AB - Purpose. Striatal single photon emission computed tomography (SPECT) imaging of the dopaminergic system is becoming increasingly used for clinical and research studies. The question about the value of nonuniform attenuation correction has become more relevant with the increasing availability of hybrid SPECT-CT scanners. In this study, the value of nonuniform attenuation correction and correction for collimator blurring were determined using both phantom data and patient data. Methods. SPECT imaging was performed using 7 anthropomorphic phantom measurements, and 14 patient studies using [I-123]-FP-CIT (DATSCAN). SPECT reconstruction was performed using uniform and nonuniform attenuation correction and collimator blurring corrections. Recovery values (phantom data) or average-specific uptake ratios (patient data) for the different reconstructions were compared at similar noise levels. Results. For the phantom data, improved recovery was found with nonuniform attenuation correction and collimator blurring corrections, with further improvement when performed together. However, for patient data the highest average specific uptake ratio was obtained using collimator blurring correction without nonuniform attenuation correction, probably due to subtle SPECT-CT misregistration. Conclusions. This study suggests that an optimal brain SPECT reconstruction (in terms of the lowest bias) in patients would include a correction for collimator blurring and uniform attenuation correction. PMID- 21603236 TI - Quantitative Accuracy of Low-Count SPECT Imaging in Phantom and In Vivo Mouse Studies. AB - We investigated the accuracy of a single photon emission computed tomography (SPECT) system in quantifying a wide range of radioactivity concentrations using different scan times in both phantom and animal models. A phantom containing various amounts of In-111 or Tc-99m was imaged until the activity had decayed close to background levels. Scans were acquired for different durations, employing different collimator pinhole sizes. VOI analysis was performed to quantify uptake in the images and the values compared to the true activity. The phantom results were then validated in tumour-bearing mice. The use of an appropriate calibration phantom and disabling of a background subtraction feature meant that absolute errors were within 12% of the true activity. Furthermore, a comparison of in vivo imaging and biodistribution studies in mice showed a correlation of 0.99 for activities over the 200 kBq to 5 MBq range. We conclude that the quantitative information provided by the NanoSPECT camera is accurate and allows replacement of dissection studies for assessment of radiotracer biodistribution in mouse models. PMID- 21603237 TI - The Clinical Value of PET with Amino Acid Tracers for Gliomas WHO Grade II. AB - The clinical management of adults with low-grade gliomas (LGGs) remains a challenge. There is no curative treatment, and management of individual patients is a matter of deciding optimal timing as well as right treatment modality. In addition to conventional imaging techniques, positron emission tomography (PET) with amino acid tracers can facilitate diagnostic and therapeutic procedures. In this paper, the clinical applications of PET with amino acid tracers (11)C-methyl L-methionine (MET) and (18)F-fluoro-ethyl-L-tyrosine (FET) for patients with LGG are summarized. We also discuss the value of PET for the long-term followup of this patient group. Monitoring metabolic activity by PET in individual patients during course of disease will provide insight in the biological behavior and evolution of these tumors. As such, spatial changes in tumor activity over time, including shifts of hot-spot regions within the tumor, may reflect intratumoral heterogeneity and correlate to clinical parameters. PMID- 21603238 TI - Comparison of in leakage from labeled endocardial and epicardial cells: impact on modeling viability of cells to be transplanted into myocardium. AB - Introduction. Previously we proposed a cellular imaging technique to determine the surviving fraction of transplanted cells in vivo. Epicardial kinetics using Indium-111 determined the Debris Impulse Response Function (DIRF) and leakage coefficient parameters. Convolution-based modeling which corrected for these signal contributions indicated that (111)In activity was quantitative of cell viability with half-lives within 20 hrs to 37 days. We determine if the 37-day upper limit remains valid for endocardial injections by comparing previous epicardial cell leakage parameter estimates to those for endocardial cells. Methods. Normal canine myocardium was injected ((111)In-tropolone) epicardially (9 injections) or endocardially (10 injections). Continuous whole body and SPECT scans for 5 hours were acquired with three weekly follow-up imaging sessions up to 20-26 days. Time-activity curves evaluated each injection type. Results. The epicardial and endocardial kinetics were not significantly different (Epi: 1286 +/- 253; Endo: 1567 +/- 470 hours P = .62). Conclusion. The original epicardial estimate of leakage kinetics has been validated for use in endocardial injections. PMID- 21603239 TI - SPECT Imaging Agents for Detecting Cerebral beta-Amyloid Plaques. AB - The development of radiotracers for use in vivo to image beta-amyloid (Abeta) plaques in cases of Alzheimer's disease (AD) is an important, active area of research. The presence of Abeta aggregates in the brain is generally accepted as a hallmark of AD. Since the only definitive diagnosis of AD is by postmortem staining of affected brain tissue, the development of techniques which enable one to image Abeta plaques in vivo has been strongly desired. Furthermore, the quantitative evaluation of Abeta plaques in the brain could facilitate evaluation of the efficacy of antiamyloid therapies currently under development. This paper reviews the current situation in the development of agents for SPECT-based imaging of Abeta plaques in Alzheimer's brains. PMID- 21603241 TI - Immunolymphoscintigraphy for metastatic sentinel nodes: test of a model. AB - Aim. To develop a method and obtain proof-of-principle for immunolymphoscintigraphy for identification of metastatic sentinel nodes. Methods. We selected one of four tumour-specific antibodies against human breast cancer and investigated (1), in immune-deficient (nude) mice with xenograft human breast cancer expressing the antigen if specific binding of the intratumorally injected, radioactively labelled, monoclonal antibody could be scintigraphically visualized, and (2) transportation to and retention in regional lymph nodes of the radioactively labelled antibody after subcutaneous injection in healthy rabbits. Results and Conclusion. Our paper suggests the theoretical possibility of a model of dual isotope immuno-lymphoscintigraphy for noninvasive, preoperative, malignant sentinel node imaging. PMID- 21603240 TI - Molecular SPECT Imaging: An Overview. AB - Molecular imaging has witnessed a tremendous change over the last decade. Growing interest and emphasis are placed on this specialized technology represented by developing new scanners, pharmaceutical drugs, diagnostic agents, new therapeutic regimens, and ultimately, significant improvement of patient health care. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) have their signature on paving the way to molecular diagnostics and personalized medicine. The former will be the topic of the current paper where the authors address the current position of the molecular SPECT imaging among other imaging techniques, describing strengths and weaknesses, differences between SPECT and PET, and focusing on different SPECT designs and detection systems. Radiopharmaceutical compounds of clinical as well-preclinical interest have also been reviewed. Moreover, the last section covers several application, of MUSPECT imaging in many areas of disease detection and diagnosis. PMID- 21603242 TI - Relationship between plasma glucose levels and malignant uterine cervical neoplasias. AB - BACKGROUND: There is a direct correlation between glycemic load and the risk of developing many malignant neoplasms. AIMS: The aim of this study was to determine the plasma glucose levels in women with cervical cancer. METHODS: The study included 177 women with anatomopathologically diagnosed uterine cervical cancer (stages 0-IV) treated between 1980 and 2008 at the Gynecology and Obstetrics outpatient service of the UFTM, Brazil. The plasma glucose levels of all patients were assayed at the time of diagnosis and correlated with tumor staging. RESULTS: We statistically compared the plasma glucose levels of group 1 (cervical intraepithelial neoplasia 2-3), group 2 (stage I-II), group 3 (stage III-IV), and group 4 (control group: leiomyomas). Patient groups with poor prognosis (groups 2 and 3) showed significantly higher plasma glucose levels (P < 0.05) than those with less aggressive lesions (group 1). Plasma glucose levels were significantly higher in groups 2 and 3 than in group 4 (P < 0.05). The comparison of number of patients with plasma glucose level >90 mg/dl showed CIN versus I/II: P = 0.0753; OR = 2.018; (95% CI: 0.9236 to 4.410) and CIN versus III/IV: P = 0.0975; OR = 2.400; (95% CI: 0.8335 to 6.911). CONCLUSION: We observed an association between high plasma glucose levels and cervical cancer cases with poor prognoses. Plasma glucose tests should be routinely used as additional prognostic parameters in patients with cervical neoplasias. PMID- 21603243 TI - A case of metastatic mucoepidermoid carcinoma complicated by resistant hypercalcemia. AB - Tumors of salivary glands are uncommon and comprise of about 2%-4% of all head and neck tumors. About 75%-80% of these tumors are benign and include pleomorphic adenoma, monomorphic adenoma, oncocytoma, and papillary cystadenoma lymphomatosum. Mucoepidermoid carcinoma is the most common malignant tumor of salivary glands, representing 5-10% of all salivary gland tumors. Although known to be metastatic to local lymph nodes, distant metastases are rare (especially, with low and intermediate grade tumors). Histologic grade and the expression of various mucin glycoproteins are useful prognostic indicators. We present a case of mucoepidermoid carcinoma of parotid gland origin with distant metastases which is an uncommon occurrence with intermediate grade tumors. Also, this is the first reported case of humoral hypercalcemia of malignancy secondary to mucoepidermoid carcinoma. PMID- 21603244 TI - Systemic therapy for elderly patients with gastrointestinal cancer. AB - The majority of patients with gastrointestinal cancers are over the age of 65. This age group comprises the minority of the patients enrolled in clinical trials, and it is unknown whether older patients achieve similar results as younger patients in terms of survival benefit and tolerability. In addition, there are few studies specifically designed for patients over 65 years. Subset analyses of individual trials and studies using pooled patient data from multiple trials provide some understanding on outcomes in older patients with gastrointestinal cancers. This article reviews the evidence on chemotherapeutic regimens in the elderly with colorectal, pancreatic, and gastroesophageal cancers, and discusses a practical approach to provide the best outcomes for older patients. PMID- 21603245 TI - Rapid Increase of the Serum PSA Level in Response to High-Intensity Focused Ultrasound Therapy may be a Potential Indicator of Biochemical Recurrence of Low- and Intermediate-Risk Prostate Cancer. AB - OBJECTIVES: To determine the incidence and magnitude of the rapid increase in the serum PSA (riPSA) level after high-intensity focused ultrasound (HIFU) therapy for prostate cancer, and its correlation with clinical factors. METHODS: A total of 176 patients with localized prostate cancer underwent HIFU therapy. Serum riPSA was determined on the basis of the same criteria as those for "PSA bounce", ie, an increase of >=0.2 ng/ml with a spontaneous return to the prebounce level or lower. Patients were stratified according to neoadjuvant PSA level, T stage, risk group, age, Gleason score, pretreatment PSA level, post-treatment PSA nadir, and number of HIFU sessions. RESULTS: riPSA was seen in 53% of patients during a median follow-up period of 43 months. A PSA nadir was achieved within 3 months for 85.1% of the treatments. In all cases, onset of riPSA was seen two days after HIFU therapy, and the median magnitude was 23.69 ng/ml. A magnitude of >2 ng/ml was seen in 89.4% of cases. Univariate analysis revealed that patients with riPSA were associated with usage of hormonal therapy and the post-treatment PSA nadir level. Multivariate Cox regression analysis revealed that riPSA and the number of HIFU sessions were predictors of biochemical recurrence. A significant statistical association was found between the presence of riPSA and the risk of biochemical failure only in the low- and intermediate-risk group. CONCLUSION: Patients treated with HIFU who experience post-treatment riPSA may have an increased risk of biochemical recurrence, especially in non-high-risk patients. PMID- 21603246 TI - The role of T lymphocytes in cancer patients undergoing immunotherapy with autologous dendritic cells. AB - INTRODUCTION: Cancer stems from mutations in specific genes that induce uncontrolled cell proliferation. Dendritic cells (DCs) are important immunologic cells and play a crucial role in the induction of an antitumour response. PATIENTS AND METHODS: We examined the immune response mediated by T lymphocytes, helper T cells, cytotoxic T cells, and regulatory T cells, as well as the cytokines [interleukin (IL)-2, IL-12, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and IL-10], produced by these cell populations, in cancer patients (N = 7) undergoing immunotheraphy with autologous DCs. RESULTS: We observed an initial increase in T helper cells (CD4+) expressing IL-2, IFN-gamma, IL-12, TNF-alpha, and IL-10 after initiation of treatment, with statistically significant for the cytokines IL-2, TNF-alpha and IL-10. A similar significant effect was observed for IL-2-expressing cytotoxic T cells (CD8+). The percentage of total T cells (CD3+) remained elevated throughout immunotherapy. Regulatory T cells (CD25+/FOXP3+) only showed high percentage of their maximum value when analyzed the pretreatment levels, with statistically significant. CONCLUSION: Immunotherapy with DCs stimulated the immune response, as evidenced by an increase in percent fluorescence of most cell populations investigated during the specified treatment period. PMID- 21603247 TI - Bevacizumab for the treatment of recurrent glioblastoma. AB - Despite advances in upfront therapy, the prognosis in the great majority of patients with glioblastoma (GBM) is poor as almost all recur and result in disease-related death. Glioblastoma are highly vascularized cancers with elevated expression levels of vascular endothelial growth factor (VEGF), the dominant mediator of angiogenesis. A compelling biologic rationale, a need for improved therapy, and positive results from studies of bevacizumab in other cancers led to the evaluation of bevacizumab in the treatment of recurrent GBM. Bevacizumab, a humanized monoclonal antibody that targets VEGF, has been shown to improve patient outcomes in combination with chemotherapy (most commonly irinotecan) in recurrent GBM, and on the basis of positive results in two prospective phase 2 studies, bevacizumab was granted accelerated approval by the US Food and Drug Administration (FDA) as a single agent in recurrent GBM. Bevacizumab therapy is associated with manageable, class-specific toxicity as severe treatment-related adverse events are observed in only a minority of patients. With the goal of addressing questions and controversies regarding the optimal use of bevacizumab, the objective of this review is to provide a summary of the clinical efficacy and safety data of bevacizumab in patients with recurrent GBM, the practical issues surrounding the administration of bevacizumab, and ongoing investigations of bevacizumab in managing GBM. PMID- 21603249 TI - Production of Cold-Active Bacterial Lipases through Semisolid State Fermentation Using Oil Cakes. AB - Production of cold active lipase by semisolid state fermentation involves the use of agroindustrial residues. In the present study, semisolid state fermentation was carried out for the production of cold active lipase using Micrococcus roseus, isolated from soil samples of Gangotri glaciers, Western Himalayas. Among various substrate tested, groundnut oil cake (GOC) favored maximal yield of lipases at 15 +/- 1 degrees C within 48 h. Supplementation of glucose 1% (w/v) as additional carbon source and ammonium nitrate 2% (w/v) as additional nitrogen source enhanced production of lipase. Addition of triglycerides 0.5% (v/v) tends to repress the lipase production. Further mixed preparation of groundnut oil cake (GOC) along with mustard oil cake (MOC) in the ratio of 1 : 1, and its optimization resulted in improved production of cold active lipase. The enzyme exhibited maximum activity at 10-15 degrees C and was stable at temperatures lower than 30 degrees C. The lipase exhibited optimum activity at pH 8 and showed more than 60% stability at pH 9. Semisolid state fermentation process by utilizing agroindustrial wastes will direct to large-scale commercialization of lipase catalyzed process in cost-effective systems. PMID- 21603248 TI - Transcriptional Factor NF-kappaB as a Target for Therapy in Parkinson's Disease. AB - Parkinson's disease (PD) is a neurodegenerative condition characterized by chronic inflammation. Nuclear factor kappaB (NF-kappaB) is a family of inducible transcription factors that are expressed in a wide variety of cells and tissues, including microglia, astrocytes, and neurons, and the classical NF-kappaB pathway plays a key role in the activation and regulation of inflammatory mediator production during inflammation. Activation of the classical NF-kappaB pathway is mediated through the activity of the IKK kinase complex, which consists of a heterotrimer of IKKalpha, IKKbeta, and IKKgamma subunits. Targeting NF-kappaB has been proposed as an approach to the treatment of acute and chronic inflammatory conditions, and the use of inhibitors specific for either IKKbeta or IKKgamma has now been found to inhibit neurodegeneration of TH+ DA-producing neurons in murine and primate models of Parkinson's disease. These studies suggest that targeting the classical pathway of NF-kappaB through the inhibition of the IKK complex can serve as a useful therapeutic approach to the treatment of PD. PMID- 21603250 TI - Respiratory syncytial virus infection as a precipitant of thyroid storm in a previously undiagnosed case of graves' disease in a prepubertal girl. AB - Graves' disease is less common in prepubertal than pubertal children, and initial presentation with thyroid storm is rare. We report an 11-year-old prepubertal Hispanic girl who presented with a one-day history of respiratory distress, fever, and dysphagia. She had exophthalmos, a diffuse bilateral goiter and was agitated, tachycardic, and hypertensive. Nasal swab was positive for respiratory syncytial virus (RSV). She was diagnosed with thyroid storm and admitted to the pediatric intensive care unit. While infection is a known precipitant of thyroid storm and RSV is a common pediatric infection, to the best of our knowledge, this is the first reported case of RSV infection apparently precipitating thyroid storm in a prepubertal child. PMID- 21603251 TI - Influences of Source - Item Contingency and Schematic Knowledge on Source Monitoring: Tests of the Probability-Matching Account. AB - The authors investigated conditions under which judgments in source-monitoring tasks are influenced by prior schematic knowledge. According to a probability matching account of source guessing (Spaniol & Bayen, 2002), when people do not remember the source of information, they match source guessing probabilities to the perceived contingency between sources and item types. When they do not have a representation of a contingency, they base their guesses on prior schematic knowledge. The authors provide support for this account in two experiments with sources presenting information that was expected for one source and somewhat unexpected for another. Schema-relevant information about the sources was provided at the time of encoding. When contingency perception was impeded by dividing attention, participants showed schema-based guessing (Experiment 1). Manipulating source - item contingency also affected guessing (Experiment 2). When this contingency was schema-inconsistent, it superseded schema-based expectations and led to schema-inconsistent guessing. PMID- 21603252 TI - Kernels vs. Ears, and Other Questions for a Science of Treatment Dissemination. AB - Combining intervention diffusion with change in clinical practice and public policy is an ambitious agenda. The impressive effort in Hawaii can be instructive, highlighting questions for a science of treatment dissemination. Among these questions, some of the most important are the following: (a) Who should be targeted for change? (e.g., "downstream" clinicians in practice, "upstream" clinicians in training, consumers, "brokers," policy makers, or payers?); (b) What should be disseminated? (e.g., full evidence-based protocols, specific treatment elements or "kernels"?); and (c) Which procedures maximize change? (e.g., what combination and duration of teaching, supervision, consultation, and other support?). Ultimately, change efforts need to assess what aspects of practice were actually altered, what measurable impact the changes had on clinical outcomes, and what changes in practices and outcomes can be sustained over time. PMID- 21603253 TI - Informed Choice in Direct-to-Consumer Genetic Testing for Alzheimer and Other Diseases: Lessons from Two Cases. AB - Health-related direct-to-consumer (DTC) genetic testing has been a controversial practice. Especially problematic is predictive testing for Alzheimer disease (AD), since the disease is incurable, prevention is inconclusive, and testing does not definitively predict an individual's future disease status. In this paper, I examine two contrasting cases of subjects who learn through genetic testing that they have an elevated risk of developing AD later in life. In these cases, the subject's emotional response to the result is related to how well prepared she was for the real-life personal implications of possible test results. Analysis leads to the conclusion that when groups of health-related genetic tests are offered as packages by DTC companies, informed consumer choice is rendered impossible. Moreover, I argue, this marketing approach contravenes U.S. Federal Trade Commission policies for non-deceptive commercial communications. I conclude by suggesting ways to improve the prospects for informed consumer choice in DTC testing. PMID- 21603254 TI - Objective monitoring of physical activity after a cancer diagnosis: challenges and opportunities for enhancing cancer control. AB - BACKGROUND: Because physical activity (PA) provides multiple medical and psychosocial benefits after a cancer diagnosis, greater integration of objective activity monitoring into research and clinical practice is warranted. OBJECTIVES: To review randomized PA trials in cancer survivors after diagnosis using an accelerometer or pedometer and make recommendations for integrating objective monitoring into research and practice. MAJOR FINDINGS: Ten published PA and post cancer diagnosis randomized trials have used pedometers (n=3), accelerometers (n=3), or both (n=4). Pedometers were primarily used to motivate PA adherence with several studies also using unblinded pedometers to assess the intervention effect on PA adherence. Accelerometers were primarily used to assess PA adherence after a PA intervention with one study using accelerometers to assess PA increase as a benefit of a non-PA intervention. One study used accelerometers to document sufficient ground forces for improving bone density in cancer survivors. Across studies, the reported objective monitoring outcome varied and was not always consistent with the stated intervention goal. CONCLUSIONS: PA and post-cancer diagnosis randomized trials have used objective monitoring primarily for motivation and/or adherence assessment. Investigators and practitioners are encouraged to expand the use of objective monitoring to also include understanding mechanisms of PA benefits and assess non-PA treatment modality effects. Future clinical and research protocols should consider the 1) outcome to be measured and reported, 2) need (or not) for blinding of the instrument outputs to participants, 3) appropriateness of activity intensity cutpoints for interpreting accelerometer data, and 4) logistical issues relevant to cancer survivors after diagnosis. PMID- 21603255 TI - Metallosurfactants of bioinorganic interest: Coordination-induced self assembly. AB - This review covers selected surfactant ligands that undergo a change in aggregate morphology upon coordination of a metal ion, with a particular focus on coordination-induced micelle-to-vesicle transitions. The surfactants include microbially produced amphiphilic siderophores, as well as synthetic amphiphilic ligands. The mechanism of the metal-induced phase change is considered in light of the coordination chemistry of the metal ions, the nature of the ligands, and changes in molecular geometry that result from metal coordination. Of particular interest are biologically produced amphiphiles that coordinate transition metal ions and amphiphilic ligands of relevance to bioinorganic chemistry. PMID- 21603256 TI - The characterization of cell line crl-2335 as a Basal-like breast carcinoma model. AB - Basal-like breast cancer has been reported to be the most aggressive and deadly carcinoma sub-type. Patients diagnosed with this subtype have a less than 50% five-year survival. In addition, many studies have reported that this sub-type is more prevalent in specific ethnic groups and is believed to be a key factor that drives certain ethnic disparities in mortality. In order to effectively study this sub-type and determine unique gene expression and biochemical pathways which sustain this cancer's growth, we sought to identify human breast cancer cell lines that represent a model for the basal-like subtype. Here, we report our findings which indicate the African American cell line CRL-2335 is a true representative of basal-like breast carcinoma. PMID- 21603257 TI - ODAM Expression Inhibits Human Breast Cancer Tumorigenesis. AB - We have posited that Odontogenic Ameloblast Associated Protein (ODAM) serves as a novel prognostic biomarker in breast cancer and now have investigated its potential role in regulating tumor growth and metastasis. Human breast cancer MDA MB-231 cells were transfected with a recombinant ODAM plasmid construct (or, as a control, the plasmid vector alone). ODAM expression increased adhesion and apoptosis of the transfected MDA-MB-231 cells and suppressed their growth rate, migratory activity, and capability to invade extracellular matrix-coated membranes. Implantation of such cells into mouse mammary fat pads resulted in significantly smaller tumors than occurred in animals that received control cells; furthermore, ODAM-expressing cells, when injected intravenously into mice, failed to metastasize, whereas the control-transfected counterparts produced extensive lung lesions. Our finding that induction of ODAM expression in human breast cancer cells markedly inhibited their neoplastic properties provides further evidence for the regulatory role of this molecule in tumorigenesis and, consequently, is of potential clinical import. PMID- 21603258 TI - Safety and Efficacy of nab-Paclitaxel in the Treatment of Patients with Breast Cancer. AB - Taxanes are highly active chemotherapeutic agents in the treatment of early-stage and metastatic breast cancer. Novel formulations have been developed to improve efficacy and decrease toxicity associated with these cytotoxic agents. nab paclitaxel is a solvent free, albumin-bound 130-nanometer particle formulation of paclitaxel (Abraxane((r)), Abraxis Bioscience), which was developed to avoid toxicities of the Cremophor vehicle used in solvent-based paclitaxel. In a phase III clinical trial, nab-paclitaxel demonstrated higher response rates, better safety and side-effect profile compared to conventional paclitaxel, and improved survival in patients receiving it as second line therapy. Higher doses can be administered over a shorter infusion time without the need for special infusion sets or pre-medications. It is now approved in the US for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy, where prior therapy included an anthracycline. Recently, several phase II studies have suggested a role for nab paclitaxel as a single agent and in combination with other agents for first-line treatment of metastatic breast cancer. PMID- 21603259 TI - Expression, Purification, and Characterisation of Dehydroquinate Synthase from Pyrococcus furiosus. AB - Dehydroquinate synthase (DHQS) catalyses the second step of the shikimate pathway to aromatic compounds. DHQS from the archaeal hyperthermophile Pyrococcus furiosus was insoluble when expressed in Escherichia coli but was partially solubilised when KCl was included in the cell lysis buffer. A purification procedure was developed, involving lysis by sonication at 30 degrees C followed by a heat treatment at 70 degrees C and anion exchange chromatography. Purified recombinant P. furiosus DHQS is a dimer with a subunit Mr of 37,397 (determined by electrospray ionisation mass spectrometry) and is active over broad pH and temperature ranges. The kinetic parameters are K(M) (3-deoxy-D-arabino heptulosonate 7-phosphate) 3.7 MUM and k(cat) 3.0 sec(-1) at 60 degrees C and pH 6.8. EDTA inactivates the enzyme, and enzyme activity is restored by several divalent metal ions including (in order of decreasing effectiveness) Cd(2+), Co(2+), Zn(2+), and Mn(2+). High activity of a DHQS in the presence of Cd(2+) has not been reported for enzymes from other sources, and may be related to the bioavailability of Cd(2+) for P. furiosus. This study is the first biochemical characterisation of a DHQS from a thermophilic source. Furthermore, the characterisation of this hyperthermophilic enzyme was carried out at elevated temperatures using an enzyme-coupled assay. PMID- 21603260 TI - 16S rRNA-Based Identification of a Glucan-Hyperproducing Weissella confusa. AB - A gram-positive, nonmotile, irregular, short, rod-shaped new strain of Weissella confusa bacterium was isolated from fermented cabbage. The isolate was physiologically and biochemically characterised. The 16S rDNA was amplified by polymerase chain reaction (PCR). The isolate was identified as Weissella confusa (GenBank accession number: GU138518.1) based on nucleotide homology and phylogenetic analysis. The isolate produces glucansucrase when grown in sucrose supplemented culture medium which catalyses glucan formation. This novel isolate possesses high capacity of industrial use due to its high productivity of glucan (34 mg/mL) as compared to other strains reported. The optimum temperature for glucansucrase production was 25 degrees C. The shaking condition gave an enzyme activity of 6.1 U/mL which was 1.5 times higher than that given by static condition (4.1 U/mL). The temperature 35 degrees C, pH 5.4, and ionic strength 10 20 mM were optimum for enzyme assay. This investigation unraveled the abundance of industrially valuable microflora of the north east India. PMID- 21603261 TI - Association between Abdominal Fat (DXA) and Its Subcomponents (CT Scan) before and after Weight Loss in Obese Postmenopausal Women: A MONET Study. AB - Introduction. Subcutaneous fat (ScF) and visceral fat (VF) measurements using CT scan are expensive and may imply significant radiation doses. Cross-sectional studies using CT scan showed that ScF and VF are significantly correlated with abdominal fat measured by DXA (AF-DXA). The association has not been studied after a weight loss. Objective. To determine (1) the associations between AF-DXA and ScF and VF before and after weight loss and (2) the associations between their changes. Methods. 137 overweight/obese postmenopausal women were divided in two groups (1-caloric restriction or 2-caloric restriction + resistance training). AF was assessed using DXA and CT scan. Results. Correlations between AF-DXA and ScF (before: r = 0.87, after; r = 0.87; P < .01) and, AF-DXA and VF (before: r = 0.61, after; r = 0.69; P < .01) are not different before and after the weight loss. Correlations between delta AF-DXA and delta ScF (r = 0.72; P < .01) or delta VF (r = 0.51; P < .01) were found. Conclusion. The use of AF-DXA as a surrogate for VF after weight loss is questionable, but may be interesting for ScF. PMID- 21603262 TI - Is there a metabolic program in the skeletal muscle of obese individuals? AB - Severe obesity (BMI >= 40 kg/m(2)) is associated with multiple defects in skeletal muscle which contribute to insulin resistance and a reduction in fatty acid oxidation (FAO) in this tissue. These metabolic derangements are retained in human skeletal muscle cells raised in culture. Together, these findings are indicative of a dysfunctional global metabolic program with severe obesity which is of an epigenetic or genetic origin. Weight loss via gastric bypass surgery can "turn off" and/or correct components of this metabolic program as insulin sensitivity is restored; however, the impairment in FAO in skeletal muscle remains evident. Physical activity can improve FAO and insulin action, indicating that this patient population is not exercise resistant and that exercise offers a pathway to circumvent the abnormal program. Findings presented in this review will hopefully increase the understanding of and aid in preventing and/or treating the severely obese condition. PMID- 21603263 TI - Phospholipases a in trypanosomatids. AB - Phospholipases are a complex and important group of enzymes widespread in nature, that play crucial roles in diverse biochemical processes and are classified as A(1), A(2), C, and D. Phospholipases A(1) and A(2) activities have been linked to pathogenesis in various microorganisms, and particularly in pathogenic protozoa they have been implicated in cell invasion. Kinetoplastids are a group of flagellated protozoa, including extra- and intracellular parasites that cause severe disease in humans and animals. In the present paper, we will mainly focus on the three most important kinetoplastid human pathogens, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp., giving a perspective of the research done up to now regarding biochemical, biological, and molecular characteristics of Phospholipases A(1) and A(2) and their contribution to pathogenesis. PMID- 21603264 TI - Differential effects of calorie restriction and exercise on the adipose transcriptome in diet-induced obese mice. AB - We tested the hypothesis that obesity reversal by calorie restriction (CR) versus treadmill exercise (EX) differentially modulates adipose gene expression using 48 female C57BL/6 mice administered a diet-induced obesity (DIO) regimen for 8 weeks, then randomized to receive for 8 weeks either: (1) a control (AIN-76A) diet, fed ad libitum (DIO control); (2) a 30% CR regimen; (3) a treadmill EX regimen (with AIN-76A diet fed ad libitum); or (4) continuation of the DIO diet. Relative to the DIO controls, both CR and EX reduced adiposity by 35-40% and serum leptin levels by 80%, but only CR increased adiponectin and insulin sensitivity. Gene expression microarray analysis of visceral white adipose tissue revealed 209 genes responsive to both CR and EX, relative to the DIO group. However, CR uniquely altered expression of an additional 496 genes, whereas only 20 were uniquely affected by EX. Of the genes distinctly responsive to CR, 17 related to carbohydrate metabolism and glucose transport, including glucose transporter (GLUT) 4. Chromatin immunoprecipitation assays of the Glut4 promoter revealed that, relative to the DIO controls, CR significantly increased histone 4 acetylation, suggesting epigenetic regulation may underlie some of the differential effects of CR versus EX on the adipose transcriptome. PMID- 21603265 TI - Obesity and type 2 diabetes prevalence in adults from two remote first nations communities in northwestern ontario, Canada. AB - Objective. To assess the prevalence rates of obesity and type 2 diabetes in adults from two First Nations communities in northwestern Ontario, Canada. Methods. Body weight, height, and waist circumference as well as fasting and postprandial glucose levels following an oral glucose tolerance test were measured in 31 men and 41 women. Results. The mean age of the sample was 43 +/- 13 y. The prevalence of obesity was 65.3% and was comparable between men and women. 90.3% of the individuals presented waist circumference levels greater than the thresholds associated with an increased risk of developing health problems. 26 of the 72 individuals (36.1%) were found to be type 2 diabetic. The prevalence of diabetes was not different between men and women. Conclusion. Using objective measurements, this study confirms that First Nations adults from remote communities of Canada continue to experience a disproportionately higher prevalence of obesity and type 2 diabetes than nonaboriginal Canadians. PMID- 21603266 TI - The role of manganese superoxide dismutase in skin cancer. AB - Recent studies have shown that antioxidant enzyme expression and activity are drastically reduced in most human skin diseases, leading to propagation of oxidative stress and continuous disease progression. However, antioxidants, an endogenous defense system against reactive oxygen species (ROS), can be induced by exogenous sources, resulting in protective effects against associated oxidative injury. Many studies have shown that the induction of antioxidants is an effective strategy to combat various disease states. In one approach, a SOD mimetic was applied topically to mouse skin in the two-stage skin carcinogenesis model. This method effectively reduced oxidative injury and proliferation without interfering with apoptosis. In another approach, Protandim, a combination of 5 well-studied medicinal plants, was given via dietary administration and significantly decreased tumor incidence and multiplicity by 33% and 57%, respectively. These studies suggest that alterations in antioxidant response may be a novel approach to chemoprevention. This paper focuses on how regulation of antioxidant expression and activity can be modulated in skin disease and the potential clinical implications of antioxidant-based therapies. PMID- 21603267 TI - Singular features of trypanosomatids' phosphotransferases involved in cell energy management. AB - Trypanosomatids are responsible for economically important veterinary affections and severe human diseases. In Africa, Trypanosoma brucei causes sleeping sickness or African trypanosomiasis, while in America, Trypanosoma cruzi is the etiological agent of Chagas disease. These parasites have complex life cycles which involve a wide variety of environments with very different compositions, physicochemical properties, and availability of metabolites. As the environment changes there is a need to maintain the nucleoside homeostasis, requiring a quick and regulated response. Most of the enzymes required for energy management are phosphotransferases. These enzymes present a nitrogenous group or a phosphate as acceptors, and the most clear examples are arginine kinase, nucleoside diphosphate kinase, and adenylate kinase. Trypanosoma and Leishmania have the largest number of phosphotransferase isoforms ever found in a single cell; some of them are absent in mammals, suggesting that these enzymes are required in many cellular compartments associated to different biological processes. The presence of such number of phosphotransferases support the hypothesis of the existence of an intracellular enzymatic phosphotransfer network that communicates the spatially separated intracellular ATP consumption and production processes. All these unique features make phosphotransferases a promising start point for rational drug design for the treatment of human trypanosomiasis. PMID- 21603268 TI - Genetic Variance in Uncoupling Protein 2 in Relation to Obesity, Type 2 Diabetes, and Related Metabolic Traits: Focus on the Functional -866G>A Promoter Variant (rs659366). AB - Uncoupling proteins (UCPs) are mitochondrial proteins able to dissipate the proton gradient of the inner mitochondrial membrane when activated. This decreases ATP-generation through oxidation of fuels and may theoretically decrease energy expenditure leading to obesity. Evidence from Ucp((-/-)) mice revealed a role of UCP2 in the pancreatic beta-cell, because beta-cells without UCP2 had increased glucose-stimulated insulin secretion. Thus, from being a candidate gene for obesity UCP2 became a valid candidate gene for type 2 diabetes mellitus. This prompted a series of studies of the human UCP2 and UCP3 genes with respect to obesity and diabetes. Of special interest was a promoter variant of UCP2 situated 866bp upstream of transcription initiation (-866G>A, rs659366). This variant changes promoter activity and has been associated with obesity and/or type 2 diabetes in several, although not all, studies. The aim of the current paper is to summarize current evidence of association of UCP2 genetic variation with obesity and type 2 diabetes, with focus on the -866G>A polymorphism. PMID- 21603269 TI - Enzyme Mechanism and Slow-Onset Inhibition of Plasmodium falciparum Enoyl-Acyl Carrier Protein Reductase by an Inorganic Complex. AB - Malaria continues to be a major cause of children's morbidity and mortality worldwide, causing nearly one million deaths annually. The human malaria parasite, Plasmodium falciparum, synthesizes fatty acids employing the Type II fatty acid biosynthesis system (FAS II), unlike humans that rely on the Type I (FAS I) pathway. The FAS II system elongates acyl fatty acid precursors of the cell membrane in Plasmodium. Enoyl reductase (ENR) enzyme is a member of the FAS II system. Here we present steady-state kinetics, pre-steady-state kinetics, and equilibrium fluorescence spectroscopy data that allowed proposal of P. falciparum ENR (PfENR) enzyme mechanism. Moreover, building on previous results, the present study also evaluates the PfENR inhibition by the pentacyano(isoniazid)ferrateII compound. This inorganic complex represents a new class of lead compounds for the development of antimalarial agents focused on the inhibition of PfENR. PMID- 21603270 TI - Interleukin-15, IL-15 Receptor-Alpha, and Obesity: Concordance of Laboratory Animal and Human Genetic Studies. AB - Interleukin-15 (IL-15) is a cytokine which inhibits lipid deposition in cultured adipocytes and decreases adipose tissue deposition in laboratory rodents. In human subjects, negative correlations between circulating IL-15 levels and both total and abdominal fat have been demonstrated. Deletions of IL15 in humans and mice are associated with obesity, while gain-of-function IL-15 overexpressing mice are resistant to diet-induced obesity. IL-15 is highly (but not exclusively) expressed at the mRNA level in skeletal muscle tissue, and the regulation of IL 15 translation and secretion is complex. Conflicting evidence exists concerning whether circulating IL-15 is released from skeletal muscle tissue in response to exercise or other physiological stimuli. The IL-15 receptor-alpha (IL-15Ralpha) subunit has a complex biochemistry, encoding both membrane-bound and soluble forms which can modulate IL-15 secretion and bioactivity. The gene encoding this receptor, IL15RA, resides on human chromosome 10p, a location linked to obesity and type-2 diabetes. Several single-nucleotide polymorphisms (SNPs) in human IL15RA and IL15 correlate with adiposity and markers of the metabolic syndrome. Genetic variation in IL15RA may modulate IL-15 bioavailability, which in turn regulates adiposity. Thus, IL-15 and the IL-15Ralpha may be novel targets for pharmacologic control of obesity in the human population. PMID- 21603271 TI - The Sphingolipid Biosynthetic Pathway Is a Potential Target for Chemotherapy against Chagas Disease. AB - The protozoan parasite Trypanosoma cruzi is the causative agent of human Chagas disease, for which there currently is no cure. The life cycle of T. cruzi is complex, including an extracellular phase in the triatomine insect vector and an obligatory intracellular stage inside the vertebrate host. These phases depend on a variety of surface glycosylphosphatidylinositol-(GPI-) anchored glycoconjugates that are synthesized by the parasite. Therefore, the surface expression of GPI anchored components and the biosynthetic pathways of GPI anchors are attractive targets for new therapies for Chagas disease. We identified new drug targets for chemotherapy by taking the available genome sequence information and searching for differences in the sphingolipid biosynthetic pathways (SBPs) of mammals and T. cruzi. In this paper, we discuss the major steps of the SBP in mammals, yeast and T. cruzi, focusing on the IPC synthase and ceramide remodeling of T. cruzi as potential therapeutic targets for Chagas disease. PMID- 21603272 TI - Synthesis of isopropyl ferulate using silica-immobilized lipase in an organic medium. AB - Immobilization of lipases has proved to be a useful technique for improving an enzyme's activity in organic solvents. In the present study, the performance of a silica-immobilized lipase was evaluated for the synthesis of isopropyl ferulate in DMSO. The biocatalyst was cross-linked onto the matrix with 1% glutaraldehyde. The effects of various parameters, molar ratio of ferulic acid to isopropyl alcohol (25 mM : 100 mM), concentration of biocatalyst (2.5-20 mg/mL), molecular sieves (25-250 mg/mL), and various salt ions, were studied consecutively as a function of percent esterification. Immobilized lipase at 25 mg/mL showed maximum esterification (~84%) of ferulic acid and isopropanol at a molar ratio of 25 mM : 100 mM, respectively, in DMSO at 45 degrees C in 3 h under shaking (150 rpm). To overcome the inhibitory effect of water (a byproduct) if any, in the reaction mixture, molecular sieves (3 A * 1.5 mm; 100 mg/mL) were added to the reaction mixture to promote the forward reaction. Salt ions like Ca(2+), Cd(2+), and Fe(2+) enhanced the activity of immobilized biocatalyst while a few ions like Co(2+), Zn(2+), Mg(2+), Mn(2+), Al(3+), and Na(+) had mild inhibitory effect. Approximately, one third of total decrease in the esterification efficacy was observed after the 5th repetitive cycle of esterification. PMID- 21603274 TI - Production of Feruloyl Esterase from Aspergillus niger by Solid-State Fermentation on Different Carbon Sources. AB - A mixture of wheat bran with maize bran as a carbon source and addition of (NH(4))SO(4) as nitrogen source was found to significantly increase production of feruloyl esterase (FAE) enzyme compared with wheat bran as a sole carbon and nitrogen source. The optimal conditions in conical flasks were carbon source (30 g) to water 1 : 1, maize bran to wheat bran 1 : 2, (NH(4))SO(4) 1.2 g and MgSO(4) 70 mg. Under these conditions, FAE activity was 7.68 mU/g. The FAE activity on the mixed carbon sources showed, high activity against the plant cell walls contained in the cultures. PMID- 21603273 TI - Microarray evidences the role of pathologic adipose tissue in insulin resistance and their clinical implications. AB - Clustering of insulin resistance and dysmetabolism with obesity is attributed to pathologic adipose tissue. The morphologic hallmarks of this pathology are adipocye hypertrophy and heightened inflammation. However, it's underlying molecular mechanisms remains unknown. Study of gene function in metabolically active tissues like adipose tissue, skeletal muscle and liver is a promising strategy. Microarray is a powerful technique of assessment of gene function by measuring transcription of large number of genes in an array. This technique has several potential applications in understanding pathologic adipose tissue. They are: (1) transcriptomic differences between various depots of adipose tissue, adipose tissue from obese versus lean individuals, high insulin resistant versus low insulin resistance, brown versus white adipose tissue, (2) transcriptomic profiles of various stages of adipogenesis, (3) effect of diet, cytokines, adipokines, hormones, environmental toxins and drugs on transcriptomic profiles, (4) influence of adipokines on transcriptomic profiles in skeletal muscle, hepatocyte, adipose tissue etc., and (5) genetics of gene expression. The microarray evidences of molecular basis of obesity and insulin resistance are presented here. Despite the limitations, microarray has potential clinical applications in finding new molecular targets for treatment of insulin resistance and classification of adipose tissue based on future risk of insulin resistance syndrome. PMID- 21603275 TI - Relationships of adrenoceptor polymorphisms with obesity. AB - Obesity, hypertension, and type 2 diabetes are rapidly growing public health problems. Heightened sympathetic nerve activity is a well-established observation in obesity, hypertension, and type 2 diabetes. Human obesity, hypertension, and diabetes have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity are mainly mediated via the beta2, and beta3-adrenergic receptors in humans. Further, beta2 adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. beta-adrenoceptor polymorphisms have also been associated with adrenoceptor desensitization, increased adiposity, insulin resistance, and enhanced sympathetic nervous activity. Many epidemiological studies have shown strong relationships between adrenoceptor polymorphisms and obesity, but the observations have been discordant. This paper will discuss the current topics involving the influence of the sympathetic nervous system and beta2- and beta3 adrenoceptor polymorphisms in obesity. PMID- 21603276 TI - Role of heme and heme-proteins in trypanosomatid essential metabolic pathways. AB - Around the world, trypanosomatids are known for being etiological agents of several highly disabling and often fatal diseases like Chagas disease (Trypanosoma cruzi), leishmaniasis (Leishmania spp.), and African trypanosomiasis (Trypanosoma brucei). Throughout their life cycle, they must cope with diverse environmental conditions, and the mechanisms involved in these processes are crucial for their survival. In this review, we describe the role of heme in several essential metabolic pathways of these protozoans. Notwithstanding trypanosomatids lack of the complete heme biosynthetic pathway, we focus our discussion in the metabolic role played for important heme-proteins, like cytochromes. Although several genes for different types of cytochromes, involved in mitochondrial respiration, polyunsaturated fatty acid metabolism, and sterol biosynthesis, are annotated at the Tritryp Genome Project, the encoded proteins have not yet been deeply studied. We pointed our attention into relevant aspects of these protein functions that are amenable to be considered for rational design of trypanocidal agents. PMID- 21603277 TI - Is Accurate Perception of Body Image Associated with Appropriate Weight-Control Behavior among Adolescents of the Seychelles. AB - Background. We examined body image perception and its association with reported weight-control behavior among adolescents in the Seychelles. Methods. We conducted a school-based survey of 1432 students aging 11-17 years in the Seychelles. Perception of body image was assessed using both a closed-ended question (CEQ) and Stunkard's pictorial silhouettes (SPS). Voluntary attempts to change weight were also assessed. Results. A substantial proportion of the overweight students did not consider themselves as overweight (SPS: 24%, CEQ: 34%), and a substantial proportion of the normal-weight students considered themselves as too thin (SPS: 29%, CEQ: 15%). Logistic regression analysis showed that students with an accurate weight perception were more likely to have appropriate weight-control behavior. Conclusions. We found that substantial proportions of students had an inaccurate perception of their weight and that weight perception was associated with weight-control behavior. These findings point to forces that can drive the upwards overweight trends. PMID- 21603278 TI - Activity Staining and Inhibition Characterization of Dipeptidylpeptidase-III Enzyme from Goat Brain. AB - Dipeptidylpeptidase-III (DPP-III) from goat brain was purified and characterized using Arginyl-Arginyl-4-methoxy-beta-naphthylamide (Arg-Arg-4mbetaNA) substrate. This enzyme retained its activity in native 10% polyacrylamide gel when stained using Arg-Arg-4mbetaNA. The activity was significantly increased by 100 mM chloride. Studies for its inhibition with some peptides and chemical inhibitors revealed that Leu-Trp-Met-Arg-Phe-Ala was most potent inhibitor followed by Arg Phe-Ala and Gly-Phe-Leu. All the studied chemical inhibitors caused 40-50% inhibition at 1 mM. Metal ions helped to regain activity of EDTA pretreated enzyme. ZnCl(2) at 50 MUM almost completely restored the enzyme activity. Further ZnCl(2) and CoCl(2) exerted protective effects on EDTA pretreated enzyme for its susceptibility to DTNB inhibition. Therefore, DPP-III is a metalloprotease with the involvement of cysteine residues either located at the catalytic site or involved in regulation. PMID- 21603279 TI - Serum resistin level in obese male children. AB - Objectives. Resistin is a member of cysteine-rich molecules. Several studies have been carried out to determine the biological effect of resistin, nevertheless a significant number are animal studies. All the studies performed regarding the relationship between serum resistin and obesity were merely accomplished in women. To the best of our knowledge, there is no survey on the correlation of the serum resistin level and obesity in male children. The aim of the present study is to assess serum concentration of resistin in obese male children. Methods. Between June 2009 and January 2010, we enrolled 42 randomly selected obese male students (body mass index (BMI) >95th percentile, age 15.7 +/- 1.5). Thirty-eight healthy age-matched male students with normal BMI (<85th percentile) were selected as a control group for the purpose of comparison of the serum resistin levels. Results. Serum resistin levels were measured in obese and control group. No significant difference was found between resistin levels of the 2 groups (obese: 9.21 +/- 5.6 ng/mL versus normal: 9.83 +/- 4.3 ng/mL; P = .582). There was no significant correlation between serum resistin level and BMI. Assessing the resistin level in male subjects was the distinct feature of our study. The outstanding finding of this research is that there is no correlation between serum resistin level and obesity. Conclusion. We have demonstrated that there is no correlation between obesity in male children and resistin level. Consequently, metabolic abnormalities of insulin resistance seen in obese male patients are not related to resistin. PMID- 21603280 TI - STAT-HI: A socio-technical assessment tool for health informatics implementations. AB - This paper proposes a socio-technical assessment tool (STAT-HI) for health informatics implementations. We explore why even projects allegedly using sound methodologies repeatedly fail to give adequate attention to socio-technical issues, and we present an initial draft of a structured assessment tool for health informatics implementation that encapsulates socio-technical good practice. Further work is proposed to enrich and validate the proposed instrument. This proposal was presented for discussion at a meeting of the UK Faculty of Health Informatics in December 2009. PMID- 21603281 TI - System-agnostic clinical decision support services: benefits and challenges for scalable decision support. AB - System-agnostic clinical decision support (CDS) services provide patient evaluation capabilities that are independent of specific CDS systems and system implementation contexts. While such system-agnostic CDS services hold great potential for facilitating the widespread implementation of CDS systems, little has been described regarding the benefits and challenges of their use. In this manuscript, the authors address this need by describing potential benefits and challenges of using a system-agnostic CDS service. This analysis is based on the authors' formal assessments of, and practical experiences with, various approaches to developing, implementing, and maintaining CDS capabilities. In particular, the analysis draws on the authors' experience developing and leveraging a system-agnostic CDS Web service known as SEBASTIAN. A primary potential benefit of using a system-agnostic CDS service is the relative ease and flexibility with which the service can be leveraged to implement CDS capabilities across applications and care settings. Other important potential benefits include facilitation of centralized knowledge management and knowledge sharing; the potential to support multiple underlying knowledge representations and knowledge resources through a common service interface; improved simplicity and componentization; easier testing and validation; and the enabling of distributed CDS system development. Conversely, important potential challenges include the increased effort required to develop knowledge resources capable of being used in many contexts and the critical need to standardize the service interface. Despite these challenges, our experiences to date indicate that the benefits of using a system-agnostic CDS service generally outweigh the challenges of using this approach to implementing and maintaining CDS systems. PMID- 21603282 TI - The morningside initiative: collaborative development of a knowledge repository to accelerate adoption of clinical decision support. AB - The Morningside Initiative is a public-private activity that has evolved from an August, 2007, meeting at the Morningside Inn, in Frederick, MD, sponsored by the Telemedicine and Advanced Technology Research Center (TATRC) of the US Army Medical Research Materiel Command. Participants were subject matter experts in clinical decision support (CDS) and included representatives from the Department of Defense, Veterans Health Administration, Kaiser Permanente, Partners Healthcare System, Henry Ford Health System, Arizona State University, and the American Medical Informatics Association (AMIA). The Morningside Initiative was convened in response to the AMIA Roadmap for National Action on Clinical Decision Support and on the basis of other considerations and experiences of the participants. Its formation was the unanimous recommendation of participants at the 2007 meeting which called for creating a shared repository of executable knowledge for diverse health care organizations and practices, as well as health care system vendors. The rationale is based on the recognition that sharing of clinical knowledge needed for CDS across organizations is currently virtually non existent, and that, given the considerable investment needed for creating, maintaining and updating authoritative knowledge, which only larger organizations have been able to undertake, this is an impediment to widespread adoption and use of CDS. The Morningside Initiative intends to develop and refine (1) an organizational framework, (2) a technical approach, and (3) CDS content acquisition and management processes for sharing CDS knowledge content, tools, and experience that will scale with growing numbers of participants and can be expanded in scope of content and capabilities. Intermountain Healthcare joined the initial set of participants shortly after its formation. The efforts of the Morningside Initiative are intended to serve as the basis for a series of next steps in a national agenda for CDS. It is based on the belief that sharing of knowledge can be highly effective as is the case in other competitive domains such as genomics. Participants in the Morningside Initiative believe that a coordinated effort between the private and public sectors is needed to accomplish this goal and that a small number of highly visible and respected health care organizations in the public and private sector can lead by example. Ultimately, a future collaborative knowledge sharing organization must have a sustainable long term business model for financial support. PMID- 21603283 TI - Standards for scalable clinical decision support: need, current and emerging standards, gaps, and proposal for progress. AB - Despite their potential to significantly improve health care, advanced clinical decision support (CDS) capabilities are not widely available in the clinical setting. An important reason for this limited availability of CDS capabilities is the application-specific and institution-specific nature of most current CDS implementations. Thus, a critical need for enabling CDS capabilities on a much larger scale is the development and adoption of standards that enable current and emerging CDS resources to be more effectively leveraged across multiple applications and care settings. Standards required for such effective scaling of CDS include (i) standard terminologies and information models to represent and communicate about health care data; (ii) standard approaches to representing clinical knowledge in both human-readable and machine-executable formats; and (iii) standard approaches for leveraging these knowledge resources to provide CDS capabilities across various applications and care settings. A number of standards do exist or are under development to meet these needs. However, many gaps and challenges remain, including the excessive complexity of many standards; the limited availability of easily accessible knowledge resources implemented using standard approaches; and the lack of tooling and other practical resources to enable the efficient adoption of existing standards. Thus, the future development and widespread adoption of current CDS standards will depend critically on the availability of tooling, knowledge bases, and other resources that make the adoption of CDS standards not only the right approach to take, but the cost effective path to follow given the alternative of using a traditional, ad hoc approach to implementing CDS. PMID- 21603284 TI - Toward scalable clinical decision support. PMID- 21603285 TI - In Vivo validation of a bioinformatics based tool to identify reduced replication capacity in HIV-1. AB - Although antiretroviral drug resistance is common in treated HIV infected individuals, it is not a consistent indicator of HIV morbidity and mortality. To the contrary, HIV resistance-associated mutations may lead to changes in viral fitness that are beneficial to infected individuals. Using a bioinformatics-based model to assess the effects of numerous drug resistance mutations, we determined that the D30N mutation in HIV-1 protease had the largest decrease in replication capacity among known protease resistance mutations. To test this in silico result in an in vivo environment, we constructed several drug-resistant mutant HIV-1 strains and compared their relative fitness utilizing the SCID-hu mouse model. We found HIV-1 containing the D30N mutation had a significant defect in vivo, showing impaired replication kinetics and a decreased ability to deplete CD4+ thymocytes, compared to the wild-type or virus without the D30N mutation. In comparison, virus containing the M184V mutation in reverse transcriptase, which shows decreased replication capacity in vitro, did not have an effect on viral fitness in vivo. Thus, in this study we have verified an in silico bioinformatics result with a biological assessment to identify a unique mutation in HIV-1 that has a significant fitness defect in vivo. PMID- 21603286 TI - Liver flukes: the malady neglected. AB - Liver fluke disease is a chronic parasitic inflammatory disease of the bile ducts. Infection occurs through ingestion of fluke-infested, fresh-water raw fish. The most well-known species that cause human infection are Clonorchis sinensis, Opisthorchis viverrini and Opisthorchis felineus. Adult flukes settle in the small intrahepatic bile ducts and then they live there for 20-30 years. The long-lived flukes cause long-lasting chronic inflammation of the bile ducts and this produces epithelial hyperplasia, periductal fibrosis and bile duct dilatation. The vast majority of patients are asymptomatic, but the patients with heavy infection suffer from lassitude and nonspecific abdominal complaints. The complications are stone formation, recurrent pyogenic cholangitis and cholangiocarcinoma. Approximately 35 million people are infected with liver flukes throughout the world and the exceptionally high incidence of cholangiocarcinoma in some endemic areas is closely related with a high prevalence of liver fluke infection. Considering the impact of this food-borne malady on public health and the severe possible clinical consequences, liver fluke infection should not be forgotten or neglected. PMID- 21603287 TI - Transient ischemic attack and stroke can be differentiated by analyzing the diffusion tensor imaging. AB - OBJECTIVE: We wanted to differentiate between transient ischemic attack (TIA) and minor stroke using fractional anisotropy and three-dimensional (3D) fiber tractography. MATERIALS AND METHODS: The clinical data, conventional magnetic resonance imaging (MRI), diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI) were obtained for 45 TIA patients and 33 minor stroke patients. The fractional anisotrophy ratio (rFA) between the lesion and the mirrored corresponding contralateral normal tissue was calculated and analyzed. The spatial relationship between the lesion and the corticospinal tract (CST) was analyzed and the lesion sizes in the minor stroke patients and TIA patients were compared. RESULTS: Twenty-two of the 45 TIA patients (49%) revealed focal abnormalities following DWI. The rFA was significantly lower (p < 0.05) in the stroke patients (0.71 +/- 0.29) compared to that of the TIA patients (1.05 +/- 0.37). The CST was involved in almost all stroke lesions, but it was not involved in 68% of the TIA lesions. The TIA patients had significantly lower CST injury scores (3.25 +/- 1.75) than did the stroke patients (8.80 +/- 2.39) (p = 0.004). CONCLUSION: Our data indicate that TIA and minor stroke can be identified by analyzing the rFA and the degree of CST involvement, and this may also allow more accurate prediction of a patient's long-term recovery or disability. PMID- 21603288 TI - Fractal dimension analysis of MDCT images for quantifying the morphological changes of the pulmonary artery tree in patients with pulmonary hypertension. AB - OBJECTIVE: The aim of this study was to use fractal dimension (FD) analysis on multidetector CT (MDCT) images for quantifying the morphological changes of the pulmonary artery tree in patients with pulmonary hypertension (PH). MATERIALS AND METHODS: Fourteen patients with PH and 17 patients without PH as controls were studied. All of the patients underwent contrast-enhanced helical CT and transthoracic echocardiography. The pulmonary artery trees were generated using post-processing software, and the FD and projected image area of the pulmonary artery trees were determined with ImageJ software in a personal computer. The FD, the projected image area and the pulmonary artery pressure (PAP) were statistically evaluated in the two groups. RESULTS: The FD, the projected image area and the PAP of the patients with PH were higher than those values of the patients without PH (p < 0.05, t-test). There was a high correlation of FD with the PAP (r = 0.82, p < 0.05, partial correlation analysis). There was a moderate correlation of FD with the projected image area (r = 0.49, p < 0.05, partial correlation analysis). There was a correlation of the PAP with the projected image area (r = 0.65, p < 0.05, Pearson correlation analysis). CONCLUSION: The FD of the pulmonary arteries in the PH patients was significantly higher than that of the controls. There is a high correlation of FD with the PAP. PMID- 21603289 TI - Comparison of usual interstitial pneumonia and nonspecific interstitial pneumonia: quantification of disease severity and discrimination between two diseases on HRCT using a texture-based automated system. AB - OBJECTIVE: To evaluate the usefulness of an automated system for quantification and discrimination of usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). MATERIALS AND METHODS: An automated system to quantify six regional high-resolution CT (HRCT) patterns: normal, NL; ground glass opacity, GGO; reticular opacity, RO; honeycombing, HC; emphysema, EMPH; and consolidation, CONS, was developed using texture and shape features. Fifty-four patients with pathologically proven UIP (n = 26) and pathologically proven NSIP (n = 28) were included as part of this study. Inter-observer agreement in measuring the extent of each HRCT pattern between the system and two thoracic radiologists were assessed in 26 randomly selected subsets using an interclass correlation coefficient (ICC). A linear regression analysis was used to assess the contribution of each disease pattern to the pulmonary function test parameters. The discriminating capacity of the system between UIP and NSIP was evaluated using a binomial logistic regression. RESULTS: The overall ICC showed acceptable agreement among the system and the two radiologists (r = 0.895 for the abnormal lung volume fraction, 0.706 for the fibrosis fraction, 0.895 for NL, 0.625 for GGO, 0.626 for RO, 0.893 for HC, 0.800 for EMPH, and 0.430 for CONS). The volumes of NL, GGO, RO, and EMPH contribute to forced expiratory volume during one second (FEV1) (r = 0.72, beta values, 0.84, 0.34, 0.34 and 0.24, respectively) and forced vital capacity (FVC) (r = 0.76, beta values, 0.82, 0.28, 0.21 and 0.34, respectively). For diffusing capacity (DL(co)), the volumes of NL and HC were independent contributors in opposite directions (r = 0.65, beta values, 0.64, -0.21, respectively). The automated system can help discriminate between UIP and NSIP with an accuracy of 82%. CONCLUSION: The automated quantification system of regional HRCT patterns can be useful in the assessment of disease severity and may provide reliable agreement with the radiologists' results. In addition, this system may be useful in differentiating between UIP and NSIP. PMID- 21603290 TI - The diagnostic accuracy, image quality and radiation dose of 64-slice dual-source CT in daily practice: a single institution's experience. AB - OBJECTIVE: We wanted to evaluate the image quality, diagnostic accuracy and radiation exposure of 64-slice dual-source CT (DSCT) coronary angiography according to the heart rate in symptomatic patients during daily clinical practice. MATERIALS AND METHODS: We performed a retrospective search for the DSCT coronary angiography reports of 729 consecutive symptomatic patients. For the 131 patients who underwent invasive coronary angiography, the image quality, the diagnostic performance (sensitivity, specificity, positive predictive value [PPV] and negative predictive value [NPV] for detecting significant stenosis >= 50% diameter) and the radiation exposure were evaluated. These values were compared between the groups with differing heart rates (HR): mean HR < 65 or >= 65 and HR variability (HRV) < 15 or >= 15. RESULTS: Among the 729 patients, the CT reports showed no stenosis or insignificant coronary artery stenosis in 72%, significant stenosis in 26% and non-diagnostic in 2%. For the 131 patients who underwent invasive coronary angiography, 95% of the patients and 97% of the segments were evaluable, and the overall per-patient/per-segment sensitivity, the perpatient/per-segment specificity, the per-patient/per-segment PPV and the per patient/per-segment NPV were 100%/90%, 71%/98%, 95%/88% and 100%/97%, respectively. The image quality was better in the HR < 65 group than in the HR >= 65 group (p = 0.001), but there was no difference in diagnostic performance between the two groups. The mean effective radiation doses were lower in the HR < 65 or HRV < 15 group (p < 0.0001): 5.5 versus 6.7 mSv for the mean HR groups and 5.3 versus 9.3 mSv for the HRV groups. CONCLUSION: Dual-source CT coronary angiography is a highly accurate modality in the clinical setting. Better image quality and a significant radiation reduction are being rendered in the lower HR group. PMID- 21603291 TI - Effects of propranolol on the left ventricular volume of normal subjects during CT coronary angiography. AB - OBJECTIVE: The purpose of this study is to determine the effects of propranolol on the left ventricular (LV) volume during CT coronary angiography. MATERIALS AND METHODS: The LV volume of 252 normal Chinese subjects (126 subjects with propranolol medication and 126 age- and gender-matched Chinese subjects without medication) was estimated using 64 slices multi-detector CT (MDCT). The heart rate difference was analyzed by the logistic linear regression model with variables that included gender, age, body height, body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP) and the dosage of propranolol. The following global LV functional parameters were calculated: the real-end diastolic volume (EDV), the real-end systolic volume (ESV) and the real-ejection fraction (EF). RESULTS: The female subjects had a greater decrease of heart rate after taking propranolol. The difference of heart rate was negatively correlated with the dosage of propranolol. The real-EDV, the real-ESV and the real-EF ranged from 48.1 to 109 mL/m2, 6.1 to 57.1 mL/m2 and 41% to 88%, respectively. There was no significant difference in the SBP and DBP between the groups without and with propranolol medication (123 +/- 17 and 80 +/- 10 mmHg; 120 +/- 14 and 80 +/- 11 mmHg, respectively). The real-EDV showed no significant difference between these two groups, but the real-ESV and real-EF showed significant differences between these two groups (69.4 +/- 9.3 and 70.6 +/- 8.9 mL/m2; 23.5 +/- 5.7 and 25.6 +/- 3.7 mL/m2, 66.5 +/- 5.1% and 63.5 +/- 4.6%, respectively). CONCLUSION: The difference of heart rate is significantly influenced by gender and the dosage of propranolol. Propranolol will also increase the ESV, which contributes to a decreased EF, while the SBP, DBP and EDV are not statistically changed. PMID- 21603292 TI - Three-dimensional evaluation of the anatomic variations of the femoral vein and popliteal vein in relation to the accompanying artery by using CT venography. AB - OBJECTIVE: We wanted to describe the three-dimensional (3D) anatomic variations of the femoral vein (FV) and popliteal vein (PV) in relation to the accompanying artery using CT venography. MATERIALS AND METHODS: We performed a retrospective review of 445 bilateral (890 limbs) lower limb CT venograms. After the 3D relationship between the FV and PV and accompanying artery was analyzed, the presence or absence of variation was determined and the observed variations were classified. In each patient, the extent and location of the variations and the location of the adductor hiatus were recorded to investigate the regional frequency of the variations. RESULTS: THERE WERE FOUR DISTINCT CATEGORIES OF VARIATIONS: agenesis (3 limbs, 0.3%), multiplication (isolated in the FV: 190 limbs, 21%; isolated in the PV: 14 limbs, 2%; and in both the FV and PV: 51 limbs, 6%), anatomical course variation (75 limbs, 8%) and high union of the tibial veins (737 limbs, 83%). The course variations included medial malposition (60 limbs, 7%), anterior rotation (11 limbs, 1%) and posterior rotation (4 limbs, 0.4%). Mapping the individual variations revealed regional differences in the pattern and frequency of the variations. CONCLUSION: CT venography helps to confirm a high incidence of variations in the lower limb venous anatomy and it also revealed various positional venous anomalies in relation to the respective artery. PMID- 21603293 TI - Diagnosing small hepatic cysts on multidetector CT: an additional merit of thinner coronal reformations. AB - OBJECTIVE: We wanted to validate the additional merit of the thinner coronal reformation images from multidetector CT (MDCT) for making the diagnosis of hepatic cysts. MATERIALS AND METHODS: For the 90 benign hepatic cysts confirmed on MRI, the transverse (5-mm thickness) and additional coronal (2-mm thickness) reformation images from MDCT were compared with each other in terms of the Hounsfield units (HUs) and the size of each hepatic cyst. RESULTS: THE ATTENUATIONS (MEAN: 17.2 HUs, standard deviation: +/- 14.4) on the thinner coronal images were significantly lower than those (mean: 40.7 HUs; standard deviation: +/- 20.6) on the thicker transverse images for the small hepatic cysts (<= 10 mm on the transverse image, p < 0.01). Twenty-three (79%) of the 29 cysts between 5 mm and 10 mm and 21 (51%) of 41 lesions up to 5 mm showed a mean HU value of 20 or less on the coronal reformation images. CONCLUSION: By reducing the partial volume effect, routine coronal reformation of MDCT with a thinner section thickness can provide another merit for making a confidential diagnosis of many small sub-centimeter hepatic cysts, and these small cysts are not easily characterized on the conventional transverse images. PMID- 21603294 TI - Clinical value of CT-guided needle biopsy for retroperitoneal lesions. AB - OBJECTIVE: The purpose of this study was to investigate retrospectively the clinical procedural performance of CT-guided needle biopsy for retroperitoneal lesions. MATERIALS AND METHODS: CT-guided needle biopsy was performed in 74 consecutive patients (M:F = 44:30; mean age, 59.7 years) with retroperitoneal lesions between April 1998 and June 2009. The target lesion ranged from 1.5 to 12.5 cm in size. The biopsy access path ranged from 3.5 to 11.5 cm in depth. A biopsy specimen was obtained using an 18-gauge core needle under a CT or CT fluoroscopy guidance and with the patient under local anesthesia. The histopathological diagnoses from the biopsies were obtained. The diagnostic confirmation of the subtype of lymphoma was evaluated. RESULTS: Satisfactory biopsy samples were obtained in 73 (99%) of 74 patients and a pathological diagnosis was made in 70 (95%) of 74 patients. Sixty three lesions were malignant (45 lymphomas, nine primary tumors, nine lymph node metastases) and seven were benign. The subtype of lymphoma was specified in 43 (96%) of 45 patients who were diagnosed with lymphoma. Analysis of the value of CT-guided biopsy in this series indicated 63 true positives, zero false positive, six true negatives and five false negatives. This test had a sensitivity of 93%, a specificity of 100% and an accuracy of 93%. No major complications were seen and minor complications were noted in seven patients (five with local hematomas, two with transient pain at the puncture site). CONCLUSION: CT-guided needle biopsy for retroperitoneal lesions is highly practical and useful, and particularly for determining the subtypes in patients with lymphoma. PMID- 21603295 TI - The T2-shortening effect of gadolinium and the optimal conditions for maximizing the CNR for evaluating the biliary system: a phantom study. AB - OBJECTIVE: Clear depiction of the common bile duct is important when evaluating neonatal cholestasis in order to differentiate biliary atresia from other diseases. During MR cholangiopancreatography, the T2-shortening effect of gadolinium can increase the contrast-to-noise ratio (CNR) of the bile duct and enhance its depiction. The purpose of this study was to confirm, by performing a phantom study, the T2-shortening effect of gadolinium, to evaluate the effect of different gadolinium chelates with different gadolinium concentrations and different magnetic field strengths for investigating the optimal combination of these conditions, and for identifying the maximum CNR for the evaluation of the biliary system. MATERIALS AND METHODS: MR imaging using a T2-weighted single-shot fast spin echo sequence and T2 relaxometry was performed with a sponge phantom in a syringe tube. Two kinds of contrast agents (Gd-DTPA and Gd-EOB-DTPA) with different gadolinium concentrations were evaluated with 1.5T and 3T scanners. The signal intensities, the CNRs and the T2 relaxation time were analyzed. RESULTS: The signal intensities significantly decreased as the gadolinium concentrations increased (p < 0.001) with both contrast agents. These signal intensities were higher on a 3T (p < 0.001) scanner. The CNRs were higher on a 1.5T (p < 0.001) scanner and they showed no significant change with different gadolinium concentrations. The T2 relaxation time also showed a negative correlation with the gadolinium concentrations (p < 0.001) and the CNRs showed decrease more with Gd-EOB-DTPA (versus Gd-DTPA; p < 0.001) on a 3T scanner (versus 1.5T; p < 0.001). CONCLUSION: A T2-shortening effect of gadolinium exhibits a negative correlation with the gadolinium concentration for both the signal intensities and the T2 relaxation time. A higher CNR can be obtained with Gd-DTPA on a 1.5T MRI scanner. PMID- 21603296 TI - Musculoskeletal applications of elastography: a pictorial essay of our initial experience. AB - Elastography is an ultrasound-based newer imaging technique that is currently being used for the evaluation of breast lesions and hepatic pathology. It is also being evaluated for characterizing lesions of the prostate, thyroid, cervix and lymph nodes. We have applied real-time sonoelastography to a variety of musculoskeletal pathologies and here we report the findings of elastography for the evaluation of various musculoskeletal pathologies. Elastography of musculoskeletal lesions is not yet being routinely used in clinical practice, but it is being extensively researched. PMID- 21603297 TI - Unusual thymic hyperplasia mimicking lipomatous tumor in an eight-year-old boy with concomitant pericardial lipomatosis and right facial hemihypertrophy. AB - We report a case of thymic hyperplasia accompanied by pericardial lipomatosis and right facial hemihypertrophy in an 8-year-old boy. On imaging studies, the hyperplastic thymus had prominent curvilinear and nodular fatty areas simulating a fat-containing anterior mediastinal mass, which is an unusual finding in children. To our knowledge, this is the first report on a child with a combination of thymic hyperplasia, pericardial lipomatosis, and right facial hemihypertrophy. The radiologic findings are presented with a brief discussion. PMID- 21603298 TI - Primary hepatic amyloidosis: report of an unusual case presenting as a mass. AB - Hepatic involvement of amyloidosis is common. Diffuse infiltration with hepatomegaly is a usual radiologic finding of hepatic amyloidosis. To our knowledge, this is the first case of amyloidosis involving the liver that presented as a mass. PMID- 21603299 TI - Redistributed regional ventilation after the administration of a bronchodilator demonstrated on xenon-inhaled dual-energy CT in a patient with asthma. AB - We report here on the redistributed regional ventilation abnormalities after the administration of a bronchodilator and as seen on xenon-inhaled dual-energy CT in a patient with asthma. The improved ventilation seen in the right lower lobe and the decreased ventilation seen in the right middle lobe after the administration of a bronchodilator on xenon-inhaled dual-energy CT could explain a positive bronchodilator response on a pulmonary function test. These changes may reflect the heterogeneity of the airway responsiveness to a bronchodilator in patients with asthma. PMID- 21603300 TI - MRI findings of pericardial fat necrosis: case report. AB - Pericardial fat necrosis is an infrequent cause of acute chest pain and this can mimic acute myocardial infarction and acute pericarditis. We describe here a patient with the magnetic resonance imaging (MRI) findings of pericardial fat necrosis and this was correlated with the computed tomography (CT) findings. The MRI findings may be helpful for distinguishing pericardial fat necrosis from other causes of acute chest pain and from the fat-containing tumors in the cardiophrenic space of the anterior mediastinum. PMID- 21603301 TI - Individual pulmonary vein atresia in adults: report of two cases. AB - We present two cases of individual pulmonary vein atresia without vestige of an involved pulmonary vein. On CT, we noted the absence or interruption of normal pulmonary venous structures, and the presence of abnormal vascular structures that represented collaterals for the involved lung parenchyma. On angiography, the atretic pulmonary vein was found to drain into the other ipsilateral pulmonary veins through the collaterals. PMID- 21603302 TI - RE: Role of Duplex Doppler US for thyroid nodules: looking for the "sword" sign. AB - Duplex Doppler US may be useful for the detection of thyroid malignancies that show either anarchic winding or penetrating "sword like" neoangiogenic vessels. It may be helpful in selecting nodules that should undergo fine needle aspiration biopsy. PMID- 21603303 TI - What is the purpose of launching World Journal of Clinical Oncology? AB - The first issue of World Journal of Clinical Oncology (WJCO), whose preparatory work was initiated on December 20, 2009, will be published on November 10, 2010. The WJCO Editorial Board has now been established and consists of 315 distinguished experts from 33 countries. Our purpose of launching WJCO is to publish peer-reviewed, high-quality articles via an open-access online publishing model, thereby acting as a platform for communication between peers and the wider public, and maximizing the benefits to editorial board members, authors and readers. PMID- 21603304 TI - Cytotoxic T-cells as imaging probes for detecting glioma. AB - Tumor vaccination using tumor-associated antigen-primed dendritic cells (DCs) is in clinical trials. Investigators are using patients' own immune systems to activate T-cells against recurrent or metastatic tumors. Following vaccination of DCs or attenuated tumor cells, clinical as well as radiological improvements have been noted due to migration and accumulation of cytotoxic T-cells (CTLs). CTLs mediated tumor cell killing resulted in extended survival in clinical trails and in preclinical models. Besides administration of primed DCs or attenuated or killed tumors cells to initiate the generation of CTLs, investigators have started making genetically altered T-cells (CTLs) to target specific tumors and showed in vivo migration and accumulation in the implanted or recurrent tumors using different imaging modalities. Our groups have also showed the utilization of both in vivo and in vitro techniques to make CTLs against glioma and used them as imaging probes to determine the sites of tumors. In this short review, the current status of vaccination therapy against glioma and utilization of CTLs as in vivo imaging probes to determine the sites of tumors and differentiate recurrent glioma from radiation necrosis will be discussed. PMID- 21603305 TI - Molecular mechanism of base pairing infidelity during DNA duplication upon one electron oxidation. AB - The guanine radical cation (G(*+)) is formed by one-electron oxidation from its parent guanine (G). G(*+) is rapidly deprotonated in the aqueous phase resulting in the formation of the neutral guanine radical [G(-H)(*)]. The loss of proton occurs at the N1 nitrogen, which is involved in the classical Watson-Crick base pairing with cytosine (C). Employing the density functional theory (DFT), it has been observed that a new shifted base pairing configuration is formed between G( H)(*) and C constituting only two hydrogen bonds after deprotonation occurs. Using the DFT method, G(-H)(*) was paired with thymine (T), adenine (A) and G revealing substantial binding energies comparable to those of classical G-C and A T base pairs. Hence, G(-H)(*) does not display any particular specificity for C compared to the other bases. Taking into account the long lifetime of the G( H)(*) radical in the DNA helix (5 s) and the rapid duplication rate of DNA during mitosis/meiosis (5-500 bases per s), G(-H)(*) can pair promiscuously leading to errors in the duplication process. This scenario constitutes a new mechanism which explains how one-electron oxidation of the DNA double helix can lead to mutations. PMID- 21603306 TI - Microfluidics: Emerging prospects for anti-cancer drug screening. AB - Cancer constitutes a heterogenic cellular system with a high level of spatio temporal complexity. Recent discoveries by systems biologists have provided emerging evidence that cellular responses to anti-cancer modalities are stochastic in nature. To uncover the intricacies of cell-to-cell variability and its relevance to cancer therapy, new analytical screening technologies are needed. The last decade has brought forth spectacular innovations in the field of cytometry and single cell cytomics, opening new avenues for systems oncology and high-throughput real-time drug screening routines. The up-and-coming microfluidic Lab-on-a-Chip (LOC) technology and micro-total analysis systems (MUTAS) are arguably the most promising platforms to address the inherent complexity of cellular systems with massive experimental parallelization and 4D analysis on a single cell level. The vast miniaturization of LOC systems and multiplexing enables innovative strategies to reduce drug screening expenditures while increasing throughput and content of information from a given sample. Small cell numbers and operational reagent volumes are sufficient for microfluidic analyzers and, as such, they enable next generation high-throughput and high-content screening of anti-cancer drugs on patient-derived specimens. Herein we highlight the selected advancements in this emerging field of bioengineering, and provide a snapshot of developments with relevance to anti-cancer drug screening routines. PMID- 21603307 TI - How can we kill cancer cells: Insights from the computational models of apoptosis. AB - Cancer cells are widely known to be protected from apoptosis, a phenomenon that is a major hurdle to successful anticancer therapy. Over-expression of several anti-apoptotic proteins, or mutations in pro-apoptotic factors, has been recognized to confer such resistance. Development of new experimental strategies, such as in silico modeling of biological pathways, can increase our understanding of how abnormal regulation of apoptotic pathway in cancer cells can lead to tumour chemoresistance. Monte Carlo simulations are in particular well suited to study inherent variability, such as spatial heterogeneity and cell-to-cell variations in signaling reactions. Using this approach, often in combination with experimental validation of the computational model, we observed that large cell to-cell variability could explain the kinetics of apoptosis, which depends on the type of pathway and the strength of stress stimuli. Most importantly, Monte Carlo simulations of apoptotic signaling provides unexpected insights into the mechanisms of fractional cell killing induced by apoptosis-inducing agents, showing that not only variation in protein levels, but also inherent stochastic variability in signaling reactions, can lead to survival of a fraction of treated cancer cells. PMID- 21603308 TI - Autograft mediated adoptive immunotherapy of cancer in the context of autologous stem cell transplantation. AB - The infused stem cell autograft in autologous stem cell transplantation (ASCT) has been viewed mainly as hematologic rescue from the myelosuppressive side effect of conditioning regimens. However, recent reports have shown that the immune effector cells collected at the same time as the stem cells can produce an autologous graft-versus-tumor effect, similar to the graft-versus-tumor effect seen in allogeneic stem cell transplantation without the detrimental effects of graft-versus-host disease. In this article, we review the different immune effector cells collected and infused from the stem cell autograft and their association with clinical outcome post-ASCT, suggesting that ASCT can be viewed not only as a therapeutic maneuver to recover bone marrow function after deliver high-dose chemotherapy, but also as an adoptive immunotherapeutic intervention capable of eradicating residual tumor cells in patients with cancer. PMID- 21603309 TI - Procathepsin D and cancer: From molecular biology to clinical applications. AB - Procathepsin D (pCD) is overexpressed and secreted by cells of various tumor types including breast and lung carcinomas. pCD affects multiple features of tumor cells including proliferation, invasion, metastases and apoptosis. Several laboratories have previously shown that the mitogenic effect of pCD on cancer cells is mediated via its propeptide part (APpCD). However, the exact mechanism of how pCD affects cancer cells has not been identified. Recent observations have also revealed the possible use of pCD/APpcD as a marker of cancer progression. The purpose of this review is to summarize the three major potentials of pCD tumor marker, potential drug, and screening agent. PMID- 21603310 TI - Eagles report: Developing cancer biomarkers from genome-wide DNA methylation analyses. AB - Analyses of DNA methylation in human cancers have identified hypermethylation of individual genes and diminished methylation at repeat elements as common alterations, and have thereby provided important mechanistic insights into cancer biology as well as biomarkers for cancer detection, prognosis and prediction of therapy responses. The techniques available in the past were best suited for investigations of individual candidate genes and sequences, whereas recently developed high-throughput techniques promise to generate unbiased and comprehensive surveys of DNA methylation states across entire genomes. In this minireview we give a short overview of established and novel techniques and outline some major questions that can now be addressed to develop further cancer biomarkers and therapies based on DNA methylation. PMID- 21603311 TI - High intensity focused ultrasound in clinical tumor ablation. AB - Recent advances in high intensity focused ultrasound (HIFU), which was developed in the 1940s as a viable thermal tissue ablation approach, have increased its popularity. In clinics, HIFU has been applied to treat a variety of solid malignant tumors in a well-defined volume, including the pancreas, liver, prostate, breast, uterine fibroids, and soft-tissue sarcomas. In comparison to conventional tumor/cancer treatment modalities, such as open surgery, radio- and chemo-therapy, HIFU has the advantages of non-invasion, non-ionization, and fewer complications after treatment. Over 100 000 cases have been treated throughout the world with great success. The fundamental principles of HIFU ablation are coagulative thermal necrosis due to the absorption of ultrasound energy during transmission in tissue and the induced cavitation damage. This paper reviews the clinical outcomes of HIFU ablation for applicable cancers, and then summarizes the recommendations for a satisfactory HIFU treatment according to clinical experience. In addition, the current challenges in HIFU for engineers and physicians are also included. More recent horizons have broadened the application of HIFU in tumor treatment, such as HIFU-mediated drug delivery, vessel occlusion, and soft tissue erosion ("histotripsy"). In summary, HIFU is likely to play a significant role in the future oncology practice. PMID- 21603312 TI - Imaging of gastroenteropancreatic neuroendocrine tumors. AB - Imaging of gastroenteropancreatic neuroendocrine tumors can be broadly divided into anatomic and functional techniques. Anatomic imaging determines the local extent of the primary lesion, providing crucial information required for surgical planning. Functional imaging, not only determines the extent of metastatic disease spread, but also provides important information with regard to the biologic behavior of the tumor, allowing clinicians to decide on the most appropriate forms of treatment. We review the current literature on this subject, with emphasis on the strengths of each imaging modality. PMID- 21603313 TI - Cancer prognosis using support vector regression in imaging modality. AB - The proposed techniques investigate the strength of support vector regression (SVR) in cancer prognosis using imaging features. Cancer image features were extracted from patients and recorded into censored data. To employ censored data for prognosis, SVR methods are needed to be adapted to uncertain targets. The effectiveness of two principle breast features, tumor size and lymph node status, was demonstrated by the combination of sampling and feature selection methods. In sampling, breast data were stratified according to tumor size and lymph node status. Three types of feature selection methods comprised of no selection, individual feature selection, and feature subset forward selection, were employed. The prognosis results were evaluated by comparative study using the following performance metrics: concordance index (CI) and Brier score (BS). Cox regression was employed to compare the results. The support vector regression method (SVCR) performs similarly to Cox regression in three feature selection methods and better than Cox regression in non-feature selection methods measured by CI and BS. Feature selection methods can improve the performance of Cox regression measured by CI. Among all cross validation results, stratified sampling of tumor size achieves the best regression results for both feature selection and non-feature selection methods. The SVCR regression results, perform better than Cox regression when the techniques are used with either CI or BS. The best CI value in the validation results is 0.6845. The best CI value corresponds to the best BS value 0.2065, which were obtained in the combination of SVCR, individual feature selection, and stratified sampling of the number of positive lymph nodes. In addition, we also observe that SVCR performs more consistently than Cox regression in all prognosis studies. The feature selection method does not have a significant impact on the metric values, especially on CI. We conclude that the combinational methods of SVCR, feature selection, and sampling can improve cancer prognosis, but more significant features may further enhance cancer prognosis accuracy. PMID- 21603314 TI - Role of optical spectroscopy using endogenous contrasts in clinical cancer diagnosis. AB - Optical spectroscopy has been intensively studied for cancer management in the past two decades. This review paper first introduces the background of optical spectroscopy for cancer management, which includes the advantages of optical techniques compared to other established techniques, the principle of optical spectroscopy and the typical setup of instrumentation. Then the recent progress in optical spectroscopy for cancer diagnosis in the following organs is reviewed: the brain, breast, cervix, lung, stomach, colon, prostate and the skin. Reviewed papers were selected from the PubMed database with keywords combining the terms of individual optical spectroscopy techniques and cancers. The primary focus is on the in vivo applications of optical spectroscopy in clinical studies. Ex vivo studies are also included for some organs to highlight special applications or when there are few in vivo results in the literature. Practical considerations of applying optical spectroscopy in clinical settings such as the speed, cost, complexity of operation, accuracy and clinical value are discussed. A few commercially available clinical instruments that are based on optical spectroscopy techniques are presented. Finally several technical challenges and standard issues are discussed and firm conclusions are made. PMID- 21603315 TI - Optical mammography: Diffuse optical imaging of breast cancer. AB - Existing imaging modalities for breast cancer screening, diagnosis and therapy monitoring, namely X-ray mammography and magnetic resonance imaging, have been proven to have limitations. Diffuse optical imaging is a set of non-invasive imaging modalities that use near-infrared light, which can be an alternative, if not replacement, to those existing modalities. This review covers the background knowledge, recent clinical outcome, and future outlook of this newly emerging medical imaging modality. PMID- 21603316 TI - Exploiting the homologous recombination DNA repair network for targeted cancer therapy. AB - Genomic instability is a characteristic of cancer cells. In order to maintain genomic integrity, cells have evolved a complex DNA repair system to detect, signal and repair a diversity of DNA lesions. Homologous recombination (HR) mediated DNA repair represents an error-free repair mechanism to maintain genomic integrity and ensure high-fidelity transmission of genetic information. Deficiencies in HR repair are of tremendous importance in the etiology of human cancers and at the same time offer great opportunities for designing targeted therapeutic strategies. The increase in the number of proteins identified as being involved in HR repair has dramatically shifted our concept of the proteins involved in this process: traditionally viewed as existing in a linear and simple pathway, today they are viewed as existing in a dynamic and interconnected network. Moreover, exploration of the targets within this network that can be modulated by small molecule drugs has led to the discovery of many effective kinase inhibitors, such as ATM, ATR, DNA-PK, CHK1, and CHK2 inhibitors. In preclinical studies, these inhibitors have been shown to sensitize cancer cells to chemotherapy and radiation therapy. The most exciting discovery in the field of HR repair is the identification of the synthetic lethality relationship between poly (ADP-ribose) polymerase (PARP) inhibitors and HR deficiency. The promises of clinical applications of PARP inhibitors and the concept of synthetic lethality also bring challenges into focus. Future research directions in the area of HR repair include determining how to identify the patients most likely to benefit from PARP inhibitors and developing strategies to overcome resistance to PARP inhibitors. PMID- 21603317 TI - Tyrosine kinase inhibitors: Multi-targeted or single-targeted? AB - Since in most tumors multiple signaling pathways are involved, many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases. The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL, SCR, platelet derived growth factor, vascular endothelial growth factor receptor and epidermal growth factor receptor families. Both multi-kinase inhibitors and single-kinase inhibitors have advantages and disadvantages, which are related to potential resistance mechanisms, pharmacokinetics, selectivity and tumor environment. In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist. Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor. Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity, while differences in gene expression exist between tumor and stromal cells. Considering these aspects, one type of inhibitor can generally not be preferred above the other, but will depend on the specific genetic constitution of the patient and the tumor, allowing personalized therapy. The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered (epi)genetics of the tumor. This strategy might result in treatment by a single multi kinase inhibitor for one patient, but in treatment by a couple of single kinase inhibitors for other patients. PMID- 21603319 TI - Interventional endoscopic ultrasonography for pancreatic cancer. AB - Endoscopic ultrasonography (EUS) represents the combination of endoscopy and intraluminal ultrasonography. This allows use of a high-frequency transducer (5 20 MHz) that, due to the short distance to the target lesion, provides ultrasonographic images of higher resolution than those obtained from other imaging modalities, including multiple-detector-row-computed tomography, magnetic resonance imaging, and positron emission tomography. EUS is now a widely accepted modality for diagnosing pancreatic diseases. However, the most important limitation of EUS has been the lack of specificity in differentiating between benign and malignant changes. In 1992, EUS-guided fine needle aspiration (FNA) of lesions in the pancreas head was introduced into clinical practice, using a curved linear-array echoendoscope. Since then, EUS has evolved from EUS imaging to EUS-FNA and wider applications. Interventional EUS for pancreatic cancer includes EUS-FNA, EUS-guided fine needle injection, EUS-guided biliary drainage and anastomosis, EUS-guided celiac neurolysis, radiofrequency ablation, brachytherapy, and delivery of a growing number of anti-tumor agents. This review focuses on interventional EUS, including EUS-FNA and therapeutic EUS for pancreatic cancer. PMID- 21603320 TI - Glucan-immunostimulant, adjuvant, potential drug. AB - beta-glucans belong to a group of biologically active natural compounds called biological response modifiers. These substances represent highly conserved structural components of cell walls in fungi, yeast, grain and seaweed. Despite almost 160 years of intensive research, the exact mechanisms of their action remain unsolved. The significant role of glucans in cancer treatment, infection immunity, stress reduction and restoration of damaged bone marrow has already been established. The present review focuses on the various less known but potentially significant roles glucans might play in medicine. In summary, glucan might represent the most important natural immunomodulator. PMID- 21603318 TI - Surgical strategy for bile duct cancer: Advances and current limitations. AB - The aim of this review is to describe recent advances and topics in the surgical management of bile duct cancer. Radical resection with a microscopically negative margin (R0) is the only way to cure cholangiocarcinoma and is associated with marked survival advantages compared to margin-positive resections. Complete resection of the tumor is the surgeon's ultimate aim, and several advances in the surgical treatment for bile duct cancer have been made within the last two decades. Multidetector row computed tomography has emerged as an indispensable diagnostic modality for the precise preoperative evaluation of bile duct cancer, in terms of both longitudinal and vertical tumor invasion. Many meticulous operative procedures have been established, especially extended hepatectomy for hilar cholangiocarcinoma, to achieve a negative resection margin, which is the only prognostic factor under the control of the surgeon. A complete caudate lobectomy and resection of the inferior part of Couinaud's segment IV coupled with right or left hemihepatectomy has become the standard surgical procedure for hilar cholangiocarcinoma, and pylorus-preserving pancreaticoduodenectomy is the first choice for distal bile duct cancer. Limited resection for middle bile duct cancer is indicated for only strictly selected cases. Preoperative treatments including biliary drainage and portal vein embolization are also indicated for only selected patients, especially jaundiced patients anticipating major hepatectomy. Liver transplantation seems ideal for complete resection of bile duct cancer, but the high recurrence rate and decreased patient survival after liver transplant preclude it from being considered standard treatment. Adjuvant chemotherapy and radiotherapy have a potentially crucial role in prolonging survival and controlling local recurrence, but no definite regimen has been established to date. Further evidence is needed to fully define the role of liver transplantation and adjuvant chemo-radiotherapy. PMID- 21603321 TI - Oncogenic activity of MCM7 transforming cluster. AB - The miniature chromosome maintenance (MCM) complex is a group of proteins that are essential for DNA replication licensing and control of cell cycle progression from G1 to S phase. Recent studies suggest that MCM7 is overexpressed and amplified in a variety of human malignancies. MCM7 genome sequence contains a cluster of miRNA that has been shown to downregulate expression of several tumor suppressors including p21, E2F1, BIM and pTEN. The oncogenic potential of MCM7 and its embedded miRNA has been demonstrated vigorously in in vitro experiments and in animal models, and they appear to cooperate in initiation of cancer. MCM7 protein also serves as a critical target for oncogenic signaling pathways such as androgen receptor signaling, or tumor suppressor pathways such as integrin alpha7 or retinoblastoma signaling. This review analyzes the transforming activity and signaling of MCM7, oncogenic function of miRNA cluster that is embedded in the MCM7 genome, and the potential of gene therapy that targets MCM7. PMID- 21603322 TI - Current status of therapy for breast cancer worldwide and in Japan. AB - The results of clinical trials conducted in Europe and North America have been incorporated into treatment strategies for breast cancer in Japan. Despite the use of similar treatment regimens, why has mortality from breast cancer been increasing in Japan? Procedures for surgical treatment and sentinel lymph node biopsy in breast cancer do not differ between Japan and Western countries, but the strategies for radiotherapy differ slightly. Hormonal therapy is now selected on the basis of scientific evidence, and similar regimens are used in Japan and Western countries. As for postoperative adjuvant chemotherapy, an anthracycline plus cyclophosphamide and taxane-based regimens are standard treatments in Japan and Western countries. In 2009, however, the results of two large clinical studies designed to determine whether intravenous or oral treatment was superior for postoperative adjuvant chemotherapy were reported in Japan. Both studies showed that relapse-free survival and overall survival (OS) at 5 years after surgery were similar for a combination of cyclophosphamide, methotrexate, and 5 fluorouracil and for tegafur/uracil. Many chemotherapeutic agents that are used to treat recurrent or metastatic breast cancer have not yet been approved in Japan. As for molecular targeted therapy, some agents that target the human epidermal growth factor receptor family have been approved in Japan, whereas angiogenesis inhibitors have not. The results of many clinical trials have been incorporated into clinical practice in Japan, therefore, the outcomes of breast cancer therapy have surpassed those in other countries. Many pivotal clinical trials have been conducted outside Japan. Treatment regimens that have been developed on the basis of these studies might be suitable for the management of breast cancer in Western women, but not for Japanese women because of differences in genetic factors, physique, body mass index, pharmacokinetics, and drug metabolism. Such regimens should be modified on the basis of the characteristics of breast cancer in Japan to develop treatment that is optimally suited for Japanese women. In particular, local studies of pharmacokinetics, pharmacodynamics, and optimal dose levels and treatment intervals should be carefully performed. The establishment of treatment regimens optimally suited for Japanese patients with breast cancer could put the brakes on the trend towards increasing mortality from breast cancer in Japan. PMID- 21603323 TI - From the Editor's Desk. PMID- 21603324 TI - Colorectal cancer. PMID- 21603325 TI - Letters to the editor. PMID- 21603326 TI - Anesthesiology-the john adriani story. AB - Several authors have told the John Adriani story, but his proper recognition in developing the specialty of anesthesiology and his place as a pioneer have never been presented as such. The following article outlines his training and experiences in the early days of anesthesiology. The story of the many problems he encountered and how he developed teaching programs that remain in existence today is one to be admired and appreciated. Much of the information is from personal conversations with Dr Adriani. During his tenure as the Director of Anesthesia at Charity Hospital, I was a surgical house officer in the early 1960s and returned as an anesthesiology trainee in the late 1970s. We became close personal friends. He gave me hundreds of his slides, and we had many discussions about the past and current state of the specialty of anesthesiology. PMID- 21603327 TI - John adriani banned from FDA by pharmaceutical industry: an historical vignette and cartoon. AB - In 1969, Food and Drug Administration Commissioner Herbert Ley offered New Orleans anesthesiologist John Adriani, MD, the role of director of the Bureau of Medicine. Dr Adriani accepted the offer, but it was quickly withdrawn, in part based on pressure from the pharmaceutical industry. It opposed Dr Adriani's appointment because of his work promoting generic drugs. This episode was the subject of a 1969 cartoon in the Hartford Times by Pulitzer Prize-winning cartoonist Ed Valtman. PMID- 21603328 TI - Orthopedic anesthesia in haiti. AB - Healthcare practitioners from around the world responded almost immediately in the aftermath of the 2010 earthquake in Haiti. This article reports on the efforts of an orthopedic trauma team in Haiti and its efforts in providing surgery without general anesthesia. PMID- 21603329 TI - Outside the operating room: unlimited directions in research and beyond. AB - The anesthesiologist's role often extends beyond the operating room and includes the realm of research. Recently, interest in investigating mesenchymal stem cells (MSCs) as therapy for myriad diseases has grown. MSCs are adult stem cells traditionally found in bone marrow that hone to damaged tissues and contribute to the tissues' repair by secreting chemokines, cytokines, and extracellular matrix proteins. Research has established a connection between the stimulation of specific Toll-like receptors and the immune-modulating responses of human MSCs, which allows for the polarization of MSCs into either a pro-inflammatory or an anti-inflammatory phenotype. It is anticipated that MSC-based therapies polarized into the anti-inflammatory phenotype will treat painful inflammatory diseases, such as diabetic peripheral neuropathy or rheumatoid arthritis. These new cell based therapies will be another tool for anesthesiologists to employ while treating patients with chronic pain. PMID- 21603330 TI - Comparison of extended-release epidural morphine with femoral nerve block to patient-controlled epidural analgesia for postoperative pain control of total knee arthroplasty: a case-controlled study. AB - BACKGROUND: Because newer anticoagulation strategies for total knee replacement present potentially increased risk of neuraxial analgesia, there is movement away from using patient-controlled epidural analgesia (PCEA) for pain control. This concern opens the door for other regional modalities in postoperative analgesia, including the use of extended-release epidural morphine (EREM) combined with a femoral nerve block (FNB). METHODS: This study was a prospective observational chart review with the use of recent historical controls in patients undergoing unilateral total knee replacement. Outcomes of interest were 0-, 24-, and 48-hour postoperative pain scores using the visual analog scale (VAS); incidence of side effects; and time spent in the postanesthesia care unit (PACU). RESULTS: Postoperative pain scores at 24 and 48 hours in the EREM and FNB group (n = 14; 2.6 +/- 0.6 and 5.0 +/- 0.9, respectively) were comparable to the PCEA group (n = 14; 3.8 +/- 0.6 and 4.2 +/- 0.9). The PACU time was shorter in the EREM and FNB group (2.4 +/- 0.3 hours) compared with PCEA (3.6 +/- 0.3 hours, P = .02). No statistically significant difference was found in the incidence of side effects between the 2 groups. CONCLUSIONS: The VAS scores at 24 and 48 hours indicate that EREM and FNB provide comparable analgesia to PCEA. The trend toward shorter PACU times represents an opportunity for cost-identification analysis. The study data are limited by their observational nature and the small number of patients involved; nevertheless, this study demonstrates a therapeutic equivalence to PCEA that may be more cost effective. PMID- 21603331 TI - Gender rather than choice of intermediate duration opioids affects emergence after craniotomy for large intracranial tumors. AB - BACKGROUND: Opioid-based anesthetic techniques are commonly used during neurosurgical procedures. In the present randomized prospective study, we studied emergence after 4 anesthetic regimens combining intermediate duration opioids with isoflurane and nitrous oxide (N(2)O), in patients undergoing craniotomy for large (> 30 mm diameter with intracranial mass effect) intracranial tumors. METHODS: One hundred seven patients were randomized into 4 groups: Group A: fentanyl (<= 5 ug/kg) + isoflurane (<= 1 minimum alveolar concentration [MAC]), Group B: sufentanil (1-2 ug/kg plus infusion) + isoflurane (<= 0.5 MAC), Group C: sufentanil (2 ug/kg bolus only) + isoflurane (<= 1 MAC), and Group D: alfentanil (100 ug/kg plus infusion) + isoflurane (<= 0.5 MAC). Boluses were administered as divided doses during induction, laryngoscopy, head pinning, and incision. Blood pressure was controlled at +/-25% of baseline levels. All infusions were discontinued at the start of dural closure. Emergence was assessed using a mini neurologic examination consisting of 7 questions. Groups were compared on time to emergence using survival analysis methods. RESULTS: The groups did not differ regarding extubation time, which occurred at a median of 4 to 6 minutes across groups after discontinuing N(2)O. The median emergence time ranged from 15 to 22.5 minutes and did not differ among groups. However, across all groups more women had emerged by 30 minutes compared with men (83% vs 57%, P = .002). The median emergence time in women was found to be significantly shorter (0-15 minutes) than in men (15-30 minutes) (P = .012). CONCLUSIONS: No between-group differences in emergence time were observed; the study was stopped early because of evidence that no differences were likely to be found if the study were continued. However, in a post hoc analysis, female gender was associated with faster emergence. PMID- 21603332 TI - Impact of hurricanes katrina and rita on the anesthesiology workforce. AB - INTRODUCTION: Hurricanes Katrina and Rita impacted a large portion of the medical community in Louisiana. We attempt to determine their impact on the anesthesiology workforce in Louisiana. METHODS: In May 2006, a survey was mailed to 368 Louisiana anesthesiologists, collecting demographic data, retirement plans, impact of Hurricanes Katrina and Rita, position vacancies, practice conditions, and the general state of healthcare in their area. All 3 anesthesiology residency programs in the state were contacted regarding their recent graduates. The 2010 RAND survey of the anesthesiology workforce was reviewed with respect to findings relevant to the state and region. RESULTS: One hundred seventy surveys were returned, yielding a 46.2% response rate. Among the respondents, 13.9% intended to retire within 5 years and another 24% in 5 to 10 years. Since 2005, 63.9% had seen an increase in their daily caseload, 46.9% saw an increase in work hours, and 36.8% stated that their practices were trying to hire new anesthesiologists and were having difficulty filling these positions. Since 2005, the number of anesthesiology residents in Louisiana had declined by almost 50%, and the number of graduates remaining to practice in Louisiana had decreased by 43% from 7 to 4 annually. CONCLUSIONS: Our 2006 survey provided qualitative evidence for a shortage of anesthesiologists in the state of Louisiana after the natural disasters in 2005 that was likely to worsen as residency output plummeted, fewer residents stayed in the state, and projected retirement increased. The regional data from the RAND survey a year later confirmed the impressions from our survey, with an estimate of an anesthesiologist shortage as high as 39% of the workforce. State membership surveys may serve as accurate barometers in the wake of major environmental upheavals affecting regional anesthesiology workforce conditions. PMID- 21603333 TI - Achieving appropriate prophylactic antibiotic administration while simultaneously implementing an automated anesthesia record. AB - The Surgical Care Improvement Project (SCIP) is a national quality partnership involving organizations interested in improving surgical care by significantly reducing surgical complications. As a partner in this effort, our group focused on improvement in antibiotic selection and timing as related to surgical incision. After forming a multidisciplinary rapid response team in 2008, enacting a plan-do-study-act (PDSA) strategy, and implementing an anesthesia information management system, we were able to improve compliance and documentation to our goal of 90% compliance in both measures. PMID- 21603334 TI - Operating room fire safety. AB - Operating room fires are a rare but preventable danger in modern healthcare operating rooms. Optimal outcomes depend on all operating room personnel being familiar with their roles in fire prevention and fire management. Despite the recommendations of major safety institutes, this familiarity is not the current practice in many healthcare facilities. Members of the anesthesiology and the surgery departments are commonly not actively involved in fire safety programs, fire drills, and fire simulations that could lead to potential delays in prevention and management of intraoperative fires. PMID- 21603335 TI - Core program education: tracking the progression toward excellence in an anesthesiology residency program over 60 years. AB - The Ochsner Clinic Foundation Anesthesiology Residency Program is the oldest continuously accredited anesthesiology residency program in the state of Louisiana. As the American College of Graduate Medical Education has developed residency training requirements, so has the Ochsner training program evolved from a structure- and process-based program to an outcomes-based program. The author, associated with the program since 1983, reviewed Program Information Forms from 1971 to the present to track the evolution of the anesthesiology residency training program. The Accreditation Council of Graduate Medical Education demanded allocation of resources to residency training and mandated the demonstration of outcomes of training. The Ochsner Clinic Foundation Anesthesiology Residency Program has kept pace with these demands. The trend for graduate performance on written examinations has been upward. Fifty years ago, graduates practiced locally, but graduates now practice throughout the United States. Many completed fellowship training at increasingly higher profile institutions. PMID- 21603336 TI - Pediatric cuffed endotracheal tubes: an evolution of care. AB - PURPOSE: To examine the history of pediatric endotracheal intubation and the issues surrounding the change from uncuffed endotracheal tubes to cuffed endotracheal tubes, including pediatric airway anatomy, endotracheal tube design, complications, and safety concerns. METHOD: Review of the literature. CONCLUSIONS: Although the use of cuffed endotracheal tubes in infants and children remains a topic of debate, the literature supports this change in practice. Meticulous attention must be given to intracuff pressure. Cuffed endotracheal tubes designed especially for the pediatric patient may increase the margin of safety. PMID- 21603338 TI - Anesthesia for left ventricular assist device insertion: a case series and review. AB - From October 2008 to June 2010, a total of 42 patients had the HeartMate II left ventricular assist device inserted surgically at Ochsner Medical Center in New Orleans, LA. A retrospective electronic record review was conducted on this series of patients to analyze elements of perioperative anesthetic care, including general anesthetic care, echocardiographic considerations, and blood product usage. Etomidate was used to induce anesthesia for 34 of 42 patients (81%) in this series, with an average dose of 16.5 mg (+/-6 mg). The average intraoperative fentanyl dose was 1,318 ug (+/-631 ug). On average, patients were extubated 91 hours (+/-72 hours) after arrival to the intensive care unit and left on day 9 (+/-5 days). The average left ventricular ejection fraction of the patients in this series was 13% (+/-5%). Sixteen patients were evaluated as having severe right-heart dysfunction preoperatively. Two of 42 patients required surgical closure of echocardiographically identified patent foramen ovale. Twelve of 42 patients underwent surgical correction of tricuspid regurgitation. On average, 3 units (+/-2.6 units) of fresh frozen plasma were transfused intraoperatively and 10 units postoperatively. Intraoperative red blood cell usage averaged 1.1 units (maximum, 7 units), with an average 9.3 units administered in the first 48 hours postoperatively. PMID- 21603337 TI - Use of alpha(2)-Agonists in Neuroanesthesia: An Overview. AB - alpha(2)-Agonists are a novel class of drugs with mechanisms of action that differ from other commonly used anesthetic drugs. They have neuroprotective, cardioprotective, and sedative effects. These unique characteristics make them potentially useful during neuroanesthesia and intensive care. We review the effects of dexmedetomidine on cerebral blood flow and cerebral metabolism, along with recent advances in using alpha(2)-agonists in neuroanesthesia and neurointensive care. PMID- 21603339 TI - Epidural Anesthesia for Cesarean Delivery in a Patient With Severe Pulmonary Artery Hypertension and a Right-to-Left Shunt. AB - A 38-year-old woman with severe pulmonary artery hypertension and a right-to-left shunt of unknown etiology presented at 32 weeks' gestational age. Determination of the cause of her pulmonary hypertension by transesophageal echocardiography was delayed until after delivery secondary to anesthetic risk. She was successfully anesthetized for cesarean delivery using epidural anesthesia. Systemic vascular resistance was maintained using phenylephrine hydrochloride before delivery and vasopressin after delivery. Transesophageal echocardiography after delivery revealed a patent foramen ovale, indicating a diagnosis of idiopathic pulmonary artery hypertension and a very poor prognosis. Differentiating between Eisenmenger syndrome and idiopathic pulmonary artery hypertension may not be important for determining the optimal anesthetic management of patients with pulmonary hypertension but is important in assessing long-term prognosis. PMID- 21603340 TI - Spinal anesthesia for cesarean delivery in a patient receiving fondaparinux. AB - Fondaparinux sodium, a selective inhibitor of factor Xa, is a new anticoagulant being used for thromboprophylaxis in all patient populations. We outline a case of neuraxial anesthesia for cesarean delivery in a patient with recent fondaparinux use and discuss most recent literature recommendations. PMID- 21603341 TI - Multidisciplinary approach to the management of placenta accreta. AB - Patients with placenta accreta have abnormally adherent placentas and are at risk for massive hemorrhage at delivery. We report 2 cases of cesarean hysterectomy in patients with placenta accreta. These patients were cared for by a multidisciplinary team consisting of a maternal fetal medicine specialist, gynecologic oncologist, anesthesiologist, neonatologist, interventional radiologist, and urologist. Favorable maternal and fetal outcomes resulted from the use of this team. PMID- 21603342 TI - Orthotopic liver transplantation in a pediatric patient with progressive intrahepatic cholestasis: a coordinated perioperative subspecialty approach. AB - This report discusses the perioperative anesthesia management of a pediatric patient with end-stage liver disease from progressive intrahepatic cholestasis, with particular emphasis on the coordinated, multidisciplinary approach our institution uses. PMID- 21603343 TI - CME Upcoming Events/Program Credit Information. PMID- 21603344 TI - CME Test/CME Application Form. PMID- 21603345 TI - From the Editor's Desk. PMID- 21603346 TI - G protein-coupled receptors as disease targets: emerging paradigms. PMID- 21603347 TI - Total laparoscopic hysterectomy: our 5-year experience (1998-2002). AB - PURPOSE: To review our experience performing total laparoscopic hysterectomy since we first introduced this procedure in 1998. METHODS: A retrospective cohort study was performed for patients undergoing total laparoscopic hysterectomy at Ochsner Clinic Foundation from February 1998 through December 2002. Rates of complications, successful completion, length of hospital stay, readmission, and reoperation were determined for this period. RESULTS: Among 511 patients who underwent attempted total laparoscopic hysterectomy, 487 procedures (95.3%) were completed by laparoscopy. The major intraoperative complication rate was 3.9%, and the major postoperative complication rate was 4.7%. No significant differences were seen in the intraoperative and postoperative complication rates of patients who were morbidly obese (body mass index >=30 kg/m(2)), patients with enlarged uteri (>=300 g), or patients who underwent concomitant procedures (unilateral or bilateral salpingo-oophorectomy and lysis of adhesions). The readmission rate was 4.1%, and the reoperation rate was 2%. None of the variables studied, including age, medical problems, morbid obesity, concomitant procedures, or enlarged uterus, were found to have an association with readmission or reoperation rates. CONCLUSIONS: Total laparoscopic hysterectomy can be performed successfully in most patients with benign indications. Morbidity is comparable to that of other types of hysterectomies, and this technique may be a more reasonable approach under some circumstances. PMID- 21603348 TI - Pseudoxanthoma Elasticum: A Novel Mutation in the ABCC6 Gene That Affects Eye Manifestations of the Disease. AB - PURPOSE: To determine whether a correlation between ABCC6 mutations and ocular phenotypic expressions exists. METHODS: In this study, 28 relatives of a consultand with known pseudoxanthoma elasticum were recruited for evaluation of the ocular manifestations of the disease, including peau d'orange appearance, angioid streaks, choroidal neovascular membranes, peripapillary atrophy, and retinal drusen. Comprehensive eye examinations were documented for all patients, who were then evaluated for the presence of known mutations in the aforementioned ABCC6 gene. RESULTS: Statistically significant correlations were noted between the gene and peau d'orange appearance (P = 0.0016), angioid streaks (P < 0.0001), and choroidal neovascular membranes (P = 0.0016). CONCLUSIONS: A statistically significant association was documented between the R39G mutation of the ABCC6 protein and 3 of 6 known manifestations of pseudoxanthoma elasticum. Although mutations of this gene are clearly associated with angioid streaks, the mechanism by which the transporter affects development of this pathology is speculative. PMID- 21603349 TI - Coenzyme q10 and statin-induced mitochondrial dysfunction. AB - Coenzyme Q10 is an important factor in mitochondrial respiration. Primary and secondary deficiencies of coenzyme Q10 result in a number of neurologic and myopathic syndromes. Hydroxyl-methylglutaryl coenzyme A reductase inhibitors or statins interfere with the production of mevalonic acid, which is a precursor in the synthesis of coenzyme Q10. The statin medications routinely result in lower coenzyme Q10 levels in the serum. Some studies have also shown reduction of coenzyme Q10 in muscle tissue. Such coenzyme Q10 deficiency may be one mechanism for statin-induced myopathies. However, coenzyme Q10 supplements have not been shown to routinely improve muscle function. Additional research in this area is warranted and discussed in this review. PMID- 21603350 TI - Long-term Alendronate Therapy and Subtrochanteric Femoral Fractures. PMID- 21603351 TI - The heart of the matter. AB - A 65-year-old Hispanic man receiving peritoneal dialysis presented to the emergency department complaining of the sudden onset of numbness and tingling of the right side of his body and face with associated nausea, vomiting, vertigo, and blurry vision. Further testing revealed a large, mobile mass on his mitral valve, leading to a diagnosis of endocarditis with embolic phenomena. The presentation, diagnosis, and treatment of endocarditis are discussed here. PMID- 21603352 TI - Implantation of cardioverter defibrillator after percutaneous closure of atrial septal defect. PMID- 21603353 TI - Novel Influenza A (H1N1) Viral Infection in Late Pregnancy: Report of a Case. AB - Health care workers, including anesthesia providers, are often exposed to different infectious disease processes. In the operating room, anesthesia providers, nurses, and surgical staff use universal precautions as a standard of practice. The novel influenza A (H1N1) epidemic has heightened concerns because diagnosis is often delayed and transmission can affect those in a close radius to the infected host. The objectives of this report are to describe the intensive care management and outcomes of severe H1N1 viral infection in a patient in the last trimester of pregnancy and to review the epidemiology, management, and outcomes of similar US cases. PMID- 21603355 TI - Thoughts on the human body. AB - "One Sunday morning when both my dad and I were working in our offices, he walked into my office and gave me this manuscript. I read it, said I enjoyed it, and asked where he was going to publish it. He answered, 'Nowhere. I just wrote it for you.' I recently came across it while cleaning out some files. I thought others would like to read it since it was written in the 1960s." - John Ochsner, MD. PMID- 21603354 TI - Doctor-patient communication: a review. AB - Effective doctor-patient communication is a central clinical function in building a therapeutic doctor-patient relationship, which is the heart and art of medicine. This is important in the delivery of high-quality health care. Much patient dissatisfaction and many complaints are due to breakdown in the doctor patient relationship. However, many doctors tend to overestimate their ability in communication. Over the years, much has been published in the literature on this important topic. We review the literature on doctor-patient communication. PMID- 21603356 TI - CME Test/CME Application Form. PMID- 21603357 TI - CME Upcoming Events/Program Credit Information. PMID- 21603358 TI - From the Editor's Desk. PMID- 21603360 TI - Pitfalls and important issues in the pathologic diagnosis of melanocytic tumors. AB - In Australia and many other countries, melanoma is a major public health problem, particularly in those individuals of Celtic ancestry. Other races are not immune, especially when acral and mucosal sites are taken into account. Accurate diagnosis requires the balancing of clinical data (including patient age and sex, family history, the anatomic site of the lesion, the history of the lesion, and other factors such as a history of trauma, sunburn, or pregnancy), histologic features (including architecture, cytology, and the host response), awareness of pitfalls, and judgment. Several types of nevi-such as regenerating nevi, combined nevi, acral nevi, deep penetrating nevi, and Spitz nevi-are prone to be misdiagnosed as melanoma. Melanomas often underdiagnosed include the nevoid, desmoplastic, Spitzoid, and regressed types. The type of biopsy and suboptimal processing may also significantly influence the diagnosis. PMID- 21603359 TI - The epidemiology, prevention, and detection of melanoma. AB - We are seeing a record number of newly diagnosed skin cancers worldwide, with the incidence of melanoma increasing at a faster rate than almost all other cancers. As clinicians, we will have, by far, the greatest impact on reducing this incidence through better methods of early detection of melanoma and proven prevention methods and techniques. The medical community must enhance its efforts to increase its training of new health care personnel who are capable of diagnosing and treating this record number of patients with skin cancer. We must also try to increase the access to our limited number of dermatologists and provide novel ways of patient education such as through skin self-examinations, total body photography, and improved education for our children. By providing easier access to skin examinations, we will increase our chances of detecting melanoma in its earliest and most curable form. The dangers of indoor tanning beds and salons must be transparent to those that use them, focusing on expanding the oversight of such facilities by our local and federal governmental agencies while establishing legislation in several states to further limit their use to our youth, who are especially at high risk for developing melanoma in the future. This review will focus on the epidemiology, prevention, and detection of melanoma. PMID- 21603361 TI - The role of DNA repair capacity in melanoma skin cancer risk in a population chronically exposed to high levels of sunlight. AB - Puerto Rican residents are exposed to some of the highest levels of environmental ultraviolet radiation in the world; paradoxically, the melanoma incidence in Puerto Rico is lower than that of the US mainland. The overall objective of this case-control pilot study was to test the hypotheses that (1) persons with melanoma have a significantly lower DNA repair capacity (DRC) in relation to controls matched by age, (2) decline in DRC is associated with vertical depth of melanoma invasion, and (3) DRC is associated with anatomical tumor location. Controls (n = 124) were examined by dermatologists; cases (n = 62) were histopathologically confirmed. The mean DRC +/- 1 SE of controls was 6.46% +/- 0.3. Melanoma patients (n = 62) had a mean decrease in DRC of 3% (6.25% +/- 0.5), which was not statistically different from controls (P = 0.697). No significant differences in DRC were evident in participants with either in situ or malignant melanoma tumors; neither were such differences evident when evaluating anatomical location of tumors (ie, non-sun-exposed versus sun exposed). DRC generally declined in participants with increased depth of melanoma tumor penetration when compared with controls and those with small in situ tumors. These findings should be examined in a larger-scale population study that includes participants with more advanced metastatic melanoma. PMID- 21603362 TI - MicroRNA in Melanoma. AB - Melanoma is a highly aggressive and deadly skin cancer. Early intervention correlates with nearly 100% patient survival, but greater than 80% mortality is associated with advanced disease. Currently, few treatment options are available for patients with metastatic melanoma, and the global incidence of melanoma is increasing faster than that of other cancers. Therefore, it is vitally important to uncover and use genetic and epigenetic regulatory mechanisms at work during the development and progression of melanoma for better prevention, diagnosis, and clinical management. MicroRNA (miRNA) is a set of small, single-stranded, noncoding RNAs that target the 3'-untranslated region of an estimated 30% of all human genes to inhibit their expression. Our understanding of miRNA-mediated regulation of cancers has grown immensely over the past decade. Here we review currently available data on melanoma-associated miRNAs, highlighting those deregulated miRNAs targeting important genes and signaling pathways involved in the progression of melanocytes to primary and metastatic melanoma. Understanding the important roles of miRNAs in melanoma progression and metastasis development will contribute to the development of miRNA-targeted therapy in the future. PMID- 21603363 TI - New horizons in melanoma treatment: targeting molecular pathways. PMID- 21603364 TI - Management of regional lymph node basins in melanoma. AB - Of all malignancies, melanoma has the most rapid increase in incidence; in 2009 it was estimated to have had the fifth highest number of new cases overall. Surgical therapy remains the primary and most effective intervention for this disease. Over the past 20 years there has been a significant paradigm shift in the management of the regional nodal basin, driven predominantly by the introduction of sentinel lymph node biopsy (SLNB). This new technique has drastically altered the method of detecting nodal disease and has become a routine component of melanoma treatment. In addition to SLNB, a better understanding of ultrasound, fine-needle biopsy, and the considerable efforts to minimize the morbidity of surgical intervention has led to innovations in the management of patients with regional metastases. An overview of the current therapeutic options for managing patients with nodal disease follows. PMID- 21603365 TI - Adjuvant Immunotherapy and Radiation in the Management of High-risk Resected Melanoma. AB - Adjuvant therapy is widely used in melanoma cases because recurrence of disease after surgery is notoriously difficult to treat and usually results in the patient's death. Clinicians have a fundamental influence on the patient's decisions regarding adjuvant therapy, beginning with providing a clear understanding of the risk of specific types of recurrence based on features of the primary melanoma and status of the sentinel nodes and then explaining the morbidity of surgical treatment with and without adjuvant therapy. This review summarizes the role of adjuvant immunotherapy and radiation in the treatment of high-risk melanoma. We review the risks of specific types of recurrence as well as the potential oncologic benefits and relevant toxicities of available adjuvant therapies for high-risk melanoma. PMID- 21603366 TI - Novel targeted therapies for the treatment of metastatic melanoma. AB - The National Comprehensive Cancer Network guidelines for the treatment of stage IV metastatic melanoma state that clinical trials should be the preferred treatment option for these patients; therefore, clinical trials for these patients are the "standard of care." Our greater understanding of the molecular biology behind the development of melanoma has guided much of the translational research in this disease and has led to the development of novel targeted therapies. Specifically, advancement in our knowledge of alterations in signal transduction pathways in melanoma has led to the rapid development of a number of pharmacologic agents that inhibit these pathways. This review will discuss changes in signal transduction pathways involved in melanoma, specifically, activated mitogen-activated protein kinase, activated PI3 kinase, and inactivated p53/Rb pathways. This article will also review new targeted therapy in the context of the molecular biology of melanoma. PMID- 21603367 TI - Guess the case. PMID- 21603369 TI - Recently published works. PMID- 21603368 TI - Ochsner research update. PMID- 21603370 TI - Introduction to research night. PMID- 21603371 TI - CME Test/CME Application Form. PMID- 21603372 TI - CME Upcoming Events/Program Credit Information. PMID- 21603373 TI - From the Editor's Desk. PMID- 21603374 TI - Epistaxis: a common problem. PMID- 21603375 TI - Pain management in the elderly population: a review. AB - The elderly population comprises the fastest growing segment of the world's population. As patients age, the incidence and prevalence of certain pain syndromes increase. Pain may be underreported as some elderly patients incorrectly believe that pain is a normal process of aging. A comprehensive pain assessment includes a thorough medical history and physical examination, review of systems and pertinent laboratory results, imaging studies, and diagnostic tests. Pain physicians should have a broad range of understanding of the pharmacologic and physiological changes that occur in the geriatric population. The present review on pain management in the elderly focuses on relevant information for the pain clinician. Included are appropriate pain assessment, physical examination, pathophysiologic changes in the elderly, pharmacokinetic and pharmacodynamic changes, and present pain management modalities. Elderly patients present with increased fat mass, decreased muscle mass, and decreased body water, all of which have important ramifications on drug distribution. Hepatic phase I reactions involving oxidation, hydrolysis, and reduction appear to be more altered by age than phase II conjugation such as acetylation, glucuronidation, sulfation, and glycine conjugation. There is a predictable age related decline in cytochrome P-450 function and, combined with the polypharmacy that much of the elderly population experiences, this may lead to a toxic reaction of medications. One of the newer opiates, oxymorphone, has recently been studied as it is metabolized in a non-cytochrome P-450 pathway and therefore bypasses many of the drug-drug interactions common to the elderly. A multidisciplinary approach is recommended to investigate all possible options for optimal management, including pharmacotherapy, interventional procedures, physical rehabilitation, and psychological support. PMID- 21603376 TI - The accuracy of intraoperative subareolar frozen section in nipple-sparing mastectomies. AB - BACKGROUND: Intraoperative subareolar frozen sections are used to assess the nipple areolar complex's suitability for preservation for patients selected for nipple-sparing mastectomy. We aim to investigate the accuracy and value of the frozen section compared to formal histopathologic results. METHODS: In our 5-year retrospective study, 52 candidates for nipple-sparing mastectomies had subareolar frozen sections analyzed intraoperatively for malignant or atypical duct changes. Women were considered for nipple-sparing mastectomy if their primary breast malignancy was greater than 3 cm from the nipple-areolar complex and not multifocal in nature. Frozen-section results were compared to the formal histopathologic results, allowing analysis of the sensitivity, specificity, and predictive value. Causes of false negatives (negative frozen-section findings, positive histopathology findings) were then examined. RESULTS: Of 52 frozen sections, 47 (90%) yielded negative results and 5 (10%) yielded positive results. Of the 47 negative results, 39 were true negatives while 8 were false negatives. Of the 5 positive results, all were true positives with no false positives. Therefore, the positive predictive value of subareolar frozen section is 100%, negative predictive value 83%, sensitivity 38%, and specificity 100%. Of the 8 false negatives, 4 (50%) were due to sampling errors, 3 (37.5%) were due to interpretation errors, and 1 (12.5%) was due to diathermy artifact. CONCLUSION: Intraoperative subareolar frozen section is a specific but nonsensitive test. It is useful in nipple-sparing mastectomy because in 10% of cases a positive result allows immediate nipple and areolar excision. Its low sensitivity and negative predictive value means that 15% of patients will need a subsequent nipple and areolar excision. Eighty-five percent of patients can, however, have a single stage excision. PMID- 21603377 TI - Immunotoxins: a promising treatment modality for metastatic melanoma? AB - The incidence of melanoma is rising in the Western population, and melanoma is the most aggressive form of skin cancer with a very poor prognosis once it has progressed to metastatic stages. Patients with stage IV melanoma (metastases to distant lymph nodes and other areas of the body) are treated with the chemotherapeutic drug dacarbazine (DTIC). However, fewer than 5% of the patients treated with DTIC sustain long-term complete responses; hence, DTIC is administered with palliative purposes. New therapy is urgently needed. We are developing another therapeutic strategy, specifically targeting melanoma cells with the 9.2.27PE immunotoxin (IT). ITs bind to antigens overexpressed on cancer cells and are therefore tumor selective. This targeted approach may potentially cause fewer side effects in a clinical situation compared to conventional approaches like chemotherapy and radiotherapy. PMID- 21603378 TI - Cutaneous manifestations of tuberous sclerosis. AB - PURPOSE: To describe a case of periungual masses probably related to tuberous sclerosis and to review the literature regarding tuberous sclerosis, including the historical, clinical, and diagnostic aspects. Also discussed is the long-term follow-up of the disease. METHODS: Report of a case of periungual masses secondary to tuberous sclerosis and review of the literature from 1999 to 2009, with the use of MEDLINE (National Library of Medicine). RESULTS: I describe a case of periungual masses occurring as a result of tuberous sclerosis. A literature review confirms periungual masses associated with tuberous sclerosis in most cases. Also, the observance of cutaneous manifestations is most helpful in the diagnosis of this disorder. CONCLUSION: Tuberous sclerosis is an uncommon disorder, which has a variable clinical presentation. Tuberous sclerosis is associated with seizures and mental retardation. In the absence of these 2 signs/symptoms, physicians should still consider the diagnosis when presented with varied dermatologic conditions. PMID- 21603379 TI - Intraoperative pulseless electrical activity and acute cardiogenic shock after administration of phenylephrine, epinephrine, and ketamine. AB - The use of phenylephrine has been well described as a potential cause of morbidity and mortality. A thorough literature review of phenylephrine use is presented in this article. The use of ketamine and epinephrine with phenylephrine can precipitate an even more potentially lethal and catastrophic syndrome. We present the case of a 21-year-old man with Hodgkin's lymphoma and lupus who experienced an abrupt hypertensive crisis followed by pulseless electrical activity and cardiogenic shock after application of 2.5% phenylephrine-soaked nasal pledgets prior to excision of a large nasopharyngeal tumor. This case report adds to the current literature on the potential dangers of phenylephrine in clinical practice and describes a case of reversible severe left ventricular dysfunction in the setting of excessive pharmacologically induced sympathetic stimulation. PMID- 21603380 TI - An incidental finding. PMID- 21603381 TI - Statistics: a brief overview. AB - The Accreditation Council for Graduate Medical Education sets forth a number of required educational topics that must be addressed in residency and fellowship programs. We sought to provide a primer on some of the important basic statistical concepts to consider when examining the medical literature. It is not essential to understand the exact workings and methodology of every statistical test encountered, but it is necessary to understand selected concepts such as parametric and nonparametric tests, correlation, and numerical versus categorical data. This working knowledge will allow you to spot obvious irregularities in statistical analyses that you encounter. PMID- 21603382 TI - Alton Ochsner's Card File: A Profile of Medical History. AB - Alton Ochsner was a giant of American surgery. His career encompassed patient care, teaching, and research as symbolized on the original seal of the Ochsner Clinic. His ideas were innovative and groundbreaking on many fronts, making him and the Ochsner Clinic nationally and internationally known. Examination of his card file, a simple metal box with 3 * 5 index cards and subject dividers, gives extraordinary insight into the professional interests of this remarkable physician and surgeon. PMID- 21603383 TI - Cancer surgery. PMID- 21603384 TI - CME Test/Application Form. PMID- 21603385 TI - CME Upcoming Events/Program Credit Information. PMID- 21603386 TI - From the Editor's Desk. PMID- 21603387 TI - Reflections on a post-katrina transplant program. PMID- 21603388 TI - Utility of the 6-minute walk test following lung transplantation. AB - BACKGROUND: The 6-minute walk test (6-MWT) has replaced standard cardiopulmonary exercises for the evaluation of lung disease. However, data on the utility and characteristics of the 6-MWT following lung transplant are lacking. This study aimed to determine if 6-MWT distance has a normal distribution at 6 months post transplant and if lower 6-MWT distance was predictive of all-cause mortality. METHODS: We performed a retrospective chart review of 6-MWT data on all patients who were lung transplant recipients at Ochsner Medical Center between 2000 and 2005. Forty-nine lung transplant recipients completed a 6-MWT at 6 months following transplant. Of these 49 patients, 34 had completed both the 6-month and 12-month 6-MWT, and data from these were used to evaluate change in distance walked over time. RESULTS: The mean age was 46 +/- 16 years, 57% were female, and 69% received a bilateral lung transplant. Normal distribution by Kolmogorov Smirnov was demonstrated for 6-MWT distance at 6 months (P = 0.873). Mean distance walked improved from 348 +/- 15 m to 478 +/-14 m at 12 months (P = 0.0001). The 6-MWT distance at 6 months was not a predictor of survival (OR = 1.002). CONCLUSIONS: Distance for the 6-MWT followed a normal distribution following lung transplant, and distances walked continued to improve for a year following transplant. Although 6-MWT distances are not a predictor of survival, other components of the test may strengthen the predictive value for morbidity and mortality post-transplant. PMID- 21603389 TI - Innovative application of immunologic principles in heart transplantation. AB - BACKGROUND: Each year, approximately 2,200 heart transplants are performed in the United States. As our understanding of the immune system grows, new tools are being developed to find compatible organ donors and to help with immune surveillance after transplantation. The purpose of this article is to review 3 of these techniques: the virtual crossmatch, the Cylex ImmuKnow assay, and the AlloMap test. METHODS: Two authors (S.A.M. and J.C.) independently performed a literature search with the PubMed database using the key words ImmuKnow, Allomap, and virtual crossmatch in conjunction with heart transplantation. Articles were selected for inclusion if they had a primary focus on the use of virtual crossmatch in heart transplantation, the Cylex ImmuKnow assay, and the AlloMap test. Articles were not excluded on the basis of sample size but were excluded if they did not include heart transplant patients. RESULTS: The virtual crossmatch is a technique that is being used successfully in heart transplant candidates to predict compatibility of donor organs by comparing the potential recipient's HLA specific antibodies with the HLA type of the prospective donor. The ImmuKnow assay is a noninvasive blood test that measures the strength of immune activity, allowing clinicians to predict risk of infection and possible rejection in heart transplant patients. The AlloMap test is a noninvasive test that quantifies intracellular mRNA levels in mononuclear cells in peripheral blood samples using real-time polymerase chain reaction; this test has been shown to distinguish the dynamic changes in gene expression that occur in the presence or absence of acute cellular rejection. CONCLUSION: As the science of transplant immunology advances, transplant cardiologists are taking advantage of the growing fund of knowledge to help their sensitized transplant candidates increase their chances of finding a compatible donor heart and are using commercially available tests to monitor the immune system and rule out rejection after transplantation. PMID- 21603390 TI - Posttransplant pacemaker placement: case series and review. AB - INTRODUCTION: Sinus node dysfunction (SND) following orthotopic heart transplantation may lead to bradycardia, atrioventricular block, sick sinus syndrome, syncope, and death, with 6%-23% of patients requiring pacemakers. METHODS: Permanent pacemakers were placed in 5% of orthotopic heart transplants conducted at our institution from January 2002 to October 2008. RESULTS: THREE DIFFERENT IMPLANT TECHNIQUES WERE USED OVER THIS TIME: (1) dual-chamber pacing in the donor atrium and ventricle (A(D)-V(D)) (62.5%); (2) single lead in the donor atrium (A(D)) (12.5%); and (3) dual leads placed in both donor and recipient atrium (A(R)-A(D)) (25%). Using the percentage of paced histograms recorded in the device, heart rate variability for the types of lead placements were 14% for A(D)-V(D), 35% for A(D), and 97% for A(R)-A(D). DISCUSSION: The transplanted heart is characterized physiologically by autonomic denervation and chronotropic incompetence. Restoration of chronotropic competence by atrial pacing increases exercise duration and peak VO(2). Rate responsiveness can be achieved in this patient population with the placement of one lead in the remnant right atrium and one lead in the transplanted donor right atrium. PMID- 21603391 TI - Right ventricular function and left ventricular assist device placement: clinical considerations and outcomes. AB - The HeartMate II is an axial-flow left ventricular assist device that is approved for the treatment of advanced heart failure as a bridge to transplant or destination therapy. Despite the success of this device, right ventricular failure remains a persistent problem in most studies. Right ventricular dysfunction is usually defined as the need for right heart mechanical support or the persistent requirement for inotropes to support right heart function beyond 14 days. Over 21 months, 45 patients with end-stage heart disease underwent placement of the HeartMate II at our institution. This continuous cohort of patients underwent a retrospective review to evaluate the incidence of right heart failure. The perioperative survival was 91% with no incidents of mechanical support for the right ventricle and no requirements for inotropes beyond 14 days. This survival was consistent to beyond 1 year at the time of the study, and 18% of patients underwent heart transplant with 100% survival. PMID- 21603392 TI - BK Virus-Associated Nephropathy in Kidney Transplant Recipients. PMID- 21603393 TI - Improving Donor Livers by Inhibiting TNF-alpha Production. AB - Hepatic ischemia/reperfusion (I/R) injury has a significant influence on the outcome of liver transplants. Inhibiting certain enzymatic reactions that occur during I/R injury may have a protective effect on the liver during transplantation. After reviewing the biochemical pathways involved in hepatic I/R injury, we describe a pharmacologic line of defense against this injury by means of the enzyme tissue inhibitor of metalloproteinase 3 (TIMP-3). Current results suggest that TIMP-3 will play a clinically relevant role in improving outcomes of liver transplants by reducing I/R injury to the donor liver. PMID- 21603394 TI - Acute respiratory failure caused by spontaneous herniation of the lung. PMID- 21603395 TI - Recently published works. PMID- 21603396 TI - Editorial consultants 2010. PMID- 21603397 TI - CME Upcoming Events/Program Credit Information. PMID- 21603398 TI - CME Test/Application Form. PMID- 21603399 TI - From the Editor's Desk. PMID- 21603400 TI - Emergency Medicine Update: What's New in Cardiovascular Disease. PMID- 21603401 TI - The acceptability of online courses as criteria for admission to medical school. AB - A national survey of medical school admissions administrators was used to assess the acceptability of applicants' qualifications that included degrees earned partly online, partly in a community college, or in a traditional program. A questionnaire was sent from The Florida State University in 2007 to admissions administrators in the 125 accredited allopathic medical schools in the United States. In each of three situations, the respondents were asked to select one of two hypothetical applicants to invite for an interview. The applicants with their coursework taken in a traditional-residential setting were overwhelmingly preferred over the applicant holding the degree earned partly online. Further analysis indicated that online courses were perceived as not presenting sufficient opportunity for students to develop important social skills through interaction with other students and mentors. PMID- 21603402 TI - The treatment of inguinal pain. PMID- 21603403 TI - Arteriovenous fistula secondary to recurrent metacarpophalangeal joint dislocation: a case report. AB - Acquired traumatic arteriovenous fistula in the hand is rare, and only a few cases have been reported in the literature. It should be considered as a possible complication when there is a persistent palpable lesion after the traumatic swelling in the hand has resolved. We report a case of a rare arteriovenous fistula secondary to recurrent metacarpophalangeal joint dislocation. PMID- 21603404 TI - Laparoscopic cholecystectomy in chronic ambulatory peritoneal dialysis. AB - Laparoscopic cholecystectomy is the established procedure for treatment of cholelithiasis. There is no consensus on its use in patients receiving chronic ambulatory peritoneal dialysis, and there is no clear recommendation in the literature of how to manage perioperative dialysis. With the increased practice of laparoscopic techniques, peritoneal dialysis can be resumed soon after the surgical procedure without interruption of hemodialysis. We present a successful case of laparoscopic cholecystectomy in a patient receiving chronic ambulatory peritoneal dialysis, and we recommend that laparoscopic cholecystectomy should be used in this patient population who are often at an increased risk for perioperative complications and would benefit from a less invasive surgical technique. PMID- 21603405 TI - Vertigo: a review of common peripheral and central vestibular disorders. PMID- 21603406 TI - Infection control and prevention: a review of hospital-acquired infections and the economic implications. AB - The Centers for Disease Control and Prevention estimates that 2 million patients suffer from hospital-acquired infections every year and nearly 100,000 of them die. Most of these medical errors are preventable. Hospital-acquired infections result in up to $4.5 billion in additional healthcare expenses annually. The U.S. government has responded to this financial loss by focusing on healthcare quality report cards and by taking strong action to curb healthcare spending. The Medicare Program has proposed changes to the Hospital Inpatient Prospective Payment System and Fiscal Year Rates: Proposed Rule CMS 1488-P-Healthcare associated infection. Payment will be linked to performance. Under the new rule, payment will be withheld from hospitals for care associated with treating certain catheter-associated urinary tract infections, vascular catheter-associated infections, and mediastinitis after coronary artery bypass graft surgery. Infection-prevention strategies are essential. In the healthcare setting, the infection control department is categorized as non-revenue-producing. Funds dedicated to resources such as staff, educational programs, and prevention measures are vastly limited. Hospital leaders will need to balance the upfront cost needed to prevent hospital-related infections with the non-reimbursed expense accrued secondary to potentially preventable infections. The purpose of this paper is to present case studies and cost analysis of hospital-acquired infections and present strategies that reduce infections and cost. PMID- 21603407 TI - Dietary intake of nuts and cardiovascular prognosis. AB - There is a general perception that fat intake increases cardiovascular (CV) risk. We review the literature regarding the consumption of a high fat food, nuts, and CV risk. We also review the effect of metabolic studies relating dietary intervention with nuts and the effect of this intervention on established CV risk factors, especially low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and weight. The consumption of nuts is associated with a marked 40%-50% decrease in CV risk in large population based studies. Nut consumption is also associated with clinically relevant reduction in LDL cholesterol (-9% to 16%) without adversely affecting HDL cholesterol or causing a significant amount of weight gain. PMID- 21603408 TI - CME Program Credit Information. PMID- 21603409 TI - CME Upcoming Events. PMID- 21603410 TI - CME Credit Application Form. PMID- 21603411 TI - CME Questions Volume 9, No. 1. PMID- 21603412 TI - From the Editor's Desk. PMID- 21603413 TI - Metabolic parameters derived from cardiopulmonary stress testing for prediction of prognosis in patients with heart failure: the ochsner experience. AB - Cardiopulmonary parameters, particularly peak oxygen consumption, have proven utility in prognostic stratification for patients with heart failure. These have been typically corrected for total body weight as opposed to lean body mass (LBM). For practical purposes, fat consumes virtually no oxygen and receives minimal perfusion. Based on this rationale and on observations from previous studies, several investigations conducted at the Ochsner Clinic Foundation have assessed the prognostic value of metabolic parameters when corrected for LBM. Three studies reviewed in this discussion consistently found greater prognostic value for LBM-corrected parameters, especially peak oxygen consumption and oxygen pulse. These findings lead to a strong recommendation for LBM correction of cardiopulmonary exercise stress test-derived parameters for more accurate prognostic stratification in patients with heart failure, especially in the obese population. Other centers have studied additional parameters such as the ventilation to carbon dioxide production slope, oxygen uptake efficiency slope, and partial pressure of end-tidal carbon dioxide during exercise and rest. In multiple studies, these ventilation-dependent parameters have shown prognostic superiority compared with the standard peak oxygen consumption even when obtained from submaximal exercise data. However, no study to our knowledge has compared these parameters with LBM-adjusted values as described herein. The prognostic validity of cardiopulmonary exercise stress test-derived parameters requires further investigation in patients treated with beta-blockers. PMID- 21603414 TI - Update on the diagnosis and treatment of caustic ingestion. AB - Caustic ingestion is a serious medical problem with a variety of clinical presentations and a complicated clinical course. This article reviews the epidemiology and pathophysiology of caustic ingestion as well as the most current approaches to diagnosis and treatment. Finally, a recent case will be presented that highlights the difficulty this problem poses to a medical team. PMID- 21603415 TI - Moving beyond the katrina crisis: from danger to opportunity overview of key lessons learned for better disaster preparedness from the american journal of the medicine sciences third post-katrina anniversary symposium issue. PMID- 21603416 TI - A modified bowel clamp technique for ischemic preconditioning. AB - We report an alternative method in the application of bowel clamp for ischemic preconditioning of pedicled flaps. The proposed method minimizes tissue damage and patient discomfort. PMID- 21603417 TI - Rate-dependent left bundle-branch block in a child with propionic aciduria. AB - In most cases, a left bundle-branch block pattern on an electrocardiogram is a postoperative phenomenon. Under rare circumstances, it can be found in patients after myocardial infarction or in patients with hypertrophic cardiomyopathy, or it can be exercised induced. We describe a pediatric patient with propionic aciduria, dilated cardiomyopathy, and rate-dependent left bundle-branch block on her electrocardiogram. PMID- 21603418 TI - Osteoporosis after breast cancer chemotherapy: a case report. AB - We describe therapeutic challenges in a patient with breast cancer during follow up after quadrantectomy. The patient had used hormone therapy for 5 years and then tamoxifen citrate, a selective estrogen receptor modulator, for 3 years. When seen by us, she was taking Arimidex, an aromatase inhibitor. In accord with recommendations in the literature, bisphosphonate therapy was prescribed by clinicians at the Menopause Center in cooperation with the Oncology Center. We suggest that cooperation between menopause centers and oncology centers should continue in the follow-up of such patients. PMID- 21603419 TI - Guess the case. PMID- 21603421 TI - Research update. PMID- 21603420 TI - Guess the case from the ochsner archives. PMID- 21603422 TI - Recently published works. PMID- 21603423 TI - CME Test/CME Application Form. PMID- 21603425 TI - CME Program Credit Information. PMID- 21603424 TI - CME Upcoming Events. PMID- 21603426 TI - From the Editor's Desk. PMID- 21603427 TI - Obesity and hypertension, heart failure, and coronary heart disease-risk factor, paradox, and recommendations for weight loss. AB - Obesity prevalence has reached epidemic proportions and is independently associated with numerous cardiovascular disease (CVD) risk factors, including diabetes mellitus, hypertension, dyslipidemia, cancers, sleep apnea, and other major CVDs. Obesity has significant negative impact on CVD, including hypertension, coronary heart disease, heart failure, and arrhythmias via its maladaptive effects on individual CVD risk factors and cardiac structure and function. Despite this negative association between obesity and the incidence and prevalence of CVD, many studies have demonstrated that obese patients with established CVD might have better short- and long-term prognosis, suggesting an "obesity paradox." This intriguing phenomenon has been well documented in populations with heart failure, coronary heart disease, and hypertension. This review summarizes the adverse effects of obesity on individual CVD risk factors; its role in the genesis of CVDs, including heart failure, coronary heart disease, and hypertension; and the obesity paradox observed in these populations and the potential underlying mechanisms behind this puzzling phenomenon and concludes with a discussion on the potential benefits of weight reduction. PMID- 21603428 TI - Obesity-related hypertension. AB - Obesity-associated arterial hypertension is characterized by activation of the sympathetic nervous system, activation of the renin-angiotensin system, and sodium retention, among other abnormalities. In this review, the following 3 facets of the obesity/hypertension nexus will be discussed: the potential mechanisms by which obesity can lead to elevated arterial pressure, the interaction of obesity with the sequelae of hypertension, and the therapies that are believed to optimally treat obesity-related hypertension. PMID- 21603429 TI - Articular cartilage degeneration: etiologic association with obesity. PMID- 21603430 TI - Exercise aspects of obesity treatment. PMID- 21603431 TI - Psychological assessment of the patient undergoing bariatric surgery. AB - The purpose of this article is to provide an overview of the critical domains assessed during the psychological evaluation of candidates for bariatric surgery. Although no formal standard exists in the literature, there is growing recognition of the important elements to be addressed and the appropriate means for collecting the necessary data to determine psychological readiness for these procedures. Information regarding the components of the clinical interview and the specific measures used for psychological testing are discussed. Given the limited data on predicting success after surgery, determining psychological contraindications for surgery is addressed. Additionally, the multiple functions served by the psychologist during this assessment procedure are highlighted along with the value of this procedure in the patients' preparation for surgery. PMID- 21603432 TI - Obstructive sleep apnea: a growing problem. AB - Obstructive sleep apnea is an underrecognized and underdiagnosed medical condition, with a myriad of negative consequences on patients' health and society as a whole. Symptoms include daytime sleepiness, loud snoring, and restless sleep. While the "gold standard" of diagnosis is by polysomnography, a detailed history and focused physical examination may help uncover previously undiagnosed cases. Undetected obstructive sleep apnea can lead to hypertension, heart disease, depression, and even death. Several modalities exist for treating obstructive sleep apnea, including continuous positive airway pressure, oral appliances, and several surgical procedures. However, conservative approaches, such as weight loss and alcohol and tobacco cessation, are also strongly encouraged in the patient with obstructive sleep apnea. With increased awareness, both the medical community and society as a whole can begin to address this disease and help relieve the negative sequelae that result from it. PMID- 21603433 TI - Long-term Management of Patients After Weight Loss Surgery. AB - Bariatric surgery is becoming very common, and most physicians will have contact with bariatric patients. Many aspects to follow-up are not generally known. The objective of this article is to help other physicians understand what follow-up entails to assist them with the care of these patients. It is expected that patients are followed up by the bariatric team for a lifetime, as care is complicated and lifetime follow-up is the key to long-term success. PMID- 21603434 TI - Developing an internet presence for your practice. AB - Yesterday, it was the Yellow Pages that informed the public where and how to reach their physicians. Today, it is the Internet. With the Internet, patients have 24/7 access to your practice that will do far more than any Yellow Pages or advertising could possibly do. This article discusses the importance of the Internet for the contemporary physician and how to create a useful and interactive Web site. PMID- 21603435 TI - Champ lyons, MD the ochsner years: 1945-1950. AB - Since its founding, the Ochsner Clinic Foundation has been associated with many "giants" in their respective fields. A hallmark of these associations has been the selection of individuals based on superior ability and integrity. Champ Lyons was a staff surgeon at Ochsner from 1945 to 1950. His time in New Orleans was the final step to the pinnacle of a brilliant, yet brief, surgical career. This bright shining star of American surgery influenced, and was influenced by, Ochsner. PMID- 21603436 TI - The development of the patient transfer center at ochsner medical center. AB - Transfers are a major source of patients for the Ochsner Medical Center. To facilitate transfers, a "transfer center" was developed. This article describes the rationale for this center, how it was developed, and the results of its implementation. PMID- 21603437 TI - CME Upcoming Events. PMID- 21603438 TI - Cme program credit information. PMID- 21603439 TI - CME Test/CME Application Form. PMID- 21603440 TI - Heart disease is still a primary emphasis. PMID- 21603441 TI - Modulatory Effect of Inflammation on Blood Pressure Reduction via Therapeutic Lifestyle Change. AB - PURPOSE: Since inflammatory status, as determined by C-reactive protein (CRP) levels, is correlated with many cardiovascular (CV) disease risk factors and major CV events, we sought to determine if median levels of CRP can modulate blood pressure changes as well as other CV risk factors that are typically improved by therapeutic lifestyle changes with formal cardiac rehabilitation and exercise training (CRET) programs. METHODS: We retrospectively evaluated CRP status and standard CV risk factors both before and after formal, phase II CRET programs (12 weeks; 36 educational and exercise sessions) in 635 consecutive patients with coronary artery disease after major CV events. RESULTS: The median CRP level at baseline was 3.2 mg/L (range, 0.2-80.1 mg/L; mean, 5.8+/-8.4 mg/L). After CRET, both the patients with high and those with low CRP concentrations exhibited statistically significant improvements in most CV risk factors when their CRP levels were divided by median levels. However, systolic, diastolic, and mean arterial blood pressure improved in patients with low CRP levels (each by 4%) but did not change significantly in patients with high CRP levels. In multiple regression models, only young age, low CRP levels, and low body mass index were significant independent predictors of improved mean arterial blood pressure after CRET. CONCLUSIONS: In contrast to patients with coronary artery disease and low levels of CRP, patients with high baseline CRP levels did not demonstrate significant reductions in blood pressure after therapeutic lifestyle changes via formal CRET programs. PMID- 21603443 TI - Clinical implications of left atrial enlargement: a review. AB - Echocardiographically determined left atrial (LA) size has been shown to be a significant predictor of cardiovascular (CV) outcomes. We review the physiology and echocardiographic assessment of LA size and functions and describe the pathophysiologic determinants and clinical implications of LA enlargement. However, despite strong evidence, standardized LA size assessment and generalized applicability of its clinical implications to patient care have yet to be determined. Nevertheless, current findings suggest that echocardiographically determined LA size may become an important clinical risk identifier in preclinical CV disease and should be assessed as a part of routine comprehensive echocardiographic evaluation. PMID- 21603442 TI - An updated concept for left ventricular hypertrophy risk in hypertension. AB - Left ventricular hypertrophy (LVH) was one of the first three "factors of risk" originally identified by the Framingham Heart Study predisposing the patient to premature morbidity and mortality resulting from coronary heart disease. Among the initial approaches toward specific risk reduction were antihypertensive agents that reduce left ventricular (LV) mass with control of arterial pressure. However, the indication to reduce risk from LVH has not been approved by the federal regulatory agency. All drugs that reduce arterial pressure are capable of decreasing LV mass. More recently, investigative efforts in the laboratory and clinic have focused on identifying specific epiphenomena that are responsible for risk; they include ischemia, fibrosis, apoptosis, dietary salt excess, and inflammatory factors. Newer clinical methods are becoming available to diagnose these alterations. Current antihypertensive therapy and management improve coronary blood flow and flow reserve, diminish ventricular fibrosis and apoptosis, employ established educational interventions to reduce dietary salt intake, and may prevent inflammatory factors (although the latter factor requires further study; and others, no doubt, will continue to be identified). Thus, present knowledge is available to apply this more current paradigm for the treatment of hypertension and to reduce risk from LVH. PMID- 21603444 TI - Salt, arterial pressure, and cardiovascular and renal damage. AB - This brief review deals with some novel developments regarding the possible role of salt in the pathogenesis of cardiovascular and renal disorders. Studies in both humans and experimental animals are discussed. Increased salt intake is usually associated with an increase in arterial pressure although some controversies still exist. Salt sensitivity of arterial pressure (defined as an increase in arterial pressure on dietary salt overload) was demonstrated in many animal species as well as in humans. However, findings in rats, the most often used animal model, also demonstrated that this salt sensitivity was not uniform; some strains are salt sensitive, while other strains are salt resistant. Salt sensitivity of arterial pressure in humans is also not uniform; less than one third of normotensive individuals and less than one-half of hypertensive individuals are salt sensitive. Of great importance are findings that excessive salt intake may damage target organs (cardiovascular system and kidneys) irrespective of arterial pressure. Together with an ever-growing consensus that sodium intake in acculturated societies is high, these findings also emphasize the need for reduction in salt intake. Therefore, the adverse cardiovascular and renal effects of salt continue to be a subject of intense study. Current data indicate that a reduction in salt intake should ameliorate, if not prevent, cardiovascular and renal morbidity and mortality, particularly among individuals with hypertension. PMID- 21603445 TI - C-Reactive Protein: How Has JUPITER Impacted Clinical Practice? AB - Inflammation plays a pivotal role in all phases of atherosclerosis. High sensitivity C-reactive protein (hsCRP), the best characterized biomarker of inflammation, is an independent predictor of future cardiovascular (CV) events and can add further insight to risk stratification. Assessment of hsCRP levels in clinical practice is feasible and inexpensive. Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) was a landmark primary prevention trial that enrolled 17,802 apparently healthy men and women with low-density lipoprotein cholesterol levels of less than 130 mg/dL and hsCRP levels of 2 mg/L or higher and randomly assigned them to rosuvastatin, 20 mg daily, or placebo. The trial demonstrated that treatment with statin was associated with significant lowering of hsCRP (37%), with 44% reduction in incident CV and 20% reduction in all-cause mortality. These compelling data from the JUPITER trial should encourage changes in our approach toward primary prevention of CV disease and lipid-lowering therapy, as these data shift the focus toward a link between inflammation, statin therapy, and prevention of atherosclerotic CV diseases. PMID- 21603448 TI - Advanced heart failure and management strategies. AB - The global healthcare burden attributable to heart failure is ever increasing. Patients presenting with refractory heart failure should be evaluated for compliance with medical regimens and sodium and/or fluid restriction, and every attempt should be made to optimize conventional strategies. Reversible causes such as ischemia should be identified and revascularization considered in persistently symptomatic patients, particularly those with a viable myocardium. Carefully selected patients who continue to deteriorate clinically in spite of optimization of medical therapy may be considered for advanced treatment strategies, such as continuous inotropic infusions, mechanical circulatory support devices, cardiac transplantation, or referral to hospice care. We discuss the clinical presentation and management of patients with advanced/refractory (Stage D) heart failure. PMID- 21603447 TI - Treatment of refractory angina. AB - It is estimated that as many as 1,000,000 people in the United States have chronic symptomatic coronary artery disease (often referred to as refractory angina) that is recalcitrant to medical therapy and unamenable to conventional revascularization procedures. Patients have reproducible lifestyle-limiting symptoms of chest pain, shortness of breath, and easy fatigability. Several new therapies are available to treat this difficult patient population, including newer drugs, enhanced external counterpulsation, transmyocardial revascularization, and cell-based therapies. This article reviews the current state of the art for treatment of refractory angina. PMID- 21603446 TI - Multisystem revascularization. AB - Atherosclerosis affects all major vascular territories. Both surgical and endovascular revascularization techniques have evolved, with more and more patients presenting with disease in multiple vascular beds. This can lead to difficult decision-making and the potential for complications. In this article, we review the available literature to help the clinician decide on optimum sequence, timing, and mode of multisystem revascularization. PMID- 21603449 TI - Pulmonary hypertension for primary care providers. AB - Pulmonary hypertension is a constellation of diseases that shares signs and symptoms of dyspnea, fatigue, chest pain, palpitations, and syncope. Research advances made over the past decade have significantly changed the natural history of this disease. Therapies initially designed to specifically target the molecular causes of increased pulmonary vascular resistance are now used in all types of patients with pulmonary hypertension. The challenge of the primary care physician is first, identifying pulmonary hypertension, and second, determining the modifiable substrates that contribute to the development and symptoms of this disease. PMID- 21603450 TI - Atrial fibrillation: current perspective. PMID- 21603451 TI - Cardiac resynchronization therapy. AB - Systolic heart failure is a major problem for Americans today, with 550,000 new cases diagnosed per year, and ultimately contributes to 287,000 deaths annually. While pharmacologic therapy has drastically improved outcomes in patients with systolic heart failure, hospitalizations from systolic heart failure continue to increase and remain a major cost burden. In response to this unmet need, recent years have seen dramatic improvements in device-based therapy targeting one cause of systolic dysfunction: dyssynchronous ventricular contraction. Cardiac resynchronization therapy aims to restore mechanical synchrony by electrically activating the heart in a synchronized manner. This review summarizes the rationale for cardiac resynchronization therapy, evidence for its use, current guidelines, and ongoing and future directions for research. PMID- 21603452 TI - Cardiac computed tomography, changing the way we look at the heart. AB - Cardiac computed tomography angiography (CCTA) produces excellent anatomic information of the coronary arteries and other cardiac structures. A high negative predictive value (99%) for the exclusion of coronary lesions establishes CCTA as a highly effective noninvasive alternative to invasive coronary angiography. It is, however, less accurate for determining degrees of lesion severity, and intermediate grade lesions require either physiologic stress testing or invasive coronary angiography. CCTA allows visualization of the vessel wall so plaque can be classified as soft, calcified, or mixed on the basis of Hounsfield units. Precise quantification of the plaque burden is readily performed with coronary artery calcium scoring (CACS). This measurement of plaque burden is one of the most predictive of future cardiac events and mortality available. CCTA also serves as an excellent tool prior to surgical and percutaneous cardiac procedures. CT scanning continues to evolve as an imaging modality for all stages of the treatment of cardiac disease: CACS for risk assessment for asymptomatic patients, CCTA to evaluate patients with symptoms, and cardiac CT to plan cardiac procedures. PMID- 21603453 TI - Magnetic resonance imaging: a wealth of cardiovascular information. AB - Cardiac magnetic resonance imaging is a relatively new noninvasive imaging modality that provides insight into multiple facets of the human myocardium not available by other imaging modalities. This one test allows for the assessment of ventricular and valvular function, ischemic and nonischemic cardiomyopathies, congenital heart disease, and cardiac tumors. It has been coined by many as "one stop shopping." As with any imaging modality, it is important to understand not only the indications of the modality but also the patient's perspective and contraindications. PMID- 21603454 TI - Induced hypothermia as a neuroprotectant in post-cardiac arrest. AB - Survivors of out-of-hospital cardiac arrest frequently suffer devastating effects from anoxic brain injury. Therapeutic hypothermia is the first therapy to show benefit in improving survival as well as limiting neurologic injury. We review the data supporting the use of therapeutic hypothermia in this patient population, the pathophysiologic basis of its neuroprotectant effects, the methods of hypothermic induction, and the clinical application. PMID- 21603455 TI - Recently published works. PMID- 21603456 TI - Editorial consultants 2009. PMID- 21603457 TI - CME Test/CME Application Form. PMID- 21603458 TI - CME Upcoming Events/Program Credit Information. PMID- 21603459 TI - From the Editor's Desk. PMID- 21603460 TI - Challenges to consider in practicing specialized medicine. PMID- 21603461 TI - The russert impact: a golden opportunity to promote primary coronary prevention. PMID- 21603462 TI - Eosinophilic fasciitis induced by fire ant bites. AB - PURPOSE: To describe a case of eosinophilic fasciitis likely related to proximate fire ant bites and review the literature to summarize the etiology and clinical, laboratory, histopathological, and therapeutic aspects of eosinophilic fasciitis. METHODS: Report of a case of eosinophilic fasciitis and review of the English language literature using a Medline search from 1950 to January 2007. RESULTS: We describe the case of a New Orleans woman who developed eosinophilic fasciitis after fire ant bites post-Hurricane Katrina. A careful literature review confirms an association of eosinophilic fasciitis with unaccustomed vigorous exercise, arthropod bites, and borreliosis, among other etiologic agents. CONCLUSIONS: Eosinophilic fasciitis, a rare disorder with unclear pathogenic mechanisms, has been associated with arthropod bites and borreliosis. Fire ant bites should be added to the list of etiologic agents for this disorder. PMID- 21603463 TI - Obstructive lesions of the pediatric subglottis. AB - PURPOSE: To compile information regarding obstructive subglottic lesions in children, including anatomy, pathogenesis, prevention, evaluation, and treatment options, required for implementation of a multi-faceted treatment plan. METHOD: Review of the literature. CONCLUSIONS: Although they are infrequent, obstructive subglottic lesions pose significant challenges to treating physicians, from airway management and injury prevention to decannulation and voice rehabilitation. Most patients with these lesions require multidisciplinary care and long-term treatment and can nearly always be treated successfully. PMID- 21603464 TI - Effects of stress after hurricanes katrina and rita on pubertal disorders in children. AB - Hurricanes Katrina and Rita caused widespread damage that resulted in increased stress levels for families living in the New Orleans area. This study examined the relationship between this stress and the onset of puberty in children by conducting a retrospective chart review of patients referred before and after the storm to a pediatric endocrine practice in New Orleans. The total number of new patients referred and the incidence of diagnoses that are unlikely to be affected by stress (ie, thyroid disease and premature adrenarche) were essentially unchanged. On the other hand, the incidence of central precocious puberty decreased by 52% after the storm, while the incidence of pubertal delay increased by 9% in the post storm period. This study thus provides evidence that stress delays the onset of puberty in children. PMID- 21603465 TI - Should immunocompromised patients have pets? AB - PURPOSE: To evaluate the risks and benefits of pet ownership by immunodeficient patients, focusing primarily on organisms that colonize animals and are transmitted to humans. Those diseases that are known to be progressive or more severe in patients with altered immune function are emphasized. METHODS: A review of the medical and veterinary literature pertaining to zoonoses transmitted by domestic animals was completed. Information pertaining to issues involving immunosuppressed patients including AIDS was carefully evaluated and summarized for inclusion. RESULTS: There are significant clinical and psychosocial benefits to pet ownership. However, numerous diseases can be acquired from these animals which may be more severe in immunocompromised individuals. CONCLUSION: Simple guidelines for pet ownership by immunosuppressed patients can be implemented to reduce their risk of disease and allow them to safely interchange with their pets. PMID- 21603466 TI - Infliximab-associated Chiasmopathy. AB - Optic neuropathy has been reported in association with the use of tumor necrosis factor-alpha antagonists such as etanercept, infliximab, and adalimumab. This is a report of a patient who began experiencing decreased vision approximately 1 month after starting infliximab therapy for rheumatoid arthritis. Visual field testing showed bitemporal hemianopic scotomas, indicating involvement of the nerve fibers in the optic chiasm. The infliximab was discontinued, and the patient experienced substantial improvement in her visual acuity and visual field. PMID- 21603467 TI - Breast-feeding and Vitamin D Supplementation Rates in the Ochsner Health System. AB - Breast-feeding imparts many benefits to both mothers and infants. Because of these numerous recognized benefits, there has been an effort to increase breast feeding rates nationwide; increasing breast-feeding rates was one of the goals of the U.S. Department of Health and Human Services' Healthy People 2010 initiative. This study examined the breast-feeding rate at the Ochsner Clinic Foundation by conducting a retrospective chart review of patients aged 0-12 months who visited any branch of the Ochsner hospital system. Our results indicate that the rate of initiation of breast-feeding for children followed at the Ochsner Clinic Foundation is 66.3%. However, as breast-feeding rates rise, there is concern that there may be a resurgence of rickets, a disease caused by the deficiency of vitamin D. Currently the American Academy of Pediatrics recommends that exclusively breast-fed infants receive vitamin D supplementation starting within the first 2 months of life. We have therefore initiated a clinical trial to determine whether vitamin D supplementation is required to prevent rickets in breast-fed children. In the course of conducting this study, we have gathered additional data regarding the patterns of breast-feeding and of vitamin D supplementation for babies born at Ochsner. PMID- 21603469 TI - CME Upcoming Events. PMID- 21603470 TI - From the Editor's Desk. PMID- 21603468 TI - Childhood immunization controversies: what are parents asking? PMID- 21603471 TI - Colorectal cancer screening. PMID- 21603472 TI - Clinicians' Guide to Statistics for Medical Practice and Research: Part II. PMID- 21603473 TI - Physician coding and reimbursement. AB - Physician reimbursement and the coding to support it are critically important to the sustained health of any physician's practice. This article reviews the recent history of physician reimbursement from the government and third-party payers and physician coding to support reimbursement. Explanations of terminology and documentation requirements are included. PMID- 21603474 TI - Can pediatric electrophysiologists safely perform electrophysiology studies on adults with congenital heart disease? AB - INTRODUCTION: Adults with congenital heart disease (ACHD) are known to have arrhythmias. The purpose of this study was to review the safety and efficacy of a pediatric electrophysiologist performing electrophysiology studies (EPS) on ACHD. METHODS: All ACHD >18 years of age who underwent an EPS performed by a pediatric electrophysiologist between 1995 and 2004 were included. Patient records were reviewed for demographics, cardiac diagnosis, surgery, arrhythmia, and catheterization issues such as vascular access, fluoroscopy time, complications, procedure performed, and success rates. RESULTS: The study identified 70 patients who underwent 93 EPS: 42 with ventricular tachycardia (VT) and 28 with supraventricular tachycardia (SVT). With respect to safety, vascular access was obtained in 100% of patients, fluoroscopy time averaged 34.2 minutes, and complications occurred in 3 patients (4%) including permanent (1) or transient (1) atrio-ventricular node injury and coagulum on the catheter (1), but no deaths. With respect to efficacy, 30 patients had an attempted radiofrequency ablation that was successful in 21 of 28 (75%) with SVT and 1 of 2 (50%) with VT. CONCLUSIONS: (1) ACHD can safely undergo an electrophysiology study performed by pediatric electrophysiologists, with low fluoroscopy times and few complications. (2) Success rates for ablation in this patient population approach 75%. PMID- 21603475 TI - Can urodynamic studies identify patients at risk for voiding difficulty after pubovaginal sling? The "voiding quality index". AB - OBJECTIVE: The value of urodynamics (UDS) as a predictor of voiding dysfunction after pubovaginal sling is controversial. We sought to determine whether individual urodynamic parameters or a "Voiding Quality Index" (VQI) can predict prolonged catheter time after sling. METHODS: Individual voiding parameters for the 75 patients who had preoperative urodynamics included maximum detrusor pressure (Pdet), voiding time (VT), maximum uroflow (Qmax), post-void residual (PVR), and abdominal straining. Each parameter was scored 1 if normal and 0 if abnormal; these urodynamic scores were added to calculate the VQI (range 0-5). Each patient had a suprapubic catheter and maintained a voiding diary. Individual voiding parameters and the VQI were compared statistically between groups who required a catheter for more than 14 days and those who did not. Informed consent was obtained from all patients and the study was conducted with Ochsner Institutional Review Board approval. RESULTS: Average catheter time for the 66 patients who completed the study was 11.1 days. Fifty patients voided within 14 days and were defined as being in the non-retention group (NR). Sixteen patients were catheter dependent at 14 days and were considered in the retention group (R). When each voiding parameter was individually analyzed between groups with respect to catheter time, the mean values in each group were not significantly different and offered no predictive value. When the VQI was analyzed between groups, the VQI was significantly lower for patients developing voiding difficulty (VQI-R = 3.81) than those who did not (VQI-NR = 2.31) p = .001. CONCLUSION: No single urodynamic voiding parameter accurately predicts prolonged catheter time following sling. A combination of voiding parameters, the "Voiding Quality Index," may predict patients at risk for prolonged catheter time following sling. PMID- 21603477 TI - Frontal sinus fistula secondary to a cranial foreign body. PMID- 21603476 TI - Rectal prolapse: a 10-year experience. AB - PURPOSE: To compare perineal to abdominal procedures for rectal prolapse over a 10-year period at a single tertiary care institution. METHODS: Between May 1, 1995, and January 1, 2005, 75 patients underwent surgical intervention for primary rectal prolapse at a tertiary referral center. Surgical techniques included perineal-based repairs (Altemeier and Delorme procedures) and abdominal procedures (open and laparoscopic resection and/or rectopexy). Medical records were abstracted for data pertaining to patient characteristics, signs and symptoms at presentation, surgical procedure, postoperative length of hospitalization, morbidity and mortality, and recurrence of rectal prolapse. RESULTS: Seventy-five patients underwent surgical intervention for rectal prolapse during the study period. The average patient age was 60.8 years. Sixty two patients (82.7%) underwent perineal-based repair (Altemeier n = 48, Delorme n = 14); eight patients (10.7%) underwent open abdominal procedures (resection and rectopexy n = 4, rectopexy only n = 4); and five patients (6.7%) underwent laparoscopic repair (laparoscopic LAR n = 3, laparoscopic resection and rectopexy n = 2). Average hospitalization was shorter with perineal procedures (2.6 days) than with abdominal procedures (4.8 days) (p < 0.0031). Postoperative complications were observed in 13.3% of cases. With a median follow-up of 39 months (range 6-123 months), there was no mortality for primary repair, a postoperative morbidity occurred in 13% of patients, and the overall rate of recurrent prolapse was 16% (16.1% for perineal-based repairs, 15.4% for abdominal procedures). CONCLUSION: Perineal resections were more common, performed in significantly older patients, and resulted in a shorter hospital stay. Their minimal morbidity and similar recurrence rates make perineal procedures the preferred option. PMID- 21603478 TI - Stomal revision using abdominal wall contouring. PMID- 21603479 TI - New Onset LSD Flashback Syndrome Triggered by the Initiation of SSRIs. AB - During the 1960s, lysergic acid diethylamide (LSD) emerged as a widely popular drug, used by a substantial portion of the adolescent and young adult population. Since Major Depressive Disorder is a common disorder, clinicians will increasingly encounter patients who used LSD in the far distant past and now require treatment with antidepressant agents. We describe such a case in the following report of a patient who experienced a troubling array of unusual side effects, which we postulate to be a new onset LSD flashback syndrome triggered by selective serotonin reuptake inhibitors (SSRIs). PMID- 21603481 TI - Ochsner research update. PMID- 21603480 TI - Ochsner in literature - fiction. AB - OCHSNER AND ITS PHYSICIANS HAVE FIGURED IN WORKS OF FICTION: novels, plays, and music. A listing of these works, along with a description of each work, is provided. PMID- 21603482 TI - CME Credit Application Form/CME Questions Volume 6, No. 2. PMID- 21603483 TI - Erratum. AB - [This corrects the article DOI: 10.1043/1524-5012(2006)6[89:PSGTLS]2.0.CO;2.]. PMID- 21603484 TI - From the Associate Editor's Desk. PMID- 21603486 TI - Why nutrition matters in healthcare outcomes. PMID- 21603485 TI - Fish oil in primary and secondary cardiovascular prevention. AB - Omega-3 fatty acid therapy shows great promise in both primary and secondary prevention of cardiovascular (CV) diseases, especially coronary heart disease (CHD). In this review, we discuss the evidence available from prospective and retrospective observational epidemiologic studies and controlled clinical trials demonstrating the effects of omega-3 fatty acids (fish oil) in primary and especially secondary prevention of major CV events, including CV mortality, fatal and nonfatal myocardial infarction (MI), and sudden cardiac death (SCD). Significant reductions in total mortality and SCD to the extent of 20% to 50% have been found in studies using doses ranging from 0.85 to 4.0 g/d. We review the compelling evidence that indicates all clinicians should strongly consider therapy with fish oil, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for patients with known CV disease and for patients at increased risk for CV disease, particularly patients at increased risk for SCD. The target DHA + EPA consumption levels are about 800 to 1000 mg/d for individuals with known CHD and at least 500 mg/d for individuals without disease. PMID- 21603487 TI - Guess the case from the ochsner archives. PMID- 21603488 TI - Education update. PMID- 21603489 TI - Recently published works. PMID- 21603490 TI - CME Upcoming Events. PMID- 21603492 TI - CME QUESTIONS VOLUME 8, No. 1. PMID- 21603491 TI - Ochsner's 5 Annual Research Night May 13, 2008 Ochsner Clinic Foundation Jefferson Highway New Orleans, LA. PMID- 21603493 TI - Cme credit application form. PMID- 21603494 TI - From the Editor's Desk. PMID- 21603495 TI - Balancing your personal and professional lives. AB - Doctors are forever making an effort to balance their personal and professional lives. This is a challenge that confronts every physician during their careers. This article provides 10 suggestions that will hopefully make the balancing act at least a little easier. PMID- 21603496 TI - Treatment of periocular malignancy by interdisciplinary approach. PMID- 21603497 TI - Sphenoid sinus myxoma: case report and literature review. AB - OBJECTIVES: We present the first known case in the English-language literature of a myxoma arising in the sphenoid sinus. By describing the patient's clinical course and the salient features of this rare neoplasm, we seek to increase the awareness of the presentation, histological features, and treatment considerations for myxomas of the head and neck. In the process, we intend to describe the work-up of isolated sphenoid sinus lesions and focus on the varying and evolving techniques for surgical access to the sphenoid sinus. STUDY DESIGN AND METHODS: Case report and literature review. RESULTS: We describe the clinical course of a patient with a myxoma of the sphenoid sinus. The patient underwent an external sphenoethmoidectomy through a lateral rhinotomy approach with medial maxillectomy under MRI-guidance. He remains without evidence of recurrent disease after 8 months. CONCLUSIONS: Myxomas of the head and neck are rare neoplasms. Their infiltrative nature and tendency to recur demand an aggressive surgical approach that may be accomplished with minimal morbidity using currently available image-guided techniques. PMID- 21603498 TI - Surgical management of minor salivary gland neoplasms of the palate. AB - OBJECTIVE: Minor salivary gland tumors are uncommon, accounting for up to 15% of salivary gland neoplasms. We describe our experience with both benign and malignant tumors of the palatal minor salivary glands, focusing on the extent of resection and options for defect reconstruction. STUDY DESIGN: Retrospective review of medical records. RESULTS: From 1994 to 2002, 37 patients with primary neoplasms originating in the palatal minor salivary glands were treated at a single institution. Patients ranged in age from the second to the seventh decades, with a female preponderance. Twenty-four percent of the lesions were benign. The most common malignant tumor encountered was low grade polymorphous adenocarcinoma, followed by mucoepidermoid carcinoma, and adenoid cystic carcinoma. The extent of surgical resection was dictated by tumor pathology and evidence of perineural spread, and defects were reconstructed with a variety of techniques. Postoperative complications included velopharyngeal insufficiency, flap fistulization or loss, and trismus. After 1 month to 8 years of follow-up, 1 patient has died with regional and systemic metastases. CONCLUSIONS: Neoplasms of the minor salivary glands in the palate may be excised, with limits dictated by tumor histopathology and perineural invasion. Improved functional results may be achieved by immediately reconstructing the defects with rotational flaps, reserving free flaps for more extensive defects of the maxilla and infratemporal fossa. PMID- 21603499 TI - Malignant melanoma of the head and neck: a brief review of pathophysiology, current staging, and management. PMID- 21603500 TI - Reconstruction of large lateral facial defects utilizing variations of the cervicopectoral rotation flap. AB - Large lateral facial defects as a result of trauma or head and neck oncologic surgery can present a challenging reconstructive dilemma for the operating surgeon. A number of options currently exist for reconstructing such defects, including skin grafts, myocutaneous flaps, and free vascularized flaps. The decision to utilize one approach versus another depends largely on the nature of the defect, anatomical location, and the experience of the surgeon. This article describes our experience utilizing cervicopectoral rotation flaps with and without myocutaneous flaps to reconstruct large lateral facial defects after head and neck oncologic surgery. PMID- 21603501 TI - Gastric carcinoid tumors. AB - Initially, carcinoid tumors were a curiosity for physicians and were so named because of their relatively benign behavior as compared to the more common adenocarcinomas. As medicine has evolved, our understanding and management have greatly improved. Our classification system has also become more specific. Gastric carcinoid tumors are unique in that three types have been described based upon each one's pathophysiology. In general, none of these give rise to the typical carcinoid syndrome as seen with metastatic ileal carcinoids.Type 1 gastric carcinoids represent 70% to 80% and are characterized by multiple small lesions and their association with hypergastrinemia secondary to chronic atrophic gastritis and pernicious anemia, and are less likely to metastasize. Type 2 is a rare entity, representing 5%, and is characterized by multiple small lesions, hypergastrinemia secondary to Zollinger-Ellison syndrome, and multiple endocrine neoplasia (MEN) type 1. The risk for metastasis is slightly higher than for type 1; however, overall prognosis is dependent upon the gastrinoma prognosis. Accounting for 20%, type 3 is known as sporadic gastric carcinoids in that there is no association with hypergastrinemia, chronic atrophic gastritis, or Zollinger Ellison syndrome. These present as large solitary lesions and are often metastatic upon diagnosis. A unique feature of type 3 is its association with an atypical carcinoid syndrome that is thought to be mediated by histamine.The treatment-including medical, endoscopic, and surgical-of gastric carcinoids is dictated by the type, size, and presence of metastasis. PMID- 21603503 TI - Combination laparoscopic radiofrequency ablation and partial excision of hepatic hemangioma. PMID- 21603502 TI - Gastrointestinal stromal tumors-diagnosis and management: a brief review. AB - Gastrointestinal stromal tumors (GISTs) are rare but are the most common mesenchymal tumor in the gastrointestinal tract. They arise from a precursor cell in the myenteric plexus, and most tumors express a characteristic CD117 antigen, which is part of a tyrosine kinase receptor. This finding has led to the development of novel chemotherapeutic agents targeted at these receptors and has revolutionized the treatment of these tumors, which had been historically disappointing. Surgery is recommended for tumors >2 cm in size and even has a role in metastatic disease. The approach to tumors <2 cm in size is more controversial, as these lesions tend to be less aggressive, but the true malignant potential of GISTs can only be determined by surgical resection and histologic evaluation. PMID- 21603504 TI - Breast cancer metastatic to the urinary bladder. AB - Breast cancer is common and has the potential to spread to multiple organs. This article describes metastasis to the urinary bladder. In most instances, breast cancer metastatic to the bladder is associated with other pelvic organ metastasis. In patients with known metastatic breast cancer, bladder screening is not warranted. However, if lower urinary tract symptoms persist, an evaluation of the bladder should be considered to rule out metastatic involvement. PMID- 21603506 TI - Guess the case. PMID- 21603505 TI - Pathogenesis of prostate cancer: lessons from basic research. AB - In the United States, prostate cancer is the second most common cause of cancer related deaths in men. While the importance of androgens and androgen receptors (ARs) in primary prostate cancer is well established, the role of ARs in prostate cancers that emerge despite androgen ablation therapies remains poorly understood. The aim of this article is to illustrate the fundamental biology of prostate cancer. We focus mainly on the AR because of its critical role in the progression and metastatic spread of prostate cancer. We also summarize the alternate pathways that may potentially contribute to the progression of prostate cancer. Identifying the underlying mechanisms of androgen independence is crucial in the design of appropriate therapies for hormone-refractory neoplasms. PMID- 21603507 TI - A brief history of the ochsner summer internship program for high school students/abstracts. PMID- 21603508 TI - Recently published works. PMID- 21603509 TI - CME Questions Volume 8, No. 4. PMID- 21603510 TI - Editorial consultants 2008. PMID- 21603511 TI - CME Credit Application Form. PMID- 21603513 TI - Erratum. AB - [This corrects the article DOI: 10.1043/1524-5012(2007)7[44:ORU]2.0.CO;2.]. PMID- 21603512 TI - CME Upcoming Events. PMID- 21603514 TI - From the Editor's Desk. PMID- 21603515 TI - Effective glycemic management in hospitalized patients: a multidisciplinary approach. AB - The dual purpose of this process paper is to describe the implementation of an intensive insulin infusion program against multiple barriers, despite the increasing evidence in the literature supporting glycemic control, and to report the glucose outcomes. Traditional hyperglycemic management has been done either by subcutaneous sliding scale or intravenous insulin infusions based on absolute glucose numbers. A review of the literature, with particular evidence within the cardiothoracic surgical (CTS) population, has shown significant deleterious effects of even mild hyperglycemia.Increasing evidence supporting prevention of hyperglycemia, along with an unsatisfactory review of current methods used in house, prompted the initiation of a pilot program to improve current methods utilizing insulin therapy. A multidisciplinary committee was formed consisting of the director of the intensive care unit, a dietician, a nursing unit director, a charge nurse, an endocrinologist, and two endocrinology nurse practitioners with extensive experience in intensive insulin therapy, including continuous subcutaneous insulin infusion. A review of literature was performed to evaluate available data and intravenous insulin infusion algorithms used by published authors. The CTS population was chosen as well as the intensive care unit. Nursing barriers in particular were extensive, and the use of a velocity driven insulin protocol required didactic instruction as well as individual reinforcement. All education, algorithm development, and oversight of patients were primarily performed by the nurse practitioners with immediate endocrinologist availability if needed. A review of glucose results indicated a significant reduction in hyperglycemia with a decrease in hypoglycemia and facilitated transition to subcutaneous therapy when necessary. PMID- 21603516 TI - Inhibition of Erythroleukemia Cell Growth by Triplex-forming RNAs. AB - OBJECTIVE: We have previously reported that oligodeoxyribonucleotides, designed to bind in a triplex fashion to a specific p53 binding site homology, inhibit the proliferation of colon cancer cells in vitro and in vivo. The present study was designed to extend these observations and to determine whether ribonucleic acid (RNA) generated from a retroviral vector (RVV) and possessing a corresponding triplex forming site can, in a similar fashion, inhibit proliferation of p53-null K-562 leukemia cells. Viral vectors may offer advantages over oligonucleotides for tumor treatment. RVVs have the potential to be taken up more efficiently than oligonucleotides and to be expressed continuously and long-term, circumventing the need for repeated and frequent oligomer administration. EXPERIMENTAL DESIGN: The p53-null human erythroleukemia cell line, K-562, was stably transfected with a tetracycline-repressible p53 expression construct (p53/pUHD10-3). p53 protein in these cells is expressed in the absence of tetracycline but down-regulated upon tetracycline treatment. Triplex-forming oligonucleotides [Hoog 1 (experimental) and Hoog 3 (control)] were cloned into RVVs in order to generate triplex-forming fusion mRNAs. Naive K-562 cells and p53/pUHD10-3-transfected K 562 cells (with and without tetracycline treatment) were infected with viruses that express the triplex-forming RNAs. Cell growth was measured by BrdU incorporation into DNA. RESULTS: RVVs encoding Hoog 1, in both orientations, inhibit the growth of naive K-562 cells and p53-transfected, tet-repressed K-562 cells. p53 expression in K-562 cells decreases growth to the same extent as Hoog 1 RVV treatment. However, Hoog 1-RVV does not further inhibit growth of p53 expressing K-562 cells. Treatment with an RVV encoding the control, Hoog 3, has no growth inhibitory effect. CONCLUSION: Triple helix-forming RNAs directed to a p53 consensus sequence homology reduce leukemia cell proliferation, suggesting a novel method of treatment. PMID- 21603517 TI - Chicken sarcoma to human cancers: a lesson in molecular therapeutics. PMID- 21603518 TI - Osler's Pupil, Henry W. Ochsner, MD (1877-1902): His Life, Lineage, and Death. AB - In multiple editions of his Principles and Practice of Medicine, a 1904 speech, and his essay "A Student Life," Sir William Osler mentions and laments the death due to typhoid of his pupil, Henry W. Ochsner (1877-1902). Harvey Cushing, MD, in his biography of Osler, describes how deeply Osler was moved by "poor" Ochsner's death. Yet little is known about Ochsner. This article describes the life story, lineage, and death of Henry W. Ochsner, MD, a son of Swiss pioneers who settled in Waumandee, Wisconsin. He was a member of a family that includes medical luminaries (e.g., Albert J. Ochsner, MD, the famous Chicago surgeon, and Alton Ochsner, MD, the founder of the Ochsner Clinic); a brilliant student and physician; a humble and beloved fellow citizen; and a favorite pupil of Osler. PMID- 21603519 TI - Henry w. Ochsner, MD - the ochsner lineage in medicine. PMID- 21603520 TI - Research at ochsner clinic: highlights in its history. PMID- 21603521 TI - CME Credit Application Form/CME Questions Volume 7, No. 2. PMID- 21603522 TI - From the Editor's Desk. PMID- 21603523 TI - New guidelines for prevention of infective endocarditis. PMID- 21603525 TI - Postoperative readmissions following laparoscopic and abdominal hysterectomy: a comparison. AB - OBJECTIVE: To quantify the readmission rates for total laparoscopic and total abdominal hysterectomy, as well as identify preoperative, intraoperative, and postoperative risk factors for readmission within 6 weeks of surgery. METHODS: A retrospective comparative study was performed using a departmental database to identify all readmissions following total laparoscopic and total abdominal hysterectomy and to assemble a control group. For each patient, the following data were systematically collected: surgery date, age, parity, body mass index, indications for surgery, type of procedure performed, uterine size, number of prior cesarean sections, number of prior laparoscopic abdominal surgeries, number of prior open abdominal surgeries, presence of adhesions at time of hysterectomy, diabetic status, operative time, postoperative hematocrit, intraoperative and postoperative complications, surgeon, use of postoperative antibiotics, postoperative day readmitted, reason for readmission, length of readmission, and whether the patient returned to the operating room during the readmission. RESULTS: From January 1, 2000 to April 1, 2007, 1,576 total abdominal and 1,198 total laparoscopic hysterectomies were performed at Ochsner Medical Center. Of these, 19 abdominal and 31 laparoscopic hysterectomy patients were readmitted within 6 weeks of surgery. Our control groups consisted of 84 laparoscopic and 53 abdominal hysterectomy patients. A statistically significant difference in readmission rates (1.2% following abdominal hysterectomy vs. 2.7% following laparoscopic hysterectomy) was identified. No correlation between readmission and operative time, adhesive disease, diabetic status, prior cesarean sections, prior open or laparoscopic procedures, postoperative antibiotic use or postoperative hematocrit could be identified. Compared to those undergoing abdominal hysterectomy, those undergoing laparoscopic hysterectomy had more readmissions due to cuff dehiscence and cuff cellulitis for (p = 0.0146), which is a previously recognized complication of total laparoscopic hysterectomy. We were unable to identify any significant difference in postoperative day of readmission, length of readmission, or return to operating room. CONCLUSION: Further investigation would benefit from an expanded study group, which may result in identification of some significance of the studied factors that were not able to be identified in this study. PMID- 21603524 TI - Evaluation and management of gastrointestinal bleeding. AB - A logical, reasoned approach is essential to the successful management of gastrointestinal hemorrhage. This article describes the approach used by the staff of the Ochsner Clinic Foundation's Department of Colon and Rectal Surgery to evaluate and manage lower gastrointestinal hemorrhage, along with the evidence and experience that guided its development. Following resuscitation, diagnostic studies localize the presence and source of hemorrhage, while management options (non-operative and operative) control the bleeding. PMID- 21603526 TI - Effect of breast core needle biopsy technique on detection of lobular intraepithelial neoplasia. AB - OBJECTIVE: Lobular intraepithelial neoplasia-atypical lobular hyperplasia and lobular carcinoma in situ-is a noninvasive breast lesion occasionally found in core needle biopsy and surgical biopsy specimens. The objective of this study is to identify the increased incidence of lobular carcinoma in situ with current stereotactic biopsy techniques. METHODS: Biopsy results from 1993 to 2004 were reviewed retrospectively. 2,940 stereotactic biopsies were performed using a 14 gauge gun-type needle; 1,807 stereotactic biopsies were performed using an 11 gauge vacuum-assisted needle; and 2,724 ultrasound-guided biopsies were performed using a 14-gauge gun-type needle. RESULTS: The incidence of lobular intraepithelial neoplasia was 0.4% using the stereotactic 14-gauge technique, 0.4% using the ultrasound-guided 14-gauge technique, and 1.7% using the 11-gauge stereotactic technique. The increased rate of detection of lobular carcinoma in situ with an 11-gauge needle was statistically significant (p<.0001). CONCLUSION: Lobular intraepithelial neoplasia is believed to be an incidental finding without specific imaging or clinical characteristics. Patients with detected lobular intraepithelial neoplasia have a significantly increased risk for subsequently developing breast cancer. Management recommendations can include no treatment, local excision, chemoprevention, and even bilateral prophylactic mastectomy. Radiologists and referring physicians need to be aware of the wide-ranging treatment recommendations, as lobular intraepithelial neoplasia is being identified more frequently. PMID- 21603527 TI - Calcium multimineral complex induced esophageal stricture. AB - Pill-induced esophageal injury remains an under-recognized event despite its potentially devastating consequences. Most cases are due to nonsteroidal anti inflammatory drugs, antibiotics, or bisphosphonates, and symptoms usually resolve upon discontinuation of the medication. Reported herein is the case of an elderly woman who experienced prolonged impaction of a calcium tablet in the upper esophagus. She reported breaking the nonprescription pill in half prior to ingestion due to its large size. Subsequently, a severe esophageal stricture developed. We are unaware of any previous cases of esophageal stricture due to an impacted tablet containing primarily calcium, among other minerals. This is relevant, as patients are being advised by both their physicians and the lay press to increase calcium intake. It also highlights the importance of proper instruction and cautions for taking both prescription and over-the-counter preparations. Management of patients with suspected pill impaction is discussed. PMID- 21603528 TI - Guess the case. PMID- 21603529 TI - Guess the case from the ochsner archives. PMID- 21603531 TI - Reflections on three decades at ochsner: lecture delivered at the house staff commencement ceremony at the ochsner clinic foundation, june 13, 2007. PMID- 21603532 TI - Ochsner in Literature-nonfiction. AB - The Ochsner institutions and their physicians have figured in nonmedical works of nonfiction. A listing of these, with a description of each work, is provided. PMID- 21603533 TI - Cme Upcoming EventsCme Program Credit Information. PMID- 21603530 TI - Isolation of endothelial cells and vascular smooth muscle cells from internal mammary artery tissue. AB - Analyses of vascular smooth muscle cell and endothelial cell function through tissue culture techniques are often employed to investigate the underlying mechanisms regulating cardiovascular disease. As diseases such as diabetes mellitus and chronic kidney disease increase a patient's risk of cardiovascular disease, the development of methods for examining the effects of these diseases on vascular smooth muscle cells and endothelial cells is needed. Commercial sources of endothelial cells and vascular smooth muscle cells generally provide minimal donor information and are in limited supply. This study was designed to determine if vascular smooth muscle cells and endothelial cells could be isolated from human internal mammary arteries obtained from donors undergoing coronary artery bypass graft surgery. As coronary artery bypass graft surgery is a commonly performed procedure, this method would provide a new source for these cells that when combined with the donor's medical history will greatly enhance our studies of the effects of complicating diseases on vascular biology. Internal mammary artery tissue was obtained from patients undergoing coronary artery bypass graft surgery. Through a simple method employing two separate tissue digestions, vascular smooth muscle cells and endothelial cells were isolated and characterized. The isolated vascular smooth muscle cells and endothelial cells exhibited the expected morphology and were able to be passaged for further analysis. The vascular smooth muscle cells exhibited positive staining for alpha smooth muscle actin and the endothelial cells exhibited positive staining for CD31. The overall purity of the isolations was > 95%. This method allows for the isolation of endothelial cells and vascular smooth muscle cells from internal mammary arteries, providing a new tool for investigations into the interplay of vascular diseases and complicating diseases such as diabetes and kidney disease. PMID- 21603534 TI - Cme credit application form. PMID- 21603535 TI - CME QUESTIONS VOLUME 7, No. 4. PMID- 21603536 TI - From The Editor's Desk. PMID- 21603537 TI - Making exercise and fitness a high priority. PMID- 21603538 TI - Quality of care indicators, health behaviors, and physical functioning in adults with diabetes. AB - PURPOSE: Physical functioning is an important and often neglected outcome in patients with diabetes. Identification of quality of care indicators and health behaviors associated with higher physical functioning may lead to improved care and outcomes for adult diabetic patients. METHODS: We studied 3,521 adult persons with diabetes mellitus from 13 geographically dispersed, multi-specialty group practices in a cross-sectional survey. The outcome variable was the 10-item physical functioning scale. Independent variables included demographics, health behaviors, diabetes management, use of services, health status, risk for depression, comorbidities, and testing for albuminuria, glycosylated hemoglobin, and low-density lipoprotein. From these data, 10 quality-of-care indicators were constructed. We evaluated relationships between physical functioning and the quality of care indicators. RESULTS: Participants had a mean age of 64.2 +/- 12.6 years, and 52% were female, 67% married, 78% had a high school education or higher, and 73% were white. Multivariate analyses revealed several factors independently associated with higher physical functioning score on the 10-item scale (each p < 0.05, R(2) = 0.54): recent test for albuminuria or low-density lipoprotein lipids; no hospitalization or emergency admission in the prior year; being married; younger age; male gender; African American or Asian race; higher formal education; regular physical exercise; fewer comorbidities; better perceived health; not at risk for depression; not more limited in activities and health not worse compared to a year ago; nonsmoker; not being obese; and not taking insulin. CONCLUSIONS: We identified quality of care and health behaviors associated with higher physical functioning in adult patients with diabetes mellitus. Interventions to enhance the modifiable risk factors may lead to improved physical functioning and delay the onset of disability in these patients. PMID- 21603540 TI - Does dilation and curettage affect future pregnancy outcomes? AB - OBJECTIVE: The purpose of this study was to determine if dilation and curettage has an effect on future pregnancy outcome. METHODS: Retrospective review of the electronic medical records of all patients who underwent D&C between January 1, 2002, and December 31, 2006, was performed. Patients who had one or more subsequent pregnancies were selected and evaluated for pregnancy outcome. Frequency and incidence of subsequent pregnancy complications were determined by Chi square and Fisher's exact tests and compared to reported statistics. RESULTS: The incidence of postpartum hemorrhage was significantly higher than previously reported averages (p < 0.0004). We found no difference in the incidence of preterm delivery, preeclampsia, placental abruption, malpresentation, cervical incompetence, first trimester bleeding, and miscarriage when compared with previously reported data. Pregnancy outcomes among patients with a history of cervical dilation and those without were not significantly different. CONCLUSION: The current study suggests that dilation and curettage may predispose to postpartum hemorrhage. It is important to consider the effects of surgical management for miscarriage on future pregnancy outcomes. PMID- 21603539 TI - Psychological factors and cardiac risk and impact of exercise training programs-a review of ochsner studies. AB - Although under-emphasized, substantial evidence indicates that psychological distress, especially depression, hostility, and anxiety, are risk factors for coronary heart disease (CHD) and affect recovery following major coronary heart disease events. We review several major studies from Ochsner Medical Center demonstrating the high prevalence of psychological distress in CHD patients and the marked benefits that occur following formal cardiac rehabilitation and exercise training programs. These benefits include reductions in psychological stress, improvements in CHD risk factors that accompany high stress, and reduced all-cause mortality. These data support the benefits of exercise training and increased levels of fitness to improve psychological stress and subsequent prognosis. PMID- 21603541 TI - Resiliency building program for children. PMID- 21603542 TI - Survival of a Newborn with 2:1 Atrioventricular Block, Long QT Syndrome, and Torsades de Pointes. AB - Long QT syndrome is a rare disorder that can manifest as syncope, Torsades de Pointes, or sudden cardiac death. We report a newborn with asymptomatic bradycardia, 2:1 atrioventricular block, long QT syndrome, and episodes of Torsades de Pointes. The patient was managed with mexiletine and propranolol and continued to have episodes of Torsades de Pointes, so she underwent epicardial pacemaker implantation. No further episodes of Torsades de Pointes were noted prior to discharge. PMID- 21603543 TI - Guess the case from the ochsner clinic. PMID- 21603544 TI - Education update. PMID- 21603545 TI - Recently published works. PMID- 21603546 TI - Cme upcoming events/program credit information. PMID- 21603547 TI - From the Editor's Desk. PMID- 21603548 TI - Colorectal cancer. PMID- 21603549 TI - Myeloma therapy-a new paradigm. PMID- 21603550 TI - Coronary circulation in hypertension and aging: an experimental study. AB - Purpose. This study was undertaken to examine adverse changes in coronary hemodynamics associated with hypertension, aging, and excessive salt intake. To dissociate from the possible effects of atherosclerosis, the study was done in rats because they do not develop atherosclerosis. Moreover, this strain of spontaneously hypertensive rats (SHR) develops hypertension similar to essential hypertension in man.Methods. Systemic and coronary hemodynamics, left ventricular mass, and collagen content in normotensive and SHR of various ages and given different treatments were determined.Results. Compared with normotensive Wistar Kyoto rats, coronary blood flow reserve was lower and minimal coronary vascular resistance was higher in SHR of all ages; an age-related decrease in flow reserve and an increase in minimal vascular resistance were observed for both strains of rats. In very old rats with isolated systolic hypertension, an increase in left ventricular collagen was associated with coronary insufficiency; antihypertensive therapy nearly normalized both measures. In SHR excessive salt intake increased pressure, increased collagen deposition in myocardial interstitium and perivascularly, and impaired coronary circulation; angiotensin II receptor blocker therapy prevented fibrosis and improved coronary hemodynamics.Conclusion. In conclusion, these data indicate that considerable coronary insufficiency associated with hypertension, aging, and salt overload exists in the absence of atherosclerotic coronary changes. Perivascular fibrosis within myocardium may significantly contribute to the coronary vascular impairment. PMID- 21603551 TI - Impact of left ventricular geometry on prognosis-a review of ochsner studies. AB - We review data from epidemiologic and population-based studies that demonstrate the impact of abnormal left ventricular geometric patterns, including both concentric remodeling and left ventricular hypertrophy, on major cardiovascular morbidity and mortality. We also review studies from Ochsner Clinic Foundation that assessed the impact of various left ventricular geometric patterns on overall cardiovascular prognosis, especially all-cause mortality. PMID- 21603552 TI - New options for the treatment of fecal incontinence. AB - Fecal incontinence, the loss of anal sphincter control leading to the unwanted release of stool or gas, is a physical and psychological handicap that has a tremendous impact on an individual's quality of life. Although medical management is the mainstay of therapy for fecal incontinence, the main focus in this review is on invasive techniques with a goal of highlighting newer technologic and therapeutic advancements. While the standard surgical treatment for fecal incontinence still remains direct sphincter repair with an overlapping sphincteroplasty, this review concentrates specifically on biofeedback, the Procon incontinence device, local injection of synthetic materials, radio frequency energy (Secca procedure), antegrade colonic enemas, sphincteroplasty, gluteoplasty, graciloplasty both stimulated and non-stimulated, the artificial bowel sphincter, and sacral nerve stimulation. PMID- 21603553 TI - Evaluation and management of constipation. AB - Constipation is a common clinical problem. The evaluation and management of most patients are within the capability of interested, well-trained primary care physicians. The diagnostic evaluation includes an adequate history to exclude treatable etiologies, anatomic evaluation of the colon, and functional studies in refractory patients. Treatment options include medication adjustment and associated disease treatment, followed by a trial of daily fiber or laxatives. Appropriate patients should be referred for consideration of surgical treatment, which usually involves a colectomy and ileoproctostomy for colonic inertia. PMID- 21603555 TI - PEDF Promotes Biosynthesis of a Novel Anti-inflammatory and Anti-apoptotic Mediator NPD1 in Retinal Pigment Epithelial Cells. AB - PURPOSE: Neuroprotectin D1 is a stereospecific cytoprotective messenger synthesized from docosahexaenoic acid in retinal pigment epithelial cells challenged by oxidative stress. A key step in neuroprotectin D1 synthesis is to define how growth factors may modulate its formation and its bioavailability. Here we have explored the action of pigment epithelium derived factor, a neurotrophin made in retinal pigment epithelial cells, on neuroprotectin D1. METHODS: ARPE-19 cells were serum starved and exposed to TNFalpha/H(2)O(2) in the presence and absence of pigment epithelium derived factor (10 mg/mL). Cells and incubation media were collected. LC-PDA-MS-MS-based lipidomic analysis was used to identify and quantitate neuroprotectin D1. Immunostaining for BCLxL was performed. RESULTS: Oxidative stress promotes increases in neuroprotectin D1 levels in ARPE-19 cells, showing a rapid increase up to 6 hrs of incubation of 12 folds measured on cell pellets. Cell media, on the other hand, show time dependent accumulation of neuroprotectin D1 up to 55-fold after 12 hrs incubation. Treatment with 50 nM pigment epithelium derived factor increased such profile by at least two fold. Deuterated docosahexaenoic acid was incorporated to cell membranes and converted into neuroprotectin D1. After cells are exposed to oxidative stress, BCLxL appears to shift to the nucleus of the cell. With the addition of pigment epithelium derived factor and docosahexaenoic acid, this translocation seems to be prevented. CONCLUSIONS: Here we demonstrate that pigment epithelium derived factor is an activator of neuroprotectin D1 synthesis in ARPE-19 cells exposed to oxidative stress. A major action of pigment epithelium derived factor-stimulated neuroprotectin D1 synthesis shown here is retinal pigment epithelial cytoprotection. Since the retinal pigment epithelial cell is impaired in retinal degeneration, these novel mechanisms potentially may be targeted in macular degeneration and other retinal degenerative diseases as a new therapeutic avenue and may be applicable for neuroprotection in glaucoma and in other neurodegenerative diseases. PMID- 21603554 TI - Transfusion-Related Acute Lung Injury (TRALI): Report of 2 Cases and a Review of The Literature. AB - Transfusion of allogeneic blood products is given for correction of coagulation deficits and for the improvement in oxygen-carrying capacity or delivery. Blood transfusion has become safer following the advancement in blood testing using state-of-the-art viral assays; however, there continues to exist a variety of noninfectious transfusion risks that still remain and that cannot be entirely eliminated. Research is now directed towards understanding these lesser-known, but serious transfusion-related complications. This purpose of this review is to discuss a serious noninfectious cause of acute lung injury, transfusion-related acute lung injury (TRALI), which occurred in 2 recent cases in the intensive care unit, and to review the current literature of this syndrome. PMID- 21603556 TI - Ochsner research update. PMID- 21603558 TI - CME Upcoming Events. PMID- 21603557 TI - CME Questions Volume 8, No. 1. PMID- 21603559 TI - CME Credit Application Form. PMID- 21603560 TI - Evaluation of quantitative EEG by classification and regression trees to characterize responders to antidepressant and placebo treatment. AB - The study objective was to evaluate the usefulness of Classification and Regression Trees (CART), to classify clinical responders to antidepressant and placebo treatment, utilizing symptom severity and quantitative EEG (QEEG) data. Patients included 51 adults with unipolar depression who completed treatment trials using either fluoxetine, venlafaxine or placebo. Hamilton Depression Rating Scale (HAM-D) and single electrodes data were recorded at baseline, 2, 7, 14, 28 and 56 days. Patients were classified as medication and placebo responders or non-responders. CART analysis of HAM-D scores showed that patients with HAM-D scores lower than 13 by day 7 were more likely to be treatment responders to fluoxetine or venlafaxine compared to non-responders (p=0.001). Youden's index gamma revealed that CART models using QEEG measures were more accurate than HAM-D based models. For patients given fluoxetine, patients with a decrease at day 2 in theta cordance at AF2 were classified by CART as treatment responders (p=0.02). For those receiving venlafaxine, CART identified a decrease in delta absolute power at day 7 at the PO2 region as characterizing treatment responders (p=0.01). Using all patients receiving medication, CART identified a decrease in delta absolute power at day 2 in the FP1 region as characteristic of nonresponse to medication (p=0.003). Optimal trees from the QEEG CART analysis primarily utilized cordance values, but also incorporated some delta absolute power values. The results of our study suggest that CART may be a useful method for identifying potential outcome predictors in the treatment of major depression. PMID- 21603561 TI - Cardiovascular diseases in pregnancy. AB - BACKGROUND: Cardiovascular diseases arise during 0,2% to 4% of all pregnancies in the industrialized world. In Germany, this type of complication, which is sometimes lethal, affects approximately 30 000 pregnant women per year. METHODS: We performed a simple literature search in the NCBI databases for publications that appeared from 2008 to 2010 and that contained the search terms "pregnancy" and one of the following: "valvular disease," "endocarditis," "coronary heart disease," "cardiomyopathy," "hypertension," "anticoagulation." We also took consideration of the relevant international medical society guidelines and of the new database of the Pharmakovigilanz- und Beratungszentrum fur Embryonaltoxikologie in Berlin (Embryotox). RESULTS: There is a rising incidence, not only of hypertension during pregnancy, but also of valvular heart disease during pregnancy. Severe valvular stenosis, particularly mitral stenosis, raises the risk of pulmonary edema and should be treated before pregnancy, by valvuloplasty or surgically. Women with high-grade valvular insufficiency and restricted left-ventricular function are at risk of heart failure. For women with mechanical heart valves, the type of anticoagulation during pregnancy must be discussed on an individual basis. Coumarin derivatives are associated with an elevated risk of hemorrhage as well as coumarin embryopathy; recent studies have shown that the latter risk is low and dose-dependent. Spontaneous dissection of the coronary arteries is best treated by catheter intervention with the implantation of a bare metal stent. CONCLUSION: Women of child-bearing age who are at risk for, or already have, cardiovascular disease should receive early counseling and treatment, not just from their family physician, but from an interdisciplinary team composed of gynecologists, cardiologists, and, if necessary, cardiac surgeons. PMID- 21603563 TI - Correspondence (letter to the editor): Easily done without triage models. PMID- 21603562 TI - Image-guided radiotherapy: a new dimension in radiation oncology. AB - BACKGROUND: The vital importance of imaging techniques in radiation oncology now extends beyond diagnostic evaluation and treatment planning. Recent technical advances have enabled the integration of various imaging modalities into the everyday practice of radiotherapy directly at the linear accelerator, improving the management of inter- and intrafractional variations. METHODS: We present the topic of image-guided radiotherapy (IGRT) on the basis of a selective review of the literature. RESULTS: IGRT can be performed with the aid of ultrasound, 2D X ray devices, and computed tomography. It enables instant correction for positioning deviations and thereby improves the precision of daily radiotherapy fractions. It also enables immediate adjustment for changes in the position and filling status of the internal organs. Anatomical changes that take place over the course of radiotherapy, such as weight loss, tumor shrinkage, and the opening of atelectases, can be detected as they occur and accounted for in dosimetric calculations. There have not yet been any randomized controlled trials showing that IGRT causes fewer adverse effects or improves tumor control compared to conventional radiotherapy. CONCLUSION: IGRT is more precise and thus potentially safer than conventional radiotherapy. It also enables the application of special radiotherapeutic techniques with narrow safety margins in the vicinity of radiosensitive organs. Proper patient selection for IGRT must take account of the goals of treatment and the planning characteristics, as well as the available technical and human resources. IGRT should be used for steep dose gradients near organs at risk, for highly conformal dose distributions in the gastrointestinal tract where adjustment for filling variations is needed, for high-precision dose escalation to avoid geographic miss, and for patients who cannot lie perfectly still because of pain or claustrophobia. PMID- 21603564 TI - Correspondence (letter to the editor): Lack of resources. PMID- 21603566 TI - Correspondence (letter to the editor): No system should be preferred. PMID- 21603568 TI - Correspondence (letter to the editor): Comment on the positive predictive value. PMID- 21603569 TI - Space use of bumblebees (Bombus spp.) revealed by radio-tracking. AB - BACKGROUND: Accurate estimates of movement behavior and distances travelled by animals are difficult to obtain, especially for small-bodied insects where transmitter weights have prevented the use of radio-tracking. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report the first successful use of micro radio telemetry to track flight distances and space use of bumblebees. Using ground surveys and Cessna overflights in a Central European rural landscape mosaic we obtained maximum flight distances of 2.5 km, 1.9 km and 1.3 km for Bombus terrestris (workers), Bombus ruderatus (worker), and Bombus hortorum (young queens), respectively. Bumblebee individuals used large areas (0.25-43.53 ha) within one or a few days. Habitat analyses of one B. hortorum queen at the landscape scale indicated that gardens within villages were used more often than expected from habitat availability. Detailed movement trajectories of this individual revealed that prominent landscape structures (e.g. trees) and flower patches were repeatedly visited. However, we also observed long (i.e. >45 min) resting periods between flights (B. hortorum) and differences in flower-handling between bumblebees with and without transmitters (B. terrestris) suggesting that the current weight of transmitters (200 mg) may still impose significant energetic costs on the insects. CONCLUSIONS/SIGNIFICANCE: Spatio-temporal movements of bumblebees can now be tracked with telemetry methods. Our measured flight distances exceed many previous estimates of bumblebee foraging ranges and suggest that travelling long distances to food resources may be common. However, even the smallest currently available transmitters still appear to compromise flower handling performance and cause an increase in resting behavior of bees. Future reductions of transmitter mass and size could open up new avenues for quantifying landscape-scale space use of insect pollinators and could provide novel insights into the behavior and requirements of bumblebees during critical life stages, e.g. when searching for mates, nest locations or hibernation sites. PMID- 21603570 TI - Effects of the distribution of female primates on the number of males. AB - The spatiotemporal distribution of females is thought to drive variation in mating systems, and hence plays a central role in understanding animal behavior, ecology and evolution. Previous research has focused on investigating the links between female spatiotemporal distribution and the number of males in haplorhine primates. However, important questions remain concerning the importance of spatial cohesion, the generality of the pattern across haplorhine and strepsirrhine primates, and the consistency of previous findings given phylogenetic uncertainty. To address these issues, we examined how the spatiotemporal distribution of females influences the number of males in primate groups using an expanded comparative dataset and recent advances in bayesian phylogenetic and statistical methods. Specifically, we investigated the effect of female distributional factors (female number, spatial cohesion, estrous synchrony, breeding season duration and breeding seasonality) on the number of males in primate groups. Using bayesian approaches to control for uncertainty in phylogeny and the model of trait evolution, we found that the number of females exerted a strong influence on the number of males in primate groups. In a multiple regression model that controlled for female number, we found support for temporal effects, particularly involving female estrous synchrony: the number of males increases when females are more synchronously receptive. Similarly, the number of males increases in species with shorter birth seasons, suggesting that greater breeding seasonality makes defense of females more difficult for male primates. When comparing primate suborders, we found only weak evidence for differences in traits between haplorhines and strepsirrhines, and including suborder in the statistical models did not affect our conclusions or give compelling evidence for different effects in haplorhines and strepsirrhines. Collectively, these results demonstrate that male monopolization is driven primarily by the number of females in groups, and secondarily by synchrony of female reproduction within groups. PMID- 21603571 TI - Area 5 influences excitability within the primary motor cortex in humans. AB - In non-human primates, Brodmann's area 5 (BA 5) has direct connectivity with primary motor cortex (M1), is largely dedicated to the representation of the hand and may have evolved with the ability to perform skilled hand movement. Less is known about human BA 5 and its interaction with M1 neural circuits related to hand control. The present study examines the influence of BA 5 on excitatory and inhibitory neural circuitry within M1 bilaterally before and after continuous (cTBS), intermittent (iTBS), and sham theta-burst stimulation (sham TBS) over left hemisphere BA 5. Using single and paired-pulse TMS, measurements of motor evoked potentials (MEPs), short interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were quantified for the representation of the first dorsal interosseous muscle. Results indicate that cTBS over BA 5 influences M1 excitability such that MEP amplitudes are increased bilaterally for up to one hour. ITBS over BA 5 results in an increase in MEP amplitude contralateral to stimulation with a delayed onset that persists up to one hour. SICI and ICF were unaltered following TBS over BA 5. Similarly, F-wave amplitude and latency were unaltered following cTBS over BA 5. The data suggest that BA 5 alters M1 output directed to the hand by influencing corticospinal neurons and not interneurons that mediate SICI or ICF circuitry. Targeting BA 5 via cTBS and iTBS is a novel mechanism to powerfully modulate activity within M1 and may provide an avenue for investigating hand control in healthy populations and modifying impaired hand function in clinical populations. PMID- 21603572 TI - Rapid and highly efficient generation of induced pluripotent stem cells from human umbilical vein endothelial cells. AB - The ability to induce somatic cells to pluripotency by ectopic expression of defined transcription factors (e.g. KLF-4, OCT4, SOX2, c-MYC, or KOSM) has transformed the future of regenerative medicine. Here we report somatic cell reprogramming of human umbilical vein endothelial cells (HUVECs), yielding induced pluripotent stem (iPS) cells with the fastest kinetics, and one of the highest reprogramming efficiencies for a human somatic cell to date. HUVEC derived iPS (Huv-iPS) cell colonies appeared as early as 6 days after a single KOSM infection, and were generated with a 2.5-3% reprogramming efficiency. Furthermore, when HUVEC reprogramming was performed under hypoxic conditions in the presence of a TGF-beta family signaling inhibitor, colony formation increased an additional ~2.5-fold over standard conditions. Huv-iPS cells were indistinguishable from human embryonic stem (ES) cells with regards to morphology, pluripotent marker expression, and their ability to generate all embryonic germ layers in vitro and in vivo. The high efficiency and rapid kinetics of Huv-iPS cell formation, coupled with the ease by which HUVECs can be collected, expanded and stored, make these cells an attractive somatic source for therapeutic application, and for studying the reprogramming process. PMID- 21603573 TI - Differential requirement for utrophin in the induced pluripotent stem cell correction of muscle versus fat in muscular dystrophy mice. AB - Duchenne muscular dystrophy (DMD) is an incurable degenerative muscle disorder. We injected WT mouse induced pluripotent stem cells (iPSCs) into mdx and mdx?utrophin mutant blastocysts, which are predisposed to develop DMD with an increasing degree of severity (mdx <<< mdx?utrophin). In mdx chimeras, iPSC dystrophin was supplied to the muscle sarcolemma to effect corrections at morphological and functional levels. Dystrobrevin was observed in dystrophin positive and, at a lesser extent, utrophin-positive areas. In the mdx?utrophin mutant chimeras, although iPSC-dystrophin was also supplied to the muscle sarcolemma, mice still displayed poor skeletal muscle histopathology, and negligible levels of dystrobrevin in dystrophin- and utrophin-negative areas. Not only dystrophin-expressing tissues are affected by iPSCs. Mdx and mdx?utrophin mice have reduced fat/body weight ratio, but iPSC injection normalized this parameter in both mdx and mdx?utrophin chimeras, despite the fact that utrophin was compromised in the mdx?utrophin chimeric fat. The results suggest that the presence of utrophin is required for the iPSC-corrections in skeletal muscle. Furthermore, the results highlight a potential (utrophin-independent) non-cell autonomous role for iPSC-dystrophin in the corrections of non-muscle tissue like fat, which is intimately related to the muscle. PMID- 21603575 TI - Metabolic profiling based quantitative evaluation of hepatocellular metabolism in presence of adipocyte derived extracellular matrix. AB - The elucidation of the effect of extracellular matrices on hepatocellular metabolism is critical to understand the mechanism of functional upregulation. We have developed a system using natural extracellular matrices [Adipogel] for enhanced albumin synthesis of rat hepatocyte cultures for a period of 10 days as compared to collagen sandwich cultures. Primary rat hepatocytes isolated from livers of female Lewis rats recover within 4 days of culture from isolation induced injury while function is stabilized at 7 days post-isolation. Thus, the culture period can be classified into three distinct stages viz. recovery stage [day 0-4], pre-stable stage [day 5-7] and the stable stage [day 8-10]. A Metabolic Flux Analysis of primary rat hepatocytes cultured in Adipogel was performed to identify the key metabolic pathways modulated as compared to collagen sandwich cultures. In the recovery stage [day 4], the collagen-soluble Adipogel cultures shows an increase in TriCarboxylic Acid [TCA] cycle fluxes; in the pre-stable stage [day 7], there is an increase in PPP and TCA cycle fluxes while in the stable stage [day 10], there is a significant increase in TCA cycle, urea cycle fluxes and amino acid uptake rates concomitant with increased albumin synthesis rate as compared to collagen sandwich cultures throughout the culture period. Metabolic analysis of the collagen-soluble Adipogel condition reveals significantly higher transamination reaction fluxes, amino acid uptake and albumin synthesis rates for the stable vs. recovery stages of culture. The identification of metabolic pathways modulated for hepatocyte cultures in presence of Adipogel will be a useful step to develop an optimization algorithm to further improve hepatocyte function for Bioartificial Liver Devices. The development of this framework for upregulating hepatocyte function in Bioartificial Liver Devices will facilitate the utilization of an integrated experimental and computational approach for broader applications of Adipogel in tissue e engineering and regenerative medicine. PMID- 21603574 TI - Potent host-directed small-molecule inhibitors of myxovirus RNA-dependent RNA polymerases. AB - Therapeutic targeting of host cell factors required for virus replication rather than of pathogen components opens new perspectives to counteract virus infections. Anticipated advantages of this approach include a heightened barrier against the development of viral resistance and a broadened pathogen target spectrum. Myxoviruses are predominantly associated with acute disease and thus are particularly attractive for this approach since treatment time can be kept limited. To identify inhibitor candidates, we have analyzed hit compounds that emerged from a large-scale high-throughput screen for their ability to block replication of members of both the orthomyxovirus and paramyxovirus families. This has returned a compound class with broad anti-viral activity including potent inhibition of different influenza virus and paramyxovirus strains. After hit-to-lead chemistry, inhibitory concentrations are in the nanomolar range in the context of immortalized cell lines and human PBMCs. The compound shows high metabolic stability when exposed to human S-9 hepatocyte subcellular fractions. Antiviral activity is host-cell species specific and most pronounced in cells of higher mammalian origin, supporting a host-cell target. While the compound induces a temporary cell cycle arrest, host mRNA and protein biosynthesis are largely unaffected and treated cells maintain full metabolic activity. Viral replication is blocked at a post-entry step and resembles the inhibition profile of a known inhibitor of viral RNA-dependent RNA-polymerase (RdRp) activity. Direct assessment of RdRp activity in the presence of the reagent reveals strong inhibition both in the context of viral infection and in reporter-based minireplicon assays. In toto, we have identified a compound class with broad viral target range that blocks host factors required for viral RdRp activity. Viral adaptation attempts did not induce resistance after prolonged exposure, in contrast to rapid adaptation to a pathogen-directed inhibitor of RdRp activity. PMID- 21603576 TI - New synthetic thrombin inhibitors: molecular design and experimental verification. AB - BACKGROUND: The development of new anticoagulants is an important goal for the improvement of thromboses treatments. OBJECTIVES: The design, synthesis and experimental testing of new safe and effective small molecule direct thrombin inhibitors for intravenous administration. METHODS: Computer-aided molecular design of new thrombin inhibitors was performed using our original docking program SOL, which is based on the genetic algorithm of global energy minimization in the framework of a Merck Molecular Force Field. This program takes into account the effects of solvent. The designed molecules with the best scoring functions (calculated binding energies) were synthesized and their thrombin inhibitory activity evaluated experimentally in vitro using a chromogenic substrate in a buffer system and using a thrombin generation test in isolated plasma and in vivo using the newly developed model of hemodilution induced hypercoagulation in rats. The acute toxicities of the most promising new thrombin inhibitors were evaluated in mice, and their stabilities in aqueous solutions were measured. RESULTS: New compounds that are both effective direct thrombin inhibitors (the best K(I) was <1 nM) and strong anticoagulants in plasma (an IC(50) in the thrombin generation assay of approximately 100 nM) were discovered. These compounds contain one of the following new residues as the basic fragment: isothiuronium, 4-aminopyridinium, or 2-aminothiazolinium. LD(50) values for the best new inhibitors ranged from 166.7 to >1111.1 mg/kg. A plasma substituting solution supplemented with one of the new inhibitors prevented hypercoagulation in the rat model of hemodilution-induced hypercoagulation. Activities of the best new inhibitors in physiological saline (1 uM solutions) were stable after sterilization by autoclaving, and the inhibitors remained stable at long-term storage over more than 1.5 years at room temperature and at 4 degrees C. CONCLUSIONS: The high efficacy, stability and low acute toxicity reveal that the inhibitors that were developed may be promising for potential medical applications. PMID- 21603577 TI - Dominant negative phenotype of Bacillus thuringiensis Cry1Ab, Cry11Aa and Cry4Ba mutants suggest hetero-oligomer formation among different Cry toxins. AB - BACKGROUND: Bacillus thuringiensis Cry toxins are used worldwide in the control of different insect pests important in agriculture or in human health. The Cry proteins are pore-forming toxins that affect the midgut cell of target insects. It was shown that non-toxic Cry1Ab helix alpha-4 mutants had a dominant negative (DN) phenotype inhibiting the toxicity of wildtype Cry1Ab when used in equimolar or sub-stoichiometric ratios (1?1, 0.5?1, mutant?wt) indicating that oligomer formation is a key step in toxicity of Cry toxins. METHODOLOGY/PRINCIPAL FINDINGS: The DN Cry1Ab-D136N/T143D mutant that is able to block toxicity of Cry1Ab toxin, was used to analyze its capacity to block the activity against Manduca sexta larvae of other Cry1 toxins, such as Cry1Aa, Cry1Ac, Cry1Ca, Cry1Da, Cry1Ea and Cry1Fa. Cry1Ab-DN mutant inhibited toxicity of Cry1Aa, Cry1Ac and Cry1Fa. In addition, we isolated mutants in helix alpha-4 of Cry4Ba and Cry11Aa, and demonstrate that Cry4Ba-E159K and Cry11Aa-V142D are inactive and completely block the toxicity against Aedes aegypti of both wildtype toxins, when used at sub-stoichiometric ratios, confirming a DN phenotype. As controls we analyzed Cry1Ab-R99A or Cry11Aa-E97A mutants that are located in helix alpha-3 and are affected in toxin oligomerization. These mutants do not show a DN phenotype but were able to block toxicity when used in 10?1 or 100?1 ratios (mutant?wt) probably by competition of binding with toxin receptors. CONCLUSIONS/SIGNIFICANCE: We show that DN phenotype can be observed among different Cry toxins suggesting that may interact in vivo forming hetero oligomers. The DN phenotype cannot be observed in mutants affected in oligomerization, suggesting that this step is important to inhibit toxicity of other toxins. PMID- 21603578 TI - Sex-dependent changes in social behaviors in motor pre-symptomatic R6/1 mice. AB - BACKGROUND: The R6/1 mouse line is one of the most widely employed models of Huntington Disease (HD), a complex syndrome characterized by motor and non-motor deficits. Surprisingly, its behavioral phenotype during the early phases of the pathology when the motor impairments are not manifest yet has been poorly investigated. It is also not clear whether the expression of HD-like symptoms at the pre-motor stage in this mouse model differs between the two sexes. METHODS: Male and female 12 weeks-old R6/1 mice and their wild-type littermates were tested on a battery of tests modeling some of the major neuropsychiatric non motor symptoms of HD: alterations in social interest, social interaction and communication, as well as disturbances in prepulse inhibition of the acoustic startle response (PPI) and circadian patterns of activity. The lack of motor symptoms was confirmed during the entire experimental period by means of the tail test for clasping. RESULTS: R6/1 mice displayed marked alterations in all social behaviors which were mainly observed in males. Male R6/1 animals were also the only ones showing reduced body weight. Both male and female transgenic mice displayed mild alterations in the circadian activity patterns, but no deficits in PPI. CONCLUSIONS: These results demonstrate the validity of the R6/1 mouse in mimicking selected neuropsychiatric symptoms of HD, the social deficits being the clearest markers of the pre-motor phase of the pathology. Furthermore, our data suggest that male R6/1 mice are more suitable for future studies on the early stages of HD. PMID- 21603580 TI - The genetic variation of RELN expression in schizophrenia and bipolar disorder. AB - Reelin plays an important role in the development and function of the brain and has been linked to different neuropsychiatric diseases. To further clarify the connection between reelin and psychiatric disorders, we studied the factors that influence the expression of reelin gene (RELN) and its different isoforms. We examined the total expression of RELN, allelic expression, and two alternative RELN isoforms in postmortem brain samples from patients with schizophrenia and bipolar disorder, as well as unaffected controls. We did not find a significant reduction in the total expression of RELN in schizophrenia or bipolar disorder. However, we did find a significant reduction of the proportion of the short RELN isoform, missing the C-terminal region in bipolar disorder, and imbalance in the allelic expression of RELN in schizophrenia. In addition, we tested the association between variation in RELN expression and rs7341475, an intronic SNP that was found to be associated with schizophrenia in women. We did not find an association between rs7341474 and the total expression of RELN either in women or in the entire sample. However, we observed a nominally significant effect of genotype-by-sex interaction on the variation in microexon skipping. Women with the risk genotype of rs7341475 (GG) had a higher proportion of microexon skipping, which is the isoform predominant in tissues outside the brain, while men had the opposite trend. Finally, we tested 83 SNPs in the gene region for association with expression variation of RELN, but none were significant. Our study further supports the connection between RELN dysfunction and psychiatric disorders, and provides a possible functional role for a schizophrenia associated SNP. Nevertheless, the positive associations observed in this study needs further replication as it may have implications for understanding the biological causes of schizophrenia and bipolar disorder. PMID- 21603579 TI - The spectrin cytoskeleton is crucial for adherent and invasive bacterial pathogenesis. AB - Various enteric bacterial pathogens target the host cell cytoskeletal machinery as a crucial event in their pathogenesis. Despite thorough studies detailing strategies microbes use to exploit these components of the host cell, the role of the spectrin-based cytoskeleton has been largely overlooked. Here we show that the spectrin cytoskeleton is a host system that is hijacked by adherent (Entropathogenic Escherichia coli [EPEC]), invasive triggering (Salmonella enterica serovar Typhimurium [S. Typhimurium]) and invasive zippering (Listeria monocytogenes) bacteria. We demonstrate that spectrin cytoskeletal proteins are recruited to EPEC pedestals, S. Typhimurium membrane ruffles and Salmonella containing vacuoles (SCVs), as well as sites of invasion and comet tail initiation by L. monocytogenes. Spectrin was often seen co-localizing with actin filaments at the cell periphery, however a disconnect between the actin and spectrin cytoskeletons was also observed. During infections with S. Typhimurium DeltasipA, actin-rich membrane ruffles at characteristic sites of bacterial invasion often occurred in the absence of spectrin cytoskeletal proteins. Additionally, early in the formation of L. monocytogenes comet tails, spectrin cytoskeletal elements were recruited to the surface of the internalized bacteria independent of actin filaments. Further studies revealed the presence of the spectrin cytoskeleton during SCV and Listeria comet tail formation, highlighting novel cytoplasmic roles for the spectrin cytoskeleton. SiRNA targeted against spectrin and the spectrin-associated proteins severely diminished EPEC pedestal formation as well as S. Typhimurium and L. monocytogenes invasion. Ultimately, these findings identify the spectrin cytoskeleton as a ubiquitous target of enteric bacterial pathogens and indicate that this cytoskeletal system is critical for these infections to progress. PMID- 21603581 TI - Genistein increases epidermal growth factor receptor signaling and promotes tumor progression in advanced human prostate cancer. AB - Genistein is an isoflavone found in soy, and its chemo-preventive and therapeutic effects have been well established from in vitro studies. Recently, however, its therapeutic actions in vivo have been questioned due to contradictory reports from animal studies, which rely on rodent models or implantation of cell lines into animals. To clarify in vivo effects of genistein in advanced prostate cancer patients, we developed a patient-derived prostate cancer xenograft model, in which a clinical prostatectomy sample was grafted into immune deficient mice. Our results showed an increased lymph node (LN) and secondary organ metastases in genistein-treated mice compared to untreated controls. Interestingly, invasive malignant cells aggregated to form islands/micrometastasis only in the secondary organs of the genistein-treated groups, not in the untreated control group. To understand the underlying mechanism for metastatic progression, we examined cell proliferation and apoptosis on paraffin-sections. Immunohistological data show that tumors of genistein-treated groups have more proliferating and fewer apoptotic cancer cells than those of the untreated group. Our immunoblotting data suggest that increased proliferation and metastasis are linked to enhanced activities of tyrosine kinases, EGFR and its downstream Src, in genistein-treated groups. Despite the chemopreventive effects proposed by earlier in vitro studies, the cancer promoting effect of genistein observed here suggests the need for careful selection of patients and safer planning of clinical trials. PMID- 21603584 TI - Law of Large Numbers: the Theory, Applications and Technology-based Education. AB - Modern approaches for technology-based blended education utilize a variety of recently developed novel pedagogical, computational and network resources. Such attempts employ technology to deliver integrated, dynamically-linked, interactive content and heterogeneous learning environments, which may improve student comprehension and information retention. In this paper, we describe one such innovative effort of using technological tools to expose students in probability and statistics courses to the theory, practice and usability of the Law of Large Numbers (LLN). We base our approach on integrating pedagogical instruments with the computational libraries developed by the Statistics Online Computational Resource (www.SOCR.ucla.edu). To achieve this merger we designed a new interactive Java applet and a corresponding demonstration activity that illustrate the concept and the applications of the LLN. The LLN applet and activity have common goals - to provide graphical representation of the LLN principle, build lasting student intuition and present the common misconceptions about the law of large numbers. Both the SOCR LLN applet and activity are freely available online to the community to test, validate and extend (Applet: http://socr.ucla.edu/htmls/exp/Coin_Toss_LLN_Experiment.html, and Activity: http://wiki.stat.ucla.edu/socr/index.php/SOCR_EduMaterials_Activities_LLN). PMID- 21603583 TI - A NEW RECOMBINANT ADENO-ASSOCIATED VIRUS (AAV)-BASED RANDOM PEPTIDE DISPLAY LIBRARY SYSTEM: INFECTION-DEFECTIVE AAV1.9-3 AS A NOVEL DETARGETED PLATFORM FOR VECTOR EVOLUTION. AB - Directed evolution through genetic engineering of viral capsids followed by selection has emerged as a powerful means to create novel recombinant adeno associated virus (rAAV) vectors with desired tropism and enhanced properties. One of the most effective approaches uses rAAV-based random peptide display libraries. Here we report a novel system based on an infection-defective rAAV1.9 3 as a platform for random peptide display, and show that biopanning of the libraries in vitro effectively identifies the peptides that restore and enhance rAAV transduction. rAAV1.9-3 has a genetically engineered AAV1 capsid with amino acids 445-568 being replaced with those of AAV9, and has been identified as a variant exhibiting significantly impaired infectivity and delayed blood clearance when infused into mice. In this study, we generated rAAV1.9-3 variant libraries in which 7- or 12-mer random peptides were expressed at the capsid amino acid position 590. Three rounds of positive selection for primary human dermal fibroblasts successfully identified new rAAV-peptide variants that transduce them more efficiently than the prototype rAAV2. Thus our study demonstrates that an infection-defective rAAV variant serves as a novel detargeted platform for random peptide display libraries. We also describe a brief review of recent progress in rAAV-based random peptide display library approaches. PMID- 21603585 TI - Mass Transfer in a Rigid Tube With Pulsatile Flow and Constant Wall Concentration. AB - An approximate-analytical solution method is presented for the problem of mass transfer in a rigid tube with pulsatile flow. For the case of constant wall concentration, it is shown that the generalized integral transform (GIT) method can be used to obtain a solution in terms of a perturbation expansion, where the coefficients of each term are given by a system of coupled ordinary differential equations. Truncating the system at some large value of the parameter N, an approximate solution for the system is obtained for the first term in the perturbation expansion, and the GIT-based solution is verified by comparison to a numerical solution. The GIT approximate-analytical solution indicates that for small to moderate nondimensional frequencies for any distance from the inlet of the tube, there is a positive peak in the bulk concentration C(1b) due to pulsation, thereby, producing a higher mass transfer mixing efficiency in the tube. As we further increase the frequency, the positive peak is followed by a negative peak in the time-averaged bulk concentration and then the bulk concentration C(1b) oscillates and dampens to zero. Initially, for small frequencies the relative Sherwood number is negative indicating that the effect of pulsation tends to reduce mass transfer. There is a band of frequencies, where the relative Sherwood number is positive indicating that the effect of pulsation tends to increase mass transfer. The positive peak in bulk concentration corresponds to a matching of the phase of the pulsatile velocity and the concentration, respectively, where the unique maximum of both occur for certain time in the cycle. The oscillatory component of concentration is also determined radially in the tube where the concentration develops first near the wall of the tube, and the lobes of the concentration curves increase with increasing distance downstream until the concentration becomes fully developed. The GIT method proves to be a working approach to solve the first two perturbation terms in the governing equations involved. PMID- 21603586 TI - Surface Estimation, Variable Selection, and the Nonparametric Oracle Property. AB - Variable selection for multivariate nonparametric regression is an important, yet challenging, problem due, in part, to the infinite dimensionality of the function space. An ideal selection procedure should be automatic, stable, easy to use, and have desirable asymptotic properties. In particular, we define a selection procedure to be nonparametric oracle (np-oracle) if it consistently selects the correct subset of predictors and at the same time estimates the smooth surface at the optimal nonparametric rate, as the sample size goes to infinity. In this paper, we propose a model selection procedure for nonparametric models, and explore the conditions under which the new method enjoys the aforementioned properties. Developed in the framework of smoothing spline ANOVA, our estimator is obtained via solving a regularization problem with a novel adaptive penalty on the sum of functional component norms. Theoretical properties of the new estimator are established. Additionally, numerous simulated and real examples further demonstrate that the new approach substantially outperforms other existing methods in the finite sample setting. PMID- 21603587 TI - Mass spectrometric analysis and mutagenesis predict involvement of multiple cysteines in redox regulation of the skeletal muscle ryanodine receptor ion channel complex. AB - The tetrameric skeletal muscle ryanodine receptor ion channel complex (RyR1) contains a large number of free cysteines that are potential targets for redox active molecules. Here, we report the mass spectrometric analysis of free thiols in RyR1 using the lipophilic, thiol-specific probe monobromobimane (MBB). In the presence of reduced glutathione, MBB labeled 14 cysteines per RyR1 subunit in tryptic peptides in five of five experiments. Forty-six additional MBB-labeled cysteines per RyR1 subunit were detected with lower frequency in tryptic peptides, bringing the total number of MBB-labeled cysteines to 60 per RyR1 subunit. A combination of fluorescence detection and mass spectrometry of RyR1, labeled in the presence of reduced and oxidized glutathione, identified two redox sensitive cysteines (C1040 and C1303). Regulation of RyR activity by reduced and oxidized glutathione was investigated in skeletal muscle mutant RyR1s in which 18 cysteines were substituted with serine or alanine, using a [(3)H]ryanodine ligand binding assay. Three single-site RyR1 mutants (C1781S, C2436S, and C2606S) and two multisite mutants with five and seven substituted cysteines exhibited a reduced redox response compared with wild-type RyR1. The results suggest that multiple cysteines determine the redox state and activity of RyR1. PMID- 21603588 TI - Synthesis and Characterization of Multilayered Diamond Coatings for Biomedical Implants. AB - With incredible hardness and excellent wear-resistance, nanocrystalline diamond (NCD) coatings are gaining interest in the biomedical community as articulating surfaces of structural implant devices. The focus of this study was to deposit multilayered diamond coatings of alternating NCD and microcrystalline diamond (MCD) layers on Ti-6Al-4V alloy surfaces using microwave plasma chemical vapor deposition (MPCVD) and validate the multilayer coating's effect on toughness and adhesion. Multilayer samples were designed with varying NCD to MCD thickness ratios and layer numbers. The surface morphology and structural characteristics of the coatings were studied with X-ray diffraction (XRD), Raman spectroscopy, and atomic force microscopy (AFM). Coating adhesion was assessed by Rockwell indentation and progressive load scratch adhesion tests. Multilayered coatings shown to exhibit the greatest adhesion, comparable to single-layered NCD coatings, were the multilayer samples having the lowest average grain sizes and the highest titanium carbide to diamond ratios. PMID- 21603590 TI - Ultrahigh dimensional feature selection: beyond the linear model. AB - Variable selection in high-dimensional space characterizes many contemporary problems in scientific discovery and decision making. Many frequently-used techniques are based on independence screening; examples include correlation ranking (Fan and Lv, 2008) or feature selection using a two-sample t-test in high dimensional classification (Tibshirani et al., 2003). Within the context of the linear model, Fan and Lv (2008) showed that this simple correlation ranking possesses a sure independence screening property under certain conditions and that its revision, called iteratively sure independent screening (ISIS), is needed when the features are marginally unrelated but jointly related to the response variable. In this paper, we extend ISIS, without explicit definition of residuals, to a general pseudo-likelihood framework, which includes generalized linear models as a special case. Even in the least-squares setting, the new method improves ISIS by allowing feature deletion in the iterative process. Our technique allows us to select important features in high-dimensional classification where the popularly used two-sample t-method fails. A new technique is introduced to reduce the false selection rate in the feature screening stage. Several simulated and two real data examples are presented to illustrate the methodology. PMID- 21603591 TI - Psychiatric Information Systems: An Analysis of Inpatient and Outpatient Unit Capabilities. AB - This paper describes how a sample of inpatient and out-patient psychiatric treatment units use technology to aid in patient care through scheduling, tracking, billing, and documenting clinical services. We conducted semi structured interviews (n = 68) at four inpatient and four outpatient psychiatric facilities in Oregon. Results indicate psychiatric facilities are assembling systems for managing information that include a combination of electronic linked clinical records, paper records, and unit-specific, unlinked databases. Barriers remain in (1) improving the sophistication of psychiatric information systems, (2) improving linkages of behavioral health with other medical information systems, and (3) increasing information technology support. PMID- 21603589 TI - Cancer stem cell radioresistance and enrichment: where frontline radiation therapy may fail in lung and esophageal cancers. AB - Many studies have highlighted the role cancer stem cells (CSC) play in the development and progression of various types of cancer including lung and esophageal cancer. More recently, it has been proposed that the presence of CSCs affects treatment efficacy and patient prognosis. In reviewing this new area of cancer biology, we will give an overview of the current literature regarding lung and esophageal CSCs and radioresistance of CSC, and discuss the potential therapeutic applications of these findings. PMID- 21603592 TI - Cytotoxic Effect of Arsenic Trioxide in Adenocarcinoma Colorectal Cancer (HT-29) Cells. AB - Arsenic is a heavy metal that exhibits a high degree of toxicity to various organ systems. In humans, this compound is associated with an increase risk of skin cancer, and may cause cancers of the lung, liver, bladder, kidney, and colon. The mechanism of arsenic-related carcinogenicity remains to be elucidated. Hence, the aim of the present study was to investigate the cytotoxic effects of arsenic trioxide (As(2)O(3)) on adenocarcinoma colorectal cancer (HT-29) cells using the MTT [3-(4,5 dimethylthiazoyl-2-yl)-2,5- diphenyltetrazolium bromide] assay for cell viability. To achieve this objective, HT-29 cells were cultured and exposed to various doses (0, 2, 4, 6, 8, 10, 12, and 14 MUg/ml) of arsenic trioxide for 24 h, 48 h, and 72 h respectively, and subsequently assessed for viability following a standard MTT test protocol. Experimental data indicated that arsenic trioxide is cytotoxic to colon cancer cells showing LD(50) values of 9.8, 9.4 and 9.0 MUg/ml upon 24, 48 and 72 h of exposure, respectively. There was a dose dependent response with regard to As(2)O(3) toxicity in HT-29 cells. Although there was a reduction in LD(50) value with increasing exposure time, this decrease was not statistically significant. PMID- 21603595 TI - Relating patenting and peer-review publications: an extended perspective on the vascular health and risk management literature. AB - PURPOSE: This investigation identifies patent applications published under the international Patent Convention Treaty between July 2010 and January 2011 in three significant fields of vascular risk management (arterial hypertension, atherosclerosis, and aneurysms) and investigates whether the inventors have also published peer reviewed papers directly describing their claimed invention. RESULTS: Out of only 48 patent documents that specifically addressed at least one of the above-mentioned fields, 15 had immediate companion papers of which 13 were published earlier than the corresponding patent applications; the majority of these papers were published by noncorporate patentees. Although the majority of patent applications (30 documents) had at least one corporate assignee, 18 came from academic environments. As expected, medical devices dominated in the aneurysm segment while pharmacology dominated hypertension and atherosclerosis. CONCLUSION: Although information related to hypertension, atherosclerosis, or aneurysms that was claimed in international patent applications reached the public quicker through the corresponding peer review document if one was published, more than two-thirds of the patent applications had no such companion paper in a scientific journal. The patent literature, which is freely available online as full text, offers information to scientists and developers in the fields of vascular risk management that is not available from the peer reviewed literature. PMID- 21603593 TI - The causes, consequences, and treatment of left or right heart failure. AB - Chronic heart failure (HF) is a cardiovascular disease of cardinal importance because of several factors: a) an increasing occurrence due to the aging of the population, primary and secondary prevention of cardiovascular events, and modern advances in therapy, b) a bad prognosis: around 65% of patients are dead within 5 years of diagnosis, c) a high economic cost: HF accounts for 1% to 2% of total health care expenditure. This review focuses on the main causes, consequences in terms of morbidity, mortality and costs and treatment of HF. PMID- 21603594 TI - Surgery in current therapy for infective endocarditis. AB - The introduction of the Duke criteria and transesophageal echocardiography has improved early recognition of infective endocarditis but patients are still at high risk for severe morbidity or death. Whether an exclusively antibiotic regimen is superior to surgical intervention is subject to ongoing debate. Current guidelines indicate when surgery is the preferred treatment, but decisions are often based on physician preferences. Surgery has shown to decrease the risk of short-term mortality in patients who present with specific symptoms or microorganisms; nevertheless even then it often remains unclear when surgery should be performed. In this review we i) systematically reviewed the current literature comparing medical to surgical therapy to evaluate if surgery is the preferred option, ii) performed a meta-analysis of studies reporting propensity matched analyses, and iii), briefly summarized the current indications for surgery. PMID- 21603596 TI - Vasodilatory effects of cinnamaldehyde and its mechanism of action in the rat aorta. AB - The vasodilatory effect of cinnamaldehyde was investigated for its mechanism of action using isolated rings of rat aorta. Cinnamaldehyde relaxed aortic rings precontracted with phenylephrine in a dose-dependent manner, was not affected by either the presence or removal of the endothelium. Pretreatment with NG-nitro-L arginine methyl ester and 1H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one could not block vasodilation by cinnamaldehyde, indicating that nitric oxide signaling is not involved. Potassium channel blockers, such as glibenclamide, tetraethylammonium, and BaCl2, had no effect on the relaxation produced by cinnamaldehyde. In addition, treatment with either indomethacin or propranolol did not affect cinnamaldehyde-induced vasodilatation. On the other hand, pretreatment of endothelium-denuded rings with cinnamaldehyde significantly inhibited vasoconstriction induced by endogenous vasoconstrictors, including angiotensin II, 5-hydroxytryptamine, dopamine, endothelin-1, and phenylephrine. In a Ca2+-free experimental setting, this natural vasodilator not only blocked Ca2+ influx-dependent vasoconstriction by either phenylephrine or KCl, but also inhibited phenylephrine-induced tonic contraction, which relies on intracellular Ca2+ release. This study shows that endothelium-independent, Ca2+ influx and/or an inhibitory release mechanism contributes to the vasodilatory effect of cinnamaldehyde. PMID- 21603597 TI - Cognitive evolution in hypertensive patients: a six-year follow-up. AB - BACKGROUND: Several studies have examined the links between hypertension, vascular damage, and cognitive impairment. The functions most commonly involved seem to be those associated with memory and executive function. AIMS: 1) to report the cognitive evolution in a cohort of hypertensive patients, 2) to identify the affected domains, and 3) to correlate the results obtained with blood pressure measurements. MATERIALS AND METHODS: Observational 6-year follow up cohort study including both males and females aged>=65 and <=80 years, and hypertensive patients under treatment. Patients with a history of any of the following conditions were excluded: stroke, transient ischemic attack, diabetes mellitus, atrial fibrillation, cardiac surgery, dementia, or depression. Four neurocognitive evaluations were performed (at baseline and every 2 years). The tests used evaluated memory and executive function domain. Blood pressure was measured on every cognitive evaluation. RESULTS: Sixty patients were followed for 76.4+/-2.8 months. The average age at baseline was 72.5+/-4.2 and 77.9+/-4.6 at 6 years (65% were women). Two patients were lost to follow up (3.3%) and 8 patients died (13.3%).The density incidence for dementia was 0.6% patients per year (pt/y) (n=3) and for depression was 1.6% pt/y (n=12). No changes were observed in either memory impairment or the Mini Mental State Examination (MMSE) results (p=ns) during follow-up. A progressive impairment of the executive function was shown regardless of the blood pressure measurements. CONCLUSION: 1) the incidence of dementia doubled to general population, 2) the initial memory impairment did not change during the evaluation period, 3) cognitive impairment worsened in the areas related to executive function (prefrontal cortex) regardless of the adequacy of anti-hypertensive treatment and blood pressure values. PMID- 21603598 TI - Families of FPGA-Based Accelerators for Approximate String Matching. AB - Dynamic programming for approximate string matching is a large family of different algorithms, which vary significantly in purpose, complexity, and hardware utilization. Many implementations have reported impressive speed-ups, but have typically been point solutions - highly specialized and addressing only one or a few of the many possible options. The problem to be solved is creating a hardware description that implements a broad range of behavioral options without losing efficiency due to feature bloat. We report a set of three component types that address different parts of the approximate string matching problem. This allows each application to choose the feature set required, then make maximum use of the FPGA fabric according to that application's specific resource requirements. Multiple, interchangeable implementations are available for each component type. We show that these methods allow the efficient generation of a large, if not complete, family of accelerators for this application. This flexibility was obtained while retaining high performance: We have evaluated a sample against serial reference codes and found speed-ups of from 150* to 400* over a high-end PC. PMID- 21603599 TI - Real-time monitoring of cisplatin-induced cell death. AB - Since the discovery of cisplatin more than 40 years ago and its clinical introduction in the 1970s an enormous amount of research has gone into elucidating the mechanism of action of cisplatin on tumor cells. With a novel cell biosensor chip system allowing continuous monitoring of respiration, glycolysis, and impedance we followed cisplatin treatment of different cancer cell lines in real-time. Our measurements reveal a first effect on respiration, in all cisplatin treated cell lines, followed with a significant delay by interference with glycolysis in HT-29, HCT-116, HepG2, and MCF-7 cells but not in the cisplatin-resistant cell line MDA-MB-231. Most strikingly, cell death started in all cisplatin-sensitive cell lines within 8 to 11 h of treatment, indicating a clear time frame from exposure, first response to cisplatin lesions, to cell fate decision. The time points of most significant changes were selected for more detailed analysis of cisplatin response in the breast cancer cell line MCF-7. Phosphorylation of selected signal transduction mediators connected with cellular proliferation, as well as changes in gene expression, were analyzed in samples obtained directly from sensor chips at the time points when changes in glycolysis and impedance occurred. Our online cell biosensor measurements reveal for the first time the time scale of metabolic response until onset of cell death under cisplatin treatment, which is in good agreement with models of p53-mediated cell fate decision. PMID- 21603600 TI - Platelets alter gene expression profile in human brain endothelial cells in an in vitro model of cerebral malaria. AB - Platelet adhesion to the brain microvasculature has been associated with cerebral malaria (CM) in humans, suggesting that platelets play a role in the pathogenesis of this syndrome. In vitro co-cultures have shown that platelets can act as a bridge between Plasmodium falciparum-infected red blood cells (pRBC) and human brain microvascular endothelial cells (HBEC) and potentiate HBEC apoptosis. Using cDNA microarray technology, we analyzed transcriptional changes of HBEC in response to platelets in the presence or the absence of tumor necrosis factor (TNF) and pRBC, which have been reported to alter gene expression in endothelial cells. Using a rigorous statistical approach with multiple test corrections, we showed a significant effect of platelets on gene expression in HBEC. We also detected a strong effect of TNF, whereas there was no transcriptional change induced specifically by pRBC. Nevertheless, a global ANOVA and a two-way ANOVA suggested that pRBC acted in interaction with platelets and TNF to alter gene expression in HBEC. The expression of selected genes was validated by RT-qPCR. The analysis of gene functional annotation indicated that platelets induce the expression of genes involved in inflammation and apoptosis, such as genes involved in chemokine-, TREM1-, cytokine-, IL10-, TGFbeta-, death-receptor-, and apoptosis-signaling. Overall, our results support the hypothesis that platelets play a pathogenic role in CM. PMID- 21603601 TI - Structure-function analysis of STRUBBELIG, an Arabidopsis atypical receptor-like kinase involved in tissue morphogenesis. AB - Tissue morphogenesis in plants requires the coordination of cellular behavior across clonally distinct histogenic layers. The underlying signaling mechanisms are presently being unraveled and are known to include the cell surface leucine rich repeat receptor-like kinase STRUBBELIG in Arabidopsis. To understand better its mode of action an extensive structure-function analysis of STRUBBELIG was performed. The phenotypes of 20 EMS and T-DNA-induced strubbelig alleles were assessed and homology modeling was applied to rationalize their possible effects on STRUBBELIG protein structure. The analysis was complemented by phenotypic, cell biological, and pharmacological investigations of a strubbelig null allele carrying genomic rescue constructs encoding fusions between various mutated STRUBBELIG proteins and GFP. The results indicate that STRUBBELIG accepts quite some sequence variation, reveal the biological importance for the STRUBBELIG N capping domain, and reinforce the notion that kinase activity is not essential for its function in vivo. Furthermore, individual protein domains of STRUBBELIG cannot be related to specific STRUBBELIG-dependent biological processes suggesting that process specificity is mediated by factors acting together with or downstream of STRUBBELIG. In addition, the evidence indicates that biogenesis of a functional STRUBBELIG receptor is subject to endoplasmic reticulum-mediated quality control, and that an MG132-sensitive process regulates its stability. Finally, STRUBBELIG and the receptor-like kinase gene ERECTA interact synergistically in the control of internode length. The data provide genetic and molecular insight into how STRUBBELIG regulates intercellular communication in tissue morphogenesis. PMID- 21603602 TI - Capsular serotype and antibiotic resistance of Streptococcus pneumoniae isolates in Malaysia. AB - BACKGROUND: Streptococcus pneumoniae is a major causative agent of severe infections, including sepsis, pneumonia, meningitis, and otitis media, that has since become a major public health concern. In this study, the serotypes distribution of pneumococcal isolates was investigated to predict the efficacy of the 7-valent pneumococcal conjugate vaccine (PCV7) among the Malaysian populations. METHODOLOGY/PRINCIPAL FINDINGS: A total of 151 clinical isolates were serotyped using multiplex PCR assays. Out of them, there were 21.2% penicillin-resistant, 29.1% penicillin-intermediate, and 49.7% penicillin susceptible S. pneumoniae strains. Serotypes detected among the Malaysian isolates were 1, 3, 10A, 11A/11D, 12F/12A, 14, 15A, 15B/15C, 16F, 18C/18B/18A/18F, 19A, 19F, 23F, 35B, 35F/47F, 6A/6B, 7C/7B/40, 7F/7A, 9V/9A, and 34. Serotype 19F and 23F were the two most prevalent serotypes detected. Serotypes are highly associated with invasiveness of isolates (p = 0.001) and penicillin susceptibility (p<0.001). Serotype 19F was observed to have increased resistance against penicillin while serotype 19A has high invasive tendency. Age of patients was an important factor underlying the pneumococcal serotypes (p = 0.03) and clinical sites of infections (p<0.001). High prevalence of pneumococcal isolates were detected among children <5 years old at nasopharyngeal sites while elderly adults >=60 years old were at increased risk for pneumococcal bacteremia. CONCLUSION/SIGNIFICANCE: Current study revealed that a number of serotypes, especially those associated with high penicillin resistance, have been formulated in the PCV7. Therefore, the protections expected from the routine use of PCV7 would be encouraging for the Malaysian. However, it is not possible to predict serotypes that might become predominant in the future and hence continued surveillance of circulating serotypes will be needed. PMID- 21603603 TI - The Rho-family GTPase Rac1 regulates integrin localization in Drosophila immunosurveillance cells. AB - BACKGROUND: When the parasitoid wasp Leptopilina boulardi lays an egg in a Drosophila larva, phagocytic cells called plasmatocytes and specialized cells known as lamellocytes encapsulate the egg. The Drosophila beta-integrin Myospheroid (Mys) is necessary for lamellocytes to adhere to the cellular capsule surrounding L. boulardi eggs. Integrins are heterodimeric adhesion receptors consisting of alpha and beta subunits, and similar to other plasma membrane receptors undergo ligand-dependent endocytosis. In mammalian cells it is known that integrin binding to the extracellular matrix induces the activation of Rac GTPases, and we have previously shown that Rac1 and Rac2 are necessary for a proper encapsulation response in Drosophila larvae. We wanted to test the possibility that Myospheroid and Rac GTPases interact during the Drosophila anti parasitoid immune response. RESULTS: In the current study we demonstrate that Rac1 is required for the proper localization of Myospheroid to the cell periphery of haemocytes after parasitization. Interestingly, the mislocalization of Myospheroid in Rac1 mutants is rescued by hyperthermia, involving the heat shock protein Hsp83. From these results we conclude that Rac1 and Hsp83 are required for the proper localization of Mys after parasitization. SIGNIFICANCE: We show for the first time that the small GTPase Rac1 is required for Mysopheroid localization. Interestingly, the necessity of Rac1 in Mys localization was negated by hyperthermia. This presents a problem, in Drosophila we quite often raise larvae at 29 degrees C when using the GAL4/UAS misexpression system. If hyperthermia rescues receptor endosomal recycling defects, raising larvae in hyperthermic conditions may mask potentially interesting phenotypes. PMID- 21603604 TI - Naturally occurring osmolyte, trehalose induces functional conformation in an intrinsically disordered activation domain of glucocorticoid receptor. AB - Intrinsically disordered (ID) regions are frequently found in the activation domains of many transcription factors including nuclear hormone receptors. It is believed that these ID regions promote molecular recognition by creating large surfaces suitable for interactions with their specific protein binding partners, which is a critical component of gene regulation by transcription factors. It has been hypothesized that conditional folding of these activation domains may be a prerequisite for their efficient interaction with specific coregulatory proteins, and subsequent transcriptional activity leading to the regulation of target gene(s). In this study, we tested whether a naturally occurring osmolyte, trehalose can promote functionally ordered conformation in glucocorticoid receptor's major activation function domain, AF1, which is found to exist as an ID protein, and requires an efficient interaction with coregulatory proteins for optimal activity. Our data show that trehalose induces an ordered conformation in AF1 such that its interaction with steroid receptor coactivator-1 (SRC-1), a critical coregulator of glucocorticoid receptor's activity, is greatly enhanced. PMID- 21603606 TI - M6 membrane protein plays an essential role in Drosophila oogenesis. AB - We had previously shown that the transmembrane glycoprotein M6a, a member of the proteolipid protein (PLP) family, regulates neurite/filopodium outgrowth, hence, M6a might be involved in neuronal remodeling and differentiation. In this work we focused on M6, the only PLP family member present in Drosophila, and ortholog to M6a. Unexpectedly, we found that decreased expression of M6 leads to female sterility. M6 is expressed in the membrane of the follicular epithelium in ovarioles throughout oogenesis. Phenotypes triggered by M6 downregulation in hypomorphic mutants included egg collapse and egg permeability, thus suggesting M6 involvement in eggshell biosynthesis. In addition, RNAi-mediated M6 knockdown targeted specifically to follicle cells induced an arrest of egg chamber development, revealing that M6 is essential in oogenesis. Interestingly, M6 associated phenotypes evidenced abnormal changes of the follicle cell shape and disrupted follicular epithelium in mid- and late-stage egg chambers. Therefore, we propose that M6 plays a role in follicular epithelium maintenance involving membrane cell remodeling during oogenesis in Drosophila. PMID- 21603605 TI - DNA damage during G2 phase does not affect cell cycle progression of the green alga Scenedesmus quadricauda. AB - DNA damage is a threat to genomic integrity in all living organisms. Plants and green algae are particularly susceptible to DNA damage especially that caused by UV light, due to their light dependency for photosynthesis. For survival of a plant, and other eukaryotic cells, it is essential for an organism to continuously check the integrity of its genetic material and, when damaged, to repair it immediately. Cells therefore utilize a DNA damage response pathway that is responsible for sensing, reacting to and repairing damaged DNA. We have studied the effect of 5-fluorodeoxyuridine, zeocin, caffeine and combinations of these on the cell cycle of the green alga Scenedesmus quadricauda. The cells delayed S phase and underwent a permanent G2 phase block if DNA metabolism was affected prior to S phase; the G2 phase block imposed by zeocin was partially abolished by caffeine. No cell cycle block was observed if the treatment with zeocin occurred in G2 phase and the cells divided normally. CDKA and CDKB kinases regulate mitosis in S. quadricauda; their kinase activities were inhibited by Wee1. CDKA, CDKB protein levels were stabilized in the presence of zeocin. In contrast, the protein level of Wee1 was unaffected by DNA perturbing treatments. Wee1 therefore does not appear to be involved in the DNA damage response in S. quadricauda. Our results imply a specific reaction to DNA damage in S. quadricauda, with no cell cycle arrest, after experiencing DNA damage during G2 phase. PMID- 21603607 TI - Parental death during childhood and adult cardiovascular risk in a developing country: the Guangzhou Biobank Cohort Study. AB - BACKGROUND: In observational studies from western countries childhood emotional adversity is usually associated with adult cardiovascular disease. These findings are open to contextual biases making evidence from other settings valuable. We examined the association of a potential marker of childhood emotional adversity with cardiovascular disease risk factors in a developing country. METHODS: We used multivariable regression in cross-sectional analysis of older (>=50 years) men (n = 7,885) and women (n = 20,886) from the Guangzhou Biobank Cohort Study (2003-8) to examine the adjusted association of early life (<18 years) parental death (none, one or two deaths) with blood pressure, fasting glucose, LDL cholesterol, HDL-cholesterol, triglycerides, body mass index (BMI), waist-hip ratio (WHR) and white blood cell count (WBC). We used seated height and delayed 10-word recall to assess content validity of parental death as a measure of childhood emotional adversity. We also examined whether associations varied by sex. RESULTS: Early life parental death was associated with shorter age- and sex adjusted seated height. It was also associated with lower 10-word recall score adjusted for age, sex, socio-economic position, leg length and lifestyle. Similarly, adjusted early life parental death was not associated with blood pressure, fasting glucose, LDL-cholesterol or HDL-cholesterol but was associated with lower BMI (-0.40, 95% confidence interval (CI) -0.62 to -0.19 for 2 compared with no early life parental deaths) and triglycerides. Associations varied by sex for WHR and WBC. Among men only, early life parental death was associated with lower WHR (-0.008, 95% CI -0.015 to -0.001) and WBC (-0.35 10(9)/L, 95% CI -0.56 to -0.13). CONCLUSIONS: In a non-western population from a developing country, childhood emotional adversity was negatively associated with some cardiovascular risk factors, particularly among men. Our study suggests that some of the observed associations in western populations may be socially rather than biologically based or may be population specific. PMID- 21603608 TI - How do honeybees attract nestmates using waggle dances in dark and noisy hives? AB - It is well known that honeybees share information related to food sources with nestmates using a dance language that is representative of symbolic communication among non-primates. Some honeybee species engage in visually apparent behavior, walking in a figure-eight pattern inside their dark hives. It has been suggested that sounds play an important role in this dance language, even though a variety of wing vibration sounds are produced by honeybee behaviors in hives. It has been shown that dances emit sounds primarily at about 250-300 Hz, which is in the same frequency range as honeybees' flight sounds. Thus the exact mechanism whereby honeybees attract nestmates using waggle dances in such a dark and noisy hive is as yet unclear. In this study, we used a flight simulator in which honeybees were attached to a torque meter in order to analyze the component of bees' orienting response caused only by sounds, and not by odor or by vibrations sensed by their legs. We showed using single sound localization that honeybees preferred sounds around 265 Hz. Furthermore, according to sound discrimination tests using sounds of the same frequency, honeybees preferred rhythmic sounds. Our results demonstrate that frequency and rhythmic components play a complementary role in localizing dance sounds. Dance sounds were presumably developed to share information in a dark and noisy environment. PMID- 21603609 TI - Inheritance of vertebral number in the three-spined stickleback (Gasterosteus aculeatus). AB - Intraspecific variation in the number of vertebrae is taxonomically widespread, and both genetic and environmental factors are known to contribute to this variation. However, the relative importance of genetic versus environmental influences on variation in vertebral number has seldom been investigated with study designs that minimize bias due to non-additive genetic and maternal influences. We used a paternal half-sib design and animal model analysis to estimate heritability and causal components of variance in vertebral number in three-spined sticklebacks (Gasterosteus aculeatus). We found that both the number of vertebrae (h(2) = 0.36) and body size (h(2) = 0.42) were moderately heritable, whereas the influence of maternal effects was estimated to be negligible. While the number of vertebrae had a positive effect on body size, no evidence for a genetic correlation between body size and vertebral number was detected. However, there was a significant positive environmental correlation between these two traits. Our results support the generalization--in accordance with results from a review of heritability estimates for vertebral number in fish, reptiles and mammals--that the number of vertebrae appears to be moderately to highly heritable in a wide array of species. In the case of the three-spined stickleback, independent evolution of body size and number of vertebrae should be possible given the low genetic correlation between the two traits. PMID- 21603610 TI - Identification of methylated genes associated with aggressive clinicopathological features in mantle cell lymphoma. AB - BACKGROUND: Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance. METHODOLOGY/PRINCIPAL FINDINGS: To identify potential methylated genes in MCL we initially investigated seven MCL cell lines treated with epigenetic drugs and gene expression microarray profiling. The methylation status of selected candidate genes was validated by a quantitative assay and subsequently analyzed in a series of primary MCL (n = 38). After pharmacological reversion we identified 252 potentially methylated genes. The methylation analysis of a subset of these genes (n = 25) in the MCL cell lines and normal B lymphocytes confirmed that 80% of them were methylated in the cell lines but not in normal lymphocytes. The subsequent analysis in primary MCL identified five genes (SOX9, HOXA9, AHR, NR2F2, and ROBO1) frequently methylated in these tumours. The gene methylation events tended to occur in the same primary neoplasms and correlated with higher proliferation, increased number of chromosomal abnormalities, and shorter survival of the patients. CONCLUSIONS: We have identified a set of genes whose methylation degree and gene expression levels correlate with aggressive clinicopathological features of MCL. Our findings also suggest that a subset of MCL might show a CpG island methylator phenotype (CIMP) that may influence the behaviour of the tumours. PMID- 21603611 TI - High-throughput sequencing, characterization and detection of new and conserved cucumber miRNAs. AB - Micro RNAS (miRNAs) are a class of endogenous small non coding RNAs involved in the post-transcriptional regulation of gene expression. In plants, a great number of conserved and specific miRNAs, mainly arising from model species, have been identified to date. However less is known about the diversity of these regulatory RNAs in vegetal species with agricultural and/or horticultural importance. Here we report a combined approach of bioinformatics prediction, high-throughput sequencing data and molecular methods to analyze miRNAs populations in cucumber (Cucumis sativus) plants. A set of 19 conserved and 6 known but non-conserved miRNA families were found in our cucumber small RNA dataset. We also identified 7 (3 with their miRNA* strand) not previously described miRNAs, candidates to be cucumber-specific. To validate their description these new C. sativus miRNAs were detected by northern blot hybridization. Additionally, potential targets for most conserved and new miRNAs were identified in cucumber genome.In summary, in this study we have identified, by first time, conserved, known non-conserved and new miRNAs arising from an agronomically important species such as C. sativus. The detection of this complex population of regulatory small RNAs suggests that similarly to that observe in other plant species, cucumber miRNAs may possibly play an important role in diverse biological and metabolic processes. PMID- 21603612 TI - NFATc1 regulation of TRAIL expression in human intestinal cells. AB - TNF-related apoptosis-inducing ligand (TRAIL; Apo2) has been shown to promote intestinal cell differentiation. Nuclear factor of activated T cells (NFAT) participates in the regulation of a variety of cellular processes, including differentiation. Here, we examined the role of NFAT in the regulation of TRAIL in human intestinal cells. Treatment with a combination of phorbol 12-myristate 13 acetate (PMA) plus the calcium ionophore A23187 (Io) increased NFAT activation and TRAIL expression; pretreatment with the calcineurin inhibitor cyclosporine A (CsA), an antagonist of NFAT signaling, diminished NFAT activation and TRAIL induction. In addition, knockdown of NFATc1, NFATc2, NFATc3, and NFATc4 blocked PMA/Io increased TRAIL protein expression. Expression of NFATc1 activated TRAIL promoter activity and increased TRAIL mRNA and protein expression. Deletion of NFAT binding sites from the TRAIL promoter did not significantly abrogate NFATc1 increased TRAIL promoter activity, suggesting an indirect regulation of TRAIL expression by NFAT activation. Knockdown of NFATc1 increased Sp1 transcription factor binding to the TRAIL promoter and, importantly, inhibition of Sp1, by chemical inhibition or RNA interference, increased TRAIL expression. These studies identify a novel mechanism for TRAIL regulation by which activation of NFATc1 increases TRAIL expression through negative regulation of Sp1 binding to the TRAIL promoter. PMID- 21603613 TI - Microtubules as platforms for assaying actin polymerization in vivo. AB - The actin cytoskeleton is continuously remodeled through cycles of actin filament assembly and disassembly. Filaments are born through nucleation and shaped into supramolecular structures with various essential functions. These range from contractile and protrusive assemblies in muscle and non-muscle cells to actin filament comets propelling vesicles or pathogens through the cytosol. Although nucleation has been extensively studied using purified proteins in vitro, dissection of the process in cells is complicated by the abundance and molecular complexity of actin filament arrays. We here describe the ectopic nucleation of actin filaments on the surface of microtubules, free of endogenous actin and interfering membrane or lipid. All major mechanisms of actin filament nucleation were recapitulated, including filament assembly induced by Arp2/3 complex, formin and Spir. This novel approach allows systematic dissection of actin nucleation in the cytosol of live cells, its genetic re-engineering as well as screening for new modifiers of the process. PMID- 21603614 TI - Perceptual anchoring in preschool children: not adultlike, but there. AB - BACKGROUND: Recent studies suggest that human auditory perception follows a prolonged developmental trajectory, sometimes continuing well into adolescence. Whereas both sensory and cognitive accounts have been proposed, the development of the ability to base current perceptual decisions on prior information, an ability that strongly benefits adult perception, has not been directly explored. Here we ask whether the auditory frequency discrimination of preschool children also improves when given the opportunity to use previously presented standard stimuli as perceptual anchors, and whether the magnitude of this anchoring effect undergoes developmental changes. METHODOLOGY/PRINCIPAL FINDINGS: Frequency discrimination was tested using two adaptive same/different protocols. In one protocol (with-reference), a repeated 1-kHz standard tone was presented repeatedly across trials. In the other (no-reference), no such repetitions occurred. Verbal memory and early reading skills were also evaluated to determine if the pattern of correlations between frequency discrimination, memory and literacy is similar to that previously reported in older children and adults. Preschool children were significantly more sensitive in the with-reference than in the no-reference condition, but the magnitude of this anchoring effect was smaller than that observed in adults. The pattern of correlations among discrimination thresholds, memory and literacy replicated previous reports in older children. CONCLUSIONS/SIGNIFICANCE: The processes allowing the use of context to form perceptual anchors are already functional among preschool children, albeit to a lesser extent than in adults. Nevertheless, immature anchoring cannot fully account for the poorer frequency discrimination abilities of young children. That anchoring is present among the majority of typically developing preschool children suggests that the anchoring deficits observed among individuals with dyslexia represent a true deficit rather than a developmental delay. PMID- 21603615 TI - The transcriptome of human epicardial, mediastinal and subcutaneous adipose tissues in men with coronary artery disease. AB - BACKGROUND: The biological functions of epicardial adipose tissue (EAT) remain largely unknown. However, the proximity of EAT to the coronary arteries suggests a role in the pathogenesis of coronary artery disease (CAD). The objectives of this study were to identify genes differentially regulated among three adipose tissues, namely EAT, mediastinal (MAT) and subcutaneous (SAT) and to study their possible relationships with the development of cardiovascular diseases. METHODS AND RESULTS: Samples were collected from subjects undergoing coronary artery bypass grafting surgeries. Gene expression was evaluated in the three adipose depots of six men using the Illumina(r) HumanWG-6 v3.0 expression BeadChips. Twenty-three and 73 genes were differentially up-regulated in EAT compared to MAT and SAT, respectively. Ninety-four genes were down-regulated in EAT compared to SAT. However, none were significantly down-regulated in EAT compared to MAT. More specifically, the expression of the adenosine A1 receptor (ADORA1), involved in myocardial ischemia, was significantly up-regulated in EAT. Levels of the prostaglandin D2 synthase (PTGDS) gene, recently associated with the progression of atherosclerosis, were significantly different in the three pairwise comparisons (EAT>MAT>SAT). The results of ADORA1 and PTGDS were confirmed by quantitative real-time PCR in 25 independent subjects. CONCLUSIONS: Overall, the transcriptional profiles of EAT and MAT were similar compared to the SAT. Despite this similarity, two genes involved in cardiovascular diseases, ADORA1 and PTGDS, were differentially up-regulated in EAT. These results provide insights about the biology of EAT and its potential implication in CAD. PMID- 21603616 TI - Leukocyte ADAM17 regulates acute pulmonary inflammation. AB - The transmembrane protease ADAM17 regulates the release and density of various leukocyte cell surface proteins that modulate inflammation, including L-selectin, TNF-alpha, and IL-6R. At this time, its in vivo substrates and role in pulmonary inflammation have not been directly examined. Using conditional ADAM17 knock-out mice, we investigated leukocyte ADAM17 in acute lung inflammation. Alveolar TNF alpha levels were significantly reduced (>95%) in ADAM17-null mice following LPS administration, as was the shedding of L-selectin, a neutrophil-expressed adhesion molecule. Alveolar IL-6R levels, however, were reduced by only ~25% in ADAM17-null mice, indicating that ADAM17 is not its primary sheddase in our model. Neutrophil infiltration into the alveolar compartment is a key event in the pathophysiology of acute airway inflammation. Following LPS inhalation, alveolar neutrophil levels and lung inflammation in ADAM17-null mice were overall reduced when compared to control mice. Interestingly, however, neutrophil recruitment to the alveolar compartment occurred earlier in ADAM17-null mice after exposure to LPS. This decrease in alveolar neutrophil recruitment in ADAM17 null mice was accompanied by significantly diminished alveolar levels of the neutrophil-tropic chemokines CXCL1 and CXCL5. Altogether, our study suggests that leukocyte ADAM17 promotes inflammation in the lung, and thus this sheddase may be a potential target in the design of pharmacologic therapies for acute lung injury. PMID- 21603617 TI - The spread of scientific information: insights from the web usage statistics in PLoS article-level metrics. AB - The presence of web-based communities is a distinctive signature of Web 2.0. The web-based feature means that information propagation within each community is highly facilitated, promoting complex collective dynamics in view of information exchange. In this work, we focus on a community of scientists and study, in particular, how the awareness of a scientific paper is spread. Our work is based on the web usage statistics obtained from the PLoS Article Level Metrics dataset compiled by PLoS. The cumulative number of HTML views was found to follow a long tail distribution which is reasonably well-fitted by a lognormal one. We modeled the diffusion of information by a random multiplicative process, and thus extracted the rates of information spread at different stages after the publication of a paper. We found that the spread of information displays two distinct decay regimes: a rapid downfall in the first month after publication, and a gradual power law decay afterwards. We identified these two regimes with two distinct driving processes: a short-term behavior driven by the fame of a paper, and a long-term behavior consistent with citation statistics. The patterns of information spread were found to be remarkably similar in data from different journals, but there are intrinsic differences for different types of web usage (HTML views and PDF downloads versus XML). These similarities and differences shed light on the theoretical understanding of different complex systems, as well as a better design of the corresponding web applications that is of high potential marketing impact. PMID- 21603618 TI - Differential genetic susceptibility to child risk at birth in predicting observed maternal behavior. AB - This study examined parenting as a function of child medical risks at birth and parental genotype (dopamine D4 receptor; DRD4). Our hypothesis was that the relation between child risks and later maternal sensitivity would depend on the presence/absence of a genetic variant in the mothers, thus revealing a gene by environment interaction (GXE). Risk at birth was defined by combining risk indices of children's gestational age at birth, birth weight, and admission to the neonatal intensive care unit. The DRD4-III 7-repeat allele was chosen as a relevant genotype as it was recently shown to moderate the effect of environmental stress on parental sensitivity. Mothers of 104 twin pairs provided DNA samples and were observed with their children in a laboratory play session when the children were 3.5 years old. Results indicate that higher levels of risk at birth were associated with less sensitive parenting only among mothers carrying the 7-repeat allele, but not among mothers carrying shorter alleles. Moreover, mothers who are carriers of the 7-repeat allele and whose children scored low on the risk index were observed to have the highest levels of sensitivity. These findings provide evidence for the interactive effects of genes and environment (in this study, children born at higher risk) on parenting, and are consistent with a genetic differential susceptibility model of parenting by demonstrating that some parents are inherently more susceptible to environmental influences, both good and bad, than are others. PMID- 21603619 TI - INSL3 in the ruminant: a powerful indicator of gender- and genetic-specific feto maternal dialogue. AB - The hormone Insulin-like peptide 3 (INSL3) is a major secretory product of the Leydig cells from both fetal and adult testes. Consequently, it is a major gender specific circulating hormone in the male fetus, where it is responsible for the first phase of testicular descent, and in the adult male. In most female mammals, circulating levels are very low, corresponding to only a small production of INSL3 by the mature ovaries. Female ruminants are exceptional in exhibiting high INSL3 gene expression by the thecal cells of antral follicles and by the corpora lutea. We have developed a specific and sensitive immunoassay to measure ruminant INSL3 and show that, corresponding to the high ovarian gene expression, non pregnant adult female sheep and cows have up to four times the levels observed in other female mammals. Significantly, this level declines during mid-pregnancy in cows carrying a female fetus, in which INSL3 is undetectable. However, in cows carrying a male fetus, circulating maternal INSL3 becomes elevated further, presumably due to the transplacental transfer of fetal INSL3 into the maternal circulation. Within male fetal blood, INSL3 is high in mid-pregnancy (day 153) corresponding to the first transabdominal phase of testicular descent, and shows a marked dependence on paternal genetics, with pure bred or hybrid male fetuses of Bos taurus (Angus) paternal genome having 30% higher INSL3 levels than those of Bos indicus (Brahman) paternity. Thus INSL3 provides the first example of a gender-specific fetal hormone with the potential to influence both placental and maternal physiology. PMID- 21603620 TI - Evolution, insular restriction, and extinction of oceanic land crabs, exemplified by the loss of an endemic Geograpsus in the Hawaiian Islands. AB - Most oceanic islands harbor unusual and vulnerable biotas as a result of isolation. As many groups, including dominant competitors and predators, have not naturally reached remote islands, others were less constrained to evolve novel adaptations and invade adaptive zones occupied by other taxa on continents. Land crabs are an excellent example of such ecological release, and some crab lineages made the macro-evolutionary transition from sea to land on islands. Numerous land crabs are restricted to, although widespread among, oceanic islands, where they can be keystone species in coastal forests, occupying guilds filled by vertebrates on continents. In the remote Hawaiian Islands, land crabs are strikingly absent. Here we show that absence of land crabs in the Hawaiian Islands is the result of extinction, rather than dispersal limitation. Analysis of fossil remains from all major islands show that an endemic Geograpsus was abundant before human colonization, grew larger than any congener, and extended further inland and to higher elevation than other land crabs in Oceania. Land crabs are major predators of nesting sea birds, invertebrates and plants, affect seed dispersal, control litter decomposition, and are important in nutrient cycling; their removal can lead to large-scale shifts in ecological communities. Although the importance of land crabs is obvious on remote and relatively undisturbed islands, it is less apparent on others, likely because they are decimated by humans and introduced biota. The loss of Geograpsus and potentially other land crabs likely had profound consequences for Hawaiian ecosystems. PMID- 21603621 TI - Decreased proliferation kinetics of mouse myoblasts overexpressing FRG1. AB - Although recent publications have linked the molecular events driving facioscapulohumeral muscular dystrophy (FSHD) to expression of the double homeobox transcription factor DUX4, overexpression of FRG1 has been proposed as one alternative causal agent as mice overexpressing FRG1 present with muscular dystrophy. Here, we characterize proliferative defects in two independent myoblast lines overexpressing FRG1. Myoblasts isolated from thigh muscle of FRG1 transgenic mice, an affected dystrophic muscle, exhibit delayed proliferation as measured by decreased clone size, whereas myoblasts isolated from the unaffected diaphragm muscle proliferated normally. To confirm the observation that overexpression of FRG1 could impair myoblast proliferation, we examined C2C12 myoblasts with inducible overexpression of FRG1, finding increased doubling time and G1-phase cells in mass culture after induction of FRG1 and decreased levels of pRb phosphorylation. We propose that depressed myoblast proliferation may contribute to the pathology of mice overexpressing FRG1 and may play a part in FSHD. PMID- 21603622 TI - Acceptability of medical male circumcision among uncircumcised men in Kenya one year after the launch of the national male circumcision program. AB - BACKGROUND: Numerous studies have demonstrated that male circumcision (MC) reduces the incidence of the Type-1 human immunodeficiency virus (HIV) among heterosexual men by at least half. METHODS: One year after the launch of a national Voluntary Medical Male Circumcision program in Kenya, this study conducted 12 focus group discussions among uncircumcised men in Nyanza Province to assess the revealed, non-hypothetical, facilitators and barriers to the uptake of MC. RESULTS: The primary barriers to MC uptake included time away from work; culture and religion; possible adverse events; and the post-surgical abstinence period. The primary facilitators of MC uptake included hygiene; social pressure; protection against HIV and other sexually transmitted infections; and improved sexual performance and satisfaction. CONCLUSIONS: Some activities which might increase MC uptake include dispelling MC misconceptions; increasing involvement of religious leaders, women's groups, and peer mobilizers for MC promotion; and increasing the relevance of MC among men who are already practicing an HIV prevention method. PMID- 21603623 TI - Spectral characterization and unmixing of intrinsic contrast in intact normal and diseased gastric tissues using hyperspectral two-photon microscopy. AB - BACKGROUND: Living tissues contain a range of intrinsic fluorophores and sources of second harmonic generation which provide contrast that can be exploited for fresh tissue imaging. Microscopic imaging of fresh tissue samples can circumvent the cost and time associated with conventional histology. Further, intrinsic contrast can provide rich information about a tissue's composition, structure and function, and opens the potential for in-vivo imaging without the need for contrast agents. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we used hyperspectral two-photon microscopy to explore the characteristics of both normal and diseased gastrointestinal (GI) tissues, relying only on their endogenous fluorescence and second harmonic generation to provide contrast. We obtained hyperspectral data at subcellular resolution by acquiring images over a range of two-photon excitation wavelengths, and found excitation spectral signatures of specific tissue types based on our ability to clearly visualize morphology. We present the two-photon excitation spectral properties of four major tissue types that are present throughout the GI tract: epithelium, lamina propria, collagen, and lymphatic tissue. Using these four excitation signatures as basis spectra, linear unmixing strategies were applied to hyperspectral data sets of both normal and neoplastic tissue acquired in the colon and small intestine. Our results show that hyperspectral unmixing with excitation spectra allows segmentation, showing promise for blind identification of tissue types within a field of view, analogous to specific staining in conventional histology. The intrinsic spectral signatures of these tissue types provide information relating to their biochemical composition. CONCLUSIONS/SIGNIFICANCE: These results suggest hyperspectral two-photon microscopy could provide an alternative to conventional histology either for in-situ imaging, or intraoperative 'instant histology' of fresh tissue biopsies. PMID- 21603624 TI - Allelic variation, alternative splicing and expression analysis of Psy1 gene in Hordeum chilense Roem. et Schult. AB - BACKGROUND: The wild barley Hordeum chilense Roem. et Schult. is a valuable source of genes for increasing carotenoid content in wheat. Tritordeums, the amphiploids derived from durum or common wheat and H. chilense, systematically show higher values of yellow pigment colour and carotenoid content than durum wheat. Phytoene synthase 1 gene (Psy1) is considered a key step limiting the carotenoid biosynthesis, and the correlation of Psy1 transcripts accumulation and endosperm carotenoid content has been demonstrated in the main grass species. METHODOLOGY/PRINCIPAL FINDINGS: We analyze the variability of Psy1 alleles in three lines of H. chilense (H1, H7 and H16) representing the three ecotypes described in this species. Moreover, we analyze Psy1 expression in leaves and in two seed developing stages of H1 and H7, showing mRNA accumulation patterns similar to those of wheat. Finally, we identify thirty-six different transcripts forms originated by alternative splicing of the 5' UTR and/or exons 1 to 5 of Psy1 gene. Transcripts function is tested in a heterologous complementation assay, revealing that from the sixteen different predicted proteins only four types (those of 432, 370, 364 and 271 amino acids), are functional in the bacterial system. CONCLUSIONS/SIGNIFICANCE: The large number of transcripts originated by alternative splicing of Psy1, and the coexistence of functional and non functional forms, suggest a fine regulation of PSY activity in H. chilense. This work is the first analysis of H. chilense Psy1 gene and the results reported here are the bases for its potential use in carotenoid enhancement in durum wheat. PMID- 21603625 TI - Chemopreventive effect of PSP through targeting of prostate cancer stem cell-like population. AB - Recent evidence suggested that prostate cancer stem/progenitor cells (CSC) are responsible for cancer initiation as well as disease progression. Unfortunately, conventional therapies are only effective in targeting the more differentiated cancer cells and spare the CSCs. Here, we report that PSP, an active component extracted from the mushroom Turkey tail (also known as Coriolus versicolor), is effective in targeting prostate CSCs. We found that treatment of the prostate cancer cell line PC-3 with PSP led to the down-regulation of CSC markers (CD133 and CD44) in a time and dose-dependent manner. Meanwhile, PSP treatment not only suppressed the ability of PC-3 cells to form prostaspheres under non-adherent culture conditions, but also inhibited their tumorigenicity in vivo, further proving that PSP can suppress prostate CSC properties. To investigate if the anti CSC effect of PSP may lead to prostate cancer chemoprevention, transgenic mice (TgMAP) that spontaneously develop prostate tumors were orally fed with PSP for 20 weeks. Whereas 100% of the mice that fed with water only developed prostate tumors at the end of experiment, no tumors could be found in any of the mice fed with PSP, suggesting that PSP treatment can completely inhibit prostate tumor formation. Our results not only demonstrated the intriguing anti-CSC effect of PSP, but also revealed, for the first time, the surprising chemopreventive property of oral PSP consumption against prostate cancer. PMID- 21603626 TI - In vitro surfactant structure-toxicity relationships: implications for surfactant use in sexually transmitted infection prophylaxis and contraception. AB - BACKGROUND: The need for woman-controlled, cheap, safe, effective, easy-to-use and easy-to-store topical applications for prophylaxis against sexually transmitted infections (STIs) makes surfactant-containing formulations an interesting option that requires a more fundamental knowledge concerning surfactant toxicology and structure-activity relationships. METHODOLOGY/PRINCIPAL FINDINGS: We report in vitro effects of surfactant concentration, exposure time and structure on the viability of mammalian cell types typically encountered in the vagina, namely, fully polarized and confluent epithelial cells, confluent but non-polarized epithelial-like cells, dendritic cells, and human sperm. Representatives of the different families of commercially available surfactants- nonionic (Triton X-100 and monolaurin), zwitterionic (DDPS), anionic (SDS), and cationic (C(n)TAB (n = 10 to 16), C(12)PB, and C(12)BZK)--were examined. Triton X 100, monolaurin, DDPS and SDS were toxic to all cell types at concentrations around their critical micelle concentration (CMC) suggesting a non-selective mode of action involving cell membrane destabilization and/or destruction. All cationic surfactants were toxic at concentrations far below their CMC and showed significant differences in their toxicity toward polarized as compared with non polarized cells. Their toxicity was also dependent on the chemical nature of the polar head group. Our results suggest an intracellular locus of action for cationic surfactants and show that their structure-activity relationships could be profitably exploited for STI prophylaxis in vaginal gel formulations. The therapeutic indices comparing polarized epithelial cell toxicity to sperm toxicity for all surfactants examined, except C(12)PB and C(12)BZK, does not justify their use as contraceptive agents. C(12)PB and C(12)BZK are shown to have a narrow therapeutic index recommending caution in their use in contraceptive formulations. CONCLUSIONS/SIGNIFICANCE: Our results contribute to understanding the mechanisms involved in surfactant toxicity, have a predictive value with regard to their safety, and may be used to design more effective and less harmful surfactants for use in topical applications for STI prophylaxis. PMID- 21603627 TI - Comparative study of hematopoietic differentiation between human embryonic stem cell lines. AB - Directed differentiation of human embryonic stem cells (hESCs) into any desired cell type has been hailed as a therapeutic promise to cure many human diseases. However, substantial roadblocks still exist for in vitro differentiation of hESCs into distinct cell types, including T lymphocytes. Here we examined the hematopoietic differentiation potential of six different hESC lines. We compare their ability to develop into CD34(+) or CD34(+)CD45(+) hematopoietic precursor populations under several differentiation conditions. Comparison of lymphoid potential of hESC derived- and fetal tissue derived-hematopoietic precursors was also made. We found diverse hematopoietic potential between hESC lines depending on the culture or passage conditions. In contrast to fetal-derived hematopoietic precursors, none of the CD34(+) precursors differentiated from hESCs were able to develop further into T cells. These data underscore the difficulties in the current strategy of hESC forward differentiation and highlight distinct differences between CD34(+) hematopoietic precursors generated in vitro versus in vivo. PMID- 21603628 TI - Prognostic impacts of angiopoietins in NSCLC tumor cells and stroma: VEGF-A impact is strongly associated with Ang-2. AB - INTRODUCTION: Angiopoietins and their receptor Tie-2 are, in concert with VEGF-A, key mediators in angiogenesis. This study evaluates the prognostic impact of all known human angiopoietins (Ang-1, Ang-2 and Ang-4) and their receptor Tie-2, as well as their relation to the prognostic expression of VEGF-A. METHODS: 335 unselected stage I-IIIA NSCLC-patients were included and tissue samples of respective tumor cells and stroma were collected in tissue microarrays (TMAs). Immunohistochemistry (IHC) was used to semiquantitatively evaluate the expression of markers in duplicate tumor and stroma cores. PRINCIPAL FINDINGS: In univariate analyses, low tumor cell expression of Ang-4 (P = 0.046) and low stromal expressions of Ang-4 (P = 0.009) and Ang-2 (P = 0.017) were individually associated with a poor survival. In the multivariate analysis, low stromal Ang-2 (HR 1.88; CI 95% 1.15-3.08) and Ang-4 (HR 1.47, CI 95% 1.02-2.11, P = 0.04) expressions were independently associated with a poor prognosis. In patients with high tumor cell expression of Ang-2, a concomitantly high tumor VEGF-A expression mediated a dramatic survival reduction (P<0.001). In the multivariate analysis of patients with high Ang-2 expression, high tumor VEGF-A expression appeared an independent poor prognosticator (HR 6.43; CI 95% 2.46-16.8; P<0.001). CONCLUSIONS: In tumor cells, only Ang-4 expression has prognostic impact in NSCLC. In tumor stroma, Ang-4 and Ang-2 are independently associated with survival. The prognostic impact of tumor cell VEGF-A in NSCLC appears strongly associated with a concomitantly high tumor cell expression of Ang-2. PMID- 21603629 TI - Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial. AB - BACKGROUND: The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. The currently recommended daily dose of artesunate (AS) is 4 mg/kg, and is administered for 3 days together with a partner antimalarial drug. This study investigated the impact of different AS doses on clinical and parasitological responses in malaria patients from an area of known artemisinin resistance in western Cambodia. METHODS: Adult patients with uncomplicated P. falciparum malaria were randomized into one of three 7-day AS monotherapy regimens: 2, 4 or 6 mg/kg/day (total dose 14, 28 and 42 mg/kg). Clinical, parasitological, pharmacokinetic and in vitro drug sensitivity data was collected over a 7-day inpatient period and during weekly follow-up to 42 days. RESULTS: 143 patients were enrolled (n = 75, 40 and 28 to receive AS 2, 4 and 6 mg/kg/day respectively). Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3. There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3. However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/uL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/uL (63 (48-75) vs. 84 (66-96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0*10(9)/L) by Day 14 and resulted in the arm being halted early. CONCLUSION: There is no pharmacodynamic benefit of increasing the daily dose of AS (4 mg/kg) currently recommended for short-course combination treatment of uncomplicated malaria, even in regions with emerging artemisinin resistance, as long as the partner drug retains high efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00722150. PMID- 21603630 TI - Contribution of each leg to the control of unperturbed bipedal stance in lower limb amputees: new insights using entropy. AB - The present study was designed to assess the relative contribution of each leg to unperturbed bipedal posture in lower limb amputees. To achieve this goal, eight unilateral traumatic trans-femoral amputees (TFA) were asked to stand as still as possible on a plantar pressure data acquisition system with their eyes closed. Four dependent variables were computed to describe the subject's postural behavior: (1) body weight distribution, (2) amplitude, (3) velocity and (4) regularity of centre of foot pressure (CoP) trajectories under the amputated (A) leg and the non-amputated (NA) leg. Results showed a larger body weight distribution applied to the NA leg than to the A leg and a more regular CoP profiles (lower sample entropy values) with greater amplitude and velocity under the NA leg than under the A leg. Taken together, these findings suggest that the NA leg and the A leg do not equally contribute to the control of unperturbed bipedal posture in TFA. The observation that TFA do actively control unperturbed bipedal posture with their NA leg could be viewed as an adaptive process to the loss of the lower leg afferents and efferents because of the unilateral lower limb amputation. From a methodological point of view, these results demonstrate the suitability of computing bilateral CoP trajectories regularity for the assessment of lateralized postural control under pathological conditions. PMID- 21603631 TI - Purification and characterization of enterovirus 71 viral particles produced from vero cells grown in a serum-free microcarrier bioreactor system. AB - BACKGROUND: Enterovirus 71 (EV71) infections manifest most commonly as a childhood exanthema known as hand-foot-and-mouth disease (HFMD) and can cause neurological disease during acute infection. PRINCIPAL FINDING: In this study, we describe the production, purification and characterization of EV71 virus produced from Vero cells grown in a five-liter serum-free bioreactor system containing 5 g/L Cytodex 1 microcarrier. The viral titer was >10(6) TCID(50)/mL by 6 days post infection when a MOI of 10(-5) was used at the initial infection. Two EV71 virus fractions were separated and detected when the harvested EV71 virus concentrate was purified by sucrose gradient zonal ultracentrifugation. The EV71 viral particles detected in the 24-28% sucrose fractions had an icosahedral structure 30-31 nm in diameter and had low viral infectivity and RNA content. Three major viral proteins (VP0, VP1 and VP3) were observed by SDS-PAGE. The EV71 viral particles detected in the fractions containing 35-38% sucrose were 33-35 nm in size, had high viral infectivity and RNA content, and were composed of four viral proteins (VP1, VP2, VP3 and VP4), as shown by SDS-PAGE analyses. The two virus fractions were formalin-inactivated and induced high virus neutralizing antibody responses in mouse immunogenicity studies. Both mouse antisera recognized the immunodominant linear neutralization epitope of VP1 (residues 211-225). CONCLUSION: These results provide important information for cell-based EV71 vaccine development, particularly for the preparation of working standards for viral antigen quantification. PMID- 21603632 TI - Dysregulation of IFN system can lead to poor response to pegylated interferon and ribavirin therapy in chronic hepatitis C. AB - BACKGROUND: Despite being expensive, the standard combination of pegylated interferon (Peg-IFN)-alpha and ribavirin used to treat chronic hepatitis C (CH) results in a moderate clearance rate and a plethora of side effects. This makes it necessary to predict patient outcome so as to improve the accuracy of treatment. Although the antiviral mechanism of genetically altered IL28B is unknown, IL28B polymorphism is considered a good predictor of IFN combination treatment outcome. METHODOLOGY: Using microarray, we quantified the expression profile of 237 IFN related genes in 87 CH liver biopsy specimens to clarify the relationship between IFN pathway and viral elimination, and to predict patients' clinical outcome. In 72 out of 87 patients we also analyzed IL28B polymorphism (rs8099917). PRINCIPAL FINDINGS: Five IFN related-genes (IFI27, IFI 44, ISG15, MX1, and OAS1) had expression levels significantly higher in nonresponders (NR) than in normal liver (NL) and sustained virological responders (SVR); this high expression was also frequently seen in cases with the minor (TG or GG) IL28B genotype. The expression pattern of 31 IFN related-genes also differed significantly between NR and NL. We predicted drug response in NR with 86.1% accuracy by diagonal linear discriminant analysis (DLDA). CONCLUSION: IFN system dysregulation before treatment was associated with poor IFN therapy response. Determining IFN related-gene expression pattern based on patients' response to combination therapy, allowed us to predict drug response with high accuracy. This method can be applied to establishing novel antiviral therapies and strategies for patients using a more individual approach. PMID- 21603633 TI - Use of the 2A peptide for generation of multi-transgenic pigs through a single round of nuclear transfer. AB - Multiple genetic modifications in pigs can essentially benefit research on agriculture, human disease and xenotransplantation. Most multi-transgenic pigs have been produced by complex and time-consuming breeding programs using multiple single-transgenic pigs. This study explored the feasibility of producing multi transgenic pigs using the viral 2A peptide in the light of previous research indicating that it can be utilized for multi-gene transfer in gene therapy and somatic cell reprogramming. A 2A peptide-based double-promoter expression vector that mediated the expression of four fluorescent proteins was constructed and transfected into primary porcine fetal fibroblasts. Cell colonies (54.3%) formed under G418 selection co-expressed the four fluorescent proteins at uniformly high levels. The reconstructed embryos, which were obtained by somatic cell nuclear transfer and confirmed to express the four fluorescent proteins evenly, were transplanted into seven recipient gilts. Eleven piglets were delivered by two gilts, and seven of them co-expressed the four fluorescent proteins at equivalently high levels in various tissues. The fluorescence intensities were directly observed at the nose, hoof and tongue using goggles. The results suggest that the strategy of combining the 2A peptide and double promoters efficiently mediates the co-expression of the four fluorescent proteins in pigs and is hence a promising methodology to generate multi-transgenic pigs by a single nuclear transfer. PMID- 21603634 TI - Pathogenesis of Candida albicans infections in the alternative chorio-allantoic membrane chicken embryo model resembles systemic murine infections. AB - Alternative models of microbial infections are increasingly used to screen virulence determinants of pathogens. In this study, we investigated the pathogenesis of Candida albicans and C. glabrata infections in chicken embryos infected via the chorio-allantoic membrane (CAM) and analyzed the virulence of deletion mutants. The developing immune system of the host significantly influenced susceptibility: With increasing age, embryos became more resistant and mounted a more balanced immune response, characterized by lower induction of proinflammatory cytokines and increased transcription of regulatory cytokines, suggesting that immunopathology contributes to pathogenesis. While many aspects of the chicken embryo response resembled murine infections, we also observed significant differences: In contrast to systemic infections in mice, IL-10 had a beneficial effect in chicken embryos. IL-22 and IL-17A were only upregulated after the peak mortality in the chicken embryo model occurred; thus, the role of the Th17 response in this model remains unclear. Abscess formation occurs frequently in murine models, whereas the avian response was dominated by granuloma formation. Pathogenicity of the majority of 15 tested C. albicans deletion strains was comparable to the virulence in mouse models and reduced virulence was associated with significantly lower transcription of proinflammatory cytokines. However, fungal burden did not correlate with virulence and for few mutants like bcr1Delta and tec1Delta different outcomes in survival compared to murine infections were observed. C. albicans strains locked in the yeast stage disseminated significantly more often from the CAM into the embryo, supporting the hypothesis that the yeast morphology is responsible for dissemination in systemic infections. These data suggest that the pathogenesis of C. albicans infections in the chicken embryo model resembles systemic murine infections but also differs in some aspects. Despite its limitations, it presents a useful alternative tool to pre-screen C. albicans strains to select strains for subsequent testing in murine models. PMID- 21603635 TI - RMDAP: a versatile, ready-to-use toolbox for multigene genetic transformation. AB - BACKGROUND: The use of transgenes to improve complex traits in crops has challenged current genetic transformation technology for multigene transfer. Therefore, a multigene transformation strategy for use in plant molecular biology and plant genetic breeding is thus needed. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe a versatile, ready-to-use multigene genetic transformation method, named the Recombination-assisted Multifunctional DNA Assembly Platform (RMDAP), which combines many of the useful features of existing plant transformation systems. This platform incorporates three widely-used recombination systems, namely, Gateway technology, in vivo Cre/loxP and recombineering into a highly efficient and reliable approach for gene assembly. RMDAP proposes a strategy for gene stacking and contains a wide range of flexible, modular vectors offering a series of functionally validated genetic elements to manipulate transgene overexpression or gene silencing involved in a metabolic pathway. In particular, the ability to construct a multigene marker-free vector is another attractive feature. The built-in flexibility of original vectors has greatly increased the expansibility and applicability of the system. A proof-of-principle experiment was confirmed by successfully transferring several heterologous genes into the plant genome. CONCLUSIONS/SIGNIFICANCE: This platform is a ready-to-use toolbox for full exploitation of the potential for coordinate regulation of metabolic pathways and molecular breeding, and will eventually achieve the aim of what we call "one-stop breeding." PMID- 21603636 TI - The microbial communities in male first catch urine are highly similar to those in paired urethral swab specimens. AB - Urine is the CDC-recommended specimen for STI testing. It was unknown if the bacterial communities (microbiomes) in urine reflected those in the distal male urethra. We compared microbiomes of 32 paired urine and urethral swab specimens obtained from adult men attending an STD clinic, by 16S rRNA PCR and deep pyrosequencing. Microbiomes of urine and swabs were remarkably similar, regardless of STI status of the subjects. Thus, urine can be used to characterize urethral microbiomes when swabs are undesirable, such as in population-based studies of the urethral microbiome or where multiple sampling of participants is required. PMID- 21603637 TI - Universal entropy of word ordering across linguistic families. AB - BACKGROUND: The language faculty is probably the most distinctive feature of our species, and endows us with a unique ability to exchange highly structured information. In written language, information is encoded by the concatenation of basic symbols under grammatical and semantic constraints. As is also the case in other natural information carriers, the resulting symbolic sequences show a delicate balance between order and disorder. That balance is determined by the interplay between the diversity of symbols and by their specific ordering in the sequences. Here we used entropy to quantify the contribution of different organizational levels to the overall statistical structure of language. METHODOLOGY/PRINCIPAL FINDINGS: We computed a relative entropy measure to quantify the degree of ordering in word sequences from languages belonging to several linguistic families. While a direct estimation of the overall entropy of language yielded values that varied for the different families considered, the relative entropy quantifying word ordering presented an almost constant value for all those families. CONCLUSIONS/SIGNIFICANCE: Our results indicate that despite the differences in the structure and vocabulary of the languages analyzed, the impact of word ordering in the structure of language is a statistical linguistic universal. PMID- 21603638 TI - Modeling routes of chronic wasting disease transmission: environmental prion persistence promotes deer population decline and extinction. AB - Chronic wasting disease (CWD) is a fatal disease of deer, elk, and moose transmitted through direct, animal-to-animal contact, and indirectly, via environmental contamination. Considerable attention has been paid to modeling direct transmission, but despite the fact that CWD prions can remain infectious in the environment for years, relatively little information exists about the potential effects of indirect transmission on CWD dynamics. In the present study, we use simulation models to demonstrate how indirect transmission and the duration of environmental prion persistence may affect epidemics of CWD and populations of North American deer. Existing data from Colorado, Wyoming, and Wisconsin's CWD epidemics were used to define plausible short-term outcomes and associated parameter spaces. Resulting long-term outcomes range from relatively low disease prevalence and limited host-population decline to host-population collapse and extinction. Our models suggest that disease prevalence and the severity of population decline is driven by the duration that prions remain infectious in the environment. Despite relatively low epidemic growth rates, the basic reproductive number, R(0), may be much larger than expected under the direct-transmission paradigm because the infectious period can vastly exceed the host's life span. High prion persistence is expected to lead to an increasing environmental pool of prions during the early phases (i.e. approximately during the first 50 years) of the epidemic. As a consequence, over this period of time, disease dynamics will become more heavily influenced by indirect transmission, which may explain some of the observed regional differences in age and sex specific disease patterns. This suggests management interventions, such as culling or vaccination, will become increasingly less effective as CWD epidemics progress. PMID- 21603639 TI - The sensitivity of massively parallel sequencing for detecting candidate infectious agents associated with human tissue. AB - Massively parallel sequencing technology now provides the opportunity to sample the transcriptome of a given tissue comprehensively. Transcripts at only a few copies per cell are readily detectable, allowing the discovery of low abundance viral and bacterial transcripts in human tissue samples. Here we describe an approach for mining large sequence data sets for the presence of microbial sequences. Further, we demonstrate the sensitivity of this approach by sequencing human RNA-seq libraries spiked with decreasing amounts of an RNA-virus. At a modest depth of sequencing, viral transcripts can be detected at frequencies less than 1 in 1,000,000. With current sequencing platforms approaching outputs of one billion reads per run, this is a highly sensitive method for detecting putative infectious agents associated with human tissues. PMID- 21603640 TI - Overestimating resource value and its effects on fighting decisions. AB - Much work in behavioral ecology has shown that animals fight over resources such as food, and that they make strategic decisions about when to engage in such fights. Here, we examine the evolution of one, heretofore unexamined, component of that strategic decision about whether to fight for a resource. We present the results of a computer simulation that examined the evolution of over- or underestimating the value of a resource (food) as a function of an individual's current hunger level. In our model, animals fought for food when they perceived their current food level to be below the mean for the environment. We considered seven strategies for estimating food value: 1) always underestimate food value, 2) always overestimate food value, 3) never over- or underestimate food value, 4) overestimate food value when hungry, 5) underestimate food value when hungry, 6) overestimate food value when relatively satiated, and 7) underestimate food value when relatively satiated. We first competed all seven strategies against each other when they began at approximately equal frequencies. In such a competition, two strategies--"always overestimate food value," and "overestimate food value when hungry"--were very successful. We next competed each of these strategies against the default strategy of "never over- or underestimate," when the default strategy was set at 99% of the population. Again, the strategies of "always overestimate food value" and "overestimate food value when hungry" fared well. Our results suggest that overestimating food value when deciding whether to fight should be favored by natural selection. PMID- 21603641 TI - Life-history evolution on tropidurinae lizards: influence of lineage, body size and climate. AB - The study of life history variation is central to the evolutionary theory. In many ectothermic lineages, including lizards, life history traits are plastic and relate to several sources of variation including body size, which is both a factor and a life history trait likely to modulate reproductive parameters. Larger species within a lineage, for example tend to be more fecund and have larger clutch size, but clutch size may also be influenced by climate, independently of body size. Thus, the study of climatic effects on lizard fecundity is mandatory on the current scenario of global climatic change. We asked how body and clutch size have responded to climate through time in a group of tropical lizards, the Tropidurinae, and how these two variables relate to each other. We used both traditional and phylogenetic comparative methods. Body and clutch size are variable within Tropidurinae, and both traits are influenced by phylogenetic position. Across the lineage, species which evolved larger size produce more eggs and neither trait is influenced by temperature components. A climatic component of precipitation, however, relates to larger female body size, and therefore seems to exert an indirect relationship on clutch size. This effect of precipitation on body size is likely a correlate of primary production. A decrease in fecundity is expected for Tropidurinae species on continental landmasses, which are predicted to undergo a decrease in summer rainfall. PMID- 21603642 TI - The SaeR/S gene regulatory system induces a pro-inflammatory cytokine response during Staphylococcus aureus infection. AB - Community-associated methicillin-resistant Staphylococcus aureus accounts for a large portion of the increased staphylococcal disease incidence and can cause illness ranging from mild skin infections to rapidly fatal sepsis syndromes. Currently, we have limited understanding of S. aureus-derived mechanisms contributing to bacterial pathogenesis and host inflammation during staphylococcal disease. Herein, we characterize an influential role for the saeR/S two-component gene regulatory system in mediating cytokine induction using mouse models of S. aureus pathogenesis. Invasive S. aureus infection induced the production of localized and systemic pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), interleukin (IL) 6 and IL-2. In contrast, mice infected with an isogenic saeR/S deletion mutant demonstrated significantly reduced pro-inflammatory cytokine levels. Additionally, secreted factors influenced by saeR/S elicited pro-inflammatory cytokines in human blood ex vivo. Our study further demonstrated robust saeR/S mediated IFN-gamma production during both invasive and subcutaneous skin infections. Results also indicated a critical role for saeR/S in promoting bacterial survival and enhancing host mortality during S. aureus peritonitis. Taken together, this study provides insight into specific mechanisms used by S. aureus during staphylococcal disease and characterizes a relationship between a bacterial global regulator of virulence and the production of pro-inflammatory mediators. PMID- 21603643 TI - Actinic skin damage and mortality--the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. AB - BACKGROUND: Exposure to sunlight may decrease the risk of several diseases through the synthesis of vitamin D, whereas solar radiation is the main cause of some skin and eye diseases. However, to the best of our knowledge, the association of sun-induced skin damage with mortality remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: Subjects were 8472 white participants aged 25-74 years in the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Cardiovascular disease mortality, cancer mortality, and all cause mortality were obtained by either a death certificate or a proxy interview, or both. Actinic skin damage was examined and recorded by the presence and severity (absent, minimal, moderate, or severe) of overall actinic skin damage and its components (i.e., fine telangiectasia, solar elastosis, and actinic keratoses). Cox regression and Kaplan-Meier methods were applied to explore the associations. A total of 672 cancer deaths, 1500 cardiovascular disease deaths, and 2969 deaths from all causes were documented through the follow-up between 1971 and 1992. After controlling for potential confounding variables, severe overall actinic skin damage was associated with a 45% higher risk for all-cause mortality (95% CI: 1.22, 1.72; P<0.001), moderate overall skin damage with a 20% higher risk (95% CI: 1.08., 1.32; P<0.001), and minimal overall skin damage with no significant mortality difference, when compared to those with no skin damage. Similar results were obtained for all-cause mortality with fine telangiectasia, solar elastosis, and actinic keratoses. The results were similar for cancer and cardiovascular disease mortality. CONCLUSIONS: The present study gives an indication of an association of actinic skin damage with cardiovascular disease, cancer and all-cause mortality in white subjects. Given the lack of support in the scientific literature and potential unmeasured confounding factors, this finding should be interpreted with caution. More independent studies are needed before any practical recommendations can be made. PMID- 21603644 TI - Estimating survival in patients with operable skeletal metastases: an application of a bayesian belief network. AB - BACKGROUND: Accurate estimations of life expectancy are important in the management of patients with metastatic cancer affecting the extremities, and help set patient, family, and physician expectations. Clinically, the decision whether to operate on patients with skeletal metastases, as well as the choice of surgical procedure, are predicated on an individual patient's estimated survival. Currently, there are no reliable methods for estimating survival in this patient population. Bayesian classification, which includes bayesian belief network (BBN) modeling, is a statistical method that explores conditional, probabilistic relationships between variables to estimate the likelihood of an outcome using observed data. Thus, BBN models are being used with increasing frequency in a variety of diagnoses to codify complex clinical data into prognostic models. The purpose of this study was to determine the feasibility of developing bayesian classifiers to estimate survival in patients undergoing surgery for metastases of the axial and appendicular skeleton. METHODS: We searched an institution-owned patient management database for all patients who underwent surgery for skeletal metastases between 1999 and 2003. We then developed and trained a machine-learned BBN model to estimate survival in months using candidate features based on historical data. Ten-fold cross-validation and receiver operating characteristic (ROC) curve analysis were performed to evaluate the BNN model's accuracy and robustness. RESULTS: A total of 189 consecutive patients were included. First degree predictors of survival differed between the 3-month and 12-month models. Following cross validation, the area under the ROC curve was 0.85 (95% CI: 0.80 0.93) for 3-month probability of survival and 0.83 (95% CI: 0.77-0.90) for 12 month probability of survival. CONCLUSIONS: A robust, accurate, probabilistic naive BBN model was successfully developed using observed clinical data to estimate individualized survival in patients with operable skeletal metastases. This method warrants further development and must be externally validated in other patient populations. PMID- 21603645 TI - Dual neonate vaccine platform against HIV-1 and M. tuberculosis. AB - Acquired immunodeficiency syndrome and tuberculosis (TB) are two of the world's most devastating diseases. The first vaccine the majority of infants born in Africa receive is Mycobacterium bovis bacillus Calmette-Guerin (BCG) as a prevention against TB. BCG protects against disseminated disease in the first 10 years of life, but provides a variable protection against pulmonary TB and enhancing boost delivered by recombinant modified vaccinia virus Ankara (rMVA) expressing antigen 85A (Ag85A) of M. tuberculosis is currently in phase IIb evaluation in African neonates. If the newborn's mother is positive for human immunodeficiency virus type 1 (HIV-1), the baby is at high risk of acquiring HIV 1 through breastfeeding. We suggested that a vaccination consisting of recombinant BCG expressing HIV-1 immunogen administered at birth followed by a boost with rMVA sharing the same immunogen could serve as a strategy for prevention of mother-to-child transmission of HIV-1 and rMVA expressing an African HIV-1-derived immunogen HIVA is currently in phase I trials in African neonates. Here, we aim to develop a dual neonate vaccine platform against HIV-1 and TB consisting of BCG.HIVA administered at birth followed by a boost with MVA.HIVA.85A. Thus, mMVA.HIVA.85A and sMVA.HIVA.85A vaccines were constructed, in which the transgene transcription is driven by either modified H5 or short synthetic promoters, respectively, and tested for immunogenicity alone and in combination with BCG.HIVA(222). mMVA.HIVA.85A was produced markerless and thus suitable for clinical manufacture. While sMVA.HIVA.85A expressed higher levels of the immunogens, it was less immunogenic than mMVA.HIVA.85A in BALB/c mice. A BCG.HIVA(222)-mMVA.HIVA.85A prime-boost regimen induced robust T cell responses to both HIV-1 and M. tuberculosis. Therefore, proof-of-principle for a dual anti HIV-1/M. tuberculosis infant vaccine platform is established. Induction of immune responses against these pathogens soon after birth is highly desirable and may provide a basis for lifetime protection maintained by boosts later in life. PMID- 21603646 TI - Oligonucleotide microarray analysis of age-related gene expression profiles in miniature pigs. AB - Miniature pigs are useful model animals for humans because they have similar anatomy and digestive physiology to humans and are easy to breed and handle. In this study, whole blood microarray analyses were conducted to evaluate variations of correlation among individuals and ages using specific pathogen-free (SPF) Clawn miniature pigs. Whole blood RNA is easy to handle compared to isolated white blood cell RNA and can be used for health and disease monitoring and animal control. In addition, whole blood is a heterogeneous mixture of subpopulation cells. Once a great change occurs in composition and expressing condition of subpopulations, their associated change will be reflected on whole blood RNA. From 12 to 30 weeks of age, fractions of lymphocytes, monocytes, neutrophils, eosinophils, and basophils in white blood cells showed insignificant differences with age as a result of ANOVA analysis. This study attempted to identify characteristics of age-related gene expression by taking into account the change in the number of expressed genes by age and similarities of gene expression intensity between individuals. As a result, the number of expressed genes was less in fetal stage and infancy period but increased with age, reaching a steady state of gene expression after 20 weeks of age. Variation in gene expression intensity within the same age was great in fetal stage and infancy period, but converged with age. The variation between 20 and 30 weeks of age was comparable to that among 30 weeks individuals. These results indicate that uniformity of laboratory animals is expected for miniature pigs after 20 weeks of age. Furthermore, a possibility was shown that whole blood RNA analysis is applicable to evaluation of physiological state. PMID- 21603647 TI - Social class differences in secular trends in established coronary risk factors over 20 years: a cohort study of British men from 1978-80 to 1998-2000. AB - BACKGROUND: Coronary heart disease (CHD) mortality in the UK since the late 1970s has declined more markedly among higher socioeconomic groups. However, little is known about changes in coronary risk factors in different socioeconomic groups. This study examined whether changes in established coronary risk factors in Britain over 20 years between 1978-80 and 1998-2000 differed between socioeconomic groups. METHODS AND FINDINGS: A socioeconomically representative cohort of 7735 British men aged 40-59 years was followed-up from 1978-80 to 1998 2000; data on blood pressure (BP), cholesterol, body mass index (BMI) and cigarette smoking were collected at both points in 4252 survivors. Social class was based on longest-held occupation in middle-age. Compared with men in non manual occupations, men in manual occupations experienced a greater increase in BMI (mean difference = 0.33 kg/m(2); 95%CI 0.14-0.53; p for interaction = 0.001), a smaller decline in non-HDL cholesterol (difference in mean change = 0.18 mmol/l; 95%CI 0.11-0.25, p for interaction<=0.0001) and a smaller increase in HDL cholesterol (difference in mean change = 0.04 mmol/l; 95%CI 0.02-0.06, p for interaction<=0.0001). However, mean systolic BP declined more in manual than non manual groups (difference in mean change = 3.6; 95%CI 2.1-5.1, p for interaction<=0.0001). The odds of being a current smoker in 1978-80 and 1998-2000 did not differ between non-manual and manual social classes (p for interaction = 0.51). CONCLUSION: Several key risk factors for CHD and type 2 diabetes showed less favourable changes in men in manual occupations. Continuing priority is needed to improve adverse cardiovascular risk profiles in socially disadvantaged groups in the UK. PMID- 21603648 TI - Firefly luciferase and RLuc8 exhibit differential sensitivity to oxidative stress in apoptotic cells. AB - Over the past decade, firefly Luciferase (fLuc) has been used in a wide range of biological assays, providing insight into gene regulation, protein-protein interactions, cell proliferation, and cell migration. However, it has also been well established that fLuc activity can be highly sensitive to its surrounding environment. In this study, we found that when various cancer cell lines (HeLa, MCF-7, and 293T) stably expressing fLuc were treated with staurosporine (STS), there was a rapid loss in bioluminescence. In contrast, a stable variant of Renilla luciferase (RLuc), RLuc8, exhibited significantly prolonged functionality under the same conditions. To identify the specific underlying mechanism(s) responsible for the disparate sensitivity of RLuc8 and fLuc to cellular stress, we conducted a series of inhibition studies that targeted known intracellular protein degradation/modification pathways associated with cell death. Interestingly, these studies suggested that reactive oxygen species, particularly hydrogen peroxide (H(2)O(2)), was responsible for the diminution of fLuc activity. Consistent with these findings, the direct application of H(2)O(2) to HeLa cells also led to a reduction in fLuc bioluminescence, while H(2)O(2) scavengers stabilized fLuc activity. Comparatively, RLuc8 was far less sensitive to ROS. These observations suggest that fLuc activity can be substantially altered in studies where ROS levels become elevated and can potentially lead to ambiguous or misleading findings. PMID- 21603649 TI - Transmission of Plasmodium vivax in south-western Uganda: report of three cases in pregnant women. AB - Plasmodium vivax is considered to be rare in the predominantly Duffy negative populations of Sub-Saharan Africa, as this red blood cell surface antigen is essential for invasion by the parasite. However, despite only very few reports of molecularly confirmed P. vivax from tropical Africa, serological evidence indicated that 13% of the persons sampled in Congo had been exposed to P. vivax. We identified P. vivax by microscopy in 8 smears from Ugandan pregnant women who had been enrolled in a longitudinal study of malaria in pregnancy. A nested polymerase chain reaction (PCR) protocol was used to detect and identify the Plasmodium parasites present. PCR analysis confirmed the presence of P. vivax for three of the women and analysis of all available samples from these women revealed clinically silent chronic low-grade vivax infections for two of them. The parasites in one woman carried pyrimethamine resistance-associated double non synonymous mutations in the P. vivax dihydrofolate reductase gene. The three women found infected with P. vivax were Duffy positive as were nine of 68 women randomly selected from the cohort. The data presented from these three case reports is consistent with stable transmission of malaria in a predominantly Duffy negative African population. Given the substantial morbidity associated with vivax infection in non-African endemic areas, it will be important to investigate whether the distribution and prevalence of P. vivax have been underestimated in Sub-Saharan Africa. This is particularly important in the context of the drive to eliminate malaria and its morbidity. PMID- 21603650 TI - One for all--a highly efficient and versatile method for fluorescent immunostaining in fish embryos. AB - BACKGROUND: For the detection and sub-cellular (co)-localization of proteins in the context of the tissue or organism immunostaining in whole mount preparations or on sections is still the best approach. So far, each antibody required its own fixation and antigen retrieval protocol so that optimizing immunostaining turned out to be tedious and time consuming. METHODOLOGY/PRINCIPAL FINDING: Here we present a novel method to efficiently retrieve the antigen in a widely applicable standard protocol, facilitating fluorescent immunostaining of both cryosections and whole mount preparations in zebrafish (Danio rerio) and medaka (Oryzias latipes). CONCLUSIONS/SIGNIFICANCE: Our method overcomes the loss of sections and damage of tissue and cell morphology, and allows parallel immunostaining in multiple colors, co-immunostaining with fluorescent proteins in transgenic fish lines and in combination with whole mount in situ hybridization. PMID- 21603651 TI - In vivo electroporation enhances the immunogenicity of an HIV-1 DNA vaccine candidate in healthy volunteers. AB - BACKGROUND: DNA-based vaccines have been safe but weakly immunogenic in humans to date. METHODS AND FINDINGS: We sought to determine the safety, tolerability, and immunogenicity of ADVAX, a multigenic HIV-1 DNA vaccine candidate, injected intramuscularly by in vivo electroporation (EP) in a Phase-1, double-blind, randomized placebo-controlled trial in healthy volunteers. Eight volunteers each received 0.2 mg, 1 mg, or 4 mg ADVAX or saline placebo via EP, or 4 mg ADVAX via standard intramuscular injection at weeks 0 and 8. A third vaccination was administered to eleven volunteers at week 36. EP was safe, well-tolerated and considered acceptable for a prophylactic vaccine. EP delivery of ADVAX increased the magnitude of HIV-1-specific cell mediated immunity by up to 70-fold over IM injection, as measured by gamma interferon ELISpot. The number of antigens to which the response was detected improved with EP and increasing dosage. Intracellular cytokine staining analysis of ELISpot responders revealed both CD4+ and CD8+ T cell responses, with co-secretion of multiple cytokines. CONCLUSIONS: This is the first demonstration in healthy volunteers that EP is safe, tolerable, and effective in improving the magnitude, breadth and durability of cellular immune responses to a DNA vaccine candidate. TRIAL REGISTRATION: ClinicalTrials.gov NCT00545987. PMID- 21603653 TI - Evolutionary time-scale of the begomoviruses: evidence from integrated sequences in the Nicotiana genome. AB - Despite having single stranded DNA genomes that are replicated by host DNA polymerases, viruses in the family Geminiviridae are apparently evolving as rapidly as some RNA viruses. The observed substitution rates of geminiviruses in the genera Begomovirus and Mastrevirus are so high that the entire family could conceivably have originated less than a million years ago (MYA). However, the existence of geminivirus related DNA (GRD) integrated within the genomes of various Nicotiana species suggests that the geminiviruses probably originated >10 MYA. Some have even suggested that a distinct New-World (NW) lineage of begomoviruses may have arisen following the separation by continental drift of African and American proto-begomoviruses ~110 MYA. We evaluate these various geminivirus origin hypotheses using Bayesian coalescent-based approaches to date firstly the Nicotiana GRD integration events, and then the divergence of the NW and Old-World (OW) begomoviruses. Besides rejecting the possibility of a<2 MYA OW NW begomovirus split, we could also discount that it may have occurred concomitantly with the breakup of Gondwanaland 110 MYA. Although we could only confidently narrow the date of the split down to between 2 and 80 MYA, the most plausible (and best supported) date for the split is between 20 and 30 MYA--a time when global cooling ended the dispersal of temperate species between Asia and North America via the Beringian land bridge. PMID- 21603652 TI - The dyad symmetry element of Epstein-Barr virus is a dominant but dispensable replication origin. AB - OriP, the latent origin of Epstein-Barr virus (EBV), consists of two essential elements: the dyad symmetry (DS) and the family of repeats (FR). The function of these elements has been predominantly analyzed in plasmids transfected into transformed cells. Here, we examined the molecular functions of DS in its native genomic context and at an ectopic position in the mini-EBV episome. Mini-EBV plasmids contain 41% of the EBV genome including all information required for the proliferation of human B cells. Both FR and DS function independently of their genomic context. We show that DS is the most active origin of replication present in the mini-EBV genome regardless of its location, and it is characterized by the binding of the origin recognition complex (ORC) allowing subsequent replication initiation. Surprisingly, the integrity of oriP is not required for the formation of the pre-replicative complex (pre-RC) at or near DS. In addition we show that initiation events occurring at sites other than the DS are also limited to once per cell cycle and that they are ORC-dependent. The deletion of DS increases initiation from alternative origins, which are normally used very infrequently in the mini-EBV genome. The sequence-independent distribution of ORC-binding, pre-RC assembly, and initiation patterns indicates that a large number of silent origins are present in the mini-EBV genome. We conclude that, in mini-EBV genomes lacking the DS element, the absence of a strong ORC binding site results in an increase of ORC binding at dispersed sites. PMID- 21603654 TI - The involvement of SMILE/TMTC3 in endoplasmic reticulum stress response. AB - BACKGROUND: The state of operational tolerance has been detected sporadically in some renal transplanted patients that stopped immunosuppressive drugs, demonstrating that allograft tolerance might exist in humans. Several years ago, a study by Brouard et al. identified a molecular signature of several genes that were significantly differentially expressed in the blood of such patients compared with patients with other clinical situations. The aim of the present study is to analyze the role of one of these molecules over-expressed in the blood of operationally tolerant patients, SMILE or TMTC3, a protein whose function is still unknown. METHODOLOGY/PRINCIPAL FINDINGS: We first confirmed that SMILE mRNA is differentially expressed in the blood of operationally tolerant patients with drug-free long term graft function compared to stable and rejecting patients. Using a yeast two-hybrid approach and a colocalization study by confocal microscopy we furthermore report an interaction of SMILE with PDIA3, a molecule resident in the endoplasmic reticulum (ER). In accordance with this observation, SMILE silencing in HeLa cells correlated with the modulation of several transcripts involved in proteolysis and a decrease in proteasome activity. Finally, SMILE silencing increased HeLa cell sensitivity to the proteasome inhibitor Bortezomib, a drug that induces ER stress via protein overload, and increased transcript expression of a stress response protein, XBP 1, in HeLa cells and keratinocytes. CONCLUSION/SIGNIFICANCE: In this study we showed that SMILE is involved in the endoplasmic reticulum stress response, by modulating proteasome activity and XBP-1 transcript expression. This function of SMILE may influence immune cell behavior in the context of transplantation, and the analysis of endoplasmic reticulum stress in transplantation may reveal new pathways of regulation in long-term graft acceptance thereby increasing our understanding of tolerance. PMID- 21603655 TI - Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model. AB - BACKGROUND: The bisphosphonate, zoledronic acid (ZOL), can inhibit osteoclasts leading to decreased osteoclastogenesis and osteoclast activity in bone. Here, we used a mixed osteolytic/osteoblastic murine model of bone-metastatic prostate cancer, RM1(BM), to determine how inhibiting osteolysis with ZOL affects the ability of these cells to establish metastases in bone, the integrity of the tumour-bearing bones and the survival of the tumour-bearing mice. METHODS: The model involves intracardiac injection for arterial dissemination of the RM1(BM) cells in C57BL/6 mice. ZOL treatment was given via subcutaneous injections on days 0, 4, 8 and 12, at 20 and 100 ug/kg doses. Bone integrity was assessed by micro-computed tomography and histology with comparison to untreated mice. The osteoclast and osteoblast activity was determined by measuring serum tartrate resistant acid phosphatase 5b (TRAP 5b) and osteocalcin, respectively. Mice were euthanased according to predetermined criteria and survival was assessed using Kaplan Meier plots. FINDINGS: Micro-CT and histological analysis showed that treatment of mice with ZOL from the day of intracardiac injection of RM1(BM) cells inhibited tumour-induced bone lysis, maintained bone volume and reduced the calcification of tumour-induced endochondral osteoid material. ZOL treatment also led to a decreased serum osteocalcin and TRAP 5b levels. Additionally, treated mice showed increased survival compared to vehicle treated controls. However, ZOL treatment did not inhibit the cells ability to metastasise to bone as the number of bone-metastases was similar in both treated and untreated mice. CONCLUSIONS: ZOL treatment provided significant benefits for maintaining the integrity of tumour-bearing bones and increased the survival of tumour bearing mice, though it did not prevent establishment of bone-metastases in this model. From the mechanistic view, these observations confirm that tumour-induced bone lysis is not a requirement for establishment of these bone tumours. PMID- 21603656 TI - De novo enzyme design using Rosetta3. AB - The Rosetta de novo enzyme design protocol has been used to design enzyme catalysts for a variety of chemical reactions, and in principle can be applied to any arbitrary chemical reaction of interest. The process has four stages: 1) choice of a catalytic mechanism and corresponding minimal model active site, 2) identification of sites in a set of scaffold proteins where this minimal active site can be realized, 3) optimization of the identities of the surrounding residues for stabilizing interactions with the transition state and primary catalytic residues, and 4) evaluation and ranking the resulting designed sequences. Stages two through four of this process can be carried out with the Rosetta package, while stage one needs to be done externally. Here, we demonstrate how to carry out the Rosetta enzyme design protocol from start to end in detail using for illustration the triosephosphate isomerase reaction. PMID- 21603657 TI - Food catches the eye but not for everyone: a BMI-contingent attentional bias in rapid detection of nutriments. AB - An organism's survival depends crucially on its ability to detect and acquire nutriment. Attention circuits interact with cognitive and motivational systems to facilitate detection of salient sensory events in the environment. Here we show that the human attentional system is tuned to detect food targets among nonfood items. In two visual search experiments participants searched for discrepant food targets embedded in an array of nonfood distracters or vice versa. Detection times were faster when targets were food rather than nonfood items, and the detection advantage for food items showed a significant negative correlation with Body Mass Index (BMI). Also, eye tracking during searching within arrays of visually homogenous food and nonfood targets demonstrated that the BMI-contingent attentional bias was due to rapid capturing of the eyes by food items in individuals with low BMI. However, BMI was not associated with decision times after the discrepant food item was fixated. The results suggest that visual attention is biased towards foods, and that individual differences in energy consumption--as indexed by BMI--are associated with differential attentional effects related to foods. We speculate that such differences may constitute an important risk factor for gaining weight. PMID- 21603659 TI - Dermatological emergencies. AB - Acute dermatological problems are seen regularly by physicians. This review aims to provide a framework for the diagnosis and management of urgent dermatological conditions. Cutaneous drug reactions are commonly seen and the different clinical presentations are discussed including the less common but important drug reactions Stevens-Johnson syndrome and toxic epidermal necrolysis. Erythrodermic patients also require prompt evaluation and management. Current guidelines for the management of urticaria and the common acquired autoimmune bullous disorders will be discussed. Patients with complications of eczema and psoriasis frequently require urgent in-patient management and patients with cellulitis and leg ulcers are also seen regularly on acute medical receiving units often requiring both medical and dermatological input. PMID- 21603658 TI - EphB2 SNPs and sporadic prostate cancer risk in African American men. AB - The EphB2 gene has been implicated as a tumor suppressor gene somatically altered in both prostate cancer (PC) and colorectal cancer. We have previously shown an association between an EphB2 germline nonsense variant and risk of familial prostate cancer among African American Men (AAM). Here we set out to test the hypothesis that common variation within the EphB2 locus is associated with increased risk of sporadic PC in AAM. We genotyped a set of 341 single nucleotide polymorphisms (SNPs) encompassing the EphB2 locus, including known and novel coding and noncoding variants, in 490 AA sporadic PC cases and 567 matched controls. Single marker-based logistical regression analyses revealed seven EphB2 SNPs showing statistically significant association with prostate cancer risk in our population. The most significant association was achieved for a novel synonymous coding SNP, TGen-624, (Odds Ratio (OR) = 0.22; 95% Confidence Interval (CI) 0.08-0.66, p = 1*10(-5)). Two other SNPs also show significant associations toward a protective effect rs10465543 and rs12090415 (p = 1*10(-4)), OR = 0.49 and 0.7, respectively. Two additional SNPs revealed trends towards an increase in risk of prostate cancer, rs4612601 and rs4263970 (p = 0.001), OR = 1.35 and 1.31, respectively. Furthermore, haplotype analysis revealed low levels of linkage disequilibrium within the region, with two blocks being associated with prostate cancer risk among our population. These data suggest that genetic variation at the EphB2 locus may increase risk of sporadic PC among AAM. PMID- 21603660 TI - Current approaches to cardiopulmonary resuscitation. AB - Cardiac arrest occurs when there is abrupt cessation of effective pumping activity of the heart. Among the likely causes are ventricular asystole (electrical or mechanical), pulseless ventricular tachycardia or ventricular fibrillation. Clinically this may present as 'sudden cardiac death'. PMID- 21603661 TI - An unusual cause of 'musculoskeletal' chest pain. AB - Chest pain is a frequent cause of admission to an acute medical unit. In most cases the cause is initially considered to be either cardiac or respiratory, with musculoskeletal causes being considered a benign diagnosis of exclusion. We report a case of sternoclavicular joint infection, treated initially as a lower respiratory tract infection. The investigation and treatment of this unusual condition are discussed. PMID- 21603662 TI - "CURB" your enthusiasm and consider HIV. AB - We present the case of a 40-year old female who was initially seen by her GP and the Emergency Department with pneumonia failing to respond to oral antibiotics. Her severity assessment score categorised her as being in a low risk group and she was discharged. Subsequent admission and further investigations diagnosed Human Immunodeficiency Virus infection and Pneumocystis jeruvici pneumonia. It is important for emergency departments and acute physicians to apply risk validation tools appropriately and to be alert to underlying immunosuppression. PMID- 21603663 TI - Trimethoprim related Hyperkalaemia in a patient with Renal Tubular Acidosis Type 4. AB - Hyperkalaemia is a common, treatable, medical emergency, often with an iatrogenic cause. This case illustrates the vulnerability of patients with pre-existing renal tubular acidosis type 4 to medications that further inhibit renin aldosterone action. The case also illustrates the danger of keeping entirely separate case notes between different hospital disciplines. PMID- 21603664 TI - Do patients really mind mixed sex bays in an emergency assessment unit? AB - Mixed sex bays are a reality on most Emergency Assessment Units (EAU). However, they are controversial having recently been the focus of political and media attention. We adapted a validated patient satisfaction questionnaire to seek the views of 1000 emergency admissions regarding mixed sex accommodation. Of 1000 respondents, 925 (92%) had been in bays and 665 (66%) shared with the opposite sex. Most 579/665 (87%) were comfortable with this, 97% (966/1000) feeling there was sufficient level of privacy, all (1000/1000) felt they were given privacy when needed. When asked "given the nature and function of EAU would you be willing to share with the opposite sex if it meant a shorter stay?", 857 (86%) said yes. Our study demonstrates that whilst single sex accommodation is ideal it is not the most important factor to most patients admitted to EAU. PMID- 21603665 TI - The Payment by Results (PbR) national tariff severely penalises efficiency and early hospital discharge. AB - The system of Payment by Results (PbR) was instituted in 2005 to reimburse secondary care for its activity. One of the features of PbR is the short stay tariff (SST), in which only 20-50% of the national tariff is paid if patients have a length of stay (LoS) of less than 2 days in hospital for certain Healthcare Resource Groups (HRGs) - or conditions. We analysed the admissions under Acute Medicine at Bradford Teaching Hospitals over a period of one year and identified the HRGs to which the SST applied. We used the 2007 PbR national tariff to calculate the additional income that would have been generated if these patients were kept in hospital for at least 2 days in order to avoid SST. We calculated an extra theoretical income of approximately L5 million if all these patients had a length of stay (LoS) more than 2 days to avoid the SST. Sixteen additional beds (assuming 85% occupancy) would have been required at a cost of around L1million per year to accommodate these patients. We show that the current PbR system is flawed and penalises hospitals with a higher turnover of patients. PMID- 21603666 TI - Out-patient detection of deep vein thrombosis using a combination of risk scoring and strain-gauge-plethysmography: a follow-up study. AB - Patients are frequently referred to hospital for exclusion of deep vein thrombosis (DVT); however, the diagnosis is only confirmed in 12% of those undergoing investigation. An effective strategy is required, which minimises the number of negative investigations, while safely excluding or confirming the diagnosis. This study investigates the combination of clinical risk scoring and strain-gauge plethysmography in the initial assessment of patients with suspected DVT. A survey was conducted of 1300 patients referred with suspected DVT over the course of a year. The results of this investigation were comparable to previous clinical trials and supports the use of strain-gauge plethysmography combined with clinical risk score in a busy acute medical unit. PMID- 21603667 TI - Picture Quiz: An Unusual cause of 'Troponinaemia'. AB - A 58 year old policeman presented with a 4 week history of cough, haemoptysis, exertional dyspnoea, ear discomfort and sore throat. He was previously healthy and taking no regular medications. He was a non-smoker and had no risk factors for coronary artery disease. He had recently completed two courses of antibiotics for a presumed ear infection. He had also experienced occasional minor epistaxis with constitutional symptoms of weight loss and night sweats over recent months. Clinical examination was unremarkable. PMID- 21603668 TI - The acute physicians unit in scarborough hospital. AB - AIM: The aim of Acute Physicians Unit (APU) in Scarborough Hospital is consultant led delivery of acute medical care. It operates weekdays from 9am to 5pm, staffed by a consultant physician, a trained nurse and an auxiliary nurse. We reviewed the APU activity over 38 months. RESULTS: 7170 patients were referred to APU, mainly from GPs (59.6%) and A&E (26.5%). The most common type of referrals: cardiovascular 21%, neurological 16.9% and respiratory 15.1%. It prevented admission in 2217 cases (30.9%): 22.4% were sent home after assessment in APU and in 8.5% telephone advice was sufficient. CONCLUSION: The APU has led to early consultant review in 53% of admissions, discharge of 31% of patients and is a useful source of consultation for GPs. PMID- 21603669 TI - Picture Quiz: An Unusual cause of 'Troponinaemia' - Answers. PMID- 21603670 TI - Diagnosis and management of deep vein thrombosis. AB - Awareness of deep venous thrombosis has increased considerably in the last decade including recognition of the importance of thromboprophylaxis for acutely ill hospital inpatients as preventative therapy. Combinations of a pre-test probability score plus a D-Dimer analysis can identify those patients where the chances of DVT are very low and radiological investigation can be obviated. The gold standard for diagnosis is still either ascending venography or venous Doppler ultrasound. Low molecular weight heparin has taken over from unfractionated calcium heparin as the initial treatment of choice. There are many challenges in management, especially deciding the optimum duration of anticoagulant treatment in order to balance the risks of drug induced bleeding against recurrent venous thromboembolic events. PMID- 21603671 TI - Advances in deep vein thrombosis management with thrombolysis. AB - Lower extremity deep vein thrombosis (DVT) is a common disease associated with serious short term and long term complications. Its conventional treatment has been anticoagulation. Thrombolytic treatment has been used for DVT for over 40 years. More recently catheter directed thrombolysis has taken over systemic thrombolysis. This technique is useful to prevent post thrombotic syndrome (PTS) after DVT. In this review article we present a case of DVT thrombolysis in our hospital, look at the pathophysiology of PTS, the mechanism of thrombolysis and the current status of thrombolysis in DVT. PMID- 21603672 TI - A non-cardiac cause of an abnormal ECG. AB - Abnormalities of the electrocardiogram are extremely useful for the diagnosis of heart disease, but they may also occur in non-cardiac conditions. The electrocardiographic abnormalities that have been described in neurological diseases are among the most striking deviations from normal. We describe a patient with an intracranial space occupying lesion (pilocytic astrocytoma) who exhibited electrocardiographic changes suggestive of acute coronary syndrome at the time of presentation with syncope. PMID- 21603673 TI - An unusual case of Fever and lymphadenopathy. AB - A 62 year old female presented to the acute medical team with headache, fevers and enlarged axillary lymph nodes. Initial biochemical, microbiological and immunological investigations were normal. However, radiological imaging revealed that her silicone breast implants had ruptured, which may have been responsible for her presentation. A brief overview of the clinical features and management of silicone breast implant rupture is provided. PMID- 21603674 TI - Tricyclic Antidepressant Overdose causing Acute Respiratory Distress Syndrome. AB - We report two recent cases of tricyclic antidepressant (TCA) overdose complicated by the development of acute respiratory distress syndrome (ARDS). The previous literature documenting an association between TCAs and ARDS is reviewed. We propose that the respiratory complications of TCA overdose should be more widely publicised and included in national toxicology databases. PMID- 21603675 TI - Paracetamol overdose presenting with hyperglycaemia, acidosis and ketonuria in a non-diabetic patient. AB - There are a number of cases reported in the literature which describe hyperglycaemia in patients following paracetamol overdose. The majority of these occur in conjunction with hepatic failure. Less well known is the occurrence of hyperglycaemia and acidosis following paracetamol overdose in the absence of hepatic failure. This report describes such a case which was initially misdiagnosed as diabetic ketoacidosis (DKA). PMID- 21603676 TI - Providing better care for patients with complex needs in acute medicine. AB - Patients with complex needs are commonly admitted on the acute medical take and comprise a significant proportion of the workload for an acute physician. An innovative multi-professional approach to the assessment of this group of patients has been developed in Edinburgh; this paper summarises the results of a 4 week review of data collected on patients assessed by the multiprofessional team on the Medical Assessment Unit at Edinburgh Royal Infirmary. PMID- 21603677 TI - Use of SimpliRED D-dimer assay and computerised tomography in the diagnosis of acute pulmonary embolism. AB - BACKGROUND: The utility of D-dimer in the diagnostic workup of pulmonary embolism has been established. Several D-dimer tests are available with different sensitivities and specificities. SimpliRED D-dimer is a rapid qualitative whole blood D-dimer assay suitable for bedside use. OBJECTIVE: To assess the utility of the SimpliRED D-dimer test in patients with suspected acute pulmonary embolism in the absence of formal 'risk scoring'. DESIGN: A prospective study measuring SimpliRED D-dimer in unselected patients undergoing computed tomographic pulmonary angiography (CTPA) examination for suspected acute pulmonary embolism. MAIN OUTCOME MEASURES: D-dimer and CTPA results were compared. Sensitivity, specificity, and positive and negative predictive values of SimpliRED D-dimer were calculated for the unselected patient group. RESULTS: Forty-seven patients underwent D-dimer testing and CTPA. SimpliRED D-dimer was positive in 23 and negative in 24 patients. D-dimer was positive in only 6 (50%) of the 12 patients with positive CTPA. Of the 35 with negative CTPA, 17 had positive D-dimer. The positive predictive value of the D-dimer was 26.1 % and the negative predictive value 75.0%. CONCLUSION: SimpliRED D-dimer should not be used in the diagnosis of pulmonary embolism in the absence of risk scoring. PMID- 21603678 TI - Clinical governance in acute medicine. AB - We are all responsible for maintaining our standards and improving the way in which we work. However, keeping up to date with the many guidelines/documents published and finding what is relevant to acute medicine can be difficult. This new section of Acute Medicine will hopefully bring together the relevant updates in the world of clinical governance. PMID- 21603680 TI - Correspondence. PMID- 21603679 TI - Gastrointestinal emergencies. AB - Gastrointestinal Emergencies describes itself as "the definitive reference guide for the management of gastrointestinal emergencies and endoscopic complications", The book covers the huge topic of acute gastroenterology in a succinct and easy to read format. At just over 200 pages it covers a lot more than what you might expect and makes for easy and enjoyable reading. PMID- 21603681 TI - Graphene-Ni (001) interface study. AB - The interfacial properties for a carbon nanotube on a Ni (001) surface are modeled by a piece of vertical graphene standing on a Ni (001) surface. The interaction between the graphene and the nickel (001) surface is investigated using density functional theory (DFT) calculations. Zigzag type graphene can stand on the hollow sites of the Ni (001) surface along the [linear span]110[linear span] direction. For such a configuration, Ni (001)-graphene interfacial mechanical properties are studied, and we find that Ni-Ni bonds near the interface will break first under tensile strain. C-C bond lengths near the interface are longer than the C-C bonds of graphene, and the charge density of those bonds decrease due to the formation of interfacial Ni-C bonds. It suggests that C-C bonds near the interface may break during the carbon nanotube growth processes. PMID- 21603682 TI - Simulation of amino acid diffusion across water/hydrophobic interfaces. AB - The mechanism of amino acid transfer across water/hydrophobic interfaces has important biological relevance but is poorly understood. Combined QM/MM simulations show that zwitterionic Gly enters the hydrophobic phase till ca. 1 nm before neutralisation occurs. Interfacial effects significantly affect the relative tautomers stability. PMID- 21603683 TI - Deciphering the mystery of hexagon holes in an all-boron graphene alpha-sheet. AB - Boron could be the next element after carbon capable of forming 2D-materials similar to graphene. Theoretical calculations predict that the most stable planar all-boron structure is the so-called alpha-sheet. The mysterious structure of the alpha-sheet with peculiar distribution of filled and empty hexagons is rationalized in terms of chemical bonding. We show that the hexagon holes serve as scavengers of extra electrons from the filled hexagons. This work could advance rational design of all-boron nanomaterials. PMID- 21603684 TI - Ab initio theoretical study of non-covalent adsorption of aromatic molecules on boron nitride nanotubes. AB - We have studied non-covalent functionalization of boron nitride nanotubes (BNNTs) with benzene molecule and with seven other different heterocyclic aromatic rings (furan, thiophene, pyrrole, pyridine, pyrazine, pyrimidine, and pyridazine, respectively). A hybrid density functional theory (DFT) method with the inclusion of dispersion correction is employed. The structural and electronic properties of the functionalized BNNTs are obtained. The DFT calculation shows that upon adsorption to the BNNT, the center of aromatic rings tend to locate on top of the nitrogen site. The trend of adsorption energy for the aromatic rings on the BNNTs shows marked dependence on different intermolecular interactions, including the dispersion interaction (area of the delocalized pi bond), the dipole-dipole interaction (polarization), and the electrostatic repulsion (lone pair electrons). The DFT calculation also shows that non-covalent functionalization of BNNTs with aromatic rings can give rise to new impurity states within the band gap of pristine BNNTs, suggesting possible carrier doping of BNNTs via selective adsorption of aromatic rings. PMID- 21603686 TI - Ultra-high resolution 17O solid-state NMR spectroscopy of biomolecules: a comprehensive spectral analysis of monosodium L-glutamate.monohydrate. AB - Monosodium L-glutamate monohydrate, a multiple oxygen site (eight) compound, is used to demonstrate that a combination of high-resolution solid-state NMR spectroscopic techniques opens up new possibilities for (17)O as a nuclear probe of biomolecules. Eight oxygen sites have been resolved by double rotation (DOR) and multiple quantum (MQ) NMR experiments, despite the (17)O chemical shifts lying within a narrow shift range of <50 ppm. (17)O DOR NMR not only provides high sensitivity and spectral resolution, but also allows a complete set of the NMR parameters (chemical shift anisotropy and electric-field gradient) to be determined from the DOR spinning-sideband manifold. These (17)O NMR parameters provide an important multi-parameter comparison with the results from the quantum chemical NMR calculations, and enable unambiguous oxygen-site assignment and allow the hydrogen positions to be refined in the crystal lattice. The difference in sensitivity between DOR and MQ NMR experiments of oxygen in bio/organic molecules is also discussed. The data presented here clearly illustrates that a high resolution (17)O solid-state NMR methodology is now available for the study of biomolecules, offering new opportunities for resolving structural information and hence new molecular insights. PMID- 21603687 TI - Metal-containing triarylboron compounds for optoelectronic applications. AB - Triarylboranes have recently emerged as a powerful new class of electron acceptors with great potential as optoelectronic materials. The empty p(z) orbital on the boron centre promotes strong charge-transfer transitions, leading to highly luminescent compounds with colors spanning the entire visible spectrum. Due to intense research efforts over the past decade, many examples now exist of organic molecules based on this structural motif. Only recently, however, have transition metal-containing triarylboranes been closely investigated. These compounds are capable of bright luminescence from a triplet excited state, and have been developed as efficient emissive materials for organic light-emitting diodes (OLEDs) as a result. In addition, their long-lived phosphorescence gives these materials potential as highly selective chemical sensors for small anions using time-gated detection, eliminating interference from background fluorescence. The research of the past several years has now led to a better understanding of the impact of the triarylboron group on the photophysical properties of metal complexes, which we expect will provide many opportunities for research into this class of functional phosphorescent materials. PMID- 21603685 TI - The shape-shifting quasispecies of RNA: one sequence, many functional folds. AB - E Unus pluribum, or "Of One, Many", may be at the root of decoding the RNA sequence-structure-function relationship. RNAs embody the large majority of genes in higher eukaryotes and fold in a sequence-directed fashion into three dimensional structures that perform functions conserved across all cellular life forms, ranging from regulating to executing gene expression. While it is the most important determinant of the RNA structure, the nucleotide sequence is generally not sufficient to specify a unique set of secondary and tertiary interactions due to the highly frustrated nature of RNA folding. This frustration results in folding heterogeneity, a common phenomenon wherein a chemically homogeneous population of RNA molecules folds into multiple stable structures. Often, these alternative conformations constitute misfolds, lacking the biological activity of the natively folded RNA. Intriguingly, a number of RNAs have recently been described as capable of adopting multiple distinct conformations that all perform, or contribute to, the same function. Characteristically, these conformations interconvert slowly on the experimental timescale, suggesting that they should be regarded as distinct native states. We discuss how rugged folding free energy landscapes give rise to multiple native states in the Tetrahymena Group I intron ribozyme, hairpin ribozyme, sarcin-ricin loop, ribosome, and an in vitro selected aptamer. We further describe the varying degrees to which folding heterogeneity impacts function in these RNAs, and compare and contrast this impact with that of heterogeneities found in protein folding. Embracing that one sequence can give rise to multiple native folds, we hypothesize that this phenomenon imparts adaptive advantages on any functionally evolving RNA quasispecies. PMID- 21603688 TI - Selection of tetracycline inducible self-cleaving ribozymes as synthetic devices for gene regulation in yeast. AB - Synthetic regulatory devices are key components for the development of complex biological systems and the reprogramming of cellular functions and networks. Here we describe the selection of tetracycline inducible hammerhead ribozymes. A tetracycline aptamer was fused to the full-length hammerhead ribozyme via a variable linker region. 11 rounds of in vitro selection were applied to isolate linker sequences that mediate tetracycline dependent hammerhead cleavage. We identified allosteric ribozymes that cleave in the presence of 1 MUM tetracycline as fast as the full-length ribozyme whereas cleavage is inhibited up to 333-fold in the absence of tetracycline. Reporter gene assays indicate that the allosteric ribozymes can be employed to control gene expression in yeast. PMID- 21603689 TI - Bioinspired catecholic chemistry for surface modification. AB - The attachment strategy based on catecholic chemistry has been arousing renewed interest since the work on polymerized catecholic amine (polydopamine) (Messersmith et al., Science, 2007, 318, 426) was published. Catechols and their derived compounds can self-assemble on various inorganic and organic materials, including noble metals, metals, metal oxides, mica, silica, ceramics and even polymers. It opens a new route to the modification of various substrates and the preparation of functional composite materials by simple chemistry. However, there is still not a full review so far about the attachment chemistry despite the dramatically increasing number of publications. This critical review describes the state-of-the-art research in the area: the design and synthesis of catecholic molecules, their adsorption mechanisms and the stability of assemblies in solution, and their applications etc. Some perspectives on future development are raised (195 references). PMID- 21603690 TI - Structure, electronic properties and catalytic behaviour of an activity-enhancing CYP102A1 (P450(BM3)) variant. AB - The substrate-free crystal structure of a five-mutation directed evolution variant of CYP102A1 (P450(BM3)) with generic activity-enhancing properties ("KT2") has been determined to 1.9-A resolution. There is a close resemblance to substrate-bound structures of the wild-type enzyme (WT). The disruption of two salt bridges that link the G- and I-helices in WT causes conformational changes that break several hydrogen bonds and reduce the angle of the kink in the I-helix where dioxygen activation is thought to take place. The side-chain of a key active site residue, Phe87, is rotated in one molecule of the asymmetric unit, and the side-chains of Phe158 and Phe261 cascade into the orientations found in fatty-acid-bound forms of the enzyme. The iron is out of the porphyrin plane, towards the proximal cysteine. Unusually, the axial water ligand to the haem iron is not hydrogen-bonded to Ala264. The first electron transfer from the reductase domain to the haem domain of substrate-free KT2 is almost as fast as in palmitate bound WT even though the reduction potential of the haem domain is only slightly more oxidising than that of substrate-free WT. However, NADPH is turned over slowly in the absence of substrate, so the catalytic cycle is gated by a step subsequent to the first electron transfer-a contrast to WT. Propylbenzene binding slightly raises the first electron transfer rate in WT but not in KT2. It is proposed that the generic rate accelerating properties of KT2 arise from the substrate-free form being in a catalytically ready conformation, such that substrate-induced changes to the structure play a less significant role in promoting the first electron transfer than in WT. PMID- 21603691 TI - Hybrid opto-electric manipulation in microfluidics-opportunities and challenges. AB - Hybrid opto-electric manipulation in microfluidics/nanofluidics refers to a set of methodologies employing optical modulation of electrokinetic schemes to achieve particle or fluid manipulation at the micro- and nano-scale. Over the last decade, a set of methodologies, which differ in their modulation strategy and/or the length scale of operation, have emerged. These techniques offer new opportunities with their dynamic nature, and their ability for parallel operation has created novel applications and devices. Hybrid opto-electric techniques have been utilized to manipulate objects ranging in diversity from millimetre-sized droplets to nano-particles. This review article discusses the underlying principles, applications and future perspectives of various hybrid opto-electric techniques that have emerged over the last decade under a unified umbrella. PMID- 21603692 TI - Merging the best of two worlds: artificial metalloenzymes for enantioselective catalysis. AB - Artificial metalloenzymes result from combining a catalytically active organometallic moiety with a macromolecular host. The resulting hybrid catalysts combine attractive features of both homogeneous and enzymatic systems. Herein we summarize the recent progress in this emerging field and outline the challenges ahead. PMID- 21603693 TI - Complexes of a [2]rotaxane ligand with terminal terpyridine groups. AB - Permanently interlocked [2]rotaxane ligands can be created by capping a pyridine terminated [2]pseudorotaxane with terpyridine containing stoppers. The robust nature of the resulting [2]rotaxane ligand allows coordination to inert metals such as Ru(II) not possible under standard self-assembly conditions. PMID- 21603694 TI - A versatile and modular approach to functionalisation of deep-cavity cavitands via"click" chemistry. AB - The surface modification of deep-cavity cavitands has been demonstrated by using the azide-alkyne "click" coupling to attach dendritic macromolecules or linear polymers onto their periphery. The resulting set of macromolecular cavitands exhibited tuneable solubility yet retained the ability to encapsulate guest molecules. PMID- 21603695 TI - Spanning QTAIM topology phase diagrams of water isomers W4, W5 and W6. AB - Structural and chemical properties of the small water clusters W(4), W(5) and W(6) are investigated with the theory of atoms and molecules (QTAIM). For the W(4), W(5) and W(6) clusters, nine, fourteen and twenty-seven conformers, respectively, have been analyzed. For the W(4), W(5) and W(6) clusters one, two and three of these structures, respectively, have not been reported before. We then proceed to extend the W(4), W(5) and W(6) water cluster topology space using QTAIM; the Poincare-Hopf topological sum rules are applied to create rules to identify the spanning set of conformer topologies, this includes finding three, ten and eight new distinct topologies that satisfy the Poincare-Hopf relation for W(4), W(5) and W(6) respectively. The topological stability of degenerate solutions to the Poincare-Hopf relation is compared by evaluating the proximity to rupturing of critical points of the gradient vector field of the charge density. We introduce a QTAIM topology space to replace the inconsistent use of Euclidean geometry to determine whether a cluster is 1-, 2- or 3-D. We show from the topology of the charge density that the conformers of the W(4), W(5) clusters are more energetically stable in less compact, planar forms, conversely the conformers of W(6) are more energetically stable with compact 3-D topologies. Quantifying the degree of covalent character in the hydrogen bonding for the W(4), W(5) and W(6) clusters independently verifies this finding. Differences in simple rules for the number of hydrogen bonds obeying the Bernal-Fowler ice rules between W(4), W(5) and W(6) reflect the transition from 2-D to 3-D structures being more energetically stable. In addition, we identify a new class of O-O bonding interactions that are up to 48% longer than the inter-nuclear separation and appear to be failed hydrogen bonds. PMID- 21603696 TI - Multiple exciton generation in nanocrystal quantum dots--controversy, current status and future prospects. AB - Multiple exciton generation is a process that can occur in quantum dots by which the energy of an absorbed photon in excess of the bandgap can be used to create one or more additional excitons instead of being wasted as heat. This effect has received considerable interest because it has the potential to significantly enhance the performance of solar cells, nanocrystal lasers, high speed electronic devices and photocatalysts. However, measuring the efficiency of multiple exciton generation is experimentally challenging and the results of these measurements have been the subject of some controversy. This Perspective describes the techniques used to determine the quantum yield of multiexcitons in nanocrystals and also details the experimental artefacts that can confuse these measurements and have been the source of much of the recent debate. The greater understanding of these artefacts that has emerged recently and the experimental techniques developed to eliminate their effects on quantum yield measurements will also be described. The efficiency of multiple exciton generation currently obtainable from nanocrystals and its potential impact on solar cell performance is assessed in the light of this improved experimental understanding. Whilst it is found the quantum yields thus far reported are insufficient to result in more than a modest increase in solar cell efficiency, an analysis of the expected performance of a nanocrystal engineered to maximise multiple exciton generation indicates that a significant improvement in solar cell performance is possible. Moreover, a nanocrystal design is proposed for optimised efficiency of multiple exciton generation which would allow its potential benefit to solar power production to be realised. PMID- 21603698 TI - Influence of polarization and wavelength on two-photon excited luminescence of single gold nanospheres. AB - The Brownian rotation of a nearly spherical gold particle capped with ligands can be observed in the correlation profile of the intensity of the two-photon excited luminescence. Here we report on a multi-parameter study of the luminescence properties, including spectral and polarization analysis of the signal at the single particle level. First, the data confirm the role of the radiative de excitation of the surface plasmons in the luminescence process. Secondly, the results obtained at low power indicate that the capped particle in water can be approximatively described as a spherical rotor acting in the far-field as a point like absorption and emission dipole of fixed directions. In addition, we show that the dynamics of the ligands, induced by the heat transfer from the particle to its environment, can be partly controlled by the choice of excitation wavelength. PMID- 21603697 TI - On-chip characterization of cryoprotective agent mixtures using an EWOD-based digital microfluidic device. AB - For tissue engineering and regenerative medicine, cryopreservation, a technique for preserving biomaterials in the frozen state with cryoprotective agents (CPAs), is critically important for preserving engineered tissues (ETs) as well as cells necessary to create ETs. As more diverse ETs are produced using various cell types, CPAs and corresponding freeze/thaw (F/T) protocols need to be developed cell/tissue-type specifically. This is because CPAs and F/T protocols that have been successful for one cell/tissue type have proven to be difficult to adapt to other cell/tissue types. The most critical barrier to address this challenge is the inability to screen and identify CPA or CPA mixtures efficiently. In this paper, we developed an "electro-wetting-on-dielectic" (EWOD) based digital microfluidic platform to characterize and screen CPA mixtures cell type specifically. The feasibility of the EWOD platform was demonstrated by characterizing and optimizing a mixture of dimethlysulfoxide (DMSO) and PBS for human breast cancer cell line as model CPA mixture and cell line. The developed platform multiplexed droplets of DMSO and PBS to create an array of DMSO-PBS mixtures, and mapped the phase change diagram of the mixture. After loading cell suspensions on the platform, the mixture was further screened on-chip for toxicity and cryoprotection. The results were discussed to illustrate the capabilities and limitations of the EWOD platform for cell and tissue-type specific optimization of CPA mixtures and F/T protocols. PMID- 21603699 TI - Hybrid organic-inorganic catalytic mesoporous materials with proton sponges as building blocks. AB - Non-ordered organic-inorganic mesoporous hybrid materials with basic sites have been synthesized following a fluoride-catalysed sol-gel process at neutral pH and low temperatures that avoids the use of structural directing agents (SDAs). Proton sponges have been used as the organic builder of the hybrids, while the inorganic part corresponds to silica tetrahedra. The proton sponges are diamines that exhibit very high basicity and, after functionalization, have been introduced as part of the walls of the mesoporous silica by one-pot synthesis. Several hybrids with different organic loadings have been synthesized and characterized by gas adsorption, thermogravimetric and elemental analysis, solid state MAS-NMR and FTIR spectroscopy. These hybrids show high activity as base catalysts and can be recycled. PMID- 21603700 TI - Ruthenium nanoparticles in ionic liquids: structural and stability effects of polar solutes. AB - Ionic liquids are a stabilizing medium for the in situ synthesis of ruthenium nanoparticles. Herein we show that the addition of molecular polar solutes to the ionic liquid, even in low concentrations, eliminates the role of the ionic liquid 3D structure in controlling the size of ruthenium nanoparticles, and can induce their aggregation. We have performed the synthesis of ruthenium nanoparticles by decomposition of [Ru(COD)(COT)] in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C(1)C(4)Im][NTf(2)], under H(2) in the presence of varying amounts of water or 1-octylamine. For water added during the synthesis of metallic nanoparticles, a decrease of the solubility in the ionic liquid was observed, showed by nanoparticles located at the interface between aqueous and ionic phases. When 1-octylamine is present during the synthesis, stable nanoparticles of a constant size are obtained. When 1-octylamine is added after the synthesis, aggregation of the ruthenium nanoparticles is observed. In order to explain these phenomena, we have explored the molecular interactions between the different species using (13)C-NMR and DOSY (Diffusional Order Spectroscopy) experiments, mixing calorimetry, surface tension measurements and molecular simulations. We conclude that the behaviour of the ruthenium nanoparticles in [C(1)C(4)Im][NTf(2)] in the presence of 1-octylamine depends on the interaction between the ligand and the nanoparticles in terms of the energetics but also of the structural arrangement of the amine at the nanoparticle's surface. PMID- 21603701 TI - Cellular uptake mechanisms of functionalised multi-walled carbon nanotubes by 3D electron tomography imaging. AB - Carbon nanotubes (CNTs) are being investigated for a variety of biomedical applications. Despite numerous studies, the pathways by which carbon nanotubes enter cells and their subsequent intracellular trafficking and distribution remain poorly determined. Here, we use 3-D electron tomography techniques that offer optimum enhancement of contrast between carbon nanotubes and the plasma membrane to investigate the mechanisms involved in the cellular uptake of shortened, functionalised multi-walled carbon nanotubes (MWNT-NH(3)(+)). Both human lung epithelial (A549) cells, that are almost incapable of phagocytosis and primary macrophages, capable of extremely efficient phagocytosis, were used. We observed that MWNT-NH(3)(+) were internalised in both phagocytic and non phagocytic cells by any one of three mechanisms: (a) individually via membrane wrapping; (b) individually by direct membrane translocation; and (c) in clusters within vesicular compartments. At early time points following intracellular translocation, we noticed accumulation of nanotube material within various intracellular compartments, while a long-term (14-day) study using primary human macrophages revealed that MWNT-NH(3)(+) were able to escape vesicular (phagosome) entrapment by translocating directly into the cytoplasm. PMID- 21603702 TI - A linear single-molecule magnet based on [Ru(III)(CN)6]3-. AB - We report the synthesis, structure and magnetic properties of the first molecular cluster and single-molecule magnet to incorporate [Ru(III)(CN)(6)](3-). Frequency domain Fourier-transform THz-EPR (FDFT THz-EPR) and magnetic susceptibility measurements indicate strongly anisotropic Mn-Ru exchange interactions. PMID- 21603703 TI - Off-equilibrium response of grafted polymer chains subject to a variable rate of compression. AB - We present Brownian dynamics simulations of single grafted semiflexible chains (i.e., "polymer mushrooms") with varying persistence lengths, intra-chain interactions, and subject to confinement. The results from different rates of compression are presented in the cases of an approaching infinite plane and a paraboloid tip. We discuss the different behaviour observed for grafted chains with strong and weak self-attraction (i.e., "hard" and "soft" polymer mushrooms). In both cases the effect on the size and shape is more pronounced for a slow compression rate, especially for "hard mushrooms". We have also studied the relaxation of the chain while the compressing plane is maintained, and when it is removed suddenly. We find that the response depends strongly on the time allowed for relaxation in the compressed state. When using instead a paraboloid tip, the overall effects are similar yet less pronounced because the chain can dodge the confining object via an "escape transition." PMID- 21603704 TI - Terahertz spectroscopy of enantiopure and racemic polycrystalline valine. AB - Experimental and computational THz (or far-infrared) spectra of polycrystalline valine samples are reported. The experimental spectra have been measured using THz time-domain spectroscopy. Spectra of the pure enantiomers, both D and L, as well as the dl racemate have been taken at room temperature and low temperature (78 K). The spectra of the pure D and L enantiomers are essentially identical, and they are markedly different from the DL racemate. In addition, a temperature dependent study of L-valine was undertaken in which the absorption maxima were found to red shift as a function of increasing temperature. The vibrational absorption spectra (frequencies and intensities) were calculated using the harmonic approximation with the Perdew-Burke-Ernzerhof (PBE) functional, localized atomic orbital basis sets, and periodic boundary conditions. The calculated and experimental spectra are in good qualitative agreement. A general method of quantifying the degree to which a calculated mode is intermolecular versus intramolecular is demonstrated, with the intermolecular motions further separated into translational versus rotational/librational motion. This allows straightforward comparison of spectra calculated using different basis sets or other constraints. PMID- 21603705 TI - Calcium-containing diatomic dications in the gas phase. AB - Sputtering (ion surface bombardment) of various calcium-containing powder samples with an energetic (17 keV), high-current (16)O(-) beam has produced the diatomic dications of CaSi(2+), CaP(2+), CaF(2+), CaH(2+), CaCl(2+), CaBr(2+) and CaI(2+). These molecular gas-phase species have been identified in positive ion mass spectra at half-integer m/z values; their ion flight times through a magnetic sector mass spectrometer were roughly 10(-5) s. Most of them appear to be novel molecular ions; the stability of the latter four (CaH(2+), CaCl(2+), CaBr(2+) and CaI(2+)) had been demonstrated in previous theoretical studies, whereas only CaF(2+) and CaBr(2+) had been observed before. Here we combine the results of our experimental search with a detailed theoretical study of the remaining three systems CaSi(2+), CaP(2+) and CaF(2+). All electronic states correlating with the first dissociation channel are characterized using high level ab initio electronic structure calculations. In their ground states, we find CaSi(2+) to be a long-lived metastable molecule, whereas CaF(2+) and CaP(2+) are thermodynamically stable, with respective equilibrium internuclear distances of 6.253, 4.740, and 5.731 a(0). CaSi(2+) has a well depth of 7116 (0.88) cm(-1) (eV) and a dissociation asymptote 7956 (0.99) cm(-1) (eV) below the ground state minimum. The dissociation energy of CaF(2+) is estimated to be 3404 (0.42) cm(-1) (eV), whereas for CaP(2+) we found 2547 (0.32) cm(-1) (eV), and a barrier height of 8118 (1.01) cm(-1) (eV). Their adiabatic double ionisation energies are 22.87, 16.91, and 17.32 eV, respectively, for the F, Si, and P containing dications. PMID- 21603706 TI - Multiscale modelling. PMID- 21603707 TI - Transcriptional response of Streptococcus pneumoniae to Zn2+) limitation and the repressor/activator function of AdcR. AB - Zinc (Zn(2+)) is an important trace metal ion that has been shown to regulate the expression of several (virulence) genes in streptococci. Previously, we analyzed the genome-wide response of S. pneumoniae to Zn(2+)-stress. In this work, we have performed a transcriptomic analysis to identify genes that are differentially expressed under intracellular Zn(2+) limitation. This revealed a number of genes that are highly upregulated in the absence of extracellular Zn(2+), amongst which the genes belonging to the regulon of the Zn(2+)-responsive repressor AdcR, like adcBCA, encoding a Zn(2+)-dependent ABC-uptake system, adcAII, encoding a Zn(2+) binding lipoprotein, and also virulence genes belonging to the Pht family (phtA, phtB, phtD and phtE). Using transcriptome analysis, lacZ-reporter studies, in vitro DNA binding experiments, and in silico operator predictions, we show that AdcR directly represses the promoters of adcRCBA, adcAII-phtD, phtA, phtB and phtE in the presence of Zn(2+). AdcR can also function as an activator, since in the presence of Zn(2+) it directly induces expression of adh that encodes a Zn(2+)-containing alcohol dehydrogenase. In conclusion, the genome-wide transcriptional response of S. pneumoniae to Zn(2+) limitation was established, which is mainly mediated via direct regulation by the Zn(2+)-dependent regulator AdcR. PMID- 21603708 TI - Catalytic hydroxylation of [closo-B12H12](2-)-adaptation of the Periana reaction to a polyhedral borane. AB - Per-B-hydroxylation of a polyhedral borane anion has been demonstrated by the catalytic hydroxylation of icosahedral [closo-B(12)H(12)](2-) using soft electrophiles such as platinum group metal catalysts or iodine cation. A new route to [closo-B(12)(OH)(12)](2-) from [closo-B(12)H(12)](2-) without the use of H(2)O(2) oxidant provides an alternative hydroxylation process. PMID- 21603709 TI - Identification of the amino acid labionin and its desulfurised derivative in the type-III lantibiotic LabA2 by means of GC/MS. AB - A GC-MS method for the rapid and unambiguous identification of the amino acid labionin (Lab) occurring in type-III lantibiotics is presented. This method will constitute a valuable tool for the characterisation and structure elucidation of labyrinthopeptins and their differentiation from lanthionine-type lantibiotics. PMID- 21603710 TI - Conformational and spectroscopic properties of pi-extended, bipyrrole-fused rubyrin and sapphyrin derivatives. AB - Two new expanded porphyrins, naphthorubyrin and naphthosapphyrin, were synthesized. The pi-extended rubyrin was isolated and structurally characterized in its monoprotonated form. The sapphyrin congener undergoes pyrrole inversion as a function of the protonation state. These conformational effects are reflected in the spectroscopic features, including the excited singlet state lifetimes. PMID- 21603711 TI - A novel method for dynamic investigations of photoinduced electron transport using functionalized-porphyrin at ITO/liquid interface. AB - A new scanning electrochemical microscopy (SECM) model provided a two-dimensional quantitative analysis on a heterogeneous electron transport (ET) process of a functionalized porpyrin by photoinduced ET at the ITO/liquid interface. The basic features of oxidized porphyrin under light source were recorded by feedback approach curves within the framework of the bimolecular ET mechanisms. PMID- 21603712 TI - Enzyme-magnetic nanoparticle conjugates as a rigid biocatalyst for the elimination of toxic aromatic hydrocarbons. AB - An enzyme-magnetic nanoparticle conjugate is prepared via conjugation of Ni(2+) ions onto the surface of magnetic nanoparticles to interact with a six histidine tagged enzyme. The catalytic properties and enzyme rigidification of the conjugates are more stable at high concentrations of aromatic hydrocarbons. PMID- 21603713 TI - pH triggered self-assembly of core cross-linked star polymers possessing thermoresponsive cores. AB - Core cross-linked star polymers possessing responsiveness to pH and temperature stimuli have been prepared, and we demonstrate how changes to pH and temperature can be used to trigger the release and uptake of a hydrophobic dye. PMID- 21603714 TI - "Clickable" pillar[5]arenes. AB - Introduction of bulky substituents such as benzyl and pyrenyl groups using click reactions inhibited or slowed the rotation of the units on the NMR chemical shift timescale. The perpyrenylated pillar[5]arene showed a thermally-responsive excimer emission, but a unit model of the perpyrenylated pillar[5]arene did not exhibit such a response. PMID- 21603715 TI - Direct exfoliation of graphene in organic solvents with addition of NaOH. AB - We report a facile method for the production of graphene sheets through the liquid-phase exfoliation of graphite in organic solvents with addition of NaOH. NaOH was found to be intercalated into the interplanar spaces of graphite, and greatly improves exfoliation efficiency up to 20 times. PMID- 21603716 TI - Highly enantioselective organocascade intermolecular iminium/enamine Michael addition on enals. AB - An unprecedented intermolecular iminium/enamine Michael addition on enals has been developed by taking advantage of the high reactivity of vinyl sulfones. This powerful organocascade allows for the rapid construction of attractive synthons in high enantioselectivities (typically 99% ee). PMID- 21603717 TI - New linear supramolecular polymers that are driven by the combination of quadruple hydrogen bonding and crown ether-paraquat recognition. AB - Novel linear supramolecular polymers, based on the combination of two classical binding interactions: the quadruple hydrogen bonding ureidopyrimidinone units and crown ether-paraquat host-guest recognition motifs, have been constructed from two heteroditopic monomers. PMID- 21603719 TI - Synthesis of a head-to-tail-type cyclodextrin-based insulated molecular wire. AB - We developed a new method for synthesizing an organic-soluble insulated molecular wire (IMW) using permethylated cyclodextrin (PMCD). The IMW obtained using this method is highly soluble in a variety of organic solvents and has a high covering ratio, regioregularity, rigidity, photoluminescence efficiency, and interchain hole mobility. PMID- 21603718 TI - Amplification of localized surface plasmon resonance signals by a gold nanorod assembly and ultra-sensitive detection of mercury. AB - Controlled assembly of gold nanorods induced by Na(3)PO(4) leads to a significant amplification of localized surface plasmon resonance (LSPR) signals. The strong affinity between Au and Hg alters the coupled LSPR signals due to the amalgamation of Hg and Au. This allows detection of Hg in aqueous solutions with ultra-high sensitivity and excellent selectivity, without sample pretreatment. PMID- 21603720 TI - Synthesis of highly ordered mesoporous alumina thin films and their framework crystallization to gamma-alumina phase. AB - Here we report the preparation of highly ordered mesoporous alumina films existing both as P6(3)/mmc and Fm-3m mesostructures by using triblock copolymer Pluronic P123 as the structure-directing agent. 2D grazing-incidence small-angle X-ray scattering (GI-SAXS) completely proves the existence of two different mesopore structures (i.e., [001]-oriented P6(3)/mmc and [111]-oriented Fm-3m symmetries). After calcination at 1000 degrees C, the amorphous alumina framework is successfully converted to gamma-alumina crystals. During the crystallization process, large uniaxial shrinkage occurs along the direction perpendicular to the substrate with the retention of horizontal mesoscale periodicity, thereby resulting in formation of partially vertical mesoporosity in the film. Through detailed electron microscopic study, we discuss the formation mechanism for the vertical mesoporosity upon calcination. The obtained mesoporous gamma-alumina film shows high thermal stability up to 1000 degrees C, which is highly useful in wide research areas such as catalyst supports and separators. PMID- 21603721 TI - Kinetic studies on visible-light-switchable photochromic fluorophores based on diarylethenes. AB - We present three recently developed photochromic fluorophores that are based on diarylethenes with elongated conjugated pi-systems. The diarylethenes 1 and 3 can be switched from their open to their closed form with visible light. The diarylethenes 1 and 2 are covalently coupled to a standard rhodamine B-based fluorophore and act as photoswitchable resonance energy acceptors. By controlling their switching state, the fluorescence intensity of the dye can be modulated. The third compound 3 is a diarylethene that shows photoswitchable inherent fluorescence due to its stilbazolium-like structure. Ensemble experiments demonstrate that diarylethene-based photoswitches show superior characteristics regarding their switching performance, thermal stability and fatigue resistance. These attributes make them promising candidates for super-resolution imaging methods that are based on the determinate fluorescence switching of fluorophores between an off- and an on-state. PMID- 21603722 TI - Pumping-induced perturbation of flow in microfluidic channels and its implications for on-chip cell culture. AB - We study the rate of response to changes in the rate of flow and the perturbations in flow in polydimethylsiloxane (PDMS) microfluidic chips that are subjected to several common flow-control systems. We find that the flow rate of liquid delivered from a syringe pump equipped with a glass syringe responds faster to the changes in the conditions of flow than the same liquid delivered from a plastic syringe; and the rate of flow delivered from compressed air responds faster than that from a glass syringe. We discover that the rate of flow that is driven by a syringe pump and regulated by an integrated pneumatic valve responds even faster, but this flow-control method is characterized by large perturbations. We also examine the possible effects of these large perturbations on NIH 3T3 cells in microfluidic channels and find that they could cause the detachment of NIH 3T3 cells in the microchannels. PMID- 21603723 TI - A magnetic resonance (MR) microscopy system using a microfluidically cryo-cooled planar coil. AB - We present the development of a microfluidically cryo-cooled planar coil for magnetic resonance (MR) microscopy. Cryogenically cooling radiofrequency (RF) coils for magnetic resonance imaging (MRI) can improve the signal to noise ratio (SNR) of the experiment. Conventional cryostats typically use a vacuum gap to keep samples to be imaged, especially biological samples, at or near room temperature during cryo-cooling. This limits how close a cryo-cooled coil can be placed to the sample. At the same time, a small coil-to-sample distance significantly improves the MR imaging capability due to the limited imaging depth of planar MR microcoils. These two conflicting requirements pose challenges to the use of cryo-cooling in MR microcoils. The use of a microfluidic based cryostat for localized cryo-cooling of MR microcoils is a step towards eliminating these constraints. The system presented here consists of planar receive-only coils with integrated cryo-cooling microfluidic channels underneath, and an imaging surface on top of the planar coils separated by a thin nitrogen gas gap. Polymer microfluidic channel structures fabricated through soft lithography processes were used to flow liquid nitrogen under the coils in order to cryo-cool the planar coils to liquid nitrogen temperature (-196 degrees C). Two unique features of the cryo-cooling system minimize the distance between the coil and the sample: (1) the small dimension of the polymer microfluidic channel enables localized cooling of the planar coils, while minimizing thermal effects on the nearby imaging surface. (2) The imaging surface is separated from the cryo cooled planar coil by a thin gap through which nitrogen gas flows to thermally insulate the imaging surface, keeping it above 0 degrees C and preventing potential damage to biological samples. The localized cooling effect was validated by simulations, bench testing, and MR imaging experiments. Using this cryo-cooled planar coil system inside a 4.7 Tesla MR system resulted in an average image SNR enhancement of 1.47 +/- 0.11 times relative to similar room temperature coils. PMID- 21603724 TI - Integrative investigation of lipidome and signal pathways in human endothelial cells under oxidative stress. AB - Phospholipids in human endothelial cells (ECs), cell line EA.hy926, were profiled by a novel lipidomics approach, combining liquid chromatography (LC)-ion trap mass spectrometry (MS) and LC-tandem quadrupole MS. More than 200 species of phospholipids were quantified. Twenty-eight were identified as the most discriminant species in response to different levels of oxidative stress induced by hydrogen peroxide (H(2)O(2)). H(2)O(2) treatment induced phosphorylation of cytosolic phospholipase A(2) (cPLA(2)) via the activation of extracellular regulated kinase 1/2 (ERK1/2), increasing the production of lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC). The release of arachidonic acid (AA, 20 : 4) increased from no H(2)O(2) exposure to 1 h exposure, decreased from 1 h to 2 h, and increased again from 2 h to 4 h exposure time. The particular increase seen of phosphatidylcholine (PC) species that include AA chains from 1 h to 2 h indicates that the released AA is reincorporating into PC molecules to reduce the extension of the AA cascade. The change in free AA levels seen suggests possible defense mechanisms to oxidative injury in ECs. We further verified nine species as potential biomarkers by adding inhibitor and demonstrated direct correlation to the activity of the cPLA(2)-AA pathway. The oxidative injury to cell line EA.hy926 provided a novel application for a combined lipidomics and signal transduction approach. This combined approach has enabled future investigations for possible therapeutic interventions in phospholipids and cPLA(2) activity for defense against oxidative cellular stress. PMID- 21603725 TI - Estimation of the contributions of long range transported aerosol in East Asia to carbonaceous aerosol and PM concentrations in Seoul, Korea using highly time resolved measurements: a PSCF model approach. AB - The contributions of long range transported aerosol in East Asia to carbonaceous aerosol and particulate matter (PM) concentrations in Seoul, Korea were estimated with potential source contribution function (PSCF) calculations. Carbonaceous aerosol (organic carbon (OC) and elemental carbon (EC)), PM(2.5), and PM(10) concentrations were measured from April 2007 to March 2008 in Seoul, Korea. The PSCF and concentration weighted trajectory (CWT) receptor models were used to identify the spatial source distributions of OC, EC, PM(2.5), and coarse particles. Heavily industrialized areas in Northeast China such as Harbin and Changchun and East China including the Pearl River Delta region, the Yangtze River Delta region, and the Beijing-Tianjin region were identified as high OC, EC and PM(2.5) source areas. The conditional PSCF analysis was introduced so as to distinguish the influence of aerosol transported from heavily polluted source areas on a receptor site from that transported from relatively clean areas. The source contributions estimated using the conditional PSCF analysis account for not only the aerosol concentrations of long range transported aerosols but also the number of transport days effective on the measurement site. Based on the proposed algorithm, the condition of airmass pathways was classified into two types: one condition where airmass passed over the source region (PS) and another condition where airmass did not pass over the source region (NPS). For most of the seasons during the measurement period, 249.5-366.2% higher OC, EC, PM(2.5), and coarse particle concentrations were observed at the measurement site under PS conditions than under NPS conditions. Seasonal variations in the concentrations of OC, EC, PM(2.5), and coarse particles under PS, NPS, and background aerosol conditions were quantified. The contributions of long range transported aerosols on the OC, EC, PM(2.5), and coarse particle concentrations during several Asian dust events were also estimated. We also investigated the performance of the PSCF results obtained from combining highly time resolved measurement data and backward trajectory calculations via comparison with those from data in low resolutions. Reduced tailing effects and the larger coverage over the area of interest were observed in the PSCF results obtained from using the highly time resolved data and trajectories. PMID- 21603726 TI - Catalytic oxidative cleavage of olefins promoted by osmium tetroxide and hydrogen peroxide. AB - Hydrogen peroxide was employed as the terminal oxidant in the osmium tetroxide mediated oxidative cleavage of olefins, producing the corresponding aldehyde and ketone products. Aryl olefins are cleaved in good to excellent yield regardless of arene electronics. Alkyl olefins cleave in moderate to good yield for di- and tri-substituted alkenes. PMID- 21603727 TI - The dollars and sense of managing drug-resistant tuberculosis in Singapore. PMID- 21603728 TI - Postgraduate training and assessment in Hong Kong. AB - The Hong Kong Academy of Medicine, established in 1993, is the only statutory body in Hong Kong to train, assess and accredit medical and dental specialists. According to the law in Hong Kong, a doctor or dentist who wishes to have his name included in the Specialist Register of Medical Council or Dental Council must either be a Fellow of the Academy or be assessed and certified by the Academy to have qualifications and training comparable to that required of an Academy Fellow. Once a doctor or dentist is on the Specialist Register, he must fulfil the continuing medical education requirements as determined by the Academy to maintain his specialist status. The Hospital Authority of Hong Kong has implemented the Doctor Work Reform (DWR) since 2006 which involves reduction of doctors' work hours and may affect training. The long-term strategy of the Academy with regards to the issue of DWR is to modernise postgraduate medical education and closely monitor the process to ensure that the quality of training would not be affected. PMID- 21603729 TI - What skills are tested in the new PACES examination? AB - The MRCP(UK) PACES examination has been sat by almost 40,000 candidates in 10 countries around the world since its introduction in 2001. The examination assesses skills of relevance to the practice and delivery of high quality clinical care and is the leading international postgraduate summative assessment of this kind. In 2009, the examination was revised, and this article describes those revisions, focussing on the clinical skills assessed. PMID- 21603730 TI - American diagnostic radiology residency and fellowship programmes. AB - American Diagnostic Radiology Residency and Fellowship programmes are Graduate Medical Education programmes in the United States (US) equivalent to the Postgraduate Medical Education programmes in Singapore. Accreditation Council for Graduate Medical Education (ACGME) accredited diagnostic radiology residency programmes require 5 years total with Post Graduate Year (PGY) 1 year internship in a clinical specialty, e.g. Internal Medicine following medical school. PGY Years 2 to 5 are the core years which must include Radiology Physics, Radiation Biology and rotations in 9 required subspecialty rotations: Abdominal, Breast, Cardiothoracic, Musculoskeletal, Neuroradiology, Nuclear and Paediatric Radiology, Obstetric & Vascular Ultrasound and Vascular Interventional Radiology. A core curriculum of lectures must be organised by the required 9 core subspecialty faculty. All residents (PGY 2 to 4) take a yearly American College of Radiology Diagnostic In-Training Examination based on national benchmarks of medical knowledge in each subspecialty. Because the American Board of Radiology (ABR) examinations are changing, until 2012, residents have to take 3 ABR examinations: (i) ABR physics examination in the PGY 2 to 3 years, (ii) a written examination at the start of the PGY 5 year and (iii) an oral exam at the end of the PGY 5 year. Beginning in 2013, there will be only 2 examinations: (i) the physics and written examinations after PGY 4 will become a combined core radiology examination. Beginning in 2015, the final certifying examination will be given 15 months after the completion of residency. After residency, ACGME fellowships in PGY 6 are all one-year optional programmes which focus on only one subspecialty discipline. There are 4 ACGME accredited fellowships which have a Board Certifi cation Examination: Neuroradiology, Nuclear, Paediatric and Vascular Interventional Radiology. Some ACGME fellowships do not have a certifying examination: Abdominal, Endovascular Surgical Neuroradiology and Musculoskeletal Radiology. One year unaccredited fellowships can also be taken in Breast, Cardiothoracic or Women's Imaging. PMID- 21603731 TI - Managing a case of extensively drug-resistant (XDR) pulmonary tuberculosis in Singapore. AB - INTRODUCTION: Extensively drug-resistant tuberculosis (XDR-TB) is an emerging global health risk. We present the first case report of XDR-TB in Singapore. CLINICAL PICTURE: A 41-year-old Indonesian lady with previously treated pulmonary tuberculosis presented with chronic cough. Her sputum was strongly acid-fast bacilli positive and grew Mycobacterium tuberculosis complex resistant to first and second-line TB medications. TREATMENT: She received 5 months of intensive multidrug treatment without sputum smear conversion. She then underwent resection of the diseased lung. The total cost incurred amounted to over S$100,000. OUTCOME: She achieved sputum smear/culture conversion post-surgery, but will require further medical therapy for at least 18 months. CONCLUSION: XDRTB is poorly responsive to therapy and extremely expensive to manage. Its prevention by strict compliance to therapy is paramount. PMID- 21603732 TI - Surgical remodelling of haemodialysis fistula aneurysms. AB - INTRODUCTION: One complication of autogenous arteriovenous fistula (AVF) for haemodialysis is the formation of a venous aneurysm. CLINICAL PICTURE: The clinical picture is typically an expanding aneurysm leading to skin atrophy and ulceration with the risk of rupture and infection. Aneurysm also reduces the potential cannulation area. TREATMENT: The cases described here used a surgical 'remodelling' technique involving complete skeletonisation of the venous aneurysm, reduction of lumen diameter and retention of vein wall using a Hegar dilatator to remodel a new fistula. OUTCOME: Six patients were treated using this method and the arterior venous shunt (AVS) was used for haemodialysis the following day. No recurrent aneurysm developed. CONCLUSION: Remodelling of aneurysmal AVF is an effective and low-risk option for managing this kind of complication, allowing direct access for haemodialysis. PMID- 21603733 TI - Radiological outcome of short segment posterior stabilisation and fusion in thoracolumbar spine acute fracture. AB - INTRODUCTION: The optimal management of thoracolumbar spine fractures remains a matter of controversy. The current literature implies that the use of short segment pedicle screw fixation may be inappropriate because of its high reported failure rate. The purpose of this study is to report the short-term results of thoracolumbar burst and compression fractures treated with short-segment pedicle instrumentation. MATERIALS AND METHODS: From 2002 to 2007, 19 patients with thoracolumbar acute traumatic fractures were instrumented with posterior short segment pedicle screws. The patients' case notes, operation records, preoperative and postoperative radiographs (sagittal index, anterior body compression and regional kyphosis), computed tomography scans, neurological findings (Frankel functional classification), and follow-up records up to 18 months were reviewed. RESULTS: A statistically significant difference was found between the patients' preoperative, postoperative and follow-up sagittal index, anterior body compression and regional kyphosis measurement. One case resulted in screw pedicle screw pullout and subsequently, kyphotic deformity. The patient underwent revision surgery to long-segment posterior instrumentation and fusion. None of the patients showed an increase in neurological deficit. CONCLUSION: In conclusion, the short-term follow-up results suggest a favourable outcome for short-segment instrumentation. Load shearing classification is essential for the selection of patient for short-segment instrumentation. However, the long-term follow-up evaluation will be needed to verify our findings. PMID- 21603734 TI - Successful transcatheter bioprosthetic heart valve paravalvular leak closure: the role of 3-dimensional transesophageal echocardiography. PMID- 21603735 TI - Sympathetic ophthalmia in an infected post-scleral buckling eye. PMID- 21603736 TI - Perianal abscess secondary to enterobius vermicularis infestation. PMID- 21603737 TI - Parkinsonism complicating acute organophosphate insecticide poisoning. PMID- 21603738 TI - Calcifying fibrous pseudotumour of the mediastinum. PMID- 21603739 TI - Role of radiology in diagnosis and treatment of an infant with acute abdomen. PMID- 21603740 TI - Special issue on canine cruciate ligament disease. PMID- 21603741 TI - Where is the evidence? PMID- 21603745 TI - Promotion of physical activity in Brazil: an issue beyond public health. PMID- 21603746 TI - [Maternal mortality in Brazil: what has the scientific literature shown in the last 30 years?]. AB - The aim of this study was to analyze maternal mortality in Brazil in the last 30 years, by means of a literature review. The authors performed an electronic search of scientific articles from 1980 to 2010 in LILACS and MEDLINE and found 486 abstracts, of which 50 articles were selected. Studies showed a decrease in the maternal mortality ratio (MMR), although varying across regions of the country. A few articles evaluated maternal mortality factors, identifying social inequalities associated with skin color and schooling. There was persistent underreporting of maternal deaths and inadequate completion of death certificates. Direct obstetric causes were the most frequent, mainly hypertensive diseases of pregnancy. Analysis of avoidability revealed deficiencies in prenatal and childbirth care. Despite the relevance of maternal mortality in Brazil, there are few studies on the subject. Although MMR has decreased, it is still above the desired levels. Improvements are thus needed in the quality of prenatal and perinatal care. PMID- 21603747 TI - [Contributions by food demand studies to the development of public policies in nutrition]. AB - Food choice in diet composition is a determinant of individual health status. Currently, there are gradually fewer conditions involving food scarcity and more involving excess food. Changes in income and relative prices generate measurable effects on the population's food intake patterns. Economic models have significant explanatory power for food demand, and the interactions between consumption, income, and prices are usually expressed as elasticity. However, the construction of some studies shows important shortcomings, especially for public policy application. This conceptual article discusses the potential contribution of food demand studies, suggesting improvements in the structural design of such studies with the inclusion of current nutritional concepts for redirecting the nutritional transition from under-nutrition to healthy eating, avoiding the present trend towards epidemic obesity. PMID- 21603748 TI - [Use of medication and associated factors: a population-based study in Campinas, Sao Paulo State, Brazil]. AB - This article analyzes prevalence rates in the use of medication according to demographic, socioeconomic, and health-related behavioral variables through a population-based cross-sectional study of individuals 18 years and older (n=941) in Campinas, Sao Paulo State, Brazil. The study used multistage sampling, both stratified and cluster. Chi-square test was performed, and adjusted prevalence ratios were estimated by gender and age, both with 95% confidence intervals. A Poisson multiple regression model was developed, and the following factors were associated with use of medication: female gender, age 40 and over, reported illness in the previous two weeks, and number of chronic diseases. The most widely consumed drugs were for the cardiovascular and nervous systems, besides herbal remedies. Prevalence of medication in Campinas was lower than in most studies. Local health surveys could help identify drug use patterns and guarantee more appropriate interventions for pharmaceutical care policy. PMID- 21603749 TI - [Silent neuropathy in patients with leprosy in the city of Fortaleza, Ceara State, Brazil]. AB - One of the clinical forms of Hansen's disease is silent neuropathy, which consists of progressive nerve damage in the absence of pain and hypersensitivity to palpation. This study estimated the proportion of silent neuropathy and associated factors. A cross-sectional study was performed in Fortaleza, Ceara State, Brazil. Patients were asked about the presence of decreased sensation involving touch, heat, pain, and numbness. Nerves were palpated to identify thickness, abscess, and pain. Lymph samples were drawn for parasitological tests. Strength of voluntary muscles in the feet and hands was evaluated. The sensitivity of specific points on the feet and hands was measured using Semmes Weinstein monofilament. The sample included 233 patients. The proportion of silent neuropathy was 5.6% (95%CI: 3.0-9.4), and factors significantly associated with silent neuropathy were: age (p = 0.011) and disability (p < 0.000). These results will help identify cases of silent neuropathy, targeting patients at higher risk. PMID- 21603750 TI - [Newborn screening for galactosemia: a health economics evaluation]. AB - This study assesses the efficiency of the galactosemia add-on test in neonatal screening performed on regular Guthrie card blood spots. Based on estimated average incidence of galactosemia (1:19,984 newborns) in Sao Paulo State, Brazil, the study develops a cost-benefit analysis model, using a B/C ratio and a 9.25% annual interest rate in order to decapitalize the results. Sensitivity analysis is also performed, varying (as a function of the interest or discount rate) from 0 and 20% and according to the 95% confidence interval (1:7,494-1:59,953 newborns). The results show that the savings obtained by improved health of galactosemic patients detected early by add-on neonatal screening is superior to the costs (B/C=1.33), characterizing galactosemia add-on testing in neonatal screening as an efficient policy. The lower the prevailing interest rate in the economy, the more efficient the neonatal screening policy. PMID- 21603751 TI - Association among physical, psychiatric and socioeconomic conditions and WHOQOL Bref scores. AB - The aim of this study is to investigate the impact of psychiatric morbidity, depression, cognitive deficit, number of self-reported illnesses and socio demographic variables on the WHOQOL-Bref domain scores. WHOQOL-Bref domain scores are substantially affected by psychiatric morbidity and income. Depression, the number of self-reported illnesses and the female gender also explain the variability of other domains to a lesser extent. PMID- 21603752 TI - [An analysis of financial flows from the Brazilian Ministry of Health for research and development in 2003-2005 according to the National Agenda for Health Research Priorities]. AB - This study mapped the application of financing in research and development in health (R&D/H) by the Brazilian Ministry of Health in 2003-2005, according to the National Agenda for Health Research Priorities, created in 2004. The analysis was based on data from a study aimed primarily at measuring these investment flows during the same period. The calculations included only direct financing with actual outlays in research, including payroll expenditures. The studies were categorized according to the 24 sub-agendas of the national priority agenda by two independent researchers, and disagreements were resolved by consensus. Research and development expenditures in health totaled 409.7 million reais, concentrated mainly in the following sub-agendas: transmissible diseases, the health industry complex, clinical research, pharmaceutical care, and non communicable diseases (79% of the total). All 24 sub-agendas received some financing during the period. The study established a baseline for subsequent evaluations of this financing instrument's inductive capacity and the relationship between R&D/H investments and the population's health needs. PMID- 21603753 TI - [Characteristics of women victims of sexual violence and their compliance with outpatient follow-up: time trends at a referral center in Campinas, Sao Paulo State, Brazil]. AB - Sexual violence is a crime against individual integrity and sexual freedom. It affects women of all socioeconomic levels, and the perpetrator does not choose the victim's color or age. It is a source of high financial cost and a serious public health problem in Brazil. The current study aimed to assess compliance with outpatient follow-up by women victims of sexual violence treated at the Center for Women's Comprehensive Healthcare at the State University in Campinas, Sao Paulo State, from January 2000 to December 2006. We observed a significant increase in the return for scheduled appointments. In 2000, 41% of the women completed the six-month follow-up, and by 2006 the proportion had increased to 70%. Some 70% of the women appeared for treatment within 24 hours after being raped. Sexual assault by perpetrators known to the victims tripled during this same period. There were changes in the forms of intimidation and a significant decreased in prescription of emergency contraception. PMID- 21603754 TI - [Weight gain rate in early childhood and overweight in children 5-11 years old in Salvador, Bahia State, Brazil]. AB - Overweight children are more prone to become overweight or obese adults. The most effective prevention is intervention in early childhood. We analyzed the association between early weight gain and overweight/obesity in 1,056 children under 11 years of age. Data were collected on lifestyle, sanitation, socioeconomic status, birth weight, and breastfeeding. Weight gain from birth until different age brackets (< 12, > 12 to 18, > 18 to 24, and > 24 to 60 months) was considered a continuous variable in z-scores. Overweight was defined as body mass index (BMI) > +1 z-score, based on 2006 and 2007 World Health Organization (WHO) guidelines. Poisson regression and linear regression were used in the multivariate statistical analysis. Weight gain rate was associated with BMI, and overweight or obesity in the 5-11-year age bracket increased twofold for each unit increase in the weight gain standard deviation between 24 and 60 months of age (RR = 2.08; 95%CI: 1.87-2.32). For all early childhood age brackets, there was an association between rapid weight gain and subsequent overweight or obesity. PMID- 21603755 TI - [Pandemic Influenza A (H1N1): changing population health habits in Cachoeira do Sul, Rio Grande do Sul State, Brazil, 2010]. AB - This quantitative exploratory-descriptive study conducted from January 5 to February 26, 2010, focused on the population's health habits in Cachoeira do Sul, Rio Grande do Sul State, Brazil, before, during, and after the influenza A (H1N1) pandemic. The total population included 11,100 individuals listed in the telephone book, of which 519 (4.7%) were interviewed by telephone. Characteristics were: age range 18-90 years; 55.3% women; 22.7% with university diplomas; and 39.9% with secondary school diplomas. The following proportions of health habits were reported after the pandemic: 74% washed their hands frequently with soap and water and 39.2% cleaned their hands with alcohol gel; 94.6% covered their faces when they sneezed or coughed; 45.5% washed their hands after coughing/sneezing; 60.9% avoided touching the mucosa of their eyes, nose, and mouth; 21% avoided crowds; 85.7% attempted to keep rooms well ventilated. During the pandemic, the interviewees incorporated good habits in all the above measures, which were maintained to variable degrees even after the seven-month pandemic ended. PMID- 21603756 TI - [Characteristics of hospital admissions in the Unified National Health System for osteoporotic hip fracture in elderly people in Brazil, 2006-2008]. AB - Osteoporosis is a multifactorial syndrome of the skeletal system, and hip fracture is the most serious consequence for the elderly, due to the high mortality and cost. This article describes osteoporotic hip fractures in Brazilian elderly in 2006-2008. Secondary data were obtained from the Authorization Forms for Hospital Admissions (AIH) and allowed the creation of indicators for hip fracture in elders. The proportion of elderly patients hospitalized for hip fractures in the Unified National Health System was 1%. The percentages of hospital admissions and deaths were higher in females, and increased with age. Hip fractures accounted for approximately 2% of health care expenditures for persons 60 years or older. Length of hospital stay ranged from one to seven days, 50.1% occurred in charity hospitals, and 42.7% occurred outside the county of residence. The findings emphasize the need for greater attention to osteoporosis and show the relevance of costs in hospital admissions for elderly with osteoporotic hip fractures. Understanding such hospitalizations can contribute to the formulation of health policies to address this issue. PMID- 21603757 TI - [Critical trajectories of female victims of gender violence: discourse analysis of women and staff professionals in Porto Alegre, Rio Grande do Sul State, Brazil]. AB - This qualitative study aims to describe the trajectories of female victims of gender violence in Porto Alegre, Rio Grande do Sul State, Brazil. The methodology included in-depth interviews with women and staff, attempting to map the critical paths of women when they made the decision to seek professional help. We interviewed 21 women victims of gender violence and 25 professionals, including law enforcement officials, health and social workers, and nongovernmental organizations. The women's trajectories in the services were mapped, identifying facilitating factors and obstacles in the process of breaking with gender violence. The victims reported: pressure by professional staff to return to their marriages and police inefficiency in providing protection. The discourse of law enforcement officials and health and social workers showed a range of different concepts regarding violence, medicalization of violence, and network fragmentation. PMID- 21603758 TI - Seroprevalence of hepatitis B and hepatitis C markers in adolescents in Southern Brazil. AB - This study was carried out to determine the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) markers among adolescents aged between 10 and 16 years old, who are elementary school students in the city of Chapeco, Santa Catarina State, Brazil. The study involved a cross-sectional survey that included 418 volunteers, from March to July, 2008. Serology comprised HBsAg, anti-HBc, anti-HBs and anti-HCV. Tests were performed using automated Microparticle Enzyme Immunosorbant Assay (Abbott, AxSYM System, Wiesbaden, Germany). The prevalence of HBsAg was found to be 0.2% (95%CI: 0.0-1.3), and the prevalence of anti-HBc was found to be 1.4% (95%CI: 0.5-3.1). Regarding anti-HBs, 48.6% had titers greater than 10UI/L. None of the volunteers presented reactive results for anti-HCV. This study showed a low prevalence of HBV and HCV markers of infection and a great number of volunteers immunized against HBV. Finally this study shows the importance of proper health campaigns and policies in reducing those prevalences. PMID- 21603759 TI - [Decentralization of workers' health surveillance in the city of Campinas, Sao Paulo State, Brazil: a process evaluation]. AB - This study evaluates the decentralization of workers' health surveillance to district teams in Campinas, Sao Paulo State, Brazil, from 1990 to 2006. The history and context of this process were retrieved from documents at the Municipal Health Department in order to establish evaluation criteria and define facilitating factors and obstacles in guideline implementation, as well as to measure the gap between guidelines and reality. The evaluation used qualitative techniques with stakeholders' focus groups. The results showed that decentralization was defined according to the prevailing political options and according to the principles of the Unified National Health System (SUS). Facilitating factors included the increase in technical capability and integration among the teams, and obstacles included excessively centralized planning with limited participation, insufficient resources, and lack of clarity between the services concerning roles and responsibilities. The discussion of these results with health system administrators, social actors, and participating health professionals has contributed to the analysis and organization of transformative measures in regional public practices in workers' health surveillance. PMID- 21603760 TI - [Prevalence of genital HPV infection in urban and rural women in the Eastern Brazilian Amazon]. AB - This study investigated the prevalence and risk factors for genital infection with HPV in women from rural and urban areas in two different regions of the Eastern Brazilian Amazon. A cross-sectional survey was performed in Pap screening programs, with a total sample of 444 women (233 urban and 211 rural). Uterine cervical swabs were collected for the detection of HPV DNA with the established PCR assay using MY09-MY11. All volunteers answered an epidemiological questionnaire. Bivariate and multivariate logistic regression analyses were performed to identify risk factors associated with HPV infection. Overall prevalence of HPV infection was 14.6% (15% in urban women and 14.2% in rural). The only factor associated with HPV was marital status in the 13-25-year-old rural population, with higher HPV prevalence among single and divorced women and widows. The findings indicate the need for risk factor control strategies targeted specifically to women in rural and urban areas. PMID- 21603761 TI - [The Family Health Strategy and healthcare for the elderly: experiences in three Brazilian cities]. AB - This study focuses on healthcare for the elderly under the Family Health Strategy in three municipalities (counties) in the State of Rio de Janeiro, Brazil, specifically analyzing the organization of the healthcare network and the knowledge of six health teams, using interviews and focus groups. The study emphasized the central role of work by community health agents, the prioritization of program activities as compared to management of problems in the community covered by the strategy, a work overload in the health teams, disorganization of the healthcare networks, and lack of systemic approaches based on the basic contents of Geriatrics and Gerontology. The article concludes that there is a need for a healthcare network for the elderly consisting of hierarchically organized services and levels of care that provide support for the healthcare teams' work. The teams could also benefit from continuing education programs. The undergraduate medical curriculum should also include more course content in geriatrics and gerontology. PMID- 21603762 TI - [Differences in prenatal care between health services under the Family Health Strategy and traditional primary care clinics in Rio Grande, Rio Grande do Sul State, Brazil]. AB - This study aimed to evaluate differences in prenatal care between services under the Family Health Strategy (FHS) and traditional public primary care clinics in Rio Grande, Rio Grande do Sul State, Brazil. A cross-sectional study was performed with all women who gave birth from January 1st to December 31st, 2007, and who received prenatal care in the municipal health system. The procedures recommended by the Ministry of Health were compared according to model of care. Among the 961 pregnant women, those treated under the FHS received a higher percentage of some forms of care (use of ferrous sulfate, tetanus vaccination, and HIV and syphilis tests). Other procedures were also more frequent under the FHS, but failed to reach the recommended levels (breast examination and Pap smear). Measurement of blood pressure, uterine height, and weight were quite frequent in both groups. Identification of pregnant women in the first trimester failed to reach 70%. Women under the FHS received better care, but some procedures still fell short of expected levels, and efforts are thus needed to improve the quality of prenatal care. PMID- 21603763 TI - [Prevalence of overweight and associated factors in adults: a population survey in Rio Branco, Acre State, Brazil, 2007-2008]. AB - Population studies in Brazil have shown an increased prevalence of overweight and obesity in adult populations in all regions of the country. The objective was to estimate prevalence and identify risk factors associated with overweight among adults in Rio Branco, Acre State, Brazil. The study included a cross-sectional population-based sample of 1,469 adults. Multivariate analysis was performed using Poisson regression, taking overweight (BMI > 25kg/m2) as the dependent variable. Prevalence of overweight was 46.9%, higher among women. Overweight tended to increase with age in both men and women. Overweight was associated with socioeconomic, demographic, and morbidity variables such as hypertension and dyslipidemia. The high prevalence of overweight in adults of both sexes suggests a public health problem. Control measures and prevention of health risks associated with excess weight are necessary. PMID- 21603764 TI - [Schistosomiasis mansoni in Maranhao State, Brazil, 1997-2003]. AB - The aim of this study was to assess the prevalence of schistosomiasis mansoni in Maranhao State, Brazil, from 1997 to 2003, based on data from the regional health offices included in the Schistosomiasis Control Program. The statistical method was polynomial regression. The municipalities (counties) of Bacabal and Sao Luis showed a constantly downward trend throughout the time series. Colinas showed an increase in prevalence until 2002, followed by a downward trend. Imperatriz witnessed a constant upward trend. Socioeconomic factors are highly significant for schistosomiasis prevalence in Maranhao, which helps explain the results. The recording of data for the regional health offices is believed to have been affected by changes resulting from decentralization of the Schistosomiasis Control Program. The study's results highlight issues that extend beyond analysis of the pattern of occurrence of schistosomiasis mansoni cases in the State of Maranhao, particularly demonstrating the need for improvements in the population's living conditions. PMID- 21603765 TI - [Benefits of combining methods to analyze the causes of maternal mortality, Bucaramanga, Colombia]. AB - OBJECTIVE: Define critical points of change in the maternal care process, guide decision-making in this area, and support the strengthening of service delivery policies, with a view to achieving the Millennium Development Goal of improving maternal health. METHODS: Retrospective descriptive study of a series of cases of maternal deaths recorded in Bucaramanga between 2004 and 2009. The study examined epidemiologic reporting cards, clinical histories, field visits, and the records of analysis committees. The road to survival (analysis of delays) and detection of critical links in care were used as the methods of analysis. The information obtained was triangulated. RESULTS: The 10 maternal deaths occurred in an urban area, and the women had received medical care from professionals at a health facility. The four types of delays-in recognizing the problem, in the timeliness of decisions and actions, in care/the logistics of referral, and in the quality of care-occurred with similar frequency in the 10 cases studied. The critical links in the prevention of maternal deaths were those related to deficiencies in the vertical and horizontal integration of the care process and the quality of care. CONCLUSIONS: Combining analysis methods made it possible to identify the deficiencies in care most related to maternal deaths. However, their use should be accompanied by other methods that make it possible to identify determinants that go beyond the context of service delivery. One documented lesson learned is the importance of the continuity and monitoring of interventions as a success factor in reducing maternal mortality. PMID- 21603766 TI - Human papillomavirus genotypes and their prevalence in a cohort of women in Trinidad. AB - OBJECTIVE: Human papillomavirus (HPV) genotypes and their relative prevalences were determined in a cohort of 310 sexually active women in Trinidad, West Indies. METHODS: Cervical samples were collected with Ayre's spatulas and endocervical brushes. Samples were used for the conventional Papanicolaou test and for determining HPV genotypes by amplification of a section of the viral L1 gene, followed by DNA sequencing and probe hybridization. RESULTS: HPV infections were identified in 126 of 310 (40.6%) women. Of them, 83 (65.8%) were infected with high-risk HPV, 16 (12.7%) with low-risk HPV, and 27 (21.4%) with HPV types of unknown risk. HPV 52 (12.7%) was the most frequently occurring high-risk type, followed by HPV 66 (10.3%), HPV 16 (9.5%), and HPV 18 (8.6%). High-risk types HPV 16 and HPV 66 were each found in 3 (20.0%) and HPV 18 was found in 1 (6.6%) of the 15 women with abnormal cytology. CONCLUSIONS: Cervical HPV prevalence and heterogeneity of HPV genotypes are high in this Trinidad cohort. The relative importance of HPV genotypes in the development of cervical lesions needs further investigation in Trinidad in order to better understand the epidemiology of HPV infections as well as to determine the role of HPV testing in the screening, prevention, and control of cervical cancer. This pilot study provided important information on the prevalence of HPV genotypes, which will be used in future nationwide studies. PMID- 21603767 TI - [Relationship between lead levels in colostrum, dietary intake, and socioeconomic characteristics of puerperal women in Goiania, Brazil]. AB - OBJECTIVE: To estimate the levels of lead in human colostrum and investigate whether they are correlated with dietary intake and socioeconomic factors in puerperal women. METHOD: This cross-sectional study was carried out with 80 puerperal women from a maternity hospital in Goiania, Brazil. Data were collected between July and December 2008. A questionnaire was used to collect socioeconomic and lifestyle information. A dietary intake frequency questionnaire was also applied. After that, colostrum samples were collected and analyzed using flame atomic absorption spectrometry to quantify lead levels. The correlation between lead levels, socioeconomic variables, and dietary intake was calculated. RESULTS: The mean concentration of lead in colostrum samples was 6.88 MUg/L, and the median concentration was 4.65 MUg/L. There was no association between socioeconomic aspects and lead levels. The intake of saturated fatty acids, eggs, pork meats, chicken, and chicken products (r = -0.26 and P = 0.020) was inversely correlated with the levels of lead in human colostrum, whereas the intake of squash (r = 0.26; P = 0.019) and eggplant (r = 0.27; P = 0.015) was positively correlated with the levels of lead. The correlation observed for cooked squash, eggs, pork and chicken meats, and chicken products was maintained after logistic regression adjustment. CONCLUSIONS: The presence of lead was detected in human colostrum in this sample, probably as a result of dietary exposure. In addition to a correlation between presence of lead and dietary intake, the present findings suggest that specific nutrients may result in increased or decreased levels of lead, without a direct relationship with socioeconomic factors. PMID- 21603768 TI - [Factors associated with incidence of dengue in Costa Rica]. AB - OBJECTIVE: Determine the extent to which socioeconomic, demographic, geographic, and climate variables affected the incidence of dengue and dengue hemorrhagic fever (D/DH) in Costa Rica during the period 1999-2007. METHODS: A correlational epidemiologic study was conducted that analyzed the cumulative incidence of D/DH from 1999 to 2007 and its association with different variables in the country's 81 cantons. Information was obtained from secondary sources, and the independent variables used for the analysis were selected on the basis of their representativeness in terms of sociodemographic, environmental, and health coverage factors that affect the epidemiology of D/DH. These variables were divided into four groups of indicators: demographic, socioeconomic, housing, and climate and geographical. The data were analyzed by means of simple and multiple Poisson regressions. RESULTS: The Costa Rican cantons with a higher incidence of D/DH were located primarily near the coast, coinciding with some of the variables studied. Temperature, altitude, and the human poverty index were the most relevant variables in explaining the incidence of D/DH, while temperature was the most significant variable in the multiple analyses. CONCLUSIONS: The analyses made it possible to correlate a higher incidence of D/DH with lower-altitude cantons, higher temperature, and a high human poverty index ranking. This information is relevant as a first step toward prioritizing and optimizing actions for the prevention and control of this disease. PMID- 21603769 TI - Outbreak of rubella after mass vaccination of children and adult women: challenges for rubella elimination strategies. AB - OBJECTIVE: To describe rubella outbreaks and control strategies in the Brazilian state of Rio Grande do Sul before rubella elimination. METHODS: We analyzed rubella and congenital rubella syndrome surveillance data for the state of Rio Grande do Sul and calculated age- and gender-specific incidence of confirmed rubella cases in 2007. We obtained data on measles-rubella doses administered during the outbreak from the state immunization program and reviewed the timing of suspect case notification and implementation of control measures. RESULTS: Of 2,842 confirmed rubella cases reported to the state health department in 2007, 2,145 (75.5%) were in males (39.5 cases per 100,000 population) and 697 (24.5%) were in females (12.3 per 100,000 population). Incidence among 15- to 39-year olds was 1.8 to 5.5 times higher in males than in females. Rubella genotype 2B was detected in nasopharyngeal specimens from 13 patients from multiple chains of transmission. Eight children were born with congenital rubella syndrome (5.9 cases per 100 000 births in 2008). Delayed notification of initial cases hampered early control efforts, resulting in outbreak spread throughout the state. Rubella transmission was interrupted after mass vaccination of adult men and women as part of a national vaccination campaign. CONCLUSIONS: Routine vaccination strategies and mass vaccination of adolescents and adults for accelerated rubella control and elimination should target men and women. PMID- 21603770 TI - Adolescent health screening practices by physicians in Jamaica. AB - OBJECTIVE: To review Jamaican physicians' adolescent health screening practices by determining their frequency in areas of biomedical, psychological, social, and educational health; the factors that influence these practices; and physicians' perceived level of self-efficacy and their awareness of screening tools and guidelines. METHODS: A questionnaire was mailed to general practitioners, family medicine specialists, and pediatricians in Jamaica. The primary outcome variable was the frequency of physician screening for a range of biomedical, psychosocial, and educational developmental issues in the majority (>= 50%) of adolescent patients. Bivariate analyses were performed to determine differences between professional groups. RESULTS: The response rate was 32.3% (n = 213), with 209 responders being suitable for further analysis. The sample comprised 48.8% general practitioners, 33.0% family medicine specialists, and 18.2% pediatricians. Physicians more often screened for biomedical risks than for psychosocial risks, with very low frequencies of screening for psychosocial issues such as mood, suicidal ideation, sexual orientation, and safety concerns. Physicians reported high levels of confidence in discussing most psychosocial issues with adolescent patients. Time limitation and an insufficient knowledge base were the main factors identified as influencing screening practices. CONCLUSIONS: The data suggest unsatisfactory frequency of adolescent health screening by Jamaican physicians, in particular for psychosocial factors. The primary factors identified by physicians as influencing their screening practices have potential for improvement through continued medical education. PMID- 21603771 TI - [Psychometric properties of a self-efficacy scale for physical activity in Brazilian adults]. AB - OBJECTIVE: To test the validity and reliability of a self-efficacy scale for physical activity (PA) in Brazilian adults. METHODS: A self-efficacy scale was applied jointly with a multidimensional questionnaire through face-to-face interviews with 1,418 individuals (63.4% women) aged >= 18 years. The scale was submitted to validity (factorial and construct) and reliability analysis (internal consistency and temporal stability). A test-retest procedure was conducted with 74 individuals to evaluate temporal stability. RESULTS: Exploratory factor analyses revealed two independent factors: self-efficacy for walking and self-efficacy for moderate and vigorous PA (MVPA). Together, these two factors explained 65.4% of the total variance of the scale (20.9% and 44.5% for walking and MVPA, respectively). Cronbach's alpha values were 0.83 for walking and 0.90 for MVPA, indicating high internal consistency. Both factors were significantly and positively correlated (rho >= 0.17, P < 0.001) with quality of life indicators (health perception, self-satisfaction, and energy for daily activities), indicating an adequate construct validity. CONCLUSIONS: The scale's validity, internal consistency, and reliability were adequate to evaluate self-efficacy for PA in Brazilian adults. PMID- 21603772 TI - Comparison of self-perceived weight and desired weight versus actual body mass index among adolescents in Jamaica. AB - OBJECTIVE: To compare self-perceived body size, desired body size, and actual body mass index (BMI) among adolescents in Jamaica, and to discuss the implications of these perceptions for chronic disease prevention. METHODS: A total of 276 Jamaican adolescents 14-19 years of age, randomly selected from grades 9-12 at 10 high schools participated in the study, which was conducted in October 2007. The perceived and desired BMI were measured using a silhouette of body figures representing nine BMI categories for males and females; these were compared to participants' actual BMI. RESULTS: Mean age was 15.6 +/- 1.2 years. Actual BMI values classified 24.6% of the participants as underweight; 39.9% as normal; 14.5% as overweight; and 21% as obese. There were significant differences between participants' actual and perceived BMI (P < 0.01), actual and desired BMI (P < 0.01), and perceived and desired BMI (P < 0.01). Gender was significantly different for actual (P < 0.05), perceived, and desired BMI (P < 0.01). Females had significantly higher actual mean BMI than males (P < 0.05). Adolescent males perceived themselves as having a higher BMI and a desired higher BMI than females. There were no differences among ethnicity, age, place of residence, and socioeconomic status on the actual, perceived, and desired BMI in this study population (P > 0.05). CONCLUSIONS: Females had higher actual BMI and lower perceived BMI than males. Jamaican adolescents, irrespective of ethnicity, age, place of residence, and socioeconomic status, had similar BMI. Interventions are needed to improve knowledge of a healthy body weight and the relationships among body weight, lifestyle choices, and the implications of excess body weight on chronic diseases. PMID- 21603773 TI - [Nutritional status in children younger than 24 months in Alagoas, Brazil]. AB - The aim of this retrospective, cross-sectional study was to compare the 1977 National Center for Health Statistics (NCHS) and the 2006 World Health Organization (WHO) growth standards to determine the nutritional status of children attending the pediatric outpatient clinic at a university hospital in Alagoas, Brazil. We reviewed 252 hospital charts of children younger than 24 months and determined the height-for-age, weight-for-age, and weight-for-height using the two standards. The sample was of low socioeconomic level and exclusively or predominantly breastfed children. TheZ-scores for both standards indicated that the children in this sample were healthy, but the WHO standard was more sensitive for the detection of growth limitations in the first 6 months of life. PMID- 21603775 TI - Rationality and methods of ACCEPT registry - Brazilian registry of clinical practice in acute coronary syndromes of the Brazilian Society of Cardiology. AB - BACKGROUND: Assessing the Brazilian clinical practice in patients with acute coronary syndrome, in public and private hospitals to identify gaps in the incorporation of clinical interventions with proven benefit. OBJECTIVE: To develop a registry of patients diagnosed with acute coronary syndrome to assess demographics, morbidity, mortality, and standard practice in the care of this condition. Besides, to assess the prescription of evidence-based interventions such as aspirin, statins, beta blockers and reperfusion, among others. METHODS: Registry-type prospective observational study intended to document hospital clinical practices of acute coronary syndrome in public and private hospitals in Brazil. In addition, longitudinal follow-up will be held until discharge and measurement of mortality and occurrence of serious events at 30 days, 6 and 12 months. RESULTS: The findings will be presented one year after the start of collection (September 2011), and consolidated after a meeting with the population to discuss the objectives sought. CONCLUSION: The analysis of this multicenter registry will design a horizontal perspective for the treatment of patients suffering from cardiovascular disease in Brazil. PMID- 21603774 TI - [Second Clinical Consensus of the Ibero-American Society of Neonatology: hemodynamic management of newborns]. AB - This study reports on the process and results of the Second Clinical Consensus of the Ibero-American Society of Neonatology. Eighty neonatologists from 23 countries were invited to collaborate and participate in the event. Several questions of clinical-physiological importance in the hemodynamic management of newborns were addressed. Participants were divided into groups to facilitate interaction and teamwork, with instructions to respond to three to five questions by analyzing the literature and local factors. Meeting in Mar del Plata, Argentina, the Consensus Group served as a form for various presentations and discussions. In all, 54 neonatologists from 21 countries attended, with the objective of reaching a consensus on such matters as concepts and definitions of hemodynamic instability, the physiopathology of hemodynamic compromise, recommended therapy strategies, and hemodynamic monitoring. It is hoped that this international experience will serve as a useful initiative for future consensus building and reduction of the existing disparities among the countries of the Region in terms of treatment and outcomes. PMID- 21603776 TI - Vascular alterations in high-fat diet-obese rats: role of endothelial L arginine/NO pathway. AB - BACKGROUND: Mechanisms underlying vascular abnormalities in obesity remain to be completely clarified. OBJECTIVE: L-arginine/nitric oxide pathway was evaluated on vascular response of high-fat diet-obese rats, focusing on endothelial and smooth muscle cells. METHODS: 30-day-old rats were divided in two groups: control (C) and obese (OB, high-fat diet for 30 weeks). After 30 weeks, body weight, adiposity index, blood pressure, and metabolic and endocrine profiles of the animals were recorded. Curves to noradrenaline were obtained in absence and presence of nitric oxide synthase inhibitor (L-NAME, 3x10-4M) on intact and denuded thoracic aorta from C and OB rats. RESULTS: Body weight, adiposity index, leptin and insulin levels were increased in OB, while blood pressure was unchanged. Obesity also produced glucose tolerance and insulin resistance. Reactivity to noradrenaline of intact aorta was similar in C and OB rats. L-NAME presence produced a similar increase in maximal responses, but a higher leftward shift of noradrenaline responses in intact aorta from C than in OB rats [EC50 (x10-7M): C = 1.84 (0.83-4.07), O = 2.49 (1.41-4.38); L-NAME presence C = 0.02 (0.01-0.04)*, O = 0.21 (0.11-0.40)**p < 0.05 vs respective control, p < 0.05 vs control plus L-NAME, n = 6-7]. None of the protocols altered the reactivity to noradrenaline of denuded aortas. CONCLUSION: High-fat diet-induced obesity promotes metabolic and vascular alterations. The vascular alteration involved an endothelial L-arginine/NO pathway improvement was probably correlated to diet induced hyperinsulinemia and hyperleptinemia. The greater resistance to L-NAME effects in aorta of obese rats raises concerns about the lower cardiovascular vulnerability of obese individuals in the presence of associated pathologies that impair NO-system activity. PMID- 21603777 TI - Rationality and methods: registry of clinical practice in high-risk cardiovascular patients. AB - BACKGROUND: To date, no Brazilian registry has been designed to document the clinical practice regarding assistance to patients at high cardiovascular risk in a large representative sample of research centers, including public and private hospitals nationwide. Thus, this study will identify gaps in the incorporation of interventions with proven benefit in our area. OBJECTIVE: To record information on the Brazilian clinical practice with regard to the patients at high cardiovascular risk. METHODS: Registry-type prospective observational study intended to document the current clinical practice applied to outpatients at high cardiovascular risk classified by the presence of one of the following variables: evidence of coronary artery disease, cerebrovascular disease, peripheral vascular disease in diabetics or non-diabetics; or in the presence of at least three of the following cardiovascular risk factors: hypertension, active smoking, dyslipidemia, age over 70 years, chronic kidney disease, family history of coronary artery disease and/or asymptomatic carotid artery disease. Patients will be collected in 43 centers across Brazil, including public and private hospitals, as well as in basic health care units, and clinically reviewed for one year after inclusion. RESULTS: The findings will be presented one year after the start of collection (September 2011), and consolidated after a meeting with the population to discuss the objectives sought. CONCLUSION: The analysis of this multicenter registry will design a horizontal perspective for the treatment of patients suffering from cardiovascular disease in Brazil. PMID- 21603778 TI - Induction of Zenk protein expression within the nucleus taeniae of the amygdala of pigeons following tone and shock stimulation. AB - In this study, we evaluated the expression of the Zenk protein within the nucleus taeniae of the pigeon's amygdala (TnA) after training in a classical aversive conditioning, in order to improve our understanding of its functional role in birds. Thirty-two 18-month-old adult male pigeons (Columba livia), weighing on average 350 g, were trained under different conditions: with tone-shock associations (experimental group; EG); with shock-alone presentations (shock group; SG); with tone-alone presentations (tone group; TG); with exposure to the training chamber without stimulation (context group; CG), and with daily handling (naive group; NG). The number of immunoreactive nuclei was counted in the whole TnA region and is reported as density of Zenk-positive nuclei. This density of Zenk-positive cells in the TnA was significantly greater for the EG, SG and TG than for the CG and NG (P < 0.05). The data indicate an expression of Zenk in the TnA that was driven by experience, supporting the role of this brain area as a critical element for neural processing of aversive stimuli as well as meaningful novel stimuli. PMID- 21603779 TI - A high-carbohydrate diet enhances the adverse effect of the S2 allele of APOC3 SstI polymorphism on the TG/HDL-C ratio only in young Chinese females. AB - Both genetic background and diet have profound effects on plasma lipid profiles. We hypothesized that a high-carbohydrate (high-CHO) diet may affect the ratios of serum lipids and apolipoproteins (apo) differently in subjects with different genotypes of the SstI polymorphism in the apoCIII gene (APOC3). Fifty-six healthy university students (27 males and 29 females, 22.89 +/- 1.80 years) were given a washout diet of 54% carbohydrate for 7 days, followed by a high-CHO diet of 70% carbohydrate for 6 days without total energy restriction. Serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoB100, apoAI, and the APOC3 SstI polymorphism were analyzed. The ratios of serum lipids and apoB100/apoAI were calculated. At baseline, the TG/HDL-C ratio was significantly higher in females, but not in males, with the S2 allele. The differences in the TG/HDL-C ratio between genotypes remained the same after the washout and the high-CHO diet in females. When compared with those before the high-CHO diet, the TC/HDL-C (male S2 carriers: 3.13 +/- 1.00 vs 2.36 +/- 0.65, P = 0.000; male subjects with the S1S1 genotype: 2.97 +/- 0.74 vs 2.09 +/- 0.55, P = 0.000; female S2 carriers: 2.68 +/- 0.36 vs 2.24 +/- 0.37, P = 0.004; female subjects with the S1S1 genotype: 2.69 +/ 0.41 vs 2.09 +/- 0.31, P = 0.000) and LDL-C/HDL-C (male S2 carriers: 1.44 +/- 0.71 vs 1.06 +/- 0.26, P = 0.012; male subjects with the S1S1 genotype: 1.35 +/- 0.61 vs 1.01 +/- 0.29, P = 0.005; female S2 carriers: 1.18 +/- 0.33 vs 1.00 +/- 0.18, P = 0.049; female subjects with the S1S1 genotype: 1.18 +/- 0.35 vs 1.04 +/ 0.19, P = 0.026) ratios were significantly decreased after the high-CHO diet regardless of gender and of genotype of the APOC3 SstI polymorphism. However, in female S2 carriers, the TG/HDL-C (1.38 +/- 0.46 vs 1.63 +/- 0.70, P = 0.039) ratio was significantly increased after the high-CHO diet. In conclusion, the high-CHO diet has favorable effects on the TC/HDL-C and LDL-C/HDL-C ratios regardless of gender and of genotype of the APOC3 SstI polymorphism. Somehow, it enhanced the adverse effect of the S2 allele on the TG/HDL-C ratio only in females. PMID- 21603780 TI - Evidence-based psychology. PMID- 21603781 TI - Sao Paulo Medical Journal: heading towards the 80th anniversary. PMID- 21603782 TI - Frequency of headache among the employees of a rubber company in the state of Sao Paulo, Brazil. AB - CONTEXT AND OBJECTIVE: Primary headaches may be responsible for absenteeism and a fall in the yield and productivity of work. The aim of this study was to establish the presence and frequency of primary headache among employees of a rubber shoe sole company, and its link to absenteeism. DESIGN AND SETTING: Cross sectional study carried out with help from the staff of the medical and social department of a rubber factory located in the municipality of Franca, Sao Paulo. METHOD: A questionnaire on headache characteristics was distributed to all employees. The returned and completed questionnaires were divided into two groups: with and without reports of headache. The headaches were classified into four main groups: migraine, tension-type headache (TTH), cluster headache and others. In terms of the reported frequency, headaches were also classified as chronic daily headache (CDH). RESULTS: The number of valid questionnaires was 392 (59%); 80.9% were from male and 19.1% from female employees. Headaches were reported by 120 subjects (30.6%), with 17.4% belonging to the migraine group and 8.9% to the TTH group. Migraine was more frequent (p < 0.001) among all participants and also among the women (p < 0.05). TTH was more frequent among the men (p < 0.05). CDH was identified in 14 individuals (3.6%). CONCLUSIONS: Headache was a common problem among the employees of this company and was a cause of absenteeism for 8.7% of the respondents to the questionnaire. PMID- 21603783 TI - Serum lipid levels in pregnancies complicated by preeclampsia. AB - CONTEXT AND OBJECTIVE: Pre-eclampsia is a disorder that occurs only during pregnancy. Postpartum changes relating to lipid metabolism may contribute towards the endothelial lesions observed in preeclampsia. Thus, the aim of the present study was to evaluate the lipid profile among patients who present preeclampsia and correlate these parameters with 24-hour proteinuria. DESIGN AND SETTING: Cross-sectional analytical study including 77 pregnant patients seen at Hospital Dorio Silva. METHODS: This study involved 42 women with preeclampsia and 35 healthy pregnant women in the third trimester of pregnancy as controls. Blood samples were obtained from all the patients, and the serum levels of triglycerides, total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL) and very low density lipoproteins (VLDL) were determined. Cases and controls were matched for maternal age, gestational week and body mass index. RESULTS: The VLDL and triglyceride values from the women with preeclampsia were significantly higher than those of the healthy women. There was a positive correlation between increased proteinuria and higher VLDL and triglyceride levels in patients with preeclampsia. CONCLUSION: Among the patients with preeclampsia, higher VLDL and triglyceride levels were positively correlated with proteinuria. These observations indicate that the pregnant women who presented elevated lipid levels were more susceptible to cardiovascular disorders and, consequently, pre eclampsia. PMID- 21603784 TI - Ministers of Health: short-term tenure for long-term goals? AB - CONTEXT AND OBJECTIVE: Healthcare investments should consider short and long-term demands. The objectives here were to compare the average tenures of ministers of health in Brazil and in another 22 countries and to evaluate the relationship between ministers' tenures and a number of indicators. DESIGN AND SETTING: Descriptive study conducted at Centro Paulista de Economia da Saude (CPES). METHODS: Twenty-two countries with the highest Human Development Indices (HDIs) and Brazil were included. The number of ministers over the past 20 years was investigated through each country's Ministry of Health website. Pearson's correlation coefficient was used to compare the number of ministers in each country with that country's indicators. The Mann-Whitney test was used to compare ministers' tenures in Brazil and other countries. RESULTS: The mean tenure (standard deviation, SD) of Brazilian ministers of health was 15 (12) months, a period that is statistically significantly shorter than the mean tenure of 33 (18) months in the other 22 countries (P < 0.05). There was a moderate and statistically significant positive correlation between the number of ministers and mortality rates for several conditions. The number of ministers also presented moderate and statistically significant negative correlations with per capita total healthcare expenditure (r = -0.567) and with per capita government healthcare expenditure (r = -0.530). CONCLUSION: On average, ministers of health have extremely short tenures. There is an urgent need to think and plan healthcare systems from a long-term perspective. PMID- 21603785 TI - Assessing the risk of bias in randomized controlled trials in the field of dentistry indexed in the Lilacs (Literatura Latino-Americana e do Caribe em Ciencias da Saude) database. AB - CONTEXT AND OBJECTIVE: Well-conducted randomized controlled trials (RCTs) represent the highest level of evidence when the research question relates to the effect of therapeutic or preventive interventions. However, the degree of control over bias between RCTs presents great variability between studies. For this reason, with the increasing interest in and production of systematic reviews and meta-analyses, it has been necessary to develop methodology supported by empirical evidence, so as to encourage and enhance the production of valid RCTs with low risk of bias. The aim here was to conduct a methodological analysis within the field of dentistry, regarding the risk of bias in open-access RCTs available in the Lilacs (Literatura Latino-Americana e do Caribe em Ciencias da Saude) database. DESIGN AND SETTING: This was a methodology study conducted at Universidade Federal de Sao Paulo (Unifesp) that assessed the risk of bias in RCTs, using the following dimensions: allocation sequence generation, allocation concealment, blinding, and data on incomplete outcomes. RESULTS: Out of the 4,503 articles classified, only 10 studies (0.22%) were considered to be true RCTs and, of these, only a single study was classified as presenting low risk of bias. The items that the authors of these RCTs most frequently controlled for were blinding and data on incomplete outcomes. CONCLUSION: The effective presence of bias seriously weakened the reliability of the results from the dental studies evaluated, such that they would be of little use for clinicians and administrators as support for decision-making processes. PMID- 21603787 TI - Functional status change in older adults undergoing coronary artery bypass surgery. AB - CONTEXT AND OBJECTIVE: Increased life expectancy has resulted in growing numbers of elderly patients undergoing heart surgery. This study aimed to identify changes in functional status among older adults undergoing coronary artery bypass grafting. DESIGN AND SETTING: Prospective observational cohort study conducted at a level IV private hospital in Brazil. METHODS: Patients were assessed using the Katz and Lawton scales and the Functional Independence Measure before admission, at hospital discharge and one month after discharge. Repeated-measurement analysis of variance was used. RESULTS: Two patients died during hospitalization. Among the 31 patients included, the Functional Independence Measure ranged from 121.7 +/- 7.4 (pre-admission) to 91.1 +/- 20.5 (discharge) and 109.0 +/- 21.7 (one month after discharge); the Katz scale from 5.92 +/- 0.32 to 4.18 +/- 1.04 and 5.13 +/- 1.30; and the Lawton scale from 24.3 +/- 4.6 to 12.8 +/- 2.0 and 16.5 +/- 4.6 (P = 0.0001). When subgroups with (18) and without (13) complications were compared, the Functional Independence Measure (P = 0.085) showed a trend, although not significantly, toward recovery one month after discharge. Delirium and blood transfusion were the intercurrent events found. There was a correlation between the scales and age (P = 0.008), APACHE II (P = 0.051), EuroSCORE (P = 0.064), intensive care unit stay (P = 0.024) and overall hospital length of stay (P = 0.040). CONCLUSION: The Functional Independence Measure proved to be a promising tool for monitoring the functional status of elderly patients undergoing coronary artery bypass grafting, especially in the subgroup with complications. PMID- 21603786 TI - Hierarchy of evidence relating to hand surgery in Brazilian orthopedic journals. AB - CONTEXT AND OBJECTIVE: There is no systematic assessment of the quality of scientific production in the specialty of hand surgery in our setting. This study aimed to systematically assess the status of evidence generation relating to hand surgery and to evaluate the reproducibility of the classification method based on an evidence pyramid. DESIGN AND SETTING: Secondary study conducted at Universidade Federal de Sao Paulo (Unifesp) and Faculdade Estadual de Medicina de Marilia (Famema). METHODS: Two researchers independently conducted an electronic database search for hand surgery studies published between 2000 and 2009 in the two main Brazilian orthopedic journals (Acta Ortopedica Brasileira and Revista Brasileira de Ortopedia). The studies identified were subsequently classified according to methodological design (systematic review of the literature, randomized clinical trial, cohort study, case-control study, case series and other studies) and evidence level (I to V). RESULTS: A total of 1,150 articles were evaluated, and 83 (7.2%) were included in the final analysis. Studies with evidence level IV (case series) accounted for 41 (49%) of the published papers. Studies with evidence level V (other studies) accounted for 12 (14.5%) of the papers. Only two studies (2.4%) were ranked as level I or II. The inter-rater reproducibility was excellent (k = 0.94). CONCLUSIONS: Hand surgery articles corresponded to less than one tenth of Brazilian orthopedic production. Studies with evidence level IV were the commonest type. The reproducibility of the classification stratified by evidence level was almost perfect. PMID- 21603788 TI - Budd-Chiari syndrome in association with Behcet's disease: review of the literature. AB - The risk that patients with Behcet's disease may develop various thrombotic complications has been previously described. Although vascular complications from Budd-Chiari syndrome associated with Behcet's disease have been described, the pathogenic mechanisms are still unknown. Severe vascular complications present in Budd-Chiari syndrome associated with Behcet's disease are very common among young male adults. The objective of this study was to review the literature and present the association of Budd-Chiari syndrome with Behcet's disease. PMID- 21603789 TI - Moyamoya syndrome associated with neurofibromatosis type I in a pediatric patient. AB - CONTEXT: Neurofibromatosis type 1 (NF-1) is the most prevalent autosomal dominant genetic disorder among humans. Moyamoya disease is a cerebral vasculopathy that is only rarely observed in association with NF-1, particularly in the pediatric age range. The present study reports an occurrence of this association in an infant. CASE REPORT: An eight-month-old female presented convulsive seizures with clonic movements. The patient suffered an ischemic stroke with hemiparesis. Magnetic resonance imaging revealed radiological findings compatible with moyamoya disease. The diagnosis of NF-1 was made at the age of 20 months. CONCLUSION: Despite the rarity of this association in childhood, children with focal neurological symptoms and a diagnosis of NF-1 deserve to be investigated for moyamoya syndrome. PMID- 21603790 TI - Scrotal hematoma as a sign of adrenal hemorrhage in newborns. AB - CONTEXT: Bluish discoloration and swelling of the scrotum in newborns can arise from a number of diseases, including torsion of the testes, orchitis, scrotal or testicular edema, hydrocele, inguinal hernia, meconium peritonitis, hematocele, testicular tumor and traumatic hematoma. Forty-two cases of scrotal abnormalities as signs of neonatal adrenal hemorrhage were found in the literature. CASE REPORT: We present a case of scrotal hematoma due to adrenal hemorrhage in a newborn. Conservative treatment with clinical follow-up was adopted, with complete resolution within 10 days. The possible differential diagnoses are reviewed and discussed. PMID- 21603791 TI - Complications from radiotherapy for breast cancer. PMID- 21603794 TI - Case 3/2011: 17-year-old male adolescent with accentuated pulmonary insufficiency as a residual lesion by prior correction of tetralogy of Fallot performed 14 years ago. PMID- 21603795 TI - Transient positional dyspnea. PMID- 21603796 TI - Right ventricular perforation by a passive-fixation pacemaker lead. PMID- 21603797 TI - Mitral valve apparatus preservation and early bioprosthetic thrombosis: a word of caution. PMID- 21603798 TI - About the use of DES (drug-eluting stents) in real life: the importance of registries. PMID- 21603799 TI - Stroke due to Chagas' cardiomyopathy or noncompaction. PMID- 21603800 TI - Referring to noncompaction of the myocardium, Chagas' disease and dysfunction. PMID- 21603801 TI - Neutrophilic dermatoses: part II. AB - This article addresses neutrophilic dermatoses, thus complementing the previous article (part I). The following dermatoses are introduced and discussed: subcorneal pustular dermatosis (Sneddon-Wilkinson disease), dermatitis cruris pustulosa et atrophicans, acute generalized exanthematous pustulosis, continuous Hallopeau acrodermatitis, palmoplantar pustulosis, infantile acropustulosis, Andrews' pustular bacteride and eosinophilic pustular folliculitis. A brief review of neutrophilic dermatoses in pediatric patients is also conducted. PMID- 21603802 TI - Criteria for submitting photos. AB - Dermatological photography is used as a supplement to dermatological examination with the function of providing additional knowledge and information. Its quality depends on the expertise of the photographer-dermatologist in recording the relevant elements present. Therefore, the dermatologist should know basic principles of photography and the journal editors should ensure that the articles have high-quality images. This article suggests criteria to improve the quality of photographs submitted to journals for publication. PMID- 21603803 TI - Early diagnosis of cutaneous melanoma: an observation in southern Brazil. AB - BACKGROUND: The incidence of melanoma cutaneous and the mortalities rates are rising in most countries worldwide. OBJECTIVE: to describe the histopathological characteristics of cutaneous melanoma, according to the criteria established by the Brazilian Group of Melanoma, and to evaluate early diagnosis in a cancer treatment referral center. METHODS: we performed a cross-sectional descriptive study of cases of primary cutaneous melanoma identified after excisional biopsy and processed at the pathology laboratory of Complexo Hospitalar Santa Casa between Jan 1st 2000 and Jan 15th 2005. The following variables were analyzed: age, gender, topography, histopathologic subtype, Breslow thickness, growth phase, Clark level, mitotic index, peritumoral and intratumoral lymphocytic inflammatory infiltrate, angiolymphatic invasion, ulceration, regression, type of regression, microscopic satellitosis, and surgical margins. RESULTS: 328 cases, 57% female and 43% male, were analyzed. Mean age was 55.6 years. For women, the most common tumor location was in inferior(29.26%) and superior limbs(23.94%), while for men melanoma was mainly found in the back(35%), followed by anterior chest/abdomen(14.29%) (p<0.05). Prevalence of histologic subtypes was the following: superficial spreading melanoma(62.8%), lentigo maligna(14.9%), nodular(14.6%), acral(7.3%), and desmoplastic(0.3%) types. Regarding Breslow, 26.2% were in situ, 36.9% had <1 mm, and only 15.9% were ? 4mm in depth. CONCLUSION: the distribution of histopathologic subtypes, as well as Breslow thickness, was in accordance with previous studies in outpatient populations. The profile of cases of cutaneous melanoma diagnosed in a tertiary hospital seems to be experiencing some changes over the last two decades, with a current trend for earlier diagnosis. PMID- 21603804 TI - Effects of long-term chronic exposure to sun radiation in immunological system of commercial fishermen in Recife, Brazil. AB - BACKGROUND: Among the various occupations which necessarily require long-term and chronic sun exposure is that of a fisherman. However, clinical experience in dermatology earned over several years of medical practice does not seem to confirm this hypothesis. OBJECTIVE: To evaluate clinical, histological and immunological effects of long-term and chronic exposure to ultraviolet radiation in fishermen. METHODS: A prospective, cross-sectional and observational study characterized skin lesions, immunological markers and histological alterations in fishermen, as well as lymphocyte subpopulations compared to a control group. Mann Whitney, Fisher's and Wilcoxon statistical tests were used at a significance level of 0.05. RESULTS: There were significant differences between the exposed group and the group protected due to elastosis (p = 0.03), ectasia of dermal vessels (p = 0.012) and number of cells in the epidermal layers between cones (p = 0.029). Most common among fishermen were CD45RO, CD68 + and mastocytes in the skin (p = 0.040, p <0.001, p = 0.001) and CD3CD8CD45RO in the blood (p = 0.016). CONCLUSION: The alterations suggest that long-term and chronic sun exposure promotes tolerance to ultraviolet radiation, which protects against immunosuppression. PMID- 21603805 TI - Epidemiologic profile of the leprosy of the city of Teresina, in the period of 2001-2008. AB - BACKGROUND: Leprosy is an infectious disease that can lead to functional and physical disability. It is a major public health problem in some regions, requiring knowledge of its epidemiological variations so that strategies for disease control can be subsidized. OBJECTIVE: To describe the epidemiological profile of the city of Teresina from 2001 to 2008. METHODS: Data on leprosy in the city of Teresina from 2001 to 2008, which were present on the official database of the Information System for Notifiable Diseases of the City Health Foundation, were analyzed. RESULTS: The data show an average detection rate of new cases of 96.21 cases per 100,000 inhabitants. Among those younger than 15, there was a peak of 40 cases per 100,000 inhabitants in 2003. Grade 2 disability evaluated at diagnosis ranged from 5 to 7% and at discharge from 2.77 to 0.14%. Prevalence is high, varying from 8 to 11 cases per 10,000 inhabitants. Regarding clinical form, there is a predominance of forms I with 30% of the cases and D with 28% of the cases at the end of the series; and in relation to operational classification, the average is 62% of paucibacillary cases and 37.86% of multibacillary cases. Among the reported cases, there is a slight predominance of females at the end of the series. CONCLUSION: Leprosy is hyperendemic in Teresina and it can lead people at working age to inactivity. PMID- 21603806 TI - Vitiligo epidemiological profile and the association with thyroid disease. AB - BACKGROUND: Vitiligo is considered the most frequent acquired hypomelanosis. Although its pathogenesis is uncertain, it is believed that autoimmune etiology is the most plausible. This theory is based on the coexistence of vitiligo with autoimmune diseases. OBJECTIVES: To describe the epidemiological profile of vitiligo patients and to estimate the prevalence of the association of vitiligo with autoimmune thyroid diseases. METHODS: A cross-sectional study was conducted through analysis of the medical records of patients diagnosed with vitiligo in the AME-UNISUL Outpatient Clinic of Dermatology and at HU-UFSC. The clinical and laboratorial characteristics of these patients were assessed. RESULTS: 85 medical records were evaluated; 56 patients were female, with a mean age of 37.14 years and mean onset age of 25.25 years. Vitiligo vulgaris occurred in 70.6%. Autoimmune thyroid diseases were found in 22.4%. Other autoimmune diseases were identified in 5.9%. Patients with positive thyroid autoantibodies showed a probability of extension of vitiligo greater than 25%. There was no statistical difference with regard to the clinical characteristics of vitiligo in patients with or without autoimmune thyroiditis with hormonal change. CONCLUSION: The findings of this study are similar to those obtained by other authors, showing that autoimmune thyroid diseases are more common in patients with vitiligo. PMID- 21603807 TI - Predictors of quality of life in patients with skin melanoma at the dermatology department of the Porto Alegre Teaching Hospital. AB - BACKGROUNDS: Some symptoms present in melanoma patients are directly related to psychological stress, which emphasizes the need to evaluate quality of life (QoL) in these patients at all the stages of their disease. OBJECTIVES: The objective of this study was to evaluate quality of life in a sample of patients diagnosed with melanoma, using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. METHODS: A descriptive, cross sectional study was conducted between July and December, 2006 with all patients with skin melanoma receiving follow-up care at the Department of Dermatology of the Porto Alegre Teaching Hospital, Federal University of Rio Grande do Sul. RESULTS: Sixty patients were included in the study. Mean age was 55.6 years. Poor education level (primary school or less) was associated with a poorer FACT-G score. Patients with a family history of the disease had higher QoL scores in 3 of the 4 categories evaluated: physical, emotional and functional wellbeing (p<0.01). QoL scores were higher in married patients (82.42) compared to single patients (70.28) (p<0.01). Patients with metastases had lower scores in the functional wellbeing category and this difference was statistically significant. CONCLUSIONS: Factors related to the tumor, as well as gender, age and employment status, were not found to be predictive of quality of life in this sample. Quality of life scores were lower in the functional wellbeing domain in patients with metastases. Married patients are able to count on greater comfort and emotional support to help them deal with the diagnosis of melanoma. Patients with a family history of melanoma had significantly higher quality of life scores, while those with poor education levels had lower scores. PMID- 21603808 TI - Moderate to severe psoriasis treated with infliximab - 53 patients: patients profile, efficacy and adverse effects. AB - BACKGROUND: Psoriasis exerts a significant negative effect on quality of life and is associated with comorbidities. The inflammatory activity of the psoriasis plaques is partially triggered by activation of the Th1 lymphocytes, which release proinflammatory cytokines such as TNF-alpha. Infliximab neutralizes the biological activity of TNF-alpha. Adverse reactions that occur during infusion or up to 24 hours afterwards are referred to as acute reactions. Delayed reactions are those occurring between 24 hours and 14 days after an infusion. OBJECTIVE: To evaluate the profile of patients with moderate to severe psoriasis that is resistant to conventional treatment, and to assess adverse reactions to infliximab. METHODS: Fifty-three patients, 40 men and 13 women, were treated with infliximab. The dose used was 5 mg/kg in weeks 0, 2 and 6 (induction phase), followed by maintenance therapy every 8 weeks. RESULTS: Of the 53 patients, 6 participated only in the induction phase. These patients reached Psoriasis Area Severity Index (PASI) of 90-100 and opted to discontinue treatment. Forty-seven patients continued therapy with the drug for at least 2-3 years. Of these, 55.3% (n=26) experienced some type of adverse event. Acute adverse events were recorded in 34% of the patients and delayed adverse events in 36.1%. The prevalence of comorbidities was 57.4%. CONCLUSION: In the present study, infliximab was found to constitute a safe and effective form of therapy. Of the comorbidities recorded in the patients in this study, obesity was associated with a delayed and less effective response to treatment. When adequately monitored, neither acute nor delayed adverse events require discontinuation of therapy, since they do not represent an uncontrolled risk to the patient. PMID- 21603809 TI - Sweet's syndrome: a study of 23 cases. AB - BACKGROUND: Sweet's syndrome or acute febrile neutrophilic dermatosis is a rare disease characterized by painful violaceous erythematous skin lesions, fever, neutrophilic leukocytosis and dense dermal neutrophilic inflammatory infiltrate. It shows excellent response to corticosteroids. OBJECTIVES: To assess cases of Sweet's syndrome in a university hospital, identifying its clinical, laboratory and epidemiological characteristics and compare them with the data found on the literature. METHODS: We conducted a retrospective epidemiological study by examining the medical records of 23 patients who met the diagnostic criteria for the disease from March 1995 to July 2009. We collected clinical and epidemiological data on the patients, such as lesion location, presence of cutaneous and extracutaneous manifestations, conditions associated with SS and some laboratory data, such as leukocyte count and ESR. RESULTS: The age of the patients in the study ranged from 2 to 75 years. There were more females. The lesions mostly affected the trunk and upper limbs. Fever was the most common systemic manifestation, followed by arthralgia and myalgia, conjunctivitis and arthritis. The triggering factors most commonly identified were infections of the respiratory tract. Associated neoplasia occurred in 30% of the patients, especially hematologic neoplasia. CONCLUSION: The clinical and epidemiological data found in our study are mostly similar to those found in the literature. Given the high prevalence of malignant diseases in patients with Sweet's syndrome, it is necessary to know how to perform the diagnosis, carry out a full investigation as well as do the patient's follow up. PMID- 21603810 TI - Topography of basal cell carcinoma and their correlations with gender, age and histologic pattern: a retrospective study of 1042 lesions. AB - BACKGROUND: Basal cell carcinoma accounts for 75% of skin cancer. Sun exposure and genetics are related to its etiology. It's expected that biological and behavioral differences provide different patterns of involvement between sexes. OBJECTIVES: To evaluate the topography of lesions and their correlations with gender, age and histological type. METHODS: Retrospective study of basal cell carcinoma patients treated between 1999 and 2008 in the Skin Cancer Clinic of Santa Casa de Misericordia of Curitiba. We evaluated sex, age, location, histological type, margins commitment, sun exposure and family skin cancer history. RESULTS: We found 1042 lesions in 545 patients (61% women), being more numerous in men (p<0.01). Their ages ranged between 27 and 95 years (median=65). Men had more sun exposure (p<0.01). The lesions were more frequent extra-cephalic recently (p<0.01). The margin involvement was higher in the head (p<0.01). The superficial type was less frequent on the head (p<0.01) and was associated with younger ages in women (p<0.01). The head housed 74% of lesions and the legs 2%. Women had a predilection for the legs, nose and upper lip and men to trunk, ears and scalp (p <0.05). The surgeries in the medial epicanthus and scalp occurred at younger ages (p=0.01). CONCLUSIONS: We identified significant associations between the topography of lesions, gender, age and histological type, demonstrating the possible pathophysiological diversity and differential risk factors operation. In the period studied we found no trend of increase in the proportion of young or women among patients. PMID- 21603811 TI - Combined use of low level laser therapy and cyclooxygenase-2 selective inhibition on skin incisional wound reepithelialization in mice: a preclinical study. AB - BACKGROUND: Low level laser therapy and cyclooxygenase-2 (ICOX2) selective inhibitors have been widely used to modulate inflammatory response; however, their effect on wound reepithelialization are not well understood. OBJECTIVE: To evaluate the isolated and combined effects of low level laser therapy and ICOX2 in the reepithelization of skin incisional wounds in mice. METHODS: We induced a 1-cm wound on the back of each mouse, which were divided into four groups (N = 20): control, laser therapy, treated with celecoxib and combined therapy. The animals in the celecoxib and combined therapy groups were treated with celecoxib for 10 days before skin incision. The experimental wounds were irradiated with He Ne low power laser (632nm, dose: 4J/cm2) in scanning for 12 seconds during three consecutive days in the laser therapy and combined therapy groups. The animals were sacrificed 3 days after surgery. Samples of the wounds were collected and stained (Masson's Trichrome) for histomorphometric analysis. RESULTS: Both the laser therapy group and the celecoxib group showed an increase in skin reepithelialization compared to the control group; however, the combined therapy group showed no differences. As for keratinization, the laser therapy and combined therapy groups showed a reduction in keratinocytes compared with the control group. CONCLUSION: The results show that the use of low level laser therapy and ICOX2 in isolation increases epithelial cells, but only low level laser therapy reduced skin keratinocytes. The combined treatment restores innate epithelialization and decreases keratinization in spite of accelerating wound contraction with improvement in the organization of the wound in the skin of mice. PMID- 21603812 TI - Validation of the commitment index of skin and mucous membranes in pemphigus vulgaris for the clinical evaluation of patients with pemphigus vulgaris. AB - BACKGROUND: Pemphigus vulgaris is a severe bullous disease, produced by the autoimmune destruction of desmosomes, resulting in the formation of intraepidermal blisters, affecting skin and mucous membranes, with a mortality of 5 to 10%. Side effects of therapy contributed to increased morbidity, accounting for considerable part of the immediate causes of death due to PV today. There is no reproducible score for clinical evaluation of patients with Pemphigus vulgaris, making the therapeutic decision subjective, and its results, uncertain. OBJECTIVES: Create and evaluate the reproducibility of a scoring system for clinical evaluation of patients with pemphigus vulgaris. METHODS: The Commitment Index of Skin and Mucous in Pemphigus Vulgaris was created, scoring easily observed findings on clinical examination. During 3 years, 7 patients with active PV were submitted to pairings of Commitment Index of Skin and Mucous in Pemphigus Vulgaris conduced by independent examiners for determinate its reproducibility. RESULTS: The Commitment Index of Skin and Mucous in Pemphigus Vulgaris proved that it is reproducible in all the statistical methods used to assess agreement between the independent examiners. In adition, it permited us to separate the patients into classes of severity. CONCLUSION: The Commitment Index of Skin and Mucous in Pemphigus Vulgaris can classify the severity of Pemphigus Vulgaris, contributing to medical research, and to the standardization of the therapy in the near future. PMID- 21603813 TI - Epidemiology of basal cell carcinoma. AB - Basal cell carcinoma is the most common malignant neoplasm in humans and its incidence has increased over the last decades. Its high frequency significantly burdens the health system, making the disease a public health issue. Despite the low mortality rates and the rare occurrence of metastases, the tumor may be locally invasive and relapse after treatment, causing significant morbidity. Exposure to ultraviolet radiation is the main environmental risk factor associated with its cause. However, other elements of risk are described, such as light skin phototypes, advanced age, family history of skin carcinoma, light eyes and blond hair, freckles in childhood and immunosuppression. Behavioral aspects such as occupational sun exposure, rural labor and sunburns at a young age also play a role. Between 30% and 75% of the sporadic cases are associated with patched hedgehog gene mutation, but other genetic changes are also described. The tumor is commonly found in concomitance with skin lesions related to chronic sun exposure, such as actinic keratoses, solar lentigines and facial telangiectasia. The prevention of basal cell carcinoma is based on the knowledge of risk factors, early diagnosis and treatment, as well as on the adoption of specific measures, particularly in susceptible populations. The authors present a review of the epidemiology of basal cell carcinoma. PMID- 21603814 TI - Human papillomavirus infection: etiopathogenesis, molecular biology and clinical manifestations. AB - Human papillomavirus (HPV) is a DNA virus that presents tropism for epithelial cells, causing infections of the skin and mucous membranes. Replication of HPV occurs in the nuclei of squamous cells and its life cycle is directly related to the differentiation program of the host cell. To date, nearly 100 different types of HPV have been characterized and there is a large number of other types that have not been sequenced yet. Besides being responsible for benign lesions of the skin and mucous membranes, HPV is also involved in the development of various mucocutaneous tumors: Bowen's disease, non-melanoma skin cancers and genital carcinomas. This review discusses the characteristics of HPV, malignant and benign mucous and skin manifestations caused by HPV, besides the main methods of detection and typing of the virus. PMID- 21603815 TI - Cutaneous manifestations in end-stage renal disease. AB - The prevalence of chronic kidney disease has increased over the last years. The effects of this disease are complex and may lead to dysfunction of multiple organs, including the skin, with most patients presenting with at least one dermatologic alteration. Sometimes these symptoms can be the first clear sign of kidney disease. This article discusses the skin manifestations related to severe renal impairment or end-stage renal disease (ESRD), which are divided into nonspecific and specific, and reviews the clinical features, etiopathogenesis and therapeutic options for these dermatoses. Early recognition and treatment reduce morbidity and improve these patients' quality of life. PMID- 21603816 TI - Generalized perforating granuloma annulare. AB - The authors present a clinicopathological case of Generalized Perforating Granuloma Annulare with extensive distribution of lesions, which are shown in various stages of development. Pustules, papular lesions in annular and arcuate distribution, erosions covered with hematic crusts, maculopapular atrophic areas and scars were the presentation forms of the disease. The histopathological aspects are discussed in detail within non-infectious granulomatous dermatitis. The text is based on the opinions of some authors in the literature. Furthermore, the therapeutic result obtained after three months of Dapsone at a dose of 100 mg per day was demonstrated by photographs. PMID- 21603817 TI - Angiokeratoma of the vulva. AB - Angiokeratomas are benign tumors characterized by ectasia of blood vessels in the papillary dermis associated with acanthosis and hyperkeratosis of the epidermis. Dermatological examination of angiokeratomas of Fordyce is characterized by papular keratotic lesions of erythematous-violet color. They are more common in the scrotum, and vulvar involvement is rarely reported. Histopathology is particularly important to distinguish them from other benign and malignant tumors. The article reports the case of a middle-aged black woman with a history of chronic constipation, varicose veins of the lower limbs and cesarean section performed 20 years ago who had had multiple vulvar angiokeratomas for three months. PMID- 21603818 TI - Acute acneiform eruption induced by interferon beta-1b during treatment for multiple sclerosis. AB - Multiple sclerosis is an inflammatory demyelinating disease of presumed autoimmune origin that affects the central nervous system. The main form of therapy is based on the use of immunomodulators such as interferon beta, which are usually well tolerated. Skin manifestations resulting from treatment with interferon beta-1b consist principally of reactions at the site of subcutaneous application of the drug. The present case report describes a female patient who developed an acneiform eruption resulting from treatment with interferon beta-1b. PMID- 21603819 TI - O'Brien's actinic granuloma: an unusually extensive presentation. AB - O'Brien's actinic granuloma is a rare skin disease. Controversy continues over whether it should be considered a specific condition or a form of granuloma annulare located in sun-exposed areas. Its pathogenesis is unknown; however, the most widely accepted hypothesis suggests that solar radiation is the triggering factor. This paper describes the case of a 78-year old, fair-skinned male, who presented with a 10-year history of an infiltrate of annular erythematous papules on his forehead and left malar region. The diagnosis of O'Brien actinic granuloma was established from histopathology, since the clinical condition of the patient was extensive, unlike cases reported in the literature. PMID- 21603820 TI - Acral microcystic lymphangioma: differential diagnosis in verrucous lesions of the extremities. AB - Lymphangiomas are a malformation caused by the abnormal migration of lymphatic tissue, leading to failures in the communication and drainage of the lymphatic system. They usually present as groups of translucent papules and vesicles in the skin or mucous membranes. Presentation as a verrucous plaque limited to a single toe is unusual and emphasizes the relevance of this case report. Although considered a benign lesion, depending on the site affected by the lymphangioma and its size, it may lead to localized pain or recurrent infections, substantially affecting the patient's quality of life. The present case report describes a patient with lymphangioma of late onset developing in adulthood in the form of a verrucous plaque confined to a single toe. Diagnosis of this unusual presentation could only be confirmed following histopathology. Surgical excision resulted in a satisfactory functional and cosmetic outcome. PMID- 21603821 TI - Neonatal lupus erythematosus: a report of four cases. AB - Neonatal lupus erythematosus is a very rare disease, clinically characterized by skin lesions that resemble those of subacute or discoid lupus erythematosus and/or congenital heart block. Generally, when patients have skin manifestations, they have no cardiac defects and vice-versa; however, in 10% of cases these manifestations may coexist. Other findings may include hematologic, hepatic and neurological abnormalities. This condition is caused by the transplacental passage of maternal autoantibodies against Ro (95%), La and, less frequently, U1 ribonucleoprotein (U1-RNP). The present case report describes four patients with clinical, histopathological and immunological findings compatible with neonatal lupus erythematosus, their treatment and progress. PMID- 21603822 TI - Molluscum contagiosum on tattoo. AB - Molluscum contagiosum is a disease caused by a poxvirus characterized by benign self-limited eruption of single or multiple cutaneous spherical and pearly papules. Transmission usually occurs by direct contact with infected hosts. It is reported the case of a 22-year-old Caucasian male who presented characteristic pearly and umbilicated papules strictly located on the region of a tattoo. Histopathologic exam confirmed the diagnosis of molluscum contagiosum. The authors describe an uncommomn manifestation of dissemination of this virus in tattoos and also present a literature review emphasizing the transmission pathways and treatment of Molluscum contagiosum. PMID- 21603823 TI - Bullous pemphigoid in younger adults: three case reports. AB - Bullous pemphigoid is an autoimmune subepidermal bullous dermatosis more commonly observed in the elderly (over 70 years old). Autoantibodies are produced for specific antigens of the epidermal basement membrane zone: BP 180 and BP 230 (hemidesmosome proteins). We report three cases of bullous pemphigoid in adults younger than 50 years old, discussing the clinical characteristics of the disease in younger patients. PMID- 21603824 TI - Hair loss due to lichen planopilaris after hair transplantation: a report of two cases and a literature review. AB - Androgenetic alopecia is often treated by follicular unit transplantation, a technique that involves minimal risk of hair loss because of the more resistant nature of the donor area. Lichen planopilaris is a cicatricial alopecia that causes permanent destruction of hair follicles. We report two cases of post transplantation lesions compatible with lichen planopilaris in both recipient and donor areas. The quality of the hair follicles in the donor area was apparently compromised by lichen planopilaris, the probable cause of hair loss. Similar reports are rare. When lichen planopilaris is suspected, a biopsy of the scalp must be performed to avoid transplantation during disease activity. PMID- 21603825 TI - Primary cutaneous alveolar rhabdomyosarcoma in a pediatric patient. AB - Rhabdomyosarcoma is the most common soft tissue tumor in childhood; however, it rarely affects only the skin. This case report describes a child with a painful nodule on her face. Histopathology and immunohistochemistry confirmed the diagnosis of rhabdomyosarcoma, and a multidisciplinary team then followed up the patient. Soft tissue tumors are responsible for 6% of all childhood tumors, and 53% of these are rhabdomyosarcomas, which may affect any part of the body. Presentation in the form of skin nodules is rare and represents a diagnostic challenge, since there are no clinical characteristics that differentiate this condition from other pathologies. PMID- 21603826 TI - Marjolin's ulcer associated with ulceration and chronic osteomyelitis. AB - This report describes a 78-year old male patient with a chronic venous ulcer on his left leg for the past 24 years, complicated by a squamous-cell carcinoma. After staging of the disease, the treatment administered was amputation of the leg above the knee. Marjolin's ulcer consists of the malignant transformation of a chronic ulcerative lesion. It is a relatively rare phenomenon. The malignant tumor most commonly described in the literature is squamous cell carcinoma, followed by basal-cell carcinoma, sarcoma and melanoma. The pathogenesis of Marjolin's ulcer remains to be fully clarified. PMID- 21603827 TI - Entodermoscopy: dermoscopy for the diagnosis of pediculosis. AB - We report a clinical case in which contactless dermoscopy was used as an aid to the diagnosis of pediculosis and clinical evaluation of the effectiveness of treatment of this condition. PMID- 21603828 TI - Jorge Lobo's disease with restricted labial presentation. AB - Jorge Lobo's Disease (JLD) is a chronic granulomatous cutaneous mycosis caused by Lacazia loboi. The most typical lesions are keloid-like growths preferentially located on limbs and ears. To the best of the authors' knowledge, only one labial case has previously been reported. We describe the case of a man who presented with a left-sided papulonodular lesion of 10 years' duration on the vermillion border of the upper lip. A successful surgical resection of the lesion was performed and there was no recurrence in eight years of follow-up. PMID- 21603829 TI - Increase in the incidence of basal cell carcinoma in a university hospital between 1999 and 2009. AB - The incidence of basal cell carcinoma is increasing worldwide. An ecological study was conducted using the pathology reports from 5169 cases of basal cell carcinoma diagnosed at the Botucatu School of Medicine, Universidade Estadual Paulista Julio de Mesquita Filho (UNESP) between January 1999 and December 2009. The mean increase in the incidence of basal cell carcinoma over this period was 90.6%, suggesting that one case of basal cell carcinoma could be expected for every 15 patients referred to dermatology. This trend was also found when the incidence was indexed according to the absolute number of histopathology exams, the total number of hospital consultations, the total number of dermatological consultations and the population of the town of Botucatu. PMID- 21603830 TI - Sentinel lymph node biopsy in cases of skin melanoma: initial experiences at a center in northeastern Brazil. AB - The incidence of skin melanoma is increasing worldwide. The presence of lymph node metastasis is the most important prognostic factor of this disease, the thicker the lesion the greater the likelihood of lymph node involvement. Approximately 20% of patients with Breslow depth 1-4 mm have lymph node metastasis. Sentinel lymph node biopsy is standard procedure in the management of patients with skin melanoma, reflecting progress in the treatment of this disease since this procedure avoids an unnecessary radical lymphadenectomy, thus reducing the morbidity of treatment. This paper describes a series of cases involving sentinel lymph node biopsy in melanoma patients in Teresina, Piaui, Brazil between 2008 and 2009. PMID- 21603831 TI - Pseudoporphyria induced by dialysis treated with oral N-acetylcysteine. AB - Pseudoporphyria is a rare bullous dermatosis that clinically and histopathologically is similar to porphyria cutanea tarda. It mainly affects patients with chronic renal failure on peritoneal dialysis or hemodialysis. Medications can also be involved in the etiology. Diagnosis and management of this condition is a challenge for dermatologists. The authors report a case of pseudoporphyria related to dialysis with favorable outcome after the use of oral N-acetylcysteine. PMID- 21603832 TI - Relapses and recurrences of basal cell face carcinomas. AB - To evaluate factors related to oncological follow-up of basal cell face carcinomas it was carried out the analysis of a series of cases. Four hundred sixty-five patients with 834 basal cell face carcinomas were evaluated; 3,1% presented recurrences. There was 14.7% of recurrence in incompletely excised tumors against 2.3% of the tumors with clear margins. Recurrences were more prevalent on the nose. Relapse rates showed a cumulative risk. These findings reinforce the importance of oncological follow-up after surgery of basal cell carcinoma. PMID- 21603833 TI - Tinea nigra in geographical forms of "heart" and "parrot beak". AB - Through a photographic essay, we identified similarities between hyperchromic maculas of two cases of Tinea Nigra with images of a heart-shaped mangrove called "Coeur de Voh", located on the French island of New Caledonia (Oceania) and of a rock formation called "Parrot Beak" located on Cabecudas Beach, Itajai, Santa Catarina State (Brazil). PMID- 21603834 TI - Do you know this syndrome? AB - Barraquer-Simons syndrome, also called acquired partial lipodystrophy or cephalothoracic lipodystrophy, is a rare form of progressive lipodystrophy, characterized by symmetrical lipoatrophy of subcutaneous adipose tissue starting in the head and spreading to the thorax, upper and lower limbs and thighs. In this work, we report the case of a patient with Barraquer-Simons syndrome without systemic complications. PMID- 21603835 TI - Do you know this syndrome? AB - Goltz syndrome is a rare genetic disease of X-linked dominant inheritance. It is more common in female patients and, in most cases, results in miscarriage of male fetuses. It has a broad scope of possible clinical manifestations. Its diagnosis consists of the sum of the many clinical, radiological and histopathological findings. The treatment options are genetic counseling, reconstructive surgery and multidisciplinary approach, aiming to improve quality of life and ensure a normal and productive life. PMID- 21603836 TI - Case for diagnosis. AB - A 27-year-old mixed-raced (pardo) female patient presented with flat ovate hypochromic plaques with a rough surface on the back and upper limbs, with an aspect resembling pityriasis versicolor. She reports family history involving a brother with similar lesions. Lab tests, including anti-HIV, showed no alterations and a histopathological examination showed enlarged keratinocytes with basophilic and microvacuolated cytoplasm occupying the upper portion of the spinous layer and the granulous layer. After anatomic-clinical correlation, the diagnosis of epidermodysplasia verruciformis pityriasis versicolor like was confirmed. PMID- 21603837 TI - Case for diagnosis. AB - Acquired perforating dermatosis is a rare condition often associated with some systemic diseases, especially diabetic patients with chronic renal failure undergoing dialysis. The main symptom is pruritus and it is clinically characterized by the presence of redish-brown papular lesions in the trunk, head and neck. Biopsy of the lesion reveals epidermal invagination with keratotic plug. The etiology is poorly understood and several therapeutic measures have been disappointing. PMID- 21603839 TI - Questioning the work "does an incomplete excision of the eyelid basal cell carcionoma mean tumor recurrence?". PMID- 21603841 TI - [Discussion about the existence of unilesional form of mycosis fungoides]. PMID- 21603842 TI - A case of mycosis fungoides unilesional. PMID- 21603843 TI - One more step... PMID- 21603845 TI - Mental health problems and smoking among adolescents from Southern Brazil. AB - OBJECTIVE: To analyze the association between mental health problems and smoking in adolescents. METHODS: A total of 4,325 adolescents aged 15 from the 1993 birth cohort of the city of Pelotas, Southern Brazil, was studied. Smoking was defined as having smoked one or more cigarettes in the previous 30 days. Mental health was assessed according to the total score of the Strengths and Difficulties Questionnaire. Score > 20 points was considered positive. Data were analyzed using Poisson regression with adjustment for robust variance. RESULTS: Smoking prevalence was 6.0% and about 30% of the adolescents presented some mental health problem. In the crude analysis, the prevalence ratio for smoking was 3.3 (95%CI 2.5; 4.2). After the adjusted analysis (for sex, age, skin color, family income, mother's level of schooling, group of friends who smoke, employment in the previous year, school failure, physical activity during leisure time and experimental use of alcohol), it decreased to 1.7 (95%CI 1.2; 2.3) among those with mental health problem. CONCLUSIONS: Mental health problems in adolescence may be related to tobacco consumption. PMID- 21603846 TI - Prevalence of self-reported traffic accidents in Rio Branco, Northern Brazil. AB - OBJECTIVE: To estimate the prevalence of self-reported traffic accidents and identify associated factors. METHODS: Cross-sectional, population-based study carried out from September 2007 to August 2008, in the urban and rural zones of Rio Branco (Northern Brazil). Data referring to adults (aged 18 to 96 years, n = 1,516) of the inquiry Health and Nutrition of Adults and Children of Rio Branco, obtained in home interviews, were analyzed. The relations between self-reported traffic accident and socioeconomic and behavior variables were analyzed by means of prevalence ratios and 95% confidence intervals; Poisson regression analysis was performed. RESULTS: The prevalence of self-reported traffic accident was 36%. In the Poisson analysis, male individuals (PR= 1.45 and 95% CI: 1.12;1.87) who reported alcohol consumption (PR= 1.25 and 95%CI: 0.97;1.62), with income above five minimum wages (PR= 1.88 and 95%CI: 1.25;2.83), aged between 18 and 25 years (PR= 1.45 and 95%CI: 1.02;2.05), presented higher probability of reporting involvement in traffic accidents. The variables age and level of schooling had inverse association with the outcome, while income had a positive association, all of them with significant tendency. CONCLUSIONS: The prevalence of self reported traffic accidents shows higher risk for men with higher income, lower level of schooling and who ingest alcoholic beverages. They should be the target of prevention campaigns. PMID- 21603847 TI - Taking the long view of COPD care. PMID- 21603848 TI - Comparison of conventional therapy, intensive therapy and modified constraint induced movement therapy to improve upper extremity function after stroke. AB - OBJECTIVE: To compare the effects of 4 weeks of intervention using conventional rehabilitation, intensive conventional rehabilitation and modified constraint induced movement therapy on the hemiplegic upper extremity in stroke patients. METHODS: Thirty stroke patients (mean age: 63.3, standard deviation 9.63 years; mean time since stroke: 11.33, standard deviation 8.29 weeks) were randomly divided into 3 groups: conventional rehabilitation, intensive conventional rehabilitation, and modified constraint-induced movement therapy (10 individuals in each). Motor function was assessed using the Wolf Motor Function Test before treatment, and 2 weeks and 4 weeks after treatment. RESULTS: The constraint induced movement therapy and intensive conventional rehabilitation groups improved their function ability scores in the Wolf Motor Function Test significantly more than the conventional rehabilitation group after 2 weeks of treatment (p < 0.05), but all groups reached comparable levels at the end of 4 weeks of intervention. However, only the constraint-induced movement therapy intervention proved to have robust and systematic effects on the function ability scores, as revealed by the large, positive and significant correlation between the initial scores and the scores 2 and 4 weeks after the intervention. The median performance time of the Wolf Motor Function Test decreased significantly in all groups after 4 weeks of treatment (p < 0.05), but only the modified constraint-induced movement therapy group showed significant improvements both 2 and 4 weeks after the initiation of treatment. CONCLUSION: Compared with classical intervention, modified constraint-induced movement therapy showed an apparent advantage over both conventional intervention and intensive conventional rehabilitation for patients after stroke. PMID- 21603849 TI - Measuring patterns of disability using the International Classification of Functioning, Disability and Health in the post-acute stroke rehabilitation setting. AB - OBJECTIVE: To determine whether the International Classification of Functioning, Disability and Health (ICF) model is adequate for assessing disability patterns in stroke survivors in the sub-acute rehabilitation setting in terms of potential changes in functional profiles over time. METHODS: Functional profiles of 197 stroke patients were assessed using the ICF Checklist and the Functional Independence Measure (FIMTM) at admission and discharge from rehabilitation hospital. The ICF Checklist was applied based on medical documentation and rehabilitation team meetings. Descriptive analyses were performed to identify changes in ICF categories and qualifiers from admission to discharge, and correlations between different improvement measures were calculated. RESULTS: Mean rehabilitation duration was 60 days; patients' mean age was 60 years, with mean FIM-score 75 at admission. Mean FIM-score improvement at discharge was 12.5. Within Body Functions, changes in at least 10% of patients were found regarding 13 categories; no categories within Body Structures, 24 within Activities and Participation, and 2 within Environmental Factors. Changes were mostly due to improvement in qualifiers, except for within Environmental Factors, where they were due to use of additional categories. Correlations between improvements in Body Functions and Activities and Participation (regarding capacity and performance), as well as between capacity and performance within Activities and Participation, were approximately 0.4. CONCLUSION: Rating ICF categories with qualifiers enables the detection of changes in functional profiles of stroke patients who underwent an inpatient rehabilitation programme. : PMID- 21603850 TI - Isolation and characterization of a gene encoding an ethylene responsive factor protein from Ceratoides arborescens. AB - Ethylene responsive factor (ERF) proteins play important roles in plant growth and development and regulate biotic and abiotic stress responses. In this study, a full length mRNA encoding a novel ERF-type transcription factor namely Ceratoides arborescens ERF protein (CeERF) was isolated from C. arborescens. The deduced amino acid of CeERF had a conserved APETALA2/ERF (AP2/ERF) domain which specifically binds to cis-acting elements GCC box. Under normal conditions, the expression level of CeERF was highest in leaves and lowest in roots. CeERF expression was induced by 20% PEG in a time-dependent pattern and peaked at 8 h. CeERF also acts in salt- and hormones-induced stresses. Transient expression analysis in onion epidermal cells indicated that CeERF protein localized to nucleus. Overexpression of CeERF in transgenic tobacco plants resulted in higher tolerance to abiotic stresses than in control plants. These results suggested that CeERF might play a role in abiotic stress signal transduction and that overexpression of CeERF might serve as a feasible approach to enhance resistance in forage, even crop. PMID- 21603851 TI - Clinicopathological pattern and Annexin A2 and Cdc42 status in patients presenting with differentiation and lymphnode metastasis of esophageal squamous cell carcinomas. AB - Annexin A2 and Cdc42 were identified by 2-dimensional electrophoresis (2-DE) and MALDI-TOF-MS between esophageal squamous cell carcinomas (ESCC) and corresponding normal esophagus mucosa in our previous study. To assess clinico-pathological pattern and Annexin A2 and Cdc42 status with respect to cell differentiation and lymphnode metastasis in patients with ESCC. The expression of Annexin A2 and Cdc42 in 22 pairs of fresh ESCC and matched tissues were detected by qRT-PCR and western blot, respectively. And it was further confirmed by immunohistochemistry with 175 pairs of formalin-fixed, paraffin-embedded ESCC. Results showed that Annexin A2 expression was significantly down-regulated, and Cdc42 was up regulated in ESCC compared to matched control on both mRNA and protein level (P < 0.05), which was in accordance with our previous results on proteomics data. Additionally, Annexin A2 and Cdc42 expression was significantly correlated with lymphoid node metastasis (P < 0.05) and pathological differentiation (P < 0.05). Taken together, we proposed that the aberrant expression of Annexin A2 and Cdc42 played a role in carcinogenesis, differentiation and metastasis of ESCC, which implied its potential target for clinical biomarkers in differentiation and lymph node metastasis. PMID- 21603852 TI - Penehyclidine hydrochloride attenuates LPS-induced iNOS production by inhibiting p38 MAPK activation in endothelial cells. AB - The aim of this study was to investigate the inhibitory effect of penehyclidine hydrochloride (PHC) on lipopolysaccharide (LPS)-induced nitric oxide (NO) and inducible nitric oxide synthase (iNOS) production in human endothelial cell. Cultured endothelial cells were pretreated with PHC, followed by LPS treatment. NO activity were determined. iNOS expression and p38 mitogen-activated protein kinase (p38 MAPK) protein expression were measured by Western blot analysis. LPS treatment significantly induced p38 MAPK activation, iNOS expression, and NO production, which could be attenuated by 2 MUg/ml PHC pretreatment. Furthermore, our study showed LPS-induced NO production and iNOS expression were suppressed by p38 MAPK inhibitor SB203580 pretreatment. We concluded that PHC attenuates NO production and iNOS expression by suppressing the activation of p38 MAPK pathway, thereby implicating a mechanism by which PHC may exert its protective effects against LPS-induced endothelial cell injury. PMID- 21603853 TI - Development of a new sensitive immunostrip assay based on mesoporous silica and colloidal Au nanoparticles. AB - A new competitive immunostrip assay was developed to detect human serum albumin (HSA) in urine sample with use of conjugated monoclonal antibody gold nanoparticles (mAb-AuNPs) and mobile crystalline material (MCM)-41-HSA bioconjugate. To prepare the immunostrip, the colloidal AuNPs with an average particle diameter of 20 nm, was synthesized, labeled with antibody and applied on the conjugate pad as the detection reagent. Then, HSA was attached to the MCM-41 mesoporous nanoparticles and immobilized to a nitrocellulose membrane as the test line. In the optimized investigational conditions, the immunostrip could detect HSA in a high linear range (from 1 to 200 MUg/ml) and low detection limit (ng/ml). The reliability of the testing procedure was examined by performing the immunostrip test with 30 urine samples and comparing the results with those obtained via immunoturbidimetry. The immunostrip was adequately sensitive and accurate for a rapid screening of HSA in the urine. This new strategy for competitive immunostrip design can be used and developed for other antigen based immunostrip assay. PMID- 21603854 TI - Karyotype analysis and genetic variation of a mutant in Siraitia grosvenorii. AB - This study analyzed the differences in karyotype and genetic variation between a mutant and wild-type Siraitia grosvenorii. Genetic variation included changes in genome and gene expression by SRAP molecular markers. Results showed that wild type S. grosvenorii was diploid, with a chromosome number of 2n = 2x = 28, whereas the mutant was tetraploid with a chromosome number of 2n = 4x = 56. 4573 DNA bands were obtained using 189 different primer combinations, 577 of which were polymorphic, averaging 3.1 bands for each primer pair, while 1998 pairs were identical. There were no apparent differences on bands amplified by most primer pairs. After comparing the diploid and tetraploid strains, the data generally indicated that the polymorphism would be quite low. 2917 cDNA bands were generated using 133 primer combinations, and stable and clearly differential fragments were sorted out, cloned and sequenced. Ninety-two differentially expressed fragments were successfully sequenced. Sequence analysis showed that most fragments had significant homologous nucleotide sequences with resistant to stress and photosynthesis genes, including ribulose-1,5-bisphosphate carboxylase/oxygenase, phosphoenolpyruvate carboxykinase, pyruvate kinase, peroxisomal membrane transporter, NBS-LRR type resistance protein, protein phosphatase and others. The results revealed that the tetraploid strain has more resistant and photosynthesis ability than its diploid relatives, which providing reference information and resources for molecular breeding and seedless Luohanguo. PMID- 21603855 TI - Patterns of genetic divergence among populations of the common dormouse, Muscardinus avellanarius in the UK. AB - Quantitative descriptions of population genetic structure allows the delineation of population units and is therefore of primary importance in population management and wildlife conservation. Yet, predicting factors that influence the gene flow patterns in populations particularly at landscape scales remains a major challenge in evolutionary biology. Here we report a population genetic study of the common dormouse, Muscardinus avellanarius, a species that is seriously threatened due to anthropogenic factors, in two regions, Bontuchel (Denbighshire) and Afonwen (Gwynedd), both in Wales, UK. Ten microsatellite loci were used to characterize patterns of genetic diversity of M. avellanarius within both regions. While the population differentiation between both regions is apparent through geographical scale separating them, by using Bayesian clustering analyses, we identified the occurrence of genetic division among populations of M. avellanarius in Bontuchel region, but no significant evidence of differentiation in Afonwen. We found a strong significant isolation-by-distance (IBD) pattern at a fine-scale (less than 1 km) within continuous habitat and between habitat patches in both regions. Overall, analyses suggest that small scale dispersal associated with the social structure and dispersal tendencies of this species is reflected in the genetic structure of populations. These findings then provide useful baseline data for supporting local management strategies. PMID- 21603856 TI - Antiviral role of Toll-like receptors and cytokines against the new 2009 H1N1 virus infection. AB - People are generally susceptible to the 2009 new mutate of H1N1 influenza due to lack of appropriate immunity. Influenza H1N1 2009 infection triggers a massive inflammatory response that contributes to fever, lung impairment or other tissue damage, eventually leading to death. Infection with pathogenic influenza virus H1N1 induces severe pulmonary immune pathology. To date, more than 10,000 cases worldwide have died of the disease. It still has strong infectious ability although the mortality of influenza isn't currently high. Therefore, to explore the pathogenesis of H1N1 influenza can help with the disease prevention, diagnosis and provide a theoretical basis and the new ideas of treatment. Laboratory confirmed cases of pandemic influenza H1N1 2009 were enrolled to collect general information on pre-clinical, clinical and laboratory data for analysis. Blood samples were obtained from patients with H1N1, healthy volunteers and patients with bacterial pneumonia. Serum were separated and collected. RT-PCR and ELISA methods were applied to detect the different expression of TLRs and cytokines. The young, pregnant and postpartum women and infant are highly susceptible to influenza H1N1 2009 infection; degree of susceptibility is not associated with BMI. Biochemical changes can be seen in the patients with influenza H1N1 2009 infection: ALT, AST, CK, LDH increased in varying degrees. TLR2, TLR3, TLR9 expression increased in the patients with influenza H1N1 2009 infection; no obvious changes of TLR4, TLR7, TLR8 can be detected. In pregnant and postpartum women group, only TLR9 expression increased. The expression of IL 2, IL-6, IFN-gamma, TNF-alpha in the patients with influenza H1N1 2009 infection was significantly increased; while IL-10 expression decreased and IL-4 expression did not change. H1N1 influenza-infected pregnant and postpartum women group, only IL-2 and TNF-alpha expression expression increased, other cytokines decreased or didn't change. TLR2, TLR3, TLR9 are the major members of TLR family in the recognition of the novel H1N1 virus to start the innate immune response and adaptive immune responses. TLR9 may be the key receptor among pattern recognized receptors to recognize and bind to H1N1 virus. Cellular immune responses induced by Th1 may participate in modulating the influenza H1N1 2009. PMID- 21603857 TI - Association between ATM 5557G>A polymorphism and breast cancer risk: a meta analysis. AB - Epidemiological studies have evaluated the association between ATM 5557G>A (p.D1853N) polymorphism and breast cancer risk. However, the results remain conflicting rather than conclusive. To derive a more precise estimation of the relationship, we performed this meta-analysis. Systematic searches of PubMed and Medline databases were performed. A total of nine studies included 3155 cases and 2752 controls were identified. When all nine studies were pooled into the meta analysis, there was no evidence for significant association between 5557G>A mutation and breast cancer risk(for G/A vs. G/G: OR = 1.05, 95% CI = 0.83-1.34; for A/A vs. G/G: OR = 0.77, 95% CI = 0.58-1.03; for dominant model: OR = 1.04, 95% CI = 0.82-1.31; for recessive model: OR = 0.87, 95% CI = 0.69-1.09). In the subgroup analyses by family history and ethnicity, significant associations were found among Amerindians (for G/A vs. G/G: OR = 2.19, 95% CI = 1.38-3.47; for dominant model: OR = 2.15, 95% CI = 1.37-3.38). In summary, the meta-analysis suggest that ATM 5557G>A polymorphism is associated with increased breast cancer risk among Amerindians. However, due to the small subjects included in analysis and the selection bias existed in some studies, the results for Amerindians should be interpreted with caution. PMID- 21603858 TI - Hereditary breast cancer in Middle Eastern and North African (MENA) populations: identification of novel, recurrent and founder BRCA1 mutations in the Tunisian population. AB - Germ-line mutations in BRCA1 breast cancer susceptibility gene account for a large proportion of hereditary breast cancer families and show considerable ethnic and geographical variations. The contribution of BRCA1 mutations to hereditary breast cancer has not yet been thoroughly investigated in Middle Eastern and North African populations. In this study, 16 Tunisian high-risk breast cancer families were screened for germline mutations in the entire BRCA1 coding region and exon-intron boundaries using direct sequencing. Six families were found to carry BRCA1 mutations with a prevalence of 37.5%. Four different deleterious mutations were detected. Three truncating mutations were previously described: c.798_799delTT (916 delTT), c.3331_3334delCAAG (3450 delCAAG), c.5266dupC (5382 insC) and one splice site mutation which seems to be specific to the Tunisian population: c.212 + 2insG (IVS5 + 2insG). We also identified 15 variants of unknown clinical significance. The c.798_799delTT mutation occurred at an 18% frequency and was shared by three apparently unrelated families. Analyzing five microsatellite markers in and flanking the BRCA1 locus showed a common haplotype associated with this mutation. This suggests that the c.798_799delTT mutation is a Tunisian founder mutation. Our findings indicate that the Tunisian population has a spectrum of prevalent BRCA1 mutations, some of which appear as recurrent and founding mutations. PMID- 21603859 TI - The effects of 1-year treatment with a haemodiafiltration with on-line regeneration of ultrafiltrate (HFR) dialysis on biomarkers of oxidative stress in patients with chronic renal failure. AB - In the last few years haemodiafiltration with on-line regeneration of ultrafiltrate (HFR) has been shown to have a positive impact on inflammation and oxidative stress biomarkers, but its effect on antioxidant levels and on oxidative damage to biomolecules in the long-term is still unknown. This is a randomised clinical study over 12 months involving 40 patients on haemodialysis, comparing the effect of HFR (n=25) dialysis with haemodialysis with polysulfone (HD-PS, n=15) on oxidative stress. Total antioxidant capacity, enzymatic antioxidant [superoxide dismutase (SOD), catalase and glutathione peroxidase], non-enzymatic (GSH) and biomarkers of oxidative stress (TBARs, carbonyl groups and 8-OH-dG) were evaluated. The antioxidant activity decreased in the lymphocytes of patients dialysed with HFR, with a significant decrease in the enzyme SOD. In the oxidative stress biomarkers, an increase was seen in the levels of 8-OH-dG in patients on HD-PS dialysis but not in those treated with HFR. Throughout the year the changes in antioxidant levels and biomarkers of oxidative damage in patients dialysed with HFR were generally more modest and fluctuated less than those dialysed with HD-PS. Our study indicates that, in general, long-term dialysis with HFR does not modified antioxidant parameters or increases the oxidative damage to biomolecules. The HFR showed to be a biocompatible technique for long-term dialysis. PMID- 21603860 TI - Soluble expression and purification of Brucella cell surface protein (BCSP31) of Brucella melitensis and preparation of anti-BCSP31 monoclonal antibodies. AB - Brucella cell surface protein (BCSP31) is potentially useful for diagnosing brucellosis. We aimed to establish a monoclonal antibody (MAb) against Brucella melitensis BCSP31 and to investigate its distribution in diagnosis. Soluble recombinant BCSP31 was successfully expressed and purified. Two MAbs (1F1 and 1E5) against B. melitensis BCSP31, effective in detecting both recombinant and cellular proteins, were obtained and characterized. The MAbs did not react with Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Mycobacterium tuberculosis, or Bacillus aeruginosus, but strongly reacted with BCSP31 and B. melitensis by ELISA and Western blot analysis. We also tested different Brucella species and brucellosis using the prepared anti-BCSP31 MAbs. BCSP31 and anti BCSP31 MAbs may play important roles in future research in diagnosing brucellosis. PMID- 21603861 TI - Molecular cloning and characterization of a flavonoid 3'-hydroxylase gene from purple-fleshed sweet potato (Ipomoea batatas). AB - Flavonoid 3'-hydroxylase (F3'H: EC 1.14.13.21) is an important enzyme which determines the hydroxylation pattern of anthocyanins. In this study, the full length cDNA and genomic DNA of F3'H were isolated and characterized from the purple-fleshed sweet potato (Ipomoea batatas). IbF3''H was 1,789 bp containing a 1,554 bp open reading frame (ORF) encoding 518 amino acids. Comparative and bioinformatic analysis revealed that IbF3'H was highly homologous with F3'Hs from other plant species. Conserved domain search revealed that IbF3'H was a cytochrome P450 dependent enzyme. Three F3'H-specific motifs (V75VVAAS80, G427GEK430 and V433DVKG437) were conserved in IbF3'H. Phylogenetic analysis revealed that IbF3'H was clustered into the same subgroup with the homologues from I. purpurea, I. tricolor and I. nil. There were multiple copies of the IbF3'H gene in the genome of I. batatas. IbF3'H was constitutively expressed in all tested tissues including fibrous roots, thick roots, storage roots, stems and leaves. During storage root formation, IbF3'H was expressed most abundantly in the storage roots, suggesting that the anthocyanin biosynthesis is also active in the under-ground organs. IbF3'H expression was associated with anthocyanin accumulation in five different sweet potato cultivars tested. Complementative analysis implied that the full-length cDNA of IbF3'H could encode a functional protein and had a special catalytic activity of flavonoid 3'-hydroxylase. PMID- 21603862 TI - S100A4 mediated cell invasion and metastasis of esophageal squamous cell carcinoma via the regulation of MMP-2 and E-cadherin activity. AB - It is well documented that S100A4 is upregulated in a large amount of invasive tumors and plays a pivotal role in tumor invasion and metastasis. However, the precise role and mechanism S100A4 exerts in the invasion and metastasis of esophageal squamous cell carcinoma (ESCC) have not been fully elucidated to date. Our data demonstrated that S100A4 was overexpressed in human ESCC tissues, especially in ESCC with poor differentiation, deep invasion and lymph node metastasis. Subsequently, the knockdown of S100A4 by RNAi in ESCC cell line (EC 1) could reduce cell invasion, metastasis and proliferation ability in vitro. Most importantly, S100A4 regulated MMP-2 positively and E-cadherin negatively in vivo and in vitro to some extent. Our results suggest that S100A4 is an important factor in the invasion, metastasis and proliferation of ESCC and may control invasion and metastasis at least in part through the regulation of MMP-2 and E cadherin activity. S100A4 may serve as a biomarker for progression of ESCC and a potential molecular target for biotherapy of ESCC. PMID- 21603863 TI - Low-selenium diet induces cell cycle arrest of thymocytes and alters serum IL-2 content in chickens. AB - The purpose of this 42-day study was to investigate the effects of low selenium (Se) on cellular immune function by determining cell cycle of thymus, serum IL-2 content, and mitogenesis of peripheral blood T-lymphocytes. One hundred twenty 1 day-old Avian broilers were randomly assigned to two groups of 60 each and were fed on a low-Se diet (0.0342 mg/kg Se) or a control diet (0.2 mg/kg Se), respectively. Cell cycle analysis by flow cytometry showed that low-Se diet caused an increase in G(0)G(1) phase cells that corresponded to a decrease in S phase cells in thymus. Ultrastructurally, mitochondria injury and increased apoptotic cells with condensed nuclei were observed. Low-Se diet decreased the serum IL-2 contents and mitogenesis of peripheral blood lymphocytes to concanavalin A in comparison with those of control group. These data indicate that low-Se diet inhibits the development of thymus by arresting the cell cycle and decreasing the IL-2 content. PMID- 21603864 TI - Study on some trace element contents in serum and nail samples obtained from Sudanese subjects. AB - This study was performed to investigate trace elements and arsenic contents among Sudanese inhabitants living in the north, east, and west of Sudan. Inductively coupled plasma atomic emission spectrometry was used to determine the contents of Zn and Cu. Graphite furnace atomic absorption spectrometry was used to determine Se in serum samples. It was found that Se and Cu are in the normal range. Zinc showed discrepancies among all studied groups. Acute Zn deficiency was detected in the northern and eastern regions of Sudan. Inductively coupled plasma mass spectroscopy was operated in the dynamic reaction cell mode to determine the arsenic content in the nail samples of the northern inhabitants of Sudan. High values of arsenic were found in the northern people compared with the control group. This elevation could be linked to the misuse of insecticides and herbicides which might be associated with the high rate of cancer incidence in this region. PMID- 21603865 TI - Relationship between selenium and selected heavy metals concentration in serum of cattle from a non-polluted area. AB - The present study was undertaken to evaluate the concentration of selenium and selected heavy metals and their possible relationship in serum of 25 healthy lactating cows (Montbeliarde) reared in a non-polluted area, in the western part of Poland. Cadmium, lead, copper, and zinc concentrations were determined by inductively coupled plasma-atomic emission spectrometry and Se concentration was determined fluorimetrically. The content of Se, Zn, and Cu was 0.083 +/- 0.026, 0.629 +/- 0.413, and 0.152 +/- 0.042 MUg/mL, respectively. The presence of the Cd and Pb was found in all serum samples. The mean concentration of these metals was 0.0009 +/- 0.0008 and 0.018 +/- 0.016 MUg/mL, respectively. Analysis of correlations between Se and toxic metals showed a negative and significant (P < 0.05) relationship between selenium concentration and lead and cadmium concentration in the serum of the animals studied, with correlation coefficients of r = -0.595 and r = -0.618, respectively. For copper and zinc, this relationship was also negative but not significant (r = -0.255 and r = -0.203). Our study demonstrated that the level of toxic metals decreased as serum selenium concentration increased. It seems necessary to conduct further research on the interactions between these elements in blood, serum, and target organs concomitantly with the determination of their intake. PMID- 21603866 TI - The marine sponge toxin agelasine B increases the intracellular Ca(2+) concentration and induces apoptosis in human breast cancer cells (MCF-7). AB - PURPOSE: In search for new drugs derived from natural products for the possible treatment of cancer, we studied the action of agelasine B, a compound purified from a marine sponge Agelas clathrodes. METHODS: Agelasine B was purified from a marine sponge Agelas clathrodes and assayed for cytotoxicity by MTT on two human breast cancer cells (MCF-7 and SKBr3), on a prostate cancer cells (PC-3) and on human fibroblasts. Changes in the intracellular Ca(2+) concentrations were assessed with FURA 2 and by confocal microscopy. Determination of Ca(2+)-ATPase activity was followed by Pi measurements. Changes in the mitochondria electrochemical potential was followed with Rhodamine 123. Apoptosis and DNA fragmentation were determined by TUNEL experiments. RESULTS: Upon agelasine B treatment, cell viability of both human breast cancer cell lines was one order of magnitude lower as compared with fibroblasts (IC(50) for MCF-7 = 2.99 MUM; SKBr3: IC(50) = 3.22 MUM vs. fibroblasts: IC(50) = 32.91 MUM), while the IC(50) for PC-3 IC(50) = 6.86 MUM. Agelasine B induced a large increase in the intracellular Ca(2+) concentration in MCF-7, SKBr3, and PC-3 cells. By the use of confocal microscopy coupled to a perfusion system, we could observe that this toxin releases Ca(2+) from the endoplasmic reticulum (ER). We also demonstrated that agelasine B produces a potent inhibition of the ER Ca(2+)-ATPase (SERCA), and that this compound induced the fragmentation of DNA. Accordingly, agelasine B reduced the expression of the anti-apoptotic protein Bcl-2 and was able to activate caspase 8, without affecting the activity of caspase 7. CONCLUSIONS: Agelasine B in MCF-7 cells induce the activation of apoptosis in response to a sustained increase in the [Ca(2+)]( i ) after blocking the SERCA activity. The reproduction of the effects of agelasine B on cell viability and on the [Ca(2+)]( I ) obtained on SKBr3 and PC-3 cancer cells strongly suggests the generality of the mechanism of action of this toxin. PMID- 21603867 TI - Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers. AB - BACKGROUND: More and more preclinical studies support the idea that curcumin, a plant-derived natural polyphenol, could be a promising anticancer drug. However, poor bioavailability has limited its efficacy in clinical trials, and plasma curcumin levels remain low despite patients taking gram doses of curcumin. METHODS: This study aimed to evaluate the safety and pharmacokinetics of newly developed nanoparticle curcumin with increased water solubility (named THERACURMIN). Six healthy human volunteers were recruited and received THERACURMIN at a single oral dose of 150 mg. After an interval of 2 weeks, the same subjects then received THERACURMIN at a single dose of 210 mg. Plasma curcumin levels were measured at 0, 1, 2, 4, 6, and 24 h after THERACURMIN intake using high-performance liquid chromatography (HPLC). RESULTS: One subject reported grade 1 diarrhea after intake of 150 mg THERACURMIN. No other toxicities were observed in this study. C (max) for THERACURMIN at 150 and 210 mg was 189 +/ 48 and 275 +/- 67 ng/ml (mean +/- SEM), respectively, and the area under the curve for 24 h was estimated to be 2,649 +/- 350 and 3,649 +/- 430 ng/ml * h (mean +/- SEM), respectively. The t (1/2) was estimated to be 9.7 +/- 2.1 h for 150 mg and 13.0 +/- 3.3 h for 210 mg. CONCLUSION: THERACURMIN can safely increase plasma curcumin levels in a dose-dependent manner at least up to 210 mg without saturating the absorption system. To the best of our knowledge, THERACURMIN is the first nanoparticle formulation of curcumin that demonstrates improved bioavailability in human subjects. We believe this compound could be a promising tool when testing the potential anticancer effects of curcumin in clinical trials. PMID- 21603868 TI - 5-fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity. AB - AIM: This study aimed to elucidate the influence of 5-fluorouracil (5-FU)-based therapy on the vascular endothelium and its association with 5-FU-induced heart ischemia. METHODS: The study prospectively accrued patients (n = 106) having completely resected colorectal cancer and receiving adjuvant treatment with 5-FU, folinic acid, and oxaliplatin. The levels of plasma von Willebrand factor (vWf), urine albumin-to-creatinine ratio (UACR), coagulation factor II + VII + X, and fibrin D-dimer were serially assessed before, during, and after chemotherapy. RESULTS: The vWf level increased from median (range) 1.43 kU/l (0.48 to >3) to 2.64 kU/l (0.23 to >3) (P = 0.001), the UACR increased from 1.1 +/- 0.2 mg/mmol (mean +/- SE) to 2.1 +/- 0.3 mg/mmol (P = 0.001), the coagulation factor II + VII + X activity decreased from 1.00 +/- 0.02 to 0.94 +/- 0.02 U/l (P = 0.001), and the fibrin D-dimer level increased from 1.1 +/- 0.2 to 2.1 +/- 0.3 kU/l (P = 0.001) at baseline and during chemotherapy, respectively. The changes in the levels of vWf (P = 0.3), UACR (P = 0.8), coagulation factor II + VII + X (P = 0.8), and fibrin D-dimer (P = 0.6) in nine (8.5%) patients having clinical signs of cardiotoxicity were not significantly different from that of the patients not having cardiotoxicity. The 5-FU-induced rise in plasma biomarkers was not significantly related to the cardiovascular morbidity or its risk factors (P = 0.9). CONCLUSIONS: 5-FU therapy induces global reversible endothelial injury leading to a procoagulant state. The ensuing endothelial dysfunction may be of significance to the pathogenesis of 5-FU-induced clinically overt cardiotoxicity. Cardiovascular disease is not significant for the vulnerability of the endothelium to 5-FU-based chemotherapy. PMID- 21603870 TI - Dual role of autophagy in colon cancer cell survival. PMID- 21603869 TI - Expression of the transient receptor potential channel c3 correlates with a favorable prognosis in patients with adenocarcinoma of the lung. AB - BACKGROUND: The cation channels of the transient receptor potential (TRP) superfamily are implicated in cancer formation; in particular, TRPC3 has been shown to contribute to the progression of human ovarian cancer. However, the relationship between TRP expression and the clinicopathological characteristics of lung cancer and patient prognosis is not well understood. Therefore, we investigated the relationship between TRP expression and the prognosis of patients with adenocarcinoma of the lung. METHODS: We used semiquantitative real time reverse transcription polymerase chain reaction to assess the expression of TRP mRNA in tumor samples from 95 patients with adenocarcinoma of the lung. We then correlated the TRP mRNA levels with clinicopathological factors. We also used immunohistochemical staining to determine the localization of expressed TRP. RESULTS: The 5-year overall and disease-free survival rates among patients expressing higher levels of TRPC3 mRNA were significantly better than the corresponding rates among patients expressing lower levels (P=0.004, P=0.002, respectively, by log-rank test). Multivariate Cox proportional hazard analyses revealed that tumor size (hazard ratio, 2.46; 95% confidence interval [CI], 1.06 to 5.79; P=0.036), n2 (hazard ratio, 3.81; 95% CI, 1.29 to 11.77; P=0.015) and TRPC3 (hazard ratio, 2.71; 95% CI, 1.33 to 5.59; P=0.006) were independent factors affecting the 5-year overall survival rate. Immunohistochemistry showed that the cytoplasm of tumor cells were stained positively for TRPC3. CONCLUSIONS: Higher levels of TRPC3 expression in tumor cells are an independent predictor of a better prognosis in patients with adenocarcinoma of the lung. PMID- 21603871 TI - High origin of the anterior band of the inferior glenohumeral ligament: MR arthrography with anatomic and histologic correlation in cadavers. AB - INTRODUCTION: The anterior band of the inferior glenohumeral ligament has been described to arise from the anteroinferior labrum, but we have observed that in some persons its origin is from the anterior or anterosuperior labrum, creating diagnostic difficulties. MATERIALS AND METHODS: Ten fresh unembalmed cadaveric shoulders underwent magnetic resonance arthrography (MRA) using a posterior approach with a 1.5 T GE magnet, with the following sequences: T1-weighted fast spin-echo in axial, coronal and sagittal planes, and T1 fat-suppressed spin-echo in the axial plane (TR/TE 600/20, section thickness 2.5 mm, 0.5 mm interslice space, number of signals acquired, two, field of view 12 * 12 cm, and matrix 512 * 256 pixels). Following imaging, the shoulders were frozen and later sectioned using a band saw into 3-mm sections corresponding to the axial imaging plane. Histological analysis was also performed to determine the origin of the anterior band. RESULTS: Four of the ten shoulders had an origin of the anterior band above or at the 3 o'clock position: one at the 1 o'clock position, two at the 2 o'clock position, and one at the 3 o'clock position. In another shoulder, the anterior band of the inferior glenohumeral ligament originated from the middle glenohumeral ligament, and in five other shoulders, the anterior band originated from the anteroinferior labrum as has been described in the literature. CONCLUSIONS: This finding is of clinical significance as a high origin of the anterior band of the inferior glenohumeral ligament leads to MR arthrographic finding that can simulate those of labral tears or detachments. PMID- 21603872 TI - Cone-beam computed tomography: a new low dose, high resolution imaging technique of the wrist, presentation of three cases with technique. AB - Cone-beam computed tomography (CBCT) is a relatively new technique. It generates a 3D image by emitting a pulsed cone-shaped X-ray beam. CBCT has become a very useful and widely used technique for dentomaxillofacial imaging over the last decade. It provides clear, high resolution multiplanar reconstruction images. Previously, the images could only be generated while the patient was sitting with his/her head fixed in position. With the presented new generation CBCT (NewTom 5G, QR, Verona, Italy), a more free positioning of the patient, either lying or sitting, is possible. In this way, skeletal imaging of various body parts becomes possible. In this article we present three clinical cases of CBCT imaging of the wrist, describe the background of the technique, and discuss the advantages and disadvantages of CBCT imaging. PMID- 21603873 TI - Recurrent anterior shoulder instability: accuracy of estimations of glenoid bone loss with computed tomography is insufficient for therapeutic decision-making. AB - OBJECTIVE: To evaluate the reliability of glenoid bone loss estimations based on either axial computed tomography (CT) series or single sagittal ("en face" to glenoid) CT reconstructions, and to assess their accuracy by comparing with actual CT-based bone loss measurements, in patients with anterior glenohumeral instability. MATERIALS AND METHODS: In two separate series of patients diagnosed with recurrent anterior glenohumeral instability, glenoid bone loss was estimated on axial CT series and on the most lateral sagittal (en face) glenoid view by two blinded radiologists. Additionally, in the second series of patients, glenoid defects were measured on sagittal CT reconstructions by an independent observer. RESULTS: In both series, larger defects were estimated when based on sagittal CT images compared to axial views. In the second series, mean measured bone loss was 11.5% (SD = 6.0) of the total original glenoid area, with estimations of 9.6% (SD = 7.2) and 7.8% (SD = 4.2) for sagittal and axial views, respectively. Correlations of defect estimations with actual measurements were fair to poor; glenoid defects tended to be underestimated, especially when based on axial views. CONCLUSION: CT-based estimations of glenoid bone defects are inaccurate. Especially for axial views, there is a high chance of glenoid defect underestimation. When using glenoid bone loss quantification in therapeutic decision-making, measuring the defect instead of estimating is strongly advised. PMID- 21603874 TI - Intra-articular nodular fasciitis of the shoulder: a case report and review of the literature. AB - Nodular fasciitis is a benign proliferation of myofibroblasts usually arising adjacent to the fascia. In this report, we describe a rare case in which nodular fasciitis occurred in an intra-articular location in the shoulder of a 26-year old man. The mass developed in the subscapularis recess of the shoulder and histological evaluation showed a myofibroblastic proliferation. MRI findings of intra-articular nodular fasciitis are discussed along with a review of previous reports. PMID- 21603875 TI - Characterization of fs10.1, a major QTL controlling fruit elongation in Capsicum. AB - We previously identified fs10.1 as a major QTL controlling fruit shape (index of length to width) in an interspecific F(2) cross of Capsicum annuum (round fruit) * C. chinense (elongated fruit) in pepper. To more precisely map and characterize the QTL, we constructed near-isogenic lines for fs10.1 and mapped it in a BC(4)F(2) population. In this population, fs10.1 segregated as a Mendelian locus and mapped 0.3 cM away from the closest molecular marker. We further verified the effect of fs10.1 in an F(2) population from an independent cross between elongated- and conical-fruited parents. To identify additional allelic variation at fruit shape loci, we screened an EMS-mutagenized population of the blocky fruited cv. Maor and identified the mutant E-1654 with elongated fruit. This fruit shape mutation was mapped to the fs10.1 region and was determined to be allelic to the QTL. By measuring fruit shape of near-isogenic lines for fs10.1 during fruit development, we found that the shape of the fruit is determined primarily in the first 2 weeks after anthesis. Histological measurements of cell size and cell shape in pericarp sections of fruits of the isogenic lines throughout fruit development indicated that the shape of the fruit is determined primarily by cell shape and that the development of fruit shape is correlated with cell shape. PMID- 21603876 TI - A series of 22 patients with adult-onset Still's disease presenting with fever of unknown origin. A difficult diagnosis? AB - Adult-onset Still's disease (AOSD) remains a perplexing, difficult to diagnose clinical entity, with clinical characteristics that are often broad and encountered in numerous other clinical entities. This vague clinical presentation is depicted in the commonly used diagnostic criteria, as the ones by Yamaguchi and Fautrel. The authors sought to investigate how diagnostic criteria apply in a series of 22 new cases of AOSD patients presenting with fever of unknown origin (FUO) and diagnosed at the Internal Medicine Department of Hatzikosta General Hospital of Ioannina, Greece. The aims of the study were: (1) to study the incidence of AOSD and (2) to retrospectively apply different classifications to the data of these patients in search of a more efficient way of diagnosing these patients in the future. The annual incidence of AOSD was estimated at two new cases per 10(5). The clinical manifestations of the patients are discussed, with an emphasis on specific manifestations being considered as criteria by Yamaguchi and Fautrel classifications. Four patients exhibited markedly increased serum D: dimers, a finding of which the potential pathophysiologic implications are discussed. Serum ferritin levels have additive values, both for diagnostic and cost-reduction purposes in cases presenting as FUO; serum ferritin values are not included in any diagnostic set of criteria at present. The finding of high levels of D-dimers in AOSD needs further studies. PMID- 21603877 TI - The changing landscape of progressive multifocal leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy (PML) is a rare but devastating neurologic disease that affects the immunosuppressed population. The etiologic agent is a polyomavirus, JC virus-a double-stranded DNA virus with a high prevalence of infection globally. PML is believed to occur from reactivation of the latent virus infection caused by immunosuppression. After 1980, a dramatic increase in the incidence and prevalence of PML was attributed to the HIV/AIDS pandemic, with a decline noted after the introduction of highly active antiretroviral treatment (HAART). Newer populations are being added to the risk pool for the development of PML with the introduction of biologic agents that target specific arms of the immune system. Natalizumab and efalizumab seem to have the highest risk for the development of PML, although PML can develop with the other biologic agents. As more patients are treated with these agents, effective risk mitigation strategies are needed to prevent PML. PMID- 21603878 TI - Meningococcal disease: shifting epidemiology and genetic mechanisms that may contribute to serogroup C virulence. AB - During the past decade, monovalent serogroup C and quadrivalent (serogroups A, C, W135, Y) meningococcal vaccination programs have been introduced in multiple industrialized countries. Many of these programs have been successful in reducing the burden of disease due to vaccine-preventable serogroups of Neisseria meningitidis in target age groups. As a result, disease burden in these countries has decreased and is primarily serogroup B, which is not vaccine preventable. Despite the success of these programs, meningococcal disease continues to occur and there is always concern that serogroup C organisms will adapt their virulence mechanisms to escape pressure from vaccination. This review highlights the current epidemiology of meningococcal disease in Europe and United States, as well as genetic mechanisms that may affect virulence of serogroup C strains and effectiveness of new vaccines. PMID- 21603879 TI - Transcriptomic analysis of the clam Meretrix meretrix on different larval stages. AB - The clam Meretrix meretrix (Mollusca: Bivalvia) is an important commercial species in China. The deficiency of genomic and transcriptomic data is becoming the bottleneck of further researches on its complex and unique developmental processes. To improve this situation, in this study, a large-scale RNA sequencing was conducted on M. meretrix on larval stages. In particular, mRNAs of trochophore, D-veliger, pediveliger, and postlarva were purified, reverse transcribed, and sequenced through 454 sequencing technology. A total of 704,671 reads were obtained and assembled into 124,737 unique sequences (35,205 contigs and 89,532 singletons). Further analysis showed that 118,075 (94.66%) of these sequences were low-expression-level transcripts. Fifteen thousand two hundred fifteen (12.20%) of the unique sequences were annotated by searching against Uniprot Protein Knowledgebase, while the others (109,522, 87.80%) were left as novel sequences. Gene ontology analysis of the annotated sequences showed that most of them were assigned to certain gene ontology terms. By analyzing the depth of each unique sequence, a preliminary quantification analysis was conducted. An amount of sequences that showed a dramatic transcript discrepancy among the four larval stages were screened, which were related to development, growth, shell formation, and immune responses etc. As the first attempt on large-scale RNA sequencing of marine bivalve larvae, this work would enrich the knowledge of larval development of marine bivalves and provide fundamental support for further researches. PMID- 21603880 TI - Significant differences when using MDRD for GFR estimation compared to radionuclide measured clearance. AB - OBJECTIVES: To evaluate Estimated Glomerular Filtration Rate (eGFR), using the Modification of Diet in Renal Disease equation, and compare with radionuclide GFR (rGFR) in a Radiology setting to assess renal function prior to contrast administration. METHODS: Five hundred and sixteen retrospective rGFR studies from a mixed referral population were selected and the eGFR calculated. Regression and Bland-Altman analysis was performed. The percentage of rGFR and eGFR studies below 30 ml/min/1.73 m2 and 60 ml/min/1.73 m2 were calculated; these are important thresholds for classifying renal insufficiency. RESULTS: A significant correlation between eGFR and rGFR (R2 = 0.62, p < 0.0001) and significant differences in the medians (p < 0.0001) were found. eGFR overestimated rGFR with a bias (mean difference) of 10.8 ml/min/1.73 m2 over the whole range of rGFR. Studies with an rGFR of under 30 ml/min/1.73 m2 had a mean bias of 4.6 ml/min/1.73 m2 (difference range -5.9 to 26.3 ml/min/1.73 m2). The bias over the range 30 to 60 ml/min/1.73 m2 was 13.2 ml/min/1.73 m2 (difference range -16.8 to 88.3 ml/min/1.73 m2). In 25.4% of studies, eGFR was less than 60 ml/min/1.73 m2 compared with 40.5% of rGFR studies. CONCLUSIONS: Awareness of the bias between eGFR and rGFR is important when assessing Radiology patients for risks of nephrotoxicity and Nephrogenic Systemic Fibrosis from contrast medium. PMID- 21603881 TI - Unrequested information from routine diagnostic chest CT predicts future cardiovascular events. AB - OBJECTIVES: An increase in the number of CT investigations will likely result in a an increase in unrequested information. Clinical relevance of these findings is unknown. This is the first follow-up study to investigate the prognostic relevance of subclinical coronary (CAC) and aortic calcification (TAC) as contained in routine diagnostic chest CT in a clinical care population. METHODS: The follow-up of 10,410 subjects (>40 years) from a multicentre, clinical care based cohort of patients included 240 fatal to 275 non-fatal cardiovascular disease (CVD) events (mean follow-up 17.8 months). Patients with a history of CVD were excluded. Coronary (0-12) and aortic calcification (0-8) were semi quantitatively scored. We used Cox proportional-hazard models to compute hazard ratios to predict CVD events. RESULTS: CAC and TAC were significantly and independently predictive of CVD events. Compared with subjects with no calcium, the adjusted risk of a CVD event was 3.7 times higher (95% CI, 2.7-5.2) among patients with severe coronary calcification (CAC score >=6) and 2.7 times higher (95% CI, 2.0-3.7) among patients with severe aortic calcification (TAC score >=5). CONCLUSIONS: Subclinical vascular calcification on CT is a strong predictor of incident CVD events in a routine clinical care population. PMID- 21603882 TI - A competing risks model for correlated data based on the subdistribution hazard. AB - Family-based follow-up study designs are important in epidemiology as they enable investigations of disease aggregation within families. Such studies are subject to methodological complications since data may include multiple endpoints as well as intra-family correlation. The methods herein are developed for the analysis of age of onset with multiple disease types for family-based follow-up studies. The proposed model expresses the marginalized frailty model in terms of the subdistribution hazards (SDH). As with Pipper and Martinussen's (Scand J Stat 30:509-521, 2003) model, the proposed multivariate SDH model yields marginal interpretations of the regression coefficients while allowing the correlation structure to be specified by a frailty term. Further, the proposed model allows for a direct investigation of the covariate effects on the cumulative incidence function since the SDH is modeled rather than the cause specific hazard. A simulation study suggests that the proposed model generally offers improved performance in terms of bias and efficiency when a sufficient number of events is observed. The proposed model also offers type I error rates close to nominal. The method is applied to a family-based study of breast cancer when death in absence of breast cancer is considered a competing risk. PMID- 21603883 TI - TCRP1 promotes radioresistance of oral squamous cell carcinoma cells via Akt signal pathway. AB - Tongue cancer resistance-associated protein 1 (TCRP1) is a novel gene located on human chromosome 11q13.4 which has been reported as a candidate related to chemotherapeutic resistance to cisplatin. Results suggest that TCRP also contribute to radioresistance in oral squamous cell carcinoma (OSCC) cells. We previously established exogenous overexpression of TCRP1 cell line Tca8113/TCRP1 and TCRP1 knockdown cell line Tca8113/PYM-siRNA and paired control cell lines, which provides a cell model system to investigate the roles and mechanisms of TCRP1-mediated radioresponse in OSCC. In this study, we first compared the radiosensitivity of up/down-regulating expression of TCRP1 cell lines and paired control cell lines by a clonogenic survival assay, Hoechst 33258 staining, cell growth assay, and comet assay. The results indicated that TCRP1 played a significant role in mediating OSCC radioresistance through decreased cells apoptosis and increased cellular proliferation and long-term survival. The further study found that TCRP1 function by up-regulating Akt activity and levels and then elevating the level of NF-kappaB. In summary, these results provided strong evidence for the linkage between TCRP1 and radiation sensitivity and may provide theoretical base of TCRP1 as a potential molecular mark of estimating the response for irradiation in OSCC. PMID- 21603884 TI - PTP1B inhibitor improves both insulin resistance and lipid abnormalities in vivo and in vitro. AB - PTP1B is a negative regulator of insulin signaling pathway. This study investigated the effects of compound CCF06240, a PTP1B inhibitor, on insulin sensitivity and lipid metabolic abnormalities in vivo and in vitro, respectively. The insulin resistant IRM mouse model was induced by HFD. The responses to insulin were determined by OGTT, ITT, and hyperinsulinemic-euglycemic clamp test. The body weight and the levels of serum TC and TG were measured to estimate the lipid metabolism in vivo. Recombinant human GST-PTP1B protein was used to measure the inhibition of CCF06240 on PTP1B activity. The hepatocyte lipid accumulation was induced by high concentrations of FFA and insulin in HepG(2) cells, and evaluated by the Oil Red O method. In IRM mice, the insulin resistance was improved; the body weight and the levels of TC and TG were also reduced by oral CCF06240 administration. In lipid accumulated model cells, CCF06240 was found to reverse the increased PTP1B activity, enhance the insulin-induced tyrosine phosphorylation in insulin signaling pathway, attenuate the FFA-insulin-induced cellular lipid accumulation, and down-regulate the expressions of genes related fatty acid synthesis. These results demonstrated that the PTP1B inhibitor, compound CCF06240, could increase insulin sensitivity through the regulation of insulin signaling pathway, and decrease FFA-insulin-induced hepatocytes lipid accumulation by reducing fatty acid syntheses. PMID- 21603885 TI - Expression, purification, and activity assay of peptide deformylase from Escherichia coli and Staphylococcus aureus. AB - Peptide deformylase (PDF) is considered an attractive target for screening novel antibiotics. The PDF from Escherichia coli and Staphylococcus aureus are representative of the gram-negative species type of PDF (type I PDF) and the gram positive species type of PDF (type II PDF), respectively. They could be used for screening broad-spectrum antibiotics. Herein, we cloned the def gene by PCR, inserted it into plasmid pET-22b-def, and transformed the plasmid into E. coli BL21 (DE3) cells, then the cells were induced by IPTG to express PDF. E. coli Ni(2+)-PDF was extracted and purified by ion-exchange chromatography and gel filtration chromatography. S. aureus PDFs were extracted and purified using the MagExtractor kit. The nickel form of S. aureus PDF was obtained by adding NiCl(2) to all reagents used for purification. Iron-enriched S. aureus PDF was obtained by adding FeCl(3) to the growth medium for E. coli BL21 (DE3) cells and adding FeCl(3) and catalase to all reagents used for purification. The activities of PDFs were analyzed, compared, and grouped according to the experimental conditions that produced optimal activity, and we used actinonin as an inhibitor of PDF and calculated the IC(50) value. We obtained high expression of E. coli and S. aureus PDF with high activity and stability. The function of PDFs was inhibited by actinonin in a dose-dependent manner. Results may be helpful for future mechanistic investigations of PDF as well as high-throughput screening for other PDF inhibitors. PMID- 21603886 TI - Calcitonin gene-related peptide released from endothelial progenitor cells inhibits the proliferation of rat vascular smooth muscle cells induced by angiotensin II. AB - We have recently demonstrated that endothelial progenitor cells (EPCs) inhibit AngII-induced proliferation of vascular smooth muscle cells (VSMCs) by inactivating MAPKs and NF-kappaB signaling pathway and reducing expression of oncogene c-myc and c-fos. The inhibitory effect of EPCs on VSMCs is associated with paracrine mechanism. However, the potential mechanism of EPCs on the regulation of AngII-induced proliferation of VSMCs was unknown. Calcitonin gene related peptide (CGRP) could inhibit AngII-induced proliferation and transformation of VSMCs. However, it has not been known whether CGRP released from EPCs is a potential regulator in regulation of AngII-induced proliferation of VSMCs. Early endothelial progenitor cell-conditioned medium(E-EPC-CM) was pre incubated with functional blocking antibodies against CGRP for 1 h or VSMCs was preteated with CGRP(837)(CGRP receptor antagonist) for 1 h before VSMCs were pretreated with CM for 30 min. DNA synthesis ability, total protein levels, cell survival, signal transduction, and expressions of c-myc and c-fos of VSMCs induced by AngII (10(-6)mol/l) were detected to assess the role of CGRP in AngII induced proliferation of VSMCs. E-EPC-CM could significantly inhibit AngII induced DNA synthesis ability, total protein levels, cell survival, phosphorylation of ERK, JNK, p38, p65, and expressions of c-myc and c-fos compared with the control group(P < 0.05). However, Pretreatment with anti-CGRP antibody and CGRP(837) could significantly weaken the inhibitory effect of E-EPC CM on proliferation of VSMCs induced by AngII (P < 0.05). EPCs exert anti proliferative effects on VSMCs mediated by the release of CGRP. PMID- 21603887 TI - Surgical management of glioneuronal tumors with drug-resistant epilepsy. AB - In this review, we discuss the options for the surgical management of glioneuronal tumors (GNTs) associated with drug-resistant epilepsy, with an emphasis on the surgical issues involved in addressing the epileptogenic nature of these lesions. We briefly summarize the pathological hallmarks of these lesions in order to outline how these tumors contribute to seizure activity. Understanding the pathophysiology of these lesions is important in discussing the advantages and disadvantages of different surgical strategies. There have been a number of studies that have investigated the utility of different surgical approaches in improving seizure outcome, and we highlight some of these studies in order to shed light on surgical issues related to these tumors. PMID- 21603888 TI - Accuracy of freehand fluoroscopy-guided placement of C1 lateral mass and C2 isthmic screws in atlanto-axial instability. AB - BACKGROUND: The C1 lateral mass and C2 isthmic stabilization, as introduced by Goel and Laheri and by Harms and Melcher, is a well-known fixation technique. We present the clinical and radiographic results with freehand fluoroscopy guided C1 lateral mass and C2 isthmic fixation in a consecutive series of 28 patients, evaluating the accuracy of screw placement. METHODS: Twenty-eight consecutive patients suffering from post-traumatic and other C1-C2 instability were operated on between 2001 and 2010. Indications for surgery were: trauma (n = 21 cases), os odontoideum (n = 1), cranio-verterbal malformation (n = 1), and arthritis (n = 3) and idiopathic instability (n = 2). C1 lateral mass and C2 isthmic screws were placed according to the usual anatomical landmarks with lateral fluoroscopy guidance. All patients underwent a postoperative CT scan. The extent of cortical lateral or medial breach was determined and classified as follows: no breach (grade A), 0-2 mm (grade B), 2-4 mm (grade C), 4-6 mm (grade D), more than 6 mm (grade E). Grade A and B screws were considered well positioned. RESULTS: A total of 56 C1 lateral mass and 55 C2 isthmic screws were placed. Accuracy of screw placement was as follows: 107 grade A (96.4%), four grade B (3.6%), and no grade C, D or E. Clinical and radiological follow-up showed improvement in symptoms (mainly pain) and stability of the implants at the end of the follow-up. CONCLUSIONS: Freehand fluoroscopy-guided insertion of C1 lateral mass and C2 isthmic screws can be safely and effectively performed. PMID- 21603889 TI - Implanted devices: biocompatibility, infection and tissue engineering. PMID- 21603891 TI - Subjective, psychomotor, and physiological effects of oxycodone alone and in combination with ethanol in healthy volunteers. AB - RATIONALE: Nonmedical use of prescription opioids is sometimes accompanied by the ingestion of ethanol. Whether ethanol increases the abuse liability-related effects of prescription opioids has not been determined. OBJECTIVE: The purpose of this study was to characterize the subjective, psychomotor, and physiological effects of oxycodone, a widely prescribed and abused opioid, and ethanol, alone and in combination. METHODS: Fourteen volunteers participated in a randomized, crossover trial in which they were exposed to placebo, oxycodone (10 mg), two doses of ethanol (0.3 and 0.6 g/kg), and oxycodone combined with the lower dose and the higher dose of ethanol on separate sessions. RESULTS: Several abuse liability-related subjective effects (drug liking, take again, pleasant bodily sensations) were not increased by the low dose of ethanol or oxycodone alone relative to placebo, but were when the two were combined. Self-reported liking of the higher dose of ethanol was higher than that of placebo, but oxycodone neither increased nor decreased this effect. Psychomotor and cognitive performance was not affected by any of the active drug conditions. Absorption of ethanol was decreased by oxycodone. CONCLUSIONS: In this study, 10 mg of oral oxycodone combined with a low dose of ethanol generated abuse liability-related effects, but when tested separately, they did not. Further psychopharmacological investigations of this combination are warranted in light of these findings and the fact that nonmedical use of prescription opioids is sometimes accompanied by use of ethanol. PMID- 21603890 TI - Pathogenesis of implant-associated infection: the role of the host. AB - Implanted devices are mainly used to improve impaired function or to replace missing anatomic structures. They are made of synthetic material or devitalized biological structures. In contrast to vital transplants, they are not rejected by the body. However, the host reacts against these foreign bodies, a process which can be designated as biocompatibility. The interaction of the device with adjacent granulocytes and complement not only induces various degrees of inflammation but also impairs local microbial clearance. Foreign surfaces are a preferred target for bacterial adherence. While adhering bacteria are highly resistant to the bactericidal activity of phagocytes, they are also resistant to most antimicrobial agents. Certain bacteria may reside within host cells, and hence, evade host defense mechanisms by persisting intracellularly around implants. Nanotechnology minimizes clotting activation and bacterial adhesion by intravascular devices. Furthermore, surface coating with appropriate substances favorably influences biocompatibility as well as susceptibility to infection. In the future, "Microsystems Technology" deployed as intelligent device may decrease the risk of implant failure due to infection. PMID- 21603892 TI - Amygdala abnormalities in first-degree relatives of individuals with schizophrenia unmasked by benzodiazepine challenge. AB - RATIONALE: Impaired emotion processing in schizophrenia predicts broader social dysfunction and has been related to negative symptom severity and amygdala dysfunction. Pharmacological modulation of emotion-processing deficits and related neural abnormalities may provide useful phenotypes for pathophysiological investigation. OBJECTIVES: We used an acute benzodiazepine challenge to identify and modulate potential emotion-processing abnormalities in 20 unaffected first degree relatives of individuals with schizophrenia, compared to 25 control subjects without a family history of psychosis. METHODS: An oral 1 mg dose of the short-acting anxiolytic benzodiazepine alprazolam was administered in a balanced crossover placebo-controlled double-blind design, preceding identical 3 T fMRI sessions approximately 1 week apart. Primary outcomes included fMRI activity in amygdala and related regions during two facial emotion-processing tasks: emotion identification and emotion memory. RESULTS: Family members exhibited abnormally strong alprazolam-induced reduction in amygdala and hippocampus activation during emotion identification, compared to equal reduction in both groups for the emotion memory task. CONCLUSIONS: GABAergic modulation with alprazolam produced differential responses in family members vs. controls, perhaps by unmasking underlying amygdalar and/or GABAergic abnormalities. Such pharmacological fMRI paradigms could prove useful for developing drugs targeting specific neural circuits to treat or prevent schizophrenia. PMID- 21603893 TI - Ketamine perturbs perception of the flow of time in healthy volunteers. AB - RATIONALE: Disturbances in the subjective experience of time have been observed both in schizophrenia and following acute administration of ketamine. However, effects of ketamine on more objective timing tasks have not yet been measured in humans, nor has it been established that timing effects are not merely secondary to a more general dysfunction in working memory (WM). OBJECTIVE AND METHODS: In a double-blind placebo-controlled crossover study, we characterised the effects of ketamine (100 ng/ml blood plasma level) on performance of perceptual timing and colour discrimination tasks, which were matched for WM and attentional demands. To test the ubiquity of ketamine's effects on timing, we also examined two distinct measures of temporal predictability. RESULTS: Ketamine significantly distorted the subjective experience of time as measured by the Clinician Administered Dissociative States Scales. Critically, ketamine also impaired accuracy on the perceptual timing task while having no effect on performance of the colour perception task. Although ketamine did not impair the ability to use prelearned temporal (or spatial) cues to predict target onset (or location), it did slow reaction times at long delays following non-informative neutral cues, suggesting an impaired ability to use the unidirectional flow of time itself to make temporal predictions. CONCLUSIONS: Ketamine induced selective impairments in timing, which could not be explained by more fundamental effects on the ability to hold information in WM. Rather our collected findings suggest that ketamine may disturb timing by selectively impairing the way in which information is temporally manipulated within WM. PMID- 21603894 TI - Priming a restrained mental set reduces alcohol-seeking independently of mood. AB - RATIONALE: Cross-sectional research demonstrates that heavy drinking is associated with elevated impulsivity, including disinhibition. However, causal effects of disinhibition on drinking behaviour are not well established. OBJECTIVE: To experimentally manipulate disinhibited versus restrained mental sets before exploring their impact on alcohol-seeking behaviour and to investigate if any effects of the manipulation occurred independently of arousal, mood, and craving. METHODS: The study utilized a between-subjects design in which participants were randomly allocated to experimental groups. Social drinkers (N = 90) attended the laboratory for a single session where they initially completed a stop-signal task. Different mental sets were induced by emphasising either the importance of cautious responding and successful inhibition (Restraint group), the importance of rapid responding (Disinhibition group), or the equal importance of rapid responding and successful inhibition (Control group). Heart rate, blood pressure, and subjective mood were assessed before participants completed a bogus taste test procedure. RESULTS: The Restraint group consumed less beer than the Disinhibition and Control groups, which did not differ from each other. There were no group differences in heart rate, blood pressure, or self-reported mood after the manipulation. Across the whole sample, cautious responding during the stop-signal task (slower reaction time to 'Go' cues, fewer inhibition errors) was associated with reduced beer consumption. CONCLUSIONS: These findings suggest that temporary fluctuations in disinhibited/restrained states may play a causal role in drinking behaviour. PMID- 21603895 TI - Altered pain responses in abstinent (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") users. AB - RATIONALE: (+/-)3,4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug that has potential to damage brain serotonin (5-HT) neurons in humans. Brain 5-HT neurons play a role in pain modulation, yet little is known about long-term effects of MDMA on pain function. Notably, MDMA users have been shown to have altered sleep, a phenomenon that can lead to altered pain modulation. OBJECTIVES: This study sought to assess pain processing in MDMA users using objective methods, and explore potential relationships between pain processing and sleep indices. METHODS: Forty-two abstinent MDMA users and 43 age matched controls participated in a 5-day inpatient study. Outcome measures included standardized measures of pain, sleep polysomnograms, and power spectral measures of the sleep EEG. When differences in psychophysiological measures of pain were found, the relationship between pain and sleep measures was explored. RESULTS: MDMA users demonstrated lower pressure pain thresholds, increased cold pain ratings, increased pain ratings during testing of diffuse noxious inhibitory control, and decreased Stage 2 sleep. Numerous significant relationships between sleep and pain measures were identified, but differences in sleep between the two groups were not found to mediate altered pain perception in MDMA users. CONCLUSIONS: Abstinent MDMA users have altered pain perception and sleep architecture. Although pain and sleep outcomes were related, differences in sleep architecture in MDMA users did not mediate altered pain responses. It remains to be determined whether alterations in pain perception in MDMA users are secondary to neurotoxicity of 5-HT-mediated pain pathways or alterations in other brain processes that modulate pain perception. PMID- 21603896 TI - The GPR55 agonist lysophosphatidylinositol directly activates intermediate conductance Ca2+ -activated K+ channels. AB - Lysophosphatidylinositol (LPI) was recently shown to act both as an extracellular mediator binding to G protein-coupled receptor 55 (GPR55) and as an intracellular messenger directly affecting a number of ion channels including large-conductance Ca(2+) and voltage-gated potassium (BK(Ca)) channels. Here, we explored the effect of LPI on intermediate-conductance Ca(2+)-activated K(+) (IK(Ca)) channels using excised inside-out patches from endothelial cells. The functional expression of IK(Ca) was confirmed by the charybdotoxin- and TRAM-34-sensitive hyperpolarization to histamine and ATP. Moreover, the presence of single IK(Ca) channels with a slope conductance of 39 pS in symmetric K(+) gradient was directly confirmed in inside-out patches. When cytosolically applied in the range of concentrations of 0.3-10 MUM, which are well below the herein determined critical micelle concentration of approximately 30 MUM, LPI potentiated the IK(Ca) single-channel activity in a concentration-dependent manner, while single channel current amplitude was not affected. In the whole-cell configuration, LPI in the pipette was found to facilitate membrane hyperpolarization in response to low (0.5 MUM) histamine concentrations in a TRAM-34-sensitive manner. These results demonstrate a so far not-described receptor-independent effect of LPI on the IK(Ca) single-channel activity of endothelial cells, thus, highlighting LPI as a potent intracellular messenger capable of modulating electrical responses in the vasculature. PMID- 21603897 TI - Pyruvate administered to newborn rats with insulin-induced hypoglycemic brain injury reduces neuronal death and cognitive impairment. AB - Based on previous studies, we had made a try to administer sodium pyruvate to newborn Wistar rats suffering repetitive and profound hypoglycemia, which can induce brain injury. Fluoro-Jade B was used to marked degenerative neurons 1 day after the third hypoglycemic insult, and Morris water navigation task was performed to assess cognitive function when the rats were 6 weeks old. We found that administration of sodium pyruvate to those rats whose hypoglycemia was terminated by dextrose can reduce neurodegeneration induced by hypoglycemia and improve the cognitive function. Supplementing sodium pyruvate with glucose to terminate severe neonatal hypoglycemia is an effective intervention. PMID- 21603898 TI - Fetus-in-fetu: imaging and pathologic findings. AB - A 3.5-month-old boy was hospitalized because of an abdominal mass found accidentally. On physical examination, a smooth, firm, nontender mass was present in the right upper quadrant. Abdominal ultrasonography revealed a large, hyperechoic, heterogenous mass with clear boundaries, and scarce blood flow. Abdominal CT scan showed a bulky right retroperitoneal mass. Three-dimensional CT imaging demonstrated spine, iliac bone, and long bones of limbs. The mass was excised successfully. After opening the sac it was noted to contain an incompletely developed fetus with grossly visible limbs, clearly discernible male genitalia, hairs, and a poorly formed head. The fetus was connected to the sac via an 8 cm cord-like structure. Microscopic examination of the mass revealed the presence of skin, cartilage, bone, intestine, and cysts with simple cuboidal epithelium. The use of CT scans enhanced the accuracy of pre-operative diagnosis. Identification of the vertebral column and the long bones of limbs are important indications for the diagnosis. Pathologically, fetus in fetu has many characteristics different from teratoma. PMID- 21603899 TI - MDCT assessment of ulcerative colitis: radiologic analysis with clinical, endoscopic, and pathologic correlation. AB - PURPOSE: Evaluate the utility of multidetector-row computed tomography (MDCT) in assessing the severity of ulcerative colitis (UC) in comparison with clinical assessment, colonoscopy, and histopathology. MATERIALS AND METHODS: Patients with UC evaluated with at least one abdominal contrast-enhanced CT study (CECT) within 7 days of colonoscopy with biopsy were included. CECT of 23 patients (12 male; mean age 40 years; age range, 20-72 years) were retrospectively evaluated in consensus by two radiologists. A total of 138 lower GI tract segments were evaluated by CECT and graded for the presence of bowel wall thickening, mucosal hyperenhancement, mural stratification, mesenteric hyperemia, pericolonic stranding, and lymph nodes. A cumulative CT severity score was calculated and correlated with clinical, colonoscopic, and histopathologic severity grades. RESULTS: The cumulative CT score and individual CECT scores for bowel wall thickening, mucosal hyperenhancement, and mural stratification showed positive correlation with clinical severity (P < 0.05). All individual CECT features as well as the cumulative CT score demonstrated statistically significant correlation with colonoscopic severity (P < 0.0001). Only wall thickening on CECT demonstrated significant correlation with histopathologic severity (P = 0.01). CONCLUSION: Disease severity assessment by MDCT demonstrates positive correlation with severity established by clinical assessment and colonoscopy. Only increasing wall thickness, as graded on MDCT, correlates with histopathologic disease severity. PMID- 21603900 TI - Multiple mutations in the Kras gene in colorectal cancer: review of the literature with two case reports. AB - PURPOSE: Kras mutations are negative predictors of anti-EGFR therapy, occurring in 40% of colorectal carcinomas (CRCs). Point substitutions in codon 12 or 13 are the most frequent mutations in Kras, but multiple mutations (MMs) in other codons can also develop. Few data exist on MMs with regard to their frequency and the codons and amino acids that are affected. We report two cases of Kras double mutations in codons 12 and 13 and review Kras MMs in primary CRC in PubMed databases. CASE REPORT: A 53-year-old woman and a 70-year-old man presented with deep, invasive, moderately differentiated CRC at an advanced clinical stage. The former had regional lymph node involvement and vaginal wall neoplastic implantation, and the latter had liver metastasis. Primary tumors were examined for Kras mutations by pyrosequencing, which were confirmed by direct sequencing. Both tumors had a mutation in codons 12 and 13, wherein codon 12 was mutated to GAT, and codon 13 became GAC. CONCLUSIONS: We identified 69 reported cases of Kras MMs and reported two other cases, representing 2.1% of all mutated tumors; the incidence of such mutations is 1.0% in CRC patients. In most cases (59%), MMs develop in a single codon, usually codon 12. Codons 12 and 13 are affected simultaneously in only 27% of cases. These findings add information about the impact of specific amino acid changes in the Kras gene. PMID- 21603901 TI - Extended abdominoperineal excision vs. standard abdominoperineal excision in rectal cancer--a systematic overview. AB - BACKGROUND: After introduction of total mesorectal excision (TME) as the gold standard for rectal cancer surgery, oncologic results appeared to be inferior for abdominoperineal excision (APE) as compared to anterior resection. This has been attributed to the technique of standard APE creating a waist at the level of the tumor-bearing segment. This systematic review investigates outcome of both standard and extended techniques of APE regarding inadvertent bowel perforation, circumferential margin (CRM) involvement, and local recurrence. METHODS: A literature search was performed to identify all articles reporting on APE after the introduction of TME using Medline, Ovid, and Embase. Extended APE was defined as operations that resected the levator ani muscle close to its origin. All other techniques were taken to be standard. Studies so identified were evaluated using a validated instrument for assessing nonrandomized studies. Rates for perforation, CRM involvement, and local recurrence were compared using chi-square statistics. RESULTS: In the extended group, 1,097 patients, and in the standard group, 4,147 patients could be pooled for statistical analysis. The rate of inadvertent bowel perforation and the rate of CRM involvement for extended vs. standard APE was 4.1% vs. 10.4% (relative risk reduction 60.6%, p = 0.004) and 9.6% vs. 15.4% (relative risk reduction 37.7%, p = 0.022), respectively. The local recurrence rate was 6.6% vs. 11.9% (relative risk reduction 44.5%, p < 0.001) for the two groups. CONCLUSION: This systematic review suggests that extended techniques of APE result in superior oncologic outcome as compared to standard techniques. PMID- 21603902 TI - Lesion detectability on diffusion-weighted imaging in transient global amnesia: the influence of imaging timing and magnetic field strength. AB - INTRODUCTION: Transient global amnesia (TGA) is a benign disease with a sudden onset, transient memory disturbance. Characteristic punctate high-signal intensity lesions in the hippocampus on diffusion-weighted imaging (DWI) have been reported in variable frequencies. We investigated the influence of the timing of DWI and the magnetic field strength on the lesion detectability in TGA. METHODS: Seventy-three patients diagnosed with TGA underwent DWI within 24 h after the symptom onset and again on day 3 at either 1.5 (n = 31) or 3 T (n = 42). The patients were divided into three subgroups according to the time lapse after the symptom onset to the first DWI (0-6 h, 6-12 h, and 12-24 h). RESULTS: The detection rate of the lesions during the first 24 h rose statistically significantly with increased time lapse after the symptom onset (34% in 0-6 h, 62% in 6-12 h, and 67% in 12-24 h). It increased up to 75% on day 3. The detection rate was higher at 3 T than at 1.5 T in all time points (41% vs. 27% in 0-6 h, 70% vs. 44% in 6-12 h, 80% vs. 57% in 12-24 h, and 86% vs. 61% on day 3), but the statistical significance was achieved only on day 3. CONCLUSION: Awareness of the different lesion detectability on DWI according to the time lapse after the symptom onset can help in diagnosing the patients with suspected TGA. High field strength is another important factor to increase the lesion detectability on DWI. PMID- 21603903 TI - Importance and benefits of dietary sodium restriction in the management of chronic kidney disease patients: experience from a single Chinese center. AB - AIM: Several studies have suggested that sodium intake may affect blood pressure (BP), proteinuria, and intrarenal transforming growth factor-beta1 (TGF-beta1) production in patients and animal models with chronic kidney disease (CKD). The Chinese population has a high prevalence of CKD and is well known for consuming salty foods. This study will investigate the role of dietary sodium intake on BP control among non-dialysis Chinese CKD patients. METHODS: A cross-sectional study was carried out in a cohort of 176 non-dialysis hypertensive CKD patients to investigate their sodium intake and its effect on BP control by measuring 24-h urine sodium excretion (24-h UNa). A total of 20 patients with immunoglobulin A nephropathy (IgAN) participated in a 7-day sodium restriction study (100 mmol/day). Their changes in BP, proteinuria, and urinary TGF-beta1 excretion were subsequently analyzed. Another 23 IgAN patients without salt restriction were included as controls. RESULTS: The average 24-h UNa of the study cohort was 149.0 +/- 66.4 mmol/day. Only 31.8% patients had a 24-h UNa less than 100 mmol/day. The OR for each 17 mmol increment in 24-h UNa (salt 1 g/day) for BP > 130/80 mmHg was 1.26 (95% CI 1.10-1.44, P = 0.001). The sodium restriction group achieved significantly more reduction in SBP (-11.1 mmHg vs. -5.0 mmHg, P = 0.022), DBP ( 9.4 mmHg vs. -2.1 mmHg, P = 0.009), and urine protein excretion [-465 (-855 to 340) mg/day vs. -150 (-570 to 40) mg/day, P = 0.024]. A positive correlation was observed between the change of 24-h UNa and the change of SBP (r = 0.450, P = 0.047) in the sodium restriction group. The change of 24-h UNa was also correlated with the 24-h TGF-beta1 excretion (r = 0.558, P = 0.011) in these patients. CONCLUSION: Dietary sodium intake restriction should be monitored and intensified in the treatment of Chinese CKD patients. PMID- 21603904 TI - Meta-structure issues for the DSM-5: how do anxiety disorders, obsessive compulsive and related disorders, post-traumatic disorders, and dissociative disorders fit together? AB - The question of how to optimally organize into chapters and label the different categories of mental disorders is an important one for DSM-5 and ICD-11. The grouping of mental disorders, or meta-structure, should arguably reflect knowledge on the validity of different conditions and their relationships, and should ideally contribute to improving the clinical utility of the nosology by guiding clinical assessment and management. The DSM-5 Anxiety, Obsessive Compulsive Spectrum, Posttraumatic, and Dissociative Disorders Workgroup has reviewed the nature of anxiety disorders, the possibility of including a new category of obsessive-compulsive spectrum disorders in the DSM-5, and the concept of traumatic stress disorders. It is difficult to devise a perfect nosology that dissects nature at her joints; instead, any particular approach to the meta structure would seem to have pros and cons that must be carefully weighed. Despite the imperfections of any meta-structure, we are hopeful that each revision of the nosology will bring with it greater diagnostic validity and clinical utility. PMID- 21603906 TI - Squamous cysts arising from segmental renal dysplasia. AB - BACKGROUND: Cystic renal dysplasia is a common developmental abnormality of fetal kidney, featuring disorganized lobar organization, undifferentiated mesenchyma, metaplastic cartilage, persisting immature collecting ducts, and cystic changes. Cystic renal dysplasia can affect the entire kidney or in a segmental fashion. Squamous cysts within the dysplastic kidney, however, are exceedingly rare; only two cases have been reported in the English literature, dating back about 25 years. CASE REPORT: This report is, to our knowledge, the second to describe this unusual finding and may be viewed as confirmation of the entity. In the two previous cases, squamous cysts arose in a generalized cystic dysplasia background; the one we are reporting instead happened in a case of segmental cystic renal dysplasia. CONCLUSIONS: We further proved, with fluorescent in situ hybridization (FISH), the negativity of 12p amplification in this lesion, supporting the notion that this lesion is not intrarenal teratomatous in nature. PMID- 21603905 TI - Rescue from lethal Shiga toxin 2-induced renal failure with a cell-permeable peptide. AB - Intestinal infection with Shiga toxin (Stx)-producing E.coli is a leading cause of hemolytic uremic syndrome and acute renal injury in otherwise healthy children in the US. Antibiotics are contraindicated and a therapeutic priority is agents that act intracellularly against the bacterial toxins that drive kidney injury. Our aim was to evaluate whether intravenous administration of a cell-permeable peptide (TVP) that binds to Stx2 will reduce disease severity and rescue juvenile baboons from a lethal Stx2 dose (50 ng/kg). TVP (5 mg/kg) was delivered i.v. simultaneously with toxin (prevention protocol) or at 6 or 24 h after toxin with daily 1 mg/kg supplements up to day 4 (rescue protocols). Biomarkers were monitored in blood and urine up to 28 days. TVP therapy resulted in either absence of clinical signs of acute kidney injury and normal urine output (prevention), or delayed and reduced BUN and creatinine levels (rescue) with concomitant survival. Delayed peptide administration significantly reduced thrombocytopenia, but surprisingly did not alter anemia even when monitored for 28 days in rescued survivors. This is the first successful cell-permeable therapeutic that counteracts Stx2 lethality in an animal model, which recapitulates many of the human responses to enteric infection. PMID- 21603907 TI - Urine IL-8 concentrations in infectious and non-infectious urinary tract conditions. AB - Urine IL-8 concentrations are known to be elevated in urinary tract infection (UTI), as well as in vesicoureteral reflux (VUR) even in the absence of infection. In this study we further investigated urine IL-8 in infants with congenital anomalies of the kidneys and urinary tract and with antenatally diagnosed isolated pelvic dilatation. Urine IL-8 was measured in 159 infants aged 1 month to 1 year with acute UTI (group A, n = 26), resolved UTI (group B, n = 16), VUR without recent UTI (group C, n = 44), non-VUR congenital urinary anomalies without recent UTI (group D, n = 30), isolated antenatal pelvic dilatation (group E, n = 14) and in infants without known urinary tract condition (control group F, n = 29). Median values of urine IL-8/creatinine levels were 61.5, 4.64, 15.5, 14.3, 1.06 and 4.19 pg/MUmol in groups A, B, C, D, E and F respectively. Compared with the control group, urine IL-8 was elevated in infants with acute UTI, VUR without acute UTI and congenital anomalies without acute UTI (p < 0.0001; p < 0.005; and p = 0.027 respectively), but not in infants with resolved UTI or with antenatal pelvic dilatation. Urine IL-8 levels are elevated in a variety of infectious and non-infectious urinary tract conditions, and hence may serve as a sensitive but not specific screening biomarker of urinary tract diseases. PMID- 21603910 TI - Intravitreal anti-VEGF therapy with prompt or deferred laser compared with steroid with prompt laser and prompt laser alone for treatment of diabetic macular edema. PMID- 21603909 TI - Integrins in renal development. AB - The kidney develops from direct interactions between the ureteric bud and the metanephric mesenchyme. The ureteric bud gives rise to the collecting system and the metanephric mesenchyme to the nephrons. The complex process of renal development which occurs between these embryologically distinct structures is mediated by numerous factors, including the communication of cells with their surrounding extracellular matrix. Integrins are the principal cellular receptors for extracellular matrix proteins, and they play a role in organ and tissue development. In this review we focus on how integrins regulate renal development. PMID- 21603911 TI - Does therapy targeting normal SBP of less than 120 mm Hg reduce major CV events in T2DM patients? PMID- 21603912 TI - Neuroendocrine Tumor of Tail of Pancreas Mimicking as Splenic Angiosarcoma : A Diagnostic Quandary: Mandates Cautious Approach. PMID- 21603913 TI - Cryptosporidium parvum oocyst viability and behaviour of the residual body during the excystation process. AB - This study was conducted as a comparative evaluation of time-dependent changes in the viability of purified Cryptosporidium parvum oocysts by means of different excystation methods. Oocyst samples were 2 weeks to 12 months old and were treated with bile or sodium taurocholate, partly after pretreatment with hypochlorite. Pretreatment markedly enhanced the excystation of younger oocyst samples but did not increase excystation rates of 9 or 12-month-old oocysts. A cell culture-PCR assay was used as a second indicator for oocyst viability and was most consistent with excystation trials including oocyst pretreatment. In experiments aiming at the determination of the behaviour of the oocyst residual body during excystation, it could be demonstrated that it might be involved in this process. PMID- 21603914 TI - Study of alkyl phosphates in industrial petroleum mixtures by comprehensive two dimensional gas chromatography time-of-flight mass spectrometry. AB - Dialkyl phosphate esters used as gellants in some oil well fracturing processes for conventional oil production can result in contamination of the collected crude. Though the exact mechanism is unclear, such compounds form volatile phosphorus that compromises refinery processes. Our initial research involved producing a comprehensive two-dimensional gas chromatographic method (GC * GC) for the detection and quantification of alkyl phosphate esters in petroleum samples, which surpassed the current method employed in sensitivity and speciation capabilities. However, selective detection is required for such analytes in petroleum matrices. This article describes the application of GC * GC with time-of-flight mass spectrometry for selective detection to the analysis of di- and tri-alkyl phosphates in petroleum samples. Features in the electron impact mass spectra of alkyl phosphates are discussed along with the GC * GC retention characteristics of the compounds. Based on these discussions, a preliminary classification and quantification of alkyl phosphate contamination in a suite of industrial samples is then presented. PMID- 21603915 TI - Analytical strategies for improving the robustness and reproducibility of bioluminescent microbial bioreporters. AB - Whole-cell bioluminescent (BL) bioreporter technology is a useful analytical tool for developing biosensors for environmental toxicology and preclinical studies. However, when applied to real samples, several methodological problems prevent it from being widely used. Here, we propose a methodological approach for improving its analytical performance with complex matrix. We developed bioluminescent Escherichia coli and Saccharomyces cerevisiae bioreporters for copper ion detection. In the same cell, we introduced two firefly luciferases requiring the same luciferin substrate emitting at different wavelengths. The expression of one was copper ion specific. The other, constitutively expressed, was used as a cell viability internal control. Engineered BL cells were characterized using the noninvasive gravitational field-flow fractionation (GrFFF) technique. Homogeneous cell population was isolated. Cells were then immobilized in a polymeric matrix improving cell responsiveness. The bioassay was performed in 384-well black polystyrene microtiter plates directly on the sample. After 2 h of incubation at 37 degrees C and the addition of the luciferin, we measured the emitted light. These dual-color bioreporters showed more robustness and a wider dynamic range than bioassays based on the same strains with a single reporter gene and that uses a separate cell strain as BL control. The internal correction allowed to accurately evaluate the copper content even in simulated toxic samples, where reduced cell viability was observed. Homogenous cells isolated by GrFFF showed improvement in method reproducibility, particularly for yeast cells. The applicability of these bioreporters to real samples was demonstrated in tap water and wastewater treatment plant effluent samples spiked with copper and other metal ions. PMID- 21603916 TI - Determination of the LOQ in real-time PCR by receiver operating characteristic curve analysis: application to qPCR assays for Fusarium verticillioides and F. proliferatum. AB - Real-time PCR (qPCR) is the principal technique for the quantification of pathogen biomass in host tissue, yet no generic methods exist for the determination of the limit of quantification (LOQ) and the limit of detection (LOD) in qPCR. We suggest using the Youden index in the context of the receiver operating characteristic (ROC) curve analysis for this purpose. The LOQ was defined as the amount of target DNA that maximizes the sum of sensitivity and specificity. The LOD was defined as the lowest amount of target DNA that was amplified with a false-negative rate below a given threshold. We applied this concept to qPCR assays for Fusarium verticillioides and Fusarium proliferatum DNA in maize kernels. Spiked matrix and field samples characterized by melting curve analysis of PCR products were used as the source of true positives and true negatives. On the basis of the analysis of sensitivity and specificity of the assays, we estimated the LOQ values as 0.11 pg of DNA for spiked matrix and 0.62 pg of DNA for field samples for F. verticillioides. The LOQ values for F. proliferatum were 0.03 pg for spiked matrix and 0.24 pg for field samples. The mean LOQ values correspond to approximately eight genomes for F. verticillioides and three genomes for F. proliferatum. We demonstrated that the ROC analysis concept, developed for qualitative diagnostics, can be used for the determination of performance parameters of quantitative PCR. PMID- 21603917 TI - Effect of sample preparation methods on the D,L-enantiomer ratio of extracted selenomethionine. AB - Effects of the two most widespread sample preparation techniques on the D,L enantiomer ratio of extracted selenomethionine were monitored through the analysis of the certified reference material selenium-enriched yeast and the isolated protein fraction of high selenium monkeypot nut. The extracted selenomethionine (SeMet) fractions were orthogonally cleaned up with anion exchange chromatography before carrying out the enantiomer-specific detection to increase the robustness and the efficiency of the subsequent o-phthal-aldehyde and n-isobutyril-cysteine-based derivatisation process and reversed phase-high performance liquid chromatography-inductively coupled plasma mass spectroscopy (ICP-MS) detection. The two techniques, namely methanesulphonic acid (MSA) based digestion and proteolytic digestion with protease XIV, resulted in significantly different ratio of D,L-selenomethionine with the final results of 2.2-2.7% and 0.5-0.6% of D-SeMet, respectively. The study revealed significant differences in the ICP-MS-related sensitivity of the derivatised selenomethionine enantiomers, which calls attention to the quantification of this selenoamino acid after MSA hydrolysis. PMID- 21603918 TI - Low incidence of long-term respiratory impairment in Hodgkin lymphoma survivors. AB - Introduction of new chemotherapy regimens over the last decade resulted in 90% survival in patients with Hodgkin lymphoma (HL), which enhances significance of abrogating chemotherapy-related long-term toxicities in young subjects. The present trial evaluated incidence of long-term respiratory complications associated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or bleomycin sulfate, etoposide phosphate, doxorubicin hydrochloride (Adriamycin), cyclophosphamide, vincristine sulfate (Oncovin), procarbazine hydrochloride, and prednisone (BEACOPP). Sixty-seven HL patients, 21 treated with ABVD and 46 with BEACOPP, underwent prospective respiratory evaluation. Median follow-up from chemotherapy completion to respiratory assessment was 61 months. Abnormal lung function tests (LFT) were found in nine patients (13.6%)-three with functional dyspnea and six asymptomatic-with reduced DLCO (<=70%), VC, and TLC. Previous history of bleomycin pulmonary toxicity was found to be the only statistically significant factor for chronic respiratory impairment (75% vs. 10%, p = 0.007, relative risk (RR) = 28; 95% CI, 2.5-313). However, abnormal LFT tended to occur more frequently in patients receiving mantle field irradiation (18% vs. 9%, RR = 2.2), those who experienced respiratory infection (25% vs. 13%, RR = 2.25), and patients treated with ABVD compared to BEACOPP (19% vs. 11%, RR = 1.9). Long-term respiratory impairment in HL survivors is unusual and rarely results in functional discomfort. BEACOPP is "respiratory safe," being associated with a nonsignificant risk for long-term respiratory dysfunction. PMID- 21603919 TI - On-line dechlorination-hydrogenation of chlorinated paraffin mixtures using GC and GC/MS. AB - Chlorinated paraffins (CPs) are straight chain hydrocarbons that are produced as complex mixtures and are used as flame retardants and paint additives. These mixtures are extremely difficult to characterize using conventional chromatographic methods, as conventional gas chromatography results in unresolved complex chromatograms that preclude the identification and quantification of individual congeners or any reasonable assessment of the average carbon chain length. Carbon chain length is an important parameter for assessing physical properties and the toxicity of these materials. We have modified and improved a previously published gas chromatography-flame ionization detector method that uses Pd catalyst held in the gas chromatograph injector to simultaneously dechlorinate the CPs and separate the resulting alkanes. In addition, we have adapted this method to gas chromatography-mass spectrometry. Dehalogenation of other compounds was also studied with this system to investigate potential application to other complex halogenated mixtures. PMID- 21603920 TI - Fractionation and mobility of cadmium and zinc in urban vegetable gardens of Kano, northern Nigeria. AB - Metal fractionation provides information on mobility and stability of various metal species which can be used to evaluate the movement of such metals in soils. The effect of wastewater irrigation on the fractions, spatial distribution, and mobility of cadmium (Cd) and zinc (Zn) was investigated in five urban gardens in Kano, Nigeria. Concentration of total Zn in the surface soils (0-20 cm) ranged from 121 to 207 mg kg(- 1) while Cd concentration was 0.3-2.0 mg kg(- 1). Speciation of both heavy metals into seven operationally defined fractions indicated that the most reactive forms extracted with ammonium nitrate and ammonium acetate, also considered as the bioavailable fractions, accounted for 29 42% of total Cd and 22-54% of total Zn, respectively. The weakly bound fractions of Cd and Zn reached up to 50% of the total Cd and Zn concentrations in the soils. Such high proportions of labile Cd and Zn fractions are indicative of anthropogenic origins, arising from the application of wastewater for irrigation and municipal biosolids for soil fertility improvement. Thus, given the predominance of sandy soil textures, high concentrations of labile Cd and Zn in these garden soils represent a potential hazard for the redistribution and translocation of these metals into the food chain and aquifer. PMID- 21603921 TI - Environmental and socio-economic impacts of pipe drainage in Pakistan. AB - Many drainage schemes and salinity control projects have been executed world wide. Pipe drainage has widely been used in Pakistan, Egypt and India to control waterlogging. The impact of pipe drainage on land and water was evaluated in this paper using data of three pipe drainage projects in Pakistan namely Khushab Salinity Control and Reclamation Project, Fourth Drainage Project in Faisalabad and Swabi Salinity Control and Reclamation Project. Data by regular monitoring of these projects were collected. The effect of pipe drainage on water table depth at these three locations has been compared. Water quality and soil salinity improvement due to the pipe drainage has also been investigated. Data, related to water table depths and discharges from drain pipes/wells, was collected. Observation wells, installed at various places by the Water and Power Development Authority, were used for collection of this data. To evaluate the impact of the projects on salinity, soil samples from all the three locations were tested. A questionnaire was prepared to get the view of the people about the projects. It was revealed that in these areas, due to subsurface pipe drainage, the percentage of the abandoned land has been considerably decreased. Over drainage was observed in a few places of the projects. The farmers at such places were asked to change their cropping patterns. Ultimately, there has been an increase in area under cultivation, crop yields and cropping intensity in the projects' area. PMID- 21603922 TI - A study of the effect of physical and chemical stressors on biological integrity within the San Diego hydrologic region. AB - Environmental agencies across the United States have searched for adequate methods to assess anthropogenic impacts on the environment. Biological assessments, which compare the taxonomic composition of an aquatic assemblage to relevant biocriteria, have surfaced as an effective method to assess the ecological integrity of US waterbodies. In this study, bioassessment data were collected and analyzed in conjunction with physical habitat and chemical stressor data for streams and rivers within the San Diego basin from 1998 through 2005. Physical stressors such as sediment loading, riparian destruction, and in-stream habitat homogenization affect many locations in the region. However, physical habitat measures alone were found to frequently overestimate the biological integrity of streams in the region. Many sites within the San Diego Basin, although unaffected by physical stressors, continue to exhibit low biological integrity scores. Sites with low biological integrity tend to possess higher specific conductance and salinity compared to sites with high biological integrity. We suggest that one possible reason for these differences is the source water used for municipal purposes. PMID- 21603923 TI - Assessing environmental impacts of treated wastewater through monitoring of fecal indicator bacteria and salinity in irrigated soils. AB - To assess the potential for treated wastewater irrigation to impact levels of fecal indicator bacteria (FIB) and salinity in irrigated soils, levels of Escherichia coli, Enterococcus, and environmental covariates were measured in a treated wastewater holding pond (irrigation source water), water leaving the irrigation system, and in irrigated soils over 2 years in a municipal parkland in Arizona. Higher E. coli levels were measured in the pond in winter (56 CFU 100 mL(-1)) than in summer (17 CFU 100 mL(-1)); however, in the irrigation system, levels of FIB decreased from summer (26 CFU 100 mL(-1)) to winter (4 CFU 100 mL( 1)), possibly related to low winter water use and corresponding death of residual bacteria within the system. For over 2 years, no increase in FIB was found in irrigated soils, though highest E. coli levels (700 CFU g(-1) soil) were measured in deeper (20-25 cm) soils during summer. Measurements of water inputs vs. potential evapotranspiration indicate that irrigation levels may have been sufficient to generate bacterial percolation to deeper soil layers during summer. No overall increase in soil salinity resulting from treated wastewater irrigation was detected, but distinct seasonal peaks as high as 4 ds m(-1) occurred during both summers. The peaks significantly declined in winter when surface ET abated and more favorable water balances could be maintained. Monitoring of seasonal shifts in irrigation water quality and/or factors correlated with increases and decreases in FIB will aid in identification of any public health or environmental risks that could arise from the use of treated wastewater for irrigation. PMID- 21603924 TI - What is the most creative thing you have ever seen? "Useful" is the new "Valuable" and dynamic systems are the key! AB - Creativity has been described by many as something which we all can recognize, yet few can completely and sufficiently define. In a discussion of Glaveanu's (2011) Creating Creativity, further topics and questions, such as pragmatism and neopragmatism as well as the nature of creativity studies are explored. Using the medium of Glaveanu's research on creativity and Romanian Easter Egg decorating, this article expands the discussion of pragmatism, neopragmatism and the future of research surrounding creativity. This future can be addressed by exploring the nature of the interconnectedness of creativity and cognition via dynamic systems approaches. To enhance this viewpoint, a brief discussion of dynamic systems theory is brought in to supplement the enhanced discussion of pragmatism and the nature of the usefulness of creativity. PMID- 21603925 TI - Benign reactive lymphoid hyperplasia affecting both the conjunctiva and the cornea. PMID- 21603926 TI - Learning effect of dark adaptation among normal subjects. AB - PURPOSE: To examine and quantify any change in the dark adaptation (DA) function of normal subjects due to learning effect on test-retest. METHODS: Sixteen normal subjects (12 women, four men) whose ages ranged between 24 and 52 years (mean 34.6 +/- 6.7 years) were studied. The interval period between test and retest ranged between 0.92 and 2.37 months (mean 1.38 +/- 0.40 months). DA was measured with a Goldmann-Weekers (GW) dark adaptometer, and subjects were pre-adapted using a light intensity of 2,700 cd/m(2) Ganzfeld background for 5 minutes. Exponential non-linear regression analysis was used to determine seven parameters of DA function. These were time of cone-rod break, cone and rod final thresholds, and magnitude of change and time constant of the cone and rod limbs. RESULTS: The mean cone-rod break time with 95% confidence intervals (CI) was 0.098 (CI: 0.527, 0.330) minutes faster on retest (p = 0.630)). Fourteen of the 16 subjects demonstrated an increase or 'worsening' of their final cone and rod thresholds on the second visit. The mean final threshold differences on retest for the cone limb was 0.105 (CI: 0.032, 0.179) log cd/m(2) (p = 0.008) and 0.093 (CI: -0.039, 0.225,) log cd/m(2) (p = 0.155) for the rod limb. The magnitude of change for the cone limb was 0.016 (CI: -0.122, 0.155) log cd/m(2) (p = 0.805) and -0.196 (CI: 0.435, 0.827) log cd/m2 (p = 0.518) for the rod limb, while the time constant on retest for the cone limb was -0.021 (CI: -0.128, 0.169) minutes, (p = 0.770) and 0.276 (CI: -0.424, 0.976) minutes (p = 0.410) for the rod limb. CONCLUSIONS: None of the DA parameters that were examined demonstrated a learning effect of clinical significance between test and retest. None of the changes in mean from test to retest for the seven parameters were found to be statistically significant, and the changes were clinically negligible. Therefore, any change among patients that may occur in dark adaptation between a visit interval may be considered real, and not due to the effect of learning. PMID- 21603927 TI - Measurement of distance objective visual acuity with the computerized optokinetic nystagmus test in patients with ocular diseases. AB - BACKGROUNDS: To evaluate the efficacy of a computerized optokinetic nystagmus (OKN) test for determination of objective visual acuity (VA) at distance in patients with various ocular diseases. METHODS: This is a prospective, non interventional study that included 85 eyes of 71 patients with one or more ocular pathologies. Study patients were classified into group C (39 eyes of 30 patients with central visual damage), group P (24 eyes of 20 patients with peripheral visual defect) and group M (22 eyes of 21 patients with media opacity). Objective distance VA was measured with OKN induction and suppression methods, and the correlation between the objective and subjective VA at distance was evaluated using linear regression analysis. Mean subjective VAs were compared among each objective VA step and among the three groups. RESULTS: Significant correlation was found between subjective distance VA and objective VA determined by both OKN induction and suppression methods in all three groups and in overall patients. In overall patients, the mean subjective VA was significantly different in several objective VA steps (Welch's ANOVA, p < 0.001 for induction and suppression methods). No significant difference in subjective VA among the three groups was found in any objective VA step. CONCLUSIONS: Our objective VA test using OKN induction and suppression methods can be useful in estimating distance VA in patients with various ocular diseases. PMID- 21603928 TI - A putative octopamine/tyramine receptor mediating appetite in a hungry fly. AB - In the blowfly Phormia regina, experience of simultaneous feeding with D: limonene exposure inhibits proboscis extension reflex (PER) due to decreased tyramine (TA) titer in the brain. To elucidate the molecular mechanism of TA signaling pathway related to the associated feeding behavior, we cloned cDNA encoding the octopamine/TA receptor (PregOAR/TAR). The deduced protein is composed of 607 amino acid residues and has 7 predicted transmembrane domains. Based on homology and phylogenetic analyses, this protein belongs to the OAR/TAR family. The PregOAR/TAR was mainly expressed in head, with low levels of expression in other tissues at adult stages. Gene expression profile is in agreement with a plethora of functions ascribed to TA in various insect tissues. The immunolabeled cell bodies and processes were localized in the medial protocerebrum, outer layer of lobula, antennal lobe, and subesophageal ganglion. These results suggest that decrease of TA level in the brain likely affects neurons expressing PregOAR/TAR, causing mediation of the sensitivity in the sensillum and/or output of motor neurons for PER. PMID- 21603929 TI - Armoured spiderman: morphological and behavioural adaptations of a specialised araneophagous predator (Araneae: Palpimanidae). AB - In a predator-prey system where both intervenients come from the same taxon, one can expect a strong selection on behavioural and morphological traits involved in prey capture. For example, in specialised snake-eating snakes, the predator is unaffetced by the venom of the prey. We predicted that similar adaptations should have evolved in spider-eating (araneophagous) spiders. We investigated potential and actual prey of two Palpimanus spiders (P. gibbulus, P. orientalis) to support the prediction that these are araneophagous predators. Specific behavioural adaptations were investigated using a high-speed camera during staged encounters with prey, while morphological adaptations were investigated using electron microscopy. Both Palpimanus species captured a wide assortment of spider species from various guilds but also a few insect species. Analysis of the potential prey suggested that Palpimanus is a retreat-invading predator that actively searches for spiders that hide in a retreat. Behavioural capture adaptations include a slow, stealthy approach to the prey followed by a very fast attack. Morphological capture adaptations include scopulae on forelegs used in grabbing prey body parts, stout forelegs to hold the prey firmly, and an extremely thick cuticle all over the body preventing injury from a counter bite of the prey. Palpimanus overwhelmed prey that was more than 200% larger than itself. In trials with another araneophagous spider, Cyrba algerina (Salticidae), Palpimanus captured C. algerina in more than 90% of cases independent of the size ratio between the spiders. Evidence indicates that both Palpimanus species possesses remarkable adaptations that increase its efficiency in capturing spider prey. PMID- 21603932 TI - Bacterial cysteine desulfurases: versatile key players in biosynthetic pathways of sulfur-containing biofactors. AB - Cysteine desulfurases are pyridoxal 5'-phosphate-dependent homodimeric enzymes that catalyze the conversion of L-cysteine to L-alanine and sulfane sulfur via the formation of a protein-bound cysteine persulfide intermediate on a conserved cysteine residue. The enzymes are capable of donating the persulfide sulfur atoms to a variety of biosynthetic pathways for sulfur-containing biofactors, such as iron-sulfur clusters, thiamin, transfer RNA thionucleosides, biotin, and lipoic acid. The enormous advances in biochemical and structural studies of these biosynthetic pathways over the past decades provide an opportunity for detailed understanding of the nature of the excellent sulfur transfer mechanism of cysteine desulfurases. PMID- 21603933 TI - Engineering polyhydroxyalkanoate content and monomer composition in the oleaginous yeast Yarrowia lipolytica by modifying the beta-oxidation multifunctional protein. AB - Recombinant strains of the oleaginous yeast Yarrowia lipolytica expressing the PHA synthase gene (PhaC) from Pseudomonas aeruginosa in the peroxisome were found able to produce polyhydroxyalkanoates (PHA). PHA production yield, but not the monomer composition, was dependent on POX genotype (POX genes encoding acyl-CoA oxidases) (Haddouche et al. FEMS Yeast Res 10:917-927, 2010). In this study of variants of the Y. lipolytica beta-oxidation multifunctional enzyme, with deletions or inactivations of the R-3-hydroxyacyl-CoA dehydrogenase domain, we were able to produce hetero-polymers (functional MFE enzyme) or homo-polymers (with no 3-hydroxyacyl-CoA dehydrogenase activity) of PHA consisting principally of 3-hydroxyacid monomers (>80%) of the same length as the external fatty acid used for growth. The redirection of fatty acid flux towards beta-oxidation, by deletion of the neutral lipid synthesis pathway (mutant strain Q4 devoid of the acyltransferases encoded by the LRO1, DGA1, DGA2 and ARE1 genes), in combination with variant expressing only the enoyl-CoA hydratase 2 domain, led to a significant increase in PHA levels, to 7.3% of cell dry weight. Finally, the presence of shorter monomers (up to 20% of the monomers) in a mutant strain lacking the peroxisomal 3-hydroxyacyl-CoA dehydrogenase domain provided evidence for the occurrence of partial mitochondrial beta-oxidation in Y. lipolytica. PMID- 21603930 TI - Sex steroids and schizophrenia. AB - The peak in incidence for schizophrenia is during late adolescence for both sexes, but within this time frame the peak is both earlier and steeper for males. Additionally, women have a second peak in incidence following menopause. Two meta analyses have reported that men have an overall ~40% greater chance of developing schizophrenia than do women (Aleman et al., 2003; McGrath et al., 2004). These and other findings have led to the suggestion that ovarian hormones may be protective against schizophrenia. Less explored is the potential role of testosterone in schizophrenia, although disruptions in steroid levels have also been reported in men with the illness. The relationship between increased gonadal hormone release per se and peri-adolescent vulnerability for psychiatric illness is difficult to tease apart from other potentially contributory factors in clinical studies, as adolescence is a turbulent period characterized by many social and biological changes. Despite the obvious opportunity provided by animal research, surprisingly little basic science effort has been devoted to this important issue. On the other hand, the animal work offers an understanding of the many ways in which gonadal steroids exert a powerful impact on the brain, both shaping its development and modifying its function during adulthood. Recently, investigators using preclinical models have described a greater male vulnerability to neurodevelopmental insults that are associated with schizophrenia; such studies may provide clinically relevant insights into the role of gonadal steroids in psychiatric illness. PMID- 21603934 TI - Cloning, functional expression, biochemical characterization, and structural analysis of a haloalkane dehalogenase from Plesiocystis pacifica SIR-1. AB - A haloalkane dehalogenase (DppA) from Plesiocystis pacifica SIR-1 was identified by sequence comparison in the NCBI database, cloned, functionally expressed in Escherichia coli, purified, and biochemically characterized. The three dimensional (3D) structure was determined by X-ray crystallography and has been refined at 1.95 A resolution to an R-factor of 21.93%. The enzyme is composed of an alpha/beta-hydrolase fold and a cap domain and the overall fold is similar to other known haloalkane dehalogenases. Active site residues were identified as Asp123, His278, and Asp249 and Trp124 and Trp163 as halide-stabilizing residues. DppA, like DhlA from Xanthobacter autotrophicus GJ10, is a member of the haloalkane dehalogenase subfamily HLD-I. As a consequence, these enzymes have in common the relative position of their catalytic residues within the structure and also show some similarities in the substrate specificity. The enzyme shows high preference for 1-bromobutane and does not accept chlorinated alkanes, halo acids, or halo alcohols. It is a monomeric protein with a molecular mass of 32.6 kDa and exhibits maximum activity between 33 and 37 degrees C with a pH optimum between pH 8 and 9. The K(m) and k(cat) values for 1-bromobutane were 24.0 mM and 8.08 s( 1). Furthermore, from the 3D-structure of DppA, it was found that the enzyme possesses a large and open active site pocket. Docking experiments were performed to explain the experimentally determined substrate preferences. PMID- 21603935 TI - Acute restraint stress in zebrafish: behavioral parameters and purinergic signaling. AB - Despite the extensive knowledge about the effects of acute restraint stress (ARS) in rodents, zebrafish research is still elementary in this field, and the consequences of stress on purinergic system are unclear. Therefore, we evaluated the effects of ARS on behavior, biochemical, and molecular parameters in zebrafish brain. Animals were submitted to a 90 min ARS protocol and tested for anxiety levels, exploratory behavior, and memory performance. Furthermore, we analyzed ectonucleotidase and adenosine deaminase activities and their gene expression profile, as well as transcription of adenosine receptors. ARS increased anxiety, but did not impair locomotion or cognition. ARS significantly increased ATP hydrolysis, decreased cytosolic ADA activity, and changed the entpd and adora gene expression. In conclusion, ARS disturbed zebrafish behavior, and we hypothesize that the augmentation in adenosine-mediated signaling may be a strategy to reestablish homeostasis and normal behavior after a stressful event. PMID- 21603936 TI - Protective effects of exogenous hydrogen sulfide on neurons of hippocampus in a rat model of brain ischemia. AB - Many studies have demonstrated the cytoprotective effects of hydrogen sulfide (H(2)S) in vitro and/or in vivo ischemic injury. The aim of the current study was to investigate whether exogenous H(2)S attenuates the neuronal injury induced by brain ischemia. As an H(2)S donor, sodium hydrosulfide (NaHS) was administered intraperitoneally (5.6 mg/kg/day, i.p.). The effects of exogenous H(2)S on neurons of ischemic hippocampus were examined by using measurement of behavior, electrophysiology, morphology and immunohistochemical staining, respectively. Our results showed that exogenous H(2)S significantly improved spatial learning and memory deficits induced by brain ischemia (P < 0.01). Exogenous H(2)S enhanced synaptic plasticity in the hippocampus of brain-ischemic rats, inhibited the edema around pyramidal neurons and the nuclear shrink induced by ischemia, and promoted the expression of growth-associated protein-43 (GAP-43) in the CA1 region of hippocampus post ischemia. The results suggest a protective effect and therapeutic potential of H(2)S in the treatment of brain ischemia. PMID- 21603937 TI - Tricarboxylic acid cycle activity measured by 13C magnetic resonance spectroscopy in rats subjected to the kaolin model of obstructed hydrocephalus. AB - Evaluating early changes in cerebral metabolism in hydrocephalus can help in the decision making and the timing of surgical intervention. This study was aimed at examining the tricarboxylic acid (TCA) cycle rate and (13)C label incorporation into neurotransmitter amino acids and other compounds 2 weeks after rats were subjected to kaolin-induced progressive hydrocephalus. In vivo and ex vivo magnetic resonance spectroscopy (MRS), combined with the infusion of [1,6 (13)C]glucose, was used to monitor the time courses of (13)C label incorporation into the different carbon positions of glutamate in the forebrains of rats with hydrocephalus as well as in those of controls. Metabolic rates were determined by fitting the measured data into a one-compartment metabolic model. The TCA cycle rate was 1.3 +/- 0.2 MUmoles/gram/minute in the controls and 0.8 +/- 0.4 MUmoles/gram/minute in the acute hydrocephalus group, the exchange rate between alpha-ketoglutarate and glutamate was 4.1 +/- 2.5 MUmoles/gram/minute in the controls and 2.7 +/- 2.6 MUmoles/gram/minute in the hydrocephalus group calculated from in vivo MRS. There were no statistically significant differences between these rates. Hydrocephalus caused a decrease in the amounts of glutamate, alanine and taurine. In addition, the concentration of the neuronal marker N acetyl aspartate was decreased. (13)C Labelling of most amino acids derived from [1,6-(13)C]glucose was unchanged 2 weeks after hydrocephalus induction. The only indication of astrocyte impairment was the decreased (13)C enrichment in glutamine C-2. This study shows that hydrocephalus causes subtle but significant alterations in neuronal metabolism already early in the course of the disease. These sub-lethal changes, however, if maintained and if ongoing might explain the delayed and programmed neuronal damage as seen in chronic hydrocephalus. PMID- 21603939 TI - Genetic analysis of fish iridoviruses isolated in Taiwan during 2001-2009. AB - To investigate the genetic relationships between field strains of iridoviruses gathered from various fish species in Taiwan, viruses that were collected from 2001 to 2009 were analyzed. Open reading frames encoding the viral major capsid protein (MCP) and adenosine triphosphatase (ATPase) were sequenced for phylogenetic analysis. Our results indicated that iridoviruses from Taiwan aquaculture fishes could be classified into two groups: prior to 2005, the viruses were closely related to members of the genus Ranavirus; and after 2005, they were similar to members of the genus Megalocytivirus. Based on the analysis of MCP amino acid sequences, virus isolates were divided into 4 major genotypes that were related to ISKNV, RSIV, FLIV, and GIV, respectively. Pairwise comparisons of MCP genes showed that the ranavirus was an epidemic pathogen for economically important species in the major production regions and cultured marine fish, while the megalocytivirus isolates were sensitive to host range. In addition, the distribution of synonymous and non-synonymous changes in the MCP gene revealed that the iridoviruses were evolving slowly, and most of the variations were synonymous mutations. The Ka/Ks values were lower than one, and hence, the viruses were under negative selection. PMID- 21603938 TI - Effects of octreotide in chronically mild stressed rats: possible role of immune and oxidative stress pathways. AB - Impairment of neuroendocrine, immune and antioxidant defenses contribute to pathophysiology of stress-induced depression. Somatostatin executes diverse regulatory effects on endocrine, exocrine and neural functions; however, the possibility that octreotide, a synthetic somatostatin analogue might mitigate stress-induced depression remains elusive. Hence, the current study aimed to explore the immunomodulatory and antioxidant effects of octreotide in a model of chronic mild stress (CMS). This paradigm was performed by exposing rats to a combination of mild unpredictable stressors for 21 days. Fifty male Wistar rats were divided into five groups; (1) control receiving saline, (2) octreotide given to normal unstressed animals. The remaining three groups were subjected to (3) CMS alone or in combination with octreotide (4) 50 MUg/kg or (5) 90 MUg/kg. Octreotide increased sucrose preference index and attenuated CMS-induced increases in plasma adrenocorticotrophic hormone and corticosterone levels. In addition, octreotide decreased plasma tumor necrosis factor-alpha concentration. Moreover, it prevented CMS-induced oxidative damage by enhancing the antioxidant defenses superoxide dismutase, glutathione reductase and glutathione in the hippocampus. Furthermore, octreotide normalized the elevated malondialdehyde and lactate dehydrogenase levels in the hippocampus. These results demonstrate a possible antidepressant-like activity of octreotide in CMS due to its antioxidant/antiinflammatory aptitude. PMID- 21603940 TI - Dynamic changes of TrkB gene expression in Streptococcus pneumoniae meningitis after treatment with antibiotics and dexamethasone. AB - BACKGROUND: Although more and more new potent antibiotics have been used, the incidence of neurological sequelae of Streptococcus pneumoniae meningitis has not improved in children over the last decade. The expression of TrkB mRNA, a receptor of brain-derived neurotrophic factor, is associated with the incidence of neurological sequelae of Streptococcus pneumoniae meningitis. METHODS: Rats of 3 weeks old were used to construct a model of Streptococcus pneumoniae meningitis and served as normal controls. They were administered with antibiotics or antibiotics plus dexamethasone, respectively. The expression of the TrkB gene was detected in the brain by in situ hybridization. RESULTS: In the brains of Streptococcus pneumoniae inoculated rats, TrkB mRNA was significantly up regulated after inoculation for 24 hours, and then down-regulated in a dose dependent manner after treatment with antibiotics. This up-regulation was seen after treatment with antibiotics plus dexamethasone. TrkB mRNA expression was also observed in some infiltrating inflammatory cells. CONCLUSIONS: The results of the study support the hypothesis that TrkB signal transduction pathways might play an important role in Streptococcus pneumoniae meningitis, probably by protecting the brain from damage. The role of TrkB might be weakened after the treatment with antibiotics. Our findings suggest that targeting TrkB receptors might be a rational strategy for prevention of neurological sequelae caused by Streptococcus pneumoniae meningitis. PMID- 21603941 TI - Competition between microorganisms for a single limiting resource with cell quota structure and spatial variation. AB - Microbial populations compete for nutrient resources, and the simplest mathematical models of competition neglect differences in the nutrient content of individuals. The simplest models also assume a spatially uniform habitat. Here both of these assumptions are relaxed. Nutrient content of individuals is assumed proportional to cell size, which varies for populations that reproduce by division, and the habitat is taken to be an unstirred chemostat where organisms and nutrients move by simple diffusion. In a spatially uniform habitat, the size structured model predicts competitive exclusion, such that only the species with lowest break-even concentration persists. In the unstirred chemostat, coexistence of two competitors is possible, if one has a lower break-even concentration and the other can grow more rapidly. In all habitats, the calculation of competitive outcomes depends on a principal eigenvalue that summarizes relationships among cell growth, cell division, and cell size. PMID- 21603942 TI - Accurate image reconstruction using real C-arm data from a Circle-plus-arc trajectory. AB - OBJECTIVE: Developing an efficient tool for accurate three-dimensional imaging from projections measured with C-arm systems. MATERIAL AND METHODS: A circle-plus arc trajectory, which is complete and thus amenable to accurate reconstruction, is used. This trajectory is particularly attractive as its implementation does not require moving the patient. For reconstruction, we use the "M-line method", which allows processing the data in the efficient filtered backprojection mode. This method also offers the advantage of not requiring an ideal data acquisition geometry, i.e., the M-line algorithm can account for known deviations in the scanning geometry, which is important given that sizeable deviations are generally encountered in C-arm imaging. RESULTS: A robust implementation scheme of the "M-line method" that applies straightforwardly to real C-arm data is presented. In particular, a numerically stable technique to compute the view dependent derivative with respect to the source trajectory parameter is applied, and an efficient way to compute the pi-line backprojection intervals via a polygonal weighting mask is presented. Projection data of an anthropomorphic thorax phantom were acquired on a medical C-arm scanner and used to demonstrate the benefit of using a complete data acquisition geometry with an accurate reconstruction algorithm versus using a state-of-the-art implementation of the conventional Feldkamp algorithm with a circular short scan of cone-beam data. A significant image quality improvement based on visual assessment is shown in terms of cone-beam artifacts. PMID- 21603943 TI - Synthesis and characterization of triphenylethylene derivatives with aggregation induced emission characteristics. AB - New aggregation-induced emission (AIE) compounds derived from triphenylethylene were synthesized. The thermal, photophysical, electrochemical and aggregation induced emissive properties were investigated. All the compounds had strong blue light emission capability and good thermal stability. Their maximum fluorescence emission wavelengths were between 443 to 461 nm in solid states, while their glass transition temperatures ranged from 86 to 129 degrees C. The decomposition temperatures of the synthesized compounds were in the range of 432-534 degrees C. The synthesized compounds possessed aggregation-induced emission properties, namely exhibited enhanced fluorescence emission in aggregated states. The highest occupied molecular orbital (HOMO) energy levels estimated from the oxidation potentials were between 5.61 and 5.66 eV and the lowest unoccupied molecular orbital/highest occupied molecular orbital (LUMO/HOMO) energy gap values were found to be in the range of 3.18-3.22 eV. The compounds 4-(4-(2,2-bis(4 (naphthalen-1-yl)phenyl)vinyl)phenyl) dibenzothiophene [(BN)(2)Bt] and 4-(4-(2,2 di(biphenyl-4-yl)vinyl)phenyl) dibenzothiophene [(BB)(2)Bt] exhibited vibronic fine-structure photoluminescence spectra when the water fraction was less than 70%. PMID- 21603944 TI - Novel classification of acute liver failure through clustering using a self organizing map: usefulness for prediction of the outcome. AB - BACKGROUND: Patients with acute liver failure are classified according to the interval between the onset of hepatitis symptoms and the development of hepatic encephalopathy. We examined the validity of such classifications. METHODS: The subjects were 1,022 patients enrolled in a nationwide survey in Japan. The intervals between the onset of the hepatitis symptoms and the development of encephalopathy were 10 days or less in 472 patients (group-A), between 11 and 56 days in 468 patients (group-B), and longer than 56 days in 82 patients (group-C). Data on a total of 104 items collected from the patients were subjected to clustering using a self-organizing map. RESULTS: The patients were classified into three clusters. The first cluster consisted of 411 patients (group-A: 57%, group-B: 39%, group-C: 4%). Their incidence of complications was low; 34% underwent liver transplantation (LT), and their survival rate was 90%, while 94% of those treated without transplant were rescued. The second cluster consisted of 320 patients (21, 65, and 14% groups A, B, and C, respectively), who showed a high incidence of complications; the survival rate was 7% in the patients treated conservatively without LT. Sixteen percent underwent LT and survival rate of these patients was 52%. There was a third cluster, of 291 patients (59, 34, and 7% groups A, B, and C, respectively). Without LT, 81% of the patients died. Seven percent were treated by LT and their survival rate was 60%. CONCLUSIONS: Clustering revealed that patients with acute liver failure could be classified into three clusters independent of the interval between the onset of disease symptoms and the development of encephalopathy. This technique may be useful, since the outcomes of the patients differed markedly among the clusters. PMID- 21603945 TI - Wnt/beta-catenin signaling in embryonic stem cell self-renewal and somatic cell reprogramming. AB - Embryonic stem cells and induced pluripotent stem (iPS) cells are characterized by their ability to self-renew and to generate differentiated cells of all three germ layers. This potential makes them an attractive source to address question of developmental and also for use in clinical regenerative medicine. Although the culture conditions to maintain pluripotency and reprogramming technologies have been established, the underlying molecular mechanisms are incompletely understood. Accumulating evidence indicates that the Wnt/beta-catenin signaling pathway plays a pivotal role in the maintenance of pluripotency as well as in the process of somatic cell reprogramming. Reciprocally, Wnt/beta-catenin signaling also plays a critical role in the lineage decision/commitment process. These dramatically different outcomes upon activation of the Wnt signaling cascade has fueled enormous controversy concerning the role of Wnt signaling in the maintenance of potency and induction of differentiation in stem cells. Here, we discuss and explore the divergent roles of the Wnt signaling pathways based on findings from our lab. Accumulated results from our lab indicate the usage of a critical switching mechanism that regulates the divergent Wnt/catenin transcriptional programs associated with either maintenance of potency or initiation of differentiation. PMID- 21603947 TI - In vitro and in vivo AM and PL tunnel positioning in anatomical double bundle anterior cruciate ligament reconstruction. AB - BACKGROUND: There have been few studies investigating the correct anatomical femoral and tibial tunnel placement in double bundle anterior cruciate ligament (ACL) reconstruction. OBJECTIVE: To compare anteromedial (AM) and posterolateral (PL) tunnel positions in anatomical double bundle ACL reconstruction in human cadaver and patient knees. MATERIALS AND METHODS: Fifteen fresh-frozen non-paired adult human knees and 27 patients (27 knees) were evaluated. In the cadaver knees, AM and PL bundles were identified by their difference in tension patterns. Their femoral centers were marked with a K-wire, and cut from the femoral insertion site. After this, each bundle was divided at the tibial side. The center of each bundle insertion was again marked with a K-wire, and 5-7-mm tunnels were drilled with transportal or outside-in technique. In patient knees, each tunnel was made according to the native ACL foot print and bony landmarks using transtibial technique (n = 5) and transportal technique (n = 22). Tunnel placement was evaluated using a C-arm X-ray device and 3D CT. For the femoral side assessment, Bernard and Hertel's technique was used. For the tibial side assessment, Amis and Jakob's technique was used. RESULTS: The femoral AM tunnel in the cadaver knees was placed in a significantly deeper position when compared to patient knees. There was no significant difference in the AM vertical placement or in the PL tunnel placement in the femur. No significant differences were observed in the tibial tunnel placements between cadaver and patient knees. CONCLUSION: In vivo positioning of the femoral AM bundle differed significantly from the in vitro positioning. PMID- 21603946 TI - Human serum is as efficient as fetal bovine serum in supporting proliferation and differentiation of human multipotent stromal (mesenchymal) stem cells in vitro and in vivo. AB - BACKGROUND: Human multipotent stromal (skeletal, mesenchymal) stem cells (hMSC) are employed in an increasing number of clinical trials for tissue regeneration of age-related degenerative diseases. However, routine use of fetal bovine sera (FBS) for their in vitro expansion is not optimal and may pose a health risk for patients. METHODS: We carried out a side-by-side comparison of the effects of allogenic pooled human serum (HuS) versus FBS on hMSC proliferation and differentiation in vitro and in vivo. As a model for hMSC, we employed telomerase immortalized hMSC; hMSC-TERT cell line. RESULTS: hMSC-TERT exhibited similar morphology and size when cultured in HuS vs. FBS as assessed by light microscopy and FACS analysis. We did not observe any significant differences in growth rates of hMSC-TERT during short-term (10 days) and long-term (100 days) culture in media supplemented with HuS vs. FBS. hMSC-TERT or primary bone marrow derived hMSC induced to osteoblastic or adipocytic differentiation in the presence of HuS or FBS showed comparable levels of gene expression and protein production of osteoblastic markers (CBFA1/Runx2, alkaline phosphastase, collagen type I and osteocalcin) or adipocytic markers (PPAR-gamma2, lipoprotein lipase (LPL), aP2), respectively. In order to test for the functional capacity of hMSC-TERT that have been maintained in long-term cultures in the presence of HuS vs. FBS, the cells were mixed with hydroxyapatite/tricalcium phosphate (HA/TCP) and implanted subcutaneously in immune deficient mice. hMSC maintained in HuS vs. FBS formed comparable heterotopic bone. DISCUSSION: Human serum can support proliferation and differentiation of hMSC in vitro and can maintain their bone forming capacity in vivo. The use of human serum in cell cultures of hMSC intended for cell-based therapy is preferable. PMID- 21603949 TI - Synthesis and characterization of natural and modified antifreeze glycopeptides: glycosylated foldamers. AB - In Arctic and Antarctic marine regions, where the temperature declines below the colligative freezing point of physiological fluids, efficient biological antifreeze agents are crucial for the survival of polar fish. One group of such agents is classified as antifreeze glycoproteins (AFGP) that usually consist of a varying number (n = 4-55) of [AAT]( n )-repeating units. The threonine side chain of each unit is glycosidically linked to beta-D: -galactosyl-(1 -> 3)-alpha-N acetyl-D: -galactosamine. These biopolymers can be considered as biological antifreeze foldamers. A preparative route for stepwise synthesis of AFGP allows for efficient synthesis. The diglycosylated threonine building block was introduced into the peptide using microwave-enhanced solid phase synthesis. By this versatile solid phase approach, glycosylated peptides of varying sequences and lengths could be obtained. Conformational studies of the synthetic AFGP analogs were performed by circular dichroism experiments (CD). Furthermore, the foldamers were analysed microphysically according to their inhibiting effect on ice recrystallization and influence on the crystal habit. PMID- 21603950 TI - Effect of agitation rate on ethanol production from sugar maple hemicellulosic hydrolysate by Pichia stipitis. AB - Concentrated dilute acid hydrolysate was obtained from hot water extracts of Acer saccharum (sugar maple) and was fermented to ethanol by Pichia stipitis in a 1.3 L-benchtop bioreactor. The conditions under which the highest ethanol yield was achieved were when the air flow rate was set to 100 cm(3) and the agitation rate was set to 150 rpm resulting in an overall mass transfer coefficient (K(L)a) of 0.108 min(-1). A maximum ethanol concentration of 29.7 g/L was achieved after 120 h of fermentation; however, after 90 h of fermentation, the ethanol concentration was only slightly lower at 29.1 g/L with a yield of 0.39 g ethanol per gram of sugar consumed. Using the same air flow rate and adjusting the agitation rate resulted in lower ethanol yields of 0.25 g/g at 50 rpm and 0.30 g/g at 300 rpm. The time it takes to reach the maximum ethanol concentration was also affected by the agitation rate. The ethanol concentration continued to increase even after 130 h of fermentation when the agitation rate was set at 50 rpm, whereas the maximum ethanol concentration was reached after only 68.5 h at 300 rpm. PMID- 21603952 TI - In vitro antioxidant potential of some soil fungi: screening of functional compounds and their purification from Penicillium citrinum. AB - Fungal isolates (Aspergillus wentii 1, A. wentii 2, Penicillium citrinum, Penicillium granulatum) were selected to study their in vitro antioxidant potential by various assay procedures. Czapek-Dox's medium was selected for the growth of fungi as it supported the best antioxidant activity based on their EC(50) values, P. citrinum was the best followed by P. granulatum, A. wentii 1, and A. wentii 2. The chromatographic analyses showed several compounds possessing antioxidant activity in the fungal extracts. Two such compounds were partially purified from P. citrinum which demonstrated potent antioxidant activity, equally effective or better than some of the standard antioxidants. PMID- 21603951 TI - Structure and pyrolysis characteristics of lignin derived from wood powder hydrolysis residues. AB - Physicochemical characteristics of wood powder acid hydrolysis residue (WAHR) were studied firstly in this study, and WAHL (lignin derived from WAHR) was separated successfully from WAHR based on an improved isolating method. The content of functional group such as phenolic hydroxyl group of guaiacyl, syringyl, and hydroxyl-phenyl units in WAHL were identified by (31)P-NMR and DFRC (derivatization followed by reductive cleavage) method. Thermal degradation experiments were carried out on a thermogravimetric (TG) analyzer to show pyrolysis characteristics of WAHL. The compositions of pyrolysis products of WAHL were also studied throughout a pyrolysis-gas chromatography-mass spectrometry (Py GC-MS) analyzer. It was shown that the pyrolysis of WAHL took place in a wide temperature range and there were two obvious peaks in the differential thermogravimetric diagram. Results of Py-GC-MS analysis indicated that pyrolysis products were mainly formed through cleavage of the beta-O-4 connection and multiple pyrolysis. PMID- 21603953 TI - Persistence of multiple emissary veins of posterior fossa with unusual origin of left petrosquamosal sinus from mastoid emissary. AB - Emissary veins are valveless veins which pass through the cranial apertures and connect the dural venous sinuses and the extracranial veins. The clinical importance of emissary veins is increasingly being appreciated. Some emissary veins like the petrosquamosal sinus and mastoid emissary vein may cause significant bleeding during middle ear and skull base surgeries. A dilated mastoid emissary vein or condylar emissary vein can sometimes be a rare cause of tinnitus. Radiological identification of these venous channels has been described in recent years and assumes significance in light of their clinical importance. We describe the CT and MRI findings of a rare case that had persistence of multiple emissary veins and presented clinically with tinnitus. The radiological findings included a dilated left mastoid emissary vein, bilateral petrosquamosal sinuses, posterior condylar veins, occipital emissary veins and an intrapetrous venule. The left petrosquamosal sinus had an unusual origin from the dilated mastoid emissary vein. The patient also had major anomalies of posterior fossa venous sinuses which are discussed. A relevant review of literature is included. PMID- 21603954 TI - Methods to determine slow diffusion coefficients of biomolecules: applications to Engrailed 2, a partially disordered protein. AB - We present new NMR methods to measure slow translational diffusion coefficients of biomolecules. Like the heteronuclear stimulated echo experiment (XSTE), these new methods rely on the storage of information about spatial localization during the diffusion delay as longitudinal polarization of nuclei with long T(1) such as nitrogen-15. The new BEST-XSTE sequence combines features of Band-selective Excitation Short-Transient (BEST) and XSTE methods. By avoiding the saturation of all protons except those of amide groups, one can increase the sensitivity by 45% in small proteins. The new experiment which combines band-Selective Optimized Flip-Angle Short-Transient with XSTE (SOFAST-XSTE) offers an alternative when very short recovery delays are desired. A modification of the HSQC-edited version of the XSTE experiment offers enhanced sensitivity and access to higher resolution in the indirect dimension. These new methods have been applied to detect changes in diffusion coefficients due to dimerization or proteolysis of Engrailed 2, a partially disordered protein. PMID- 21603956 TI - [Prevention and management of complications in hip arthroplasty]. PMID- 21603957 TI - Sponge swabs increase sensitivity of sterility testing of processed bone and tendon allografts. AB - Sterility testing is the final, and critical, step in quality control of tissue banking. It informs the decision whether to release the tissue allografts for clinical use, or not. The most common method for sterility testing of structural bone and tendon allografts is to swab using cotton tip streaks. This method provides low recovery efficiency; and therefore may pass allografts with low bioburden, providing false negatives. Our pilot data revealed organism recovery efficiencies of 60, 30 and 100% from cotton swab, membrane filtration and sponge swaps, respectively. Our aim was to develop a high sensitivity sterility test for structural bone and tendon allografts using a sponge sampling method. Eighty-one bone and tendon allograft samples were inoculated with organism suspensions (10(2) or less organisms per 0.1 mL) of Clostridium sporogenes, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Bacillus subtilis, Aspergillus niger, Staphylococcus epidermidis and Micrococcus spp. Nasco sponges (4 * 8 cm) were used to aseptically sample the whole surface of allograft samples. The sponges were cut in half and cultured in either tryptone soya or fluid thioglycollate broths for 14 days. Positive culture samples were further examined for microbial morphology. The results showed that the sensitivity of the method, and negative predictive value, is 100% for all inoculated organisms incubated with thioglycollate. We conclude that this sponge sampling method should be applied as the standard for sterility testing of structural bone and tendon allografts. PMID- 21603959 TI - [Neuroendocrine tumors. More variety than uniformity]. PMID- 21603960 TI - [Pancreatic necrosis: pro surgical therapy]. AB - Currently, patients with severe necrotizing pancreatitis rarely need interventional or surgical treatment. However, in case of pancreatic infection and septic complications they should be treated with the step up approach, primarily with an interventional or endoscopic drainage. If further clinical deterioration occurs necrosectomy is indicated. This should ideally be postponed until the third or fourth week after onset of pancreatitis to optimize surgical conditions including demarcation of the necrosis. Open necrosectomy with postoperative continuous lavage is a valid treatment option with low mortality, low morbidity and good long-term outcome. In recent years, several minimally invasive techniques for necrosectomy have been developed and are alternative approaches in about 70% of cases. In most cases, the retroperitoneoscopic approach is used, although the endoscopic transgastric route is also being used more and more frequently. While the reduced operative trauma should theoretically also reduce the onset of postoperative organ failure, no study has actually proven this. PMID- 21603961 TI - Microcantilever sensing arrays from biodegradable, pH-responsive hydrogels. AB - Biodegradable, pH-responsive hydrogels composed of poly(methacrylic acid) crosslinked with varying molar percentages of polycaprolactone diacrylate were synthesized. The equilibrium swelling properties of these pH-responsive materials were studied. Methods were developed to incorporate these novel hydrogels as sensing components in silicon-based microsensors. Extremely thin layers of hydrogels were prepared by photopolymerization atop silicon microcantilever arrays that served to transduce the pH-responsive volume change of the hydrogel into an optical signal. Organosilane chemistry allowed covalent adhesion of the hydrogel to the silicon beam. As the hydrogel swelled, the stress generated at the surface between the hydrogel and the silicon caused a beam deflection downward. The resulting sensor demonstrated a maximum sensitivity of 1 nm/5.7*10( 5) pH unit. Sensors were tested in protein-rich solutions to mimic biological conditions and found to retain their high sensitivity. The existing theory was evaluated and developed to predict deflection of these composite cantilever beams. PMID- 21603962 TI - On-chip analysis of respiratory viruses from nasopharyngeal samples. AB - Point-of-care (PoC) testing followed by personalized efficient therapy of infectious diseases may result in a considerable reduction of associated health care costs. Lab-on-a-chip (LoC) systems represent a potentially high efficient class of PoC tools. Here, we present a LoC system for automated pathogen analysis of respiratory viruses from nasopharyngeal specimens. The device prepares total nucleic acids from extracted swab samples using magnetic silica beads. After reverse transcription the co-purified viral RNA is amplified in accordance with the QIAplex multiplex PCR technology. Hybridized to corresponding QIAGEN LiquiChip beads and labelled with streptavidin R-phycoerythrin, the amplified target sequences are finally detected using a QIAGEN LiquiChip200 workstation. All chemicals needed are either stored freeze-dried on the disposable chip or are provided in liquid form in a reagent cartridge for up to 24 runs. Magnetic stir bars for mixing as well as turning valves with metering structures are integrated into the injection-moulded disposable chip. The core of the controlling instrument is a rotating heating bar construction providing fixed temperatures for fast cycling. PCR times of about half an hour (for 30 cycles) could be achieved for 120 MUl reactions, making this system the fastest currently available high-volume PCR chip. The functionality of the system was shown by comparing automatically processed nasopharyngeal samples to ones processed manually according to the QIAGEN "ResPlexTM II Panel v2.0" respiratory virus detection kit. A prototype of the present instrument revealed slightly weaker signal intensities with a similar sensitivity in comparison to the commercially available kit and automated nucleic acid preparation devices, even without protocol optimization. PMID- 21603963 TI - Particle manipulation in a microfluidic channel using acoustic trap. AB - A high frequency sound beam was employed to explore an experimental method that could control particle motions in a microfluidic device. A 24 MHz single element lead zirconate titanate (PZT) transducer was built to transmit a focused ultrasound of variable duty factors (pulse duration/pulse repetition time), and its 1-3 piezocomposite structure established a tight focusing with f-number (focal depth/aperture size) of one. The transducer was excited by the Chebyshev windowed chirp signal sweeping from 18 MHz to 30 MHz with a 50% of duty factor, in order to ensure that enough sound beams were penetrated into the microfluidic device. The device was fabricated from a polydimethylsiloxane (PDMS) mold, and had a main channel composed of three subchannels among which particles flowed in the middle. A 60~70 MUm diameter single droplet in the flow could be trapped near the channel bifurcation, and subsequently diverted into the sheath flow by releasing or shifting the acoustic trap. Hence, the results showed the potential use of a focused sound beam in microfluidic devices, and further suggested that this method could be exploited in the development of ultrasound-based flow cytometry and cell sorting devices. PMID- 21603964 TI - Patterns of missing mini mental status exam (MMSE) in radiation therapy oncology group (RTOG) brain cancer trials. AB - The Mini Mental Status Exam (MMSE) instrument has been commonly used in the Radiation Therapy Oncology Group (RTOG) to assess mental status in brain cancer patients. Evaluating patient factors in relation to patterns of incomplete MMSE assessments can provide insight into predictors of missingness and optimal MMSE collection schedules in brain cancer clinical trials. This study examined eight RTOG brain cancer trials with ten treatment arms and 1,957 eligible patients. Patient data compliance patterns were categorized as: (1) evaluated at all time points (Complete), (2) not evaluated from a given time point or any subsequent time points but evaluated at all the previous time points (Monotone drop-out), (3) not evaluated at any time point (All missing), and (4) all other patterns (Mixed). Patient characteristics and reasons for missingness were summarized and compared among the missing pattern groups. Baseline MMSE scores and change scores after radiation therapy (RT) were compared between these groups, adjusting for differences in other characteristics. There were significant differences in frequency of missing patterns by age, treatment type, education, and Zubrod performance status (ZPS; P < 0.001). Ninety-two percent of patients were evaluated at least once: seven percent of patients were complete pattern, 49% were Monotone pattern, and 36% were mixed pattern. Patients who received RT only regimens were evaluated at a higher rate than patients who received RT + other treatments (49-64% vs. 27-45%). Institutional error and request to not be contacted were the most frequent known reasons for missing data, but most often, reasons for missing MMSE was unspecified. Differences in baseline mean MMSE scores by missing pattern (Complete, Monotone dropout, Mixed) were statistically significant (P < 0.001) but differences were small (<1.5 points) and significance did not persist after adjustment for age, ZPS, and other factors related to missingness. Post-RT change scores did not differ significantly by missing pattern. While baseline and change scores did not differ widely by missing pattern for available measurements, incomplete data was common and of unknown reason, and has potential to substantially bias conclusions. Higher compliance rates may be achievable by addressing institutional compliance with assessment schedules and patient refusal issues, and further exploration of how educational and health status barriers influence compliance with MMSE and other tools used in modern neurocognitive batteries. PMID- 21603965 TI - Ischemic stroke and intracranial hemorrhage in glioma patients on antiangiogenic therapy. AB - Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), recently received FDA approval for recurrent glioblastoma. Additionally, several VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have entered trials for recurrent glioma. Phase II studies of bevacizumab for recurrent GBM have reported incidents of ischemic stroke (IS) and intracranial hemorrhage (ICH); however, their clinical features and outcomes were not described in detail. We conducted a retrospective study of recurrent malignant glioma patients with radiographically-confirmed IS or ICH while on antiangiogenic therapy. The study population included patients treated between 2005 and 2010 at the National Cancer Institute on four different phase I and II trials of antiangiogenic agents for recurrent malignant glioma, as well as patients receiving bevacizumab off clinical trial during this same period. Eight patients developed IS (50% lacunar) and 14 experienced ICH (79% intratumoral) while on antiangiogenic therapy for malignant glioma recurrence. The median age was 53 years, 17 patients (77%) were men, and 59% had glioblastoma. The frequencies of IS and ICH were 1.9% and 1.9% in bevacizumab trials. None of the patients on VEGFR TKI trials developed IS, while 3.8% experienced ICH. Patients with IS were treated with antiangiogenic agents longer than those with ICH (median, 16.2 vs. 2.6 months, P = 0.001). Median survival was 7.8 months after IS and 2.6 months after ICH. The most common IS subtype was lacunar, while most ICHs were asymptomatic and intratumoral. Overall, IS seems to be a complication of prolonged antiangiogenic therapy, while intratumoral bleeds often occur in the setting of tumor progression. PMID- 21603966 TI - Clinical effectiveness of a one-step self-etch adhesive in non-carious cervical lesions at 2 years. AB - A 2-year randomized, controlled prospective study evaluated the clinical effectiveness of a one-step self-etch adhesive and a "gold-standard" three-step etch-and-rinse adhesive in non-carious Class-V lesions. The null hypothesis tested was that the one-step self-etch adhesive does perform clinically equally well as the three-step etch-and-rinse adhesive. A total of 161 lesions in 26 patients were restored with Clearfil AP-X (Kuraray). The restorations were bonded either with the "all-in-one" adhesive Clearfil S3 Bond (Kuraray) or with the three-step etch-and-rinse adhesive Optibond FL (Kerr). The restorations were evaluated at baseline and after 6 months, 1 and 2 years, regarding their retention, marginal adapation, marginal discoloration, caries occurrence, preservation of tooth vitality and post-operative sensivity. Retention loss, severe marginal defects and/or discoloration that needed intervention (repair or replacement) and the occurrence of caries were considered as clinical failures. The recall rate at 2 years was 93.8%. Only one Clearfil S3 Bond restoration was lost at the 2-year recall. All other restorations were clinically acceptable. The number of restorations with defect-free margins decreased severely during the 2 year study period (to 6.7% and 25.3% for Clearfil S3 Bond and Optibond FL, respectively). The Clearfil S3 Bond restorations presented significantly more small marginal defects at the enamel side than the Optibond FL restorations (Clearfil S3 Bond: 93.3%; Optibond FL: 73.3%; p = 0.000). Superficial marginal discoloration increased in both groups (to 53.3% and 36% for Clearfil S3 Bond and Optibond FL, respectively) and was also more pronounced in the Clearfil S3 Bond group (p = 0.007). After 2 years, the simplified one-step self-etch adhesive Clearfil S3 Bond and the three-step etch-and-rinse adhesive Optibond FL were clinically equally successful, even though both adhesives were characterized by progressive degradation in marginal integrity. Clearfil S3 Bond exhibited more small enamel marginal defects and superficial marginal discolorations. PMID- 21603967 TI - Prevalence and risk of psychiatric disorders as a function of variant rape histories: results from a national survey of women. AB - PURPOSE: Rape is an established risk factor for mental health disorders, such as posttraumatic stress disorder (PTSD), major depressive episodes (MDE), and substance use disorders. The majority of studies have not differentiated substance-involved rape or examined comorbid diagnoses among victims. Therefore, the aim of the present study was to estimate the prevalence of common trauma related psychiatric disorders (and their comorbidity) in a national sample of women, with an emphasis on distinguishing between rape tactics. A secondary objective was to estimate the risk for psychiatric disorders among victims of variant rape tactics, in comparison to non-victims. METHODS: A nationally representative population-based sample of 3,001 non-institutionalized, civilian, English or Spanish speaking women (aged 18-86 years) participated in a structured telephone interview assessing rape history and DSM-IV criteria for PTSD, MDE, alcohol abuse (AA), and drug abuse (DA). Descriptive statistics and multivariate logistic regression analyses were employed. RESULTS: Women with rape histories involving both substance facilitation and forcible tactics reported the highest current prevalence of PTSD (36%), MDE (36%), and AA (20%). Multivariate models demonstrated that this victim group was also at highest risk for psychiatric disorders, after controlling for demographics and childhood and multiple victimization history. Women with substance-facilitated rapes reported higher prevalence of substance abuse in comparison to women with forcible rape histories. Comorbidity between PTSD and other psychiatric disorders was higher among rape victims in comparison to non-rape victims. CONCLUSIONS: Researchers and clinicians should assess substance-facilitated rape tactics and attend to comorbidity among rape victims. Empirically supported treatments are needed to address the complex presentations observed among women with variant rape histories. PMID- 21603968 TI - Relationships between stereotyped beliefs about mental illness, discrimination experiences, and distressed mood over 1 year among persons with schizophrenia enrolled in rehabilitation. AB - PURPOSE: Research suggests stereotype endorsement or self-stigma serves as a barrier to functioning and well-being among persons with schizophrenia. Little is known about how stable self-stigma is and whether it is linked over time with related constructs such as discrimination experiences and psychological distress. METHODS: Stereotype endorsement and discrimination experiences were assessed using the Internalized Stigma of Mental Illness Scale and psychological distress was assessed using the Emotional Discomfort component of the Positive and Negative Syndrome Scale, at three points in time across 1 year. RESULTS: Path analyses indicated that the constructs of stereotype endorsement and discrimination experiences are stable over periods of 5-7 months and may fluctuate over 12 months. Further, the constructs of stereotype endorsement and discrimination experiences were related to one another concurrently, but analyses failed to detect a relationship over time. Neither construct was related to psychological distress over time. CONCLUSIONS: Self-stigma is a stable construct in the short term, and is distinct from related constructs such as discrimination experiences and psychological distress. PMID- 21603969 TI - Subtypes of psychopathy in the British household population: findings from the national household survey of psychiatric morbidity. AB - BACKGROUND: Cleckley asserted in 1941 that psychopathic personalities are found in the community as well as prisons. Subtypes of abnormal personality may be identifiable in the general population using contemporary measures of psychopathy. METHODS: Cluster analysis of PCL:SV scores using the four-facet model with a representative sample of 624 adults aged 16-74 years living in households interviewed in the second of a two-phase survey in Great Britain. RESULTS: Analysis confirmed an optimum 5-cluster solution and existence in the general population of prototypical or criminal psychopaths, non-psychopathic habitual criminals, and "successful psychopaths". Two additional clusters were identified, one uniquely characterised by impulsive/irresponsible (Facet 3) items and the other by social failure associated with low scores on each facet. CONCLUSIONS: The study confirmed previously hypothesised and two new subtypes of psychopathy within the general population. This prototypical classification may compliment existing typologies during clinical assessment following further refinement. PMID- 21603970 TI - Parthenolide, a sesquiterpene lactone, expresses multiple anti-cancer and anti inflammatory activities. AB - Parthenolide, a naturally occurring sesquiterpene lactone derived from feverfew (Tanacetum parthenium), exhibits exceptional anti-cancer and anti-inflammatory properties, making it a prominent candidate for further studies and drug development. In this review, we briefly investigate molecular events and cell specific activities of this chemical in relation to cytochrome c, nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB), signal transduction and activation of transcription (STAT), reactive oxygen species (ROS), TCP, HDACs, microtubules, and inflammasomes. This paper reports that parthenolide shows strong NF-kappaB- and STAT-inhibition-mediated transcriptional suppression of pro-apoptotic genes. This compound acts both at the transcriptional level and by direct inhibition of associated kinases (IKK-beta). Similarly, this review discusses parthenolide-induced ROS-mediated apoptosis of tumor cells via the intrinsic apoptotic signaling pathway. The unique ability of this compound to not harm normal cells but at the same time induce sensitization to extrinsic as well as intrinsic apoptosis signaling in cancer cells provides an important, novel therapeutic strategy for treatment of cancer and inflammation-related disorders. PMID- 21603972 TI - Ethanol extract of Elaeocarpus petiolatus inhibits lipopolysaccharide-induced inflammation in macrophage cells. AB - Elaeocarpus petiolatus is known to exert active oxygen scavenging, anti-aging, and whitening actions. However, the biological effects of E. petiolatus on inflammation and the underlying mechanisms are yet to be established. In the present study, we investigated the anti-inflammatory effects of the ethanol extract from E. petiolatus (EPE) bark in murine Raw264.7 macrophages stimulated with lipopolysaccharide (LPS). EPE inhibited the production of PGE(2), TNF-alpha, and IL-1beta in a dose-dependent manner in Raw264.7 cells stimulated with LPS. The decrease in PGE(2) production was correlated with reduced COX-2 expression. Furthermore, EPE suppressed the phosphorylation of extracellular signal-related kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 as well as translocation of the NF-kappaB p65 subunit from the cytosol to nucleus. Our results suggest that EPE exerts anti-inflammatory activity through inhibition of inflammatory mediators, such as PGE(2), TNF-alpha, and IL-1beta, and downregulation of COX-2 via suppression of NF-kappaB translocation and phosphorylation of ERK, JNK, and p38 in LPS-stimulated Raw264.7 cells. PMID- 21603971 TI - The new vitamin E derivative, ETS-GS, protects against cecal ligation and puncture-induced systemic inflammation in rats. AB - Sepsis-related systemic inflammation frequently occurs in the critical care setting. Systemic inflammation is implicated in the progression of organ injury, which is associated with a high mortality rate. Recently, vitamin E and glutamic acid have been reported to attenuate inflammation. We therefore investigated whether the vitamin E derivative, ETS-GS, could inhibit the secretion of cytokines and high-mobility group box 1 (HMGB1), and thereby reduce organ damage in a rat model of cecal ligation and puncture (CLP)-induced sepsis. Male Wistar rats weighing 250-300 g were used. Rats received water or ETS-GS (10 mg/kg) by oral administration for 3 weeks, and then sepsis was induced by CLP under sevoflurane anesthesia. Serum levels of interleukin-6, tumor necrosis factor alpha, and HMGB1 were determined at 3, 6, and 12 h after CLP; lung histology was assessed at 12 h. Histology results showed markedly reduced interstitial edema and leukocytic infiltration in lung tissue harvested at 12 h in ETS-GS-treated mice compared with untreated controls. ETS-GS treatment also attenuated the CLP induced increase in serum levels of cytokines and HMGB1. To investigate the mechanisms by which ETS-GS exerts its anti-inflammatory effects, the phosphorylation of Akt, IkappaBalpha, and mitogen-activated protein kinase (MAPK) was assessed in mouse macrophage RAW264.7 cells stimulated with LPS, with and without ETS-GS. In these in vitro studies, ETS-GS-induced phosphoinositide 3 kinase (PI3K)-Akt phosphorylation and inhibited IkappaBalpha and MAPK phosphorylation. ETS-GS blocked the CLP-induced septic shock response and protected against acute lung injury. This mechanism appeared to be mediated by the induction of PI3K-Akt and the inhibition of IkappaBalpha and MAPK phosphorylation. Given these results, ETS-GS shows promise as a potential therapeutic agent for sepsis. PMID- 21603973 TI - Expression profile and role of EphrinA1 ligand after spinal cord injury. AB - Spinal cord injury (SCI) triggers the re-expression of inhibitory molecules present in early stages of development, contributing to prevention of axonal regeneration. Upregulation of EphA receptor tyrosine kinases after injury suggest their involvement in the nervous system's response to damage. However, the expression profile of their ephrinA ligands after SCI is unclear. In this study, we determined the expression of ephrinA ligands after contusive SCI. Adult Sprague-Dawley female rats were injured using the MASCIS impactor device at the T10 vertebrae, and levels of ephrinA mRNA and protein determined at different time points. Identification of the cell phenotype expressing the ephrin ligand and colocalization with Eph receptors was performed with immunohistochemistry and confocal microscopy. Behavioral studies were made, after blocking ephrinA1 expression with antisense (AS) oligonucleotides, to assess hindlimb locomotor activity. Real-time PCR demonstrated basal mRNA levels of ephrin (A1, A2, A3, and A5) in the adult spinal cord. Interestingly, ephrinA1 was the only ligand whose mRNA levels were significantly altered after SCI. Although ephrinA1 mRNA levels increased after 2 weeks and remain elevated, we did not observe this pattern at the protein level as revealed by western blot analysis. Immunohistochemical studies showed ephrinA1 expression in reactive astrocytes, axons, and neurons and also their colocalization with EphA4 and A7 receptors. Behavioral studies revealed worsening of locomotor activity when ephrinA1 expression was reduced. This study suggests that ephrinA1 ligands play a role in the pathophysiology of SCI. PMID- 21603974 TI - The beta2-subtype of adrenoceptors mediates inhibition of pro-fibrotic events in human lung fibroblasts. AB - Fibrosis is part of airway remodelling observed in bronchial asthma and COPD. Pro fibrotic activity of lung fibroblasts may be suppressed by beta-adrenoceptor activation. We aimed, first, to characterise the expression pattern of beta adrenoceptor subtypes in human lung fibroblasts and, second, to probe beta adrenoceptor signalling with an emphasis on anti-fibrotic actions. Using reverse transcription PCR, messenger RNA (mRNA) encoding beta(2)-adrenoceptors was detected in MRC-5, HEL-299 and primary human lung fibroblasts, whereas transcripts for beta(1)- and beta(3)-adrenoceptors were not found. Real-time measurement of dynamic mass redistribution in MRC-5 cells revealed beta-agonist induced G(s)-signalling. Proliferation of MRC-5 cells (determined by [(3)H] thymidine incorporation) was significantly inhibited by beta-agonists including the beta(2)-selective agonist formoterol (-logIC(50), 10.2) and olodaterol ( logIC(50), 10.6). Formoterol's effect was insensitive to beta(1)-antagonism (GCP 20712, 3 MUM), but sensitive to beta(2)-antagonism (ICI 118,551; apparent, pA (2), 9.6). Collagen synthesis in MRC-5 cells (determined by [(3)H]-proline incorporation) was inhibited by beta-agonists including formoterol (-logIC(50), 10.0) and olodaterol (-logIC(50), 10.3) in a beta(2)-blocker-sensitive manner. alpha-Smooth muscle actin, a marker of myo-fibroblast differentiation, was down regulated at the mRNA and the protein level by about 50% following 24 and 48 h exposure to 1 nM formoterol, a maximally active concentration. In conclusion, human lung fibroblasts exclusively express beta(2)-adrenoceptors and these mediate inhibition of various markers of pro-fibrotic cellular activity. Under clinical conditions, anti-fibrotic actions may accompany the therapeutic effect of long-term beta(2)-agonist treatment of bronchial asthma and COPD. PMID- 21603975 TI - Global warming, plant paraquat resistance, and light signal transduction through nucleoside diphosphate kinase as a paradigm for increasing food supply. AB - Light signal transduction was studied in extracts of mycelia of the fungus Neurospora crassa, and the third internodes of dark-grown Pisum sativum cv Alaska. Both processes increased the phosphorylation of nucleoside diphosphate kinase (NDPK). NDPK may function as a carrier of reduction equivalents, as it binds NADH, thereby providing electrons to transform singlet oxygen to superoxide by catalases (CAT). As the C-termini of NDPK interact with CAT which receive singlet oxygen, emitted from photoreceptors post light perception (which is transmitted to ambient triplet oxygen), we hypothesize that this may increase phospho-NDPK. Singlet oxygen, emitted from the photoreceptor, also reacts with unsaturated fatty acids in membranes thereby forming malonedialdehyde, which in turn could release ions from, e.g., the thylacoid membrane thereby reducing the rate of photosynthesis. A mutant of Alaska pea, which exhibited two mutations in chloroplast NDPK-2 and one mutation in mitochondrial localized NDPK-3, was resistant to reactive oxygen species including singlet oxygen and showed an increase in the production of carotenoids, anthocyanine, and thereby could reduce the concentration of singlet oxygen. The reduction of the concentration of singlet oxygen is predicted to increase the yield of crop plants, such as Alaska pea, soybean, rice, wheat, barley, and sugarcane. This approach to increase the yield of crop plants may contribute not only to enhance food supply, but also to reduce the concentration of CO(2) in the atmosphere. PMID- 21603976 TI - ?(9)-Tetrahydrocannabinol decreases NOP receptor density and mRNA levels in human SH-SY5Y cells. AB - Several studies demonstrated a cross-talk between the opioid and cannabinoid system. The NOP receptor and its endogenous ligand nociceptin/orphanin FQ represent an opioid-related functional entity that mediates some non-classical opioid effects. The relationship between cannabinoid and nociceptin/NOP system is yet poorly explored. In this study, we used the neuroblastoma SH-SY5Y cell line to investigate the effect of delta-9-tetrahydrocannabinol (?(9)-THC) on nociceptin/NOP system. Results revealed that the exposure to ?(9)-THC (100, 150, and 200 nM) for 24 h produces a dose-dependent NOP receptor B (max) down regulation. Moreover, ?(9)-THC caused a dose-dependent decrease in NOP mRNA levels. The selective cannabinoid receptor CB1 antagonist AM251 (1-(2,4 dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3 carboxamide) reduces both effects, suggesting that ?(9)-THC activation of CB1 receptor is involved in the observed effects. These data show evidence of a cross talk between NOP and CB1 receptors, thus suggesting a possible interplay between cannabinoid and nociceptin/NOP system. PMID- 21603977 TI - Novel types of frontotemporal lobar degeneration: beyond tau and TDP-43. AB - Most cases of frontotemporal lobar degeneration (FTLD) are characterized by the abnormal accumulation of either the microtubule-associated protein tau or the transactive response DNA-binding protein with M(r) 43 kDa, TDP-43 (FTLD-tau and FTLD-TDP, respectively). However, there remain ~10% of cases, composed of a heterogenous collection of uncommon disorders, for which the molecular basis remains uncertain. In this review, we describe the characteristic genetic, clinical, and pathological features of the major tau/TDP-negative FTLD subtypes, with focus on recent advances in our understanding of their molecular basis. This includes the discovery that the pathological changes in atypical FTLD with ubiquitinated inclusions, neuronal intermediate filament inclusion disease, and basophilic inclusion body disease are immunoreactive for the fused in sarcoma (FUS) protein, resulting in the creation of a new molecular subgroup (FTLD-FUS), and studies clarifying the functional consequences of pathogenic CHMP2B mutations. PMID- 21603978 TI - FUS immunogold labeling TEM analysis of the neuronal cytoplasmic inclusions of neuronal intermediate filament inclusion disease: a frontotemporal lobar degeneration with FUS proteinopathy. AB - Fused in sarcoma (FUS)-immunoreactive neuronal and glial inclusions define a novel molecular pathology called FUS proteinopathy. FUS has been shown to be a component of inclusions of familial amyotrophic lateral sclerosis with FUS mutation and three frontotemporal lobar degeneration entities, including neuronal intermediate filament inclusion disease (NIFID). The pathogenic role of FUS is unknown. In addition to FUS, many neuronal cytoplasmic inclusions (NCI) of NIFID contain aggregates of alpha-internexin and neurofilament proteins. Herein, we have shown that: (1) FUS becomes relatively insoluble in NIFID and there are no apparent posttranslational modifications, (2) there are no pathogenic abnormalities in the FUS gene in NIFID, and (3) immunoelectron microscopy demonstrates the fine structural localization of FUS in NIFID which has not previously been described. FUS localized to euchromatin, and strongly with paraspeckles, in nuclei, consistent with its RNA/DNA-binding functions. NCI of varying morphologies were observed. Most frequent were the "loosely aggregated cytoplasmic inclusions," 81% of which had moderate or high levels of FUS immunoreactivity. Much rarer "compact cytoplasmic inclusions" and "tangled twine ball inclusions" were FUS-immunoreactive at their granular peripheries, or heavily FUS-positive throughout, respectively. Thus, FUS may aggregate in the cytoplasm and then admix with neuronal intermediate filament accumulations. PMID- 21603980 TI - Detection of Brk expression in non-small cell lung cancer: clinicopathological relevance. AB - Breast tumor kinase (Brk), also known as protein tyrosine kinase 6, is a nonreceptor tyrosine kinase containing SH3, SH2, and tyrosine kinase catalytic domains. Brk upregulation and oncogenic properties have been found in several malignant tumors, including breast, colon carcinomas, and melanomas, but the expression of Brk and its clinical significance in non-small cell lung cancer (NSCLC) remains unclear. In the current study, we examined the expression of Brk and its correlation with clinicopathological features involving p53, ki67, and E cadherin status in NSCLC tissue using immunohistochemistry. We also used immunocytochemistry and immunofluorescent staining to examine the Brk expression and its subcellular localization in NSCLC cell lines, including LTE and H460. We further confirmed cytoplasmic and nucleus expression of Brk in LTE and H460 cells using Western blotting. The Brk expression in NSCLC cells was mainly found in cytoplasm (59/122, 48.4%) with some nucleus staining (17/122, 13.9%) with a total positive rate of 53.3% (65/122). Cytoplasmic Brk expression in NSCLC was higher than that in normal lung tissues (24/122, 19.7%) (P < 0.05). Increased cytoplasmic Brk expression in NSCLC was associated with large tumor size (>= 3 cm), lymph node metastasis, and advanced tumor-node-metastasis (TNM) stages (III and IV) (P < 0.05). Moreover, increased cytoplasmic Brk expression was positively associated with Ki67 status in NSCLC (P < 0.05). Reduced E-cadherin expression was also found to be associated with lymph node metastasis and advanced TNM stages (III and IV) in NSCLC (P < 0.05). Brk expression was not associated with E cadherin expression and P53 status in NSCLC (P > 0.05). The present findings indicate an increase of cytoplasmic Brk expression in NSCLC which may play a role in tumor development, including tumor expansion and lymph node metastasis in which Ki67, but not E-cadherin, and P53 status may be involved. PMID- 21603979 TI - ZIP2 and ZIP4 mediate age-related zinc fluxes across the retinal pigment epithelium. AB - Decreases in systemic and cellular levels of zinc (Zn(2+)) during normal aging correlate with several age-related pathologies including age-related macular degeneration. Zn(2+) homeostasis in tissues is not only dependent on dietary intake but also on optimal expression and function of its influx (ZIP) and efflux (ZnT) transporters. We recently showed that many of the Zn(2+) transporters are expressed by the retinal pigment epithelial (RPE) cells. In this study, we present evidence that RPE cells contain less endogenous Zn(2+) with increased aging and transport this ion vectorially with greater transport from the basal to apical direction. Expression of two Zn(2+) influx transporters, ZIP2 and ZIP4, is reduced as a function of RPE age. Gene silencing of ZIP2 and ZIP4 in RPE cells from young donors or their overexpression in cells from older donors confirms that these two transporters are essential in controlling Zn(2+) influx and sequestration in RPE cells. Both transporters are distributed on the basal surface of the RPE where they are likely to control Zn(2+) homeostasis in the outer retina. PMID- 21603981 TI - Gene polymorphisms involved in folate and methionine metabolism and increased risk of sporadic colorectal adenocarcinoma. AB - This pilot study has compared the polymorphic genotype frequencies of methylenetetrahydrofolate reductase (MTHFR A1298C and C677T), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), and thymidylate synthase (TS 2R/3R) in 113 patients with sporadic colorectal adenocarcinoma (SCA) and 188 healthy blood donors, used as matched controls. The aim was to assess the role of these genotypes in the increased risk of SCA among the southeastern Brazilian population. Carriers of genotype MTRR 66GG, or the combined variants MTHFR 1298AC + CC plus 677CT + TT, or MTHFR 677CT + TT plus MTR 2756AG + GG, or MTHFR 1298AC + CC plus 677CT + TT plus MTR 2756AG + GG, or yet, MTHFR 1298AC + CC plus 677CT + TT plus MTRR 66AG + GG, respectively, showed an increased risk of the order of 1.99-, 3.26-, 2.22-, 10.92-, and 14.88-fold of developing SCA when compared with carriers of the other studied polymorphic genotypes, whether in isolation or in combination. In addition, individuals with the MTHFR 677CT + TT or the MTR 2756AG + GG genotypes had a 2.12- and a 1.42-fold increased risks of SCA onset before 50 years of age. African-Brazilians with the MTRR 66GG genotype had a 1.98-fold increased risk of SCA while individuals with the MTR 2756AG + GG and the MTHFR 677CT + TT genotypes showed a 2.11- and a 1.62-fold increased risk of undifferentiated and advanced tumors at diagnosis, respectively. Carriers of genotype MTHFR 1298AC + CC or MTHFR 1298AC + CC plus MTRR 66AG + GG had a 1.42- and a 3.07-fold increased risk of rectal tumor, respectively. Additionally, carriers of MTHFR 677CT + TT or MTHFR 677CT + TT plus TS 2R/3R + 3R/3R had a 1.55 and a 5.39-fold increased risk for colon tumor, respectively, in comparison with carriers of the wild genotypes. These data suggest that all polymorphisms coding for folate and methionine-dependent enzymes, particularly when present in combination with other polymorphisms, have consistent roles in the increased risk of SCA among the southeastern population of Brazil. PMID- 21603982 TI - Genetic characterization of swine influenza viruses (H3N2) isolated from Minnesota in 2006-2007. AB - Triple-reassortant (TR) H3N2 swine influenza viruses (SIV) are a major cause of respiratory disease in swine worldwide, causing considerable morbidity and mortality. Continuous surveillance of circulating SIV strains is imperative for effective control and prediction of new emerging strains with interspecies transmission potential. The current study characterized SIV isolates from commercial swine population in USA (2006-2007). Nine isolates were completely sequenced, and the molecular evolution of all gene segments was analyzed. Phylogenetic analysis of the nine H3N2 viruses indicated that these strains belonged to cluster-IV of the human/swine/avian TR genotype, grouping with H3N2 viruses of turkey origin, while forming a separate sub-lineage from those of human and avian origin strains. Ten amino acid changes were observed at the major antigenic sites of HA1 region compared to the cluster-III reference strain, with differences in glycosylation sites. All the nine strains were antigenically related to the cluster-IV turkey strain than the cluster-III reference strain. The results of this study suggest that contemporary TR H3N2 strains circulating in North America share the same genetic constellation, thus maintaining the gene pool without any further event of genetic reassortment unlike swine-origin pandemic strain A/California/04/2009/H1N1. These findings strongly support the need for continuous surveillance and monitoring of genetic changes in SIV, to identify evolving strains that might pose a threat to human or animal health. PMID- 21603983 TI - Cancer worry among Norwegian male BRCA1/2 mutation carriers. AB - This qualitative study explored the experiences of Norwegian men after being identified as BRCA 1/2 mutation-positive. Only limited knowledge is available on this topic; therefore, the aim of this study was to gain a deeper insight from the men's own perspectives. Data were collected from in-depth interviews with 15 men and seven of their partners. The participants described fear of cancer development, and two main narrative patterns were identified: fear for their own health, including fear of developing cancer, and negative feelings about responsibility for others' health. The men expressed fear of developing cancer themselves and described a need for genetic risk information. They were also deeply concerned about how the mutation might affect their children and other relatives. There is a need for guidelines concerning genetic risk information and follow-up programs for male BRCA 1/2 mutation carriers. This study adds valuable contextual insights into their experiences of living with fear of cancer. PMID- 21603984 TI - The 32nd International Congress of the European Hernia Society, 6-9 October 2010, Istanbul, Turkey. PMID- 21603985 TI - Effects of benzalkonium chloride- and polyquad-preserved combination glaucoma medications on cultured human ocular surface cells. AB - INTRODUCTION: The aim of this study is to investigate potential adverse effects of fixed combination glaucoma medications preserved with either benzalkonium chloride (BAK) or Polyquad(r) (PQ; Alcon Research Ltd., Fort Worth, TX, USA) on cultured ocular epithelial cells. METHODS: Confluent cultures of human cornea and conjunctival cell lines were exposed for 25 minutes to different glaucoma medications as well as a range of concentrations of BAK (0.001%-0.050%). Balanced salt solution was used as the "live" control and a solution containing 70% methanol and 0.2% saponin was used as a "dead" control. The number of dead and live cells were determined via ethidium homodimer (Eth-1) and calcein acetoxymethyl ester (AM) fluorescence, respectively. RESULTS: The toxicity of the prostaglandin analog with beta-blocker timolol fixed-combination formulations preserved with BAK was different from that observed in the respective BAK concentrations. Travoprost plus timolol fixed combination with BAK performed better than its respective BAK concentration alone, while the latanoprost plus timolol fixed combination performed worse than its respective BAK concentration. Travoprost plus timolol fixed combination preserved with PQ had greater corneal and conjunctival cell survival than either the travoprost plus timolol fixed combination preserved with BAK or the latanoprost plus timolol fixed combination. CONCLUSION: Ocular surface side effects have previously been demonstrated with chronic, long-term exposure to intraocular-pressure-lowering medications containing the common preservative BAK. BAK alone has significant in-vitro cytotoxicity to cultured ocular epithelial cells. Substitution of BAK with PQ resulted in significantly higher percentages of live conjunctival and corneal cells. Further studies are needed to understand the clinical implications of these findings. PMID- 21603986 TI - Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy. AB - The dipeptidyl peptidase 4 (DPP-4) inhibitors comprise a promising new class of agent for the management of type 2 diabetes. They possess a range of physiological effects associated with improved glycemic control including stimulation of glucose-dependent insulin secretion and suppression of glucagon secretion, and lower blood glucose levels through different, but potentially complementary, mechanisms to standard oral therapies. Linagliptin is the latest DPP-4 inhibitor to complete pivotal phase 3 trials. The data show that linagliptin provides significant, clinically meaningful and sustained improvements in glycemic control, with an incidence of adverse events similar to placebo and an excellent tolerability profile. In addition, linagliptin has been shown to be weight neutral and, importantly, there was no increased risk of hypoglycemia attributed to linagliptin use in monotherapy or combination therapy with metformin or pioglitazone. A unique characteristic of linagliptin that differentiates it from other members of the class is its primarily nonrenal route of excretion. The linagliptin phase 3 program included several hundred patients with type 2 diabetes and different stages of renal disease and the data suggest that the drug would not need dose adjustment, regardless of the degree of renal impairment. There is a particular need for safe and effective therapeutic agents that can be used when renal function declines. Linagliptin has recently been approved by the US Food and Drug Administration and may find a place in therapy as a treatment option for the significant number of patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment. PMID- 21603987 TI - Recent advances in understanding the structure, function, and biotechnological usefulness of the hemoglobin from the bacterium Vitreoscilla. AB - The hemoglobin from the bacterium Vitreoscilla (VHb) is the first microbial hemoglobin that was conclusively identified as such (in 1986). It has been extensively studied with respect to its ligand binding properties and mechanisms, structure, biochemical functions, and the mechanisms by which its expression is controlled. In addition, cloning of its gene (vgb) into a variety of heterologous hosts has proved that its expression results substantial increases in production of a variety of useful products and ability to degrade potentially harmful compounds. Recent studies (since 2005) have added significant knowledge to all of these areas and shown the broad range of biotechnological applications in which VHb can have a positive effect. PMID- 21603988 TI - Treatment of acute radiodermatitis with an oil-in-water emulsion following radiation therapy for breast cancer: a controlled, randomized trial. AB - BACKGROUND: A side effect of radiotherapy for breast cancer is acute radiodermatitis. It is a common practice to keep irradiated skin dry on account of data from the 1950s that suggested this regimen limits dermatitis. However, severe dryness of the skin induced by irradiation results in itching and discomfort. Dry skin is characterized by scaliness, epidermal barrier dysfunction, and reduced stratum corneum hydration, and these signs and symptoms are reduced by treatment with an emulsion. PATIENTS AND METHODS: We performed a randomized, controlled, open-label study with 66 patients (ITT population), treating the irradiated skin in one group (n = 34) with an oil-in-water emulsion (WO1932), while leaving the other group untreated (n = 32). Clinical scoring (ONS radiation skin reaction scoring, pruritus) and biophysical measurements (stratum corneum hydration and transepidermal water loss (TEWL), as a marker of skin barrier function) were determined at day 1 (directly after termination of the radiation therapy), day 8, and day 47 (+/- 7). RESULTS: Irradiation increased the ONS score and pruritus, whereas skin hydration and TEWL were reduced. The primary hypothesis that the increase in skin hydration was significantly greater in the emulsion-treated compared to the untreated group as early as after 8 days of treatment could not be confirmed. At the end of the study (day 47 +/- 7), however, normalization of stratum corneum hydration was more advanced in the treatment group compared to the untreated group and nearly reached the values of the contralateral healthy breast skin. ONS score and pruritus also revealed an advantage for the emulsion-treated group. TEWL did not show significant changes during emulsion treatment. No adverse events were caused by the treatment regimens CONCLUSION: Treatment of radiodermatitis with an oil-in-water emulsion was well tolerated, enhanced stratum corneum hydration, improved clinical indicators, and provided relief from itching. PMID- 21603990 TI - Incidence of dermatitis in head and neck cancer patients treated with primary radiotherapy and cetuximab. AB - PURPOSE: To retrospectively assess the incidence of radiation dermatitis in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who received primary radiotherapy in combination with cetuximab in a curative intent. PATIENTS AND METHODS: A total of 112 consecutively treated patients who received cetuximab in combination with radiotherapy at the Departments of Radiotherapy at the Medical University in Vienna and the Hospital Hietzing (Vienna) were analyzed. Radiotherapy was administered either as conventional radiotherapy (70 Gy in 7 weeks) or using a concomitant boost protocol (72 Gy in 6 weeks). The incidence of dermatitis and mucositis within the radiation portals in 103 eligible patients was compared with a historical control group treated at the Medical University of Vienna as well as with published data. RESULTS: The incidence of grade 1/2, 3, and 4 dermatitis was 57%, 29%, and 1% in the radiotherapy plus cetuximab treated collective. The incidence of grade 1/2, 3, and 4 mucositis was 37%, 47%, and 4%, respectively. The incidence of grade 3 dermatitis during concurrent radiotherapy plus cetuximab was 29% in our patient collective. Only one case of grade 4 dermatitis was observed. CONCLUSION: These results do not statistically differ significantly from the incidence reported in the Bonner trial and indicate that cetuximab in combination with radiotherapy is well tolerated. PMID- 21603989 TI - Interobserver variability of clinical target volume delineation in supra diaphragmatic Hodgkin's disease: a multi-institutional experience. AB - BACKGROUND: To determine interobserver variability in clinical target volume (CTV) of supra-diaphragmatic Hodgkin's lymphoma. MATERIALS AND METHODS: At the 2008 AIRO (Italian Society of Radiation Oncology) Meeting, the Radiation Oncology Department of Chieti proposed a multi-institutional contouring dummy-run of two cases of early stage supra-diaphragmatic Hodgkin's lymphoma after chemotherapy. Clinical history, diagnostics, and planning CT imaging were available on Chieti's radiotherapy website (www.radioterapia.unich.it). Participating centers were requested to delineate the CTV and submit it to the coordinating center. To quantify interobserver variability of CTV delineations, the total volume, craniocaudal, laterolateral, and anteroposterior diameters were calculated. RESULTS: A total of 18 institutions for case A and 15 institutions for case B submitted the targets. Case A presented significant variability in total volume (range: 74.1-1,157.1 cc), craniocaudal (range: 6.5-22.5 cm; median: 16.25 cm), anteroposterior (range: 5.04-14.82 cm; median: 10.28 cm), and laterolateral diameters (range: 8.23-22.88 cm; median: 15.5 cm). Mean CTV was 464.8 cc (standard deviation: 280.5 cc). Case B presented significant variability in total volume (range: 341.8-1,662 cc), cranio-caudal (range: 8.0-28.5 cm; median: 23 cm), anteroposterior (range: 7.9-1.8 cm; median: 11.1 cm), and laterolateral diameters (range: 12.9-24.0 cm; median: 18.8 cm). Mean CTV was 926.0 cc (standard deviation: 445.7 cc). CONCLUSION: This significant variability confirms the need to apply specific guidelines to improve contouring uniformity in Hodgkin's lymphoma. PMID- 21603991 TI - Effectiveness of postoperative radiotherapy in patients with small oral and oropharyngeal squamous cell carcinoma and concomitant ipsilateral singular cervical lymph node metastasis (pN1) : A meta-analysis. AB - BACKGROUND: The positive effect of radiation therapy for patients with advanced oropharyngeal squamous cell carcinoma (OSCC) has been substantially verified. The present work investigated whether a meta-analysis of current data is able to evaluate the effectiveness of postoperative radiotherapy (PORT) in patients with small OSCC (pT1, pT2) and a single ipsilateral lymph node metastasis (pN1). METHODS: The meta-analysis comprises randomized and non-randomized studies. High risk tumors were excluded and defined by size >= pT3/pT4, lymph node involvement >= pN2, or presence of additional histological risk factors, e.g., involved positive resection margins, extra nodal spread of the disease, or lymphangiosis carcinomatosa. The primary outcome analyzed mortality between the different treatment arms. RESULTS: Only one prospective randomized clinical trial and six retrospective observational studies were adequate for evaluation. Descriptive analysis revealed a marginally higher mortality in the irradiation group (44% vs. 34%). In contrast, a forest plot presentation of two of seven studies with and without events in the control and therapy arms presented an advantage for the irradiation group with the limitation of large heterogeneity and a lack of statistical significance. CONCLUSION: Present data are poor and exhibit limited internal and external validity; thus, direct comparison was not possible with the eligible studies. Therefore, a meta-analysis of present data may not serve as the basis for a general treatment recommendation but underlines the need of prospective, randomized, controlled clinical trials. PMID- 21603992 TI - Adjuvant chemoradiation after laparoscopically assisted vaginal radical hysterectomy (LARVH) in patients with cervical cancer: oncologic outcome and morbidity. AB - PURPOSE: Compared to laparotomic surgery, laparoscopically assisted radical vaginal hysterectomy (LARVH) offers decreased blood loss during surgery and faster convalescence of the patient postoperatively, while at the same time delivering similar oncologic results. However, there is no data on outcome and toxicity of LARVH followed by (chemo)radiation. PATIENTS AND METHODS: A total of 55 patients (range 28-78 years) with cervical cancer on FIGO stages IB1-IIIA (Tables 1 and 2) with risk factors were submitted to either external beam radiotherapy alone [EBRT, n = 8 (14%), including paraaortic irradiation, n = 4 (2.2%); EBRT and brachytherapy (BT), n = 33 (60%); BT alone, n = 14 (25.5%)] or chemoradiation after LARVH. RESULTS: At a median follow-up of 4.4 years, the 5 year disease-free survival (DFS) was 81.8% with 84.5% overall survival (OS). Acute grade 3 side effects were seen in 4 patients. These were mainly gastrointestinal (GI) and genitourinary (GU) symptoms. Grade 4 side effects were not observed. CONCLUSION: With similar oncologic outcome data and mostly mild side effects, LARVH followed by (chemo)radiation is a valid alternative in the treatment of cervical cancer patients. PMID- 21603993 TI - Advantage of robotic needle placement on a prostate model in HDR brachytherapy. AB - PURPOSE: To compare the accuracy of the robot-assisted needle positioning with that of the conventional template-guided method with the help of a prostate model in high dose rate (HDR) brachytherapy. MATERIALS AND METHODS: A prostate model of fresh porcine abdomen and special polyvinylchloride (PVC) sheets was developed. To verify the model, deviations from 311 needle placements of real prostate implants were analyzed. Second, the accuracy of the template-guided positioning versus robot-assisted positioning was measured with 20 needle insertions in the model. For robot-assisted positioning, different velocities (2.7, 5.4, 9.8 mm/s) of needle insertion were investigated. RESULTS: The average needle positioning accuracies of manual template guidance on the model closely resembled those of real patients (approximately 3 mm). The average needle positioning accuracy for the robot-assisted method on the prostate model was 1.8 +/- 0.6 mm, at a velocity of 2.7 mm/s and, in comparison to the template-guided method (2.7 +/- 0.7 mm), was statistically more precise (p < 0.001). At higher robotic velocities, the measured needle positioning accuracy showed no significant difference from that of the manual insertion procedure. CONCLUSION: By employing a prostate model, we showed for the first time that robot-assisted needle placement for HDR brachy therapy is significantly more precise than the conventional method at a velocity of 2.7 mm/s. The robot-assisted needle positioning technique improves the degree of freedom by providing additional oblique insertion channels and could be potentially exploited not only for LDR but also for HDR brachytherapy. PMID- 21603994 TI - Prospective study on the dose distribution to the acoustic structures during postoperative 3D conformal radiotherapy for parotid tumors: dosimetric and audiometric aspects. AB - BACKGROUND AND PURPOSE: To analyze dose distribution in the hearing organ and to evaluate the dose effect on the hearing thresholds in patients treated with post parotidectomy 3-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS: A total of 17 patients received post-parotidectomy 3D-CRT (median dose: 63 Gy). The audiometric evaluation comprised pure tone audiometry and tympanometry performed before radiotherapy (RT) and 3, 6, and 24 months after RT. The ear structures were delineated on planning computer tomography scans. Mean and maximum doses were calculated and dose-volume histograms were plotted. RESULTS: Before RT, the median baseline audiometric thresholds were normal. At 3 months post-RT, 3 patients were diagnosed as having middle ear underpressure and/or effusion that resolved completely by 6 months. During 2-year follow-up, none of the ears showed perceptive hearing loss at speech frequencies. The mean doses at ipsilateral external auditory canal, mastoids cells, tympanic case, Eustachian tube, semicircular canals, and cochlea were 44.8 Gy, 39.0 Gy, 30.9 Gy, 33.0 Gy, 19.6 Gy, and 19.2 Gy, respectively. The doses to the contralateral ear were negligible, except for the Eustachian tube (up to 28.2 Gy). CONCLUSION: Post parotidectomy 3D-CRT is associated with relatively low doses to the ear and the surrounding structures. Post-RT audiometry did not show any permanent (neither conductive nor perceptive) hearing impairment. Only in 3 patients were there signs of transient unilateral dysfunction of the Eustachian tube observed during the first few months after RT. Longer follow-up and larger patient series are warranted to confirm these preliminary findings. PMID- 21603995 TI - Polycyclic aromatic hydrocarbons in household dust near diesel transport routes. AB - A river-dredging project has been undertaken in Nantou, Taiwan. A large number of diesel vehicles carrying gravel and sand shuttle back and forth on the main roads. Ten stations along major thoroughfares were selected as the exposure sites for testing, while a small village located about 9 km from a main traffic route was selected as the control site. Levels of household dust loading at the exposure sites (60.3 mg/m(2)) were significantly higher than those at the control site (38.2 mg/m(2)). The loading (MUg/m(2)) of t-PAHs (total polycyclic aromatic hydrocarbons) in the household dust at the exposure sites was significantly higher (P < 0.05) than was the case at the control site. The diagnostic ratios of PAHs showed that diesel emissions were the dominant source of PAHs at the exposure sites. The lack of a significant correlation between the concentrations of Fe and t-PAHs suggested that the t-PAHs in household dust might come from diverse sources. However, a significant correlation (P = 0.003) between the concentrations of Mo and t-PAHs implied that the most of the t-PAHs in the household dust might have resulted from diesel emissions. The lifetime cancer risks of BaP(eq) from household dust exposure were markedly higher than those resulting from inhalation exposure. PMID- 21603997 TI - The biochemical, physiological and psychological consequences of a "1,000 miles in 1,000 hours" walking challenge. AB - The combined effects of 42 days of chronic sleep disruption and repeated hourly bouts of physical exertion have not been described. This case study reports the physiological and psychological demands placed on one individual who walked 1 mile in each consecutive hour for a period of 1,000 h (42 days), covering a total distance of 1,000 miles. The participant walked at a mean speed of 1.75 m/s completing each mile in approximately 15 min. Over the course of the challenge, the individual lost 1.6 kg in body weight. Markers of skeletal muscle damage, increased gradually whilst free testosterone levels decreased over the course of the challenge. Stress hormones increased whilst inflammatory markers (CRP) initially rose but then returned towards baseline over the course of the study. Cognitive motor performance measured via reaction time was maintained throughout the 42 days. The participant also displayed mood states typical of an elite athlete at baseline and throughout the challenge. Participation in this novel '1,000 mile 1,000 h' walking challenge evoked considerable physiological stress in a fit, healthy middle-aged participant but did not markedly alter cognitive performance or mood over the 42-day period. PMID- 21603996 TI - Production and characterization of interspecific somatic hybrids between Brassica oleracea var. botrytis and B. nigra and their progenies for the selection of advanced pre-breeding materials. AB - Somatic hybridization is a potential method for gene transfer from wild relatives to cultivated crops that can overcome sexual incompatibilities of two distantly related species. In this study, interspecific asymmetric somatic hybrids of Brassica oleracea var. botrytis (cauliflower) and Brassica nigra (black mustard) were obtained by protoplast fusion and their backcrossed (BC(3)) and selfed (S(3)) offspring were analyzed. Cytological analysis showed that the B. nigra chromosomes were successively eliminated in the backcrosses with cauliflower. The fertility of the hybrid progenies was quite different due to the asynchronous and abnormal chromosome behavior of pollen mother cells (PMC) during meiosis. Analysis of sequence-related amplified polymorphism (SRAP) showed that all of these hybrids mainly had the DNA banding pattern from the two parents with some alterations. Genetically, the selfed generations were closer to B. nigra, while the backcrossed generations were closer to the cauliflower parent. Analysis of cleaved amplified polymorphic sequences (CAPS) and restriction fragment length polymorphisms (RFLP) showed that all somatic hybrids in this study contained chloroplast (cp) DNA of the donor parent black mustard, while mitochondrial (mt) DNA showed evidence of recombination and variations in the regions analyzed. Furthermore, three BC(3) plants (originated from somatic hybrids 3, 4, 10) with 2 8 B. nigra-derived chromosomes shown by genomic in situ hybridization (GISH) displayed a more cauliflower-like morphology and high resistance to black-rot. These plants were obtained as bridge materials for further analysis and breeding. PMID- 21603998 TI - Role of left ventricular untwisting in diastolic dysfunction after long duration exercise. AB - Numerous studies have reported that long duration exercise induces transient left ventricular (LV) dysfunction. Using 2D-strain echocardiography, we aimed to describe cardiac mechanics following 2 h of exercise. We focused especially on LV twist since untwisting is crucial in the development of intraventricular pressure gradient, a key element of LV early filling. Twenty healthy males (20-41 years) underwent a resting echocardiography including a 2D-strain evaluation based on velocity vector imaging before and after 2-h of cycling at a moderate intensity. Measurements included LV longitudinal, radial and circumferential strains, and LV rotations and twist. After the prolonged exercise, the depressed diastolic function (peak E: 77.5 +/- 11.4 vs. 71.9 +/- 10.9, P < 0.01) was associated with a delay in peak untwisting velocity (110 +/- 14 vs. 119 +/- 14% of systolic duration, P < 0.05), whereas LV peak diastolic strain rates, indexes of LV relaxation, were unchanged. LV global systolic function and LV peak systolic strain rates remained normal after the exercise (fractional shortening: 36.8 +/- 2.8 vs. 36.9 +/- 5.7, NS). In conclusion, the present study gives new insight into cardiac dysfunction following long duration exercise. It demonstrates that depressed diastolic function is associated with delayed untwisting velocity, but depressed LV relaxation and contractility following exercise remains controversial. PMID- 21604000 TI - Confocal microscopy for modeling electron microbeam irradiation of skin. AB - For radiation exposures employing targeted sources such as particle microbeams, the deposition of energy and dose will depend on the spatial heterogeneity of the sample. Although cell structural variations are relatively minor for two dimensional cell cultures, they can vary significantly for fully differentiated tissues. Employing high-resolution confocal microscopy, we have determined the spatial distribution, size, and shape of epidermal keratinocyte nuclei for the full-thickness EpiDermTM skin model (MatTek, Ashland, VA). Application of these data to calculate the microdosimetry and microdistribution of energy deposition by an electron microbeam is discussed. PMID- 21603999 TI - Angiogenic activity of sera from pulmonary tuberculosis patients in relation to IL-12p40 and TNFalpha serum levels. AB - The role of angiogenesis in the pathogenesis of tuberculosis (TB) is not clear. The aim of this study was to examine the effect of sera from TB patients on angiogenesis induced by different subsets of normal human mononuclear cells (MNC) in relation to IL-12p40 and TNFalpha serum levels. Serum samples from 36 pulmonary TB patients and from 22 healthy volunteers were evaluated. To assess angiogenic reaction the leukocytes-induced angiogenesis test according to Sidky and Auerbach was performed. IL-12p40 and TNFalpha serum levels were evaluated by ELISA. Sera from TB patients significantly stimulated angiogenic activity of MNC compared to sera from healthy donors and PBS (p < 0.001). The number of microvessels formed after injection of lymphocytes preincubated with sera from TB patients was significantly lower compared to the number of microvessels created after injection of MNC preincubated with the same sera (p < 0.016). However, the number of microvessels created after the injection of lymphocytes preincubated with sera from healthy donors or with PBS alone was significantly higher (p < 0.017). The mean levels of IL-12p40 and TNFalpha were significantly elevated in sera from TB patients compared to healthy donors. We observed a correlation between angiogenic activity of sera from TB patients and IL-12p40 and TNFalpha serum levels (p < 0.01). Sera from TB patients constitute a source of mediators that participate in angiogenesis and prime monocytes for production of proangiogenic factors. The main proangiogenic effect of TB patients' sera is mediated by macrophages/monocytes. TNFalpha and IL-12p40 may indirectly stimulate angiogenesis in TB. PMID- 21604001 TI - Effects of 2-deoxyglucose and dehydroepiandrosterone on intracellular NAD(+) level, SIRT1 activity and replicative lifespan of human Hs68 cells. AB - 2-Deoxy-D-glucose (2-DG) and dehydroepiandrosterone (DHEA) have been hypothesized to extend lifespan via mimicking calorie restriction (CR). Activation of sirtuins has been proposed to contribute to life extension of CR by increasing intercellular levels of NAD(+) in several organisms. However, it is unclear whether 2-DG and DHEA may affect intracellular NAD(+) levels and human sirtuin 1 (SIRT1) activities. Here, using human fibroblast Hs68 cells we showed that 2-DG increased intracellular NAD(+) levels in both time- and concentration-dependent manners. 2-DG also dose-dependently increased SIRT1 activities and the lifespan (measured as the cumulated growth curve of population doubling levels) of Hs68 cells. In contrast, DHEA at non-cytotoxic concentrations (<=50 MUM) did not significantly affect NAD(+) levels, SIRT1 activities or the lifespan of Hs68 cells. These results suggest that 2-DG extends the lifespan of Hs68 cells by increased NAD(+) levels and SIRT1 activities, and that 2-DG has a potential as a CR mimetic. PMID- 21604002 TI - First-degree relatives of persons with type 1 diabetes: insulin resistance and enterovirus infection are associated with different patterns of islet cell autoimmunity. AB - Type 1 diabetes (T1D) results from the interaction of genetic and environmental factors. Previous studies indicate an association between detection of Enterovirus (EV) genome in blood and the clinical onset of T1D. Insulin resistance can also represent a risk factor for progression to clinically overt T1D. This study aimed at evaluating whether there is association between both EV infection and insulin resistance with islet autoantibodies in first-degree relatives of persons with type 1 diabetes. We collected sera from 94 first-degree relatives with (32) or without (64) islet cell antibodies (ICA) from the Cuban T1D prediction program. Blood glucose and insulin concentrations were determined. Antibodies to GAD65 and IA-2 were determined by radioimmunoassay. Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). EV-RNA was detected in serum using a highly sensitive reverse transcriptase-polymerase chain reaction method. The occurrence of EV-RNA was higher in ICA-positive relatives than in ICA-negative ones [15.6% (5/32) vs. 1.6% (1/62), P = 0.016]. GAD65 autoantibodies were more frequent in subjects with insulin resistance [34.5% (10/29) vs. 13.9% (9/65), P = 0.028] as defined by the HOMA-IR value. GAD65 autoantibodies also positively correlated with HOMA-IR (r.bis = 0.28, P < 0.01). IA-2 autoantibodies did correlate neither with EV-RNA nor with insulin resistance. There was no association between the presence of EV-RNA and insulin resistance. Our data suggest that enterovirus infection and insulin resistance are two independent events associated with ICA and GAD65 autoantibodies, respectively. These observations support the multifactorial nature of T1D. PMID- 21604003 TI - Carotid artery intima-media thickness and elasticity in relation to glucose tolerance. AB - The association between diabetes and subclinical atherosclerosis is well established. The effect of non-diabetic glucose intolerance on early atherosclerosis is not as straightforward, and the data regarding sex-related differences in this matter are limited. Therefore, our aim was to investigate these associations in men and women separately. We studied 1,304 Finnish men and women over 45 years of age who participated in the Finnish Health 2000 Survey. Ultrasonically determined carotid artery intima-media thickness and elasticity were used as markers of early atherosclerosis. Glucose tolerance was categorized according to the American Diabetes Association criteria for diabetes mellitus. Age-adjusted means for carotid artery intima-media thickness and elasticity indices were significantly (P < 0.05) associated with glucose tolerance status in both sexes. There was a trend of increasing early atherosclerosis with the worsening of glucose tolerance in men and women. These associations were weakened in both sexes after further adjustments for other cardiovascular risk factors. In women, but not in men, significant (P < 0.05) associations between glucose tolerance status and carotid artery elasticity were seen even after these further adjustments. Diabetes and non-diabetic glucose intolerance are associated with increased early carotid atherosclerosis compared with normal glucose tolerance in both sexes. Our results suggest that women with glucose intolerance may be in greater risk than men. PMID- 21604004 TI - Background sound modulates the performance of odor discrimination task. AB - Even though we often perceive odors in the presence of various background sounds, surprisingly little is known about the effects of background sound on odor perception. This study aimed to investigate the question whether background sound can modulate performance in an odor discrimination task. In Experiment 1, participants were asked to perform the odor discrimination task while listening to either background noise (e.g., verbal or non-verbal noise) or no additional sound (i.e., silent condition). Participants' performance in the odor discrimination task was significantly deteriorated in the presence of background noise compared with in the silent condition. Rather, the detrimental effect of verbal noise on the task performance was significantly higher than that of non verbal noise. In Experiment 2, participants were asked to conduct the odor discrimination task while listening to either background music (Mozart's sonata for two pianos in D major, K448) or no additional sound (silent condition). Background music relative to silent condition did not significantly alter the task performance. In conclusion, our findings provide new empirical evidence that background sound modulates the performance in an odor discrimination task. PMID- 21604005 TI - Decreased selenium levels after peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine tumours: implications for the antioxidant status. PMID- 21604006 TI - Effects of diabetes mellitus on the rat liver during the postmenopausal period. AB - The present study investigated whether diabetes worsened the onset of liver injury/damage during the ovariectomized (OVX)-induced postmenopausal period in rats. Diabetes results in severe complications in humans, such as liver failure. Estrogen and its derivatives are medically acceptable, powerful antioxidant agents that can enable liver and other important organs to defend themselves against oxidative related injury. Estrogen deficiency, which occurs in the postmenopausal period and in individuals with diabetes, may play a significant role in the progression of liver failure. In the present study, rats were divided into four groups: control (Group I), diabetic (Group II), ovariectomy (Group III) and ovariectomy plus diabetes (Group IV). After the experiments, quantitative histopathological and immunohistochemical changes in liver were detected using light microscopy and modern stereological systems. Histopathological examinations showed that there were many necrotic and apoptotic hepatocytes in the lobules of Group II. In addition, there were a larger number of necrotic cells in Group III than Group II. In contrast to Group II, there were also apoptotic cells in the portal areas in Group III. Moreover, evidence of liver injury was higher in the sections of Group IV compared with all other groups. In biochemical findings, there were statistically significant differences between all the groups (P < 0.001) for catalase (CAT), glutathione peroxidase (GSH) and myeloperoxidase (MPx) activity. In addition, the amount of lipid peroxidation (LPO) was significantly different between groups. In stereological results, there were significant differences between Groups I and II and Groups II and IV. The present study provided novel insight into the pernicious effects of ovariectomy on liver injury following the onset of diabetes. Indeed, the present study found that increases in liver oxidative activity in OVX rats following the onset of diabetes correlates with elevated MPx, LPO and histopathological changes in rat liver. PMID- 21604007 TI - Late outcome following open surgical management of secondary aortoenteric fistula. AB - OBJECTIVE: We reviewed the perioperative and long-term outcomes after the surgical management of secondary aortoenteric fistulas. METHOD: Over a 20-year period (1989-2009), 48 patients (33 men and 15 women; mean age, 64 years) were treated for secondary aortoenteric fistulas (SAEF). Most of the patients presented with symptoms of gastrointestinal bleeding (42 cases), or of serious septicaemia and general septic conditions (19 cases). Twenty-eight patients (58.3%) required an emergency procedure and were admitted with an unstable hemodynamic status. Repairs were accomplished by graft removal and an axillobifemoral bypass (n = 11), in situ reconstruction with a silver-impregnated prosthetic replacement (n = 21), a Dacron graft replacement (n = 7), a cryopreserved homograft replacement (n = 8) or an in situ deep vein replacement (n = 2). RESULTS: Early perioperative (<30 day) mortality was 45.8%. There was a significant difference in the mortality rates between patients who had an emergency procedure (59.2%) and patients who underwent urgent (38.0%) operations (p < 0.04). The average follow-up period was 48.6 +/- 16 months. There were eight late deaths; three of which were related to the SAEF treatment. The cumulative mortality rate was 34% at 3 years. The in situ silver graft replacement group cumulative survival rate was 72% at 3 years. No significant difference was observed in mortality on the complete or partial graft removal. Six late graft failures occurred; four of them resulted in amputation and three of them were associated with a recurrent infection. Freedom from amputation was 76.5% at both 3 and 5 years. Late infections occurred in six patients. Freedom from recurrent infection was 80.8% and 81.4% at 3 years in the whole study group and in the in situ silver graft group, respectively. The infect free rate at 3 years was the same compared the complete or partial graft removal CONCLUSION: The long-term outcomes associated with aortoenteric fistula repair might be favourable when silver-impregnated grafts were used as an in situ strategy. The eradication of infection is possible in mid-term follow-up with partial graft replacement, which associated with a lesser operative load. PMID- 21604008 TI - Bisphosphonate prescribing, persistence and cumulative exposure in Ontario, Canada. AB - We studied new users of oral bisphosphonates and found that less than half persisted with therapy for 2 years, and interruptions in use were common. During a median observation period of 4.7 years, 10% of patients filled only a single prescription, 37% switched therapies and median cumulative exposure was 2.2 years. INTRODUCTION: We sought to describe bisphosphonate prescribing, persistence and cumulative exposure among seniors in Ontario, Canada. METHODS: We used Ontario Drug Benefit pharmacy claims to identify residents aged >= 66 years who initiated oral bisphosphonate therapy between April 1996 and March 2009. The first date of bisphosphonate dispensing was considered the index date. Persistence with therapy was defined as continuous treatment with no interruption exceeding 60 days. We examined persistence with therapy and the number of extended gaps (>60 days) between prescriptions over time periods ranging from 1 to 9 years. We also identified the proportion of patients filling only a single prescription and switching to a different bisphosphonate, and calculated the median days of exposure irrespective of gaps in therapy. RESULTS: A total of 451,113 eligible new bisphosphonate users were identified: mean age = 75.6 years (SD = 6.9), 84% female, and median follow-up length = 4.7 years. Persistence with therapy declined from 63% at 1 year to 46% at 2 years and 12% at 9 years. Among those with at least 5 years of follow-up (n = 213,029), 61% had one or more extended gaps in bisphosphonate therapy. Overall, 10% of patients filled only a single prescription, 37% switched to a different bisphosphonate and the median exposure was 2.2 years. CONCLUSION: Less than half of patients persisted with bisphosphonate therapy for 2 years and interruptions in therapy were common, with most patients experiencing two or more >60-day gaps in therapy. Interventions are needed to improve persistence with bisphosphonate therapy and reduce the frequency of gaps in treatment. PMID- 21604010 TI - Retraction Note: The influence of a balanced volume replacement concept on inflammation, endothelial activation, and kidney integrity in elderly cardiac surgery patients. PMID- 21604011 TI - Retraction Note: Noninvasive assessment of cardiac output using thoracic electrical bioimpedance in hemodynamically stable and unstable patients after cardiac surgery: a comparison with pulmonary artery thermodilution. PMID- 21604009 TI - Bone health in multiple sclerosis. AB - People who are disabled with multiple sclerosis (MS) may be at increased risk of osteoporosis. This review discusses issues relevant to bone health in MS and makes practical recommendations regarding prevention and screening for osteoporosis and fracture risk in MS. A search of the literature up until 5 April 2011 was performed using key search terms, and articles pertinent to bone health in MS were analysed. Bone mineral density (BMD) is reduced at the lumbar spine, hip and total body in MS, with the degree of reduction being greatest at the hip. A strong relationship exists between the disability level, measured by the Expanded Disability Status Score, and BMD at the lumbar spine and femoral neck, particularly the latter. The rate of loss of BMD also correlates with the level of disability. Pulsed corticosteroids for acute episodes of MS, even with a high cumulative steroid dose, do not significantly affect BMD, but an effect on fracture risk is yet to be elucidated. There appears to be no correlation between vitamin D levels and BMD, and the relationship between disability and vitamin D levels remains unclear. Falls and fractures are more common than in healthy controls, and the risk rises with increasing levels of disability. The principal factor resulting in low BMD and increased fracture risk in MS is immobility. Antiresorptive therapy with bisphosphonates and optimising vitamin D levels are likely to be effective interventions although there are no randomised studies of this therapy. PMID- 21604012 TI - Retraction Note: Influence of different volume replacement strategies on inflammation and endothelial activation in the elderly undergoing major abdominal surgery. PMID- 21604013 TI - Retraction Note: Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: comparison of a new starch preparation with gelatin. PMID- 21604014 TI - Retraction Note: Prophylactic use of the phospodiesterase III inhibitor enoximone in elderly cardiac surgery patients: effect on hemodynamics, inflammation, and markers of organ function. PMID- 21604015 TI - Prognostic value of acquired uniparental disomy (aUPD) in primary breast cancer. AB - Many studies have examined DNA copy number changes or gene expression profiling and their association with clinical outcomes in breast cancer. However, until now no study has investigated whether acquired uniparental disomy (aUPD), in which both chromosomes in a pair are derived from the same parent, may have an association with clinical outcome including initiation and recurrence of breast cancer. In this study, we used high-density SNP and expression microarrays data from primary tumors of 313 lymph node-negative breast cancer patients who had not received adjuvant systemic therapy to evaluate the association of aUPD with metastasis-free survival (MFS) and overall survival (OS). In 55.9% (175/313) of the tumors, we defined aUPD, which was most frequent in the regions at chr17q (30.3%) and chr13q (19.4%). In Cox univariate regression analysis including all patients, aUPD at four regions at chr17q, ranging in size from 2.9 to 4.0 Mb, were associated with a poor OS. Only aUPD at one region, region B, on chr17q was associated with a poor MFS. Similarly, aUPD at two regions, A and B, on chr13q, with sizes of 3.5 and 3.1 Mb, were associated with a poor OS, but not with MFS. In ER-subgroup analyses, regions B and D at 17q were associated with poor MFS and OS in ER-negative patients. Various differentially expressed genes within the identified aUPD regions at chr17q were associated with MFS and OS in all patients (PPM1D, C17orf71, and TRIM37) and/or in the ER-negative patients (PPM1D, PPM1E, and SLCA3R1). We thus conclude that aUPD is a frequent event in breast cancer and that aUPD at specific regions in the genome has implications in this disease. PMID- 21604017 TI - The current role of contrast-enhanced ultrasound (CEUS) imaging in the evaluation of renal pathology. AB - BACKGROUND: By using a microbubble contrast agent and contrast-specific imaging software, the contrast-enhanced ultrasound (CEUS) is able to depict the micro and macrocirculation of the target organ. METHODS: A review of the peer reviewed literature was done regarding the current role of ultrasound CEUS imaging in the evaluation of renal pathology with reference to the diagnosis of renal ischaemia, in the characterization of complex cystic lesions and in those with equivocal enhancement at CT. RESULTS: CEUS provides information on tissue perfusion and may play a role in kidney mass characterization similar to the role of contrast enhanced CT and MRI. In this context, the characterization of cystic lesions is probably the most consolidated field of application of contrast agents on kidney ultrasound imaging. Finally, CEUS provides a good alternative to CT, especially in patients with contraindications to iodinated contrast agents. CONCLUSIONS: The usefulness of CEUS in these applications is confirmed by extensive literature production and this article focuses on the potential clinical applications of recent advances in CEUS technology in urology. PMID- 21604016 TI - Pathological characteristics of BRCA-associated breast cancers in Hispanics. AB - The immunophenotype of BRCA-associated breast cancer has been studied in predominantly non-Hispanic whites (NHW). We evaluated the pathological characteristics of BRCA-associated invasive breast cancer in Hispanics. A case control study was conducted on breast cancers from Hispanic and NHW women who enrolled in an IRB-approved registry and underwent BRCA gene analysis. BRCA negative controls (41 Hispanic, 39 NHW) were matched on age and ethnicity to BRCA positive cases (39 Hispanic, 35 NHW). A tissue array was constructed to characterize the expression of estrogen receptor (ER), progesterone receptor (PR), HER2, Ki-67 and p53 by immunohistochemistry. Mean age at diagnosis was 37.1 years (range 24-59) for Hispanics (80% with Mexican ancestry) and 40.1 years (range 21-63) for NHW (P = 0.03). Hispanic BRCA1 cases were more likely than BRCA negative controls to have tumors that were ER-negative (P < 0.001) and PR negative (P = 0.001), had higher levels of Ki-67 (P = 0.001) and p53 expression, and lower levels of HER2 overexpression. When stratified by genes, there were no significant differences in expression of ER, Ki-67, HER2, and p53 by ethnicity among mutation carriers. However, a significantly higher proportion of BRCA positive Hispanics had PR-negative tumors compared to BRCA-positive NHW (80 vs. 57%, OR = 2.9, 95% CI 1.0-8.1, P = 0.04). Hispanic BRCA-associated breast cancers were found to have the unique immunophenotype associated with BRCA mutations; however, there was a trend toward a difference in PR expression among Hispanic BRCA1 and BRCA2 cases. Additional research on the molecular mechanisms involved in the loss of PR in this population is warranted as it could have important implications for the treatment and prevention of breast cancer in Hispanics. PMID- 21604018 TI - Male genital tuberculosis: epidemiology and diagnostic. AB - INTRODUCTION: Urogenital TB (UGTB) is the second most common form of extrapulmonary TB (EPTB) in countries with severe epidemic situation and the third most common form in regions with low incidence of TB. Male genital TB (MGTB) seems to be a rare disease. Nevertheless, 77% of men who died from TB of all localizations had prostate TB that had mostly been overlooked during their life time. MATERIALS AND METHODS: A Medline/PubMed research with key words "male genital tuberculosis" was conducted. Estimates of incidence and spectrum of EPTB in Siberia are presented on the basis of statistical reports for 1999-2010. Additionally, the clinical features and laboratory findings of 310 patients with UGTB are reported. RESULTS: A Medline/PubMed research with key words "male genital tuberculosis" resulted in a total of 861 titles only. During the last decade, the incidence rate of TB in Siberia increased up to 20%. Every year in Siberia, there are about 1000 new EPTB patients; the proportion of UGTB decreased from 42.9 to 33.9%. Late diagnosed complicated forms predominated. CONCLUSION: In Siberia, there is still a severe epidemic situation now. Low living standard, poverty, as well as poor knowledge lead to late diagnosis of EPTB with complicated multi-organ forms. PMID- 21604019 TI - Preoperative radiographic parameters predict long-term renal impairment following partial nephrectomy. AB - PURPOSE: We analyzed radiographic parameters describing anatomic features of renal tumors to identify preoperative characteristics that could help predict long-term decline in renal function following partial nephrectomy. METHODS: We retrospectively reviewed the records of 194 consecutive patients who underwent partial nephrectomy from January 2006 to March 2009 and analyzed a cohort of 53 patients for whom complete clinical, radiographic, and operative information was available. Computed tomography images were reviewed by a single radiologist. Radiographic criteria for describing renal tumor size and location included diameter, volume, endophytic properties, proximity to collecting system, anterior/posterior location, location relative to polar lines, and R.E.N.A.L. nephrometry score. Postoperative estimated glomerular filtration rate was calculated using the MDRD study group equation with serum creatinine at last follow-up. RESULTS: The median preoperative and postoperative GFR values were 75 (IQR 65-97) and 66 (IQR 55-84) mL/min/1.73 m(2), respectively. At a median follow up of 38 months, the median percentage decrease in GFR was 12%. On univariate analyses, tumor diameter (P = 0.002), tumor volume (P < 0.0001), nearness of tumor to collecting system (P = 0.017), and location relative to polar lines (P = 0.017) were associated with percentage decrease in GFR. Furthermore, higher R.E.N.A.L. nephrometry score was also associated with poorer renal functional outcomes following partial nephrectomy (P = 0.019). CONCLUSIONS: Anatomic features of renal tumors defined by preoperative radiographic characteristics correlate with the degree of renal functional decline after partial nephrectomy. Identification of these parameters may assist in patient counseling and clinical decision making following partial nephrectomy. Validation in larger prospective studies is necessary. PMID- 21604020 TI - Uselessness of radiological differentiation of oncocytoma and renal cell carcinoma in management of small renal masses. PMID- 21604021 TI - Cytotoxicity of the new antimetabolite-bisphosphonate (5-FdU-alendronate) in comparison to standard therapeutics on breast and ovarian cancer cell lines in the ATP tumor chemosensitivity assay. PMID- 21604023 TI - Ethical review of global short-term medical volunteerism. AB - Global short-term medical volunteerism is growing, and properly conducted, is a tool in the fight for greater global health equity. It is intrinsically "ethical" (i.e., it involves ethics at every step) and depends upon ethical conduct for its success. At present, ethical guidelines remain in their infancy, which presents a unique opportunity. This paper presents a set of basic ethical principles, building on prior work in this area and previously developed guidelines for international clinical research. The content of these principles, and the benchmarks used to evaluate them, remain intentionally vague and can only be filled by collaboration with those on-the-ground in local communities where this work occurs. Ethical review must additionally take into consideration the different obligations arising from the type of institution, type of intervention, and type of relationship involved. This paper argues that frequent and formalized ethical review, conducted from the beginning with the local community (where this community helps define the terms of debate), remains the most important ethical safeguard for this work. PMID- 21604022 TI - The context of ethical problems in medical volunteer work. AB - Ethical problems are common in clinical medicine, so medical volunteers who practice clinical medicine in developing countries should expect to encounter them just as they would in their practice in the developed world. However, as this article argues, medical volunteers in developing countries should not expect to encounter the same ethical problems as those that dominate Western biomedicine or to address ethical problems in the same way as they do in their practice in developed countries. For example, poor health and advanced disease increase the risks and decrease the potential benefits of some interventions. Consequently, when medical volunteers intervene too readily, without considering the nutritional and general health status of patients, the results can be devastating. Medical volunteers cannot assume that the outcomes of interventions in developing countries will be comparable to the outcomes of the same interventions in developed countries. Rather, they must realistically consider the complex medical conditions of patients when determining whether or not to intervene. Similarly, medical volunteers may face the question of whether to provide a pharmaceutical or perform an intervention that is below the acceptable standard of care versus the alternative of doing nothing. This article critically explores the contextual features of medical volunteer work in developing countries that differentiate it from medical practice in developed countries, arguing that this context contributes to the creation of unique ethical problems and affects the way in which these problems should be analyzed and resolved. PMID- 21604024 TI - A failure of TNFAIP3 negative regulation maintains sustained NF-kappaB activation in Sjogren's syndrome. AB - Sjogren's syndrome (SS) is characterized by the features of systemic autoimmunity and exocrine gland dysfunction and inflammation. Deregulated cytokine production is known to contribute to the etiology of SS but the underlying molecular mechanism is still remains to be unclear. TNF-alpha-induced protein 3 or TNFAIP3 is involved in the negative feedback regulation of nuclear factor-kappaB (NF kappaB) signaling in response to specific pro-inflammatory stimuli in different cell types. To define the contribution of TNFAIP3 to SS, the levels of TNFAIP3 expression in human salivary gland epithelial cells (SGEC) derived from active primary SS patients were analyzed. Histological analysis was performed on paraffin-embedded human Sjogren's samples and healthy tissues. In separate experiments, immunofluorescence staining, western blot analysis and quantitative real-time PCR for TNFAIP3 was conducted in SGEC from SS and healthy subjects. Our findings clearly demonstrate changes in levels of the protein and gene expression between healthy controls and SS patients, depicting a very weak positivity for TNFAIP3 in SS samples. TNFAIP3 was found down-regulated in SGECs derived from SS patients in comparison with controls, and the cells with down-regulated TNFAIP3 expression exhibited enhanced NF-kappaB activities. In addition, to investigate the role of TNFAIP3 in the activation of NF-kappaB, we depleted TNFAIP3 expression by siRNA in healthy SGEC after treatment with or without TNF-alpha. Intriguingly, the silencing of TNFAIP3 by its siRNA in healthy SGEC increased NF kappaB activation that could explain the deregulated cytokines production observed in SS. PMID- 21604025 TI - Multifaceted role of tocotrienols in cardioprotection supports their structure: function relation. AB - Tocotrienols are a class of vitamin E which modulates several mechanisms associated with cardioprotection, anti-cancer, anti-diabetic, and neuroprotection. Unlike other Vitamin E-like compounds, tocotrienols possess inimitable properties. Quite a lot of studies have determined the cardioprotective abilities of tocotrienols and have been shown to possess novel hypocholesterolemic effects together with an ability to reduce the atherogenic apolipoprotein and lipoprotein plasma levels. In addition, tocotrienol has been suggested to have an antioxidant, anti-thrombotic, and anti-tumor effect indicating that tocotrienol may serve as an effective agent in the prevention and/or treatment of cardiovascular disease and cancer. The bioactivity exhibited is due to the structural characteristics of tocotrienols. Rich sources of tocotrienols which include rice bran, palm oil, and other edible oils exhibit protective effect against cardiovascular disorders. The conclusions drawn from the early literature that vitamin E group of compounds provides an inevitable role in cardioprotection is sustained in many more recent studies. PMID- 21604026 TI - [Reimbursement. Case report: Medical implication as precondition for reimbursement by German health insurance on the example of HRpQCT diagnosis of osteoporosis]. AB - The main condition that has to be met for reimbursement is the medical implication of the chosen method. This issue is discussed based on the case of a 72-year-old patient suffering from osteoporotic fractures of the spine. Drug treatment of osteoporosis was observed with a high-resolution peripheral CT (HR pQCT/XtremeCT). A German court came to the conclusion that there is no added value of the procedure in comparison with the well-established DXA. Judges rejected the need for reimbursement in that particular case and ruled in favor of the insurance company, which had originally refused the refund. PMID- 21604027 TI - [Treatment practice in patients with isolated blunt splenic injuries. A survey of Swiss traumatologists]. AB - BACKGROUND: The non-operative management (NOM) of blunt splenic injuries has gained widespread acceptance. However, there are still many controversies regarding follow-up of these patients. The purpose of this study was to survey active members of the Swiss Society of General and Trauma Surgery (SGAUC) to determine their practices regarding the NOM of isolated splenic injuries. MATERIALS AND METHODS: A survey of active SGAUC members with a written questionnaire was carried out. The questionnaire was designed to elicit information about personal and facility demographics, diagnostic practices, in hospital management, preferred follow-up imaging and return to activity. RESULTS: Out of 165 SGAUC members 52 (31.5%) completed the survey and 62.8% of all main trauma facilities in Switzerland were covered by the sample. Of the respondents 14 (26.9%) have a protocol in place for treating patients with splenic injuries. For initial imaging in hemodynamically stable patients 82.7% of respondents preferred ultrasonography (US). In cases of suspected splenic injury 19.2% of respondents would abstain from further imaging. In cases of contrast extravasation from the spleen half of the respondents would take no specific action. For low-grade injuries 86.5% chose to admit patients for an average of 1.6 days (range 0-4 days) with a continuously monitored bed. No differences in post-discharge activity restrictions between moderate and high-grade splenic injuries were found. CONCLUSION: The present survey showed considerable practice variation in several important aspects of the NOM of splenic injuries. Not performing further CT scans in patients with suspected splenic injuries and not intervening in cases of a contrast extravasation were the most important discrepancies to the current literature. Standardization of the NOM of splenic injuries may be of great benefit for both surgeons and patients. PMID- 21604028 TI - [Penetrating laryngotracheal injury during a suicide attempt]. AB - The authors present a case of a 40-year-old man who intentionally stabbed himself several times in the trachea and larynx during a suicide attempt, and also inflicted other penetrating injuries of the stomach and liver upon himself. The preoperative examination using fiber-optic tracheoscopy and CT revealed only transection of the ligamentum cricothyroideum; the remaining two defects were discovered later, during the surgical revision. All three injuries were successfully treated with sutures, in one case using the transtracheal approach. PMID- 21604030 TI - [Injury to the median nerve after minimally invasive decompression: discrepancy between the surgical report and actual course of surgery]. AB - A 72-year-old man suffering from carpal tunnel syndrome had undergone minimally invasive decompression by using a SafeGuard(r) Mini-Open Carpal Tunnel Release System. After the operation the patient presented with a paraesthesia in the median nerve distribution. Two months later an operative revision was performed in another hospital. A partial transection of the median nerve and an incomplete release was seen. The surgeon of the first operation stated that detailed informed consent including the risk of iatrogenic nerve injury had been obtained. Furthermore he referred to the operative report, which mentioned the accuracy of the procedure without any problems or complications during surgery. The Arbitration Board stated that the operative report could not exculpate the surgeon because the findings of the operative revision disagreed with the first operative report. The expert opinion declared that the lesion was a result of an inaccurate operative procedure as the surgeon was not able to demonstrate an anatomical variation of the median nerve. PMID- 21604029 TI - [Urgency of neurosurgical interventions for severe traumatic brain injury]. AB - BACKGROUND: The aim of this study was to assess whether the time interval between accident and neurosurgical intervention has an influence on functional neurological outcome and mortality in severe traumatic brain injury (sTBI) or whether the further clinical course has already been determined by the initial severity of the injury. METHODS: Data were derived from the Trauma Registry of the German Society of Trauma Surgery. A total of 770 patients were identified who had undergone decompressive surgery, had an ISS >= 9 and for whom time of accident and start of surgery had been documented. To evaluate the possible influence of the time factor on outcome and mortality, these patients were subdivided into five groups according to time until decompression (I: < 2 h, II: 2-3 h, III: 3-6 h, IV: 6-24 h and V: > 24 h). Aside from mortality we analysed AIS, GCS, age and ISS in survivors and non-survivors. RESULTS: Complete data were available for 770 patients with sTBI (AIS skull >=3). The average age was 39.9 years and 71.6% were male. The average overall injury severity was reflected by an ISS score of 31.3 and the average AIS head score was 4.51. Of the 570 who underwent surgery in less than 6 h (groups 1-III), 33% died (188/570). Of the remaining 200 patients 40 died (20%). Mortality decreased throughout the groups (49 to 14%), as did the severity of the head injury (AIS 4.66 to 4.23); GCS on the other hand increased with the time between accident and surgery (5.9 to 8.8). CONCLUSION: We could not substantiate that reducing the time between accident and neurosurgical decompression could decrease mortality. It rather seems that the initial magnitude of brain damage determines prognosis and outcome after sTBI. The interval between the appearance of neurological symptoms (e.g. anisocoria) and neurosurgical intervention plays an important role and should be kept as short as possible. PMID- 21604031 TI - [Preparedness of hospital physicians for a mass casualty incident. A German survey amongst 7,700 physicians]. AB - INTRODUCTION: The bomb attacks in Madrid (2004) and London (2005) have increased awareness that terrorist attacks are also a real threat in Germany. Hospitals and health care providers should be prepared. METHODS: We distributed an anonymous online questionnaire to physicians working in trauma centers of different categories. The results were analyzed using descriptive statistical methods. RESULTS: The questionnaire was returned by 1,204 of 7,700 physicians. This reflects a response rate of 15.6%. Of the participants, 53.3% answered that their hospital had a disaster control plan and that they knew the content; 33.9% reported that their hospital had participated in a disaster training scenario. CONCLUSION: As only 53.3% of physicians in hospitals know their disaster control plan and only 33.9% of hospitals have participated in a disaster training scenario we conclude that more action is needed to increase awareness of the problem. Furthermore standardized training programs are needed to disseminate knowledge and skills in order to enable health care providers to face the occurrence of terroristic attacks in Germany. PMID- 21604032 TI - [Diagnosis and treatment of radiocarpal fracture dislocations]. AB - In contrast to the common intra- or extra-articular fractures of the distal radius, radiocarpal fracture dislocations are rare injuries. Concerning this issue, only a small number of publications can be found. Nevertheless, it is important to be informed about this injury since prompt operative treatment is often required and immobilization alone will not be sufficient. Sometimes, radiocarpal fracture dislocations are combined with carpal injuries. In such cases, both the radiocarpal dislocation and carpal injury have to be treated. Diagnostic difficulties can lead to misinterpretation or underdiagnosis. Insufficient reduction and fixation may result in joint incongruity and subsequent osteoarthritis. Reconstruction of the radiocarpal ligaments is a substantial part of operative treatment. PMID- 21604033 TI - [Control of diffuse bleeding in unstable pelvic fractures with compression plate packing: presentation of the surgical technique]. AB - Current recommendations on surgical management of unstable pelvic fracture with hemorrhagic shock include reduction and fixation, i.e., with a C-clamp and external fixator, angiographic embolization of injured pelvic arteries, and preferably extraperitoneal packing to control diffuse bleeding from the venous plexus and fracture site. However, the recently reported lethality at 40-60% remains seriously high. One possible reason could be the unsatisfactory efficiency of extraperitoneal packing in the case of a traumatically or surgically opened retroperitoneal compartment. In this paper, a new approach, so called compression plate packing, is proposed to control diffuse bleeding. In this technique, the essential pressure of the packing on the bleeding site is set up with small fragment plates with screw fixation to the pelvic ring. In two first clinical cases of severe pelvic trauma the hemorrhage could be controlled reliably. PMID- 21604034 TI - [Post-traumatic proximal radioulnar synostosis. Surgical technique and review of the literature]. AB - Synostosis of the radioulnar joint can appear after severe fractures of the elbow, which leads to distinctive limitation in forearm rotation. We describe a surgical technique according to Morrey in a case of a young girl with resection osteotomy of the proximal radius without excision of the synostosis. Different therapeutic options for post-traumatic proximal radioulnar synostosis are discussed on the basis of the current literature. PMID- 21604035 TI - [Occurrence of complex regional pain syndrome after intramedullary nailing of a clavicular shaft fracture]. PMID- 21604036 TI - [Appearance of complex regional pain syndrome after intramedullary nailing of a clavicle fracture]. AB - After operative correction of a clavicle fracture using an elastic stable intramedullary nail the patient presented signs of delayed fracture healing after 2 months. During the sixth postoperative month the 28-year-old obviously pain ridden female patient showed dystonia of the shoulder girdle and allodynia surrounding the operation field. Upon these findings, we decided - as a result of the complex regional pain syndrome that had not been previously described in this location - to treat the patient by administering bisphosphonates, multimodal analgetic therapy, physiotherapy and occupational therapy. Fourteen months after surgery, the patient showed no remaining symptoms, and the fracture had consolidated at that time. PMID- 21604037 TI - [Results after Judet radial head prosthesis for non-reconstructable radial head fractures]. AB - BACKGROUND: With regard to the treatment of non-reconstructable radial head fractures, both the resection and the implantation of a prosthesis are considered. Various studies have shown poor results concerning the resection of the radial head with accompanying osteoligamentous injuries. Due to these experiences, different types of prosthesis have been developed. However, the majority of them were not convincing. Judet developed a type of a bipolar prosthesis which had been modeled on the anatomy of the radial head. The aim of our retrospective study consists in examining the results of the Judet prosthesis. PATIENTS AND METHODS: Between 1995 and 2007, 50 patients were treated with an arthroplasty. These were, corresponding to the classification by McKee and Jupiter, 19 type III and 31 type IV fractures. Thirty patients were available for a follow-up after 2.5 years on average. RESULTS: According to the Morrey Score, 16 very good, 7 good, 3 fair and 4 bad results could be obtained. Following the criteria of Radin and Riseborough, 17 patients achieved a good, 9 a fair and 4 a bad result. The complications which appeared were: one patient with aseptic loosening, one patient with luxation of a prosthesis, one persistent radial joint instability, three patients with heterotopic ossification and four patients with protrusion relative to the capitulum humeri. PMID- 21604038 TI - [Fractures of the forefoot]. AB - Fractures of the forefoot are common and comprise approximately two thirds of all foot fractures. Forefoot fractures are caused by direct impact or the effect of indirect force. The forces exerted can range from repetitive minor load (stress fractures) to massive destructive forces (complex trauma). The clinical course in forefoot fractures is typically more favourable than in fractures of the mid- and hindfoot. The incidence of complications like infection or pseudarthrosis is low. Exceptions are rare fractures of the proximal shaft of the fifth metatarsal and the sesamoids with higher pseudarthrosis rates. Malunited metatarsal fractures can cause painful conditions that should even be treated operatively. Differences in structure and function of the different forefoot areas and specific fracture types require an adapted management of these special injuries. PMID- 21604039 TI - [Arthroscopic implant removal after fixed-angle plate osteosynthesis of the proximal humerus. Technique and initial results in comparison to open implant removal]. AB - BACKGROUND: Implant removal is necessary in up to 25% of patients with plate osteosynthesis after proximal humeral fracture. Our new technique of arthroscopic implant removal offers all the advantages of minimally invasive surgery. This study outlines the first results after arthroscopic implant removal in comparison with those of open implant removal. MATERIAL AND METHODS: Twenty patients [median age 64 (30-82) years] had arthroscopic and nine patients [median age 53 (34-76) years] had open implant removal. Median 9.5 months after implant removal subjective patient satisfaction, Constant-Murley Score (CMS) and Simple Shoulder Test (SST) were determined. RESULTS: Arthroscopic implant removal showed first results comparable to open implant removal. The SST outlined advantages for the arthroscopic technique. In 85% of arthroscopically treated patients concomitant intra-articular lesions were observed. CONCLUSION: Arthroscopic implant removal offers all the advantages of minimally invasive surgery and first results comparable to open implant removal. The subjective and objective satisfaction of the patients is high. The technique can be applied and established by all skilled arthroscopic shoulder surgeons. PMID- 21604040 TI - Breastfeeding-what do father's of first born know and think? PMID- 21604041 TI - Carbohydrate provision in the era of tight glucose control. AB - Glycemic control in the critically ill patient has remained a controversial issue over the last decade. Several large trials, with widely varying results, have generated significant interest in defining the optimal target for blood-glucose control necessary for improving care while minimizing morbidity. Nutritional support has evolved into an additional area of critical care where appropriate practices have been associated with improved patient outcomes. Carbohydrate provision can impact blood-glucose levels, and the relationship between nutrition and glucose levels has become more complex in the era of improved glycemic control. This review discusses the controversy surrounding intensive-insulin therapy in the intensive care unit and explores the relationship with nutritional support, both in the enteral and parenteral form. Achieving realistic goals in both carbohydrate provision and glycemic control may improve patient outcome, and are not mutually exclusive practices. PMID- 21604042 TI - The optimal lipid formulation in enteral feeding in critical illness: clinical update and review of the literature. AB - Suitable and timely early enteral nutrition is paramount to providing optimal patient care for the critically ill. Lipids serve many essential roles throughout the human body, and are important components of most enteral formulations. This paper reviews lipid structure, function, and optimal utility for this macronutrient in enteral feeds. The use of omega-3 fatty acids has become common in critical care formulations, and their clinical efficacy is outlined separately. Available evidence is reviewed, and future directions are discussed. PMID- 21604043 TI - Solitary epidural amyloidoma of C2-4 without osteolysis of the spine in a multiple myeloma patient. PMID- 21604044 TI - Histological finding of atypical subtrochanteric fracture after long-term alendronate therapy. PMID- 21604045 TI - Revision total hip replacement using a cementless interlocking distal femoral stem with allograft-cemented composite and the application of intramedullary and onlay cortical strut allografts: two case reports. PMID- 21604046 TI - Ligamentum flavum hematoma in the lumbar spine. PMID- 21604047 TI - Proteomic insights into cold adaptation of psychrotrophic and mesophilic Acidithiobacillus ferrooxidans strains. AB - Cold tolerant strains of Acidithiobacillus ferrooxidans play a role in metal leaching and acid mine drainage (AMD) production in northern latitude/boreal mining environments. In this study we used a proteomics and bioinformatics approach to decipher the proteome changes related to sustained growth at low temperatures to increase our understanding of cold adaptation mechanisms in A. ferrooxidans strains. Changes in protein abundance in response to low temperatures (5 and 15 degrees C) were monitored and protein analyses of a psychrotrophic strain (D6) versus a mesophilic strain (F1) showed that both strains increased levels of 11 stress-related and metabolic proteins including survival protein SurA, trigger factor Tig, and AhpC-Tsa antioxidant proteins. However, a unique set of changes in the proteome of psychrotrophic strain D6 were observed. In particular, the importance of protein fate, membrane transport and structure for psychrotrophic growth were evident with increases in numerous chaperone and transport proteins including GroEL, SecB, ABC transporters and a capsule polysaccharide export protein. We also observed that low temperature iron oxidation coincides with a relative increase in the key iron metabolism protein rusticyanin, which was more highly expressed in strain D6 than in strain F1 at colder growth temperatures. We demonstrate that the psychrotrophic strain uses a global stress response and cold-active metabolism which permit growth of A. ferrooxidans in the extreme AMD environment in colder climates. PMID- 21604048 TI - Interdisciplinary approach to a diachronic medical symbol of healing. PMID- 21604049 TI - Teamwork and team decision-making at multidisciplinary cancer conferences: barriers, facilitators, and opportunities for improvement. AB - BACKGROUND: Anecdotally, multidisciplinary cancer conferences (MCCs) do not always function optimally. MCC members' experiences with and attitudes toward MCCs are explored, and barriers to and facilitators of effective team-working are identified. METHODS: A total of 19 semistructured interviews were conducted with surgeons, oncologists, nurses, and administrators. Interviews explored participants' opinions on MCC attendance, information presentation, case discussion, leadership, team decision-making, and possible improvements to MCC meetings. RESULTS: Nonattendance was associated with not having protected time to attend the MCC. Contributions to MCC discussions were unequal among the participants, and patient-centered information was ignored. Good leadership was necessary to foster inclusive case discussion. Members were positive about MCCs, but protected time, improved case selection, and working in a more structured way were possible improvements. CONCLUSIONS: Results are consistent with previous research: Members of the MCC are positive about the benefits of MCCs, although improving the way MCCs work is a goal. PMID- 21604050 TI - Swan-Ganz catheter use in trauma patients can be reduced without negatively affecting outcomes. AB - OBJECTIVE: The use of pulmonary artery catheter (PAC) is controversial. The purpose of this study was to document the changing pattern of PAC use and to determine its effect on outcome. METHODS: The use of PAC was analyzed in patients >=16 years old admitted to the surgical intensive care unit (SICU) over a 9-year period starting in 2000. Patients with SICU length of stay exceeding 30 days were excluded. For the evaluation of PAC's effect on outcome, PAC and no-PAC patients were matched utilizing propensity scores. RESULTS: During the 9-year study period, a total of 5,192 trauma patients were admitted to the SICU. Of these, 426 (8.2%) were <16 years old, and 174 (3.4%) had a SICU length of stay that exceeded 30 days. For the remaining 4,592 patients, the mean +/- SD age was 39.5 +/- 18.8 years, and the mean ISS was 19.9 +/- 12.4. PAC was utilized in 19.5% (n = 896) of all the patients admitted to the SICU. The trend for PAC use decreased significantly over the years (P value for trend <0.001), from 38.6% in the year 2000 to 4.2% in the year 2008. This decrease was noted in all age and injury severity groups of patients. The overall mortality, however, remained at the same levels (P value for trend = 0.111). Patients managed with a PAC were significantly older, more severely injured, more frequently injured by a blunt mechanism, and were admitted more often in a hypotensive or comatose status. In the early part of the study, the PAC was utilized on the first day and for 4.1 days on average. In the later part of the study, however, the PAC was used on the second day and for a shorter period of time (3 days on average, P < 0.001). In the matched study population, patients in the PAC group had almost twofold higher odds for death, when compared to the no-PAC group [34.2% vs. 22.5%, Odds Ratio (95% CI): 1.78 (1.42, 2.26), P < 0.001]. Patients younger than 50 years of age who had an ISS >=16 had worse outcome when managed with a PAC, whereas patients aged 30-69 years with an ISS <16 had a higher survival. The overall complication rate was fivefold higher in patients receiving a PAC [46.3% vs. 14.2%, Odds Ratio (95% CI): 5.22 (4.04, 6.74), P < 0.001]. CONCLUSION: The use of PAC has decreased almost 10-fold over the last decade at our institution. The PAC is being used later during the ICU course and for a shorter period of time. In a matched population, the use of PAC is associated with a significantly higher mortality and complication rate, but the reason for this association remains uncertain. The use of PAC is invasive and is associated with known complications and financial costs. While the use of PAC maybe useful in a select population, routine and widespread use of the PAC should be avoided. PMID- 21604051 TI - Laparoscopic repair of duodenal atresia: revisited. AB - BACKGROUND: Since the initial reports of laparoscopic repair of duodenal atresia in neonates, further reports have been scant. Could this be because of unacceptable rates of complications, like anastomotic leakage, as mentioned in later reports? In the present study the laparoscopic repair of duodenal atresia in neonates is revisited. PATIENTS: Group 1 consisted of 22 patients with duodenal obstruction between 2000-2005 until the laparoscopic approach was abandoned. Of these 22 patients, 10 had Down syndrome and 8 had concomitant malformations. In this group 18 patients were operated laparoscopically. Four patients underwent an open procedure. Group 2 consisted of six patients that underwent operation between 2008 and February 2010. RESULTS: In group 1 there were four conversions. In 14 patients the procedure could be completed laparoscopically. In five patients postoperative leakage occurred. The complication rate was found to be unacceptably high, and the laparoscopic approach was abandoned. After gaining additional experience in intracorporeal suturing and adjusting the technique, the procedure was started up again in 2008. Since then six consecutive neonates have undergone laparoscopic repair of duodenal atresia without complications. CONCLUSIONS: Laparoscopic repair of duodenal atresia is one of the most demanding pediatric laparoscopic surgical procedures. After initial promising results at the beginning of the twenty-first century a relative "radio silence" followed, apparently caused by unsatisfactory results. Only considerable adjustments in technique and extensive improvement in experience has led to acceptable outcomes more recently. Laparoscopic repair of duodenal atresia should therefore be restricted to pediatric centers with extensive experience in laparoscopic surgery and intracorporeal suturing. PMID- 21604052 TI - An approach to give prospective life-span of the copper/low-density-polyethylene nanocomposite intrauterine device. AB - As a novel copper-containing intrauterine device (IUD), the prospective life-span of the copper/low-density-polyethylene (Cu/LDPE) nanocomposite IUD is very important for the future clinical use and should be given in advance. Here a novel approach, cupric ions accelerated release in diluted nitric acid solution and cupric ions concentration release in various volume of simulated uterine solution (SUS), is reported to verify the type of cupric ions release model of the cylindrical matrix-type nanocomposite IUD, and to obtain the minimal cupric ions release rate that need to ensure contraceptive efficacy and the thickness of copper particles exhausted layer of the cylindrical matrix-type nanocomposite IUD within two difficult immersion durations in experimental volume of SUS, respectively. Using these results, the prospective life-span of the cylindrical matrix-type nanocomposite IUD can be obtained. For instance, the prospective life span of the novel gamma-shape nanocomposite IUD with 25 wt% of copper nanoparticles and 2 mm of diameter and a total weight of 285 mg can be given in advance and it is about 5 years in the future clinical use. PMID- 21604054 TI - Hormesis associated with a low dose of methylmercury injected into mallard eggs. AB - We injected mallard (Anas platyrhynchos) eggs with methylmercury chloride at doses of 0, 0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 MUg mercury/g egg contents on a wet-weight basis. A case of hormesis seemed to occur because hatching success of eggs injected with 0.05 MUg/g mercury (the lowest dose) was significantly greater (93.3%) than that of controls (72.6%), whereas hatching success decreased at progressively greater doses of mercury. Our finding of hormesis when a low dose of methylmercury was injected into eggs agrees with a similar observation in a study in which a group of female mallards was fed a low dietary concentration of methylmercury and hatching of their eggs was significantly better than that of controls. If methylmercury has a hormetic effect at low concentrations in avian eggs, these low concentrations may be important in a regulatory sense in that they may represent a no-observed adverse effect level (NOAEL). PMID- 21604053 TI - A novel in vitro model for preclinical testing of the hemocompatibility of intravascular stents according to ISO 10993-4. AB - Subacute stent thrombosis, caused by undesired interactions between blood and the stent surface, is a major concern in the first few weeks following coronary artery stent implantation. The aim of this study was to establish a novel in vitro model for hemocompatibility testing of coronary artery stents according to ISO 10993-4. The model consists of a modified Chandler-Loop design with closed heparin-coated PVC Loops and a thermostated water bath. The tests were performed with anticoagulated human whole blood. After incubation in the loop, blood was analyzed for coagulation and inflammatory activation markers (TAT, beta-TG, sP selectin, SC5b-9 and PMN-elastase). Three different stent types with varying thrombogenicity were tested; statistically significant differences were found between the three stent types in measures of coagulation and platelet activation. The new Chandler-Loop model can be used as an alternative to animal and current in vitro models, especially for the determination of early events after stent implantation. PMID- 21604055 TI - Biosorption of Ni (II) by Schizosaccharomyces pombe: kinetic and thermodynamic studies. AB - The potential of the dried yeast, wild-type Schizosaccharomyces pombe, to remove Ni(II) ion was investigated in batch mode under varying experimental conditions including pH, temperature, initial metal ion concentration and biosorbent dose. Optimum pH for biosorption was determined as 5.0. The highest equilibrium uptake of Ni(II) on S. pombe, q (e), was obtained at 25 degrees C as 33.8 mg g(-1). It decreased with increasing temperature within a range of 25-50 degrees C denoting an exothermic behaviour. Increasing initial Ni(II) concentration up to 400 mg L( 1) also elevated equilibrium uptake. No more adsorption took place beyond 400 mg L(-1). Equilibrium data fitted better to Langmuir model rather than Freundlich model. Sips, Redlich-Peterson, and Kahn isotherm equations modelled the investigated system with a performance not better than Langmuir. Kinetic model evaluations showed that Ni(II) biosorption process followed the pseudo-second order rate model while rate constants decreased with increasing temperature. Gibbs free energy changes (DeltaG degrees ) of the system at 25, 30, 35 and 50 degrees C were found as -1.47E + 4, -1.49E + 4, -1.51E + 4, and -1.58E + 4 J mol( 1), respectively. Enthalpy change (DeltaH degrees ) was determined as -2.57E + 3 J mol(-1) which also supports the observed exothermic behaviour of the biosorption process. Entropy change (DeltaS degrees ) had a positive value (40.75 J mol(-1) K(-1)) indicating an increase in randomness during biosorption process. Consequently, S. pombe was found to be a potential low-cost agent for Ni(II) in slightly acidic aqueous medium. In parallel, it has been assumed to act as a separating agent for Ni(II) recovery from its aqueous solution. PMID- 21604056 TI - Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics. AB - Fragment Based Drug Discovery (FBDD) continues to advance as an efficient and alternative screening paradigm for the identification and optimization of novel chemical matter. To enable FBDD across a wide range of pharmaceutical targets, a fragment screening library is required to be chemically diverse and synthetically expandable to enable critical decision making for chemical follow-up and assessing new target druggability. In this manuscript, the Pfizer fragment library design strategy which utilized multiple and orthogonal metrics to incorporate structure, pharmacophore and pharmacological space diversity is described. Appropriate measures of molecular complexity were also employed to maximize the probability of detection of fragment hits using a variety of biophysical and biochemical screening methods. In addition, structural integrity, purity, solubility, fragment and analog availability as well as cost were important considerations in the selection process. Preliminary analysis of primary screening results for 13 targets using NMR Saturation Transfer Difference (STD) indicates the identification of uM-mM hits and the uniqueness of hits at weak binding affinities for these targets. PMID- 21604057 TI - Care with regard to details improves the outcome of Longo mucoprolapsectomy: long term follow up. AB - In this study we evaluated the results of stapled hemorrhoidopexy considering the histological features of the resected tissue obtained after the intervention, the staple line height and the improvement of the quality of life after the treatment. From January 2003 to December 2006, 72 patients with symptomatic grade 3 and 4 hemorrhoid that underwent stapled hemorrhoidopexy in our clinic were enroled in the study. Preoperative, intraoperative and postoperative characteristics of the patients were evaluated, including demographics, staple line height, specimen histology, complications, recurrence, day to return to work, quality of life (QoL) score and use of analgesics. Staple line height was always above 2.5 cm from the dentate line. Smooth muscle fibers were observed in 97.2%. The complication rate was 18%. Bleeding was observed in 5.5%. Fecal urgency was referred in 6.9%. Recurrence rate was 6.9%. Mean follow-up was 68 months. Hemorrhoidopexy is safe and effective but extreme attention must be paid to some critical details. We consider the placement of the purse string suture as a critical factor in the outcome of the patients. We find that some amount of the muscle fibers would invariably be involved in the resected specimen, without any significant impact in the clinical outcome or in the quality of life improvement. PMID- 21604058 TI - Mycobiota and mycotoxins contamination in raw materials and finished feed intended for fattening pigs production in eastern Argentina. AB - The aim of the present study was to determine the mycobiota and natural levels of mycotoxins such as zearalenone, fumonisin B(1), aflatoxin B(1) and ochratoxin A present in raw materials and finished fattening pig feed. Samples were examined for total fungi and genera distribution. Zearalenone, FB(1), AFB(1) and OTA contamination were determined using high pressure liquid chromatography and thin layer chromatography. Milled maize and finished feed samples showed fungal contamination over than 1 * 10(4) CFU/g. All samples contained at least one of the main mycotoxigenic genera Aspergillus, Fusarium and Penicillium. A. flavus and F. verticillioides were the most prevalent species. Only some Aspergillus section Nigri strains from suckling pig to growing pig samples were able to produce OTA. A. flavus strains from milled maize, wheat bran, suckling pig to growing pig samples were able to produce AFB(1). All samples were positive for FB(1). Sucking pig, piglet, growing and boar feed samples showed ZEA natural contamination. AFB(1) and OTA contamination were not detected. There was a 100% correlation between FB(1) and ZEA contamination in sucking pig, piglet, growing and boar feed samples; 50% piglet samples and 67% suckling pig samples showed ZEA levels over the recommended limits. The present study has shown the occurrence of two mycotoxins, FB(1) and ZEA in feed intended for fattening pig consumption. In animal production, the simultaneous presence of toxicogenic fungi and low dietary levels of mycotoxins in field conditions can cause possible health impacts and lost performance in pigs from feeding spoiled feeds. PMID- 21604059 TI - Between hope and fear: patient's expectations prior to pelvic organ prolapse surgery. AB - INTRODUCTION AND HYPOTHESIS: The aim of our study was to analyse the patient's expectations (fears and goals (hopes)) in women who are scheduled for pelvic organ prolapse (POP) surgery. METHODS: All consecutive women awaiting surgery for POP in a tertiary urogynaecological centre were included. A short questionnaire with two open questions on goals and fears with regard to the operation was used. RESULTS: Ninety-six out of 111 distributed questionnaires (86%) were analysed. Goals and fears were categorized into five groups. De novo symptoms (63%), POP recurrence (34%) and surgical complications (29%) were the most important fears. Symptom release (96%), improved lifestyle (physical capabilities; 30%) and improved sexual life (18%) were important goals. CONCLUSIONS: A wide variety of expectations both positive and negative can be found in women before POP surgery and should be an integral part of preoperative counselling. Achieving the individual goals as based on expectations, positive (goals) and negative (fears), should be part of the POP surgery evaluation. PMID- 21604060 TI - Anal sphincter complex muscles defects and dysfunction in asymptomatic parous women. AB - INTRODUCTION AND HYPOTHESIS: We aimed to determine anatomy and function of anal sphincter complex using three-dimensional ultrasound (3D-US) and manometry in asymptomatic parous women. METHODS: 3D-US of puborectalis muscle (PRM), external (EAS), and internal anal sphincters (IAS) anatomy was performed in 45 women without pelvic floor dysfunction. To assess function, rest and squeeze vaginal and anal pressures were measured. Based on 3D-US, subjects were divided into injured and uninjured groups. RESULTS: Forty-four of 45 subjects had adequate PRM images. The injured PRM (N = 14) group had significantly lower vaginal pressures as compared with uninjured PRM group (N = 30; p = 0.001). Four of 45 subjects with IAS and EAS defects had lower resting and squeeze anal canal pressure. Muscle injury to IAS, EAS and PRM in the same individual was uncommon. CONCLUSIONS: In asymptomatic parous women, PRM defects were more common than the EAS/IAS defects but defects in more than one muscle were infrequent. Subjects with injured PRM had low vaginal pressure than the ones without. PMID- 21604062 TI - Association of rheumatoid arthritis risk with EGFR genetic polymorphisms in Taiwan's Han Chinese population. AB - The involvement of the epidermal growth factor receptor (EGFR) in the pathogenesis of cancer is well documented. In contrast, its role in rheumatoid arthritis (RA) development is not that well defined although previous studies suggested the possible link between autoimmune diseases and malignancy. Therefore, we aimed to examine whether there is a link between the EGFR genetic polymorphisms and the RA. Our study gauged the effects of EGFR (rs11543848 and rs17337023) single-nucleotide polymorphisms (SNPs) on RA among Taiwan's Han Chinese population. Polymorphism of EGFR gene was analyzed in 188 RA patients and 128 control subjects. Genotyping for EGFR SNPs was performed by restriction fragment length polymorphism (RFLP) assay. Our data confirmed statistically significant increased risk of RA development in subjects with A carrier at rs17337023 SNP (P < 0.0001), and subjects with A allele at rs17337023 SNP (odds ratio [OR] = 1.52; 95% confidence interval [CI] = 1.10-2.09). Furthermore, comparison of haplotype frequencies between patients and controls suggested GA and AT haplotypes were more "at-risk" for RA development (P < 0.0001 and P < 0.01, respectively). However, comparisons of the clinical features of RA patients according to different genotypes and haplotypes revealed no significant difference. In conclusion, our data yield the new information on EGFR polymorphisms (rs11543848 and rs17337023) with the susceptibility of RA development and polymorphism revealed by this study merit further investigation. PMID- 21604063 TI - Renal function assessment in patients with systemic lupus erythematosus. AB - Few studies have evaluated the glomerular filtration rate (GFR) in patients with systemic lupus erythematosus (SLE). Even though the National Kidney Foundation (NKF) suggests using the equations to estimate GFR, rheumatologists continue using creatinine clearance (CCl). The main objective of our study was the assessment of different equations to estimate GFR in patients with SLE: Simplified MDRD study equation (sMDRD), CCl, Cockcroft Gault (CG), CG calculated with ideal weight (CGi), Mayo Clinic Quadratic (MCQ), and Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI). CKD-EPI was considered as the reference standard, and it was compared with the other equations to evaluate bias, correlation (r), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), percentage of measurement of GFR between 70-130% of GFR measured through CKD-EPI (P30) and to compute the ROC curves. Adequacy of the 24-h urine collection was evaluated. To classify patients into GFR < 60 ml/min/1.73 m(2), the best sensitivity and NVP were obtained with sMDRD: the best PPV and specificity with MCQ. P30 was 99.3% with sMDRD, 77.5% CCl, 91.7% CG, 96.7% CGi, and 77.2% with MCQ. The lowest bias was for sMDRD and the highest for CCl. Only 159 (52.6%) urine collections were considered adequate, and when these patients were re-evaluated, the statistical results improved for CCl. CGi was better in general than CG. CCl should not be considered as an adequate GFR estimation. Ideal weight is better than real weight to calculate GFR through CG in patients with SLE. PMID- 21604061 TI - Investigational therapies for ischemic stroke: neuroprotection and neurorecovery. AB - Stroke is one of the leading causes of death and disability worldwide. Current treatment strategies for ischemic stroke primarily focus on reducing the size of ischemic damage and rescuing dying cells early after occurrence. To date, intravenous recombinant tissue plasminogen activator is the only United States Food and Drug Administration approved therapy for acute ischemic stroke, but its use is limited by a narrow therapeutic window. The pathophysiology of stroke is complex and it involves excitotoxicity mechanisms, inflammatory pathways, oxidative damage, ionic imbalances, apoptosis, angiogenesis, neuroprotection, and neurorestoration. Regeneration of the brain after damage is still active days and even weeks after a stroke occurs, which might provide a second window for treatment. A huge number of neuroprotective agents have been designed to interrupt the ischemic cascade, but therapeutic trials of these agents have yet to show consistent benefit, despite successful preceding animal studies. Several agents of great promise are currently in the middle to late stages of the clinical trial setting and may emerge in routine practice in the near future. In this review, we highlight select pharmacologic and cell-based therapies that are currently in the clinical trial stage for stroke. PMID- 21604064 TI - Risk for HIV and unprotected sexual behavior in male primary partners of transgender women. AB - Men who have sex with transgender women are a potentially high-risk population for HIV and other sexually transmitted infections (STIs). We administered structured quantitative surveys to 174 men whose primary partner was a transgender woman. We assessed men's demographic characteristics, sexual behaviors, substance use, and social-psychological factors, including condom use self-efficacy and depression. Overall, 19% reported being HIV-positive (8% had been diagnosed with AIDS), 11% had at least one other STI during the past year, and 16% reported being in a HIV serodiscordant relationship with their primary partner. In the past 3 months, 40% had unprotected anal or vaginal sex with any partner. In multivariate analysis, significant correlates of having unprotected sex included younger age, concurrent partnerships, alcohol intoxication, and low condom use self-efficacy; depression was marginally associated with having unprotected sex. Interventions are needed to reduce risk for HIV and other STIs among men who have sex with transgender women. Prevention programs for these men should build condom use self-efficacy and address the contributions of alcohol intoxication, concurrent sex partnerships, and depression to sexual risk behavior. PMID- 21604065 TI - A comparison of audio computer-assisted self-interviews to face-to-face interviews of sexual behavior among perinatally HIV-exposed youth. AB - Computer-assisted interview methods are increasingly popular in the assessment of sensitive behaviors (e.g., substance abuse and sexual behaviors). It has been suggested that the effect of social desirability is diminished when answering via computer, as compared to an interviewer-administered face-to-face (FTF) interview, although studies exploring this hypothesis among adolescents are rare and yield inconsistent findings. This study compared two interview modes among a sample of urban, ethnic-minority, perinatally HIV-exposed U.S. youth (baseline = 148 HIV+, 126 HIV-, ages 9-16 years; follow-up = 120 HIV+, 110 HIV-, ages 10-19 years). Participants were randomly assigned to receive a sexual behavior interview via either Audio Computer-Assisted Self-Interview (ACASI) or FTF interview. The prevalence of several sexual behaviors and participants' reactions to the interviews were compared. Although higher rates of sexual behaviors were typically reported in the ACASI condition, the differences rarely reached statistical significance, even when limited to demographic subgroups--except for gender. Boys were significantly more likely to report several sexual behaviors in the ACASI condition compared to FTF, whereas among girls no significant differences were found between the two conditions. ACASI-assigned youth rated the interview process as easier and more enjoyable than did FTF-assigned youth, and this was fairly consistent across subgroup analyses as well. We conclude that these more positive reactions to the ACASI interview give that methodology a slight advantage, and boys may disclose more sexual behavior when using computer assisted interviews. PMID- 21604066 TI - Editorial: a new series of commentaries entitled "Landmark publications in the pharmaceutical sciences: the backstory". PMID- 21604067 TI - Sleep and inflammation: psychoneuroimmunology in the context of cardiovascular disease. AB - BACKGROUND: Poor sleep is prospectively linked to all-cause and cardiovascular mortality. Inflammatory processes may be an important biological mechanism linking poor sleep to cardiovascular disease. Such processes involve active participation of signaling molecules called cytokines in development of atherosclerotic plaques. PURPOSE: I review evidence from experimental sleep deprivation and clinical observational studies suggesting a bidirectional relationship between sleep and inflammatory cytokines. RESULTS: Findings from sleep deprivation studies indicate that sleep loss is associated with increases in these cytokines. Similarly, studies in clinical populations with sleep problems, such as primary insomnia patients and those diagnosed with major depression, also show elevations in these same cytokines. CONCLUSIONS: Bidirectional communication between the brain and the immune system is carried out through a complex network of autonomic nerves, endocrine hormones, and cytokines. Disturbed sleep appears to perturb the functioning of this network and therefore contribute to elevations in inflammatory mediators linked to cardiovascular disease. PMID- 21604068 TI - Attrition and adherence rates of sustained vs. intermittent exercise interventions. AB - BACKGROUND: No conclusions have been drawn regarding the relative attrition and adherence rates associated with sustained vs. intermittent exercise programs. PURPOSE: The study aims to systematically examine randomized controlled exercise intervention trials that report attrition and/or adherence rates to sustained vs. intermittent aerobic exercise programs. METHODS: A comprehensive literature search was conducted, and references from qualifying articles were searched for additional papers. RESULTS: Fourteen articles met inclusion criteria, capturing 783 (76% female) enrolled and 599 (74% female) retained participants (mean age = 42.3 +/- 6.6 years). Study durations ranged from 8 weeks to 18 months (mean duration = 22.7 +/- 21.9 weeks). Although results varied, no consistent differences in attrition or adherence rates between sustained and intermittent exercise protocols were revealed. CONCLUSIONS: Given the universally low rate of regular exercise participation and the ongoing problem of adherence to exercise protocols, the field may benefit from randomized controlled trials examining sustained vs. intermittent exercise programs in greater depth. PMID- 21604069 TI - Acceptability of prenatal diagnosis by a sample of parents of sickle cell anemia patients in Cameroon (sub-Saharan Africa). AB - Little is known about attitudes of parents of Sickle Cell Anemia patients in sub Saharan Africa regarding prenatal genetic diagnosis and termination of an affected pregnancy. In this study, structured face-to-face interviews were conducted with a sample of 130 parents in Cameroon that had at least one living child with Sickle Cell Anemia. The majority of participants lived in urban areas (89%), were female (80%), Christian (93%), married (60.2%) in monogamous households (81.1%), were employed (61.7%), and had at least a secondary or tertiary education (82%). The majority of parents accepted the principle of prenatal genetic diagnosis for Sickle Cell Anemia (89.8%) and termination of pregnancy (62.5%). Acceptance of the principle of pregnancy termination increased with unemployment (p<.01) and single marital status (p<.05). The results of this study suggest Cameroonian parents with children affected with Sickle Cell Anemia generally accept the principles of prenatal diagnosis and in some cases termination of a pregnancy affected with Sickle Cell Anemia. Additional findings, policy and practice implications, and research recommendations are presented. PMID- 21604070 TI - Enhanced anti-tumor activity of interferon-alpha in SOCS1-deficient mice is mediated by CD4+ and CD8+ T cells. AB - Interferon-alpha (IFN-alpha) is an immunomodulatory cytokine that is used clinically for the treatment of melanoma in the adjuvant setting. The cellular actions of IFN-alpha are regulated by the suppressors of cytokine signaling (SOCS) family of proteins. We hypothesized that the anti-tumor activity of exogenous IFN-alpha would be enhanced in SOCS1-deficient mice. SOCS1-deficient (SOCS1(-/-)) or control (SOCS1(+/+)) mice on an IFN-gamma(-/-) C57BL/6 background bearing intraperitoneal (i.p.) JB/MS murine melanoma cells were treated for 30 days with i.p. injections of IFN-A/D or PBS (vehicle). Log-rank Kaplan-Meier survival curves were used to evaluate survival. Tumor-bearing control SOCS1(+/+) mice receiving IFN-A/D had significantly enhanced survival versus PBS-treated mice (P = 0.0048). The anti-tumor effects of IFN-A/D therapy were significantly enhanced in tumor-bearing SOCS1(-/-) mice; 75% of these mice survived tumor challenge, whereas PBS-treated SOCS1(-/-) mice all died at 13-16 days (P = 0.00038). Antibody (Ab) depletion of CD8(+) T cells abrogated the anti-tumor effects of IFN-A/D in SOCS1(-/-) mice as compared with mice receiving a control antibody (P = 0.0021). CD4(+) T-cell depletion from SOCS1(-/-) mice also inhibited the effects of IFN-A/D (P = 0.0003). IFN-A/D did not alter expression of CD80 or CD86 on splenocytes of SOCS1(+/+) or SOCS1(-/-) mice, or the proportion of T regulatory cells or myeloid-derived suppressor cells in SOCS1(+/+) or SOCS1(-/-) mice. An analysis of T-cell function did reveal increased proliferation of SOCS1-deficient splenocytes at baseline and in response to mitogenic stimuli. These data suggest that modulation of SOCS1 function in T-cell subsets could enhance the anti-tumor effects of IFN-alpha in the setting of melanoma. PMID- 21604071 TI - Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signaling in CD4+ T cells from patients with GI malignancy. AB - Interferon-alpha (IFN-alpha) promotes anti-tumor immunity through its actions on immune cells. We hypothesized that elevated percentages of myeloid-derived suppressor cells (MDSC) and increased pro-inflammatory cytokines in peripheral blood would be associated with impaired response to IFN-alpha in patients with gastrointestinal (GI) malignancies. This study evaluated relationships between plasma IL-6, IL-10, circulating MDSC subsets, and IFN-alpha-induced signal transduction in 40 patients with GI malignancies. Plasma IL-6 and IL-10 were significantly higher in patients versus normal donors. CD33(+)HLADR( )CD11b(+)CD15(+) and CD33(+)HLADR(-/low)CD14(+) MDSC subsets were also elevated in patients versus normal donors (P < 0.0001). Plasma IL-6 was correlated with CD33(+)HLADR(-)CD15(+) MDSC (P = 0.008) and IL-10 with CD33(+)HLADR(-)CD15(-) MDSC (P = 0.002). The percentage of CD15(+) and CD15(-) but not CD14(+) MDSC subsets were inversely correlated with IFN-alpha-induced STAT1 phosphorylation in CD4(+) T cells, while co-culture with in vitro generated MDSC led to reduced IFN alpha responsiveness in both PBMC and the CD4(+) subset of T cells from normal donors. Exploratory multivariable Cox proportional hazards models revealed that an increased percentage of the CD33(+)HLADR(-)CD15(-) MDSC subset was associated with reduced overall survival (P = 0.049), while an increased percentage of the CD33(+)HLADR(-/low)CD14(+) subset was associated with greater overall survival (P = 0.033). These data provide evidence for a unique relationship between specific cytokines, MDSC subsets, and IFN-alpha responsiveness in patients with GI malignancies. PMID- 21604072 TI - Role of transoral CO(2) laser surgery for severe pediatric laryngomalacia. AB - Controversy exists as to the preferred treatment modality for managing refractory pediatric laryngomalacia (LM). Simultaneous bilateral procedures have been associated with supraglottic stenosis. Unilateral operations have a higher rate of secondary intervention. This prospective study was conceptualized to ascertain a preferred approach. A secondary goal was to correlate the surgical outcome with presenting symptoms and signs. Twenty-two children with severe LM met the criteria for enrollment. Bilateral CO(2) laser-assisted supraglottic laryngoplasties were performed in all cases. The procedure mainly consisted of division of the aryepiglottic fold. Nineteen (86%) patients met our defined success criteria. There were no surgical complications. Bilateral supraglottic laryngoplasty has a role in the management of severe refractory LM. PMID- 21604073 TI - Radiosurgical correlation of obstructive adenoids in children. AB - The aim of this prospective work was to study the radiological and surgical correlation of adenoid size in children symptomatic with obstructive adenoid hypertrophy, and carried out at Tertiary care referral teaching hospital. Data of 25 randomly selected patients were used for analysis. Post nasal space images (lateral soft tissue neck X-ray) were analyzed using Fujioka's method. Surgical findings based on endoscopic picture of choanal view using 0-2.7 mm endoscope were analyzed. The comparison between the two results was subjected for statistical analysis. A total of 25 cases were included in the study. The mean age was 7 +/- 0.45 years. The findings showed good correlation between adenoid sizes on X-ray films compared to the size seen intraoperatively using the methods mentioned above. The current study showed positive correlation between adenoid size on lateral view X-ray films and surgical findings. X-rays can be used as a helpful diagnostic tool when post nasal endoscopy is not available or not possible. PMID- 21604074 TI - Pure-tone auditory threshold in school children. AB - To determine pure-tone auditory thresholds, 197 screened children at a typical primary school in a German town (~70,000 inhabitants) were examined. All children underwent a tympanometry and an audiometry at 17 frequencies from 125 to 16 kHz. Regarding age effects, two groups (6-8 and 9-12 years) were analyzed. The cross sectional research was supplemented by a follow-up study with 35 children of the first graders 3 years later. School children have the poorest hearing sensitivity at low frequencies (below 1 kHz) and the best sensitivity at the extended high frequencies above 8 kHz. Hearing thresholds are rising significantly with age. Through all frequencies, averaged improvements were 3.8 dB (right ear) and 3.7 dB (left ear) at the cross-sectional study and 3.7 dB (right ear) and 5.1 dB (left ear) at the longitudinal study. The overall deviation (left and right) from the standard thresholds for adults were 7.4 and 3.6 dB for the younger and older age groups, respectively. The ear canal volume (ECV) measured by tympanometric tests was at mean with 1.06 cm(3) for the 6- to 8-year age group significantly lower (p < 0.001) in comparison with 1.18 cm(3) for the 9- to 12-year age group. Also, girls had significant (p < 0.001) smaller ECV (mean 1.07 cm(3)) than boys (1.17 cm(3)). Auditory performance improves with rising age in school children. PMID- 21604075 TI - Population PK and IgE pharmacodynamic analysis of a fully human monoclonal antibody against IL4 receptor. AB - PURPOSE: For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4Ralpha, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response. METHODS: Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients. RESULTS: The best structural model was a two compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0 mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03 L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured. CONCLUSION: The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure. PMID- 21604076 TI - Age and receipt of guideline-recommended medications for heart failure: a nationwide study of veterans. AB - BACKGROUND: Older patients often receive less guideline-concordant care for heart failure than younger patients. OBJECTIVE: To determine whether age differences in heart failure care are explained by patient, provider, and health system characteristics and/or by chart-documented reasons for non-adherence to guidelines. DESIGN AND PATIENTS: Retrospective cohort study of 2,772 ambulatory veterans with heart failure and left ventricular ejection fraction <40% from a 2004 nationwide medical record review program (the VA External Peer Review Program). MAIN MEASURES: Ambulatory use of ACE inhibitors, angiotensin receptor blockers (ARBs), and beta blockers. RESULTS: Among 2,772 patients, mean age was 73 +/- 10 years, 87% received an ACE inhibitor or ARB, and 82% received a beta blocker. When patients with explicit chart-documented reasons for not receiving these drugs were excluded, 95% received an ACE inhibitor or ARB and 89% received a beta blocker. In multivariable analyses controlling for a variety of patient and health system characteristics, the adjusted odds ratio for ACE-inhibitor and ARB use was 0.43 (95% CI 0.24-0.78) for patients age 80 and over vs. those age 50 64 years, and the adjusted odds ratio for beta blocker use was 0.66 (95% CI 0.48 0.93) between the two age groups. The magnitude of these associations was similar but not statistically significant after excluding patients with chart-documented reasons for not prescribing ACE inhibitors or ARBs and beta blockers. CONCLUSIONS: A high proportion of veterans receive guideline-recommended medications for heart failure. Older veterans are consistently less likely to receive these drugs, although these differences were no longer significant when accounting for patients with chart-documented reasons for not prescribing these drugs. Closely evaluating reasons for non-prescribing in older adults is essential to assessing whether non-treatment represents good clinical judgment or missed opportunities to improve care. PMID- 21604077 TI - Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. AB - Mutations in the gene encoding the fused in sarcoma (FUS) protein are responsible for ~3% of familial amyotrophic lateral sclerosis (ALS) and <1% of sporadic ALS (ALS-FUS). Descriptions of the associated neuropathology are few and largely restricted to individual case reports. To better define the neuropathology associated with FUS mutations, we have undertaken a detailed comparative analysis of six cases of ALS-FUS that include sporadic and familial cases, with both juvenile and adult onset, and with four different FUS mutations. We found significant pathological heterogeneity among our cases, with two distinct patterns that correlated with the disease severity and the specific mutation. Frequent basophilic inclusions and round FUS-immunoreactive (FUS-ir) neuronal cytoplasmic inclusions (NCI) were a consistent feature of our early-onset cases, including two with the p.P525L mutation. In contrast, our late-onset cases that included two with the p.R521C mutation had tangle-like NCI and numerous FUS-ir glial cytoplasmic inclusions. Double-labeling experiments demonstrated that many of the glial inclusions were in oligodendrocytes. Comparison with the neuropathology of cases of frontotemporal lobar degeneration with FUS-ir pathology showed significant differences and suggests that FUS mutations are associated with a distinct pathobiology. PMID- 21604079 TI - Single brain death examination is equivalent to dual brain death examinations. AB - BACKGROUND: Although the new Practice Parameters for brain death support a single examination, there is paucity of data comparing its impact to dual brain death (DBD) examinations. METHODS: We reviewed all brain deaths in our hospital over a 39-month period and compared the optional single brain death (SBD) exam requiring an apnea and a mandatory confirmatory blood flow test to the DBD for organ function at the time of death, rate of donation, and cost. RESULTS: Thirty-six patients had a SBD and 59 DBD exams, without any of them regaining neurological functioning. There was no difference in serum electrolytes (except for higher Na(+) and Cl(-) in the SBD group), blood urea nitrogen, creatinine, blood gases, incidence of diabetes insipidus, apnea completion, consent for donation, and organs recovered and transplanted. During the second BD exam, 35% of patients with DBD were on higher dose of vasopressors, but had lower systolic blood pressure (P = 0.046). For DBD patients, the mean interval between the two exams was 14.4 h, which contributed to a higher cost of $43,707.67 compared to SBD. There was a trend for increased consent rates (adjusted for age, race, and type of exam) when patients were declared by the neurointensivist service following a strict family approach protocol (P = 0.06). CONCLUSION: SBD exam is easier, faster to perform, with no brain function recovery and leads to similar donation rates, equivalent or better organ function status at the time of BD and lower cost than conventional DBD exams. PMID- 21604078 TI - Systematic review for paediatric metachronous contralateral inguinal hernia: a decreasing concern. AB - PURPOSE: Controversy still surrounds the treatment of the asymptomatic inguinal region in paediatric patients with a unilateral inguinal hernia. The concern is the development of a future metachronous contralateral inguinal hernia (MCIH) and therefore the need for a second operation. Our aim was to provide a current systematic review of the evidence for routine contralateral exploration, and identify potential at-risk groups. METHODS: Comprehensive review of the literature utilising broad search terms to identify all relevant publications. Precise inclusion and exclusion criteria to identify studies that included paediatric unilateral inguinal hernia repair without routine contralateral exploration. DATA ANALYSIS: Chi-square with Yates' correction or a Fisher's exact test as appropriate. Numbers needed to treat (NNT) calculated with 95% confidence intervals. RESULTS: A total of 7,130 titles and abstracts were screened and 61 studies included with data on 49,568 paediatric patients with a unilateral inguinal hernia fulfilling the inclusion criteria. 2,857 of these patients later developed a MCIH, revealing an overall risk is 5.76% (95% CI: 5.55-5.97%). The NNT for a MCIH is 18 (95% CI: 16.8-18) with 18 contralateral exploration required for the prevention of one MCIH. Patients <6 months at the time of the initial intervention were more likely to develop a MCIH; 183/1,470 (<6/12) versus 144/2,044 (>=6/12), P < 0.0001. As were patients with an original left-sided hernia; 815/6,739 versus 865/12,615, P < 0.0001. The NNTs for both of these groups were 9. There was no association with the gender of the patient; 888/14,480 (?) versus 268/4,206 (?), P = 0.37. CONCLUSIONS: There is insufficient evidence to support the routine contralateral inguinal exploration in all paediatric patients presenting with a unilateral inguinal hernia. However, with patients presenting with an originally left-sided hernia or who are less than 6 months old, a parental discussion should occur about the possible benefits and risks of contralateral exploration. PMID- 21604080 TI - Terson's syndrome. AB - BACKGROUND: Terson's syndrome is intraocular hemorrhage (IOH) subsequent to subarachnoid hemorrhage (SAH). Its presence is associated with higher mortality in SAH. We report a case of Terson's syndrome and review the literature. CASE REPORT: A 71-year-old Caucasian gentleman collapsed and became comatose. Past medical history was notable for chronic anticoagulation for previous transient ischemia attacks. CT head scans showed severe SAH of Fisher grade 4 and a lesion suspicious for aneurysm. Formal angiography confirmed a supraclinoid right internal carotid artery aneurysm which was coiled. ICU admission was complicated by a stormy course. The patient eventually regained consciousness and was transferred to a regular ward. On hospital day 20, impaired vision was noted. Review of CT head scans revealed previously missed retinal hemorrhages and funduscopy confirmed vitreous hemorrhage. However, the patient remained in a poor neurologic state and expired several days later. DISCUSSION: Terson's syndrome occurs in up to 40% of acute aneurysmal bleeds. The sudden spike in intracranial pressure (ICP) with aneurysmal rupture is thought to underlie the cause of IOH as well as the high incidence of coma, higher Hunt and Hess grades, and mortality in these patients. Gold-standard diagnosis is funduscopy, and retinal hemorrhages may occasionally be seen on CT. CONCLUSIONS: Terson's syndrome occurs frequently following SAH, although it is under-reported. Suspected visual loss following SAH should prompt a search for Terson's syndrome by funduscopy, as its presence is an adverse prognostic factor. PMID- 21604081 TI - The role of spiritual experiences and activities in the relationship between chronic illness and psychological well-being. AB - Our research explores the correlates of spiritual experiences over a 2-year period in a sample of older adults (N = 164; mean age 81.9 years) living in a continuing care retirement community. Utilizing responses to the Daily Spiritual Experiences Scale, scores were analyzed for changes over time and for their hypothesized moderating effect in the relationship between chronic illness impact and markers of psychological well-being (as measured by the Geriatric Depression and Life Satisfaction scales). Repeated measures ANOVA indicated a significant decline (P < .01) in the reported spiritual experiences over a 2-year period of time, and t tests showed a significant difference by gender (P < .01) in years 1 and 2, with women reporting higher levels of spiritual experiences than men. Analyses found low spirituality scores associated with low life satisfaction in all years (baseline: r = -.288, P < .01; year 1: r = -.209, P < .05; year 2: r = .330, P < .001). Only weak associations were detected between low spirituality and the presence of depressive symptoms at baseline (r = .186, P < .05) and year 2 (r = .254, P < .01). Moderation effects of spirituality on the relationship between chronic illness impact and markers of psychological well-being were explored in all years, with a statistically significant effect found only for the presence of depressive symptoms in year 2. Higher impact of chronic illnesses is associated with more depressive symptoms under conditions of low spirituality. Future research may center upon longer-duration evaluation of reliance upon spiritual practices and their impact in care management models. PMID- 21604082 TI - Characterization of mitral valve prolapse with cardiac computed tomography: comparison to echocardiographic and intraoperative findings. AB - A single imaging modality that can accurately assess both coronary anatomy and mitral valve (MV) anatomy prior to surgery may be desirable. We sought to determine the diagnostic accuracy of cardiac computed tomography (CT) to detect and characterize mitral valve prolapse (MVP) compared to echocardiography. Consecutive patients referred for 'single-source' cardiac CT for investigation prior to non-coronary cardiac sugery were identified. MV anatomy was assessed for MVP and results were compared to echocardiography and to intra-operative visual assessment of the MV. Comparison between the three modalities was performed at the per-patient, per-leaflet and per-scallop levels. A total of 67 consecutive patients that were referred for Cardiac CT prior to non-coronary cardiac surgery and were prospectively recruited into a Cardiac CT registry. Of these, 65 patients underwent cardiac surgery. 63 patients had echocardiography and 32 patients had intra-operative visual assessment of the mitral valve. Compared to echocardiography, cardiac CT had excellent sensitivity (92.6%) and specificity (97.1%) for the detection of any MVP, but had poor sensitivity (68.5%) for the detection of individual prolapsing scallop. Compared to intra-operative visual assessment of the prolapsing scallop, both cardiac CT and echocardiography had low sensitivity (58.1 and 78.1%, respectively). Cardiac CT was able to identify patients with MVP but had difficulty identifying the prolapsed scallops compared to echocardiography. Single-source CT may not be ready for characterization of individual mitral valve scallops. PMID- 21604083 TI - The influence of neighborhood factors on the quality of life of older adults attending New York City senior centers: results from the Health Indicators Project. AB - PURPOSE: To examine the association between self-assessed quality of life (QOL) and perceived neighborhood safety, social cohesion, and walkability among older adults in New York City (NYC). METHODS: We used data from the 2008 Health Indicators Project, a cross-sectional survey of 1,870 older adults attending 56 NYC senior centers. QOL, a binary measure, was created by dichotomizing a 5-point Likert-scaled global assessment. Neighborhood safety, social cohesion, and walkability were multi-component scale variables that were standardized due to varying response metrics. Multivariate binomial logistic regression analysis was performed on 1,660 participants with complete data. RESULTS: After adjusting for covariates, QOL was significantly associated with neighborhood safety and social cohesion. A one-standard deviation increase in neighborhood safety and social cohesion increased the log odds of having higher QOL by 30% (odds ratio (OR) = 1.30; 95% confidence interval (CI) = 1.14, 1.48; P <= 0.001) and 36% (OR = 1.36; 95% CI = 1.16, 1.59; P <= 0.001), respectively. Higher QOL was not significantly associated with neighborhood walkability. CONCLUSION: The results of this study underscore the need for initiatives that focus on enhancing age-friendly neighborhood features in large urban centers such as NYC and beyond. PMID- 21604085 TI - Dipeptidyl peptidase-4 inhibition increases portal concentrations of intact glucagon-like peptide-1 (GLP-1) to a greater extent than peripheral concentrations in anaesthetised pigs. PMID- 21604084 TI - The previously reported T342P GCK missense variant is not a pathogenic mutation causing MODY. PMID- 21604086 TI - Critical illness-related corticosteroid insufficiency in cancer patients. AB - PURPOSE: Critically ill cancer patients with sepsis represent a high-risk sub group for the development of critical illness-related corticosteroid insufficiency (CIRCI); however, the incidence of CIRCI in this population is unknown. The purpose of this study was to determine the incidence of CIRCI in cancer patients with severe sepsis or septic shock. METHODS: A single-center, retrospective, observational study was conducted in a 52-bed medical-surgical intensive care unit of a National Cancer Institute-recognized academic oncology institution. Eighty-six consecutive patients with a diagnosis of severe sepsis or septic shock who received a high-dose 250-MUg cosyntropin stimulation test were included. CIRCI was identified by a maximum delta serum cortisol of 9 MUg/dL or less post cosyntropin. RESULTS: Overall, 59% (95% CI, 48-70%) of cancer patients with severe sepsis or septic shock were determined to have CIRCI. When compared to patients without CIRCI, patients with CIRCI had higher baseline serum cortisol (median, 26.3 versus 14.7 MUg/dL; p = 0.002) and lower delta cortisol levels (median, 3.1 versus 12.5 MUg/dL; p < 0.001). Mortality did not differ between the two groups. An inverse relationship was identified between baseline serum cortisol and maximum delta cortisol (maximum delta cortisol = -0.27 * baseline cortisol + 14.30; R (2) = 0.208, p < 0.001). CONCLUSIONS: The incidence of CIRCI in cancer patients with severe sepsis or septic shock appears high. Further large scale prospective trials are needed to confirm these findings. PMID- 21604087 TI - Two X-linked chronic granulomatous disease patients with unusual NADPH oxidase properties. AB - BACKGROUND: Chronic granulomatous disease (CGD) is an immune deficiency syndrome caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the enzyme that generates reactive oxygen species (ROS) in phagocytizing leukocytes. This study evaluates the NADPH oxidase capacity in two X-linked CGD patients with mutations in gp91(phox) that alter the regions in this membrane bound NADPH oxidase component involved in docking of the cytosolic component p47(phox). MATERIALS AND METHODS: Hydrogen peroxide and superoxide generation, bactericidal activity, and NADPH oxidase protein expression by the patients' neutrophils were measured, and genetic analysis was performed. RESULTS: We report two patients, each with a novel missense mutation in CYBB, the gene that encodes gp91(phox). Surprisingly, neutrophils from these patients showed total absence of superoxide production, although they retained 13-30% of the hydrogen peroxide production capability. We speculate that this is due to direct electron transfer from flavin adenine dinucleotide (FAD) in gp91(phox) to oxygen, leading to inefficient hydrogen peroxide formation instead of efficient superoxide production. CONCLUSIONS: X-linked CGD patients with mutations that alter the gp91(phox) protein in regions involved in docking of the cytosolic NADPH oxidase component p47(phox) may have higher than expected hydrogen peroxide generation capability. PMID- 21604088 TI - Mutation prediction by PolyPhen or functional assay, a detailed comparison of CYP27B1 missense mutations. AB - Vitamin D-dependent rickets type 1 (VDDR-I) is caused by mutation in CYP27B1. The glycine residue at codon 102 is not conserved between human (G(102)) and rodent (S(102)). G102E mutation results in 80% reduction in its enzymatic activity but PolyPhen predicts benign change. It is not known whether G102S has any damaging effect on 1alpha-hydroxylase activity. We investigated the effect of CYP27B1 (G102S) on its enzymatic activity and compared mutation prediction accuracy for all known CYP27B1 mutations among three free online protein prediction programs: PolyPhen, PolyPhen-2, and PSIPRED. G102S has no damaging effect on 1alpha hydroxylase activity. G102D retained 30% enzymatic activity. All three programs correctly predicted damaging change for G102D. PolyPhen predicted benign change for G102S, whereas PolyPhen-2 and PSIPRED indicated possible damaging effect. Among 24 reported damaging mutations, PSIPRED, PolyPhen-2, and PolyPhen achieved 100%, 91.7% (22/24), and 75% (18/24) accuracy rate, respectively. The residues of incorrectly predicted mutations were not conserved. We conclude that G102D resulted in a significant reduction in 1alpha-hydroxylase activity, whereas G102S did not. PSIPRED and PolyPhen-2 are superior to PolyPhen in predicting damaging mutations. PMID- 21604090 TI - Pharmacological effect of carvacrol on D: -galactosamine-induced mitochondrial enzymes and DNA damage by single-cell gel electrophoresis. AB - The present study aimed at investigating the effect of carvacrol on hepatic mitochondrial enzyme activities and DNA damage in D: -galactosamine (D: -GalN) induced hepatotoxicity in male albino Wistar rats. The activities of hepatic mitochondrial enzymes such as isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADPH dehydrogenase and cytochrome c oxidase significantly decreased in D: -GalN-hepatotoxic rats, and administration of carvacrol brought these parameters towards normality. In D: -GalN-hepatotoxic rats, the hepatic mitochondrial concentration of thiobarbituric acid reactive substances significantly increased, and administration of carvacrol significantly reduced them towards normality. Furthermore, the activities of enzymatic antioxidants such as superoxide dismutase and glutathione peroxidase and the levels of non-enzymatic antioxidants such as vitamin C, vitamin E and reduced glutathione decreased significantly in the liver mitochondria. Administration of carvacrol returned the enzymatic and non-enzymatic antioxidants towards normality. D: -GalN-hepatotoxic rats had increased DNA damage, which administration of carvacrol significantly decreased. These results suggest that carvacrol has liver mitochondrial antioxidant properties and possesses a defensive effect against mitochondrial enzymes and DNA damage in D: -GalN-induced rats. PMID- 21604092 TI - The current role of simulators in teaching surgical techniques. PMID- 21604093 TI - One hundred and two consecutive robotic-assisted minimally invasive colectomies- an outcome and technical update. AB - BACKGROUND: The objective of this study was to review 102 consecutive robotic colectomies at our institution. We evaluated the 8-year experience of one surgeon (DLC) in Peoria, IL using the da Vinci system. METHODS: An IRB-approved retrospective review was performed. Results were compared with the literature. Changes in technique over the years were evaluated. RESULTS: One hundred and two robotic colectomies, right (59) and sigmoid (43), were performed. Mean age is 63.5 years and mean BMI 27.4 kg/m2. Preoperative indications are polyps (53), diverticular disease (27), cancer (19), and carcinoid (3). Mean total case time (TCT) for all cases is 219.6 +/- 45.1 (50-380) min, and mean robot operating time (ROT) is 126.6 +/- 41.6 (12-306) min. Operative times for Right: Port setup time (PST) 32.4 +/- 10.5 (20-64) min, ROT 145.2 +/- 39.6 (53-306) min, TCT 212.3 +/- 46.4 (50-380) min; times for sigmoid: PST 31.2 +/- 9.6 (10-57) min, ROT 101.2 +/- 29.2 (12-165) min, TCT 229.7 +/- 41.6 (147-323) min. Median length of stay for all patients is 3 (2-27) days. The overall complication rate is 18.6%, the overall conversion rate 8.8%, and the anastomotic leak rate is 0.98%. Residents PGY 1-5 participated in 61 cases (59.8%). CONCLUSION: We report our updated procedural sequence and technical alterations. Experience has allowed residents to evolve to be primary surgeons. We add our results to the current robotic literature. PMID- 21604094 TI - Raising argument strength using negative evidence: a constraint on models of induction. AB - Both intuitively, and according to similarity-based theories of induction, relevant evidence raises argument strength when it is positive and lowers it when it is negative. In three experiments, we tested the hypothesis that argument strength can actually increase when negative evidence is introduced. Two kinds of argument were compared through forced choice or sequential evaluation: single positive arguments (e.g., "Shostakovich's music causes alpha waves in the brain; therefore, Bach's music causes alpha waves in the brain") and double mixed arguments (e.g., "Shostakovich's music causes alpha waves in the brain, X's music DOES NOT; therefore, Bach's music causes alpha waves in the brain"). Negative evidence in the second premise lowered credence when it applied to an item X from the same subcategory (e.g., Haydn) and raised it when it applied to a different subcategory (e.g., AC/DC). The results constitute a new constraint on models of induction. PMID- 21604095 TI - Is surface-based orientation influenced by a proportional relationship of shape parameters? AB - We investigated the extent to which parameters of environmental shape - namely the major and minor principal axes of space which pass through the centroid and approximate length and width of the entire space, respectively, were subject to similar psychophysical principles as those involved in distance discriminations. We developed an orientation task that allowed us to manipulate the ratio of the major to the minor principal axes of an enclosure during training and control for orientation by alternative cues other than principal axes such as wall lengths or corner angles during testing. Participants trained in an environment with a larger hypothetical discriminability ratio allocated more responses to locations specified by the principal axes of space across novel enclosure types compared to a group trained with a smaller hypothetical discriminability ratio. Results suggest that psychophysical principles may operate on the discrimination of environmental shape parameters and delineate a potential mechanism for experiential and developmental changes in orientation ability. PMID- 21604096 TI - Inhibition of the bacterial lectins of Pseudomonas aeruginosa with monosaccharides and peptides. AB - Pseudomonas aeruginosa (PA) can cause infections in compromised hosts by interacting with the glycocalyx of host epithelial cells. It binds to glycostructures on mucosal surfaces via two lectins, which are carbohydrate binding proteins, named PA-IL and PA-IIL, and blocking this interaction is, thus, an attractive anti-adhesive strategy. The aim of this study was to determine by ciliary beat frequency (CBF) analysis whether monosaccharides or peptides mimicking glycostructures represent blockers of PA lectin binding to human airway cilia. The treatment with monosaccharides and peptides alone did not change the CBF compared to controls and the tested compounds did not influence the cell morphology or survival, with the exception of peptide pOM3. PA-IL caused a decrease of the CBF within 24 h. D-galactose as well as the peptides mimicking HNK-1, polysialic acid and fucose compensated the CBF-modulating effect of PA-IL with different affinities. PA-IIL also bound to the human airway cilia in cell culture and resulted in a decrease of the CBF within 24 h. L(-)-fucose and pHNK-1 blocked the CBF-decreasing effect of PA-IIL. The HNK-1-specific glycomimetic peptide had a high affinity for binding to both PA-IL and PA-IIL, and inhibited the ciliotoxic effect of both lectins, thus, making it a strong candidate for a therapeutic anti-adhesive drug. PMID- 21604097 TI - Natural orifice surgery: endoluminal pouch reduction following failed vertical banded gastroplasty. AB - BACKGROUND: Following vertical banded gastroplasty (VBG), patients may develop pouch complications such as dilation and staple-line dehiscence. This may contribute to weight regain, and if conservative measures are exhausted, traditionally, open revisional surgery of the pouch or conversion of the VBG to Roux-en-Y gastric bypass (RYGB) would be considered. StomaphyX(TM) is an endoscopic device used with a conventional gastroscope for the approximation of tissue in gastric pouches or across gastroenteric anastomoses to enhance restriction. The objective of this study is to analyze the outcomes of StomaphyX(TM) endoluminal pouch revision following failed VBG. METHODS: Patients with weight gain following VBG had endoluminal pouch reduction performed using the StomaphyX(TM) device in revisional bariatric surgery clinic, tertiary care hospital, Canada. Pre- and postoperative weights were compared, and a regression model was developed to examine for predictors of weight loss following StomaphyX(TM). RESULTS: Fourteen patients were included in the study. Patients had a mean age of 47.3 +/- 7.9 years, and 13 of 14 were female. Significant reductions were appreciated between pre- and postoperative weight and BMI (119.5 +/- 25.9 kg vs. 109.6 +/- 24.4 kg; 43.4 +/- 9.7 kg/m(2) vs. 39.8 +/- 9.1 kg/m(2), respectively). There was no correlation between preoperative pouch status and weight loss. Three patients had two separate StomaphyX(TM) procedures performed. Only minor complications (headache, back pain) were identified. CONCLUSIONS: The StomaphyX(TM) device may be safely used for reduction of pouch size in patients following VBG. Further studies are required to determine the role of StomaphyX(TM) endoluminal pouch reduction in comparison to open or laparoscopic revisional surgery. PMID- 21604098 TI - Candida northwykensis sp. nov., a novel yeast isolated from the gut of the click beetle Melanotus villosus. AB - Two yeast morphotypes, BET 4(T) and BET 7, were isolated from the gut of click beetle Melanotus villosus. Click beetles were collected from the decaying timber within the woodlands of North Wyke Research, South West England, UK (latitude, 50 degrees 46'29"N; longitude, 3 degrees 55'23"W). Morphotype BET 7 was identified as Debaryomyces hansenii, and the other morphotype, BET 4(T), was found to differ from Priceomyces castillae and Priceomyces haplophilus, its closest phylogenetic neighbours, by 5.0% with respect to the nucleotide sequence of the D1/D2 domain of the large-subunit (LSU) rRNA gene, and by 8.0% with respect to the ribosomal internal-transcribed spacer (ITS) region. BET 4(T) also differ from P. castillae and P. haplophilus in a number of different phenotypic characteristics. Thus, based on the unique nucleotide sequences of its D1/D2 domain and ITS region, its physiological characteristics and an inability to sporulate, strain BET 4(T) is assigned the status of a new species of Candida, for which the name Candida northwykensis sp. nov., is proposed. The type strain is BET 4(T) (NCYC 3525(T) = CBS 11370(T)). PMID- 21604099 TI - Effects of co-inoculation with arbuscular mycorrhizal fungi and rhizobia on fungal occupancy in chickpea root and nodule determined by real-time PCR. AB - Legume roots in nature are usually colonized with rhizobia and different arbuscular mycorrhizal fungi (AMF) species. Light microscopy that visualizes the presence of AMF in roots is not able to differentiate the ratio of each AMF species in the root and nodule tissues in mixed fungal inoculation. The purpose of this study was to characterize the dominant species of mycorrhiza in roots and nodules of plants co-inoculated with mycorrhizal fungi and rhizobial strains. Glomus intraradices (GI), Glomus mosseae (GM), their mix (GI + GM), and six Mesorhizobium ciceri strains were used to inoculate chickpea. Quantitative real time polymerase chain reaction (qRT-PCR) was used to assess occupancy of these fungal species in roots and nodules. Results showed that GI molecular ratio and relative density were higher than GM in both roots and nodules. These differences in molecular ratio and density between GI and GM in nodules were three folds higher than roots. The results suggested that M. ciceri strains have different effects on nodulation and mycorrhizal colonization pattern. Plants with bacterial S3 and S1 strains produced the highest root nodulation and higher fungal density in both the roots and nodules. PMID- 21604101 TI - 2nd Biennial Meeting of the Eurasian Colorectal Technologies Association (ECTA) : Turin, Italy, 15-17 June 2011 ECTA President: F. Seow-Choen Congress President: M. Morino. PMID- 21604102 TI - Nonlinear ionic pulses along microtubules. AB - Microtubules are cylindrically shaped cytoskeletal biopolymers that are essential for cell motility, cell division and intracellular trafficking. Here, we investigate their polyelectrolyte character that plays a very important role in ionic transport throughout the intra-cellular environment. The model we propose demonstrates an essentially nonlinear behavior of ionic currents which are guided by microtubules. These features are primarily due to the dynamics of tubulin C terminal tails which are extended out of the surface of the microtubule cylinder. We also demonstrate that the origin of nonlinearity stems from the nonlinear capacitance of each tubulin dimer. This brings about conditions required for the creation and propagation of solitonic ionic waves along the microtubule axis. We conclude that a microtubule plays the role of a biological nonlinear transmission line for ionic currents. These currents might be of particular significance in cell division and possibly also in cognitive processes taking place in nerve cells. PMID- 21604103 TI - Atrial fibrillation with a giant left atrial appendage can be successfully treated with pulmonary vein antrum isolation. PMID- 21604104 TI - Early double stent thrombosis associated with clopidogrel hyporesponsivenesss. AB - A 57-year-old male patient without cardiovascular history suffered an acute myocardial infarction and underwent drug-eluting stent implantation in the left anterior descending artery. A few days later, the right coronary artery was also stented (drug-eluting stent). Three days later, he was re-admitted to our hospital in cardiogenic shock. Emergent coronary angiography showed total occlusion of both stents. Platelet function analysis (PFA) showed attenuated platelet inhibition in response to clopidogrel treatment. The patient was the carrier of a loss-of-function polymorphism in the CYP2C19 gene, which has been associated with increased incidence of adverse thrombotic events. Antiplatelet therapy was switched to prasugrel and PFA revealed an adequate antiplatelet effect. PMID- 21604105 TI - Native atretic coarctation of the aorta in a 37-year-old hypertensive woman, treated with a low-profile covered stent. PMID- 21604106 TI - Ebstein's anomaly may be caused by mutations in the sarcomere protein gene MYH7. AB - Ebstein's anomaly is a rare congenital heart malformation characterised by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. Associated abnormalities of left ventricular morphology and function including left ventricular noncompaction (LVNC) have been observed. An association between Ebstein's anomaly with LVNC and mutations in the sarcomeric protein gene MYH7, encoding beta-myosin heavy chain, has been shown by recent studies. This might represent a specific subtype of Ebstein's anomaly with a Mendelian inheritance pattern. In this review we discuss the association of MYH7 mutations with Ebstein's anomaly and LVNC and its implications for the clinical care for patients and their family members. PMID- 21604107 TI - Automated analysis of three-dimensional stress echocardiography. AB - Real-time three-dimensional (3D) ultrasound imaging has been proposed as an alternative for two-dimensional stress echocardiography for assessing myocardial dysfunction and underlying coronary artery disease. Analysis of 3D stress echocardiography is no simple task and requires considerable expertise. In this paper, we propose methods for automated analysis, which may provide a more objective and accurate diagnosis. Expert knowledge is incorporated via statistical modelling of patient data. Methods for identifying anatomical views, detecting endocardial borders, and classification of wall motion are described and shown to provide favourable results. We also present software developed especially for analysis of 3D stress echocardiography in clinical practice. Interobserver agreement in wall motion scoring is better using the dedicated software (96%) than commercially available software not dedicated for this purpose (79%). The developed tools may provide useful quantitative and objective parameters to assist the clinical expert in the diagnosis of left ventricular function. PMID- 21604108 TI - How can community health programmes build enabling environments for transformative communication? Experiences from India and South Africa. AB - Much research has examined how to empower the poor to articulate demands for health-enabling living conditions. Less is known about creating receptive social environments where the powerful heed the voices of the poor. We explore the potential for 'transformative communication' between the poor and the powerful, through comparing two well-documented case studies of HIV/AIDS management. The Entabeni Project in South Africa sought to empower impoverished women to deliver home-based nursing to people with AIDS. It successfully provided short-term welfare, but did not achieve local leadership or sustainability. The Sonagachi Project in India, an HIV-prevention programme targeting female sex workers, became locally led and sustainable. We highlight the strategies through which Sonagachi, but not Entabeni, altered the material, symbolic and relational contexts of participants' lives, enabling transformative communication and opportunities for sexual health-enabling social change. PMID- 21604112 TI - Mass spectrometry-driven proteomics: an introduction. AB - Proteins are reckoned to be the key actors in a living organism. By studying proteins, one engages into deciphering a complex series of events occurring during a protein's life span. This starts at the creation of a protein, which is tightly controlled on both a transcriptional (Williams and Tyler, 2007, Curr Opin Genet Dev 17, 88-93) and a translational level (Van Der Kelen et al., 2009, Crit Rev Biochem Mol Biol 44, 143-168). During translation, a primary strand of amino acids undergoes a complex folding process in order to obtain a native three dimensional protein structure (Gross et al., 2003, Cell 115, 739-750). Proteins take on a plethora of functions, such as complex formation, receptor activity, and signal transduction, which ultimately adds up to a cellular phenotype. Consequently, protein analysis is of major interest in molecular biology and involves annotating their presence and localization, as well as their modification state and biochemical context. To accomplish this, many methods have been developed over the last decades, and their general principles and important recent advances in large-scale protein analysis or proteomics are discussed in this review. PMID- 21604113 TI - Metabolic labeling of model organisms using heavy nitrogen (15N). AB - Quantitative proteomics aims to identify and quantify proteins in cells or organisms that have been obtained from different biological origin (e.g., "healthy vs. diseased"), that have received different treatments, or that have different genetic backgrounds. Protein expression levels can be quantified by labeling proteins with stable isotopes, followed by mass spectrometric analysis. Stable isotopes can be introduced in vitro by reacting proteins or peptides with isotope-coded reagents (e.g., iTRAQ, reductive methylation). A preferred way, however, is the metabolic incorporation of heavy isotopes into cells or organisms by providing the label, in the form of amino acids (such as in SILAC) or salts, in the growth media. The advantage of in vivo labeling is that it does not suffer from side reactions or incomplete labeling that might occur in chemical derivatization. In addition, metabolic labeling occurs at the earliest possible moment in the sample preparation process, thereby minimizing the error in quantitation. Labeling with the heavy stable isotope of nitrogen (i.e., (15)N) provides an efficient way for accurate protein quantitation. Where the application of SILAC is mostly restricted to cell culture, (15)N labeling can be used for micro-organisms as well as a number of higher (multicellular) organisms. The most prominent examples of the latter are Caenorhabditis elegans and Drosophila (fruit fly), two important model organisms for a range of regulatory processes underlying developmental biology. Here we describe in detail the labeling with (15)N atoms, with a particular focus on fruit flies and C. elegans. We also describe methods for the identification and quantitation of (15)N-labeled proteins by mass spectrometry and bioinformatic analysis. PMID- 21604114 TI - Trypsin-catalyzed oxygen-18 labeling for quantitative proteomics. AB - Stable isotope labeling based on relative peptide/protein abundance measurements is commonly applied for quantitative proteomics. Recently, trypsin-catalyzed oxygen-18 labeling has grown in popularity due to its simplicity, cost effectiveness, and its ability to universally label peptides with high sample recovery. In (18)O labeling, both C-terminal carboxyl group atoms of tryptic peptides can be enzymatically exchanged with (18)O, thus providing the labeled peptide with a 4 Da mass shift from the (16)O-labeled sample. Peptide (18)O labeling is ideally suited for generating a labeled "universal" reference sample used for obtaining accurate and reproducible quantitative measurements across large number of samples in quantitative discovery proteomics. PMID- 21604115 TI - ICPL labeling strategies for proteome research. AB - Stable isotope labeling in combination with mass spectrometry has emerged as a powerful tool to identify and quantify thousands of proteins within complex protein mixtures. Isotope-coded protein label (ICPL) is capable of high throughput quantitative proteome profiling on a global scale. Since ICPL is based on stable isotope tagging at the free amino groups of intact proteins, it is applicable to any protein sample, including extracts from tissues or body fluids. After labeling of up to four different proteome states, the samples can be combined and the complexity reduced by any separation method currently employed in protein chemistry. After enzymatic cleavage of the protein fractions the ratios of peptides in the different proteome states can be calculated by simple MS-based mass spectrometric analyses. Only peptides that exhibit regulations in the different proteome states are further investigated for identification by tandem-mass spectrometry. The quantification of multiplexed ICPL experiments is greatly facilitated by the recently published ICPLQuant software, which was especially designed to cover the whole ICPL workflow. The method shows highly accurate and reproducible quantification of proteins, yields high sequence coverage, and is indispensable for the comprehensive detection of posttranslational modifications and protein isoforms. PMID- 21604116 TI - Quantitative proteome analysis using isobaric peptide termini labeling (IPTL). AB - The quantitative comparison of proteome level changes across biological samples has become an essential feature in proteomics that remains challenging. We have recently introduced isobaric peptide termini labeling (IPTL), a novel strategy for isobaric quantification based on the derivatization of peptide termini with complementary isotopically labeled reagents. Unlike non-isobaric quantification methods, sample complexity at the MS level is not increased, providing improved sensitivity and protein coverage. The distinguishing feature of IPTL when comparing it to more established isobaric labeling methods (iTRAQ and TMT) is the presence of quantification signatures in all sequence-determining ions in MS/MS spectra, not only in the low mass reporter ion region. This makes IPTL a quantification method that is accessible to mass spectrometers with limited capabilities in the low mass range. Also, the presence of several quantification points in each MS/MS spectrum increases the robustness of the quantification procedure. PMID- 21604117 TI - Complete chemical modification of amine and acid functional groups of peptides and small proteins. AB - The chemical modification of protein thiols by reduction and alkylation is common in the preparation of proteomic samples for analysis by mass spectrometry (MS). Modification at other functional groups has received less attention in MS-based proteomics. Amine modification (Lys, N-termini) by reductive dimethylation or by acylation (e.g., iTRAQ labeling) has recently gained some popularity in peptide based approaches (bottom-up MS). Modification at acidic groups (Asp, Glu, C termini) has been explored very minimally. Here, we describe a sequential labeling strategy that enables complete modification of thiols, amines, and acids on peptides or small intact proteins. This method includes (1) the reduction and alkylation of thiols, (2) the reductive dimethylation of amines, and (3) the amidation of acids with any of several amines. This chemical modification scheme offers several options both for the incorporation of stable isotopes for relative quantification and for improving peptides or proteins as MS analytes. PMID- 21604118 TI - Production and use of stable isotope-labeled proteins for absolute quantitative proteomics. AB - In the field of analytical chemistry, stable isotope dilution assays are extensively used in combination with liquid chromatography-mass spectrometry (LC MS) to provide confident quantification results. Over the last decade, the principle of isotope dilution has been adopted by the proteomic community in order to accurately quantify proteins in biological samples. In these experiments, a protein's concentration is deduced from the ratio between the MS signal of a tryptic peptide and that of a stable isotope-labeled analog, which serves as an internal standard. The first isotope dilution standards introduced in proteomics were chemically synthesized peptides incorporating a stable isotope tagged amino acid. These isotopically labeled peptide standards, which are currently widely used, are generally added to samples after protein isolation and digestion. Thus, if protein enrichment is necessary, they do not allow correction for protein losses that may occur during sample pre-fractionation, nor do they allow the tryptic digestion yield to be taken into account. To reduce these limitations we have developed the PSAQ (Protein Standard Absolute Quantification) strategy using full-length stable isotope-labeled proteins as quantification standards. These standards and the target proteins share identical biochemical properties. This allows standards to be spiked into samples at an early stage of the analytical process. Thanks to this possibility, the PSAQ method provides highly accurate quantification results, including for samples requiring extensive biochemical pre-fractionation. In this chapter, we describe the production of full-length stable isotope-labeled proteins (PSAQ standards) using cell-free expression devices. The purification and quality control of protein standards, crucial for good-quality and accurate measurements, are also detailed. Finally, application of the PSAQ method to a typical protein quantification assay is presented. PMID- 21604119 TI - Organelle proteomics. AB - Proteomics has significantly contributed to improve our understanding of cell structures and functions in the last decade. The possibility to identify large sets of proteins from minute amount of material, linked with the isolation of cellular organelles using various cell fractionation methods, has provided unique insights into the molecular mechanisms governing cell functions in health and disease. The success of this approach relies on the isolation of highly enriched cell fractions enabling the separation of organelles with minimal contamination by other cellular structures. PMID- 21604120 TI - Membrane protein digestion - comparison of LPI HexaLane with traditional techniques. AB - Membrane protein profiling and characterization is of immense importance for the understanding of vital processes taking place across cellular membranes. Traditional techniques used for soluble proteins, such as 2D gel electrophoresis, are sometimes not entirely applicable to membrane protein targets, due to their low abundance and hydrophobic character. New tools have been developed that will accelerate research on membrane protein targets. Lipid-based protein immobilization (LPI) is the core technology in a new approach that enables immobilization and digestion of native membrane proteins inside a flow cell format. The presented method is described in the context of comparing the method to traditional approaches where the sample amount that is digested and analyzed is the same. PMID- 21604121 TI - GeLCMS for in-depth protein characterization and advanced analysis of proteomes. AB - In recent years the array of mass spectrometry (MS) applications to address questions in molecular and cellular biology has greatly expanded and continues to grow. Modern mass spectrometers allow for identification, characterization, as well as quantification of protein compositions and their modifications in complex biological samples. Prior to MS analysis any biological sample needs to be properly prepared for the experiment. Here we present a protocol that combines pre-separation of proteins by 1D gel electrophoresis followed by analysis of in situ digested protein products by tandem mass spectrometry (MS/MS). All steps of the sample preparation are explained in detail, and the procedure is compatible with downstream analysis on any mass spectrometer available. With minor adjustments the protocol can be used with 2D gels as well. The protocol provided can be applied to analyze specific proteins of particular interest as well as entire proteomes. If SILAC-labeled protein samples are mixed prior to gel separation, the protein content of the sample can furthermore be accurately quantified. PMID- 21604122 TI - Exploring new proteome space: combining Lys-N proteolytic digestion and strong cation exchange (SCX) separation in peptide-centric MS-driven proteomics. AB - The current advances in mass spectrometry technology have led to the possibility of analyzing more complex biological samples such as entire proteomes. Here, we describe a new and powerful methodology that combines the use of the metalloendopeptidase Lys-N and strong cation exchange with mass spectrometric analysis. The approach described here allows one to separate peptides with different functional groups. The peptides we are able to isolate are N-terminal peptides, phosphorylated peptides with a single lysine, peptides with a single basic residue (lysine), and peptides with multiply basic residues. When this separation strategy is combined with tandem mass spectrometry that involves both collision-induced dissociation and electron transfer dissociation, one can achieve an optimal targeted strategy for proteome analysis. PMID- 21604123 TI - Quantitation of newly synthesized proteins by pulse labeling with azidohomoalanine. AB - Measuring protein synthesis and degradation rates on a proteomic scale is an important step toward modeling the kinetics in complicated cellular response networks. A gel-free method, able to quantify changes in the formation of new proteins on a 15 min timescale, compatible with mass spectrometry is described. The methionine analogue, azidohomoalanine (azhal), is used to label newly formed proteins during a short pulse-labeling period following an environmental switch in Escherichia coli. Following digestion a selective reaction against azhal containing peptides is applied to enrich these peptides by diagonal chromatography. This technique enables quantitation of hundreds of newly synthesized proteins and provides insight into immediate changes in newly synthesized proteins on a proteomic scale after an environmental perturbation. PMID- 21604124 TI - Analytical strategies in mass spectrometry-based phosphoproteomics. AB - Phosphoproteomics, the systematic study of protein phosphorylation events and cell signaling networks in cells and tissues, is a rapidly evolving branch of functional proteomics. Current phosphoproteomics research provides a large toolbox of strategies and protocols that may assist researchers to reveal key regulatory events and phosphorylation-mediated processes in the cell and in whole organisms. We present an overview of sensitive and robust analytical methods for phosphopeptide analysis, including calcium phosphate precipitation and affinity enrichment methods such as IMAC and TiO(2). We then discuss various tandem mass spectrometry approaches for phosphopeptide sequencing and quantification, and we consider aspects of phosphoproteome data analysis and interpretation. Efficient integration of these stages of phosphoproteome analysis is highly important to ensure a successful outcome of large-scale experiments for studies of phosphorylation-mediated protein regulation. PMID- 21604125 TI - A protocol on the use of titanium dioxide chromatography for phosphoproteomics. AB - Over the past decade phosphoproteomics has become an emerging discipline within proteomics research, focusing on detection of the reversible modification of proteins by phosphorylation of serine, threonine, and tyrosine residues. For successful analysis, phosphopeptide enrichment is often a prerequisite due to their low stoichiometry, heterogeneity, and low abundance. The enrichment of phosphopeptides is often performed manually, which is inherently labor intensive and a major hindrance in large-scale analyses. Automation of the enrichment method would vastly improve reproducibility and thereby facilitate "high throughput" phosphoproteomics research. Here, we describe the setup of a simple, robust, and automated online TiO(2)-based nanoscale chromatographic approach to selectively enrich and separate phosphorylated peptides from proteolytic digests of moderate and high complexity. PMID- 21604126 TI - Positional proteomics at the N-terminus as a means of proteome simplification. AB - One strategy to reduce complexity in proteome analysis is through rational reduction of the proteolytic peptides that constitute the analyte for mass spectrometric analysis. Methods for selective isolation of C- and N-terminal peptides have been developed. In this chapter, we outline the context and variety of methods for selective isolation of N-terminal peptides and detail one method based on negative selection through differential removal of internal peptides. PMID- 21604127 TI - N-terminomics: a high-content screen for protease substrates and their cleavage sites. AB - Proteases play vital roles in many cellular processes and signaling cascades through specific limited cleavage of their targets. It is important to identify what proteins are substrates of proteases and where their cleavage sites are so as to reveal the molecular mechanisms and specificity of signaling. We have developed a method to achieve this goal using a strategy that chemically tags the substrate's alpha amine generated by proteolysis, enriches for tagged peptides, and identifies them using liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS). Peptide MS/MS data are searched against a database to reveal what proteins are cleaved, whereby peptide N-termini demarcate sites of protease cleavage. PMID- 21604128 TI - Protease specificity profiling by tandem mass spectrometry using proteome-derived peptide libraries. AB - Protease specificity profiling using proteome-derived, database-searchable peptide libraries is a novel approach to define the active site specificity of proteolytic enzymes we call PICS (Proteomic Identification of protease Cleavage Sites). Proteome-derived peptide libraries are generated by trypsin, GluC, or chymotrypsin digestion of biologically relevant proteomes, such as cytosolic lysates, to generate three separate libraries that each differ from the others in their C-terminal amino acid residues according to the protease specificity. Primary amines of all peptides are then chemically protected so that after incubation with a test protease, the neo-N-termini of the prime-side cleavage products with exposed alpha-amines can be specifically biotinylated, enriched, and identified by liquid chromatography-tandem mass spectrometry. The corresponding nonprime-side sequences are derived bioinformatically. Suited for all protease classes except carboxyproteases and those aminoproteases and dipeptidases requiring a free alpha-amine for cleavage, PICS simultaneously profiles the specificity of prime and nonprime positions and directly determines scissile peptide bonds of up to hundreds of cleavage site sequences in a single experiment. This wealth of sequence specificity information also allows for the investigation of subsite cooperativity. Herein we describe a simplified procedure to produce PICS peptide libraries, the methods to perform a PICS assay, and a new method of data analysis. PMID- 21604129 TI - Identification of proteolytic products and natural protein N-termini by Terminal Amine Isotopic Labeling of Substrates (TAILS). AB - Determining the sequence of protein N-termini and their modifications functionally annotates proteins since translation isoforms, posttranslational modifications, and proteolytic truncations direct localization, activity, and the half-life of most proteins. Here we present in detail the steps required to perform our recently described approach we call Terminal Amine Isotopic Labeling of Substrates (TAILS), a combined N-terminomics and protease substrate discovery degradomics platform for the simultaneous quantitative and global analysis of the N-terminome and proteolysis in one MS/MS experiment. By a 3-day procedure with flexible alpha- and E-amine labeling and blocking options, TAILS removes internal tryptic and C-terminal peptides by binding to a dendritic polyglycerol aldehyde polymer. Therefore, by negative selection, this enriches for both the N-terminal labeled peptides and all forms of naturally blocked N-terminal peptides. In addition to providing valuable proteome annotation, the simultaneous analysis of the original mature N-terminal peptides enables these peptides to be used for higher confidence protein substrate identification by two or more different and unique peptides. Second, the analysis of the N-terminal peptides forms a statistical classifier to determine valid isotope ratio cutoffs in order to identify with high-confidence protease-generated neo-N-terminal peptides. Third, quantifying the loss of acetylated or cyclized N-terminal peptides that have been cleaved extends overall substrate coverage. Hence, TAILS allows for the global analysis of the N-terminome and determination of cleavage site motifs and substrates for protease including those with unknown or broad specificity. PMID- 21604130 TI - Lectins as tools to select for glycosylated proteins. AB - Glycosylation has been recognized as one of the most important modifications on proteins. The interactions between proteins and glycans are known to play an important role in many biological processes. Lectins are carbohydrate-binding proteins that can specifically interact with and select for carbohydrate structures. The technique of lectin affinity chromatography takes advantage of this specific interaction and enables the selection and purification of glycoproteins with carbohydrate structures complementary to the lectin-binding site. Depending on the carbohydrate specificity of the lectin glycoprotein fractions enriched for example, high mannose or complex N-glycans or O-glycans can be obtained. Afterward both the protein part and the glycan part can be analyzed in more detail allowing the identification of the interacting partners and the type of glycans involved. PMID- 21604131 TI - Strong cation exchange chromatography for analysis of sialylated glycopeptides. AB - Glycosylations represent major and essential co- and post-translational modification forms of proteins and facilitate a multitude of functions such as cell-cell interactions as well as protein folding and stability. The analysis of protein glycosylation is still an enormous task due to the vast heterogeneity and multitude of different possible carbohydrate structures. The elucidation of glycosylation sites - the attachment points of carbohydrate structures to the polypeptide backbone - is often among the first necessary steps of analysis. Therefore, we here present a simple protocol for charge-based enrichment of sialylated glycopeptides by strong cation exchange chromatography and subsequent analysis of glycosylation sites by mass spectrometry. PMID- 21604132 TI - Titanium dioxide enrichment of sialic acid-containing glycopeptides. AB - Glycosylation is one of the many post-translational protein modifications that regulate several biological processes of proteins and lipids. In particular aberrant sialylation, at the terminal position of the glycan structures of cell surface proteins, occurs in numerous diseases such as cancer metastasis and viral infections. Methodological improvements in the sample preparation and analysis currently enable the detailed identification of the glycosylation sites and glycan structure characterization. In this context, the aim of this chapter is to describe a methodology to identify the glycosylation site of N-linked sialylated glycoproteins. The method relies on the specificity of titanium dioxide affinity chromatography to isolate sialic acid-containing glycopeptides. After enzymatic release of the glycans, the enriched sialylated glycopeptides are analyzed by mass spectrometry. This strategy was applied to a crude membrane fraction of EGF stimulated HeLa cells metabolically labeled with SILAC enabling both qualitative and quantitative analyses of sialoglycopeptides. PMID- 21604133 TI - Chemical de-O-glycosylation of glycoproteins for applications in LC-based proteomics. AB - This paper describes a cyclic on-column procedure for the sequential degradation of complex O-glycans on proteins by periodate oxidation of sugars and cleavage of oxidation products by elimination. Glycoproteins are immobilized to alkali stable, reversed-phase Poros 20 beads, desialylated by treatment with dilute trifluoroacetic acid, and de-O-glycosylated by two degradation cycles before the eluted apoproteins are digested with trypsin for analysis by liquid chromatography electrospray ionization-mass spectrometry. Even complex glycan moieties are removed under mild conditions with only minimal effects on structural integrity of the peptide core by fragmentation, dehydration, or racemization of lysine and arginine residues. The protocol is also applicable on gel-immobilized glycoproteins after 1D or 2D gel electrophoresis. Conversion of O glycoproteins into their corresponding apoproteins results in facilitated accessibility of tryptic cleavage sites, increases the numbers of peptide fragments, and accordingly enhances protein coverage and identification rates within the subproteome of mucin-type O-glycoproteins. The protocol is suitable for automatization, but due to partial elution from the Poros 20 columns it is not recommended for applications on the glycopeptide level. PMID- 21604134 TI - Ubiquitination and degradation of proteins. AB - Modification by ubiquitin (Ub) and ubiquitin-like proteins (UbLs) is involved in the regulation of numerous cellular processes and has therefore become an important subject of research in various areas of biomedicine. The large number of components of the system (~1,500), most of them being ligases (~800) that recognize their target substrates specifically, along with the complexity of the ubiquitination process, mostly the synthesis of the hallmark polyubiquitin chains, has rendered studies of many of the processes related to the activity of the system resistant to detailed mechanistic analysis. Thus, our knowledge of the modes of recognition of target substrates by ligases and of consensus ubiquitination sites is sparse. We also lack basic tools such as antibodies directed against specific internal polyubiquitin chain linkages and analytical methods to decipher the structure of intact chains and their formation. All these tools are essential in order to understand the mechanisms that underlie the diverse activities of the system, proteolytic as well as non-proteolytic, and the manner in which it exerts its high specificity and selectivity toward its myriad substrates. Here we describe selected basic procedures that allow one to become acquainted with this rapidly evolving field, realizing that one cannot provide a comprehensive coverage of all or even a small part of the methodologies related to this research area. We provide information on how to set up a cell-free system for ubiquitination - a powerful tool that enables researchers to reconstitute the modification from purified components - and how to identify ubiquitin adducts in cells. Additionally, we describe methods to follow stability (degradation) of proteins in cell-free systems and in cells. PMID- 21604135 TI - Bioinformatics challenges in mass spectrometry-driven proteomics. AB - Mass spectrometry-based proteomics has become an essential part of the analytical toolbox of the life sciences. With the ability to identify and quantify hundreds to thousands of proteins in high throughput, the field has contributed its fair share to the data avalanche coming from the so-called omics fields. As a result, the challenges involved in processing and managing this flood of data have grown as well. This chapter will point out and discuss these challenges, starting from the processing of raw mass spectrometry data into peaks, over the identification of peptides and proteins, to the quantification of the identified molecules. Finally, the informatics aspects of the nascent field of targeted proteomics are outlined as well. PMID- 21604136 TI - A case study on the comparison of different software tools for automated quantification of peptides. AB - MS-driven proteomics has evolved over the past two decades to a high tech and high impact research field. Two distinct factors clearly influenced its expansion: the rapid growth of an arsenal of instrument and proteomic techniques that led to an explosion of high quality data and the development of software tools to analyze and interpret these data which boosted the number of scientific discoveries. In analogy with the benchmarking of new instruments and proteomic techniques, such software tools must be thoroughly tested and analyzed. Recently, new tools were developed for automatic peptide quantification in quantitative proteomic experiments. Here we present a case study where the most recent and frequently used tools are analyzed and compared. PMID- 21604137 TI - In vitro bio-immunological and cytotoxicity studies of poly(2-oxazolines). AB - Poly(2-oxazolines) with varying alkyl chain lengths (e.g., methyl, ethyl, aryl) and molar masses have been tested for cell cytotoxicity in vitro. A standard 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used for the estimation of cell viability. Two monomers, 2-methyl-2-oxazoline and 2 ethyl-2-oxazoline, were found to provide polymers with non-cytotoxic properties. The dependence of cell viability on molar mass confirmed the expected trend; the viability increased with the higher molar mass of poly(2-ethyl-2-oxazoline) (PETOX), up to 15,000 g/mol. The results obtained for the polymers with aliphatic side chains were compared with the analogues that possessed an aromatic moiety. All results confirmed low cytotoxicity of the polymers prepared by cationic polymerization of 2-alkyl- and 2-aryl-2-oxazolines, which supports their utilization in biomedical applications. Fluorescence microscopy and steady-state fluorescence were used to observe pyrene-labeled polymer interactions with living cells. Polymer accumulated within the cells was found to be dependent on polymer concentration in media. The immunoefficiency of aromatic and aliphatic oxazoline polymers and copolymers was also studied. Phagocytic and metabolic activities of macrophages were used to assess the immunosuppressive effects of the selected copolymers for possible applications in drug delivery and immunobiology. Overall, the tested polymers demonstrated no significant influences on the cellular immunological parameters. PMID- 21604138 TI - beta-tricalcium-phosphate stimulates the differentiation of dental follicle cells. AB - The use of dental progenitor cells is a straightforward strategy for regenerative dentistry. For example a cell based therapy with dental follicle cells (DFCs) could be a novel therapeutic strategy for the regeneration of oral tissues in the future. For the regeneration of large bone defects for example dental progenitor cells have to be combined with bone substitutes as scaffolds. This study therefore investigated cell attachment (scanning electron microscopy), cell vitality/proliferation (WST-1 assay) and cell differentiation (under in vitro conditions) of human DFCs on synthetic beta-tricalcium phosphate (TCP). DFCs showed considerable cell attachment and proliferation on TCP. Moreover, TCP stimulates osteogenic differentiation in comparison to DFCs with a standard protocol. Here, for example, the osteoblast marker bone sialoprotein (BSP) was highly expressed on TCP, but almost absent in differentiated DFCs without TCP. In conclusion, our study shows that TCP is an excellent scaffold for DFCs for oral tissue regeneration. PMID- 21604139 TI - Functionalisation of PLLA nanofiber scaffolds using a possible cooperative effect between collagen type I and BMP-2: impact on growth and osteogenic differentiation of human mesenchymal stem cells. AB - Mesenchymal stem cell differentiation of osteoblasts is triggered by a series of signaling processes including integrin and bone morphogenetic protein (BMP), which therefore act in a cooperative manner. The aim of this study was to analyze whether these processes can be remodeled in an artificial poly-(L)-lactide acid (PLLA) based nanofiber scaffold. Matrices composed of PLLA-collagen type I or BMP 2 incorporated PLLA-collagen type I were seeded with human mesenchymal stem cells (hMSC) and cultivated over a period of 22 days, either under growth or osteoinductive conditions. During the course of culture, gene expression of alkaline phosphatase (ALP), osteocalcin (OC) and collagen I (COL-I) as well as Smad5 and focal adhesion kinase (FAK), two signal transduction molecules involved in BMP-2 or integrin signaling were analyzed. Furthermore, calcium and collagen I deposition, as well as cell densities and proliferation, were determined using fluorescence microscopy. The incorporation of BMP-2 into PLLA-collagen type I nanofibers resulted in a decrease in diameter as well as pore sizes of the scaffold. Mesenchymal stem cells showed better adherence and a reduced proliferation on BMP-containing scaffolds. This was accompanied by an increase in gene expression of ALP, OC and COL-I. Furthermore the presence of BMP-2 resulted in an upregulation of FAK, while collagen had an impact on the gene expression of Smad5. Therefore these different strategies can be combined in order to enhance the osteoblast differentiation of hMSC on PLLA based nanofiber scaffold. By doing this, different signal transduction pathways seem to be up regulated. PMID- 21604141 TI - CT Colonography to exclude colorectal cancer in symptomatic patients. AB - OBJECTIVES: CT Colonography (CTC) is being increasingly used for the radiological evaluation of colorectal symptoms. Aim of this study was to assess the role of CTC in excluding a colorectal cancer (CRC) in older symptomatic patients. METHODS: 1,359 CTC studies performed between March 2002 and December 2007 were analysed retrospectively. Gold standard was an endoscopic examination within 1 year and/or clinical, endoscopic and/or radiological follow-up until the time of data analysis. Patients not diagnosed as having a CRC on CTC were assumed as true negatives if the gold standard was negative and did not feature on the regional cancer registry (at least 18 months post-CTC). Sensitivity, specificity, positive and negative predictive values were calculated for detection of colorectal cancer. RESULTS: After exclusions, 1,177 CTC studies were included. These were undertaken in 463 men and 714 women. Median age of patients undergoing CTC was 71 (range, 27-96) years. 59 invasive CRC were detected. Median follow-up was 34.5 (range 18-84) months. Three small colorectal cancers were missed. Sensitivity and negative predictive value for CRC were 94.9% (95% CI:84.9%-98.7%) and 99.7% (95% CI:99.1%-99.9%) respectively. CONCLUSIONS: CTC has a high sensitivity and negative predictive value in excluding a CRC in patients with colorectal symptoms. PMID- 21604142 TI - Profile of French community-dwelling older adults supplemented with vitamin D: findings and lessons. AB - INTRODUCTION: The vast majority of older French adults exhibit some degree of hypovitaminosis D. The objective of this cross-sectional study was to determine the rate and the reasons for vitamin D prescription among older French adult community dwellers. METHODS: Vitamin D supplementation was systematically assessed among 1876 French community dwellers aged >= 65 years. Theoretical indications for vitamin D supplementation were collected, ie, the causes of hypovitaminosis D (older age, male gender, kidney failure, undernutrition, polymorbidity) or its clinical complications (vertebral or non-vertebral fractures, gait disturbances, history of falls, muscle weakness, and cognitive impairment). RESULTS: In total, 13.8% of the subjects (n=258) had vitamin D supplementation. They were more often malnourished (P=0.002), exhibited polymorbidity (P<0.001) and muscle weakness (P<0.001), and had a history of vertebral fractures (P<0.001), non-vertebral fractures (P<0.001), and accidental falls (P<0.001). Vitamin D supplementation was explained by the number of complications of hypovitaminosis D (odds ratio [OR]=1.61, P<0.001) including vertebral fractures (adjusted OR=1.49, P=0.007), non-vertebral fractures (adjusted OR=1.74, P=0.026), accidental falls (adjusted OR=1.44, P=0.015), and muscle weakness (adjusted OR=3.96, P<0.001), but not by the number of causes of hypovitaminosis D (P=0.464). CONCLUSION: Even if vitamin D supplementation is selected well for appropriate patients, the rate of supplementation remains insufficient in France, and probably comes too late, ie, at the stage of complications of hypovitaminosis D. These findings should encourage physicians to supplement vitamin D more often and sooner in their elderly patients. PMID- 21604143 TI - Sequence correction of random coil chemical shifts: correlation between neighbor correction factors and changes in the Ramachandran distribution. AB - Random coil chemical shifts are necessary for secondary chemical shift analysis, which is the main NMR method for identification of secondary structure in proteins. One of the largest challenges in the determination of random coil chemical shifts is accounting for the effect of neighboring residues. The contributions from the neighboring residues are typically removed by using neighbor correction factors determined based on each residue's effect on glycine chemical shifts. Due to its unusual conformational freedom, glycine may be particularly unrepresentative for the remaining residue types. In this study, we use random coil peptides containing glutamine instead of glycine to determine the random coil chemical shifts and the neighbor correction factors. The resulting correction factors correlate to changes in the populations of the major wells in the Ramachandran plot, which demonstrates that changes in the conformational ensemble are an important source of neighbor effects in disordered proteins. Glutamine derived random coil chemical shifts and correction factors modestly improve our ability to predict (13)C chemical shifts of intrinsically disordered proteins compared to existing datasets, and may thus improve the identification of small populations of transient structure in disordered proteins. PMID- 21604144 TI - Normality and naturalness: a comparison of the meanings of concepts used within veterinary medicine and human medicine. AB - This article analyses the different connotations of "normality" and "being natural," bringing together the theoretical discussion from both human medicine and veterinary medicine. We show how the interpretations of the concepts in the different areas could be mutually fruitful. It appears that the conceptions of "natural" are more elaborate in veterinary medicine, and can be of value to human medicine. In particular they can nuance and correct conceptions of nature in human medicine that may be too idealistic. Correspondingly, the wide ranging conceptions of "normal" in human medicine may enrich conceptions in veterinary medicine, where the discussions seem to be sparse. We do not argue that conceptions from veterinary medicine should be used in human medicine and vice versa, but only that it could be done and that it may well be fruitful. Moreover, there are overlaps between some notions of normal and natural, and further conceptual analysis on this overlap is needed. PMID- 21604145 TI - Response to peginterferon-alfa 2b and ribavirin in Japanese patients with chronic hepatitis C genotype 2. AB - BACKGROUND: The current standard treatment for patients infected with hepatitis C virus (HCV) of genotype 2 is the combination of peginterferon (PEG-IFN) plus ribavirin (RBV) for 24 weeks. AIMS: We assessed the sustained virological response (SVR) rates in HCV genotype 2-infected Japanese patients in relation to the duration of treatment. METHODS: Between 2006 and 2009, among 147 patients with HCV genotype 2-infection in Chiba Prefecture, 138 consecutive patients were finally enrolled. Twenty-one, 97 and 20 patients were treated with PEG-IFN-alfa 2b plus RBV for 16, 24 and 48 weeks, respectively. Epidemiological data and treatment outcomes were retrospectively evaluated. HCV RNA was measured with COBAS AMPLICOR HCV Monitor Test v. 2.0. RESULTS: The overall SVR rate was 82.6% (114 of 138): treatment-naive patients, 86.4% (89 of 103); patients with history of previous treatment, 71.4% (25 of 35). Patients treated for 16, 24 and 48 weeks obtained SVR rates of 66.6% (14 of 21), 86.5% (84 of 97) and 80.0 (16 of 20), respectively. CONCLUSIONS: The SVR rates of PEG-IFN-alfa 2b plus RBV in Japanese patients were similar to those in previous studies. Combination treatment for 24 weeks for some patients infected with HCV genotype 2 may be superior to that for 16 weeks. More precise patient selection will be needed to shorten the combination treatment. PMID- 21604146 TI - Computational modeling of bone density profiles in response to gait: a subject specific approach. AB - The goal of this study is to explore the potential of computational growth models to predict bone density profiles in the proximal tibia in response to gait induced loading. From a modeling point of view, we design a finite element-based computational algorithm using the theory of open system thermodynamics. In this algorithm, the biological problem, the balance of mass, is solved locally on the integration point level, while the mechanical problem, the balance of linear momentum, is solved globally on the node point level. Specifically, the local bone mineral density is treated as an internal variable, which is allowed to change in response to mechanical loading. From an experimental point of view, we perform a subject-specific gait analysis to identify the relevant forces during walking using an inverse dynamics approach. These forces are directly applied as loads in the finite element simulation. To validate the model, we take a Dual Energy X-ray Absorptiometry scan of the subject's right knee from which we create a geometric model of the proximal tibia. For qualitative validation, we compare the computationally predicted density profiles to the bone mineral density extracted from this scan. For quantitative validation, we adopt the region of interest method and determine the density values at fourteen discrete locations using standard and custom-designed image analysis tools. Qualitatively, our two- and three-dimensional density predictions are in excellent agreement with the experimental measurements. Quantitatively, errors are less than 3% for the two dimensional analysis and less than 10% for the three-dimensional analysis. The proposed approach has the potential to ultimately improve the long-term success of possible treatment options for chronic diseases such as osteoarthritis on a patient-specific basis by accurately addressing the complex interactions between ambulatory loads and tissue changes. PMID- 21604147 TI - Live en face imaging of aortic valve leaflets under mechanical stress. AB - Soft tissues, such as tendons, skin, arteries, or lung, are constantly subject to mechanical stresses in vivo. None more so than the aortic heart valve that experiences an array of forces including shear stress, cyclic pressure, strain, and flexion. Anisotropic biaxial cyclic stretch maintains valve homeostasis; however, abnormal forces are implicated in disease progression. The response of the valve endothelium to deviations from physiological levels has not been fully characterized. Here, we show the design and validation of a novel stretch apparatus capable of applying biaxial stretch to viable heart valve tissue, while simultaneously allowing for live en face endothelial cell imaging via confocal laser scanning microscopy (CLSM). Real-time imaging of tissue is possible while undergoing highly characterized mechanical conditions and maintaining the native extracellular matrix. Thus, it provides significant advantages over traditional cell culture or in vivo animal models. Planar biaxial tissue stretching with simultaneous live cell imaging could prove useful in studying the mechanobiology of any soft tissue. PMID- 21604148 TI - Comparative analysis of budded virus infectivity of Bombyx mandarina and B. mori nucleopolyhedroviruses. AB - Bombyx mandarina nucleopolyhedrovirus (BomaNPV) is a variant of Bombyx mori nucleopolyhedrovirus (BmNPV). BomaNPV S1 strain has been reported to be significantly less virulent than the BmNPV T3 strain via the oral infection route in B. mori larvae, but other features of S1 including budded virus (BV) infectivity and virus propagation in cultured cells are still unknown. In this study, we compared BV infectivity of S1 and T3 in B. mori larvae and cultured cells. Larval bioassays by intrahemocoelic BV injection revealed that the median lethal dose of S1's BV was approximately three times lower than that of T3. In addition, S1 produced more BVs and occlusion bodies (OBs) in the hemolymph of B. mori larvae compared with T3. Furthermore, we observed that the locomotion was enhanced earlier and the median lethal time was shorter in S1-infected larvae compared with those in T3-infected larvae. Western blot analysis of S1- and T3 infected BmN cells revealed that expression of late and very late gene products in S1-infected cells was higher than that in T3-infected cells. Collectively, these results clearly show that S1's BV infectivity is higher than that of T3 in both B. mori larvae and cultured cells, although S1's OBs are much less infectious to B. mori larvae than T3's. PMID- 21604149 TI - Comparative complete genome analysis of Indian type A foot-and-mouth disease virus field isolates. AB - Comparative complete genome analysis of 17 serotype A Indian field isolates representing different genotypes and sub-lineages is presented in this report. Overall 79% of amino acids were invariant in the coding region. Chunk deletion of nucleotide was observed in S and L fragment of 5'-UTR. More variability which is comparable to that of capsid coding region was found in L and 3A region. Functional motifs and residues critical for virus biology were conserved most. Polyprotein cleavage sites accepted few changes. Many sites were detected to be under positive selection in L, P1, 2C, 3A, 3C, and 3D region and of which some are functionally important and antigenically critical. Genotype/lineage specific signature residues could be identified which implies evolution under different selection pressure. Transmembrane domain could be predicted in 2B, 2C, 3A, and 3C proteins in agreement with their membrane binding properties. Phylogenetic analysis at complete coding region placed the isolates in genotype IV, VI, and VII and two broad clusters comprising VP3(59)-deletion and non-deletion group within genotypes VII. The VP3(59)-deletion group has diversified genetically with time giving rise to three lineages. Incongruence in tree topology observed for different non structural protein coding region and UTRs-based phylogeny indicate suspected recombination. PMID- 21604150 TI - Molecular characterization of a new Tospovirus infecting soybean. AB - A new, widespread disease was recently observed in soybean in the United States. The disease, named Soybean vein necrosis, is manifested by intraveinal chlorosis and necrosis, and has been found in almost all of the 50 fields visited over a period of 3 years in the midwest and midsouth part of the United States. A virus was isolated from symptomatic material, and detection protocols were developed. More than 150 symptomatic specimens collected from seven US States were tested, and all were found positive for the virus unlike 75 asymptomatic samples, revealing the absolute association between virus and disease. Protein pairwise comparisons coupled with phylogenetic analyses indicate that the virus is a new member of the genus Tospovirus. PMID- 21604151 TI - Predicting urban outdoor thermal comfort by the Universal Thermal Climate Index UTCI--a case study in Southern Brazil. AB - Recognising that modifications to the physical attributes of urban space are able to promote improved thermal outdoor conditions and thus positively influence the use of open spaces, a survey to define optimal thermal comfort ranges for passers by in pedestrian streets was conducted in Curitiba, Brazil. We applied general additive models to study the impact of temperature, humidity, and wind, as well as long-wave and short-wave radiant heat fluxes as summarised by the recently developed Universal Thermal Climate Index (UTCI) on the choice of clothing insulation by fitting LOESS smoothers to observations from 944 males and 710 females aged from 13 to 91 years. We further analysed votes of thermal sensation compared to predictions of UTCI. The results showed that females chose less insulating clothing in warm conditions compared to males and that observed values of clothing insulation depended on temperature, but also on season and potentially on solar radiation. The overall pattern of clothing choice was well reflected by UTCI, which also provided for good predictions of thermal sensation votes depending on the meteorological conditions. Analysing subgroups indicated that the goodness-of-fit of the UTCI was independent of gender and age, and with only limited influence of season and body composition as assessed by body mass index. This suggests that UTCI can serve as a suitable planning tool for urban thermal comfort in sub-tropical regions. PMID- 21604152 TI - The influence of altitude and urbanisation on trends and mean dates in phenology (1980-2009). AB - Long-term studies on urban phenology using network data are commonly limited by the small number of observation sites within city centres. Moreover, cities are often located on major rivers and consequently at lower altitudes than their rural surroundings. For these reasons, it is important (1) to go beyond a plain urban-rural comparison by taking the degree of urbanisation into account, and (2) to evaluate urbanisation and altitudinal effects simultaneously. Temporal phenological trends (1980-2009) for nine phenological spring events centred on the German cities of Frankfurt, Cologne and Munich were analysed. Trends of phenological onset dates were negative (i.e. earlier onset in phenology) for 96% of the 808 time series and significantly negative for 56% of the total number. Mean trends for the nine phenological events ranged between -0.23 days year(-1) for beech and -0.50 days year(-1) for hazel. The dependence of these trends and of mean dates on altitude and on the degree of urbanisation was explored. For mean dates, we demonstrated an earlier phenological onset at lower altitude and with a higher degree of urbanisation: altitude effects were highly significant and ranged between 1.34 days (100 m)(-1) (beech) and 4.27 days (100 m)(-1) (hazel). Coefficients for the log-transformed urban index were statistically significant for five events and varied greatly between events (coefficients from 1.74 for spruce to -5.08 for hazel). For trends in phenology, altitude was only significant for Norway maple, and no urban effects were significant. Hence, trends in phenology did not change significantly with higher altitudes or urbanised areas. PMID- 21604153 TI - The influence of wind direction on the capture of the wood warbler (Phylloscopus sibilatrix), an uncommon migratory species in the western Mediterranean. AB - The wood warbler (Phylloscopus sibilatrix) is a migratory species in the western Mediterranean wintering in the Gulf of Guinea region, West Africa. In autumn and spring, this species, along with the populations breeding in Ireland and Britain, uses the Italian peninsula as its main axis of migration. From the data of captured birds at several ringing stations in the western Mediterranean (Balearic Islands and coastal Iberian Peninsula), we analyzed capture rates of the species during spring migration from 1993 to 2007. Based on the selection of days with a significant number of captures and those without captures, we analyzed the effect of wind direction over the western Mediterranean to determine a relationship between winds and the number of captures. From a total of 663 wood warblers captured between 1993 and 2007, a total of 31 days have been selected as significant days with a high number of captures, and 31 days have been selected as no-capture days. On days of maximum captures, winds coming from an easterly direction, i.e. Algeria and Tunisia, were dominant, indicating days with a clear eastern component. Contrary to expected results, captures were also made on days when the wind direction was predominantly from a northerly direction. Analysis of the origin of the winds in north eastern Spain (western Mediterranean) revealed that the majority of northerly winds originated from Africa and not from Europe as is usual for this region. Days or periods selected as no-capture days were characterized by winds coming from a northerly (European origin) or westerly direction. PMID- 21604154 TI - Role of endoplasmic reticulum stress in the amygdaloid kindling model of rats. AB - Endoplasmic reticulum (ER) is an organelle responsible for correct folding and sorting of proteins contributing to neurogenesis and neuronal cell death. We used rapid kindling to analyze specific ER stress marker expression underlying focal epileptogenesis. Seven-week-old rats were divided into three groups: sham (n = 6), partially kindled (n = 8), and over-kindled rats (n = 9). Over kindled rats received over100 stimuli. Partially kindled animals had stimuli halted at stage 2. Protein from ipsilateral hippocampus was electrophoresed on SDS-PAGE, followed by hybridization with primary antibodies, anti-KDEL (-Lys-Asp-Glu-coo-), Bcl-2, BDNF (brain-derived neurotrophic factor), CHOP (C/EBP-homolog protein), C/EBP (CCAAT/enhancer-binding protein), NMDA (N-methyl-D-aspartate; -R1 &2A), GluR1 (glutamate receptor), and beta-tubulin. Western blotting revealed that the ER stress marker BiP (immunoglobulin heavy chain-binding protein) was markedly increased in both partially- and over-kindled groups. BiP expression was ninefold greater than control in partially kindling while twofold greater than control in over-kindled animals. Although ER stress response was accelerated, CHOP expression, which upregulates when apoptosis signaling is accelerated by ER stress, was suppressed. Bcl-2, which acts as an anti-apoptotic molecule, was upregulated in the over-kindled group. Remarkable elevation of BiP was found in partially kindled animals, but not in over-kindled. Over-kindled rats had spontaneous generalized seizure, while partially kindled ones had only partial seizures. Elevation of markers of ER stress in partial seizures might reflect transfer of discharge to contralateral limbic structures. We observed indications of functional changes and neurogenesis in limbic structure during kindling. Widespread indications of functional changes in several membrane and secreted proteins, including NMDA-R1 & R2A and BDNF, for mossy fiber re-construction on the CA3 area, which are related to protein synthesis in the ER, may be important in epileptogenesis. PMID- 21604155 TI - Mini-ruby is rapidly taken up by neurons and astrocytes in organotypic brain slices. AB - Cholinergic neurons are intensively studied, because they degenerate in Alzheimer's disease. Although neurotracer techniques are widely used to study axonal transport, guidance, regeneration or sprouting it is not clear if cholinergic neurons can be stained by tracer techniques and studied in brain slices. The aim of the present study was to evaluate the characteristics of the neurotracer Mini-ruby in organotypic brain slices of the basal nucleus of Meynert (nBM), focusing on cholinergic neurons. Mini-ruby is a biotinylated dextran amine and is taken up very fast by a variety of cells. When 2-week old nerve growth factor-incubated brain slices of the nBM were treated with Mini-ruby crystals for 1 h, only a few (2-3%) cholinergic neurons were clearly labeled as shown by co localization with choline acetyltransferase. The staining was found in neuN positive neurons and microtubule associated protein-2 (MAP-2)-positive nerve fibers. A very rapid dynamic change was observed in these labeled varicosities within seconds. However, Mini-ruby was taken up also by many glutamine synthethase-positive astrocytes. At the site of Mini-ruby application an intense CD11b-positive microglial staining was evident. In conclusion, neurons and astrocytes in organotypic brain slices can be labeled very fast with the fluorescent dye Mini-ruby which undergoes dynamic processes. PMID- 21604156 TI - Association between the p53 polymorphisms and breast cancer risk: meta-analysis based on case-control study. AB - p53 is a tumor suppressor gene and plays an important role in the etiology of breast cancer. However, studies on the association between p53 polymorphisms and breast cancer risk have yielded conflicting results. We performed a meta-analysis to investigate the association between breast cancer and the p53 polymorphisms codon 72 (27,046 cases and 30,998 controls), IVS3 16 bp (3,332 cases and 3,700 controls) and IVS6+62A>G (8,787 cases and 9,869 controls) in different inheritance models. When all the eligible studies of codon 72 polymorphism were pooled into this meta-analysis, there was no evidence of significant association between breast cancer risk and p53 codon 72 polymorphism in any genetic model. However, in the stratified analysis for Indian population, significantly association was observed in additive model (OR = 0.62, 95% CI = 0.46-0.82, P value of heterogeneity test [P (h)] = 0.153) and recessive model (OR = 0.70, 95% CI = 0.50-0.92, P (h) = 0.463). IVS3 16 bp was significantly associated with breast cancer risk in a pooled 15 studies dataset (dominant model: OR = 1.14, 95% CI = 1.02-1.27, P (h) = 0.30; recessive model: OR = 1.61, 95% CI = 1.21-2.25, P(h) = 0.25; additive model: OR = 1.66, 95% CI = 1.24-2.21, P (h) = 0.28). No significant association was found between IVS6+62A>G polymorphism and breast cancer risk in a total of 14 studies. In summary, these results indicate that IVS3 16 bp is likely an important genetic marker contributing to susceptibility of breast cancer, and codon 72 homozygous mutants may be associated with decreased breast cancer risk in Indian population. PMID- 21604157 TI - Breast cancer risk assessment in women aged 70 and older. AB - Although the benefit of screening mammography for women over 69 has not been established, it is generally agreed that screening recommendations for older women should be individualized based on health status and breast cancer risk. However, statistical models to assess breast cancer risk have not been previously evaluated in this age group. In this study, the original Gail model and three more recent models that include mammographic breast density as a risk factor were applied to a cohort of 19,779 Vermont women aged 70 and older. Women were followed for an average of 7.1 years and 821 developed breast cancer. The predictive accuracy of each risk model was measured by its c-statistic and associations between individual risk factors and breast cancer risk were assessed by Cox regression. C-statistics were 0.54 (95% CI = 0.52-0.56) for the Gail model, 0.54 (95% CI = 0.51-0.56) for the Tice modification of the Gail model, 0.55 (95% CI = 0.53-0.58) for a model developed by Barlow and 0.55 (95% CI = 0.53 0.58) for a Vermont model. These results indicate that the models are not useful for assessing risk in women aged 70 and older. Several risk factors in the models were not significantly associated with outcome in the cohort, while others were significantly related to outcome but had smaller relative risks than estimated by the models. Age-related attenuation of the effects of some risk factors makes the prediction of breast cancer in older women particularly difficult. PMID- 21604158 TI - [Histology-based algorithm in the molecular diagnosis of mutations of the Epidernal Growth Factor Receptor (EGFR) in non-small cell lung cancer]. AB - Patients with stage IIIB and IV non-small cell lung carcinoma (NSCLC) harboring an activating mutation of the Epidermal Growth Factor Receptor (EGFR) Gene should be treated first-line with Gefitinib, an EGFR tyrosine kinase inhibitor (TKI). EGF receptor mutations are most common in adenocarcinomas, especially non mucinous type, rare in squamous cell carcinomas and sarcomatoid carcinomas, and do not occur in neuroendocrine carcinomas. Therefore, the Pulmonary Pathology Working Group of the Austrian Society of Pathology, after intense discussions and in consensus with Oncologists and Pulmonologists, recommends a priori EGFR mutation analysis for all cases of adenocarcinoma, and for all other NSCLC upon clinical request. This will markedly reduce waiting time for those patients, which most likely will have the greatest benefit from EGFR TKI therapy. PMID- 21604159 TI - In vivo protective effect of dietary curcumin in fish Anabas testudineus (Bloch). AB - The present study describes, for the first time, the protective effect of natural curcumin in vivo in a lower vertebrate, a teleost, Anabas testudineus (Bloch). Two doses of curcumin 0.5 and 1% were supplemented in the 40% protein feed and fed to fish for the periods, 2 and 8 weeks. The antioxidant status, protein content, and the tissue structure in experimental fish were examined after the short-term and long-term feeding. In all the curcumin fed groups, the lipid peroxidation product, thiobarbituric acid reactive substances content either decreased or unaffected. The glutathione content increased while the antioxidant enzyme activity pattern varied with time and dose. The histological analysis also confirmed the safety of curcumin retaining the normal arrangement of hepatocytes, hepatopancreas, macrophage-melanocyte centers in Anabas. The improved antioxidant status and protein content suggest a favorable effect for curcumin in cultured fish. PMID- 21604160 TI - Ontogeny of the digestive tract and enzymes in rock bream Oplegnathus fasciatus (Temminck et Schlegel 1844) larvae. AB - Histological development of the digestive tract and specific activities of three digestive enzymes (trypsin, alkaline phosphatase, and pepsin) were studied in rock bream Oplegnathus fasciatus from hatching to 50 days after hatching (DAH). At hatching, the digestive tract appeared as an undifferentiated straight tube and differentiated into the buccopharynx, esophagus, stomach, intestine, and rectum at mouth opening by 3 DAH. The taste bud and mandibular teeth were present in the buccopharyx at 8 DAH. The goblet cells appeared in the esophagus at 8 DAH and in the buccopharyx at 9 DAH. The stomach anlage was formed at 2 DAH and developed into cardia, fundus, and pylorus at 14 DAH. The gastric glands were visible at 16 DAH, and the pepsin was firstly detected on 22 DAH. At 2 DAH, the intestinal valve appeared and divided the intestine into anterior intestine (AI) and posterior intestine (PI). The rectum was differentiated from the PI at 3 DAH. The supranuclear vacuoles were visible in the rectum by 6 DAH, and the lipid inclusions were present in the AI at 8 DAH. The alkaline phosphatase was detected at 1 DAH, and the increase in its activity indicated the maturation of the intestine after 40 DAH. The hepatocytes and pancreatic cells were differentiated from the blast cells at 2 DAH, and the acidophilic zymogen granules in the exocrine pancreas were observed simultaneously. The trypsin was detected by 1 DAH and increased to the maximum at 19 DAH, followed by a decrease as the stomach became functional. PMID- 21604161 TI - Nitric oxide inhibited the melanophore aggregation induced by extracellular calcium concentration in snakehead fish, Channa punctatus. AB - We studied the role of nitric oxide (NO) and extra-cellular Ca(2+) on the melanophores in Indian snakehead teleost, Channa punctatus. Increase of Ca(2+) level in the external medium causes pigment aggregation in melanophores. This pigment-aggregating effect was found to be inhibited when the external medium contained spontaneous NO donor, sodium nitro prusside (SNP) at all the levels of concentration tested. Furthermore, it has been observed that SNP keeps the pigment in dispersed state even after increasing the amount of Ca(2+). In order to test whether NO donor SNP causes dispersion of pigments or not is checked by adding the inhibitor of nitric oxide synthase, N-omega-Nitro-L-arginine (L-NNA) in the medium. It has been noted that the inhibitor L-NNA blocked the effect of NO donor SNP causing aggregation of pigments. In that way NO is inhibiting the effect of extracellular Ca(2+), keeping the pigment dispersed. PMID- 21604162 TI - Amino acid biosynthetic cost and protein conservation. AB - Protein products of highly expressed genes tend to favor amino acids that have lower average biosynthetic costs (i.e., they exhibit metabolic efficiency). While this trend has been observed in several studies, the specific sites where cost reducing substitutions accumulate have not been well characterized. Toward that end, weighted costs in conserved and variable positions were evaluated across a total of 9,119 homologous proteins in four mammalian orders (primate, carnivore, rodent, and artiodactyls), which together contain a total of 20,457,072 amino acids. Degree of conservation at homologous positions in these mammalian proteins and average-weighted cost across all positions within a single protein are significantly correlated. Dividing human genes into two classes (those with and those without CpG islands in their promoters) suggests that humans also preferentially utilize less costly amino acids in highly expressed genes. In contrast to the intuitive expectation that the relatively weak selective force associated with metabolic efficiency would be a selection pressure in complex multicellular organisms, the overall level of selective constraint within the variable regions of mammalian proteins allows the metabolic efficiency to derive a reduction of overall biosynthetic cost, particularly in genes with the highest levels of expression. PMID- 21604163 TI - Integrative management of commercialized wild mushroom: a case study of Thelephora ganbajun in Yunnan, southwest China. AB - The management of wild mushroom is interdisciplinary in nature, whereby the biophysical considerations have to be incorporated into the context of a wide range of social, economic and political concerns. However, to date, little documentation exists illustrating an interdisciplinary approach to management of wild mushrooms. Moreover, the empirical case studies necessary for developing applicable and practical methods are even more rare. This paper adopted an interdisciplinary approach combining participatory methods to improve the habitat management of Thelephora ganbajun, an endemic and one of the most economically valuable mushroom species in Southwest China. The paper documents an empirical case of how an interdisciplinary approach facilitated the development of a scientific basis for policy and management practice, and built the local capacity to create, adopt and sustain the new rules and techniques of mushroom management. With this integrative perspective, a sustainable management strategy was developed, which was found not only technically feasible for farmers, but also acceptable to the government from an ecological and policy-related perspective. More importantly, this approach has greatly contributed to raising the income of farmers. The paper highlights how the integration of biophysical and socioeconomic factors and different knowledge systems provided a holistic perspective to problem diagnosis and resolution, which helped to cope with conventional scientific dilemmas. Finally, it concludes that the success of this interdisciplinary approach is significant in the context of policy decentralization and reform for incorporating indigenous knowledge and local participation in forest management. PMID- 21604164 TI - Forest fires in Mediterranean countries: CO2 emissions and mitigation possibilities through prescribed burning. AB - Forest fires are an integral part of the ecology of the Mediterranean Basin; however, fire incidence has increased dramatically during the past decades and fire is expected to become more prevalent in the future due to climate change. Fuel modification by prescribed burning reduces the spread and intensity potential of subsequent wildfires. We used the most recently published data to calculate the average annual wildfire CO(2) emissions in France, Greece, Italy, Portugal and Spain following the IPCC guidelines. The effect of prescribed burning on emissions was calculated for four scenarios of prescribed burning effectiveness based on data from Portugal. Results show that prescribed burning could have a considerable effect on the carbon balance of the land use, land-use change and forestry (LULUCF) sector in Mediterranean countries. However, uncertainty in emission estimates remains large, and more accurate data is needed, especially regarding fuel load and fuel consumption in different vegetation types and fuel layers and the total area protected from wildfire per unit area treated by prescribed burning, i.e. the leverage of prescribed burning. PMID- 21604165 TI - Effects of soundscapes on perceived crowding and encounter norms. AB - Soundscapes in recreation settings are becoming an important issue, but there are few studies of the effects of sounds on recreation experiences, especially crowding perceptions and encounter norms. This study compared effects of six types of sounds (an airplane, a truck engine, children playing, birds, water, and a control) on perceived crowding (PC) and encounter norms for hikers. Data were collected from 47 college students through lab experiments using simulated images, with moving hikers inserted in the original photo taken in the Jungmeori area of Mudeungsan Provincial Park in Korea. Overall, the motor-made sounds of the airplane and truck engine increased PC and decreased acceptability ratings, and the natural sounds of birds and water decreased PC and increased acceptability ratings. Ratings of the sound of children playing were similar to those in the control (i.e., no sound). In addition, as numbers of hikers increased, the overall effects of sounds decreased, and there were few significant differences in PC or acceptability ratings at the highest encounter levels. Theoretical and methodological implications are discussed. PMID- 21604166 TI - Direct quantification of deoxynivalenol glucuronide in human urine as biomarker of exposure to the Fusarium mycotoxin deoxynivalenol. AB - The direct quantification of deoxynivalenol glucuronide (DON-GlcA) by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application as a biomarker of exposure to the Fusarium mycotoxin deoxynivalenol (DON) is reported. Usually, DON exposure is estimated from dietary average intakes or by measurement of the native toxin in urine after enzymatic hydrolysis with beta-glucuronidase. These methods are time-consuming, expensive, and fail to determine the ratio of DON to DON-GlcA in a simple one-step procedure. One of the main reasons for the use of indirect methods is the unavailability of DON-GlcA standards. Consequently, DON-3-O-glucuronide (D3GlcA) was synthesized and used to develop a method allowing quantification of both DON and D3GlcA by a simple "dilute and shoot" approach without the need for any cleanup. Limit of detection and apparent recovery of D3GlcA was 3 MUg l(-1) and 88%, respectively. The identity of D3GlcA in human urine was confirmed by comparison with LC-MS/MS measurements of the synthetically produced D3GlcA standard which was also used for external calibration. The applicability of the method was demonstrated through the analysis of urine samples obtained from a volunteer during regular and cereal restricted diet, respectively. In regular-diet urine samples, D3GlcA was quantified in concentrations >30 MUg l(-1) by this approach. PMID- 21604167 TI - MALDI-MS imaging of lipids in ex vivo human skin. AB - Lipidomics is a rapidly expanding area of scientific research and there are a number of analytical techniques that are employed to facilitate investigations. One such technique is matrix-assisted laser desorption ionisation (MALDI) mass spectrometry (MS). Previous MALDI-MS studies involving lipidomic investigation have included the analysis of a number of different ex vivo tissues, most of which were obtained from animal models, with only a few being of human origin. In this study, we describe the use of MALDI-MS, MS/MS and MS imaging methods for analysing lipids within cross-sections of ex vivo human skin. It has been possible to tentatively identify lipid species via accurate mass measurement MALDI-MS and also to confirm the identity of a number of these species via MALDI MS/MS, in experiments carried out directly on tissue. The main lipid species detected include glycerophospholipids and sphingolipids. MALDI images have been generated at a spatial resolution of 150 and 30 MUm, using a MALDI quadrupole time-of-flight Q-Star Pulsar-i (TM) (Applied Biosystems/MDS Sciex, Concord, ON, Canada) and a MALDI high-definition MS (HDMS) SYNAPT G2-HDMS(TM) system (Waters, Manchester, UK), respectively. These images show the normal distribution of lipids within human skin, which will provide the basis for assessing alterations in lipid profiles linked to specific skin conditions e.g. sensitisation, in future investigations. PMID- 21604168 TI - 3D configuration of mandibles and controlling muscles in rove beetles based on micro-CT technique. AB - X-ray micro-CT is a powerful tool to visualize without damage details of the inner structures of beetles, the largest order of insects with a hard external skeleton. This contribution shows the three-dimensional (3D) reconstruction of the head morphology of three rove beetle species (Insecta, Coleoptera, Staphylinidae)--Noddia sp., Creophilus maxillosus, and Hesperosoma sp.--using X ray microtomography at a spatial resolution of 6 MUm. The details of skeletal muscle fiber insertions are described, giving a comprehensive overview of mandible mobility and organization. With the support of 3D rendering, we discuss the relationship among the mandible forms, the development of the muscles controlling the movement, and the head morphology. The well-developed posterior part of the head capsule is always accompanied by a well-developed mandible, a large adductor muscle, and a large apodeme for the wide areas of the muscle fiber attachment. In Noddia sp., muscles connected to the posterolateral angle of the head capsule are mainly short muscles, whereas in Creophilus maxillosus, the latter are mainly long muscles, and in Hesperosoma sp. no mandible adductor muscle fibers are present on the posterolateral angle of the head capsule. These results offer new invaluable information regarding the biting functions of beetle mandibles and the trend of their morphological change during their long-term evolution. PMID- 21604169 TI - Shell-bound iron dependant nitric oxide synthesis in encysted Artemia parthenogenetica embryos during hydrogen peroxide exposure. AB - Artemia is a tiny marine crustacean, serves as an excellent tool in both basic and applied aspects of stress biology research. In the current manuscript, we report that Artemia parthenogenetica embryos (cysts), in diapause stage, undergo iron transition changes when exposed to chemical diapause deactivation stimulus (hydrogen peroxide). X-ray surface analysis of A. parthenogenetica embryos exposed to H(2)O(2) showed significant transitional changes in iron, as seen in cyst cross-sections. Electron paramagnetic resonance study revealed that upon H(2)O(2) exposure, increased nitric oxide (NO) production was observed in non decapsulated cysts (ND), but not in decapsulated cysts (DC) (shell-removed cysts). Spin trapping studies also showed an increase in hydroxyl radical formation in NDs exposed to H(2)O(2) through Fenton-like reaction. On the contrary, exposure of DCs to H(2)O(2) did not induce hydroxyl radical formation. Taken together, results from the present study indicate a key role of cyst shell bound iron and reactive oxygen species on successful diapause termination in eukaryotic extremophile animal model, such as Artemia. PMID- 21604170 TI - Cloning and functional characterization of a caffeic acid O-methyltransferase from Trigonella foenum-graecum L. AB - A cDNA encoding an O-methyltransferase (namely FGCOMT1) was identified from the medicinal plant Trigonella foenum-graecum L. The FGCOMT1 enzyme is a functional caffeic acid O-methyltransferase (COMT) and is localized in the cytosol. Kinetic analysis indicated that FGCOMT1 protein exhibited the highest catalyzing efficiency towards 5-hydroxy ferulic acid and caffeic acid as substrates, but did not possess the abilities to methylate either quercetin or tricetin in vitro. Furthermore, transformation of Arabidopsis loss-of-function Atomt1 mutant with a FGCOMT1 cDNA partially complements accumulation of sinapoyl derivatives but did not function to produce the major methylated flavonol isorhamnetin in seeds. The results from this study indicated that FGCOMT1 is a COMT with substrate preference to monomeric lignin precursors but is not involved in the flavonoid methylation in T. foenum-graecum L. PMID- 21604171 TI - Tumor necrosis factor alpha 308 G/A polymorphism and Guillain-Barre syndrome risk. AB - Guillain-Barre syndrome (GBS) is an inflammatory disorder that may implicate proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) in its pathogenesis. The association between TNF-alpha 308 G/A polymorphism and GBS largely remains unknown. The aim of this study was to investigate the association between TNF-alpha 308 G/A polymorphism and GBS in Chinese Han patients. TNF-alpha 308 G/A polymorphism in 150 GBS patients and 150 healthy controls were studied using polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) assay. Patients with GBS had a significantly higher frequency of TNF-alpha 308AA genotype [odds ratio (OR) = 3.79, 95% confidence interval (CI) = 1.03, 13.94; P = 0.04] than controls. When stratified by the GBS subtype, there was a significantly higher frequency of TNF-alpha 308AA genotype in patients with AMAN (OR = 6.05, 95% CI = 1.45, 25.31; P = 0.01) and AMSAN (OR = 5.56, 95% CI = 1.18, 26.23; P = 0.03) than controls. There was no significant difference in the distribution of each genotype between patients with AIDP and the control group. These data indicated that TNF-alpha 308AA genotype was associated with a higher risk of GBS in Chinese population, especially to AMAN and AMSAN. PMID- 21604172 TI - Transcriptional control of human CD2AP expression: the role of Sp1 and Sp3. AB - The CD2 associated protein (CD2AP) is characterized as a T-lymphocyte CD2 adapter protein and is found to be related to glomerulosclerosis, and CD2AP knockout mice develop a rapid onset nephrotic syndrome and die of renal failure. Here we report that the transcription factor Sp1 and Sp3 up-regulate the basal transcriptional activity of CD2AP and increase CD2AP expression at mRNA level. We show by Chromatin immunoprecipitation (ChIP) assay that Sp1 and Sp3 interact with the CD2AP promoter region in vivo. By transient transfection analysis we also demonstrate the mutations of Sp1/3 binding sites result in a profound reduction of CD2AP promoter activity. Overexpression of Sp1 and Sp3 transactivates the CD2AP promoter, whereas small interfering RNA-mediated (siRNA) blockage of Sp1 and Sp3 genes expressions inhibits markedly its activity. These results suggest that Sp1 and Sp3 play an important role in regulating CD2AP transcription through binding to the Sp1/3 binding sites. PMID- 21604173 TI - Elementary research of the formation mechanism of sex-related fluorescent cocoon of silkworm, Bombyx mori. AB - To understand mechanisms for the difference of uptaking and transporting the pigments between the male and female in the silkworm, Bombyx mori strain of sex related fluorescent cocoon, the fluorescent pigments in the midgut lumen, midgut, blood, silk glands and cocoon were analyzed with thin-layer chromatography, and showed that fluorescent colors of cocoons consisted with that of blood and silk glands. The different fluorescent colors of cocoons between the male and female may be mainly caused by the difference of accumulation and transportation for fluorescent pigments in the midgut and in the silk glands. Furthermore the midgut proteins were separated with Native-PAGE, and the proteins respectively recovered from three fluorescent regions presenting on a Native-PAGE gel for the female silkworms were determined using shotgun proteomics and mass spectrometry sequencing, of which 60, 40 and 18 proteins respectively from the region 1, 2 and 3 were identified. It was found that the several kinds of low molecular mass 30 kDa lipoproteins and the actins could be detected in all three regions, troponin, 30 kDa lipoprotein and 27 kDa glycoprotein precursor could be detected in the region 2 and 3, suggesting these proteins may be fluorescent pigments binding candidates proteins. Analysis of gene ontology indicated that the identified proteins in the three regions linked to the cellular component, molecular function, and biological process categories. These results provide a new clew to understand the formation mechanism of sex-related fluorescent cocoon of silkworm. PMID- 21604174 TI - Molecular characterization, expression analysis and association study with immune traits of porcine PSMB6 gene. AB - PSMB6 subunit belongs to the 20S proteasomal subunit family, which plays an importance role in the antigen presentation by MHC class I molecular. The full length genomic DNA sequence was obtained by PCR and the full-length CDS of porcine PSMB6 was isolated by the reverse transcriptase-polymerase chain reaction (RT-PCR). The deduced protein of 239 amino acids showed 86% identity to the corresponding human sequence. RT-PCR revealed that porcine PSMB6 gene was expressed in seven tissues studied (heart, liver, spleen, lung, kidney, skeletal muscle and fat) and SYBR Green real-time RT-PCR analysis showed PSMB6 gene was expressed highest in spleen. A single nucleotide substitution resulting in the amino acid change (19Pro-19His) was detected within exon 1 and other two single nucleotide polymorphisms were detected in intron 1. The Genetic variations were identified in eight pig breeds showed diverse results. Furthermore, we found that the single nucleotide polymorphisms (SNP, G/T300) was significantly associated with delayed type hypersensitivity (DTH, P < 0.05), immunoglobin G (IgG1, P < 0.05), white blood cell count (WBC, P < 0.05). Using the pig/rodent somatic cell hybrid panel (SCHP), we mapped the porcine PSMB6 gene to SSC12, in agreement with comparative mapping data. PMID- 21604175 TI - Characterization of acute renal allograft rejection by proteomic analysis of renal tissue in rat. AB - Rapid and reliable biomarkers of renal allograft rejection have not been available. This study aimed to investigate biomarkers in renal allograft tissue using proteomic analysis. Orthotopic kidney transplantations were performed using Fisher (F344) or Lewis rats as donors and Lewis rats as recipients. Syngenic control group (Group I) constituted F344-to-F344 orthotopic kidney allo transplantations (n = 8); and allogenic group (Group II) consisted of F344-to Lewis orthotopic kidney allo-transplantations (n = 8). Renal tissues were harvested 7 days after transplantation. Samples were analyzed using 2-D electrophoresis and matrix assisted laser desorption ionization-time of flight mass spectrometry. 6 differentially expressed proteins were identified between allogenic group and syngenic control group. A rat model of acute renal allograft rejection was successfully set up. Differentially expressed proteins in renal allograft tissue of rat were detected using proteomic analysis and might serve as novel diagnostic and therapeutic targets in human. Quantitative proteomics, using MALDL-TOF-MS methodology has the potential to provide a profiling and a deeper understanding of acute renal rejection. PMID- 21604176 TI - Polymorphisms of XRCC1 and gastric cancer susceptibility: a meta-analysis. AB - Studies investigating the association between X-ray repair cross-complementing gene 1 (XRCC1) polymorphisms and gastric cancer (GC) risk have reported conflicting results. We performed a meta-analysis of published case-control and cohort studies to better compare results between studies. Published literature from PubMed, EMBASE, and China National Knowledge Infrastructure were retrieved. 18 studies with 3,915 GC cases and 6,759 controls were selected. For XRCC1 Arg194Trp polymorphism, we only found the Trp/Trp genotype carriers might be at high risk of GC (TT vs. CC+CT: OR = 1.31, 95%CI = 1.04-1.65). When stratifying for ethnicity, the results showed there was a significant difference in genotype distribution between GC cases and controls among Asians (especially, in Chinese population), but not among Caucasians. When stratifying for control sources, significant association between Arg194Trp polymorphism and GC risk was only observed in the hospital-based controls' subgroup (TT vs. CC+CT: OR = 1.45, 95%CI = 1.13-1.87). Additionally, no significant association was detected in the gastric cardia cancer's subgroup. The results of the overall meta-analysis did not suggest any association between Arg280His/Arg399Gln polymorphisms and GC susceptibility for all genetic models. There was no evidence for the association between these two gene polymorphisms and GC risk in subgroup analyses based on study design, ethnicity, country, tumor location, Helicobacter pylori infection and the Lauren's classification of GC. In conclusion, XRCC1 Arg194Trp homozygous mutant genotype (Trp/Trp) was found to be associated with increased risk of GC. PMID- 21604177 TI - Adiposity and the risk of colorectal adenomatous polyps: a meta-analysis. AB - OBJECTIVE: The findings from epidemiological studies addressing the association between adiposity and the risk of colorectal adenomatous polyps are inconsistent. We performed a meta-analysis of epidemiological studies including cross sectional, case-control, and cohort studies. METHODS: We searched PubMed and EMBASE in June, 2010. All searched articles were reviewed and selected independently by two evaluators according to pre-determined selection criteria. RESULTS: We included 25 studies (nine cross-sectional studies, eleven case control studies, and five prospective cohort studies) that comprised a total of 300,671 participants and 20,903 cases in the final analysis. When all studies were pooled, the odds ratio (OR) or relative risk (RR) of adiposity and abdominal adiposity for colorectal adenomatous polyp risk was 1.43 (95% confidence interval (CI) 1.23-1.67; n = 22) and 1.42 (95% CI 1.30-1.56; n = 12), respectively. Similarly, an increased risk of colorectal adenomatous polyps was observed in most of the subgroup meta-analyses. CONCLUSIONS: Overall, we found that adiposity and abdominal adiposity significantly increased the risk of colorectal adenomatous polyps in a meta-analysis of epidemiological studies. PMID- 21604178 TI - Current and novel renal biomarkers in heart failure. AB - Renal function is the most important predictor of clinical outcome in heart failure (HF). It is therefore essential to have accurate and reliable measurement of renal function and early specific markers of renal impairment in patients with HF. Several renal functional entities exist, including glomerular filtration (GFR), glomerular permeability, tubulointerstitial damage, and endocrine function. Different markers have been studied that can be used to determine changes and the effect of treatment in these entities. In the present review, we summarize current and novel markers that give an assessment of renal function and prognosis in the setting of acute and chronic HF. PMID- 21604179 TI - Optimizing fluid management in patients with acute decompensated heart failure (ADHF): the emerging role of combined measurement of body hydration status and brain natriuretic peptide (BNP) levels. AB - The study tests the hypothesis that in patients admitted with acutely decompensated heart failure (ADHF), achievement of adequate body hydration status with intensive medical therapy, modulated by combined bioelectrical vectorial impedance analysis (BIVA) and B-type natriuretic peptide (BNP) measurement, may contribute to optimize the timing of patient's discharge and to improve clinical outcomes. Three hundred patients admitted for ADHF underwent serial BIVA and BNP measurement. Therapy was titrated to reach a BNP value of <250 pg/ml, whenever possible. Patients were categorized as early responders (rapid BNP fall below 250 pg/ml); late responders (slow BNP fall below 250 pg/ml, after aggressive therapy); and non-responders (BNP persistently >250 pg/ml). Worsening of renal function (WRF) was evaluated during hospitalization. Death and rehospitalization were monitored with a 6-month follow-up. BNP value on discharge of <=250 pg/ml led to a 25% event rate within 6 months (Group A: 17.4%; Group B: 21%, Chi2; n.s.), whereas a value >250 pg/ml (Group C) was associated with a far higher percentage (37%). At discharge, body hydration was 73.8 +/- 3.2% in the total population and 73.2 +/- 2.1, 73.5 +/- 2.8, 74.1 +/- 3.6% in the three groups, respectively. WRF was observed in 22.3% of the total. WRF occurred in 22% in Group A, 32% in Group B, and 20% in Group C (P = n.s.). Our study confirms the hypothesis that combined BNP/BIVA sequential measurements help to achieve adequate fluid balance status in patients with ADHF and can be used to drive a "tailored therapy," allowing clinicians to identify high-risk patients and possibly to reduce the incidence of complications secondary to fluid management strategies. PMID- 21604180 TI - Gender differences in suicide methods. AB - INTRODUCTION: Gender differences in suicide completion rates have been attributed to the differences in lethality of suicide methods chosen by men and women, but few empirical studies have investigated factors other than demographic characteristics that might explain this differential. METHODS: Data from the 621 suicides in Summit County, Ohio during 1997-2006 were disaggregated by gender to compare known correlates of suicide risk on three methods of suicide-firearm, hanging and drug poisoning. RESULTS: Compared to women, men who completed suicide with firearms were more likely to be married and committed the act at home. Unmarried men were likelier to hang themselves than married men, but unmarried women were less likely to hang themselves than married women. Men with a history of depression were more likely to suicide by hanging, but women with depression were half as likely to hang themselves compared to the women without a history of depression. Men with a history of substance abuse were more likely to suicide by poisoning than men without such history, but substance abuse history had no influence on women's use of poisoning to suicide. For both sexes, the odds of suicide by poisoning were significantly higher for those on psychiatric medications. PMID- 21604181 TI - Identification and characterization of CbeI, a novel thermostable restriction enzyme from Caldicellulosiruptor bescii DSM 6725 and a member of a new subfamily of HaeIII-like enzymes. AB - Potent HaeIII-like DNA restriction activity was detected in cell-free extracts of Caldicellulosiruptor bescii DSM 6725 using plasmid DNA isolated from Escherichia coli as substrate. Incubation of the plasmid DNA in vitro with HaeIII methyltransferase protected it from cleavage by HaeIII nuclease as well as cell free extracts of C. bescii. The gene encoding the putative restriction enzyme was cloned and expressed in E. coli with a His-tag at the C-terminus. The purified protein was 38 kDa as predicted by the 981-bp nucleic acid sequence, was optimally active at temperatures between 75 degrees C and 85 degrees C, and was stable for more than 1 week when stored at 35 degrees C. The cleavage sequence was determined to be 5'-GG/CC-3', indicating that CbeI is an isoschizomer of HaeIII. A search of the C. bescii genome sequence revealed the presence of both a HaeIII-like restriction endonuclease (Athe 2438) and DNA methyltransferase (Athe 2437). Preliminary analysis of other Caldicellulosiruptor species suggested that this restriction/modification activity is widespread in this genus. A phylogenetic analysis based on sequence alignment and conserved motif searches identified features of CbeI distinct from other members of this group and classified CbeI as a member of a novel subfamily of HaeIII-like enzymes. PMID- 21604182 TI - Effects of allitridin on acute and chronic mouse cytomegalovirus infection. AB - This study investigated the effects of allitridin on acute and chronic mouse cytomegalovirus (MCMV) infections in vivo. The results demonstrated that allitridin reduced the titers of MCMV in salivary glands, and reductions in viral loads were confirmed by determining viral DNA and RNA levels in susceptible organs during the acute infection phase. Although allitridin did not eliminate MCMV, treatment reduced viral levels and facilitated healing of pathologic lesions in organs, particularly during the chronic infection phase. The results presented in this report suggest that allitridin could act as an effective agent against MCMV infections in vivo. PMID- 21604183 TI - Isolation and characterization of canine astrovirus in China. AB - In this study, we first investigated the prevalence of astrovirus in stools of dogs with and without diarrhea in Shanghai, China. Of all the specimens, 22 (12.02%) from the 183 dogs with diarrhea and none (0%) from the 138 healthy controls were positive for astrovirus. Furthermore, we cloned partial sequences of ORF1b (442 bp) and the entire sequences of ORF2 (2475 bp). Phylogenetic analysis showed that the new isolates were belonged to genus Mamastrovirus and most closely clustered with the Italy strain, based on the ORF2 sequences available. However, the new isolates and the Italy strain were divided into two different clusters. The new isolates may be a new strain of canine astrovirus. PMID- 21604184 TI - Religious motivation and cardiovascular reactivity among middle aged adults: is being pro-religious really that good for you? AB - Religiousness has been observed to have a beneficial relationship with blood pressure, however, specific aspects of religiousness that interact with physiological mechanisms to influence this relationship are not known. This study explored laboratory cardiovascular reactivity (blood pressure, heart rate) to psychological stress among middle aged community dwelling individuals grouped by religious motivation (Intrinsic, Pro-religious, Non-religious). Measures of personality, cynical hostility, aggression, sense of coherence, and compassion were administered. Results indicated that the Pro-religious group demonstrated dampened reactivity compared to the other research groups. However, the Pro religious also demonstrated a less positive psychological profile (e.g., greater cynicism, aggression, and neuroticism; less compassion and sense of coherence) and poorer self-reported health compared with the Intrinsic group and behavioral observations demonstrated that the Pro-religious were unreliable in keeping appointments and appeared rushed during the experiment. These findings indicate a complicated interface between personality, coping, and religious motivation in response to stressors and emphasize the need for naturalistic and longitudinal investigations of individuals who vary in terms of religious motivation. PMID- 21604185 TI - Fibroblast activation protein-alpha promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions. AB - Fibroblast activation protein-alpha (FAP) is a cell surface, serine protease of the post-prolyl peptidase family that is expressed in human breast cancer but not in normal tissues. Previously, we showed that FAP expression increased tumor growth rates in a mouse model of human breast cancer. Here the role of the proteolytic activities of FAP in promoting tumor growth, matrix degradation and invasion was investigated. Mammary fat pads of female SCID mice were inoculated with breast cancer cells that express FAP and the mice treated with normal saline or Val-boroPro (talabostat); Glu-boroPro (PT-630); or 1-[[(3-hydroxy-1 adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine (LAF-237) that inhibit prolyl peptidases. Other mice were injected with breast cancer cells expressing a catalytically inactive mutant of FAP and did not receive inhibitor treatment. PT 630 and LAF-237 did not slow growth of tumors produced by any of the three cell lines expressing FAP. Talabostat slightly decreased the growth rates of the FAP expressing tumors but because PT-630 and LAF-237 did not, the growth retardation was likely not related to the inhibition of FAP or the related post-prolyl peptidase dipeptidyl peptidase IV. Breast cancer cells expressing a catalytically inactive mutant of FAP (FAP(S624A)) also produced tumors that grew rapidly. In vitro studies revealed that cells expressing wild type FAP or FAP(S624A) degrade extracellular matrix (ECM) more extensively, accumulate higher levels of matrix metalloproteinase-9 (MMP-9) in conditioned medium, are more invasive in type I collagen gels, and have altered signaling compared to control transfectants that do not express FAP and form slow growing tumors. We conclude that the proteolytic activity of FAP participates in matrix degradation, but other functions of the protein stimulate increased tumor growth. PMID- 21604186 TI - Evolution of a predictive internal model in an embodied and situated agent. AB - We show how simulated robots evolved for the ability to display a context dependent periodic behavior can spontaneously develop an internal model and rely on it to fulfill their task when sensory stimulation is temporarily unavailable. The analysis of some of the best evolved agents indicates that their internal model operates by anticipating sensory stimuli. More precisely, it anticipates functional properties of the next sensory state rather than the exact state that sensors will assume. The characteristics of the states that are anticipated and of the sensorimotor rules that determine how the agents react to the experienced states, however, ensure that they produce very similar behaviour during normal and blind phases in which sensory stimulation is available or is self-generated by the agent, respectively. Agents' internal models also ensure an effective transition during the phases in which agents' internal dynamics is decoupled and re-coupled with the sensorimotor flow. Our results suggest that internal models might have arisen for behavioral reasons and successively exapted for other cognitive functions. Moreover, the obtained results suggest that self-generated internal states should not necessarily match in detail the corresponding sensory states and might rather encode more abstract and motor-oriented information. PMID- 21604187 TI - Facilitated neurogenesis in the developing hippocampus after intake of theanine, an amino acid in tea leaves, and object recognition memory. AB - Theanine, gamma-glutamylethylamide, is one of the major amino acid components in green tea. In this study, cognitive function and the related mechanism were examined in theanine-administered young rats. Newborn rats were fed theanine through dams, which were fed water containing 0.3% theanine, and then fed water containing 0.3% theanine after weaning. Theanine level in the brain was under the detectable limit 6 weeks after the start of theanine administration. Theanine administration did not influence locomotor activity in the open-field test. However, rearing behavior was significantly increased in theanine-administered rats, suggesting that exploratory activity is increased by theanine intake. Furthermore, object recognition memory was enhanced in theanine-administered rats. The increase in exploratory activity in the open-field test seems to be associated with the enhanced object recognition memory after theanine administration. On the other hand, long-term potentiation (LTP) induction at the perforant path-granule cell synapse was not changed by theanine administration. To check hippocampal neurogenesis, BrdU was injected into rats 3 weeks after the start of theanine administration, and brain-derived neurotropic factor (BDNF) level was significantly increased at this time. Theanine intake significantly increased the number of BrdU-, Ki67-, and DCX-labeled cells in the granule cell layer 6 weeks after the start of theanine administration. This study indicates that 0.3% theanine administration facilitates neurogenesis in the developing hippocampus followed by enhanced recognition memory. Theanine intake may be of benefit to the postnatal development of hippocampal function. PMID- 21604188 TI - Ethical aspects of aging research. AB - During the last 50-60 years, due to development of medical care and hygienically safe living conditions, the average life span of European citizens has substantially increased, with a rapid growth of the population older than 65 years. This trend places ever-growing medical and economical burden on society, as many of the older subjects suffer from age-related diseases and frailty. Coping with these problems requires not only appropriate medical treatment and social support but also extensive research in many fields of aging-from biology to sociology, with involvement of older people as the research subjects. This work anticipates development and application of ethical standards suited to dynamic advances in aging research. The aim of this review is to update the knowledge in ethical requirements toward recruitment of older research subjects, obtaining of informed consent, collection of biological samples, and use of stem cells in preclinical and clinical settings. It is concluded that application of adequate ethical platform markedly facilitates recruitment of older persons for participation in research. Currently, the basic ethical concepts are subjected to extensive discussion, with participation of all interested parties, in order to guarantee successful research on problems of human aging, protect older people from undesired interference, and afford their benefits through supporting innovations in research, therapy, and care. PMID- 21604189 TI - Human nephron number: implications for health and disease. AB - Several studies have shown that total nephron (glomerular) number varies widely in normal human kidneys. Whereas the studies agree that average nephron number is approximately 900,000 to 1 million per kidney, numbers for individual kidneys range from approximately 200,000 to >2.5 million. Several studies have shown loss of glomeruli due to age-related glomerulosclerosis. The rates of loss vary among individuals depending upon blood pressure, diseases affecting the kidney, and other attributes of health, but most of the variation in nephron number is present at birth and is therefore developmentally determined. For example, in a relatively small study of nephron number in 15 children <3 months of age, we found that nephron number ranged from approximately 250,000 to 1.1 million. Given that no new nephrons are formed in human kidneys after approximately 36 weeks' gestation, much interest has focused on renal function and health in individuals born with relatively low nephron endowment. Several studies have reported a direct correlation between birth weight and nephron number and an indirect association between nephron number and blood pressure. Associations between low birth weight and cardiovascular disease, including hypertension, have also been widely reported. This report provides an update on our current knowledge of human nephron number and the associations with adult health and disease. PMID- 21604190 TI - Conditioning effects of cavities prepared with an Er,Cr:YSGG laser and an air turbine. AB - The purpose of this study was to examine, morphologically and histochemically, five types of conditioning effects on cavities prepared with an Er,Cr:YSGG laser and an air-turbine. Cavities were prepared using a Waterlase((r)) MD turbo handpiece (W) and an air-turbine (AT) on human extracted molars. The cavity conditionings used were non-conditioned (G1), K-etchant Gel (G2), K-etchant Gel + AD Gel (G3), Clearfil SE Bond primer (G4) and Clearfil S(3) Bond (G5). On naked eye observations, enamel of G1, G2 and G3 in the W cavities and etched enamel of G2 and G3 in the AT cavities were observed as rough and dull in appearance. G4 and G5 in W and AT cavities were observed as shiny surfaces. On SEM observations, no smeared layer was observed in W cavities, while a smeared layer and bur scratches were observed in AT cavities. In W cavities, rough surfaces were observed on enamel. That is, cracks and minute rough surfaces were observed. In contrast, equally etched scale-shaped enamel rods were observed in AT cavities. Widely opened dentinal tubules and protruding peritubular matrices of dentin were observed in W cavities. A few remaining smeared plugs could be observed at the AT cavities. On LM observations, 13-16 MUm layers of the dentin in G1, G2, G4 and G5 of W cavities were stained red in color by the Azan staining method, while redness was not observed in G3. No groups were stained red in AT cavities. It was considered that layers stained red in color were thermal degeneration layers of dentin induced by W. Namely 30 s etching of 40% phosphoric acid gel followed by 90 s treatment of 10% NaClO gel should be recommended for use when combined with an Er,Cr:YSGG laser for cavity preparation. PMID- 21604191 TI - Biodegradation of petroleum sludge and petroleum polluted soil by a bacterial consortium: a laboratory study. AB - This article presents a study of the efficiency and degradation pattern of samples of petroleum sludge and polluted sandy soil from an oil refinery. A bacterial consortium, consisting of strains from the genera Pseudomonas, Achromobacter, Bacillus and Micromonospora, was isolated from a petroleum sludge sample and characterized. The addition of nitrogen and phosphorus nutrients and a chemical surfactant to both the samples and bioaugmentation to the soil sample were applied under laboratory conditions. The extent of biodegradation was monitored by the gravimetric method and analysis of the residual oil by gas chromatography. Over a 12-week experiment, the achieved degree of TPH (total petroleum hydrocarbon) degradation amounted to 82-88% in the petroleum sludge and 86-91% in the polluted soil. Gas chromatography-mass spectrometry was utilized to determine the biodegradability and degradation rates of n-alkanes, isoprenoids, steranes, diasteranes and terpanes. Complete degradation of the n-alkanes and isoprenoids fractions occurred in both the samples. In addition, the intensities of the peaks corresponding to tricyclic terpenes and homohopanes were decreased, while significant changes were also observed in the distribution of diasteranes and steranes. PMID- 21604193 TI - CSN1 inhibits c-Jun phosphorylation and down-regulates ectopic expression of JNK1. AB - CSN1 is a component of the COP9 signalosome (CSN), a conserved protein complex with pleiotropic functions in many organs and cell types. CSN regulates ubiquitinproteasome dependent protein degradation via the deneddylation and the associated deubiquitination activities. In addition, CSN associates with protein kinases and modulates cell signaling, particularly the activator protein 1 (AP-1) pathway. We have shown previously that CSN1 suppresses AP-1 transcription activity and inhibits ultraviolet (UV) and serum activation of c-fos expression. Here we show that CSN1 can inhibit phosphorylation of proto-oncogene c-Jun product and repress c-Jun dependent transcription. Further, CSN1 dramatically downregulates ectopic expression of c-Jun N-terminal kinase 1 (JNK1) in cultured cells. The decline in JNK1 is not caused by excessive proteolysis or by 3' UTR dependent mRNA instability, but by CSN1-dependent repression of one or multiple steps in transcriptional and posttranscriptional mechanisms. Thus, in contrast to CSN5/Jab1, which promotes AP-1 activity, CSN1 displays a negative effect on the AP-1 pathway. Finally, we discuss about the dynamic equilibrium of the CSN complexes in regulation of the AP-1 pathway. PMID- 21604192 TI - The direction of effects between perceived parental behavioral control and psychological control and adolescents' self-reported GAD and SAD symptoms. AB - This study examined the direction of effects and age and sex differences between adolescents' perceptions of parental behavioral and psychological control and adolescents' self-reports of generalized anxiety disorder (GAD) and separation anxiety disorder (SAD) symptoms. The study focused on 1,313 Dutch adolescents (early-to-middle cohort n = 923, 70.3%; middle-to-late cohort n = 390, 29.7%) from the general population. A multi-group, structural equation model was employed to analyze the direction of the effects between behavioral control, psychological control and GAD and SAD symptoms for the adolescent cohorts. The current study demonstrated that a unidirectional child effect model of the adolescents' GAD and SAD symptoms predicting parental control best described the data. Additionally, adolescent GAD and SAD symptoms were stronger and more systematically related to psychological control than to behavioral control. With regard to age-sex differences, anxiety symptoms almost systematically predicted parental control over time for the early adolescent boys, whereas no significant differences were found between the late adolescent boys and girls. PMID- 21604194 TI - An active murine-human chimeric Fab antibody derived from Escherichia coli, potential therapy against over-expressing VEGFR2 solid tumors. AB - Many recombinant murine monoclonal antibodies (mAbs) were studied under pre clinical or clinical development and became one of the most prolific drug classes in oncology. Vascular endothelial growth factors receptor 2 (VEGFR2) has been implicated to play an important role in tumors. We have established a murine anti VEGFR2 mAb. To reduce the shortcoming of the mAb, a murine-human chimeric Fab (cFab) named FA8H1 was constructed with gene engineering techniques and expressed as a soluble and functional protein in Escherichia coli Top10F'. Several immunological methods were used to characterize the cFab, including ELISA, affinity and kinetics assay, IP, IF, FACS, and IHC. The results illuminated that cFab maintained the specificity for the VEGFR2 antigen. The active cFab also effectively identified VEGFR2 over-expressing cells in a number of archived human cancer tissues, compared to its parental antibody. The FA8H1 provided the basis for potential therapy research against over-expressing VEGFR2 human solid tumors. PMID- 21604195 TI - Factors associated with an individuals' decision to withdraw from genetic counseling for BRCA1 and BRCA2 genes mutations: are personality traits involved? AB - The aim of the study was to evaluate factors associated with early withdrawal from oncogenetic counseling. A comparison of psycho-social and personality characteristics of two samples of subjects, attendees and withdrawers was carried out. Self-report questionnaires were completed by 112 individuals who had completed counseling and to 56 individuals who withdrew from it. Individuals with few children (OR. 1,724; p = 0,017; CI = 1,101-2,700), a lower number of cancer affected relatives (OR. 1,301; p = 0,000; CI = 1,145-1,479), and with a lower hypomanic scale score (OR. 1,070; p = 0,004; CI = 1,022-1,121), were more likely to withdraw from counseling. It is important for the counselees to draw more attention to the fact that their cancer risk management and prevention is as fundamental as that of their children. Also, it is important to highlight the fact that having less cancer affected relatives does not necessarily mean being at lower risk. In conclusion, that subjects with low levels of psychological and emotional energy are those who probably need greater psychological support during the decision making process. We deem necessary that psychologists, involved in genetic counseling, investigate these aspects during their sessions in order to implement suitable interventions of psychological support during the entire counseling process. PMID- 21604196 TI - Risk-based assessment of multimetallic soil pollution in the industrialized peri urban area of Huelva, Spain. AB - The peri-urban soils of Huelva, one of the first industrial cities in Spain, are subject to severe pollution problems primarily due to past poor management of industrial wastes and effluents. In this study, soil cores were collected in seven sites potentially contaminated with toxic chemicals arising from multiple anthropogenic sources, in order to identify trace elements of concern and to assess human health risks associated with them. In most soil core samples, total concentrations of As (up to 4,390 mg kg(-1)), Cd (up to 12.9 mg kg(-1)), Cu (up to 3,162 mg kg(-1)), Pb (up to 6,385 mg kg(-1)), Sb (up to 589 mg kg(-1)) and Zn (up to 4,874 mg kg(-1)) were by more than one order of magnitude greater than the site-specific reference levels calculated on the basis of regional soil geochemical baselines. These chemicals are transferred from the hazardous wastes, mainly crude pyrite and roasted pyrite cinders, to the surrounding soils by acid drainage and atmospheric deposition of wind-blown dust. Locally, elevated concentrations of U (up to 96.3 mg kg(-1)) were detected in soils affected by releases of radionuclides from phosphogypsum wastes. The results of the human health risk-based assessment for the hypothetical exposure of an industrial worker to the surface soils indicate that, in four of the seven sites monitored, cancer risk due to As (up to 4.4 * 10(-5)) is slightly above the target health risk limit adopted by the Spanish legislation (1 * 10(-5)). The cumulative non carcinogenic hazard index ranged from 2.0 to 12.2 indicating that there is also a concern for chronic toxic effects from dermal contact with soil. PMID- 21604198 TI - Unusual penetrating preauricular injury by firework rocket. PMID- 21604197 TI - Regulation of long-term plasticity induction by the channel and C-terminal domains of GluN2 subunits. AB - Conventional long-term potentiation (LTP) and long-term depression (LTD) are induced by different patterns of synaptic stimulation, but both forms of synaptic modification require calcium influx through NMDA receptors (NMDARs). A prevailing model (the "calcium hypothesis") suggests that high postsynaptic calcium elevation results in LTP, whereas moderate elevations give rise to LTD. Recently, additional evidence has come to suggest that differential activation of NMDAR subunits also factors in determining which type of plasticity is induced. While the growing amount of data suggest that activation of NMDARs containing specific GluN2 subunits plays an important role in the induction of plasticity, it remains less clear which subunit is tied to which form of plasticity. Additionally, it remains to be determined which properties of the subunits confer upon them the ability to differentially induce long-term plasticity. This review highlights recent studies suggesting differential roles for the subunits, as well as findings that begin to shed light on how two similar subunits may be linked to the induction of opposing forms of plasticity. PMID- 21604199 TI - High correlation of babA 2-positive strains of Helicobacter pylori with the presence of gastric cancer. AB - Helicobacter pylori (H. pylori) is a Gram-negative bacterium that is well known in the involvement of chronic inflammation in the gastric mucosa of the human stomach. Several studies have investigated the possible role of H. pylori presence in different gastroduodenal disorders with conflicting results. This study aimed to further investigate such a field. Helicobacter pylori strains were cultured from 160 patients (mean age of 42 years; range 15-75; 90 were male, and 70 were female) [40 gastric cancer (GC), 55 duodenal ulcer (DU) and 65 non-ulcer dyspepsia (NUD)]. In this study, allelic variants of iceA 1, iceA 2 and babA 2 were identified by polymerase chain reaction. The overall prevalence of babA 2 gene was 40.6% (65/160). The prevalence of babA 2 gene was 95% with gastric cancer, 18.1% with duodenal ulcer and 26.1% with non ulcer dyspepsia, respectively. The prevalence of babA 2 in GC patients was significantly higher as compared to either NUD or UD patients (P = 0.0004), while no statistical significance was found between the latter two patient groups. Our study finds that babA 2 and iceA 1 genes are more prevalent in GC compared to either NUD or DU patients in Iran. PMID- 21604201 TI - Human subcutaneous adipose tissue Glut 4 mRNA expression in obesity and type 2 diabetes. AB - Cellular resistance to insulin caused by reduced glucose transport and metabolism is a primary defect leading to the development of metabolic disease. While the etiology of insulin resistance is multifactorial, reduced insulin action is associated with impaired activity of the glucose transporter GLUT4 in insulin sensitive tissues. Yet, the role of adipose tissue GLUT4 deregulation in the pathogenesis of insulin resistance, obesity, and diabetes is still unclear. In this study, we assessed the relative GLUT4 level in human subcutaneous adipose tissue from obese, diabetic, and diabetic obese versus control subjects, using a real-time PCR method. GLUT4 mRNA levels were considerably decreased among type 2 diabetic patients compared with those of the controls (P < 0.01), whereas no such difference was found between obese and normal-weight controls. Multiple linear regressions analysis in both diabetic non-obese and diabetic obese groups showed a negative correlation between GLUT4 mRNA expression and both markers of obesity or insulin resistance (P < 0.01). However, in obese group, GLUT4 was inversely associated only with HOMA-IR (P < 0.01). Our findings showed that adipose GLUT4 gene expression changes were more related to insulin resistance and type 2 diabetes rather than to obesity. PMID- 21604202 TI - Sample taking during orthopedic surgery: sensitivity and specificity using the BACTEC blood culture system. AB - The use of blood culture systems for sterile body fluids other than blood has proven to be superior to routine culture methods. This study was conducted in order to assess the performance of the BACTEC blood culture system compared to swab/tissue sample collection for the detection of infection from intraoperative samples taken during surgical procedures. Sensitivity was determined by taking samples (BACTEC and swab/tissue samples) from patients with clinically evident infection (Infection group). Specificity was tested by taking the same sample sets from patients who had aseptic operations with no history of infection (Control group). The sensitivity was found to be much higher for the BACTEC group (50 isolates from 56 samples, sensitivity: 89%) compared to the swab/tissue samples (29 isolates out of 56 samples, sensitivity: 52%). The specificity was lower in the BACTEC group (32 isolates out of 44 samples, specificity: 27%) compared to the swab/tissue samples (1 isolate out of 44 samples, specificity: 98%). We conclude that BACTEC is useful for intraoperative sample collection in cases of low-grade infection. However, it is less specific and there is always the possibility for contamination. Therefore, it is advisable to use this technique in combination with regular tissue samples. PMID- 21604200 TI - Deciphering enzyme function using peptide arrays. AB - Enzymes are key molecules in signal-transduction pathways. However, only a small fraction of more than 500 human kinases, 300 human proteases and 200 human phosphatases is characterised so far. Peptide microarray based technologies for extremely efficient profiling of enzyme substrate specificity emerged in the last years. This technology reduces set-up time for HTS assays and allows the identification of downstream targets. Moreover, peptide microarrays enable optimisation of enzyme substrates. Focus of this review is on assay principles for measuring activities of kinases, phosphatases or proteases and on substrate identification/optimisation for kinases. Additionally, several examples for reliable identification of substrates for lysine methyl-transferases, histone deacetylases and SUMO-transferases are given. Finally, use of high-density peptide microarrays for the simultaneous profiling of kinase activities in complex biological samples like cell lysates or lysates of complete organisms is described. All published examples of peptide arrays used for enzyme profiling are summarised comprehensively. PMID- 21604203 TI - The role of mitochondria in neurodegenerative diseases. AB - Mitochondria are implicated in several metabolic pathways including cell respiratory processes, apoptosis, and free radical production. Mitochondrial abnormalities have been documented in neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Several studies have demonstrated that mitochondrial impairment plays an important role in the pathogenesis of this group of disorders. In this review, we discuss the role of mitochondria in the main neurodegenerative diseases and review the updated knowledge in this field. PMID- 21604204 TI - Seasonal and spatial diversity of microbial communities in marine sediments of the South China Sea. AB - This study was conducted to characterize the diversity of microbial communities in marine sediments of the South China Sea by means of 16S rRNA gene clone libraries. The results revealed that the sediment samples collected in summer harboured a more diverse microbial community than that collected in winter, Deltaproteobacteria dominated 16S rRNA gene clone libraries from both seasons, followed by Gammaproteobacteria, Acidobacteria, Nitrospirae, Planctomycetes, Firmicutes. Archaea phylotypes were also found. The majority of clone sequences shared greatest similarity to uncultured organisms, mainly from hydrothermal sediments and cold seep sediments. In addition, the sedimentary microbial communities in the coastal sea appears to be much more diverse than that of the open sea. A spatial pattern in the sediment samples was observed that the sediment samples collected from the coastal sea and the open sea clustered separately, a novel microbial community dominated the open sea. The data indicate that changes in environmental conditions are accompanied by significant variations in diversity of microbial communities at the South China Sea. PMID- 21604205 TI - Tyrosine phosphatase SHP-1 is expressed higher in multisystem than in single system Langerhans cell histiocytosis by immunohistochemistry. AB - Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cell (LC)-like CD1a-positive cell (LCH cell) with unknown causes. LCH consists of two subtypes: single-system LCH (LCH-SS) with favorable prognosis and multisystem LCH (LCH-MS) with poor prognosis. LCH has been indicated as a neoplastic disorder from monoclonal characteristics of LCH cells. This study aimed to investigate an expression of tyrosine phosphatase SHP-1 in LCH, since its expression levels were variously reported in many tumors, overexpression in ovarian cancers (a candidate oncoprotein), and downregulation by methylation in gastric cancers, prostate cancers, malignant lymphomas, and leukemias (a putative tumor suppressor). By immunohistochemistry (IHC), the SHP-1 expression in LCs and LCH cells was compared in LCH (two subtypes: LCH-SS = 21, LCH-MS = 12), dermatopathic lymphadenopathy (DLA) (n = 9) and normal epidermal LCs (n = 3) near LCH lesion. IHC results were analyzed semiquantitatively using a Photoshop software. The mean intensity score (IS) of DLA, LCH-SS, LCH-MS, and LCs were 47, 100, 139, and 167 (in arbitrary unit), respectively. The IS had significant differences among LCH SS, LCH-MS, and DLA (p < 0.01). SHP-1 is expressed significantly higher in LCH-MS than in LCH-SS. SHP-1 can be a progression marker of LCH. SHP-1 is also useful for differential diagnosis between LCH in lymph nodes and DLA. PMID- 21604206 TI - Efficacy of five alcohol-based skin antiseptics on sebaceous skin used at shorter application times than the current recommendation of 10 minutes. AB - Alcohol-based skin antiseptics are recommended with a minimum application time of 10 min on skin containing high numbers of sebaceous glands. In clinical practice, a 10-min application time is often too long. Therefore, we determined the efficacy of skin antiseptics on the forehead and lower back using shorter application times. Five alcoholic solutions were tested in a double-blind trial for their colony-forming units (cfu) reduction after 3, 4, 5 and 10 min on the forehead of 20 healthy volunteers and the lower back of 10 healthy volunteers and 10 patients against the reference alcohol 70% propan-2-ol, 10 min. After an application time of 3 min, 3/5 (forehead) and 5/5 (lower back) preparations were at least equally as effective compared to the reference alcohol and an application time of 10 min. Alcohol-based skin antiseptics do not require a 10 min application time. For all of the tested antiseptics, a minimum application time of 3 min on sebaceous skin can be recommended. PMID- 21604207 TI - Paradoxical fluorescence after administration of 5-aminolevulinic acid for resection of a cerebral melanoma metastasis. PMID- 21604208 TI - Sacrococcygeal teratoma in infants and children. AB - BACKGROUND: The purpose of this study is to share our experience with extensive sacrococcygeal teratoma, paying particular attention to neurological function, intraoperative hemorrhage, rate of tumor recurrence, and the surgical procedure. METHODS: Infants and children with sacrococcygeal teratoma were selected and generally examined in order to detect other associated anomalies. Patients with giant sacrococcygeal tumor and high output heart failure were managed by the abdominosacral route while patients with small sacrococcygeal tumor and normal cardiac function were managed by the sacral approach. All operated patients were observed and followed-up regularly for a period of 1-3 years after tumor excision. RESULTS: This study presents 22 patients with sacrococcygeal teratoma managed over a period of 40 months; 18 patients presented in the first 2 months of life and four children aged 2-4 years. Fifteen patients were treated by sacral excision and seven patients were corrected by abdomenosacral excision and temporary colostomy. Benign teratoma presented in 17 patients, one of whom died (6%), and five patients had malignant tumor, one of whom died (20%). The fecal and urinary state was good in all patients treated by the sacral route. Patients corrected by abdominosacral excision showed varied degrees of urinary incontinence and constipation. Survival in excised malignant tumor was good following chemotherapy; three patients received chemotherapy with a 70% survival rate. CONCLUSION: Benign sacrococcygeal teratoma has an excellent outcome after early surgery, but the incidences of malignancy increase if resection is delayed. PMID- 21604209 TI - 11th International Workshop in Developmental Nephrology (IWDN). PMID- 21604210 TI - MRI of the lumbar spine at 7 Tesla in healthy volunteers and a patient with congenital malformations. AB - OBJECTIVE: The aim of this study was to evaluate sequences that are established at lower magnetic field strengths for lumbar spine imaging at 7 Tesla (7 T) MR imaging. MATERIALS AND METHODS: The lumbar spine of five healthy volunteers and a patient with spina bifida and meningocele were evaluated at 7 T. The examination included a T2-TSE (turbo spin echo), a 3D-DESS (double-echo steady-state sequence), a 3D-CISS (constructive interference in steady-state sequence), and a 3D-VIBE (volumetric interpolated breath hold examination) sequence. Imaging quality was evaluated by two raters on a three-level scale. The assessment included visualization of intraforaminal structures, the cauda equina, facet joints, and any abnormalities. Contrast ratios for intervertebral discs/vertebral bodies, vertebral bodies/cerebrospinal fluid (CSF) and CSF/spinal cord were calculated. RESULTS: The 3D-VIBE sequence provided best differentiation between intraforaminal structures. Visualization of the facet joints was reliable with VIBE, DESS, and CISS. Individual nerve roots of the cauda equina could only be delineated with the 3D-CISS sequence. CISS and DESS provided good contrast between vertebral bodies and intervertebral discs. Contrast between CSF and vertebral bodies was most pronounced for the T2-TSE sequence. Sufficient contrast between CSF and the spinal cord was only achieved with the T2-TSE sequence. VIBE and DESS sequences demonstrated best the bony malformations. Visualization of the meningocele was only possible with the 3D-CISS sequence. CONCLUSION: At 7 T most structures of the lumbar spine were visualized with a combination of sequences. At present, imaging quality is not superior to 1.5 T or 3 T, precluding routine clinical use. PMID- 21604211 TI - Beneficial impact of aerobic exercises on bone mineral density in obese premenopausal women under caloric restriction. AB - OBJECTIVE: The aim of this study was to assess the impact of caloric restriction diet versus caloric restriction diet combined with aerobic exercises on bone mineral density (BMD) in obese premenopausal women. SUBJECTS AND METHODS: Forty premenopausal obese women were classified randomly into two groups equal in number. The first group (group A) received caloric restriction diet, while the second (group B) received caloric restriction diet combined with a program of aerobic exercises, over 3 months. The variables measured in this study included age, weight, height, body mass index, fat weight, lean mass, fat percent, basal metabolic rate, and BMD. RESULTS: The comparison between group A and group B showed significantly higher post-treatment lean mass, basal metabolic rate, and BMD in weight-bearing bones (L2-L4 lumbar spine and total hip) in group B compared to group A. In contrast to the BMD of the weight-bearing bones, the BMD of the radius showed significant decrease between the pre- and post-treatment results in groups A and B with no significant differences between the two groups. CONCLUSION: A greater improvement in the BMD of weight-bearing bones was observed in obese premenopausal women undergoing caloric restriction combined with exercise than in those not undergoing exercise. Anaerobic exercises incorporated into weight loss programs help offset the adverse effects of dietary restriction on bone. PMID- 21604212 TI - The teres minor muscle in rotator cuff tendon tears. AB - OBJECTIVES: Although the teres minor has received little attention in the literature compared to the other musculotendinous units of the rotator cuff, it is an important component of shoulder function. Our purpose was to study the appearance of the teres minor muscle on CT and MRI images in various patterns of rotator cuff tears. MATERIALS AND METHODS: We analyzed the appearance of the teres minor according to the Walch classification (normal, hypertrophic, atrophic, or absent) in 1,332 CT and in 240 MRI images of rotator cuff tears and we correlated it with the type of rotator cuff tears, time period between initial onset of symptoms and diagnostic imaging, age of the patient at the time of imaging, and degree of fatty infiltration of other rotator cuff muscles. RESULTS: The teres minor was classified as normal in 90.8% of cases, hypertrophic in 5.8%, atrophic in 3.2%, and absent in 0.2%. Significant variability existed in the appearance of the teres minor muscle among different patterns of rotator cuff tears in the CT (P < 0.0001) and MRI groups (P < 0.0001). The teres minor appeared most frequently hypertrophic in anterior tears and atrophic in posterior superior tears. CONCLUSIONS: The teres minor was normal in most rotator cuff tears. A morphologic classification system allowed the appearance of the teres minor to be defined in isolated and multiple rotator cuff tears in CT and MRI images. PMID- 21604213 TI - A case of enteropathy-associated T-cell lymphoma: diagnosis by flow cytometric immunophenotyping and genome analysis using ascitic fluid. AB - Enteropathy-associated T-cell lymphoma (ETCL) is a primary extranodal T-cell lymphoma arising in the gastrointestinal tract, and is known as a rare and highly aggressive disease with a poor prognosis. The diagnosis of ETCL is usually established by histological examination using resected tumors or biopsy specimens during endoscopic studies. If tumor specimens for histopathological investigation are not available, then such a case might be difficult to accurately diagnose. We report here a case of ETCL which was diagnosed by cytopathology and flow cytometric immunophenotyping using paracentesis fluid without tumor specimens. Immunophenotyping by flow cytometry (FCM) of the ascitic fluid (AF) was invaluable in the final diagnosis of ETCL. Moreover, genetic alterations in the current case were also demonstrated. We emphasize the usefulness of effusion cytology for the expeditious diagnosis of ETCL. In particular, even in cases without tumor specimens, immunophenotyping by FCM using AF can play an important role in the diagnosis of ETCL, and simultaneous genome analysis may be useful to elucidate the biological characteristics of ETCL. PMID- 21604214 TI - Accelerated hippocampal volume reduction in post-menopausal women: an additional study with Atlas-based method. AB - Our aim in the present additional study was to investigate the absolute hippocampal volume in normal adults who were divided into eight groups according to their age and gender, because our previous study with voxel-based morphometry (VBM) was not able to show the absolute hippocampal volume. High-spatial resolution T1-weighted images with 3.0 Tesla magnetic resonance scanners were obtained on 412 healthy adults who were divided into 8 groups, according to age and gender, for analysis of brain volume change focusing on hippocampal volume. Hippocampal regions of interest were obtained with WFU PickAtlas software. As a result, the present study revealed a significant difference bilaterally between the groups of females in their forties and those in their fifties. Because this result is the same as that of our previous study with VBM, it adds evidence to the hypothesis that menopause is associated with hippocampal volume reduction. However, the result between groups of males in their sixties and those in their seventies was inconsistent in both studies. In conclusion, the present study showed that reduction in the hippocampal volume over one decade was small compared to the standard deviation in each group. This study is useful for improving our understanding of the correlation between menopause and hippocampal volume reduction. PMID- 21604215 TI - Value of impedance cardiography in patients studied for pulmonary hypertension. AB - The aim of this study was to evaluate the accuracy and precision of impedance cardiography as a method for noninvasive hemodynamic evaluation of patients with pulmonary hypertension (PH). We performed a prospective and blinded study of patients who underwent right heart catheterization (RHC) for evaluation of known or presumed PH at the University of Florida from August 2009 to March 2010. The cohort consisted of a total of 39 patients (age = 57 +/- 14 years, 87% women) with presumed (23%) or confirmed PH (77%) of different etiologies. Patients underwent RHC and impedance cardiography using the PhysioFlow PF-05. The PhysioFlow PF-05 measures cardiac output (CO) and LV end-diastolic volume (LVEDV), among other parameters. The median pulmonary artery pressure was 36 (IQR 26-56) mmHg. The CO (mean +/- SD) by thermodilution (CO-T) and by impedance cardiography (CO-IC) was 5.9 +/- 2.2 and 5.6 +/- 1.5 L/min, respectively. Bland Altman analysis of CO-T versus CO-IC revealed a mean of 0.3 L/min (95% LoA: -2.2 to +2.8). In patients with PH, the correlation of CO-T and CO-IC had a mean of 0.4 L/min (95% LoA: 2.9 and -2.2). Pulmonary artery occlusion pressure (PAOP) correlated with LVEDV (R (2) = 0.2, p = 0.005). By ROC analysis, EDV >= 200 ml had a sensitivity of 53% and a specificity of 86% for PAOP > 15 mmHg (AUC = 0.78). In patients with PH, impedance cardiography had good accuracy and fair precision for CO determination when compared with thermodilution. Impedance cardiography may provide information about the preload status and has the potential to become a cost-effective and noninvasive method for the follow-up of patients with PH. PMID- 21604216 TI - The effect of butenolide on behavioral and morphological changes in two marine fouling species, the barnacle Balanus amphitrite and the bryozoan Bugula neritina. AB - Butenolide [5-octylfuran-2(5H)-one] is a very promising antifouling compound. Here, the effects of butenolide on larval behavior and histology are compared in two major fouling organisms, viz. cypris larvae of Balanus amphitrite and swimming larvae of Bugula neritina. Butenolide diminished the positive phototactic behavior of B. amphitrite (EC50=0.82 MUg ml(-1)) and B. neritina (EC50=3 MUg ml(-1)). Its effect on the attachment of cyprids of B. amphitrite was influenced by temperature, and butenolide increased attachment of larvae of B. neritina to the bottom of the experimental wells. At concentrations of 4 MUg ml( 1) and 10 MUg ml(-1), butenolide decreased attachment of B. amphitrite and B. neritina, respectively, but the effects were reversible within a certain treatment time. Morphologically, butenolide inhibited the swelling of secretory granules and altered the rough endoplasmic reticulum (RER) in the cement gland of B. amphitrite cyprids. In B. neritina swimming larvae, butenolide reduced the number of secretory granules in the pyriform-glandular complex. PMID- 21604217 TI - Effects of biofilm formation on membrane performance in submerged membrane bioreactors. AB - The effects of biofilm formation on membrane performance were evaluated for a submerged membrane bioreactor (sMBR) system with six different types of micro- and ultrafiltration membranes (working volume=19 l). After operation for 24 h the permeability of the membranes with a larger pore size (microfiltration) decreased to that of the membranes with a much smaller pore size (ultrafiltration). Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) confirmed that biofilms could reduce the influence of the membrane surface properties. The chemical oxygen demand (COD) removal efficiency was 95% for the oily wastewater treatment in the sMBR where the filtration process made an important contribution (47% based on feed COD). Significant enhancement in COD removal occurred at the initial filtration stage because of biofilm formation and the dynamic member role of the biofilm layer. Membranes with various pore sizes had approximately the same permeate quality that was attributed to the biofilm on the membrane surfaces. Nevertheless, the ultrafiltration membranes had 43% more COD removal efficiency than the other applied membranes at the beginning of filtration (before biofilm formation) because of the smaller pore sizes and better sieving. PMID- 21604218 TI - Influence of EPS isolated from thermophilic sulphate-reducing bacteria on carbon steel corrosion. AB - Extracellular polymeric substances (EPS) were isolated by centrifugation of thermophilic sulphate-reducing bacteria (SRB) grown in API-RP38 culture medium. The protein and polysaccharide fractions were quantified and the highest concentrations were extracted from a 14-day old culture. The effect of EPS on carbon steel corrosion was investigated by electrochemical techniques. At 30 degrees C, a small amount of EPS in 3% NaCl solution inhibited corrosion, whilst excessive amounts of EPS facilitated corrosion. In addition, the inhibition efficiency of EPS decreased with temperature due to thermal desorption of the EPS. The results suggest that adsorbed EPS layers could be beneficial to anti corrosion by hindering the reduction of oxygen. However, the accumulation of an EPS film could stimulate the anodic dissolution of the underlying steel by chelation of Fe2+ ions. PMID- 21604219 TI - Biomechanical study on the edge shapes for penetrating keratoplasty. AB - A parametric study to investigate the compressive and the shear stress distributions for various edge shapes created during penetrating keratoplasty (PK) using femtosecond laser is reported. The finite element analysis has been implemented using ABAQUS to study the cornea with various edge shapes, namely the standard edge shape, the zigzag edge shape, the top hat edge shape and the mushroom edge shape for PK. The ratio of maximum compressive stress to maximum shear stress is used as the main factor to assess the relative merits of wound healing rate for different edge shapes. For the typical values of tissue mechanical properties, the zigzag edge shape has the highest ratio of maximum compressive stress to maximum shear stress (11.1 in the xy-direction and 3.7 in the yz-direction), followed by the mushroom edge shape (7.7 in the xy-direction and 3.2 in the yz-direction). The ratios for the top hat and the standard edge shapes are even lower in both directions. A sensitivity analysis of the model has been done to demonstrate that the zigzag edge shape always results in the highest ratios of stresses regardless of the difference in the tissue mechanical properties. The zigzag edge shape also gives the lowest dioptric power D = 45.4. The present results imply that the zigzag edge shape provides the best wound healing rate and optical outcome among the four edge shapes models for PK. PMID- 21604220 TI - An assessment of swinger techniques for the playground swing oscillatory motion. AB - Much attention has been devoted to how playground swing amplitudes are built up by swinger techniques, i.e. body actions. However, very little attention has been given to the requirements that such swinger techniques place on the swinger himself. The purpose of this study was to find out whether different swinger techniques yield significantly different maximum torques, endurance and coordinative skills, and also to identify preferable techniques. We modelled the seated swinger as a rigid dumbbell and compared three different techniques. A series of computer simulations were run with each technique, testing the performance with different body rotational speeds, delayed onset of body rotation and different body mass distributions, as swing amplitudes were brought up towards 90 degrees . One technique was found to be extremely sensitive to the timing of body actions, limiting swing amplitudes to 50 degrees and 8 degrees when body action was delayed by 0.03 and 0.3 s, respectively. Two other more robust techniques reached 90 degrees even with the largest of these delays, although more time (and endurance) was needed. However, these two methods also differed with respect to maximum torque and endurance, and none was preferable in both these aspects, being dependent on the swinger goals and abilities. PMID- 21604221 TI - A theoretical study of bone remodelling under PEMF at cellular level. AB - Pulsed electromagnetic field (PEMF) devices have been used clinically to slow down osteoporosis and accelerate the healing of bone fractures for many years. However, the underlying mechanism by which bone remodelling under PEMF is regulated remains poorly understood. In this paper, a mathematical model of bone cell population of bone remodelling under PEMF at cellular level is developed to address this issue for the first time. On the basis of this model and control theory, parametric study of control mechanisms is carried out and a number of possible control mechanisms are identified. These findings will help further the understanding of bone remodelling under PEMF and advance therapies and pharmacological developments in clinical trials. PMID- 21604222 TI - Computer-based assessment of movement difficulties in Parkinson's disease. AB - The prevalence of Parkinson's disease (PD) is increasing due to an ageing population. It is an unpredictable disease which requires regular assessment and monitoring. Current techniques used to assess PD are subjective. Clinicians observe movements made by a patient and subsequently rate the level of severity of, for example tremor or slowness of movement. Within this work, we have developed and evaluated a prototype computer-based assessment tool capable of collecting information on the movement difficulties present in PD. Twenty participants took part in an assessment of the tool, 10 of whom were diagnosed with PD and 10 were without the disease. Following the usage of the tool, it was found that there was a significant difference (p = 0.038) in the speed of movement between the two groups. We envisage that this tool could have the potential to enable more objective clinical conclusions to be made. PMID- 21604223 TI - A numerically validated probabilistic model of a simplified total hip replacement construct. AB - Hip replacement constructs are paradigms of uncertain systems, and as such are suited to the application of probabilistic methods to assess their structural integrity. In order to gain confidence in a probabilistic model, it would be useful to verify the findings with experimental data; however, this is difficult to achieve in practice because of the exhaustive number of parameter combinations that need to be tested. As an alternative to experimental testing, benchmarking can be carried out provided a known analytical solution is available. To this end, a simplified 2D two-beam model of the femoral part of a total hip replacement construct was utilised to analyse uncertainties and variability in the construct as it is subjected to load. The use of a simplified model enabled geometric parameters to be investigated; these are commonly not considered in probabilistic models due to the increased complexity involved. Analytical and finite element representations of the model were developed and compared. The probabilistic study used the Monte Carlo simulation technique and the first-order reliability method to look at the inducible displacement of a hip implant, a phenomenon that has been linked to the most common cause of hip implant failure, aseptic loosening. Excellent correlation was observed between the analytical and probabilistic solutions, and it was shown that probabilistic approaches could efficiently predict the response of the simplified beam model while readily identifying the parameters most likely to compromise the structural integrity of the construct. PMID- 21604224 TI - Case Study: Deepwater horizon response workers exposure assessment at the source: MC252 well No. 1. PMID- 21604225 TI - The relative age effect and success in German elite U-17 soccer teams. AB - The aim of the study was to determine whether there is empirical evidence for advantages in performance of soccer teams because of their relative age. The practice of selecting youth players according to their momentary performance leads to relative age effects, which in turn lead to inefficient talent selection. We used the median of the birth dates as a measure of the effect size of the relative age effect and the Kolmogorov-Smirnov test to assess its significance. For the 2008-2009 season, birth dates in the three German U-17 first leagues for soccer were examined (911 players). More than half of the 41 teams differed significantly from the distribution of the corresponding German cohort. There was a significant correlation between the relative age effect and success defined by teams' final rankings (Spearman's rho = 0.328, P = 0.036). Regression analyses revealed that with a median of birth dates one month earlier the team is expected to finish 1.035 ranks better. Accordingly, selecting early born athletes is an important aspect of success in youth soccer. However, teams with no relative age effect are able to compete in the league, having the benefit to promote players with a better perspective for long and successful careers at an adult age. PMID- 21604226 TI - Accelerometer-measured daily physical activity related to aerobic fitness in children and adolescents. AB - Maximum oxygen uptake (VO(2PEAK)) is generally considered to be the best single marker for aerobic fitness. While a positive relationship between daily physical activity and aerobic fitness has been established in adults, the relationship appears less clear in children and adolescents. The purpose of this paper is to summarise recently published data on the relationship between daily physical activity, as measured by accelerometers, and VO(2PEAK) in children and adolescents. A PubMed search was performed on 29 October 2010 to identify relevant articles. Studies were considered relevant if they included measurement of daily physical activity by accelerometry and related to a VO(2PEAK) either measured directly at a maximal exercise test or estimated from maximal power output. A total of nine studies were identified, with a total number of 6116 children and adolescents investigated. Most studies reported a low-to-moderate relationship (r = 0.10-0.45) between objectively measured daily physical activity and VO(2PEAK). No conclusive evidence exists that physical activity of higher intensities are more closely related to VO(2PEAK), than lower intensities. PMID- 21604227 TI - Physiological determinants of speciality of elite middle- and long-distance runners. AB - The aim of this study was to determine which physiological variables predict excellence in middle- and long-distance runners. Forty middle-distance runners (age 23 +/- 4 years, body mass 67.2 +/- 5.9 kg, stature 1.80 +/- 0.05 m, VO(2max) 65.9 +/- 4.5 ml . kg(-1) . min(-1)) and 32 long-distance runners (age 25 +/- 4 years, body mass 59.8 +/- 5.1 kg, stature 1.73 +/- 0.06 m, VO(2max) 71.6 +/- 5.0 ml . kg(-1) . min(-1)) competing at international standard performed an incremental running test to exhaustion. Expired gas analysis was performed breath by-breath and maximum oxygen uptake (VO(2max)) and two ventilatory thresholds (VT(1) and VT(2)) were calculated. Long-distance runners presented a higher VO(2max) than middle-distance runners when expressed relative to body mass (P < 0.001, d = 1.18, 95% CI [0.68, 1.68]). At the intensities corresponding to VT(1) and VT(2), long-distance runners showed higher values for VO(2) expressed relative to body mass or %VO(2max), speed and oxygen cost of running (P < 0.05). When oxygen uptake was adjusted for body mass, differences between groups were consistent. Logistic binary regression analysis showed that VO(2max) (expressed as l . min(-1) and ml . kg(-1) . min(-1)), VO(2VT2) (expressed as ml . kg(-0.94) . min(-1)), and speed at VT(2) (v(VT2)) categorized long-distance runners. In addition, the multivariate model correctly classified 84.7% of the athletes. Thus, VO(2max), VO(2VT2), and v(VT2) discriminate between elite middle-distance and long-distance runners. PMID- 21604228 TI - The use of GPS to evaluate activity profiles of elite women hockey players during match-play. AB - The aim of the study was to assess the match-play activity patterns of elite women field-hockey players using a global positioning system (SPI Elite, GPSports, Fyshwick, Australia). The activity of 25 players was analysed for 13 international matches, totalling 158 player-match analyses. Overall mean playing time was 48 +/- 4 min but this varied according to playing position (defenders: 56 +/- 11 min; midfielders: 50 +/- 10 min; forwards: 38 +/- 7 min; P < 0.001, d = 0.57-1.92). In total, 55.5 +/- 6.3% of match time was spent performing low intensity exercise (standing: 5.8 +/- 2.7%; walking: 49.7 +/- 5.6%). Moderate intensity exercise accounted for 38.1 +/- 5.0% (jogging: 25.8 +/- 3.5%; running: 12.3 +/- 2.9%) of player match-time, with the remainder made up of high-intensity exercise (fast running: 4.9 +/- 1.4%; sprinting: 1.5 +/- 0.6%). Forwards spent more time performing moderate- (41.4%) and high-intensity (7.7%) exercise than defenders and midfield players (P < 0.001). This is the first study to use a global positioning system to assess the activity characteristics of elite female hockey players and demonstrate that these characteristics differ according to playing position. These differences are probably attributable to the ways in which substitution of players occurs. PMID- 21604229 TI - Behavioural facilitation following brain stimulation: implications for neurorehabilitation. AB - Studies showing facilitation of behavioural performance by transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) in sensory and perceptual domains, spatial attention, working memory, and executive and emotional tasks are reviewed. In these domains the performance of neurologically unimpaired participants may be modulated, with behavioural facilitation or interference, by TMS, and by tDCS. The mapping of the frequency-dependent effects of TMS, and of the polarity-dependent effects of tDCS on behaviour does not systematically and mechanistically result in an increase or decrease of behavioural performance. Factors such as the parameters of the cerebral stimulation (localisation, duration, intensity), and the features of the task (complexity, phase of training) contribute to determine the final net effect on the participants' performance. Non-invasive brain stimulation (NIBS), which modulates learning, and appears to have, under some conditions, long lasting effects, is a promising tool to be used in the rehabilitation of a variety of neurological and cognitive disorders, that typically involve repeated behavioural training sessions. PMID- 21604230 TI - Differences in life expectancy by education and occupation in Italy, 1980-94: indirect estimates from maternal and paternal orphanhood. AB - In the present study, we use the modified orphanhood method to analyse mortality differences by socio-economic status in Italy. This technique permits the indirect estimation of adult mortality from survey-based information on parents' survival in developed populations and helps to overcome several limitations of conventional studies on mortality differences by social class. We estimate a time series of life tables by education and occupation and analyse the differences in life expectancy by socio-economic status along with their changes between 1980 84, 1985-89, and 1990-94. Whereas mortality differences between the highest social class and the other socio-economic status groups increased among men, they decreased among women. We speculate about the reasons for these sex-specific trends and evaluate the application of indirect estimation techniques to the populations of developed countries. PMID- 21604231 TI - Application of chemical reaction mechanistic domains to an ecotoxicity QSAR model, the KAshinhou Tool for Ecotoxicity (KATE). AB - The validity of chemical reaction mechanistic domains defined by skin sensitisation in the Quantitative Structure-Activity Relationship (QSAR) ecotoxicity system, KAshinhou Tools for Ecotoxicity (KATE), March 2009 version, has been assessed and an external validation of the current KATE system carried out. In the case of the fish end-point, the group of chemicals with substructures reactive to skin sensitisation always exhibited higher root mean square errors (RMSEs) than chemicals without reactive substructures under identical C- or log P judgements in KATE. However, in the case of the Daphnia end-point this was not so, and the group of chemicals with reactive substructures did not always have higher RMSEs: the Schiff base mechanism did not function as a high error detector. In addition to the RMSE findings, the presence of outliers suggested that the KATE classification rules needs to be reconsidered, particularly for the amine group. Examination of the dependency of the organism on the toxic action of chemicals in fish and Daphnia revealed that some of the reactive substructures could be applied to the improvement of the KATE system. It was concluded that the reaction mechanistic domains of toxic action for skin sensitisation could provide useful complementary information in predicting acute aquatic ecotoxicity, especially at the fish end-point. PMID- 21604232 TI - When less is heard than meets the ear: change deafness in a telephone conversation. AB - During a conversation, we hear the sound of the talker as well as the intended message. Traditional models of speech perception posit that acoustic details of a talker's voice are not encoded with the message whereas more recent models propose that talker identity is automatically encoded. When shadowing speech, listeners often fail to detect a change in talker identity. The present study was designed to investigate whether talker changes would be detected when listeners are actively engaged in a normal conversation, and visual information about the speaker is absent. Participants were called on the phone, and during the conversation the experimenter was surreptitiously replaced by another talker. Participants rarely noticed the change. However, when explicitly monitoring for a change, detection increased. Voice memory tests suggested that participants remembered only coarse information about both voices, rather than fine details. This suggests that although listeners are capable of change detection, voice information is not continuously monitored at a fine-grain level of acoustic representation during natural conversation and is not automatically encoded. Conversational expectations may shape the way we direct attention to voice characteristics and perceive differences in voice. PMID- 21604233 TI - [Latest trends and recommendations on epidemiology, diagnosis, and treatment of benign prostatic hyperplasia (BPH)]. AB - BACKGROUND: A re-evaluation of established tests and treatments has become necessary after publication of several new guidelines on BPH during the past two years. This article describes the latest developments concerning epidemiology, diagnosis, and treatment of BPH. MATERIAL AND METHODS: Diagnostic and treatment guidelines on BPH of the German, European, or North American urologists as well as UK doctors were reviewed according to key articles and latest modifications. RESULTS: The only German epidemiological trial on BPH demonstrated that all components of the BPH disease (symptoms - prostate enlargement - bladder outlet obstruction) increase with ageing. 27 % of German men will have disease progression within the next 5 years. Risk factors for disease progression are: age, symptoms, prostate size, PSA, urinary flow rate, and postvoiding residual urine. Diagnosis aims to distinguish BPH from other diseases with similar symptoms, quantify the BPH components, and estimate the individual risk of disease progression. BPH is an exclusion diagnosis. Ultrasonic measurement of detrusor wall thickness at the anterior wall of bladders filled with >= 250 mL can securely detect bladder outlet obstruction if the value is >= 2 mm. Watchful waiting and lifestyle modifications are suitable for men with mild symptoms and low disease progression risk. All drugs used in BPH treatment reduce symptoms but have no influence on bladder outlet obstruction. alpha-blockers are first-line drugs and may be combined with muscarinic receptor antagonists or 5alpha reductase inhibitors to further increase efficacy. Prostate surgery is indicated when drug treatment is insufficient, the patient develops complications in the upper or lower urinary tract (absolute indications), or has severe bladder outlet obstruction. Standard operations are TURP in small (<= 80 mL) or open prostatectomy in large prostates (> 80 mL). Minimally invasive, alter-native surgeries may be considered in selected men and -offer advantages with regard to the risk of bleeding, duration of catheterisation, or maintenance of sexual function. CONCLUSIONS: Current guidelines have integrated the latest knowledge and developments on BPH and are likely to improve assessment and treatment. PMID- 21604234 TI - [Operations with scrotal approach]. PMID- 21604235 TI - [Pars plana vitrectomy for idiopathic macular hole--visual improvement or merely surgical stress?]. AB - BACKGROUND: The aim of this study was to compare the functional results of surgical treatment of idiopathic macular holes in controlled clinical studies with those of the "real world" in the clinical routine. METHODS: The operated eyes of patients of a rural district (Saalfeld-Rudolstadt, Germany) during 2000 2009 were analysed based on the documentation of the postoperative care of all ophthalmologists in this region. RESULTS: 37 eyes of 37 patients (age 71 years, 45; 80) (median, [min; max]) operated in 7 clinical institutes were analysed. The past medical history until surgery was 4 months (1; 72) and the preoperative visual acuity (VA) 0.2 (0.01; 0.5). The observational period after surgery was 2.3 years (1; 6 years), all eyes were documented over more then 1 year thereafter. At the last control the VA improved >= 2 lines in 17 eyes (46%) and decreased >= 2 lines in 8 (22%). 13 eyes (35%) obtained a VA >= 0.5. A short preoperative period corresponded with a visual improvement (K = 0.40, p = 0.01). A further increase of VA after one year could be observed only due to cataract surgery or Nd:YAG laser capsulotomy. 8 eyes (22%) needed at least one more vitreoretinal surgery. DISCUSSION: Reasons for the disappointing functional results compared with the literature could be long medical history, not differentiated grades of macular holes and developing surgical techniques during the analysis period. Retrospective analyses of the outcome of routine practical work seems to be a necessary complement of controlled clinical studies despite their methodical deficits. New prognostic criteria are needed for a better indication for surgery and an improved counselling of the patient. PMID- 21604236 TI - [Giant cell arteritis (temporal arteritis, Horton's arteritis): clinical characteristics and management]. AB - Giant cell arteritis can cause diagnostic difficulties due to its heterogeneous symptomatology. Characteristic ophthalmic and systemic symptoms of Horton's disease are discussed. The clinical course is described on the basis of typical patients, which shows that generic symptoms do not have to coexist. The Horton's arteritis potentially represents a systemic vasculitis that requires early diagnosis and treatment in order to avoid dramatic ophthalmic consequences, in worst cases blindness. The erythrocyte sedimentation rate (ESR) represents the most important laboratory parameter. Although temporal artery biopsy remains the only confirmatory procedure for a definite diagnosis, imaging procedures such as sonography, magnetic resonance imaging, ultrasound biomicroscopy are useful in supporting the clinical diagnosis. Highly dosed corticosteroid therapy should always be indicated when suspicious clinical symptoms are present, even without any dramatic laboratory parameter changes. Initial high dosages are indicated up to 1 gram daily depending on the severity of the disease. Subsequently a slow ESR titrated reduction of the dose is necessary under control of inflammation values, symptomatology and side effects. Occasionally a lifelong immunsuppressive therapy is indispensable. The long-term treatment should take place in close cooperation with the general practitioner, rheumatologist, neurologist and if necessary further specialists. PMID- 21604237 TI - [Dystrophies of Bowman's layer]. PMID- 21604238 TI - [Changes of macular pigment and drusen morphology in patients with lutein supplementation]. PMID- 21604239 TI - Chrysindins A-D, polyacetylenes from the flowers of Chrysanthemum indicum. AB - Four new polyacetylenes, namely chrysindins A-D, together with 6 known polyacetylenes, were isolated from the flowers of Chrysanthemum indicum. Their structures were established on the basis of comprehensive spectroscopic analyses. Chrysindins A and B bear a novel carbon skeleton. PMID- 21604240 TI - Absolute/relative bioavailability and metabolism of dodeca-2E,4E,8Z,10E/Z tetraenoic acid isobutylamides (tetraenes) after intravenous and oral single doses to rats. AB - The present study assessed the absolute and relative bioavailabilities of dodeca 2 E,4 E,8 Z,10 E/ Z-tetraenoic acid isobutylamides (tetraenes), the main bioactive constituents in Echinacea, administered as pure compounds or in the form of an Echinacea purpurea root extract preparation. Tetraenes were administered orally by gavage or intravenously in a dose of 0.75 mg/kg. The extract was administered orally in a dose of 158.6 mg/kg which corresponds to the same amount of tetraenes. Pharmacokinetic parameters of tetraenes were calculated by non-compartmental analysis using WinNonlin(r) 5.2 software. Mean dodeca-2 E,4 E,8 Z,10 E/ Z-tetraenoic acid isobutylamide dose-normalized plasma area under the concentration-time curve (AUC0-infinity/dose) was 3.24 +/- 0.32 min . ng/mL/ug and 0.95 +/- 0.16 min . ng/mL/ug after iv and oral administrations, respectively, and 1.53 +/- 0.18 min . ng/mL/ug after oral administration of the Echinacea root extract. The absolute oral bioavailability of dodeca-2 E,4 E,8 Z,10 E/ Z tetraenoic acid isobutylamides was 29.2 +/- 2.3 %, which was increased to 47.1 +/ 7.2 % (1.6-fold) by administration of the Echinacea extract. Administration of an Echinacea extract increased blood exposure with no impact on C(max), but prolonged the elimination half-life to 123.3 +/- 15.7 min in comparison to 35.8 +/- 6.5 min after administration of the pure dodeca-2 E,4 E,8 Z,10 E/ Z tetraenoic acid isobutylamides. PMID- 21604241 TI - Current concepts on the mechanisms of dystonia and the beneficial effects of deep brain stimulation. AB - The application of lesioning procedures in the basal ganglia and, more recently, of deep brain stimulation (DBS) has revolutionalized dystonia treatment. However, our understanding of the mechanism of action of DBS is only minimal. This is largely due to a rudimentary understanding of dystonia pathophysiology itself, which in turn reflects an insufficient understanding of the functional significance of the cortico-striato-pallido-thalamocortical loops. The initial dystonia pathophysiology concept was one of changes in oscillation rate. Soon, it was realized that not only rate but also the pattern of basal ganglia activity is crucial in the etiology of the disease. The observations of altered somatosensory responsiveness and cortical neuroplasticity, along with the vast array of clinical phenotypes, imply the need for a wholistic neuronal pathophysiology model; one in which an underlying defect of basal ganglia function results in increased cortical excitability, misprocessing of sensory feedback, aberrant cortical plasticity, and ultimately clinical dystonia. This unified dystonia pathophysiology model, although simplistic, may provide the scaffold on which all incoming research and clinical data becomes united in a meaningful and practical way. In light of this model, the dramatic response of some forms of dystonia to pallidal stimulation, the time latency for the beneficial effect and even the presence of non-responders may be explained. Additionally, it may help in developing a rationale for more efficacious DBS programming, better selection of the timing of surgery, and more successful identification of those candidates that are most likely to respond to DBS. PMID- 21604242 TI - Osteoinductive biomaterials: current knowledge of properties, experimental models and biological mechanisms. AB - In the past thirty years, a number of biomaterials have shown the ability to induce bone formation when implanted at heterotopic sites, an ability known as osteoinduction. Such biomaterials--osteoinductive biomaterials--hold great potential for the development of new therapies in bone regeneration. Although a variety of well characterised osteoinductive biomaterials have so far been reported in the literature, scientists still lack fundamental understanding of the biological mechanism underlying the phenomenon by which they induce bone formation. This is further complicated by the observations that larger animal models are required for research, since limited, if any, bone induction by biomaterials is observed in smaller animals, including particularly rodents. Besides interspecies variation, variations among individuals of the same species have been observed. Furthermore, comparing different studies and drawing general conclusions is challenging, as these usually differ not only in the physico chemical and structural properties of the biomaterials, but also in animal model, implantation site and duration of the study. Despite these limitations, the knowledge of material properties relevant for osteoinduction to occur has tremendously increased in the past decades. Here we review the properties of osteoinductive biomaterials, in the light of the model and the conditions under which they were tested. Furthermore, we give an insight into the biological processes governing osteoinduction by biomaterials and our view on the future perspectives in this research field. PMID- 21604243 TI - Alkali treatment of microrough titanium surfaces affects macrophage/monocyte adhesion, platelet activation and architecture of blood clot formation. AB - Titanium implants are most commonly used for bone augmentation and replacement due to their favorable osseointegration properties. Here, hyperhydrophilic sand blasted and acid-etched (SBA) titanium surfaces were produced by alkali treatment and their responses to partially heparinized whole human blood were analyzed. Blood clot formation, platelet activation and activation of the complement system was analyzed revealing that exposure time between blood and the material surface is crucial as increasing exposure time results in higher amount of activated platelets, more blood clots formed and stronger complement activation. In contrast, the number of macrophages/monocytes found on alkali-treated surfaces was significantly reduced as compared to untreated SBA Ti surfaces. Interestingly, when comparing untreated to modified SBA Ti surfaces very different blood clots formed on their surfaces. On untreated Ti surfaces blood clots remain thin (below 15 mm), patchy and non-structured lacking large fibrin fiber networks whereas blood clots on differentiated surfaces assemble in an organized and layered architecture of more than 30 mm thickness. Close to the material surface most nucleated cells adhere, above large amounts of non nucleated platelets remain entrapped within a dense fibrin fiber network providing a continuous cover of the entire surface. These findings might indicate that, combined with findings of previous in vivo studies demonstrating that alkali-treated SBA Ti surfaces perform better in terms of osseointegration, a continuous and structured layer of blood components on the blood-facing surface supports later tissue integration of an endosseous implant. PMID- 21604244 TI - A 3D in vitro bone organ model using human progenitor cells. AB - Three-dimensional (3D) organotypic culture models based on human cells may reduce the use of complex and costly animal models, while gaining clinical relevance. This study aimed at developing a 3D osteoblastic-osteoclastic-endothelial cell co culture system, as an in vitro model to mimic the process of bone turnover. Osteoprogenitor and endothelial lineage cells were isolated from the stromal vascular fraction (SVF) of human adipose tissue, whereas CD14+ osteoclast progenitors were derived from human peripheral blood. Cells were co-cultured within 3D porous ceramic scaffolds using a perfusion-based bioreactor device, in the presence of typical osteoclastogenic factors. After 3 weeks, the scaffolds contained cells with endothelial (2.0+/-0.3%), pre/osteoclastic (14.0+/-1.4%) and mesenchymal/osteoblastic (44.0+/-8.4%) phenotypes, along with tartrate-resistant acid phosphatase-positive (TRAP+) osteoclastic cells in contact with deposited bone-like matrix. Supernatant analysis demonstrated sustained matrix deposition (by C-terminus procollagen-I propeptides), resorption (by N-terminus collagen-I telopeptides and phosphate levels) and osteoclastic activity (by TRAP-5b) only when SVF and CD14+ cells were co-cultured. Scanning electron microscopy and magnetic resonance imaging confirmed the pattern of matrix deposition and resorption. The effectiveness of Vitamin D in replacing osteoclastogenic factors indicated a functional osteoblast-osteoclast coupling in the system. The formation of human-origin bone-like tissue, blood vessels and osteoclasts upon ectopic implantation validated the functionality of the developed cell types. The 3D co-culture system and the associated non-invasive analytical tools can be used as an advanced model to capture some aspects of the functional coupling of bone like matrix deposition and resorption and could be exploited toward the engineering of multi-functional bone substitute implants. PMID- 21604245 TI - Application of rapid prototyping techniques for modelling of anatomical structures in medical training and education. AB - Rapid prototyping has become an innovative method of fast and cost-effective production of three-dimensional models for manufacturing. Wide access to advanced medical imaging methods allows application of this technique for medical training purposes. This paper presents the feasibility of rapid prototyping technologies: stereolithography, selective laser sintering, fused deposition modelling, and three-dimensional printing for medical education. Rapid prototyping techniques are a promising method for improvement of anatomical education in medical students but also a valuable source of training tools for medical specialists. PMID- 21604246 TI - A review of Morgagni and Bochdalek hernias in adults. AB - The incidence of Bochdalek and Morgagni hernias among adults is very rare. The purpose of this study was to determine retrospectively the prevalence and characteristics of adult Bochdalek and Morgagni hernias in a decade. Consequently, we demonstrated 12 patients with Bochdalek and 8 patients with Morgagni hernias. We presented plain radiography, operation images, and computed tomography findings of an adult patient with symptoms due to Bochdalek and Morgagni hernias. In surgical repair, the Morgagni hernia is best approached via laparotomy, and the Bochdalek hernia can be treated through thoracotomy or laparotomy. PMID- 21604247 TI - The relationship between the dimensions of the right coronary artery and the type of coronary vasculature in human foetuses. AB - BACKGROUND: The area of vascular supply of particular coronary arteries is directly linked to the varying typology of the coronary vasculature. This factor may have a significant influence on the coronary vessel diameters. To date there has been no published research that analyses the relationship between the type of coronary vasculature and the dimensions of the epicardial arteries in the human foetus. There are only a few papers that deal with this issue in the postnatal period of human life. MATERIAL AND METHODS: The study was carried out on a group of 187 human foetuses aged five to seven months of intrauterine life. Prior to examination all foetuses had been conserved in a 9% formaldehyde solution for a minimum of three months. All foetuses had been aborted naturally. None of them had any external signs of malformations or developmental abnormalities. The number of foetuses in the particular age groups was variable. Adachi/Bianchi classification was used to categorize the particular vasculature types: type I -- classic, neither artery is dominating; type II -- dominant right coronary artery; type III -- dominant left coronary artery. RESULTS AND CONCLUSIONS: The analysis of differences between the artery dimensions in particular types of coronary vasculature revealed that such differences existed between types I and II and also between types II and III. PMID- 21604248 TI - Follicular dynamics in neonate vitrified ovarian grafts after host treatment with melatonin. AB - This study evaluates the effect of melatonin on follicular dynamics in neonate vitrified ovarian grafts. Vitrified ovaries from neonate F1 hybrid mice, candidates for transplantation to treated or non-treated groups, were thawed under standard conditions with or without the addition of 100 MUM melatonin, respectively. Following transplantation, melatonin (20 mg/kg/day) or saline solution was injected i.p. into the treated and the non-treated groups, respectively. Vaginal cytology to monitor estrogenic activity together with follicle survival and development in the ovary grafts was examined. The results showed that the sites of transplantation became obvious within the oestrous phase. Histological analysis showed that there was a dynamic of the ovogenesis process in the vitrified ovary grafts. However, in the ovary graft the empty cavity together with jumbled oocyte-granulosa complex in the non-treated group was higher than in the melatonin treated group. Overall, the number of primary follicles in the ovary grafts of both groups remained constant throughout the oestrous period. However, the treated ovary grafts contained more secondary follicles throughout the oestrous period in comparison to non-treated ovary grafts. The antral follicle rates were more marked in the melatonin treated group than in the non-treated group during the oestrous period, whereas at other days of the cycle no significant difference was observed. The fresh corpora lutea rates were significantly higher in the treatment group than in the non-treatment group. The study showed that there is a positive effect with melatonin resulting in more grafts restoring puberty. Furthermore, the associated increase in healthy follicles suggests that melatonin has a preventative ischaemia/antioxidant action and may be useful to follicles. PMID- 21604249 TI - Variant origin of superior polar artery and unusual hilar branching pattern of renal artery with clinical correlation. AB - Classically, a single renal artery arising from the abdominal aorta supplies the respective kidney on each side. Near the hilum of the kidney each renal artery divides into anterior and posterior branchs, which in turn divide into segmental arteries supplying the different renal segments. A total of 84 formalin fixed cadavers (73 male and 11 female, 168 kidneys in total) constituted the material for the study. During routine abdominal dissection conducted for medical undergraduates, the kidneys and their arteries were explored and variations in morphological patterns of renal arteries were noted. We observed superior polar renal artery in 22.6% cases. Superior polar renal arteries had different sources of origin. In 10.7% of cases it came directly from the abdominal aorta as an accessory renal artery; in 5.4% of cases as a direct branch from the main renal artery; in 3.6% of cases from the superior hilar renal artery (from one of the duplicated renal arteries); and in 3.0% of cases from a segmental branch of the renal artery. We also observed unusual hilar branching patterns of renal arteries, which included a fork pattern in 11.3% of cases, ladder pattern in 7.7% of cases, net pattern in 5.9% of cases, and triplicate in 3.0% of cases. Understanding the anatomy of vascular variations of the kidney is essential for the clinician to be able to perform procedures such as renal transplantation, interventional radiological procedures, and renal vascular operations more safely and efficiently. PMID- 21604250 TI - Early development of the human palate in stages 16 and 17. AB - A study was performed on 12 human embryos at developmental stages 16 and 17 (6(th) week). In the investigated embryos the primary palate is formed from medial nasal, lateral nasal, and maxillary processes. The medial and lateral nasal processes merge and form the nasal fin at stage 16. This fin regresses and at stage 17 and persists as the oronasal membrane. The primordia of the secondary palate appear at stage 17. PMID- 21604251 TI - Stereolithographic biomodelling to create tangible hard copies of the ethmoidal labyrinth air cells based on the visible human project. AB - Rapid prototyping (RP), or stereolithography, is a new clinical application area, which is used to obtain accurate three-dimensional physical replicas of complex anatomical structures. The aim of this study was to create tangible hard copies of the ethmoidal labyrinth air cells (ELACs) with stereolithographic biomodelling. The visible human dataset (VHD) was used as the input imaging data. The Surfdriver software package was applied to these images to reconstruct the ELACs as three-dimensional DXF (data exchange file) models. These models were post-processed in 3D-Doctor software for virtual reality modelling language (VRML) and STL (Standard Triangulation Language) formats. Stereolithographic replicas were manufactured in a rapid prototyping machine by using the STL format. The total number of ELACs was 21. The dimensions of the ELACs on the right and left sides were 52.91 x 13.00 x 28.68 mm and 53.79 x 12.42 x 28.55 mm, respectively. The total volume of the ELACs was 4771.1003 mm(3). The mean ELAC distance was 27.29 mm from the nasion and 71.09 mm from the calotte topologically. In conclusion, the combination of Surfdriver and 3D-Doctor could be effectively used for manufacturing 3D solid models from serial sections of anatomical structures. Stereolithographic anatomical models provide an innovative and complementary tool for students, researchers, and surgeons to apprehend these anatomical structures tangibly. The outcomes of these attempts can provide benefits in terms of the visualization, perception, and interpretation of the structures in anatomy teaching and prior to surgical interventions. PMID- 21604252 TI - The median nerve in the carpal tunnel. AB - A study of the variations of the course and branching pattern of the median nerve within the carpal tunnel were carried out on 60 wrists from 30 fresh cadavers autopsied in the Department of Forensic Medicine of Jagiellonian University Medical College. The results were compared with the literature. The study confirmed that the extraligamentous type of motor branch variation is most common. The transligamentous course of the nerve is of special importance: it is usually accompanied by hypertrophic muscle, and the nerve hidden within this muscle can easily be cut during transection of the retinaculum. The results proved the necessity of approaching the median nerve from the ulnar side when opening the carpal tunnel. PMID- 21604253 TI - Anatomical study of the carotid bifurcation and origin variations of the ascending pharyngeal and superior thyroid arteries. AB - BACKGROUND: Human anatomy texts in current use have very little precise information as to the frequency of variations in the bifurcation of the common carotid artery, and a clear description of the relation between external and internal carotid arteries as well as the variation of the origin of the ascending pharyngeal and superior thyroid arteries is limited. MATERIAL AND METHODS: Sixty common carotid arteries in the sagittal section of the head and neck of 30 human adult cadavers were obtained from the Anatomy Department of King Abdulaziz University. The data collected were analysed using the Chi square-test. RESULTS: The carotid bifurcation was at the level of the superior border of the thyroid cartilage in 48.3% of cases, 25% were opposite the hyoid bone, and 18.3% were at the level between the thyroid cartilage and the hyoid bone. The bifurcation appeared at a lower level than the superior border of the thyroid cartilage in 5% of cases, while in 3.3% of cases the bifurcation level was seen higher than the hyoid bone. The usual anteromedial position of the external carotid artery to the internal carotid artery was found in 51.7% of cases, whereas it was medial to the internal carotid artery in 36.7% of cases. In 10% it was seen in an anterior position and only in 1.7% the external carotid artery was lateral to the internal carotid artery. In 93.3% of the cases the ascending pharyngeal artery originated from one root, while in the remaining 6.7% of cases it originated from two roots. In 80% of cases the superior thyroid artery arose from the external carotid artery. In 18.3% of cases it originated from the common carotid artery, and in 1.7% it arose from a thyrolingofacial trunk. CONCLUSIONS: The carotid bifurcation can occur as high as the hyoid bone, or as low as the cricoid cartilage. The anteromedial position of the external carotid artery (ECA) in relation to the internal carotid artery (ICA) was the most common anatomical position. The origins and configurations of the ascending pharyngeal artery and the superior thyroid artery are variable. PMID- 21604254 TI - A lower polar additional renal artery in an ectopic intraperitoneal kidney. AB - BACKGROUND: The kidneys are positioned retroperitoneally and they are normally supplied by the paired renal arteries. We describe a long left additional renal artery which supplies the lower pole of an intraperitoneal, labile, and smaller than usual left kidney, a variation that might complicate uroradiological procedures or surgery and cause failure of lithotripsy. MATERIAL AND METHODS: The reported anatomical variations were discovered during routine educational dissection in a female cadaver. RESULTS: The left kidney was found inside the parietal peritoneum (intraperitoneal), and it was lying free among the small bowel loops, without any underlying supportive tissues. Moreover, it was smaller than it should have been (length: 9.3 cm, diameter 3.1 cm) and possessed a lower polar additional left renal artery rising from the lateral side of the abdominal aorta, passing posterior to the ureter, and which was rather long (length: 8.8 cm). At the right side we did not find any variations of the renal region. CONCLUSIONS: Such a variation should be taken into consideration as it may lead to complications or explain some of them, if they occur. PMID- 21604256 TI - Modelling the effect of venous disease on quality of life. AB - BACKGROUND: A clear understanding of the relationship between venous reflux, clinical venous disease and the effects on quality of life (QoL) remains elusive. This study aimed to explore the impact of venous disease, and assess any incremental direct effect of progressive disease on health-related QoL, with the ultimate aim to model venous morbidity. METHODS: Consecutive patients with venous disease were assessed for inclusion in the study. Patients with isolated, unilateral, single superficial axial incompetence diagnosed on duplex imaging were included. Clinical grading was performed with the Clinical Etiologic Anatomic Pathophysiologic (CEAP) classification and Venous Clinical Severity Score (VCSS). Patients completed generic (Short Form 36, SF-36((r)); EuroQol 5D, EQ-5D(TM)) and disease-specific (Aberdeen Varicose Vein Questionnaire, AVVQ) QoL instruments. Multivariable regression modelling was performed, taking account of demographic and anatomical factors, to explore the effect of clinical severity on QoL impairment. RESULTS: Some 456 patients with C2-6 venous disease were included, along with control data for 105 people with C0-1 disease. Increasing clinical grade corresponded strongly with deterioration in disease-specific QoL (P < 0.001). This could be stratified into three distinguishable groups: C0-1, C2 4 and C5-6 (P < 0.001 to P = 0.006). Increasing clinical grade also corresponded with deterioration in the physical domains of SF-36((r)) (P < 0.001 to P = 0.016), along with EQ-5D(TM) index utility (quality-adjusted life year) scores (P < 0.001). CONCLUSION: Demonstrable morbidity was seen, even with uncomplicated venous disease. The physical impairment seen with venous ulceration was comparable with that seen in congestive cardiac failure and chronic lung disease. PMID- 21604257 TI - Negative regulation of signaling by a soluble form of toll-like receptor 9. AB - Nucleic acid structures are highly conserved through evolution and when self nucleic acids are aberrantly detected by toll-like receptors (TLRs) they contribute to autoimmune disease. For this reason, multiple regulatory mechanisms exist to prevent immune responses to self nucleic acids. TLR9 is a nucleic acid sensing TLR that is regulated at multiple levels including association with accessory proteins, intracellular localization and proteolytic processing. In the endolysosomal compartment TLR9 is proteolytically processed to an 80 kDa form (p80) and this processing is a prerequisite for activation. Here, we identified a soluble form of TLR9 (sTLR9) generated by a novel proteolytic event that cleaved TLR9 between amino acids 724-735. Similar to p80, sTLR9 was generated in endosomes. However, generation of sTLR9 was independent of the cysteine protease cathepsin B, active at acidic pH, but partially dependent on cathepsin S, a protease active at neutral pH. Most importantly, sTLR9 inhibited TLR9-dependent signaling. Altogether, these data support a model where an intrinsic proteolytic processing mechanism negatively regulates TLR9 signaling. A proper balance between the independent proteolytic events probabably contributes to regulation of TLR9-mediated innate immunity and prevention of autoimmune disease. PMID- 21604258 TI - Batf3 transcription factor-dependent DC subsets in murine CMV infection: differential impact on T-cell priming and memory inflation. AB - Priming of CD8(+) T cells specific for viruses that interfere with the MHC class I presentation pathway is a challenge for the immune system and is believed to rely on cross-presentation. Cytomegalovirus (CMV) infection induces vigorous CD8(+) T-cell responses despite its potent immune evasion strategies. Furthermore, CD8(+) T cells specific for a subset of viral epitopes accumulate and are maintained at high levels exhibiting an activated phenotype - referred to as "inflationary T cells". Taking advantage Batf3(-/-) mice in which the development of cross-presenting CD8alpha(+) and CD103(+) DCs is severely compromised, we analyzed their role in the induction and inflation of murine (M)CMV-specific CD8(+) T-cell responses. We found that priming of MCMV-specific CD8(+) T cells was severely impaired in the absence of cross-presenting DCs. However, inflation of two immuno-dominant MCMV-specific CD8(+) T-cell populations was largely normal in the absence of cross-presenting DCs, indicating that inflation during latency was mainly dependent on direct antigen presentation. These results highlight differential antigen presentation requirements during acute and latent MCMV infection. PMID- 21604259 TI - Efficient generation of B lymphocytes by recognition of self-antigens. AB - Antibody diversity is generated by a random gene recombination process with the inherent risk of the production of autoreactive specificities. The current view suggests that B cells expressing such specificities are negatively selected at an early developmental stage. Using the knock-in model system of the 3-83 autoreactive B-cell antigen receptor (BCR) in combination with precursor-BCR (pre BCR) deficiency, we show here that the 3-83 BCR mediates efficient generation of B cells in the presence, but not the absence, of a strongly recognized auto antigen. Experiments with mixed bone marrow chimeras showed that combining the 3 83 BCR with the corresponding auto-antigen resulted in efficient reconstitution of B-cell development in immune-deficient mice. These results suggest that B cells are positively selected by recognition of self-antigens during developmental stages that precede receptor editing. Moreover, the data indicate that the pre-BCR functions as a specialized autoreactive BCR to initiate positive selection at a stage where the cells express immunoglobulin heavy but not light chains. PMID- 21604261 TI - Susceptibility loci for the defective foreign protein-induced tolerance in New Zealand Black mice: implication of epistatic effects of Fcgr2b and Slam family genes. AB - In contrast to normal mice, autoimmune-prone New Zealand Black (NZB) mice are defective in susceptibility to tolerance induced by deaggregated bovine gamma globulin (DBGG). To examine whether this defect is related to the loss of self tolerance in autoimmunity, susceptibility loci for this defect were examined by genome-wide analysis using the F(2) intercross of nonautoimmune C57BL/6 (B6) and NZB mice. One NZB locus on the telomeric chromosome 1, designated Dit (Defective immune tolerance)-1, showed a highly significant linkage. This locus overlapped with a locus containing susceptibility genes for autoimmune disease, namely Fcgr2b and Slam family genes. To investigate the involvement of these genes in the defective tolerance to DBGG, we took advantage of two lines of Fcgr2b deficient B6 congenic mice: one carries autoimmune-type, and the other carries B6 type, Slam family genes. Defective tolerance was observed only in Fcgr2b deficient mice with autoimmune-type Slam family genes, indicating that epistatic effects of both genes are involved. Thus, common genetic mechanisms may underlie the defect in foreign protein antigen-induced tolerance and the loss of self tolerance in NZB mouse-related autoimmune diseases. PMID- 21604260 TI - DNA fusion gene vaccines induce cytotoxic T-cell attack on naturally processed peptides of human prostate-specific membrane antigen. AB - For long-term attack on tumor cells in patients with prostate cancer, induction of cytolytic T cells is desirable. Several lineage-specific target proteins are known and algorithms have identified candidate MHC class I-binding peptides, particularly for HLA-A*0201. We have designed tolerance-breaking DNA fusion vaccines incorporating a domain of tetanus toxin fused to candidate tumor-derived peptide sequences. Using three separate peptide sequences from prostate-specific membrane antigen (PSMA) (peptides PSMA(27) , PSMA(663) , and PSMA(711) ), this vaccine design induced high levels of CD8(+) T cells against each peptide in a HLA-A(*) 0201 preclinical model. In contrast, the full-length PSMA sequence containing all three epitopes was poorly immunogenic. Induced T cells were cytotoxic against peptide-loaded tumor cells, but only those against PSMA(27) or PSMA(663) peptides, and not PSMA(711) , were able to kill tumor cells expressing endogenous PSMA. Cytotoxicity was also evident in vivo. The preclinical model provides a powerful tool for generating CD8(+) T cells able to predict whether target cells can process and present peptides, essential for planning peptide vaccine-based clinical trials. PMID- 21604262 TI - Suppressor of cytokine signaling 4 (SOCS4): moderator of ovarian primordial follicle activation. AB - Mammalian ovarian primordial follicle activation and regulation is considered as one of the most important stages of folliculogenesis and as such requires exquisite control. Selection of quiescent follicles to enter the growing pool determines the rate of supply of maturing follicles over the female reproductive lifespan. To coordinate this process a range of positive and negative input signals contribute to determine follicle fate. This study demonstrates that the cytokine Leukemia Inhibitory Factor (LIF) activates the Janus Kinase 1/Signal Transducers and Activators of Transcription 3 (JAK1/STAT3) signaling pathway in pre-granulosa cells and positively regulates primordial follicle activation. Negative regulation of the JAK/STAT pathway is controlled by the suppressor of cytokine signaling 4 (SOCS4) protein, which target members of negative feedback loops, Cardiotrophin like Cytokine (CLC), Poly (rC) Binding Protein 1 (PCBP1), and Cytosolic Malate Dehydrogenase (MDH1) to suppress follicle growth and development. PMID- 21604263 TI - Transcriptomic profiling of astrocytes treated with the Rho kinase inhibitor fasudil reveals cytoskeletal and pro-survival responses. AB - Inhibitors of Rho kinase (ROCK) have potential for management of neurological disorders by inhibition of glial scarring. Since astrocytes play key roles in brain physiology and pathology, we determined changes in the astrocytic transcriptome produced by the ROCK inhibitor Fasudil to obtain mechanistic insights into its beneficial action during brain injury. Cultured murine astrocytes were treated with Fasudil (100 uM) and morphological analyses revealed rapid stellation by 1 h and time-dependent (2-24 h) dissipation of F-actin labelled stress fibres. Microarray analyses were performed on RNA and the time course of global gene profiling (2, 6, 12 and 24 h) provided a comprehensive description of transcriptomic changes. Hierarchical clustering of differentially expressed genes and analysis for over-represented gene ontology groups using the DAVID database focused attention on Fasudil-induced changes to major biological processes regulating cellular shape and motility (actin cytoskeleton, axon guidance, transforming growth factor-beta (TGFbeta) signalling and tight junctions). Bioinformatic analyses of transcriptomic changes revealed how these biological processes contributed to changes in astrocytic motility and cytoskeletal reorganisation. Here genes associated with extracellular matrix were also involved, but unexpected was a subset of alterations (EAAT2, BDNF, anti oxidant species, metabolic and signalling genes) indicative of adoption by astrocytes of a pro-survival phenotype. Expression profiles of key changes with Fasudil and another ROCK inhibitor Y27632 were validated by real-time PCR. Although effects of ROCK inhibition have been considered to be primarily cytoskeletal via reduction of glial scarring, we demonstrate additional advantageous actions likely to contribute to their ameliorative actions in brain injury. PMID- 21604264 TI - A pathway from JNK through decreased ERK and Akt activities for FOXO3a nuclear translocation in response to UV irradiation. AB - Forkhead box O (FOXO) transcription factors play an important role in physiological and pathological processes. Extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) can phosphorylate FOXO and cause its degradation or cytoplasmic retention, respectively, leading to tumorigenesis. In addition, C Jun N-terminal protein kinase (JNK) can promote FOXO nuclear localization, leading to apoptosis. Using confocal imaging of cells transfected with GFP FOXO3a, we visualized the dynamic translocation of GFP-FOXO3a from the cytoplasm to the nucleus after UV irradiation in a time- and dose-dependent manner. We also found that UV irradiation caused activation of JNK, which in turn inactivated ERK and Akt, leading to FOXO3a translocation and Bim expression. Our results indicate that nuclear translocation of FOXO3a can be regulated by UV irradiation through the JNK-ERK/Akt pathway. PMID- 21604265 TI - Differential response of nucleus pulposus intervertebral disc cells to high salt, sorbitol, and urea. AB - Nucleus pulposus intervertebral disc cells are routinely confronted with high osmolality in their microenvironment and respond to this stress in vitro by regulating cell cycle progression and by activating a DNA repair machinery in order to counteract its genotoxic effect. In the present study, we attempted to identify the origin of this osmo-regulatory response, by using an ionic NaCl/KCl solution, the compatible osmolyte sorbitol, and the readily permeant urea. High salt and sorbitol were found to activate similar molecular pathways, including the p38 MAPK and the p53-p21(WAF1)-pRb axis, that were not stimulated by high urea. On the other hand, only high urea led to the phosphorylation of ERKs and JNKs. Furthermore, salt- and sorbitol-treated cells were able to phosphorylate histone H2A.X on Ser139, in contrast to cells exposed to urea, indicating a common mechanism for DNA repair, which was achieved by a p53-dependent activation of the G1 checkpoint by both solutes. DNA repair, as directly measured by a host cell reactivation assay, occurred under conditions of hyperosmolar salt and sorbitol, although to a lesser extent in sorbitol-treated cells than in cells exposed to high salinity. Taken as a whole, our findings suggest that the hyperosmolality-provoked DNA damage and the responses of nucleus pulposus cells induced by this genotoxic stress most probably originate from cell volume alterations mediated by hypertonicity and not from increased intracellular ionic concentration. PMID- 21604266 TI - Decreased oxygen tension lowers reactive oxygen species and apoptosis and inhibits osteoblast matrix mineralization through changes in early osteoblast differentiation. AB - Accumulating data show that oxygen tension can have an important effect on cell function and fate. We used the human pre-osteoblastic cell line SV-HFO, which forms a mineralizing extracellular matrix, to study the effect of low oxygen tension (2%) on osteoblast differentiation and mineralization. Mineralization was significantly reduced by 60-70% under 2% oxygen, which was paralleled by lower intracellular levels of reactive oxygen species (ROS) and apoptosis. Following this reduction in ROS the cells switched to a lower level of protection by down regulating their antioxidant enzyme expression. The downside of this is that it left the cells more vulnerable to a subsequent oxidative challenge. Total collagen content was reduced in the 2% oxygen cultures and expression of matrix genes and matrix-metabolizing enzymes was significantly affected. Alkaline phosphatase activity and RNA expression as well as RUNX2 expression were significantly reduced under 2% oxygen. Time phase studies showed that high oxygen in the first phase of osteoblast differentiation and prior to mineralization is crucial for optimal differentiation and mineralization. Switching to 2% or 20% oxygen only during mineralization phase did not change the eventual level of mineralization. In conclusion, this study shows the significance of oxygen tension for proper osteoblast differentiation, extra cellular matrix (ECM) formation, and eventual mineralization. We demonstrated that the major impact of oxygen tension is in the early phase of osteoblast differentiation. Low oxygen in this phase leaves the cells in a premature differentiation state that cannot provide the correct signals for matrix maturation and mineralization. PMID- 21604267 TI - Tau splicing and the intricacies of dementia. AB - Tau is a microtubule-associated protein that fulfills several functions critical for neuronal formation and health. Tau discharges its functions by producing multiple isoforms via regulated alternative splicing. These isoforms modulate tau function in normal brain by altering the domains of the protein, thereby influencing its localization, conformation, and post-translational modifications and hence its availability and affinity for microtubules and other ligands. Disturbances in tau expression result in disruption of the neuronal cytoskeleton and formation of tau structures (neurofibrillary tangles) found in brains of dementia sufferers. More specifically, aberrations in tau splicing regulation directly cause several neurodegenerative diseases, which lead to dementia. In this review, I present our cumulative knowledge of tau splicing regulation in connection with neurodegeneration and also briefly go over the still-extensive list of questions that are connected to tau (dys)function. PMID- 21604268 TI - Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli. AB - Sorafenib increases survival rate of patients with advanced hepatocellular carcinoma (HCC). The mechanism underlying this effect is not completely understood. In this work we have analyzed the effects of sorafenib on autocrine proliferation and survival of different human HCC cell lines. Our results indicate that sorafenib in vitro counteracts autocrine growth of different tumor cells (Hep3B, HepG2, PLC-PRF-5, SK-Hep1). Arrest in S/G2/M cell cycle phases were observed coincident with cyclin D1 down-regulation. However, sorafenib's main anti-tumor activity seems to occur through cell death induction which correlated with caspase activation, increase in the percentage of hypodiploid cells, activation of BAX and BAK and cytochrome c release from mitochondria to cytosol. In addition, we observed a rise in mRNA and protein levels of the pro-apoptotic "BH3-domain only" PUMA and BIM, as well as decreased protein levels of the anti apoptotic MCL1 and survivin. PUMA targeting knock-down, by using specific siRNAs, inhibited sorafenib-induced apoptotic features. Moreover, we obtained evidence suggesting that sorafenib also sensitizes HCC cells to the apoptotic activity of transforming growth factor-beta (TGF-beta) through the intrinsic pathway and to tumor necrosis factor-alpha (TNF) through the extrinsic pathway. Interestingly, sensitization to sorafenib-induced apoptosis is characteristic of liver tumor cells, since untransformed hepatocytes did not respond to sorafenib inducing apoptosis, either alone or in combination with TGF-beta or TNF. Indeed, sorafenib effectiveness in delaying HCC late progression might be partly related to a selectively sensitization of HCC cells to apoptosis by disrupting autocrine signals that protect them from adverse conditions and pro-apoptotic physiological cytokines. PMID- 21604270 TI - Age-related differences in cellular and molecular profiles of inflammatory responses after spinal cord injury. AB - Previous experimental and clinical studies have suggested that the behavioral and pathological outcomes of spinal cord injury (SCI) are affected by the individual's age at the time of injury. However, the underlying mechanism responsible for these differences remains elusive because it is difficult to match injuries of similar severities between young and adult animals due to differences in the sizes of their respective spinal cords. In this study, the spinal cord size-matched young (4-week-old) and adult (10-week-old) mice were compared to evaluate their locomotor functions and inflammatory cellular/molecular responses after standardized contusion SCI. During the acute phase of SCI, young mice showed better functional recovery and lower pro inflammatory cytokines/chemokines compared to adult mice. Flow-cytometric analysis revealed that the time courses of leukocyte infiltration were comparable between both groups, while the number of infiltrating neutrophils significantly decreased from 6 h after SCI in young mice. By combining flow-cytometric isolation and gene expression analysis of each inflammatory cell fraction, we found that microglial cells immediately initiate the production of several cytokines in response to SCI, which serve as major sources of IL-6, TNFa, and CXCL1 in injured spinal cord. Interestingly, the secretion of pro-inflammatory cytokines/chemokines but not anti-inflammatory cytokines by microglia was significantly lower in young mice compared to that in adult mice at 3 h after SCI, which will be attributed to the attenuation of the subsequent neutrophil infiltration. These results highlight age-related differences in pro-inflammatory properties of microglial cells that contribute to the amplification of detrimental inflammatory responses after SCI. PMID- 21604271 TI - Occurrence, biochemical profile of vascular endothelial growth factor (VEGF) isoforms and their functions in endochondral ossification. AB - Vascular endothelial growth factor (VEGF), initially detected in bovine pituitary follicular cells, is widely localized in hypertrophic zones of chondrocytes in various tissues where focus is on bone growth. Similarly, VEGF found in chondrocytes of articular cartilage of osteo-arthritic/rheumato-arthritic joints reflected need for bone repair. Members of VEGF family of human origin are seven homo-dimeric, heparin-binding glyco-proteins, encoded by different genes located on different chromosomes. They encode seven isoforms: VEGF-A, -B, -C, -D, -E, -F, and PLGF, each catalyzing distinct functions. They are compared with VEGFs derived from bovine origin in biochemical composition and functions. Each isoform and subtype has specific receptors for binding, necessary for expression of specific functions in bone growth or repair. VEGF control is by diffusion of isoforms, hypoxic conditions, and bone (mandibular) positioning. Thus, transformation of cartilage into bone involves proliferation of mesenchymal cells, hypertrophy in chondrocytes, capillary invasion, and calcification by extra cellular matrix (ECM). Inherent limitations of in vitro/in vivo models and chronology of appearance of different isoforms have eluded precise mechanism of VEGF action and regulation. Nonetheless, central role of VEGF in bone growth is quite obvious. PMID- 21604269 TI - Amelioration of type I diabetes-induced osteoporosis by parathyroid hormone is associated with improved osteoblast survival. AB - Type 1 diabetic osteoporosis results from impaired osteoblast activity and death. Therefore, anti-resorptive treatments may not effectively treat bone loss in this patient population. Intermittent parathyroid hormone (PTH) treatment stimulates bone remodeling and increases bone density in healthy subjects. However, PTH effects may be limited in patients with diseases that interfere with its signaling. Here, we examined the ability of 8 and 40 ug/kg intermittent PTH to counteract diabetic bone loss. PTH treatment reduced fat pad mass and blood glucose levels in non-diabetic PTH-treated mice, consistent with PTH-affecting glucose homeostasis. However, PTH treatment did not significantly affect general body parameters, including the blood glucose levels, of type 1 diabetic mice. We found that the high dose of PTH significantly increased tibial trabecular bone density parameters in control and diabetic mice, and the lower dose elevated trabecular bone parameters in diabetic mice. The increased bone density was due to increased mineral apposition and osteoblast surface, all of which are defective in type 1 diabetes. PTH treatment suppressed osteoblast apoptosis in diabetic bone, which could further contribute to the bone-enhancing effects. In addition, PTH treatment (40 ug/kg) reversed preexisting bone loss from diabetes. We conclude that intermittent PTH may increase type 1 diabetic trabecular bone volume through its anabolic effects on osteoblasts. PMID- 21604272 TI - NADPH oxidase-derived superoxide anion-induced apoptosis is mediated via the JNK dependent activation of NF-kappaB in cardiomyocytes exposed to high glucose. AB - Hyperglycemia-induced generation of reactive oxygen species (ROS) can lead to cardiomyocyte apoptosis and cardiac dysfunction. However, the mechanism by which high glucose causes cardiomyocyte apoptosis is not clear. In this study, we investigated the signaling pathways involved in NADPH oxidase-derived ROS-induced apoptosis in cardiomyocytes under hyperglycemic conditions. H9c2 cells were treated with 5.5 or 33 mM glucose for 36 h. We found that 33 mM glucose resulted in a time-dependent increase in ROS generation as well as a time-dependent increase in protein expression of p22(phox), p47(phox), gp91(phox), phosphorylated IkappaB, c-Jun N-terminal kinase (JNK) and p38, as well as the nuclear translocation of NF-kB. Treatment with apocynin or diphenylene iodonium (DPI), NADPH oxidase inhibitors, resulted in reduced expression of p22(phox), p47(phox), gp91(phox), phosphorylated IkappaB, c-Jun N-terminal kinase (JNK) and p38. In addition, treatment with JNK and NF-kB siRNAs blocked the activity of caspase-3. Furthermore, treatment with JNK, but not p38, siRNA inhibited the glucose-induced activation of NF-kappaB. Similar results were obtained in neonatal cardiomyocytes exposed to high glucose concentrations. Therefore, we propose that NADPH oxidase-derived ROS-induced apoptosis is mediated via the JNK dependent activation of NF-kappaB in cardiomyocytes exposed to high glucose. PMID- 21604273 TI - Targeting of substance P induces cancer cell death and decreases the steady state of EGFR and Her2. AB - NK1 is a tachykinin receptor highly relevant to tumorigenesis and metastasis development in breast cancer and other carcinomas. Despite the substantial efforts done to develop potent NK1 receptor antagonists, none of these antagonists had shown good antitumor activity in clinical trials. Now, we have tested the effect of inhibition of the neuropeptide Substance P (SP), a NK1 ligand, as a potential therapeutic approach in cancer. We found that the inhibition of SP with antibodies strongly inhibit cell growth and induce apoptosis in breast, colon, and prostate cancer cell lines. These effects were accompained by a decrease in the mitogen-activated kinase singaling pathway. Interestingly, in some cell lines SP abrogation decreased the steady state of Her2 and EGFR, suggesting that SP-mediated signaling is important for the basal activity of these ErbB receptors. In consequence, we observed a blockade of the cell cycle progression and the inhibition of several cell cycle-related proteins including mTOR. SP inhibition also induced cell death in cell lines resistant to Lapatinib and Trastuzumab that have increased levels of active Her2, suggesting that this therapeutic approach could be also effective for those cancers resistant to current anti-ErbB therapies. Thus, we propose a new therapeutic strategy for those cancers that express NK1 receptor and/or other tachykinin receptors, based in the immuno-blockade of the neuropeptide SP. PMID- 21604274 TI - Bradykinin-mediated cell proliferation depends on transactivation of EGF receptor in corneal fibroblasts. AB - In previous studies, bradykinin (BK) has been shown to induce cell proliferation through BK B2 receptor (B2R) via p42/p44 MAPK in Statens Seruminstitut Rabbit Corneal Cells (SIRCs). In addition to this pathway, EGFR transactivation pathway has been implicated in linking a variety of G-protein coupled receptors to MAPK cascades. Here, we further investigate whether these transactivation mechanisms participating in BK-induced cell proliferation in SIRCs. Using an immunofluorescence staining and RT-PCR, we initially characterize that SIRCs were corneal fibroblasts and predominantly expressed B2R by BK. Inhibition of p42/p44 MAPK by the inhibitors of Src, EGFR, and Akt or transfection with respective siRNAs prevents BK-induced DNA synthesis in SIRCs. The mechanisms underlying these responses were mediated through phosphorylation of Src and EGFR via the formation of Src/EGFR complex which was attenuated by PP1 and AG1478. Moreover, BK-induced p42/p44 MAPK and Akt activation was mediated through EGFR transactivation, which was diminished by the inhibitors of MMP-2/9 and heparin binding EGF-like factor (HB-EGF). Finally, increased nuclear translocation of Akt and p42/p44 MAPK turns on early gene expression leading to cell proliferation. These results suggest that BK-induced cell proliferation is mediated through c Src-dependent transactivation of EGFR via MMP2/9-dependent pro-HB-EGF shedding linking to activation of Akt and p42/p44 MAPK in corneal fibroblasts. PMID- 21604275 TI - NMR investigation of a novel excipient, alpha-glucosylhesperidin, as a suitable solubilizing agent for poorly water-soluble drugs. AB - alpha-Glucosylhesperidin (Hsp-G), a functional food additive, significantly enhances the solubility and bioavailability of poorly water-soluble drugs despite little surface activity. Herein, we present investigations into the underlying mechanism by nuclear magnetic resonance techniques. A concentration dependence of the chemical shift of Hsp-G protons correlated well with a mass-action law model, indicating self-association of Hsp-G molecules. The critical micelle concentration was 5.0 mg/mL (6.5 mM) at 37 degrees C. The gradual rather than abrupt chemical shift variation upon Hsp-G aggregation would be different mode to conventional surfactants. Dynamic light scattering and two-dimensional nuclear Overhauser effect spectroscopy measurements demonstrated that Hsp-G molecules self-associated into particular small micelles, with the flavanone skeleton forming a hydrophobic core, and surrounding sugar groups working as a shell. The packing of the hydrophobic portion is not strictly oriented and the intermolecular arrangement of micelle shell is loose. Solubility enhancement was due to the incorporation of drugs into Hsp-G micelle, with naringenin being more soluble than flurbiprofen. This difference is possibly related to the structural similarities between the hydrophobic portion and the micelle core. Hsp-G micellization process with little loss of surface tension is a unique observation in surface and interface science. PMID- 21604276 TI - Changes in scopoletin concentration in cassava chips from four varieties during storage. AB - BACKGROUND: The use of the root crop cassava (Manihot esculenta Crantz) is constrained by its rapid deterioration after harvesting. Chemical and spectroscopic examination earlier revealed the accumulation of the four hydroxycoumarins esculetin, esculin, scopolin and scopoletin derived from the phenylpropanoid pathway, during the time course of postharvest deterioration. In this investigation the scopoletin level in parenchymal samples of four cassava cultivars used in Benin, i.e. Kpaki kpika, Kpaki soan, Logoguesse kotorou and BEN 86052, was investigated by high-performance liquid chromatography (HPLC). RESULTS: Presence was shown in all four varieties with a mean in fresh roots between 4.1 and 11.1 mg kg(-1) dry weight. A strong increase in the content of scopoletin was noticed after a peeling and drying process (6 days) for chip production, the mean content reaching 242.5 mg kg(-1) dry weight in the cultivar BEN 86052. After 3 months of storage this had decreased to 0.7 mg kg(-1) dry weight. CONCLUSION: Strong accumulation of scopoletin in cassava roots used for chip production in Benin is followed by a decrease in its concentration. PMID- 21604277 TI - Development of a fermented goats' milk containing Lactobacillus rhamnosus: in vivo study of health benefits. AB - BACKGROUND: Lactobacillus rhamnosus CRL1505, a strain of goats' milk origin, is able to stimulate mucosal immunity and protect immunocompetent mice from intestinal and respiratory infections. RESULTS: In this work we developed and characterized a fermented goats' milk containing L. rhamnosus CRL1505, and we demonstrated in a model of immunosuppression in mice that the final dairy product preserves the immunomodulatory properties of the strain. L. rhamnosus CRL1505 survived the manufacturing process of fermented milk and maintained a viability of 10(6) cfu g(-1) during storage. The fermented goats' milk was accepted by 90.48% of the panelists and was considered as having an acid taste and pleasant aroma. We also demonstrated that the developed product, used as a supplement during the repletion of immunocompromised malnourished mice, was effective in accelerating the recovery of clinical parameters altered by malnutrition and to induce increased resistance against intestinal and respiratory infections. CONCLUSION: Goats' milk fermented with L. rhamnosus CRL1505 could be manufactured as an alternative probiotic dairy product since this new food has the ability to stimulate the common mucosal immune system and to improve defenses against respiratory and intestinal infections. PMID- 21604278 TI - Organo-mineral fertilisers from glass-matrix and organic biomasses: a new way to release nutrients. A novel approach to fertilisation based on plant demand. AB - BACKGROUND: A glass-matrix fertiliser (GMF), a by-product from ceramic industries, releases nutrients only in the presence of complexing solutions, similar to those exuded by plant roots. This ensures a slow release of nutrients over time, limiting the risk of their loss in the environment. With the aim to improve fertiliser performance, GMF was mixed with vine vinasse (DVV), pastazzo (a by-product of the citrus processing industry, PAS) or green compost (COMP) and nutrient release was evaluated by citric and chloridric acid extraction, at different concentrations. RESULTS: Theoretical and actual nutrients release were compared to evaluate possible synergistic effects due to the organic component added to the mineral fertiliser: phosphorus (+7.1%), K (+4.8%), Fe (+8.5%) and Zn (+5.5%) were released more efficiently by 2% citric acid from GMF + DVV, while Ca availability was increased (+5.3%) by 2% citric acid from GMF + PAS mixture. Both DVV and COMP increased by 12-18% the Fe release from GFM matrix. CONCLUSION: Organic biomasses added to GMF increased the release of some macro and micronutrients through an 'activation effect', which suggests the employment of these organo-mineral fertilisers also in short-cycle crops production. Moreover, the re-use of some agro-industrial organic residues gives another 'adding value' to this novel organo-mineral fertilfertilisers. PMID- 21604279 TI - Enzymatic changes in pectic polysaccharides related to the beneficial effect of soaking on bean cooking time. AB - BACKGROUND: Cooking time decreases when beans are soaked first. However, the molecular basis of this decrease remains unclear. To determine the mechanisms involved, changes in both pectic polysaccharides and cell wall enzymes were monitored during soaking. Two cultivars and one breeding line were studied. RESULTS: Soaking increased the activity of the cell wall enzymes rhamnogalacturonase, galactanase and polygalacturonase. Their activity in the cell wall was detected as changes in chemical composition of pectic polysaccharides. Rhamnose content decreased but galactose and uronic acid contents increased in the polysaccharides of soaked beans. A decrease in the average molecular weight of the pectin fraction was induced during soaking. The decrease in rhamnose and the polygalacturonase activity were associated (r = 0.933, P = 0.01, and r = 0.725, P = 0.01, respectively) with shorter cooking time after soaking. CONCLUSION: Pectic cell wall enzymes are responsible for the changes in rhamnogalacturonan I and polygalacturonan induced during soaking and constitute the biochemical factors that give bean cell walls new polysaccharide arrangements. Rhamnogalacturonan I is dispersed throughout the entire cell wall and interacts with cellulose and hemicellulose fibres, resulting in a higher rate of pectic polysaccharide thermosolubility and, therefore, a shorter cooking time. PMID- 21604280 TI - Antioxidant activity and free radical-scavenging capacity of a selection of wild growing Colombian plants. AB - BACKGROUND: The replacement of some synthetic food antioxidants by safe natural antioxidants has fostered research on the screening of raw materials to find new vegetable sources of antioxidants. In this study the antioxidant activity of eight wild-growing Colombian plants was assessed by four complementary assays. RESULTS: An evaluation of the antioxidant activity of ten ethanolic extracts from Baccharis chilco, Cinnamomum triplinerve, Ilex laurina, Lachemilla orbiculata, Lepechinia conferta, Quercus humboldtii, Rubus urticifolius and Tephrosia cinerea was carried out. Furthermore, the total phenolic content was determined by the Folin-Ciocalteu method, and the relationship between phenolic content and activity was also statistically investigated. Cinnamomum triplinerve, L. conferta and I. laurina were found to have the highest phenolic contents. Baccharis chilco, C. triplinerve, I. laurina, L. conferta, Q. humboldtii and R. urticifolius showed higher radical-scavenging activity (DPPH and superoxide assays) than commercial rosemary oleoresin (reference). Lachemilla orbiculata and R. urticifolius showed higher antioxidant activity (beta-carotene-bleaching test) than the reference. The protection factor of all studied plant extracts was below that of the reference according to the Rancimat test. CONCLUSION: On the basis of the results obtained, C. triplinerve, Q. humboldtii and R. urticifolius seem to be the most promising species for further investigation in order to identify the compounds responsible for their activity. PMID- 21604282 TI - The ethics of medical publication. PMID- 21604283 TI - Open-tubular capillary electrochromatography of small polar molecules using etched, chemically modified capillaries. AB - The migration characteristics of small polar molecules are evaluated on etched, chemically modified capillaries with four different moieties (C5, C18, diol and cholesterol) bonded onto a silica hydride surface. The effects of pH on migration are used to determine the possible contributions of eletrophoretic mobility, electroosmotic flow (EOF) and analyte/bonded phase interactions. The EOF on etched capillaries is more complicated than on ordinary fused capillaries because it changes from anodic to cathodic as the pH is raised. A mixture of neurotransmitters and related compounds is used to further evaluate the effects of the bonded moiety on the separation properties of this particular electrophoretic format. PMID- 21604284 TI - Confirmation analysis of ethyl glucuronide and ethyl sulfate in human serum and urine by CZE-ESI-MS(n) after intake of alcoholic beverages. AB - CZE coupled to sheath liquid-based electrospray ionization (ESI) and multiple stage ion trap mass spectrometry (MS(n) ) was used for the confirmation analysis of ethyl glucuronide (EtG) and ethyl sulfate (EtS) in human serum and urine collected after intake of alcoholic beverages. Electrophoretic separations were performed in uncoated fused-silica capillaries using a pH 9.5 ammonium acetate background electrolyte and normal polarity. MS detection of EtG and EtS occurred after negative ionization using a spray liquid containing 0.5% v/v ammonia in isopropanol/water (60:40%, v/v). CZE-MS and CZE-MS2 results obtained after injection of solid-phase extracts for EtG and EtS and of diluted urine confirmed the presence of EtG and EtS in samples whose levels were previously determined by CZE with indirect UV detection. Detection limits of each compound were estimated to be around 2.0 (injection of diluted urine) and 0.2 MUg/mL (extracts). PMID- 21604285 TI - High-performance separation techniques hyphenated to mass spectrometry for ganglioside analysis. AB - Gangliosides, sialic-acid-containing glycosphingolipids are involved in numerous biological processes and play essential roles in severe pathologies, with predilection in those of the central nervous system. Formerly, ganglioside composition and quantity were assessed exclusively by thin-layer chromatographic (TLC), immunochemical, and immunohistochemical methods, which have limited effectiveness being unable to detect minor components in mixtures of high heterogeneity. Increased awareness of the biological importance of gangliosides stimulated the development of analytical methods that are better amenable to complex ganglioside mixtures. More recently, MS in online conjunction with high performance separation techniques brought a significant progress to the field. This review highlights the state-of-the-art development and application of separation methods online coupled to MS for ganglioside analysis. Most original and successful protocols based on GC-MS, LC-MS, and CE-MS are presented here together with the special instrumental and sample preparation requirements to be met for effective ganglioside separation, detection, and structural identification. Finally, the advantages and downsides of each methodology as well as the perspectives for simplification, standardization, and upgrading are assessed. PMID- 21604286 TI - Aneuploidy screening: a position statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis, January 2011. PMID- 21604288 TI - Modeling and testing treated tumor growth using cubic smoothing splines. AB - Human tumor xenograft models are often used in preclinical study to evaluate the therapeutic efficacy of a certain compound or a combination of certain compounds. In a typical human tumor xenograft model, human carcinoma cells are implanted to subjects such as severe combined immunodeficient (SCID) mice. Treatment with test compounds is initiated after tumor nodule has appeared, and continued for a certain time period. Tumor volumes are measured over the duration of the experiment. It is well known that untreated tumor growth may follow certain patterns, which can be described by certain mathematical models. However, the growth patterns of the treated tumors with multiple treatment episodes are quite complex, and the usage of parametric models is limited. We propose using cubic smoothing splines to describe tumor growth for each treatment group and for each subject, respectively. The proposed smoothing splines are quite flexible in modeling different growth patterns. In addition, using this procedure, we can obtain tumor growth and growth rate over time for each treatment group and for each subject, and examine whether tumor growth follows certain growth pattern. To examine the overall treatment effect and group differences, the scaled chi squared test statistics based on the fitted group-level growth curves are proposed. A case study is provided to illustrate the application of this method, and simulations are carried out to examine the performances of the scaled chi squared tests. PMID- 21604289 TI - Integrating microsatellite and pedigree analyses to facilitate the captive management of the endangered Mississippi sandhill crane (Grus canadensis pulla). AB - The minimization of kinship in captive populations is usually achieved through the use of pedigree information. However, pedigree knowledge alone is not sufficient if pedigree information is missing, questionable, or when the founders of the captive population are related to one another. If this is the case, higher levels of inbreeding and lower levels of genetic diversity may be present in a captive population than those calculated by pedigree analyses alone. In this study, the genetic status of the critically endangered Mississippi sandhill crane (MSC) (Grus canadensis pulla) was analyzed using studbook data from the U.S. Fish and Wildlife Service managed captive breeding program as well as microsatellite DNA data. These analyses provided information on shared founder genotypes, allowing for refined analysis of genetic variation in the population, and the development of a new DNA-based studbook pedigree that will assist in the genetic management of the MSC population. PMID- 21604287 TI - High-fat diet activates pro-inflammatory response in the prostate through association of Stat-3 and NF-kappaB. AB - BACKGROUND: Signal transducer and activator of transcription (Stat)-3 and nuclear factor-kappa B (NF-kappaB) are important signaling pathways constitutively activated during inflammation. We previously reported that high-fat diet (HFD) intake induces oxidative stress in the prostate through elevated expression of NADPH oxidase subunits causing NF-kappaB activation. We sought to determine whether Stat-3 is involved in the activation of NF-kappaB in the prostate as a result of HFD feeding, leading to inflammation. METHODS: C57BL/6 mice were either fed with regular diet (RD) or HFD for 4 and 8 weeks. Plasma cytokine levels were determined by multiplex analysis. Western blotting was performed to determine the expression of NF-kappaB, Stat-3, Akt, PDK1, PKCepsilon, and their phosphorylated forms along with pathologic evaluation of the prostate. Immunoprecipitation and electrophoretic mobility shift assay (EMSA) were conducted to study the association between Stat-3 and NF-kappaB. RESULTS: C57BL/6 mice fed with HFD showed a significant increase in the plasma levels of IL-1beta, IL-6, IL-17, and TNFalpha after 4 and 8 weeks of feeding, compared with RD controls. HFD feeding elevated the intraprostatic expression of IL-6 and caused activation of PKCepsilon and Akt, the upstream kinase regulating Stat-3 and NF-kappaB. Nuclear extracts from the prostates of mice fed with HFD exhibited constitutively activated levels of Stat-3 and NF-kappaB/p65. Increased association between the activated forms of Stat-3 and NF-kappaB/p65 was observed in the nucleus as a result of HFD feeding, a finding that was accompanied by morphologic evidence of increased intraprostatic inflammation. CONCLUSIONS: Our findings suggest that HFD activates Stat-3 and NF-kappaB/p65 in the prostate, and their interaction is associated with increased inflammation in the prostate. PMID- 21604290 TI - Parallel reconstruction using null operations. AB - A novel iterative k-space data-driven technique, namely parallel reconstruction using null operations (PRUNO), is presented for parallel imaging reconstruction. In PRUNO, both data calibration and image reconstruction are formulated into linear algebra problems based on a generalized system model. An optimal data calibration strategy is demonstrated by using singular value decomposition, and an iterative conjugate-gradient approach is proposed to efficiently solve missing k-space samples during reconstruction. With its generalized formulation and precise mathematical model, PRUNO reconstruction yields good accuracy, flexibility, and stability. Both computer simulation and in vivo studies have shown that PRUNO produces much better reconstruction quality than generalized autocalibrating partially parallel acquisition (GRAPPA), especially under high accelerating rates. With the aid of PRUNO reconstruction, ultra-high accelerating parallel imaging can be performed with decent image quality. For example, we have done successful PRUNO reconstruction at a reduction factor of 6 (effective factor of 4.44) with eight coils and only a few autocalibration signal lines. PMID- 21604291 TI - Phase-based arterial input function measurements in the femoral arteries for quantification of dynamic contrast-enhanced (DCE) MRI and comparison with DCE-CT. AB - Dynamic contrast-enhanced (DCE) MRI is useful for diagnosis, treatment monitoring and follow-up of prostate cancer. However, large differences have been reported in the parameter range of the transfer constant K(trans) , making longitudinal studies and comparison of DCE-MRI findings between studies difficult. Large part of this inconsistency in K(trans) values can be attributed to problems with the accurate measurement of the arterial input function (AIF) from the magnitude signal (AIF(MAG) (N) ). Phase-based AIF measurements (AIF(PHASE) ) have been proposed as a more robust alternative to AIF(MAG) (N) measurements. This study compares AIF(PHASE) with AIFs measured with DCE-CT (AIF(CT) ), and the corresponding K(trans) maps in 12 prostate cancer patients. The shape of AIF(PHASE) and AIF(CT) are similar, although differences in the peak height and peak width exist as a result of differences in injection protocol. No significant differences in K(trans) values were found between the DCE-MRI and DCE-CT exams, with median K(trans) values of 0.10 and 0.08 min(-1) for healthy peripheral zone tissue and 0.44 and 0.36 min(-1) for regions suspected of tumor respectively. Therefore, robust quantification of K(trans) values from DCE-MRI exams in the cancerous prostate is feasible with the use of AIF(PHASE) . PMID- 21604292 TI - Simultaneous T2 and lipid quantitation using IDEAL-CPMG. AB - Muscle damage, edema, and fat infiltration are hallmarks of a range of neuromuscular diseases. The T(2) of water, T(2,w) , in muscle lengthens with both myocellular damage and inflammation and is typically measured using multiple spin echo or Carr-Purcell-Meiboom-Gill acquisitions. However, microscopic fat infiltration in neuromuscular diseases prevents accurate T(2,w) quantitation as the longer T(2) of fat, T(2,f) , masks underlying changes in the water component. Fat saturation can be inconsistent across the imaging volume and removes valuable physiological fat information. A new method is presented that combines iterative decomposition of water and fat with echo asymmetry and least squares estimation with a Carr-Purcell-Meiboom-Gill-sequence. The sequence results in water and fat separated images at each echo time for use in T(2,w) and T(2,f) quantification. With knowledge of the T(2,w) and T(2,f) , a T(2) -corrected fat fraction map can also be calculated. Monte-Carlo simulations and measurements in phantoms, volunteers, and a patient with inclusion body myositis are demonstrated. In healthy volunteers, uniform T(2,w) and T(2) -corrected fat fraction maps are present within all muscle groups. However, muscle-specific patterns of fat infiltration and edema are evident in inclusion body myositis, which demonstrates the power of separating and quantifying the fat and water components. PMID- 21604293 TI - Reducing peripheral nerve stimulation due to gradient switching using an additional uniform field coil. AB - This study shows that larger rates of change of gradient with time (dG/dt) can be achieved at the threshold for peripheral nerve stimulation by applying a uniform concomitant field varying synchronously with a transverse field gradient and that this increase may be achieved without significant reduction of the spatial extent of the region over which imaging can be carried out. Realization of similar benefits through application of a uniform, z-directed field varying synchronously with an axial gradient is also demonstrated. The design and construction of transverse and axial coil arrangements is described, along with the results of volunteer studies that were carried out on 20 subjects, with the subjects positioned with four different regions (head, heart, hips, and knees) centered in the coils. These experiments were carried out at zero-field on a prototype system in which the coils were not actively shielded. The uniform concomitant field coil was not torque balanced. The increase in the rate of change of gradient at the threshold for peripheral nerve stimulation that could be achieved by the addition of the uniform field depends on body position and was larger for the transverse coils (head = * 1.9 +/- 0.6; heart = * 0.9 +/- 0.3; hips = * 1.4 +/- 0.4; knees = * 1.5 +/- 0.4) than for the axial coils (head = * 1.5 +/- 0.6; heart = * 0.8 +/- 0.3; hips = * 1.3 +/- 0.4; knees = * 1.1 +/- 0.3). PMID- 21604294 TI - Local specific absorption rate control for parallel transmission by virtual observation points. AB - The supervision of local specific absorption rate (SAR) in parallel transmission applications in MRI is crucial. One existing approach is to use electromagnetic simulations including human anatomical models and to precalculate the electric field distributions of each individual channel. These can be superposed later with respect to certain combined excitations under investigation, and the local SAR distribution can be evaluated. Local SAR maxima can be obtained by exhaustive search over all investigated subvolumes of the body model. Practical challenges arise for the adequate handling and comparing of precalculated field distributions as long as the expected combined radiofrequency excitations are still undetermined. Worst-case approximations for local SAR lead to significant radiofrequency pulse performance limitations. Optimizing local SAR in radiofrequency pulse design using constraints for each subvolume is impractical. A method is proposed to significantly reduce the complexity without restriction to particular radiofrequency excitations. By constructing several matrices, it becomes sufficient to consider only these so-called Virtual Observation Points for an adequate, conservative estimation of the maximum local SAR. The applied techniques involve concepts of vector optimization as well as semidefinite programming. PMID- 21604295 TI - In vivo molecular MRI of cell survival and teratoma formation following embryonic stem cell transplantation into the injured murine myocardium. AB - Embryonic stem cells (ESCs) have shown the potential to restore cardiac function after myocardial injury. Superparamagnetic iron oxide nanoparticles (SPIO) have been widely employed to label ESCs for cellular MRI. However, nonspecific intracellular accumulation of SPIO limits long-term in vivo assessment of the transplanted cells. To overcome this limitation, a novel reporter gene (RG) has been developed to express antigens on the ESC surface. By employing SPIO conjugated monoclonal antibody against these antigens (SPIO-MAb), the viability of transplanted ESCs can be detected in vivo. This study aims to develop a new molecular MRI method to assess in vivo ESC viability, proliferation, and teratoma formation. The RG is designed to express 2 antigens (hemagglutinin A and myc) and luciferase on the ESC surface. The two antigens serve as the molecular targets for SPIO-MAb. The human and mouse ESCs were transduced with the RG (ESC-RGs) and transplanted into the peri-infarct area using the murine myocardial injury model. In vivo MRI was performed following serial intravenous administration of SPIO MAb. Significant hypointense signal was generated from the viable and proliferating ESCs and subsequent teratoma. This novel molecular MRI technique enabled in vivo detection of early ESC-derived teratoma formation in the injured murine myocardium. PMID- 21604296 TI - Layer-specific functional and anatomical MRI of the retina with passband balanced SSFP. AB - The retina consists of multiple cellular and synaptic layers and is nourished by two distinct (retinal and choroidal) circulations bounding the retina, separated by an avascular layer. High spatiotemporal resolution, layer-specific MRI of the retina remains challenging due to magnetic inhomogeneity-induced artifacts. This study reports passband balanced steady-state free-precession (bSSFP) MRI at 45*45*500 MUm and 1.6 s temporal resolution to image the mouse retina, overcoming geometric distortion and signal dropout while maintaining rapid acquisition and high signal-to-noise ratio. bSSFP images revealed multiple alternating dark bright-dark-bright retinal layers. Hypoxic (10% O(2) ) inhalation decreased bSSFP signals in the two layers bounding the retina, corresponding to the retinal and choroidal vasculatures. The layer in between showed no substantial response and was assigned the avascular photoreceptor layers. Choroidal responses (-25.9 +/- 6.4%, mean +/- SD, n=6) were significantly (P<0.05) larger than retinal vascular responses (-11.6+/-2.4%). bSSFP offers very high spatiotemporal resolution and could have important applications in imaging layer-specific changes in retinal diseases. PMID- 21604297 TI - Nonrigid retrospective respiratory motion correction in whole-heart coronary MRA. AB - A nonrigid retrospective respiratory motion correction scheme is presented for whole-heart coronary imaging with interleaved acquisition of motion information. The quasi-periodic nature of breathing is exploited to populate a 3D nonrigid motion model from low-resolution 2D imaging slices acquired interleaved with a segmented 3D whole-heart coronary scan without imposing scan time penalty. Reconstruction and motion correction are based on inversion of a generalized encoding equation. Therein, a forward model describes the transformation from the motion free image to the motion distorted k-space data, which includes nonrigid spatial transformations. The effectiveness of the approach is demonstrated on 10 healthy volunteers using free-breathing coronary whole-heart scans. Although conventional respiratory-gated acquisitions with 5-mm gating window resulted in an average gating efficiency of 51% +/- 11%, nonrigid motion correction allowed for gate-free acquisitions, and hence scan time reduction by a factor of two without significant penalty in image quality. Image scores and quantitative image quality measures for the left coronary arteries showed no significant differences between 5-mm gated and gate-free acquisitions with motion correction. For the right coronary artery, slightly reduced image quality in the motion corrected gate-free scan was observed as a result of the close vicinity of anatomical structures with different motion characteristics. Magn Reson Med, 2011. (c) 2011 Wiley Periodicals, Inc. PMID- 21604298 TI - Robust fat suppression at 3T in high-resolution diffusion-weighted single-shot echo-planar imaging of human brain. AB - Single-shot echo-planar imaging is the most common acquisition technique for whole-brain diffusion tensor imaging (DTI) studies in vivo. Higher field MRI systems are readily available and advantageous for acquiring DTI due to increased signal. One of the practical issues for DTI with single-shot echo-planar imaging at high-field is incomplete fat suppression resulting in a chemically shifted fat artifact within the brain image. Unsuppressed fat is especially detrimental in DTI because the diffusion coefficient of fat is two orders of magnitude lower than that of parenchyma, producing brighter appearing fat artifacts with greater diffusion weighting. In this work, several fat suppression techniques were tested alone and in combination with the goal of finding a method that provides robust fat suppression and can be used in high-resolution single-shot echo-planar imaging DTI studies. Combination of chemical shift saturation with slice-select gradient reversal within a dual-spin-echo diffusion preparation period was found to provide robust fat suppression at 3 T. PMID- 21604299 TI - Determination of regional variations and reproducibility in in vivo 1H NMR spectroscopy of the rat brain at 16.4 T. AB - In vivo (1)H NMR spectroscopy was used to obtain the neurochemical profile in the posterior parts of the brain, the cerebellum and the medulla oblongata in comparison to the hippocampus and the thalamus. Using small voxel sizes between 16 and 32 MUl to avoid partial volume effects, most metabolites demonstrated significant regional differences except acetate, gamma-aminobutyric acid, and phosphorylcholine. Noticeable regional differences in metabolite concentrations were the significant increase of total creatine in the cerebellum and the substantial decrease of taurine in thalamus and medulla oblongata. In particular, the glycine concentration in the medulla oblongata was determined to be 4.37 +/- 0.68 MUmol/g (Cramer-Rao lower bounds 7%) and thus significantly higher than in the other regions, consistent with findings reported in both in vivo (1)H NMR spectroscopy and in vitro biochemical assays. Intraindividual reproducibility and interindividual variability were investigated by acquiring spectra from the thalamus of the same rats in two sessions. No prominent influence on measurement session was observed in metabolite concentrations with coefficients of variations being below 20% in 16 metabolites. PMID- 21604300 TI - Results for diffusion-weighted imaging with a fourth-channel gradient insert. AB - Diffusion-weighted imaging suffers from motion artifacts and relatively low signal quality due to the long echo times required to permit the diffusion encoding. We investigated the inclusion of a noncylindrical fourth gradient coil, dedicated entirely to diffusion encoding, into the imaging system. Standard three axis whole body gradients were used during image acquisition, but we designed and constructed an insert coil to perform diffusion encodings. We imaged three phantoms on a 3-T system with a range of diffusion coefficients. Using the insert gradient, we were able to encode b values of greater than 1300 s/mm(2) with an echo time of just 83 ms. Images obtained using the insert gradient had higher signal to noise ratios than those obtained using the whole body gradient: at 500 s/mm(2) there was a 18% improvement in signal to noise ratio, at 1000 s/mm(2) there was a 39% improvement in signal to noise ratio, and at 1350 s/mm(2) there was a 56% improvement in signal to noise ratio. Using the insert gradient, we were capable of doing diffusion encoding at high b values by using relatively short echo times. PMID- 21604301 TI - Botulinum toxin modulates basal ganglia but not deficient somatosensory activation in orofacial dystonia. AB - The etiology of idiopathic orofacial dystonia is incompletely understood. Neurophysiological studies indicated that a sensory dysfunction could play a key role in the pathophysiology of focal dystonia. To explore if central sensory processing is abnormal in patients with blepharospasm and Meige's syndrome and to study the effects of botulinum toxin (BTX) treatment, we systematically mapped the somatotopic representations of punctate tactile stimuli in these patients before and after therapy. METHODS: Standardized tactile stimuli were pseudorandomly applied to the forehead, upper lip, and hand by a MR-compatible stimulation device during event-related fMRI. RESULTS: Patients showed a deficient activation in primary and secondary somatosensory representations of affected and unaffected (right hand) body regions compared to healthy controls. Although clinically effective BTX treatment did not modulate this impaired cortical activation, it reduced the activation of the thalamus and contralateral putamen during forehead stimulation. CONCLUSIONS: This study reveals a more generalized dysfunction of the somatosensory cortex including asymptomatic body representations in orofacial dystonia. Deficient cortical sensory activation may be due to a dedifferentiation of somatosensory representations and could represent a critical functional change within the basal ganglia-thalamocortical loops facilitating dystonic movements. Modulation of basal ganglia activation might reflect an indirect remote effect of BTX treatment on these sensorimotor circuits. PMID- 21604302 TI - Fast approximations of the rotational diffusion tensor and their application to structural assembly of molecular complexes. AB - We present and evaluate a rigid-body, deterministic, molecular docking method, called ELMDOCK, that relies solely on the three-dimensional structure of the individual components and the overall rotational diffusion tensor of the complex, obtained from nuclear spin-relaxation measurements. We also introduce a docking method, called ELMPATIDOCK, derived from ELMDOCK and based on the new concept of combining the shape-related restraints from rotational diffusion with those from residual dipolar couplings, along with ambiguous contact/interface-related restraints obtained from chemical shift perturbations. ELMDOCK and ELMPATIDOCK use two novel approximations of the molecular rotational diffusion tensor that allow computationally efficient docking. We show that these approximations are accurate enough to properly dock the two components of a complex without the need to recompute the diffusion tensor at each iteration step. We analyze the accuracy, robustness, and efficiency of these methods using synthetic relaxation data for a large variety of protein-protein complexes. We also test our method on three protein systems for which the structure of the complex and experimental relaxation data are available, and analyze the effect of flexible unstructured tails on the outcome of docking. Additionally, we describe a method for integrating the new approximation methods into the existing docking approaches that use the rotational diffusion tensor as a restraint. The results show that the proposed docking method is robust against experimental errors in the relaxation data or structural rearrangements upon complex formation and is computationally more efficient than current methods. The developed approximations are accurate enough to be used in structure refinement protocols. PMID- 21604303 TI - Binding to the open conformation of HIV-1 protease. AB - A recent crystal structure of HIV-1 protease (HIVp) was the first to experimentally observe a ligand targeting an open-flap conformation. Researchers studying a symmetric pyrrolidine inhibitor found that two ligands cocrystallized with the protease, forcing an unusual configuration and unique crystallographic contacts. One molecule is centered in the traditional binding site (alpha pose) and the other binds between the flaps (beta pose). The ligands stack against each other in a region termed the "eye" site. Ligands bound to the eye site should prevent flap closure, but it is unclear if the pyrrolidine inhibitors or the crystal packing are causing the open state. Molecular dynamics simulations were used to examine the solution-state behavior of three possible binding modes: the ternary complex of HIVp+alphabeta and the binary complexes, HIVp+alpha and HIVp+beta. We show that HIVp+alpha is the most stable of the three states. During conformational sampling, alpha takes an asymmetric binding pose, with one naphthyl ring occupying the eye site and the other reoriented down to occupy positions seen with traditional inhibitors. This finding supports previous studies that reveal a requirement for asymmetric binding at the eye site. In fact, if the alpha pose is modified to splay both naphthyl rings across the binding site like traditional inhibitors, one ring consistently flips to occupy the eye site. Our simulations reveal that interactions to the eye site encourage a conformationally restrained state, and understanding those contacts may aid the design of ligands to specifically target alternate conformations of the protease. PMID- 21604304 TI - In silico predictions of LH2 ring sizes from the crystal structure of a single subunit using molecular dynamics simulations. AB - Most of the currently known light-harvesting complexes 2 (LH2) rings are formed by 8 or 9 subunits. As of now, questions like "what factors govern the LH2 ring size?" and "are there other ring sizes possible?" remain largely unanswered. Here, we investigate by means of molecular dynamics (MD) simulations and stochastic modeling the possibility of predicting the size of an LH2 ring from the sole knowledge of the high resolution crystal structure of a single subunit. Starting with single subunits of two LH2 rings with known size, that is, an 8 ring from Rs. moliscianum (MOLI) and a 9-ring from Rps. acidophila (ACI), and one with unknown size (referred to as X), we build atomic models of subunit dimers corresponding to assumed 8-, 9-, and 10-ring geometries. After inserting each of the dimers into a lipid-water environment, we determine the preferred angle between the corresponding subunits by three methods: (1) energy minimization, (2) free MD simulations, and (3) potential of mean force calculations. We find that the results from all three methods are consistent with each other, and when taken together, it allows one to predict with reasonable level of confidence the sizes of the corresponding ring structures. One finds that X and ACI very likely form a 9-ring, while MOLI is more likely to form an 8-ring than a 9-ring. Finally, we discuss both the merits and limitations of all three prediction methods. PMID- 21604305 TI - The PR/SET domain in PRDM4 is preceded by a zinc knuckle. PMID- 21604306 TI - Crystal structure of a novel dimer form of FlgD from P. aeruginosa PAO1. PMID- 21604307 TI - De novo protein structure prediction by dynamic fragment assembly and conformational space annealing. AB - Ab initio protein structure prediction is a challenging problem that requires both an accurate energetic representation of a protein structure and an efficient conformational sampling method for successful protein modeling. In this article, we present an ab initio structure prediction method which combines a recently suggested novel way of fragment assembly, dynamic fragment assembly (DFA) and conformational space annealing (CSA) algorithm. In DFA, model structures are scored by continuous functions constructed based on short- and long-range structural restraint information from a fragment library. Here, DFA is represented by the full-atom model by CHARMM with the addition of the empirical potential of DFIRE. The relative contributions between various energy terms are optimized using linear programming. The conformational sampling was carried out with CSA algorithm, which can find low energy conformations more efficiently than simulated annealing used in the existing DFA study. The newly introduced DFA energy function and CSA sampling algorithm are implemented into CHARMM. Test results on 30 small single-domain proteins and 13 template-free modeling targets of the 8th Critical Assessment of protein Structure Prediction show that the current method provides comparable and complementary prediction results to existing top methods. PMID- 21604308 TI - Structural insights into the metal binding properties of hypothetical protein MJ0754 from Methanococcus jannaschii. PMID- 21604309 TI - Screening of Australian plants for antimicrobial activity against Campylobacter jejuni. AB - Campylobacter jejuni is the most common cause of acute enteritis in humans, with symptoms such as diarrhoea, fever and abdominal cramps. In this study, 115 extracts from 109 Australian plant species were investigated for their antimicrobial activities against two C. jejuni strains using an in vitro broth microdilution assay. Among the plants tested, 107 (93%) extracts showed activity at a concentration between 32 and 1024 ug/mL against at least one C. jejuni strain. Seventeen plant extracts were selected for further testing against another six C. jejuni strains, as well as Campylobacter coli, Escherichia coli, Salmonella typhimurium, Bacillus cereus, Proteus mirabilis and Enterococcus faecalis. The extract from Eucalyptus occidentalis demonstrated the highest antimicrobial activity, with an inhibitory concentration of 32 ug/mL against C. jejuni and B. cereus. This study has shown that extracts of selected Australian plants possess antimicrobial activity against C. jejuni and thus may have application in the control of this organism in live poultry and retail poultry products. PMID- 21604310 TI - In vitro cytotoxic effect of ethanol extract prepared from sporophyll of Undaria pinnatifida on human colorectal cancer cells. AB - Brown seaweed Undaria pinnatifida (Harvey) Suringar is popular as a foodstuff, and used for medical care in East Asian countries. The major components of this seaweed are shown to benefit hypertension and hyperlipidemia, and considered to reduce the risks of infarction and ischemic diseases. Furthermore, the intake of dietary fiber of seaweeds is considered to prevent the production and proliferation of cancer in the gastrointestinal tract. The direct effect of an ethanol extract prepared from Undaria pinnatifida sporophyll (mekabu) on HCT116 human colorectal cancer cells was examined, and the mekabu extract was shown to induce the non-oxidative apoptotic damage to the cells, thus resulting in the reduction of their viabilities in a concentration-dependent manner. Moreover, the cytotoxic effects of carcinostatic drugs, such as 5-fluorouracil (5-FU) and irinotecan (CPT-11), were observed only in the medium containing sera, while the mekabu extract could effectively reduce the cell viabilities even in the serum free medium. These findings suggest that the mekabu extract may contain a potential active substance inducing the non-oxidative apoptotic cell death probably through a mechanism different from those of 5-FU and CPT-11, and hence mekabu is possibly useful as an auxiliary drug to the chemotherapy of colorectal cancer. PMID- 21604311 TI - Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T1 and T2 contrast agents. AB - The extracellular pH (pH(e) ) of solid tumors is acidic, and there is evidence that an acidic pH(e) is related to invasiveness. Herein, we describe an MRI single-infusion method to measure pH(e) in gliomas using a cocktail of contrast agents (CAs). The cocktail contained gadolinium-1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraaminophosphonate (GdDOTA-4AmP) and dysprosium-1,4,7,10 tetraazacyclododecane-N,N',N'',N'''-tetrakis(methylenephosphonic acid) (DyDOTP), whose effects on relaxation are sensitive and insensitive to pH, respectively. The Gd-CA dominated the spin-lattice relaxivity DeltaR(1) , whereas the Dy-CA dominated the spin-spin relaxivity DeltaR(2)*. The DeltaR(2)* effects were used to determine the pixel-wise concentration of [Dy] which, in turn, was used to calculate a value for [Gd] concentration. This value was used to convert DeltaR(1) values to the molar relaxivity Deltar(1) and, hence, pH(e) maps. The development of the method involved in vivo calibration and measurements in a rat brain glioma model. The calibration phase consisted of determining a quantitative relationship between DeltaR(1) and DeltaR(2)* induced by the two pH-independent CAs, gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) and DyDOTP, using echo planar spectroscopic imaging (EPSI) and T(1) -weighted images. The intensities and linewidths of the water peaks in EPSI images were affected by CA and were used to follow the pharmacokinetics. These data showed a linear relationship between inner- and outer-sphere relaxation rate constants that were used for CA concentration determination. Nonlinearity in the slope of the relationship was observed and ascribed to variations in vascular permeability. In the pH(e) measurement phase, GdDOTA-4AmP was infused instead of GdDTPA, and relaxivities were obtained through the combination of interleaved T(1) -weighted images (R(1) ) and EPSI for DeltaR(2)*. The resulting r(1) values yielded pH(e) maps with high spatial resolution. PMID- 21604312 TI - Controlled dispersion of silver nanoparticles into the bulk of thermosensitive polymer microspheres: tunable plasmonic coupling by temperature detected by surface enhanced Raman scattering. AB - By in situ reduction of Ag(+) ions pre-dispersed inside thermosensitive microspheres of poly[(N-isopropylacrylamide)-co-(methacrylic acid)] (P(NIPAM-co MAA)), a 3D copolymer-supported network of silver nanoparticles is created and extensively characterized by surface-enhanced Raman scattering (SERS). The effective dispersion and the suitable density of the silver nanoparticles in the composite microspheres are demonstrated by the thermal-induced SERS signal and its high reproducibility during thermocycling. When the temperature of the system increases above 32 degrees C, spatial separation of the silver nanoparticles decreases and the numbers of Ag nanoparticles and P(NIPAM-co-MAA) microspheres under illumination spot increase as a result of the shrinkage of the P(NIPAM-co MAA) chains, leading to the ramp of the SERS effect. By means of the high reversibility of the thermosensitive phase transition of the P(NIPAM-co-MAA) microspheres, SERS activity of the silver nanoparticle network embedded in the microsphere can be well controlled by thermal-induced variation of special separation. PMID- 21604313 TI - From polyesters to polyamides via O-N acyl migration: an original multi-transfer reaction. AB - A new strategy for the synthesis of polyamides from polyesters of hydroxyl containing amino acids using a multi O-N acyl transfer reaction was developed. This original approach allowed the synthesis of three generations of polymers from the same starting monomer. The polymerization of N-benzyloxycarbonyl-serine and its gamma-homologated derivative provided the Z-protected polyesters; then the water-soluble polycationic polyesters were obtained by removal of the Z protecting group; and finally the polyamides were obtained by a base-induced multi O-N acyl transfer, both in aqueous or organic medium. The key step transfer reaction was monitored by the disappearance and appearance of characteristic NMR proton signals and IR bands of polyesters and polyamides. PMID- 21604315 TI - Depression in patients with head and neck cancer and a functional genetic polymorphism of the serotonin transporter gene. AB - BACKGROUND: Polymorphism of the serotonin transporter gene, 5-HTTLPR (short allele) has been associated with depression. The purpose of this study was to show the evaluated depression in patients with head and neck cancer and a possible association with the 5-HTTLPR. METHODS: The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID for DSM IV) was administered to 94 patients with head and neck cancer, of which 33 patients were genotyped for 5-HTTLPR. We also evaluated the prevalence of 5 HTTLPR polymorphism in 121 patients with head and neck cancer and 97 controls. RESULTS: Forty-three percent of the patients met the criteria for a depressive diagnosis, 19% of which was new onset. In depressed patients, 85.7% (n = 12 of 14) had at least 1 short allele versus 68.4% (n = 13 of 19) of the patients without depressive diagnosis (p < .04). No difference was noted in the prevalence of the short allele in head and neck cancer cases versus controls (odds ratio = 0.8; p = .490). CONCLUSION: Despite the high rate of depressive diagnosis, patients with head and neck cancer did not demonstrate a higher prevalence of this short allele of the 5-HTTLPR compared with a control population. PMID- 21604314 TI - Cortical bone mass and geometry: age, sex, and intraskeletal variation in nineteenth-century Euro-Canadians. AB - OBJECTIVES: This study seeks to understand the interaction of cortical bone strength and mass within individuals and across age-groups in male and female adults from a relatively active, long-lived nineteenth-century Euro-Canadian population. METHODS: Strength and relative cortical area are measured in paired femora (weight-bearing elements) and metacarpals (manipulative elements) from 139 adults (M = 82; F = 52). Sex and age patterns are tested using linear multiple regression and analysis of covariance. Intra-individual divergence between femora and metacarpals is quantified using the Pearson residual from regression of femur on metacarpal values. Association of residuals with age is tested with curve estimation, factorial analysis of variance and X(2) tests. RESULTS: Strength is maintained but cortical mass declines with age. In females, the slope of cortical mass against age is steeper in the metacarpal than in the femur. However, the degree of divergence between femur and metacarpal within individuals does not increase clearly with age. CONCLUSIONS: Age change in bone strength is systemically controlled and homeostatic, but change in bone mass may vary with limb-specific mechanical environment, particularly in females. However, the distribution of within-individual divergence between femur and metacarpal values suggests that idiosyncratic factors, rather than age, have the strongest influence on intraskeletal divergence. Attempts to reconstruct skeletal ageing in past populations may benefit from an approach that models whole-bone integrity, rather than bone mass alone, and that represents age-related variation in both weight-bearing and nonweight-bearing sites. PMID- 21604316 TI - Minimally invasive endoscopic-assisted resection of benign tumors in the accessory parotid gland: 5 case studies. AB - BACKGROUND: A modified Blair's incision or standard facelift incision is recommended to remove tumors in the accessory parotid gland. These incisions frequently result in long and visible scars. Therefore, the authors have introduced an endoscopic approach via a small preauricular incision to achieve excision of benign tumors in the accessory parotid gland. METHODS: The endoscopic surgical technique was performed on 5 patients with benign tumors in the accessory parotid gland. RESULTS: Endoscopic-assisted resection of the benign tumors in the accessory parotid gland was feasible in all 5 patients. This procedure lasted 105 minutes on average. Facial paralysis, salivary fistula, and ear-lobular numbness were not found postoperatively. The follow-up period was 1 year, during which no Frey's syndrome and recurrence were found. All preauricular scars were aesthetically satisfactory. CONCLUSIONS: The minimally invasive endoscopic approach via a small preauricular incision is an optional method of the accessory parotid gland benign tumor resection. PMID- 21604317 TI - Gastrostomy tube placement and use in patients with head and neck cancer. AB - BACKGROUND: Enteral nutritional support is used in care for patients with head and neck cancer. This study describes the frequency and timing of gastrostomy tube placement and corresponding Medicare nutritional support claims in patients with head and neck cancer. METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare data for patients with head and neck cancer diagnosed from 2000 to 2005 were used in this descriptive study (N = 16,458). RESULTS: In all, 35.1% of patients undergoing treatment had gastrostomy tubes placed; 16.9% had tubes placed before treatment, whereas 83.1% had them placed after treatment. Of those having tubes placed prior to treatment 23.7% had Medicare claims for nutritional support before treatment and 40.9% had claims after treatment began. A total of 35.4% of patients who had tubes placed before treatment and 35.5% who had tubes placed after treatment had no claims for nutritional support. CONCLUSIONS: Future work is warranted to identify predictors and outcomes associated with provision and timing of enteral nutrition support for patients with head and neck cancer. PMID- 21604318 TI - Early tongue carcinoma: analysis of failure. AB - BACKGROUND: Failure rate of surgery for early tongue carcinoma remains high. We sought to identify patterns of failure and recurrence risk factors. METHODS: Data review was carried out on 50 patients treated for early tongue carcinoma (T1/2N0M0); surgery was unsuccessful in 11 of these patients. All patients underwent transoral resection of the tongue tumor and prophylactic neck dissection (supraomohyoid). RESULTS: Tumor recurred within 3 to 18 months. Nine died of disease. Four had failure in neck level 4, 6 in level 1, and 1 simultaneously in level 1 and locally. Most tumors were moderately differentiated. Average depth was 6.64 mm. CONCLUSIONS: We report 11 patients with early tongue carcinoma who failed local excision with neck dissection. Failures occurred in level 4 (4 patients) and level 1 (7 patients). This group may benefit from extended neck surgery. Sex, age, stage, and depth of tumor were not significantly different in the group with treatment failure. Tumors in the group with treatment failure were more poorly differentiated. PMID- 21604319 TI - Initial staging of the neck in head and neck squamous cell carcinoma: a comparison of CT, PET/CT, and ultrasound-guided fine-needle aspiration cytology. AB - BACKGROUND: The aim of this study was to compare imaging modalities for staging the neck in a prospective cohort of patients evaluated by CT, ultrasound with fine-needle aspiration cytology (FNAC), and [(18)F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/CT with the histologic evaluation of the neck dissection as the standard of reference. METHODS: In all, 76 consecutive patients were prospectively enrolled. RESULTS: Ultrasound-guided FNAC showed the highest level of agreement with histology for exact N classification. Ultrasound-guided FNAC showed the smallest percentage of overstaged patients, 7%, versus 16% with PET/CT, 13% with CT, and 13% with ultrasound. The rate of understaged patients was comparable between the imaging modalities. With regard to the endpoint N0 versus N+ there were no statistically significant differences to be found. CONCLUSIONS: Ultrasound-guided FNAC seems to correlate best with histologic staging compared with PET/CT and CT. None of the modality is reliable enough to replace elective neck treatment in cN0 necks. PMID- 21604320 TI - Prognostic value of fluorine-18 fluorodeoxyglucose positron-emission tomography imaging in patients with head and neck squamous cell carcinoma. AB - BACKGROUND: High tumor uptake of fluorodeoxyglucose (FDG) is associated with an unfavorable outcome in patients with cancer. We evaluated FDG uptake as a prognostic factor in patients with head and neck squamous cell carcinoma. METHODS: Maximum standardized uptake values (SUVmax) of tumor, liver, and pulmonary artery were recorded. Ratios of SUVmax from tumor to liver (T/L) and from tumor to pulmonary artery (T/PA) were calculated for each patient. Clinical data, tumor, and SUVmax ratios were compared with disease-free survival (DFS) and overall survival (OS). RESULTS: Eighty-nine patients were included: 48 presented a local recurrent disease or distant metastases and 42 died. For both DFS and OS, tumor SUVmax value of 7 was the best cutoff value and 4 and 5 for T/L and T/PA ratios. Multivariate analysis confirmed the independent prognostic value of these 3 thresholds for DFS and OS. CONCLUSIONS: FDG uptake has a significant and independent relationship with recurrence and survival. PMID- 21604321 TI - Tgfbeta/Alk5 signaling is required for shear stress induced klf2 expression in embryonic endothelial cells. AB - Endothelial cells (EC) translate biomechanical forces into functional and phenotypic responses that play important roles in cardiac development. Specifically, EC in areas of high shear stress, i.e., in the cardiac outflow tract and atrioventricular canal, are characterized by high expression of Kruppel like factor 2 (Klf2) and by transforming growth factor-beta (Tgfbeta)-driven endothelial-to-mesenchymal transition. Extraembryonic venous obstruction (venous clip model) results in congenital heart malformations, and venous clip-induced alterations in shear stress-related gene expression are suggestive for an increase in cardiac shear stress. Here, we study the effects of shear stress on Klf2 expression and Tgfbeta-associated signaling in embryonic EC in vivo using the venous clip model and in vitro by subjecting cultured EC to fluid flow. Cellular responses were assessed by analysis of Klf2, Tgfbeta ligands, and their downstream signaling targets. Results show that, in embryonic EC, shear stress activates Tgfbeta/Alk5 signaling and that induction of Klf2 is an Alk5 dependent process. PMID- 21604322 TI - Ultrastructural comparison of the ocelli of Sinopanorpa tincta and Bittacus planus (Mecoptera). AB - On the contrary to compound eyes, dorsal ocelli are poorly investigated for their ultrastructure in many insect groups, including Mecoptera. The ocellar ultrastructure of the scorpionfly Sinopanorpa tincta (Navas) in Panorpidae and the hangingfly Bittacus planus (Cheng) in Bittacidae was examined using transmission electron microscope. Both species possess three ocelli on the vertex of their heads and each ocellus has a corneal lens, some pigment cells at the outer rim of the lens, and fused rhabdoms. Beneath the corneal lens lies a single layer of corneagenous cells, which is very thick with the nuclei located proximally in S. tincta and quite thin in B. planus. A portion of rhabdom is composed of rhabdomeres from two adjacent retinula cells in S. tincta, but from four retinula cells in B. planus. Each rhabdomere comprises parallel microvilli projecting laterally from the apposed retinula cells. In addition, abundant electron-lucent granules are present at the middle part around each retinula in B. planus. Only pigment granules exist around the retinula proximally at the nucleate level in S. tincta. PMID- 21604323 TI - The effect of fluoride therapies on the morphology of bleached human dental enamel. AB - The aim of this in vitro study was to evaluate qualitatively the surface morphology of enamel bleached with 35% hydrogen peroxide (HP) followed by application of fluoridated agents. Forty intact pre molars were randomly distributed into four groups (n = 10), treated as follows: Group I (control group) remained stored in artificial saliva at 37 degrees C, Group II - 35% HP; Group III - 35% HP + acidulated fluoride (1.23%) and Group IV - 35% HP + neutral fluoride (2%). The experimental groups received three applications of bleaching gel and after the last application all specimens were polished. This procedure was repeated after 7 and 14 days, and during the intervals of applications, the specimens were stored in artificial saliva at 37 degrees C. Scanning electron microscopy (SEM) analysis showed superficial irregularities and porosities to varying degrees in bleached enamel compared to control group. Sample evaluation was made by attributing scores, and data were statistically analyzed using Kruskal-Wallis and Dunn tests (P < 0.05). SEM qualitative investigation demonstrated that 35% hydrogen peroxide affected human dental enamel morphology, producing porosities, depressions, and superficial irregularities at various degrees. These morphological changes were higher after the application of 1.23% acidulated fluoride gel. PMID- 21604324 TI - Acquisition speed comparison of microscope software programs. AB - Reliable software is a prerequisite for successful operation of a modern wide field fluorescence microscope. When used for live cell imaging, acquisition speed is of particular interest. This is both because biological processes can be highly-dynamic, and to avoid unnecessary photobleaching and phototoxicity of living samples. This article shows that besides the hardware (microscope) components themselves, the acquisition control software is an important influencing factor of speed performance. We tested and compared the speed performance of five different generic applications (Image-Pro Plus, MetaMorph, Micro-Manager, SlideBook, and Volocity) using typical experimental setups involving a single specific state-of-the-art fluorescence microscope configuration. The test measurements included multichannel experiments, z stacking, burst acquisition, as well as combinations of these measurements with time-lapse acquisitions. The measured data provided values for guiding the testing and analysis of other microscope systems with similar configurations. Despite the identical hardware settings, significant and surprisingly large speed differences were evident among the various software applications. Additionally, no application was identifiable as the fastest in all tests. Our work pinpoints the importance of the control software in determining a system's "real" maximal imaging speed. The study could serve as basis for further tests, eventually influencing the system selection criteria for speed-sensitive applications. PMID- 21604325 TI - Morphological organization of the dorsal protuberance of Linepithema humile (Mayr, 1868) ant's larvae (Hymenoptera, Formicidae). AB - The Argentine ant Linepithema humile is an important invasive species because of the levels of infestation that it can reach; however, there is little information about its presence, histological organization, and function of the dorsal protuberance, which is found exclusively in their larvae. The objective of this study was to describe it in L. humile through scanning electron microscopy and transmission electron microscopy, bringing information about this structure. The epidermis of these larvae have cuticles covering the whole body, and is formed by a sequence of overlapping lamellas where the inner ones were thicker and presented lower electron density, whereas the outer ones were thinner and highly electron dense. Pores or pore-like channels were not observed. A thick and acellular region composed of granular material was found under the cuticular layer. Out of this region, the flattened epidermic cells formed an epithelial layer. For the dorsal protuberance region, these cells become prismatic, and similarly to the cuticle, presents significant thickening. These cells presented extended microvilli, as well as a great amount of lamellar rough endoplasmic reticulum. Under this epithelium was observed a concentration of fat body cells, more numerous in the dorsal protuberance region. This study indicated that the dorsal protuberance present in the first segment of L. humile larvae has apparently no secretory function because no pores were found. This fact allowed to conclude that in L. humile larvae the dorsal protuberance would have the function to make it easier for the worker ants to carry them within the colony. PMID- 21604326 TI - Fluctuations of body images in anorexia nervosa: patients' perception of contextual triggers. AB - Body image disturbance is a central diagnostic criterion of anorexia nervosa (AN). To a great extent, previous studies have conceptualized body image disturbance as a relatively stable and trait-like characteristic of the patient. There is, however, growing evidence that body images fluctuate in different situations and contexts. The aim of the present study was to explore which everyday contexts that patients with AN themselves associate with fluctuations in body image. Thirty-two women (20-35 years) who had been diagnosed with AN (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) within the last year participated. Semi-open and focused qualitative interviews were conducted, transcribed and analyzed using Grounded Theory techniques. The results suggest that body image is a dynamic phenomenon that may fluctuate in different situations and contexts. The participants linked such fluctuations to their own uncertainty about their real appearance. In lack of a stable and integrated experience of their own body, they were extremely sensitive towards body image threats and challenges in their daily life and reacted to these situations by fluctuations in their body image. Four contextual cues were found to trigger such changes in body image: these were eating food, being reminded of one's body appearance, relating to one's own emotional signals and interpreting other people's expressed and unexpressed opinions about oneself and one's appearance. Clinical and theoretical implications are discussed. KEY PRACTITIONER MESSAGE: Individuals with anorexia nervosa may have quite varied body image experiences in different contexts. The contexts identified in this study may be a point of departure for clinicians in helping their patients to explore their subjective body image experiences and to connect these with emotional, cognitive and relational contexts in a psychologically meaningfully way. PMID- 21604327 TI - Inhibition of osteogenic differentiation of human adipose-derived stromal cells by retinoblastoma binding protein 2 repression of RUNX2-activated transcription. AB - Histone methylation is regarded as an important type of histone modification defining the epigenetic program during the lineage differentiation of stem cells. A better understanding of this epigenetic mechanism that governs osteogenic differentiation of human adipose-derived stromal cells (hASCs) can improve bone tissue engineering and provide new insights into the modulation of hASC-based cell therapy. Retinoblastoma binding protein 2 (RBP2) is a histone demethylase that specifically catalyzes demethylation of dimethyl or trimethyl histone H3 lysine 4 (H3K4me2 or H3K4me3), which is normally associated with transcriptionally active genes. In this study, the roles of RBP2 in osteogenic differentiation of hASCs were investigated. We found that RBP2 knockdown by lentiviruses expressing small interfering RNA promoted osteogenic differentiation of hASCs in vitro and in vivo. In addition, we demonstrated that knockdown of RBP2 resulted in marked increases of mRNA expression of osteogenesis-associated genes such as alkaline phosphatase (ALP), osteocalcin (OC), and osterix (OSX). RBP2 was shown to occupy the promoters of OSX and OC to maintain the level of the H3K4me3 mark by chromatin immunoprecipitation assays. Furthermore, coimmunoprecipitation and luciferase reporter experiments suggested that RBP2 was physically and functionally associated with RUNX2, an essential transcription factor that governed osteoblastic differentiation. Significantly, RUNX2 knockdown impaired the repressive activity of RBP2 in osteogenic differentiation of hASCs. Altogether, our study is the first to demonstrate the functional and biological roles of H3K4 demethylase RBP2 in osteogenic differentiation of hASCs and to link RBP2 to the transcriptional regulation of RUNX2. PMID- 21604328 TI - Prevalence and management of anemia in children, adolescents, and adults with inflammatory bowel disease. AB - BACKGROUND: Children and adolescents with inflammatory bowel disease (IBD) are more likely to have Crohn's disease (CD) than ulcerative colitis (UC) and their disease tends to be more extensive and severe than in adults. We hypothesized that the prevalence of anemia would therefore be greater in children and adolescents than in adults attending IBD outpatient clinics. METHODS: Using the WHO age-adjusted definitions of anemia we assessed the prevalence, severity, type, and response to treatment of anemia in patients attending pediatric, adolescent, and adult IBD clinics at our hospital. RESULTS: The prevalence of anemia was 70% (41/59) in children, 42% (24/54) in adolescents, and 40% (49/124) in adults (P < 0.01). Overall, children (88% [36/41]) and adolescents (83% [20/24]) were more often iron-deficient than adults (55% [27/49]) (P < 0.01). Multivariate logistic regression showed that both active disease (odds ratio [OR], 4.7 95% confidence interval [CI], 2.5, 8.8) and attending the pediatric clinic (OR 3.7; 95% CI, 1.6, 8.4) but not the adolescent clinic predicted iron deficiency anemia. Fewer iron-deficient children (13% [5/36]) than adolescents (30% [6/20]) or adults (48% [13/27]) had been given oral iron (P < 0.05); none had received intravenous iron compared with 30% (6/20) adolescents and 41% (11/27) adults (P < 0.0001). CONCLUSIONS: Anemia is even more common in children than in older IBD patients. Oral iron was given to half of adolescents and adults but, despite similar tolerance and efficacy, only a quarter of children with iron deficient anemia. Reasons for the apparent underutilization of iron therapy include a perceived lack of benefit and concerns about side effects, including worsening of IBD activity. PMID- 21604329 TI - Characterization of the gastrointestinal microbiota in health and inflammatory bowel disease. AB - The enteric bacterial flora play a key role in maintaining health. Inflammatory bowel disease is associated with quantitative and qualitative alterations in the microbiota. Early characterization of the microbiota involved culture-dependent techniques. The advent of metagenomic techniques, however, allows for structural and functional characterization using culture-independent methods. Changes in diversity, together with quantitative alterations in specific bacterial species, have been identified. The functional significance of these changes, and their pathogenic role, remain to be elucidated. PMID- 21604330 TI - Idiopathic megacolon associated with ulcerative colitis: a rare association. PMID- 21604331 TI - Therapy modifies HLA-G secretion differently in Crohn's disease and ulcerative colitis patients. PMID- 21604332 TI - Managing postoperative clinical recurrence of Crohn's disease: is it time to shift our paradigm? PMID- 21604333 TI - Pulmonary nodules as respiratory manifestation of inflammatory bowel disease: case report and review. PMID- 21604334 TI - Homocysteinemia and B vitamin status among adult patients with inflammatory bowel disease: a one-year prospective follow-up study. AB - BACKGROUND: The aim of this study was to longitudinally study serum homocysteine levels in patients with Crohn's disease (CD) and ulcerative colitis (UC) in relation to disease activity and B vitamin status. METHODS: In all, 98 consecutive adult patients (age 25-55 years) with CD (n = 70) and UC (n = 28) were enrolled and assessed at three timepoints over 1 year. RESULTS: There were no significant differences in levels of homocysteine, B vitamins, or dietary intake by disease type, disease activity, or across visits. 13% of all inflammatory bowel disease (IBD) patients had elevated homocysteine at least once during the study. Nine patients with CD had fluctuating homocysteine levels during the study but these were inconsistent, ranging from within normal range to elevated levels in any individual. Six of these nine patients were persistently in remission. 30% of all IBD patients had vitamin B6 deficiency, 11% had vitamin B12 deficiency, and one patient (CD) had folate deficiency. All vitamins showed a significant correlation between intake and serum levels (B6; r = 0.46, P < 0.001, B12; r = 0.42, P < 0.001, and folate; r = 0.26, P = 0.008). There was an inverse relationship between serum homocysteine in the blood and serum vitamin B12 (r = 0.241, P = 0.017). CONCLUSIONS: Serum homocysteine was mostly normal in patients with IBD and changed minimally over time. There was no association between disease activity and elevation of serum homocysteine. 30% of patients have vitamin B6 deficiency but vitamin B6 is not associated with elevated homocysteine. The routine measurement of homocysteine is not warranted. PMID- 21604336 TI - High-temperature wetting transition on micro- and nanostructured surfaces. PMID- 21604337 TI - Enantioselective amine-catalyzed [4+2] annulations of allenoates and oxo-dienes: an asymmetric synthesis of dihydropyrans. PMID- 21604339 TI - Manipulating sticky and non-sticky properties in a single material. PMID- 21604340 TI - Electrically tunable hysteretic photonic gels for nonvolatile display pixels. PMID- 21604341 TI - Oleylamine-mediated shape evolution of palladium nanocrystals. PMID- 21604342 TI - Oxygen reactions in a non-aqueous Li+ electrolyte. PMID- 21604343 TI - Total synthesis of (-)-isatisine A. PMID- 21604344 TI - Palladium-catalyzed diastereo- and enantioselective synthesis of substituted cyclopentanes through a dynamic kinetic asymmetric formal [3+2]-cycloaddition of vinyl cyclopropanes and alkylidene azlactones. PMID- 21604345 TI - Identification of the elusive hydronium ion exchanging roles with a proton in an enzyme at lower pH values. PMID- 21604346 TI - Dual hydrogen-bond/enamine catalysis enables a direct enantioselective three component domino reaction. PMID- 21604347 TI - Photoredox catalysis: a mild, operationally simple approach to the synthesis of alpha-trifluoromethyl carbonyl compounds. PMID- 21604348 TI - Enhanced nucleophilic behavior of a dimolybdenum phosphinidene complex: multicomponent reactions with activated alkenes and alkynes in the presence of CO or CNXyl. PMID- 21604349 TI - CO2-"neutral" hydrogen storage based on bicarbonates and formates. PMID- 21604350 TI - Illusory molecular expression of "Penrose stairs" by an aromatic hydrocarbon. PMID- 21604352 TI - The kinetics of ferrocene volatilisation from an ionic liquid. AB - The volatilisation of ferrocene (Fc), dissolved in the ionic liquid N-butyl-N methylpyrrolidinium bis(trifluoromethylsulfonyl)imide, [C(4)mpyrr][NTf(2)], to the gas phase has been indirectly monitored by cyclic voltammetry and chronoamperometry. Simulation of the observed trends in concentration with time using a simple model allowed quantification of the process. Volatilisation of dissolved Fc under flowing wet and dry dinitrogen gas (N(2)) was found to be kinetically limited with a rate constant in the region of 2*10(-7) cm s(-1). The activation energy of diffusion for Fc was found to be 28.2+/-0.7 kJ mol(-1), while the activation energy of volatilisation of Fc from [C(4)mpyrr][NTf(2)] to dry N(2) was found to be 85+/-2 kJ mol(-1). PMID- 21604353 TI - Biological activity of natural phytoecdysteroids from Ajuga iva against the sweetpotato whitefly Bemisia tabaci and the persea mite Oligonychus perseae. AB - BACKGROUND: Ecdysteroids are steroid hormones that control moulting and govern several changes during metamorphoses in arthropods. The discovery of the same molecules (phytoecdysteroids) in several plant species displayed a wide array of rather beneficial agricultural impact. Many representatives of the genus Ajuga plants contain phytoecdysteroids with a 5beta-7-ene-6-one system exhibiting physiological activities in insects. RESULTS: By means of chromatographic (silica gel column, TLC) and LC-MS, two major ecdysteroids (20-hydroxyecdysone and cyasterone) have been isolated and identified from Israeli carpet bugle Ajuga iva (L.) Schreber (Lamiales: Lamiaceae) plants. Ajuga iva extract fractionated on the silica gel column yielded two fractions that showed high activity against the sweetpotato whitefly Bemisis tabaci and the persea mite Oligonychus perseae. A dose of 5 mg AI L(-1) of the purely identified A. iva ecdysterone significantly reduced fecundity, fertility and survival of these pests, while commercial 20 hydroxyecdysone at the same dose had lesser effects. CONCLUSION: The results demonstrate considerable efficacy of natural phytoecdysteroids against major agricultural pests, and suggests that these materials should be considered for potential development of friendly control agents. PMID- 21604354 TI - Volatiles emitted by Carya illinoinensis (Wang.) K. Koch as a prelude for semiochemical investigations to focus on Acrobasis nuxvorella Nuenzig (Lepidoptera: Pyralidae). AB - BACKGROUND: Plant volatiles have complex intra- and interspecific effects in the environment that include plant/herbivore interactions. Identifying the quantity and quality of volatiles produced by a plant is needed to aid the process of determining which chemicals are exerting what effects and then examining whether these effects can be manipulated to benefit society. The qualitative characterization of volatile compounds emitted by pecan, Carya illinoinensis (Wang.) K. Koch, was begun in order to establish a database for investigating how these volatiles affect Acrobasis nuxvorella Nuenzig, a monophagous pest of pecan. Headspace solid-phase microextraction combined with gas chromatography-mass spectrometry was used for the analysis of the volatile constituents of pecan during three phenological stages (dormant buds, intact new shoot growth and intact nutlets) of the Western Schley and Wichita cultivars. RESULTS: About 111 distinct compounds were identified from the two cultivars, accounting for ~99% of the headspace volatiles. The chromatographic profiles of both varieties revealed variations in the volatile composition and proportion between cultivars, with a predominance of terpene hydrocarbons, of the sesquiterpenes class, as well as monoterpenes. CONCLUSION: The significantly higher responsiveness recorded for the larvae of A. nuxvorella to C. illinoinensis shoots indicates that the larvae may be activated by terpenes emanating from the new shoot growth. This is the first study that has examined volatiles of pecan in Mexico. PMID- 21604355 TI - Liver transplantation for erythropoietic protoporphyria in Europe. AB - Liver transplantation is an established lifesaving treatment for patients with severe protoporphyric liver disease, but disease recurrence in the graft occurs for the majority of recipients. Severe burn injuries may occur when protective light filters are not used with surgical luminaires. Motor neuropathy with an unclear pathogenesis is a frequent complication. We retrospectively studied 35 transplants performed for protoporphyric liver disease in 31 European patients between 1983 and 2008. Most of the patients were male (61.3%), and the mean age at the time of primary transplantation was 39 years (range = 9-60 years). The overall patient survival rates were 77% at 1 year and 66% at 5 and 10 years. The overall rate of disease recurrence in the graft was 69%. Forty-three percent of the patients experienced recurrence within a year, but this was often a transient finding that was associated with other graft complications. Phototoxic injuries due to surgical luminaires were seen in 25.0% of the patients who were not protected by filters, but these injuries were not seen in the 9 patients who were protected by filters. Significant motor neuropathies requiring prolonged ventilation complicated the postoperative course for 5 of the 31 patients (16.1%). Hematopoietic stem cell transplantation was performed for 3 patients to prevent graft loss due to disease recurrence. Prognostic markers are needed to identify patients prone to severe protoporphyric liver disease so that curative stem cell transplantation can be offered to select patients instead of liver transplantation. PMID- 21604356 TI - Ambivalence in living liver donors. AB - All right hepatic lobe (RHL) donors in our program are asked to participate in a longitudinal quality-of-life study that begins at their evaluation and continues throughout the first postdonation year. Here we report the characteristics of donor candidates who completed the donation process despite ambivalence. In all, 183 RHL candidates consented, and 133 became donors. Ambivalent donors (ADs; n = 45) identified themselves through verbal statements or written comments, or they were identified by staff during the evaluation. ADs were predominantly male (73.3%), were older than unambivalent donors (UADs; >35 years: 76% of ADs versus 53% of UADs, P = 0.008), and were well educated (college graduate: 60% of ADs versus 17% of UADs, P = 0.01). Brother-to-brother and son-to-father combinations were most common among ADs. Alcohol (22% versus 11%, P = 0.04) and hepatitis C virus (51% versus 27%, P = 0.008) were more common as disease etiologies for recipients with ADs versus recipients with UADs. More ADs than UADs considered themselves to be religious (68.9% versus 43.2%, P = 0.007). Ambivalence about RHL donation was present in 33.8% of the candidates who completed the donation process. These results suggest that ambivalence should not be the sole reason for disqualifying a potential donor who otherwise satisfies program requirements. PMID- 21604357 TI - Impact of center volume on outcomes of increased-risk liver transplants. AB - The use of high-risk donor livers, which is reflective of the gross national shortage of organs available for transplantation, has gained momentum. Despite the demand, many marginal livers are discarded annually. We evaluated the impact of center volume on survival outcomes associated with liver transplantation using high-donor risk index (DRI) allografts. We queried the Scientific Registry of Transplant Recipients database for deceased donor liver transplants (n = 31,576) performed between 2002 and 2008 for patients who were 18 years old or older, and we excluded partial and multiple liver transplants. A high-DRI cohort (n = 15,668), which was composed of patients receiving grafts with DRIs > 1.90, was analyzed separately. Transplant centers (n = 102) were categorized into tertiles by their annual procedure volumes: high-volume centers (HVCs; 78-215 cases per year), medium-volume centers (MVCs; 49-77 cases per year), and low-volume centers (LVCs; 5-48 cases per year). The endpoints were allograft survival and recipient survival. In comparison with their lower volume counterparts, HVCs used donors with higher mean DRIs (2.07 for HVCs, 2.01 for MVCs, and 1.91 for LVCs), more donors who were 60 years old or older (18.02% for HVCs, 16.85% for MVCs, and 12.39% for LVCs), more donors who died after a stroke (46.52% for HVCs, 43.71% for MVCs, and 43.36% for LVCs), and more donation after cardiac death organs (5.04% for HVCs, 4.45% for MVCs, and 3.51% for LVCs, all P values < 0.001). Multivariate risk-adjusted frailty models showed that increased procedure volume at a transplant center led to decreased risks of allograft failure [hazard ratio (HR) = 0.93, 95% confidence interval (CI) = 0.89-0.98, P = 0.002] and recipient death (HR = 0.90, 95% CI = 0.83-0.97, P = 0.004) for high-DRI liver transplants. In conclusion, HVCs more frequently used higher DRI livers and achieved better risk-adjusted allograft and recipient survival. A greater understanding of the outcomes of transplantation with high-DRI livers may improve their utilization, the postoperative outcomes, and future allocation practices. PMID- 21604358 TI - Risk factors for long-term mortality in a large cohort of patients wait-listed for liver transplantation in Brazil. AB - Liver donor shortage and long waiting times are observed in many liver transplant programs worldwide. The aim of this study was to evaluate the wait list in a developing country, before and after the introduction of the MELD scoring system. In addition, the MELD score ability to predict mortality in this setting was assessed. A single-center retrospective study of patients wait-listed for liver transplantation between 1997 and 2010 was undertaken. There were 1339 and 762 patients on the list in pre-MELD and MELD era, respectively. A competitive risk analysis was performed to assess age, gender, disease diagnosis, serum sodium, MELD, Child-Pugh, ABO type, and body mass index. Also, MELD score predictive ability at 3, 6, 12, and 24 months after list enrollment was evaluated. The overall mortality rates on waiting list were 31.0% and 28.1% (P = 0.16), and the median waiting times were 412 and 952 days (P < 0.001), in pre and MELD eras, respectively. The competitive risk analysis yielded the following significant P values for both eras: HCC (0.03 and <0.001), MELD (<0.001 and 0.002), sodium level (0.002 and <0.001), and Child-Pugh (0.02 and <0.001). The MELD mortality predictions at 3, 6, 12, and 24 months were similar. In conclusion, in a liver transplant program with long waiting times, the MELD system introduction did not improve mortality rate. In either pre and MELD eras, HCC diagnosis, serum sodium, Child-Pugh, and MELD were significant predictors of prognosis. Short- and long term MELD based mortality predictions were similarly accurate. Strategies for increasing the liver donor pool should be implemented to improve mortality. PMID- 21604361 TI - Coming soon: NIH genetic test registry. PMID- 21604362 TI - Noninvasive prenatal tests for Down syndrome are near. PMID- 21604365 TI - Long-term stability of self-assembled monolayers on electropolished L605 cobalt chromium alloy for stent applications. AB - Commercially available drug-eluting stents have the potential to induce inflammatory and hypersensitive adverse reactions due to their polymer coating. The use of self assembled monolayers (SAMs) as an alternate drug delivery platform for stents has recently been demonstrated. In this study, the formation and stability of phosphonic acid SAMs were investigated using the material and surface preparation commonly used to make ultra-thin stent struts-electropolished L605 Cobalt Chromium (CoCr) alloy. Methyl (-CH3) and carboxylic acid (-OOH) terminated phosphonic acid SAMs were coated on electropolished CoCr alloy using a combination of solution immersion and dip-evaporation cycle deposition methods. SAMs-coated CoCr alloy specimens were thoroughly characterized using contact angle goniometry, Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). These characterizations suggested that uniform and well-ordered monolayers were coated on the electropolished CoCr alloy. The long-term physiological stability of monolayers was investigated in tris-buffered saline (TBS) at 37 degrees C for up to 28 days. Contact angles, FTIR, XPS, and AFM suggested that both -CH3 and -COOH terminated phosphonic acid SAMs desorb from electropolished CoCr alloy surfaces in a biphasic manner. A significant desorption of -CH3 and -COOH terminated SAMs occurs within 1-3 days followed by a slower desorption for up to 28 days. Thus, there is a need to develop techniques that can improve the long-term stability of SAMs on electropolished CoCr alloy for stent and other biomedical applications. PMID- 21604364 TI - Optimizing gelling parameters of gellan gum for fibrocartilage tissue engineering. AB - Gellan gum is an attractive biomaterial for fibrocartilage tissue engineering applications because it is cell compatible, can be injected into a defect, and gels at body temperature. However, the gelling parameters of gellan gum have not yet been fully optimized. The aim of this study was to investigate the mechanics, degradation, gelling temperature, and viscosity of low acyl and low/high acyl gellan gum blends. Dynamic mechanical analysis showed that increased concentrations of low acyl gellan gum resulted in increased stiffness and the addition of high acyl gellan gum resulted in greatly decreased stiffness. Degradation studies showed that low acyl gellan gum was more stable than low/high acyl gellan gum blends. Gelling temperature studies showed that increased concentrations of low acyl gellan gum and CaCl2 increased gelling temperature and low acyl gellan gum concentrations below 2% (w/v) would be most suitable for cell encapsulation. Gellan gum blends were generally found to have a higher gelling temperature than low acyl gellan gum. Viscosity studies showed that increased concentrations of low acyl gellan gum increased viscosity. Our results suggest that 2% (w/v) low acyl gellan gum would have the most appropriate mechanics, degradation, and gelling temperature for use in fibrocartilage tissue engineering applications. PMID- 21604366 TI - Synthesis, self-assembly, and cytotoxicity of well-defined trimethylated chitosan O-poly(epsilon-caprolactone): effect of chitosan molecular weight. AB - Structurally well-defined trimethylated chitosan-O-poly(epsilon-caprolactone) (TMC-O-PCL) was synthesized under mild homogeneous conditions, using sodium dodecyl sulfate-dimethylated chitosan complex (SDC) as an organosoluble intermediate. The effect of chitosan molecular weight (MW) on the preparation, organosolubility, self-assembly, and cytotoxicity of the copolymers was investigated. The copolymers with low-MW chitosan backbone had improved solubility in common organic solvents. Spherical micelles with average diameter of 25-55 nm and uniform morphology were formed through self-assembly of TMC-O-PCL in pH 7.4 PBS. When trimethylation degree of the copolymers was above 44%, the micelles could remain stable in neutral aqueous media. The critical aggregation concentration of TMC-O-PCL slightly increased with a decrease in the MW of chitosan backbone. The cytotoxicity of the cationic micelles could be suppressed by increasing PCL grafting levels, reducing trimethylation degree, and MW of the chitosan backbone. PMID- 21604367 TI - Effects of N-acetylcysteine on TEGDMA- and HEMA-induced suppression of osteogenic differentiation of human osteosarcoma MG63 cells. AB - Triethyleneglycol dimethacrylate (TEGDMA) and 2-hydroxyethyl methacrylate (HEMA) are major resinous components of dental restorative materials and dentin bonding adhesives. Resin monomers are known to cause cytotoxicity in mammalian cells via oxidative stress and inhibit differentiation of dental pulp cells and osteoblasts. This study was aimed to investigate whether oxidative stress was involved in the inhibition of TEGDMA- and HEMA-induced differentiation. TEGDMA and HEMA reduced alkaline phosphatase (ALP) activity and the mRNA expression of the osteopontin (OPN) gene in MG63 cells at noncytotoxic concentrations. On the other hand, N-acetylcysteine (NAC) did not affect ALP activity at concentrations below 10 mM. Reduced ALP activity and OPN mRNA expression by TEGDMA were partially recovered via cotreatment with NAC. However, NAC did not exhibit significant effects in HEMA-treated cells. Glutathione (GSH) levels were also down-regulated by both TEGDMA and HEMA. The addition of NAC induced the partial recovery of GSH in cells treated with 0.5 mM TEGDMA. On the other hand, the levels of GSH in HEMA-treated cells were not affected by NAC. These results suggest that oxidative stress is involved in the suppression of differentiation by TEGDMA. Translocation of Nrf2 from the cytoplasm to the nucleus has been known to play a role in the suppression of osteogenic differentiation by oxidative stress. However, Nrf2 did not move into the nucleus in resin monomer-treated MG63 cells, suggesting the contribution of other signaling pathways to the suppressive effects of resin monomers. PMID- 21604368 TI - Development of an ionic liquid-based dispersive liquid-liquid micro-extraction method for the determination of phthalate esters in water samples. AB - Ionic liquid-based dispersive liquid-liquid micro-extraction (IL-DLLME) was coupled with high-performance liquid chromatography-ultraviolet (HPLC-UV) for the determination of four phthalate esters, including butyl benzyl phthalate, di-n butyl phthalate, dicyclohexyl phthalate and bis(2-ethylhexyl) phthalate in water samples. The mixture of ionic liquid (IL) and dispersive solvent was rapidly injected into 10 mL aqueous sample. Then, IL phase was separated by centrifugation and was determined by high-performance liquid chromatography ultraviolet. The factors influencing the extraction efficiency, such as type and volume of IL, disperse solvent, extraction time, centrifuging time and ionic strength, were investigated and optimized. Under the optimized conditions, the extraction recoveries by the proposed ionic liquid-based dispersive liquid-liquid micro-extraction for the four phthalates ranged from 83.0 to 91.7%. The relative standard deviations were between 7.8 and 15%. The limits of quantification for four phthalates were between 10.6 and 28.5 MUg/L. The proposed method was successfully applied for the analysis of PAEs in tap, lake and treated wastewater samples. PMID- 21604369 TI - Disposable pipette extraction for gas chromatographic determination of codeine, morphine, and 6-monoacetylmorphine in vitreous humor. AB - The availability of a sensitive and rapid analytical method for the determination of opiates, and other substances of forensic interest, in a variety of biological specimens is of utmost importance to forensic laboratories. Solid-phase extraction is very popular in the pre-treatment of forensic samples. Nevertheless, a new approach, disposable pipette extraction (DPX), is gaining increasing interest in sample preparation. DPX has already been applied to the analysis of drugs of abuse in common biological matrices, such as urine and blood, but has not yet been evaluated on alternative biological samples, such as vitreous humor. The objective of this study was to evaluate the applicability of DPX on the analysis of opiates in vitreous humor. The currently developed method is fast, reliable, and easy to perform. The sensitivity, precision, and accuracy are satisfactory. Recoveries obtained are within the range of 72-91%, whereas the sample volume of vitreous humor required is only 100 MUL. PMID- 21604370 TI - Macroporous monolithic supports for affinity chromatography. AB - In the early 1990s, three research groups simultaneously developed continuous macroporous rod-shaped polymeric systems to eliminate the problem of flow through the interparticle spaces generally presented by the chromatography columns that use particles as filler. The great advantage of those materials, forming a continuous phase rod, is to increase the mass transfer by convective transport, as the mobile phase is forced to go through all means of separation, in contrast to particulate media where the mobile phase flows through the interparticle spaces. Due to their special characteristics, the monolithic polymers are used as base-supports in different separation techniques, those chromatographic processes being the most important and, to a greater extent, those involving the separation of biomolecules as in the case of affinity chromatography. This mini-review reports the contributions of several groups to the development of macroporous monoliths and their modification by immobilization of specific ligands on the products for their application in affinity chromatography. PMID- 21604373 TI - Metaproteome analysis of sewage sludge from membrane bioreactors. AB - Microbial dynamics and enzymatic activities of activated sludge processes are not completely understood yet. A better understanding about the biology is indispensable for further process optimization. Since proteins play a key role as catalysts in sludge processes, a protocol for protein extraction and analysis by 2-D PAGE was established. It is based on phenol extraction of alkaline extracts and on a subsequent precipitation with ammonium sulphate. 2-D protein patterns obtained from different sludges collected from membrane bioreactors showed- besides common spots--significant differences. Selected proteins were identified with nano-HPLC-ESI-MS/MS. All membrane biological reactor (MBR) sludge samples investigated in this study contained elastase 3A, which implies that this human serine protease is a significant constituent of municipal wastewater. Although the identification of proteins from ammonia-oxidizing bacterium Nitrosomonas europaea was expected, the detection of a protein with homology to the marine bacterium Saprospira grandis in MBR1 was surprising. PMID- 21604374 TI - Structure and function of the symbiosis partners of the lung lichen (Lobaria pulmonaria L. Hoffm.) analyzed by metaproteomics. AB - Environmental proteomics, also referred to as metaproteomics, is an emerging technology to study the structure and function of microbial communities. Here, we applied semi-quantitative label-free proteomics using one-dimensional gel electrophoresis combined with LC-MS/MS and normalized spectral counting together with fluorescence in situ hybridization and confocal laser scanning microscopy to characterize the metaproteome of the lung lichen symbiosis Lobaria pulmonaria. In addition to the myco- and photobiont, L. pulmonaria harbors proteins from a highly diverse prokaryotic community, which is dominated by Proteobacteria and including also Archaea. While fungal proteins are most dominant (75.4% of all assigned spectra), about the same amount of spectra were assigned to prokaryotic proteins (10%) and to the green algal photobiont (9%). While the latter proteins were found to be mainly associated with energy and carbohydrate metabolism, a major proportion of fungal and bacterial proteins appeared to be involved in PTMs and protein turnover and other diverse functions. PMID- 21604375 TI - Generic, anthracene-based hydrogel crosslinkers for photo-controllable drug delivery. AB - Light-responsive polymers with controllable, reversible crosslink mechanisms have the potential to create unique biomaterials with stimulus-controlled swelling, degradation and diffusion properties useful in tissue engineering and drug delivery applications. Generic photodimerizing polyethylene glycol-anthracene macromolecules that may be grafted to various polymers to effectively control their crosslinking via a photodimerization mechanism have been developed. These generic crosslinkers were shown to effectively introduce photoresponsive properties into hyaluronate and alginate as model hydrophilic polymers. In vitro testing using human corneal epithelial cells was used to demonstrate cytocompatibility of the resulting photogels. The effective crosslinking density of the photogels could be increased resulting in a decrease in the release rate of small and large molecules from the photogels following exposure to 365 nm light. This tuneable crosslinking has the potential to manipulate the delivery rates of therapeutics resulting in control over treatment profiles and may lend itself to various applications, which may benefit from light induced changes in crosslinking. PMID- 21604376 TI - Direct dehydrative pyridylthio-glycosidation of unprotected sugars in aqueous media using 2-chloro-1,3-dimethylimidazolinium chloride as a condensing agent. AB - Various 2-pyridyl 1-thioglycosides, important synthetic intermediates and enzyme inhibitors in sugar chemistry, have been synthesized directly from the corresponding unprotected sugars in good yields by using 2-chloro-1,3 dimethylimidazolinium chloride (DMC) as dehydrative condensing agent. The reaction proceeds in aqueous media without using any protecting groups, affording 2-pyridyl 1-thioglycosides with beta-configuration selectively. According to the present method, not only unprotected monosaccharides but also unprotected oligosaccharides, such as cello-oligosaccharides, chito-oligo-saccharides, malto oligosaccharides, and glucosamine oligomers, can be converted to the corresponding 2-pyridylthio derivatives, which would greatly expand the utility of aryl 1-thioglycosides in sugar chemistry. PMID- 21604377 TI - Piezofluorochromic and aggregation-induced-emission compounds containing triphenylethylene and tetraphenylethylene moieties. AB - New fluorescent compounds containing triphenylethylene and tetraphenylethylene moieties were synthesized, and their piezofluorochromic and aggregation-induced emission behaviors were investigated. The results show that all compounds exhibit aggregation-induced emission characteristics and only the crystalline compound possesses piezofluorochromic properties. The color, emission spectra, and morphological structures of the one piezofluorochromic compound exhibit reversibility upon grinding and annealing (or fuming) treatments. The piezofluorochromic behaviors are caused by a change between different modes of solid state molecular packing under external pressure. The single crystal X-ray diffraction analysis reveals that the twisted conformation of the aggregation induced emission compound leads to the formation of metastable crystal lattice with cavity which is readily destroyed under external pressure. A possible mechanism of piezofluorochromic phenomenon has been proposed. PMID- 21604378 TI - Microchannel-patterned and heparin micro-contact-printed biodegradable composite membranes for tissue-engineering applications. AB - Microchannel-patterned starch-poly(capro-lactone)/hydydroxyapatite (SPCL-HA) and starch-poly(lactic acid) (SPLA) composite membranes were produced for use as a laminated tissue-engineering scaffold that incorporates both physical and biochemical patterns. For this purpose, SPCL (30% starch) blended with inorganic hydroxyl apatite (50%) and SPLA (50% starch) membranes were made with compressive moulding. Consequently, the microchannel structures (width 102 um, 174 um intervals) were developed on the composite membranes by means of micro-patterned metal mould(s) and hydraulic pressing. An elastomer poly(dimetylsiloxane) stamp was used to transfer heparin as a biochemical cue over the microchannel surfaces by micro-contact printing (uCP). Toluidine blue staining of developed capillaries and heparin uCP-coated membranes showed that heparin was transferred predominantly over the microchannel surfaces. Fibroblast cell culture over the microchannel-formed and heparin uCP-modified SPCL-HA and SPLA membranes showed distinct growth patterns. In contrast to the uniform cell layer formed on unmodified microchannels, the cells were bridging across the grooves of heparin printed microchannels. At extended culture periods, the heparin-printed microchannels were covered with a layer of fibroblast cells without cellular ingrowths inside. This study indicated that the topographical pattern could induce an organization of fibroblasts only with the biochemical cue and the cells' functions can be controlled spatially over the microchannels by using both cues. PMID- 21604379 TI - Optimization of electrical stimulation parameters for cardiac tissue engineering. AB - In vitro application of pulsatile electrical stimulation to neonatal rat cardiomyocytes cultured on polymer scaffolds has been shown to improve the functional assembly of cells into contractile engineered cardiac tissues. However, to date, the conditions of electrical stimulation have not been optimized. We have systematically varied the electrode material, amplitude and frequency of stimulation to determine the conditions that are optimal for cardiac tissue engineering. Carbon electrodes, exhibiting the highest charge-injection capacity and producing cardiac tissues with the best structural and contractile properties, were thus used in tissue engineering studies. Engineered cardiac tissues stimulated at 3 V/cm amplitude and 3 Hz frequency had the highest tissue density, the highest concentrations of cardiac troponin-I and connexin-43 and the best-developed contractile behaviour. These findings contribute to defining bioreactor design specifications and electrical stimulation regime for cardiac tissue engineering. PMID- 21604380 TI - Rapid vascularization of starch-poly(caprolactone) in vivo by outgrowth endothelial cells in co-culture with primary osteoblasts. AB - The successful integration of in vitro-generated tissues is dependent on adequate vascularization in vivo. Human outgrowth endothelial cells (OECs) isolated from the mononuclear cell fraction of peripheral blood represent a potent population of circulating endothelial progenitors that could provide a cell source for rapid anastomosis and scaffold vascularization. Our previous work with these cells in co-culture with primary human osteoblasts has demonstrated their potential to form perfused vascular structures within a starch-poly(caprolactone) biomaterial in vivo. In the present study, we demonstrate the ability of OECs to form perfused vascular structures as early as 48 h following subcutaneous implantation of the biomaterial in vivo. The number of OEC-derived vessels increased throughout the study, an effect that was independent of the OEC donor. This finding of rapid and thorough OEC-mediated scaffold vascularization demonstrates the great potential for OEC-based strategies to promote vascularization in tissue engineering. OECs have the potential to contribute to host-derived scaffold vascularization, and formed vascular structures at a similar density as those arising from the host. Additionally, immunohistochemical evidence demonstrated the close interaction between OECs and the co-cultured osteoblasts. In addition to the known paracrine activity osteoblasts have in modulating angiogenesis of co cultured OECs, we demonstrate the potential of osteoblasts to provide additional structural support for OEC-derived vessels, perhaps acting in a pericyte-like role. PMID- 21604381 TI - Differential response of cartilage oligomeric matrix protein (COMP) to morphogens of bone morphogenetic protein/transforming growth factor-beta family in the surface, middle and deep zones of articular cartilage. AB - Cartilage oligomeric matrix protein (COMP) is a prominent non-collagenous component of the extracellular matrix (ECM) in articular cartilage. The regulation of COMP synthesis and secretion is critical for the understanding of cartilage homeostasis in health and disease. We therefore investigated the role of bone morphogenetic protein/transforming growth factor-beta (BMP/TGFbeta) superfamily members on COMP. Articular chondrocytes were isolated from three distinct zones (surface, middle and deep) and cultured as monolayers in serum free chemically defined medium. Protein levels of COMP were determined in the medium by enzyme-linked immunosorbent assay. The mRNA expression was determined by quantitative real-time reverse-transcription polymerase chain reaction (RT PCR). TGFbeta1 significantly stimulated the expression of COMP at the mRNA and protein levels in the superficial zone in a time-dependent manner. An unexpected discovery was that surface chondrocytes were more responsive to TGFbeta isoforms than those in the deep layer. However, BMP-7 and growth differentiation factor-5 (GDF-5) also upregulate COMP expression; the effects were not as potent as those of TGFbeta1. Activins A, B and AB demonstrated no effects on COMP in any of the zones. In conclusion, COMP synthesis is differentially regulated by TGFbeta1 in the surface and middle zones of bovine articular cartilage. PMID- 21604382 TI - Gellan gum-based hydrogels for intervertebral disc tissue-engineering applications. AB - Intervertebral disc (IVD) degeneration is a challenging clinical problem that urgently demands viable nucleus pulposus (NP) implant materials. The best suited biomaterial for NP regeneration has yet to be identified, but it is believed that biodegradable hydrogel-based materials are promising candidates. In this work, we have developed ionic- and photo-crosslinked methacrylated gellan gum (GG-MA) hydrogels to be used in acellular and cellular tissue-engineering strategies for the regeneration of IVDs. The physicochemical properties of the developed hydrogels were investigated by Fourier-transform infrared spectroscopy, (1) H nuclear magnetic resonance and differential scanning calorimetry. The swelling ability and degradation rate of hydrogels were also analysed in phosphate buffered saline solution at physiological pH for a period of 30 days. Additionally, the morphology and mechanical properties of the hydrogels were assessed under a scanning electron microscope and dynamic compression, respectively. An in vitro study was carried out to screen possible cytotoxicity of the gellan gum-based hydrogels by culturing rat lung fibroblasts (L929 cells) with hydrogel leachables up to 7 days. The results demonstrated that gellan gum was successfully methacrylated. We observed that the produced GG-MA hydrogels possess improved mechanical properties and lower water uptake ability and degradation rate as compared to gellan gum. This work also revealed that GG-MA hydrogels are non-cytotoxic in vitro, thus being promising biomaterials to be used in IVD tissue-engineering strategies. PMID- 21604383 TI - Bacterial cellulose modified with xyloglucan bearing the adhesion peptide RGD promotes endothelial cell adhesion and metabolism--a promising modification for vascular grafts. AB - Today, biomaterials such as polytetrafluorethylene (ePTFE) are used clinically as prosthetic grafts for vascular surgery of large vessels (>5 mm). In small diameter vessels, however, their performance is poor due to early thrombosis. Bacterial-derived cellulose (BC) is a new promising material as a replacement for blood vessels. This material is highly biocompatible in vivo but shows poor cell adhesion. In the native blood vessel, the endothelium creates a smooth non thrombogenic surface. In order to sustain cell adhesion, BC has to be modified. With a novel xyloglucan (XG) glycoconjugate method, it is possible to introduce the cell adhesion peptide RGD (Arg-Gly-Asp) onto bacterial cellulose. The advantage of the XG-technique is that it is an easy one-step procedure carried out in water and it does not weaken or alter the fiber structure of the hydrogel. In this study, BC was modified with XG and XGRGD to asses primary human vascular endothelial cell adhesion, proliferation, and metabolism as compared with unmodified BC. This XG-RGD-modification significantly increased cell adhesion and the metabolism of seeded primary endothelial cells as compared with unmodified BC whereas the proliferation rate was affected only to some extent. The introduction of an RGD-peptide to the BC surface further resulted in enhanced cell spreading with more pronounced stress fiber formation and mature phenotype. This makes BC together with the XG-method a promising material for synthetic grafts in vascular surgery and cardiovascular research. PMID- 21604384 TI - Bone marrow-derived mesenchymal stem cells co-cultured with pancreatic islets display beta cell plasticity. AB - The direct co-culturing effect of rat bone-marrow-derived mesenchymal stem cells (rBM-MSCs) on the pancreatic-islets (PIs) was studied to obtain functional islet cells. MSCs were isolated from rat bone marrow and cultivated under standard conditions. Following their characterization, the rBM-MSCs were directly (with cell-islet contact) co-cultured with recovered PIs together with the single cell cultures of those cell cultures as a control. The effect of direct co-cultures of rBM-MSCs with the PIs of normal rats was investigated using immunophenotypical and functional methods. The change in the amount of insulin secretion was evaluated as an indicator for differentiation of rBM-MSCs. One approache for in vitro differentiation to achieve reprogramming for differentiation into suitable cell types by changing the microenvironment of the cells to provide signals that might activate metabolic pathways is to use co-cultures with the microenvironment of the specific cells of the desired cell type, tissue/organ extracts, extracellular matrix compounds or biologically absorbable materials. Differentiated rBM-MSCs were found to be immunopositive for the specific insulin producing cell marker, insulin, but not in undifferentiated rBM-MSCs. The functionality tests by ELISA confirmed that insulin secretion of co-cultured MSCs with islets was higher than that of islets. These evidences indicated that PIs could be regarded as critical components of the stem cell niche, such that MSCs can be differentiated into insulin-producing cells (IPCs). Moreover, direct cell to-cell contact might provide additional and independent support. This approach would circumvent the need for PI-stem cell co-culture and could potentially facilitate the production of functional IPCs for future clinical applications. PMID- 21604385 TI - Evaluation of methods for the construction of collagenous scaffolds with a radial pore structure for tissue engineering. AB - Type I collagen is used widely as a biomaterial. The structure of collagenous biomaterials, including pore sizes and general architecture, can be varied by a number of techniques. In this study, we developed a method to construct flat fibrillar type I collagen scaffolds, 6 cm in diameter and with a radially orientated pore structure, by the use of directional freezing. Different methodologies were tested, the optimal one being freezing of a collagen suspension inside-out, using a centrally positioned liquid nitrogen-cooled tube. Pore sizes could be varied by the use of different tube materials. Use of aluminium tubes resulted in radial scaffolds with a pore size of 20-30 um, whereas use of stainless steel produced radial scaffolds with 70-100 um pore sizes. Brass- and copper-based tubes produced scaffolds with less homogeneous radial pores, pore sizes being 90-100 and 50-80 um, respectively. Fibreglass tubes gave even less uniformity (pore size 100-150 um). Scaffolds were free of cracks, except in case of aluminium. Scaffolds with a radial inner structure may be especially suitable for tissue engineering of organs with a radial scaffold structure, such as the diaphragm. PMID- 21604386 TI - Transforming growth factor-beta3 regulates assembly of a non-fibrotic matrix in a 3D corneal model. AB - Corneal tissue engineering has attracted the attention of many researchers over the years, in part due to the cornea's avascularity and relatively straightforward structure. However, the highly organized and structured nature of this optically clear tissue has presented a great challenge. We have previously developed a model in which human corneal fibroblasts (HCFs) are stimulated by a stable vitamin C (VitC) derivative to self-assemble an extracellular matrix (ECM). Addition of TGFbeta1 enhanced the assembly of ECM; however, it was accompanied by the upregulation of specific fibrotic markers. In this study, we tested the effects of all three TGFbeta isoforms (-beta1, -beta2 and -beta3) on ECM production, as well as expression of fibrotic markers. HCFs were grown in four media conditions for 4 weeks: control, VitC only; T1, VitC + TGFbeta1; T2, VitC + TGFbeta2; and T3, VitC + TGFbeta3. The cultures were analysed with western blots, TEM and indirect immunofluorescence (IF). Compared to controls, all TGFbeta isoforms stimulated matrix production by about three-fold. IF showed the presence of type III collagen and smooth muscle actin (SMA) in T1 and T2; however, T3 showed little to no expression. In western blots, T3 stimulated a lower type III:type I collagen ratio when compared to the other conditions. In addition, TEM indicated that T3 stimulated a higher level of matrix alignment and organization. HCFs stimulated by VitC and TGFbeta3 appear to generate a matrix that mimics the normal adult or developing human cornea, whereas TGF-beta1 and beta2 drive the constructs towards a more fibrotic path. PMID- 21604388 TI - [Sialic acids and O-acetyl groups as markers of biological activity of microbial polysaccharides in plague and cholera agents]. AB - AIM: To determine sialic acids and O-acetyl groups content in Yersinia pestis and Vibrio cholerae antigens in order to establish their association with biological activity. MATERIALS AND METHODS: The following antigens of Y. pestis EV NIIEG strain--capsular antigen (F1), major somatic antigen (MSA), lipopolysaccharide (LPS), Pla-protease, allergen pestin PP--as well as O-antigens (O-AG) of V. cholerae serogroups O1 and O139 were used in the study. Sialic acids were identified by the thiobarbituric method, and O-acetyl groups--according to Alicino. Specific polysaccharides in the MSA and O-antigens were detected by the immunodiffusion assay. RESULTS: Sialic acids were found in LPS, Pla-protease, allergen pestin PP, and all cholera O-AG; their absence was demonstrated in MSA and F1. O-acetyl groups were identified in cholera O-AG of both studied serogroups as well as in LPS, Pla-protease, MSA and pestin PP of Y. pestis. Tendency to correlation between O-acetyl groups content in MSA and serological activity titer was observed. CONCLUSION: Sialic acids and O-acetyl groups identified in carbohydrate-containing antigens of Y. pestis and V. cholerae could be characterized as reaction-active markers of pathogenetic mechanisms of cholera and plague infections as well as immunochemical activity of microbial polysaccharides. PMID- 21604389 TI - [Evaluation of toxin producing abilities of non-O1/non-O139 serogroup Vibrio cholerae isolated from humans]. AB - AIM: Determination of non-O1/non-O139 Vibrio cholerae toxin (CT) gene expression by using EIA, and biological effect of non-O1/non-O139 V. cholerae supernatant on cell cultures evaluation. MATERIALS AND METHODS: 39 V. cholerae strains from various serological groups were studied. Hemolytic activity of strains was determined by using Greig test, and cholera toxin production--in GM1-EIA and in continuous cell lines by registering cytotonic, cytotoxic and proteolitic effect. RESULTS: GM1-EIA method does not detect CT production in 29 museum strains of non O1/non-O139 V. cholerae in vitro. CT was detected only in 1 non-O1/non-O139 V. cholerae strain supernatant with OD = 0.577 that is substantially lower than in O1 V. cholerae strains (OD = 2.176). In cell cultures non-O1/non-O139 V. cholerae supernatants diluted to 1:100 caused elongation only in single cells. CONCLUSION: Cytological model is a more sensitive technique to evaluate toxin producing abilities of non-O1/non-O139 V. cholerae strains and is appropriate for use. PMID- 21604390 TI - [Influence of pertussis preparations on primary culture of peritoneal macrophages and continuous human monocyte-like cell line U937]. AB - AIM: Selection of optimal tests for pertussis formulations (PF) cytotoxicity evaluation using mononuclear phagocytes model cells. MATERIALS AND METHODS: A cellular pertussis vaccine, pertussis dialysated antigen and pertussis dialysated antigen fraction 2 cytotoxicity evaluation was performed by using primary mice peritoneal macrophage culture and human monocyte-like cell line U937. RESULTS: Mononuclear phagocytes are a simple, sensitive and easily accessible model for PF cytotoxicity evaluation. The results of analysis are available within 6 hours. CONCLUSION: This model may be recommended as screening test for detection of PF toxicity. PMID- 21604392 TI - [Organizing the supervision over the turnover of nanomaterials presenting a potential hazard to human health]. AB - Nanoindustry encompasses very different branches of industry today. It should be noted that these are precisely the investigators who deal with researches and developments of nanomaterials will be to the largest measure exposed and hence the likelihood of the potential harm to their health is greatest. To elaborate the special regulations and programs, normative documents and guidelines designed to afford safety and health protection of the employees at work, which should consider the specific characteristics of nanotechnologies. Since 2007, work has proceeded on the safety evaluation of nanoparticles and nanomaterials. Nanotechnology as a key priority in the foreseeable future poses a number of problems facing hygiene science to develop hygienic safety criteria for the production, usage, utilization and storage of various nanomaterials and to elaborate procedures for determination of nanoparticles in different media. Russia will be able to rapidly progress in solving the safety problems in emerging nanoindustry and to minimize human health and environmental risks associated with the manufacture and use of nanoproducts. PMID- 21604391 TI - [Bacterial proteases and bacterial resistance against human innate immunity factors]. AB - The molecular and cell-mediated mechanisms that are developed by certain opportunistic and pathogenic bacteria and were obtained over the course of evolution to preserve resistance against principal components of human body innate immunity are summarized. PMID- 21604387 TI - My what big eyes you have: how the Drosophila retina grows. AB - The compound eye of the fruit fly, Drosophila melanogaster, has for decades been used extensively to study a number of critical developmental processes including tissue development, pattern formation, cell fate specification, and planar cell polarity. To a lesser degree it has been used to examine the cell cycle and tissue proliferation. Discovering the mechanisms that balance tissue growth and cell death in developing epithelia has traditionally been the realm of those using the wing disc. However, over the last decade a series of observations has demonstrated that the eye is a suitable and maybe even preferable tissue for studying tissue growth. This review will focus on how growth of the retina is controlled by the genes and pathways that govern the specification of tissue fate, the division of the epithelium into dorsal-ventral compartments, the initiation, and progression of the morphogenetic furrow and the second mitotic wave. PMID- 21604394 TI - [Actual use of milk and its products and estimation of the degree of their contamination]. AB - The actual use of milk and its products was studied in the population of the Fergana Valley and the daily intake of heavy metals, pesticides, nitrates, antibiotics, and other foreign substances was hygienically evaluated. Guidelines were developed to set up critical control points for the hazard analysis of production factors and the sale and storage of dairy products, which were approved by the Ministry of Health of the Republic of Uzbekistan. PMID- 21604393 TI - [The immunometabolic status in persons exposed to technogenous factors of industrial production]. AB - The immune system and lymphocyte activity of HADP-dependent dehydrogenases were studied in the patients living in the high incidence areas of Krasnoyarsk. The enhanced activity of cellular immunity was found to show up in the presence of considerable impaired lymphocyte metabolic processes, the change of the rate of which depended on the type of environmental pollution. PMID- 21604395 TI - [Scientific and methodological rationale for the pathomorphism of Lamblia infection in children during chemical contamination of the biosphere]. AB - The paper analyzes the clinical and laboratory features of Lamblia infection in children living under long-term low-dose chemical load. The scientific search methodology comprised the meticulous examination of the patients randomized by the presence or absence of protozoonosis and the statistical processing and expert analysis of the results. The comprehensive approach could define the main signs of the pathomorphism of lambliosis in the areas with high anthropogenic loads and identify immunological disorders, intoxication, and hepatobiliary dysfunctions. The impact of environmentally induced chemical contamination of the biosphere on the natural history of protozoonosis should be borne in mind when evaluating the biological hazard and risk of environmental biological factors on the population health and when scheduling and implementing hygienic and sanitary and-epidemiological measures to prevent lambliosis in the high anthropogenic load areas. PMID- 21604396 TI - [Comparative characteristics of the physiometric parameters of schoolchildren' physical development]. AB - The physiometric parameters (exercise performance, muscle strength, and lung capacity) were monitored in schoolchildren over the 15-year period. There has been a reduction in exercise performance, muscle strength and an increase in lung capacity in the past 15 years, which the pediatricians should take into account to detect physical development abnormalities in schoolchildren. PMID- 21604397 TI - [Nanotechnologies: prediction of the possible negative effect of insoluble nanoparticles on the body]. AB - In addition to the devices given in the guidelines of the Russian Inspectorate for the Protection of Consumer Rights and Human Welfare "Evaluation of the Safety of Nanomaterials" (2007) to characterize the biological activity of nanoparticles, one should use a chemiluminometer, a cheaper and easy-to-use device that gives unique information on the activation of the nonspecific bactericidal system of phagocytes in contact with nanoparticles. According to the nature of activation, all nanomaterials can be divided into 5 classes of potential hazard and carcinogenicity. PMID- 21604398 TI - [Substantiation of the markers of senescence of the heart and vessels to evaluate the long-term consequences of chemical exposure]. AB - The physiological, biochemical, and morphometric parameters of the cardiovascular system were studied in rats of different age. There was a significant association of its physiological, biochemical, and morphometric parameters with animal age. The biological age of an animal was shown to be determined from the value of a parameter. The results form a basis for the accelerated standardization of chemicals having a gerontogenic effect on the cardiovascular system. PMID- 21604399 TI - [Alzheimer's: new light shed on genetic factors]. PMID- 21604400 TI - [Not Available]. PMID- 21604401 TI - [Not Available]. PMID- 21604403 TI - [Not Available]. PMID- 21604402 TI - [Not Available]. PMID- 21604404 TI - Reform the hard way. Healthcare providers say budget committee plan's would dismantle Medicare, Medicaid. AB - The House Budget Committee's 2012 budget plan proposes massive changes to Medicare and Medicaid. New Medicare beneficiaries starting in 2022 would choose from a list of health plans while the proposal for the Medicaid program would convert federal dollars to block grants for states. Sister Carol Keenan, left, of the CHA, says, "Clearly, going to vouchers doesn't take into consideration the best use of the Medicare dollar or the Medicare population". PMID- 21604405 TI - Data debate. HAC numbers on website draw criticism. PMID- 21604406 TI - 'The more you look...' Adverse-events tools may underestimate numbers. PMID- 21604407 TI - Testing ACOs. Medicare seeks trial run with physician group. PMID- 21604409 TI - Exit interview. Former ONC head Blumenthal reflects on accomplishments, plans. PMID- 21604408 TI - 'Good start' on ACO model. PMID- 21604410 TI - Miles to go. Proposed ACO regs are lacking on clinical integration, increase risks and costs. PMID- 21604411 TI - Nurses as the nexus. For more hospitals and health systems, a clinical background has become the preferred track to the top jobs, including CEO. PMID- 21604412 TI - Largest PAC donations from groups representing health professionals. Ranked by total political action committee contributions to federal candidates for 2010 election cycle. PMID- 21604413 TI - Unsatisfactory. HHS' new payment system for hospitals rewards quality, but not everyone likes the final rules. AB - The final rule for value-based purchasing for hospital services is in, and it contains a few things hospitals didn't want. But some are praising the effort. "We don't have many worries, since we've been working on the core elements of these for some time," says Dr. Charles O'Brien, left, of the Sanford University of South Dakota Medical Center. PMID- 21604414 TI - Revamp of IRS rules urged. Not-for-profit hospitals want clear, usable guidance. PMID- 21604415 TI - RAC appeals data sought. 85% overturned in favor of providers, AHA says. PMID- 21604416 TI - Community hits back. Defends admissions policies in face of Tenet's suit. PMID- 21604417 TI - Ascension looks to Chicago. Alexian deal would be area's latest consolidation. PMID- 21604418 TI - Quality reporting expands. Inpatient rehab, hospice are added to program. PMID- 21604419 TI - Artificial intelligence. J&J looks to expand device holdings with Synthes. PMID- 21604420 TI - 'In the hands of providers'. Docs: Cost reduction required to prevent cuts. PMID- 21604421 TI - Baby proofing. Ascension works on obstetrics quality, safety. PMID- 21604422 TI - Largest healthcare real estate investment trusts. Publicly traded healthcare REITs ranked by market capitalization, as of Feb. 28. PMID- 21604423 TI - Brain health linked to heart health. What's good for your heart may also be good for your brain--and prevent Alzheimer's disease. PMID- 21604425 TI - Exercise benefits arthritic knees. Patients with knee OA are encouraged to be as active as possible to enhance mobility. PMID- 21604424 TI - BBTI: successful short-term treatment for chronic insomnia. Counting sheep to fall or stay asleep now may be a thing of the past. PMID- 21604426 TI - Metabolic syndrome may raise memory loss risk. Now, more evidence on the connection between cardiovascular risk factors and cognitive function. PMID- 21604427 TI - New gene mutation implicated in renal cancer. Study findings could shed light on the intricate biology of kidney cancer. PMID- 21604428 TI - I am facing knee replacement surgery due to severe arthritis in both knees. Is it possible to have both replaced at the same time, or is it better to have them done separately? PMID- 21604429 TI - [Neurogenic and septic inductions of synthesis of peptide antibiotics in larvae of Calliphora vicina R.-D. (Diptera: Calliphoridae)]. AB - Synthesis of antimicrobial peptides in diapausing larvae Calliphora vicina can be induced by two different pathways. One pathway is well known in insects and includes recognition of microbial particles by the pattern-recognizing receptors. The other pathway includes perception and transduction of stress signal to immunocompetent cells by neuroendocrine system. This phenomenon consists in stimulation of synthesis of defensins, cecropins, and diptericins under effect of chromic stimulation of mechanoreceptors with ligature applied on the larva head end. Formation of immune response in brain is established to need less than 30 s, after which isolation of the neuroendocrine complex does not eliminate activation of immune response As judging from rate of the neurogenic induction, transduction of the stimulating signal from brain to the immune system cells can be connected with release into hemolymph of biogenic amines or other neurohormones stored preliminarily in the neurohemal organ. The nature of this inductor at present remains unknown, as analysis of role of octopamine, dopamine, and adipokynetic hormone did not reveal stimulating effect on synthesis of bactericidal peptides. Physiological mechanism of this phenomenon is not finally understood, its key links seem to be CNS, hormonal factor of cardial bodies, and system of antimicrobial peptides. Synthesis of antimicrobial peptides is directly regulated by the neuroendocrine system that can produce both stimulating and stress action by reminding in this aspect the known immunoneuroendocrine interrelations in vertebrates. The existence of similar integrating mechanisms in such polar animal kingdom groups which are insects and vertebrates indicate that they are more ancient than this was considered earlier. PMID- 21604430 TI - [Advances in hepatic pathology]. PMID- 21604432 TI - [How to improve the histopathological diagnosis of hepatocellular carcinoma in daily practice?]. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers in the world with an increasing incidence. Recently, an East-West consensus on the histopathologic criteria for the diagnosis of high-grade dysplastic nodules and early hepatocellular carcinoma was published. In addition to classical morphological criteria such as nucleocytoplasmic ratio, thickness of cell plates, mitotic index, and architectural disturbance, a new one--the stromal invasion- was recognized as a crucial criterion for the diagnosis of early HCC. Immunohistochemical detection of glypican--3 was shown as a specific marker for HCC that can be used to distinguish between the benign hepatocellular lesions and HCC. PMID- 21604433 TI - [Viral hepatitis at the beginning of the 21st century--value of liver biopsy in the context of development of new non-invasive diagnostic methods and in relation to the modern therapy of chronic viral hepatitis]. AB - The rapid progress in the development of virostatic agents over the past 15 years has changed chronic viral hepatitis from causally incurable diseases to diseases that may be treated or even cured. But, the treatment is a long-term process and it remains very expensive. Therefore, it is important to establish the correct diagnosis with the exact stratification of the disease (in terms of serological findings, regarding the activity of the inflammation and alterations of liver parenchyma) to determine the appropriate treatment schedule. The text includes an overview of histopathological classifications of chronic hepatitis from the clinical perspective; we discuss the contribution of liver biopsy in the era of the development of non-invasive diagnostic methods for determining the degree of alteration of liver parenchyma (elastography in particular). Furthermore, the principles of modern therapy of the most common chronic viral hepatitis (i.e. B and C) are summarized with emphasis on situations where the histopathological examination of liver tissue plays a role in the indication or affects the treatment schedule. PMID- 21604434 TI - [Prague Hepatology Meeting 2010--hepatopathology news]. AB - This review summarizes the highlights in hepatopathology presented during the Prague Hepatology Meeting 2010. Gut flora (microbiome) and intestinal permeability seems to play an important role during progression into liver cirrhosis in patients with non-alcoholic steatohepatitis. Molecular diagnosis allows the distinction of several types of hepatocellular adenoma with different risks of malignant progression. Experimental hepatology is currently focused on the role of epigenetics during pathogenesis of alcoholic liver disease. The most studied topic in viral hepatitis C is the mechanisms of resistance to antiviral treatment. Pathogenesis of liver fibrosis and the role of keratins in the pathology of liver disease are areas of scientific interest as well. PMID- 21604435 TI - [What is your diagnosis?]. PMID- 21604436 TI - [Fibrosing cholestatic hepatitis--disease not only of transplanted patients. A report of eight cases]. AB - Fibrosing cholestatic hepatitis (FCH) is a rapidly progressive, sometimes fatal form of hepatitis B or C in patients who are under immunosuppressive treatment. This condition was originally described in hepatitis B virus-infected recipients after a liver transplantation. It is characterized clinically by cholestatic hepatic dysfunction, and pathologically by marked hepatocyte swelling, cholestasis, periportal peritrabecular fibrosis, and only mild inflammation. Here we present 8 patients with hepatitis B and C related FCH. Three patients developed FCH after liver transplantation, two of them died due to hepatic failure. One recipient of a kidney/pancreas transplant developed "de novo" hepatitis C with features of FCH. He underwent antiviral treatment and survived with good liver function, unfortunately both of his grafts failed. Four patients suffered from a reactivation of their respective hepatitis B infections after chemotherapy treated hematological malignancy. Three of them needed an urgent liver transplantation and survived with good liver function and with a remission of their hematological diseases. The last patient died due to liver failure. Although FCH is a rare variant of viral hepatitis, it should be emphasized that prompt diagnosis is important for the management of patients. PMID- 21604437 TI - [Histological registry of mammary carcinomas]. PMID- 21604438 TI - [Pathology in Ostrava in changing times]. PMID- 21604439 TI - [The origin, distribution and relocability of supravital hemorrhages]. AB - The hemorrhage as a result of intravital bleeding is considered, from forensic point of view, as important sign of vital reaction of injury. However, in special cases it must be accepted that hemorrhage occurred after the death. The formation of supravital changes is evident, e.g., in organ donors whose blood circulation and pulmonary ventilation is kept after the brain death. The post-mortem origin of hemorrhages can also be seen in donors of eyeballs after enucleation made before the autopsy at Institute of Forensic Medicine and Toxicology. These hemorrhages are manifested after several hours when eyeballs were removed. Moreover, we observed the origin of hemorrhage in orbit which was caused nor by intravital bleeding neither by direct force. Its origin could not be explained nothing but postmortem propagation of the hemorrhage from the fracture of anterior fossa of the scull base. We did not find information about postmortem origin or relocation of hemorrhage of such extent in the literature. In the frame of knowledge about supravital reaction, this finding is of general importance with forensic impact. The documentation from the scene of death allowed correcting the appreciation of the mechanism of injury and traumatic process from the point of view of foreign culpability which should be considered in such case (e.g., a blow to the orbit with following fall under passing subway train). PMID- 21604440 TI - [Homicide, suicide or fatal accident?]. AB - A forensic explanation of womandrinker's death is presented in the article. Exsanguination from multiple cut wounds was cause of death. Origin of wounds was unable to explain due to its atypical character and localisation on body surface. Only a subsequent exact allocation of wounding object made clear biomechanical aspects of wounds. A hard ethanol alteration of psychical, senzorical et motorical functions with strong posttraumatic et toxometabolic changes of the body took share on mechanism of death. PMID- 21604441 TI - [Breath alcohol analysis]. AB - Alcohol in drivers remains a major threat to traffic safety. Forensic breath alcohol measurement remains a prominent tool for on-site detection of the alcohol impaired drivers thoughout Europe, North America, and Australia (Gullberg, 2005). Despite significant advancements in the technology of detection devices, many challenges still remain, seen from the medical and legal aspects in particular. PMID- 21604442 TI - [Effect of soft tissue crush injury on tensions of thoracic aortic rings in rats]. AB - OBJECTIVE: To observe the effect of soft tissue crush injury on the tensions of thoracic aortic rings (TARs) in rats and to investigate the potential roles of nitric oxide in the change of the tensions. METHODS: Thirty adult SD rats were randomly divided into control group and crush injury (8 h and 16 h after injury) groups. Two kinds of TARs (one with endothelium and the other without endothelium) in vitro were prepared. In the TARs with endothelium, the tensions induced by phenylephrine (PE), acetylcholine (Ach), calcium ionophore A23187 and angiotensin II (AngI) were measured by the vascular tension detective technique. Then the TARs with endothelium were preincubated with nitric oxide synthase inhibitor N-nitro-L-arginine (L-NNA) for 20 minutes, the tensions induced by PE and Ang II were measured again. In the TARs without endothelium, the tensions induced by PE and Ang II were measured by the same method. RESULTS: In the TARs with endothelium, the tension of relaxation induced by cumulative doses of Ach and A23187 decreased significantly in 8 h and 16h groups. The tension of contraction induced by cumulative doses of PE and Ang II also decreased significantly (P<0.05). The tension of contraction increased after the preincubation with L-NNA. In the TARs without endothelium, the tension of contraction induced by PE and Ang II increased comparing to that of TARs with endothelium. CONCLUSION: The soft tissue crush injury can influence the tensions of TARs in rats and the vascular-derived NO can mediate the effects. PMID- 21604443 TI - [The expression of VCAM-1 in organs of rats died of anaphylactic shock]. AB - OBJECTIVE: To investigate the effect and expression of the vascular cell adhesion molecule-1 (VCAM-1) in organs of rats died of anaphylactic shock. METHODS: The models of anaphylactic shock in rats were made and the immunohistochemistry of SABC was used to detect as follows: (1) The expression of VCAM-1 in rat lung, heart, brain, kidney, liver, spleen, stomach and intestine. (2) VCAM-1 levels in lungs at 10 min, 30 min after the allergic shock, and the time of death. (3) VCAM 1 levels in lungs of rats after the intervention of anti-VCAM-1. RESULTS: After the death, the expression VCAM-1 in lungs increased significantly relative to the control group and followed the extension of shock. In the rats which were injected with the anti-VCAM-1, the expression of VCAM-1 in lungs reduced. CONCLUSION: (1) The expression of VCAM-1 shows difference in the various organs of rats after anaphylactic shock. The change of VCAM-1 is the most obvious in lungs and would increase followed the extension of anaphylactic shock. (2) After the anaphylactic shock, anti-VCAM-1 can inhibit the expression of VCAM-1 in rat lung. PMID- 21604444 TI - [Correlation of pattern reversal visual evoked potentials P100 with visual acuity]. AB - OBJECTIVE: To explore pattern reversal visual evoked potential (PRVEP) P100 components in the patients with different visual acuity and the correlation of P100 components with visual acuity using different visual simulation angles. METHODS: PRVEPs were recorded at Oz point in the patients (100 eyes) with different visual acuity including 0.2, 0.4, 0.6, 0.8 and 1.0 and induced by pattern reversal visual simulation with the different spatial frequencies(check sizes: 8 degrees-7.5'). The latency and amplitude of components P100 were analyzed and statistical analysis was performed using SPSS 13.0 software. RESULTS: The latency and amplitude of P100 wave showed a curvilinear relationship with check sizes. With check size 10 simulation in 0.2 visual acuity group, the P100 latency reached to the minimum and the P100 amplitude showed peak value. Other groups displayed the best value with check size 30'. The P100 latency and amplitude showed a linear correlation with visual acuity. With the increase of visual acuity, the P100 wave latency decreased and the amplitude increased gradually. Regression models between visual acuity and the Pic wave latency and amplitude were also established. CONCLUSION: The regression functions can be an objective and accurate method to evaluate the visual acuity based on the better simulation angles using PRVEP examination. PMID- 21604445 TI - [Relationship between best corrected visual acuity and refraction parameters in myopia]. AB - OBJECTIVE: To explore the relationship between best corrected visual acuity (BCVA) and refraction parameters in myopia. METHODS: Two thousand two hundred and seventy-four patients (4245 eyes) with different degrees of myopia were collected. Their BCVA, diopter of spherical (DS), diopter of cylinder (DC), astigmatism axis, axial length (AL) and corneal thickness were detected. The influence of those parameters on BCVA was studied and the mathematical model of the relationship between BCVA and other parameters including the age and gender of patients was established. RESULTS: The logistic regression analysis showed that there were correlations between the BCVA (y) and DS (x1), DC (x2), gender (x3), AL (x4), corneal thickness (x5), astigmatism axis (x6) and age (x7) (P<0.05): y=0.580 6-0.034 0 x1-0.046 8 x2+0.056 5 x3+0.016 5 x4+ 0.0007 x5+0.000 2 x6-0.005 8 x7. CONCLUSION: For people with myopia, age, gender and corneal thickness have small effect on BCVA, while the DS, DC, AL and astigmatism axis have significant effect on BCVA. The BCVA would decline following the extension of DS, DC and AL. It is helpful to assess the vision of myopia by analyzing the refraction parameters comprehensively. PMID- 21604446 TI - [Comparison of evaluation methods on upper limb dysfunction caused by elbow joint injury]. AB - OBJECTIVE: To compare the degrees of upper limb impairment, which was caused by elbow movement dysfunction, evaluated by "Assessment for Body Impairment of the Injured in Road Traffic Accident" (ABIR) with that evaluated by "Guides to the Evaluation of Permanent Impairment (GEPI)". METHODS: The impairment degrees of 70 persons with elbow joint movement dysfunction were evaluated by ABIR and GEPI, respectively. And the evaluation results were analyzed and compared. RESULTS: There was statistical difference between the results. When the elbow movement could not reach to the functional position, there was great difference between the results. When the elbow movement could reach to the functional position, the difference became smaller. The degrees of impairment, which were evaluated by ABIR, were the same when the elbow joint was rigidity with ankylosis in different positions. The degrees of the dysfunction evaluated by ABIR did not change, but the degrees evaluated by GEPI were V-shape change. CONCLUSION: The difference of upper limb dysfunction degrees evaluated by ABIR and GEPI dependent on whether or not to consider the position of elbow joint rigidity. PMID- 21604447 TI - [A primary study of criterion for source identification of gastrointestinal tumor sample with Identifiler multiplex system]. AB - OBJECTIVE: To investigate the criterion for source identification of gastrointestinal tumor based on the number of identical allele (IAn) and the number of matched STR locus with 2 identical alleles (A2) in Identifiler system. METHODS: One hundred and five pairs of gastrointestinal tumor samples and homologous normal samples (TN group) were genotyped with Identifiler system. The numbers of STR locus with genotypic alteration (STRGA) in each tumor were determined by comparing the genotype of the matched STR loci in each pair of samples. According to the limited distribution of IAn and A2, 16 different values of IAn was substituted into the published discriminant functions to obtain the cut-off values of IAn and A2 for source identification of tumor sample. Indices including sensitivity (SEN), specificity (SPE), accuracy (AC), positive predictive value (PPV) and negative predictive value (NPV) for distinguishing tumor from an unrelated individual or a full sibling of the patient were calculated. Concordance of the identification results based on the determined criteria and the definite facts were statistically tested with Kappa index. RESULTS: The total frequency of STRGA was 5.46%. There were 31.43% of the 105 tumor samples carried at least one STR locus with STRGA mutation. According to the Fisher discrimination rules, criteria I (IAn>or=23 and A2>or=8) and criteriall (IAn>or=26 and A2>or=11) meet the requirements of distinguishing tumor sample from an unrelated individual or a full sibling of the patient with tumor, respectively. SEN=0.971 0, PPV=1.000 0, PPV=0.891 9 and Kappa=0.923 5, when the criteria were used to determine the specified relatives. CONCLUSION: Criteria I and criteria II were powerful for distinguishing tumor sample from an unrelated individual or a full sibling of the patient with tumor, respectively, when the Identifiler system was adopted for source identification of gastrointestinal tumor sample. PMID- 21604448 TI - [Expression of proteins in serum and hippocampus after closed brain injury in rats]. AB - OBJECTIVE: To explore the difference of expression of proteins between the serum and hippocampus after brain injury in rats. METHODS: Male SD rats were used to establish brain injury model. The changes of proteins expression profile in serum and hippocampus at different time after brain injury were analyzed using weak cationic exchanger (WCX2) chips and immobilized metal affinity capture arrays-Cu (IMAC-Cu) chips by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. RESULTS: A total of 436 protein peaks were detected in serum and 346 protein peaks were detected in hippocampus using WCX2 chips. A total of 229 protein peaks were detected in serum and 345 protein peaks were detected in hippocampus using IMAC-Cu chips. The same 10 protein peaks were respectively detected in serum and hippocampus using WCX2 chips. The same 13 protein peaks were respectively detected in serum and hippocampus using IMAC-Cu chips. CONCLUSION: The changes of protein expression profile in serum and hippocampus are obvious after closed brain injury and show a significant difference. The different proteins detected in serum and hippocampus using the same chip could be biochemical markers for determining brain injury. PMID- 21604449 TI - [Genetic differentiation and patterns of gene flow of ten minorities in Yunnan province]. AB - OBJECTIVE: To explore the features of genetic differentiation and gene flow of ten minorities in Yunnan province according to nine CODIS short tandem repeat(STR) loci (CSF1PO, FGA, THO1, TPOX, v WA, D3S1358, D5S818, D7S820 and D13S317). METHODS: Heterozygosity and parameters of population differentiation such as F, theta, f and Gst at each locus were calculated. DA genetic distance and fixation index Fst were calculated by Phylip 3.6 and Arlequin 3.0 software, respectively. Phylogenetic trees were constructed by Mega 3.0, and the patterns of gene flow were analyzed by R-matrix model. RESULTS: It showed that average genetic heterogeneity in ten minorities was above 0.7. Significant difference was found for most of the loci in genetic differentiation. Phylogenetic tree analysis showed that the ten minorities were divided into two clusters. The results of the R-matrix analysis showed that the gene flow of Yi and Dai minorities were higher than that of other minorities, while the pattern of gene flow of Dulong minority demonstrated some of the isolation. CONCLUSION: Nine STR loci commonly used in forensic identification show a high polymorphism. Heterozygosity can be used for investigating genetic differentiation and gene flow of minority. The ten minorities in Yunnan are independent populations, while the level of differentiation is not high. The relationship in evolution is not far from each other and shows a widely gene flow among the minorities. PMID- 21604450 TI - [Stability of estazolam in dog tissues preserved in formaldehyde solution]. AB - OBJECTIVE: To investigate the stability of estazolam in biological samples preserved in formaldehyde solution. METHODS: The dog was given intragastric administration of estazolam with a dose of 37.6 mg/kg and killed 2 h later. Heart, liver, kidney and brain of the dog were cut up into 1 g and preserved in 4% formaldehyde solution respectively. The content of estazolam in biological samples and formaldehyde solution were analyzed by HPLC at different times. RESULTS: The content of estazolam in heart, liver, kidney and brain or in formaldehyde solution reduced gradually followed with the extention of preservation time. At the 63rd day, estazolam content in four tissues were 0.8%, 1.7%, 1.0% and 2.2% of the original content respectively. CONCLUSION: Estazolam in tissues can diffuse into formaldehyde solution and decomposed quickly, so biological samples contained estazolam should not be preserved in formaldehyde solution. PMID- 21604451 TI - [Correlation between the eicosapentaenoic acid, docosahexaenoic acid and the aggressive behavior in mice]. AB - OBJECTIVE: To explore the correlation between the eicosapentaenoic acid(EPA), docosahexaenoic acid (DHA) and the aggressive behavior in mice. METHODS: Seventy two male Kunming mice were divided into control group, fish oil group, simvastatin group and aggressive reference group randomly. The control group, fish oil group and simvastatin group were given normal saline, fish oil and simvastatin by irrigation respectively for 3 months consecutively, each mouse was raised isolatedly. The latent period of assault, the frequencies of tail swing and assault, and the cumulative time of assault were recorded at the beginning and the end of the intervention. Finally, the EPA and DHA in brain were analyzed by gas chromatography-mass spectrometry (GC-MS). The aggressive reference group was raised without intervention and was evaluated as aggressive reference only. RESULTS: (1) Before intervention, the latent period of assault, the frequencies of tail swing, the frequencies of assault, and the cumulative time of assault were not significantly different from each other group. After intervention, the differences were significant (P<0.05). (2) After the intervention, the content of EPA and DHA in mice brain was the most in the fish oil group, and the least in the simvastatin group. (3) The content of EPA was negatively related with the four indexes (P<0.05) before and after the intervention. The content of DHA was negatively related with the frequencies of tail swing and assault (P<0.05). CONCLUSION: There is a correlation between the EPA, DHA and aggressive behavior in mice under stress. PMID- 21604452 TI - [Twenty autopsy cases of anaphylactic shock induced by cephalosporins]. AB - OBJECTIVE: To explore the characteristics of autopsy cases of anaphylactic shock induced by cephalosporins and provide the evidences in forensic medicine. METHODS: Twenty cases of anaphylactic shock induced by cephalosporins were collected from April 2005 to August 2009 in judicial expertise center of China Medical University, and the characteristics of the cases were analyzed retrospectively. RESULTS: The age of decedents ranged from 40 to 60 years. Ninety percent of cases were from local medical centers and private clinics. The symptoms of the shock appeared 30 s-150 min after the administration of the drug, and death occurred 10 min-210 min after the appearance of the shock symptoms. In all cases, various degrees of eosinophil infiltration were observed in trachea and the lungs. Serum IgE detected by ELISA method was normal value in 14 cases. CONCLUSION: In fatal anaphylactic cases, little specific findings are detected during postmortem and microscope examination. For this reason, the determination of cause of death in these cases requires comprehensive analysis combined with clinic information and excludes other diseases leading to the sudden death. PMID- 21604453 TI - [The prediction and assessment of youth violence]. AB - Youth violence is a public health and social issue of global concern. It will be helpful to reduce the incidence of youth violence if the risk factors and prediction methods can be fully comprehended. This paper summarized the risk factors of youth violence in the aspects of the individual factors, the social psychological factors and the biological factors. Meanwhile, the status of prediction and assessment of youth violence are reviewed, with expectation to reduce youth violence and contribute to further research. PMID- 21604454 TI - [Application of mtDNA polymorphism in species identification of sarcosaphagous insects]. AB - Species identification of sarcosaphagous insects is one of the important steps in forensic research based on the knowledge of entomology. Recent studies reveal that the application of molecular biology, especially the mtDNA sequences analysis, works well in the species identification of sarcosaphagous insects. The molecular biology characteristics, structures, polymorphism of mtDNA of sarcosaphagous insects, and the recent studies in species identification of sarcosaphagous insects are reviewed in this article. PMID- 21604455 TI - [Progress of transcranial magnetic stimulation-motor evoked potential and its forensic application]. AB - Transcranial magnetic stimulation-motor evoked potential (TMS-MEP) test is one of the electrophysiological examination methods to evaluate the function of central nervous system. The value of the TMS-MEP has been recognized by some clinical forensic workers recently. This article reviews the principle and advantages of TMS-MEP and its application in functional evaluation of central nervous system and clinical treatment. The value of TMS-MEP in forensic medicine, especially in objective assessment of muscle strength after injury of central nervous system is also discussed. PMID- 21604456 TI - [Snake venom metalloproteinases: structure, biosynthesis and function(s)]. AB - The biochemical and the pharmacological characterization of snake venoms revealed an important structural and functional polymorphism of proteins which they contain. Among them, snake venom metalloproteases (SVMPs) constitute approximatively 20 to 60% of the whole venom proteins. During the last decades, a significant progress was performed against structure studies and the biosynthesis of the SVMPs. Indeed, several metalloproteases were isolated and characterized against their structural and pharmacological properties. In this review, we report the most important properties concerning the classification, the structure of the various domains of the SVMPs as well as their biosynthesis and their activities as potential therapeutic agents. PMID- 21604457 TI - [Risk of vertical transmission of hepatitis B virus in Tunisia]. AB - The risk of vertical transmission of hepatitis B virus (HBV) varies with type of viral endemicity, degree of maternal infection and genomic characteristics of the virus. The aim of this study is to estimate this risk in Tunisia using serological and molecular methods to evaluate HBV replication, to determine viral genotypes and to detect presence of occult hepatitis in 2709 pregnant women. Serological markers were detected by ELISA methods, Genotype was determined by PCR-RFLP and occult hepatitis by nested-PCR. Four percent of women were positive for HBsAg; only 3% of them were also positive for HBeAg. Viral replication, over than 10(3) copies/ml, was detected in 61% of positive HBsAg patients. Three viral genotypes were detected: D (95%), B (3%) and A (3%). Occult hepatitis was detected in 4% of sera with "anti-HBc isolated" profile. In conclusion, the risk of vertical transmission of HBV exists in Tunisia. It increases by frequency of precore mutants, predominance of the genotype previously associated with high levels of replication and possibility of occult hepatitis B. These results show the importance of screening by serological HBV markers systematically during pregnancy with evaluation of viral replication in order to prevent vertical risk by efficient tools. PMID- 21604458 TI - [Relationship between temperature and mortality in the city of Tunis: 2005-2007]. AB - The influence of thermal stress on health is proved. In the light of the current climate change this relationship should be extensively investigated. This study aims to describe the relationship between temperature and total mortality in the city of Tunis over a period of three years, from 2005 to 2007 using time series analysis. The form of the relation (crude and adjusted) between mortality and temperatures was investigated using Poisson generalized additive models (GAM). Confounders included in the models were pollutant, trend, calendar month, day of the week, the period of Ramadan, and holidays. The adjusted relationship between mortality and temperature was "V" shaped with a steeper slope for low temperatures than for high temperatures. The impact of heat on mortality will be further analyzed to refine our findings and to contribute to the elaboration of guidelines for preventive strategies. PMID- 21604459 TI - [Distribution of surgical hydatidosis in Tunisia, results of 2001-2005 study and trends between 1977 and 2005]. AB - We have performed an exhaustive retrospective study in all surgical wards (54 services in 35 hospitals) which usually carry out surgical treatment of hydatic cysts in the country, covering the period between January 2001 and December 2005, in order to determine the annual surgical incidence of human cystic hydatidosis in Tunisia. A total of 6249 surgical interventions were recorded during the period 2001-2005. The highest proportion was recorded in the hospitals of Tunis District (42.9%). The service of thoracic surgery from Ariana hospital occupies the first rank (95%). The yearly incidence rate varies between 11 and 13.6 per 100,000. Calculated over the 5 years period, the incidence rate is 63.2 per 100,000 inhabitants, which means an average yearly incidence rate of 12.6 per 100,000 [12.28-12.99]. Governorates of the North West and the Western Central regions of the country are the most endemic area with an average annual incidence rates varying between 19.2 and 33.9 per 100,000, which is at least once and half higher than the national level. After 30 years (1977-2005), the average annual incidence rate slightly dropped, from 15 to 12.6 per 100,000, proving that such zoonosis remains a problem of public health in Tunisia. In order, to control in more or less short term this heavy burden disease and public health expenditure, the only efficient way is the prevention of the diseases with a mass treatment campaign of dogs, principal host of the parasite. PMID- 21604460 TI - [Immune recovery after allogeneic stem cell transplantation: study of 19 patients]. AB - The aim of this study was to access average delays for novogeneration of myeloid and lymphoid cells after allogeneic bone marrow transplantation (BMT) outcome and factors affecting this organization. A prospective analysis over 2 years (01/01/07 to 31/12/08) enrolling 19 children treated with allogeneic intrafamilial bone marrow transplantation. Indications for bone marrow transplantation were: aplastic anemia (3 cases), bemoglobinopathies (9 cases), myelodysplastic syndrome (1 case) and primary immunodeficiency (6 cases). Different conditioning regiments were used according to the indication. The study of immune reconstitution was based on the quantitative determination of immunoglobulin and lymphocyte subpopulation. These tests were routinely requested to 1 month, 2 months, 3 months, 6 months, 9 months and 12 months. The average time of engraftment was 18 days (12-24). A rate of CD4+T lymphocytes>200/mm3 was provided within an average of 2,5 months (1-7). The average time to obtain CD8+T lymphocytes>200/mm3 was 2 months (1-5). The humoral immune reconstitution was made within an average of 2 months (1-4). A report of CD4+/CD8+T lymphocytes>I was obtained within 10 months and a half (1-24). Univaried analysis showed a correlation between the bone marrow sex matched and the faster reorganization of CD8+T cells (p=0.042). A quantity of CD34+>6 10(6)/kg was significantly associated with the recapture of a formula lymphocyte CD4+/CD8+T>1 (p=0.03) Immune recovery post bone marrow transplantation in children begins with myeloid lineage then lymphoid B then lymphoid T The inversion of the report CD4+/CD8+T lymphocytes, seems to be influenced by the high contain of CD34+cells in the graft as well as the type of conditioning. PMID- 21604461 TI - [Neonatal screening of G6PD deficiency in Tunisia]. AB - The Glucose-6-phosphate dehydrogenase (G6PI) deficiency is the most common enzymopathy worldwide. WHO had classified Tunisia among countries that are moderately affected by this affection. However, no mass-screening reflecting the real incidence was realized. The aim of this study is to determine the prevalence of this enzymopathy and its molecular basis in Tunisia. A total of 1102 neonates, born in CMNT center of Maternity and of Neonatology of Tunis during the going periods from April, 2005 till May, 2005 and from June, 2006 till September, 2006, have been enclosed in the study. The samplings included 953peripheral venous blood and 149 blood cordon. Among 1102 samplings, only 976 were of use to the screening. In our mass-screening, we consider all newborns that were born in the CMNT during the period of study and were included in the screening. A dosage of the enzymatic activity was realized using spectrophotometric method. G6PD electrophoresis and molecular study by PCR/RFLP were realized for the overdrawn newborn children. Among 976 screening neonates, 43 individuals (4.4%) were found to be G6PD deficient by quantitative enzyme assay. Newborn affected were distributed in 23 boys and 20 girls (sex ratio of 1.15). The electrophoretic mobility and the molecular biology were realized for the affected newborn. Molecular characterization of 30 G6PD deficient neonates revealed that the G6PD A was the most common and was detected in 20 of 43 individuals (66.7%), followed by G6PD Mediterranean that was detected in 6 (13.3%). At least, 4 other unknown mutations were not able to be determined by PCR/RFLP (n=4). In conclusion G6PD deficiency is frequent in our country, justifying a systematic neonatal screening, to avoid the arisen of grave consequences of this affection. The African variant is the most frequent in our country followed by the Mediterranean one. PMID- 21604462 TI - [Association of IL-1beta gene -31T/C polymorphism with chronic rhinosinusitis]. AB - OBJECTIVE: To investigate the relationship between polymorphism of IL-1beta gene 31T/C and chronic rhinosinusitis. METHOD: One hundred and twenty-three patients with chronic rhinosinusitis and 239 healthy controls were collected to determine the genotypes by polymerase chain reaction-restriction fragment length polymorphism. RESULT: There was significant difference in genotype and allelic frequencies between the CRS and control group (P < 0.05). -31CC genotype was an independent risk factor with CRS (P < 0.05, OR = 1.639). There was no significant difference in TIgE and ECP among these genotypes (P > 0.05). CONCLUSION: IL-1beta gene 31CC genotype may be an independent risk factor with chronic rhinosinusitis. PMID- 21604463 TI - [The observation of the inflamed cells in the mucosa at the medial site compare with that at the lateral site of the normal uncinate process]. AB - OBJECTIVE: To determine the inflammatory cells in the mucosa at the medial aspect of the normal uncinate process compared with that on the protected lateral aspect of the normal uncinate process. METHOD: The mucosa of 20 uncinate process from the nasal cavity of 17 patients with no evidence of sinus disease undergoing functional endoscopic sinus surgery were recruited for the study. The material was stained with HE, Chromotrope 2R, Alcian blue-periodic acid-schiff, Toluidine blue. Specimens were observed using an Olympus microscope. RESULT: The number of mast cells and goblet cells were found to be higher on the lateral aspect of the normal uncinate process than on the medial aspect. The number of plasma cells was obviously different from that of lymphocytes. We did not found any eosinophils on either sides of uncinate process. CONCLUSION: There are differences in the number of mast cells and goblet cells between the mucosa at the medial aspect of the normal uncinate process and the mucosa at the protected lateral aspect of the normal uncinate process. PMID- 21604464 TI - [The association between genetic polymorphisms of GSTM1, GSTT1, GSTP1 and susceptibility to laryngeal carcinoma from the Han people in Guangdong zone]. AB - OBJECTIVE: To analyze the association between genetic polymorphisms of xenobiotic metabolizing enzymes GSTM1, GSTT1, GSTP1 and susceptibility to laryngeal carcinoma from the Han people in Guangdong zone. METHOD: A case-control study was conducted involving 233 LSCC (laryngeal squamous cell carcinoma) patients and 102 healthy controls to investigate the association between polymorphisms of GSTM1, GSTT1, GSTP1 (Ile/Val) and LSCC from the Han people in Guangdong zone. All blood samples of the Han people from the Guangdong zone was analyzed with methods of PCR, ASA and the DNA sequencing technique with sequenator. We explored the association between polymorphisms and the clinical pathologic characteristics of LSCC. The data was processed with SPSS13.0. Odds Ratios (ORs) with 95% CI for relevancy intensity were calculated using binary logistic regression analysis. RESULT: The frequency of GSTM1(-) and GSTT1(-) genotype was higher in LSCC than that in healthy controls (OR = 2.61, 3.05, P < 0.01). There was synergic effect between GSTT1 (-) genotype and heavily smoking during carcinogenesis of LSCC (OR = 3.51, 95% CI 2.05-5.01; OR = 2.99, 95% CI 2.00-4.49). The frequency of GSTM1(-) and GSTT1(-) genotype was higher in LSCC whose family had carcinoma history. The frequency of advanced LSCC was higher in patients who were with GSTM1(-) and GSTT1 (-) genotype (P < 0.05). There was no difference of the frequency of GSTP1(I le/Val) genotype between and in healthy controls (P > 0.05). CONCLUSION: There may be an association between the susceptibility to carcinoma and GSTT1(-), GSTM1(-) genotype. The GSTT1(-) polymorphism c gene cooperating with heavily smoking boost up the susceptibility of individual to laryngeal carcinoma. The GSTM1(-) polymorphism c may not cooperating with smoking during carcinogenesis of LSCC in the Han people in Guangdong zone. The morphisms of GSTT1 and GSTM1 gene may affect the carcino-genesis of LSCC in the Han people in Guangdong zone. There may be no association between the susceptibility to laryngeal carcinoma and the GSTP1(Ile/Val) type. PMID- 21604465 TI - [The prevention cerebrospinal fluid leakage during operating anterior skull base meningioma involving paranasal sinuses]. AB - OBJECTIVE: To introduce a kind of method for skull base reconstruction after resecting anterior skull base tumors involving paranasal sinuses. METHOD: A retrospective analysis was carried out on 13 patients who underwent anterior skull base reconstruction. Pericranial flap were detached with integrity from the frontal bone during craniotomy, after the tumor had been resected partitionedly, the cribriform plate of ethmoid bone which was involved by tumor was resected. Using the fat tissue to fill the skull-base defects and sutured the pedicled pericranial flap with surrounding normal dura mater. Then reinforced at the junction of pericranial flap and dura mater with biogel. RESULT: The pathogenic diagnosis of all cases were meningioma. I grade resection was acquired in 12 cases and II grade in 1 case according to Simpson grading standard of meningioma resection. The postoperative complications were 3 cases aseptic meningitis, 3 cases frontal syndrome. No CSF leakage, intracranial infection, nor death occurred. An average of 3. 4-year follow-up was achieved in all the cases from 9 months to 8 years, no tumor relapse. CONCLUSION: CSF leakage can be effectively prevented by filling the skull-base defects with the fat tissue, suturing the pedicled pericranial flap with surrounding normal dura mater, and reinforcing at the junction of pericranial flap and dura mater with biogel. PMID- 21604466 TI - [Evaluation of the medical and surgical treatment of pediatric chronic rhinosinusitis]. AB - OBJECTIVE: To compare the effect of the medical and surgical treatment of pediatric chronic rhinosinusitis (CRS). METHOD: Seventy-two cases of pediatric CRS were randomly divided into medical group (35 cases) and surgical group (37 cases). The patients in medical group received a 12-week course of clarithromycin, alkaline nasal douche and intranasal mometasone furoate. The patients in surgical group underwent adenoidectomy or (and) tonsillectomy or ESS. All patients underwent pre- and post-treatment assessments of visual analogue score (VAS) and nasal endoscopy. The assessments of CT were arranged before starting the treatment and post-treatment in 12-month. RESULT: Both groups of pediatric CRS significantly improved in VAS and endoscopic parameters of CRS in all stages. There were no significant difference between two groups in 1-month (P > 0.05). The surgical group demonstrated greater change than medical group in 3 month, 6-month and 12-month (P < 0.01). In surgical group, 37 cases underwent three different styles of operation: adenoidectomy (n = 19), adenoidectomy and tonsillectomy (n = 10) and ESS (n = 8). VAS and endoscopic parameters were not significantly different among three groups in all stages except in 1-month. CONCLUSION: The results of this study warrant further that both medical and surgical treatment of pediatric CRS significantly improve in VAS and endoscopic parameters of CRS. The mainstay of management is medical treatment. Long-term, low-dose macrolide is an effective therapy and a valid alternative in pediatric CRS. Surgical intervention is necessary for cases that do not respond to prolonged course medical treatment. Adenoidectomy or (and) tonsillectomy seems to be a recommended surgical procedure for children with adenoid or (and) tonsil hypertrophy. PMID- 21604467 TI - [Clinical diagnosis and treatment of nasal sinus mucoceles with visual loss]. AB - OBJECTIVE: To review the clinical manifestations and management of nasal sinus mucoceles with visual loss. METHOD: Medical records for 23 patients of paranasal sinus mucoceles with visual impairment were re viewed retrospectively during 8 year period (from 2002 to 2010). Ten mucoceles were found in the frontal or fronto-ethmoidal sinuses, 6 in the ethmoidal sinuses, 7 in the sphenoidal or spheno-ethmoidal sinuses. Because the majority of early chief complaints were problems related to vision, patients were often seen by ophthalmologists first. Poor vision was more common in patients with sphenoid or spheno-ethmoidal sinus mucoceles because of their proximity to the optic nerve. CT and MRI were important tools for diagnosing nasal sinus mucocele. The patients received endoscopic surgery to remove mucocele and to decompress the optic nerve. Steroid therapy was given postoperatively and routine examination with endoscopy were carried out during follow-up. RESULT: Postoperatively, the majority of symptoms, such as exophthalmos, epiphora, diplopia and headache, disappeared in all patients. However, vision recovery was observed only in some patients. Recovery of vision depended on the timing of surgery and severity of initial visual loss. Delay in treatment can seriously compromise recovery of vision impairment. Moreover, patients without light perception before surgery had poor visual recovery even if optic nerve decompressions were performed. CONCLUSION: Endoscopic surgery is effective to nasal sinus mucocele with visual loss. Because visual recovery depends on prompt diagnosis and surgical intervention, a good understanding of the disease and prompt imaging studies are important. PMID- 21604468 TI - [Survey on the distribution of common allergens responsible for cases with allergic rhinitis in Tianjin district]. AB - OBJECTIVE: To investigate the distribution of common allergens responsible for cases with allergic rhinitis in Tianjin district. METHOD: A total of 676 cases who are diagnosed with allergic rhinitis in Tianjin district, underwent a skin prick tests with 23 kinds of inhaling allergens and 20 kinds of ingestive ones. The samples were stratified on four age group. Then, an analysis was made to determine the distributive characteristics of allergens responsible for difference groups. RESULT: Among the surveyed local 676 cases with allergic rhinitis, higher positive rates was all inhaling group of allergens. CONCLUSION: It is concluded that the mostly responsible common allergens for attacks of allergic rhinitis among local cases in Tianjin district are mites, flowers pollen in inhaling group of allergens. PMID- 21604469 TI - [Diagnosis, treatment and medical evaluation of head and neck tumors in aircrew]. AB - OBJECTIVE: To sum up the experiences of diagnosis, treatment and medical evaluation of head and neck tumors in aircrew. METHOD: Sixty-seven cases of pilot patients with head and neck tumors in our hospital since September in 1979 to July in 2009 were retrospective analyzed in the study. RESULT: Among 44 aircrew with benign head and neck tumors there were 37 cases continued their flying jobs and 7 cases were permanently grounded; whereas in 23 aircrew with malignant tumors there were 6 cases qualified for flight and 17 patients unqualified. CONCLUSION: Benign or malignant of the head and neck neoplasm in the pilots are not the exclusive basis for their medical assessment. Tumor nature, location, efficacy of treatment and the impact on the function of their body should be considered as making the flight medical evaluation for the aircrew with head and neck tumors. Early diagnosis and treatment of head and neck tumors in aircrew are very important for reducing the rate of grounded. PMID- 21604470 TI - [Surgical management of sinonasal and adjacent skull base benign fibro-osseous lesions]. AB - OBJECTIVE: To explore the use of transnasal endoscopy and open surgical approaches for management of sinonasal and adjacent skull base benign fibro osseous lesions, the surgical methods, precautions, clinical efficacies were also described. METHOD: Fifteen patients were reviewed, including osteoma in 6 cases, Ossifying fibroma in 2 cases and fibrous dysplasia in 7 cases. Analyzed the pathological features and CT images, and to select surgical approach according to the location and extent of lesions. Eleven patients were operated through transnasal endoscopic procedure, including 7 cases with ipsilateral nasal approach and 4 cases with extended binasal approach; 4 cases with open surgical approach, including trans-eyebrow approach in 1 case and bicoronal approach in 3 cases. RESULT: All patients were followed up for 2 months to 4 years, gross resection of lesions in 10 cases but partial resection in 5 cases with fibrous dysplasia. The clinical symptoms and facial deformity in all cases were eliminated or significantly relieved postoperatively. Cerebrospinal fluid leakage occurred in 1 case, was successfully repaired during the endoscopic operation. Preoperative diplopia in 3 cases, 2 cases disappeared after six months, one case was improved significantly. There were no postoperative orbital or intracranial complications. CONCLUSION: Surgery is an effective means to resect lesions which had obviously clinical symptoms. The location and extent of lesions were the decisive factor to choose an open or endoscopic approach. Endoscopic sinus surgery can manage the midline skull base lesions which extend from the posterior wall of the frontal sinus to the clivus, well the open surgical approach is suitable for lesions locating the area beyond the medial orbital wall. No matter choosing which approach, osteoma, ossifying fibroma can be completely removed. For the fibrous dysplasia, as an extensive but self-limiting lesion, the surgery is performed only for relieving symptoms and facial deformity. So the partial resection is preferred and reasonable other than radical total resection. Even the severe fibrous dysplasia lesions caused the optic canal stenosis but present normal vision, it is unnecessary to perform prophylactic decompression of the optic nerve. PMID- 21604471 TI - [The effect of the fluticasone propionate to the dynamic process of the nasal mucosal remodeling in allergic rhinitis of the rats model]. AB - OBJECTIVE: To investigate the dynamic process of the nasal mucosal remodeling, and the effect of the fluticasone propionate (FP) to remodeling, by establish animal model of allergic rhinitis (AR). METHOD: One hundred and twenty Sprague Dawley (SD) rats were randomly divided into three groups: the normal Group A used as controls and experimental groups: Group B and C, each group had 40 rats. After the animal model were established successfully by OVA+ Al (OH)3 and disposed, then, the dynamic process of the nasal mucosal remodeling was observed, through HE staining and transmission electron microscopic section in special times. RESULT: The Group B, C nasal epithelium and cilia were not complete, eosinophil based inflammatory cell infiltration, basement membrane thickening, collagen deposition, and a small amount of fibrosis could be found, but the structure of cells were not damaged. While those changes could not be observed in the Group A. The morphological changes of the nasal mucosa of Group B aggravated gradually under persistent allergen exposure, even stripped to the basement membrane in whole epithelial layers, cell and tissue structure were destroyed seriously. The morphological changes of nasal mucosa of Group C did not further increase, but still showed varying degrees of cilia arranged in uneven fashion, basement membrane thickening, collagen deposition and fibrous hyperplasia after treatment by FP. CONCLUSION: Remodeling happens in the nasal mucosa, which would be aggravated, and even becomes irreversible if the allergen exposure continues persistently. The FP can relieve the clinical symptoms, slow down and even reverse the remodeling of AR. And it is ineffective when the changes become irreversible. PMID- 21604472 TI - [Research on high-order Windkessel model for assessing vascular compliance]. AB - In this paper, we propose the construction of a fifth-order Windkessel model, and give complete mathematical solutions for this model. Utilizing the diastolic pulse wave analytical methods, we derived the parameters of the mathematical model. The parameters were further applied to estimate arterial compliance, blood flow inertia, peripheral resistance and other indices. With simulation tools we assess the validity of the model, and built a simulation circuit with the model parameters R, C and L. The model parameters were obtained from the high-order Windkessel model. The stroke volume of left ventricle is employed as the input of the simulation circuit. At the end of the circuit, the responding signal was gained. And it in turn was compared with the measured pulse waveform. The results show that the fifth-order Windkessel model is superior to the third-order Windkessel model in the pulse wave fitting and stability, and thus better reflects the role of microvessles in the circulatory system. PMID- 21604473 TI - [Decoupling of multi-channel RF coil and its application in the intraoperative MRI]. AB - The coupling from different elements of the multi-channel coil leads to the splitting of the resonance frequency and deviation from the Lamor frequency. Decoupling between different elements is the key technology in the design of the radiofrequency (RF) coil. The electrical decoupling circuits should vary with different arrangements of the elements. A novel method of decoupling for the RF coil used in the intraoperative MR-guided focused ultrasound system is reported in the paper. The prototype RF coil was made according to the proposed decoupling method. The bench test of the prototype showed that the performance of the decoupling of the coil was excellent. The images in vivo were acquired with the designed prototype RF coil. PMID- 21604474 TI - [Speech coding strategy based on amplitude and frequency modulation for cochlear implants]. AB - To enhance speech recognition in noise, as well as tone recognition, we presented a new kind of speech coding strategy, called one-octave wavelet transform zero crossing stimulation (WTZS), for cochlear implants based on amplitude and frequency modulation. We selected 15 volunteers with normal hearing ability to carry out hearing simulation experiments by picking up the amplitude (amplitude modulation, AM), zero-crossings (frequency modulation, FM) and gradient parameters from processed speech signal in the domain of one-octave wavelet transform to synthesize the stimulating pulstile series. The experimental results demonstrated that the phonetic recognition in quiet surroundings with amplitude modulation only strategy (CIS) is similar to that of amplitude and frequency modulations strategies (FAME and WTZS), while the tone perception of CIS is inferior to that of FAME and WTZS strategies. However, in noisy environment, the phonetic recognition, tone perception, as well as sentence recognition of WTZS strategy are better than those of CIS and FAME strategies. WTZS strategy, utilizing amplitude (AM), zero-crossings (FM) and gradient parameters to synthesize stimulus, can enhance the phonetic and tonal language recognition in noise environment effectively, and could be used in cochlear implant system for speech processor design after arithmetic optimization. PMID- 21604475 TI - [Anionic long circulation liposomes mediated antisense scintigraphy in tumor bearing rats]. AB - This paper was aimed to investigate the biodistribution and ability of free 131 bcl-2/bcl-xl ASON (FA) and anionic long circulation liposomes encapsulated with 131I-bcl-2/bcl-xlASON (NA), in tumor-bearing rats, to image breast cancer. We investigated the tissue distribution of NA in virgin female Sprague-Dawley (SD) rats with n-methyl nitrosourea (MNU)-induced breast cancers in situ. The percentage of the injected dose per gram (%ID/g) was calculated, with the maximum ratios of tumor to blood and tumor to muscle, after injections of NA and FA for 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 12 h and 24 h, respectively. The ability of NA to image breast cancer in tumor-bearing rats was determined using emission computed tomography (ECT). Seventy percent (90/130) SD rats in the study developed mammary tumors after MNU injection with the average latency (NA) (96 +/- 1.2)days. The %ID/g of NA in breast cancer tissue, tumor bearing rats in liver and spleen tumor tissues after 10 hours were (6.23 +/- 0.23) %ID/g, (12.00 +/- 0.26) %ID/g and (18.25 +/- 1.33)% ID/g, respectively. The ratios of tumor to blood 6.29 +/- 0.76 and tumor to muscle 10.55 +/- 0.68 in tumor bearing rats slowly maximized at 10 h post injection of NA, most probably due to the enhanced permeability and retention effect. Hence in radionuclide antisense scintigraphy, the breast cancer in rat was clearly displayed at 10h after iv administration of NA-D. However, tumors were not visualized in rats with the iv injection of NS and NN even at the delayed time. Due to the inhibition of rapid uptake of NA by the reticulo endothelial system, NA displays valuable pharmacologic properties characterized by the enhanced accumulation in tumor. PMID- 21604476 TI - [A GPU-based fast volume CT reconstructive algorithm method]. AB - In order to solve the time-consuming problem in volume CT image reconstruction field, we brought forward a fast reconstructive algorithm method to fit the clinic medicine. First, using the great parallel and Floating-Point power of graphic processing unit (GPU), we proposed a volume CT GPU- based reconstruction method. Second, in order to reduce the repetitive operation, we separated the geometry computation and pixel computation. As a result, the computation efficiency was further improved. At last, based on the background of medical engineering, the parallel of volume CT scan and reconstruction was implemented. The results demonstrated that the volume CT reconstruction time could reduce up to 70 times compared to the previous one in common PC by the fast reconstructive algorithm method. PMID- 21604477 TI - [A study of mechanomyography analysis for muscle fatigue with Hilbert-Huang transform]. AB - The mechanomyography (MMG) records and quantifies the low-frequency lateral oscillations of active muscle fibers. It can represent the mechanical characteristics of muscle activity. MMG has been used to evaluate muscle fatigue. Hilbert-Huang transform (HHT) is a time-frequency method with the feature of self adaptation, and designed specifically for nonlinear and nonstationary signal analysis. In this study, MMG signal was recorded from biceps brachii during isometric fatigue contraction. HHT was used to calculate the difference between the maximum and minimum values of instantaneous frequency, named as the band ratio, to estimate muscle fatigue. The results showed that the band ratios were 0.431 +/- 0.607 and 0.286 +/- 0.218 after fatigue for the maximum voluntary contraction (MVC) of 50% and 70%, respectively. These indicated that the frequency declined after muscles fatigue. PMID- 21604478 TI - [The analysis method of the Hilbert spectrum entropy of dividing frequency range for signals of heart rate variability]. AB - The signal analysis of heart rate variability (HRV) has been very significant for heart disease of aided diagnosis, monitoring and evaluation. We proposed a new method of HRV signal analysis based on the Hilbert spectrum entropy dividing frequency range. According to Hilbert spectrum characteristics of the multi resolution and the characteristic of HRV signal frequency spectrum, the Hilbert time-frequency spectrum entropy of HRV signal in different frequency range and the full frequency Hilbert time-frequency spectrum entropy with weighting factor were calculated. This approach was analyzed after the appropriate separation for various physiological factors based on the frequency range and it is more conducive to reflect the physiological and the pathological characteristics. Applying the new approach to the actual HRV signal of the MIT-BIH standard database, we obtained the results which showed that this method could effectively differentiate from the sample group for the young, the elder and the patients with atrial fibrillation, and for the sample group for the healthy persons and CHF patients, the performance in statistical analysis was superior to those of the general time-frequency entropy method. The approach could provide an effective analysis method for clinical HRV signal. PMID- 21604479 TI - [MDCT features and anatomic-pathology in right thoracic-abdominal junctional region diseases]. AB - This paper was objected to determine the relationship between MDCT features and anatomic-pathology of diseases in right thoracic-abdominal junctional region. We cut 3 cadavers transversely and another 3 vertically to observe the anatomy of thoracic-abdominal junctional zone. We scanned 69 patients with diseases in right thoracic-abdominal junctional zone by MDCT. The correlation between MDCT features of right thoracic-abdominal junctional region and the anatomic-pathology in this region was evaluated. We found results as that in cadaver sections, the right pulmonary ligament, which was below inferior pulmonary vein, attached the inferior lobe of right lung to the esophagus, that the coronary ligament, which interiorly extended from falciform ligament and laterally formed into right triangular ligament, contained two layers, and that the bare area of liver, which positioned between the two layers of coronary ligament, was directly next to diaphragm with no peritoneum covered. There were 50 cases with both pleural and ascitic fluid, while the pleural fluid was divided into anterior and posterior compartments by the right pulmonary ligament, whereas the ascitic fluid was limited in perihepatic space in majority. Among the 50 cases, 5 patients had lung cancer with diaphragmatic pleura, diaphragm and upper abdomen involved. 5 patients had right hepatic lobe cancer with subdiaphragmatic peritoneum, crura diaphragmatis and lower thoracic cavity involved. 1 patient had right adrenal carcinoma with phrenic metastasis. 8 patients had inflammation in right lower thorax and/or right upper abdomen. The spreads of these diseases include mainly direct invasion, blood and lymphatic spread routs in the region. Conclusion could be drawn that the MDCT features and distribution of right thoracic-abdominal junctional region diseases correlate with the anatomical characteristics in this region. PMID- 21604480 TI - [An intelligent stimulator based on electromyography feature extraction]. AB - In order to improve the conventional stimulator with non-standard parameters and poor efficacy using the passive mode of the treatment, we developed an intelligent stimulator to combine biofeedback with functional electrical stimulation. Through the non-invasive measurement and feature extraction of electromyography signals, a value of root mean square can be obtained based on delta-sigma computational technique. In the newly designed stimulator, electromyography feature extraction and feedback control were used to intelligently control the rehabilitation treatment. Both bidirectional detection technologies for stimulated current and programmable interactive way using touchscreen were employed so that the treatment parameters can be accurately quantified and set up. The experiment showed that the design requirements were achieved. PMID- 21604481 TI - [Roles and expressions of the NMDA receptor subunits (NR2A and NR2B) in visual cortex area of kittens with the normal visual development and anisometropic amblyopia]. AB - In order to understand the roles of the other subunits, we investigated expression of the NMDA receptor subunits (NR2A and NR2B) in visual cortex of normal and anisometropic amblyopia kittens with different ages in the present study. We examined the expressions of NR2A and NR2B in the visual cortex of the kittens by immunohistochemistry with polyclonal anti-NR2A antibody and anti-NR2B antibody, respectively. Using immunohisto-chemical Streptavidin Perosidase (SP) method, we observed the dynamic changes of NR2A and NR2B with microscope and computer-assisted image analyses. We found that NR2A and NR2B remained low expression after the peak of the critical period of kitten visual development; compared with normal group of the same age, NR2A expresses low. However, the difference is not significant for NR2B before maturation period of visual development. NR2B rises after the maturation period of visual development. According to this, the component of NR2A and NR2B can be affected by anisometropia. This research suggests that the difference of NR2A and NR2B expressions may affect the formation of amblyopia. PMID- 21604482 TI - [Color features of fluorescent image for cervix cancer and its judgments]. AB - Fluorescent image of human mucous can display a special color to demonstrate a cancer at its early stage. This will provide a novel method for early diagnose of the Pathological Changes. This research firstly extracted the color characteristics of the clinic images and then calculated all RGB components in different local areas. Finally, a stability analysis was performed. On the above basis we showed a conclusion that G/R can be used as a judge index for pathologic changes. PMID- 21604483 TI - [The acquisition and analysis of heart sound signals based on DSP]. AB - Heart sound signals acquisition is the primary basis for achieving non-invasive diagnosis of coronary heart disease. In this paper, a digital signal processor (DSP)-based on miniaturized circuit of heart sound signals acquisition and analysis platform was designed to achieve the functions of filtering, collecting, processing, displaying and the communicating with PC. With the self-developed experimental platform, we collected 228 cases of heart sounds of clinical data, and processed the signals using de-noising method with wavelet transform. These experimental results indicated that the db6 wavelet has the most obvious de noising effect among the four most commonly used wavelets, i.e., haar, db6, sym8, and coif5. One wavelet at different levels possessed different de-noising effects, with level-5 db6 decomposition obtaining the most desirable result. PMID- 21604484 TI - [Application of SVM and wavelet analysis in EEG classification]. AB - We employed two methods of support vector machines (SVM) combined with two kinds of wavelet analysis to classify these EEG signals, on the basis of the different profiles, energy, and frequency characteristics of the EEG during the seizures. One method was to classify these signals using waveform characteristics of the EEG signal. The other was to classify these signals based on fluctuation index and variation coefficient of the EEG signal. We compared the classification accuracies of these two methods with the intermittent EEG and epileptic EEG. The results of the experiments showed that both the two methods for distinguishing epileptic EEG and interictal EEG can achieve an effective performance. It was also confirmed that the latter, the method based on the fluctuation index and variation coefficient, possesses a better effect of classification. PMID- 21604485 TI - [Key technique research and system realization for C-arm based spinal surgical navigation]. AB - C-arm based surgical navigation system is a kind of computer assisted surgery (CAS) system. In this paper, key techniques concerning this kind of system are presented. The key techniques mainly include XRII image distortion correction and C-arm imaging system calibration. On this basis, we designed relevant tools and made them fabricated, and developed a software system. Experimental results of human fresh spine sample showed that with the surgical navigation system, screw insertion accuracy was much higher than that without the surgical navigation system. PMID- 21604486 TI - [Appraisement of stellate ganglion block therapy for uncertainty statements syndrome with infrared thermography]. AB - We treated 20 patients suffering from uncertainty statements syndrome (USS) with stellate ganglion block (SGB) therapy. The medical infrared thermography was examined before and after the SGB therapy. Analysis on the changes of surface temperature as well as the outcome of the patients was carried out. Among the mentioned 20 patients, 15 (75%) got obvious effect, 4 (20%) fairly good effect and 1 (5%) a little improvement after the SGB therapy. The corresponding surface temperatures of these patients were 1.32 +/- 0.27 degrees C, 0.97 +/- 0.31 degrees C, and 0.76 +/- 0.33 degrees C, respectively. The more the surface temperature changed, the better the efficacy of the therapy was. The medical infrared thermography may objectively represent the therapeutic effect of SGB on the USS. PMID- 21604487 TI - [Characteristics of pneumoconiosis on multi-detector row CT and its' anatomic pathologic basis]. AB - In order to investigate the fine distinction of the tomographic images and the dominant anatomic distributions, we carefully reviewed and analyzed the features and predominant anatomic distribution of forty-nine pneumoconiosis patients with confirmed diagnosis on multi-detector row CT (MDCT). It was found that the round and small opacity p and irregular small opacity were mostly shown in the MDCT features of pneumoconiosis, while the large opacity and progressive massive fibrosis (PMF) were less frequently depicted in the MDCT. Distributions of round and small opacity and irregular small opacity in the six lung lobes were significantly different (P < 0.01). The most common p opacity was significantly seen in the upper and lower left lungs as well as in the upper right lung's opacity was in the upper left lung as well as lower left and right lungs. The large opacity commonly distributed in upper left and right lungs, while the PMF was often shown in both of two lungs. The results demonstrated that the MDCT could be an effective modality for detecting tiny lesions and anatomic distribution of pneumoconiosis, and it would be helpful for early diagnosis and accurate staging of the pneumoconiosis disease. PMID- 21604488 TI - [Cardiac arrhythmia classification based on multi-features and support vector machines]. AB - To solve the problem of cardiac arrhythmias classification, we proposed a novel algorithm based on the multi-feature fusion and support vector machines (SVM). Kernel independent component analysis (KICA) was used to extract nonlinear features and wavelet transform (WT) was used to extract time-frequency features. Combining these features could include more information about the disease. We designed the classification model based on SVM combined with error correcting output codes (ECOC). Receiver operating characteristic curve (ROC) and Area Under the ROC curve (AUC) value were used to assess the classification model. The value of AUC is 0.956 against MIT-BIH arrhythmia database. Experimental results showed effectiveness of the proposed method. PMID- 21604489 TI - [The impact of four metal ions on the phase behavior of phosphatidylcholine at the air/water interface]. AB - The impact of metal ions on the phase behavior of phosphatidylcholine (PC) was investigated at the air/water interface by surface pressure-area (pi-A) isotherm measurements. The analysis of the pi-A isotherms showed that with the metal ionic radius decreasing, the concentration of the metal ions C increasing, and the valence of metal ions Q increasing, the amount of the corresponding curves of A0 decreases, the phase transition point would change more apparently, the collapse pressure would become larger subsequently, and the curve would be extended outside. The phenomenon could be approached when the metal ion concentration C became great enough. These experiments were identified with the rules on Langmuir films, by a variety of properties of metal ions (ion radius, ion concentration, ion valence, etc.). Among all the factors, the ionic valence showed the greatest impact on the phase changes, followed by the ion concentration, while the ionic radius influences were less on the phase-change characteristics. PMID- 21604490 TI - [Study on pharmacokinetics of lansoprozole in concentration of blood plasma healthy volunteers intravenous infusion by improved HPLC]. AB - This work aimed to set up a high performance liquid chromatography (HPLC) method to determine the concentration of lansoprazole in human plasma and study the pharmacokinetic characters of lansoprazole in Chinese healthy volunteers after intravenous (IV) infusion. In accordance with double 3 x 3 Latin square design with self-crossover design, 12 volunteers were randomly divided into six groups, with half males and half females. The volunteers were administered with single dose of 15, 30, 60 mg of lansoprazole by IV infusion at a constant speed respectively, to study the clinical pharmacokinetics of lansoprazole. The linear range of lansoprazole in human plasma was 0.020-4.970 microg/ml (r = 0.9999); The intra-day and inter-day RSD were less than 10%. After receiving single doses of 15, 30 and 60 mg of lansoprazole, t(1/2) were (1.663 +/- 0.405) h, (1.541 +/- 0.339)h and (1.747 +/- 0.156) h; Cmax were (1.065 +/- 0.094) microg/ml, (2.104 +/ 0.312) microg/ml and (3.786 +/- 0.356) microg/ml; AUC(0-infinity) were (2.376 +/ 0. 432) microg x h/ ml, (4.722 +/- 0.753) microg x h/ml and (10.495 +/- 2.129) microg x h/ml respectively. The improved HPLC method is simple, rapid and reproducible. It could be used for determination of the concentration of lansoprazole in human plasma. The pharmacokinetics of lansoprazole for injection was found to fit the linear dynamics in vivo within the dose range of 15 to 60 mg. In addition, the results suggested that gender had no statistic significant effect on the pharmacokinetic process of lansoprazole after IV infusion of single dose. PMID- 21604491 TI - [Preparation and cytocompatibility study of poly (epsilon-caprolactone)/silk sericin nanofibrous scaffolds]. AB - Three-dimensional poly (epsilon-caprolactone)/silk sericin (PCL/SS) porous nanofibrous scaffolds were prepared by electrospinning. The structure and properties of the scaffolds were characterized by Scanning Electron Microscope (SEM), Transmission Electron Microscope (TEM), Fourier Transform Infrared Spectroscopy (FTIR) and water contact angle instrument. Studies on cell adhension and proliferation were carried out by culturing human primary skin fibroblast cells (FEK4) on these scaffolds using SEM and MTS. The experimental results showed that the PCL/SS nanofibrous scaffolds with SS nanoparticles had porous non woven mesh structure with nanofibrous cross-linked with each other. Fiber diameter was very uniform and precise, and the secondary structure of SS protein had not been changed. Furthermore, the capability of hydrophile increased with the SS addition, which improved FEK4 cells adhesion and proliferation on the scaffolds. PMID- 21604492 TI - [Controlled release of fuctional proteins IGF-1, aFGF and VEGF through self assembling peptide nanofiber hydrogel]. AB - Peptide RADA can undergo spontaneous assembly into well ordered nanofibers and hydrogels in its water solution. In this work, a variety of proteins, including IGF-1, aFGF and VEGF with different molecular weight and isoelectric points, were chosen and encapsulated within the RADA peptide hydrogel. UV-vis spectroscopy was used to determine the concentration of the released proteins in the solution. The release kinetics suggested that protein diffusion through nanofiber hydrogels depended primarily on the size of the protein and the density of the peptide nanofiber. Circular dichroism (CD) spectroscopy indicated that the encapsulation and release by RADA hydrogel did not affect the secondary structure of the proteins studied. PMID- 21604493 TI - [PLA-O-CMC nanoparticles: HGF loading and delivery behaviors in vitro]. AB - This paper is aimed to observe the hepatocyte growth factor (HGF) loading and delivery ability of polylactic acid and oxygen carboxymethylated chitosan copolyer nanoparticles (PLA-O-CMC NPs). We prepared PLA-O-CMC NPs loaded with HGF by ultrasound in combination with magnetic stirring method. The NPs were characterized by transmission electron microscopy, embedding ratio; drug loading and drug delivery behaviors were observed by ELISA. The characteristics of PLA-O CMC NPs loaded with HGF showed that the mean size was 139. 82 nm, polydispersity was 0.108, maximal HGF-embedding ratio was 76. 32%. The cumulative HGF release gradually increased in the first 24 hours in vitro, with sharp increasing in the first 7 hours, and moderate and steady increasing in the following 17 hours. The HGF had a burst release in the first 24 hours, and in this process the released HGF took up 36.7% of the whole release. From the second day,the HGF release decreased obviously, while it kept on releasing steadily (45-55 ng/d) for quite long time up to 30 days. The experiment proved that PLA-O-CMC NPs is a favourable carrier of HGF. PLA-O-CMC NPs loaded with HGF could rapidly release HGF in vitro. The released HGF reached the effective drug concentration and maintained the certain effective drug concentration for a long time. PMID- 21604494 TI - [A preliminary study of application of the antibacterial solution containing silver ion to the surface of soft lining material]. AB - We tried to find the effects of the application of the antibacterial solution containing silver ions on the surface of the denture soft lining material. We selected the right concentration of the silver-containing solution and coated a soft lining material with the solution so that the soft lining material could be antibacterial. The antibacterial solution containing silver ions was prepared by sol-gel method. MIC of C. a and S. a were tested by broth dilution test. The surface property and thickness were tested after coated. The in vitro antibacterial ratio against C. a and S. a were demonstrated by the method of plate-counting. A film was formed after coating, while the adequacy was not changed. Antibacterial ratio of 0.64 mg/ml group against C. a was 90.82%, and that against S. a was 94.96% in 24 hours, respectively. It was found that the antibacterial property of the soft lining material can be acquired by coating this antibacterial solution with silver ion, without changing the adequacy. PMID- 21604495 TI - [The study of absorbable sustained-release implants and animal experiments to prevent recurrence of bladder cancer]. AB - This paper aims to prepare polyanhydride-Pirarubicin dose long-acting sustained release implants for the treatment of bladder cancer and for the prevention of postoperative recurrence of bladder cancer. Pirarubicin hydrochloride (THP) and polyanhydride, in accordance with a certain proportion, were fully mixed in the agate morta and dissolved in dichloromethane, and then were cast into a film within a mold put in the dryer set at 4 degrees C. Each tablet implanted contained 5.0 mg of THP. Polyanhydride-pirarubicin sustained-release was implanted into the bladder mucosa of the rabbits, and blood and urine samples were taken at different times after the operation. The THP drug concentrations in urine and blood were determined with high-performance liquid chromatography. The THP concentration in urine was significantly higher than the THP concentration in plasma. The drug concentration in urine reached (92.5 +/- 7.4) microg/L at 250 d time after the operation. Polyanhydride-pirarubicin implants possess long-acting sustained-release level dynamics in the body. It can maintain a stable long-term drug release and can be expected to last a year and can effectively prevent recurrence of bladder cancer. The present experiments proved that the implants with sustained-release drug treatment are expected to be useful in the clinical application in prevention of bladder cancer recurrence. PMID- 21604496 TI - [Construction of replication-deficient recombinant adenovirus vector with hTFPI-2 gene by AdMax system and expression in U937 monocytes in vitro]. AB - We tried to construct and identify the recombinant replication-deficient adenovirus vector coding for human tissue factor pathway inhibitor 2 (hTFPI-2) gene by AdMax system in HEK293 cells. Firstly, we obtained hTFPI-2 gene from the recombinant plasmid pIRES2-EGFP-TFPI-2 by PCR using primers with restriction endonuclease site of EcoRI or SacI. After digesting the hTFPI-2 gene and plasmid PDC316-IRES-EGFP shuttle vector, we ligated them with T4 ligase and formed the recombinant shuttle vector PDC316-IRES-EGFP-hTFPI-2. It was confirmed that the ligation product was inserted the gene of hTFPI-2 correctly by sequencing. Then we took cotransfection of HEK293 cells with the recombinant shuttle vector and genomic plasmid pBHGloxdeltaE1,3Cre by liposome lipofectamine2000, and finished the package of recombinant adenovirus Ad-hTFPI-2. The results of the PCR test and restriction endonuclease digestion confirmed the successful construction of the recombinants Ad-hTFPI-2. Furthermore, we measured the titre of Ad-hTFPI-2 with the aid of green fluorescence protein expression after multiplication and purification. The titre was 0.931 x 10(12) pfu/ml. Finally, we infected U937 monocytes by purified Ad-hTFPI-2, and determined the infection efficiency and the TFPI-2's level and activity. The efficiency of Ad-hTFPI-2 infection in U937 cells was 89.33%. After infected by Ad-hTFPI-2, the TFPI-2's level in supernatant increased about 7 fold. Also the TFPI-2 in supernatant had activities of inhibiting trypsin and plasmin. The recombinant adenovirus with the hTFPI-2 gene was constructed successfully. It will be helpful for the further investigation of its potentiality to be applied in antiatherosclerosis. PMID- 21604497 TI - [The expression of X-linked inhibitor of apoptosis protein and cell apoptosis in caerulein-stimulated rat pancreatic acinus AR42J cell lines]. AB - To study the expression of X-linked inhibitor of apoptosis protein (XIAP) and cell apoptosis in vitro model of acute pancreatitis (AP), we carried out experiments to stimulate AR42J cell line with caerulein (10(-8) mol/L) for 12 hours, then collected cells at various time points (0 h, 4 h, 8 h, 12 h, and 24 h, respectively). We then observed the morphologic changes of AR42J cells with the stimulation of caerulein with electronic microscope. The gene expression of XIAP, caspase-3 and caspase-9 was detected using real-time fluorescence quantitative polymerase chain reaction (FQ-PCR), and the protein expression of XIAP was assessed by western blot. The activation of nuclear factor-kappa B (NF kappaB) was measured by flow cytometry (FCM). With the stimulation of caerulein, the expression of XIAP and the NF-kappaB activation could first decrease and then increase, but the change of caspase-3 and caspase-9 expressions were opposite. XIAP may inhibit the cell apoptosis in rat pancreatic acinus AR42J cell lines at first with the stimulation of caerulein, then NF-kappaB can upgrade the expression of XIAP and increase the cell apoptosis. PMID- 21604498 TI - [Morphological characteristics of human adipose-derived stem cells]. AB - This paper is aimed to isolate and to cultivate human adipose-derived stem cells (hADSCs) from the adipose tissue by a combination of collagenase digestion, adherence to flasks and monoclonal cultural method so as to observe the morphological characteristics of the hADSCs. The immunophenotypes of hADSCs were detected by flow cytometry techniques. The general morphological characteristics of hADSCs were observed by cytochemical and immunofluorescent techniques. The ultrastructure of hADSCs was observed by transmission electron microscopy (TEM). The experimental results showed that hADSCs had unique immunophenotypes and they were positive for CD29, CD44, CD90, CD105 and CD166, but negative for CD31, CD45 and HLA-DR. Cytochemistry showed that cytoplasm of hADSCs was stained with light blue by hematoxylin-eosin, negative for Oil red O and AKP, and positive for immunofluorescence CD29 and CD166. There were abundant organella and microvilli in the ultrastructure of hADSCs. The results validate that they will offer a morphological foundation for application of the hADSCs. PMID- 21604499 TI - [Transgene complete silencing may associate with rearrangement of retroviral vector]. AB - Transgene silencing is one of two major obstacles in both basic biomedical research for transgene and clinical practice of gene therapy. Based on the model of HT1080 cell clones, which transduced single copy of retroviral vector MGPN2, the mechanism of transgene silencing was explored in this investigation by a serial molecular techniques. In the HT1080 cell clone that absence of GFP protein synthesized, no significant aberration of epigenetic modification was detected, but the transcript size and the sequence changed that resulted in the reading frame shift. In addition to chromosomal position effect leading to transgene silencing, the transcript reading frame shift associated with retroviral vector rearrangements could induce complete silencing of transgene. PMID- 21604500 TI - [A novel recombinant human interferon alpha2b with high antivirus activity by combinatorial mutagenesis]. AB - In order to create a novel recombinant human interferon alpha2b (rh-IFN alpha2b) with higher biological activity, we subjected the rational designed sequence of rh-IFN alpha2b to direct evolution by strategy of the combinatorial mutagenesis. The amino acid residues at multiple sites of 52-53-55, 103-107, and 121-125 were simultaneously mutated. The resulted gene of the mutated rh-IFN a2b was cloned into the pET28a and expressed in E. coli BL21 Condon plus (RIL). The anti-virus activity of the novel interferon alpha2b was 9.3 x 10(7) IU/mg, 93 times higher than the wild type (1 x 10(6) IU/mg). The results showed that the multiple point mutation used in this study could effectively combine the site effects of rh-IFN alpha2b and increase its biological activity. PMID- 21604501 TI - [Research on finger key-press gesture recognition based on surface electromyographic signals]. AB - This article reported researches on the pattern recognition of finger key-press gestures based on surface electromyographic (SEMG) signals. All the gestures were defined referring to the PC standard keyboard, and totally 16 sorts of key-press gestures relating to the right hand were defined. The SEMG signals were collected from the forearm of the subjects by 4 sensors. And two kinds of pattern recognition experiments were designed and implemented for exploring the feasibility and repeatability of the key-press gesture recognition based on SEMG signals. The results from 6 subjects showed, by using the same-day templates, that the average classification rates of 16 defined key-press gestures reached above 75.8%. Moreover, when the training samples added up to 5 days, the recognition accuracies approached those obtained with the same-day templates. The experimental results confirm the feasibility and repeatability of SEMG-based key press gestures classification, which is meaningful for the implementation of myoelectric control-based virtual keyboard interaction. PMID- 21604502 TI - [Application of objective image quality measures on CT image]. AB - Computed tomography (CT) is an essential imaging modality. To solve the problem caused by increasing radiation exposure from CT scanner and to elevate the image quality, we aimed to apply the general objective image quality methods in CT image quality evaluation. After analyzing the perceptual features of CT image, we tested several popular objective image quality metrics, which focus on the similar perceptual features, on the CT image of phantom and animals. Experiments for verifying the feasibility were carried out. Compared with the subjective ratings from two professional radiation physicians, the complex wavelet-based structural similarity metric presents the better prediction results of the image quality. PMID- 21604503 TI - [ECG signal preprocessing based on morphological filtering]. AB - Electrocardiogram (ECG) signals are usually interfered by noises and base-line drift. A morphological filtering approach is put forward to remove the noise of the ECG signals and to calibrate the base-line drift in this paper. Different sizes of structuring elements were used to process the signals for different properties of ECG signal and noise. The morphological filtering approach is simple, fast and real-time in processing the signals, and it keeps the ECG signal shape unchanged while removing the noise. An experiment was carried out to simulate the morphological filtering approach with LabVIEW, and it was shown that this approach was effective in removing noise and in calibrating the base-line drift. PMID- 21604504 TI - [Prediction and research on homology of B-cell epitopes of Epstein-Barr virus nuclear antigen-1]. AB - We predict in this paper B-cell epitopes of Epstein-Barr virus nuclear antigen-1 (EBNA-1) and analyze the results matched with the related autoantigens sequence of human. We selected EBV-1 standard strain NA-1 amino acid sequence as the basis. We predicted B-cell dominant epitopes of EBNA-1 with the methods of SOPMA, GOR and HNN, combined with the multi-parameter analysis of transmembrane domain, hydrophilicity profile, surface probability, antigenicity index, polarity and average flexibility. The blastp method was adopted to analyze the matched results between the predicted B-cell epitopes of EBNA-1 and the related autoantigens sequence of human. The results have shown that the possible B-cell dominant epitopes of EBNA-1 were located in the N terminal regions of 16-23, 35-78, 332 337, 340-357, 398-404, 419-432 and 620-637, in which different regions gained higher scores when matched with small nuclear ribonucleoprotein SmB, SmD, ribonucleoprotein SSA, heterogeneous nuclear ribonucleoprotein hnRNP A1, hnRNP G, respectively. It was available to predict B-cell dominant epitopes of EBNA-1 with multiparameter methods and to analyze the same or similar autoantigens sequences of human, which laid a theory foundation for the study of pathogenesis, diagnosis and treatment of autoimmune diseases. PMID- 21604505 TI - [The primary research and development of software oversampling mapping system for electrocardiogram]. AB - We put forward a new concept of software oversampling mapping system for electrocardiogram (ECG) to assist the research of the ECG inverse problem to improve the generality of mapping system and the quality of mapping signals. We then developed a conceptual system based on the traditional ECG detecting circuit, Labview and DAQ card produced by National Instruments, and at the same time combined the newly-developed oversampling method into the system. The results indicated that the system could map ECG signals accurately and the quality of the signals was good. The improvement of hardware and enhancement of software made the system suitable for mapping in different situations. So the primary development of the software for oversampling mapping system was successful and further research and development can make the system a powerful tool for researching ECG inverse problem. PMID- 21604506 TI - [Preparation and clinical application of polyvinyl alcohol/drug-loaded chitosan microsphere composite wound dressing]. AB - In order to prepare and apply the polyvinyl alcohol/drug-loaded chitosan microspheres composite wound dressing, we first prepared chitosan microspheres by emulsion cross-linking method, and then added chitosan microspheres into the reactants during the acetalization of polyvinyl alcohol and formaldehyde. We further studied the morphology, water absorption, swelling degree, mechanical properties and in vitro release of the sponge with different amount of chitosan microspheres. The results showed that polyvinyl alcohol/drug-loaded chitosan composite sponge has porous structure with connectionism. Increasing the amount of chitosan microspheres would make the apertures smaller, so that the water absorption and the swelling of sponge decreased, but the tensile strength and compressive strength increased. With the increase of the amount of chitosan microspheres, the drug absorption of cefradine and the release rate increase, and the release time become longer. With the results of toxicity grade of 0 to 1, this type of composite sponge is non-toxic and meets the requirement of biocompatibility. The observation of rabbit nasal cavity after surgical operation suggested that polyvinyl acetal sponge modified with the chitosan has antiphlogistic, hemostatic and non-adherent characteristic, and can promote the healing and recovering of the nasalmucosa. After using this composite material, best growing surroundings for patients' granulation tissue were provided. Exposed bone and tendon were covered well with granulation tissue. PMID- 21604507 TI - [Research, design and application of model NSE-1 neck muscle training machine for pilots]. AB - Pain in the cervical region of air force pilots, who are exposed to high G forces, is a specifically occupational health problem. To minimize neck problems, the cervical muscles need specific strength exercise. It is important that the training for the neck must be carried out with optimal resistance in exercises. The model NSE-1 neck training machine for pilots was designed for neck strengthening exercises under safe and effective conditions. In order to realize the functions of changeable velocity and resistant (CVR) training and neck isometric contractive exercises, the techniques of adaptive hydraulics, sensor, optic and auditory biological feedback, and signal processing were applied to this machine. The training system mainly consists of mechanical parts (including the chair of flexion and extension, the chair of right and left lateral flexion, the components of hydraulics and torque transformer, etc.), and the software of signal processing and biological feedback. Eleven volunteers were selected for the experiments of neck isometric contractive exercises, three times a week for 6 weeks, where CVR training (flexion, extension, right, left lateral flexion) one time a week. The increase in relative strength of the neck (flexion, extension, left and right lateral flexion) was 70.8%, 83.7%, 78.6% and 75.2%, respectively after training. Results show that the strength of the neck can be increased safely, effectively and rapidly with NSE-1 neck training machine to perform neck training. PMID- 21604508 TI - [Research progress of olfactory receptor neurons and its application in olfactory biosensors]. AB - Olfactory organ is an important sensory system and therefore it can serve as the research object of the neural information processing and biologic evolution due to its simplicity and ancient characteristics of the system. Besides, the olfactory biosensors based on olfactory receptor neurons (ORNs) have prosperous applications in environmental monitoring and food testing. This review introduces configuration and signal transduction of ORNs. Then it examines neuronal coding strategies and how the characteristic of responses to mechanical stimuli applied to olfactory processing. Finally, it illustrates the recent research of olfactory biosensors based on ORNs/olfactory receptors and puts forward the direction of future research. PMID- 21604509 TI - [New applications and the comparison between atomic force microscope and electron microscope in regenerative medicine]. AB - This article introduces the basic theories about atomic force microscope (AFM) and electron microscope (EM), respectively. New applications of each microscopic technology in regenerative medicine, covering both material science and life science, are discussed. The advantages or disadvantages of the kinds of microscopes in working conditions, sample preparation, resolution and the like, are discussed and compared systematically to make clear each scope of applications. This could be a useful guide for selecting the appropriate microscopic analysis in research work about regenerative medicine. PMID- 21604510 TI - [PTD mediated protein transduction technology and its application in medical field]. AB - The delivery of bioactive macromolecular substances into cells provides an efficient approach to changing cellular conditions, and is thus of enormously potential therapeutic significance. It has also been an extremely difficult approach due the the impediment and protective nature of cell membrance until the protein transduction domain's (PTD's) capability to ferry macromolecule across cell membrance was discovered. PTD's efficient transductive function has rendered an exciting promise to the clinical treatment of diseases, therapeutic proteins drug development, and basic medical and applied research. The technology has been successfully applied to deliver a variety of substances into cells or tissue organs, and its superior application values have been explicitly demonstrated. PMID- 21604511 TI - [Potential of cell transplantation as an alternative to liver transplantation]. AB - Human hepatocyte transplantation to treat liver-based metabolic deficiencies and acute liver failure has shown promising early improvement in liver function; however, long-term success has not been achieved. Stem cell transplantation to restore liver function as an alternative to whole liver transplantation has not been successful in humans. As alternative sources of cells for human hepatocyte transplantation, stem cells are under investigation. The liver extracellular matrix presents an ideal scaffold for stem cell differentiation into hepatocytes, as well as cell transplantation. The innovative technique of the decellularized liver matrix presents great potential as the scaffold for hepatocyte maturation and transplantation, and allows the development of engineered recellularized liver graft for transplantation. PMID- 21604512 TI - [An overview of feature selection algorithm in bioinformatics]. AB - Feature selection (FS) techniques have become an important tool in bioinformatics field. The core algorithm of it is to select the hidden significant data with low dimension from high-dimensional data space, and thus to analyse the basic built in rule of the data. The data of bioinformatics fields are always with high dimension and small samples, so the research of FS algorithm in the bioinformatics fields has great foreground. In this article, we make the interested reader aware of the possibilities of feature selection, provide basic properties of feature selection techniques, and discuss their uses in the sequence analysis, microarray analysis, mass spectra analysis etc. Finally, the current problems and the prospects of feature selection algorithm in the application of bioinformatics is also discussed. PMID- 21604513 TI - [Developments in research of local bisphosphonate delivery system of implant denture]. AB - Dental implant is an advanced prosthodontic treatment widely accepted by patients with missing tooth. However, peri-implant bone loss is still an important reason which limits wider application of the implants to a certain extent. Bisphosphonates is an osteoclastic bone resorption inhibitor that is widely used in clinical practice with the function of inhibiting bone resorption and increasing bone density. As the defect of systemic BPs treatment, local application of BPs in implant has become a research hotspot recently. Calcium phosphate ceramics, polylactic acid, fibrinogen film and collagen membrane have been reported as BPs carriers. This article summarizes the researches on the mechanism of bone regulation and local delivering system of BPs. PMID- 21604514 TI - [The metal tantalum in orthopedic applications]. AB - This paper describes the biological characteristics of the metal tantalum (Ts) and the application status of tantalum in artificial joints, bone necrosis, spine, defects of bone and other aspects of bone. The early clinical application results of tantalum in bone diseases were satisfactory, but it is necessary to do further study of tantalum in a deep going way, and further detailed comparison between the tantalum with other metals as orthopedics implants. The advantage of tantalum materials as orthopedic implants still needs to be verified by a great deal of clinical cases for a long period of time. PMID- 21604515 TI - [Biological significance of IgA1 proteases]. AB - The IgA1 proteases are a group of proteolytic enzymes, which are produced by pathogenic bacteria that infect and colonize mucosal surfaces. This group of proteolytic enzymes was found to cleave specific peptide bonds within the sequence TPPTPSPSTPPTPSPS (T, P and S are threonine, proline and serine residues, respectively) found in the hinge region of human IgA1. Several findings support the role of IgA1 protease, for example, its ability to cleave human LAMP1 (hLAMP1), TNF-RII, the CD8 molecule of T lymphocytes and granulocyte-macrophage colony-stimulating factor (GM-CSF), synaptobrevin II, hormone human chorionic gonadotropin, and its ability to exhibit important immunomodulatory properties, etc. , in particular the induction of proinflammatory cytokines. The IgA1 proteases have been found to instigate part of the T cell inflammatory response, especially to stimulate the release of cytokines such as tumour necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and interleukin-8 (IL-8). All these suggest that this enzyme plays a significant role in pathogenesis. There are many other researches to explore new biological treatments of diseases using the biological characteristics of IgA1 protease. PMID- 21604516 TI - [Application of ozone concentration detection in the medical aspects and its development]. AB - This article introduces some commonly used methods of ozone concentration detection, including chemical method, UV absorption method, and electrochemical method etc., introduces the latest four ozone concentration sensors, and summarizes the advantages and disadvantages of each method. In addition, the article emphatically introduces the ozone's applications and development in the medical aspects. Prospects for the use of ozone concentration detection, ozone treatment and ozone therapy instrument are also demonstrated in it. The literature collected and reviewed on ozone concentration detection and ozone therapy includes 37 papers in English, and 50 papers in Chinese, but only 30 articles among them are included in this review (19 in Chinese and 11 in English), according to the principle of eliminating the old information and repetitive contents. The present paper selects only those on ozone, ozone concentration, ozone therapy and ozone therapy instrument. PMID- 21604517 TI - [Effect of interspinous stabilization system on spinal motion preservation]. PMID- 21604518 TI - [Analysis and strategy on the early complications of lumbar disc herniation with Coflex system]. AB - OBJECTIVE: To explore the short-term effectiveness and the cause of the early complications of lumbar disc herniation with Coflex system in order to provide evidence for the prevention. METHODS: From November 2007 to August 2008, 37 patients (20 males and 17 females) were treated with Coflex system. The age was from 33 to 70 years with an average of 52 years and the history was from 6 to 50 months with an average of 16.5 years. Complications were observed and the short term effectiveness was evaluated by scores of JOA and ODI before and after operation. RESULTS: All patients were followed up from 1 to 2 years with an average 20 months. The JOA score increased from 9.09 +/- 1.10 preoperatively to 25.40 +/- 1.20 in the last follow-up. ODI decreased from 24.70 +/- 4.80 preoperatively to 4.80 +/- 1.00 in the last follow-up. The VAS score decreased from 7.86 +/- 0.80 preoperatively to 3.20 +/- 0.50 in the last follow-up. The symptoms remarkably improved. Complications occurred in 4 pa-tients (10.8%), among them, persistent low back pain was in 1 case and conservative treatment did not work; opposite lower limb pain was in 1 case at the 3rd week after operation and symptomatic treatment was effective; displacement of Coflex was in 1 case and Coflex breakage happened in 1 case at the 6th month after operation, but both did not have related clinical symptom. CONCLUSION: Coflex can obtain good clinical outcomes in treating lumbar disc herniation, but it has special complications. The indications and manipulations should be chosen properly. PMID- 21604519 TI - [Spinal fusion combined with dynamic interspinous fixation with Coflex system for lumbar degenerative disease]. AB - OBJECTIVE: To summarize the effect of the implantation of Coflex interspious stabilization device combined with pinal fusion for the treatment of lumbar degenerative disease. METHODS; From March 2008 to March 2010, 18 patients with two levels lumbar degenerative disease were treated with spinal fusion and dynamic interspinous fixation with Coflex system. There were 11 males and 7 females. The average age was 50.2 years (range 41 to 62 years). The VAS and the Oswestry Disability Index (ODI) were used to assess clinical symptoms preoperatively and postoperatively. All patients underwent flexion/extension radiographs examinations before surgery and at last follow-up. Range of motion (ROM) and disc height index (DHI) were recorded. RESULTS: All patients were followed up for 12 months averagely (range 6-30 months). At final follow-up, leg VAS, back VAS and ODI functional score were significant improved than those of preoperation [back VAS: 1.50 +/- 0.90 vs 7.20 +/- 0.90; leg VAS: 1.10 +/- 0.80 vs 5.20 +/- 0.90; ODI functional score: (15.90 +/- 5.80)% vs (52.50 +/- 5.90)%]. The DHI increased from 0.23 +/- 0.05 preoperatively to 0.35 +/- 0.06 postoperatively and to 0.33 +/- 0.04 at final follow-up, the height of intervertebral space were not found significant loss. The ROM at the Coflex stabilized levels on the X-ray views was (8.90 +/- 1.80) degrees preoperatively, (8.30 +/- 1.90) degrees postoperatively, and (8.10 +/- 1.80) degrees at final follow-up. There was no significant difference between final follow-up and preoperative (P = 0.19). The ROM of the lumbar spine (L2-S1) was (20.20 +/- 5.60) degrees preoperatively, (14.40 +/- 5.70) degrees postoperatively, and (15.50 +/- 5.20) degrees at final follow-up. There was significant reduction of the [E-S, ROM at final follow-up (P = 0.01). CONCLUSION: Posterior interspinous stabilization with Coflex system combined with spinal fusion can obtain satisfactory outcomes for patients with two levels lumbar degenerative disease in the short follow-up duration. Nevertheless,no overwhelming evidence suggested that the system is better than traditional fusion at present. The selection of surgical indication is important for the treatment of lumbar degenerative disease. PMID- 21604520 TI - [The clinical observation about Coflex of dynamic interspinous implant on the treatment of lumbar spinal stenonis]. AB - OBJECTIVE: To identify the initial effect of dynamic interspinous implant of Coflex on the treatment of lumbar spinal stenosis. METHODS: A retrospective study of 18 patients who underwent posterior lumbar decompression and fixation with interspinous implant of Coflex between March 2008 and October 2009 was taken to compare the Cobb angel of nature and dynamic position on the segment of Coflex fixation at the time of before and after operation and following time,including 10 males and 8 females with average age of 62.2 years old (54 to 71 years). The symptoms of patients included chronic lower back pain and intermittent claudication and lower extremity numbness. All cases including 17 cases of L4,5 and 1 case of L3,4 were central canal stenosis without obviously segmental instability. Clinical outcomes were evaluated with VAS and ODI. RESULTS: All patients were followed up from 10 to 18 months with an average of 14.4 months. There did not about internal fixation failure. It was found that postoperative Cobb angel of fixation segment [(12.1 +/- 2.6) degrees] was significantly decreased than preoperative [(14.8 +/- 3.2) degrees] (t = 2.61, P = 0.03). But the Cobb angel [(14.9 +/- 4.1) degrees] increased at final follow-up, even reached the level of before operation (t = 1.39, P = 0.65). The Cobb angle of upper adjacent segment did not obviously change in preoperation, postoperation and final follow-up [(12.1 +/- 2.3) degrees, (12.3 +/- 3.2) degrees, (11.9 +/- 3.0) degrees, respectively]. Dynamic measure showed that Coflex can adequately limit the ROM of extension (t = 4.01, P = 0.001), but the ROM of flexion increased (t = 2.57, P = 0.02). The VAS score in follow-up (2.2 +/- 0.7) was significantly decreased than before operation (4.9 +/- 1.1, t = 2.95, P = 0.02). The ODI score in follow-up [(29.1 +/- 9.0)%] was significantly decreased than before operation [(56.5 +/- 14.2)%, (t = 3.02, P = 0.02)]. CONCLUSION: The Coflex implanting combined with decompression can get good result clinically, but imaging showed that Coflex can not maintain the relatively kyphosis gained after operation except for extension limitation. PMID- 21604521 TI - [Application of Bioflex dynamic stabilization system in treating multi-segment lumbar degenerative disease]. AB - OBJECTIVE: To explore the value of application of Bioflex dynamic stabilization system in treating multi-segment lumbar degenerative disease. METHODS: Clinical datas of 13 patients with multi-segment lumbar degenerative disease (8 males and 5 females,ranging in age from 51 to 72 year with an average of 65.0) were retrospectively analyzed between April 2008 and May 2009. The involved area included L3-S1 in 7 cases, L2-S1 in 3 cases, L3-L5 in 1 cases, L4-S1 in 2 cases. All patients underwent decompression, dynamic stabilization with Bioflex system, according to the severity of degenerative disc with/without interbody fusion. The clinical effects were evaluated by VAS, ODI. ROM and fusion segments were also observed. RESULTS: The mean follow up period was 19.5 months (from 12 to 26 months). The mean operative time was 183.4 min (from 90 to 240 min) and the mean volume of blood loss was 610.2 ml (from 400 to 1 220 ml). The mean VAS score was 7.8 +/- 1.3 preoperatively, 2.3 +/- 0.9 postoperatively and 2.1 +/- 0.8 at the last follow up. The average ODI was (60.50 +/- 4.40)% preoperatively, (17.80 +/- 2.10)% postoperatively and (16.20 + 2.40)% at the last follow up. The VAS and ODI significant improved in postoperatively (P < 0.05), and there was no statistical difference between postoperative and last follow up (P > 0.05). ROM of whole lumbar and non-fused segment showed obviously decreased and adjacent segment showed insignificant increased. The fusion rate of interbody fusion level was 95.0% (19/20). CONCLUSION: The preliminary clinical results show the Bioflex system combined with intebody fusion is a safe and effective technique in treating multi-segment lumbar degenerative disease. PMID- 21604522 TI - [Treatment of Colles fractures with manipulation of pulling and shaking]. PMID- 21604523 TI - [Clinical analysis of interspinous dynamic internal fixation with the Coflex system in treating lumbar degenerative disease]. AB - OBJECTIVE: To compare the clinical effects between interspinous dynamic internal fixation with Coflex system and posterior lumbar interbody fusion in treating lumbar degenerative disease. METHODS: From Jan. 2007 to Jan. 2010, 42 patients with lumbar degenerative disease were treated with interspinous dynamic internal fixation with Coflex system (non-fusion group, 21 cases) and posterior lumbar interbody fusion (fusion group, 21 cases), including 19 males and 23 females with an average age of (46.5 +/- 8.5) years (range, 33 to 62 years). The range of course of disease was from 6 to 84 months with an average of 36 months. All pathological changes were single segment in L4.5 by X-ray films or CT scanning, among them, single lumbar disc herniation was in 14 cases,combined with lumbar spinal stenosis in 28 cases. The clinical effects of all patients were evaluated according to Japanese orthopaedic association (JOA, 29 points) and Oswestry disability index (ODI); range of motion (ROM) of lumbar segments were measured by X-ray films; operative time, intraoperative blood loss,hospital stay were compared between two groups. RESULTS: All patients were followed up for 10 months at least. In non-fusion group, JOA increased from 13.8 +/- 3.7 preoperatively to 24.6 +/- 4.6 at final follow-up (P < 0.01); ODI decreased from 65.8 +/- 7.5 to 25.6 +/- 5.1 (P < 0.01), ROM improved from 4.2 +/- 0.7 to 5.3 +/- 0.6 at L4,5 (P < 0.01 ). In fusion group,JOA increased from 13.2 +/- 3.2 preoperatively to 24.5 +/-4.3 at final follow-up (P < 0.01); ODI decreased from 65.5 +/- 8.2 to 26.5 +/- 6.1 (P < 0.01); all ROM at L.4,5 had lose (decreased from 4.2 +/- 3.2 to 0). There were significant differences in the operative time, intraoperative blood loss, hospital stay between two groups (P < 0.01), in non-fusion group was respectively (71.2 +/- 12.8) min, (56.6 +/- 25.5) ml, (4.4 +/- 1.3) d and in fusion group was respectively (121.0 +/- 23.2) min, (135.8 +/- 19.8) ml, (12.6 +/ 2.4) d. No complications were found with the Coflex system. CONCLUSION: Interspinous dynamic internal fixation with Coflex system in treating lumbar degenerative disease is better than that of posterior lumbar interbody fusion in some aspects. Coflex system have high safety, less trauma, and can reserve lumbar mobility, which is effective in preventing adjacent intervertebral disc degeneration. PMID- 21604525 TI - [The study of pedicle imaging and reformation with the multi-slice spiral CT in the surgical treatment of lumbar spondylolisthesis]. AB - OBJECTIVE: To evaluate the value of pedicle parameter obtained by the reformation images on multi-slice spiral CT (MSCT) in the surgical treatment of lumbar spondylolisthesis. METHODS: From January 2009 to March 2010, 60 patients with lumbar spondylolisthesis failing in conservative treatment were enrolled into the study and divided into experimental and control group randomly (each group with 30 patients). There were 26 males and 34 females ranging in age from 18 to 59 years with an average of (42.60 +/- 9.36) years. The experimental group was examined with volumetric scanning on MSCT before operation. Reformation such as multiplanar reconstruction (MPR) and volume rendering (VR) were carried out at the work station. Transverse section angle (TSA), sagittal section angle (SSA), pedicle length (PL), pedicle width (PW) and pedicle height (PH) were measured on different images and pedicle screws were implanted according pedicle parameter. In control group, the pedicle screws were implanted according to conventional anatomic landmark. Preparative time of screw canal and accuracy of screw were compared between two groups. RESULTS: A hundred fifty-six screws were inserted in experiment group,143 screws were excellent, 11 good, and 2 poor. A hundred fifty screws were inserted in control group, 101 screws were excellent, 26 good, and 23 poor. There was significant difference in accuracy of screw between two groups (P < 0.001). The preparative time of screw canal in experiment group was (66.20 +/- 7.31) s, and was shorter than that of control group [(104.11 +/- 9.51) s, P < 0.001)]. CONCLUSION: Abundant information and parameter could be obtained with the MSCT reconstruction images. The images and parameters could make a perfect operative strategy before operation, adjust the direction of pedicle screws during operation, avoid and decrease operative complications effectively. PMID- 21604524 TI - [Comparison of the status of STAT4 tyrosine phosphorylation in peripheral T lymphocytes induced by IL-12 in rheumatoid arthritis and osteoarthritis]. AB - OBJECTIVE: To compare the levels of STAT4 tyrosine phosphorylation in peripheral T-lymphocytes induced by IL-12 in rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: From May 2007 to August 2009, peripheral blood mononuclear cells (PBMCs) were isolated from RA patients [RA group, all the cases were female, the age was from 28 to 55 years with an average of (45.0 +/- 13.0) years] and OA patients [OA group, all the cases also were female; the age was from 55 to 75 years with an average of (67.0 +/- 9.6) years]. The purity of T-lymphocytes from PBMCs was accredited by flow cytometry. The IL-12 of 50 ng/ml added in T lymphocytes, the levels of STAT4 tyrosine phosphorylation were detected by western blot after different time intervals (0, 10, 30, 60 min). RESULTS: The purity of T-lymphocytes were above 91% through diremption and depuration for peripheral blood monouclear cells. The levels of STAT4 tyrosine phosphorylation in T-lymphocytes from RA induced by IL-12 were higher than that from OA in the different times (10, 30, 60 min); after 30 min, its levels from RA and OA achieved to crest value. CONCLUSION: STAT4 in peripheral T-lymphocytes of rheumatoid arthritis was more easily to be activated than osteoarthritis. PMID- 21604526 TI - [Bilateral distal clavicle fractures: a case report]. PMID- 21604527 TI - [A study of 22 displaced intraarticular calcaneal fractures using locking plates with and without bone graft]. AB - OBJECTIVE: To analyze locking plates with bone graft fusion in treating displaced intraarticular calcaneal fractures and determine whether it is beneficial in maintaining restoration of calcaneal height and anatomic reduction of the articular surface. METHODS: From January 2007 to January 2008, 22 patients with displaced intraarticular calcaneal fractures were treated with locking plates with and without bone graft (divided into the bone graft group and non-bone graft group). There were 17 males and 5 females, ranging in age from 18 to 59 years with the mean of 35 years. Sanders III was in 14 cases and Sanders IV in 8 cases. Autologous iliac bone filled defects with locking plates fixation for the bone graft group; just locking plates fixation were performed for non-bone graft group. The Bohler angle and Gissane angle were measured before and after operation. The foot function of two groups were compared according to Maryland standard at the 6th month, 1, 2 years after operation. RESULTS: All patients were followed up with an average of 25 months. There was no significant difference in the recovery of Bohler angle and Gissane angle between two groups (P > 0.05). After the 6 months,1, 2 years, there was no significant difference in the foot function between two groups (P > 0.05), in bone graft group, excellent result was in 6, 7 ,7 cases respectively; and in non-bone graft group, excellent results in 5, 6, 7 cases respectively. CONCLUSION: Bone graft in the surgical treatment of calcaneal fractures is not an advantage. PMID- 21604528 TI - [Technique of bending rod reduction in situ for low lumbar burst fracture]. AB - OBJECTIVE: To evaluate the efficacy and the feasibility of bending rod reduction in situ technique in treating low lumbar burst fracture. METHODS: From March 2007 to June 2009, 21 patients with low lumbar burst fracture were retrospectively analyzed, 11 cases were in L3,6 in L4 and 4 in L5. There were 16 males and 5 females, ranging in age from 25 to 59 year with an average of 37.9 years. According to ASIA classification, nerve function was level A in 2 cases, level B in 2, level C in 10, level D in 4 and level E in 3. Pedicle screws were implanted and bending rod reduction in situ technique was applied through posterior approach. Radiographic and neurological scores were compared before and after operation. RESULTS: All patients were followed up from 12 to 39 months with an average of 16.5 months. Radiographic examinations demonstrated that anterior height of fractured vertebral body was from 57.9% preoperatively to 94.1% postoperatively (P < 0.01 ); sagittal index was from 29.1 preoperatively to 0.240 postoperatively (P < 0.01). Spinal canal occupation ratio was from 49.6% preoperatively to 13.4% postoperatively (P < 0.01). Nerve function was level A in 2 cases,level B in 0, level C in 0, level D in 4 and level E in 15. CONCLUSION: Bending rod in situ technique could achieve 3-column reduction in 3-dimentionally at the same time, and reconstruct the stability of low lumbar. PMID- 21604529 TI - [Application of modified posterior decompression for the treatment of thoracolumbar burst fractures]. AB - OBJECTIVE: To study therapeutic effects of self-designed canal decompressor in the posterior surgical treatment of thoracolumbar burst fractures, and provide evidence for widespread application. METHODS: From January 2008 to December 2008, the self-designed canal decompressor was used in 43 patients (30 males and 13 females, ranging in age from 22 to 49 years) with thoracolumbar burst fractures. According to Denis classification, there were 12 cases of type A, 24 cases of type B, 6 cases of type D and 1 case of type E. Affected segment: 16 patients in T12,19 patients in L1 and 8 patients in L2. The index of intra-operative blood loss, postoperative 24 h wound drainage volume, and operative time were compared with those of 16 patients who undergone traditional operation. The preoperative and postoperative vertebral canal volume, Cobb angles, residual vertebral body height, neurological outcome, and back pain were evaluated and compared. RESULTS: All the patients healed without wound infection, neurological symptoms and other complications. Forty-three patients were followed up ranging from 12 to 24 months, with a mean of (16.5 +/- 2.5) months. Compared with traditional posterior operation, the blood loss and operative time in modified posterior approach group had statistically significant difference, but the postoperative 24 h wound drainage had no significant difference between the two groups. CT scan indicated that applying the canal decompressor allowed efficient restore of canal volume from preoperative (49.4 +/- 16.7)% to postoperative (12.8 +/- 4.2)%. The X-ray showed Cobb angles reduced from preoperative (30.1 +/- 2.4)degrees to postoperative (5.1 +/- 0.6) degrees. Mean vertebral height was restored to (81.5 +/- 5.5)% after operation. Follow-up evaluation indicated that neurological recovery presented in 33 patients,with an average improvement of 0.87 Frankel grades. Neurological deterioration was not observed. CONCLUSION: Applying the canal decompressor enables efficient and safe spinal decompression, restore the height of the injured vertebrae, reconstruction of the anterior-middle column stability,and prevention of postoperative vertebral height and Cobb angle lost. PMID- 21604530 TI - [Analysis of therapeutic effects of cannulated compression screws for the treatment of femoral neck fractures]. AB - OBJECTIVE: To evaluate the therapeutic effects of cannulated compression screws for the treatment of femoral neck fractures, and to investigate the related factors influencing the avascular necrosis of femoral head after surgery. METHODS: A retrospective review was done for 96 patients with femoral neck fractures treated with cannulated compression screws from January 2003 to June 2009. Among them, there were 44 males and 52 females with 21 to 88 years old (averaged 56.3 years old). According to Garden classification, 4 patients were type I, 34 patients were type II, 37 patients were type III and 21 patients were type IV. Factors such as patients' age, gender, fracture type, duration from injury to surgery and fracture reduction quality were statistically analysed to find correlations with nonunion and avascular necrosis of femoral head. RESULTS: Eighty-four patients were followed up ranging from 9 to 60 months and the mean time was 25.4 months. Postoperative complications included deep venous thrombosis of lower extremity in 2 cases, bone nonunion in 8 cases and avascular necrosis of femoral head in 11 cases. According to Harris criterion, the total postoperative Harris score was 86.20 +/- 11.00, and 40 patients got an excellent result, 32 good, 7 fair and 5 poor. The incidence of avascular necrosis of femoral head in nondisplaced fracture group and displaced fractures group were 3.22% and 18.87% respectively;and there were significant difference between the two groups (P = 0.037). The incidence of avascular necrosis of femoral head in anatomical reduction group and non-anatomical reduction group were 5.00% and 20.45% respectively; also,significant difference was existed between the two groups (P = 0.036). However, there was no statistically significant difference of the incidence of avascular necrosis of femoral head according to different age, sex, operative time. CONCLUSION: The therapeutic effect of cannulated compression screws for non-displaced femoral neck fractures is good. The fracture type and reduction quality are found to be main factors correlated with avascular necrosis of femoral head statistically. For young patients with a displaced femoral neck fracture,in order to avoid incidence of avascular necrosis of femoral head, anatomical reduction should be ensured. For elder patients with a severe displaced femoral neck fracture, the total hip replacement should be recommended. PMID- 21604531 TI - [Comparison of clinical effects for three methods in treating comminuted patellar fractures]. AB - OBJECTIVE: To compare clinical effects of different fixations in order to provide the best therapeutic choice for comminuted patellar fractures. METHODS: From February 2003 to June 2009, 56 patients with comminuted patellar fractures were treated with three methods of fixation. Of them, 18 patients (group A) were treated with Kirschner-wire with steel wire fixation, there were 9 males and 9 females, ranging in age from 32 to 52 years with an average of (47.62 +/- 4.82) years; 13 patients (group B) with circular silk thread fixation and plaster immobilization, there were 3 males and 10 females,ranging in age from 38 to 65 years with an average of (48.58 +/- 8.28) years; 25 patients (group C) with memory alloy patella holder fixation, there were 9 males and 16 females, ranging in age from 32 to 68 years with an average of (48.36 +/- 9.59) years. According to criteria of Bostman, eight indexes were compared, including the range of motion of the knee, pain, walking and so on. RESULTS: All patients were followed up from 8 to 26 months with an average of 15.6 months. All the fractures healed. The Bostman scoring of group A, B, C were respectively 26.00 +/- 4.6, 22.08 +/- 5.31, 26.44 +/- 3.77. The clinical effects of group A and C were better than that of group B (P < 0.05). CONCLUSION: The method of Kirschner-wire with steel wire fixation or memory alloy patella holder fixation can obtain satisfactory effects in treating comminuted patellar fractures because of steady fixation and early function recovery. PMID- 21604532 TI - [Treatment of dislocation of ankle and its adjacent multi-joints]. PMID- 21604533 TI - [Surgical treatment for the thoracolumbar spinal tuberculosis with paraplegia]. AB - OBJECTIVES: To explore the long-term effects,operating opportunity,indication of anterior debridement and decompression and bone graft in treating thoracolumbar tuberculosis with paraplegia. METHODS: From March 2006 to September 2008, the data of 56 patients with spinal tuberculosis were retrospectively analyzed. They were 36 cases male and 20 cases female, the age in ranging from 19 to 78 years with the mean of 42.5 years; course of disease in ranging from 3 months to 4 years. The lesion level was in T11-L2, including one stage in 6 cases, two stages in 42 cases, three stages in 7 cases, four stages in 1 case. According to the Frankel grade, grade A in 5 cases, B in 25, C in 21, D in 5. Preoperative Cobb angle had 30 cases under 30 degrees, 24 cases in 30 degrees-60 degrees, 2 cases more than 60 degrees [averaged in (35.0 +/- 3.3) degrees]. The mean VAS was 7.3 +/- 2.1 preoperatively. All patients had chemotherapy for 2-3 weeks. The clinical effects were evaluated by Cobb angle, VAS, condition of Frankel grade and fusion segments. RESULTS: All patients were followed up from 12 to 38 months with an average of 24 months. All wound obtained primary healing. The Cobb angle was(19.0 +/- 5.5) degrees immediately after operation, and lost (1.8 +/- 0.7) degrees at the follow up. The mean VAS was 1.4 +/- 0.3 postoperatively and 1.3 +/- 0.4 at final follow up. The Cobb angle and VAS significant improved in postoperatively (P < 0.05), and there was no statically difference between after operation and last follow up(P > 0.05). At 1 year after operation, all patients obstained successful bony fusion. Among 51 cases incomplete paraplegia recovered partially or completely (over Frankel D) through chemotherapy and rehabilitation training for 1-1.5 years; 5 cases of complete paraplegia had partially recovered, 3 cases from Frankel A to C, 2 cases from Frankel A to B. CONCLUSION: Base on the chemotherapeutic effect, paraplegia reason and location, total body condition to select different operative opportunity can effectively relieve spinal compression, stabilize spinal column, correct kyphosis and promote recovery of paraplegia. PMID- 21604534 TI - [Effect of removing dampness and promoting diuresis method on IgG, IgM and IL 1beta, IL-8 in serum of rats with autoimmunity induced by nucleus pulposus]. AB - OBJECTIVE: To explore the effects of removing dampness and promoting diuresis method on autoimmune and immuno-inflammatory response caused by nucleus pulposus of rats, in order to provide the basis for the treatment of lumbar disc herniation with Chinese medical immunotherapy. METHODS: Forty male Wistar rats were divided into 4 groups randomly according to body weight layer:sham operation group (group A), model contrast group (group B), colchicine tablets group (group C), modified Qingyao decoction group (group D). There were 10 rats in each group. Nucleus pulposus of coccygeal vertebra was transplanted to the gluteal muscle by operation in groups B, C, D, which can lead to autoimmune and immuno-inflammatory response of rats; the rats of group A were only treated with sham operation. At the 3rd day after operation, the rats were fed through intragastric administration, the group A and B with distilled water (10 ml/kg), the group C and D respectively with suspension of colchicine tablets (10 ml/kg, 0.01 mg/ml) and water-decocted liquid of modified Qingyao decoction (10 ml/kg,1.035 g/ml), once a day and continuous medication for 18 days. All rats were killed at the 21th day after operation. The immunoglobulin G (IgG), immunoglobulin M (IgM) and interleukin-1beta (IL-1beta), interleukin-8 (IL-8) level in serum of different groups were detected by ELISA method. At the same time, surrounding tissues of the transplanted nucleus pulposus were observed by pathological section. RESULTS: The level of IgG, IgM, IL-1beta, IL-8 in serum of group B was significantly higher than that of group A (P < 0.01), while the level of IgG, IgM, IL-1beta, IL 8 in serum of group C, D was significantly lower than that of group B (P < 0.05 or P < 0.01). Moreover, pathological section indicated that immuno-inflammatory response was hardly found in surgical site of group A, while local immuno inflammatory response of surrounding tissues of the transplanted nucleus pulposus of group C and D was much lighter than that of group B. CONCLUSION: Removing dampness and promoting diuresis method could inhibit autoimmune and immuno inflammatory response caused by nucleus pulposus of rats. PMID- 21604535 TI - [Experiment on articular cartilage defect repaired with autologous cancellous bone or cancellous bone enriching bone marrow stem cell]. AB - OBJECTIVE: To compare and evaluate the effect of autologous cancellous bone and cancellous bone enriching bone marrow stem cell for the repairing the defects of articular cartilage, and purpose the experimental basis for clinical application. METHODS: By using the completely random design, 16 adult rabbits were divided into two groups randomly. Autologous cancellous bone and cancellous bone enriching bone marrow stem cells were applied for repairing size-matched, full thickness articular cartilage defects on the femoral condyle of the knees. The reconstructed tissues were observed by gross, optical and microscopy view and Wakitani score at 12 weeks respectively. RESULTS: In cancellous bone enriching bone marrow stem cells group, articular surface was ivory white and relative evenness, the regenerated tissues integrated well with the surrounding normal cartilage with obscure boundary between them. The thickness of regenerated tissues was two-third of normal cartilage, the Wakitani score was 4.44 +/- 1.41. In autologous cancellous bone group, articular surface was gray and introcession, the regenerated tissues was very thin, the thickness of regenerated tissues was one thirds or one half of normal cartilage, the Wakitani score was 8.93 +/- 1.18. The differences between two groups were significant (P < 0.01). CONCLUSION: Cancellous bone enriching bone marrow stem cells are feasible for repairing of large articular cartilage defects with hyaline cartilage. The repairing ability of autologous cancellous bone is inferior. PMID- 21604536 TI - [Closed reduction and percutaneous Kirschner pin fixation combined with plaster support for the treatment of supracondylar humerus fractures in children]. AB - OBJECTIVE: To investigate the therapeutic effects of closed reduction and percutaneous Kirschner pin fixation combined with plaster support for the treatment of supracondylar humerus fractures in children. METHODS: From June 2007 to December 2008, 27 patients with Gartland III supracondylar fractures were treated with closed reduction and percutaneous Kirschner wire fixation combined with plaster support. Among the patients, 18 patients were male and 9 patients were female, ranging in age from 6 to 12 years,with an average of 8.1 years. Fifteen patients were extension type, 12 patients were buckling type; fourteen patients were ulnar deviation, 13 patients were radial deviation. The duration from injury to treatment ranged from 0.5 to 8 days, averaged 3.6 days. RESULTS: Twenty-seven patients were followed up, and the duration ranged from 6 to 24 months, averaged 13.5 months. The healing time ranged from 4 to 6 weeks after surgery, with a mean of 4.5 weeks. Complications including implants loosening, fracture re-displacement, Volkmarm contraction, needle point or deep infection, ulnar nerve injury, myositis ossificans were found during follow-up. Two patients had postoperative elbow varus, but the varus angle was not more than 15 degree,which may be due to inappropriate functional exercise or early removal of external fixation. According to Flynn criteria, 19 patients got an excellent result, 5 good, 2 poor and 1 bad. CONCLUSION: Closed reduction and percutaneous Kirschner wire fixation combined plaster support for the treatment of unstable supracondylar fractures in children has advantages including little trauma, reliable fixation, good elbow function and appearance. PMID- 21604537 TI - [Posterior debridement for the treatment of iatrogenic purulent lumbar spinal infection]. AB - OBJECTIVE: To discuss diagnosis and treatment of iatrogenic purulent lumbar spinal infection. METHODS: From December 2006 to January 2010, 4 patients with iatrogenic purulent lumbar spinal infection were treated with posterior debridement. There were 2 males and 2 females, ranging in age from 50 to 66 years (respectively in 52, 66, 58, 50 years); in course of disease from 2 weeks to 2.5 months (respectively in 21, 14, 60, 75 days ). All patients had fever, lumbago, local tenderness and limited lumbar activity before operation. White blood cell count (WBC), erythrocyte sedimentation rate (ESR) were abnormal. The clinical effects were evaluated by symptoms and laboratory examination. RESULTS: Symptoms of lumbago and fever vanished in 4 patients, of which wounds were primary healing without complications. The patients were followed up for 3 months, no infection (WBC, C-reactive protein and ESR were normal) and lumbar instability were found. CONCLUSION: Iatrogenic purulent lumbar spinal infection can be diagnosed according to course of disease, clinical symptoms and signs, imaging finding. In the items, magnetic resonance imaging finding have necessarily specificity, once finding abscess-formation, will promptly operate. PMID- 21604538 TI - [The operative treatment of Ruedi II-III Pilon fractures with the ventr-lateral approach]. AB - OBJECTIVE: To investigate the effects of the ventralateral approach in treating severe Pilon fracture. METHODS: From February 2002 to March 2008, 63 patients with Ruedi II-III Pilon fractures were treated with the ventralateral approach, including 36 males and 27 females with an average age of 37 years ranging from 19 to 71 years. The mean time from injury to operation was 8 days (ranged for 2 h-19 d). According to the Ruedi classification system, type II was 32 cases (6 cases of them combined with soft tissue lesion, 4 with open fracture) and type III was 31 cases (9 cases of them combined with soft tissue lesion, 8 with open fracture). The clinical effects were evaluated according to Helfet criteria and the complications were observed including condition of wound healing, infection, bone union, deformity union, motion of the ankle, the degree of the pain and so on. RESULTS: The first intention achieved in 59 cases, the delayed healing in 4 cases. Stiffness of the ankle was found in 5 cases because of bone disunion. All patients were followed up from 8 to 31 months with an average of 15.3 months. The ranging in bone healing time was from 8 to14 weeks with an average of 10 weeks. According to the Helfet criteria, 28 cases obtained excellent results, 30 good, 5 poor. CONCLUSION: The operative treatment of Ruedi I-III Pilon fractures with the ventralateral approach can obtain satisfactory results and avoid complications effectively. PMID- 21604539 TI - [Surgical treatment of fibrous dysplasia in proximal femur]. AB - OBJECTIVE: To summarize the oncological and functional results of patients with fibrous dysplasia in the proximal femur and explore its clinical effect. METHODS: From Apr. 2007 to Jan. 2009, 15 patients with fibrous dysplasia in proximal femur were treated. There were 9 males and 6 females, ranging in age from 16 to 32 years with an average of 25 years. The course of disease was from 2 months to 16 years with an average of 2 years. Among them, 12 cases were unilateral affection and 3 cases were hibateral affections; 12 cases were one bone and 3 cases more than two bones. The collodiaphyseal angles of 2 cases with coxa adducta was 80 degrees and 100 degrees respectively; and femur lengths were shorter than opposite side (5 cm and 3 cm, respectively). The curettage and allogenous and/or autogenous bone-grafting combined with internal fixation were performed in all patients and valgus osteotomies was performed in 2 case with shepherd's crook deformity. RESULTS: All patients were followed up from 12 to 32 months. Two cases with shepherd's crook deformity, the collodiaphyseal angles recovered after surgery, the relative length of femur was increased 4 cm and 3 cm respectively and they can walk with stick at 4 months after operation. No found recurrence and loosening of internal fixation. Bone graft was absorbed at 3 months and bone healing at 8-12 months after operation. The pain vanished and functions were normal. CONCLUSION: It is an effective method to treat fibrous dysplasia in proximal femur with curettage and bone-grafting combined with internal fixation. Corrective osteotomy and internal fixation with a dynamic hip screw is a good and effective method in treating severe symptomatic shepherd's crook deformity. PMID- 21604540 TI - [Technology of finite-element analysis and its application in the field of acetabular prosthesis]. AB - The hip with distinctive anatomical structure and complicated function plays an important role in normal standing and activity. The clinical doctors have paid attention to studies on hip biomechanics of normal structure and reconstruction. It was difficult for us to analyze hip in vivo because of its complex structure. Many examinations were preformed on animal models, but the reliability of results was unavoidably affected. Technology of finite-element analysis as one of the main methods of mechanics had been successfully applied in many fields, especially in analyzing on irregular bodies. The application in the field of orthopaedic surgery, for example the optimal design for prosthesis, stress analysis of grafts etc, had made great progress. The method could help us to improve current thoughts on study of biomechanics and make continuous advance in the future. PMID- 21604541 TI - [Experimental research progress of warming yang and reinforcing kidney of Chinese medicine to promote the differentiation of bone marrow stromal cells]. AB - Bone marrow stromal cells (BMSCs), a kind of stem cells residing in bone marrow, have self-renewal, high proliferative capacity and the potential of multilineage differentiation. It has a good prospect in application of the cell replacement therapy, the gene therapy and the tissue engineering and so on. As the content of BMSCs is extremely low in bone marrow, BM-SCs must be amplified in vitro and induced to differentiation to meet the clinical needs. Researches of the recent years suggest there is a very promising way that Chinese medicine could induce BMSCs proliferation, differentiation. Based on the Chinese medicine theory, "the kidney generating marrow and dominating bone" and "kidney storing essence, essence and marrow", the TCM scholars have done some researches to explore the function of warming yang and reinforcing kidney of Chinese medicine to promote bone marrow stromal cells and found that these drugs can promote the BMSCs to proliferate and to differentiate into osteogenic, cartilage and nerve cells. This article elaborates and presents the researches on this aspect. PMID- 21604542 TI - [Advances in bacterial type VI secretion system--a review]. AB - Type VI secretion system (T6SS) is a newly found secretion system, which distributes widely in Gram-negative bacteria. It consists of structural proteins (constitute secretion system), translocated proteins (form transmembrane pipe structure), secretory proteins and a few auxiliary function proteins for secretion systems. T6SS can enhance the adaptability of bacteria on the environment,mediate pathogenicity to host cells and has some other functions. PMID- 21604543 TI - [Application of microorganisms in biosynthesis nanomaterials--a review]. AB - Biosynthesis of nanomaterials, as a novel "green synthesis technology", has attracted increasing interests. Many microorganisms such as bacteria, actinomycetes (eukaryotes), as well as yeasts and fungi (prokaryotes) have been found to have ability to biosynthesize nanomaterials intracellularly or extracellularly. A series of metal and semiconductor nanomaterials with the excellent features of high monodispersity, stabilization, adjustable size,and biological activity,such as Au, Ag, Au-Ag, Fe3 O4/Fe3 S,Titanium and CdS, CdSe, and Silica, have been biosynthesized. Here, we provided a brief overview of the current research on the use of microorganisms in the biosynthesis of nanomaterials. The biological procedures, biosynthesis mechanism, controlled biosynthesis on the shape and size,and their applications were summarized. The prospects of biosynthesis using microorganism have also been addressed. PMID- 21604544 TI - [Microbial NAD synthetase and its inhibitors--a review]. AB - Nicotinamide-adenine dinucleotide (phosphate) (NAD(P)) metabolism involves many fundamental cellular events, such as energy metabolism, maintenance of redox homeostasis and regulation of cell longevity. Inhibitors of essential enzymes of NAD(P) biosynthetic pathways might be promising leads for novel antibiotics, such as the NAD synthase inhibitors. This review described the crystal structural, functional properties, regulator and structure-based inhibitors design for NAD synthase. This might provide the basis for developing NAD-based therapeutics. PMID- 21604545 TI - [Isolation and identification of a pyrene-degrading bacterial strain from contaminated soil]. AB - OBJECTIVE: The aim of this study was to isolate high-molecular-weight polycyclic aromatic hydrocarbons (HMW-PAHs) degrading bacterial strains, and to study their degradation potential. METHODS: We used sublimation method to enrich and isolate the degrading bacteria from coking plant samples. Morphological properties, the sequence homology of 16S rRNA and gyrb genes were used to identify the isolated strains. GC-MS was used to analyze the degradation potential against some HMW PAHs. RESULTS: An HMW-PAHs degrading bacterium,HBS1, was obtained. HBS1 could use several HMW-PAHs such as pyrene, benzoanthracene, benzopyrene, chyrsene, indeno[ 1,2,3-cd] pyrene, benzo[g,h,i]perylene and fluoranthene as sole carbon source for growth. HBS1 was identified as Gordonia sp., based on the high sequence similarities (more than 99%) of both 16S rRNA gene and gyrb gene to those of Gordonia amicalis. When the initial concentration of pyrene was 50 mg/L, HBS1 could consume 97% of the pyrene in 17 days. One fragment of the dioxygenase gene was obtained by PCR with size about 300 bp, which was closest to the counterpart from Mycobacterium sp. with 93.8% similarity. CONCLUSION: We isolated a strain HBS1 from seriously PAHs-polluted soils and identified as a Gordonia sp. The isolate had the degradation potential of high-molecular weight polycyclic aromatic hydrocarbons. PMID- 21604546 TI - [Sequence-based typing of enviromental Legionella pneumophila isolates in Guangzhou]. AB - OBJECTIVE: To characterize the genes of Legionella pneumophila isolated from different water source in Guangzhou from 2006 to 2009. To genotype the strains by using sequence-based typing (SBT) scheme. METHODS: In total 44 L. pneumophila strains were identified by SBT with 7 diversifying genes of flaA, asd, mip, pilE, mompS, proA and neuA. Analysis of the amplicons sequence was taken in the European Working Group for Legionella Infections (EWGLI) international SBT database to obtain the allelic profiles and sequence types (STs). Serogroups were typed by latex agglutination test. RESULTS: Data from SBT revealed a high diversity among the strains and ST01 accounts for 30% (13/ 44). Fifteen new STs were discovered from 20 STs and 2 of them were newly assigned (ST887 and ST888) by EWGLI. SBT Phylogenetic tree was generated by SplitsTree and BURST programs. CONCLUSION: High diversity and specificity were observed of the L. pneumophila strains in Guangzhou. SBT is useful for L. pneumophila genomic study and epidemiological surveillance. PMID- 21604547 TI - [Analysis of the chromosome ploidy of Candida glycerinogenes]. AB - OBJECTIVE: To determine the chromosome DNA ploidy of Candida glycerinogenes. METHODS: We screened the haploid cell of Saccharomyces cerevisiae and the diploid of Candida tropicalis as the reference cell to identify the ploidy of Candida glycerinogenes. The concentrations of chromosome DNA extracted from both haploid and diploid cells were determined by the diphenylamine reaction method. Meanwhile, the cell number of Candida tropicalis, Candida glycerinogenes, Saccharomyces cerevisiae and its haploid were accounted by hemocytometer measurement method, respectively. Because in the same UV irradiation conditions,the haploid cells was more easy died than diploid cells, so we used the UV irradiation test to further verification. RESULTS: The results of the content of chromosome DNA in a single cell showed that Candida glycerinogenes was a diploid cell. Moreover, it was also further confirmed because the haploid cell of Saccharomyces cerevisiae was more sensitive than Candida glycerinogenes under UV treatment. CONCLUSION: By this study, we confirmed that Candida glycerinogenes was a diploid cell. PMID- 21604548 TI - [Physiological characteristics of a low-pH tolerant strain Torulopsis glabrata RT 6]. AB - OBJECTIVE: With the aim of elucidating the physiological characteristics of a low pH tolerant strain Torulopsis glabrata RT-6. METHODS: The intracellular pH, ATP level, the membrane bound H(+)-ATPase activity, the membrane fatty acid composition and the intracellular polyphosphate content of the parent strain CCTCC M202019 and the mutant strain RT-6 were determined and compared under different pH conditions. RESULTS: Compared to that of the parent strain, the cell growth and pyruvate concentration of the mutant strain RT-6 were increased by 60.6% and 85.4% (56 h), respectively. Similarly, the strain RT-6 had higher intracellular pH compared to the control strain at external pH5.0, 4.5, and 4.0. The ATP content, the membrane bound H(+)-ATPase activity and the intracellular polyphosphate content of the mutant strain RT-6 were increased by 11.7%, 13.6%, and 3.5% at external pH 5.5, while at external pH 4.0, increased by 61%, 38.6%, and 30.8%, respectively. Furthermore, the mutant strain RT-6 exhibited higher content of the unsaturated fatty acids and higher membrane fluidity. CONCLUSION: Discharging more intracellular H+ and inhibiting the intracellular H+ production contributed to the strain RT-6's higher intracellular pH, and therefore the acid tolerance. PMID- 21604549 TI - [Breeding and characterization of laccase-producing Phanerochaete chrysosporium mutant resistant to nutritional repression]. AB - OBJECTIVE: To screen Phanerochaete chrysosporium mutants resisting nutritional repression and to characterize laccase produced by the mutants. METHODS: We used repeated UV mutagenesis and screened the mutant strains by using the guaiacol nitrogen sufficient differential medium. We characterized enzymes production mechanism of the nutritional regulation through comparing the differences of cell growth and enzyme-production kinetics under different nutritional conditions; We validated production of laccase by Phanerochaete chrysosporium through measurements of the heat treatment, removal of manganese ion and addition of the catalase. RESULTS: Three different methods were validated that both strains of pcR5305 and pcR5324 can produce laccase under the nitrogen limitation (N-L) and nitrogen sufficient (N-S) conditions. Under the N-L conditions, pcR5305 can produce 203.5 U/L laccase and pcR5324 can produce 187.6 U/L laccase; Under the N S conditions, pcR5305 can produce 220.6 U/L laccase and pcR5324 can produce 183.9 U/L laccase. The original strain pc530 only can produce very little laccase under either conditions. The laccase-production regulation mechanisms of the two strains are different: Production of laccase and the cell growth by pcR5305 are in synchronism. However production of the laccase by pcR5324 is repressed by nutrition. Both strains have the capacity of resisting nutritional repression and produce lignin peroxidase and manganese peroxidase with high yield. (LiP 1343.2, MnP 252.2 U/L and LiP 1169.5, MnP 172.4 U/L respectively). CONCLUSION: The mutants of Phanerochaete chrysosporium can produce laccase. At same time they showed the capacity of resisting nutritional repression and production of laccase, lignin peroxidase and manganese peroxidase. Our results possess high value for production, application and fundamental research. We provided new strains and established a very good foundation for the further research of metabolic regulation of ligninolytic enzymes production. PMID- 21604550 TI - [Cloning and expression of Ser/Thr protein phosphatase type 5 during microcycle conidiation in Metarhizium ansopliae]. AB - OBJECTIVE: To clone Ser/Thr protein phosphatase type 5 gene (PP5) from Metarhizium anisopliae, analyze the structure of PP5 gene with its encoding protein and expression profile during two conidiation program (microcycle conidiation and normal conidiation). METHODS: The DNA sequence of PP5 was isolated by blasting the expressed sequence tags (EST) of PP5 in subtracted library with genomic data of M. anisopliae. Primers were designed based on the DNA sequence to clone the full length cDNA of PP5 by PCR, and the characteristics of the encoded protein was analyzed by online tools and biological softwares. The PP5 expression profile was quantified by real time PCR at different stages of microcycle conidiation and hyphal stage of normal conidiation in M. anisopliae. RESULTS: The genomic DNA, which was interrupted by six introns, was 2100 bp long. The cDNA, encoding 325 amino acid residues, is 1428 bp. Analysis to Ser/ Thr protein phosphatase type 5 in M. anisopliae show a conserved structure features. Quantitative real time PCR analysis showed that PP5 expression varied obviously in different stages of microcycle conidiation. Expression was sharply up regulated after 16 h, with the highest transcript levels at 24 h in microcycle conidiation, but lowly expressed in normal conidiation. CONCLUSION: This work presents the first report about the detailed sequence and structure of PP5 from entomopathogenic fungi. Comparison of expression profile of microcycle conidiation and normal conidiation reveals that PP5 is principally involved in microcycle conidiation in M. anisopliae, and it provides ideal candidate for further studies to PP5 and its molecular regulation. PMID- 21604551 TI - [Screening endophytic bacteria against plant-parasitic nematodes]. AB - OBJECTIVE: Plant-parasite nematode is one of the most important pathogens in plant. Our objective is to screen endophytic bacteria against plant-parasitic nematodes from plant. METHODS: Endophytic bacteria were isolated and screened by testing their metabolite against Bursaphelenchus xylophilus in vitro. Those strains inhibiting B. xylophilus were selected to culture in liquid medium and fermentation conditions were optimized by orthogonal test. The stability of the antinematode substances was evaluated by various. In addition, four strains were identified by 16SrDNA sequence analysis. RESULTS: In total 13 strains of endophytic bacteria secreting antinematode metabolite were isolated from 6 species of plant. The supernatant of the fermentation broth of these endophytic bacteria gave 100% mortality of nematodes after treated as the follows: 1 ml each was mixed with 0.2 ml of the suspension of nematodes (2000 nematodes/ml) then incubated at 250C for 24 h, some of which could led to leakage or dissolution of nematodes. Among them, four strains, BCM2, SZ5, CCM7 and DP1, showed stronger activity than others. The supernatants diluted three times also gave not less than 95% mortality after 24 h treatment, and those from DP1 and SZ5 even gave 100% mortality. The fermentation conditions of the four strains were optimized and the antinematode activity grew up four times after optimization. The antinematode substances of these strains were found stable when treated with protease or heating or stored at 4 degrees C after 100 days, while instable when treated with acid or alkali. DP1 and CCM7 were identified to be Bacillus subtilis, while SZ5 and BCM2 to be Bacillus cereus. CONCLUSION: Endophytic bacteria secreting antinematode metabolite were found in economic crops. The metabolite of some strains showed strong and stable antinematode activity. Our results indicate the real potential of biocontrol by endophytic bacteria. PMID- 21604552 TI - [Comparison of bacterial diversity of polluted and unpolluted sediment by brominated flame retardant]. AB - OBJECTIVE: By using brominated flame retardant we compared the bacterial diversity of highly polluted river sediment with that of nearby unpolluted lake. METHOD: Total DNA was extracted from unpolluted and highly polluted sediment sample by brominated flame retardant in Guiyu of China. The 16S rRNA gene was amplified by PCR using bacterial primer 27F and 1500R. The plasmid libraries of the amplicons were constructed. The positive clones with insert were screened on plates with IPTG/X-gal/Ap. Amplified ribosmal DNA restriction analysis (ARDRA) was carried out with restriction enzymes Hha I and Hinf I. Representative clones of each operational taxonomic unit based on the ARDRA patterns were selected to be sequenced. After proof reading and careful comparison to remove the chimeric sequences, the partial sequence of 16S rRNA gene were used for construction of the phylogenetic tree. RESULT: The result of blast searching showed that clones from unpolluted sediment sample belonged to alpha-Proteobacteria, beta Proteobacteria, gamma-Proteobacteria, delta-Proteobacteria, Planctomycetes, Acidobacteria, Actinobacteria, Chloroflexi, Verrucomicrobia, Firmicutes, the predominant bacteria (30.2% of total clones) is Acidobacteria; most clones from polluted sediment belonged to alpha-Proteobacteria, beta-Proteobacteria, epsilon Proteobacteria, delta-Proteobacteria, Planctomycetes, Acidobacteria, Actinobacteria, Chloroflexi, Bacteroidetes, Firmicutes, candidate division 0P01, candidate division OP08, the predominant bacteria (44.9% of total clones) are epsilon-Proteobacteria and Chloroflexi. CONCLUSION: Bacterial community structure of polluted sediment has distinguished feature and obviously different from the unpolluted sediment sample, which is mainly reflected in the dominant position of epsilon-Proteobacteria and Chloroflexi in the bacterial flora. PMID- 21604553 TI - [Construction and in vitro assay of the sortase BCD geneknock-out mutant of Streptococcus suis 2]. AB - OBJECTIVE: Streptococcus suis 2 is an emerging zoonotic pathogen responsible for a wide range of life-threatening diseases in pigs and humans. In this study, we investigated the functionality of one of Streptococcus suis 2 sortases, known as the srtBCD. METHODS: To obtain the isogenic mutant srtBCD, the competent cells of 05ZYH33 were subjected to electrotrans formation with recombinant plasmid based on the principle of homologous recombination. The resulting mutant strains was further confirmed by a series of PCR and reverse transcription PCR. To better assess the role of srtBCD gene in the virulence of 05ZYH33, cell adherence assays and experimental infection of mice was adopted. RESULTS: A SrtBCD defective mutant of 05ZYH33 was found to be associated with growth curve upon cultivation in standard laboratory used in our in vitro assays. Furthermore, abolishment of the expression of srtBCD result in impaired interactions of S. suis with human laryngeal epithelial cell line. However, there is no differences when infection mice by the WT and mutant strain. CONCLUSION: These results suggest that srtBCD are critical for the pathogen-host interaction of S. suis 2, but abolishment of srtBCD does not impair the full virulence of 05ZYH33. It is to expect that future study carried out with S. suis 2 to verification the conclusions. PMID- 21604554 TI - [Bactericidal effect of soybean peroxidase-hydrogen peroxide-potassium iodide system]. AB - OBJECTIVE: To study the bactericidal effect and the possible mechanisms of the three components system [soybean peroxidases (SBP)-hydrogen peroxide (H2O2) potassium iodide (KI), SBP-H2O2-KI]. METHODS: The inhibition and bactericidal effect of SBP-H2O2-KI system to bacteria was detected by OD600 and the number of live bacteria (CFU). The sensitivity was tested by comparing the minimum inhibitory concentration (MIC) of bacterial cultures before and after cultured under sub-lethal dose of SBP-H2O2-KI system. Oxidizing activity groups were detected with physical and chemical methods in order to explain the bactericidal mechanisms of SBP-H2O2-KI system. RESULTS: SBP-H2O2-KI ternary system had rapid and high efficient bactericidal effect to a variety of bacterial strains in just several minutes. The MICs had no significant changes when bacterial cultures continuously cultured in sub-lethal dose of SBP-H2O2-KI system, and no resistance/tolerance mutant strains could be isolated from them. Both physical and chemical test results showed that no hydroxyl radical produced in SBP- H2O2 KI reaction system, chemical test results showed that no superoxide anion but a singlet oxygen and iodine produced in SBP-H2O2-KI reaction system. CONCLUSION: These results suggested that singlet oxygen and iodine or the iodine intermediate state may possible be the main sterilization factors for SBP-H2O2-KI system, and hydroxyl radical and superoxide anion not. In addition, the both characteristics of SBP-H2O2-KI system: rapid and high efficient bactericidal effect, and bacteria difficultly resisting to it, indicated it would have a good potential application in medical and plant protection area. PMID- 21604555 TI - [Function of the granaticin biosynthetic gene orf20 from Streptomyces vietnamensis]. AB - OBJECTIVE: The transcription factor SoxR, which serves as a cellular redox sensor, is a global activator of antioxidative stress in Escherichia coli. The granaticin biosynthetic gene orf20 from Streptomyces vietnamensis was found to be a soxR-like gene. This study was carried out towards understanding the physiological function of this gene. METHODS: The orf20 gene was cloned and expressed in E. coli. An orf20 deletion mutant of S. vietnamensis was constructed by using a modified PCR-targeting disruption method. The growth curves of the recombinant E. coli strains and the mutant S. vietnamensis at various paraquat concentrations were assayed to resolve any changes of resistance levels. RESULTS: Soluble expression of orf20 gene in E. coli was achieved, and the recombinant ORF20 protein was tagged by seven histidines at the carboxylic end. An orJ20 deletion mutant of S. vietnamensis DMR20 was successfully constructed. The DMR20 mutant showed no growth changes to the wild, and the ability of sporulation was retained, too. However, the production of granaticin was improved for more than three folds. Compared to the wild type, the DMR20 mutant had no visible changes of resistance to paraquat, however, E. coli carrying the recombinant plasmid pET28b-orf20 received an elevated resistance to paraquat. CONCLUSION: The orf20 gene can complement the soxR gene in E. coli, but is not involved in the regulation of anti-oxidative stress response in S. vietnamensis. Instead, it imposes a negative effect on granaticin production. PMID- 21604556 TI - [Cloning and prokaryotic expression of cyp107z gene from Streptomyces ahygroscopicus ZB01]. AB - OBJECTIVE: We cloned and expressed a cytochrome P450 gene cyp107z from Streptomyces ahygroscopicus ZB01, and determined the kinetic parameters of the recombinant enzyme in vitro. METHOD: Degenerate primers were designed by the conserved sequence of cyp genes and were used to amplify partial sequence of cyp107z gene from Streptomyces ahygroscopicus ZB01 genome. The full-length cyp107z gene sequence was obtained by genome walking, and linked with pET28a to construct pET-cyp1O7z13 expressing vector which was then transferred into Escherichia coli, and the expressed recombinant protein was purified by Ni-NTA affinity chromatography. The catalysis system of the recombinant protein was constructed with avermectin as substrate, and the kinetic parameters of the recombinant protein were determined by monitoring the consumption of NADPH in the system in vitro. RESULTS: A cyp107z homologous gene named cyp107z13 was cloned from Streptomyces ahygroscopicus ZB01 genome, which was 1290 bp in length encoding 429 amino acid residues. The Km of purified recombinant protein of CYP107Z13 expressed in E. coli was 1.4 micromol/L, the Vmax was 0.041 micromol/min x mg and the k(cat), was 0.033 s(-1) in a reaction system with avermectin as substrate. CONCLUSION: A cyp10z3 gene from Streptomyces ahygroscopicus ZB01 was cloned, the heterologous expressed recombinant protein can catalyze the oxidizing reaction with avermectin as substrate. PMID- 21604557 TI - [Induced synthesis of hydroxyapatite by Aspergillus niger]. AB - OBJECTIVE: The research objective is to induce hydroxyapatite (HAP) synthesis by using fungus. METHODS: We used the PDA (Potato Dextrose Agar Medium) liquid medium containing different concentrations of Na2HPO4 and CaCO3 to study the way Aspergillus niger synthesize HAP, to observe the induced mineral crystal structure and to analyze the induced mineral type with transmission electron microscopy (TEM) and X-ray diffraction (XRD). RESULTS: The main results are as follows: (1) A. niger can induce HAP synthesis in PDA liquid medium with the proper concentration of Na2HPO4 and CaCO3. (2) The reaction of A. niger inducing HAP synthesis depends on the time of the response system. Longer time is more advantageous in producing HAP. The main reason for A. niger inducing HAP crystals formation are as follows: fungal metabolism produces the acidic substances to dissolve CaCO, and the growth mycelia absorbing Ca2+ lead to Ca2+ enriched on the surface, to promote the production of secondary mineral apatite and further transform into HAP in the mycelia spheres. CONCLUSION: A. niger can inducing HAP crystals formation in PDA liquid medium containing Na2HPO4 and CaCO3. Considering the importance of HAP in bio-medicine materials and its costly prices, our method for HAP bio-induction is of the temperate response condition, simple preparation craft, and lower cost, which has the potential application prospect. PMID- 21604558 TI - [Diversity of receptor recognition site of type Asial foot-and-mouth disease virus]. AB - OBJECTIVE: Foot-and-Mouth Disease Virus (FMDV) initiates infection by binding to integrin receptors via a highly conserved Arg-Gly-Asp (RGD) sequence found in the G-H loop of the structural protein VP1. However, FMDV is an RNA virus, which harbors the evolutionary potential to render the RGD motif dispensable upon changes in constant environment. We studied mutation of RGD motif upon short-time passages FMDV Asial/JS/China/2005 field strain in different host. METHODS: VP1 gene was amplified from Asial/JS/China/05 field strain, the fourth passage virus in sulking mice (MF4) of the above strain and the virus isolated from a pig housing with cattle inoculated with the above strain followed eight passages in BHK-21 cell (PBF8) by RT-PCR, and the VP1 genes were sequenced and their deduced amino acid sequences were compared with each other. RESULT: Dominant population with RGD and Arg-Ser-Asp (RSD) receptor recognition site motif was generated after four passages of Asial/JS/China/2005 field virus in sulking mice and another dominant population with Arg-Asp-Asp (RDD) motif was produced after eight passages the virus isolated from housing pig with cattle inoculated with the above field strain. CONCLUSION: This study indicated that the dominant FMDV virus populations with RSD or RDD receptor binding site instead of original RGD motif were produced upon short-time evolution of FMDV field isolates with RGD motif in different environment. These studies not only increase number of viable mutants with substitutions in the RGD region, but also these profoundly altered, but viable, mutants with different receptor recognition site will provide useful tools for studies of cell recognition by FMDV and host tropism modifications. PMID- 21604559 TI - [Identification specific T lymphocyte epitopes on E6 protein of human papillomavirus type 18 in mice]. AB - OBJECTIVE: To identify specific T lymphocyte epitope on E6 protein of human papillomavirus type 18 in mice. METHODS: Infection with one recombinant vaccinia virus rVVJ18 E7, E6 respectively in C57 BL/6 and BALB/c mice, specific cellular immune responses were detected by ELISPOT or intracellular cytokine stainings by using a series of overlapping synthetic peptides covering full length of the amino acid sequence of E6 and E7 proteins or various truncated peptides. RESULTS: The rVVJ18 E7, E6 generated significant E6 specific T-cell immune responses in vaccinated mice. Mapping of the epitope of E6 revealed that the peptides E6(67-75 ( KCIDFYSRI) and E6(60-68) (IPHAAGHKC) presented respectively by C57BL/6 and BALB/c mice were the optimal peptides to activate E6-specific CD8+ T lymphocytes. However no positive cellular immune responses stimulated with various E7 peptides were detected by ELISPOT in immunized mice. CONCLUSIONS: Two specific T lymphocyte epitopes were identified on E6 protein in C57BL/6 and BALB/c mice, which will provide the basis to evaluate cellular immune response elicited by HPV18 E6 protein based vaccine. PMID- 21604560 TI - [Study on antineoplastic effect of earthworm coelomic fluid in vitro]. AB - OBJECTIVE: To explore the antineoplastic effect in vitro of earthworm coelomic fluid (ECF)on growth inhibition and its mechanism for the tumor cell lines Siha, SW480, Colo205 and PC12. METHODS: MTT colorimetric assay, flow cytometry and morphological analysis were used to test its antitumor activity on tumor cell lines and normal cell line Cos7 in vitro. RESULTS: ECF can inhibit the cell growth of Siha, SW480, Colo205, PC12 and Cos7. But different tumor cell lines showed different sensitivity. CONCLUSION: EFC can significantly inhibit the proliferation of tumor cells in vitro by inducing tumor cells apoptosis. PMID- 21604561 TI - [Study on characteristics of cellular-mediated immune responses of novel H1N1 influenza A patients with pneumonia]. AB - OBJECTIVE: To investigate the phenotype, frequency and function of CD4+ T cell subsets and the relevant cytokines, as well as the relationship between these cells and appearance of pneumonia of novel (H1N1) influenza A patients. METHODS: 68 healthy people, 53 confirmed novel A(H1N1) influenza patients without pneumonia and 16 confirmed severe novel A (H1N1) influenza patients with pneumonia were enrolled in this study. Viral load in nasopharyngeal swabs specimens was measured by real time PCR assay. The phenotype and percentage of CD4+ T cell subsets including Th1, Th2, Th17, and Treg cells were measured by Flow cytometry analysis. The relevant cytokines in plasma including TGF-beta, IL 6 and IFN-gamma were measured by ELISA. Data was analyzed by one way ANOVA. RESULTS: It was found that peak viral load and viral shedding period of severe patients with pneumonia was significantly increased compared with mild patients without pneumonia (P < 0.05). The percentage of Th17 cells of severe patients with pneumonia was significantly diminished compared to that of healthy subjects and mild patients without pneumonia (P < 0.05). However, Th1, Th2, Treg cells frequencies had no significant differences (P > 0.05) among these three groups. The level of TGF-beta in plasma for the severe patients with pneumonia was also significantly decreased compared to that of healthy subject and mild patients without pneumonia (P < 0.05). The viral shedding period inversely correlated with the frequency of Th17 cells (r = - 0.38, P < 0.05). CONCLUSION: H1N1 influenza A virus can inhibit Th17 cells to differentiate, particularly more extent in patients with pneumonia. Impaired Th17 cells may correlate with viral clearance and pneumonia of novel H1N1 influenza A patients. PMID- 21604563 TI - [Study on HLA-DRB1 alleles in patients with familial hepatitis B in Shanxi]. AB - OBJECTIVE: To study the association between HLA-DRB1 alleles and familial hepatitis B. METHODS: HLA-DRB1 alleles of 151 people in the familial hepatitis B families were detected,by using the the polymerase chain reaction-sequence specific oligonucleotide probing (PCR-SSOP) technique. RESULTS: The allele frequency of HLA-DRB1 * 0701 in the chronic hepatitis B (CHB) group was markedly higher than that in the normal control group (17.8% vs 7.4%), with significant correlation between them (P < 0.05, A = 1/0.367 approximately 2.725). The allele frequencies of HLA-DRB1 * 0401/0403/0405 and HLA-DRB1 * 1301/1302 in the normal control group (16.2%, 4.4% ) were markedly higher than that in the CHB group (5.1%, 0), with statistical significance (P < 0.05, A = 3.602; P < 0.05). The other alleles between the CHB group and the normal control group are no significant differences. CONCLUSION: HLA-DRB1 * 0701 is closely associated with the susceptibility to familial hepatitis B,and may be the susceptible or linkage gene. HLA-DRB1* 0401/0403/0405 and HLA-DRB1 * 1301/1302,in inverse proportion to the susceptibility to familial hepatitis B, may be the resistant gene. They may regulate the outcome of familial HBV infection in a patient. PMID- 21604562 TI - [Immunogenicity of plasmid DNA and adenoviral vectors encoding HIV-1 subtype B env gene]. AB - OBJECTIVE: To construct DNA and recombinant adenovirus vector vaccines containing an env gene from the prevalent subtype B strain in China and try to use them for therapeutic and prophylactic vaccines. METHODS: The candidate plasmid DNA vaccine pVR-gp160 and recombinant adenovirus vaccine rAdV-gp160 were constructed separately. BALB/c mice were immunized with these two vaccines in different administration schemes. HIV-1 Gp120-specific cellular responses and antibody levels were detected by ELISPOT and ELISA respectively. RESULTS: DNA vaccine alone and combined vaccines in a DNA prime/rAdV-gp160 boost vaccination regimen induced high level of Gp120-specific cellular responses. While low level of Gp120 specific antibodies were elicited in all groups. CONCLUSION: DNA and rAdV vaccines could efficiently express Gp160 protein and activate specific cellular responses. PMID- 21604564 TI - [RT-PCR identification and genetic characterizations of VP1 region of human enterovirus 71 isolated in Beijing in 2008]. AB - OBJECTIVE: To study the genetic characterizations of VP1 region of Human enterovirus 71 (HEV71) isolated from clinical specimens of hand, foot and mouth disease (HFMD) patients in Beijing in 2008. METHODS: 285 clinical samples were collected from HFMD patients in hospitals and day-care centers in Chaoyang district. They were performed by reverse transcription-polymerase chain reaction (RT-PCR) specific for HEV71. 10 HEV71 isolates were selected for entire VP1 coding gene amplification and sequencing. RESULTS: 129 samples were RT-PCR positive, the positive rate is 45.26%. The homology of the nucleotide and the amino acid of the 10 strains were 94.6%-99.6% and 95.9%-100%. The phylogenetic tree revealed that 10 Beijing strains clustered within the C4a evolution branch of C4 subgenotype. CONCLUSIONS: RT-PCR played an important role in identifying HFMD outbreak in Beijing in 2008. The HEV71 strains were all belong to C4a evolution branch of C4 subgenotype with several transmission chains, and it showed that C4 subgenotype HEV71 spread in mainland China widely after 1998. The molecular epidemiology surveillance and the research of genetic characterizations of HEV71 should be strengthened in mainland China. PMID- 21604565 TI - [The analysis of "a" dominant mutation of hepatitis B virus in community-based population of Shandong Province, China]. AB - OBJECTIVE: To determine the rate and type of "a" dominant mutation of hepatitis B virus (HBV) in community-based population of Shandong province and the possible effect of hepatitis B vaccination upon "a" dominant mutation. METHODS: The anticipants aged 1-59 years were selected by multi-stage random sampling from the general population of Shandong province. Hepatitis B vaccination status was obtained by inquisition (for those over 15 years old) or immunization record (for those under 14 years old). The blood samples were collected and detected for HBsAg by ELISA. HBV DNA was extracted from the sera with positive HBsAg and S gene was amplified by nested-PCR. The PCR produce was sequenced and compared with the standard sequence. RESULTS: Overall, 7601 anticipants were investigated. HBV DNA was successfully amplified and sequenced in 102 of 239 samples with positive HBsAg. 14.70% sera samples mutated in HBV "a" determinant region and 13 mutation types were detected. There were no statistically differences in the mutation rate by age groups (born before or after national universal infant hepatitis B vaccination) and hepatitis B vaccination status. CONCLUSION: The "a" determinant mutation seemed to be uncommon in community-based population of Shandong province and the mutation sites were relatively scattered. Hepatitis B vaccination has no effect on "a" dominant mutation of hepatitis B virus. PMID- 21604566 TI - [Experimental study on anti-influenza virus infection with yinqiao-decoction by orthogonal design]. AB - OBJECTIVE: To investigate composition principle of Yinqiao-decoction through experiment of anti-influenza. METHODS: The effects of different compositions of Yinqiao-decoction on the index of hemagglutinin titre of virus in the lung tissue of mice infected with virus from nose were investigated by orthogonal design. RESULTS: According to the hemagglutinin titre of virus in the lung tissue of mice, the necessary effective drugs of Yinqiao-decoction are forsythia suspense, flos lonicerae, fructus arctii, schizonepeta tenuifolia, folium phyllostach lophatheri, glycyrrhiza uralensis, platycodon grandiflorum and mentha haplocalyx, and semen sojae preparatum isn't necessary. There is interaction between forsythia suspense and flos lonicerae, forsythia suspense and fructus arctii, forsythia suspense and schizonepeta tenuifolia, fructus arctii and mentha haplocalyx, schizonepeta tenuifolia and platycodon grandiflorum. CONCLUSION: The optimal combination of Yinqiao-decoction is flos lonicerae, forsythia suspense, fructus arctii, folium phyllostach lophatheri, glycyrrhiza uralensis, mentha haplocalyx of the second level and schizonepeta tenuifolia, platycodon grandiflorum, semen sojae preparatum of the first level. PMID- 21604567 TI - [Construction of sub-unit dengue vaccines and analysis of its immunogenicity]. AB - OBJECTIVE: To construct sub-unit vaccines of dengue virus type 1 to 4 and to analyze its immunogenicity. METHODS: Envelope domain III s of dengue serotypes 1 and 2, as well as 3 and 4, were spliced by a linker (Gly-Gly-Ser-Gly-Ser)3 and cloned into vector pET-30a, then transformed into E. coli to express recombinant fusion proteins. The recombinant proteins were purified by high-performance liquid chromatography and mixed to immunize BALB/c mice. The neutralizing antibodies were tested by neutralizing assay, as well as in newborn mice challenged intracranially with dengue virus type 1 to 4. RESULTS: Mice immunized with proteins could produce neutralizing antibodies, with titers of 1:34. 9, 1: 45.3, 1: 24.7 and 1:38.4 for DEN-1 to 4 respectively. 100% newborn mice challenged with DEN-1 or 2 in combination with sera from mice immunized with recombinant proteins were protected, whereas 83% protection was obtained when challenged with DEN-3 or 4. CONCLUSION: The recombinant proteins possess excellent immunogenicity to induce neutralizing antibodies and would be valuable for development of a tetravalent sub-unit vaccine. PMID- 21604568 TI - [Fluvastatin's effect on atherogenesis in apolipoprotein-E knockout mice infected by cytomegalovirus]. AB - OBJECTIVE: The goal of this study was to investigate whether murine cytomegalovirus (MCMV) is able to exacerbate the atherosclerotic process in apolipoprotein E knockout (apoE -/-) mice, and the effect of fluvastatin on the atherogenesis. METHODS: The apoE-/- mice kept on a west diet were given low dosage of MCMV. At 14,18 and 24 weeks post infection, AS lesion were measured on aorta. The fluvastatin was administered, and AS lesion were measured accordingly above. RESULTS: We observed that in the chronic phase of the infection, AS lesion area was significantly increased. MCMV gB mRNA was not amplified by real-time PCR from the arterial wall. The IgG antibody level of MCMV in blood plasma and the content of virus DNA in salivary gland were not correlated with AS lesions. After the administration of fluvastatin, there was no significant difference of AS lesions between MCMV infected group and mock-infected group. CONCLUSION: MCMV may aggravate the AS lesion in apoE -/- mice in the chronic phase of infection, and promote more severe type of AS lesions. But it might not be the direct effects of mechanism of MCMV on the local lesion of AS. Fluvastatin could meliorate the progression of AS after MCMV infection, but this was not accomplished by decreasing MCMV duplication. PMID- 21604569 TI - [Human enterovirus 71 that firstly isolated in Qinghai Province and their genetic features of VP1 region]. AB - OBJECTIVE: To study the genetic characterizations of VP1 gene of human enterovirus 71 (HEV71) isolated from clinical specimens of Hand, Foot and Mouth Disease (HFMD) patients in Qinghai Province in 2008. METHODS: 335 clinical samples including stools, throat swabs and vesicle fluids were collected from HFMD patients in Qinghai Province. Viral isolation was performed, and molecular typing was performed with the positive isolates. Then 30 identified HEV71 isolates were performed for entire VP1 coding region amplification and sequencing. RESULTS: Among the 355 clinical samples, 45 human enteroviruses were isolated, and among them, 30 were identified as HEV71. Then 30 HEV71 positive isolates were performed by nucleotide sequencing. It showed that there was some difference in the nucleotide and the amino acid among the 30 HEV71 strains, the homology were 95.2%-100% and 96.6%-100%, respectively. But they all closed to HEV71 strains isolated in China after 1998, and from the phylogenetic tree constructed with 30 Qinghai HEV71 strains and other 35 HEV71 strains represented all known genotype and subgenotype HEV71 strains available from GenBank, it revealed that the 30 Qinghai HEV71 strains clustered within the C4a evolution branch of C4 subgenotype. CONCLUSION: HEV71 was isolated in HFMD patients in Qinghai province, and the HEV71 strains causing HFMD outbreaks in Qinghai province in 2008 were all belong to C4a evolution branch of C4 subgenotype with several transmission chains. PMID- 21604570 TI - [The association between HBV genotyping and clinical characteristics and expression of TH1/TH2 cytokines]. AB - OBJECTIVE: To explore the association between HBV genotyping and clinical characteristics and expression of TH1/TH2 cytokines. METHODS: The expression of IL-4 and IFN-gamma was detected with flow cytometry for 102 HBV infections and 48 healthy controls. 50 CHB patients were randomly selected for HBV genotyping with real-time fluorescence PCR assay. RESULTS: Higher expression of IL-4 in peripheral blood was detected in patients with HBV infection than healthy controls (P < 0.001); No significant differences on expression of Th1/Th2 cytokines were observed in CHB patients with different HBV DNA levels or HBeAg status (P > 0.05). There were 34 (68%) patients with genotype B infection and 16 (32%) with genotype C infection. Compared to patients with genotype B infection, the patients with genotype C infection showed higher levels of IL-4 (P = 0.018), and Th1/Th2 ratio decreased,but the difference was not statistically significant (P = 0.2262). CONCLUSION: The different expression of TH1/TH2 cytokines may elucidate cellular immune response and clinical outcome difference between patients with genotype B infection and genotype C infection. PMID- 21604571 TI - [A cross-sectional survey of occult hepatitis B virus infection in HIV-infected patients in acquired immune deficiency syndrome area]. AB - OBJECTIVE: To assess the prevalence of occult HBV infection in HIV-infected patients inacquired immune deficiency syndrome area. METHODS: Serum samples were obtained from 97 HIV-infected patients who transmitted by paid blood donation. ELISA was used to detect HBV erologic markers (HBsAg, Anti-HBs, HBeAg, anti-HBe and anti-HBc) and HCV antibody. Flow Cytometry were used to detect CD4+ T cell count. Nested PCR was used to amplify surface protein region of HBV DNA. RESULTS: Ninety two patients were HBsAg negative in the 97 HIV-infected patients (94.85%). Twenty seven patients were co-infected with occult hepatitis B virus infection in the 92 HBsAg negative patients (29.35%). Seventy three patients were co-infected with HCV in the 92 HBsAg negative patients(79.35%). CD4 cell count of subjects with occult HBV infection were significantly lower (212.11 +/- 133.1 cells/mm3 versus 318.9 +/- 172.2 cells/mm3, respectively, P < 0.01). A significantly higher prevalence of isolated anti-HBc was observed in HIV-infected subjects co infectioned with occult HBV infection [62.96% (13 of 27) versus 18.46% (15 of 65), P < 0.01]. No statistical significant association could be established between the age, sex and whether co-infected with HCV. CONCLUSION: It is found that occult HBV infection did occurs in HIV-infected patients. Individuals co infected with HIV and occult HBV infection are more likely to have isolated anti HBc than subjects with HIV alone. Co-infection with HIV and occult HBV is more likely to occue in subjects with lower CD4. PMID- 21604572 TI - [Clinical value of CD64 expression in adults with measles complicating bacterial pneumonia]. AB - OBJECTIVE: To study the clinical value of expression of peripheral blood neutrophil CD64 in adults with measles complicating pneumonia. METHODS: 106 patients were divided into two groups by clinical manifestation and bacteria study: measles complicating bacterial pneumonia group and measles complicating viral pneumonia, using flow cytometry determination of CD64, C-reactive protein (CRP) and white blood cell (WBC) count. RESULTS: The expression of CD64 in the bacterial pneumonia group with eruptive stage was (32.15 +/- 11.07) MFI, which was significantly higher than that in the group of with recovery stage (10.6 +/- 3.23) MFI (P < 0.01) and viral pneumonia (9.55 +/- 3.48) MFI (P < 0.01). These markers were considered positive if CD64 > or = 8.5 MFI, CRP > or = 10 mg/L and WBC > or = 9.05 x 10(9)/L. Their sensitivity was 78.12%, 80.48% and 59.37%. Their specificity was 76.19% ,67.67% and 64.28%. Their accuracy rate was 77.35%, 74.52%, 61.32%; CD64 has a positive relationship with CRP. CONCLUSION: Compared to CRP, expression of peripheral blood neutrophil CD64 can be a better marker in the early diagnosis of patients with measles complicating bacterial pneumonia and as one of the indicators of disease conditions. PMID- 21604573 TI - [Analysis on clinical and epidemiological characteristics of severe cases infected by EV71]. AB - OBJECTIVE: To explore the clinical and epidemiological characteristics of serious cases of hand-foot-and-mouth disease (HFMD) infected by EV71, in order to provide scientific evidence for prevention and control of HFMD. METHODS: Information was collected by questionaires through consulting medical cases. Data was input by Epidata, and analysed by software SAS 9.13. RESULT: 201 severe cases were investigated. 84.65% of the cases were below 3 years old. The youngest one was 5 months and the oldest one was 8 years old. The ratio for male and female was 2.2: 1.85. 08% of the cases were distributed sporadically. 51.74% of them lived in rural, 29.36% of them lived in urban and 19.9% of them lived at the fringe area of rural and urban. 81.59% of the cases became serious between 1 and 4 days after infected. 100% cases had fever and 99.95% of them had a rash. 96.52% of them had nerve system symptoms. The main complications were virulent spinal encephalitis, pneumonia and breathing exhaustion. 98.01% of the patients were recovered or cured. CONCLUSION: The cases aged below 3 years old are high risk persons. Rural area and the fringe area of rural and urban are the key area for disease control. 1-4 days after onset is the key period to prevent complications. PMID- 21604574 TI - [Study on the ubiquitin ligase activity of rotavirus NSP1 protein]. AB - OBJECTIVE: To confirm the activity of non structural protein 1 (NSP1) of Rotavirus (RV) as E3 ubiquitin ligase by experiments and to provide some clues for NSP1 on the pathogenic mechanisms and replication of RV. METHODS: The whole gene and RING deleted mutation gene of NSP1 were coloned into pEGFPC1 expression plasmid, and transfected into human embryonic kidney (HEK) 293 FT cells with pBlue-Script-HA-Ubiquitin. The expression of proteins were proved by using con focal microscope and western blotting. The ubiquination of proteins were detected by co-immunoprecite. RESULTS: The cellular proteins of HEK293FT are ubiquinated by NSP1 protein and NSP1 protein was self-ubiquinated also. CONCLUSIONS: It revealed that RV NSP1 had the activity of E3 ubiquitin ligase and it may play a role on the modulate mechanisms of ubiquination. PMID- 21604575 TI - [Incidence and relationship of human cytomegalovirus infection and human herpesvirus 6 infection in pediatric patients after hemopoietic stem cell transplantation]. AB - OBJECTIVE: To study the incidence of human cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6) infection in pediatric patients with hemopoietic stem cell transplantation (HSCT), and to explore the relationship between CMV and HHV-6 infection in pediatric patients with HSCT. METHODS: Pediatric patients with HSCT in hemotology center of Beijing Children's Hospital were enrolled into this study from June 2007 to October 2009. Peripheral blood were collected every week after HSCT, and Fluorescent quantitation PCR and conventional PCR were used to detect CMV DNA load in serum and HHV-6 DNA in peripheral blood respectively. Genetic typing was conducted on HHV-6. RESULTS: Fifty two pediatric patients with HSCT were enrolled into this study, and six hundreds and thirty six specimens were collected totally. CMV DNA was detected in fifty two specimens from twenty cases. The median time was 56 days after HSCT. The incidence of CMV infection was 38.5% (20/52) in all HSCT patients and 47.6% (20/42) in allogene HSCT patients. The incidence of late CMV infection was 22.2% (6/27) in allogene HSCT. Three patients died of CMV infection,and two died of CMV interstitial pneumonia. HHV-6 DNA was detected in thirty three specimens from fourteen cases. The median time was 23 days after HSCT. The incidence of HHV-6 infection was 26.9% (14/52)in all HSCT patients and 31% (13/42) in allogene HSCT patients. The genotype of HHV6 was all type B. HHV-6 DNA was positive in six of twenty cases with CMV infection. The incidence of co-infection was 30% (6/20). CONCLUSIONS: There was a substantial incidence of CMV and HHV6 infection after HSCT. The relationship between earlier HHV6 infection and later CMV infection in pediatric patients with HSCT need further study. PMID- 21604576 TI - [Prognostic analysis of 336 patients with chronic severe hepatitis B]. AB - OBJECTIVE: To investigate the risk factors related to outcome of chronic severe hepatitis B. METHODS: A total of 336 consecutive patients with chronic severe hepatitis B (CSHB) were analysed retrospectively. According to the outcome, objects were divided into survival group (n = 137) and death group(n = 199), then to observe the differences between them in respect to age, sex, family history, prothrombin activity (PTA), complications including ascites, infection, electrolyte disturbance, upper gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome and the corresponding quantity of complications in each individual, antivirus therapy, artificial liver support system (ALSS) therapy, and alprostadil therapy. Finally, risk factors related to prognosis were selected by stepwise Logistic regression analyse. RESULTS: In univariate analyse, significant differences between the two groups were found related to age, PTA, complications and its quantity (P < 0.01 for all), and antivirus therapy (P < 0.05) rather than sex, family history and treatment of ALSS or alprostadil. Logistic regression revealed that risk factors comprised of PTA and quantity of complications, antivirus therapy was the only protective factor. CONCLUSION: A numbers of factors including age, PTA, complications and its quantity, and antivirus therapy affect the prognosis of CSHB, among which, antivirus therapy can reduce the death rate. PMID- 21604577 TI - [Clinical application studies on AFP-L3 detected by micro-spin column method]. AB - OBJECTIVE: To explore the clinical value of Lens culinaris agglutinin-reactive alpha-fetoprotein in the differentiation diagnosis between benign and malignant liver diseases, as well as the early warning of hepatocellular carcinoma. METHODS: Alpha-fetoprotein variants from 300 patients with liver diseases were isolated with micro-spin column equipped lens culinaris agglutinin (LCA). The AFP and AFP-L3 were detected by the electrochemical luminescence (ECL) method, and the proportions of AFP-L3 were calculated. RESULTS: The positive rates of AFP-L3 of HCC patients and chronic liver disease patients were 95% and 64% respectively, there were significant difference in two groups (chi2 = 134.72, P < 0.01), the HCC incidence rates of AFP-L3 positive and negative chronic liver disease patients showed significant difference (chi2 = 80.158, P < 0.01). there were no correlations between the proportion of AFP-L3 and AFP consistency(r = 0.046, P > 0.05). CONCLUSIONS: The detection of AFP-L3 by micro-spin column assay show great clinical value in the differentiation diagnosis of benign and malignant liver diseases, as well as the early warning of hepatocellular carcinoma. PMID- 21604578 TI - [Clinicopathological analysis on hepatitis B virus-associated glomerulonephritis in 205 patients]. AB - OBJECTIVE: To investigate liver and kidney lesions in HBV-GN patients and relationship between them and provide evidences to make early diagnosis of HBV GN. METHODS: Reviewing the clinicopathological and laboratory indexes of 205 patients with HBV-GN diagnosed by renal biopsy in our hospital from September 1995 to November 2008. RESULTS: HBV-GN account for 5.6% of all renal biopsies at the same time. Among them, 157 (76.5%) patients were male,123 (60%) was 19-45 years-old. 95 (46%) patients break out with kidney disease. HBsAg, HBeAg, HBcAg were the most common HBV makers. 102 (49.8%) patients present nephrotic syndrome, 18 (8.8%) suffered kidney dysfunction; 18 patients with hepatic cirrhosis. Patients with or without liver disfunction got no different in clinic manifestation and renal pathology. With the rising of the content of HBV-DNA in surum, the urinary protein increases. Renal data shows that membranous nephropathy(MN) was the most frequent type (60.5%). CONCLUSION: The peak incidence of HBV-GN is in the twentieth to forth decade of life. There was a 3:1 predominance of males. Nephrotic syndrome was the most common clinic manifestation and membranous nephropathy was the most common pathology. 10% persent patisnts had loss of renal function at the time of renal biopsy. The HBV copies in serum correlated with the albuminuria. HBV-GN patients had desynchroneity lesions in kidney and liver. As the high rate of HBV infection in China, It needs to prevent the kidney damage in HBV infectious people and to elevate early diagnosis and therapy. PMID- 21604579 TI - [Association between PCT levels and liver function in liver cirrhosis patients]. AB - OBJECTIVE: To explore the association between procalcitonin (PCT) levels and liver function in liver cirrhosis patients. METHODS: Collect serum samples from 44 liver cirrhosis patients, detect the PCT levels by semi-quantitative solid immunoassay, and at the same time, detect the serum levels of ALT, AST, TBIL, ALB, CHE, CHOL, PTA etc, then rate the patients by Child-pugh scoring system into Child-pugh A, B, C. RESULTS: set PCT > 0.5 microg/L as the positive threshold, significantly the PCT positive patients have higher ALT, TBIL but lower CHOL, PTA compared with the PCT negative patients. With the increasing of PCT levels, the ALT, AST, TBIL levels are gradually increased too, but PTA decreased. We find that the PCT positive patients are mainly Child-pugh B and C patients, and PCT negative patients are mainly Child-pugh C patients. PCT positive patient's lymphocyte count are lower than PCT negative patient's. CONCLUSION: Liver injury increase the risk of infection in liver cirrhosis patients. As the severity of the injury, the patients are easier to progress into severe infection. Combined with monitoring the PCT levels, pay more attention to protect the liver function will be helpful in early detecting infections and controlling of infection in liver cirrhosis patients. PMID- 21604580 TI - [MiR-196a-2 gene polymorphism and the antiviral therapy of chronic hepatitis C]. AB - OBJECTIVE: To investigate the relationship between the SNP rs11614913 on miR196a 2 gene and the treatment effects of Peg-IFN-a plus Ribavirin on chronic hepatitis C patients. METHODS: The total 139 patients of chronic hepatitis C infection who received the treatment of Peg-IFN-alpha-2a or Peg-IFN-alpha-2b plus Ribavirin were enrolled in this study. The patients were divided into two groups: sustained virological response (SVR) (n = 82) group and non virological response (NVR) or recurrence (n = 57) group. Blood samples were collected and chromosomal DNA was extracted. The miR-196a-2 polymorphism was determined with the method of polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). RESULTS: In our study, there was statistically association between miR-196a-2 polymorphism and the antiviral therapy efficacy of hepatitis C patients. There was statistically significance in the CT genotype and the TT genotype of miR-196a 2 between the two groups [P = 0.009, A = 2.924 (1.285 -6.652)]. There was statistically significance in the CC genotype and the TT genotype between the two groups [P = 0.036, A = 3.091(1.052 -9.078)]. There was statistically significance in the C allele and the T allele between the two groups [P = 0.036, A = 3.091 (1.052 - 9.078)]. CONCLUSION: These findings suggested that the rs11614913 SNP in miR - 196a-2 be associated with the antiviral therapy efficacy of hepatitis C patients, and the TT genotype or T alleles be associated with the SVR while the CC genotype or C allele could be related to the NVR or recurrence. PMID- 21604582 TI - [Determination of circulating HBV specific CD8+ T cells in hepatitis B patients by flow cytometry and its clinical significance]. AB - OBJECTIVE: To explore the levels of circulating HBV specific CD8+ T cells in hepatitis B patients and analysis its clinical significance. METHODS: HBV specific CD8+ T cells in whole blood samples of twenty-five acute hepatitis B patients, thirty-five chronic hepatitis B patients and ten healthy control were stained with pentamers complex of HLA-A2 and HBV core 18-27 peptide and counted by flow cytometry. RESULTS: The medians of HBV core 18-27 specific CD8+ T cells quantities among total CD8+ cells were 2.93% (1.12% -0.63%) in 12 HLA-A2+ acute hepatitis B patients and 0.75% (< 0.01% - 1.76%) in 16 HLA-A2+ chronic hepatitis B patients respectively. There was showed a marked significant between the two groups (P < 0.01). The medians of HBV core 18-27 specific CD8+ T cells of 10 HLA A2+ healthy control, 13 HLA-A2- acute hepatitis B patients and 19 HLA-A2- chronic hepatitis B patients were all lower than 0.02% separately. CONCLUSION: HLA peptides pentamers staining flow cytometry is a direct ex vivo method to detect the levels of circulating HBV specific CD8+ T cells which may be play a crucial role in complete clearance of HBV and relates to clinical consequence in hepatitis B patients. PMID- 21604581 TI - [Development of multicolour real time PCR for detection of drug resistance mutation in hepatitis B virus]. AB - OBJECTIVE: To set up a rapid method for detection of drug resistance mutation in HBV, based on multicolour real time PCR. To detect the mutation of blood serum, which were collected from patients. METHOD: To establish two reaction systems, each reaction system contains four resistance loci. On the new multicolor real time PCR method, the sensitivity and specificity were analysed, and detecting the drug resistant mutation of blood serum collected from 30 cases patients. RESULTS: Construction of a multicolor fluorescence PCR for detection drug resistance in HBV was constructed, better specificity, sensitivity analysis of up to 1 x 10(3) copies/ml. Sample of 30 cases were detected, there were 2 YVDD (6.67%), 1 YIDD (3.33%), and there were 5 cases of 1896 variation, accounting for 16.67%. Other sites were not detected mutations. CONCLUSION: The multicolor real time PCR detection system could be used for rapid and simple analysis of drug resistance for the clinical hospital. The 1986 mutation in HBV pre-C region are relatively high. PMID- 21604583 TI - [Establishment of internally controlled real-time PCR for the detection of human parvovirus B19 DNA in serum]. AB - OBJECTIVE: To establish a TaqMan-based Real-time PCR assay with internal control for the detection of parvovirus B19 DNA in human serum. METHODS: Two DNA fragments in length of 113 bp each were artificially synthesized, cloned into T vector and used as standard DNA or internal control, respectively. One pair of primers and two probes were included in the Real-time PCR. The probes were labeled with different fluoresceins and could bind B19 DNA or internal control, respectively. Precision and specificity of the method were evaluated. Specimens of human serum were examined by this assay to find B19 DNA. RESULTS: The standard curve was constructed using the quantified standard B19 DNA. The Real-time PCR method was established. It was stable according to precision evaluation by the intra- and inter-assay and specific without any evident cross-reaction with human hepatitis B virus (HBV). Among 160 samples of human serum, B19 DNA was detected in 2 with a concentration of 2.1 x 10(5) Geq/ml and 3.6 x 10(3) Geq/ml, respectively. CONCLUSION: The Real-time PCR for B19 DNA detection was developed successfully, in which the internal control was helpful to exclude false-negative results. PMID- 21604584 TI - [Pain for 2 years in the right elbow. Movement not restricted. Osteochondrosis]. PMID- 21604585 TI - [Wheezing in infants and young children. Signs of asthma risk or remission with age?]. PMID- 21604586 TI - [Efavirenz in fixed combination with tenofovir and emtricitabine. Long-term effectiveness verified in new studies]. PMID- 21604587 TI - [Early treatment makes it possible: an almost normal life with HIV]. PMID- 21604588 TI - [Suspicion of HIV-infection: which symptoms should be warning lights?]. PMID- 21604589 TI - [HIV-positive: what to do?]. PMID- 21604590 TI - [CCR5 antagonist Maraviroc: effective and well tolerated. "A very promising substance"]. PMID- 21604591 TI - [Utilizing the potential of maraviroc early. "Clear in second line therapy" (interview by Dr. Felicitas Zorn)]. PMID- 21604592 TI - [HAART-update for the general practitioner]. PMID- 21604593 TI - [HIV postexposure prophylaxis after suspicious (hetero-)sexual contact]. PMID- 21604594 TI - [Deviating from classical triple therapy. Nuke sparing concepts as interest focus]. PMID- 21604595 TI - [Highly active antiretroviral therapy. Building on experience in developing new strategies]. PMID- 21604596 TI - [Important questions for HIV-infected employees]. PMID- 21604597 TI - [Multiple drugs--a challenge for HIV-patients and doctors]. PMID- 21604598 TI - [Neuropsychiatric side effects of HAART]. PMID- 21604599 TI - [Long-term therapy strategy with raltegravir. Appropriate in all illness phases]. PMID- 21604600 TI - [Painful neuropathy of the HIV-patient--new therapeutic strategies]. PMID- 21604601 TI - [Management of hepatitis B/C in patients with HIV-infection]. PMID- 21604602 TI - [Persistence in focus. Atazanavir proves itself anew in long-term therapy]. PMID- 21604603 TI - Rate increase disclosure and review. Final rule with comment period. AB - This final rule with comment period implements requirements for health insurance issuers regarding disclosure and review of unreasonable premium increases under section 2794 of the Public Health Service Act. The final rule establishes a rate review program to ensure that all rate increases that meet or exceed a specified threshold are reviewed by a State or CMS to determine whether they are unreasonable and that certain rate information be made public. PMID- 21604604 TI - [Q & A Development of skin eruption of legs subsequent to epigastric pain]. PMID- 21604605 TI - Bug breakfast in the Bulletin: Biosecurity and infectious diseases. PMID- 21604606 TI - Factsheet: Murray Valley encephalitis. PMID- 21604607 TI - Inform patients-and colleagues-about HZ vaccine. PMID- 21604608 TI - Gun control is not clinically relevant. PMID- 21604609 TI - The place of sedation in dentistry: controlling acute pain by local anesthesia is not the end of the story. PMID- 21604610 TI - Using nudges in exercise commitment contracts. PMID- 21604611 TI - The asset cost of poor health. PMID- 21604612 TI - Hold onto 'art of medicine' IOM urges standards for clinical guidelines. PMID- 21604613 TI - Funding threatened. Despite bipartisan support, centers face 46% cut. PMID- 21604614 TI - In the spotlight. Charity disclosures will draw unwelcome attention to hospital tax breaks. PMID- 21604615 TI - Going beyond saying you're sorry. More hospitals using quick remediation strategies following medical errors. PMID- 21604616 TI - 50 ways to improve your life in 2011: your health. PMID- 21604617 TI - 50 ways to improve your life in 2011: your mind. PMID- 21604618 TI - Communication drives change. PMID- 21604619 TI - Older people. How to get leaner, but not meaner. PMID- 21604620 TI - Outcomes. Unravel the reasons for readmissions. PMID- 21604621 TI - Efficiency. How you can become a model of innovation. PMID- 21604622 TI - A vision of effective involvement. PMID- 21604623 TI - Ahead of the curve. PMID- 21604624 TI - Hot news for the partnership way. PMID- 21604625 TI - Services that rise to any challenge. PMID- 21604626 TI - Any willing price. PMID- 21604627 TI - Drawing new life from the 'well'. PMID- 21604628 TI - Set up the right connections. PMID- 21604630 TI - But can you back it up? PMID- 21604629 TI - In and out and getting about. PMID- 21604631 TI - Out of the blocks. PMID- 21604632 TI - Science fiction to fact. PMID- 21604633 TI - Facing up to the big four. PMID- 21604634 TI - Health and wellbeing is a local responsibility. PMID- 21604635 TI - Service redesign: Part 1 of 2. Nice idea, shame about efficiency. PMID- 21604636 TI - Change management. How to help your top team triumph. PMID- 21604637 TI - A new era. The revolution has started. How information is collected, and the technology employed to utilise it, is transforming. Now all clinicians have to do is embrace the changes and reap the rewards... PMID- 21604638 TI - Building a record of trust. Allowing patients access to their own records has become easier thanks to the internet. It's obviously empowering for the patient but what are the pros and cons of opening the online door to clinical files? PMID- 21604639 TI - Clinical portals. Installing a whole new electronic health record system is a costly business. But with the use of an information portal access to patient data could be both a cost effective and speedy tool. PMID- 21604640 TI - Take the lead. The implementation of nationally-led schemes has resulted in a lack of expertise in project managing. Now IT leaders are being challenged to step up to the plate. PMID- 21604641 TI - We still need to care about care. PMID- 21604642 TI - Community children's services. Running towards a happier future. PMID- 21604643 TI - Training. Putting together a first-class act. PMID- 21604645 TI - Lucky to be me. PMID- 21604644 TI - A&E benchmarking. How to head off a major emergency. PMID- 21604646 TI - Best of both worlds? PMID- 21604647 TI - You can defuse workplace stress. PMID- 21604648 TI - On the same page. PMID- 21604649 TI - 7 ways to super-charge your front office. PMID- 21604650 TI - Applied science. PMID- 21604651 TI - Understand your financial statement. PMID- 21604652 TI - Do your insurance homework. PMID- 21604653 TI - Fall in love with medicine again. PMID- 21604655 TI - Telehealth. Home comfort. PMID- 21604654 TI - Tort reform must be factored in. PMID- 21604656 TI - Fit to work. A friendly ear. PMID- 21604657 TI - A closer look at quality. PMID- 21604658 TI - Public health. How hastings is fighting the battle of vascular health. PMID- 21604659 TI - Skills development. Commisssioning with confidence. PMID- 21604660 TI - Reform. Get your health and wellbeing boards in gear. PMID- 21604661 TI - Waivers under fire. IT grants given as GOP escalates criticism of ACA. PMID- 21604662 TI - Fork in the circuit. Healthcare IT needs continued support to make a truly connected system. PMID- 21604663 TI - Making lemonade. Revamping care of homeless when funding is cut. PMID- 21604664 TI - Barely making the grade. Feds receive mixed marks on IT initiatives, annual survey shows. PMID- 21604665 TI - Help wanted. Large majority of hospitals to add IT staff. PMID- 21604666 TI - Taking a bigger bite. IT to consume larger share of capital budgets. PMID- 21604667 TI - Meaningful results. Providers expect to meet federal criteria. PMID- 21604668 TI - Lower anxiety. Most see no impact from privacy policies. PMID- 21604669 TI - 'Imperfect but effective'. Majority of healthcare leaders support healthcare reform law but say more work still needed, poll shows. PMID- 21604671 TI - Thermal dissociation behavior and dissociation enthalpies of methane-carbon dioxide mixed hydrates. AB - Replacement of methane with carbon dioxide in hydrate has been proposed as a strategy for geologic sequestration of carbon dioxide (CO(2)) and/or production of methane (CH(4)) from natural hydrate deposits. This replacement strategy requires a better understanding of the thermodynamic characteristics of binary mixtures of CH(4) and CO(2) hydrate (CH(4)-CO(2) mixed hydrates), as well as thermophysical property changes during gas exchange. This study explores the thermal dissociation behavior and dissociation enthalpies of CH(4)-CO(2) mixed hydrates. We prepared CH(4)-CO(2) mixed hydrate samples from two different, well defined gas mixtures. During thermal dissociation of a CH(4)-CO(2) mixed hydrate sample, gas samples from the head space were periodically collected and analyzed using gas chromatography. The changes in CH(4)-CO(2) compositions in both the vapor phase and hydrate phase during dissociation were estimated based on the gas chromatography measurements. It was found that the CO(2) concentration in the vapor phase became richer during dissociation because the initial hydrate composition contained relatively more CO(2) than the vapor phase. The composition change in the vapor phase during hydrate dissociation affected the dissociation pressure and temperature; the richer CO(2) in the vapor phase led to a lower dissociation pressure. Furthermore, the increase in CO(2) concentration in the vapor phase enriched the hydrate in CO(2). The dissociation enthalpy of the CH(4) CO(2) mixed hydrate was computed by fitting the Clausius-Clapeyron equation to the pressure-temperature (PT) trace of a dissociation test. It was observed that the dissociation enthalpy of the CH(4)-CO(2) mixed hydrate lays between the limiting values of pure CH(4) hydrate and CO(2) hydrate, increasing with the CO(2) fraction in the hydrate phase. PMID- 21604670 TI - Push-pull perfusion sampling with segmented flow for high temporal and spatial resolution in vivo chemical monitoring. AB - Low-flow push-pull perfusion is a sampling method that yields better spatial resolution than competitive methods like microdialysis. Because of the low flow rates used (50 nL/min), it is challenging to use this technique at high temporal resolution which requires methods of collecting, manipulating, and analyzing nanoliter samples. High temporal resolution also requires control of Taylor dispersion during sampling. To meet these challenges, push-pull perfusion was coupled with segmented flow to achieve in vivo sampling at 7 s temporal resolution at 50 nL/min flow rates. By further miniaturizing the probe inlet, sampling with 200 ms resolution at 30 nL/min (pull only) was demonstrated in vitro. Using this method, L-glutamate was monitored in the striatum of anesthetized rats. Up to 500 samples of 6 nL each were collected at 7 s intervals, segmented by an immiscible oil and stored in a capillary tube. The samples were assayed offline for L-glutamate at a rate of 15 samples/min by pumping them into a reagent addition tee fabricated from Teflon where reagents were added for a fluorescent enzyme assay. Fluorescence of the resulting plugs was monitored downstream. Microinjection of 70 mM potassium in physiological buffered saline evoked l-glutamate concentration transients that had an average maxima of 4.5 +/- 1.1 MUM (n = 6 animals, 3-4 injections each) and rise times of 22 +/- 2 s. These results demonstrate that low-flow push-pull perfusion with segmented flow can be used for high temporal resolution chemical monitoring and in complex biological environments. PMID- 21604673 TI - Convergent and stereodivergent synthesis of complex 1-aza-7 oxabicyclo[2.2.1]heptanes. AB - A convergent and stereodivergent pathway to highly substituted 1-aza-7 oxabicyclo[2.2.1]heptanes is described. It begins with a coupling reaction involving allylic alcohol, aldehyde, and LiHMDS to produce stereodefined primary homoallylic amines. Subsequent N-oxidation and condensation with formaldehyde or glyoxylate defines a convenient entry to densely functionalized homoallylic nitrones whose intramolecular annulation can be controlled to deliver one of two distinct heterocyclic skeletons, each with >=20:1 stereoselection. Control of the stereochemistry in these reactions results from both control of the nitrone geometry and selective partitioning of the reaction pathway between direct [3 + 2] cycloaddition and tandem [3,3] rearrangement/[3 + 2] cycloaddition. PMID- 21604672 TI - Structure-activity relationships of C-17-substituted estratriene-3-O-sulfamates as anticancer agents. AB - The synthesis and antiproliferative activities of analogues of 2-substituted estradiol-3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent confirm that an H-bond acceptor is essential for high activity; its optimal linkage to C-17 and the local environment in which it resides are defined. In the non-sulfamoylated series 17beta-acyl substitution delivers 48b, the most potent compound identified to date. In the sulfamate series a number of permutations of linker and H-bond acceptor deliver excellent activity, with 55, 61, 65, 49a, and 49b proving especially promising. The in vivo potential of these compounds was explored in the NCI hollow fiber assay and also in a mouse Matrigel model of antiangiogenesis in which 49 and 55 show significant inhibitory activity. PMID- 21604674 TI - Lester Lave, visionary economist. PMID- 21604675 TI - Fate of Cry1Ab protein in agricultural systems under slurry management of cows fed genetically modified maize (Zea mays L.) MON810: a quantitative assessment. AB - The objective of the study was to track the fate of recombinant Cry1Ab protein in a liquid manure field trial when feeding GM maize MON810 to dairy cows. A validated ELISA was applied for quantification of Cry1Ab in the agricultural chain from GM maize plants, feed, liquid manure and soil to crops grown on manured fields. Starting with 23.7 MUg of Cry1Ab g(-1) dry weight GM maize material, a rapid decline of Cry1Ab levels was observed as 2.6% and 0.9% of Cry1Ab from the GM plant were detected in feed and liquid manure, respectively. Half of this residual Cry1Ab persisted during slurry storage for 25 weeks. After application to experimental fields, final degradation of Cry1Ab to below detectable levels in soil was reported. Cry1Ab exhibited a higher rate of degradation compared to total protein in the agricultural processes. Immunoblotting revealed a degradation of the 65 kDa Cry1Ab into immunoreactive fragments of lower size in all analyzed materials. PMID- 21604676 TI - Amplified on-chip fluorescence detection of DNA hybridization by surface initiated enzymatic polymerization. AB - We describe the incorporation of multiple fluorophores into a single stranded DNA (ssDNA) chain using terminal deoxynucleotidyl transferase (TdT), a template independent DNA polymerase that catalyzes the sequential addition of deoxynucleotides (dNTPs) at the 3'-OH group of an oligonucleotide primer; we term this methodology surface initiated enzymatic polymerization (SIEP) of DNA. We found that long (>1 Kb) ssDNA homopolymer can be grown by SIEP, and that the length of the ssDNA product is determined by the monomer to oligonucleotide initiator ratio. We observed efficient initiation (>=50%) and narrow polydispersity of the extended product when fluorescently labeled nucleotides are incorporated. TdT's ability to incorporate fluorescent dNTPs into a ssDNA chain was characterized by examining the effect of the molar ratios of fluorescent dNTP to natural dNTP on the degree of fluorophore incorporation and the length of the polymerized DNA strand. These experiments allowed us to optimize the polymerization conditions to incorporate up to ~50 fluorescent Cy3-labeled dNTPs per kilobase into a ssDNA chain. With the goal of using TdT as an on-chip labeling method, we also quantified TdT mediated signal amplification on the surface by immobilizing ssDNA oligonucleotide initiators on a glass surface followed by SIEP of DNA. The incorporation of multiple fluorophores into the extended DNA chain by SIEP translated to a ~45 fold signal amplification compared to the incorporation of a single fluorophore. SIEP was then employed to detect hybridization of DNA, by the posthybridization, on-chip polymerization of fluorescently labeled ssDNA that was grown from the 3'-OH of target strands that hybridized to DNA probes that were printed on a surface. A dose-response curve for detection of DNA hybridization by SIEP was generated, with a ~1 pM limit of detection and a linear dynamic range of 2 logs. PMID- 21604677 TI - P-glycoprotein substrate models using support vector machines based on a comprehensive data set. AB - P-glycoprotein (P-gp) is one of the major ABC transporters and involved in many essential processes such as lipid and steroid transport across cell membranes but also in the uptake of drugs such as HIV protease and reverse transcriptase inhibitors. Despite its importance, reliable models predicting substrates of P-gp are scarce. In this study, we have built several computational models to predict whether or not a compound is a P-gp substrate, based on the largest data set yet published, employing 332 distinct structures. Each molecule is represented by ADRIANA.Code, MOE, and ECFP_4 fingerprint descriptors. The models are computed using a support vector machine based on a training set which includes 131 substrates and 81 nonsubstrates that were evaluated by 5-, 10-fold, and leave-one out (LOO) cross-validation. The best model gives a Matthews Correlation Coefficient of 0.73 and a prediction accuracy of 0.88 on the test set. Examination of the model based on ECFP_4 fingerprints revealed several substructures which could have significance in separating substrates and nonsubstrates of P-gp, such as the nitrile and sulfoxide functional groups which have a higher frequency in nonsubstrates than in substrates. In addition structural isomerism in sugars was found to result in remarkable differences regarding the likelihood of a compound to be a substrate for P-gp. PMID- 21604678 TI - Robust method for high-throughput surface patterning of deformable substrates. AB - We describe a simple and robust method for high-throughput surface patterning of deformable substrates such as silicone rubber films covered with a thin layer of protein and cell antifouling hydrogel (PLL-g-PEG). The irradiation with deep UV (<200 nm) of PLL-g-PEG-coated rubber substrates through a synthetic quartz photomask created micropatterns over a large area of the substrate. Incubation with proteins resulted in stable patterns with high feature resolution. RPE1 cells seeded on fibronectin patterns were constrained for days even after stretching. We also propose the crossbow feature as an interesting example allowing the stretching of normalized stress fibers. PMID- 21604679 TI - Wetting and dewetting transitions on hierarchical superhydrophobic surfaces. AB - Many natural superhydrophobic structures have hierarchical two-tier roughness which is empirically known to promote robust superhydrophobicity. We report the wetting and dewetting properties of two-tier roughness as a function of the wettability of the working fluid, where the surface tension of water/ethanol drops is tuned by the mixing ratio, and compare the results to one-tier roughness. When the ethanol concentration of deposited drops is gradually increased on one-tier control samples, the impalement of the microtier-only surface occurs at a lower ethanol concentration compared to the nanotier-only surface. The corresponding two-tier surface exhibits a two-stage wetting transition, first for the impalement of the microscale texture and then for the nanoscale one. The impaled drops are subsequently subjected to vibration-induced dewetting. Drops impaling one-tier surfaces could not be dewetted; neither could drops impaling both tiers of the two-tier roughness. However, on the two-tier surface, drops impaling only the microscale roughness exhibited a full dewetting transition upon vibration. Our work suggests that two-tier roughness is essential for preventing catastrophic, irreversible wetting of superhydrophobic surfaces. PMID- 21604681 TI - Theoretical study of the 1:1 and 2:1 (homo- and heterochiral) complexes of XOOX' (X, X' = H, CH3) with lithium cation. AB - A theoretical study of the 1:1 and 2:1 complexes of XOOX' (X, X' = H, CH(3)) with the lithium cation has been carried out by means of ab initio computational methods up to the MP2/aug-cc-pVTZ level. The optical rotatory power and NMR parameters (absolute chemical shielding and indirect coupling constants) have been calculated. In addition, the racemization barriers within the complexes formed have been evaluated. Special attention has been paid concerning the differences between the 2:1 homo- and heterochiral complexes. PMID- 21604682 TI - Comparison of hydrated hydroperoxide anion (HOO-)(H2O)n clusters with alkaline hydrogen peroxide (HOOH)(OH-)(H2O)(n-1) clusters, n = 1-8, 20: an ab initio study. AB - Hydroperoxide anion (HOO(-)), the conjugate base of hydrogen peroxide (HOOH), has been relatively little studied despite the importance of HOOH in commercial processes, atmospheric science, and biology. The anion has been shown to exist as a stable species in alkaline water. This project explored the structure of gas phase (HOO(-))(H(2)O)(n) clusters and identified the lowest energy configurations for n <= 8 at the B3LYP/6-311++G** level of theory and for n <= 6 at the MP2/aug cc-pVTZ level of theory. As a start toward understanding equilibration between HOO(-) and HOOH in an alkaline environment, (HOOH)(OH(-))(H(2)O)(n-1) clusters were likewise examined, and the lowest energy configurations were determined for n <= 8 (B3LYP/6-311++G**) and n <= 6 (MP2/aug-cc-pVTZ). Some studies were also done for n = 20. The two species have very different solvation behaviors. In low energy (HOOH)(OH(-))(H(2)O)(n-1) clusters, HOOH sits on the surface of the cluster, is 4-coordinated (each O is donor once and acceptor once), and donates to the hydroxide ion. In contrast, in low energy (HOO(-))(H(2)O)(n) clusters, (HOO(-)) takes a position in the cluster center surrounded on all sides by water molecules, and its optimum coordination number appears to be 7 (one O is donor acceptor-acceptor while the other is a 4-fold acceptor). For n <= 6 the lowest (HOOH)(OH(-))(H(2)O)(n-1) cluster lies 1.0-2.1 kcal/mol below the lowest (HOO( ))(H(2)O)(n) cluster, but the lowest clusters found for n = 20 favor (HOO( ))(H(2)O)(20). The results suggest that ambient water could act as a substantial kinetic brake that slows equilibration between (HOOH)(OH(-)) and (HOO(-))(H(2)O) because extensive rearrangement of solvation shells is necessary to restabilize either species after proton transfer. PMID- 21604683 TI - Chirality transfer from a single chiral molecule to 2D superstructures in alaninol on the Cu(100) surface. AB - The formation of 2D chiral monolayers obtained by self-assembly of chiral molecules on surfaces has been widely reported in the literature. Control of chirality transfer from a single molecule to surface superstructures is a challenging and important aspect for tailoring the properties of 2D nanostructures. However, despite the wealth of investigations performed in recent years, how chiral transfer takes place on a large scale still remains an open question. In this paper we report a coupling of scanning tunneling microscopy and low energy electron diffraction measurements with an original theoretical approach, combining molecular dynamics and essential dynamics with density functional theory, to investigate self-assembled chiral structures formed when alaninol adsorbs on Cu(100). The peculiarity of this system is related to the formation of tetrameric molecular structures which constitute the building blocks of the self-assembled chiral monolayer. Such characteristics make alaninol/Cu(100) a good candidate to reveal chiral expression changes. We find that the deposition of alaninol enantiomers results in the formation of isolated tetramers that are aligned along the directions of the substrate at low coverage or when geometrical confinement prevents long-range order. Conversely, a rotation of 14 degrees with respect to the Cu(100) unit vectors is observed when small clusters of tetramers are formed. An insight to the process leading to a 2D globally chiral surface has been obtained by monitoring molecular assemblies as they grow from the early stages of adsorption, suggesting that the distinctive orientation of the self-assembled monolayer originates from a balance of cooperating forces which start acting only when tetramers pack together to form small clusters. PMID- 21604684 TI - Study of PEGylated lipid layers as a model for PEGylated liposome surfaces: molecular dynamics simulation and Langmuir monolayer studies. AB - We have combined Langmuir monolayer film experiments and all-atom molecular dynamics (MD) simulation of a bilayer to study the surface structure of a PEGylated liposome and its interaction with the ionic environment present under physiological conditions. Lipids that form both gel and liquid-crystalline membranes have been used in our study. By varying the salt concentration in the Langmuir film experiment and including salt at the physiological level in the simulation, we have studied the effect of salt ions present in the blood plasma on the structure of the poly(ethylene glycol) (PEG) layer. We have also studied the interaction between the PEG layer and the lipid bilayer in both the liquid crystalline and gel states. The MD simulation shows two clear results: (a) The Na(+) ions form close interactions with the PEG oxygens, with the PEG chains forming loops around them and (b) PEG penetrates the lipid core of the membrane for the case of a liquid-crystalline membrane but is excluded from the tighter structure of the gel membrane. The Langmuir monolayer results indicate that the salt concentration affects the PEGylated lipid system, and these results can be interpreted in a fashion that is in agreement with the results of our MD simulation. We conclude that the currently accepted picture of the PEG surface layer acting as a generic neutral hydrophilic polymer entirely outside the membrane, with its effect explained through steric interactions, is not sufficient. The phenomena we have observed may affect both the interaction between the liposome and bloodstream proteins and the liquid-crystalline-gel transition and is thus relevant to nanotechnological drug delivery device design. PMID- 21604685 TI - RIBAR and xRIBAR: Methods for reproducible relative MS/MS-based label-free protein quantification. AB - Mass spectrometry-driven proteomics is increasingly relying on quantitative analyses for biological discoveries. As a result, different methods and algorithms have been developed to perform relative or absolute quantification based on mass spectrometry data. One of the most popular quantification methods are the so-called label-free approaches, which require no special sample processing, and can even be applied retroactively to existing data sets. Of these label-free methods, the MS/MS-based approaches are most often applied, mainly because of their inherent simplicity as compared to MS-based methods. The main application of these approaches is the determination of relative protein amounts between different samples, expressed as protein ratios. However, as we demonstrate here, there are some issues with the reproducibility across replicates of these protein ratio sets obtained from the various MS/MS-based label-free methods, indicating that the existing methods are not optimally robust. We therefore present two new methods (called RIBAR and xRIBAR) that use the available MS/MS data more effectively, achieving increased robustness. Both the accuracy and the precision of our novel methods are analyzed and compared to the existing methods to illustrate the increased robustness of our new methods over existing ones. PMID- 21604686 TI - The effect of spin-orbit coupling on the surface dynamical properties and electron-phonon interaction of Tl(0001). AB - We present an ab initio study of the effect of spin-orbit coupling on the dynamical properties of the Tl(0001) surface as well as on the electron-phonon interaction at the surface. The calculations based on density-functional theory were carried out using a linear response approach and a mixed-basis pseudopotential method. It is shown that the spin-orbit effects on the phonon spectrum and the electron-phonon interaction at the Fermi level of the surface are weak but conspire to a reduction in the electron-phonon coupling strength by 16%. PMID- 21604687 TI - Toward a better pharmacophore description of P-glycoprotein modulators, based on macrocyclic diterpenes from Euphorbia species. AB - Multidrug resistance related to the increased expression of P-glycoprotein (P-gp) by cancer cells is the major contributor for the failure of chemotherapeutic treatments. Starting from pharmacophores and data already published and in macrocyclic diterpenes isolated from Euphorbia species, a comprehensive study of pharmacophore definitions of features was performed in order to obtain a new improved four-point pharmacophore able to detect literature and in-house modulators and simultaneously specific enough to avoid the detection of most nonactive molecules in a universe of 152 (literature), 74 (in-house), and 46 (inactive) molecules. This pharmacophore detects 84.2% of the molecules described in the literature, along with 100% detection of in-house isolated compounds and 19.5% of false positives. The importance of the hydrophobic and electron acceptor moieties as essential features for recognition of different molecules by the P-gp drug-binding site is clarified. The best combination of acceptor, donor, hydrophobic, and aromatic characteristics that contribute for the increased selectivity shown by the described pharmacophore is evaluated, and the protonation state of the molecules is also addressed. PMID- 21604688 TI - New Pickering emulsions stabilized by bacterial cellulose nanocrystals. AB - We studied oil in water Pickering emulsions stabilized by cellulose nanocrystals obtained by hydrochloric acid hydrolysis of bacterial cellulose. The resulting solid particles, called bacterial cellulose nanocrystals (BCNs), present an elongated shape and low surface charge density, forming a colloidal suspension in water. The BCNs produced proved to stabilize the hexadecane/water interface, promoting monodispersed oil in water droplets around 4 MUm in diameter stable for several months. We characterized the emulsion and visualized the particles at the surface of the droplets by scanning electron microscopy (SEM) and calculated the droplet coverage by varying the BCN concentration in the aqueous phase. A 60% coverage limit has been defined, above which very stable, deformable droplets are obtained. The high stability of the more covered droplets was attributed to the particle irreversible adsorption associated with the formation of a 2D network. Due to the sustainability and low environmental impact of cellulose, the BCN based emulsions open opportunities for the development of environmentally friendly new materials. PMID- 21604689 TI - Stereoselective synthesis of E,Z-configured 1,3-dienes by ring-closing metathesis. Application to the total synthesis of lactimidomycin. AB - Strategic positioning of a silyl group on the diene unit of a diene-ene substrate allows rigorous regio- and stereocontrol to be exerted during metathesis-based macrocyclization reactions. The versatility of this concise approach to E,Z configured 1,3-dienes of ring sizes of 12 or larger is demonstrated by an application to the total synthesis of lactimidomycin, a potent translation and cell-migration inhibitor. PMID- 21604690 TI - Proteomics approach to identify the interacting partners of cellular prion protein and characterization of Rab7a interaction in neuronal cells. AB - The present study was undertaken to identify proteins interacting with PrP(C) that could provide new insights into its physiological functions and pathological role. Human PrP(C) was expressed in prion protein-deficient murine hippocampus (HpL3-4) neuronal cells. The PrP(C) along with its interacting proteins were affinity purified using STrEP-Tactin-chromatography, in-gel digested, and identified by Q-TOF MS/MS analysis. Forty-three proteins appeared to interact with PrP(C) in this neuronal cell line. Of these, 15 were already known for their interaction with PrP(C) or PrP(Sc), while 28 new proteins were identified. Interaction of a novel interacting partner of GTPase family-Rab7a, having a suggested role in vesicle trafficking, was further investigated using confocal laser scanning microscopy and reverse coimmunoprecipitation. Both reverse coimmunoprecipitation and immunofluorescence results confirmed potential interaction of Rab7a with the PrP(C). siRNA against the Rab7a gene decreased expression of Rab7a protein, in PrP(C) expressing HpL3-4 and SH-SY5Y cells. This depleted Rab7a expression led to the enhanced accumulation of PrP(C) in Rab9 positive endosomal compartments and consequently an increased colocalization between PrP(C)/Rab9. However, the Rab9 accumulated PrP(C) remained sensitive to proteinase-K digestion. The work described demonstrated for the first time that Rab7a interacts with PrP(C) and highlighted the involvement of endosomal compartments in the trafficking and regulation of PrP(C). PMID- 21604691 TI - Probing insertion and solubilization effects of lysolipids on supported lipid bilayers using microcantilevers. AB - The interaction of surfactants with lipid membranes can result in composition change, area expansion, solubilization, or the formation of protrusion features of the membranes. Amphipathic surfactant molecules are simplified analogues to membrane-active drugs and peptides which are known for inserting into lipid bilayers; however, the effect of these amphipathic molecules on supported membranes is not well characterized. In this paper we explore the use of microcantilever sensors to quantify surfactants' effects on lipid membranes. We use microcantilevers which are coated with lipid membranes to probe the interactions between lysolipids and supported lipid bilayers (SLBs). In particular, we investigate the effects of four zwitterionic surfactants similar to phospholipids: lysolipids of different aliphatic chain lengths (lysophosphocholines, lysoPCs, 12:0, 14:0, 16:0, and 18:0) on 1-palmitoyl-2 oleoyl-sn-glycero-3-phosphocholine-supported lipid bilayers. By monitoring the deflection of the microcantilevers, real-time free energy changes in the SLBs upon the addition of lysolipids can be detected. Additionally, the bending direction reveals whether the lysoPCs incorporate into or solubilize the SLB. When the bulk lysoPC concentration is less than its critical micelle concentration (CMC), we observe a compressive bending of the microcantilever, indicating adsorption to the SLB. Additionally, the change in surface stress is found to be proportional to the amount of membrane-bound lysoPCs. For bulk concentrations greater than the CMC, lysoPCs 12:0 and 14:0, there is tensile bending, indicating that the lysoPCs begin to solubilize and destroy the SLBs. Interestingly, this is not observed for lysoPCs with longer chain lengths. This new method of using microcantilevers for detecting and quantifying the surfactant insertion and solubilization of SLBs offers additional insights into the interactions between small amphipathic molecules and lipid membranes. PMID- 21604692 TI - Efficient bifunctional decadentate ligand 3p-C-DEPA for targeted alpha radioimmunotherapy applications. AB - A new bifunctional ligand 3p-C-DEPA was synthesized and evaluated for use in targeted alpha-radioimmunotherapy. 3p-C-DEPA was efficiently prepared via regiospecific ring opening of an aziridinium ion and conjugated with trastuzumab. The 3p-C-DEPA-trastuzumab conjugate was extremely rapid in binding (205/6)Bi, and the corresponding (205/6)Bi-3p-C-DEPA-trastuzumab complex was stable in human serum. Biodistribution studies were performed to evaluate in vivo stability and tumor targeting of (205/6)Bi-3p-C-DEPA-trastuzumab conjugate in tumor bearing athymic mice. (205/6)Bi-3p-C-DEPA-trastuzumab conjugate displayed excellent in vivo stability and targeting as evidenced by low organ uptake and high tumor uptake. The results of the in vitro and in vivo studies indicate that 3p-C-DEPA is a promising chelator for radioimmunotherapy of (212)Bi and (213)Bi. PMID- 21604693 TI - Possible involvement of Nemo-like kinase 1 in Xenopus oocyte maturation as a kinase responsible for Pumilio1, Pumilio2, and CPEB phosphorylation. AB - Members of the mitogen-activated protein kinase (MAPK) family play important roles in Xenopus oocyte maturation. Nemo-like kinase (NLK), an atypical MAPK, is known to function in multiple developmental processes in vertebrates and invertebrates, but its involvement in gametogenesis and gamete maturation is unknown. In this study, we biochemically examined NLK1 during Xenopus oocyte maturation. NLK1 is expressed in immature oocytes, and its protein level remains constant during maturation. NLK1 is inactive in immature oocytes but is activated during maturation, depending on Mos protein synthesis but not on p42 MAPK activation. Overexpression of NLK1 by injection of 5 ng of mRNA accelerates progesterone-induced oocyte maturation by enhancing Cyclin B1 protein synthesis through the translational activation of its mRNA, in accordance with precocious phosphorylation of Pumilio1 (Pum1), Pumilio2 (Pum2), and cytoplasmic polyadenylation element-binding protein (CPEB), key regulators of the translational control of mRNAs stored in oocytes. A higher level of NLK1 expression by injection of 50 ng of mRNA induces Pum1/Pum2/CPEB phosphorylation, CPEB degradation, Cyclin B1 protein synthesis, and oocyte maturation in the absence of progesterone. NLK1 phosphorylates Pum1, Pum2, and CPEB in vitro. These findings provide the first evidence for the involvement of NLK1 in Xenopus oocyte maturation. We suggest that NLK1 acts as a kinase downstream of Mos and catalyzes phosphorylation of Pum1, Pum2, and CPEB to regulate the translation of mRNAs, including Cyclin B1 mRNA, stored in oocytes. PMID- 21604694 TI - Pro-oxidant activity of aluminum: stabilization of the aluminum superoxide radical ion. AB - The pro-oxidant activity of aluminum, a nonredox metal, through superoxide formation is studied by theoretical methods, determining the ESR g-tensor values of O2(*-) with a variety of metals and the reaction energies for Al3+ superoxide affinity in solution. First, the intrinsic ability of aluminum to induce a splitting of the pig levels is compared to that of other significant biological metals, such as Na+, K+, Mg2+, and Ca2+. Additional properties such as bond lengths, ionization potentials, and electron affinities are also determined, and the coherency with the trends observed from ESR g-tensor values is analyzed. As it corresponds to the high charge and its small size, there is a strong interaction between Al3+ and the superoxide. We predict that this strong inherent interaction remains when aluminum is microsolvated. Finally, we analyze the possibility of Al3+ superoxide formation in solution, leading to the conclusion that substitution of the first coordination shell water molecules is plausible, but not of hydroxides. This points to the possibility of Al3+ superoxide formation in solution, which would be pH-dependent. Taking into account the earlier established linear relationship between metal-superoxide interactions and promoting effects in electron-transfer reactions, our work reinforces the idea that the presence of aluminum in biological systems could lead to an important pro-oxidant activity through a superoxide formation mechanism. PMID- 21604695 TI - Donor-substituted diphenylacetylene derivatives act as electron donors and acceptors. AB - Despite the predominant electron donor character of p-phenylenediamine, our studies on extended p-phenylenediamine derivatives show that they can not only be chemically oxidized, giving well-known Wurster-type radical cations, but also be chemically reduced, giving radical anions. Making use of EPR/ENDOR spectroscopy and supported by DFT calculations, we were able to reveal the extent of pi electron delocalization in the paramagnetic species and to shed light onto the geometry and bond lengths. While for the radical anions spin was found to be mostly delocalized into the pi-system, the radical cations can be described as essentially N-centered. Furthermore, we performed electrochemical characterizations using cyclic voltammetry to gain insight into the thermodynamics of the redox processes. The photophysical properties of the parent extended p-phenylenediamine were investigated by absorption, emission, and excitation spectroscopy. The fluorescence quantum yield and the excited-state lifetime of the neutral precursors in hexane and acetonitrile were determined to establish elementary differences originating from solvent effects. PMID- 21604696 TI - pH-responsive polysaccharide-based polyelectrolyte complexes as nanocarriers for lysosomal delivery of therapeutic proteins. AB - Nanopharmaceutics composed of a carrier and a protein have the potential to improve the activity of therapeutical proteins. Therapy for lysosomal diseases is limited by the lack of effective protein delivery systems that allow the controlled release of specific proteins to the lysosomes. Here we address this problem by developing functional polyelectrolyte-based nanoparticles able to promote acidic pH-triggered release of the loaded protein. Trimethyl chitosan (TMC) was synthesized and allowed to form polyelectrolyte complexes (PECs) with the lysosomal enzyme alpha-GAL through self-assembly and ionotropic gelation, with average particle size <200 nm, polydispersity index (PDI) <0.2, zeta potential of ~ 20 mV, and a protein loading efficiency close to 65%. These polyelectrolyte nanoparticles were stable and active under physiological conditions and able to release the enzyme at acidic pH, as demonstrated by in situ atomic force microscopy (AFM). These nanoparticles were further functionalized with Atto 647N for single-particle characterization and tracking their cellular uptake and fate using high-resolution fluorescence microscopy. In contrast with their precursor, TMC, PECs were efficiently internalized by human endothelial cells and mostly accumulated in lysosomal compartments. The superior physicochemical characteristics of the TMC/alpha-GAL PECs together with their excellent cellular uptake properties indicate their enormous potential as advanced protein delivery systems for the treatment of lysosomal storage diseases. PMID- 21604697 TI - Bonding nature and vibrational signatures of oxirane:(water)(n=1-3). Assessment of the performance of the dispersion-corrected DFT methods compared to the ab initio results and Fourier transform infrared experimental data. AB - Spectroscopic properties of 1:n complexes (n = 1, 2, and 3) formed between an oxirane molecule and water clusters have been evaluated using experimental techniques (FTIR spectroscopy using a new supersonic jet experiment coupled to the infrared AILES beamline of synchrotron SOLEIL and also cryogenic neon matrix device) and theoretical approaches (SAPT, ab initio, DFT, and topological analyses). From a systematic comparison between the theoretical results (obtained with both wave function based methods and several newly hydrogen bonded adapted functionals) with the available experimental results on the studied compounds, it was concluded that only the wave function based methods (particularly coupled clusters ones) are able to well describe these compounds, while the newly hydrogen bonded adapted functionals (long-range and/or dispersion-corrected ones and also double hybrids) cannot adequately describe all the spectroscopic properties in a systematic way. The MP2 method, although more expensive than DFT, still offers a reliable method to study both isolated molecules and hydrogen bonded complexes provided the contribution of the dispersion energy in total energy is properly taken into account. The nature of interaction between oxirane and water molecules has been analyzed using the symmetry adapted perturbation theory (SAPT) method. It was evidenced that the water-oxirane interaction corresponds to the hydrogen-bonded systems with a large contribution of the dispersion energy. The nature of the oxirane-water bonding has been studied using two topological methods: atoms in molecules and electron-localization function (ELF). Geometrical structures of the titled complexes were rationalized from the spatial arrangement of ELF attractors. Secondary interaction was also accounted for the bond critical points found at H(oxirane)...O(water) bond paths. PMID- 21604698 TI - Molecular photoelectric switch using a mixed SAM of organic [60]fullerene and [70]fullerene doped with a single iron atom. AB - We describe a photoswitch fabricated on indium tin oxide (ITO) as a self assembled monolayer (SAM) of two fullerene molecules, a purely organic [60]fullerene that generates an anodic current and a [70]fullerene doped with a single iron atom. This device generates a bidirectional photocurrent upon irradiation at 340 and 490 nm. The new [70]fullerene iron complex bearing three rigid carboxylic acid legs, Fe[C(70)(C(6)H(4)C(6)H(4)COOH)(3)]Cp, generates only a cathodic current upon photoexcitation between 350 and 700 nm, whereas the organic [60]fullerene absorbs at wavelengths shorter than 500 nm. The quantum efficiency of the photocurrent generation by the mixed SAM is comparable to that of a single-component SAM, indicating that the individual diode molecules on ITO generate photocurrents independently with little cross talk. PMID- 21604699 TI - Using consensus-shape clustering to identify promiscuous ligands and protein targets and to choose the right query for shape-based virtual screening. AB - Ligand-based shape matching approaches have become established as important and popular virtual screening (VS) techniques. However, despite their relative success, many authors have discussed how best to choose the initial query compounds and which of their conformations should be used. Furthermore, it is increasingly the case that pharmaceutical companies have multiple ligands for a given target and these may bind in different ways to the same pocket. Conversely, a given ligand can sometimes bind to multiple targets, and this is clearly of great importance when considering drug side-effects. We recently introduced the notion of spherical harmonic-based "consensus shapes" to help deal with these questions. Here, we apply a consensus shape clustering approach to the 40 protein ligand targets in the DUD data set using PARASURF/PARAFIT. Results from clustering show that in some cases the ligands for a given target are split into two subgroups which could suggest they bind to different subsites of the same target. In other cases, our clustering approach sometimes groups together ligands from different targets, and this suggests that those ligands could bind to the same targets. Hence spherical harmonic-based clustering can rapidly give cross docking information while avoiding the expense of performing all-against-all docking calculations. We also report on the effect of the query conformation on the performance of shape-based screening of the DUD data set and the potential gain in screening performance by using consensus shapes calculated in different ways. We provide details of our analysis of shape-based screening using both PARASURF/PARAFIT and ROCS, and we compare the results obtained with shape-based and conventional docking approaches using MSSH/SHEF and GOLD. The utility of each type of query is analyzed using commonly reported statistics such as enrichment factors (EF) and receiver-operator-characteristic (ROC) plots as well as other early performance metrics. PMID- 21604700 TI - Electocatalytic water oxidation by cobalt(III) hangman beta-octafluoro corroles. AB - Cobalt hangman corrole, bearing beta-octafluoro and meso-pentafluorophenyl substituents, is an active water splitting catalyst. When immobilized in Nafion films, the turnover frequencies for the 4e(-)/4H(+) process at the single cobalt center of the hangman platform approach 1 s(-1). The pH dependence of the water splitting reaction suggests a proton-coupled electron transfer (PCET) catalytic mechanism. PMID- 21604701 TI - pH-Dependent spectroscopic and luminescent properties, and metal-ion recognition studies of Re(I) complexes containing 2-(2'-pyridyl)benzimidazole and 2-(2' pyridyl)benzimidazolate. AB - A series of Re(I) complexes, [Re(CO)(3)Cl(HPB)] (1), [Re(CO)(3)(PB)H(2)O] (2), [Re(CO)(3)(NO(3))(PB-AuPPh(3))] (3), and [Re(CO)(3)(NO(3))(PB)Au(dppm-H)Au](2) (4) [HPB = 2-(2'-pyridyl)benzimidazole; dppm = 2,2' bis(diphenylphosphinomethane)], have been synthesized and characterized by X-ray diffraction. Complex 1, which exhibits interesting pH-dependent spectroscopic and luminescent properties, was prepared by reacting Re(CO)(5)Cl with an equimolar amount of 2-(2'-pyridyl)benzimidazole. The imidazole unit in complex 1 can be deprotonated to form the imidazolate unit to give complex 2. Addition of 1 equiv of AuPPh(3)(NO(3)) to complex 2 led to the formation of a heteronuclear complex 3. Addition of a half an equivalent of dppm(Au(NO(3)))(2) to complex 2 yielded 4. In both 3 and 4, the imidazolate unit acts as a multinuclear bridging ligand. Complex 4 is a rare and remarkable example of a Re(2)Au(4) aggregate in combination with MU(3)-bridging 2-(2'-pyridyl)benzimidazolate. Finally, complex 2 has been used to examine the Hg(2+)-recognition event among group 12 metal ions. Its reversibility and selectivity toward Hg(2+) are also examined. PMID- 21604702 TI - 2-D array photonic crystal sensing motif. AB - We have developed the first high-diffraction-efficiency two-dimensional (2-D) photonic crystals for molecular recognition and chemical sensing applications. We prepared close-packed 2-D polystyrene particle arrays by self-assembly of spreading particle monolayers on mercury surfaces. The 2-D particle arrays amazingly diffract 80% of the incident light. When a 2-D array was transferred onto a hydrogel thin film showing a hydrogel volume change in response to a specific analyte, the array spacing was altered, shifting the 2-D array diffraction wavelength. These 2-D array photonic crystals exhibit ultrahigh diffraction efficiencies that enable them to be used for visual determination of analyte concentrations. PMID- 21604703 TI - Eu(3+)-mediated polymerization of benzenetetracarboxylic acid studied by spectroscopy, temperature-dependent calorimetry, and density functional theory. AB - Thermodynamic parameters for the complexation of Eu(3+) with pyromellitic acid (1,2,4,5-benzenetetracarboxylic acid, BTC) as a model system for polymerizable metal-complexing humic acids were determined using temperature-dependent time resolved laser-induced fluorescence spectroscopy (TRLFS) and isothermal titration calorimetry (ITC). At low metal and ligand concentrations (<50 MUM Eu(3+), <1 mM BTC), a 1:1 monomeric Eu-BTC complex was identified in the range of 25-60 degrees C. At elevated concentrations (>500 MUM Eu(3+) and BTC) a temperature dependent polymerization was observed, where BTC monomers are linked via coordinating shared Eu(3+) ions. The two methods lead to comparable thermodynamic data (DeltaH = 18.5 +/- 1.5/16.5 +/- 0.1 kJ mol(-1); DeltaS = 152 +/- 5/130 +/- 5 J mol(-1) K(-1); TRLFS/ITC) in the absence of polymerization. With the onset of polymerization, TRLFS reveals the water coordination number of the lanthanide, whereas calorimetry is superior in determining the thermodynamic data in this regime. Evaluating the heat uptake kinetics, the monomer and polymer formation steps could be separated by "time-resolved" ITC, revealing almost identical binding enthalpies for the sequential reactions. Structural features of the complexes were studied by Fourier-transform infrared (FTIR) spectroscopy in combination with density functional theory (DFT) calculations showing predominantly chelating coordination with two carboxylate groups in the monomeric complex and monodentate binding of a single carboxylate group in the polymeric complex of the polycarboxylate with Eu(3+). The data show that pyromellitic acid is a suitable model for the study of metal-mediated polymerization as a crucial factor in determining the effect of humic acids on the mobility of heavy metals in the environment. PMID- 21604704 TI - Polytypism in the lithium-aluminum layered double hydroxides: the [LiAl2(OH)6]+ layer as a structural synthon. AB - The [LiAl(2)(OH)(6)](+) layer obtained from gibbsite-Al(OH)(3) belongs to the layer group symmetry P-312/m. This layer satisfies the defining characteristics of a synthon in that it predicts all the polymorphic modifications of the layered double hydroxides of Li and Al. The various possible ways of stacking these layers can be derived by the systematic elimination of the principal symmetry elements comprising the layer group. This approach yields the complete universe of possible structures. When the 3 axis of the layer is conserved in the stacking, the resultant crystal adopts the structure of the 1H, 2H, or 3R polytypes (H, hexagonal; R, rhombohedral). When the 3 axis is destroyed and the 2/m axis is retained, the crystal adopts monoclinic symmetry and crystallizes in the structures of the 1M(1) or 1M(2) (M, monoclinic) polytypes; the two polytypes differ only in their translational component. Experimentally, gibbsite-based precursors yield the 2H polytype, and bayerite-based precursors yield the 1M polytype. Faulted structures incorporating differently oriented 1M(1) motifs or a mixture of 1M(1) and 1M(2) motifs are also obtained. These stacking faults result in cation disorder along the c axis and produce signature effects on the line shapes of select reflections in the powder X-ray diffraction patterns. This symmetry-guided approach is general and can be extended to other classes of layered solids. PMID- 21604705 TI - Extending the family of titanium heterometallic-oxo-alkoxy cages. AB - Here we investigate the synthesis of high-nuclearity heterometallic titanium oxo alkoxy cages using the reactions of metal chlorides with [Ti(OEt)(4)] or the pre formed homometallic titanium-oxo-alkoxy cage [Ti(7)O(4)(OEt)(20)] (A). The octanuclear Ti(7)Co(II) cage [Ti(7)CoO(5)(OEt)(19)Cl] (1) (whose low-yielding synthesis we reported earlier) can be made in better yield, reproducibly by the reaction of a mixture of heptanuclear [Ti(7)O(4)(OEt)(20)] (A) and [KOEt] with [Co(II)Cl(2)] in toluene. A alone reacts with [Co(II)Cl(2)] and [Fe(II)Cl(2)] to form [Ti(7)Co(II)O(5)(OEt)(18)Cl(2)] (2) and [Ti(7)Fe(II)O(5)(OEt)(18)Cl(2)] (3), respectively. Like 1, compounds 2 and 3 retain the original Ti(7) fragment of A and the II-oxidation state of the transition metal ions (Tm). In contrast, from the reaction of [Ti(OEt)(4)] with [Cr(II)Cl(2)] it is possible to isolate [Ti(3)Cr(V)O(OEt)(14)Cl] (4) in low yield, containing a Ti(3)Cr(V) core in which oxidation of Cr from the II to V oxidation state has occurred. Reaction of [Mo(V)Cl(5)] with [Ti(OEt)](4) in [EtOH] gives the Ti(8)Mo(V)(4) cage [{Ti(4)Mo(2)O(8)(OEt)(10)}(2)] (5). The single-crystal X-ray structures of the new cages 2, 3, 4, and 5 are reported. The results show that the size of the heterometallic cage formed can be influenced by the nuclearity of the precursor. In the case of 5, the presence of homometallic Mo-Mo bonding also appears to be a significant factor in the final structure. PMID- 21604706 TI - Rational approach to endo/exocoordinated heteronuclear macrocyclic network: supramolecular Hg(ll), Cu(ll), and Hg(ll)/Cu(ll) complexes of a NS4 macrocycle. AB - A rationally designed sulfur-rich macrocycle L incorporating one pyridine and one benzo subunit was synthesized and structurally characterized. From the assembly reactions of L with copper(II) nitrate and mercury(II) iodide, an endocyclic monocopper(II) complex and an exocyclic dimercury(II) complex were prepared, respectively. On the basis of these results, the construction of a Hg(II)/Cu(II) heteronuclear 1D network complex with an endo/exocyclic coordination mode was achieved by one-pot assembly reaction of L with mercury(II) iodide in the presence of copper(II) nitrate. PMID- 21604707 TI - Four-coordinate organoboron compounds with a pi-conjugated chelate ligand for optoelectronic applications. AB - Four-coordinate organoboron compounds with a pi-conjugated chelate backbone have emerged recently as highly attractive materials for a number of applications including use as emitters and electron-transport materials for organic light emitting diodes (OLEDs) or organic field transistors, photoresponsive materials, and sensory and imaging materials. Many applications of this class of boron compounds stem from the electronic properties of the pi-conjugated chelate backbone. Charge-transfer transitions from an aromatic substituent attached to the boron center of the pi-conjugated chelate backbone and steric congestion have also been found to play important roles in the luminescent and photochromic properties of the four-coordinate boron compounds. This article provides an update-to-date account on the application aspects of this important class of compounds in materials science with the emphasis on OLED applications and photochromic switching. PMID- 21604708 TI - Probing the wurtzite conduction band structure using state filling in highly doped InP nanowires. AB - We have grown InP nanowires doped with hydrogen sulfide, which exhibit sulfur concentrations of up to 1.4%. The highest doped nanowires show a pure wurtzite crystal structure, in contrast to bulk InP which has the zinc blende structure. The nanowires display photoluminescence which is strongly blue shifted compared with the band gap, well into the visible range. We find evidence of a second conduction band minimum at the gamma point about 0.23 eV above the band edge, in excellent agreement with recent theoretical predictions. Electrical measurements show high conductivity and breakdown currents of 10(7) A/cm(2). PMID- 21604709 TI - Nanoscale electrowetting effects observed by using friction force microscopy. AB - We report the study of electrowetting (EW) effects under strong electric field on poly(methyl methacrylate) (PMMA) surface by using friction force microscopy (FFM). The friction force dependence on the electric field at nanometer scale can be closely related to electrowetting process based on the fact that at this scale frictional behavior is highly affected by capillary phenomena. By measuring the frictional signal between a conductive atomic force microscopy (AFM) tip and the PMMA surface, the ideal EW region (Young-Lippmann equation) and the EW saturation were identified. The change in the interfacial contact between the tip and the PMMA surface with the electric field strength is closely associated with the transition from the ideal EW region to the EW saturation. In addition, a reduction of the friction coefficient was observed when increasing the applied electric field in the ideal EW region. PMID- 21604710 TI - Atomic-scale electron-beam sculpting of near-defect-free graphene nanostructures. AB - In order to harvest the many promising properties of graphene in (electronic) applications, a technique is required to cut, shape, or sculpt the material on the nanoscale without inducing damage to its atomic structure, as this drastically influences the electronic properties of the nanostructure. Here, we reveal a temperature-dependent self-repair mechanism that allows near-damage-free atomic-scale sculpting of graphene using a focused electron beam. We demonstrate that by sculpting at temperatures above 600 degrees C, an intrinsic self-repair mechanism keeps the graphene in a single-crystalline state during cutting, even though the electron beam induces considerable damage. Self-repair is mediated by mobile carbon ad-atoms that constantly repair the defects caused by the electron beam. Our technique allows reproducible fabrication and simultaneous imaging of single-crystalline free-standing nanoribbons, nanotubes, nanopores, and single carbon chains. PMID- 21604712 TI - Sonochemical preparation of functionalized graphenes. AB - A convenient sonochemical method is described for the preparation of polystyrene functionalized graphenes starting from graphite flakes and a reactive monomer, styrene. Ultrasonic irradiation of graphite in styrene results in the mechanochemical exfoliation of graphite flakes to single-layer and few-layer graphene sheets combined with functionalization of the graphene with polystyrene chains. The polystyrene chains are formed from sonochemically initiated radical polymerization of styrene and can make up to ~18 wt % of the functionalized graphene, as determined by thermal gravimetric analysis. This one-step protocol can be generally applied to the functionalization of graphenes with other vinyl monomers for graphene-based composite materials. PMID- 21604713 TI - Perovskite, LiNbO3, corundum, and hexagonal polymorphs of (In(1-x)M(x))MO3. AB - LiNbO(3) (LN), corundum (cor), and hexagonal (hex) phases of (In(1-x)M(x))MO(3) (x = 0.143; M = Fe(0.5)Mn(0.5)) were prepared. Their crystal structures were investigated with synchrotron X-ray powder diffraction, and their properties were studied by differential thermal analysis, magnetic measurements, and Mossbauer spectroscopy. The LN-phase was prepared at high pressure of 6 GPa and 1770 K; it crystallizes in space group R3c with a = 5.25054(7) A, c = 13.96084(17) A, and has a long-range antiferromagnetic ordering near T(N) = 270 K. The cor- and hex phases were obtained at ambient pressure by heating the LN-phase in air up to 870 and 1220 K, respectively. The cor-phase crystallizes in space group R-3c with a = 5.25047(10) A, c = 14.0750(2) A, and the hex-phase in space group P6(3)/mmc with a = 3.34340(18) A, c = 11.8734(5) A. T(N) of the cor-phase is about 200 K, and T(N) of the hex-phase is about 140 K. During irreversible transformations of LN (In(1-x)M(x))MO(3) with the (partial) cation ordering, the In(3+), Mn(3+), and Fe(3+) cations become completely disordered in one crystallographic site of the corundum structure, and then they are (partially) ordered again in the hex-phase. LN-(In(1-x)M(x))MO(3) exhibits a reversible transformation to a perovskite GdFeO(3)-type structure (space group Pnma; a = 5.2946(3) A, b = 7.5339(4) A, c = 5.0739(2) A at 10.3 GPa) at room temperature and pressure of about 5 GPa. PMID- 21604711 TI - Inhibitors of SARS-3CLpro: virtual screening, biological evaluation, and molecular dynamics simulation studies. AB - SARS-CoV from the coronaviridae family has been identified as the etiological agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CL(pro), a cysteine protease indispensible to the viral life cycle, has been identified as one of the key therapeutic targets against SARS. A combined ligand and structure based virtual screening was carried out against the Asinex Platinum collection. Multiple low micromolar inhibitors of the enzyme were identified through this search, one of which also showed activity against SARS-CoV in a whole cell CPE assay. Furthermore, multinanosecond explicit solvent simulations were carried out using the docking poses of the identified hits to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Cumulative analysis of the evaluated compounds and the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts. PMID- 21604714 TI - Practicable group testing method to evaluate weight/weight GMO content in maize grains. AB - Because of the increasing use of maize hybrids with genetically modified (GM) stacked events, the established and commonly used bulk sample methods for PCR quantification of GM maize in non-GM maize are prone to overestimate the GM organism (GMO) content, compared to the actual weight/weight percentage of GM maize in the grain sample. As an alternative method, we designed and assessed a group testing strategy in which the GMO content is statistically evaluated based on qualitative analyses of multiple small pools, consisting of 20 maize kernels each. This approach enables the GMO content evaluation on a weight/weight basis, irrespective of the presence of stacked-event kernels. To enhance the method's user-friendliness in routine application, we devised an easy-to-use PCR-based qualitative analytical method comprising a sample preparation step in which 20 maize kernels are ground in a lysis buffer and a subsequent PCR assay in which the lysate is directly used as a DNA template. This method was validated in a multilaboratory collaborative trial. PMID- 21604715 TI - Rescue of the orphan enzyme isoguanine deaminase. AB - Cytosine deaminase (CDA) from Escherichia coli was shown to catalyze the deamination of isoguanine (2-oxoadenine) to xanthine. Isoguanine is an oxidation product of adenine in DNA that is mutagenic to the cell. The isoguanine deaminase activity in E. coli was partially purified by ammonium sulfate fractionation, gel filtration, and anion exchange chromatography. The active protein was identified by peptide mass fingerprint analysis as cytosine deaminase. The kinetic constants for the deamination of isoguanine at pH 7.7 are as follows: k(cat) = 49 s(-1), K(m) = 72 MUM, and k(cat)/K(m) = 6.7 * 10(5) M(-1) s(-1). The kinetic constants for the deamination of cytosine are as follows: k(cat) = 45 s(-1), K(m) = 302 MUM, and k(cat)/K(m) = 1.5 * 10(5) M(-1) s(-1). Under these reaction conditions, isoguanine is the better substrate for cytosine deaminase. The three-dimensional structure of CDA was determined with isoguanine in the active site. PMID- 21604716 TI - Ultrafast branching of reaction pathways in 2-(2'-hydroxyphenyl)benzothiazole in polar acetonitrile solution. AB - In a combined study on the photophysics of 2-(2'-hydroxyphenyl)-benzothiazole (HBT) in polar acetonitrile utilizing ultrafast infrared spectroscopy and quantum chemical calculations, we show that a branching of reaction pathways occurs on femtosecond time scales. Apart from the excited-state intramolecular hydrogen transfer (ESIHT) converting electronically excited enol tautomer into the keto tautomer, known to be the dominating mechanism of HBT in nonpolar solvents such as cyclohexane and tetrachloroethene, in acetonitrile solution twisting also occurs around the central C-C bond connecting the hydroxyphenyl and benzothiazole units in both electronically excited enol and keto tautomers. The solvent-induced intramolecular twisting enables efficient internal conversion pathways to both enol and keto tautomers in the electronic ground state. Whereas relaxation to the most stable enol tautomer with twisting angle Theta = 0 degrees implies full ground state recovery, a small fraction of HBT molecules persists as the keto twisting conformer with the twisting angle Theta = 180 degrees for delay times extending beyond 120 ps. PMID- 21604717 TI - Loss of allostery and coenzyme B12 delivery by a pathogenic mutation in adenosyltransferase. AB - ATP-dependent cob(I)alamin adenosyltransferase (ATR) is a bifunctional protein: an enzyme that catalyzes the adenosylation of cob(I)alamin and an escort that delivers the product, adenosylcobalamin (AdoCbl or coenzyme B(12)), to methylmalonyl-CoA mutase (MCM), resulting in holoenzyme formation. Failure to assemble holo-MCM leads to methylmalonic aciduria. We have previously demonstrated that only 2 equiv of AdoCbl bind per homotrimer of ATR and that binding of ATP to the vacant active site triggers ejection of 1 equiv of AdoCbl from an adjacent site. In this study, we have mimicked in the Methylobacterium extorquens ATR, a C-terminal truncation mutation, D180X, described in a patient with methylmalonic aciduria, and characterized the associated biochemical penalties. We demonstrate that while k(cat) and K(M)(Cob(I)) for D180X ATR are only modestly decreased (by 3- and 2-fold, respectively), affinity for the product, AdoCbl, is significantly diminished (400-fold), and the negative cooperativity associated with its binding is lost. We also demonstrate that the D180X mutation corrupts ATP-dependent cofactor ejection, which leads to transfer of AdoCbl from wild-type ATR to MCM. These results suggest that the pathogenicity of the corresponding human truncation mutant results from its inability to sequester AdoCbl for direct transfer to MCM. Instead, cofactor release into solution is predicted to reduce the capacity for holo-MCM formation, leading to disease. PMID- 21604718 TI - RGD-conjugated copolymer incorporated into composite of poly(lactide-co glycotide) and poly(L-lactide)-grafted nanohydroxyapatite for bone tissue engineering. AB - Various surface modification methods of RGD (Arg-Gly-Asp) peptides on biomaterials have been developed to improve cell adhesion. This study aimed to examine a RGD-conjugated copolymer RGD/MPEG-PLA-PBLG (RGD-copolymer) for its ability to promote bone regeneration by mixing it with the composite of poly(lactide-co-glycotide) (PLGA) and hydroxyapatite nanoparticles surface grafted with poly(L-lactide) (g-HAP). The porous scaffolds were prepared using solvent casting/particulate leaching method and grafted to repair the rabbit radius defects after seeding with autologous bone marrow mesenchymal cells (MSCs) of rabbits. After incorporation of RGD-copolymer, there were no significant influences on scaffold's porosity and pore size. Nitrogen of RGD peptide, and calcium and phosphor of g-HAP could be exposed on the surface of the scaffold simultaneously. Although the cell viability of its leaching liquid was 92% that was lower than g-HAP/PLGA, its cell adhesion and growth of 3T3 and osteoblasts were promoted significantly. The greatest increment in cell adhesion ratios (131.2-157.1% higher than g-HAP/PLGA) was observed when its contents were 0.1-1 wt % but only at 0.5 h after cell seeding. All the defects repaired with the implants were bridged after 24 weeks postsurgery, but the RGD-copolymer contained composite had larger new bone formation and better fusion interface. The composites containing RGD-copolymer enhanced bone ingrowth but presented more woven bones than others. The combined application of RGD-copolymer and bone morphological protein 2 (BMP-2) exhibited the best bone healing quality and was recommended as an optimal strategy for the use of RGD peptides. PMID- 21604719 TI - Gas chromatographic determination of N-nitrosamines, aromatic amines, and melamine in milk and dairy products using an automatic solid-phase extraction system. AB - A reliable analytical method was presented for the simultaneous determination of six N-nitrosamines, nine aromatic amines, and melamine in milk and dairy products using gas chromatography coupled with mass spectrometry. The sample treatment includes the precipitation of proteins with acetonitrile, centrifugation, solvent changeover by evaporation, and continuous solid-phase extraction for cleanup and preconcentration purposes. Samples (5 g) containing 0.15-500 ng of each amine were analyzed, and low detection limits (15-130 ng/kg) were achieved. Recoveries for milk and dairy products samples spiked with 1, 10, and 50 MUg/kg ranged from 92% to 101%, with intraday and interday relative standard deviation values below 7.5%. The method was successfully applied to determine amine residues in several milk types (human breast, cow, and goat) and dairy products. PMID- 21604720 TI - Starch characterization and ethanol production of sorghum. AB - This study aimed to characterize and compare the chemical structures, physical properties, and enzymatic hydrolysis rates of five sorghum starches (6B73, 6C21, 6C69, 7R34, and X789) with that of corn starch (B73). Sorghum kernels consisted of 68.7-70.6% starch, more than the B73 corn (67.4%). Sorghum starches displayed higher gelatinization temperatures (66.6-67.4 degrees C), greater gelatinization enthalpy changes (13.0-14.0 J/g), and greater percentages of retrogradation (60.7 69.1%), but slower enzymatic hydrolysis rates (83.8-87.8% at 48 h) than the B73 corn starch (61.7 degrees C, 10.1 J/g, 51.5%, and 88.5%, respectively). These differences could result from the sorghum amylopectins consisting of fewer short branch chains (DP 6-12) (12.8-14.0%) than the corn amylopectin (15.0%). The sorghum starches showed greater peak and breakdown viscosities but lower setback viscosities than the B73 corn starch, resulting from the lower amylose content of the sorghum starches. After 96 h of fermentation, most ground sorghums exhibited lower ethanol yields (30.5-31.8%) than the ground B73 corn (31.8%). PMID- 21604721 TI - Interactions in monolayers: a study of the behavior of poly(methyl methacrylate) lysozyme mixed films from surface pressure-area and ellipsometric measurements. AB - Mixed monolayers of PMMA-lysozyme show the existence of negative deviations from the additivity of the molecular areas (A(m)) when the composition of polymer mixtures is less than X(PMMA) 0.6, regardless of the surface pressure of the monolayers. The maximum deviation occurs in the mixed monolayer with composition X(PMMA) 0.25, which is attributed to the formation of a complex consisting of one polymer molecule and three protein molecules (1:3 stoichiometry), stabilized by hydrogen bonds between the NH groups of the protein and the CO groups of the polymer as well as by van der Waals attractive forces between the hydrocarbon chains of both components. When the relative proportion of the components in the mixed films significantly differs from the value corresponding to the stoichiometry of the complex (as in mixtures with X(PMMA) > 0.6), this complex cannot be formed, causing an immiscible system where the values of the experimental molecular areas coincide with those corresponding to ideal behavior. Measurements of monolayer thickness and BAM images allow confirmation on the microscopic level of the structural characteristics deduced from the pi-A isotherms. PMID- 21604722 TI - Configuration of spheroidene in the photosynthetic reaction center of Rhodobacter sphaeroides : a comparison of wild-type and reconstituted R26. AB - We compare the resonance Raman spectra acquired at two excitation wavelengths, 496.5 and 514.5 nm, of spheroidene in the wild-type reaction center of Rhodobacter sphaeroides and reconstituted into the reaction center of the Rhodobacter sphaeroides mutant R26. Our earlier work showed that the reconstituted R26 reaction center holds spheroidene in two configurations: 15,15' cis and another configuration. Here we show that in the wild-type reaction center only 15,15'-cis spheroidene is present. In the resonance Raman spectra of the reconstituted R26 reaction centers, a transition is identified that arises exclusively from the second configuration. According to density-functional-theory calculations, this transition is specific for the 13,14-cis configuration. PMID- 21604723 TI - Quantitative NIR chemical imaging in heritage science. AB - Until recently, applications of spectral imaging in heritage science mostly focused on qualitative examination of artworks. This is partly due to the complexity of artworks and partly due to the lack of appropriate standard materials. With the recent advance of NIR imaging spectrometers, the interval 1000-2500 nm became available for exploration, enabling us to extract quantitative chemical information from artworks. In this contribution, the development of 2D NIR quantitative chemical maps of heritage objects is discussed along with presentation of the first quantitative image. Further case studies include semiquantitative mapping of plasticiser distribution in a plastic object and identification of historic plastic materials. In the NIR imaging studies discussed, sets of 256 spatially registered images were collected at different wavelengths in the NIR region of 1000-2500 nm. The data was analyzed as a spectral cube, both as a stack of wavelength-resolved images and as a series of spectra, one per each sample pixel, using multivariate analysis. This approach is only possible using well-characterized reference sample collections, as quantitative imaging applications need to be developed, thus enabling spatial maps of damaged and degraded areas to be visualized to a level of chemical detail previously not possible. Such quantitative chemical mapping of vulnerable areas of heritage objects is invaluable, as it enables damage to historic objects to be quantitatively visualized. PMID- 21604724 TI - Benchmark theoretical study on the dissociation energy of chlorine. AB - The currently accepted D(0)((35)Cl(2)) is 239.221 +/- 0.001 kJ/mol, whereas popular theoretical model chemistries provide values in the range of 233-247 kJ/mol, and even the so-called high-accuracy protocols can yield values as low as 237.9 kJ/mol and as high as 240.1 kJ/mol for D(0)((35)Cl(2)). The aim of this study was to uncover the sources of error inherent in the theoretical approaches. Therefore, a coupled-cluster-based composite model chemistry was utilized that included contributions of up to pentuple excitations, as well as corrections beyond the nonrelativistic and Born-Oppenheimer approximations. In our calculations, correlation consistent basis set families were used up to octuple zeta basis sets. It was found that the following factors, in order of significance, can be identified as the most important error sources: (i) the considerably large relativistic contributions carrying large uncertainties, (ii) the very slow convergence of the Moller-Plesset (MP2) correlation energy (with the octuple-zeta basis set, it still contains an error of a few tenth of a kJ/mol), (iii) the slow convergence of the coupled-cluster singles and doubles (CCSD) contribution (it needs a octuple-zeta basis set to converge within 0.1 kJ/mol), and (iv) the relatively large basis set (quadruple-zeta) needed in the calculation of an accurate perturbative quadruples contribution. It is also notable that, for chlorine, the use of a quintuple-zeta basis set for the Hartree Fock energy, the MP2 correlation energy, and for the CCSD and perturbative triples contributions, which is the usual treatment in almost every high-accuracy model chemistry, resulted in the overestimation of all of these contributions (altogether about by 1.8 kJ/mol). However, this overestimation is accidentally compensated by (i) using an inappropriate, small basis set for the valence electron contribution due to quadruple excitations (~1.2 kJ/mol), (ii) neglecting the effects of core electron contributions due to quadruple excitations (~0.2 kJ/mol), and (iii) neglecting relativistic effects beyond the scalar relativistic treatment (~0.3 kJ/mol). The most reliable theoretical estimate for D(0)((35)Cl(2)) obtained in this study, 239.27 +/- 1.30 kJ/mol, differs by only 0.05 kJ/mol from the most accurate experimental result. This study also underpins the effect of relativistic contributions, which precludes current model chemistries to enter the range of sub-kJ/mol accuracy for second-row systems. PMID- 21604725 TI - An approach to control of band gap energy and photoluminescence upon band gap excitation in Pr(3+)-doped perovskites La(1/3)MO3 (M=Nb, Ta):Pr3+. AB - We synthesized polycrystalline pristine and Pr(3+)-doped perovskites La(1/3)MO(3) (M = Nb, Ta):Pr(3+) and investigated their crystal structure, optical absorption, and luminescence properties. The optical band gap of La(1/3)NbO(3) (3.2 eV) is smaller than that of La(1/3)TaO(3) (3.9 eV), which is primarily due to the difference in electronegativity between Nb and Ta. In La(1/3)NbO(3):Pr(3+), the red emission assigned to the f-f transition of Pr(3+) from the excited (1)D(2) level to the ground (3)H(4) state upon band gap photoexcitation (near-UV) was observed, whereas the f-f transition of Pr(3+) with blue-green emission from the excited (3)P(0) level to the ground (3)H(4) state was quenched. On the other hand, in La(1/3)TaO(3):Pr(3+), the blue-green emission upon band gap photoexcitation was observed. Their differences in emission behavior are attributed to the energy level of the ground and excited states of 4f(2) for Pr(3+), relative to the energy levels of the conduction and valence bands, and the trapped electron state, which mediates the relaxation of electron from the conduction band to the excited state of Pr(3+). La(1/3)NbO(3):Pr(3+) is a candidate red phosphor utilizing near-UV LED chips (e.g., lambda = 375 nm) as an excitation source. PMID- 21604726 TI - Syntheses and photophysical properties of luminescent mono-cyclometalated gold(III) cis-dialkynyl complexes. AB - A series of novel luminescent neutral cyclometalated gold(III) complexes of the type cis-[(N^C)Au(C=CR)(2)] (R = aryl, silyl groups) having different cyclometalating cores (N^C) have been synthesized by CuI promoted halide to alkynyl metathesis with NEt(3) as in situ deprotonating agent. Along with spectroscopic characterizations (nuclear magnetic resonance and infrared spectroscopies and electrospray ionization mass spectrometry) and elemental analysis, the molecular structures of some of the complexes have been established by single-crystal X-ray diffraction studies. Photophysical studies reveal that the complexes exhibit room-temperature phosphorescence (RTP). Experimental observations and density functional theory calculations qualitatively suggest limited participation of the metal and alkynyl ligands in the lowest energy emitting state. The nature of the emission is mainly governed by metal-perturbed (3)IL(pi-pi*) transitions originating from the cyclometalate part of the molecule, and its variation readily leads to the tuning of the emission wavelengths. Cyclic voltammetry measurements of selected complexes showed irreversible redox behavior with near-equivalent cathodic peak potential (E(p,c)) assigned to the C^N core. PMID- 21604727 TI - Can atom-surface potential measurements test atomic structure models? AB - van der Waals (vdW) atom-surface potentials can be excellent benchmarks for atomic structure calculations. This is especially true if measurements are made with two different types of atoms interacting with the same surface sample. Here we show theoretically how ratios of vdW potential strengths (e.g., C3(K)/C3(Na)) depend sensitively on the properties of each atom, yet these ratios are relatively insensitive to properties of the surface. We discuss how C3 ratios depend on atomic core electrons by using a two-oscillator model to represent the contribution from atomic valence electrons and core electrons separately. We explain why certain pairs of atoms are preferable to study for future experimental tests of atomic structure calculations. A well chosen pair of atoms (e.g., K and Na) will have a C3 ratio that is insensitive to the permittivity of the surface, whereas a poorly chosen pair (e.g., K and He) will have a ratio of C3 values that depends more strongly on the permittivity of the surface. PMID- 21604728 TI - First-principle electronic, elastic, and optical study of cubic gallium nitride. AB - The ab initio pseudopotential (PP) method within the generalized gradient approximation (GGA) has been used to investigate the electronic, elastic constants, and optical properties of zinc-blende GaN. An underestimated band gap along with higher DOS and squeezed energy bands around the fermi level is obtained. The d-band effect is briefly discussed for electronic band structure calculations. With the help of elastic constants, acoustic wave speeds are calculated in [100], [110], and [111] planes. The dielectric constant, refractive index, and its pressure coefficient are well illustrated. The effect of hydrostatic pressure is explicated for all these properties. The results of the present study are evaluated with the existing experimental and first-principle calculations. PMID- 21604729 TI - Computed vibrational frequencies of actinide oxides AnO(0/+/2+) and AnO2(0/+/2+) (An = Th, Pa, U, Np, Pu, Am, Cm). AB - The vibrational frequencies of the actinide oxides AnO and AnO(2) (An = Th, Pa, U, Np, Pu, Am, Cm) and of their mono- and dications have been calculated using advanced quantum chemical techniques. The stretching fundamental frequencies of the monoxides have been determined by fitting the potential function to single point energies obtained by relativistic CASPT2 calculations along the stretching coordinate and on this basis solving numerically the ro-vibrational Schrodinger equation. To obtain reliable fundamental frequencies of the dioxides, we developed an empirical approach. In this approach the harmonic vibrational frequencies of the AnO(2)(0/+/2+) species were calculated using eight different exchange-correlation DFT functionals. On the basis of the good correlation found between the vibrational frequencies and computed bond distances, the final frequency values were derived for the CASPT2 reference bond distances from linear regression equations fitted to the DFT data of each species. As a test, the approach provided excellent agreement with accurate experimental data of ThO, ThO(+), UO, and UO(+). The joint analysis of literature experimental and our computed data facilitated the prediction of reliable gas-phase molecular properties for some oxides. They include the stretching frequencies of PuO, ThO(2), UO(2), and UO(2)(+) and the bond distance of PuO (1.818 A, being likely within 0.002 A of the real value). Also the derived equilibrium bond distances of ThO(2), UO(2), and UO(2)(+) (1.896, 1.790, and 1.758 A, respectively) should approximate closely the (yet unknown) experimental values. On the basis of the present results, we suggest that the ground electronic state of PuO(2) in Ar and Kr matrices is probably different from that in the gaseous phase, similarly to UO(2) observed previously. PMID- 21604730 TI - Titanium oxide complexes with dinitrogen. Formation and characterization of the side-on and end-on bonded titanium oxide-dinitrogen complexes in solid neon. AB - The reactions of titanium oxide molecules with dinitrogen have been studied by matrix isolation infrared spectroscopy. The titanium monoxide molecule reacts with dinitrogen to form the TiO(N(2))(x) (x = 1-4) complexes spontaneously on annealing in solid neon. The TiO(eta(1)-NN) complex is end-on bonded and was predicted to have a (3)A'' ground state arising from the (3)Delta ground state of TiO. Argon doping experiments indicate that TiO(eta(1)-NN) is able to form complexes with one or more argon atoms. Argon atom coordination induces a large red-shift of the N-N stretching frequency. The TiO(eta(2)-N(2))(2) complex was characterized to have C(2v) symmetry, in which both the N(2) ligands are side-on bonded to the titanium metal center. The tridinitrogen complex TiO(eta(1)-NN)(3) most likely has C(3v) symmetry with three end-on bonded N(2) ligands. The TiO(eta(1)-NN)(4) complex was determined to have a C(4v) structure with four equivalent end-on bonded N(2) ligands. In addition, evidence is also presented for the formation of the TiO(2)(eta(1)-NN)(x) (x = 1-4) complexes, which were predicted to be end-on bonded. PMID- 21604731 TI - Should the Gibbs analysis be revised? AB - Recently, some arguments were published that cast doubt on the validity of the Gibbs adsorption isotherm. The doubt was on whether the often visible linearly declining part in the surface tension versus logarithm of concentration plot of a surfactant solution, just before the critical micelle concentration, really represents a situation of constant adsorption. Those published arguments are partly of a conceptual nature and partly based on experimental evidence. The conceptual arguments appear to be based on a misunderstanding of the theory, while the arguments based on experimental evidence stem from an inaccurate treatment of these data. Our conclusion is that none of the relevant arguments put forward are valid. The experimental evidence, if properly treated, is in line with the Gibbs theory. PMID- 21604733 TI - Cascade intramolecular N-arylation/intermolecular carboamination reactions for the construction of tricyclic heterocycles. AB - A new method for the stereoselective synthesis of tetrahydropyrroloindoles and hexahydropyrroloquinolines of general structure 8 is described. These products are formed through cascade Pd-catalyzed coupling reactions between aryl chlorides and unsaturated amine substrates 5. A single catalyst effects an intramolecular N arylation reaction followed by an intermolecular alkene carboamination reaction to generate two rings, three bonds, and one stereocenter with good chemoselectivity, diastereoselectivity, and chemical yield. PMID- 21604734 TI - Measurements of isoprene-derived organosulfates in ambient aerosols by aerosol time-of-flight mass spectrometry - part 1: single particle atmospheric observations in Atlanta. AB - Organosulfate species have recently been identified as a potentially significant class of secondary organic aerosol (SOA) species, yet little is known about their behavior in the atmosphere. In this work, organosulfates were observed in individual ambient aerosols using single particle mass spectrometry in Atlanta, GA during the 2002 Aerosol Nucleation and Characterization Experiment (ANARChE) and the 2008 August Mini-Intensive Gas and Aerosol Study (AMIGAS). Organosulfates derived from biogenically produced isoprene were detected as deprotonated molecular ions in negative-ion spectra measured by aerosol time-of-flight mass spectrometry; comparison to high-resolution mass spectrometry data obtained from filter samples corroborated the peak assignments. The size-resolved chemical composition measurements revealed that organosulfate species were mostly detected in submicrometer aerosols and across a range of aerosols from different sources, consistent with secondary reaction products. Detection of organosulfates in a large fraction of negative-ion ambient spectra - ca. 90-95% during ANARChE and ~65% of submicrometer particles in AMIGAS - highlights the ubiquity of organosulfate species in the ambient aerosols of biogenically influenced urban environments. PMID- 21604735 TI - A highly efficient access to spiroketals, mono-unsaturated spiroketals, and furans: Hg(II)-catalyzed cyclization of alkyne diols and triols. AB - Hg(II) salts are identified as highly efficient catalysts for the versatile construction of spiroketals from alkyne diols in aqueous conditions. Monounsaturated spiroketals and furans were accessed with equal ease when propargylic triols (or propargylic diols) were subjected to similar conditions. Even the semiprotected alkyne diols gave the corresponding spiroketals with the same ease in a cascade manner. The reactions are instant and high yielding at ambient temperatures. Regioselectivity issues are well addressed. PMID- 21604736 TI - Charging effects in an electron bombarded Ar matrix and the role of chemiluminescence-driven relaxation. AB - The relaxation processes in pure and doped Ar films preirradiated by an electron beam are studied with the focus on charging effects. Correlated real time measurements have been performed applying current and optical activation spectroscopy methods. Thermally stimulated exoelectron emission and thermally stimulated luminescence are detected in the vacuum ultraviolet and visible range. An appreciable accumulation of electrons in the matrix is found, and prerequisites for negative space charge formation are ascertained. The part played by pre-existing and radiation-induced defects as well as dopants is considered and the temperature range of the electron trap stability is elucidated. It is shown that laser-induced electron detachment from O(-) centers results in an enhancement of electron detrapping via the chemiluminescence mechanism, viz. neutralized and thermally mobilized O atoms recombine. Formation of O(2)* results in the emission of visible photons. These photons act as a stimulating factor for electron release and transport, terminating in exoelectron emission and charge recombination. Chemiluminescence therefore plays an important role in the decay of charged centers. PMID- 21604737 TI - Dating archeological lead artifacts from measurement of the corrosion content using the voltammetry of microparticles. AB - A methodology for dating archeological lead artifacts based on the voltammetry of microparticles is described. This methodology is based on the comparison of the height of specific voltammetric features from PbO(2) and PbO corrosion products formed under long-term alteration conditions. Calibration of the method was performed with the help of a series of well-documented lead pieces from the funds of different museums of the Comunitat Valenciana (Spain) covering from the fifth century B.C. to present day. The variation of peak currents with the time of corrosion can be fitted to the same potential rate law as that found by Reich (alpha = 0.070 +/- 0.005), using measurements on the Meissner fraction in the superconducting state of lead. The proposed electrochemical methodology enables the dating of archeological lead artifacts with a time-dependent uncertainty estimated to be +/-150 years for the most ancient samples in this study. PMID- 21604738 TI - Information content in fluorescence correlation spectroscopy: binary mixtures and detection volume distortion. AB - When properly implemented, fluorescence correlation spectroscopy (FCS) reveals numerous static and dynamic properties of molecules in solution. However, complications arise whenever the measurement scenario is complex. Specific limitations occur when the detection region does not match the ideal Gaussian geometry ubiquitously assumed by FCS theory, or when properties of multiple fluorescent species are assessed simultaneously. A simple binary solution of diffusers, where both mole fraction and diffusion constants are sought, can face interpretive difficulty. In order to better understand the limits of FCS, this study systematically explores the relationship between detection-volume distortion, diffusion constants, species mole fraction, and fitting methodology in analyses that utilize a two-component autocorrelation model. FCS measurements from solution mixtures of dye-labeled protein and free dye are compared to simulations, which predict the performance of FCS under a variety of experimental circumstances. The results reveal a range of conditions necessary for performing accurate measurements and describe experimental scenarios that should be avoided. The findings also provide guidelines for obtaining meaningful measurements when grossly distorted detection volumes are utilized and generally assess the latent information contained in FCS datasets. PMID- 21604739 TI - Curtin-Hammett and steric effects in HOBt acylation regiochemistry. AB - While hydroxybenzotriazole is commonly used in a variety of bond-forming reactions, its acylation has been shown to produce a regiochemical (O vs N) mixture with complex kinetic behavior. Increased steric bulk on the electrophile favors formation of the oxygen-acylated product. Upon standing as a solid, the mixture can isomerize completely to the nitrogen adduct. An equilibrium ratio of regioisomers can be re-established in solution by adding either nucleophilic or electrophilic reagents, suggesting that the composition of the mixture is not significant to subsequent reactivity. Solvents can affect this regiochemical equilibrium through a Curtin-Hammett effect, where the shift in the tautomeric equilibrium of HOBt in polar solvents biases the reaction toward the oxygen adduct. PMID- 21604741 TI - Multivariate hyperspectral Raman imaging using compressive detection. AB - A multivariate hyperspectral imaging (MHI) instrument has been designed and constructed to achieve greatly increased Raman imaging speeds by utilizing a compressive spectral detection strategy. The instrument may be viewed as a generalized spectrometer, which can function either as a conventional monochromator or in a wide variety of other hyperspectral modalities. The MHI utilizes a spatial light modulator (SLM) to produce programmable optical filters to rapidly detect and map particular sample components. A sequence of Hadamard transform or random filter functions may be used to regenerate full Raman spectra. Compressive detection is achieved either using multivariate signal processing filter functions or the actual component spectra. Compressive detection is shown to be capable of achieving sampling speeds exceeding 1 ms per image pixel and the collection of chemical images in less than a minute. PMID- 21604740 TI - Synthesis of purine nucleosides built on a 3-oxabicyclo[3.2.0]heptane scaffold. AB - The photochemical [2 + 2] cycloaddition of chiral 3-chloro and 3-fluoro-5 hydroxymethyl-2(5H)-furanone to ethylene and acetylene has been studied. The effect of the halogen atom on the chemical yield and facial diastereoselectivity of the cycloaddition process has been evaluated. From the major anti cycloadducts, practical syntheses of several purine cyclobutane and cyclobutene fused nucleosides containing a halogen atom have been developed. The anti-HIV activity of the new nucleoside analogues has been evaluated. PMID- 21604742 TI - Designed biointerface using near-infrared quantum dots for ultrasensitive surface plasmon resonance imaging biosensors. AB - The surface plasmon resonance imaging chip biointerface is fully designed using near-infrared (NIR) quantum dots (QDs) for the enhancement of surface plasmon resonance imaging (SPRi) signals in order to extend their application for medical diagnostics. The measured SPRi detection signal following the QD binding to the surface was amplified 25-fold for a 1 nM concentration of single-stranded DNA (ssDNA) and 50-fold for a 1 MUg/mL concentration of prostate-specific antigen (PSA), a cancer biomarker, thus substantiating their wide potential to study interactions of a diverse set of small biomolecules. This significant enhancement is attributed to the QD's mass-loading effect and spontaneous emission coupling with propagating surface plasmons, which allowed the SPRi limit of detection to be reduced to 100 fM and 100 pg/mL for ssDNA and PSA, respectively. Furthermore, this study illustrates the potential of SPRi to be easily integrated with fluorescent imaging for advanced correlative surface-interaction analysis. PMID- 21604743 TI - Characterizing the distribution of sodium alkyl sulfate surfactant homologues in water-based, acrylic pressure-sensitive adhesive films. AB - The distributions of three sodium alkyl sulfate surfactants in dry adhesive films cast from water-based latexes were characterized using confocal Raman microscopy (CRM) and contact angle (CA) and tack measurements. Sodium dodecyl sulfate (SDS), sodium tetradecyl sulfate (STS), and sodium octadecyl sulfate (SODS) were added to dialyzed commercial adhesive latex at various concentrations. Uneven distributions were found for all three surfactants along with a tendency to enrich film-air interfaces and, to a much lesser extent, film-glass interfaces. SDS demonstrated the greatest tendency to concentrate near film surfaces followed by STS and SODS. For all three surfactants, water CA values for dried films decreased sharply with increasing concentrations in the latex, but significant differences were observed, with SDS again having the greatest impact followed by STS and SODS. Tack of dried polymer films was also found to decrease with increasing latex surfactant levels, with SDS producing the sharpest drop as well as the lowest plateau values. Results indicate that interfacial enrichment by surfactants is detectable via both CRM and CA measurements, and this enrichment can significantly affect the performance of films. Finally, surface enrichment levels are qualitatively related to measures of the surfactants' affinity for aqueous solutions, as characterized by the logarithm of their 1-octanol-water distribution coefficients (K(ow)). PMID- 21604744 TI - [13C2]-Acetaldehyde promotes unequivocal formation of 1,N2-propano-2' deoxyguanosine in human cells. AB - Acetaldehyde is an environmentally widespread genotoxic aldehyde present in tobacco smoke, vehicle exhaust and several food products. Endogenously, acetaldehyde is produced by the metabolic oxidation of ethanol by hepatic NAD dependent alcohol dehydrogenase and during threonine catabolism. The formation of DNA adducts has been regarded as a critical factor in the mechanisms of acetaldehyde mutagenicity and carcinogenesis. Acetaldehyde reacts with 2' deoxyguanosine in DNA to form primarily N(2)-ethylidene-2'-deoxyguanosine. The subsequent reaction of N(2)-ethylidenedGuo with another molecule of acetaldehyde gives rise to 1,N(2)-propano-2'-deoxyguanosine (1,N(2)-propanodGuo), an adduct also found as a product of the crotonaldehyde reaction with dGuo. However, adducts resulting from the reaction of more than one molecule of acetaldehyde in vivo are still controversial. In this study, the unequivocal formation of 1,N(2) propanodGuo by acetaldehyde was assessed in human cells via treatment with [(13)C(2)]-acetaldehyde. Detection of labeled 1,N(2)-propanodGuo was performed by HPLC/MS/MS. Upon acetaldehyde exposure (703 MUM), increased levels of both 1,N(2) etheno-2'-deoxyguanosine (1,N(2)-epsilondGuo), which is produced from alpha,beta unsaturated aldehydes formed during the lipid peroxidation process, and 1,N(2) propanodGuo were observed. The unequivocal formation of 1,N(2)-propanodGuo in cells exposed to this aldehyde can be used to elucidate the mechanisms associated with acetaldehyde exposure and cancer risk. PMID- 21604745 TI - Redox control of a ring-opening polymerization catalyst. AB - The activity of an yttrium alkoxide complex supported by a ferrocene-based ligand was controlled using redox reagents during the ring-opening polymerization of L lactide. The oxidized complex was characterized by X-ray crystallography and (1)H NMR, XANES, and Mossbauer spectroscopy. Switching in situ between the oxidized and reduced yttrium complexes resulted in a change in the rate of polymerization of L-lactide. Synthesized polymers were analyzed by gel permeation chromatography. Polymerization of trimethylene carbonate was also performed with the reduced and oxidized forms of an indium alkoxide complex. The indium system showed the opposite behavior to that of yttrium, revealing a metal-based dependency on the rate of polymerization. PMID- 21604747 TI - Ultrafast dynamics of surface-enhanced Raman scattering due to Au nanostructures. AB - Ultrafast dynamics of surface-enhanced Raman scattering (SERS) was investigated at cleaved graphite surfaces bearing deposited gold (Au) nanostructures (~10 nm in diameter) by using sensitive pump-probe reflectivity spectroscopy with ultrashort (7.5 fs) laser pulses. We observed enhancement of phonon amplitudes (C?C stretching modes) in the femtosecond time domain, considered to be due to the enhanced electromagnetic (EM) field around the Au nanostructures. Finite difference time-domain (FDTD) calculations confirmed the EM enhancement. The enhancement causes drastic increase of coherent D-mode (40 THz) phonon amplitude and nanostructure-dependent changes in the amplitude and dephasing time of coherent G-mode (47 THz) phonons. This methodology should be suitable to study the basic mechanism of SERS and may also find application in nanofabrication. PMID- 21604746 TI - Design, synthesis, biological evaluation, and structure-activity relationships of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates as new tubulin inhibitors mimicking combretastatin A-4. AB - Sixty-one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and 13 of their tetrahydro-2-oxopyrimidin-1(2H)-yl analogues (PPB-SOs) were prepared and biologically evaluated. The antiproliferative activities of PIB-SOs on 16 cancer cell lines are in the nanomolar range and unaffected in cancer cells resistant to colchicine, paclitaxel, and vinblastine or overexpressing the P-glycoprotein. None of the PPB-SOs exhibit significant antiproliferative activity. PIB-SOs block the cell cycle progression in the G(2)/M phase and bind to the colchicine-binding site on beta-tubulin leading to cytoskeleton disruption and cell death. Chick chorioallantoic membrane tumor assays show that compounds 36, 44, and 45 efficiently block angiogenesis and tumor growth at least at similar levels as combretastatin A-4 (CA-4) and exhibit low to very low toxicity on the chick embryos. PIB-SOs were subjected to CoMFA and CoMSIA analyses to establish quantitative structure-activity relationships. PMID- 21604748 TI - Raman spectroscopy of few-quintuple layer topological insulator Bi2Se3 nanoplatelets. AB - We report on Raman spectroscopy of few quintuple layer topological insulator bismuth selenide (Bi2Se3) nanoplatelets (NPs), synthesized by a polyol method. The as-grown NPs exhibit excellent crystalline quality, hexagonal or truncated trigonal morphology, and uniformly flat surfaces down to a few quintuple layers. Both Stokes and anti-Stokes Raman spectroscopy for the first time resolve all four optical phonon modes from individual NPs down to 4 nm, where the out-of plane vibrational A(1g)(1) mode shows a few wavenumbers red shift as the thickness decreases below ~15 nm. This thickness-dependent red shift is tentatively explained by a phonon softening due to the decreasing of the effective restoring force arising from a decrease of the van der Waals forces between adjacent layers. Quantitatively, we found that the 2D phonon confinement model proposed by Faucet and Campbell cannot explain the red shift values and the line shape of the A(1g)(1) mode, which can be described better by a Breit-Wigner Fano resonance line shape. Considerable broadening (~17 cm(-1) for six quintuple layers) especially for the in-plane vibrational mode E(g)(2) is identified, suggesting that the layer-to-layer stacking affects the intralayer bonding. Therefore, a significant reduction in the phonon lifetime of the in-plane vibrational modes is probably due to an enhanced electron-phonon coupling in the few quintuple layer regime. PMID- 21604749 TI - Self-powered system with wireless data transmission. AB - We demonstrate the first self-powered system driven by a nanogenerator (NG) that works wirelessly and independently for long-distance data transmission. The NG was made of a free cantilever beam that consisted of a five-layer structure: a flexible polymer substrate, ZnO nanowire textured films on its top and bottom surfaces, and electrodes on the surfaces. When it was strained to 0.12% at a strain rate of 3.56% S(-1), the measured output voltage reached 10 V, and the output current exceeded 0.6 MUA (corresponding power density 10 mW/cm(3)). A system was built up by integrating a NG, rectification circuit, capacitor for energy storage, sensor, and RF data transmitter. Wireless signals sent out by the system were detected by a commercial radio at a distance of 5-10 m. This study proves the feasibility of using ZnO nanowire NGs for building self-powered systems, and its potential application in wireless biosensing, environmental/infrastructure monitoring, sensor networks, personal electronics, and even national security. PMID- 21604750 TI - Patterned radial GaAs nanopillar solar cells. AB - Photovoltaic devices using GaAs nanopillar radial p-n junctions are demonstrated by means of catalyst-free selective-area metal-organic chemical vapor deposition. Dense, large-area, lithographically defined vertical arrays of nanowires with uniform spacing and dimensions allow for power conversion efficiencies for this material system of 2.54% (AM 1.5 G) and high rectification ratio of 213 (at +/-1 V). The absence of metal catalyst contamination results in leakage currents of ~236 nA at -1 V. High-resolution scanning photocurrent microscopy measurements reveal the independent functioning of each nanowire in the array with an individual peak photocurrent of ~1 nA at 544 nm. External quantum efficiency shows that the photocarrier extraction highly depends on the degenerately doped transparent contact oxide. Two different top electrode schemes are adopted and characterized in terms of Hall, sheet resistance, and optical transmittance measurements. PMID- 21604751 TI - Hot-spot engineering in polygonal nanofinger assemblies for surface enhanced Raman spectroscopy. AB - Multiparticle assemblies of nanoscale structures are the fundamental building blocks for powerful plasmonic devices. Here we show the controlled formation of polygonal metal nanostructure assemblies, including digon, trigon, tetragon, pentagon, and hexagon arrays, which were formed on top of predefined flexible polymer pillars that undergo self-coalescence, analogous to finger closing, with the aid of microcapillary forces. This hybrid approach of combining top-down fabrication with self-assembly enables the formation of complex nanoplasmonic structures with sub-nanometer gaps between gold nanoparticles. On comparison of the polygon-shaped assemblies, the symmetry dependence of the nanoplasmonic structures was determined for application to surface enhanced Raman spectroscopy (SERS), with the pentagonal assembly having the largest Raman enhancement for the tested molecules. Electromagnetic simulations of the polygonal structures were performed to visualize the field enhancements of the hot spots so as to guide the rational design of optimal SERS structures. PMID- 21604753 TI - Efficient route to atropisomeric ligands--application to the synthesis of MeOBIPHEP analogues. AB - A highly efficient Pd-catalyzed P-C coupling reaction of easily accessible atropisomeric bisphosphane is described in the presence of various electron-poor aromatic iodides. The reactions are conducted in the presence of a Pd(II)/dppf catalyst in acetonitrile at 80 degrees C. The reaction conditions are compatible with several electron-withdrawing groups such as esters, cyano, chloro, and trifluoromethyl groups and lead to atropisomeric MeOBIPHEP derivatives in good to excellent yields and high enantiomeric purities. PMID- 21604752 TI - Defining the RNA internal loops preferred by benzimidazole derivatives via 2D combinatorial screening and computational analysis. AB - RNA is an important therapeutic target; however, RNA targets are generally underexploited due to a lack of understanding of the small molecules that bind RNA and the RNA motifs that bind small molecules. Herein, we describe the identification of the RNA internal loops derived from a 4096 member 3 * 3 nucleotide loop library that are the most specific and highest affinity binders to a series of four designer, druglike benzimidazoles. These studies establish a potentially general protocol to define the highest affinity and most specific RNA motif targets for heterocyclic small molecules. Such information could be used to target functionally important RNAs in genomic sequence. PMID- 21604754 TI - An efficient approach to fused indolines via a copper(I)-catalyzed reaction of sulfonyl azide with 2-ethynylaryl methylenecyclopropane. AB - A cascade reaction of 2-ethynylaryl methylenecyclopropane with sulfonyl azide catalyzed by copper(I) iodide under mild conditions is described, which provides a novel and efficient route for the generation of fused indolines. PMID- 21604755 TI - Fluorescence anisotropy analysis for mapping aptamer-protein interaction at the single nucleotide level. AB - Structural characterization of aptamer-protein interactions is challenging and limited despite the tremendous applications of aptamers. Here we for the first time report a fluorescence anisotropy (FA) approach for mapping the interaction of an aptamer and its protein target at the single nucleotide level. Nine fluorescently labeled aptamers, each conjugated to a single tetramethylrhodamine at a specified nucleotide in the aptamer, were used to study their interactions with thrombin. Simultaneous monitoring of both fluorescence anisotropy changes and electrophoretic mobility shifts upon binding of the fluorescently modified aptamer to the protein provides unique information on the specific nucleotide site of binding. T25, T20, T7 and the 3'-end were identified as the close contact sites, and T3, C15T, and the 5'-end were identified as the sites distant from the binding. This approach is highly sensitive and does not require cross-linking reactions. Studies of aptamer-protein interactions using this technique are potentially useful for design, evolution, and modification of functional aptamers for a range of bioanalytical, diagnostic, and therapeutic applications. PMID- 21604756 TI - Mobile aliphatic domains in humic substances and their impact on contaminant mobility within the matrix. AB - Using a novel NMR option, magic angle spinning pulsed field gradient (MAS PFG) NMR, the mobility of aliphatic domains in humic substances in the presence of toluene (about 4.5 wt. %) has been monitored. Results show a strong correlation between the diffusivities of the mobile aliphatic chains and those of the adsorbed toluene molecules in the matrix as a function of temperature. Particularly, a strong influence of structural relaxation of the humic matrix on the diffusivity of toluene is observed. Our findings confirm that the aliphatic domains in humic substances play an important role in the mobility of sorbed contaminants within this matrix. These findings further confirm the potential of MAS PFG NMR method in monitoring diffusion processes in particulate humic substances. PMID- 21604757 TI - Fukushima wildlife dose reconstruction signals ecological consequences. PMID- 21604758 TI - New strategy for expression of recombinant hydroxylated human-derived gelatin in Pichia pastoris KM71. AB - Gelatin is a well-known biopolymer, and it has a long history of use mainly as a gelling agent in the food industry. This paper reports a new method for producing recombinant hydroxylated human-derived gelatin in Pichia pastoris KM71. Three independent expression cassettes encoding for specific length of gelatin, prolyl 4-hydroxylase (P4H, EC 1.14.11.2), alpha-subunit (alphaP4H), and protein disulfide isomerase (PDI) were individually cloned in one expression vector, pPIC9K. The modified gelatin gene and two subunit genes of P4H were under the control of two different inducible promoters, namely, alcohol oxidase 1 promoter (PAOX1) and formaldehyde dehydrogenase 1 promoter (PFLD1), respectively. The results of sodium dodecylsulfate-polyacrylamide gel electrophoresis show that a recombinant gelatin was successfully expressed in P. pastoris KM71 by methanol induction. Liquid chromatography coupled with tandem mass spectrometry analysis indicates that the expressed gelatin was hydroxylated with approximately 66.7% of proline residues in the Y positions of Gly-X-Y triplets. The results of nuclear magnetic resonance spectroscopy of recombinant gelatin test show that the (1)H and (13)C spectra have many corresponding characteristic displacement peaks, and amino acids composition analysis shows that it contains hydroxyproline and its UV absorption is consistent with the characteristics of gelatin. PMID- 21604759 TI - Simplextones A and B, unusual polyketides from the marine sponge Plakortis simplex. AB - Two novel polyketides, simplextones A (1) and B (2), were isolated from the sponge Plakortis simplex. Their structures were established by spectroscopic methods. The absolute configurations were assigned by modified Mosher's method, X ray crystallographic analysis, and quantum mechanical calculation of the electronic circular dichroism (ECD) spectrum. Compounds 1 and 2 featured an unprecedented polyketide skeleton via the connection of a single carbon-carbon bond to form a cyclopentane. These compounds also exhibited moderate cytotoxicity. PMID- 21604760 TI - Structure-based design of potent aromatase inhibitors by high-throughput docking. AB - Cytochrome P450 aromatase catalyzes the conversion of androgen substrates into estrogens. Aromatase inhibitors (AIs) have been used as first-line drugs in the treatment of estrogen-dependent breast cancer in postmenopausal women. However, the search for new, more potent, and selective AIs still remains necessary to avoid the risk of possible resistances and reduce toxicity and side effects of current available drugs. The publication of a high resolution X-ray structure of human aromatase has opened the way to structure-based virtual screening to identify new small-molecule inhibitors with structural motifs different from all known AIs. In this context, a high-throughput docking protocol was set up and led to the identification of nanomolar AIs with new core structures. PMID- 21604761 TI - Binding inhibitors of the bacterial sliding clamp by design. AB - The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The beta(2) sliding clamp is an essential component of the replicative machinery, providing a platform for recruitment and function of other replisomal components and ensuring polymerase processivity during DNA replication and repair. A single binding region of the clamp is utilized by its binding partners, which all contain conserved binding motifs. The C-terminal Leu and Phe residues of these motifs are integral to the binding interaction. We acquired three-dimensional structural information on the binding site in beta(2) by a study of the binding of modified peptides. Development of a three-dimensional pharmacophore based on the C-terminal dipeptide of the motif enabled identification of compounds that on further development inhibited alpha beta(2) interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to beta(2), as a starting point for further inhibitor design. PMID- 21604762 TI - Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26 triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa 1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. AB - Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2 aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC(50) = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC(50) = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC(50) = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma. PMID- 21604763 TI - Toxic effects of methylated benzo[a]pyrenes in rat liver stem-like cells. AB - The methylated benzo[a]pyrenes (MeBaPs) are present at significant levels in the environment, especially in the sediments contaminated by petrogenic PAHs. However, the existing data on their toxic effects in vitro and/or in vivo are still largely incomplete. Transcription factor AhR plays a key role in the metabolic activation of PAHs to genotoxic metabolites, but the AhR activation may also contribute to the tumor promoting effects of PAHs. In this study, the AhR mediated activity of five selected MeBaP isomers was estimated in the DR-CALUX reporter gene assay performed in rat hepatoma cells. Detection of other effects, including induction of CYP1A1, CYP1B1, and AKR1C9 mRNAs, DNA adduct formation, production of reactive oxygen species, oxidation of deoxyguanosine, and cell cycle modulation and apoptosis, was performed in the rat liver epithelial WB-F344 cell line, a model of liver progenitor cells. We identified 1-MeBaP as the most potent inducer of AhR activation, stable DNA adduct formation, checkpoint kinase 1 and p53 phosphorylation, and apoptosis. These effects suggest that 1-MeBaP is a potent genotoxin eliciting a typical sequence of events ascribed to carcinogenic PAHs: induction of CYP1 enzymes, formation of high levels of DNA adducts, activation of DNA damage responses (including p53 phosphorylation), and cell death. In contrast, 10-MeBaP, representing BaP isomers substituted with the methyl group in the angular ring, elicited only low levels DNA adduct formation and apoptosis. Other MeBaPs under study also elicited strong apoptotic responses associated with DNA adduct formation as the prevalent mode of toxic action of these compounds in liver cells. MeBaPs induced a weak production of ROS, which did not lead to significant oxidative DNA damage. Importantly, 1-MeBaP and 3 MeBaP were found to be potent AhR agonists, one order of magnitude more potent than BaP, thus suggesting that the AhR-dependent modulations of gene expression, deregulation of cell survival mechanisms, and further nongenotoxic effects associated with AhR activation may further contribute to their tumor promotion and carcinogenicity. PMID- 21604764 TI - Acute hypertriglyceridemia promotes intestinal lymphatic lipid and drug transport: a positive feedback mechanism in lipid and drug absorption. AB - Elevated systemic levels of triglyceride-rich lipoproteins (TRL) are a risk factor for the development of atherosclerosis. In patients with metabolic syndrome (MetS), intestinal TRL overproduction contributes to high systemic TRL levels, and recent studies suggest that systemic changes in MetS such as increases in plasma fatty acids and insulin resistance stimulate intestinal TRL production. The current study has examined whether increases in systemic TRL influence intestinal lipid transport and lipoprotein assembly pathways and evaluates the impact of these changes on the absorption and lymphatic transport of lipids and a model lipophilic drug (halofantrine). Mesenteric lymph-duct or bile-duct cannulated rats were administered IV saline or (14)C-labeled chylomicron (CM) (to increase systemic TRL) and intraduodenal (3)H lipids and drug. Changes to biliary lipid output and lymphatic lipid and drug transport were subsequently examined. Increasing systemic TRL concentrations stimulated a significant increase in lymphatic lipid and drug transport. The increased lipids in lymph were not derived from bile or the intestinal blood supply (fatty acid or IV infused (14)C-CM). Rather, an increase in lymphatic transport of duodenally sourced lipids was evident. Increasing plasma levels of TRL therefore stimulated lipid absorption and lymphatic transport via a positive feedback process. The data also suggest that the changes to intestinal TRL formation that result from raised systemic TRL levels may impact on the absorption of highly lipophilic drugs and therefore the reproducibility of drug treatments. PMID- 21604765 TI - Autocatalysis for C-H bond activation by ruthenium(II) complexes in catalytic arylation of functional arenes. AB - Kinetic data for the C-H bond activation of 2-phenylpyridine by Ru(II)(carboxylate)(2)(p-cymene) I (acetate) and I' (pivalate) are available for the first time. They reveal an irreversible autocatalytic process catalyzed by the coproduct HOAc or HOPiv (acetonitrile, 27 degrees C). The overall reaction is indeed accelerated by the carboxylic acid coproduct and water. It is retarded by a base, in agreement with an autocatalytic process induced by HOAc or HOPiv that favors the dissociation of one carboxylate ligand from I and I' and consequently the ensuing complexation of 2-phenylpyridine (2-PhPy). The C-H bond activation initially delivers Ru(O(2)CR)(o-C(6)H(4)-Py)(p-cymene) A or A', containing one carboxylate ligand (OAc or OPiv, respectively). The overall reaction is accelerated by added acetates. Consequently, C-H bond activation (faster for acetate I than for pivalate I') proceeds via an intermolecular deprotonation of the C-H bond of the ligated 2-PhPy by the acetate or pivalate anion released from I or I', respectively. The 18e complexes A and A' easily dissociate, by displacement of the carboxylate by the solvent (also favored by the carboxylic acid), to give the same cationic complex B(+) {[Ru(o-C(6)H(4) Py)(p-cymene)(MeCN)](+)}. Complex B(+) is reactive toward oxidative addition of phenyl iodide, leading to the diphenylated 2-pyridylbenzene. PMID- 21604766 TI - Sensitivity gains in chemosensing by optical and structural modulation of ordered assembly arrays of ZnO nanorods. AB - Nanomaterials and -structures have attracted much attention owing to their applications to ultrasensitive nanodevices. In this work, ordered assembly arrays of ZnO nanorods have been hydrothermally fabricated and used as optical substrates of fluorescence sensors for toxic vapors. The unique fastigiate nanorod assembly combines merits of single fibers and clusters, possessing identical orientation, large surface-to-volume ratio, evanescent transmission, and evanescent coupling. As coated on the assembly arrays, different sensing materials all generated amplified spontaneous emission (ASE) action such that the fluorescence intensity of the narrowed spectrum was 52.4-fold enhanced. Results of sensing experiments indicate that sensors based on the assembly arrays displayed 100% elevated normalized quenching rate and several times longer full load time compared with reference sensors. This work provides a facile method to fabricate secondary structures of 1D rigid material and presents a new way to design highly sensitive optic sensors. Furthermore, evanescent excitation caused ASE action of fluorescent organics, and the correlative sensitivity gain is of interest in both theoretical research and the applications field. PMID- 21604767 TI - Enhanced incident photon-to-electron conversion efficiency of tungsten trioxide photoanodes based on 3D-photonic crystal design. AB - In this study, 3D-photonic crystal design was utilized to enhance incident photon to-electron conversion efficiency (IPCE) of WO(3) photoanodes. Large-area and high-quality WO(3) photonic crystal photoanodes with inverse opal structure were prepared. The photonic stop-bands of these WO(3) photoanodes were tuned experimentally by variation of the pore size of inverse opal structures. It was found that when the red-edge of the photonic stop-band of WO(3) inverse opals overlapped with the WO(3) electronic absorption edge at E(g) = 2.6-2.8 eV, a maximum of 100% increase in photocurrent intensity was observed under visible light irradiation (lambda > 400 nm) in comparison with a disordered porous WO(3) photoanode. When the red-edge of the stop-band was tuned well within the electronic absorption range of WO(3), noticeable but less amplitude of enhancement in the photocurrent intensity was observed. It was further shown that the spectral region with a selective IPCE enhancement of the WO(3) inverse opals exhibited a blue-shift in wavelength under off-normal incidence of light, in agreement with the calculated stop-band edge locations. The enhancement could be attributed to a longer photon-matter interaction length as a result of the slow light effect at the photonic stop-band edge, thus leading to a remarkable improvement in the light-harvesting efficiency. The present method can provide a potential and promising approach to effectively utilize solar energy in visible light-responsive photoanodes. PMID- 21604768 TI - Development of a low-resource RNA extraction cassette based on surface tension valves. AB - Nucleic acid-based diagnostics are highly sensitive and specific, but are easily disrupted by the presence of interferents in biological samples. In a laboratory or hospital setting, the influence of these interferents can be minimized using an RNA or DNA extraction procedure prior to analysis. However, in low-resource settings, limited access to specialized instrumentation and trained personnel presents challenges that impede sample preparation. We have developed a self contained nucleic acid extraction cassette suitable for operation in a low resource setting. This simple design contains processing solutions preloaded within a continuous length of 1.6 mm inner diameter Tygon tubing. Processing solutions are separated by air gaps and held in place during processing by the surface tension forces at the liquid-air interface, viz. surface tension valves. Nucleic acids preferentially adsorbed to silica-coated magnetic particles are separated from sample interferents using an external magnet to transfer the nucleic acid biomarker through successive solutions to precipitate, wash and elute in the final cassette solution. The efficiency of the extraction cassette was evaluated using quantitative reverse transcriptase PCR (qRT-PCR) following extraction of respiratory syncytial virus (RSV) RNA. RNA was recovered from TE buffer or from lysates of RSV infected HEp-2 cells with 55 and 33% efficiency, respectively, of the Qiagen RNeasy kit. Recovery of RSV RNA from RSV infected HEp 2 cells was similar at 30% of the RNeasy kit. An overall limit of detection after extraction was determined to be nearly identical (97.5%) to a laboratory-based commercially available kit. These results indicate that this extraction cassette design has the potential to be an effective sample preparation device suitable for use in a low-resource setting. PMID- 21604769 TI - Modeling the self-assembly of lipids and nanotubes in solution: forming vesicles and bicelles with transmembrane nanotube channels. AB - Via dissipative particle dynamics (DPD), we simulate the self-assembly of end functionalized, amphiphilic nanotubes and lipids in a hydrophilic solvent. Each nanotube encompasses a hydrophobic stalk and two hydrophilic ends, which are functionalized with end-tethered chains. With a relatively low number of the nanotubes in solution, the components self-assemble into stable lipid-nanotube vesicles. As the number of nanotubes is increased, the system exhibits a vesicle to-bicelle transition, resulting in stable hybrid bicelle. Moreover, our results reveal that the nanotubes cluster into distinct tripod-like structures within the vesicles and aggregate into a ring-like assembly within the bicelles. For both the vesicles and bicelles, the nanotubes assume trans-membrane orientations, with the tethered hairs extending into the surrounding solution or the encapsulated fluid. Thus, the hairs provide a means of regulating the transport of species through the self-assembled structures. Our findings provide guidelines for creating nanotube clusters with distinctive morphologies that might be difficult to achieve through more conventional means. The results also yield design rules for creating synthetic cell-like objects or microreactors that can exhibit biomimetic functionality. PMID- 21604770 TI - Suppressing the skin-core structure of injection-molded isotactic polypropylene via combination of an in situ microfibrillar network and an interfacial compatibilizer. AB - Injection-molded semicrystalline polymer parts generally exhibited a so-called skin-core structure basically as a result of the large gradients of temperature, shear rate, stress, and pressure fields created by the boundary conditions of injection molding. Suppression of the skin-core structure is a long-term practical challenge. In the current work, the skin-core structure of the conventional injection-molded isotactic polypropylene (iPP) was largely relieved by the cooperative effects of an in situ microfibrillar network and interfacial compatibilizer. The in situ poly(ethylene terephthalate) microfibrils of 1-8 MUm in diameter and large aspect ratios of above 40 tended to entangle with each other to generate a microfibrillar network in the iPP melt. During injection molding, the iPP molecules experienced confined flow in the microchannels or pores formed by the microfibrillar network, which could redistribute and homogenize the flow field of polymer melt. Addition of the compatibilizer, glycidyl methacrylate-grafted iPP, restrained the molecular orientation but facilitated preservation of oriented molecules due to the chemical bonds at the interface between PET microfibrils and iPP. The cooperative effects of in situ microfibrillar network and interfacial compatibilizer led to almost the same molecular orientation across the whole thickness of the injection-molded parts. Additionally, the content of beta crystals in different layers of injection molded iPP parts depended on the combined effects of the molecular orientation, the amount of oriented crystals, and the crystallization time between 105 and 140 degrees C. The presence of the interfacial compatibilizer facilitated formation of the beta crystals because of preservation of the oriented molecules. PMID- 21604771 TI - Fluorescence properties of photonic crystals doped with perylenediimide. AB - This study aims to present the fabrication of colloidal photonic crystals (PC) with increased fluorescence properties. The use of a highly fluorescent perylenediimide derivate (PDI) during the soap-free emulsion polymerization of styrene-acrylic acid resulted in monodisperse core-shell particles which allowed the fabrication of PC films. The properties of the hybrid material were studied in comparison with hybrid materials obtained by impregnation of films with chromophore solutions. In both cases an increase of the fluorescence response was observed in addition to a blue shift for the PDI core particles, proving the incorporation of the dye inside the copolymer particles. PMID- 21604772 TI - Supported lipid bilayer composition microarray fabricated by pattern-guided self spreading. AB - We report on the fabrication of a microarray of supported lipid bilayers (SLBs) with different chemical compositions and demonstrate its biosensing application. The technique utilizes the phenomenon of lipid self-spreading on a patterned surface, which offers complete positional selectivity for a supported lipid bilayer. We describe the fabrication of parallel 10-MUm-wide lines, each filled with an SLB with a unique composition, at 5 MUm intervals. Structures obtained with our new technique are finer and more highly integrated than previously reported structures that employ the vesicle fusion technique on patterned surfaces. We also detected specific binding between biotin and streptavidin with high contrast, indicating that the microarray is valuable for biosensing applications. PMID- 21604773 TI - Naphthiporphyrins. AB - Benziporphyrins, cross-conjugated porphyrin analogues with a benzene ring in place of one of the usual pyrrole units, have varying degrees of macrocyclic aromaticity because the 6pi electron arene needs to give up its aromatic characteristics to facilitate conjugation over the entire system. As naphthalene would lose less resonance stabilization energy in giving up one of its benzene units, it was proposed that naphthiporphyrins would exhibit enhanced diatropicity compared to the related benziporphyrins. A naphthiporphyrin was prepared using the "3 + 1" variant of the MacDonald condensation by reacting 1,3 naphthalenedicarbaldehyde with a tripyrrane in the presence of TFA, followed by oxidation with DDQ. Although the free base form of naphthiporphyrin showed no overall diatropicity, the corresponding dication in TFA-CDCl(3) demonstrated a significant diatropic ring current where the internal CH shifted upfield to between 4.0 and 4.6 ppm. Naphthiporphyrin was converted to the corresponding palladium(II) complexes by reaction with Pd(OAc)(2) in acetonitrile, and the complex was further characterized by X-ray crystallography. Oxynaphthiporphyrins were similarly prepared by the "3 + 1" methodology from 4-methoxy-1,3-naphthalene dicarbaldehyde, and these showed slightly enhanced diatropic character compared to oxybenziporphyrins. Reaction of oxybenziporphyrins or oxynaphthiporphyrins with silver(I) acetate afforded the corresponding silver(III) organometallic derivatives. A meso-tetraphenyl naphthiporphyrin was also synthesized in 4% yield by reacting a 1,4-naphthalene dicarbinol with 2 equiv of benzaldehyde and 3 equiv of pyrrole in the presence of BF(3).Et(2)O, followed by oxidation with DDQ. However, this 1,4-naphthiporphyrin showed reduced diatropic character compared to the corresponding p-benziporphyrin system. The NMR spectra for the 1,4 naphthiporphyrin show that the naphthalene unit pivots over the macrocycle and this presumably leads to further steric interactions that reduce the planarity of the macrocycle. These results demonstrate that while naphthiporphyrins can show enhanced aromatic properties as predicted, other factors may overwhelm this effect. PMID- 21604774 TI - Conjugated "B-entacenes": polycyclic aromatics containing two borepin rings. AB - The synthesis and characterization of functionalized bora-acenes (B-entacenes) where Stille and Sonogashira cross-couplings were used to attach a series of electron-donating and -withdrawing substituents is reported. Photophysical, electrochemical, and computational analyses revealed that the LUMO level can be tuned by changing the para-conjugated substituent. Furthermore, the dimethylamino functionalized molecule exhibited intense solvatochromism due to the intramolecular charge-transfer interaction. PMID- 21604775 TI - Hydrophilic quaternary ammonium type ionic liquids. Systematic study of the relationship among molecular structures, osmotic pressures, and water-solubility. AB - This Letter examines the relationship between the structures of ionic liquids and their water-solubility or osmotic pressure with a number of synthesized quaternary ammonium type ionic liquids and organic salts containing a hydroxyl group as hydrophilic substituted groups on ammonium group cations, and bromide or methylsulfonate as anions. The study found a linear relation between the amount and osmotic pressure of the water-soluble ionic liquids synthesized here, strongly indicating that these water-soluble ionic liquids are perfectly ionized in water like inorganic salts with small diameter ions. PMID- 21604776 TI - Ruthenium-catalyzed regio- and stereoselective addition of carboxylic acids to aryl and trifluoromethyl group substituted unsymmetrical internal alkynes. AB - The regio- and stereoselective addition of carboxylic acids to aryl and trifluoromethyl group substituted unsymmetrical internal alkynes has been accomplished: the Ru(3)(CO)(12)/3PPh(3) catalyst system has effectively catalyzed the reaction to afford the trifluoromethyl group substituted (E)-enol esters with high regio- and stereoselectivities. PMID- 21604777 TI - Effect of viscoelasticity on adhesion of bioinspired micropatterned epoxy surfaces. AB - The effect of viscoelasticity on adhesion was investigated for micropatterned epoxy surfaces and compared to nonpatterned surfaces. A two-component epoxy system was used to produce epoxy compositions with different viscoelastic properties. Pillar arrays with flat punch tip geometries were fabricated with a two-step soft lithography process. Adhesion properties were measured with a home built adhesion tester using a spherical sapphire probe as a counter-surface. Compared to flat controls, micropatterned epoxy samples with low viscoelasticity (i.e., low damping factors) showed at least a 20-fold reduction in pull-off force per actual contact area for both low (E' = 2.3 MPa) and high (E' = 2.3 GPa) storage moduli. This antiadhesive behavior may result from poor contact formation and indicates that the adhesion performance of commonly used elastomers for dry adhesives (e.g., polydimethylsiloxane) is governed by the interfacial viscoelasticity. Adhesion significantly increased with increasing viscoelasticity. Micropatterned samples with high viscoelasticity showed a 4-fold reduction in adhesion for aspect ratio (AR) 1.1 patterns but a 2-fold enhancement in adhesion for AR 2.2 patterns. These results indicate that viscoelasticity can enhance the effect of surface patterning on adhesion and should be considered as a significant parameter in the design of artificial patterned adhesives. PMID- 21604778 TI - Synthesis of pyridine-N-oxide-borane intramolecular complexes by palladium catalyzed reaction of 2-bromopyridine-N-oxides with alkynyltriarylborates. AB - Pyridine-N-oxide-borane intramolecular complexes having an aza-stilbene pi framework were synthesized by the palladium-catalyzed reaction of 2-bromopyridine N-oxides with alkynyltriarylborates. PMID- 21604779 TI - Influence of plasticizer content on the transition of electromechanical behavior of PVC gel actuator. AB - The actuation performance of plasticized poly(vinyl chloride) (PVC) gel actuators in an electric field depends on their chemical composition and electrical and mechanical properties. The influence of plasticizer (dibutyl adipate) content on electromechanical behavior of PVC gels was investigated by impedance spectroscopy and space charge measurement. By plasticizing the PVC, the dielectric constant and space charge density of PVC gel were drastically increased at 1:2 w/w ratio of PVC to plasticizer. To apply the results obtained from the impedance spectroscopy and space charge measurement, electrostatic adhesive forces generated between the PVC gel and the anode were measured. The electrostatic adhesive force at the anode was also dramatically increased at the same plasticizer content. All of the results indicated a transition of electromechanical behavior of PVC gel in the electric field, which was considered to originate from the orientation of polarized plasticizer molecules and dipole rotation of PVC chains. By using the electrostatic adhesive force of PVC gel derived from the electromechanical transition, a new electroactive actuator can be developed for novel applications. PMID- 21604780 TI - Stepwise fusion of porphyrin beta,beta'-pyrrolic positions to imidazole rings. AB - A strategy for the stepwise annulation of pyrrolic rings of a porphyrin to imidazole rings is presented. Mono(imidazole), Janus and corner bis(imidazole), T shaped tris(imidazole), and tetrakis(imidazole) porphyrins have been synthesized and characterized. PMID- 21604781 TI - Stable tris(2,2'-bipyridine)ruthenium(III) for chemiluminescence detection. AB - Two exceedingly stable [Ru(bipy)(3)](3+) reagents were prepared by dissolving either [Ru(bipy)(3)](ClO(4))(2) in acetonitrile (containing 0.05 M HClO(4)) or [Ru(bipy)(3)]Cl(2).6H(2)O in 95:5 glacial acetic acid-acetic anhydride (containing 0.05 M H(2)SO(4)) followed by oxidation with PbO(2). These conveniently prepared solutions provide highly reproducible chemiluminescence detection over long periods of analysis, avoiding the need for recalibration or preparation of fresh reagent solutions and without the complications associated with online chemical or electrochemical oxidations. The reagent prepared in acetonitrile produced much greater signal intensities with a range of analytes and was deemed most suitable for high-performance liquid chromatography (HPLC) with postcolumn chemiluminescence detection. PMID- 21604782 TI - Protein and lipid binding parameters in rainbow trout (Oncorhynchus mykiss) blood and liver fractions to extrapolate from an in vitro metabolic degradation assay to in vivo bioaccumulation potential of hydrophobic organic chemicals. AB - Binding of hydrophobic chemicals to colloids such as proteins or lipids is difficult to measure using classical microdialysis methods due to low aqueous concentrations, adsorption to dialysis membranes and test vessels, and slow kinetics of equilibration. Here, we employed a three-phase partitioning system where silicone (polydimethylsiloxane, PDMS) serves as a third phase to determine partitioning between water and colloids and acts at the same time as a dosing device for hydrophobic chemicals. The applicability of this method was demonstrated with bovine serum albumin (BSA). Measured binding constants (K(BSAw)) for chlorpyrifos, methoxychlor, nonylphenol, and pyrene were in good agreement with an established quantitative structure-activity relationship (QSAR). A fifth compound, fluoxypyr-methyl-heptyl ester, was excluded from the analysis because of apparent abiotic degradation. The PDMS depletion method was then used to determine partition coefficients for test chemicals in rainbow trout (Oncorhynchus mykiss) liver S9 fractions (K(S9w)) and blood plasma (K(bloodw)). Measured K(S9w) and K(bloodw) values were consistent with predictions obtained using a mass-balance model that employs the octanol-water partition coefficient (K(ow)) as a surrogate for lipid partitioning and K(BSAw) to represent protein binding. For each compound, K(bloodw) was substantially greater than K(S9w), primarily because blood contains more lipid than liver S9 fractions (1.84% of wet weight vs 0.051%). Measured liver S9 and blood plasma binding parameters were subsequently implemented in an in vitro to in vivo extrapolation model to link the in vitro liver S9 metabolic degradation assay to in vivo metabolism in fish. Apparent volumes of distribution (V(d)) calculated from the experimental data were similar to literature estimates. However, the calculated binding ratios (f(u)) used to relate in vitro metabolic clearance to clearance by the intact liver were 10 to 100 times lower than values used in previous modeling efforts. Bioconcentration factors (BCF) predicted using the experimental binding data were substantially higher than the predicted values obtained in earlier studies and correlated poorly with measured BCF values in fish. One possible explanation for this finding is that chemicals bound to proteins can desorb rapidly and thus contribute to metabolic turnover of the chemicals. This hypothesis remains to be investigated in future studies, ideally with chemicals of higher hydrophobicity. PMID- 21604783 TI - A novel photoelectrochemical sensor for the organophosphorus pesticide dichlofenthion based on nanometer-sized titania coupled with a screen-printed electrode. AB - A novel photoelectrochemical sensor for detection of the organophosphorus pesticide (OP) dichlofenthion using nanometer-sized titania coupled with a screen printed electrode is presented. Nonelectroactive dichlofenthion can be indirectly determined through the photocatalytical degradation of dichlofenthion with nanometer-sized titania. The electrochemical characterization and anodic stripping voltammetric performance of dichlofenthion were evaluated using cyclic voltammetric (CV) and differential pulse anode stripping voltammetric (DPASV) analysis, respectively. DPASV analysis was used to monitor the amount of dichlofenthion and provide a simple, fast, and facile quantitative method for dichlofenthion. Operational parameters, including the photocatalysis time, pH of buffer solution, deposition potential, and accumulation time have been optimized. The stripping voltammetric response is linear over the 0.02-0.1 and 0.2-1.0 MUmol/L ranges with a detection limit of 2.0 nmol/L. The assay result of dichlofenthion in green vegetable with the proposed method was in acceptable agreement with that of the gas chromatograph-mass spectrometer (GC-MS) method. The promising sensor opens a new opportunity for fast, portable, and sensitive analysis of OPs in environmental samples. PMID- 21604784 TI - Chemically treating poly(3-hexylthiophene) defects to improve bulk heterojunction photovoltaics. AB - Defect engineering has been of vital importance to the development of inorganic semiconductors. Here, we report the chemical modification of electrical defects in the prototypical organic semiconductor, regioregular poly(3-hexylthiophene), P3HT. Previously, we have covalently treated defect sites with either a nucleophile or an electrophile, leaving the defects of primarily opposite polarity. Consecutively using both nucleophilic and electrophilic treatments allows us to covalently fix both positively and negatively charged defect sites in a single procedure. Here we describe the effects of treating P3HT first with lithium aluminum hydride, LAH, to decrease the overall defect density, and then with dimethylsulfate, Me(2)SO(4), to eliminate some of the remaining n-type defects (equivalent to a p-type doping process). The resulting polymer, P3HT_LAH_Me(2)SO(4), behaves differently than the polymer obtained when the order of treatments is reversed, P3HT_Me(2)SO(4)_LAH. Slightly improved structural and optical differences between these two new polymers and the starting P3HT are observed, whereas greatly improved electrical differences are found. Both treatments improve the performance of the photovoltaic cells, especially the short circuit current and the fill factor, and increase the stability against photodegradation. The significantly decreased series resistance and increased shunt resistance with a combined treatment suggest improved charge transport in the cell. The effective doping density can be increased or decreased with these treatments while the carrier mobility and the exciton diffusion length increase. It should be possible to employ these simple chemical treatments with any pi conjugated polymer to beneficially modify, or eliminate, some of its electronic defects. As a consequence, our approach provides a new method of improving the air-stability and electrical characteristics for organic photovoltaic and other electronic applications. PMID- 21604785 TI - Photoelectrochemical and photocatalytic properties of biphasic organic p- and n type semiconductor nanoparticles fabricated by a reprecipitation process. AB - The visible-light-responsive photoelectrochemical and photocatalytic properties of nanoparticles of C(60), partially hydrolyzed aluminum phthalocyanine chloride (denoted as AlPc), and a composite of the two are reported. The three types of nanoparticles were obtained through a reprecipitation method from N-methyl-2 pyrrolidone solutions of C(60), aluminum phthalocyanine chloride (AlPcCl), and their mixture, respectively. The nanoparticle composite's ultraviolet-visible absorption, diffuse-reflectance and Fourier transform IR spectra, X-ray diffraction pattern, and scanning electron microscopy image are all similar to the sum of those of the C(60) and AlPc particles, respectively. The nano-ordered composite exhibits p/n junctionlike photoelectrochemical characteristics, which were investigated in comparison with those of vapor-deposited C(60) (n-type), AlPcCl (p-type), C(60)/AlPcCl (n/p), and AlPcCl/C(60) (p/n) electrodes. The nanoparticle composite further shows photocatalytic activity for the decomposition of trimethylamine to carbon dioxide in a suspension system. PMID- 21604786 TI - Tailoring the near-surface composition profiles of pressure-sensitive adhesive films and the resulting mechanical properties. AB - We present a possibility of tailoring the near-surface composition profiles of pressure sensitive adhesive (PSA) films by an exposure to atmospheres of different relative humidities (RHs). The statistical copolymer P(EHA-stat-20MMA) with a majority of ethylhexylacrylate (EHA) and a minority of methylmethacrylate (MMA), being cast from a toluene based solution, is chosen as a model system. The near-surface composition profile is probed with X-ray reflectivity. All probed samples show an enrichment of PMMA at the sample surface; however, the near surface PMMA content strongly increases with increasing RH. The influence of the RH on the composition profile is present down to a depth of 50 nm. Therefore the surface tensions being derived from contact angle measurements do not show any measurable humidity dependence. In contrast, in a mechanical tack test with a smooth punch surface, a strong influence is probed. This observation can be explained by considering the integrated PMMA content over an appropriate near surface region and the resulting impact on the cavitation process. PMID- 21604788 TI - Stimulus-responsiveness and drug release from porous silicon films ATRP-grafted with poly(N-isopropylacrylamide). AB - In this report, we employ surface-initiated atom transfer radical polymerization (SI-ATRP) to graft a thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAM), of controlled thickness from porous silicon (pSi) films to produce a stimulus-responsive inorganic-organic composite material. The optical properties of this material are studied using interferometric reflectance spectroscopy (IRS) above and below the lower critical solution temperature (LCST) of the PNIPAM graft polymer with regard to variation of pore sizes and thickness of the pSi layer (using discrete samples and pSi gradients) and also the thickness of the PNIPAM coatings. Our investigations of the composite's thermal switching properties show that pore size, pSi layer thickness, and PNIPAM coating thickness critically influence the material's thermoresponsiveness. This composite material has considerable potential for a range of applications including temperature sensors and feedback controlled drug release. Indeed, we demonstrate that modulation of the temperature around the LCST significantly alters the rate of release of the fluorescent anticancer drug camptothecin from the pSi-PNIPAM composite films. PMID- 21604787 TI - Structure and activity of Aspergillus nidulans copper amine oxidase. AB - Aspergillus nidulans amine oxidase (ANAO) has the unusual ability among the family of copper and trihydroxyphenylalanine quinone-containing amine oxidases of being able to oxidize the amine side chains of lysine residues in large peptides and proteins. We show here that in common with the related enzyme from the yeast Pichia pastoris, ANAO can promote the cross-linking of tropoelastin and oxidize the lysine residues in alpha-casein proteins and tropoelastin. The crystal structure of ANAO, the first for a fungal enzyme in this family, has been determined to a resolution of 2.4 A. The enzyme is a dimer with the archetypal fold of a copper-containing amine oxidase. The active site is the most open of any of those of the structurally characterized enzymes in the family and provides a ready explanation for its lysine oxidase-like activity. PMID- 21604789 TI - Triphenylene-fused porphyrins. AB - Triphenylene has been successfully fused to the porphyrin periphery through a convenient oxidative ring-closure reaction. Bistriphenylene-fused porphyrins and a dibenzo[fg,op]tetracene-fused porphyrin have also been obtained using a similar approach. These pi-extended porphyrins exhibited broadened and bathochromic shifted UV-vis absorptions. PMID- 21604790 TI - Rhodium-catalyzed selective C-H activation/olefination of phenol carbamates. AB - Rh(III)-catalyzed ortho C-H activation/olefination of phenol carbamates has been developed. High regioselectivity is observed with a range of phenol carbamates enabling efficient coupling with acrylates and styrenes. This reaction exhibits different reactivity as compared to the Pd-catalyzed ortho-arylation reaction of phenol esters and provides a new approach for the synthesis of ortho-substituted phenols. PMID- 21604791 TI - A reactive conjugated allene involved in the biosynthesis of volatile oxylipins in the moss Dicranum scoparium. AB - We addressed the role of the unusual acetylenic fatty acid dicranin as a precursor for volatile oxylipins in the moss Dicranum scoparium. Dicranin is transformed immediately after mechanical wounding of moss tissue to volatile C5- and C6-oxylipins. The transformation of synthetic deuterium labeled dicranin was monitored using LC/MS analysis and multivariate statistics to identify polar metabolites produced during volatile formation. Among the newly formed oxylipins is a highly reactive conjugated C13 allene with similar degrees of labeling compared to the C5 volatiles suggesting that it results as second cleavage product from the biosynthesis of pentenal and pentenone. PMID- 21604793 TI - Locally oxidized silicon surface-plasmon Schottky detector for telecom regime. AB - We experimentally demonstrate an on-chip nanoscale silicon surface-plasmon Schottky photodetector based on internal photoemission process and operating at telecom wavelengths. The device is fabricated using a self-aligned approach of local-oxidation of silicon (LOCOS) on silicon on insulator substrate, which provides compatibility with standard complementary metal-oxide semiconductor technology and enables the realization of the photodetector and low-loss bus photonic waveguide at the same fabrication step. Additionally, LOCOS technique allows avoiding lateral misalignment between the silicon surface and the metal layer to form a nanoscale Schottky contact. The fabricated devices showed enhanced detection capability for shorter wavelengths that is attributed to increased probability of the internal photoemission process. We found the responsivity of the nanodetector to be 0.25 and 13.3 mA/W for incident optical wavelengths of 1.55 and 1.31 MUm, respectively. The presented device can be integrated with other nanophotonic and nanoplasmonic structures for the realization of monolithic opto-electronic circuitry on-chip. PMID- 21604792 TI - Synthesis of unsymmetrical diarylureas via Pd-catalyzed C-N cross-coupling reactions. AB - A facile synthesis of unsymmetrical N,N'-diarylureas is described. The utilization of the Pd-catalyzed arylation of ureas enables the synthesis of an array of diarylureas in good to excellent yields from benzylurea via a one-pot arylation-deprotection protocol, followed by a second arylation. PMID- 21604794 TI - Evaluation of the role of Au in improving catalytic activity of Ni nanoparticles for the formation of one-dimensional carbon nanostructures. AB - In situ dynamic imaging, using an environmental transmission electron microscope, was employed to evaluate the catalytic activity of Au/SiO(2), Ni/SiO(2), and Au Ni/SiO(2) nanoparticles for the formation of one-dimensional (1-D) carbon nanostructures such as carbon nanofibers (CNFs) and nanotubes (CNTs). While pure Au thin-film samples were inactive for carbon deposition at 520 degrees C in 0.4 Pa of C(2)H(2), multiwalled CNTs formed from Ni thin films samples under these conditions. The number of nanoparticles active for CNF and CNT formation increased for thin films containing 0.1 mol fraction and 0.2 mol fraction of Au but decreased as the overall Au content in thin films was increased above 0.5 mol fraction. Multiwalled CNTs formed with a root growth mechanism for pure Ni samples, while with the addition of 0.1 mol fraction or 0.2 mol fraction of Au, CNFs were formed via a tip growth mechanism at 520 degrees C. Single-walled CNTs formed at temperatures above 600 degrees C in samples doped with less than 0.2 mol fraction of Au. Ex situ analysis via high-resolution scanning transmission electron microscopy (STEM) and energy-dispersive X-ray spectroscopy (EDS) revealed that catalytically active particles exhibit a heterogeneous distribution of Au and Ni, where only a small fraction of the overall Au content was found in the portion of each particle actively involved in the nucleation of graphitic layers. Instead, the majority of the Au was found to be segregated to an inactive capping structure at one the end of the particles. Using density-functional theory calculations, we show that the activation energy for bulk diffusion of carbon in Ni reduces from ~1.62 eV for pure Ni to 0.07 eV with the addition of small amounts (~0.06 mol fraction) of Au. This suggests that the enhancement of C diffusion through the bulk of the particles may be responsible for improving the number of particles active for nucleating the 1-D carbon nanostructures and thereby the yield. PMID- 21604795 TI - Structure-property relationship of highly pi-conjugated Schiff-base moiety in liquid crystal diepoxide polymerization and mesophases stabilization. AB - A study of the structure-property relationship of the highly pi-conjugated Schiff base moiety in polymerization of a liquid crystal (LC) diepoxide oligomer (PBMBA) and mesophases stabilization has been investigated. We first proposed two exothermic peaks distinctly observed in nonisothermal polymerization curves for thermal copolymerization of PBMBA monomer with a diamine comonomer that corresponded to two different reactions, namely, an epoxy-amine polymerization and anionic polymerization. For PBMBA, note that an unexpected homopolymerization accompanying an appearance of enantiotropic mesophase transitions had taken place in the absence of any initiators, evidencing the possibility of an anionic mechanism yielding a homopolymer. A novel Schiff-base model compound (SBM) was synthesized and used to induce the polymerization of different types of epoxies. Based on the structure-property relationship, we considered a specific role of highly pi-conjugated Schiff-base moieties in the anionic polymerization of PBMBA and hoped the mesophases could be stabilized using this mechanism, which may provide a key strategy for design of the polymer-dispersed liquid crystal (PDLC) materials via a chemical process. PMID- 21604796 TI - C-H functionalization of 1,4-naphthoquinone by oxidative coupling with anilines in the presence of a catalytic quantity of copper(II) acetate. AB - The oxidative addition of anilines (2) with 1,4-naphthoquinone (3) to give N-aryl 2-amino-1,4-naphthoquinones (1) was found to be catalyzed by copper(II) acetate. In the absence of the catalyst, the reactions are slower and give lower yields with the formation of many colateral products. In the presence of 10 mol % hydrated copper(II) acetate, the reactions are generally more efficient in that they are cleaner, higher yielding, and faster. PMID- 21604797 TI - Isotopic signature transfer and mass pattern prediction (IsoStamp): an enabling technique for chemically-directed proteomics. AB - Directed proteomics applies mass spectrometry analysis to a subset of information rich proteins. Here we describe a method for targeting select proteins by chemical modification with a tag that imparts a distinct isotopic signature detectable in a full-scan mass spectrum. Termed isotopic signature transfer and mass pattern prediction (IsoStamp), the technique exploits the perturbing effects of a dibrominated chemical tag on a peptide's mass envelope, which can be detected with high sensitivity and fidelity using a computational method. Applying IsoStamp, we were able to detect femtomole quantities of a single tagged protein from total mammalian cell lysates at signal-to-noise ratios as low as 2.5:1. To identify a tagged-peptide's sequence, we performed an inclusion list driven shotgun proteomics experiment where peptides bearing a recoded mass envelope were targeted for fragmentation, allowing for direct site mapping. Using this approach, femtomole quantities of several targeted peptides were identified in total mammalian cell lysate, while traditional data-dependent methods were unable to identify as many peptides. Additionally, the isotopic signature imparted by the dibromide tag was detectable on a 12-kDa protein, suggesting applications in identifying large peptide fragments, such as those containing multiple or large posttranslational modifications (e.g., glycosylation). IsoStamp has the potential to enhance any proteomics platform that employs chemical labeling for targeted protein identification, including isotope coded affinity tagging, isobaric tagging for relative and absolute quantitation, and chemical tagging strategies for posttranslational modification. PMID- 21604798 TI - Use of simple kinetic and reaction-order measurements for the evaluation of the mechanism of surfactant-liposome interactions. AB - Surfactant-liposome interactions have been previously studied through different methods and techniques. We present here a classical physical chemistry study on liposome solutions added to destabilizing agents at concentrations well above the solubilization concentration, which enable us to draw useful and interesting conclusions about the mechanism of surfactant-induced liposomal breakdown by simply exploiting the kinetics and the reaction order of the liposomal content release. In such excess of surfactant, the mechanism of surfactant-induced rupture of the liposomes has been demonstrated to be different from that proposed for low surfactant concentrations. Thus, depending on the surfactant concentration, two prevailing processes have been evidenced: (i) a cooperative mechanism that implies the assembly of a critical number of surfactant molecules to trigger the formation of a channel and therefore the release of the liposomal content and (ii) a mechanism driven by direct interaction of the surfactant molecules with the lipids that causes the complete solubilization of the liposomes. The former mechanism occurs at low surfactant concentrations, whereas the latter occurs at higher concentrations and above the CMC of the surfactants. The effect of different guests embedded into the liposomal bilayer on the mechanism of surfactant-induced liposomal breakdown has been compared by using the second-order rate constants measured for the liposome breakdown process. PMID- 21604799 TI - Volumetric properties and spectroscopic studies of pyridine or nicotine solutions in liquid polyethylene glycols. AB - Densities and molar excess volumes of the solutions of pyridine or nicotine in liquid polyethylene glycol, PEG200 and PEG400, have been determined at several temperatures. The experimental molar excess volumes are negative, thus indicating strong attractive interactions between the components, as could be expected considering their highly polar nature and good hydrogen bond abilities. For the pyridine systems, this negativity is slightly increased as the temperature rises, while the opposite tendency is observed for the nicotine mixtures. When pyridine and nicotine solutions are compared, the former-particularly those with PEG400 exhibit substantially more negative molar excess volumes than the latter. The effect of the polymer chain length on the results for the nicotine solutions is almost negligible. However, this is not the case when pyridine is one of the components: a longer chain induced considerably higher compression on mixing. The Fourier-transform infrared analysis allowed interpretation of the negative experimental molar excess volumes in terms of specific inter- and intramolecular interactions. PMID- 21604800 TI - Pharmer: efficient and exact pharmacophore search. AB - Pharmacophore search is a key component of many drug discovery efforts. Pharmer is a new computational approach to pharmacophore search that scales with the breadth and complexity of the query, not the size of the compound library being screened. Two novel methods for organizing pharmacophore data, the Pharmer KDB tree and Bloom fingerprints, enable Pharmer to perform an exact pharmacophore search of almost two million structures in less than a minute. In general, Pharmer is more than an order of magnitude faster than existing technologies. The complete source code is available under an open-source license at http://pharmer.sourceforge.net . PMID- 21604801 TI - Hierarchical interactions and their influence upon the adsorption of organic molecules on a graphene film. AB - The competition between intermolecular interactions and lateral variations in the molecule-substrate interactions has been studied by scanning tunneling microscopy (STM), comparing the phase formation of (sub)monolayers of the organic molecule 2,4'-BTP on buckled graphene/Ru(0001) and Ag(111) oriented thin films on Ru(0001). On the Ag films, the molecules form a densely packed 2D structure, while on graphene/Ru(0001), only the areas between the maxima are populated. The findings are rationalized by a high corrugation in the adsorption potential for 2,4'-BTP molecules on graphene/Ru(0001). These findings are supported by temperature programmed desorption (TPD) experiments and theoretical results. PMID- 21604803 TI - Water-dispersible sugar-coated iron oxide nanoparticles. An evaluation of their relaxometric and magnetic hyperthermia properties. AB - Synthesis of functionalized magnetic nanoparticles (NPs) for biomedical applications represents a current challenge. In this paper we present the synthesis and characterization of water-dispersible sugar-coated iron oxide NPs specifically designed as magnetic fluid hyperthermia heat mediators and negative contrast agents for magnetic resonance imaging. In particular, the influence of the inorganic core size was investigated. To this end, iron oxide NPs with average size in the range of 4-35 nm were prepared by thermal decomposition of molecular precursors and then coated with organic ligands bearing a phosphonate group on one side and rhamnose, mannose, or ribose moieties on the other side. In this way a strong anchorage of the organic ligand on the inorganic surface was simply realized by ligand exchange, due to covalent bonding between the Fe(3+) atom and the phosphonate group. These synthesized nanoobjects can be fully dispersed in water forming colloids that are stable over very long periods. Mannose, ribose, and rhamnose were chosen to test the versatility of the method and also because these carbohydrates, in particular rhamnose, which is a substrate of skin lectin, confer targeting properties to the nanosystems. The magnetic, hyperthermal, and relaxometric properties of all the synthesized samples were investigated. Iron oxide NPs of ca. 16-18 nm were found to represent an efficient bifunctional targeting system for theranostic applications, as they have very good transverse relaxivity (three times larger than the best currently available commercial products) and large heat release upon application of radio frequency (RF) electromagnetic radiation with amplitude and frequency close to the human tolerance limit. The results have been rationalized on the basis of the magnetic properties of the investigated samples. PMID- 21604805 TI - Extreme variability of steroid profiles in cow feces and pig slurries at the regional scale: implications for the use of steroids to specify fecal pollution sources in waters. AB - Thirty-five samples of cow feces (cowpat and cow manure) and pig slurries subjected to different treatment processes and different storage times before land spreading were extracted and analyzed by gas chromatography-mass spectrometry to determine their fecal stanol profiles. The fresh pig slurry data presented here increase considerably the classical range of values obtained for steroid ratios, resulting in an overlap with the range for cow feces. These results lead to the inability to distinguish species source of feces on the basis of steroid ratios alone. The cause of these differences is not known, although it appears likely to be related to differences in the metabolism of animals in relation to their age and/or variations in diet, rather than to secondary mechanisms of steroid degradation during storage or/and treatment of the feces. Nevertheless, the specificity of steroids to serve as a tool to differentiate cow feces from pig slurries is restored by considering the fecal stanol profile, notably, the six most diagnostic stanol compounds, which are 5beta-cholestan 3beta-ol (coprostanol), 5beta-cholestan-3alpha-ol (epicoprostanol), 24-methyl 5alpha-cholestan-3beta-ol (campestanol), 24-ethyl-5alpha-cholestan-3beta-ol (sitostanol), 24-ethyl-5beta-cholestan-3beta-ol (24-ethylcoprostanol), and 24 ethyl-5beta-cholestan-3alpha-ol (24-ethylepicoprostanol). In this study, chemometric analysis of the fingerprint of these six stanols using principal components analysis (PCA) distinguished pig slurries from cow feces. The application of PCA to the stanol profiles, as developed in this study, could be a promising tool for identifying the animal source in fecal contamination of waters. PMID- 21604804 TI - Label-free protein profiling of adipose-derived human stem cells under hyperosmotic treatment. AB - Our previous work suggested that treatment of cells with hyperosmotic media during 2D passaging primes cells for cartilage tissue engineering applications. Here, we used label-free proteomic profiling to evaluate the effects of control and hyperosmotic treatment environments on the phenotype of multipotent adipose derived stem cells (ASCs) cultivated with a chondrogenic growth factor cocktail. Spectra were recorded in a data-independent fashion at alternate low (precursor) and high (product) fragmentation voltages (MS(E)). This method was supplemented with data mining of accurate mass and retention time matches in precursor ion spectra across the experiment. The results indicated a complex cellular response to osmotic treatment, with a number of proteins differentially expressed between control and treated cell groups. The roles of some of these proteins have been documented in the literature as characteristic of the physiological states studied, especially aldose reductase (osmotic stress). This protein acted as a positive control in this work, providing independent corroborative validation. Other proteins, including 5'-nucleotidase and transgelin, have been previously linked to cell differentiation state. This study demonstrates that label-free profiling can serve as a useful tool in characterizing cellular responses to chondrogenic treatment regimes, recommending its use in optimization of cell priming protocols for cartilage tissue engineering. PMID- 21604806 TI - Adiabatic versus nonadiabatic photoisomerization in photochromic ruthenium sulfoxide complexes: a mechanistic picture from density functional theory calculations. AB - Polypyridine ruthenium sulfoxide complexes are intriguing compounds which can display both photochromic and electrochromic properties. These properties are based on the Ru-S -> Ru-O linkage isomerization capability of the sulfoxide group. The photoisomerization mechanism is of particular importance in order to understand the photophysical properties of such molecules. Density functional theory calculations demonstrate that the main photoisomerization mechanism is nonadiabatic for the system under study in agreement with the experimental observations. Indeed, funnels for efficient radiationless decay back to the ground state are shown to be easily accessible compared to transition states on the adiabatic triplet potential energy surface. However, we highlight for the first time that triplet metal-centered states play a central role in the photoisomerization mechanism of these compounds. PMID- 21604807 TI - Kinetic study of the thermal hydrolysis of Agave salmiana for mezcal production. AB - The kinetics of the thermal hydrolysis of the fructans of Agave salmiana were determined during the cooking step of mezcal production in a pilot autoclave. Thermal hydrolysis was achieved at different temperatures and cooking times, ranging from 96 to 116 degrees C and from 20 to 80 h. A simple kinetic model of the depolymerization of fructans to monomers and other reducing sugars and of the degradation of reducing sugars to furans [principally 5-(hydroxymethyl)furfural, HMF] was developed. From this model, the rate constants of the reactions were calculated, as well as the pre-exponential factors and activation energies of the Arrhenius equation. The model was found to fit the experimental data well. The tradeoff between a maximum fructan hydrolysis and a critical furan concentration in allowing for the best ethanol yield during fermentation was investigated. The results indicated that the thermal hydrolysis of agave was optimal, from the point of view of ethanol yield in the ensuing fermentation, in the temperature range of 106-116 degrees C and the cooking range time of 6-14 h. The optimal conditions corresponded to a fructan hydrolysis of 80%, producing syrups with furan and reducing sugar concentrations of 1 +/- 0.1 and 110 +/- 10 g/L, respectively. PMID- 21604808 TI - More at ACS Nano. PMID- 21604811 TI - The role of nanomaterials in translational medicine. AB - There are a range of definitions for nanomaterials and a range of length scales that are considered nano, but one thing is consistent among fields: nanomaterials are small and special. Nanomaterials have the potential to have tremendous impact on medical treatments. In one example, nanomaterials are permitting the tracking of cells via magnetic resonance imaging (MRI) in clinical trials to assess the efficacy and safety of cellular therapies. In a second example, nanomaterials are acting as drug delivery vehicles for the targeted delivery of therapies to increase efficacy and to reduce side effects. However, there are distinct challenges that must be considered in the development and application of these materials, including careful analysis of the distribution and clearance of nanomaterials and their potential off-target effects. By carefully assessing materials early in their development at the bench, one may be able to move successful approaches through to the clinic more rapidly, which is indeed the goal of the field. For far too many conditions and diseases, the tools we have are less than adequate, and nanomaterials have the potential to fill that void. To realize this potential, investigators must be willing to invest time and resources to develop and to translate these technologies to the point where the risk is low enough that they have real commercial possibilities. Working collaboratively and leveraging resources and experience play important roles in moving technologies through preclinical and clinical testing. It requires incredible dedication of teams of researchers, but the result is new treatments and therapies. PMID- 21604812 TI - All the dope on nanotube films. AB - Transparent, conducting, nanotube thin films have shown promise in a number of applications, the range of which has just been increased significantly. Scientists at the National Renewable Energy Laboratory have done much in recent years to advance the understanding and application of these films. In this issue of ACS Nano, Blackburn and colleagues report their study of the doping power of n type charge transfer donor dopants, finding that hydrazine effects n-type doping approximately comparable in strength to the p-type doping induced by nitric acid. This expands the potential range of applications for such films to electron injection and collection. PMID- 21604810 TI - A boost for the emerging field of RNA nanotechnology. AB - This Nano Focus article highlights recent advances in RNA nanotechnology as presented at the First International Conference of RNA Nanotechnology and Therapeutics, which took place in Cleveland, OH, USA (October 23-25, 2010) ( http://www.eng.uc.edu/nanomedicine/RNA2010/ ), chaired by Peixuan Guo and co chaired by David Rueda and Scott Tenenbaum. The conference was the first of its kind to bring together more than 30 invited speakers in the frontier of RNA nanotechnology from France, Sweden, South Korea, China, and throughout the United States to discuss RNA nanotechnology and its applications. It provided a platform for researchers from academia, government, and the pharmaceutical industry to share existing knowledge, vision, technology, and challenges in the field and promoted collaborations among researchers interested in advancing this emerging scientific discipline. The meeting covered a range of topics, including biophysical and single-molecule approaches for characterization of RNA nanostructures; structure studies on RNA nanoparticles by chemical or biochemical approaches, computation, prediction, and modeling of RNA nanoparticle structures; methods for the assembly of RNA nanoparticles; chemistry for RNA synthesis, conjugation, and labeling; and application of RNA nanoparticles in therapeutics. A special invited talk on the well-established principles of DNA nanotechnology was arranged to provide models for RNA nanotechnology. An Administrator from National Institutes of Health (NIH) National Cancer Institute (NCI) Alliance for Nanotechnology in Cancer discussed the current nanocancer research directions and future funding opportunities at NCI. As indicated by the feedback received from the invited speakers and the meeting participants, this meeting was extremely successful, exciting, and informative, covering many groundbreaking findings, pioneering ideas, and novel discoveries. PMID- 21604813 TI - Effects of cooking on the cell walls (dietary fiber) of 'Scarlet Warren' winter squash ( Cucurbita maxima ) studied by polysaccharide linkage analysis and solid state (13)C NMR. AB - Cell wall polysaccharides of 'Scarlet Warren' winter squash ( Cucurbita maxima ) were investigated before and after thermal processing. Linkage analysis of polysaccharides was done by gas chromatography coupled to mass spectrometry (GC MS). The linkage analysis showed the cell wall polysaccharide compositions of raw and cooked squash were similar. The total pectic polysaccharides (galacturonan, rhamnogalacturonan, arabinan, and arabinogalactan) contents of the cell walls of both raw and cooked squash were 39 mol %. The amounts of pectic polysaccharides and xyloglucan in the cell walls of squash showed little alteration on heating. The cellulose content of the raw and cooked cell walls was relatively high at 47 mol %, whereas the xyloglucan content was low at 4 mol %. Solid-state (13)C nuclear magnetic resonance (NMR) spectroscopy techniques were used to examine the molecular motion of the polysaccharides in the cell walls. The mobility of highly flexible galactan depends on the water content of the sample, but no difference was seen between raw and cooked samples. Likewise, the mobility of semimobile pectic polysaccharides was apparently unaltered by cooking. No change was detected in the rigid cellulose microfibrils on cooking. PMID- 21604814 TI - Metabolic influence of Botrytis cinerea infection in champagne base wine. AB - Botrytis cinerea infection of grape berries leads to changes in the chemical composition of grape and the corresponding wine and, thus, affects wine quality. The metabolic effect of Botrytis infection in Champagne base wine was investigated through a (1)H NMR-based metabolomic approach. Isoleucine, leucine, threonine, valine, arginine, proline, glutamine, gamma-aminobutyric acid (GABA), succinate, malate, citrate, tartarate, fructose, glucose, oligosaccharides, amino acid derivatives, 2,3-butanediol, acetate, glycerol, tyrosine, 2-phenylethanol, trigonelline, and phenylpropanoids in a grape must and wine were identified by (1)H NMR spectroscopy and contributed to metabolic differentiations between healthy and botrytized wines by using multivariate statistical analysis such as principal component analysis (PCA). Lowered levels of glycerol, 2,3-butanediol, succinate, tyrosine, valine derivative, and phenylpropanoids but higher levels of oligosaccharides in the botrytized wines were main discriminant metabolites, demonstrating that Botrytis infection of grape caused the fermentative retardation during alcoholic fermentation because the main metabolites responsible for the differentiation are fermentative products. Moreover, higher levels of several oligosaccharides in the botrytized wines also indicated the less fermentative behavior of yeast in the botrytized wines. This study highlights a metabolomic approach for better understanding of the comprehensive metabolic influences of Botrytis infection of grape berries in Champagne wines. PMID- 21604816 TI - Absolute quantification of human serum transferrin by species-specific isotope dilution laser ablation ICP-MS. AB - We report for the first time the absolute quantification of a metalloprotein separated by nondenaturing gel electrophoresis (GE) using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) in combination with species-specific isotope dilution mass spectrometry (IDMS). The proposed method is based on the use of an isotopically enriched (57)Fe-transferrin complex to quantify natural transferrin (Tf) in human serum samples. First, the saturation process of Tf with natural abundance or isotopically enriched (57)Fe was accomplished by using freshly synthesized Fe-citrate solutions. The stability of the metal-protein complex as well as its stoichiometry was investigated by spectrophotometry and ICP-MS, demonstrating a satisfactory stability over a period of at least one month and a molar ratio Fe:Tf of 1.94 +/- 0.09, which is close to the expected value of 2. The species-specific IDMS method was compared with external calibration using the Fe-Tf (absolute Tf amount between 2 and 10 MUg) and different sample preparation procedures (stained and nonstained gels) as well as two laser ablation strategies (single line ablation in the direction perpendicular or horizontal to the electrophoretic migration) were evaluated. The proposed species-specific GE-LA-ICP-IDMS method was tested for the analysis of a serum certified reference material (ERM-DA470k/IFCC). The results were in good agreement with the certified value with relative standard deviation values in the range of 0.9-2.7% depending on the data treatment procedure used. Furthermore, the analysis time has been drastically reduced in comparison with previous approaches to less than 15 min. The quantification by species-specific GE-LA-ICP IDMS allowed us to obtain accurate and precise results not only by analyzing the protein spot in the middle position but also in the adjacent ablation line to the center. PMID- 21604817 TI - Multifunctional hollow mesoporous silica nanocages for cancer cell detection and the combined chemotherapy and photodynamic therapy. AB - Highly uniform and multifunctional hollow mesoporous silica nanocages that combined excellent properties (good biocompatibility, fluorescence imaging, drug delivery, and dual-mode cancer therapy) in one single system were synthesized. Dye molecules labeled in the nanocages could be used as traceable detectors in fluorescence imaging. A chemotherapeutic drug, doxorubicin (DOX), has been loaded into the nanocages with a high storage capacity due to the large cubic cavities and could be released through the penetrating mesoporous channels in a sustained fashion. Hematoporphyrin molecules were also covalently doped in the nanocages and allowed for photodynamic therapy. More importantly, a cooperative, synergistic therapy combining chemotherapy and photodynamic therapy exhibited high therapeutic efficacy for cancer therapy in vitro. PMID- 21604815 TI - pK(a) coupling at the intein active site: implications for the coordination mechanism of protein splicing with a conserved aspartate. AB - Protein splicing is a robust multistep posttranslational process catalyzed by inteins. In the Mtu RecA intein, a conserved block-F aspartate (D422) coordinates different steps in protein splicing, but the precise mechanism is unclear. Solution NMR shows that D422 has a strikingly high pK(a) of 6.1, two units above the normal pK(a) of aspartate. The elevated pK(a) of D422 is coupled to the depressed pK(a) of another active-site residue, the block-A cysteine (C1). A C1A mutation lowers the D422 pK(a) to normal, while a D422G mutation increases the C1 pK(a) from 7.5 to 8.5. The pK(a) coupling and NMR structure determination demonstrate that protonated D422 serves as a hydrogen bond donor to stabilize the C1 thiolate and promote the N-S acyl shift, the first step of protein splicing. Additionally, in vivo splicing assays with mutations of D422 to Glu, Cys, and Ser show that the deprotonated aspartate is essential for splicing, most likely by deprotonating and activating the downstream nucleophile in transesterification, the second step of protein splicing. We propose that the sequential protonation and deprotonation of the D422 side chain is the coordination mechanism for the first two steps of protein splicing. PMID- 21604818 TI - Seasonal variations in the deoxypodophyllotoxin content and yield of Anthriscus sylvestris L. (Hoffm.) grown in the field and under controlled conditions. AB - Deoxypodophyllotoxin (DPT) is the main lignan in Anthriscus sylvestris . For this study two sets of experiments with 16 plants and seeds, collected from a wide geographical range, were carried out. The DPT content in roots was significantly lower (p < 0.05) when the plants were cultivated in a non-native environment. For field-grown plants the highest DPT content was found in March (second year): 0.15% w/w (dry weight) in roots; 0.03% w/w in aerial parts. For plants grown in the climate room, the highest concentration (0.14% w/w) was observed in April (second year) in the roots and in July (first year) in the aerial parts (0.05% w/w). For the isolation of DPT, roots are the most suitable part. The best harvest times are March (second year) for outdoor plants and April (second year) for indoor plants when height content and adequate biomass give the optimal DPT yield. PMID- 21604819 TI - Strain-driven oxygen deficiency in self-assembled, nanostructured, composite oxide films. AB - Oxide self-assembly is a promising bottom-up approach for fabricating new composite materials at the nanometer length scale. Tailoring the properties of such systems for a wide range of electronic applications depends on the fundamental understanding of the interfaces between the constituent phases. We show that the nanoscale strain modulation in self-assembled systems made of high T(c) superconducting films containing nanocolumns of BaZrO(3) strongly affects the oxygen composition of the superconductor. Our findings explain the observed reduction of the superconducting critical temperature. PMID- 21604820 TI - The role of topical moxifloxacin, a new antibacterial in Europe, in the treatment of bacterial conjunctivitis. AB - This article discusses current practice in the treatment of conjunctivitis and how the use of topical moxifloxacin can increase therapeutic effectiveness, reduce treatment failures and, consequently, be cost effective and reduce the societal burden of the disorder. Current practice and effectiveness data were derived from the literature. Data on healthcare utilization as a result of treatment failure were collected by survey and the cost of treatment was defined using national costings. A decision-analytic model to assess cost effectiveness was developed and the impact on the healthcare budget was calculated to define the health economic impact. Bacterial conjunctivitis represents a significant health problem and accounts for an estimated 1-1.5% of primary-care consultations. The disorder is highly contagious and causes a substantial healthcare and societal burden. Bacterial conjunctivitis is generally self limiting, resolving within 1-2 weeks. However, the use of antibacterials significantly improves clinical and microbiological remission, shortens symptom duration, and enables more effective use of healthcare resources, compared with placebo. From a health economic perspective this benefits the healthcare system and society, since fewer healthcare resources are needed and the adult affected, or the parent/caregiver of the child affected, can return to full work capacity sooner, reducing loss of productivity. Treatment strategies vary significantly between countries. Most patients are first seen in primary care, where 'wait-and see', lubrification and antiseptic or antibacterial treatment is provided. In Europe, when antibacterials are prescribed most general practitioners (GPs) prescribe a broad-spectrum topical antibacterial. The most commonly used drugs are chloramphenicol and fusidic acid, with fluoroquinolones rarely reported as first-line treatment by GPs. At the specialist (ophthalmologist) level, or for second-line treatment at the GP level, topical antibacterials are frequently used. However, in most countries, topical fluoroquinolones, particularly those recently approved by the European Medicines Agency, such as topical levofloxacin and topical moxifloxacin, are rarely used and instead are reserved for use as a last resort. In other parts of the world topical lomefloxacin, gatifloxacin and/or besifloxacin are also available. The strategy of using novel topical fluoroquinolones as a last resort reflects a belief that the use of topical fluoroquinolones may enhance the development of resistance, jeopardizing future availability of antibacterial treatment for ocular infections. In fact, most cases of bacterial resistance arise as a result of systemic treatment. Thus, this concern should not be extrapolated to topical use of fluoroquinolones, which results in antibacterial concentrations at the ocular surface that can significantly exceed mutant prevention concentrations. In addition, with products such as topical moxifloxacin, a dual-step mutation is required for resistance to emerge. Moxifloxacin restricts the selection of resistant mutants, meaning that emergence of resistance is unlikely. The strategy of not using the most effective fluoroquinolones such as topical moxifloxacin may lead to more patients with no improvement or worsening of symptoms, requiring re-intervention, additional examination and new treatment; these outcomes are defined as 'treatment failures'. Treatment failures cause an extra societal burden and increased costs due to the extra healthcare resources required (additional GP/specialist visits, laboratory tests, additional treatment, etc.). Compared with non fluoroquinolones, topical moxifloxacin has a higher potency and faster in vitro 'speed-to-kill'. It has also been shown that, within the fluoroquinolone class, topical moxifloxacin and besifloxacin achieve the highest mean concentrations in conjunctival tissue, have the longest residence times and display favourable area under the concentration-time curve from time zero to 24 hours (AUC(24))/minimum inhibitory concentration ratio required to inhibit the growth of 90% of organisms (MIC(90)) and thus favourable pharmacokinetic/pharmacodynamic characteristics. This can result in reduced time-to-cure and a lower number of treatment failures, leading to better disease management and a healthcare-economic benefit arising from the associated reduction in utilization of healthcare resources. The high potency and mean concentration in conjunctival tissue combined with the long residence time of topical moxifloxacin enables a dosing strategy of three times daily for 5 days. Topical moxifloxacin is also the first ophthalmic antibacterial in Europe provided as a multidose, self-preserved, topical solution, thus avoiding the risk of benzalkonium chloride preservative-related allergic reactions and swelling. In addition, topical moxifloxacin has a near neutral pH (6.8) and is well tolerated by patients. Given the characteristics of the novel topical fluoroquinolones, a change in the healthcare treatment strategy for acute infectious conjunctivitis is to be recommended. Topical application of fluoroquinolones, such as moxifloxacin multidose self-preserved solution, should be considered earlier in the treatment path for conjunctivitis. Notwithstanding the premium price attached to this novel topical antibacterial, use of topical moxifloxacin for bacterial conjunctivitis can be cost effective and even generate total healthcare budget savings by reducing both the costs of managing treatment failures and the use of clinicians' time to manage such failures. PMID- 21604821 TI - Challenges in health state valuation in paediatric economic evaluation: are QALYs contraindicated? AB - With the growth in the use of health economic evaluation to inform healthcare resource allocation decisions, the challenges in applying standard methods to child health have become apparent. A unique limitation is the paucity of child specific preference-based measures. A single, valid, preference-based measure of utility that can be used in children of all ages does not exist. Thus, the ability to derive a QALY for use in cost-utility analysis (CUA) is compromised. This paper presents and discusses existing and novel options for deriving utilities for paediatric health states for use in CUAs. While a direct elicitation may be preferred, a child's ability to complete a standard gamble or time trade-off task is hampered by cognitive and age limitations. The abstract notions contained in indirect instruments such as the EQ-5D and Health Utilities Index may also pose challenges for young children. Novel approaches to overcome these challenges include the development of age-appropriate instruments such as the EQ-5D-Y, the development of new child-specific utility instruments such as the Child Health Utility-9D and the re-calibration of existing adult instruments to derive preference weights for health states from children themselves. For children aged <6 years, researchers have little choice but to use a proxy reporter such as parents. While parents may be reliable reporters for physical activity limitations and externally manifest symptoms, their ability to accurately report on subjective outcomes such as emotion is questionable. Catalogues of utility weights for a range of conditions are increasingly becoming available but retain many of the same limitations as valuing health states from children or from proxies. Given the dynamic relationship in quality of life (QOL) between family members when a child is ill, it seems appropriate to consider a 'family perspective' rather than an individual perspective in child health state valuation. In a collective approach, health state utilities derived from multiple family members may be combined mathematically. Alternatively, in a unitary approach, a single utility estimate may be determined to represent the family's perspective. This may include deriving utilities through parent-child dyad estimation or by using a household model that combines the utility weights of the patient and family members, incorporating reciprocal QOL effects. While these various approaches to child health state valuation represent novel research developments, the measurement challenges and threats to validity persist. Given the importance of non-health benefits to child health, especially in the domains of education and public policy, it may be worthwhile to consider an approach that allows incorporation of externalities to produce a cost-benefit analysis. The use of discrete-choice methods to assess willingness to pay for novel child health interventions holds promise as a means to produce meaningful economic evidence. Regardless of the approach taken, the highest degree of methodological rigour is essential. The increasing attention being paid by health economic researchers to the measurement challenges of paediatric health state valuation can only increase the value of child health economic evidence for decision making. PMID- 21604822 TI - Cost-of-illness studies: a guide to critical evaluation. AB - Cost-of-illness (COI) studies aim to assess the economic burden of health problems on the population overall, and they are conducted for an ever widening range of health conditions and geographical settings. While they attract much interest from public health advocates and healthcare policy makers, inconsistencies in the way in which they are conducted and a lack of transparency in reporting have made interpretation difficult, and have ostensibly limited their usefulness. Yet there is surprisingly little in the literature to assist the non-expert in critically evaluating these studies. This article aims to provide non-expert readers with a straightforward guide to understanding and evaluating traditional COI studies. The intention is to equip a general audience with an understanding of the most important issues that influence the validity of a COI study, and the ability to recognize the most common limitations in such work. PMID- 21604823 TI - Distinguishing sluggish cognitive tempo from attention-deficit/hyperactivity disorder in adults. AB - Researchers who study subtypes of attention-deficit/hyperactivity disorder (ADHD) in children have identified a subset having a sluggish cognitive tempo (SCT) typified by symptoms of daydreaming, mental confusion, sluggish-lethargic behavior, and hypoactivity, among others who differ in many respects from ADHD. No studies have examined the nature and correlates of SCT in adults. This study sought to do so using a general population sample in which those having high levels of SCT symptoms were identified (>=95th percentile) and compared to adults having high levels of ADHD symptoms and adults having both SCT and ADHD symptoms. From a representative sample of 1,249 U.S. adults 18-96 years four groups were created: (a) high levels of SCT but not ADHD (N = 33), (b) high levels of ADHD but not SCT (N = 46), (c) high levels of both SCT and ADHD (N = 39), and (d) the remaining adults as a control group (N = 1,131). As in children, SCT formed a distinct dimension from ADHD symptoms that was unrelated to age, sex, or ethnicity. Adults in both ADHD groups were younger than those with SCT only or control adults. The SCT-only group had less education than the control group, whereas both SCT groups earned less annual income than the control or ADHD-only group. More individuals in the combined group were out of work on disability. In their EF, both SCT groups reported greater difficulties with self-organization and problem solving than controls or the ADHD-only group. Otherwise, the SCT + ADHD group reported significantly greater problems with all other domains of EF than the other groups. But both the SCT-only and ADHD-only groups had significantly more EF difficulties than controls though not differing from each other. A similar pattern was evident on most ratings of psychosocial impairment, except in work and education where SCT was more impairing than ADHD alone and in driving where ADHD was more impairing. SCT contributed unique variance to EF deficits and psychosocial impairment apart from ADHD inattention and hyperactive impulsive symptoms. Results further suggested that a symptom threshold of 5 or more out of 9 along with a requirement of impairment would result in 5.1% of the population as having SCT. It is concluded that SCT may be a separate disorder from ADHD yet with comorbidity occurring in approximately half of all cases of each. PMID- 21604824 TI - Alcohol effects on performance monitoring and adjustment: affect modulation and impairment of evaluative cognitive control. AB - Alcohol is known to impair self-regulatory control of behavior, though mechanisms for this effect remain unclear. Here, we tested the hypothesis that alcohol's reduction of negative affect (NA) is a key mechanism for such impairment. This hypothesis was tested by measuring the amplitude of the error-related negativity (ERN), a component of the event-related brain potential (ERP) posited to reflect the extent to which behavioral control failures are experienced as distressing, while participants completed a laboratory task requiring self-regulatory control. Alcohol reduced both the ERN and error positivity (Pe) components of the ERP following errors and impaired typical posterror behavioral adjustment. Structural equation modeling indicated that effects of alcohol on both the ERN and posterror adjustment were significantly mediated by reductions in NA. Effects of alcohol on Pe amplitude were unrelated to posterror adjustment, however. These findings indicate a role for affect modulation in understanding alcohol's effects on self regulatory impairment and more generally support theories linking the ERN with a distress-related response to control failures. PMID- 21604825 TI - Visuospatial attention in schizophrenia: deficits in broad monitoring. AB - Although selective attention is thought to be impaired in people with schizophrenia (PSZ), prior research has found no deficit in the ability to select one location and withdraw attention from another. PSZ and healthy control subjects (HCS) performed a stimulus detection task in which one, two, or all four peripheral target locations were cued. When one or two locations were cued, both PSZ and HCS responded faster when the target appeared at a cued than uncued location. However, increases in the number of validly cued locations had much more deleterious effects on performance for PSZ than HCS, especially for targets of low contrast whose detection was more dependent on attention. PSZ also responded more slowly in trials with four cued locations relative to trials with one or two invalidly cued locations. Thus, visuospatial attention deficits in schizophrenia arise when broad monitoring is required rather than when attention must be focused narrowly. PMID- 21604826 TI - Peritraumatic dissociation and experiential avoidance as prospective predictors of posttraumatic stress symptoms. AB - Peritraumatic dissociation (PD) and experiential avoidance (EA) have been implicated in the etiology of posttraumatic stress symptomatology (PTSS); however, the function of these two factors in the onset and maintenance of PTSS following a potentially traumatic event is unclear. The temporal relationships between EA, PD, and the four clusters of PTSS proposed by the Simms/Watson dysphoria model (Simms, Watson, & Doebbeling, 2002) were examined in a three-wave prospective investigation of 532 undergraduate women participating in an ongoing longitudinal study at the time of a campus shooting. Path analyses indicated that preshooting EA predicted greater PD, intrusions, and dysphoria symptoms approximately one month postshooting. PD was associated with increased symptomatology across all four clusters 1-month postshooting, while 1-month postshooting EA was associated with higher dysphoria and hyperarousal symptoms eight months postshooting. PD had a significant indirect effect on all four PTSS clusters eight months postshooting via 1-month postshooting symptom reports. The results suggest that both EA and PD show unique influences as risk factors for PTSS following a potentially traumatic event. PMID- 21604828 TI - Reduced automatic motivational orientation towards food in restricting anorexia nervosa. AB - A striking and characteristic feature of the restricting subtype of anorexia nervosa (AN) is that they are extremely successful in regulating their food intake in a destructive manner. A possible explanation for the persistent character of their restricted food intake could be a loss of the motivational saliency of food in restricting AN patients. The present study aimed to investigate motivational orientation for food in the restricting subtype of anorexia nervosa with an indirect performance-based measure and a self-report measure of craving. An indirect approach avoidance task was administered to measure automatic approach tendencies for high-fat and low-fat food in restricting adolescent AN-like patients (n=89) and a group of healthy adolescents (n=76). As predicted, restricting AN-like patients showed less automatic motivational orientation toward food than healthy controls. In a similar vein, AN like patients reported less craving for food than the group of healthy controls. The loss of an automatic motivational orientation toward food together with the deliberate strategy to avoid food might help explain the ability of restricting AN-like patients to regulate their food intake. PMID- 21604827 TI - Are anxiety and depression just as stable as personality during late adolescence? Results from a three-year longitudinal latent variable study. AB - Although considerable evidence shows that affective symptoms and personality traits demonstrate moderate to high relative stabilities during adolescence and early adulthood, there has been little work done to examine differential stability among these constructs or to study the manner in which the stability of these constructs is expressed. The present study used a three-year longitudinal design in an adolescent/young adult sample to examine the stability of depression symptoms, social phobia symptoms, specific phobia symptoms, neuroticism, and extraversion. When considering one-, two-, and three-year durations, anxiety and personality stabilities were generally similar and typically greater than the stability of depression. Comparison of various representations of a latent variable trait-state-occasion (TSO) model revealed that whereas the full TSO model was the best representation for depression, a trait stability model was the most parsimonious of the best-fitting models for the anxiety and personality constructs. Over three years, the percentages of variance explained by the trait component for the anxiety and personality constructs (73-84%) were significantly greater than that explained by the trait component for depression (46%). These findings indicate that symptoms of depression are more episodic in nature, whereas symptoms of anxiety are more similar to personality variables in their expression of stability. PMID- 21604829 TI - Distinguishing general and specific personality disorder features and implications for substance dependence comorbidity. AB - Clinical and population-based samples show high comorbidity between Substance Use Disorders (SUDs) and Axis II Personality Disorders (PDs). However, Axis II disorders are frequently comorbid with each other, and existing research has generally failed to distinguish the extent to which SUD/PD comorbidity is general or specific with respect to both specific types of PDs and specific types of SUDs. We sought to determine whether ostensibly specific comorbid substance dependence-Axis II diagnoses (e.g., alcohol use dependence and borderline personality disorder) are reflective of more pervasive or general personality pathology or whether the comorbidity is specific to individual PDs. Face-to-face interview data from Wave 1 and Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions were analyzed. Participants included 34,653 adults living in households in the United States. We used hierarchical factor models to statistically partition general and specific personality disorder dimensions while simultaneously testing for specific PD-substance dependence relations. Results indicated that substance dependence-Axis II comorbidity is characterized by general (pervasive) pathology and by Cluster B PD pathology over and above the relationship to the general PD factor. Further, these relations between PD factors and substance dependence diagnoses appeared to largely account for the comorbidity among substance dependence diagnoses in the younger but not older participants. Our findings suggest that a failure to consider the general PD factor, which we interpret as reflecting interpersonal dysfunction, can lead to potential mischaracterizations of the nature of certain PD and SUD comorbidities. PMID- 21604830 TI - How drunk am I? Misperceiving one's level of intoxication in the college drinking environment. AB - One effective event-level index that can assist in identifying risky intoxication levels among college students is blood alcohol concentration (BAC). Despite widespread exposure to BAC information, doubt exists as to whether American college students can accurately estimate their own BAC level or drinking behaviors while intoxicated. This study assessed whether students can accurately guesstimate their BAC level and drinking behaviors used to estimate BAC (eBAC) while drinking in social college settings. Participants (N = 225; 56.4% male) consisted of emerging adults attending either a 2- or 4-year college who had at least one alcoholic drink within the 2 hr before assessment. Participants were approached at night when returning from parties and/or alcohol-serving establishments. They completed an initial questionnaire, gave a breath sample to assess breath alcohol content, and then completed an online follow-up questionnaire within 48 hr of baseline assessment. Participants at lower levels of intoxication tended to slightly overestimate their BAC level, while those at higher levels tended to markedly underestimate their BAC level. In addition, discrepancies among breath alcohol content, guesstimated BAC, and eBAC were found as a function of gender. Lastly, differences in eBAC scores did not differ when drinking behaviors were obtained via in vivo versus retrospective methodology. Findings suggest that college students generally have difficulty assessing their BAC level and drinking behaviors while drinking in the college social setting. This study offers particular insight for research relying on estimates of BAC as well as interventions utilizing BAC education. PMID- 21604831 TI - Gambling cognition and subjective well-being as mediators between perceived stress and problem gambling: a cross-cultural study on White and Chinese problem gamblers. AB - This study aimed to delineate various pathways whereby cognitive and emotional vulnerabilities triggered by stress would lead to disruptive gambling. A multiple mediation framework was proposed to specify that gambling cognition and subjective well-being would mediate the influence of perceived stress on problem gambling. The cross-cultural validity of the proposed framework was examined with 132 White gamblers in Australia and 154 Chinese gamblers in China. They completed psychological scales on perceived stress, gambling expectancy bias, gambling refusal efficacy, negative affect, life satisfaction, and problem gambling. Compared to Chinese gamblers, White gamblers reported higher levels of perceived stress, gambling expectancy bias, and problem gambling as well as more pervasive negative affect and lower levels of life satisfaction. Results showed that the proposed multiple mediation framework fit the data better than two alternative plausible models. Life satisfaction and gambling refusal efficacy were two consistent mediators across White and Chinese gamblers. PMID- 21604832 TI - The role of negative urgency and expectancies in problem drinking and disordered eating: testing a model of comorbidity in pathological and at-risk samples. AB - The aim of this study was to test hypotheses derived from a model that explains both the comorbidity of problem drinking and eating disorder symptoms and the difference in risk process between the two disorders. In Study One, the authors examined four personality constructs typically associated with rash action (sensation seeking, lack of planning, lack of persistence, and negative urgency) and disorder-specific expectancies in samples of women with eating disorders, substance dependence disorders, comorbid conditions, and no symptoms (N = 104). Negative urgency, the tendency to act rashly when distressed, differentiated the disordered groups from the control group. In contrast, learned expectancies differentiated among clinical groups. Women with eating disorders endorsed high levels of eating and dieting expectancies and women with substance use disorders endorsed high levels of alcohol expectancies, while comorbid women endorsed high levels of both. In Study Two, this pattern of findings was replicated in a sample of fifth grade girls (N = 905). Girls who had engaged in binge eating, alcohol use, or both had higher levels of negative urgency than asymptomatic girls, and the pattern of outcome expectancy endorsement was disorder specific. Negative urgency may represent a general, personality influence on both eating disordered behaviors and symptoms of alcohol dependence, which, when combined with learned, behavior-specific expectancies, leads to specific addictive behavior patterns. PMID- 21604833 TI - Health and turnover of working mothers after childbirth via the work-family interface: an analysis across time. AB - This study examined organizational levers that impact work-family experiences, participant health, and subsequent turnover. Using a sample of 179 women returning to full-time work 4 months after childbirth, we examined the associations of 3 job resources (job security, skill discretion, and schedule control) with work-to-family enrichment and the associations of 2 job demands (psychological requirements and nonstandard work schedules) with work-to-family conflict. Further, we considered subsequent impact of work-to-family conflict and enrichment on women's health (physical and mental health) 8 months after women returned to work and the impact of health on voluntary turnover 12 months after women returned to work. Having a nonstandard work schedule was directly and positively related to conflict, whereas schedule control buffered the effect of psychological requirements on conflict. Skill discretion and job security, both job resources, directly and positively related to enrichment. Work-to-family conflict was negatively related to both physical and mental health, but work-to family enrichment positively predicted only physical health. Physical health and mental health both negatively influenced turnover. We discuss implications and opportunities for future research. PMID- 21604834 TI - The risky business of dopamine agonists in Parkinson disease and impulse control disorders. AB - Risk-taking behavior is characterized by pursuit of reward in spite of potential negative consequences. Dopamine neurotransmission along the mesocorticolimbic pathway is a potential modulator of risk behavior. In patients with Parkinson's disease (PD), impulse control disorder (ICD) can result from dopaminergic medication use, particularly dopamine agonists (DAA). Behaviors associated with ICD include hypersexuality as well as compulsive gambling, shopping, and eating, and these behaviors are potentially linked to alterations to risk processing. Using the Balloon Analogue Risk Task, we assessed the role of agonist therapy on risk-taking behavior in PD patients with (n = 22) and without (n = 19) active ICD symptoms. Patients performed the task both "on" and "off" DAA. DAA increased risk taking in PD patients with active ICD symptoms, but it did not affect risk behavior of PD controls. DAA dose was also important in explaining risk behavior. Both groups similarly reduced their risk-taking in high compared to low risk conditions and following the occurrence of a negative consequence, suggesting that ICD patients do not necessarily differ in their abilities to process and adjust to some aspects of negative consequences. Our findings suggest dopaminergic augmentation of risk-taking behavior as a potential contributing mechanism for the emergence of ICD in PD patients. PMID- 21604835 TI - Glossopharyngeal nerve transection impairs unconditioned avoidance of diverse bitter stimuli in rats. AB - There is growing evidence of heterogeneity among responses to bitter stimuli at the peripheral, central and behavioral levels. For instance, the glossopharyngeal (GL) nerve and neurons receiving its projections are more responsive to bitter stimuli than the chorda tympani (CT) nerve, and this is particularly true for some bitter stimuli like PROP & cycloheximide that stimulate the GL to a far greater extent. Given this information, we hypothesized that cutting the GL would have a greater effect on behavioral avoidance of cycloheximide and PROP than quinine and denatonium, which also stimulate the CT, albeit to a lesser degree than salts and acids. Forty male SD rats were divided into four surgery groups: bilateral GL transection (GLX), chorda tympani transection (CTX), SHAM surgery, and combined transection (CTX + GLX). Postsurgical avoidance functions were generated for the four bitter stimuli using a brief-access test. GLX significantly compromised avoidance compared to both CTX and SHAM groups for all stimuli (p < .02), while CTX and SHAM groups did not differ. Contrary to our hypothesis, GLX had a greater effect on quinine than cycloheximide (mean shift of 1.02 vs. 0.27 log10 units). Moreover, combined CTX + GLX transection shifted the concentration-response function further than GLX alone for every stimulus except cycloheximide (ps < .03), suggesting that the GSP nerve is capable of maintaining avoidance of this stimulus to a large degree. This hypothesis is supported by reports of cycloheximide-responsive cells with GSP-innervated receptive fields in the NST and PBN. PMID- 21604836 TI - Rumination partially mediates the associations between perceived ethnic discrimination, emotional distress, and aggression. AB - Research suggests that perceived ethnic discrimination is associated with poor psychological and physiological health. Rumination, or perseverative thoughts about negative experiences, may constitute a maladaptive coping strategy that mediates the associations between perceived discrimination, emotional distress, and aggression. Our sample consisted of 170 ethnic minority and 134 White American participants. For ethnic minority participants, we found a pattern of correlations consistent with rumination partially mediating a causal link between perceived discrimination and depressive symptoms, hostility, anger, and aggression. In White participants, by contrast, the significant associations between perceived discrimination and these indices of emotional and behavioral distress were not statistically mediated by rumination. We discuss possible theoretical and clinical implications of these results. PMID- 21604837 TI - Liking is not the opposite of disliking: the functional separability of positive and negative attitudes toward minority groups. AB - Two studies tested the hypotheses that positive and negative attitudes toward minority groups are not interchangeable in predicting positive versus negative behaviors toward those groups. In Study 1, positive attitudes about Latinos were a better predictor of a positive behavior toward Latinos than were negative attitudes or stereotyped positive attitudes. In Study 2, positive attitudes about African Americans were a better predictor of positive behavioral intentions toward that group than were negative attitudes, whereas negative attitudes were better predictors of negative behavioral intentions than were positive attitudes. Taken together, the studies support the perspective that positive and negative attitudes toward minority groups are theoretically and functionally distinct constructs. We conclude that it is important to measure both positive and negative attitudes to understand and predict behaviors toward minority groups. PMID- 21604838 TI - Measuring ethnic identity in the Ethnic Identity Scale and the Multigroup Ethnic Identity Measure-Revised. AB - This study examined the newly developed ethnic identity measures of the Ethnic Identity Scale (EIS) and the Multigroup Ethnic Identity Measure-Revised (MEIM-R) from psychometric and theoretical perspectives. Survey data from 289 counseling students in California were analyzed. Confirmatory factor analyses supported three correlated factors of the EIS (exploration, resolution, and affirmation) and two correlated factors of the MEIM-R (exploration, commitment) for both European American and minority students. Consistent with the theories of Erikson's and Marcia's identity development, the EIS and the MEIM-R nicely depicted (a) Marcia's 4 (2 * 2) identity statuses of diffusion, foreclosure, moratorium, and achievement and (b) the hierarchy of identity statuses in relation to subjective well-being as an indicator of adjustment, especially for minority students. Additionally, European American and minority students revealed differences as to the salience and importance of ethnic identity. Recommendations for using the EIS and the MEIM-R are provided. PMID- 21604839 TI - Race-related stress, racial identity status attitudes, and emotional reactions of Black Americans. AB - The current study explored the relationship between race-related stress, racial identity status attitudes and emotional states among 229 Black Americans. Canonical correlation analyses revealed a shared variate between emotions and racial identity status attitudes in which anger, depression confusion and tension were related positively to Conformity and inversely related to Internalization status attitudes. Implications for research are discussed. PMID- 21604840 TI - Measuring multiple minority stress: the LGBT People of Color Microaggressions Scale. AB - Lesbian, gay, and bisexual individuals who are also racial/ethnic minorities (LGBT-POC) are a multiply marginalized population subject to microaggressions associated with both racism and heterosexism. To date, research on this population has been hampered by the lack of a measurement tool to assess the unique experiences associated with the intersection of these oppressions. To address this gap in the literature, we conducted a three-phase, mixed method empirical study to assess microaggressions among LGBT-POC. The LGBT People of Color Microaggressions Scale is an 18-item self-report scale assessing the unique types of microaggressions experienced by ethnic minority LGBT adults. The measure includes three subscales: (a) Racism in LGBT communities, (b) Heterosexism in Racial/Ethnic Minority Communities, and (c) Racism in Dating and Close Relationships, that are theoretically consistent with prior literature on racial/ethnic minority LGBTs and have strong psychometric properties including internal consistency and construct validity in terms of correlations with measures of psychological distress and LGBT-identity variables. Men scored higher on the LGBT-PCMS than women, lesbians and gay men scored higher than bisexual women and men, and Asian Americans scored higher than African Americans and Latina/os. PMID- 21604841 TI - An item factor analysis and item response theory-based revision of the Everyday Discrimination Scale. AB - The Everyday Discrimination Scale (EDS), a widely used measure of daily perceived discrimination, is purported to be unidimensional, to function well among African Americans, and to have adequate construct validity. Two separate studies and data sources were used to examine and cross-validate the psychometric properties of the EDS. In Study 1, an exploratory factor analysis was conducted on a sample of African American law students (N = 589), providing strong evidence of local dependence, or nuisance multidimensionality within the EDS. In Study 2, a separate nationally representative community sample (N = 3,527) was used to model the identified local dependence in an item factor analysis (i.e., bifactor model). Next, item response theory (IRT) calibrations were conducted to obtain item parameters. A five-item, revised-EDS was then tested for gender differential item functioning (in an IRT framework). Based on these analyses, a summed score to IRT-scaled score translation table is provided for the revised-EDS. Our results indicate that the revised-EDS is unidimensional, with minimal differential item functioning, and retains predictive validity consistent with the original scale. PMID- 21604842 TI - Asymmetrical effects of contact between minority groups: Asian and Black students in a small college. AB - Recent meta-analyses of intergroup contact research revealed that majority members' attitudes toward minorities are improved to a greater degree by contact compared to those of minority members (Tropp & Pettigrew, 2005). While previous research focused on contact between majority and minority groups, this study explored effects of intergroup contact between two minority groups that differ in status: Black and Asian college students. Because of different stereotypes and social status, the college experiences of the two groups were expected to differ in the extent to which they felt their group was respected by others (public regard). A survey conducted with 104 Black and Asian American students in a small, Midwestern liberal arts college demonstrated that the two groups differed in public regard, which led to differences in attitudes toward the majority Whites, contact with Whites, experiences of discrimination, and trust in college authorities. Further, while contact with Black students was positively associated with more favorable attitudes toward Blacks for Asians (higher status minority), contact with Asian students was not related to attitudes toward Asians for Blacks (lower status minority). The role of public regard and attitudes toward the majority as potential moderators of the relationship between contact with Asians and Blacks' attitudes toward Asians were explored. Implications for multicultural solidarity between targeted groups were discussed. PMID- 21604843 TI - Minority stress and college persistence attitudes among African American, Asian American, and Latino students: perception of university environment as a mediator. AB - We examined whether perception of university environment mediated the association between minority status stress and college persistence attitudes after controlling for perceived general stress. Participants were 160 Asian American, African American, and Latino students who attended a predominantly White university. Results of a path model analysis showed that university environment was a significant mediator for the association between minority status stress and college persistence attitudes. Additionally, minority status stress was distinct from perceived general stress. Finally, the results from a multiple-group comparison indicated that the magnitude of the mediation effect was invariant across Asian American, African American, and Latino college students, thus supporting the generalizability of the mediation model. PMID- 21604844 TI - Ethnicity matters for undergraduate majors in challenges, experiences, and perceptions of psychology. AB - In this investigation of a national sample of undergraduate psychology majors, we directly compare the experiences and perceptions of students of color with those of European Americans. Our aim was to identify factors that might contribute to our discipline's educational pipeline, in which the relative lack of ethnic diversity is a recognized problem. We found that students of color and European American majors are similar in a number of ways but also different in others. Students of color are challenged by less encouragement from and interaction with faculty, perceive a lack of respect, and wish to see more attention to diversity in curriculum, research, faculty, and textbooks. It is not surprising that students of color were significantly less satisfied than European Americans with their studies in psychology. PMID- 21604845 TI - Language and the bicultural dialectical self. AB - We examined the effect of language priming on naive dialecticism, with special attention paid to effects on dialectical beliefs about the self. European Americans responding in English and bilingual Chinese responding in either Chinese or English completed several measures designed to tap dialectical thinking and dialectical self-perceptions, including tolerance of contradiction, change in thoughts and behavior over time and context, holistic beliefs, and self concept inconsistency. As expected, those answering in Chinese reported greater dialecticism on most of these measures, relative to those responding in English. European American responses were highly similar to those of bilinguals responding in English. We discuss advantages of language priming and offer directions for future research. PMID- 21604846 TI - The impact of mental health problems and religiosity on African-American girls' HIV-risk. AB - We investigated the relationship between religiosity, mental health problems, and two sexual risk behaviors-condom use and number of partners. Participants were 80 sexually active African American girls in psychiatric care and their caregivers. Results indicated differential relationships, depending on parent versus youth report. Mother's religiosity was positively related to girls' condom use and not to girls' number of partners. Controlling for other predictors in the models, mother's religiosity explained as much as 15% of the variance in girls' condom use. Whereas parent and adolescent reports of girls' depression/anxiety and rule breaking were positively associated with number of partners, reports of aggression were associated with having fewer partners. Neither parent nor youth reports of girls' mental health problems were associated with condom use. Controlling for other predictors in the models, girls' mental health problems accounted for as much as 31% of the variance in number of partners. Findings underscore the importance of adopting an ecological framework to understand both the risk and promotive factors for sexual risk taking among troubled girls. The roles of specific aspects of psychopathology and religiosity in relation to sexual risk behavior among African American girls in psychiatric care are discussed. PMID- 21604849 TI - Evolutionary persistence of chemically elicited ophiophagous antipredator responses in gartersnakes (Thamnophis sirtalis). AB - The ability to detect and respond to potential predators is key for the survival of individuals, but this ability is sometimes lost via relaxation of antipredator behavior when prey species are separated from predators. Adult and predator-naive neonate gartersnakes (Thamnophis sirtalis) from mainland and insular sites where they do and do not occur with ophiophagous (snake-eating) snakes were tested to determine if responses to such predators have been lost, reduced, or retained, and what might be causing differences in such responses. Our data indicate that, overall, adult snakes from populations syntopic with ophiophagous milksnakes are more responsive to chemical stimuli from milksnakes than adults from areas where they are not syntopic with milksnakes, whereas there were few differences with neonate gartersnakes. Experiments with neonates with or without periodic ophiophagous snake chemical experience over several weeks showed that gartersnakes with such experience became more responsive to ophiophagous cues rather than habituating to them. Such evidence of both genetic and experiential factors underlying the antipredator responses to ophiophagous snakes indicates that antipredator responses have persisted despite separation of predator and prey. PMID- 21604850 TI - Win-shift and win-stay learning in the rainbow lorikeet (Trichoglossus haematodus). AB - The tendency to win-shift (to better learn to avoid, rather than return to, recently rewarded locations) has been demonstrated in a variety of nectarivorous birds and in honeybees. It is hypothesized to be a cognitive adaptation to the depleting nature of nectar. In the present study we report the first attempt to test for a win-shift bias in a nectarivorous parrot, the rainbow lorikeet (Trichoglossus hematodus). This species differs from others tested for a win shift bias in that it is a facultative, rather than an obligate, nectarivore. We tested a captive-reared population of the birds on a shift/stay task at long and short retention intervals. The data show no evidence of either a win-shift or a win-stay bias. The birds demonstrated efficient spatial search ability and above chance performance for both shift and stay contingencies at long and short delays. These data suggest that an innate tendency to win-shift may not be present in all avian nectarivores, or that the role experience plays in shaping such behaviors is different for different species. PMID- 21604851 TI - What you see is what you get--reloaded: can jackdaws (Corvus monedula) find hidden food through exclusion? AB - Choice by exclusion, that is, the ability to base the choice of a target on the rejection of potential alternatives, is becoming increasingly interesting for comparative cognition research. Recently, ravens have been shown to solve an exclusion task and it had been suggested that this ability might benefit ravens in a food-caching context. To investigate this possibility, the raven study was replicated with a closely related, but noncaching, species, the jackdaw (Corvus monedula). In the first test, the birds had to find food hidden in one of two differently shaped tubes. The results suggest that the jackdaws found the food through intensive search behavior, with little evidence for exclusion abilities. In a follow-up experiment, the tubes were replaced by cups, and before the birds made a choice, one of the cups was lifted to inform them about its content. In a final task, this procedure was modified to control for the influence of local enhancement. In both experiments, the jackdaws were successful only if they had seen the food before. These findings are in contrast to the previous results on ravens and support the idea that exclusion abilities may have evolved as specific adaptations to food caching. PMID- 21604852 TI - Organization of mating behavior in male hamsters (Mesocricetus auratus). AB - Factor analysis was applied to standard measures of sexual behavior in 73 male hamsters (Mesocricetus auratus) as they interacted with hormone-primed females. The results suggest that 5 factors, or conceptual mechanisms, function in the organization of the behaviors observed in the first 2 copulatory series. Of these, the 3 that relate to the behaviors in the first copulatory series were compared to those emerging from prior analyses of other rodents. These comparisons revealed similarities and differences in factor structure across species. Whereas all of these analyses identify factors related to the initiation and efficiency of copulatory behavior, hamsters seem to differ from other species in the measures that best define these factors. In addition, the copulatory rate factor that has been prominent in previous analyses of rats seems to be absent in hamsters. These results suggest that male sexual behavior in hamsters is organized differently from that in other rodents. In more general terms, they suggest that even species with generally similar copulatory patterns can show significant differences in behavioral organization, in turn suggesting the need for additional factor analytic studies to better establish the extent of these species differences. PMID- 21604853 TI - Association, inhibition, and object permanence in dogs' (Canis familiaris) spatial search. AB - The relative role of associative processes and the use of explicit cues about object location in search behavior in dogs (Canis familiaris) was assessed by using a spatial binary discrimination reversal paradigm in which reversal conditions featured: (1) a previously rewarded location and a novel location, (2) a previously nonrewarded location and a novel location, or (3) a previously rewarded location and a previously nonrewarded location. Rule mediated learning predicts a similar performance in these different reversal conditions whereas associative learning predicts the worst performance in Condition 3. Evidence for an associative control of search emerged when no explicit cues about food location were provided (Experiment 1) but also when dogs witnessed the hiding of food in the reversal trials (Experiment 2) and when they did so in both the prereversal and the reversal trials (Experiment 3). Nevertheless, dogs performed better in the prereversal phase of Experiment 3 indicating that their search could be informed by the knowledge of the food location. Experiment 4 confirmed the results of Experiments 1 and 2, under a different arrangement of search locations. We conclude that knowledge about object location guides search behavior in dogs but it cannot override associative processes. PMID- 21604854 TI - Chimpanzee (Pan troglodytes) relational matching: playing by their own (analogical) rules. AB - Chimpanzees (Pan troglodytes) have been known to exhibit rudimentary abilities in analogical reasoning (Flemming, Beran, Thompson, Kleider, & Washburn, 2008; Gillian, Premack, & Woodruff, 1981; Haun & Call, 2009; Thompson & Oden, 2000; Thompson, Oden, & Boysen, 1997). With a wide array of individual differences, little can be concluded about the species' capacity for analogies, much less their strategies employed for solving such problems. In this study, we examined analogical strategies in 3 chimpanzees using a 3-dimensional search task (e.g., Kennedy & Fragaszy, 2008). Food items were hidden under 1 of 2 or 3 plastic cups of varying sizes. Subsequently, chimpanzees searched for food under the cup of the same relative size in their own set of cups--reasoning by analogy. Two chimpanzees initially appeared to fail the first relational phase of the task. Meta-analyses revealed, however, that they were instead using a secondary strategy not rewarded by the contingencies of the task--choosing on the basis of the same relative position in the sample. Although this was not the intended strategy of the task, it was nonetheless analogical. In subsequent phases of the task, chimpanzees eventually learned to shift their analogical reasoning strategy to match the reward contingencies of the task and successfully choose on the basis of relative size. This evidence not only provides support for the analogical ape hypothesis (Thompson & Oden, 2000), but also exemplifies how foundational conceptually mediated analogical behavior may be for the chimpanzee. PMID- 21604855 TI - Physical intuitions about support relations in monkeys (Macaca fuscata) and apes (Pan troglodytes). AB - Nonhuman primates, like humans, have demonstrated various physical intuitions. Cacchione and Krist (2004) examined chimpanzees' intuitions about support relations with the violation-of-expectation task. They reported that the chimpanzees possessed intuitions about support, but their intuitions differed from those of humans in part; they were sensitive to "contact/no-contact" and "amount of contact" but not "type of contact" rule. To further explore intuitions about support in nonhuman primates, we conducted similar experiments on monkeys (Japanese monkeys) and apes (chimpanzees). In three experiments, we presented physically possible and impossible events of different support relations to the participants and measured their looking times. The results reveal that the chimpanzees and monkeys detect the violations of "contact/no-contact" and "amount of contact" but not "type of contact" variable. Therefore, the apes and monkeys possess similar intuitions; however, these intuitions differ in part from those of humans. The present study provides new and corroborative evidence of intuitions about support in nonhuman primates. However, this again leads to the question of distinctive understanding about support relations among primate species. PMID- 21604856 TI - The development of preschool children's (Homo sapiens) uses of objects and their role in peer group centrality. AB - The ways in which objects were used by preschool children (Homo sapiens) was examined by directly observing them across one school year. In the first objective we documented the relative occurrence of different forms of object use and their developmental growth curves. Second, we examined the role of different types of object use, as well as novel and varied uses of objects, in predicting peer group centrality. Results indicated that noninstrumental object play was the most frequently observed category, followed by tool use, exploration, and construction; sex moderated the growth curve of children's exploration. Noninstrumental object play, not other types of object use, was significantly related to novel and varied object uses and only the latter category predicted peer group centrality. Results are discussed in terms of the social transmission of novel object use. PMID- 21604857 TI - Visual discrimination and reversal learning in rough-necked monitor lizards (Varanus rudicollis). AB - Reptile learning has been studied with a variety of methods and has included numerous species. However, research on learning in lizards has generally focused on spatial memory and has been studied in only a few species. This study explored visual discrimination in two rough-necked monitors (Varanus rudicollis). Subjects were trained to discriminate between black and white stimuli. Both subjects learned an initial discrimination task as well as two reversals, with the second reversal requiring fewer sessions than the first. This reduction in trials required for reversal acquisition provides evidence for behavioral flexibility in the monitor lizard genus. PMID- 21604858 TI - Valuing clients' perspective and the effects on the therapeutic alliance: a randomized controlled study of an adjunctive instruction. AB - The patterns of growth and development of the therapeutic alliance over the course of therapy have been of continued interest to psychotherapy researchers. The purpose of this study was to investigate whether a simple institutional metacommunication intervention with clients had an effect on the development of the alliance. This adjunctive instruction involved inviting therapy clients to take a proactive role in their treatment by encouraging feedback to their therapist about various aspects of the therapy process. In this randomized controlled study (N = 94), clients were assigned to 1 of 2 conditions: (a) an institutional adjunctive instruction condition in which patients were contacted by clinic personnel at the beginning of the remediation phase (Session 5) and encouraged to take a proactive role in their treatment and (b) a control condition that contained no institutional adjunctive instruction. Between condition differences in the alliance were tested, controlling for baseline influences and the early therapeutic alliance. Clients' postsession reports from Sessions 1 to 24 indicated that the adjunctive instruction increased the alliance over the course of therapy vis-a-vis the control condition. The adjunctive instruction appeared to have fostered clients' evaluation of their therapists' interest in their welfare. The results indicate that interventions, even brief or subtle, can produce lasting benefits in the alliance when targeted at specific psychological processes. Systematic metacommunication from the institutional level appeared to reinforce clients' therapeutic alliance with their therapists in individual treatment. PMID- 21604859 TI - U.S. Muslim women and body image: links among objectification theory constructs and the hijab. AB - This study tested tenets of objectification theory and explored the role of the hijab in body image and eating disorder symptoms with a sample of 118 Muslim women in the United States. Results from a path analysis indicated that individual differences in wearing the hijab were related negatively with reported sexual objectification experiences. Sexual objectification experiences, in turn, had significant positive indirect relations with body surveillance, body shame, and eating disorder symptoms, primarily through the mediating role of internalization. Internalization of cultural standards of beauty also had a significant positive direct relation with body shame and significant positive direct and indirect relations with eating disorder symptoms. By contrast, the direct and indirect relations of body surveillance were significant only when the role of internalization was constrained to 0 (i.e., eliminated), suggesting that internalization of cultural standards of beauty subsumed the hypothesized role of body surveillance in the model. Taken together, these results support some of the tenets of objectification theory with a sample of U.S. Muslim women, point to the importance of internalization of dominant cultural standards of beauty within that framework, and suggest the utility of considering individual differences in wearing the hijab among U.S. Muslim women. PMID- 21604860 TI - Culturally adapted psychotherapy and the legitimacy of myth: a direct-comparison meta-analysis. AB - Psychotherapy is a culturally encapsulated healing practice that is created from and dedicated to specific cultural contexts (Frank & Frank, 1993; Wampold, 2007; Wrenn, 1962). Consequently, conventional psychotherapy is a practice most suitable for dominant cultural groups within North America and Western Europe but may be culturally incongruent with the values and worldviews of ethnic and racial minority groups (e.g., D. W. Sue, Arredondo, & McDavis, 1992). Culturally adapted psychotherapy has been reported in a previous meta-analysis as more effective for ethnic and racial minorities than a set of heterogeneous control conditions (Griner & Smith, 2006), but the relative efficacy of culturally adapted psychotherapy versus unadapted, bona fide psychotherapy remains unestablished. Furthermore, one particular form of adaptation involving the explanation of illness-known in an anthropological context as the illness myth of universal healing practices (Frank & Frank, 1993)-may be responsible for the differences in outcomes between adapted and unadapted treatments for ethnic and racial minority clients. The present multilevel-model, direct-comparison meta-analysis of published and unpublished studies confirms that culturally adapted psychotherapy is more effective than unadapted, bona fide psychotherapy by d = 0.32 for primary measures of psychological functioning. Adaptation of the illness myth was the sole moderator of superior outcomes via culturally adapted psychotherapy (d = 0.21). Implications of myth adaptation in culturally adapted psychotherapy for future research, training, and practice are discussed. PMID- 21604861 TI - Working through: in-session processes that promote between-session thoughts and activities. AB - This study examined whether clients' ratings of the working alliance as well as their perception of cognitive-behavioral (CB) and psychodynamic-interpersonal (PI) techniques (delivered by therapists who used both) were associated with clients' intersession processes (i.e., their thoughts about therapy and therapeutic activity between sessions). Seventy-five clients who were currently in therapy at a large university counseling center participated in the current study. Multilevel regression analyses demonstrated that alliance and clients' perceptions of their therapists' use of PI techniques were positively associated with clients' general thoughts about therapy between sessions. Also, stronger alliances were associated with more therapeutic activities between sessions and more positive (and less negative) thoughts about therapy between sessions. In addition, clients at later sessions who described their therapists as using more PI techniques also reported engaging in more therapeutic activities between sessions (after controlling for the variance in the other variables, such as use of CB techniques). Clients' perceptions of their therapists' use of CB techniques in the most recent session were not related to thinking about therapy or therapeutic activities after controlling for the variance in the other variables. PMID- 21604862 TI - Impressions of psychotherapists' offices. AB - For counseling settings, research suggests that softness, personalization, and order might affect the experience and the perceived expertness, trustworthiness, and social attractiveness of the therapist. This article discusses exploratory studies on college students' perception of the counseling office environment and whether the likely client experience was associated with the softness/personalization and order of the office. As stimuli, the studies used 30 color photographs of psychotherapists' offices viewed from the client's perspective. After obtaining ratings of the characteristics of each office, we obtained ratings from different groups of students of the quality of care and comfort expected in each office (Study 1) and how qualified, bold, and friendly the therapist in the office would be (Study 2). Additional studies examined the likelihood of choosing a therapist based on the office, and the first thought or feeling that came to mind about the office, the therapist, and the patient experience. There were strong correlations in response between groups (by whether they had experienced therapy; their level in school; their gender; and their major, location, and school size). The quality of care, comfort, therapist boldness, qualifications of the therapist, and the likelihood that one would choose a therapist based on the office improved with increases in the office's softness/personalization and order. Friendliness improved with increases in softness/personalization. The office choices, open-ended responses, and reported reasons for the ratings confirmed the importance of softness (comfort) and order. Research should test longer term exposure and behavior. PMID- 21604863 TI - Preschoolers distribute scarce resources according to the moral valence of recipients' previous actions. AB - Children aged 3 years and 41/2 years old watched a puppet, struggling to achieve goals, who was helped by a 2nd puppet and violently hindered by a 3rd. The children then distributed wooden biscuits between the helper and hinderer. In Experiment 1, when distributing a small odd number of biscuits, 41/2-year-olds (N = 16) almost always gave more to the helper. Children verbally justified their unequal distributions by reference to the helper's prosocial behavior or the hinderer's antisocial behavior. In Experiment 2, when biscuits were more plentiful, 41/2-year-olds (N = 16) usually gave equal numbers to helper and hinderer, indicating that 41/2-year-olds usually preferred not to distribute unequally unless forced to by resource scarcity. Three-year-olds (N = 16 in Experiment 1, N = 20 in Experiment 3) gave more biscuits equally often to the helper and to the hinderer. In many cases, this was because they were confused as to the identities and actions of the puppets, possibly because they were shocked by the hinderer's actions. Two fundamental moral behaviors are therefore demonstrated in young preschoolers: indirect reciprocity of morally valenced acts and a preference for equality when distributing resources, although the cognitive bases for these behaviors remain unclear. These results join other recent studies in demonstrating that the seeds of complex moral understanding and behavior are found early in development. PMID- 21604864 TI - Visual experience influences 12-month-old infants' perception of goal-directed actions of others. AB - In the present study, we investigated whether infants' own visual experiences affected their perception of the visual status of others engaging in goal directed actions. In Experiment 1, infants viewed video clips of successful and failed goal-directed actions performed by a blindfolded adult, with half the infants having previously experienced being blindfolded. The results showed that 12-month-old infants who were previously blindfolded preferred to look longer at the demonstrator's successful actions, whereas no such preference was observed in 8-month-old infants. In Experiment 2, infants watched the same 2 actions when the adult demonstrator was not blindfolded. The responses of 12-month-old infants were the opposite of those observed in Experiment 1: they showed a preference for the failed actions. These findings suggest that previous experience influenced the subsequent perception of others' goal-directed actions in the 12-month-old infants. We favor the interpretation that the preference for the successful actions in the 12-months-old infants provided with blindfolded experience demonstrates the influence of perceptual experience on considering the visual status of others engaging in goal-directed actions. PMID- 21604865 TI - Adolescents' implicit theories predict desire for vengeance after peer conflicts: correlational and experimental evidence. AB - Why do some adolescents respond to interpersonal conflicts vengefully, whereas others seek more positive solutions? Three studies investigated the role of implicit theories of personality in predicting violent or vengeful responses to peer conflicts among adolescents in Grades 9 and 10. They showed that a greater belief that traits are fixed (an entity theory) predicted a stronger desire for revenge after a variety of recalled peer conflicts (Study 1) and after a hypothetical conflict that specifically involved bullying (Study 2). Study 3 experimentally induced a belief in the potential for change (an incremental theory), which resulted in a reduced desire to seek revenge. This effect was mediated by changes in bad-person attributions about the perpetrators, feelings of shame and hatred, and the belief that vengeful ideation is an effective emotion-regulation strategy. Together, the findings illuminate the social cognitive processes underlying reactions to conflict and suggest potential avenues for reducing violent retaliation in adolescents. PMID- 21604866 TI - Elevated social anxiety among early maturing girls. AB - Adolescence is a key period in terms of the development of anxiety psychopathology. An emerging literature suggests that early pubertal maturation is associated with enhanced vulnerability for anxiety symptomatology, although few studies have examined this association with regard to social anxiety. Accordingly, the current study was designed to further elucidate the relation between pubertal timing and social anxiety, with a focus on clarifying the role of gender. Participants were 138 adolescents (ages 12-17 years) recruited from the general community. Level of social anxiety was examined as a function of gender and within-sample pubertal timing. As expected, early maturing girls evidenced significantly higher social anxiety, compared with on-time girls and early maturing boys, and no other differences were found as a function of gender or developmental timing. Findings and future directions are discussed in terms of forwarding developmentally sensitive models of social anxiety etiology and prevention. PMID- 21604867 TI - When people want what others have: the impulsive side of envious desire. AB - Envy is the unpleasant emotion that can arise when people are exposed to others with superior possessions. Common wisdom and scholarly opinion suggest that when people experience envy they may be motivated to obtain the others' superior possession. Despite the vast interpersonal, societal, and economical consequences attributed to this potential aspect of envious responding, experimental demonstrations of the affective and behavioral consequences of envy-inducing situations are scarce. We propose that social comparisons with better-off others trigger an impulsive envious response that entails a behavioral tendency to strive for their superior good. However, given that the experience of envy is painful, self-threatening, and met with social disapproval, people typically attempt to control their envious reactions. Doing so requires self-control capacities, so that envious reactions may only become apparent if self-control is taxed. In line with these predictions, four experiments show that only when self control resources are taxed, upward comparisons elicit envy paired with an increased willingness to pay for, to spontaneously purchase and to impulsively approach the superior good. PMID- 21604868 TI - The role of fear and expectancies in capture of covert attention by spiders. AB - Fear-related stimuli are often prioritized during visual selection but it remains unclear whether capture by salient objects is more likely to occur when individuals fear those objects. In this study, participants with high and low fear of spiders searched for a circle while on some trials a completely irrelevant fear-related (spider) or neutral distractor (butterfly/leaf) was presented simultaneously in the display. Our results show that when you fear spiders and you are not sure whether a spider is going to be present, then any salient distractor (i.e., a butterfly) grabs your attention, suggesting that mere expectation of a spider triggered compulsory monitoring of all irrelevant stimuli. However, neutral stimuli did not grab attention when high spider fearful people knew that a spider could not be present during a block of trials, treating the neutral stimuli just as the low spider fearful people do. Our results show that people that fear spiders inspect potential spider-containing locations in a compulsory fashion even though directing attention to this location is completely irrelevant for the task. Reduction of capture can only be accomplished when people that fear spiders do not expect a spider to be present. PMID- 21604869 TI - Seeing yourself helps you see others. AB - It has been proposed that self-face representations are involved in interpreting facial emotions of others. We experimentally primed participants' self-face representations. In Study 1, we assessed eye tracking patterns and performance on a facial emotion discrimination task, and in Study 2, we assessed emotion ratings between self and nonself groups. Results show that experimental priming of self face representations increases visual exploration of faces, facilitates the speed of facial expression processing, and increases the emotional distance between expressions. These findings suggest that the ability to interpret facial expressions of others is intimately associated with the representations we have of our own faces. PMID- 21604870 TI - Happy guys finish last: the impact of emotion expressions on sexual attraction. AB - This research examined the relative sexual attractiveness of individuals showing emotion expressions of happiness, pride, and shame compared with a neutral control. Across two studies using different images and samples ranging broadly in age (total N = 1041), a large gender difference emerged in the sexual attractiveness of happy displays: happiness was the most attractive female emotion expression, and one of the least attractive in males. In contrast, pride showed the reverse pattern; it was the most attractive male expression, and one of the least attractive in women. Shame displays were relatively attractive in both genders, and, among younger adult women viewers, male shame was more attractive than male happiness, and not substantially less than male pride. Effects were largely consistent with evolutionary and socio-cultural-norm accounts. Overall, this research provides the first evidence that distinct emotion expressions have divergent effects on sexual attractiveness, which vary by gender but largely hold across age. PMID- 21604872 TI - Attentional selection is biased toward mood-congruent stimuli. AB - One can exert significant volitional control over the attentional filter so that stimuli that are consistent with one's explicit goals are more likely to receive attention and become part of one's conscious experience. Here we pair a mood induction procedure with an inattentional blindness task to show that one's current mood has a similar influence on attention. A positive, negative, or neutral mood manipulation was followed by an attentionally demanding multiple object tracking task. During the tracking task, participants were more likely to notice an unexpected face when its emotional expression was congruent with participants' mood. This was particularly true for the frowning face, which was detected almost exclusively by participants in the sad mood induction condition. This attentional bias toward mood-congruent stimuli provides evidence that one's temporary mood can influence the attentional filter, thereby affecting the information that one extracts from, and how one experiences the world. PMID- 21604871 TI - The substitutability of physical and social warmth in daily life. AB - Classic and contemporary research on person perception has demonstrated the paramount importance of interpersonal warmth. Recent research on embodied cognition has shown that feelings of social warmth or coldness can be induced by experiences of physical warmth or coldness, and vice versa. Here we show that people tend to self-regulate their feelings of social warmth through applications of physical warmth, apparently without explicit awareness of doing so. In Study 1, higher scores on a measure of chronic loneliness (social coldness) were associated with an increased tendency to take warm baths or showers. In Study 2, a physical coldness manipulation significantly increased feelings of loneliness. In Study 3, needs for social affiliation and for emotion regulation, triggered by recall of a past rejection experience, were subsequently eliminated by an interpolated physical warmth experience. Study 4 provided evidence that people are not explicitly aware of the relationship between physical and social warmth (coldness), as they do not consider a target person who often bathes to be any lonelier than one who does not, with all else being equal. Together, these findings suggest that physical and social warmth are to some extent substitutable in daily life and that this substitution reflects an unconscious self-regulatory mechanism. PMID- 21604873 TI - Turning shame inside-out: "humiliated fury" in young adolescents. AB - The term "humiliated fury" refers to the anger people can experience when they are shamed. In Study 1, participants were randomly exposed to a prototypical shameful event or control event, and their self-reported feelings of anger were measured. In Study 2, participants reported each school day, for 2 weeks, the shameful events they experienced. They also nominated classmates who got angry each day. Narcissism was treated as a potential moderator in both studies. As predicted, shameful events made children angry, especially more narcissistic children. Boys with high narcissism scores were especially likely to express their anger after being shamed. These results corroborate clinical theory holding that shameful events can initiate instances of humiliated fury. PMID- 21604874 TI - Compatibility between tones, head movements, and facial expressions. AB - The study tests the hypothesis of an embodied associative triangle among relative tone pitch (i.e., high or low tones), vertical movement, and facial emotion. In particular, it is tested whether relative pitch automatically activates facial expressions of happiness and anger as well as vertical head movements. Results show robust congruency effects: happiness expressions and upward head tilts are imitated faster when paired with high rather than low tones, while anger expressions and downward head tilts are imitated faster when paired with low rather than high tones. The results add to the growing evidence favoring an embodiment account that emphasizes multimodal representations as the basis of cognition, emotion, and action. PMID- 21604875 TI - Detection of emotional faces is modulated by the direction of eye gaze. AB - Emotionally expressive faces have shown enhanced detectability over neutral faces, but little is known about the effect of eye gaze on detecting the presence of emotional faces. Emotional expressions and gaze direction are both cues to the intentions of another person, and gaze direction has been shown to affect recognition accuracy and perceived intensity of emotional faces. The current study showed that fearful faces were detected more frequently with an averted gaze than with a direct gaze in an attentional blink task, whereas angry and happy faces were detected more frequently with a direct gaze than with an averted gaze. The results are in line with the shared signal hypothesis and appraisal theory and suggest that selection for awareness was based on a rapid evaluation of the intentions of another person as conveyed by their facial expression and gaze direction. PMID- 21604876 TI - The role of adherence in the relationship between conscientiousness and perceived health. AB - OBJECTIVE: Conscientious individuals experience better physical health, in part because of their greater propensity to behave in ways that maintain wellness. In the current study we examined whether and how adherence mediates the relation between conscientiousness and physical health. Moreover, we examined whether these effects differed for adhering to doctor's orders (doctor adherence) versus adhering to medication regimens (medication adherence), as the latter is likely more relevant for older adults' health. METHOD: A nationwide sample of adults (N = 2,136, Mage = 51 years) completed personality and adherence measures, in addition to a self-report measure of perceived general health, in an online survey. Correlational analyses were performed to examine the basic relations between the constructs of interest. A bootstrapping approach was employed for examining whether the indirect effect through adherence was conditional on age. RESULTS: Doctor adherence partially mediated the relation between conscientiousness and perceived health across adulthood. However, the indirect effect of medication adherence was conditional on age, insofar that medication adherence mediated the link between conscientiousness and perceived health only for older adults in the sample (i.e., those around age 51 and over). CONCLUSION: These results suggest that although conscientious individuals report higher levels of both doctor and medication adherence, the role of adherence in explaining the link between conscientiousness and health may differ across adulthood. PMID- 21604877 TI - Goal disengagement, functional disability, and depressive symptoms in old age. AB - OBJECTIVES: This longitudinal study examined the associations between older adults' goal adjustment capacities (i.e., goal disengagement and goal reengagement capacities), functional disability, and depressive symptoms. It was expected that goal disengagement capacities would prevent an adverse effect of heightened functional disability on increases in depressive symptoms. METHOD: Multivariate regression analyses were conducted, using four waves of data from a six-year longitudinal study of 135 community-dwelling older adults (>60 years old). RESULTS: Depressive symptoms and functionality disability increased over time. Moreover, poor goal disengagement capacities and high levels of functional disability forecasted six-year increases in depressive symptoms. Finally, goal disengagement buffered the association of functional disability with increases in depressive symptoms. No associations were found for goal reengagement capacities. CONCLUSION: The findings suggest an adaptive role for goal disengagement capacities in older adulthood. When confronted with increases in functional disability, the capacity to withdraw effort and commitment from unattainable goals can help protect older adults from experiencing long-term increases in depressive symptoms. PMID- 21604878 TI - Childhood intelligence and midlife inflammatory and hemostatic biomarkers: the National Child Development Study (1958) cohort. AB - OBJECTIVE: In a prospective cohort study the authors examined associations between childhood intelligence at age 11 and inflammatory and hemostatic biomarkers in middle age. METHOD: Participants were 9,377 men and women born in the United Kingdom in March 1958, and whose blood plasma samples at age 45 years were analyzed for levels of C-reactive protein (CRP), D-dimer, fibrinogen, tissue plasminogen activator (t-PA) antigen, and von Willebrand factor (VWF). Sex adjusted linear regression models tested cognition-blood biomarker associations, with and without adjustment for potential confounding by parental socioeconomic status and potential mediation by cardiovascular disease (CVD) risk factors at midlife. Cognitive tests taken at age 50 enabled the inflammation-cognition association to be tested for reverse causation, by adjusting for age 11 intelligence. RESULTS: Higher childhood intelligence test scores were significantly associated (p < .001) with lower adult levels of CRP (beta coefficient = -0.068), t-PA antigen (beta = -0.014), D-dimer (beta = -0.011), fibrinogen (beta = -0.011), and VWF antigen (beta = -0.008). Early life factors including parental socioeconomic status accounted for 24%-44% of these associations, whereas further adjustment for adult CVD risk factors largely attenuated the effects (82%-100%). The significant inverse associations between age 45 biomarker levels and age 50 cognition could be accounted for to a substantial degree by childhood intelligence (50%-100% attenuation). CONCLUSIONS: Childhood intelligence is predictive of inflammatory and hemostatic biomarker status at middle age, which may be largely explained by health behaviors. This highlights the need to consider possible bidirectional associations between cognition and inflammation (and hemostasis) in lifecourse models of CVD-related health. PMID- 21604879 TI - The impact of accumulated experience on children's appraisals of risk and risk taking decisions: implications for youth injury prevention. AB - OBJECTIVES: This study assessed whether repeated experience with a physical activity leads to increased risk taking and compared what factors (risk appraisals, emotion ratings, child attributes) predict risk taking before and after practice doing the activity. METHOD: Children 7 to 12 years of age participated in an ecologically valid risk-taking task in which they chose the highest height at which to set a balance beam before and after they practiced walking across it. RESULTS: Prior to accumulating experience, predictors of risk taking included appraisals of risk, child attributes, and extent of past experience with the activity. After accumulating experience, risk taking increased and was predicted by behavioral attributes (low inhibitory control, high sensation seeking) and appraisal of perceived vulnerability. CONCLUSION: When aiming to reduce risk taking, the best approach will be one that targets different determinants depending on children's extent of experience with the recreational activity. PMID- 21604880 TI - Choosing the right medicare prescription drug plan: the effect of age, strategy selection, and choice set size. AB - OBJECTIVE: The Medicare Modernization Act of 2003 (better known as Medicare Part D) represents the most important change to Medicare since its inception in the mid-1960s. The large number of drug plans being offered has raised concern over the complex design of the program. The purposes of this article are to examine the effect of age and choice set size (3 vs. 9 drug plans) on decision processes, strategy selection, and decision quality within the Medicare Part D program. METHOD: One hundred fifty individuals completed a MouselabWeb study, a computer based program that allowed us to trace the information acquisition process, designed to simulate the official Medicare Web site. RESULTS: The data reveal that participants identified the lowest cost plan only 46% of the time. As predicted, an increase in choice set size (3 vs. 9) was associated with 0.25 times the odds of correctly selecting the lowest cost plan, representing an average loss of $48.71. Older participants, likewise, tended to make poorer decisions. CONCLUSION: The study provides some indication that decision strategy mediates the association between age and choice quality and provides further insight regarding how to better design a choice environment that will improve the performance of older consumers. PMID- 21604881 TI - Subjective well-being and mortality revisited: differential effects of cognitive and emotional facets of well-being on mortality. AB - OBJECTIVE: Subjective well-being (SWB) is an important predictor of mortality. To date, surprisingly little is known about whether cognitive and emotional facets of SWB independently predict mortality, and whether such effects vary by age. METHOD: This study examined differential effects of life satisfaction (LS), positive affect (PA), and negative affect (NA) on mortality in a conjoint analysis using data of German adults between the ages of 40 to 85 years (N = 3,124). Effects of SWB facets were analyzed using Cox Proportional Hazards Models. RESULTS: LS and PA predicted mortality over and above sociodemographic factors and physical health (HRLS = .89, 95% CI = .79-1.00, p < .05, HRPA = .81, 95% CI = .70-.93, p < .05). However, this effect diminished when including self rated health and physical activity. NA was not associated with mortality. Age group comparative analyses revealed that PA predicted mortality in older adults (65+) even after controlling for self-rated health and physical activity (HRPA = .82, 95% CI = .70-.97, p < .05). In middle-aged participants, no SWB indicator predicted mortality when controlling for covariates. CONCLUSIONS: These findings suggest a differential impact of cognitive and emotional well-being on mortality and suggest that in middle-aged adults the effects of SWB on mortality are attenuated by self-rated health and physical activity. The study underscores the importance of SWB for health and longevity, particularly for older adults. PMID- 21604882 TI - Conscientiousness and longevity: an examination of possible mediators. AB - OBJECTIVE: Conscientious individuals tend to experience a number of health benefits, not the least of which being greater longevity. However, it remains an open question as to why this link with longevity occurs. The current study tested two possible mediators (physical health and cognitive functioning) of the link between conscientiousness and longevity. METHOD: We tested these mediators using a 10-year longitudinal sample (N = 512), a subset of the long-running Health and Retirement Study of aging adults. Measures included an adjective-rating measure of conscientiousness, self-reported health conditions, and three measures of cognitive functioning (word recall, delayed recall, and vocabulary) included in the 1996 wave of the HRS study. RESULTS: Our results found that conscientiousness significantly predicted greater longevity, even in a model including the two proposed mediator variables, gender, age, and years of education. Moreover, cognitive functioning appears to partially mediate this relationship. CONCLUSIONS: This study replicates previous research showing that conscientious individuals tend to lead longer lives, and provides further insight into why this effect occurs. In addition, it underscores the importance of measurement considerations. PMID- 21604883 TI - Relationship characteristics and sexual risk-taking in young men who have sex with men. AB - OBJECTIVE: Young men who have sex with men (MSM), particularly young men of color, are experiencing the largest increase in HIV incidence of any risk group in the United States Epidemiological research suggests that the majority of transmissions among MSM are occurring in the context of primary partnerships, but little research has been done on the processes within these dyads that increase HIV risk behaviors. The aim of this study was to use longitudinal partnership level data to explore the effects of partner and relationship characteristics on the frequency of unprotected sex within young MSM relationships. METHOD: One hundred twenty-two young MSM (age 16-20 at baseline) were assessed at three time points six months apart, with 91% retention at the 12-month follow-up wave. Over 80% were racial/ethnic minorities. At each wave, participants reported on characteristics of the relationships and partners for up to three sexual partners. Hierarchical linear modeling was used for analyses. RESULTS: The largest effect was for considering the relationship to be serious, which was associated with nearly an eightfold increase in the rate of unprotected sex. Other factors that increased risk behaviors included older partners, drug use prior to sex, physical violence, forced sex, and partnership lasting more than six months. Partners met online were not associated with significantly more sexual risk. CONCLUSIONS: These data provide insight into the relationship processes that should be addressed in prevention programs targeted at young MSM. Relationships may serve as a promising unit for HIV prevention interventions, although more formative research will be required to address potential logistical obstacles to implementing such interventions. The partner-by-partner analytic approach (i.e., evaluating situational variables associated with several partners for a given participant) holds promise for future HIV behavioral research. PMID- 21604884 TI - Personality traits in old age: measurement and rank-order stability and some mean level change. AB - Lothian Birth Cohorts, 1936 and 1921 were used to study the longitudinal comparability of Five-Factor Model (McCrae & John, 1992) personality traits from ages 69 to 72 years and from ages 81 to 87 years, and cross-cohort comparability between ages 69 and 81 years. Personality was measured using the 50-item International Personality Item Pool (Goldberg, 1999). Satisfactory measurement invariance was established across time and cohorts. High rank-order stability was observed in both cohorts. Almost no mean-level change was observed in the younger cohort, whereas Extraversion, Agreeableness, Conscientiousness, and Intellect declined significantly in the older cohort. The older cohort scored higher on Agreeableness and Conscientiousness. In these cohorts, individual differences in personality traits continued to be stable even in very old age, mean-level changes accelerated. PMID- 21604886 TI - Age-related deficits in low-level inhibitory motor control. AB - Inhibitory control functions in old age were investigated with the "masked prime" paradigm in which participants executed speeded manual choice responses to simple visual targets. These were preceded--either immediately or at some earlier time- by a backward-masked prime. Young adults produced positive compatibility effects (PCEs)--faster and more accurate responses for matching than for nonmatching prime-target pairs--when prime and target immediately followed each other, and the reverse effect (negative compatibility effect, NCE) for targets that followed the prime after a short interval. Older adults produced similar PCEs to young adults, indicating intact low-level motor activation, but failed to produce normal NCEs even with longer delays (Experiment 1), increased opportunity for prime processing (Experiment 2), and prolonged learning (Experiment 3). However, a fine-grained analysis of each individual's time course of masked priming effects revealed NCEs in the majority of older adults, of the same magnitude as those of young adults. These were significantly delayed (even more than expected on the basis of general slowing), indicating a disproportionate impairment of low level inhibitory motor control in old age. PMID- 21604885 TI - What contributes to perceived stress in later life? A recursive partitioning approach. AB - One possible explanation for the individual differences in outcomes of stress is the diversity of inputs that produce perceptions of being stressed. The current study examines how combinations of contextual features (e.g., social isolation, neighborhood quality, health problems, age discrimination, financial concerns, and recent life events) of later life contribute to overall feelings of stress. Recursive partitioning techniques (regression trees and random forests) were used to examine unique interrelations between predictors of perceived stress in a sample of 282 community-dwelling adults. Trees provided possible examples of equifinality (i.e., subsets of people with similar levels of perceived stress but different predictors) as well as identification both of contextual combinations that separated participants with very high and very low perceived stress. Random forest analyses aggregated across many trees based on permuted versions of the data and predictors; loneliness, financial strain, neighborhood strain, ageism, and to some extent life events emerged as important predictors. Interviews with a subsample of participants provided both thick description of the complex relationships identified in the trees, as well as additional risks not appearing in the survey results. Together, the analyses highlight what may be missed when stress is used as a simple unidimensional construct and can guide differential intervention efforts. PMID- 21604887 TI - Social knowledge and goal-based influences on social information processing in adulthood. AB - Effective social functioning is reflected in the ability to accurately characterize other people and then use this information in the service of social goals. To examine this type of social functioning, the authors conducted two studies that investigated potential influences of social experience and chronic socioemotional goals on adults' social judgments in an impression formation task. In line with a social expertise framework, middle-aged and older adults were more sensitive to trait-diagnostic behavioral information than were younger adults. Relative to younger adults, older adults paid more attention to negative than to positive information when it related to morality traits. Increasing the salience of the social context, and presumably activating socioemotional goals, did not alter this pattern of performance. In contrast, when more global social evaluations were examined (e.g., suitability as a social partner), older adults were less likely than younger or middle-aged adults to adjust their evaluations in response to situational goals. Consistent with a heightened focus on socioemotional goals, older adults' judgments were more consistently influenced by their attributions of traits that would likely impact the affective outcomes associated with interpersonal interactions. The results demonstrate the interaction between social knowledge, situational social goals, and chronic socioemotional goals in determining age differences in social information processing. PMID- 21604888 TI - Providing support for distinctive processing: the isolation effect in young and older adults. AB - The isolation paradigm is the classic method for studying the effects of distinctiveness on memory (Hunt, 1995). Previous studies using the isolation paradigm with older adults (Bireta, Suprenant, & Neath, 2008; Cimbalo & Brink, 1982; Geraci, McDaniel, Manzano, & Roediger (2009); Vitali et al., 2006) placed the isolated items late in the study list. The current experiments, which are the first to investigate the isolation effect in young and older adults when the isolated item occurs early in the list, were motivated by a new framework for understanding age-related differences in the beneficial effects of distinctive processing. The framework, which is motivated by Hunt's (2006) discussion of distinctiveness and Craik's (1986) environmental support view, proposes that when contextual support is provided for the processing of both the difference and similarity components, older adults are more likely to show beneficial effects of distinctiveness. In Experiment 1, young adults showed both early and late isolation effects, while older adults showed only a late isolation effect. In the first experiment the isolated item was the word "table" in a list of fish names. In Experiment 2, the contrast between the isolated item and background items was increased by isolating numbers in a list of words. In the second experiment older adults, as well as young adults, showed an early isolation effect. PMID- 21604889 TI - Changes in peripheral social partners and loneliness over time: the moderating role of interdependence. AB - We examined the relationships between age, changes in the number of peripheral partners, and changes in loneliness over 2 years among 365 Hong Kong Chinese aged 18-91 years. We also tested the moderating role of interdependent self-construal in the relationships. Results showed that the well-documented negative association between age and number of peripheral partners over time was only significant for individuals with low and medium interdependence but not for those with high interdependence. Moreover, only older and middle-aged adults high in interdependence benefitted from having more peripheral social partners by showing decreased loneliness in the 2-year interval. PMID- 21604891 TI - Self-regulation and recall: growth curve modeling of intervention outcomes for older adults. AB - Memory training has often been supported as a potential means to improve performance for older adults. Less often studied are the characteristics of trainees that benefit most from training. Using a self-regulatory perspective, the current project examined a latent growth curve model to predict training related gains for middle-aged and older adult trainees from individual differences (e.g., education), information processing skills (strategy use) and self-regulatory factors such as self-efficacy, control, and active engagement in training. For name recall, a model including strategy usage and strategy change as predictors of memory gain, along with self-efficacy and self-efficacy change, showed comparable fit to a more parsimonious model including only self-efficacy variables as predictors. The best fit to the text recall data was a model focusing on self-efficacy change as the main predictor of memory change, and that model showed significantly better fit than a model also including strategy usage variables as predictors. In these models, overall performance was significantly predicted by age and memory self-efficacy, and subsequent training-related gains in performance were best predicted directly by change in self-efficacy (text recall), or indirectly through the impact of active engagement and self-efficacy on gains (name recall). These results underscore the benefits of targeting self regulatory factors in intervention programs designed to improve memory skills. PMID- 21604890 TI - Models of self and others and their relation to positive and negative caregiving responses. AB - The burden of providing informal care to a family member can lead to caregiver depression and potentially harmful caregiving behavior. Given the interpersonal nature of caregiving, the relationship between caregivers and care recipients may impact caregiver responses. We applied attachment theory to understanding caregiver depression, and both potentially harmful and exemplary caregiving responses. We present data from 430 caregivers in the Family Relationships in Late Life (FRILL 2) Project, a multisite, longitudinal study of caregiving. Age, gender, and model of self were related to caregiving responses, suggesting that model of self may help identify caregivers at risk for poor responses. PMID- 21604892 TI - Target adjustment and self-other agreement: utilizing trait observability to disentangle judgeability and self-knowledge. AB - Are well-adjusted individuals good targets or accurate self-judges? Across two round-robin studies, the current research first demonstrates that well-adjusted individuals' personalities are viewed with greater distinctive self-other agreement by new acquaintances. Is this enhanced self-other agreement a function of greater judgeability, improving others' ability to form an accurate impression? Or is it a function of greater self-knowledge, having a more accurate impression about oneself? By examining the relationship between psychological adjustment and self-other agreement as a function of trait observability, it becomes clear that psychological adjustment fosters self-other agreement through judgeability more so than through self-knowledge. Specifically, well-adjusted individuals provide new acquaintances with greater information regarding their less observable traits, enhancing others' knowledge and thus distinctive self other agreement. This effect was replicated with close informant-other agreement, indicating that the well-adjusted individual's tendency to make his or her less visible traits more accessible to others allows those who just met the target to agree better with people who know the target well. In sum, although well-adjusted individuals are in part good self-judges, it is their greater judgeability that seems most critical in enhancing self-other agreement in first impressions. PMID- 21604893 TI - Relationship specificity of aggressogenic thought-behavior processes. AB - The purpose of this longitudinal study was to examine the relationship specificity of aggressogenic thought-behavior processes and to investigate the role of self-esteem in translating or inhibiting aggressogenic thought into aggression toward personally liked and disliked targets. Participants (186 Finnish boys and girls; 11-12 years old at Time 1) completed measures twice over a 1-year interval. We assessed children's attributions of hostility, relational goals, expectations of anger, and self-efficacy at Time 1 as well as aggression, at both time points, toward their previously identified liked and disliked peers. Our results mostly supported our hypothesis that cognitions guide behavior mainly within the relationship context. Moreover, high self-esteem potentiated cognition behavior links toward children's own liked peer but inhibited the actualization of aggressogenic thought toward children's disliked peer. These findings highlight the importance of taking a Person * Situation approach when studying cognition-behavior processes. PMID- 21604894 TI - What is more important for national well-being: money or autonomy? A meta analysis of well-being, burnout, and anxiety across 63 societies. AB - What is more important: to provide citizens with more money or with more autonomy for their subjective well-being? In the current meta-analysis, the authors examined national levels of well-being on the basis of lack of psychological health, anxiety, and stress measures. Data are available for 63 countries, with a total sample of 420,599 individuals. Using a 3-level variance-known model, the authors found that individualism was a consistently better predictor than wealth, after controlling for measurement, sample, and temporal variations. Despite some emerging nonlinear trends and interactions between wealth and individualism, the overall pattern strongly suggests that greater individualism is consistently associated with more well-being. Wealth may influence well-being only via its effect on individualism. Implications of the findings for well-being research and applications are outlined. PMID- 21604895 TI - You probably think this paper's about you: narcissists' perceptions of their personality and reputation. AB - Do narcissists have insight into the negative aspects of their personality and reputation? Using both clinical and subclinical measures of narcissism, the authors examined others' perceptions, self-perceptions, and meta-perceptions of narcissists across a wide range of traits for a new acquaintance and close other (Study 1), longitudinally with a group of new acquaintances (Study 2), and among coworkers (Study 3). Results bring 3 surprising conclusions about narcissists: (a) they understand that others see them less positively than they see themselves (i.e., their meta-perceptions are less biased than are their self-perceptions), (b) they have some insight into the fact that they make positive first impressions that deteriorate over time, and (c) they have insight into their narcissistic personality (e.g., they describe themselves as arrogant). These findings shed light on some of the psychological mechanisms underlying narcissism. PMID- 21604896 TI - How does disclosing countertransference affect perceptions of the therapist and the session? AB - Therapist self-disclosure has been theorized and found to have both positive and negative effects. These effects depend, in part, on the nature of the disclosure. This study sought to examine the differential effects of therapist disclosures of more and less resolved countertransference issues on perceptions of therapists and therapy sessions. Using an analogue method, undergraduate participants (N = 116) were randomly assigned to watch one of two videos in which a therapist disclosed personal issues that were relatively resolved or relatively unresolved. As hypothesized, therapist disclosure of issues that were more resolved caused the therapist to be rated as more attractive and trustworthy and instilled greater hope than therapist disclosure of less resolved issues. The type of therapist disclosure, however, did not affect ratings of the expertness of the therapist, the depth or smoothness of the session, or the perceived universality between client and therapist. Implications of the results for the judicious use of self-disclosure are discussed. PMID- 21604897 TI - What a man wants: the male perspective on therapeutic alliance formation. AB - Although the link between client ratings of therapeutic alliance quality and psychotherapy outcome has been well established by previous research, there is still much to be done to clarify what variables are important to clients, particularly men, in the formation of an alliance. Thirty-seven male clients currently undergoing psychotherapy categorized 74 critical incidents for alliance formation in an open-ended manner on the basis of self-perceived relatedness. Multivariate concept-mapping statistical techniques were used to identify the typical way in which the participants conceptualized variables that are important to alliance formation. Nine categories of variables were identified (Bringing out the Issues, Nonverbal Psychotherapist Actions, Emotional Support, Formal Respect, Practical Help, Office Environment, Information, Client Responsibility, and Choice of Professional). Bringing out the Issues emerged as the highest rated and most consistently understood category across the men in this study. The results of this study add to a small but growing body of research on the client's perspective of alliance formation and provide an initial conceptual model of how men understand the variables of common alliance formation. The developed model also provides several hypotheses, which are presented for verification in future research and clinical practice. PMID- 21604898 TI - Implications of attachment theory and research for the assessment and treatment of eating disorders. AB - In this paper, we review the research literature on attachment and eating disorders and suggest a framework for assessing and treating attachment functioning in patients with an eating disorder. Treatment outcomes for individuals with eating disorders tend to be moderate. Those with attachment associated insecurities are likely to be the least to benefit from current symptom-focused therapies. We describe the common attachment categories (secure, avoidant, anxious), and then describe domains of attachment functioning within each category: affect regulation, interpersonal style, coherence of mind, and reflective functioning. We also note the impact of disorganized mental states related to loss or trauma. Assessing these domains of attachment functioning can guide focused interventions in the psychotherapy of eating disorders. Case examples are presented to illustrate assessment, case formulation, and group psychotherapy of eating disorders that are informed by attachment theory. Tailoring treatments to improve attachment functioning for patients with an eating disorder will likely result in better outcomes for those suffering from these particularly burdensome disorders. PMID- 21604899 TI - Interpersonal subtypes and change of interpersonal problems in the treatment of patients with generalized anxiety disorder: a pilot study. AB - Interpersonal problems are highly relevant to the treatment of generalized anxiety disorder (GAD) patients. Previous studies using the Inventory of Interpersonal Problems identified several interpersonal subtypes in GAD patients. In this study, we wanted to replicate earlier findings of interpersonal subtypes in GAD. We investigated whether these interpersonal subtypes are characterized by different types of interpersonal problems and different levels of interpersonal distress, and we further examined whether they differed with regard to improvement of interpersonal problems after short-term treatment. This study is based on results from a randomized controlled trial that investigated short-term treatments in GAD outpatients. For secondary analysis, interpersonal subtypes were identified by cluster analysis and Inventory of Interpersonal Problems profiles were calculated for both the total sample (N = 52) and the interpersonal subtypes using the Structural Summary Method for Circumplex Data. This study confirmed previous results demonstrating the existence of interpersonal subtypes in GAD. Four interpersonal subtypes were identified: Overly Nurturant, Intrusive, Socially Avoidant, and Nonassertive. Short-term treatment significantly improved interpersonal problems (d = 0.46) within the total GAD sample. Interestingly, the effect sizes of the four clusters differed considerably (d = 0.19-1.24) and the clusters displayed different changes in the two circumplex axes Dominance and Nurturance. Our study indicates that change of interpersonal problems needs to be specifically analyzed, even within homogenous diagnostic groups. PMID- 21604900 TI - The relationship between activating affects, inhibitory affects, and self compassion in patients with Cluster C personality disorders. AB - In the short-term dynamic psychotherapy model termed "Affect Phobia Treatment," it is assumed that increase in patients' defense recognition, decrease in inhibitory affects (e.g., anxiety, shame, guilt), and increase in the experience of activating affects (e.g., sadness, anger, closeness) are related to enhanced self-compassion across therapeutic approaches. The present study aimed to test this assumption on the basis of data from a randomized controlled trial, which compared a 40-session short-term dynamic psychotherapy (N = 25) with 40-session cognitive treatment (N = 25) for outpatients with Cluster C personality disorders. Patients' defense recognition, inhibitory affects, activating affects, and self-compassion were rated with the Achievement of Therapeutic Objectives Scale (McCullough et al., 2003b) in Sessions 6 and 36. Results showed that increase in self-compassion from early to late in therapy significantly predicted pre- to post-decrease in psychiatric symptoms, interpersonal problems, and personality pathology. Decrease in levels of inhibitory affects and increase in levels of activating affects during therapy were significantly associated with higher self-compassion toward the end of treatment. Increased levels of defense recognition did not predict higher self-compassion when changes in inhibitory and activating affects were statistically controlled for. There were no significant interaction effects with type of treatment. These findings support self compassion as an important goal of psychotherapy and indicate that increase in the experience of activating affects and decrease in inhibitory affects seem to be worthwhile therapeutic targets when working to enhance self-compassion in patients with Cluster C personality disorders. PMID- 21604901 TI - Patients' disclosures about therapy: discussing therapy with spouses, significant others, and best friends. AB - This study investigated patterns of disclosure by psychotherapy patients about their own therapy to confidants. A total of 135 patients (M age = 29.4; 18 male; 117 female) currently in individual psychotherapy completed the Disclosure About Therapy Inventory (DATI), a questionnaire of 90 Likert-type items designed to investigate patients' experiences of disclosing aspects of their therapy to their spouses, significant others, or best friends. Findings indicate that most patients are moderately self-disclosing to their confidants about their therapy, endorse highly positive attitudes regarding such disclosure, and report primarily positive feelings after disclosing personal information about their therapy to their confidants. In addition, a significant relationship was found between the extent to which patients disclose about their therapy to their confidants and the extent to which they disclose to their therapists. Therapists, it is suggested, might well glean important clinical data from attending to their patients' patterns of disclosing the details of their treatment to others. PMID- 21604902 TI - The relationship between adult attachment style and therapeutic alliance in individual psychotherapy: a meta-analytic review. AB - The present study examined the relationship between adult attachment style and therapeutic alliance in individual psychotherapy. Search procedures yielded 17 independent samples (total N = 886, average n = 52, standard deviation = 24) for inclusion in the meta-analysis. Results indicated that greater attachment security was associated with stronger therapeutic alliances, whereas greater attachment insecurity was associated with weaker therapeutic alliances, with an overall weighted effect size of r = .17, p < .001 (95% confidence interval = .10 .23). Publication bias analyses did not indicate any cause for concern regarding the results. The data were not demonstrably heterogeneous (Q = 6.10, df = 16, p = .99), and all between-study moderator analyses were nonsignificant (p values > .10) with the exception of the source of alliance ratings; results indicated that patient-rated alliance demonstrated a significantly larger relationship with attachment compared with therapist-rated alliance (Qbetween = 3.95, df = 1, p = .047). Implications for clinical practice and future research are discussed. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21604903 TI - "Co-constructing" stigma and the therapist-parent alliance. AB - Just as many relationships are susceptible to the distorting and distancing effects of stigmatization, so are therapist-parent relationships, particularly in instances where children/youth present with significant mental illness. Therapist awareness and attunement to the dynamics of stigma are critical to the development of engaged therapist-parent alliances, and therapist-parent alliances are key to successful child/youth psychotherapy. Intersubjectivity theory offers a useful lens by which to understand stigma dynamics as mutually reinforced, "co constructed" experiences between therapists and parents. Applying this perspective provides direction for therapists to work in ways that recognize and reduce the negative impact of stigma dynamics on this important alliance. PMID- 21604904 TI - Relation of the real relationship and the working alliance to the outcome of brief psychotherapy. AB - In this study, the (a) association of the client- and therapist-rated strength of the real relationship to the outcome of brief psychotherapy, and (b) extent to which the real relationship predicted outcome above and beyond the predictive power of the working alliance were examined. A total of 50 clients at the counseling center of a university in Italy received brief therapy and completed measures before treatment, after the third session, and at the end of treatment. From the clients' perspective, both the Genuineness element of the real relationship and the Bond scale of the working alliance were found to relate significantly to treatment outcome. When we examined the real relationship and working alliance as predictors in a hierarchical regression format, the client rated real relationship, especially the Genuineness element, did predict outcome and, moreover, added significantly and substantially to the working alliance in predicting outcome. Neither the strength of the real relationship from the therapist's perspective nor the therapist-rated working alliance was found to relate to outcome. The findings are discussed in the context of methodological differences with other investigations of the real relationship. PMID- 21604905 TI - Relationships among client-therapist personality congruence, working alliance, and therapeutic outcome. AB - Despite the importance of the working alliance in therapeutic outcome, little is known about the factors associated with its formation. We advance that personality similarity between client and therapist is one such factor pertinent to the working alliance. In this study, personality similarity in 32 client therapist dyads was examined for its relations to the bond, task, and goal elements of the working alliance (Bordin, 1979, Psychotherapy: Theory, Research, and Practice, 16, 252-260) and therapeutic outcome. Personality similarity was conceptualized using Holland's (1997, Making vocational choices [3rd ed.]) congruence construct. Therapists completed the Self-Directed Search pretreatment and clients completed the Working Alliance Inventory-Short Revised and Self Directed Search after the third session. Results indicated that (a) client therapist personality congruence was associated with the bond, (b) bond was associated with task and goal, and (c) task and goal were associated with therapeutic outcome. Congruence was not associated with task, goal, or therapeutic outcome. Holland's theory provides a framework for adapting to clients of varying personality types. By understanding how client-therapist personalities relate to each other in therapy, client-therapist bonds may be more efficiently realized. PMID- 21604906 TI - Parent-offspring conflict theory: an evolutionary framework for understanding conflict within human families. AB - Decades of research demonstrate that conflict shapes and permeates a broad range of family processes. In the current article, we argue that greater insight, integration of knowledge, and empirical achievement in the study of family conflict can be realized by utilizing a powerful theory from evolutionary biology that is barely known within psychology: parent-offspring conflict theory (POCT). In the current article, we articulate POCT for psychological scientists, extend its scope by connecting it to the broader framework of life history theory, and draw out its implications for understanding conflict within human families. We specifically apply POCT to 2 instances of early mother-offspring interaction (prenatal conflict and weaning conflict); discuss the effects of genetic relatedness on behavioral conflict between parents, children, and their siblings; review the emerging literature on parent-offspring conflict over the choice of mates and spouses; and examine parent-offspring conflict from the perspective of imprinted genes. This review demonstrates the utility of POCT, not only for explaining what is known about conflict within families but also for generating novel hypotheses, suggesting new lines of research, and moving us toward the "big picture" by integrating across biological and psychological domains of knowledge. PMID- 21604907 TI - Geometry, features, and panoramic views: ants in rectangular arenas. AB - When tested in rectangular arenas, the navigational behavior of the ant Gigantiops destructor can produce results similar to vertebrates. Such results are usually interpreted as supporting the ability of animals to segregate spatial geometry and features. Here, we combine a detailed analysis of ants' paths with panoramic images taken from the ant's perspective that can serve as a basis for developing view-based matching models. The corner choices observed in ants were better predicted by the use of panoramic views along with a simple matching process [rotational image difference function (rIDF)] than by models assuming segregation of geometry and features (G/F). Our view-based matching model could also explain some aspects of the ants' path (i.e., initial direction, length) resulting from the different visual conditions, suggesting that ants were using such a taxon-like strategy. Analyzed at the individual level, the results show that ants' idiosyncratic paths tend to evolve gradually from trial to trial, revealing that the ants were partially updating their route memory after each trial. This study illustrates the remarkable flexibilities that can arise from the use of taxon-like strategies and stresses the importance of considering them in vertebrates. PMID- 21604908 TI - Overshadowing between landmarks on the touchscreen and in arena with pigeons. AB - The role of generalization decrement in spatial overshadowing was evaluated using a landmark-based spatial search task in both a touchscreen preparation (Experiment 1a) and in an Automated Remote Environmental Navigation Apparatus (ARENA, Experiment 1b). A landmark appeared as a colored circle among a row of eight (touchscreen) or six (ARENA) potential locations. On overshadowing trials, Landmark X was located two positions away from a hidden goal, while another landmark, A, was in the position between X and the goal. On control trials, Landmark Y was positioned two locations away from the goal but without a closer landmark. All subjects were then tested with separate trials of A, X, Y, and BY. Testing revealed poor spatial control by X relative to A and Y, thereby replicating the spatial overshadowing effect. Spatial control by Y was similar when tested in compound with novel landmark (BY) and on trials of Y alone. Thus, overshadowing in a small-scale environment does not appear to be due to a process of generalization decrement between training and testing. PMID- 21604909 TI - The impact of salient advertisements on reading and attention on web pages. AB - Human vision is sensitive to salient features such as motion. Therefore, animation and onset of advertisements on Websites may attract visual attention and disrupt reading. We conducted three eye tracking experiments with authentic Web pages to assess whether (a) ads are efficiently ignored, (b) ads attract overt visual attention and disrupt reading, or (c) ads are covertly attended with distraction showing up indirectly in the reading performance. The Web pages contained an ad above a central text and another ad to the right of the text. In Experiments 1, 2, and 3A the task was to read for comprehension. Experiment 1 examined whether the degree of animation affects attention toward the ads. The results showed that ads were overtly attended during reading and that the dwell times on ads were the longest when the ad above was static and the other ad was animated. In Experiments 2 and 3, the ads appeared abruptly after a random time interval. The results showed that attention (i.e., the time when the eyes first entered an ad) was related to the ad onset time. This happened especially for the ad to the right, indicating that ads appearing close to the text region capture overt attention. In Experiment 3B the participants browsed the Web pages according to their own interest. The study demonstrated that salient ads attract overt visual attention and disrupt reading, but during free browsing, ads were viewed more frequently and for longer time than during reading. PMID- 21604910 TI - Trust my face: cognitive factors of head fakes in sports. AB - In many competitive sports, players try to deceive their opponents about their behavioral intentions by using specific body movements or postures called fakes. For example, fakes are performed in basketball when a player gazes in one direction but passes or shoots the ball in another direction to avert efficient defense actions. The present study aimed to identify the cognitive processes that underlie the effects of fakes. The paradigmatic situation studied was the head fake in basketball. Observers (basketball novices) had to decide as quickly as possible whether a basketball player would pass a ball to the left or to the right. The player's head and gaze were oriented in the direction of an intended pass or in the opposite direction (i.e., a head fake). Responding was delayed for incongruent compared to congruent directions of the player's gaze and the pass. This head fake effect was independent of response speed, the presence of a fake in the immediately preceding trial, and practice with the task. Five further experiments using additive-factors logic and locus-of-slack logic revealed a perceptual rather than motor-related origin of this effect: Turning the head in a direction opposite the pass direction appears to hamper the perceptual encoding of pass direction, although it does not induce a tendency to move in the direction of the head's orientation. The implications of these results for research on deception in sports and their relevance for sports practice are discussed. PMID- 21604911 TI - Control of a virtual vehicle influences postural activity and motion sickness. AB - Everyday experience suggests that drivers are less susceptible to motion sickness than passengers. In the context of inertial motion (i.e., physical displacement), this effect has been confirmed in laboratory research using whole body motion devices. We asked whether a similar effect would occur in the context of simulated vehicles in a visual virtual environment. We used a yoked control design in which one member of each pair of participants played a driving video game (i.e., drove a virtual automobile). A recording of that performance was viewed (in a separate session) by the other member of the pair. Thus, the two members of each pair were exposed to identical visual motion stimuli, but the risk of behavioral contagion was minimized. Participants who drove the virtual vehicle (drivers) were less likely to report motion sickness than participants who viewed game recordings (passengers). Data on head and torso movement revealed that drivers tended to move more than passengers, and that the movements of drivers were more predictable than the movements of passengers. Before the onset of subjective symptoms of motion sickness movement differed between participants who (later) reported motion sickness and those who did not, consistent with a prediction of the postural instability theory of motion sickness. The results confirm that control is an important factor in the etiology of motion sickness and extend this finding to the control of noninertial virtual vehicles. PMID- 21604912 TI - The perceptual basis of the modality effect in multimedia learning. AB - Various studies have demonstrated an advantage of auditory over visual text modality when learning with texts and pictures. To explain this modality effect, two complementary assumptions are proposed by cognitive theories of multimedia learning: first, the visuospatial load hypothesis, which explains the modality effect in terms of visuospatial working memory overload in the visual text condition; and second, the temporal contiguity assumption, according to which the modality effect occurs because solely auditory texts and pictures can be attended to simultaneously. The latter explanation applies only to simultaneous presentation, the former to both simultaneous and sequential presentation. This paper introduces a third explanation, according to which parts of the modality effect are due to early, sensory processes. This account predicts that-for texts longer than one sentence-the modality effect with sequential presentation is restricted to the information presented most recently. Two multimedia experiments tested the influence of text modality across three different conditions: simultaneous presentation of texts and pictures versus sequential presentation versus presentation of text only. Text comprehension and picture recognition served as dependent variables. An advantage for auditory texts was restricted to the most recent text information and occurred under all presentation conditions. With picture recognition, the modality effect was restricted to the simultaneous condition. These findings clearly support the idea that the modality effect can be attributed to early processes in perception and sensory memory rather than to a working memory bottleneck. PMID- 21604914 TI - Word recognition and syntactic attachment in reading: evidence for a staged architecture. AB - In 3 experiments, the author examined how readers' eye movements are influenced by joint manipulations of a word's frequency and the syntactic fit of the word in its context. In the critical conditions of the first 2 experiments, a high- or low-frequency verb was used to disambiguate a garden-path sentence, while in the last experiment, a high- or low-frequency verb constituted a phrase structure violation. The frequency manipulation always influenced the early eye movement measures of first-fixation duration and gaze duration. The context manipulation had a delayed effect in Experiment 1, influencing only the probability of a regressive eye movement from later in the sentence. However, the context manipulation influenced the same early eye movement measures as the frequency effect in Experiments 2 and 3, though there was no statistical interaction between the effects of these variables. The context manipulation also influenced the probability of a regressive eye movement from the verb, though the frequency manipulation did not. These results are shown to confirm predictions emerging from the serial, staged architecture for lexical and integrative processing of the E-Z Reader 10 model of eye movement control in reading (Reichle, Warren, & McConnell, 2009). It is argued, more generally, that the results provide an important constraint on how the relationship between visual word recognition and syntactic attachment is treated in processing models. PMID- 21604913 TI - Attentional episodes in visual perception. AB - Is one's temporal perception of the world truly as seamless as it appears? This article presents a computationally motivated theory suggesting that visual attention samples information from temporal episodes (episodic simultaneous type/serial token model; Wyble, Bowman, & Nieuwenstein, 2009). Breaks between these episodes are punctuated by periods of suppressed attention, better known as the attentional blink (Raymond, Shapiro, & Arnell, 1992). We test predictions from this model and demonstrate that participants were able to report more letters from a sequence of 4 targets presented in a dense temporal cluster than from a sequence of 4 targets interleaved with nontargets. However, this superior report accuracy comes at a cost in impaired temporal order perception. Further experiments explore the dynamics of multiple episodes and the boundary conditions that trigger episodic breaks. Finally, we contrast the importance of attentional control, limited resources, and memory capacity constructs in the model. PMID- 21604915 TI - Order or disorder? Impaired Hebb learning in dyslexia. AB - The present study offers an integrative account proposing that dyslexia and its various associated cognitive impairments reflect an underlying deficit in the long-term learning of serial-order information, here operationalized as Hebb repetition learning. In nondyslexic individuals, improved immediate serial recall is typically observed when one particular sequence of items is repeated across an experimental session, a phenomenon known as the Hebb repetition effect. Starting from the critical observation that individuals with dyslexia seem to be selectively impaired in cognitive tasks that involve processing of serial order, the present study is the first to test and confirm the hypothesis that the Hebb repetition effect is affected in dyslexia, even for nonverbal modalities. We present a theoretical framework in which the Hebb repetition effect is assumed to be a laboratory analogue of naturalistic word learning, on the basis of which we argue that dyslexia is characterized by an impairment of serial-order learning that affects language learning and processing. PMID- 21604916 TI - The Finnish Diabetes Risk Score (FINDRISC) and other non-invasive scores for screening of hepatic steatosis and associated cardiometabolic risk. PMID- 21604917 TI - The Finnish Diabetes Risk Score (FINDRISC) as a screening tool for hepatic steatosis. AB - INTRODUCTION. Hepatic steatosis due to non-alcoholic fatty liver disease is associated with obesity, dyslipidemia, insulin resistance, and type 2 diabetes. The Finnish Diabetes Risk Score (FINDRISC) is a prognostic screening tool to detect people at risk for type 2 diabetes without the use of any blood test. The objective of this study was to evaluate whether FINDRISC can also be used to screen for the presence of hepatic steatosis. PATIENTS AND METHODS. Steatosis was determined by ultrasound. The study sample consisted of 821 non-diabetic subjects without previous hepatic disease; 81% were men (mean age 45 +/- 9 years) and 19% women (mean age 41 +/- 10 years). RESULTS. Steatosis was present in 44% of men and 10% of women. The odds ratio for one unit increase in the FINDRISC associated with the risk of steatosis was 1.30 (95% CI 1.25-1.35), similar for men and women. The area under the receiver operating characteristics curve for steatosis was 0.80 (95% CI 0.77-0.83); 0.80 in men (95% CI 0.77-0.83) and 0.83 (95% CI 0.73 0.93) in women. CONCLUSIONS. Our data suggest that the FINDRISC could be a useful primary screening tool for the presence of steatosis. PMID- 21604919 TI - Endothelial dysfunction predicts clinical restenosis after percutaneous coronary intervention. AB - BACKGROUND: Endothelial dysfunction is associated with increased risk for cardiovascular events in patients with coronary artery disease and may predict in stent restenosis after percutaneous coronary intervention. We evaluated if endothelial dysfunction could predict clinical and angiographic restenosis in patients after percutaneous coronary intervention with stent implantation for angina pectoris or acute coronary syndrome. METHODS: One hundred patients were consecutively included after successful percutaneous coronary intervention with stenting for angiographic single vessel disease. All patients were evaluated with ultrasound detection of brachial artery reactivity at four weeks and with a symptom limited exercise stress test at six months and were followed for the occurrence of clinical or angiographic restenosis for 18 +/- 6 months. RESULTS: Twenty patients showed clinical signs of restenosis during 18 months follow-up and were referred to re-angiography. Patients with clinical restenosis had impaired flow mediated vasodilation compared to patients without clinical restenosis (5.8 +/- 3.4 vs. 9.0 +/- 4.8, p = 0.005). In multivariate analysis flow mediated vasodilation was the only independent predictor for the risk of clinical restenosis (OR 4.5, 95% CI 1.11 to 17.8). CONCLUSIONS: Impaired flow mediated vasodilation four weeks after percutaneous coronary intervention independently predicts the risk of clinical restenosis. PMID- 21604920 TI - Survival and sudden cardiac death after septal ablation for hypertrophic obstructive cardiomyopathy. AB - OBJECTIVES: Reports of long-term survival and the risk of sudden cardiac death (SCD) after percutaneous transluminal septal myocardial ablation (PTSMA) in patients with hypertrophic obstructive cardiomyopathy (HOCM) are sparse. DESIGN: Survival and SCD in 77 PTSMA-treated patients (follow-up 3.5 +/- 2.8 years) were analyzed. The future risk of SCD was assessed by risk stratification for SCD in 57 PTSMA patients at long-term follow-up (3.8 +/- 2.8 years). RESULTS: The five years survival of the PTSMA cohort (age 61 +/- 12 years) was 83% compared to 79% in a control cohort (n = 90) of patients (age 52 +/- 17 years) with hypertrophic cardiomyopathy (HCM) (Log Rank p = 0.8), and 91% (p = 0.01) in the background population. Five-year survival free of SCD was 94% after PTSMA compared to 99% (p = 0.13) in the HCM control cohort. Eight percent of patients had two or more risk factors for SCD at follow-up. CONCLUSION: The survival in the PTSMA-treated patients and in the HCM control cohorts was similar. The incidence of SCD and the future risk of SCD assessed by risk factors were not increased in the PTSMA cohort compared to the HCM control cohort. The excess mortality in the PTSMA cohort compared to the background population seems to be related to HCM rather than PTSMA. PMID- 21604921 TI - Impact of obesity on the severity and therapeutic responsiveness of acute episodes of asthma. AB - BACKGROUND: It has been suggested that obesity adversely influences both the severity and the therapeutic responsiveness of chronic asthma. However, it is unclear if it also impacts acute situations. METHODS: To determine whether adiposity worsens the clinical and physiological manifestations of acute asthma and limits therapeutic effectiveness of standard treatment, we contrasted signs, symptoms, medication use, arterial oxygen saturation, peak expiratory flow rate, and the bronchodilator response to standard doses of albuterol in 90 non-obese and 90 obese asthmatics as they presented for urgent care. Treatment and clinical decisions were systematized using published care paths and the peak flow was measured with standard techniques. Body mass index (BMI) was calculated according to consensus criteria. RESULTS: Other than BMI (p < .001), there were no between group differences in age, gender, race, signs, symptoms, pulse oximetry, or pre presentation medication use. The pretreatment peak flow in the obese population was 22.4% higher on average (p = .007), but there were no differences in the distribution of severity (p = .38), the response to albuterol (p = .61), or admission-discharge ratios (p = .62). CONCLUSIONS: Obesity does not adversely influence the severity or the resolution of acute episodes of asthma. PMID- 21604923 TI - Cefepime neurotoxicity despite renal adjusted dosing. AB - Neurotoxicity is a rare side-effect of cefepime. There are previous reports of cefepime neurotoxicity in patients whose dosages were not adjusted for their kidney disease. We report a toxic case of non-convulsive status epilepticus in a patient receiving renally-dosed cefepime. A 70-y-old woman was admitted with febrile neutropenia for which renally-dosed cefepime was started. On day 4 she developed altered mental status with orofacial myokymia. Blood and urine cultures were negative. Cerebrospinal fluid analysis was normal. Head computed tomography and magnetic resonance imaging showed no acute intracranial process. An electroencephalogram showed non-convulsive status epilepticus. Anticonvulsants were started, but she continued to have seizures. At this time, careful review of her medication list with temporal association of symptoms suggested cefepime as a probable cause and the drug was stopped. Within 24 h of discontinuation, her mental status began to improve and returned to baseline in 3 days. Our case illustrates that cefepime toxicity may still occur in patients who are dose adjusted for renal insufficiency. It also underscores the importance of assessing for additional risk factors like history of stroke and seizures. Because cefepime induced status epilepticus is completely reversible, prompt recognition and medication discontinuance can prevent further morbidity and mortality. PMID- 21604922 TI - Vaccine herd effect. AB - Vaccination ideally protects susceptible populations at high risk for complications of the infection. However, vaccines for these subgroups do not always provide sufficient effectiveness. The herd effect or herd immunity is an attractive way to extend vaccine benefits beyond the directly targeted population. It refers to the indirect protection of unvaccinated persons, whereby an increase in the prevalence of immunity by the vaccine prevents circulation of infectious agents in susceptible populations. The herd effect has had a major impact in the eradication of smallpox, has reduced transmission of pertussis, and protects against influenza and pneumococcal disease. A high uptake of vaccines is generally needed for success. In this paper we aim to provide an update review on the herd effect, focusing on the clinical benefit, by reviewing data for specific vaccines. PMID- 21604924 TI - Emergence of oseltamivir-resistant pandemic H1N1 in an immunocompetent child with severe status asthmaticus. AB - INTRODUCTION: Pandemic influenza A (H1N1) may cause severe illness in pediatric patient with chronic lung disease. CASE REPORT: We describe the emergence of oseltamivir resistance in an immunocompetent child with status asthmaticus triggered by pandemic influenza A (H1N1). This case highlights the possible relationship between influenza viral load and risk of resistance emergence in children with asthma. Influenza vaccination should continue to be emphasized as the mainstay of prevention in children with chronic lung disease. CONCLUSION: Influenza virus can lead to severe status asthmaticus and can develop oseltamivir resistance in immunocompetent children. PMID- 21604925 TI - Generation of neural stem cells from embryonic stem cells using the default mechanism: in vitro and in vivo characterization. AB - Neural stem cell-based approaches to repair damaged white matter in the central nervous system have shown great promise; however, the optimal cell population to employ in these therapies remains undetermined. A default mechanism of neural induction may function during development, and in embryonic stem cells (ESCs) neural differentiation is elicited in the absence of any extrinsic signaling in minimal, serum-free culture conditions. The default mechanism can be used to derive clonal neurosphere-forming populations of neural stem cells that have been termed leukemia inhibitory factor-dependent primitive neural stem cells (pNSCs), which subsequently give rise to fibroblast growth factor 2-dependent definitive NSCs (dNSCs). Here we characterized the neural differentiation pattern of these two cell types in vitro and in vivo when transplanted into the dysmyelinated spinal cords of shiverer mice. We compared the differentiation pattern to that observed for neural stem/progenitor cells derived from the adult forebrain subependymal zone [adult neural precursor cells (aNPCs)]. dNSCs produced a differentiation pattern similar to that of aNPCs in vitro and in the shiverer model in vivo, where both cell types produced terminally differentiated oligodendrocytes that associated with host axons and expressed myelin basic protein. This is the first demonstration of the in vivo differentiation of NSCs, derived from ESCs through the default mechanism, into the oligodendrocyte lineage. We conclude that dNSCs derived through the default pathway of neural induction are a similar cell population to aNPCs and that the default mechanism is a promising approach to generate NSCs from pluripotent cell populations for use in cell therapy or other research applications. PMID- 21604926 TI - Efficacy of a brief acute neurobehavioural intervention following traumatic brain injury: a preliminary investigation. AB - PRIMARY OBJECTIVE: To evaluate the effectiveness of a brief acute neurobehavioural intervention, the First Steps Acute Neurobehavioural and Cognitive Intervention (FANCI), with persons who have traumatic brain injury (TBI). RESEARCH DESIGN: Prospective, controlled, repeated measures design. METHODS AND PROCEDURES: Seventy-two patients in acute TBI rehabilitation participated either as FANCI subjects or as control participants who watched videos to control for time and attention. Outcome measures included the Neurobehavioural Rating Scale-Revised (NRS-R), Functional Independence Measure (FIMTM), a FANCI Learning Assessment (LA) and the Satisfaction with Life Scale (SWLS). MAIN OUTCOMES AND RESULTS: In comparison with controls, FANCI participants had significantly greater neurobehavioural (cognitive, emotional and behavioural) as well as FIM motor improvements. Significantly greater learning occurred and persisted over time for FANCI subjects as compared to controls. Pre treatment cognitive and neurobehavioural status, length of coma and number of sessions completed were moderating variables for functional and cognitive outcomes. CONCLUSIONS: Persons with TBI can benefit from comprehensive, manualized neurobehavioural interventions, over and above standard rehabilitation care, even during the acute phase of recovery. PMID- 21604927 TI - Non-impact, blast-induced mild TBI and PTSD: concepts and caveats. AB - PRIMARY OBJECTIVE: A volumetric blood surge (rapid physical movement/displacement of blood) is hypothesized to cause the non-impact, mild TBI and battlefield PTSD induced by a blast over-pressure wave. RESEARCH DESIGN: Systematic review of the literature. METHODS AND PROCEDURES: Articles relating to the fields of blast injury, brain injury and relevant disorders were searched between the years 1968 2010 for keywords such as 'brain injury', 'post-traumatic stress disorder' and 'blast pressure wave'. Articles found through journal and Internet databases were cross-referenced. MAIN OUTCOMES AND RESULTS: The blood surge, which is driven by elevated overall pressure in the ventral body cavity after exposure of the torso to blast wave, may move through blood vessels to the low-pressure cranial cavity from the high-pressure ventral body cavity. It dramatically increases cerebral perfusion pressure and causes damage to both tiny cerebral blood vessels and the BBB. CONCLUSIONS: Three factors may be critical to the induction of blast-induced brain injuries: (1) the difference in pressure between the ventral body cavity and cranial cavity; (2) blood that acts as a transmission medium to propagate a pressure wave to the brain; and (3) the vulnerability of cerebral blood vessels and the BBB to a sudden fluctuation in perfusion pressure. PMID- 21604928 TI - Integrating situated learning theory and neuropsychological research to facilitate patient participation and learning in traumatic brain injury rehabilitation patients. AB - PURPOSE: Traumatic brain injury (TBI) constitutes a major health problem throughout the world. Despite interdisciplinary efforts, patients reach varying outcomes in terms of every-day life functioning and quality-of-life. This paper suggests that a situated learning perspective supplemented with evidence from neurophysiologic and neuropsychological research provides a perspective to get a grasp of problems typically encountered in rehabilitation. Applying such a perspective may help to facilitate patient participation and learning during the rehabilitation process by taking their altered abilities into consideration. METHOD: Qualitative study. Theoretical analysis and synthesis of 'situated learning theory', neuropsychological theory and empirical studies of cognitive and emotional functioning following a TBI collected through interviews with 11 interdisciplinary rehabilitation experts and a field study of two patients at a rehabilitation hospital. The data were analysed from a hermeneutic perspective using N-VIVO 8. RESULTS/CONCLUSION: Patients with severe TBI pose challenges in terms of being participants in the 'rehabilitation practice community'. Two levels of pedagogical challenges seem to exist: Helping the patient regain or compensate for changed learning abilities and supporting the patient in learning or compensating for lost abilities. This study highlighted six main categories of changed abilities that need to be considered in developing a practice which fosters re-learning: perception, attention, memory, language, physical competencies and emotion/model of behaviour. PMID- 21604929 TI - Injury severity, age and pre-injury exercise history predict adherence to a home based exercise programme in adults with traumatic brain injury. AB - PURPOSE: To explore factors that may influence exercise adherence in adults with traumatic brain injury (TBI) within the International Classification of Functioning, Disability and Health (ICF) theoretical model. PARTICIPANTS: Thirty participants with TBI who had been randomized to a home-based exercise programme in a recently conducted randomized controlled trial. METHODS: Impairments in body functions, environmental factors and personal factors were explored as predictors for exercise adherence. Significant variables were entered into binary logistic regression analyses to determine their combined power to predict exercise adherence. RESULTS: Greater injury severity, older age and a pre-injury exercise history of walking or jogging positively influenced exercise adherence. As a combined set the three predictor variables accurately classified 82% of participants as adherent or non-adherent and were able to explain 49% of the variance (sensitivity = 67%; specificity = 89%). CONCLUSION: These results demonstrate people with severe injuries are able to exercise independently and suggest that in order to maximize adherence to an exercise programme, clinicians need to consider exercise history when prescribing the type of exercise. The results also provide factors within the ICF theoretical model to investigate in a large-scale study of exercise adherence after TBI. PMID- 21604930 TI - Post-traumatic stress symptoms and psychological functioning in children of parents with acquired brain injury. AB - INTRODUCTION/OBJECTIVES: The effect of parental brain injury on children has been relatively little investigated. This study examines post-traumatic stress symptoms (PSS) and psychological functioning in children with a parent with an acquired brain injury. PARTICIPANTS, MATERIALS AND METHODS: The participants were 35 patients with acquired brain injury, their spouses and children aged 7-14 years recruited from out-patient brain injury rehabilitation units across Denmark. Children self-reported psychological functioning using the Becks Youth Inventory (BYI) and Child Impact of Events revised (CRIES) measuring PSS symptoms. Emotional and behavioural problems among the children were also identified by the parents using the Achenbach's Child Behaviour Checklist (CBCL). A matched control group, consisting of 20 children of parents suffering from diabetes, was recruited from the National Danish Diabetes Register. RESULTS: Post traumatic stress symptoms above cut-off score (<30) were found (CRIES) in 46% of the children in the brain injury group compared to 10% in the diabetes group. The parents in the brain injury group reported more emotional and behavioural problems in their children when compared to published norms (CBCL). CONCLUSIONS: When parents have acquired brain injury, their children appear to be at a substantial risk for developing post-traumatic stress symptoms. These results indicate the need for a child-centred family support service to reduce the risk of children being traumatized by parental brain injury, with a special focus on the relational changes within the family. PMID- 21604931 TI - Quality of clinical practice guidelines for persons who have sustained mild traumatic brain injury. AB - BACKGROUND: Mild TBI is one of the most common neurological disorders occurring today. For individuals who experience persistent symptoms following mild TBI, consequences can include functional disability, stress and time away from one's occupation. The objective of the study was to evaluate the quality of clinical practice guidelines (CPGs) that include recommendations on the care of persons who have sustained mild TBI and associated persistent symptoms. METHODS: A minimum of four appraisers used the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument to evaluate seven CPGs found via a systematic search of bibliographic databases and internet resources. RESULTS: High AGREE scores were obtained for the domains Scope and Purpose and Clarity and Presentation. The CPGs fared less well on Rigour of Development, Stakeholder Involvement, Editorial Independence and Applicability. The number of recommendations addressing the care of persistent symptoms following mild TBI was meager, with the exception of military guidelines. CONCLUSIONS: There is considerable variability in the quality of guidelines addressing mild TBI and, overall, the CPGs reviewed score lower on Rigour of Development than CPGs for other medical conditions. There is a clear need for clinical guidance on the management of individuals who experience persistent symptoms following mild TBI. PMID- 21604933 TI - Screening for prostate cancer: defining critical issues. PMID- 21604932 TI - Introduction from the chairmen of the WHO International Consultation on Prostate Cancer. PMID- 21604934 TI - Screening for prostate cancer---the controversy continues, but can it be resolved? AB - BACKGROUND: In 2009, the European Randomized Study of Screening for Prostate Cancer (ERSPC) was one of two studies to report interim data on the effect of screening for prostate cancer (PC) on the disease specific mortality. Contradictory results caused considerable discussion and misunderstanding in secondary literature. METHODS: This document is based on a non systematic review of recent evidence for and against screening for PC, specifically considering three recently published randomized screening trials [ 1-3 ]. RESULTS: The ERSPC data are based on a core age group of 162 387 men, aged 55-69 years, who were identified through population registries in seven European countries. Men were randomized between a screening group that received screening at an average of once every four years and a control group. After a median follow-up of nine years, a reduction in the rate of death from PC by 20% was shown which increased to 31% after adjusting for non-compliance and contamination. Overdetection and subsequent overtreatment (with a number needed to treat (NNT) of 48) are considered to be the major down sides of screening. The recently published 14 year results have shown that these down sides strongly depend on the duration of follow-up. In response to the outcomes of the ERSPC, several points of discussion have been brought up by various authors concerning the usefulness of screening considering benefits, harms and costs, the methodology of the ERSPC and the interpretation of its outcomes. Important issues to address regarding PC screening are addressed. CONCLUSIONS: This paper sheds a light on the controversial points of the ERSPC as well as on the priority issues of PC screening. On July 2, 2010 the Swedish section of ERSPC (Goteborg screening trial) published their results with a median follow-up of 14 years. With longer follow-up the data confirm the trend seen in improvement of PC mortality and suggest much more favorable future outcomes also with respect to the NNT to prevent one PC death. PMID- 21604935 TI - The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: the prostate cancer screening results in context. AB - BACKGROUND: The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) was conducted in sites around USA during a period of marked secular changes in the use of prostate specific antigen (PSA) screening for prostate cancer. MATERIAL AND METHODS: Trends in prostate cancer incidence, stage at presentation and mortality are useful when interpreting the results from a screening trial that commenced in 1993 and enrolled participants through 2001. The last participants completed active screening in 2006. Incidence and mortality data published to date on PLCO need to be placed into the context of the secular trends. Additional data analyses have been conducted on subsets of the participants and these results can also enhance the interpretation of the trial. Additionally, the accompanying biospecimen repository has served as a rich research resource yielding informative findings. RESULTS: The PLCO is best viewed as a trial comparing a regimented active annual screening program of PSA screening for six rounds, four of which had accompanying digital rectal examination (DRE) to patterns of screening that were occurring in the population in many academic and community settings across the USA. The epidemiology and molecular genetics of prostate cancer is becoming better understood and analyses of the PLCO resource have contributed. One approach to risk assessment utilizing genetic markers from selected members of the PLCO prostate cancer cohort has been developed. A modeling effort with CISNET-ERSPC-PLCO is underway to compare and contrast findings such as effects of different PSA thresholds and screening intervals. CONCLUSIONS: The information emerging from PLCO is useful to inform the debate around prostate cancer screening. An understanding of the biologic differences underpinning indolent and aggressive prostate cancer will better guide the future development of screening and treatment strategies. PMID- 21604936 TI - Early detection of prostate cancer with emphasis on genetic markers. AB - BACKGROUND: The recent advances in genomic research have made it possible to identify several new genomic-based biomarkers for prostate cancer. In this review we evaluate these new markers and speculate about future scenarios. RESULTS: Today 35 single nucleotide polymorphisms (SNPs) have been identified and independently validated to associate with prostate cancer. These SNPs are common in the population (>5%) but the effect of these SNPs in these regions on prostate cancer risk is modest with odds ratios typically ranging between 1.1 and 1.3. It is estimated that these markers explain 25% of the familial risk of prostate cancer. However, it is anticipated that additional 50-75 prostate cancer SNPs will be identified in the near future. The SNPs associated with prostate cancer so far are not associated with disease stage or outcome. There are several efforts to identify germline genetic markers that can be used as prognostic markers. There are also tumor-based methods that are promising in identifying new genetic markers that can be easily measured in plasma or urine. CONCLUSION: There are several new "genetic" markers that in the near future might be used in clinical routine. These markers are easy to measure and stable over time. However the challenge is not only to identify new biomarkers but the real test is to validate new biomarkers in several large well-characterized patient populations. This validation must be done together will all other known biomarkers at the same time as it not likely that one single marker is enough, but a panel of different markers. Today 2010 there are over 19 000 publications in the area of biomarkers and prostate cancer, but only one biomarker, PSA, is used in the clinic today! PMID- 21604937 TI - Introduction. Dilemmas in the field of prostate cancer detection and treatment. PMID- 21604938 TI - State-of-the-art uroradiologic imaging in the diagnosis of prostate cancer. AB - In the diagnostic process of prostate cancer, several radiologic imaging modalities significantly contribute to the detection and localization of the disease. These range from transrectal ultrasound (TRUS) and magnetic resonance imaging (MRI) to positron emission tomography (PET). Within this review, after evaluation of the literature, we will discuss the advantages and disadvantages of these imaging modalities in clarifying the patient's clinical status as to whether he has prostate cancer or not and if so, where it is located, so that therapy appropriate to the patient's disease may be administered. TRUS, specifically with the usage of intravenous contrast agents, provides an excellent way of directing biopsy towards suspicious areas within the prostate in the general (screening) population. MRI using functional imaging techniques allows for highly accurate detection and localization, particularly in patients with prior negative ultrasound guided biopsies. A promising new development is the performance of biopsy within the magnetic resonance scanner. Subsequently, a proposal for optimal use of radiologic imaging is presented and compared with the European and American urological guidelines on prostate cancer. PMID- 21604940 TI - Pathology in prostate research: optimizing the pathological data. AB - Pathology remains the gold standard for the diagnosis and local staging and grading of prostate cancer. However, as in any discipline, there are variations in national standards and protocols leading to possible significant intra observer variations. This can significantly impact on the data supplied to clinical trials. Diagnostic and grading criteria. Error rates in the diagnosis of prostate cancer have improved but the possibility that diagnostic error may be discovered has to be addressed in any research series. Major changes in Gleason grading have occurred in the past 40 years and this may lead to suboptimal application of grades in research cohorts, falsely raising the prognostic power of new biomarkers. Tumor measurements and staging criteria. Further information that may provide additional prognostic information include various measures of tumor extent and peri-neural invasion in biopsy specimens. Standardization of measures of tumor extent is necessary to give more useful assessments of prognosis. In radical prostatectomy specimens there are a number of other staging measurements which might be applied, including tumor volume, margin status, extra capsular extension and nodal positivity though many of these variables are interdependent. Conclusion. Appropriate utilization of such pathological material will produce improved cohorts in which it will be possible to test new biomarkers with increased rigor. PMID- 21604939 TI - Developing imaging strategies for castration resistant prostate cancer. AB - Recent advances in the understanding of castrate-resistant prostate cancer (CRPC) have lead to a growing number of experimental therapies, many of which are directed against the androgen-receptor (AR) signaling axis. These advances generate the need for reliable molecular imaging biomarkers to non-invasively determine efficacy, and to better guide treatment selection of these promising AR targeted drugs. Methods. We draw on our own experience, supplemented by review of the current literature, to discuss the systematic development of imaging biomarkers for use in the context of CRPC, with a focus on bone scintigraphy, F 18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) and PET imaging of the AR signaling axis. Results. The roadmap to biomarker development mandates rigorous standardization and analytic validation of an assay before it can be qualified successfully for use in an appropriate clinical context. The Prostate Cancer Working Group 2 (PCWG2) criteria for "radiographic" progression by bone scintigraphy serve as a paradigm of this process. Implemented by the Prostate Cancer Clinical Trials Consortium (PCCTC), these consensus criteria may ultimately enable the co-development of more potent and versatile molecular imaging biomarkers. Purported to be superior to single-photon bone scanning, the added value of Na(18)F-PET for imaging of bone metastases is still uncertain. FDG PET already plays an integral role in the management of many diseases, but requires further evaluation before being qualified in the context of CRPC. PET tracers that probe the AR signaling axis, such as (18)F-FDHT and (89)Zr-591, are now under development as pharmacodynamic markers, and as markers of efficacy, in tandem with FDG-PET. Semi-automated analysis programs for facilitating PET interpretation may serve as a valuable tool to help navigate the biomarker roadmap. Conclusions. Molecular imaging strategies, particularly those that probe the AR signaling axis, have the potential to accelerate drug development in CRPC. The development and use of analytically valid imaging biomarkers will increase the likelihood of clinical qualification, and ultimately lead to improved patient outcomes. PMID- 21604941 TI - Pathology in prostate research: optimizing tissue quality. AB - The collection of tissue from the prostate gland for research creates unique challenges in the identification of cancer and in preserving pathological material. VALUE AND USES OF FORMALIN FIXED TISSUE: Formalin fixed paraffin embedded (FFPE) tissue is often available in abundance after pathological processing and reporting of specimens but is limited in value for detailed molecular tests. Tissue micro-array if carefully performed is a helpful technique for examining many FFPE specimens with immunohistochemical or fluorescence in situ hybridization tests. VALUE AND USES OF FROZEN TISSUE: The collection of fresh tissue prior to formalin fixation and later validation samples of fresh prostate cancer is difficult as prostate cancer is very difficult to identify macroscopically on cut prostate specimens. Also, the act of manipulation and dissection of the gland while fresh and without compromising surgical margins is challenging. Methods which have been used to dissect the fresh prostate gland and also collect fresh tissue from other prostatic specimens are discussed. The ethical challenges of collecting research tissue without compromising patient care are discussed. CONCLUSIONS: Prostate cancer tissue banks, particularly of frozen tissue are still relatively few in number. Enhanced collection methods which do not prohibit full pathological examination are available but require expertise to maximize their potential. PMID- 21604942 TI - Role of histopathology and molecular markers in the active surveillance of prostate cancer. AB - Surgery or radiation therapy remain the standard curative treatments for newly diagnosed prostate cancer patients. Nonetheless, these aggressive treatments are associated with decreased quality of life with altered sexual and urinary functions. The objective was a systematic review of active surveillance protocols to investigate the role of histopathology and molecular markers in the active surveillance of prostate cancer. Medline was searched using the following terms: prostate cancer, active surveillance and expectant management. Selection criteria, follow-up strategies and outcomes. Using modern risk stratification, several centres have gained significant experience in identifying patients with a low risk of prostate cancer progression and have adopted an active surveillance program with delayed curative therapy. Interestingly, only limited numbers of patients under active surveillance require additional treatment. Recent data suggest that delayed treatment does not appear to alter the clinical outcome among those highly selected patients. The future and conclusions. A better understanding of the molecular determinants of prostate cancer behaviour would not only enable healthcare professionals to identify which cases need aggressive treatment but, perhaps more importantly, would also indicate potential targets for the development of novel therapeutic strategies. PMID- 21604944 TI - Tumour markers in prostate cancer II: diagnostic and prognostic cellular biomarkers. AB - The main goal of prostate cancer tissue biomarkers is to improve diagnostic and prognostic accuracy. A particularly important question is whether the cancer needs immediate treatment or if treatment can be deferred. It is highly unlikely that a single biomarker that provides comprehensive prognostic information about a newly diagnosed prostate cancer will be forthcoming. Despite extensive research efforts, very few biomarkers of prostate cancer have been successfully implemented into clinical practice today. This can be partly explained by a lack of standardised methods for performance and interpretation of immunohistochemistry, but also by poor study design with insufficient biomaterial or inappropriate statistical analysis. Also appropriate cohorts to test prostate cancer biomarkers do not exist. It must be kept in mind that unsuccessful integration of new biomarkers in nomograms can also be explained by the good performance of the clinical and pathological base model with serum PSA as the only independent biomarker. A new biomarker must be powerful enough to improve this prediction model and not merely replace. MATERIAL AND METHODS: In this report, we focus on diagnostic and prognostic cellular biomarkers in prostate cancer, recent advances and future aspects by reviewing currently available literature. RESULTS: Similar to other malignancies, the proliferation marker Ki 67 seems to be a prognostic tissue biomarker and a strong candidate for integration in prediction models. Circulating tumour cells are promising markers of response to treatments in patients with metastatic disease. CONCLUSION: Important technical advances together with histological techniques of antibody or probes conjugated with different fluorophores will certainly improve standardisation and make immunohistochemical biomarker research more reliable and precise in the future. Cellular biomarker studies are also expected to change in the future towards a complexed individualised profiling of human tumours with integrative analysis using different technologies, genome-wide scanning and expression profiling. PMID- 21604945 TI - Tumour markers in prostate cancer III: biomarkers in urine. AB - The serum PSA test still is the most important biomarker for the detection and follow-up of prostate cancer. PSA-based screening can reduce disease specific mortality but coinciding unnecessary testing and overdiagnosis warrant further research for more specific biomarkers. Numerous studies of both serum and urine based prostate cancer biomarker candidates have been presented the last ten years. However, biomarkers for identifying the most aggressive subsets of this malignancy are still missing. Being non-invasive, urine-based tests might be suitable for both clinical and (mass) screening purposes, but also for prediction and to gain prognostic information. Protein-based, DNA-based and RNA-based urine biomarkers have been developed and tested. PROTEIN MARKERS IN URINE: Data on protein-based urine biomarkers (i.e. Annexin A3, matrix metalloproteinases and the urinary:serum PSA ratio) show up to now contradictory results and further studies are warranted to be able to assess their clinical value in which the cost aspect should not be overlooked. DNA markers in urine. Studies on DNA-based urine biomarkers focus on hypermethylation of gene panels with GSTP1 hypermethylation being the most promising individual marker. Larger prospective clinical studies of single markers and gene panels are however needed to validate their clinical utility. RNA MARKERS IN URINE: RNA-based urine biomarkers are by far the most developed. The PCA3 test, the TMPRSS2-ERG fusion gene, transcript expression levels of GOLPH2, SPINK1 and their combination have been subject of many studies showing encouraging results. CONCLUSION: Up to now urine-based biomarkers represent a promising alternative or addition to serum-based biomarkers. Prospective studies in a multivariate setting, including larger sample sizes and avoiding attribution bias caused by preselection on the basis of serum PSA are however required. PMID- 21604943 TI - Tumor markers in prostate cancer I: blood-based markers. AB - The introduction of total prostate specific antigen (total PSA) testing in blood has revolutionized the detection and management of men with prostate cancer (PCa). The objective of this review was to discuss the challenges of PCa biomarker research, definition of the type of PCa biomarkers, the statistical considerations for biomarker discovery and validation, and to review the literature regarding total PSA velocity and novel blood-based biomarkers. METHODS: An English-language literature review of the Medline database (1990 to August 2010) of published data on blood-based biomarkers and PCa was undertaken. RESULTS: The inherent biological variability of total PSA levels affects the interpretation of any single result. Men who will eventually develop PCa have increased total PSA levels years or decades before the cancer is diagnosed. Total PSA velocity improves predictiveness of total PSA only marginally, limiting its value for PCa screening and prognostication. The combination of PSA molecular forms and other biomarkers improve PCa detection substantially. Several novel blood-based biomarkers such as human glandular kallikrein 2 (hK2), urokinase plasminogen activator (uPA) and its receptor (uPAR), transforming growth factor beta 1 (TGF-beta1); interleukin-6 (IL-6) and its receptor (IL-6R) may help PCa diagnosis, staging, prognostication, and monitoring. Panels of biomarkers that capture the biologic potential of PCa are in the process of being validated for PCa prognostication. CONCLUSIONS: PSA is a strong prognostic marker for long-term risk of clinically relevant cancer. However, there is a need for novel biomarkers that aid clinical decision making about biopsy and initial treatment. There is no doubt that progress will continue based on the integrated collaboration of researchers, clinicians and biomedical firms. PMID- 21604946 TI - Introduction: therapy with curative intent. PMID- 21604947 TI - Radical retropubic prostatectomy: a review of outcomes and side-effects. AB - BACKGROUND: Radical prostatectomy (RP) is worldwide probably the most common procedure to treat localized prostate cancer (PC). Due to a more widespread use of Prostate-Specific Antigen (PSA) testing, patients operated today are often younger and have organ confined disease justifying a more preservative surgery. At the same time, surgical technique has improved resulting in lower risk of permanent side-effects. This paper aims to give an overview of results from modern surgery regarding cancer control and side-effects. A brief overview of the history is given. MATERIAL AND METHODS: A literature research identified recently published papers focusing on outcome and side-effects after RP. RESULTS: One large randomized study (SPCG-4) compared RP and watchful waiting (WW). The study showed that RP was superior to WW in preventing local progression (RR = 0.36), distant metastasis (RR = 0.65) and death from PC (RR = 0.65). Observational studies also show a better outcome for men treated with RP compared to WW. Peri operative mortality after RP is low in most material around 0.1%. The risk of stricture of the vesico-urethral anastomosis has decreased with improved technique from historically 10-20% to a low incidence of around 2-9% today. Also the risk of incontinence has declined with improved technique. However, while the rates of severe incontinence is usually very low, as many as 30% still report light incontinence after long-term follow-up. Erectile dysfunction (ED) is still a frequent side-effect after RP. This risk is dependent on age, pre-operative sexual function, surgical technique and other risk factors for ED such as smoking, diabetes, etc. In selected subgroups the risk of ED is low. Inguinal hernia is a more recently described complication after open retropubic RP with a postoperative incidence of 15-20% within three years of surgery. CONCLUSION: RP is an effective method to achieve cancer control in selected patients. With modern technique it is a safe procedure with a low risk of permanent side-effects except for ED. PMID- 21604948 TI - Curative radiation therapy in prostate cancer. AB - Radiotherapy has experienced an extremely rapid development in recent years. Important improvements such as the introduction of multileaf collimators and computed tomography (CT)-based treatment planning software have enabled three dimensional conformal external beam radiation therapy (3DCRT). The development of treatment planning systems and technology for brachytherapy has been very rapid as well. Development of accelerators with integrated on-board imaging equipment and technology, for example image-guided radiation therapy (IGRT) has further improved the precision with reduced margins to adjacent normal tissues. This has, in turn, led to the possibility to administer even higher doses to the prostate than previously. Although radiotherapy and radical prostatectomy have been used for the last decades as curative treatment modalities, still there are no randomized trials published comparing these two options. Outcome data show that the two treatment modalities are highly comparable when used for low- and intermediate-risk prostate cancer. PMID- 21604949 TI - Four and five dimensional radiotherapy with reference to prostate cancer- definitions, state of the art and further directions--an overview. AB - Radiotherapy (RT) always requires a compromise between tumor control and normal tissue side-effects. Technical innovation in radiation therapy (RT), such as three dimensional RT, is now established. Concerning prostate cancer (PC), it is reasonable to assume that RT of PC will increase in the future. The combination of small margins, a movable target (prostate), few fractions and high doses will probably demand dynamically positioning systems and in real time. This is called four dimensional radiotherapy (4DRT). Moreover, biological factors must be included in new treatments such as hypofractionation schedules. This new era is called five dimensional radiotherapy, 5DRT. In this paper we discuss new concepts in RT in respect to PC. PMID- 21604950 TI - Hypofractionation for radiotherapy of prostate cancer using a low alfa/beta ratio -possible reasons for concerns? An example of five dimensional radiotherapy. AB - It is very attractive, due to the assumed low alfa/beta ratio of prostate cancer (PC), to construct new treatment schedules for prostate cancer using only a few large fractions of radiation (hypofractionation). This will widen the therapeutic window since the ratio for PC might be lower than that of the organs at risk (OAR). PC is an extremely variable disease and often contains both highly and poorly differentiated cells. It is reasonable to assume that different cells have different patterns of radiosensitivity, i.e. alfa/beta ratios and proliferation. In this study we will simulate the effect on the outcome of the treatment with different fractionations and different ratios. MATERIAL AND METHODS: In this simulation we use an extension of the Linear Quadratic (LQ)/Biological Effective Dose (BED) formula called the dose volume inhomogeneity corrected BED (DVIC-BED). In the formula the tumour volume is divided in 50 subvolumes (step of 2%) and it is possible to calculate the relative effect of the treatment with different ratios (1.5, 4 and 6.5) in different subvolumes. RESULTS: The simulations demonstrate that only a small portion (5-10%) of cells with a higher ratio will dramatically change the effect of the treatment. Increasing the total dose can compensate this, but this will on the other hand increase the dose to the OAR and also the risk for severe side effects. CONCLUSION: These simulations highlight possible reasons for concerns about the use of hypofractionation for pathologically heterogeneous tumours, such as prostate cancer, and also demonstrate the need for testing new treatment schedules using both high and low ratios. PMID- 21604951 TI - Natural history of prostate cancer, chemoprevention and active surveillance. PMID- 21604952 TI - When is active surveillance the appropriate treatment for prostate cancer? AB - BACKGROUND: The incidence of prostate cancer has increased dramatically worldwide during the past few decades in part because of increased testing for prostate specific antigen (PSA). The aggressive use of this screening tool has resulted in the identification of many localized prostate cancers a majority of which are relatively low volume, low grade tumors. Older autopsy studies have documented that incidental prostate cancer is quite common especially in older men. The finasteride chemoprevention trial confirmed these findings. Many prostate cancers are not destined to progress to clinically significant tumors. Several case series have documented the natural history of clinically detected prostate cancer. The progression of disease identified by PSA testing is less certain. These studies uniformly show that many men with low grade tumors can survive for over two decades in the absence of treatment. Furthermore, randomized clinical trials have shown only a modest ten year survival advantage for those men undergoing either surgery or radiation. RESULTS: As a consequence, men with low risk of disease progression may wish to consider active surveillance as a treatment option. To date, several case series have documented that men following an active surveillance protocol that includes regular PSA testing and periodic re biopsy have an excellent outcome. The majority of these men have not demonstrated evidence of progression during the first decade of follow-up and among those that have the majority have undergone either surgery or radiation without compromise of their long-term outcome. Unfortunately, until better biomarkers become available, the outcome of any individual patient defies accurate prediction. CONCLUSION: Men with newly diagnosed prostate cancer must weigh the risk of disease progression against the potential efficacy and safety of treatment when making a decision whether to consider active surveillance as an appropriate treatment. PMID- 21604953 TI - Chemoprevention of prostate cancer. AB - Over the past two decades, many more men are diagnosed with prostate cancer then die of the disease. This increase in diagnosis has led to aggressive treatment of indolent disease in many individuals and has been the impetus for finding a means of reducing the risk of prostate cancer. In the past decade, there have been eight large trials of prostate cancer risk reduction using dietary supplements, 5alpha-reductase inhibitors, or anti-estrogens. The only two trials which have demonstrated efficacy are those involving 5alpha-reductase inhibitors: the PCPT (finasteride) and REDUCE (dutasteride). This review examines prostate cancer risk reduction, with emphasis on conclusions that can be drawn from these two landmark studies. PMID- 21604954 TI - Management of advanced prostate cancer--new drugs. PMID- 21604955 TI - Broadening horizons in medical management of prostate cancer. AB - HORMONAL THERAPY: Testosterone suppression achieved either medically or surgically is the standard initial treatment for men with advanced prostate cancer. Most men respond but the disease progresses after a median of 1-2 years. Clinical trials suggest that intermittent androgen deprivation therapy (ADT) provides equal or longer time to castration-independence than continuous ADT, and is preferred, especially since there are subtle long-term toxicities associated with ADT. Further hormonal manipulations (including addition and withdrawal of peripheral antiandrogens, steroid synthesis inhibitors such as ketoconazole, and estrogens) can be transiently effective in selected patients with castration resistant prostate cancer (CRPC). Androgen-dependent signalling pathways remain active in most men with CRPC and are associated with mutation, changes in expression or modulation of the androgen receptor (AR); abiraterone acetate and MDV3100 are promising drugs being evaluated in clinical trials that may lead to further hormonal response. CHEMOTHERAPY: Eventually men who progress rapidly, are symptomatic, and/or develop metastasis to visceral organs require chemotherapy. Three-weekly docetaxel with prednisone has been shown to improve survival and relieve symptoms but eventually men develop progressive disease or become intolerant to docetaxel. Multiple trials are evaluating new drugs (mainly molecular targeted agents) either given first line with docetaxel chemotherapy, or to men who have progressive disease after receiving docetaxel. Cabazitaxel was shown recently to improve survival as compared to mitoxantrone when used second line and has been approved by the United States Food and Drug Administration (FDA). CONCLUSION: Despite major advances, treatment of men with advanced CRPC remains a challenge both for the seeker and giver of care. PMID- 21604956 TI - Prostate cancer from the horizon of the patient. AB - The democratization of civil society and the development of modern medicine changed the sacrosanct doctor-patient relationship to a doctor-partner dialogue. Values and respect were lost in the process where common courtesy and empathy in trust were replaced by patient rights. LAUNCH OF EUROPA UOMO: Europa Uomo, the European prostate cancer coalition, represents 22 national, autonomous patient support groups. Its aim includes increasing the awareness of prostate diseases, support individualized treatment as a balance between optimal medical treatment and personalized care delivered by a multiprofessional team. We expect our information/education from dedicated professional societies while in return we share care for properly informed members as well as a fast, unbiased and cheap distribution of information/innovation across the European continent. THE ROLE OF A PATIENT GROUP: Our advocacy role is focused on quality of life, tailored treatment, knowledge of risk factors, support for research and last but not least active partnerships. We believe that we can play a modest but basic role in common actions to overcome inequalities in treatment and care in Europe. Our responsibilities range from defining patient obligations to facilitating translational research and saving scarce health resources. THE HORIZON OF THE PATIENT: Our hope is to plead for a treatment policy on the man first and then on his cancer and to improve treatment outcomes by multiprofessional collaboration and the development of expert Prostate Units. FUTURE EXPECTATIONS: A transparent, open communication line between the multiprofessional team and the patient is mandatory. The existing uncertainties should be discussed with common sense but always leave a factor of hope in survival or quality of life. PMID- 21604957 TI - Weighting of cues for fricative place of articulation perception by children wearing cochlear implants. AB - OBJECTIVE: To determine how children wearing cochlear implants weight cues for fricative perception compared to age-matched children with normal hearing. DESIGN: Two seven-step continua of synthetic CV syllables were constructed, with frication pole varied from /s/ to /f/ within the continuum, and appropriate formant transition values varied across continua. Relative weights applied to the frication, transition, and interaction cues were determined. STUDY SAMPLE: Ten 5?7-year-old children with normal hearing and ten 5?8-year-old children wearing cochlear implants participated. RESULTS: Both groups of children gave more perceptual weight to the frication spectral cue than to the formant transition cue. Children with normal hearing gave small but significant weight to formant transitions, but the children wearing cochlear implants did not. The degree of cue interaction was significant for children with normal hearing but was not for children wearing cochlear implants. CONCLUSIONS: Children wearing a cochlear implant use similar cue-weighting strategies as normal listeners (i.e. all apply more weight to the frication noise than to the transition cue), but may have limitations in processing formant transitions and in cue interaction. PMID- 21604958 TI - Failure of de-activation in the medial frontal cortex in mania: evidence for default mode network dysfunction in the disorder. AB - OBJECTIVES: Manic patients have been found to show reduced activation in the prefrontal cortex and other regions during performance of cognitive tasks. However, little is known about de-activations associated with the disorder. This study aimed to examine, at the whole-brain level, abnormal patterns of task related activation and de-activation during performance of a working memory task. METHODS: Twenty-nine DSM-IV bipolar patients and 46 healthy controls underwent fMRI during performance of the n-back task. The patients were scanned while they were in a manic episode. Linear models were used to obtain maps of within-group activations and areas of differential activation between the groups. RESULTS: The manic patients showed reduced activation compared to the controls in the bilateral dorsolateral prefrontal cortex and the right parietal cortex. They also showed failure of de-activation in the medial frontal cortex, extending to the temporal poles and parts of the limbic system bilaterally. The failure of activation in the dorsolateral prefrontal cortex disappeared when differences in task performance were controlled for in the analysis. However, the medial frontal failure of de-activation survived controlling for this. CONCLUSIONS: This study suggests that, in addition to reduced prefrontal activation, failure of de activation is an important functional imaging abnormality in mania. This, together with its location in the medial prefrontal cortex, implies default mode network dysfunction in the disorder. PMID- 21604959 TI - Health-related quality of life among women with breast cancer - a population based study. AB - BACKGROUND: High incidence rates of breast cancer emphasize the importance of increased knowledge about the health-related quality of life (HRQoL) in this patient group. The aim of the present study was to describe and compare HRQoL among breast cancer patients shortly after diagnosis with normative data from the general population, and to investigate how clinical, demographic, and socio economic factors and social support are associated with HRQoL. MATERIAL AND METHODS: Participants were identified in a population-based Breast Cancer Quality Register in central Sweden. Of 1573 women newly diagnosed with breast cancer during a one-year period (2007-2008), 69% (n = 1086) completed a questionnaire including the EORTC QLQ-C30, BR23 and the HADS. RESULTS: Compared to age-adjusted normative data, breast cancer patients (mean age 62 years, range 25-94), especially younger women (<50 years), experienced clinically meaningful poorer HRQoL. Clinically significant levels of anxiety and depressive symptoms were found among 14% and 6% of the patients, respectively. Factors associated with more problems/symptoms among study participants included chemotherapy, lack of social support, sick leave and a poor financial situation. Adding socio-economic factors diminished the association between age and HRQoL (p > 0.05). CONCLUSION: Recently diagnosed breast cancer patients reported poorer HRQoL in several dimensions compared to normative data. In addition to clinical and demographic factors, an unfavorable socio-economic standing was associated with more problems/symptoms. The present findings emphasize the importance of taking a variety of factors into account when assessing HRQoL in the clinical setting. PMID- 21604960 TI - The clinical course of immediate breast implant reconstruction after breast cancer. AB - BACKGROUND: The number of women suitable for breast conserving treatment as well as immediate reconstruction after breast cancer has been increasing, and studies of complications hereafter are needed. MATERIAL AND METHODS: The cohort was identified in the prospective database of the Danish Registry for Plastic Surgery of the Breast during the period 1999 to 2006; 167 women with 189 immediate breast reconstructions (40 one-stage and 149 two-stage procedures) after breast cancer without a history of radiation therapy. The women were followed for complications until November 2009. Cumulative incidence risks were computed for infection, hematoma, seroma, severe capsular contracture (modified Baker III and IV), extrusion of the implant, implant rupture, asymmetry/displacement of the implant, any complication, and reoperation. In addition, we compared the postoperative course of immediate two-stage procedures with delayed two-stage procedures. RESULTS: The overall eight-year risk estimates for the immediate procedures were 76.4% for any complication, 5.3% for severe capsular contracture, 29.5% for displacement/asymmetry of the implant and 40.6% for reoperation. Significantly higher risk for reoperation was observed after immediate one-stage than after two stage procedures. For immediate two-stage procedures acute complications such as infection, seroma and hematoma were higher in the expansion period than after the second planned surgery. Higher risks for acute complications were observed after immediate than after delayed two-stage procedures. CONCLUSION: Immediate breast implant reconstruction was found to have substantial risks of complications in non-radiated women, which should be considered in the guidance of breast cancer patients before choosing reconstructive procedure. PMID- 21604961 TI - Over-the-counter laxative polyethylene glycol 3350: an evidence-based appraisal. AB - OBJECTIVE: To explore the clinical dimensions of chronic constipation and the role played in its treatment by laxatives in general and by polyethylene glycol 3350 (MiraLAX * ) in particular. * MiraLAX is a registered trade name of Schering Plough HealthCare Products, Inc., Memphis, TN, USA, a subsidiary of Merck & Co., Inc. RESEARCH DESIGN AND METHODS: Published reports of clinical trials involving polyethylene glycol 3350, together with published articles examining the epidemiology, demographics, etiology, evaluation, and management of chronic constipation, were identified in a literature search through November 2009 using PubMed. Congress proceedings and guideline databases of leading national and international gastroenterology associations were also explored for relevant recommendations and evaluations. MAIN OUTCOME MEASURES: Constipation, often defined differently by patients and physicians, is typically associated with excessive straining, hard stools, infrequent bowel movements, and sensations of incomplete evacuation. Specific criteria are available to aid physicians in making a diagnosis of functional constipation. Initial patient management typically involves dietary and lifestyle changes, although this approach is supported by limited clinical evidence and is often a source of considerable patient frustration. A laxative is needed when these changes do not sufficiently relieve constipation. Multiple agents from several different laxative classes are available, differing in mechanism of action, safety and efficacy profile, and clinical evidence supporting their use. RESULTS: Twenty-one studies involving a total of 1949 patients were included in the overall review of polyethylene glycol 3350. Fifteen studies used randomized designs, eight were comparative trials, seven were conducted in pediatric populations, and three had elderly components. LIMITATIONS: Limitations of this review included lack of comparability among the various patient populations described; focus on a single agent; potential publication bias; non-systematic review. CONCLUSIONS: Polyethylene glycol 3350, an osmotic laxative available over the counter, has been shown to be safe and effective in treating chronic constipation in children and adults, including the elderly, across multiple clinical trials, with a safety profile comparable to that of placebo. Polyethylene glycol 3350 received a grade A recommendation for improving stool frequency and consistency from the American College of Gastroenterology Task Force on Chronic Constipation. PMID- 21604962 TI - A short-term cost-effectiveness study comparing robot-assisted laparoscopic and open retropubic radical prostatectomy. AB - OBJECTIVE: To evaluate cost effectiveness and cost utility comparing robot assisted laparoscopic prostatectomy (RALP) versus retropubic radical prostatectomy (RRP). METHODS: In a retrospective cohort study a total of 231 men between the age of 50 and 69 years and with clinically localised prostate cancer underwent radical prostatectomy (RP) at the Department of Urology, Aarhus University Hospital, Skejby from 1 January 2004 to 31 December 2007, were included. The RALP and RRP patients were matched 1:2 on the basis of age and the D'Amico Risk Classification of Prostate Cancer; 77 RALP and 154 RRP. An economic evaluation was made to estimate direct costs of the first postoperative year and an incremental cost-effectiveness ratio (ICER) per successful surgical treatment and per quality-adjusted life-year (QALY). A successful RP was defined as: no residual cancer (PSA <0.2 ng/ml, preserved urinary continence and erectile function. A one-way sensitivity analysis was made to investigate the impact of changing one variable at a time. RESULTS: The ICER per extra successful treatment was ?64,343 using RALP. For indirect costs, the ICER per extra successful treatment was ?13,514 using RALP. The difference in effectiveness between RALP and RRP procedures was 7% in favour of RALP. In the present study no QALY was gained 1 year after RALP, however this result is uncertain due to a high degree of missing data. The sensitivity analysis did not change the results noticeably. LIMITATIONS: The study was limited by the design resulting in a low percentage of information on the effect of medication for erectile dysfunction and only short term quality of life was measured at 1 year postoperatively. CONCLUSION: RALP was more effective and more costly. A way to improve the cost effectiveness may be to perform RALP at fewer high volume urology centres and utilise the full potential of each robot. PMID- 21604963 TI - Relative survival after CABG surgery is poorer in women and in patients younger than 70 years at surgery. AB - OBJECTIVE: The difference in survival between genders after coronary artery bypass surgery (CABG) have been studied with varying results. We wanted to investigate gender and age specific relative survival in the CABG population. Risk factors increasing hazard of death in female patients were isolated. DESIGN: Retrospectively, 6699 primary isolated CABG procedures were investigated. Long term survival compared to expected survival in the background population was described through Kaplan-Meier plots. Two subgroups of female patients were described through baseline characteristics, t-tests, odds ratio and multivariate analysis to investigate risk factors for death within one year after surgery. RESULTS: Women had significantly decreased relative long-term survival compared to men in this study. Relative survival was lower in patients below 70 years of age at surgery with about the same gender difference. Low ejection fraction, left main stem stenosis and reduced renal function were found to increase risk of death within one year after CABG in women, while body size quantified by body surface area (BSA) did not. CONCLUSION: Relative long-term survival after CABG was poorer in female compared to male patients. This tendency was kept or strengthened when only those less than 70 years of age at surgery were investigated. Lower female survival was most likely due to more comorbidity in female patients. Relative survival was lower in patients <70 years. PMID- 21604964 TI - Longitudinal associations between reported sleep duration in early childhood and the development of body mass index, fat mass index and fat free mass index until age 7. AB - OBJECTIVE: Epidemiological studies in children and adolescents have revealed short sleep duration as a risk factor for weight gain. However, only few studies have addressed sleep in early childhood. Our aim was to determine whether sleep in the second year of life is associated with the development of body composition throughout childhood. METHODS: Analysis included 481 DONALD participants with parental reported data on sleep duration and annually measured body composition until age 7. Using median splits of sleeping time at 1.5 and 2 years we defined sleep duration categories: consistently short (CS, n = 122), inconsistent (I, n = 143) and consistently long (CL, n = 216). Polynomial mixed effects regression models were used to analyze differences in the trajectories of body mass index (BMI, kg/m(2)), fat mass index (FMI, kg/m(2)) and fat free mass index (FFMI, kg/m(2)) from ages 2-7 years between the sleep duration categories. RESULTS: Compared to CL-children, CS-sleepers differed in their FMI development with respect to linear, quadratic and cubic trend (all p < 0.04), resulting in progressively higher FMI levels until age 7 independently of early life or socioeconomic factors. Trajectories of BMI and FFMI did not differ between the sleep duration categories. CONCLUSION: Consistently short sleep duration in the critical window of early childhood appears to exert a moderate but sustained adverse effect on the development of fat mass - but not fat free mass - until age 7. PMID- 21604965 TI - Randomized controlled trial of a good practice approach to treatment of childhood obesity in Malaysia: Malaysian Childhood Obesity Treatment Trial (MASCOT). AB - CONTEXT: Few randomized controlled trials (RCTs) of interventions for the treatment of childhood obesity have taken place outside the Western world. AIM: To test whether a good practice intervention for the treatment of childhood obesity would have a greater impact on weight status and other outcomes than a control condition in Kuala Lumpur, Malaysia. METHODS: Assessor-blinded RCT of a treatment intervention in 107 obese 7- to 11-year olds. The intervention was relatively low intensity (8 hours contact over 26 weeks, group based), aiming to change child sedentary behavior, physical activity, and diet using behavior change counselling. Outcomes were measured at baseline and six months after the start of the intervention. Primary outcome was BMI z-score, other outcomes were weight change, health-related quality of life (Peds QL), objectively measured physical activity and sedentary behavior (Actigraph accelerometry over 5 days). RESULTS: The intervention had no significant effect on BMI z score relative to control. Weight gain was reduced significantly in the intervention group compared to the control group (+1.5 kg vs. +3.5 kg, respectively, t-test p < 0.01). Changes in health-related quality of life and objectively measured physical activity and sedentary behavior favored the intervention group. CONCLUSIONS: Treatment was associated with reduced rate of weight gain, and improvements in physical activity and quality of life. More substantial benefits may require longer term and more intensive interventions which aim for more substantive lifestyle changes. PMID- 21604966 TI - Ameliorative effect of thymoquinone on ovalbumin-induced allergic conjunctivitis in Balb/c mice. AB - OBJECTIVE: Thymoquinone (TQ) is an active and potent compound in the oil of Nigella sativa, which has anti-inflammatory properties. The aim of this study was to evaluate the effects of TQ on ovalbumin (OVA)-induced allergic conjunctivitis (AC) in Balb/c. METHODS: The mice were divided into seven experimental groups; PBS Con, OVA Con, Conj, 0.05%TQ, 0.1%TQ, 0.5%TQ and Dex group. The mice were immunized and exposed to OVA, and eyes were treated with TQ and dexamethasone. Ocular symptoms were observed after last exposure to OVA. Eosinophils count in blood and Ophthalmic lavage fluid (OLF), recruitment of inflammatory cells in conjunctiva, serum IgE and OVA-specific IgE were evaluated by Giemsa and HE staining, and Enzyme-Linked Immunosorbent Assay (ELISA) respectively. High Performance Liquid Chromatography (HPLC) was used to determine the histamine level in OLF. The mRNA expression and protein level of cytokines were examined by real time RT-PCR and ELISA respectively. RESULTS: Ocular symptoms of AC and other characteristics of allergic inflammation including IgE and OVA-specific immunoglobulin E (IgE) level, recruitment of eosinophils, histamine level, mRNA expressions and protein level of cytokines were remarkably increased in OVA exposed mice compared with the control groups. Administration of TQ suppressed the ocular symptoms, inflammatory cell infiltration in conjunctiva, blood and OLF, increased level of serum IgE and OVA-specific IgE, and OLF histamine level in OVA-exposed mice. Furthermore, TQ abrogated the mRNA expression and serum level of interleukin including 1L-4, IL-5, IL-13 and transforming growth factor beta (TGF-beta) in mice immunized and exposed to OVA. CONCLUSION: Administration of TQ significantly reduced the ocular symptoms in AC by attenuating the recruitment of eosinophils, level of IgE, histamine and cytokines. Our findings suggest that TQ might be a useful intimation for the treatment and future research for AC. PMID- 21604967 TI - Age and gender differences in the association between Nt-proBNP and glucometabolic disturbances. AB - OBJECTIVES: Glucometabolic disturbances are associated with myocardial dysfunction. Brain natriuretic peptides (BNP) are used for detecting myocardial dysfunction in clinical practice. However, studies on elderly subjects and gender specific analyses are sparse. DESIGN: We examined cross-sectional associations between Nt-proBNP and 1) fasting plasma glucose (FPG), and 2) categories of glucometabolic disturbances, in middle-aged and older subjects (1266 men, 526 women), applying multivariate linear regression analysis. RESULTS: FPG was positively correlated with Nt-proBNP among middle-aged men (p = 0.04) and negatively albeit non-significantly (p = 0.1) among middle-aged women. Weaker non significant correlations were seen among older subjects. Middle-aged men with new onset and prevalent diabetes had higher Nt-proBNP than the reference group (FPG <=5.0 mmol/L): 9.53 (p = 0.002) and 8.23 (p = 0.02) vs. 5.71 pmol/L. No differences in Nt-proBNP between categories of glucometabolic disturbance were observed among older men or women. CONCLUSIONS: The results indicate an age- and gender difference in the ability of Nt-proBNP to identify myocardial dysfunction in relation to glucometabolic disturbances. Therefore, Nt-proBNP should be used with caution as a general surrogate marker for myocardial dysfunction in this setting. PMID- 21604969 TI - Relationship between ZnT8Ab, the SLC30A8 gene and disease progression in children with newly diagnosed type 1 diabetes. AB - Autoantibodies against the newly established autoantigen in type 1 diabetes, zinc transporter 8, ZnT8, are presented as two types, ZnT8RAb and ZnT8WAb. The rs13266634 variant of the SLC30A8 gene has recently been found to determine the type of ZnT8Ab. The aim of this study was to explore the impact of this genetic variant and the ZnT8Ab on the residual beta-cell function during disease progression the first year after disease diagnosis in children with newly diagnosed type 1 diabetes. This cohort consists of 257 children aged < 16 years, all patients were newly diagnosed with type 1 diabetes. A Boost-test was carried out at 1, 6, and 12 months to characterize the residual beta-cell function. Carriers of the CC and CT genotype groups of the rs13266634 SNP of the SLC30A8 gene had higher stimulated C-peptide levels the first year after onset compared with those of the TT genotype group (29%, p = 0.034). CC genotype carriers were highly associated with the presence of ZnT8RAb subtype during disease progression (compared with TT, p < 0.0001). On the other hand, the TT genotype was associated with the presence of ZnT8WAb subtype during disease progression (compared with CC, p < 0.0001). The C allele of the SLC30A8 gene is associated with preserved beta-cell function in type 1 diabetes patients. The genetic determination of the rs13266634 variant on the ZnT8Ab specificity is sustained the first 12 months after the diagnosis of type 1 diabetes in a pediatric cohort. PMID- 21604970 TI - Uric acid and HMGB1 are involved in the induction of autoantibodies elicited in mice infected with mouse hepatitis virus A59. AB - We have shown that mice infected with mouse hepatitis virus A59 develop autoantibodies (autoAb) to liver and kidney fumarylacetoacetate hydrolase (FAH). Because it has been proposed that the immune system is stimulated by alarm signals called damage-associated molecular patterns or alarmins, we investigated the participation of uric acid and high-mobility group box protein 1 (HMGB1) in the autoimmune response elicited by mouse hepatitis virus (MHV). Mice subjected to MHV infection had increased plasmatic uric acid concentration that significantly decreased after 20 days of daily treatment with allopurinol and, simultaneously, autoAb to FAH were undetected. Furthermore, this autoAb disappeared after 30 days of treatment with ethyl pyruvate, along with a substantial reduction in serum HMGB1 concentration. Both results indicated a remarkable relationship between the autoimmune process induced by the virus and uric acid and HMGB1 liberation. Unexpectedly, it was found that allopurinol and ethyl pyruvate inhibited the release of both uric acid and HMGB1. Because HMGB1 is activated through binding to interleukin 1beta, and that this cytokine is produced by the NLRP3 inflammasome that could be stimulated by uric acid, we propose that both alarmins could be acting in concert with the induction of the autoAb to FAH in MHV-infected mice. PMID- 21604971 TI - Transfer of cell membrane components via trogocytosis occurs in CD4+ Foxp3+ CD25+ regulatory T-cell contact-dependent suppression. AB - A key component of the immune system is its ability to establish and maintain peripheral tolerance. Naturally occurring CD4+ CD25+ Foxp3+ regulatory T (nTreg) cells represent an important means by which this is accomplished, through their potent ability to suppress the actions of both CD4+ and CD8+ effector (Teff) cells in vitro and in vivo. We hypothesized that direct contact between nTreg and Teff cells is sufficient for nTreg cell-contact suppression. We first show that nTreg cell suppression is independent of APCs and their derived co-stimulatory signals. We then used a two-colour, lipid dye labelling and quantification approach to formally demonstrate that nTreg cells specifically form cell conjugates with responding T (Tresp) cells only under TCR activating conditions. Strikingly, activated CD4+ nTreg cells undergo progressive trogocytosis, a process by which membrane fragments are transferred from one cell subset to another, with Tresp cells more readily than Teff cells. These results are the first to show that nTreg cell cognate interactions with Tresp cells leads to trogocytosis between the cells, and the first to relate the degree of trogocytosis with the level of nTreg-mediated suppression. PMID- 21604972 TI - Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis. AB - Current treatments for rheumatoid arthritis (RA) have long-term side effects such that new treatments are needed that can safely help manage the disease. There is a growing appreciation that GABA receptors (GABA-Rs) on immune cells provide new targets that can be used to modulate immune cell activity. Here, we show for the first time that activation of peripheral GABA-Rs can inhibit the development of disease in the collagen-induced arthritis (CIA) mouse model of RA. Mice that received oral GABA had a reduced incidence of CIA, and those mice that did develop CIA had milder symptoms. T cells from GABA-treated mice displayed reduced proliferative responses to collagen and their APC had a reduced ability to promote the proliferation of collagen-reactive T cells. Thus, GABA downregulated both T-cell autoimmunity and APC activity. Collagen-reactive T cells from GABA treated mice displayed reduced recall responses in the presence of GABA ex vivo, indicating that GABA consumption did not desensitize these cells to GABA. GABA treated mice had reduced collagen-reactive IgG2a, but not IgG1 antibodies, consistent with reduced Th1 help. The levels of serum anti-collagen IgG2a antibodies were correlated significantly with the CIA disease scores of individual mice. Our results suggest that activation of peripheral GABA-Rs may provide a new modality to modulate T cell, B cell, and APC activity and help ameliorate RA and other inflammatory diseases. PMID- 21604973 TI - Decreased frequencies of CD4+CD25+Foxp3+ cells and the potent CD103+ subset in peripheral lymph nodes correlate with autoimmune disease predisposition in some strains of mice. AB - The CD4(+)CD25(+)Foxp3(+) cells are essential for regulation of the immune response, and the integrin, CD103 (alpha(E)beta(7)), identifies a potent subset of these cells. Defects in CD4(+)CD25(+)Foxp3(+) cells are thought to contribute to susceptibility to autoimmune disease in predisposed individuals. Studies evaluating the quality and quantity of CD4(+)CD25(+)Foxp3(+) regulatory cell populations in the context of autoimmune disease susceptibility have been inconclusive, and few if any, have analyzed the CD103 subset. In this study, we analyzed regulatory T cells (Tregs) from different strains of mice with varying degrees of susceptibility to autoimmune disease. We found no differences in the ability of CD4(+)CD25(+) or the CD103(+) subset of Tregs from young female (NZB * NZW)F1 (BWF1), SJL, C57BL/6, or BALB/c mice to suppress CD4(+)CD25(- ) responders in vitro. Analysis of CD4(+)Foxp3(+) and CD4(+)CD25(+)CD103(+) cell frequencies in lymphoid organs revealed that BWF1 mice had dramatically lower percentages of both populations in the lymph node (LN) than the other strains, and lower percentages in the spleen in all but the C57BL/6 strain. We next determined whether these findings extended to another autoimmune-prone strain. Similar to BWF1 mice, percentages of CD4(+)Foxp3(+) and CD4(+)CD25(+)CD103(+) cells were significantly lower in predisease NOD mice. The low frequencies of CD4(+)Foxp3(+) and CD4(+)CD25(+)CD103(+) cells in BWF1 and NOD mice were not due to deficiencies in either thymic production or homeostatic proliferation. These data indicate that decreased percentages of CD4(+)Foxp3(+) cells and particularly, CD4(+)CD25(+)CD103(+) cells in LN correlate with the predisposition to spontaneous development of autoimmune disease. PMID- 21604974 TI - Vaccines in clinical trials: infectious disease. PMID- 21604976 TI - Emerging vector-borne flavivirus diseases: are vaccines the solution? PMID- 21604975 TI - Meningococcal serogroup B vaccines: will they live up to expectations? PMID- 21604977 TI - Pediatric influenza immunization. PMID- 21604979 TI - A combination recombinant protein and outer membrane vesicle vaccine against serogroup B meningococcal disease. AB - Although meningococcal disease caused by serogroup B remains an important public health concern, a licensed vaccine providing broad protection against this pathogen is not yet available. Advances in genomics have paved the way for the discovery of new vaccine candidates for inclusion into a multicomponent serogroup B vaccine. In this article, we will review recent advances in the development of these vaccines, focussing particularly on one of the 'next generation' MenB vaccines, 4CMenB. PMID- 21604980 TI - The RTS,S vaccine candidate for malaria. AB - Malaria continues to be a worldwide leading cause of morbidity and mortality, and the development of an effective malaria vaccine remains a research imperative. Of the multiple approaches that have been pursued, the RTS,S/AS01 vaccine candidate represents the most developed and clinically validated malaria vaccine formulation. Throughout its development, increasingly more effective adjuvants have been key in improving the potency of the vaccine. RTS,S-based vaccine formulations have been demonstrated to be safe, well tolerated, immunogenic, and to confer partial efficacy in both malaria-naive and -experienced adults as well as children. Further research to optimize and improve vaccine efficacy is ongoing. PMID- 21604981 TI - Safety and immunogenicity of a chimeric vaccine for West Nile virus in aged subjects. AB - A recent Phase II clinical trial has demonstrated comparable safety and immunogenicity of ChimeriVax-WN02, a chimeric West Nile virus (WNV) vaccine candidate based on yellow fever 17D, in small cohorts of healthy adults aged 18 40, 41-64 and 65-80 years. Adults >=65 years of age are an important target population for candidate WNV vaccines as they have a high risk for severe WNV neuroinvasive disease. The apparent safety and immunogenicity of ChimeriVax-WN02 in this population indicates that further development and clinical testing are justified. PMID- 21604982 TI - Review of diphtheria, tetanus and pertussis vaccines in clinical development. AB - Diphtheria, tetanus and pertussis vaccines have formed the cornerstone of childhood immunization programs for decades. Historically, these have comprised diphtheria and tetanus toxoids combined with inactivated whole-cell pertussis. More recently, advances have been made with the development of purified acellular pertussis vaccines, with improved reactogenicity profiles, and formulation with additional vaccines such as Haemophilus influenzae type b, hepatitis B virus and inactivated poliovirus. Development is currently focused on maximizing the number of vaccines that can be combined in a single formulation and strategies to provide protection against pertussis before the commencement of routine infant immunization. PMID- 21604983 TI - New frontiers in meningococcal vaccines. AB - Challenges remain in developing effective meningococcal vaccines and vaccination programs in both the industrialized and developing worlds. Vaccination programs should ideally provide broad coverage of disease-causing strains to prevent disease and also promote the herd immunity important for extending protection to the at-risk unvaccinated population. The success of meningococcal serogroup C conjugate vaccination programs during the last 10 years demonstrates the tremendous positive impact on human health that may be attainable; however, significant challenges remain to implement effective use of serogroup A vaccines for the developing world and to develop broadly protective vaccines against serogroup B disease. The effectiveness of vaccination programs, and shifts in disease epidemiology, must be monitored continuously to evaluate protection levels and to identify gaps in disease coverage. As these challenges are met, the possibility for removing the fear of meningococcal disease from all societies is now becoming a reality. PMID- 21604984 TI - Clinical development of a novel inactivated poliomyelitis vaccine based on attenuated Sabin poliovirus strains. AB - Following achievement of polio eradication, the routine use of all live attenuated oral poliovirus vaccines should be discontinued. However, the costs per vaccine dose for the alternative inactivated poliovirus vaccine (IPV) are significantly higher and the current production capacity is not sufficient for worldwide distribution of the vaccine. In order to achieve cost-prize reduction and improve affordability, IPV production processes and dose-sparing strategies should be developed to facilitate local manufacture at a relatively lower cost. The use of attenuated Sabin instead of wild-type polio strains will provide additional safety during vaccine production and permits production in low-cost settings. Sabin-IPV is under development by several manufacturers. This article gives an overview of results from clinical trials with Sabin-IPV and discusses the requirements and challenges in the clinical development of this novel IPV. PMID- 21604985 TI - Tuberculosis vaccines in clinical trials. AB - Effective prophylactic and/or therapeutic vaccination is a key strategy for controlling the global TB epidemic. The partial effectiveness of the existing TB vaccine, bacille Calmette-Guerin (BCG), suggests effective vaccination is possible and highlights the need for an improved vaccination strategy. Clinical trials are evaluating both modifications to the existing BCG immunization methods and also novel TB vaccines, designed to replace or boost BCG. Candidate vaccines in clinical development include live mycobacterial vaccines designed to replace BCG, subunit vaccines designed to boost BCG and therapeutic vaccines designed as an adjunct to chemotherapy. There is a great need for validated animal models, identification of immunological biomarkers of protection and field sites with the capacity for large-scale efficacy testing in order to develop and license a novel TB vaccine or regimen. PMID- 21604987 TI - Long-term protection after immunization with protein-polysaccharide conjugate vaccines in infancy. AB - The polysaccharide-encapsulated bacteria, Haemophilus influenzae type b, Neisseria meningitidis and Streptococcus pneumoniae are important causes of invasive bacterial infection in childhood, accounting for most of the cases of bacterial pneumonia and meningitis worldwide. Protein-polysaccharide conjugate vaccines have been developed over the last 20 years and have proven very effective in controlling these infections. Although studies have consistently shown that herd immunity is critical for population protection, long-term individual protection against polysaccharide-encapsulated bacteria appears to depend on persisting antibody and, perhaps to a lesser extent, immunological memory. However, some studies have reported that the concentration of serum antibody and vaccine effectiveness are not sustained after infant immunization, despite persistence of immunological memory. In this article, we detail the mechanisms of protection against invasion by encapsulated bacteria, describe the age-dependent B-cell and antibody responses to protein-polysaccharide conjugate vaccines and propose strategies to guarantee protection during periods of increased disease burden. PMID- 21604988 TI - An update on vaccination against group B streptococcus. AB - Streptococcus agalactiae (group B streptococcus) is an important cause of disease in infants, pregnant women, the elderly and immunosuppressed adults. An effective vaccine is likely to prevent the majority of infant disease (both early and late onset), to avoid the limitations of intrapartum antibiotic prophylaxis and to be cost effective. A number of candidates, including capsular conjugate vaccines, have the potential to be successful vaccines. Phase II human studies with capsular conjugate vaccines have been completed successfully. Issues yet to be resolved include the safety and acceptability of vaccination during pregnancy, the durability of vaccine-derived immunity and the regulatory issues required for licensure. PMID- 21604989 TI - Strategies for and advances in the development of Staphylococcus aureus prophylactic vaccines. AB - Staphylococcus aureus is a common human commensal organism and also a major cause of nosocomial infections worldwide associated with high death rates, prolonged hospitalization and increased medical costs. Severe S. aureus infections are becoming progressively more difficult to treat because of the spread of strains resistant to antibiotics, and community-acquired disease is also increasing. There are many clinical presentations of disease including superficial skin and soft-tissue infections, as well as severe invasive infections including bacteremia, pneumonia and endocarditis. The diverse array of virulence factors expressed by S. aureus contributes to pathogenesis and has provided the basis for antigen selection for new vaccines in clinical development. Key prerequisites for vaccine development include the development of approaches to monitor the immunological responses generated by the vaccine in a way that can predict the vaccine effectiveness. Careful consideration of the patient populations in which candidate vaccines are initially evaluated for their efficacy will also play a key role for vaccine development. There are now several vaccines at different stages of clinical development that offer exciting prospects for the prevention of this devastating disease. The composition and the early clinical results from the evaluation of these vaccines are discussed in this article. PMID- 21604986 TI - Vaccination for hepatitis C virus: closing in on an evasive target. AB - Hepatitis C virus (HCV) infects more than 170 million people globally and is a leading cause of liver cirrhosis, transplantation and hepatocellular carcinoma. Current gold-standard therapy often fails, has significant side effects in many cases and is expensive. No vaccine is currently available. The fact that a significant proportion of infected people spontaneously control HCV infection in the setting of an appropriate immune response suggests that a vaccine for HCV is a realistic goal. A comparative analysis of infected people with distinct clinical outcomes has enabled the characterization of many important innate and adaptive immune processes associated with viral control. It is clear that a successful HCV vaccine will need to exploit and enhance these natural immune defense mechanisms. New HCV vaccine approaches, including peptide, recombinant protein, DNA and vector-based vaccines, have recently reached Phase I/II human clinical trials. Some of these technologies have generated robust antiviral immunity in healthy volunteers and infected patients. The challenge now is to move forward into larger at-risk or infected populations to truly test efficacy. PMID- 21604991 TI - The influence of different lipid environments on the structure and function of the hepatitis C virus p7 ion channel protein. AB - Abstract The hepatitis C virus (HCV) encodes the p7 protein that oligomerizes to form an ion channel. The 63 amino acid long p7 monomer is an integral membrane protein predominantly found in the endoplasmic reticulum (ER). Although it is currently unknown whether p7 is incorporated into secreted virions, its presence is crucial for the release of infectious virus. The molecular and biophysical mechanism employed by the p7 ion channel is largely unknown, but in vivo it is likely to be embedded in membranes undergoing changes in lipid composition. In this study we analyze the influence of the lipid environment on p7 ion channel structure and function using electrophysiology and synchrotron radiation circular dichroism (SRCD) spectroscopy. We incorporated chemically synthesized p7 polypeptides into artificial planar membranes of various lipid compositions. A lipid bilayer composition comprising phosphatidylcholine (PC) and phosphatidylethanolamine (PE) (4:1 PC:PE) led to burst-like patterns in the channel recordings with channel openings lasting up to 0.5 s. The reverse ratio of PC:PE (1:4) gave rise to individual channels continuously opening for up to 8 s. SRCD spectroscopy of p7 embedded into liposomes of corresponding lipid compositions suggests there is a structural effect of the lipid composition on the p7 protein. PMID- 21604993 TI - Psychometric characteristics of Duruoz Hand Index in patients with traumatic hand flexor tendon injuries. AB - INTRODUCTION: The aim of the study was to assess reliability, validity and responsiveness of Duruoz Hand Index (DHI), which has been developed for evaluation of activity limitation in rheumatoid arthritis in patients with traumatic hand flexor tendon injuries. MATERIAL AND METHOD: Sixty-five patients older than 16 years who underwent surgical intervention after flexor tendon injuries were enrolled. Reliability was assessed by internal consistency (with Cronbach's-alpha) and test-retest intraclass correlation coefficient (ICC). Construct validity was estimated correlating the scale with the DASH and VAS-hd. Also responsiveness was estimated using standardised response mean (SRM) and effect size (ES). RESULT: Mean age of the patients was 30.25 +/- 11.07 years and totally 140 fingers were evaluated. Cronbach's-alpha and ICC values of DHI were found to be 0.87 and 0.99, respectively. In validation study, highly significant correlation was detected between DHI with DASH and VAS-hd (r = 0.86, r = 0.54, p < 0.0001, respectively). SRM values and ES values (excepting workplaces subgroup score) were higher than 0.80 for total and all subgroup scores. CONCLUSION: DHI is a reliable, valid questionnaire to assess hand-related activity limitation in patients with traumatic hand flexor tendon injuries. Also, due to its high level responsiveness DHI can be used for assessing the clinical course of the traumatic hand flexor tendon injured patient. PMID- 21604995 TI - Intrapartum cardiotocography (CTG) and ST-analysis of labor in diabetic patients. AB - AIM: To determine the prevalence and types of intrapartum cardiotocography (CTG) patterns and investigate their relationship to moderate acidemia in term fetuses of diabetic mothers. Also, to assess if the combination of fetal electrocardiogram (FECG) and those CTG patterns strengthens the association with moderate acidemia. MATERIAL AND METHODS: The material for this study is obtained from the Swedish randomized control trial and the European Union ST-analysis trial. We developed an analytical model for CTG patterns based on the progress in CTG changes, in a longitudinal periodic manner. The model was then combined with information regarding changes in ST interval that indicate threatening asphyxia, and the findings were analyzed to determine correlation with the presence of moderate acidemia at birth. RESULTS: This study involved data of 413 diabetic mothers. A preterminal CTG was more common in the diabetes mellitus (DM) group (6/70, 8.6%) than in the gestational diabetes (GD) group (3/307, 1.0%; P=0.003). For diabetic mothers (i.e., DM+GD) with a normal CTG at the start of monitoring, the presence of FECG data indicating asphyxia significantly increased the likelihood of an umbilical artery pH<7.15 at birth [odds ratio (OR)=3.65, 95% confidence interval (CI)=1.33-10.05]. Among labors where the CTG was non reassuring at the start of monitoring, no significant association was found between pH<7.15 and indication to intervene according to FECG information (OR=1.51, 95% CI=0.33-7.0). CONCLUSIONS: A preterminal CTG is more common in the fetuses of DM than GD mothers during labor. When CTG was normal at the start of recording, the addition of FECG information gave a significant add on information to predict moderate acidemia. PMID- 21604994 TI - Glial cell line-derived neurotrophic factor gene transfer exerts protective effect on axons in sciatic nerve following constriction-induced peripheral nerve injury. AB - Damage to peripheral nerves following trauma or neurodegenerative diseases often results in various sensory and motor abnormalities and chronic neuropathic pain. The loss of neurotrophic factor support has been proposed to contribute to the development of peripheral neuropathy. The main objective of this study was to investigate the protective effect of glial cell line-derived neurotrophic factor (GDNF) using peripheral gene delivery in a rat model of constriction-induced peripheral nerve injury. In this study, it was shown that mechanical and thermal hypersensitivity increased on the injured limb at day 7 after chronic constrictive injury (CCI) was induced. The neurological changes were correlated with the structural changes and loss of GDNF/Akt signaling, particularly in the distal stump of the injured sciatic nerve. Subsequently, recombinant adenovirus was employed to evaluate the potential of intramuscular GDNF gene delivery to alleviate the CCI-induced nerve degeneration ad neuropathic pain. After CCI for 3 days, intramuscular injection of adenovirus encoding GDNF (Ad-GDNF) restored the protein level and activity of GDNF/Akt signaling pathway in the sciatic nerve. This was associated with an improved myelination profile and behavioral outcomes in animals with CCI. In conclusion, the present study demonstrates the involvement of GDNF loss in the pathogenesis of CCI-induced neuropathic pain and the therapeutic potential of intramuscular GDNF gene delivery for the treatment of peripheral nerve degeneration. PMID- 21604996 TI - Oxytocin versus dinoprostone vaginal insert for induction of labor after previous cesarean section: a retrospective comparative study. AB - OBJECTIVE: To compare the efficacy and safety of two methods for induction of labor after previous cesarean section. METHODS: To compare 247 women with a previous cesarean section who were induced with a dinoprostone vaginal insert and 279 women with a previous cesarean section induced with oxytocin, between 2001 and 2008. We evaluated vaginal delivery rate, maternal morbidity and newborn morbidity and mortality. RESULTS: The overall rate of vaginal delivery was 65.2%. We did not find significant differences between induction with dinoprostone vaginal insert and oxytocin in the rate of cesarean section performed (35.6% vs. 34.1%, P=0.71). There were nine cases of uterine rupture (rate of 1.7%), of which four occurred with dinoprostone vaginal insert and five when using oxytocin (P=0.89). We found no significant differences in neonatal outcomes. CONCLUSIONS: Both tested methods appear to be equally safe and effective for induction of labor in women with a previous cesarean section. PMID- 21604997 TI - Domains of apoE4 required for the biogenesis of apoE-containing HDL. AB - INTRODUCTION. We have studied the functions of truncated apoE4 forms in vitro and in vivo in order to identify the domains of apoE4 required for the biogenesis of apoE-containing high-density lipoprotein (HDL). RESULTS. We have found that apoE4 185, -202, -229, or -259 could promote ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux in vitro, although less efficiently than Full-length apoE4, and had diminished capacity to activate lecithin cholesterol acyltransferase (LCAT). Formation of HDL in vivo was assessed by various methods following gene transfer in apolipoprotein A-I(-/-) * apoE(-/-) mice. Fast protein liquid chromatography of plasma showed that the truncated apoE forms, except apoE4-185, generated an apoE-containing HDL peak. Two-dimensional gel electrophoresis of plasma and electron microscopy showed that truncated apoE forms generated distinct HDL subpopulations and formed discoidal HDL particles which could be converted to spherical by co-administration of truncated apoE4-202 and LCAT. CONCLUSION. Overall, the in-vivo and in-vitro data are consistent and indicate that apoE4-185 is the shortest truncated form that supports formation of discoidal apoE4-containing HDL particles. PMID- 21604999 TI - Maternal and neonatal profile of late-preterm survivors in a poorly resourced country. AB - OBJECTIVE: To determine maternal indicators and adverse perinatal outcomes among late-preterm infants during birth hospitalization in a low-income country. METHODS: Cross-sectional study of late-preterm and term survivors in a tertiary maternity hospital in southwest Nigeria using multivariable logistic regression analysis and population attributable risk (PAR) percentage. Adjusted odds ratios (OR) and 95% confidence intervals (CI) of significant factors are stated. RESULTS: Of 4176 infants enrolled, 731 (17.5%) were late preterm and 3445 (82.5%) were full-term. Late-preterm delivery was independently associated with mothers who were unmarried (OR: 1.71, CI: 1.06-2.75), lacked formal education (OR: 1.75, CI: 1.06-2.89), human immunodeficiency virus positive (OR: 1.61, CI: 1.17-2.20), with hypertensive disorders (OR: 3.07, CI: 2.32-4.08), antepartum hemorrhage (OR: 3.66, CI: 1.97-6.84), and were unlikely to have induced labor (OR: 0.010, CI: 0.01-0.69). Hypertensive disorders and antepartum hemorrhage had a combined PAR of 48.4%. Infants born late preterm were more likely to have low 5-min Apgar scores (OR: 1.70, CI: 1.01-2.83), sepsis (OR: 1.62, CI: 1.05-2.50), hyperbilirubinemia (OR: 1.56, CI: 1.05-2.33), admission into special care baby unit (OR: 1.85, CI: 1.38-2.48), and nonexclusive breast-feeding (OR: 1.49, CI: 1.49, CI: 1.18-1.89). CONCLUSIONS: These findings suggest that late-preterm infants in low-resource settings are at risk of severe morbidity and suboptimal feeding. Education and close monitoring of high-risk mothers are warranted to prevent avoidable late-preterm delivery and facilitate the proactive management of unavoidable late-preterm births. PMID- 21605000 TI - Fatty acid-binding protein-4 plasma levels are associated to metabolic abnormalities and response to therapy in girls and young women with androgen excess. AB - OBJECTIVE: To assess the usefulness of circulating fatty acid-binding protein 4 (FABP4) as a predictive marker of long-term therapeutic outcome in girls with ovarian androgen excess and a history of precocious pubarche (PP) and low birth weight (LBW) and in young women with polycystic ovary syndrome (PCOS). METHODS: We included 97 patients. Thirty-nine had a history of LBW-PP and were randomized to remain untreated (n = 13) or to receive metformin (n = 26). PCOS women (n = 58) received low-dose flutamide-metformin plus an oral contraceptive. Auxology, androgens, glucose, insulin, homeostasis model assessment (HOMA)-insulin resistance (IR), lipid profile, FABP4, and body composition (by dual-energy X-ray absorptiometry) were assessed at baseline and after 2 years. RESULTS: At baseline, FABP4 was associated with anthropometric measurements and fat body mass (all P < 0.05). FABP4 levels increased less after follow-up in the PP-treated girls (P < 0.05); in the PCOS patients, basal FABP4 levels were inversely associated with changes in systolic blood pressure, HOMA-IR, and total fat mass (all P < 0.05). Body mass index-standard deviation scores was the main independent predictor of FABP4 variations (33%, P < 0.001). CONCLUSION: FABP4 is a strong clinical biomarker of adiposity, IR, and the presence of the components of the metabolic syndrome in non-obese hyperandrogenic girls and young women; pretreatment FABP4 levels appear to predict therapeutic long-term response. PMID- 21605001 TI - High throughput miniaturization of artificial cells. AB - In this study, inkjet bio-printing has been used to produce miniaturized alginate microcapsules. A parametric study using subsequent Taguchi L(18) (3(1) * 2(7)) and L(16) (4(5)) designs was performed to elucidate the effect of inkjet parameters on microcapsule size. A 120-minute pilot run using the optimal waveform parameters and 0.5% alginate ink yielded a throughput of 1.8*10(6) microcapsules/hr, averaging 40 MUm in diameter. Real-time stable jetting conditions were confirmed visually by the generation of a single droplet with a straight trajectory and non-fluctuating Ohnesorge numbers. The rate of stirring of the cross-linking CaCl(2) solution determined scaffold vs. single vesicle formation. PMID- 21605002 TI - Are thyroid cancer patients sensitive to ionising radiation? AB - PURPOSE: To determine the ionising radiation sensitivity of peripheral blood lymphocytes in a group of differentiated thyroid cancer (DTC) patients. MATERIAL AND METHODS: A total of 53 thyroid cancer patients (26 women and 27 men) and 50 donors (23 women and 27 men) were included in the study. The cytokinesis-block micronucleus assay (CBMN) in G0 peripheral blood lymphocytes was carried out using the cytochalasin B technique. Four cultures were established per each donor, two were irradiated with 0.5 Gy 137Cs g-rays, while the other two remained untreated. RESULTS: No significant differences were observed in the frequency of binucleated cells with micronuclei (BNMN) between patients and controls, for both spontaneous and after the irradiation frequencies. Nevertheless, a positive and significant correlation was found between the frequencies of both spontaneous and after irradiation DNA damage, for control and patient groups. CONCLUSIONS: We have found that DTC patients do not present particular sensitivity to ionising radiation when an in vitro treatment is performed in G0 stage of the cell cycle, but this result does not discard the hypothesis about an increased sensitivity in other stages of the cell cycle in DTC patients. PMID- 21605003 TI - The interrealtionship between locally applied heat, ageing and skin blood flow on heat transfer into and from the skin. AB - In response to a thermal stress, skin blood flow (BF) increases to protect the skin from damage. When a very warm, noxious, heat source (44 degrees C) is applied to the skin, the BF increases disproportionately faster than the heat stress that was applied, creating a safety mechanism for protecting the skin. In the present investigation, the rate of rise of BF in response to applied heat at temperatures between 32 degrees C and 40 degrees C was examined as well as the thermal transfer to and from the skin with and without BF in younger and older subjects to see how the skin responds to a non-noxious heat source. Twenty male and female subjects (10 - 20-35 years, 10 - 40-70 years) were examined. The arms of the subjects were passively heated for 6 min with and without vascular occlusion by a thermode at temperatures of 32, 36, 38 or 40 degrees C. When occlusion was not used during the 6 min exposure to heat, there was an exponential rise in skin temperature and BF in both groups of subjects over the 6 min period. However, the older subjects achieved similar skin temperatures but with the expenditure of fewer calories from the thermode than was seen for the younger subjects (p<0.05). BF was significantly less in the older group than the younger group at rest and after exposure to each of the three warmest thermode temperatures (p<0.05). As was seen for noxious temperatures, after a delay, the rate of rise of BF at the three warmest thermode temperatures was faster than the rise in skin temperature in the younger group but less in the older group of subjects. Thus, a consequence of ageing is reduced excess BF in response to thermal stress increasing susceptibility to thermal damage. This must be considered in modelling of BF. PMID- 21605004 TI - Influence of polymorphisms in MTHFR 677 C->T, TYMS 3R->2R and MTR 2756 A->G on NSCLC risk and response to platinum-based chemotherapy in advanced NSCLC. AB - AIMS: Genetic factors may contribute to individual differences in cancer susceptibility, drug efficacy and toxicity. This study was designed to investigate the effects of the polymorphisms of methylenetetrahydrofolate reductase 677 C->T (MTHFR 677 C->T), thymidylate synthase (TYMS 3R->2R),and methionine synthase 2756 A->G (MTR 2756 A->G) on the risk of lung cancer and response to platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). MATERIALS & METHODS: We conducted a case-control study involving 438 NSCLC cases (including 101 follow-up cases) and 641 healthy controls in North China. RESULTS & CONCLUSION: Using a genetic model analysis, the polymorphism MTHFR 677 C->T showed a significantly increased risk for NSCLC in women but not in men, which was observed in the codominant model (CT vs CC adjusted odds ratio [OR] = 2.46; 95% confidence interval [CI]: 1.37-4.42; p = 0.003; TT vs CC adjusted OR: 2.04; 95% CI: 1.09-3.81; p = 0.03) and the dominant model (CT + TT vs CC adjusted OR: 2.30; 95% CI: 1.31-4.05; p = 0.004). In addition, we found that patients with the MTHFR 677 TT genotype showed a better response to platinum based chemotherapy in the recessive model (TT vs CT + CC adjusted OR: 0.24; 95% CI: 0.09-0.68; p = 0.007), the generalized OR was 0.44 (0.22-0.88; p = 0.04). There were no significant associations of the polymorphisms of TYMS 3R->2R or MTR 2756 A->G with the risk of NSCLC or response to platinum-based chemotherapy in advanced NSCLC in any genetic model. Our results suggest that genetic polymorphisms of MTHFR 677 C->T may contribute to NSCLC development in Chinese women and could also influence treatment response for advanced NSCLC patients with platinum-based chemotherapy. Further studies with larger sample sizes are required to validate this association. PMID- 21605005 TI - A strategy to assemble nanoparticles with polymers for mitigating cytotoxicity and enabling size tuning. AB - AIM: We aim to develop a facile strategy for assembling nanoparticles within cross-linked polymer micelles that enables tuning of their overall hydrodynamic size and surface charge and to mitigate toxicity. MATERIALS & METHODS: Hydrophobic nanoparticles and amphiphilic co-polymers self-assembled upon solvent selective precipitation. Size-tunability of the assembled nanostructure was achieved by controlling both the nanoparticle and polymer ratio and the kinetics of the assembly process. RESULTS & CONCLUSION: We were successful in creating polymer shells on the surface of inorganic nanoparticles. The shell thickness could be tuned, and protect the nanoparticles from environmental degradation and minimize the cytotoxicity of inorganic nanoparticles. This strategy provides a method to engineer the interactions of nanoparticles with biological systems, including their targeted delivery to diseased tissues and their safety of use without significantly altering their original materials properties. PMID- 21605006 TI - The role of iron in Libby amphibole-induced acute lung injury and inflammation. AB - Complexation of host iron (Fe) on the surface of inhaled asbestos fibers has been postulated to cause oxidative stress contributing to in vivo pulmonary injury and inflammation. We examined the role of Fe in Libby amphibole (LA; mean length 4.99 um +/- 4.53 and width 0.28 um +/- 0.19) asbestos-induced inflammogenic effects in vitro and in vivo. LA contained acid-leachable Fe and silicon. In a cell-free media containing FeCl(3), LA bound #17 ug of Fe/mg of fiber and increased reactive oxygen species generation #3.5 fold, which was reduced by deferoxamine (DEF) treatment. In BEAS-2B cells exposure to LA, LA loaded with Fe (FeLA), or LA with DEF did not increase HO-1 or ferritin mRNA expression. LA increased IL-8 expression, which was reduced by Fe loading but increased by DEF. To determine the role of Fe in LA-induced lung injury in vivo, spontaneously hypertensive rats were exposed intratracheally to either saline (300 uL), DEF (1 mg), FeCl(3) (21 ug), LA (0.5 mg), FeLA (0.5 mg), or LA + DEF (0.5 mg). LA caused BALF neutrophils to increase 24 h post-exposure. Loading of Fe on LA but not chelation slightly decreased neutrophilic influx (LA + DEF > LA > FeLA). At 4 h post-exposure, LA induced lung expression of MIP-2 was reduced in rats exposed to FeLA but increased by LA + DEF (LA + DEF > LA > FeLA). Ferritin mRNA was elevated in rats exposed to FeLA compared to LA. In conclusion, the acute inflammatory response to respirable fibers and particles may be inhibited in the presence of surface complexed or cellular bioavailable Fe. Cell and tissue Fe-overload conditions may influence the pulmonary injury and inflammation caused by fibers. PMID- 21605007 TI - Airway purinergic responses in healthy, atopic nonasthmatic, and atopic asthmatic subjects exposed to ozone. AB - CONTEXT: Ozone exposure triggers airway inflammatory responses that may be influenced by biologically active purine metabolites. OBJECTIVE: To examine the relationships between airway purine metabolites and established inflammatory markers of ozone exposure, and to determine if these relationships are altered in individuals with atopy or asthma. MATERIALS AND METHODS: Mass spectrometry was utilized to measure concentrations of purine metabolites (adenosine monophosphate [AMP], adenosine, hypoxanthine, uric acid) and non-purine metabolites (taurine, urea, phenylalanine, tyrosine) in induced sputum obtained from 31 subjects with normal lung function (13 healthy controls, eight atopic nonasthmatics, and 10 atopic asthmatic [AA]) before and 4 h after ozone exposure. RESULTS: At baseline, the purines AMP and hypoxanthine correlated with multiple inflammatory markers including neutrophil counts and the cytokines interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-alpha), and IL-1beta (r ranged from 0.41 to 0.66, all P < 0.05). Following ozone exposure, these purines remained correlated with IL-6, IL-8, and TNF-alpha (r = 0.37-0.68). However, AMP and hypoxanthine increased significantly post ozone exposure in atopic nonasthmatics but not in AA. In contrast, the non-purine metabolite taurine correlated with baseline neutrophil counts (r = 0.56) and IL-6 (r = 0.53) and was elevated post-exposure in both atopic cohorts. DISCUSSION AND CONCLUSIONS: The purine metabolites AMP and hypoxanthine are correlated with multiple inflammatory markers at baseline and after ozone exposure. However, changes in these purine metabolites after ozone appear to differ from other inflammatory markers, with less response in AA relative to atopic nonasthmatics. Purine metabolites may play a role in the signaling responses to ozone, but these responses may be altered in subjects with asthma. PMID- 21605008 TI - Performance of a human inhalation challenge exposure system. I. Gases. AB - The purpose of this study was to characterize and evaluate the performance of a whole-body human exposure chamber for controlled test atmospheres of gases and particulates. This article is a report on the performance of the system with gas phase agents. Results of the performance of the system with particulate phase agents will be presented in a separate report. The chamber was constructed from Plexiglas with a volume of 2.13 m(3) (75 ft(3)) and operating at a flow rate about 1.0 m(3)/min (34 cfm). Both the makeup and exhaust air were HEPA-filtered. CO(2) was used as a tracer gas and its concentration was measured using Metrosonics aq-5000 instruments. The CO(2) concentrations used in this study ranged from about 5000 to 12,000 ppm. Observed and predicted concentrations at equilibrium of test material were in agreement within 1.7%. Concentration of CO(2) was found to be even horizontally throughout the chamber, with a small initial lag of about 30 sec between the maximum concentration at the top and the bottom of the chamber. The system can thus be reliably used for inhalation challenge procedures for gases. PMID- 21605009 TI - EGFR upregulates inflammatory and proliferative responses in human lung adenocarcinoma cell line (A549), induced by lower dose of cadmium chloride. AB - Exposure to cadmium is associated with the development of pulmonary damage such as emphysema and lung cancer. This metal is also a powerful inducer of different proinflammatory and cell cycle regulatory proteins in many biologic models. Previously, we showed that prolonged exposure of low concentration of cadmium resulted in upregulation of proinflammatory cytokines and cell cycle regulatory molecules in mice lung cell. The present study was undertaken to determine molecular mechanism of inflammation and its relation to cell proliferation in a transformed human lung adenocarcinoma epithelial cell line (A549) in response to cadmium chloride. In comparative studies, we examine that short-duration exposure to lower doses of cadmium significantly increase the growth of A549 cells, whereas higher doses are toxic and cause cell death. We also observed that cadmium induced elevated expression of epidermal growth factor receptor (EGFR) along with different proinflammatory cytokines like interleukin-1 beta (IL 1beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). The possible occurrence of cell proliferation events was evaluated via analysis of the physical state of the DNA and the expression of Ki-67 and proliferating cell nuclear antigen (PCNA). We also checked the pattern of expression of different cell cycle regulatory molecules involved in the onset of cell proliferation. Our results indicate that cadmium treatment appears to induce inflammatory and growth responses in transformed A549 cell line by activating EGFR and its downstream modulators. These results may contribute to better understand the toxic mechanism of cadmium; moreover, the expression profile of cadmium-induced regulatory molecules could provide potential biomarkers for cadmium exposure. PMID- 21605010 TI - Health effects of subchronic inhalation exposure to simulated downwind coal combustion emissions. AB - CONTEXT: There have been no animal studies of the health effects of repeated inhalation of mixtures representing downwind pollution from coal combustion. Environmental exposures typically follow atmospheric processing and mixing with pollutants from other sources. OBJECTIVE: This was the fourth study by the National Environmental Respiratory Center to create a database for responses of animal models to combustion-derived pollutant mixtures, to identify causal pollutants-regardless of source. METHODS: F344 and SHR rats and A/J, C57BL/6, and BALB/c mice were exposed 6 h/day 7 days/week for 1 week to 6 months to three concentrations of a mixture simulating key components of "downwind" coal combustion emissions, to the highest concentration filtered to remove particulate matter (PM), or to clean air. Emissions from low-sulfur subbituminous coal were modified to create a mixture recommended by an expert workshop. Sulfur dioxide, nitrogen oxides, and PM were the dominant components. Nonanimal-derived PM mass concentrations of nominally 0, 100, 300, and 1000 ug/m(3) were mostly partially neutralized sulfate. RESULTS: Only 17 of 270 species-gender-time-outcome comparisons were significantly affected by exposure; some models showed no effects. There was strong evidence that PM participated meaningfully in only three responses. CONCLUSION: On a total mass or PM mass basis, this mixture was less toxic overall than diesel and gasoline exhausts or wood smoke. The largely sulfate PM contributed to few effects and was the sole cause of none. The study did not allow identification of causal pollutants, but the potential role of NOx in some effects is suggested by the literature. PMID- 21605011 TI - c-Jun N-terminal kinases in memory and synaptic plasticity. AB - The c-Jun N-terminal kinases (JNK) belong to the subfamily of mitogen-activated protein kinases (MAPK). JNK is an important signaling enzyme that is involved in many facets of cellular regulation including gene expression, cell proliferation and programmed cell death. Activation of JNK isoforms (JNK1, 2, and 3) is regarded as a molecular switch in stress signal transduction. The activation of JNK pathways is also critical for pathological death associated with neurodegenerative diseases. Considering that a variety of stressors activate JNK, it is surprising that the role of hippocampal JNK in memory and synaptic plasticity has not yet been systematically investigated. Here we summarize the emerging evidence for the functions of hippocampal JNK in memory and synaptic plasticity, including our recent demon-stration that JNK isoforms play critical roles in regulation of contextual fear conditioning under stressful and baseline conditions. We postulate that sustained activation of the hippocampal JNK2 and JNK3 pathways is involved in the initial stress response that ultimately leads to deficits in memory and long-term potentiation, whereas transient JNK1 activation regulates baseline contextual fear conditioning. Results obtained within the framework of our recent findings will be used for future work, which will differentiate mechanisms underlying beneficial short-term JNK action from prolonged JNK activation that may lead to memory deficits and neurodegeneration. PMID- 21605012 TI - International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine position on bone marker standards in osteoporosis. AB - The International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Working Group on Bone Marker Standards (WG-BMS) has evaluated the clinical potential of bone turnover markers (BTMs) in the prediction of fracture risk and for monitoring treatment. Research evidence suggests that BTMs may provide information on fracture risk independently from BMD, so that fracture risk prediction might be enhanced by their inclusion in assessment algorithms. The potential use of BTMs to predict the response to treatments for osteoporosis in the individual patient is also of great interest. Treatment-induced changes in specific markers account for a substantial proportion of fracture risk reduction. However, there is still a need for stronger evidence on which to base practice in both situations. IOF/IFCC recommends one bone formation marker (serum procollagen type I N propeptide, s PINP) and one bone resorption marker (serum C-terminal cross-linking telopeptide of type I collagen, s-CTX) to be used as reference markers and measured by standardised assays in observational and intervention studies in order to enlarge the international experience of the application of markers to clinical medicine and to help resolve uncertainties over their clinical use. PMID- 21605013 TI - Prognostic value of cystatin C in acute coronary syndromes: enhancer of atherosclerosis and promising therapeutic target. AB - BACKGROUND: Cystatin C (CC) has been proposed to play a role in atherosclerosis. We aimed to review the prognostic value of CC serum/plasma levels in patients with acute coronary syndromes (ACS). METHODS: Fifteen observational longitudinal studies were selected by Medline. RESULTS: Increased CC over threshold values ranging from 0.93 to 1.3 mg/L were prognostic for death (hazard ratio; HR: 2.04 3.6) and for the occurrence of any fatal and non-fatal cardiovascular events (HR: 1.7-9.6) for patients with either ACS only or coronary heart disease and prevalent ACS. Only one study showed an increased risk for future myocardial infarction (MI) in patients with marker levels higher than 1.0 mg/L. Three studies reported the risk associated with a change of one unit of CC for long term death (HR ranging from 1.9 to 6.3) and for the composite end point of 1 year MI and death (HR 2.15). Some studies showed the additional prognostic value contributed from CC measurements to other markers and to conventional risk scores. CONCLUSION: Despite low to moderate evidence, there is a general agreement on the significant prognostic value of CC in ACS that might encourage further research focused on risk assessment for patients with MI. PMID- 21605014 TI - Pre-analytical effects of different lithium heparin plasma separation tubes in the routine clinical chemistry laboratory. AB - BACKGROUND: In this study the pre-analytical effects of sample storage on frequently used routine clinical chemistry assays were evaluated by comparing four different lithium heparin plasma separation tubes to a reference collection procedure. METHODS: Blood was collected from 20 healthy volunteers using plasma separation tubes from four different manufacturers together with manually separated plasma as reference. In total, 15 clinical chemistry parameters were determined at 0 h, 24 h, and 72 h. Samples were stored at 4 degrees C. Statistical differences were evaluated using a generalized estimating equation regression model. RESULTS: Significant differences could be demonstrated for almost every parameter when comparing the separation tubes to the reference collection system. The estimated maximum allowable storage time in the primary tube was considerably reduced using separation tubes, e.g., for glucose the maximum storage time was reduced from >72 h to 7-15 h, and for potassium from 60 h to 10-13 h, respectively. CONCLUSIONS: These data indicate that sample storage in the primary tube using plasma separation tubes is associated with clinically relevant changes for certain parameters. Therefore, storing samples for retesting should be avoided when using plasma separation tubes, in particular for parameters susceptible to interference by erythrocyte or platelet contamination. PMID- 21605015 TI - Sulfonylureas: do we need to introspect safety again? AB - INTRODUCTION: Sulfonylureas (SUs) are the most commonly prescribed medications for type 2 diabetes mellitus worldwide. Differences among SUs for kinetic and adenosine triphosphate sensitive potassium (KATP) channels selectivity and consequential extrapancreatic effects, although recognized in literature, are not considered by treatment guidelines. AREAS COVERED: The roles of SUs in various system-related adverse effects have not been well understood. Inconsistencies in the literature and lack of clinical trials assessing the long-term effects of monotherapy or combination therapy with SUs add to the concern. This review provides insights in issues concerning safety of SUs based on literature published between 1980 and 2011. A comprehensive search was carried out on PubMed, Embase and Cochrane databases using the search terms: sulfonylureas, sulfonylureas and KATP channels, sulfonylureas and cardiovascular (CV) effects and sulfonylureas side effects. EXPERT OPINION: SUs have been linked to CV events, growth hormone (GH) disorder, malignancy, weight gain, erectile dysfunction and central nervous system (CNS) adverse effects. These adverse effects generally get masked as they are thought to be related to diabetes per se. The current article will allow the fraternity to ponder and undertake further research on the ill effects of largely prescribed antidiabetic medication. PMID- 21605016 TI - Treatment of hepatitis C-virus-reinfection after liver transplant with silibinin in nonresponders to pegylated interferon-based therapy. AB - OBJECTIVES: Hepatitis C-virus-persistence after orthotopic liver transplant leads to reduced patient and graft survival compared to other indications. Current interferon-based antiviral therapy of hepatitis C-virus-infection posttransplant provides a sustained response rate of 30% to 40%. This study, performed in an hepatitis C-virus-reinfected liver transplant population, examines the antiviral effect of intravenously administered silibinin, recently reported to exhibit strong antiviral properties in the natural setting of hepatitis C-virus-related liver disease. PATIENTS AND METHODS: Four patients after orthotopic liver transplant with hepatitis C-virus-recurrence, previously having not responded to peg-interferon-ribavirin therapy, were treated with intravenous silibinin and additionally, after the 10th day, with standard interferon-based therapy. Aminotransferases and hepatitis C-virus-RNA were measured during treatment. RESULTS: All patients demonstrated normalization of liver enzymes and significant decline of hepatitis C-virus-RNA measured at day 10 (mean 2.8 logarithmic levels: 1.7, 2.3, 2.9, and 4.3) during silibinin monotherapy. One patient cleared hepatitis C-virus-RNA under silibinin monotherapy and another patient eliminated hepatitis C virus under subsequent interferon-based therapy. No adverse effects were observed during silibinin application. CONCLUSIONS: Intravenous silibinin is an effective therapeutic approach for treating hepatitis C-virus-reinfection after liver transplant and should be evaluated further. PMID- 21605017 TI - Cytomegalovirus reactivation after matched sibling donor reduced-intensity conditioning allogeneic hematopoietic stem cell transplant correlates with donor killer immunoglobulin-like receptor genotype. AB - OBJECTIVES: Cytomegalovirus reactivation is common after reduced-intensity conditioning allogeneic hematopoietic stem cell transplant. Natural killer and T cells mediate immunity against viruses including cytomegalovirus. The alloreactivity of natural killer cells and some T-cell subsets is mediated through the interaction of their killer immunoglobulin-like receptors with target cell ligands. This study sought to assess whether donor inhibitory or activating killer immunoglobulin-like receptor genotypes may influence post-transplant cytomegalovirus reactivation in transplant recipients. MATERIALS AND METHODS: We analyzed 64 patients who underwent T-cell replete, matched sibling donor reduced intensity conditioning allogeneic hematopoietic stem cell transplantation at our institution. Transplant recipients were categorized according to their HLA inhibitory killer immunoglobulin-like receptor ligand groups. Donor killer immunoglobulin-like receptor genotypes were determined and then were assessed for correlations with cytomegalovirus reactivation in transplant recipients. RESULTS: No differences in cytomegalovirus reactivation were observed when comparing those with or without missing inhibitory killer immunoglobulin-like receptor ligands. When considering the number of donor activating killer immunoglobulin-like receptor genes, those with 5 or 6 had less cytomegalovirus reactivation than those with 1 to 4 (19% vs 48%; P = .029). The difference could not be attributed to baseline patient or transplant characteristics. No specific activating killer immunoglobulin-like receptor genotype was found to be associated with cytomegalovirus reactivation. CONCLUSIONS: These observations indicate that assessment of donor killer immunoglobulin-like receptor genotype may have important implications for predicting cytomegalovirus reactivation after T-cell replete, matched sibling donor reduced intensity conditioning allogeneic hematopoietic stem cell transplant. PMID- 21605018 TI - End-stage renal disease among living-kidney donors: single-center experience. AB - OBJECTIVES: Renal transplant from living donors is widely accepted as a highly effective treatment for end-stage renal disease. Donors undergo a major operation with considerable perioperative risks of morbidity and mortality. Living with a single kidney also confers long-term risks. This study sought the incidence and causes of end-stage renal disease among living kidney donors. MATERIALS AND METHODS: This study included all donors who had reached end-stage renal disease among 2000 consecutive living-kidney donors. All operations and follow-up were performed in a single center. We studied the onset of renal disease, cause of end stage renal disease, date of replacement therapy, and outcome. We also revised the donor's medical records related to their corresponding recipients. RESULTS: Of 2000 living donors, 8 developed end-stage renal disease; 6 were men (mean age, 30.87 +/- 5.84 years. Renal failure occurred 5 to 27 years after donation. Renal transplant was done in 1 donor. Medical complications were proteinuria (6 patients), hypertension (7 patients), diabetes (3 patients), gout (3 patients), ischemic heart disease (5 patients), and hepatitis viral infection (4 patients). The causes of end-stage renal disease were diabetic nephropathy in 3 patients. Other possible causes included toxic nephropathy, chronic pyelonephritis, and preeclampsia. CONCLUSIONS: Living kidney donation is safe, and development of renal failure after donation is caused by the same causes as in the general population. PMID- 21605019 TI - Retroperitoneoscopic live-donor right nephrectomy: a Chinese single center. AB - OBJECTIVES: To evaluate our right-retro- peritoneoscopic live-donor nephrectomy by comparing the left side with the right side, and reporting our single-center experience for rightretroperitoneoscopic live-donor nephrectomy. PATIENTS AND METHODS: In China, live-kidney transplant is limited. It is even more essential now, because the deceased-donor kidney has become fewer after enacting the Chinese Regulation on Human Organ Transplantation. Therefore, there is a continued need to use the limited live-donor population. We chose 103 consecutive cases (84 left and 19 right) that underwent retroperitoneoscopic live-donor nephrectomy between December 2005 and December 2009, to compare the intraoperative and postoperative characteristics between the left and right sides, and report our experiences for 19 right-retroperitoneoscopic live-donor nephrectomies. RESULTS: All 84 left and 19 right-retro peritoneoscopic live-donor nephrectomies were accomplished successfully without open conversion and transfusion. No significant differences were observed between the 2 groups regarding operative time, warm ischemia time, estimated blood loss, length of hospital stay, and serum creatinine level at discharge (Table 1). Eight of the donors and 3 of the grafts had minor complications that were all resolved with conservative treatment. The recipient's serum creatinine levels at 1 day and 1 month after surgery were the same in both groups. No acute renal tubule necrosis or delayed graft function was observed in the recipients. CONCLUSIONS: Our right retroperitoneoscopic live-donor nephrectomy achieves comparable outcomes with the left side and proves to be a feasible, cost-effective, safe, and minimally invasive alternative for live-kidney donation. This maximally uses the innately limited donors and potentially increases the donor pool in China. PMID- 21605020 TI - Comparison of intima-media thickness of the common carotid artery in dialysis and kidney transplant recipient patients. AB - OBJECTIVES: Cardiovascular events are a major cause of mortality and morbidity of chronic renal failure causing 40% to 50% of all deaths in these patients. The intima-media thickness of the common carotid artery is used to predict atherosclerosis. To assess the effect of early renal transplant on the vascular atherosclerosis, we compared the common carotid intima-media thickness between dialysis and transplant patients. MATERIALS AND METHODS: In a cross-sectional study, 75 kidney transplant recipients and 75 dialysis patients were assessed in a subspecialized renal and urethral diseases center from April 2008 to March 2010. Demographic characteristics, smoking history, and information on comorbid and kidney diseases were recorded through a checklist. The common carotid intima media thickness was measured using ultrasonography. Spearman's rank correlation coefficient was used to find any correlation between duration of dialysis and intimamedia thickness. RESULTS: In all, 79 patients (53%) were male. The mean age (SD) of dialysis and transplant patients was 55 +/- 11 and 51 +/- 15 years. The 2 groups had no statistically significant sex or age differences (P > .05). Considering all patients, 54 (36%) had a history of hypertension, 30 (20%) had a history of diabetes mellitus, 15 (10%) had a history of hyperlipidemia, and 41 (27.3%) had a history of smoking. There were no significant differences between the 2 groups when these variables were considered (P > .05). The mean thickness of the common carotid intima-media was 1.2 mm (0.35 mm) in the dialysis patients, which was higher compared with 0.73 mm (0.18 mm) in the transplanted group (P < .001). There was a significant correlation between duration of dialysis and intima-media thickness (P < .001, r=0.882) in the dialysis group. CONCLUSIONS: Common carotid intima-media thickness in dialysis patients is significantly higher compared with kidney transplant recipients. Carotid intima-media thickness increases by prolongation of dialysis duration. PMID- 21605021 TI - Mortality prediction after kidney transplantation: comparative clinical use of 7 comorbidity indices. AB - OBJECTIVES: Despite comorbidity associated with chronic kidney disease, little data exist applying comorbidity scoring systems to renal transplant recipients. This study compared the performance of 7 established comorbidity scores in predicting mortality after kidney transplantation. MATERIALS AND METHODS: We retrospectively analyzed prospectively collected data from 2033 incident renal transplant recipients. Comorbidity was assessed at baseline, and the following scores were derived: Recipient Risk Score, Charlson Comorbidity Index, Age adjusted Charlson Comorbidity Index, Modified End-Stage Renal Disease Charlson Comorbidity Index, Foley Score, Wright-Khan Index, and Davies Index. Cox models investigated the association of each comorbidity score with mortality; performance characteristics were tested using receiver operating characteristic curve analysis. RESULTS: Age-stratified Cox analyses showed the Recipient Risk Score-based model displayed the best fit, and receiver operating characteristic curve analysis showed the Recipient Risk Score demonstrated greatest predictive use (5-year mortality c-statistic: 0.787). The independent effect of age on mortality was demonstrated after analysis of scores not containing age as a component (the Charlson Comorbidity Index, the Modified End-Stage Renal Disease Charlson Comorbidity Index, the Davies Index); addition of age to these scores improved fit. CONCLUSIONS: Of the currently available comorbidity scores, the Recipient Risk Score demonstrated greatest use. This has implications for deceased-donor allocation algorithms, assessment of confounders in clinical research, and potentially, individual patient management. PMID- 21605022 TI - Conversion from cyclosporine to sirolimus in chronic renal allograft dysfunction: a 4-year prospective study. AB - OBJECTIVES: The long-term use of cyclosporine always contributes to chronic renal allograft dysfunction. Converting from cyclosporine to sirolimus and reducing cyclosporine dosage under high mycophenolate mofetil levels are 2 common therapies. Their efficacy and safety have not been compared in Chinese patients. MATERIALS AND METHODS: In this prospective, open label, randomized study, 51 kidney recipients with an estimated glomerular filtration rate between 30 and 60 mL/min/1.73 m2 were enrolled. Patients in the sirolimus group (n=22) initiated sirolimus 12 hours after cessation of cyclosporine. Patients in the cyclosporine group (n=29) significantly reduced cyclosporine dosage under high mycophenolate mofetil dosages. Both groups were followed-up for 4 years. RESULTS: The baseline estimated glomerular filtration rate was 36.46 +/- 6.22 mL/min/1.73 m2 in sirolimus group and 36.07 +/- 6.18 mL/min/1.73 m2 in the cyclosporine group (P = NS). In cyclosporine group, the estimated glomerular filtration rate declined significantly at 12, 18, 24, 30, 36, 42, and 48 months after inclusion compared with baseline, and was lower than the sirolimus group at 30, 36, 42, and 48 months after inclusion (P < .05). As for the endpoints of graft loss and return to dialysis, the 4-year graft survival was 77.3% in the sirolimus group and 55.2% in the cyclosporine group (P = NS). As for the endpoint of serum creatinine doubling, 4-year survival was 77.3% in the sirolimus group and 41.4% in the cyclosporine group (P < .05). Three patients in sirolimus group (2 acute rejections, 1 pneumonia) and 2 patients in the cyclosporine group (owing to acute rejection) dropped out (P = NS). CONCLUSIONS: Conversion from cyclosporine to sirolimus could improve long-term survival of renal grafts in Chinese patients. PMID- 21605023 TI - Importance of socioeconomic, clinical, and psychological factors on health related quality of life in adolescents after kidney transplant. AB - OBJECTIVES: Health-related quality of life after kidney transplant in adolescents is a major concern; nevertheless, there is a paucity of data on the variables that have an effect on it. This study evaluated the extent to which socioeconomic, clinical, and psychological characteristics explain the variance in the health-related quality of life of adolescent Iranian kidney transplant recipients. MATERIALS AND METHODS: Into a hierarchical regression analysis, the cross-sectional socioeconomic, clinical, and psychological characteristics were entered among 55 adolescent Iranian kidney transplant recipients. RESULTS: The relative predictive power of socioeconomic, clinical, and psychological variables with respect to health-related quality of life was 21.8% (P = .088), 21.2% (P = .014), and 27.6% (P = .001). CONCLUSIONS: Psychological factors had a greater relative predictive power in postrenal transplant health-related quality of life of adolescents than did socioeconomic and clinical characteristics. Further research should target improvement of health-related quality of life in adolescent kidney recipients by psychological intervention. PMID- 21605024 TI - Analysis of right lobe living-liver donor complications: a single center experience. AB - OBJECTIVES: Living-donor liver transplant provides an alternative source of organ to patients with end-stage liver disease. This study sought to determine and classify the donor morbidities after right lobe donor hepatectomy in a single center. MATERIALS AND METHODS: One hundred eighty-one right lobe living-donor hepatectomy were performed in our center between January 2004 and December 2009. Of the 181 donors, 104 donors were men and 77 donors were women. Mean age of the donors was 38 years (range, 18-63 years). The mean follow-up was 33.3 months (range, 3-66 months). Complications after the operation were stratified according to the Clavien classification. RESULTS: Eighty-one complications occurred in 73 of the 181 donors (40.3%). The most common complication was wound infection, which was seen in 14 of 181 donors (7.7%). Biliary complications were seen in 4.4% of donors. There was no postoperative mortality. Also, grade 4 complications, which are life-threatening, did not occur. Blood transfusion were not required during the operation. The incidence of reoperation was 1.6% in all donors. CONCLUSIONS: Living-donor liver transplant ensures a new graft to patients with end-stage liver disease. Donor morbidity is one of the realities of the donor hepatectomy procedure. Because the donors are healthy individuals, the aim of the process must be to eliminate the donor mortality while decreasing the complication rates. PMID- 21605025 TI - Successful en bloc renal transplant from a 19-month-old nonheart-beating donor into an adult recipient: case report. AB - Worldwide, there is a shortage of organs available for transplant into patients with end-stage renal failure. This has led to donor selection of the most marginal donors. These strategies, so far, have failed to meet the requirements. Further adaptations are required to maximize the donor pool. One such pool is nonheart-beating pediatric donors less than 2 years of age. This report highlights a successful en bloc renal transplant using a 19-month-old nonheart beating pediatric donor kidney into an adult recipient. Renal transplant from a nonheart-beating pediatric donor kidney can be a way forward toward increasing the organ donor pool. PMID- 21605026 TI - Acute appendicitis after diaphragmatic hernia after pediatric liver transplant. AB - Multiple complications in liver transplant have been described in the literature. However, appendicitis and diaphragmatic hernia have rarely been reported after solid-organ transplant. The clinical presentation of appendicitis is similar to that of nontransplant patients, but complications are more frequent, because the majority of the patients do not have leukocytosis. Diaphragmatic hernia can present with a variety of atypical clinical symptoms. In this report, 1 patient who developed a diaphragmatic hernia and appendicitis after liver transplant is presented. A 2-year-old boy with end-stage liver cirrhosis owing to progressive familial intrahepatic cholestasis type-2 received a living-donor liver transplant. The posttransplant course was complicated. The diagnosis of diaphragmatic hernia was confirmed by thoracoabdominal computed tomography, and we decided to proceed with surgical repair. The patient had evidence of perforation, and the appendix was removed. After repositioning the intestine in the abdomen, a chest tube was placed, and the defect repaired with interrupted polypropylene sutures. The patient recovered after surgery without untoward sequelae. PMID- 21605027 TI - Meningoencephalitis with Aspergillus and mycobacterium tuberculosis in a renal transplant recipient. AB - OBJECTIVES: We report a case of central nervous system coinfection with 2 types of opportunistic organisms-Aspergillus and Mycobacterium tuberculosis-in a 33 year-old woman who underwent a renal transplant. MATERIALS AND METHODS: She developed a high-grade fever and right-sided weakness 1 month after the transplant while on mycophenolate mofetil, prednisolone, and cyclosporine. RESULTS: Brain magnetic resonance imaging revealed multiple mass lesions with peripheral ring enhancement. Colony-stimulating factor polymerase chain reaction was positive for Aspergillus and Mycobacterium tuberculosis. CONCLUSIONS: Broad spectrum antibiotics, antituberculous agents, and amphotericin were started. Unfortunately, the woman's condition deteriorated, and she died 2 weeks after admission to the hospital. PMID- 21605028 TI - Inhaled pentamidine for Pneumocystis jiroveci prophylaxis in a heart transplant recipient with allergy for trimethoprim sulfamethoxazole. AB - Pneumocystis jiroveci is an important cause of mortality and morbidity among heart transplant recipients. This raises the question of prophylactic treatment for this infection. Trimethoprimsulfamethoxazole is commonly used in P. jiroveci pneumonia prophylaxis with mild to severe adverse effects. We present the use of inhaled pentamidine as P. jiroveci prophylaxis in a patient with an allergy to trimethoprim sulfamethoxazole. PMID- 21605029 TI - Role of APP and Abeta in synaptic physiology. AB - Alzheimer's disease (AD) is the most common cause of dementia in aging populations. Although amyloid plaques are the hallmark of AD, loss of synapses and synaptic dysfunction are closely associated with the duration and severity of cognitive impairment in AD patients. Amyloid precursor protein (APP) and its cleavage products including Abeta have been suggested as homeostatic regulators of synaptic activity. APP manipulation and Abeta application, in vitro and in vivo, affect synapse formation and synaptic transmission. Moreover, synaptic dysfunction and learning deficits precede Abeta plaque deposition, suggesting that synaptic alterations may underlie the initial development of the disease. Because of the pivotal role of APP and Abeta in AD pathogenesis, it is essential to understand how APP and Abeta modulate synaptic function. Here, we review the roles that APP and Abeta play at the synapses, with particular focus on recent findings for the importance of APP in synaptogenesis and synaptic function. PMID- 21605030 TI - gamma-Secretase, apolipoprotein E and cellular cholesterol metabolism. AB - Genetic studies demonstrate that the 4 allele of the apolipoprotein (apo) E is a risk factor for late onset Alzheimer's disease (AD). Apo E is the major component of lipoprotein particles in the brain that mediate transport of cholesterol and other lipids between neurons and glial cells, indicating an implication of cerebral lipid metabolism in the pathogenesis of AD. In addition, apo E is also involved in the metabolism and aggregation of the amyloid beta-peptide (Abeta) that derives from proteolytic processing of the amyloid precursor protein (APP) and is found in plaques of AD brains. The generation of Abeta involves sequential cleavages of APP by proteases called beta- and gamma-secretase. gamma-Secretase is a high molecular weight protein complex containing presenilins as catalytically active subunits. Importantly, mutations in the genes of APP and the two homologous PS proteins are a major cause of familial early onset AD, indicating that the metabolism of APP and generation of Abeta play critical roles in the initiation of the disease. This review focuses on the functional relation of gamma-secretase complexes and the metabolism of lipoproteins in the brain. It is hypothesized that gamma-secretase activity is critically involved in cellular lipid homeostasis and that impaired lipid metabolism contributes to the pathogenesis of AD. PMID- 21605031 TI - alpha-Secretase in Alzheimer's disease and beyond: mechanistic, regulation and function in the shedding of membrane proteins. AB - Proteases regulate numerous physiological functions in all living organisms. Because of their contribution to betaAPP processing, alpha-, beta- and gamma secretases have focused particular attention of researchers in the field of Alzheimer's disease (AD) during the past 20 years. Whereas the beta-secretase BACE1 and the heterotetrameric presenilin-dependent gamma- secretase complex were identified between 1995 and 2002, alpha-secretase activity was attributed to previously described ADAM10 and ADAM17, two members of the type I integral membrane protein family called ADAMs (A Disintegrin And Metalloprotease). ADAM10 and/or ADAM17 target numerous substrates through various modes of action. This review focuses on the complex physiology of these alpha-secretases and will document their contribution to cancers, diabetes, rheumatoid arthritis, and prion diseases besides their well characterized role in Alzheimer's disease. PMID- 21605033 TI - Alpha-secretase cleavage of the amyloid precursor protein: proteolysis regulated by signaling pathways and protein trafficking. AB - alpha-secretase is the name for a metalloprotease activity, which is assumed to play a key role in the prevention of the molecular mechanisms underlying Alzheimer's disease (AD). Proteases similar to alpha-secretase are essential for a wide range of biological processes, such as cell adhesion and embryonic development. The molecular culprit in AD is the amyloid beta peptide (Abeta), which derives from the amyloid precursor protein (APP) through sequential cleavage by the two proteases beta- and gamma-secretase. In contrast, alpha secretase, which is the metalloprotease ADAM10, cleaves APP within the Abeta domain, thus preventing Abeta generation. Additionally, it produces a secreted APP ectodomain with neurotrophic and neuroprotective properties. An increase in alpha-secretase cleavage is considered a therapeutic approach for AD, but the molecular mechanisms regulating alpha-secretase cleavage are only partly known. Protein kinase C and mitogen-activated protein kinase constitute central signaling hubs for the regulation of alpha-secretase cleavage. Additionally, recent studies increasingly demonstrate that the correct spatial and temporal localization of the two membrane proteins APP and alpha-secretase is essential for efficient alpha-secretase cleavage of APP. This review highlights the role of signaling pathways and protein trafficking in the control of APP alpha-secretase cleavage. PMID- 21605034 TI - BACE1 Dependent Neuregulin Proteolysis. AB - Neuregulin-1 (NRG1), which is also called acetylcholine receptor inducing activity (ARIA) or glial growth factor (GGF), signals as a ligand of ErbB receptors in a variety of important developmental processes but also later in life. NRG1 mediated signaling is crucial for cardiogenesis and the development of the breast. In the nervous system, NRG1 functions are essential for peripheral myelination, the establishment and maintenance of neuromuscular and sensorimotoric systems as well as for the plasticity of cortical neuronal circuits. There is strong evidence that deregulation of NRG1 is involved in breast cancer and schizophrenia. Many splice variants of NRG1 are expressed in the brain and all contain an EGF-like domain, which exerts the NRG1 function by limited proteolysis from its membrane bound precursor protein. In addition, most NRG1 isoforms contain a transmembrane domain, which is processed by gamma secretase after shedding. beta-Secretase (beta-site amyloid precursor protein cleaving enzyme 1; BACE1) has been identified based on its role as the rate limiting enzyme of amyloid-beta-peptide (Abeta) production. Abeta is the major component of amyloid plaques in Alzheimer's disease (AD). More recently it was shown that Neuregulin-1 activity is highly dependent on the cleavage by BACE1 during early postnatal development. In BACE1 KO mice a role for BACE1 dependent proteolysis of NRG1 in the process of peripheral myelination could be demonstrated. Here we summarize the current knowledge about the role of NRG1 proteolysis for ErbB receptor mediated signaling during development and in Alzheimer's disease. PMID- 21605032 TI - An overview of notch signaling in adult tissue renewal and maintenance. AB - The Notch pathway is a critical mediator of short-range cell-cell communication that is reiteratively used to regulate a diverse array of cellular processes during embryonic development and the renewal and maintenance of adult tissues. Most Notch-dependent processes utilize a core signaling mechanism that is dependent on regulated intramembrane proteolysis: Upon ligand binding, Notch receptors undergo ectodomain shedding by ADAM metalloproteases, followed by gamma secretase-mediated intramembrane proteolysis. This releases the Notch intracellular domain, which translocates to the nucleus to activate transcription. In this review, we highlight the roles of Notch signaling particularly in self-renewing tissues in adults and several human diseases and raise some key considerations when targeting ADAMs and gamma-secretase as disease modifying strategies for Alzheimer's Disease. PMID- 21605035 TI - AICD nuclear signaling and its possible contribution to Alzheimer's disease. AB - Altered proteolytic processing of the beta-amyloid precursor protein (APP) is a central event in familial and sporadic Alzheimer's disease (AD). In a process termed regulated intramembrane proteolysis (RIP), APP first undergoes ectodomain shedding executed either by alpha- secretases at the plasma membrane or by beta secretase in the endosomal compartment. The remaining membrane-anchored stubs are cleaved within the membrane plane by the gamma-secretase complex, releasing the APP intracellular domain (AICD) into the cytosol and leading to the generation of the Abeta peptide in the amyloidogenic pathway that is initiated by beta secretase. The Abeta peptides aggregate to form soluble oligomers and finally deposit into amyloid plaques that are a hallmark of AD. Recent evidence indicates a role for Abeta oligomers in regulating synaptic plasticity with excess amounts of oligomers disrupting synaptic function. The amyloid cascade hypothesis of AD is centered on the Abeta peptide, the APP fragment that has been most intensely studied, while other cleavage products have been largely neglected. The secreted ectodomain generated after alpha-cleavage in the non-amyloidogenic pathway has neurotrophic and neuroproliferative activities, thus opposing the neurotoxicity observed with high concentrations of Abeta. Further, in analogy to many other membrane proteins that are subject to RIP, AICD can translocate to the nucleus to regulate transcription. Many RIP substrates are localized to the synapse and thus could convey a direct signal from the synapse to the nucleus upon cleavage. Evidence indicates that only the amyloidogenic pathway generates AICD capable of nuclear signaling, due to the subcellular compartmentalization of APP processing. In aging and sporadic AD there is an increase in beta-secretase levels and activity generating more Abeta peptides and concomitantly leading to an increase in AICD nuclear signaling. In this review, I summarize the current knowledge on AICD nuclear signaling and propose mechanisms to explain how this physiological function of APP might impact the pathology seen in AD. PMID- 21605037 TI - A clinical perspective: anti tau's treatment in Alzheimer's disease. AB - Alzheimer?s Disease (AD) physiopathology is not yet totally established. Nevertheless it is known that a metabolism dysfunction of the amyloid beta precursor protein (APP) and the abnormal tau protein phosphorylation lead to the formation of neuritic plaques and neurofibrillary tangles, respectively. These events finally drive to the clinical expression of dementia. Formally approved during the past decade, treatments for AD are lacking of an updating, being essentially symptomatic. Anticholinesterase agents have failed in providing a substantial improvement in the mental health condition of AD patients. On the other hand, antiamyloid strategies, have failed in their efficacy or security on their last development phases. In this context, tau represents a potential therapeutic target, by the action of drugs that diminish its aggregation, or acting by altering its phosphorylation or filaments formation. There is also anti tau miscellaneous strategies such as normal microtubule-stabilizing agents. Thus, it might be possible that in a near future the neurodegenerative process could be stopped. PMID- 21605036 TI - The Role of the anti-amyloidogenic secretase ADAM10 in shedding the APP-like proteins. AB - ADAM10 (A disintegrin and metalloproteinase 10) has been demonstrated as an enzyme with protective properties in Alzheimer's disease: in mouse models it not only lowered generation of toxic A-beta peptides and formation of senile plaques but also alleviated learning deficits and enhanced synaptic density. This is due to cleavage of the amyloid precursor protein (APP) within its A-beta stretch and to the release of the extracellular domain of APP with neuroprotective function. Aside from cleaving APP, ADAM10 has been linked to over 40 putative substrates at least in cell culture. These substrates are connected with important cellular functions such as cell migration, stress response and transport. For this contribution we focussed on ADAM10 acting on the APP-like proteins since for some of their representatives - in particular APLP2 and APP-L - a shedding by ADAM10 has been demonstrated in vivo. In addition, the importance of these proteins, especially of APLP2, has been repeatedly shown by intense analysis of double and triple transgenic mice which lack APP in combination with one or both APLPs: several phenotypes such as defects in migration of neuroblasts, in formation of synapses and synaptic transmission have been reported. However, the specific contribution of either the uncleaved full-length proteins or their extracellular domains secreted upon ADAM10 activity has not been elucidated. In this review, we report on recent findings concerning shedding of APP-like proteins and resulting functional consequences. PMID- 21605039 TI - Tau oligomers as potential targets for immunotherapy for Alzheimer's disease and tauopathies. AB - The aggregation and accumulation of the microtubule-associated protein (Tau) is a pathological hallmark of Alzheimer disease (AD) and many neurodegenerative diseases. For a long time research has focused on neurofibrillary tangles (NFTs) and other large meta-stable inclusions composed of aggregated hyperphosphorylated tau protein. The correlation between these structures and disease progression produced conflicting results; moreover, the mechanism of their formation remains poorly understood. Lately, the significance and toxicity of NFTs have been challenged and a new aggregated tau entity has emerged as the true pathogenic species in tauopathies and a possible mediator of Abeta toxicity in AD; specifically, aggregates of a size intermediate between monomers and NFTs the so called tau oligomers. Tremendous efforts have been devoted toward the optimization of a safe vaccine for AD by targeting Abeta peptide; despite the disappointing results, these studies produced a wealth of useful knowledge, which should be considered in developing tau-based immunotherapy. Herein, we discuss the evidence supporting the critical role of tau oligomers in AD, the potential and challenges for targeting them by immunotherapy as a novel approach for AD treatment. PMID- 21605038 TI - Novel drugs affecting tau behavior in the treatment of Alzheimer's disease and tauopathies. AB - The anomalous aggregation of proteins into pathological filaments is a common feature of a many human diseases, often related to aging. In this context, neurodegenerative pathologies such as Alzheimer's disease (AD) account for a major part of these protein misfolding diseases. AD is characterized by pathological aggregation of two proteins, tau and Abeta-amyloid. The intracellular neurofibrillary tangles (NFTs) and neuropil threads consists of filaments of the modified microtubule-associated protein tau, while extracellular amyloid plaques consists of filaments of Abeta-peptide. It is noteworthy that tau oligomers with a prefilamentous structure appear to play a role at early stages of AD and tauopathies, but also in asymptomatic patients with Braak-stage I neuropathology, where clinical symptoms of AD and NFTs in frontal cortex are absent. This suggests that an increase in tau oligomers levels occurs before individuals manifest clinical symptoms of AD. NFTs are one of the hallmarks of Alzheimer disease and other tauphaties. These aggregates are thought to be toxic to neurons, either by causing some neurotoxic signalling defects or by obstructing the cell function. Factors contributing to accumulation of tau aggregates include the increased rate of protein misfolding, generation of amyloidogenic oligomers, underactivity of repair systems such as chaperones and ubiquitin-proteasome system, or a failure of energy supply and antioxidant defense mechanisms. There is not clear evidence if the aggregated tau or oligomers cause cellular damage, but on the basis of the emergent need to have an early and effective treatment, lowering the production or removal of these aggregates appears as a pathway toward alleviating the disease. In the context of some of most relevant reports, we analyze why tau protein seems to be an interesting target for AD treatment, and the importance to understand the pathways of tau. aggregation. This knowledge will allow us to identify and optimize potential inhibitors that interact with aggregated forms of tau and hyperphosphorylated tau before the formation of the NFTs, offering a possible therapeutic route for AD treatment. PMID- 21605040 TI - Molecular targets in the rational design of AD specific PET tracers: tau or amyloid aggregates? AB - A major limitation in finding therapeutic solutions for Alzheimer's disease (AD) has been the lack of a reliable method for early diagnosis of this devastating disease. Besides the development of biomarkers in biological fluids of patients, the search for a pathology-specific neuroimaging tools is critical at the present stage in which almost 30 million people suffer this disease worldwide. Several interesting approaches have been developed, however their clinical impact has been low. One of the difficulties has been to find the proper molecular tracers to specifically tag pathognomonic lesions in AD brain, including not only amyloid aggregates but also filaments of the modified microtubule-associated protein tau. In this review, we analyze the evidence towards developing pathology-specific diagnostic tools for AD. We analyze the current evidence and clinical implications of new imaging technologies for AD, and how tau hypothesis and the amyloid cascade hypothesis will impact on these scientific efforts in the near future. PMID- 21605041 TI - C-Abl tyrosine kinase signaling: a new player in AD tau pathology. AB - Hyperphosphorylated tau is a cardinal feature of Alzheimer's disease (AD) pathology. The deregulation of kinases that phosphorylate tau can alter normal tau-related processes, including microtubule dynamics, growth cones, and axonal transport, and induce tau aggregation in paired helical filaments. Here we discuss the possible roles of the Abl family of tyrosine kinases, which are essential regulators of cytoskeleton cellular signaling cascades, in AD tau pathology and how the physiological roles of Abl kinases could be connected with the cytoskeletal alterations induced by Abeta aggregates and AD progression. PMID- 21605042 TI - A novel perspective on tau in Alzheimer's disease. AB - Mainstream thinking is dominated by the notion that the aggregation of specific proteins within neurons, and their subsequent formation into cytoplasmic and extracellular lesions, directly elicits neuronal dysfunction and death. Current dogma, for example, maintains that phosphorylated tau protein, the major component of neurofibrillary tangles, is a central mediator of disease pathogenesis. In this article, we challenge this classic notion by proposing that tau phosphorylation represents a compensatory response mounted by neurons against oxidative stress that serves a protective function. This concept provides a better understanding of the mechanisms underlying disease pathophysiology and also provides a window for therapeutic intervention. PMID- 21605043 TI - Loss of medial septum cholinergic neurons in THY-Tau22 mouse model: what links with tau pathology? AB - Alzheimer's disease (AD) is a neurodegenerative disorder histologically defined by the cerebral accumulation of amyloid deposits and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Loss of basal forebrain cholinergic neurons is another hallmark of the disease thought to contribute to the cognitive dysfunctions. To this date, the mechanisms underlying cholinergic neurons degeneration remain uncertain. The present study aimed to investigate the relationship between neurofibrillary degeneration and cholinergic defects in AD using THY-Tau22 transgenic mouse model exhibiting a major hippocampal AD-like tau pathology and hyperphosphorylated tau species in the septohippocampal pathway. Here, we report that at a time THY-Tau22 mice display strong reference memory alterations, the retrograde transport of fluorogold through the septohippocampal pathway is altered. This impairment is associated with a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum. Analysis of nerve growth factor (NGF) levels supports an accumulation of the mature neurotrophin in the hippocampus of THY-Tau22 mice, consistent with a decrease of its uptake or retrograde transport by cholinergic terminals. Finally, our data strongly support that tau pathology could be instrumental in the cholinergic neuronal loss observed in AD. PMID- 21605044 TI - Role of protein phosphatase 2A in Alzheimer's disease. AB - Alzheimer disease (AD) is the most common cause of dementia in adults. Aberrant hyperphosphorylation of microtubule associated protein Tau and neurofilament-M/H is one of the pathological hallmarks of AD. Most of the therapeutic strategies for treating AD are based on the inhibition of protein kinases such as glycogen synthase kinase-3beta, cyclin-dependent kinase 5, and other Tau kinases. Here, we focus on protein phosphatase 2A (PP2A) as a key player in AD. PP2A expression and activity are downregulated in AD brain, contributing to the aberrant phosphorylation of Tau and NF proteins in AD. Recent data published from our lab as well as others on PP2A deregulation in AD is reviewed. The role of peptidyl prolyl isomerase Pin1 in regulation of PP2A mediated neurodegeneration is further analyzed. Development of drugs for AD could be based on restoration of PP2A activity or targeting Pin1. PMID- 21605045 TI - Pin1: a new outlook in Alzheimer's disease. AB - Neurodegenerative diseases termed Tauopathies, including Alzheimer disease, are characterized by the presence of intraneuronal neurofibrillary tangles (NFTs), composed by hyperphosphorylated protein Tau. Peptidyl-prolyl cis/trans isomerase Pin1 plays a pivotal role in the regulation of Tau phosphorylation/dephosphorylation state. Indeed, Pin1 specifically recognizes pThr231-Pro232 motif of Tau, catalyzes its isomerisation and, in dependence of the cellular environment, promotes its dephosphorylation by PP2A phosphatase: in the dephosphorylated state Tau is able to exert its physiological activity, promoting microtubules polymerization. However, Pin1 activity in Tauopathies in which Tau is mutated can be harmful, because the isomerase can accelerate progression of the disease. Taking into account the complexity of pathways in which Pin1, under a strict regulation, exerts its biological functions, this isomerase can be consider a promising target in the improvement and design of new therapies against Tauopathies. PMID- 21605046 TI - Mechanisms of tau self-aggregation and neurotoxicity. AB - Pathological tau protein aggregates can be found in brain of patients with some of the neurodegenerative diseases collectively known as tauopathies, which include Alzheimer's disease (AD). Since tau post-translational modifications including phosphorylations, glycosylations, truncation and the subsequent aggregation in oligomers, paired helical filaments (PHFs) and neurofibrillary tangles (NFTs), correlate with cognitive impairment and neurodegeneration in AD, a pathogenic role for tau and its modifications has been raised. Here we summarize the current status of knowledge about tau modifications under pathologic conditions and the evidence supporting neurotoxic - or neuroprotective - roles of the diverse forms of modified and aggregated tau. Finally, we analyze the structural and functional tau alterations found in different tauopathies and how these modifications are related to the pathophysiologic mechanisms of neurodegeneration. PMID- 21605047 TI - Mediterranean diet in predementia and dementia syndromes. AB - There is a critical need to potentially individualize new strategies able to prevent and to slow down the progression of predementia and dementia syndromes. Only recently higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline although the Mediterranean diet (MeDi) combines several foods, micro- and macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. In fact, elevated saturated fatty acids could have negative effects on age-related cognitive decline and mild cognitive impairment (MCI). Furthermore, at present, epidemiological evidence suggested a possible association among fish consumption, monounsaturated fatty acids and polyunsaturated fatty acids (PUFA) (particularly, n-3 PUFA) and reduced risk of cognitive decline and dementia. Light to moderate alcohol use may be associated with a reduced risk of incident dementia and Alzheimer's disease (AD), while for vascular dementia, cognitive decline, and predementia syndromes the current evidence is only suggestive of a protective effect. Finally, the limited epidemiological evidence available on fruit and vegetable consumption and cognition generally supported a protective role of these macronutrients against cognitive decline, dementia, and AD. Moreover, recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from MCI to AD, reduced risk of AD, and decreased all causes mortality in AD patients. These findings suggested that adherence to the MeDi may affect not only the risk for AD, but also for predementia syndromes and their progression to overt dementia. Nonetheless, at present, no definitive dietary recommendations are possible. However, high levels of consumption of fats from fish, vegetable oils, non-starchy vegetables, low glycemic fruits, and diet low in foods with added sugars and with moderate wine intake should be encouraged. In fact, this dietary advice is in accordance with recommendations for lowering the risk of cardiovascular disease, obesity, diabetes, and hypertension and might open new ways for the prevention and management of cognitive decline and dementia. PMID- 21605048 TI - Dietary patterns in Alzheimer's disease and cognitive aging. AB - Much of the attention on diet and Alzheimer's disease (AD) or cognition among the elderly has focused on the role of single nutrients or foods, while available information on dietary pattern (DP) analysis, which better reflects the complexity of the diet, is sparse. In this review, we describe different patterning approaches and present studies performed to date that have assessed the associations between DPs and risk of AD or cognitive function in the elderly. Three patterning approaches have been most commonly used: (i) hypothesis-based that use dietary quality indexes or scores (e.g. Mediterranean pattern), (ii) data-driven that use factor or cluster analysis to derive DPs, (iii) reduced rank regression which combines characteristics of the former two approaches. Despite differences existing among the approaches, DPs characterized by higher intake of fruits, vegetables, fish, nuts and legumes, and lower intake of meats, high fat dairy, and sweets seemed to be associated with lower odds of cognitive deficits or reduced risk of AD. Overall, the inherent advantages as well as the existing evidence of DP analyses strongly suggest that this approach may be valuable in AD and aging research. Further studies are warranted, though, to confirm the findings in different population settings, to address some methodological issues, and possibly utilize the information for future clinical trial design. PMID- 21605049 TI - Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against amyloid-beta-induced toxicity. Involvement of the NF-kappaB signaling. AB - Alzheimer's disease (AD) is the most common form of dementia. Recently, a number of epidemiological studies have evidence that some dietary factors such as low antioxidants and vitamins intake could increase the risk of AD. In the opposite, diets rich in unsaturated fatty acids, in polyphenols, vitamins and antioxidants were identified as preventive factors. Several studies have reported that adherence to the Mediterranean diet (MeDi) was associated with a reduction in incident of dementia. The beneficial effect of MeDi may be the result of the association of some individual and non-identified food components and high consumption of olive oil. In this study we have investigated the protective effects of two components of olive oil, tyrosol (Tyr) and hydroxytyrosol (OH Tyr), against Abeta-induced toxicity. In cultured neuroblastoma N2a cells, we found that Abeta(25-35) (100 ug/ml) treatment induced a decrease of glutathione (GSH) and the activation of the transcription factor NF-kappaB and cell death. Our results demonstrated that the number of cell death decreased when cells were co-treated with Abeta and Tyr or OH-Tyr. However, neither of these phenolic compounds was able to prevent the decrease of GSH induced by H(2)O(2) or Abeta. We found that the increase in the nuclear translocation of the NF-kappaB subunits after Abeta exposure was attenuated in the presence of Tyr or OH-Tyr. These results identified two individual food components of the MeDi as neuroprotective agent against Abeta and their potential involvement in the beneficial effect of the MeDi for the prevention of AD. PMID- 21605050 TI - Metabolic syndrome, mild cognitive impairment, and dementia. AB - At present, the search for preventive strategies for cognitive decline and dementia appears to be of crucial importance, given that the therapeutic options currently available have demonstrated limited efficacy. Cumulative epidemiological evidence suggested that vascular and vascular-related factors may be important for the development of age-related cognitive decline (ARCD), mild cognitive impairment (MCI), and cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). Among vascular-related factors, metabolic syndrome (MetS) has been associated with the reduced risk of predementia syndromes (ARCD and MCI), overall dementia, and VaD, but contrasting findings also exist on the possible role of MetS in AD. In the next future, trials could then be undertaken to determine if modifications of these risks including inflammation, another factor probably related to MetS, could lower risk of developing cognitive decline. If MetS is associated with increased risk of developing cognitive impairment, then early identification and treatment of these individuals at risk might offer new avenues for disease course modification. Future research aimed at identifying mechanisms that underlie comorbid associations will not only provide important insights into the causes and interdependencies of predementia and dementia syndromes, but will also inspire novel strategies for treating and preventing these disorders. At present, vascular risk factor management could be decisive in delaying the onset of dementia syndromes or in preventing the progression of predementia syndromes. PMID- 21605051 TI - Omega-3 polyunsaturated fatty acids in Alzheimer's disease: key questions and partial answers. AB - The current rise in the prevalence of Alzheimer's disease (AD) is unfortunately not matched by new treatment options. In the last 10 years, epidemiological, preclinical and clinical data have enlightened the possible preventive action of omega-3 polyunsaturated fatty acids (n-3 PUFA) in AD and other diseases. While the contribution of recent studies to our general knowledge is priceless, many important new questions have been raised. In the present review, we aim at addressing some of these timely interrogations. First, the transport of n-3 PUFA across the blood-brain barrier is underscored based on preclinical data. Second, the relative contribution of two neuroactive n-3 PUFA found in fish oil, docosahexaenoic acid (DHA; 22:6 n-3) and eicosapentaenoic acid (EPA, 20:5 n-3), remains unclear and is reviewed. Third, clinical trials on neurodegenerative diseases consistently remind us that treating early is critical, and this is likely to be the case with n-3 PUFA in AD as well. Fourth, we draw attention to the possibility that the current knowledge translation approach to make health recommendations might have to be adapted to non-patentable endogenous compounds like n-3 PUFA. We propose that answers to these critical questions will be instrumental toward a rational use of n-3 PUFA in AD. PMID- 21605052 TI - Nutritional approaches to modulate oxidative stress in Alzheimer's disease. AB - Alzheimer's disease (AD) brain is characterized by amyloid beta-peptide (Abeta) deposits, neurofibrillary tangles, synapse loss, and extensive oxidative stress. Abeta-induced oxidative stress is indexed by protein oxidation, lipid peroxidation, free radical formation, DNA oxidation and neuronal cell death. Oxidative stress is combated by antioxidants. Antioxidants and nutrition have long been considered as an approach to slow down AD progression. In this review, we focus on antioxidants that have been shown to protect against Abeta-induced oxidative stress, particularly vitamin E, ferulic acid, various polyphenols, including quercetin and resveratrol, alpha-lipoic acid, N-acetyl-L-cysteine (NAC), curcumin, epigallocatechin gallate (EGCG), and gamma-glutamylcysteine ethyl ester (GCEE). Brain-accessible antioxidants with both radical scavenging properties and ability to induce protective genes are hypothesized to be helpful in treatment for AD. PMID- 21605053 TI - Possible involvement of programmed cell death pathways in the neuroprotective action of polyphenols. AB - One of the hallmarks of Alzheimer's disease is the accumulation of senile plaques composed of extra-cellular aggregates of beta-amyloid (Abeta) peptides. It is well established that at least in vitro, Abeta triggers apoptotic cell death via the activation of caspase-dependent and -independent cell death effectors, namely caspase-3 and apoptosis inducing factor (AIF), respectively. Epidemiological studies have reported that elderly people have a lower risk (up to 50%) of developing dementia if they regularly eat fruits and vegetables and drink tea and red wine (in moderation). Numerous studies indicate that polyphenols derived from these foods and beverages account for the observed neuroprotective effects. In particular, we have reported that polyphenols extracted from green tea (i.e. epigallocatechin gallate or EGCG) and red wine (i.e. resveratrol) block Abeta induced hippocampal cell death, by at least partially inhibiting Abeta fibrillisation. It has been shown that polyphenols may also modulate caspase dependent and -independent programmed cell death (PCD) pathways. Indeed, polyphenols including resveratrol, EGCG and luteolin significantly inhibit the activation of the key apoptotic executioner, caspase-3 and are able to modulate mitogen-activated protein kinases known to play an important role in neuronal apoptosis. Moreover, it has been reported that polyphenols may exert their anti apoptotic action by inhibiting AIF release from mitochondria, thus providing new mechanism of action for polyphenols. This review aims to update the current knowledge regarding the differential effects of polyphenols on PCD pathways and discuss their putative neuroprotective action resulting from their capacity to modulate these pathways. PMID- 21605055 TI - Predicting apoptosis protein subcellular location with PseAAC by incorporating tripeptide composition. AB - The function of the protein is closely correlated with its subcellular localization. Probing into the mechanism of protein sorting and predicting protein subcellular location can provide important clues or insights for understanding the function of proteins. In this paper, we introduce a new PseAAC approach to encode the protein sequence based on the physicochemical properties of amino acid residues. Each of the protein samples was defined as a 146D (dimensional) vector including the 20 amino acid composition components and 126 adjacent triune residues contents. To evaluate the effectiveness of this encoding scheme, we did jackknife tests on three datasets using the support vector machine algorithm. The total prediction accuracies are 84.9%, 91.2%, and 92.6%, respectively. The satisfactory results indicate that our method could be a useful tool in the area of bioinformatics and proteomics. PMID- 21605056 TI - Introduction of Pro and its analogues in the conserved P1' position of trypsin inhibitor SFTI-1 retains its inhibitory activity. AB - A number of monocyclic SFTI-1 analogues modified in the conserved inhibitor P1' position by Pro, its L-hydroxyproline (Hyp) derivative as well as mimetics with different ring size were synthesized by the solid-phase method. Replacement of Ser6 by Pro, Hyp, and a four-member ring, L-azetidine-2-carboxylic acid (Aze), retained trypsin or chymotrypsin inhibitory activity. The determined association equilibrium constants of these analogues with a cognate enzyme were about two orders of magnitude lower than those obtained for ones with conserved Ser6. In all analogues, with the exception of one, [Phe5,Aze6]SFTI-1, the P1-P1' reactive site remained intact. The results provide first evidence that the conserved Ser in the P1' position of Bowman-Birk inhibitors can be successfully replaced by an amino acid with a secondary amine group. PMID- 21605054 TI - Dietary omega 3 polyunsaturated fatty acids and Alzheimer's disease: interaction with apolipoprotein E genotype. AB - Epidemiological studies suggest a protective role of omega-3 poly-unsaturated fatty acids (n-3 PUFA) against Alzheimer's disease (AD). However, most intervention studies of supplementation with n-3 PUFA have yielded disappointing results. One reason for such discordant results may result from inadequate targeting of individuals who might benefit from the supplementation, in particular because of their genetic susceptibility to AD. The epsilon4 allele of the apolipoprotein E gene (ApoE) is a genetic risk factor for late-onset AD. ApoE plays a key role in the transport of cholesterol and other lipids involved in brain composition and functioning. The action of n-3 PUFA on the aging brain might therefore differ according to ApoE polymorphism. The aim of this review is to examine the interaction between dietary fatty acids and ApoE genotype on the risk for AD. Carriers of the epsilon4 allele tend to be the most responsive to changes in dietary fat and cholesterol. Conversely, several epidemiological studies suggest a protective effect of long-chain n-3 PUFA on cognitive decline only in those who do not carry epsilon4 but with inconsistent results. An intervention study showed that only non-carriers had increased concentrations of long-chain n-3 PUFA in response to supplementation. The mechanisms underlying this gene-by-diet interaction on AD risk may involve impaired fatty acids and cholesterol transport, altered metabolism of n-3 PUFA, glucose or ketones, or modification of other risk factors of AD in epsilon4 carriers. Further research is needed to explain the differential effect of n-3 PUFA on AD according to ApoE genotype. PMID- 21605057 TI - Soluble fusion expression and characterization of human beta-defensin 3 using a novel approach. AB - Human beta-defensin 3 (DEFB103) is a recently identified small cysteine-rich cationic peptide expressed ubiquitously upon local microbial invasion. A number of accumulating evidences indicate that this peptide is involved in many biological processes, including microbicidal activities, chemoattraction, and immunomodulation. In this article, we describe a novel approach through which we performed the expression and purification of the recombinant DEFB103 peptide in Escherichia coli (E. coli) based on the pTWIN1 expression system. This approach does not introduce any extra residues to the peptide product, and also eliminates the requirement of removing the fusion tag by exogenous proteases. A high yield of 112 mg of soluble fusion DEFB103 was obtained in 1 liter of Luria-Bertani (LB) medium. By one-step affinity chromatography and on-column, auto-cleavage of the fusion tag, the mature DEFB103 peptide was produced with a yield of 30 mg/L LB. The purified DEFB103 peptide demonstrated strong antimicrobial activities against E. coli, S. aureus and C. albicans, which were representatives of Gram-negative and Gram-positive bacteria and fungi, respectively. Using this novel approach, we have successfully expressed and purified several human defensins with significant bioactivities. Our work may be helpful for structural and functional studies of other human defensins, and also for the production of human defensins. PMID- 21605058 TI - The effects of Leu or Val residues on cell selectivity of alpha-helical peptides. AB - In this study, the peptides were designed to compare the effect of multiple Leu or Val residues as the hydrophobic side of an alpha-helical model on their structure, function, and interaction with model membranes. The Leu-rich peptides displayed 4- to 16-fold stronger antimicrobial activity than Val-rich peptides, while Val-containing peptides showed no haemolysis and weak cytotoxicity. The peptides LR and VR showed an alpha-helical-rich structure under a membranemimicking environment. Different cell selectivity for Leu- or Val containing peptides correlated with the targeted cell membranes. The Leu-rich peptide LR(W) and Val-rich peptide VR(W) interacted preferentially with negatively charged phospholipids over zwitterionic phospholipids. VR(W) displayed no interaction with zwitterionic phospholipids, which was consistent with its lack of haemolytic activity. The ability of LR to depolarize bacterial cells was much greater than that of VR. Val- and Leu-rich peptides appeared to kill bacteria in a membrane-targeted fashion, with different modes of action. Leu-rich peptides appeared to be active via a membrane-disrupting mode, while Val-rich peptides were active via the formation of small channels. PMID- 21605059 TI - Dependence of peptide self-association on intermolecular interaction by PFGNMR in TFE aqueous solution: C-terminal analogues of NPY as model peptides. AB - We have investigated the dependence of peptide oligomerization on intermolecular interaction in terms of both energetic and structural effect by PFGNMR. Three peptides, NPY[20-36], Pro34-NPY[20-36] and NPY[21-31], which are related to human NPY, were synthesized as models in this work. In contrast to NPY[20-36], both Pro34-NPY[20-36] and NPY[21-31] were found with descendent affinity with TFE cluster and continuous dissociating with increased temperature. The observed results can be accounted by the entropic change with temperature and the varied hydrophobic interactions between species due to the differed structures of peptides from each other. The removal of helical secondary structure or residues from C-terminal region may increase the energetic difference between peptide peptide self-associating and peptidesolvent binding. This increased energetic difference leads to larger dependence of association-dissociation equilibrium on temperature and entropic increase while dissociating. PMID- 21605060 TI - Activation of large form galanin-LI by extracellular processing in small cell lung carcinoma tissue. AB - Galanin is a neuropeptide that is widely distributed in the central and peripheral nervous systems. Some small cell lung carcinoma (SCLC) cell lines such as SBC-3A release only the high-molecular-mass form, with lower molecular mass forms being undetectable. To investigate the mechanism of processing of progalanin to active peptide, we studied galanin-LI in both the culture media of SBC-3A cells and in extracts from in vivo mouse SBC-3A tumors. SBC-3A cells were found to release high molecular mass galanin, but did not release active peptides. In contrast, tumor extract contained both high-molecular-mass galanin, and a cleaved lower-molecular-mass form of the peptide (8, 5 and 2 kDa). The lower-molecular-mass peptide was identified as galanin(1-20) by MALDI-TOF mass spectrometry. We then looked at MMP-2 and MMP-9 release from SBC-3A cells and tumor tissue treated with galanin and progalanin, as revealed by gelatin zymography. Galanin elicited pro-MMP-2 and pro-MMP-9 release from SBC-3A cells and tumor tissue; however, recombinant progalanin induced pro-MMP-2 and pro-MMP-9 release from tumor tissue only. This study has shown that the galanin-LI released from SCLC SBC-3A cells consisted of the high-molecular-mass peptide form, and was processed extracellularly to galanin(1-20). Furthermore, galanin was seen to induce pro-MMP-2 and pro-MMP-9 release from SBC-3A cells. PMID- 21605061 TI - The ability of tolfenamic acid to penetrate the brain: a model for testing the brain disposition of candidate Alzheimer's drugs using multiple platforms. AB - Evidence from our laboratory suggests that tolfenamic acid has a potential for slowing the progression of Alzheimer's disease (AD) through lowering cortical levels of the beta-amyloid precursor protein (APP) and its pathogenic amyloid beta (Abeta) intermediates [1]. In this study, we examined the ability of tolfenamic acid to cross the blood brain barrier (BBB) by predicting its logBB and logPS values, the indexes of BBB permeability, using computational models. We also determined, via in vitro methods, the brain penetration capacity factor [(K(IAM)/MW(4))x10(10)] using phosphatidylcholine column chromatography. The obtained logBB, logPS and (K(IAM)/MW(4))x10(10) values predicted that tolfenamic acid can passively transfer into the central nervous system (CNS). These results were validated in vivo using LC-MS analysis after administration of tolfenamic acid intravenously to guinea pigs and mice. The present study provides the first evidence of the ability of tolfenamic acid to cross the BBB and offers a comparative analysis of approaches used to predict the ability of compounds to penetrate into the brain. PMID- 21605062 TI - The role for oxidative stress in aberrant DNA methylation in Alzheimer's disease. AB - Alzheimer's disease (AD) is a common, progressive neurodegenerative disorder without highly effective therapies. The etiology of AD is heterogeneous with amyloid-beta plaques, neurofibrillary tangles, oxidative stress, and aberrant DNA methylation all implicated in the disease pathogenesis. DNA methylation is a well established process for regulating gene expression and has been found to regulate a growing number of important genes involved in AD development and progression. Additionally, aberrations in one-carbon metabolism are a common finding in AD patients with individuals exhibiting low S-adenosylmethionine and high homocysteine levels as well as low folate and vitamin B. Oxidative stress is considered one of the earliest events in AD pathogenesis and is thought to contribute largely to neuronal cell death. Emerging evidence suggests an interaction exists between oxidative stress and DNA methylation; however, the mechanism(s) remain unclear. This review summarizes known and potential genes implicated in AD that are regulated by DNA methylation and oxidative stress. We also highlight the evidence for the role of oxidative damage contributing to DNA hypomethylation in AD patients through several mechanisms as well as implications for disease understanding and therapeutic development. PMID- 21605063 TI - Genetic polymorphisms in sigma-1 receptor and apolipoprotein E interact to influence the severity of Alzheimer's disease. AB - Apolipoprotein E (APOE) epsilon4 allele and sigma-1 receptor (SIGMAR1) c.5C (Q2P) polymorphisms have been acknowledged as risk factors for developing Alzheimer's disease (AD). However, whether these polymorphisms influence the disease process is unclear. Therefore, two cohorts with a clinical diagnosis of AD were recruited, a postmortem confirmed Australian cohort (82 cases) from the Australian Brain Bank Network, and a Chinese cohort with detailed clinical assessments recruited through an epidemiology study in Shanghai and through the neurology department outpatients clinic of Shanghai Ruijin Hospital (330 cases). SIGMAR1 Q2P and APOE genotyping was performed on all cases. Dementia severity in the Chinese cohort was assessed using MMSE scores, and the stages of senile plaques and neurofibrillary tangles (NFT) assessed in the Australian cohort. Associations between SIGMAR1 Q2P and APOE genotypes and disease severity were assessed using SPSS. Results confirmed that APOE 4 allele associated with increased NFT stages and cognitive decline, with carriers with one APOE epsilon2 or epsilon3 allele often having better clinical outcomes compared to carriers with none or two epsilon2 or epsilon3 alleles respectively. SIGMAR1 c.5C polymorphism alone did not associate with MMSE score variability in Chinese or with pathological stages in Caucasians. However, the association studies revealed a significant genetic interaction between the APOE epsilon4 allele and SIGMAR1 2P carriers in both populations, i.e., in APOE non epsilon4 allele carriers, SIGMAR1 2P variant had increased cognitive dysfunction and more advanced stages of NFT. Our data demonstrate that SIGMAR1 and APOE interact to influence AD severity across ethnic populations. PMID- 21605065 TI - Chemical constituents and biological activity of Chinese medicinal herb 'Xihuangcao'. AB - The application of Isodon species in Chinese folk medicine has a long histroy, especially the ones called 'Xihuangcao' in Chinese. 'Xihuangcao' has been successfully applied to treat acute hepatitis, cholecystitis, enteritis, dysentery and trauma. The original species of 'Xihuangcao' is Isodon lophanthoides (Buch.-Ham.ex D.Don). However, there are five sources of Chinese medicinal herb 'Xihuangcao' due to their similar morphology and close pharmaceutical activity. Each source belongs to Isodon. However, their chemical composition and bioactivities are significantly different. In order to differentiate these sources of 'Xihuangcao' and to know their pharmaceutical effects, this review summarizes the chemical constituents, bioactive properties of 'Xihuangcao' and their available application. PMID- 21605064 TI - BDNF serum concentrations show no relationship with diagnostic group or medication status in neurodegenerative disease. AB - Brain-derived neurotrophic factor (BDNF) is a growth factor implicated in neuronal survival. Studies have reported altered BDNF serum concentrations in patients with Alzheimer's disease (AD). However, these studies have been inconsistent. Few studies have investigated BDNF concentrations across multiple neurodegenerative diseases, and no studies have investigated BDNF concentrations in patients with frontotemporal dementia. To examine BDNF concentrations in different neurodegenerative diseases, we measured serum concentrations of BDNF using enzyme-linked immunoassay in subjects with behavioral-variant frontotemporal dementia (bvFTD, n=20), semantic dementia (SemD, n=16), AD (n=34), and mild cognitive impairment (MCI, n=30), as well as healthy older subjects (HS, n=38). BDNF serum concentrations were compared across diagnoses and correlated with cognitive tests and patterns of brain atrophy using voxelbased morphometry. We found small negative correlations between BDNF serum concentrations and some of the cognitive tests assessing learning, information processing speed and cognitive control in complex situations, however, BDNF did not predict disease group membership despite adequate power. These findings suggest that BDNF serum concentration may not be a reliable diagnostic biomarker to distinguish among neurodegenerative diseases. PMID- 21605066 TI - Comparison of metabolic soft spot predictions of CYP3A4, CYP2C9 and CYP2D6 substrates using MetaSite and StarDrop. AB - Metabolite identification study plays an important role in determining the sites of metabolic liability of new chemical entities (NCEs) in drug discovery for lead optimization. Here we compare the two predictive software, MetaSite and StarDrop, available for this purpose. They work very differently but are used to predict the site of oxidation by major human cytochrome P450 (CYP) isoforms. Neither software can predict non-CYP catalyzed metabolism nor the rates of metabolism. For the purpose of comparing the two software packages, we tested known probe substrate for these enzymes, which included 12 substrates of CYP3A4 and 18 substrates of CYP2C9 and CYP2D6 were analyzed by each software and the results were compared. It is possible that these known substrates were part of the training set but we are not aware of it. To assess the performance of each software we assigned a point system for each correct prediction. The total points assigned for each CYP isoform experimentally were compared as a percentage of the total points assigned theoretically for the first choice prediction for all substrates for each isoform. Our results show that MetaSite and StarDrop are similar in predicting the correct site of metabolism by CYP3A4 (78% vs 83%, respectively). StarDrop appears to do slightly better in predicting the correct site of metabolism by CYP2C9 and CYP2D6 metabolism (89% and 93%, respectively) compared to MetaSite (63% and 70%, respectively). The sites of metabolism (SOM) from 34 in-house NCEs incubated in human liver microsomes or human hepatocytes were also evaluated using two prediction software packages and the results showed comparable SOM predictions. What makes this comparison challenging is that the contribution of each isoform to the intrinsic clearance (Clint) is not known. Overall the software were comparable except for MetaSite performing better for CYP2D6 and that MetaSite has a liver model that is absent in StarDrop that predicted with 82% accuracy. PMID- 21605067 TI - Glycobiology in malignant gliomas: expression and functions of galectins and possible therapeutic options. AB - Malignant gliomas, the most common malignant primary brain tumors, have a deleterious clinical prognosis of approximately 12 months in unselected series. The resistance against antineoplastic therapy is apparently not only associated with a high proliferative potential, marked antiapoptotic resistance and high migratory capacity. Effective mechanisms to escape the immune response of the organism and an intense neoangiogenesis also contribute to the aggressive growth of these neoplasms. In addition to a number of molecular mechanisms, the group of glycohydrate-binding galectins seems to contribute to the aggressive growth of malignant gliomas. Galectin-1, -3, -4 and -8 have been shown to be overexpressed in malignant gliomas. Galectin-1 is known to be involved in glioma cell migration and possibly also in proliferation. In this review, various aspects of glioma biology and their therapeutic relevance is discussed. The role of galectins in apoptosis-resistance, immune response and angiogenesis is discussed and explained why these molecules are interesting targets of glioma therapy. PMID- 21605068 TI - The tumor stroma as mediator of drug resistance--a potential target to improve cancer therapy? AB - Tumors irrespective of their origin are heterogeneous cellular entities whose growth and progression greatly depend on reciprocal interactions between genetically altered (neoplastic) cells and their non-neoplastic microenvironment. Thus, microenvironmental factors promote many steps in carcinogenesis, e.g. proliferation, invasion, angiogenesis, metastasis and chemoresistance. Drug resistance, either intrinsic or acquired, essentially limits the efficacy of chemotherapy in many cancer patients. To some extent, this resistance is maintained by reduced drug accumulation, alterations in drug targets and increased repair of drug-induced DNA damage. However, the pivotal mechanism by which tumor cells elude the cytotoxic effect of chemotherapeutic drugs is their efficient protection from induction and excecution of apoptosis. It is meanwhile well established that cellular and non-cellular components of the tumoral microenvironment, e.g. myofibroblasts and extracellular matrix (ECM) proteins, respectively, contribute to the anti-apoptotic protection of tumor cells. Cellular adhesion molecules (e.g. L1CAM or CD44), chemokines (e.g. CXCL12), integrins and other ECM receptors which are involved in direct and indirect interactions between tumor cells and their microenvironment have been identified as suitable molecular targets to overcome chemoresistance. Accordingly, several therapeutic strategies based on these targets have been already elaborated and tested in preclinical and clinical studies, including inhibitors and blocking antibodies for CD44/hyaluronan, integrins, L1CAM and CXCL12. Even though these approaches turned out to be promising, the upcoming challenge will be to prove the efficacy of these strategies in improving treatment and prognosis of cancer patients. PMID- 21605069 TI - Apoptosis signalling activated by TNF in the lower gastrointestinal tract- review. AB - The tumor necrosis factor (TNF) gene is an immediate early gene, rapidly transcribed in a variety of cell types following exposure to a broad range of pathogens and signals of inflammation and stress. Regulation of TNF gene expression at the transcriptional level is cell type- and stimulus-specific, involving epigenetic mechanisms or miRNAs. A better knowledge of the molecular mechanisms that control TNF gene regulation and TNF signalling will provide deeper understanding of the initiation and development of apoptotic and inflammatory processes triggered by TNF cytokine in the gut. The described efforts to embed TNF in clinical treatment regiments reflect its attractive effectiveness in killing tumor cells. Whether the described strategies will achieve the success of incorporating TNF in lower gastrointestinal tract therapy for inflammatory diseases and cancer remains to be determined. PMID- 21605071 TI - Apoptotic potency of angiostatic compounds in the treatment of cancer. AB - When tumours outgrow their vascular supply, they become hypoxic because of nutrient deficiency. This increases the expression and secretion of proangiogenic factors, like vascular endothelial growth factor (VEGF), leading to the activation of endothelial cells. The activated endothelial cells migrate, proliferate and form new blood vessels, resulting in increased tumour growth. This process is called tumour angiogenesis. Inhibiting tumour angiogenesis and therefore tumour growth is a well known concept in the treatment of cancer, such as hepatocellular carcinoma (HCC). This can be done by endogenous angiogenesis inhibitors, like angiostatin and its derivates. These are known to affect endothelial cell functions including the induction of apoptosis. The impact of these angiostatic factors on the cell is manifold. This also applies for so called small molecules, which affect tyrosine kinases such as receptors or intracellular signal transduction proteins. Other approaches, like monoclonal antibodies, target a single molecule, mainly VEGF, to inhibit receptor binding and downstream signal transduction. Gene silencing, mainly via RNA interference (RNAi) intervenes on RNAlevel, leading to reduced gene expression and protein secretion. Due to intense research in this field, there is rising evidence that also tumour cells themselves are influenced by angiostatic treatment approaches and the underlying molecular mechanisms are more and more revealed. Here we give a (short) review regarding the pro-apoptotic potency of antiangiogenic compounds like angiostatic molecules, sequestering antibodies, small molecules and RNAi approaches targeting endothelial and tumour cell survival to inhibit angiogenesis and tumour growth. PMID- 21605070 TI - Combination of hypoxia and RNA-interference targeting VEGF induces apoptosis in hepatoma cells via autocrine mechanisms. AB - Control of VEGF signaling is an intense objective of pre-clinical and clinical studies in HCC disease with steadily increasing clinical application. Despite its emerging role, several aspects of anti-VEGF based treatments are poorly investigated, like the impact on tumor cells themselves, such as the effect on intracellular signaling and apoptosis induction in hepatoma cells. Effects of siRNA-VEGF on VEGF, VEGF-receptor expression and VEGF-A signaling such as AKT and JNK phosphorylation were determined under normoxic or hypoxic conditions in murine hepatoma cells. Apoptosis induction was analyzed by SubG1-fraction, JC1 staining and caspase-8 activation. VEGF receptor expression was analysed by semiquantitative real time PCR. Independent of oxygen status, siRNA-VEGF reduced VEGF levels resulting in decreased AKT and increased JNK phosphorylation in Hepa129 cells. The VEGF-receptors neuropilin-1 (Nrp1) and neuropilin-2 (Nrp2) were downregulated following siRNA-VEGF treatment or hypoxia induction respectively. Functionally, hypoxia significantly increased the apoptosis rate (as analyzed by SubG1-fraction, JC1-staining and JNKphosphorylation) which was further stimulated by siRNA-VEGF treatment. Our data indicate that antitumoral efficacy of an anti-VEGF based treatment with siRNA is partly based on negative autocrine feedback mechanisms which are even enhanced under hypoxic conditions. This observation helps to understand why antitumoral efficacy can be maintained despite of counteracting stimulation of tumoral VEGF secretion due to hypoxia. The direct impact on tumor cells further underscores the attractiveness of an anti-VEGF based siRNA treatment. PMID- 21605072 TI - The therapeutic potential of RNA interference: novel approaches for cancer treatment. AB - Exo- and endogenous RNA interference (RNAi) is a recently developed post transcriptional gene silencing system and is regarded as one of the most effective and specific gene silencing techniques with therapeutic potential. siRNA technology is also expected to be an invaluable treatment tool for viral infections, dominant disorders, neurological disorders, and cancers. Novel and increasingly effective therapies are urgently needed as conventional radio/chemotherapy is of limited efficacy in advanced stages of some malignant diseases. In some cancers, it is known that resistance to chemotherapy is mainly attributed to increased expression of anti-apoptotic genes, e.g. members of the bcl-2 family that stabilize the mitochondrial membrane. The siRNA-mediated knockdown of bcl-2 leads to pronounced anti-tumor effects in a pancreatic cancer model, especially in combination with chemotherapy even at otherwise ineffective concentrations. The future success of this approach will depend on the development of effective, specific, and safe delivery systems. In addition to therapeutic RNAi, endogenous RNAi processes may also contribute to cancer development. For example, miRNAs have been shown to suppress target gene expression through binding to the 3'-untranslated regions (3'-UTR) of target mRNAs. miRNAs control many functions in regard to cell viability, including differentiation, proliferation, and apoptosis, especially during cancer progression. More investigation into miRNAs will lead to new diagnostic and therapeutic approaches in the near future. PMID- 21605073 TI - Therapeutic targeting of apoptotic pathways: novel aspects in pancreatic cancer. AB - Pancreatic cancer constitutes one of the most aggressive tumours with a 5-year survival rate of less than 5%. It is characterized by a high degree of resistance to apoptosis which is associated by high expression levels of multiple prosurvival proteins of the extrinsic and intrinsic apoptosis signalling cascades. This review focuses on current knowledge of apoptotic pathways involved in pancreatic cancer and mechanisms of resistance to apoptosis, including alterations in the death receptor and mitochondrial pathways, as well as anti apoptotic effects of NF-kB and Akt signalling and the impact of histone-modifying enzymes such as histondeacetylases (HDAC). Furthermore, the therapeutic implications of modulating pro-survival pathways by specific inhibitors investigated in preclinical and clinical trials will be discussed. PMID- 21605074 TI - Current status of therapeutic targeting of developmental signalling pathways in oncology. AB - Signalling pathways such as Hedgehog (Hh), Wnt, Notch, bone morphogenetic protein (BMP) and transforming growth factor-beta (TGF-beta) hold a central position in regulation of vertebrate development by controlling vital processes such as migration, differentiation and proliferation. Insights into the mechanistic aspects of cancer initiation and progression have pointed to striking similarities between tumourigenesis and embryonic development. These observations can partly be explained by the fact that similar cellular signalling mechanisms are employed in both situations. This review focuses on the role and therapeutic potential of Hh, Wnt, Notch and BMP/TGF-beta signalling and discusses i) their signal transduction mechanisms during development and tumourigenesis, ii) evidence of pathway activation in different types of cancers, and, iii) strategies for pharmacological targeting. Numerous studies have demonstrated a crucial role of developmental signalling in a variety of tumours, where their signalling mechanisms contribute to oncogenic properties such as tumour cell proliferation, apoptosis inhibition and / or metastatic migration. From the literature available, it is obvious that the relative importance and the oncogenic mechanisms of developmental pathways vary with the tumour type, the stage of the disease as well as the interaction with the tumour microenvironment, thus highlighting the complexity of cellular signalling strategies employed during tumourigenesis. Intensive research activities are devoted to identification of drugs that interfere with oncogenic signalling by developmental pathways. First clinical data for such compounds--e.g. GDC-0449 for the Hh pathway--are promising and indicate that targeted therapy of developmental signalling pathways has potential for future anti-cancer therapies. PMID- 21605075 TI - Biomarkers for hepatocellular apoptosis in the management of liver diseases. AB - Apoptosis is a rare event in normal hepatocytes. However, multiple signals can trigger apoptosis in hepatocytes and it plays a role in the pathogenesis of many liver diseases. This review summarizes the mechanisms of hepatocellular apoptosis and the importance of apoptosis in the pathological processes of liver disease. The potential for non-invasive biomarkers of apoptosis to gauge the extent and follow the evolution of clinical disease is emphasized. PMID- 21605076 TI - New drugs, old fashioned ways: ER stress induced cell death. AB - Discovery of small molecules able to induce several cellular self-killing mechanisms improved cancer therapy in the last years. Research focused on canonical apoptotic (mitochondria or death receptor related) pathways to induce cell death in several hematologic and solid malignancies, showing that treatment with different synthetic and natural compounds reactivates the cell death machinery previously silenced in resistant cancer cells. Besides the canonical apoptotic pathways, alternative pathways of cell death induction have recently been rediscovered as potential new targets for cancer therapy. Under certain conditions, protein folding can be disturbed causing an accumulation of unfolded proteins inside the endoplasmic reticulum (ER). This situation leads to stress ER, involving the transcriptional and translational machinery to induce the expression and post-transcriptional modifications of many factors involved in ER stress response mediated cell death. In this scenario, some apoptotic players like caspase 4 or caspase 12 start to control cell fate by inducing downstream cell death proteins. Recently, inhibitors of protein deacetylases have been demonstrated to potently induce this alternative cell death pathway and will be reviewed here. PMID- 21605077 TI - Editorial: novel aspects of apoptosis modulating drugs. PMID- 21605078 TI - Ser756 of beta2 integrin controls Rap1 activity during inside-out activation of alphaMbeta2. AB - During alphaMbeta2-mediated phagocytosis, the small GTPase Rap1 activates the beta2 integrin by binding to a region between residues 732 and 761. Using COS-7 cells transfected with alphaMbeta2, we show that alphaMbeta2 activation by the phorbol ester PMA involves Ser(756) of beta2. This residue is critical for the local positioning of talin and biochemically interacts with Rap1. Using the CaM (calmodulin) antagonist W7, we found Rap1 recruitment and the inside-out activation of alphaMbeta2 to be affected. We also report a role for CaMKII (calcium/CaM-dependent kinase II) in the activation of Rap1 during integrin activation. These results demonstrate a distinct physiological role for Ser(756) of beta2 integrin, in conjunction with the actions of talin and Rap1, during alphaMbeta2 activation in macrophages. PMID- 21605079 TI - Suppression of mucin 2 enhances the proliferation and invasion of LS174T human colorectal cancer cells. AB - Altered expression of MUC2 (mucin 2) is related to tumour development in colorectal cancer. Colorectal mucinous carcinomas are positive for MUC2 expression, whereas MUC2 is down-regulated in non-mucinous adenocarcinomas. In the present study, we down-regulated MUC2 expression by RNAi (RNA interference) and investigated the in vitro and in vivo effects on the proliferation and invasion/migration potential of the LS174T human colorectal cancer cells. The LS174T cell line is a goblet-cell-like colorectal cancer cell line that continuously produces high levels of MUC2. Inhibition of MUC2 expression in vitro by transfection of LS174T cells with the recombinant plasmid pcDNA6.2-GW/EmGFP miR-MUC2 led to the production of a stably transfected MUC2-RNAi LS174T cell line. The proliferation and invasion/migration of MUC2-RNAi cells in vitro were significantly higher than those in control cells, as assessed by MTT [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide], colony formation and transwell assays. Subcutaneous injection of MUC2-RNAi LS174T cells into nude mice resulted in the development of subcutaneous tumours visible to the naked eye after 1 week. The growth rate of tumours derived from MUC2-RNAi LS174T cells was greater than that of tumours derived from control cells. Ki67 and matrix metalloproteinase-9 proteins were detected by immunohistochemistry in the xenografts. The expression levels of these proteins were higher in the MUC2-RNAi derived xenografts than in xenografts derived from control cells. Although the role of MUC2 in colorectal tumorigenesis is not fully understood, these results strongly suggest a relationship between the proliferation and invasion of LS174T cells and the expression of MUC2. PMID- 21605080 TI - Gadolinium inhibits prostate cancer PC3 cell migration and suppresses osteoclast differentiation in vitro. AB - This study examined whether Gd (gadolinium) could suppress prostate cancer cell migration and prostate cancer cell-induced osteoclast differentiation. MTT [3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] and colony forming assay showed that GdCl3 treatment inhibited both cell viability and colony forming ability in PC3 cells more significantly than that in DU145 cells. Annexin/PI (propidium iodide) staining showed an increase in apoptotic death of PC3 cells in the presence of GdCl3. Wound healing and adhesion assay indicated that GdCl3 suppressed PC3 cell migration. Western-blot analysis demonstrated that GdCl3 treatment inhibited phosphorylation of ERK (extracellular-signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase). Pretreatment with PTx (pertussis toxin), a Gi protein inhibitor, conferred resistance to GdCl3-induced colony formation, ERK and p38 phosphorylation in PC3 cells. Moreover, GdCl3 inhibited PC3 cell-induced osteoclast differentiation. RT-PCR (reverse transcription-PCR) indicated that GdCl3 decreased the expression of RANKL (receptor activator of nuclear factor-kappaB ligand) in PC3 cells, whereas it increased the expression of OPG (osteoprotegerin) in PC3 and DU145 cells. In conclusion, the present study indicated that GdCl3 inhibited PC3 cell migration mediated by the inactivation of both ERK and p38 MAPK pathways via PTx-sensitive G proteins, and also suppressed PC3 cell-induced osteoclast differentiation via regulating the mRNA expression of OPG and RANKL. PMID- 21605083 TI - Multipotent differentiation of the EGFP gene transgenic stem cells derived from amniotic fluid of goat at terminal gestational age. AB - We have isolated stem cells from amniotic fluid of goat at terminal gestational age and transferred the EGFP (enhanced green fluorescent protein) gene into the stem cells previously. The aim of this study was to determine whether the transgenic stem cells have the capability of multipotent differentiation. The transgenic stem cells were induced to differentiate into neurogenic, adipogenic, osteogenic and endothelial cells in vitro. Markers associated with AFS (amniotic fluid-derived stem) cells and the differentiated cells were tested by RT-PCR (reverse transcription-PCR). The results demonstrated that the transgenic AFS cells were capable of self-renewal, a defining property of stem cells. AFS cells were positive for the undifferentiated cell markers, Oct4, Nanog, Sox2 and Hes1, while following differentiation cells expressed markers for neurogenic cells such as astrocyte [GFAP (glial fibrillary acidic protein)] and NSE (neuron-specific enolase), adipogenic cells [LPL+ (lipoprotein lipase+)], osteogenic cells (osteocalcin+ and osteonectin+) and endothelium [CD34+ and eNOS+ (endothelial nitric oxide synthase)]. The results demonstrated that the EGFP gene transgenic AFS cells have the capability of multipotent differentiation, which means that the transgenic AFS cells may be useful in cell-transplantation studies in future. PMID- 21605082 TI - Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPARgamma agonist. AB - The cholesterol biosynthetic pathway produces not only sterols but also non sterol mevalonate metabolites involved in isoprenoid synthesis. Mevalonate metabolites affect transcriptional and post-transcriptional events that in turn affect various biological processes including energy metabolism. In the present study, we examine whether mevalonate metabolites activate PPARgamma (peroxisome proliferator-activated receptor gamma), a ligand-dependent transcription factor playing a central role in adipocyte differentiation. In the luciferase reporter assay using both GAL4 chimaera and full-length PPARgamma systems, a mevalonate metabolite, FPP (farnesyl pyrophosphate), which is the precursor of almost all isoprenoids and is positioned at branch points leading to the synthesis of other longer-chain isoprenoids, activated PPARgamma in a dose-dependent manner. FPP induced the in vitro binding of a co-activator, SRC-1 (steroid receptor co activator-1), to GST (glutathione transferase)-PPARgamma. Direct binding of FPP to PPARgamma was also indicated by docking simulation studies. Moreover, the addition of FPP up-regulated the mRNA expression levels of PPARgamma target genes during adipocyte differentiation induction. In the presence of lovastatin, an HMG CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor, both intracellular FPP levels and PPARgamma-target gene expressions were decreased. In contrast, the increase in intracellular FPP level after the addition of zaragozic acid, a squalene synthase inhibitor, induced PPARgamma-target gene expression. The addition of FPP and zaragozic acid promotes lipid accumulation during adipocyte differentiation. These findings indicated that FPP might function as an endogenous PPARgamma agonist and regulate gene expression in adipocytes. PMID- 21605081 TI - Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity and pharmacologically induced endoplasmic reticulum stress. AB - Obesity is associated with induction of the ER (endoplasmic reticulum)-stress response signalling and insulin resistance. PTP1B (protein tyrosine phosphatase 1B) is a major regulator of adiposity and insulin sensitivity. The aim of the present study was to investigate the role of L-PTP1B (liver-specific PTP1B) in chronically HFD (high-fat diet) and pharmacologically induced (tunicamycin and thapsigargin) ER-stress response signalling in vitro and in vivo. We assessed the effects of ER-stress response induction on hepatic PTP1B expression, and consequences of hepatic-PTP1B deficiency, in cells and mouse liver, on components of ER-stress response signalling. We found that PTP1B protein and mRNA expression levels were up-regulated in response to acute and/or chronic ER stress, in vitro and in vivo. Silencing PTP1B in hepatic cell lines or mouse liver (L-PTP1B(-/-)) protected against induction of pharmacologically induced and/or obesity-induced ER stress. The HFD-induced increase in CHOP (CCAAT/enhancer-binding protein homologous protein) and BIP (binding immunoglobulin protein) mRNA levels were partially inhibited, whereas ATF4 (activated transcription factor 4), GADD34 (growth-arrest and DNA-damage-inducible protein 34), GRP94 (glucose-regulated protein 94), ERDJ4 (ER-localized DnaJ homologue) mRNAs and ATF6 protein cleavage were completely suppressed in L-PTP1B(-/-) mice relative to control littermates. L-PTP1B(-/-) mice also had increased nuclear translocation of spliced XBP-1 (X box-binding protein-1) via increased p85alpha binding. We demonstrate that the ER stress response and L-PTP1B expression are interlinked in obesity- and pharmacologically induced ER stress and this may be one of the mechanisms behind improved insulin sensitivity and lower lipid accumulation in L-PTP1B(-/-) mice. PMID- 21605084 TI - Doxorubicin-induced cardiac dysfunction is attenuated by ciclosporin treatment in mice through improvements in mitochondrial bioenergetics. AB - We tested whether inhibition of mitochondrial membrane potential dissipation by CsA (ciclosporin A) would prevent doxorubicin-induced myocardial and mitochondrial dysfunction. Acute and subchronic models of doxorubicin exposition were performed in mice with either a single intraperitoneal bolus (10 mg/kg of body weight, intraperitoneal) or one injection of 4 mg.kg(-1) of body weight.week(-1) during 5 weeks. Follow-up was at 1.5 weeks and 16 weeks in acute and subchronic models respectively. Mice received either CsA (1 mg/kg of body weight, intraperitoneal on alternate days) or saline until follow-up. Heart function was evaluated by echocardiography. Mitochondrial measurements included oxygen consumption, membrane potential and externally added calcium-induced mitochondrial permeability transition. Mitochondrial mass was evaluated by transmission electronic microscopy and mtDNA (mitochondrial DNA) content. Mitochondrial dynamics were detected as the expression of GTPases involved in mitochondrial fusion and fission. In both the acute and chronic models, doxorubicin decreased left ventricular fractional shortening and survival. Heart function and survival were improved by CsA, but not by tacrolimus (FK506), a ciclosporin derivative with no inhibitory effect on the mitochondrial transition pore. In the acute model, doxorubicin exposure was associated with increased mtDNA content, mitochondrial fragmentation and changes in mitochondrial fusion- and fission-related transcripts [increases in Mfn2 (mitofusin 2), Opa1 (optic atrophy 1 homologue) and Fis1 (fission 1 homologue), and no changes in Drp1 (dynamin 1-like)]. CsA did not alter mitochondrial biogenesis, but prevented mitochondrial fragmentation and partially restored the mitochondrial energy producing capacity. These findings suggest that in vivo CsA treatment may limit MPTP (mitochondrial permeability transition pore) opening, mitochondrial potential loss and contractile depression in acute and chronic models of cardiac toxicity induced by doxorubicin. PMID- 21605085 TI - A case of congenital solitary Langerhans cell histiocytoma. AB - A newborn baby boy was referred to the Paediatric Dermatology Unit with a solitary asymptomatic nodule overlying his right nasolabial fold. Complete physical examination, full blood count, serum chemistry, liver function tests and baseline imaging were unremarkable. Histopathological examination showed an atypical dermal infiltrate of mononuclear cells that stained positive with CD1a and S100. A diagnosis of congenital solitary Langerhans cell histiocytoma was made. The lesion completely resolved by 4 months of age. The baby is now 15 months old and repeat systemic evaluation has remained normal. PMID- 21605086 TI - Dermatomyositis and pemphigus vulgaris: association or coincidence? AB - A 76-year-old woman presented with a pruritic photodistributed rash and dysphagia. Serum anti-nuclear antibody was positive (titre 1/1280) and skin and muscle biopsies confirmed a diagnosis of dermatomyositis. She was treated with oral prednisolone (5-50 mg/day), mometasone furoate 0.1% ointment and lotion, and tacrolimus 0.03% ointment. Four years later she presented with multiple painful scaly erosions on the face, scalp and trunk. Histopathology and direct and indirect immunofluorescence confirmed a diagnosis of pemphigus vulgaris. Repeated malignancy screens were negative. She was treated with methotrexate (10 mg/week) and prednisolone (50 mg/day slowly tapered to 5 mg/day), with good control of both diseases. PMID- 21605087 TI - Segmental lichen aureus: a report of two cases treated with methylprednisolone aceponate. AB - Two cases of segmental lichen aureus with a response to topical 0.1% methylprednisolone aceponate ointment are reported. A 9-year-old child and a 23 year-old man showed complete resolution of their lesions following treatment with the latter after 7 months and 4 months, respectively. Lichen aureus is a rare form of the pigmented purpuric dermatoses characterized by golden-brown and lichenoid macules and papules, most often on the lower extremities. Segmental presentations have seldom been described. Histology showed a lichenoid infiltrate with extravasation of red blood cells and haemosiderin deposition. The aetiology is unclear and treatment is disappointing. We report an uncommon segmental presentation of lichen aureus with resolution of the lesions after treatment with a topical corticosteroid. PMID- 21605088 TI - Disseminated cutaneous with nasopharyngeal rhinosporidiosis: Light microscopy changes following dapsone therapy. AB - We report a case of disseminated cutaneous and nasopharyngeal rhinosporidiosis in a 48-year-old man. The patient complained of a 6-month history of six subcutaneous skin-coloured swellings on the body and a 5-year history of a pea sized swelling on the inner aspect of the left lower eyelid. Histopathological examination from one of these lesions showed multiple globular cysts packed with endospores that were typical of rhinosporidiosis. We report this case because of its rarity and to describe the morphological effects of dapsone in promotion of a host inflammatory response to the organism. PMID- 21605089 TI - Metastatic malignant melanoma and dermatomyositis: A paraneoplastic phenomenon. AB - Malignant melanoma has previously been reported with paraneoplastic syndromes including dermatomyositis. We report a case involving a 34-year-old woman who presented with a persistent skin rash over her neck and upper body, with clinical features suggestive of dermatomyositis. The patient had a history of a right shoulder lesion that was previously removed; a solitary axillary lymph node was detected on additional imaging and biopsy results were consistent with malignant melanoma. The following year, surveillance positron emission tomography scan detected a solitary lung metastasis, leading to a partial lobectomy and confirmation of further spread of the malignant melanoma. PMID- 21605090 TI - Role of genetics and sex steroid hormones in male androgenetic alopecia and female pattern hair loss: an update of what we now know. AB - The role of genetic predisposition and the influence of sex steroid hormones are indisputable to the pathogenesis of male androgenetic alopecia (MAGA). The role of sex steroid hormones in female pattern hair loss (FPHL) is less known. A good knowledge of the pathophysiology underlying MAGA and FPHL empowers the clinician to confidently counsel patients and make informed therapeutic decisions. Vigorous research in recent years has provided greater insight into the role of genetics and sex steroids in physiological hair growth and cycling, as well as in hair follicle miniaturization, the histological hallmark of MAGA and FPHL. In the present review article directed towards clinicians, we discuss the current understanding of the role of androgens and oestrogens, as well as genetic associations with MAGA and FPHL. We also briefly discuss the interpretation of direct-to-consumer genetic testing for baldness to help clinicians understand the limitations of such tests. PMID- 21605091 TI - First experiences using reflectance confocal microscopy on equivocal skin lesions in Queensland. AB - BACKGROUND/OBJECTIVES: Reflectance confocal microscopy (RCM) is a non-invasive method of imaging human skin in vivo. The purpose of this study was to observe the experience of using RCM on equivocal skin lesions in a tertiary clinical setting in Queensland. METHODS: Fifty equivocal lesions on 42 patients were imaged using a reflectance confocal microscope immediately prior to being excised. The images were then analysed blind to the histopathological diagnosis. The experience and problems encountered when using RCM on skin lesions for the first time was also observed. RESULTS: On RCM analysis 12/13 melanomas (92.3% sensitivity, 75% specificity), 19/22 benign naevi (86% sensitivity, 95% specificity), 6/9 basal cell carcinomas (66.7% sensitivity, 100% specificity)and 6/6 squamous cell carcinomas and its precursors (100% sensitivity, 75% specificity) were diagnosed correctly when using histology as the gold standard. We identified three common problems that affected image quality: object artefacts; positioning artefacts; and movement artefacts. CONCLUSIONS: Using simple techniques we found that common RCM features were readily identifiable and common artefacts could be minimized, making RCM a useful tool to aid the diagnosis of equivocal skin lesions in a clinical setting. PMID- 21605092 TI - Mohs surgery in Australia: a survey of work practices. AB - BACKGROUND: Mohs micrographic surgery is the preferred treatment for certain skin cancers. It had already been considerably refined prior to its introduction into Australia in 1978, refinement has continued since. Documenting the work practices of Australian Mohs surgeons serves to clarify the current role of Mohs surgery and may help tailor future Mohs fellowship programs. METHODS: A survey was conducted to investigate the characteristics and clinical practices of Australian Mohs surgeons, particularly as they relate to skin cancer management and aesthetic dermatology. RESULTS: The typical Australian Mohs surgeon is male (90%), works in a group private practice (70%), and is aged 40-44 years (37%). Mohs surgery is generally reserved for tumours that are located on the head, neck, digits or genitals (98%), and flap reconstructions are the commonest repair types performed (48%). Laser and cosmetic injectable treatments form part of many Mohs surgeon's repertoires. CONCLUSION: Australian Mohs surgeons make an important contribution to the management of skin cancer in Australia and many are skilled in laser and cosmetic procedures. The increasing number of cases performed annually and the familiarity with laser and cosmetic therapies reinforces Australian dermatologists as leaders in these important areas of dermatology. PMID- 21605093 TI - Pigmented spindle cell naevus of Reed: a controversial diagnostic entity in Australia. AB - BACKGROUND/OBJECTIVES: The Reed naevus or pigmented spindle cell naevus of Reed (PSCN) was previously considered a pigmented variant of the spindle cell-type of Spitz naevus. It is now considered a distinct entity and may overlap with cutaneous melanoma in both clinical and dermatoscopic features. We hypothesised that PSCN is an under-recognised entity in Australia and present a typical case. To test our hypothesis, we performed a clinically based survey of Australian dermatology trainees (Registrars). A further aim of our study was to determine the approach of dermatology trainees in this country to the management of this type of lesion. METHODS: A web-based survey questionnaire based on the presented case was circulated to trainees of the Australasian College of Dermatologists. Responses, including level of training and initial approach to management, were collated and form the basis of the results presented herein. RESULTS: Of 39 respondents, 13 (33%) diagnosed the lesion as PSCN. The majority (33/39; 84.6%) indicated they would biopsy the lesion, with most of these (91%) preferring excisional biopsy. CONCLUSIONS: The results support our hypothesis that PSCN is under-recognised in Australia. The results also show that despite difficulty distinguishing this lesion, management of these lesions by dermatology trainees in Australia is consistent and parallels current recommendations. PMID- 21605094 TI - Predicting melanoma risk for the Australian population. AB - BACKGROUND: As melanoma incidence in Australia continues to rise, targeting high risk individuals for early detection is of paramount importance. OBJECTIVES: We aimed to design a population-specific risk assessment tool to improve on the use of intuition alone for assignment of surveillance strategies for high-risk individuals and help communicate risk more accurately and effectively to patients. METHODS: Methods used in the development of breast cancer risk models were adopted. Data from a large meta-analysis was used to determine risk estimates. Attributable risk was calculated for each risk factor using data from the Victorian Melanoma Service. Local prevalence data from state cancer registries was incorporated to estimate 5-year risk of melanoma. RESULTS: Independent risk factors identified were common naevi, atypical naevi, hair colour, freckles, family history of melanoma and personal history of non-melanoma skin cancer. Personal history of melanoma was the strongest risk factor for developing another (relative risk 7.28, 7.24). Absolute risk for individuals varies greatly with age, risk factor profiles and proximity to the equator. CONCLUSION: We have developed a melanoma risk assessment tool based on the best available information (http://www.victorianmelanomaservice.org/calculator). The tool is easily modified as new information becomes available. PMID- 21605095 TI - Targetoid spongiotic reaction pattern: A case series of seven paediatric patients. AB - We present seven cases of a targetoid eruption, clinically mimicking erythema multiforme, occurring in paediatric patients aged 12 months to 14 years. All patients presented with a pruritic targetoid eruption on body and acral sites which spared mucosal areas. All patients demonstrated a spongiotic reaction pattern on histology without lichenoid change and demonstrated excellent responses to either oral prednisolone or topical corticosteroids. We propose the term 'targetoid spongiotic reaction pattern (TSRP)' for our subset of paediatric patients. We review the literature regarding targetoid eruptions in the paediatric population. PMID- 21605096 TI - Thirty-five units of botulinum toxin type A for treatment of axillary hyperhidrosis in female patients. AB - We present a retrospective audit on efficacy and impact of 35 units of botulinum toxin type A per axilla on quality of life in female patients with axillary hyperhidrosis. This audit shows that 35 units of botulinum toxin type A is a reasonable starting dose and could significantly improve patients' quality of life and reduce the cost of treatment. PMID- 21605097 TI - Three cases of osteoma cutis occurring in infancy. A brief overview of osteoma cutis and its association with pseudo-pseudohypoparathyroidism. AB - We report three cases of primary osteoma cutis in children, two of whom (siblings) were associated with Albright's hereditary osteodystrophy (AHO), manifesting as short stature with autosomal dominant inheritance from the father, but no dysmorphic features and no parathyroid hormone (PTH) resistance. Osteoma cutis can manifest as an isolated skin disease, a secondary condition to other skin diseases (such as acne), or in association with several syndromes, including AHO, which in turn may be associated with PTH resistance. The management and prognosis of patients diagnosed with osteoma cutis is determined by whether the skin manifestation has occurred in isolation, in association with a syndrome, or as a secondary skin disease. These three paediatric cases highlight the importance of understanding the aetiology and associations of osteoma cutis in order to appropriately investigate and manage patients who present with this rare skin disease. PMID- 21605098 TI - Treatment of female pattern hair loss with the androgen receptor antagonist flutamide. AB - Female pattern hair loss is a common but difficult to manage condition. Commonly used treatments include oral antiandrogens such as spironolactone and topical minoxidil. The response to treatment is variable. We report a woman whose hair loss progressed while using spironolactone and topical minoxidil in combination, but reversed with flutamide, a potent androgen receptor antagonist. PMID- 21605099 TI - Haem arginate as effective maintenance therapy for hereditary coproporphyria. AB - A 35-year-old woman presented with skin fragility and photosensitivity with blisters affecting her face and hands. Other symptoms included intermittent headache, fatigue, abdominal pain and nausea. Porphyrin studies were markedly raised, with features consistent with hereditary coproporphyria (HCP). Despite strict precautions, symptoms remained significantly problematic. Regular haem arginate infusions of 3 mg/kg per day over 4 days on a monthly basis were commenced and resulted in significant improvement of the patient's symptoms and a reduction in urinary porphobilinogen. Although haem arginate infusion is known as a treatment for severe acute attacks of HCP, the effectiveness of regular infusions as maintenance therapy has not been established. This is the first report of effective symptom control correlating with normalization of biochemical markers in a patient receiving regular haem arginate infusions for the treatment of HCP. PMID- 21605100 TI - A case of autoimmune progesterone dermatitis diagnosed by progesterone pessary. AB - Autoimmune progesterone dermatitis is a rare, cyclical eruption that occurs in the luteal phase of the menstrual cycle and during pregnancy. Many manifestations have been reported including cyclical eczema, urticaria, erythema multiforme, stomatitis and even anaphylaxis. The condition spontaneously resolves after menopause. As histopathology is non-specific, the diagnosis rests on history with precipitation of the eruption by a progesterone challenge, usually by the intradermal, intramuscular or oral route. We present the case of a 34-year-old woman with a premenstrual papular and eczematous eruption that was exacerbated after pregnancy. Biopsy showed subacute spongiotic dermatitis. To confirm the diagnosis, we used an intravaginal progesterone pessary as a provocation challenge. There was recurrence of the rash 12 h after insertion of the pessary with spontaneous resolution thereafter. We propose that use of a progesterone pessary is an effective tool in the diagnosis of autoimmune progesterone dermatitis. PMID- 21605101 TI - Naevus anaemicus-like hypopigmented macules in dyskeratosis congenita. AB - In the present paper we report on a Taiwanese case of X-linked recessive dyskeratosis congenita (DC), confirmed by detection of a 214 C->T mutation in the DKC1 gene, and provide a detailed description of mottled pigmentary changes of the skin, specifically numerous small, whitish macules dispersed against a background of diffuse, finely reticulated hyperpigmentation. The hypopigmented macules showed no discernible erythema upon rubbing or the local application of heat. The naevus anaemicus-like macules may be a relatively common but under recognized feature in DC. More studies are required to determine the incidence and histopathology of these macules. PMID- 21605102 TI - Mutation analysis of the CYLD gene in two Chinese families with multiple familial Trichoepithelioma. PMID- 21605103 TI - On isotretinoin dosing, adverse effects, and efficacy. PMID- 21605106 TI - Unique brown star shape on dermatoscopy of generalized Dowling-Degos disease. PMID- 21605107 TI - Fractional filling with the microdepot technique as an alternative to bolus hyaluronic acid injections in facial volume restoration. AB - For volume restoration of the face, hyaluronic acid is conventionally injected through long, large-bore, 18-gauge needles because of the higher viscosity subtypes required. These hyaluronic acids are either more highly cross-linked or larger in particle size than the less-viscous subtypes. The microdepot injection technique involves using the 31-gauge BD insulin syringe (Becton-Dickinson, North Ryde, NSW Australia) to deposit small amounts of filler (0.05-0.1 mL) throughout the area of volume loss. The procedure is extremely well tolerated, requiring only topical and ice anaesthesia. Using this method, volume restoration can be achieved naturally and progressively over a period of time. Fractional filling every 3-4 months is continued until the desired level of volume correction is attained. Patients undergoing fractional filling followed over a 12-month period did not indicate any observable compromise in filler longevity, even when highly viscous hyaluronic acid fillers were injected through small-bore, 31-gauge insulin syringes. PMID- 21605108 TI - Confocal microscopic features of scarring alopecia: preliminary report. AB - BACKGROUND: Lichen planopilaris (LPP) and discoid lupus erythematosus (DLE) are the most common causes of lymphocytic primary cicatricial alopecia. The management of scarring alopecia can be difficult. The combination of clinical, dermoscopy and reflectance confocal microscopy (RCM), a noninvasive, high resolution imaging technique, examinations have already been demonstrated to be useful for choosing the correct biopsy site in patients with inflammatory skin disease and obtaining microscopic diagnostic criteria. OBJECTIVES: We evaluated the usefulness in practice of RCM for the identification of criteria for LPP and DLE involving the scalp and their management during therapeutic follow-up. METHODS: Seven white patients with a previously established histological diagnosis of DLE (three) and LPP (four), were included in the study. RCM criteria for primary scarring alopecia were selected: epidermal disarray, spongiosis, exocytosis of inflammatory cells in the epidermis, interface dermatitis, peri- and intra-adnexal infiltration of inflammatory cells, dilated vessels in the dermis, dermal infiltration of inflammatory cells and melanophages and dermal sclerosis. All patients were followed up using RCM during the treatment. During follow-up the RCM evolution of the epidermal, junctional and dermal inflammation were evaluated. RESULTS: A series of RCM features of scalp LPP and DLE were identified that show correlation with the histopathological evaluation. During the treatment follow-up of the cases RCM was shown to be sensitive for the identification of therapeutic response. CONCLUSION: In our preliminary study the effective usefulness of RCM for the diagnosis of scarring alopecia and follow-up seemed to be evident. Moreover, RCM seems to be also promising for differential diagnosis between the different entities. PMID- 21605109 TI - Is occupational solar ultraviolet irradiation a relevant risk factor for basal cell carcinoma? A systematic review and meta-analysis of the epidemiological literature. AB - BACKGROUND: The most important risk factor for basal cell carcinoma (BCC) is ultraviolet (UV) radiation. It is reasonable to assume that outdoor workers with a long history of work-related UV exposure are at increased risk of developing BCC. OBJECTIVES: To analyse systematically the epidemiological literature concerning the evidence of an association between occupational UV exposure and BCC risk in outdoor workers. METHODS: Systematic literature review of cohort studies and case-control studies providing data on occupational UV exposure and BCC occurrence. PubMed (up to 28 January 2011) was searched, supplemented by hand searching and consultation of experts in the field. The association between occupational UV exposure and BCC risk is presented as odds ratios (ORs). A random effects meta-analysis and sensitivity analysis including meta-regression on study specific covariates were performed. RESULTS: Twenty-four relevant epidemiological studies (five cohort studies, 19 case-control studies) were identified. Twenty three studies reported sufficient data to be included in the meta-analysis. The pooled OR for the association between outdoor work and BCC risk was 1.43 (95% confidence interval 1.23-1.66; P = 0.0001). Studies adjusting for sex (P < 0.0001) and individual nonoccupational UV exposure (P = 0.014) showed a significantly stronger association of occupational UV exposure and BCC risk. Meta regression revealed a significant inverse relationship between occupational UV radiation exposure and BCC risk with latitude (P = 0.015). CONCLUSIONS: Published epidemiological literature indicates that outdoor workers are at significantly increased risk for BCC. This finding is highly relevant for health policy to stimulate the implementation of effective prevention strategies. PMID- 21605110 TI - Patients with delusional infestation (delusional parasitosis) often require prolonged treatment as recurrence of symptoms after cessation of treatment is common: an observational study. AB - BACKGROUND: Delusional infestation (DI) is an uncommon psychiatric disorder in which patients present with the false and fixed belief of infestation. Numerous studies have demonstrated improvement with pharmacological treatment; however, recurrence rates on cessation of treatment remain unknown. OBJECTIVES: To assess the clinical response and recurrence rates following treatment for DI. METHODS: All patients with DI seen in our combined dermatology/psychiatry clinic to date (n=73) were offered pharmacological therapy. Patients were contacted to complete a telephone questionnaire to assess clinical outcomes, including remission and recurrence rates following treatment. RESULTS: Fifty-nine of 73 (81%) patients with DI received treatment, of whom 40/59 (68%) reported improvement or resolution of symptoms, and the remaining 19/59 (32%) failed to respond. Fifteen of 40 patients with DI completed a course of treatment, 12/40 patients are still undergoing treatment, and outcomes are unknown for 13/40. Of those who completed treatment, 11/15 (73%) reported total remission for at least 9months after discontinuing treatment (range 9months-2.5years). Recurrence of symptoms occurred in 4/15 (27%) within 4months of stopping treatment. CONCLUSIONS: Pharmacological treatment of DI can be effective, particularly in a combined dermatology/psychiatry clinic. Most treated patients have a good prognosis, and a remission period can be expected. However, more than 25% of patients may relapse on stopping treatment, with the greatest risk being within the first few months of discontinuation. These patients may require longer treatment courses, or long term maintenance therapy for symptom control, although further studies are needed to provide recommended guidelines on drug and dosing regimen. PMID- 21605111 TI - Calciphylaxis, occurring 10 weeks after hypercalcaemia, in a patient with multiple myeloma. PMID- 21605112 TI - A critical role for FcgammaRIIB in up-regulation of Fas ligand induced by a microbial polysaccharide. AB - The microbial capsular polysaccharide glucuronoxylomannan (GXM) from the opportunistic fungus Cryptoccocus neoformans is able to alter the innate and adaptive immune response through multi-faceted mechanisms of immunosuppression. The ability of GXM to dampen the immune response involves the induction of T cell apoptosis, which is dependent on GXM-induced up-regulation of Fas ligand (FasL) on antigen-presenting cells. In this study we elucidate the mechanism exploited by GXM to induce up-regulation of FasL. We demonstrate that (i) the activation of FasL is dependent on GXM interaction with FcgammaRIIB (FcgammaRIIB); (ii) GXM induces activation of c-Jun NH(2) -terminal kinase (JNK) and p38 signal transduction pathways via FcgammaRIIB; (iii) this leads to downstream activation of c-Jun; (iv) JNK and p38 are simultaneously, but independently, activated; (v) FasL up-regulation occurs via JNK and p38 activation; and (vi) apoptosis occurs via FcgammaRIIB engagement with consequent JNK and p38 activation. Our results highlight a fast track to FasL up-regulation via FcgammaRIIB, and assign to this receptor a novel anti-inflammatory role that also accounts for induced peripheral tolerance. These results contribute to our understanding of the mechanism of immunosuppression that accompanies cryptococcosis. PMID- 21605113 TI - Incidental CD8 T cell reactivity against caspase-cleaved apoptotic self-antigens from ubiquitously expressed proteins in islets from prediabetic human leucocyte antigen-A2 transgenic non-obese diabetic mice. AB - Apoptosis is known as a major mechanism which contributes to beta cell decay in type 1 diabetes. Commitment to this pathway generally involves caspase-mediated protein cleavage and was found to induce cross-presentation of a specific antigen repertoire under certain inflammatory conditions. We aimed to assess the significance of the CD8 T cell population reactive against such caspase-cleaved apoptotic self-antigens in pancreatic islets of prediabetic human leucocyte antigen (HLA)-A2 transgenic non-obese diabetic chimeric monochain transgene construct (NOD.HHD) mice. We have reproduced a unique peptide library consisting of human CD8 T cell-derived apoptosis-specific antigens, all of which belong to structural proteins expressed ubiquitously in human islets. Pancreatic islets from prediabetic NOD.HHD mice, harbouring humanized major histocompatibilty complex (MHC) class I, were isolated and handpicked at various ages, and islet infiltrating CD8 T cells were expanded in vitro and used as responders in an interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) assay. Human T2 cells were used as antigen-presenting cells (APC) to avoid endogenous antigen presentation. Analogous to the interindividual variability found with peptides from known islet autoantigens such as islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) and insulin, some mice showed variable, low-degree CD8 T cell reactivity against caspase-cleaved self-antigens. Because reactivity was predominantly minor and often undetectable, we conclude that beta cell apoptosis does not routinely provoke the development of dominant cytotoxic T lymphocyte (CTL) reactive against caspase-cleaved self-antigens in the NOD.HHD model. PMID- 21605115 TI - The biological hallmarks of ileal carcinoids. AB - Endocrine tumours derived from the small intestine, ileal carcinoids, produce and secrete the hormones tachykinins and serotonin, which induces the specific symptoms related to the tumour. Because of their low proliferation rate, they are often discovered at late stages when metastases have occurred. The biology that characterizes these tumours differs in many ways from what is generally recognized for other malignancies. In this overview, the current knowledge on the development and progression of ileal carcinoids is described. PMID- 21605114 TI - Lack of evidence of CD40 ligand involvement in transfusion-related acute lung injury. AB - Activated platelets have been implicated in playing a major role in transfusion related acute lung injury (TRALI), as platelets can trigger neutrophils, resulting in vascular damage. We hypothesized that binding of platelet CD40 ligand (CD40L) to endothelial CD40 is essential in the onset of TRALI. Mice were challenged with monoclonal major histocompatibility complex (MHC)-1 antibody which induced TRALI, evidenced by pulmonary oedema, accompanied by significantly elevated bronchoalveolar fluid (BALF) levels of total protein and elevated plasma levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein 2 (MIP-2) compared to infusion of isotype antibody (all Ps < 0.05). Treatment with ciglitazone, which inhibits platelet CD40L expression, had no effect on pulmonary and systemic inflammation compared to controls. In addition, treatment with anti-CD40L antibody, which antagonizes all CD40-CD40L interactions, also did not abrogate the TRALI reaction. Furthermore, levels of soluble CD40L were measured in a cohort of cardiac surgery patients, who were followed prospectively for the onset of TRALI after transfusion. Plasma levels of sCD40L at baseline and at time of developing TRALI did not differ between TRALI patients and controls (transfused cardiac surgery patients not developing acute lung injury) (275 +/- 192 versus 258 +/- 346 and 93 +/- 82 versus 93 +/- 123 pg/ml, respectively, not significant). In conclusion, these results do not support the idea that the CD40 CD40L interaction is involved in mediating TRALI. PMID- 21605117 TI - Latitudinal insect body size clines revisited: a critical evaluation of the saw tooth model. AB - 1. Insect body size is predicted to increase with decreasing latitude because time available for growth increases. In insects with changing voltinism (i.e. number of generations per season), sharp decreases in development time and body size are expected at season lengths where new generations are added to the phenology of a species, giving rise to saw-tooth clines in these traits across latitudes. Growth rate variation may affect the magnitude of variation in body size or even reverse the saw-tooth cline. 2. In this study, we analyse latitudinal body size clines in four geometrid moths with changing voltinism in a common laboratory environment. In addition to body size, we measured larval development time and growth rate and genetic correlations among the three traits. 3. The patterns of clinal variation in body size were diverse, and the theory was not supported even when saw-tooth body size clines were found. Larval development time increased and growth rate decreased consistently with increasing season length, the clines in these traits being uniform. 4. The consistencies of development time and growth rate clines suggest a common mechanism underlying the observations. Such a mechanism is discussed in relation to the complex interdependencies among the traits. PMID- 21605118 TI - Assessing the efficacy of low-level image content descriptors for computer-based fluorescence microscopy image analysis. AB - The increasing prevalence of automated image acquisition systems and state-of-the art information technology has enabled new types of microscopy experiments based on automatic processing of massive image data sets, and numerous methods of high content screening using machine vision and pattern recognition methods have been proposed. However, as a relatively young discipline, it is important to validate these methods and ensure that the machine vision and pattern recognition techniques reliably reflect the actual morphology, and can be effectively used for finding and validating scientific discoveries. In this report we show that some of the previously reported experimental results using automatic microscopy image analysis might be biased, and discuss practices and methods that can be used to obtain objective and reliable automatic analysis of microscopy images. PMID- 21605119 TI - Peroxisome proliferator-activated receptor gamma is inhibited by histone deacetylase 4 in cortical neurons under oxidative stress. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) serves an essential protective function in neurons. Although PPARgamma activation is known to reduce brain tissue damage in distinct models of brain diseases, the regulation of PPARgamma activity in neurons is unclear. Here, we report that histone deacetylase 4 (HDAC4) mediates PPARgamma inhibition in cultured cortical neurons under oxidative stress. Our data indicate that HDAC4 physically interacts with PPARgamma and represses PPARgamma transcription activity in cultured cortical neurons. Upon H(2) O(2) treatment, HDAC4 translocates from the cytoplasm to the nucleus, where it inhibits PPARgamma transcription. This inhibition rendered neurons more vulnerable to H(2) O(2) insult. In contrast, knockdown of HDAC4 by introduction of a specific microRNA abolishes the oxidative stress-induced repression of PPARgamma in neurons and also reduces the number of dead neurons induced by H(2) O(2.) Furthermore, over-expression of PPARgamma protects neurons from either HDAC4 over-expression- or H(2) O(2) -induced damage. These data suggest that HDAC4 works to repress PPARgamma transcription and regulates neuronal death by inhibiting PPARgamma pro-survival activity. PMID- 21605120 TI - School competence and emotional/behavioral problems among Norwegian school children as rated by teachers on the Teacher Report Form. AB - Of 1,409 eligible children aged 6-13 years in grades 1 to 7 who were randomly selected from a national sample of Norwegian schools, 858 participated in the present study (60.9%). The sample was stratified by school centrality, region and size of grade cohort. The teachers assessed their children's academic performance, adaptive school functioning, and levels of emotional/behavioral problems using the 2001 version of the Teacher Report Form (TRF). Only one child was randomly selected from each grade cohort. Girls had significantly higher scores than boys in the Working Hard, Appropriate Behavior, Learning, and Total Adaptive Functioning domains. For girls, only the Working Hard domain was of medium effect size. While boys had significantly higher scores than girls on Attention, Thought Problems, Rule-Breaking, Aggression, Externalizing Problems and Total problems, only Attention Problems showed a medium effect size. Significant sex by age interaction effects were also found for Rule-Breaking, Externalizing, Internalizing, Anxious-Depressed and Total Problems. In all these comparisons, 10-13-year-old boys had significantly higher scores than 6-9-year olds, while girls had similar problem levels across age groups. Our mean Total Problems score (17.2) was lower than the grand mean (21.6) reported in a multi country comparison but higher than in another Norwegian large-scale survey. Overall, our findings indicate that teachers in Scandinavia report, just as do parents, relatively low levels of emotional/behavioral problems among school-aged children. PMID- 21605121 TI - Exploring the enactment effect from an information processing view: what can we learn from serial position analyses? AB - The focus of the present article was to analyze processes that determine the enactment and age effect in a multi-trial free recall paradigm by looking at the serial position effects. In an experimental study (see Schatz et al 2010), the performance-enhancing effect of enactive encoding and repeated learning was tested with older and younger participants. As expected, there was a steady improvement of memory performance as a function of repeated learning regardless of age. In addition, enactive encoding led to a better memory performance than verbal encoding in both age groups. Furthermore, younger adults outperformed the elderly regardless of type of encoding. Analyses in the present article show that encoding by enacting seems to profit especially from remembering the last items of a presented list. Regarding age differences, younger outperformed older participants in nearly all item positions. The performance enhancement after task repetition is due to a higher amount of recalled items in the middle positions in a subject performed task (SPT) and a verbal task (VT) as well as the last positions of a learned list in VT. PMID- 21605122 TI - Bus drivers' exposure to bullying at work: an occupation-specific approach. AB - The present study employs an occupation-specific approach to examine bus drivers' exposure to bullying and their trait anger, job engagement, job satisfaction and turnover intentions. A total of 1,023 bus drivers from a large public transport organization participated in the study. The findings show that bus driving can be a high risk occupation with regard to bullying, since 70% of the bus drivers had experienced one or more acts typical of bullying during the last six months. As many as 11% defined themselves as victims of bullying, 33% of whom (i.e. 3.6% of the total sample) see themselves as victims of frequent bullying. Colleagues were most frequently reported as perpetrators. Exposure to bullying was negatively related to job engagement and job satisfaction and positively related to turnover intentions. Job engagement and job satisfaction mediated the relationship between bullying and intention to leave, respectively. Trait anger had an interaction effect on the relationship between bullying and turnover intentions. This study indicates that workplace bullying has context-specific aspects that require increased use of context-specific policies and intervention methods. PMID- 21605123 TI - Actions taken by schools when tobacco policies are violated: associations with adolescent smoking prevalence. AB - This study examined the association of adolescent smoking prevalence with actions taken by schools (i.e., informing parents or disciplining pupils at school) for violating the school tobacco policy. Interaction terms between actions taken by schools and role models' smoking behavior or support for adolescents were also examined. Data were collected using self-completed questionnaires from a nationally representative Norwegian sample of 15-year-olds (1,404 pupils, 51% males) and 73 staff members. Informing parents when the school tobacco policy was violated by contrast with other actions taken by schools was not associated with lower levels of adolescent smoking. Disciplining pupils was associated with lower levels of adolescent smoking but the association was no longer significant when examined together with parents' and teachers' smoking behavior or support. Exposure to parents' and teachers' smoking, and teachers' support were associated with adolescent smoking prevalence, irrespective of actions taken by schools. Identifying the mechanism under which these different home and school factors relate to adolescent smoking may be worthwhile to inform intervention initiatives. PMID- 21605124 TI - Dose-response effects of TPI ASM8 in asthmatics after allergen. AB - BACKGROUND: TPI ASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (beta(c) ) of the IL-3, IL-5, GM-CSF receptors and the chemokine receptor CCR3. A previous study suggested that TPI ASM8 had broader effects than just inhibition of eosinophils in asthmatics. OBJECTIVE: We assessed whether TPI ASM8 caused a dose-dependent attenuation in the inflammatory and physiological changes after inhaled allergen challenge (AIC). METHODS: This single-center, open-label, stepwise-ascending dose study was conducted in fourteen stable, mild allergic asthmatics. Following placebo AIC, subjects underwent AIC after 4 days treatment with 1, 2, and 4 mg BID and finally 8 mg once daily (OD) of TPI ASM8, inhaled via the I-NebTM nebuliser. Treatments were separated by 2-3-week washout periods. RESULTS: TPI ASM8 was safe and well tolerated at all doses. TPI ASM8 8 mg OD reduced eosinophils in sputum after AIC (by 60.9% at 7 h and 68.4% at 24 h post-AIC, P=0.016 and P=0.007, respectively). Additionally, TPI ASM8 8 mg OD significantly attenuated the early and late airway responses as shown by the reduction in the area under the curve by 45% (P=0.016) and 59%, (P=0.0015), respectively, the increase in eosinophil cationic protein (ECP) by up to 57% (P=0.021), and airway responsiveness to methacholine by more than 1 doubling dose (P=0.012). A dose-response relationship was noted, and efficacy was maintained with once per day administration. CONCLUSIONS: TPI ASM8 attenuated a broad range of inflammatory and physiological changes after AIC, suggesting that CCR3, IL-3, and GM-CSF also are important targets for the management of asthma. PMID- 21605125 TI - Chronic rhinosinusitis in Europe--an underestimated disease. A GA2LEN study. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a common health problem, with significant medical costs and impact on general health. Even so, prevalence figures for Europe are unavailable. In this study, conducted by the GA2LEN network of excellence, the European Position Paper on Rhinosinusitis and nasal Polyps (EP3OS) diagnostic criteria are applied to estimate variation in the prevalence of Chronic rhinosinusitis (CRS) for Europe. METHOD: A postal questionnaire was sent to a random sample of adults aged 15-75 years in 19 centres in Europe. Participants reported symptoms of CRS, and doctor diagnosed CRS, allergic rhinitis, age, gender and smoking history. Definition of CRS was based on the EP3OS diagnostic criteria: the presence of more than two of the symptoms: (i) nasal blockage, (ii) nasal discharge, (iii) facial pain/pressure or (iv) reduction in sense of smell, for >12 weeks in the past year--with at least one symptom being nasal blockage or discharge. RESULTS: Information was obtained from 57,128 responders living in 19 centres in 12 countries. The overall prevalence of CRS by EP3OS criteria was 10.9% (range 6.9-27.1). CRS was more common in smokers than in nonsmokers (OR 1.7: 95% CI 1.6-1.9). The prevalence of self-reported physician-diagnosed CRS within centres was highly correlated with the prevalence of EP3OS-diagnosed CRS. CONCLUSION: This is the first European international multicentre prevalence study of CRS. In this multicentre survey of adults in Europe, about one in ten participants had CRS with marked geographical variation. Smoking was associated with having CRS in all parts of Europe. PMID- 21605126 TI - Cooperative and redundant signaling of leukotriene B4 and leukotriene D4 in human monocytes. AB - BACKGROUND: Leukotriene B(4) (LTB(4)) and cysteinyl leukotrienes (cysLTs) are important immune mediators, often found concomitantly at sites of inflammation. Although some of the leukotriene-mediated actions are distinctive (e.g., bronchial constriction for cysLTs), many activities such as leukocyte recruitment to tissues and amplification of inflammatory responses are shared by both classes of leukotrienes. OBJECTIVE: We used human monocytes to characterize leukotriene specific signaling, gene expression signatures, and functions and to identify interactions between LTB(4)- and cysLTs-induced pathways. METHODS: Responsiveness to leukotrienes was assessed using oligonucleotide microarrays, real-time PCR, calcium mobilization, kinase activation, and chemotaxis assays. RESULTS: Human monocytes were found to express mRNA for high- and low-affinity LTB(4) receptors, BLT(1) and BLT(2), but signal predominantly through BLT(1) in response to LTB(4) stimulation as shown using selective agonists, inhibitors, and gene knock down experiments. LTB(4) acting through BLT(1) coupled to G-protein alpha inhibitory subunit activated calcium signaling, p44/42 mitogen-activated protein kinase, gene expression, and chemotaxis. Twenty-seven genes, including immediate early genes (IEG), transcription factors, cytokines, and membrane receptors were significantly up-regulated by LTB(4). LTB(4) and LTD(4) had similar effects on signaling, gene expression, and chemotaxis indicating redundant cell activation pathways but costimulation with both lipid mediators was additive for many monocyte functions. CONCLUSION: Leukotriene B(4) and LTD(4) display both redundant and cooperative effects on intracellular signaling, gene expression, and chemotaxis in human monocytes. These findings suggest that therapies targeting either leukotriene alone may be less effective than approaches directed at both. PMID- 21605127 TI - The effect of Penaeus merguiensis densovirus on Penaeus merguiensis production in Queensland, Australia. AB - Penaeus merguiensis densovirus (PmergDNV) is currently present on several Queensland prawn farms culturing Penaeus merguiensis. Densoviruses have been linked to mortality and stunting that has caused significant financial loss to prawn farms in Asia. A histopathological study for PmergDNV was initially undertaken to compare broodstock to grow out factors from 60 broodstock animals from each of 22 ponds. There was a significant negative correlation (r = -0.61) between the number of animals with PmergDNV lesions and healthy animals. Furthermore, a higher number of septic hepatopancreatic tubules was correlated (r = 0.48) to high PmergDNV loads. Hence, a polymerase chain reaction analysis of 10 day-old post-larvae (PL) was conducted to determine whether PmergDNV infection was resulting in production losses. An attributable risk analysis of PL from 190 ponds over a 2-year period revealed that 28-29% of ponds with below average survival will have at least average survival following the removal of or decreased levels of PmergDNV. P. merguiensis culture facilities in Queensland should have at least a 14.5% increase in production, equating to an increase of $2.25 million within the first year alone, following the removal or reduction of PmergDNV in their ponds. Hence, focussing efforts on prevention, better management practices and maintaining healthy stock should be of top priority. PMID- 21605128 TI - Plasma and pulmonary disposition of ceftiofur and its metabolites after intramuscular administration of ceftiofur crystalline free acid in weanling foals. AB - The objectives of this study were to determine the plasma and pulmonary disposition of ceftiofur crystalline free acid (CCFA) in weanling foals and to compare the plasma pharmacokinetic profile of weanling foals to that of adult horses. A single dose of CCFA was administered intramuscularly to six weanling foals and six adult horses at a dose of 6.6 mg/kg of body weight. Concentrations of desfuroylceftiofur acetamide (DCA) were determined in the plasma of all animals, and in pulmonary epithelial lining fluid (PELF) and bronchoalveolar lavage (BAL) cells of foals. After intramuscular (IM) administration to foals, median time to maximum plasma and PELF concentrations was 24 h (12-48 h). Mean (+/- SD) peak DCA concentration in plasma (1.44 +/- 0.46 MUg/mL) was significantly higher than that in PELF (0.46 +/- 0.03 MUg/mL) and BAL cells (0.024 +/- 0.011 MUg/mL). Time above the therapeutic target of 0.2 MUg/mL was significantly longer in plasma (185 +/- 20 h) than in PELF (107 +/- 31 h). The concentration of DCA in BAL cells did not reach the therapeutic level. Adult horses had significantly lower peak plasma concentrations and area under the curve compared to foals. Based on the results of this study, CCFA administered IM at 6.6 mg/kg in weanling foals provided plasma and PELF concentrations above the therapeutic target of 0.2 MUg/mL for at least 4 days and would be expected to be an effective treatment for pneumonia caused by Streptococcus equi subsp. zooepidemicus at doses similar to the adult label. PMID- 21605129 TI - Atrial fibrillation in a LQTS patient with an ICD programmed for managed ventricular pacing: what is the cause? PMID- 21605130 TI - Increased intraatrial conduction abnormality assessed by P-wave signal-averaged electrocardiogram in patients with Brugada syndrome. AB - BACKGROUND: Atrial fibrillation (AF) is observed in patients with Brugada syndrome (BS), especially those showing coved-type electrocardiogram (ECG) pattern. Using P-wave signal-averaged ECG (P-SAE), we investigated whether increased intraatrial conduction abnormality contributed to AF generation in BS patients. METHODS: Twenty BS patients and 20 age- and gender-matched healthy controls were enrolled. At the P-SAE recording, 12 of the 20 BS patients showed coved-type (C-BS) and eight showed saddleback-type (S-BS). The total duration (Ad) and root mean square voltage for the terminal 20 ms (LP(20) ) of the filtered P wave were measured. P-wave dispersion (P-disp) was defined as the difference between the maximum and minimum, measured from 16 precordial recording sites. RESULTS: BS patients had a significantly longer Ad (128.2 +/- 7.6 vs 116.3 +/- 8.2 ms, P < 0.0001), lower LP(20) (2.6 +/- 0.9 vs 3.4 +/- 0.8 MUV, P < 0.01), and greater P-disp (15.5 +/- 7.0 vs 7.4 +/- 3.2 ms, P < 0.0001) than the controls. C-BS patients had significantly longer Ad (131.0 +/- 7.2 vs 124.1 +/- 6.8 ms, P < 0.05) and lower LP(20) (2.2 +/- 0.6 vs 3.2 +/- 1.0 MUV, P < 0.05) than S-BS patients. All C-BS patients and only three S-BS patients had atrial late potential (100% vs 38%, P < 0.01). CONCLUSION: Intraatrial conduction delay and its heterogeneity may exist in BS patients, especially those showing coved type ECG patterns. These atrial electrical abnormalities could be a substrate for atrial reentrant tachycardia such as AF. PMID- 21605131 TI - Prognostic significance of atrial arrhythmias in a primary prevention ICD population. AB - INTRODUCTION: We investigated whether primary prevention implantable cardioverter defibrillator (ICD) patients with atrial arrhythmias are at higher risk for ICD shocks and mortality compared to patients without atrial arrhythmias in a subanalysis of the PREPARE study. METHODS AND RESULTS: Details of the PREPARE study design and results have been previously reported. We now included 537 of the 700 patients enrolled in PREPARE. These patients had a dual or biventricular device and at least one device follow-up after implantation. Continuously collected device diagnostics data were used to classify patients into two groups during follow-up: with (n = 133) or without (n = 404) atrial tachycardia/atrial fibrillation (AT/AF). The primary outcomes were ICD shocks and mortality. Subjects were followed for a mean of 333 +/- 73 (range 5-365) days. During a follow-up of 1 year, ICD shocks occurred in 44 (8%) patients. Significantly, more patients with AT/AF received a shock (13.0% vs 6.9%, P = 0.03), with inappropriate shocks accounting for the majority of the difference (6.9% vs 2.6%, P = 0.02). There was no difference in prevalence of shocks between patients with and without a history of AF. Mortality was similar in patients with and without AT/AF, whether detected during the study or prior to the study. In addition, the 34 subjects with high average ventricular rate (>=110 beats per minute) during AT/AF had a higher risk of an inappropriate shock (21.0% vs 2.1%, P < 0.01). CONCLUSION: Primary prevention ICD patients with AT/AF are more likely to receive shocks, especially inappropriate shocks. Mortality was not higher in AT/AF patients. (PACE 2011; 34:1070-1079). PMID- 21605132 TI - Noninvasive time and frequency predictors of long-standing atrial fibrillation early recurrence after electrical cardioversion. AB - BACKGROUND: Several clinical factors have been studied to predict atrial fibrillation (AF) recurrence after electrical cardioversion (ECV) with limited predictive value. METHODS: A method able to predict robustly long-standing AF early recurrence by characterizing noninvasively the electrical atrial activity (AA) with parameters related to its time course and spectral features is presented. To this respect, 63 patients (20 men and 43 women; mean age 73.4 +/- 9.0 years; under antiarrhythmic drug treatment with amiodarone) who were referred for ECV of persistent AF were studied. During a 4-week follow-up, AF recurrence was observed in 41 patients (65.1%). RESULTS: RR variability and the studied AA spectral features, including dominant atrial frequency (DAF), its first harmonic and their amplitude, provided poor statistical differences between groups. On the contrary, f waves power (fWP) and Sample Entropy (SampEn) of the AA behaved as very good predictors. Patients who relapsed to AF presented lower fWP (0.036 +/- 0.019 vs 0.081 +/- 0.029 n.u.(2) , P < 0.001) and higher SampEn (0.107 +/- 0.022 vs 0.086 +/- 0.033, P < 0.01). Furthermore, fWP presented the highest predictive accuracy of 82.5%, whereas SampEn provided a 79.4%. The remaining features revealed accuracies lower than 70%. A stepwise discriminant analysis (SDA) provided a model based on fWP and SampEn with 90.5% of accuracy. CONCLUSIONS: The fWP has proved to predict long-standing AF early recurrence after ECV and can be combined with SampEn to improve its diagnostic ability. Furthermore, a thorough analysis of the results allowed outlining possible associations between these two features and the concomitant status of atrial remodeling. PMID- 21605133 TI - Marked QT prolongation and ventricular tachycardia of a transient nature in young children with cardiomyopathy. AB - Significant prolongation of the QT interval in pediatric patients with cardiomyopathy is rare. We report two cases of dilated myopathy with transient and dramatic QT prolongation. Both had associated ventricular arrhythmias, with one having torsade de pointes, and the other nonsustained ventricular tachycardia. Normalization of their QTc occurred as their ventricular function improved. PMID- 21605134 TI - Autonomic dysfunction in patients with Brugada syndrome: further biochemical evidence of altered signaling pathways. AB - BACKGROUND: In patients with Brugada syndrome (BrS), life-threatening ventricular tachyarrhythmias predominantly occur during vagal stimulation at rest or during sleep. Previous imaging studies displayed an impaired autonomic function in BrS patients. However, it remains unclear whether these alterations primarily stem from a reduction of synaptic release of norepinephrine (NE) or an enhanced presynaptic reuptake. Both conditions could lead to reduced NE concentrations in the synaptic cleft. Therefore, we analyzed key components of the sympathoadrenergic signaling pathways in patients with BrS. METHODS AND RESULTS: Endomyocardial biopsies were obtained from eight BrS patients (seven male; age 49 +/- 15 years) and five controls (three male; age 43 +/- 13 years; P = ns). The concentrations of NE, epinephrine (Epi), NE transport (NET) carrier protein, cyclic adenosine 5'monophosphate (cyclic adenosine monophosphate [cAMP]), inhibitory G-proteins (G(i1,2) alpha), troponin-I (TNI), and phosphorylated TNI were analyzed. Levels of NET, G(i1,2) alpha, TNI, Epi, and phosphorylated TNI were comparable between the groups. Compared to controls, patients with BrS showed reduced cAMP and NE concentrations. CONCLUSIONS: The current findings expand the concept of adrenergic dysfunction in BrS: the reduction of NE in BrS could lead to an impaired stimulation of beta-adrenoceptors resulting in a reduction of cAMP and alterations of the subsequent signaling pathway with potential implication for arrhythmogenesis. PMID- 21605135 TI - Wide complex tachycardia causing congestive heart failure. PMID- 21605137 TI - Electromagnetic interference between external defibrillator and cardiac resynchronization therapy-pacemaker (CRT-P) devices. AB - BACKGROUND: Implantable heart rhythm devices are susceptible to interference in hospitals where electromagnetic interference (EMI) sources are ubiquitous. CASE DESCRIPTION: We report three cases in which EMI from the external defibrillator caused the inability to interrogate Boston Scientific cardiac resynchronization therapy-pacemaker (CRT-P) devices. We have documented interference with the Boston Scientific CRT-P Contact Renewal device model numbers H120/H125 (Natick, MA, USA) and two brands of external defibrillators: the Philips Heartstart XL model number M4735A (Andover, MA, USA) and the Hewlett-Packard Codemaster model number M1722B (Palo Alto, CA, USA). For device implants, we routinely place external pacing pads with the external defibrillator in the "standby" mode for transcutaneous pacing so that only the pacer "start/stop" button needs to be pressed when necessary. We have not been able to interrogate three consecutive Boston Scientific CRT-P devices prior to closure while the external defibrillator had the back-up pacing mode on "standby." In our initial case, a second device was opened because this interaction was not recognized. We documented EMI with the standby pacing mode ON and discovered that by disabling only the "standby" pacing mode on the external defibrillator, the device could be interrogated without difficulty. CONCLUSIONS: This is a case series reporting EMI with a Boston Scientific CRT-P Contact Renewal device H120/H125 telemetry from an external defibrillator with pacing mode on "standby." Failure to recognize this important interaction may lead to inappropriate device and resource utilization. PMID- 21605136 TI - Alternate site right ventricular pacing: defining template scoring. AB - BACKGROUND: Prolonged right ventricular (RV) apical pacing produces dysynchronous ventricular contraction, which may result in left ventricular (LV) dysfunction, whereas septal pacing sites might reflect a more synchronous LV activation. This study examined a method of evaluating alternate RV pacing sites using a template scoring system based on measuring the angle of lead attachment in the 40 degrees left anterior oblique (LAO) fluoroscopic view and its effect on altering the loop of lead in the RV. METHODS: Twenty-three consecutive patients for RV pacing were enrolled. Conventional active fixation leads were positioned in either the RV outflow tract (RVOT) or mid RV using a stylet designed for septal placement (Model 4140, St. Jude Medical, St. Paul, MN, USA). Using LAO cine fluoroscopy, a generous loop of lead was inserted into the RV chamber and the change in angle of attachment determined. RESULTS: Successful positioning of pacing leads at the RVOT septum (18 patients) and mid-RV septum (five patients) was achieved. With introduction of more lead into the RV chamber, the angle of attachment in the LAO projection altered over a range of 6 degrees 32 degrees for all patients with a mean of 14.6 +/- 6.6 degrees . In 87% of patients, the range was predominantly within the same template score with only minor overlap into another zone. CONCLUSIONS: This study shows that the angle of lead attachment in the RV is altered by introducing more lead, but in most cases, the template score remains the same. Further studies are required to determine the accuracy and efficacy of the templates. PMID- 21605138 TI - Why recording of an electrocardiogram should be required in every inpatient and outpatient encounter of patients with heart failure. AB - The electrocardiogram (ECG) has not as yet realized its potential in the diagnosis and management of patients with heart failure (HF). The current model of using the ECG qualitatively with reference to the presence of arrhythmias, heart rate changes, hypertrophy, previous myocardial infarctions, ischemia, and conduction abnormalities is nonspecific and of modest value. The author argues, using examples, that the employment of the ECG metrics of amplitude(s) of leads aVR, sum of leads I & II, sum of all six limb leads, and dimensions and the area of the negative component of the P-wave from lead V1, in repeat ECGs from different clinical encounters, could provide the clinician with a powerful specific diagnostic and follow-up instrument in the management of the edematous state of patients with HF. Although "eye-balling" of changes in ECG hardcopies could suffice for this purpose, the increased availability at the "point of care" of automated measurements of ECG management systems renders application of these ideas all too easy. PMID- 21605139 TI - Atrial fibrillation induced and converted by domestic supply electric shock. AB - We present a case of persistent atrial fibrillation induced by a low-voltage electric shock reverting back to sinus rhythm after a similar repeat shock. PMID- 21605140 TI - Atrial flutter in a patient with postoperative AV block and right infero-septal accessory pathway: how to preserve AV conduction. AB - We report a case of postoperative acquired atrioventricular (AV) block and successful ablation of isthmus-dependent atrial flutter using "cryomapping" in combination with a mapping system preserving AV conduction via right infero septal accessory pathway. PMID- 21605142 TI - Data interpretation: using probability. PMID- 21605143 TI - Improvised transvenous cardiac pacing during Operation Enduring Freedom. AB - We report a case of combat cardiology at a military medical facility in Afghanistan. The patient had a high-degree heart block following inferior ST elevation myocardial infarction requiring cardiac pacing. Transcutaneous pacing failed, leading to asystolic arrest during critical care air transport. An available transvenous pacing wire was soldered to leads from transcutaneous pacing pads allowing effective in-flight cardiac pacing until definitive therapy was available. This case demonstrates use of available resources under austere conditions, has the potential to inform physicians in similar circumstance, and addresses an area of need at military medical facilities. PMID- 21605145 TI - Coagulant and antibacterial activities of the water-soluble seed lectin from Moringa oleifera. AB - AIMS: The aim of this work was to analyse the coagulant and antibacterial activities of lectin isolated from Moringa oleifera seeds that are used for water treatment. METHODS AND RESULTS: The water-soluble M. oleifera lectin (WSMoL) was separated from nonhemagglutinating components (NHC) by chitin chromatography. WSMoL fluorescence spectrum was not altered in the presence of ions that are often present in high concentrations in polluted waters. Seed extract, NHC and WSMoL showed coagulant activity on a turbid water model. Both NHC and WSMoL reduced the growth of Staphylococcus aureus, but only WSMoL caused a reduction in Escherichia coli. WSMoL was also more effective in reducing the growth of ambient lake water bacteria. CONCLUSIONS: Data obtained from this study indicate that WSMoL is a potential natural biocoagulant for water, reducing turbidity, suspended solids and bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Moringa oleifera seeds are a material effective in the treatment of water. PMID- 21605144 TI - Predictors of unusual ECG characteristics in cavotricuspid isthmus-dependent atrial flutter ablation. AB - BACKGROUND: An unusual 12-lead electrocardiographic pattern may be present in patients with cavotricuspid isthmus (CTI)-dependent flutter. OBJECTIVE: Using baseline patient characteristics and echocardiography, we sought to study predictors of unusual electrocardiogram (ECG) characteristics in patients with CTI-dependent atrial flutter. METHODS: This was a dual-center, retrospective cohort study of 147 patients undergoing electrophysiology study and ablation for CTI-dependent atrial flutter. RESULTS: Among this cohort, 23 patients (16%) had unusual 12-lead ECG characteristics. Using multivariate logistic regression, we found two clinical predictors for having an unusual ECG pattern. A clockwise (CW) pattern at time of electrophysiology study was the strongest predictor of an unusual ECG pattern (odds ratio 15.3, 95% confidence interval [CI] 4.0-59.4, P < 0.005). In addition, patients with decreased systolic function had a 3.5 greater odds (95% CI 1.1-11.5, P = 0.037) of having an unusual ECG pattern. CONCLUSIONS: Our data demonstrate that among patients suffering from CTI-dependent atrial flutter who are referred for ablation, 16% will have unusual ECG patterns. Patients with CW atrial activation and left ventricle dysfunction have greater odds of manifesting unusual patterns by surface electrocardiogram. PMID- 21605147 TI - Sexual performance of male mosquito Aedes albopictus. AB - Issues of male fertility must be addressed to support the development of a sterile insect technique (SIT) programme for the control of Aedes albopictus Skuse (Diptera: Culicidae) populations on Reunion Island in the Indian Ocean. The mating ability of a local strain of Ae. albopictus was tested using several batches of females and different cage sizes under laboratory conditions. Individual males were able to inseminate up to 14 females at an average of 9.5 females per male when exposed to 20 females over 7 days. Males filled between three and 27 spermathecal capsules at an average of 15.5 capsules per male. The average number of females inseminated per male was 5.3 when two virgin females were introduced to one male and replaced every day for 12 days, and 8.6 when 10 virgin females were introduced to one male and replaced every day for 14 days. A continuous decrease in the number of both inseminated females and filled spermathecal capsules was observed over time, until no mating occurred after 14 days. The high number of females inseminated by one male and the duration of male activity may have strong implications for SIT control of mosquitoes. PMID- 21605146 TI - The combination of sorafenib with transarterial chemoembolisation for hepatocellular carcinoma. AB - BACKGROUND: Standard of practice involves using transarterial therapy for multifocal hepatocellular carcinoma (HCC) alone and sorafenib only for more advanced HCC, but the sorafenib and transarterial therapy combination may provide greater efficacy. AIM: To evaluate the safety and efficacy of concurrent sorafenib and transarterial therapy in HCC. METHODS: Consecutive cases of HCC were treated with sorafenib and transarterial therapy, receiving sorafenib 2 to 4weeks before transarterial therapy. Baseline clinical parameters, adverse events (AEs) and survival were collected. RESULTS: A total of 47 patients received sorafenib and transarterial therapy. The majority of the patients were male (70%) with HCV (60%), median age of 60years, good performance status (0-1), stable cirrhosis (Child: A 72%; B 28%), unresectable tumour (stage: B 81%; C 19%) and median AFP of 24ng/mL. Median follow-up was 12months and median time on sorafenib was 6months. LC Bead TACE was used with a median frequency of 3. The majority of the patients (89%) experienced AEs. The most common AEs were fatigue (51%), hand foot skin reaction (51%) and diarrhoea (43%). Grade 3 and 4 AEs included fatigue (13%) and hand-foot skin reaction (26%). Most patients required a dose reduction (66%). The main AE related to transarterial therapy was post-TACE syndrome (23%). The disease control rate was 68% at 6months. Overall median survival rate was 18.5months (95% CI 16.1-20.9months). CONCLUSION: Concurrent sorafenib and transarterial therapy is overall safe with no unexpected side effects and encouraging efficacy that warrants further study. PMID- 21605148 TI - Effects of natal habitat odour, reinforced by adult experience, on choice of oviposition site in the mosquito Aedes aegypti. AB - The effects of natal experience on the oviposition behaviour of adult female mosquitoes were investigated in the laboratory using Aedes aegypti (L.) (Diptera: Culicidae). 'Treatment' mosquitoes were exposed to a dilute repellent (inducing stimulus) in their breeding water (aquatic stages) and/or in the air (adults) during various combinations of life stages [larval only (L regime); larval and pupal (LP regime); larval, pupal and emergent adult (LPE regime); larval, pupal, emergent adult and adult (LPEA regime); pupal, emergent adult and adult (PEA regime); adult only (A regime)]. 'Control' mosquitoes were raised in an identical manner, but were not exposed to the inducing stimulus. The oviposition behaviour of treatment and control females was assessed in an oviposition assay that presented a choice of water with or without the inducing stimulus. Of the 435 mosquitoes tested in the experiment, 176 were non-distributors (i.e. laid all of their eggs in only one of the choices). Treatment females (distributors plus non distributors) reared in the presence of the inducing stimulus throughout their lives (LPEA regime) showed a significant preference for the oviposition option containing the inducing stimulus (24/36 females) compared with corresponding controls (5/39 females). Distributors reared under the LPEA and PEA regimes also showed this preference (6/6 treatment vs. 2/29 control females, and 13/18 treatment vs. 7/23 control females, respectively). Females that had been exposed to the inducing stimulus as either immatures or adults only showed no preference for, and some showed an aversion to, the treatment oviposition option. This is interpreted as evidence for a natal habitat preference induction (NHPI) in this species, albeit one that requires extensive reinforcement in the adult stage. This adult experience-reinforced NHPI (AER-NHPI) is discussed in terms of its adaptive significance for container breeders, the possible timing mechanism and sensory basis of induction and potential practical consequences. PMID- 21605149 TI - Risk analysis of Safety Service Patrol (SSP) systems in Virginia. AB - The transportation infrastructure is a vital backbone of any regional economy as it supports workforce mobility, tourism, and a host of socioeconomic activities. In this article, we specifically examine the incident management function of the transportation infrastructure. In many metropolitan regions, incident management is handled primarily by safety service patrols (SSPs), which monitor and resolve roadway incidents. In Virginia, SSP allocation across highway networks is based typically on average vehicle speeds and incident volumes. This article implements a probabilistic network model that partitions "business as usual" traffic flow with extreme-event scenarios. Results of simulated network scenarios reveal that flexible SSP configurations can improve incident resolution times relative to predetermined SSP assignments. PMID- 21605150 TI - The effect of proximity to hurricanes Katrina and Rita on subsequent hurricane outlook and optimistic bias. AB - This study evaluated how individuals living on the Gulf Coast perceived hurricane risk after Hurricanes Katrina and Rita. It was hypothesized that hurricane outlook and optimistic bias for hurricane risk would be associated positively with distance from the Katrina-Rita landfall (more optimism at greater distance), controlling for historically based hurricane risk and county population density, demographics, individual hurricane experience, and dispositional optimism. Data were collected in January 2006 through a mail survey sent to 1,375 households in 41 counties on the coast (n = 824, 60% response). The analysis used hierarchal regression to test hypotheses. Hurricane history and population density had no effect on outlook; individuals who were male, older, and with higher household incomes were associated with lower risk perception; individual hurricane experience and personal impacts from Katrina and Rita predicted greater risk perception; greater dispositional optimism predicted more optimistic outlook; distance had a small effect but predicted less optimistic outlook at greater distance (model R(2) = 0.21). The model for optimistic bias had fewer effects: age and community tenure were significant; dispositional optimism had a positive effect on optimistic bias; distance variables were not significant (model R(2) = 0.05). The study shows that an existing measure of hurricane outlook has utility, hurricane outlook appears to be a unique concept from hurricane optimistic bias, and proximity has at most small effects. Future extension of this research will include improved conceptualization and measurement of hurricane risk perception and will bring to focus several concepts involving risk communication. PMID- 21605151 TI - The value of instructional communication in crisis situations: restoring order to chaos. AB - This article explores the nature of instructional communication in responding to crisis situations. Through the lens of chaos theory, the relevance of instructional messages in restoring order is established. This perspective is further advanced through an explanation of how various learning styles impact the receptivity of various instructional messages during the acute phase of crises. We then summarize an exploratory study focusing on the relationship between learning styles and the demands of instructional messages in crisis situations. We conclude the article with a series of conclusions and implications. PMID- 21605152 TI - A cross-cultural study of perceived benefit versus risk as mediators in the trust acceptance relationship. AB - Several recent studies have identified the significant role social trust in regulatory organizations plays in the public acceptance of various technologies and activities. In a cross-cultural investigation, the current work explores empirically the relationship between social trust in management authorities and the degree of public acceptability of hazards for individuals residing in either developed or emerging Latin American economies using confirmatory rather than exploratory techniques. Undergraduates in Mexico, Brazil, and Chile and the United States and Spain assessed trust in regulatory authorities, public acceptance, personal knowledge, and the risks and benefits for 23 activities and technological hazards. Four findings were encountered. (i) In Latin American nations trust in regulatory entities was strongly and significantly (directly as well as indirectly) linked with the public's acceptance of any activity or technology. In developed countries trust and acceptability are essentially linked indirectly (through perceived risk and perceived benefit). (ii) Lack of knowledge strengthened the magnitude and statistical significance of the trust acceptability relationship in both developed and developing countries. (iii) For high levels of claimed knowledge, the impact on the trust-acceptability relationship varied depending upon the origin of the sample. (iv) Confirmatory analysis revealed the relative importance of perceived benefit over perceived risk in meditating the trust-acceptability causal chain. PMID- 21605153 TI - Prehospital experiences of older men with a first myocardial infarction: a qualitative analysis within the Northern Sweden MONICA Study. AB - AIM: To explore older men's prehospital experiences of their first myocardial infarction (MI). BACKGROUND: The delay between the onset of symptoms to the initiation of medical care is a major determinant of prognosis in MI. The majority of people experiencing MI are men. But few studies have been conducted solely on men's experiences before seeking medical care for MI. The objective of this study was to explore older men's experiences of symptoms and their reasoning during the prehospital phase of their first MI. METHOD: Data collection was carried out through individual interviews with 20 men representing the age range 65-80 (mean 71) years. The participants were interviewed 3 days after admission for a confirmed first MI. The interviews were designed to prompt the men to describe their symptoms and their reasoning up to the decision to seek care. A qualitative content analysis was used to analyse the interviews. FINDINGS: The prehospital phase in older men was found to be a complex and extended journey. The symptoms were perceived from diffuse ill-being to a cluster of alarming symptoms. The participants dealt with conceptions about MI symptoms. They were unsure about the cause of their symptoms, which did not correspond to their expectations about an MI, and whether they should seek medical care. They had difficulty making the final decision to seek care and strived to maintain a normal life. They initially tried to understand, reduce or treat the symptoms by themselves. The decision to seek medical care preceded a movement from uncertainty to conviction. CONCLUSIONS: Understanding older men's prehospital experiences of MI is essential to reduce their patient decision times. This requires knowledge about the complexity and dynamic evolvement of symptoms, beliefs and strategies to maintain an ordinary life. PMID- 21605154 TI - Living with haemodialysis when nearing end of life. AB - AIMS AND OBJECTIVES: The aim of this study was to describe and to elucidate the meanings of being severely ill living with haemodialysis when nearing end of life. INTRODUCTION: To have end stage renal disease and to be treated with maintenance haemodialysis implies being dependent on lifelong treatment. Several studies have reported that these patients suffer a high symptom burden and an impaired quality of life due to both disease and treatment. In the dialysis unit, where the focus is on handling technology and maintaining life, end of life care may be neglected or overlooked. Nevertheless, mortality rates show that about one fourth of patients in haemodialysis care are in their last year of life. DESIGN: A qualitative interpretative design was used. METHODS: Serial qualitative interviews over a period of 12 months were conducted with eight patients (aged 66 87). Altogether text of 31 interviews was interpreted using a phenomenological hermeneutical method in three phases. The study is ethically approved. FINDINGS: The structural analysis resulted in 11 subthemes and thereafter the following three themes were formulated; being subordinate to the deteriorating body, changing outlook on life and striving for upheld dignity. The comprehensive interpretation revealed that being severely ill living with haemodialysis near the end of life means living with suffering simultaneously with reconciliation and well-being. Further, the meanings are understood as intertwined with being old. CONCLUSIONS: Findings contribute to an increased awareness of the complexities of these patients' life worlds and their meanings, and thus of the importance to listen to their experiences and their understandings. Findings suggest that to integrate the philosophy of palliative care in haemodialysis units may improve care for patients who are living with haemodialysis and approaching the end of their lives. PMID- 21605155 TI - Serum myostatin levels and grip strength in normal subjects and patients on maintenance haemodialysis. AB - OBJECTIVE: Myostatin, a negative regulator of skeletal muscle growth, may modulate grip strength, an indicator of muscle function. Its serum levels could be modulated by maintenance haemodialysis (MHD). DESIGN: A descriptive cross sectional study. PATIENTS: Forty-one normal controls and 60 MHD patients using different dialyzers at a medical centre. MEASUREMENTS: The grip strength of the dominant hand, body composition, and the predialysis and postdialysis serum myostatin and IGF-1 levels were measured. RESULTS: The MHD patients had lower body mass index, IGF-1 level, and grip strength than the normal controls. The patients using the high-flux dialyzer had better grip strength than those using the low-flux dialyzer (25.5 vs 19.2 kg). The predialysis myostatin level was higher in low-flux dialyzer than high-flux dialyzer (31.0 vs 18.5 MUg/ml). Interestingly, the high-flux dialyzer reduced the serum myostatin by 36%, whereas low-flux dialyzer increased it by 25%. The myostatin was inversely related to age and the use of high-flux dialyzer. Furthermore, the grip strength was negatively related to age, female gender, muscle mass, myostatin levels and haemodialysis, but positively to the use of high-flux dialyzer in linear regression. The risk of low grip strength was 7.6 times higher in those with higher serum myostatin with the adjustment of age, gender, muscle mass, haemodialysis and mode of dialysis in a logistic regression. CONCLUSIONS: The mode of dialyzer modulates the blood levels of myostatin. Higher myostatin is associated with lower muscle function. The use of myostatin assay in various clinical settings merits further investigation. PMID- 21605156 TI - Systematic review and meta-analysis: islet autotransplantation after pancreatectomy for minimizing diabetes. AB - OBJECTIVE: Islet autotransplantation (IAT) may decrease the morbidity and mortality of postpancreatectomy diabetes mellitus. The current systematic review and meta-analysis examined the rate of insulin independence (II) and mortality after IAT post-total (TP) or partial pancreatectomy (PP). METHODS: Ovid MEDLINE, EMBASE, Web of Science, SCOPUS and reference lists were searched until 31 January 2011. Eligible studies enrolled adult patients with IAT post-TP or PP, regardless of study design, sample size and language. Two investigators identified eligible studies and extracted data independently. From each study, 95% confidence intervals (CIs) were estimated and pooled using random effects meta-analysis. RESULTS: Fifteen observational studies were eligible (11 IAT post-TP, two post-PP and two including both). The II rates for IAT post-TP at last follow-up and transiently during the study were 4.62 per 100 person-years (95% CI: 1.53-7.72) and 8.34 per 100 person-years (95% CI: 3.32-13.37), respectively. In the later group, patients achieved transient II lasting 15.57 months (95% CI: 10.35-20.79). The II rate at last follow-up for IAT post-PP was 24.28 per 100 person-years (95% CI: 0.00-48.96). Whereas the 30-day mortality for IAT post-TP and post-PP was 5% (95% CI: 2-10%) and 0, respectively, the long-term mortality was 1.38 per 100 person-years (95% CI: 0.66-2.11) and 0.70 per 100 person-years (95% CI: 0.00 1.80) respectively. CONCLUSIONS: IAT postpancreatectomy offers some patients a chance for insulin independence. Better data reporting are essential to establish the risks and benefits of IAT after pancreatic surgery. PMID- 21605157 TI - Anxiety is associated with hormonal and metabolic profile in women with polycystic ovarian syndrome. AB - BACKGROUND: Increased prevalence of psychological morbidities, including anxiety, depression and eating disorders, has been reported in women with polycystic ovary syndrome (PCOS) in comparison with normal ovulating, nonhyperandrogenemic women. AIM OF THE STUDY: To investigate the relationship between the degree of anxiety, depression and eating disorders via self-reported symptoms and the severity of hormonal and metabolic aberrations in women with PCOS. For this purpose, the PCOS cohort was subdivided into three subgroups according to the degree of anxiety. METHODS: One hundred and thirty women with PCOS of similar age and BMI were studied. In each subject, hormonal and metabolic status as well as psychological profile was assessed with the use of specific questionnaires. Specifically, anxiety (trait and state) was assessed with the use of STAI-T and STAI-S, while depression and eating disorders were evaluated with the use of the Beck Depression Inventory and the Eating Attitudes test, respectively. RESULTS: The subgroups did not differ in age and BMI. Subjects with the highest STAI-S compared with those with the lowest STAI-S displayed significantly higher the homeostasis assessment model-insulin resistance (HOMA-IR) and free androgen index values (P < 0.05), respectively. Regarding trait anxiety, assessed by STAI-T, HOMA-IR values were significantly elevated (P < 0.05) in the subgroup with the higher STAI-T score compared with the HOMA-IR in the group with the lower STAI-T score. CONCLUSIONS: In women with PCOS, the degree of anxiety, state and trait (STAI-S, STAI-T) appears to vary in a pattern similar to that of hyperandrogenemia and insulin resistance, independently of age and BMI. The pathophysiological mechanisms underlying the association of psychological morbidities with androgen excess and insulin resistance in PCOS remain to be elucidated. PMID- 21605158 TI - Increased concentrations of antibody against heat shock protein in patients with myeloperoxidase anti-neutrophil cytoplasmic autoantibody positive microscopic polyangiitis. AB - To determine serum antibody against human and bacterial heat shock protein (HSP) 60/70 in myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibody (ANCA) positive microscopic polyangiitis (MPA), 58 patients with MPO-ANCA positive MPA, 48 with RA (rheumatoid arthritis) and 40 with SLE (systemic lupus erythematosus) were studied. Serum antibodies against HSP (human HSP 70, human HSP 60, Mycobacterium HSP 70, and Escherichia coli HSP 60) were measured by sandwich ELISA. The frequency of anti-human HSP 60/70 antibody positive patients was significantly greater in MPO-ANCA positive MPA than SLE and healthy controls. Anti-human HSP 60/70 antibody titers in patients with MPO-ANCA positive MPA were significantly higher than those of healthy controls; anti-bacterial HSP 60/70 antibody titers were also higher. There was a significant correlation between titers of anti-human HSP 70 antibody and anti-Mycobacterium HSP 70 antibody. A correlation was also found between titers of anti-human HSP 70 antibody and anti human HSP 60 antibody. Anti-human and bacterial HSP 60/70 antibody titers changed in parallel with disease activity in patients with antibody positive MPA. The anti-HSP antibody titer was also increased in patients with RA and SLE. These results suggest that an immunological background via anti-HSP 60/70 antibodies might be associated with pathogenesis in MPO-ANCA positive MPA. PMID- 21605159 TI - Th17 cells contribute to nontypeable Haemophilus influenzae-specific protective immunity induced by nasal vaccination with P6 outer membrane protein and alpha galactosylceramide. AB - Nasal vaccination is an effective therapeutic means of preventing upper respiratory infection. Recently, nasal vaccination with P6 outer membrane protein of nontypeable Haemophilus influenzae (NTHi) and alpha-galactosylceramide (alpha GalCer) was reported to induce NTHi-specific protective immunity. The present study investigated the role of the Th17 cells induced by nasal vaccination. Mice were immunized with P6 and alpha-GalCer, and their P6-specific immune responses were examined. Cytokine-producing cells were analyzed by flow cytometry, and expression of cytokines in P6-specific CD4+ T cells was determined by reverse transcription-polymerase chain reaction. Bacterial challenges were performed with live NTHi. To examine the role of Th17 cells, bacterial clearance was also evaluated after interleukin (IL)-17 neutralization. P6-specific nasal wash immunoglobulin (Ig) A and serum IgG were increased after immunization with P6 and alpha-GalCer. Specific IgA-producing cells increased markedly in the nasal passages (NPs) of the immunized mice. In addition to P6-specific Th1 and Th2 cells, IL-17-producing Th17 cells were induced in the NPs and spleen. Bacterial clearance was enhanced by nasal vaccination. Interestingly, impaired NTHi clearance was shown after IL-17 neutralization. These findings suggest that nasal vaccination with P6 and alpha-GalCer is an effective regimen for the induction of NTHi-specific protective immunity in the upper respiratory tract. In addition to antigen-specific secretory-IgA, specific Th17 cells induced by nasal vaccination contribute to protection against NTHi. PMID- 21605160 TI - Mycoplasma pneumoniae infection induces a neutrophil-derived antimicrobial peptide, cathelin-related antimicrobial peptide. AB - In innate immunity, cationic antimicrobial peptides including cathelin-related antimicrobial peptide (CRAMP) are known to play critical roles in protecting the host from infection by invasive microbes, including Gram-positive and -negative bacteria. However, little is known about the interactions between CRAMP and mycoplasmas. In the present study, the antimicrobial activity of CRAMP against M. pneumoniae and the expression of CRAMP in bronchoalveolar lavage fluid (BALF) of M. pneumoniae-infected mice was examined. CRAMP at 10-20 MUg/mL reduced the growth of two strains of M. pneumoniae by 100 to 1000-fold. The amount of CRAMP in the BALF of M. pneumoniae-infected mice was 20~25 ng/mL by ELISA. The presence of mature CRAMP in BALF was observed by Western blotting. Neutrophils in BALF showed a fair amount of CRAMP in their cytoplasm by immunofluorescence. Furthermore, the addition of M. pneumoniae resulted in the release of a large amount of CRAMP from neutrophils induced by thioglycolate. These results suggest that CRAMP from neutrophils may play an important role in protection against M. pneumoniae infection. PMID- 21605161 TI - Anatomical changes in the structure of the temporomandibular joint caused by complete edentulousness. AB - BACKGROUND: The posterior slope of the articular eminence of completely edentulous patients compared to patients with maintained occlusion shows significant flattening. OBJECTIVE: The aim of this present study was to reveal a possible correlation between edentulousness and the flattening of the eminence and to find out whether this deformation is connected to age. MATERIAL AND METHODS: Thirty patients were examined in three groups, each consisting of 10 persons (group I: 18- to 25-year-old patients with maintained occlusion, group II: patients over 60 with maintained occlusion, group III: edentulous patients over 60). The three groups were compared according to dental status, age, sex and side. Measurements were carried out on orthopantomographic images taken with Kodak 8000 Digital Panoramic System. The angle of the posterior slope of the articular eminence relative to the Frankfort plane was measured on both sides. Data were analysed statistically with the one-way anova test (alpha = 0.05). RESULTS: The highest values were measured in group I (right side: 39.8 +/- 5.4 degrees , left side: 43.0 +/- 5.9 degrees ), values were somewhat lower in group II (right side: 38.9 +/- 4.7 degrees , left side: 39.5 +/- 7.4 degrees ) and were the lowest in group III, which was significantly lower on both sides than the results of group I and group II (right side: 29.8 +/- 6.0 degrees , left side: 31.9 +/- 5.2 degrees , p < 0.01). The correlation coefficient between age and the flattening of the eminence in group I, II and III was 0.23, 0.35 and 0.92, respectively. CONCLUSION: The flattening of the articular eminence could be correlated with age; however, the rate of deformation is significantly higher in completely edentulous patients than in patients with maintained occlusion. PMID- 21605162 TI - Melatonin levels, determined by LC-ESI-MS/MS, fluctuate during the day/night cycle in Vitis vinifera cv Malbec: evidence of its antioxidant role in fruits. AB - The identification of melatonin in plants has inspired new investigations to understand its biological function and which endogenous and external factors control its levels in these organisms. Owing to the therapeutical and nutraceutical properties of melatonin, it should be important to develop reliable analytical methods for its quantification in vegetal matrices containing this indoleamine, such as grape and wine. The main objectives of the present study were to test whether melatonin levels fluctuate during the day in berry skins of Vitis vinifera L. cv Malbec, thereby possibly relating its abundance to its putative antioxidant function, to determine whether daylight reaching clusters negatively controls melatonin levels, and to evaluate whether total polyphenols and anthocyanins also change through a 24-hr period. Grapes were harvested throughout the day/night to determine the moment when high levels of these components are present in grapes. The presence of melatonin in grapes was evaluated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry. It is shown for the first time that melatonin levels fluctuate during the day/night cycle in plants grown under field conditions in a fruit organ of the species Vitis vinifera. We also determined that the diurnal decay of melatonin in berry skins is induced by sunlight, because covered bunches retained higher melatonin levels than exposed ones, thus explaining at least part of the basis of its daily fluctuation. Evidence of melatonin's antioxidant role in grapes is also suggested by monitoring malondialdehyde levels during the day. PMID- 21605164 TI - Functional interplay between melatonin receptor-mediated antiproliferative signaling and androgen receptor signaling in human prostate epithelial cells: potential implications for therapeutic strategies against prostate cancer. AB - Recently, a novel melatonin MT(1) receptor-mediated antiproliferative signaling mechanism involving transcriptional up-regulation of p27(Kip1) due to paralleled stimulation of protein kinase A (PKA) and protein kinase C (PKC), as a result of respective dual activation of upstream Galpha(s) and Galpha(q) , has been reported in 22Rv1 and RWPE-1 human prostate epithelial cells. Here, we demonstrate that melatonin inhibits the proliferation of LNCaP and VCaP prostate cancer cells via activation of the same MT(1) receptor-mediated antiproliferative signaling pathway. Knockdown of the expression of wild-type androgen receptor (AR) and/or structural/functional AR variants in LNCaP, VCaP, 22Rv1, and RWPE-1 cells resulted in abrogation of melatonin receptor-mediated antiproliferation, indicating that the antiproliferative signaling pathway MT(1) /(Galpha(s) ) PKA + (Galpha(q) ) PKC/p27(Kip1) activated by melatonin in human prostate epithelial cells is AR dependent. Furthermore, melatonin was shown to decrease androgen/AR mediated transactivation of the prostate-specific antigen promoter in the prostate epithelial cell lines. Together, our data indicate the presence of reciprocal functional interactions between MT(1) receptor and AR signaling in malignant and nontumorigenic prostate epithelial cells. Notably, the dual actions of the MT(1) receptor-mediated antiproliferative signaling, leading to down regulation of activated AR signaling and up-regulation of p27(Kip1) , constitute the mechanistic basis for the potential use of melatonin in chemoprevention of prostate cancer, as well as in a novel therapeutic strategy, comprising a combination of melatonin repletion and androgen depletion, for the treatment of advanced or relapsed disease. PMID- 21605163 TI - Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night. AB - This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary, and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light at night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT(1) melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (ERalpha+) human breast cancer cells, melatonin suppresses both ERalpha mRNA expression and estrogen induced transcriptional activity of the ERalpha via MT(1) -induced activation of G(alphai2) signaling and reduction of 3',5'-cyclic adenosine monophosphate (cAMP) levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase, and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT(1) -mediated suppression of cAMP leading to blockade of linoleic acid uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13 HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN. PMID- 21605165 TI - Melatonin treatment following stroke induction modulates L-arginine metabolism. AB - The efficacy of melatonin treatment in experimental stroke has been established. Some of the neuroprotective properties have been attributed to its anti-oxidant and anti-inflammatory effects. Nitric oxide synthases (NOS) and cyclooxygenases (COX) are considered to have a significant role in the inflammatory milieu occurring in acute stroke. While previous reports have shown that pretreatment with melatonin in a stroke model can modulate NOS isoforms, the effect of post treatment with melatonin on l-arginine metabolism has not been investigated. This study initially examined the effect of melatonin (1 nm-1 mm) on l-arginine metabolism pathways in human fibrosarcoma fibroblasts (HT-1080) fibroblasts. Evidence of neuroprotection with melatonin was evaluated in rats subjected to middle cerebral artery occlusion (MCAO). Animals were treated with three daily doses of 5 mg/kg i.p., starting 1 hr after the onset of ischemia. Constitutive NOS activity but not expression was significantly increased by in vitro exposure (72 hr) to melatonin. In addition, melatonin treatment increased arginase activity by increasing arginase II expression. In vivo studies showed that melatonin treatment after MCAO significantly inhibited inducible NOS activity and attenuated expression of the inducible isoform, resulting in decreased total NOS activity and tissue nitrite levels. COX activity was significantly reduced with melatonin treatment. The neuroprotective anti-inflammatory effects of melatonin were consistent with the substantial reduction in infarct volume throughout the cortex and striatum and recovery of mitochondrial enzyme activities. The evidence presented here suggests that modulation of l-arginine metabolism by melatonin make it a valuable neuroprotective therapy for stroke. PMID- 21605166 TI - A novel treatment approach for paediatric Gorham-Stout syndrome with chylothorax. AB - AIM: To expand the treatment options in paediatric Gorham-Stout syndrome (GSS) when conventional therapy is ineffective. METHOD: Two children with biopsy confirmed GSS, a rare disorder with progressive lymphangiomatosis, were treated with a combination of interferon-alpha-2b, low anticoagulant, low molecular weight heparin, radiotherapy and surgery. RESULTS: The combined therapy resolved the symptoms in the acute phase, and both patients have since been free of symptoms for >2 years. CONCLUSION: The successful addition of a low anticoagulant, low molecular weight heparin (tafoxiparin) to the treatment protocol in two paediatric cases of the GSS may justify the use of this approach in similar cases. PMID- 21605167 TI - The linear excisional wound: an improved model for human ex vivo wound epithelialization studies. AB - BACKGROUND/PURPOSE: Wound healing is a complex process that involves multiple intercellular and intracellular processes and extracellular interactions. Explanted human skin has been used as a model for the re-epithelialization phase of human wound healing. The currently used standard technique uses a circular punch biopsy tool to make the initial wound. Despite its wide use, the geometry of round wounds makes it difficult to measure them reliably. METHODS: Our group has designed a linear wounding tool, and compared the variability in ex vivo human linear and circular wounds. RESULTS: An F test for differences in variances demonstrated that the linear wounds provided a population of wound size measurements that was 50% less variable than that obtained from a group of matched circular wounds. This reduction in variability would provide substantial advantages for the linear wound technique over the circular wound punch technique, by reducing the sample sizes required for comparative studies of factors that alter healing. CONCLUSION: This linear wounding tool thus provides a method for wounding that is standardized, provides minimal error in wound gap measurements, and is easily reproducible. We demonstrate its utility in an ex vivo model for the controlled investigation of human skin wounds. PMID- 21605168 TI - Thermography as a predictor of postherpetic neuralgia in acute herpes zoster patients: a preliminary study. AB - BACKGROUND/PURPOSE: Infrared thermal images in patients suffering from herpes zoster (HZ) may exhibit thermal asymmetry due to the unilateral distribution of HZ lesions. This study examined the usefulness of infrared thermography in acute HZ as a predictor for the development of postherpetic neuralgia (PHN). METHODS: The authors collected demographic and clinical data including age, sex, onset of skin lesion, pain intensity by a visual analogue scale (VAS) and the development of PHN from a total of 55 patients diagnosed with HZ. We evaluated the body surface thermographic parameters between the lesion and contralateral normal skin: maximal difference in the temperature (DeltaT) and the size of the body surface area (BSA) showing thermal asymmetry. RESULTS: Temperatures of the lesions were found to be warmer than the control side in most patients with acute HZ. We compared the patient group who developed PHN with those who did not. In univariate analysis, patients with PHN were older (P=0.004), had a higher VAS score for pain (P<0.001), higher DeltaT (P<0.001) and larger BSA (P=0.001). In logistic regression analysis to identify independent risk factors of PHN, older age (>60 years old) and DeltaT more than 0.5 degrees C were found to be statistically significant. PMID- 21605169 TI - Ability to estimate relative percutaneous penetration via a surrogate maker - trans epidermal water loss? AB - AIMS: This study measures the dynamic change of the trans-epidermal water loss (TEWL) rate and in vitro skin permeation data of tritiated water and [(14) C] clonidine HCl in order to refine our knowledge in the relationship between percutaneous penetration and TEWL. MEASURES: TEWL values were measured before and during the experimental period. Single application of tritiated water and [(14) C]-clonidine HCl were dosed at the same time on dermatomed human skin samples collected from 12 donors in a flow through diffusion cell system. Radioactivity of absorbed dose: stratum corneum, epidermis, dermis, receptor fluid collected every 4 hours, as well as removable dose residue was counted to determine accountability, percent dose, MUg equivalent, and flux rate. These data were further combined with TEWL values to analyze their possible relationship. RESULTS: Results showed that baseline TEWL values correlated with the thickness of dermatomed skin (r=-0.44, P=0.007), and with tritiated water fluxes (r=0.34, P=0.04) and [(14) C]-clonidine HCl (r=0.36; P=0.03). The fluxes of tritiated water and [(14) C]-clonidine HCl were correlated (r=0.67, P<0.001). When TEWL and permeation data were compared, the pattern of tritiated water expressed as a percent dose permeated in receptor fluid resembled the TEWL pattern. CONCLUSION: The methodology described provides evidences of the correlation of TEWL and skin integrity and skin permeation and further demonstrates to be a rapid alternative to tritiated water permeation for measuring skin barrier functions in vitro. To develop TEWL measurement as a possible predictive model to assess in vitro percutaneous absorption, however more chemicals with various physical-chemical properties need to be examined, and the relationships to TEWL and tritiated water flux better defined. PMID- 21605170 TI - Acne analysis, grading and computational assessment methods: an overview. AB - INTRODUCTION: This paper presents a comprehensive review of acne grading and measurement. Acne is a chronic disorder of the pilosebaceous units, with excess sebum production, follicular epidermal hyperproliferation, inflammation and Propionibacterium acnes activity. Most patients are affected with acne vulgaris, which is the prevalent type of acne. Acne vulgaris consists of comedones (whitehead and blackhead), papules, pustules, nodules and cysts. OBJECTIVES: To review and identify the issues for acne vulgaris grading and computational assessment methods. To determine the future direction for addressing the identified issues. METHODS: There are two main methods of assessment for acne severity grading, namely, lesion counting and comparison of patient with a photographic standard. For the computational assessment method, the emphasis is on computational imaging techniques. RESULTS: Current acne grading methods are very time consuming and tedious. Generally, they rely on approximation for counting lesions and hence the assessment is quite subjective, with both inter and intra-observer variability. It is important to accurately assess acne grade to evaluate its severity as this influences treatment selection and assessment of response to therapy. This will further help in better disease management and more efficacious treatment. CONCLUSION: Semi-automated or automated methods based on computational imaging techniques should be devised for acne grade assessment. PMID- 21605171 TI - Clinical course of vesicoureteral reflux in patients with hypospadias. AB - OBJECTIVES: The prevalence of vesicoureteral reflux (VUR) in hypospadic patients is reportedly higher than in healthy children. We investigated the prevalence and the clinical course of VUR in hypospadic patients. METHODS: We carried out intraoperative cystography to detect VUR in 338 patients who underwent hypospadias repair. Age, severity of hypospadias and the presence of VUR were investigated. A dimercaptosuccinic acid renal scan and follow-up voiding cystourethrography (VCUG) were carried out if VUR was detected. RESULTS: VUR was detected in 41 patients (12.1%). Of 156 patients who were younger than 1 year-of age, 34 (21.8%) were found to have VUR. The prevalence of VUR was significantly higher in patients younger than 1year (P<0.001), but was not associated with hypospadias type (P=0.212). The reflux grades were I, II and III in 6, 52 and 1 renal units, respectively. Renal scarring was shown in one of 36 patients. Follow up VCUG was carried out in 30 patients at a mean of 14.28+/-3.89months, and reflux resolved in 27 and improved from grade II to grade I in three patients. CONCLUSIONS: Although its prevalence is higher in hypospadic children than in healthy children, it is not necessary to screen for VUR in hypospadic patients, because it is likely to be low-grade and to resolve in most cases. PMID- 21605172 TI - Effect of hyaluronic acid on urine nerve growth factor in cyclophosphamide induced cystitis. AB - OBJECTIVES: To investigate how hyaluronic acid (HA) affects nerve growth factor (NGF) production and bladder overactivity in a cyclophosphamide (CYP)-induced cystitis rat model. METHODS: Female Sprague-Dawley rats received three intermittent intraperitoneal injections of CYP (75 mg/kg) or saline. Before or after CYP injection, HA was given intravesically and urine NGF was checked with creatinine correction. Bladder function was evaluated by cystometrograms under Zoletil anesthesia. Furthermore, the effect of HA was counteracted with hyaluronidase (HYAL). Bladder structural change was compared among groups with trichrome stain. RESULTS: The intercontraction interval (ICI) significantly decreased in CYP-injected rats in comparison to the saline-injected controls. In the CYP-injected groups, bladder HA instillation significantly increased the ICI, but did not change the maximum voiding pressure in comparison to the saline instillation. NGF production significantly increased in CYP-injected rats, but decreased significantly with HA treatment. Treatment with HA had a more significant effect on urine NGF and the use of HYAL would eliminate this effect. Specific staining showed mucosa swelling after CYP treatment. Little HA coating on bladder mucosa could be found in HA-treated rats. CONCLUSIONS: Present findings raise the possibility that HA could be an effective treatment for CYP related bladder overactivity through the involvement of NGF signaling. PMID- 21605173 TI - Reflectance confocal microscopy criteria of lichen planus-like keratosis. AB - BACKGROUND: Lichen planus-like keratosis (LPLK) may be difficult to differentiate from melanoma and other skin cancers on sun-damaged skin based on clinical and dermoscopic examination. Reflectance confocal microscopy (RCM) allows evaluation of skin lesions at high resolution. OBJECTIVES: The aim of this study was to identify criteria for specific diagnosis of LPLK using in vivo RCM. METHODS: Lesions included in the study were derived from patients presenting for skin examination at a private dermatology practice specializing in skin cancer. We retrospectively analysed RCM features of 28 biopsy-proven LPLK and compared them to RCM findings in skin cancers on sun-damaged skin, including five in situ squamous cell carcinomas, six actinic keratoses, seven superficial basal cell carcinomas and eight melanomas. RESULTS: The main RCM features of LPLK and their relative frequencies were: (i) typical honeycomb pattern of the spinous layer (78.6%); (ii) elongated cords and/or bulbous projections at the dermal-epidermal junction (75%); and (iii) numerous plump-bright cells and/or bright stellate spots in the superficial dermis (92.9%). These RCM features correlated with the following histopathological findings respectively: (i) spinous-granular layers without significant atypia of keratinocytes; (ii) elongated, bulbous rete ridges; and (iii) dense infiltration of melanophages and lymphocytes in superficial dermis. We propose diagnostic criteria that classify correctly 71.4% of LPLK, while avoiding misclassification of any of the skin cancers in the present series as LPLK. CONCLUSIONS: We identified RCM criteria for diagnosis of LPLK that correlate well with histopathological findings and that allow differentiation of LPLK from skin cancer. PMID- 21605174 TI - Experience with ustekinumab for the treatment of moderate to severe hidradenitis suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a severe chronic inflammatory follicular disease characterized by nodules and abscesses affecting apocrine gland-bearing regions. HS is not well-controlled with conventional medical therapies such as topical therapy, oral antibiotics and retinoids, however, abrogation of tumour necrosis factor-alpha (TNF-alpha) function has proven effective in some patients. OBJECTIVE: To assess the safety and efficacy of the interleukin-12/23 inhibitor, ustekinumab for treatment of HS in three patients with moderate-severe disease. METHODS: The subjects received 3-45 mg subcutaneous injections of ustekinumab at 0, 1 and 4 months. Improvement was assessed by the dermatology life quality index (DLQI), visual analogue scale of pain (VAS) and physician's global assessment (PGA) at each monthly visit. RESULTS: Prior to treatment, subjects had moderate-severe HS (Hurley stage II-III) with a DLQI score between 8 and 12. At 6 months, one patient showed complete disease remission, while a 25-49% improvement was seen in a second patient and no change in a third. A moderate but statistically significant relationship was observed between VAS and DLQI scores (r=0.75; P<0.01). CONCLUSION: Ustekinumab may provide a safe and effective new treatment strategy for HS in some patients. Interleukin 12/23 inhibition is a potential therapeutic option for patients in which other therapies prove ineffective. PMID- 21605175 TI - The effect of a corticosteroid cream and a barrier-strengthening moisturizer in hand eczema. A double-blind, randomized, prospective, parallel group clinical trial. AB - BACKGROUND: Hand eczema is a common and persistent disease with a relapsing course. Clinical data suggest that once daily treatment with corticosteroids is just as effective as twice daily treatment. OBJECTIVES: The aim of this study was to compare once and twice daily applications of a strong corticosteroid cream in addition to maintenance therapy with a moisturizer in patients with a recent relapse of hand eczema. METHODS: The study was a parallel, double-blind, randomized, clinical trial on 44 patients. Twice daily application of a strong corticosteroid cream (betamethasone valerate 0.1%) was compared with once daily application, where a urea-containing moisturizer was substituted for the corticosteroid cream in the morning. The investigator scored the presence of eczema and the patients judged the health-related quality of life (HRQoL) using the Dermatology Life Quality Index (DLQI), which measures how much the patient's skin problem has affected his/her life over the past week. The patients also judged the severity of their eczema daily on a visual analogue scale. RESULTS: Both groups improved in terms of eczema and DLQI. However, the clinical scoring demonstrated that once daily application of corticosteroid was superior to twice daily application in diminishing eczema, especially in the group of patients with lower eczema scores at inclusion. CONCLUSIONS: Twice daily use of corticosteroids was not superior to once daily use in treating eczema. On the contrary, the clinical assessment showed a larger benefit from once daily treatment compared with twice daily, especially in the group of patients with a moderate eczema at inclusion. PMID- 21605176 TI - Effect of saponins from Enterolobium cyclocarpum on in vitro microbial fermentation of the tropical grass Pennisetum purpureum. AB - The effect of Enterolobium cyclocarpum saponins on the fermentation of Pennisetum purpureum was studied in vitro, with P. purpureum incubated alone (PP), in combination with E. cyclocarpum (EC), E. cyclocarpum without saponins (ER) or with saponins extracted from the same amount of E. cyclocarpum (SP). Gas production was monitored and contents sampled after 24 h for short-chain fatty acid (SCFA) and total microbial mass analyses. SCFA and microbial attachment to P. purpureum using (15)N as marker were determined from different bottles at 6, 12 and 24 h. Up to 8 h, gas production was highest for SP and lowest for ER (p < 0.05), probably because highly fermentable solubles were also extracted. Gas from PP was highest from 16 h (p < 0.05). Treatments including saponins (SP and EC) increased propionate (p < 0.001) and decreased acetate and butyrate (p < 0.01) proportions. Stoichiometrically estimated methane concentration was lowest for SP and EC (p < 0.01). Microbial attachment after 24 h was lower for EC and SP than for ER (p < 0.05). Saponins from E. cyclocarpum are responsible for the reduction in gas production when supplemented with P. purpureum and modify the fermentation pattern by increasing propionate proportion and decreasing methane production. Besides, saponins increase total microbial mass, although microbial attachment to the grass substrate was reduced. PMID- 21605177 TI - Effects of dietary supplementation of synbiotic on growth performance, serum biochemical parameters and carcass composition in rainbow trout (Oncorhynchus mykiss) fingerlings. AB - The aim of this study was to evaluate the influence of a synbiotic (Biomin IMBO) on serum parameters and feeding efficiency in rainbow trout (Oncorhynchus mykiss) fingerlings. The fish with initial average weight of 4.59 +/- 0.2 g were randomly assigned to four dietary treatments for two months. The dietary treatment (0.5, 1 and 1.5 g/kg of diet) was supplemented with basal diet and non-supplemented basal diet was used as control. After two months, all treatments supplemented with synbiotic showed significant (p < 0.05) increase in final mean weight, weight gain percentage, specific growth rate, condition factor, food conversion efficiency and survival rate, compared to the control group. Among all supplemented treatments, the best result in terms of growth factors and survival was observed in the treatment supplemented with 1 g synbiotic per kilogram of diet. Furthermore, supplementation with symbiotic, specifically 1 and 1.5 g/kg, significantly (p < 0.05) increased the total serum protein, but there was no significant (p > 0.05) difference in globulin content, albumin/globulin ratio, and triglyceride content among experimental treatments. In terms of body composition, carcass protein content of fish fed with synbiotic significantly (p < 0.05) increased compared to the control. These results revealed that a feeding regime with synbiotic for two months led to a significant increase in growth performance, survival rate and feeding efficiency in rainbow trout fingerlings. PMID- 21605178 TI - Effectiveness of chlorhexidine on the disinfection of complete dentures colonised with fluconazole-resistant Candida albicans: in vitro study. AB - This in vitro study evaluated different concentrations of chlorhexidine (CHX) solution on the disinfection of dentures colonised with a reference (ATCC 90028) and azole-resistant (R1, R2 e R3) strains of Candida albicans. Sterile dentures were individually inoculated with one of the strains and incubated at 37 degrees C for 24 h. Then, each denture was immersed in sterile saline (control) or CHX (2%, 1% or 0.2%) for 10 min. Samples of serial dilutions were spread on Agar Sabouraud Dextrose and incubated at 37 degrees C for 48 h. The colonies were counted and the values of log(cfu ml(-1)) were analysed by Kruskal-Wallis test (P < 0.05). Dentures immersed in CHX were incubated for 7 days. For all strains, the cfu ml(-1) values of 0.2% CHX were significantly higher than those of 2% and 1% CHX. There was no difference between the cfu ml(-1) values of 2% and 1% CHX. For dentures immersed in CHX, ATCC 90028 strain showed lower cfu ml(-1) values than R2 and R3 strains. For control dentures, cfu ml(-1) values of ATCC 90028 strain were higher than those of R strains. Immersion in 2% CHX resulted in the highest number of dentures without fungal growth after 7 days. For denture disinfection, 2% CHX was the most effective concentration, and R strains were less susceptible to disinfection. Chlorhexidine is effective in disinfection of dentures contaminated with azole-resistant C. albicans. PMID- 21605179 TI - Characteristics of Paecilomyces lilacinus infection comparing immunocompetent with immunosuppressed murine model. AB - The characteristics of Paecilomyces lilacinus infection were evaluated using two murine experimental models: immunocompetent and immunosuppressed. The evaluation criteria for characteristics of infection were clinical signs, weight loss, survival rates, histopathological alterations and the number of viable fungal cells re-isolated from different organs; and those for immunological status were in vitro lymphoproliferative response, cell surface phenotyping and IFN-gamma production. Morphological evaluation showed that P. lilacinus isolates presented morphological characteristics consistent with those described in the literature. The immunocompetent mice could be infected by the fungi, but they did not develop the disease, unlike the immunosuppressed mice, which showed clinical signs of mycosis in an environment of suppressed cellular immune response. The hypothesis of latent infection reactivation in mice was not confirmed. The difference observed in the infection rate of the two fungi isolates points to an intrinsic variation between strains of P. lilacinus and led us to hypothesise that even in the presence of immunosuppressed environment, the fungus virulence can play a role in the pathogenesis of hyalohyphomycosis. PMID- 21605180 TI - Difference in virulence between fluconazole-susceptible and fluconazole-resistant Candida albicans in a mouse model. AB - Two Candida albicans isolates were collected from a HIV-positive patient with recurrent oropharyngeal candidosis (OPC). One isolate was taken during the first episode of oral candidosis [fluconazole susceptible (FLU-S), minimal inhibitory concentration (MIC) = 0.25 mg l(-1) ] and the second after the patient developed refractory OPC and resistance to fluconazole (FLU-R, MIC = 64 mg l(-1)). Both isolates were clonally identical. Different in vitro studies were carried out to assess putative virulence factors of both isolates. Gene expressions of efflux pumps and CSH1 were determined as well as adherence to human epithelial cells, determination of proteinase secretion and biofilm formation activity. Virulence was studied using a disseminated mouse model. All mice challenged with the FLU-S isolate survived the experiment when FLU was given. However, when FLU was absent, the mortality of the FLU-S isolate was higher than that of the FLU-R isolate with no mice surviving the experiment. In vitro studies showed pronounced growth rates of the FLU-S isolate and a more intense biofilm-building activity compared with the FLU-R isolate. The FLU-R isolate highly up-regulated MDR1 and CSH1. This isolate also adhered stronger to the epithelial cell line. The results showed that FLU-S and FLU-R isolates exhibit different virulence factors, which enable the survival of both isolates in adapted environments. PMID- 21605181 TI - Clinical significance of Aspergillus sensitisation in bronchial asthma. AB - Numerous studies have suggested a link between fungal sensitisation and severity of asthma. However, few studies have specifically evaluated the relationship between Aspergillus sensitisation and asthma severity. This study was aimed at investigating the clinical significance of Aspergillus sensitisation in asthma. In this prospective cross-sectional study, patients with asthma were subjected to pulmonary function test and an intradermal Aspergillus skin test (AST) apart from a detailed clinical history and physical examination. Assessment of asthma severity was carried according to the Global Initiative for Asthma (GINA) recommendations, Asthma Control Test (ACT) and the mini Asthma Quality of Life Questionnaire (mini AQLQ). Based on AST, the cases were dichotomised into Aspergillus-sensitive and AST-negative groups. There were 417 (193 males, 224 females; mean age, 34 years) asthmatic patients of whom 219 (52.5%) showed Aspergillus sensitisation. The severity of disease as per the GINA criteria and the dose of ICS required for asthma control were similar in the two groups. The Aspergillus-sensitive group had poorer pulmonary function than the AST-negative group [AST positive vs. negative: percentage predicted mean (SD) forced expiratory volume in the first second: 73.1(23.8) vs. 77.9(22.7), P = 0.04; mean (SD) FEV(1) /forced vital capacity (FVC) ratio: 68.2(13.3) vs. 74.3(15.7), P = 0.0001]. The mini AQLQ scores were similar in the two groups. In the ACT, the numbers of patients in the domain pertaining to nocturnal awakenings were significantly higher in the Aspergillus-sensitive group (P = 0.014). There was a weak association between Aspergillus sensitisation and severity of asthma. Whether Aspergillus sensitisation is causally linked to asthma severity remains to be seen. PMID- 21605182 TI - Severe kerion with dermatophytid reaction presenting with diffuse erythema and pustules. PMID- 21605183 TI - Successful conservative treatment of peripheral candidal thrombophlebitis: case report. PMID- 21605184 TI - Genetic relationship of fluconazole non-susceptible Candida glabrata isolates from nine Korean hospitals. PMID- 21605185 TI - Incubation of fungal cultures: how long is long enough? AB - Fungal cultures are traditionally incubated for 4 weeks or longer to maximise the recovery of slowly growing fungi. However, the data in support of this are scarce. The objectives of this study were to determine the optimum incubation time for specimens in which moulds or yeast are suspected and to review the literature. A total of 3036 fungal cultures of 2216 dermatological and 820 non dermatological specimens were analysed. The day on which fungal growth was first noted, was recorded. Eleven of 820 non-dermatological specimens were positive after day 14; in 10 cases, the fungus was considered clinically non-relevant and in one case, the cerebrospinal fluid of a patient receiving therapy for cryptococcosis was positive with Cryptococcus neoformans. Fourteen and three of 2216 dermatological samples showed the growth of a dermatophyte in the third week and fourth week respectively. The results indicate that for specimens sent for the detection of yeast or moulds (except dermatophytes and systemic dimorphic fungi), an incubation period of 2 weeks is sufficient, whereas for dermatophytes, a 4-week incubation period is necessary. Based on these results and previous literature, an algorithm for the incubation time of fungal cultures is proposed. PMID- 21605186 TI - Necrotic ulcer caused by Trichosporon asahii in an immunocompetent adolescent. PMID- 21605187 TI - In vitro antifungal activity of coumarin extracted from Loeselia mexicana Brand. AB - The bis-coumarin daphnoretin and its monomeric precursors scopoletin and umbelliferone were isolated for the first time from the aerial part of Loeselia mexicana Brand (a vegetal species used in Mexican traditional medicine) using chromatographic techniques. The structures of these compounds were determined by (1) H and (13) C NMR analyses. These coumarins were evaluated for in vitro antifungal activity. The three compounds tested showed significant antifungal activity. PMID- 21605188 TI - Occurrence of influenza A(H1N1)v infection and concomitant invasive pulmonary aspergillosis in a patient with chronic obstructive pulmonary disease. PMID- 21605189 TI - Olecranon bursa with Fusarium solani infection in an otherwise healthy patient. PMID- 21605190 TI - A morphogenetic regulatory role for ethyl alcohol in Candida albicans. AB - Regulation of morphogenesis through the production of chemical signalling molecules such as isoamyl alcohol, 2-phenylethyl alcohol, 1-dodecanol, E nerolidol and farnesol is reported in Candida albicans. The present study focuses on the effect of ethyl alcohol on C. albicans dimorphism and biofilm development. Ethyl alcohol inhibited germ tube formation induced by the four standard inducers in a concentration-dependent manner. The germ tube inhibitory concentration (4%) did not have any effect on the growth and viability of C. albicans cells. Ethyl alcohol also inhibited the elongation of germ tubes. Four percentage of ethyl alcohol significantly inhibited biofilm development on polystyrene and silicone surfaces. We suggest a potential morphogenetic regulatory role for ethyl alcohol, which may influence dissemination, virulence and establishment of infection. PMID- 21605191 TI - A case of primary cutaneous histoplasmosis acquired in the laboratory. PMID- 21605192 TI - Endogenous filamentous fungal endophthalmitis--single-centre survey in patients with acute leukaemia or postallogeneic stem cell transplantation and review of the literature. AB - Endogenous endophthalmitis caused by filamentous fungi has been infrequently described and its prognosis in immunocompromised patients is largely unknown. Patients were identified through a single-centre database containing patients with endophthalmitis. Cases published since 2002 were reviewed. Clinical and treatment features as well as outcomes were analysed. Six patients were identified from the database. Underlying conditions were haematological malignancies (HM) and/or allogeneic haematopoietic stem cell transplantation (HSCT). Three patients underwent vitrectomy. None of the patients survived and the median time from first evidence of endophthalmitis until death was 33 days. The median time from first evidence of an invasive fungal infection to endophthalmitis was only 5 days. Fifty-six patients were identified from the literature. The majority of these patients underwent vitrectomy (27) or enucleation (10) and received intraocular antifungal therapy (28). Only 13 (23%) of 56 patients experienced an improved vision. The survival rate was 52% in all 56 patients but was significantly less in patients with HM or post-HSCT when compared with all others (26% vs. 70%, respectively; P = 0.003). Endogenous endophthalmitis caused by filamentous fungi is frequently associated with a permanent decrease or loss of vision. This type of fungal infection carries a particular poor prognosis in patients with profound immunosuppression, requiring improved treatment strategies. PMID- 21605193 TI - Microscopical analysis of Candida albicans biofilms on heat-polymerised acrylic resin after chlorhexidine gluconate and sodium hypochlorite treatments. AB - The ability of Candida albicans to form biofilms on denture surfaces is a significant cofactor in the pathogenesis of denture stomatitis. In this study, we applied a differential staining approach and scanning electron microscopy (SEM) to analyse the effect of sodium hypochlorite and chlorhexidine gluconate on the viability, removal and morphology of C. albicans forming biofilms on denture acrylic using an in vitro model. Immediately after treatment, to distinguish live from dead C. albicans cells in the remaining biofilms, the specimens were stained differentially and analysed by confocal scanning laser microscopy. Moreover, morphological alterations of fungal cells were investigated using scanning electron microscopy. All disinfectant solutions killed all remaining fungal cells on the specimens. Interestingly, 4% chlorhexidine did not remove these cells from the acrylic resin surface whereas sodium hypochlorite solutions (1% and 2%) provided almost complete biofilm removal. Furthermore, treating the specimens with sodium hypochlorite induced cell morphology alterations, as seen in the residual fungal cells. Finally, according to our findings, it can be suggested that sodium hypochlorite solutions are the first choice as denture cleanser when compared with 4% chlorhexidine because those solutions not only killed C. albicans biofilms but also removed them from the heat-polymerised acrylic resin. PMID- 21605194 TI - Inflammatory tinea capitis due to Trichophyton tonsurans in a high school wrestler. PMID- 21605195 TI - Serum galactomannan strongly correlates with outcome of invasive aspergillosis in acute leukaemia patients. AB - Invasive aspergillosis (IA) remains an important cause of mortality in acute leukaemia patients. Previous studies reported that serum galactomannan (GM) levels correlate strongly with IA outcomes in patients with haematological cancers. This study aimed to clarify the usefulness of serial GM testing for outcome evaluation of IA in acute leukaemia patients. We retrospectively analysed 58 acute leukaemia patients who had IA during neutropenic period after chemotherapy and whose serum GM was serially monitored until discharge or death. The kappa correlation coefficient was used to determine the strength of correlation between GM and clinical outcome (survival or death) of IA. The correlation between clinical outcome and GM kinetics was good at week 6 [kappa = 0.663, 95% confidence interval (CI): 0.465-0.861] and excellent at week 12 (kappa = 0.819, 95% CI: 0.667-0.91). Survival was significantly better in patients whose GM values normalised than in patients with persistently positive GM (P < 0.0001) regardless of whether neutropenia resolved or acute leukaemia responded to chemotherapy. In neutropenic patients with acute leukaemia, serum GM correlated strongly with survival outcome of IA. This finding further supports the usefulness of the GM index as a surrogate marker for assessing IA outcome and the need for serial GM testing in therapeutic monitoring. PMID- 21605196 TI - In vitro antifungal activity of phenothiazines and their combination with amphotericin B against different Candida species. AB - Candidiosis is a mycosis that is currently increasingly affecting the population in consequence of its frequency and the severity of its complications, especially among immunocompromised hosts. In this work, the in vitro anticandidal activities of two phenothiazines (PTZs), chlorpromazine (CPZ) and trifluoperazine (TFP), and their combinations with amphotericin B (AMB) were tested against 12 different Candida strains representing 12 species (Candida albicans, Candida glabrata, Candida guillermondii, Candida inconspicua, Candida krusei, Candida lusitaniae, Candida lypolitica, Candida norvegica, Candida parapsilosis, Candida pulcherrima, Candida tropicalis and Candida zeylanoides). When used alone, both tested PTZs exerted antifungal effects against these strains. In their combinations, these PTZs and AMB mainly acted antagonistically at higher concentrations, but additively and synergistically at lower concentrations as concerns the clinically most important species (C. albicans and C. parapsilosis). For C. albicans, only synergistic interactions were revealed between CPZ and AMB. Synergistic, additive or no interactions were demonstrated between the investigated compounds for the most PTZ-susceptible (C. glabrata to TFP and C. krusei to CPZ) and insusceptible strains (C. glabrata to CPZ and C. lypolitica to TFP). PMID- 21605197 TI - alphav beta3 Integrin may participate in conceptus attachment by regulating morphologic changes in the endometrium during peri-implantation in ovine. AB - The objective of this study was to determine expression and potential functions of alpha(v) and beta(3) integrin subunits in ovine endometrium during the peri implantation period (days 8-17 after fertilization). The morphologic changes in the endometrium were observed histochemically following haematoxylin/eosin (HE) staining, whereas the expressions of alpha(v) and beta(3) integrin subunits were analysed by RT-PCR, immunohistochemistry and Western blot. The filamentous conceptus attached to the luminal epithelium (LE) on day 17 of pregnancy, with no differences in endometrial morphology between days 8-12 of pregnancy. However, endometrial glands in the endometrial stroma (S) underwent extensive hyperplasia from day 14 to day 17, increased reductus of the LE with an obvious proliferation of caruncles, and an increased number and diameter of blood vessels (V) in the endometrium. The relative expression levels of alpha(v) and beta(3) integrin subunits mRNA gradually increased until day 16, but sharply declined on day 17. Western blot analysis revealed that the expression pattern of alpha(v) and beta(3) integrin subunit proteins paralleled that of the corresponding mRNA. In addition, immunohistochemical localization of alpha(v) and beta(3) integrin subunits confirmed their presence in the glandular epithelium (GE), LE and endometrial stroma. Immunostaining on LE and stroma varied with the increasing days of pregnancy, with the strongest immunostaining on days 16 and 17. In conclusion, expression of alpha(V) and beta(3) integrin subunits was closely related to the early progression of pregnancy and conceptus attachment; therefore, we inferred that alpha(v) beta(3) integrin may participate in conceptus attachment by the regulation of endometrial morphology during peri implantation in ovine. PMID- 21605198 TI - Limited availability and higher cost of gluten-free foods. AB - BACKGROUND: A gluten-free diet is the only treatment for patients with coeliac disease, although it can be burdensome to follow and result in inadequate nutrient intake. The cost and availability of a gluten-free diet has been cited as a cause of incomplete dietary compliance; however, this has not been extensively investigated. The aim was to investigate the availability and cost of gluten-free foods across a wide range of stores. METHODS: The availability and cost of 20 foods (both wheat-based and everyday foods) was surveyed at 30 different stores across five different store categories. For each of the 20 foods, four products were selected (branded gluten-free, cheapest gluten-free, branded standard, cheapest standard) resulting in sampling of up to 80 products in each of the 30 stores. RESULTS: In general, there was limited availability of gluten-free foods, with an average of 8.2 of the 20 (41%) foods being available in a gluten-free version per store. Regular supermarkets had a greater availability (18.0/20, 90%), whereas budget supermarkets (1.8/20, 9%) and corner shops (1.8/20, 9%) had almost no gluten-free versions (P < 0.001). All 10 gluten free versions of wheat-based foods were more costly than their standard counterparts (76-518% more expensive; P < 0.001). Some gluten-free versions of everyday foods were also more costly than standard counterparts (2-124%). CONCLUSIONS: There is limited availability of gluten-free foods and they are generally more expensive than their standard counterparts. This may impact on compliance to a gluten-free diet, with potential nutritional and clinical consequences, together with an increased risk of complications. PMID- 21605199 TI - Dietary intake, nutritional status and rehabilitation outcomes of stroke patients in hospital. AB - BACKGROUND: Nutrition affects rehabilitation through its influence on physical and mental functioning, although little attention has been paid to effects on rehabilitation outcomes. The present study aimed to describe nutritional status and food consumption in stroke patients within 2 weeks of hospital admission and before discharge, as well as to investigate the effects of nutritional and dietary factors on rehabilitation outcomes. METHODS: One hundred patients from a consecutive cohort admitted to a metropolitan hospital with acute stroke were recruited and assessed by a single researcher, with 38 reassessed at discharge. Nutritional status was assessed using Mini-Nutritional Assessment and anthropometric indices and dietary intake was assessed by 1-day weighed dietary records. Rehabilitation outcomes were changes in Barthel index scores and the rehabilitation efficiency index. RESULTS: Few (n = 9; 10%) consumed >=100% of the estimated average requirement (EAR) for energy within 2 weeks of admission and 13 (33%) had energy intakes <50% of EAR before discharge. A small but increasing proportion (7% at admission, 13% at discharge) were identified as being malnourished across the inpatient stay. Younger age, lower Barthel index and a higher energy intake in the early stages of admission predicted the extent and rate of restoration of functional abilities by discharge (F = 7.503, P = 0.001; F = 14.558, P < 0.001). CONCLUSIONS: Given a general finding of nutritional deterioration identified for these patients, as well as the identification of energy intake as a modifiable influence on the extent and rate of recovery, there is clearly scope for the multidisciplinary development of nutritional support for stroke patients to improve rehabilitation outcomes. PMID- 21605201 TI - Risk of cancer by transferrin saturation levels and haemochromatosis genotype: population-based study and meta-analysis. AB - OBJECTIVE: Increased iron overload, whether or not owing to the presence of the haemochromatosis genotype C282Y/C282Y, may be associated with an increased risk of cancer. The aim of this study was to test the hypothesis that elevated transferrin saturation levels (as a proxy for iron overload) and haemochromatosis genotype C282Y/C282Y are associated with an increased risk of cancer. METHODS: We conducted a population-based study of 8763 individuals, of whom 1417 developed a first cancer during 15years of follow-up, and a meta-analysis. We stratified absolute 10-year risk of cancer by smoking status, an important risk factor. RESULTS: In women, transferrin saturation above 60% versus below 50% was associated with a hazard ratio of 3.6 (95% confidence interval (CI): 2.0-6.5; P<0.001) for any cancer; risk of liver cancer was increased in both women and men. In women, the corresponding absolute 10-year risk of any cancer was 34% and 30% in smokers and nonsmokers, respectively. In men, haemochromatosis genotype C282Y/C282Y versus wild type/wild type was associated with a hazard ratio of 3.7 (95% CI: 1.2-12; P=0.01) for any cancer, with a similar trend in women. In men, the corresponding absolute 10-year risk of cancer was 39% and 27% in smokers and nonsmokers, respectively. Other haemochromatosis genotypes were not associated with increased risk of cancer in women or men. From the meta-analysis, the odds ratio of any cancer for transferrin saturation >=60% versus a reference group was 1.5 (95% CI: 1.2-1.8) for women and men combined. CONCLUSIONS: We have demonstrated that elevated transferrin saturation levels in women and haemochromatosis genotype C282Y/C282Y in men are associated with increased risk of cancer. Thus, our results support the implementation of cancer screening programmes in patients with iron overload or with C282Y/C282Y. PMID- 21605202 TI - Haemolysis after treatment with intravenous immunoglobulin due to anti-A. AB - BACKGROUND: Intravenous immunoglobulin (IVIG) is used to treat an increasing number of conditions. IVIG contains immunoglobulin G (IgG) directed against many targets, including red blood cell (RBC) antigens. METHODS/MATERIALS: We report on three patients identified within a 7-month period in a single institution who developed haemolysis because of passively transferred anti-A. RESULTS: The patients were a 34-year-old A (non-A1) D-positive male with aplastic anaemia, a 61-year-old A1 D-negative female with myasthenia gravis and a 57-year-old AB D positive female lung transplant recipient. The haemoglobin decreased from 11.1 to 5.3 g dL(-1) over 2 days, 12.8 to 7.8 g dL(-1) over 6 days and 7.8 to 6.0 g dL( 1) over several hours, respectively. All three patients had a negative antibody screen, positive direct antiglobulin test for IgG only and an elution containing anti-A1 reactivity. The patients were transfused with O RBC with an appropriate rise in haemoglobin. CONCLUSION: These cases illustrate the potential severity of haemolysis after IVIG because of passively transferred antibodies to blood group antigens. Lack of recognition of IVIG as a cause for haemolysis by clinicians may be further confounded if routine testing fails to detect the passively transferred ABO blood group antibodies. PMID- 21605203 TI - A postal intervention for dependent cannabis users. AB - INTRODUCTION AND AIMS. In Australia, many would-be treatment seekers for problematic cannabis use live in rural and remote areas, thereby limiting their access to face-to-face treatments. In order to address this gap in treatment availability, the present study aimed to assess the feasibility of a mail-based intervention for regular cannabis users. DESIGN AND METHODS: Treatment was based upon cognitive-behavioural and motivational interviewing principles, and consisted of six treatment modules posted fortnightly to participants. In addition to the standardised modules, participants received personalised feedback at four points, based upon their mailed-in responses to the modules. Participants were recruited via advertisements in rural newspapers and a Google advertisement. RESULTS: A total of 268 people expressed interest in this study and 36 participants went on to complete treatment. Treatment completers demonstrated a significant reduction in cannabis use at the 1 month follow-up. DISCUSSION AND CONCLUSIONS: Transposing face-to-face treatments into a mailed format has shown some promise and future research is warranted to determine the efficacy of such treatments in a controlled study. PMID- 21605204 TI - Why (not) alcohol energy drinks? A qualitative study with Australian university students. AB - INTRODUCTION AND AIMS: Alcohol energy drinks (AEDs) are a recent entry to the ready-to-drink market, but there is an absence of research into the reasons young people consume these products and their consumption-related experiences. The aim of the current study was to investigate university students' perceptions of, and experiences with, pre-mixed AEDs. DESIGN AND METHODS: Four focus groups with undergraduate university students in a large regional city in New South Wales; with transcripts coded for key themes. RESULTS: Participants reported a number of benefits of AED consumption, many of which were similar to other ready-to-drinks, such as taste and image. However, the primary benefits of AEDs related to their capacity to wake the drinker up at the beginning of the evening and facilitate partying and drinking over a longer period. Many of the participants reported experiencing or observing negative effects from drinking AEDs, some quite severe, but this did not appear to act as a deterrent to their consumption. DISCUSSION AND CONCLUSIONS: Given the popularity and perceived benefits of AEDs-and evidence from previous research that their consumption is associated with increases in intoxication levels, risky behaviours and harmful alcohol-related consequences there is a need to consider a range of strategies to reduce harmful consumption of AEDs. While educational interventions may be of benefit, there is also a role for regulation of the packaging and marketing of a product that is associated with substantial harms. PMID- 21605205 TI - Implementation and evaluation of brief depression and anxiety screening in clients contacting a drug and alcohol service. AB - INTRODUCTION AND AIMS: High prevalence mental health (HPMH) comorbidity is common in clients seeking alcohol and other drug (AOD) treatment yet can remain undetected. Although research has reported on the introduction of screening into AOD services, little research has reported on the processes surrounding the introduction or evaluated its effectiveness. This study reports on the implementation and evaluation of brief anxiety and depression screening within a specialised, publicly funded AOD service in South-East Victoria. DESIGN AND METHODS: Study one examined the implementation of standardised HPMH screening with 114 adult clients (Mean age=35.49, SD=9.53; 64% male) telephoning an AOD service over a 5week period. Measures included severity of HPMH problems, AOD use, care plans and referrals. Study two used semistructured interviews with nine staff/managers to evaluate the effectiveness of screening and its impact on service delivery. RESULTS: Ninety-four per cent of clients were identified at risk of anxiety or depression. Most care plans incorporated counselling, and concurrent referrals commonly involved a general practitioner. Staff and management found systematic screening increased identification and understanding of comorbid issues and enhanced client interaction but impacted on resource requirements. DISCUSSION AND CONCLUSIONS: Most AOD treatment seekers were identified HPMH comorbid and care plans generally included counselling. Adjunctive referrals were more common for severely depressed clients. Screening was effective and enhanced client rapport. Evaluations revealed low confidence in treating HPMH issues in-house. Training may increase worker confidence in managing mental health interventions with subclinical cases, enhancing services' ability to move towards dual diagnosis capability. PMID- 21605206 TI - Recruitment of a duplicated primary metabolism gene into the nicotine biosynthesis regulon in tobacco. AB - Gene duplication is a powerful source of phenotypic diversity in plants, but the molecular mechanisms that generate new functions in duplicated genes are not fully documented. Here, we analyzed how duplicated genes encoding quinolinate phosphoribosyltransferase (QPT), an enzyme involved in the synthesis of nicotinamide adenine dinucleotide (NAD) and the pyridine moiety of nicotine, are regulated by the jasmonate-responsive transcriptional factor ERF189 that functions critically for nicotine biosynthesis in tobacco (Nicotiana tabacum). The tobacco genome contains duplicated QPT genes; QPT1 is expressed at a constitutive basal level, whereas QPT2 is regulated coordinately with other structural genes involved in nicotine biosynthesis, in terms of tissue specificity, jasmonate induction, and regulation by ERF189. The binding-site specificity of ERF189 was defined as 5'-(A/C)GC(A/C)(A/C)NCC-3' by using a characterized tobacco putrescine N-methyltransferase promoter, and was then used to search for potential binding sites in the QPT promoters. Assays involving in vitro DNA binding, transient transactivation, and transgenic hairy roots revealed that the QPT2 promoter contains three functional ERF189-binding sites, which individually confer incremental ERF189-mediated activation to the promoter. The QPT1 promoter is not bound and regulated by ERF189. These results indicate that one copy of the duplicated QPT genes was recruited to a tobacco alkaloid regulon by evolving multiple target cis-regulatory elements of ERF189 in its promoter, to cope with an increased metabolic demand for pyridine precursors during active alkaloid biosynthesis. PMID- 21605207 TI - In vivo grapevine anthocyanin transport involves vesicle-mediated trafficking and the contribution of anthoMATE transporters and GST. AB - In cells, anthocyanin pigments are synthesized at the cytoplasmic surface of the endoplasmic reticulum, and are then transported and finally accumulated inside the vacuole. In Vitis vinifera (grapevine), two kinds of molecular actors are putatively associated with the vacuolar sequestration of anthocyanins: a glutathione-S-transferase (GST) and two MATE-type transporters, named anthoMATEs. However, the sequence of events by which anthocyanins are imported into the vacuole remains unclear. We used MYBA1 transformed hairy roots as a grapevine model tissue producing anthocyanins, and took advantage of the unique autofluorescence of anthocyanins to study their cellular trafficking. In these tissues, anthocyanins were not only visible in the largest vacuoles, but were also present at higher concentrations in several vesicles of different sizes. In the cell, small vesicles actively moved alongside the tonoplast, suggesting a vesicular trafficking to the vacuole. Subcellular localization assays revealed that anthoMATE transporters were closely related with these small vesicles, whereas GST was localized in the cytoplasm around the nucleus, suggesting an association with the endoplasmic reticulum. Furthermore, cells in hairy roots expressing anthoMATE antisense did not display small vesicles filled with anthocyanins, whereas in hairy roots expressing GST antisense, anthocyanins were accumulated in vesicles but not in the vacuole. This suggests that in grapevine, anthoMATE transporters and GST are involved in different anthocyanin transport mechanisms. PMID- 21605208 TI - In vivo analysis of local wall stiffness at the shoot apical meristem in Arabidopsis using atomic force microscopy. AB - Whereas the morphogenesis of developing organisms is relatively well understood at the molecular level, the contribution of the mechanical properties of the cells to shape changes remains largely unknown, mainly because of the lack of quantified biophysical parameters at cellular or subcellular resolution. Here we designed an atomic force microscopy approach to investigate the elastic modulus of the outer cell wall in living shoot apical meristems (SAMs). SAMs are highly organized structures that contain the plant stem cells, and generate all of the aerial organs of the plant. Building on modeling and experimental data, we designed a protocol that is able to measure very local properties, i.e. within 40 100 nm deep into the wall of living meristematic cells. We identified three levels of complexity at the meristem surface, with significant heterogeneity in stiffness at regional, cellular and even subcellular levels. Strikingly, we found that the outer cell wall was much stiffer at the tip of the meristem (5 +/- 2 MPa on average), covering the stem cell pool, than on the flanks of the meristem (1.5 +/- 0.7 MPa on average). Altogether, these results demonstrate the existence of a multiscale spatialization of the mechanical properties of the meristem surface, in addition to the previously established molecular and cytological zonation of the SAM, correlating with regional growth rate distribution. PMID- 21605209 TI - Unique morphological changes in plant pathogenic phytoplasma-infected petunia flowers are related to transcriptional regulation of floral homeotic genes in an organ-specific manner. AB - Abnormal flowers are often induced by infection of certain plant pathogens, e.g. phytoplasma, but the molecular mechanisms underlying these malformations have remained poorly understood. Here, we show that infection with OY-W phytoplasma (Candidatus Phytoplasma asteris, onion yellows phytoplasma strain, line OY-W) affects the expression of the floral homeotic genes of petunia plants in an organ specific manner. Upon infection with OY-W phytoplasma, floral morphological changes, including conversion to leaf-like structures, were observed in sepals, petals and pistils, but not in stamens. As the expression levels of homeotic genes differ greatly between floral organs, we examined the expression levels of homeotic genes in each floral organ infected by OY-W phytoplasma, compared with healthy plants. The expression levels of several homeotic genes required for organ development, such as PFG, PhGLO1 and FBP7, were significantly downregulated by the phytoplasma infection in floral organs, except the stamens, suggesting that the unique morphological changes caused by the phytoplasma infection might result from the significant decrease in expression of some crucial homeotic genes. Moreover, the expression levels of TER, ALF and DOT genes, which are known to participate in floral meristem identity, were significantly downregulated in the phytoplasma-infected petunia meristems, implying that phytoplasma would affect an upstream signaling pathway of floral meristem identity. Our results suggest that phytoplasma infection may have complex effects on floral development, resulting in the unique phenotypes that were clearly distinct from the mutant flower phenotypes produced by the knock-out or the overexpression of certain homeotic genes. PMID- 21605210 TI - Arabidopsis ENHANCED DISEASE RESISTANCE 1 is required for pathogen-induced expression of plant defensins in nonhost resistance, and acts through interference of MYC2-mediated repressor function. AB - Arabidopsis thaliana exhibits durable resistance, called nonhost resistance, against non-adapted fungal pathogens that typically terminates pathogen entry. The PEN2-dependent indole glucosinolate metabolism pathway is involved in preventing the entry of a range of non-adapted fungi. Here, we report that ENHANCED DISEASE RESISTANCE 1 (EDR1) functions in pre-invasive nonhost resistance. Plants lacking EDR1 exhibit impaired entry resistance to the non adapted hemibiotrophic Colletotrichum gloeosporioides, in contrast to the enhanced resistance of edr1 against biotrophic infection of a host-adapted powdery mildew fungus. Analysis of the edr1 pen2 double mutant indicates that EDR1 acts in a defense pathway independent from the PEN2 indole glucosinolate pathway. The edr1 mutant also exhibited enhanced susceptibility to host-adapted pathogens, including Colletotrichum higginsianum and necrotrophic Alternaria brassicicola. Comparative transcript profiling revealed that upon C. gloeosporioides inoculation, the expression of four plant defensin genes was severely impaired in edr1, indicating that EDR1 is required for the induced expression of these antifungal proteins. Inactivation of the MYC2-encoded transcription factor fully restored defensin expression in edr1, implying that EDR1 interferes with MYC2 function to abrogate repression of defensin expression. Furthermore, constitutive expression of plant defensin PDF1.2b largely rescued pre-invasive resistance responses in edr1 plants. These results indicate that EDR1 exerts a positive and critical role in resistance responses to hemibiotrophic/necrotrophic fungi, in part by inducing antifungal protein expression through derepression of MYC2 function. PMID- 21605211 TI - NIMA-related kinases 6, 4, and 5 interact with each other to regulate microtubule organization during epidermal cell expansion in Arabidopsis thaliana. AB - NimA-related kinase 6 (NEK6) has been implicated in microtubule regulation to suppress the ectopic outgrowth of epidermal cells; however, its molecular functions remain to be elucidated. Here, we analyze the function of NEK6 and other members of the NEK family with regard to epidermal cell expansion and cortical microtubule organization. The functional NEK6-green fluorescent protein fusion localizes to cortical microtubules, predominantly in particles that exhibit dynamic movement along microtubules. The kinase-dead mutant of NEK6 (ibo1 1) exhibits a disturbance of the cortical microtubule array at the site of ectopic protrusions in epidermal cells. Pharmacological studies with microtubule inhibitors and quantitative analysis of microtubule dynamics indicate excessive stabilization of cortical microtubules in ibo1/nek6 mutants. In addition, NEK6 directly binds to microtubules in vitro and phosphorylates beta-tubulin. NEK6 interacts and co-localizes with NEK4 and NEK5 in a transient expression assay. The ibo1-3 mutation markedly reduces the interaction between NEK6 and NEK4 and increases the interaction between NEK6 and NEK5. NEK4 and NEK5 are required for the ibo1/nek6 ectopic outgrowth phenotype in epidermal cells. These results demonstrate that NEK6 homodimerizes and forms heterodimers with NEK4 and NEK5 to regulate cortical microtubule organization possibly through the phosphorylation of beta-tubulins. PMID- 21605212 TI - A self-management intervention to improve quality of life and psychosocial impact for people with type 2 diabetes. AB - AIM: To evaluate the effectiveness of self-management intervention for people with diabetes mellitus. BACKGROUND: Enhancing self-efficacy and improving health quality of life for persons with diabetes are ongoing challenges for health care providers. There currently is a need to develop and test the effects of a self management programme. DESIGN: A quasi-experimental design. METHOD: The study was carried out in the outpatient clinic of a municipal hospital in Taipei. Patients aged 30 and over with type 2 diabetes and an oral medication regimen were recruited. One hundred and forty-five participants completed the six-month post treatment assessments (72 in the intervention group and 73 in the control group). Both control and intervention groups received a standard diabetic educational programme. The self-management intervention is to improve psychosocial skills or addressing attitudes and beliefs specific to diabetes or the regimen behaviours. The intervention group received the following additional interventions: (1) a diabetic booklet (2) DVD viewing (3) four counselling sessions (4) and a telephone follow-up. The main outcome measures were Short Form 12 for health related quality of life, the Medical Outcomes Study Social Support scale and the Center for Epidemiology Studies Short Depression Scale. RESULTS: The scores for social support were significantly increased in the intervention group at Time 2 and Time 3 (three and six months from commencement of the intervention) compared with those of the control group (p < 0.01), whereas health-related quality of life and depression were not significantly different. Conclusions. The diabetic self-management intervention programme improved social support for participants, but future studies are needed. Replication of this study in various settings, with other populations, or with additional outcome measures may result in different findings. RELEVANCE TO CLINICAL PRACTICE: Self-management programmes should be held regularly and evaluated in clinical practices, especially in developing countries. Providing practical screening tools and conducting psychological research on diabetes drive policy and health care system change. PMID- 21605213 TI - Infant well-being following neonatal cardiac surgery. AB - AIMS AND OBJECTIVES: To investigate infant well-being as measured by feeding and sleeping and parental support following discharge from the NICU in infants following major cardiac surgery. BACKGROUND: Infant feeding and sleeping have been identified as two of the most important concerns reported by parents. These concerns have been reported anecdotally for infants who have undergone cardiac surgery in the neonatal period. DESIGN: A prospective study using questionnaires and phone interviews followed a cohort of parents of neonates who underwent surgery in the neonatal period for congenital heart disease. METHODS: The study was conducted using validated questionnaires and phone interviews with a semi structured questionnaire. The questionnaires were administered prior to discharge from the NICU and interviews took place following discharge on five occasions within nine months. RESULTS: Fifty six infants and mothers were followed for nine months following discharge from NICU. Sixty-eight per cent were breastfeeding on discharge however the rates decline over time in line with healthy infants. Mothers were not bothered by their infant's sleep patterns which were consistent with those of healthy infants at six months. There were 37 episodes of re hospitalisation and the average time of further surgery was five months following discharge from their initial period of hospitalisation. CONCLUSION: The issues from this pilot study warrant further investigation. Factors such as multiple hospitalisations, parent education and support may vary within contexts and need to be studied to ensure optimal supports are identified for this high risk population. RELEVANCE TO CLINICAL PRACTICE: This study identified several issues that can improve care provided to these infants and their parents. Support following discharge could include: lactation consultant to provide follow-up calls to identify concerns with breastfeeding, lactation course for paediatric nurses providing follow-up and education for Early Childhood Clinics on Congenital Heart Disease. PMID- 21605214 TI - Effect of parasitic sex-ratio distorters on host gene frequencies in a mainland island context. AB - It was previously argued that infection by parasitic sex-ratio distorters can enhance both random genetic drift and genetic influx from outside the population. However, these two enhancement effects have been studied independently. Here, we study the equilibrium frequencies of alleles (neutral and selected) in a mainland island scenario where both genetic drift and genetic influx are enhanced due to infection by a cytoplasmic feminizing element. Interestingly, our model reveals that at neutral loci, the two effects almost exactly cancel each other out, such that infection has only a very minor effect on the equilibrium frequency distributions of alleles. At selected loci, in contrast, the two effects are unbalanced and infection has conspicuous effects. Despite the cryptic effects of infection at neutral loci, we demonstrate that temporally spaced data can be used to evaluate the effect of infection on genetic drift and that on gene flow separately. PMID- 21605215 TI - Optimally weighted Z-test is a powerful method for combining probabilities in meta-analysis. AB - The inverse normal and Fisher's methods are two common approaches for combining P values. Whitlock demonstrated that a weighted version of the inverse normal method, or 'weighted Z-test', is superior to Fisher's method for combining P values for one-sided T-tests. The problem with Fisher's method is that it does not take advantage of weighting and loses power to the weighted Z-test when studies are differently sized. This issue was recently revisited by Chen, who observed that Lancaster's variation of Fisher's method had higher power than the weighted Z-test. Nevertheless, the weighted Z-test has comparable power to Lancaster's method when its weights are set to square roots of sample sizes. Power can be further improved when additional information is available. Although there is no single approach that is the best in every situation, the weighted Z test enjoys certain properties that make it an appealing choice as a combination method for meta-analysis. PMID- 21605216 TI - Sexual and lifetime selection on body size in a marine fish: the importance of life-history trade-offs. AB - Many field measurements of viability and sexual selection on body size indicate that large size is favoured. However, life-history theory predicts that body size may be optimized and that patterns of selection may often be stabilizing rather than directional. One reason for this discrepancy may be that field estimates of selection tend to focus on limited components of fitness and may not fully measure life-history trade-offs. We use an 8-year, demographic field study to examine both sexual selection and lifetime selection on body size of a coral reef fish (the bicolour damselfish, Stegastes partitus). Selection via reproductive success of adults was very strong (standardized selection differential=1.04). However, this effect was balanced by trade-offs between large adult size and reduced cumulative survival during the juvenile phase. When we measured lifetime fitness (net reproductive rate), selection was strongly stabilizing and only weakly directional, consistent with predictions from life-history theory. PMID- 21605217 TI - Mating stimulates female feeding: testing the implications for the evolution of nuptial gifts. AB - Nutritional benefits from nuptial gifts have been difficult to detect in some species, raising the question: what maintains nuptial feeding when gifts do not benefit females? The sensory trap hypothesis proposes that nuptial feeding may be explained by pre-existing sensory responses that predispose females to ingest gifts. Recent studies have shown that male seminal proteins can induce a nonspecific increase in female feeding after mating, which may represent a sensory trap for nuptial feeding if it results in increased intake of post-mating gifts. I tested these ideas using female beetles that ingest a spermatophore after mating. I show that males stimulate strongly increased female feeding post mating. However, there was little evidence for dose dependence in the feeding response that could allow males to stimulate feeding beyond the female optimum. Moreover, the post-mating feeding response could not explain nuptial feeding: despite feeding more in general, newly mated females were less likely than nonmated females to ingest spermatophore gifts. PMID- 21605218 TI - A formal theory of the selfish gene. AB - Adaptation is conventionally regarded as occurring at the level of the individual organism. In contrast, the theory of the selfish gene proposes that it is more correct to view adaptation as occurring at the level of the gene. This view has received much popular attention, yet has enjoyed only limited uptake in the primary research literature. Indeed, the idea of ascribing goals and strategies to genes has been highly controversial. Here, we develop a formal theory of the selfish gene, using optimization theory to capture the analogy of 'gene as fitness-maximizing agent' in mathematical terms. We provide formal justification for this view of adaptation by deriving mathematical correspondences that translate the optimization formalism into dynamical population genetics. We show that in the context of social interactions between genes, it is the gene's inclusive fitness that provides the appropriate maximand. Hence, genic selection can drive the evolution of altruistic genes. Finally, we use the formalism to assess the various criticisms that have been levelled at the theory of the selfish gene, dispelling some and strengthening others. PMID- 21605219 TI - Rapid loss of MHC class II variation in a bottlenecked population is explained by drift and loss of copy number variation. AB - Population bottlenecks may reduce genetic variation and potentially increase the risk of extinction. Here, we present the first study to use historic samples to analyse loss of variation at the major histocompatibility complex (MHC), which plays a central role in vertebrate disease resistance. Balancing selection acts on the MHC and could moderate the loss of variation expected from drift; however, in a Wisconsin population of greater prairie-chickens (Tympanuchus cupido), the number of MHC class II B alleles per individual declined by 44% following a population bottleneck, compared to a loss of only 8% at microsatellites. Simulations indicate that drift likely reduced MHC variation at the population level, as well as within individuals by reducing the number of gene copies per individual or by fixing the same alleles across multiple loci. These multiple effects of genetic drift on MHC variation could have important implications for immunity and fitness. PMID- 21605220 TI - Helpers at the nest compensate for reduced maternal investment in egg size in carrion crows. AB - Life history theory predicts that mothers should trade off current and future reproductive attempts to maximize lifetime fitness. When breeding conditions are favourable, mothers may either increase investment in the eggs to improve the quality of the offspring or save resources for future reproduction as the good raising environment is likely to compensate for a 'bad start'. In cooperatively breeding birds, the presence of helpers improves breeding conditions so that mothers may vary the number, size and quality of the eggs in response to the composition of the group. Here, we show that in cooperatively breeding carrion crows Corvus corone corone, where nonbreeding males are more philopatric and more helpful at the nest than females, breeding females decreased egg size as the number of subordinate males in the group increased. However, despite the smaller investment in egg size, fledglings' weight increased in groups with more male subordinates, improving post-fledging survival and indicating that helpers fully compensated for the initial 'bad start'. These results highlight a 'hidden effect' of helpers that bears profound implications for understanding the ultimate function of helping. PMID- 21605221 TI - Can AFLP genome scans detect small islands of differentiation? The case of shell sculpture variation in the periwinkle Echinolittorina hawaiiensis. AB - Genome scans have identified candidate regions of the genome undergoing selection in a wide variety of organisms, yet have rarely been applied to broadly dispersing marine organisms experiencing divergent selection pressures, where high recombination rates can reduce the extent of linkage disequilibrium (LD) and the ability to detect genomic regions under selection. The broadly dispersing periwinkle Echinolittorina hawaiiensis exhibits a heritable shell sculpture polymorphism that is correlated with environmental variation. To elucidate the genetic basis of phenotypic variation, a genome scan using over 1000 AFLP loci was conducted on smooth and sculptured snails from divergent habitats at four replicate sites. Approximately 5% of loci were identified as outliers with Dfdist, whereas no outliers were identified by BayeScan. Closer examination of the Dfdist outliers supported the conclusion that these loci were false positives. These results highlight the importance of controlling for Type I error using multiple outlier detection approaches, multitest corrections and replicate population comparisons. Assuming shell phenotypes have a genetic basis, our failure to detect outliers suggests that the life history of the target species needs to be considered when designing a genome scan. PMID- 21605222 TI - Innovation in rural health: sound the trumpet! PMID- 21605223 TI - Reorienting primary health care for addressing chronic conditions in remote Australia and the South Pacific: review of evidence and lessons from an innovative quality improvement process. AB - This paper reviews what is known about the challenges of implementing quality improvement programs and draws on data from a systematic continuous quality improvement (CQI) project in remote communities in Australia and Fiji, known as Audit and Best practice for Chronic Disease, to synthesise lessons and discuss the potential for broader application in low and middle income countries, including Pacific Island countries and territories. Although a number of systematic reviews have indicated that quality improvement programs can be effective in changing professional practice and improving the quality of care and patient outcomes, little is known about the key ingredients for change or how services use and implement different strategies to achieve improvements. We identify key features of an innovative CQI model and factors related to implementation that support improvement in diabetes service delivery and intermediate outcomes. Requirements for supporting CQI are identified and the potential for wider application discussed. It is argued that the participatory action research approach supports innovation and broad-based change and the evidence it has produced extends the current knowledge base and facilitates the translation of knowledge into action, for both policy and practice. PMID- 21605224 TI - Sustainable primary health care services in rural and remote areas: innovation and evidence. AB - OBJECTIVE: To highlight how evidence from studies of innovative rural and remote models of service provision can inform global health system reform in order to develop appropriate, accessible and sustainable primary health care (PHC) services to 'difficult-to-service' communities. METHODS: The paper synthesises evidence from remote and rural PHC health service innovations in Australia. RESULTS: There is a strong history of PHC innovation in Australia. Successful health service models are 'contextualised' to address diverse conditions. They also require systemic solutions, which address a range of interlinked factors such as governance, leadership and management, adequate funding, infrastructure, service linkages and workforce. An effective systemic approach relies on alignment of changes at the health service level with those in the external policy environment. Ideally, every level of government or health authority needs to agree on policy and funding arrangements for optimal service development. A systematic approach in addressing these health system requirements is also important. Service providers, funders and consumers need to know what type and level of services they can reasonably expect in different community contexts, but there are gaps in agreed indicators and benchmarks for PHC services. In order to be able to comprehensively monitor and evaluate services, as well as benchmarks, we need adequate national information systems. CONCLUSIONS: Despite the gaps in our knowledge, we do have a significant amount of information about what works, where and why. At a time of global PHC reform, applying this knowledge will contribute significantly to the development of appropriate, sustainable PHC services and improving access. PMID- 21605225 TI - Implementation of diabetes prevention programs in rural areas: Montana and south eastern Australia compared. AB - OBJECTIVE: To identify the key elements that enabled the Greater Green Triangle Diabetes Prevention Project (GGT DPP) and the Montana Cardiovascular Disease and Diabetes Prevention (CDDP) programs successful establishment and implementation in rural areas, as well as identifying specific challenges or barriers for implementation in rural communities. METHODS: Focus groups were held with the facilitators who delivered the GGT DPP in Australia and the Montana CDDP programs in the USA. Interview questions covered the facilitators' experiences with recruitment, establishing the program, the components and influence of rurality on the program, barriers and challenges to delivering the program, attributes of successful participants, and the influence of community resources and partnerships on the programs. RESULTS: Four main themes emerged from the focus groups: establishing and implementing the diabetes prevention program in the community; strategies for recruitment and retention of participants; what works in lifestyle intervention programs; and rural-centred issues. CONCLUSIONS: The results from this study have assisted in determining the factors that contribute to developing, establishing and implementing successful diabetes prevention programs in two rural areas. Recommendations to increase the likelihood of success of programs in rural communities include: securing funding early for the program; establishing support from community leaders and developing positive relationships with health care providers; creating a professional team with passion for the program; encouraging participants to celebrate their small and big successes; and developing procedures for providing post-intervention support to help participants maintain their success. PMID- 21605226 TI - The psychosocial impacts of fly-in fly-out and drive-in drive-out mining on mining employees: a qualitative study. AB - OBJECTIVE: To explore how fly-in fly-out (FIFO) and drive-in drive-out (DIDO) mining affects the psychosocial well-being of miners resident in a rural north Queensland town as well as the sources of support miners identify and use in managing these effects. DESIGN: A descriptive qualitative study, using semistructured interviews. SETTING: Charters Towers, a rural town in north Queensland, and a remote north-western Queensland mine. PARTICIPANTS: Eleven people, resident in or near Charters Towers, currently or formerly employed in FIFO or DIDO mining. MAIN OUTCOME MEASURES: Self-reported effects on psychosocial well-being and sources of support. RESULTS: Participants reported positive and negative psychosocial impacts across domains including family life, relationships, social life, work satisfaction, mood, sleep and financial situation. Concerns about the impact on participants' partners were described. Awareness of onsite support, such as Employee Assistance Programs, varied. Other supports included administration staff and nurses or medics. Trusted friends or colleagues at the mine site were considered a preferred means of support. Some, but not most, had experienced coworkers discussing problems with them. A reluctance to seek support was described, with a number of barriers identified. Those having problems might not recognise their own stress and thus not seek support. CONCLUSIONS: This study identifies numerous psychosocial impacts on FIFO/DIDO miners and their partners, and provides insights into preferences regarding support. Employee Assistance Programs cannot be relied upon as the sole means of support. Further studies exploring the impact upon and supports for FIFO/DIDO workers and their partners will assist in better understanding these issues. PMID- 21605227 TI - Exposure therapy for problem gambling in rural communities: a program model and early outcomes. AB - OBJECTIVE: Rural South Australia contains a higher share of electronic gaming machines and gambling expenditure per capita than metropolitan areas, raising concerns about the risk of problem gambling in these communities. This paper describes the implementation and outcomes of an outreach behavioural psychotherapy (exposure therapy) program for problem gambling in rural South Australia. METHODS: A retrospective cohort study design was used for 551 adult treatment-seeking problem gamblers who presented to the Statewide Gambling Therapy Service in South Australia. Fifty-one gamblers were from rural areas and participated in the outreach program. Outcomes were compared between gamblers who participated in either the metropolitan-based or rural outreach program. Outcome measures used: South Oaks Gambling Screen, Kessler Psychological Distress Scale, Work and Social Adjustment Scale, and hours gambled the previous month. RESULTS: Sixty-one per cent of clients (n = 551) completed treatment. There was no significant association between service location and number of treatment completers. Significant improvements were recorded across all outcome measures for both groups with small to large effect sizes, and there were no significant differences in outcomes at post-treatment between the groups while controlling for baseline scores. CONCLUSIONS: Both metropolitan and rural clients reported significant clinical improvement. Given the risk of problem gambling in rural communities, these early outcomes are encouraging. These findings will inform future treatment planning and service delivery for rural clients, and guide further research into the effectiveness of exposure therapy for problem gambling. PMID- 21605228 TI - The John Flynn Placement Program: evidence for repeated rural exposure for medical students. AB - OBJECTIVE: This paper reports on an evaluation of the John Flynn Placement Program (JFPP) for medical students. JFPP aims for medical students to experience both rural medicine and rural life as a way of increasing rural career intentions. DESIGN: Medical students experience two weeks a year over four years with a rural doctor. Students are evaluated at the end of each placement for clinical and social experiences and career intent. They are followed up annually to monitor career intent. Mentors are evaluated annually on clinical and rural experiences during a placement. SETTING: The Australian Government has several initiatives to encourage recruitment into rural medicine. One initiative is the JFPP. Students from all medical schools are placed with experienced general practitioners in rural and remote areas 4-7 locations across Australia. PARTICIPANTS: Evaluation data from 1450 placements from 2005-2009 are reported. OUTCOME MEASURES: Data are presented highlighting evaluation of student and mentor perceptions of clinical and social experiences. Longitudinal tracking data provide an indication of the success of the program in terms of recruitment into the rural workforce. RESULTS: Overall mean for clinical and rural experiences is extremely positive for both students and mentors. After four JFPP placements 65% of students intend to work in rural areas. After one JFPP experience 9% indicate intent to practise as a rural general practitioner while after their fourth JFPP nearly 20% are indicating intent to practise as a rural general practitioner. CONCLUSIONS: Longitudinal experiences, such as the JFPP, are positively influencing intention to enter the rural workforce but the impact of urban centric vocational training might be negating this impact. PMID- 21605229 TI - Comparison of the results of two rural allied health workforce surveys in the Hunter New England region of New South Wales: 2005 versus 2008. AB - OBJECTIVE: To compare the results of the 2005 and 2008 surveys of the rural allied health workforce in the study region. DESIGN: Comparative analysis of two cross-sectional surveys. SETTING: The rural, northern sector of the Hunter New England region of NSW, Australia. PARTICIPANTS: Both surveys targeted 12 different allied health professions. There were 225 respondents in 2005 and 205 in 2008. MAIN OUTCOME MEASURES: Comparison is made for 15 dependent variables. RESULTS: There was no significant difference for most variables between 2005 and 2008. Mean age and mean years qualified decreased slightly, from 43 to 41 years and from 20 to 17 years, respectively. The proportion of respondents of rural origin was about two-thirds in both studies and about half had a rural placement during training. While more than half supervised students, only about one-third had received training for that role. In both 2005 and 2008, the proportion working 35 or more hours each week was about 66% but the proportion working more than 40 hours had doubled to about 36%. In both surveys about half intended leaving their job within 10 years, while the proportion satisfied with continuing professional development access had halved, from 70% to 35%. CONCLUSIONS: Most results of the 2005 Hunter New England survey were verified. It was confirmed that a large proportion of the allied health workforce in the region intend leaving their job in the next 5 to 10 years. This is a concern for the development of new service delivery models. PMID- 21605230 TI - Impact of clinical audit in the care of coronary heart disease: the experience of a rural general practice. PMID- 21605232 TI - Laser treatment of superficial leg veins: a review. AB - BACKGROUND: Superficial leg veins affect millions of people worldwide, and treatment of these vessels is a common dermatologic request. The advance of lasers in recent years has led to numerous laser and light devices intended to treat these superficial vessels. OBJECTIVE AND METHOD: A review of the literature on the laser and light devices available for the treatment of superficial leg vessels with historical and recent trends is presented. RESULTS AND CONCLUSIONS: The appropriate choice of light system to treat telangiectases, venulectases, and reticular veins varies depending on anatomical, physiological, and biological differences in the vessels. Safe and efficacious treatment of superficial leg vessels can be achieved with multiple lasers by taking advantage of the oxyhemoglobin absorption peaks. The authors have indicated no significant interest with commercial supporters. PMID- 21605233 TI - Commentary: Lasers and leg veins ... the Saga to be continued. PMID- 21605234 TI - The role of sirolimus in the prevention of cutaneous squamous cell carcinoma in organ transplant recipients. AB - Skin cancers are common in organ transplant recipients (OTRs). In this review, we discuss the epidemiology of and risk factors for cutaneous neoplasms, particularly squamous cell carcinoma (SCC) in OTRs. The pathogenesis of SCC is reviewed, as well as the potential mechanisms for tumor progression and metastasis associated with two commonly used immunosuppressive medications: tacrolimus and cyclosporine. Finally, we discuss the mechanism of action and potential preventative use of sirolimus, a member of a newer class of immunosuppressants, the mammalian target of rapamycin inhibitors. The authors have indicated no significant interest with commercial supporters. PMID- 21605235 TI - Soft tissue augmentation using in vitro differentiated adipocytes: a clinical pilot study. AB - BACKGROUND: Although various commercially available filler materials are now commonly used, their variable degrees of resorption require repeated percutaneous injections. To overcome these drawbacks, a new injectable in vitro differentiated adipocyte filler has been developed, and animal studies have demonstrated that implantation of the filler successfully enhances in vivo adipose tissue formation. This study was undertaken to evaluate the clinical efficacy of this method, particularly in soft tissue augmentation. MATERIALS AND METHODS: Autologous adipose-derived stromal cells were isolated, cultured, and differentiated to adipocytes in vitro. The differentiated adipocytes were suspended in Dulbecco's modified Eagle medium and injected into the lesion requiring soft tissue augmentation. Eight patients were treated with this tissue engineered filler. Long-term follow-up for longer than 1 year was possible in all patients. RESULTS: Two or 3 weeks after the injection, volume increment of subcutaneous tissue was observed around the injection area in the ensuing 1 to 5 weeks. Thereafter, additional volume augmentation was not found and the augmentation effect was well-maintained. All patients agreed on the clinical effectiveness of the procedure, and no complications occurred. CONCLUSIONS: The results obtained indicate that this method is well tolerated and may be an effective means of achieving soft tissue augmentation. The authors have indicated no significant interest with commercial supporters. PMID- 21605236 TI - Efficacy and durability of two hyaluronic acid-based fillers in the correction of nasolabial folds: results of a prospective, randomized, double-blind, actively controlled clinical pilot study. AB - BACKGROUND: This pilot study compared a monophasic hyaluronic acid dermal filler with a biphasic filler for the correction of nasolabial folds. METHODS: Participant- and assessor-blinded, randomized clinical trial involving participants with moderate to severe nasolabial folds. Split-face design comparing a monophase hyaluronic acid (HA) filler (mono-HA) with a biphasic HA filler (bi-HA). Injection with touch-up after 1 month. Wrinkle improvement was measured before and after injection and after 1, 2, 4, and 7 months, using the Wrinkle Severity Rating Scale and the Global Aesthetic Improvement Scale as outcome criteria. An optional treatment was offered at the end of the study, with participants allowed to choose one of the products. OBJECTIVE: Evaluation of efficacy and safety of both products. RESULTS: Both products showed immediate, good results after injection and touch-up and demonstrated good durability over time. Participant preference for optional treatment at the end of the study favoured mono-HA. Both products were well tolerated, without serious adverse events. CONCLUSION: The effect after injection of mono-HA and bi-HA is generally comparable, although there was a trend in favor of mono-HA. Materials and funding for this study were provided by Teoxane, Geneva, Switzerland. PMID- 21605237 TI - High-fluence and high-density treatment of perioral rhytides using a new, fractionated 2,790-nm ablative erbium-doped Yttrium Scandium Gallium Garnet Laser. AB - BACKGROUND: In this study, we evaluated the safety and efficacy of a novel 2,790 nm erbium-doped yttrium scandium gallium garnet (Er:YSGG) laser system for the treatment of facial photodamage and perioral wrinkles using a single-treatment, high-fluence, high-density protocol. METHODS: Eleven female participants with Fitzpatrick skin types II to III and facial wrinkles underwent a single full-face fractional ablative treatment with a 2,790-nm Er:YSGG laser. Follow-up visits were completed at 1, 2, and 6 weeks 3 and 6 months. Quartile improvement scale (0 4) and Fitzpatrick wrinkle scores (1-9) were used for the assessments. RESULTS: Based on blinded photographic assessments, the mean difference in Fitzpatrick wrinkle scores for full face wrinkles was 1.5 +/- 1.2 (a reduction from 6.6 to 5.1; paired t-test, p = .003). There was also a statistically significant mean reduction of 1.7 +/- 1.3 in perioral wrinkle scores (from 6.7 to 5.0; p = .002). No serious adverse events were reported. CONCLUSION: A novel, fractionated, ablative 2,790-nm Er:YSGG laser can safely and effectively treat photodamage and perioral wrinkles in a single treatment using a high-fluence, high-density protocol. Cutera provided the equipment used in this study and funding to Dr. Goldberg. PMID- 21605238 TI - Commentary: High-fluence, high-density treatment of perioral rhytides using a new fractionated ablative laser. PMID- 21605239 TI - A split-face comparison of two ablative fractional carbon dioxide lasers for the treatment of photodamaged facial skin. AB - OBJECTIVE: To compare the safety and efficacy of two fractional carbon dioxide (CO(2)) laser devices for the treatment of photodamaged facial skin. METHODS: Eight healthy subjects underwent full-face resurfacing for photodamaged skin with two fractionated CO(2) laser devices using manufacturer-recommended settings for facial rejuvenation. For each subject, one device with a rolling handpiece was used on one side and a second device with a stamping handpiece was used on the other. Patients were evaluated 3 months postoperatively and photographed. A blinded physician investigator assessed the photographs and rated each side for improvement in four categories (wrinkles, pigmentation, skin laxity, and overall appearance). Patient ratings for overall improvement for each side were also recorded. RESULTS: All patients had improved on the basis of photographic and clinical assessments at 3 months. No significant differences in patient ratings of overall improvement and physician-measured parameters of clinical improvement were found, although intraoperative times and pain ratings were greater with the laser with the stamping handpiece. No complications were experienced with either device. CONCLUSIONS: Both fractionated CO(2) resurfacing devices used in the study were safe and effective for the treatment of photodamaged facial skin, but the modality using a stamping handpiece was associated with longer operative times and greater intraoperative pain. The authors have indicated no significant interest with commercial supporters. PMID- 21605240 TI - Xanthelasma palpebrarum treatment with a 1,450-nm-diode laser. AB - BACKGROUND: Various treatments of xanthelasma palpebrarum have been studied, including surgical excision, treatment with chemicals, and ablative laser therapy, but these methods have some disadvantages. Recently, nonablative laser therapy has been proposed as a treatment for xanthelasma palpebrarum. OBJECTIVE: To investigate the efficacy and safety of a 1,450-nm-diode laser in the treatment of xanthelasma. MATERIALS AND METHODS: Sixteen patients were treated using a 1,450-nm-diode laser. Fluences of 12 J/cm(2) , a 6-mm spot size, and a dynamic cooling device setting of 20 to 30 ms were used. One to four treatments 4 to 6 weeks apart were given to each patient. Photographs were taken before each treatment session and 4 to 6 weeks after the last treatment. RESULTS: Two (12.5%), eight (50%), and four (25%) of the 16 patients were scored as having some (20-40% clearing), moderate (40-60% clearing), and marked (60-80% clearing) improvement, respectively. Focal mild transient hyperpigmentation was noted in five patients. Post-treatment local swelling lasted 3 to 4 days. CONCLUSION: The 1,450-nm-diode laser treatment is a new, valuable treatment option for xanthelasma palpebrarum, offering relatively mild side effects. Studies including long term follow up and a comparison with alternative treatment modalities are necessary to further assess the clinical utility of this treatment. The authors have indicated no significant interest with commercial supporters. PMID- 21605241 TI - Treatment of infraorbital dark circles using a low-fluence Q-switched 1,064-nm laser. AB - OBJECTIVE: To evaluate the efficacy and safety of the low-fluence 1,064-nm Q switched neodymium-doped yttrium aluminium garnet (QSNY) laser in treating infraorbital dark circles. PARTICIPANTS AND METHODS: Thirty women with infraorbital dark circles (predominant color dark brown) participated in this open-label study. Participants underwent eight sessions of low-fluence QSNY laser treatment at 4.2 J/cm(2) at 3- to 4-day intervals. A spot size of 3.5 mm was used, with a pulse duration of 8 ns. The melanin deposition in the lesional skin was observed in vivo using reflectance confocal microscopy (RCM). Morphologic changes were evaluated using a global evaluation, an overall self-assessment, a narrow-band reflectance spectrophotometer, and a skin hydration measurement instrument. RESULTS: Twenty-six of 30 patients showed global improvement that they rated as excellent or good. Twenty-eight rated their overall satisfaction as excellent or good. The melanin index indicated a substantial decrease, from 225.84 at baseline to 182.65 (p < .05). RCM results showed a dramatic decrease of melanin deposition in the upper dermis. Adverse effects were minimal. CONCLUSIONS: The characteristic finding for dark-brown infraorbital dark circles is melanin deposition in the upper dermis. Treatment of infraorbital dark circles using low-fluence 1,064-nm QSNY laser is safe and effective. The authors have indicated no significant interest with commercial supporters. PMID- 21605242 TI - Outcomes of ultrasound-guided foam sclerotherapy for varicose veins of the lower extremities: a single center experience. AB - OBJECTIVE: Ultrasound-guided foam sclerotherapy is increasing in popularity as a method to treat varicose veins of the lower extremities. In 2001, we began using ultrasound-guided foam sclerotherapy to treat varicose veins of the lower extremities. The outcomes of our treatment are described in this study. METHODS: One hundred four patients underwent ultrasound-guided foam sclerotherapy for 138 extremities over a 5-year period, from January 2004 to December 2008, at Tokyo Women's Medical University Hospital. The outcomes were studied retrospectively using chart review. The average age, sex, and recurrence rates were calculated. At 24 months after treatment, the primary and secondary success rates were analyzed. RESULTS: The mean age of the patients was 63.2; 30 (22%) were male. Twenty-five (27%) patients had recurrences in 35 (34%) extremities. At 24 months, the primary success rate was 62.2%, and the secondary success rate was 75.8%. CONCLUSIONS: None of the patients experienced adverse events. The recurrence rates were slightly higher than those of other published data, which may be due to the lower dose of foam used in GSV. In summary, ultrasound-guided foam sclerotherapy can be easily and effectively performed in an outpatient clinical setting. The authors have indicated no significant interest with commercial supporters. PMID- 21605243 TI - Commentary: Outcomes of ultrasound-guided foam sclerotherapy for varicose veins of the lower extremities: single center experience. PMID- 21605244 TI - Absence of concentration congruity in six compounded polidocanol samples obtained for leg sclerotherapy. AB - BACKGROUND: In the arena of venous sclerotherapy, sodium tetradecyl sulfate (STS), hypertonic saline, and polidocanol (POL) are the most widely used agents in the world for treating endothelial vein wall destruction. Pharmaceutical-grade STS and hypertonic saline are available from manufacturers. Until 2010, POL was only available in the United States through compounding pharmacies. OBJECTIVE: To identify whether a risk exists when using freely available compounded POL samples for venous sclerotherapy. MATERIALS AND METHODS: Six samples of 1% POL solutions obtained from four compounding pharmacies were evaluated using gas chromatography mass spectrometry (GC/MS) assays for POL concentration and identification of material impurities. RESULTS: Disparities in POL concentrations between six samples ranged from 1.0% to 3.1%. The GC/MS analysis showed impurities in all six compounded POL samples. CONCLUSIONS: In this study, compounded POL solutions did not deliver the claimed concentration five out of six times. This inconsistency poses risks to the patient and the treating physician during venous sclerotherapy with pharmacy-compounded POL. Merz Aesthetics provided funding for this study. PMID- 21605245 TI - Electrochemotherapy of cutaneous metastases of melanoma--a case series study and systematic review of the evidence. AB - OBJECTIVES: Electrochemotherapy (ECT) is a novel therapeutic option for the treatment of cutaneous and subcutaneous metastases of malignant melanoma. During the treatment, electric pulses are applied to tumor nodules to deliver nonpermeant or poorly permeant chemotherapeutic agents into the cells, increasing local cytotoxicity of anticancer drugs. We compared the clinical effectiveness of ECT as an alternative palliative treatment option for unresectable metastatic lesions of malignant melanoma with a systematic review of reported outcomes. METHODS: One hundred fifty-eight cutaneous and subcutaneous metastases of nine patients were treated with ECT. All treatments were performed under general anesthesia using intravenous bleomycin injection. Median follow-up was 195 days. RESULTS: In our case series, complete response rate was 23%, and partial response rate was 39%. We observed no change in 30% and progressive disease in 8% of cases. CONCLUSIONS: ECT is a simple and effective treatment of single or multiple cutaneous and subcutaneous metastases of melanoma with minimal side effects. Our results provide further data for the growing body of evidence in recently published studies that ECT used for palliation has clinical benefit. The authors have indicated no significant interest with commercial supporters. PMID- 21605246 TI - Surgical approach to extensive hidradenitis suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic suppurative disease of skin with high recurrence. OBJECTIVE: To determine factors affecting complications and recurrence of HS in patients who underwent surgery. MATERIALS AND METHODS: We operated on 15 patients with HS at 36 sites between 1999 and 2009. The affected areas were classified as groin, axilla, buttocks, nuchae, perianal, and perineal. All patients were treated using wide surgical excision under general anesthesia. The methods of reconstruction varied depending on the size and location of the defect. RESULTS: The female:male ratio of patients was 4:11. Mean age was 41.8 +/- 10.6. Twenty-eight (77%) of the lesions were Stage III according to Hurley's staging system. Mean follow-up was 42 months. Radical excision was performed on all lesions; 20 were reconstructed with primary closure, nine with fasciocutaneous flaps, and five with split-thickness skin grafts. The overall complication rate was 25% (9/36) and complications occurred mostly in perineal, perianal, and buttocks sites. Two (5.5%) recurrences were seen only in buttocks site. CONCLUSION: To prevent complication, avoid recurrence of HS, and improve patients' quality of life, early and wide surgical excision is important and effective. The recurrence and complications are mostly related to the location of the disease. The authors have indicated no significant interest with commercial supporters. PMID- 21605247 TI - Rapid induction of suction blisters by intra-cavity positive pressure enhancement. PMID- 21605248 TI - Acne scar treatment with subcision using a 20-G cataract blade. PMID- 21605249 TI - Single-stage reconstruction of nasal ala and perialar defect with island pedicle flap and Burow's graft. PMID- 21605250 TI - Squamous cell carcinoma arising from giant porokeratosis. PMID- 21605251 TI - Treatment of Bowen's disease on the penis with low concentration of a standard mixture of solasodine glycosides and liquid nitrogen. PMID- 21605252 TI - Using the "feed and wrap" technique and Mohs surgery to eradicate congenital dermatofibrosarcoma protuberans in a 4-month-old. PMID- 21605253 TI - Metophyma: case report and review of a rare phyma variant. PMID- 21605254 TI - Skin cooling provides minimal relief of patient discomfort during periocular botulinum toxin type A injection. PMID- 21605255 TI - Arteriovenous fistula following hair transplantation. PMID- 21605256 TI - Nare obstruction due to massive rhinophyma treated using the Shaw scalpel. PMID- 21605257 TI - Linear morphea-induced atrophy treated with hyaluronic acid filler injections. PMID- 21605258 TI - Letter: Light-emitting diode photomodulation and radiation dermatitis. PMID- 21605259 TI - Letter: letter to editor regarding "Acute fatal fat tissue embolism after autologous fat transfer in a patient with lupus profundus". PMID- 21605260 TI - The effectiveness of an exercise programme for elders with dementia in a Taiwanese day-care centre. AB - The purpose was to examine the effectiveness of an exercise programme for elders with dementia in Taiwan aimed to maintain their activities of daily living such as feeding, dressing, grooming, washing and toileting. This was a single study group, repeated measure research design. Twenty-six dementia elders were recruited from a day-care centre located in southern Taiwan. Caregivers of the day-care centre provided all subjects an exercise programme. The exercise programme consisted of stretching and walking five times per week, and leg-weight bearing at least three times per week for 20-30 min each. The data were obtained three times (baseline, 2 months post intervention and 4 months post intervention). Results showed slight changes in the scores of one-leg-standing, 30 s chair rise, functional reach and get up and go test but were not statistically significant. Results also indicated that scores in the performance of activities of daily living were significantly higher than at baseline and at 4 months post intervention. In conclusion, this study provides information for dementia day-care centres in Taiwan about how elders with dementia can maintain physical fitness and perform activities of daily living. PMID- 21605261 TI - Self-management among Egyptian heart failure patients. AB - The purpose of this study was to describe heart failure patients' abilities to manage their disease. A descriptive correlational design was used in this study. A convenient sample of 120 adult patients with heart failure was surveyed using Self-Management of Heart Failure tool; the New York Heart Association (NYHA) Functional Classification was used to measure functional status. The findings of this study showed that 60% of patients' age ranged from 50 to < 60 years. Men accounted for 66.7% of the patient population; 33.3% were women. Most participants were married. The study showed that recognizing a change in signs and symptoms was positively correlated with both implementing and evaluating treatment with statistical significance. In addition, the results showed the statistical significant differences between levels of patients' education and both implementing and evaluating treatment. Finally, statistically significant differences were found between functional status of patients and their ability to recognize change as well as evaluate treatment. Findings of this study highlight the need for using the Self-Management of Heart Failure tool in practice to direct the medical and nursing staff towards the specific problem area for each patient. PMID- 21605262 TI - Debunking the manual handling myth: an investigation of manual handling knowledge and practices in the Australian private health sector. AB - Nursing care involves complex patient handling tasks. Strategies to address associated manual handling issues commonly include training programmes, despite conflicting evidence regarding training efficacy for manual handling injury reduction. Resultant knowledge acquisition and skills transfer from training programmes are prerequisites for subsequent practice changes in the clinical setting. This paper draws upon the findings from a questionnaire completed by 100 nurses in an Australian private hospital in 2008. A substantial knowledge deficit was identified, despite previous training undertaken by participants. A striking finding was that although 82% (n = 82) of nurses surveyed believed they used safe manual handling practices, only 18% (n = 15) of these nurses correctly answered items assessing manual handling knowledge. The study suggests prudence in the assumption of skills and knowledge acquisition during manual handling training. It informs the development of future implementation strategies, and provides a contributory explanation for the limited application of recommended practices after training completion. PMID- 21605263 TI - An exploration of rural women's knowledge of heart disease and the association with lifestyle behaviours. AB - Heart disease is the leading cause of morbidity and mortality in Australian women. The purpose of the study was to investigate Australian rural women's knowledge of heart disease and the association with lifestyle behaviours. A questionnaire was developed to collect data on rural women's knowledge and risk of heart disease. Despite having an overall good knowledge of heart disease, there was an identified lack of health promoting behaviours by the women to reflect their knowledge. Over half of the women participants of this study reported two or more lifestyle risk factors for heart disease. This study shows that women might know about heart disease risk factors, nevertheless they might be unaware of their susceptibility to heart disease in relation to the risk factors. Without an awareness of personal susceptibility, women might be less likely to take action to reduce the risk of heart disease. PMID- 21605264 TI - Decision-making theories and their usefulness to the midwifery profession both in terms of midwifery practice and the education of midwives. AB - What are the strengths and limitations of existing Decision-Making Theories as a basis for guiding best practice clinical decision-making within a framework of midwifery philosophy? Each theory is compared in relation with how well they provide a teachable framework for midwifery clinical reasoning that is consistent with midwifery philosophy. Hypothetico-Deductive Theory, from which medical clinical reasoning is based; intuitive decision-making; Dual Processing Theory; The International Confederation of Midwives Clinical Decision-Making Framework; Australian Nursing and Midwifery Council Midwifery Practice Decisions Flowchart and Midwifery Practice. Best practice midwifery clinical Decision-Making Theory needs to give guidance about: (i) effective use of cognitive reasoning processes; (ii) how to include contextual and emotional factors; (iii) how to include the interests of the baby as an integral part of the woman; (iv) decision-making in partnership with woman; and (v) how to recognize/respond to clinical situations outside the midwife's legal/personal scope of practice. No existing Decision Making Theory meets the needs of midwifery. Medical clinical reasoning has a good contribution to make in terms of cognitive reasoning processes. Two limitations of medical clinical reasoning are its reductionistic focus and privileging of reason to the exclusion of emotional and contextual factors. Hypothetico deductive clinical reasoning is a necessary but insufficient condition for best practice clinical decision-making in midwifery. PMID- 21605265 TI - The developing role of transition to practice programs for newly graduated mental health nurses. AB - A number of significant challenges face graduate mental health nurses entering the workforce. In response, Transition to Practice programs have been promoted as a potential strategy for improving recruitment and retention within the mental health system. This review explores the experience of transition for mental health nurse graduates and identifies key aspects of Transition to Practice programs that facilitate the transition to practising professional. A comprehensive review of qualitative research, which sought to provide insight into the experience of transition for graduate mental health nurses, was conducted. Nine studies were identified through a search of MEDLINE, CINAHL, PsychINFO, PsychArticles, Psychology, AMED, EMBASE and Health Source: Nursing/academic edition. Findings showed a disparity between undergraduate perceptions of the mental health nurse role and what is actually observed during placement, highlighting the need for the positive contribution of preceptors and mentors within a transitional support model for newly graduated mental health nurses. PMID- 21605266 TI - Nurses' knowledge of prevention and management of pressure ulcer at a health insurance hospital in Alexandria. AB - Nurses' knowledge of pressure ulcer prediction, prevention and management plays a very important role in the incidence and prevalence of pressure ulcers in health care systems. The aim of the current study was to assess the nurse's knowledge about prevention and management of pressure ulcer at one of the largest health insurance hospitals in Alexandria. A descriptive cross-sectional study using an interview questionnaire format to assess the nurses' knowledge (n = 122) regarding prevention of pressure ulcers. The overall mean per cent score for nurses was below the minimum acceptable level. The mean per cent score for nurses was below 70% for nine measures of the 15 correct measures, which accounted for 60% of the measures of pressure ulcer prevention. Correct answers for non-useful measures for preventing pressure ulcers accounted for 66% of the non-useful measures on the questionnaire. It had been concluded that the nurses' knowledge regarding pressure ulcer prevention is below the acceptable levels. PMID- 21605267 TI - A novel educational programme to improve knowledge regarding health care associated infection and hand hygiene. AB - Lack of hand hygiene by health-care workers is the most significant cause of health care-associated infection. This programme was designed to make health-care workers want to wash their hands, to change their knowledge regarding hand hygiene and health care-associated infection, and influence practice. Improvement between pre- and post-test scores was statistically significant. Compliance is a multifactorial problem that involves knowledge and behaviour. Educational awareness and frequent reminders are critical to maintain high rates of hand hygiene compliance. PMID- 21605268 TI - Impact of hand injury on patients: psychosocially oriented nurse care. AB - Psychosocially oriented nurse care Psychological and social post-traumatic adjustments consequent to hand injury deeply affect patients' needs. Nurses are the professional figures who, within the surgery, work more closely in terms of frequency and time with patients: a targeted nurse training must be implemented. A systematic review was conducted to assess hand-injured patients nurse care. In total, 335 articles were identified, of which 20 met inclusion criteria. Issues identified included psychological response to hand injury, social implications, nurse's recognition and assessment of psychosocial needs, appropriate intervention. The results show how important it is to train nurses who are well prepared to deal with the psychological status when caring for hand-injured patients, in order to set the most correct psychosocial assistance. PMID- 21605269 TI - Help-seeking behaviour: a concept analysis. AB - The concept 'help-seeking behaviour' has gained popularity in recent years as an important vehicle for exploring and understanding patient delay and prompt action across a variety of health conditions. The term is used interchangeably with health seeking and is described as part of both illness behaviour and health behaviour. Concept clarification is required to aid nurses and other health-care professionals understanding of the attributes of help-seeking behaviour and to guide theory development, practice and research. The Walker and Avant method of concept analysis was used to guide the analysis. Help-seeking behaviour was shown to be a complex decision-making process instigated by a problem that challenges personal abilities. According to the literature, the process is characterized by the following attributes: problem focused, intentional action and interpersonal interaction. Help-seeking behaviour for a health problem can therefore be defined as a problem focused, planned behaviour, involving interpersonal interaction with a selected health-care professional. PMID- 21605270 TI - Religion, faith and the empowerment process: stories of Iranian people with diabetes. AB - Empowerment concerning people with diabetes is well researched. However, few researchers specifically focus on the barriers to and facilitators of empowerment in Iranian people with diabetes. Understanding the factors could help health professionals facilitate self-empowerment more effectively. This study aims to determine the barriers to and facilitators of empowerment in Iranian people with diabetes. A qualitative exploratory study was conducted using in-depth interviews to collect the data from 11 women and men in 2007. Themes were identified using constant comparative analysis method. Common barriers to empowerment were similar to other chronic diseases: prolonged stress, negative view about diabetes, ineffective health-care systems, poverty and illiteracy. Diabetes education, fear of diabetes' complications, self-efficacy and hope for a better future emerged as being crucial to empowerment. Facilitators specific to Iranians were: the power of religion and faith, the concept of the doctor as holy man, accepting diabetes as God's will, caring for the body because it was God's gift and support from families especially daughters. Empowerment was strongly influenced by cultural and religious beliefs in Iran and the power of faith emerged as an important facilitator of diabetes empowerment. The findings will help health professionals understand how Iranian people with diabetes view life and the factors that facilitate empowerment. PMID- 21605271 TI - The nursing rounds system: effect of patient's call light use, bed sores, fall and satisfaction level. AB - The nursing round system (NRS) means checking patients on an hourly basis during the A (0700-2200 h) shift and once every 2 h during the B (2200-0700 h) by the assigned nursing staff. The overall goal of this prospective study is to implement an NRS in a major rehabilitation centre-Sultan Bin Abdulaziz Humanitarian City-in the Riyadh area of the Kingdom of Saudi Arabia. The purposes of this study are to measure the effect of the NRS on: (i) the use of patient call light; (ii) the number of incidences of patients' fall; (iii) the number of incidences of hospital-acquired bed sores; and (iv) the level of patients' satisfaction. All patients hospitalized in the male stroke unit will be involved in this study. For the period of 8 weeks (17 December 2009-17 February 2010) All Nursing staff on the unit will record each call light and the patient's need. Implementation of the NRS would start on 18 February 2010 and last for 8 weeks, until 18 April 2010. Data collected throughout this period will be compared with data collected during the 8 weeks period immediately preceding the implementation of the NRS (17 December 2009-17 February 2010) in order to measure the impact of the call light use. The following information were collected on all subjects involved in the study: (i) the Demographic Information Form; (ii) authors' developed NRS Audit Form; (iii) Patient Call Light Audit Form; (iv) Patient Fall Audit Record; (v) Hospital-Acquired Bed Sores Audit Form; and (vi) hospital developed Patient Satisfaction Records. The findings suggested that a significant reduction on the use of call bell (P < 0.001), a significant reduction of fall incidence (P < 0.01) while pressure ulcer reduced by 50% before and after the implementation of NRS. Also, the implementation of NRS increased patient satisfaction by 7/5 (P < 0.05). PMID- 21605272 TI - Nursing activities in intensive care units in Turkey. AB - This cross-sectional study was conducted to determine applications practiced by nurses working in intensive care units of various institutions in Turkey. The research setting was neurosurgery, surgery, coronary and general intensive care units. The population of the study comprised nurses working in intensive care units, which were under the scope of this study, and these nurses' functions were studied. Data were collected using a Personal Information Form, the Cheltenham Patient Classification Scale and Nursing Activity List. It was observed that nurses spend most of their time on direct nursing care, clerical nursing duties and patient assessment. The most frequent activities included recording observations, calculating fluid balance, recording ventilator parameters, talking to patients, conversation not task orientated, drug preparation and administration. Although nurses spend most of their time on direct nursing care, they might also be obliged to get around to activities not in relation with direct patient care. PMID- 21605273 TI - Task-shifting in the delivery of hormonal contraceptive methods: validation of a questionnaire and preliminary results. AB - In order to palliate the access problem to effective contraceptive methods in Quebec, Canada, as well as to legitimate nurses' practices in family planning, a collaborative agreement was developed that allow nurses, in conjunction with pharmacists, to give hormonal contraceptives to healthy women of reproductive age for a 6 month period. Training in hormonal contraception was offered to targeted nurses before they could begin this practice. A questionnaire, based on Rogers's theory of diffusion of innovations, was elaborated and validated to specifically evaluate this phenomenon. Preliminary results show that the translation of training into practice might be suboptimal. The validated questionnaire can now be used to fully understand the set of factors influencing this new practice. PMID- 21605274 TI - Communication barriers to patient education in cardiac inpatient care: a qualitative study of multiple perspectives. AB - Growing evidence in a variety of health-care settings supports the need to strengthen nurse-physician communication and interprofessional collaboration to optimize patient-health outcomes. The objective of this study is to explore communication barriers from the perspective of nurses themselves, as well as physicians, patients and families in a hospital-based cardiac care setting. Qualitative analysis of individual interviews with 35 participants was taken in two hospitals in Tehran, Iran. Interview questions asked about experiences with patient education and communication barriers among physicians, nurses and patients. The three major themes identified were: (i) lack of collegiality and communication between nurses and physicians; (ii) problematic communication between the health-care team, patients and their families; and (iii) cultural challenges. Findings from this study support the need for health-care organizations to be more collaborative and inclusive of nursing professionals. PMID- 21605275 TI - Exhaled air dispersion and removal is influenced by isolation room size and ventilation settings during oxygen delivery via nasal cannula. AB - BACKGROUND AND OBJECTIVE: We compared the exhaled air dispersion distances during oxygen delivery via nasal cannula to a human-patient simulator (HPS) in two different isolation rooms. METHODS: Airflow was marked with intrapulmonary smoke for visualization. Oxygen flow was gradually increased from 1 to 5 L/min, with the HPS sitting at 45 degrees . The leakage jet plume was revealed by laser light sheet and images captured by high-definition video. Smoke concentration in the plume was estimated from the light scattered by smoke particles. The experiments were conducted at a double-door, negative pressure isolation room with a dimension of 4.1 * 5.1 * 2.6 m, pressure of -7.4 Pa and 16 air exchanges/h (ACH) (room A). Results were compared with experiments repeated in a smaller isolation room with a dimension of 2.7 * 4.2 * 2.4 m, pressure of -5 Pa and 12 ACH (room B). RESULTS: Room A: an exhalation jet spread almost horizontally outward from the nostrils of the HPS to 0.66 m and 1 m towards the end of bed when oxygen flow was increased from 1 to 5 L/min respectively. Room B: there was interaction between the downward ceiling ventilation current and the exhaled air from the HPS, leading to deflection of exhaled smoke towards the head of the HPS at an oxygen flow rate of 1 L/min. As oxygen flow was increased gradually to 5 L/min, more room contamination with smoke was noted. CONCLUSIONS: Substantial exposure to exhaled air occurs within 1 m towards the end of the bed from patients receiving oxygen via nasal cannula. Room dimension and air exchange rate are important factors in preventing contamination in isolation rooms. PMID- 21605276 TI - Plasma neutrophil elastase correlates with pulmonary vascular permeability: a prospective observational study in patients with pneumonia. AB - BACKGROUND AND OBJECTIVE: Little is known about plasma neutrophil elastase (PNE) levels in patients with community-acquired pneumonia (CAP) requiring treatment in the intensive care unit (ICU) or high care unit (HCU). In addition, the influence of PNE on pulmonary vascular permeability in a clinical setting has not been investigated. The aims of this study were (i) to investigate PNE levels in patients with CAP and (ii) to explore the relationship between PNE and pulmonary vascular permeability. METHODS: Fourteen consecutive CAP patients who were admitted to the HCU (n = 8) or ICU (n = 6) were prospectively investigated over a 6-month period. A group of eight patients with hydrostatic pulmonary oedema without CAP served as a control group (CG). PNE levels were measured at regular intervals. The pulmonary vascular permeability index (PVPI) was monitored in all ICU and CG patients, using the PiCCO system. RESULTS: PNE levels were higher in the CAP patients (132 (84-261) ng/mL) than in the CG patients (77 (64-107) ng/mL) (P = 0.04), and were highest in the ICU patients (186 (75-466) ng/mL). The PVPI was higher in the ICU patients (2.85 (1.90-4.00)) than in the CG patients (1.15 (0.75-2.35)) (P = 0.02). PNE levels correlated with PVPI in the ICU patients (r = 0.81, P < 0.001) but there was no correlation among the CG patients (r = 0.14, P = 0.73). CONCLUSIONS: Patients with severe CAP had high levels of PNE, which was closely correlated with PVPI. PNE may be involved in the pathogenesis of severe pneumonia. PMID- 21605277 TI - Factors predicting outcome following airway stenting for post-tuberculosis tracheobronchial stenosis. AB - BACKGROUND AND OBJECTIVE: Silicone airway stents are used to widen narrowed airways in patients with post-tuberculosis tracheobronchial stenosis (PTTS). After mechanical stabilization, stents can be removed from the majority of patients leaving restored airway patency. However, in a significant minority re stenosis develops post-sten removal thus necessitating surgical intervention or long-term stenting. In this study, we sought to establish prognostic factors for successful airway intervention in PTTS. METHODS: We retrospectively investigated 71 patients who underwent silicone stenting due to PTTS. After stenting, bronchoscopic toileting and/or repositioning was performed during follow up. At 6 12 months after clinical stabilization, stents were planned to be removed. Patients with patent airways were followed if no further intervention was required. If restenosis developed, patients underwent re-stenting or operation. Clinical parameters were analysed to determine favourable prognostic factors. RESULTS: Stents were successfully removed in 40 patients at a median 12.5 months after insertion. In 27 patients, stent re-insertion was carried out and four patients underwent surgical management. Multivariate logistic regression analysis revealed that successful stent removal was independently associated with atelectasis <1 month before bronchoscopic intervention, and absence of complete lobar atelectasis. CONCLUSIONS: Airway intervention, including silicone stenting, can be successful in patients with PTTS, when the intervention is performed within 1 month of atelectasis and before complete lobar atelectasis. PMID- 21605278 TI - A randomized controlled trial of the efficacy of cosmetic talc compared with iodopovidone for chemical pleurodesis. AB - BACKGROUND AND OBJECTIVE: Talc is an effective and widely used agent for chemical pleurodesis. However, limited availability and high cost hamper the routine use of talc in resource poor countries. In this study, we compared the efficacy and safety of iodopovidone with that of cosmetic talc, for chemical pleurodesis. METHODS: Patients with recurrent pleural effusions and/or spontaneous pneumothorax were prospectively randomized to undergo pleurodesis with cosmetic talc (5g) or iodopovidone (20mL of a 10% solution) by tube thoracostomy. The cosmetic talc was pretested for impurities (asbestos-free) and particle size (20 60um), using energy dispersive analysis by X-ray and scanning electron microscopy. The success rate (complete or partial), time to pleurodesis and safety of these two agents was compared. RESULTS: Pleurodesis was performed in 73 patients (39 with iodopovidone, 34 with cosmetic talc; 56 men, 17 women; mean age 51.7 years; 38 pleural effusions, 35 pneumothoraces). A complete response was obtained in all patients with pneumothorax in both the iodopovidone and talc groups. Among patients with pleural effusions, a complete response was observed in 16/19 and 15/19 patients in the iodopovidone and talc groups, respectively. A partial response was observed in two additional patients from each group. The time to pleurodesis was similar in the two groups. Minor side-effects (fever, chest pain) were observed with similar frequencies in the two groups. None of the patients experienced hypotension or ARDS. CONCLUSIONS: Iodopovidone and cosmetic talc are equally efficacious and safe agents for chemical pleurodesis. PMID- 21605279 TI - Clinical and molecular microbiological characteristics of carbapenem-resistant Acinetobacter baumannii strains in an NICU. AB - BACKGROUND: Seventeen cases of Acinetobacter baumannii infection in a neonatal intensive care unit (NICU) were evaluated. The strains were characterized as resistant to carbapenems. The aim of the present study was therefore to investigate the clinical and molecular epidemiological characteristics of the 17 carbapenem-resistant A. baumannii strains. METHODS: Samples were isolated from blood or sputum from the patients in the NICU, cultured using conventional techniques and an automated system. Multiplex polymerase chain reaction (PCR) was used to detect blaOXA-51-like, blaOXA-23-like, OXA-24, OXA-58 and Ambler class B carbapenemases. The genotype of the strains was identified on pulsed-field gel electrophoresis (PFGE). RESULTS: BlaOXA-23 was detected in all of the isolates. PFGE genotype analysis suggested three clones among the 17 strains. Two clones were isolated from other wards of the hospital including the adult ICU and Department of Pulmonology. The other clone was proved to be the first appearance in the hospital as genotype analysis. CONCLUSION: BlaOXA-23 was the drug resistant gene that made A. baumannii resistant to carbepenem. The source of blaOXA-23 in the 17 isolates was different. PMID- 21605280 TI - Serum KL-6 and surfactant protein D in children with 2009 pandemic H1N1 influenza infection. AB - BACKGROUND: A global pandemic influenza A (H1N1) outbreak occurred in 2009. Rapid progress of respiratory distress is one of the characteristic features of pandemic influenza A (H1N1) infection. The physiologic mechanism causing hypoxia in pandemic influenza A (H1N1) infection, however, has not been elucidated. METHODS: The serum levels of KL-6 and surfactant protein D (SP-D) were evaluated in 21 cases of pandemic influenza A (H1N1) infection associated with chest radiographic abnormality in order to estimate alveolar involvement. The clinical features were also analyzed. RESULTS: All of the patients had high fever, and rapidly progressed to respiratory distress within several days of disease onset. Despite mild radiographic abnormality in these patients, dyspnea was severe and they had low blood oxygen saturation levels. Many of the patients had a history of allergic diseases including asthma. Serum KL-6 and SP-D levels on admission were 191 +/- 69 U/mL and 32.6 +/- 18.9 ng/mL, respectively. These two levels were still below the upper normal limit 1 week later. There were no clear relationships between specific clinical symptoms and KL-6 or SP-D levels. All patients were treated with oseltamivir and/or zanamivir, and improved without mechanical ventilation management. CONCLUSION: KL-6 and SP-D elevation were not significant in pandemic influenza A (H1N1) infection associated with chest radiographic abnormality. In pandemic influenza A (H1N1) infection, alveolar involvement was estimated to be little, and severe respiratory distress was probably caused by obstruction of peripheral bronchi. PMID- 21605281 TI - Risk factors for bronchopulmonary dysplasia in neonates born at <= 1500 g (1999 2009). AB - BACKGROUND: Advances in perinatal care have improved the survival rate for very low-birthweight (VLBW) infants in China. The incidence of bronchopulmonary dysplasia (BPD), however, has not been reduced. The objective of the present study was to identify the perinatal risk factors for BPD in neonates born at <= 1500 g. METHODS: A retrospective analysis of data for neonates born at <= 1500 g between 1999 and 2009 in the neonatal intensive care unit (NICU) of Second Affiliated Hospital of Sun Yat-Sen University, Guangzhou city, China, was carried out. RESULTS: Out of a total of 11,506 live births, 3538 infants were admitted to level II nursery and NICU (level III nursery). Among 149 preterm infants born at <= 1500 g, 77.8% survived until day 28, and the incidence of BPD was 48.3%. Logistic regression analysis showed that gestational age (GA) <= 30 weeks (odds ratio [OR], 9.507; 95% confidence intervals [95%CI]: 2.604-34.707), maternal chorioamnionitis (OR, 41.987; 95%CI: 6.048-291.492), ventilation-associated pneumonia (OR, 11.600; 95%CI: 2.847-47.268), and more than three blood transfusions (OR, 10.214; 95%CI: 2.191-47.623) were associated with the development of BPD. CONCLUSION: Clinical evidence has been provided for possibly significant risk factors associated with BPD in neonates born at <= 1500 g, which can provide useful information for further research to improve survival of VLBW infants and decrease the incidence of BPD. PMID- 21605283 TI - Characterization of the EP receptor types that mediate longitudinal smooth muscle contraction of human colon, mouse colon and mouse ileum. AB - BACKGROUND: Prostaglandin E(2) (PGE(2) ) is an inflammatory mediator implicated in several gastrointestinal pathologies that affect normal intestinal transit. The aim was to establish the contribution of the four EP receptor types (EP(1-4) ), in human colon, that mediate PGE(2) -induced longitudinal smooth muscle contraction. METHODS: Changes in isometric muscle tension of human colon, mouse colon and mouse ileum were measured in organ baths in response to receptor specific agonists and antagonists. In addition, lidocaine was used to block neurogenic activity to investigate whether EP receptors were pre- or post junctional. KEY RESULTS: PGE(2) contracted longitudinal muscle from human and mouse colon and mouse ileum. These contractions were inhibited by the EP(1) receptor antagonist, EP(1) A in human colon, whereas a combination of EP(1) A and the EP(3) antagonist, L798106 inhibited agonist responses in both mouse preparations. The EP(3) agonist, sulprostone also increased muscle tension in both mouse tissues, and these responses were inhibited by lidocaine in the colon but not in the ileum. Although PGE(2) consistently contracted all three muscle preparations, butaprost decreased tension by activating smooth muscle EP(2) receptors in both colonic tissues. Alternatively, in mouse ileum, butaprost responses were lidocaine-sensitive, suggesting that it was activating prejunctional EP(2) receptors on inhibitory motor neurons. Conversely, EP(4) receptors were not functional in all the intestinal muscle preparations tested. CONCLUSIONS & INFERENCES: PGE(2) -induced contraction of longitudinal smooth muscle is mediated by EP(1) receptors in human colon and by a combination of EP(1) and EP(3) receptors in mouse intestine, whereas EP(2) receptors modulate relaxation in all three preparations. PMID- 21605282 TI - Diagnosis and treatment of chronic constipation--a European perspective. AB - BACKGROUND: Although constipation can be a chronic and severe problem, it is largely treated empirically. Evidence for the efficacy of some of the older laxatives from well-designed trials is limited. Patients often report high levels of dissatisfaction with their treatment, which is attributed to a lack of efficacy or unpleasant side-effects. Management guidelines and recommendations are limited and are not sufficiently current to include treatments that became available more recently, such as prokinetic agents in Europe. PURPOSE: We present an overview of the pathophysiology, diagnosis, current management and available guidelines for the treatment of chronic constipation, and include recent data on the efficacy and potential clinical use of the more newly available therapeutic agents. Based on published algorithms and guidelines on the management of chronic constipation, secondary pathologies and causes are first excluded and then diet, lifestyle, and, if available, behavioral measures adopted. If these fail, bulk forming, osmotic, and stimulant laxatives can be used. If symptoms are not satisfactorily resolved, a prokinetic agent such as prucalopride can be prescribed. Biofeedback is recommended as a treatment for chronic constipation in patients with disordered defecation. Surgery should only be considered once all other treatment options have been exhausted. PMID- 21605284 TI - Prolonged sympathetic innervation of sensory neurons in rat thoracolumbar dorsal root ganglia during chronic colitis. AB - BACKGROUND: Peripheral irritation-induced sensory plasticity may involve catecholaminergic innervation of sensory neurons in the dorsal root ganglia (DRG). METHODS: Catecholaminergic fiber outgrowth in the thoracolumbar DRG (T13 L2) was examined by tyrosine hydroxylase (TH) immunostaining, or by sucrose potassium phosphate-glyoxylic acid histofluorescence method. TH level was examined by Western blot. Colonic afferent neurons were labeled by retrograde neuronal tracing. Colitis was induced by intracolonic instillation of tri nitrobenzene sulfonic acid (TNBS). KEY RESULTS: The catecholaminergic fibers formed 'basket-like' structures around the DRG cells. At 7 days following TNBS treatment, the number of DRG neurons surrounded by TH-immunoreactive fibers and the protein levels of TH were significantly increased in T13, L1, and L2 DRGs (two- to threefold, P < 0.05). The DRG neurons that were surrounded by TH immunoreactivity were 200 kDa neurofilament-positive, but not isolectin IB4 positive or calcitonin gene-related peptide-positive. The TH-immunoreactive fibers did not surround but adjoin the specifically labeled colonic afferent neurons, and was co-localized with glial marker S-100. Comparison of the level of TH and the severity of colonic inflammation showed that following TNBS treatment, the degree of colonic inflammation was most severe at day 3, subsided at day 7, and significantly recovered by day 21. However, the levels of TH in T13-L2 DRGs were increased at both 3 days and 7 days post TNBS treatment and persisted up to 21 days (two- to fivefold increase, P < 0.05) as examined. CONCLUSIONS & INFERENCES: Colonic inflammation induced prolonged catecholaminergic innervation of sensory neurons, which may have relevance to colitis-induced chronic visceral hypersensitivity and/or referred pain. PMID- 21605286 TI - Detection of nine microorganisms from the initial carious root lesions using a TaqMan-based real-time PCR. AB - OBJECTIVE: The purpose of this study was to quantify nine selected cariogenic bacteria in plaque from sound root surfaces and initial carious root lesions using TaqMan PCR and to analyse a putative dependence on the kind of initial periodontal treatment. MATERIAL AND METHODS: Fifty-four subjects with generalized chronic periodontitis were randomly allocated to one of the following initial periodontal therapies: full-mouth disinfection, full-mouth scaling and root planing or scaling and root planing within 7 days. Plaque samples were taken before and after periodontal treatment and analysed by TaqMan PCR. RESULTS: The quantity of the cariogenic bacteria Actinomyces spp., Streptococcus mutans, Streptococcus sobrinus, Lactobacilllus spp., Rothia dentocariosa, Parvimonas micra, Propionibacterium acnes and Neisseria mucosa were significantly higher, while the quantity of Veillonella parvula was significantly lower on initial carious lesions than on the sound surfaces both before and after periodontal therapy. No significant differences could be found in any of the tested bacteria except P. micra on initial carious lesions and sound surfaces for both examinations between the groups. CONCLUSION: All the nine species analysed were found to be present in initial carious root lesions as well as sound root surfaces but in different quantities, independent of the different periodontal therapies. PMID- 21605287 TI - How does genome instability affect lifespan?: roles of rDNA and telomeres. AB - The genome is composed not only of genes but also of several noncoding functional elements (NOCs/ncFE, here I use NOCs), such as transcriptional promoters, enhancers, replication origins, centromeres and telomeres. rDNA has both gene and NOC characteristics. Thus, the rDNA encodes ribosomal RNAs, components of the ribosomes, that account for approximately 80% of the total RNA in a cell. However, rDNA may also act as a NOC with respect to cellular senescence by limiting the number of times a cell can divide. Here, I discuss how rDNA might function as a NOC to influence life span in a manner analogous to telomeres. PMID- 21605285 TI - Generalized neuromuscular hypoplasia, reduced smooth muscle myosin and altered gut motility in the klotho model of premature aging. AB - BACKGROUND: Gastrointestinal symptoms, particularly constipation, increase with aging, but their underlying mechanisms are poorly understood due to lack of experimental models. Previously we established the progeric klotho mouse as a model of aging-associated anorexia and gastric dysmotility. We also detected reduced fecal output in these animals; therefore, the aim of this study was to investigate in vivo function and cellular make-up of the small intestinal and colonic neuromuscular apparatus. METHODS: Klotho expression was studied by RT-PCR and immunohistochemistry. Motility was assessed by dye transit and bead expulsion. Smooth muscle and neuron-specific gene expression was studied by Western immunoblotting. Interstitial cells of Cajal (ICC) and precursors were analyzed by flow cytometry, confocal microscopy, and three-dimensional reconstruction. HuC/D(+) myenteric neurons were enumerated by fluorescent microscopy. KEY RESULTS: Klotho protein was detected in neurons, smooth muscle cells, and some ICC classes. Small intestinal transit was slower but whole-gut transit of klotho mice was accelerated due to faster colonic transit and shorter intestinal lengths, apparent only after weaning. Fecal water content remained normal despite reduced output. Smooth muscle myosin expression was reduced. ICC, ICC precursors, as well as nitrergic and cholinergic neurons maintained their normal proportions in the shorter intestines. CONCLUSIONS & INFERENCES: Progeric klotho mice express less contractile proteins and develop generalized intestinal neuromuscular hypoplasia mainly arising from stunted postweaning growth. As reduced fecal output in these mice occurs in the presence of accelerated colonic and whole-gut transit, it likely reflects reduced food intake rather than intestinal dysmotility. PMID- 21605288 TI - FancJ/Brip1 helicase protects against genomic losses and gains in vertebrate cells. AB - Defects in the FANCJ/BRIP1 helicase gene are associated with genome instability disorders such as familial breast cancer or Fanconi anemia (FA). Although FANCJ has an in vitro activity to resolve G-quadruplex (G4) structures, and FANCJ ortholog in C. elegans prevents G4-associated deletions during replication, how FANCJ loss affects genome integrity in higher organisms remains unclear. Here, we report that FANCJ, but not other FA genes FANCD2 or FANCC, protected against large-scale genomic deletion that occurred frequently at the rearranged immunoglobulin heavy chain (IgH) locus in chicken DT40 cell line, suggesting that FancJ protects the genome independently of the FA ubiquitination pathway. In a more unbiased approach using array-comparative genomic hybridization, we identified de novo deletions as well as amplifications in fancj cells kept in culture for 2 months. A cluster of G4 sequence motifs was found near the breakpoint of one amplified region, but G4 sequence motifs were not detected at the breakpoints of two deleted regions. These results collectively suggest that, unlike in C. elegans, actions of vertebrate FANCJ to promote genome stability may not be limited to protection against the G4-mediated gene deletions. PMID- 21605289 TI - Quality assessment of capture-recapture studies in resource-limited countries. AB - OBJECTIVES: Resource-limited countries often lack robust routine surveillance systems to accurately assess the burden of human attributes and diseases. In these settings capture-recapture analysis can be an alternative tool to obtain prevalence and incidence rates. Performance of capture-recapture analyses in resource-limited countries has not been systematically reviewed. METHODS: Systematic review of the performance of capture-recapture analyses in the categories of human attributes, non-infectious and infectious diseases in resource-limited countries, assessing individual study quality criteria and a minimum quality criterion per category, using PRISMA methodology. RESULTS: A total of 1671 potentially relevant PubMed citations were screened, resulting in 52 eligible publications: 36% in human attributes, i.e. hidden populations, injuries and mortality; 48% in non-infectious and 15% in infectious disease categories. Twenty-one per cent of selected studies were from low income countries, 40% from lower-middle-income countries and 38% from upper-middle income countries. Thirteen per cent achieved good individual study quality criteria, 25% were intermediate and 19% were poor. Of the good studies, six were performed on human attributes and one on a non-infectious disease. The proportions of publications meeting the minimum quality criterion per category were 42%, 20% and 37%, respectively. CONCLUSIONS: Few capture-recapture studies in resource-limited countries achieved good individual quality criteria and a minority met the minimum quality criterion per category. Capture-recapture techniques in these settings should be carefully considered and implemented rigorously and are not a panacea for strengthening of routine surveillance systems. PMID- 21605290 TI - Does targeting key-containers effectively reduce Aedes aegypti population density? AB - OBJECTIVES: The elimination of Aedes aegypti breeding sites has been broadly adopted worldwide to keep vector population density below a critical threshold. We observed the effectiveness of targeting the most productive containers on adult A. aegypti females density, which was evaluated weekly. METHODS AND RESULTS: Adult mosquitoes were collected weekly over 55 weeks and pupal surveys were done in intervals of 4 months to determine container productivity and guidelines for interventions. Pupal surveys indicated that water tanks (72% of pupae in first survey) and metal drums (30.7% of pupae in second survey) were the most productive container types. We observed a dramatic but short-term decrease in weekly adult female A. aegypti density after covering 733 water tanks with nylon net. A long-term decrease in female adult population density was achieved only when we covered both water tanks and metal drums. Overall, pupae abundance and pupae standing crop diminished after netting water tanks and metal drums. Pupae per person, per hectare and per house decreased gradually between the first and the third pupal surveys, suggesting that targeting the most productive container types (water tanks and metal drums) produced a reduction in adult population density and infestation levels. CONCLUSION: Overall, targeting the most productive container types caused the adult mosquito density to decrease over time, supporting the assumption that this intervention is an effective tool for dengue control. However, this effect was observed only when both water tanks and metal drums were covered, possibly due to the functional similarity between these container types, which are large, often shaded, perennial water storage containers. PMID- 21605291 TI - Role of alpha-phosphoglucomutase and phosphoglucose isomerase activities at the branching point between sugar catabolism and anabolism in Lactobacillus casei. AB - AIMS: To evaluate the role of alpha-phosphoglucomutase (alpha-Pgm) and phosphoglucose isomerase (Pgi) activities in growth rate, sugar-phosphates, UDP sugars and lactate biosynthesis in Lactobacillus casei. METHODS AND RESULTS: The pgm and pgi genes coding for alpha-Pgm and Pgi activities in L. casei BL23, respectively, were identified, cloned and shown to be functional by homologous overexpression. In MRS fermentation medium with glucose, overexpression of pgm gene in L. casei resulted in a growth rate reduced to 75% and glucose-6P levels reduced to 47%. By contrast, with lactose, the growth rate was raised to 119%. An increment of alpha-Pgm activity had no significant effect on UDP-sugar levels. Remarkably, Pgi overexpression in L. casei grown in lactose or galactose resulted in almost a double growth rate with respect to the control strain. The increased Pgi activity also resulted in glucose-6P levels reduced to 25 and 59% of control strain cultured in glucose and lactose, respectively, and the fructose-6P levels were increased to 128% on glucose. UDP-glucose and UDP-galactose levels were reduced to 66 and 55%, respectively, of control strain levels cultured in galactose. In addition, the lactate yield increased to 115% in the strain overproducing Pgi grown in galactose. CONCLUSIONS: The physiological amount of alpha-Pgm and Pgi activities is limited for L. casei growth on lactose, and lactose and galactose, respectively, and that limitation was overcome by pgm and pgi gene overexpression. The increment of alpha-Pgm and Pgi activities, respectively, resulted in modified levels of sugar-phosphates, sugar-nucleotides and lactate showing the modulation capacity of the carbon fluxes in L. casei at the level of the glycolytic intermediate glucose-6P. SIGNIFICANCE AND IMPACT OF THE STUDY: Knowledge of the role of key enzymes in metabolic fluxes at the branching point between anabolic and catabolic pathways would allow a rational design of engineering strategies in L. casei. PMID- 21605292 TI - Public health physicians: here to help. PMID- 21605293 TI - Fabry disease and Factor V Leiden: a potent vascular risk combination. AB - A 45-year-old man with heterozygous Factor V Leiden presented with his third cerebrovascular accident despite being on warfarin at a therapeutic international normalized ratio. Subsequent investigation revealed a second genetic diagnosis of Fabry disease. He then had an acute myocardial infarction whilst on aspirin and warfarin. PMID- 21605294 TI - New onset of electrocardiographic abnormalities heralding hypertrophic cardiomyopathy in an adult athlete. AB - A 41-year-old male asymptomatic athlete with unremarkable personal and family history of heart disease underwent annual preparticipation screening. No abnormalities were noted on prior testing. On this occasion, a 12-lead electrocardiogram showed diffused and marked repolarization abnormalities. He was therefore referred for echocardiography, which showed moderate asymmetric hypertrophy localized at the mid-apical portions of the left ventricular anterolateral wall. Cardiac magnetic resonance confirmed the diagnosis of hypertrophic cardiomyopathy. Re-evaluation of the electrocardiogram performed the previous year revealed a completely normal tracing. PMID- 21605295 TI - A point prevalence survey of hospital inpatients to define the proportion with palliation as the primary goal of care and the need for specialist palliative care. AB - The direct burden of people whose goal of care is a palliative approach has not been estimated in the acute care setting. Using a single time point, cross sectional survey of all inpatient beds, an estimate was generated across a network of three South Australian public hospitals. One in three inpatients had a palliative approach as the goal of care and of these, only one in five had been referred to specialist palliative care services. Those referred were significantly more likely to have cancer and be younger men. Active recognition and documentation that a palliative approach frames the goals of care for this person needs to be incorporated more systematically into clinical practice in the acute care setting. At the same time, triggers for needs-based referral for specialist assessment should be implemented. Specialist palliative care services must also provide direct care for a wider range of patients than just those with cancer. PMID- 21605296 TI - Coeliac disease inducing mesenteric lymphadenopathy and intussusception. PMID- 21605297 TI - Multiple penetrating atherosclerotic ulcers of the aorta. PMID- 21605298 TI - Pyoderma gangrenosum developing over an arteriovenous fistula scar. PMID- 21605299 TI - Combination antiretroviral therapy as treatment for human immunodeficiency virus associated mucosa-associated lymphoid tissue type lymphoma of the nasopharynx. PMID- 21605300 TI - Analysis and evaluation of geriatricians' working routines in German hospitals. AB - BACKGROUND: Geriatricians are physicians who work primarily with the elderly and deal with diseases that often accompany old age, such as Alzheimer's disease. In the last few years, data from questionnaires have demonstrated increasing criticism of geriatricians regarding their working conditions in geriatric medicine. Ideally, such rather subjective statements should be compared to data about work strain that is not merely accurate but also evaluated on an objective real-time basis. Therefore, the aim of the current study is to deliver exact data about geriatricians' work in different geriatric departments to evaluate their working routines and afterwards to optimize their working conditions. METHODS: An observational real-time study was conducted by shadowing 15 physicians in geriatric medicine individually during weekday shifts at four hospitals in urban German settings. A total of 368 h of observations were recorded by using an ultra mobile computer. RESULTS: The average workday lasted 9 h 36 min 14 s (95% CI = 9.07:35-10.01:23 h) with a high amount of elderly patients to deal with (M = 18) every day. Overall, they spent 14.75% of each workday on indirect patient care, 7.29% on direct patient care and 13.19% on administrative work. Communication took up 4.68% of geriatricians' time, breaks and disruptions 7.5%. CONCLUSION: To our knowledge, this is the first real-time analysis on how geriatricians deal with their working demands and how working routines are organized in geriatric hospital departments. Geriatricians' subjective statements on their working conditions have been partially confirmed. Improving geriatricians work flow could increase work efficiency, job satisfaction and quality of care. PMID- 21605301 TI - Vitamin D deficiency: implications for acute care in the elderly and in patients with chronic illness. AB - There is evidence that the vast majority of hospitalized patients have vitamin D deficiency. Vitamin D deficiency is a poorly recognized pandemic with evidence to indicate inadequate testing and monitoring of response to treatment in high-risk populations. Vitamin D receptors are ubiquitous in the human body and while the endocrine effects of vitamin D are well recognized, the autocrine and paracrine effects of this steroid hormone are less well appreciated. These functions include antimicrobial and immunomodulation effects as well benefits on cardiovascular health, autoimmune disease, cancer and metabolism. Vitamin D deficiency increases mortality and even a modest amount of vitamin D may enhance longevity. Emerging evidence suggests that a vitamin D replete state carries significant health benefits in acute illness. In this review, we discuss the role of vitamin D deficiency and potential benefits in treating this deficiency focusing on the implications for managing acute illness in elderly patients and those with an underlying chronic illness. PMID- 21605302 TI - Deconstructing the DSM-IV-TR: a critical perspective. AB - This paper examines and offers a critique of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR), underlying principles and assumptions, and the nature and consequences of its nosological framework. The reason for this critique is to look at the rationale for some of the diagnostic categories and also why some categories are retained, including some of the long-standing diagnostic groups, such as schizophrenia. It is not the intention here to rehearse the problems of biological psychiatric thinking, nor argue the strengths and weaknesses of the DSM-IV-TR in its definitions and descriptions of particular syndromes and illnesses. The ideas presented here derive from a range of previous research that argued that the DSM-IV-TR colludes in a system of psychiatric care in which all people, by virtue of characteristically human foibles and idiosyncrasies, are potentially classifiable into a variety of diagnostic mental health categories. In the present study, it was argued that because of resource constraints, professional dispute, and public concern, the major criterion for attracting a formal diagnosis is not classifiability according to the DSM-IV-TR, but rather, that of 'social risk', defined in terms of risk to oneself and/or others and embodying obvious social control functions. Here, we expand and develop some of these ideas, and relate them more specifically to insights offered by critical or deconstructive psychology and the development of the forthcoming the DSM-V. PMID- 21605303 TI - The pGRT1 plasmid of Pseudomonas putida DOT-T1E encodes functions relevant for survival under harsh conditions in the environment. AB - Pseudomonas putida DOT-T1E has the capacity to grow in the presence of high concentrations of toluene. This ability is mainly conferred by an efflux pump encoded in a self-transmissible 133 kb plasmid named pGRT1. Sequence analysis of the pGRT1 plasmid revealed several key features. Most of the genes related to the plasmid maintenance functions show similarity with those encoded on pBVIE04 from Burkholderia vietnamensis G4, and knock-out mutants in several of these genes confirmed their roles. Two additional plasmid DNA fragments were incorporated into the plasmid backbone by recombination and/or transposition; in these DNA regions, apart from multiple recombinases and transposases, several stress related and environmentally relevant functions are encoded. We report that plasmid pGRT1 not only confers the cells with tolerance to toluene but also resistance to ultraviolet light. We show here the implication of a new protein in solvent tolerance which controls the level of expression of the TtgGHI efflux pump, as well as the implication of a protein with homology to the universal stress protein in solvent tolerance and ultraviolet light resistance. Furthermore, this plasmid encodes functions that allow the cells to chemotactically respond to toluene and participate in iron scavenging. PMID- 21605304 TI - Bacterial chemotaxis towards aromatic hydrocarbons in Pseudomonas. AB - Bacterial chemotaxis is an adaptive behaviour, which requires sophisticated information-processing capabilities that cause motile bacteria to either move towards or flee from chemicals. Pseudomonas putida DOT-T1E exhibits the capability to move towards different aromatic hydrocarbons present at a wide range of concentrations. The chemotactic response is mediated by the McpT chemoreceptor encoded by the pGRT1 megaplasmid. Two alleles of mcpT are borne on this plasmid and inactivation of either one led to loss of this chemotactic phenotype. Cloning of mcpT into a plasmid complemented not only the mcpT mutants but also its transfer to other Pseudomonas conferred chemotactic response to high concentrations of toluene and other chemicals. Therefore, the phenomenon of chemotaxis towards toxic compounds at high concentrations is gene-dose dependent. In vitro experiments show that McpT is methylated by CheR and McpT net methylation was diminished in the presence of hydrocarbons, what influences chemotactic movement towards these chemicals. PMID- 21605305 TI - Trophic interactions between viruses, bacteria and nanoflagellates under various nutrient conditions and simulated climate change. AB - Population dynamics in the microbial food web are influenced by resource availability and predator/parasitism activities. Climatic changes, such as an increase in temperature and/or UV radiation, can also modify ecological systems in many ways. A series of enclosure experiments was conducted using natural microbial communities from a Mediterranean lagoon to assess the response of microbial communities to top-down control [grazing by heterotrophic nanoflagellates (HNF), viral lysis] and bottom-up control (nutrients) under various simulated climatic conditions (temperature and UV-B radiations). Different biological assemblages were obtained by separating bacteria and viruses from HNF by size fractionation which were then incubated in whirl-Pak bags exposed to an increase of 3 degrees C and 20% UV-B above the control conditions for 96 h. The assemblages were also provided with an inorganic and organic nutrient supply. The data show (i) a clear nutrient limitation of bacterial growth under all simulated climatic conditions in the absence of HNF, (ii) a great impact of HNF grazing on bacteria irrespective of the nutrient conditions and the simulated climatic conditions, (iii) a significant decrease in burst size (BS) (number of intracellular lytic viruses per bacterium) and a significant increase of VBR (virus to bacterium ratio) in the presence of HNF, and (iv) a much larger temperature effect than UV-B radiation effect on the bacterial dynamics. These results show that top-down factors, essentially HNF grazing, control the dynamics of the lagoon bacterioplankton assemblage and that short term simulated climate changes are only a secondary effect controlling microbial processes. PMID- 21605307 TI - Distinct roles of extracellular polymeric substances in Pseudomonas aeruginosa biofilm development. AB - Bacteria form surface attached biofilm communities as one of the most important survival strategies in nature. Biofilms consist of water, bacterial cells and a wide range of self-generated extracellular polymeric substances (EPS). Biofilm formation is a dynamic self-assembly process and several distinguishable stages are observed during bacterial biofilm development. Biofilm formation is shown to be coordinated by EPS production, cell migration, subpopulation differentiation and interactions. However, the ways these different factors affect each other and contribute to community structural differentiation remain largely unknown. The distinct roles of different EPS have been addressed in the present report. Both Pel and Psl polysaccharides are required for type IV pilus-independent microcolony formation in the initial stages of biofilm formation by Pseudomonas aeruginosa PAO1. Both Pel and Psl polysaccharides are also essential for subpopulation interactions and macrocolony formation in the later stages of P. aeruginosa PAO1 biofilm formation. Pel and Psl polysaccharides have different impacts on Pseudomonas quinolone signal-mediated extracellular DNA release in P. aeruginosa PAO1 biofilms. Psl polysaccharide is more important than Pel polysaccharide in P. aeruginosa PAO1 biofilm formation and antibiotic resistance. Our study thus suggests that different EPS materials play distinct roles during bacterial biofilm formation. PMID- 21605306 TI - A freshwater cyanophage whose genome indicates close relationships to photosynthetic marine cyanomyophages. AB - Bacteriophage S-CRM01 has been isolated from a freshwater strain of Synechococcus and shown to be present in the upper Klamath River valley in northern California and Oregon. The genome of this lytic T4-like phage has a 178,563 bp circular genetic map with 297 predicted protein-coding genes and 33 tRNA genes that represent all 20-amino-acid specificities. Analyses based on gene sequence and gene content indicate a close phylogenetic relationship to the 'photosynthetic' marine cyanomyophages infecting Synechococcus and Prochlorococcus. Such relatedness suggests that freshwater and marine phages can draw on a common gene pool. The genome can be considered as being comprised of three regions. Region 1 is populated predominantly with structural genes, recognized as such by homology to other T4-like phages and by identification in a proteomic analysis of purified virions. Region 2 contains most of the genes with roles in replication, recombination, nucleotide metabolism and regulation of gene expression, as well as 5 of the 6 signature genes of the photosynthetic cyanomyophages (hli03, hsp20, mazG, phoH and psbA; cobS is present in Region 3). Much of Regions 1 and 2 are syntenic with marine cyanomyophage genomes, except that a segment encompassing Region 2 is inverted. Region 3 contains a high proportion (85%) of genes that are unique to S-CRM01, as well as most of the tRNA genes. Regions 1 and 2 contain many predicted late promoters, with a combination of CTAAATA and ATAAATA core sequences. Two predicted genes that are unusual in phage genomes are homologues of cellular spoT and nusG. PMID- 21605308 TI - Methanogenesis in the sediments of Rio Tinto, an extreme acidic river. AB - Rio Tinto (Iberian Pyritic Belt, SW Spain) is well known for its low pH (mean pH 2.3), high redox potential (> +400 mV) and high concentration of heavy metals. In this work we describe and analyse the presence of methanogenic archaea in the extreme acidic and oxidizing environment of the Tinto basin. Methane formation was measured in microcosms inoculated with sediments from the Rio Tinto basin. Methanol, formate, volatile fatty acids and lactate stimulated the production of methane. Methane formation was associated with a decrease of redox potential and an increase in pH. Cores showed characteristic well-defined black bands in which a high acetate concentration was measured among the otherwise reddish-brown sediments with low acetate concentration. Methanosaeta concilii was detected in the black bands. In enrichment cultures, M. concilii (enriched with a complex substrate mixture), Methanobacterium bryantii (enriched with H(2)) and Methanosarcina barkeri (enriched with methanol) were identified. Our results suggest that methanogens thrive in micro-niches with mildly acidic and reducing conditions within Rio Tinto sediments, which are, in contrast, immersed in an otherwise extremely acidic and oxidizing environment. PMID- 21605309 TI - Isolation of obligately alkaliphilic magnetotactic bacteria from extremely alkaline environments. AB - Large numbers of magnetotactic bacteria were discovered in mud and water samples collected from a number of highly alkaline aquatic environments with pH values of ~ 9.5. These bacteria were helical in morphology and biomineralized chains of bullet-shaped crystals of magnetite and were present in all the highly alkaline sites sampled. Three strains from different sites were isolated and cultured and grew optimally at pH 9.0-9.5 but not at 8.0 and below, demonstrating that these organisms truly require highly alkaline conditions and are not simply surviving/growing in neutral pH micro-niches in their natural habitats. All strains grew anaerobically through the reduction of sulfate as a terminal electron acceptor and phylogenetic analysis, based on 16S rRNA gene sequences, as well as some physiological features, showed that they could represent strains of Desulfonatronum thiodismutans, a known alkaliphilic bacterium that does not biomineralize magnetosomes. Our results show that some magnetotactic bacteria can be considered extremophilic and greatly extend the known ecology of magnetotactic bacteria and the conditions under which they can biomineralize magnetite. Moreover, our results show that this type of magnetotactic bacterium is common in highly alkaline environments. Our findings also greatly influence the interpretation of the presence of nanometer-sized magnetite crystals, so-called magnetofossils, in highly alkaline environments. PMID- 21605310 TI - Photosynthetic performance of phototrophic biofilms in extreme acidic environments. AB - Photosynthesis versus irradiance curves and their associated photosynthetic parameters from different phototrophic biofilms isolated from an extreme acidic environment (Rio Tinto, SW, Spain) were studied in order to relate them to their species composition and the physicochemical characteristics of their respective sampling locations. The results indicated that the biofilms are low light acclimated showing a photoinhibition model; only floating communities of filamentous algae showed a light saturation model. Thus, all the biofilms analysed showed photoinhibition over 60 umol photon m(-2) s(-1) except in the case of Zygnemopsis sp. sample, which showed a light-saturated photosynthesis model under irradiations higher that 200 umol photon m(-2) s(-1). The highest values of compensation light intensity (I(c)) were showed also by Zygnemosis sp. biofilm (c. 40 umol photon m(-2) s(-1)), followed by Euglena mutabilis and Chlorella sp. samples (c. 20 umol photon m(-2) s(-1)). The diatom sample showed the lowest I(c) values (c. 5 umol photon m(-2) s(-1)). As far as we know this is the first attempt to determine the photosynthetic activity of low pH and heavy metal tolerant phototrophic biofilms, which may give light in the understanding of the ecological importance of these biofilms for the maintenance of the primary production of these extreme and unique ecosystems. PMID- 21605311 TI - Molecular evidence that deep-branching fungi are major fungal components in deep sea methane cold-seep sediments. AB - The motile cells of chytrids were once believed to be relics from the time before the colonization of land by fungi. However, the majority of chytrids had not been found in marine but freshwater environments. We investigated fungal diversity by a fungal-specific PCR-based analysis of environmental DNA in deep-sea methane cold-seep sediments, identifying a total of 35 phylotypes, 12 of which were early diverging fungi (basal fungi, ex 'lower fungi'). The basal fungi occupied a major portion of fungal clones. These were phylogenetically placed into a deep branching clade of fungi and the LKM11 clade that was a divergent group comprised of only environmental clones from aquatic environments. As suggested by Lara and colleagues, species of the endoparasitic genus Rozella, being recently considered of the earliest branching taxa of fungi, were nested within the LKM11 clade. In the remaining 23 phylotypes identified as the Dikarya, the majority of which were similar to those which appeared in previously deep-sea studies, but also highly novel lineages associated with Soil Clone Group I (SCGI), Entorrhiza sp. and the agaricomycetous fungi were recorded. The fungi of the Dikarya may play a role in the biodegradation of lignin and lignin-derived materials in deep-sea, because the characterized fungal species related to the frequent phylotypes within the Dikarya have been reported to possess an ability to degrade lignin. PMID- 21605313 TI - If you can differentiate your apostrophe from your elbow, should you? PMID- 21605314 TI - Genetics-genomics competencies and nursing regulation. AB - PURPOSE: The aim of this article is to explore the interaction between the integration of genetics-genomics competencies into nursing curricula and regulatory standards. By taking a global perspective of activity in this field, we aim to develop a framework that can inform strategic planning in relation to international genetics-genomics and nursing education. METHODS: We focus our exploration around a small-scale international survey on the progress, achievements, and critical success factors of 10 countries in relation to the integration of genetics-genomics into nursing education, with exemplars from three of those countries. FINDINGS: Analysis of the data generated 10 themes, each with several subthemes that play a critical role in the development of genetics-genomics in nursing education and practice. The themes were organized into three overarching themes: nursing in genetics, genetics in nursing, and recognition and support. Genetics-genomics competence is not fully integrated into nursing education at an appropriate level in any country, nor was it reflected robustly in current standards for registration and licensure. CONCLUSION: Strong leadership from the specialist genetics community plays a critical role in defining genetics-genomics competence but the engagement of nursing professionals at senior levels in both government and regulatory institutions is essential if nurses are to be active participants in the innovations offered by genomic healthcare. CLINICAL RELEVANCE: Safe and effective nursing practice must incorporate the needs of those with, at risk for, or susceptible to genetic-genomic conditions, as well as those who might benefit from the application of genomic technologies in the diagnosis and management of common conditions such as cancer and heart disease. The scope of such practice can be articulated though competence statements. Professional regulation defines the standard of competence that practicing nurses should demonstrate at initial registration and licensure. PMID- 21605315 TI - Accuracy and efficiency of novice nurse practitioners using personal digital assistants. AB - PURPOSE: To determine if using personal digital assistants (PDAs) increased accuracy and efficiency of clinical decisions made by novice nurse practitioners (NPs). DESIGN: Experimental with a repeated measures design. METHODS: The study sample included 40 novice NPs. Data were collected from December 2003 to March 2004 following a stratified random assignment of the subjects to a textbook or PDA group. Participants identified appropriate laboratory value assessments, diagnosis, and medication decisions using the assigned resources when given two randomly administered clinical scenarios. Accuracy was determined by the correct response score to each clinical question. The completion of the scenario was timed by the investigator. Length of time necessary to answer each part of the scenario determined efficiency. Data analysis included mixed design repeated measures analysis of variance. FINDINGS: There was a significant interaction and difference in accuracy in the laboratory analysis section of the case scenarios (F(1,38) = 21.256, p <= .001) in the PDA group when compared with the textbook group. There were no differences in accuracy by section. In three of six efficiency variables measured, the PDA users were significantly more efficient. CONCLUSIONS: In both laboratory values and one of the treatment sections, the PDA users were more efficient in determining an answer to the clinical questions. Accuracy of PDA users was equal to textbook users. CLINICAL RELEVANCE: The findings lend support to benefits for novice practitioners using PDAs when evaluating clinical situations, both in accessing certain correct information and doing this in a timely manner. PMID- 21605316 TI - Taiwanese nursing students' perceived knowledge and clinical comfort with genetics. AB - PURPOSE: To examine perceived knowledge and clinical comfort with genetics among Taiwanese undergraduate nursing students. Information about the integration of genetics into the nursing curriculum was also assessed. DESIGN: A descriptive, cross-sectional study. METHODS: A self-report survey designed to assess perceived knowledge and clinical comfort with genetics was distributed to 501 Taiwanese undergraduate nursing students; 434 returned the completed survey. The survey also included questions concerning the integration of genetics in the nursing curriculum. Descriptive statistics and a one-way analysis of variance were used for data analysis. FINDINGS: Perceptions of genetic knowledge differed significantly among the different levels of nursing students; juniors had the highest genetic knowledge mean scores, followed by seniors, sophomores, and freshmen. Juniors also reported receiving the greatest number of hours of genetic content in lecture. Clinical comfort with genetics did not vary significantly among the different levels of nursing students. The majority of nursing students considered lectures to be the most effective method for learning genetic information. CONCLUSIONS: Findings reinforced evidence that perceived knowledge and clinical comfort with genetics among Taiwanese undergraduate nursing students are limited. It is imperative for practicing nurses and nursing students to promote the use of genetic information and technologies as a central science in the context of health care. More effort must be made to integrate genetic content into the Taiwanese nursing school curricula. CLINICAL RELEVANCE: With the increasing pace of the genomic revolution, nursing students are required to integrate genetic information into the art of nursing practice with the goal of promoting the health of individuals, families, and communities. PMID- 21605317 TI - Behaviors and characteristics of African American and European American females that impact weight management. AB - PURPOSE: This report explores the extent to which sociodemographic and psychosocial factors could explain differences in obesity or dietary and exercise behaviors between middle-aged African American (AA) and European American (EA) women seen in primary care. We focus on "race * predictor" interactions that could explain how AA and EA women differ in ways that affect the prevalence of obesity. DESIGN: This comparative exploratory study uses data from the baseline examination of the Reasonable Eating and Activity to Change Health (REACH) trial, which included 173 AA women and 278 EA women. Inclusion criteria were membership in one of the study family medicine practices, an elevated body mass index (greater than 27 kg/m(2) ), age 40 to 69 years, and no contraindications to increased activity and dietary change. METHODS: Secondary data analyses were employed. FINDINGS: There was evidence of race differences in the level of multiple variables related to weight management but there were only three significant "race * predictor" interactions out of 48 comparisons: (a) race * physical health, with BMI as the dependent variable; (b) race * the percentage of dietary fat, with total dietary kilocalories as the dependent variable; and (c) race * median income, with exercise minutes per week as the dependent variable. CONCLUSIONS: The results support the proposition that the weight management experience of AA and EA primary care women is similar after different exposure levels are taken into account. The results contribute to the body of literature that addresses obesity management for AA and EA women in primary care settings. CLINICAL RELEVANCE: Findings illustrate the need for obesity prevention and management efforts from both multidisciplinary primary care providers and community-wide public health interventions. AA and EA women have different resources, but the same factors generally influence weight management, whether one is AA or EA. This suggests that clinical interventions and public health interventions for AA and EA women can be designed around the same principles while paying attention to relevant cultural issues. PMID- 21605318 TI - The concept of motherhood among three generations of African American women. AB - PURPOSE: To provide an understanding of the experiences of three generations of African American women in the transition to motherhood. DESIGN AND METHODS: Hermeneutic phenomenology from an Afrocentric feminist perspective is the methodological approach used in this study. Using the snowball technique, a purposive sample of 18 African American women from three generations who were mostly middle class, partnered, and educated was recruited. Individual open-ended interviews were used to identify information-rich cases that would provide an in depth understanding of the phenomenon. Generation 1 included seven women, between the ages of 65 and 83 years, who became mothers between 1950 and 1970, prior to the Civil Rights Movement. Generation 2 included five women, between the ages of 51 and 58 years, who became mothers between 1971 and 1990, after the Civil Rights Movement. There were six women in Generation 3, between the ages of 30 and 41 years, who became mothers between 1991 and 2003. FINDINGS: Three constitutive patterns and their associated themes were identified. The first pattern, It Took Me a Minute, had three themes: Finding Out, Realizing What Mothers Do, and Way Tricked! The second pattern, Preserving Our Home, had four themes: Mothering Within the isms: Racism, Classism, and Sexism, I Did the Best I Could, Mothers and Others, and Spiritual Mothers. Eat the Meat, Throw Away the Bone, the third pattern, had two themes: The Ways in Which We Learn and Someone Who Looks Like Me. CONCLUSIONS: The results of this study reveal some consistency with current descriptions of maternal identity and becoming a mother and add to our understanding of the complexities that racism, classism, and sexism play in the lives of African American mothers and their families. The data from this study also suggest that future development of theoretical frameworks and analytical tools, used to assess the effects of stress and other psychosocial factors on health, need to be grounded in a historic understanding of the African American experience and of the African influence on family and cultural knowledge. Additionally, this study demonstrated the impact that the media, both professional and mass media outlets, have in defining and perpetuating our beliefs and feelings of the "good mother-bad mother" dualism. The description of motherhood for this group of African American women illustrates that motherhood is a source of power and provides significant meaning, satisfaction, and respect within the family and the larger community. It also highlighted the communal role that "othermothers" and spiritual mothers have in facilitating the transition to motherhood and providing strong social support. CLINICAL RELEVANCE: Analysis of the stories in this study adds to the current literature on becoming a mother and Black feminist descriptions of motherhood. This study adds to our understanding of how negative portrayals of African American mothers and the lack of representation in the media perpetuate negative stereotypes of African American motherhood. The stories, told by the 18 women in this study, provide a positive description of African American motherhood. PMID- 21605319 TI - Electronic nursing documentation as a strategy to improve quality of patient care. AB - PURPOSE: Electronic health records are expected to improve the quality of care provided to hospitalized patients. For nurses, use of electronic documentation sources becomes highly relevant because this is where they obtain the majority of necessary patient information. METHODS: An integrative review of the literature examined the relationship between electronic nursing documentation and the quality of care provided to hospitalized patients. Donabedian's quality framework was used to organize empirical literature for review. RESULTS: To date, the use of electronic nursing documentation to improve patient outcomes remains unclear. CONCLUSIONS AND IMPLICATIONS: Future research should investigate the day-to-day interactions between nurses and electronic nursing documentation for the provision of quality care to hospitalized patients. CLINICAL RELEVANCE: The majority of U.S. hospital care units currently use paper-based nursing documentation to exchange patient information for quality care. However, by 2014, all U.S. hospitals are expected to use electronic nursing documentation on patient care units, with the anticipated benefit of improved quality. However, the extent to which electronic nursing documentation improves the quality of care to hospitalized patients remains unknown, in part due to the lack of effective comparisons with paper-based nursing documentation. PMID- 21605320 TI - An integrative review of expert nursing practice. AB - PURPOSE: To review relevant literature on expert practice in nursing to assess common characteristics across the breadth of nursing specialties and work settings. ORGANIZING CONSTRUCT: An integrative literature search was conducted with inclusion criteria: (a) primary studies of how clinical staff nurses develop and demonstrate expert practice; (b) subjects from variety of specialties, employment settings, and countries of origin; and (c) studies of clinical staff nurses and not nurses in advanced practice roles. METHODS: Literature published between 1996 and 2009 was reviewed using MEDLINE and the Cumulative Index of Nursing and Allied Health Literature (CINAHL) using the key words "nursing,""expert," and "practice." FINDINGS: The characteristics of expert practice as explicated across a variety of specialty areas of practice and international settings included the following: knowing the patient, intuitive knowledge, reflective practice, risk taking, and skilled know-how. Involvement and engagement of the expert nurse with her or his patients underpin these characteristics. Themes were illustrated in a star model of nursing expert practice surrounded by support and grounded in emotional involvement. CONCLUSIONS: Expert practice develops as nurses gain experience in a specialized practice setting, reflect on and learn from their experience, and develop meaningful relationships with their patients, families, and colleagues. CLINICAL RELEVANCE: The findings provide an understanding of expert nursing practice that can serve as a foundation for efforts to transfer knowledge from expert nurses to less expert nurses in all practice settings to reduce the expertise gap that is now widening. PMID- 21605321 TI - Barriers for nurses to safe medication management in nursing homes. AB - PURPOSE: This study aims to identify and compare the relevance of barriers that nurses in nursing homes experience in medication management in Belgium. DESIGN: The mixed-method study started with an expert meeting in November 2008 and was followed by a cross-sectional survey in February-March 2009, questioning 246 nurses and 270 nurse assistants in 20 nursing homes. METHODS: Twelve nurses represented nursing homes in an expert meeting and listed all barriers that might cause suboptimal medication management. Based on the results, a survey was developed in which respondents could indicate whether they were involved in a particular stage of the medication process and if yes, rate the relevance of the barriers in that stage on a continuous scale, varying from 1 =no barrier to 10 =strong barrier. Barriers scored 7 or more were defined as strong. FINDINGS: Nurses experienced a large number of barriers to safe medication management related to the nurse, organization, interdisciplinary cooperation, or to the patient and family. In preparing medication, medication administration and monitoring, being interrupted, not knowing enough on interactions, and barriers in interdisciplinary cooperation caused the most hindrance. In general, barriers in medication monitoring scored the strongest. CONCLUSIONS: In order to improve safe medication management by tailored interventions in nursing homes, through the use of a standard questionnaire, nurses and nurse assistants can give an overview of barriers they experience and rate their relevance. Nurses and nurse assistants had different opinions on the relevance of barriers, especially in the stage of medication monitoring. Job expectations in medication management were not always clear, creating additional barriers in medication safety. CLINICAL RELEVANCE: This study provides an overview of potential barriers to safe medication management in nursing homes, which can be addressed in practice. The relevance scoring of the barriers enables prioritization. PMID- 21605322 TI - Hospital nurses' perceptions of the geriatric care environment in one Canadian health care region. AB - PURPOSE: To identify and compare perceptions of the geriatric care environment among nurses in three different urban hospital types in one health authority in a Midwestern Canadian province. DESIGN: The Geriatric Institutional Assessment Profile developed by the Nurses Improving Healthsystem Elders (NICHE) program was administered to staff in eight urban hospitals between 2005 and 2006: two geriatric-chronic care hospitals, four community hospitals, and two tertiary hospitals. The study focused on 1,189 nurses who completed the survey (n= 298 for geriatric-chronic care hospitals; n= 387 for community hospitals, n= 504 for tertiary hospitals). METHODS: Analyses focused on items related to the concept of the geriatric nursing practice environment, including a composite measure of overall perceptions and three subscales (institutional values regarding older adults and staff, resource availability, and capacity for collaboration). Nurses' perceptions of the extent to which facilities supported the provision of aging sensitive or aging-relevant care to older adults and their families was also examined. Univariate analysis of variance was performed to determine significant group differences among nurses in the three hospital types. FINDINGS: Perceptions of the geriatric nurse practice environment (both in terms of the composite scale and the three subscales) were least positive among nurses in community hospitals relative to the other two hospital types. Perceptions in tertiary hospitals were significantly more positive than those in community hospitals in terms of institutional values and resource availability, albeit not capacity for collaboration. Perceptions were most positive in the geriatric-chronic care hospitals. Perceptions of aging-sensitive care delivery were also less positive in community and tertiary hospitals, relative to geriatric-chronic care hospitals; perceptions in community and tertiary hospitals did not differ from each other. CONCLUSIONS: In this Canadian study, nurses' perception of the care environment varied by hospital type, with nurses in community hospitals expressing the most concern and nurses in geriatric-chronic care hospitals being the most positive. This research highlights the importance of the hospital setting in understanding nurses' ability to provide quality geriatric care. CLINICAL RELEVANCE: Enhancing the quality of care for older patients requires an understanding of the challenges and obstacles experienced by nurses. Assessing their perceptions of the care environment they work in, therefore, becomes a key issue in targeting policy and programs. PMID- 21605323 TI - Nurse specialty certification, inpatient mortality, and failure to rescue. AB - PURPOSE: To determine if hospital proportion of staff nurses with specialty certification is associated with risk-adjusted inpatient 30-day mortality and failure to rescue (deaths in surgical inpatients following a major complication). DESIGN: Secondary analysis of risk-adjusted adult general, orthopedic, and vascular surgical inpatients discharged during 2005-2006 (n= 1,283,241) from 652 nonfederal hospitals controlling for state, hospital, patient, and nursing characteristics by linking outcomes, administrative, and nurse survey data (n= 28,598). METHOD: Nurse data, categorized by education and certification status, were aggregated to the hospital level. Logistic regression models were used to estimate effects of specialty certification and other nursing characteristics on mortality and failure to rescue. FINDINGS: Hospital proportion of baccalaureate and certified baccalaureate staff nurses were associated with mortality and failure to rescue; no effect of specialization was seen in the absence of baccalaureate education. A 10% increase in hospital proportion of baccalaureate and certified baccalaureate staff nurses, respectively, decreased the odds of adjusted inpatient 30-day mortality by 6% and 2%; results for failure to rescue were identical. CONCLUSIONS: Nurse specialty certification is associated with better patient outcomes; effect on mortality and failure to rescue in general surgery patients is contingent upon baccalaureate education. CLINICAL RELEVANCE: Investment in a baccalaureate-educated workforce and specialty certification has the potential to improve the quality of care. PMID- 21605324 TI - Nurse practitioner certification and practice settings: implications for education and practice. AB - PURPOSE: Nurse Practitioners (NPs) are certified within a population-focused specialty area, practice in a variety of settings, and treat a wide range of patients. Little is known about what agreement exists between certification obtained and actual site of practice. The purpose of this study was to examine NP practice sites as compared with their certification and examine additional education they received after employment. DESIGN: Adult (ANP), family (FNP), and acute care nurse practitioners (ACNPs) certified by the American Nurses Credentialing Center were surveyed regarding certification, demographic information, practice setting, routine responsibilities, and additional training they may have obtained. METHODS: An expert panel defined categories of traditional practice settings consistent with NP credentialing examinations and scopes of practice. Equal numbers of randomly chosen ANPs, ACNPs, and FNPs (N = 2,000) were mailed surveys. Responses were coded and analyzed. FINDINGS: The overall survey response was 69.8% (n= 1216). Of the FNP, ANP, and ACNP respondents, 5%, 7%, and 42%, respectively, reported practicing in a nontraditional practice setting. Of nurses practicing in a nontraditional setting, 74% (135 of 182) were ACNPs, with 90% practicing in a nontraditional, ambulatory care setting. Sixty-five percent (13 of 20) of the FNPs practicing in a nontraditional setting were practicing in a high-acuity emergency department, and 56% (15 of 27) of the ANPs practicing in a nontraditional setting were practicing in a high-acuity intensive care unit. The top responses of additional education received were pharmacology, laboratory interpretation, and ordering diagnostic tests. CONCLUSIONS: While greater than 90% of ANPs and FNPs practice in settings consistent with their certification, a proportion of NPs practice in nontraditional settings and may benefit from additional education (formal, on-the job, and continuing education) and mentoring. PMID- 21605325 TI - Workplace violence against nursing students and nurses: an Italian experience. AB - BACKGROUND: Nurses and nursing students are exposed to workplace violence. OBJECTIVES: To compare the characteristics and effects of violence in nursing students and nurses in order to assess the phenomenon and take preventive action. METHODS: A retrospective survey was conducted in three Italian university schools of nursing. At the end of a lecture, 346 of 349 students agreed to fill out a questionnaire that included domains on violence, mental health, job stress, and organizational justice. This group was compared with 275 nurses from a general hospital (94.2% participation rate). RESULTS: The prevalence of subjects reporting at least one upsetting episode of physical or verbal violence during their lifetime activity in clinical settings was 43% in nurses and 34% in nursing students. Nurses reported more physical assaults (odds ratio [OR] 2.89, 95% confidence interval [CI] 1.35-6.18), threats (OR 2.84, 95% CI 1.39-5.79), and sexual harassment (OR 2.3, 95% CI 1.15-5.54) during the previous 12 months than students. Nurses were mostly assaulted or harassed by patients or their relatives and friends ("external" violence), whereas students often reported verbal and also physical violence on the part of colleagues, staff, and others, including teachers, doctors, and supervisors ("internal" violence). Verbal violence was associated with high levels of psychological problems, as measured by the 12-item version of the General Health Questionnaire, in both students and nurses. Verbal violence was also associated with high job strain, low social support, and low organizational justice, but only among nursing students. CONCLUSIONS: Preventive action is urgently needed to control patient-to-worker and worker-to-worker violence in clinical settings. CLINICAL RELEVANCE: Not only nurses, but also nursing students, would benefit from multilevel programs of violence prevention. PMID- 21605326 TI - Management of mass casualty events: the Israeli experience. AB - PURPOSE: Among all the emergency scenarios, the most common medical emergency event in Israel is the conventional mass casualty event (MCE). This article describes the Israeli model of emergency preparedness and management at the national level, step-by-step emergency management at the hospital level, and nursing roles in emergency events. SETTING: Israel has a unique national and local model of organizing and managing an emergency event, characterized by a central national organization that is responsible for emergency policy, management, coordination, quality control, and ongoing improvement. CONCLUSIONS: Well-planned emergency preparedness training for a multidisciplinary staff is crucial. Nurses play significant roles both clinically and managerially in leading and organizing emergency events on all levels. CLINICAL RELEVANCE: Lessons gained from the special model of management of MCEs in Israel, particularly regarding unique nursing roles, may be considered for applicability in other countries. PMID- 21605327 TI - The AVAIL ME Extension: a multinational Middle Eastern survey of venous thromboembolism risk and prophylaxis. AB - BACKGROUND: Venous thromboembolism (VTE) is a major worldwide problem. OBJECTIVES: The primary objectives of this survey were to identify patients at risk for VTE, to define the rate of patients receiving appropriate VTE prophylaxis and to examine the frequency of the presence of guidelines and their application. PATIENTS AND METHODS: Ten countries, 101 hospitals and a total of 4983 patients were included in this multinational cross-sectional survey. Standardized case report forms were filled out by trained individuals on one predefined day. Risks were categorized according to the Caprini Risk Assessment Model. Logistic regressions were carried out to assess factors that determined VTE prophylaxis. RESULTS: Of 4983 patients, 3368 (68%) and 1615 (32%) were surgical and medical, respectively. Seven hundred and seventy-two (15.5%) were considered to be at low risk, 1001 (20%) at moderate risk, 1289 (26%) at high risk and 1921 (38.5%) at very high risk for VTE. Of 3575 (72%) patients who were eligible to receive VTE prophylaxis, 2747 (77%) received any drug prophylaxis. Among these patients 720/1056 (68%) and 2027/2519 (80%) were medical and surgical patients, respectively. The overall compliance with ACCP guidelines was 38%, being 24% for medical patients and 44% for surgical patients. CONCLUSIONS: The results of this large multinational survey, although indicating overall improvement in VTE prophylaxis, identify a considerable number of patients who either did not receive any VTE prophylaxis or received it inappropriately. Although more medical patients were at risk for VTE, they were given prophylaxis less frequently than surgical patients. Concordance with VTE prophylaxis guidelines was higher in surgical patients, but overall application of these tools was unacceptably low. PMID- 21605328 TI - Epigenetic, polymorphic and mutational (Alphaalpha167Arg->Lys) contribution to a functionally abnormal fibrinogen. PMID- 21605330 TI - Thrombin-inhibiting perfluorocarbon nanoparticles provide a novel strategy for the treatment and magnetic resonance imaging of acute thrombosis. AB - BACKGROUND: As a regulator of the penultimate step in the coagulation cascade, thrombin represents a principal target of direct and specific anticoagulants. OBJECTIVE: A potent thrombin inhibitor complexed with a colloidal nanoparticle was devised as a first-in-class anticoagulant with prolonged and highly localized therapeutic impact conferred by its multivalent thrombin-absorbing particle surface. METHODS: PPACK (Phe[D]-Pro-Arg-Chloromethylketone) was secured covalently to the surface of perfluorocarbon-core nanoparticle structures. PPACK and PPACK nanoparticle inhibition of thrombin were assessed in vitro via thrombin activity against a chromogenic substrate. In vivo antithrombotic activity of PPACK, heparin, non-functionalized nanoparticles and PPACK nanoparticles was assessed through intravenous (i.v.) administration prior to acute photochemical injury of the common carotid artery. Perfluorocarbon particle retention in extracted carotid arteries from injured mice was assessed via (19) F magnetic resonance spectroscopy (MRS) and imaging (MRI) at 11.7 T. Activated partial thromboplastin time (APTT) measurements determined the systemic effects of the PPACK nanoparticles at various times after injection. RESULTS: An optical assay verified that PPACK nanoparticles exceeded PPACK's intrinsic activity against thrombin. Application of an in vivo acute arterial thrombosis model demonstrated that PPACK nanoparticles outperformed both heparin (P=0.001) and uncomplexed PPACK (P = 0.0006) in inhibiting thrombosis. (19) F MRS confirmed that PPACK nanoparticles specifically bound to sites of acute thrombotic injury. APTT normalized within 20 min of PPACK nanoparticles injection. CONCLUSIONS: PPACK nanoparticles present thrombin-inhibiting surfaces at sites of acutely forming thrombi that continue to manifest local clot inhibition even as systemic effects rapidly diminish and thus represent a new platform for localized control of acute thrombosis. PMID- 21605331 TI - Acute respiratory tract infection leads to procoagulant changes in human subjects. PMID- 21605332 TI - G-protein coupled and ITAM receptor regulation of the formin FHOD1 through Rho kinase in platelets. PMID- 21605333 TI - Thrombin generation assay using factor IXa as a trigger to quantify accurately factor VIII levels in haemophilia A. AB - BACKGROUND: The available methods for measuring factor VIII (FVIII) activity suffer reportedly from lack of sensitivity and precision in the < 1 IU dL(-1) range. This precludes correlation of clinical phenotype with FVIII levels. OBJECTIVES: To study a possible association between clinical phenotype in patients with FVIII levels < 1 IU dL(-1). METHODS/RESULTS: The FIXa-driven FVIII assay (FVIII-CAT) has a detection limit of 0.05 IU dL(-1). For the range of 0-2 IU dL(-1) FVIII, the intra-assay coefficient of variation (CV) is around 2% and the inter-assay CV is about 8%. We tested 30 hemophiliacs with FVIII:C between < 1 and 6 IU dL(-1) as measured in the one-stage clotting assay using the FVIII-CAT assay. For genetic defects related to moderate hemophilia, the FVIII-CAT test finds FVIII levels that are in good agreement with those determined with the one stage assay. Of the 21 hemophilic patients with FVIII < 1 IU dL(-1), four patients exhibited a mild bleeding phenotype. When we applied TF-initiated thrombin generation, patients with a mild clinical phenotype showed significantly higher endogenous thrombin potentials. CONCLUSION: The novel developed FVIII assay measures accurately FVIII levels below 1 IU dL(-1). Its application demonstrated that the clinical heterogeneity in individuals with < 1 IU dL(-1) FVIII is not associated with their FVIII level. PMID- 21605334 TI - Statins prevent tissue factor induction by protease-activated receptors 1 and 2 in human umbilical vein endothelial cells in vitro. AB - BACKGROUND: Protease-activated receptors (PARs) are G-protein-coupled receptors that function in hemostasis and thrombosis, as well as in the inflammatory and proliferative responses triggered by tissue injury. We have previously shown that PAR1 or PAR2 occupancy by specific PAR-agonist peptides (PAR-APs) induces tissue factor (TF) expression in human umbilical vein endothelial cells (HUVECs), where TF regulation by PAR1 (but not by PAR2) requires intact endothelial caveolin enriched membrane microdomains in which PAR1 and caveolin-1 associate. OBJECTIVES: The aim of this study was to determine the effects of cholesterol lowering agents (statins) and cholesterol-loading lipoprotein on PAR1-AP-mediated and PAR2-AP-mediated TF induction in HUVECs. RESULTS: Statins completely prevented TF induction by PAR-APs in an isoprenoid-independent manner, induced the delocalization of PAR1 from caveolin-enriched membrane microdomains without affecting PAR1 mRNA, and decreased PAR2 mRNA and protein levels. Statins also prevented PAR-AP-mediated extracellular signal-related kinase 1/2 activation, which is crucial for TF induction. The redistribution of PAR1 is accompanied by the relocation of the membrane microdomain-associated G-protein alpha, caveolin 1, and Src, which we previously showed to play a key role in signal transduction and TF induction. Conversely, cholesterol loading potently amplified PAR1-AP induced TF, probably as a result of the increased abundance of PAR1 and the Src and G-protein alpha signaling molecules in the caveolin-1-enriched fraction, without affecting PAR1 mRNA. CONCLUSIONS: As PARs have important functions in hemostasis, cancer, thrombosis, and inflammatory processes, our findings that statins prevent TF induction by PAR-APs altering the membrane localization of PAR1 and the expression of PAR2 suggest that they may provide health benefits other than reducing atherosclerosis. PMID- 21605336 TI - Vascular endothelial growth factor confers endothelial resistance to apoptosis through poly(ADP-ribose) polymerase. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) inhibits the endothelial apoptosis that is induced by caspases during vascular remodeling; however, the underlying mechanisms have not been completely elucidated. OBJECTIVES: We hypothesized that VEGF upregulates poly(ADP-ribose) polymerase-1 (PARP) as a caspase mediator, and sought to investigate the link between apoptosis inhibition by VEGF and PARP regulation in the human vasculature. METHODS: Human endothelial cells (primary cells, macrovascular/microvascular lines) were incubated with 100 pg mL(-1) to 1 MUg mL(-1) VEGF-A(165) in the absence or presence of PARP small interfering RNA (siRNA). Apoptosis induced by integrin inhibition was measured by flow cytometry, trypan blue exclusion, and nuclear morphology. PARP expression and activity were determined by real-time RT-PCR, Western blot, and ribosylation assay. VEGF receptors and signal transduction were analyzed by inhibitor experiments, enzyme assays, western blot, and immunofluorescence microscopy. Immunohistochemistry was applied to a vascular culture model and to 24 atherosclerotic and 10 normal human arteries. RESULTS: VEGF-A(165) induced resistance to apoptosis caused by caspase activation in endothelial cells in a time-dependent manner. VEGF, but not fibroblast growth factor-2 or transforming growth factor-beta, time-dependently and dose-dependently induced PARP expression and activity, involving VEGF receptor-2 colocalized with neuropilin-1 as well as the signal transduction molecules c-Jun N-terminal kinase and Akt. The antiapoptotic effect of VEGF was abrogated by PARP siRNA. The relationship between local VEGF influence and endothelial PARP expression was confirmed in human arteries and the vascular culture model. CONCLUSIONS: VEGF exerts its antiapoptotic effect on the endothelium through the regulation of PARP expression. PARP has been attributed an ambiguous role in apoptosis; here, we show that PARP promotes vascular endothelial integrity in VEGF-associated processes. PMID- 21605335 TI - Oxidized von Willebrand factor is efficiently cleaved by serine proteases from primary granules of leukocytes: divergence from ADAMTS-13. AB - BACKGROUND: The leukocyte serine proteases (LSPs) elastase, proteinase 3 and cathepsin G cleave von Willebrand factor (VWF) near or at the same cleavage site (Tyr1605-Met1606) as ADAMTS-13, the metalloprotease that specifically controls the proteolytic processing of VWF. Recent studies have shown that oxidation of VWF at Met1606 with formation of methionine sulfoxide (MetSO) severely impairs its proteolysis by ADAMTS-13. METHODS: This study was aimed at assessing whether or not oxidation of VWF by reactive oxygen species (ROS) can also affect its cleavage by elastase, proteinase 3, and cathepsin G. In this study, the catalytic specificity of hydrolysis by LSPs of the VWF peptide substrate VWF74 and full length VWF, both unaltered and in the oxidized form, was measured by RP-HPLC, electrophoretic and mass spectrometry methods. RESULTS: LSPs cleaved both VWF multimers and VWF74 near or at the same peptide bond as is cleaved by ADAMTS-13, with k(cat)/K(m) values similar to those of the metalloprotease. However, unlike ADAMTS-13, cathepsin G cleaved VWF74 containing a MetSO residue at position 1606 with a k(cat)/K(m) value higher than that for VWF74, whereas the catalytic efficiencies of both elastase and proteinase 3 were unaffected by the replacement of Met1606 with MetSO. Likewise, oxidation of VWF multimers by hypochlorous acid and ROS, produced by activated leukocytes, improved their hydrolysis by LSPs. CONCLUSIONS: Oxidation by leukocyte ROS has a net positive effect on the cleavage of VWF multimers by LSPs, under conditions where high concentrations of oxidant species would severely reduce the proteolytic efficiency of ADAMTS-13. PMID- 21605337 TI - Gene-environment interactions between CRHR1 variants and physical assault in suicide attempts. AB - Risk factors for suicidal behaviors are partly heritable, including genetic variants that drive diathesis-stress in addition to, or by interaction with, exposure to certain stressful life events (SLEs). Hypothalamic-pituitary-adrenal (HPA) axis regulatory genes are candidates for association with suicide as well as its endophenotypes. Using a family-based design of offspring who attempted suicide (SA) and both parents, we investigated gene-environment interactions (G*Es) of SLE exposures with single nucleotide polymorphisms (SNPs) in corticotropin-releasing hormone receptor-1 (CRHR1), a major HPA axis regulatory gene. We observed a novel G*E among predominantly female SA between 5'-SNP rs7209436 and childhood/adolescence physical assault or attack (PA), as well as a second novel and male-specific G*E between 3'-SNP rs16940665 and adulthood PA exposure. A third male-specific G*E previously reported by us among depressed SA, between SNP rs4792887 and cumulative SLEs, was also further confirmed. The two novel G*Es presented here shared the SA characteristic of aggression, while showing differences on other aspects of SA heterogeneity. We conclude that different SA subjects were observed to differentially associate with two novel G*Es involving exposures to PA with different life timing and SNPs located in opposite ends of CRHR1. Concerning sex differences, we observed three subsets of distinct male SA that associated with each of the three observed G*Es, whereas female SAs were affected by only one of the G*Es. These results are consistent with a diathesis-stress model of suicidal behavior and may help to explain SA heterogeneity. PMID- 21605338 TI - Functional dissection of Odorant binding protein genes in Drosophila melanogaster. AB - Most organisms rely on olfaction for survival and reproduction. The olfactory system of Drosophila melanogaster is one of the best characterized chemosensory systems and serves as a prototype for understanding insect olfaction. Olfaction in Drosophila is mediated by multigene families of odorant receptors and odorant binding proteins (OBPs). Although molecular response profiles of odorant receptors have been well documented, the contributions of OBPs to olfactory behavior remain largely unknown. Here, we used RNAi-mediated suppression of Obp gene expression and measurements of behavioral responses to 16 ecologically relevant odorants to systematically dissect the functions of 17 OBPs. We quantified the effectiveness of RNAi-mediated suppression by quantitative real time polymerase chain reaction and used a proteomic liquid chromatography and tandem mass spectrometry procedure to show target-specific suppression of OBPs expressed in the antennae. Flies in which expression of a specific OBP is suppressed often show altered behavioral responses to more than one, but not all, odorants, in a sex-dependent manner. Similarly, responses to a specific odorant are frequently affected by suppression of expression of multiple, but not all, OBPs. These results show that OBPs are essential for mediating olfactory behavioral responses and suggest that OBP-dependent odorant recognition is combinatorial. PMID- 21605339 TI - In search for significant cognitive features in Klinefelter syndrome through cross-species comparison of a supernumerary X chromosome. AB - The behavioral characterization of animals that carry genetic disorder abnormalities in a controlled genetic and environmental background may be used to identify human deficits that are significant to understand underlying neurobiological mechanisms. Here, we studied whether previously reported object recognition impairments in mice with a supernumerary X chromosome relate to specific cognitive deficits in Klinefelter syndrome (47,XXY). We aimed to optimize face validity by studying temporal object recognition in human cognitive assays. Thirty-four boys with Klinefelter syndrome (mean age 12.01) were compared with 90 age-matched normal controls, on a broad range of visual object memory tasks, including tests for pattern and temporal order discrimination. The results indicate that subjects with Klinefelter syndrome have difficulty in the processing of visual object and pattern information. Visual object patterns seem difficult to discriminate especially when temporal information needs to be processed and reproduced. On the basis of cross-species comparison, we propose that impaired temporal processing of object pattern information is an important deficit in Klinefelter syndrome. The current study shows how cross-species behavioral characterization may be used as a starting point to understand the neurobiology of syndromal phenotypic expression. The features of this study may serve as markers for interventions in Klinefelter syndrome. Similar cross-species evaluations of standard mouse behavioral paradigms in different genetic contexts may be powerful tools to optimize genotype-phenotype relationships. PMID- 21605340 TI - Fine mapping of qPAA8, a gene controlling panicle apical development in rice. AB - In rice, one detrimental factor influencing single panicle yield is the frequent occurrence of panicle apical abortion (PAA) under unfavorable climatic conditions. Until now, no detailed genetic information has been available to avoid PAA in rice breeding. Here, we show that the occurrence of PAA is associated with the accumulation of excess hydrogen peroxide. Quantitative trait loci (QTLs) mapping for PAA in an F(2) population derived from the cross of L 05261 (PAA line) * IRAT129 (non-PAA variety) identified seven QTLs over a logarithm of the odd (LOD) threshold of 2.5, explaining approximately 50.1% of phenotypic variance for PAA in total. Five of the QTLs with an increased effect from L-05261, were designated as qPAA3-1, qPAA3-2, qPAA4, qPAA5 and qPAA8, and accounted for 6.8%, 5.9%, 4.2%, 13.0% and 12.2% of phenotypic variance, respectively. We found that the PAA in the early heading plants was mainly controlled by qPAA8. Subsequently, using the sub-populations specific for qPAA8 based on marker-assisted selection, we further narrowed qPAA8 to a 37.6-kb interval delimited by markers RM22475 and 8-In112. These results are beneficial for PAA gene clone. PMID- 21605341 TI - Characterization and genetic analysis of a light- and temperature-sensitive spotted-leaf mutant in rice. AB - A rice spotted-leaf mutant was isolated from an ethane methyl sulfonate (EMS) induced IR64 mutant bank. The mutant, designated as spl30 (spotted-leaf30), displayed normal green leaf color under shade but exhibited red-brown lesions under natural summer field conditions. Initiation of the lesions was induced by light and the symptom was enhanced at 33 ( degrees ) C relative to 26 ( degrees ) C. Histochemical staining did not show cell death around the red-brown lesions. Chlorophyll contents in the mutant were significantly lower than those of the wild type while the ratio of chlorophyll a/b remained the same, indicating that spl30 was impaired in biosynthesis or degradation of chlorophyll. Disease reaction patterns of the mutant to Xanthomonas oryzae pv. oryzae were largely unchanged to most races tested except for a few strains. Genetic analysis showed that the mutation was controlled by a single recessive gene, tentatively named spl30(t), which co-segregated with RM15380 on chromosome 3, and was delimited to a 94 kb region between RM15380 and RM15383. Spl30(t) is likely a novel rice spotted-leaf gene since no other similar genes have been identified near the chromosomal region. The genetic data and recombination populations provided in this study will enable further fine-mapping and cloning of the gene. PMID- 21605342 TI - Characterizing the complexity of enzymes on the basis of their mechanisms and structures with a bio-computational analysis. AB - Enzymes are basically composed of 20 naturally occurring amino acids, yet they catalyse a dizzying array of chemical reactions, with regiospecificity and stereospecificity and under physiological conditions. In this review, we attempt to gain some understanding of these complex proteins, from the chemical versatility of the catalytic toolkit, including the use of cofactors (both metal ions and organic molecules), to the complex mapping of reactions to proteins (which is rarely one-to-one), and finally the structural complexity of enzymes and their active sites, often involving multidomain or multisubunit assemblies. This work highlights how the enzymes that we see today reflect millions of years of evolution, involving de novo design followed by exquisite regulation and modulation to create optimal fitness for life. PMID- 21605343 TI - Efficient ATP synthesis by thermophilic Bacillus FoF1-ATP synthase. AB - F(o)F(1)-ATP synthase (F(o)F(1)) synthesizes ATP in the F(1) portion when protons flow through F(o) to rotate the shaft common to F(1) and F(o). Rotary synthesis in isolated F(1) alone has been shown by applying external torque to F(1) of thermophilic origin. Proton-driven ATP synthesis by thermophilic Bacillus PS3 F(o)F(1) (TF(o)F(1)), however, has so far been poor in vitro, of the order of 1 s(-1) or less, hampering reliable characterization. Here, by using a mutant TF(o)F(1) lacking an inhibitory segment of the epsilon-subunit, we have developed highly reproducible, simple procedures for the preparation of active proteoliposomes and for kinetic analysis of ATP synthesis, which was driven by acid-base transition and K(+)-diffusion potential. The synthesis activity reached ~ 16 s(-1) at 30 degrees C with a Q(10) temperature coefficient of 3-4 between 10 and 30 degrees C, suggesting a high level of activity at the physiological temperature of ~ 60 degrees C. The Michaelis-Menten constants for the substrates ADP and inorganic phosphate were 13 MUM and 0.55 mM, respectively, which are an order of magnitude lower than previous estimates and are suited to efficient ATP synthesis. PMID- 21605344 TI - Comparison of the changes in sexual function of premenopausal and postmenopausal women following transvaginal mesh surgery. AB - INTRODUCTION: The effect of transvaginal mesh (TVM) surgery on sexual function between premenopausal and postmenopausal women remains controversial. AIM: To compare the changes in sexual function of premenopausal and postmenopausal women following TVM repair. METHODS: One hundred and fifty-two consecutive women with symptomatic pelvic organ prolapse (POP) stages II to IV were referred for TVM procedures at our hospitals. Sixty-eight women were included because they were sexually active and had complete follow-up. All subjects were divided into the premenopausal (N = 36) and postmenopausal (N = 32) groups. Preoperative and postoperative assessments included pelvic examination using the POP quantification (POP-Q) system and a personal interview with the Female Sexual Function Index (FSFI), Urogenital Distress Inventory (UDI-6), and Incontinence Impact Questionnaire (IIQ-7). MAIN OUTCOME MEASURES: The FSFI, UDI-6, and IIQ-7 questionnaires. RESULTS: The mean age, rates of hypertension, and previous hysterectomy were significantly higher in the postmenopausal group (P < 0.05) compared with the premenopausal group. As for the POP-Q analysis, there was a significant improvement at points Aa, Ba, C, Ap, and Bp (P < 0.001) in both groups except for total vaginal length (P > 0.05). Similarly, the UDI-6 and IIQ-7 scores significantly decreased postoperatively (P < 0.01). After POP surgery, the score of the dyspareunia domain decreased significantly in the premenopausal group (P < 0.01) but was not the case for the postmenopausal group (P > 0.05). There were no significant changes in other domains and total scores in both groups (P > 0.05). However, higher rates of worsening dyspareunia and total scores were noted in the premenopausal group (P = 0.03 vs. 0.033). CONCLUSION: TVM procedure is effective for the anatomical restoration of POP. However, individual domain of FSFI such as dyspareunia may worsen in the premenopausal women. Additionally, our results revealed that over one third of premenopausal women could have a worsening sexuality domain postoperatively, with significantly higher rate of deteriorated dyspareunia and total FSFI scores than postmenopausal women. PMID- 21605345 TI - Insights into the structural requirements of PKCbetaII inhibitors based on HQSAR and CoMSIA analyses. AB - Diabetic cardiomyopathy is a clinical condition diagnosed when ventricular dysfunction develops in patients with diabetes devoid of coronary atherosclerosis and hypertension. The selective inhibition of PKCbetaII represents an effective approach for treating microvascular complications. HQSAR and CoMSIA studies were performed on a data set of 43 maleimide-based molecules acting as potent inhibitors of PKCbetaII. HQSAR model yielded an of 0.98 and a cross-validated of 0.85, while CoMSIA modeling of these same data generated an of 0.98 and a cross validated of 0.85. Both the models show good predictive power having for HQSAR and CoMSIA as 0.63 and 0.75, respectively, indicating the reliability of models. The analysis shows that the terminal substitution with electronegative atom at indole or azaindole ring is essential for PKCbetaII inhibition, while substitution of bulkier group in linker connecting two heteroaryl rings diminishes the activity. This study is presumably helpful in designing new potent molecules as PKCbetaII inhibitors in fighting against various diseases related to PKCbetaII. PMID- 21605346 TI - Increased numbers of circulating ECs are associated with systemic GVHD. AB - INTRODUCTION: Circulating endothelial cells (ECs) are known to reflect endothelial injury, and endothelial injury is associated with graft-versus-host disease (GVHD). We hypothesised that circulating ECs might be associated with systemic acute graft-versus-host disease (aGVHD). METHODS: BALB/c (H-2k(d) ) mice were treated with total body irradiation and then infused with C57B/6-derived T cell-depleted bone marrow (TCD-BM) cells or TCD-BM cells and splenocytes. Cyclosporine was used to prevent aGVHD. Circulating ECs and allogeneic lymphocytes were analysed by flow cytometry at multiple time points. The morphology and ultrastructure of the endothelium were examined by light microscopy or transmission electron microscopy. RESULTS: The results indicated that the number of circulating ECs peaked at day 5 after lethal irradiation in all mice; allogenic transplanted mice (TCD-BM cells and splenocytes) developed typical aGVHD beginning at day 7, exhibiting both histological and clinical symptoms of disease. Circulating ECs peaked a second time at day 9 with aGVHD progression. However, following the administration of CSA, an absence of or a reduction in the amount of subsequent endothelial injury was observed. CONCLUSION: Circulating ECs might be associated with systemic aGVHD. PMID- 21605347 TI - The presence of bluetongue virus serotype 8 RNA in Belgian cattle since 2008. AB - After a short winter break, bluetongue virus serotype 8 was responsible in 2007 for a large-scale epidemic among ruminant populations in Western Europe. Little is known about the mechanisms allowing the virus to survive winter conditions. A yearly mass vaccination of cattle and sheep started in spring 2008, which was recognized as successful in terms of clinical protection, but occult circulation of the bluetongue virus has not been adequately addressed. We studied the carriage of bluetongue RNA in the spleen of cattle in the vector-free period and the circulation of bluetongue virus in cattle populations in Belgium since the introduction of vaccination programmes. Overall, the results presented here show evidence for the long-term carriage of bluetongue virus RNA in the spleen of cattle and demonstrated a low but significant circulation and transplacental transmission of bluetongue virus in Belgian cattle in 2009, with apparent disappearance in 2010. PMID- 21605348 TI - Modeling the asymmetric evolution of a mouse and rat-specific microRNA gene cluster intron 10 of the Sfmbt2 gene. AB - BACKGROUND: The total number of miRNA genes in a genome, expression of which is responsible for the miRNA repertoire of an organism, is not precisely known. Moreover, the question of how new miRNA genes arise during evolution is incompletely understood. Recent data in humans and opossum indicate that retrotranspons of the class of short interspersed nuclear elements have contributed to the growth of microRNA gene clusters. METHOD: We studied a large miRNA gene cluster in intron 10 of the mouse Sfmbt2 gene using bioinformatic tools. RESULTS: Mice and rats are unique to harbor a 55-65 Kb DNA sequence in intron 10 of the Sfmbt2 gene. This intronic region is rich in regularly repeated B1 retrotransposons together with inverted self-complementary CA/TG microsatellites. The smallest repeats unit, called MSHORT1 in the mouse, was duplicated 9 times in a tandem head-to-tail array to form 2.5 Kb MLONG1 units. The center of the mouse miRNA gene cluster consists of 13 copies of MLONG1. BLAST analysis of MSHORT1 in the mouse shows that the repeat unit is unique for intron 10 of the Sfmbt2 gene and suggest a dual phase model for growth of the miRNA gene cluster:arrangement [corrected] of 10 MSHORT1 units into MLONG1 and further duplication of 13 head-to-tail MLONG1 units in the center of the miRNA gene cluster. Rats have a similar arrangement [corrected] of repeat units in intron 10 of the Sfmbt2 gene. The discrepancy between 65 miRNA genes in the mouse cluster as compared to only 1 miRNA gene in the corresponding rat repeat cluster is ascribed to sequence differences between MSHORT1 and RSHORT1 that result in lateral-shifted, less-stable miRNA precursor hairpins for RSHORT1. CONCLUSION: Our data provides new evidence for the emerging concept that lineage-specific retroposons have played an important role in the birth of new miRNA genes during evolution. The large difference in the number of miRNA genes in two closely related species (65 versus 1, mice versus rats) indicates that this species specific evolution can be a rapid process. PMID- 21605349 TI - The existence of an insulin-stimulated glucose and non-essential but not essential amino acid substrate interaction in diabetic pigs. AB - BACKGROUND: The generation of energy from glucose is impaired in diabetes and can be compensated by other substrates like fatty acids (Randle cycle). Little information is available on amino acids (AA) as alternative energy-source in diabetes. To study the interaction between insulin-stimulated glucose and AA utilization in normal and diabetic subjects, intraportal hyperinsulinaemic euglycaemic euaminoacidaemic clamp studies were performed in normal (n=8) and streptozotocin (120 mg/kg) induced diabetic (n=7) pigs of ~40-45 kg. RESULTS: Diabetic vs normal pigs showed basal hyperglycaemia (19.0+/-2.0 vs 4.7+/-0.1 mmol/L, P<.001) and at the level of individual AA, basal concentrations of valine and histidine were increased (P<.05) whereas tyrosine, alanine, asparagine, glutamine, glutamate, glycine and serine were decreased (P<.05). During the clamp, diabetic vs normal pigs showed reduced insulin-stimulated glucose clearance (4.4+/-1.6 vs 16.0+/-3.0 mL/kg.min, P<.001) but increased AA clearance (166+/-22 vs 110+/-13 mL/kg. min, P<.05) at matched arterial euglycaemia (5-7 mmol/L) and euaminoacidaemia (2.8-3.5 mmol/L). The increase in AA clearance was mainly caused by an increase in non-essential AA clearance (93.6+/-13.8 vs 46.6+/ 5.4 mL/kg.min, P<.01), in particular alanine (14.2+/-2.4 vs 3.2+/-0.4 mL/kg.min, P<.001). Essential AA clearance was largely unchanged (72.9+/-8.5 vs 63.3+/-8.5 mL/kg. min), however clearances of threonine (P<.05) and tyrosine (P<.01) were increased in diabetic vs normal pigs (8.1+/-1.3 vs 5.2+/-0.5, and 14.3+/-2.5 vs 6.4+/-0.7 mL/kg. min, respectively). CONCLUSIONS: The ratio of insulin-stimulated glucose versus AA clearance was decreased 5.4-fold in diabetic pigs, which was caused by a 3.6-fold decrease in glucose clearance and a 2.0-fold increase in non essential AA clearance. In parallel with the Randle concept (glucose-fatty acid cycle), the present data suggest the existence of a glucose and non-essential AA substrate interaction in diabetic pigs whereby reduced insulin-stimulated glucose clearance seems to be partly compensated by an increase in non-essential AA clearance whereas essential AA are preferentially spared from an increase in clearance. PMID- 21605350 TI - Underestimation of weight and its associated factors among overweight and obese adults in Pakistan: a cross sectional study. AB - BACKGROUND: Weight loss is known to decrease the health risks associated with being overweight and obese. Awareness of overweight status is an important determinant of weight loss attempts and may have more of an impact on one's decision to lose weight than objective weight status. We therefore investigated the perception of weight among adults attending primary care clinics in Karachi, Pakistan, and compared it to their weight categories based on BMI (Body Mass Index), focusing on the underestimation of weight in overweight and obese individuals. We also explored the factors associated with underestimation of weight in these individuals. METHODS: This was a cross sectional study conducted on 493 adults presenting to the three primary care clinics affiliated with a tertiary care hospital in Karachi, Pakistan. We conducted face to face interviews to gather data on a pre-coded questionnaire. The questionnaire included detail on demographics, presence of comorbid conditions, and questions regarding weight assessment. We measured height and weight of the participants and calculated the BMI. The BMI was categorized into normal weight, overweight and obese based on the revised definitions for Asian populations. Perception about weight was determined by asking the study participants the following question: Do you consider yourself to be a) thin b) just right c) overweight d) obese. We compared the responses with the categorized BMI. To identify factors associated with underestimation of weight, we used simple and multiple logistic regression to calculate crude odds Ratios (OR) and adjusted Odds Ratios (AOR) with 95% Confidence Intervals. RESULTS: Overall 45.8% (n = 226) of the study participants were obese and 18% (n = 89) were overweight. There was poor agreement between self perception and actual BMI (Kappa = 0.24, SE = 0.027, p < 0.001). Among obese participants a large proportion (73%) did not perceive themselves as obese, although half (n = 102) of them thought they may be overweight. Among the overweight participants, half (n = 41) of them didn't recognize themselves as overweight. Factors associated with misperception of weight in overweight and obese participants were age >= 40 years (AOR = 3.4; 95% CI: 1.8-6.4), male gender (AOR = 2.97; 95% CI: 1.6-5.5), being happy with ones' weight (AOR = 6.4; 95% CI: 3.4-12.1), and not knowing one's ideal weight (AOR = 2.45, 95% CI: 1.10-5.47). CONCLUSION: In this cross sectional survey, we observed marked discordance between the actual and perceived weight. Underestimation of individual weight was more common in older participants (>= 40 years), men, participants happy with their weight and participants not aware of their ideal weight. Accurate perception of one's actual weight is critical for individuals to be receptive to public health messages about weight maintenance or weight loss goals. Therefore educating people about their correct weight, healthy weights and prevention of weight gain are important steps towards addressing the issue of obesity in Pakistan. PMID- 21605351 TI - The complete linkage disequilibrium test: a test that points to causative mutations underlying quantitative traits. AB - BACKGROUND: Genetically, SNP that are in complete linkage disequilibrium with the causative SNP cannot be distinguished from the causative SNP. The Complete Linkage Disequilibrium (CLD) test presented here tests whether a SNP is in complete LD with the causative mutation or not. The performance of the CLD test is evaluated in 1000 simulated datasets. METHODS: The CLD test consists of two steps i.e. analysis I and analysis II. Analysis I consists of an association analysis of the investigated region. The log-likelihood values from analysis I are next ranked in descending order and in analysis II the CLD test evaluates differences in log-likelihood ratios between the best and second best markers. Under the null-hypothesis distribution, the best SNP is in greater LD with the QTL than the second best, while under the alternative-CLD-hypothesis, the best SNP is alike-in-state with the QTL. To find a significance threshold, the test was also performed on data excluding the causative SNP. The 5th, 10th and 50th highest TCLD value from 1000 replicated analyses were used to control the type-I error rate of the test at p = 0.005, p = 0.01 and p = 0.05, respectively. RESULTS: In a situation where the QTL explained 48% of the phenotypic variance analysis I detected a QTL in 994 replicates (p = 0.001), where 972 were positioned in the correct QTL position. When the causative SNP was excluded from the analysis, 714 replicates detected evidence of a QTL (p = 0.001). In analysis II, the CLD test confirmed 280 causative SNP from 1000 simulations (p = 0.05), i.e. power was 28%. When the effect of the QTL was reduced by doubling the error variance, the power of the test reduced relatively little to 23%. When sequence data were used, the power of the test reduced to 16%. All SNP that were confirmed by the CLD test were positioned in the correct QTL position. CONCLUSIONS: The CLD test can provide evidence for a causative SNP, but its power may be low in situations with closely linked markers. In such situations, also functional evidence will be needed to definitely conclude whether the SNP is causative or not. PMID- 21605352 TI - The effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle-closure glaucoma (EAGLE): study protocol for a randomized controlled trial. AB - BACKGROUND: Glaucoma is the leading cause of irreversible blindness. Although primary open-angle glaucoma is more common, primary angle-closure glaucoma (PACG) is more likely to result in irreversible blindness. By 2020, 5.3 million people worldwide will be blind because of PACG. The current standard care for PACG is a stepped approach of a combination of laser iridotomy surgery (to open the drainage angle) and medical treatment (to reduce intraocular pressure). If these treatments fail, glaucoma surgery (eg, trabeculectomy) is indicated. It has been proposed that, because the lens of the eye plays a major role in the mechanisms leading to PACG, early clear lens extraction will improve glaucoma control by opening the drainage angle. This procedure might reduce the need for drugs and glaucoma surgery, maintain good visual acuity, and improve quality of life compared with standard care.EAGLE aims to evaluate whether early lens extraction improves patient-reported, clinical outcomes, and cost-effectiveness, compared with standard care. METHODS/DESIGN: EAGLE is a multicentre pragmatic randomized trial. All people presenting to the recruitment centres in the UK and east Asia with newly diagnosed PACG and who are at least 50 years old are eligible.The primary outcomes are EQ-5D, intraocular pressure, and incremental cost per quality adjusted life year (QALY) gained. Other outcomes are: vision and glaucoma specific patient-reported outcomes, visual acuity, visual field, angle closure, number of medications, additional surgery (e.g., trabeculectomy), costs to the health services and patients, and adverse events.A single main analysis will be done at the end of the trial, after three years of follow-up. The analysis will be based on all participants as randomized (intention to treat). 400 participants (200 in each group) will be recruited, to have 90% power at 5% significance level to detect a difference in EQ-5D score between the two groups of 0.05, and a mean difference in intraocular pressure of 1.75 mm Hg. The study will have 80% power to detect a difference of 15% in the glaucoma surgery rate. TRIAL REGISTRATION: ISRCTN44464607. PMID- 21605353 TI - Helping boys at-risk of criminal activity: qualitative results of a multi component intervention. AB - BACKGROUND: This qualitative study examines parent and child experiences of participation in a multi-component community-based program aimed at reducing offending behaviour, and increasing social competence in boys 6 to 11 years old in Hamilton, Ontario, Canada. The program builds on the concept of crime prevention through social development, and includes structured groups for the identified boy, parents, and siblings. METHODS: A sample of 35 families participating in the multi-component program took part in the qualitative study. Individual interviews with the boys, parents and siblings asked about changes in themselves, relationships with family and peers, and school after the group. Interviews were taped, transcribed and content analysis was used to code and interpret the data. RESULTS: Parents reported improvement in parenting skills and attainment of more effective communication skills, particularly with their children. Parents also found the relationships they formed with other parents in the program and the advice that they gained to be beneficial. Boys who participated in the program also benefited, with both parents and boys reporting improvements in boys' anger management skills, social skills, impulse control, and ability to recognize potentially volatile situations. Both parents and boys described overall improvement in family relationships and school-related success. CONCLUSIONS: The qualitative data revealed that parents and boys participating in the multi-component program perceived improvements in a number of specific areas, including social competence of the boys. This has not been demonstrated as clearly in other evaluations of the program. PMID- 21605354 TI - GPCR-SSFE: a comprehensive database of G-protein-coupled receptor template predictions and homology models. AB - BACKGROUND: G protein-coupled receptors (GPCRs) transduce a wide variety of extracellular signals to within the cell and therefore have a key role in regulating cell activity and physiological function. GPCR malfunction is responsible for a wide range of diseases including cancer, diabetes and hyperthyroidism and a large proportion of drugs on the market target these receptors. The three dimensional structure of GPCRs is important for elucidating the molecular mechanisms underlying these diseases and for performing structure based drug design. Although structural data are restricted to only a handful of GPCRs, homology models can be used as a proxy for those receptors not having crystal structures. However, many researchers working on GPCRs are not experienced homology modellers and are therefore unable to benefit from the information that can be gleaned from such three-dimensional models. Here, we present a comprehensive database called the GPCR-SSFE, which provides initial homology models of the transmembrane helices for a large variety of family A GPCRs. DESCRIPTION: Extending on our previous theoretical work, we have developed an automated pipeline for GPCR homology modelling and applied it to a large set of family A GPCR sequences. Our pipeline is a fragment-based approach that exploits available family A crystal structures. The GPCR-SSFE database stores the template predictions, sequence alignments, identified sequence and structure motifs and homology models for 5025 family A GPCRs. Users are able to browse the GPCR dataset according to their pharmacological classification or search for results using a UniProt entry name. It is also possible for a user to submit a GPCR sequence that is not contained in the database for analysis and homology model building. The models can be viewed using a Jmol applet and are also available for download along with the alignments. CONCLUSIONS: The data provided by GPCR-SSFE are useful for investigating general and detailed sequence-structure function relationships of GPCRs, performing structure-based drug design and for better understanding the molecular mechanisms underlying disease-associated mutations in GPCRs. The effectiveness of our multiple template and fragment approach is demonstrated by the accuracy of our predicted homology models compared to recently published crystal structures. PMID- 21605355 TI - Extension of the bayesian alphabet for genomic selection. AB - BACKGROUND: Two bayesian methods, BayesCpi and BayesDpi, were developed for genomic prediction to address the drawback of BayesA and BayesB regarding the impact of prior hyperparameters and treat the prior probability pi that a SNP has zero effect as unknown. The methods were compared in terms of inference of the number of QTL and accuracy of genomic estimated breeding values (GEBVs), using simulated scenarios and real data from North American Holstein bulls. RESULTS: Estimates of pi from BayesCpi, in contrast to BayesDpi, were sensitive to the number of simulated QTL and training data size, and provide information about genetic architecture. Milk yield and fat yield have QTL with larger effects than protein yield and somatic cell score. The drawback of BayesA and BayesB did not impair the accuracy of GEBVs. Accuracies of alternative Bayesian methods were similar. BayesA was a good choice for GEBV with the real data. Computing time was shorter for BayesCpi than for BayesDpi, and longest for our implementation of BayesA. CONCLUSIONS: Collectively, accounting for computing effort, uncertainty as to the number of QTL (which affects the GEBV accuracy of alternative methods), and fundamental interest in the number of QTL underlying quantitative traits, we believe that BayesCpi has merit for routine applications. PMID- 21605356 TI - Extracting scientific articles from a large digital archive: BioStor and the Biodiversity Heritage Library. AB - BACKGROUND: The Biodiversity Heritage Library (BHL) is a large digital archive of legacy biological literature, comprising over 31 million pages scanned from books, monographs, and journals. During the digitisation process basic metadata about the scanned items is recorded, but not article-level metadata. Given that the article is the standard unit of citation, this makes it difficult to locate cited literature in BHL. Adding the ability to easily find articles in BHL would greatly enhance the value of the archive. DESCRIPTION: A service was developed to locate articles in BHL based on matching article metadata to BHL metadata using approximate string matching, regular expressions, and string alignment. This article locating service is exposed as a standard OpenURL resolver on the BioStor web site http://biostor.org/openurl/. This resolver can be used on the web, or called by bibliographic tools that support OpenURL. CONCLUSIONS: BioStor provides tools for extracting, annotating, and visualising articles from the Biodiversity Heritage Library. BioStor is available from http://biostor.org/. PMID- 21605357 TI - Logistic random effects regression models: a comparison of statistical packages for binary and ordinal outcomes. AB - BACKGROUND: Logistic random effects models are a popular tool to analyze multilevel also called hierarchical data with a binary or ordinal outcome. Here, we aim to compare different statistical software implementations of these models. METHODS: We used individual patient data from 8509 patients in 231 centers with moderate and severe Traumatic Brain Injury (TBI) enrolled in eight Randomized Controlled Trials (RCTs) and three observational studies. We fitted logistic random effects regression models with the 5-point Glasgow Outcome Scale (GOS) as outcome, both dichotomized as well as ordinal, with center and/or trial as random effects, and as covariates age, motor score, pupil reactivity or trial. We then compared the implementations of frequentist and Bayesian methods to estimate the fixed and random effects. Frequentist approaches included R (lme4), Stata (GLLAMM), SAS (GLIMMIX and NLMIXED), MLwiN ([R]IGLS) and MIXOR, Bayesian approaches included WinBUGS, MLwiN (MCMC), R package MCMCglmm and SAS experimental procedure MCMC.Three data sets (the full data set and two sub datasets) were analysed using basically two logistic random effects models with either one random effect for the center or two random effects for center and trial. For the ordinal outcome in the full data set also a proportional odds model with a random center effect was fitted. RESULTS: The packages gave similar parameter estimates for both the fixed and random effects and for the binary (and ordinal) models for the main study and when based on a relatively large number of level-1 (patient level) data compared to the number of level-2 (hospital level) data. However, when based on relatively sparse data set, i.e. when the numbers of level-1 and level-2 data units were about the same, the frequentist and Bayesian approaches showed somewhat different results. The software implementations differ considerably in flexibility, computation time, and usability. There are also differences in the availability of additional tools for model evaluation, such as diagnostic plots. The experimental SAS (version 9.2) procedure MCMC appeared to be inefficient. CONCLUSIONS: On relatively large data sets, the different software implementations of logistic random effects regression models produced similar results. Thus, for a large data set there seems to be no explicit preference (of course if there is no preference from a philosophical point of view) for either a frequentist or Bayesian approach (if based on vague priors). The choice for a particular implementation may largely depend on the desired flexibility, and the usability of the package. For small data sets the random effects variances are difficult to estimate. In the frequentist approaches the MLE of this variance was often estimated zero with a standard error that is either zero or could not be determined, while for Bayesian methods the estimates could depend on the chosen "non-informative" prior of the variance parameter. The starting value for the variance parameter may be also critical for the convergence of the Markov chain. PMID- 21605358 TI - A cross-sectional study of patients with and without substance use disorders in Community Mental Health Centres. AB - BACKGROUND: Epidemiological studies have consistently established high comorbidity between psychiatric disorders and substance use disorders (SUD). This comorbidity is even more prominent when psychiatric populations are studied. Previous studies have focused on inpatient populations dominated by psychotic disorders, whereas this paper presents findings on patients in Community Mental Health Centres (CMHCs) where affective and anxiety disorders are most prominent. The purpose of this study is to compare patients in CMHCs with and without SUD in regard to differences in socio-demographic characteristics, level of morbidity, prevalence of different diagnostic categories, health services provided and the level of improvement in psychiatric symptoms. METHODS: As part of the evaluation of the National Plan for Mental Health, all patients seen in eight CMHCs during a 4-week period in 2007 were studied (n = 2154). The CMHCs were located in rural and urban areas of Norway. The patients were diagnosed according to the ICD-10 diagnoses and assessed with the Health of the Nation Outcome Scales, the Alcohol Use Scale and the Drug Use Scale. RESULTS: Patients with SUD in CMHCs are more frequently male, single and living alone, have more severe morbidity, less anxiety and mood disorders, less outpatient treatment and less improvement in regard to recovery from psychological symptoms compared to patients with no SUD. CONCLUSION: CMHCs need to implement systematic screening and diagnostic procedures in order to detect the special needs of these patients and improve their treatment. PMID- 21605359 TI - Missing clinical information in NHS hospital outpatient clinics: prevalence, causes and effects on patient care. AB - BACKGROUND: In Britain over 39,000 reports were received by the National Patient Safety Agency relating to failures in documentation in 2007 and the UK Health Services Journal estimated in 2008 that over a million hospital outpatient visits each year might take place without the full record available. Despite these high numbers, the impact of missing clinical information has not been investigated for hospital outpatients in the UK.Studies in primary care in the USA have found 13.6% of patient consultations have missing clinical information, with this adversely affecting care in about half of cases, and in Australia 1.8% of medical errors were found to be due to the unavailability of clinical information.Our objectives were to assess the frequency, nature and potential impact on patient care of missing clinical information in NHS hospital outpatients and to assess the principal causes. This is the first study to present such figures for the UK and the first to look at how clinicians respond, including the associated impact on patient care. METHODS: Prospective descriptive study of missing information reported by surgeons, supplemented by interviews on the causes.Data were collected by surgeons in general, gastrointestinal, colorectal and vascular surgical clinics in three teaching hospitals across the UK for over a thousand outpatient appointments. Fifteen interviews were conducted with those involved in collating clinical information for these clinics.The study had ethics approval (Hammersmith and Queen Charlotte's & Chelsea Research Ethics Committee), reference number (09/H0707/27). Participants involved in the interviews signed a consent form and were offered the opportunity to review and agree the transcript of their interview before analysis. No patients were involved in this research. RESULTS: In 15% of outpatient consultations key items of clinical information were missing. Of these patients, 32% experienced a delay or disruption to their care and 20% had a risk of harm. In over half of cases the doctor relied on the patient for the information, making a clinical decision despite the information being missing in 20% of cases. Hospital mergers, temporary staff and non integrated IT systems were contributing factors. CONCLUSIONS: If these findings are replicated across the NHS then almost 10 million outpatients are seen each year without key clinical information, creating over a million unnecessary appointments, and putting nearly 2 million patients at risk of harm. There is a need for a systematic, regular audit of the prevalence of missing clinical information. Only then will we know the impact on clinical decision making and patient care of new technology, service reorganisations and, crucially given the present financial climate, temporary or reduced staffing levels. Further research is needed to assess the relationship between missing clinical information and diagnostic errors; to examine the issue in primary care; and to consider the patients perspective. PMID- 21605360 TI - Prevalence of obesity and associated risk factors among adults in Kinondoni municipal district, Dar es Salaam Tanzania. AB - BACKGROUND: Obesity is on the rise worldwide, not sparing developing countries. Both demographic and socio-economic factors play parts in obesity causation. Few surveys have been conducted in Tanzania to determine the magnitude of obesity and its association with these risk factors. This study aimed at determining the prevalence of obesity and its associated risk factors among adults aged 18 - 65 years in Kinondoni municipality, Dar es Salaam, Tanzania from April 2007 to April 2008. METHODS: Random sampling of households was performed. Interviews and anthropometric measurement were carried out to eligible and consenting members of the selected households. Obesity was defined using Body Mass Index (BMI). RESULTS: Out of 1249 subjects recruited, 814 (65.2%) were females. The overall prevalence of obesity was 19.2% (240/1249). However, obesity was significantly more prevalent in women (24.7%) than men (9%), p < 0.001, among respondents with high socio-economic status (29.2%) as compared to those with medium (14.3%) and low socio-economic status (11.3%), p value for trend < 0.001, and among respondents with light intensity activities (26.0%), p value for trend < 0.001. CONCLUSION: This study revealed a higher prevalence of obesity among Kinondoni residents than previously reported in other parts of the country. Independent predictors of obesity in the population studied were increasing age, marriage and cohabitation, high SES, female sex and less vigorous physical activities. PMID- 21605361 TI - The initial pharmaceutical development of an artesunate/amodiaquine oral formulation for the treatment of malaria: a public-private partnership. AB - BACKGROUND: Artemisinin-based combination therapy is currently recommended worldwide for the treatment of uncomplicated malaria. Fixed-dose combinations are preferred as they favour compliance. This paper reports on the initial phases of the pharmaceutical development of an artesunate-amodiaquine (ASAQ) bilayer co formulation tablet, undertaken following pre-formulation studies by a network of scientists and industrials from institutions of both industrialized and low income countries. METHODS: Pharmaceutical development was performed by a research laboratory at the University Bordeaux Segalen, School of Pharmacy, for feasibility and early stability studies of various drug formulations, further transferred to a company specialized in pharmaceutical development, and then provided to another company for clinical batch manufacturing. The work was conducted by a regional public-private not-for-profit network (TropiVal) within a larger Public Private partnership (the FACT project), set up by WHO/TDR, Medecins Sans Frontieres and the Drugs for Neglected Disease initiative (DNDi). RESULTS: The main pharmaceutical goal was to combine in a solid oral form two incompatible active principles while preventing artesunate degradation under tropical conditions. Several options were attempted and failed to provide satisfactory stability results: incorporating artesunate in the external phase of the tablets, adding a pH regulator, alcoholic wet granulation, dry granulation, addition of an hydrophobic agent, tablet manufacturing in controlled conditions. However, long term stability could be achieved, in experimental batches under GMP conditions, by physical separation of artesunate and amodiaquine in a bilayer co-formulation tablet in alu-alu blisters. Conduction of the workplan was monitored by DNDi. CONCLUSIONS: Collaborations between research and industrial groups greatly accelerated the process of development of the bi-layered ASAQ tablet. Lack of public funding was the main obstacle hampering the development process, and no intellectual property right was claimed. This approach resulted in a rapid technology transfer to the drug company Sanofi-Aventis, finalizing the process of development, registration and WHO pre-qualification of the fixed-dose co formulation together with DNDi. The bi-layered tablet is made available under the names of Coarsucam(r) and Artesunate amodiaquine Winthrop(r), Sanofi-Aventis. The issue related to the difficulty of public institutions to valorise their participation in such initiative by lack of priority and funding of applied research is discussed. PMID- 21605362 TI - Duration of viral shedding in hospitalized patients infected with pandemic H1N1. AB - BACKGROUND: The first influenza pandemic of the 21th century was ignited by a new strain of influenza A virus (A/H1N1pdm). Specific patient groups, including those with comorbidities, pregnant women, young children, older and immunocompromised patients, are at increased risk for serious influenza-related disease. This study was aimed at investigating the influence of clinical presentation, antiviral treatment and possible drug resistance-associated mutations, on the extent and duration of viral shedding in patients infected with A/H1N1pdm. METHODS: An observational study was performed, based on retrospective review of clinical and laboratory records of patients who were hospitalized for A/H1N1pdm infection at the National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy, between April 24 and December 31, 2009. Among 119 hospitalized patients, 39 were selected for a post hoc analysis, based on the availability of serial nasopharyngeal swabs samples and related information. RESULTS: Eleven out of the 39 study patients (28.2%) presented with pneumonia; 29 (74.4%) received antiviral treatment. Patients with pneumonia were significantly older than patients without pneumonia. The mean values of viral RNA concentration were not significantly increased in patients with pneumonia, but a significant increase in the duration of viral shedding was observed as compared to patients without pneumonia. In patients receiving antivirals, the viral RNA concentration was significantly reduced in comparison to untreated patients at days 4-5 after symptom onset, while the overall duration of viral shedding was only marginally affected. A significant correlation between duration of viral shedding and time elapsed between symptom onset and therapy start was observed, with a significant reduction of days of viral shedding when therapy was initiated within 2 days of symptoms appearance. No known drug resistance mutations were detected in patients with prolonged viral shedding. CONCLUSIONS: Our results show that severe respiratory illness is associated with delayed virus clearance in patients with A/H1N1pdm infection. Antivirals caused an early reduction of viral load, but only marginally affected the overall duration of shedding. Prolonged shedding was not associated with the emergence of strains carrying known drug-resistance mutations. PMID- 21605363 TI - Seroprevalence of transfusion-transmissible infections and evaluation of the pre donation screening performance at the Provincial Hospital of Tete, Mozambique. AB - BACKGROUND: The World Health Organization recommends universal and quality controlled screening of blood donations for the major transfusion-transmissible infections (TTIs): human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and syphilis. The study objectives were to determine the seroprevalence of these TTIs among blood donors at the Provincial Hospital of Tete, Mozambique, and to assess the local pre-donation screening performance. METHODS: All consenting voluntary and replacement candidate blood donors were consecutively included from February to May 2009. Sera of all candidates, independent of deferral by questionnaire, were submitted to screening with quality-assured rapid or simple assays for HIV, HBV surface antigen (HBsAg), HCV and syphilis. Assays locally used by the blood bank for HBV and syphilis screening were run in parallel to quality-assured external assays supplied during the study, and all discordant samples were submitted to confirmation testing in reference laboratories in Mozambique and Belgium. RESULTS: Of 750 consenting candidates (50.5% of voluntary donors), 71 (9.5%) were deferred by the questionnaire, including 38 specifically because of risk behavior for TTI. Of the 679 non-deferred candidates, 127 (18.7%) had serological confirmation of at least one TTI, with a lower prevalence in voluntary than in replacement donors (15.2% versus 22.4%, p = 0.016). Seroprevalence of HIV, HBsAg and syphilis infections was 8.5%, 10.6 % and 1.2%. No confirmed HCV infection was found. Seroprevalence of TTIs was similar in the 38 candidates deferred for TTI risk as in the non deferred group, except for HBsAg (26.3 % versus 10.6 %; p = 0.005). The local assays used for HBV and syphilis had sensitivities of 98.4% and 100% and specificities of 80.4% and 98.8% respectively. This resulted in the rejection of 110 of the 679 blood donations (16.2%) because of false positive results. CONCLUSIONS: The seroprevalence of TTIs after questionnaire screening is high in Tete, Mozambique, but HCV infection does not appear as a major issue. The questionnaire did not exclude effectively HIV-infected donor candidates, while the locally used assays led to unnecessary rejection of many safe donations. A contextualized questionnaire and consistent use of quality-assured assays would considerably improve the current screening procedure for blood donation. PMID- 21605364 TI - Innovative public-private partnerships to maximize the delivery of anti-malarial medicines: lessons learned from the ASAQ Winthrop experience. AB - BACKGROUND: This case study describes how a public-private partnership initiated to develop a new anti-malarial combination, ASAQ Winthrop, has evolved over time to address issues posed by its effective deployment in the field. CASE DESCRIPTION: In 2002, DNDi created the FACT project to develop two fixed-dose combinations, artesunate-amodiaquine and artesunate-mefloquine, to meet the WHO anti-malarial treatment recommendations and international regulatory agencies approval standards. In 2002, Sanofi-Aventis had started a development programme for a fixed-dose combination of artesunate and amodiaquine, to replace its co blister combination. DNDi and Sanofi-Aventis joined forces in 2004, with the objective of developing within the shortest possible time frame a non-patented, affordable and easy to use fixed-dose combination of artesunate and amodiaquine adapted to the needs of patients, in particular, those of children. The partners developed Coarsucam(r)/Artesunate Amodiaquine Winthrop(r) ("ASAQ Winthrop") which was prequalified by the WHO in 2008. Additional partnerships have since been established by DNDi and Sanofi-Aventis to ensure: 1) the adoption of this new medicine by malaria-endemic countries, 2) its appropriate usage through a broad range of information tools, and 3) the monitoring of its safety and efficacy in the field through an innovative Risk Management Plan. DISCUSSION AND EVALUATION: The partnership between DNDi and Sanofi-Aventis has enabled the development and pre-qualification of ASAQ Winthrop in a short timeframe. As a result of the multiple collaborations established by the two partners, as of late 2010, ASAQ Winthrop was registered in 30 sub-Saharan African countries and in India, with over 80 million treatments distributed in 21 countries. To date, 10 clinical studies, involving 3432 patients with ASAQ Winthrop were completed to document efficacy and safety issues identified in the Risk Management Plan. CONCLUSIONS: The speed at which ASAQ Winthrop was adopted in the field shows that this drug fits the needs of patients and health authorities. It also demonstrates the power of partnerships that combine different sets of strengths and skills, and that evolve to include additional actors to meet new global health challenges for poverty-related diseases. PMID- 21605365 TI - Home mechanical ventilation and specialised health care in the community: Between a rock and a hard place. AB - BACKGROUND: Home mechanical ventilation probably represents the most advanced and complicated type of medical treatment provisioned outside a hospital setting. The aim of this study was both to explore the challenges experienced by health care professionals in community health care services when caring for patients dependent on home mechanical ventilation, continual care and highly advanced technology, and their proposed solutions to these challenges. METHODS: Using qualitative research methods, a grounded theory influenced approach was used to explore the respondents' experiences and proposed solutions. A total of 34 multidisciplinary respondents from five different communities in Norway were recruited for five focus groups. RESULTS: The core category in our findings was what health care professionals in community health care services experience as "between a rock and a hard place," when working with hospitals, family members, and patients. We further identified four subcategories, "to be a guest in the patient's home," "to be accepted or not," "who decides," and "how much can we take." The main background for these challenges seems to stem from patients living and receiving care in their private homes, which often leads to conflicts with family members. These challenges can have a negative effect on both the community health caregivers' work environment and the community health service's provision of professional care. CONCLUSIONS: This study has identified that care of individuals with complex needs and dependent on home mechanical ventilation presents a wide range of immense challenges for community health care services. The results of this study point towards a need to define the roles of family caregivers and health care professionals and also to find solutions to improve their collaboration. The need to improve the work environment for caregivers directly involved in home-care also exists. The study also shows the need for more dialogue concerning eligibility requirements, rights, and limitations of patients in the provision and use of ventilatory support in private homes. PMID- 21605366 TI - Incidence, risk factors and mortality of tuberculosis in Danish HIV patients 1995 2007. AB - BACKGROUND: Human Immunodeficiency Virus (HIV) infection predisposes to tuberculosis (TB). We described incidence, risk factors and prognosis of TB in HIV-1 infected patients during pre (1995-1996), early (1997-1999), and late Highly Active Antiretroviral Therapy (HAART) (2000-2007) periods. METHODS: We included patients from a population-based, multicenter, nationwide cohort. We calculated incidence rates (IRs) and mortality rates (MRs). Cox's regression analysis was used to estimate risk factors for TB infection with HAART initiation included as time updated variable. Kaplan-Meier was used to estimate mortality after TB. RESULTS: Among 2,668 patients identified, 120 patients developed TB during the follow-up period. The overall IR was 8.2 cases of TB/1,000 person years of follow-up (PYR). IRs decreased during the pre-, early and late-HAART periods (37.1/1000 PYR, 12.9/1000 PYR and 6.5/1000 PYR respectively). African and Asian origin, low CD4 cell count and heterosexual and injection drug user route of HIV transmission were risk factors for TB and start of HAART reduced the risk substantially. The overall MR in TB patients was 34.4 deaths per 1,000 PYR (95% Confidence Interval: 22.0-54.0) and was highest in the first two years after the diagnosis of TB. CONCLUSIONS: Incidence of TB still associated with conventional risk factors as country of birth, low CD4 count and route of HIV infection while HAART reduces the risk substantially. The mortality in this patient population is high in the first two years after TB diagnosis. PMID- 21605367 TI - Antidepressant and antipsychotic use in an Italian pediatric population. AB - BACKGROUND: The safety and effectiveness of psychotropic drug use in the paediatric population is widely debated, in particular because of the lack of data concerning long term effects.In Italy the prevalence of psychotropic drug prescriptions increased in the early 2000s and decreased afterwards. In such a context, a study with the aim to estimate the incidence and prevalence of psychotropic drug prescription in the paediatric population and to describe diagnostic and therapeutic approaches was performed. METHODS: The study population was composed of 76,000 youths less than 18 years and living in the area covered by the local health unit of Verona, Italy. The data source was the Verona local health unit's administrative prescription database. Prevalence and incidence of antidepressant and/or antipsychotic drug prescriptions in the 2004 2008 period were estimated. Children and adolescents receiving antidepressant and/or antipsychotic drug prescriptions between 1 January 2005 and 31 December 2006 were identified and questionnaires were sent to the prescribers with the aim to collect data concerning diagnostic and therapeutic approaches, and care strategies. RESULTS: The prevalence of psychotropic drug prescriptions did not change in the 2004-2008 period, while incidence slightly increased (from 7.0 in 2005 to 8.3 per 10,000 in 2008). Between 1 January 2005 and 31 December 2006, 111 youths received at least one psychotropic drug prescription, 91 of whom received antidepressants. Only 28 patients attended child and adolescent psychiatry services. Information concerning diagnostic and therapeutic approaches, and care strategies was collected for 52 patients (47%). Anxiety-depressive syndrome and attention disorders were the diseases for which psychotropic drugs were most commonly prescribed. In all, 75% youths also received psychological support and 20% were prescribed drugs for 2 or more years. CONCLUSIONS: Despite the low drug prescription prevalence, the finding that most children were not cared for by child and adolescent psychiatric services is of concern and calls for a systematic, continuous monitoring of psychopharmacological treatments. PMID- 21605368 TI - Exon sequence requirements for excision in vivo of the bacterial group II intron RmInt1. AB - BACKGROUND: Group II intron splicing proceeds through two sequential transesterification reactions in which the 5' and 3'-exons are joined together and the lariat intron is released. The intron-encoded protein (IEP) assists the splicing of the intron in vivo and remains bound to the excised intron lariat RNA in a ribonucleoprotein particle (RNP) that promotes intron mobility. Exon recognition occurs through base-pairing interactions between two guide sequences on the ribozyme domain dI known as EBS1 and EBS2 and two stretches of sequence known as IBS1 and IBS2 on the 5' exon, whereas the 3' exon is recognized through interaction with the sequence immediately upstream from EBS1 [(delta-delta' interaction (subgroup IIA)] or with a nucleotide [(EBS3-IBS3 interaction (subgroup IIB and IIC))] located in the coordination-loop of dI. The delta nucleotide is involved in base pairing with another intron residue (delta') in subgroup IIB introns and this interaction facilitates base pairing between the 5' exon and the intron. RESULTS: In this study, we investigated nucleotide requirements in the distal 5'- and 3' exon regions, EBS-IBS interactions and delta-delta' pairing for excision of the group IIB intron RmInt1 in vivo. We found that the EBS1-IBS1 interaction was required and sufficient for RmInt1 excision. In addition, we provide evidence for the occurrence of canonical delta delta' pairing and its importance for the intron excision in vivo. CONCLUSIONS: The excision in vivo of the RmInt1 intron is a favored process, with very few constraints for sequence recognition in both the 5' and 3'-exons. Our results contribute to understand how group II introns spread in nature, and might facilitate the use of RmInt1 in gene targeting. PMID- 21605369 TI - Serum levels of inflammatory and regulatory cytokines in patients with hemorrhagic fever with renal syndrome. AB - BACKGROUND: Hantaviruses are the causative agents of two zoonotic diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The pathogenesis of HFRS is poorly understood. However, it has been suggested that immune mechanisms, including cytokines, might have an important role in HFRS pathogenesis. Thus, the aim of our study was to investigate cytokine profiles in serum samples of HFRS patients from Slovenia and explore a possible correlation between cytokine levels and disease severity. METHODS: Acute-phase serum samples from 52 patients, diagnosed with DOBV infection, and 61 patients, diagnosed with PUUV infection, were included in this study. Patients were divided into two groups--severe or mild--based on disease severity. Levels of IL-10, IL-12, INF-gamma and TNF-alpha were measured in the serum samples with commercial ELISA tests. RESULTS: Increased levels of IL-10, INF-gamma, and TNF-alpha were found in almost all the serum samples tested. On average, higher concentrations were detected in patients infected with DOBV than PUUV. Furthermore, significantly higher levels of IL-10 (P=0.001) and TNF-alpha (P=0.003) were found in patients with a more severe clinical course of disease. The same association between IL-10 (P<0.001) and TNF-alpha (P=0.021), and the severity of the disease was observed also when only patients infected with DOBV were considered. No differences in cytokine concentrations according to disease severity were observed in patients infected with PUUV. Concentrations of serum IL 12 in HFRS patients were in the normal range, however, higher levels were detected in patients infected with PUUV than in patients infected with DOBV. CONCLUSIONS: We suggest that imbalance in production of proinflammatory and regulatory cytokines might be in part responsible for a more severe course of HFRS. PMID- 21605370 TI - Anchored FRET sensors detect local caspase activation prior to neuronal degeneration. AB - BACKGROUND: Recent studies indicate local caspase activation in dendrites or axons during development and in neurodegenerative disorders such as Alzheimer's disease (AD). Emerging evidences point to soluble oligomeric amyloid-beta peptide as a causative agent in AD. RESULTS: Here we describe the design of fluorescence resonance energy transfer (FRET)-based caspase sensors, fused to the microtubule associated protein tau. Specific caspase sensors preferentially cleaved by caspase-3, -6 or -9 were expressed in differentiated human neuroblastoma SH-SY5Y cells. The anchoring of the sensors resulted in high FRET signals both in extended neurites and soma and made analysis of spatiotemporal signal propagation possible. Caspase activation was detected as loss of FRET after exposure to different stimuli. Interestingly, after staurosporine treatment caspase-6 activation was significantly delayed in neurites compared to cell bodies. In addition, we show that exposure to oligomer-enriched amyloid-beta peptide resulted in loss of FRET in cells expressing sensors for caspase-3 and -6, but not -9, in both soma and neurites before neurite degeneration was observed. CONCLUSIONS: Taken together, the results show that by using anchored FRET sensors it is possible to detect stimuli-dependent differential activation of caspases and to distinguish local from global caspase activation in live neuronal cells. Furthermore, in these cells oligomer-enriched amyloid-beta peptide induces a global, rather than local activation of caspase-3 and -6, which subsequently leads to neuronal cell death. PMID- 21605371 TI - Hospitalizations for varicella in children and adolescents in a referral hospital in Hong Kong, 2004 to 2008: a time series study. AB - BACKGROUND: Varicella accounts for significant morbidities and remains a public health issue worldwide. Climatic factors have been shown to associate with the incidence and transmission of various infectious diseases. We describe the epidemiology of varicella in paediatric patients hospitalized at a tertiary referral hospital in Hong Kong from 2004 to 2008, and to explore the possible association between the occurrence of varicella infection and various climatic factors. METHODS: The hospital discharge database of Princess Margaret Hospital was retrospectively analyzed for admissions associated with varicella from 2004 to 2008. Meteorological data were obtained from the monthly meteorological reports from the Hong Kong Observatory website. Time series analysis was performed with Poisson regression using a Generalized Estimating Equation (GEE) approach. RESULTS: During the study period, 598 children were hospitalized for varicella. The mean age on admission was 57.6 months, and the mean duration of hospitalization was 3.7 days. The overall complication rate was 47%. The mean monthly relative humidity, especially in cool seasons, was inversely correlated with the monthly varicella cases of the same month. CONCLUSIONS: Varicella can lead to serious complications and prolonged hospitalization, even in previously healthy children. Lower relative humidity in cool seasons is associated with higher number of paediatric varicella hospital admissions. These findings are useful for a better understanding of the pattern of paediatric varicella hospitalization in Hong Kong. PMID- 21605372 TI - Mitochondrial targeted catalase suppresses invasive breast cancer in mice. AB - BACKGROUND: Treatment of invasive breast cancer has an alarmingly high rate of failure because effective targets have not been identified. One potential target is mitochondrial generated reactive oxygen species (ROS) because ROS production has been associated with changes in substrate metabolism and lower concentration of anti-oxidant enzymes in tumor and stromal cells and increased metastatic potential. METHODS: Transgenic mice expressing a human catalase gene (mCAT) were crossed with MMTV-PyMT transgenic mice that develop metastatic breast cancer. All mice (33 mCAT positive and 23 mCAT negative) were terminated at 110 days of age, when tumors were well advanced. Tumors were histologically assessed for invasiveness, proliferation and metastatic foci in the lungs. ROS levels and activation status of p38 MAPK were determined. RESULTS: PyMT mice expressing mCAT had a 12.5 per cent incidence of high histological grade primary tumor invasiveness compared to a 62.5 per cent incidence in PyMT mice without mCAT. The histological grade correlated with incidence of metastasis with 56 per cent of PyMT mice positive for mCAT showing evidence of pulmonary metastasis compared to 85.4 per cent of PyMT mice negative for mCAT with pulmonary metastasis (p <= 0.05). PyMT tumor cells expressing mCAT had lower ROS levels and were more resistant to hydrogen peroxide-induced oxidative stress than wild type tumor cells, suggesting that mCAT has the potential of quenching intracellular ROS and subsequent invasive behavior. The metastatic tumor burden in PyMT mice expressing mCAT was 0.1 mm2/cm2 of lung tissue compared with 1.3 mm2/cm2 of lung tissue in PyMT mice expressing the wild type allele (p <= 0.01), indicating that mCAT could play a role in mitigating metastatic tumor progression at a distant organ site. Expression of mCAT in the lungs increased resistance to hydrogen peroxide-induced oxidative stress that was associated with decreased activation of p38MAPK suggesting ROS signaling is dependent on p38MAPK for at least some of its downstream effects. CONCLUSION: Targeting catalase within mitochondria of tumor cells and tumor stromal cells suppresses ROS-driven tumor progression and metastasis. Therefore, increasing the antioxidant capacity of the mitochondrial compartment could be a rational therapeutic approach for invasive breast cancer. PMID- 21605373 TI - A canine model of Cohen syndrome: Trapped Neutrophil Syndrome. AB - BACKGROUND: Trapped Neutrophil Syndrome (TNS) is a common autosomal recessive neutropenia in Border collie dogs. RESULTS: We used a candidate gene approach and linkage analysis to show that the causative gene for TNS is VPS13B. We chose VPS13B as a candidate because of similarities in clinical signs between TNS and Cohen syndrome, in human, such as neutropenia and a typical facial dysmorphism. Linkage analysis using microsatellites close to VPS13B showed positive linkage of the region to TNS. We sequenced each of the 63 exons of VPS13B in affected and control dogs and found that the causative mutation in Border collies is a 4 bp deletion in exon 19 of the largest transcript that results in premature truncation of the protein. Cohen syndrome patients present with mental retardation in 99% of cases, but learning disabilities featured in less than half of TNS affected dogs. It has been implied that loss of the alternate transcript of VPS13B in the human brain utilising an alternate exon, 28, may cause mental retardation. Mice cannot be used to test this hypothesis as they do not express the alternate exon. We show that dogs do express alternate transcripts in the brain utilising an alternate exon homologous to human exon 28. CONCLUSION: Dogs can be used as a model organism to explore the function of the alternately spliced transcript of VPS13B in the brain. TNS in Border collies is the first animal model for Cohen syndrome and can be used to study the disease aetiology. PMID- 21605374 TI - Mitochondrial oxidative stress drives tumor progression and metastasis: should we use antioxidants as a key component of cancer treatment and prevention? AB - The functional role of oxidative stress in cancer pathogenesis has long been a hotly debated topic. A study published this month in BMC Cancer by Goh et al., directly addresses this issue by using a molecular genetic approach, via an established mouse animal model of human breast cancer. More specifically, alleviation of mitochondrial oxidative stress, via transgenic over-expression of catalase (an anti-oxidant enzyme) targeted to mitochondria, was sufficient to lower tumor grade (from high-to-low) and to dramatically reduce metastatic tumor burden by >12-fold. Here, we discuss these new findings and place them in the context of several other recent studies showing that oxidative stress directly contributes to tumor progression and metastasis. These results have important clinical and translational significance, as most current chemo-therapeutic agents and radiation therapy increase oxidative stress, and, therefore, could help drive tumor recurrence and metastasis. Similarly, chemo- and radiation-therapy both increase the risk for developing a secondary malignancy, such as leukemia and/or lymphoma. To effectively reduce mitochondrial oxidative stress, medical oncologists should now re-consider the use of powerful anti-oxidants as a key component of patient therapy and cancer prevention. Please see related research article: http://www.biomedcentral.com/1471-2407/11/191. PMID- 21605375 TI - Translation and validation of the Korean Confusion Assessment Method for the Intensive Care Unit. AB - BACKGROUND: Delirium is a common problem and associated with poor outcomes in intensive care unit (ICU) patients. Diagnosis of delirium in ICU patients is limited and usually underdiagnosed by physicians. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is one of the most widely used screening methods for detection of ICU delirium. Our goal was to translate and validate the CAM-ICU for use in the Korean ICU setting. METHODS: Translation of the CAM-ICU was done according to the guidelines suggested by the Translation and Cultural Adaptation Group. For validation and interrater reliability assessment of the Korean CAM-ICU, two nurses independently assessed delirium in ICU patients and the results were compared with the reference evaluation, which was done by a psychiatrist using the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV). RESULTS: Twenty-two patients were evaluated by two nurses and one psychiatrist expert independently. During the study period, we have continuously educated study nurses. Based on DSM-IV criteria, 16 out of 22 (72.7%) patients developed delirium. The sensitivities of the two nurses' evaluations using the Korean CAM-ICU were 89.80% for nurse 1 and 77.40% for nurse 2. Their specificities were 72.40% and 75.80% and their overall accuracy was 83.33% and 88.37% respectively. The Korean CAM-ICU was done with reasonable interrater reliability between nurse 1 and nurse 2 (kappa = 0.81, p < 0.001). CONCLUSIONS: The Korean CAM-ICU showed good validity and could be incorporated into clinical practice in Korean ICUs. TRIAL REGISTRATION: ISRCTN: ISRCTN50265663. PMID- 21605376 TI - Modelling effectiveness of herd level vaccination against Q fever in dairy cattle. AB - Q fever is a worldwide zoonosis caused by the bacterium Coxiella burnetii. The control of this infection in cattle is crucial: infected ruminants can indeed encounter reproductive disorders and represent the most important source of human infection. In the field, vaccination is currently advised in infected herds but the comparative effectiveness of different vaccination protocols has never been explored: the duration of the vaccination programme and the category of animals to be vaccinated have to be determined. Our objective was to compare, by simulation, the effectiveness over 10 years of three different vaccination strategies in a recently infected dairy cattle herd.A stochastic individual-based epidemic model coupled with a model of herd demography was developed to simulate three temporal outputs (shedder prevalence, environmental bacterial load and number of abortions) and to calculate the extinction rate of the infection. For all strategies, the temporal outputs were predicted to strongly decrease with time at least in the first years of vaccination. However, vaccinating only three years was predicted inadequate to stabilize these dynamic outputs at a low level. Vaccination of both cows and heifers was predicted as being slightly more effective than vaccinating heifers only. Although the simulated extinction rate of the infection was high for both scenarios, the outputs decreased slower when only heifers were vaccinated.Our findings shed new light on vaccination effectiveness related to Q fever. Moreover, the model can be further modified for simulating and assessing various Q fever control strategies such as environmental and hygienic measures. PMID- 21605377 TI - Administration of probiotics influences F4 (K88)-positive enterotoxigenic Escherichia coli attachment and intestinal cytokine expression in weaned pigs. AB - This study evaluated the effect of the probiotics Pediococcus acidilactici and Saccharomyces cerevisiae boulardii on the intestinal colonization of O149 enterotoxigenic Escherichia coli harbouring the F4 (K88) fimbriae (ETEC F4) and on the expression of ileal cytokines in weaned pigs. At birth, different litters of pigs were randomly assigned to one of the following treatments: 1) control without antibiotics or probiotics (CTRL); 2) reference group in which chlortetracycline and tiamulin were added to weanling feed (ATB); 3) P. acidilactici; 4) S. cerevisiae boulardii; or 5) P. acidilactici + S. cerevisiae boulardii. Probiotics were administered daily (1 * 10(9) CFU per pig) during the lactation period and after weaning (day 21). At 28 days of age, all pigs were orally challenged with an ETEC F4 strain, and a necropsy was performed 24 h later. Intestinal segments were collected to evaluate bacterial colonization in the small intestine and ileal cytokine expressions. Attachment of ETEC F4 to the intestinal mucosa was significantly reduced in pigs treated with P. acidilactici or S. cerevisiae boulardii in comparison with the ATB group (P = 0.01 and P = 0.03, respectively). In addition, proinflammatory cytokines, such as IL-6, were upregulated in ETEC F4 challenged pigs treated with P. acidilactici alone or in combination with S. cerevisiae boulardii compared with the CTRL group. In conclusion, the administration of P. acidilactici or S. cerevisiae boulardii was effective in reducing ETEC F4 attachment to the ileal mucosa, whereas the presence of P. acidilactici was required to modulate the expression of intestinal inflammatory cytokines in pigs challenged with ETEC F4. PMID- 21605379 TI - High rates of burnout among maternal health staff at a referral hospital in Malawi: A cross-sectional study. AB - BACKGROUND: Burnout among maternal healthcare workers in sub-Saharan Africa may have a negative effect on services provided and efforts to mitigate high maternal mortality rates. In Malawi, research on burnout is limited and no empirical research has been conducted specifically among maternal health staff. Therefore, the aims of the study were to examine the prevalence and degree of burnout reported by healthcare workers who provide antenatal, intrapartum, and postnatal services in a district referral hospital in Malawi; and, to explore factors that may influence the level of burnout healthcare workers experience. METHODS: In the current cross-sectional study, levels of burnout among staff working in obstetrics and gynaecology at a referral hospital in Malawi were examined, in addition to individual and job characteristics that may be associated with burnout. RESULTS: In terms of the three dimensions of burnout, of the 101 participants, nearly three quarters (72%) reported emotional exhaustion, over one third (43%) reported depersonalization while almost three quarters (74%) experienced reduced personal accomplishment. CONCLUSIONS: Based on these findings, burnout appears to be common among participating maternal health staff and they experienced more burnout than their colleagues working in other medical settings and countries. Further research is needed to identify factors specific to Malawi that contribute to burnout in order to inform the development of prevention and treatment within the maternal health setting. PMID- 21605378 TI - Profiling the venom gland transcriptomes of Costa Rican snakes by 454 pyrosequencing. AB - BACKGROUND: A long term research goal of venomics, of applied importance for improving current antivenom therapy, but also for drug discovery, is to understand the pharmacological potential of venoms. Individually or combined, proteomic and transcriptomic studies have demonstrated their feasibility to explore in depth the molecular diversity of venoms. In the absence of genome sequence, transcriptomes represent also valuable searchable databases for proteomic projects. RESULTS: The venom gland transcriptomes of 8 Costa Rican taxa from 5 genera (Crotalus, Bothrops, Atropoides, Cerrophidion, and Bothriechis) of pitvipers were investigated using high-throughput 454 pyrosequencing. 100,394 out of 330,010 masked reads produced significant hits in the available databases. 5.165,220 nucleotides (8.27%) were masked by RepeatMasker, the vast majority of which corresponding to class I (retroelements) and class II (DNA transposons) mobile elements. BLAST hits included 79,991 matches to entries of the taxonomic suborder Serpentes, of which 62,433 displayed similarity to documented venom proteins. Strong discrepancies between the transcriptome-computed and the proteome-gathered toxin compositions were obvious at first sight. Although the reasons underlaying this discrepancy are elusive, since no clear trend within or between species is apparent, the data indicate that individual mRNA species may be translationally controlled in a species-dependent manner. The minimum number of genes from each toxin family transcribed into the venom gland transcriptome of each species was calculated from multiple alignments of reads matched to a full length reference sequence of each toxin family. Reads encoding ORF regions of Kazal-type inhibitor-like proteins were uniquely found in Bothriechis schlegelii and B. lateralis transcriptomes, suggesting a genus-specific recruitment event during the early-Middle Miocene. A transcriptome-based cladogram supports the large divergence between A. mexicanus and A. picadoi, and a closer kinship between A. mexicanus and C. godmani. CONCLUSIONS: Our comparative next-generation sequencing (NGS) analysis reveals taxon-specific trends governing the formulation of the venom arsenal. Knowledge of the venom proteome provides hints on the translation efficiency of toxin-coding transcripts, contributing thereby to a more accurate interpretation of the transcriptome. The application of NGS to the analysis of snake venom transcriptomes, may represent the tool for opening the door to systems venomics. PMID- 21605380 TI - Computed tomography to estimate cardiac preload and extravascular lung water. A retrospective analysis in critically ill patients. AB - BACKGROUND: In critically ill patients intravascular volume status and pulmonary edema need to be quantified as soon as possible. Many critically ill patients undergo a computed tomography (CT)-scan of the thorax after admission to the intensive care unit (ICU). This study investigates whether CT-based estimation of cardiac preload and pulmonary hydration can accurately assess volume status and can contribute to an early estimation of hemodynamics. METHODS: Thirty medical ICU patients. Global end-diastolic volume index (GEDVI) and extravascular lung water index (EVLWI) were assessed using transpulmonary thermodilution (TPTD) serving as reference method (with established GEDVI/EVLWI normal values). Central venous pressure (CVP) was determined. CT-based estimation of GEDVI/EVLWI/CVP by two different radiologists (R1, R2) without analyzing software. Primary endpoint: predictive capabilities of CT-based estimation of GEDVI/EVLWI/CVP compared to TPTD and measured CVP. Secondary endpoint: interobserver correlation and agreement between R1 and R2. RESULTS: Accuracy of CT-estimation of GEDVI (< 680, 680-800, > 800 mL/m2) was 33%(R1)/27%(R2). For R1 and R2 sensitivity for diagnosis of low GEDVI (< 680 mL/m2) was 0% (specificity 100%). Sensitivity for prediction of elevated GEDVI (> 800 mL/m2) was 86%(R1)/57%(R2) with a specificity of 57%(R1)/39%(R2) (positive predictive value 38%(R1)/22%(R2); negative predictive value 93%(R1)/75%(R2)). Estimated CT-GEDVI and TPTD-GEDVI were significantly different showing an overestimation of GEDVI by the radiologists (R1: mean difference +/- standard error (SE): 191 +/- 30 mL/m2, p < 0.001; R2: mean difference +/- SE: 215 +/- 37 mL/m2, p < 0.001). CT GEDVI and TPTD-GEDVI showed a very low Lin-concordance correlation coefficient (ccc) (R1: ccc = +0.20, 95% CI: +0.00 to +0.38, bias-correction factor (BCF) = 0.52; R2: ccc = -0.03, 95% CI: -0.19 to +0.12, BCF = 0.42). Accuracy of CT estimation in prediction of EVLWI (< 7, 7-10, > 10 mL/kg) was 30% for R1 and 40% for R2. CT-EVLWI and TPTD-EVLWI were significantly different (R1: mean difference +/- SE: 3.3 +/- 1.2 mL/kg, p = 0.013; R2: mean difference +/- SE: 2.8 +/- 1.1 mL/kg, p = 0.021). Again ccc was low with -0.02 (R1; 95% CI: -0.20 to +0.13, BCF = 0.44) and +0.14 (R2; 95% CI: 0.05 to +0.32, BCF = 0.53). GEDVI, EVLWI and CVP estimations of R1 and R2 showed a poor interobserver correlation (low ccc) and poor interobserver agreement (low kappa-values). CONCLUSIONS: CT-based estimation of GEDVI/EVLWI is not accurate for predicting cardiac preload and extravascular lung water in critically ill patients when compared to invasive TPTD-assessment of these variables. PMID- 21605381 TI - Effects of online palliative care training on knowledge, attitude and satisfaction of primary care physicians. AB - BACKGROUND: The Spanish Palliative Care Strategy recommends an intermediate level of training for primary care physicians in order to provide them with knowledge and skills. Most of the training involves face-to-face courses but increasing pressures on physicians have resulted in fewer opportunities for provision of and attendance to this type of training. The effectiveness of on-line continuing medical education in terms of its impact on clinical practice has been scarcely studied. Its effect in relation to palliative care for primary care physicians is currently unknown, in terms of improvement in patient's quality of life and main caregiver's satisfaction. There is uncertainty too in terms of any potential benefits of asynchronous communication and interaction among on-line education participants, as well as of the effect of the learning process.The authors have developed an on-line educational model for palliative care which has been applied to primary care physicians in order to measure its effectiveness regarding knowledge, attitude towards palliative care, and physician's satisfaction in comparison with a control group.The effectiveness evaluation at 18 months and the impact on the quality of life of patients managed by the physicians, and the main caregiver's satisfaction will be addressed in a different paper. METHODS: Randomized controlled educational trial to compared, on a first stage, the knowledge and attitude of primary care physicians regarding palliative care for advanced cancer patients, as well as satisfaction in those who followed an on line palliative care training program with tutorship, using a Moodle Platform vs. traditional education. RESULTS: 169 physicians were included, 85 in the intervention group and 84 in the control group, of which five were excluded. Finally 82 participants per group were analyzed. There were significant differences in favor of the intervention group, in terms of knowledge (mean 4.6; CI 95%: 2.8 to 6.5 (p = 0.0001), scale range 0-33), confidence in symptom management (p = 0.02) and confidence in terms of communication (p = 0.038). Useful aspects were pointed out, as well as others to be improved in future applications. The satisfaction of the intervention group was high. CONCLUSIONS: The results of this study show that there was a significant increase of knowledge of 14%-20% and a significant increase in the perception of confidence in symptom management and communication in the intervention group in comparison with the control group that received traditional methods of education in palliative care or no educational activity at all. The overall satisfaction with the intervention was good-very good for most participants.This on-line educational model seems a useful tool for palliative care training in primary care physicians who have a high opinion about the integration of palliative care within primary care. The results of this study support the suggestion that learning effectiveness should be currently investigated comparing different Internet interventions, instead of Internet vs. no intervention. PMID- 21605382 TI - Characteristics of tuberculosis patients at intake in Cambodia, two provinces in China, and Viet Nam. AB - BACKGROUND: The tuberculosis register is a critical data source for the information system of national tuberculosis control programs. From the information in the tuberculosis case register, it is possible to extend the standard analysis of age and sex characteristics among sputum smear-positive cases to all tuberculosis case categories. National tuberculosis programs might utilize such information to identify problems related to referral and access to diagnosis and treatment. OBJECTIVES: Based on the electronic database we created, our objectives were to provide a detailed description of age and sex characteristics of tuberculosis patients at registration and to provide a comparison of age-specific sex characteristics among incident and prevalent sputum smear-positive cases. METHODS: A representative sample of tuberculosis case registers from 1 January 2003 to 31 December 2005 was selected in Cambodia, two provinces in China and Viet Nam. Age and sex characteristics of cases in the three separate prevalence surveys in the three jurisdictions (Cambodia: year 2002; China: year 2000; and Viet Nam: year 2006-2007) were obtained for comparison. RESULTS: A total 37,635 patients had been registered during the period in the selected units in the three countries. Cases were more frequently male in all three countries with 53%, 71%, and 69% in Cambodia, China, and Viet Nam, respectively.The ratios of the female-to-male odds in the notification system to that in the prevalence survey in smear-positive cases in Cambodia, China and Viet Nam were 2.1, 0.9, and 1.8, respectively. Because of the small proportion of extrapulmonary tuberculosis registered in China, we limited the analysis on age and sex distribution for extrapulmonary cases to Cambodia and Viet Nam. The proportion with extrapulmonary tuberculosis among all cases was 18.5% in Cambodia and 15.7% in Viet Nam, decreasing in frequency with increasing age. CONCLUSIONS: Characteristics of patients greatly differed between countries and between patient categories. In Cambodia and Viet Nam, efforts should be made for improved case-finding of sputum smear-positive tuberculosis among males. PMID- 21605383 TI - Cost-effectiveness of early detection of breast cancer in Catalonia (Spain). AB - BACKGROUND: Breast cancer (BC) causes more deaths than any other cancer among women in Catalonia. Early detection has contributed to the observed decline in BC mortality. However, there is debate on the optimal screening strategy. We performed an economic evaluation of 20 screening strategies taking into account the cost over time of screening and subsequent medical costs, including diagnostic confirmation, initial treatment, follow-up and advanced care. METHODS: We used a probabilistic model to estimate the effect and costs over time of each scenario. The effect was measured as years of life (YL), quality-adjusted life years (QALY), and lives extended (LE). Costs of screening and treatment were obtained from the Early Detection Program and hospital databases of the IMAS Hospital del Mar in Barcelona. The incremental cost-effectiveness ratio (ICER) was used to compare the relative costs and outcomes of different scenarios. RESULTS: Strategies that start at ages 40 or 45 and end at 69 predominate when the effect is measured as YL or QALYs. Biennial strategies 50-69, 45-69 or annual 45-69, 40-69 and 40-74 were selected as cost-effective for both effect measures (YL or QALYs). The ICER increases considerably when moving from biennial to annual scenarios. Moving from no screening to biennial 50-69 years represented an ICER of 4,469? per QALY. CONCLUSIONS: A reduced number of screening strategies have been selected for consideration by researchers, decision makers and policy planners. Mathematical models are useful to assess the impact and costs of BC screening in a specific geographical area. PMID- 21605384 TI - The evolution of health status and chronic conditions in Catalonia, 1994-2006: the paradox of health revisited using the Blinder - Oaxaca decomposition. AB - BACKGROUND: The paradox of health refers to the improvement in objective measures of health and the increase in the reported prevalence of chronic conditions. The objective of this paper is to test the paradox of health in Catalonia from 1994 to 2006. METHODS: Longitudinal cross-sectional study using the Catalonia Health Interview Survey of 1994 and 2006. The approach used was the three-fold Blinder - Oaxaca decomposition, separating the part of the differential in mean visual analogue scale value (VAS) due to group differences in the predictors (prevalence effect), due to differences in the coefficients (severity effect), and an interaction term. Variables included were the VAS value, education level, labour status, marital status, all common chronic conditions over the two cross sections, and a variable for non-common chronic conditions and other conditions. Sample weights have been applied. RESULTS: Results show that there is an increase in mean VAS for men aged 15-44, and a decrease in mean VAS for women aged 65-74 and 75 and more. The increase in mean VAS for men aged 15-44 could be explained by a decrease in the severity effect, which offsets the increase in the prevalence effect. The decrease in mean VAS for women aged 65-74 and 75 and more could be explained by an increase in the prevalence effect, which does not offset the decrease in the severity effect. CONCLUSIONS: The results of the present analysis corroborate the paradox of health hypothesis for the population of Catalonia, and highlight the need to be careful when measuring population health over time, as well as their usefulness to detect population's perceptions. PMID- 21605385 TI - Health information management and perceptions of the quality of care for children with tracheotomy: a qualitative study. AB - BACKGROUND: Children with tracheotomy receive health care from an array of providers within various hospital and community health system sectors. Previous studies have highlighted substandard health information exchange between families and these sectors. The aim of this study was to investigate the perceptions and experiences of parents and providers with regard to health information management, care plan development and coordination for children with tracheotomy, and strategies to improve health information management for these children. METHODS: Individual and group interviews were performed with eight parents and fifteen healthcare (primary and specialty care, nursing, therapist, equipment) providers of children with tracheotomy. The primary tracheotomy-associated diagnoses for the children were neuromuscular impairment (n = 3), airway anomaly (n = 2) and chronic lung disease (n = 3). Two independent reviewers conducted deep reading and line-by-line coding of all transcribed interviews to discover themes associated with the objectives. RESULTS: Children with tracheotomy in this study had healthcare providers with poorly defined roles and responsibilities who did not actively communicate with one another. Providers were often unsure where to find documentation relating to a child's tracheotomy equipment settings and home nursing orders, and perceived that these situations contributed to medical errors and delayed equipment needs. Parents created a home record that was shared with multiple providers to track the care that their children received but many considered this a burden better suited to providers. Providers benefited from the parent records, but questioned their accuracy regarding critical tracheotomy care plan information such as ventilator settings. Parents and providers endorsed potential improvement in this environment such as a comprehensive internet-based health record that could be shared among parents and providers, and between various clinical sites. CONCLUSIONS: Participants described disorganized tracheotomy care and health information mismanagement that could help guide future investigations into the impact of improved health information systems for children with tracheotomy. Strategies with the potential to improve tracheotomy care delivery could include defined roles and responsibilities for tracheotomy providers, and improved organization and parent support for maintenance of home based tracheotomy records with web-based software applications, personal health record platforms and health record data authentication techniques. PMID- 21605386 TI - Improved functional overview of protein complexes using inferred epistatic relationships. AB - BACKGROUND: Epistatic Miniarray Profiling(E-MAP) quantifies the net effect on growth rate of disrupting pairs of genes, often producing phenotypes that may be more (negative epistasis) or less (positive epistasis) severe than the phenotype predicted based on single gene disruptions. Epistatic interactions are important for understanding cell biology because they define relationships between individual genes, and between sets of genes involved in biochemical pathways and protein complexes. Each E-MAP screen quantifies the interactions between a logically selected subset of genes (e.g. genes whose products share a common function). Interactions that occur between genes involved in different cellular processes are not as frequently measured, yet these interactions are important for providing an overview of cellular organization. RESULTS: We introduce a method for combining overlapping E-MAP screens and inferring new interactions between them. We use this method to infer with high confidence 2,240 new strongly epistatic interactions and 34,469 weakly epistatic or neutral interactions. We show that accuracy of the predicted interactions approaches that of replicate experiments and that, like measured interactions, they are enriched for features such as shared biochemical pathways and knockout phenotypes. We constructed an expanded epistasis map for yeast cell protein complexes and show that our new interactions increase the evidence for previously proposed inter-complex connections, and predict many new links. We validated a number of these in the laboratory, including new interactions linking the SWR-C chromatin modifying complex and the nuclear transport apparatus. CONCLUSION: Overall, our data support a modular model of yeast cell protein network organization and show how prediction methods can considerably extend the information that can be extracted from overlapping E-MAP screens. PMID- 21605387 TI - Percutaneous coronary intervention in Asians--are there differences in clinical outcome? AB - BACKGROUND: Ethnic differences in clinical outcome after percutaneous coronary intervention (PCI) have been reported. Data within different Asian subpopulations is scarce. We aim to explore the differences in clinical profile and outcome between Chinese, Malay and Indian Asian patients who undergo PCI for coronary artery disease (CAD). METHODS: A prospective registry of consecutive patients undergoing PCI from January 2002 to December 2007 at a tertiary care center was analyzed. Primary endpoint was major adverse cardiovascular events (MACE) of myocardial infarction (MI), repeat revascularization and all-cause death at six months. RESULTS: 7889 patients underwent PCI; 7544 (96%) patients completed follow-up and were included in the analysis (79% males with mean age of 59 years +/- 11). There were 5130 (68%) Chinese, 1056 (14%) Malays and 1001 (13.3%) Indian patients. The remaining 357 (4.7%) patients from other minority ethnic groups were excluded from the analysis. The primary end-point occurred in 684 (9.1%) patients at six months. Indians had the highest rates of six month MACE compared to Chinese and Malays (Indians 12% vs. Chinese 8.2% vs. Malays 10.7%; OR 1.55 95%CI 1.24-1.93, p < 0.001). This was contributed by increased rates of MI (Indians 1.9% vs. Chinese 0.9% vs. Malays 1.3%; OR 4.49 95%CI 1.91-10.56 p = 0.001), repeat revascularization (Indians 6.5% vs. Chinese 4.1% vs. Malays 5.1%; OR 1.64 95%CI 1.22-2.21 p = 0.0012) and death (Indians 11.4% vs. Chinese 7.6% vs. Malays 9.9%; OR 1.65 95%CI 1.23-2.20 p = 0.001) amongst Indian patients. CONCLUSION: These data indicate that ethnic variations in clinical outcome exist following PCI. In particular, Indian patients have higher six month event rates compared to Chinese and Malays. Future studies are warranted to elucidate the underlying mechanisms behind these variations. PMID- 21605388 TI - Variations in food and drink advertising in UK monthly women's magazines according to season, magazine type and socio-economic profile of readers: a descriptive study of publications over 12 months. AB - BACKGROUND: Overweight and obesity are recognised nationally and internationally as key public health challenges. Food and drink advertising is one of the array of factors that influence both diet and physical activity choices and, hence, body weight and obesity. Little previous work has focused on food and drink advertising in magazines. We studied food and drink advertising in a wide range of popular UK monthly women's magazines published over a full year. We explored differences in the prevalence of food and drink advertising and the type of food and drinks advertised according to season, magazine type and socio-economic profile of readers. METHODS: All advertisements in all issues of 18 popular UK monthly women's magazines published over 12 months were identified. For each food or drink advertisement, branded food and drinks were noted and categorised into one of seven food groups. All analyses were at the level of the individual advertisement. RESULTS: A total of 35 053 advertisements were identified; 1380 (3.9%) of these were for food or drink. The most common food group represented was 'food and drinks high in fat and/or sugar' (28.0% of food advertisements), the least common group was 'fruits & vegetables' (2.0% of food advertisements). Advertisements for alcohol accounted for 10.1% of all food advertisements. Food and drink advertisements were most common in summer, general interest magazines, and those with the most affluent readerships. There were some differences in the type of food and drink advertised across season, magazine type and socio-economic profile of readers. CONCLUSIONS: Food and drink advertisements represented only a small proportion of advertisements in UK women's monthly magazines. Food and drink advertisements in these magazines feature a high proportion of 'less healthy' foods. There were a number of differences across season, magazine type and according to the socio-economic profile of readers in the prevalence of food and drink advertisements. Fewer differences were seen in the type of food and drinks advertised. PMID- 21605390 TI - The association of quality of life with potentially remediable disruptions of circadian sleep/activity rhythms in patients with advanced lung cancer. AB - BACKGROUND: Cancer patients routinely develop symptoms consistent with profound circadian disruption, which causes circadian disruption diminished quality of life. This study was initiated to determine the relationship between the severity of potentially remediable cancer-associated circadian disruption and quality of life among patients with advanced lung cancer. METHODS: We concurrently investigated the relationship between the circadian rhythms of 84 advanced lung cancer patients and their quality of life outcomes as measured by the EORTC QLQ C30 and Ferrans and Powers QLI. The robustness and stability of activity/sleep circadian daily rhythms were measured by actigraphy. Fifty three of the patients in the study were starting their definitive therapy following diagnosis and thirty one patients were beginning second-line therapy. Among the patients who failed prior therapy, the median time between completing definitive therapy and baseline actigraphy was 4.3 months, (interquartile range 2.1 to 9.8 months). RESULTS: We found that circadian disruption is universal and severe among these patients compared to non-cancer-bearing individuals. We found that each of these patient's EORTC QLQ C30 domain scores revealed a compromised capacity to perform the routine activities of daily life. The severity of several, but not all, EORTC QLQ C30 symptom items correlate strongly with the degree of individual circadian disruption. In addition, the scores of all four Ferrans/Powers QLI domains correlate strongly with the degree of circadian disruption. Although Ferrans/Powers QLI domain scores show that cancer and its treatment spared these patients' emotional and psychological health, the QLI Health/Function domain score revealed high levels of patients' dissatisfaction with their health which is much worse when circadian disruption is severe. Circadian disruption selectively affects specific Quality of Life domains, such as the Ferrans/Powers Health/Function domain, and not others, such as EORTC QLQ C30 Physical Domain. CONCLUSIONS: These data suggest the testable possibility that behavioral, hormonal and/or light-based strategies to improve circadian organization may help patients suffering from advanced lung cancer to feel and function better. PMID- 21605391 TI - Obesity is a negative predictor of success after surgery for complex anal fistula. AB - BACKGROUND: It was the aim of this study to compare the outcome of surgery for complex anal fistulas in obese and non-obese patients. METHODS: All patients with complex anorectal fistulas who underwent fistulectomy and/or rectal advancement flap repair were prospectively recorded. Surgery was performed in a standardized technique. Body mass index (BMI [kg/m2]) was used as objective measure to indicate morbid obesity. Patients with a BMI greater than 30 were defined as obese, and patients with a BMI below 30 were defined as non-obese. The parameters analyzed related to BMI included success or failure, and reoperation rate due to recurrent abscess. Success was defined as closure of both internal and external openings, absence of drainage without further intervention, and absence of abscess formation. RESULTS: Within two years, 220 patients underwent advancement flap repair and met the inclusion criteria. 55% of patients were females, mean age was 39 (range 18-76) years, and the majority of fistulas were located at the posterior site. 69% of patients (152/220) were non-obese (BMI < 30), whereas 31% (68/220) were obese (BMI > 30). After a median follow-up of 6 months, primary healing rate ("success") for the whole collective was 82% (180/220). Success was significantly different between non-obese and obese patients: In non-obese patients, recurrence rate was significantly lower than in obese patients (14% vs. 28%; p < 0.01). Moreover, reoperation rate due to recurrent abscess with the need for seton drainage in the failure groups was significantly higher in obese patients when compared to non-obese patients (73% vs. 52%; p < 0.01). Using multivariate analysis, obesity was identified as independent predictive factor of success or failure (p < 0.02). CONCLUSION: Obese patients are at higher risk for failure after surgery for complex anal fistula. PMID- 21605392 TI - Psychometric properties of the OLQ-13 scale to measure Sense of Coherence in a community-dwelling older population. AB - BACKGROUND: With the ongoing demographic shift, the quality of life and health promotion among older individuals are becoming increasingly important. Recent research suggests that Sense of Coherence positively affects quality of life. Hence, a valid and reliable measurement of Sense of Coherence is pivotal. The 13 item Orientation to Life Questionnaire (OLQ-13) can be used to measure Sense of Coherence. The purpose of the present study is to assess the psychometric properties, validity, and reliability, of the OLQ-13 in community-dwelling individuals, aged 65 and older. METHODS: The OLQ-13 scale was administered as part of a healthy aging project for non-institutionalized people aged 65 years and older. Internal consistency and reliability were assessed by means of inter item and test-halves correlations and Cronbach's alpha. Construct validity was explored using cluster analysis and exploratory factor analysis (n = 703) and tested using confirmatory factor analysis on a separate subset of individuals (n = 658). Item face validity was investigated by means of 12 semi-structured interviews. RESULTS: The reliability and the validity of the OLQ-13 in this population of non-institutionalized individuals aged 65 years and older was ambiguous, at least partly due to the poor performance of two items (b and d), which was confirmed by results from the qualitative part of this study. The psychometric properties of the proposed OLQ-11, obtained by deleting the two items, were better. In particular, the interpretation of exploratory factor solution improved. Whereas the underlying theoretical constructs could not be linked to the exploratory analyses of OLQ-13, this was to some extent possible in OLQ-11. The superior validity of OLQ-11 over OLQ-13 was supported by the better model fit in the confirmatory factor analysis. CONCLUSIONS: The present mixed method study suggests the proposed OLQ-11 as a more suitable instrument for measuring Sense of Coherence than the OLQ-13 in a population of ageing individuals. This study confirms that the validity and reliability of OLQ-13 may differ substantially in different populations. PMID- 21605393 TI - An adjuvant free mouse model of oral allergenic sensitization to rice seeds protein. AB - BACKGROUND: Rice is commonly known as a staple crop consumed worldwide, though with several rice proteins being reported for allergic properties in clinical studies. Thus, there is a growing need for the development of an animal model to better understand the allergenicity of rice proteins and the immunological and pathophysiological mechanisms underlying the development of food allergy. METHODS: Groups of BALB/c mice were sensitized daily with freshly homogenized rice flour (30 mg or 80 mg) without adjuvant by intragastric gavage. In addition, the mice were challenged with extracted rice flour proteins at several time points intragastrically. Hypersensitivity symptoms in mice were evaluated according to a scoring system. Vascular leakage, ELISA of rice protein-specific IgE, histopathology of small intestine, and passive cutaneous anaphylaxis were conducted on challenged mice. RESULTS: An adjuvant free mouse model of rice allergy was established with sensitized mice showing increased scratching behaviors and increased vascular permeability. Rice protein-specific IgE was detected after eighteen days of sensitization and from the fifth challenge onwards. Inflammatory damage to the epithelium in the small intestine of mice was observed beyond one month of sensitization. Passive cutaneous anaphylaxis results confirmed the positive rice allergy in the mouse model. CONCLUSIONS: We introduced a BALB/c mouse model of rice allergy with simple oral sensitization without the use of adjuvant. This model would serve as a useful tool for further analysis on the immunopathogenic mechanisms of the various rice allergens, for the evaluation of the hypersensitivity of rice or other cereal grains, and to serve as a platform for the development of immunotherapies against rice allergens. PMID- 21605394 TI - Renal effects of dexmedetomidine during coronary artery bypass surgery: a randomized placebo-controlled study. AB - BACKGROUND: Dexmedetomidine, an alpha2-adrenoceptor agonist, has been evaluated as an adjunct to anesthesia and for the delivery of sedation and perioperative hemodynamic stability. It provokes dose-dependent and centrally-mediated sympatholysis. Coronary artery bypass grafting (CABG) with extracorporeal circulation is a stressful procedure increasing sympathetic nervous system activity which could attenuate renal function due the interrelation of sympathetic nervous system, hemodynamics and renal function. We tested the hypothesis that dexmetomidine would improve kidney function in patients undergoing elective CABG during the first two postoperative days. METHODS: This was a double-blind, randomized, parallel-group study. Patients with normal renal function and scheduled for elective CABG were randomized to placebo or to infusion of dexmedetomidine to achieve a pseudo steady-state plasma concentration of 0.60 ng/ml. The infusion was started after anesthesia induction and continued until 4 h after surgery. The primary endpoint was creatinine clearance. Other variables included urinary creatinine and output, fractional sodium and potassium excretion, urinary potassium, sodium and glucose, serum and urinary osmolality and plasma catecholamine concentrations. The data were analyzed with repeated measures ANOVA or Cochran-Mantel-Haenszel test. RESULTS: Sixty-six of 87 randomized patients were evaluable for analysis. No significant between-group differences were recorded for any indices of renal function except for a mean 74% increase in urinary output with dexmedetomidine in the first 4 h after insertion of a urinary catheter (p < 0.001). Confidence interval examination revealed that the sample size was large enough for the no-difference statement for creatinine clearance. CONCLUSIONS: Use of intravenous dexmedetomidine did not alter renal function in this cohort of relatively low-risk elective CABG patients but was associated with an increase in urinary output.This study was carried out in 1994 1997 and was thus not registered. PMID- 21605389 TI - The role of gender in a smoking cessation intervention: a cluster randomized clinical trial. AB - BACKGROUND: The prevalence of smoking in Spain is high in both men and women. The aim of our study was to evaluate the role of gender in the effectiveness of a specific smoking cessation intervention conducted in Spain. METHODS: This study was a secondary analysis of a cluster randomized clinical trial in which the randomization unit was the Basic Care Unit (family physician and nurse who care for the same group of patients). The intervention consisted of a six-month period of implementing the recommendations of a Clinical Practice Guideline. A total of 2,937 current smokers at 82 Primary Care Centers in 13 different regions of Spain were included (2003-2005). The success rate was measured by a six-month continued abstinence rate at the one-year follow-up. A logistic mixed-effects regression model, taking Basic Care Units as random-effect parameter, was performed in order to analyze gender as a predictor of smoking cessation. RESULTS: At the one-year follow-up, the six-month continuous abstinence quit rate was 9.4% in men and 8.5% in women (p = 0.400). The logistic mixed-effects regression model showed that women did not have a higher odds of being an ex-smoker than men after the analysis was adjusted for confounders (OR adjusted = 0.9, 95% CI = 0.7-1.2). CONCLUSIONS: Gender does not appear to be a predictor of smoking cessation at the one-year follow-up in individuals presenting at Primary Care Centers. CLINICALTRIALS.GOV IDENTIFIER: NCT00125905. PMID- 21605395 TI - (Correcting) misdiagnoses of asthma: a cost effectiveness analysis. AB - BACKGROUND: The prevalence of physician-diagnosed-asthma has risen over the past three decades and misdiagnosis of asthma is potentially common. OBJECTIVE: to determine whether a secondary-screening-program to establish a correct diagnosis of asthma in those who report a physician diagnosis of asthma is cost effective. METHOD: Randomly selected physician-diagnosed-asthmatic subjects from 8 Canadian cities were studied with an extensive diagnostic algorithm to rule-in, or rule out, a correct diagnosis of asthma. Subjects in whom the diagnosis of asthma was excluded were followed up for 6-months and data on asthma medications and heath care utilization was obtained. Economic analysis was performed to estimate the incremental lifetime costs associated with secondary screening of previously diagnosed asthmatic subjects. Analysis was from the perspective of the Canadian healthcare system and is reported in Canadian dollars. RESULTS: Of 540 randomly selected patients with physician diagnosed asthma 150 (28%; 95%CI 19-37%) did not have asthma when objectively studied. 71% of these misdiagnosed patients were on some asthma medications. Incorporating the incremental cost of secondary screening for the diagnosis of asthma, we found that the average cost savings per 100 individuals screened was $35,141 (95%CI $4,588-$69,278). CONCLUSION: Cost savings primarily resulted from lifetime costs of medication use averted in those who had been misdiagnosed. PMID- 21605396 TI - Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study. AB - BACKGROUND: The inhaled corticosteroid (ICS) fluticasone propionate (fluticasone) and the long-acting beta2-agonist (LABA) formoterol fumarate (formoterol) are being made available as a combination product (fluticasone/formoterol, flutiform (r)) in a single aerosol inhaler. This 12-week, open-label, randomized, active controlled, parallel-group, multicentre, phase 3 study compared the efficacy and safety of fluticasone/formoterol with the commercially available combination product fluticasone/salmeterol. METHODS: Patients aged >= 18 years (N = 202) with mild-to-moderate-severe, persistent asthma for >= 6 months prior to screening were included in the study. After a screening phase (4-10 days), eligible patients were randomized 1:1 to receive fluticasone/formoterol or fluticasone/salmeterol during the 12-week treatment period. The primary objective was to demonstrate non-inferiority of fluticasone/formoterol versus fluticasone/salmeterol, measured by pre-dose forced expiratory volume in the first second (FEV1), at week 12. RESULTS: Fluticasone/formoterol was comparable to fluticasone/salmeterol for the primary efficacy endpoint, mean pre-dose FEV1 at week 12. The new combination was also comparable to fluticasone/salmeterol for change from baseline to week 12 in pre-dose FEV1, change from pre-dose FEV1 at baseline to 2-hour post-dose FEV1 at week 12 and discontinuations due to lack of efficacy. Importantly, fluticasone/formoterol was superior to fluticasone/salmeterol in time to onset of action throughout the duration of the study. The two treatments demonstrated similar results for various other secondary efficacy parameters, including other lung function tests, patient reported outcomes, rescue medication use, asthma exacerbations and Asthma Quality of Life Questionnaire scores. Fluticasone/formoterol was well tolerated and had a good safety profile that was similar to fluticasone/salmeterol. CONCLUSIONS: The results of this study indicate that fluticasone/formoterol is as effective as fluticasone/salmeterol, and has a more rapid onset of action, reflecting the faster bronchodilatory effects of formoterol compared with those of salmeterol. If patients perceive the benefits of therapy with fluticasone/formoterol more rapidly than with fluticasone/salmeterol, this could have a positive impact on preference and adherence. PMID- 21605397 TI - Responsiveness differences in outcome instruments after revision hip arthroplasty: what are the implications? AB - Responsiveness to change is an important psychometric property of an outcome instrument. Assessment of health-related quality of life (HRQoL) is critical to outcome assessment after total joint replacement, a surgery aimed at improving pain, function and HRQoL of the patients undergoing these procedures. In a recent study, Shi et al. examined the responsiveness to change of various subscales of two instruments, physician-administered Harris Hip Score and patient self administered Short Form-36 (SF-36), 6 months after revision total hip arthroplasty. The responsiveness statistics for both scales were reasonable, higher for Harris Hip Score than SF-36. This is the first study to examine responsiveness of these instruments in revision THA patients in a systematic fashion. PMID- 21605398 TI - Decline in Health-Related Quality of Life reported by more than half of those waiting for joint replacement surgery: a prospective cohort study. AB - BACKGROUND: In many healthcare systems, people with severe joint disease wait months to years for joint replacement surgery. There are little empirical data on the health consequences of this delay and it is unclear whether people with substantial morbidity at entry to the waiting list continue to deteriorate further while awaiting surgery. This study investigated changes in Health-Related Quality of Life (HRQoL), health status and psychological distress among people waiting for total hip (THR) and knee replacement (TKR) surgery at a major metropolitan Australian public hospital. METHODS: 134 patients completed questionnaires including the Assessment of Quality of Life (AQoL) instrument, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Kessler Psychological Distress Scale after entering an orthopaedic waiting list (baseline) and before surgery (preadmission). To quantify potential decline in wellbeing, we calculated the proportion of people experiencing clinically important deterioration using published guidelines and compared HRQoL and psychological distress outcomes with population norms. RESULTS: Most participants (69%) waited >=6 months for surgery (median 286 days, IQR 169-375 days). Despite poor physical and psychological wellbeing at baseline, there was an overall deterioration in HRQoL during the waiting period (mean AQoL change -0.04, 95%CI 0.08 to -0.01), with 53% of participants experiencing decline in HRQoL (>=0.04 AQoL units). HRQoL prior to surgery remained substantially lower than Australian population norms (mean sample AQoL 0.37, 95%CI 0.33 to 0.42 vs mean population AQoL 0.83, 95%CI 0.82 to 0.84). Twenty-five per cent of participants showed decline in health status (>=9.6 WOMAC units) over the waiting period and prevalence of high psychological distress remained high at preadmission (RR 3.5, 95%CI 2.8 to 4.5). Most participants considered their pain (84%), fatigue (76%), quality of life (73%) and confidence in managing their health (55%) had worsened while waiting for surgery. CONCLUSIONS: Despite substantial initial morbidity, over half of the participants awaiting joint replacement experienced deterioration in HRQoL during the waiting period. These data provide much-needed evidence to guide health professionals and policymakers in the design of care pathways and resource allocation for people who require joint replacement surgery. PMID- 21605399 TI - The biomedical discourse relation bank. AB - BACKGROUND: Identification of discourse relations, such as causal and contrastive relations, between situations mentioned in text is an important task for biomedical text-mining. A biomedical text corpus annotated with discourse relations would be very useful for developing and evaluating methods for biomedical discourse processing. However, little effort has been made to develop such an annotated resource. RESULTS: We have developed the Biomedical Discourse Relation Bank (BioDRB), in which we have annotated explicit and implicit discourse relations in 24 open-access full-text biomedical articles from the GENIA corpus. Guidelines for the annotation were adapted from the Penn Discourse TreeBank (PDTB), which has discourse relations annotated over open-domain news articles. We introduced new conventions and modifications to the sense classification. We report reliable inter-annotator agreement of over 80% for all sub-tasks. Experiments for identifying the sense of explicit discourse connectives show the connective itself as a highly reliable indicator for coarse sense classification (accuracy 90.9% and F1 score 0.89). These results are comparable to results obtained with the same classifier on the PDTB data. With more refined sense classification, there is degradation in performance (accuracy 69.2% and F1 score 0.28), mainly due to sparsity in the data. The size of the corpus was found to be sufficient for identifying the sense of explicit connectives, with classifier performance stabilizing at about 1900 training instances. Finally, the classifier performs poorly when trained on PDTB and tested on BioDRB (accuracy 54.5% and F1 score 0.57). CONCLUSION: Our work shows that discourse relations can be reliably annotated in biomedical text. Coarse sense disambiguation of explicit connectives can be done with high reliability by using just the connective as a feature, but more refined sense classification requires either richer features or more annotated data. The poor performance of a classifier trained in the open domain and tested in the biomedical domain suggests significant differences in the semantic usage of connectives across these domains, and provides robust evidence for a biomedical sublanguage for discourse and the need to develop a specialized biomedical discourse annotated corpus. The results of our cross-domain experiments are consistent with related work on identifying connectives in BioDRB. PMID- 21605400 TI - The cost of changing physical activity behaviour: evidence from a "physical activity pathway" in the primary care setting. AB - BACKGROUND: The 'Physical Activity Care Pathway' (a Pilot for the 'Let's Get Moving' policy) is a systematic approach to integrating physical activity promotion into the primary care setting. It combines several methods reported to support behavioural change, including brief interventions, motivational interviewing, goal setting, providing written resources, and follow-up support. This paper compares costs falling on the UK National Health Service (NHS) of implementing the care pathway using two different recruitment strategies and provides initial insights into the cost of changing physical activity behaviour. METHODS: A combination of a time driven variant of activity based costing, audit data through EMIS and a survey of practice managers provided patient-level cost data for 411 screened individuals. Self reported physical activity data of 70 people completing the care pathway at three month was compared with baseline using a regression based 'difference in differences' approach. Deterministic and probabilistic sensitivity analyses in combination with hypothesis testing were used to judge how robust findings are to key assumptions and to assess the uncertainty around estimates of the cost of changing physical activity behaviour. RESULTS: It cost L53 (SD 7.8) per patient completing the PACP in opportunistic centres and L191 (SD 39) at disease register sites. The completer rate was higher in disease register centres (27.3% vs. 16.2%) and the difference in differences in time spent on physical activity was 81.32 (SE 17.16) minutes/week in patients completing the PACP; so that the incremental cost of converting one sedentary adult to an 'active state' of 150 minutes of moderate intensity physical activity per week amounts to L 886.50 in disease register practices, compared to opportunistic screening. CONCLUSIONS: Disease register screening is more costly than opportunistic patient recruitment. However, additional costs come with a higher completion rate and better outcomes in terms of behavioural change in patients completing the care pathway. Further research is needed to rigorously evaluate intervention efficiency and to assess the link between behavioural change and changes in quality adjusted life years (QALYs). PMID- 21605401 TI - Comparative evaluation of two rapid field tests for malaria diagnosis: Partec Rapid Malaria Test(r) and Binax Now(r) Malaria Rapid Diagnostic Test. AB - BACKGROUND: About 90% of all malaria deaths in sub-Saharan Africa occur in children under five years. Fast and reliable diagnosis of malaria requires confirmation of the presence of malaria parasites in the blood of patients with fever or history suggestive of malaria; hence a prompt and accurate diagnosis of malaria is the key to effective disease management. Confirmation of malaria infection requires the availability of a rapid, sensitive, and specific testing at an affordable cost. We compared two recent methods (the novel Partec Rapid Malaria Test(r) (PT) and the Binax Now(r) Malaria Rapid Diagnostic Test (BN RDT) with the conventional Giemsa stain microscopy (GM) for the diagnosis of malaria among children in a clinical laboratory of a hospital in a rural endemic area of Ghana. METHODS: Blood samples were collected from 263 children admitted with fever or a history of fever to the pediatric clinic of the Agogo Presbyterian Hospital. The three different test methods PT, BN RDT and GM were performed independently by well trained and competent laboratory staff to assess the presence of malaria parasites. Results were analyzed and compared using GM as the reference standard. RESULTS: In 107 (40.7%) of 263 study participants, Plasmodium sp. was detected by GM. PT and BN RDT showed positive results in 111 (42.2%) and 114 (43.4%), respectively. Compared to GM reference standard, the sensitivities of the PT and BN RDT were 100% (95% CI: 96.6-100) and 97.2% (95% CI: 92.0-99.4), respectively, specificities were 97.4% (95% CI: 93.6-99.3) and 93.6% (95% CI: 88.5-96.9), respectively. There was a strong agreement (kappa) between the applied test methods (GM vs PT: 0.97; p < 0.001 and GM vs BN RDT: 0.90; p < 0.001). The average turnaround time per tests was 17 minutes. CONCLUSION: In this study two rapid malaria tests, PT and BN RDT, demonstrated a good quality of their performance compared to conventional GM. Both methods require little training, have short turnaround times, are applicable as well as affordable and can therefore be considered as alternative diagnostic tools in malaria endemic areas. The species of Plasmodium cannot be identified. PMID- 21605402 TI - Lineage relationship of prostate cancer cell types based on gene expression. AB - BACKGROUND: Prostate tumor heterogeneity is a major factor in disease management. Heterogeneity could be due to multiple cancer cell types with distinct gene expression. Of clinical importance is the so-called cancer stem cell type. Cell type-specific transcriptomes are used to examine lineage relationship among cancer cell types and their expression similarity to normal cell types including stem/progenitor cells. METHODS: Transcriptomes were determined by Affymetrix DNA array analysis for the following cell types. Putative prostate progenitor cell populations were characterized and isolated by expression of the membrane transporter ABCG2. Stem cells were represented by embryonic stem and embryonal carcinoma cells. The cancer cell types were Gleason pattern 3 (glandular histomorphology) and pattern 4 (aglandular) sorted from primary tumors, cultured prostate cancer cell lines originally established from metastatic lesions, xenografts LuCaP 35 (adenocarcinoma phenotype) and LuCaP 49 (neuroendocrine/small cell carcinoma) grown in mice. No detectable gene expression differences were detected among serial passages of the LuCaP xenografts. RESULTS: Based on transcriptomes, the different cancer cell types could be clustered into a luminal like grouping and a non-luminal-like (also not basal-like) grouping. The non luminal-like types showed expression more similar to that of stem/progenitor cells than the luminal-like types. However, none showed expression of stem cell genes known to maintain stemness. CONCLUSIONS: Non-luminal-like types are all representatives of aggressive disease, and this could be attributed to the similarity in overall gene expression to stem and progenitor cell types. PMID- 21605403 TI - Urethral catheters: can we reduce use? AB - BACKGROUND: Indwelling urinary catheters are the main cause of healthcare associated urinary tract infections. It can be expected that reduction of the use of urinary catheters will lead to decreased numbers of urinary tract infection. METHODS: The efficacy of an intervention programme to improve adherence to recommendations to reduce the use of urethral catheters was studied in a before after comparison in ten Dutch hospitals. The programme detected barriers and facilitators and each individual facility was supported with developing their own intervention strategy. Outcome was evaluated by the prevalence of catheters, alternatives such as diapers, numbers of urinary tract infections, the percentage of correct indications and the duration of catheterization. The costs of the implementation as well as the catheterization were evaluated. RESULTS: Of a population of 16,495 hospitalized patients 3335 patients of whom 2943 were evaluable for the study, had a urethral catheter. The prevalence of urethral catheters decreased insignificantly in neurology (OR 0.93; 95% CI 0.77 - 1.13) and internal medicine wards (OR 0.97; 95% CI 0.83 - 1.13), decreased significantly in surgical wards (OR 0.84; 95% CI 0.75 - 0.96), but increased significantly in intensive care (IC) and coronary care (CC) units (OR 1.48; 95% CI 1.01 - 2.17). The use of alternatives was limited and remained so after the intervention. Duration of catheterization decreased insignificantly in IC/CC units (ratio after/before 0.95; 95% CI 0.78 - 1.16) and neurology (ratio 0.97; 95% CI 0.80 - 1.18) and significantly in internal medicine (ratio 0.81; 95% CI 0.69 - 0.96) and surgery wards (ratio 0.80; 95% CI 0.71 - 0.90). The percentage of correct indications on the day of inclusion increased from 50 to 67% (p < 0.0001). The prevalence of urinary tract infections in catheterized patients did not change. The mean cost saved per 100 patients was ? 537. CONCLUSION: Targeted implementation of recommendations from an existing guideline can lead to better adherence and cost savings. Especially, hospitals which use a lot of urethral catheters or where catheterization is prolonged, can expect important improvements. PMID- 21605404 TI - Biomechanical analysis and modeling of different vertebral growth patterns in adolescent idiopathic scoliosis and healthy subjects. AB - BACKGROUND: The etiology of AIS remains unclear, thus various hypotheses concerning its pathomechanism have been proposed. To date, biomechanical modeling has not been used to thoroughly study the influence of the abnormal growth profile (i.e., the growth rate of the vertebral body during the growth period) on the pathomechanism of curve progression in AIS. This study investigated the hypothesis that AIS progression is associated with the abnormal growth profiles of the anterior column of the spine. METHODS: A finite element model of the spinal column including growth dynamics was utilized. The initial geometric models were constructed from the bi-planar radiographs of a normal subject. Based on this model, five other geometric models were generated to emulate different coronal and sagittal curves. The detailed modeling integrated vertebral body growth plates and growth modulation spinal biomechanics. Ten years of spinal growth was simulated using AIS and normal growth profiles. Sequential measures of spinal alignments were compared. RESULTS: (1) Given the initial lateral deformity, the AIS growth profile induced a significant Cobb angle increase, which was roughly between three to five times larger compared to measures utilizing a normal growth profile. (2) Lateral deformities were absent in the models containing no initial coronal curvature. (3) The presence of a smaller kyphosis did not produce an increase lateral deformity on its own. (4) Significant reduction of the kyphosis was found in simulation results of AIS but not when using the growth profile of normal subjects. CONCLUSION: Results from this analysis suggest that accelerated growth profiles may encourage supplementary scoliotic progression and, thus, may pose as a progressive risk factor. PMID- 21605405 TI - Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target. AB - BACKGROUND: The role of microRNAs (miRNAs) in regulating gene expression is currently an area of intense interest. Relatively little is known, however, about the role of miRNAs in inflammatory and immunologically-driven disorders. In a mouse model, we have previously shown that miRNAs are potentially important therapeutic targets in allergic asthma, because inhibition of miR-126, one of a small subset of miRNAs upregulated in the airway wall, effectively suppressed Th2 driven airway inflammation and other features of asthma. In the present study, we extended investigation of the therapeutic potential of miRNA inhibition to our well-established model of chronic asthma. METHODS: Female BALB/c mice were systemically sensitised with ovalbumin (OVA) and chronically challenged with low mass concentrations of aerosolised OVA for up to 6 weeks. Airway tissue was obtained by blunt dissection and RNA was isolated for miRNA profiling. On the basis of the results obtained, animals were subsequently treated with either an antagomir to miR-126 (ant-miR-126) or a scrambled control antagomir once weekly during the 6 weeks of chronic challenge, and the effects on airway inflammation and remodelling were assessed using established morphometric techniques. RESULTS: Compared to naive mice, there was selective upregulation of a modest number of miRNAs, notably miR-126, in the airway wall tissue of chronically challenged animals. The relative increase was maximal after 2 weeks of inhalational challenge and subsequently declined to baseline levels. Compared to treatment with the scrambled control, ant-miR-126 significantly reduced recruitment of intraepithelial eosinophils, but had no effect on the chronic inflammatory response, or on changes of airway remodelling. CONCLUSIONS: In this model of chronic asthma, there was an initial increase in expression of a small number of miRNAs in the airway wall, notably miR-126. However, this later declined to baseline levels, suggesting that sustained changes in miRNA may not be essential for perpetuation of chronic asthma. Moreover, inhibition of miR-126 by administration of an antagomir suppressed eosinophil recruitment into the airways but had no effect on chronic inflammation in the airway wall, or on changes of remodelling, suggesting that multiple miRNAs are likely to regulate the development of these lesions. PMID- 21605406 TI - Weight gain and incident obesity among male snus users. AB - BACKGROUND: Snus is a moist smokeless tobacco product which has recently reached beyond its original market of Scandinavia. Snus is now being increasingly used in both the United States and South Africa. The effect of snus use on weight is unknown. This study has therefore investigated the relationship between the use of snus, weight gain (>=5%) and the incidence of obesity (body mass index >=30 kg/m(2)). METHODS: The study participants (n = 9,954 males living in Stockholm County, Sweden) were recruited in 2002 and reassessed in 2007. Tobacco use was categorized according to information obtained in both the baseline and follow-up surveys. Outcomes were assessed by comparing self-reported weight and body mass index between the baseline and follow-up surveys. RESULTS: Stable current snus use (according to both surveys), compared to never having used any kind of tobacco, seemed to be associated with both weight gain (odds ratio = 1.31, 95% confidence interval: 1.04-1.65) and incident obesity (odds ratio = 1.93, 95% confidence interval: 1.13-3.30) after adjustment for age, baseline weight, alcohol consumption, physical activity, education, consumption of fruit and berries, and the frequency of having breakfast. No associations with incident obesity or weight gain were seen for stable former users of snus (according to both surveys) or among men who quit or began using snus during follow-up. CONCLUSIONS: These data suggest that the use of snus is moderately associated with weight gain and incident obesity among men. PMID- 21605407 TI - Novel transposable elements from Anopheles gambiae. AB - BACKGROUND: Transposable elements (TEs) are DNA sequences, present in the genome of most eukaryotic organisms that hold the key characteristic of being able to mobilize and increase their copy number within chromosomes. These elements are important for eukaryotic genome structure and evolution and lately have been considered as potential drivers for introducing transgenes into pathogen transmitting insects as a means to control vector-borne diseases. The aim of this work was to catalog the diversity and abundance of TEs within the Anopheles gambiae genome using the PILER tool and to consolidate a database in the form of a hyperlinked spreadsheet containing detailed and readily available information about the TEs present in the genome of An. gambiae. RESULTS: Here we present the spreadsheet named AnoTExcel that constitutes a database with detailed information on most of the repetitive elements present in the genome of the mosquito. Despite previous work on this topic, our approach permitted the identification and characterization both of previously described and novel TEs that are further described in detailed. CONCLUSIONS: Identification and characterization of TEs in a given genome is important as a way to understand the diversity and evolution of the whole set of TEs present in a given species. This work contributes to a better understanding of the landscape of TEs present in the mosquito genome. It also presents a novel platform for the identification, analysis, and characterization of TEs on sequenced genomes. PMID- 21605408 TI - Validating child vaccination status in a demographic surveillance system using data from a clinical cohort study: evidence from rural South Africa. AB - BACKGROUND: Childhood vaccination coverage can be estimated from a range of sources. This study aims to validate vaccination data from a longitudinal population-based demographic surveillance system (DSS) against data from a clinical cohort study. METHODS: The sample includes 821 children in the Vertical Transmission cohort Study (VTS), who were born between December 2001 and April 2005, and were matched to the Africa Centre DSS, in northern KwaZulu-Natal. Vaccination information in the surveillance was collected retrospectively, using standardized questionnaires during bi-annual household visits, when the child was 12 to 23 months of age. DSS vaccination information was based on extraction from a vaccination card or, if the card was not available, on maternal recall. In the VTS, vaccination data was collected at scheduled maternal and child clinic visits when a study nurse administered child vaccinations. We estimated the sensitivity of the surveillance in detecting vaccinations conducted as part of the VTS during these clinic visits. RESULTS: Vaccination data in matched children in the DSS was based on the vaccination card in about two-thirds of the cases and on maternal recall in about one-third. The sensitivity of the vaccination variables in the surveillance was high for all vaccines based on either information from a South African Road-to-Health (RTH) card (0.94-0.97) or maternal recall (0.94-0.98). Addition of maternal recall to the RTH card information had little effect on the sensitivity of the surveillance variable (0.95-0.97). The estimates of sensitivity did not vary significantly, when we stratified the analyses by maternal antenatal HIV status. Addition of maternal recall of vaccination status of the child to the RTH card information significantly increased the proportion of children known to be vaccinated across all vaccines in the DSS. CONCLUSION: Maternal recall performs well in identifying vaccinated children aged 12-23 months (both in HIV-infected and HIV-uninfected mothers), with sensitivity similar to information extracted from vaccination cards. Information based on both maternal recall and vaccination cards should be used if the aim is to use surveillance data to identify children who received a vaccination. PMID- 21605409 TI - A facile nanoparticle immunoassay for cancer biomarker discovery. AB - BACKGROUND: Gold nanoparticles (AuNPs) scatter light intensely at or near their surface plasmon wavelength region. Using AuNPs coupled with dynamic light scattering (DLS) detection, we developed a facile nanoparticle immunoassay for serum protein biomarker detection and analysis. A serum sample was first mixed with a citrate-protected AuNP solution. Proteins from the serum were adsorbed to the AuNPs to form a protein corona on the nanoparticle surface. An antibody solution was then added to the assay solution to analyze the target proteins of interest that are present in the protein corona. The protein corona formation and the subsequent binding of antibody to the target proteins in the protein corona were detected by DLS. RESULTS: Using this simple assay, we discovered multiple molecular aberrations associated with prostate cancer from both mice and human blood serum samples. From the mice serum study, we observed difference in the size of the protein corona and mouse IgG level between different mice groups (i.e., mice with aggressive or less aggressive prostate cancer, and normal healthy controls). Furthermore, it was found from both the mice model and the human serum sample study that the level of vascular endothelial growth factor (VEGF, a protein that is associated with tumor angiogenesis) adsorbed to the AuNPs is decreased in cancer samples compared to non-cancerous or less malignant cancer samples. CONCLUSION: The molecular aberrations observed from this study may become new biomarkers for prostate cancer detection. The nanoparticle immunoassay reported here can be used as a convenient and general tool to screen and analyze serum proteins and to discover new biomarkers associated with cancer and other human diseases. PMID- 21605410 TI - Characterization of hepatitis C Virus genotype 3a hypervariable region 1 in patients achieved rapid virological response to alpha interferon and ribavirin combination therapy. AB - BACKGROUND: Hepatitis C virus roots a chronic liver disease. Currently approved treatment strategy includes administration of alpha interferon and ribavirin combined therapy for 24-48 weeks. One of the predictor of sustained virological response is an early virological response to treatment characterized as rapid response. Hyper variable region 1 (HVR1) of E2 protein is responsible for viral entry and acts as a target for neutralizing antibodies. Any mutation in this region would effect virus interaction with target cell and viral persistence. METHODS: Thirty one clones of six pre-treatment samples subjected to combination therapy were investigated. Three of the patients were rapid responders (R1, R2 and R3) and two were breakthrough responders (BT1 and BT2). Envelope 2 gene was amplified, cloned and sequenced. Amino acid substitution, frequency, composition and antigenic properties of HVR 1 of E2 protein were studied. RESULTS: In both rapid responders (R.R) (14 amino acid sites) and breakthrough responders (BT.R) (13 amino acid sites) half of the amino acid sites were either conserved or resistant to any physiochemical change due to amino acid substitution. It also indicated that average composition of hydrophilic and basic amino acids were comparatively lower in rapid responders than other samples affecting probable interaction of virus with target cells. A central non antigenic region was constant among the breakthrough responders but differed in length significantly among rapid responders reflecting the adaptive nature of HVR1 to the immune response. CONCLUSIONS: We observed that although HVR1is quite variable region in HCV 3a patients responding differently to treatment it still maintains its physiochemical properties for its proper functioning and viability. PMID- 21605411 TI - Mental fatigue caused by prolonged cognitive load associated with sympathetic hyperactivity. AB - BACKGROUND: It is known that chronic fatigue is associated with sympathetic hyperactivity. However, the relationship between autonomic function and mental fatigue caused by a prolonged mental load in healthy humans is still unclear. Thus, in order to clarify the mechanisms underlying mental fatigue, we examined the association between mental fatigue and autonomic functions. METHODS: The study group comprised 10 healthy participants. To induce mental fatigue, participants performed mental tasks, which consisted of the advanced trail making test, kana pick-out test and mirror drawing test, for 8 hr, corresponding to a normal work day. Autonomic functions were measured by accelerated plethysmography before and after the fatigue-inducing mental tasks. As a control, the same participants completed an 8-hr relaxation session 4 weeks before the fatigue session. RESULTS: After the 8-hr relaxation session, low-frequency component power (LF), high-frequency component power (HF) and low-frequency component power/high-frequency component power ratio (LF/HF ratio) were not changed from baseline. In contrast, after the fatigue session, the HF and LF/HF ratio were significantly changed from baseline; specifically, the HF was lower and LF/HF ratio was higher as compared to those after the relaxation session. CONCLUSIONS: Sympathetic hyperactivity based on decreased parasympathetic activity is associated with mental fatigue induced by prolonged cognitive load. PMID- 21605412 TI - Genes in the terminal regions of orthopoxvirus genomes experience adaptive molecular evolution. AB - BACKGROUND: Orthopoxviruses are dsDNA viruses with large genomes, some encoding over 200 genes. Genes essential for viral replication are located in the center of the linear genome and genes encoding host response modifiers and other host interacting proteins are located in the terminal regions. The central portion of the genome is highly conserved, both in gene content and sequence, while the terminal regions are more diverse. In this study, we investigated the role of adaptive molecular evolution in poxvirus genes and the selective pressures that act on the different regions of the genome. The relative fixation rates of synonymous and non-synonymous mutations (the d(N)/d(S) ratio) are an indicator of the mechanism of evolution of sequences, and can be used to identify purifying, neutral, or diversifying selection acting on a gene. Like highly conserved residues, amino acids under diversifying selection may be functionally important. Many genes experiencing diversifying selection are involved in host-pathogen interactions, such as antigen-antibody interactions, or the "host-pathogen arms race." RESULTS: We analyzed 175 gene families from orthopoxviruses for evidence of diversifying selection. 79 genes were identified as experiencing diversifying selection, 25 with high confidence. Many of these genes are located in the terminal regions of the genome and function to modify the host response to infection or are virion-associated, indicating a greater role for diversifying selection in host-interacting genes. Of the 79 genes, 20 are of unknown function, and implicating diversifying selection as an important mechanism in their evolution may help characterize their function or identify important functional residues. CONCLUSIONS: We conclude that diversifying selection is an important mechanism of orthopoxvirus evolution. Diversifying selection in poxviruses may be the result of interaction with host defense mechanisms. PMID- 21605413 TI - Fearful or functional--a cross-sectional survey of the concepts of childhood fever among German and Turkish mothers in Germany. AB - BACKGROUND: Fever is one of the most common presenting complaints in paediatrics and general practice. In the majority of cases nothing harmful is diagnosed. However, the subjective meaning of fever often varies between doctors and parents. Knowledge of the parents' concept of fever may help tailor counselling to their needs.In this study we determine 1) the influence of socio-economic status and cultural background on two concepts of fever which we labelled "functional" and "fearful", each representing typical experiences of mothers, and 2) the actions taken by the mothers related to these concepts. METHODS: A standardized interview study was conducted among German and Turkish mothers in Germany in 2009. The questionnaire consisted of 36 questions and 205 items. Interviews were conducted in 16 private practices of paediatricians and 2 paediatric emergency departments in an urban region of Germany. The two fever concepts were represented in 6 statements that could be rated with a six-point Likert scale. The association of the socio-economic status and the cultural background with one of the fever concepts was determined by a multiple logistic regression. RESULTS: A total of 338 mothers (49% with a Turkish background) completed the interview (response rate 92%). The average age of mothers with a German background was higher (34.1 years vs. 32.0 years, p=0.0001). Mothers with a Turkish background were more likely to relate to the concept "fearful" [adjusted Odds Ratio (AOR) 1.99; confidence interval (CI) 1.16-3.44]. Mothers with a middle or high socio-economic status were more likely to respond to the concept "functional" [middle: AOR, 0.53; CI, 0.30-0.92; high: AOR, 0.44; CI, 0.21 0.95].Mothers adhering to the concept "fearful" more often gave acetaminophen before the recommended interval of 6 hours (46.8% vs. 31.3%, p=0.005) and visited out-of-hours services more frequently in the preceding 9 months than the other group (0.7 vs. 0.4, p=0.001). CONCLUSIONS: A Turkish migrant background and a low socio-economic status are associated with the fever concept "fearful". Mothers with these attributes seem to require specific and reassuring counselling as they use antipyretic drugs extensively and out-of-hours services frequently. PMID- 21605414 TI - Symbolic flux analysis for genome-scale metabolic networks. AB - BACKGROUND: With the advent of genomic technology, the size of metabolic networks that are subject to analysis is growing. A common task when analyzing metabolic networks is to find all possible steady state regimes. There are several technical issues that have to be addressed when analyzing large metabolic networks including accumulation of numerical errors and presentation of the solution to the researcher. One way to resolve those technical issues is to analyze the network using symbolic methods. The aim of this paper is to develop a routine that symbolically finds the steady state solutions of large metabolic networks. RESULTS: A symbolic Gauss-Jordan elimination routine was developed for analyzing large metabolic networks. This routine was tested by finding the steady state solutions for a number of curated stoichiometric matrices with the largest having about 4000 reactions. The routine was able to find the solution with a computational time similar to the time used by a numerical singular value decomposition routine. As an advantage of symbolic solution, a set of independent fluxes can be suggested by the researcher leading to the formation of a desired flux basis describing the steady state solution of the network. These independent fluxes can be constrained using experimental data. We demonstrate the application of constraints by calculating a flux distribution for the central metabolic and amino acid biosynthesis pathways of yeast. CONCLUSIONS: We were able to find symbolic solutions for the steady state flux distribution of large metabolic networks. The ability to choose a flux basis was found to be useful in the constraint process and provides a strong argument for using symbolic Gauss-Jordan elimination in place of singular value decomposition. PMID- 21605415 TI - Adverse effect profile of trichlormethiazide: a retrospective observational study. AB - BACKGROUND: Trichlormethiazide, a thiazide diuretic, was introduced in 1960 and remains one of the most frequently used diuretics for treating hypertension in Japan. While numerous clinical trials have indicated important side effects of thiazides, e.g., adverse effects on electrolytes and uric acid, very few data exist on serum electrolyte levels in patients with trichlormethiazide treatment. We performed a retrospective cohort study to assess the adverse effects of trichlormethiazide, focusing on serum electrolyte and uric acid levels. METHODS: We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2010, to identify cohorts of new trichlormethiazide users (n = 99 for 1 mg, n = 61 for 2 mg daily dosage) and an equal number of non-users (control). We used propensity-score matching to adjust for differences between users and control for each dosage, and compared serum chemical data including serum sodium, potassium, uric acid, creatinine and urea nitrogen. The mean exposure of trichlormethiazide of 1 mg and 2 mg users was 58 days and 64 days, respectively. RESULTS: The mean age was 66 years, and 55% of trichlormethiazide users of the 1 mg dose were female. In trichlormethiazide users of the 2 mg dose, the mean age was 68 years, and 43% of users were female. There were no statistically significant differences in all covariates (age, sex, comorbid diseases, past drugs, and current antihypertensive drugs) between trichlormethiazide users and controls for both doses. In trichlormethiazide users of the 2 mg dose, the reduction of serum potassium level and the elevation of serum uric acid level were significant compared with control, whereas changes of mean serum sodium, creatinine and urea nitrogen levels were not significant. In trichlormethiazide users of the 1 mg dose, all tests showed no statistically significant change from baseline to during the exposure period in comparison with control. CONCLUSIONS: Our study showed adverse effects of decreased serum potassium and increased serum uric acid with trichlormethiazide treatment, and suggested that a lower dose of trichlormethiazide may minimize these adverse effects. These findings support the current trend in hypertension therapeutics to shift towards lower doses of thiazides. PMID- 21605416 TI - Differences and similarities of postprandial lipemia in rodents and humans. AB - BACKGROUND: The rat has been a mainstay of physiological and metabolic research, and more recently mice. This study aimed at characterizing the postprandial triglyceride profile of two members of the Muridae family: the Wistar rats (Rattus norvegicus albinus) and C57BL/6 mice (Mus musculus) plus comparing them to the profile obtained in humans. METHODS: Thirty-one male and twelve female Wistar rats, ten C57BL/6 male and nine female mice received a liquid meal containing fat (17%), protein (4%) and carbohydrates (4%), providing 2 g fat/Kg. Thirty-one men and twenty-nine women received a standardized liquid meal containing fat (25%), dextromaltose (55%), protein (14%), and vitamins and minerals (6%), and providing 40 g of fat per square meter of body surface. Serial blood samples were collected at 2, 4, 6, 8 and 10 h after the ingestion in rats, at 1, 2, 3, 4, 5 and 6 h in mice and in humans at 2, 4, 6 and 8 h. Wilcoxon and Mann-Whitney tests were used. RESULTS/DISCUSSION: The triglyceride responses were evaluated after the oral fat loads. Fasting and postprandial triglyceridemia were determined sequentially in blood sample. AUC, AUIC, AR, RR and late peaks were determined. CONCLUSIONS: Rats are prone to respond in a pro-atherogenic manner. The responses in mice were closer to the ones in healthy men. This study presents striking differences in postprandial triglycerides patterns between rats and mice not correlated to baseline triglycerides, the animal baseline body weight or fat load in all animal groups. PMID- 21605417 TI - Metformin therapy in a hyperandrogenic anovulatory mutant murine model with polycystic ovarian syndrome characteristics improves oocyte maturity during superovulation. AB - BACKGROUND: Metformin, an oral biguanide traditionally used for the treatment of type 2 diabetes, is widely used for the management of polycystic ovary syndrome (PCOS)-related anovulation. Because of the significant prevalence of insulin resistance and glucose intolerance in PCOS patients, and their putative role in ovulatory dysfunction, the use of metformin was touted as a means to improve ovulatory function and reproductive outcomes in PCOS patients. To date, there has been inconsistent evidence to demonstrate a favorable effect of metformin on oocyte quality and competence in women with PCOS. Given the heterogeneous nature of this disorder, we hypothesized that metformin may be beneficial in mice with aberrant metabolic characteristics similar to a significant number of PCOS patients. The aim of this study was to gain insight into the in vitro and in vivo effects of metformin on oocyte development and ovulatory function. METHODS: We utilized metformin treatment in the transgenic ob/ob and db/db mutant murine models which demonstrate metabolic and reproductive characteristics similar to women with PCOS. RESULTS: Metformin did not improve in vitro oocyte maturation nor did it have an appreciable effect on in vitro granulosa cell luteinization (progesterone production) in any genotype studied. Although both mutant strains have evidence of hyperandrogenemia, anovulation, and hyperinsulinemia, only db/db mice treated with metformin had a greater number of mature oocytes and total overall oocytes compared to control. There was no observed impact on body mass, or serum glucose and androgens in any genotype. CONCLUSIONS: Our data provide evidence to suggest that metformin may optimize ovulatory performance in mice with a specific reproductive and metabolic phenotype shared by women with PCOS. The only obvious difference between the mutant murine models is that the db/db mice have elevated leptin levels raising the questions of whether their response to metformin is related to elevated leptin levels and/or if a subset of PCOS women with hyperleptinemia may be responsive to metformin therapy. Further study is needed to better define a subset of women with PCOS that may be responsive to metformin. PMID- 21605418 TI - To use or not to use a condom: a prospective cohort study comparing contraceptive practices among HIV-infected and HIV-negative youth in Uganda. AB - BACKGROUND: Unwanted pregnancy and HIV infection are issues of significant concern to young people. Limited data exists on contraceptive decision-making and practices among HIV-infected and HIV-negative young people in low resource settings with generalized HIV epidemics. METHODS: From July 2007 until April 2009, we recruited, and followed up over a one year period, a cohort of 501 HIV negative and 276 HIV-infected young women and men aged 15-24 years residing in Kampala and Wakiso districts. We compared contraceptive use among HIV-infected and HIV-negative young people and assessed factors associated with contraceptive decision-making and use, using multivariate logistic regression modelling to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Contraceptive use among sexually active HIV-infected young people was 34% while it was 59% among the HIV-negative group. The condom was the most frequently used method of contraception. Only 24% of the HIV-infected used condoms consistently compared to 38% among the negative group OR 0.56 (95% CI 0.38, 0.82). HIV infected young people were more likely to discuss safe sex behaviour with health workers OR 1.70 (95% CI 1.13, 2.57), though its effect on fertility decision making was not significant. Throughout the year's follow-up, only 24% among the HIV-negative and 18% among the HIV-infected continued to use contraception while 12% and 28% among the HIV-negative and infected respectively did not use contraception at all. At multivariate analysis, the HIV-infected young people were less likely to maintain contraceptive use. Other factors independently associated with sustained contraceptive use were age of the respondent, marital status and being a male. Conversely, HIV-infected young people were less likely to initiate use of contraception. Being married or in a relationship was associated with higher odds of initiating contraceptive use. CONCLUSION: Compared to the HIV-negative group, sexually active HIV-infected young people are less likely to use contraception and condoms. Initiating or sustaining contraceptive use was also significantly less among the HIV-infected group. Strengthening family planning services and developing new innovative ideas to re-market condom use are needed. Policy and guidelines that empower health workers to help young people (especially the HIV infected) express their sexuality and reproduction should urgently be developed. PMID- 21605419 TI - On-chip constructive cell-network study (I): contribution of cardiac fibroblasts to cardiomyocyte beating synchronization and community effect. AB - BACKGROUNDS: To clarify the role of cardiac fibroblasts in beating synchronization, we have made simple lined-up cardiomyocyte-fibroblast network model in an on-chip single-cell-based cultivation system. RESULTS: The synchronization phenomenon of two cardiomyocyte networks connected by fibroblasts showed (1) propagation velocity of electrophysiological signals decreased a magnitude depending on the increasing number of fibroblasts, not the lengths of fibroblasts; (2) fluctuation of interbeat intervals of the synchronized two cardiomyocyte network connected by fibroblasts did not always decreased, and was opposite from homogeneous cardiomyocyte networks; and (3) the synchronized cardiomyocytes connected by fibroblasts sometimes loses their synchronized condition and recovered to synchronized condition, in which the length of asynchronized period was shorter less than 30 beats and was independent to their cultivation time, whereas the length of synchronized period increased according to cultivation time. CONCLUSIONS: The results indicated that fibroblasts can connect cardiomyocytes electrically but do not significantly enhance and contribute to beating interval stability and synchronization. This might also mean that an increase in the number of fibroblasts in heart tissue reduces the cardiomyocyte 'community effect', which enhances synchronization and stability of their beating rhythms. PMID- 21605420 TI - Immunological and molecular epidemiological characteristics of acute and fulminant viral hepatitis A. AB - BACKGROUND: Hepatitis A virus is an infection of liver; it is hyperendemic in vast areas of the world including India. In most cases it causes an acute self limited illness but rarely fulminant. There is growing concern about change in pattern from asymptomatic childhood infection to an increased incidence of symptomatic disease in the adult population. OBJECTIVE: In-depth analysis of immunological, viral quantification and genotype of acute and fulminant hepatitis A virus. METHODS: Serum samples obtained from 1009 cases of suspected acute viral hepatitis was employed for different biochemical and serological examination. RNA was extracted from blood serum, reverse transcribed into cDNA and amplified using nested PCR for viral quantification, sequencing and genotyping. Immunological cell count from freshly collected whole blood was carried out by fluorescence activated cell sorter. RESULTS: Fulminant hepatitis A was mostly detected with other hepatic viruses. CD8+ T cells count increases in fulminant hepatitis to a significantly high level (P = 0.005) compared to normal healthy control. The immunological helper/suppressor (CD4+/CD8+) ratio of fulminant hepatitis was significantly lower compared to acute cases. The serologically positive patients were confirmed by RT-PCR and total of 72 (69.2%) were quantified and sequenced. The average quantitative viral load of fulminant cases was significantly higher (P < 0.05). There was similar genotypic distribution in both acute and fulminant category, with predominance of genotype IIIA (70%) compared to IA (30%). CONCLUSIONS: Immunological factors in combination with viral load defines the severity of the fulminant hepatitis A. Phylogenetic analysis of acute and fulminant hepatitis A confirmed genotypes IIIA as predominant against IA with no preference of disease severity. PMID- 21605421 TI - Assessment of genome integrity with array CGH in cattle transgenic cell lines produced by homologous recombination and somatic cell cloning. AB - BACKGROUND: Transgenic cattle carrying multiple genomic modifications have been produced by serial rounds of somatic cell chromatin transfer (cloning) of sequentially genetically targeted somatic cells. However, cloning efficiency tends to decline with the increase of rounds of cloning. It is possible that multiple rounds of cloning compromise the genome integrity or/and introduce epigenetic errors in the resulting cell lines, rendering a decline in cloning. To test these possibilities, we performed 9 high density array Comparative Genomic Hybridization (CGH) experiments to test the genome integrity in 3 independent bovine transgenic cell lineages generated from genetic modification and cloning. Our plan included the control hybridizations (self to self) of the 3 founder cell lines and 6 comparative hybridizations between these founders and their derived cell lines with either high or low cloning efficiencies. RESULTS: We detected similar amounts of differences between the control hybridizations (8, 13 and 39 differences) and the comparative analyses of both "high" and "low" cell lines (ranging from 7 to 57 with a mean of ~20). Almost 75% of the large differences (>10 kb) and about 45% of all differences shared the same type (loss or gain) and were located in nearby genomic regions across hybridizations. Therefore, it is likely that they were not true differences but caused by systematic factors associated with local genomic features (e.g. GC contents). CONCLUSIONS: Our findings reveal that large copy number variations are less likely to arise during genetic targeting and serial rounds of cloning, fortifying the notion that epigenetic errors introduced from serial cloning may be responsible for the cloning efficiency decline. PMID- 21605422 TI - Major histocompatibility complex class I-related chain A/B (MICA/B) expression in tumor tissue and serum of pancreatic cancer: role of uric acid accumulation in gemcitabine-induced MICA/B expression. AB - BACKGROUND: Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind the immunoreceptor NKG2D and play an important role in mediating the cyotoxicity of NK and T cells. In this study, we sought to study MICA/B expression in pancreatic cancer and to determine whether and how genotoxic drugs such as gemcitabine can affect MICA/B expression and natural killer cytotoxity. METHODS: Seven pancreatic cancer cell lines were analyzed for MICA/B expression by flow cytometry and for their sensitivity to NK 92 cell killing by a 51Cr release assay. MICA/B expression in tumor tissues and sera of pancreatic cancer was analyzed by immunohistochemical staining (IHC) and ELISA, respectively. RESULTS: Two MICA/B-positive cell lines were sensitive to the cytotoxic activity of NK-92 cells. Other two MICA/B-positive cell lines and three MICA/B-negative cell lines were resistant to NK-92 cell killing. MICA/B expression was positive in 17 of 25 (68%) pancreatic ductal adenocarcinomas but not in normal pancreatic ductal epithelial cells. Serum MICA/B levels were significantly elevated in patients with pancreatic adenocarcinomas but did not correlate with the stage of pancreatic cancer and patient survival. Gemcitabine therapy led to increased serum MICA levels in 6 of 10 patients with detectable serum MICA. Allopurinol, an inhibitor of xanthine oxidoreductase that converts xanthine to uric acid, blocked uric acid production, MICA/B expression, and sensitivity to NK-92 cell killing toward a PANC-1 cancer cell line exposed to radiation and two genotoxic drugs, gemcitabine and 5-fluorouracil. CONCLUSIONS: The levels of MICA/B expression in serum and tissue of pancreatic cancer are elevated. DNA damage-induced MICA/B expression is mediated through increased uric acid production. PMID- 21605423 TI - Serum non-high-density lipoprotein cholesterol concentration and risk of death from cardiovascular diseases among U.S. adults with diagnosed diabetes: the Third National Health and Nutrition Examination Survey linked mortality study. AB - BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-C) measures all atherogenic apolipoprotein B-containing lipoproteins and predicts risk of cardiovascular diseases (CVD). The association of non-HDL-C with risk of death from CVD in diabetes is not well understood. This study assessed the hypothesis that, among adults with diabetes, non-HDL-C may be related to the risk of death from CVD. METHODS: We analyzed data from 1,122 adults aged 20 years and older with diagnosed diabetes who participated in the Third National Health and Nutrition Examination Survey linked mortality study (299 deaths from CVD according to underlying cause of death; median follow-up length, 12.4 years). RESULTS: Compared to participants with serum non-HDL-C concentrations of 35 to 129 mg/dL, those with higher serum levels had a higher risk of death from total CVD: the RRs were 1.34 (95% CI: 0.75-2.39) and 2.25 (95% CI: 1.30-3.91) for non HDL-C concentrations of 130-189 mg/dL and 190-403 mg/dL, respectively (P = 0.003 for linear trend) after adjustment for demographic characteristics and selected risk factors. In subgroup analyses, significant linear trends were identified for the risk of death from ischemic heart disease: the RRs were 1.59 (95% CI: 0.76 3.32) and 2.50 (95% CI: 1.28-4.89) (P = 0.006 for linear trend), and stroke: the RRs were 3.37 (95% CI: 0.95-11.90) and 5.81 (95% CI: 1.96-17.25) (P = 0.001 for linear trend). CONCLUSIONS: In diabetics, higher serum non-HDL-C concentrations were significantly associated with increased risk of death from CVD. Our prospective data support the notion that reducing serum non-HDL-C concentrations may be beneficial in the prevention of excess death from CVD among affected adults. PMID- 21605424 TI - Molecular analysis of iduronate -2- sulfatase gene in Tunisian patients with mucopolysaccharidosis type II. AB - Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is X-linked recessive lysosomal storage disorder resulting from the defective activity of the enzyme iduronate-2-sulfatase (IDS). Hunter disease can vary from mild to severe, depending on the level of enzyme deficiency. We report the IDS mutation and polymorphisms causing the Hunter syndrome in patients from one family in Tunisia PATIENTS AND METHODS: A preliminary diagnosis was made by qualitative detection of urinary glycosaminoglycans of the suspected MPS II probands. The IDS mutation and polymorphisms were determined on these probands and their family members by amplifying and sequencing each of the exons and intron-exon junctions of IDS gene. RESULTS: The studied probands were homoallelic for p.R88P mutation. In addition, three known polymorphisms/sequence variants: IVS3-16 (c.419-16 delT), T214M (c.641C > T), T146T (c.438 C > T), IVS5-87(c.709-87G > A) and one previously unknown: IVS7+38(c.1006+38T > C were identified in the MPS II patients. These are the first Tunisian MPS II patients to be genotyped. CONCLUSION: The identification of these mutation and polymorphisms and their genotype-phenotype correlation should facilitate prenatal diagnosis and counseling for MPS II in Tunisia, where a very high rate of consanguinity exists. PMID- 21605425 TI - Time series gene expression profiling and temporal regulatory pathway analysis of BMP6 induced osteoblast differentiation and mineralization. AB - BACKGROUND: BMP6 mediated osteoblast differentiation plays a key role in skeletal development and bone disease. Unfortunately, the signaling pathways regulated by BMP6 are largely uncharacterized due to both a lack of data and the complexity of the response. RESULTS: To better characterize the signaling pathways responsive to BMP6, we conducted a time series microarray study to track BMP6 induced osteoblast differentiation and mineralization. These temporal data were analyzed using a customized gene set analysis approach to identify temporally coherent sets of genes that act downstream of BMP6. Our analysis identified BMP6 regulation of previously reported pathways, such as the TGF-beta pathway. We also identified previously unknown connections between BMP6 and pathways such as Notch signaling and the MYB and BAF57 regulatory modules. In addition, we identify a super-network of pathways that are sequentially activated following BMP6 induction. CONCLUSION: In this work, we carried out a microarray-based temporal regulatory pathway analysis of BMP6 induced osteoblast differentiation and mineralization using GAGE method. This novel temporal analysis is more informative and powerful than the classical static pathway analysis in that: (1) it captures the interconnections between signaling pathways or functional modules and demonstrates the even higher level organization of molecular biological systems; (2) it describes the temporal perturbation patterns of each pathway or module and their dynamic roles in osteoblast differentiation. The same set of experimental and computational strategies employed in our work could be useful for studying other complex biological processes. PMID- 21605426 TI - Enriching for correct prediction of biological processes using a combination of diverse classifiers. AB - BACKGROUND: Machine learning models (classifiers) for classifying genes to biological processes each have their own unique characteristics in what genes can be classified and to what biological processes. No single learning model is qualitatively superior to any other model and overall precision for each model tends to be low. The classification results for each classifier can be complementary and synergistic suggesting the benefit of a combination of algorithms, but often the prediction probability outputs of various learning models are neither comparable nor compatible for combining. A means to compare outputs regardless of the model and data used and combine the results into an improved comprehensive model is needed. RESULTS: Gene expression patterns from NCI's panel of 60 cell lines were used to train a Random Forest, a Support Vector Machine and a Neural Network model, plus two over-sampled models for classifying genes to biological processes. Each model produced unique characteristics in the classification results. We introduce the Precision Index measure (PIN) from the maximum posterior probability that allows assessing, comparing and combining multiple classifiers. The class specific precision measure (PIC) is introduced and used to select a subset of predictions across all classes and all classifiers with high precision. We developed a single classifier that combines the PINs from these five models in prediction and found that the PIN Combined Classifier (PINCom) significantly increased the number of correctly predicted genes over any single classifier. The PINCom applied to test genes that were not used in training also showed substantial improvement over any single model. CONCLUSIONS: This paper introduces novel and effective ways of assessing predictions by their precision and recall plus a method that combines several machine learning models and capitalizes on synergy and complementation in class selection, resulting in higher precision and recall. Different machine learning models yielded incongruent results each of which were successfully combined into one superior model using the PIN measure we developed. Validation of the boosted predictions for gene functions showed the genes to be accurately predicted. PMID- 21605427 TI - Insurance type and sepsis-associated hospitalizations and sepsis-associated mortality among US adults: a retrospective cohort study. AB - INTRODUCTION: Socio-demographic and clinical factors associated with increased sepsis risk, including older age, non-white race and specific co-morbidities, are more common among patients with Medicare or Medicaid or no health insurance. We hypothesized that patients with Medicare and/or Medicaid or without health insurance have a higher risk of sepsis-associated hospitalization or sepsis associated death than those with private health insurance. METHODS: We performed a retrospective cohort study of records from the 2003 Nationwide Inpatient Sample. We stratified the study cohort by Medicare age-qualification (18 to 64 and 65+ years old). We examined the association between insurance category and sepsis diagnosis and death among admissions involving sepsis. We used validated diagnostic codes to determine the presence of sepsis, co-morbidities and organ dysfunction and to provide risk-adjustment. RESULTS: Among patients 18 to 64 years old, those with Medicaid (adjusted odds ratio (AOR) 1.50), Medicare (AOR 1.96), Medicaid + Medicare (AOR 2.22) and the uninsured (AOR 1.18) had significantly higher risk-adjusted odds of a sepsis-associated admission than those with private insurance (all P < 0.0001). Those with Medicaid (AOR 1.17, P < 0.001) and those without insurance (AOR 1.45, P < 0.001) also had significantly higher adjusted odds of sepsis-associated hospital mortality than those with private insurance. Among those 65+ years old, those with Medicaid (AOR 1.43), Medicare alone (AOR 1.13) or Medicaid + Medicare (AOR 1.62) had significantly higher risk-adjusted odds of sepsis-associated admission than those with private insurance and Medicare (all P < 0.0001). Among sepsis patients 65+, uninsured patients had significantly higher risk-adjusted odds (AOR 1.45, P = 0.0048) and those with Medicare alone had significantly lower risk-adjusted odds (AOR 0.92, P = 0.0072) of hospital mortality than those with private insurance and Medicare. Lack of health insurance remained associated with sepsis-associated mortality after stratification of hospitals into quartiles based on rates of sepsis associated admissions or mortality in both age strata. CONCLUSIONS: Risks of sepsis-associated hospitalization and sepsis-associated death vary by insurance. These increased risks were not fully explained by the available socio-demographic factors, co-morbidities or hospital rates of sepsis-related admissions or deaths. PMID- 21605428 TI - Etiological spectrum and treatment outcome of Obstructive jaundice at a University teaching Hospital in northwestern Tanzania: A diagnostic and therapeutic challenges. AB - BACKGROUND: Obstructive jaundice poses diagnostic and therapeutic challenges to general surgeons practicing in resource-limited countries. This study was undertaken to highlight the etiological spectrum, treatment outcome of obstructive jaundice in our setting and to identify prognostic factors for morbidity and mortality. METHODS: This was a descriptive prospective study which was conducted at Bugando Medical Centre between July 2006 and June 2010. All patients with a clinical diagnosis of obstructive jaundice were, after informed consent for the study, consecutively enrolled into the study. Data were collected using a pre-tested structured questionnaire and analyzed using SPSS computer software version 11.5. RESULTS: A total of 116 patients were studied. Females outnumbered males by a ratio of 1.3:1. Patients with malignant obstructive jaundice were older than those of benign type. Ca head of pancreas was the commonest malignant cause of jaundice where as choledocholithiasis was the commonest benign cause. Abdominal ultrasound was the only diagnostic imaging done in all patients and revealed dilated intra and extra-hepatic ducts, common bile stones and abdominal masses in 56.2%, 78.9%, 58.1% and 72.4% of the cases respectively. A total of 110 (94.8%) patients underwent surgical treatment and the remaining 6 (5.2%) patients were unfit for surgery. The complication rate was 22.4% mainly surgical site infections. The mean hospital stay and mortality rate were 14.54 days and 15.5% respectively. A low haematocrit and presence of postoperative sepsis were the main predictors of the hospital stay (P < 0.001), whereas age > 60 years, prolonged duration of jaundice, malignant causes and presence of postoperative complications mainly sepsis significantly predicted mortality (P < 0.001). CONCLUSION: Obstructive jaundice in our setting is more prevalent in females and the cause is mostly malignant. The result of this study suggests that early diagnosis and treatment plays an important role in the prognosis of patients with obstructive jaundice. PMID- 21605429 TI - The role of mutational analysis of KIT and PDGFRA in gastrointestinal stromal tumors in a clinical setting. AB - Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Most GIST harbor a mutation affecting either the KIT or PDGFRA genes, whereas a small subgroup of tumors is wild type for mutations.Mutation of tyrosine kinase receptors is a mechanism of drug resistance that can occur either at the beginning of treatment (primary resistance) or during the course of therapy (secondary resistance). In addition, mutational status can predict the response to treatment with tyrosine kinase inhibitors, but the role of mutational status as a prognostic factor remains controversial.Evidence of a potential role of mutational status as a prognostic factor has emerged over the past decade. The presence of KIT exon 11 insertion/deletion involving either one or both Trp557-Lys558 amino acids correlates with a poorer clinical outcome if compared to patients with tumors wild type for KIT exon 11 mutations. A malignant clinical behavior has also been documented for KIT exon 13 and KIT exon 9 mutant GIST. Patients with GIST harboring a PDGFRA mutation seem to have a better prognosis than the others.The aim of this paper is to review the clinical significance of tyrosine kinase mutational status. PMID- 21605430 TI - Stereochemical errors and their implications for molecular dynamics simulations. AB - BACKGROUND: Biological molecules are often asymmetric with respect to stereochemistry, and correct stereochemistry is essential to their function. Molecular dynamics simulations of biomolecules have increasingly become an integral part of biophysical research. However, stereochemical errors in biomolecular structures can have a dramatic impact on the results of simulations. RESULTS: Here we illustrate the effects that chirality and peptide bond configuration flips may have on the secondary structure of proteins throughout a simulation. We also analyze the most common sources of stereochemical errors in biomolecular structures and present software tools to identify, correct, and prevent stereochemical errors in molecular dynamics simulations of biomolecules. CONCLUSIONS: Use of the tools presented here should become a standard step in the preparation of biomolecular simulations and in the generation of predicted structural models for proteins and nucleic acids. PMID- 21605431 TI - Why my disease is important: metrics of disease occurrence used in the introductory sections of papers in three leading general medical journals in 1993 and 2003. AB - BACKGROUND: We assessed the metrics used in claims about disease importance made in the introductory sections of scientific papers published in 1993 and 2003. We were interested in the choice of metric in circumstances where establishing the relative social importance of a disease was, presumptively, a primary objective. METHODS: This study consisted of a textual examination of the introductory statements from papers retrieved from MEDLINE. Papers were published in the New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association during the first halves of 1993 and 2003, and were selected on the basis of keywords found in a pilot study to be associated with claims about disease importance. RESULTS: We found 143 papers in 1993 and 264 papers in 2003 included claims about disease importance in their introductory sections, and characteristics of these claims were abstracted. Of the quotes identified in the papers and articles examined, most used counts, prevalence, or incidence measurements. Some also used risk estimates and economic quantities to convey the importance of the disease. There was no change in the types of metrics used between 1993 and 2003. Very few articles, even in 2003, used metrics that weighted disease onsets by the expected consequent loss of healthy time -- such as years of life lost, quality-adjusted life years, and/or disability-adjusted life years. CONCLUSIONS: Claims about the relative importance of diseases continued to be overwhelmingly expressed in terms of counts (of deaths and disease onsets) and comparisons of counts, rates, and risks. Where the aim is to convey the burden that a given disease imposes on a society, "event-based" metrics might be less fit for the purpose than "time-based" metrics. More attention is needed to how the choice of metric should relate to the purpose at hand. PMID- 21605432 TI - Biphasic synovial sarcoma in the cervical spine: Case report. AB - Synovial sarcoma is a rare malignant neoplasm of soft tissue that typically arising near large joints of the upper and lower extremities in young adult males. Only 3% of these neoplasms have been found to arise in the head and neck region. To our knowledge, there are limited reports in the literature of this neoplasm in the cervical spine.A case of biphasic synovial sarcoma of the cervical spine is reviewed. A 29 year-old male presented with pain on the left side of the cervical spine. Physical examination revealed a global loss of cervical motion and large, palpable mass in the left paravertebral area. The long delayed Magnetic Resonance (MR) scan revealed a soft tissue mass measuring 8.3 centimeters (cm) * 5.7 cm that was surgically removed. A malignant biphasic synovial sarcoma was diagnosed on pathologic examination.The clinical and imaging findings of an atypically located synovial sarcoma are reviewed. This case report emphasizes the consequences of a limited differential diagnosis, prolonged treatment and the failure to perform timely diagnostic imaging in the presence of a paraspinal mass. PMID- 21605433 TI - Acceptability of medical male circumcision in the traditionally circumcising communities in Northern Tanzania. AB - BACKGROUND: Data from traditionally circumcising communities show that non circumcised males and those circumcised in the medical settings are stigmatised. This is because traditional circumcision embodies local notions of bravery as anaesthetics are not used. This study was conducted to assess the acceptability of safe medical circumcision before the onset of sexual activity for HIV infection risk reduction in a traditionally circumcising community in Tanzania. METHODS: A cross-sectional study was conducted among males and females aged 18-44 years in traditionally circumcising communities of Tarime District in Mara Region, North-eastern Tanzania. A face-to-face questionnaire was administered to females to collect information on the attitudes of women towards circumcision and the preferred age for circumcision. A similar questionnaire was administered to males to collect information on socio-demographic, preferred age for circumcision, factors influencing circumcision, client satisfaction, complications and beliefs surrounding the practice. RESULTS: Results were available for 170 males and 189 females. Of the males, 168 (98.8%) were circumcised and 61 (36.3%) of those circumcised had the procedure done in the medical setting. Of those interviewed, 165 (97.1%) males and 179 (94.7%) females supported medical male circumcision for their sons. Of these, 107 (64.8%) males and 130 (72.6%) females preferred prepubertal medical male circumcision (12 years or less). Preference for prepubertal circumcision was significantly associated with non-Kurya ethnic group, circumcision in the medical setting and residence in urban areas for males in the adjusted analysis. For females, preference for prepubertal circumcision was significantly associated non-Kurya ethnic group and being born in urban areas in the adjusted analysis. CONCLUSIONS: There is a shift of preference from traditional male circumcision to medical male circumcision in this traditionally circumcising population. However, this preference has not changed the circumcision practices in the communities because of the community social pressure. Male circumcision national program should take advantage of this preference of medical male circumcision by introducing safe and affordable circumcision services and mobilising communities in a culturally sensitive manner to take up circumcision services. PMID- 21605434 TI - MINE: Module Identification in Networks. AB - BACKGROUND: Graphical models of network associations are useful for both visualizing and integrating multiple types of association data. Identifying modules, or groups of functionally related gene products, is an important challenge in analyzing biological networks. However, existing tools to identify modules are insufficient when applied to dense networks of experimentally derived interaction data. To address this problem, we have developed an agglomerative clustering method that is able to identify highly modular sets of gene products within highly interconnected molecular interaction networks. RESULTS: MINE outperforms MCODE, CFinder, NEMO, SPICi, and MCL in identifying non-exclusive, high modularity clusters when applied to the C. elegans protein-protein interaction network. The algorithm generally achieves superior geometric accuracy and modularity for annotated functional categories. In comparison with the most closely related algorithm, MCODE, the top clusters identified by MINE are consistently of higher density and MINE is less likely to designate overlapping modules as a single unit. MINE offers a high level of granularity with a small number of adjustable parameters, enabling users to fine-tune cluster results for input networks with differing topological properties. CONCLUSIONS: MINE was created in response to the challenge of discovering high quality modules of gene products within highly interconnected biological networks. The algorithm allows a high degree of flexibility and user-customisation of results with few adjustable parameters. MINE outperforms several popular clustering algorithms in identifying modules with high modularity and obtains good overall recall and precision of functional annotations in protein-protein interaction networks from both S. cerevisiae and C. elegans. PMID- 21605435 TI - Up-beat UK: a programme of research into the relationship between coronary heart disease and depression in primary care patients. AB - BACKGROUND: Coronary heart disease and depression are both common health problems and by 2020 will be the two leading causes of disability worldwide. Depression has been found to be more common in patients with coronary heart disease but the nature of this relationship is uncertain. In the United Kingdom general practitioners are now being remunerated for case-finding for depression in patients with coronary heart disease, however it is unclear how general practitioners should manage these patients. We aim to explore the relationship between coronary heart disease and depression in a primary care population and to develop an intervention for patients with coronary heart disease and depression. METHODS/DESIGN: This programme of research will consist of 4 inter-related studies. A 4 year prospective cohort study of primary care patients with coronary heart disease will be conducted to explore the relationship between coronary heart disease and depression. Within this, a nested case-control biological study will investigate genetic and blood-biomarkers as predictors of depression in this sample. Two qualitative studies, one of patients' perspectives of treatments for coronary heart disease and co-morbid depression and one of primary care professionals' views on the management of patients with coronary heart disease and depression will inform the development of an intervention for this patient group. A feasibility study for a randomised controlled trial will then be conducted. DISCUSSION: This study will provide information on the relationship between coronary heart disease and depression that will allow health services to determine the efficiency of case-finding for depression in this patient group. The results of the cohort study will also provide information on risk factors for depression. The study will provide evidence on the efficacy and feasibility of a joint patient and professional led intervention and data necessary to plan a definitive randomised controlled trial of the intervention. PMID- 21605436 TI - Mutation scanning of peach floral genes. AB - BACKGROUND: Mutation scanning technology has been used to develop crop species with improved traits. Modifications that improve screening throughput and sensitivity would facilitate the targeted mutation breeding of crops. Technical innovations for high-resolution melting (HRM) analysis are enabling the clinic based screening for human disease gene polymorphism. We examined the application of two HRM modifications, COLD-PCR and QMC-PCR, to the mutation scanning of genes in peach, Prunus persica. The targeted genes were the putative floral regulators PpAGAMOUS and PpTERMINAL FLOWER I. RESULTS: HRM analysis of PpAG and PpTFL1 coding regions in 36 peach cultivars found one polymorphic site in each gene. PpTFL1 and PpAG SNPs were used to examine approaches to increase HRM throughput. Cultivars with SNPs could be reliably detected in pools of twelve genotypes. COLD PCR was found to increase the sensitivity of HRM analysis of pooled samples, but worked best with small amplicons. Examination of QMC-PCR demonstrated that primary PCR products for further analysis could be produced from variable levels of genomic DNA. CONCLUSIONS: Natural SNPs in exons of target peach genes were discovered by HRM analysis of cultivars from a southeastern US breeding program. For detecting natural or induced SNPs in larger populations, HRM efficiency can be improved by increasing sample pooling and template production through approaches such as COLD-PCR and QMC-PCR. Technical advances developed to improve clinical diagnostics can play a role in the targeted mutation breeding of crops. PMID- 21605437 TI - Integrating intensified case finding of tuberculosis into HIV care: an evaluation from rural Swaziland. AB - BACKGROUND: Swaziland has the highest HIV prevalence in the world and the highest estimated tuberculosis incidence rate in the world. An estimated 80% of TB patients are also infected with HIV. TB detection through intensified case finding (ICF) has yet to become a routine aspect of integrated tuberculosis and HIV care. The purpose of this study was to evaluate implementation of ICF for TB into routine integrated tuberculosis and HIV care at 16 community clinics and one district hospital in Swaziland. METHODS: Nurses and lay counsellors conducted ICF using a TB screening tool and patient pathway at all HIV service entry points in clinics and the hospital. The patient pathway had three-stages; screening, sputum smear diagnosis and TB treatment initiation. Outcomes and losses to follow up were monitored at each stage. Patient demographics, access, and service feasibility and effectiveness were compared at hospital and clinic sites. RESULTS: 1467 HIV patients at clinics and the hospital were screened over a 3 month period. Large losses to follow up occurred prior to the sputum diagnosis stage; only 47% (n = 172) of TB suspects provided a specimen. 28 cases of smear positive TB were diagnosed and 24 commenced treatment. People screened at clinics were significantly more likely to be female, older, and from rural or geographically remote areas (p < 0.001). There was no significant difference between the hospital and clinics sites in the proportion of all participants screened who were smear positive (x2 = 1.909; p = 0.16). The number needed to screen to detect one sputum positive TB case was 34 at clinics and 63 at the district hospital. CONCLUSIONS: ICF was operationally feasible and became established as a routine aspect of tuberculosis and HIV integrated care. ICF in community clinics was potentially more accessible to an underserved, rural population and was as effective as the hospital service in detecting smear positive TB. PMID- 21605438 TI - Formative evaluation of the telecare fall prevention project for older veterans. AB - BACKGROUND: Fall prevention interventions for community-dwelling older adults have been found to reduce falls in some research studies. However, wider implementation of fall prevention activities in routine care has yielded mixed results. We implemented a theory-driven program to improve care for falls at our Veterans Affairs healthcare facility. The first project arising from this program used a nurse advice telephone line to identify patients' risk factors for falls and to triage patients to appropriate services. Here we report the formative evaluation of this project. METHODS: To evaluate the intervention we: 1) interviewed patient and employee stakeholders, 2) reviewed participating patients' electronic health record data and 3) abstracted information from meeting minutes. We describe the implementation process, including whether the project was implemented according to plan; identify barriers and facilitators to implementation; and assess the incremental benefit to the quality of health care for fall prevention received by patients in the project. We also estimate the cost of developing the pilot project. RESULTS: The project underwent multiple changes over its life span, including the addition of an option to mail patients educational materials about falls. During the project's lifespan, 113 patients were considered for inclusion and 35 participated. Patient and employee interviews suggested support for the project, but revealed that transportation to medical care was a major barrier in following up on fall risks identified by nurse telephone triage. Medical record review showed that the project enhanced usual medical care with respect to home safety counseling. We discontinued the program after 18 months due to staffing limitations and competing priorities. We estimated a cost of $9194 for meeting time to develop the project. CONCLUSIONS: The project appeared feasible at its outset but could not be sustained past the first cycle of evaluation due to insufficient resources and a waning of local leadership support due to competing national priorities. Future projects will need both front-level staff commitment and prolonged high-level leadership involvement to thrive. PMID- 21605439 TI - Histoplasmosis infection in patients with rheumatoid arthritis, 1998-2009. AB - BACKGROUND: Patients with rheumatic diseases including rheumatoid arthritis (RA) are at increased risk for infections related to both the disease and its treatments. These include uncommonly reported infections due to histoplasmosis. METHODS: Medical record review of all patients with a diagnosis of RA who developed new histoplasmosis infection in an endemic region between Jan 1, 1998 and Jan 30, 2009 and who were seen at Mayo Clinic in Rochester, Minnesota was performed. RESULTS: Histoplasmosis was diagnosed in 26 patients. Most patients were on combination therapies; 15 were on anti-tumor necrosis factor (anti-TNF) agents, 15 on corticosteroids and 16 on methotrexate. Most received more than 6 months of itraconazole and/or amphotericin treatment. Two patients died of causes unrelated to histoplasmosis. Anti-TNF treatment was restarted in 4/15 patients, with recurrence of histoplasmosis in one. CONCLUSIONS: In this largest single center series of patients with RA and histoplasmosis in the era of immunomodulatory therapy, we found that most patients had longstanding disease and were on multiple immunomodulatory agents. Most cases were pulmonary; typical signs and symptoms of disease were frequently lacking. PMID- 21605440 TI - Empiric treatment of protracted idiopathic purpura fulminans in an infant: a case report and review of the literature. AB - INTRODUCTION: Idiopathic purpura fulminans is a cutaneous thrombotic disorder usually caused by autoimmune-mediated protein C or S deficiency. This disorder typically presents with purpura and petechiae that eventually slowly or rapidly coalesce into extensive, necrotic eschars on the extremities. We present the first known case of idiopathic purpura fulminans consistent with prior clinical presentations in the setting of a prothrombotic genetic mutation, but without hallmark biochemical evidence of protein C or protein S deficiency. Another novel feature of our patient's presentation is that discontinuation of anti-coagulation has invariably led to recurrence and formation of new lesions, which is unexpected in idiopathic purpura fulminans because clearance of autoimmune factors should be followed by restoration of anti-coagulant function. Although this disease is rare, infants with suspected idiopathic purpura fulminans should be rapidly diagnosed and immediately anti-coagulated to prevent adverse catastrophic outcomes such as amputation and significant developmental delay. CASE PRESENTATION: A six-month-old Caucasian boy was brought to our pediatric hospital service with a low-grade fever and subacute, symmetric, serpiginous, stellate, necrotic eschars on his forearms, legs and feet that eventually spread non-contiguously to his toes, thighs and buttocks. In contrast to his impressive clinical presentation, his serologic evaluation was normal, and he was not responsive to corticosteroids and antibiotics. Full-thickness skin biopsies revealed dermal vessel thrombosis, leading to a diagnosis of idiopathic purpura fulminans and successful treatment with low-molecular-weight heparin, which was transitioned to warfarin. Long-term management has included chronic anti coagulation because of recurrence of lesions with discontinuation of treatment. CONCLUSION: In infants with necrotic eschars, it is important to first consider infectious, inflammatory and hematologic etiologies. In the absence of etiology for protracted idiopathic purpura fulminans, management should include tissue biopsy, in which thrombotic findings warrant a trial of empiric anti-coagulation. Some infants, including our patient, may need long-term anti-coagulation, especially when the underlying etiology of coagulation remains unidentified and symptoms recur when treatment is halted. Given that our patient still requires anti-coagulation, he may have a yet to be identified autoimmune-mediated mechanism for his truly idiopathic case of protracted purpura fulminans. PMID- 21605441 TI - Kaposiform hemangioendothelioma in tonsil of a child associated with cervical lymphangioma: a rare case report. AB - Kaposiform hemangioendothelioma (KHE) is an uncommon vascular tumor of intermediate malignant potential, usually occurs in the extremities and retroperitoneum of infants and is characterized by its association with lymphangiomatosis and Kasabach-Merritt phenomenenon (KMP) in certain cases. It has rarely been observed in the head and neck region and at times, can present without KMP. Herein, we present an extremely uncommon case of KHE occurring in tonsil of a child, associated with a neck swelling, but unassociated with KMP. A 2-year-old male child referred to us with history of sore throat, dyspnoea and right-sided neck swelling off and on, since birth, was clinicoradiologically diagnosed with recurrent tonsillitis, including right sided peritonsillar abscess, for which he underwent right-sided tonsillectomy, elsewhere. Histopathological sections from the excised tonsillar mass were reviewed and showed a tumor composed of irregular, infiltrating lobules of spindle cells arranged in kaposiform architecture with slit-like, crescentic vessels. The cells displayed focal lumen formation containing red blood cells (RBCs), along with platelet thrombi and eosinophilic hyaline bodies. In addition, there were discrete foci of several dilated lymphatic vessels containing lymph and lymphocytes. On immunohistochemistry (IHC), spindle cells were diffusely positive for CD34, focally for CD31 and smooth muscle actin (SMA), the latter marker was mostly expressed around the blood vessels. Immunostaining for HHV8 was negative and Ki-67 (proliferation marker) displayed focal positivity. Diagnosis of KHE was made. Platelet count was towards lower side of range. Postoperative imaging showed discrete, multiple fluid containing lesions in the right neck that were high on T2-weighed sequences, on magnetic resonance imaging (MRI) and ipsilateral intraoral mucosal growth. Fine needle aspiration cytology (FNAC) smears from neck swelling showed blood, fluid and lymphocytes. Possibility of a coexisting lymphangioma was considered. The patient was offered sclerotherapy and is on follow-up. This case forms the second documented case of KHE at this site, along with its unique association with neck lymphangioma. KHE has distinct histopathological features and can be sorted out from its other differentials like juvenile hemangioma and Kaposi's sarcoma. IHC stains are useful in substantiating a definite diagnosis. PMID- 21605442 TI - Cell-free synthesis of a functional G protein-coupled receptor complexed with nanometer scale bilayer discs. AB - BACKGROUND: G protein coupled receptors (GPCRs) represent the largest family of membrane proteins in the human genome and the richest source of targets for the pharmaceutical industry. A major limitation to characterizing GPCRs has been the difficulty in developing high-level heterologous expression systems that are cost effective. Reasons for these difficulties include inefficient transport and insertion in the plasma membrane and cytotoxicity. Additionally, GPCR purification requires detergents, which have a negative effect on receptor yields and stability. RESULTS: Here we report a detergent-free cell-free protein expression-based method to obtain pharmacologically active GPCRs in about 2 hours. Our strategy relies on the co-translational insertion of modified GPCRs into nanometer-sized planar membranes. As a model we employed an engineered beta2 adrenergic receptor in which the third intracellular loop has been replaced with T4 lysozyme (beta2AR -T4L). We demonstrated that nanolipoprotein particles (NLPs) are necessary for expression of active beta2AR -T4L in cell-free systems. The binding specificity of the NLP- beta2AR-T4L complex has been determined by competitive assays. Our results demonstrate that beta2AR-T4L synthesized in vitro depends on similar oxidative conditions as those required by an in vivo-expressed receptor. CONCLUSIONS: Although the activation of beta2AR-T4L requires the insertion of the T4 lysozyme sequence and the yield of that active protein limited, our results conceptually prove that cell-free protein expression could be used as a fast approach to express these valuable and notoriously difficult-to express proteins. PMID- 21605443 TI - Reconstruction of oral mucosal defects using the nasolabial flap: clinical experience with 22 patients. AB - BACKGROUND: Various surgical options are available for reconstruction of intraoral soft tissue defects. For smaller defects of the oral mucosa in different anatomic locations of the oral cavity the nasolabial flap is a very useful and simple alternative to other pedicled flaps and free flaps. METHODS: The results of reconstruction of oral mucosal defects or facial skin defects using 29 nasolabial flaps in 22 patients were reviewed retrospectively. RESULTS: The patient group consisted of 16 patients (70%) with squamous cell carcinoma of the oral cavity, 2 patients (10%) with cystic lesions of the maxilla, 3 patients (15%) with osteonecrosis of the jaw, and 1 patient with an oral metastasis of a lung carcinoma. Healing was uneventful in 93%, partial or complete flap loss was observed in 7%. CONCLUSIONS: The nasolabial flap is a valuable alternative for reconstruction of smaller defects of the oral cavity in particular in older and medically compromised patients. PMID- 21605444 TI - Local problems; local solutions: an innovative approach to investigating and addressing causes of maternal deaths in Zambia's Copperbelt. AB - BACKGROUND: Maternal mortality in developing countries is high and international targets for reduction are unlikely to be met. Zambia's maternal mortality ratio was 591 per 100,000 live births according to survey data (2007) while routinely collected data captured only about 10% of these deaths. In one district in Zambia medical staff reviewed deaths occurring in the labour ward but no related recommendations were documented nor was there evidence of actions taken to avert further deaths. The Investigate Maternal Deaths and Act (IMDA) approach was designed to address these deficiencies and is comprised of four components; identification of maternal deaths; investigation of factors contributing to the deaths; recommendations for action drawn up by multiple stakeholders and monitoring of progress through existing systems. METHODS: A pilot was conducted in one district of Zambia. Maternal deaths occurring over a period of twelve months were identified and investigated. Data was collected through in-depth interviews with family, focus group discussions and hospital records. The information was summarized and presented at eleven data sharing meetings to key decision makers, during which recommendations for action were drawn up. An output indicator to monitor progress was included in the routine performance assessment tool. High impact interventions were identified using frequency analysis. RESULTS: A total of 56 maternal deaths were investigated. Poor communication, existing risk factors, a lack of resources and case management issues were the broad categories under which contributing factors were assigned. Sixty three recommendations were drawn up by key decision-makers of which two thirds were implemented by the end of the pilot period. Potential high impact actions were related to management of AIDS and pregnancy, human resources, referral mechanisms, birth planning at household level and availability of safe blood. CONCLUSION: In resource constrained settings the IMDA approach promotes the use of existing systems to reduce maternal mortality. In turn the capacity of local health officers to use data to determine, plan and implement relevant interventions that address the local factors contributing to maternal deaths is strengthened. Monitoring actions taken against the defined recommendations within the routine performance assessment ensures sustainability. Suggestions for further research are provided. PMID- 21605445 TI - Hypoglycaemia and severe Plasmodium falciparum malaria among pregnant Sudanese women in an area characterized by unstable malaria transmission. AB - BACKGROUND: Pregnant women are more susceptible to severe Plasmodium falciparum malaria, which can lead to poor maternal and fetal outcomes. Few data exist on the epidemiology of severe P. falciparum malaria in pregnant women.A hospital based study was carried out to assess the pattern of severe P. falciparum malaria among pregnant women at the Kassala and Medani maternity hospitals, which are located in areas of unstable malaria transmission, in eastern and central Sudan, respectively. Pre-tested questionnaires were used to gather socio-demographic, clinical and obstetrical data. Suitable tests were performed for clinical and biochemical investigations. RESULTS: Among 222 pregnant women diagnosed with malaria at the two hospitals, 40 (18.0%) women at mean (SD) gestational age of 29.3 (6.7) weeks fulfilled one or more of the WHO criteria for severe P. falciparum malaria. These were hypoglycaemia (14; 35.5%), severe anaemia (12; 30%), hypotension (10; 25%), jaundice (9; 22.5%), cerebral malaria (6; 15%), repeated convulsions (4; 10%), hyperparasitaemia (4; 10.0%) and more than one manifestation (9; 22.5%). While the mean (SD) presenting temperature was significantly lower for women presenting with hypoglycaemia [38.2(0.6) versus 38.8(0.7) degrees C, P = 0.04], other clinical and biochemical characteristics were not significantly different among women with different manifestations of severe P. falciparum malaria. CONCLUSION: Preventive measures for pregnant women such as insecticide-treated bednets and chemoprophylaxis may be beneficial in areas of unstable malaria transmission. Early detection and prompt treatment of severe malaria, especially in pregnant women with hypoglycaemia, are needed. PMID- 21605446 TI - Urban - rural disparities in antenatal care utilization: a study of two cohorts of pregnant women in Vietnam. AB - BACKGROUND: The use of antenatal care (ANC) varies between countries and in different settings within each country. Most previous studies of ANC in Vietnam have been cross-sectional, and conducted in rural areas before the year 2000. This study aims to compare the pattern and the adequacy of ANC used in rural and urban Vietnam following two cohorts of pregnant women. METHODS: A comparative study with two cohorts comprising totally 2132 pregnant women were followed in two health and demographic surveillance sites, one rural and one urban in Hanoi province, Vietnam. The women were quarterly interviewed using a structured questionnaire until delivery. The primary information obtained was the number and the content of ANC visits. RESULTS: Almost all women reported some use of ANC. The average number of visits was much lower in the rural setting (4.4) than in the urban (7.7). In the rural area, 77.2% of women had at least three visits and 69.1% attended ANC during the first trimester. The corresponding percentages for the urban women were 97.2% and 97.2%. Only 20.3% of the rural women compared to 81.1% of the urban women received all core ANC services. As a result, the adequate use of ANC was 5.2 times in the urban than in the rural setting (78.3% compared to 15.2%). Nearly all women received ultrasound examination during pregnancy with a mean value of 6.0 scans per woman in the urban area and 3.5 in the rural. Most rural women used ANC at commune health centres and private clinics while urban women mainly visited public hospitals. Expenditure related to ANC utilization for the urban women was 7.1 times that for the urban women. CONCLUSION: The women in the rural area attended ANC later, had fewer visits and received much fewer services than urban women. The large disparity in ANC adequacy between the two settings suggests special attention for the ANC programme in rural areas focusing on its content. Revision and enforcement of the national guidelines to improve the behaviour and practice of both users and providers are necessary. PMID- 21605447 TI - To screen or not to screen for peripheral arterial disease in subjects aged 80 and over in primary health care: a cross-sectional analysis from the BELFRAIL study. AB - BACKGROUND: Peripheral arterial disease (PAD) is common in older people. An ankle brachial index (ABI) < 0.9 can be used as an indicator of PAD. Patients with low ABI have increased mortality and a higher risk of serious cardiovascular morbidity. However, because 80% of the patients are asymptomatic, PAD remains unrecognised in a large group of patients. The aims of this study were 1) to examine the prevalence of reduced ABI in subjects aged 80 and over, 2) to determine the diagnostic accuracy of the medical history and clinical examination for reduced ABI and 3) to investigate the difference in functioning and physical activity between patients with and without reduced ABI. METHODS: A cross sectional study embedded within the BELFRAIL study. A general practitioner (GP) centre, located in Hoeilaart, Belgium, recruited 239 patients aged 80 or older. Only three criteria for exclusion were used: urgent medical need, palliative situation and known serious dementia. The GP recorded the medical history and performed a clinical examination. The clinical research assistant performed an extensive examination including Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS-15), Activities of Daily Living (ADL), Tinetti test and the LASA Physical Activity Questionnaire (LAPAQ). ABI was measured using an automatic oscillometric appliance. RESULTS: In 40% of patients, a reduced ABI was found. Cardiovascular risk factors were unable to identify patients with low ABI. A negative correlation was found between the number of cardiovascular morbidities and ABI. Cardiovascular morbidity had a sensitivity of 65.7% (95% CI 53.4-76.7) and a specificity of 48.6% (95% CI 38.7-58.5). Palpation of the peripheral arteries showed the highest negative predictive value (77.7% (95% CI 71.8-82.9)). The LAPAQ score was significantly lower in the group with reduced ABI. CONCLUSION: The prevalence of PAD is very high in patients aged 80 and over in general practice. The clinical examination, cardiovascular risk factors and the presence of cardiovascular morbidity were not able to identify patients with a low ABI. A screening strategy for PAD by determining ABI could be considered if effective interventions for those aged 80 and over with a low ABI become available through future research. PMID- 21605448 TI - Military veteran mortality following a survived suicide attempt. AB - BACKGROUND: Suicide is a global public health problem. Recently in the U.S., much attention has been given to preventing suicide and other premature mortality in veterans returning from Iraq and Afghanistan. A strong predictor of suicide is a past suicide attempt, and suicide attempters have multiple physical and mental comorbidities that put them at risk for additional causes of death. We examined mortality among U.S. military veterans after hospitalization for attempted suicide. METHODS: A retrospective cohort study was conducted with all military veterans receiving inpatient treatment during 1993-1998 at United States Veterans Affairs (VA) medical facilities following a suicide attempt. Deaths occurring during 1993-2002, the most recent available year at the time, were identified through VA Beneficiary and Records Locator System data and National Death Index data. Mortality data for the general U.S. adult population were also obtained from the National Center for Health Statistics. Comparisons within the veteran cohort, between genders, and against the U.S. population were conducted with descriptive statistics and standardized mortality ratios. The actuarial method was used estimate the proportion of veterans in the cohort we expect would have survived through 2002 had they experienced the same rate of death that occurred over the study period in the U.S. population having the age and sex characteristics. RESULTS: During 1993-1998, 10,163 veterans were treated and discharged at a VA medical center after a suicide attempt (mean age = 44 years; 91% male). There was a high prevalence of diagnosed alcohol disorder or abuse (31.8%), drug dependence or abuse (21.8%), psychoses (21.2%), depression (18.5%), and hypertension (14.2%). A total of 1,836 (18.1%) veterans died during follow up (2,941.4/100,000 person years). The cumulative survival probability after 10 years was 78.0% (95% CI = 72.9, 83.1). Hence the 10-year cumulative mortality risk was 22.0%, which was 3.0 times greater than expected. The leading causes overall were heart disease (20.2%), suicide (13.1%), and unintentional injury (12.7%). Whereas suicide was the ninth leading cause of death in the U.S. population overall (1.8%) during the study period, suicide was the leading and second leading cause among women (25.0%) and men (12.7%) in the cohort, respectively. CONCLUSIONS: Veterans who have attempted suicide face elevated risks of all-cause mortality with suicide being prominent. This represents an important population for prevention activities. PMID- 21605449 TI - Participation of the oviductal s100 calcium binding protein G in the genomic effect of estradiol that accelerates oviductal embryo transport in mated rats. AB - BACKGROUND: Mating changes the mechanism by which E2 regulates oviductal egg transport, from a non-genomic to a genomic mode. Previously, we found that E2 increased the expression of several genes in the oviduct of mated rats, but not in unmated rats. Among the transcripts that increased its level by E2 only in mated rats was the one coding for an s100 calcium binding protein G (s100 g) whose functional role in the oviduct is unknown. METHODS: Herein, we investigated the participation of s100 g on the E2 genomic effect that accelerates oviductal transport in mated rats. Thus, we determined the effect of E2 on the mRNA and protein level of s100 g in the oviduct of mated and unmated rats. Then, we explored the effect of E2 on egg transport in unmated and mated rats under conditions in which s100 g protein was knockdown in the oviduct by a morpholino oligonucleotide against s100 g (s100 g-MO). In addition, the localization of s100 g in the oviduct of mated and unmated rats following treatment with E2 was also examined. RESULTS: Expression of s100 g mRNA progressively increased at 3-24 h after E2 treatment in the oviduct of mated rats while in unmated rats s100 g increased only at 12 and 24 hours. Oviductal s100 g protein increased 6 h following E2 and continued elevated at 12 and 24 h in mated rats, whereas in unmated rats s100 g protein increased at the same time points as its transcript. Administration of a morpholino oligonucleotide against s100 g transcript blocked the effect of E2 on egg transport in mated, but not in unmated rats. Finally, immunoreactivity of s100 g was observed only in epithelial cells of the oviducts of mated and unmated rats and it was unchanged after E2 treatment. CONCLUSIONS: Mating affects the kinetic of E2-induced expression of s100 g although it not changed the cellular localization of s100 g in the oviduct after E2 . On the other hand, s100 g is a functional component of E2 genomic effect that accelerates egg transport. These findings show a physiological involvement of s100 g in the rat oviduct. PMID- 21605450 TI - Short term non-invasive ventilation post-surgery improves arterial blood-gases in obese subjects compared to supplemental oxygen delivery - a randomized controlled trial. AB - BACKGROUND: In the immediate postoperative period, obese patients are more likely to exhibit hypoxaemia due to atelectasis and impaired respiratory mechanics, changes which can be attenuated by non-invasive ventilation (NIV). The aim of the study was to evaluate the duration of any effects of early initiation of short term pressure support NIV vs. traditional oxygen delivery via venturi mask in obese patients during their stay in the PACU. METHODS: After ethics committee approval and informed consent, we prospectively studied 60 obese patients (BMI 30 45) undergoing minor peripheral surgery. Half were randomly assigned to receive short term NIV during their PACU stay, while the others received routine treatment (supplemental oxygen via venturi mask). Premedication, general anaesthesia and respiratory settings were standardized. We measured arterial oxygen saturation by pulse oximetry and blood gas analysis on air breathing. Inspiratory and expiratory lung function was measured preoperatively (baseline) and at 10 min, 1 h, 2 h, 6 h and 24 h after extubation, with the patient supine, in a 30 degrees head-up position. The two groups were compared using repeated measure analysis of variance (ANOVA) and t-test analysis. Statistical significance was considered to be P < 0.05. RESULTS: There were no differences at the first assessment. During the PACU stay, pulmonary function in the NIV group was significantly better than in the controls (p < 0.0001). Blood gases and the alveolar to arterial oxygen partial pressure difference were also better (p < 0.03), but with the addition that overall improvements are of questionable clinical relevance. These effects persisted for at least 24 hours after surgery (p < 0.05). CONCLUSION: Early initiation of short term NIV during in the PACU promotes more rapid recovery of postoperative lung function and oxygenation in the obese. The effect lasted 24 hours after discontinuation of NIV. Patient selection is necessary in order to establish clinically relevant improvements. TRIAL REGISTRATION#: DRKS00000751; http://www.germanctr.de. PMID- 21605451 TI - Multi tyrosine kinase inhibitor dasatinib as novel cause of severe pre-capillary pulmonary hypertension? AB - BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease with poor prognosis. Encouraging efforts have been made to target the main vasoproliferative aspects of the disease. Promising emerging therapeutics are tyrosine kinase inhibitors such as imatinib. CASE PRESENTATION: Here, we discuss the relevance of previously published cases and add another well-characterised patient who developed pre-capillary PH under long-term therapy with the multi tyrosine kinase inhibitor dasatinib approved for therapy of chronic myeloic leukaemia (CML) and Philadelphia chromosome positive acute lymphocytic leukaemia (mean time of all patients on dasatinib: 26 months). Hence, we discuss the possibility of dasatinib itself causing PH after long-term therapy and turn specialist's attention to this possible severe side effect.At present, the true incidence of dasatinib-associated PH remains illusive and systematic data regarding haemodynamics are missing. CONCLUSION: We therefore recommend systematic screening of dasatinib-treated patients for pulmonary hypertension and subsequent collection of haemodynamic data. PMID- 21605452 TI - Evolutionary patterns and processes in the radiation of phyllostomid bats. AB - BACKGROUND: The phyllostomid bats present the most extensive ecological and phenotypic radiation known among mammal families. This group is an important model system for studies of cranial ecomorphology and functional optimisation because of the constraints imposed by the requirements of flight. A number of studies supporting phyllostomid adaptation have focused on qualitative descriptions or correlating functional variables and diet, but explicit tests of possible evolutionary mechanisms and scenarios for phenotypic diversification have not been performed. We used a combination of morphometric and comparative methods to test hypotheses regarding the evolutionary processes behind the diversification of phenotype (mandible shape and size) and diet during the phyllostomid radiation. RESULTS: The different phyllostomid lineages radiate in mandible shape space, with each feeding specialisation evolving towards different axes. Size and shape evolve quite independently, as the main directions of shape variation are associated with mandible elongation (nectarivores) or the relative size of tooth rows and mandibular processes (sanguivores and frugivores), which are not associated with size changes in the mandible. The early period of phyllostomid diversification is marked by a burst of shape, size, and diet disparity (before 20 Mya), larger than expected by neutral evolution models, settling later to a period of relative phenotypic and ecological stasis. The best fitting evolutionary model for both mandible shape and size divergence was an Ornstein-Uhlenbeck process with five adaptive peaks (insectivory, carnivory, sanguivory, nectarivory and frugivory). CONCLUSIONS: The radiation of phyllostomid bats presented adaptive and non-adaptive components nested together through the time frame of the family's evolution. The first 10 My of the radiation were marked by strong phenotypic and ecological divergence among ancestors of modern lineages, whereas the remaining 20 My were marked by stasis around a number of probable adaptive peaks. A considerable amount of cladogenesis and speciation in this period is likely to be the result of non-adaptive allopatric divergence or adaptations to peaks within major dietary categories. PMID- 21605453 TI - Effect of remote ischemic conditioning on atrial fibrillation and outcome after coronary artery bypass grafting (RICO-trial). AB - BACKGROUND: Pre- and postconditioning describe mechanisms whereby short ischemic periods protect an organ against a longer period of ischemia. Interestingly, short ischemic periods of a limb, in itself harmless, may increase the ischemia tolerance of remote organs, e.g. the heart (remote conditioning, RC). Although several studies have shown reduced biomarker release by RC, a reduction of complications and improvement of patient outcome still has to be demonstrated. Atrial fibrillation (AF) is one of the most common complications after coronary artery bypass graft surgery (CABG), affecting 27-46% of patients. It is associated with increased mortality, adverse cardiovascular events, and prolonged in-hospital stay. We hypothesize that remote ischemic pre- and/or post conditioning reduce the incidence of AF following CABG, and improve patient outcome. METHODS/DESIGN: This study is a randomized, controlled, patient and investigator blinded multicenter trial. Elective CABG patients are randomized to one of the following four groups: 1) control, 2) remote ischemic preconditioning, 3) remote ischemic postconditioning, or 4) remote ischemic pre- and postconditioning. Remote conditioning is applied at the arm by 3 cycles of 5 minutes of ischemia and reperfusion. Primary endpoint is the incidence AF in the first 72 hours after surgery, detected using a Holter-monitor. Secondary endpoints include length-of-stay on the intensive care unit and in-hospital, and the occurrence of major adverse cardiovascular events at 30 days, 3 months and 1 year.Based on an expected incidence in the control group of 27%, 195 patients per group are needed to detect with 80% power a reduction by 45% following either pre or postconditioning, while allowing for a 10% dropout and at an alpha of 0.05. With the combined intervention expected to be stronger, we need 75 patients in this group to detect a reduction in incidence of AF of 60%. DISCUSSION: The RICO trial (the effect of Remote Ischemic Conditioning on atrial fibrillation and Outcome) is a randomized controlled multicenter trial, designed to investigate whether remote ischemic pre- and/or post-conditioning of the arm reduce the incidence of AF following CABG surgery. TRIAL REGISTRATION: ClinicalTrials.gov under NCT01107184. PMID- 21605454 TI - Immortalized cells and one oncogene in malignant transformation: old insights on new explanation. AB - BACKGROUND: Nearly thirty years ago, it was first shown that malignant transformation with single oncogene necessarily requires the immortal state of the cell. From that time this thesis for the cells of human origin was not disproved. The basic point which we want to focus on by this short communication is the correct interpretation of the results obtained on the widely used human embryonic kidney 293 (HEK293) cells. RESULTS: Intensive literature analysis revealed an increasing number of recent studies discovering new oncogenes with non-overlapping functions. Since the 1970s, dozens of oncogenes have been identified in human cancer. Cultured cell lines are often used as model systems in these experiments. In some investigations the results obtained on such cells are interpreted by the authors as a malignant transformation of normal animal or even normal human cells (as for example with HEK293 cells). However, when a cell line gains the ability to undergo continuous cell division, the cells are not normal any more, they are immortalized cells. Nevertheless, the authors consider these cells as normal human ones, what is basically incorrect. Moreover, it was early demonstrated that the widely used human embryonic kidney 293 (HEK293) cells have a relationship to neurons. CONCLUSIONS: Thus, the experiments with established cell lines reinforce the notion that immortality is an essential requirement for malignant transformation that cooperates with other oncogenic changes to program the neoplastic state and substances under such investigation should be interpreted as factors which do not malignantly transform normal cells alone, but possess the ability to enhance the tumorigenic potential of already immortalized cells. PMID- 21605455 TI - Intestinal microflora and body mass index during the first three years of life: an observational study. AB - BACKGROUND: Recent research on obesity has demonstrated that the intestinal microflora can have an important influence on host energy balance. The aim of the study was to investigate the relationship between the intestinal microflora and the body mass index in the first 3 years of life. RESULTS: In a prospective study, a faecal sample from 138 infants was taken at the age of 3, 26 and 52 weeks and cultured on selective media for 6 bacterial genera. Between the age of 1 and 3 years the Body Mass Index Standard Deviation Score (BMI SDS) of these children was determined. The association between the intestinal flora and BMI SDS was assessed for each bacterial genus. A positive correlation was found between the Bacteroides fragilis concentration and the BMI SDS at the age of 3 and 26 weeks. The Staphylococcus concentration showed a negative correlation with the BMI SDS at the age of 3 and 52 weeks. A low intestinal ratio of Staphylococcus/Bacteroides fragilis at the age of 3 weeks, corresponding to a low Staphylococcus and a high Bacteroides fragilis concentration, was associated with a higher BMI SDS during the first three years of life. CONCLUSION: High intestinal Bacteroides fragilis and low Staphylococcus concentrations in infants between the age of 3 weeks and 1 year were associated with a higher risk of obesity later in life. This study could provide new targets for a better and more effective modulation of the intestinal microflora in infants. PMID- 21605456 TI - A retrospective study of risk factors for poor outcomes in methicillin-resistant Staphylococcus aureus (MRSA) infection in surgical patients. AB - BACKGROUND: Since its isolation, Methicillin-resistant Staphlococcus aureus (MRSA) has become a major cause of hospital acquired infection (HAI), adverse patient outcome and overall resource utilisation. It is endemic in Scotland and widespread in Western hospitals. MRSA has been the subject of widespread media interest--a manifestation of concerns about sterile surgical techniques and hospital cleanliness. This study aimed to investigate patient outcome of MRSA infections over the last decade at a major orthopaedic trauma centre. The objective was to establish the association of variables, such as patient age and inpatient residence, against patient outcome, in order to quantify significant relationships; facilitating the evaluation of management strategies with an aim to improving patient outcomes and targeting high-risk procedures. METHODS: This is a retrospective study of the rates and outcomes of MRSA infection in orthopaedic trauma at the Royal Infirmary of Edinburgh. Data was collated using SPSS 14.0 for Windows(R). Shapiro-Wilkes testing was performed to investigate the normality of continuous data sets (e.g: age). Data was analysed using both Chi Squared and Fisher's exact tests (in cases of expected values under 5) RESULTS: This study found significant associations between adverse patient outcome (persistent deep infection, osteomyelitis, the necessity for revision surgery, amputation and mortality) and the following patient variables: Length of inpatient stay, immuno-compromise, pre-admission residence in an institutional setting (such as a residential nursing home) and the number of antibiotics used in patient care. Despite 63% of all infections sampled resulting from proximal femoral fractures, no association between patient outcome and site of infection or diagnosis was found. Somewhat surprisingly, the relationship between age and outcome of infection was not proved to be significant, contradicting previous studies suggesting a statistical association. Antibiotic prophylaxis, previously identified as a factor in reducing overall incidence of MRSA infection, was not found to be significantly associated with outcome. CONCLUSIONS: Early identification of high-risk patients as identified by this study could lead to more judicious use of therapeutic antibiotics and reductions in adverse outcome, as well as socioeconomic cost. These results could assist in more accurate risk stratification based on evidence based evaluation of the significance of the risk factors investigated. PMID- 21605457 TI - Natural and synthetic cathelicidin peptides with anti-microbial and anti-biofilm activity against Staphylococcus aureus. AB - BACKGROUND: Chronic, infected wounds typically contain multiple genera of bacteria, including Staphylococcus aureus, many of which are strong biofilm formers. Bacterial biofilms are thought to be a direct impediment to wound healing. New therapies that focus on a biofilm approach may improve the recovery and healing rate for infected wounds. In this study, cathelicidins and related short, synthetic peptides were tested for their anti-microbial effectiveness as well as their ability to inhibit the ability of S. aureus to form biofilms. RESULTS: The helical human cathelicidin LL-37 was tested against S. aureus, and was found to exhibit effective anti-microbial, anti-attachment as well as anti biofilm activity at concentrations in the low MUg/ml range. The effect of peptide chirality and associated protease-resistance was explored through the use of an all-D amino acid peptide, D-LL-37, and in turn compared to scrambled LL-37. Helical cathelicidins have been identified in other animals such as the Chinese cobra, Naja atra (NA-CATH). We previously identified an 11-residue imperfectly repeated pattern (ATRA motif) within the sequence of NA-CATH. A series of short peptides (ATRA-1, -2, -1A), as well as a synthetic peptide, NA-CATH:ATRA1-ATRA1, were designed to explore the significance of the conserved residues within the ATRA motif for anti-microbial activity. The CD spectrum of NA-CATH and NA CATH:ATRA1-ATRA1 revealed the structural properties of these peptides and suggested that helicity may factor into their anti-microbial and anti-biofilm activities. CONCLUSIONS: The NA-CATH:ATRA1-ATRA1 peptide inhibits the production of biofilm by S. aureus in the presence of salt, exhibiting anti-biofilm activity at lower peptide concentrations than NA-CATH, LL-37 and D-LL-37; and demonstrates low cytoxicity against host cells but does not affect bacterial attachment. The peptides utilized in this anti-biofilm approach may provide templates for a new group of anti-microbials and potential future topical therapeutics for treating chronic wound infections. PMID- 21605458 TI - Is there a role for expectation maximization imputation in addressing missing data in research using WOMAC questionnaire? Comparison to the standard mean approach and a tutorial. AB - BACKGROUND: Standard mean imputation for missing values in the Western Ontario and Mc Master (WOMAC) Osteoarthritis Index limits the use of collected data and may lead to bias. Probability model-based imputation methods overcome such limitations but were never before applied to the WOMAC. In this study, we compare imputation results for the Expectation Maximization method (EM) and the mean imputation method for WOMAC in a cohort of total hip replacement patients. METHODS: WOMAC data on a consecutive cohort of 2,062 patients scheduled for surgery were analyzed. Rates of missing values in each of the WOMAC items from this large cohort were used to create missing patterns in the subset of patients with complete data. EM and the WOMAC's method of imputation are then applied to fill the missing values. Summary score statistics for both methods are then described through box-plot and contrasted with the complete case (CC) analysis and the true score (TS). This process is repeated using a smaller sample size of 200 randomly drawn patients with higher missing rate (5 times the rates of missing values observed in the 2,062 patients capped at 45%). RESULTS: Rate of missing values per item ranged from 2.9% to 14.5% and 1,339 patients had complete data. Probability model-based EM imputed a score for all subjects while WOMAC's imputation method did not. Mean subscale scores were very similar for both imputation methods and were similar to the true score; however, the EM method results were more consistent with the TS after simulation. This difference became more pronounced as the number of items in a subscale increased and the sample size decreased. CONCLUSIONS: The EM method provides a better alternative to the WOMAC imputation method. The EM method is more accurate and imputes data to create a complete data set. These features are very valuable for patient-reported outcomes research in which resources are limited and the WOMAC score is used in a multivariate analysis. PMID- 21605459 TI - How do patient characteristics influence informal payments for inpatient and outpatient health care in Albania: results of logit and OLS models using Albanian LSMS 2005. AB - BACKGROUND: Informal payments for health care are common in most former communist countries. This paper explores the demand side of these payments in Albania. By using data from the Living Standard Measurement Survey 2005 we control for individual determinants of informal payments in inpatient and outpatient health care. We use these results to explain the main factors contributing to the occurrence and extent of informal payments in Albania. METHODS: Using multivariate methods (logit and OLS) we test three models to explain informal payments: the cultural, economic and governance model. The results of logit models are presented here as odds ratios (OR) and results from OLS models as regression coefficients (RC). RESULTS: Our findings suggest differences in determinants of informal payments in inpatient and outpatient care. Generally our results show that informal payments are dependent on certain characteristics of patients, including age, area of residence, education, health status and health insurance. However, they are less dependent on income, suggesting homogeneity of payments across income categories. CONCLUSIONS: We have found more evidence for the validity of governance and economic models than for the cultural model. PMID- 21605460 TI - Epidemiology of tuberculosis in a low-incidence Italian region with high immigration rates: differences between not Italy-born and Italy-born TB cases. AB - BACKGROUND: Emilia Romagna, a northern Italian region, has a population of 4.27 million, of which 9.7% are immigrants. The objective of this study was to investigate the epidemiology of tuberculosis (TB) during the period 1996-2006 in not Italy-born compared to Italy-born cases. METHODS: Data was obtained from the Regional TB surveillance system, from where personal data, clinical features and risk factors of all notified TB cases were extracted. RESULTS: 5377 TB cases were reported. The proportion of immigrants with TB, over the total number of TB cases had progressively increased over the years, from 19.1% to 53.3%. In the not Italy born population, TB incidence was higher than in Italians (in 2006: 100.7 cases per 100,000 registered not Italy-born subjects and 83.9/100,000 adding 20% of estimated irregular presences to the denominators. TB incidence among Italians was 6.5/100,000 Italians). A progressive rise in the not Italy-born incident cases was observed but associated with a decline in TB incidence. Not Italy-born cases were younger compared to the Italy-born cases, and more frequently classified as "new cases" (OR 2.0 95%CI 1.61-2.49 for age group 20-39); 60.7% had pulmonary TB, 31.6% extra pulmonary and 7.6% disseminated TB. Risk factors for TB in this population group were connected to lower income status (homeless: OR 149.9 95%CI 20.7-1083.3 for age group 40-59). CONCLUSIONS: In low-incidence regions, prevention and control of TB among sub-groups at risk such as the foreign-born population is a matter of public health concern. In addition, increasing immigration rates may affect TB epidemiology. TB among immigrants is characterized by particular clinical features and risk factors, which should be analyzed in order to plan effective action. PMID- 21605461 TI - Bacterial syntenies: an exact approach with gene quorum. AB - BACKGROUND: The automatic identification of syntenies across multiple species is a key step in comparative genomics that helps biologists shed light both on evolutionary and functional problems. RESULTS: In this paper, we present a versatile tool to extract all syntenies from multiple bacterial species based on a clear-cut and very flexible definition of the synteny blocks that allows for gene quorum, partial gene correspondence, gaps, and a partial or total conservation of the gene order. CONCLUSIONS: We apply this tool to two different kinds of studies. The first one is a search for functional gene associations. In this context, we compare our tool to a widely used heuristic--I-ADHORE--and show that at least up to ten genomes, the problem remains tractable with our exact definition and algorithm. The second application is linked to evolutionary studies: we verify in a multiple alignment setting that pairs of orthologs in synteny are more conserved than pairs outside, thus extending a previous pairwise study. We then show that this observation is in fact a function of the size of the synteny: the larger the block of synteny is, the more conserved the genes are. PMID- 21605462 TI - Thyroid disease is a favorable prognostic factor in achieving sustained virologic response in chronic hepatitis C undergoing combination therapy: A nested case control study. AB - BACKGROUND: Interferon-alpha in combination with ribavirin is the current gold standard for treatment of chronic hepatitis C. It is unknown if the development of autoimmune thyroid disease (TD) during treatment confers an improved chance of achieving sustained virologic response. The aim of this study is to assess the chance of achieving sustained virologic response (SVR) in patients who developed TD during treatment when compared with those who did not. METHODS: We performed a tertiary hospital-based retrospective nested case-control analysis of 19 patients treated for hepatitis C who developed thyroid disease, and 76 controls (matched for age, weight, gender, cirrhosis and aminotransferase levels) who did not develop TD during treatment. Multivariate logistic-regression models were used to compare cases and controls. RESULTS: The development of TD was associated with a high likelihood of achieving SVR (odds ratio, 6.0; 95% confidence interval, 1.5 to 24.6) for the pooled group containing all genotypes. The likelihood of achieving SVR was increased in individuals with genotype 1 HCV infection who developed TD (odds ratio, 5.2; 95% confidence interval, 1.2 to 22.3), and all genotype 3 patients who developed TD achieved SVR. CONCLUSIONS: Development of TD during treatment for hepatitis C infection is associated with a significantly increased chance of achieving SVR. The pathophysiogical mechanisms for this observation remain to be determined. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRB12610000830099. PMID- 21605463 TI - Inference of chromosome-specific copy numbers using population haplotypes. AB - BACKGROUND: Using microarray and sequencing platforms, a large number of copy number variations (CNVs) have been identified in humans. In practice, because our human genome is a diploid, these platforms are limited to or more accurate for detecting total copy numbers rather than chromosome-specific copy numbers at each of the two homologous chromosomes. Nevertheless, the analysis of linkage disequilibrium (LD) between CNVs and SNPs indicates that distinct copy numbers often sit on their own background haplotypes. RESULTS: We propose new computational models for inferring chromosome-specific copy numbers by distinguishing background haplotypes of each copy number. The formulated problems are shown to be NP-hard and approximation/heuristic algorithms are developed. Simulation indicates that our method is accurate and outperforms the existing approach. By testing the program in 60 parent-offspring trios, the inferred chromosome-specific copy numbers are highly consistent with the law of Mendelian inheritance. The distributions of copy numbers at chromosomal level are provided for 270 individuals in three HapMap panels. CONCLUSIONS: The estimation of chromosome-specific copy numbers using microarray or sequencing platforms was often confounded by a number of factors. This study showed that the integration of background haplotypes is able to improve the accuracies of copy number estimation at chromosome level, especially for the CNVs having strong LD with SNPs in proximity. PMID- 21605464 TI - Functional characterization of the ER stress induced X-box-binding protein-1 (Xbp 1) in the porcine system. AB - BACKGROUND: The unfolded protein response (UPR) is an evolutionary conserved adaptive reaction for increasing cell survival under endoplasmic reticulum (ER) stress conditions. X-box-binding protein-1 (Xbp1) is a key transcription factor of UPR that activates genes involved in protein folding, secretion, and degradation to restore ER function. The UPR induced by ER stress was extensively studied in diseases linked to protein misfolding and aggregations. However, in the porcine system, genes in the UPR pathway were not investigated. In this study, we isolated and characterized the porcine Xbp1 (pXbp1) gene in ER stress using porcine embryonic fibroblast (PEF) cells and porcine organs. ER stress was induced by the treatment of tunicamycin and cell viability was investigated by the MTT assay. For cloning and analyzing the expression pattern of pXbp1, RT-PCR analysis and Western blot were used. Knock-down of pXbp1 was performed by the siRNA-mediated gene silencing. RESULTS: We found that the pXbp1 mRNA was the subject of the IRE1alpha-mediated unconventional splicing by ER stress. Knock down of pXbp1 enhanced ER stress-mediated cell death in PEF cells. In adult organs, pXbp1 mRNA and protein were expressed and the spliced forms were detected. CONCLUSIONS: It was first found that the UPR mechanisms and the function of pXbp1 in the porcine system. These results indicate that pXbp1 plays an important role during the ER stress response like other animal systems and open a new opportunity for examining the UPR pathway in the porcine model system. PMID- 21605465 TI - Association of the MAOA promoter uVNTR polymorphism with suicide attempts in patients with major depressive disorder. AB - BACKGROUND: The MAOA uVNTR polymorphism has been documented to affect the MAOA gene at the transcriptional level and is associated with aggressive impulsive behaviors, depression associated with suicide (depressed suicide), and major depressive disorder (MDD). We hypothesized that the uVNTR polymorphism confers vulnerability to MDD, suicide or both. The aim of this study was to explore the association between the MAOA uVNTR and depressed suicide, using multiple controls. METHODS: Four different groups were included: 432 community controls, 385 patients with MDD who had not attempted suicide, 96 community subjects without mental disorders who had attempted suicide, and 109 patients with MDD who had attempted suicide. The MAOA uVNTR polymorphism was genotyped by a PCR technique. The symptom profiles and personal characteristics in each group were also compared. RESULTS: The MAOA 4R allele was more frequent in males with MDD than in male community controls (chi2 = 4.182, p = 0.041). Logistic regression analysis showed that, among the depressed subjects, those younger in age, more neurotic or who smoked had an increased risk of suicide (beta = -0.04, p = 0.002; beta = 0.15, p = 0.017; beta = 0.79, p = 0.031, respectively). Moreover, among those who had attempted suicide, those younger in age, with more paternal overprotection, and more somatic symptoms were more likely to be in the MDD group than in the community group (beta = -0.11, p < 0.001; beta = 0.15, p = 0.026; beta = 1.11, p < 0.001). Structural equation modeling (SEM) showed that nongenetic factors, such as age, paternal overprotection, and somatic symptoms, were associated with MDD, whereas depressed suicide were associated with severity of depression, personality traits, age, marital status, and inversely associated with anxiety symptoms. However, depression did not affect suicidal behavior in the community group. CONCLUSION: The MAOA 4R allele is associated with enhanced vulnerability to suicide in depressed males, but not in community subjects. The MAOA 4R allele affects vulnerability to suicide through the mediating factor of depressive symptoms. Further large-scale studies are needed to verify the psychopathology of the relationships among MAOA uVNTR polymorphism, symptom profiles, and suicidal behavior. PMID- 21605466 TI - Mapping the distribution of packing topologies within protein interiors shows predominant preference for specific packing motifs. AB - BACKGROUND: Mapping protein primary sequences to their three dimensional folds referred to as the 'second genetic code' remains an unsolved scientific problem. A crucial part of the problem concerns the geometrical specificity in side chain association leading to densely packed protein cores, a hallmark of correctly folded native structures. Thus, any model of packing within proteins should constitute an indispensable component of protein folding and design. RESULTS: In this study an attempt has been made to find, characterize and classify recurring patterns in the packing of side chain atoms within a protein which sustains its native fold. The interaction of side chain atoms within the protein core has been represented as a contact network based on the surface complementarity and overlap between associating side chain surfaces. Some network topologies definitely appear to be preferred and they have been termed 'packing motifs', analogous to super secondary structures in proteins. Study of the distribution of these motifs reveals the ubiquitous presence of typical smaller graphs, which appear to get linked or coalesce to give larger graphs, reminiscent of the nucleation condensation model in protein folding. One such frequently occurring motif, also envisaged as the unit of clustering, the three residue clique was invariably found in regions of dense packing. Finally, topological measures based on surface contact networks appeared to be effective in discriminating sequences native to a specific fold amongst a set of decoys. CONCLUSIONS: Out of innumerable topological possibilities, only a finite number of specific packing motifs are actually realized in proteins. This small number of motifs could serve as a basis set in the construction of larger networks. Of these, the triplet clique exhibits distinct preference both in terms of composition and geometry. PMID- 21605467 TI - Predominance of Th2 polarization by vitamin D through a STAT6-dependent mechanism. AB - BACKGROUND: Vitamin D has several reported immunomodulatory properties including the reduced generation of pro-inflammatory CD4+ T helper 1 (Th1) cells and the increase in levels of the anti-inflammatory Th2 subset. Less clear has been the impact of vitamin D on the pro-inflammatory Th17 subset, and whether and how vitamin D may preferentially drive the polarization of one of the T helper subsets. METHODS: Using human peripheral blood-derived mononuclear cells and mouse splenocytes and lymph node cells in culture, we examined whether and how vitamin D preferentially skews T cells towards the Th1, Th2 or Th17 subsets. Mice afflicted with the multiple sclerosis-like condition, experimental autoimmune encephalomyelitis (EAE), were examined in vivo for the relevance of the tissue culture-derived results. RESULTS: We report that the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 {1,25(OH)2D3}, consistently generates human and murine Th2 cells in culture, frequently leaving unchanged the levels of Th1/Th17 cytokines. As a result, the ratio of Th2 to Th1 and Th17 is increased by 1,25(OH)2D3. The upregulation of Th2 to Th1 or Th17 subsets by 1,25(OH)2D3 is enabled by an increase of the GATA-3 transcription factor, which itself is promoted upstream by an elevation of the STAT6 transcription factor. In mice, the alleviation of EAE severity by 1,25(OH)2D3 is accompanied by elevation of levels of GATA-3 and STAT6. Significantly, the efficacy of 1,25(OH)2D3 in ameliorating EAE is completely lost in mice genetically deficient for STAT6, which was accompanied by the inability of 1,25(OH)2D3 to raise GATA-3 in STAT6 null lymphocytes. CONCLUSIONS: These results of vitamin D promoting a Th2 shift through upstream GATA-3 and STAT6 transcription factors shed mechanistic understanding on the utility of vitamin D in MS. PMID- 21605468 TI - Cellular HIV-1 DNA levels in patients receiving antiretroviral therapy strongly correlate with therapy initiation timing but not with therapy duration. AB - BACKGROUND: Viral reservoir size refers to cellular human immunodeficiency virus 1 (HIV-1) DNA levels in CD4(+) T lymphocytes of peripheral blood obtained from patients with plasma HIV-1-RNA levels (viral load, VL) maintained below the detection limit by antiretroviral therapy (ART). We measured HIV-1 DNA levels in CD4(+) lymphocytes in such patients to investigate their clinical significance. METHODS: CD4(+) T lymphocytes were isolated from the peripheral blood of 61 patients with a VL maintained at less than 50 copies/ml for at least 4 months by ART and total DNA was purified. HIV-1 DNA was quantified by nested PCR to calculate the copy number per 1 million CD4(+) lymphocytes (relative amount) and the copy number in 1 ml of blood (absolute amount). For statistical analysis, the Spearman rank or Wilcoxon signed-rank test was used, with a significance level of 5%. RESULTS: CD4 cell counts at the time of sampling negatively correlated with the relative amount of HIV-1 DNA (median = 33 copies/million CD4(+) lymphocytes; interquartile range [IQR] = 7-123 copies/million CD4(+) lymphocytes), but were not correlated with the absolute amounts (median = 17 copies/ml; IQR = 5-67 copies/ml). Both absolute and relative amounts of HIV-1 DNA were significantly lower in six patients in whom ART was initiated before positive seroconversion than in 55 patients in whom ART was initiated in the chronic phase, as shown by Western blotting. CD4 cell counts before ART introduction were also negatively correlated with both the relative and absolute amounts of HIV-1 DNA. Only the relative amounts of HIV-1 DNA negatively correlated with the duration of VL maintenance below the detection limit, while the absolute amounts were not significantly correlated with this period. CONCLUSIONS: The amounts of cellular HIV-1 DNA in patients with VLs maintained below the detection limit by the introduction of ART correlated with the timing of ART initiation but not with the duration of ART. In addition, CD4(+) T lymphocytes, which were newly generated by ART, diluted latently infected cells, indicating that measurements of the relative amounts of cellular HIV-1 DNA might be underestimated. PMID- 21605469 TI - Factors related to knowledge and perception of women about smoking: a cross sectional study from a developing country. AB - BACKGROUND: Smoking rates among women are currently low, but they are the fastest growing segment of cigarette smoking population in developing countries. We aimed to assess the knowledge and perceptions towards smoking and to identify the factors related with level of knowledge and perceptions among adult women in urban slums. METHODS: This was a cross sectional study conducted on 250 adult (>=18 years of age) women attending primary care clinics in three slums of Karachi, Pakistan. A pre-tested and structured, interviewer administered questionnaire was used for data collection. Factors associated with level of understanding about smoking were analyzed with chi-square test. RESULTS: Most of the women knew that smoking has adverse effects on women and children's health but the knowledge of specific health effects was limited. About one third of the women knew that active smoking can cause lung disease, but only a small percentage (7%) knew that it could lead to heart disease. None of the women were aware that smoking contributes to infertility and osteoporosis. A small proportion of women were aware that smoking can lead to low birth weight (7%), congenital anomalies (5%) and less than 1% of women knew that it contributes to pregnancy loss, still birth and preterm delivery. The understanding of passive smoking affecting children's lung was low (20%) and a similar proportion voiced concern about the bad influence of maternal smoking on children. Educated women had better knowledge of health effects of smoking. Education was associated with having better knowledge about effects on women health in general (p = 0.02) and specific effects like lung (p = 0.03) and reproductive health effects (p < 0.001). Education was also associated with knowledge regarding effects on fetus (p < 0.001) and children (p < 0.005). Although most of the women disliked being around smokers, more than one third thought that smoking decreases boredom (39%), tension (38%) and also helps to relax (40%). A large proportion (48%) of women had the misconception that smoking helps to reduce weight. CONCLUSIONS: This study reveals that women are aware of the general ill effects of smoking but fail to identify smoking to be associated with female maladies particularly those who were illiterate and had lower levels of education. Understanding and attitudes needs to be improved by increasing health awareness and education of women in these urban communities with special emphasis on the effects of smoking on women's health. PMID- 21605470 TI - A novel mode of chromosomal evolution peculiar to filamentous Ascomycete fungi. AB - BACKGROUND: Gene loss, inversions, translocations, and other chromosomal rearrangements vary among species, resulting in different rates of structural genome evolution. Major chromosomal rearrangements are rare in most eukaryotes, giving large regions with the same genes in the same order and orientation across species. These regions of macrosynteny have been very useful for locating homologous genes in different species and to guide the assembly of genome sequences. Previous analyses in the fungi have indicated that macrosynteny is rare; instead, comparisons across species show no synteny or only microsyntenic regions encompassing usually five or fewer genes. To test the hypothesis that chromosomal evolution is different in the fungi compared to other eukaryotes, synteny was compared between species of the major fungal taxa. RESULTS: These analyses identified a novel form of evolution in which genes are conserved within homologous chromosomes, but with randomized orders and orientations. This mode of evolution is designated mesosynteny, to differentiate it from micro- and macrosynteny seen in other organisms. Mesosynteny is an alternative evolutionary pathway very different from macrosyntenic conservation. Surprisingly, mesosynteny was not found in all fungal groups. Instead, mesosynteny appears to be restricted to filamentous Ascomycetes and was most striking between species in the Dothideomycetes. CONCLUSIONS: The existence of mesosynteny between relatively distantly related Ascomycetes could be explained by a high frequency of chromosomal inversions, but translocations must be extremely rare. The mechanism for this phenomenon is not known, but presumably involves generation of frequent inversions during meiosis. PMID- 21605471 TI - A new in-silico method for determination of helical transmembrane domains based on the PepLook scan: application to IL-2Rbeta and IL-2Rgammac receptor chains. AB - BACKGROUND: Modeling of transmembrane domains (TMDs) requires correct prediction of interfacial residues for in-silico modeling and membrane insertion studies. This implies the defining of a target sequence long enough to contain interfacial residues. However, too long sequences induce artifactual polymorphism: within tested modeling methods, the longer the target sequence, the more variable the secondary structure, as though the procedure were stopped before the end of the calculation (which may in fact be unreachable). Moreover, delimitation of these TMDs can produce variable results with sequence based two-dimensional prediction methods, especially for sequences showing polymorphism. To solve this problem, we developed a new modeling procedure using the PepLook method. We scanned the sequences by modeling peptides from the target sequence with a window of 19 residues. RESULTS: Using sequences whose NMR-structures are already known (GpA, EphA1 and Erb2-HER2), we first determined that the hydrophobic to hydrophilic accessible surface area ratio (ASAr) was the best criterion for delimiting the TMD sequence. The length of the helical structure and the Impala method further supported the determination of the TMD limits. This method was applied to the IL 2Rbeta and IL-2Rgamma TMD sequences of Homo sapiens, Rattus norvegicus, Mus musculus and Bos taurus. CONCLUSIONS: We succeeded in reducing the variation in the TMD limits to only 2 residues and in gaining structural information. PMID- 21605472 TI - Payment for performance (P4P): any future in Italy? AB - BACKGROUND: Pay for Performance (P4P) programs, based on provision of financial incentives for service quality, have been widely adopted to enhance quality of care and to promote a more efficient use of health care resources whilst improving patient outcomes. In Italy, as in other countries, the growing concern over the quality of health services provided and the scarcity of resources would make P4P programs a useful means of improving their performance. The aim of this paper is to evaluate whether it is possible to implement P4P programs in the Lombardy Region, in Italy, based on the existing data set. METHODS: Thirteen quality measures were identified regarding four clinical conditions (acute myocardial infarction (AMI), heart failure (HF), ischemic stroke and hip and knee replacement) on the basis of an international literature review. Data was collected using the database of three institutions, which included hospital discharge records (Scheda di Dimissione ospedaliera-SDO-) and letters of discharge. The study population was identified using both the Principal ICD-9-CM diagnosis codes and the discharge date. A Statistical Analysis System (SAS) program was used for the text analysis. RESULTS: It was possible to calculate almost all the parameters pertaining to the three hospitals as all the data required was available with the exception of inpatient mortality in two hospitals and smoking cessation advice/counseling in one hospital. CONCLUSIONS: On the ground of this analysis, we believe that it is possible to implement a P4P program in the Lombardy Region. However, for this program to be initiated, all necessary data must be available in electronic format and uniformly collected. Moreover, several other factors must be assessed: which clinical conditions should be included, the threshold for each quality parameter, the amount of financial incentives offered and how they will be provided. PMID- 21605473 TI - Obesity, smoking, alcohol consumption and years lived with disability: a Sullivan life table approach. AB - BACKGROUND: To avoid strong declines in the quality of life due to population ageing, and to ensure sustainability of the health care system, reductions in the burden of disability among elderly populations are urgently needed. Life style interventions may help to reduce the years lived with one or more disabilities, but it is not fully understood which life style factor has the largest potential for such reductions. Therefore, the primary aim of this paper is to compare the effect of BMI, smoking and alcohol consumption on life expectancy with disability, using the Sullivan life table method. A secondary aim is to assess potential improvement of the Sullivan method by using information on the association of disability with time to death. METHODS: Data from the Dutch Permanent Survey of the Living Situation (POLS) 1997-1999 with mortality follow up until 2006 (n = 6,446) were used. Using estimated relative mortality risks by risk factor exposure, separate life tables were constructed for groups defined in terms of BMI, smoking status and alcohol consumption. Logistic regression models were fitted to predict the prevalence of ADL and mobility disabilities in relationship to age and risk factor exposure. Using the Sullivan method, predicted age-specific prevalence rates were included in the life table to calculate years lived with disability at age 55. In further analysis we assessed whether adding information on time to death in both the regression models and the life table estimates would lead to substantive changes in the results. RESULTS: Life expectancy at age 55 differed by 1.4 years among groups defined in terms of BMI, 4.0 years by smoking status, and 3.0 years by alcohol consumption. Years lived with disability differed by 2.8 years according to BMI, 0.2 years by smoking and 1.6 by alcohol consumption. Obese persons could expect to live more years with disability (5.9 years) than smokers (3.8 years) and drinkers (3.1 years). Employing information on time to death led to lower estimates of years lived with disability, and to smaller differences in these years according to BMI (2.1 years), alcohol (1.2 years), and smoking (0.1 years). CONCLUSIONS: Compared with smoking and drinking alcohol, obesity is most strongly associated with an increased risk of spending many years of life with disability. Although employing information on the relation of disability with time to death improves the precision of Sullivan life table estimates, the relative importance of risk factors remained unchanged. PMID- 21605475 TI - Community-acquired bacteremia and acute cholecystitis due to Enterobacter cloacae: a case report. AB - INTRODUCTION: Enterobacter cloacae is responsible for 65-75% of all Enterobacter infections, bacteremia being the most common syndrome. The majority of infections are nosocomially acquired and in patients with predisposing factors. CASE PRESENTATION: We present a case of E. cloacae bacteremia secondary to acute cholecystitis in a 60-year-old man with recent diagnosis of cholelithiasis. The diagnosis was established with abdominal echography and positive blood and biliary cultures. The patient was managed successfully with cholecystectomy and antibiotic therapy. CONCLUSION: The peculiarity of our case is the development of community-acquired bacteremia due to E. cloacae with a clear infectious focus, as a single agent isolated in several blood cultures, in a patient without severe underlying diseases, prior antimicrobial use or previous hospital admission. Although the majority of Enterobacter spp. infections are nosocomially acquired, primary bacteremia being the most common syndrome, these pathogens may also be responsible for community-acquired cases. Patients without predisposing factors may also be affected. PMID- 21605474 TI - The burden and treatment of HIV in tuberculosis patients in Papua Province, Indonesia: a prospective observational study. AB - BACKGROUND: New diagnoses of tuberculosis (TB) present important opportunities to detect and treat HIV. Rates of HIV and TB in Indonesia's easternmost Papua Province exceed national figures, but data on co-infection rates and outcomes are lacking. We aimed to measure TB-HIV co-infection rates, examine longitudinal trends, compare management with World Health Organisation (WHO) recommendations, and document progress and outcome. METHODS: Adults with newly-diagnosed smear positive pulmonary TB managed at the Timika TB clinic, Papua Province, were offered voluntary counselling and testing for HIV in accordance with Indonesian National Guidelines, using a point-of-care antibody test. Positive tests were confirmed with 2 further rapid tests. Study participants were assessed using clinical, bacteriological, functional and radiological measures and followed up for 6 months. RESULTS: Of 162 participants, HIV status was determined in 138 (85.2%), of whom 18 (13.0%) were HIV+. Indigenous Papuans were significantly more likely to be HIV+ than Non-Papuans (Odds Ratio [OR] 4.42, 95% confidence interval [CI] 1.38-14.23). HIV prevalence among people with TB was significantly higher than during a 2003-4 survey at the same TB clinic, and substantially higher than the Indonesian national estimate of 3%. Compared with HIV- study participants, those with TB-HIV co-infection had significantly lower exercise tolerance (median difference in 6-minute walk test: 25 m, p = 0.04), haemoglobin (mean difference: 1.3 g/dL, p = 0.002), and likelihood of cavitary disease (OR 0.35, 95% CI 0.12 1.01), and increased occurrence of pleural effusion (OR 3.60, 95% CI 1.70-7.58), higher rates of hospitalisation or death (OR 11.80, 95% CI 1.82-76.43), but no difference in the likelihood of successful 6-month treatment outcome. Adherence to WHO guidelines was limited by the absence of integration of TB and HIV services, specifically, with no on-site ART prescriber available. Only six people had CD4+ T-cell counts recorded, 11 were prescribed co-trimoxazole and 4 received ART before, during or after TB treatment, despite ART being indicated in 14 according to 2006 WHO guidelines. CONCLUSIONS: TB-HIV co-infection in southern Papua, Indonesia, is a serious emerging problem especially among the Indigenous population, and has risen rapidly in the last 5 years. Major efforts are required to incorporate new WHO recommendations on TB-HIV management into national guidelines, and support their implementation in community settings. PMID- 21605476 TI - Bacteriological differences between COPD exacerbation and community-acquired pneumonia. AB - OBJECTIVE: To study the differences in pathogen distribution and antibiotic susceptibility between patients with COPD exacerbation and patients with community-acquired pneumonia, and develop guidance for antibiotic treatment of those conditions. METHODS: We retrospectively analyzed the medical records of 586 COPD-exacerbation patients and 345 community-acquired-pneumonia patients from January 2007 to December 2008, including sputum culture results, antibiotic susceptibilities of the microorganisms, and clinical characteristics. RESULTS: 276 (47%) of the COPD-exacerbation patients, and 183 (53%) of the community acquired-pneumonia patients had a positive sputum culture. In order, the most common pathogens in the COPD-exacerbation patients were Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Acinetobacter baumannii, and Haemophilus influenzae. The most common pathogens in the community acquired-pneumonia patients were Streptococcus pneumoniae, H. influenzae, K. pneumoniae, S. aureus, and E. coli. CONCLUSIONS: P. aeruginosa was the most common pathogen in our patients with COPD exacerbation, and S. pneumoniae was the most common in our patients with community-acquired pneumonia. P. aeruginosa is especially common in the patients with serious or extremely serious COPD. PMID- 21605477 TI - Endotracheal tube extubation force: adhesive tape versus endotracheal tube holder. AB - BACKGROUND: Adhesive tape is commonly used to secure the endotracheal tube (ETT) in anesthesia and intensive-care settings. OBJECTIVE: To determine the force required to extubate when the ETT is secured with adhesive tape or commercially available ETT holders. METHODS: We orally intubated a simulation manikin with a standard 8.0-mm inner-diameter ETT, inflated the cuff to 20 cm H(2)O, and measured the force required to extubate with the ETT secured in several ways. We tested 3 brands of tape (Durapore, Multipore Dry, and Wardel) with 6 methods, and 2 commercially available ETT holders (LockTite and Thomas) with one method. We also tested a bite block (Universal Bite Block) with 2 methods. We used a releasable cable tie with the bite block and/or ETT holder. We connected the ETT to a digital force gauge and pulled perpendicular to the oral cavity, until the entire cuff was removed from the trachea. In each trial we considered the largest force recorded the extubation force. RESULTS: One of the conventional tape methods (with wider tape and longer tape strips) required the largest force to extubate. CONCLUSIONS: With tape strips of sufficient length and width, a conventional tape method was superior to the 2 tested commercial ETT holders in holding the ETT in place in the manikin. PMID- 21605478 TI - Pulmonary hypertension: a fatal complication of neurofibromatosis type 1. AB - We report a very rare case of severe pulmonary arterial hypertension in a patient with neurofibromatosis type 1, and discuss the pathology, pathogenesis, current pulmonary hypertension classification system, and outcomes of pulmonary arterial hypertension in patients with neurofibromatosis type 1. PMID- 21605479 TI - Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome. AB - BACKGROUND: The sleep apnea-hypopnea syndrome is associated with elevated oxidative stress, which is associated with reduced levels and functional impairment of progenitor cells. OBJECTIVE: To evaluate whether one month of CPAP treatment affects circulating-progenitor-cell levels and oxidative stress in patients with sleep apnea-hypopnea syndrome. METHODS: We enrolled 13 patients with sleep apnea-hypopnea syndrome who required nasal CPAP. We evaluated white blood-cell oxidative stress and CD45-, CD34+, KDR+, and CD133+ cell levels via flow-cytometry, before and one month after CPAP treatment. RESULTS: Superoxide anion and hydrogen peroxide were reduced, and markers of protection against oxidative stress were increased after CPAP. Progenitor-cell levels increased significantly after CPAP. There was a significant negative correlation between CD45-, CD34+, KDR+, and CD133+ cell levels and the severity of sleep apnea hypopnea syndrome and superoxide anion. CONCLUSIONS: CD45-, CD34+, KDR+, and CD133+ cell levels rose significantly and reached values close to those in the control group after one month of CPAP. This change was accompanied by a significant decrease in oxidative stress, and no change in anthropometric or metabolic variables, including insulin resistance, weight, blood pressure, or lipid levels; consequently, the increase in progenitor-cell levels might be attributable to reduced oxidative stress. PMID- 21605480 TI - Long-term survival in patients with tracheostomy and prolonged mechanical ventilation in Olmsted County, Minnesota. AB - BACKGROUND: An increasing number of patients require prolonged mechanical ventilation (PMV), which is associated with high morbidity and poor long-term survival, but there are few data regarding the incidence and outcome of PMV patients from a community perspective. METHODS: We retrospectively reviewed the electronic medical records of adult Olmsted county, Minnesota, residents admitted to the intensive care units at the 2 Mayo Clinic Rochester hospitals from January 1, 2003, to December 31, 2007, who underwent tracheostomy for PMV. RESULTS: Sixty five patients, median age 68 years (interquartile range [IQR] 49-80 y), 39 male, underwent tracheostomy for PMV, resulting in an age-adjusted incidence of 13 (95% CI 10-17) per 100,000 patient-years at risk. The median number of days on mechanical ventilation was 24 days (IQR 18-37 d). Forty-six patients (71%) survived to hospital discharge, and 36 (55%) were alive at 1-year follow-up. After adjusting for age and baseline severity of illness, the presence of COPD was independently associated with 1-year mortality (hazard ratio 3.4, 95% CI 1.4 8.2%). CONCLUSIONS: There was a considerable incidence of tracheostomy for PMV. The presence of COPD was an independent predictor of 1-year mortality. PMID- 21605481 TI - Skin ulcers: a sign of disseminated tuberculosis. PMID- 21605482 TI - Surgical resection and liposomal amphotericin B to treat cavitary pulmonary zygomycosis in a patient with diabetes. AB - We describe a 24-year-old man with type 1 diabetes mellitus and a cavitary lesion in the right upper lobe, caused by a zygomycete. Surgical resection plus liposomal amphotericin B therapy was successful. We discuss predisposing condition, clinical findings, diagnosis, and treatment of pulmonary zygomycosis. PMID- 21605483 TI - A bench study of the effects of leak on ventilator performance during noninvasive ventilation. AB - BACKGROUND: During noninvasive ventilation (NIV), leak around the mask may cause inadequate ventilatory support or patient-ventilator asynchrony such as auto triggering. Some NIV ventilators may be better than others at compensating for leak. METHODS: We bench studied 3 NIV ventilators (Vision, Carina, and Trilogy100) and 2 ICU ventilators (Puritan Bennett 840 and Evita XL) to assess how they coped with 2 leak levels and zero leak during NIV. With a 2-bellows-in-a box lung model we simulated spontaneous breathing with tidal volumes of 300 mL and 500 mL, at pressure support of 0 and 10 cm H(2)O and PEEP of 5 and 10 cm H(2)O. We affixed the airway opening of the lung model to the mouth of a mannequin head and secured a mask on the mannequin face. We created a medium leak and a large leak with different size holes, and measured PEEP in the presence of leak. We also measured the actual pressure-support values and calculated the deviations from the set pressure-support value and the pressure-time product (PTP) of the airway opening pressure below and above baseline. RESULTS: With the medium leak only the Vision and Carina maintained the set PEEP and pressure support. With the large leak the pressure support was decreased with all the tested ventilators. With the larger leak and pressure support of 10 cm H(2)O the PTP below baseline for triggering increased with 2 ventilators, and the PTP above baseline for supporting the patient's inspiratory effort decreased with all 5 ventilators. The larger tidal volume increased the PTP below baseline with all 5 ventilators and at all leak sizes. CONCLUSIONS: Some of the ventilators compensated for leak better than others. With the larger leak none of the ventilators maintained the set PEEP or pressure support. PMID- 21605484 TI - High-frequency chest-wall oscillation in a noninvasive-ventilation-dependent patient with type 1 spinal muscular atrophy. AB - With the recent increased use of noninvasive ventilation, the prognoses of children with neuromuscular disease has improved significantly. However, children with muscle weakness remain at risk for recurrent respiratory infection and atelectasis. We report the case of a young girl with type 1 spinal muscular atrophy who was dependent on noninvasive ventilation, and in whom conventional secretion-clearance physiotherapy became insufficient to clear secretions. We initiated high-frequency chest-wall oscillation (HFCWO) as a rescue therapy, and she had improved self-ventilation time. This is the first case report of HFCWO for secretion clearance in a severely weak child with type 1 spinal muscular atrophy. In a patient with neuromuscular disease and severe respiratory infection and compromise, HFCWO can be used safely in combination with conventional secretion-clearance physiotherapy. PMID- 21605485 TI - Comparison of the lower confidence limit to the fixed-percentage method for assessing airway obstruction in routine clinical practice. AB - BACKGROUND: Although the statistically derived lower limit of normal (LLN) for the ratio of FEV(1) to FVC is considered superior to a fixed cutoff value (such as 0.70) for diagnosing airway obstruction, the fixed-cutoff method continues to be used and advocated. OBJECTIVE: To evaluate the misclassification of spirometrically determined airway obstruction arising from the use of the fixed percent method, in comparison to the LLN method for FEV(1)/FVC. METHODS: We reviewed 27,307 spirometry records from adult men, and diagnosed airway obstruction based on the LLN (predicted value minus 1.645 times the standard error of estimate from a north Indian reference equation for FEV(1)/FVC) and based on a fixed cutoff of 0.70. We computed agreement and discordance between the two methods, and determined the sensitivity, specificity, and predictive values of the fixed-percent method in identifying true obstruction. RESULTS: The results were discordant in 1,622 subjects (6%). Overall agreement between the two methods was good (kappa estimate 0.869), but worsened considerably with advancing age. 1,290 subjects (5%) who were deemed normal with the LLN method were diagnosed as having airway obstruction with the fixed-percentage method. Overall the sensitivity, specificity, and positive predictive value of the fixed percentage method were 0.963, 0.929, and 0.871, respectively. Specificity and positive predictive value decreased sharply with advancing age. CONCLUSIONS: The negative age-dependence of FEV(1)/FVC results in over-diagnosis of airway obstruction in middle-aged and elderly men, and under-diagnosis in young men, with the fixed-percentage method. Airway obstruction should be assessed with the LLN of FEV(1)/FVC, with the LLN derived from appropriate reference equations. PMID- 21605486 TI - Time to desaturation less than one minute predicts the need for long-term home oxygen therapy. AB - BACKGROUND: Exercise desaturation in patients with COPD is a pathophysiological phenomenon that is not wholly understood and whose clinical consequences are still unclear. METHODS: Eighty-three patients with moderate to severe COPD and P(aO(2)) > 60 mm Hg who desaturated during the 6-min walk test were followed for 5 years. Forty-eight patients had early desaturation (S(pO(2)) fell below 90% less than one minute after starting the walk test). Spirometry, blood-gas measurements, and 6-min walk tests were performed every 6 months. We recorded 6 min walk distance, baseline S(pO(2)), lowest S(pO(2)), and the time to S(pO(2)) < 90%. In each control, stable patients with severe hypoxia at rest who required long-term oxygen therapy were identified. RESULTS: Upon completion of the study, 65% of the early desaturators had developed severe hypoxemia and required long term home oxygen, versus 11% in the non-early desaturators (P < .001). CONCLUSIONS: In patients with moderate to severe COPD, desaturation within the first minute of the 6-min walk test predicts the need for long-term home oxygen at 5-year follow-up. PMID- 21605487 TI - Acute hypoxemic respiratory failure in sarcoidosis: a case report and literature review. PMID- 21605488 TI - Bench evaluation of 7 home-care ventilators. AB - BACKGROUND: Portable ventilators continue to decrease in size while increasing in performance. We bench-tested the triggering, battery duration, and tidal volume (V(T)) of 7 portable ventilators: LTV 1000, LTV 1200, Puritan Bennett 540, Trilogy, Vela, iVent 101, and HT50. METHODS: We tested triggering with a modified dual-chamber test lung to simulate spontaneous breathing with weak, normal, and strong inspiratory effort. We measured battery duration by fully charging the battery and operating the ventilator with a V(T) of 500 mL, a respiratory rate of 20 breaths/min, and PEEP of 5 cm H(2)O until breath-delivery ceased. We tested V(T) accuracy with pediatric ventilation scenarios (V(T) 50 mL or 100 mL, respiratory rate 50 breaths/min, inspiratory time 0.3 s, and PEEP 5 cm H(2)O) and an adult ventilation scenario (V(T) 400 mL, respiratory rate 30 breaths/min, inspiratory time 0.5 s, and PEEP 5 cm H(2)O). We measured and analyzed airway pressure, volume, and flow signals. RESULTS: At the adult settings the measured V(T) range was 362-426 mL. On the pediatric settings the measured V(T) range was 51-182 mL at the set V(T) of 50 mL, and 90-141 mL at the set V(T) of 100 mL. The V(T) delivered by the Vela at both the 50 mL and 100 mL, and by the HT50 at 100 mL, did not meet the American Society for Testing and Materials standard for V(T) accuracy. Triggering response and battery duration ranged widely among the tested ventilators. CONCLUSIONS: There was wide variability in battery duration and triggering sensitivity. Five of the ventilators performed adequately in V(T) delivery across several settings. The combination of high respiratory rate and low V(T) presented problems for 2 of the ventilators. PMID- 21605489 TI - Use of lambda-mu-sigma-derived Z score for evaluating respiratory impairment in middle-aged persons. AB - BACKGROUND: The lambda-mu-sigma (LMS) method calculates the lower limit of normal for spirometric values as the 5th percentile of the distribution of Z scores. Conceptually, LMS-derived Z scores account for normal age-related changes in pulmonary function, including variability and skewness in reference data. Evidence is limited, however, on whether the LMS method is valid for evaluating respiratory impairment in middle-aged persons. OBJECTIVE: To evaluate the association of LMS-defined respiratory impairment (airflow limitation and restrictive pattern) with mortality and respiratory symptoms. METHODS: We analyzed spirometric data from white participants ages 45-64 years in the Third National Health and Nutrition Examination Survey (NHANES III, n = 1,569) and the Atherosclerosis Risk in Communities study (ARIC, n = 8,163). RESULTS: LMS-defined airflow limitation was significantly associated with mortality (adjusted hazard ratios: NHANES III 1.90, 95% CI 1.32-2.72, ARIC 1.28, 95% CI 1.06-1.57), and respiratory symptoms (adjusted odds ratios: NHANES III 2.48, 95% CI 1.75-3.51, ARIC 2.27, 95% CI 1.98-2.62). LMS-defined restrictive-pattern was also significantly associated with mortality (adjusted hazard ratios: NHANES III 1.98, 95% CI 1.08-3.65, ARIC 1.38, 95% CI 1.03-1.85), and respiratory symptoms (adjusted odds ratios: NHANES III 2.34, 95% CI 1.44-3.80, ARIC 1.89, 95% CI 1.46 2.45). CONCLUSIONS: In white middle-age persons, LMS-defined airflow limitation and restrictive-pattern were significantly associated with mortality and respiratory symptoms. Consequently, an approach that reports spirometric values based on LMS-derived Z scores might provide an age-appropriate and clinically valid strategy for evaluating respiratory impairment. PMID- 21605490 TI - Distance learning and the internet in respiratory therapy education. AB - BACKGROUND: The profession of respiratory therapy (RT) continues to grow both in number, due to population growth and an ever-increasing aging population, and scope of practice, due to both new and expanded roles and responsibilities in divergent areas of clinical practice. Instructional technology, including distance learning, will probably play a key role in training, educating, and assessing RT students to meet the increasing demand for practitioners. OBJECTIVE: To assess current uses of distance learning and opinions concerning the appropriate use of distance education in RT education programs nationwide. METHODS: A 13-item on-line survey was designed to collect information about the frequency of use of various types of distance education typically utilized in RT education programs. The survey was sent to directors of 343 Committee on Accreditation for Respiratory Care accredited programs of RT education that offer entry-level or advanced courses of study. RESULTS: The response rate was 50% (169 respondents). Fifty-two percent of the respondents indicated that their courses included some form of on-line learning component. Most directors anticipated that the distance composition of their course offerings will remain unchanged or increase in the near future. CONCLUSIONS: Our results indicate that, while distance education plays an important supportive role in RT education, there is still a preference for face-to-face instruction and Internet-facilitated courses among program directors. Program directors continue to view the laboratory and clinical settings as hands-on environments that require instructor supervision in order for students to demonstrate proficiency and critical thinking skills. When used appropriately, distance learning may be an efficient and effective approach to address the many barriers to education faced by the health workforce in general, including budget constraints, overloaded schedules, the need for on-the-job learning opportunities, and lack of access. PMID- 21605491 TI - Respiratory care work assignment based on work rate instead of work load. AB - BACKGROUND: We previously reported a new management variable, work rate, defined as work load due per hour, based on cumulative standard treatment times. We found that work rates were unachievable (ie, exceeded 1 hour of scheduled work per hour of available labor) for 75% of scheduled due times, despite presumed achievable average work load. OBJECTIVE: To determine the optimal strategy for creating work assignments based on work rate. METHODS: A focus group used root-cause analysis to identify ways to balance assignments based on work rate. We surveyed employees to assess their willingness to start earlier. We determined the ratio of scheduled to unscheduled work during a 12-month period. The scheduled work comprised administering small-volume nebulizer, metered-dose inhaler, noninvasive ventilation, and mechanical ventilation. The unscheduled work consisted of all other modalities. We also developed a spreadsheet model to assess the effect of shifting the start time on work-rate distribution in a representative 24-hour period. RESULTS: The focus group determined that starting treatments 1 hour earlier would help. Fifteen of the 24 clinicians surveyed responded, and 13 of the respondents were willing to start earlier. The scheduled work load averaged approximately 55% of the total work load, but there was high variability per assignment area (range 0-99%). The spreadsheet model showed that shifting treatment start times improved the distribution of work rate throughout the day, but did not guarantee that labor demand never outstrips supply. CONCLUSIONS: Our studies to date suggest that: basing assignments on average work load leads to periods of unachievable work rate, resulting in missed treatments and staff dissatisfaction. We have only limited ability to reduce peaks in work rate, but staggering treatment times is effective. Fair assignment of work should differentiate scheduled from unscheduled work. PMID- 21605492 TI - Redox biology and gastric carcinogenesis: the role of Helicobacter pylori. AB - Almost half the world's population is infected by Helicobacter pylori (H. pylori). This bacterium increases the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in human stomach, and this has been reported to impact upon gastric inflammation and carcinogenesis. However, the precise mechanism by which H. pylori induces gastric carcinogenesis is presently unclear. Although the main source of ROS/RNS production is possibly the host neutrophil, H. pylori itself produces O2*-. Furthermore, its cytotoxin induces ROS production by gastric epithelial cells, which might affect intracellular signal transduction, resulting in gastric carcinogenesis. Excessive ROS production in gastric epithelial cells can cause DNA damage and thus might be involved in gastric carcinogenesis. Understanding the molecular mechanism of H. pylori induced carcinogenesis is important for developing new strategies against gastric cancer. PMID- 21605493 TI - Protective effect of aminoguanidine against cyclophosphamide-induced oxidative stress and renal damage in rats. AB - BACKGROUND: Cyclophosphamide (CP) is widely used in the treatment of tumors and B cell malignant disease, such as lymphoma, myeloma, chronic lymphocytic leukemia, and Waldenstrom's macroglobulinemia. Renal damage is one of the dose-limiting side effects of CP. Oxidative stress is reported to play important roles in CP induced renal damage. AIM: To find out whether aminoguanidine (AG) protects against CP-induced oxidative stress and renal damage. METHOD: Renal damage was induced in the rats by administration of a single injection of CP at a dose of 150 mg/kg body weight intraperitoneally. For the AG pretreatment studies, the rats were injected intraperitoneally with AG at a dose of 200 mg/kg body weight 1 hour before administration of CP. The control rats received AG or saline alone. All the rats were killed 16 hours after the administration of CP or saline. The kidneys were used for histological examination by light microscopy and biochemical assays--malondialdehyde, protein carbonyl content, reduced glutathione (GSH), and the activities of antioxidant enzymes including glutathione peroxidase (GPx), glutathione S transferase (GSTase), catalase, glutathione reductase, and myeloperoxidase (MPO), a marker of neutrophil infiltration. RESULTS: Pretreatment with AG attenuated CP-induced renal damage histologically. Pretreatment with AG prevented CP-induced lipid peroxidation, protein oxidation, depletion of reduced GSH, and loss of activities of the antioxidant enzymes including GPx, catalase, and GSTase and also MPO activity. CONCLUSION: The results of the present study reveal that AG can prevent CP induced renal damage by inhibiting oxidative stress. Thus, AG may be useful for prevention of the nephrotoxicity of CP. PMID- 21605494 TI - Acetate but not propionate induces oxidative stress in bakers' yeast Saccharomyces cerevisiae. AB - The influence of acetic and propionic acids on baker's yeast was investigated in order to expand our understanding of the effect of weak organic acid food preservatives on eukaryotic cells. Both acids decreased yeast survival in a concentration-dependent manner, but with different efficiencies. The acids inhibited the fluorescein efflux from yeast cells. The inhibition constant of fluorescein extrusion from cells treated with acetate was significantly lower in parental strain than in either PDR12 (ABC-transporter Pdr12p) or WAR1 (transcriptional factor of Pdr12p) defective mutants. The constants of inhibition by propionate were virtually the same in all strains used. Yeast exposure to acetate increased the level of oxidized proteins and the activity of antioxidant enzymes, while propionate did not change these parameters. This suggests that various mechanisms underlie the yeast toxicity by acetic and propionic acids. Our studies with mutant cells clearly indicated the involvement of Yap1p transcriptional regulator and de novo protein synthesis in superoxide dismutase up-regulation by acetate. The up-regulation of catalase was Yap1p independent. Yeast pre-incubation with low concentrations of H2O2 caused cellular cross protection against high concentrations of acetate. The results are discussed from the point of view that acetate induces a prooxidant effect in vivo, whereas propionate does not. PMID- 21605495 TI - Ischemia-induced nitrotyrosine formation and nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase in human retinal pigment epithelium in vivo. AB - Reactive oxidative compounds including superoxide anions and nitric oxide are believed to play a central role in many blinding eye diseases. In the present study, we examine the effect of ischemia on human retinal pigment epithelial (RPE) cells in an unusual clinical case. We show that ischemia leads to extensive nitrotyrosine deposition in the RPE and choroid, thus indicating NO-dependent oxidative stress. We also show for the first time the in vivo translocation of glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) to the nuclei of RPE cells. This enzyme's nuclear translocation has previously been demonstrated in vitro where it is a marker of apoptosis. Furthermore, nitrotyrosine deposition and GAPDH translocation have been duplicated in vitro using human RPE cells. Thus, nitrotyrosine formation and GAPDH trafficking to the nucleus may be observed during ischemic conditions. PMID- 21605496 TI - Protein tyrosine phosphatase alpha regulates cell detachment and cell death profiles induced by nitric oxide donors in the A431 human carcinoma cell line. AB - We investigated the role of protein tyrosine phosphatase-alpha (PTPalpha) expression in the cell death profile of the A431 human carcinoma cell line that was induced by cytotoxic concentrations of the nitric oxide (NO) donors sodium nitroprusside (SNP) and 3,3-bis-(aminoethyl)-1-hydroxy-2-oxo-1-triazene (NOC-18). Both NO donors promoted extensive cell detachment in A431 parental cells as compared to the detachment observed for A431 cells that ectopically expressed PTPalpha (A431 (A27B(PTPalpha)) cells). The NO-induced cell death characteristics for both cell lines were examined. After incubation for 10 hours with 2.0 mM SNP, attached or detached A431 cells underwent apoptosis. Cells were highly positive for Annexin-V, featured increased cleavage of procaspase-8, activation of downstream caspase-3, and activation of poly-ADP-ribose polymerase 1 (PARP-1). In contrast, exposure of A431 (A27B(PTPalpha)) cells to 2.0 mM SNP produced an increase in the release of lactate dehydrogenase and enhanced incorporation of propidium iodide. In addition, A431 (A27B(PTPalpha)) cells showed partial inhibition of the activities of caspase-8, caspase-3, and PARP-1 upon detachment and cell death induced by SNP treatment. Results indicate that necrotic cell damage was induced, characterized by cellular swelling and lysis. We conclude from these results that PTPalpha regulates the A431 tumor cell death profile mediated by NO donors. Expression of PTPalpha or its absence may determine the occurrence of NO-induced cell death with necrotic or apoptotic features, respectively. PMID- 21605497 TI - Mustard seeds (Sinapis Alba Linn) attenuate azoxymethane-induced colon carcinogenesis. AB - Mustard seeds (MS), which are consumed in considerable amounts by the Japanese people that, interestingly, have the longest life expectancy in the world, are known to contain a number of yet not fully defined but quite powerful anti oxidants. A suspension of extracted MS was found to suppress oxidized-LDL-induced macrophage respiratory burst in vitro, to prevent growth, and to induce apoptotic death of SW480 cells (a human colon cancer cell line), while no such effects were found for normal 3T3 cells. A diet enriched with MS decreased plasma levels of the lipid peroxidation product malonaldehyde in mice exposed to the colon cancer inducer azoxymethane (AOM). Such a diet also dose-dependently enhanced the activity of several anti-oxidant enzymes, such as superoxide dismutase (SOD), catalase, and GSH-peroxidase and, moreover, reduced AOM-mediated formation of colon adenomas by about 50%. Further studies are required to detail and explore the beneficial effects of MS and their rich content of powerful anti-oxidants. PMID- 21605498 TI - Evaluation of oxidative stress status in children with pervasive developmental disorder and attention deficit hyperactivity disorder using urinary-specific biomarkers. AB - Pervasive developmental disorder (PDD) and attention deficit hyperactivity disorder (ADHD) are likely to be associated with increased oxidative stress, particularly that of lipid peroxidation. We evaluated the oxidative stress status of pediatric PDD and ADHD patients using their urine samples. Urinary acrolein lysine levels in 11 PDD and 10 ADHD children (205 +/- 97 and 234 +/- 75 nmol/mg Cr, respectively) appeared higher than those of the control subjects (155 +/- 59 nmol/mg Cr). Measurement of urinary specific biomarkers is comfortable, non invasive, and easy to perform in children. Our findings might provide a scientific guide for use in further clinical and biochemical studies of these disorders. PMID- 21605499 TI - Depressed hippocampal MEK/ERK phosphorylation correlates with impaired cognitive and synaptic function in zinc-deficient rats. AB - An experiment was performed to observe changes of mitogen-activated protein kinase ERK (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways in the hippocampus of zinc-deficient (ZD) rats and the correlation with cognitive dysfunction. Forty-four male weanling Wistar rats were randomly assigned to ZD (n = 22) and control (pair-fed, n = 22) groups. After a 4-week treatment, Y-maze was used to test the spatial memory of the rats. The long-term potentiation (LTP) in rat hippocampal dentate gyrus was observed simultaneously. pMEK, pERK1/2, and pCREB protein levels were examined by Western blot assays. The results demonstrated that the latency period in Y-maze was significantly shorter for the ZD rats. LTP amplitude in the ZD group decreased significantly compared with the control group. pMEK, pERK1/2, and pCREB protein expression of hippocampus in the ZD group decreased significantly. The results implicated a possibility that zinc deficiency-induced cognitive and synaptic impairment may be relevant to the MEK/ERK signaling pathway. PMID- 21605500 TI - Mild experimental ketosis increases brain uptake of 11C-acetoacetate and 18F fluorodeoxyglucose: a dual-tracer PET imaging study in rats. AB - Brain glucose and ketone uptake was investigated in Fisher rats subjected to mild experimental ketonemia induced by a ketogenic diet (KD) or by 48 hours fasting (F). Two tracers were used, (11)C-acetoacetate ((11)C-AcAc) for ketones and (18)F fluorodeoxyglucose for glucose, in a dual-tracer format for each animal. Thus, each animal was its own control, starting first on the normal diet, then undergoing 48 hours F, followed by 2 weeks on the KD. In separate rats on the same diet conditions, expression of the transporters of glucose and ketones (glucose transporter 1 (GLUT1) and monocarboxylic acid transporter (MCT1)) was measured in brain microvessel preparations. Compared to controls, uptake of (11)C AcAc increased more than 2-fold while on the KD or after 48 hours F (P < 0.05). Similar trends were observed for (18)FDG uptake with a 1.9-2.6 times increase on the KD and F, respectively (P < 0.05). Compared to controls, MCT1 expression increased 2-fold on the KD (P < 0.05) but did not change during F. No significant difference was observed across groups for GLUT1 expression. Significant differences across the three groups were observed for plasma beta-hydroxybutyrate (beta-HB), AcAc, glucose, triglycerides, glycerol, and cholesterol (P < 0.05), but no significant differences were observed for free fatty acids, insulin, or lactate. Although the mechanism by which mild ketonemia increases brain glucose uptake remains unclear, the KD clearly increased both the blood-brain barrier expression of MCT1 and stimulated brain (11)C-AcAc uptake. The present dual tracer positron emission tomography approach may be particularly interesting in neurodegenerative pathologies such as Alzheimer's disease where brain energy supply appears to decline critically. PMID- 21605501 TI - Fetal and neonatal iron deficiency causes volume loss and alters the neurochemical profile of the adult rat hippocampus. AB - OBJECTIVE: Perinatal iron deficiency results in persistent hippocampus-based cognitive deficits in adulthood despite iron supplementation. The objective of the present study was to determine the long-term effects of perinatal iron deficiency and its treatment on hippocampal anatomy and neurochemistry in formerly iron-deficient young adult rats. METHODS: Perinatal iron deficiency was induced using a low-iron diet during gestation and the first postnatal week in male rats. Hippocampal size was determined using volumetric magnetic resonance imaging at 8 weeks of age. Hippocampal neurochemical profile, consisting of 17 metabolites indexing neuronal and glial integrity, energy reserves, amino acids, and myelination, was quantified using high-field in vivo (1)H NMR spectroscopy at 9.4T (N = 11) and compared with iron-sufficient control group (N = 10). RESULTS: The brain iron concentration was 56% lower than the control group at 7 days of age in the iron-deficient group, but had recovered completely at 8 weeks. The cross-sectional area of the hippocampus was decreased by 12% in the formerly iron deficient group (P = 0.0002). The hippocampal neurochemical profile was altered: relative to the control group, creatine, lactate, N-acetylaspartylglutamate, and taurine concentrations were 6-29% lower, and glutamine concentration 18% higher in the formerly iron-deficient hippocampus (P < 0.05). DISCUSSION: Perinatal iron deficiency was associated with reduced hippocampal size and altered neurochemistry in adulthood, despite correction of brain iron deficiency. The neurochemical changes suggest suppressed energy metabolism, neuronal activity, and plasticity in the formerly iron-deficient hippocampus. These anatomic and neurochemical changes are consistent with previous structural and behavioral studies demonstrating long-term hippocampal dysfunction following perinatal iron deficiency. PMID- 21605502 TI - Evidence for a second meal cognitive effect: glycaemic responses to high and low glycaemic index evening meals are associated with cognition the following morning. AB - Low glycaemic index (GI) foods consumed at breakfast can enhance memory in comparison to high-GI foods; however, the impact of evening meal GI manipulations on cognition the following morning remains unexplored. Fourteen healthy males consumed a high-GI evening meal or a low-GI evening meal in a counterbalanced order on two separate evenings. Memory and attention were assessed before and after a high-GI breakfast the following morning. The high-GI evening meal elicited significantly higher evening glycaemic responses than the low-GI evening meal. Verbal recall was better the morning following the high-GI evening meal compared to after the low-GI evening meal. In summary, the GI of the evening meal was associated with memory performance the next day, suggesting a second meal cognitive effect. The present findings imply that an overnight fast may not be sufficient to control for previous nutritional consumption. PMID- 21605503 TI - Early and post-weaning malnutrition impairs alpha-MSH expression in the hypothalamus: a possible link to long-term overweight. AB - The present study explored the effects of early and post-weaning malnutrition and nutritional rehabilitation on orexigenic (orexin (ORX) and neuropeptide Y (NPY)) and anorexigenic peptides (alpha-melanocyte stimulating hormone (alpha-MSH)) expressed in hypothalamic nuclei. Male Wistar rats were malnourished during gestation-lactation (MGL) or from weaning to post-natal day 55 (MPW; P55). Two groups of rats were rehabilitated with a balanced diet until P90 (MGL-R and MPW R, respectively). After a glucose tolerance test (GTT) brains were processed for immunohistochemistry. Malnourished groups were hyperglycemic after GTT. ORX expression did not display any difference. Only MGL rats showed increased NPY immunoreactivity in ARC and PVN nuclei, and both malnourished groups showed low alpha-MSH expression in the PVN and DMH, as compared with their controls. After nutritional rehabilitation rats showed normal GTT, increased rate of body and adipose tissue weights and high proportion of food ingestion. Both rehabilitated groups maintained low alpha-MSH expression in the PVN, indicating a deleterious long-lasting effect. PMID- 21605505 TI - Nano-hydroxyapatite/chitosan/konjac glucomannan scaffolds loaded with cationic liposomal vancomycin: preparation, in vitro release and activity against Staphylococcus aureus biofilms. AB - The objective of this study was to design a novel artificial bone scaffold for the therapy and prevention of refractory bacterial infections. Porous nano hydroxyapatite/chitosan/konjac glucomannan (n-HA/CS/KGM) scaffolds were loaded with cationic liposomal vancomycin (CLV) to form a novel complex drug carrier (LLS). The kinetics of CLV release from LLS and the effects of the amount of konjac glucomannan (KGM) and CLV in LLS were examined in vitro. The anti-biofilm activity of LLS was also studied. Electron microscopy indicated that the liposomes were well preserved in the scaffold, and that CLV rather than free vancomycin is released from the scaffold. The weight percentage of KGM or CLV greatly influenced the release behavior of the scaffolds. LLS could provide sustained CLV release and inhibited the formation of Staphylococcus aureus biofilms better than scaffolds without CLV loaded. LLS may be a novel, effective drug-delivery system for the antibiotic treatment of osteomyelitis caused by biofilm infections. PMID- 21605504 TI - Effects of intracellular zinc depletion on the expression of VDAC in cultured hippocampal neurons. AB - An experiment was conducted to investigate whether intracellular zinc depletion can actually change expression of voltage-dependent anion channel 1 (VDAC1) and VPAC2 in cultured hippocampal neurons as well as their significance. Hippocampal neurons were obtained by primary culture from hippocampus of newborn Wistar rats. Cultured hippocampal neurons were exposed to a cell membrane-permeable zinc chelator N,N,N',N'-tetrakis (2-pyridyl methyl) ethylenediamine (TPEN) (2 uM), and to TPEN plus zinc sulfate (5 uM) for 1 or 24 hours. Cultures were then processed to detect neuronal injury by lactate dehydrogenase (LDH) assay, intracellular Ca(2+) with the fluorescent probe fluo-3/AM, reactive oxygen species (ROS) generation using 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay, nuclear morphology by Hoechst 33342, VDAC1, and VDAC2 protein levels by western blot, and VDAC1 and VDAC2 mRNA levels by RT-PCR. The results demonstrated that exposure of hippocampal neurons to TPEN (2 uM) for 24 hours induced notably neuronal injury, significantly increased the number of apoptotic nuclei, up-regulated the expression of VDAC1 protein level and down-regulated the expression of VDAC2 protein level. Significant down-regulation of mRNA levels for VDAC1 and VDAC2 were observed in TPEN-treated neurons. Co-addition of zinc almost completely reversed TPEN-induced neuronal injury and above alterations in VDAC1 and VDAC2 protein levels and mRNA levels. Present results implicate a possibility that up regulation of VDAC1 and down-regulation of VDAC2 may participate in hippocampal neuron injury induced by zinc deficiency. PMID- 21605506 TI - How to make the most of the hours we have left. PMID- 21605507 TI - Laparoscopic sigmoidectomy for diverticulitis: a prospective study. AB - BACKGROUND: Surgical treatment of complicated colonic diverticular disease is still debatable. The aim of this prospective study was to evaluate the outcome of laparoscopic sigmoid colectomy in patients with diverticulitis. Patients offered laparoscopic surgery presented with acute complicated diverticulitis (Hinchey type I, II, III), chronically recurrent diverticulitis, bleeding, or sigmoid stenosis caused by chronic diverticulitis. METHOD: All patients who underwent laparoscopic colectomy within a 12-year period were prospectively entered into a database registry. One-stage laparoscopic resection and primary anastomosis constituted the planned procedure. A 4-trocar approach with suprapubic minilaparotomy was performed. Main data recorded were age, sex, postoperative pain, return of bowel function, operation time, duration of hospital stay, and early and late complications. RESULTS: During the study period, 260 sigmoid colectomies were performed for diverticulitis. The cohort included 104 male and 156 female patients; M to F ratio was 4:6. Postoperative pain was controlled by NSAIDs or weak opioid analgesia. Fifteen patients (5.7%) required conversion from laparoscopic to open colectomy. The most common reasons for conversion were directly related to the inflammatory process, abscess, and peritonitis. Mean operative time was 130+/-54. Average postoperative hospital stay was 10+/-3 days. A longer hospital stay was recorded for Hinchey type IIb patients. Complications were recorded in 30 patients (11.5%). The most common complications that required reoperation were hemorrhage in 2 patients (0.76) and anastomotic leak in 5 patients (only 3 of them required reoperation). The mortality among them was 2 patients (0.76%). CONCLUSIONS: Laparoscopic surgery for diverticular disease is safe, feasible, and effective. Therefore, laparoscopic colectomy has replaced open resection as standard surgery for recurrent and complicated diverticulitis at our institution. PMID- 21605508 TI - Postoperative Symptoms, after-care, and return to routine activity after laparoscopic cholecystectomy. AB - BACKGROUND AND OBJECTIVES: Surgeons are usually not involved in the postdischarge care of patients after uncomplicated laparoscopic cholecystectomy (LC). The aim of this study was to document the the symptomatic recovery of patients following LC, because this has a bearing on the planning of a postoperative care package. METHODS: Consecutive patients undergoing uncomplicated LC were followed up by a weekly telephone questionnaire survey for 6 weeks. RESULTS: The study cohort comprised 102 patients who all completed the study. Postoperatively, only 2.9% of all patients had postoperative nausea/vomiting lasting greater than or equal too 2 days. Pain was symptomatic in 11.7% of patients. Port-site wounds were a source of significant symptoms in 70.5% of the patients. Postoperative review by a community nurse and primary-care doctor were necessary in 77.4% and 32% patients, respectively, with a combined average of 3.1 reviews per patient. Less than 4% of patients believed that they would benefit from a surgeon's review 6 weeks after LC. Median time taken to return to routine preoperative activity after surgery was 22 days (IQR, 17 to 34), which was affected by the degree of activity undertaken, wound-related symptoms persisting for greater than or equal to 3, planned follow-up clinic appointment, and discharge as an outpatient. CONCLUSION: Wound-related symptoms are common after LC, require substantial input from the community health service in their management, and may delay return to preoperative routine. PMID- 21605509 TI - Port-site hernia following laparoscopic cholecystectomy. AB - BACKGROUND: Port-site hernia is a rare but potentially serious complication of laparoscopic cholecystectomy. This study aimed to review the current literature, assess the incidence and causes of port-site hernias, and identify methods to reduce the risk. METHODS: A systematic search of the literature published in English from 1995 to 2010 was conducted using PubMed to identify all reports of port-site, trocar-site, or incisional hernia following laparoscopic cholecystectomy. Studies in over 100 patients were identified before the application of defined exclusion criteria. The incidence of port-site hernia was calculated and compared with historical data. Predisposing factors were reviewed. RESULTS: Seven studies met the search criteria, with 99 port-site hernias in 5984 patients. The overall incidence of port-site hernia was 1.7% (range, 0.3% to 5.4). The most important factors were older age, higher body mass index, preexisting hernia, trocar design, trocar diameter, increased duration of surgery, and extension of the port site for gallbladder extraction. CONCLUSION: The incidence of port-site hernia is low but likely to be underestimated and has not declined over time. Awareness of the predisposing factors and modification of techniques may help to reduce the risk. PMID- 21605510 TI - Endoscopically obtained bile aspirate is an accurate adjunct in the diagnosis of symptomatic gallbladder disease. AB - OBJECTIVES: The experience of a single surgeon in a rural hospital over a 10-year period was analyzed with respect to the utilization of endoscopically obtained bile aspirates as an adjunct in the diagnosis of symptomatic gallbladder disease. METHODS: A retrospective study of the author's entire cholecystectomy experience over a 10-year period with 641 patients was conducted to evaluate the utility of the bile aspirate in the preoperative selection of operative candidates and with respect to the ultimate pathologic diagnostic accuracy of the test. RESULTS: Derivation of preoperative diagnosis via traditional standard means was possible in 479 patients. An endoscopically obtained positive bile aspirate was found in 162 additional patients who failed to have positive traditional diagnostic studies (acalculous gallbladder disease). Micro-pathology was determined to be present in 603 patients (94.07%). In 27 of the 38 negatives, there had been positive radiological studies (71%). In 11 of the 38, a positive preoperative bile aspirate had been obtained (28.9%). Of the 162 patients with a positive bile aspirate, 151 (93.21%) of the gallbladder specimens had confirmatory histologic analysis (92.1% confidence interval +/- 3.95%). CONCLUSION: In patients with symptoms suggestive of clinical gallbladder disease and negative traditional diagnostic studies, the endoscopically obtained bile aspirate has been shown to be a highly reliable tool in establishing the diagnosis and is recommended as an aid in the appropriate selection of candidates who may benefit from cholecystectomy. PMID- 21605511 TI - Laparoscopic sleeve gastrectomy: our first 100 patients. AB - BACKGROUND: Laparoscopic sleeve gastrectomy is becoming a popular procedure for the morbidly obese patient. Its utilization as a standalone procedure has good results with weight loss in short- and midterm reports. The aim of this study was to assess our technique and whether it warranted any modifications in the early postoperative period. METHODS: Our first 100 consecutive patients undergoing laparoscopic sleeve gastrectomy were retrospectively reviewed. Data analysis was conducted at 3 and 6 months to assess the percentage of excess body weight loss and comorbidity status change. RESULTS: The percentage of excess body weight loss at the 3- and 6-month marks was 34.2% and 49.1%, respectively. Comorbidities were also improved at the 3- and 6-month marks. Hypertension resolved in 38%, hyperlipidemia resolved in 19%, and diabetes in 46%. Complication rate during the first 6 months was 10%. Major complications included 2 patients with postoperative bleeding, 2 patients with acute renal failure from dehydration, and 1 postoperative bleeding patient who developed a gastric fistula. No surgical reintervention was required for any complication. CONCLUSION: Our technique is a safe method that is easily reproducible and does not require any modification. Laparoscopic sleeve gastrectomy is an excellent surgical option with a low complication rate. PMID- 21605513 TI - Single-layer versus double-layer laparoscopic intracorporeally sutured gastrointestinal anastomoses in the canine model. AB - OBJECTIVE: The objective of this study was to compare the gross and histopathologic changes following 1- versus 2-layer hand-sewn suture techniques in laparoscopic gastrointestinal anastomosis in dogs. METHODS: This was an experimental prospective study of 16 healthy mixed breed male and female dogs. Animals were randomly divided into 2 groups. Two-layer side-to-side hand-sewn laparoscopic gastrojejunostomies were performed in group A, so that simple interrupted sutures were placed in the outer layer and simple continuous suture was used in the inner layer. The 1-layer simple continuous anastomosis between the stomach and jejunum was done in group B precisely. Specimen were collected from the sites of anastomosis, and H&E statining was performed for light microscopic studies. RESULTS: All animals survived the surgery. There was no gross inflammation, ischemia, apparent granulation tissue, abscess or fistula formation, leakage or stricture formation, and all sites of anastomosis were patent. Several adhesion formations were found in the abdomen with the higher incidence in the control group. Mean scores of leukocyte infiltration and granulation tissue formation at the sites of anastomosis were statistically insignificant between groups (P>0.05). CONCLUSIONS: Gross and histopathologic findings revealed that hand-sewn laparoscopic gastrointestinal anastomosis with the 1-layer suture technique is comparable to the 2-layer suture technique. PMID- 21605512 TI - Laparoscopic cholecystectomy conversion rates two decades later. AB - BACKGROUND AND OBJECTIVES: Now nearly 2 decades into the laparoscopic era, nationwide laparoscopic cholecystectomy conversion rates remain around 5% to 10%. We analyzed patient- and surgeon-specific factors that may impact the decision to convert to open. METHODS: We retrospectively analyzed 2205 LCs performed at a large tertiary community hospital over a 52 month period (May 2004 through October 2008). RESULTS: The overall conversion rate was 4.9%. The most common reason for conversion was adhesions, and the majority of these patients had prior abdominal surgery. Males and patients >50 years old had a significantly higher likelihood of open conversion. The conversion rate of high-volume surgeons (>=100 total cases) in comparison to low-volume surgeons (40 to 99 total cases) was significantly lower. Conversion rates were lower among surgeons with fellowship training and those who completed residency training after 1990. Interestingly, the percentage of conversions due to technical difficulty was lower among those with fellowship training but higher among those who completed training after 1990. CONCLUSION: Conversion occurred in ~5% of all laparoscopic cholecystectomies. Males, patients >50 years old, and cases performed by low volume surgeons had a higher likelihood of conversion. Other surgeon-specific factors did not have a significant impact on conversion rate. PMID- 21605514 TI - Contemporary referral pattern for robotic prostatectomy. AB - BACKGROUND AND OBJECTIVES: In spite of the current widespread application of robotic surgery in the treatment of prostate cancer, it remains unclear whether current patterns of use are based on patient benefit or driven by marketing. We sought to investigate this possibility by analyzing the source of our patient population for robot-assisted laparoscopic prostatectomy (RALP). METHODS: We reviewed 200 consecutive patients who underwent robotic prostatectomy by a single surgeon (RA) at our institution. The source of referral for each patient was analyzed along with individual patient characteristics to identify whether only low-risk or unusually ideal candidates were referred. RESULTS: Of the 200 patients, 90.5% were referred by a urologist with only 5.5% being referred by another urologist at our institution. Only <10 patients cited media or marketing sources as the reason for self-referral, and 10 were referred by primary care physicians or other acquaintances. This referral pattern did not change between the first and second 100 patients. Referred patients included those up to 80 years of age, up to 51 kg/m(2) in body mass index, and up to Gleason 9 on biopsy, with 36% of those referred by urologists having some history of previous abdominal or prostate surgery. CONCLUSION: The referral pattern for RALP at our institution may reflect a growing acceptance of robotic surgery among urologists in our region and is unlikely driven by patient-directed marketing. Additionally, urologists may also be more confident in the role of RALP as evidenced by their referral of even complex and higher-risk patients. PMID- 21605516 TI - Supracervical robotic-assisted laparoscopic sacrocolpopexy for pelvic organ prolapse. AB - BACKGROUND: Supracervical robotic-assisted laparoscopic sacrocolpopexy (SRALS) is a new surgical treatment for pelvic organ prolapse that secures the cervical remnant to the sacral promontory. We present our initial experience with SRALS in the same setting as supracervical robotic-assisted hysterectomy (SRAH). METHODS: Women with vaginal vault prolapse and significant apical defects as defined by a Baden-Walker score of greater than or equal to 3 who had not undergone hysterectomy were offered SRALS in combination with SRAH. A chart review was performed to analyze operative and perioperative data. Outcome data also included patients who underwent robotic-assisted laparoscopic sacrocolpopexy (RALS) without any other procedure. RESULTS: Thirty-three patients underwent RALS, including 12 patients who underwent SRALS. All SRALS were performed following SRAH in the same setting. The mean follow-up for the RALS and SRALS patients was 38.4 months and 20.7 months, respectively. One patient in the RALS group had an apical recurrence. There were no recurrences in the SRALS group. CONCLUSIONS: SRALS is effective for repair of apical vaginal defects in patients with significant pelvic organ prolapse who have not undergone previous hysterectomy. Complications are few and recurrences rare in short- and medium-term follow-up. Greater follow-up and numbers are needed to further establish the role of this procedure. PMID- 21605515 TI - Posterior reconstruction before anastomosis improves the anastomosis time during robot-assisted radical prostatectomy. AB - BACKGROUND AND OBJECTIVES: Our goal was to evaluate posterior reconstruction of the rhabdosphincter during robot-assisted radical prostatectomy and determine whether this technique decreased anastomotic time of a surgeon in training to perform vesicourethral reconstruction. METHODS: We reviewed the first 25 robot assisted prostatectomies performed by 2 urology surgeons in training (surgeon 1 and surgeon 2). The patient populations were matched for age, Gleason score, clinical stage, and PSA. Whereas surgeon 1 performed the vesicourethral anastomosis without posterior reconstruction, surgeon 2 reapproximated Denonvilliers' fascia of the posterior bladder to the rhabdosphincter. Time for each surgeon to complete the anastomosis and clinical factors was compared. RESULTS: Surgeon 1 had a median anastomosis time of 25 minutes (range, 17 to 48), whereas surgeon 2 had a median anastomosis time of 15 minutes (range, 10 to 30) (P<0.001). Biopsy Gleason score, pathological tumor stage, perineural invasion, median age at the time of surgery, PSA, prostate weight, and estimated blood loss were not significantly different between surgeons (P>0.05). Pathological Gleason score (P=0.045) and total console time (surgeon 1-216 minutes, surgeon 2-176 minutes; P=0.002) were significantly different between surgeons. CONCLUSION: Posterior reconstruction prior to anastomosis decreases anastomosis time for robotic surgeons in training. PMID- 21605517 TI - Ureteral clipping simplifies hand-assisted laparoscopic donor nephrectomy. AB - OBJECTIVES: We describe a technique of doubly clipping the distal ureter during hand-assisted laparoscopic donor nephrectomy (HALDN) to prevent urine accumulation, thereby simplifying renal hilar division and potentially decreasing the graft warm ischemic time. METHODS: A technique of placing polymer-locking clips across the distal ureter prior to division was developed to prevent urine accumulation and the need for suctioning during critical hilar vessel division. RESULTS: We found that ureteral clipping and the elimination of urine accumulation simplified renal hilar division. Retrospective assessment of a series of 27 sequential HALDNs (15 without and 12 with clipping) demonstrated similar estimated blood loss, total operative and warm ischemic times (P 0.13 to 0.18). No adverse impact on graft viability or recipient outcome was observed. CONCLUSION: Distal ureter clipping to prevent urine accumulation around the renal hilum during HALDN is safe and helpful. PMID- 21605518 TI - Laparoscopic nephrectomy in patients undergoing hemodialysis treatment. AB - BACKGROUND AND OBJECTIVES: To report our experience with laparoscopic nephrectomy (LN) in patients undergoing hemodialysis compared with normal counterparts. METHODS: Seventeen patients (20 renal units, Group 1) undergoing hemodialysis underwent LN, which was indicated due to nonfunctioning kidney in 17 and suspected malignancy in 3 renal units. Radical nephrectomy (RN), simple nephrectomy (SN), and simple nephroureterectomy (SNU) were performed in 3, 9, and 8 cases, respectively. For comparison, 101 patients (Group 2) without CRF (chronic renal failure) who had undergone LN were evaluated. In this group, RN, SN, SNU and radical nephroureterectomy (RNU) were performed in 48, 41, 8, and 4 patients, respectively. RESULTS: The mean age (36.9 +/-13.1 vs. 48.7+/-19.4yr, P=0.002) and BMI (22.1+/-4.8 vs. 26.2+/-5.1kg/m(2), P=0.001) were lower in Group 1, whereas ASA (physical status score of American Society of Anesthesiologists) score (2.8+/-0.4 vs. 1.5+/-0.7, P<0.001) was lower in Group 2. The estimated blood loss (111+/-114 vs. 184+/-335mL, P=0.34) was higher in Group 2. Both groups were comparable in regard to mean operative time (133+/-79 vs. 119+/-45, P+/ 0.70), hematocrit drop (4.69+/-3.9 vs. 3.86+/-3.0, P=0.29) and hospital stay (3.6+/-3.3 vs. 3.3+/-2.4 days, P=0.34). Meanwhile, when only patients undergoing SN and SNU in the study cohort (n=17 in Group 1 and n=49 in Group 2) are taken into consideration, no significant difference was observed between the 2 groups in terms of any kind of above-mentioned perioperative parameters. No case in Group 1 was converted to open surgery due to metabolic problems. CONCLUSIONS: LN in patients undergoing hemodialysis may be performed safely by an experienced laparoscopy team. PMID- 21605519 TI - Bulging of the mesh after laparoscopic repair of ventral and incisional hernias. AB - BACKGROUND AND OBJECTIVES: To investigate the prevalence, diagnosis, clinical significance, and treatment strategies for bulging in the area of laparoscopic repair of ventral hernia that is caused by mesh protrusion through the hernia opening, but with intact peripheral fixation of the mesh and actually a still sufficient repair. METHODS: Medical records of all 765 patients who underwent laparoscopic ventral hernia repair were reviewed, and all patients with a swelling in the repaired area were identified and analyzed. RESULTS: Twenty-nine patients were identified. They all underwent a computed tomography assessment. Seventeen patients (2.2% of the total group) had a hernia recurrence; in an additional 12 patients (1.6%), radiologic examinations indicated only bulging of the mesh but no recurrence. Bulging was associated with pain in 4 patients who underwent relaparoscopy and got a new, larger mesh tightly stretched over the entire previous repair. Eight asymptomatic patients decided on "watchful waiting." All patients remained symptom free during a median follow-up of 22 months. CONCLUSION: Symptomatic bulging, though not a recurrence, requires a new repair and must be considered as an important negative outcome of laparoscopic ventral hernia repair. In asymptomatic patients, "watchful waiting" seems justified. PMID- 21605520 TI - Laparoscopic Splenectomy Using LigaSure. AB - BACKGROUND: Laparoscopic splenectomy (LS) has become the standard approach for most splenectomy cases. Bleeding is the main complication and cause for conversion. We present our experience with the LigaSure and discuss its advantage as a vessel sealing system in achieving safe vascular control. METHOD: Over a 3 year period, we performed 12 consecutive LS using LigaSure at a single center. A literature review of all the patients who had undergone laparoscopic splenectomy with of the LigaSure to achieve vascular control at the hilum was carried out, assessing its advantages and outcome. RESULTS: Twelve LS were performed. Eleven of these patients had ITP, and one patient had sickle cell disease. The mean blood loss was 70mL (range, 50 to 460), and operating time was 126 minutes (range, 110 to 240). Two postoperative complications occurred: portal vein thrombosis in one case and subphrenic collection in the other. The literature review revealed 8 studies with 231 cases in which the LigaSure was used to perform laparoscopic splenectomy. A significant reduction in operating time (average 102 minutes) and intraabdominal blood loss (66mL) was observed with the LigaSure compared with endostaplers. CONCLUSION: The use of LigaSure and the semilateral position results in a gain of time and safety in addition to low intraoperative bleeding, need for transfusion, minimal complications and a low conversion rate. PMID- 21605521 TI - Use of ultrasound measurements to direct laparoscopic pyloromyotomy in infants. AB - BACKGROUND: Laparoscopic pyloromyotomy is associated with an increased risk of incomplete myotomy compared with open myotomy. We hypothesized that utilizing ultrasound measured length to direct laparoscopic pyloromyotomy would reduce the risk of incomplete pyloromyotomy without a concomitant increase in the risk of mucosal perforation. METHODS: Infants (n=43) with hypertrophic pyloric stenosis diagnosed by ultrasound and subsequent laparoscopic pyloromyotomy over a 2-year period (December 2006 through December 2008) were studied. Pyloromyotomy length was guided by preoperative ultrasound measurements. Pyloromyotomy was considered complete if the measured length was >= the ultrasound measurement. Infants were followed prospectively for time to full feeding, time to discharge, and complications. RESULTS: The cohort included 38 male and 5 female infants (age, 37+/-13 days; range, 17 to 72 days) who underwent ultrasound (length 1.9+/-0.2cm; thickness 4.4+/-0.9mm) and laparoscopic pyloromyotomy. Infants achieved full feeding 28+/-16 hours postoperatively and were discharged 34+/-18 hours postoperatively. No infant required reoperation for incomplete myotomy. One infant sustained mucosal perforation (2%). No patient suffered other complications. CONCLUSION: Preoperative ultrasound measurement of pyloric length to determine the length of laparoscopic pyloromyotomy, rather than visual cues alone, appears to minimize the risk of incomplete pyloromyotomy. PMID- 21605522 TI - Single-incision laparoscopic-assisted right colon resection for cancer. AB - INTRODUCTION: We present an approach to laparoscopic right colon resection utilizing a single port placed through the umbilicus. The technique described is performed through a single small umbilical incision with a virtually scar-free result. METHODS: A 77-year-old woman with a tubulovillous adenoma in her cecum underwent a laparoscopic right colectomy using a single port placed through the umbilicus. Straight and reticulating laparoscopic instruments were utilized. RESULTS: The total operative time was 112 minutes. No intraoperative or postoperative complications occurred. The patient was discharged home on day 5 postoperatively with normal bowel function and tolerance of a solid diet. CONCLUSIONS: Laparoscopic right colectomy can be safely performed through a single incision through the umbilicus with an excellent cosmetic result. PMID- 21605523 TI - Laparoscopic approach for metachronous cecal and sigmoid volvulus. AB - BACKGROUND: Metachronous colonic volvulus is a rare event that has never been approached laparoscopically. METHODS: Here we discuss the case of a 63-year-old female with a metachronous sigmoid and cecal volvulus. RESULTS: The patient underwent 2 separate successful laparoscopic resections. DISCUSSION AND CONCLUSION: The following is a discussion of the case and the laparoscopic technique, accompanied by a brief review of colonic volvulus. In experienced hands, laparoscopy is a safe approach for acute colonic volvulus. PMID- 21605524 TI - Single incision laparoscopic pancreas resection for pancreatic metastasis of renal cell carcinoma. AB - BACKGROUND: Transumbilical single incision laparoscopic surgery (SILS) offers excellent cosmetic results and may be associated with decreased postoperative pain, reduced need for analgesia, and thus accelerated recovery. Herein, we report the first transumbilical single incision laparoscopic pancreatectomy case in a patient who had renal cell cancer metastasis on her pancreatic corpus and tail. METHODS: A 59-year-old female who had metastatic lesions on her pancreas underwent laparoscopic subtotal pancreatectomy through a 2-cm umbilical incision. RESULTS: Single incision pancreatectomy was performed with a special port (SILS port) and articulated equipment. The procedure lasted 330 minutes. Estimated blood loss was 100mL. No perioperative complications occurred. The patient was discharged on the seventh postoperative day with a low-volume (20mL/day) pancreatic fistula that ceased spontaneously. Pathology result of the specimen was renal cell cancer metastases. CONCLUSION: This is the first reported SILS pancreatectomy case, demonstrating that even advanced surgical procedures can be performed using the SILS technique in well-experienced centers. Transumbilical single incision laparoscopic pancreatectomy is feasible and can be performed safely in experienced centers. SILS may improve cosmetic results and allow accelerated recovery for patients even with malignancy requiring advanced laparoscopic interventions. PMID- 21605525 TI - Adrenalectomy by retroperitoneal laparoendoscopic single site surgery. AB - BACKGROUND: Laparoscopic adrenalectomy is the current standard for treatment of benign adrenal disease. To reduce the invasiveness of surgery, new techniques have been recently proposed, such as mini-laparoscopy, natural orifice transluminal endoscopic surgery, and laparoendoscopic single site surgery (LESS). Herein, we describe one case of adrenalectomy by retroperitoneal LESS using conventional laparoscopic instruments and ports. CASE REPORT: A 52-year-old female patient with an incidental finding of a 3-cm mass in the left adrenal was referred to us. Preoperative blood concentrations of catecholamines, aldosterone, and cortisol, and urinary excretion of vanilmandelic acid were normal. She underwent an adrenalectomy by retroperitoneal LESS using conventional instruments and ports. Operative time and estimated blood loss were 82 minutes and <=50cc, respectively. She was discharged 12 hours after surgery. No intra- or postoperative complications occurred. Pathological analysis of the specimen identified an adrenal cortical adenoma. CONCLUSION: Adrenalectomy by retroperitoneal LESS using conventional laparoscopic instruments is feasible. Further studies must be performed to evaluate safety, indications and benefits of this approach. PMID- 21605526 TI - Bleeding after right laparoscopic adrenalectomy. AB - The current standard of care for treating benign adrenal disease is laparoscopic adrenalectomy. Surgical tools, such as ultrasonic shears and vessel sealing systems, have increased in popularity and improved surgical outcomes. However, the safety profile of clipless and sutureless adrenalectomy has not been completely established. We report on a complicated 74-year-old male who underwent significant postoperative hemorrhage following laparoscopic adrenalectomy. Interventional radiology with renal artery stent insertion was successful for the management of postoperative bleeding in this high-risk patient. PMID- 21605527 TI - Laparoscopic resection of periadrenal paraganglioma mimicking an isolated adrenal hydatid cyst. AB - We present the case of a 64-year-old female with a periadrenal paraganglioma. The mass was diagnosed during abdominal ultrasonography performed to investigate right flank pain. Magnetic resonance imaging showed a lesion 48mm in diameter with an irregular hyperintense central margin, thickened septa, centrally located cystic component, and contrast enhancing peripheral portions. These findings made us think it was an isolated adrenal hydatid cyst. The mass was excised via laparoscopy without complications. Histopathological examination was consistent with periadrenal paraganglioma. We believe that the paraganglioma can mimic the radiological appearance of an isolated adrenal hydatid cyst, which should be taken into consideration during diagnosis. PMID- 21605528 TI - Laparoscopic abdomino-paracoccygeal resection of anorectal cystic teratoma. AB - Sacrococcygeal teratoma rarely presents in adulthood (reported incidence of 1:87 000). It is more common in females. Adult anorectal teratoma is a rare variant of sacrococcygeal teratoma. The majority of tumors spare the sacrococcygeal bone. The size and location of the tumor within the pelvis dictates whether it is approached surgically through a transabdominal, posterior, or a combined approach. We present in this article the case of a young woman with a large cystic anorectal teratoma treated successfully with a combined laparoscopic abdomino-paracoccygeal resection. PMID- 21605529 TI - Bile duct injury after single incision laparoscopic cholecystectomy. AB - BACKGROUND: The advancement and development of laparoscopic cholecystectomy revolutionized surgery and case management. Many procedures are routinely performed laparoscopically. Single incision laparoscopic surgery has been introduced with the hope of further reduction of scarring and possibly procedural pain. With no established technique for this procedure, the safety of single incision laparoscopic cholecystectomy has not been determined. METHODS AND RESULTS: A 30-year-old man underwent single incision laparoscopic cholecystectomy for symptomatic cholelithiasis at an outside hospital. The operation was uneventful, and the patient was discharged home. The patient returned to the Emergency Department 4 days postoperatively, and a bile duct injury was diagnosed. A percutaneous drain was placed, and the patient was transferred to the Hepato-Pancreato-Biliary (HPB) service of a tertiary care center for definitive care. A delayed repair approach was used to allow the inflammation around the porta to decrease. Six weeks after injury, the patient underwent Roux en-Y hepaticojejunostomy. The patient did well postoperatively. CONCLUSION: Although single incision laparoscopic surgery will play a prominent role in the future, its development and application are not without risks as demonstrated from this case. It is imperative that surgeons better define the surgical approach to achieve the critical view and select appropriate patients for single incision laparoscopic cholecystectomy. PMID- 21605530 TI - Jejunal Bezoar causing obstruction after laparoscopic Roux-en-Y gastric bypass. AB - Bowel obstruction is a known complication of Roux-en-Y gastric bypass. It can be caused by adhesions, internal hernia, incarcerated ventral hernia, or intussusception. Sometimes the underlying cause may be unusual. These 2 case reports describe patients who underwent laparoscopic Roux-en-Y gastric bypass and whose postoperative courses were complicated by small-bowel obstruction due to phytobezoars in the ileum, distal to the jejunojejunal anastomosis. We reviewed the literature by using PubMed and Medline for causes, pathogenesis, classifications, diagnosis, and management. PMID- 21605531 TI - Post Colonoscopy Colonic Intussusception Reduced via a Laparoscopic Approach. AB - Intussusception occurs when a mass in the bowel is pulled forward by normal peristalsis, with resultant invagination of the involved bowel wall. In the absence of a mass, intussusception may be caused by functional disturbances without gross mural abnormality. Colo-colonic intussusception in adult is relatively rare and usually secondary to a definable lesion, the majority of which are malignant in nature. Idiopathic intussusception in adults is rare and its pathogenesis is poorly understood. We present a case report of an adult colo colonic intussusception occurring after colonoscopy, which was treated successfully with laparoscopic reduction. We speculate that the intussusception was induced by post-polypectomy mucosal edema acting as a lead point and therefore can be treated without resection. PMID- 21605532 TI - Safe laparoscopic removal of a 3200 gram fibroid uterus. AB - BACKGROUND AND OBJECTIVES: Hysterectomy using minimally invasive techniques yields fewer complications, less blood loss, and quicker recovery time compared with traditional abdominal hysterectomy. Despite these advantages, 65% of all hysterectomies in the United States are still performed using traditional laparotomy, and many clinicians still exclude patients with a history of prior abdominal surgery, significant obesity, or a large fibroid uterus from these procedures. Among physicians skilled in minimally invasive surgery, the prior largest uteri removed included a 2421g uterus removed vaginally, and a 2418g uterus removed via hand-assisted laparoscopic hysterectomy. METHODS: We performed a laparoscopic-assisted hysterectomy on a significantly obese 50-year-old woman with a 3200g uterus. The patient required a 2-day hospital stay and recovered unremarkably. The patient was able to return to work within one week and quickly returned to activities of daily life. CONCLUSION: In the hands of experienced minimally invasive surgeons, laparotomy can be avoided in almost all instances of hysterectomy for benign disease. PMID- 21605533 TI - Combined robotic radical prostatectomy and robotic radical nephrectomy. AB - A 60-year-old man with prostatic adenocarcinoma and an enhancing left-sided renal mass underwent successful combined robotic radical prostatectomy and robotic radical nephrectomy. We describe the initial report of this combined robotic procedure to remove 2 synchronous urological malignancies and describe our technique. An analysis was conducted of the operating room and postanesthesia care unit charges of this procedure compared with the 2 procedures performed independently. PMID- 21605534 TI - A technique to address peritoneal dialysis catheter malfunction. AB - BACKGROUND: A 66-year-old male with a history of severe ischemic myopathy and renal failure underwent a combined heart and kidney transplant. Postoperative failure of the transplanted kidney eventually led to the need for peritoneal dialysis (PD). METHODS: After one month, the PD catheter was laparoscopically repositioned after it was found to have migrated from its correct position in the pelvis and twisted and clogged in the omentum. After one more month, the same complication recurred. Laparoscopy was again used to clear the clogged catheter and reposition it. This time, a testicular prosthesis was sewn to the catheter and used as an anchoring weight for the proper position in the pelvis. RESULTS: Six months after anchoring with the testicular prosthesis, the peritoneal dialysis catheter continues to function appropriately, and the patient has no complaints. CONCLUSIONS: Mal-positioned peritoneal dialysis catheters may be repositioned and anchored by using a testicular prosthesis in the event that weighted catheters are not available. PMID- 21605535 TI - Symptomatic "H" type duplex gallbladder. AB - Gallbladder duplication with an incidence at autopsy of about 1 in 4000 is important in clinical practice, because it may cause some clinical, surgical, and diagnostic problems. Preoperative identification of this rare anomaly avoids biliary injuries and the other consequences of missed diagnosis. In this report, we present a case of ductular type duplex gallbladder diagnosed preoperatively by magnetic resonance cholangiopancreatography (MRCP) and ultrasound and managed successfully by laparoscopy. PMID- 21605536 TI - Laparoscopic resection of a small bowel lipoma with incidental intussusception. AB - BACKGROUND: Small bowel tumors are rare entities that often present with nonspecific symptoms. The diagnosis is more likely in patients with occult gastrointestinal bleeding of unknown origin or in adults with small bowel intussusception. Even with exhaustive diagnostic testing, small bowel tumors are often not diagnosed preoperatively. Because 60% to 70% of small bowel tumors are malignant, surgical excision is always recommended. METHODS: We report the case of a 73-year-old man with occult gastrointestinal bleeding. A small bowel tumor was discovered only after video capsule endoscopy, computed tomography, and multiple endoscopies were performed. RESULTS: The patient underwent laparoscopic exploration. An incidental intussusception made the tumor simple to identify. By extending the umbilical port, the tumor was easily removed. The final pathology demonstrated a submucosal lipoma. CONCLUSIONS: Small bowel lipomas can cause intussusception and gastrointestinal bleeding. When diagnosed preoperatively, laparoscopic resection is feasible. PMID- 21605537 TI - Environmental factors affecting transmission risk for hantaviruses in forested portions of southern Brazil. AB - Using ecological niche modeling approaches, we assessed suites of environmental factors to identify areas of transmission risk in forested regions of southern Brazil. We studied all officially confirmed cases from the Epidemiological Surveillance System of the Brazilian Health Ministry from Atlantic Forest and Araucaria forest areas of southern Brazil (n=264), during 1993-2008. Among climate-related influences associated with hantavirus cases, winter precipitation and high photosynthetic mass (EVI) were particularly closely related to case distributions. Models identified broad risk areas for hantavirus transmission, extending along the coastal Atlantic Forest region from Sao Paulo to Rio Grande do Sul, eastern Paraguay, and Argentina. Host distribution maps indicate overlap of several species of Oligoryzomys in the transmission area, showing the necessity of more detailed reservoir-based studies to detect finer-scale infection foci. PMID- 21605538 TI - Habitats of the sandfly vectors of Leishmania tropica and L. major in a mixed focus of cutaneous leishmaniasis in southeast Tunisia. AB - From 2009 to 2010, 3129 sandflies were caught in CDC light traps placed in various habitats in Ghomrassen, Tataouine governorate, southeast Tunisia, a mixed focus of human cutaneous leishmaniasis caused by Leishmania tropica and Leishmania major. Species diversity was quantified in anthropogenic, semi anthropogenic and semi-natural locations. Sandflies were identified according to morphological characters and also by the comparative sequence analysis of a fragment of the mitochondrial cytochrome b gene to distinguish between two putative local vectors of L. tropica, namely Phlebotomus chabaudi and Phlebotomus riouxi. The lowest sandfly diversities were found in L. major sites, where the incriminated vector P. papatasi predominated in the burrows of the rodent reservoir hosts (Meriones) as well as inside and outside houses of human cases. In L. tropica sites, the incriminated peri-domestic vector Phlebotomus sergenti was the most abundant species inside houses, whereas P. riouxi or P. chabaudi was the dominant species in the semi-natural rocky habitats favoured by the putative rodent reservoir, Ctenodactylus gundi. All specimens of P. chabaudi identified molecularly had the diagnostic cytochrome b characters of P. riouxi, indicating either that the latter represents only a geographical variant of P. chabaudi or that these two species may sometimes hybridize. PMID- 21605539 TI - Old focus of cysticercosis in a senegalese village revisited after half a century. AB - The objective of this epidemiological study was to determine whether cysticercosis and especially neurocysticercosis is endemic in Soutou village about half a century after the 1962 outbreak. This study was carried out from September 2009 to February 2010. It involved a questionnaire administration, serology, treatment, coproscopy and neuro-imaging. Four hundred and three serum samples were collected from the village people, which covered 94% of the village population. By using a parallel combination of the antigen-detection ELISA and the enzyme-linked immunoelectrotransfer blot (EITB) a cysticercosis seroprevalence of 11.9% (95% CI: 8.9-15.4%) was found. Cerebral CT-scans showed that 23.3% (10/43) of the seropositives were affected by neurocysticercosis. Four out of these 43 (9.3%) were tapeworm carriers. Seropositivity was significantly associated to older age groups (41-60 years old; p=0.001 and 61-91 years old; p=0.028) and absence of a household toilet (p=0.001). It can be concluded that Soutou village is an active focus of Taenia solium cysticercosis about 50 years after the first reported epidemic outbreak. PMID- 21605540 TI - A method for concentrating organic dyes: colorimetric measurements of nitric oxides and sialic acids. AB - A new method for extraction and concentration of organic dyes that uses a reagent composed of a nonionic detergent mixed with an alcohol is described. We have observed that water-soluble organic dyes are also soluble in nonionic detergents and can be extracted by adding salt, which separates the dye-detergent component from the aqueous phase. We have also found that mixing nonionic detergents with alcohols markedly reduces their viscosity and produces stable, free-flowing, and effective reagents for color extraction. On the basis of these observations, we used a mixture of Triton X-100 and 1-butanol and observed that water-soluble natural and synthetic chromophores, as well as dyes generated in biochemical reactions, can be extracted, concentrated, and analyzed spectrophotometrically. Trypan blue and phenol red are used as examples of synthetic dyes, and red wine is used as an example of phenolic plant pigments. Applications for quantification of nitric oxides and sialic acids are described in more detail and show that as little as 0.15 nmol of nitric oxide and 0.20 nmol of sialic acid can be detected. A major advantage of this method is its ability to concentrate chromophores from dye-containing solutions that otherwise cannot be measured because of their low concentrations. PMID- 21605541 TI - Thylakoid protein phosphorylation in dynamic regulation of photosystem II in higher plants. AB - In higher plants, the photosystem (PS) II core and its several light harvesting antenna (LHCII) proteins undergo reversible phosphorylation cycles according to the light intensity. High light intensity induces strong phosphorylation of the PSII core proteins and suppresses the phosphorylation level of the LHCII proteins. Decrease in light intensity, in turn, suppresses the phosphorylation of PSII core, but strongly induces the phosphorylation of LHCII. Reversible and differential phosphorylation of the PSII-LHCII proteins is dependent on the interplay between the STN7 and STN8 kinases, and the respective phosphatases. The STN7 kinase phosphorylates the LHCII proteins and to a lesser extent also the PSII core proteins D1, D2 and CP43. The STN8 kinase, on the contrary, is rather specific for the PSII core proteins. Mechanistically, the PSII-LHCII protein phosphorylation is required for optimal mobility of the PSII-LHCII protein complexes along the thylakoid membrane. Physiologically, the phosphorylation of LHCII is a prerequisite for sufficient excitation of PSI, enabling the excitation and redox balance between PSII and PSI under low irradiance, when excitation energy transfer from the LHCII antenna to the two photosystems is efficient and thermal dissipation of excitation energy (NPQ) is minimised. The importance of PSII core protein phosphorylation is manifested under highlight when the photodamage of PSII is rapid and phosphorylation is required to facilitate the migration of damaged PSII from grana stacks to stroma lamellae for repair. The importance of thylakoid protein phosphorylation is highlighted under fluctuating intensity of light where the STN7 kinase dependent balancing of electron transfer is a prerequisite for optimal growth and development of the plant. This article is part of a Special Issue entitled: Photosystem II. PMID- 21605542 TI - The small CAB-like proteins of the cyanobacterium Synechocystis sp. PCC 6803: their involvement in chlorophyll biogenesis for Photosystem II. AB - The five small CAB-like proteins (ScpA-E) of the cyanobacterium Synechocystis sp. PCC 6803 belong to the family of stress-induced light-harvesting-like proteins, but are constitutively expressed in a mutant deficient of Photosystem I (PSI). Using absorption, fluorescence and thermoluminescence measurements this PSI-less strain was compared with a mutant, in which all SCPs were additionally deleted. Depletion of SCPs led to structural rearrangements in Photosystem II (PSII): less photosystems were assembled; and in these, the Q(B) site was modified. Despite the lower amount of PSII, the SCP-deficient cells contained the same amount of phycobilisomes (PBS) as the control. Although the excess PBS were functionally disconnected, their fluorescence was quenched under high irradiance by the activated Orange Carotenoid Protein (OCP). Additionally the amount of OCP, but not of the iron-stress induced protein (isiA), was higher in this SCP-depleted mutant compared with the control. As previously described, the lack of SCPs affects the chlorophyll biosynthesis (Vavilin, D., Brune, D. C., Vermaas, W. (2005) Biochim Biophys Acta 1708, 91-101). We demonstrate that chlorophyll synthesis is required for efficient PSII repair and that it is partly impaired in the absence of SCPs. At the same time, the amount of chlorophyll also seems to influence the expression of ScpC and ScpD. PMID- 21605543 TI - Allosteric cooperativity in respiratory proteins. PMID- 21605544 TI - Reprint of: Regulation of photosynthetic electron transport. AB - The photosynthetic electron transport chain consists of photosystem II, the cytochrome b(6)f complex, photosystem I, and the free electron carriers plastoquinone and plastocyanin. Light-driven charge separation events occur at the level of photosystem II and photosystem I, which are associated at one end of the chain with the oxidation of water followed by electron flow along the electron transport chain and concomitant pumping of protons into the thylakoid lumen, which is used by the ATP synthase to generate ATP. At the other end of the chain reducing power is generated, which together with ATP is used for CO(2) assimilation. A remarkable feature of the photosynthetic apparatus is its ability to adapt to changes in environmental conditions by sensing light quality and quantity, CO(2) levels, temperature, and nutrient availability. These acclimation responses involve a complex signaling network in the chloroplasts comprising the thylakoid protein kinases Stt7/STN7 and Stl1/STN7 and the phosphatase PPH1/TAP38, which play important roles in state transitions and in the regulation of electron flow as well as in thylakoid membrane folding. The activity of some of these enzymes is closely connected to the redox state of the plastoquinone pool, and they appear to be involved both in short-term and long-term acclimation. This article is part of a Special Issue entitled: Regulation of Electron Transport in Chloroplasts. PMID- 21605545 TI - Modeling Photosystem I with the alternative reaction center protein PsaB2 in the nitrogen fixing cyanobacterium Nostoc punctiforme. AB - Five nitrogen fixing cyanobacterial strains have been found to contain PsaB2, an additional and divergent gene copy for the Photosystem I reaction center protein PsaB. In all five species the divergent gene, psaB2, is located separately from the normal psaAB operon in the genome. The protein, PsaB2, was recently identified in heterocysts of Nostoc punctiforme sp. strain PCC 73102. 12 conserved amino acid replacements and one insertion, were identified by a multiple sequence alignment of several PsaB2 and PsaB1 sequences. Several, including an inserted glutamine, are located close to the iron-sulfur cluster F(X) in the electron transfer chain. By homology modeling, using the Photosystem I crystal structure as template, we have found that the amino acid composition in PsaB2 will introduce changes in critical parts of the Photosystem I protein structure. The changes are close to F(X) and the phylloquinone (PhQ) in the B branch, indicating that the electron transfer properties most likely will be affected. We suggest that the divergent PsaB2 protein produces an alternative Photosystem I reaction center with different structural and electron transfer properties. Some interesting physiologcial consequences that this can have for the function of Photosystem I in heterocysts, are discussed. PMID- 21605546 TI - C-terminal peptides of chemokine-like factor 1 signal through chemokine receptor CCR4 to cross-desensitize the CXCR4. AB - CKLF1, a human cytokine that is a functional ligand for CCR4, is upregulated in various inflammation and autoimmune diseases. CKLF1 contains at least two secreted forms, the C-terminal peptides C19 and C27. Chemically synthesized C19 and C27 can interact with CCR4 and attenuate allergic inflammation. In this study, we found C19 and C27 could inhibit SDF-1-induced CXCR4-mediated chemotaxis and promote CXCR4 internalization. The inhibitory effect was due to desensitization of CXCR4, which was mediated by CCR4. Further experiments confirmed that CXCR4 desensitization required activation of PI3K/PKC pathway. Altogether our data elucidate the mechanism of C19- and C27-induced CXCR4 desensitization. PMID- 21605547 TI - Structure-function analysis of the tertiary bile acid TUDCA for the resolution of endoplasmic reticulum stress in intestinal epithelial cells. AB - Inflammatory bowel diseases (IBD) are chronically relapsing and immune-mediated disorders of the gastrointestinal tract. Endoplasmic reticulum (ER) stress mechanisms in the epithelium have been demonstrated to be implemented into the pathogenesis of intestinal inflammation. Chemical chaperones have been demonstrated to exhibit beneficial effects in various diseases associated with ER stress mechanisms by prohibiting the unfolded protein response (UPR). In a structure-function analysis, we tested the potential of the conjugated bile salt sodium tauroursodeoxycholate (TUDCA), naturally present in the small bowel, to resolve ER stress in intestinal epithelial cells. TUDCA efficiently inhibited the expression of UPR dependent genes like GRP78 triggered by the ER stressor tunicamycin in the small intestinal epithelial cell line Mode-K. TUDCA inhibited upstream signaling events in all three branches of the UPR cascade and diminished binding of UPR activated transcription factors to the grp78 promoter. A structure function analysis revealed that UDCA but not its conjugation partner taurine, known as a chemical chaperone, is responsible for the inhibition of GRP78 induction and that UDCA is 10 times more effective than its taurine conjugate. This inhibitory effect was confirmed in a cell free assay, where TUDCA and UDCA but not taurine effectively inhibited the aggregation of thermally denatured BSA. We conclude that TUDCA and UDCA are potent anti-aggregants for the resolution of ER stress in intestinal epithelial cells and should be considered as a potential drug target to resolve ER stress mechanisms underlying the pathology of IBD. PMID- 21605548 TI - Cl-/HCO3- exchange activity in fMLP-stimulated human neutrophils. AB - It is well known that chemotactic agents active Na(+)/H(+) exchanger, increasing intracellular pH of neutrophils, but their effect on bicarbonate transporters have not been established yet. To study the effect of fMLP on the activity of Cl( )/HCO(3)(-) exchange, the rate of pH recovery after acute Cl(-) readmission in cell subjected to an alkaline load by CO(2) washout in a Cl-free medium was measured. The activity of the exchanger was reduced to 72% of control when cells were pre-incubated for 5 min with 0.1 MUM fMLP and reached 48% of control in steady state after acute exposure. After extracellular bicarbonate or TMA addition the rate recovery of intracellular pH was reduce at 72% and at 84%, respectively. The inhibitory effect on the intracellular pH recovery was not affected by blockers of Na(+)/H(+) exchange. We conclude from these studies that an increase of pH(i) produced for this chemotactic agent is facilitated by the simultaneous activation of Na(+)/H(+) exchange and inhibition of Cl(-)/HCO(3)(-) exchange in neutrophils. PMID- 21605549 TI - Retinoic acid inhibits BMP4-induced C3H10T1/2 stem cell commitment to adipocyte via downregulating Smad/p38MAPK signaling. AB - Increased adipocyte formation from mesenchymal stem cells (MSCs) is typical for obesity. It is recently observed that bone morphogenetic proteins (BMPs) provide instructive signals for the commitment of MSCs to adipocytes. We examined potential role of retinoic acid (RA) in inhibiting the BMP4 induction of MSC commitment toward adipocyte. BMP4-treated C3H10T1/2 MSCs, when further exposed to adipogenic differentiation media, displayed distinct adipocytic commitment and differentiation. This could be inhibited by RA exposure during the BMP4 treatment stage (commitment stage before adipogenic hormonal inducers were given), as was observed by reductions in key adipogenic genes/transcription factors (C/EBPalpha, PPARgamma, aP2), lipogenic genes (LPL, FAS, GLUT4), and lipid accumulation. Among RA receptors (RARs) screened, RARbeta was mainly upregulated under RA exposure. BMP4 signaled through both Smad1/5/8 and p38 mitogen-activated protein kinase (MAPK) and RA significantly suppressed the BMP4-triggered phosphorylation of both Smad1/5/8 and p38MAPK. These data suggest that RA has inhibitory effects on the BMP4 induction of C3H10T1/2 adipocytic commitment via downregulating Smad/p38MAPK signaling. How to inhibit MSC adipocytic commitment, as partly revealed in this study, will have a significant impact on treating obesity and related diseases. PMID- 21605550 TI - Beta-35 is a transferrin-derived inhibitor of angiogenesis and tumor growth. AB - An angiogenesis inhibitor named Beta-35 has been identified and purified from the conditioned medium of mouse pancreatic beta cells tumor cells. Beta-35 has a molecular weight of 35 kDa and inhibits DNA synthesis of bovine capillary endothelial cells at a half-maximal concentration of approximately 5 nM. It shows anti-angiogenic activity in the chick embryo chorioallantoic membrane at a dose of about 1 MUg/embryo. Amino acid microsequencing and mass spectrometric analysis of the purified protein demonstrate that Beta-35 contains the first 314 residues of the N-terminal sequence of bovine transferrin. We have cloned and expressed this protein in Escherichia coli using the corresponding gene segment of Beta-35 contained in the cDNA of human transferrin. The recombinant protein of Beta-35 shows significant anti-tumor activity at a dose of 5mg/kg/day against human pancreatic cancer or melanoma implanted subcutaneously in SCID mice. PMID- 21605551 TI - Dephosphorylated NPr of the nitrogen PTS regulates lipid A biosynthesis by direct interaction with LpxD. AB - Bacterial phosphoenolpyruvate-dependent phosphotransferase systems (PTS) play multiple roles in addition to sugar transport. Recent studies revealed that enzyme IIA(Ntr) of the nitrogen PTS regulates the intracellular concentration of K(+) by direct interaction with TrkA and KdpD. In this study, we show that dephosphorylated NPr of the nitrogen PTS interacts with Escherichia coli LpxD which catalyzes biosynthesis of lipid A of the lipopolysaccharide (LPS) layer. Mutations in lipid A biosynthetic genes such as lpxD are known to confer hypersensitivity to hydrophobic antibiotics such as rifampin; a ptsO (encoding NPr) deletion mutant showed increased resistance to rifampin and increased LPS biosynthesis. Taken together, our data suggest that unphosphorylated NPr decreases lipid A biosynthesis by inhibiting LpxD activity. PMID- 21605552 TI - High-sensitive troponin T and I are related to invasive hemodynamic data and mortality in patients with left-ventricular dysfunction and precapillary pulmonary hypertension. AB - BACKGROUND: High-sensitive (hs) cardiac troponin assays are clinically useful in various cardiac conditions. We aimed to extend current evidence by assessing the relations of hs-cardiac troponin T (hs-cTnT) and I (hs-cTnI) to invasive hemodynamic data and outcome in stable patients with left-ventricular (LV) dysfunction or precapillary pulmonary hypertension (PAH). METHODS: Hs-cTnT (Roche Diagnostics) and hs-cTnI (Beckman-Coulter) were measured in 103 stable patients with LV-dysfunction and 56 patients with precapillary PAH referred for right heart catheterization. RESULTS: Up to 47.6% of patients with LV-dysfunction, and up to 37.5% of patients with precapillary PAH had hs-troponin levels above the respective 99th percentiles. In patients with LV-dysfunction, both hs-troponins exhibited significant associations to hemodynamics, NT-proBNP and mortality (hs cTnT: age/sex-adjusted HR 2.0 [95% CI 1.3-3.1]; hs-cTnI: age/sex-adjusted HR 1.9 [1.2-2.8]). Both hs-troponins demonstrated weaker associations to hemodynamics in patients with precapillary PAH but correlated significantly to NT-proBNP. Mortality was only predicted by hs-cTnI (age/sex-adjusted HR 3.0 [1.5-6.1]). CONCLUSIONS: Hs-troponins are related to indices of impaired myocardial performance in patients with LV-dysfunction and precapillary PAH. Both hs troponins were also predictive for mortality in patients with LV-dysfunction. In precapillary PAH, only hs-cTnI was independently prognostic which might depend on the superior analytical performance of this assay. PMID- 21605553 TI - Glutamine, ornithine, citrulline and arginine levels in children with phenylketonuria: The diet effect. AB - BACKGROUND: Phenylketonuria (PKU) therapeutic diet is characterized by the great replacement of natural protein with a phenylalanine-free formula. AIM: To investigate the effect of diet on the amino acid serum levels in PKU patients and their total antioxidant status (TAS). METHODS: Thirty-seven poorly controlled patients (group A), 43 patients who strictly adhered to their diet (group B) and 50 controls were included in the study. In patients and controls blood chemistry, TAS and serum amino acid level determinations were performed. RESULTS: Phenylalanine levels significantly differed among the groups. Glutamine and ornithine levels were significantly higher in group A, while TAS (416+/-30 vs 228+/-23MUmol/L, p<0.001), citrulline (39+/-15 vs 26+/-5MUmol/L, p<0.001) and arginine levels (61+/-11 vs 80+/-12MUmol/L, p<0.001) were higher in group B. The other determined amino acid serum levels did not differ among the groups of patients and controls. CONCLUSIONS: The high glutamine and ornithine levels in group A may reflect the high natural protein intake. High phenylalanine levels in these patients may locally affect the hepatocyte, enterocyte, and/or renal function resulting in low citrulline and arginine levels contributing to their low TAS. PMID- 21605554 TI - The possible mechanism of hypotensive activity of some pyrrolidin-2-one derivatives with antagonist properties at alpha1-adrenoceptors. AB - In the search for new hypotensive agents a series of pyrrolidin-2-one derivatives was obtained with alpha-adrenoceptor blocking properties. The aim of the present study was to examine the possible involvement of other mechanisms in the observed hypotensive properties. In the present study the affinities for beta1 adrenoreceptors, vasorelaxant effect and the involvement in NO pathway of pyrrolidin-2-one derivatives were assessed. In the next step compounds were also evaluated for their alpha1-adrenoreceptor subtypes in functional bioassays. The data from our experiments indicate that the hypotensive activity of tested pyrrolidin-2-one derivatives is a result of their alpha-adrenoceptor blocking properties and the compounds have stronger antagonist potency for the alpha(1D)- than for alpha(1B)-subtype. Among investigated compounds EP-46 is the most potent and selective antagonist for the alpha(1D)- and alpha(1A)- than for alpha(1B) subtype. Compound EP-43 can enhance NO production additionally. PMID- 21605555 TI - Distinct structural plasticity in the hippocampus and amygdala of the middle-aged common marmoset (Callithrix jacchus). AB - Adult neurogenesis in the primate brain is generally accepted to occur primarily in two specific areas; the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricles. Hippocampal neurogenesis is well known to be downregulated by stress and aging in rodents, however there is less evidence documenting the sensitivity of neuroblasts generated in the SVZ. In primates, migrating cells generated in the SVZ travel via a unique temporal stream (TS) to the amygdala and entorhinal cortex. Using adult common marmoset monkeys (Callithrix jacchus), we examined whether i) adult-generated cells in the marmoset amygdala differentiate into doublecortin-positive (DCX+) neuroblasts, and ii) whether lasting changes occur in DCX-expressing cells in the DG or amygdala when animals are exposed to 2 weeks of psychosocial stress. A surprisingly large population of DCX+ immature neurons was found in the amygdala of these 4-year-old monkeys with an average density of 163,000 DCX+ cells per mm(3). Co-labeling of these highly clustered cells with PSA-NCAM supports that a subpopulation of these cells are migratory and participate in chain-migration from the SVZ to the amygdala in middle-aged marmosets. Exposure to 2 weeks of isolation and social defeat stress failed to alter the numbers of BrdU+, or DCX+ cells in the hippocampus or amygdala when evaluated 2 weeks after psychosocial stress, indicating that the current stress paradigm has no long-term consequences on neurogenesis in this primate. PMID- 21605556 TI - Timing and spacing of ubiquitin-dependent DNA damage bypass. AB - During its duplication, DNA, the carrier of our genetic information, is particularly vulnerable to decay, and the capacity of cells to deal with replication stress has been recognised as a major factor protecting us from genome instability and cancer. One of the major pathways controlling the bypass of DNA lesions during replication is activated by ubiquitylation of the sliding clamp, PCNA. Whereas monoubiquitylation of PCNA allows mutagenic translesion synthesis by damage-tolerant DNA polymerases, polyubiquitylation is required mainly for an error-free pathway that likely involves template switching. This review is focussed on our understanding of the timing of damage bypass during the cell cycle and the question of how it is coordinated with the progression of replication forks. PMID- 21605557 TI - Influence of Ca2+ and pH on the folding of the prourotensin II precursor. AB - Proper folding is a crucial step for the trafficking of proteins through the secretory pathway. We hypothesized that the secretory granules of endocrine cells provide optimal folding conditions of prohormone precursors for cleavage. Here, using circular dichroism and in vitro processing on purified prourotensin II (ProUII), we show that the precursor undergoes pH- and Ca(2+)-dependent conformational and stability changes. ProUII has a stable tertiary structure at pH 5.5 in presence of Ca(2+) and is correctly cleaved in these conditions by prohormone convertases. Taken together, our results support the notion that precursors may need to be optimally folded in the lumen of secretory granules for their processing. PMID- 21605558 TI - Regulation of the Na+/K+ ATPase by Klotho. AB - Klotho-hypomorphic (Klotho(hm)) mice suffer from renal salt wasting and hypovolemia despite hyperaldosteronism. The present study explored the effect of Klotho on renal Na(+)/K(+) ATPase activity. According to immunohistochemistry and confocal microscopy Na(+)/K(+) ATPase protein abundance in isolated collecting ducts was lower in Klotho(hm) mice than in their wild type littermates (Klotho(+/+)). Analysis with dual electrode voltage clamp recording showed that expression of Klotho in Xenopus oocytes increased the Na(+)/K(+) ATPase pump current. Treatment of Xenopus oocytes with Klotho protein similarly increased the pump current. In conclusion, Klotho increases the membrane abundance and activity of the Na(+)/K(+) ATPase. Decreased Na(+)/K(+) ATPase activity could thus contribute to the volume-depletion of klotho(hm) mice. PMID- 21605559 TI - Ubiquitylation and the Fanconi anemia pathway. AB - The Fanconi anemia (FA) pathway maintains genome stability through co-ordination of DNA repair of interstrand crosslinks (ICLs). Disruption of the FA pathway yields hypersensitivity to interstrand crosslinking agents, bone marrow failure and cancer predisposition. Early steps in DNA damage dependent activation of the pathway are governed by monoubiquitylation of FANCD2 and FANCI by the intrinsic FA E3 ubiquitin ligase, FANCL. Downstream FA pathway components and associated factors such as FAN1 and SLX4 exhibit ubiquitin-binding motifs that are important for their DNA repair function, underscoring the importance of ubiquitylation in FA pathway mediated repair. Importantly, ubiquitylation provides the foundations for cross-talk between repair pathways, which in concert with the FA pathway, resolve interstrand crosslink damage and maintain genomic stability. PMID- 21605561 TI - Pituitary gonadotropin and testicular gonadotropin receptor expression in Atlantic cod (Gadusmorhua L.) during the first reproductive season: Effects of photoperiod modulation. AB - Pituitary mRNA levels of gonadotropin beta-subunits and of their cognate receptors in the testis were studied during puberty in Atlantic cod under normal and experimental photoperiod conditions that suppressed, delayed or accelerated testis maturation. Results are discussed in context with changes in testicular histology and plasma androgen levels, considered as end points of gonadotropic regulation. Up-regulation of fshb was closely associated with the onset of puberty, decreased when spermatogenesis was completed and reached minimum levels after spawning. These results demonstrate, for the first time using an experimental approach, that activation of Fsh-dependent signaling is associated with spermatogonial proliferation and formation of spermatogenic cysts. Changes in fshr expression were less prominent and could be explained by changes in the cellular composition and RNA content of cod testis tissue. At more advanced stages of development (spermiogenesis, spermiation and spawning), lhb and, one month later, lhcgr transcript levels increased and reached peak values in spawning fish, in a positive feedback loop involving plasma androgens and Lh/Lhcgr-dependent signaling. This loop was broken by a loss of lhb expression at the end of the spawning season. Continuous light (LL) from summer solstice, ~8 months prior to spawning, suppressed the start of testis maturation and the changes in gonadotropin and receptor mRNA levels, while LL from winter solstice initially up-regulated lhb and lhcgr expression, before resulting in a precocious termination of the spawning season and low expression of all four genes. Our studies provide experimental evidence for a clear functional discrimination of cod gonadotropins. PMID- 21605562 TI - Novel antigen design for the generation of antibodies to G-protein-coupled receptors. AB - Antibodies are important tools for the study of G-protein-coupled receptors, key proteins in cellular signaling. Due to their large hydrophobic membrane spanning regions and often very short loops exposed on the surface of the cells, generation of antibodies able to recognize the receptors in the endogenous environment has been difficult. Here, we describe an antigen-design method where the extracellular loops and N-terminus are combined to a single antigen for generation of antibodies specific to three selected GPCRs: NPY5R, B2ARN and GLP1R. The design strategy enabled straightforward antigen production and antibody generation. Binding of the antibodies to intact receptors was analyzed using flow cytometry and immunofluorescence based confocal microscopy on A-431 cells overexpressing the respective GPCR. The antibody-antigen interactions were characterized using epitope mapping, and the antibodies were applied in immunohistochemical staining of human tissues. Most of the antibodies showed specific binding to their respective overexpressing cell line but not to the non transfected cells, thus indicating binding to their respective target receptor. The epitope mapping showed that sub-populations within the purified antibody pool recognized different regions of the antigen. Hence, the genetic combination of several different epitopes enables efficient generation of specific antibodies with potential use in several applications for the study of endogenous receptors. PMID- 21605560 TI - Epigenetic codes of PPARgamma in metabolic disease. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-regulated nuclear hormone receptor, plays critical roles in metabolism and adipogenesis. PPARgamma ligands such as thiazolidinediones (TZDs) exert insulin sensitizing and anti-inflammatory effects primarily through action on adipocytes, and are thus widely used to treat metabolic syndrome, especially type II diabetes. A number of PPARgamma interacting partners have been identified, many of which are known epigenetic regulators, including enzymes for histone acetylation/deacetylation and histone methylation/demethylation. However, their functional roles in the PPARgamma transcriptional pathway are not well defined. Recent advances in ChIP based and deep sequencing technology are revealing previously underappreciated epigenomic mechanisms and therapeutic potentials of this nuclear receptor pathway. PMID- 21605563 TI - Thermodynamics of cuticular transpiration. AB - Water conservation is a significant physiological problem for many insects, particularly as temperature increases. Early experimental work supported the concept of a transition temperature, above which water-loss rates increase rapidly as temperature increases. The transition phenomenon was hypothesized to result from melting of epicuticular lipids, the main barrier to cuticular transpiration. This explanation has been challenged on theoretical grounds, leading to thermodynamic analyses of cuticular transpiration based on reaction rate theory. These studies have not directly addressed the mechanistic basis of the transition temperature. Models developed in the context of cell membrane transport provide potential explanations that can be tested experimentally. These models include changes in the activation entropy for diffusion through the cuticular lipids, increased solubility of water in melted lipids, and lateral heterogeneity of the cuticle. PMID- 21605564 TI - Structure and expression of glutathione S-transferase genes from the midgut of the Common cutworm, Spodoptera litura (Noctuidae) and their response to xenobiotic compounds and bacteria. AB - Glutathione S-transferases (GSTs) play a pivotal role in detoxifying endogenous and xenobiotic compounds and oxidative stress resistance in cells. In this study, five GST genes, including three Sigma GSTs (SlGSTs1, SlGSTs2, and SlGSTs3), one Omega GST (SlGSTo1) and one un-classified GST (SlGSTu1) were identified from the midgut of the Common cutworm, Spodoptera litura. Structure analyses of the eight (including the previously identified Epsilon GST genes, SlGSTe1, SlGSTe2 and SlGSTe3 from the same insect) SlGSTs genes showed that the Epsilon SlGSTe genes do not contain any intron, while the Sigma SlGSTs contain three introns and the Omega SlGSTo1 and the un-classified SlGSTu1 contain five introns. Analysis of the spatial and temporal expression of these eight SlGSTs indicated that SlGSTe1, SlGSTs2 and SlGSTo1 expressed in all stages of development from the egg to the adult stages. SlGSTe2, SlGSTe3, SlGSTs1, SlGSTs3 and SlGSTu1 had higher expression levels in the larval stages than in other stages and their expression levels in the midgut were higher than in other tissues. SlGSTs1 was expressed in the larval midgut but not in the fat body and could be induced by bacterial infections. The expression of SlGSTe1, SlGSTe3, SlGSTs1 and SlGSTs3 was increased by chlorpyrifos to various degrees, while the expression of SlGSTe1, SlGSTe3, SlGSTs1, SlGSTs3 and SlGSTo1 was increased by xanthotoxin. Levels of malonaldehyde, an indicator of oxidative stress, were higher in the larval midgut than in the pupal midgut. Chlorpyrifos induced the malonaldehyde content in the larvae, whereas xanthotoxin did not. It is hypothesized that high expression levels of the midgut SlGSTs might be due to the increased levels of oxidative stress caused by feeding, bacterial infection and xenobiotic compounds. PMID- 21605565 TI - The monomeric, tetrameric, and fibrillar organization of Fib: the dynamic building block of the bacterial linear motor of Spiroplasma melliferum BC3. AB - Spiroplasmas belong to the class Mollicutes, representing the minimal, free living, and self-replicating forms of life. Spiroplasmas are helical wall-less bacteria and the only ones known to swim by means of a linear motor (rather than the near-universal rotary bacterial motor). The linear motor follows the shortest path along the cell's helical membranal tube. The motor is composed of a flat monolayered ribbon of seven parallel fibrils and is believed to function in controlling cell helicity and motility through dynamic, coordinated, differential length changes in the fibrils. The latter cause local perturbations of helical symmetry, which are essential for net directional displacement in environments with a low Reynolds number. The underlying fibrils' core building block is a circular tetramer of the 59-kDa protein Fib. The fibrils' differential length changes are believed to be driven by molecular switching of Fib, leading consequently to axial ratio and length changes in tetrameric rings. Using cryo electron microscopy, diffractometry, single-particle analysis of isolated ribbons, and sequence analyses of Fib, we determined the overall molecular organization of the Fib monomer, tetramer, fibril, and linear motor of Spiroplasma melliferum BC3 that underlies cell geometry and motility. Fib appears to be a bidomained molecule, of which the N-terminal half is apparently a globular phosphorylase. By a combination of reversible rotation and diagonal shift of Fib monomers, the tetramer adopts either a cross-like nonhanded conformation or a ring-like handed conformation. The sense of Fib rotation may determine the handedness of the linear motor and, eventually, of the cell. A further change in the axial ratio of the ring-like tetramers controls fibril lengths and the consequent helical geometry. Analysis of tetramer quadrants from adjacent fibrils clearly demonstrates local differential fibril lengths. PMID- 21605567 TI - A linearized and incompressible constitutive model for arteries. AB - In many biomechanical studies, blood vessels can be modeled as pseudoelastic orthotropic materials that are incompressible (volume-preserving) under physiological loading. To use a minimum number of elastic constants to describe the constitutive behavior of arteries, we adopt a generalized Hooke's law for the co-rotational Cauchy stress and a recently proposed logarithmic-exponential strain. This strain tensor absorbs the material nonlinearity and its trace is zero for volume-preserving deformations. Thus, the relationships between model parameters due to the incompressibility constraint are easy to analyze and interpret. In particular, the number of independent elastic constants reduces from ten to seven in the orthotropic model. As an illustratory study, we fit this model to measured data of porcine coronary arteries in inflation-stretch tests. Four parameters, n (material nonlinearity), Young's moduli E1 (circumferential), E2 (axial), and E3 (radial) are necessary to fit the data. The advantages and limitations of this model are discussed. PMID- 21605568 TI - The ability of individuals to assess population density influences the evolution of emigration propensity and dispersal distance. AB - We analyze the simultaneous evolution of emigration and settlement decisions for actively dispersing species differing in their ability to assess population density. Using an individual-based model we simulate dispersal as a multi-step (patch to patch) movement in a world consisting of habitat patches surrounded by a hostile matrix. Each such step is associated with the same mortality risk. Our simulations show that individuals following an informed strategy, where emigration (and settlement) probability depends on local population density, evolve a lower (natal) emigration propensity but disperse over significantly larger distances - i.e. postpone settlement longer - than individuals performing density-independent emigration. This holds especially when variation in environmental conditions is spatially correlated. Both effects can be traced to the informed individuals' ability to better exploit existing heterogeneity in reproductive chances. Yet, already moderate distance-dependent dispersal costs prevent the evolution of multi-step (long-distance) dispersal, irrespective of the dispersal strategy. PMID- 21605566 TI - Conformational changes in bacteriophage P22 scaffolding protein induced by interaction with coat protein. AB - Many prokaryotic and eukaryotic double-stranded DNA viruses use a scaffolding protein to assemble their capsid. Assembly of the double-stranded DNA bacteriophage P22 procapsids requires the interaction of 415 molecules of coat protein and 60-300 molecules of scaffolding protein. Although the 303-amino-acid scaffolding protein is essential for proper assembly of procapsids, little is known about its structure beyond an NMR structure of the extreme C-terminus, which is known to interact with coat protein. Deletion mutagenesis indicates that other regions of scaffolding protein are involved in interactions with coat protein and other capsid proteins. Single-cysteine and double-cysteine variants of scaffolding protein were generated for use in fluorescence resonance energy transfer and cross-linking experiments designed to probe the conformation of scaffolding protein in solution and within procapsids. We showed that the N terminus and the C-terminus are proximate in solution, and that the middle of the protein is near the N-terminus but not accessible to the C-terminus. In procapsids, the N-terminus was no longer accessible to the C-terminus, indicating that there is a conformational change in scaffolding protein upon assembly. In addition, our data are consistent with a model where scaffolding protein dimers are positioned parallel with one another with the associated C-termini. PMID- 21605569 TI - Mathematical modeling of pulmonary tuberculosis therapy: Insights from a prototype model with rifampin. AB - There is a critical need for improved and shorter tuberculosis (TB) treatment. Current in vitro models of TB, while valuable, are poor predictors of the antibacterial effect of drugs in vivo. Mathematical models may be useful to overcome the limitations of traditional approaches in TB research. The objective of this study was to set up a prototype mathematical model of TB treatment by rifampin, based on pharmacokinetic, pharmacodynamic and disease submodels. The full mathematical model can simulate the time-course of tuberculous disease from the first day of infection to the last day of therapy. Therapeutic simulations were performed with the full model to study the antibacterial effect of various dosage regimens of rifampin in lungs. The model reproduced some qualitative and quantitative properties of the bactericidal activity of rifampin observed in clinical data. The kill curves simulated with the model showed a typical biphasic decline in the number of extracellular bacteria consistent with observations in TB patients. Simulations performed with more simple pharmacokinetic/pharmacodynamic models indicated a possible role of a protected intracellular bacterial compartment in such a biphasic decline. This modeling effort strongly suggests that current dosage regimens of RIF may be further optimized. In addition, it suggests a new hypothesis for bacterial persistence during TB treatment. PMID- 21605570 TI - Impact of cadmium on hOGG1 and APE1 as a function of the cellular p53 status. AB - The tumor suppressor protein p53, often called the guardian of the genome, is involved in important cellular processes, such as cell cycle control, apoptosis and DNA repair. With respect to BER, p53 might physically interact with and affect the transcription of different BER proteins such as hOGG1, APE1 or Polbeta. In studies in HCT116 p53(-/-) cells previously published, activity and mRNA expression of hOGG1 were found to be significantly decreased, while down regulation of APE1 mRNA and protein levels in response to genotoxic stress were only described in HCT116 p53(+/+) cells, but not in the isogenic p53 knockout cell line. The predominantly indirect genotoxic carcinogen cadmium inhibits the BER pathway and potentially interferes with zinc binding proteins such as p53. Therefore, this study was accomplished to investigate whether p53 is involved in the cadmium-induced inhibition of BER activity. To address this issue we applied a non-radioactive cleavage test system based on a Cy5-labeled oligonucleotide. We present evidence that p53 is not essential for hOGG1 and APE1 gene expression as well as OGG and APE activity in unstressed HCT116 cells; however, it plays an important role in the cellular response to cadmium treatment. Here, a direct involvement of p53 was only observed with respect to APE1 gene expression contributing to an altered APE activity, while OGG activity was presumably affected indirectly due to a stronger accumulation of cadmium in HCT116 p53(+/+) cells. In summary, p53 indeed affects the BER pathway directly and indirectly in response to cadmium treatment. PMID- 21605571 TI - Therapeutic opportunities: telomere maintenance in inducible pluripotent stem cells. AB - It has been demonstrated that exogenous expression of a combination of transcription factors can reprogram differentiated cells such as fibroblasts and keratinocytes into what have been termed induced pluripotent stem (iPS) cells. These iPS cells are capable of differentiating into all the tissue lineages when placed in the right environment and, in the case of mouse cells, can generate chimeric mice and be transmitted through the germline. Safer and more efficient methods of reprogramming are rapidly being developed. Clearly, iPS cells present a number of exciting possibilities, including disease modeling and therapy. A major question is whether the nuclei of iPS cells are truly rejuvenated or whether they might retain some of the marks of aging from the cells from which they were derived. One measure of cellular aging is the telomere. In this regard, recent studies have demonstrated that telomeres in iPS cells may be rejuvenated. They are not only elongated by reactivated telomerase but they are also epigenetically modified to be similar but not identical to embryonic stem cells. Upon differentiation, the derivative cells turn down telomerase, the telomeres begin to shorten again, and the telomeres and the genome are returned to an epigenetic state that is similar to normal differentiated somatic cells. While these preliminary telomere findings are promising, the overall genomic integrity of reprogrammed cells may still be problematic and further studies are needed to examine the safety and feasibility of using iPS cells in regenerative medicine applications. PMID- 21605573 TI - MLC901, a traditional Chinese medicine protects the brain against global ischemia. AB - Global ischemia leads to damage in the hippocampal CA1 region and is associated with behavioral deficits. NeuroAid (MLC601 and MLC901), a Traditional Chinese Medicine is used in China for patients after stroke. We have investigated here the effects of MLC901 on brain injury and deficits after global ischemia in the rat. Global ischemia induced by four-vessel occlusion resulted in degeneration of CA1 neurons. MLC901 (0.074 mg/ml) prevented both necrosis and apoptosis of neurons up to 3 h after ischemia. These positive MLC901 effects were associated with a decrease in Bax expression and in levels of the lipid peroxidation product malondialdehyde. Using the PI3-kinase inhibitor LY294002 we also demonstrated the critical role of the Akt pathway in MLC901-mediated neuroprotection. MLC901 enhanced neurogenesis. Furthermore, MLC901 improved functional recovery of rats after global ischemia as assessed by the Morris water maze. In this test MLC901 reduced the increase in escape latency and in swim distance induced by ischemia. MLC901 also improved post-ischemic grip strength. If observations made with rats can be extended to humans, then MLC901 will represent a novel therapeutic strategy after cardiac arrest with a clinically interesting time window of protection. PMID- 21605572 TI - Opioid-mediated regulation of A11 diencephalospinal dopamine neurons: pharmacological evidence of activation by morphine. AB - Dopamine (DA) neurons of the A11 diencephalospinal system represent the sole source of DA innervation to the spinal cord in mice, serving neuromodulatory roles in the processing of nociceptive input and movement. These neurons originate in the dorso-caudal diencephalon and project axons unilaterally throughout the rostrocaudal extent of the spinal cord, terminating predominantly in the dorsal horn. The density of A11 DA axon terminals in the lumbar region is greater in males compared to females, while in both sexes the activity of neurons terminating in the thoracic spinal cord is greater than those terminating in the lumbar region. The present study was designed to test the hypothesis that A11 DA neurons are activated by opioids. To test this hypothesis, male and female mice were systemically treated with agonists or antagonists acting at the MU-opioid receptor, and spinal cord concentrations of DA and its metabolite DOPAC were determined in the thoracic and lumbar spinal cord using high performance liquid chromatography coupled with electrochemical detection. Systemic administration of the MU-opioid agonist morphine led to a dose- and time-dependent increase in spinal cord DOPAC/DA ratio (an estimate of DA neuronal activity) in both male and female mice, with greater changes occurring in the lumbar segment. Blockade of opioid receptors with the opioid antagonist naloxone reversed the stimulatory effects of morphine on A11 DA neurons in both male and female mice, but had little to no effect on the activity of these neurons when administered alone. Present findings are consistent with the conclusion that spinal cord-projecting axon terminals of A11 DA neurons are activated by opioids in both male and female mice, most likely through a dis-inhibitory mechanism. PMID- 21605574 TI - Non-spatial neglect for the mental number line. AB - Several psychophysical investigations, expanding the classical introspective observations by Galton, have suggested that the mental representation of numbers takes the form of a number line along which magnitude is positioned in ascending order according to reading habits, i.e. from left to right in Western cultures. In keeping with the evidence, pathological rightward deviations in the bisection of number intervals due to right brain damage are generally interpreted as originating from a purely spatial-attentional deficit in the processing of the left side of number intervals. However, consistent double dissociations between defective processing of the left side of physical and mental number space have called into question the universality of this interpretation. Recent evidence suggests a link between rightward deviations in number space and defective memory for both spatial and non-spatial sequences of items. Here we describe the case of a left brain-damaged patient exhibiting right-sided neglect for extrapersonal and representational space, and left-sided neglect on the mental number line. Accurate neuropsychological examination revealed that the apparent left-sided neglect in the bisection of number intervals had a purely non-spatial origin and was based on mnemonic difficulties for the initial items of verbal sequences presented visually at an identical spatial position. These findings show that effective position-based verbal working memory might be crucial for numerical tasks that are usually considered to involve purely spatial representation of numerical magnitudes. PMID- 21605575 TI - Glucocorticoid metabolites in rabbit faeces--influence of environmental enrichment and cage size. AB - The concentration of glucocorticoid metabolites (GCM) in rabbit faeces has been suggested as a non-invasive indicator of stress. In the present study, GCM concentrations were measured in faeces of fattening rabbits kept in groups of eight, at seven different stocking densities (between 5 and 20 animals/m(2)), with or without environmental enrichment (a wooden structure used mainly for gnawing and resting). Transport (30 min) was used as an acute novel stressor to assess the glucocorticoid response to stress under the different housing conditions. GCM concentrations were elevated post-transport (P<0.001). Whilst cage size had no influence on GCM, enrichment reduced GCM concentrations before as well as after transport (P=0.007 in both cases). Effects of cage size and enrichment on growth characteristics were negligible, whilst enrichment decreased cage manipulation and social contact. The results indicate that even short transport durations may be stressful for rabbits, and that enrichment may decrease housing stress. They suggest that measuring baseline GCM concentrations in faeces is a useful tool to evaluate chronic stress in rabbits, whilst measuring the response to a novel stressor did not provide additional insight. PMID- 21605576 TI - Flavor preferences conditioned by post-oral infusion of monosodium glutamate in rats. AB - Monosodium glutamate (MSG), the prototypical umami source, can enhance preference for associated flavors in humans and rodents. Although MSG flavor preference has been attributed to its taste, vagally-mediated post-oral detection has also been demonstrated. Recent studies showed that water-restricted rats acquired a preference for a flavor paired with intragastric (IG) infusion of 60 mM MSG in rats. The present study extends this work by comparing MSG-based flavor conditioning in water- and food-restricted rats and testing the persistence of flavor preferences. Rats with IG catheters drank flavored solutions paired with volume-matched infusions of 60 mM MSG or water in daily 30-min sessions. Two training/test cycles were conducted, each with eight one-bottle training sessions followed by two two-bottle preference tests without infusions. Food- and water restricted groups displayed similar preferences for the MSG-paired flavor. When non-reinforced testing was continued after the second cycle, the food-restricted group sustained its preference across three 2-day tests, but water-restricted rats lost their preference. Other food-restricted rats learned to prefer a flavor paired with intraduodenal infusion, indicating that gastric stimulation by MSG is not required. A third experiment showed that adding 2 mM of the nucleotide inosine monophosphate to the IG infusion of MSG did not significantly enhance flavor conditioning. Because MSG-based flavor preferences can be obtained with infusions that bypass the stomach, the site for detecting MSG reinforcement may be intestinal. PMID- 21605577 TI - Maternal stress and high-fat diet effect on maternal behavior, milk composition, and pup ingestive behavior. AB - Chronic variable prenatal stress or maternal high-fat diet results in offspring that are significantly heavier by the end of the first postnatal week with increased adiposity by weaning. It is unclear, however, what role maternal care and diet play in the ontogenesis of this phenotype and what contributions come from differences already established in the rat pups. In the present studies, we examined maternal behavior and milk composition as well as offspring ingestive behavior. Our aim was to better understand the development of the obese phenotype in offspring from dams subjected to prenatal stress and/or fed a high-fat (HF) diet during gestation and lactation. We found that dams maintained on a HF diet through gestation and lactation spent significantly more time nursing their pups during the first postnatal week. In addition, offspring of prenatal stress dams consumed more milk at postnatal day (PND) 3 and offspring of HF dams consume more milk on PND 7 in an independent ingestion test. Milk from HF dams showed a significant increase in fat content from PND 10-21. Together these results suggest that gestational dietary or stress manipulations can alter the rat offspring's developmental environment, evidence of which is apparent by PND 3. Alterations in maternal care, milk composition, and pup consumption during the early postnatal period may contribute to long-term changes in body weight and adiposity induced by maternal prenatal stress or high-fat diet. PMID- 21605578 TI - Using the lymphatics to study nutrient absorption and the secretion of gastrointestinal hormones. AB - The lymph fistula rat model has traditionally been used to study the intestinal absorption of nutrients, especially lipids, but recently this model has also been used for studying the secretion of incretin hormones by the small intestine. The small intestine is not only responsible for the digestion and transport of dietary triacylglycerol, through the formation of chylomicrons, but it also secretes the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) from enteroendocrine cells. Ultimately, both chylomicrons and incretins are found in lymph. Advantages of the lymph fistula rat model in studying chylomicron and incretin secretion are numerous and include: 1) the concentrations of incretin hormones are higher in lymph than in peripheral or portal plasma; 2) there is reduced degradation of incretin hormones by DPP-IV in the lymph compartment; 3) less dilution by the circulating fluid; 4) this model allows the continuous collection of lymph from conscious animals, eliminating any potential side effects on lymph flow and gastrointestinal function due to anesthesia; and finally, and perhaps most importantly, and 5) the concentration in the intestinal lymph provides a physiologically accurate representation of the hormonal milieu within the intestinal mucosa where incretins may interact with enteroendocrine and/or dendritic cells and signal through the enteric or autonomic neurons. The importance of GIP and GLP-1 in health and disease is becoming more apparent, especially as the prevalence of type 2 diabetes and other metabolic disorders increases. This review focuses on the use of the lymph fistula rat as a model to study the secretion of incretins, as well as dietary lipid. PMID- 21605580 TI - Asymmetry of behavioral responses to a human approach in young naive vs. trained horses. AB - The aim of this study was to investigate the impact of training experience on young horses (Equus caballus)' lateralized responses to an approaching human. The results show that the one year old untrained horses display asymmetrical responses to an approaching human, with more negative reactions (escapes, threats) when approached from the left side, while approaches towards the right shoulder elicited more positive behaviors. On the contrary, two years old trained horses reacted equally positively to approaches and contact on both sides. Our findings support those of previous studies investigating a link between emotionality and laterality and confirm the role of the left hemisphere in the processing of novel or negative stimuli. Moreover, the data underline the impact work and training can have on this laterality in horses. PMID- 21605579 TI - Refeeding after a 24-hour fasting deepens NREM sleep in a time-dependent manner. AB - Sleep/wake cycle is regulated by a variety of neuropeptides in the hypothalamus, a brain region that also regulates energy homeostasis and feeding behavior. Since circadian rhythms are affected by energy metabolism and feeding condition, we investigated whether changes in feeding regimen would influence sleep/wake parameters and body temperature. We monitored sleep and body temperature across three days of baseline (day 1), fasting (day 2), and refeeding (day 3) conditions under ordinary ambient temperature and employed different refeeding schedules. Refeeding at ZT1 following the 24-h fasting enhanced EEG delta power in NREM sleep. However, when the time of refeeding was set at either ZT7 or ZT12, the enhancement of EEG delta power was attenuated. The amount of NREM sleep was not largely affected by a 24-h fasting started at ZT1, although fasting that started at ZT12 changed the temporal distribution of NREM sleep. Hypothalamic nNOS mRNA level was increased both before and after refeeding at ZT1 compared with control condition, while there was no significant change in mice refed at ZT7. Level of NPY mRNA in the arcuate nucleus was increased before the refeeding only at ZT1. These results suggest that refeeding after a 24-h fasting makes NREM sleep deeper in a time-dependent manner. PMID- 21605581 TI - Synthesis, in vitro antifungal activity and mechanism of action of four sterol hydrazone analogues against the dimorphic fungus Paracoccidioides brasiliensis. AB - The design and synthesis of novel sterol hydrazone analogues (9, 10, 11 and 12) are described, followed by their evaluation as inhibitors of fungal growth, using Paracoccidioides brasiliensis as the biological tester. Compounds 9, 10, 11 and 12 generated a dose-dependent effect in fungal growth, particularly 9, 11 and 12, which were active at nanomolar concentrations (100 nM). When P. brasiliensis in its pathogenic yeast-like phase was treated individually with each of the aforementioned compounds at concentrations that reduced growth rate around 50%, the analysis of sterol composition in the resulting surviving cells demonstrated a 50% reduction of the final sterols brasicasterol and ergosterol, and concomitant increase in the levels of lanosterol. These results indicate that these compounds inhibit the enzyme Delta(24)-sterol methyl transferase (SMT), in a manner dependent on the stereochemical location of the hydrazone group. Compound 12, instead, induced a good antiproliferative activity not associated with blockage of any step in the pathway to sterol biosynthesis, suggesting a different mode of action. The X-ray crystal structure of H1 was determined to obtain information regarding the rings and side chain conformation of the sterol hydrazones. Comparison of the inhibitory effects of sterol hydrazones (9-12) and azasterols (AZA1-AZA3) on SMT with the molecular electrostatic potential, negative isopotential energy surfaces (-10 kcal/mol) and local ionization potential calculated via DFT methods, showed that changes in the electronic moiety introduced by the N and O atoms were not as important as the additional flexibility of the side chain introduced by an extra methylene group. PMID- 21605582 TI - MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity. AB - Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity. PMID- 21605583 TI - Relationship between occupational exposure to lead and local arterial stiffness and left ventricular diastolic function in individuals with arterial hypertension. AB - Relationship between occupational exposure to lead and frequency of complications in persons with arterial hypertension has been poorly investigated. This study aimed at evaluation of the relationship between occupational exposure to lead and manifestation of an increased local arterial stiffness and left ventricular diastolic dysfunction. The studies included 105 men (mean age: 44.47+/-9.12years) with arterial hypertension, treated with hypotensive drugs: group I - men occupationally exposed to lead (n=53), and group II - men not exposed to lead (n=52). In echocardiographic examination, the left ventricular diastolic dysfunction was diagnosed significantly more frequently in group I than in group II. In eTracking examination mean values of stiffness parameter (beta), augmentation index (AI) and one-point pulse wave velocity (PWV-beta) were significantly higher and mean values of arterial compliance (AC) were significantly lower in group I than in group II. The logistic regression showed that in the group of persons with arterial hypertension occupationally exposed to lead a more advanced age, higher blood lead concentration and higher mean values of augmentation index represent independent risk factors of left ventricular diastolic dysfunction. The multifactorial regression showed that amongst persons with arterial hypertension occupationally exposed to lead higher blood zinc protoporphyrin concentration, a more advanced age and higher value of body mass index (BMI) represent independent risk factors of an increased local arterial stiffness. In summary, we should note that in the group of persons with arterial hypertension occupationally exposed to lead the study has demonstrated a significantly more frequent manifestation of left ventricular diastolic dysfunction and an increase in local arterial stiffness. PMID- 21605584 TI - Inhibition of arsenic-induced rat liver injury by grape seed exact through suppression of NADPH oxidase and TGF-beta/Smad activation. AB - Chronic arsenic exposure induces oxidative damage to liver leading to liver fibrosis. We aimed to define the effect of grape seed extract (GSE), an antioxidant dietary supplement, on arsenic-induced liver injury. First, Male Sprague-Dawley rats were exposed to a low level of arsenic in drinking water (30ppm) with or without GSE (100mg/kg, every other day by oral gavage) for 12months and the effect of GSE on arsenic-induced hepatotoxicity was examined. The results from this study revealed that GSE co-treatment significantly attenuated arsenic-induced low antioxidant defense, oxidative damage, proinflammatory cytokines and fibrogenic genes. Moreover, GSE reduced arsenic stimulated Smad2/3 phosphorylation and protein levels of NADPH oxidase subunits (Nox2, Nox4 and p47phox). Next, we explored the molecular mechanisms underlying GSE inhibition of arsenic toxicity using cultured rat hepatic stellate cells (HSCs). From the in vitro study, we found that GSE dose-dependently reduced arsenic-stimulated ROS production and NADPH oxidase activities. Both NADPH oxidases flavoprotein inhibitor DPI and Nox4 siRNA blocked arsenic-induced ROS production, whereas Nox4 overexpression suppressed the inhibitory effects of GSE on arsenic-induced ROS production and NADPH oxidase activities, as well as expression of TGF-beta1, type I procollagen (Coll-I) and alpha-smooth muscle actin (alpha-SMA) mRNA. We also observed that GSE dose-dependently inhibited TGF beta1-induced transactivation of the TGF-beta-induced smad response element p3TP Lux, and that forced expression of Smad3 attenuated the inhibitory effects of GSE on TGF-beta1-induced mRNA expression of Coll-I and alpha-SMA. Collectively, GSE could be a potential dietary therapeutic agent for arsenic-induced liver injury through suppression of NADPH oxidase and TGF-beta/Smad activation. PMID- 21605585 TI - Biochemical and molecular characterization of the venom from the Cuban scorpion Rhopalurus junceus. AB - This communication describes the first general biochemical, molecular and functional characterization of the venom from the Cuban blue scorpion Rhopalurus junceus, which is often used as a natural product for anti-cancer therapy in Cuba. The soluble venom of this arachnid is not toxic to mice, injected intraperitoneally at doses up to 200 MUg/20 g body weight, but it is deadly to insects at doses of 10 MUg per animal. The venom causes typical alpha and beta effects on Na+ channels, when assayed using patch-clamp techniques in neuroblastoma cells in vitro. It also affects K+ currents conducted by ERG (ether a-go-go related gene) channels. The soluble venom was shown to display phospholipase, hyaluronidase and anti-microbial activities. High performance liquid chromatography of the soluble venom can separate at least 50 components, among which are peptides lethal to crickets. Four such peptides were isolated to homogeneity and their molecular masses and N-terminal amino acid sequence were determined. The major component (RjAa12f) was fully sequenced by Edman degradation. It contains 64 amino acid residues and four disulfide bridges, similar to other known scorpion toxins. A cDNA library prepared from the venomous glands of one scorpion allowed cloning 18 genes that code for peptides of the venom, including RjA12f and eleven other closely related genes. Sequence analyses and phylogenetic reconstruction of the amino acid sequences deduced from the cloned genes showed that this scorpion contains sodium channel like toxin sequences clearly segregated into two monophyletic clusters. Considering the complex set of effects on Na+ currents verified here, this venom certainly warrant further investigation. PMID- 21605586 TI - Scorpion envenoming in the north of Mali (West Africa): epidemiological, clinical and therapeutic aspects. AB - Scorpion envenomation remains a poorly known problem in sub-Saharan Africa, particularly in Mali, where the incidence is high in Northern area of the country (Sahara desert). We conducted a prospective study in two district health centers, Kidal and Tessalit (North-east of Mali), to describe the epidemiological, clinical and therapeutic features of scorpion stings. This study consisted of an exhaustive follow-up from admission to discharge of all patients stung by scorpions. Of a total of 282 cases recorded during one year, 207 (73.4%) occurred in Kidal, and the remaining 75 (26.6%) took place in Tessalit. The annual incidence was significantly higher in Tessalit (437 cases/100,000 population/year) than in Kidal (243 cases/100,000 population/year) (p < 10-6). Two hundred two (71.6%) stings occurred inside human dwellings, 142 (50.4%) during sleeping/resting, especially in August. One hundred ninety-one (67.7%) were on the lower extremities. Nocturnal stings, 168 (59.6%), occurred more often than diurnal stings, 114 (40.4%). Most patients, 163 (57.8%), were admitted less than 1 h after being stung. Local pain at the sting site was the common primary complaint. However, moderate and severe clinical signs were significantly higher in children than in adults (p < 0.05). The death rate (3.9%) was higher in children (3.5%) than in adults (0.3%) (p = 8.10-6; RR = 0.90 [IC: 0.84-0.06]). Of the 22 scorpion species identified, 13 (59.1%) were Leiurus quinquestriiatus, 8 (36.4%) were Androctonus amoreuxi, and 1 (4.5%) specimen was Buthiscus bicalcaratus. From these species, L. quinquestriiatus and A. amoreuxi were responsible of stings. The medical treatment was only symptomatic, and one hundred twenty-eight (45.3%) patients received traditional remedies before seeking medical attention. Our findings suggest that scorpion stings are common in the north of Mali and are a significant threat to human health. PMID- 21605587 TI - Effects of dopamine D(1) receptor blockade on the intensity-response function of ERG b- and d-waves under different conditions of light adaptation. AB - The effect of dopamine D(1) receptor blockade by SCH 23390 on the V-logI function of the ERG b- and d-waves was investigated in dark and light adapted frog eyes. We obtained that the blocker enhanced the amplitude of the b- and d-waves in both conditions of adaptation. The enhancing effect of the blocker was more pronounced on the rod- than cone-dominated responses for the both ERG waves. The absolute sensitivity of the b-wave was not altered, but that of the d-wave was significantly increased. The intensity-response function of the b-wave, but not that of the d-wave, was shifted to the left along the intensity axis. The b-wave V-logI function had steeper slope and narrower dynamic range in both dark and light adapted eyes after the D(1) receptor blockade. The results obtained indicate that the endogenous dopamine, acting through D(1) receptors, does not play a crucial role in the process of retinal adaptation, although it changes in a specific manner the intensity-response function of both the ERG b- and d-waves. PMID- 21605588 TI - Simultaneous adaptation to non-collinear retinal motion and smooth pursuit eye movement. AB - Simultaneously adapting to retinal motion and non-collinear pursuit eye movement produces a motion aftereffect (MAE) that moves in a different direction to either of the individual adapting motions. Mack, Hill and Kahn (1989, Perception, 18, 649-655) suggested that the MAE was determined by the perceived motion experienced during adaptation. We tested the perceived-motion hypothesis by having observers report perceived direction during simultaneous adaptation. For both central and peripheral retinal motion adaptation, perceived direction did not predict the direction of subsequent MAE. To explain the findings we propose that the MAE is based on the vector sum of two components, one corresponding to a retinal MAE opposite to the adapting retinal motion and the other corresponding to an extra-retina MAE opposite to the eye movement. A vector model of this component hypothesis showed that the MAE directions reported in our experiments were the result of an extra-retinal component that was substantially larger in magnitude than the retinal component when the adapting retinal motion was positioned centrally. However, when retinal adaptation was peripheral, the model suggested the magnitude of the components should be about the same. These predictions were tested in a final experiment that used a magnitude estimation technique. Contrary to the predictions, the results showed no interaction between type of adaptation (retinal or pursuit) and the location of adapting retinal motion. Possible reasons for the failure of component hypothesis to fully explain the data are discussed. PMID- 21605589 TI - Influences of activity wheel access on the body temperature response to MDMA and methamphetamine. AB - Recreational ingestion of the drug 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") can result in pathologically elevated body temperature and even death in humans. Such incidents are relatively rare which makes it difficult to identify the relative contributions of specific environmental and situational factors. Although animal models have been used to explore several aspects of MDMA induced hyperthermia and it is regularly hypothesized that prolonged physical activity (e.g., dancing) in the nightclub environment increases risk, this has never been tested directly. In this study the rectal temperature of male Wistar rats was monitored after challenge with doses of MDMA and methamphetamine (MA), another drug frequently ingested in the rave/nightclub environment, either with or without access to an activity wheel. Results showed that wheel activity did not modify the hyperthermia produced by 10.0mg/kg MDMA. However, individual correlations were observed in which wheel activity levels after a locomotor stimulant dose of MDMA were positively related to body temperature change and lethal outcome. A modest increase in the maximum body temperature observed after 5.6mg/kg MA was caused by wheel access but this was mostly attributable to a drop in temperature relative to vehicle treatment in the absence of wheel activity. These results suggest that nightclub dancing in the human Ecstasy consumer may not be a significant factor in medical emergencies. PMID- 21605590 TI - The evolving role of new imaging methods in breast screening. AB - The potential to avert breast cancer deaths through screening means that efforts continue to identify methods which may enhance early detection. While the role of most new imaging technologies remains in adjunct screening or in the work-up of mammography-detected abnormalities, some of the new breast imaging tests (such as MRI) have roles in screening groups of women defined by increased cancer risk. This paper highlights the evidence and the current role of new breast imaging technologies in screening, focusing on those that have broader application in population screening, including digital mammography, breast ultrasound in women with dense breasts, and computer-aided detection. It highlights that evidence on new imaging in screening comes mostly from non-randomised studies that have quantified test detection capability as adjunct to mammography, or have compared measures of screening performance for new technologies with that of conventional mammography. Two RCTs have provided high-quality evidence on the equivalence of digital and conventional mammography and on outcomes of screen-reading complemented by CAD. Many of these imaging technologies enhance cancer detection but also increase recall and false positives in screening. PMID- 21605591 TI - The interleukins of fish. AB - Interleukins are a subgroup of cytokines, molecules involved in the intercellular regulation of the immune system. The term interleukin was first coined in 1979 to refer to molecules that signal between different leucocyte types, although not exclusively restricted to leucocyte communication. Whilst it is now known that interleukins are produced by a wide variety of cell types, nevertheless many are synthesised by CD4(+) T helper cells, macrophages/monocytes and endothelial cells. The nomenclature is relatively straightforward, with interleukin 1 the first discovered and interleukin 2 the second, etc. However, whilst 35 interleukins are currently described in mammals, several are in fact terms referring to subfamilies of more molecules, as with the IL-1 family where 11 members (IL-1F1-IL-1F11) are present, and the IL-17 family where 6 members (IL 17A-IL-17F) are present. So the total is much higher and splice variants and allelic variation increase this diversity further. This review will focus on what is known about interleukins in fish, and will refer to the major subfamilies rather than try to work through 35 descriptions in a row. It is clear that many direct homologues of molecules known in mammals are present in fish, but that not all are present and some novel interleukins exist that may have arisen from fish specific gene duplication events. PMID- 21605593 TI - Mefloquine neurotoxicity and gap junction blockade: critical insights in drug repositioning. PMID- 21605592 TI - Thalamic mediodorsal nucleus and working memory. AB - Working memory is a dynamic neural system for temporarily maintaining and processing information. The prefrontal cortex (PFC) plays an important role in working memory. However, several evidences indicate that the thalamic mediodorsal nucleus (MD) also participates in working memory. Neurophysiological studies revealed that MD neurons exhibit sustained delay activity, which is considered to be a neural correlate of the temporary maintenance of information. Most MD neurons with delay activity represented information regarding motor responses, whereas some represented information regarding visual cues, suggesting that the MD participates more in prospective aspects of working memory, in contrast to the PFC, in which a minority participates in prospective aspects of working memory. A population vector analysis revealed that the transformation of sensory-to-motor information occurred during the earlier phase of the delay period in the MD compared with the PFC. These results indicate that reverberating neural circuits constructed by reciprocal connections between the MD and the PFC could be an important component for constructing prospective information in the PFC. PMID- 21605594 TI - Pharmacological interventions for spinal cord injury: where do we stand? How might we step forward? AB - Despite numerous studies reporting some measures of efficacy in the animal literature, there are currently no effective therapies for the treatment of traumatic spinal cord injuries (SCI) in humans. The purpose of this review is to delineate key pathophysiological processes that contribute to neurological deficits after SCI, as well as to describe examples of pharmacological approaches that are currently being tested in clinical trials, or nearing clinical translation, for the therapeutic management of SCI. In particular, we will describe the mechanistic rationale to promote neuroprotection and/or functional recovery based on theoretical, yet targeted pathological events. Finally, we will consider the clinical relevancy for emerging evidence that pharmacologically targeting mitochondrial dysfunction following injury may hold the greatest potential for increasing tissue sparing and, consequently, the extent of functional recovery following traumatic SCI. PMID- 21605596 TI - A new cross-correlation algorithm for the analysis of "in vitro" neuronal network activity aimed at pharmacological studies. AB - Modern drug discovery for Central Nervous System pathologies has recently focused its attention to in vitro neuronal networks as models for the study of neuronal activities. Micro Electrode Arrays (MEAs), a widely recognized tool for pharmacological investigations, enable the simultaneous study of the spiking activity of discrete regions of a neuronal culture, providing an insight into the dynamics of networks. Taking advantage of MEAs features and making the most of the cross-correlation analysis to assess internal parameters of a neuronal system, we provide an efficient method for the evaluation of comprehensive neuronal network activity. We developed an intra network burst correlation algorithm, we evaluated its sensitivity and we explored its potential use in pharmacological studies. Our results demonstrate the high sensitivity of this algorithm and the efficacy of this methodology in pharmacological dose-response studies, with the advantage of analyzing the effect of drugs on the comprehensive correlative properties of integrated neuronal networks. PMID- 21605597 TI - Do transmembrane domain neuregulin 1 mutant mice exhibit a reliable sensorimotor gating deficit? AB - Evidence suggests that the heterozygous transmembrane domain mutant mouse model for the schizophrenia candidate gene neuregulin 1 (Nrg1 HET) exhibits a deficit in prepulse inhibition (PPI). However, not all mouse models for Nrg1 exhibit PPI deficits. Thus, our study intended to clarify the severity of the initially described PPI deficit in Nrg1 HET mice. For this, Nrg1 mutant mice and wild type like littermates of one breeding colony were tested for PPI in four different phenotyping facilities in Australia employing a variety of different PPI protocols with fixed and variable interstimulus intervals (ISIs). Testing mutant and wild type-like mice in three Australian phenotyping facilities using PPI protocols with variable ISIs revealed no effect of mutant transmembrane domain Nrg1 on sensorimotor gating. Changes to the startle response and startle response habituation were site/protocol-specific. The employment of two different PPI protocols at the same phenotyping facility revealed a protocol-dependent and site specific facilitation of PPI in Nrg1 mutant mice compared to wild type-like mice. In conclusion, the often-noted PPI phenotype of the transmembrane domain Nrg1 mutant mouse model is highly PPI protocol-specific and appears sensitive to the particular conditions of the test laboratory. Our study describes wild type-like PPI under most test conditions and across three different laboratories. The research suggests that analysing one of the alleged hallmarks of animal models for schizophrenia must be done carefully: to obtain reliable PPI data it seems necessary to use more than one particular PPI protocol. PMID- 21605595 TI - Cysteinyl cathepsins and mast cell proteases in the pathogenesis and therapeutics of cardiovascular diseases. AB - The initiation and progression of cardiovascular diseases involve extensive arterial wall matrix protein degradation. Proteases are essential to these pathological events. Recent discoveries suggest that proteases do more than catabolize matrix proteins. During the pathogenesis of atherosclerosis, abdominal aortic aneuryms, and associated complications, cysteinyl cathepsins and mast cell tryptases and chymases participate importantly in vascular cell apoptosis, foam cell formation, matrix protein gene expression, and pro-enzyme, latent cytokine, chemokine, and growth factor activation. Experimental animal disease models have been invaluable in examining each of these protease functions. Deficiency and pharmacological inhibition of cathepsins or mast cell proteases have allowed their in vivo evaluation in the setting of pathological conditions. Recent discoveries of highly selective and potent inhibitors of cathepsins, chymase, and tryptase, and their applications in vascular diseases in animal models and non vascular diseases in human trials, have led to the hypothesis that selective inhibition of cathepsins, chymases, and tryptase will benefit patients suffering from cardiovascular diseases. This review highlights recent discoveries from in vitro cell-based studies to experimental animal cardiovascular disease models, from protease knockout mice to treatments with recently developed selective and potent protease inhibitors, and from patients with cathepsin-associated non vascular diseases to those affected by cardiovascular complications. PMID- 21605598 TI - Abnormal functional connectivity in patients with vascular cognitive impairment, no dementia: a resting-state functional magnetic resonance imaging study. AB - The functional connectivity (FC) method was used to investigate the changes in the resting state of patients with vascular cognitive impairment, no dementia (VCIND). Resting-state functional magnetic resonance images (fMRIs) were acquired from 16 patients with subcortical ischemic vascular disease (SIVD) who fulfilled the criteria for VCIND, as well as 18 age- and sex-matched subjects with SIVD with no cognitive impairment (control group). Posterior cingulate cortex connectivity was gathered by investigating synchronic low-frequency fMRI signal fluctuations with a temporal correlation method. Compared with the control group, the patients showed FC decrease in the left middle temporal gyrus, the left anterior cingulate/left middle frontal gyrus, the right caudate, the right middle frontal gyrus, and the left medial frontal gyrus/paracentral lobule. There were also some regions that showed increased connectivity. These regions included the right inferior temporal gyrus, the left middle temporal gyrus, the left precentral gyrus, and the left superior parietal lobule. Our findings revealed the change in resting-state patterns of neuronal activity in patients with VCIND. This change may be caused by subcortical white matter lesions that destroyed direct and indirect fiber tract connectivity across the cerebral white matter and influenced the cortical FC and hypoperfusion resulted from small vascular disease. The results of the increased connectivity may be evoked by the compensatory recruitment and plasticity mechanism. Our findings suggest that the simplicity and noninvasiveness of this method makes it a potential tool to help thoroughly understand the pathogenesis of VCIND. PMID- 21605599 TI - Polysome profiling of the malaria parasite Plasmodium falciparum. AB - In the malaria parasite Plasmodium falciparum, global studies of translational regulation have been hampered by the inability to isolate malaria polysomes. We describe here a novel method for polysome profiling in P. falciparum, a powerful approach which allows both a global view of translation and the measurement of ribosomal loading and density for specific mRNAs. Simultaneous lysis of infected erythrocytes and parasites releases stable, intact malaria polysomes, which are then purified by centrifugation through a sucrose cushion. The polysomes are resuspended, separated by velocity sedimentation and then fractionated, yielding a characteristic polysome profile reflecting the global level of translational activity in the parasite. RNA isolated from specific fractions can be used to determine the density of ribosomes loaded onto a particular transcript of interest, and is free of host ribosome contamination. Thus, our approach opens translational regulation in malaria to genome-wide analysis. PMID- 21605600 TI - Insights into blood feeding by schistosomes from a proteomic analysis of worm vomitus. AB - Whilst the schistosome tegument has been intensively studied there is little information about processes in the gut, the other major interface with the bloodstream, apart from the well characterised cascade of proteases involved in haemoglobin digestion. To gain insights into gut function we undertook a proteomic analysis of worm vomitus and performed in vitro erythrocyte feeding experiments. Additional to known gut constituents we identified two proline carboxypeptidases as well as enzymes capable of hydrolysing carbohydrate and ester linkages. Schistosome serpin and a2 macroglobulin protease inhibitors were also present. A series of "carrier proteins", principally lipid-binding saposins and cholesterol-binding NPC-2 were also detected, together with ferritins and calumenin that bind ferric iron and calcium, respectively. The presence of these lysosomal proteins and other lysosomal markers in the vomitus, plus observations on the cytology of the gut epithelium suggest that lysosomes directly secrete their contents into the gut lumen to digest incoming plasma constituents as well as haemoglobin. It is also likely that the carrier proteins function to sequester essential organic and inorganic nutrients for uptake into the epithelium. The feeding experiments indicate that erythrocytes are uncoated as they pass through the oesophagus, intersecting with its secretions, whilst the endocytosis of space filling dextran into the gut epithelium provides a potential mechanism for carrier uptake by macropinocytosis. PMID- 21605602 TI - Use of immunomagnetic separation for the detection of Desulfovibrio vulgaris from environmental samples. AB - Immunomagnetic separation (IMS) has proved highly efficient for recovering microorganisms from heterogeneous samples. Current investigation targeted the separation of viable cells of the sulfate-reducing bacterium, Desulfovibrio vulgaris. Streptavidin-coupled paramagnetic beads and biotin labeled antibodies raised against surface antigens of this microorganism were used to capture D. vulgaris cells in both bioreactor grown laboratory samples and from extremely low biomass environmental soil and subsurface drilling samples. Initial studies on detection, recovery efficiency and viability for IMS were performed with laboratory grown D. vulgaris cells using various cell densities. Efficiency of cell isolation and recovery (i.e., release of the microbial cells from the beads following separation) was followed by microscopic imaging and acridine orange direct counts (AODC). Excellent recovery efficiency encouraged the use of IMS to capture Desulfovibrio spp. cells from low-biomass environmental samples. The environmental samples were obtained from a radionuclide-contaminated site in Germany and the chromium (VI)-contaminated Hanford site, an ongoing bioremediation project of the U.S. Department of Energy. Field deployable IMS technology may greatly facilitate environmental sampling and bioremediation process monitoring and enable transcriptomics and proteomics/metabolomics-based studies directly on cells collected from the field. PMID- 21605601 TI - Intracellular alpha(2C)-adrenoceptors: storage depot, stunted development or signaling domain? AB - G-protein coupled receptors (GPCRs) are generally considered to function as cell surface signaling structures that respond to extracellular mediators, many of which do not readily access the cell's interior. Indeed, most GPCRs are preferentially targeted to the plasma membrane. However, some receptors, including alpha(2C)-Adrenoceptors, challenge conventional concepts of GPCR activity by being preferentially retained and localized within intracellular organelles. This review will address the issues associated with this unusual GPCR localization and discuss whether it represents a novel sub-cellular niche for GPCR signaling, whether these receptors are being stored for rapid deployment to the cell surface, or whether they represent immature or incomplete receptor systems. PMID- 21605603 TI - Multiplex PCR as a tool for validating plasmid content of Borrelia burgdorferi. AB - Borrelia burgdorferi has an unusual genomic structure containing 21 plasmids. These plasmids carry genes that are essential for infectivity and survival of the spirochetes in vivo. Several plasmids are lost during cultivation in vitro, which might lead to a heterogeneous population after multiple passages and loss of infectivity in laboratory animals. Herein, we present a simple and inexpensive multiplex PCR method that detects the complete plasmid profile of B. burgdorferi B31 in just two PCR tubes. PMID- 21605604 TI - Drosophila Nora virus capsid proteins differ from those of other picorna-like viruses. AB - The recently discovered Nora virus from Drosophila melanogaster is a single stranded RNA virus. Its published genomic sequence encodes a typical picorna-like cassette of replicative enzymes, but no capsid proteins similar to those in other picorna-like viruses. We have now done additional sequencing at the termini of the viral genome, extending it by 455 nucleotides at the 5' end, but no more coding sequence was found. The completeness of the final 12,333-nucleotide sequence was verified by the production of infectious virus from the cloned genome. To identify the capsid proteins, we purified Nora virus particles and analyzed their proteins by mass spectrometry. Our results show that the capsid is built from three major proteins, VP4A, B and C, encoded in the fourth open reading frame of the viral genome. The viral particles also contain traces of a protein from the third open reading frame, VP3. VP4A and B are not closely related to other picorna-like virus capsid proteins in sequence, but may form similar jelly roll folds. VP4C differs from the others and is predicted to have an essentially alpha-helical conformation. In a related virus, identified from EST database sequences from Nasonia parasitoid wasps, VP4C is encoded in a separate open reading frame, separated from VP4A and B by a frame-shift. This opens a possibility that VP4C is produced in non-equimolar quantities. Altogether, our results suggest that the Nora virus capsid has a different protein organization compared to the order Picornavirales. PMID- 21605605 TI - Apoptosis and necrosis in vaccinia virus-infected HeLa G and BSC-40 cells. AB - In most cells, vaccinia virus (VACV) infection is considered to cause a lytic cell death, an equivalent of necrosis. However, upon infection of the epithelial cell lines HeLa G and BSC-40 with VACV strain Western Reserve (WR), we have previously observed an increased activation of and activity attributable to caspases, a typical sign of apoptosis. In this paper, we have further analyzed the type of cell death in VACV-infected cells HeLa G and BSC-40. In a cell-based flow cytometric assay, we showed a specific activation of caspase-2 and 4 in HeLa G and BSC-40 cells infected with VACV, strain WR, while we did not find any effects of inhibitors of calpain and cathepsin D and E. The actual activity of the two caspases, but also of caspase-3, was then confirmed in lysates of infected HeLa G, but not in BSC-40 cells. Accordingly, poly(ADP)-ribose polymerase (PARP) cleavage was found increased only in infected HeLa G cells. Consequently, we have determined morphological features of apoptosis and/or activity of the executioner caspase-3 in infected HeLa G cells in situ, while only a background apoptosis was observed in infected BSC-40 cells. Finally, vaccination strains Dryvax and Praha were found to induce apoptosis in both HeLa G and BSC-40 cells, as characterized morphologically and by PARP cleavage. These findings may be important for understanding the differences in VACV-host interactions and post-vaccination complications in different individuals. PMID- 21605606 TI - Search for factors involved in the rapid shift in Watermelon mosaic virus (WMV) populations in South-eastern France. AB - Watermelon mosaic virus (WMV, genus Potyvirus, family Potyviridae) was reported for the first time in France in 1974, and it is now the most prevalent virus in cucurbit crops. In 2000, new strains referred as 'emerging' (EM) strains were detected in South-eastern France. EM strains are generally more severe and phylogenetically distinct from those previously reported in this country and referred as 'classic' (CL) strains. Since 2000, EM strains have been progressively replacing CL strains in several areas where they co-exist. In order to explain this rapid shift in virus populations, the biological properties of a set of 17 CL and EM WMV isolates were compared. No major differences were observed when comparing a limited host range including 48 different plant species or cultivars. Only two species were differential; Chenopodium quinoa was systemically infected by CL and not by EM isolates whereas Ranunculus sardous was systemically infected by EM and not by CL isolates. A considerable variability was observed in aphid transmission efficiencies but this could not be correlated to the CL or EM types. Two subsets of five isolates of each group were used to compare aphid transmission efficiencies from single and double (CL-EM) infections using six different cucurbit and non-cucurbit hosts. EM isolates were generally better transmitted from mixed CL-EM infections than CL isolates and CL transmission rates were significantly lower from double than from single infections. Cross-protection was only partial between CL and EM strains leading to frequent double infections, and only a slight asymmetry was observed in cross protection efficiencies. Since double infections occur very commonly in fields, the preferential transmission of EM from mixed CL-EM infections could be one of the factors leading to the displacement of CL isolates by EM isolates. PMID- 21605607 TI - Adaptive micro and nanoparticles: temporal control over carrier properties to facilitate drug delivery. AB - Recent studies have led to significant advances in understanding the impact of key drug carrier properties such as size, surface chemistry and shape on their performance. Converting this knowledge into improved therapeutic outcomes, however, has proved challenging. This owes to the fact that successful drug delivery carriers have to navigate through multiple physiological hurdles including reticuloendothelial system (RES) clearance, target accumulation, intracellular uptake and endosomal escape. Each of these processes may require unique, and often conflicting, design parameters, thus making it difficult to choose a design that addresses all these hurdles. This challenge can be addressed by designing carriers whose properties can be changed in time so as to successfully navigate them through various biological hurdles. Several carriers have been reported that implement this strategy. This review will discuss the current status and future prospects of this emerging field of "adaptive micro and nanoparticles". PMID- 21605608 TI - Caffeine ingestion, affect and perceived exertion during prolonged cycling. AB - Caffeine's metabolic and performance effects have been widely reported. However, caffeine's effects on affective states during prolonged exercise are unknown. Therefore, this was examined in the present study. Following an overnight fast and in a randomised, double-blind, counterbalanced design, twelve endurance trained male cyclists performed 90 min of exercise at 70% VO(2 max) 1h after ingesting 6 mg kg-1 BM of caffeine (CAF) or placebo (PLA). Dimensions of affect and perceived exertion were assessed at regular intervals. During exercise, pleasure ratings were better maintained (F(3,38)=4.99, P < 0.05) in the CAF trial compared to the PLA trial with significantly higher ratings at 15, 30 and 75 min (all P < 0.05). Perceived exertion increased (F(3,38) = 19.86, P < 0.01) throughout exercise and values, overall, were significantly lower (F(1,11) = 9.26, P < 0.05) in the CAF trial compared to the PLA trial. Perceived arousal was elevated during exercise but did not differ between trials. Overall, the results suggest that a moderate dose of CAF ingested 1h prior to exercise maintains a more positive subjective experience during prolonged cycling. This observation may partially explain caffeine's ergogenic effects. PMID- 21605609 TI - Novel antihypertensive hexa- and heptapeptides with ACE-inhibiting properties: from the in vitro ACE assay to the spontaneously hypertensive rat. AB - Bioactive ACE inhibiting peptides are gaining interest in hypertension treatment. We have designed and screened six synthetic heptapeptides (PACEI48 to PACEI53) based on two hexapeptide leads (PACEI32 and PACEI34) to improve ACE inhibitory properties and assess their antihypertensive effects. ACE activity was assayed in vitro and ex vivo. Selected peptides were administered to spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. In vitro cytotoxicity was assessed with the MTT reduction test. The six heptapeptides at low micromolar concentration produced different degrees of in vitro inhibition of ACE activity using the synthetic substrate HHL or the natural substrate angiotensin I; and ex vivo inhibition of ACE-dependent, angiotensin I-induced vasoconstriction, but not angiotensin II-induced vasoconstriction. Oral administration of the hexapeptide PACEI32L, and the heptapeptides PACEI50L and PACEI52L, induced reductions in systolic blood pressure lasting up to 3h in SHRs but not in WKY rats. Intravenous injection of PACEI32L and PACEI50L, but not PACEI52L, induced acute transient reductions in mean blood pressure of SHRs. d Amino acid peptides showed five-fold less ACE inhibitory potency, no inhibitory effect on angiotensin I-induced vasoconstriction, and antihypertensive effect in SHRs after i.v. injection, but not after oral administration. The toxicity of peptides to reduce the viability of cultured cells was in the millimolar range. In conclusion, we have obtained novel rationally designed heptapeptides with improved ACE inhibitory properties when compared to lead hexapeptides. One selected hexapeptide and two heptapeptides show oral antihypertensive effects in SHRs and appear safe in cytotoxicity assays. PMID- 21605610 TI - Determination of a new antibacterial peptide S-thanatin in rat plasma by an indirected-ELISA. AB - In this study, antimicrobial peptide S-thanatin (Ts) was chemically synthesized and linked to keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA) by carbodiimide reagent. Rabbits were immunized with Ts-KLH and polyclonal antibody against Ts was purified by fractional precipitation of ammonium sulfate, coupled with anion-exchange chromatography. The purified antibody specifically binding to Ts residues but not BSA molecules was observed by Western-Blot analysis. Ts-BSA was selected as immobilized antigen and reacted with the residual antibody after the excess of anti-Ts antibody was combined with Ts in the sample. The binding antibody was recognized by HRP-conjugated secondary antibody. Finally, the horseradish peroxidase in the complex could catalyze the TMB substrate, resulting in color development. The method was evaluated by analysis of linearity, precision and accuracy and successfully applied in determination of Ts in rat plasma. The data of the pharmacokinetic parameters were also obtained. The proposed ELISA has a great value in routine analysis of Ts for its therapeutic monitoring and pharmacokinetic studies. PMID- 21605611 TI - Concomitant vascular GRP-receptor and VEGF-receptor expression in human tumors: molecular basis for dual targeting of tumoral vasculature. AB - Gastrin-releasing peptide (GRP) and GRP receptors (GRPR) play a role in tumor angiogenesis. Recently, GRPR were found to be frequently expressed in the vasculature of a large variety of human cancers. Here, we characterize these GRPR by comparing the vascular GRPR expression and localization in a selection of human cancers with that of an established biological marker of neoangiogenesis, the vascular endothelial growth factor (VEGF) receptor. In vitro quantitative receptor autoradiography was performed in parallel for GRPR and VEGF receptors (VEGFR) in 32 human tumors of various origins, using 125I-Tyr-bombesin and 125I VEGF165 as radioligands, respectively. Moreover, VEGFR-2 was evaluated immunohistochemically. All tumors expressed GRPR and VEGFR in their vascular system. VEGFR were expressed in the endothelium in the majority of the vessels. GRPR were expressed in a subpopulation of vessels, preferably in their muscular coat. The vessels expressing GRPR were all VEGFR-positive whereas the VEGFR expressing vessels were not all GRPR-positive. GRPR expressing vessels were found immunohistochemically to co-express VEGFR-2. Remarkably, the density of vascular GRPR was much higher than that of VEGFR. The concomitant expression of GRPR with VEGFR appears to be a frequent phenomenon in many human cancers. The GRPR, localized and expressed in extremely high density in a subgroup of vessels, may function as target for antiangiogenic tumor therapy or angiodestructive targeted radiotherapy with radiolabeled bombesin analogs alone, or preferably together with VEGFR targeted therapy. PMID- 21605612 TI - Pituitary adenylate cyclase-activating polypeptide plays an anti-inflammatory role in endotoxin-induced airway inflammation: in vivo study with gene-deleted mice. AB - The presence of pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors in capsaicin-sensitive peptidergic sensory nerves, inflammatory and immune cells suggest its involvement in inflammation. However, data on its role in different inflammatory processes are contradictory and there is little known about its functions in the airways. Therefore, our aim was to examine intranasal endotoxin-induced subacute airway inflammation in PACAP gene-deficient (PACAP-/-) and wild-type (PACAP+/+) mice. Airway responsiveness to inhaled carbachol was determined in unrestrained mice with whole body plethysmography 6 h and 24 h after LPS. Myeloperoxidase (MPO) activity referring to the number of accumulated neutrophils and macrophages was measured with spectrophotometry and interleukin 1beta (IL-1beta) concentration with ELISA from the lung homogenates. Histological evaluation and semiquantitative scoring were also performed. Bronchial responsiveness, as well as IL-1beta concentration and MPO activity markedly increased at both timepoints. Perivascular edema dominated the histological picture at 6 h, while remarkable peribronchial granulocyte accumulation, macrophage infiltration and goblet cell hyperplasia were seen at 24h. In PACAP-/- mice, airway hyperreactivity was significantly higher 24 h after LPS and inflammatory histopathological changes were more severe at both timepoints. MPO increase was almost double in PACAP-/- mice compared to the wild-types at 6 h. In contrast, there was no difference between the IL-1beta concentrations of the PACAP+/+ and PACAP-/- mice. These results provide evidence for a protective role for PACAP in endotoxin-induced airway inflammation and hyperreactivity. PMID- 21605613 TI - Hepatitis B virus markers among teenagers in the Araguaia region, Central Brazil: assessment of prevalence and vaccination coverage. AB - The Brazilian hepatitis B (HBV) vaccination program for neonates was implemented in 1998 and broadened to include young people up to 20 years of age in 2001. However, HBV coverage of teenagers has not been systematically assessed in Brazil. A cross-sectional study was performed to estimate the magnitude of HBV infection and vaccine coverage among adolescent students regularly enrolled in the public schools of Barra do Garcas, a city located in the state of Mato Grosso, Brazil. A representative sample was randomly obtained and participants were interviewed and had blood samples collected to test for HBV markers. The sample was composed of 576 subjects, 51% of which were females. The average age was 15, with the group ranging from 12 to 20 years of age. There were 29 anti-HBc reactive participants (5.0%). Four out of 29 were HBsAg positive (0.7%). Anti-HBs alone (vaccinated profile) showed in 323 (56.1%) students and 224 (38.9%) were negative for all HBV markers. Increasing age was associated with HBV exposure in a chi(2) for trend analysis (p=0.004). The prevalence of anti-HBs alone decreased as the subjects' age increased. Multivariate analysis showed independent association between HBV infection and the start of sexual activity. Another associated variable was the fact that the some students were enrolled in two low income neighborhood schools. Our findings classify this area as low endemic for HBV and suggest that there is a progressive decrease in the spread of HBV in the region due to the introduction of universal vaccination of neonates. Approximately half of the adolescents 15 years or older were not immunized, which raises a concern in terms of the need to increase the vaccination rate for this segment of the population. PMID- 21605614 TI - Bovine Neonatal Pancytopenia: is this alloimmune syndrome caused by vaccine induced alloreactive antibodies? AB - Bovine Neonatal Pancytopenia (BNP) is a new emerging disease observed since 2007 in Germany and neighbouring countries. The syndrome affects newborn calves and is characterized by pancytopenia, severe bleeding and high lethality. So far, a causative role of infectious or toxic agents has been ruled out. Instead, the syndrome is induced after ingestion of colostrum, the first milk that supplies the calf with maternal antibodies. In analogy to similar diseases in humans it has therefore been postulated that BNP is caused by alloreactive, maternal antibodies. There is a striking association between BNP and a previous vaccination of the respective dams with a particular vaccine against Bovine Virus Diarrhoea (BVD). This association has led to a suspension of the marketing authorisation for the vaccine, by the European Commission. The current study investigates the role of this vaccine in the pathogenesis of BNP. By flow cytometry we were able to demonstrate that sera of BNP dams (dams that gave birth to a BNP calf) harbour alloreactive antibodies binding to surface antigens on bovine leukocytes. A significantly weaker alloreactivity was observed with sera of non-BNP dams that have been vaccinated with the same vaccine but delivered healthy calves. No binding was seen with non-BVD-vaccinated control cows and animals that were vaccinated with other inactivated BVD vaccines so far not associated with BNP. The binding is functionally relevant, because opsonization of bovine leukocytes with alloantibodies led to an elevated cytophagocytosis by bovine macrophages. To test whether the vaccine induces alloreactive antibodies two strategies were employed: Guinea pigs were vaccinated with a panel of commercially available BVD-vaccines. Only the incriminated vaccine induced antibodies binding surface antigens on bovine leukocytes. Additionally, two calves were repeatedly vaccinated with the suspected vaccine and the development of alloreactivity was monitored. In dependence of the number of booster immunizations the induction of alloreactive antibodies could be observed. Finally, by affinity purification we were able to directly demonstrate that BNP associated alloantibodies cross react with the bovine kidney cell line used for vaccine production. Together this provides strong evidence that this particular BVD vaccine has the potential to induce BNP associated alloantibodies. PMID- 21605615 TI - Improvements in both psychosis and motor signs in Parkinson's disease, and changes in regional cerebral blood flow after electroconvulsive therapy. AB - PURPOSE: Psychotic symptoms in Parkinson's disease (PD) are relatively common and, in addition to creating a disturbance in patients' daily lives, have consistently been shown to be associated with poor outcome. The use of anti-PD medications has been the most widely identified risk factor for PD psychosis (PDP). However, the pathophysiology of PDP remains unclear. Although the efficacy of electroconvulsive therapy (ECT) for PD had been pointed out, only one study has demonstrated the effectiveness of ECT on both psychotic symptoms and motor symptoms. The aim of this study was to examine the acute effectiveness of ECT on PD and to identify the brain areas associated with PDP. METHODS: The study was conducted at Juntendo University Hospital in Tokyo. Eight patients with L-DOPA- or dopamine (DA) agonist-induced PDP, who were resistant to quetiapine treatment, were enrolled. Severity of PD was evaluated using the Hoehn and Yahr stage. Psychotic symptoms were evaluated using multiple measures from the Scale for the Assessment of Positive Symptoms (SAPS). Technetium-99m ethyl cysteinate dimer single photon emission computed tomography (99mTc ECD SPECT) was used to assess regional cerebral blood flow (rCBF) before and after a course of ECT. A voxel-by voxel group analysis was performed using Statistical Parametric Mapping (SPM5). RESULTS: Our study clearly demonstrated that PDP was significantly less severe after ECT than before ECT, as indicated by change in mean SAPS total domain score (t=7.2, P=0.0002). Furthermore, the patients showed significant improvement in Hoehn and Yahr stage after ECT (t=11.7, P<0.0001). A further notable observation was significant increase in rCBF in the right middle frontal gyrus after ECT. CONCLUSION: We conclude that a course of ECT produced notable improvements not only in PDP but also in the severity of PD. The findings of change in rCBF suggest implications for dysfunction in the middle frontal region for patients with PDP. PMID- 21605616 TI - Rutin attenuates cisplatin induced renal inflammation and apoptosis by reducing NFkappaB, TNF-alpha and caspase-3 expression in wistar rats. AB - Cisplatin is an effective chemotherapeutic agent that displays dose-limiting nephrotoxicity. In the present study the wistar rats were subjected to concurrent prophylactic oral treatment of rutin (75 and 150 mg/kgb.wt.) against the nephrotoxicity induced by intraperitoneal administration of cisplatin (7 mg/kgb.wt.). Efficacy of rutin against the nephrotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes and expression levels of molecular markers of inflammation and apoptosis. Rutin pretreatment prevented deteriorative effects induced by cisplatin through a protective mechanism that involved reduction of increased oxidative stress as well as caspase-3, TNF-alpha and NFkappaB protein expression levels. We found that the beneficial effect of rutin pretreatment is mediated partially by its inhibitory effect on NFkappaB and TNF-alpha pathway mediated inflammation, caspase-3 mediated-tubular cell apoptosis, as well as by restoration of histopathological changes against cisplatin administration. PMID- 21605617 TI - An assessment of the impact of physico-chemical and biochemical characteristics on the human kinetic adjustment factor for systemic toxicants. AB - The objective of this study was to evaluate the magnitude of the human kinetic adjustment factor (HKAF) as a function of physico- and bio-chemical characteristics impacting the systemic clearance of chemicals. This factor is intended to replace the default value of 3.16 in non-cancer risk assessments and aims at accounting for interindividual variability in toxicokinetics. A steady state algorithm was used to compute the internal dose metrics (blood concentration (C(blood)) and rate of metabolite produced/L liver (RAM)) of hypothetical chemicals in neonates, adults, elderly, and pregnant women. After evaluating the algorithm with chemical-specific experimental data, C(blood) and RAM were calculated for hypothetical chemicals exhibiting blood:air partition coefficients (Pb) between 1 and 10,000 and hepatic extraction ratios in the average adult (E) between 0.01 and 0.99. Based on Monte Carlo simulation results, HKAF values were computed as the ratio of the 95th percentile value for each subpopulation to the 50th percentile value in adults. The highest HKAF among those obtained for each subpopulation was reported in route-, pathway-, and dose metric-specific HKAF matrices as a function of Pb and E. These matrices allowed the recognition of cases where the default HKAF could be exceeded, and these occurred in neonates based on C(blood) in two situations. First, when the average adult-to-neonate ratio of body weight-adjusted systemic clearance was at least equal to 2.2 for a given systemic exposure (i.e., for CYP1A2 substrates only). Second, when E=0.01-0.2 and Pb >= 300 or when E=0.3-0.7 and Pb >= 100 for inhalation exposures to CYP2E1 substrates, with comparable values for the other substrates (higher for CYP1A2). Overall, this study showed the dependency of the HKAF on the dose metrics, chemical characteristics, metabolic pathways, and subpopulations considered. PMID- 21605618 TI - Potential carcinogenic hazards of non-regulated disinfection by-products: haloquinones, halo-cyclopentene and cyclohexene derivatives, N-halamines, halonitriles, and heterocyclic amines. AB - Drinking water disinfectants react with natural organic material (NOM) present in source waters used for drinking water to produce a wide variety of by-products. Several hundred disinfections by-products (DBPs) have been identified, but none have been identified with sufficient carcinogenic potency to account for the cancer risks projected from epidemiological studies. In a search for DBPs that might fill this risk gap, the present study projected reactions of chlorine and chloramine that could occur with substructures present in NOM to produce novel by products. A review of toxicological data on related compounds, supplemented by use of a quantitative structure toxicity relationship (QSTR) program TOPKAT(r)) identified chemicals with a high probability of being chronically toxic and/or carcinogenic among 489 established and novel DBPs. Classes of DBPs that were specifically examined were haloquinones (HQs), related halo-cyclopentene and cyclohexene (HCP&H) derivatives, halonitriles (HNs), organic N-chloramines (NCls), haloacetamides (HAMs), and nitrosamines (NAs). A review of toxicological data available for quinones suggested that HQs and HCP&H derivatives appeared likely to be of health concern and were predicted to have chronic lowest observed adverse effect levels (LOAELs) in the low MUg/kg day range. Several HQs were predicted to be carcinogenic. Some have now been identified in drinking water. The broader class of HNs was explored by considering current toxicological data on haloacetonitriles and extending this to halopropionitriles. 2,2 dichloropropionitrile has been identified in drinking water at low concentrations, as well as the more widely recognized haloacetonitriles. The occurrence of HAMs has been previously documented. The very limited toxicological data on HAMs suggests that this class would have toxicological potencies similar to the dihaloacetic acids. Organic N-halamines are also known to be produced in drinking water treatment and have biological properties of concern, but no member has ever been characterized toxicologically beyond bacterial or in vitro studies of genotoxicity. The documented formation of several nitrosamines from secondary amines from both natural and industrial sources prompted exploration of the formation of additional nitrosamines. N-diphenylnitrosamine was identified in drinking waters. Of more interest, however, was the formation of phenazine (and subsequently N-chorophenazine) in a competing reaction. These are the first heterocyclic amines that have been identified as chlorination by-products. Consideration of the amounts detected of members of these by-product classes and their probable toxicological potency suggest a prioritization for obtaining more detailed toxicological data of HQs>HCP&H derivatives>NCls>HNs. Based upon a ubiquitous occurrence and virtual lack of in vivo toxicological data, NCls are the most difficult group to assign a priority as potential carcinogenic risks. This analysis indicates that research on the general problem of DBPs requires a more systematic approach than has been pursued in the past. Utilization of predictive chemical tools to guide further research can help bring resolution to the DBP issue by identifying likely DBPs with high toxicological potency. PMID- 21605619 TI - The potential use of the neurotensin high affinity receptor 1 as a biomarker for cancer progression and as a component of personalized medicine in selective cancers. AB - A growing challenge in medicine today, is the need to improve the suitability of drug treatments for cancer patients. In this field, biomarkers have become the "flags" to provide additional information in tumor biology. They are a relay between the patient and practitioner and consequently, aid in the diagnosis, providing information for prognosis, or in some cases predicting the response to specific therapies. In addition to being markers, these tumor "flags" can also be major participants in the process of carcinogenesis. Neurotensin receptor 1 (NTSR1) was recently identified as a prognosis marker in breast, lung, and head and neck squamous carcinomas. Neurotensin (NTS) was also shown to exert numerous oncogenic effects involved in tumor growth and metastatic spread. These effects were mostly mediated by NTSR1, making the NTS/NTSR1 complex an actor in cancer progression. In this review, we gather information on the oncogenic effects of the NTS/NTSR1 complex and its associated signaling pathways in order to illuminate its significant role in tumor progression and its potential as a biomarker and a therapeutic target in some tumors. PMID- 21605620 TI - Humanized VB22B minibody for human Mpl stimulates human megakaryopoiesis but does not enhance platelet aggregation. AB - OBJECTIVE: Thrombopoietin stimulates megakaryopoiesis and platelet production by binding to its receptor, Mpl, on hematopoietic progenitor cells. Previously, a murine VB22B minibody for Mpl was shown to stimulate megakaryocyte colony formation in vitro and increase the platelet count in cynomolgus monkeys. In this study, we directly compared the effects of a humanized VB22B minibody (huVB22B) with those of thrombopoietin and eltrombopag under the hypothesis that Mpl agonists might have different biological effects on megakaryopoiesis, platelet production, intracellular signal transduction, and platelet function. MATERIALS AND METHODS: Human bone marrow-derived CD34(+) cells were used for colony formation assays and proplatelet formation assays in vitro. The DNA ploidy in megakaryocytes was analyzed by flow cytometry. Phosphorylation of signal transducers and activators of transcription and mitogen-activated protein kinase was detected by Western blotting using specific antibodies. The effects of the Mpl agonists on platelet aggregation were analyzed by aggregometry using human platelets. RESULTS: HuVB22B was as potent as thrombopoietin and eltrombopag in its ability to form mature megakaryocytes using human CD34(+) cells in vitro. It did not affect granulocyte-macrophage or erythroid colony formation. HuVB22B increased the number of proplatelet-forming megakaryocytes more efficiently than thrombopoietin or eltrombopag. Despite stronger phosphorylation of signal transducers and activators of transcription and mitogen-activated protein kinase compared with thrombopoietin in human platelets, huVB22B did not enhance adenosine diphosphate- or collagen-induced platelet aggregation. Eltrombopag did not enhance agonist-induced platelet aggregation. CONCLUSIONS: We found that huVB22B, eltrombopag, and thrombopoietin have different effects on megakaryopoiesis, platelet function, and intracellular signaling. The precise mechanisms for these different biological effects regarding stimulation through the same receptor, Mpl, remain to be elucidated. PMID- 21605621 TI - Localized activation of proteins in a free intracellular space: dependence of cellular morphologies and reaction schemes. AB - Localized activation of proteins in a cell is crucial for the segregation of cellular functions leading, for example, to the development of polarized cells and chemotaxis. If there is a physical diffusion barrier, localized activation of proteins will emerge. In case of no physical barrier, however, it is not clear to what extent the protein activation is localized within a three dimensional intracellular space. In the previous report we showed a simulation result of localized activation of Ca(2+)/calmodulin-dependent kinase II (CaMKII) within a dendritic spine of a neuron, and this localization was enhanced by the diffusion of calmodulin. However, a dendritic spine will act as a physical diffusion barrier. Here, we report that the localization of activated proteins is seen in more simplified morphology with no diffusion barrier. Furthermore, this localization was seen with a simple reaction scheme. In case that a Ca(2+) source was located at the center of the spherical cell with diameter of 20MUm, which is the extreme case without any physical diffusion barrier, the simulation results showed localized activation of a protein around the Ca(2+) source. This localized activation was also enhanced by the diffusion of calmodulin. These localizations were not blurred with time within the tested time range. The reason for the increase in the localization by the diffusion of calmodulin was the replenishment of free calmodulin from surrounding regions. These simulation results indicate that the localized activation of proteins emerges in biological cells without any physical diffusion barrier, and the replenishment of proteins by diffusion can act as an enhancer of localized activation of downstream proteins. PMID- 21605622 TI - Comparison of metabolite profiles in U87 glioma cells and mesenchymal stem cells. AB - Gas chromatography-mass spectrometry (GC-MS) profiles were generated from U87 glioma cells and human mesenchymal stem cells (hMSC). 37 metabolites representing glycolysis intermediates, TCA cycle metabolites, amino acids and lipids were selected for a detailed analysis. The concentrations of these metabolites were compared and Pearson correlation coefficients were used to calculate the relationship between pairs of metabolites. Metabolite profiles and correlation patterns differ significantly between the two cell lines. These profiles can be considered as a signature of the underlying biochemical system and provide snap shots of the metabolism in mesenchymal stem cells and tumor cells. PMID- 21605623 TI - Dynamics of coregulator-induced conformational perturbations in androgen receptor ligand binding domain. AB - Androgen receptor (AR) coregulators modulate ligand-induced gene expression in a tissue specific manner. The molecular events that follow coactivator binding to AR and the mechanisms that govern the sequence-specific effects of AR coregulators are poorly understood. Using consensus coactivator sequence D11 FxxLF and biophysical techniques, we show that coactivator association is followed by conformational rearrangement in AR ligand binding domain (AR-LBD) that is enthalpically and entropically favorable with activation energy of 29.8+/ 4.2 kJ/mol. Further characterization of ARA70 and SRC3-1 based consensus sequences reveal that each coactivator induces a distinct conformational state in the dihydrotestosterone:AR-LBD:coactivator complex. Complementary computational modeling revealed that coactivator induced specific alterations in the backbone flexibility of AR-LBD distant from the site of coactivator binding and that the intramolecular rearrangements in AR-LBD backbone induced by the two coactivator peptides were different. These data suggest that coactivators may impart specificity in the transcriptional machinery by changing the steady-state conformation of AR-LBD. These data provide direct evidence that even in the presence of same ligand, AR-LBD can occupy distinct conformational states depending on its interactions with specific coactivators in the tissues. We posit that this coactivator-specific conformational gating may then dictate subsequent binding partners and interaction/affinity for the DNA-response elements. PMID- 21605624 TI - Molecular effects of oestrogen deprivation in breast cancer. AB - This paper reviews the effects of oestrogen deprivation by third generation aromatase inhibitors on molecular profiles in breast cancers. It particularly focuses on results obtained as a result of pre-operative and neoadjuvant therapy in which primary breast cancers have been biopsied or excised before and during treatment with letrozole, anastrozole or exemestane. Studies may be subdivided into those evaluating early (10-14 days) or late (3-4 months) changes; a single investigation charted sequential changes. Early changes involved downregulation of genes classically induced by oestrogen or associated with cell cycle and proliferation. In contrast, expressions of genes associated with stromal signatures were upregulated. Considerably more genes were changed at later time points; these probably represent not only primary effects on cellular expression but secondary consequences of cell death and clonal selection. Thus, after 3-4 months of treatment mitochondrial-related genes and those associated with cell cycle and cell division were downregulated whereas genes associated with extracellular matrix (ECM) remodelling, vascularization, inflammatory responses and cell adhesion were upregulated. Recently, observations have been reported from a study in which tumours were sequentially sampled to include pretreatment and both early and later time-points. This allowed direct monitoring of the dynamic changes in gene expression. Different patterns of changes in gene expression were identified which were also associated with general differences in sub-cellular distribution of corresponding proteins. The effect of treatment on expression of specific genes and processes such as aromatase, oestrogen receptor (ER), oestrogen-regulated genes, HER2, p53, ribosomal proteins, markers of proliferation, oxidative phosphorylation and stromal response are summarized. PMID- 21605625 TI - Sphingosine-1-phosphate acting via the S1P1 receptor is a downstream signaling pathway in ceramide-induced hyperalgesia. AB - Ceramide is a potent pro-inflammatory sphingolipid recently shown to exert potent hyperalgesic responses in rats. Once generated, ceramide is converted by sphingosine kinase (SphK) 1 and/or 2 to one of its active metabolite sphingosine 1-phosphate (S1P), which in turn signals through G-protein coupled S1P receptors. The objectives of this paper were to define whether ceramide-induced hyperalgesia is driven by S1P. Our results show that intraplantar injection of ceramide in rats led to a time-dependent development of thermal hyperalgesia that was associated with an increase in tumor necrosis factor-alpha (TNF-alpha) in paw tissues. The development of hyperalgesia was significantly attenuated by a soluble TNF receptor I. TNF-alpha is known to activate SphK1, thus S1P production, and our results demonstrate that, the development of hyperalgesia was attenuated in a dose-dependent fashion by a well characterized inhibitor of SphK1 and SphK2 (SK-I) and by a murine monoclonal anti-S1P antibody (LT1002). LT1017, the isotype-matched control monoclonal antibody for LT1002, had no effect. Our results further demonstrate that S1P contributes to the development of hyperalgesia via the S1P receptor 1 subtype (S1PR(1)), since responses were blocked by a well characterized S1PR(1) antagonist, W146, but not by its inactive enantiomer, W140. Collectively, these results provide mechanistic evidence implicating the S1P-to-S1PR(1) pathway as a downstream signaling pathway in ceramide-induced hyperalgesia. Targeting S1P may be a novel therapeutic approach in pain management. PMID- 21605627 TI - Neuroprotective effect of Jatrorrhizine on hydrogen peroxide-induced cell injury and its potential mechanisms in PC12 cells. AB - The neuroprotective effects of Jatrorrhizine from Coptidis Rhizoma against hydrogen peroxide (H(2)O(2))-induced rat pheochromocytoma line PC12 injury and its potential mechanisms were evaluated in the present study. When cells were exposed to H(2)O(2) (200 MUM) for 12h, there was a significant reduction in cell survival and activity of antioxidant enzyme (SOD and HO-1) and LDH release. In addition, increased ROS production, declined MMP and increased production of malondialdehyde (MDA) were observed. Preincubation of cells with Jatrorrhizine (0.01-10.0 MUM) 24h prior to H(2)O(2) exposure markedly elevated cell viability and activities of antioxidant enzyme (SOD and HO-1), prevented LDH release and lipid peroxidation (MDA) production, attenuated the decrease of MMP and scavenged ROS formation. Jatrorrhizine also attenuated caspase-3 activation of the downstream cascade following ROS. Our results suggest that Jatrorrhizine holds potential for neuroprotective effects against H(2)O(2)-induced injury. PMID- 21605626 TI - Visuo-motor gain adaptation and generalization following left hemisphere stroke. AB - During gain adaptation, participants must learn to adapt to novel visuo-motor mappings in which the movement amplitudes they produce do not match the visual feedback they receive. The aim of the present study was to investigate the neural substrates of gain adaptation by examining its possible disruption following left hemisphere stroke. Thirteen chronic left hemisphere stroke patients and five healthy right-handed control subjects completed three experimental phases involving reaching with the left hand, which was the less-affected hand in patients. First, participants reached without visual feedback to six different target locations (baseline phase). Next, in the adaptation phase, participants executed movements to one target under conditions in which the perceived movement distance was 70% of the produced movement distance. Last, in order to test the generalization of this new visuomotor mapping, participants made movements without visual feedback to untrained target locations (generalization phase). Significant between-patient differences were observed during adaptation. Lesion analyses indicated that these between-patient differences were predicted by the amount of damage to the supramarginal gyrus (Brodmann area 40). In addition, patients performed more poorly than controls in the generalization phase, suggesting that different processes are involved in adaptation and generalization periods. PMID- 21605628 TI - In vitro fertilization: four decades of reflections and promises. AB - BACKGROUND: In 2010, Robert Edwards was awarded the Nobel Prize in Medicine for his pioneering work in the development of in vitro fertilization, a field that has touched millions of lives across the globe. Edwards dedicated his career to helping couples overcome infertility. He first established principles of early embryo development that served as the foundation for his later work. In the 1960s, he achieved the first human fertilized oocyte in vitro while at the Johns Hopkins Hospital. He then continued his work at Cambridge University. In 1978, the world witnessed the birth of the first "test tube baby". This achievement is a landmark not only in the reproductive sciences but also in the history of mankind's technological evolution. SCOPE OF REVIEW: This article outlines the development and progression of IVF from its infancy to the refined and broadly utilized technology offered to patients today. We describe the evolution of the field and the current state of IVF, including its current technological and social challenges. MAJOR CONCLUSIONS: We congratulate Professor Edwards for his well-deserved recognition as Nobel Laureate in Medicine. GENERAL SIGNIFICANCE: This article is a tribute to Edwards for his exceptional accomplishments in this specific and rewarding field of modern medicine. PMID- 21605629 TI - Structure-activity relationships of various amino-hydroxy-benzenesulfonic acids and sulfonamides as tyrosinase substrates. AB - BACKGROUND: o-Aminophenols have been long recognised as tyrosinase substrates. However their exact mode of interaction with the enzyme's active site is unclear. Properly vic-substituted o-aminophenols could help gain some insight into tyrosinase catalytic mechanism. METHODS: Eight vic-substituted o-aminophenols belonging to two isomeric series were systematically evaluated as tyrosinase substrates and/or activators and/or inhibitors, by means of spectrophotometric techniques and HPLC-MS analysis. Some relevant kinetic parameters have also been obtained. RESULTS: Four o-aminophenolic compounds derived from 3 hydroxyorthanilic acid (2-amino-3-hydroxybenzenesulfonic acid) and their four counterparts derived from the isomeric 2-hydroxymetanilic acid (3-amino-2 hydroxybenzenesulfonic acid) were synthesised and tested as putative substrates for mushroom tyrosinase. While the hydroxyorthanilic derivatives were quite inactive as both substrates and inhibitors, the hydroxymetanilic compounds on the contrary all acted as substrates for the enzyme, which oxidised them to the corresponding phenoxazinone derivatives. GENERAL SIGNIFICANCE: Based on the available structures of the active sites of tyrosinases, the different affinities of the four metanilic derivatives for the enzyme, and their oxidation rates, we propose a new hypothesis regarding the interaction between o-aminophenols and the active site of tyrosinase that is in agreement with the obtained experimental results. PMID- 21605630 TI - Heat shock proteins in oncology: diagnostic biomarkers or therapeutic targets? AB - Heat shock proteins (HSP) are a family of proteins induced in cells exposed to different insults. This induction of HSPs allows cells to survive stress conditions. Mammalian HSPs have been classified into six families according to their molecular size: HSP100, HSP90, HSP70, HSP60, HSP40 and small HSPs (15 to 30kDa) including HSP27. These proteins act as molecular chaperones either helping in the refolding of misfolded proteins or assisting in their elimination if they become irreversibly damaged. In recent years, proteomic studies have characterized several different HSPs in various tumor types which may be putative clinical biomarkers or molecular targets for cancer therapy. This has led to the development of a series of molecules capable of inhibiting HSPs. Numerous studies speculated that over-expression of HSP is in part responsible for resistance to many anti-tumor agents and chemotherapeutics. Hence, from a pharmacological point of view, the co-administration of HSP inhibitors together with other anti-tumor agents is of major importance in overcoming therapeutic resistance. In this review, we provide an overview of the current status of HSPs in autoimmune, cardiovascular, and neurodegenerative diseases with special emphasis on cancer. PMID- 21605631 TI - Rat strain differences in restraint stress-induced brain cytokines. AB - Induction of brain cytokines during times of stress has potent effects on altering behavior, mood, and cognitive functioning. Currently, it is unknown why exposure to some stressors such as tailshock and footshock elevate brain cytokines, while exposure to swim, predator odor, and restraint stress do not. Recent data indicate that brain noradrenergic signaling mediates brain cytokine production suggests magnitude of norepinephrine release during stress may be critical in initiating brain cytokine production. The aim of the current study was to investigate stress-induced brain cytokines between rat strains that differ in their magnitude of stress responsiveness as measured by brain norepinephrine and HPA responses. Sprague-Dawley and Fischer rats were placed in a restraint bag for 1 h or 2 h and sacrificed immediately following stressor termination. Exposure to restraint significantly elevated hypothalamic interleukin (IL)-1beta and IL-1 receptor type (R) 2 mRNA after 1 h and IL-1beta protein after 2 h in the high stress responsive Fischer rats, but not in Sprague-Dawley rats. IL-6, IL 1R1, Il-1 receptor antagonist (RA), and cyclooxygenase (Cox)-2 mRNA were not altered and neither there was expression of any cytokines in the hippocampus or circulating cytokines in either strain. Administration of desipramine (a norepinephrine reuptake inhibitor) to Sprague-Dawley rats was sufficient either alone or in combination with stress to increase IL-1beta mRNA in the hypothalamus and desipramine combined with stress was sufficient to increase IL-1R2 mRNA in the hypothalamus. These data support our hypothesis that there is a critical threshold of brain norepinephrine necessary to stimulate brain cytokines, which may help to explain why severe stressors are more commonly reported to induce brain cytokines. These data also suggest an organisms' susceptibility to stress induced brain cytokine production, depends on responsiveness and regulation of noradrenergic neurons. PMID- 21605633 TI - The role of glutamate receptors in traumatic brain injury: implications for postsynaptic density in pathophysiology. AB - Traumatic brain injury (TBI) is the major cause of death and disability, and the incidence of TBI continues to increase rapidly. In recent years, increasing attention has been paid to an important structure at the postsynaptic membrane: the postsynaptic density (PSD). Glutamate receptors, as major components of the PSD, are highly responsive to alterations in the glutamate concentration at excitatory synapses and activate intracellular signal transduction via calcium and other second messengers following TBI. PSD scaffold proteins (PSD-95, Homer, and Shank), which anchor glutamate receptors and form a network structure, also have potential effects on these downstream signaling pathways. The changes in the function and structure of these major PSD proteins are also induced by TBI, indicating that there is a more complicated mechanism associated with PSD proteins in the pathophysiological process of TBI. PMID- 21605634 TI - APP/SOD1 overexpressing mice present reduced neuropathic pain sensitivity. AB - There are controversies regarding pain expression in mentally disabled people, including Down syndrome patients. The aim of this study was to examine neuropathic pain-related behavior and peripheral nerve regeneration in mouse model of Down syndrome. Sciatic nerves of double transgenic mice, overexpressing both amyloid precursor protein (APP) and Cu/Zn superoxide dismutase (SOD1) genes, and FVB/N wild type mice were transected and immediately resutured. Evaluation of autotomy and functional recovery was carried out during 4-week follow-up. We found markedly less severe autotomy in transgenic animals, although the onset of autotomy was significantly delayed in control mice. Interestingly, neuroma formation at the injury site was significantly more prominent in transgenic animals. Sciatic function index outcome was better in transgenic mice than in wild-type group. Histological evaluation revealed no statistically significant differences in the number of GAP-43-positive growth cones and macrophages in the distal stump of the transected nerve between groups. However, in transgenic animals, the regenerating axons were arranged more chaotically. The number of Schwann cells in the distal stump of the transected nerves was significantly lower in transgenic mice. The number of surviving motoneurons was markedly decreased in transgenic group. We measured also the atrophy of denervated muscles and found it decreased in APP/SOD1 overexpressing mice. Taken together, in this model of Down syndrome, we observed increased neuroma formation and decreased autotomy after peripheral nerve injury. Our findings suggest that APP/SOD1 overexpressing mice are less sensitive for neuropathic pain associated with neuroma. PMID- 21605632 TI - Neurons responsive to face-view in the primate ventrolateral prefrontal cortex. AB - Studies have indicated that temporal and prefrontal brain regions process face and vocal information. Face-selective and vocalization-responsive neurons have been demonstrated in the ventrolateral prefrontal cortex (VLPFC) and some prefrontal cells preferentially respond to combinations of face and corresponding vocalizations. These studies suggest VLPFC in nonhuman primates may play a role in communication that is similar to the role of inferior frontal regions in human language processing. If VLPFC is involved in communication, information about a speaker's face including identity, face-view, gaze, and emotional expression might be encoded by prefrontal neurons. In the following study, we examined the effect of face-view in ventrolateral prefrontal neurons by testing cells with auditory, visual, and a set of human and monkey faces rotated through 0 degrees , 30 degrees , 60 degrees , 90 degrees , and -30 degrees . Prefrontal neurons responded selectively to either the identity of the face presented (human or monkey) or to the specific view of the face/head, or to both identity and face view. Neurons which were affected by the identity of the face most often showed an increase in firing in the second part of the stimulus period. Neurons that were selective for face-view typically preferred forward face-view stimuli (0 degrees and 30 degrees rotation). The neurons which were selective for forward face-view were also auditory responsive compared to other neurons which responded to other views or were unselective which were not auditory responsive. Our analysis showed that the human forward face (0 degrees ) was decoded better and also contained the most information relative to other face-views. Our findings confirm a role for VLPFC in the processing and integration of face and vocalization information and add to the growing body of evidence that the primate ventrolateral prefrontal cortex plays a prominent role in social communication and is an important model in understanding the cellular mechanisms of communication. PMID- 21605635 TI - Pentacyclic triterpenes from the resin of Liquidambar formosana. AB - Two new pentacyclic triterpenes and eight known pentacyclic triterpenes were isolated from the petroleum ether extract of Liquidambaris Resina. The structural elucidation of these compounds was determined by spectroscopic data interpretation. Their cytotoxic and antiplatelet aggregation activities were examined to find potent cytotoxic and antiplatelet aggregation compounds from natural resources. The results showed that 3-keto oleane triterpenes had strong cytotoxicity against MDA-MB-435S cancer cells and that 28-carboxyl oleane triterpenes possessed significant inhibition of platelet aggregation induced by ADP. PMID- 21605636 TI - Ginsenoside Rh1 inhibits the invasion and migration of THP-1 acute monocytic leukemia cells via inactivation of the MAPK signaling pathway. AB - Ginsenoside Rh1 has been reported to possess antiallergic and anti-inflammatory activities, but its effects on monocytes remain to be determined. Herein, we investigated the effects of Rh1 on the expression of MCP-1 and CCR2, activation of MAPK signaling, and chemotaxis of monocytes. Treatment of Rh1 decreased the levels of MCP-1 and CCR2 and the expression of VLA5 and activated beta1 integrin on the cell surface, and attenuated the phosphorylation of MAPKs. Based on these results, the inhibitory effects of Rh1 on monocyte function should be regarded as a promising new anti-inflammatory response with a potential therapeutic role against inflammation-dependent diseases. PMID- 21605637 TI - In vitro suppression of quercetin on hypertrophy and extracellular matrix accumulation in rat glomerular mesangial cells cultured by high glucose. AB - Quercetin's protective effects on the glomerulosclerosis of diabetic nephropathy (DN) in rat mesangial cells were investigated. The cell cycles, type IV collagen and laminin, TGF-beta(1) mRNA, Smad 2/3 and Smad 7, and activities of cell antioxidases were measured. Compared with the high glucose group, quercetin may decrease the cell percentages of G(0)/G(1) phase, Smad 2/3 expression, laminin and type IV collagen, and TGF-beta(1) mRNA level significantly. The antioxidant capacity, the cell percentages of S phase and Smad 7 expression was significantly increased by quercetin. These results suggest that quercetin is a protective agent against glomerulosclerosis in DN. PMID- 21605638 TI - Activity of taspine isolated from Radix et Rhizoma Leonticis against estrogen receptor-positive breast cancer. AB - The aim of our study was to investigate the effect of taspine isolated from Radix et Rhizoma Leonticis on the growth of oestrogen-receptor-positive breast cancer xenografts in vivo and the possible mechanism for this action. In vivo taspine studies were conducted with ZR-75-30 human breast cancer xenografts in athymic mice, and then tumors tissue lysates were subjected to Western blotting analysis of estrogen receptor (ER) and progesterone receptor (PR), which was related to inhibition of tumor growth. For in vitro study, cell proliferation, cell cycle and apoptosis of ZR-75-30 cell treated with or without taspine were detected. ER and PR expression were detected by Western blotting, ER and PR mRNA were verified by reverse transcription polymerase chain reaction (RT-PCR). The results showed that treatment over 14 days resulted in a sustained and significant reduction in xenograft weight compared with untreated controls. Cell cycle and apoptosis analysis documented that taspine could change cell cycle and induce cell apoptosis. There was a significant decrease observed in the expression of ER and PR both in tumor tissue and cells after treatment with taspine, RT-PCR also showed a reduction in the expression of mRNA for ER and PR in the group treated with taspine. Taken together, these results suggested that taspine might serve as a promising candidate of ER antagonist in the treatment of oestrogen-independent breast cancer. PMID- 21605639 TI - Hypoglycemic effect of lupin seed gamma-conglutin in experimental animals and healthy human subjects. AB - A lupin seed gamma-conglutin-enriched preparation was tested in a glucose overload trial with both murine models and adult healthy volunteers. The results with rats showed a dose-dependent significant decrease of blood glucose concentration, which confirmed previous findings obtained with the purified protein. Moreover, three test-product doses equivalent to 630, 315, and 157.5 mg gamma-conglutin, orally administered 30 min before the carbohydrate supply, showed a relevant hypoglycemic effect in human trials. Insulin concentrations were not significantly affected. The general hematic parameters did not change at all. This is the first report on the glucose-lowering effect of lupin gamma conglutin in human subjects. PMID- 21605640 TI - Influence of saponin plants on the volatile fraction of thyme in herbal teas. AB - Combinations of thyme, cowslip and liquorice roots are often used in the treatment of upper respiratory tract infections. Therefore the volatile fraction of herbal teas prepared from thyme (Thymus vulgaris) and the effect of combining with cowslip (Primula veris/P. elatior) and liquorice roots (Glycyrrhiza glabra) on the volatiles were analyzed. Volatile compounds were isolated by hydrodistillation and solid phase extraction and analyzed by GC-MS. Thymol was also quantified by HPLC. The total amount of volatiles as well the thymol content was decreased with increasing proportions of cowslip or liquorice in the infusion extracts whereas the proportion of monoterpene hydrocarbons increased. PMID- 21605641 TI - Functional coupling of transcription factor HiNF-P and histone H4 gene expression during pre- and post-natal mouse development. AB - Transcription factor Histone Nuclear Factor P (HiNF-P; gene symbol Hinfp) mediates cell cycle control of histone H4 gene expression to support the packaging of newly replicated DNA as chromatin. The HiNF-P/p220(NPAT) complex controls multiple H4 genes in established human cell lines and is critical for cell proliferation. The mouse Hinfp(LacZ) null allele causes early embryonic lethality due to a blastocyst defect. However, neither Hinfp function nor its temporal expression relative to histone H4 genes during fetal development has been explored. Here, we establish that expression of Hinfp is biologically coupled with expression of twelve functional mouse H4 genes during pre- and post natal tissue-development. Both Hinfp and H4 genes are robustly expressed at multiple embryonic (E) days (from E5.5 to E15.5), coincident with ubiquitous LacZ staining driven by the Hinfp promoter. Five highly expressed mouse H4 genes (Hist1h4d, Histh4f, Hist1h4m and Hist2h4) account for >90% of total histone H4 mRNA throughout development. Post-natal expression of H4 genes in mice is most evident in lung, spleen, thymus and intestine, and with few exceptions (e.g., adult liver) correlates with Hinfp gene expression. Histone H4 gene expression decreases butHinfp levels remain constitutive upon cell growth inhibition in culture. The in vivo co-expression of Hinfp and histone H4 genes is consistent with the biological function of Hinfp as a principal transcriptional regulator of histone H4 gene expression during mouse development. PMID- 21605642 TI - Effects of maternal cadmium exposure during late pregnant period on testicular steroidogenesis in male offspring. AB - Cadmium (Cd) is a testicular toxicant and endocrine disruptor. In the present study, we investigated the effects of maternal Cd exposure during the late pregnant period on testicular development and steroidogenesis in male offspring. Pregnant mice were injected intraperitoneally with CdCl(2) (0.5mg/kg) daily from gestational day (gd) 13 to gd 17. As expected, fetal weight and crown length were significantly decreased in pups whose mothers were exposed to Cd. Importantly, absolute and relative weights of testes were significantly decreased in male fetuses. In addition, maternal Cd exposure during pregnancy markedly reduced serum T level and downregulated the expression of steroidogenic acute regulatory (StAR) protein, P450scc, P45017alpha and 17beta-HSD in testes of male fetuses. Interestingly, the level of serum and testicular T at adulthood remained decreased in male offspring of Cd-exposed mice. Correspondingly, the expression of testicular P450scc was downregulated in male adult offspring whose mothers were exposed to Cd during pregnancy. Fertility analysis found that the number of live fetuses per litter in F2 generation was significantly decreased in Cd treated group. Additional experiment showed that placental Cd level was increased about 750 folds in dams injected with Cd. However, only traces of blood Cd was measured in fetuses whose mothers were exposed to Cd during the late pregnant period. Taken together, these results suggest that placenta could deter most of Cd from passing from dams to fetuses. The impairments on testicular steroidogenesis in male offspring could not be attributed to a direct action of Cd on fetal testes. PMID- 21605643 TI - Thirteenth International Medical Chemical Defence Conference 2011 "New developments in the treatment of intoxications by chemical warfare agents with focus on neurotoxic agents". PMID- 21605644 TI - Stabilization of tetanus toxoid formulation containing aluminium hydroxide adjuvant against freeze-thawing. AB - Exposure to subzero temperature leads to loss of vaccine potency. This can happen due to degradation of adjuvant surface and/or inactivation of the antigen. When adsorbed on aluminium hydroxide and subjected to freeze-thawing, tetanus toxoid was desorbed from the gel matrix and the preparation was found to lose its antigenicity. Analyses showed that the gel particles were denatured after freezing. When freeze-thawing was carried out in the presence of glucose, sorbitol and arginine, the degradation of gel particles was inhibited. A higher fraction of the protein could be retained on the gel. However, the antigenicity of these preparations was quite low. In the presence of trehalose, the protein could be partially retained on aluminium hydroxide. Being a cryoprotectant, trehalose was also able to inhibit the freezing-induced denaturation of tetanus toxoid, which resulted in retention of antigenicity of the adjuvanted toxoid. PMID- 21605645 TI - Drug targeting to inflammation: studies on antioxidant surface loaded diclofenac liposomes. AB - Inflammation is associated with enhanced vascular permeability, production of inflammatory markers and over production of reactive oxygen species (ROS) with depletion of endogenous antioxidants. Several drug targeting approaches to inflammation taking clues from these events have been evolved. Surprisingly, a drug targeting approach utilizing abundant oxidative stress at inflammatory site has not been followed. Antioxidant surface loaded liposomes might preferentially localize at inflammatory sites via redox interaction where at high level of ROS exist. The present study was focused to investigate the role of antioxidant as a targeting ligand on the surface of liposome employing rat granuloma air pouch model of inflammation. We developed conventional and antioxidant loaded diclofenac (DFS) liposomes (co-enzyme Q10 and ascorbyl palmitate) for i.v. administration and characterized for vesicle size, zeta potential and percent entrapment. In vivo drug targeting studies showed an increase in AUC, therapeutic availability of DFS in air pouch fluid (APF) and APF/serum DFS concentration ratios from antioxidant loaded liposomes compared to conventional liposomes and drug solution. The promising results suggest the role of antioxidant as a possible ligand in drug targeting to a site where at abundant ROS exist. PMID- 21605646 TI - A compressibility and compactibility study of real tableting mixtures: the impact of wet and dry granulation versus a direct tableting mixture. AB - The purpose of this study was to investigate the influence of various powder agglomeration processes on tableting mixture flow and compaction properties. Four different granulation methods of the same model placebo formulation were tested at a semi-industrial scale and their properties were compared to those of the directly compressed mixture. The wet granulated mixtures had superior flow properties compared to other mixtures and showed better compressibility, measured by the Heckel and Walker models. This was attributed to work hardening due to the double particle processing and also to shorter contact times due to higher initial densities of dry granulated mixtures, allowing a shorter time for deformation. A strong linear correlation was established between the Heckel and Walker coefficients, which was further confirmed by the net energy results of force-displacement measurements. It was shown that the Walker model had slightly better discriminative power to differentiate tableting mixtures according to compressibility. The compactibility was considerably lower for the slugged mixture; however, the roller-compacted mixture produced tablets with unexpectedly high tensile strength. In conclusion, it is important to emphasize that general assumptions like higher porosity => better compressibility or better compressibility => better compactibility cannot be established for complex tableting mixtures. PMID- 21605647 TI - Real-time in-die compaction monitoring of dry-coated tablets. AB - The practicability of a pulse-echo ultrasonic approach developed for the real time quality monitoring of dry-coated tablets in the tablet press during compaction is evaluated. The punch-tablet interface (i.e., steel-tablet) is the boundary condition that dictates the viability of acoustic in-die compaction monitoring. The current study utilizes compacted tablets with a simulated punch tablet interface to achieve the required waveform detectability levels needed for in-die compaction monitoring. The geometric and mechanical properties of a dry coated tablet are crucial to its structural functions and therapeutic effectiveness, therefore they are monitored especially when the control of dissolution rates of their active ingredients are critically important. Acquired pulse-echo ultrasonic waveforms in the tablet could provide the time-of-flight information needed to determine the thickness, elasticity and/or integrity of the relevant layer, and bonding quality between layers depending on the given parameters. Since the amplitudes of the reflected waves are extremely low due to the high acoustic impedance mismatches of tablet materials and die/punch materials, signal processing techniques are required to extract the wave arrival times. In current study, it is demonstrated that the reflection of an ultrasonic pulse generated by a transducer embedded in a die or a punch from the coat-core interface can be acquired by the same transducer. PMID- 21605649 TI - In vitro anthelmintic activity of crude extracts of five medicinal plants against egg-hatching and larval development of Haemonchus contortus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Senna occidentalis, Leonotis ocymifolia, Leucas martinicensis, Rumex abyssinicus, and Albizia schimperiana are traditionally used for treatment of various ailments including helminth infection in Ethiopia. MATERIALS AND METHODS: In vitro egg hatch assay and larval development tests were conducted to determine the possible anthelmintic effects of crude aqueous and hydro-alcoholic extracts of the leaves of Senna occidentalis, aerial parts of Leonotis ocymifolia, Leucas martinicensis, Rumex abyssinicus, and stem bark of Albizia schimperiana on eggs and larvae of Haemonchus contortus. RESULTS: Both aqueous and hydro-alcoholic extracts of Leucas martinicensis, Leonotis ocymifolia and aqueous extract of Senna occidentalis and Albizia schimperiana induced complete inhibition of egg hatching at concentration less than or equal to 1mg/ml. Aqueous and hydro-alcoholic extracts of all tested medicinal plants have shown statistically significant and dose dependent egg hatching inhibition. Based on ED(50), the most potent extracts were aqueous and hydro-alcoholic extracts of Leucas martinicensis (0.09 mg/ml), aqueous extracts of Rumex abyssinicus (0.11 mg/ml) and Albizia schimperiana (0.11 mg/ml). Most of the tested plant extracts have shown remarkable larval development inhibition. Aqueous extracts of Leonotis ocymifolia, Leucas martinicensis, Albizia schimperiana and Senna occidentalis induced 100, 99.85, 99.31, and 96.36% inhibition of larval development, respectively; while hydro-alcoholic extracts of Albizia schimperiana induced 99.09 inhibition at the highest concentration tested (50mg/ml). Poor inhibition was recorded for hydro-alcoholic extracts of Senna occidentalis (9%) and Leonotis ocymifolia (37%) at 50mg/ml. CONCLUSIONS: The overall findings of the current study indicated that the evaluated medicinal plants have potential anthelmintic effect and further in vitro and in vivo evaluation is indispensable to make use of these plants. PMID- 21605648 TI - Cochlear infrastructure for electrical hearing. AB - Although the cochlear implant is already the world's most successful neural prosthesis, opportunities for further improvement abound. Promising areas of current research include work on improving the biological infrastructure in the implanted cochlea to optimize reception of cochlear implant stimulation and on designing the pattern of electrical stimulation to take maximal advantage of conditions in the implanted cochlea. In this review we summarize what is currently known about conditions in the cochlea of deaf, implanted humans and then review recent work from our animal laboratory investigating the effects of preserving or reinnervating tissues on psychophysical and electrophysiological measures of implant function. Additionally we review work from our human laboratory on optimizing the pattern of electrical stimulation to better utilize strengths in the cochlear infrastructure. Histological studies of human temporal bones from implant users and from people who would have been candidates for implants show a range of pathologic conditions including spiral ganglion cell counts ranging from approximately 2% to 92% of normal and partial hair cell survival in some cases. To duplicate these conditions in a guinea pig model, we use a variety of deafening and implantation procedures as well as post-deafening therapies designed to protect neurons and/or regenerate neurites. Across populations of human patients, relationships between nerve survival and functional measures such as speech have been difficult to demonstrate, possibly due to the numerous subject variables that can affect implant function and the elapsed time between functional measures and postmortem histology. However, psychophysical studies across stimulation sites within individual human subjects suggest that biological conditions near the implanted electrodes contribute significantly to implant function, and this is supported by studies in animal models comparing histological findings to psychophysical and electrophysiological data. Results of these studies support the efforts to improve the biological infrastructure in the implanted ear and guide strategies which optimize stimulation patterns to match patient-specific conditions in the cochlea. PMID- 21605650 TI - Pharmacokinetics comparative study of a novel Chinese traditional herbal formula and its compatibility. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Da Chuan Xiong Decoction Compound preparation (DCXDCP), the formulation of a classical Chinese prescription recorded in "Xuanminglunfang", was clinically employed to treat migraine's disease. AIM OF THE STUDY: In order to investigate the influence of compatibility on the pharmacokinetics of the active ingredient gastrodin (GAS), the comparative evaluations on pharmacokinetics of DCXDCP with various combinations of its constituent herbs in plasma after oral administration were studied. MATERIALS AND METHODS: The rats were randomly assigned to four groups and orally administered with different prescription proportion of Gastrodia elata Bl. and Ligusticum chuanxiong Hort. (1:0; 1:0.25; 1:2.1; 1:4.2), respectively. At different predetermined time points after administration, the concentrations of GAS in rat plasma were determined by using HPLC, and main pharmacokinetic parameters were investigated. RESULTS: The results showed that the pharmacokinetic parameters, AUC and C(max) of GAS were dramatically different (p<0.05) after oral administration of G. elata Bl. and the different combinations of its constituent herbs. CONCLUSIONS: These indicated that the compatibility effects of other ingredients present in DCXDCP could affect the pharmacokinetics of the prescription. PMID- 21605651 TI - Transcriptional profiling analysis of HMP-treated rats with experimentally induced myocardial infarction. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Heart-protecting musk pill (HMP), a traditional Chinese medicine prescription, has extensive cardioprotective effects against angina pectoris and myocardial infarction (MI), but the molecular mechanism behind such cardio protective effects still remains unclear. In this article, we aim to investigate the effect of HMP on mRNA expression in MI rat. MATERIALS AND METHODS: A rat model of coronary artery ligation was used to assess the cardioprotective effects of HMP. Microarray technology was applied to detect the gene expression in the heart of MI rats treated with HMP. Besides, quantitative real-time PCR was performed to verify the microarray results. RESULTS: Our results showed that HMP could ameliorate heart function, and diminish infarct size in MI rats. Compared with sham-operated rats, 500 genes' expression changed, with 234 genes down-regulated and 266 genes up-regulated. And the expression of 129 genes was different between HMP administrated rats and MI rats, with 22 genes down-regulated and 107 genes up-regulated. CONCLUSIONS: Citrate cycle (TCA cycle), Valine, leucine and isoleucine degradation, Glycolysis/Gluconeogenesis and Pyruvate metabolism pathway are probably involved in the cardioprotective effects of HMP. PMID- 21605652 TI - Pharmacokinetic study of the prokinetic compounds meranzin hydrate and ferulic acid following oral administration of Chaihu-Shugan-San to patients with functional dyspepsia. AB - AIM OF THE STUDY: The prokinetic activity of ferulic acid derived from Ligusticum chuanxiong hort in the Chaihu-Shugan-San formula has been shown to be similar to Chaihu-Shugan-San, a popular traditional Chinese medicine for treating functional dyspepsia. The effects of meranzin hydrate, a compound isolated from Fructus aurantii in the Chaihu-Shugan-San formula, are unclear, as the pharmacokinetics have never been studied in patients with functional dyspepsia. This study aimed to describe the pharmacokinetics of ferulic acid and merazin hydrate by evaluating the prokinetics induced by Chaihu-Shugan-San and meranzin hydrate. MATERIALS AND METHODS: Gastric emptying and intestinal transit were measured after oral administration of a single dose of Chaihu-Shugan-San or meranzin hydrate in rats. The tone of rat ileum was selected as direct evidence of the prokinetic activity of meranzin hydrate. Patients with functional dyspepsia were recruited, and meranzin hydrate and ferulic acid were identified by ultra performance liquid chromatography with tandem mass spectrometry in the plasma of patients following a single oral administration of Chaihu-Shugan-San. The resulting pharmacokinetic properties were determined by ultra performance liquid chromatography coupled to photo diode array. RESULTS: In rats, single doses of Chaihu-Shugan-San (20 g/kg) and meranzin hydrate (28 mg/kg) significantly accelerated gastric emptying and intestinal transit (Chaihu-Shugan-San: 68.9 +/- 5.6% and 72.3 +/- 4.7%, meranzin hydrate: 72.9 +/- 3.8% and 75.2 +/- 3.1%) compared with the control (55.45 +/- 3.7% and 63.51 +/- 5.1%, P<0.05), showing similar results as cisapride (69.6 +/- 4.8% and 71.6 +/- 6.3%). Meranzin hydrate (30, 100 MUmol/L) directly increased the amplitude of rat ileum compared with the control (P<0.01). The pharmacokinetics profiles of meranzin hydrate and ferulic acid in patient plasma was fitted with a two-compartment model detected by a simple, rapid and accurate UPLC method. Time to reach peak concentration of meranzin hydrate (0.371 mg/L) and ferulic acid (0.199 mg/L) was 23.57 min and 27.50 min, respectively. The elimination half-life and area under the concentration-time curve from t=0 to the last time of meranzin hydrate and ferulic acid were 139.53 min and 31.445 MUg min/mL and 131.27 min and 14.835 MUg min/mL, respectively. The absorption constant and volume of distribution of meranzin hydrate and ferulic acid were 0.185 +/- 0.065 min(-1) and 3782.89 +/- 2686.72 L/kg and 0.524 +/- 0.157 min(-1) and 11713 +/- 7618.68 L/kg, respectively. The experimental results of the pharmacokinetic parameters of meranzin hydrate and ferulic acid indicate that they were absorbed and distributed rapidly. CONCLUSIONS: The pharmacodynamics and pharmacokinetics of prokinetic Chaihu-Shugan-San and its compounds are useful for monitoring Chaihu Shugan-San formulas in clinical practice and for understanding therapeutic mechanisms. PMID- 21605653 TI - The effects of Buyang Huanwu Decoction on hemorheological disorders and energy metabolism in rats with coronary heart disease. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine (TCM) formula, has been recognized as a clinical treatment for coronary heart disease (CHD) with qi deficiency and blood stasis syndrome. The effects of BYHWD on hemorheological disorders and energy metabolism in CHD with qi deficiency and blood stasis syndrome are still unclear. AIM OF THE STUDY: To investigate whether the ameliorative effects of BYHWD on CHD rats with qi deficiency and blood stasis syndrome are associated with the regulation of hemorheological disorders and energy metabolism. MATERIALS AND METHODS: The rats were lavaged with 25.68, 12.84 and 6.42 g/kg BYHWD (g weight of mixed crude drugs/kg body weight), respectively, once a day for 21 days. The body weight, exhaustive swimming time and tongue characters were observed and recorded. The whole blood viscosity and plasma viscosity were determined by hematology analyzer. The level of fibrinogen (Fbg) in plasma was determined by using Fbg assay kit. The platelet aggregation induced by adenosine diphosphatase was measured by semi-automatic whole blood platelet analyzer. The level of blood glucose (BG) was determined by LifeScan. The activity of Na(+)-K(+)-ATPase in heart tissues was detected by spectrophotometer. RESULTS: BYHWD improved the exterior signs of qi deficiency and blood stasis syndrome in rats with CHD, including the body weight, exhaustive swimming time and tongue quality. The whole blood viscosity in rats treated with 25.68 g/kg BYHWD decreased at the shear rate of 10s(-1) (P<0.05) and the plasma viscosity decreased in rats treated with 25.68 and 12.84 g/kg BYHWD (P<0.05). The plasma Fbg level and the platelet aggregation decreased in rats treated with 25.68 g/kg BYHWD (P<0.01). The results also revealed that the BG level decreased and the Na(+)-K(+)-ATPase activity in heart tissues increased in rats treated with 25.68 and 12.84 g/kg BYHWD (P<0.01). CONCLUSION: The results suggest that the ameliorative effects of BYHWD on CHD rats with qi deficiency and blood stasis syndrome are mediated by the improvement of hemorheological disorders and energy metabolism. PMID- 21605654 TI - Bioactive proteins from mushrooms. AB - Mushrooms have been used as food or medicine for thousands of years. Due to low fat content and absence of cholesterol, many mushrooms are excellent sources of protein. There are various mushroom proteins with interesting biological activities, such as lectins, fungal immunomodulatory proteins (FIP), ribosome inactivating proteins (RIP), ribonucleases, laccases, and other proteins, which have become popular sources of natural antitumor, antiviral, antimicrobial, antioxidative, and immunomodulatory agents. The aim of this review is to update the present status of bioactive proteins in mushrooms, and to discuss their biomedical potential and future prospectives. PMID- 21605655 TI - Impact of Francisella tularensis pilin homologs on pilus formation and virulence. AB - Francisella tularensis is a facultative intracellular bacterium and the causative agent of tularemia. Virulence factors for this bacterium, particularly those that facilitate host cell interaction, remain largely uncharacterized. However, genes homologous to those involved in type IV pilus structure and assembly, including six genes encoding putative major pilin subunit proteins, are present in the genome of the highly virulent Schu S4 strain. To analyze the roles of three putative pilin genes in pili structure and function we constructed individual pilE4, pilE5, and pilE6 deletion mutants in both the F. tularensis tularensis strain Schu S4 and the Live Vaccine Strain (LVS), an attenuated derivative strain of F. tularensis holarctica. Transmission electron microscopy (TEM) of Schu S4 and LVS wild-type and deletion strains confirmed that pilE4 was essential for the expression of type IV pilus-like fibers by both subspecies. By the same method, pilE5 and pilE6 were dispensable for pilus production. In vitro adherence assays with J774A.1 cells revealed that LVS pilE4, pilE5, and pilE6 deletion mutants displayed increased attachment compared to wild-type LVS. However, in the Schu S4 background, similar deletion mutants displayed adherence levels similar to wild type. In vivo, LVS pilE5 and pilE6 deletion mutants were significantly attenuated compared to wild-type LVS by intradermal and subcutaneous murine infection, while no Schu S4 deletion mutant was significantly attenuated compared to wild-type Schu S4. While pilE4 was essential for fiber expression on both Schu S4 and LVS, neither its protein product nor the assembled fibers contributed significantly to virulence in mice. Absent a role in pilus formation, we speculate PilE5 and PilE6 are pseudopilin homologs that comprise, or are associated with, a novel type II related secretion system in Schu S4 and LVS. PMID- 21605656 TI - Localization of Chlamydia trachomatis hypothetical protein CT311 in host cell cytoplasm. AB - The chlamydia-specific hypothetical protein CT311 was detected both inside and outside of the chlamydial inclusions in Chlamydia trachomatis-infected cells. The extra-inclusion CT311 molecules were distributed in the host cell cytoplasm with a pattern similar to that of CPAF, a known Chlamydia-secreted protease. The detection of CT311 was specific since the anti-CT311 antibody labeling was only removed by absorption with CT311 but not CPAF fusion proteins. In addition, both anti-CT311 and anti-CPAF antibodies only detected their corresponding endogenous proteins without cross-reacting with each other or any other antigens in the whole cell lysates of C. trachomatis-infected cells. Although both CT311 and CPAF proteins were first detected 12 h after infection, localization of CT311 into host cell cytosol was delayed until 24 h while CPAF secretion into host cell cytosol was already obvious by 18 h after infection. The host cell cytosolic localization of CT311 was further confirmed in human primary cells. CT311 was predicted to contain an N-terminal secretion signal sequence and the CT311 signal sequence directed secretion of PhoA into bacterial periplasmic region in a heterologous assay system, suggesting that a sec-dependent pathway may play a role in the secretion of CT311 into host cell cytosol. This hypothesis is further supported by the observation that secretion of CT311 in Chlamydia-infected cells was blocked by a C16 compound known to inhibit signal peptidase I. These findings have provided important molecular information for further understanding the C. trachomatis pathogenic mechanisms. PMID- 21605657 TI - Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. AB - BACKGROUND: Inflammation has been linked to depression and suicide risk. One inflammatory process that has been minimally investigated in this regard is cytokine-stimulated production of kynurenine (KYN) from tryptophan (TRP). Recent data suggest that KYN increases in cerebrospinal fluid (CSF) are associated with depressive symptoms secondary to immune activation. KYN may alter dopaminergic and glutamatergic tone, thereby contributing to increased arousal, agitation and impulsivity - important risk factors in suicide. We hypothesized that patients with major depressive disorder (MDD) and a history of suicide attempt would have higher levels of KYN than depressed nonattempters, who in turn would have higher levels than healthy volunteers. METHODS: Plasma KYN, TRP, and neopterin were assayed by high performance liquid chromatography in three groups: healthy volunteers (n=31) and patients with MDD with (n=14) and without (n=16) history of suicide attempt. Analysis of variance tested for group differences in KYN levels. RESULTS: KYN levels differed across groups (F=4.03, df=(2,58), and p=0.023): a priori planned contrasts showed that KYN was higher in the MDD suicide attempter subgroup compared with MDD non-attempters (t=2.105, df=58, and p=0.040), who did not differ from healthy volunteers (t=0.418, df=58, and p=0.677). In post hoc testing, KYN but not TRP was associated with attempt status, and only suicide attempters exhibited a positive correlation of the cytokine activation marker neopterin with the KYN:TRP ratio, suggesting that KYN production may be influenced by inflammatory processes among suicide attempters. CONCLUSION: These preliminary results suggest that KYN and related molecular pathways may be implicated in the pathophysiology of suicidal behavior. PMID- 21605658 TI - Social affiliation relates to tyrosine hydroxylase immunolabeling in male and female zebra finches (Taeniopygia guttata). AB - The catecholamines dopamine and norepinephrine are implicated in affiliative behaviors, yet few studies have addressed the extent to which affiliative behaviors within distinct social settings rely upon similar or distinct catecholaminergic mechanisms. To explore the role of catecholamines in affiliative behavior within distinct long-term social contexts, we examined the density of the catecholamine synthetic enzyme tyrosine hydroxylase (TH) in brain regions within both the mesolimbic dopaminergic system and "social behavior network" in male and female zebra finches (Taeniopygia guttata) paired for 21 days with either a same- or opposite-sex conspecific. On days 16-21 after pairing, members of both same- and mixed-sex pairs produced similar rates of affiliative behaviors. Measures of affiliation related to TH labeling in the ventral tegmental area (VTA), nucleus accumbens (Ac), medial preoptic nucleus (POM), and ventromedial nucleus of the hypothalamus (VMH). Relationships between TH labeling density and specific measures of affiliative behavior differed in rostral compared to caudal subregions of Ac and VTA, suggesting distinct roles for these subregions in the regulation of affiliative behavior. Finally, TH labeling density in the VMH and rostral VTA were positively related to the amount of courtship received from the partner and TH labeling in Ac was denser in opposite-sex pairs compared to same-sex pairs, indicative of socially induced brain plasticity. Overall, results highlight a complex region- and behavior specific role for catecholamines in vertebrate affiliation. PMID- 21605659 TI - FoxP2 brainstem neurons project to sodium appetite regulatory sites. AB - The transcription factor Forkhead box protein 2 (FoxP2) is expressed in two cell groups of the brainstem that have been implicated in sodium appetite regulation: the pre-locus coeruleus (pre-LC) and parabrachial nucleus--external lateral-inner subdivision (PBel-inner). Because the connections of these two groups are unknown, neuroanatomical tracing methods were used to define their central projections. The pre-LC outputs were first analyzed using an anterograde axonal tracer--Phaseolus vulgaris leucoagglutinin (PHAL) to construct a brain map. Next, we examined whether the FoxP2 immunoreactive (FoxP2+) neurons of the pre-LC contribute to these projections using a retrograde neuronal tracer--cholera toxin beta-subunit (CTb). CTb was injected into selected brain regions identified in the anterograde tracing study. One week later the rats were killed, and brainstem sections were processed by a double immunohistochemical procedure to determine whether the FoxP2+ neurons in the pre-LC and/or PBel-inner contained CTb. FoxP2+ pre-LC neurons project to: (1) ventral pallidum; (2) substantia innominata and bed nucleus of the stria terminalis; (3) paraventricular, central medial, parafascicular, and subparafascicular parvicellular thalamic nuclei; (4) paraventricular (PVH), lateral, perifornical, dorsomedial (DMH), and parasubthalamic hypothalamic nuclei; and (5) ventral tegmental area (VTA), periaqueductal gray matter (PAG), dorsal and central linear raphe nuclei. FoxP2+ PBel-inner neurons project to the PVH and DMH, with weaker connections to the LHA, VTA, and PAG. Both the pre-LC and PBel-inner project to central sites implicated in sodium appetite, and related issues, including foraging behavior, hedonic responses to salt intake, sodium balance, and cardiovascular regulation, are discussed. PMID- 21605660 TI - Vitamin E prevents NRF2 suppression by allergens in asthmatic alveolar macrophages in vivo. AB - Asthma is a chronic inflammatory airway disease associated with increased generation of reactive oxidant species and disturbed antioxidant defenses. NRF2 is the master transcription factor that regulates the expression of Phase II antioxidant and detoxifying enzymes. Disruption of NRF2 augments oxidative stress and inflammation in a mouse model of asthma, suggesting a protective role for NRF2 in the lungs in vivo. Yet, little is known about the regulation and function of NRF2 in human asthmatics. Using segmental allergen challenge, a well established experimental model of IgE-mediated asthma exacerbation in human atopic asthmatics, we investigated the effects of a specific allergen and the modulatory role of vitamin E on NRF2 and a NRF2-target gene, superoxide dismutase, in alveolar macrophages recovered from the airways at 24h after allergen instillation in vivo. Allergen-provoked airway inflammation in sensitive asthmatics caused a profound inhibition of macrophage NRF2 activity and superoxide dismutase, rendering them incapable of responding to the NRF2 inducers. Prolonged treatment with high doses of the antioxidant vitamin E lessened this allergen-induced drop in alveolar macrophage NRF2. These results are the first to demonstrate that NRF2 expression in human asthmatics is compromised upon allergen challenge but can be rescued by vitamin E in vivo. PMID- 21605661 TI - Soy isoflavones sensitize cancer cells to radiotherapy. AB - Soy isoflavones are dietary compounds isolated from soybeans, which are safe for human use and have mild anti-cancer properties. Soy isoflavones inhibit the activity of transcription factors and genes essential for tumor cell proliferation, invasion, and neovascularization, and it appears that soy isoflavones may enhance the effectiveness of conventional therapies against cancer. Soy isoflavones could be an effective complementary treatment given that they inhibit the survival signaling pathways of various cancer cells through altered activation of APE1/Ref-1, NF-kappaB, and HIF-1alpha, which are genes essential for tumor cell survival, tumor growth, and angiogenesis, thus making such cells more sensitive to radiotherapy. Studies in which soy isoflavones were given in conjunction with radiotherapy to prostate cancer patients suggest that soy isoflavones might also mitigate the adverse effects of radiation on normal tissues, probably by acting as antioxidants. These observations open new avenues for exploiting soy isoflavones as supplements to conventional therapies. PMID- 21605662 TI - Protein sulfenic acid formation: from cellular damage to redox regulation. AB - Protein sulfenic acid formation has long been regarded as unwanted damage caused by reactive oxygen species (ROS). However, over the past 10 years, accumulating evidence has shown that the reversible oxidation of cysteine thiol groups to sulfenic acid functions as a redox-based signal transduction mechanism. Here, we review the mechanisms of sulfenic acid formation by ROS. We present some of the most important roles played by sulfenic acids in living cells as well as the pathways that regulate sulfenic acid formation. We highlight the experimental tools that have been developed to study the cellular sulfenome and show how computational approaches might help to better understand the mechanisms of sulfenic acid formation. PMID- 21605663 TI - The C609T inborn polymorphism in NAD(P)H:quinone oxidoreductase 1 is associated with susceptibility to multiple sclerosis and affects the risk of development of the primary progressive form of the disease. AB - Oxidative stress plays a pivotal role in the pathogenesis of multiple sclerosis (MS). Inactivating polymorphisms of genes encoding detoxification enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), could influence susceptibility to MS. To test this hypothesis we performed a case-control study in which we compared the distribution of NQO1 genotypes between 231 MS patients and 380 controls, using both PCR-RFLP and real-time PCR assays. Correlations with MS clinical subtype classification and gender were also evaluated. A significantly higher frequency of the homozygous (T/T) and heterozygous (C/T) NQO1 C(609)T variant genotypes was observed among MS patients compared to controls (P=0.01), with MS patients showing a 1.5-fold increased risk of carrying at least one variant T allele (P=0.009). Interestingly, patients belonging to the primary progressive subgroup exhibited a significantly higher incidence of the heterozygous C/T variant genotype, compared to the other forms of MS (P=0.019). There was no correlation of the NQO1 polymorphism with gender. These results provide the first evidence for a pathogenetic role for the NQO1 C(609)T polymorphism in MS susceptibility and suggest a possible role for the NQO1 genetic background in the development of primary progressive MS. PMID- 21605664 TI - Loss of NRF2 impairs gastric nitrergic stimulation and function. AB - Emerging research suggests that antioxidant gene expression has the potential to suppress the development of gastroparesis. However, direct genetic evidence that definitively supports this concept is lacking. We used mice carrying a targeted disruption of Nfe2l2, the gene that encodes the transcription factor NRF2 and directs antioxidant Phase II gene expression, as well as mice with a targeted disruption of Gclm, the modifier subunit for glutamate-cysteine ligase, to test the hypothesis that defective antioxidant gene expression contributes to development of gastroparesis. Although expression of heme oxygenase-1 remained unchanged, expression of GCLC, GCLM, SOD1, and CAT was down-regulated in gastric tissue from Nrf2(-/-) mice compared to wild-type animals. Tetrahydrobiopterin oxidation was significantly elevated and nitrergic relaxation was impaired in Nrf2(-/-) mouse gastric tissue. In vitro studies showed a significant decrease in NO release in Nrf2(-/-) mouse gastric tissue. Nrf2(-/-) mice displayed delayed gastric emptying. The use of Gclm(-/-) mice demonstrated that the loss of glutamate-cysteine ligase function enhanced tetrahydrobiopterin oxidation while impairing nitrergic relaxation. These results provide genetic evidence that loss of antioxidant gene expression can contribute to the development of gastroparesis and suggest that NRF2 represents a potential therapeutic target. PMID- 21605665 TI - Nitric oxide counteracts the hyperoxia-induced proliferation and proinflammatory responses of mouse astrocytes. AB - Preclinical studies in the premature baboon evaluating the efficacy and potential toxicity of inhaled nitric oxide indicated a significant effect on astrocyte area density, suggesting phenotypic and functional changes in astrocytes upon exposure to nitric oxide. However, the effects of nitric oxide and oxygen, the two major therapeutic gases utilized in neonatal intensive care, on astrocyte morphology and function remain vastly unknown. Herein, we report that exposure of mouse neonatal cortical astrocytes to hyperoxia results in a proinflammatory phenotype and increase in proliferation without significant changes in cellular morphology or levels of intermediate filament proteins. The proinflammatory phenotype was evident by a significant increase in cellular levels of cyclooxygenase-2 and a concomitant increase in prostaglandin E(2) secretion, a decline in the intracellular and secreted levels of apolipoprotein E, and a significant increase in the intracellular levels of clusterin. This proinflammatory phenotype was not evident upon simultaneous exposure to hyperoxia and nitric oxide. These results suggest that exposure to nitric oxide in the setting of hyperoxia confers unrecognized beneficial effects by suppressing astrocytic inflammation. PMID- 21605667 TI - Determination of OATP-, NTCP- and OCT-mediated substrate uptake activities in individual and pooled batches of cryopreserved human hepatocytes. AB - While the utility of cryopreserved human hepatocyte suspensions (CHHS) for in vitro drug metabolism assays has been established, less is known about the effects of cryopreservation on transporter activity in human hepatocytes. In the present study, the activities of NTCP (sodium taurocholate co-transporting polypeptide; SLC10A1), as well as of the hepatic OATP (organic anion transporting polypeptide; SLCO gene family) and OCT (organic cation transporter; SLC22A) isoforms were assessed in 14 individual and four pooled batches of CHHS. For comparative purposes, substrate accumulation rates were also measured in sandwich cultured human hepatocytes. In CHHS, the mean accumulation clearance of the NTCP substrate taurocholate (1 MUM) was 27.5 (+/-15.0) MUl/min/million cells and decreased by 10-fold when extracellular sodium was replaced by choline. The accumulation clearance of digoxin and of the OATP substrates estrone-3-sulfate and estradiol-17beta-D-glucuronide (E(2)-17beta-G; 1 MUM) amounted to 9.5 (+/ 4.9), 99 (+/-67) and 5.2 (+/-2.6) MUl/min/million cells, respectively. Presence of the known OATP inhibitor rifampicin (25 MUM) significantly (p<0.01) decreased the accumulation of estrone-3-sulfate and E(2)-17beta-G to 48% and 70% of the control value, respectively, while no significant effect on digoxin accumulation was observed. The mean accumulation clearance of the OCT substrate 1-methyl-4 phenylpyridinium amounted to 19.8 (+/-10.9) MUl/min/million cells. Co-incubation with the OCT1 inhibitor prazosin (3 MUM) and the OCT3 inhibitor corticosterone (1 MUM) resulted in a significant (p<0.01) decrease to 72% and 85% of the accumulation in control conditions, respectively. Experiments in pooled CHHS generally showed accumulation values that were comparable with the mean of the individual batches. A good correlation (R(2)=0.93) was observed between estrone-3 sulfate accumulation values and OATP1B3 mRNA levels, as determined in five batches of CHHS. Compared to substrate accumulation measured in sandwich-cultured human hepatocytes, accumulation values in CHHS were comparable (taurocholate and digoxin) to slightly higher (estrone-3-sulfate). Our data indicate that cryopreserved human hepatocyte suspensions are a reliable in vitro model to study transporter-mediated substrate uptake in the liver. Systematic characterization of multiple batches of CHHS for transporter activity supports rational selection of human hepatocytes for specific applications. PMID- 21605668 TI - Characterization of rhodamine-123, calcein and 5(6)-carboxy-2',7' dichlorofluorescein (CDCF) export via MRP2 (ABCC2) in MES-SA and A549 cells. AB - Based on our initial results on the effects of several ATP-binding cassette (ABC) transporter inhibitors on rhodamine-123 efflux from A549, a human lung carcinoma, and MES-SA, a human uterine sarcoma cell line, the aim of this study was to identify the transporter responsible for this export. Export of two fluorescent dyes, rhodamine-123 and calcein, was investigated in both cell lines by testing five commonly used inhibitors of ABC transporters: verapamil, cyclosporin A, MK571, GF129018 and fumitremorgin C. A very high degree of correlation (R(2)=0.91 0.99) between results obtained in the two cell lines suggested that the same transporter was involved in the export of tested fluorescent substrates in both cell lines. Expression analysis and gene silencing techniques, as well as transport of additional substrate 5(6)-carboxy-2',7'-dichlorofluorescein (CDCF) on membrane vesicles revealed that the transporter was multidrug resistance related protein 2 (MRP2, ABCC2). Furthermore, it was found that the tested modulators showed very diverse effects on the export of three fluorescent substrates via MRP2, with some modulators being inhibitory in one, while having no effect or even stimulating the transport in the other fluorescent dye assay. Verapamil inhibited rhodamine-123, but stimulated CDCF transport and did not affect calcein export. GF129018 did not affect calcein and CDCF transport, but it inhibited rhodamine-123 transport. These results demonstrate the importance of studying various combinations of potential substrates and modulators of MRP2 in order to estimate possible drug-drug interactions in living organisms. In addition, A549 and MES-SA cells were shown to be good cell models for studying interactions of compounds with human MRP2. PMID- 21605666 TI - Liganded and unliganded activation of estrogen receptor and hormone replacement therapies. AB - Over the past two decades, our understanding of estrogen receptor physiology in mammals widened considerably as we acquired a deeper appreciation of the roles of estrogen receptor alpha and beta (ERalpha and ERbeta) in reproduction as well as in bone and metabolic homeostasis, depression, vascular disorders, neurodegenerative diseases and cancer. In addition, our insights on ER transcriptional functions in cells increased considerably with the demonstration that ER activity is not strictly dependent on ligand availability. Indeed, unliganded ERs may be transcriptionally active and post-translational modifications play a major role in this context. The finding that several intracellular transduction molecules may regulate ER transcriptional programs indicates that ERs may act as a hub where several molecular pathways converge: this allows to maintain ER transcriptional activity in tune with all cell functions. Likely, the biological relevant role of ER was favored by evolution as a mean of integration between reproductive and metabolic functions. We here review the post-translational modifications modulating ER transcriptional activity in the presence or in the absence of estrogens and underline their potential role for ER tissue-specific activities. In our opinion, a better comprehension of the variety of molecular events that control ER activity in reproductive and non-reproductive organs is the foundation for the design of safer and more efficacious hormone-based therapies, particularly for menopause. This article is part of a Special Issue entitled: Translating Nuclear receptors from health to disease. PMID- 21605669 TI - Liposomes radiolabeled with (159)Gd: in vitro antitumoral activity, biodistribution study and scintigraphic image in Ehrlich tumor bearing mice. AB - PEG-coated pH-sensitive and PEG-folate-coated pH-sensitive liposomes containing the Gd-DTPA-BMA complex were prepared and radiolabeled by neutron activation. The radiolabeled liposomes presented significant in vitro cytotoxic activity against Ehrlich tumor cells when compared with controls. The biodistribution profile of these liposomes and free (159)Gd-DTPA-BMA were studied in mice bearing a previously-developed solid Ehrlich tumor. The results demonstrated an important uptake of the formulations by the tumor tissue, with a tissue/blood partition coefficient (Kp) 3.88 and 14.16 times higher than that of the free complex for pH sensitive PEG-coated and PEG-folate-coated liposomes containing the (159)Gd-DTPA BMA complex, respectively. Both formulations accumulated in the liver and spleen, thereby revealing some difficulty in escaping the action of the MPS cells. The formulation without folate presented a lower renal uptake, which is desirable in patients with chronic renal failure due to the potential risk of nephrogenic systemic fibrosis (NFS). The scintigraphic study revealed that the target/non target ratio is always greater than three for pH-sensitive PEG-coated liposome formulations and above nine for pH-sensitive PEG-folate-coated liposome formulations. The results obtained in this study demonstrated that the formulations employed can be considered to be a potential alternative for the treatment of cancer, including patients with chronic renal failure. PMID- 21605670 TI - A new nitrosyl ruthenium complex nitric oxide donor presents higher efficacy than sodium nitroprusside on relaxation of airway smooth muscle. AB - Nitric oxide (NO) has been demonstrated to be the primary agent in relaxing airways in humans and animals. We investigated the mechanisms involved in the relaxation induced by NO-donors, ruthenium complex [Ru(terpy)(bdq)NO(+)](3+) (TERPY) and sodium nitroprusside (SNP) in isolated trachea of rats contracted with carbachol in an isolated organs chamber. For instance, we verified the contribution of K(+) channels, the importance of sGC/cGMP pathway, the influence of the extra and intracellular Ca(2+) sources and the contribution of the epithelium on the relaxing response. Additionally, we have used confocal microscopy in order to analyze the action of the NO-donors on cytosolic Ca(2+) concentration. The results demonstrated that both compounds led to the relaxation of trachea in a dependent-concentration way. However, the maximum effect (E(max)) of TERPY is higher than the SNP. The relaxation induced by SNP (but not TERPY) was significantly reduced by pretreatment with ODQ (sGC inhibitor). Only TERPY induced relaxation was reduced by tetraethylammonium (K(+) channels blocker) and by pre-contraction with 75mM KCl (membrane depolarization). The response to both NO-donors was not altered by the presence of thapsigargin (sarcoplasmic reticulum Ca(2+)-ATPase inhibitor). The epithelium removal has reduced the relaxation only to SNP, and it has no effect on TERPY. The both NO-donors reduced the contraction evoked by Ca(2+) influx, while TERPY have shown a higher inhibitory effect on contraction. Moreover, the TERPY was more effective than SNP in reducing the cytosolic Ca(2+) concentration measured by confocal microscopy. In conclusion, these results show that TERPY induces airway smooth muscle relaxation by cGMP independent mechanisms, it involves the fluxes of Ca(2+) and K(+) across the membrane, it is more effective in reducing cytosolic Ca(2+) concentration and inducing relaxation in the rat trachea than the standard drug, SNP. PMID- 21605671 TI - Improved efficacy in the treatment of contact dermatitis in rats by a dermatological nanomedicine containing clobetasol propionate. AB - We developed a dermatological nanomedicine containing clobetasol propionate loaded nanocapsules and evaluated its efficacy in a model of contact dermatitis after topical administration in rats. Hydrogels containing clobetasol propionate loaded lipid-core nanocapsules or nanoemulsion (HG-CP-NC and HG-CP-NE, respectively) were prepared to evaluate the influence of the polymeric wall. They presented adequate pH values (5.50-6.50) and drug content (0.5 mg g(-1)) and their rheograms exhibited a non-Newtonian pseudoplastic behavior. The best in vitro drug release control was obtained for HG-CP-NC (1.03+/-0.11 MUg cm(-2) h) compared to the HG-CP-NE (1.65+/-0.19 MUg cm(-2) h) and the hydrogels containing nonencapsulated drug (HG-CP) (2.79+/-0.22 MUg cm(-2) h). A significant increase in NTPDase activity was observed in lymphocytes for the group treated with 0.05% HG-CP-NC every other day compared to the group treated with 0.05% HG-CP every day using the in vivo model of contact dermatitis. The nanoencapsulation of clobetasol in nanocapsules led to a better control of the drug release from the semisolid nanomedicine and provided better in vivo dermatological efficacy. PMID- 21605672 TI - The ratio of serum 24,25-dihydroxyvitamin D(3) to 25-hydroxyvitamin D(3) is predictive of 25-hydroxyvitamin D(3) response to vitamin D(3) supplementation. AB - 24,25-Dihydroxyvitamin D (24,25VD) is a major catabolite of 25-hydroxyvitamin D (25VD) metabolism, and may be physiologically active. Our objectives were to: (1) characterize the response of serum 24,25VD(3) to vitamin D(3) (VD(3)) supplementation; (2) test the hypothesis that a higher 24,25VD(3) to 25VD(3) ratio (24,25:25VD(3)) predicts 25VD(3) response. Serum samples (n=160) from wk 2 and wk 6 of a placebo-controlled, randomized clinical trial of VD(3) (28,000IU/wk) were analyzed for serum 24,25VD(3) and 25VD(3) by mass spectrometry. Serum 24,25VD(3) was highly correlated with 25VD(3) in placebo- and VD(3)-treated subjects at each time point (p<0.0001). At wk 2, the 24,25:25VD(3) ratio was lower with VD(3) than with placebo (p=0.035). From wk 2 to wk 6, the 24,25:25VD(3) ratio increased with the VD(3) supplement (p<0.001) but not with placebo, such that at wk 6 this ratio did not significantly differ between groups. After correcting for potential confounders, we found that 24,25:25VD(3) at wk 2 was inversely correlated to the 25VD(3) increment by wk 6 in the supplemented group (r=-0.32, p=0.02) but not the controls. There is a strong correlation between 24,25VD(3) and 25VD(3) that is only modestly affected by VD(3) supplementation. This indicates that the catabolism of 25VD(3) to 24,25VD(3) rises with increasing 25VD(3). Furthermore, the initial ratio of serum 24,25VD(3) to 25VD(3) predicted the increase in 25VD(3). The 24,25:25VD(3) ratio may therefore have clinical utility as a marker for VD(3) catabolism and a predictor of serum 25VD(3) response to VD(3) supplementation. PMID- 21605673 TI - Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects. AB - Bisphenol A (BPA) is one of the highest volume chemicals produced worldwide. This compound is a building block of polycarbonate plastics often used for food and beverage storage, and BPA is also a component of epoxy resins that are used to line food and beverage containers. Studies have shown that BPA can leach from these and other products in contact with food and drink, and as a result, routine ingestion of BPA is presumed. This compound is also found in an enormous number of other products that we come into contact with daily, and therefore it is not surprising that it has been detected in the majority of individuals examined. BPA is a known endocrine disruptor. Although initially considered to be a weak environmental estrogen, more recent studies have demonstrated that BPA may be similar in potency to estradiol in stimulating some cellular responses. Moreover, emerging evidence suggests that BPA may influence multiple endocrine-related pathways. Studies in rodents have identified adverse effects of BPA at levels at or below the current acceptable daily intake level for this compound. The various reported adverse effects of BPA are reviewed, and potential mechanisms of BPA action are discussed. Much more investigation is needed to understand the potential adverse health effects of BPA exposure in humans and to understand the multiple pathways through which it may act. Although many questions remain to be answered, it is becoming increasingly apparent that exposure to BPA is ubiquitous and that the effects of this endocrine disruptor are complex and wide-ranging. PMID- 21605674 TI - [F-18]FDDNP microPET imaging correlates with brain Abeta burden in a transgenic rat model of Alzheimer disease: effects of aging, in vivo blockade, and anti Abeta antibody treatment. AB - In vivo detection of Alzheimer's disease (AD) neuropathology in living patients using positron emission tomography (PET) in conjunction with high affinity molecular imaging probes for beta-amyloid (Abeta) and tau has the potential to assist with early diagnosis, evaluation of disease progression, and assessment of therapeutic interventions. Animal models of AD are valuable for exploring the in vivo binding of these probes, particularly their selectivity for specific neuropathologies, but prior PET experiments in transgenic mice have yielded conflicting results. In this work, we utilized microPET imaging in a transgenic rat model of brain Abeta deposition to assess [F-18]FDDNP binding profiles in relation to age-associated accumulation of neuropathology. Cross-sectional and longitudinal imaging demonstrated that [F-18]FDDNP binding in the hippocampus and frontal cortex progressively increases from 9 to 18months of age and parallels age-associated Abeta accumulation. Specificity of in vivo [F-18]FDDNP binding was assessed by naproxen pretreatment, which reversibly blocked [F-18]FDDNP binding to Abeta aggregrates. Both [F-18]FDDNP microPET imaging and neuropathological analyses revealed decreased Abeta burden after intracranial anti-Abeta antibody administration. The combination of this non-invasive imaging method and robust animal model of brain Abeta accumulation allows for future longitudinal in vivo assessments of potential therapeutics for AD that target Abeta production, aggregation, and/or clearance. These results corroborate previous analyses of [F 18]FDDNP PET imaging in clinical populations. PMID- 21605675 TI - Presynaptic silencing is an endogenous neuroprotectant during excitotoxic insults. AB - Glutamate release is a root cause of acute and delayed neuronal damage in response to hypoxic/ischemic insults. Nevertheless, therapeutics that target the postsynaptic compartment have been disappointing clinically. Here we explored whether presynaptic silencing (muting) of glutamatergic terminals is sufficient to reduce excitotoxic damage resulting from hypoxia and oxygen/glucose deprivation. Our evidence suggests that strong depolarization, previously shown to mute glutamate synapses, protects neurons by a presynaptic mechanism that is sensitive to inhibition of the proteasome. Postsynaptic Ca2+ rises in response to glutamate application and toxicity in response to exogenous glutamate treatment were unaffected by depolarization preconditioning. These features strongly suggest that reduced glutamate release explains preconditioning protection. We addressed whether hypoxic depolarization itself induces presynaptic silencing, thereby participating in the damage threshold for hypoxic insult. Indeed, we found that the hypoxic insult increased the percentage of mute glutamate synapses in a proteasome-dependent manner. Furthermore, proteasome inhibition exacerbated neuronal loss to mild hypoxia and prevented hypoxia-induced muting. In total our results suggest that presynaptic silencing is an endogenous neuroprotective mechanism that could be exploited to reduce damage from insults involving excess synaptic glutamate release. PMID- 21605676 TI - The l-Ser analog #290 promotes bone recovery in OP and RA mice. AB - We previously characterized the l-Ser analog #290, H(tBut)-l-Ser-O-Methyl.HCl, as a novel inhibitor of osteoclastogenesis which functions in both mouse and human cells. Here, we assessed the activity of #290 in animal models of osteoporosis and rheumatoid arthritis. Treatment of animals with #290 both prevented bone loss and led to the recovery of lost bone in osteoporotic mice. When inflammatory arthritis was induced in SKG mice, #290 treatment suppressed arthritis scores and significantly prevented the destruction of calcaneous bones. Additionally, #290 reciprocally modulated the mammalian target of rapamycin (mTOR) pathway in osteoclasts and osteoblasts in vitro, suggesting a dual effect on bone homeostasis. Our results demonstrate that #290 is a potential novel therapeutic tool for the treatment and/or study of diseases associated with bone destruction. PMID- 21605677 TI - Refolding and characterization of methionine adenosyltransferase from Euglena gracilis. AB - Methionine adenosyltransferase from Euglena gracilis (MATX) is a recently discovered member of the MAT family of proteins that synthesize S adenosylmethionine. Heterologous overexpression of MATX in Escherichia coli rendered the protein mostly in inclusion bodies under all conditions tested. Therefore, a refolding and purification procedure from these aggregates was developed to characterize the enzyme. Maximal recovery was obtained using inclusion bodies devoid of extraneous proteins by washing under mild urea (2M) and detergent (5%) concentrations. Refolding was achieved in two steps following solubilization in the presence of Mg(2+); chaotrope dilution to <1M and dialysis under reducing conditions. Purified MATX is a homodimer that exhibits Michaelis kinetics with a V(max) of 1.46 MUmol/min/mg and K(m) values of approximately 85 and 260 MUM for methionine and ATP, respectively. The activity is dependent on Mg(2+) and K(+) ions, but is not stimulated by dimethylsulfoxide. MATX exhibits tripolyphosphatase activity that is stimulated in the presence of S adenosylmethionine. Far-UV circular dichroism revealed beta-sheet and random coil as the main secondary structure elements of the protein. The high level of sequence conservation allowed construction of a structural model that preserved the main features of the MAT family, the major changes involving the N-terminal domain. PMID- 21605679 TI - Expression, purification, and refolding of active human and mouse secreted group IIE phospholipase A2. AB - Secreted phospholipase A2s form a large family of proteins involved in diverse biological and pathophysiological processes. Group IIE secreted phospholipase A2 (sPLA2-IIE) is one of the latest discovered members of this family. Previous studies revealed that the expression profile of sPLA2-IIE was restricted to a few tissue types including brain, heart, lung and placenta compared to the broad expression profile of other isoforms. Accumulating evidence suggests that sPLA2 IIE might play a pivotal role in the progression of inflammatory processes. However, functional study of sPLA2-IIE was hindered by the low yield of soluble expressed protein. In this study, we have expressed human and mouse sPLA2-IIE in Escherichia coli in the form of inclusion bodies. The inclusion bodies were dissolved, purified and refolded in a step-wise dialysis approach and further purified. We obtained soluble and active proteins for human and mouse sPLA2-IIE with a final yield of 1.1 and 1.2 mg/500 mL bacterial culture, respectively. The refolded sPLA2-IIEs exhibited similar calcium and pH dependence of their enzymatic activity with those expressed in COS cells. This protein expression and purification protocol will facilitate the further structural and functional studies of human and mouse sPLA2-IIEs. PMID- 21605678 TI - Purification and characterization of tagless recombinant human elongation factor 2 kinase (eEF-2K) expressed in Escherichia coli. AB - The eukaryotic elongation factor 2 kinase (eEF-2K) modulates the rate of protein synthesis by impeding the elongation phase of translation by inactivating the eukaryotic elongation factor 2 (eEF-2) via phosphorylation. eEF-2K is known to be activated by calcium and calmodulin, whereas the mTOR and MAPK pathways are suggested to negatively regulate kinase activity. Despite its pivotal role in translation regulation and potential role in tumor survival, the structure, function, and regulation of eEF-2K have not been described in detail. This deficiency may result from the difficulty of obtaining the recombinant kinase in a form suitable for biochemical analysis. Here we report the purification and characterization of recombinant human eEF-2K expressed in the Escherichia coli strain Rosetta-gami 2(DE3). Successive chromatography steps utilizing Ni-NTA affinity, anion-exchange, and gel filtration columns accomplished purification. Cleavage of the thioredoxin-His(6)-tag from the N-terminus of the expressed kinase with TEV protease yielded 9 mg of recombinant (G-D-I)-eEF-2K per liter of culture. Light scattering shows that eEF-2K is a monomer of ~85 kDa. In vitro kinetic analysis confirmed that recombinant human eEF-2K is able to phosphorylate wheat germ eEF-2 with kinetic parameters comparable to the mammalian enzyme. PMID- 21605680 TI - Production and single-step purification of EGFP and a biotinylated version of the Human Rhinovirus 14 3C protease. AB - The fluorescent reporter enhanced Green Fluorescent Protein (EGFP) has been used for assaying a wide range of biological activities ranging from gene expression, or localization of target proteins through to intermolecular interactions. However, over-production of this protein in Escherichia coli has resulted in the presence of inclusion bodies, which complicates recovery of the protein in significant quantities. In this paper, we describe a single-step method for isolating the protein from a Glutathione-S-Transferase (GST) fusion protein, release of the EGFP protein from the fusion was demonstrated using a biotinylated variant of Human Rhinovirus 14 3C protease that we have also constructed. We also suggest the potential uses of the biotinylated protease for bionanotechnology and synthetic biology. PMID- 21605681 TI - A centrifugation-free high-throughput protein purification system using in-line microfluidization. AB - The majority of current high-throughput protein purification protocols include rate-limiting centrifugation steps. A column and nozzle assembly was developed that can be used in-line with microfluidization for the purification of bacterially-overexpressed, His-tagged proteins directly from bacterial cultures. Yields and purity are comparable with standard protocols. This large-scale protein purification protocol is easy to use and widely-applicable. PMID- 21605682 TI - Recording information on protein complexes in an information management system. AB - The Protein Information Management System (PiMS) is a laboratory information management system (LIMS) designed for use with the production of proteins in a research environment. The software is distributed under the CCP4 licence, and so is available free of charge to academic laboratories. Like most LIMS, the underlying PiMS data model originally had no support for protein-protein complexes. To support the SPINE2-Complexes project the developers have extended PiMS to meet these requirements. The modifications to PiMS, described here, include data model changes, additional protocols, some user interface changes and functionality to detect when an experiment may have formed a complex. Example data are shown for the production of a crystal of a protein complex. Integration with SPINE2-Complexes Target Tracker application is also described. PMID- 21605683 TI - xtalPiMS: a PiMS-based web application for the management and monitoring of crystallization trials. AB - A major advance in protein structure determination has been the advent of nanolitre-scale crystallization and (in a high-throughput environment) the development of robotic systems for storing and imaging crystallization trials. Most of these trials are carried out in 96-well (or higher density) plates and managing them is a significant information management challenge. We describe xtalPiMS, a web-based application for the management and monitoring of crystallization trials. xtalPiMS has a user-interface layer based on the standards of the Protein Information Management System (PiMS) and a database layer which links the crystallization trial images to the meta-data associated with a particular crystallization trial. The user interface has been optimized for the efficient monitoring of high-throughput environments with three different automated imagers and work to support a fourth imager is in progress, but it can even be of use without robotics. The database can either be a PiMS database or a legacy database for which a suitable mapping layer has been developed. PMID- 21605684 TI - Crystal structures of YwqE from Bacillus subtilis and CpsB from Streptococcus pneumoniae, unique metal-dependent tyrosine phosphatases. AB - Unique metal-dependent protein tyrosine phosphatases that belong to the polymerase and histindinol phosphatase (PHP) family are present in Gram-positive bacteria. They are distinct from the Cys-based, low-molecular-weight phosphotyrosine protein phosphatases (LMPTPs). Two representative members of the PHP family tyrosine phosphatases are YwqE from Bacillus subtilis and CpsB from Streptococcus pneumoniae. YwqE is involved in polysaccharide biosynthesis, bacterial DNA metabolism, and DNA damage response in B. subtilis. CpsB regulates capsular polysaccharide biosynthesis via tyrosine dephosphorylation of CpsD, its cognate tyrosine kinase, in S. pneumoniae. To gain insights into the active site and possible conformational changes of the metal-dependent tyrosine phosphatases from Gram-positive bacteria, we have determined the crystal structures of B. subtilis YwqE (in both the apo form and the phosphate-bound form) and S. pneumoniae CpsB (in the sulfate-bound form). Comparisons of the three structures reveal conformational plasticity of two active site loops. Furthermore, in both structures of the phosphate-bound YwqE and the sulfate-bound CpsB, the phosphate (or sulfate) ion is bound to a cluster of three metal ions in the active site, thus providing insight into the pre-catalytic state. PMID- 21605685 TI - Comments on a skeleton design paradigm for a demosponge. AB - The ball-shaped marine sponge Cinachyrellalevantinensis is 3-5 cm in diameter. It filters large quantities of seawater for feeding. Sponges contain numerous, hydrated, brittle amorphous SiO2 spicules of several types that form 70-80% by weight of the sponge. We performed mechanical tests to determine the functionality of the sponge skeleton. The potential effect of habitat on skeleton properties was investigated by comparing sponges from 0.5 m and 30 m depth. We determined how spicules contribute to maintaining the strength and macroscopic structural integrity of a sponge, and studied their deformation mechanisms under external loading, and their microscopic design parameters. Compression tests of cylindrical samples cut from sponges revealed their macroscopic deformation mechanisms. Experiments solely with the organic material (following spicules dissolution) revealed the contribution of the spicules to the load carrying capacity and structural integrity of the sponge. Cantilever bending tests of anchored spicules determined the strength of individual spicules, the sponge's main skeletal elements. As the strength of brittle spicules is statistical in nature, we used Weibull Statistics to define their strength and evaluate their Young's modulus. Shallow and deep-water sponges did not differ significantly neither in response to compression, nor in spicule strength under bending and tension. Spicule weight fraction within a sponge was significantly higher in shallow-water individuals. We conclude that the structural integrity and strength of this sponge's skeleton is derived from its low-strength, small spicules, produced by a cost-effective process. The operating deformation of the spicules (bending) and their design parameters make them highly efficient. PMID- 21605686 TI - Oral immunization of olive flounder (Paralichthys olivaceus) with recombinant live viral hemorrhagic septicemia virus (VHSV) induces protection against VHSV infection. AB - A recombinant viral hemorrhagic septicemia virus (rVHSV-DeltaNV-EGFP) that has enhanced green fluorescent protein (EGFP) gene instead of NV gene was previously generated using reverse genetics technology. In this study, potential of the rVHSV-DeltaNV-EGFP to be used as a live oral vaccine candidate was assessed. The presence of the recombinant virus in internal organs of orally administered olive flounder (Paralichthys olivaceus) was analyzed by semi-quantitative RT-PCR. Although the recombinant VHSV-specific band was detected only when the number of PCR cycle was increased to 35, the band was detected from internal organs, such as kidney, spleen, and liver of fish that were reared at either 15 degrees C or 20 degrees C till even 20 days, suggesting that a few orally administered rVHSV DeltaNV-EGFP might be transported to internal organs, and might keep weak replication ability in the organs. VHSV-neutralizing activity was induced by oral immunization of olive flounder with the NV gene knock-out recombinant VHSV not only in skin and intestinal mucus but also in serum, suggesting that mucosal and systemic adaptive immune responses were elicited by oral immunization. In challenge experiment, groups of fish immunized with 104, 105, and 2 * 105 PFU of rVHSV-DeltaNV-EGFP/fish showed 25%, 50%, and 70% of relative percent survival (RPS), respectively. The RPSs were elevated to 60%, 75%, and 90% by a boost immunization in fish boost immunized with 104, 105, and 2 * 105 PFU of rVHSV DeltaNV-EGFP, respectively. The cumulative mortality of fish in the control groups was 100%. Conclusionly, the present results demonstrate that the NV gene knock-out recombinant VHSV administered orally to olive flounder can induce dose- and boosting-dependent VHSV-neutralizing antibody in mucus and serum, and can provide a high protection in olive flounder against a virulent VHSV challenge. PMID- 21605687 TI - Molecular characterization of the autophagy-related gene Beclin-1 from the olive flounder (Paralichthys olivaceus). AB - Autophagy is an important cellular response to starvation and stress, and plays critical roles in embryogenesis, development, cell death, cancer, and immunity. Beclin-1 is one of the central regulators of autophagy in mammals. In the present study, we isolated a PoBeclin-1 cDNA from the olive flounder (Paralichthys olivaceus) by screening a flounder gill cDNA library and rapid amplification of cDNA ends (RACE). The PoBeclin-1 cDNA we isolated encodes a 447-amino acid polypeptide containing a conserved Bcl-2-binding domain. The deduced amino acid sequence of PoBeclin-1 showed high degrees of sequence identity (80.5-95.3%) with Beclin-1 from human, frog, mouse, zebrafish, and pufferfish. PoBeclin-1 transcripts were detected from 1 day post-hatching and were found to be ubiquitously expressed in the healthy flounder. Expression of PoBeclin-1 mRNA was increased in the kidney and spleen of flounders challenged with viral hemorrhagic septicemia virus (VHSV). When infected with VHSV, PoBeclin-1-overexpressing HINAE cells had low level (about 26%) of VHSV G transcripts compared to control cells. Taken together, these results suggest that PoBeclin-1 may play a role in the innate immune response to viral infection in the flounder. PMID- 21605688 TI - A tutorial in connectome analysis: topological and spatial features of brain networks. AB - High-throughput methods for yielding the set of connections in a neural system, the connectome, are now being developed. This tutorial describes ways to analyze the topological and spatial organizations of the connectome at the macroscopic level of connectivity between brain regions as well as the microscopic level of connectivity between neurons. We will describe topological features at three different levels: the local scale of individual nodes, the regional scale of sets of nodes, and the global scale of the complete set of nodes in a network. Such features can be used to characterize components of a network and to compare different networks, e.g. the connectome of patients and control subjects for clinical studies. At the global scale, different types of networks can be distinguished and we will describe Erdos-Renyi random, scale-free, small-world, modular, and hierarchical archetypes of networks. Finally, the connectome also has a spatial organization and we describe methods for analyzing wiring lengths of neural systems. As an introduction for new researchers in the field of connectome analysis, we discuss the benefits and limitations of each analysis approach. PMID- 21605689 TI - Effect of head size on diffusion tensor imaging. AB - Head size markedly differs among individuals. To our knowledge, there have been no studies that systematically investigated the effect of head size on diffusion tensor measures of the brain. The purpose of this study was to evaluate the effect of head size or total intracranial volume on diffusion tensor measures (FA and MD). A total of 821 normal subjects (304 females and 517 males) were included in this study. We investigated the effect of total intracranial volume on FA and MD mainly using tract-based spatial statistics (TBSS). There were a number of regions where FA or MD was significantly correlated with total intracranial volume. There was no significant interaction between total intracranial volume and sex. The results indicate that total intracranial volume significantly influences diffusion tensor measures such as FA and MD. The possible explanations of the relationship between diffusion tensor measures and total intracranial volume may be 'partial volume effects' or micro-architectural differences related to head size. When total intracranial volumes are significantly different between groups, it may be necessary to control for total intracranial volume in the statistical analysis, depending on the hypothesis being tested. PMID- 21605690 TI - A non-coding plastid DNA phylogeny of Asian Begonia (Begoniaceae): evidence for morphological homoplasy and sectional polyphyly. AB - Maximum likelihood and Bayesian analyses of non-coding plastid DNA sequence data based on a broad sampling of all major Asian Begonia sections (ndhA intron, ndhF rpl32 spacer, rpl32-trnL spacer, 3977 aligned characters, 84 species) were used to reconstruct the phylogeny of Asian Begonia and to test the monophyly of major Asian Begonia sections. Ovary and fruit characters which are crucial in current sectional circumscriptions were mapped on the phylogeny to assess their utility in infrageneric classifications. The results indicate that the strong systematic emphasis placed on single, homoplasious characters such as undivided placenta lamellae (section Reichenheimia) and fleshy pericarps (section Sphenanthera), and the recognition of sections primarily based on a suite of plesiomorphic characters including three-locular ovaries with axillary, bilamellate placentae and dry, dehiscent pericarps (section Diploclinium), has resulted in the circumscription of several polyphyletic sections. Moreover, sections Platycentrum and Petermannia were recovered as paraphyletic. Because of the homoplasy of systematically important characters, current classifications have a certain diagnostic, but only poor predictive value. The presented phylogeny provides for the first time a reasonably resolved and supported phylogenetic framework for Asian Begonia which has the power to inform future taxonomic, biogeographic and evolutionary studies. PMID- 21605691 TI - Parallel evolution and phenotypic divergence in lichenized fungi: a case study in the lichen-forming fungal family Graphidaceae (Ascomycota: Lecanoromycetes: Ostropales). AB - A molecular phylogeny of combined mtSSU, nuLSU, and RPB2 data revealed previously unrecognized levels of parallel evolution and phenotypic divergence in the lichen family Graphidaceae. Five clades were supported within the family: the Fissurina, Ocellularia, Graphis, Topeliopsis, and Thelotrema clades, containing 33 of the 42 currently accepted genera within the family. The results for the first time provide a fully resolved phylogeny of this family and confirm the synonymy of Graphidaceae and Thelotremataceae. Ancestral character state reconstruction using likelihood, Bayesian, and parsimony approaches indicate that lirellate ascomata evolved independently in each of the five clades. Carbonized ascomata evolved independently in at least four of the five clades. An unexpected result was the independent evolution of columella structures in the Fissurina and Ocellularia clades. Besides these more general findings, we document several cases in which evolution of several traits in parallel resulted in striking look-alikes within unrelated lineages, such as Topeliopsismuscigena and Chapsameridensis in the Topeliopsis and Thelotrema clades, Leptotremawightii, Myriotremalaeviusculum, and Leucodectonphaeosporum in the Ocellularia and Thelotrema clades, Ocellulariastylothecia and Melanotremameiosporum in the Fissurina and Ocellularia clades, and Myriotremapycnoporellum, Myriotremaclandestinum and Wirthiotremaglaucopallens in the Fissurina, Ocellularia, and Topeliopsis clades. Pagel's test of independent character evolution suggested that at least for some of the traits involved in these cases, ecological constraints may have caused their evolution in parallel. The most intriguing find is the correlation between gall-forming thalli and vertical columns of calcium oxalate crystals, suggesting that these crystals do not function as light distributors, as previously assumed, but instead stabilize the thalli which are usually hollow beneath, similar to a dome-shaped structure. Ancestral character state reconstruction together with an approach to visualize the phenotype of putative ancestral lineages suggested the alpha-Graphidaceae to resemble some of the extant species currently classified in Myriotrema s.lat., with pore-like ascomata, and non-amyloid ascospores with lens shaped lumina. PMID- 21605692 TI - Changes in broiler chick tissue concentrations of lipid-soluble antioxidants immediately post-hatch. AB - The antioxidant protection of the chicken (Gallus gallus) embryo during incubation and early postnatal development plays an important role in chick viability. To assess the antioxidant capacity of the newly hatched chick, we determined the concentrations of vitamin A, vitamin E, carotenoids and coenzyme Q10 in the major tissues of chicks which had been held in an incubator for up to 36 h post-hatch. Concentrations of total carotenoids and free retinol and retinol esters in the tissues did not differ significantly over the 36 h period post hatch (p>0.05). In contrast concentrations of vitamin E (alpha-tocopherol, gamma tocopherol, and alpha-tocotrienol and gamma-tocotrienol) in various tissues (liver, heart, brain and leg muscle) decreased significantly in chicks that had been held in the incubator for 36 h when compared to younger chicks that were held for up to 18 h. Comparatively high concentrations of coenzyme Q10 were detected in the yolk sac membrane, liver and heart, the concentrations being dependent on age of chicks, the highest value being recorded 18 h post-hatch. In most of the tissues studied, coenzyme Q10 concentrations decreased substantially between 18 and 36 h post-hatch. This study demonstrated that there are tissue specific changes in the concentrations of the major antioxidants (vitamin E and coenzyme Q10) during the 36 h post-hatch. PMID- 21605693 TI - Acclimation temperature affects the metabolic response of amphibian skeletal muscle to insulin. AB - Frog skeletal muscle mainly utilizes the substrates glucose and lactate for energy metabolism. The goal of this study was to determine the effect of insulin on the uptake and metabolic fate of lactate and glucose at rest in skeletal muscle of the American bullfrog, Lithobates catesbeiana, under varying temperature regimens. We hypothesize that lactate and glucose metabolic pathways will respond differently to the presence of insulin in cold versus warm acclimated frog tissues, suggesting an interaction between temperature and metabolism under varying environmental conditions. We employed radiolabeled tracer techniques to measure in vitro uptake, oxidation, and incorporation of glucose and lactate into glycogen by isolated muscles from bullfrogs acclimated to 5 degrees C (cold) or 25 degrees C (warm). Isolated bundles from Sartorius muscles were incubated at 5 degrees C, 15 degrees C, or 25 degrees C, and in the presence and absence of 0.05 IU/mL bovine insulin. Insulin treatment in the warm acclimated and incubated frogs resulted in an increase in glucose incorporation into glycogen, and an increase in intracellular [glucose] of 0.5 MUmol/g (P<0.05). Under the same conditions lactate incorporation into glycogen was reduced (P<0.05) in insulin-treated muscle. When compared to the warm treatment group, cold acclimation and incubation resulted in increased rates of glucose oxidation and glycogen synthesis, and a reduction in free intracellular glucose levels (P<0.05). When muscles from either acclimation group were incubated at an intermediate temperature of 15 degrees C, insulin's effect on substrate metabolism was attenuated or even reversed. Therefore, a significant interaction between insulin and acclimation condition in controlling skeletal muscle metabolism appears to exist. Our findings further suggest that one of insulin's actions in frog muscle is to increase glucose incorporation into glycogen, and to reduce reliance on lactate as the primary metabolic fuel. PMID- 21605694 TI - Change of cardiac function, but not form, in postprandial pythons. AB - Pythons are renowned for a rapid and pronounced postprandial growth of the heart that coincides with a several-fold elevation of cardiac output that lasts for several days. Here we investigate whether ventricular morphology is affected by digestive state in two species of pythons (Python regius and Python molurus) and we determine the cardiac right-to-left shunt during the postprandial period in P. regius. Both species experienced several-fold increases in metabolism and mass of the digestive organs by 24 and 48 h after ingestion of meals equivalent to 25% of body mass. Surprisingly there were no changes in ventricular mass or dimensions as we used a meal size and husbandry conditions similar to studies finding rapid and significant growth. Based on these data and literature we therefore suggest that postprandial cardiac growth should be regarded as a facultative rather than obligatory component of the renowned postprandial response. The cardiac right-to left shunt, calculated on the basis of oxygen concentrations in the left and right atria and the dorsal aorta, was negligible in fasting P. regius, but increased to 10-15% during digestion. Such shunt levels are very low compared to other reptiles and does not support a recent proposal that shunts may facilitate digestion in reptiles. PMID- 21605695 TI - Mitochondria: a sulfhydryl oxidase and fission GTPase connect mitochondrial dynamics with pluripotency in embryonic stem cells. AB - Mitochondria have long been recognized as cellular energy power houses that also regulate cellular redox signaling to arbitrate cell survival. Recent studies of mitochondria in stem cells (SCs) demonstrate that they have critical roles beyond this traditional view. Embryonic (E) SCs, termed pluripotent for their ability to differentiate into all cell types within an organism, maintain a limited number of morphologically undifferentiated (electron translucent and poorly formed cristae) mitochondria. As these cells differentiate, their mitochondria undergo a tightly choreographed gain of number, mass and morphological complexity. Therefore, mechanisms that regulate mitochondrial growth, localization, division and partition must play active roles in the maintenance of pluripotency and execution of differentiation. Aberrant mitochondrial dynamics are associated with a plethora of human disorders, for which SCs hold curative potential. Hence, a comprehensive understanding of the mechanisms that regulate mitochondrial dynamics and function in SCs and their overall relationship to the maintenance of pluripotency is pivotal for the progression of therapeutic regenerative medicine. PMID- 21605696 TI - Mitochondria and endoplasmic reticulum: mitochondria-endoplasmic reticulum interplay in type 2 diabetes pathophysiology. AB - Mitochondria and endoplasmic reticulum (ER) are two important metabolic organelles for the maintenance of cellular homeostasis and their functional defects are suspected to participate to the aetiology of type 2 diabetes (T2D). Particularly, excessive lipid intake and/or ectopic lipid accumulation in tissues (referred as lipotoxicity) are involved in alterations of both organelles and are closely linked to peripheral insulin resistance and defective insulin secretion. Since, mitochondria and ER are physically and functionally interconnected, their respective alterations during T2D could be interrelated. However, the mechanisms that coordinate the interplay between mitochondrial dysfunction and ER stress, and its relevance in the control of glucose homeostasis are unknown. Among these mechanisms, we will discuss on the potential role of altered mitochondria/ER crosstalk in organelle dysfunctions and in T2D pathophysiology. PMID- 21605697 TI - To measure is to know: an approach to CADD performance metrics. AB - With the financial and productivity challenges currently facing the pharmaceutical industry, there is constant pressure to justify resources and improve efficiency. With process-driven activities, understanding the contribution of these resources is reasonably straightforward. By contrast, measuring the contribution of knowledge workers is less obvious. Here, we present an impact-oriented approach to assessing the performance of an industrial computer-assisted drug design group. We discuss how these metrics are used to understand and optimize resource allocation in support of drug discovery programs. PMID- 21605698 TI - A molecular informatics view on best practice in multi-parameter compound optimization. AB - The difference between biologically active molecules and drugs is that the latter balance an array of related and unrelated properties required for administration to patients. Inevitability, during optimization, some of these multiple factors will conflict. Although informatics has a crucial role in addressing the challenges of modern compound optimization, it is arguably still undervalued and underutilized. We present here some of the basic requirements of multi-parameter drug design, the crucial role of informatics and examples of favorable practice. The most crucial of these best practices are the need for informaticians to align their technologies and insights directly to discovery projects and for all scientists in drug discovery to become more proficient in the use of in silico methods. PMID- 21605700 TI - Increased Delta5- and Delta6-desaturase, cyclooxygenase-2, and lipoxygenase-5 expression and activity are associated with fatty acid and eicosanoid changes in cystic fibrosis. AB - Patients with cystic fibrosis consistently demonstrate selective abnormalities in essential fatty acid concentrations, including decreased linoleate (LA) and docosahexaenoate (DHA), with variably increased arachidonate (AA). These changes appear important for the pathophysiology of the disease. However, the mechanisms of these changes are not clearly understood. The current study demonstrates that metabolism of LA and alpha linolenate (LNA) to AA and eicosapentaenoate (EPA), respectively, are significantly increased in two different cell culture models of cystic fibrosis. These changes correlated with increased expression of fatty acid Delta5- and Delta6-desaturases, key enzymes in this metabolic pathway. In contrast, cystic fibrosis cells showed decreased metabolism of AA and EPA to docosapentaenoate (DPA) and docosahexaenoate (DHA), respectively, although metabolism of 22:5n-3 to DHA was relatively unchanged. In addition, the expression and activity of both cyclooxygenase-2 and lipoxygenase-5 was markedly increased in these cells. Taken together, these findings are consistent with the conclusion that the diminished LA and increased AA in cystic fibrosis result from increased metabolism of LA, while the observed decrease in DHA is at least partly due to decreased elongation and desaturation beyond EPA. PMID- 21605699 TI - Initial steps of metastasis: cell invasion and endothelial transmigration. AB - Metastasis is the leading cause of cancer mortality. The metastatic cascade represents a multi-step process which includes local tumor cell invasion, entry into the vasculature followed by the exit of carcinoma cells from the circulation and colonization at the distal sites. At the earliest stage of successful cancer cell dissemination, the primary cancer adapts the secondary site of tumor colonization involving the tumor-stroma crosstalk. The migration and plasticity of cancer cells as well as the surrounding environment such as stromal and endothelial cells are mandatory. Consequently, the mechanisms of cell movement are of utmost relevance for targeted intervention of which three different types have been reported. Tumor cells can migrate either collectively, in a mesenchymal or in an amoeboid type of movement and intravasate the blood or lymph vasculature. Intravasation by the interaction of tumor cells with the vascular endothelium is mechanistically poorly understood. Changes in the epithelial plasticity enable carcinoma cells to switch between these types of motility. The types of migration may change depending on the intervention thereby increasing the velocity and aggressiveness of invading cancer cells. Interference with collective or mesenchymal cell invasion by targeting integrin expression or metalloproteinase activity, respectively, resulted in an amoeboid cell phenotype as the ultimate exit strategy of cancer cells. There are little mechanistic details reported in vivo showing that the amoeboid behavior can be either reversed or efficiently inhibited. Future concepts of metastasis intervention must simultaneously address the collective, mesenchymal and amoeboid mechanisms of cell invasion in order to advance in anti-metastatic strategies as these different types of movement can coexist and cooperate. Beyond the targeting of cell movements, the adhesion of cancer cells to the stroma in heterotypic circulating tumor cell emboli is of paramount relevance for anti-metastatic therapy. PMID- 21605701 TI - Effect of mercury ions on cysteine metabolism in Xenopus laevis tissues. AB - The effect of mercury ions on the level of cysteine, glutathione, sulfane sulfur, and on the activity of rhodanese, 3-mercaptopyruvate sulfurtransferase (MPST) and gamma-cystathionase in brain, heart muscle, liver, kidneys, testes and skeletal muscle of adult Xenopus laevis was investigated. Frogs of both sexes were exposed for 7 or 14 days to 1.353mgL(-1) (ppm) of mercury chloride (HgCl(2)) dissolved in water. The activity of the investigated enzymes participating in cysteine metabolism depends on cysteine in their active sites. Mercury ions can bind to SH groups and, therefore, lower the activity of enzymes and change the level of sulfane sulfur, a product of l-cysteine desulfuration. The effect of mercury was found to depend on the time of exposure and the kind of tissue. In the liver, the main site of glutathione biosynthesis, the ratio of GSH to GSSG was essentially unchanged. The total glutathione level was decreased after 7 days of exposure to mercury, similarly as the activity of rhodanese. Sulfane sulfur levels were significantly increased after a shorter duration, while they decreased after a longer time of exposure. The kidney, brain and testes were able to enhance the level of GSH, probably thanks to high gamma-glutamyltranspeptidase activity. These tissues showed an increased value of GSH/GSSG ratio during the shorter exposure to mercury. The activity of sulfurtransferases was decreased, especially after the longer exposure to mercury. In the heart and skeletal muscle, the level of GSH, sulfane sulfur, and the activity of the investigated sulfurtransferases was diminished after 14 days of exposure to Hg. It can be concluded that the main mechanism of toxic Hg activity is generation of reactive oxygen species in cells due to depleted GSH level, and a decreased sulfurtransferases activity either by blocking or oxidation of their -SH groups, what in consequence results in a diminished sulfane sulfur levels in tissues, especially the heart and testes. PMID- 21605702 TI - miRWalk--database: prediction of possible miRNA binding sites by "walking" the genes of three genomes. AB - MicroRNAs are small, non-coding RNA molecules that can complementarily bind to the mRNA 3'-UTR region to regulate the gene expression by transcriptional repression or induction of mRNA degradation. Increasing evidence suggests a new mechanism by which miRNAs may regulate target gene expression by binding in promoter and amino acid coding regions. Most of the existing databases on miRNAs are restricted to mRNA 3'-UTR region. To address this issue, we present miRWalk, a comprehensive database on miRNAs, which hosts predicted as well as validated miRNA binding sites, information on all known genes of human, mouse and rat. All mRNAs, mitochondrial genes and 10 kb upstream flanking regions of all known genes of human, mouse and rat were analyzed by using a newly developed algorithm named 'miRWalk' as well as with eight already established programs for putative miRNA binding sites. An automated and extensive text-mining search was performed on PubMed database to extract validated information on miRNAs. Combined information was put into a MySQL database. miRWalk presents predicted and validated information on miRNA-target interaction. Such a resource enables researchers to validate new targets of miRNA not only on 3'-UTR, but also on the other regions of all known genes. The 'Validated Target module' is updated every month and the 'Predicted Target module' is updated every 6 months. miRWalk is freely available at http://mirwalk.uni-hd.de/. PMID- 21605704 TI - Transmission probabilities and durations of immunity for three pathogenic group B Streptococcus serotypes. AB - Group B Streptococcus (GBS) remains a major cause of neonatal sepsis and is an emerging cause of invasive bacterial infections. The 9 known serotypes vary in virulence, and there is little cross-immunity. Key parameters for planning an effective vaccination strategy, such as average length of immunity and transmission probabilities by serotype, are unknown. We simulated GBS spread in a population using a computational model with parameters derived from studies of GBS sexual transmission in a college dormitory. Here we provide estimates of the duration of immunity relative to the transmission probabilities for the 3 GBS serotypes most associated with invasive disease: Ia, III, and V. We also place upper limits on the durations of immunity for serotype Ia (570 days), III (1125 days) and V (260 days). Better transmission estimates are required to establish the epidemiological parameters of GBS infection and determine the best vaccination strategies to prevent GBS disease. PMID- 21605705 TI - Optimal sample storage and extraction procotols for reliable multilocus genotyping of the human parasite Schistosoma mansoni. AB - Genotyping individual larval stages and eggs of natural parasite populations is complicated by the difficulty of obtaining reliable genotypes from low quantity DNA template. A suitable storage and extraction protocol, together with a thorough quantification of genotyping errors are therefore crucial for molecular epidemiological studies. Here we test the robustness, handling time, ease of use, cost effectiveness and success rate of various fixation (Whatman FTA((r)) Classic and Elute Cards, 70% EtOH and RNAlater((r))) and subsequent DNA extraction methods (commercial kits and proteinase K protocol). None of these methods require a cooling chain and are therefore suitable for field collection. Based on a multiplex microsatellite PCR with nine loci the success and reliability of each technique is evaluated by the proportion of samples with at least eight scored loci and the proportion of genotyping errors. If only the former is taken into account, FTA((r)) Elute is recommended (83% success; 44% genotyping error; 0.2 ?/sample; 1h 20 m handling time). However, when also considering the genotyping errors, handling time and ease of use, we opt for 70% EtOH with the 96-well plate technology followed by a simple proteinase K extraction (73% success; 0% genotyping error; 0.2 ?/sample; 15m handling time). For eggs we suggest (1) to pool all eggs per person in 1.5 ml tubes filled with 70% EtOH for transport and (2) to identify each egg to species level prior to genotyping. To this end we extended the Rapid diagnostic PCR developed by Webster et al. (2010) with a S. mansoni-specific primer to discriminate between S. mansoni, S. haematobium and S. bovis in a single PCR reaction. The success rate of genotyping eggs was 75% (0% genotyping error). This is the first study to incorporate genotyping errors through re-amplification for the evaluation of schistosome sampling protocols and the identification of error-prone loci. PMID- 21605706 TI - Venlafaxine inhibits the development and differentiation of dendritic cells through the regulation of P-glycoprotein. AB - Dendritic cells (DC) are professional antigen-presenting cells that have the ability to detect infectious materials; antigens to T lymphocytes, and serve as a bridge between innate and adaptive immunities. DC express the ATP-binding cassette transporters P-glycoprotein (P-gp). P-gp is a 170-kDa transmembrane protein encoded by the mdr-1 gene, a member of highly conserved superfamily of ATP-binding cassette transport proteins. Functionally, P-gp transporters have been described to be required for efficient DC and T cell migration. We report for the first time, at the best of our knowledge, P-gp is also required for DC development and differentiation in mouse bone marrow-derived DC. In this study, we found that an mdr-1 gene and P-gp protein level was increased during DC development and LPS-induced maturation. Moreover, the activity of P-gp was increased LPS-induced DC maturation. Next, we have attempted to determine whether the modulation of P-gp regulates surface molecules expression and cytokine production in DC. Specifically, down-regulation of P-gp by Venlafaxine (VLX) inhibits the differentiation of DC and cytokine production, such as IL-1, IL-10, and IL-12 during DC maturation. Moreover, the P-gp-decreased DC by VLX was displayed impaired induction of T cell polarizations, proliferation, and cytokine production, including IFN-gamma, IL-4, and IL-2. Taken together, these findings also broaden current perspective concerning our understanding of the immunopharmacological functions of VLX and the development of therapeutic adjuvants for the treatment of DC-related acute and chronic diseases. PMID- 21605707 TI - Why are there no proven therapies for genetic mitochondrial diseases? AB - Although mitochondrial disease research in general is robust, adequate treatment of these life-threatening conditions has lagged, partly because of a persistence of clinical anecdotes as substitutes for scientifically and ethically rigorous clinical trials. Here I summarize the key lessons learned from some of the "first generation" of randomized controlled trials for genetic mitochondrial diseases and suggest how future trials may benefit from both past experience and exciting new resources available for patient-oriented research and training in this field. PMID- 21605708 TI - Surface hydrophilic modification with a sugar moiety for a uniform-sized polymer molecularly imprinted for phenobarbital in serum. AB - A uniform-sized polymer molecularly imprinted for phenobarbital, which is surface modified by a sugar moiety, has been prepared through a two-step swelling polymerization method using polystyrene beads as seeds, phenobarbital as the template, 4-vinylpyridine as a functional monomer, ethylene glycol dimethacrylate as a cross-linker and 2-O-meth-acryloyloxyethoxyl-(2,3,4,6- tetra-O-acetyl-beta-d galactopyranosyl)-(1-4)-2,3,6-tri-O-acetyl-beta-d-glucopyranoside as a surface modifying glycomonomer, respectively. After deprotecting the glycopolymer, a surface sugar moiety-modified, hydrophilic, molecularly imprinted polymer for phenobarbital (glyco-MIP) was obtained. The resulting polymer beads were packed into a stainless steel column to evaluate their chromatographic characteristics by high-performance liquid chromatography (HPLC). Good selectivity for phenobarbital was obtained with the glyco-MIP compared to the unmodified molecularly imprinted polymer, which revealed that the recognition sites of phenobarbital were unchanged with sugar moiety surface modification. Furthermore, bovine serum albumin was almost completely recovered from the glyco-MIP column, which indicates that the glyco-MIP materials can be used to separate and analyze drugs in complex samples, such as biological samples. The results of pretreatment with and analysis of phenobarbital in serum suggest that this material can be used to analyze phenobarbital in serum through a pretreatment and reverse-phase HPLC analysis process. PMID- 21605709 TI - Proteome analysis of Thermococcus onnurineus NA1 reveals the expression of hydrogen gene cluster under carboxydotrophic growth. AB - Thermococcus onnurineus NA1 is a typical sulfur-reducing hyperthermophilic archaeon. Genome sequence analysis has shown that T. onnurineus NA1 retains the metabolic pathways necessary not only for organotrophic, but also for carboxydotrophic, growth. T. onnurineus NA1 carboxydotrophic growth may result in hydrogen production, as this archaeon produces hydrogen during oxidizing formate. In this study, we profiled the proteome of T. onnurineus NA1 cultured under carboxydotrophic conditions using CO as an electron donor by the SDS-PAGE/LC MS/MS method. A total of 1395 proteins were identified by two independent proteomic analyses, which corresponds to ~71% of the total predicted open reading frames. To our knowledge, this level of identification coverage exceeds those of other global proteome profiling studies in Archaea. Furthermore, the biological functions of the identified proteins were predicted and cognate enzymes were mapped to the appropriate metabolic pathways. More than 90% of the genes belonging to hydrogenase gene clusters such as Mbx, Sulf-I, Mbh, Hyg4-I, Hyg4-II, and Hyf4-III were expressed during CO culture. This means that hydrogenases induced under carboxydotrophic conditions surpass those induced under an organotrophic condition (yeast extract-peptone-sulfur). Our data suggest that hydrogen production is caused by the expression and functional assembly of T. onnurineus NA1 hydrogenase genes during culture in the presence of CO. PMID- 21605710 TI - Proteomic expression profiles of virulent and avirulent strains of Listeria monocytogenes isolated from macrophages. AB - Listeria monocytogenes is able to survive and proliferate within macrophages. In the current study, the ability of three L. monocytogenes strains (serovar 1/2a strain EGDe, serovar 4b strain F2365, and serovar 4a strain HCC23) to proliferate in the murine macrophage cell line J774.1 was analyzed. We found that the avirulent strain HCC23 was able to initiate an infection but could not establish prolonged infection within the macrophages. By contrast, strains EGDe and F2365 proliferated within macrophages for at least 7 h. We further analyzed these strains by comparing their protein expression profiles at 0 h, 3 h, and 5 h post infection using multidimensional protein identification technology coupled with electrospray ionization tandem mass spectrometry. Our results indicated that similar metabolic and cell wall associated proteins were expressed by all three strains at 3 h post-infection. However, increased expression of stress response and DNA repair proteins was associated with the ability to proliferate in macrophages at 5 h post-infection. By comparing the protein expression patterns of these three L. monocytogenes strains during intracellular growth in macrophages, we were able to detect biological differences that may determine the ability of L. monocytogenes to survive in macrophages. PMID- 21605711 TI - N-glycoproteomics in plants: perspectives and challenges. AB - In eukaryotes, proteins that are secreted into the ER are mostly modified by N glycans on consensus NxS/T sites. The N-linked glycan subsequently undergoes varying degrees of processing by enzymes which are spatially distributed over the ER and the Golgi apparatus. The post-ER N-glycan processing to complex glycans differs between animals and plants, with consequences for N-glycan and glycopeptide isolation and characterization of plant glycoproteins. Here we describe some recent developments in plant glycoproteomics and illustrate how general and plant specific technologies may be used to address different important biological questions. PMID- 21605712 TI - Studies of variability in Holm oak (Quercus ilex subsp. ballota [Desf.] Samp.) through acorn protein profile analysis. AB - Studies of variability in Holm oak (Quercus ilex subsp. ballota [Desf.] Samp.), the dominant tree species in the typical Mediterranean forest, have been carried out by using electrophoresis-based proteomic analysis of acorns. Ten populations distributed throughout the Andalusia region have been surveyed. Acorns were sampled from individual trees and proteins extracted from seed flour by using the TCA-acetone precipitation protocol. Extracts were subjected to SDS-PAGE and 2-DE for protein separation, gel images captured, spot or bands quantified, and subjected to statistical analysis (ANOVA, SOM and clustering). Variable bands or spots among populations were subjected to MALDI-TOF/TOF and LC-MS/MS for identification. The protein yield of the used protocol varied among populations, and it was in the 2.92-5.92 mg/g dry weight range. A total of 23 bands were resolved by SDS-PAGE in the 3-35 kDa Mr range, with 8 and 12, out of the total, showing respectively qualitative and quantitative statistically significant differences among populations. Data allowed grouping populations, with groups being correlated according to geographical location and climate conditions, to northern and southern, as well as the discrimination of both mesic and xeric groups. Acorn flour extracts from the most distant populations were analyzed by 2 DE, and 56 differential spots were proposed as markers of variability. Identified proteins were classified into two principal categories; storage and stress/defense protein. Besides providing the first reference map of mature acorn seeds, the use of SDS-PAGE and proteomics in characterizing natural biodiversity in forest trees will be discussed. PMID- 21605713 TI - Role of miRNAs and siRNAs in biotic and abiotic stress responses of plants. AB - Small, non-coding RNAs are a distinct class of regulatory RNAs in plants and animals that control a variety of biological processes. In plants, several classes of small RNAs with specific sizes and dedicated functions have evolved through a series of pathways. The major classes of small RNAs include microRNAs (miRNAs) and small interfering RNAs (siRNAs), which differ in their biogenesis. miRNAs control the expression of cognate target genes by binding to reverse complementary sequences, resulting in cleavage or translational inhibition of the target RNAs. siRNAs have a similar structure, function, and biogenesis as miRNAs but are derived from long double-stranded RNAs and can often direct DNA methylation at target sequences. Besides their roles in growth and development and maintenance of genome integrity, small RNAs are also important components in plant stress responses. One way in which plants respond to environmental stress is by modifying their gene expression through the activity of small RNAs. Thus, understanding how small RNAs regulate gene expression will enable researchers to explore the role of small RNAs in biotic and abiotic stress responses. This review focuses on the regulatory roles of plant small RNAs in the adaptive response to stresses. This article is part of a Special Issue entitled: Plant gene regulation in response to abiotic stress. PMID- 21605714 TI - siRNA-mediated chromatin maintenance and its function in Arabidopsis thaliana. AB - Small interfering RNAs (siRNAs) are widespread in various eukaryotes and are involved in maintenance of chromatin modifications, especially those for inert states represented by covalent modifications of cytosine and/or histones. In contrast to mammalian genomes, in which cytosine methylation is restricted mostly to CG dinucleotide sequences, inert chromatin in plants carries cytosine methylation in all sequence contexts, and siRNAs play a major role in directing cytosine methylation through the process of RNA-directed DNA methylation. Recent advances in this field have revealed that siRNA-mediated maintenance of inert chromatin has diverse roles in development as well as in plant responses to the environment. Various proteinaceous factors required for siRNA-mediated chromatin modification have been identified in Arabidopsis thaliana, and much effort has been invested in understanding their function and interaction, resulting in the assignment of many of these factors to specific biochemical activities and engagement with specific steps such as transcription of intergenic RNAs, RNA processing, and cytosine methylation. However, the precise functions of a number of factors remain undesignated, and interactions of distinct pathways for siRNA mediated chromatin modification are largely unknown. In this review, we summarize the roles of siRNA-mediated chromatin modification in various biological processes of A. thaliana, and present some speculation on the functions and interactions of silencing factors that, while not yet assigned to defined biochemical activities, have been loosely assigned to specific events in siRNA mediated chromatin modification pathways. Special Issue entitled: Epigenetic control of cellular and developmental processes in plants. PMID- 21605715 TI - Regional differences in treatment for osteoporosis. The Global Longitudinal Study of Osteoporosis in Women (GLOW). AB - PURPOSE: To determine if important geographic differences exist in treatment rates for osteoporosis and whether this variation can be explained by regional variation in risk factors. METHODS: The Global Longitudinal Study of Osteoporosis in Women is an observational study of women >=55 years sampled from primary care practices in 10 countries. Self-administered questionnaires were used to collect data on patient characteristics, risk factors for fracture, previous fractures, anti-osteoporosis medication, and health status. RESULTS: Among 58,009 women, current anti-osteoporosis medication use was lowest in Northern Europe (16%) and highest in U.S.A. and Australia (32%). Between 48% (U.S.A., Southern Europe) and 68% (Northern Europe) of women aged >=65 years with a history of spine or hip fracture since age 45 were untreated. Among women with osteoporosis, the percentage of treated cases was lowest in Europe (45-52% versus 62-65% elsewhere). Women with osteopenia and no other risk factors were treated with anti-osteoporosis medication most frequently in U.S.A. (31%) and Canada (31%), and least frequently in Southern Europe (12%), Northern Europe (13%), and Australia (16%). After adjusting for risk factors, U.S. women were threefold as likely to be treated with anti-osteoporosis medication as Northern European women (odds ratio 2.8; 95% confidence interval 2.5-3.1) and 1.5 times as likely to be treated as Southern European women (1.5, 1.4-1.6). Up to half of women reporting previous hip or spine fracture did not receive treatment. CONCLUSIONS: The likelihood of being treated for osteoporosis differed between regions, and cannot be explained by variation in risk factors. Many women at risk of fracture do not receive prophylaxis. PMID- 21605716 TI - Effect of eldecalcitol, an active vitamin D analog, on hip structure and biomechanical properties: 3D assessment by clinical CT. AB - The effects of an active vitamin D analog, eldecalcitol (ELD), on bone mineral density (BMD), bone geometry, and biomechanical properties of the proximal femur were investigated by using clinical CT. The subjects--a subgroup of a recent randomized, double-blind study comparing anti-fracture efficacy of ELD with alfacalcidol (ALF) - constituted 193 ambulatory patients with osteoporosis (189 postmenopausal women and 4 men aged 52-85 years, average +/- SD: 70.9 +/- 6.92 years) enrolled at 11 institutions. Multidetector-row CT data was acquired at baseline and at completion of 144 weeks' treatment. Cross-sectional densitometric and geometric parameters of the femoral neck were derived from three-dimensional CT data. Biomechanical properties including cross-sectional moment of inertia (CSMI), section modulus (SM) and buckling ratio (BR) of the femoral neck, and CSMI of the femoral shaft were also calculated. We found that, (1) with respect to the femoral neck cross-sectional parameters (total bone), in the ALF group, volumetric BMD (vBMD) decreased but bone mass was maintained and cross-sectional area (CSA) increased. In contrast, ELD maintained vBMD with a significant increase in bone mass and a trend toward increased CSA. (2) With respect to the femoral neck cross-sectional parameters (cortex), cortical thickness decreased in the ALF group, but was maintained in the ELD group. In the ALF group, vBMD and bone mass increased, and CSA was maintained. In the ELD group, vBMD, CSA, and bone mass increased. (3) With respect to the biomechanical properties of the femoral neck, ELD improved CSMI and SM to a greater extent than did ALF. BR increased in both the ALF and ELD groups. (4) With respect to the femoral shaft parameters, overall the results of bone geometry and CSMI of the femoral shaft were very consistent with the results for the femoral neck; however, cortical vBMD of the femoral shaft decreased significantly in both the ELD and ALF groups. In conclusion, our longitudinal analysis of hip geometry by clinical CT revealed the unexpected potential of ELD to increase cortical CSA, vBMD, and bone mass, and to maintain cortical thickness, probably through the more potent effect of ELD in mitigating endocortical bone resorption than ALF. By improving the biomechanical properties of the proximal femur, ELD may have the potential to reduce the risk of hip fractures. PMID- 21605717 TI - Graves' disease: diagnostic and therapeutic challenges (multimedia activity). AB - Graves' disease is the most common cause of hyperthyroidism in the United States. Graves' disease occurs more often in women with a female:male ratio of 5:1 and a population prevalence of 1% to 2%. A genetic determinant to the susceptibility to Graves' disease is suspected because of familial clustering of the disease, a high sibling recurrence risk, the familial occurrence of thyroid autoantibodies, and the 30% concordance in disease status between identical twins. Graves' disease is an autoimmune thyroid disorder characterized by the infiltration of immune effector cells and thyroid antigen-specific T cells into the thyroid and thyroid-stimulating hormone receptor expressing tissues, with the production of autoantibodies to well-defined thyroidal antigens, such as thyroid peroxidase, thyroglobulin, and the thyroid-stimulating hormone receptor. The thyroid stimulating hormone receptor is central to the regulation of thyroid growth and function. Stimulatory autoantibodies in Graves' disease activate the thyroid stimulating hormone receptor leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Below-normal levels of baseline serum thyroid-stimulating hormone receptor, normal to elevated serum levels of T4, elevated serum levels of T3 and thyroid-stimulating hormone receptor autoantibodies, and a diffusely enlarged, heterogeneous, hypervascular (increased Doppler flow) thyroid gland confirm diagnosis of Graves' disease (available at: http://supplements.amjmed.com/2010/hyperthyroid/faculty.php). This Resource Center is also available through the website of The American Journal of Medicine (www.amjmed.com). Click on the "Thyroid/Graves' Disease" link in the "Resource Centers" section, found on the right side of the Journal homepage. PMID- 21605718 TI - Chronic anemia as first clinical manifestation of a prolactin-secreting pituitary macroadenoma in a male patient. PMID- 21605719 TI - Viral reactivation and drug rash: causal or casual association? PMID- 21605721 TI - HITECH, electronic health records, and Facebook: a health information trifecta. PMID- 21605722 TI - Chemical cardiomyopathies: the negative effects of medications and nonprescribed drugs on the heart. AB - The heart is a target of injury for many chemical compounds, both medically prescribed and not medically prescribed. Pathophysiologic mechanisms underlying the development of chemical-induced cardiomyopathies vary depending on the inciting agent, including direct toxic effects, neurohormonal activation, altered calcium homeostasis, and oxidative stress. Numerous chemicals and drugs are implicated in cardiomyopathy. This article discusses examples of medication and nonprescribed drug-induced cardiomyopathies and reviews their pathophysiologic mechanisms. PMID- 21605723 TI - From bench to bedside: what physicians need to know about endothelial progenitor cells. AB - Since the discovery of endothelial progenitor cells in 1997, the scientific world has seen their ups and downs. There has been much discussion about the detection methods of endothelial progenitor cells and their diagnostic and predictive value. A lack of standardized methods to define endothelial progenitor cells has led to a number of nomenclatures and measuring methods that are difficult for clinicians to oversee. Therefore, only specialized hematologists and cardiologists were aware of their existence. Now it is time for a change: Most of the controversies have been eliminated by elaborate studies. This review aims to give an overview to the clinically working physician about the measurement, diagnostic potential, predictive value, and therapeutic potential of endothelial progenitor cells. PMID- 21605724 TI - Office management of hypertension in older persons. AB - Antihypertensive drug therapy reduces cardiovascular events in older persons. In the Hypertension in the Very Elderly Trial, at 1.8-year follow-up, patients aged 80 years and older treated with antihypertensive drug therapy had a 30% reduction in fatal or nonfatal stroke (P=.06), a 39% reduction in fatal stroke (P=.05), a 21% reduction in all-cause mortality (P=.02), a 23% reduction in death from cardiovascular causes (P=.06), and a 64% reduction in heart failure (P<.001). The goal of treatment of hypertension is to lower the blood pressure to less than 140/90 mm Hg in older persons and to less than 130/80 mm Hg in older persons with diabetes or chronic kidney disease if tolerated. The selection of antihypertensive drug therapy in persons with associated medical conditions depends on their medical conditions. Large meta-analyses of published trials show that thiazide diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, angiotensin receptor antagonists, and beta-blockers do not significantly differ in their ability to lower blood pressure and to exert cardiovascular protection in older and younger persons. If the blood pressure is more than 20/10 mm Hg above the goal blood pressure, drug therapy should be initiated with 2 antihypertensive drugs. Other coronary risk factors must be treated. PMID- 21605725 TI - Web of confusion. PMID- 21605726 TI - Resting tachycardia in an athlete. PMID- 21605727 TI - What else is back there? PMID- 21605728 TI - Cardiovascular screening with electrocardiography and echocardiography in collegiate athletes. AB - BACKGROUND: Current guidelines for preparticipation screening of competitive athletes in the US include a comprehensive history and physical examination. The objective of this study was to determine the incremental value of electrocardiography and echocardiography added to a screening program consisting of history and physical examination in college athletes. METHODS: Competitive collegiate athletes at a single university underwent prospective collection of medical history, physical examination, 12-lead electrocardiography, and 2 dimensional echocardiography. Electrocardiograms (ECGs) were classified as normal, mildly abnormal, or distinctly abnormal according to previously published criteria. Eligibility for competition was determined using criteria from the 36(th) Bethesda Conference on Eligibility Recommendations for Competitive Athletes with Cardiovascular Abnormalities. RESULTS: In 964 consecutive athletes, ECGs were classified as abnormal in 334 (35%), of which 95 (10%) were distinctly abnormal. Distinct ECG abnormalities were more common in men than women (15% vs 6%, P<.001) as well as black compared with white athletes (18% vs 8%, P<.001). Echocardiographic and electrocardiographic findings initially resulted in exclusion of 9 athletes from competition, including 1 for long QT syndrome and 1 for aortic root dilatation; 7 athletes with Wolff-Parkinson-White patterns were ultimately cleared for participation. (Four received further evaluation and treatment, and 3 were determined to not need treatment.) After multivariable adjustment, black race was a statistically significant predictor of distinctly abnormal ECGs (relative risk 1.82, 95% confidence interval, 1.22-2.73; P=.01). CONCLUSIONS: Distinctly abnormal ECGs were found in 10% of athletes and were most common in black men. Noninvasive screening using both electrocardiography and echocardiography resulted in identification of 9 athletes with important cardiovascular conditions, 2 of whom were excluded from competition. These findings offer a framework for performing preparticipation screening for competitive collegiate athletes. PMID- 21605729 TI - Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. AB - BACKGROUND: Concerns have been raised about the risk of fractures with acid suppressive medications, such as proton pump inhibitors and histamine(2)-receptor antagonists. METHODS: This meta-analysis evaluated the association between proton pump inhibitor or histamine(2)-receptor antagonist use and fractures. We performed a systematic search of published literature (1970 to October 10, 2010) in MEDLINE, EMBASE, and other sources. Ten publications reporting 11 studies were considered eligible for analysis. RESULTS: All studies were observational case control or cohort studies and primarily evaluated older adults. The summary effect estimate for risk of hip fracture increased modestly among individuals taking proton pump inhibitors (relative risk [RR] 1.30, 95% confidence interval [CI], 1.19-1.43). There also was an increase in spine (RR 1.56, 95% CI, 1.31 1.85) and any-site fractures (RR 1.16, 95% CI, 1.04-1.30) among proton pump inhibitor users. These findings were similar in both men and women and after stratification by duration of use. In contrast, histamine(2)-receptor antagonist use was not significantly associated with increased risk of hip fracture (RR 1.12, 95% CI, 0.97-1.30). CONCLUSION: In this meta-analysis of observational studies, proton pump inhibitors modestly increased the risk of hip, spine, and any-site fractures, whereas histamine(2)-receptor antagonists were not associated with fracture risk. The possibility of residual confounding cannot be excluded. Further skeletal evaluation should be considered for patients who are taking proton pump inhibitors and also at risk for osteoporotic fracture. PMID- 21605730 TI - Reversal of overanticoagulation in very elderly hospitalized patients with an INR above 5.0: 24-hour INR response after vitamin K administration. AB - BACKGROUND: Reversal of overanticoagulation to minimize the bleeding risk is important in elderly inpatients receiving vitamin K antagonist therapy. However, no study has specifically focused on this population. The objective of this study is to evaluate whether guidelines based on American College of Chest Physicians recommendations for the management of overanticoagulation (international normalized ratio [INR] >=5.0) can apply to elderly inpatients, and notably allow 24-hour INRs to return to the 1.8-3.2 range in this population. The influence of different factors on the vitamin K response also was evaluated. METHODS: Inpatients aged >=75 years with INR >=5.0 were included in this observational study. INRs were assessed on the day of the overdosage (Day 0) and on the following day (Day 1). RESULTS: Of 385 Day 0 INRs >=5.0 (239 patients; 86+/-6 years), 217 were managed according to recommendations, with a mean INR decreasing from 6.8+/-2.4 (range: 5.0-20.0) on Day 0 to 2.7+/-1.3 (range: 1.1-10.1) on Day 1 (P<.0001); 55% of INRs were within the 1.8-3.2 range, 20% <1.8, and 25% >3.2. In the subset of Day 0 INRs between 5.0 and 6.0, mean INR decreased from 5.5+/-0.3 to 2.7+/-1.0 (P<.0001) on Day 1 after oral administration of 1 mg vitamin K1 (n=121) and from 5.3+/-0.3 to 5.0+/-1.6 (P=.149) without vitamin K1 administration (n=48). Among covariates entered in the multivariate analysis, including co-medications, only the vitamin K1 dose influenced Day 1 INRs, with higher doses of vitamin K1 associated with Day 1 INRs <1.8 (P<.0001). CONCLUSION: In elderly inpatients with INR >=5.0, both vitamin K antagonist dose omission and vitamin K1 administration according to recommendations were effective in reversing overanticoagulation, allowing most INRs to return to the 1.8-3.2 range without excessive overcorrection. Therefore, American College of Chest Physicians recommendations may be applied to elderly inpatients. PMID- 21605731 TI - Cardiovascular risk factors in patients with lichen planus. AB - BACKGROUND: Chronic inflammation was found to play an important role in the development of cardiovascular risk factors. Recently a case-control study found that lichen planus was associated with dyslipidemia in a large series of patients. However, no data were presented about lipid values, glucose levels, or blood pressure. OBJECTIVE: The objective of this case-control study was to evaluate cardiovascular risk factors included in Adult Treatment Panel III criteria for metabolic syndrome in men and women with lichen planus and in healthy controls. PATIENTS AND METHODS: This case-control study included 200 patients, 100 with lichen planus (50 men and 50 women) and 100 controls consecutively admitted to the outpatient clinic in Dermatology departments in Granada, Spain. RESULTS: Analysis of metabolic syndrome parameters revealed a higher significant prevalence of dyslipidemia in patients with lichen planus. No significant differences were observed in glucose levels, abdominal obesity, or blood pressure. Elevated levels of C-reactive protein, erythrocyte sedimentation rate, and fibrinogen were noted in patients with lichen planus. Adjusted odds ratio for dyslipidemia in patients with lichen planus was 2.85 (95% confidence interval, 1.33-5.09; P=.001). CONCLUSION: Chronic inflammation in patients with lichen planus may explain the association with dyslipidemia. Lipid levels screening in men or women with lichen planus may be useful to detect individuals at risk and start preventive treatment against the development of cardiovascular disease. PMID- 21605732 TI - Use of a decision aid to improve treatment decisions in osteoporosis: the osteoporosis choice randomized trial. AB - OBJECTIVE: Poor adherence to therapy, perhaps related to unaddressed patient preferences, limits the effectiveness of osteoporosis treatment in at-risk women. A parallel patient-level randomized trial in primary care practices was performed. METHODS: Eligible postmenopausal women with bone mineral density T scores less than -1.0 and not receiving bisphosphonate therapy were included. In addition to usual primary care, intervention patients received a decision aid (a tailored pictographic 10-year fracture risk estimate, absolute risk reduction with bisphosphonates, side effects, and out-of-pocket cost), and control patients received a standard brochure. Knowledge transfer, patient involvement in decision making, and rates of bisphosphonate start and adherence were studied. Data came from medical records, post-visit written and 6-month phone surveys, video recordings of clinical encounters, and pharmacy prescription profiles. RESULTS: A total of 100 patients (range of 10-year fracture risk, 6%-60%) were allocated randomly to receive the decision aid (n=52) or usual care (n=48). Patients receiving the decision aid were 1.8 times more likely to correctly identify their 10-year fracture risk (49% vs 28%; 95% confidence interval [CI], 1.03-3.2) and 2.7 times more likely to identify their estimated risk reduction with bisphosphonates (43% vs 16%; 95% CI, 1.3-5.7). Patient involvement improved with the decision aid by 23% (95% CI, 13.6-31.4). Bisphosphonates were started by 44% of patients receiving the decision aid and 40% of patients receiving usual care. Adherence at 6 months was similarly high across both groups, but the proportion with more than 80% adherence was higher with the decision aid (n=23 [100%] vs n=14 [74%]; P = .009). CONCLUSION: A decision aid improved the quality of clinical decisions about bisphosphonate therapy in at-risk postmenopausal women, did not affect start rates, and may have improved adherence. PMID- 21605733 TI - Activating peripheral arterial disease patients to reduce cholesterol: a randomized trial. AB - BACKGROUND: Peripheral arterial disease patients are less likely than other high risk patients to achieve ideal low-density lipoprotein (LDL) cholesterol levels. This randomized controlled trial assessed whether a telephone counseling intervention, designed to help peripheral arterial disease patients request more intensive cholesterol-lowering therapy from their physician, achieved lower LDL cholesterol levels than 2 control conditions. METHODS: There were 355 peripheral arterial disease participants with baseline LDL cholesterol >=70 mg/dL enrolled. The primary outcome was change in LDL cholesterol level at 12-month follow-up. There were 3 parallel arms: telephone counseling intervention, attention control condition, and usual care. The intervention consisted of patient-centered counseling, delivered every 6 weeks, encouraging participants to request increases in cholesterol-lowering therapy from their physician. The attention control condition consisted of telephone calls every 6 weeks providing information only. The usual care condition participated in baseline and follow-up testing. RESULTS: At 12-month follow-up, participants in the intervention improved their LDL cholesterol level, compared with those in attention control ( 18.4 mg/dL vs -6.8 mg/dL, P=.010) but not compared with those in usual care ( 18.4 mg/dL vs -11.1 mg/dL, P=.208). Intervention participants were more likely to start a cholesterol-lowering medication or increase their cholesterol-lowering medication dose than those in the attention control (54% vs 18%, P=.001) and usual care (54% vs 31%, P <.001) conditions. CONCLUSION: Telephone counseling that helped peripheral arterial disease patients request more intensive cholesterol-lowering therapy from their physician achieved greater LDL cholesterol decreases than an attention control arm that provided health information alone. PMID- 21605735 TI - Valuing the education mission: implementing an educational value units system. PMID- 21605734 TI - Associations of serum alkaline phosphatase with metabolic syndrome and mortality. AB - BACKGROUND: Recent data suggest that elevated serum alkaline phosphatase levels are associated with increased mortality, but the mechanisms for this association are unknown. As metabolic syndrome is associated with higher serum alkaline phosphatase levels, we examined the joint association of mortality with metabolic syndrome and serum alkaline phosphatase levels in the US general population. METHODS: Retrospective observational study of 15,234 adult participants in the National Health and Nutrition Examination Survey III. Multivariable Cox regression analyses were used to jointly relate mortality risk to serum alkaline phosphatase and indicators of metabolic syndrome. RESULTS: Prevalence of metabolic syndrome was 14% to 41% among patients in lowest and higher quartiles, respectively, for baseline serum alkaline phosphatase. The mortality hazard ratio for each doubling of serum alkaline phosphatase was 1.52 (95% confidence interval [CI], 1.35-1.72) adjusting only for demographic factors, and 1.37 (95% CI, 1.21 1.56) adjusting for both demographic and metabolic syndrome factors in the full cohort, and was 1.83 (95% CI, 1.36-2.46) adjusting for demographic factors in the subgroup without any of the component conditions of metabolic syndrome. CONCLUSIONS: In the US general population, higher levels of serum alkaline phosphatase is a predictor of mortality independent of the baseline prevalence of metabolic syndrome. Further studies are warranted to unravel the mechanisms of this association. PMID- 21605736 TI - Effects of milk composition, stir-out time, and pressing duration on curd moisture and yield. AB - A study was undertaken to investigate the effects of milk composition (i.e., protein level and protein:fat ratio), stir-out time, and pressing duration on curd moisture and yield. Milks of varying protein levels and protein:fat ratios were renneted under normal commercial conditions in a pilot-scale cheese vat. During the syneresis phase of cheese making, curd was removed at differing times, and curd moisture and yield were monitored over a 22-h pressing period. Curd moisture after pressing decreased with longer stir-out time and pressing duration, and an interactive effect was observed of stir-out time and pressing duration on curd moisture and yield. Milk total solids were shown to affect curd moisture after pressing, which has implications for milk standardization; that is, it indicates a need to standardize on a milk solids basis as well as on a protein:fat basis. In this study, a decreased protein:fat ratio was associated with increased total solids in milk and resulted in decreased curd moisture and increased curd yield after pressing. The variation in total solids of the milk explains the apparent contradiction between decreased curd moisture and increased curd yield. This study points to a role for process analytic technology in minimizing variation in cheese characteristics through better control of cheesemilk composition, in-vat process monitoring (coagulation and syneresis), and post-vat moisture reduction (curd pressing). Increased control of curd composition at draining would facilitate increased control of the final cheese grade and quality. PMID- 21605737 TI - Factors associated with coliform count in unpasteurized bulk milk. AB - The objective of this study was to identify factors associated with bulk milk coliform count (CC). Dairy farms (n=10) were visited once weekly on sequential weekdays over a period of 10 wk. During each visit, in-line drip samplers were used to collect 1 milk sample from 2 points of the milk line (between the receiver jar and milk filters, and after the plate cooler). During the same period that in-line milk samples were collected, university personnel observed milking performance and hygiene and collected liner (n=40) and teat skin swabs (n=40). Coliform counts were determined for milk samples and swabs using Petrifilm CC plates (3M, St. Paul, MN). A mixed model was used to assess the association between in-line milk CC (ILCC) and several potential predictor variables. The mean duration of each visit was 73 min and the time between start of milking and beginning of milk sampling was 154 min. The mean number of cows milked during each visit was 236. For all milk samples (n=181), geometric mean ILCC was 37 cfu/mL. In-line milk CC varied by farm, ranging from 5 to 1,198 cfu/mL. Rate of fall-offs, rate of cluster washes, outdoor and indoor temperature, indoor humidity, sampling duration, and parity group were unconditionally associated with ILCC but did not enter the final multivariate model. In-line milk CC was 4 times greater (115 cfu/mL) when milking machine wash failures occurred compared with ILCC after normal washes (26 cfu/mL). Pre-filter and post-cooler ILCC were not different when milk samples were collected at the beginning (<33% of herd milked) or at mid-milking (33 to 66% of the herd milked), whereas pre-filter ILCC was less than post-cooler for samples collected at the end of milking (>67% of the herd milked). Geometric mean ILCC (cfu/mL) increased 6.3% for every 10% increase in in-line milk SCC (cells/mL). Geometric mean ILCC increased 2.3% for every 10% increase in liner CC (cfu/mL). Results of this study provide novel information about farm factors associated with CC, as estimated in milk before storage in tankers or bulk tanks, and highlight the importance of proper and consistent milking machine washes in minimizing bulk milk coliform contamination. The nature of the associations between liner CC, rate of cluster washes, rate of milking units fall-offs, and ILCC indicates that managing and monitoring such events has the potential for improving bacteriological quality of farm bulk milk. PMID- 21605738 TI - Effect of different curd-washing methods on the insoluble Ca content and rheological properties of Colby cheese during ripening. AB - A curd-washing step is used in the manufacture of Colby cheese to decrease the residual lactose content and, thereby, decrease the potential formation of excessive levels of lactic acid. The objective of this study was to investigate the effect of different washing methods on the Ca equilibrium and rheological properties of Colby cheese. Four different methods of curd-washing were performed. One method was batch washing (BW), where cold water (10 degrees C) was added to the vat, with and without stirring, where curds were in contact with cold water for 5 min. The other method used was continuous washing (CW), with or without stirring, where curds were rinsed with continuously running cold water for approximately 7 min and water was allowed to drain immediately. Both methods used a similar volume of water. The manufacturing pH values were similar in all 4 treatments. The insoluble (INSOL) Ca content of cheese was measured by juice and acid-base titration methods and the rheological properties were measured by small amplitude oscillatory rheology. The levels of lactose in cheese at 1 d were significantly higher in CW cheese (0.06-0.11%) than in BW cheeses (~0.02%). The levels of lactic acid at 2 and 12 wk were significantly higher in CW cheese than in BW cheeses. No differences in the total Ca content of cheeses were found. Cheese pH increased during ripening from approximately 5.1 to approximately 5.4. A decrease in INSOL Ca content of all cheeses during ripening occurred, although a steady increase in pH took place. The initial INSOL Ca content as a percent of total Ca in cheese ranged from 75 to 78% in all cheeses. The INSOL Ca content of cheese was significantly affected by washing method. Stirring during manufacturing did not have a significant effect on the INSOL Ca content of cheese during ripening. Batch-washed cheeses had significantly higher INSOL Ca contents than did CW cheeses during the first 4 wk of ripening. The maximum loss tangent values (meltability index) of CW cheese at 1 d and 1 wk were significantly higher compared with those of BW cheeses. In conclusion, different curd washing methods have a significant effect on the levels of lactose, lactic acid, meltability, and INSOL Ca content of Colby cheese during ripening. PMID- 21605739 TI - Manufacture of low-sodium Minas fresh cheese: effect of the partial replacement of sodium chloride with potassium chloride. AB - We investigated the effect of sodium reduction by partial substitution of sodium chloride (NaCl) with potassium chloride (KCl) on the manufacture of Minas fresh cheese during 21 d of refrigerated storage. Four treatments of low-sodium Minas fresh cheese were manufactured, with partial replacement of NaCl by KCl at 0, 25, 50, and 75% (wt/wt), respectively. The cheeses showed differences in the content of moisture, ash, protein, salt, and lipid contents, as well as on the extent of proteolysis and hardness throughout the storage period. However, no difference was observed among treatments within each storage day tested. The partial substitution of NaCl by KCl decreased up to 51.8% the sodium concentration of the cheeses produced. The consumer test indicated that it is possible to manufacture a low-sodium Minas fresh cheese that is acceptable to consumers by partial substitution of NaCl by KCl at 25% (wt/wt) in the salting step. PMID- 21605740 TI - The composition of interfacial material from skim milk foams. AB - The foaming properties of skim milk vary with temperature of foaming in the range from 5 to 85 degrees C, with foams of maximum stability being formed at approximately 45 degrees C. This paper reports the significance of different milk fractions in the foam and concludes that the micellar casein fraction plays an important role in stabilization of milk foam formed at higher temperatures. This finding was supported by the fact that added calcium chloride increased and calcium-chelating agents decreased foam stability. These effects were attributed to the increase and decrease, respectively, in the amount of micellar casein in the milk. Furthermore, bubble ghost material sedimented by low-speed centrifugation of foam was found to contain predominantly caseins, and electron micrographs of foams formed at 45 degrees C clearly showed casein micelles spread over the interface. However, other structures observed in the electron micrographs suggest that soluble milk proteins and possibly polar lipids are also present in the foams and play a role in formation of milk foams. PMID- 21605741 TI - Standardization of milk using cold ultrafiltration retentates for the manufacture of Swiss cheese: effect of altering coagulation conditions on yield and cheese quality. AB - Fortification of cheesemilk with membrane retentates is often practiced by cheesemakers to increase yield. However, the higher casein (CN) content can alter coagulation characteristics, which may affect cheese yield and quality. The objective of this study was to evaluate the effect of using ultrafiltration (UF) retentates that were processed at low temperatures on the properties of Swiss cheese. Because of the faster clotting observed with fortified milks, we also investigated the effects of altering the coagulation conditions by reducing the renneting temperature (from 32.2 to 28.3 degrees C) and allowing a longer renneting time before cutting (i.e., giving an extra 5min). Milks with elevated total solids (TS; ~13.4%) were made by blending whole milk retentates (26.5% TS, 7.7% CN, 11.5% fat) obtained by cold (<7 degrees C) UF with part skim milk (11.4% TS, 2.5% CN, 2.6% fat) to obtain milk with CN:fat ratio of approximately 0.87. Control cheeses were made from part-skim milk (11.5% TS, 2.5% CN, 2.8% fat). Three types of UF fortified cheeses were manufactured by altering the renneting temperature and renneting time: high renneting temperature=32.2 degrees C (UFHT), low renneting temperature=28.3 degrees C (UFLT), and a low renneting temperature (28.3 degrees C) plus longer cutting time (+5min compared to UFLT; UFLTL). Cutting times, as selected by a Wisconsin licensed cheesemaker, were approximately 21, 31, 35, and 32min for UFHT, UFLT, UFLTL, and control milks, respectively. Storage moduli of gels at cutting were lower for the UFHT and UFLT samples compared with UFLTL or control. Yield stress values of gels from the UF fortified milks were higher than those of control milks, and decreasing the renneting temperature reduced the yield stress values. Increasing the cutting time for the gels made from the UF-fortified milks resulted in an increase in yield stress values. Yield strain values were significantly lower in gels made from control or UFLTL milks compared with gels made from UFHT or UFLT milks. Cheese composition did not differ except for fat content, which was lower in the control compared with the UF-fortified cheeses. No residual lactose or galactose remained in the cheeses after 2 mo of ripening. Fat recoveries were similar in control, UFHT, and UFLTL but lower in UFLT cheeses. Significantly higher N recoveries were obtained in the UF-fortified cheeses compared with control cheese. Because of higher fat and CN contents, cheese yield was significantly higher in UF-fortified cheeses (~11.0 to 11.2%) compared with control cheese (~8.5%). A significant reduction was observed in volume of whey produced from cheese made from UF-fortified milk and in these wheys, the protein was a higher proportion of the solids. During ripening, the pH values and 12% trichloroacetic acid-soluble N levels were similar for all cheeses. No differences were observed in the sensory properties of the cheeses. The use of UF retentates improved cheese yield with no significant effect on ripening or sensory quality. The faster coagulation and gel firming can be decreased by altering the renneting conditions. PMID- 21605742 TI - Zinc-binding capacity of yak casein hydrolysate and the zinc-releasing characteristics of casein hydrolysate-zinc complexes. AB - Many factors affect the bioavailability of dietary Zn, which leads to its low availability in some food systems and Zn nutrient deficiency. However, some proteins or peptides can form complexes with Zn and increase its absorption and bioavailability in intestinal conditions. The purpose of this work was to determine the Zn-binding activity of yak casein hydrolysate (YCH) and examine its stability, solubility, and dialyzability in a simulated intestinal environment. The Zn-binding activity of YCH, prepared using alcalase, pepsin, trypsin, Flavozyme (Novo Nordisk Biochem Inc., Franklinton, NC), or papain, was investigated. Evidence for the formation of complexes between Zn and YCH also were detected by UV-visible spectroscopy and Fourier transform infrared spectroscopy. Results were that YCH prepared with alcalase and trypsin possessed the highest Zn-binding capacity compared with YCH prepared with pepsin, Flavozyme, or papain. The 6-h YCH obtained with alcalase showed the highest Zn binding capacity. Compared with native yak casein, the Zn-binding activity of YCH was significantly lower, but its solubility and dialyzability were markedly higher under intestinal basic pH ranges. This is important because high solubility and dialyzability is associated with better bioavailability. Both UV visible spectroscopy and Fourier transform infrared spectroscopy spectra indicated that some sites of YCH can bind with Zn ions and form complexes that make Zn more soluble and dialyzable under simulated intestinal conditions. Therefore, YCH-Zn complexes may have potential to improve Zn bioavailability. PMID- 21605743 TI - The effect of substituting NaCl with KCl on Nabulsi cheese: chemical composition, total viable count, and texture profile. AB - The effect of substituting NaCl with KCl on Nabulsi cheese characteristics was investigated. Nabulsi cheese was made and stored in 4 different brine solutions at 18%, including NaCl only (A; control); 3NaCl:1KCl (wt/wt; B); 1NaCl:1KCl (wt/wt; C); and 1NaCl:3KCl (wt/wt; D). Chemical composition, proteolysis, total viable count, and texture profile analysis were assessed at monthly intervals for 5 mo. No significant effect was found among experimental cheeses in terms of chemical composition or texture profile. Proteolytic activities were higher in cheeses kept in brine solutions that contained higher KCl (B, C, and D) compared with the control. At the end of the storage period, water-soluble nitrogen in Nabulsi cheeses stored in B, C, and D was higher than that in the control cheese (A). In addition, total viable count increased significantly after 1 mo of storage for all salt treatments. Hardness and gumminess generally decreased significantly during storage within the same salt treatment. PMID- 21605744 TI - Goat milk during iron repletion improves bone turnover impaired by severe iron deficiency. AB - The effect of goat or cow milk-based diets, with either normal Fe content or an Fe overload, on bone turnover and the mineralization process was studied in control and anemic rats during chronic Fe repletion. One hundred eighty male Wistar rats were studied during a pre-experimental period of 40 d in which they were randomly divided into 2 groups, a control group receiving the AIN-93G diet with normal Fe content (45 mg/kg of diet) and the Fe-deficient group receiving the AIN-93G diet with low Fe content (5mg/kg of diet) for 40 d. After the pre experimental period, the rats were fed for 10, 30, or 50 d with goat or cow milk based diets with a normal Fe content (45 mg/kg of diet) or an Fe overload (450 mg/kg of diet). In anemic rats, goat milk with normal Fe content increased levels of the biomarker of bone formation N-terminal propeptides of type I procollagen and diminished parathyroid hormone levels after only 10 d of supplying this diet, indicating the beginning of restoration of the bone demineralization induced by the anemia, which was not observed with cow milk. After 30 d of supplying the milk-based diets with normal Fe content or an Fe overload, biomarkers of bone formation and bone resorption were not different between control and anemic rats, indicating that the bone demineralization induced by the Fe-deficiency anemia had recovered, although the process of stabilization of bone turnover began earlier in the animals fed goat milk. In addition, a higher Ca deposit was observed in femur, which positively affects bone mineralization, as well as an increase of Fe in sternum, which indicates that the hematopoietic process essentially recovered earlier on the goat milk diet compared with the cow milk diet. PMID- 21605745 TI - Proteolysis of milk fat globule membrane proteins during in vitro gastric digestion of milk. AB - The influence of gastric proteolysis on the physicochemical characteristics of milk fat globules and the proteins of the milk fat globule membrane (MFGM) in raw milk and cream was examined in vitro in simulated gastric fluid (SGF) containing various pepsin concentrations at pH 1.6 for up to 2h. Apparent flocculation of the milk fat globules occurred in raw milk samples incubated in SGF containing pepsin, but no coalescence was observed in either raw milk samples or cream samples. The changes in the particle size of the fat globules as a result of the flocculation were dependent on the pepsin concentration. Correspondingly, the physical characteristics of the fat globules and the composition of the MFGM proteins in raw milk changed during incubation in SGF containing pepsin. The major MFGM proteins were hydrolyzed at different rates by the pepsin in the SGF; butyrophilin was more resistant than xanthine oxidase, PAS 6, or PAS 7. Peptides with various molecular weights, which altered with the time of incubation and the pepsin concentration, were present at the surfaces of the fat globules. PMID- 21605746 TI - Short communication: Proteins in heat-processed skim milk powder have no positive effects on bone loss of ovariectomized rats. AB - Milk has positive effects on bone growth. However, the effect of skim milk powder (SMP) on bone properties has not been reported. This study investigated the effect of SMP on bone loss in ovariectomized (OVX) rats. Forty female Sprague Dawley rats were ovariectomized and another 10 rats received a sham operation. The OVX rats were randomly separated into 4 groups: OVX control, OVX SMP1 (SMP at 0.04 g/d), OVX SMP2 (SMP at 0.20 g/d), and OVX SMP3 (SMP at 0.40 g/d). Skim milk powder was supplied in the rat diet for 12 wk, and the rats were gavaged once per day. The effects of SMP on calcium content and bone mineral density of femur were determined by atomic absorption spectrophotometry and dual-energy x-ray absorptiometry, respectively. Compared with the control, SMP at all dose levels tested had no particular effect on weight:length, calcium content, or bone mineral density of femurs. It was demonstrated that SMP (0.04 to 0.40 g/d) had no positive effect on bone loss in OVX rats, probably because the heat treatment used during SMP processing caused a loss of biological activity in the protein. PMID- 21605747 TI - Short communication: Occurrence of aflatoxin M1 in the Manchego cheese supply chain. AB - The importance of ewe milk lies in the production of high quality cheeses, such as Manchego cheese with a Protected Designation of Origin, whose safety must be guaranteed. In a 2-yr study, 407 bulk tank milk samples from farms and 82 silo milk and curd samples from cheese factories were collected from southeast Spain and tested for aflatoxin M1 (AFM1) using 2 commercial ELISA tests. Of these, 99.3% of the bulk tank samples had AFM1 levels below the European Union (EU) legal limit for milk (50 ng/kg), and well below the limit adopted by the Codex Alimentarius (500 ng/kg). Moreover, 98.8% of the silo milk and curd samples from cheese factories had AFM1 levels below the EU limit for milk. When considering median AFM1 concentrations, an average 4-fold increase was found in the final curd in relation to the corresponding silo milk. Control of AFM1 in Manchega ewe milk would enhance dairy product safety by the possible detection of faults in the manufacture of Manchego cheese. PMID- 21605748 TI - First evidence of the presence of genomic islands in Escherichia coli P4, a mammary pathogen frequently used to induce experimental mastitis. AB - Mastitis pathogens belonging to Escherichia coli species are often considered as environmental opportunistic pathogens that invade the udder and are rapidly killed by the immune system of cows. However, several studies have reported that some of these strains are able to persist in the udder for prolonged periods or to adhere and invade mammary epithelial cells, suggesting that they might possess some specific properties or genes that could be involved in their capacity to provoke mastitis. The aim of this work was to search for such specific genes in the E. coli strain P4, which was isolated from a case of severe mastitis and is often used to induce experimental mastitis. We established that this strain belongs to phylogenetic group A of the E. coli species, and that its core genome is very similar to that of the commensal nonpathogenic strain E. coli K-12 MG1655. Seventeen transfer RNA loci, known to be frequently associated with genomic islands, were screened and an altered structure was detected for 7 of them. The partial characterization of 5 of these loci (asnT, leuX, pheV, serU, and thrW) and the complete characterization of 1 (argW) revealed the presence of genomic islands that differ from those already described in pathogenic or nonpathogenic E. coli strains. PMID- 21605749 TI - Further investigation of lameness in cows at pasture: an analysis of the lesions found in, and some possible risk factors associated with, lame New Zealand dairy cattle requiring veterinary treatment. AB - Previous descriptive analysis of data collected from veterinary visits to lame cows in the Taranaki region of New Zealand between December 1995 and July 2007 showed an association between both breed and age and lesion type and site. However, that simple analysis had significant limitations as it did not take account of more than 2 factors at the same time and did not evaluate the effect of time (either year or season). This analysis was designed to overcome those limitations. First, correspondence analysis, a multivariate method of analysis, was used to simultaneously evaluate the relationship between the 3 most commonly recorded causes of lameness (i.e., white line disease, sole injury, and axial disease, all of which are diseases of the claw horn), and 4 groups of predictor variables: foot (front or hind), breed (Jersey or Friesian), age (heifer or cow), and claw (lateral or medial). Second, time series analysis was used to ascertain the effect of season on lesion type and identify the change over years in proportional morbidity. The correspondence analysis clearly separated the 3 diseases, showing that differences between these 3 diseases in their risk factors and their etiology. Each disease clustered with a group of predictor variables. White line disease was linked to lateral claw, hind foot, cow, and Friesian breed; sole injury was linked to heifer and medial claw; and axial disease to Jersey and front foot. As sole injury and axial disease are diseases that occur principally in cows at pasture, this is the first full analysis of risk factors for those diseases. The time series analysis further strengthened the conclusion that these 3 diseases have different risk factors, as, even in the strongly seasonal New Zealand system, significant differences in seasonality occurred between them. This analysis adds further to the data which show that claw horn diseases have different etiologies and need to be treated separately for both research purposes and for lameness management on-farm. This analysis is only a starting point; more research is required, particularly longitudinal studies, to better understand the differences in etiology between the main causes of lameness due to claw horn disease, especially in cows kept at pasture, so that we can better target prevention. PMID- 21605750 TI - Luteolytic effects of cloprostenol sodium in lactating dairy cows treated with G6G/Ovsynch. AB - The probability of a pregnancy decreases substantially in lactating dairy cows treated with Ovsynch if luteolysis is delayed or incomplete. Two PGF(2alpha) products are currently approved in the United States for luteolysis in lactating dairy cattle, dinoprost tromethamine and cloprostenol sodium. Cloprostenol has a longer half-life compared with dinoprost, is more resistant to endogenous metabolism, and is maintained in circulation longer. We hypothesized that cloprostenol could reduce the time to complete luteolysis compared with dinoprost because of differences in half-life. Lactating dairy cows received the same presynchronization strategy (G6G; 25mg of PGF(2alpha) - 2 d - 100 MUg of GnRH - 6 d - 100 MUg of GnRH - 7 d - final PGF(2alpha) treatment). At the time of the final PGF(2alpha), cows (n=35) were randomly assigned to receive either 500MUg of cloprostenol or 25mg of dinoprost. Blood samples were collected daily before and serially after PGF(2alpha) treatment to analyze circulating concentrations of progesterone (P(4)) and estradiol (E(2)). Ultrasound examinations of ovaries were performed to measure sizes of follicles and corpora lutea (CL) and determine time of ovulation. Considering only cows with complete luteolysis, mean circulating P(4) was lower for cows given cloprostenol than for those given dinoprost between 0 and 12h postinjection, but not at 24, 36, or 48 h. A rapid decrease in P(4) was observed 1h after PGF(2alpha) (6.54 +/- 0.27 to 3.77 +/- 0.22 ng/mL) followed by a complete rebound 1h later (3.77 +/- 0.22 to 5.07 +/- 0.31 ng/mL) followed by a steady decline in both treatment groups. Serum concentrations of E(2) were greater at 48 h posttreatment in cloprostenol-treated cows (2.74 +/- 0.15 pg/mL) than in dinoprost-treated cows (2.37 +/- 0.19 pg/mL). Cows that did not have complete luteolysis did not ovulate (0/7) during the 6-d period following treatment. Time to complete luteolysis and ovulation was 29.1 +/- 1.1 versus 29.4 +/- 1.7 and 101 versus 103 h posttreatment in cloprostenol compared with dinoprost. A negative relationship was observed between P(4) at 12h posttreatment and concentrations of E(2) 48 h posttreatment (b=-0.6905; R(2)=0.23). In summary, cows treated with cloprostenol had lower concentrations of P(4) for the first 12h following treatment and subsequently greater concentrations of E(2) compared with dinoprost, although no differences were observed in these 2 PGF(2alpha) analogs for time to complete luteolysis or time to ovulation. PMID- 21605751 TI - Effects of cloprostenol sodium at final prostaglandin F2alpha of Ovsynch on complete luteolysis and pregnancy per artificial insemination in lactating dairy cows. AB - Luteolysis is a key event in Ovsynch programs of lactating dairy cows. Studies indicate that as many as 20% of cows treated with a Presynch/Ovsynch program have delayed or incomplete luteolysis using dinoprost tromethamine. Cows must have complete luteolysis to have a chance to become pregnant. Dinoprost tromethamine has a short half-life of approximately 7 to 8min. Cloprostenol sodium is more resistant to endogenous metabolism and is maintained in circulation for a longer time (half-life=3h). The objective was to determine if cloprostenol sodium could increase the percentage of cows with complete luteolysis and subsequent pregnancy per artificial insemination (P/AI) in lactating dairy cows compared with dinoprost tromethamine when administered within a presynchronization plus Ovsynch program for first artificial insemination (n=652) and an Ovsynch resynchronization program for second or later AI (second+; n=394). Blood samples were collected daily for 5 d beginning at the PGF(2alpha) of Ovsynch in a subset of cows (n=680) for first and second+ AI to measure circulating concentrations of progesterone (P(4)) and estradiol (E(2)). Complete luteolysis was defined as cows with functional corpus luteum (CL) at time of treatment and serum concentrations of P(4) <0.5 ng/mL at 56, 72, and 96 h after treatment. Percentage of cows with functional CL that had complete luteolysis after treatment was not greater for cloprostenol sodium compared with dinoprost tromethamine in first (79 vs. 80%, respectively) or second+ AI (70 vs. 72%, respectively). In addition, mean serum concentrations of P(4) were not less for cows treated with cloprostenol sodium following treatment. Pregnancy per AI of cows treated with cloprostenol sodium tended to be greater than dinoprost tromethamine for first (40 vs. 35%; respectively) but not second+ AI (23 vs. 21%, respectively). Cows with greater serum P(4) concentrations at time of PGF(2alpha) of Ovsynch had a greater probability of undergoing complete luteolysis after PGF(2alpha) of Ovsynch and pregnancy at 39 d after timed AI (i.e., 50% pregnant at 8 vs. 28% pregnant at 4 ng/mL P(4)). Serum concentrations of E(2) at 56 h after PGF(2alpha) of Ovsynch were a positive predictor of pregnancy at 39 d after timed AI. In summary, cloprostenol sodium tended to improve P/AI. Cows with greater serum concentrations of P(4) at time of PGF(2alpha) of Ovsynch had a greater chance of luteolysis and pregnancy. PMID- 21605752 TI - Case-control study: Productivity and longevity of dairy cows that tested positive for infection with Mycobacterium avium ssp. paratuberculosis as heifers compared to age-matched controls. AB - A case-control study was performed to determine if dairy heifers testing positive for Mycobacterium avium ssp. paratuberculosis (MAP) before 2 yr of age by either fecal culture or serum ELISA had decreased productivity and longevity as cows compared with age-matched herdmates. Cases were individually matched with 4 controls. Survival analysis was conducted to determine differences in longevity between cases and controls. Conditional logistic regression was used to assess differences in mean 3.5% fat-corrected 305-d mature-equivalent milk, milk fat, and milk protein production, linear somatic cell count, and MAP test and clinical status as mature cows. No significant difference was found between cases and controls for any parameter assessed. Herd production performance and longevity did not appear to be impaired; therefore, testing immature dairy heifers for MAP is not economically justifiable, using currently available culture methods and commercial serum ELISA tests. PMID- 21605753 TI - Sources other than unused sawdust can introduce Klebsiella pneumoniae into dairy herds. AB - A longitudinal study was carried out to detect intramammary infections caused by Klebsiella pneumoniae and to identify potential sources of this bacterial species in the environment of the cows. The study was performed in 6 well-managed Belgian dairy herds from May 2008 to May 2009. Monthly (n=13), unused and used sawdust bedding samples as well as individual quarter milk and feces samples were collected from 10 randomly selected cohort cows in each herd. Cases of clinical mastitis of all lactating cows in the 6 herds were also sampled (n=64). From the 3,518 collected samples, 153 K. pneumoniae isolates were obtained, of which 2 originated from milk (clinical mastitis cases). In feces (n=728), used bedding (n=73), and unused bedding (n=73), respectively, 125 (17.2%), 20 (27.4%), and 6 (8.2%) isolates were found. The isolates were fingerprinted by means of pulsed field gel electrophoresis. In total, 109 different pulsotypes were differentiated, indicating a high degree of genetic diversity within the isolates. All isolates from unused bedding belonged to pulsotypes other than those from the other sources, suggesting that sources other than unused sawdust may introduce K. pneumoniae into the herd. Only 2 pulsotypes contained isolates originating from different sources. Pulsotype 10 was found in milk and used bedding and pulsotype 21 was found in feces and used bedding. The 2 milk isolates originated from 2 cows in the same herd but they belonged to a different pulsotype. The results indicate that K. pneumoniae can be prevalent in the environment without causing significant mastitis problems. Most cows were shedding K. pneumoniae in feces, substantiating findings under very different conditions (i.e., American dairy herds). Contamination of used bedding in the cubicles with K. pneumoniae from feces was confirmed, whereas unused bedding was not an important source of K. pneumoniae for the environment of the cows. PMID- 21605754 TI - Rumen pH and fermentation characteristics in dairy cows supplemented with Megasphaera elsdenii NCIMB 41125 in early lactation. AB - This study investigated the effect of using the lactate-utilizing bacterium Megasphaera elsdenii NCIMB 41125 as a probiotic supplement on rumen fermentation and pH in dairy cows in the immediate postcalving period. Fourteen multiparous rumen-fistulated Holstein cows, blocked according to 305-d milk yield in the previous lactation, were used in a randomized complete block design. From d 1 to 28 postcalving, cows were fed ad libitum a total mixed ration with a forage to concentrate ratio of 392:608 and a starch concentration of 299g/kg of dry matter. Treatments consisting of a minimum of 10(10) cfu of Megasphaera elsdenii NCIMB 41125 or autoclaved M. elsdenii (placebo) were administered via the rumen cannula on d 3 and 12 of lactation (n=7 per treatment). Mid-rumen pH was measured every 15min, and eating and ruminating behaviors were recorded for 24h on d 2, 4, 6, 8, 11, 13, 15, 17, 22, and 28. Rumen fluid for volatile fatty acid and lactic acid analysis was collected at 11 time points on each of d 2, 4, 6, 13, and 15. Yields of milk and milk protein and lactose were similar, but milk fat concentration tended to be higher in cows that received the placebo. Time spent eating and ruminating and dry matter intake were similar across treatments. Ruminal lactic acid concentrations were highly variable between animals, and no cases of clinical acidosis were observed. Both treatment groups had rumen pH <5.6 for more than 3h/d (a commonly used threshold to define subacute ruminal acidosis), but the length of time with rumen pH <5.6 was markedly reduced in the days immediately after dosing and fluctuated much less from day to day in cows that received M. elsdenii compared with those that received the placebo. Ruminal total volatile fatty acid concentrations were similar across treatments, but the acetate:propionate ratio tended to be smaller in cows that received M. elsdenii. Despite the lack of a measurable treatment effect on ruminal lactic acid concentration, supplementation of early lactation dairy cows with lactate utilizing M. elsdenii altered the rumen fermentation patterns in favor of propionate, with potential benefits for energy balance and animal productivity. PMID- 21605756 TI - Effect of trans-10, cis-12 conjugated linoleic acid on performance, adipose depot weights, and liver weight in early-lactation dairy cows. AB - In feeding practice, conjugated linoleic acid (CLA) supplements are used to decrease milk fat excretion in early-lactation dairy cows to save energy to counteract the physiological negative energy balance. The present study was conducted to examine the effects of CLA on energy metabolism, changes in liver weight, and the weight of different adipose depots during early lactation. Primiparous lactating German Holstein cows (n=25) were divided into 5 groups and each group contained 5 animals. The experiment started 21 d prepartum and continued until 105 d in milk (DIM). Cows were slaughtered at 1, 42, and 105 DIM. The experiment was divided into a prepartum period (21 d prepartum until calving), period 1 (1 until 42 DIM), and period 2 (>42 until 105 DIM). In the prepartum period, all animals were housed together and fed the same diet with no CLA supplementation. At 1 DIM, an initial group, with no CLA supplementation, was slaughtered. The 20 remaining cows were assigned to 2 diets. One group received 100g/d of a control fat supplement (CON; n=10) and the other group 100g/d of a CLA supplement (CLA; n=10) from 1 DIM until slaughter. Five cows of each feeding group were slaughtered after 42 DIM and the remaining animals after 105 DIM. The CLA supplement contained approximately 10% each of trans-10, cis-12 CLA and cis 9, trans-11 CLA. During the slaughter process the empty body weight was recorded and the omental, mesenteric, retroperitoneal, and s.c. adipose depots, as well as the liver, were dissected and weighed. The CLA treatment decreased milk fat content in period 1 (14.1%). In period 2, milk fat content (25.4%) and yield (17.1%) were lower in the CLA group. No effect of CLA on milk yield was observed. The net energy intake, milk energy output, and the calculated energy balance remained unchanged by CLA supplementation. No effect of CLA on the weights of liver, omental, mesenteric, or s.c. adipose depots was observed when related to empty body weight. Liver weight increased with DIM, whereas the retroperitoneal adipose depot weight decreased at the same time. Compared with the initial group, the retroperitoneal adipose depot weight for control animals slaughtered after 42 DIM was decreased (47.7%); however, for the CLA group slaughtered after 42 DIM, a trend to a lower retroperitoneal adipose depot weight (34.0%) was observed. This suggests a CLA-induced deceleration of mobilization of the retroperitoneal adipose depot during the first 42 DIM. PMID- 21605755 TI - Supranutritional selenium increases mammary gland vascularity in postpartum ewe lambs. AB - Objectives were to determine the effects of maternal dietary supranutritional Se and nutritional plane during gestation on capillary surface density, capillary area density, and angiogenic factor expression in the developing mammary gland of primiparous ewes. Selenium treatments were initiated at breeding [adequate Se (ASe; 9.5 MUg/kg of body weight) vs. high Se (HSe; 81.8 MUg/kg of body weight)] and nutritional planes at d 50 of gestation [Low, 60%; moderate (Mod), 100%; and High, 140% of requirements). Mammary glands were collected within 24h postpartum. Vascular development was assessed in the glandular portion of the mammary gland. Vascularity was determined for mammary tissue with the following measurements taken: the cross-sectional capillary area density (total capillary area as a proportion of tissue area) and capillary surface density (CSD; total capillary circumference per unit of tissue area). High-Se ewes had greater capillary surface and area densities compared with ASe ewes. A tendency existed for an Se * plane of nutrition interaction for CSD with maternal diet not affecting CSD in HSe ewes, but Low ewes had a decreased CSD compared with Mod ewes, with High being intermediate in ASe ewes. Moreover, HSe-Low and HSe-High ewes had increased CSD compared with ASe-Low and ASe-High, respectively. Although Se status did not influence angiogenic factor mRNA expression, mammary glands from Low ewes tended to have increased VEGF and FLT1 mRNA expression compared with High ewes, with Mod being intermediate. Maternal plane of nutrition did not affect mammary gland glutathione peroxidase activity, but it was increased in HSe compared with ASe ewes. Increased mammary capillary nutrient exchange area may contribute to previously observed changes in colostrum quality. PMID- 21605757 TI - Physiological and conjugated linoleic acid-induced changes of adipocyte size in different fat depots of dairy cows during early lactation. AB - The aim of this study was to investigate the effects of lactation and conjugated linoleic acid (CLA) supplementation on adipocyte sizes of subcutaneous (s.c.) and visceral (VC) fat depots in primiparous dairy cows during the first 105 d in milk (DIM). German Holstein heifers (n=25) were divided into a control (CON) and a CLA group. From 1 DIM until sample collection, CLA cows were fed 100g of CLA supplement/d (about 6% of c9,t11 and t10,c12 isomers each), whereas the CON cows received 100g of fatty acid mixture/d instead of CLA. The CON cows (n=5 each) were slaughtered at 1, 42, and 105 DIM, and the CLA cows (n=5 each) were slaughtered at 42 and 105 DIM. Adipose tissues from 3s.c. depots (tailhead, withers, and sternum) and from 3 VC depots (omental, mesenteric, and retroperitoneal) were sampled. Hematoxylin-eosin staining was done to measure adipocyte area (MUm(2)). Retroperitoneal adipocyte sizes were mostly larger than adipocytes from the other sites, independent of lactation time and treatment. Significant changes related to duration of lactation were limited to retroperitoneal fat: adipocyte sizes were significantly smaller at 105 DIM than at 1 DIM in CON cows. Adipocyte sizes were decreased in s.c. depots from the tailhead at 105 DIM and from the sternum at 42 DIM in CLA versus CON cows, whereas for VC depots, adipocyte sizes were decreased in mesenteric fat at 42 and 105 DIM, and in omental and retroperitoneal fat, at 105 DIM in CLA versus CON cows. Within the CLA group, adipocyte sizes were smaller in the s.c. depot from the tailhead at 105 DIM than at 42 DIM. Adipocyte sizes and depot weights were significantly correlated in s.c. depots (r=0.795) in the CLA group and in retroperitoneal fat both in the CON (r=0.698) and the CLA (r=0.723) group. In conclusion, CLA-induced decreases in adipocyte size indicate lipolytic or antilipogenic effects of CLA, or both effects, on adipose tissue in primiparous dairy cows. PMID- 21605758 TI - The effect of lameness on the resting behavior and metabolic status of dairy cattle during the transition period in a freestall-housed dairy herd. AB - The objective of this observational study was to examine the effect of lameness on the resting behavior of dairy cattle through the transition period in a mattress-bedded commercial freestall facility, and explore the relationships between lameness, behavior, and metabolic indicators of disease. A convenience sample was used, comprised of 40 multiparous and 17 primiparous Holstein cows that were recruited as they entered the close-up pen and tracked through the maternity, hospital, and fresh pens. At recruitment, 87.5% of multiparous cows and 23.5% of primiparous cows showed evidence of abnormal gait. Lying time decreased from 16 d before calving from a least squares means +/- standard error of 13.5 +/- 0.6 h/d to a nadir of 10.6 +/- 0.38 h/d on the day of calving. After a period of increased rest after calving, lying time stabilized by d 6 to between 9.8 and 10.8h/d. This change was accompanied by an increase in the number of lying bouts per day from least squares means (95% confidence limits) of 11.2 (10.0 to 12.4) bouts per day to a peak of 17.7 (16.5 to 18.8) bouts per day on the day before calving, and a decrease in the duration of each lying bout. Resting behavior was influenced by calving month, temperature humidity index, body condition, parity, and lameness. Moderate and severely lame cows had significantly longer lying times throughout the transition period before and after calving, but most notable was a dramatic increase in the number of lying bouts observed 3 d before and after calving. In the straw-bedded, loose-housed maternity pen, moderate and severely lame cows had 20.3 (19.1 to 21.5) bouts per day, compared with 15.6 (14.3 to 16.8) bouts per day for nonlame cows. We hypothesized that this alteration in behavior may be associated with hypersensitivity to pain due to lameness. A total of 26.3% of cows tested above a threshold of 1,400 MUM beta-hydroxybutyrate. Moderate and severely lame cows had a least squares means (95% confidence limits) beta-hydroxybutyrate concentration of 1,165 (1,037 to 1,291) MUM that was significantly greater than 697 (560 to 834) MUM for slightly lame cows and 687 (551 to 824) MUM for nonlame cows. In summary, lameness significantly altered the resting behavior of cows during the transition period and was associated with elevated risk for ketosis in the study herd. PMID- 21605759 TI - Measurement of acceleration while walking as an automated method for gait assessment in dairy cattle. AB - The aims were to determine whether measures of acceleration of the legs and back of dairy cows while they walk could help detect changes in gait or locomotion associated with lameness and differences in the walking surface. In 2 experiments, 12 or 24 multiparous dairy cows were fitted with five 3-dimensional accelerometers, 1 attached to each leg and 1 to the back, and acceleration data were collected while cows walked in a straight line on concrete (experiment 1) or on both concrete and rubber (experiment 2). Cows were video-recorded while walking to assess overall gait, asymmetry of the steps, and walking speed. In experiment 1, cows were selected to maximize the range of gait scores, whereas no clinically lame cows were enrolled in experiment 2. For each accelerometer location, overall acceleration was calculated as the magnitude of the 3 dimensional acceleration vector and the variance of overall acceleration, as well as the asymmetry of variance of acceleration within the front and rear pair of legs. In experiment 1, the asymmetry of variance of acceleration in the front and rear legs was positively correlated with overall gait and the visually assessed asymmetry of the steps (r >= 0.6). Walking speed was negatively correlated with the asymmetry of variance of the rear legs (r=-0.8) and positively correlated with the acceleration and the variance of acceleration of each leg and back (r >= 0.7). In experiment 2, cows had lower gait scores [2.3 vs. 2.6; standard error of the difference (SED)=0.1, measured on a 5-point scale] and lower scores for asymmetry of the steps (18.0 vs. 23.1; SED=2.2, measured on a continuous 100-unit scale) when they walked on rubber compared with concrete, and their walking speed increased (1.28 vs. 1.22 m/s; SED=0.02). The acceleration of the front (1.67 vs. 1.72 g; SED=0.02) and rear (1.62 vs. 1.67 g; SED=0.02) legs and the variance of acceleration of the rear legs (0.88 vs. 0.94 g; SED=0.03) were lower when cows walked on rubber compared with concrete. Despite the improvements in gait score that occurred when cows walked on rubber, the asymmetry of variance of acceleration of the front leg was higher (15.2 vs. 10.4%; SED=2.0). The difference in walking speed between concrete and rubber correlated with the difference in the mean acceleration and the difference in the variance of acceleration of the legs and back (r >= 0.6). Three-dimensional accelerometers seem to be a promising tool for lameness detection on farm and to study walking surfaces, especially when attached to a leg. PMID- 21605760 TI - Estimating test characteristics of somatic cell count to detect Staphylococcus aureus-infected dairy goats using latent class analysis. AB - The aim of this study was to estimate test properties of composite somatic cell count (cSCC) to detect subclinically Staphylococcus aureus-infected dairy goats. Staphylococcus aureus is the most prevalent major pathogen in goats, and responsible for the majority of clinical mastitis cases. Therefore, a diagnostic tool that detects subclinical Staph. aureus infections may be useful in decreasing the number of clinical cases. We collected samples from 384 animals in 4 herds for bacteriological culture and cSCC on 3 occasions in lactation: once in early lactation, once around peak lactation, and once in late lactation. Latent class models were used to estimate test properties of cSCC and bacteriological culture in the absence of a gold standard reference test under the assumption that both tests detect Staph. aureus intramammary infection. Estimates for test properties of cSCC in early lactation at a cut-off value of 1,500 * 10(3) cells/mL were 0.90 for sensitivity and 0.95 for specificity, making cSCC a useful screening tool for detection of Staph. aureus. An effect of lactation stage was observed, causing an increased sensitivity and decreased specificity in late lactation. The sensitivity of bacteriological culture was estimated to be very low in the latent class models and the models suggested that the true prevalence of Staph. aureus in dairy goat herds is much higher than what is commonly reported based on bacteriological culture. This implies that intramammary infection by Staph. aureus may be an underestimated problem in dairy goat herds, and that cSCC can be used to diagnose infected animals. PMID- 21605761 TI - Glucose transporter and hypoxia-associated gene expression in the mammary gland of transition dairy cattle. AB - Glucose is an important energy substrate, especially needed by dairy cows postpartum to support the onset of lactation. The prioritization and regulation of glucose uptake is accomplished, in part, by changes in expression of cellular glucose transport molecules (GLUT) within the mammary gland. The objectives of this study were to (1) evaluate the expression and cell-type specific localization of GLUT and hypoxia-associated genes that may regulate GLUT expression over the transition period and through lactation in bovine mammary tissue and (2) determine functionality of GLUT on primary bovine mammary endothelial cells (BMEC). Mammary tissue biopsies were taken from cows at 15 d before calving and again at 1, 15, 30, 60, 120, and 240 d post-parturition for quantitative real-time PCR analysis of GLUT and hypoxia-associated genes. Additional mammary tissue samples were used to localize GLUT within the cells of the lobulo-alveolar system via fluorescence microscopy. Cultures of primary bovine mammary endothelial cells were used to confirm the functionality of GLUT with a fluorescent glucose analog uptake assay. Significant increases in GLUT1 gene expression were observed during early lactation, whereas both GLUT3 and GLUT4 gene expression increased during late lactation. The gene expression for 2 receptors of vascular endothelial growth factor increased significantly during early lactation and remained increased throughout lactation when compared with gene expression during the transition period. All GLUT were detected on cultured BMEC and were capable of internalizing glucose through GLUT-mediated mechanisms. These data suggest mammary vascular tissues express GLUT during lactation and BMEC express functional glucose transporters. A better understanding of glucose uptake at the endothelial level may prove to be critical to improve glucose absorption from the blood for utilization by mammary epithelial cells. PMID- 21605762 TI - Online evaluation of milk quality according to coagulation properties for its optimal distribution for industrial applications. AB - The potential for application of online devices for providing real-time analysis of milk-clotting parameters during milking was studied. The experiment tested established relationships between glandular-level bacterial infection and milk clotting parameters as evaluated by visible or near-infrared spectroscopy. The parameters yielded by the AfiLab (S.A.E. Afikim, Afikim, Israel) online device were shown to be applicable to derivation of real-time estimations of milk clotting parameters on the individual cow level. The ability of the AfiLab to perform this task was validated online and statistically by calibration against laboratory testing procedures. PMID- 21605763 TI - Distribution of coagulase-negative Staphylococcus species from milk and environment of dairy cows differs between herds. AB - In many parts of the world, coagulase-negative staphylococci (CNS) are the predominant pathogens causing intramammary infections (IMI) in dairy cows. The cows' environment is thought to be a possible source for CNS mastitis and this was investigated in the present paper. A longitudinal field study was carried out in 6 well-managed dairy herds to determine the distribution and epidemiology of various CNS species isolated from milk, causing IMI and living freely in the cows' environment, respectively. In each herd, quarter milk samples from a cohort of 10 lactating cows and environmental samples from stall air, slatted floor, sawdust from cubicles, and sawdust stock were collected monthly (n=13). Isolates from quarter milk samples (n=134) and the environment (n=637) were identified to species level using amplified fragment length polymorphism (AFLP) genotyping. Staphylococcus chromogenes, S. haemolyticus, S. epidermidis, and S. simulans accounted for 81.3% of all CNS milk isolates. Quarters were considered infected with CNS (positive IMI status) only when 2 out of 3 consecutive milk samples yielded the same CNS AFLP type. The species causing IMI were S. chromogenes (n=35 samples with positive IMI status), S. haemolyticus (n=29), S. simulans (n=14), and S. epidermidis (n=6). The observed persistent IMI cases (n=17) had a mean duration of 149.4 d (range 63.0 to 329.8 d). The CNS species predominating in the environment were S. equorum, S. sciuri, S. haemolyticus, and S. fleurettii. Herd to-herd differences in distribution of CNS species were observed in both milk and the environment, suggesting that herd-level factors are involved in the establishment of particular species in a dairy herd. Primary reservoirs of the species causing IMI varied. Staphylococcus chromogenes and S. epidermidis were rarely found in the environment, indicating that other reservoirs were more important in their epidemiology. For S. haemolyticus and S. simulans, the environment was found as a reservoir, suggesting that IMI with these species were possibly environmental in origin. PMID- 21605764 TI - Does the Milk Income Loss Contract program improve the technical efficiency of US dairy farms? AB - Due to volatility in the income of dairy farmers, the 2002 farm bill introduced the Milk Income Loss Contract (MILC) payments that were extended in the 2008 farm bill. It has been argued that MILC payments would help large dairy farms and squeeze out small dairy operations. This paper contributes to this policy issue by empirically assessing the effect of MILC payments on the technical efficiency of US dairy farms. Using a large-scale dairy farm survey containing information from 2005, we apply a data envelopment analysis method to estimate technical efficiency of the dairy farms. A Tobit regression model was estimated to examine the roles of human capital of the farm operator, different farming practices, farm sizes, and MILC payments on technical efficiency of the dairy farms. Results indicate that the effects of the MILC payments were heterogeneous among farms of different sizes. Significant effects of MILC payments were only evident among large farms. In contrast, no significant effects were found for medium and small farms. PMID- 21605765 TI - Risk factors associated with hair loss, ulceration, and swelling at the hock in freestall-housed UK dairy herds. AB - The objective of this study was to identify the risk factors associated with 3 presentations of hock lesions (hair loss, ulceration, and swelling) in freestall housed lactating cattle. By independent identification and scoring of, and analysis of the factors associated with, hair loss, ulceration, and swelling, the aim was to identify whether risk factors were common to all 3, or differed among the presentations. A cross-sectional study was conducted on 76 herds in the UK during the winter housing period of 2007 to 2008, with a total of 3,691 cows examined for hock lesions. A randomly selected sample of approximately 50 cows in each herd were scored for body condition, lameness, cleanliness, rising behavior, and lesions at the hocks. For all cows, hair loss, ulceration, and swelling were scored separately on 4-point scales, with both left and right hocks scored. Based on a review of the literature, potential risk factors were identified and measured, collected from milk-recording data, or obtained through interviews with the farmers. Risk factors associated with hocks lesions in cattle were examined using data from the 2,982 cows housed in the 63 freestall-housed herds visited. Risk factors for each of the 3 lesion presentations were considered separately in multilevel logistic regression models, with moderate or severe hair loss, any degree of ulceration, and moderate or severe swelling as the outcome variables. Thirty risk factors were identified, none of which were common to all 3 lesion presentations. Five risk factors (locomotion score, number of days of winter housing, mean milk yield, freestall base material, and herd size) were common to both hair loss and ulceration. The stall bedding material was a common risk factor for both hair loss and swelling. A further 8, 5, and 11 risk factors were unique to hair loss, ulceration, and swelling, respectively. The existence of several differential risk factors between the 2 lesion presentations suggests that ulceration may not always be a direct extension of hair loss, as has been implied in previous scoring systems. Of the 12 risk factors associated with swelling, only 1 was common to another lesion presentation, which suggests that swelling may have a different etiology than hair loss and ulceration. The variables associated with the lesions indicate the importance of factors that affect the lying and rising behavior of the animal, including freestall structure and design, and the lying surface. PMID- 21605766 TI - Evaluation of portal blood flow using transcutaneous and intraoperative Doppler ultrasonography in dairy cows with fatty liver. AB - The objective of the study was to investigate portal blood flow (PBF) in dairy cows with fatty liver by means of Doppler ultrasonography. Eighty lactating German Holstein cows less than 100 d in milk were used (mean +/- standard error of the mean; body weight: 583 +/- 9 kg, age: 5 +/- 0.2 yr, withers height: 145.4 +/- 0.5 cm, milk yield: 9 +/- 0.6 kg). All cows had left abomasal displacement and underwent omentopexy via right flank laparotomy. The size of the liver and the thickness over the portal vein were determined ultrasonographically. Doppler ultrasonographic examinations of PBF were carried out transcutaneously and intraoperatively directly via liver surface. The PBF velocities [peak maximum (v(max)), peak minimum (v(min)), and mean maximum (v(mean)) velocity] were recorded. Venous pulsatility index (VPI) was calculated. Because transcutaneous Doppler ultrasonography revealed images of very poor quality in 58 of the 80 cows, only data obtained intraoperatively were presented. Liver biopsies were used for hepatic triacylglycerol (TAG) determination and histological examination. Based on histopathologic and ultrasonographic examinations, none of the cows suffered from hepatic disorders other than hepatic lipidosis. Hepatic TAG content ranged from 5 to 292 mg/g of liver fresh weight (FW). Cows were allocated to 1 of 4 groups according to their hepatic TAG content (very severe: TAG >150 mg/g of FW, n=27; severe: >100-150 mg/g of FW, n=18; moderate: >= 50 100mg/g of FW, n=19; mild: <50mg/g of FW, n=16). The VPI decreased with increasing TAG content (r=-0.55). The VPI did not differ between cows with severe and very severe fatty liver but it differed between cows of these 2 groups and cows with mild and moderate fatty liver. Velocities of PBF (v(mean), v(min), v(max)) correlated negatively with hepatic TAG content (r=-0.26 to -0.37). Mean PBF velocity of the cows with very severe fatty liver differed from cows with severe, moderate, and mild fatty liver. Variables of PBF were inversely related to hepatic size and thickness (r=-0.06 to -0.35). In conclusion, the lower VPI and PBF velocities in cows with fatty liver and the negative correlations with the degree of hepatosteatosis may be explained by a reduction of vascular compliance in the liver because of fatty infiltration. These changes, which are believed to result from parenchymal swelling, were particularly pronounced when hepatic TAG content exceeded 150 mg/g FW. PMID- 21605767 TI - Short communication: Farm and socioeconomic characteristics of the top 100 dairy farm counties in the United States. AB - The objectives of this study are to describe dairy farm demographic and socioeconomic conditions in the top 100 counties in the United States for dairy sales in 2007, and to describe the association of dairy farm demographics with socioeconomic conditions. The top 100 counties were responsible for 56% of all US dairy sales in 2007 with a median growth rate of 78% compared with 1997. Counties varied widely for farm demographics with as few as 5 very large dairy farms that averaged $17,924,000 in dairy sales per farm to as many as 1,730 dairy farms with less than $250,000 in dairy sales per farm. Most of the top 100 dairy counties had higher illiteracy rates, a higher proportion of residents without a high school degree, and lower median incomes than state averages, but unemployment rates were similar to the state average. The socioeconomic measures were from public records and not collected specifically for this research. Nevertheless, the top dairy counties in the western states tended to have poorer socioeconomic conditions than the top dairy counties in other regions, and significant associations were observed between dairy farm demographics and socioeconomic conditions. Having many dairy farms was associated more favorably with county socioeconomic conditions than having high dairy sales. PMID- 21605768 TI - Effect of ruminal pulse dose of polyunsaturated fatty acids on ruminal microbial populations and duodenal flow and milk profiles of fatty acids. AB - The objective of this study was to examine the effect of ruminal pulse dose of free linoleic acid (LA) and free docosahexaenoic acid (DHA) on microbial populations in the rumen, duodenal fatty acid (FA) flow, milk composition, and milk FA profiles of Chinese Holstein dairy cows. Four rumen- and duodenal fistulated Chinese Holstein cows in mid lactation (138.5 +/- 10d in milk) were randomly assigned to 3 treatment groups and 1 control group in a 4 * 4 Latin square design over 4 periods (3 wk per period). Diets contained either no LA or 2.7% LA and either no DHA or 0.5% DHA in a 2 * 2 factorial arrangement of treatments. Ruminal pulse dose with DHA increased counts of Megasphaera elsdenii, decreased Fibrobacter succinogenes, but did not affect Butyrivibrio fibrisolvens or Ruminococcus flavefaciens. The pulse dose of LA at 2.7% dry matter had no effect on the population sizes of the 3 major cellulolytic bacterial species or M. elsdenii, and no interaction was observed between LA and DHA. The pulse dose of LA or DHA, either alone or in combination, increased the duodenal flow of vaccenic acid (VA). The milk VA and cis-9,trans-11 conjugated linoleic acid (CLA) contents also increased in response to the fatty acid pulse dose, and the pulse dose of both LA and DHA together had the most profound stimulatory effect. This study indicated that ruminal pulse dose of LA or DHA could be used to increase duodenal flow of VA and the milk contents of potentially health-promoting FA, such as VA and cis-9,trans-11 CLA. These results might be useful in formulating dietary interventions to improve milk cis-9,trans-11 CLA contents. PMID- 21605769 TI - Relation of net portal flux of nitrogen compounds with dietary characteristics in ruminants: a meta-analysis approach. AB - Decrease of N intake (NI) with the aim of increasing efficiency of N utilization and decreasing the negative environmental effects of animal production requires assessment of the forms in which N is absorbed. A meta-analysis was conducted on 68 publications (90 experiments and 215 treatments) to study the effect of NI on net portal appearance (NPA) of nitrogenous nutrients [amino acids (AA), ammonia, and urea] in ruminants. In addition, the effect of several dietary energy and protein factors on this relationship was investigated. These factors were: dry matter intake; proportion of concentrate; diet concentrations and intakes of nonfiber carbohydrates and neutral detergent fiber (NDF); diet concentrations of total digestible nutrients (TDN) and crude protein; rumen-degradable protein and rumen-undegradable protein, as percent dry matter or percent crude protein. The effect of species and physiological stage was also investigated. Within experiment analyses revealed that the NPA of AA-N and ammonia-N increased linearly, whereas the NPA of urea-N decreased (or recycling of urea-N increased) linearly with NI. Besides NI, many significant covariates could be introduced in each NPA model. However, only TDN and neutral detergent fiber intake (NDFi) were common significant covariates of NI in each NPA model. In this database, ruminants converted 60% of incremental NI into NPA of AA-N with no species effect on that slope. However, at similar NI, TDN, and NDFi, sheep absorbed more AA-N than did cattle and dairy cows. On the other hand, species tended to affect the slope of the relationship between NPA of ammonia-N and NI, which varied from 0.19 for the sheep to 0.38 for dairy cows. On average, the equivalent of 11% of incremental NI was recycled as urea-N to the gut through the portal-drained viscera, which excludes salivary contribution, and no species difference was detected. Overall, at similar TDN and NDFi, sheep and cattle increased their NPA of AA-N relative to NI increment by a similar magnitude. The higher absorption of AA-N observed in sheep compared with cattle, at similar NI, TDN, and NDFi, might result from lower losses of AA through portal-drained viscera metabolism. PMID- 21605770 TI - Is rumen development in newborn calves affected by different liquid feeds and small intestine development? AB - The objective of the study was to determine the effect of different liquid feeds on calf small intestine and rumen development. Twenty-one bull calves (5 +/- 1 d old) were randomly allocated to 3 groups and fed whole milk (WM), milk replacer (MR; 22% CP and 17.5% fat), or MR supplemented with sodium butyrate (MR+SB; 0.3% as fed). Liquid feed dry matter intake was equal between treatments and amounted to 1% of BW at the beginning of the trial. Starter diet was offered ad libitum. Animals were slaughtered at 26 (+/- 1) d of age. Calves fed WM had higher average daily gain in the whole trial and higher starter diet dry matter intake between d 15 to 21 of the trial as compared with calves fed MR and MR+SB. Calves fed MR lost on average 1.4 kg of BW within first 14 d of the trial and their BW tended to be lower at d 7, 14, and 21 of the study as compared with calves fed MR+SB. The empty jejunum and ileum weight, crypt depth, mitotic index in the middle jejunum were higher, and apoptotic index tended to be lower in calves fed WM as compared with calves fed MR and MR+SB. Calves fed WM also had higher aminopeptidase N activity in the middle jejunum and tended to have higher maltase activity in the distal jejunum as compared with calves fed MR and MR+SB. The mitotic index was higher and apoptotic index was lower in the middle jejunum, and aminopeptidase A activity tended to be higher in the distal jejunum of calves fed MR+SB as compared with those fed MR. Calves fed WM had greater papillae length and width, and tended to have greater muscle layer thickness as compared with calves fed MR and MR+SB. Reticulorumen weight, reticulorumen weight expressed as percent of whole stomach weight, and papillae length and width were higher in calves fed MR+SB as compared with those fed MR. Additionally, calves fed WM had higher plasma glucose and urea in the whole trial period as compared with calves fed MR and MR+SB, and plasma glucose was higher in calves fed MR+SB as compared with those fed MR. Significant positive Pearson correlations were found between small intestine and reticulorumen weights as well as between activity of brush border lactase, maltase, aminopeptidase A, and aminopeptidase N and reticulorumen weight. Different liquid feeds affect small intestine development, animal growth, solid feed intake and metabolic status of calves and this effect can indirectly influence the development of forestomachs. PMID- 21605771 TI - Prospects for using nonconventional feeds in diets for Awassi dairy sheep in Syria. AB - High feed costs are major obstacles for resource-poor dairy sheep farmers in West Asia, along with large fluctuation in grain and straw prices. Farmers need low cost diets using locally available feeds that can provide sufficient milk of good quality. Two experimental trials were conducted on Awassi milking ewes to evaluate nonconventional and balanced low-cost diets against the traditional unbalanced diet used by farmers (control) on the total yields (milk, fat, protein, and total solids) and milk composition (fat, protein, total solids, and lactose), an important indicator of milk quality. The first trial was conducted at the research station of the International Center for Agricultural Research in the Dry Areas (ICARDA, Aleppo, Syria) to test 6 low-cost balanced diets using locally available feeds and agro byproducts against the control diet. Each diet was tested on 8 ewes that were kept on pasture as a basal diet, but received different supplements, including barley, wheat bran and nonconventional feeds (urea-treated wheat straw, molasses, sugar beet pulp, and cotton seed cake). Five balanced diets enhanced the total yields of milk, fat, protein, and total solids, in 2 cases, significantly. These diets increased total milk yield by 17.7 to 50.2% and decreased supplement feeding costs by 43% compared with the control. However, milk composition remained unaffected. The second trial was conducted on 3 different farms in northern Syria to assess in each farm a low-cost balanced diet on milking ewes (n=15) in comparison to the farmer's control (n=15). The balanced diet was a modification requested by farmers of the best performing diet in the on-station trial. Confirming the first trial's research results, the balanced diet outperformed the control in total yields; for instance, it increased total milk yield by 28 to 40% and raised net income by 30%, without affecting milk composition. Both trials showed that using locally available nonconventional feedstuffs, such as molasses, integrated into balanced dairy sheep diets can decrease feed costs of resource-poor farmers, while enhancing total yields of milk and milk constituents without compromising milk quality components. This will greatly improve the profitability of dairy sheep production in dry areas. PMID- 21605772 TI - Effects of feeding different levels of dietary fiber through the addition of corn stover on nutrient utilization of dairy heifers precision-fed high and low concentrate diets. AB - The objective of this experiment was to assess the effects of manipulating dietary fiber by replacing corn silage (CS) with lower quality forage as corn stover (CST) when used in high concentrate (HC) and low concentrate (LC) diets for precision-fed dairy heifers. Eight Holstein heifers (335.6 +/- 7.41 kg of body weight) were randomly assigned to 2 levels of concentrate: HC (20% forage) and LC (80% forage), and to a forage type sequence [0% of forage as corn stover (CST), 100% corn silage (CS); 20% CST, 80% CS; 40% CST, 60% CS; and 60% CST, 40% CS] within concentrate level administered according to a split-plot, 4 * 4 Latin square design (21-d periods). Heifers fed HC had higher apparent total-tract dry matter digestibility (DMD). Increasing the fiber level by increasing the amount of CST in the diet resulted in a linear decrease of DMD and organic matter digestibility. Heifers fed LC diets had higher neutral detergent fiber (NDF) digestibility and tended to have lower acid detergent fiber (ADF) digestibility than those fed HC diets. Substituting CS with 20% CST resulted in the highest NDF and ADF digestibilities. Digestibility of N was not different, but N retention increased for HC and decreased quadratically for LC diets. Heifers fed HC diets decreased fecal output, and CST linearly increased these parameters. Urine volume tended to be higher for HC-fed heifers, and increasing dietary fiber through CST inclusion tended to decrease urine output. This shift in water excretion resulted in similar total manure output. Total purine derivative excretion did not differ between treatments, but interacted with CST addition, resulting in a linear increase in microbial protein flow to the duodenum in HC-fed heifers and in a linear decrease in LC diets as CST increased. In conclusion, increasing dietary fiber through CST decreased DMD and organic matter digestibility linearly, whereas NDF and ADF digestibility were maximized when 20% CST was added to HC and LC diets. Microbial protein synthesis increased and decreased linearly with CST addition in HC and LC diets, respectively. Retention of N increased and decreased quadratically with CST addition in HC and LC diets, respectively. Total manure excretion was not different between HC or LC diets. PMID- 21605773 TI - Effects of including corn distillers dried grains with solubles in dairy calf feeds. AB - A series of 5 trials was conducted to determine the effect of distillers dried grains with solubles (DG) in calf diets. Trial 1 compared 0 or 49% DG in 18% crude protein (CP) starters (as-fed basis) fed to calves initially 2 to 3 d old for 56 d. Digestibility was estimated during d 52 to 56 using chromic oxide. Trial 2 compared 0 or 39% DG in 16% CP growers fed to calves from 8 to 12 wk of age from 28 d. Trial 3 compared 0, 10, or 20% DG in 18% CP starters fed to calves initially 2 to 3 d old for 56 d. Trial 4 compared 0 or 20% DG in 16% CP growers fed to calves from 8 to 12 wk of age from 28 d. As DG increased in all diets, acid detergent fiber, neutral detergent fiber, and fat increased and calculated metabolizable energy was similar but not equalized. In trials 1 and 3, calves (n=48/trial) housed in individual pens were fed 26% CP, 17% fat milk replacer powder and weaned at 28 d. Trials 2 and 4 used calves (n=48/trial) housed in group pens (6 calves/pen) that had been weaned for 28 d before the trials' start. Trial 5 (n=18 calves) had the same starter treatments as trial 3 fed in combination with high or low milk replacer intake, with calves killed at 35 d to determine effects of DG and milk replacer intake on rumen development. In trial 1, average daily gain (ADG) was 6% greater and dry matter digestibility was 10% greater for calves fed 0% versus 49% DG. In trial 2, ADG (9%), feed efficiency (10%), and hip width change (19%) were greater for calves fed 0% versus 39% DG. Performance measures did not differ among starter treatments in Trials 3 and 5. In trial 4, ADG (4%), feed efficiency (5%), and hip width change (19%) were greater for calves fed 0% versus 20% DG. In trial 5, rumen development was not affected by DG inclusion, but was greater for calves fed milk replacer at 630 versus 940 g/d, which had greater starter intake. Overall, we conclude that high levels of distillers in calf starters and growers decrease growth of calves; however, starters with <= 20% DG allow for normal growth rates and rumen development. PMID- 21605774 TI - Corn grain and liquid feed as nonfiber carbohydrate sources in diets for lactating dairy cows. AB - Interactions of sources and processing methods for nonstructural carbohydrates may affect the efficiency of animal production. Five rumen-cannulated cows in late lactation were placed in a 5 * 5 Latin square design and fed experimental diets for 2 wk. In the production trial, 54 cows were fed the experimental diets for 12 wk beginning at d 60 in milk. Diets contained 24% corn silage and 22% hay, averaging 20% alfalfa and 2% grass but being adjusted as needed to maintain dietary concentrations of 36% neutral detergent fiber. The control diet contained steam-flaked corn (SFC) and the other diets contained either finely (FGC; 0.8 mm) or coarsely ground corn (CGC; 1.9 mm), factorialized with or without 3.5% liquid feed (LF). The LF diets provided 1.03% of dietary dry matter as supplemental sugar. The FGC decreased rumen pH and concentration of NH(3)N compared with CGC. The SFC and FGC tended to increase the molar percentage of ruminal propionate and decrease the acetate:propionate ratio. The LF increased molar percentage of ruminal butyrate with FGC but not CGC. The LF tended to decrease starch digestibility with the CGC but not with the FGC. As expected, the SFC and FGC increased total tract starch digestibility. The DMI and milk yield were similar among dietary treatments. Compared with ground corn diets, the SFC tended to decrease milk fat percentage; thus, 3.5% fat-corrected milk and feed efficiency were decreased with SFC. The LF decreased milk protein percentage but had no effect on milk protein yield. The SFC compared with dry ground corn decreased the concentration of milk urea nitrogen. Sugar supplementation using LF appeared to be more beneficial with FGC than CGC. Increasing the surface area by finely grinding corn is important for starch digestibility and optimal utilization of nutrients. PMID- 21605775 TI - Mustard bran in lactating dairy cow diets. AB - Two trials using lactating Holstein cows were conducted to evaluate effects of a diet containing oriental mustard bran on dry matter intake (DMI), milk production, milk components, and organoleptic properties. In experiment 1, 34 lactating cows (24 multiparous and 10 primiparous; days in milk >= 50 d) were used in a switchback design to determine the lactational response and organoleptic quality of milk when the diet contained 8% oriental mustard bran (MB) versus a control diet (CON). Mustard bran replaced a portion of soybean meal and all the beet pulp in the CON diet. Milk yields were greater for cows fed the MB diet; however, no differences were found in DMI, 3.5% fat- (FCM) or solids corrected milk. Milk components and components production were not affected by treatment. Milk organoleptic qualities were not affected by diet. In experiment 2, 22 lactating cows (16 multiparous and 6 primiparous; days in milk >= 21 d) were assigned randomly within parity to receive MB or CON from wk 4 to 19 postpartum in a randomized complete block design. Cows were fed CON wk 1 to 3 postpartum. The MB diet contained the same ingredients as the CON, except sunflower seed and a portion of soybean meal were replaced with mustard bran. Milk and components data were collected during wk 3 postpartum and used as covariates to adjust treatment means. Intake was greater for cows fed the MB diet; however, daily milk, 3.5% FCM, and solids-corrected milk yields were not different between diets. Milk components and component yields were not affected by treatment. Milk urea concentration was less for cows fed the MB diet. Although cows fed the MB diet had greater DMI, this was not translated into a higher milk 3.5% FCM/DMI production efficiency ratio. During experiment 2, many cows fed MB experienced minor to severe hemolysis with bloody urine. This hemolysis believed to be caused by the S-methyl-cysteine sulfoxide contained in mustard bran could have affected milk production efficiency. The increased milk yield observed in experiment 1 was not observed in experiment 2. Adding 8% of MB to lactating cow diets had a mixed effect on DMI and milk production. Milk component yields and milk quality were not affected. Feeding this level of MB presents a hemolytic danger to lactating dairy cows. PMID- 21605776 TI - Evaluation of models to predict the stoichiometry of volatile fatty acid profiles in rumen fluid of lactating Holstein cows. AB - Volatile fatty acids (VFA), produced in the rumen by microbial fermentation, are the main energy source for ruminants. The VFA profile, particularly the nonglucogenic (acetate, Ac; butyrate, Bu) to glucogenic (propionate, Pr) VFA ratio (NGR), is associated with effects on methane production, milk composition, and energy balance. The aim of this study was to evaluate extant rumen VFA stoichiometry models for their ability to predict in vivo VFA molar proportions. The models were evaluated using an independent data set consisting of 101 treatments from 24 peer-reviewed publications with lactating Holstein cows. All publications contained a full diet description, rumen pH, and rumen VFA molar proportions. Stoichiometric models were evaluated based on root mean squared prediction error (RMSPE) and concordance correlation coefficient (CCC) analysis. Of all models evaluated, the 1998 Friggens model had the lowest RMSPE for Ac and Bu (7.2 and 20.2% of observed mean, respectively). The 2006 Bannink model had the lowest RMSPE and highest CCC for Pr (14.4% and 0.70, respectively). The 2008 Bannink model had comparable predictive performance for Pr to that of the 2006 Bannink model but a larger error due to overall bias (26.2% of MSPE). The 1982 Murphy model provided the poorest prediction of Bu, with the highest RMSPE and lowest CCC (24.6% and 0.15, respectively). The 1988 Argyle and Baldwin model had the highest CCC for Ac with an intermediate RMSPE (0.47 and 8.0%, respectively). The 2006 Sveinbjornsson model had the highest RMSPE (13.9 and 34.0%, respectively) and lowest CCC (0.31 and 0.40, respectively) for Ac and Pr. The NGR predictions had the lowest RMSPE and highest CCC in the 2 models of Bannink, whereas the lowest predictive performance was in the 2006 Sveinbjornsson model. It appears that the type of VFA produced is not a simple linear relationship between substrate inputs and pH as currently represented. The analysis demonstrates that most rumen VFA stoichiometric approaches explain a large part of the variation in VFA molar proportions among diets, in particular for Ac, whereas predictive power for Pr and Bu differ largely among approaches. The move toward feed evaluation systems based on animal response might necessitate an improved representation of rumen fermentation, focused on improving our understanding of VFA proportions in diets that vary from the mean. PMID- 21605777 TI - Effect of forage-to-concentrate ratio in dairy cow diets on emission of methane, carbon dioxide, and ammonia, lactation performance, and manure excretion. AB - Holstein cows housed in a modified tie-stall barn were used to determine the effect of feeding diets with different forage-to-concentrate ratios (F:C) on performance and emission of CH(4), CO(2) and manure NH(3)-N. Eight multiparous cows (means +/- standard deviation): 620 +/- 68 kg of body weight; 52 +/- 34 d in milk and 8 primiparous cows (546 +/- 38 kg of body weight; 93 +/- 39 d in milk) were randomly assigned to 1 of 4 air-flow controlled chambers, constructed to fit 4 cows each. Chambers were assigned to dietary treatment sequences in a single 4 * 4 Latin square design. Dietary treatments, fed as 16.2% crude protein total mixed rations included the following F:C ratio: 47:53, 54:46, 61:39, and 68:32 [diet dry matter (DM) basis]. Forage consisted of alfalfa silage and corn silage in a 1:1 ratio. Cow performance and emission data were measured on the last 7 d and the last 4 d, respectively of each 21-d period. Air samples entering and exiting each chamber were analyzed with a photo-acoustic field gas monitor. In a companion study, fermentation pattern was studied in 8 rumen-cannulated cows. Increasing F:C ratio in the diet had no effect on DM intake (21.1 +/- 1.5 kg/d), energy-corrected milk (ECM, 37.4 +/- 2.2 kg/d), ECM/DM intake (1.81 +/- 0.18), yield of milk fat, and manure excretion and composition; however, it increased milk fat content linearly by 7% and decreased linearly true protein, lactose, and solids-not-fat content (by 4, 1, and 2%, respectively) and yield (by 10, 6, and 6%, respectively), and milk N-to-N intake ratio. On average 93% of the N consumed by the cows in the chambers was accounted for as milk N, manure N, or emitted NH(3)-N. Increasing the F:C ratio also increased ruminal pH linearly and affected concentrations of butyrate and isovalerate quadratically. Increasing the F:C ratio from 47:53 to 68:32 increased CH(4) emission from 538 to 648 g/cow per day, but had no effect on manure NH(3)-N emission (14.1 +/- 3.9 g/cow per day) and CO(2) emission (18,325 +/- 2,241 g/cow per day). In this trial, CH(4) emission remained constant per unit of neutral detergent fiber intake (1g of CH(4) was emitted for every 10.3g of neutral detergent fiber consumed by the cow), but increased from 14.4 to 18.0 g/kg of ECM when the percentage of forage in the diet increased from 47 to 68%. Although the pattern of emission within a day was distinct for each gas, emissions were higher between morning feeding (0930 h) and afternoon milking (1600 h) than later in the day. Altering the level of forage within a practical range and rebalancing dietary crude protein with common feeds of the Midwest of the United States had no effects on manure NH(3)-N emission but altered CH(4) emission. PMID- 21605778 TI - Dietary inclusion of diallyl disulfide, yucca powder, calcium fumarate, an extruded linseed product, or medium-chain fatty acids does not affect methane production in lactating dairy cows. AB - Two similar experiments were conducted to assess the effect of diallyl disulfide (DADS), yucca powder (YP), calcium fumarate (CAFU), an extruded linseed product (UNSAT), or a mixture of capric and caprylic acid (MCFA) on methane production, energy balance, and dairy cow performance. In experiment 1, a control diet (CON1) and diets supplemented with 56 mg of DADS/kg of dry matter (DM), 3g of YP/kg of DM, or 25 g of CAFU/kg of DM were evaluated. In experiment 2, an inert saturated fat source in the control diet (CON2) was exchanged isolipidically for an extruded linseed source (100g/kg of DM; UNSAT) or a mixture of C8:0 and C10:0 (MCFA; 20.3g/kg of DM). In experiment 2, a higher inclusion level of DADS (200mg/kg of DM) was also tested. Both experiments were conducted using 40 lactating Holstein-Friesian dairy cows. Cows were adapted to the diet for 12 d and were subsequently kept in respiration chambers for 5 d to evaluate methane production, diet digestibility, energy balance, and animal performance. Feed intake was restricted to avoid confounding effects of possible differences in ad libitum feed intake on methane production. Feed intake was, on average, 17.5 and 16.6 kg of DM/d in experiments 1 and 2, respectively. None of the additives reduced methane production in vivo. Methane production in experiment 1 was 450, 453, 446, and 423 g/d for CON1 and the diets supplemented with DADS, YP, and CAFU, respectively. In experiment 2, methane production was 371, 394, 388, and 386 g/d for CON2 and the diets supplemented with UNSAT, MCFA, and DADS, respectively. No effects of the additives on energy balance or neutral detergent fiber digestibility were observed. The addition of MCFA increased milk fat content (5.38% vs. 4.82% for control) and fat digestibility (78.5% vs. 59.8% for control), but did not affect milk yield or other milk components. The other products did not affect milk yield or composition. Results from these experiments emphasize the need to confirm methane reductions observed in vitro with in vivo data. PMID- 21605779 TI - The effect of high-sugar grass on predicted nitrogen excretion and milk yield simulated using a dynamic model. AB - High-sugar grass varieties have received considerable attention for their potential to reduce nitrogen (N) excretion and increase milk yield in cattle. However, considerable variation exists in the magnitude of response in published results. The purpose of this study is to explain the variation in response using a dynamic mechanistic model to predict observed N and milk yield results from the literature, and from simulated data. Examined effects were (1) water-soluble carbohydrate [WSC; g/kg of dry matter (DM)] increase; (2) change in crude protein (CP) and neutral detergent fiber (NDF) content of the plant with WSC increase; and (3) the level of N fertilization. The database for evaluation of model N and milk yield predictions consisted of 4 published studies with 28 treatment means for which high-sugar grasses were being evaluated. Water-soluble carbohydrate content of the diets ranged from 95 to 248 g/kg of DM, CP content ranged from 115 to 263 g/kg of DM, and the NDF content ranged from 400 to 568 g/kg of DM. Urine N, milk N, and total N excretion were predicted well by the model and followed the directional pattern of observed values within each study. Simulation results showed that the N utilization ratio increased as the WSC content of the diet increased, but to varying degrees depending on the grass scenario examined. The greatest benefit in terms of N utilization ratio and urine N levels were seen when the WSC content of grass increased at the expense of CP, followed by a 50:50 CP and NDF mix, followed by a trade for NDF. Simulated milk yield decreased slightly when WSC increased at the expense of CP, increased slightly when it increased at the expense of a CP and NDF mix, and increased most when WSC increased at the expense of NDF. Results were amplified slightly under conditions of low-N fertilization and in the absence of grain feeding. Overall, modeling is useful as an explanatory tool. The variation from results in the literature with high-WSC grass feeding may be, at least in part, the result of the level of WSC (g/kg of DM) increase, concurrent changes occurring within the CP and NDF fractions of the plant, and the plane of nutrition of the diet (grain feeding and N fertilization levels). PMID- 21605780 TI - Short communication: Responses to supplemental Saccharomyces cerevisiae fermentation product and triticale grain in dairy cows grazing high-quality pasture in early lactation. AB - Supplementing cows grazing highly digestible pasture with a Saccharomyces cerevisiae fermentation product (SCFP) was hypothesized to increase dry matter (DM) intake and milk production. Sixty multiparous dairy cows were fed 3 kg of crushed triticale DM/cow per day for 23 +/- 4.4 d before calving. Half of the cows received SCFP (60 g/d; Diamond V Original XP; Diamond V Mills, Inc., Cedar Rapids, IA). Cows in both treatment groups were randomly allocated at calving to 1 of 2 amounts (3 or 6 kg of DM/d) of triticale feeding with or without 60 g of SCFP/day (n=15/treatment) until 84 days in milk. The amount of pasture harvested (kg of DM/cow per day) and milk yield (kg/cow per day) were not affected by SCFP. Milk protein content and yield were greater in cows receiving 6 kg of crushed triticale DM/d. Plasma nonesterified fatty acids and beta-hydroxybutyrate concentrations were not affected by SCFP supplementation, but were lower in cows fed 6 kg of crushed triticale DM/d than those fed 3 kg of DM/d. Supplementation with SCFP increased milk lactose content without affecting milk production under the conditions investigated. PMID- 21605781 TI - Short communication: Limit feeding dairy heifers: effect of feed bunk space and provision of a low-nutritive feedstuff. AB - The objectives of this study were to examine the behavioral effects of providing limit-fed dairy heifers an increased amount of feed bunk space compared with recommended feed bunk allowance, and to determine if the effects of provision of extra bunk space would be comparable to those seen when limit-fed heifers are provided a low-nutritive feedstuff. Twelve Holstein dairy heifers (381.1 +/- 44.8 d of age, 417.3 +/- 47.9 kg), divided into groups of 4, were exposed to each of 3 treatments using a 3 * 3 Latin square design with 7-d periods. The treatments were (1) 0.68 m of feed bunk space/heifer (TMR-0.68), (2) 0.34 m of feed bunk space/heifer (TMR-0.34), and (3) 0.34 m of feed bunk space/heifer with an additional 0.34 m of feed bunk space available for free-choice straw (TMR-S). The total mixed ration was fed once daily at a restricted level (1.83% of body weight) and contained (dry matter basis) 19.9% alfalfa/grass haylage, 20.1% corn silage, 49.6% high-moisture corn, and 10.4% protein supplement. Group dry matter intake (DMI) was recorded daily. Behavior at the feed bunk was recorded for the last 4 d of each treatment period. Due to the provision of straw, DMI was highest on the TMR-S treatment compared with the other treatments (9.4 vs. 7.8 kg/d). Heifers spent the most time feeding when on the TMR-S treatment (147.7 min/d), with no difference in feeding time between the limit-fed TMR treatments (64.5 min/d). Within the TMR-S treatment, feeding time on the straw was 76.9 min/d; thus, the rate of consumption of only the TMR was similar across all treatments. Unrewarded time at the feed bunk (when no feed was present) did not differ between treatments. Heifers did not differ in competitive behavior when on the limit-fed TMR treatments (13.1 displacements/heifer per day). However, while on the TMR-S treatment, heifers displaced each other more frequently (23.8 displacements/heifer per day) than while on the other 2 treatments. Overall, results suggest that neither increased feed bunk space nor provision of straw will reduce competition for, or slow consumption rates of, a limit-fed TMR. The provision of straw alongside a limit-fed TMR did increase DMI, which would contribute to further rumen fill, and allowed heifers to increase their time spent feeding throughout the day. PMID- 21605782 TI - Technical note: Contribution of ammonia emitted from livestock to atmospheric fine particulate matter (PM2.5) in the United States. AB - Ammonia emitted from animal feeding operations is an air pollutant contributing to the formation of fine particulate matter (PM(2.5)), considered a major environmental risk to human health. In the United States, farm animals are the greatest contributor to gaseous ammonia emissions. Ammonia reacts with atmospheric nitric and sulfuric acids to form PM(2.5) (nitrate and sulfate), but the proportion of PM(2.5) attributable to ammonia emitted from animal farming operations has not been quantified. Thus, the objective of this analysis was to estimate the contribution of ammonia emitted from farm animals to PM(2.5) in the United States. The following approach was used: (1) the amount of ammonium in sulfate and nitrate PM(2.5) was calculated based on chemically speciated measurements published by the United States Environmental Protection Agency; and (2) the amount of ammonium in sulfate and nitrate PM(2.5) originating from livestock was assumed equal to the fraction of the total ammonia emissions attributable to livestock. Across different regions of the United States and under different weather conditions, PM(2.5) formed from ammonia emitted from livestock operations were estimated to contribute on average from 5 to 11% of the total PM(2.5) concentrations. In certain areas (North Central, for example) and in cool weather, farm animal contribution to atmospheric PM(2.5) concentration may be as much as 20%. PMID- 21605783 TI - Simultaneous estimation of genotype by environment interaction accounting for discrete and continuous environmental descriptors in Irish dairy cattle. AB - Genotype by environment interaction can be analyzed by using a multi-trait model in which a trait measured in different environments is considered as separate traits. Alternatively, it can be analyzed by using a reaction norm model, in which the trait is considered a function of an environmental descriptor. Here, a model is developed where the 2 approaches are combined such that the effect of a continuous environmental descriptor can be analyzed in 2 or more discrete environments. The model is applied to somatic cell score (SCS) in relation to average herd milk production in 2 production environments: spring calving and year-round calving in Ireland. Heritabilities and additive genetic variances for SCS increased somewhat with increasing milk production and were higher in year round calving. Under the combined model, the genetic correlation between spring and year-round calving was estimated at 0.82 to 0.84, clearly lower than obtained in a bivariate analysis ignoring effects of herd milk production. Thus, when estimating the genetic correlation between environments, effects of one environmental descriptor may be obscured by another, but can be disentangled in an analysis combining the reaction norm and the multi-trait approach. Such models will be especially useful for analyzing questions such as whether the effect of increasing production or temperature is more severe in different production systems or geographic regions. PMID- 21605784 TI - Whole-genome association study for milk protein composition in dairy cattle. AB - Our objective was to perform a genome-wide association study for content in bovine milk of alpha(S1)-casein (alpha(S1)-CN), alpha(S2)-casein (alpha(S2)-CN), beta-casein (beta-CN), kappa-casein (kappa-CN), alpha-lactalbumin (alpha-LA), beta-lactoglobulin (beta-LG), casein index, protein percentage, and protein yield using a 50K single nucleotide polymorphism (SNP) chip. In total, 1,713 Dutch Holstein-Friesian cows were genotyped for 50,228 SNP and a 2-step association study was performed. The first step involved a general linear model and the second step used a mixed model accounting for all family relationships. Associations with milk protein content and composition were detected on 20 bovine autosomes. The main genomic regions associated with milk protein composition or protein percentage were found on chromosomes 5, 6, 11, and 14. The number of chromosomal regions showing significant (false discovery rate <0.01) effects ranged from 3 for beta-CN and 3 for beta-LG to 12 for alpha(S2)-CN. A genomic region on Bos taurus autosome (BTA) 6 was significantly associated with all 6 major milk proteins, and a genomic region on BTA 11 was significantly associated with the 4 caseins and beta-LG. In addition, regions were detected that only showed a significant effect on one of the milk protein fractions: regions on BTA 13 and 22 with effects on alpha(S1)-CN; regions on BTA 1, 9, 10, 17, 19, and 28 with effects on alpha(S2)-CN; a region on BTA 6 with an effect on beta-CN; regions on BTA 13 and 21 with effects on kappa-CN; regions on BTA 1, 5, 9, 16, 17, and 26 with effects on alpha-LA; and a region on BTA 24 with an effect on beta-LG. The proportion of genetic variance explained by the SNP showing the strongest association in each of these genomic regions ranged from <1% for alpha(S1)-CN on BTA 22 to almost 100% for casein index on BTA 11. Variation associated with regions on BTA 6, 11, and 14 could in large part but not completely be explained by known protein variants of beta-CN (BTA 6), kappa-CN (BTA 6), and beta-LG (BTA 11) or DGAT1 variants (BTA 14). Our results indicate 3 regions with major effects on milk protein composition, in addition to several regions with smaller effects involved in the regulation of milk protein composition. PMID- 21605785 TI - Technical note: Comparative analyses of the quality and yield of genomic DNA from invasive and noninvasive, automated and manual extraction methods. AB - Several new automated methods have recently become available for high-throughput DNA extraction, including the Maxwell 16 System (Promega UK, Southampton, UK). The purpose of this report is to compare automated with manual DNA extraction methods, and invasive with noninvasive sample collection methods, in terms of DNA yield and quality. Milk, blood, and nasal swab samples were taken from 10 cows for DNA extraction. Nasal swabs were also taken from 10 calves and semen samples from 15 bulls for comparative purposes. The Performagene Livestock (DNA Genotek, Kanata, Ontario, Canada) method was compared with similar samples taken from the same animal using manual extraction methods. All samples were analyzed using both the Qubit Quantification Platform (Invitrogen Ltd., Paisley, UK) and NanoDrop spectrophotometer (NanoDrop Technologies, Inc., Wilmington, DE) to accurately assess DNA quality and quantity. In general, the automated Maxwell 16 System performed best, consistently yielding high quantity and quality DNA across the sample range tested. Average yields of 28.7, 10.3, and 19.2 MUg of DNA were obtained from 450 MUL of blood, 400 MUL of milk, and a single straw of semen, respectively. The quality of DNA obtained from buffy coat and from semen was significantly higher with the automated method than with the manual methods (260/280 ratio of 1.9 and 1.8, respectively). Centrifugation of whole blood facilitated the concentration of leukocytes in the buffy coat, which significantly increased DNA yield after manual extraction. The Performagene method also yielded 18.4 and 49.8 MUg of high quality (260/280 ratio of 1.8) DNA from the cow and calf nasal samples, respectively. These results show the advantages of noninvasive sample collection and automated methods for high throughput extraction and biobanking of high quality DNA. PMID- 21605786 TI - Risk factors associated with selected indicators of milk quality in semiarid northeastern Brazil. AB - The aim of this study was to gain information on quality traits, mainly bacterial and somatic cell counts of bulk milk, produced by small- and medium-scale producers in a semiarid northeastern region of Brazil and to identify and characterize possible risk factors associated with those quality traits. A cross sectional study was performed on 50 farms. Bulk milk samples were collected for bacterial and somatic cell counts. Additionally, information about farm demographics, general management practices, hygiene, and milking procedures was also obtained. Multivariable analysis using logistic regression was performed with predictors previously identified by univariate analysis using a Fisher's Exact test. Aerobic mesophilic bacteria counts varied from 3.59 log to 6.95 log cfu/mL, with geometric mean of 5.27 log cfu/mL. Mean total coliform count was 3.27 log (1.52 log to 5.89 log) most probable number (MPN)/mL, whereas mean thermotolerant coliforms was 2.38 log (1.48 log to 4.75 log) MPN/mL. A high positive correlation was observed between aerobic mesophilic bacteria and coliform counts. Although most farms met the standard for the current regulations for total bacteria (88%) and somatic cell counts (94%), nearly half of the producers (46%) would have problems in achieving the 2012 threshold limit for total bacteria count if no improvement in milk quality occurs. Mean value for staphylococci was 3.99 log (2.31 log to 6.24 log) cfu/mL, and Staphylococcus aureus was detected in 33 (66%) farms. Premilking teat-end wash procedure (odds ratio=0.191) and postmilking teat dip (odds ratio=0.67) were associated with lower aerobic mesophilic bacteria and Staphylococcus aureus counts in bulk milk, respectively. Considering that the farm characteristics in this study are representative of the semiarid northeastern region, these findings encourage further investigations for supporting intervention measures intended to improve the quality of milk produced by smallholders. PMID- 21605787 TI - When cheese gets the blues: Pseudomonas fluorescens as the causative agent of cheese spoilage. AB - A bacterial contamination of fresh, low-acid cheese that resulted in production of a blue fluorescent pigment on the surface of the cheese was determined to be caused by Pseudomonas fluorescens biovar IV, a gram-negative bacteria that produces a blue, nondiffusible pigment as well as the soluble pigment pyoverdin, which fluoresces under UV light. Ten isolates collected from contaminated cheese and environmental samples were initially identified as P. fluorescens using 16S rDNA sequencing, but only 8 of the isolates produced blue pigment and fluoresced under UV light when re-inoculated onto fresh, low-acid cheese. The Biolog Metabolic Fingerprint system (Biolog Inc., Hayward, CA) and the Analytical Profile Index (BioMerieux Vitek Inc., Hazelwood, MO) for nonenteric gram-negative species as well as EcoRI ribotyping did not differentiate between the isolates that produced blue color and those that did not. Pulsed field gel electrophoresis with the enzyme XbaI was able to distinguish between the isolates that produced pigment and those that did not and allowed for identification of a specific environmental site (i.e., an overhead cheese vat agitator system) as the likely source of product contamination. PMID- 21605788 TI - Maximizing profit on New England organic dairy farms: an economic comparison of 4 total mixed rations for organic Holsteins and Jerseys. AB - The objective of these experiments was to compare 4 total mixed rations fed to USDA-certified organic dairy cows in New England. Forty-eight Jersey cows from the University of New Hampshire (UNH) and 64 Holstein cows from the University of Maine (UMaine) were assigned to a 2 * 2 factorial arrangement of treatments testing the main effects of corn silage versus grass silage as the forage base and commodity concentrates versus a complete pelleted concentrate mixture. Treatment diets were fed as a total mixed ration for 8 wk during the winter and spring months of 2007, 2008, and 2009. Milk yield, component, and quality data were recorded and used to calculate the value of the milk produced for each cow. The dry matter intake (DMI) was recorded and used to calculate the average cost per cow per day of each diet. Income over feed costs were calculated for each diet using milk value and feed cost data. Feed cost and income over feed cost data were resampled using bootstrap methodology to examine potential patterns. Milk yield, milk fat and true protein concentrations, and SCC were similar among treatments. Cows at UNH fed corn silage tended to have higher DMI and lower milk urea nitrogen than did cows fed grass silage, whereas cows fed pellets had higher DMI than cows fed commodities. Cows at UNH fed commodities tended to have higher body condition scores than those fed pellets. Cows at UMaine fed commodities tended to have higher DMI than did cows fed pellets, and cows fed corn silage had lower milk urea nitrogen than did cows fed grass silage. Body weights and body condition scores were not different for cows at UMaine. Feed costs were significantly higher for corn silage diets and diets at UNH containing pellets, but not at UMaine. The calculated value of the milk and income over feed costs did not differ among treatments at either university. Bootstrap replications indicated that the corn silage with commodities diet generally had the highest feed cost at both UNH and UMaine, whereas grass silage diets containing commodities generally had the lowest cost. In contrast, the grass silage with commodities diets had the highest income over feed cost in the majority of the replications at both UNH and UMaine replications, whereas the corn silage with commodities diets had the lowest rank. Similar results were observed when forage prices were increased or decreased by 5, 10, and 25% above or below the actual feed price. Feeding a grass silage-based diet supplemented with commodity concentrates may have an economic advantage for dairy producers in New England operating under an organic system of production. PMID- 21605789 TI - The genomic evaluation system in the United States: past, present, future. AB - Implementation of genomic evaluation has caused profound changes in dairy cattle breeding. All young bulls bought by major artificial insemination organizations now are selected based on such evaluation. Evaluation reliability can reach approximately 75% for yield traits, which is adequate for marketing semen of 2-yr old bulls. Shortened generation interval from using genomic evaluations is the most important factor in increasing the rate of genetic improvement. Genomic evaluations are based on 42,503 single nucleotide polymorphisms (SNP) genotyped with technology that became available in 2007. The first unofficial USDA genomic evaluations were released in 2008 and became official for Holsteins, Jerseys, and Brown Swiss in 2009. Evaluation accuracy has increased steadily from including additional bulls with genotypes and traditional evaluations (predictor animals). Some of that increase occurs automatically as young genotyped bulls receive a progeny test evaluation at 5 yr of age. Cow contribution to evaluation accuracy is increased by decreasing mean and variance of their evaluations so that they are similar to bull evaluations. Integration of US and Canadian genotype databases was critical to achieving acceptable initial accuracy and continues to benefit both countries. Genotype exchange with other countries added predictor bulls for Brown Swiss. In 2010, a low-density chip with 2,900 SNP and a high density chip with 777,962 SNP were released. The low-density chip has increased greatly the number of animals genotyped and is expected to replace microsatellites in parentage verification. The high-density chip can increase evaluation accuracy by better tracking of loci responsible for genetic differences. To integrate information from chips of various densities, a method to impute missing genotypes was developed based on splitting each genotype into its maternal and paternal haplotypes and tracing their inheritance through the pedigree. The same method is used to impute genotypes of nongenotyped dams based on genotyped progeny and mates. Reliability of resulting evaluations is discounted to reflect errors inherent in the process. Further increases in evaluation accuracy are expected because of added predictor animals and more SNP. The large population of existing genotypes can be used to evaluate new traits; however, phenotypic observations must be obtained for enough animals to allow estimation of SNP effects with sufficient accuracy for application to the general population. PMID- 21605790 TI - Maxillomandibular advancement for treatment of obstructive sleep apnea syndrome: a systematic review. AB - PURPOSE: To perform a systematic review of the published data concerning maxillomandibular advancement for the treatment of obstructive sleep apnea syndrome. MATERIALS AND METHODS: A systematic literature search was performed in the PubMed database. Original articles in the English language were reviewed to obtain information about patient data, success rates, and outcome measures. RESULTS: The systematic literature search yielded 1,113 citations, of which 101 articles met our inclusion criteria. After a review of the full text, 39 studies were included in the analysis. Most articles were classified as evidence level 4, and 5 met the inclusion criteria for level 2b. The only prospective randomized controlled study had been published in January 2010 and was assigned level 1b. CONCLUSIONS: A recommendation grade of A to B was achieved with regard to the levels of evidence-based medicine. Our results have shown that maxillomandibular advancement is the most successful surgical therapy, and the postoperative polysomnography results are comparable to those under ventilation therapy. PMID- 21605791 TI - Is it possible to shorten the jaws using contraction osteogenesis? AB - PURPOSE: This study investigated whether shortening of osteotomized jaws is possible. MATERIALS AND METHODS: Nine sheep were used (2 as controls and 7 as experimental subjects). Distraction devices that had previously been activated to 10 mm were fixed to the mandibles of all animals bilaterally and used in reverse as a contraction device. Control and experimental animals were sacrificed at 1 month and 3 months. Bone in the area of contraction was evaluated using radiodensitometry and microscopy. RESULTS: The mandibles were shortened an average of 5.5 mm. Exaggerated bone formation was seen around the osteotomized cortical bone. When histologic slices from experimental animals were examined 1 month after the contraction period, fibrous pseudoarthrosis formation was seen centrally, with hyaline cartilage around it, whereas normal bone formation was seen in the outer part. The hyaline cartilage had turned into normal bone 3 months after the end of contraction. CONCLUSIONS: It is possible to shorten bones using contraction osteogenesis. PMID- 21605792 TI - Internal carotid artery pseudoaneurysm after Le Fort I osteotomy: report of a case and its management. PMID- 21605793 TI - Comparison of microsuture, interpositional nerve graft, and laser solder weld repair of the rat inferior alveolar nerve. AB - PURPOSE: Intraosseous repair of nerves involves difficulty of access and there is concern that bone healing may interfere with repair outcomes. The present report describes the effect of 3 separate repair techniques on recovery from section of the rat intraosseous inferior alveolar nerve, with reference to the mental nerve distal and the trigeminal ganglion proximal to the nerve section. MATERIALS AND METHODS: Unilateral exposure of the inferior alveolar nerves of 28 rats was achieved through bone windows. Nerves were sectioned and rats were assigned to 1 of 4 groups (n = 7): untreated controls, microsuture repair, interpositional nerve grafts from the femoral nerve, or laser solder weld repair. Animals were sacrificed 1 year after surgery for histologic evaluation of the mental nerve, inferior alveolar nerve, and trigeminal ganglion compared with unoperated contralateral nerves. RESULTS: Compared with the unoperated contralateral nerves, nerve section substantially decreased mental nerve fiber number, mental nerve myelination, mental nerve fiber diameter, inferior alveolar nerve vascularity, trigeminal neuron number, and trigeminal neuron horseradish peroxidase tracer uptake and increased trigeminal ganglion degenerate neurons (P < .001). All 3 forms of repair substantially decreased these effects (P < .05). Interpositional nerve graft was least effective (P < .05). Nonetheless, mental nerve fiber diameter was significantly decreased compared with unsectioned nerves after microsuture and laser solder weld repair (P < .05). CONCLUSIONS: Intraosseous repair of the inferior alveolar nerve decreases peripheral and central signs of degeneration. Clinical hyperesthesia after repair may reflect a predominance of small fibers after recovery. PMID- 21605794 TI - Surgical training: is dabbling enough? PMID- 21605796 TI - Reducing risk of IAN injury during SSRO. PMID- 21605797 TI - Diagnosis of primary invasive oral aspergillosis. PMID- 21605799 TI - Avoidance of the mandibular nerve with implant placement: a new "mental loop". PMID- 21605800 TI - Preface: Autoimmune blistering diseases: part I--pathogenesis and clinical features. PMID- 21605801 TI - Direct and indirect immunofluorescence for the diagnosis of bullous autoimmune diseases. AB - DIF and IIF evaluates in vivo bound and circulating autoantibodies and are the preferred methods for diagnosing AIBDs. In pemphigus diseases and dermatitis herpetiformis, the titer of circulating autoantibodies reflects the disease activity. In patients with a classical clinical picture, the DIF confirms the diagnosis. Furthermore, this technique is essential in subtypes of AIBDs with atypical clinical manifestations (eg, no blisters or erosions) or clinically similar presenting manifestations, such as bullous pemphigoid, MMP, or EBA. A direct or indirect SSST is often crucial for the differential diagnosis between subtypes of these diseases, leading to proper treatment for severely affected patients. PMID- 21605802 TI - Diagnosis and clinical features of pemphigus vulgaris. AB - Autoimmune bullous diseases are associated with autoimmunity against structural components that maintain cell-cell and cell-matrix adhesion in the skin and mucous membranes. They include those where the skin blisters at the basement membrane zone and those where the skin blisters within the epidermis (pemphigus vulgaris, pemphigus foliaceus, and other subtypes of pemphigus). The variants of pemphigus are determined according to the level of intraepidermal split formation. There are 5 main variants of pemphigus: pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, drug-induced pemphigus, and paraneoplastic pemphigus. This review focuses only on pemphigus vulgaris. PMID- 21605803 TI - The genetics of pemphigus. AB - Pemphigus vulgaris (PV) is an autoimmune blistering disorder with a complex etiology involving an interplay of genetic as well as environmental factors, most of which remain unknown. Despite the identification of several human leukocyte antigen (HLA) alleles as risk factors for disease, no other non-HLA genes have clearly been implicated in disease susceptibility. Newer candidate gene and whole genome approaches are needed to illuminate the full palate of genetic risk elements in PV. Based on this information, genetic-based tools can be expected to provide a scientific rationale for future clinical decision-making by physicians and facilitate an era of personalized medicine. PMID- 21605804 TI - A globally available internet-based patient survey of pemphigus vulgaris: epidemiology and disease characteristics. AB - The authors developed an anonymous, Web-based survey instrument available globally, and collected data from 171 pemphigus vulgaris (PV) patients to assemble epidemiologic data pertaining to an extensive set of clinical parameters in demographically diverse populations. The results showed female predominance, prevalent onset of disease in the fifth decade of life, and a strong correlation of PV with thyroid disease and type 1 diabetes in patients and family members. Most patients have a history of either mucosal-only or mucocutaneous lesions, but numerous patients self-report cutaneous lesions only, without previous or concurrent mucosal lesions, especially in the non-North American PV population. PMID- 21605806 TI - Pathogenesis of endemic pemphigus foliaceus. AB - Pemphigus refers to a group of human autoimmune blistering diseases involving skin and/or mucous membranes. Endemic pemphigus foliaceus (EPF), or fogo selvagem is an organ-specific autoimmune blistering disease, first reported in the beginning of the 20th century in rural areas of Brazil. The disease follows the course of streams and creeks, and vanishes after urbanization of the endemic areas. The auto-antigen related to EPF is desmoglein 1, a 160 kDa glycoprotein of the desmossomal core, targeted by in situ and circulating IgG autoantibodies, mainly of the IgG4 subclass. PMID- 21605807 TI - Paraneoplastic pemphigus (paraneoplastic autoimmune multiorgan syndrome): clinical presentations and pathogenesis. AB - Paraneoplastic pemphigus is a rare condition with extremely high rates of mortality. Although its pathogenesis is incompletely understood, its pathologic findings have significant overlap with other autoimmune blistering diseases, such as pemphigus vulgaris, bullous pemphigoid, erythema multiforme and erosive lichen planus. A universally accepted consensus definition is needed to firmly define the condition. This would aid in identification of paraneoplastic pemphigus and the institution of timely and appropriate treatment to avoid rapid patient deterioration as well as recruitment for trials to further examine the pathogenesis and new therapeutic modalities. This article reviews the varied clinical presentations and pathologic characteristics pertaining to paraneoplastic pemphigus. PMID- 21605805 TI - Diagnosis and clinical features of pemphigus foliaceus. AB - Pemphigus foliaceus is an acquired autoimmune blistering disease in which the body's immune system produces IgG autoantibodies that target the intercellular adhesion glycoprotein desmoglein-1, which is principally expressed in the granular layer of the epidermis, resulting in the loss of intercellular connections between keratinocytes (acantholysis) and the formation of subcorneal blisters within the epidermis. This article summarizes the epidemiology, clinical features, techniques for diagnosis, and drugs associated with treatment of this rare disease. PMID- 21605808 TI - Clinical features and practical diagnosis of bullous pemphigoid. AB - Bullous pemphigoid (BP) represents the most common autoimmune subepidermal blistering disease. BP typically affects the elderly and is associated with significant morbidity. It has usually a chronic course with spontaneous exacerbations. The cutaneous manifestations of BP can be extremely protean. While diagnosis of BP in the bullous stage is straightforward, in the non-bullous stage or in atypical variants of BP signs and symptoms are frequently non-specific with eg, only itchy excoriated, eczematous, papular and/or urticarial lesions that may persist for several weeks or months. Diagnosis of BP critically relies on immunopathologic examinations including direct immunofluorescence microscopy and detection of serum autoantibodies by indirect immunofluorescence microscopy or BP180-ELISA. PMID- 21605809 TI - Pathogenesis of bullous pemphigoid. AB - Bullous pemphigoid, the most common autoimmune blistering disease, is induced by autoantibodies against type XVII collagen. Passive transfer of IgG or IgE antibodies against type XVII collagen into animals has revealed not only the pathogenicity of these antibodies but also the subsequent immune responses, including complement activation, mast cell degranulation, and infiltration of neutrophils and/or eosinophils. In vitro studies on ectodomain shedding of type XVII collagen have also provided basic knowledge on the development of bullous pemphigoid. The pathogenic role of autoreactive CD4+ T lymphocytes in the development of the pathogenic autoantibodies to type XVII collagen should also be noted. PMID- 21605810 TI - Pemphigoid gestationis: pathogenesis and clinical features. AB - Pemphigoid gestationis is a rare, autoimmune bullous disease of pregnancy that involves autoantibodies directed against type XVII collagen in the basement membrane zone. This article discusses the immunopathogenesis, diagnostic methods, and clinical features of this fascinating disease. PMID- 21605811 TI - Linear IgA disease: clinical presentation, diagnosis, and pathogenesis. AB - Linear IgA disease is one of the rarer subepidermal blistering diseases. Linear IgA disease is a chronic, acquired, autoimmune blistering disease that is characterized by subepidermal blistering and linear deposition of IgA basement membrane antibodies. The disease affects both children and adults and, although there are some differences in their clinical presentations, there is considerable overlap with shared immunopathology and immunogenetics. PMID- 21605812 TI - Clinical features, diagnosis, and pathogenesis of chronic bullous disease of childhood. AB - Chronic bullous disease of childhood (CBDC) is the most common acquired autoimmune blistering disorder of childhood and is characterized by linear IgA staining of the basement membrane zone on direct immunofluorescence. This autoimmune attack on structural proteins, usually proteolytic fragments of collagen XVII, renders the dermal-epidermal junction prone to blistering. Diagnosis is confirmed by characteristic histology and direct immunofluorescence. Prognosis is generally favorable, with spontaneous remission usually occurring by puberty; however, cases with severe morbidity and cases persisting into adulthood have been reported. This article discusses the clinical features, diagnosis, and pathogenesis of CBDC in more detail. PMID- 21605813 TI - An exception within the group of autoimmune blistering diseases: dermatitis herpetiformis, the gluten-sensitive dermopathy. AB - Dermatitis herpetiformis (DH) is characterized by chronic, itching papules, seropapules, small vesicles and, exceptionally, large blisters. The distribution of these polymorphic symptoms around the elbow, knee, buttock, and back is suggestive of the diagnosis. DH is further confirmed by the accumulation of granulocytes at the papillary dermis, resulting in a subepidermal split formation and by the presence of a unique, granular IgA precipitate in the uppermost dermis. Prognosis is predominantly determined by other autoimmune pathologies, malabsorption, or very rarely by lymphomas. Some of these diseases can be prevented by an early-onset, strict gluten-free diet, which is therefore the suggested treatment option. PMID- 21605814 TI - Pathophysiology of dermatitis herpetiformis: a model for cutaneous manifestations of gastrointestinal inflammation. AB - Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease in which antigen presentation in the gastrointestinal mucosa results in cutaneous IgA deposition and distinct, neutrophil-driven cutaneous lesions. Our findings suggest that the qualitatively different immune response to gluten in the intestinal mucosa of patients with DH results in minimal clinical symptoms, allowing the continued ingestion of gluten and the eventual development of DH. Our model may provide a new way to understand the pathogenesis of other skin diseases associated with gastrointestinal inflammation such as pyoderma gangrenosum or erythema nodosum, or explain association of seronegative inflammatory arthritis with inflammatory bowel disease. PMID- 21605815 TI - Pathogenesis of mucous membrane pemphigoid. AB - Mucous membrane pemphigoid (MMP) is the clinical phenotype of a group of autoimmune blistering diseases characterized by autoantibodies directed against different structural proteins in epidermal basement membranes. The clinical course and prognosis of MMP are affected by the specific autoantigen targeted, the titer and bioactivity profile of corresponding autoantibodies, and the specific mucosal sites of disease activity. Irreversible scarring and loss of function must be prevented by early diagnosis and appropriate interventions. PMID- 21605816 TI - Diagnosis and clinical features of epidermolysis bullosa acquisita. AB - Epidermolysis bullosa acquisita (EBA) is a rare autoimmune subepidermal blistering disease characterized by immune deposits on anchoring fibrils of cutaneous and mucosal basement membrane zones. It is due to circulating antibodies directed to type VII collagen. Clinical manifestations include a classical form with skin fragility, blisters and scars on trauma-prone surfaces, an inflammatory form, and a cicatricial pemphigoid-like form. Specialized tests available in only certain laboratories are necessary to confirm a diagnosis of EBA, such as immunoelectron microscopy, immunoblotting, or ELISA using recombinant proteins. A frequent association between EBA and Crohn disease has been observed. PMID- 21605817 TI - Pathogenesis of epidermolysis bullosa acquisita. AB - Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering skin disease characterized by autoantibodies to type VII collagen. Clinically, a noninflammatory and an inflammatory variant of EBA can be distinguished. Despite major achievements in the understanding of EBA, current therapeutic options are far from optimal. However, with an emerging and more detailed understanding of the events ultimately leading to blister formation in EBA, novel therapeutic options may become available for patients with EBA. Therefore, this article reviews the current understanding of the pathogenesis of EBA and may indicate possible avenues towards a more targeted therapy for EBA and possibly other antibody-mediated autoimmune diseases. PMID- 21605818 TI - Hair loss in autoimmune cutaneous bullous disorders. AB - The expression of the basement membrane zone (BMZ) components in the anagen hair follicles of the human scalp is similar to that of interfollicular epidermis. Expression of the BMZ components varies according to the different follicular portions. Blistering of the scalp, involving lamina lucida and below, usually leads to scarring alopecia secondary to the inflammatory process in the interfollicular epidermis and in the upper portion of the hair follicle. This article discusses the presence of alopecia in the most common acquired forms of bullous disorders. PMID- 21605819 TI - Nail involvement in autoimmune bullous disorders. AB - Autoimmune bullous disorders frequently cause nail abnormalities, particularly paronychia and onychomadesis. In pemphigus vulgaris (PV) nail abnormalities can even precede skin findings. Nail lesions often relapse just before generalized disease exacerbation or recurrence. Severe nail changes are often associated with extensive and severe disease. Fingernails are more commonly affected. A report in the literature associates hemorrhagic nail abnormalities with poor prognosis in patients with PV. Nail scarring and pterygium are a rare complication of bullous pemphigoid. Nail loss has been occasionally reported in epidermolysis bullosa acquisita. PMID- 21605820 TI - Objective scoring systems for disease activity in autoimmune bullous disease. AB - Objectively evaluating disease activity in autoimmune bullous disease (AIBD) is important in terms of the clinical assessment of patients and as an outcome measure for clinical trials. Measures need to be general enough to capture the issues specific to each of the bullous dermatoses but specific enough to capture any changes to disease status for a patient. Different tools have been put forward over the last 15 years, but presently the Autoimmune Bullous Skin Disorder Intensity Score and Pemphigus Disease Area Index seem to be the most promising tools to assess disease activity in AIBD. PMID- 21605821 TI - Pemphigus and quality of life. AB - Measuring the impact of disease on quality of life (QOL) is important for evaluating effectiveness of care and capturing aspects of health that may not correlate with clinical severity. Few QOL studies have been conducted on pemphigus, and a disease-specific QOL questionnaire for this condition has not been developed. The 5 previous studies of the effect of pemphigus on QOL used generic health or skin-specific measures. These measures have limitations, and results from these studies have sometimes been conflicting. The development of a disease-specific measure for pemphigus would allow for better monitoring of patients' QOL and improve management. PMID- 21605822 TI - Nitric oxide and quality and safety of muscle based foods. AB - Preservation of meat with nitrite or nitrate has become important to mankind in controlling meat spoilage and in producing safe and palatable meat products with good keeping properties even at ambient temperature. Nitric oxide was early recognised as pivotal for colour and colour stability of such meat products. Later specific effects on microbial growth became evident, followed by an understanding of nitric oxide as an antioxidant in processed meat, while a future recognition of nitric oxide as modulator of transmetallisation reactions in meat seems possible. Central for all these functions of nitric oxide in meat is the heme cavity in the meat pigment myoglobin with its facile conversions among reactive oxygen and nitrogen species in certain cases assisted by curing additives such as ascorbate and with a possible involvement of nitroxyl. PMID- 21605823 TI - The proposed Criminal Evidence (Experts) Bill......moving in the right direction..? PMID- 21605825 TI - Characterisation of triacetone triperoxide (TATP) conformers using LC-NMR. AB - Previous studies [1,2] have reported the existence of two conformers of TATP. This study demonstrates the ability of LC-NMR to separate and characterise the individual conformers. The NMR data is consistent with the proposed structures for the two conformers. Re-equilibration can be followed by NMR and the kinetics of the process studied. Over the past decade the use of the explosive TATP in terrorist devices has increased. Therefore, the ability to analyse and characterise this material has assumed greater importance. PMID- 21605826 TI - Dichroism measurements in forensic fibre examination Part 1--Dyed polyester fibres. AB - One hundred and twenty dyed polyester samples were examined with plane polarized light on their dichroic behaviour by optical light microscopy (OLM) and microspectrophotometry in the visible range (MSP Vis). It was found that most of these disperse dyed polyester fibres possess a strong dichroism, which fall into two broad categories. Either a decrease of intensity (hypochromic effect) or a change of hue (hypsochromic or bathochromic shift of absorption bands) is noted. These dichroic effects are related to the orientation of the dye structure with respect to the polymer chains. PMID- 21605824 TI - Evidence evaluation: a response to the court of appeal judgment in R v T. AB - This is a discussion of a number of issues that arise from the recent judgment in R v T [1]. Although the judgment concerned with footwear evidence, more general remarks have implications for all disciplines within forensic science. Our concern is that the judgment will be interpreted as being in opposition to the principles of logical interpretation of evidence. We reiterate those principles and then discuss several extracts from the judgment that may be potentially harmful to the future of forensic science. A position statement with regard to evidence evaluation, signed by many forensic scientists, statisticians and lawyers, has appeared in this journal [2] and the present paper expands on the points made in that statement. PMID- 21605827 TI - Synthetic flock fibres: a population and target fibre study. AB - One hundred garments were examined for synthetic flock fibres. Flock fibres were found on 82% of garments. The majority of flock fibres were nylon (6 or 6,6) with a round cross-section, a diameter between 15 and 20 MUm and a length between 0.5 and 1 mm. Black pigmented flock fibres (polyester or nylon) were present on 33% of garments. Each garment was examined for several target automotive flock fibres from the glove compartments and window channels of a range of vehicles. None of the dyed target flock fibres were found on the garments. The black pigmented target flock fibres were found on 3-4% of the garments examined. PMID- 21605828 TI - Attempted ignition of petrol vapour by lit cigarettes and lit cannabis resin joints. AB - A recent murder enquiry prompted experimentation to confirm and visually demonstrate that lit cigarettes are not a viable source of ignition of petrol vapour. In addition, tests comprising the attempted ignition of petrol vapour using hot and smouldering cannabis resin were also undertaken. A series of experiments was also designed to recreate circumstances specific to the crime under investigation by undertaking cigarette/joint ignition tests involving a mannequin clothed in a cotton garment onto which petrol was applied. The ultimate aim of the experiments was to produce a visual aid for use during court proceedings. Thirty nine (39) ignition attempts that involved exposing lit commercial cigarettes, hand-rolled cigarettes and cannabis resin joints to petrol vapour were undertaken; ignition was not achieved in any of the scenarios. In addition, a single attempt to ignite petrol vapour emanating from a pool of liquid fuel was effected with a smouldering piece of cannabis resin; no ignition occurred. In all cases the petrol was clearly present within the limits of flammability since ignition was subsequently effected using a naked flame. PMID- 21605829 TI - Characterization of soils from the Algarve region (Portugal): a multidisciplinary approach for forensic applications. AB - The Algarve is located at a very short distance from North Africa, in Southern Portugal, and as one of the most touristic regions of Portugal, it is accessible by air, land and sea. It is very susceptible to many illegal activities, such as illegal migration, drug trafficking, kidnapping, and murder, among others. Therefore, an Algarve soils database for forensic purposes is being conducted with the conjunction of geological and palynological methodologies on soils characterization, since this is of fundamental importance to assess reliable evidence on forensic investigations. In this study, the properties of soils from several proximate sites from the Algarve were investigated, namely: (i) colour determined by spectrophotometry; (ii) particle size distribution determined by laser granulometry; (iii) low-field magnetic susceptibility by a susceptibility meter; and (iv) pollen content using a light microscope. Finally, a hierarchical cluster analysis was applied to ascertain the capacity of the different soil properties for discrimination between samples. The study reveals the utility of geobotanical techniques for forensic discrimination of soils. Even though some similarities between some of the samples were found, each one presented a combination of colour, particle size distribution, magnetic susceptibility and pollen features that enable the determination of a fingerprint expected to reveal a specific site for future selection of coastal search areas in the Algarve region. PMID- 21605830 TI - Reporting of research quality characteristics of studies published in 6 major clinical dental specialty journals. AB - The objective of this article was to record reporting characteristics related to study quality of research published in major specialty dental journals with the highest impact factor (Journal of Endodontics, Journal of Oral and Maxillofacial Surgery, American Journal of Orthodontics and Dentofacial Orthopedics; Pediatric Dentistry, Journal of Clinical Periodontology, and International Journal of Prosthetic Dentistry). The included articles were classified into the following 3 broad subject categories: (1) cross-sectional (snap-shot), (2) observational, and (3) interventional. Multinomial logistic regression was conducted for effect estimation using the journal as the response and randomization, sample calculation, confounding discussed, multivariate analysis, effect measurement, and confidence intervals as the explanatory variables. The results showed that cross-sectional studies were the dominant design (55%), whereas observational investigations accounted for 13%, and interventions/clinical trials for 32%. Reporting on quality characteristics was low for all variables: random allocation (15%), sample size calculation (7%), confounding issues/possible confounders (38%), effect measurements (16%), and multivariate analysis (21%). Eighty-four percent of the published articles reported a statistically significant main finding and only 13% presented confidence intervals. The Journal of Clinical Periodontology showed the highest probability of including quality characteristics in reporting results among all dental journals. PMID- 21605831 TI - Chlorhexidine varnish may prevent dental caries in children and adolescents. PMID- 21605832 TI - Impact of retained separated endodontic instruments during root canal treatment on clinical outcomes remains uncertain. PMID- 21605833 TI - There is weak evidence that a single, universal dental recall interval schedule reduces caries incidence. PMID- 21605834 TI - Periodontal treatment may control glycemic status among diabetic patients. PMID- 21605835 TI - Evidence for survival of implants placed into infected sites is limited. PMID- 21605836 TI - Home bleaching and in-office bleaching may not be equally effective clinically. PMID- 21605837 TI - In individuals with loss of molar support, the treatment based on shortened dental arch concept may not decrease the risk of tooth loss compared with molar replacement with removable partial prosthesis. PMID- 21605838 TI - Accidents, sports, and physical leisure activities are the most frequent causes of traumatic dental injury and the rate of pulp necrosis is high following its occurrence in Pilsen, The Czech Republic. PMID- 21605839 TI - One-third of orthodontic patients receiving fixed appliances in a US graduate clinic have new iatrogenic demineralized white lesions at the end of treatment. PMID- 21605840 TI - Dentists in a practice-based research network show considerable variation in their choices for caries prevention agents. PMID- 21605841 TI - Patients differ in the amount of information they want to know about risks and complications before consenting to treatment. PMID- 21605842 TI - Use of dietary fluoride supplements by children living in Berlin, Germany, may have a dose-response preventive effect against dental caries, regardless of their use of fluoridated salt. PMID- 21605843 TI - Genetics may play a factor in oral health. PMID- 21605844 TI - Current use of calcium channel blockers (CCBs) is associated with an increased risk of gingival hyperplasia. PMID- 21605845 TI - Nutrition and the risk of oral and pharyngeal cancer: the evidence for any association remains weak and clinical significance remains limited. PMID- 21605846 TI - The relationship between leadership style and provision of the first Danish publicly reimbursed cognitive pharmaceutical service--a qualitative multicase study. AB - BACKGROUND: Evidence suggests that leadership style is important to the sustainability of cognitive pharmaceutical services, yet only scarce literature on the relationship exists. OBJECTIVES: Support of the sustainability of the first publicly reimbursed cognitive service in Denmark, the Inhaler Technique Assessment Service (ITAS), was ascertained through a qualitative study to explore how leadership style shapes the implementation process of the service. Sustainability in this project was defined as the state where those asthma patients whose symptom status is negatively clinically affected (as defined by Global Initiative for Asthma guidelines) by inappropriate inhalation technique are identified and offered the service by pharmacy staff. METHODS: The study was an exploratory qualitative multicase study that used triangulation of both data sources and methods. A theoretical framework of Bolman and Deal inspired the analysis of how leadership style influenced the local process of implementation of the ITAS. Four pharmacies were selected for the analysis because they differed in terms of leadership actions in their implementation process and achievement of ITAS sustainability. The analysis was inductive and linked factors that influence ITAS provision as perceived by employees with the interpreted leadership style of the owner. RESULTS: Three main themes emerged: (1) the alignment of the owner and staff values, (2) whether owners perceived ITAS development as being under their own control, and (3) whether owners explicated the responsibilities of employees in the implementation process. The themes were interrelated. CONCLUSIONS: Pharmacy owner's leadership style was significant to sustainability of the ITAS. A strong wish by the owner to have ITAS implemented was important, followed by aligning the owner's values and visions with those of the employees. The widespread perception by owners that experienced users are not interested in the ITAS needs to be addressed to achieve sustainability. PMID- 21605847 TI - Perspectives April 2011. PMID- 21605848 TI - [Primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma: report of a case with spontaneous resolution]. PMID- 21605849 TI - [Ethics in medical research in humans: a historical perspective]. PMID- 21605850 TI - Fatty acid synthase inhibitors from the hulls of Nephelium lappaceum L. AB - Natural products inhibiting fatty acid synthase (FAS) are appearing as potential therapeutic agents to treat cancer and obesity. The bioassay-guided chemical investigation of the hulls of Nephelium lappaceum L. resulted in the isolation of ten compounds (1-10) mainly including flavonoids and oleane-type triterpene oligoglycosides, in which all of the compounds were isolated from this plant for the first time. Additionally, compounds 8 and 9 were new hederagenin derivatives and were elucidated as hederagenin 3-O-(2,3-di-O-acetyl-alpha-l-arabinofuranosyl) (1->3)-[alpha-l-rhamnopyranosyl(1->2)]-beta-l-arabinopyranoside and hederagenin 3 O-(3-O-acetyl-alpha-l-arabinofuranosyl)-(1->3)-[alpha-l-rhamnopyranosyl-(1->2)] beta-l-arabinopyranoside, respectively. All these isolates were evaluated for inhibitory activities of FAS, which showed these isolates had inhibitory activity against FAS with IC(50) values ranging from 6.69 to 204.40 MUM, comparable to the known FAS inhibitor EGCG (IC(50)=51.97 MUM). The study indicates that the hulls of Nephelium lappaceum L. could be considered as potential sources of promising FAS inhibitors and the oleane-type triterpene oligoglycosides could be considered as another type of natural FAS inhibitors. PMID- 21605851 TI - Antibacterial activity and mechanism of action of chitosan solutions against apricot fruit rot pathogen Burkholderia seminalis. AB - The in vitro antibacterial activity and mechanism of action of two kinds of acid soluble chitosan and one water-soluble chitosan against apricot fruit rot pathogen Burkholderia seminalis was examined in this study. Results showed that water-soluble chitosan displayed limited antibacterial activity at four tested concentrations. However, two kinds of acid-soluble chitosan solution at 2.0 mg/mL had strong antibacterial activity against B. seminalis although weak antibacterial activity was observed at a concentration lower than 1 mg/mL. The antibacterial activity of acid-soluble chitosan may be due to membrane disruption, cell lysis, abnormal osmotic pressure, and additional chitosan coating around the bacteria based on integrity of cell membranes test, out membrane permeability assays and transmission electron microscopy observation. In addition, biofilm biomass were markedly reduced after treating with two kinds of acid-soluble chitosan at concentrations of 2.0 and 1.0 mg/mL for 3 and 12 h, indicating the importance of biofilm formation in the antibacterial mechanism of chitosan. Overall, the results clearly indicated that two kinds of acid-soluble chitosan had a potential to control the contamination of apricot fruits caused by B. seminalis. PMID- 21605852 TI - [Gastric incarceration in an infraumbilical ventral hernia]. PMID- 21605853 TI - An image feature approach for computer-aided detection of ischemic stroke. AB - We present a computer-aided detection (CAD) scheme for early detection of ischemic stroke with small lesions using image feature characteristics. A novel Circular Adaptive Region of Interest (CAROI) method is proposed to analyze the Computed Tomography (CT) images of the brain. Our result indicates that for the emergency physicians and radiology residents, there is a significant improvement in sensitivity and specificity when using CAD (P < 0.005). A mathematical model is established incorporating the weighting of the feature changes. Our CAD scheme is promising for early detection of ischemic stroke and helps improve the efficiency and accuracy of clinical practice. PMID- 21605854 TI - Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes. AB - Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study. Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose-response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50MUg/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50MUg/l in drinking water and those who carried the PNP A-T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79-23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50MUg/l). PMID- 21605855 TI - Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome with a single uterus. AB - OBJECTIVE: To describe an unusual case of obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome with a single uterus. DESIGN: Case report. SETTING: Major academic medical center. PATIENT(S): A 12-year-old girl with OHVIRA syndrome. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): None. RESULT(S): A 12-year-old girl presented with presumed OHVIRA syndrome and had surgical correction of the obstructed hemivagina. Two years later she presented with increasing pelvic pain and underwent laparoscopy for presumed endometriosis. A single uterus with a broad flat fundus was found as well as endometriosis. CONCLUSION(S): OHVIRA syndrome is typically associated with a didelphys uterus with two cervices and two vaginas, one of which is obstructed. The obstruction usually occurs on the same side as the renal anomaly. We report a rare congenital anomaly of the female reproductive tract: OHVIRA syndrome with a single uterus. From a fertility standpoint, cases of a single uterus with two cervices are managed differently than two uteri with two cervices. Healthcare providers managing complex reproductive tract anomalies should be aware of this potential variant. PMID- 21605857 TI - Letrozole and gonadotropins versus luteal estradiol and GnRH-antagonist protocol: additional concerns. PMID- 21605859 TI - Impaired expansion of trophoblast spheroids cocultured with endometrial cells overexpressing cellular retinoic acid-binding protein 2. AB - We previously showed that the cellular retinoic acid-binding protein 2 (CRABP2) gene was up-regulated during the implantation window period in the endometrium of patients with unexplained recurrent spontaneous abortion. Here, we report that trophoblast spheroids cocultured with a human endometrial cell line stably overexpressing CRABP2 are defective in expansion and exhibit apoptosis, suggesting that the altered expression level of endometrial CRABP2 is involved in abnormal endometrium-trophoblast interaction, which leads to implantation failure. PMID- 21605860 TI - Discussion on letrozole-Gn-antagonist group needing an early start of antagonist. PMID- 21605861 TI - Rat serum albumin is not equal to human serum albumin. PMID- 21605862 TI - Predictive value of remnant lipoprotein for cardiovascular events in patients with coronary artery disease after achievement of LDL-cholesterol goals. AB - OBJECTIVES: Triglycerides-rich lipoproteins are related to residual cardiovascular risk in patients on lipid-lowering treatment who achieve low density lipoprotein cholesterol (LDL-C) goals. This study examined the predictive value of remnant lipoprotein levels for cardiovascular events in patients with coronary artery disease (CAD) with LDL-C levels <100mg/dL on lipid-lowering therapy. METHODS: Serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method in 560 patients with CAD who had LDL-C levels <100mg/dL on lipid-lowering therapy, including statin (58%), fibrate (13%) or diet only (29%). All the patients were followed prospectively for a period of <= 36 months or until occurrence of one of the following events: cardiac death, non fatal myocardial infarction, unstable angina requiring coronary revascularization, or ischemic stroke. RESULTS: During a mean follow-up period of 33 months, 40 events occurred. Stepwise multivariate Cox proportional hazard analysis showed that RLP-C was a significant predictor of cardiovascular events after adjustment for known risk factors and lipid variables including triglycerides, non-high-density lipoprotein (HDL)-C, and total apolipoprotein B (HR 1.53, 95% CI 1.35-1.97, p<0.01). The c-statistics showed that addition of RLP-C had a greater incremental effect on the predictive value of conventional risk factors than addition of non-HDL-C or total apolipoprotein B. CONCLUSIONS: RLP-C was superior to non-HDL-C for predicting cardiovascular events in CAD patients with LDL-C levels <100mg/dL on lipid-lowering treatment. Remnant lipoprotein may therefore be an important target for residual risk reduction after LDL-C goals on lipid lowering therapy. PMID- 21605863 TI - A pattern of disperse plaque microcalcifications identifies a subset of plaques with high inflammatory burden in patients with acute myocardial infarction. AB - AIMS: Inflammation plays a crucial role in plaque vulnerability. Calcifications can be detected by means of in vivo imaging techniques. The study purpose is to assess a potential association between tissue localization of calcifications and the inflammatory biomarkers, C-reactive protein (CRP), osteopontin and lipoprotein-associated phospholipase A2 (Lp-PLA2), in plaque tissue of patients with acute myocardial infarction (AMI). METHODS AND RESULTS: Thrombectomy materials obtained from patients with electrocardiographically documented ST segment elevation type of AMI (STEMI) were histologically screened for presence of thrombus, plaque tissues and calcifications. Size of calcifications was measured morphometrically, and their colocalization with the inflammatory biomarkers macrophages, CRP, osteopontin and Lp-PLA2 was assessed with immunostaining. A total of 171 samples containing plaque tissues were obtained from 562 thrombectomy procedures. Calcifications were observed in 67 (39%) plaque fragments, with diameters ranging from 4 to 170 MUm. Plaque tissues with calcifications contained more frequently extracellular CRP and intracellular CRP in macrophages than those without calcifications (85%, 59% vs. 64%, 32%, P=0.012 and 0.005 respectively). Similar results were obtained with osteopontin immunostaining (98%, 76% vs. 56%, 40%; P<0.001 both). Furthermore, samples with calcifications were immunostained for CRP more intensely than those without calcifications (P=0.001). Finally, 96% of the plaque tissues stained positively for Lp-PLA2, but there was no association with presence of microcalcifications. CONCLUSIONS: A pattern of disperse microcalcifications is positively associated with presence of the inflammatory biomarkers macrophages, CRP and osteopontin in thrombectomy materials of STEMI patients. Based on these findings, we speculate that such microcalcifications could have the potential to serve as a surrogate marker for plaques with high inflammatory burden. PMID- 21605864 TI - Oxidative stress is associated with impaired arterial elasticity. AB - AIMS: Arterial stiffening may lead to hypertension, greater left ventricular after-load and adverse clinical outcomes. The underlying mechanisms influencing arterial elasticity may involve oxidative injury to the vessel wall. We sought to examine the relationship between novel markers of oxidative stress and arterial elastic properties in healthy humans. METHODS AND RESULTS: We studied 169 subjects (mean age 42.6 +/- 14 years, 51.6% male) free of traditional cardiovascular risk factors. Indices of arterial stiffness and wave reflections measured included carotid-femoral Pulse Wave Velocity (PWV), Augmentation Index (Aix) and Pulse Pressure Amplification (PPA). Non-free radical oxidative stress was assessed as plasma oxidized and reduced amino-thiol levels (cysteine/cystine, glutathione/GSSG) and their ratios (redox potentials), and free radical oxidative stress as derivatives of reactive oxygen metabolites (dROMs). Inflammation was assessed as hsCRP and interleukin-6 levels. The non-free radical marker of oxidative stress, cystine was significantly correlated with all arterial indices; PWV (r=0.38, p<0.001), Aix (r=0.35, p<0.001) and PPA (r=-0.30, p<0.001). Its redox potential, was also associated with PWV (r=0.22, p=0.01), while the free radical marker of oxidative stress dROMS was associated with Aix (r=0.25, p<0.01). After multivariate adjustment for age, gender, arterial pressure, height, weight, heart rate and CRP, of these oxidative stress markers, only cystine remained independently associated with PWV (p=0.03), Aix (p=0.01) and PPA (p=0.05). CONCLUSIONS: In healthy subjects without confounding risk factors or significant systemic inflammation, a high cystine level, reflecting extracellular oxidant burden, is associated with increased arterial stiffness and wave reflections. This has implications for understanding the role of oxidant burden in pre-clinical vascular dysfunction. PMID- 21605865 TI - Thyroid hormone enhances the ability of serum to accept cellular cholesterol via the ABCA1 transporter. AB - OBJECTIVE: The goal of this study was to examine the effects of thyroid hormone status on the ability of serum to accept cellular cholesterol. METHODS AND RESULTS: Sera from hypophysectomized rats treated +/- T(3) was used to evaluate the role of thyroid hormone on serum efflux capacity. 2D-DIGE analysis of serum proteins showed that T(3) treated rats had increased ApoA-I, ApoA-IV and fetuin A levels with decreased Apo E levels. Microarray and real-time RT-PCR analysis of rat liver revealed large increases in ApoA-I, ApoA-IV, ABCG5, and ABCG8 in response to T(3). J774 macrophages, BHK cells, and Fu5AH rat hepatoma cells were used to measure cholesterol efflux mediated by ABCA1, ABCG1 transporters or SR BI. Sera from T(3)-treated rats stimulated efflux via ABCA1 but not by ABCG1 or SR-BI. Gel filtration chromatography revealed that T(3) treatment caused a decrease in HDL particle size accompanied by higher levels of lipid-poor ApoA-I. CONCLUSIONS: Thyroid hormone enhances the ability of serum to accept cellular cholesterol via the ABCA1 transporter. This effect is most likely attributable to increases in small HDL and lipid poor ApoA-I in response to T(3). PMID- 21605867 TI - Influence of protein adsorption kinetics on breakthrough broadening in membrane affinity chromatography. AB - Existing mathematical models developed to describe membrane affinity chromatography are unable to match the complete breakthrough curve when a single Langmuir adsorption isotherm is used, because important deviations from the observed behavior are systematically encountered in the simulation of breakthrough broadening near saturation. The relevant information required to overcome that limitation has been obtained by considering simultaneously both loading and washing curves, thus evaluating the adsorption data at equilibrium and recognizing what are the appropriate adsorption mechanisms affecting the observed behavior. The analysis indicates that a bi-Langmuir binding kinetics is essential for a correct process description up to the saturation of the stationary phase, together with the use of the relevant transport phenomena already identified for the experimental system investigated. The input parameters used to generate the resulting simulations are evaluated from separate experiments, independent from the chromatographic process. Model calibration and validation is accomplished comparing model simulations with experimental data measured by feeding pure human immunoglobulin G (IgG) solutions as well as a cell culture supernatant containing human monoclonal IgG(1) to B14-TRZ-Epoxy2 bio mimetic affinity membranes. The simulations obtained are in good agreement with the experimental data over the entire adsorption and washing stages, and breakthrough tailing appears to be associated to the reversible binding sites of the bi-Langmuir mechanism. Remarkably, the model proposed is able to predict with good accuracy the purification of IgG from a complex mixture simply on the basis of the results obtained from pure IgG solutions. PMID- 21605866 TI - Smokers show reduced circulating adiponectin levels and adiponectin mRNA expression in peripheral blood mononuclear cells. AB - OBJECTIVES: Circulating adiponectin levels in cigarette smokers are lower than those in nonsmokers. We have previously shown that adiponectin is expressed in human monocytes. The aim of this study was to further investigate the effect of smoking on adiponectin expression in peripheral blood mononuclear cells (PBMCs). METHODS: A group of 77 cigarette smokers and 51 nonsmokers were consecutively enrolled in this study. The participants' body weight, blood pressure, and metabolic parameters, including plasma glucose and plasma adiponectin levels, were recorded. The RNA from the PBMCs was assessed with real-time polymerase chain reaction (PCR) to determine the levels of adiponectin mRNA. RESULTS: Of the 77 smokers, 67 (87.0%) were male. Their mean (standard deviation) age was 43.17 (11.47) years, and they smoked 24.56 (12.53) cigarettes/day. The duration of smoking was 23.73 (11.69) years. Both circulating adiponectin levels (p=0.0262) and adiponectin mRNA levels in PBMCs (p<0.0001) of smokers were significantly lower than those in nonsmokers. Both circulating adiponectin levels and adiponectin mRNA levels were negatively correlated with the number of cigarettes smoked per day (p<0.01). In multiple linear regression analysis, smoking was an independent factor affecting adiponectin mRNA expression in PBMCs (p<0.0001). CONCLUSIONS: Circulating adiponectin levels and adiponectin expression in PBMCs were lower in smokers; this finding suggested that attenuation of both systemic and local actions of adiponectin might contribute to the atherosclerotic process in cigarette smokers. PMID- 21605868 TI - A new strategy to simultaneous microextraction of acidic and basic compounds. AB - The simultaneous extraction of acidic and basic pollutants from water samples is an interesting and debatable work in sample preparation techniques. A novel and efficient method named ion pair based surfactant assisted microextraction (IP SAME) was applied for extraction and preconcentration of five selected acidic and basic aromatic species as model compounds in water samples, followed by high performance liquid chromatography-ultraviolet detection. A mixture including 1 mL of ultra-pure water (containing ionic surfactant as emulsifier agent) and 60 MUL 1-octanol (as extraction solvent) was rapidly injected using a syringe into a 10.0 mL water sample which formed an emulsified solution. IP-SAME mechanism can be interpreted by two types of molecular mass transfer into the organic solvent (partitioning and ion pairing for non-ionized and ionized compounds, respectively) during emulsification process. The effective parameters on the extraction efficiency such as the extraction solvent type and its volume, type of the surfactant and its concentration, sample pH and ionic strength of the sample were optimized. Under the optimum conditions (60 MUL of 1-octanol; 1.5 mmol L(-1) cethyltrimethyl ammonium bromide (CTAB) as emulsifier agent and sample pH 10.0), the preconcentration factors (PFs), detection limits and linear dynamic ranges (LDRs) were obtained in the range of 87-348, 0.07-0.6 MUg L(-1) and 0.1-200 MUg L(-1) respectively. All of natural water samples were successfully analyzed by the proposed method. PMID- 21605869 TI - Liquid chromatographic resolution of 1-aryl-1,2,3,4-tetrahydroisoquinolines on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. AB - A liquid chromatographic chiral stationary phase (CSP) based on (+)-(18-crown-6) 2,3,11,12-tetracarboxylic acid was applied for the first time to the resolution of biologically important 1-aryl-1,2,3,4-tetrahydroisoquinolines. The unusual resolution of cyclic secondary amino compounds on a chiral crown ether-based CSP was quite successful with the use of a mixture of methanol-acetonitrile triethylamine at a ratio of 30/70/0.5 (v/v/v) as a mobile phase. From the chromatographic behaviours for the resolution of seven 1-aryl-1,2,3,4 tetrahydroisoquinolines, the steric bulkiness of the 1-phenyl ring at the chiral center of analytes was concluded to play an important role in the chiral recognition. PMID- 21605870 TI - Controlling the size and morphology of anisotropic nanostructures of nickel borate using microemulsions and their magnetic properties. AB - Anisotropic nanostructures of nickel borate with controlled size and morphology have been synthesized by a precursor-mediated route. The nickel boron precursor has been synthesized using microemulsions using Tergitol as a surfactant. Microemulsions with various co-surfactants (1-butanol, 1-hexanol and 1-octanol) have been used to obtain uniform nanorods (dia 3-5 nm, length 25 nm) and nanospindles (dia 30 nm, length 400 nm). A higher chain length of the co surfactant (octanol) leads to more uniform rods rather than spindles (butanol). These nanorods show antiferromagnetic behavior with the Neel temperature ranging from 44 to 47 K. Though there is no marked variation in Neel temperature, the magnetic moment increases drastically with the anisotropy of nanorods (thinner rods). PMID- 21605871 TI - Hand preference for pointing gestures and bimanual manipulation around the vocabulary spurt period. AB - This study investigated the development of hand preference for bimanual manipulative activities and pointing gestures in toddlers observed longitudinally over a 5-month period, in relation to language acquisition. The lexical spurt was found to be accompanied by an increase in the right-sided bias for pointing but not for manipulation. Moreover, results revealed a significant correlation between hand preference for imperative pointing gestures and manipulative activities in children who did not experience the lexical spurt during the observational period. By contrast, measures of handedness for declarative pointing were never correlated with those of handedness for manipulation. This study illustrates the complex relationship between handedness and language development and emphasizes the need to take the different functions of pointing gestures into account. PMID- 21605872 TI - Distraction induced enterogenesis: a unique mouse model using polyethylene glycol. AB - BACKGROUND: Recent studies have demonstrated that the small intestine can be lengthened by applying mechanical forces to the bowel lumen-distraction-induced enterogenesis. However, the mechanisms which account for this growth are unknown, and might be best examined using a mouse model. The purpose of this study is to establish the feasibility of developing distractive-induced small bowel growth in mouse. METHODS: Twelve-week old C57BL/6J mice had a jejunal segment taken out of continuity, and distended with polyethylene glycol (PEG: 3350 KDa); this group was compared with a control group without stretching. Segment length and diameter were measured intra-operatively and after 5 d. Villus height, crypt depth, and muscle thickness in the isolated segment were assessed. Rate of epithelial cell proliferation (5-bromo-2-deoxyuridine: BrdU incorporation) in crypts were also examined. The mucosal mRNA expression of targeted factors was performed to investigate potential mechanisms which might lead to distraction-induced enterogenesis. RESULTS: At harvest, the PEG-stretched group showed a significant increase in length and diameter versus controls. Villus height, crypt depth, and muscular layer thickness increased in the PEG group. The PEG group also showed significantly increased rates of epithelial cell proliferation versus controls. Real-time PCR showed a trend toward higher beta-catenin and c-myc mRNA expression in the PEG-stretched group; however, this difference was not statistically significant. CONCLUSIONS: Radial distraction-induced enterogenesis with PEG is a viable method for increasing small intestinal length and diameter. This model may provide a new method for studying the mechanisms leading to distraction-induced enterogenesis. PMID- 21605873 TI - Orexin A (hypocretin-1) levels are not reduced while cocaine/amphetamine regulated transcript levels are increased in the cerebrospinal fluid of patients with multiple sclerosis: no correlation with fatigue and sleepiness. AB - BACKGROUND: Fatigue and sleep disturbance are common features of multiple sclerosis (MS). Our objectives were to determine cerebrospinal fluid levels of orexin A (hypocretin-1), a hypothalamic peptide involved in sleep, in patients with MS, and correlate them with fatigue, sleepiness, and levels of cocaine and amphetamine regulated transcript (CART) another neuropeptide regulating metabolism with wider nervous system distribution. METHODS: Consecutive patients with MS (n=34), other inflammatory (n=24) or non-inflammatory (n=42) neurological diseases, undergoing lumbar puncture were investigated. Orexin and CART were measured by RIA by investigators unaware of the patients' diagnosis. RESULTS: Orexin A was slightly decreased in the cerebrospinal fluid of patients with inflammatory disease. There was no evidence of orexin A deficiency in MS, although there was a non-significant trend toward a decrease compared to non inflammatory neurological diseases (p=0.06). CART levels were increased in MS compared to the non-inflammatory disease group (p=0.03). There were no significant correlations between CSF levels of orexin A and CART, fatigue, and hypersomnolence. CONCLUSIONS: Cerebrospinal fluid orexin A is decreased in CNS inflammatory diseases other than MS, where it shows a trend toward reduction, but does not correlate significantly with CART or with measures of fatigue and hypersomnolence. PMID- 21605874 TI - Patient blood management during cardiac surgery: do we have enough evidence for clinical practice? PMID- 21605875 TI - [Tocilizumab effectiveness in adult Still's disease]. PMID- 21605876 TI - [Neuropsychiatric disturbances in essential tremor]. AB - This review focuses on the neuropsychiatric manifestations (personality disturbances, depressive symptoms, cognitive impairment and dementia), which have been described in this last decade in patients with essential tremor. We compared the data derived from the Neurologic Disorders in Central Spain (NEDICES) study, a prospective population-based survey, with those derived from the literature. The traditional view of essential tremor as a mono-symptomatic condition characterized by action tremor is now changing. First, it is known that many patients also have other motor manifestations apart from tremor (e.g., ataxic gait). Second, in the last years, the presence of a variety of non-motor neuropsychiatric features has been described. Mild cognitive changes (especially executive dysfunction) have been documented in several independent studies. Further, two population-based studies have demonstrated an association between essential tremor with mild cognitive impairment and dementia. Psychiatric manifestations include specific personality traits, anxiety, social phobia, and depressive symptoms. Taking together, the neuropsychiatric dysfunction pattern and the new data on neuropathology of essential tremor suggest that this disease is a neurodegenerative cerebellar disorder and let us to question the classical concept of essential tremor as a benign mono-symptomatic disorder. PMID- 21605877 TI - [Esophageal cancer incidence and survival in the province of Zaragoza (Spain): a population-based study]. AB - BACKGROUND AND OBJECTIVE: The objective of the present paper is to study the incidence and survival of esophageal cancer from data of the Population-Based Cancer Registries of Zaragoza. PATIENTS AND METHODS: Crude and adjusted incidence rates were calculated according to sex and the Joinpoint log-linear regression was utilized to calculate trends in adjusted incidence rates for the period 1978 2002. The observed survival was calculated by utilizing the Kaplan-Meier method. For relative survival, the automate calculation of the Oncology Institute of Catalonia was utilized. RESULTS: Joinpoint analysis revealed stability in the incidence rates with Annual Percentage Change of 0.16 (CI 95%: -0.8; 1.1) for men and 0.04 for women (CI 95%: -2.8; 2.8). Observed survival in the period 1978-2002 was 33.2% in the first year and 15.3% in the last year. Relative 1-year survival for males and females was 36.3% (CI 95%: 32.7-40.4) and 23.8% (CI 95%: 20.0-28.4) after 5 years. CONCLUSIONS: Data suggest that there were no significant changes in the incidence rates of esophageal cancer in the province of Zaragoza and that survival was low. PMID- 21605878 TI - [The smallpox vaccines and the definitive destruction of the last virus strains]. PMID- 21605879 TI - [Effects of three different disease management programs on outcomes in patients hospitalized with heart failure: a randomized trial]. AB - BACKGROUND AND OBJECTIVE: Despite the recognized benefit of intervention programs in patients with heart failure (HF), it is unknown whether different types of programs have similar efficacy. The aim of our study was to compare the effectiveness of three different types of intervention. PATIENTS AND METHODS: 208 patients discharged with the diagnosis of HF were randomized. Fifty-two were assigned to each one of different groups of intervention (home visits, telephone follow-up, HF unit) and 52 patients to usual care (control group). RESULTS: Median follow-up was 10.8+/-3.2 months. During the study, the primary end point (HF hospitalization or death) was reached in: 20 patients (38.5%) in control group, 19 (36.5%) in telephone follow-up (HR 1.11; IC95% [0.59-2.01], p=0.79), 24 (46.2%) in home visits (HR 1.27; IC95% [0.69-2.32], p=0.78) and 23 patients (44.2%) in HF unit (HR 1.33; IC95% [0.73-0.42], p=0.79). There was a trend to higher hospitalizations (shorter) with lower mortality in intervention groups (mortality: 23.1% intervention groups vs 33.3% in control group, HR 0.61 IC al 95% [0.35-1.01], p=0.08). CONCLUSIONS: In our study, the application of three different intervention programs in patients with HF has a little non-significant prognosis benefit, with a slight increase in the number of shorts hospitalizations in HF unit. PMID- 21605880 TI - Glycolipid composition of Hevea brasiliensis latex. AB - Glycolipids of fresh latex from three clones of Hevea brasiliensis were characterized and quantified by HPLC/ESI-MS. Their fatty acyl and sterol components were further confirmed by GC/MS after saponification. The four detected glycolipid classes were steryl glucosides (SG), esterified steryl glucosides (ESG), monogalactosyl diacylglycerols (MGDG) and digalactosyl diacylglycerols (DGDG). Sterols in SG, ESG and total latex unsaponifiable were stigmasterol, beta-sitosterol and Delta5-avenasterol. The latter was found instead of fucosterol formerly described. Galactolipids were mainly DGDG and had a fatty acid composition different from that of plant leaves as they contained less than 5% C18:3. Glycolipids, which represented 27-37% of total lipids, displayed important clonal variations in the proportions of the different fatty acids. ESG, MGDG and DGDG from clone PB235 differed notably by their higher content in furan fatty acid, which accounted for more than 40% of total fatty acids. Clonal variation was also observed in the relative proportions of glycolipid classes except MGDG (8%), with 43-51% DGDG, 30-34% SG and 7-19% ESG. When compared with other plant cell content, the unusual glycolipid composition of H. brasiliensis latex may be linked to the peculiar nature of this specialized cytoplasm expelled from laticiferous system, especially in terms of functional and structural properties. PMID- 21605881 TI - Secondary product glucosyltransferase and putative glucosyltransferase expression during Citrus paradisi (c.v. Duncan) growth and development. AB - Flavonoids are secondary metabolites that have significant roles in plant defense and human nutrition. Glucosyltransferases (GTs) catalyze the transfer of sugars from high energy sugar donors to other substrates. Several different secondary product GTs exist in the tissues of grapefruit making it a model plant for studying their structure and function. The goal of this investigation was to determine the expression patterns of seven putative secondary product GTs during grapefruit growth and development by quantifying mRNA expression levels in the roots, stems, leaves, flowers, and mature fruit to establish whether the genes are expressed constitutively or if one or more could be expressed in a tissue specific manner and/or developmentally regulated. Six growth stages were defined from which RNA was extracted, and expression levels were quantified by standardized densitometry of gene-specific RT-PCR products. Results show that there were variable degrees of PGT expression in different tissues and at different developmental stages. These results add to the growing knowledge base of dynamics of expression and potential regulation of secondary metabolism in Citrus paradisi. PMID- 21605882 TI - A limited outbreak of Ebola haemorrhagic fever in Etoumbi, Republic of Congo, 2005. AB - Ebolavirus has caused highly lethal outbreaks of haemorrhagic fever in the Congo basin. The 2005 outbreak in the Republic of Congo occurred in the Etoumbi district of Cuvette Ouest Department between April and May. The two index cases were infected while poaching. The sanitary response consisted of active surveillance and contact tracing, public awareness campaigns and community mobilization, case management and safe burial practices, and laboratory confirmation. Twelve cases and ten deaths were reported (lethality 83%). A transmission tree was constructed from a sample collected by a medical team. This outbreak was remarkable by its short duration and limited size. Increased awareness among these previously affected populations and the rapid response of the healthcare system probably contributed to its extinction. PMID- 21605883 TI - A molecular epidemiological investigation of Ascaris on Unguja, Zanzibar using isoenyzme analysis, DNA barcoding and microsatellite DNA profiling. AB - Ascariasis is of public health importance on the islands of Zanzibar (Unguja and Pemba). To shed light on the molecular epidemiology of this parasite, 68 Ascaris worms, obtained from 14 individuals in four Ungujan villages, were examined by isoenzyme analysis (ISA), DNA barcoding and microsatellite DNA profiling. ISA revealed genetic variation, which was confirmed by DNA barcoding. Nineteen worms recovered from individuals in Uganda were included for comparison. Sixteen unique DNA barcodes were identified, 15 on Unguja and three in Uganda with two shared between. These two barcodes were found in all four Ungujan villages. Worms from Tumbatu-Jongowe, an isolated village on an islet off Unguja, seemed particularly diverse. Within our barcodes, three exact matches were found with Chinese Ascaris retrieved from pigs, which is perhaps surprising given the present rarity of these animals on Unguja. Microsatellite profiling and population genetic analysis revealed further genetic diversity within our samples although population sub structuring within Unguja was minor in comparison to that between Unguja and Uganda. As African Ascaris has not been subjected to detailed molecular scrutiny, this new diversity represents an important piece in its evolutionary jigsaw and such population markers are informative in monitoring worm dynamics during ongoing control. PMID- 21605884 TI - Planned ilioinguinal nerve excision for prevention of chronic pain after inguinal hernia repair: a meta-analysis. AB - BACKGROUND: Inguinal hernia repair is a common operative procedure, but the development of chronic postoperative pain is a dreaded potential complication. The role of neurectomy in decreasing the incidence of chronic pain after inguinal hernia repair is currently unknown. Our objective was to determine whether a planned ilioinguinal nerve excision results in a decrease in the development of chronic pain experienced after inguinal hernia repair. METHODS: A systematic literature review was carried out to identify studies investigating the influence of ilioinguinal nerve excision on the development of chronic pain after inguinal hernia repair. A quantitative analysis of the pooled data was carried out. RESULTS: Of 6,023 abstracts reviewed, 4 high-quality, randomized-controlled trials were identified. The pooled mean difference in degree of pain at 6 months postoperatively on a 10-point scale was -0.29 (95% confidence interval: -0.48 to 0.11), favoring neurectomy to decrease the chance of developing chronic pain. Not surprisingly, those individuals undergoing neurectomy were also more likely to develop altered sensation at the same time point (odds ratio: 3.70, 95% confidence interval: 2.61-5.25). CONCLUSION: A planned resection of the ilioinguinal nerve at the time of inguinal hernia repair is associated with a decrease in the incidence of chronic postoperative pain. Thus, carrying out this simple maneuver at the time of operation might decrease a major source of postoperative patient morbidity. PMID- 21605885 TI - Role of the RNA recognition motif of the E1B 55 kDa protein in the adenovirus type 5 infectious cycle. AB - Although the adenovirus type 5 (Ad5) E1B 55 kDa protein can bind to RNA in vitro, no UV-light-induced crosslinking of this E1B protein to RNA could be detected in infected cells, under conditions in which RNA binding by a known viral RNA binding protein (the L4 100 kDa protein) was observed readily. Substitution mutations, including substitutions reported to inhibit RNA binding in vitro, did not impair synthesis of viral early or late proteins or alter significantly the efficiency of viral replication in transformed or normal human cells. However, substitutions of conserved residues in the C-terminal segment of an RNA recognition motif specifically inhibited degradation of Mre11. We conclude that, if the E1B 55 kDa protein binds to RNA in infected cells in the same manner as in in vitro assays, this activity is not required for such well established functions as induction of selective export of viral late mRNAs. PMID- 21605887 TI - Characterization of natural organic matter adsorption in granular activated carbon adsorbers. AB - The removal of natural organic matter (NOM) from lake water was studied in two pilot-scale adsorbers containing granular activated carbon (GAC) with different physical properties. To study the adsorption behavior of individual NOM fractions as a function of time and adsorber depth, NOM was fractionated by size exclusion chromatography (SEC) into biopolymers, humics, building blocks, and low molecular weight (LMW) organics, and NOM fractions were quantified by both ultraviolet and organic carbon detectors. High molecular weight biopolymers were not retained in the two adsorbers. In contrast, humic substances, building blocks and LMW organics were initially well and irreversibly removed, and their effluent concentrations increased gradually in the outlet of the adsorbers until a pseudo steady state concentration was reached. Poor removal of biopolymers was likely a result of their comparatively large size that prevented access to the internal pore structure of the GACs. In both GAC adsorbers, adsorbability of the remaining NOM fractions, compared on the basis of partition coefficients, increased with decreasing molecular size, suggesting that increasingly larger portions of the internal GAC surface area could be accessed as the size of NOM decreased. Overall DOC uptake at pseudo-steady state differed between the two tested GACs (18.9 and 28.6 g-C/kg GAC), and the percent difference in DOC uptake closely matched the percent difference in the volume of pores with widths in the 1-50 nm range that was measured for the two fresh GACs. Despite the differences in NOM uptake capacity, individual NOM fractions were removed in similar proportions by the two GACs. PMID- 21605886 TI - Arsenic mediated disruption of promyelocytic leukemia protein nuclear bodies induces ganciclovir susceptibility in Epstein-Barr positive epithelial cells. AB - Promyelocytic leukemia protein nuclear bodies (PML NBs) have been implicated in host immune response to viral infection. PML NBs are targeted for degradation during reactivation of herpes viruses, suggesting that disruption of PML NB function supports this aspect of the viral life cycle. The Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1) has been shown to suppress EBV reactivation. Our finding that LMP1 induces PML NB immunofluorescence intensity led to the hypothesis that LMP1 may modulate PML NBs as a means of maintaining EBV latency. Increased PML protein and morphometric changes in PML NBs were observed in EBV infected alveolar epithelial cells and nasopharyngeal carcinoma cells. Treatment with low dose arsenic trioxide disrupted PML NBs, induced expression of EBV lytic proteins, and conferred ganciclovir susceptibility. This study introduces an effective modality to induce susceptibility to ganciclovir in epithelial cells with implications for the treatment of EBV associated pathologies. PMID- 21605888 TI - Different behaviours in the solubilization of polycyclic aromatic hydrocarbons in water induced by mixed surfactant solutions. AB - Water solubility of polycyclic aromatic hydrocarbons (PAHs), viz, naphthalene and phenanthrene, in micellar solutions at 25 degrees C was investigated, using two series of different binary mixtures of anionic and nonionic surfactants. Tween 80 and Brij-35 were used as nonionic surfactants whereas fatty acids or amphiphilic cyclodextrins (Mod-beta-CD) synthesized in our laboratory were used as anionic ones. Solubilization capacity has been quantified in terms of the molar solubilization ratio and the micelle-water partition coefficient, using UV visible spectrophotometry. Anionic surfactants exhibited less solubilization capacity than nonionics. The mixtures between Tween 80 and Mod-beta-CD did not show synergism to increase the solubilization of PAHs. On the other hand, the mixtures formed by Tween 80 and fatty acids at all mole fractions studied produced higher enhancements of the solubility of naphthalene than the individual surfactants. The critical micellar concentration of the mixtures of Tween 80/sodium laurate was determined by surface tension measurements and spectrofluorimetry using pyrene as probe. The system is characterized by a negative interaction parameter (beta) indicating attractive interactions between both surfactants in the range of the compositions studied. PMID- 21605889 TI - Cytotoxicity and physicochemical properties of hafnium oxide nanoparticles. AB - Nano-sized hafnium oxide (HfO(2)) particles are being considered for applications within the semiconductor industry. However, little is known about their cytotoxicity. The objective of this work was to assess several HfO(2) nanoparticles (NPs) samples for their acute cytotoxicity. Dynamic light scattering analysis of the samples indicated that the average particle size of the HfO(2) in aqueous dispersions was in the submicron range with a fraction of particles having nano-dimensions. The media used in the toxicity assays decreased or increased the average particle size of HfO(2) NPs due to dispersion or agglomeration. Static time-of-flight secondary ion mass spectrometry (ToF-SIMS) revealed numerous surface contaminants on the NPs. Only one HfO(2) sample caused moderate cytotoxicity to human cell lines. The inhibitory sample caused a 50% response in the Live/Dead assay with HaCaT skin cells at 2200 mg L(-1); and a 50% response in the mitochondrial toxicity test at 300 mg L(-1). A microbial inhibition assay based on methanogenic activity also revealed that another HFO(2) sample caused moderate inhibition. The difference in toxicity between samples could not be attributed to size. Instead the difference in toxicity was likely due to differences in the contaminants of the HfO(2). The ToF-SIMS analysis indicated unique signatures of Br and P in the sample toxic to human cell lines suggesting a distinct synthesis was used for that sample which may have been accompanied by inhibitory impurities. The results taken as a whole indicate that HfO(2) itself is relatively non-toxic. PMID- 21605890 TI - Antiangiogenic activities of bemiparin sodium, enoxaparin sodium, nadroparin calcium and tinzaparin sodium. AB - INTRODUCTION: The low-molecular-weight heparins have been demonstrated to have antiangiogenic effects in various assays. We aimed to demonstrate and compare the antiangiogenic effects of four types of commercially available low-molecular weight heparins in the chick embryo chorioallantoic membrane model. MATERIALS AND METHODS: The antiangiogenic efficacies of bemiparin, enoxaparin, nadroparin, and tinzaparin were examined in vivo in the chick chorioallantoic membrane model. Drug solutions are prepared in three different concentrations (100 IU, 10 IU, or 1 IU/10 MUl). For each set of experiment twenty fertilized eggs were used. The decrease of vessel formation is examined and scored according to previous literature. RESULTS: Bemiparin, enoxaparin, nadroparin, and tinzaparin sodium all have antiangiogenic effects on chick chorioallantoic membrane at the concentration of 100 IU/10 MUl. This effect was also observed in 10 IU/10 MUl concentrations of nadroparin and tinzaparin. CONCLUSIONS: The low molecular weight heparins studied have obvious antiangiogenic effects. There may be a difference in the potency of the drugs that could have a significant implication for further clinical research. PMID- 21605891 TI - The use of an "old-fashioned method" to assess the clinical and economic impact of a HPV vaccination program. PMID- 21605892 TI - A pilot study to investigate the treatment of cervical human papillomavirus infection with zinc-citrate compound (CIZAR(r)). AB - OBJECTIVE: In the present study the potential therapeutic effects of zinc-citrate compound (CIZAR(r)) in women infected with high-risk human papillomavirus (HR HPV) was investigated. METHODS: A total of 194 women diagnosed with HR-HPV infection using the Hybrid capture (HC) II assay with no evidence of high grade squamous intraepithelial lesions (HSIL) or worse by Pap smear and colposcopy were enrolled. Among them, 76 women were treated by twice weekly self administered intra-vaginal infusion of 0.5 mM zinc citrate solution containing CIZAR(r) for 12 weeks and were evaluated for clearance of the HR-HPV infection compared to 118 women without treatment (Control group). RESULTS: The 12 weeks zinc citrate solution treatment resulted in the elimination of HR-HPV in 49/76 (64.47%) patients compared to the spontaneous clearance of 15.25% (18/118) in the control group (p=0.000). By logistic regression analysis, the 12 week zinc citrate solution treatment reduced the risk of persistent HR-HPV infection significantly (OR 0.079; 95% CI 0.039-0.165; p=0.000). CONCLUSION: The results of this study showed for the first time that treatment with intra-vaginal infusion of a zinc citrate compound (CIZAR(r)) can result in elimination of HR-HPV infection from the uterine cervix. PMID- 21605893 TI - Comparison of estrogen and progesterone receptor status of circulating tumor cells and the primary tumor in metastatic breast cancer patients. AB - OBJECTIVES: The expression of predictive markers including the estrogen (ER) and progesterone receptor (PR) expression can change during the course of the disease. Therefore, reassessment of these markers at the time of disease progression might help to optimize treatment decisions. Metastatic tissue may be difficult to obtain for repeated analysis. In this context, characterization of circulating tumor cells (CTCs) could be of relevance. It was the purpose of the present study (1) to reevaluate the ER/PR expression by CTCs and (2) to compare the hormone receptor status expression profile of CTCs with the primary tumor. METHODS: We evaluated 193 blood samples from metastatic breast cancer patients at the time of first diagnosis of metastatic disease or disease progression. All samples underwent immunomagnetic enrichment using the AdnaTest BreastCancerSelect (AdnaGen AG, Germany) within 4h after blood withdrawal followed by RNA isolation and subsequent gene expression analysis by reverse transcription and Multiplex PCR in separated tumor cells using the AdnaTest BreastCancerDetect. CTCs were analyzed for the three breast cancer-associated markers: EpCAM, Muc-1, Her-2 and actin as an internal PCR control. Expression of the ER and PR was assessed in an additional RT-PCR. The analysis of PCR products was performed by capillary electrophoresis on the Agilent Bioanalyzer 2100. RESULTS: The overall detection rate for CTCs was 45% (87/193 patients) with the expression rates of 71% for EpCAM (62/87 patients), 73% for MUC1 (64/87 patients), 48% for HER2 (42/87 patients), 19% for ER (17/87 patients) and 10% for PR (9/87 patients), respectively. Comparisons with the primary tumor were only performed in CTC+ patients (n=87). In 48/62 (77%) patients with ER+ tumors, CTCs were ER- and 46/53 (87%) patients with PR+ tumors did not express PR on CTCs. Primary tumors and CTCs displayed a concordant ER and PR status in only 41% (p=0.260) and 45% (p=0.274) of cases, respectively. CONCLUSION: Most of the CTCs were ER/PR negative despite the presence of an ER/PR- positive primary tumor. The predictive value of hormone receptor status expression profile of CTCs for palliative endocrine therapy has to be prospectively evaluated. STATEMENT: We recently demonstrated in more than 400 primary breast cancer patients that the expression profile between CTCs and the primary tumor with regard to ER/PR/HER2 positivity differs. The concordance rate between ER, PR and HER2 status of CTCs and the primary tumor was 29%, 25% and 53%, respectively (Fehm T et al., Breast Cancer Res Aug 10 2009, 11(4) pR59). Based on these results we studied blood samples of 193 metastatic breast cancer patients participating in the German DETECT study (1) to reevaluate the ER/PR expression by CTCs and (2) to compare the hormone receptor status expression profile of CTCs with the primary. As already shown for primary breast cancer, most of the CTCs were ER/PR-negative despite the presence of an ER/PR- positive primary tumor. In the metastatic setting the phenotype of CTC reflects the phenotype of metastatic disease. Therefore palliative treatment selected based on the expression profile may not be effective since the phenotype has changed during disease progression. To our knowledge, this study is one of the biggest to compare hormonal receptor expression on CTC and the primary tumor. We hope that our manuscript is suitable for publication in Gynecologic Oncology. PMID- 21605894 TI - Lobular endocervical glandular hyperplasia with extensive mucinous differentiation of endometrium and endometrial mucinous adenocarcinoma in situ: a case report and review of literature. PMID- 21605895 TI - High matrix interference affecting detection of PAH metabolites in bile of Atlantic hagfish (Myxine glutinosa) used for biomonitoring of deep-water oil production. AB - The characteristic biology and wide distribution of hagfish species makes them relevant for use in pollution biomonitoring at great water depths, particularly in regions where deep-water oil production may take place. The exposure of fish to petrogenic contaminants can normally be detected from the level of polycyclic aromatic hydrocarbon (PAH) metabolites in bile fluid. Some of these metabolites are strong fluorophores, allowing analytical detection by means of simple fluorometric techniques such as fixed wavelength fluorescence (FF) and synchronous fluorescence scanning (SFS). In the present study bile from Atlantic hagfish (Myxine glutinosa) collected in pristine areas (Barents Sea and southwestern Norway) displayed strong bile fluorescence levels, suggesting the presence of PAH contaminants. However, gas-chromatography-mass spectrometry (GC MS) analyses ruled out PAHs as the origin for this fluorescence signal. Rather, the bile of Myxine contains components resulting in unusually strong background fluorescence interfering at the wavelength pairs used for detection of PAH metabolites. Possible background for the observed matrix interference and implications for detection of PAH metabolites in hagfish is discussed. PMID- 21605896 TI - The structural and biological properties of hydroxyapatite-modified titanate nanowire scaffolds. AB - Hydroxyapatite-modified titanate nanowire scaffolds as alternative materials for tissue engineering have been developed via a titanate nanowire matrix assisted electrochemical deposition method. The macroporous titanate nanowire matrix on Ti metal was fabricated by a hydrothermal method, and then followed by an electrochemical synthesis of hydroxyapatite nanoparticles on titanate nanowire. The incorporation of titanate nanowire matrix with high oriented hydroxyapatite nanoparticles generates hierarchical scaffolds with highly osteogenic, structural integrity and excellent mechanical performance. As-prepared porous three dimensional interconnected hydroxyapatite-modified titanate nanowire scaffolds, mimicking the nature's extracellular matrix, could provide a suitable microenvironment for tissue cell ingrowth and differentiation. The ceramic titanate nanowire core with HA nanoparticle sheath structure displays superhydrophilicity, which facilitates the cell attachment and proliferation, and induces the in vitro tissue-engineered bone. Human osteoblast-like MG63 cells were cultured on the hydroxyapatite-modified titanate nanowire scaffolds, and the results showed that the scaffolds highly promote the bioactivity, osteoconductivity and osteoblast differentiation. PMID- 21605897 TI - Engineering of large osteogenic grafts with rapid engraftment capacity using mesenchymal and endothelial progenitors from human adipose tissue. AB - We investigated whether the maintenance in culture of endothelial and mesenchymal progenitors from the stromal vascular fraction (SVF) of human adipose tissue supports the formation of vascular structures in vitro and thereby improves the efficiency and uniformity of bone tissue formation in vivo within critically sized scaffolds. Freshly-isolated human SVF cells were seeded and cultured into hydroxyapatite scaffolds (1 cm-diameter, 1 cm-thickness) using a perfusion-based bioreactor system, which resulted in maintenance of CD34(+)/CD31(+) endothelial lineage cells. Monolayer-expanded isogenic adipose stromal cells (ASC) and age matched bone marrow stromal cells (BMSC), both lacking vasculogenic cells, were used as controls. After 5 days in vitro, SVF-derived endothelial and mesenchymal progenitors formed capillary networks, which anastomosed with the host vasculature already 1 week after ectopic nude rat implantation. As compared to BMSC and ASC, SVF-derived cells promoted faster tissue ingrowth, more abundant and uniform bone tissue formation, with ossicles reaching a 3.5 mm depth from the scaffold periphery after 8 weeks. Our findings demonstrate that maintenance of endothelial/mesenchymal SVF cell fractions is crucial to generate osteogenic constructs with enhanced engraftment capacity. The single, easily accessible cell source and streamlined, bioreactor-based process makes the approach attractive towards manufacturing of clinically relevant sized bone substitute grafts. PMID- 21605898 TI - Endosomal escape and the knockdown efficiency of liposomal-siRNA by the fusogenic peptide shGALA. AB - An siRNA that specifically silences the expression of mRNA is a potential therapeutic agent for dealing with many diseases including cancer. However, the poor cellular uptake and bioavailability of siRNA remains a major obstacle to clinical development. For efficient delivery to tumor tissue, the pharmacokinetics and intracellular trafficking of siRNA must be rigorously controlled. To address this issue, we developed a liposomal siRNA carrier, a multi-functional nano device (MEND). We describe herein an approach for systemic siRNA delivery to tumors by combining the MEND system with shGALA, a fusogenic peptide. In cultured cell experiments, shGALA-modification enhanced the endosomal escape of siRNA encapsulated in a polyethylene glycol modified MEND (PEG-MEND), resulting in an 82% knockdown of the target gene. In vivo systemic administration clarified that the shGALA-modified MEND (shGALA-MEND) showed 58% gene silencing in tumor tissues at a dose of 4 mg of siRNA/kg body weight. In addition, a significant inhibition of tumor growth was observed only for the shGALA-MEND and no somatic or hepatic toxicity was observed. Given the above data, this peptide modified delivery system, a shGALA-MEND has great potential for the systemic delivery of therapeutic siRNA aimed at cancer therapy. PMID- 21605899 TI - Prevention of capsular opacification after accommodative lens refilling surgery in rabbits. AB - Silicone gel-like polymers have been proposed to replace the cataractous lens and therewith restore both vision and accommodation. Lens replacement is associated with opacification of the capsular bag due to the lens epithelial cell response. In this study, the in vivo effectiveness of a 5 min treatment with actinomycin D and/or cycloheximid to prevent the development of capsular opacification after filling the capsular bag with a silicone polymer as an accommodating lens was studied. It was found that treating the inside of the capsular bag with a solution containing actinomycin D reduced the development of visible capsular opacification for three months. In some animals, the lens capsules were completely clear, indicating the potential of this method. Side effects of the treatment in the form of visible cornea opacification occurred and ranged from mild to severe in some animals, while in other animals no toxicity occurred. This indicates that a safe application of the cytotoxic substances is feasible. In view of the side effects and the fact that not all lens capsules of the animals treated with actinomycin D were clear, improvements in the methods used are necessary and seem to be possible. PMID- 21605900 TI - Comparison of different tissue-derived stem cell sheets for periodontal regeneration in a canine 1-wall defect model. AB - Cytotherapeutic approaches have been investigated to overcome the limitations of existing procedures for periodontal regeneration. In this study, cell sheet transplantation was performed using three kinds of mesenchymal tissue (periodontal ligament, alveolar periosteum, and bone marrow)-derived cells to compare the differences between cell sources in a canine severe defect model (one wall intrabony defect). Periodontal ligament cells (PDLCs), iliac bone marrow mesenchymal stromal cells (BMMSCs), and alveolar periosteal cells (APCs) were obtained from each dog; a total of four dogs were used. Three-layered cell sheets of each cell source supported with woven polyglycolic acid were autologously transplanted to the denuded root surface. One-wall intrabony defects were filled with a mixture of beta-tricalcium phosphate (beta-TCP) and collagen. Eight weeks after the transplantation, periodontal regeneration was significantly observed with both newly formed cementum and well-oriented PDL fibers more in the PDLC group than in the other groups. In addition, nerve filament was observed in the regenerated PDL tissue only in the PDLC group. The amount of alveolar bone regeneration was highest in the PDLC group, although it did not reach statistical significance among the groups. These results indicate that PDLC sheets combined with beta-TCP/collagen scaffold serve as a promising tool for periodontal regeneration. PMID- 21605901 TI - The use of cationic nanogels to deliver proteins to myeloma cells and primary T lymphocytes that poorly express heparan sulfate. AB - Fusion proteins containing protein transduction domain (PTD) are widely used for intracellular delivery of exogenous proteins. PTD-mediated delivery requires expression of heparan sulfate on the surface of the target cells. However, some of metastatic tumor cells and primary lymphocytes poorly express heparan sulfate. Here we demonstrate that proteins complexed with nanosize hydrogels formed by cationic cholesteryl group-bearing pullulans (cCHP) are efficiently delivered to myeloma cells and primary CD4(+) T lymphocytes probably by induction of macropinocytosis, although these cells are resistant to PTD-mediated protein delivery as a consequence of poor heparan sulfate expression. The anti-apoptotic protein Bcl-xL delivered by cCHP nanogels efficiently blocked apoptosis of these cells, establishing functional regulation of cells by proteins delivered by cCHP nanogels. Thus, cCHP nanogel is a useful tool to deliver proteins for development of new cancer therapy and immune regulation. PMID- 21605902 TI - FMN-coated fluorescent iron oxide nanoparticles for RCP-mediated targeting and labeling of metabolically active cancer and endothelial cells. AB - Riboflavin is an essential vitamin for cellular metabolism and is highly upregulated in metabolically active cells. Consequently, targeting the riboflavin carrier protein (RCP) may be a promising strategy for labeling cancer and activated endothelial cells. Therefore, Ultrasmall SuperParamagnetic Iron Oxide nanoparticles (USPIO) were adsorptively coated with the endogenous RCP ligand flavin mononucleotide (FMN), which renders them target-specific and fluorescent. The core diameter, surface morphology and surface coverage of the resulting FMN coated USPIO (FLUSPIO) were evaluated using a variety of physico-chemical characterization techniques (TEM, DLS, MRI and fluorescence spectroscopy). The biocompatibility of FLUSPIO was confirmed using three different cell viability assays (Trypan blue staining, 7-AAD staining and TUNEL). In vitro evaluation of FLUSPIO using MRI and fluorescence microscopy demonstrated high labeling efficiency of cancer cells (PC-3, DU-145, LnCap) and activated endothelial cells (HUVEC). Competition experiments (using MRI and ICP-MS) with a 10- and 100-fold excess of free FMN confirmed RCP-specific uptake of the FLUSPIO by PC-3 cells and HUVEC. Hence, RCP-targeting via FMN may be an elegant way to render nanoparticles fluorescent and to increase the labeling efficacy of cancer and activated endothelial cells. This was shown for FLUSPIO, which due to their high T(2) relaxivity, are favorably suited for MR cell tracking experiments and cancer detection in vivo. PMID- 21605903 TI - Novel model of placental tissue explants infected by cytomegalovirus reveals different permissiveness in early and term placentae and inhibition of indoleamine 2,3-dioxygenase activity. AB - Human cytomegalovirus (HCMV) is the most common cause of viral intrauterine infection. Placental infection suggests hematogenous spread and permissiveness may vary according to the age of pregnancy. We set up and investigate permissivity of early and term placenta to HCMV with an ex vivo model of placental histocultures and evaluate the activity profile of IDO. Fourteen first trimester placentae were obtained following elective abortion and twelve term placentae after elective caesarean section. Fresh placental chorionic villi were isolated, washed and distributed on collagen sponge gels after overnight incubation with the virus. The culture medium was collected and fresh medium renewed regularly. Histology and immunohistochemistry showed preserved villous integrity in cultured placental histocultures. Infection could be seen in tissue sections of both early and term placentae, although early placentae were more permissive. Indoleamine 2,3-dioxygenase (IDO) is highly expressed in the placenta and is known to prevent maternal immune rejection. Constitutive IDO activity was higher in early, compared to term placentae and HCMV infection inhibited IDO activity in early placentae. IFN-gamma-induced IDO activity was suppressed by HCMV in both early and term placentae. Our work shows a novel method of placenta organ culture. Our findings suggest that HCMV infects early placentae more strongly than term placentae. Early placental dysfunction through the inhibition of IDO activity may reveal a possible mechanism for miscarriages. PMID- 21605904 TI - Histamine regulates cyclooxygenase 2 gene activation through Orai1-mediated NFkappaB activation in lung cancer cells. AB - Histamine, an important chemical mediator, has been shown to regulate inflammation and allergic responses. Stimulation of histamine receptors results in a significant increase in cytoplasmic Ca(2+), which could be mediated by inositol trisphosphate (IP(3))-dependent store-operated Ca(2+) channels (SOC). However, the link between histamine-mediated signaling and activation of inflammatory genes such as cyclooxygenase 2 (COX-2) is still unknown. Our study indicated that the COX-2 protein was highly expressed in human lung cancer cells. Following stimulation with 10 MUM of histamine, both store-operated Ca(2+) entry (SOCE) and COX-2 gene expression were evoked. Histamine-mediated COX-2 activation can be prevented by 2-APB and SKF-96365, SOC channel inhibitors. In addition, deletion analysis of the COX-2 promoter suggested that the region between -80 bp and -250 bp, which contains NFkappaB binding sites, is the key element for histamine-mediated signaling. Knocking down ORAI1, one of the essential molecules of store-operated calcium channels, attenuated histamine-mediated COX-2 expression and NFkappaB activation. These results indicated that ORAI1-mediated NFkappaB activation was an important signaling pathway, responsible for transmitting histamine signals that trigger inflammatory reactions. PMID- 21605905 TI - Chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation are resistant to dasatinib: is that true for all the patients? PMID- 21605906 TI - Residues and dissipation dynamics of molluscicide metaldehyde in cabbage and soil. AB - The dissipation of metaldehyde on cabbage and in soil was studied and half-life (DT(50)) was estimated in a field study carried out at three different locations. Metaldehyde was sprayed on cabbage at 937.5 and 1406.25 ga.i.ha(-1) for residue study and 1,875 ga.i.ha(-1) for dissipation study in cabbage and soil. Samples of cabbage and soil for dissipation experiment were collected at 0, 1, 2, 3, 5, 7, 14 and 21 days after treatment. For residue studies, cabbage and soil samples were sampled at 5, 7 and 10 days after treatment. Quantification of residues was done by LC-MS/MS. The DT(50) of metaldehyde in cabbage and soil were 0.48-1.61 days and 0.75-1.02 days, respectively, when applied at 2 times of the recommended high dosage. Residues of metaldehyde in cabbage were all below the maximum residue levels of 1.0 mg kg(-1) at both recommended high dosage and 1.5 times the recommended high dosage. PMID- 21605907 TI - Crystal structure of human germline antibody 3-23/B3. AB - The human antibody repertoire is dominated by a few combinations of germline sequences, with the genes 3-23 for the heavy chain and B3 for the light chain being among the most frequently used. Despite this fact, there was no experimental structure of the antibody composed of 3-23 and B3. The crystal structure of the Fab fragment of the synthetic antibody composed of the 3-23 and B3 germline sequences was determined to provide a template for antibody modeling. The antigen-binding loops were found in the canonical conformations. Comparison to the other structures where either 3-23 or B3 is paired with a different chain reveals a significant deviation in the orientation of the variable domains. PMID- 21605909 TI - Pneumocystis pneumonia and S-adenosylmethionine plasma levels. PMID- 21605910 TI - Do GPs' medical records demonstrate a good recognition of depression? A new perspective on case extraction. AB - BACKGROUND: Previous estimates of depression recognition in primary care are low and inconsistent. This may be due to registration artifacts and limited extraction efforts. This study investigated a) whether GPs' medical records demonstrate an accurate recognition of depression and b) which combinations of indications within the record most accurately reflect a diagnosis of depression. METHODS: GPs' registrations were compared with a reference standard, the Composite International Diagnostic Interview (CIDI), according to DSM-IV criteria. Six definitions of GPs' recognition of depression were tested using diagnostic codes, medication data, referral data and free text in the medical records. The Youden-index was used to select the optimal definition of recognition. Data were derived from the Netherlands Study of Depression and Anxiety. 816 primary care patients from 33 general practitioners were included in the vicinities of Amsterdam and Leiden, The Netherlands. RESULTS: Registration of antidepressant prescriptions was the best single indicator of GPs' recognition of CIDI depression with a recognition rate of 0.43. The best combination of indicators increased the recognition rate to 0.69. All indications except the specific diagnostic codes for 'depressive disorder' and 'depressive feelings' were included in this definition. LIMITATIONS: Potential bias due to the selection of participating GPs might have influenced our recognition rates. CONCLUSION: GPs are aware of mental health problems in most depressed patients, but labeling with specific diagnostic codes is weak. Researchers should consider that diagnostic coding alone is not an accurate measure of the diagnostic ability of depression and strongly underestimates the accuracy of the GP. PMID- 21605911 TI - Are "social drugs" (tobacco, coffee and chocolate) related to the bipolar spectrum? AB - BACKGROUND: Across all ages and cultures, mankind has always used substances in order to induce pleasurable sensations or desirable psychophysical states. These substances, notably caffeine, tobacco, alcohol and chocolate, can be labeled 'social drugs'. METHODS: We analyzed the social drug habits of 562 patients suffering from mood disorders, according to DSM-IV-R criteria (major depressive episode, recurrent depression, bipolar type I and II disorders and depression not otherwise specified). The sample was also divided into bipolar and non-bipolar according to Hypomania Check-list 32 (HCL-32), which proposes a broader concept of hypomania and soft bipolarity, comprising the spectrum of bipolar disorders proper, along with other, "softer" expressions of bipolarity intermediate between bipolar disorder and normality. RESULTS: Using HCL-32 criteria, but DSM-IV-R criteria, a link was confirmed between bipolar spectrum and substance use including social drugs such as tobacco and coffee. LIMITATION: Observational correlational study. CONCLUSION: This study is in support of earlier theoretical formulations within the framework of the Pisa-San Diego collaboration. PMID- 21605912 TI - Motor activity in depressed children. AB - BACKGROUND: Motor retardation is a cardinal feature in adult depression. Limited information exists about motor activity in depressed children. The present study evaluated motor activity in depressed children compared to controls and investigated whether motor activity can be linked with the severity of symptoms in depressed children. METHOD: Motor activity during both day- and night time was recorded by actigraphy in twenty-two depressed children and their controls. A K SADS-PL interview of the child and his/her mother was used to diagnose depression. The depressed children filled in the Child Depression Inventory (CDI) as a self-report of the severity of depression. Parents and teachers of both depressed children and controls filled in the Child Behavior Checklist (CBCL) and the Teacher Report Form (TRF). RESULTS: Motor activity was reduced during the daytime in depressed children compared to controls (p<0.001). Depressed children spent more time in total immobility during the night time than their peers (p<0.05). In depressed children motor activity was linked with the severity of self- (r=-0.45, p<0.05) and teacher-reported (r=-0.52, p<0.05) symptoms. Depressed children with suicidal ideation (n=10) differed significantly in motor activity compared to depressed children without suicidal ideation (n=12) and controls (n=22). LIMITATIONS: Sample size was only moderate. CONCLUSIONS: Reduced motor activity is an important feature of childhood depression. Objectively measured motor activity can distinguish depressed children from their peers. Motor retardation can be linked with the severity of depression, especially suicidal ideation and possibly subtype depressed children into groups with different etiology, treatment needs and course of illness. PMID- 21605913 TI - The effect of severity and personality on the psychotic presentation of major depression. AB - The aim of the present study was to evaluate whether symptom severity or personality traits are associated with psychotic symptoms in major depression (MD), since it is still debated whether psychotic depression represents the most severe form of depression or the effect of personality structure. The study included 163 patients affected by MD who were divided into four groups on the basis of the presence/absence of melancholic features and psychotic symptoms. All subjects completed the Structured Clinical Interview for DSM-IV Disorders (SCID IV), the Structured Clinical Interview for DSM-IV Personality Disorders (SIDP-IV) and the Hamilton Rating Scale for Depression (Ham-D). Personality was assessed after MD remission (absence of DSM-IV criteria and Ham-D score lower than 7 for at least 2 months). Psychotic symptoms were positively associated with symptom severity (higher Ham-D total score) and with paranoid and schizotypal traits and negatively related to histrionic traits. Our data support the view that the effect of paranoid-schizotypal traits and symptom severity on the presence of psychotic symptoms in MD occurs separately and they are independent of each other. PMID- 21605915 TI - Global gene expression analysis of chicken caecal response to Campylobacter jejuni. AB - Campylobacter jejuni colonises the caecum of more than 90% of commercial chickens. Even though colonisation is asymptomatic, we hypothesised that it is mediated by activation of several biological pathways. We therefore used chicken specific 20K oligonucleotide microarrays to examine global gene expression in C. jejuni-challenged birds. Microarray results demonstrate small but significant fold-changes in expression of 270 genes 20 h post-challenge, corresponding to a wide range of biological processes including cell growth, nutrient metabolism and immunological activity. Expression of NOX1 (2.3-fold) and VCAM1 (1.5-fold) were significantly increased in colonised birds (P<0.05), indicating oxidative burst and endothelial cell activation, respectively. Microarray results, supplemented by qRT-PCR analyses demonstrated increased TOPK (1.9-fold), IL17 (3.6-fold), IL21 (2.1-fold), IL7R (4-fold) and CTLA4 (2.5-fold) gene expression (P<0.05), which was suggestive of T cell mediated activity. Combined these results suggest that C. jejuni has nominal effects on global caecal gene expression in the chicken but significant changes detected are suggestive of a protective intestinal T cell response. PMID- 21605916 TI - Intestinal gene expression in pigs experimentally co-infected with PCV2 and PPV. AB - The objective of the present study was to characterize the local immune reaction in the intestine of pigs experimentally infected with PCV2 and PPV. Archived intestinal material from an experimental study in which pigs were co-infected with a Swedish isolate of PCV2 (S-PCV2) and PPV, or a reference isolate of PCV2 (PCV2-1010) and PPV, were used. The intestinal samples were analysed by qPCR for expression of a number of selected cytokines and the overall gene expression in the intestine was screened by cDNA microarray. Analyses by qPCR showed that pigs infected with PCV2-1010/PPV displayed a significantly increased mRNA expression for IL-6 (p<0.05), IL-10 (p<0.05) and IFN-gamma (p<0.05). The microarray screening revealed a strong up-regulation of IFITM3 along with several other interferon-stimulated genes (ISGs) in pigs infected with PCV2/PPV. The analyses also indicated differences between the two isolates. Fewer pigs infected with S PCV2/PPV expressed the cytokines detected by qPCR, compared to pigs infected with PCV2-1010/PPV, and pigs infected with S-PCV2/PPV displayed a higher proportion of down-regulated genes than PCV2-1010/PPV-infected pigs. PMID- 21605914 TI - Suicidal ideation in Huntington disease: the role of comorbidity. AB - Huntington disease (HD) is a neurodegenerative condition characterized by cognitive impairments, motor abnormalities, and psychiatric disturbance. An increased risk for suicide has been documented. The majority of HD research has focused on cognitive and motor features of HD; the implications of psychiatric manifestations have received less consideration. Recent studies have sought to identify the stages of HD in which patients are at increased risk to experience suicidal ideation, though no study has examined possible risk factors for suicidality. The current study examines the presence of psychiatric comorbidity and its involvement in suicidal ideation. Suicidal ideation was examined in 1941 HD patients enrolled in the Huntington Study Group. Of those, 19% (N=369) endorsed current suicidal ideation. Logistic regression analyses indicated that depression/anxiety and aggression/irritability are significant predictors of suicidal ideation. In a subsample with the greatest suicidal ideation, alcohol and drug abuse were also predictive. It is recommended that all individuals with HD (specifically those with features of depression, aggression, substance abuse) have routine suicide assessment; further research is needed to understand the high rate of suicide in HD. PMID- 21605917 TI - Canal wall window mastoidectomy for extensive labyrinthine cholesteatoma: total dissection and hearing preservation. AB - This case report highlights outcomes of a 6-year-old patient who preserved functional hearing after complete dissection of an extensive labyrinthine cholesteatoma causing two semicircular canals fistulas with endolymph leak, tympanic and labyrinthine fallopian canal erosion of the facial nerve and internal auditory canal invasion with cerebrospinal fluid leak. The patient preserved 40 dB average of bone conduction threshold and 92% of speech discrimination score at 26 months postoperatively. This article reveals that canal wall window mastoidectomy might be an option even in cases of extensive cholesteatomatous labyrinthine fistula therefore avoiding hearing loss and long life cleaning of a canal wall down mastoid cavity. PMID- 21605918 TI - Feasibility and limitation of coronary plaque volumetry by contrast-enhanced 64 row multi-detector computed tomography. PMID- 21605919 TI - N-acetyl cysteine reduces chromosomal DNA damage in circulating lymphocytes during cardiac catheterization procedures: a pilot study. AB - BACKGROUND: N-acetylcysteine (NAC) is considered a promising radio-protector for its antioxidant and anticarcinogenic properties. We examined the ability of NAC to confer protection against radiation-induced chromosomal DNA damage during cardiac catheterization procedures. METHODS: Sixty-five patients (52 males, age 64.4 +/- 11.9 years) undergoing invasive cardiovascular procedures (peripheral transluminal angioplasty, n=45; cardiac resynchronization therapy, n=15 and ablation therapy n=5) were enrolled: 35 patients (26 males, age 63.4 +/- 11.1 years) received the standard hydration protocol consisting of intravenous isotonic saline for 12h after catheterization (Group I), and 30 patients (26 males, age 65.5 +/- 12.9 years) received a clinically driven double intravenous dose of NAC (6 mg/kg/h diluted in 250 mL of NaCl 0.9%) for 1h before and a standard dose (6 mg/kg/h diluted in 500 mL of NaCl 0.9%) for 12h following catheterization (Group II). Micronucleus assay (MN) was performed as biomarker of chromosomal DNA damage before, 2 and 24h after the radiation exposure. Dose-area product (DAP; Gy cm(2)) was assessed as physical measure of radiation load. RESULTS: DAP was higher in NAC-treated patients (I=54.7 +/- 23.6 vs II=126.2 +/- 79.2 Gy cm(2), p=0.0001). MN frequency was 13.7 +/- 4.7 0/00 at baseline and showed a significant rise at 2h (18.0 +/- 6.8 p=0.01) and 24h (17.6 +/- 5.9, p=0.03) in the Group I. There was no significant increase of MN in the Group II (13.7 +/- 7.0, 15.5 +/- 6.0 and 14.9 +/- 6.3 for baseline, 2h and 24h respectively, p=0.4). CONCLUSION: NAC treatment given to prevent contrast-induced nephropathy may also reduce DNA damage induced by ionizing radiation exposure during cardiac catheterization procedures. PMID- 21605920 TI - Extensive mid-wall myocardial oedema after aborted sudden death in hypertrophic cardiomyopathy. PMID- 21605921 TI - Burden of acute myocardial infarction. PMID- 21605922 TI - Description of 44 biosecurity errors while entering and exiting poultry barns based on video surveillance in Quebec, Canada. AB - The effectiveness of biosecurity measures depends largely on the consistency of their applications by all those involved in poultry production. Unfortunately, poor biosecurity compliance has been reported repeatedly in poultry, as well in all other major animal productions. As part of a larger study, we conducted an investigation on eight poultry farms in Quebec, Canada, to evaluate compliance of existing biosecurity measures using hidden cameras. The objectives were to evaluate and describe the application of biosecurity measures when entering and exiting poultry barns. A total of 44 different mistakes were observed from 883 visits done by 102 different individuals. On average, four errors were recorded per visit. The maximum number of errors made by one individual during one visit was 14. People observed over several visits made on average six different errors. Twenty-seven out of the 44 errors (61.4%) were related to area delimitation (clean versus contaminated), six to boots (13.6%), five to hand washing (11.4%), three to coveralls (6.8%) and three to logbooks (6.8%). The nature and frequency of errors suggest a lack of understanding of biosecurity principles. There is thus a need to improve biosecurity training by making educational material available to all poultry personnel demonstrating why and how to apply biosecurity measures. PMID- 21605923 TI - Antibacterial activity of chemically defined chitosans: influence of molecular weight, degree of acetylation and test organism. AB - Chitosans, polysaccharides obtained from the exoskeleton of crustaceans, have been shown to exert antibacterial activity in vitro and their use as a food preservative is of growing interest. However, beyond a consensus that chitosan appears to disrupt the bacterial cell membrane, published data are inconsistent on the chemical characteristics that confer the antibacterial activity of chitosan. While most authors agree that the net charge density of the polymer (reflected in the fraction of positively charged amino groups at the C-2 position of the glucosamine unit) is an important factor in antibacterial activity, conflicting data have been reported on the effect of molecular weight and on the susceptibility among different bacterial species to chitosan. Therefore, we prepared batches of water-soluble hydrochloride salts of chitosans with weight average molecular weights (M(w)) of 2-224kDa and degree of acetylation of 0.16 and 0.48. Their antibacterial activity was evaluated using tube inhibition assays and membrane integrity assays (N-Phenyl-1-naphthylamine fluorescence and potassium release) against Bacillus cereus, Escherichia coli, Salmonella Typhimurium and three lipopolysaccharide mutants of E. coli and S. Typhimurium. Chitosans with lower degree of acetylation (F(A)=0.16) were more active than the more acetylated chitosans (F(A)=0.48). No trends in antibacterial action related to increasing or decreasing M(w) were observed although one of the chitosans (M(w) 28.4kDa, F(A)=0.16) was more active than the other chitosans, inhibiting growth and permeabilizing the membrane of all the test strains included. The test strains varied in their susceptibility to the different chitosans with wild type S. Typhimurium more resistant than the wild type E. coli. Salmonellae lipopolysaccharide mutants were more susceptible than the matched wild type strain. Our results show that the chitosan preparation details are critically important in identifying the antibacterial features that target different test organisms. PMID- 21605924 TI - Addressing the burden of type 2 diabetes and cardiovascular disease through the management of postprandial hyperglycaemia: an Asian-Pacific perspective and expert recommendations. AB - The world is facing an epidemic of cardiovascular disease (CVD) and type 2 diabetes, with populations in low- to middle-income countries, including many in the Asia Pacific (AP) region, being disproportionately affected. Emerging data identify postprandial hyperglycaemia (PPHG) as an important predictor of CVD, and several professional bodies, including the International Diabetes Federation, have issued guidelines on the management of PPHG in type 2 diabetes. Guidance on how international recommendations could be implemented in Asian populations is currently lacking. Therefore, a panel of experts from the AP region convened to consider the current status of PPHG and CVD in the region, and to develop recommendations for clinical practice. The group concluded that improved awareness of the impact of PPHG on CVD risk, among clinicians and the general public, and more widespread use of routine screening for PPHG, using oral glucose tolerance testing in those without recognised diabetes, are required. Additionally, frequent meal-based testing and effective PPHG management are essential to the management of IGT and type 2 diabetes. PMID- 21605925 TI - Synthesis, characterization and cytotoxicity of some novel 1,3-disubstituted-2,3 dihydro-2-iminobenzimidazoles. AB - Some new 1,3-disubstituted-2,3-dihydro-2-iminobenzimidazoles were synthesized using 1-(un)substituted-2-aminobenzimidazoles as precursors in order to determine their cytotoxicity. The structures of the compounds were confirmed by IR, (1)H NMR, (13)C NMR and elemental analysis. Compounds 4, 7-11 and 13-14 were evaluated for their cytotoxical effect on two cancer cell lines: human colorectal cancer cell line HT-29, breast cancer cells MDA-MB-231 and as well as normal spleen cells. The distinctly marked antiproliferative activity of 1,3-bis(3-phenylpropyl 1)-1,3-dihydro-2H-benzimidazol-2-imine hydro bromide 7, N-(aminopropyl)-2-(3-{2 [(aminopropyl)-amino]-2-oxoethyl}-2-imino-2,3-dihydro-1H-benzimidazol-1 yl)acetamide 9 and 1,3-bis[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2,3-dihydro-2H benzimidazol-2-imine 11 against human colorectal cancer cell line HT-29 was ascertained and the calculated IC(50) were 9.26, 0.56 and 0.013 nM respectively. Compounds 4, 9, 10 and 13 exhibited relative high cytotoxic activity against MDA MB-231 cells. The calculated IC(50) values were in the range 0.123-1.65 nM. All tested compounds excluding compound 1,3-bis[2-(4-methylpiperazin-1-yl)-2 oxoethyl]-2,3-dihydro-2H-benzimidazol-2-imine (11) revealed proliferative activities to normal spleen cells. The computed EC(50) values varied from 0.05 to 16.91 nM. PMID- 21605926 TI - Ligand-based discovery of novel trypanosomicidal drug-like compounds: in silico identification and experimental support. AB - Two-dimensional bond-based linear indices and linear discriminant analysis are used in this report to perform a quantitative structure-activity relationship study to identify new trypanosomicidal compounds. A database with 143 anti trypanosomal and 297 compounds having other clinical uses, are utilized to develop the theoretical models. The best discriminant models computed using bond based linear indices provides accuracies greater than 90 for both training and test sets. Our models identify as anti-trypanosomals five out of nine compounds of a set of already-synthesized substances. The in vitro anti-trypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Both models show a perfect agreement between theoretical predictions and experimental results. The compounds identified as active ones show more than 98% of anti-epimastigote elimination (AE) at a concentration of 100 MUg/mL. Besides, three compounds show more than 70% of AE at a concentration of 10 MUg/mL. Finally, compounds with the best "activity against epimastigote forms/unspecific cytotoxicity" ratio are evaluated using an amastigote susceptibility assay. It should be noticed that, compound Va7-71 exhibit a 100% of intracellular amastigote elimination and shows similar activity when compared to a standard trypanosomicidal as nifurtimox. Finally, we can emphasize that, the present algorithm constitutes a step forward in the search for efficient ways of discovering new anti-trypanosomal compounds. PMID- 21605927 TI - Muscle work is increased in pre-swing during hemiparetic walking. AB - BACKGROUND: Muscle mechanical work is likely affected by gait abnormalities in hemiparetic walking during the paretic pre-swing phase (i.e., double support phase preceding paretic toe-off). Previous experimental studies suggest that muscle work may be decreased in the paretic leg, but paretic work may have been underestimated since experimental approaches based on net joint moments do not account for co-contraction of antagonist muscles. Also, whether the non-paretic leg does more work compared to control subjects at matched speeds and how work generation may differ between hemiparetic subjects walking with different self selected speeds remains unknown. METHODS: Three-dimensional forward dynamics simulations of two representative hemiparetic subjects walking with different self-selected speeds (i.e., limited community=0.45 m/s and community walkers=0.9 m/s) and a speed and age-matched control subject were generated to quantify musculotendon (fiber and in-series tendon) work during paretic pre-swing. FINDINGS: Total paretic and non-paretic fiber work were increased in both the limited community and community hemiparetic walkers compared to the control. Increased fiber work in the limited community walker was primarily related to decreased fiber and tendon work by the paretic plantar flexors requiring compensatory work by other muscles. Increased fiber work in the community walker was primarily related to increased work by the hip abductors and adductors. INTERPRETATION: The hemiparetic walkers would expend more metabolic energy during pre-swing if the hemiparetic and control subjects were to perform work with the same mechanical efficiency. These results may partly explain the increased metabolic cost of hemiparetic walkers compared to nondisabled walkers at matched speeds. PMID- 21605928 TI - Emerging options in the treatment of deep vein thrombosis and pulmonary embolism. AB - The incidence of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is increasing and the disease has been found to account for over 500,000 annual deaths in the European Union. VTE is associated with increased mortality and may lead to serious long-term complications. Unfractionated heparin (UFH), low molecular weight heparin (LMWH) and vitamin K antagonists (VKA) have remained standard of care for many years. Recent trials of novel anticoagulants have indicated that new therapeutical options may soon become available. Studies on the role of new agents in VTE prevention in patients undergoing orthopaedic surgery have provided the evidence suggesting potential value of these drugs for the management of acute events. At present, investigation of new anticoagulants has reached the stage when phase III clinical studies on some novel agents have been completed and others are in progress. Of those furthest along are the direct Factor Xa inhibitors, rivaroxaban and apixaban, and the direct thrombin inhibitor, dabigatran. Findings of ongoing trials are expected to determine potential impact of these agents on current clinical practice. PMID- 21605929 TI - Ozone affects pollen viability and NAD(P)H oxidase release from Ambrosia artemisiifolia pollen. AB - Air pollution is frequently proposed as a cause of the increased incidence of allergy in industrialised countries. We investigated the impact of ozone (O(3)) on reactive oxygen species (ROS) and allergen content of ragweed pollen (Ambrosia artemisiifolia). Pollen was exposed to acute O(3) fumigation, with analysis of pollen viability, ROS and nitric oxide (NO) content, activity of nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase, and expression of major allergens. There was decreased pollen viability after O(3) fumigation, which indicates damage to the pollen membrane system, although the ROS and NO contents were not changed or were only slightly induced, respectively. Ozone exposure induced a significant enhancement of the ROS-generating enzyme NAD(P)H oxidase. The expression of the allergen Amb a 1 was not affected by O(3), determined from the mRNA levels of the major allergens. We conclude that O(3) can increase ragweed pollen allergenicity through stimulation of ROS-generating NAD(P)H oxidase. PMID- 21605930 TI - Do new cohorts of family physicians work less compared to their older predecessors? The evidence from Canada. AB - Although demographics, cohort, and contextual factors are expected to influence physician supply at the intensive margin, much of the literature has examined the demographics and very limited cohort analysis is undertaken. This paper employs a cross-classified fixed-effects methodology to examine the importance of age, period and cohort, and contextual factors in explaining the declining work hours of Canadian family physicians. We define cohorts with five-year intervals according to year of graduation from medical school. Contrary to the previous literature, we find no evidence of reduced hours of work provided by the new cohorts of physicians. Compared to the 1995-99 cohort, older male cohorts perform similar total hours of work per week except those who graduated in the 1960's while older female cohorts consistently perform fewer total work hours in the range of 3-10 h per week. Consistent with the literature, it is found that female and older physicians provide fewer hours of work compared to the male and younger counterparts, respectively. Although there has been a decline in total hours of work for all physicians in the range of 2-3 h per week in each period, we find a large decline in direct patient care hours (about 4-6 h) and a marginal increase in indirect patient care (about 2-4 h) over the period. Having children less than 6 years and children aged 6-15 years in the physician's family reduce the work hours of female family physicians by about 7 h and 3 h, respectively. A number of other contextual factors influence work hours of physicians in the expected direction. PMID- 21605931 TI - Infant mortality and adult stature in Spain. AB - This paper presents new evidence concerning the relationship between environmental conditions in the year of birth (as reflected in the infant mortality rate (IMR) and gross domestic product per capita) and adult health (adult height). We perform an analysis across Spanish regions for cohorts born between 1961 and 1980, a period when the country underwent a socioeconomic and political transformation. We find that a reduction in the IMR of 30 individuals per 1000 (similar to that achieved by Spain between 1961 and 1980) explains an increase in average height of about 2.7 cm, about 70% of the gain in average adult stature during this period. Our results, which are robust to several adjustments, suggest that the burden of disease in childhood can have long lasting effects on health, and that these are reflected in differences in adult stature. PMID- 21605933 TI - Unfolding and aggregation of lysozyme: a thermodynamic and kinetic study by FTIR spectroscopy. AB - The unfolding of hen egg-white lysozyme dissolved both in D(2)O and CH(3)CH(2)OD/D(2)O was studied by Fourier Transform Infrared (FTIR) absorption spectroscopy at different protein concentrations. A detailed description of the local and global rearrangement of the secondary structure upon a temperature increase, in the range 295 to 365K, was obtained through the analysis of the amide I band. Thermodynamic parameters for the melting, and the effect of the co solvent in determining a change in thermal stability of the protein were evaluated. The protein-protein interactions were also followed as a function of temperature: a strong dependence of the cluster stability and aggregation yield on the solvent composition was observed. Finally, FTIR spectra taken at successive time steps of the aggregation enabled intermolecular contacts to be monitored as a function of time, and kinetic information to be obtained showing that both unfolded and folded states of lysozyme act as reactants for the clustering event. PMID- 21605932 TI - Kinetic mechanism of the ssDNA recognition by the polymerase X from African Swine Fever Virus. Dynamics and energetics of intermediate formations. AB - Kinetic mechanism of the ssDNA recognition by the polymerase X of African Swine Fever Virus (ASFV) and energetics of intermediate formations have been examined, using the fluorescence stopped-flow method. The association is a minimum three step process PolX + ssDNA k(1) <-- --> k(-1) (P-ssDNA)(1) k(2) <-- --> k(-2) (P ssDNA)(2) k(3) <-- --> k(-3) (P-ssDNA)(3). The nucleic acid makes the initial contact through the C-terminal domain, which generates most of the overall DeltaG degrees . In the second step the nucleic acid engages the N-terminal domain, assuming the bent structure. In equilibrium, the complex exists in at least two different states. Apparent enthalpy and entropy changes, characterizing formations of intermediates, reflect association of the DNA with the C-terminal domain and gradual engagement of the catalytic domain by the nucleic acid. The intrinsic DNA-binding steps are entropy-driven processes accompanied by the net release of water molecules. The final conformational transition of the complex does not involve any large changes of the DNA topology, or the net release of the water molecules. PMID- 21605934 TI - Stability, denaturation and refolding of Mycobacterium tuberculosis MfpA, a DNA mimicking protein that confers antibiotic resistance. AB - MfpA from Mycobacterium tuberculosis is a founding member of the pentapeptide repeat class of proteins (PRP) that is believed to confer bacterial resistance to the drug fluoroquinolone by mimicking the size, shape and surface charge of duplex DNA. We show that phenylalanine side chain stacking stabilizes the N terminus of MfpA's pentapeptide thus extending the DNA mimicry analogy. The Lumry Eyring model was applied to multiple spectral measures of MfpA denaturation revealing that the MfpA dimer dissociates to monomers which undergo a structural transition that leads to aggregation. MfpA retains high secondary and tertiary structure content under denaturing conditions. Dimerization stabilizes MfpA's pentapeptide repeat fold. The high Arrhenius activation energy of the barrier to aggregate formation rationalizes its stability. The mechanism of MfpA denaturation and refolding is a 'double funnel' energy landscape where the 'native' and 'aggregate' funnels are separated by the high barrier that is not overcome during in vitro refolding. PMID- 21605935 TI - Internal noise enhanced oscillation in a delayed circadian pacemaker. AB - The effect of internal noise in a delayed circadian oscillator is studied by using both chemical Langevin equations and stochastic normal form theory. It is found that internal noise can induce circadian oscillation even if the delay time tau is below the deterministic Hopf bifurcation tau(h). We use signal-to-noise ratio (SNR) to quantitatively characterize the performance of such noise induced oscillations and a threshold value of SNR is introduced to define the so-called effective oscillation. Interestingly, the tau-range for effective stochastic oscillation, denoted as Deltatau(EO), shows a bell-shaped dependence on the intensity of internal noise which is inversely proportional to the system size. We have also investigated how the rates of synthesis and degradation of the clock protein influence the SNR and thus Deltatau(EO). The decay rate K(d) could significantly affect Deltatau(EO), while varying the gene expression rate K(e) has no obvious effect if K(e) is not too small. Stochastic normal form analysis and numerical simulations are in good consistency with each other. This work provides us comprehensive understandings of how internal noise and time delay work cooperatively to influence the dynamics of circadian oscillations. PMID- 21605936 TI - Municipal solid waste compost application improves productivity, polyphenol content, and antioxidant capacity of Mesembryanthemum edule. AB - Organic wastes were successfully used as soil amendment to improve agrosystems productivity. Yet, the effectiveness of this practice to enhance plant antioxidant capacities has received little attention. Here, we assess the effect of municipal solid waste (MSW) compost (at 40 t ha(-1)) on growth, polyphenol contents and antioxidant activities of Mesembryanthemum edule. MSW compost application significantly increased the soil contents of carbon, nitrogen, calcium, phosphorus and potassium. This was associated with higher nutrient (N, P, and K) uptake, which likely led to the significant improvement of the plant biomass and relative growth rate (RGR) (+93% on average) as compared to the control. In the same way, the fertilizing effect of the added organic matter significantly enhanced the antioxidant potential M. edule, assessed by radical scavenging activity, iron reducing power and beta-carotene bleaching capacity. This was associated with significantly higher antioxidant contents, mainly total phenols and flavonoids. Heavy metal (Pb, Cd, Cu, and Zn) concentrations were slightly increased upon compost application, but remained lower than phytotoxic values. Overall, our results point out that short-term MSW compost application at 40 t ha(-1) is efficient in enhancing the productivity together with the antioxidant potentiality of M. edule without any adverse environmental impact. PMID- 21605937 TI - Importance of monitoring renal function in patients with cancer. AB - Monitoring renal function in patients with solid tumors and hematologic malignancies is vital to the safe administration of therapeutic agents. Renal impairment is frequent in elderly patients (i.e., age >= 65) with cancer, despite normal serum creatinine levels in most patients. Because serum creatinine levels do not accurately reflect clearance rates, renal function should be estimated by calculation (either Cockcroft-Gault or abbreviated Modification of Diet in Renal Disease [aMDRD] equations) or by measuring creatinine clearance using a 24-h urine collection. Additionally, patients with cancer often have preexisting comorbidities or other risk factors that increase the probability of renal impairment before receiving potentially nephrotoxic therapies. Patient age, preexisting renal dysfunction, and chronic comorbidities (e.g., diabetes, kidney disease, hypertension, and cardiac insufficiency) all contribute to the risk of renal impairment. Furthermore, both cancer and its therapies may lead to renal impairment. A number of cancer therapy agents are nephrotoxic, including chemotherapy agents, molecular targeted agents, pain management agents, radiopharmaceuticals, contrast agents used in radiology, and antiresorptive agents, and contrast agents used in radiology are nephrotoxic as well. Undetected decreases in clearance rates by the kidneys can greatly increase exposure to treatment agents, possibly decreasing the safety of treatment and exacerbating renal impairment. In conclusion, all cancer patients, not only those receiving potentially nephrotoxic agents, require renal monitoring. PMID- 21605938 TI - Immune recognition of transplacentally acquired lymphoid allografts selects for increased major histocompatibility polymorphism. AB - The extreme polymorphism of mammalian major histocompatibility (MHC) Class I and Class II alleles has been attributed to inbreeding avoidance, heterozygote advantage and pathogen driven selection for rare MHC alleles. However, MHC alleles can be classified into a limited number of allele supertypes based on the specificity of their peptide binding grooves (about 10 supertypes in the case of human MHC Class I alleles). The paradox is that if antigen presentation can be accomplished by a limited number of binding groove motifs, why are these loci so polymorphic? An unexplored driver of this complexity may be selection pressure to enhance the antigenicity and immune recognition of transplacentally acquired lymphoid allografts during pregnancy. The exchange of lymphoid cells between mother and fetus probably occurs in all pregnancies and may lead to fetal and/or maternal lymphoid microchimerism, a known cause of autoimmune disease. Natural selection may have favoured increased polymorphism at MHC Class I and Class II loci in order to improve immune surveillance of these cells and thereby reduce the incidence of maternal and fetal autoimmune disease. At the same time, selection may have favoured the retention of a limited set of allele supertypes which optimally present immunodominant antigens. PMID- 21605939 TI - Use of consumer insight in the new product development process in the meat sector. AB - Successful new product development requires input from the market throughout the product development process, from identification of opportunities via screening of ideas, development of concepts, development of physical prototypes and to launch. Drawing on work done in the EU FP6 projects PROSAFEBEEF and Q-PORKCHAINS and a Danish project, all dealing with new product development in the meat sector, it is shown how the use of consumer insight techniques can a) support the identification of market opportunities, b) make sure that technologies applied are acceptable to consumers, c) aid the selection and optimisation of new product concepts and related communication, and d) be used to test product prototypes before final launch. PMID- 21605940 TI - A polymorphism within the promoter of the TGFbeta1 gene is associated with radiation sensitivity using an objective radiologic endpoint. AB - PURPOSE: To evaluate whether single nucleotide polymorphisms (SNPs) in the transforming growth factor-beta1 (TGFbeta1) gene are associated with radiation sensitivity using an objective radiologic endpoint. METHODS AND MATERIALS: Preradiation therapy and serial postradiation therapy single photon emission computed tomography (SPECT) lung perfusion scans were obtained in patients undergoing treatment for lung cancer. Serial blood samples were obtained to measure circulating levels of TGFbeta1. Changes in regional perfusion were related to regional radiation dose yielding a patient-specific dose-response curve, reflecting the patient's inherent sensitivity to radiation therapy. Six TGFbeta1 SNPs (-988, -800, -509, 869, 941, and 1655) were assessed using high resolution melting assays and DNA sequencing. The association between genotype and slope of the dose-response curve, and genotype and TGFbeta1 ratio (4 week/preradiation therapy), was analyzed using the Kruskal-Wallis test. RESULTS: 39 white patients with preradiation therapy and >= 6-month postradiation therapy SPECT scans and blood samples were identified. Increasing slope of the dose response curve was associated with the C(-509)T SNP (p = 0.035), but not the other analyzed SNPs. This SNP was also associated with higher TGFbeta1 ratios. CONCLUSIONS: This study suggests that a polymorphism within the promoter of the TGFbeta1 gene is associated with increased radiation sensitivity (defined objectively by dose-dependent changes in SPECT lung perfusion). PMID- 21605941 TI - Tumor volume reduction rate after preoperative chemoradiotherapy as a prognostic factor in locally advanced rectal cancer. AB - PURPOSE: To investigate the prognostic significance of tumor volume reduction rate (TVRR) after preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC). METHODS AND MATERIALS: In total, 430 primary LARC (cT3-4) patients who were treated with preoperative CRT and curative radical surgery between May 2002 and March 2008 were analyzed retrospectively. Pre- and post-CRT tumor volumes were measured using three-dimensional region-of-interest MR volumetry. Tumor volume reduction rate was determined using the equation TVRR (%) = (pre-CRT tumor volume--post-CRT tumor volume) * 100/pre-CRT tumor volume. The median follow-up period was 64 months (range, 27-99 months) for survivors. Endpoints were disease-free survival (DFS) and overall survival (OS). RESULTS: The median TVRR was 70.2% (mean, 64.7% +/- 22.6%; range, 0-100%). Downstaging (ypT0-2N0M0) occurred in 183 patients (42.6%). The 5-year DFS and OS rates were 77.7% and 86.3%, respectively. In the analysis that included pre-CRT and post-CRT tumor volumes and TVRR as continuous variables, only TVRR was an independent prognostic factor. Tumor volume reduction rate was categorized according to a cutoff value of 45% and included with clinicopathologic factors in the multivariate analysis; ypN status, circumferential resection margin, and TVRR were significant prognostic factors for both DFS and OS. CONCLUSIONS: Tumor volume reduction rate was a significant prognostic factor in LARC patients receiving preoperative CRT. Tumor volume reduction rate data may be useful for tailoring surgery and postoperative adjuvant therapy after preoperative CRT. PMID- 21605942 TI - Comparison between infrared optical and stereoscopic X-ray technologies for patient setup in image guided stereotactic radiotherapy. AB - PURPOSE: To compare infrared (IR) optical vs. stereoscopic X-ray technologies for patient setup in image-guided stereotactic radiotherapy. METHODS AND MATERIALS: Retrospective data analysis of 233 fractions in 127 patients treated with hypofractionated stereotactic radiotherapy was performed. Patient setup at the linear accelerator was carried out by means of combined IR optical localization and stereoscopic X-ray image fusion in 6 degrees of freedom (6D). Data were analyzed to evaluate the geometric and dosimetric discrepancy between the two patient setup strategies. RESULTS: Differences between IR optical localization and 6D X-ray image fusion parameters were on average within the expected localization accuracy, as limited by CT image resolution (3 mm). A disagreement between the two systems below 1 mm in all directions was measured in patients treated for cranial tumors. In extracranial sites, larger discrepancies and higher variability were observed as a function of the initial patient alignment. The compensation of IR-detected rotational errors resulted in a significantly improved agreement with 6D X-ray image fusion. On the basis of the bony anatomy registrations, the measured differences were found not to be sensitive to patient breathing. The related dosimetric analysis showed that IR-based patient setup caused limited variations in three cases, with 7% maximum dose reduction in the clinical target volume and no dose increase in organs at risk. CONCLUSIONS: In conclusion, patient setup driven by IR external surrogates localization in 6D featured comparable accuracy with respect to procedures based on stereoscopic X ray imaging. PMID- 21605943 TI - Standardized Total Average Toxicity score: a scale- and grade-independent measure of late radiotherapy toxicity to facilitate pooling of data from different studies. AB - PURPOSE: The search for clinical and biologic biomarkers associated with late radiotherapy toxicity is hindered by the use of multiple and different endpoints from a variety of scoring systems, hampering comparisons across studies and pooling of data. We propose a novel metric, the Standardized Total Average Toxicity (STAT) score, to try to overcome these difficulties. METHODS AND MATERIALS: STAT scores were derived for 1010 patients from the Cambridge breast intensity-modulated radiotherapy trial and 493 women from the University Hospitals of Leicester. The sensitivity of the STAT score to detect differences between patient groups, stratified by factors known to influence late toxicity, was compared with that of individual endpoints. Analysis of residuals was used to quantify the effect of these covariates. RESULTS: In the Cambridge cohort, STAT scores detected differences (p < 0.00005) between patients attributable to breast volume, surgical specimen weight, dosimetry, acute toxicity, radiation boost to tumor bed, postoperative infection, and smoking (p < 0.0002), with no loss of sensitivity over individual toxicity endpoints. Diabetes (p = 0.017), poor postoperative surgical cosmesis (p = 0.0036), use of chemotherapy (p = 0.0054), and increasing age (p = 0.041) were also associated with increased STAT score. When the Cambridge and Leicester datasets were combined, STAT was associated with smoking status (p < 0.00005), diabetes (p = 0.041), chemotherapy (p = 0.0008), and radiotherapy boost (p = 0.0001). STAT was independent of the toxicity scale used and was able to deal with missing data. There were correlations between residuals of the STAT score obtained using different toxicity scales (r > 0.86, p < 0.00005 for both datasets). CONCLUSIONS: The STAT score may be used to facilitate the analysis of overall late radiation toxicity, from multiple trials or centers, in studies of possible genetic and nongenetic determinants of radiotherapy toxicity. PMID- 21605944 TI - Megavoltage image-based dynamic multileaf collimator tracking of a NiTi stent in porcine lungs on a linear accelerator. AB - PURPOSE: To investigate the accuracy and potential limitations of MV image-based dynamic multileaf collimator (DMLC) tracking in a porcine model on a linear accelerator. METHODS AND MATERIALS: A thermo-expandable NiTi stent designed for kilovoltage (kV) X-ray visualization of lung lesions was inserted into the bronchia of three anaesthetized Gottingen minipigs. A four-dimensional computed tomography scan was used for planning a five-field conformal treatment with circular multileaf collimator (MLC) apertures. A 22.5 Gy single fraction treatment was delivered to the pigs. The peak-to-peak stent motion was 3 to 8 mm, with breathing periods of 1.2 to 4 s. Before treatment, X-ray images were used for image-guided setup based on the stent. During treatment delivery, continuous megavoltage (MV) portal images were acquired at 7.5 Hz. The stent was segmented in the images and used for continuous adaptation of the MLC aperture. Offline, the tracking error in beam's eye view of the treatment beam was calculated for each MV image as the difference between the MLC aperture center and the segmented stent position. The standard deviations of the systematic error Sigma and the random error sigma were determined and compared with the would-be errors for a nontracking treatment with pretreatment image-guided setup. RESULTS: Reliable stent segmentation was obtained for 11 of 15 fields. Segmentation failures occurred when image contrast was dominated by overlapping anatomical structures (ribs, diaphragm) rather than by the stent, which was designed for kV rather than MV X-ray visibility. For the 11 fields with reliable segmentation, Sigma was 0.5 mm/0.4 mm in the two imager directions, whereas sigma was 0.5 mm/1.1 mm. Without tracking, Sigma and sigma would have been 1.7 mm/1.4 mm and 0.8 mm/1.4 mm, respectively. CONCLUSION: For the first time, in vivo DMLC tracking has been demonstrated on a linear accelerator showing the potential for improved targeting accuracy. The study mimicked the envisioned patient workflow of future patient treatments. Clinical implementation of MV image-based tracking would require markers designed for MV visibility. PMID- 21605945 TI - Physician beliefs and practices for adjuvant and salvage radiation therapy after prostatectomy. AB - PURPOSE: Despite results of randomized trials that support adjuvant radiation therapy (RT) after radical prostatectomy (RP) for prostate cancer with adverse pathologic features (APF), many clinicians favor selective use of salvage RT. This survey was conducted to evaluate the beliefs and practices of radiation oncologists (RO) and urologists (U) regarding RT after RP. METHODS AND MATERIALS: We designed a Web-based survey of post-RP RT beliefs and policies. Survey invitations were e-mailed to a list of 926 RO and 591 U. APF were defined as extracapsular extension, seminal vesicle invasion, or positive surgical margin. Differences between U and RO in adjuvant RT recommendations were evaluated by comparative statistics. Multivariate analyses were performed to evaluate factors predictive of adjuvant RT recommendation. RESULTS: Analyzable surveys were completed by 218 RO and 92 U (overallresponse rate, 20%). Adjuvant RT was recommended based on APF by 68% of respondents (78% RO, 44% U, p <0.001). U were less likely than RO to agree that adjuvant RT improves survival and/or biochemical control (p < 0.0001). PSA thresholds for salvage RT were higher among U than RO (p < 0.001). Predicted rates of erectile dysfunction due to RT were higher among U than RO (p <0.001). On multivariate analysis, respondent specialty was the only predictor of adjuvant RT recommendations. CONCLUSIONS: U are less likely than RO to recommend adjuvant RT. Future research efforts should focus on defining the toxicities of post-RP RT and on identifying the subgroups of patients who will benefit from adjuvant vs. selective salvage RT. PMID- 21605947 TI - Volume-dependent expression of in-field and out-of-field effects in the proton irradiated rat lung. AB - PURPOSE: To investigate whether occurrence of early radiation effects in lung tissue depends on local dose only. METHODS AND MATERIALS: Twenty-five percent, 50%, 66%, 88%, or 100% of the rat lung was irradiated using single fractions of 150-MeV protons. For all volumes, in-field and out-of-field dose-response curves were obtained 8 weeks after irradiation. The pathohistology of parenchymal inflammation, infiltrates, fibrosis, and vascular damage and the relative expression of proinflammatory cytokines interleukin (IL)-1alpha, transforming growth factor-beta, IL-6, and tumor necrosis factor-alpha were assessed. RESULTS: For all histologic endpoints, irradiated dose- and volume-dependent in-field and out-of-field effects were observed, albeit with different dynamics. Of note, the out-of-field effects for vascular damage were very similar to the in-field effects. Interestingly, only IL-6 showed a clear dose-dependent increase in expression both in-field and out-of-field, whereas the expression levels of IL 1alpha, transforming growth factor-beta, and tumor necrosis factor-alpha were either very low or without a clear dose-volume relation. As such, none of the radiation effects studied depended only on local dose to the tissue. CONCLUSION: The effects of radiation to lung tissue do not only depend on local dose to that tissue. Especially at high-volume irradiation, lung damage seems to present globally rather than locally. The accuracy of predictive modeling may be improved by including nonlocal effects. PMID- 21605946 TI - Development of a multicomponent prediction model for acute esophagitis in lung cancer patients receiving chemoradiotherapy. AB - PURPOSE: To construct a model for the prediction of acute esophagitis in lung cancer patients receiving chemoradiotherapy by combining clinical data, treatment parameters, and genotyping profile. PATIENTS AND METHODS: Data were available for 273 lung cancer patients treated with curative chemoradiotherapy. Clinical data included gender, age, World Health Organization performance score, nicotine use, diabetes, chronic disease, tumor type, tumor stage, lymph node stage, tumor location, and medical center. Treatment parameters included chemotherapy, surgery, radiotherapy technique, tumor dose, mean fractionation size, mean and maximal esophageal dose, and overall treatment time. A total of 332 genetic polymorphisms were considered in 112 candidate genes. The predicting model was achieved by lasso logistic regression for predictor selection, followed by classic logistic regression for unbiased estimation of the coefficients. Performance of the model was expressed as the area under the curve of the receiver operating characteristic and as the false-negative rate in the optimal point on the receiver operating characteristic curve. RESULTS: A total of 110 patients (40%) developed acute esophagitis Grade >=2 (Common Terminology Criteria for Adverse Events v3.0). The final model contained chemotherapy treatment, lymph node stage, mean esophageal dose, gender, overall treatment time, radiotherapy technique, rs2302535 (EGFR), rs16930129 (ENG), rs1131877 (TRAF3), and rs2230528 (ITGB2). The area under the curve was 0.87, and the false-negative rate was 16%. CONCLUSION: Prediction of acute esophagitis can be improved by combining clinical, treatment, and genetic factors. A multicomponent prediction model for acute esophagitis with a sensitivity of 84% was constructed with two clinical parameters, four treatment parameters, and four genetic polymorphisms. PMID- 21605948 TI - Locoregional treatment for breast carcinoma after Hodgkin's lymphoma: the breast conservation option. AB - PURPOSE: To report clinical and pathologic characteristics and outcome of breast cancer (BC) after irradiation for Hodgkin's lymphoma (HL) in women treated at the Institut Curie, with a special focus on the breast-conserving option. METHODS AND MATERIALS: Medical records of 72 women who developed either ductal carcinoma in situ or Stage I-III invasive carcinoma of the breast after HL between 1978 and 2009 were retrospectively reviewed. RESULTS: Median age at HL diagnosis was 23 years (range, 14-53 years). Median total dose received by the mediastinum was 40 Gy, mostly by a mantle-field technique. Breast cancers occurred after a median interval of 21 years (range, 5-40 years). Ductal invasive carcinoma and ductal carcinoma in situ represented, respectively, 51 cases (71%) and 14 cases (19%). Invasive BCs consisted of 47 cT0-2 tumors (82%), 5 cN1-3 tumors (9%), and 20 Grade 3 tumors (35%). Locoregional treatment for BCs consisted of mastectomy with (3) or without (36) radiotherapy in 39 patients and lumpectomy with (30) or without (2) adjuvant radiotherapy in 32 patients. The isocentric lateral decubitus radiation technique was used in 17 patients after breast-conserving surgery (57%). With a median follow-up of 7 years, 5-year overall survival rate and locoregional control rate were, respectively, 74.5% (95% confidence interval [CI], 64-88%) and 82% (95% CI, 72-93%) for invasive carcinoma and 100% (95% CI, 100 -100%) and 92% (95% CI, 79-100%) for in situ carcinoma. In patients with invasive tumors, the 5-year distant disease-free survival rate was 79% (95% CI, 69-91%), and 13 patients died of progressive BC. Contralateral BC was diagnosed in 10 patients (14%). CONCLUSIONS: Breast-conserving treatment can be an option for BCs that occur after HL, despite prior thoracic irradiation. It should consist of lumpectomy and adjuvant breast radiotherapy with use of adequate techniques, such as the lateral decubitus isocentric position, to protect the underlying heart and lung. PMID- 21605949 TI - Early choline levels from 3-tesla MR spectroscopy after exclusive radiation therapy in patients with clinically localized prostate cancer are predictive of plasmatic levels of PSA at 1 year. AB - PURPOSE: To investigate the time course response of prostate metabolism to irradiation using magnetic resonance spectroscopy (MRS) at 3-month intervals and its impact on biochemical control. METHODS AND MATERIALS: Between January 2008 and April 2010, 24 patients with localized prostate cancer were prospectively enrolled in the Evaluation of the Response to Irradiation with MR Spectroscopy (ERIS) trial. All the patients had been treated with intensity-modulated radiation therapy with or without long-term adjuvant hormonal therapy (LTHT) and underwent 3-T MRS and prostate-specific antigen (PSA) assays at baseline and every 3 months thereafter up to 12 months. RESULTS: After radiation, the mean normalized citrate level (citrate/water) decreased significantly over time, both in the peripheral zone (PZ) (p = 0.0034) and in the entire prostate (p = 0.0008), whereas no significant change was observed in mean normalized choline levels (choline/water) in the PZ (p = 0.84) and in the entire prostate (p = 0.95). At 6 months after radiation, the mean choline level was significantly lower in the PZ for patients with a PSA value of <=0.5 ng/mL at 12 months (4.9 +/- 1.7 vs. 7.1 +/ 1.5, p = 0.0378). Similar results were observed at 12 months in the PZ (6.2 +/- 2.3 vs. 11.4 +/- 4.1, p = 0.0117 for choline level and 3.4 +/- 0.7 vs. 16.1 +/- 6.1, p = 0.0054 for citrate level) and also in the entire prostate (6.2 +/- 1.9 vs. 10.4 +/- 3.2, p = 0.014 for choline level and 3.0 +/- 0.8 vs. 13.3 +/- 4.7, p = 0.0054 for citrate level). For patients receiving LTHT, there was no correlation between choline or citrate levels and PSA value, either at baseline or at follow-up. CONCLUSIONS: Low normalized choline in the PZ, 6 months after radiation, predicts which patients attained a PSA <=0.5 ng/mL at 1 year. Further analyses with longer follow-up times are warranted to determine whether or not these new biomarkers can conclusively predict the early radiation response and the clinical outcome for patients with or without LTHT. PMID- 21605950 TI - Molecular investigation of transplacental and vector-borne transmission of bovine haemoplasmas. AB - The present study was carried out in a herd with concurrent infections of Mycoplasma wenyonii and 'Candidatus M. haemobos', to investigate if transplacental and/or vector-borne transmission is possible for one or both bovine haemoplasma species. For this purpose blood samples were collected from 38 mother animals and their newborn calves; as well as from 17 uninseminated cows twice three months apart. In addition, 311 mosquitoes and blood-sucking flies (Diptera: Culicidae, Tabanidae, Muscidae) were cought near the animals. DNA was extracted from all samples, followed by real-time PCR analysis. In 10.5% of neonate calves, that were born to cows harbouring both haemoplasmas, M. wenyonii and/or 'Candidatus M. haemobos' positivity was detected. Copy numbers in positive samples from cows and their calves indicated that - in comparison with M. wenyonii - 'Candidatus M. haemobos'-bacteraemia had usually lower levels. In samples of uninseminated cows the rate of infection with the latter species decreased. These findings may explain why M. wenyonii was significantly more frequently detected in blood-sucking flies, than 'Candidatus M. haemobos'. In conclusion, molecular evidence is provided for the first time on the transplacental transmission of bovine haemoplasmas. Regarding their spread by blood-sucking arthropods, new potential vectors were identified, i.e. the horn fly (Haematobia irritans), the stable fly (Stomoxys calcitrans) and two species of horse flies (Tabanus bovinus, T. bromius). PMID- 21605951 TI - Isolation in cell cultures and initial characterisation of two novel bocavirus species from swine in Northern Ireland. AB - We report the isolation in cell cultures of two novel bocavirus species in pigs from farms in Northern Ireland with clinical postweaning multisystemic wasting syndrome (PMWS). We have designated the isolates as porcine bocavirus-3 (PBoV3) and porcine bocavirus-4 (PBoV4). To date 5082 and 4125 bps of PBoV3 and PBoV4 have been sequenced, respectively. PBoV3 and PBoV4 show nucleotide homology to other known bocaviruses in swine and other organisms. Open reading frame (ORF) analysis has shown that these viruses have a third small ORF, equivalent to the NP1 ORF that distinguishes the bocaviruses from other parvoviruses. A panel of porcine field sera was screened by indirect immunofluorescence against both viruses. Of the 369 samples analysed, 32 (8.7%) and 35 (9.5%) sera were seropositive for PBoV3 and PBoV4 respectively, thus providing serological evidence of the exposure of swine in the field to bocavirus-like viruses. To date, the clinico-pathological significance of these novel swine bocaviruses, as primary pathogens or as immunosuppresive triggers for other infectious agents, is undetermined. PMID- 21605952 TI - Stillbirth as a risk factor for subsequent infant mortality. AB - BACKGROUND: Infant mortality is an important indicator of the health and wellness of a society. Multiple risk factors for infant mortality have been identified and investigated; however, the influence of prior pregnancy experience on subsequent infant mortality is under-researched. AIMS: To examine the association between stillbirth in the first pregnancy and risk for infant mortality in the second pregnancy in a large population-based dataset. STUDY DESIGN: Population-based, retrospective cohort study SUBJECTS: Missouri maternally linked cohort data files were utilized from 1989 through 2005. Analyses were restricted to women who had two singleton pregnancies during the study period. OUTCOME MEASURES: The exposure was stillbirth in the first pregnancy, while the primary outcome was infant mortality in the second pregnancy. RESULTS: Women who experienced stillbirth in their first pregnancy were more likely to be of advanced age, black, and obese and had higher rates of pregnancy-related complications (p<0.01). Previous stillbirth was associated with an elevated risk for subsequent infant mortality (AHR=2.51, 95% CI: 1.73-3.65) and neonatal mortality (AHR=3.04, 95% CI: 1.99 4.65), after adjustment for socio-demographic variables and pregnancy complications. Risk estimates for mortality in the second pregnancy were most profound among black mothers with a history of stillbirth in the first pregnancy [risk for infant mortality: (AHR=2.68, 95% CI: 1.41-5.09) and neonatal death: (AHR=4.25, 95% CI: 2.34-7.60)]. CONCLUSIONS: Women with prior stillbirth bear elevated risks for subsequent infant mortality. Women's previous childbearing experiences could serve as important criteria in determining appropriate interconception strategies to improve subsequent feto-infant health and survival. PMID- 21605953 TI - Association of endometriosis-related infertility with age at menopause. AB - OBJECTIVE: The influence of past history of infertility, which is closely associated with reproductive factors, on menopause has not been clarified. The purpose of this study was to clarify the association of reproductive factors, including past history of infertility, with menopause in Japanese women. STUDY DESIGN: This study was a cross-sectional analysis of the Japan Nurses' Health Study (JNHS) baseline survey. The JNHS is a nationwide prospective cohort study on the health of Japanese women, and the baseline survey was conducted between 2001 and 2007. MAIN OUTCOME MEASURE: We analyzed data for 24,153 pre- and postmenopausal women who were enrolled in the JNHS at the ages 40-59 years. The main outcome measure was menopause. RESULTS: Reproductive factors influencing the onset of natural menopause were past history of infertility [relative risk (RR) (age-adjusted odds ratio and 95% confidence interval): 1.28 (1.10-1.48)], past history of endometriosis: 1.32 (1.07-1.64), age at menarche: 0.919 (0.886-0.953) and number of pregnancies: 0.943 (0.911-0.976). Endometriosis as the cause of infertility was significantly associated with earlier onset of menopause (3.43 [2.17-5.44]) after adjustment for age. The strong association of past history of infertility related to endometriosis was still significant after multivariate adjustment. CONCLUSION: Menopause in women who have a past history of infertility, especially in those who have suffered from endometriosis, is significantly earlier than that in women without such a history. PMID- 21605954 TI - Correlation between tumor size and surveillance of lymph node metastasis for IB and IIA cervical cancer by magnetic resonance images. AB - PURPOSE: To assess the feasibility of preoperative MRI based measurement of tumor size with regard to lymph node (LN) metastasis in early uterine cervical cancer. MATERIAL AND METHODS: A retrospective review of patients with FIGO stage IB-IIA cervical cancer who underwent lymphadenectomy was performed. Diagnostic accuracy of MRI in detecting LN metastasis and rate of LN recurrence in terms of tumor size (<=4cm versus >4cm) were analyzed. ROC curve analysis was used to determine LN size for differentiating LN metastasis in terms of tumor size. P<0.05 was considered statistically significant. RESULTS: Of the 200 patients, 45 (22.3%) had LN metastasis. There was no statistical difference between patients-based and region-specific analysis. The patients with tumor size with >4cm revealed higher diagnostic accuracy of MRI in detecting LN metastasis (85.4% versus 50.6%, P=0.023) and rate of LN recurrence (20.0% versus 6.4%, P=0.031) in than those with size with <=4cm, the differences were statistically significant. Discriminant analysis of LN size for the differentiation of metastasis from non metastasis resulted in cut-off values (11.8mm; size with >4cm versus 8.3mm; size with <=4cm) and diagnostic accuracy (84.0% of size with >4cm versus 72.0% of size with <=4cm). CONCLUSION: MRI has limited sensitivity, but high specificity in predicting surveillance of LN metastasis in the preoperative early cervical cancer, especially useful tool for patients with tumor size with >4cm. PMID- 21605955 TI - An unexpected cause of emesis. PMID- 21605957 TI - Liver resection and local ablation of breast cancer liver metastases--a systematic review. AB - AIM: To analyze surgical treatment of breast cancer liver metastases (BCLM) regarding selection criteria, outcome and prognostic parameters. METHODS: We searched Embase and Medline for all studies published 1999-2010. RESULTS: Resection was associated with a median survival (MOS) of 20-67 months and 5-year survival of 21-61%. Local ablation also had a favorable outcome; MOS was 30-60 months and 5-year survival 27-41%. Regarding selection, no specific limits regarding the number and size of BCLM can be given. Features of the primary breast cancer (BC) were not significant for the prognosis. Microscopically radical (R0) resection is a positive prognostic factor, while the effects of disease interval, hormone receptor status and response to preoperative chemotherapy were divergent. The presence of EHD had a negative effect on survival in some studies, but failed to have so in other studies. CONCLUSIONS: Surgical therapy may benefit a subset of patients with BCLM. Resection may be indicated, if an RO-resection can be done with a low risk of mortality. Liver resection in the presence of extrahepatic disease remains controversial, while patients with BCLM and bone metastases could possibly be managed differently than other EHD. PMID- 21605956 TI - Provider factors and patient-reported healthcare discrimination in the Diabetes Study of California (DISTANCE). AB - OBJECTIVE: We examined provider-level factors and reported discrimination in the healthcare setting. METHODS: With data from the Diabetes Study of Northern California (DISTANCE) - a race-stratified survey of diabetes patients in Kaiser Permanente Northern California - we analyzed patient-reported racial/ethnic discrimination from providers. Primary exposures were characteristics of the primary care provider (PCP, who coordinates care in this system), including specialty/type, and patient-provider relationship variables, including racial concordance. RESULTS: Subjects (n=12,151) included 20% black, 20% Latino, 23% Asian, 30% white, and 6% other patients, with 2-8% reporting discrimination by racial/ethnic group. Patients seeing nurse practitioners as their PCP (OR=0.09; 95% CI: 0.01-0.67) and those rating their provider higher on communication (OR=0.70; 95% CI: 0.66-0.74) were less likely to report discrimination, while those with more visits (OR=1.10; 95% CI: 1.03-1.18) were more likely to report discrimination. Racial concordance was not significant once adjusting for patient race/ethnicity. CONCLUSIONS: Among diverse diabetes patients in managed care, provider type and communication were significantly related to patient-reported discrimination. PRACTICE IMPLICATIONS: Given potential negative impacts on patient satisfaction and treatment decisions, future studies should investigate which interpersonal aspects of the provider-patient relationship reduce patient perceptions of unfair treatment. PMID- 21605959 TI - Violent offending and IQ level as predictors of suicide in schizophrenia: national cohort study. AB - Currently there is a lack of strong epidemiological evidence for violent offending and intelligence quotient (IQ) level as predictors of suicide risk among people with schizophrenia. We interlinked several Swedish routinely collected national registers, including the Hospital Discharge, Crime, Conscript, Migration and Cause of Death Registers, to identify 13,804 patients admitted at least twice with a schizophrenia diagnosis during 1973-2004. All deaths by specific cause were ascertained and suicides identified, and rate ratios were estimated using Poisson regression models with adjustment for age and period effects. There were 871 suicides: 6.3% of the cohort. Almost 80% of these cases were aged 20-39 years, and 80% occurred within 10 years of second discharge, with almost a quarter taking place within a year. The following risk factors were identified: younger age, 15-19 versus 40 years and older (rate ratio 3.18, 95% confidence interval 1.82-5.56), male sex (rate ratio 1.37, 1.18-1.59) and history of violent offending (rate ratio 1.45, 1.21-1.73). Intelligence quotient data were unavailable for women, but in men, lower IQ appeared protective compared to those of average or higher levels of intelligence (rate ratio 0.71, 0.58-0.86). Further stratified analyses to identify effect modification indicated that the elevated risk associated with past violent offending was restricted to males, and specifically to those with a lower IQ. Further research is needed to identify additional risk and protective factors for suicide that may be unique to people diagnosed with schizophrenia, and also other modifiers of the increased risk linked with violent offending. PMID- 21605960 TI - High prevalence of CTX-M-15-producing Klebsiella pneumoniae isolates in Asian countries: diverse clones and clonal dissemination. AB - The characteristics of 218 Klebsiella pneumoniae isolates from patients with hospital-acquired pneumonia in nine Asian countries were investigated. In total, 92 isolates (42.2%) produced extended-spectrum beta-lactamases (ESBLs), amongst which 67 (72.8%) possessed CTX-M ESBL genes; CTX-M-15 was the major ESBL (55 isolates; 59.8%). Multilocus sequence typing (MLST) and plasmid replicon typing were performed to investigate the genetic backgrounds of the 55 CTX-M-15 producing K. pneumoniae isolates. Twenty-five sequence types (STs) were identified. Clonal complex 11 (CC11) including ST11 was the most prevalent clone (20 isolates; 36.4%) and was distributed in all Asian countries except Taiwan. ST15 was the next most frequently identified clone (8 isolates; 14.5%). An IncFIIA-type plasmid was predominantly associated with bla(CTX-M-15) (45 isolates; 81.8%). However, another plasmid type (IncA/C) was also identified and replicon types of seven isolates could not be determined. The high prevalence of CTX-M-15 amongst K. pneumoniae isolates in Asian countries may be due both to the acquisition of plasmids carrying bla(CTX-M-15) and the spread of certain clones such as ST11 and ST15. PMID- 21605958 TI - Expression of mutant human DISC1 in mice supports abnormalities in differentiation of oligodendrocytes. AB - Abnormalities in oligodendrocyte (OLG) differentiation and OLG gene expression deficit have been described in schizophrenia (SZ). Recent studies revealed a critical requirement for Disrupted-in-Schizophrenia 1 (DISC1) in neural development. Transgenic mice with forebrain restricted expression of mutant human DISC1 (DeltahDISC1) are characterized by neuroanatomical and behavioral abnormalities reminiscent of some features of SZ. We sought to determine whether the expression of DeltahDISC1 may influence the development of OLGs in this mouse model. OLG- and cell cycle-associated gene and protein expression were characterized in the forebrain of DeltahDISC1 mice during different stages of neurodevelopment (E15 and P1 days) and in adulthood. The results suggest that the expression of DeltahDISC1 exerts a significant influence on oligodendrocyte differentiation and function, evidenced by premature OLG differentiation and increased proliferation of their progenitors. Additional findings showed that neuregulin 1 and its receptors may be contributing factors to the observed upregulation of OLG genes. Thus, OLG function may be perturbed by mutant hDISC1 in a model system that provides new avenues for studying aspects of the pathogenesis of SZ. PMID- 21605961 TI - Time-dependent mussel-inspired functionalization of poly(L-lactide-co-E caprolactone) substrates for tunable cell behaviors. AB - Surface properties of biomaterials, such as hydrophobic/hydrophilic balance, chemical group distribution, and topography play important roles in regulation of many cellular behaviors. In this study, we present a bio-inspired coating of synthetic biodegradable poly(L-lactide-co-E-caprolactone) (PLCL) films by using polydopamine for tunable cell behaviors such as adhesion and proliferation. Polydopamine coating decreased the water contact angles of the PLCL film from 75 degrees to 40 degrees , while the amount of coated polydopamine increased from 0.6 MUg/cm(2) to 177.9 MUg/cm(2). During the process, dopamine could be directly polymerized on the surface of the PLCL film to form a thin layer or nanosized particles of self-aggregates, which resulted in increase of overall roughness in a time-dependent manner. Characterization of surface atomic composition revealed an increase in signals from nitrogen and the C-N bond, both suggesting homogeneous polydopamine coating with prolonged coating time. The mechanical properties were similar following reaction with polydopamine for a time shorter than 30 min, while alterations in elongation and Young's modulus were observed when the coating time exceeded 240 min. Cell adhesion and proliferation on the polydopamine-coated films were significantly greater than those on the non-coated films. Interestingly, these cell behaviors were significantly improved even under the minimal coating time (5 min). In summary, the bio-inspired coating is of use to generate modular surface of biomaterial based on synthetic poly(alpha-hydroxy ester)s for tunable cell behaviors with optimization of coating time within the range in which their mechanical properties are not compromised. PMID- 21605962 TI - Dissipative crystallization of potassium salt of poly(riboadenylic acid). AB - Dissipative patterns during the course of dryness of aqueous solution of potassium salt of poly(riboadenylic acid) (KPolyA) in the presence of potassium chloride were studied on a cover glass, a watch glass and a glass dish. Accumulation of KPolyA polymers forming the broad ring area and the drastic change in size and shape of the polymer single crystals depending on the location of the dried film, which are the typical effects of the dissipative crystallization, took place. Polymer crystals formed were spherulites, dendritic and rod-like assemblies, which are composed of the single or double helical chains depending on the pH-value of the initial solution. PMID- 21605963 TI - Primary excision margins and sentinel lymph node biopsy in clinically node negative melanoma of the trunk or extremities. AB - AIMS: For patients with early-stage melanoma, uncertainty exists regarding optimal surgical excision margins of the primary tumour and surgical management of the clinically node-negative lymph node basin. We describe the process of creating a provincial guideline for the treatment of node-negative melanoma of the trunk and extremities. The following research questions were addressed: What are the optimal excision margins for clinically node-negative cutaneous melanoma and should these patients undergo sentinel lymph node biopsy? MATERIALS AND METHODS: Outcomes were local and regional recurrence, overall and disease-free survival, and morbidity. The MEDLINE and EMBASE databases, National Guideline Clearinghouse, CMA Infobase and websites of guideline development organisations were systematically searched. Using the AGREE instrument, relevant guidelines were assessed and an updated literature search completed. A systematic review and practice guideline was written, reviewed and approved by the Melanoma Site Group and the Program in Evidence-based Care Report Approval Panel. External review by three melanoma experts was completed, as was an online consultation with healthcare professionals who were intended users of the guideline. RESULTS: One guideline was selected for adoption: the Australian Cancer Network National Health and Medical Research Council and the New Zealand Guidelines group 2008 melanoma guideline. An updated literature search was undertaken to include relevant studies published since the adopted guideline was completed. CONCLUSIONS: Excision margins range from 5mm to 2cm depending on the melanoma depth. Patients with a melanoma greater than 1.0mm in thickness should be given the opportunity to discuss sentinel lymph node biopsy to provide staging and prognostic information. PMID- 21605964 TI - Stabilization/solidification of fly ashes and concrete production from bottom and circulating ashes produced in a power plant working under mono and co-combustion conditions. AB - Two combustion tests were performed in a fluidized bed combustor of a thermo electric power plant: (1) combustion of coal; (2) co-combustion of coal (68.7% w/w), sewage sludge (9.2% w/w) and meat and bone meal (MBM) (22.1% w/w). Three samples of ashes (bottom, circulating and fly ashes) were collected in each combustion test. The ashes were submitted to the following assays: (a) evaluation of the leaching behaviour; (b) stabilization/solidification of fly ashes and evaluation of the leaching behaviour of the stabilized/solidified (s/s) materials; (c) production of concrete from bottom and circulating ashes. The eluates of all materials were submitted to chemical and ecotoxicological characterizations. The crude ashes have shown similar chemical and ecotoxicological properties. The s/s materials have presented compressive strengths between 25 and 40 MPa, low emission levels of metals through leaching and were classified as non-hazardous materials. The formulations of concrete have presented compressive strengths between 12 and 24 MPa. According to the Dutch Building Materials Decree, some concrete formulations can be used in both scenarios of limited moistening and without insulation, and with permanent moistening and with insulation. PMID- 21605965 TI - Colistin-functionalised CdSe/ZnS quantum dots as fluorescent probe for the rapid detection of Escherichia coli. AB - Intensely fluorescent, colistin-functionalised CdSe/ZnS QDs (Colis-QDs) nanoparticles, are synthesized and used as sensitive probes for the detection of Escherichia coli, a Gram-negative bacteria. Colistin molecules are attached to the terminal carboxyl of the mercaptoacetic acid-capped QDs in the presence of 1 ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N hydroxysuccinimide (NHS) as amide bond promoters. The TEM analysis of bacteria treated with Colis-QDs conjugates showed the accumulation of Colis-QDs in the cell wall of E. coli. Under the recommended working conditions, the method provides a detection limit as few as 28 E. coli cells per mL, which is competitive which more elaborate detection systems. The simplicity of the method together with short analysis time (< 15 min, without including preparation and photoactivation of the Colis-QDs conjugate) make the proposed approach useful as quick bacteria screening system. PMID- 21605966 TI - Label-free optical detection of single-base mismatches by the combination of nuclease and gold nanoparticles. AB - We report here an optical approach that enables highly selective and colorimetric single-base mismatch detection without the need of target modification, precise temperature control or stringent washes. The method is based on the finding that nucleoside monophosphates (dNMPs), which are digested elements of DNA, can better stabilize unmodified gold nanoparticles (AuNPs) than single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with the same base-composition and concentration. The method combines the exceptional mismatch discrimination capability of the structure-selective nucleases with the attractive optical property of AuNPs. Taking S1 nuclease as one example, the perfectly matched 16-base synthetic DNA target was distinctively differentiated from those with single-base mutation located at any position of the 16-base synthetic target. Single-base mutations present in targets with varied length up to 80-base, located either in the middle or near to the end of the targets, were all effectively detected. In order to prove that the method can be potentially used for real clinic samples, the single base mismatch detections with two HBV genomic DNA samples were conducted. To further prove the generality of this method and potentially overcome the limitation on the detectable lengths of the targets of the S1 nuclease-based method, we also demonstrated the use of a duplex-specific nuclease (DSN) for color reversed single-base mismatch detection. The main limitation of the demonstrated methods is that it is limited to detect mutations in purified ssDNA targets. However, the method coupled with various convenient ssDNA generation and purification techniques, has the potential to be used for the future development of detector-free testing kits in single nucleotide polymorphism screenings for disease diagnostics and treatments. PMID- 21605967 TI - Gold-nanoparticle-based graphite furnace atomic absorption spectrometry amplification and magnetic separation method for sensitive detection of mercuric ions. AB - We have developed a sensitive gold-nanoparticle-based (AuNP-based) graphite furnace atomic absorption spectrometry (GFAAS) amplification and magnetic separation method for the detection of mercuric ions (Hg2+). The assay relies on (i) a sandwich-type structure containing two thymine-thymine (T-T) mismatches for selectively recognizing Hg2+ ions; (ii) magnetic beads for homogeneous separation; and (iii) AuNP-based GFAAS amplification detection. The limit of detection (LOD) of this assay is 0.45 nM (0.09 MUg L-1)--one order of magnitude lower than the United States Environmental Protection Agency (US EPA) limit for Hg2+ in drinking water. Furthermore, because a shorter hybridization step and a simpler AuNP-based GFAAS amplification detection were employed, a faster analytical run time allowing us to analyze a batch of 24 samples within 0.5 h. We demonstrated the feasibility of the developed approach for the determination of Hg2+ in urine and aqueous environmental samples. PMID- 21605968 TI - Immobilization of microbial cells on inner epidermis of onion bulb scale for biosensor application. AB - Inner epidermis of onion bulb scales was used as a natural support for immobilization of microbial cells for biosensor application. A bacterium Sphingomonas sp. that hydrolyzes methyl parathion into a chromophoric product, p nitrophenol (PNP), has been isolated and identified in our laboratory. PNP can be detected by electrochemical and colorimetric methods. Whole cells of Sphingomonas sp. were immobilized on inner epidermis of onion bulb scale by adsorption followed by cross-linking methods. Cells immobilized onion membrane was directly placed in the wells of microplate and associated with the optical transducer. Methyl parathion is an organophosphorus pesticide that has been widely used in the field of agriculture for insect pest control. This pesticide causes environmental pollution and ecological problem. A detection range 4-80 MUM of methyl parathion was estimated from the linear range of calibration plot of enzymatic assay. A single membrane was reused for 52 reactions and was found to be stable for 32 days with 90% of its initial hydrolytic activity. The applicability of the cells immobilized onion membrane was also demonstrated with spiked samples. PMID- 21605969 TI - Microbial biosensor for detection of methyl parathion using screen printed carbon electrode and cyclic voltammetry. AB - Whole cells of recombinant Escherichia coli were immobilized on the screen printed carbon electrode (SPCE) using glutaraldehyde. Recombinant E. coli was having high periplasmic expression of organophosphorus hydrolase enzyme, which hydrolyzes the methyl parathion into two products, p-nitrophenol and dimethyl thiophosphoric acid. Cells immobilized SPCE was studied under SEM. Cells immobilized SPCE was associated with cyclic voltammetry and cyclic voltammograms were recorded before and after hydrolysis of methyl parathion. Detection was calibrated based on the relationship between the changes in the current observed at +0.1 V potential, because of redox behavior of the hydrolyzed product p nitrophenol. As concentration of methyl parathion was increased the oxidation current also increased. Only 20 MUl volume of the sample was required for analysis. Detection range of biosensor was calibrated between 2 and 80 MUM of methyl parathion from the linear range of calibration plot. A single immobilized SPCE was reused for 32 reactions with retention of 80% of its initial enzyme activity. PMID- 21605970 TI - Neurobiology of obsessive-compulsive disorder: insights into neural circuitry dysfunction through mouse genetics. AB - The precise causal factors for obsessive-compulsive disorder (OCD) are not known, although, decades of research have honed in on the cortico-striatal-thalamo cortical (CSTC) circuitry in the brain as a critical pathway involved in obsessions and the intimately linked compulsive-repetitive behaviors. Recent progress in human and mouse genetics have led to the identification of novel candidate susceptibility genes, which in turn have facilitated a more focused approach to unraveling the nature of circuitry dysfunction in OCD. The ability to perform invasive techniques in genetic animal models of OCD will be crucial for rapid advances in this field, and as such we review the most recent developments and highlight the importance of searching out common circuitry defects underlying compulsive-repetitive behaviors. PMID- 21605972 TI - Training in surgical oncology - the role of VR simulation. AB - There have been dramatic changes in surgical training over the past two decades which have resulted in a number of concerns for the development of future surgeons. Changes in the structure of cancer services, working hour restrictions and a commitment to patient safety has led to a reduction in training opportunities that are available to the surgeon in training. Simulation and in particular virtual reality (VR) simulation has been heralded as an effective adjunct to surgical training. Advances in VR simulation has allowed trainees to practice realistic full length procedures in a safe and controlled environment, where mistakes are permitted and can be used as learning points. There is considerable evidence to demonstrate that the VR simulation can be used to enhance technical skills and improve operating room performance. Future work should focus on the cost effectiveness and predictive validity of VR simulation, which in turn would increase the uptake of simulation and enhance surgical training. PMID- 21605971 TI - Identification of a novel cell binding site of periostin involved in tumour growth. AB - INTRODUCTION: Periostin (PN), a member of the fasciclin family of proteins, is a TGF-beta-induced extracellular matrix protein involved in cell survival, angiogenesis, invasion and metastasis. It is considered a potent angiogenic factor and a marker of tumour progression in many types of human cancer. Many different kinds of cells bind to PN by means of the integrins alphavbeta3 and alphavbeta5, but the periostin epitope recognised by these integrins is not formally demonstrated. The aim of our study was to identify which domain of PN could be involved in cell adhesion and its potential role in tumour growth. METHODS: We generated the monoclonal antibody OC-20 (mAb OC-20) by hybridoma technology. Different PN recombinant fragments were used to characterise the periostin epitope recognised by the mAb OC-20 and to localise a new cell binding site of the protein. A murine model of human melanoma was used in the preclinical in vivo experiments. RESULTS: We formally demonstrate that the periostin epitope recognised by OC-20 is a new binding site for the integrins alphavbeta3 and alphavbeta5, localised in the second FAS1 domain (FAS1-2) of the protein. Moreover the in vivo use of this antibody significantly inhibits tumour growth and angiogenesis. CONCLUSION: Our results show that the FAS1-2 domain of PN plays a role in tumour progression. Moreover this novel antibody may likewise prove to be very useful in clarifying the role of PN in angiogenesis and may contribute to the design of novel anti-angiogenesis drugs. PMID- 21605973 TI - Potent and selective oxindole-based vasopressin 1b receptor antagonists with improved pharmacokinetic properties. AB - Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity. PMID- 21605974 TI - Inhibition of multi-drug resistant HIV-1 reverse transcriptase by nucleoside beta triphosphates. AB - Despite the success of potent reverse transcriptase (RT) inhibitors against human immunodeficiency virus type 1 (HIV-1) in combination regimens, the development of drug resistant RTs constitutes a major hurdle for the long-term efficacy of current antiretroviral therapy. Nucleoside beta-triphosphate analogs of adenosine and nucleoside reverse transcriptase inhibitors (NRTIs) (3'-azido-2',3' dideoxythymidine (AZT), 3'-fluoro-2',3'-dideoxythymidine (FLT), and 2',3' didehydro-2',3'-dideoxythymidine (d4T)) were synthesized and their inhibitory activities were evaluated against wild-type and multidrug resistant HIV-1 RTs. Adenosine beta-triphosphate (1) and AZT beta-triphosphate (2) completely inhibited the DNA polymerase activity of wild type, the NRTI multi resistant, and nonnucleoside RT inhibitors (NNRTI) resistant HIV-1 RT at 10nM, 10 and 100 MUM, respectively. PMID- 21605975 TI - Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model. AB - A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90 inhibitory activity at least 24h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth. PMID- 21605976 TI - Optimal adjuvant therapy for very young breast cancer patients. AB - Approximately one in forty women diagnosed with early breast cancer is very young (<35 years) and this age group has a worse prognosis. The inferior prognosis in very young women appears to have two aspects. Very young women present more frequently with tumors with adverse histo-pathologic features. However, even when the histo-pathologic features appear favorable (ie. endocrine responsive tumors), analyses suggest that very young women with hormone receptor positive tumors are a sub-group at particular risk for adverse outcomes, compared to older premenopausal women with similar tumors. Chemotherapy induced amenorrhea has been shown to be associated with better outcomes and very young women are less likely to develop amenorrhea. Trials to determine the optimal adjuvant hormonal therapy for very young women are important. After breast conserving surgery, very young women are at increased risk for local recurrence and require particular attention to adequacy of surgical excision, including DCIS. Younger women undergoing breast conservation benefit from a boost dose of radiation. The option of genetic counseling should be provided to women diagnosed at a very young age. When considering adjuvant systemic treatments, fertility and contraception may be important considerations for this age group. Pregnancy after a diagnosis of adequately treated early breast cancer does not appear to be associated with an increased risk for relapse. Very young women are at higher risk for psycho-social distress and non-compliance with adjuvant systemic therapy. Young women should be informed that lifestyle factors after diagnosis may reduce the risk of recurrence. PMID- 21605977 TI - Cell uptake of a biosensor detected by hyperpolarized 129Xe NMR: the transferrin case. AB - For detection of biological events in vitro, sensors using hyperpolarized (129)Xe NMR can become a powerful tool, provided the approach can bridge the gap in sensitivity. Here we propose constructs based on the non-selective grafting of cryptophane precursors on holo-transferrin. This biological system was chosen because there are many receptors on the cell surface, and endocytosis further increases this density. The study of these biosensors with K562 cell suspensions via fluorescence microscopy and (129)Xe NMR indicates a strong interaction, as well as interesting features such as the capacity of xenon to enter the cryptophane even when the biosensor is endocytosed, while keeping a high level of polarization. Despite a lack of specificity for transferrin receptors, undoubtedly due to the hydrophobic character of the cryptophane moiety that attracts the biosensor into the cell membrane, these biosensors allow the first in-cell probing of biological events using hyperpolarized xenon. PMID- 21605978 TI - Quality control and quality assurance procedures at the THOR BNCT facility. AB - Various quality control (QC) and quality assurance (QA) procedures of the boron neutron capture therapy (BNCT) beam at the Tsing Hua Open-pool Reactor (THOR) are established to ensure beam availability and quality. The QC/QA methods mainly employ foil activation and paired ionization chambers, respectively, for beam intensity check and dose assessment. Beam intensity is monitored on-line by using three dead-time corrected fission chambers. In addition to the periodic QC/QA activities regarding beam quality and the monitoring system, the quick QC/QA performed in an all-in-one phantom will be executed less than 70 min before the clinical treatment to guarantee beam quality. The QC/QA procedures have been gradually established and the actual performance satisfied the preset criteria defined for the BNCT facility at THOR. PMID- 21605979 TI - Fully automated synthesis of the M1 receptor agonist [11C]GSK1034702 for clinical use on an Eckert & Ziegler Modular Lab system. AB - A fully automated and GMP compatible synthesis has been developed to reliably label the M1 receptor agonist GSK1034702 with carbon-11. Stille reaction of the trimethylstannyl precursor with [11C]methyl iodide afforded [11C]GSK1034702 in an estimated 10 +/- 3% decay corrected yield. This method utilises the commercially available modular laboratory equipment and provides high purity [11C]GSK1034702 in a formulation suitable for human use. PMID- 21605980 TI - Elucidation of physiological and biochemical mechanisms of an endemic halophyte Centaurea tuzgoluensis under salt stress. AB - In this study, physiological and biochemical responses of Centaurea tuzgoluensis, a Turkish endemic halophyte, to salinity were studied. Therefore, the changes in shoot growth, leaf relative water content (RWC), ion concentrations, lipid peroxidation, hydroxyl (OH.) radical scavenging activity, proline (Pro) content, and antioxidant system [superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and glutathione reductase (GR)] were investigated. The 60 days (d) old C. tuzgoluensis seedlings were subjected to 0, 150 and 300 mM NaCl for 7 d and 14 d. The relative shoot growth was generally did not change in the 150 mM NaCl, but reduced with 300 mM NaCl stress at 7 d and 14 d. RWC was higher in 150 mM NaCl-treated leaves than that of 300 mM NaCl. Salinity decreased K+/Na+ ratio, but increased Na+, Cl-, Ca+2 and Na+/Cl- ratio in the leaves. On the other hand, it did not change or increase the K+ content at 150 and 300 mM NaCl, respectively. MDA content in the 150 and 300 mM NaCl-treated leaves remained close to control at 7 d. This was related to enhanced activities of SOD, CAT, APX and GR enzymes, and their isoenzymes especially Fe-SOD in the leaves. On the other hand, the higher sensitivity to 300 mM NaCl at 14 d was associated with inadequate increase in antioxidant enzymes and the decreased OH radical scavenging activity. All these results suggest that C. tuzgoluensis has different antioxidant metabolisms between short- (7 d) and long-term (14 d) salt treatments and salinity tolerance of C. tuzgoluensis might be closely related to increased capacity of antioxidative system to scavenge reactive oxygen species (ROS) and accumulation of osmoprotectant proline under salinity conditions. PMID- 21605981 TI - The role of the GATA2 transcription factor in normal and malignant hematopoiesis. AB - Hematopoiesis involves an elaborate regulatory network of transcription factors that coordinates the expression of multiple downstream genes, and maintains homeostasis within the hematopoietic system through the accurate orchestration of cellular proliferation, differentiation and survival. As a result, defects in the expression levels or the activity of these transcription factors are intimately linked to hematopoietic disorders, including leukemia. The GATA family of nuclear regulatory proteins serves as a prototype for the action of lineage-restricted transcription factors. GATA1 and GATA2 are expressed principally in hematopoietic lineages, and have essential roles in the development of multiple hematopoietic cells, including erythrocytes and megakaryocytes. Moreover, GATA2 is crucial for the proliferation and maintenance of hematopoietic stem cells and multipotential progenitors. In this review, we summarize the current knowledge regarding the biological properties and functions of the GATA2 transcription factor in normal and malignant hematopoiesis. PMID- 21605982 TI - Beneficial effects of l-leucine and l-valine on arrhythmias, hemodynamics and myocardial morphology in rats. AB - Branched chain amino acids (BCAA) have been shown to have a general protective effect on the heart in different animal models as well as in humans. However, so far no attempt has been made to specifically elucidate their influence on arrhythmias. Our study was performed to evaluate whether an infusion of either l leucine or l-valine in a dose of 1mgkg(-1)h(-1) 10min before a 7-min period of left anterior descending artery occlusion followed by 15min of reperfusion, had an effect on arrhythmias measured during the reperfusion phase in the ischemia- and reperfusion-induced arrhythmias model in rats in vivo. The effect of the infusion of these substances on mean arterial blood pressure was monitored throughout the experiment. Both of the tested amino acids exhibited significant antiarrhythmic properties. l-Leucine reduced the duration of ventricular fibrillation (P<0.05) and l-valine decreased the duration of ventricular fibrillation (P<0.001) and ventricular tachycardia (P<0.05). The two amino acids were generally hypotensive. l-Valine lowered blood pressure in all phases of the experiment (P<0.05) while l-leucine lowered this parameter mainly towards the end of occlusion and reperfusion (P<0.05). In addition, 30min infusion of the amino acids in the used dose did not produce any apparent adverse histological changes that were remarkably different from control. In summary, the results of our study suggest that l-leucine and l-valine in the dose that was used attenuates arrhythmias and are hypotensive in their influence. Our findings lend support to the many ongoing investigations into the benefit of the application of l-leucine and l-valine in cardiology like their addition to cardioplegic solutions. PMID- 21605983 TI - Letter to the editor: regarding "Hemochromatosis genotypes and risk of iron overload-a meta-analysis". PMID- 21605984 TI - Biomechanical reorganisation of stepping initiation during acute dorsiflexor fatigue. AB - During voluntary step initiation (SI), propulsive forces are generated during anticipatory postural adjustments (APA) which displace the centre-of-gravity (CoG) in the desired direction. These propulsive forces are implemented by ankle synergy, bilateral soleus inhibition followed by activation of tibialis anterior (TA). The aim of this study was to investigate the effect of fatigue applied to ankle dorsiflexors on APA associated with SI and on related motor performance. Eight young healthy participants initiated stepping before and after a protocol designed to generate fatigue in ankle dorsiflexors. Fatigue was induced by series of high-level isometric contractions performed until exhaustion. Results showed that, with fatigue, the level of TA activation during APA, anticipatory postural dynamics (backward centre-of-pressure displacement and forward CoG velocity) and related motor performance (peak of CoG velocity) were attenuated, while APA duration and total SI duration increased. These changes were interpreted as reflecting a protective strategy aiming to preserve the integrity of the fatigued muscles, rather than an impairment associated with muscle weakness. PMID- 21605985 TI - Recognition memory performance as a function of reported subjective awareness. AB - Three experiments introduced a recognition memory paradigm designed to investigate reported subjective awareness during retrieval. At study, in Experiments 1A and 2, words were either generated or read (generation), while modality of presentation (auditory versus visual) was manipulated in Experiment 1B. Word pairs (old/new or new/new) were presented during test trials, and participants indicated if they contained an old word by responding "remember", "know" or "new" in Experiments 1A and 1B, and by responding "strong no", "weak no", "weak yes", or "strong yes" in Experiment 2. Participants were then required to decide which of the 2 words was old. We demonstrated that the proportion measures used in the Remember Know paradigm substantially underestimated the influence of generation on familiarity resulting in an artificial dissociation between indices of knowing (familiarity) and remembering (recollection). We also found a qualitatively different pattern of forced-choice recognition performance as a function of claimed awareness. PMID- 21605986 TI - Notes from the field: Dr. Evan Lyon, HIV care, and the crisis in Haiti. PMID- 21605987 TI - Synovial osteochondromatosis of the second metatarsophalangeal joint: a case report. AB - Synovial osteochondromatosis is usually monoarticular, involving a large joint. Common locations include the knee, elbow, shoulder, and hip. It is not very common in the ankle, and it is very rare in the smaller joints of the foot. To our knowledge, and with the exception of 4 cases that occurred in the great toe, this condition has never been described in other metatarsophalangeal joints. In this report, we presented a case of synovial osteochondromatosis in the second metatarsophalangeal joint and reviewed the literature. PMID- 21605988 TI - Nonunion in proximal phalanx of great toe treated by grafting with precisely processed autologous bone PEG. AB - We report a rare case of nonunion in the proximal phalanx of the great toe treated by grafting with a precisely processed autologous bone peg. The concept of this surgical method was to fix the nonunion of the proximal phalanx of the great toe using press-fit fixation and a bone peg precisely formed to fit the medullary cavity similar to an intramedullary nail. We believe that our new technique is a viable alternative for the treatment of phalanx fractures or nonunions requiring bone grafts. PMID- 21605989 TI - Comments Regarding 'Use of Viabahn open revascularisation technique for above knee femoro-popliteal anastomosis: a technical note'. PMID- 21605990 TI - The effects of amino-acid mutations on specific interactions between urokinase type plasminogen activator and its receptor: Ab initio molecular orbital calculations. AB - During cancer invasion, the binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) on the surface of a cancer cell is considered a trigger for invasion. Here, we present a stable structure of the solvated complex formed between uPA and uPAR (uPA-uPAR) and investigate the specific interactions between uPA and uPAR by ab initio fragment molecular orbital (FMO) calculations. The result indicates that the electrostatic interactions between the charged amino acid residues existing in both uPA and uPAR make a large contribution to the binding between uPA and uPAR. In particular, Lys23, Lys46, Lys98 and Lys61 of uPA are found to have strong attractive interactions with uPAR. To elucidate the effect of these residues on the interactions between uPA and uPAR, we substituted each of them with the uncharged amino acid Leu and investigated the interactions between the mutated uPA and wild-type uPAR. The interaction energies indicate that Lys46 and Lys98, which bind uPA to the rim of the central ligand-binding cavity of uPAR, make greater contributions to the binding between uPA and uPAR than Lys23, which is positioned at the bottom of the ligand-binding cavity of uPAR. The effect of hydrating water molecules located between uPA and uPAR is also investigated to be significant for the specific interactions between uPA and uPAR. These results are expected to be informative for developing new peptide antagonists that block the binding of uPA to uPAR. PMID- 21605991 TI - Computational modeling of a rotary nanopump. AB - The dynamics of a rotary nanopump, consisting of three coaxial carbon nanotubes and a number of graphene blades, has been simulated via application of the molecular dynamics (MD) method. In this nanopump the inner nanotube, the middle carbon nanotube with together the graphene blades and the outer nanotube are used as the shaft, rotor, and sleeve of the pump, respectively. The rotary motion of the rotor is due to the mechanical rotation of the two first carbon rings of the rotor's carbon nanotube. We found that this pump flow the gas atoms between two sides of the nanopump and it can produce an atomic gradient. Also it is observed that a rotary frequency of the rotor affected on the pump performance for generating the density gradient and the maximum performance is occurred at a special frequency of the rotor. This special rotary frequency can be computed by an analytical formula, for given material and temperatures. Moreover, the results indicate that the number of the rotor's graphene blades do not have a significant effect on the pumping capacity. Our finding provides a potentially useful mechanism for gas purification process. PMID- 21605992 TI - Probing the reactivation process of sarin-inhibited acetylcholinesterase with alpha-nucleophiles: hydroxylamine anion is predicted to be a better antidote with DFT calculations. AB - Inactivation of acetylcholinesterase (AChE) due to inhibition by organophosphorus (OP) compounds is a major threat to human since AChE is a key enzyme in neurotransmission process. Oximes are used as potential reactivators of OP inhibited AChE due to their alpha-effect nucleophilic reactivity. In search of more effective reactivating agents, model studies have shown that alpha-effect is not so important for dephosphylation reactions. We report the importance of alpha effect of nucleophilic reactivity towards the reactivation of OP-inhibited AChE with hydroxylamine anion. We have demonstrated with DFT [B3LYP/6-311G(d,p)] calculations that the reactivation process of sarin-serine adduct 2 with hydroxylamine anion is more efficient than the other nucleophiles reported. The superiority of hydroxylamine anion to reactivate the sarin-inhibited AChE with sarin-serine adducts 3 and 4 compared to formoximate anion was observed in the presence and absence of hydrogen bonding interactions of Gly121 and Gly122. The calculated results show that the rates of reactivation process of adduct 4 with hydroxylamine anion are 261 and 223 times faster than the formoximate anion in the absence and presence of such hydrogen bonding interactions. The DFT calculated results shed light on the importance of the adjacent carbonyl group of Glu202 for the reactivation of sarin-serine adduct, in particular with formoximate anion. The reverse reactivation reaction between hydroxylamine anion and sarin-serine adduct was found to be higher in energy compared to the other nucleophiles, which suggests that this alpha-nucleophile can be a good antidote agent for the reactivation process. PMID- 21605993 TI - The effect of electrostatics on factor H function and related pathologies. AB - Factor H (FH) contributes to the regulation of the complement system by binding to polyanionic surfaces and the proteins C3b/C3c/C3d. This implicates charge and electrostatic interactions in recognition and binding of FH. Despite the large amount of experimental and pathology data the exact mechanism at molecular level is not yet known. We have implemented a computational framework for comparative analysis of the charge and electrostatic diversity of FH modules and C3b domains to identify electrostatic hotspots and predict potential binding sites. Our electrostatic potential clustering analysis shows that charge distributions and electrostatic potential distributions are more useful in understanding C3b-FH interactions than net charges alone. We present a model of non-specific electrostatic interactions of FH with polyanion-rich surfaces and specific interactions with C3b, using our computational data and existing experimental data. We discuss the electrostatic contributions to the formation of the C3b-FH complex and the competition between FH and Factor Bb (Bb) for binding to C3b. We also discuss the significance of mutations of charged amino acids in the pathobiology of FH-mediated disease, such as age-related macular degeneration, atypical hemolytic uremic syndrome, and dense deposit disease. Our data can be used to guide future experimental studies. PMID- 21605994 TI - A second Ig-like domain identified in dystroglycan by molecular modelling and dynamics. AB - Dystroglycan (DG) is a cell surface receptor which is composed of two subunits that interact noncovalently, namely alpha- and beta-DG. In skeletal muscle, DG is the central component of the dystrophin-glycoprotein complex (DGC) that anchors the actin cytoskeleton to the extracellular matrix. To date only the three dimensional structure of the N-terminal region of alpha-DG has been solved by X ray crystallography. To expand such a structural analysis, a theoretical molecular model of the murine alpha-DG C-terminal region was built based on folding recognition/threading techniques. Although there is no a significant (<30%) sequence homology with the N-terminal region of alpha-DG, protein fold recognition methods found a significant resemblance to the alpha-DG N-terminal crystallographic structure. Our in silico structural prediction identified two subdomains in this region. Amino acid residues ~ 500-600 of alpha-DG were predicted to adopt an immunoglobulin-like (Ig-like) beta-sandwich fold. Such modeled domain includes the beta-DG binding epitope of alpha-DG and, confirming our previous experimental results, suggests that the linear epitope (residues 550 565) assumes a beta-strand conformation. The remaining segment of the alpha-DG C terminal region (residues 601-653) is organized in a coil-helix-coil motif. A 20 ns molecular dynamics simulation in explicit water solvent provided support to the predicted Ig-like model structure. The identification of a second Ig-like domain in DG represents another important step towards a full structural and functional description of the alpha/beta DG interface. Preliminary characterization of a novel recombinant peptide (505-600) encompassing this second Ig-like domain demonstrates that it is soluble and stable, further corroborating our in silico analysis. PMID- 21605995 TI - Expanded molecular features of carnitine acyl-carnitine translocase (CACT) deficiency by comprehensive molecular analysis. AB - Carnitine-acylcarnitine translocase (CACT) deficiency is a rare autosomal recessive disease of fatty acid oxidation, mainly affecting long chain fatty acid utilization. The disease usually presents at neonatal period with severe hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy and/or arrhythmia, hepatic dysfunction, skeletal muscle weakness, and encephalopathy. Definitive diagnosis of CACT deficiency by molecular analysis of the SLC25A20 gene has recently become clinically available. In contrast to biochemical analysis, sequence analysis is a more rapid and reliable method for diagnosis of CACT deficiency. In this study, we used Sanger sequencing and target array CGH to identify molecular defects in the SLC25A20 gene of patients with clinical features and an acylcarnitine profile consistent with CACT deficiency. Eight novel mutations, including a large 25.9 kb deletion encompassing exons 5 to 9 of SLC25A20 were found. Review of the published cases revealed that CACT deficiency is a pan-ethnic disorder with a broad mutation spectrum. Mutations are distributed along the entire gene without a hot spot. Two thirds of them are nonsense, frame-shift, or splice site mutations resulting in premature stop codons. This study underscores the importance of comprehensive molecular analysis, including sequencing and targeted array CGH of the SLC25A20 gene when CACT deficiency is suspected. PMID- 21605996 TI - Expanding the clinical spectrum of late-onset Pompe disease: dilated arteriopathy involving the thoracic aorta, a novel vascular phenotype uncovered. AB - PURPOSE: Cerebro-vascular arteriopathy has been reported in late-onset Pompe disease (LOPD). Evidence of increased aortic stiffness in some patients and smooth muscle involvement in LOPD raises the possibility of aortic involvement. Our aim was to determine if aortic arteriopathy may be a complication of LOPD. METHODS: One patient with LOPD was diagnosed with aortic dilatation at Duke Metabolic clinic, 4 others were diagnosed at University of Mainz, Germany, where chest X-ray and echocardiography are routinely done for patients. Other causes of aortic vascular disease were assessed. RESULTS: We report evidence of dilated arteriopathy involving primarily the ascending thoracic aorta in 5 females with late-onset Pompe disease. One patient had a bicuspid aortic valve and developed dissection. Another patient with juvenile onset disease had both thoracic and basilar artery aneurysms. CONCLUSIONS: Aneurysmal dilatation of the thoracic aorta is an underreported vascular complication of LOPD, probably due to the same pathological process that occurs in the brain. Chest X-ray together with echocardiography should be incorporated as initial screening tools for aortic aneurysms in patients with LOPD. When ectasia is suspected, or the ascending aorta is not visualized, contrast- mediated thoracic CT or MRA may be necessary. Large-scale studies are warranted to determine the prevalence and extent of aortic vascular involvement. PMID- 21605997 TI - Recent advances in leishmaniasis treatment. AB - About 1.5 million new cases of cutaneous leishmaniasis and 500,000 new cases of visceral leishmaniasis occur each year around the world. For over half a century, the clinical forms of the disease have been treated almost exclusively with pentavalent antimonial compounds. In this review, we describe the arsenal available for treating Leishmania infections, as well as recent advances from research on plants and synthetic compounds as source drugs for treating the disease. We also review some new drug-delivery systems for the development of novel chemotherapeutics. We observe that the pharmaceutical industry should employ its modern technologies, which could lead to better use of plants and their extracts, as well as to the development of synthetic and semi-synthetic compounds. New studies have highlighted some biopharmaceutical technologies in the design of the delivery strategy, such as nanoparticles, liposomes, cochleates, and non-specific lipid transfer proteins. These observations serve as a basis to indicate novel routes for the development and design of effective anti Leishmania drugs. PMID- 21605998 TI - 'I had to go to the hospital and it was freaking me out': needle phobic encounter space. AB - Recent research in the geography of health care moves beyond distributive concerns focusing more sensitively on the nature of health care settings. As part of this, a growing number of studies explore the importance of individuals' personal circumstances on their emplaced experiences and agency. Extending this line of inquiry, and drawing on ideas in emotional geographies, the current study illustrates how experiences and agency can be impacted profoundly by needle phobia. Interviews with 11 self-identifying sufferers explore the physical, emotional, behavioral and spatial manifestations of their condition. Specifically how their fear of, and reactions to, clinical objects and procedures (needles and their insertion by health professionals into the body) and health care settings (that possess the risk of encountering or host the encounters with, these objects and procedures), can combine as a single spatial affect. PMID- 21605999 TI - Neighbourhood environment and positive mental health in older people: the Hertfordshire Cohort Study. AB - Little is known about the potential effects of neighbourhood environment on positive mental health in older people. We examined cross-sectional associations between the index of multiple deprivation score of the census area of residence, perceptions of neighbourhood cohesion and neighbourhood problems and mental wellbeing, as measured by the Warwick-Edinburgh Mental Wellbeing Scale, in 1157 men and women aged 69-78 years from Hertfordshire, UK. We found no association between area-level deprivation and mental wellbeing. People who felt a stronger sense of cohesion within their neighbourhood and reported fewer neighbourhood problems had higher levels of mental wellbeing, independently of social class, income, presence of limiting illness or disability, mobility problems, and perceived social support. Adjustment for emotional stability attenuated the associations between mental wellbeing and both of these measures of perceived neighbourhood environment, particularly in the case of neighbourhood problems. How older people feel about their neighbourhood may be important for positive mental health in later life. PMID- 21606000 TI - 'Only old ladies would do that': age stigma and older people's strategies for dealing with winter cold. AB - Concerns over the welfare of older people in winter have led to interventions and advice campaigns meant to improve their ability to keep warm, but older people themselves are not always willing to follow these recommendations. In this paper we draw on an in-depth study that followed twenty one older person households in the UK over a cold winter and examined various aspects of their routine warmth related practices at home and the rationales underpinning them. We find that although certain aspects of ageing did lead participants to feel they had changing warmth needs, their practices were also shaped by the problematic task of negotiating identities in the context of a wider stigmatisation of older age and an evident resistance to ageist discourses. After outlining the various ways in which this was manifest in our study, we conclude by drawing out the implications for future policy and research. PMID- 21606001 TI - Analysis of Arctic ices by remote Raman spectroscopy. AB - A portable remote Raman instrument for field analysis has been developed. This instrument has been tested in the Arctic conditions during AMASE (Arctic Mars Analog Svalbard Expedition) campaigns 2007, 2008 and 2009. Besides its capability for mineral detection the remote system proved to be a very useful tool for ice structural analysis of icebergs and ice-wall in glaciers. For the first time at our knowledge Arctic ice has been analyzed in situ in different conditions and at distances ranging from 10 to 120m. The spectra obtained have enough quality to be used for quantitative spectral analysis. PMID- 21606002 TI - Isolation of Pseudozyma churashimaensis sp. nov., a novel ustilaginomycetous yeast species as a producer of glycolipid biosurfactants, mannosylerythritol lipids. AB - An ustilaginomycetous anamorphic yeast species isolated from the leaves of Saccharum officinarum (sugarcane) in Okinawa, Japan, was identified as a novel Pseudozyma species based on morphological and physiological aspects and molecular taxonomic analysis using the D1/D2 domains of the large subunit (26S) rRNA gene and the internal transcribed spacer 1 (ITS1)-5.8S-ITS2 regions. The name Pseudozyma churashimaensis sp. nov. was proposed for the novel species, with JCM 16988(T) as the type strain. Interestingly, P. churashimaensis was found to produce glycolipid biosurfactants, a mixture of mannosylerythritol lipids (MELs), including a novel tri-acetylated derivative (MEL-A2), from glucose. The observed critical micelle concentration (CMC) and the surface tension at CMC of MEL-A2 were 1.7 * 10-6 M and 29.2 mN/m, respectively. Moreover, on a water-penetration scan, MEL-A2 efficiently formed different lyotropic liquid crystalline phases, including the lamella phase at a wide range of concentrations, indicating its excellent surface-active and self-assembling properties. The novel strain of the genus Pseudozyma should thus facilitate the application of glycolipid biosurfactants in combination with other MEL producers. PMID- 21606003 TI - Treatment end point determinants for pulmonary tuberculosis: human resistin as a surrogate biomarker. AB - Treatment of tuberculosis (TB), which takes one human life every 15 s, globally, requires a prolonged (>6 months) antitubercular treatment (ATT) which, is known to have hepatotoxic side effects. This study was designed to explore the utility of human resistin, a proinflammatory hormone, as a sensitive biomarker to determine TB treatment end points. Patients for pulmonary tuberculosis enrolled under the directly observed treatment, short-course (DOTS) program were followed up for six months and were monitored by sputum analysis, body weight and ELISA based serum resistin and C-reactive protein (CRP) levels at 0, 2, 4 and 6 months, along with close family contacts of TB patients and healthy controls. The mean circulating resistin levels were found to be significantly higher (P < 0.001) in patients (n = 48, 25.74 +/- 9.45 ng/ml) reporting for the first time for treatment (T0) as compared to healthy subjects (n = 45, 7.18 +/- 2.40 ng/ml). Resistin levels in contacts (n = 48, 19.61 +/- 7.88 ng/ml) also were found to be significantly (P < 0.001) elevated as compared to healthy controls. Significant increase in body weight after four months (P = 0.006) and at 6 months (P < 0.001) of treatment inversely correlated with resistin levels. Our data suggest resistin could be a surrogate marker for TB treatment in addition to its utility as an early prognostic biomarker for monitoring TB disease onset. PMID- 21606004 TI - Prolonged episode of dystonia and dyskinesia resembling status epilepticus following acute intrathecal baclofen withdrawal. AB - Spasticity is a state of sustained pathological increase in the tension of a muscle. Treatment for spasticity has been revolutionized by the introduction of intrathecal baclofen (ITB) continuous infusion. ITB is associated with a 30% rate of complications mostly as a result of catheter problems that lead to acute ITB withdrawal. We describe a 10-year-old girl with spastic quadriplegia caused by cerebral palsy successfully treated with ITB who developed dystonic-dyskinetic status following acute ITB withdrawal because of a catheter kink resolved by external manipulation. The patient presented with a subacute onset of generalized malaise characterized by anorexia, difficulty in speaking and swallowing, insomnia, worsening of hypertonus with a left predominance, and late appearance of dystonic-dyskinetic movements. Soon after hospitalization the child had a generalized tonic-clonic seizure followed by unresponsiveness. One hour later she developed multiple muscle contractions with dystonic posturing and continuous chaotic movements. She also had pyrexia, tachycardia, and hypertension. A video/EEG recording showed the nonepileptic nature of the symptoms and revealed dystonic-dyskinetic status. We report the clinical features and the video recording of the status. The prompt recognition of this life-threatening complication is essential, as rapid treatment may reduce the increased risk of death. Misdiagnosis is possible, and video/EEG monitoring is useful to this end. Although differing among patients, all symptoms are related to overexcitability of the extrapyramidal and autonomic systems. PMID- 21606005 TI - Stigma of people with epilepsy in China: views of health professionals, teachers, employers, and community leaders. AB - To identify possible sources of stigma of epilepsy in key informant groups, "mini ethnographic" studies were conducted in rural and urban locations in China. Data collected from 45 semistructured interviews and 8 focus group discussions (6 persons each) were analyzed to investigate the world experienced by people with epilepsy. Underpinned by a social constructionist approach to data analysis, emerging themes were identified with the use of computer-assisted data analysis (NVivo 8). A hierarchical model was then constructed, to include practical level issues (attitudes toward risk, attitudes toward costs of epilepsy) and cultural level issues (contrast between rurality and tradition and urbanization and modernity in the Chinese context). The analysis enriches current research on factors and sources of stigma of epilepsy and highlights issues for future practice. PMID- 21606006 TI - Rapid determination of para-phenylenediamine by gas chromatography-mass spectrometry with selected ion monitoring in henna-containing cosmetic products. AB - A rapid method for the determination of para-phenylenediamine (PPD) in cosmetic products, such as henna tattoos has been developed and evaluated. This analytical procedure involved extracting a 10mg test portion of cosmetic product in 10 mL of ethyl acetate, followed by determination by gas chromatography-mass spectrometry in the selected ion monitoring mode (GC/MS-SIM). 1,4-Phenylenediamine-2,3,5,6 d(4) was selected as an internal standard that was added at the beginning of the extraction procedure and used to correct for recovery and matrix effects. The linearity ranged from 1.0 to 1275 MUg/mL with a coefficient of determination (r(2)) greater than 0.999. LOQ and LOD were 1.0 and 0.10 MUg/mL, respectively. The recovery in a tattoo product containing PPD was 94% and that for a tattoo product containing no PPD reached 105%. Extraction efficiency of 98% was obtained. This method has been successfully applied to henna temporary tattoo and other henna-related cosmetic products for the determination and quantitation of PPD. PMID- 21606007 TI - Determination of the active constituents in Arnebia euchroma (Royle) Johnst. by ionic liquid-based ultrasonic-assisted extraction high-performance liquid chromatography. AB - Shikonin and beta,beta'-dimethylacrylshikonin in Arnebia euchroma (Royle) Johnst. were extracted by ionic liquid-based ultrasonic-assisted extraction (IL-based UAE) and determined by high-performance liquid chromatography (HPLC). The dried powder of A. euchroma (Royle) Johnst. was mixed with a room temperature ionic liquid [C(6)MIM][BF(4)] to form a suspension, and then the ultrasonic extraction was performed in a water bath at ambient temperature. The calibration curve showed good linear relationship (r>0.9998) in the concentration range of 1.75-140 MUg/mL for shikonin and 2.15-1360 MUg/mL for beta,beta'-dimethylacrylshikonin. The recoveries were between 69.79% and 82.35%. The IL-based UAE is free of volatile organic solvents, and consumes less sample, time and solvent, compared with regular ultrasonic and Soxhlet extraction. There was no obvious difference in the extraction yields of active constitutions obtained by the three extraction methods. PMID- 21606008 TI - Quantitative determination of buagafuran in human plasma by liquid chromatography tandem mass spectrometry. AB - A sensitive and selective high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the determination of buagafuran in human plasma. The analyte was extracted from plasma samples with hexane after addition of isotopic internal standard and chromatographed on a RP C(8) column. The mobile phase consisted of methanol-water (90:10, v/v) and the flow rate was 0.2 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer in multiple reactions monitoring (MRM) mode using positive electrospray ionization (ESI). The method was validated over the concentration range of 0.5-200 ng/mL. Inter- and intra-day precision (RSD%) were all within 15% and the accuracy (RE%) was equal or lower than 9.5%. The lower limit of quantitation (LLOQ) was 0.5 ng/mL. The extraction recovery was on average 38.1% and the detection was not affected by the matrix. The method was successfully applied to the pharmacokinetic study of buagafuran in healthy Chinese volunteers. PMID- 21606009 TI - Risk factors and clinical characteristics of Stenotrophomonas maltophilia infections in neonates. AB - BACKGROUND: The aim of this study was to review the risk factors and clinical, bacteriological, and epidemiological characteristics of Stenotrophomonas maltophilia infections in our neonatal intensive care unit. METHODS: A retrospective matched case-control study was performed by comparing 23 cases of S maltophilia with 45 controls to identify the potential risk factors. To identify the case patients, the admission and medical records of patients in the neonatal intensive care unit and records from the Microbiology Department were reviewed between 2003 and 2008. RESULTS: Sepsis in two neonates (9%), conjunctivitis in two neonates (9%), and ventilator-associated pneumonia in 19 (82%) neonates were determined. Invasive-procedures, exposure to aminoglycoside and carbapenem, total parenteral nutrition, histamine 2 blockers, exposure to steroids, cholestasis, and duration of hospitalization were significantly associated with S maltophilia infections (p<0.05). On multivariate analysis, invasive procedures (odds ratio, 18.81) and duration of hospitalization (odds ratio, 1.06) were determined to be the risk factors for S maltophilia infection. The most active antimicrobial agent was trimethoprim/sulfamethoxazole (87%) for S maltophilia infection, and the mortality rate was 17%. CONCLUSIONS: Neonatologists should avoid from unnecessary invasive procedures and broad-spectrum antibiotics to reduce S maltophilia infections. Invasive procedures should be finished in the shortest time possible. Agent/factor-specific antibacterial treatment should be administered. Patients being discharged as early as possible will also reduce infection frequency. Stenotrophomonas maltophilia should be considered in patients with high Stenotrophomonas infection risk factors. PMID- 21606010 TI - Preface. PMID- 21606012 TI - Macrolane injections for breast enhancement in undiagnosed breast malignancy: a case report. AB - We report a case of cosmetic breast enhancement with Macrolane injections in an un-diagnosed breast cancer. This delayed cancer diagnosis and complicated surgical resection and reconstruction. It should therefore be mandatory for clinicians to exclude breast malignancy with imaging prior to Macrolane injection. PMID- 21606011 TI - Neonatal cardiomyopathies and metabolic crises due to oxidative phosphorylation defects. AB - Neonatal cardiomyopathies due to mitochondrial oxidative phosphorylation (OXPHOS) defects are extremely severe conditions which can be either isolated or included in a multi-organ disease, with or without metabolic crises, of which profound lactic acidosis is the prominent feature. Cardiomyopathy is more often hypertrophic than dilated. Antenatal manifestations such as fetal cardiomyopathy, arrhythmia and/or hydrops have been reported. Pathophysiological mechanisms are complex, going beyond ATP deficiency of the high-energy-consuming neonatal myocardium. Birth is a key metabolic period when the myocardium switches ATP production from anaerobic glycolysis to mitochondrial fatty acid oxidation and OXPHOS. Heart-specificity of the defect may be related to the specific localization of the defect, to the high myocardium dependency on OXPHOS, and/or to interaction between the primary genetic alteration and other factors such as modifier genes. Therapeutic options are limited but standardized diagnostic procedures are mandatory to confirm the OXPHOS defect and to identify its causal mutation, allowing genetic counseling and potential prenatal diagnosis. PMID- 21606013 TI - Comparison of stubbing and the double swab method for collecting offender epithelial material from a victim's skin. AB - After manual strangulation, epithelial cells originating from the offender can often be found on the skin of the victim. In order to obtain a conclusive DNA profile, it is important to secure as many epithelial cells from the offender and as few epithelial cells from the victim as possible. In this study, two methods for securing offender DNA were compared: the double swab method and an adapted tape-lifting method, so-called stubbing. 50 male volunteers were asked to simulate manual strangulation on the forearm of a female volunteer. After securing the epithelial material, DNA profiles were generated. The contribution of both donors to the samples was determined from the number of detected alleles, specific for each donor, and the average peak height of the donor-specific alleles. For the offender, in all cases except one, partial or full profiles were obtained and no difference between the double swab and the stubbing method was observed. For the victim, fewer alleles were detected by means of double swab than by means of stubbing. In conclusion, the double swab method performs slightly better than the stubbing method. However, from a practical point of view, the stubbing method may be preferred over the double swab technique. PMID- 21606014 TI - Quantifying differences in breast cancer survival between England and Norway. AB - BACKGROUND: Survival from breast cancer is lower in the UK than in some other European countries. We compared survival in England and Norway by age and time from diagnosis. METHODS: We included 303,648 English and 24,919 Norwegian cases of breast cancer diagnosed 1996-2004 using flexible parametric relative survival models, enabling improved quantification of differences in survival. Crude probabilities were estimated to partition the probability of death due to all causes into that due to cancer and other causes and to estimate the number of "avoidable" deaths. RESULTS: England had lower relative survival for all ages with the difference increasing with age. Much of the difference was due to higher excess mortality in England in the first few months after diagnosis. Older patients had a higher proportion of deaths due to other causes. At 5 years post diagnosis, a woman aged 85 in England had probabilities of 0.35 of dying of cancer and 0.32 of dying of other causes, whilst in Norway they were 0.26 and 0.35. By eight years the number of "avoidable" all-cause deaths in England was 1020 with the number of "avoidable" breast cancer related deaths 1488. CONCLUSION: Lower breast cancer survival in England is mainly due to higher mortality in the first year after diagnosis. Crude probabilities aid our understanding of the impact of disease on individual patients and help assess different treatment options. PMID- 21606015 TI - Cyclin D1 (CCND1) G870A gene polymorphism is an ethnicity-dependent risk factor for digestive tract cancers: a meta-analysis comprising 20,271 subjects. AB - Published data on the association between Cyclin D1 (CCND1) G870A gene polymorphism and digestive tract cancers (DTC) are inconclusive. We carried out a meta-analysis of published case-control studies to derive a more precise estimation of the association. Relevant studies were identified from PubMed, EMBASE, and China National Knowledge Infrastructure up to February 1st, 2011. Crude odds ratios (OR) and 95% confidence intervals (CI) were used to investigate the strength of the association. Data were available from a total of 33 case control studies with 8534 cases and 11,737 controls. The combined results based on all studies showed that there was a statistically significant link between CCND1 G870A polymorphism and DTC risk (GG vs. AA: OR=0.83, 95%CI=0.71-0.96). In the analysis of ethnic groups, we found the A allele carriers had a significantly increased DTC susceptibility among Caucasians, but not among Asians. When stratified for tumor location, the results based on all studies only showed the variant allele 870A might have a significantly increased risk of colorectal cancer (CRC), especially of rectal cancer (GG vs. AA: OR=0.71, 95%CI=0.58-0.89). When stratifying by the stage and histological differentiation of CRC, we only observed that patients had a significantly higher frequency of CCND1 870 AA than non-cancer patients among Caucasians. The A allele carriers (hetero- or homozygotes) were significantly more common in cases with a family history of CRC than in controls. There was no evidence of publication bias for CCND1 G870A polymorphism with DTC risk. In summary, this meta-analysis demonstrates that the CCND1 G870A polymorphism may be an ethnicity-dependent risk factor for DTC. And this genetic variant may increase the risk of rectal cancer, but not colon cancer. PMID- 21606016 TI - Measuring body-cover vibration of vocal folds based on high frame rate ultrasonic imaging and high-speed video. AB - Vibration of vocal folds is a body-cover layered vibration pattern due to the two layer tissue structures of vocal folds. A method based on a synchronal imaging system is proposed in order to image and measure the body-cover vibration pattern of vocal folds. This imaging system contains two parts: high-frame-rate ultrasonic imaging part and high-speed video part, which can synchronously image the vibration of the body and cover layers a thigh speed. Then, image analysis methods are applied to measure the body-cover vibration of vocal folds from both recorded image sequences. We analyze characteristics of body-layer vibration based on the measurements from designed experiments. Moreover, these results meet simulations of a body-cover model. PMID- 21606017 TI - Needle electrode-based electromechanical reshaping of rabbit septal cartilage: a systematic evaluation. AB - Electromechanical reshaping (EMR) provides a means of producing shape change in cartilage by initiating oxidation-reduction reactions in mechanically deformed specimens. This study evaluates the effect of voltage and application time on specimen shape change using needle electrodes. Rabbit septal cartilage specimens (20 x 8 x 1 mm, n = 200) were bent 90 degrees in a precision-machined plastic jig. Optimal electrode placement and the range of applied voltages were estimated using numerical modeling of the initial electric field within the cartilage sample. A geometric configuration of three platinum needle electrodes 2 mm apart from each other and inserted 6 mm from the bend axis on opposite ends was selected. One row of electrodes served as the anode and the other as the cathode. Constant voltage was applied at 1, 2, 4, 6, and 8 V for 1, 2, and 4 minutes, followed by rehydration in phosphate buffered saline. Samples were then removed from the jig and bend angle was measured. In accordance with previous studies, bend angle increased with increasing voltage and application time. Below a voltage threshold of 4 V, 4 minutes, no clinically significant reshaping was observed. The maximum bend angle obtained was 35.7 +/- 1.7 o at 8 V, 4 minutes. PMID- 21606018 TI - A new method to analyze distortion product otoacoustic emissions (DPOAEs) in the high-frequency range up to 18 kHz using windowed periodograms. AB - Distortion product otoacoustic emissions (DPOAEs) are widely used as an objective examination procedure to determine cochlear function. In a clinical routine setting, the amplitude of the DPOAE signal at 2f1 .. f2 is applied as an indicator for a potential hearing loss up to 8 kHz. Due to their poor signal to noise ratio, meatal nodes from standing waves and calibration issues, high frequency DPOAEs > 8 kHz have hardly been addressed in experimental and clinical audiology so far. Here, we present a new method of measuring DPOAE signal levels based on optimal maximum likelihood estimation with windowed power spectral density estimation of stochastic signals and filtering theory. Analysis of simulated data showed that the proposed method effectively reduces the disturbing noise floor compared to conventional averaging techniques. Robust DPOAE signals were measured in 20 ears from 10 normally hearing young adults (21 to 27 years) from 0:5 to 18 kHz. Repeated DPOAE recordings in one individual yielded a good to very good testretest reliability of the proposed method. These observations are discussed in the context of DPOAE signal processing and possible clinical applications of high-frequency DPOAE measurements. PMID- 21606019 TI - Compressed sensing for real-time energy-efficient ECG compression on wireless body sensor nodes. AB - Wireless body sensor networks (WBSN) hold the promise to be a key enabling information and communications technology for next-generation patient-centric telecardiology or mobile cardiology solutions. Through enabling continuous remote cardiac monitoring, they have the potential to achieve improved personalization and quality of care, increased ability of prevention and early diagnosis, and enhanced patient autonomy, mobility, and safety. However, state-of-the-art WBSN enabled ECG monitors still fall short of the required functionality, miniaturization, and energy efficiency. Among others, energy efficiency can be improved through embedded ECG compression, in order to reduce airtime over energy hungry wireless links. In this paper, we quantify the potential of the emerging compressed sensing (CS) signal acquisition/compression paradigm for low complexity energy-efficient ECG compression on the state-of-the-art Shimmer WBSN mote. Interestingly, our results show that CS represents a competitive alternative to state-of-the-art digital wavelet transform (DWT)-based ECG compression solutions in the context of WBSN-based ECG monitoring systems. More specifically, while expectedly exhibiting inferior compression performance than its DWT-based counterpart for a given reconstructed signal quality, its substantially lower complexity and CPU execution time enables it to ultimately outperform DWT-based ECG compression in terms of overall energy efficiency. CS based ECG compression is accordingly shown to achieve a 37.1% extension in node lifetime relative to its DWT-based counterpart for "good" reconstruction quality. PMID- 21606020 TI - A real-time ECG data compression and transmission algorithm for an e-health device. AB - This paper introduces a real-time data compression and transmission algorithm between e-health terminals for a periodic ECGsignal. The proposed algorithm consists of five compression procedures and four reconstruction procedures. In order to evaluate the performance of the proposed algorithm, the algorithm was applied to all 48 recordings of MIT-BIH arrhythmia database, and the compress ratio (CR), percent root mean square difference (PRD), percent root mean square difference normalized (PRDN), rms, SNR, and quality score (QS) values were obtained. The result showed that the CR was 27.9:1 and the PRD was 2.93 on average for all 48 data instances with a 15% window size. In addition, the performance of the algorithm was compared to those of similar algorithms introduced recently by others. It was found that the proposed algorithm showed clearly superior performance in all 48 data instances at a compression ratio lower than 15:1, whereas it showed similar or slightly inferior PRD performance for a data compression ratio higher than 20:1. In light of the fact that the similarity with the original data becomes meaningless when the PRD is higher than 2, the proposed algorithm shows significantly better performance compared to the performance levels of other algorithms. Moreover, because the algorithm can compress and transmit data in real time, it can be served as an optimal biosignal data transmission method for limited bandwidth communication between e-health devices. PMID- 21606021 TI - A supervised patch-based approach for human brain labeling. AB - We propose in this work a patch-based image labeling method relying on a label propagation framework. Based on image intensity similarities between the input image and an anatomy textbook, an original strategy which does not require any nonrigid registration is presented. Following recent developments in nonlocal image denoising, the similarity between images is represented by a weighted graph computed from an intensity-based distance between patches. Experiments on simulated and in vivo magnetic resonance images show that the proposed method is very successful in providing automated human brain labeling. PMID- 21606022 TI - Identifying regional cardiac abnormalities from myocardial strains using nontracking-based strain estimation and spatio-temporal tensor analysis. AB - Myocardial strain is a critical indicator of many cardiac diseases and dysfunctions. The goal of this paper is to extract and use the myocardial strain pattern from tagged magnetic resonance imaging (MRI) to identify and localize regional abnormal cardiac function in human subjects. In order to extract the myocardial strains from the tagged images, we developed a novel nontracking-based strain estimation method for tagged MRI. This method is based on the direct extraction of tag deformation, and therefore avoids some limitations of conventional displacement or tracking-based strain estimators. Based on the extracted spatio-temporal strain patterns, we have also developed a novel tensor based classification framework that better conserves the spatio-temporal structure of the myocardial strain pattern than conventional vector-based classification algorithms. In addition, the tensor-based projection function keeps more of the information of the original feature space, so that abnormal tensors in the subspace can be back-projected to reveal the regional cardiac abnormality in a more physically meaningful way. We have tested our novel methods on 41 human image sequences, and achieved a classification rate of 87.80%. The regional abnormalities recovered from our algorithm agree well with the patient's pathology and clinical image interpretation, and provide a promising avenue for regional cardiac function analysis. PMID- 21606023 TI - Embedded feature ranking for ensemble MLP classifiers. AB - A feature ranking scheme for multilayer perceptron (MLP) ensembles is proposed, along with a stopping criterion based upon the out-of-bootstrap estimate. To solve multi-class problems feature ranking is combined with modified error correcting output coding. Experimental results on benchmark data demonstrate the versatility of the MLP base classifier in removing irrelevant features. PMID- 21606024 TI - A co-saliency model of image pairs. AB - In this paper, we introduce a method to detect co-saliency from an image pair that may have some objects in common. The co-saliency is modeled as a linear combination of the single-image saliency map (SISM) and the multi-image saliency map (MISM). The first term is designed to describe the local attention, which is computed by using three saliency detection techniques available in literature. To compute the MISM, a co-multilayer graph is constructed by dividing the image pair into a spatial pyramid representation. Each node in the graph is described by two types of visual descriptors, which are extracted from a representation of some aspects of local appearance, e.g., color and texture properties. In order to evaluate the similarity between two nodes, we employ a normalized single-pair SimRank algorithm to compute the similarity score. Experimental evaluation on a number of image pairs demonstrates the good performance of the proposed method on the co-saliency detection task. PMID- 21606025 TI - Fast bi-directional prediction selection in H.264/MPEG-4 AVC temporal scalable video coding. AB - In this paper, we propose a fast algorithm that efficiently selects the temporal prediction type for the dyadic hierarchical-B prediction structure in the H.264/MPEG-4 temporal scalable video coding (SVC). We make use of the strong correlations in prediction type inheritance to eliminate the superfluous computations for the bi-directional (BI) prediction in the finer partitions, 16*8/8*16/8*8 , by referring to the best temporal prediction type of 16 * 16. In addition, we carefully examine the relationship in motion bit-rate costs and distortions between the BI and the uni-directional temporal prediction types. As a result, we construct a set of adaptive thresholds to remove the unnecessary BI calculations. Moreover, for the block partitions smaller than 8 * 8, either the forward prediction (FW) or the backward prediction (BW) is skipped based upon the information of their 8 * 8 partitions. Hence, the proposed schemes can efficiently reduce the extensive computational burden in calculating the BI prediction. As compared to the JSVM 9.11 software, our method saves the encoding time from 48% to 67% for a large variety of test videos over a wide range of coding bit-rates and has only a minor coding performance loss. PMID- 21606026 TI - Bayesian robust principal component analysis. AB - A hierarchical Bayesian model is considered for decomposing a matrix into low rank and sparse components, assuming the observed matrix is a superposition of the two. The matrix is assumed noisy, with unknown and possibly non-stationary noise statistics. The Bayesian framework infers an approximate representation for the noise statistics while simultaneously inferring the low-rank and sparse outlier contributions; the model is robust to a broad range of noise levels, without having to change model hyperparameter settings. In addition, the Bayesian framework allows exploitation of additional structure in the matrix. For example, in video applications each row (or column) corresponds to a video frame, and we introduce a Markov dependency between consecutive rows in the matrix (corresponding to consecutive frames in the video). The properties of this Markov process are also inferred based on the observed matrix, while simultaneously denoising and recovering the low-rank and sparse components. We compare the Bayesian model to a state-of-the-art optimization-based implementation of robust PCA; considering several examples, we demonstrate competitive performance of the proposed model. PMID- 21606027 TI - RASIM: a novel rotation and scale invariant matching of local image interest points. AB - This paper presents a novel algorithm for matching image interest points. Potential interest points are identified by searching for local peaks in Difference-of-Gaussian (DoG) images. We refine and assign rotation, scale and location for each keypoint by using the SIFT algorithm . Pseudo log-polar sampling grid is then applied to properly scaled image patches around each keypoint, and a weighted adaptive lifting scheme transform is designed for each ring of the log-polar grid. The designed adaptive transform for a ring in the reference keypoint and the general non-adaptive transform are applied to the corresponding ring in a test keypoint. Similarity measure is calculated by comparing the corresponding transform domain coefficients of the adaptive and non adaptive transforms. We refer to the proposed versatile system of Rotation And Scale Invariant Matching as RASIM. Our experiments show that the accuracy of RASIM is more than SIFT, which is the most widely used interest point matching algorithm in the literature. RASIM is also more robust to image deformations while its computation time is comparable to SIFT. PMID- 21606028 TI - Fourier-domain multichannel autofocus for synthetic aperture radar. AB - Synthetic aperture radar (SAR) imaging suffers from image focus degradation in the presence of phase errors in the received signal due to unknown platform motion or signal propagation delays. We present a new autofocus algorithm, termed Fourier-domain multichannel autofocus (FMCA), that is derived under a linear algebraic framework, allowing the SAR image to be focused in a noniterative fashion. Motivated by the mutichannel autofocus (MCA) approach, the proposed autofocus algorithm invokes the assumption of a low-return region, which generally is provided within the antenna sidelobes. Unlike MCA, FMCA works with the collected polar Fourier data directly and is capable of accommodating wide angle monostatic SAR and bistatic SAR scenarios. Most previous SAR autofocus algorithms rely on the prior assumption that radar's range of look angles is small so that the phase errors can be modeled as varying along only one dimension in the collected Fourier data. And, in some cases, implicit assumptions are made regarding the SAR scene. Performance of such autofocus algorithms degrades if the assumptions are not satisfied. The proposed algorithm has the advantage that it does not require prior assumptions about the range of look angles, nor characteristics of the scene. PMID- 21606029 TI - Real-time affine global motion estimation using phase correlation and its application for digital image stabilization. AB - We propose a fast and robust 2D-affine global motion estimation algorithm based on phase-correlation in the Fourier-Mellin domain and robust least square model fitting of sparse motion vector field and its application for digital image stabilization. Rotation-scale-translation (RST) approximation of affine parameters is obtained at the coarsest level of the image pyramid, thus ensuring convergence for a much larger range of motions. Despite working at the coarsest resolution level, using subpixel-accurate phase correlation provides sufficiently accurate coarse estimates for the subsequent refinement stage of the algorithm. The refinement stage consists of RANSAC based robust least-square model fitting for sparse motion vector field, estimated using block-based subpixel-accurate phase correlation at randomly selected high activity regions in finest level of image pyramid. Resulting algorithm is very robust to outliers such as foreground objects and flat regions. We investigate the robustness of the proposed method for digital image stabilization application. Experimental results show that the proposed algorithm is capable of estimating larger range of motions as compared to another phase correlation method and optical flow algorithm. PMID- 21606030 TI - Natural matting for degraded pictures. AB - A new approach for image matting is proposed based on the Kalman filter, to extract the matte and original foreground, despite the presence of noise in the observed image. Different filter formulations with a discontinuity-adaptive Markov random field prior are proposed for handling additive white Gaussian noise and film-grain noise. PMID- 21606031 TI - High-quality reflection separation using polarized images. AB - In this paper, we deal with a problem of separating the effect of reflection from images captured behind glass. The input consists of multiple polarized images captured from the same view point but with different polarizer angles. The output is the high quality separation of the reflection layer and the background layer from the images. We formulate this problem as a constrained optimization problem and propose a framework that allows us to fully exploit the mutually exclusive image information in our input data. We test our approach on various images and demonstrate that our approach can generate good reflection separation results. PMID- 21606032 TI - Capacity analysis for orthogonal halftone orientation modulation channels. AB - Halftone dot orientation modulation has recently been proposed as a method for data hiding in printed images. Extraction of data embedded with halftone orientation modulation is accomplished by computing, from the scanned hardcopy image, detection statistics that uniquely identify the embedded orientation. From a communications perspective, this data hiding setup forms an interesting class of channels with dot orientation as input and a vector of statistics as the output. This paper derives capacity expressions for these channels that allow for numerical evaluation of the capacity. Results provide significant insight for orientation modulation based print-scan resilient data hiding: the capacity varies significantly as a function of the image graylevel and experimentally observed error free data rates closely mirror the variation in capacity. PMID- 21606033 TI - Discretization of parametrizable signal manifolds. AB - Transformation-invariant analysis of signals often requires the computation of the distance from a test pattern to a transformation manifold. In particular, the estimation of the distances between a transformed query signal and several transformation manifolds representing different classes provides essential information for the classification of the signal. In many applications, the computation of the exact distance to the manifold is costly, whereas an efficient practical solution is the approximation of the manifold distance with the aid of a manifold grid. In this paper, we consider a setting with transformation manifolds of known parameterization. We first present an algorithm for the selection of samples from a single manifold that permits to minimize the average error in the manifold distance estimation. Then we propose a method for the joint discretization of multiple manifolds that represent different signal classes, where we optimize the transformation-invariant classification accuracy yielded by the discrete manifold representation. Experimental results show that sampling each manifold individually by minimizing the manifold distance estimation error outperforms baseline sampling solutions with respect to registration and classification accuracy. Performing an additional joint optimization on all samples improves the classification performance further. Moreover, given a fixed total number of samples to be selected from all manifolds, an asymmetric distribution of samples to different manifolds depending on their geometric structures may also increase the classification accuracy in comparison with the equal distribution of samples. PMID- 21606034 TI - Collinear segment detection using HT neighborhoods. AB - In this paper, geometrical analysis is used to extract novel straight line segment features from the wings around the peaks of the Hough Transform (HT). Based on these features, a practical segment detection method is proposed which has the ability to determine complete straight line segment parameters including the location of the center, length, slope and the Euclidean distance to the origin. The proposed method does not rely on edge point verification in the image space, i.e., the complete set of segment features are determined only using the information embodied in the HT data. The proposed method can distinguish between highly collinear straight line segments. Segment detection is robust to disturbing edge points, especially ones collinear with the object. A predefined collinear segment resolution that provides a theoretical criterion to determine straight line contiguity is derived. Image processing and analysis experiments show consistent robust performance. PMID- 21606035 TI - Edge strength filter based color filter array interpolation. AB - For economic reasons, most digital cameras use color filter arrays instead of beam splitters to capture image data. As a result of this, only one of the required three color samples becomes available at each pixel location and the other two need to be interpolated. This process is called Color Filter Array (CFA) interpolation or demosaicing. Many demosaicing algorithms have been introduced over the years to improve subjective and objective interpolation quality. We propose an orientation-free edge strength filter and apply it to the demosaicing problem. Edge strength filter output is utilized both to improve the initial green channel interpolation and to apply the constant color difference rule adaptively. This simple edge directed method yields visually pleasing results with high CPSNR. PMID- 21606036 TI - Period coded phase shifting strategy for real-time 3-D structured light illumination. AB - Phase shifting structured light illumination for range sensing involves projecting a set of grating patterns where accuracy is determined, in part, by the number of stripes. However, high pattern frequencies introduce ambiguities during phase unwrapping. This paper proposes a process for embedding a period cue into the projected pattern set without reducing the signal-to-noise ratio. As a result, each period of the high frequency signal can be identified. The proposed method can unwrap high frequency phase and achieve high measurement precision without increasing the pattern number. Therefore, the proposed method can significantly benefit real-time applications. The method is verified by theoretical and experimental analysis using prototype system built to achieve 120 fps at 640 * 480 resolution. PMID- 21606037 TI - Homogenous polynomially parameter-dependent Hinfinity filter designs of discrete time fuzzy systems. AB - This paper proposes a novel H(infinity) filtering technique for a class of discrete-time fuzzy systems. First, a novel kind of fuzzy H(infinity) filter, which is homogenous polynomially parameter dependent on membership functions with an arbitrary degree, is developed to guarantee the asymptotic stability and a prescribed H(infinity) performance of the filtering error system. Second, relaxed conditions for H(infinity) performance analysis are proposed by using a new fuzzy Lyapunov function and the Finsler lemma with homogenous polynomial matrix Lagrange multipliers. Then, based on a new kind of slack variable technique, relaxed linear matrix inequality-based H(infinity) filtering conditions are proposed. Finally, two numerical examples are provided to illustrate the effectiveness of the proposed approach. PMID- 21606038 TI - Monitoring and evaluation of blood pressure changes with a home healthcare system. AB - We investigated changes in blood pressure with exercise, including walking and ergometer training, sleep, and body weight. Blood pressure was monitored over a period of about 1 year in 61 subjects in Osaka, Japan. The morning systolic blood pressures were analyzed using multivariate regression analysis, and the correlations between systolic blood pressure and the above parameters were determined. The systolic blood pressure distribution was classified into improved, stable, and ingravescence groups. In the improved group, exercise intensity and total calories were important factors controlling the systolic blood pressure. More than 300 kcal per day was needed to improve the systolic blood pressure. In the stable and ingravescence groups, body weight control was also an important factor in maintaining blood pressure. An increase of 1 kg in body weight was associated with systolic blood pressure increases of 3 and 6 mm Hg in the stable and ingravescence groups, respectively. The long-term repeated use of home blood pressure testing may be a good self-care strategy for monitoring daily health. PMID- 21606039 TI - Colon segmentation for prepless virtual colonoscopy. AB - A novel segmentation framework for a prepless virtual colonoscopy (VC) is presented, which reduces the necessity for colon cleansing before the CT scan. The patient is injected rectally with a water-soluble iodinated contrast medium using manual insufflators and a small rectal catheter. Compared to the air-based contrast medium, this technique can better preserve the color lumen and reduce the partial volume effect. However, the contrast medium, together with the fecal materials and air, makes colon wall segmentation challenging. Our solution makes no assumptions about the shape, size, and location of the fecal material in the colon. This generality allows us to label the fecal material accurately and extract the colon wall reliably. The accuracy of our technique has been verified on 60 human subjects. Compared with current VC technologies, our method is shown to be better in terms of both sensitivity and specificity. Further, in our experiments, the accuracy of the technique was comparable to that of optical colonoscopy results. PMID- 21606040 TI - Mobile social network services for families with children with developmental disabilities. AB - As Internet technologies evolve, their applications have changed various aspects of human life. Here, we attempt to examine their potential impact on services for families with developmentally delayed children. Our research is thus designed to utilize wireless mobile communication technologies, location services, and search technology in an effort to match families of specific needs with potential care providers. Based on the investigation conducted by our counselors, this paper describes a platform for smooth communication between professional communities and families with children with developmental disabilities (CDD). This research also looks into the impact of management of mobile social network services and training on the operation of these services. Interaction opportunities, care, and support to families with CDD are introduced. PMID- 21606041 TI - Measuring and reflecting depth of anesthesia using wavelet and power spectral density. AB - This paper evaluates depth of anesthesia (DoA) monitoring using a new index. The proposed method preconditions raw EEG data using an adaptive threshold technique to remove spikes and low-frequency noise. We also propose an adaptive window length technique to adjust the length of the sliding window. The information pertinent to DoA is then extracted to develop a feature function using discrete wavelet transform and power spectral density. The evaluation demonstrates that the new index reflects the patient's transition from consciousness to unconsciousness with the induction of anesthesia in real time. PMID- 21606042 TI - IEEE 802.15.4 MAC with GTS transmission for heterogeneous devices with application to wheelchair body-area sensor networks. AB - In wireless personal area networks, such as wireless body-area sensor networks, stations or devices have different bandwidth requirements and, thus, create heterogeneous traffics. For such networks, the IEEE 802.15.4 medium access control (MAC) can be used in the beacon-enabled mode, which supports guaranteed time slot (GTS) allocation for time-critical data transmissions. This paper presents a general discrete-time Markov chain model for the IEEE 802.15.4-based networks taking into account the slotted carrier sense multiple access with collision avoidance and GTS transmission phenomena together in the heterogeneous traffic scenario and under nonsaturated condition. For this purpose, the standard GTS allocation scheme is modified. For each non-identical device, the Markov model is solved and the average service time and the service utilization factor are analyzed in the non-saturated mode. The analysis is validated by simulations using network simulator version 2.33. Also, the model is enhanced with a wireless propagation model and the performance of the MAC is evaluated in a wheelchair body-area sensor network scenario. PMID- 21606043 TI - Complications of endoscopic retrograde cholangiopancreatography (ERCP) and their risk factors. AB - PURPOSE: Determination of the type and frequency of complications developing after diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP) as well as the risk factors predisposing to them. MATERIAL/METHODS: The retrospective study, including 734 ERCP performed in 550 patients, with 404 (55%) ES (endoscopic sphincterotomy) during a 4-year period. RESULTS: Among 734 ERCP procedures, 76.4% (561) had both diagnostic and therapeutic purpose, 15.2% (112) were only diagnostic. Complications developed after 26 procedures (3.5%): acute pancreatitis (AP) in 8 patients (1.09%), cholangitis in 7 (0.95%) and delayed bleeding in 11 (1.5%) patients. After 49 (6.7%) ES immediate bleeding was observed. The risk factors for AP were: unintentional pancreatic duct contrasting, mechanical lithotripsy, the use of the "pre-cut" technique and bile duct dilatation. Cholangitis was more common in cases with difficult cannulation at older age and with lower baseline bilirubin level. The risk factors for delayed bleeding were: location of the ampulla of Vater in the diverticulum and the use of the "precut" technique. Immediate bleeding was more frequent after revision of bile ducts with Dormia's basket or with balloon, after introduction of contrast medium to the pancreatic duct or in ductal cholelithiasis. CONCLUSIONS: ERCP performed in the endoscopy unit of a specialist hospital department is a relatively safe procedure, with a low burden of complications as compared to the benefits it provides to appropriately qualified patients. PMID- 21606044 TI - Ultrastructural changes in lung tissue after acute lead intoxication in the rat. AB - Pulmonary toxicity of lead was studied in rats after an intraperitoneal administration of lead acetate at a dose of 25 mg/kg. Three consecutive days of treatment increased lead content in the whole blood to 2.1 ug/dl and in lung homogenate it attained 9.62 ug/g w.w. versus control values of 0.17 ug/dl and 0.78 ug/g w.w., respectively. At the ultrastructural level, the effects of lead toxicity were observed in lung capillaries, interstitium, epithelial cells and alveolar lining layer. Accumulation of aggregated platelets, leucocytic elements and monocytes was found within capillaries. Interstitium comprised a substantial number of collagen, elastin filaments and lipofibroblasts. Lamellar bodies of type II pneumocytes contained phospolipid lamellae, which stratified into an irregular arrangement. Pulmonary alveoli were filled with macrophages. The extracellular lining layer of lung alveoli was partially destroyed. This study provided evidence that acute lead intoxication affects the whole lung parenchyma and by impairing production of the surfactant might disturb the regular respiratory function. PMID- 21606045 TI - Transmural myocardial ischaemia complicating recovery after dobutamine-atropine stress echocardiography in patients with non-significant coronary artery disease: insights from invasive assessment of coronary physiology. AB - In the proposed selection of cases, traditional imaging is integrated with contemporary diagnostic tools available in the cath-lab to navigate the potential mechanisms underlying a very rare complication occurring in the recovery phase of dobutamine-atropine stress echocardiography. The data, collected in a time frame of nearly 15 years, provide interesting elements to possibly evolve from speculative considerations to plausible confirmation of the candidate pathophysiological mechanism mediating the occurrence of transmural myocardial ischaemia after beta-blockers administration. PMID- 21606046 TI - Echocardiographic assessment of regional left ventricular wall motion abnormalities in patients with tako-tsubo cardiomyopathy: comparison with anterior myocardial infarction. AB - AIMS: The aim of this study was to assess the echocardiographic distribution of regional wall motion abnormalities (RWMA) in patients with tako-tsubo cardiomyopathy (TTC) compared with anterior ST-elevation myocardial infarction (ant-STEMI). METHODS AND RESULTS: Thirty-seven TTC and 37 ant-STEMI patients underwent standard echocardiographic examination at the time of hospital admission. RWMA and the involvement of the left ventricular territories supplied by each coronary artery according to the American Society of Echocardiography classification were reported. TTC patients showed a lower left ventricular ejection fraction (37.6 +/- 5.1 vs. 40.9 +/- 3.7%; P = 0.002) and a higher wall motion score index (WMSI; 1.98 +/- 0.2 vs. 1.51 +/- 0.14; P < 0.001) compared with ant-STEMI patients. No significant differences were observed between groups with regard to detection of RWMA in the territory supplied by the left anterior descending coronary artery (LAD) (37 vs. 37; P = 1). Conversely, in TTC patients, the territories supplied by the LAD/left circumflex coronary artery (LCX) (37 vs. 31; P = 0.011), LAD/right coronary artery (RCA) (34 vs. 13; P < 0.001), RCA (33 vs. 5; P < 0.001), and RCA/LCX (31 vs. 2; P < 0.001) were more frequently involved. A cut-off value of WMSI >=1.75 (area under the curve 0.956) and for the number of territories with RWMA >=4 (AUC = 0.928) predicted TTC with a sensitivity of 83 and 84% and a specificity of 100 and 97%, respectively. CONCLUSION: Echocardiography revealed a distinctive pattern of contractility in TTC patients, characterized by symmetrical RWMA extending equally into the territory of distribution of all coronary arteries. PMID- 21606047 TI - Cognitive hearing science: the legacy of Stuart Gatehouse. AB - Stuart Gatehouse was one of the pioneers of cognitive hearing science. The ease of language understanding (ELU) model (Ronnberg) is one example of a cognitive hearing science model where the interplay between memory systems and signal processing is emphasized. The mismatch notion is central to ELU and concerns how phonological information derived from the signal, matches/mismatches phonological representations in lexical and semantic long-term memory (LTM). When signals match, processing is rapid, automatic and implicit, and lexical activation proceeds smoothly. Given a mismatch, lexical activation fails, and working or short-term memory (WM/STM) is assumed to be invoked to engage in explicit repair strategies to disambiguate what was said in the conversation. In a recent study, negative long-term consequences of mismatch were found by means of relating hearing loss to episodic LTM in a sample of old hearing-aid wearers. STM was intact (Ronnberg et al.). Beneficial short-term consequences of a binary masking noise reduction scheme on STM was obtained in 4-talker babble for individuals with high WM capacity, but not in stationary noise backgrounds (Ng et al.). This suggests that individuals high on WM capacity inhibit semantic auditory distraction in 4-talker babble while exploiting the phonological benefits in terms of speech quality provided by binary masking (Wang). Both long-term and short-term mismatch effects, apparent in data sets including behavioral as well as subjective (Rudner et al.) data, need to be taken into account in the design of future hearing instruments. PMID- 21606049 TI - Ostial left coronary stenosis following aortic root reconstruction with BioGlue. AB - Haemorrhage is a major concern during repair of acute aortic dissection. In such circumstances, glue is often used for tissue reconstruction and also to fortify vascular anastomoses. In this report, we describe a rare case of ostial left main coronary artery stenosis potentially related to previous use of BioGlue. PMID- 21606048 TI - Sudden sensorineural hearing loss: a review of diagnosis, treatment, and prognosis. AB - Sudden sensorineural hearing loss (SSNHL) is commonly encountered in audiologic and otolaryngologic practice. SSNHL is most commonly defined as sensorineural hearing loss of 30 dB or greater over at least three contiguous audiometric frequencies occurring within a 72-hr period. Although the differential for SSNHL is vast, for the majority of patients an etiologic factor is not identified. Treatment for SSNHL of known etiology is directed toward that agent, with poor hearing outcomes characteristic for discoverable etiologies that cause inner ear hair cell loss. Steroid therapy is the current mainstay of treatment of idiopathic SSNHL in the United States. The prognosis for hearing recovery for idiopathic SSNHL is dependent on a number of factors including the severity of hearing loss, age, presence of vertigo, and shape of the audiogram. PMID- 21606050 TI - Right coronary translocation for anomalous origin of right coronary artery from the left coronary sinus. AB - We describe right coronary translocation as a simplified surgical procedure for right coronary artery arising from the left sinus with an intramural course. At surgery, the right coronary artery was transected, distal to the intramural segment and subsequently anastomosed to the ascending aorta above the right coronary sinus. This translocation was performed in four consecutive patients with good early and medium-term results. This technique of right coronary translocation is an alternative strategy to coronary artery bypass or the unroofing technique. PMID- 21606051 TI - Plasma neutrophil gelatinase-associated lipocalin measured in consecutive patients after congenital heart surgery using point-of-care technology. AB - Neutrophil gelatinase-associated lipocalin (NGAL) is an early predictive biomarker of acute kidney injury. Plasma NGAL was measured in 218 consecutive patients aged three days to 21.1 years after admission to the intensive care unit after cardiopulmonary bypass surgery using a commercially available point-of-care test to evaluate its diagnostic value in daily practice. Plasma NGAL was between 60 and 644 ng/ml in all patients [median 134 (interquartile range 94-194) ng/ml]. In 31% of patients, serum creatinine increased more than 50% within three days after surgery, but no patient needed renal replacement therapy. In the early neonatal period, NGAL was positively correlated to baseline serum creatinine (r=0.47; P=0.02). In patients aged more than 10 days, plasma NGAL was correlated to peak serum creatinine in the postoperative course (r=0.21; P=0.003), and to the severity of acute kidney injury (r=0.15; P=0.032). However, NGAL values were substantially scattered. Plasma NGAL levels early after congenital heart surgery are correlated to acute kidney injury, but the severity of kidney injury cannot be deduced from an individual NGAL value. Therefore, the value of one single plasma NGAL measurement performed early after cardiac bypass surgery for congenital heart disease is limited. PMID- 21606052 TI - Bilateral simultaneous inflammatory myofibroblastic tumor of the lung with distant metastatic spread. AB - Inflammatory myofibroblastic tumors (IMT) of the lung are considered rare and benign; however, involvement of adjacent thoracic organs, local recurrence and distant metastases have been described. The potential presence of distant metastases supports the hypothesis that those tumors should not be considered 'clinically' benign, although histological features suggest this attitude; thus, complete resection and careful follow-up are mandatory. We present a case of a bilateral pulmonary IMT with left adrenal gland metastasis in a patient with dyspnea and cough. PMID- 21606053 TI - In patients undergoing lung resection for non-small cell lung cancer, is lymph node dissection or sampling superior? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'In patients undergoing lung resection for non-small cell lung cancer, is lymph node dissection or sampling superior?' Altogether 845 papers were found using the reported search, of which 14 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that in stage I tumours there is little difference in survival when performing either mediastinal lymph node dissection (MLND) or lymph node sampling. However, survival is increased when performing MLND in stage II to IIIa tumours. Increased accuracy in staging is not observed with MLND. However, MLND reliably identifies more positive N2 nodes which may offer advantages in postoperative adjuvant treatment in more advanced disease. PMID- 21606054 TI - Laparoscopic repair of post-esophagectomy diaphragmatic hernias using human acellular dermal matrix. AB - Diaphragmatic hernias occur in up to 2% of patients after esophagectomy with gastric pull-up, and the surgical repair in the setting of a previous esophagectomy is a challenge with high complication rates, in particular with regards to the gastric conduit and its critical vascular supply. We describe two cases and the technique of minimally invasive, laparoscopic repair of diaphragmatic defects with organ herniation after esophagectomy using absorbable human acellular dermal matrix. PMID- 21606055 TI - Assessment of the mode of anger expression in alcohol dependent male inpatients. AB - AIMS: To assess the relationships between trait anger (T-Anger) and anger expression styles and emotional states-suicide probability, depression, state and trait anxiety and self-esteem--in alcohol-dependent inpatients. METHODS: The patients included in this study were 142 male inpatients with alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. The Suicide Probability Scale, the Coopersmith Self-Esteem Inventory, the Beck Depression Inventory, the Beck Hopelessness Scale, the Spielberger State Trait Anxiety Scales, and the T-Anger and Anger Expressions Scales were used for the assessment of the emotional states of the patients. Pearson correlation, analysis of variance and linear regression were used in the statistical analysis. RESULTS: There were significant correlations between suicide probability, depression, state and the trait anxiety, and the T-Anger and all of the anger expression subscales. The presence of high probability for suicide was related to a high level of T-Anger, Anger-out and Anger-in. Finally, a low level of hopelessness was associated with a high level of T-Anger, and a high level of the trait anxiety was associated with a low level of the Anger Control (AEX-Con). CONCLUSION: The findings indicated that suicide probability, hopelessness and trait anxiety predict T-Anger levels and anger expression styles. Therefore, anxiety, hopelessness and suicide probability must be considered as risk for anger and anger expressions in alcohol-dependent patients. Furthermore, alcohol treatment programmes should attach importance to anger management and AEX-Con training. PMID- 21606057 TI - The history of ethical decision making in neonatal intensive care. AB - Neonatal ethics has focused on 2 questions: is withholding potentially live saving treatment from neonates ethically justified? and if so, who has the authority to decide? This article details how these questions developed and provides a description of the possible answers. In the first section, we review a selection of seminal articles by noted authors in the fields of ethics, medicine, and law. The second section provides a detailed account of the development of the Baby Doe Regulations and the impact they had on neonatal ethics, with particular attention to the emergence of the Best Interest Standard as a guideline for decision making. In the last section, we review the landmark position statements by the American Academy of Pediatric (AAP), and the focus on evidence-based decision making. We conclude that forgoing life-saving treatment is ethically justified. However, this requires a rigorous evidence-based process and is limited by the Best Interest Standard. The second question is more difficult to answer, but we feel that in light of legal limitations, physicians acting as both the infant advocate and a proxy for the state, decide what falls in the range of acceptable treatment options, with the parents free to choose within that range. PMID- 21606056 TI - Angiosperm ovules: diversity, development, evolution. AB - BACKGROUND: Ovules as developmental precursors of seeds are organs of central importance in angiosperm flowers and can be traced back in evolution to the earliest seed plants. Angiosperm ovules are diverse in their position in the ovary, nucellus thickness, number and thickness of integuments, degree and direction of curvature, and histological differentiations. There is a large body of literature on this diversity, and various views on its evolution have been proposed over the course of time. Most recently evo-devo studies have been concentrated on molecular developmental genetics in ovules of model plants. SCOPE: The present review provides a synthetic treatment of several aspects of the sporophytic part of ovule diversity, development and evolution, based on extensive research on the vast original literature and on experience from my own comparative studies in a broad range of angiosperm clades. CONCLUSIONS: In angiosperms the presence of an outer integument appears to be instrumental for ovule curvature, as indicated from studies on ovule diversity through the major clades of angiosperms, molecular developmental genetics in model species, abnormal ovules in a broad range of angiosperms, and comparison with gymnosperms with curved ovules. Lobation of integuments is not an atavism indicating evolution from telomes, but simply a morphogenetic constraint from the necessity of closure of the micropyle. Ovule shape is partly dependent on locule architecture, which is especially indicated by the occurrence of orthotropous ovules. Some ovule features are even more conservative than earlier assumed and thus of special interest in angiosperm macrosystematics. PMID- 21606058 TI - Clinical outcomes of linezolid vs vancomycin in methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia: retrospective analysis. AB - BACKGROUND: Vancomycin has been the treatment standard for methicillin-resistant Staphylococcus aureus (MRSA) infections, but clinical efficacy is limited. We report outcomes of a cohort with MRSA ventilator-associated pneumonia (VAP) treated with vancomycin vs linezolid. METHODS: Retrospective analysis of 113 participants with MRSA VAP confirmed by bronchoscopy who have been initiated on therapy with either vancomycin or linezolid within 24 hours after bronchoscopy and completed >=7 days of therapy during their hospitalization from July 2003 to June 2007. The primary endpoints were hospital survival and clinical cure, defined as resolution of signs and symptoms of VAP or microbiological eradication after completion of therapy along with clinical pulmonary infection score (CPIS) <=6 at day 7 of therapy. RESULTS: At hospital discharge, 23/27 (85.2%) of linezolid and 72/86 (83.7%) of vancomycin recipients had survived (P = .672). In comparison to linezolid recipients, the adjusted odds ratio (OR) for survival was 0.72 (95% confidence interval [CI]: 0.16-3.27) with vancomycin therapy. Clinical cure was achieved in 24/27 (88.9%) of linezolid and 63/86 (73.3%) of vancomycin recipients (P = .066). Compared to linezolid recipients, the adjusted OR for clinical cure was 0.24 (95% CI: 0.05-1.10) with vancomycin therapy. Survival and clinical cure did not differ significantly between vancomycin recipients with trough level >=15 and <15 MUg/mL, respectively. CONCLUSIONS: Our results suggested no survival benefit but a trend toward higher cure rate with linezolid therapy. The optimal treatment of MRSA VAP requires further study through randomized, controlled trials. PMID- 21606059 TI - Preliminary evidence for leukocyte transcriptional signatures for pediatric ventilator-associated pneumonia. AB - OBJECTIVE: Ventilator-associated pneumonia (VAP) is a significant contributor to intensive care unit (ICU) morbidity and mortality and presents a significant diagnostic challenge. Our hypothesis was that blood RNA expression profiles can be used to track the response to VAP in children, using the same methods that proved informational in adults. DESIGN: A pilot, nonrandomized, repeated measures case-control study of changes in the abundance of total RNA in buffy coat and clinical scores for VAP. SETTING: A large, multispecialty university-based pediatric ICU and cardiac ICU. PATIENTS: Seven children requiring intubation and mechanical ventilation. INTERVENTIONS: Blood samples were drawn at time of enrollment and every 48 hours for a maximum of 11 samples (21 days). Patients ranged in age from 1 to 18 months (mean 8 months). All patients survived to the end of the study. Of the 7 patients studied, 4 developed VAP. MEASUREMENTS AND MAIN RESULTS: Statistical analysis of the Affymetrix Human Genome Focus GeneChip signal was conducted on normalized expression values of 8793 probe sets using analysis of variance (ANOVA) with a false discovery rate of 0.10. The expression patterns of 48 genes appeared to discriminate between the 2 classes of ventilated children: those with and those without pneumonia. Gene expression network analysis revealed several gene ontologies of interest, including cell proliferation, differentiation, growth, and apoptosis, as well as genes not previously implicated in sepsis. CONCLUSIONS: These preliminary data are the first in critically ill children supporting the hypothesis that there is a detectable VAP signal in gene expression profiles. Larger studies are needed to validate these preliminary findings and test the diagnostic value of longitudinal changes in leukocyte RNA signatures. PMID- 21606060 TI - Diagnosis and management of life-threatening pulmonary embolism. AB - Pulmonary embolus (PE) is estimated to cause 200 000 to 300 000 deaths annually. Many deaths occur in hemodynamically unstable patients and the estimated mortality for inpatients with hemodynamic instability is between 15% and 25%. The diagnosis of PE in the critically ill is often challenging because the presentation is nonspecific. Computed tomographic pulmonary angiography appears to be the most useful study for diagnosis of PE in the critically ill. For patients with renal insufficiency and contrast allergy, the ventilation perfusion scan provides an alternative. For patients too unstable to travel, echocardiography (especially transesophageal echocardiography) is another option. A positive result on lower extremity Doppler ultrasound can also aid in the decision to treat. The choice of treatment in PE depends on the estimated risk of poor outcome. The presence of hypotension is the most significant predictor of poor outcome and defines those with massive PE. Normotensive patients with evidence of right ventricular (RV) dysfunction, as assessed by echocardiography, comprise the sub-massive category and are at intermediate risk of poor outcomes. Clinically, those with sub-massive PE are difficult to distinguish from those with low-risk PE. Cardiac troponin, brain natriuretic peptide, and computed tomographic pulmonary angiography can raise the suspicion that a patient has sub massive PE, but the echocardiogram remains the primary means of identifying RV dysfunction. The initial therapy for patients with PE is anticoagulation. Use of vasopressors, inotropes, pulmonary artery (PA) vasodilators and mechanical ventilation can stabilize critically ill patients. The recommended definitive treatment for patients with massive PE is thrombolysis (in addition to anticoagulation). In massive PE, thrombolytics reduce the risk of recurrent PE, cause rapid improvement in hemodynamics, and probably reduce mortality compared with anticoagulation alone. For patients with a contraindication to anticoagulation and thrombolytic therapy, surgical embolectomy and catheter-based therapies are options. Thrombolytic therapy in sub-massive PE results in improved pulmonary perfusion, reduced PA pressures, and a less complicated hospital course. No survival benefit has been documented, however. If one is considering the use of thrombolytic therapy in sub-massive PE, the limited documented benefit must be weighed against the increased risk of life-threatening hemorrhage. The role of surgical embolectomy and catheter-based therapies in this population is unclear. Evidence suggests that sub-massive PE is a heterogeneous group with respect to risk. It is possible that those at highest risk may benefit from thrombolysis, but existing studies do not identify subgroups within the sub massive category. The role of inferior vena cava (IVC) filters, catheter-based interventions, and surgical embolectomy in life-threatening PE has yet to be completely defined. PMID- 21606061 TI - Sperm proteasome and fertilization. AB - The omnipresent ubiquitin-proteasome system (UPS) is an ATP-dependent enzymatic machinery that targets substrate proteins for degradation by the 26S proteasome by tagging them with an isopeptide chain composed of covalently linked molecules of ubiquitin, a small chaperone protein. The current knowledge of UPS involvement in the process of sperm penetration through vitelline coat (VC) during human and animal fertilization is reviewed in this study, with attention also being given to sperm capacitation and acrosome reaction/exocytosis. In ascidians, spermatozoa release ubiquitin-activating and conjugating enzymes, proteasomes, and unconjugated ubiquitin to first ubiquitinate and then degrade the sperm receptor on the VC; in echinoderms and mammals, the VC (zona pellucida/ZP in mammals) is ubiquitinated during oogenesis and the sperm receptor degraded during fertilization. Various proteasomal subunits and associated enzymes have been detected in spermatozoa and localized to sperm acrosome and other sperm structures. By using specific fluorometric substrates, proteasome-specific proteolytic and deubiquitinating activities can be measured in live, intact spermatozoa and in sperm protein extracts. The requirement of proteasomal proteolysis during fertilization has been documented by the application of various proteasome-specific inhibitors and antibodies. A similar effect was achieved by depletion of sperm-surface ATP. Degradation of VC/ZP-associated sperm receptor proteins by sperm-borne proteasomes has been demonstrated in ascidians and sea urchins. On the applied side, polyspermy has been ameliorated by modulating sperm-associated deubiquitinating enzymes. Diagnostic and therapeutic applications could emerge in human reproductive medicine. Altogether, the studies on sperm proteasome indicate that animal fertilization is controlled in part by a unique, gamete associated, extracellular UPS. PMID- 21606062 TI - Asymptomatic adults with isolated, unilateral right pulmonary vein atresia: multidetector CT findings. AB - We report two cases of a very rare congenital anomaly, i.e. isolated unilateral pulmonary vein atresia. The patients were asymptomatic and the diagnosis was made using multidetector CT (MDCT), which also showed cyst formation in the right lung. Asymptomatic adult cases or association with cystic lung lesions have never been reported in this condition before. PMID- 21606063 TI - MRI of a microcystic adnexal carcinoma of the skin mimicking a fibrous tumour: case report and literature review. AB - Microcystic adnexal carcinoma of the skin is a very rare malignant tumour arising from the sweat glands. As far as we know, the MRI features of this tumour have not been described in the literature before. In this report we present the MRI features and pathological description of a case of a microcystic adnexal carcinoma in the cheek that was incidentally imaged during brain MRI examination. A review of the relevant literature as well as a discussion of MRI of skin tumours is also presented. PMID- 21606064 TI - Post-traumatic rapidly enlarging mucinous carcinoma of the breast with intratumoural haemorrhage: MRI appearances with pathological correlation. AB - Pure mucinous carcinoma of the breast is a histological type of invasive carcinoma and generally shows a slow growth pattern. Rapid growth and intratumoural haemorrhage are rare and there have been no reports presenting such a clinical course and associated radiographic findings. We report a case with atypical rapidly enlarging mucinous carcinoma of the breast after trauma, in which MRI closely reflected the histopathological background and was thought to be useful for differential diagnosis from other highly malignant breast tumours. PMID- 21606065 TI - Intrascrotal extratesticular epidermoid cyst. AB - Epidermoid cysts are rare tumours, which account for 1% of all testicular tumours. Very rarely, they are intrascrotal but extratesticular. We present a rare case of an intrascrotal extratesticular cyst. The triad of findings were sonographic appearance of an onion ring, avascularity on Doppler sonography and negative results of tumour markers; these are highly suggestive of an epidermoid cyst. PMID- 21606066 TI - Cauda equina syndrome and dural ectasia: rare manifestations in chronic ankylosing spondylitis. AB - Cauda equina syndrome (CES) is a rare manifestation in patients with long standing ankylosing spondylitis (AS). We report a 57-year-old male patient with a 30-year history of AS who developed CES in the past 4 years. The CT and MRI examinations showed unique appearances of dural ectasia, multiple dorsal dural diverticula, erosion of the vertebral posterior elements, tethering of the conus medullaris to the dorsal aspect of the spinal canal and adhesion of the nerve roots of the cauda equina to the wall of the dural sac. A large dural defect was found at surgery. De-adhesion of the tethered conus medullaris was performed but without significant clinical improvement. The possible aetiologies of CES and dural ectasia in patients with chronic AS are discussed and the literature is reviewed. PMID- 21606067 TI - Facial wrigglies: live extralymphatic filarial infestation in subcutaneous tissues of the head and neck. AB - We report a rare case of a 32-year-old male with live extralymphatic filarial infestation presenting as a facial subcutaneous soft-tissue swelling. To the best of our knowledge these imaging findings have not been previously reported in the head and neck region in the existing English language literature. Real-time high resolution ultrasonography revealed a solitary well-defined subcutaneous cystic lesion over the right zygomatic arch. It showed multiple linear, echogenic, undulating structures exhibiting a persistent twirling motion during the examination. This typical ultrasonographic appearance was consistent with the filarial dance sign (FDS) of live adult filarial worms. Subsequent MRI confirmed the cystic and solitary nature of the lesion. Complete excision of the cyst was performed, which revealed intracystic straw-coloured fluid and multiple white coloured adult worms within the lesion. Histopathological examination confirmed multiple adult filarial worms with surrounding reactive inflammatory changes. In an endemic region, identification of the FDS in any normal anatomical structure or abnormal swelling, however remote or unusual the location within the body, should strongly suggest the diagnosis of live active filarial infestation. In view of the increasing migratory trends in the global population, it is imperative for radiologists in all countries to be aware of the typical imaging findings of this disease to arrive at the correct diagnosis. PMID- 21606068 TI - The physical basis and future of radiation therapy. AB - The remarkable progress in radiation therapy over the last century has been largely due to our ability to more effectively focus and deliver radiation to the tumour target volume. Physics discoveries and technology inventions have been an important driving force behind this progress. However, there is still plenty of room left for future improvements through physics, for example image guidance and four-dimensional motion management and particle therapy, as well as increased efficiency of more compact and cheaper technologies. Bigger challenges lie ahead of physicists in radiation therapy beyond the dose localisation problem, for example in the areas of biological target definition, improved modelling for normal tissues and tumours, advanced multicriteria and robust optimisation, and continuous incorporation of advanced technologies such as molecular imaging. The success of physics in radiation therapy has been based on the continued "fuelling" of the field with new discoveries and inventions from physics research. A key to the success has been the application of the rigorous scientific method. In spite of the importance of physics research for radiation therapy, too few physicists are currently involved in cutting-edge research. The increased emphasis on more "professionalism" in medical physics will tip the situation even more off balance. To prevent this from happening, we argue that medical physics needs more research positions, and more and better academic programmes. Only with more emphasis on medical physics research will the future of radiation therapy and other physics-related medical specialties look as bright as the past, and medical physics will maintain a status as one of the most exciting fields of applied physics. PMID- 21606069 TI - Quality assurance of RapidArc in clinical practice using portal dosimetry. AB - OBJECTIVE: Quality assurance data from five centres were analysed to assess the reliability of RapidArc radiotherapy delivery in terms of machine and dosimetric performance. METHODS: A large group of patients was treated with RapidArc radiotherapy and treatment data recorded. Machine quality assurance was performed according to Ling et al (Int J Radiat Oncol Biol Phys 2008;72:575-81). In addition, treatment to a typical clinical case was delivered biweekly as a constancy check. Pre-treatment dosimetric validation of plan delivery was performed for each patient. All measurements and computations were performed at the depth of the maximum dose in water according to the GLAaS method using electronic portal imaging device measurements. Evaluation was carried out according to a gamma agreement index (GAI, the percentage of field area passing the test); the threshold dose difference was 3% and the threshold distance to agreement was 3 mm. RESULTS: A total of 275 patients (395 arcs) were included in the study. Mean delivery parameters were 31.0+/-20.0 degrees (collimator angle), 4.7+/-0.5 degrees s(-1) (gantry speed), 343+/-134 MU min(-1) (dose rate) and 1.6+/-1.4 min (beam-on time) for prescription doses ranging from 1.8 to 16.7 Gy/fraction. Mean deviations from the baseline dose rate and gantry speed ranged from -0.61% to 1.75%. Mean deviations from the baseline for leaf speed variation ranged from -0.73% to 0.41%. The mean GAI of repeated clinical fields was 99.2+/ 0.2%. GAI varied from 84.7% to 100%; the mean across all patients was 97.1+/ 2.4%. CONCLUSION: RapidArc can provide a reliable and accurate delivery of radiotherapy for a variety of clinical conditions. PMID- 21606070 TI - Lumbar spine radiography--poor collimation practices after implementation of digital technology. AB - OBJECTIVES: The transition from analogue to digital radiography may have reduced the motivation to perform proper collimation, as digital techniques have made it possible to mask areas irradiated outside the area of diagnostic interest (ADI). We examined the hypothesis that collimation practices have deteriorated since digitalisation. METHODS: After defining the ADI, we compared the proportion of the irradiated field outside the ADI in 86 digital and 86 analogue frontal lumbar spine radiographs using the Mann-Whitney test. 50 digital images and 50 analogue images were from a Norwegian hospital and the remainder from a Danish hospital. Consecutive digital images were compared with analogue images (from the hospitals' archives) produced in the 4 years prior to digitalisation. Both hospitals' standard radiographic procedures remained unchanged during the study. For digital images, the irradiated field was assessed using non-masked raw-data images. RESULTS: The proportion of the irradiated field outside the ADI was larger in digital than in analogue images (mean 61.7% vs 42.4%, p<0.001), and also in a subsample of 39 image pairs that could be matched for patient age (p<0.001). The mean total field size was 46% larger in digital than in analogue images (791 cm(2) vs 541 cm(2)). CONCLUSION: Following the implementation of digital radiography, considerably larger areas were irradiated. This causes unnecessarily high radiation doses to patients. PMID- 21606071 TI - Rapid vision loss in a 15-year-old boy. PMID- 21606072 TI - A patient with acute lymphoblastic leukaemia presenting with an extremely high level (21.0%) of HbA(1c). AB - A 52-year-old Japanese woman was referred to our hospital because of fever and coxalgia. She had a white blood cell count of 241 * 10(2)/MUL with 59.6% blasts, which had a high nuclear/cytoplasmic ratio and variably condensed nuclear chromatin. Flow cytometry and chromosomal analysis of bone marrow cells indicated positive findings of CD10, CD19, CD34, HLA-DR antigens and t(9; 22)(q34; q11.2), respectively. No rearrangements of bcr/abl in peripheral blood neutrophils were found by fluorescence in situ hybridization, suggesting that she had B-acute lymphoblastic leukaemia with Ph chromosome. Blood glucose and HbA(1c) (glycated haemoglobin) levels on admission were 23.4 mmol/L and 21.0%, respectively. The results of 1.5 anhydro-d-glucitol and glycoalbumin tests revealed that she certainly had diabetes mellitus (DM). Insulin therapy was initiated. Her high level of HbA(1c) also suggested the possibility that the patient suffered from haemoglobinopathies in addition to DM. Sequencing analyses of alpha1-, alpha2- and beta-globin genes were all normal. The patient achieved complete remission (CR) by one month after her first course of chemotherapy, and the HbA(1c) level decreased to 10.4% following insulin therapy and chemotherapy, which were initiated when she attained CR. Her extremely high HbA(1c) level was due mainly to DM. Also, suppression of erythropoiesis by proliferation of leukaemic cells and latent iron deficiency might have partially contributed to the increased HbA(1c). This could result in a transient but extremely high HbA(1c) level. To our knowledge, this is the first report of an acute leukaemia patient who expressed an extremely high level of HbA(1c). PMID- 21606073 TI - Transient congenital hypothyroidism due to thyroid-stimulating hormone receptor blocking antibodies: a case series. AB - We describe seven infants with transient congenital hypothyroidism (CH) due to maternal thyroid-stimulating hormone receptor (TSH-R) blocking antibodies (TRAb) identified over three decades of newborn screening for CH in Wales, UK that represents a minimum incidence of 1.6% of CH cases. Infants with transient CH due to maternal TRAb presented with a spectrum of clinical and biochemical hypothyroidism. Blood spot TSH concentrations ranged 60.5-332 mIU/L. CH was confirmed by plasma thyroid function tests in all cases (plasma TSH ranged 21-752 mIU/L). The seven infants belonged to five different families. On examination, four infants were clinically hypothyroid. Five infants had a thyroid ultrasound, of which three were abnormal. All infants were treated with thyroxine, which was subsequently withdrawn from three. Following thyroxine withdrawal, one infant resumed normal thyroid function and two developed compensated hypothyroidism. Of the five mothers, two had undiagnosed hypothyroidism and three were receiving thyroxine for longstanding hypothyroidism. Thyroid peroxidase antibody (aTPO) was measured in four and was negative in two, borderline positive in one and strongly positive in another. TRAb was measured in all five women and was strongly positive in all of them. This case series highlights the importance of identifying CH due to TRAb by investigating both the infant and the mother following a raised TSH found on newborn screening. The identification of those infants with transient CH caused by maternal transfer of TRAb is essential for optimizing management during childhood (including potential withdrawal of thyroxine replacement in the longer term) and in any subsequent pregnancy. PMID- 21606074 TI - First-degree atrioventricular block is associated with heart failure and death in persons with stable coronary artery disease: data from the Heart and Soul Study. AB - AIMS: First-degree atrioventricular block (AVB) has traditionally been considered a benign electrocardiographic finding in healthy individuals. However, the clinical significance of first-degree AVB has not been evaluated in patients with stable coronary heart disease. We investigated whether first-degree AVB is associated with heart failure (HF) and mortality in a prospective cohort study of outpatients with stable coronary artery disease (CAD). METHODS AND RESULTS: We measured the P-R interval in 938 patients with stable CAD and classified them into those with (P-R interval >= 220 ms) and without (P-R interval <220 ms) first degree AVB. Hazard ratios (HRs) and 95% confidence intervals were calculated for HF hospitalization and all-cause mortality. During 5 years of follow-up, there were 123 hospitalizations for HF and 285 deaths. Compared with patients who had normal atrioventricular conduction, those with first-degree AVB were at increased risk for HF hospitalization (age-adjusted HR 2.33: 95% CI 1.49-3.65; P= 0.0002), mortality [age-adjusted HR 1.58; 95% CI (1.13-2.20); P = 0.008], cardiovascular (CV) mortality [age-adjusted HR 2.33; 95% CI (1.28-4.22); P= 0.005], and the combined endpoint of HF hospitalization or CV mortality (age-adjusted HR 2.43: 95% CI 1.64-3.61; P <= 0.0001). These associations persisted after multivariable adjustment for heart rate, medication use, ischaemic burden, and QRS duration. Adjustment for left ventricular systolic and diastolic function partially attenuated the effect, but first-degree AVB remained associated with the combined endpoint of HF or CV death (HR 1.61, CI 1.02-2.54; P= 0.04). CONCLUSION: In a large cohort of patients with stable coronary artery disease, first-degree AVB is associated with HF and death. PMID- 21606075 TI - CC chemokine CCL5 plays a central role impacting infarct size and post-infarction heart failure in mice. AB - AIMS: The chemokine CCL5 plays a critical role as neutrophil and macrophage activator do in atherosclerosis and myocardial infarction. Thus, we investigated whether the treatment with a neutralizing monoclonal antibody (mAb) to mouse CCL5 would provide therapeutic benefit when provoking a coronary-associated ischaemic event. METHODS AND RESULTS: C57Bl/6 mice were submitted to left coronary artery permanent ligature. Then, various parameters were monitored for up to 21 days. At5 min and 3 days after coronary occlusion, mice received one intravenous injection of the rat anti-mouse CCL5 mAb or isotype IgG control. Infarct size was assessed histologically and by measuring serum cardiac troponin I levels. Kinetics of CCL5 tissue expression, leucocyte infiltration, matrix metalloproteinase (MMP) levels, and collagen deposition were histologically assessed. Serum chemokine levels were measured by enzyme-linked immunosorbent assay. Cardiac function and dimensions were assessed by magnetic resonance imaging (MRI). Chronic ischaemia increased both circulating and intracardiac levels of CCL5. At 24 h, treatment with the anti-CCL5 mAb resulted in a smaller infarct size and reduced circulating levels of chemokines. This effect was associated with reduction of neutrophil and macrophage infiltration within the infarcted myocardium. After 3 days of chronic ischaemia, anti-CCL5 mAb treatment reduced cardiac MMP-9. At 7 days, collagen content was significantly lower. At 21 days, neutralizing CCL5 improved mouse survival, cardiac myocyte size, and cardiac function. CONCLUSION: Treatment with anti-CCL5 mAb significantly reduced both infarct size and post-infarction heart failure in a mouse model of chronic cardiac ischaemia. Cardioprotective effects were associated with the reduction of leucocyte recruitment within infarcted hearts. PMID- 21606076 TI - Resistance artery mechanics and composition in angiotensin II-infused mice: effects of cyclooxygenase-1 inhibition. AB - AIMS: The aim of this study was to investigate the role of cyclooxygenase (COX)-1 on vascular alterations in structure, mechanics, and extracellular matrix (ECM) components induced by angiotensin (Ang) II in mesenteric arteries from wild-type (WT) and COX-1 knockout (COX-1(-/-)) mice. METHODS AND RESULTS: Animals were infused with vehicle or Ang II (400 ng/kg/min, s.c.) +/- SC-560 (COX-1 inhibitor), DFU (COX-2 inhibitor), or SQ-29548 (TP receptor antagonist). After 2 weeks, vessels were isolated and exposed to intraluminal pressures (3-140 mmHg, pressurized myograph) to determine mechanical properties. Angiotensin II-induced vascular hypertrophic remodelling in WT was reversed by SC-560 or SQ-29548, but unaffected by DFU. Angiotensin II increased vessel stiffness (P< 0.01), this effect being ameliorated by SC-560 or SQ-29548, but unmodified by DFU. Angiotensin II failed to modify vessel elasticity in COX-1(-/-) mice. In WT vessels, Ang II enhanced COX-1 immunostaining, induced collagen and fibronectin depositions and decreased elastin content (P< 0.01). These effects were reversed by SC-560 or SQ-29548, but unaffected by DFU. In COX-1(-/-) mice, Ang II did not affect ECM contents. In WT, Ang II increased COX-1 and decreased COX-2 expression, and enhanced the vascular release of 6-keto-PGF1alpha which was prevented by COX-1 blockade. Human coronary artery smooth muscle cells, incubated with Ang II, showed an increased expression of procollagen I, which was abrogated by SC-560 or SQ-29548. CONCLUSION: Angiotensin II-induced alterations of resistance arteries in structure, mechanics, and ECM composition were prevented by COX-1 inhibition and TP receptor antagonism, indicating that Ang II-mediated vascular damage is mediated by COX-1-derived prostanoid prostacyclin, activating TP receptors. PMID- 21606077 TI - Prolonged overcirculation-induced pulmonary arterial hypertension as a cause of right ventricular failure. AB - AIMS: Three-month chronic systemic-to-pulmonary shunting in growing piglets has been reported as an early pulmonary arterial hypertension (PAH) model with preserved right ventricular (RV) function. We sought to determine whether prolonged shunting might be associated with more severe PAH and RV failure. METHODS AND RESULTS: Fourteen growing piglets were randomized to a sham operation or the anastomosis of the left innominate artery to the pulmonary arterial trunk. Six months later, the shunt was closed and the animals underwent haemodynamic evaluation followed by tissue sampling for pathobiological assessment. Prolonged shunting had resulted in increased mean pulmonary artery pressure (22 +/- 2 versus 17 +/- 1 mmHg) and pulmonary arteriolar medial thickness, while cardiac output was decreased. However, RV-arterial coupling was markedly deteriorated, with a ~50% decrease in the ratio of end-systolic to pulmonary arterial elastances (Ees/Ea). Lung tissue expressions of endothelin-1, angiopoietin-1, and bone morphogenetic protein receptor-2 were similarly altered compared with previously observed after 3-month shunting. At the RV tissue level, pro-apoptotic ratio of Bax-to-Bcl-2 expressions and caspase-3 activation were increased, along with an increase in cardiomyocyte size, while expressions in voltage-gated potassium channels (Kv1.5 and Kv2.1) and angiogenic factors (angiopoietin-2 and vascular endothelial growth factor) were decreased. Right ventricular expressions of pro-inflammatory cytokines [interleukin (IL)-1alpha, IL-1beta, tumour necrosis factor-alpha (TNF-alpha)] and natriuretic peptide precursors (NPPA and NPPB) were increased. There was an inverse correlation between RV Ees/Ea and pro-apoptotic Bax/Bcl-2 ratios. CONCLUSIONS: Prolonged left-to-right shunting in piglets does not further aggravate pulmonary vasculopathy, but is a cause of RV failure, which appears related to an activation of apoptosis and inflammation. PMID- 21606078 TI - Successful 'quadrangular' pacing in a non-responder patient to cardiac resynchronization therapy. PMID- 21606079 TI - Associations of plasma renin with 10-year cardiovascular mortality, sudden cardiac death, and death due to heart failure. AB - AIMS: Renin is the key regulator of the renin-angiotensin-aldosterone system. Previous studies have reported conflicting results on the relation of plasma renin with fatal cardiovascular events. This study in a large cohort of patients sought to evaluate the association between plasma renin concentration (PRC) and cardiovascular mortality after long-term follow-up of almost 10 years. METHODS AND RESULTS: Plasma renin concentration [median: 11.4 (6.0-24.6) pg/mL] was measured in 3303 patients (mean age: 62.7 +/- 10.6 years; 30.3% women) referred to coronary angiography. After a median follow-up of 9.9 years, 554 participants (16.8%) with PRC measurement at baseline had died due to fatal cardiovascular events. Multivariable-adjusted Cox analysis revealed that when compared with participants in the lowest PRC quartile, those in the highest quartile were at increased risk of cardiovascular mortality (hazard ratio: 1.79, 95% CI 1.28 2.48). Analyses of specific causes of cardiovascular death showed that for each standard deviation increase in log-PRC there was a 22% (P = 0.006) increase in risk of sudden cardiac death and a 23% (P = 0.033) greater risk of death due to heart failure. The association of PRC with cardiovascular mortality remained stable after adjustment for established cardiovascular risk factors, ongoing antihypertensive medication, immunoreactive angiotensin II, and aldosterone levels. Age, N-terminal pro-B-type natriuretic peptide levels, coronary artery disease, the use of angiotensin-converting enzyme-inhibitors, beta-blockers, diuretics, and kidney function were important effect modifiers. CONCLUSIONS: Plasma renin concentration is associated with long-term cardiovascular mortality in patients referred to coronary angiography. Further intervention studies should determine whether renin is a potential therapeutic target or only a marker of mortality risk in various cardiovascular risk groups. PMID- 21606080 TI - Percutaneous edge-to-edge MitraClip therapy in the management of mitral regurgitation. AB - MitraClip therapy consists of percutaneous edge-to-edge coaptation of the mitral leaflets that is analogous to the surgical Alfieri technique. The safety profile of the MitraClip device is favourable, and survival outcomes in high-surgical risk patients are superior to historical controls. However, questions remain regarding long-term efficacy and durability. In the U.S.A., the MitraClip device has been studied in a safety and feasibility trial, a randomized pivotal trial against surgical mitral valve repair, and a non-randomized high-risk registry. In addition, the MitraClip now has over 2 years of CE-mark approval and a rapidly expanding clinical experience in Europe, primarily in patients at high risk for surgery. A dedicated multidisciplinary team is necessary, as well as thoughtful patient selection, familiarity with the technical aspects of the procedure including transesophageal ultrasound imaging and post-procedure monitoring. Currently available clinical data are herein reviewed, with emphasis on the current role of MitraClip therapy in relation to existing surgical techniques. Since the MitraClip procedure is still relatively new, continued investigation is required to further define patient populations that will benefit most. PMID- 21606081 TI - In a pinch. PMID- 21606082 TI - Synergistic effect of liver X receptor activation and simvastatin on plaque regression and stabilization: an magnetic resonance imaging study in a model of advanced atherosclerosis. AB - AIMS: The aim of this study was to investigate the effects of liver X receptors (LXRs)-beta preferential activation by LXR-623 (WAY-252623), a novel LXRs agonist, on plaque progression/regression in a rabbit model of advanced atherosclerosis. METHODS AND RESULTS: Advanced atherosclerosis was induced in New Zealand White Rabbits (n= 41). At the end of atherosclerosis induction, animals underwent a baseline magnetic resonance imaging (MRI) and were randomized to receive LXR-623 (1.5, 5, or 15 mg/kg/day), simvastatin (5 mg/kg/day), or placebo. The combination of LXR-1.5/simvastatin was also tested. After a final MRI, animals were euthanized and their aortas processed for further analysis. Simvastatin significantly reduced lesion progression (-25%; P< 0.01) in comparison with the placebo group. A similar effect was observed in the LXR-1.5 and -5 groups. A significant regression (16.5%; P< 0.01) of existing atherosclerosis was observed in the LXR-1.5/simvastatin group. Histological and molecular analysis showed plaque stabilization in the animals treated with the LXR-1.5 and -5, and LXR-1.5/simvastatin. The effects of LXR-623 were observed in the presence of a non-significant effect on total-cholesterol, low-density lipoproteins-cholesterol, and triglyceride levels. CONCLUSION: The results of the present study show that LXR-623 significantly reduces the progression of atherosclerosis and induces plaque regression in combination with simvastatin. These observations could drive future development of novel anti-atherosclerotic therapeutic approaches. PMID- 21606083 TI - Iron deficiency is associated with adverse outcome in Eisenmenger patients. AB - AIMS: Iron deficiency is common in patients with Eisenmenger syndrome (ES). This study aimed at evaluating (i) whether iron deficiency is related with adverse outcome, (ii) the determinants of iron deficiency, and (iii) the relation between iron reserves and haemoglobin level in a contemporary cohort of ES patients. METHODS AND RESULTS: All ES patients, older than 18 years, selected from the Belgian Eisenmenger registry, were prospectively followed using a web-based registry. Univariate Cox-regression analysis was performed to evaluate the relation with outcome, defined as all-cause mortality, transplantation, and hospitalisation due to cardiopulmonary causes. Bivariate analysis was performed where applicable. A total of 68 patients with a complete dataset (mean age 36.9 +/- 14.2 years; 30.9% male) were included. During a median follow-up time of 3.1 years, 21 patients (30.9%) reached the predefined endpoint. New York Heart Association (NYHA) class >= III (HR 4.76; 95% CI 1.84-12.30; P = 0.001), iron deficiency (HR 5.29; 95% CI 2.04-13.76; P = 0.001), mean corpuscular volume (MCV) (HR 0.94; 95% CI 0.90-0.99; P = 0.021), and mean corpuscular haemoglobin (MCH) (HR 0.87; 95% CI 0.76-0.98; P = 0.027) were related with adverse outcome. The use of oral anticoagulation and frequent phlebotomies were independently related with iron deficiency (P = 0.005 and P = 0.008). In iron-deplete patients, MCV (R = 0.408; P= 0.014) and MCH (R = -0.437; P = 0.026) were inversely related with haematocrit. In patients with low oxygen saturation, iron reserves were related with haemoglobin levels (R = 0.587; P = 0.001). CONCLUSIONS: Iron deficiency was associated with a higher risk of adverse outcome. Moreover, the use of oral anticoagulation OAC and frequent phlebotomies were related to iron deficiency. Patients under anticoagulation should be monitored rigorously for iron deficiency. However, in patients with low oxygen saturations, careful iron substitution to avoid too high haemoglobin levels is suggested. PMID- 21606084 TI - Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial. AB - AIMS: On the basis of the current knowledge, cardiac resynchronization therapy (CRT) cannot be recommended as a first-line treatment for patients with severely symptomatic permanent atrial fibrillation undergoing atrioventricular (AV) junction ablation. We examined whether CRT was superior to conventional right ventricular (RV) pacing in reducing heart failure (HF) events. METHODS AND RESULTS: In this prospective, multi-centre study, we randomly assigned 186 patients, in whom AV junction ablation and CRT device implantation had been successfully performed, to receive optimized echo-guided CRT (97 patients) or RV apical pacing (89 patients). The data were analysed according to the intention-to treat principle. During a median follow-up of 20 months (interquartile range 11 24), the primary composite endpoint of death from HF, hospitalization due to HF, or worsening HF occurred in 11 (11%) patients in the CRT group and 23 (26%) patients in the RV group [CRT vs. RV group: sub-hazard ratio (SHR) 0.37 ( 95% CI 0.18-0.73), P = 0.005]. In the CRT group, compared with the RV group, fewer patients had worsening HF [SHR 0.27 (95% CI 0.12-0.58), P = 0.001] and hospitalizations for HF [SHR 0.20 (95% CI 0.06-0.72), P = 0.013]. Total mortality was similar in both groups [hazard ratio (HR) 1.57 (95% CI 0.58-4.27), P = 0.372]. The beneficial effects of CRT were consistent in patients who had ejection fraction <=35%, New York Heart Association Class >=III and QRS width >=120 and in those who did not. At multi-variable Cox regression, only CRT mode remained an independent predictor of absence of clinical failure during the follow-up [HR = 0.23 (95% CI 0.08-0.66), P = 0.007]. CONCLUSIONS: In patients undergoing 'Ablate and Pace' therapy for severely symptomatic permanent atrial fibrillation, CRT is superior to RV apical pacing in reducing the clinical manifestations of HF. (ClinicalTrials.gov number: NCT00111527). PMID- 21606085 TI - Predictive utility of the Framingham general cardiovascular disease risk profile for cognitive function: evidence from the Whitehall II study. AB - Aims Vascular risk factors are associated with cognitive impairment and dementia, although most of the research in this domain focuses on cerebrovascular factors. We examined the relationship between the recently developed Framingham general cardiovascular risk profile and cognitive function and 10-year decline in late midlife. Methods and results Study sample comprised of 3486 men and 1341 women, mean age 55 years [standard deviation (SD)=6], from the Whitehall II study, a longitudinal British cohort study. The Framingham General Cardiovascular Risk profile, assessed between 1997 and 1999, included age, sex, HDL cholesterol, total cholesterol, systolic blood pressure, smoking status, and diabetes status. Measures of cognitive function consisted of tests of reasoning (Alice Heim 4-I), memory, phonemic and semantic fluency, and vocabulary (Mill-Hill), assessed three times (1997-1999, 2002-2004, 2007-2009) over 10 years. In cross-sectional age adjusted models, 10% point increments in cardiovascular risk were associated with poor performance in all cognitive domains in both men and women (all P-values <0.001). In models adjusted for age, ethnicity, marital status, and education, 10% higher cardiovascular risk was associated with greater overall 10-year cognitive decline in men, reasoning in particular (-0.47; 95% CI: -0.81, -0.11). Conclusion In middle-aged individuals free of cardiovascular disease, an adverse cardiovascular risk profile is associated with poor cognitive function, and decline in at least one cognitive domain in men. PMID- 21606086 TI - Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury. AB - AIMS: Mesenchymal stem cells (MSCs) can ameliorate myocardial infarction (MI) injury. However, older-donor MSCs seem less efficacious than those from younger donors, and the contributing underlying mechanisms remain unknown. Here, we determine how age-related expression of pigment epithelium-derived factor (PEDF) affects MSC therapeutic efficacy for MI. METHODS AND RESULTS: Reverse transcriptase-polymerized chain reaction and enzyme-linked immunosorbent assay analyses revealed dramatically increased PEDF expression in MSCs from old mice compared to young mice. Morphological and functional experiments demonstrated significantly impaired old MSC therapeutic efficacy compared with young MSCs in treatment of mice subjected to MI. Immunofluorescent staining demonstrated that administration of old MSCs compared with young MSCs resulted in an infarct region containing fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts. Pigment epithelium-derived factor overexpression in young MSCs impaired the beneficial effects against MI injury, and induced cellular profile changes in the infarct region similar to administration of old MSCs. Knocking down PEDF expression in old MSCs improved MSC therapeutic efficacy, and induced a cellular profile similar to young MSCs administration. Studies in vitro showed that PEDF secreted by MSCs regulated the proliferation and migration of cardiac fibroblasts. CONCLUSIONS: This is the first evidence that paracrine factor PEDF plays critical role in the regulatory effects of MSCs against MI injury. Furthermore, the impaired therapeutic ability of aged MSCs is predominantly caused by increased PEDF secretion. These findings indicate PEDF as a promising novel genetic modification target for improving aged MSC therapeutic efficacy. PMID- 21606087 TI - Burden of atherosclerosis improves the prediction of coronary heart disease but not cerebrovascular events: the Rotterdam Study. AB - AIMS: Since atherosclerosis is a systemic process, risk prediction would benefit from targeting multiple components of cardiovascular disease simultaneously. To this end, it is useful to examine the predictive value of non-invasive measures of atherosclerosis in various vascular beds for both coronary heart disease (CHD) and cerebrovascular disease. METHODS AND RESULTS: Between September 2003 and February 2006, 2153 asymptomatic participants (69.6+/-6.6 years) from the Rotterdam Study underwent a multi-detector computed tomography scan. During a median follow-up of 3.5 years, 58 CHD events (myocardial infarction and CHD death) and 52 cerebrovascular events (TIA and stroke) occurred. Participants were classified into low (<5%), intermediate (5-10%), and high (>10%) 5-year risk categories based on a refitted Framingham risk model. The model was extended by coronary, aortic arch, or carotid calcium and reclassification percentages were calculated. For the outcome CHD, the C-statistic improved from 0.693 for the Framingham refitted model to 0.743, 0.740, and 0.749 by addition of coronary, aortic arch, and carotid calcium, respectively. Reclassification was most substantial in the intermediate risk group where addition of coronary calcium reclassified 56% of persons [net reclassification improvement (NRI): 15%; P<0.01)]. Adding aortic arch calcium led to a reclassification of 32% of persons (NRI: 8%; P=0.01) and adding carotid calcium reclassified 51% (NRI: 9%; P=0.02). In contrast, calcification in any of the three vascular beds did not improve cerebrovascular risk prediction. CONCLUSION: Coronary, aortic arch, and carotid artery calcification significantly improved risk prediction of CHD but not of cerebrovascular events. PMID- 21606088 TI - In vitro and in vivo evidence for the role of elastase shedding of CD163 in human atherothrombosis. AB - AIMS: CD163 is a macrophage receptor for haemoglobin-haptoglobin (Hb-Hp) complexes, responsible for the clearance of haemoglobin. We hypothesized that production of soluble CD163 (sCD163) may be due to proleolytic shedding of membrane CD163 by neutrophil elastase, reported to be increased in culprit atherosclerotic plaques. We analysed the relationship between CD163 solubilization and elastase in vitro, in macrophage culture, ex vivo in human atherosclerotic plaque samples, and in vivo, in plasma of patients with coronary artery disease. METHODS AND RESULTS: Neutrophil elastase was shown to enhance CD163 shedding and to decrease the uptake of Hb-Hp complexes by cultured macrophages. In addition, cultured carotid endarterectomy samples showing features of intraplaque haemorrhage released more sCD163 and elastase/alpha1 antitrypsin (alpha1-AT) complexes than non-haemorrhagic plaques (n= 44). Plasma levels of sCD163 and neutrophil elastase (complexed with alpha1-AT) were measured in patients with an acute coronary syndrome (ACS, n= 42), stable angina pectoris (SAP, n= 28), or normal coronary angiograms without subclinical atherosclerosis (n= 21). Acute coronary syndrome patients had higher sCD163 and elastase/alpha1 AT complexes plasma concentrations than subjects without coronary atherosclerosis. Circulating sCD163 and elastase/alpha1-AT complexes were positively correlated in patients with ACS (r = 0.56, P< 0.0002) and SAP (r = 0.62, P< 0.0005). CONCLUSION: Our results suggest that neutrophil elastase promotes CD163 shedding, resulting in a decreased clearance of Hb by macrophages, which may favour plaque destabilization. This may be reflected by increased plasma levels of sCD163 and elastase/alpha1-AT complexes which are positively correlated in patients with coronary artery disease. PMID- 21606089 TI - Effects of social networks on the quality of life in an elder and middle-aged deaf community sample. AB - This article endeavors to investigate the role of social networks in contributing to the quality of life of an elder and middle-aged Deaf population. In particular, it poses the question of whether a certain network composition (deaf and hearing network persons) provides positive resources to improve quality of life and attempts to identify moderating and mediating connections between social networks and quality of life. Based on the data collected in a survey of 107 members of the Deaf community aged 45-81 years, it was possible to ascertain the fact that a larger social network is significantly associated with a higher quality of life, but the size of the deaf network is principally decisive. The hypothesis that a bicultural network composition would have a particular positive effect on the quality of life could not be confirmed. Findings revealed that the effect of deaf network size on the quality of life is mediated by personal resources concerning self-efficacy and communication skills. Moreover, evidence was sound for the functional equivalence of social and personal resources, which suggests that potential negative effects of reduced personal resources on the quality of life could possibly be compensated by a larger deaf network and vice versa. PMID- 21606090 TI - The "top 5" lists in primary care: meeting the responsibility of professionalism. AB - BACKGROUND: Physicians can adhere to the principles of professionalism by practicing high-quality, evidence-based care and advocating for just and cost effective distribution of finite clinical resources. To promote these principles, the National Physicians Alliance (NPA) initiated a project titled "Promoting Good Stewardship in Clinical Practice" that aimed to develop a list of the top 5 activities in family medicine, internal medicine, and pediatrics where the quality of care could be improved. METHODS: Working groups of NPA members in each of the 3 primary care specialties agreed that an ideal activity would be one that was common in primary care practice, that was strongly supported by the evidence, and that would lead to significant health benefits and reduce risks, harms, and costs. A modification of nominal group process was used to generate a preliminary list of activities. A first round of field testing was conducted with 83 primary care physicians, and a second round of field testing with an additional 172 physicians. RESULTS: The first round of field testing resulted in 1 activity being deleted from the family medicine list. Support for the remaining activities was strong. The second round of field testing showed strong support for all activities. The family medicine and internal medicine groups independently selected 3 activities that were the same, so the final lists reflect 12 unique activities that could improve clinical care. CONCLUSIONS: Physician panels in the primary care specialties of family medicine, internal medicine, and pediatrics identified common clinical activities that could lead to higher quality care and better use of finite clinical resources. Field testing showed support among physicians for the evidence supporting the activities, the potential positive impact on medical care quality and cost, and the ease with which the activities could be performed. We recommend that these "Top 5" lists of activities be implemented in primary care practice across the United States. PMID- 21606091 TI - Copy/paste documentation of lifestyle counseling and glycemic control in patients with diabetes: true to form? PMID- 21606092 TI - Pseudodisease, the next great epidemic in coronary atherosclerosis?: comment on "Impact of coronary computed tomographic angiography results on patient and physician behavior in a low-risk population". PMID- 21606093 TI - Impact of coronary computed tomographic angiography results on patient and physician behavior in a low-risk population. AB - BACKGROUND: The impact of screening coronary computed tomographic angiography (CCTA) on physician and patient behavior is unclear. METHODS: We studied asymptomatic patients from a health-screening program. Our study population comprised 1000 patients who underwent CCTA as part of a prior study and a matched control group of 1000 patients who did not. We assessed medication use, secondary test referrals, revascularizations, and cardiovascular events at 90 days and 18 months. RESULTS: A total of 215 patients in the CCTA group had coronary atherosclerosis (CCTA positive). Medication use was increased in the CCTA positive group compared with both the CCTA-negative (no atherosclerosis) and control groups at 90 days (statin use, 34% vs 5% vs 8%, respectively; aspirin use, 40% vs 5% vs 8%, respectively), and 18 months (statin use, 20% vs 3% vs 6%, respectively; aspirin use, 26% vs 3% vs 6%, respectively). After multivariable risk adjustment, the odds ratios for statin and aspirin use in the CCTA-positive group at 18 months were 3.3 (95% confidence interval [CI], 1.3-8.3) and 4.2 (95% CI, 1.8-9.6), respectively. At 90 days, in the total CCTA group vs controls, there were more secondary tests (55 [5%] vs 22 [2%]; P < .001) and revascularizations (13 [1%] vs 1 [0.1%]; P < .001). One cardiovascular event occurred in each group over 18 months. CONCLUSIONS: An abnormal screening CCTA result was predictive of increased aspirin and statin use at 90 days and 18 months, although medication use lessened over time. Screening CCTA was associated with increased invasive testing, without any difference in events at 18 months. Screening CCTA should not be considered a justifiable test at this time. PMID- 21606094 TI - Colorectal cancer screening among ethnically diverse, low-income patients: a randomized controlled trial. AB - BACKGROUND: Patient navigators may increase colorectal cancer (CRC) screening rates among adults in underserved communities, but prior randomized trials have been small or conducted at single sites and have not included substantial numbers of Haitian Creole-speaking or Portuguese-speaking patients. METHODS: We identified 465 primary care patients from 4 community health centers and 2 public hospital-based clinics who were not up-to-date with CRC screening and spoke English, Haitian Creole, Portuguese, or Spanish as their primary language. We enrolled participants from September 1, 2008, through March 31, 2009, and followed them up for 1 year after enrollment. We randomly allocated patients to receive a patient navigation-based intervention or usual care. Intervention patients received an introductory letter from their primary care provider with educational material, followed by telephone calls from a language-concordant navigator. The navigators offered patients the option of being screened by fecal occult blood testing or colonoscopy. The primary outcome was completion of any CRC screening within 1 year. Secondary outcomes included the proportions of patients screened by colonoscopy who had adenomas or cancer detected. RESULTS: During a 1-year period, intervention patients were more likely to undergo CRC screening than control patients (33.6% vs 20.0%; P < .001), to be screened by colonoscopy (26.4% vs 13.0%; P < .001), and to have adenomas detected (8.1% vs 3.9%; P = .06). In prespecified subgroup analyses, the navigator intervention was particularly beneficial for patients whose primary language was other than English (39.8% vs 18.6%; P < .001) and black patients (39.7% vs 16.7%; P = .004). CONCLUSIONS: Patient navigation increased completion of CRC screening among ethnically diverse patients. Targeting patient navigation to black and non English-speaking patients may be a useful approach to reducing disparities in CRC screening. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01141114. PMID- 21606095 TI - Building blocks of the patient-centered medical/health home: comment on "colorectal cancer screening among ethnically diverse, low-income patients". PMID- 21606096 TI - Inhaled anticholinergic drug therapy and the risk of acute urinary retention in chronic obstructive pulmonary disease: a population-based study. AB - BACKGROUND: Inhaled anticholinergic medications (IACs) are widely used treatments for chronic obstructive pulmonary disease (COPD). The systemic anticholinergic effects of IAC therapy have not been extensively studied. This study sought to determine the risk of acute urinary retention (AUR) in seniors with COPD using IACs. METHODS: A nested case-control study of individuals with COPD aged 66 years or older was conducted from April 1, 2003, to March 31, 2009, using population based linked databases from Ontario, Canada. A hospitalization, same-day surgery, or emergency department visit for AUR identified cases, which were matched with up to 5 controls. Exposure to IACs was determined using a comprehensive drug benefits database. Conditional logistic regression analysis was conducted to determine the association between IAC use and AUR. RESULTS: Of 565,073 individuals with COPD, 9432 men and 1806 women developed AUR. Men who just initiated a regimen of IACs were at increased risk for AUR compared with nonusers (adjusted odds ratio [OR], 1.42; 95% confidence interval [CI], 1.20-1.68). In men with evidence of benign prostatic hyperplasia, the risk was increased further (OR, 1.81; 95% CI, 1.46-2.24). Men using both short- and long-acting IACs had a significantly higher risk of AUR compared with monotherapy users (OR, 1.84; 95% CI, 1.25-2.71) or nonusers (2.69; 1.93-3.76). CONCLUSIONS: Use of short- and long acting IACs is associated with an increased risk of AUR in men with COPD. Men receiving concurrent treatment with both short- and long-acting IACs and those with evidence of benign prostatic hyperplasia are at highest risk. PMID- 21606097 TI - Inhaled anticholinergics for chronic obstructive pulmonary disease: comment on "Inhaled anticholinergic drug therapy and the risk of acute urinary retention in chronic obstructive pulmonary disease". PMID- 21606098 TI - Geriatric drug evaluation: where are we now and where should we be in the future? AB - The older population is currently the fastest growing age group in the United States, and this trend is expected to continue for several decades. Older individuals, in general, have a higher disease burden compared with younger adults and are the major users of medications, yet premarketing drug clinical trials have often excluded them even for the drugs that have high utility in this age group. Extrapolation of clinical results from younger to older individuals does not provide adequate benefit-risk estimation, and the frequent need for dose adjustment in older patients from initially approved doses exemplifies the current lack of adequate clinical data in the elderly. Herein, we discuss the information gap for older individuals and the need for a better understanding of the effect of aging on drug responses. We also present cases for future directions, urging the implementation of improved clinical trial designs using new and emerging pharmacokinetic and pharmacodynamic methods to allow the provision of evidence-based individualized treatment to this high drug use group. PMID- 21606099 TI - One-hour glucose, mortality, and risk of diabetes: a 44-year prospective study in men. PMID- 21606100 TI - Incidence of physician-diagnosed carpal tunnel syndrome in the general population. PMID- 21606101 TI - A quantitative analysis of adverse events and "overwarning" in drug labeling. PMID- 21606102 TI - Invited commentary--prescription drug label adverse events: a call for prioritization: comment on "A quantitative analysis of adverse events and 'overwarning' in drug labeling". PMID- 21606103 TI - Process changes to increase compliance with the universal protocol for bedside procedures. PMID- 21606104 TI - Racial disparities in end-of-life care. PMID- 21606105 TI - Monacolin levels in red yeast rice: methodological questions. PMID- 21606106 TI - Percutaneous intervention for non-ST-segment elevation myocardial infarction within the therapeutic time window for acute myocardial infarction. PMID- 21606107 TI - EHRs and health care quality: correlation with out-of-date, differently purposed data does not equate with causality. PMID- 21606108 TI - Electronic health records, the PINNACLE registry, and quality care. PMID- 21606109 TI - pH-dependent modulation of connexin-based gap junctional uncouplers. AB - Gap junction (GJ) channels formed from connexin (Cx) proteins provide a direct pathway for electrical and metabolic cell-cell communication exhibiting high sensitivity to intracellular pH (pH(i)). We examined pH(i)-dependent modulation of junctional conductance (g(j)) of GJs formed of Cx26, mCx30.2, Cx36, Cx40, Cx43, Cx45, Cx46, Cx47 and Cx50 by reagents representing several distinct groups of uncouplers, such as long carbon chain alkanols (LCCAs), arachidonic acid, carbenoxolone, isoflurane, flufenamic acid and mefloquine. We demonstrate that alkalization by NH4Cl to pH ~8 increased g(j) in cells expressing mCx30.2 and Cx45, yet did not affect g(j) of Cx26, Cx40, Cx46, Cx47 and Cx50 and decreased it in Cx43 and Cx36 GJs. Unexpectedly, cells expressing Cx45, but not other Cxs, exhibited full coupling recovery after alkalization with NH4Cl under the continuous presence of LCCAs, isoflurane and mefloquine. There was no coupling recovery by alkalization in the presence of arachidonic acid, carbenoxolone and flufenamic acid. In cells expressing Cx45, IC50 for octanol was 0.1, 0.25 and 2.68 mm at pH(i) values of 6.9, 7.2 and 8.1, respectively. Histidine modification of Cx45 protein by N-bromosuccinimide reduced the coupling-promoting effect of NH4Cl as well as the uncoupling effect of octanol. This suggests that LCCAs and some other uncouplers may act through the formation of hydrogen bonds with the as of-yet unidentified histidine/s of the Cx45 GJ channel protein. PMID- 21606110 TI - Behaviour of the motoneurone pool in a fatiguing submaximal contraction. AB - During fatigue caused by a sustained maximal voluntary contraction (MVC), motoneurones become markedly less responsive when tested during the silent period following transcranial magnetic stimulation (TMS). To determine whether this reduction depends on the repetitive activation of the motoneurones, responses to TMS (motor evoked potentials, MEPs) and to cervicomedullary stimulation (cervicomedullary motor evoked potentials, CMEPs) were tested during a sustained submaximal contraction at a constant level of electromyographic activity (EMG). In such a contraction, some motoneurones are repetitively activated whereas others are not active. On four visits, eight subjects performed a 10 min maintained-EMG elbow flexor contraction of 25% maximum. Test stimuli were delivered with and without conditioning by TMS given 100 ms prior. Test responses were MEPs or CMEPs (two visits each, small responses evoked by weak stimuli on one visit and large responses on the other). During the sustained contraction, unconditioned CMEPs decreased ~20% whereas conditioned CMEPs decreased ~75 and 30% with weak and strong stimuli, respectively. Conditioned MEPs were reduced to the same extent as CMEPs of the same size. The data reveal a novel decrease in motoneurone excitability during a submaximal contraction if EMG is maintained. Further, the much greater reduction of conditioned than unconditioned CMEPs shows the critical influence of voluntary drive on motoneurone responsiveness. Strong test stimuli attenuate the reduction of conditioned CMEPs which indicates that low-threshold motoneurones active in the contraction are most affected. The equivalent reduction of conditioned MEPs and CMEPs suggests that, similar to findings with a sustained MVC, impaired motoneurone responsiveness rather than intracortical inhibition is responsible for the fatigue-related impairment of the MEP during a sustained submaximal contraction. PMID- 21606111 TI - Activation of kappa opioid receptors increases intrinsic excitability of dentate gyrus granule cells. AB - The dentate gyrus of the hippocampus is thought to control information flow into the rest of the hippocampus. Under pathological conditions, such as epilepsy, this protective feature is circumvented and uninhibited activity flows throughout the hippocampus. Many factors can modulate excitability of the dentate gyrus and ultimately, the hippocampus. It is therefore of critical importance to understand the mechanisms involved in regulating excitability in the dentate gyrus. Dynorphin, the endogenous ligand for the kappa (kappa) opioid receptor (KOR), is thought to be involved in neuromodulation in the dentate gyrus. Both dynorphin and its receptor are widely expressed in the dentate gyrus and have been implicated in epilepsy and other complex behaviours such as stress-induced deficits in learning and stress-induced depression-like behaviours. Administration of KOR agonists can prevent both the behavioural and electroencephalographic measures of seizures in several different models of epilepsy. Antagonism of the KORs also prevents stress-induced behaviours. This evidence suggests the KORs as possible therapeutic targets for various pathological conditions. In addition, KOR agonists prevent the induction of LTP. Although there are several mechanisms through which dynorphin could mediate these effects, no studies to date investigated the effects of KOR activation on intrinsic membrane properties and cell excitability. We used whole-cell, patch clamp recordings from acute mouse hippocampus slices to investigate the effect of KOR activation on dentate gyrus granule cell excitability. The agonist U69,593 (U6, 1 MUM) resulted in a lower spike threshold, a decreased latency to first spike, an increased spike half-width, and an overall increase in spike number with current injections ranging from 15 to 45 pA. There was also a reduction in the interspike interval (ISI) both early and late in the spike train, with no change in membrane potential or input resistance. Preincubation of the slice with the selective KOR antagonist, nor-binalthorphimine (BNI, 1 MUM) inhibited the effect of U6 on the latency to first spike and spike half-width suggesting that these effects are mediated through KORs. The inclusion of GDP-betaS (1 mM) in the recording pipette prevented all of the U6 effects, suggesting that all effects are mediated via a G-protein-dependent mechanism. Inclusion of the A-type K+ current blocker, 4-aminopyridine (4-AP, 5 mM) in the pipette also antagonised the effects of U6. Kv4.2 is one of the channel alpha subunits thought to be responsible for carrying the A-type K+ current. Incubation of hippocampus slices with U6 resulted in a decrease in the Kv4.2 subunit protein at the cell surface. These results are consistent with an increase in cell excitability in response to KOR activation and may reflect new possibilities for additional opioid functions. PMID- 21606112 TI - K(Ca)3.1 channels facilitate K+ secretion or Na+ absorption depending on apical or basolateral P2Y receptor stimulation. AB - Human mammary epithelial (HME) cells express several P2Y receptor subtypes located in both apical and basolateral membranes. Apical UTP or ATP-gamma-S stimulation of monolayers mounted in Ussing chambers evoked a rapid, but transient decrease in short circuit current (I(sc)), consistent with activation of an apical K+ conductance. In contrast, basolateral P2Y receptor stimulation activated basolateral K+ channels and increased transepithelial Na+ absorption. Chelating intracellular Ca2+ using the membrane-permeable compound BAPTA-AM, abolished the effects of purinoceptor activation on I(sc). Apical pretreatment with charybdotoxin also blocked the I(sc) decrease by >90% and similar magnitudes of inhibition were observed with clotrimazole and TRAM-34. In contrast, iberiotoxin and apamin did not block the effects of apical P2Y receptor stimulation. Silencing the expression of K(Ca)3.1 produced ~70% inhibition of mRNA expression and a similar reduction in the effects of apical purinoceptor agonists on I(sc). In addition, silencing P2Y2 receptors reduced the level of P2Y2 mRNA by 75% and blocked the effects of ATP-gamma-S by 65%. These results suggest that P2Y2 receptors mediate the effects of purinoceptor agonists on K+ secretion by regulating the activity of K(Ca)3.1 channels expressed in the apical membrane of HME cells. The results also indicate that release of ATP or UTP across the apical or basolateral membrane elicits qualitatively different effects on ion transport that may ultimately determine the [Na+]/[K+] composition of fluid within the mammary ductal network. PMID- 21606114 TI - Inhibition of K+ secretion in the distal nephron in nephrotic syndrome: possible role of albuminuria. AB - Nephrotic syndrome features massive proteinuria and retention of sodium which promotes ascite formation. In the puromycin aminonucleoside-induced rat model of nephrotic syndrome, sodium retention originates from the collecting duct where it generates a driving force for potassium secretion. However, there is no evidence for urinary potassium loss or hypokalaemia in the nephrotic syndrome. We therefore investigated the mechanism preventing urinary potassium loss in the nephrotic rats and, for comparison, in hypovolaemic rats, another model displaying increased sodium reabsorption in collecting ducts. We found that sodium retention is not associated with urinary loss of potassium in either nephrotic or hypovolaemic rats, but that different mechanisms account for potassium conservation in the two models. Collecting ducts from hypovolaemic rats displayed high expression of the potassium-secreting channel ROMK but no driving force for potassium secretion owing to low luminal sodium availability. In contrast, collecting ducts from nephrotic rats displayed a high driving force for potassium secretion but no ROMK. Down-regulation of ROMK in nephrotic rats probably stems from phosphorylation of ERK arising from the presence of proteins in the luminal fluid. In addition, nephrotic rats displayed a blunted capacity to excrete potassium when fed a potassium-rich diet, and developed hyperkalaemia. As nephrotic patients were found to display plasma potassium levels in the normal to high range, we would recommend not only a low sodium diet but also a controlled potassium diet for patients with nephrotic syndrome. PMID- 21606113 TI - Dihydrotestosterone stimulates amino acid uptake and the expression of LAT2 in mouse skeletal muscle fibres through an ERK1/2-dependent mechanism. AB - Dihydrotestosterone (DHT) has acute/non-genomic actions in adult mammalian skeletal muscles whose physiological functions are still poorly understood. Therefore, the primary aim of this study was to investigate the acute/non-genomic effects of DHT on amino acid uptake as well as the cellular signal transduction events underlying these actions in mouse fast- and slow-twitch skeletal muscle fibre bundles. 14C-Labelled amino acids were used to investigate the effects of DHT and testosterone (T) on amino acid uptake and pharmacological interventions were used to determine the cellular signal transduction events mediating these actions. While T had no effect on the uptake of isoleucine (Ile) and alpha methylaminoisobutyric acid (MeAIB) in both fibre types, DHT increased their uptake in the fast-twitch fibre bundles. This effect was reversed by inhibitors of protein translation, the epidermal growth factor receptor (EGFR), system A, system L, mTOR and MEK. However, it was relatively insensitive to inhibitors of transcription, androgen receptors and PI3K/Akt. Additionally, DHT treatment increased the expression of LAT2 and the phosphorylation of the EGFR in the fast twitch fibre bundles and that of ERK1/2, RSK1/2 and ATF2 in both fibre types. Also, it decreased the phosphorylation of eEF2 and increased the incorporation of Ile into proteins in both fibre types. Most of these effects were reversed by EGFR and MEK inhibitors. From these findings we suggest that another physiological function of the acute/non-genomic actions of DHT in isolated mammalian skeletal muscle fibres is to stimulate amino acid uptake. This effect is mediated through the EGFR and involves the activation of the MAPK pathway and an increase in LAT2 expression. PMID- 21606115 TI - Impact of precision grip tasks on cervical spinal network excitability in humans. AB - Motor skill acquisition in the lower limb may induce modifications of spinal network excitability. We hypothesized that short-term motor adaptation in precision grip tasks would also induce modifications of cervical spinal network excitability. In a first series of experiments, we studied the impact of two different precision grip force control tasks (a visuomotor force-tracking task and a control force task without visual feedback) on cervical spinal network excitability in healthy subjects. We separately tested the efficacy of two key components of the spinal circuitry: (i) presynaptic inhibition on flexor carpi radialis (FCR) Ia terminals, and (ii) disynaptic inhibition directed from extensor carpi radialis (ECR) to FCR. We found that disynaptic inhibition decreased temporarily after both force control tasks, independently of the presence of visual feedback. In contrast, the amount of presynaptic inhibition on FCR Ia terminals decreased only after the visuomotor force tracking task. This temporary decrease was correlated with improved tracking accuracy during the task (i.e. short-term motor adaptation). A second series of experiments confirmed these results and showed that the visuomotor force-tracking task resulted also in an increase of the Hmax/Mmax ratio and the slope of the ascending part of the H reflex recruitment curve. In order to address the role of presynaptic inhibition in the motor adaptation process, we conducted a third series of experiments during which presynaptic inhibition was recorded before and after two consecutive sessions of visuomotor force tracking. The results showed that (i) improved tracking accuracy occurred during both sessions, and (ii) presynaptic inhibition decreased only after the first session of visuomotor force tracking. Taken together, these results suggest thus that the nature of the motor task performed has a specific impact on the excitability of these cervical spinal circuits. These findings also suggest that early motor adaptation is associated with a modulation of presynaptic Ia inhibition in the upper limb. PMID- 21606116 TI - Eschewing definitions of the therapeutic misconception: a family resemblance analysis. AB - Twenty-five years after the term "therapeutic misconception' (TM) first entered the literature, most commentators agree that it remains widespread. However, the majority of scholarly attention has focused on the reasons why a patient cum human subject might confuse the goals of research with the goals of therapy. Although this paper addresses the social and cultural factors that seem to animate the TM among subjects, it also fills a niche in the literature by examining why investigators too might operate under a similar confusion. In framing these issues, the paper expressly adopts a Wittgensteinian approach to evaluating the TM, suggesting that interlocutors do not need any analytic definition of the TM to use the term meaningfully in thinking about the moral implications of the TM in practice. PMID- 21606117 TI - Development of a high-dynamic range, GFP-based FRET probe sensitive to oxidative microenvironments. AB - We report the optimization of a novel redox-sensitive probe with enhanced dynamic range and an exceptionally well-positioned oxidative midpoint redox potential. The present work characterizes factors that contribute to the improved Forster resonance energy transfer (FRET) performance of this green fluorescent protein (GFP)-based redox sensor. The alpha-helical linker, which separates the FRET donor and acceptor, has been extended in the new probe and leads to a decreased FRET efficiency in the linker's reduced, 'FRET-off' state. Unexpectedly, the FRET efficiency is increased in the new linker's oxidized, 'FRET-on' state compared with the parent probe, in spite of the longer linker sequence. The combination of a lowered baseline 'FRET-off' and an increased 'FRET-on' signal significantly improves the dynamic range of the probe for a more robust discrimination of its reduced and oxidized linker states. Mutagenesis of the cysteine residues within the alpha-helix linker reveals the importance of the fourth, C-terminal cysteine and the relative insignificance of the second cysteine in forming the disulfide bridge to clamp the linker into the high-FRET, oxidized state. To further optimize the performance of the redox probe, various cyan fluorescent protein (CFP)/yellow fluorescent protein (YFP) FRET pairs, placed at opposite ends of the improved redox linker (RL7), were quantitatively compared and exchanged. We found that the CyPet/YPet and ECFP/YPet FRET pairs when attached to RL7 do not function well as sensitive redox probes due to a strong tendency to form heterodimers, which disrupt the alpha-helix. However, monomeric versions of CyPet and YPet (mCyPet and mYPet) eliminate dimerization and restore redox sensitivity of the probe. The best performing probe, ECFP-RL7-EYFP, exhibits an approximately six fold increase in FRET efficiency in vitro when passing from the oxidized to the reduced state. We determined the midpoint redox potential of the probe to be -143 +/- 6 mV, which is ideal for measuring glutathione (GSH/GSSG) redox potentials in oxidative compartments of mammalian cells (e.g. the endoplasmic reticulum). PMID- 21606118 TI - Temperature preconditioning is optimal at 26 degrees C and confers additional protection to hypothermic cardioplegic ischemic arrest. AB - We have recently shown that brief episodes of hypothermic perfusion interspersed with periods of normothermic perfusion, referred to as temperature preconditioning (TP), are cardioprotective and can be mimicked by consecutive isoproterenol/adenosine treatment. Here we investigate the optimal temperature for TP and whether TP further enhances protection provided by hypothermic ischemia with or without polarized cardioplegic arrest. Three experimental groups of Langendorff-perfused rat hearts were used. In the first group, hearts were subjected to three episodes of hypothermic perfusion at 7, 17, 26 and 32 degrees C during the TP protocol, followed by 30 min normothermic index ischemia and 60 min reperfusion (37 degrees C). Protein kinase A (PKA) activity and cyclic AMP (cAMP) concentrations were measured prior to index ischemia. In the second group, TP (26 degrees C) hearts were subjected to two hours hypothermic index ischemia at 26 degrees C and two hours normothermic reperfusion. In the third group, TP (26 degrees C) hearts or hearts treated with isoproterenol/adenosine (pharmacological simulation of TP) were subjected to four hours hypothermic index ischemia with procaine-induced polarized cardioplegia at 26 degrees C followed by two hours normothermic reperfusion. Hemodynamic function recovery, lactate dehydrogenase release and infarct size were used to assess cardioprotection. TP at 26 degrees C resulted in highest cardioprotection, increased cAMP concentration and PKA activity, while TP at 7 degrees C exacerbated ischemia/reperfusion damage, and had no effect on cAMP concentration or PKA activity. TP at 26 degrees C also protected hearts during hypothermic ischemia with or without polarized cardioplegia. Isoproterenol/adenosine treatment conferred additional protection similar to TP. In conclusion, the study shows that TP-induced cardioprotection is temperature dependent and is optimal at 26 degrees C; TP confers additional protection to hypothermia and polarized cardioplegia; and that the pharmacological treatment based on the mechanism of TP (consecutive isoproterenol/adenosine treatment) is a potential cardioprotective strategy that can be used during heart surgery and transplantation. PMID- 21606119 TI - Effect of stem cells seeded onto biomaterial on the progression of experimental chronic kidney disease. AB - Different routes for the administration of bone marrow-derived cells (BMDC) have been proposed to treat the progression of chronic renal failure (CRF). We investigated whether (1) the use of bovine pericardium (BP) as a scaffold for cell therapy would retard the progression of CRF and (2) the efficacy of cell therapy differently impacts distinct degrees of CRF. We used 2/3 and 5/6 models of renal mass reduction to simulate different stages of chronicity. Treatments consisted of BP seeded with either mesenchymal or mononuclear cells implanted in the parenchyma of remnant kidney. Renal function and proteinuria were measured at days 45 and 90 after cell implantation. BMDC treatment reduced glomerulosclerosis, interstitial fibrosis and lymphocytic infiltration. Immunohistochemistry showed decreased macrophage accumulation, proliferative activity and the expression of fibronectin and alpha-smooth muscle-actin. Our results demonstrate: (1) biomaterial combined with BMDC did retard the progression of experimental CRF; (2) cellular therapy stabilized serum creatinine (sCr), improved creatinine clearance and 1/sCr slope when administered during the less severe stages of CRF; (3) treatment with combined therapy decreased glomerulosclerosis, fibrosis and the expression of fibrogenic molecules; and (4) biomaterials seeded with BMDC can be an alternative route of cellular therapy. PMID- 21606120 TI - Study of methyl transferase (G9aMT) and methylated histone (H3-K9) expressions in unexplained recurrent spontaneous abortion (URSA) and normal early pregnancy. AB - We investigated the expression of methyl transferase G9a and methylated histone H3-K9 in fresh human decidual/endometrial tissue of 12 normal early pregnancies and 15 unexplained recurrent spontaneous abortions (URSA). The samples were obtained through dilatation and curettage and collected as per strict inclusion exclusion criteria. The tissue was subjected to immunohistochemical analysis (IHC), western blotting (WB) and RT-PCR analysis. The results demonstrated methyl transferase G9a to have a lower expression in abortions when compared with that in normal pregnancy (P < 0.05). The sensitivity of RT-PCR, IHC and WB were respectively 66.67, 75 and 71.43%, while specificity of the same were 66.67, 60 and 78.92%, respectively. Methylated histone H3-K9 was significantly lower (P < 0.0001) in URSA tissues than in controls. This study suggests that methylation may cause URSA and indicates the need for further work to explore the role of methylation in URSA and its possible prevention through locally acting methylating/demethylating agents. PMID- 21606122 TI - Peritoneal catheter site metastasis in a patient with advanced ovarian cancer. AB - Refractory ascites can significantly reduce quality of life in patients with advanced stage ovarian cancer. Paracentesis is a commonly used procedure for the management of refractory ascites. However, there are potential risks associated with paracentesis such as pain, infection, and injury to intra-abdominal organs. In an effort to decrease the number of serial paracentesis, placement of intraperitoneal catheters has been described for the management of intractable ascites. Here we describe a case of metastasis involving a palliative peritoneal catheter in a patient with recurrent ovarian cancer. PMID- 21606123 TI - Treating constipation in palliative care: the impact of other factors aside from opioids. AB - Opioids are major contributing factors to the problem of constipation in palliative care. Whilst this is without doubt, it remains unclear how much other factors also contribute to the problem. The aim of this audit is to review what other contributing factors are present when methylnaltrexone, the peripheral opioid antagonist is prescribed for constipation. The medical records of people prescribed methylnaltrexone over a four-month period were reviewed to examine certain characteristics of people including the whether the reason for constipation was charted, whether other factors that could contribute to constipation were considered and the effectiveness of methylnaltrexone. Over the study period, 10 people received methylnaltrexone, only 4 of whom had a bowel action less than 24 hours after administration with 3 not having any bowel actions reported 6 days after administration. Whilst all were receiving opioids, the opioids doses were in the moderate range (61-200 mg morphine equivalent). However, all had other factors that could contribute to constipation including impaired functional status and medications with anti-cholinergic effects (mean anti-cholinergic load 4.5). In conclusion, methylnaltrexone is targeted treatment for the management of opioid-induced constipation. However, there is a percentage of people who fail to respond. The impact of other factors on the problem of constipation requires greater clarification. PMID- 21606121 TI - Mathematical modeling of calcium signaling during sperm hyperactivation. AB - Mammalian sperm must hyperactivate in order to fertilize oocytes. Hyperactivation is characterized by highly asymmetrical flagellar bending. It serves to move sperm out of the oviductal reservoir and to penetrate viscoelastic fluids, such as the cumulus matrix. It is absolutely required for sperm penetration of the oocyte zona pellucida. In order for sperm to hyperactivate, cytoplasmic Ca(2+) levels in the flagellum must increase. The major mechanism for providing Ca(2+) to the flagellum, at least in mice, are CatSper channels in the plasma membrane of the principal piece of the flagellum, because sperm from CatSper null males are unable to hyperactivate. There is some evidence for the existence of other types of Ca(2+) channels in sperm, but their roles in hyperactivation have not been clearly established. Another Ca(2+) source for hyperactivation is the store in the redundant nuclear envelope of sperm. To stabilize levels of cytoplasmic Ca(2+), sperm contain Ca(2+) ATPase and exchangers. The interactions between channels, Ca(2+) ATPases, and exchangers are poorly understood; however, mathematical modeling can help to elucidate how they work together to produce the patterns of changes in Ca(2+) levels that have been observed in sperm. Mathematical models can reveal interesting and unexpected relationships, suggesting experiments to be performed in the laboratory. Mathematical analysis of Ca(2+) dynamics has been used to develop a model for Ca(2+) clearance and for CatSper-mediated Ca(2+) dynamics. Models may also be used to understand how Ca(2+) patterns produce flagellar bending patterns of sperm in fluids of low and high viscosity and elasticity. PMID- 21606124 TI - Free-text comments: understanding the value in family member descriptions of hospice caregiver relationships. AB - Invitations for free-text comments on surveys provide family members of hospice patients an opportunity to "tell" their story of the hospice experience and caregiver relationships during the last months of life. These comments are a rich source of data for understanding the complex interpersonal relationships that influence patient/family perceptions of both quality of care and quality of life. Analysis of 438 free-text comments provided by 243 hospice family members revealed 5 emergent caregiver relationship themes: knowledge, skills, and abilities; empathy and compassion; trust and acceptance; communication experience and time spent with caregiver. Findings support the value of free-text comments to explain or add depth to quality assessments, modify therapeutic interventions, and identify strategies for process improvement that advance hospice quality of care. PMID- 21606125 TI - Combined aliskiren-amlodipine treatment for hypertension in African Americans: clinical science and management issues. AB - While it may seem at first that antihypertensive drug combinations run counter to the desire to 'personalize' the management of hypertension, the best combinations have predictable efficacy in different individuals and subpopulations. Race is probably not a valid surrogate for clinically meaningful genetic variation or guide to therapy. Most guidelines suggest similar blood pressure goals for different races but drug treatment recommendations have diverged. In the United States, race is not considered to be a major factor in drug choice, but in England and other countries, initial therapy with renin-angiotensin system blocking drugs is not recommended in Blacks. In this review we: (1) examine new trends in race-based research; (2) emphasize the weaknesses of race-based treatment recommendations; and (3) explore the effects of a new combination, renin inhibition (aliskiren) and amlodipine, in African Americans. PMID- 21606126 TI - An observational study to determine the prevalence of alcohol use disorders in advanced cancer patients. AB - CONTEXT: observational studies in North America suggest alcohol dependence is a common problem in advanced cancer patients and is associated with a high burden of physical and psychological symptoms. The prevalence of all types of alcohol use disorders, and the relationship between alcohol use disorders and symptoms, has not been studied. OBJECTIVES: this observational, cross-sectional study was designed to determine the prevalence of alcohol use disorders in patients with advanced cancer and establish if such patients have a higher symptom burden. METHODS: sequential patients referred to the palliative medicine team at a United Kingdom cancer centre completed the Alcohol Use Disorders Identification Test, Hospital Anxiety and Depression Scale (HADS) and Memorial Symptom Assessment Scale-Short Form (MSAS-SF). RESULTS: 120 patients participated in the study. Twenty-two (18%) patients screened positively for the presence of an alcohol use disorder. This study found no significant association between alcohol use disorders and the presence of anxiety (P = 0.38) or depression (P = 0.81) on the HADS or the global distress index subscale (P = 0.142), physical symptom distress index subscale (P = 0.734), or the psychological distress index subscale (P = 0.154) on the MSAS-SF. Current smoking status was the only independent predictor for the presence of an alcohol use disorder (P < 0.001). Seven (6%) patients screened positively for high-risk alcohol use disorders. Current smoking status (P < 0.001) and male gender (p < 0.001) were independent predictors of this problem. CONCLUSIONS: alcohol use disorders in this cohort of patients were not associated with a higher symptom burden, and the prevalence was lower than the general United Kingdom population. PMID- 21606127 TI - Bereaved relatives' views about participating in cancer research. AB - BACKGROUND: Bereaved relatives are considered to be a vulnerable group and there is debate as to whether it is ethical to engage them in research at a time that can be difficult for them. AIM: We conducted a cross-sectional study using cognitive interviewing with the aim of exploring the acceptability of a mortality follow-back survey among bereaved relatives of recently deceased cancer patients to inform the development of a large-scale survey about end-of-life care. RESULTS: Thirty-three next-of-kin of recently deceased cancer patients were invited to participate in a face-to-face interview, or to complete a postal questionnaire. At the end, they were asked about their views of engaging in the study. Nine bereaved relatives participated in a face-to-face interview and 11 completed the postal questionnaire. Eleven relatives reported it was helpful to take part in the study; of these, six did not consider it distressing, and five stated whilst it had been distressing it had been helpful. Thoughts about bringing back memories, altruism and therapeutic value emerged. CONCLUSIONS: We have new evidence that although engaging in follow-back surveys can evoke distress, many participants report it to be a positive experience. We therefore believe that this approach is acceptable when conducted sensitively. PMID- 21606128 TI - Impact of age on end-of-life care for adult Taiwanese cancer decedents, 2001 2006. AB - BACKGROUND: With increasing patient age in Western countries, evidence indicates a pervasive pattern of decreasing healthcare expenditures and less aggressive medical care, including end-of-life (EOL) care. However, the impact of age on EOL care for Asian cancer patients has not been investigated. PURPOSE: To explore how healthcare use at EOL varies by age among adult Taiwanese cancer patients. METHODS: Retrospective cohort study using administrative data among 203,743 Taiwanese cancer decedents, 2001-2006. Age was categorized as 18-64, 65-74, 75 84, and >=85 years. RESULTS: Elderly (>=65 years) Taiwanese cancer patients were significantly less likely than those 18-64 years to receive aggressive treatment in their last month of life, including chemotherapy, >1 emergency room visits, >1 hospital admissions, >14 days of hospitalization, hospital death, intensive care unit admission, cardiopulmonary resuscitation, intubation, and mechanical ventilation. However, they were significantly more likely to receive hospice care in their last year of life. CONCLUSION: Elderly Taiwanese cancer patients at EOL received less chemotherapy, less aggressive management of health crises associated with the dying process, and fewer life-extending treatments, but they were more likely to receive hospice care in their last year and to achieve the culturally highly valued goal of dying at home. PMID- 21606129 TI - Racial disparities in length of stay in hospice care by tumor stage in a large elderly cohort with non-small cell lung cancer. AB - This study examined whether there are racial disparities for length of stay in hospice for patients with non-small cell lung cancer (NSCLC).We studied 53,626 deceased patients aged >=66 years diagnosed with American Joint Committee on Cancer stages I-IV NSCLC identified from the Surveillance, Epidemiology, and End Results-Medicare linked data who used hospice services in the last six months before death, and died between 1 January 1991 and 31 December 2005. Median time (days) and percent length of stay in hospice, and multivariate incidence rate ratios (IRRs) with 95% confidence intervals (CIs) using zero-truncated negative binomial regression described relationships. In 2000-2005, most patients (64.1%) had <30 days, including those (30.2%) with <7 days length of stay in hospice care. After adjusting for confounders, the IRR for length of stay in hospice compared to whites was 38% increased for blacks (IRR = 1.38; 95% CI: 1.01-1.89), and almost three-fold increased for Hispanics (IRR = 2.91;95% CI: 1.15-7.37) at stages I-II. However, blacks at stages III-IV had slightly decreased use of hospice services (IRR = 0.91; 95% CI: 0.85-0.97). Length of stay decreased slightly among blacks diagnosed with late stage (III-IV) NSCLC in 2000-2005.The gap in disparity for length of stay in hospice has narrowed for ethnic minorities compared to whites, while some ethnic minorities had greater length of stay at early disease stage. PMID- 21606130 TI - Epidemiology of back pain in older adults: prevalence and risk factors for back pain onset. AB - OBJECTIVES: To determine the prevalence of disabling and non-disabling back pain across age in older adults, and identify risk factors for back pain onset in this age group. METHODS: Participants aged >= 75 years answered interviewer administered questions on back pain as part of a prospective cohort study [Cambridge City over-75s Cohort Study (CC75C)]. Descriptive analyses of data from two surveys, 1988-89 and 1992-93, estimated prevalence and new onset of back pain. Relative risks (RRs) and 95% CIs were estimated using Poisson regression, adjusted for age and gender. RESULTS: Prevalence of disabling and non-disabling back pain was 6 and 23%, respectively. While prevalence of non-disabling back pain did not vary significantly across age (chi2trend : 0.90; P = 0.34), the prevalence of disabling back pain increased with age (chi2trend : 4.02; P = 0.04). New-onset disabling and non-disabling back pain at follow-up was 15 and 5%, respectively. Risk factors found to predict back pain onset at follow-up were: poor self-rated health (RR 3.8; 95% CI 1.8, 8.0); depressive symptoms (RR 2.2; 95% CI 1.3, 3.7); use of health or social services (RR 1.7; 95% CI 1.1, 2.7); and previous back pain (RR 2.1; 95% CI 1.2-3.5). From these, poor self rated health, previous back pain and depressive symptoms were found to be independent predictors of pain onset. Markers of social networks were not associated with the reporting of back pain onset. Conclusion. The risk of disabling back pain rises in older age. Older adults with poor self-rated health, depressive symptoms, increased use of health and social services and a previous episode of back pain are at greater risk of reporting future back pain onset. PMID- 21606131 TI - Use of metformin before and during assisted reproductive technology in non-obese young infertile women with polycystic ovary syndrome: a prospective, randomized, double-blind, multi-centre study. AB - BACKGROUND: To study the effect of metformin before and during assisted reproductive technology (ART) on the clinical pregnancy rate (CPR) in non-obese women with polycystic ovary syndrome (PCOS). METHODS: A multi-centre, prospective, randomized, double-blind study was conducted in eight IVF clinics in four Nordic countries. We enrolled 150 PCOS women with a body mass index <28 kg/m(2), and treated them with 2000 mg/day metformin or identical placebo tablets for >= 12 weeks prior to and during long protocol IVF or ICSI and until the day of pregnancy testing. The primary outcome measure was CPR. Secondary outcome measures included spontaneous pregnancy rates during the pretreatment period, and the live birth rate (LBR). RESULTS: Among IVF treated women (n = 112), biochemical pregnancy rates were identical in both groups (42.9%), and there were no significant differences in the metformin versus the placebo group in CPR [39.3 versus 30.4%; 95% confidence interval (CI): -8.6 to 26.5]. The LBR was 37.5 versus 28.6% (95% CI: -8.4 to 26.3). However, prior to IVF there were 15 (20.3%) spontaneous pregnancies in the metformin group and eight (10.7%) in the placebo group (95% CI: -1.9 to 21.1; P = 0.1047). According to intention to treat analyses (n = 149); significantly higher overall CPR were observed in the metformin versus placebo group (50.0 versus 33.3%; 95% CI: -1.1 to 32.3; P = 0.0391). LBR was also significantly higher with use of metformin versus placebo (48.6 versus 32.0; 95% CI: 1.1 to 32.2; P = 0.0383). No major unexpected safety issues or multiple births were reported. More gastrointestinal side effects occurred in the metformin group (41 versus 12%; 95% CI: 0.15 to 0.42; P < 0.001). CONCLUSIONS: Metformin treatment for 12 weeks before and during IVF or ICSI in non-obese women with PCOS significantly increases pregnancy and LBRs compared with placebo. However, there was no effect on the outcome of ART per se. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00159575. PMID- 21606132 TI - Metformin as adjuvant therapy to IVF in women with PCOS: when is intention-to treat unintentional? PMID- 21606133 TI - ImageMiner: a software system for comparative analysis of tissue microarrays using content-based image retrieval, high-performance computing, and grid technology. AB - OBJECTIVE AND DESIGN: The design and implementation of ImageMiner, a software platform for performing comparative analysis of expression patterns in imaged microscopy specimens such as tissue microarrays (TMAs), is described. ImageMiner is a federated system of services that provides a reliable set of analytical and data management capabilities for investigative research applications in pathology. It provides a library of image processing methods, including automated registration, segmentation, feature extraction, and classification, all of which have been tailored, in these studies, to support TMA analysis. The system is designed to leverage high-performance computing machines so that investigators can rapidly analyze large ensembles of imaged TMA specimens. To support deployment in collaborative, multi-institutional projects, ImageMiner features grid-enabled, service-based components so that multiple instances of ImageMiner can be accessed remotely and federated. RESULTS: The experimental evaluation shows that: (1) ImageMiner is able to support reliable detection and feature extraction of tumor regions within imaged tissues; (2) images and analysis results managed in ImageMiner can be searched for and retrieved on the basis of image-based features, classification information, and any correlated clinical data, including any metadata that have been generated to describe the specified tissue and TMA; and (3) the system is able to reduce computation time of analyses by exploiting computing clusters, which facilitates analysis of larger sets of tissue samples. PMID- 21606134 TI - Evaluating the utility of syndromic surveillance algorithms for screening to detect potentially clonal hospital infection outbreaks. AB - OBJECTIVE: The authors evaluated algorithms commonly used in syndromic surveillance for use as screening tools to detect potentially clonal outbreaks for review by infection control practitioners. DESIGN: Study phase 1 applied four aberrancy detection algorithms (CUSUM, EWMA, space-time scan statistic, and WSARE) to retrospective microbiologic culture data, producing a list of past candidate outbreak clusters. In phase 2, four infectious disease physicians categorized the phase 1 algorithm-identified clusters to ascertain algorithm performance. In phase 3, project members combined the algorithms to create a unified screening system and conducted a retrospective pilot evaluation. MEASUREMENTS: The study calculated recall and precision for each algorithm, and created precision-recall curves for various methods of combining the algorithms into a unified screening tool. RESULTS: Individual algorithm recall and precision ranged from 0.21 to 0.31 and from 0.053 to 0.29, respectively. Few candidate outbreak clusters were identified by more than one algorithm. The best method of combining the algorithms yielded an area under the precision-recall curve of 0.553. The phase 3 combined system detected all infection control-confirmed outbreaks during the retrospective evaluation period. LIMITATIONS: Lack of phase 2 reviewers' agreement indicates that subjective expert review was an imperfect gold standard. Less conservative filtering of culture results and alternate parameter selection for each algorithm might have improved algorithm performance. CONCLUSION: Hospital outbreak detection presents different challenges than traditional syndromic surveillance. Nevertheless, algorithms developed for syndromic surveillance have potential to form the basis of a combined system that might perform clinically useful hospital outbreak screening. PMID- 21606137 TI - Safe thresholds for hybrid capture 2 test in primary cervical screening. PMID- 21606135 TI - A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease. AB - BACKGROUND: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). METHODS AND RESULTS: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7*10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3*10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4*10(-3)). CONCLUSIONS: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD. PMID- 21606136 TI - Human papillomavirus testing in primary cervical screening and the cut-off level for hybrid capture 2 tests: systematic review. AB - OBJECTIVE: To determine the trade-off between the sensitivity and the specificity for high grade cervical intraepithelial neoplasia at hybrid capture 2 cut-off values above the standard >= 1 relative light units/cut-off level (rlu/co). DESIGN: Systematic review. DATA SOURCES: PubMed. STUDY SELECTION: Randomised controlled trials in primary cervical screening using hybrid capture 2 testing in the intervention arms. Articles published until August 2010 were included if the numbers of women with positive test results and with cervical intraepithelial neoplasia were stratified by hybrid capture 2 cut-off levels. PARTICIPANTS: Women in the baseline screening rounds of the trials. INTERVENTIONS: Hybrid capture 2 screening in the baseline round including the diagnostic follow-up as practised in the randomised controlled trials and as reported by hybrid capture 2 cut-off values. RESULTS: Owing to heterogeneity in the trials, meta-analysis was not possible. Including cut-off values up to >= 10 rlu/co, 25 observation points were available for analysis. The relative sensitivity for cervical intraepithelial neoplasia grade III or higher at cut-off levels of >= 2, >= 4 or >= 5, and >= 10 rlu/co compared with a cut-off level of >= 1 rlu/co varied by trial, but at their lowest they were 0.97, 0.92, and 0.91, respectively. A similar pattern was observed for cervical intraepithelial neoplasia grade II or higher. The specificity would increase by at least 1%, 2%, and 3%, respectively, so that up to 24%, 39%, and 53%, of positive hybrid capture 2 test results not associated with high grade neoplasia could be avoided. Only two outliers existed to this general pattern. CONCLUSIONS: Although the data were derived from the baseline screening rounds only, the decrease in the sensitivity for high grade cervical intraepithelial neoplasia using a hybrid capture 2 cut-off level between >= 2 rlu/co and >= 10 rlu/co seemed acceptable given the international recommendations for testing for human papillomavirus DNA in cervical screening, which require 90% or more sensitivity for cervical intraepithelial neoplasia grade II or higher compared with hybrid capture 2 at >= 1 rlu/co. The data suggest that the hybrid capture 2 cut-off level could be increased in primary screening; this seems reasonably safe and is significantly less burdensome for women. PMID- 21606138 TI - Giant cell arteritis. PMID- 21606139 TI - Training on death and dying: handle with care. PMID- 21606140 TI - UK audit shows major rise in lung cancer surgery over past five years. PMID- 21606141 TI - President's commission considers how to protect human rights after Guatemala experiment. PMID- 21606144 TI - Coprescription of antibiotics and asthma drugs in children. AB - BACKGROUND: In children, antibiotics as well as asthma drugs are frequently prescribed. We investigated the effects of the codispensing of antibiotics and asthma drugs to children. METHODS: Using a health insurance database, we examined dispensing and codispensing of antibiotics and asthma drugs for the period of a 1 year in 892 841 Belgian children aged <18 years. RESULTS: For a 1-year period, an antibiotic was dispensed to 44.21% of children: 73.05% aged <3 years; 49.62% aged 3 to 7 years; and 34.21% aged 8 to <18 years. An asthma drug was dispensed to 16.04% of children: 44.81% aged <3 years; 17.90% aged 3 to 7 years; and 7.64% aged 8 to <18 years. Overall, an antibiotic was dispensed without an asthma drug to 38.62% of children versus with an asthma drug to 73.50% of children (P < .0001). More frequent dispensing of antibiotics to children who received an asthma drug (odds ratio: 1.90; 95% confidence interval: 1.89-1.91) occurred in all age categories (P < .0001). In 35.64% of children with an asthma drug dispensed, an antibiotic was dispensed on the same day. CONCLUSIONS: In all age groups, dispensing of antibiotics is more likely in children who have an asthma drug dispensed in the same year. In all age groups, codispensing of antibiotics and asthma drugs is a common practice. Efforts to decrease antibiotic use in children could be improved by focusing on children who are being treated with asthma drugs. PMID- 21606145 TI - Hypoglycemia in pediatric sulfonylurea poisoning: an 8-year poison center retrospective study. AB - OBJECTIVE: The goal of this study was to describe the clinical effects and time of onset of hypoglycemia in pediatric sulfonylurea poisoning. METHODS: This was a retrospective, descriptive study of pediatric (<6 years old) sulfonylurea exposures with hypoglycemia (glucose concentration <60 mg/dL) that were consulted on by the California Poison Control System for the 8-year period between January 1, 2002, and December 31, 2009. RESULTS: Of the 1943 consultations for pediatric sulfonylurea exposure in the study period, 300 children developed hypoglycemia. Ten percent had hypoglycemia occurring or persisting >= 12 hours after ingestion despite receiving treatment. All 5 children with seizures experienced these before hospital presentation. The mean (SD) time to onset of hypoglycemia in children not given any prophylactic treatment was 2.0 (1.2) hours. The mean (SD) times in children receiving prophylactic food only, intravenous glucose only, and both food and intravenous glucose were 5.9 (3.9), 5.7 (2.5), and 8.9 (3.6) hours, respectively. Ranges were 1 to 18, 1.5 to 9, and 2.5 to 15 hours. Seven of 40 patients (18%) receiving prophylactic food only had an onset of hypoglycemia >8 hours after sulfonylurea ingestion. CONCLUSIONS: Pediatric sulfonylurea exposure can result in significant poisoning. Severe effects such as seizures occurred only in cases of unrecognized sulfonylurea ingestion. The onset of hypoglycemia after pediatric sulfonylurea ingestion can be delayed by as much as 18 hours by either free access to food or administration of intravenous glucose. PMID- 21606147 TI - Regulatory monitoring of feeding during the birth hospitalization. PMID- 21606146 TI - Quality measures for the care of children with otitis media with effusion. AB - BACKGROUND: Current national efforts provide an opportunity to integrate performance measures into clinical practice and improve outcomes for children. OBJECTIVE: The goal of this study was to explore issues in developing and testing measures of care for children with otitis media with effusion (OME). METHODS: We assessed compliance with diagnostic, evaluation, and treatment measures for OME adapted from preliminary work of the Physician Consortium for Performance Improvement, using chart data in a convenience sample of practices from 2 primary care networks (Cincinnati Pediatric Research Group and the American Academy of Pediatrics Quality Improvement Innovation Network). Children aged 2 months to 12 years with at least 1 visit with a specified OME code during a 1-year period were included. RESULTS: Of 23 practices, 4 could not locate eligible visits. Nineteen practices submitted 378 abstractions (range: 3-37 per practice) with 15 identifying <30 eligible visits. Performance on diagnosis (33%) and hearing evaluation (29%) measures was low but high on measures of appropriate medication use (97% decongestant/antihistamine, 87% antibiotics, and 95% corticosteroids). Thirty-five percent of records documented antibiotic use concurrent with OME; only 16% of the 94 cases that cited reason for prescribing were appropriate. Using methods that consider appropriate clinical action, a more accurate rate for appropriate use of antibiotics was 68%. CONCLUSIONS: Coding, case finding, and evaluating appropriateness of treatment are some of the issues that will need to be considered to assess the care of children with OME. This study emphasizes the importance of testing proposed quality of care measures in "real-world" settings. PMID- 21606148 TI - Antibiotic prescription with asthma medications: why is it so common? PMID- 21606149 TI - Equimolar nitrous oxide/oxygen versus placebo for procedural pain in children: a randomized trial. AB - OBJECTIVE: This randomized, single-dose, double-blind, Phase III study was designed to compare the level of procedural pain after use of premixed equimolar mixture of 50% oxygen and nitrous oxide (EMONO) or placebo (premixed 50% nitrogen and oxygen). METHODS: Patients aged 1 to 18 years were randomly assigned to receive EMONO (n = 52) or placebo (n = 48) delivered by inhalation through a facial mask 3 minutes before cutaneous, muscle, or bone/joint procedures. Pain was evaluated (on a scale from 0-10) using a self-reported Faces Pain Scale Revised (FPS-R) or a Spanish observational pain scale (LLANTO). Rescue analgesia (with propofol or sevoflurane) was administered if pain scores were greater than or equal to 8. Collaboration, acceptance, ease of use and safety were evaluated by the attending nurse. RESULTS: There were significant differences between the 2 groups (EMONO versus placebo) for both scales (mean values): LLANTO: 3.5 vs 6.7, respectively (P = .01) and FPS-R: 3.2 vs 6.6, respectively (P = .0003). Patients not receiving EMONO (P = .0208)-in particular those aged younger than 3 years (P < .0001)-required more rescue analgesia. There were also significant differences between the 2 groups (EMONO versus placebo) for adequate collaboration (80% vs 35%; P < .0001) and acceptance (73% vs 25%; P < .0001). Ease of use was not significantly different between groups (98.1% vs 95.8%; P > .05). Only 2 patients (in the EMONO group) presented with mild adverse events. CONCLUSIONS: EMONO inhalation was well tolerated and had an estimated analgesic potency of 50%, and it is therefore suitable for minor pediatric procedures. PMID- 21606150 TI - Prospective evaluation of residents on call: before and after duty-hour reduction. AB - BACKGROUND: On July 1, 2009, in Ontario the maximum period of continuous duty that residents were permitted to work was reduced from 28 to 24 hours. We evaluated the effect of regulation on residents in 3 eras: 2 before (2005 and early 2009) and 1 after (late 2009) the duty-hour reduction. METHODS: On-call pediatric residents on pediatric medicine rotations prospectively recorded the numbers of patients (assigned and admitted) and the durations of direct patient care, documentation, staff supervision, and education attended. Sleep was measured with actigraphy. RESULTS: The 51 residents worked 180 duty periods, were assigned a median of 6 (interquartile range: 4 -12) daytime patients and 24 (interquartile range: 19-30) overnight patients. Residents reported spending means of 239 minutes providing direct patient care, 235 minutes documenting, and 243 minutes sleeping and receiving 73 minutes of staff supervision and 52 minutes of education. From early 2009 to after duty-hour reduction, residents provided 47 fewer (19.6%) minutes of direct patient care (P = .056) and received 44 fewer minutes (60.3%) of supervision (P = .0005) but spent similar times documenting, receiving education, and sleeping. In early 2009, residents provided 73 more minutes (30.5%) of direct patient care (P = .0016), spent 63 more minutes (26.8%) documenting, and slept 105 fewer minutes (43.0%) (P = .0062) than in 2005. DISCUSSION: After duty-hour reduction in 2009, we found reduced supervision and direct patient care. Comparison of the 2 periods before duty-hour reduction showed less sleep and longer patient contact in early 2009, which suggests that changes occurred without regulation. PMID- 21606151 TI - Prenatal or early-life exposure to antibiotics and risk of childhood asthma: a systematic review. AB - CONTEXT: The increasing prevalence of childhood asthma has been associated with low microbial exposure as described by the hygiene hypothesis. OBJECTIVE: We sought to evaluate the evidence of association between antibiotic exposure during pregnancy or in the first year of life and risk of childhood asthma. METHODS: PubMed was systematically searched for studies published between 1950 and July 1, 2010. Those that assessed associations between antibiotic exposure during pregnancy or in the first year of life and asthma at ages 0 to 18 years (for pregnancy exposures) or ages 3 to 18 years (for first-year-of-life exposures) were included. Validity was assessed according to study design, age at asthma diagnosis, adjustment for respiratory infections, and consultation rates. RESULTS: For exposure in the first year of life, the pooled odds ratio (OR) for all studies (N = 20) was 1.52 (95% confidence interval [CI]: 1.30-1.77). Retrospective studies had the highest pooled risk estimate for asthma (OR: 2.04 [95% CI: 1.83-2.27]; n = 8) compared with database and prospective studies (OR: 1.25 [95% CI: 1.08-1.45]; n = 12). Risk estimates for studies that adjusted for respiratory infections (pooled OR: 1.16 [95% CI: 1.08-1.25]; n = 5) or later asthma onset (pooled OR for asthma at or after 2 years: OR: 1.16 [95% CI: 1.06 1.25]; n = 3) were weaker but remained significant. For exposure during pregnancy (n = 3 studies), the pooled OR was 1.24 (95% CI: 1.02-1.50). CONCLUSIONS: Antibiotics seem to slightly increase the risk of childhood asthma. Reverse causality and protopathic bias seem to be possible confounders for this relationship. PMID- 21606152 TI - Trends in the prevalence of developmental disabilities in US children, 1997-2008. AB - OBJECTIVE: To fill gaps in crucial data needed for health and educational planning, we determined the prevalence of developmental disabilities in US children and in selected populations for a recent 12-year period. PARTICIPANTS AND METHODS: We used data on children aged 3 to 17 years from the 1997-2008 National Health Interview Surveys, which are ongoing nationally representative samples of US households. Parent-reported diagnoses of the following were included: attention deficit hyperactivity disorder; intellectual disability; cerebral palsy; autism; seizures; stuttering or stammering; moderate to profound hearing loss; blindness; learning disorders; and/or other developmental delays. RESULTS: Boys had a higher prevalence overall and for a number of select disabilities compared with girls. Hispanic children had the lowest prevalence for a number of disabilities compared with non-Hispanic white and black children. Low income and public health insurance were associated with a higher prevalence of many disabilities. Prevalence of any developmental disability increased from 12.84% to 15.04% over 12 years. Autism, attention deficit hyperactivity disorder, and other developmental delays increased, whereas hearing loss showed a significant decline. These trends were found in all of the sociodemographic subgroups, except for autism in non-Hispanic black children. CONCLUSIONS: Developmental disabilities are common and were reported in ~1 in 6 children in the United States in 2006-2008. The number of children with select developmental disabilities (autism, attention deficit hyperactivity disorder, and other developmental delays) has increased, requiring more health and education services. Additional study of the influence of risk-factor shifts, changes in acceptance, and benefits of early services is needed. PMID- 21606153 TI - Fermented milk containing Bifidobacterium lactis DN-173 010 in childhood constipation: a randomized, double-blind, controlled trial. AB - BACKGROUND: Constipation is a frustrating symptom affecting 3% of children worldwide. A fermented dairy product containing Bifidobacterium lactis strain DN 173 010 was effective in increasing stool frequency in constipated women. Our aim was to assess the effects of this product in constipated children. METHODS: In this prospective randomized, double-blind, controlled trial, 159 constipated children (defecation frequency < 3 times per week) were randomly allocated to receive either a fermented dairy product that contains B lactis DN-173 010 (n = 79) or a control product (n = 80) twice a day for 3 weeks. The primary endpoint was the change in stool frequency from baseline to after 3 weeks of product consumption. Analyses were by intention to treat. RESULTS: Eleven children did not return to any follow-up visit (5 in the probiotic group, 6 in the control group) and were therefore excluded from the final analysis. Thus, 74 children in each group were analyzed. The change in stool frequency from baseline to after 3 weeks of product consumption increased in both groups, but the difference was not statistically significant (2.9 +/- 3.2 in probiotic group versus 2.6 +/- 2.6 in control group, P = .35). There were no serious adverse events. CONCLUSIONS: In constipated children, the fermented dairy product containing B lactis strain DN 173 010 did increase stool frequency, but this increase was comparable in the control group. There is currently not sufficient evidence to recommend fermented dairy products containing B lactis strain DN-173 010 in this category of patients. Future studies should focus on whether a longer period of probiotic products is more effective in children who have a short history of constipation. PMID- 21606154 TI - Disparities in child access to emergency care for acute oral injury. AB - OBJECTIVE: We examined the impact of insurance status on dental practices' willingness to schedule an appointment for a child with a symptomatic fractured permanent front tooth. PATIENTS AND METHODS: Between February and May 2010, 6 research assistants posed as mothers of a 10-year-old boy seeking an urgent dental appointment. Two calls 4 weeks apart, with the same clinical scenario, were made by the same caller to a stratified random sample of dental practices, one-half of which were enrolled in the state's combined Medicaid and Children's Health Insurance Program (CHIP) dental program. The only difference in the calls was the child's insurance coverage (Medicaid/CHIP versus private Blue Cross dental coverage). We estimated differences in the log-odds probability of scheduling an appointment for a child with public versus private insurance by using exact conditional (fixed-effects) logistic regression, which accounts for paired data. RESULTS: Of 170 paired calls to 85 dental practices (41 participating in the Medicaid program), only 36.5% of Medicaid beneficiaries obtained any appointment compared with 95.4% of Blue Cross-insured children with the same oral injury. Among dental providers enrolled in the Medicaid program, children with Medicaid were still 18.2 times more likely to be denied an appointment than privately insured counterparts (95% confidence interval: 3.1 to infinity; P < .001). CONCLUSIONS: Illinois dentists, including those participating in Medicaid, are less likely to see a child for an urgent dental complaint if the child has public versus private dental coverage. These results have implications for developing policies that improve access to oral health care. PMID- 21606155 TI - Antibiotic prescribing during pediatric ambulatory care visits for asthma. AB - OBJECTIVE: National guidelines do not recommend antibiotics as an asthma therapy. We sought to examine the frequency of inappropriate antibiotic prescribing during US ambulatory care pediatric asthma visits as well as the patient, provider, and systemic variables associated with such practice. PATIENTS AND METHODS: Data from the National Ambulatory Medical Care Surveys and National Hospital Ambulatory Medical Care Survey were examined to assess office and emergency-department asthma visits made by children (aged < 18 years) for frequencies of antibiotic prescription. International Classification of Diseases, Ninth Revision (ICD-9) codes were used to assess the presence of coexisting conditions warranting antibiotics. Multivariable logistic regression models assessed associations with the prescription of antibiotics. RESULTS: From 1998 to 2007, an estimated 60.4 million visits occurred for asthma without another ICD-9 code justifying antibiotic prescription. Antibiotics were prescribed during 16% of these visits, most commonly macrolides (48.8%). In multivariate analysis, controlling for patient age, gender, race, insurance type, region, and controller medication use, systemic corticosteroid prescription (odds ratio [OR]: 2.69 [95% confidence interval (CI): 1.68-4.30]) and treatment during the winter (OR: 1.92 [95% CI: 1.05-3.52]) were associated with an increased likelihood of antibiotic prescription, whereas treatment in an emergency department was associated with decreased likelihood (OR: 0.48 [95% CI: 0.26-0.89]). A second multivariate analysis of only office-based visits demonstrated that asthma education during the visits was associated with reduced antibiotic prescriptions (OR: 0.46 [95% CI: 0.24-0.86]). CONCLUSIONS: Antibiotics are prescribed during nearly 1 in 6 US pediatric ambulatory care visits for asthma, ~ 1 million prescriptions annually, when antibiotic need is undocumented. Additional education and interventions are needed to prevent unnecessary antibiotic prescribing for asthma. PMID- 21606156 TI - Targeting protein kinase C by Enzastaurin restrains proliferation and secretion in human pancreatic endocrine tumors. AB - Dysregulation of the protein kinase C (PKC) signaling pathway has been implicated in tumor progression. In this study, we investigate the effects of a PKC inhibitor, Enzastaurin, in human pancreatic neuroendocrine neoplasms (PNN) primary cultures and in the human pancreatic endocrine cancer cell line, BON1. To this aim six human PNN dispersed in primary cultures and BON1 cells were treated without or with 1-10 MUM Enzastaurin and/or 100 nM IGF1 in the presence or absence of serum. Cell viability and apoptosis were evaluated after 48-72 h; Chromogranin A (CgA) and/or insulin secretion was assessed after 6 h of incubation. PKC expression was investigated by immunofluorescence and western blot. We found that Enzastaurin significantly reduced human PNN primary culture cell viability, as well as CgA and insulin secretion. Moreover, in the BON1 cell line Enzastaurin inhibited cell proliferation at 5 and 10 MUM by inducing caspase mediated apoptosis, and reduced phosphorylation of glycogen synthetase kinase 3beta (GSK3beta) and of Akt, both downstream targets of PKC pathway and pharmacodynamic markers for Enzastaurin. In addition, Enzastaurin blocked the stimulatory effect of IGF1 on cell proliferation, and reduced CgA expression and secretion in BON1 cells. Two different PKC isoforms are expressed at different levels and have partially different subcellular localization in BON1 cells. In conclusion, Enzastaurin reduces cell proliferation by inducing apoptosis, with a mechanism likely involving GSK3beta signaling, and inhibits secretory activity in PNN in vitro models, suggesting that Enzastaurin might represent a possible medical treatment of human PNN. PMID- 21606157 TI - Insulin receptor and cancer. AB - The widespread epidemic of obesity and type 2 diabetes has raised concern for the impact of these disorders as risk factors for cancer and has renewed the interest for studies regarding the involvement of hyperinsulinemia and insulin receptor (IR) in cancer progression. Overexpression of IR in cancer cells may explain their increased sensitivity to hyperinsulinemia. Moreover, IR isoform A (IR-A) together with autocrine production of its ligand IGF2 is emerging as an important mechanism of normal and cancer stem cell expansion and is a feature of several malignancies. De novo activation of the IR-A/IGF2 autocrine loop also represents a mechanism of resistance to anticancer therapies. Increasing knowledge of the IR role in cancer has important implications for cancer prevention, which should include control of insulin resistance and hyperinsulinemia in the population and meticulous evaluation of new antidiabetic drugs for their metabolic:mitogenic ratio. We are now aware that several anticancer treatments may induce or worsen insulin resistance that may limit therapy efficacy. Future anticancer therapies need to target the IR-A pathway in order to inhibit the tumor promoting effect of IR without impairing the metabolic effect of insulin. PMID- 21606158 TI - Protein expression and fucosylated glycans of the serum haptoglobin-{beta} subunit in hepatitis B virus-based liver diseases. AB - Glycosylation, which regulates the configuration and function of glycoproteins, is the most important post-translational modification. The aim of this study was to observe the differential patterns in glycan and protein parts of the serum haptoglobin-beta subunit (Hp-beta) purified from patients with hepatitis B virus (HBV) infection, liver cirrhosis (LC), or hepatocellular carcinoma (HCC). 2-D gel electrophoresis and multiplexed proteomics staining technique were employed to investigate whether the Hp-beta glycan level was proportional to the protein level. Multi-lectin blot, high-performance liquid chromatography (HPLC), and western blot analysis were carried out to identify the glycoform of Hp-beta quantitatively. Our experiments showed that the ratio of total serum Hp-beta to the glycosylated form of Hp-beta varied among the patients with different liver diseases. The total Hp-beta protein expression level was much higher in HCC than LC, while an incremental proportion of fucosylated Hp-beta was also observed in LC and HCC patients compared with that in HBV and healthy controls. Differential fucosylation was further identified as a Lewis X structure by HPLC and anti-human Sialyl-Lewis X antibody. In conclusion, the aberrant alternation of Hp-beta glycan and total protein expression may be a promising biomarker for early hepatocarcinogenesis. PMID- 21606159 TI - Mark B. Mirsky: a leading Russian historian of medicine and surgery (1930-2010). PMID- 21606160 TI - Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma. AB - BACKGROUND: To date, multiple myeloma remains an incurable malignancy due to the persistence of minimal residual disease in the bone marrow. In this setting, monoclonal antibodies against myeloma-specific cell surface antigens represent a promising therapeutic approach, which is however hampered by a lack of appropriate target structures expressed across all pathogenic myeloma cell populations. We, therefore, investigated functionally relevant immunoreceptors specifically associated with myeloma cells as well as their clonogenic precursors. DESIGN AND METHODS: Potential target proteins were identified using antibody arrays against phosphorylated immunoreceptors with lysates from myeloma cell lines. CD229 expression was confirmed in primary myeloma cells by reverse transcriptase polymerase chain reaction, western blot, fluorescence-activated cell sorting, and immunohistochemistry. Apoptosis, clonogenic growth, and sensitivity to chemotherapy were determined following short-interfering RNA mediated downregulation of CD229. Antibody-dependent cellular and complement dependent cytotoxicity were analyzed using a monoclonal antibody against CD229 to demonstrate the antigen's immunotherapeutic potential. RESULTS: Our screening assay identified CD229 as the most strongly over-expressed/phosphorylated immunoreceptor in myeloma cell lines. Over-expression was further demonstrated in the CD138-negative population, which has been suggested to represent myeloma precursors, as well as on primary tumor cells from myeloma patients. Accordingly, CD229 staining of patients' bone marrow samples enabled the identification of myeloma cells by flow cytometry and immunohistochemistry. Down-regulation of CD229 led to a decreased number of viable myeloma cells and clonal myeloma colonies, and enhanced the anti-tumor activity of conventional chemotherapeutics. Targeting CD229 with a monoclonal antibody resulted in complement- and cell mediated lysis of myeloma cells. CONCLUSIONS: Our results demonstrate that the immunoreceptor CD229 is specifically over-expressed on myeloma cells including their clonogenic precursors and contributes to their malignant phenotype. Monoclonal antibodies against this protein may represent a promising diagnostic and immunotherapeutic instrument in this disease. PMID- 21606161 TI - Familial myelodysplastic syndromes: a review of the literature. AB - Familial cases of myelodysplastic syndromes are rare, but are immensely valuable for the investigation of the molecular pathogenesis of myelodysplasia in general. The best-characterized familial myelodysplastic syndrome is that of familial platelet disorder with propensity to myeloid malignancy, caused by heterozygous germline RUNX1 mutations. Recently, there has been an increase in the number of reported cases, allowing for better understanding of the incidence, clinical features, and pathogenesis of this disorder. These recent cases have highlighted the clinical variability of the disorder and confirmed that many patients lack a bleeding and/or thrombocytopenia history. Additionally, several cases of T-acute lymphoblastic leukemia have now been reported, confirming a risk of lymphoid leukemia in patients with inherited RUNX1 mutations. Furthermore, an increased awareness of clinicians has helped detect a number of additional families affected by inherited myelodysplastic syndromes, resulting in the identification of novel causative mechanisms of disease, such as RUNX1 deficiency resulting from constitutional microdeletions of 21q22 and myelodysplasia-associated with telomerase deficiency. Awareness of predisposition to myelodysplastic syndromes and acute myeloid leukemia in families may be of critical importance in the management of younger patients with myelodysplasia in whom allogeneic hematopoietic stem cell transplantation is considered. Such families should be investigated for inherited deficiencies of RUNX1 and/or telomerase to prevent the use of an affected sibling as a donor for transplantation. Here we provide an update on familial platelet disorder in addition to a review of other known familial myelodysplastic syndromes. PMID- 21606162 TI - ADAMTS13 activity and antigen during therapy and follow-up of patients with idiopathic thrombotic thrombocytopenic purpura: correlation with clinical outcome. AB - BACKGROUND: The assay for ADAMTS13 activity helps clinicians to confirm the clinical diagnosis of idiopathic thrombotic thrombocytopenic purpura. The clinical value of testing for the antigen level of ADAMTS13 protein is, however, less clear. DESIGN AND METHODS: In this study, both ADAMTS13 antigen and activity levels were measured in 835 sequential samples from 40 consecutive patients who were followed for an average of 29 months throughout the course of acute episode plasma exchange treatment and clinical remission. RESULTS: During acute episodes, ADAMTS13 activity was severely deficient while ADAMTS13 antigen levels were more variable, ranging from severely deficient to as high as within the reference range. A severe depletion of ADAMTS13 antigen level during acute disease was, however, statistically associated with disease mortality (P=0.0322). For patients who achieved initial clinical responses, ADAMTS13 antigen levels appeared to be restored faster than ADAMTS13 activity to the normal range. Further analysis demonstrated that the ADAMTS13 antigen level at the time of initial clinical recovery was significantly higher in the patients who subsequently achieved a sustained clinical remission than in the group who soon after had an exacerbation (P=0.0187). CONCLUSIONS: Our data suggest that evaluation of ADAMTS13 antigen levels during the course of therapy and follow-up may offer additional useful information for the management of patients with thrombotic thrombocytopenic purpura. PMID- 21606163 TI - The DNA binding factor Hmg20b is a repressor of erythroid differentiation. AB - BACKGROUND: In erythroblasts, the CoREST repressor complex is recruited to target promoters by the transcription factor Gfi1b, leading to repression of genes mainly involved in erythroid differentiation. Hmg20b is a subunit of CoREST, but its role in erythropoiesis has not yet been established. DESIGN AND METHODS: To study the role of Hmg20b in erythropoiesis, we performed knockdown experiments in a differentiation-competent mouse fetal liver cell line, and in primary mouse fetal liver cells. The effects on globin gene expression were determined. We used microarrays to investigate global gene expression changes induced by Hmg20b knockdown. Functional analysis was carried out on Hrasls3, an Hmg20b target gene. RESULTS: We show that Hmg20b depletion induces spontaneous differentiation. To identify the target genes of Hmg20b, microarray analysis was performed on Hmg20b knockdown cells and controls. In line with its association to the CoREST complex, we found that 85% (527 out of 620) of the deregulated genes are up-regulated when Hmg20b levels are reduced. Among the few down-regulated genes was Gfi1b, a known repressor of erythroid differentiation. Among the consistently up-regulated targets were embryonic beta-like globins and the phospholipase HRAS-like suppressor 3 (Hrasls3). We show that Hrasls3 expression is induced during erythroid differentiation and that knockdown of Hrasls3 inhibits terminal differentiation of proerythroblasts. CONCLUSIONS: We conclude that Hmg20b acts as an inhibitor of erythroid differentiation, through the down-regulation of genes involved in differentiation such as Hrasls3, and activation of repressors of differentiation such as Gfi1b. In addition, Hmg20b suppresses embryonic beta-like globins. PMID- 21606164 TI - Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia. AB - BACKGROUND: A combination of horse anti-thymocyte globulin and cyclosporine produces responses in 60-70% of patients with severe aplastic anemia. We performed a phase II study of rabbit anti-thymocyte globulin and cyclosporine as first-line therapy for severe aplastic anemia. DESIGN AND METHODS: Twenty patients with severe aplastic anemia treated with rabbit anti-thymocyte globulin were compared to 67 historical control cases with matched clinical characteristics treated with horse anti-thymocyte globulin. RESULTS: Response rates at 3, 6 and 12 months were similar for patients treated with rabbit anti thymocyte globulin or horse anti-thymocyte globulin: 40% versus 55% (P=0.43), 45% versus 58% (P=0.44) and 50% versus 58% (P=0.61), respectively. No differences in early mortality rates or overall survival were observed. We then performed multivariable analyses of response at 6 months and overall survival and identified the presence of a paroxysmal nocturnal hemoglobinuria clone (P=0.01) and a pretreatment absolute reticulocyte count greater than 30*10(9)/L (P=0.007) as independent predictors of response and younger age (P=0.003), higher pretreatment absolute neutrophil (P=0.02) and absolute lymphocyte counts (P=0.03) as independent predictors of overall survival. None of the immunogenetic polymorphisms studied was predictive of response to immunosupressive therapy. CONCLUSIONS: Despite reports suggesting differences in biological activity of different anti-thymocyte globulin preparations, rabbit and horse anti-thymocyte globulin appear to have a similar efficacy for up-front treatment of severe aplastic anemia. Clinicaltrial.gov: NCT01231841). PMID- 21606165 TI - The heterozygote advantage of the Chuvash polycythemia VHLR200W mutation may be protection against anemia. AB - The germ-line loss-of-function VHL(R200W) mutation is common in Chuvashia, Russia and occurs in other parts of the world. VHL(R200W) homozygotes have elevated hypoxia inducible factor (HIF)-1 and HIF-2 levels, increased hemoglobin concentration, propensity to thrombosis and early mortality. Because the mutation persists from an ancient origin, we hypothesized that there is a heterozygote advantage. Thirty-four VHL(R200W) heterozygotes and 44 controls over 35 years of age from Chuvashia, Russia were studied. Anemia was defined as hemoglobin less than 130 g/L in men and less than 120 g/L in women. Mild anemia was present in 15% of VHL(R200W) heterozygotes and 34% of controls without a mutated VHL allele. By multivariate logistic regression, the odds of anemia were reduced an estimated 5.6-fold in the VHL(R200W) heterozygotes compared to controls (95% confidence interval 1.4-22.7; P=0.017). In conclusion, heterozygosity for VHL(R200W) may provide protection from anemia; such protection could explain the persistence of this mutation. PMID- 21606166 TI - Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-beta1. AB - BACKGROUND: Natural killer cell cytotoxicity is decreased in patients with acute myeloid leukemia in comparison to that in normal controls. Tumor-derived microvesicles present in patients' sera exert detrimental effects on immune cells and may influence tumor progression. DESIGN AND METHODS: We investigated the microvesicle protein level, molecular profile and suppression of natural killer cell activity in patients with newly diagnosed acute myeloid leukemia. RESULTS: The patients' sera contained higher levels of microvesicles compared to the levels in controls (P<0.001). Isolated microvesicles had a distinct molecular profile: in addition to conventional microvesicle markers, they contained membrane-associated transforming growth factor-beta1, MICA/MICB and myeloid blasts markers, CD34, CD33 and CD117. These microvesicles decreased natural killer cell cytotoxicity (P<0.002) and down-regulated expression of NKG2D in normal natural killer cells (P<0.001). Sera from patients with acute myeloid leukemia contained elevated levels of transforming growth factor-beta, and urea mediated dissociation of microvesicles further increased the levels of this protein. Neutralizing anti-transforming growth factor-beta1 antibodies inhibited microvesicle-mediated suppression of natural killer cell activity and NKG2D down regulation. Interleukin-15 protected natural killer cells from adverse effects of tumor-derived microvesicles. CONCLUSIONS: We provide evidence for the existence in acute myeloid leukemia of a novel mechanism of natural killer cell suppression mediated by tumor-derived microvesicles and for the ability of interleukin-15 to counteract this suppression. PMID- 21606167 TI - Prognostic impact of white blood cell count in intermediate risk acute myeloid leukemia: relevance of mutated NPM1 and FLT3-ITD. AB - BACKGROUND: High white blood cell count at presentation is an unfavorable prognostic factor for treatment outcome in intermediate cytogenetic risk acute myeloid leukemia. Since the impact of white blood cell count on outcome of subgroups defined by the molecular markers NPMc(+) and FLT3-internal tandem duplication (ITD) is unknown, we addressed this issue. DESIGN AND METHODS: We studied the effect of white blood cell count on outcome in a clinically and molecularly well-defined cohort of 525 patients with acute myeloid leukemia using these molecular markers. In addition, since an increased white blood cell count has been associated with an increased FLT3-ITD/FLT3 (wild-type) ratio, we investigated whether the effect of white blood cell count on outcome could be explained by the FLT3-ITD/FLT3 ratio. RESULTS: This analysis revealed that white blood cell count had no impact on outcome in patients with the genotypic combinations 'NPMc(+) without FLT3-ITD' and 'NPM1 wild-type with or without FLT3 ITD'. In contrast, white blood cell count had a significant impact on complete remission rate (P=0.034), event-free survival (P=0.009) and overall survival (P<0.001) in patients with the genotypic combination 'NPMc(+) with FLT3-ITD'. A FLT3-ITD/FLT3 ratio greater than 1 was also associated with a reduced complete remission rate (P=0.066) and significantly reduced event-free survival (P= 0.001) and overall survival (P=0.001) in patients with the genotypic combination 'NPMc(+) with FLT3-ITD'. Multivariable analysis revealed that white blood cell count and FLT3-ITD/FLT3 ratio were independent prognostic indicators for outcome in the subgroup with the genotypic combination 'NPMc(+) with FLT3-ITD'. CONCLUSIONS: Our results demonstrate that both high white blood cell count and FLT3-ITD/FLT3 ratio are prognostic factors in patients with acute myeloid leukemia with the genotypic combination 'NPMc(+) with FLT3-ITD'. PMID- 21606168 TI - Synergistic effect of Bcl2, Myc and Ccnd1 transforms mouse primary B cells into malignant cells. AB - BACKGROUND: A synergistic effect resulting from a combination of BCL2 and MYC or MYC and CCND1 has been implicated in human B-cell lymphomas. Although the identification of other cooperative genes involved is important, our present understanding of such genes remains scant. The objective of this study was to identify the additional cooperative gene(s) associated with BCL2 and MYC or MYC and CCND1. First, we assessed whether Bcl2, Myc and Ccnd1 could cooperate. Next, we developed a synergism-based functional screening method for the identification of other oncogene(s) that act with Bcl2 and Myc. DESIGN AND METHODS: Growth in culture, colony formation and oncogenicity in vivo were assessed in mouse primary B cells exogenously expressing various combinations of Bcl2, Myc and Ccnd1. For the functional screening, Bcl2- and Myc-expressing primary B cells were infected with a retroviral cDNA library. Inserted cDNA of transformed cells in culture were then identified. RESULTS: Primary B cells exogenously expressing Bcl2, Myc and Ccnd1 showed factor-independent growth ability, enhanced colony-forming capability and aggressive oncogenicity, unlike the cases observed with the expression of any combination of only two of the genes. We identified CCND3 and NRAS as cooperative genes with Bcl2 and Myc through the functional screening. CONCLUSIONS: Bcl2, Myc and Ccnd1 or Bcl2, Myc and CCND3 synergistically transformed mouse primary B cells into aggressive malignant cells. Our new synergism-based method is useful for the identification of synergistic gene combinations in tumor development, and may expand our systemic understanding of a wide range of cancer-causing elements. PMID- 21606169 TI - Paroxysmal nocturnal hemoglobinuria and pregnancy before the eculizumab era: the French experience. AB - BACKGROUND: Pregnancy in women with paroxysmal nocturnal hemoglobinuria is rare, with few reports on maternal and fetal mortality rates. DESIGN AND METHODS: A specific questionnaire designed to solicit data on pregnancies in women with paroxysmal nocturnal hemoglobinuria was sent to all members of the French Society of Hematology in January 2008. RESULTS: We identified 27 pregnancies in 22 women at 10 French Society of Hematology centers between 1978 and 2008. The median age was 21.5 years at diagnosis of paroxysmal nocturnal hemoglobinuria and 27 years at pregnancy. None of these women had received eculizumab during their pregnancy. Maternal complications, consisting mostly of cytopenias requiring transfusions, occurred in 95% of cases. Two cases of severe aplastic anemia (de novo in one case and relapse in the other) were recorded. No thrombotic events occurred during pregnancy, whereas 4 postpartum thromboses (16%) were recorded, 2 of which were fatal (maternal mortality rate 8%). Most patients received antithrombotic prophylaxis during pregnancy and postpartum (n=16; 64%). Delivery was preterm in 29% of cases, and birth weight was less than 3 kg in 53% of cases. Fetal mortality rate was 4%. CONCLUSIONS: Pregnancy during paroxysmal nocturnal hemoglobinuria is associated with increased maternal and fetal mortality rates (8% and 4%, respectively, in this series). Maternal mortality is related to postpartum thromboses. Prophylactic anticoagulation is recommended during pregnancy and for six weeks postpartum. PMID- 21606170 TI - Comparison of genetic and clinical aspects in patients with acute myeloid leukemia and myelodysplastic syndromes all with more than 50% of bone marrow erythropoietic cells. AB - BACKGROUND: The World Health Organization separates acute erythroid leukemia (erythropoiesis in >=50% of nucleated bone marrow cells; >=20% myeloblasts of non erythroid cells) from other entities with increased erythropoiesis - acute myeloid leukemia with myelodysplasia-related changes (>=20% myeloblasts of all nucleated cells) or myelodysplastic syndromes - and subdivides acute erythroid leukemia into erythroleukemia and pure erythroid leukemia subtypes. We aimed to investigate the biological/genetic justification for the different categories of myeloid malignancies with increased erythropoiesis (>=50% of bone marrow cells). DESIGN AND METHODS: We investigated 212 patients (aged 18.5-88.4 years) with acute myeloid leukemia or myelodysplastic syndromes characterized by 50% or more erythropoiesis: 108 had acute myeloid leukemia (77 with acute erythroid leukemia, corresponding to erythroid/myeloid erythroleukemia, 7 with pure erythroid leukemia, 24 with acute myeloid leukemia with myelodysplasia-related changes) and 104 had myelodysplastic syndromes. Morphological and chromosome banding analyses were performed in all cases; subsets of cases were analyzed by polymerase chain reaction and immunophenotyping. RESULTS: Unfavorable karyotypes were more frequent in patients with acute myeloid leukemia than in those with myelodysplastic syndromes (42.6% versus 13.5%; P<0.0001), but their frequency did not differ significantly between patients with acute erythroid leukemia (39.0%), pure erythroid leukemia (57.1%), and acute myeloid leukemia with myelodysplasia related changes (50.0%). The incidence of molecular mutations did not differ significantly between the different categories. The 2-year overall survival rate was better for patients with myelodysplastic syndromes than for those with acute myeloid leukemia (P<0.0001), without significant differences across the different acute leukemia subtypes. The 2-year overall survival rate was worse in patients with unfavorable karyotypes than in those with intermediate risk karyotypes (P<0.0001). In multivariate analysis, only myelodysplastic syndromes versus acute myeloid leukemia (P=0.021) and cytogenetic risk category (P=0.002) had statistically significant effects on overall survival. CONCLUSIONS: The separation of acute myeloid leukemia and myelodysplastic syndromes with 50% or more erythropoietic cells has clinical relevance, but it might be worth discussing whether to replace the subclassifications of different subtypes of acute erythroid leukemia and acute myeloid leukemia with myelodysplasia-related changes by the single entity, acute myeloid leukemia with increased erythropoiesis >=50%. PMID- 21606171 TI - Abnormal N-terminal fragment of brain natriuretic peptide in patients with light chain amyloidosis without cardiac involvement at presentation is a risk factor for development of cardiac amyloidosis. PMID- 21606172 TI - ATP Binding Cassette transporters associated with chemoresistance: transcriptional profiling in extreme cohorts and their prognostic impact in a cohort of 281 acute myeloid leukemia patients. AB - BACKGROUND: A major issue in the treatment of acute myeloid leukemia is resistance to chemotherapeutic drugs. An increasing number of ATP-Binding Cassette transporters have been demonstrated to cause resistance to cancer drugs. The aim of this study was to highlight the putative role of other ATP-Binding Cassette transporters in primary chemoresistant acute myeloid leukemia. DESIGN AND METHODS: In the first part of this study, using taqman custom arrays, we analyzed the relative expression levels of 49 ATP-Binding-Cassette genes in 51 patients divided into two extreme cohorts, one very sensitive and one very resistant to chemotherapy. In the second part of this study, we evaluated the prognostic impact, in a cohort of 281 patients, of ATP-Binding-Cassette genes selected in the first part of the study. RESULTS: In the first part of the study, six genes (ATP-Binding-CassetteA2, ATP-Binding-CassetteB1, ATP-Binding CassetteB6, ATP-Binding-CassettC13, ATP-Binding-CassetteG1, and ATP-Binding CassetteG2) were significantly over-expressed in the resistant group compared with the sensitive group. In the second cohort, overexpression of 5 of these 6 ATP-Binding-Cassette genes was correlated with outcome in univariate analysis, and only the well-known ATP-Binding-CassetteB1 and G2, and the new ATP-Binding CassetteG1 in multivariate analysis. Prognosis decreased remarkably with the number of these over-expressed ABC genes. Complete remission was achieved in 71%, 59%, 54%, and 0%, (P=0.0011) and resistance disease in 21%, 37%, 43%, and 100% (P<0.0001) of patients over-expressing 0, 1, 2, or 3, ABC genes, respectively. The number of ATP-Binding-Cassette genes expressed, among ATP-Binding-CassetteB1, G1, and G2, was the strongest prognostic factor correlated, in multivariate analysis, with achievement of complete remission (P=0.01), resistant disease (P=0.01), and overall survival (P=0.02). CONCLUSIONS: Using expression profiling, we have emphasized the diversity of ATP-Binding-Cassette transporters that cooperate to promote chemoresistance rather than overexpression of single transporters and the putative role of new ATP-Binding-Cassette tranporters, such as ATP-Binding-CassetteG1. Modulation of these multiple transporters might be required to eradicate leukemic cells. PMID- 21606173 TI - Chronic exertional compartment syndrome testing: a minimalist approach. PMID- 21606174 TI - Influence of dosing time on the efficacy and safety of finasteride in rats. AB - Finasteride (FIN), a widely used medication for the treatment of androgen dependent diseases, blocks the conversion of testosterone to a more potent androgen, dihydrotestosterone (DHT). In this study, we investigated a dosing time dependent effect and safety of FIN in rats. Androgen receptor (AR) mRNA and nuclear protein levels exhibited clear daily rhythms with the peak during the dark period in the prostate and during the light period in the liver. Repeated oral administration of FIN (5 or 100 mg/kg) at 3 h after lights on (HALO) for 2 weeks decreased serum DHT concentration throughout a 24-h period, whereas the dosing of the agent at 15 HALO decreased its level only transiently even in the higher dose group. FIN caused laboratory abnormalities in the 3 HALO group but not in the 15 HALO group. However, the effect of FIN on the prostate weight was not influenced by the dosing time. These results suggest that the safety, but not effect, of FIN depends on its dosing time in rats. The dosing of FIN in the active period might be a rational dosage regimen, which is needed to be confirmed in human subjects. PMID- 21606175 TI - NADPH oxidase pathway is involved in aortic contraction induced by A3 adenosine receptor in mice. AB - The NADPH oxidase (Nox) subunits 1, 2 (gp91 phox), and 4 are the major sources for reactive oxygen species (ROS) in vascular tissues. In conditions such as ischemia-reperfusion and hypoxia, both ROS and adenosine are released, suggesting a possible interaction. Our aim in this study was to examine the A(3) adenosine receptor (A(3)AR)-induced vascular effects and its relation to ROS and Nox1, 2, and 4 using aortic tissues from wild-type (WT) and A(3)AR knockout (A(3)KO) mice. The selective A(3)AR agonist 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N methyluronamide (Cl-IBMECA) (10(-10)-10(-5) M) induced contraction of the aorta from WT but not from A(3)KO mice, and this contraction was inhibited by the Nox inhibitor apocynin (10(-5) M) and the ROS scavengers superoxide dismutase polyethylene glycol and catalase-polyethylene glycol (100 U/ml each). Cl-IBMECA induced contraction was not affected by the mast cell degranulator compound 48/80 (100 MUg/ml) or the stabilizer cromolyn sodium (10(-4) M). In addition, Cl-IBMECA (10(-7) M) increased intracellular ROS generation by 35 +/- 14% in WT but not in A(3)KO aorta, and this increase was inhibited by apocynin (10(-5) M), diphenyleneiodonium chloride (10(-5) M), and the A(3)AR antagonist 3-propyl-6 ethyl-5-[(ethylthio)carbonyl]-2 phenyl-4-propyl-3-pyridine carboxylate (MRS1523) (10(-5) M). Furthermore, Cl-IBMECA selectively increased the protein expression of the Nox2 subunit by 150 +/- 15% in WT but not in A(3)KO mice without affecting either Nox1 or 4, and this increase was inhibited by apocynin. The mRNA of Nox2 was unchanged by Cl-IBMECA in either WT or A(3)KO aortas. In conclusion, A(3)AR enhances ROS generation, possibly through activation of Nox2, with subsequent contraction of the mouse aorta. PMID- 21606176 TI - The affinity of D2-like dopamine receptor antagonists determines the time to maximal effect on cocaine self-administration. AB - Differences in the time to maximal effect (T(max)) of a series of dopamine receptor antagonists on the self-administration of cocaine are not consistent with their lipophilicity (octanol-water partition coefficients at pH 7.4) and expected rapid entry into the brain after intravenous injection. It was hypothesized that the T(max) reflects the time required for maximal occupancy of receptors, which would occur as equilibrium was approached. If so, the T(max) should be related to the affinity for the relevant receptor population. This hypothesis was tested using a series of nine antagonists having a 2500-fold range of K(i) or K(d) values for D(2)-like dopamine receptors. Rats self-administered cocaine at regular intervals and then were injected intravenously with a dose of antagonist, and the self-administration of cocaine was continued for 6 to 10 h. The level of cocaine at the time of every self-administration (satiety threshold) was calculated throughout the session. The satiety threshold was stable before the injection of antagonist and then increased approximately 3-fold over the baseline value at doses of antagonists selected to produce this approximately equivalent maximal magnitude of effect (maximum increase in the equiactive cocaine concentration, satiety threshold; C(max)). Despite the similar C(max), the mean T(max) varied between 5 and 157 min across this series of antagonists. Furthermore, there was a strong and significant correlation between the in vivo T(max) values for each antagonist and the affinity for D(2)-like dopamine receptors measured in vitro. It is concluded that the cocaine self-administration paradigm offers a reliable and predictive bioassay for measuring the affinity of a competitive antagonist for D(2)-like dopamine receptors. PMID- 21606177 TI - Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons. AB - The organic cation/carnitine transporters OCTN1 and OCTN2 are related to other organic cation transporters (OCT1, OCT2, and OCT3) known for transporting oxaliplatin, an anticancer drug with dose-limiting neurotoxicity. In this study, we sought to determine whether OCTN1 and OCTN2 also transported oxaliplatin and to characterize their functional expression and contributions to its neuronal accumulation and neurotoxicity in dorsal root ganglion (DRG) neurons relative to those of OCTs. [(14)C]Oxaliplatin uptake, platinum accumulation, and cytotoxicity were determined in OCTN-overexpressing human embryonic kidney (HEK) 293 cells and primary cultures of rat DRG neurons. Levels of mRNA and functional activities of rat (r)Octns and rOcts in rat DRG tissue and primary cultures were characterized using reverse transcription-polymerase chain reaction and uptake of model OCT/OCTN substrates, including [(3)H]1-methyl-4-phenylpyridinium (MPP(+)) (OCT1 3), [(14)C]tetraethylammonium bromide (TEA(+)) (OCT1-3 and OCTN1/2), [(3)H]ergothioneine (OCTN1), and [(3)H]l-carnitine (OCTN2). HEK293 cells overexpressing rOctn1, rOctn2, human OCTN1, and human OCTN2 showed increased uptake and cytotoxicity of oxaliplatin compared with mock-transfected HEK293 controls; in addition, both uptake and cytotoxicity were inhibited by ergothioneine and L-carnitine. The uptake of ergothioneine mediated by OCTN1 and of L-carnitine mediated by OCTN2 was decreased during oxaliplatin exposure. rOctn1 and rOctn2 mRNA was readily detected in rat DRG tissue, and they were functionally active in cultured rat DRG neurons, more so than rOct1, rOct2, or rOct3. DRG neuronal accumulation of [(14)C]oxaliplatin and platinum during oxaliplatin exposure depended on time, concentration, temperature, and sodium and was inhibited by ergothioneine and to a lesser extent by L-carnitine but not by MPP(+). Loss of DRG neuronal viability during oxaliplatin exposure was inhibited by ergothioneine but not by L-carnitine or MPP(+). OCTN1 and OCTN2 both transport oxaliplatin and are functionally expressed by DRG neurons. OCTN1-mediated transport of oxaliplatin appears to contribute to its neuronal accumulation and treatment-limiting neurotoxicity more so than OCTN2 or OCTs. PMID- 21606178 TI - Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and independent prostate cancer growth and invasion. AB - PURPOSE: The development of new effective therapeutic agents with minimal side effects for prostate cancer (PC) treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine-Qing Dai (Indigo naturalis), has been used to treat leukemia for decades. However, the anticancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in PC. EXPERIMENTAL DESIGN: The growth kinetics and invasion ability of on human PC cell lines with or without Natura-alpha treatment were measured by cell proliferation and invasion assays. The antitumor effects of Natura-alpha were examined in nude mice tumor xenograft models, and in a patient with advanced hormone-refractory metastatic PC. Signal network proteins targeted by Natura-alpha were analyzed by using proteomic pathway array analysis (PPAA) on xenografts. RESULTS: Natura-alpha inhibited the growth of both androgen-dependent (LNCaP) and androgen-independent (LNCaP-AI, PC-3, and DU145) PC cells with IC(50) between 4 to 10 mmol/L, and also inhibited invasion of androgen-independent PC cells. Its antitumor effects were further evident in in vivo tumor reduction in androgen-dependent and androgen-independent nude mice tumor xenograft models and reduced tumor volume in the patient with hormone refractory metastatic PC. PPAA revealed that antiproliferative and antiinvasive activities of Natura-alpha on PC might primarily be through its downregulation of Forkhead box M1 (FOXM1) protein. Forced overexpression of FOXM1 largely reversed the inhibition of growth and invasion by Natura-alpha. CONCLUSION: Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone-sensitive and hormone refractory PC with minimal side effects. PMID- 21606179 TI - HCV IRES domain IIb affects the configuration of coding RNA in the 40S subunit's decoding groove. AB - Hepatitis C virus (HCV) uses a structured internal ribosome entry site (IRES) RNA to recruit the translation machinery to the viral RNA and begin protein synthesis without the ribosomal scanning process required for canonical translation initiation. Different IRES structural domains are used in this process, which begins with direct binding of the 40S ribosomal subunit to the IRES RNA and involves specific manipulation of the translational machinery. We have found that upon initial 40S subunit binding, the stem-loop domain of the IRES that contains the start codon unwinds and adopts a stable configuration within the subunit's decoding groove. This configuration depends on the sequence and structure of a different stem-loop domain (domain IIb) located far from the start codon in sequence, but spatially proximal in the IRES*40S complex. Mutation of domain IIb results in misconfiguration of the HCV RNA in the decoding groove that includes changes in the placement of the AUG start codon, and a substantial decrease in the ability of the IRES to initiate translation. Our results show that two distal regions of the IRES are structurally communicating at the initial step of 40S subunit binding and suggest that this is an important step in driving protein synthesis. PMID- 21606180 TI - Health warning messages on tobacco products: a review. AB - OBJECTIVE: To review evidence on the impact of health warning messages on tobacco packages. DATA SOURCES: Articles were identified through electronic databases of published articles, as well as relevant 'grey' literature using the following keywords: health warning, health message, health communication, label and labelling in conjunction with at least one of the following terms: smoking, tobacco, cigarette, product, package and pack. STUDY SELECTION AND DATA EXTRACTION: Relevant articles available prior to January 2011 were screened for six methodological criteria. A total of 94 original original articles met inclusion criteria, including 72 quantitative studies, 16 qualitative studies, 5 studies with both qualitative and qualitative components, and 1 review paper: Canada (n=35), USA (n=29) Australia (n=16), UK (n=13), The Netherlands (n=3), France (n=3), New Zealand (n=3), Mexico (n=3), Brazil (n=2), Belgium (n=1), other European countries (n=10), Norway (n=1), Malaysia (n=1) and China (n=1). RESULTS: The evidence indicates that the impact of health warnings depends upon their size and DESIGN: whereas obscure text-only warnings appear to have little impact, prominent health warnings on the face of packages serve as a prominent source of health information for smokers and non-smokers, can increase health knowledge and perceptions of risk and can promote smoking cessation. The evidence also indicates that comprehensive warnings are effective among youth and may help to prevent smoking initiation. Pictorial health warnings that elicit strong emotional reactions are significantly more effective. CONCLUSIONS: Health warnings on packages are among the most direct and prominent means of communicating with smokers. Larger warnings with pictures are significantly more effective than smaller, text-only messages. PMID- 21606182 TI - How to stabilize unstable plaque. PMID- 21606181 TI - Epigenetic factors and cardiac development. AB - Congenital heart malformations remain the leading cause of death related to birth defects. Recent advances in developmental and regenerative cardiology have shed light on a mechanistic understanding of heart development that is controlled by a transcriptional network of genetic and epigenetic factors. This article reviews the roles of chromatin remodelling factors important for cardiac development with the current knowledge of cardiac morphogenesis, regeneration, and direct cardiac differentiation. In the last 5 years, critical roles of epigenetic factors have been revealed in the cardiac research field. PMID- 21606183 TI - Principal role of adenylyl cyclase 6 in K+ channel regulation and vasodilator signalling in vascular smooth muscle cells. AB - AIMS: Membrane potential is a key determinant of vascular tone and many vasodilators act through the modulation of ion channel currents [e.g. the ATP sensitive potassium channel (K(ATP))] involved in setting the membrane potential. Adenylyl cyclase (AC) isoenzymes are potentially important intermediaries in such vasodilator signalling pathways. Vascular smooth muscle cells (VSMCs) express multiple AC isoenzymes, but the reason for such redundancy is unknown. We investigated which of these isoenzymes are involved in vasodilator signalling and regulation of vascular ion channels important in modulating membrane potential. METHODS AND RESULTS: AC isoenzymes were selectively depleted (by >75%) by transfection of cultured VSMCs with selective short interfering RNA sequences. AC6 was the predominant isoenzyme involved in vasodilator-mediated cAMP accumulation in VSMCs, accounting for ~60% of the total response to beta adrenoceptor (beta-AR) stimulation. AC3 played a minor role in beta-AR signalling, whereas AC5 made no significant contribution. AC6 was also the principal isoenzyme involved in beta-AR-mediated protein kinase A (PKA) signalling (determined using the fluorescent biosensor for PKA activity, AKAR3) and the substantial beta-AR/PKA-dependent enhancement of K(ATP) current. K(ATP) current was shown to play a vital role in setting the resting membrane potential and in mediating the hyperpolarization observed upon beta-AR stimulation. CONCLUSION: AC6, but not the closely related AC5, plays a principal role in vasodilator signalling and regulation of the membrane potential in VSMCs. These findings identify AC6 as a vital component in the vasodilatory apparatus central to the control of blood pressure. PMID- 21606184 TI - A novel sensor kinase is required for Bordetella bronchiseptica to colonize the lower respiratory tract. AB - Bacterial virulence is influenced by the activity of two-component regulator systems (TCSs), which consist of membrane-bound sensor kinases that allow bacteria to sense the external environment and cytoplasmic, DNA-binding response regulator proteins that control appropriate gene expression. Respiratory pathogens of the Bordetella genus require the well-studied TCS BvgAS to control the expression of many genes required for colonization of the mammalian respiratory tract. Here we describe the identification of a novel gene in Bordetella bronchiseptica, plrS, the product of which shares sequence homology to several NtrY-family sensor kinases and is required for B. bronchiseptica to colonize and persist in the lower, but not upper, respiratory tract in rats and mice. The plrS gene is located immediately 5' to and presumably cotranscribed with a gene encoding a putative response regulator, supporting the idea that PlrS and the product of the downstream gene may compose a TCS. Consistent with this hypothesis, the PlrS-dependent colonization phenotype requires a conserved histidine that serves as the site of autophosphorylation in other sensor kinases, and in strains lacking plrS, the production and/or cellular localization of several immune-recognized proteins is altered in comparison to that in the wild type strain. Because plrS is required for colonization and persistence only in the lower respiratory tract, a site where innate and adaptive immune mechanisms actively target infectious agents, we hypothesize that its role may be to allow Bordetella to resist the host immune response. PMID- 21606185 TI - The hybrid histidine kinase Hk1 is part of a two-component system that is essential for survival of Borrelia burgdorferi in feeding Ixodes scapularis ticks. AB - Two-component systems (TCS) are principal mechanisms by which bacteria adapt to their surroundings. Borrelia burgdorferi encodes only two TCS. One is comprised of a histidine kinase, Hk2, and the response regulator Rrp2. While the contribution of Hk2 remains unclear, Rrp2 is part of a regulatory pathway involving the spirochete's alternate sigma factors, RpoN and RpoS. Genes within the Rrp2/RpoN/RpoS regulon function to promote tick transmission and early infection. The other TCS consists of a hybrid histidine kinase, Hk1, and the response regulator Rrp1. Hk1 is composed of two periplasmic sensor domains (D1 and D2), followed by conserved cytoplasmic histidine kinase core, REC, and Hpt domains. In addition to its REC domain, Rrp1 contains a GGDEF motif characteristic of diguanylate cyclases. To investigate the role of Hk1 during the enzootic cycle, we inactivated this gene in two virulent backgrounds. Extensive characterization of the resulting mutants revealed a dramatic phenotype whereby Hk1-deficient spirochetes are virulent in mice and able to migrate out of the bite site during feeding but are killed within the midgut following acquisition. We hypothesize that the phosphorelay between Hk1 and Rrp1 is initiated by the binding of feeding-specific ligand(s) to Hk1 sensor domain D1 and/or D2. Once activated, Rrp1 directs the synthesis of cyclic dimeric GMP (c-di-GMP), which, in turn, modulates the expression and/or activity of gene products required for survival within feeding ticks. In contrast to the Rrp2/RpoN/RpoS pathway, which is active only within feeding nymphs, the Hk1/Rrp1 TCS is essential for survival during both larval and nymphal blood meals. PMID- 21606186 TI - Biochemical and localization analyses of putative type III secretion translocator proteins CopB and CopB2 of Chlamydia trachomatis reveal significant distinctions. AB - Chlamydia spp. are among the many pathogenic Gram-negative bacteria that employ a type III secretion system (T3SS) to overcome host defenses and exploit available resources. Significant progress has been made in elucidating contributions of T3S to the pathogenesis of these medically important, obligate intracellular parasites, yet important questions remain. Chief among these is how secreted effector proteins traverse eukaryotic membranes to gain access to the host cytosol. Due to a complex developmental cycle, it is possible that chlamydiae utilize a different complement of proteins to accomplish translocation at different stages of development. We investigated this possibility by extending the characterization of C. trachomatis CopB and CopB2. CopB is detected early during infection but is depleted and not detected again until about 20 h postinfection. In contrast, CopB2 was detectible throughout development. CopB is associated with the inclusion membrane. Biochemical and ectopic expression analyses were consistent with peripheral association of CopB2 with inclusion membranes. This interaction correlated with development and required both chlamydial de novo protein synthesis and T3SS activity. Collectively, our data indicate that it is unlikely that CopB serves as the sole chlamydial translocation pore and that CopB2 is capable of association with the inclusion membrane. PMID- 21606187 TI - Tyrosine-phosphorylated Ehrlichia chaffeensis and Ehrlichia canis tandem repeat orthologs contain a major continuous cross-reactive antibody epitope in lysine rich repeats. AB - A small subset of major immunoreactive proteins have been identified in Ehrlichia chaffeensis and Ehrlichia canis, including three molecularly and immunologically characterized pairs of immunoreactive tandem repeat protein (TRP) orthologs with major continuous species-specific epitopes within acidic tandem repeats (TR) that stimulate strong antibody responses during infection. In this study, we identified a fourth major immunoreactive TR-containing ortholog pair and defined a major cross-reactive epitope in homologous nonidentical 24-amino-acid lysine rich TRs. Antibodies from patients and dogs with ehrlichiosis reacted strongly with recombinant TR regions, and epitopes were mapped to the N-terminal TR region (18 amino acids) in E. chaffeensis and the complete TR (24 amino acids) in E. canis. Two less-dominant epitopes were mapped to adjacent glutamate/aspartate rich and aspartate/tyrosine-rich regions in the acidic C terminus of E. canis TRP95 but not in E. chaffeensis TRP75. Major immunoreactive proteins in E. chaffeensis (75-kDa) and E. canis (95-kD) whole-cell lysates and supernatants were identified with TR-specific antibodies. Consistent with other ehrlichial TRPs, the TRPs identified in ehrlichial whole-cell lysates and the recombinant proteins migrated abnormally slow electrophoretically a characteristic that was demonstrated with the positively charged TR and negatively charged C-terminal domains. E. chaffeensis TRP75 and E. canis TRP95 were immunoprecipitated with anti-pTyr antibody, demonstrating that they are tyrosine phosphorylated during infection of the host cell. PMID- 21606188 TI - Mycobacterium tuberculosis culture filtrate protein 10-specific effector/memory CD4+ and CD8+ T cells in tubercular pleural fluid, with biased usage of T cell receptor Vbeta chains. AB - T cell-mediated immunity is critical for the control of Mycobacterium tuberculosis infection. Identifying the precise immune mechanisms that lead to control of initial M. tuberculosis infection and preventing reactivation of latent infection are crucial for combating tuberculosis. However, a detailed understanding of the role of T cells in the immune response to infection has been hindered. In addition, there are few flow cytometry studies characterizing the Vbeta repertoires of T cell receptors (TCRs) at local sites of M. tuberculosis infection in adult tuberculosis. In this study, we used culture filtrate protein 10 (CFP-10) from M. tuberculosis to characterize T cells at local sites of infection. We simultaneously analyzed the correlation of the production of cytokines with TCR Vbeta repertoires in CFP-10-specific CD4(+) and CD8(+) T cell subsets. For the first time, we demonstrate that CFP-10-specific CD4(+) or CD8(+) T cells from tubercular pleural fluid can produce high levels of gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) and upregulate the expression of CD107a/b on the cell surface. The CFP-10-specific cells were effector/memory cells with a CD45RO(+) CD62L(-) CCR7(-) CD27(-) expression profile. In addition, we found CFP-10-specific CD4(+) and CD8(+) T cells in tubercular pleural fluid, with biased usage of TCR Vbeta9, Vbeta12, or Vbeta7.2. Our findings of CFP-10-specific CD4(+) and CD8(+) T cells in tubercular pleural fluid are critical for understanding the mechanisms of the local cellular immune response and developing more effective therapeutic interventions in cases of M. tuberculosis infection. PMID- 21606189 TI - Discovery of a role for Hsp82 in Histoplasma virulence through a quantitative screen for macrophage lethality. AB - The application of forward genetics can reveal new factors required for the virulence of intracellular pathogens. To facilitate such virulence screens, we developed macrophage cell lines with which the number of intact host cells following infection with intracellular pathogens can be rapidly and easily ascertained through the expression of a constitutive lacZ transgene. Using known virulence mutants of Francisella novicida and Histoplasma capsulatum, we confirmed the applicability of these host cells for the quantitative assessment of bacterial and fungal virulence, respectively. To identify new genes required for Histoplasma virulence, we employed these transgenic macrophage cells to screen a collection of individual transfer DNA (T-DNA) insertion mutants. Among the mutants showing decreased virulence in macrophages, we identified an insertion in the locus encoding the Histoplasma Hsp82 homolog. The lesion caused by the T-DNA insertion localizes to the promoter region, resulting in significantly decreased HSP82 expression. Reduced HSP82 expression markedly attenuates the virulence of Histoplasma yeast in vivo. While the HSP82 hypomorph grows normally in vitro at 37 degrees C and under acid and salinity stresses, its ability to recover from high-temperature stress is impaired. These results provide genetic proof of the role of stress chaperones in the virulence of a thermally dimorphic fungal pathogen. PMID- 21606190 TI - Non-glycemic effects of insulin therapy: a comparison between insulin aspart and regular human insulin during two consecutive meals in patients with type 2 diabetes. AB - OBJECTIVE: To control postprandial hyperglycemia in insulin-treated type 2 diabetic patients, prandial therapy with regular human insulin (HI) or fast acting insulin analogs is used. Postprandial hyperglycemia seems to be reduced more effectively with insulin analogs than with normal insulin, but there are no data concerning the effect on lipolysis or pancreatic insulin and proinsulin secretion of normal insulin in comparison to insulin analogs. DESIGN AND METHODS: We included 13 patients with type 2 diabetes mellitus (age 62.2+/-10.3 years) with preexisting insulin therapy in this crossover, prospective, open-labeled, randomized trial comparing regular HI with insulin aspart (IA) in the setting of a standardized breakfast and a standardized lunch 4 h later. Blood samples for determination of glucose, free fatty acids (FFA), triglycerides, C-peptide, and intact proinsulin were drawn during fasting and every 30 min until 4 h after the second test meal. Statistical analysis was performed with ANOVA for repeated measurements and paired Student's t-test. RESULTS: The mean increase in blood glucose was significantly lower after IA (24.18+/-16.33 vs 34.92+/-29.07 mg/dl, P=0.02) compared with HI. Both therapies reduced FFA; however, the mean reduction was significantly higher after IA than after HI (-0.47+/-0.16 vs -0.35+/-0.15 MUmol/l, P<0.001). The mean increase in intact proinsulin was significantly lower after IA than after HI (10.53+/-5 vs 15.20+/-6.83 pmol/l, P<0.001). No differences were observed in the C-peptide levels between the two groups. CONCLUSION: In the setting of two consecutive meals, IA reduces lipolysis and proinsulin secretion more effectively than HI. PMID- 21606191 TI - Hypoparathyroidism and autoimmunity in the 22q11.2 deletion syndrome. AB - OBJECTIVE: To characterize the endocrine and autoimmune disturbances with emphasis on parathyroid dysfunction in patients with 22q11.2 deletion syndrome (22q11.2 DS). Design In this nationwide survey; 59 patients (age 1-54 years) out of 86 invited with a 22q11.2 DS were recruited through all the genetic institutes in Norway. METHODS: Data was collected from blood tests, medical records, a physical examination and a semi-structured interview. We registered autoimmune diseases and measured autoantibodies, hormone levels and HLA types. RESULTS: Twenty-eight (47%) patients had hypoparathyroidism or a history of neonatal or transient hypocalcemia. Fifteen patients had neonatal hypocalcemia. Fourteen patients had permanent hypoparathyroidism including seven (54%) of those above age 15 years. A history of neonatal hypocalcemia did not predict later occurring hypoparathyroidism. Parathyroid hormone levels were generally low indicating a low reserve capacity. Twenty-eight patients were positive for autoantibodies. Six (10%) persons had developed an autoimmune disease, and all were females (P<0.02). Hypoparathyroidism correlated with autoimmune diseases (P<0.05), however, no antibodies were detected against the parathyroid glands. CONCLUSIONS: Hypoparathyroidism and autoimmunity occur frequently in the 22q11.2 DS. Neonatal hypocalcemia is not associated with later development of permanent hypoparathyroidism. Hypoparathyroidism may present at any age, also in adults, and warrants regular measurement of calcium levels. Hypoparathyroidism and autoimmunity occur frequently together. Our findings of autoimmune diseases in 10% of the patients highlight the importance of stringent screening and follow-up routines. PMID- 21606192 TI - Long-term DHEA substitution in female adrenocortical failure, body composition, muscle function, and bone metabolism: a randomized trial. AB - CONTEXT: Adrenal derived androgens are low in women with adrenal failure. The physiological consequences of substitution therapy are uncertain. OBJECTIVE: To investigate the effects of DHEA substitution in women with adrenal failure on body composition, fuel metabolism, and inflammatory markers. DESIGN, PARTICIPANTS AND INTERVENTION: In this study, ten female patients (median age 38.5 years, range 28-52) with adrenal failure were treated with DHEA 50 mg for 6 months in a double-blind, randomized, placebo-controlled, and crossover study. The participants underwent dual-energy X-ray absorptiometry (DXA) scan, computed tomography scan of abdominal fat, indirect calorimetry, bicycle ergometry, muscle and fat biopsies, and blood samples. RESULTS: Baseline androgens were normalized to fertile range during active treatment. Anthropometric data were unaffected, but lean body mass (LBM) slightly increased compared with placebo (delta LBM (kg) placebo versus DHEA: -0.48+/-6.1 vs 1.6+/-3.4, P=0.02) with no alterations in total or abdominal fat mass. PTH increased with DHEA, but no significant changes were observed in other bone markers or in bone mineral content. The mRNA levels of markers of tissue inflammation (adiponectin, interleukin 6 (IL6), IL10, monocyte chemoattractant protein 1, and tumor necrosis factor alpha) in fat and muscle tissue were unaffected by DHEA treatment, as was indirect calorimetry and maximal oxygen uptake. A high proportion of self-reported seborrheic side effects were recorded (60%). CONCLUSION: In female adrenal failure, normalization of androgens with DHEA 50 mg for 6 months had no effects on muscle, fat, and bone tissue and on fuel metabolism in this small study. A small increase in LBM was observed. Treatment was associated with a high frequency of side effects. PMID- 21606193 TI - Exogenous signal-independent nuclear IkappaB kinase activation triggered by Nkx3.2 enables constitutive nuclear degradation of IkappaB-alpha in chondrocytes. AB - NF-kappaB is a multifunctional transcription factor involved in diverse biological processes. It has been well documented that NF-kappaB can be activated in response to various stimuli. While signal-inducible NF-kappaB activation mechanisms have been extensively characterized, exogenous signal-independent intrinsic NF-kappaB activation processes remain poorly understood. Here we show that IkappaB kinase beta (IKKbeta) can be intrinsically activated in the nucleus by a homeobox protein termed Nkx3.2 in the absence of exogenous IKK-activating signals. We found that ubiquitin chain-dependent, but persistent, interactions between Nkx3.2 and NEMO (also known as IKKgamma) can give rise to constitutive IKKbeta activation in the nucleus. Once the Nkx3.2-NEMO-IKKbeta complex is formed in the nucleus, IKKbeta-induced Nkx3.2 phosphorylation at Ser148 and Ser168 allows betaTrCP to be engaged to cause IkappaB-alpha ubiquitination independent of IkappaB-alpha phosphorylation at Ser32 and Ser36. Taken together, our results provide a novel molecular explanation as to how an intracellular factor such as Nkx3.2 can accomplish persistent nuclear IKK activation to enable intrinsic and constitutive degradation of IkappaB in the nucleus in the absence of exogenous NF kappaB-activating signals, which, in turn, plays a role in chondrocyte viability maintenance. PMID- 21606194 TI - Coordinated action of CK1 isoforms in canonical Wnt signaling. AB - Activation of the Wnt pathway promotes the progressive phosphorylation of coreceptor LRP5/6 (low-density lipoprotein receptor-related proteins 5 and 6), creating a phosphorylated motif that inhibits glycogen synthase kinase 3beta (GSK 3beta), which in turn stabilizes beta-catenin, increasing the transcription of beta-catenin target genes. Casein kinase 1 (CK1) kinase family members play a complex role in this pathway, either as inhibitors or as activators. In this report, we have dissected the roles of CK1 isoforms in the early steps of Wnt signaling. CK1epsilon is constitutively bound to LRP5/6 through its interaction with p120-catenin and E-cadherin or N-cadherin and is activated upon Wnt3a stimulation. CK1alpha also associates with the LRP5/6/p120-catenin complex but, differently from CK1epsilon, only after Wnt3a addition. Binding of CK1alpha is dependent on CK1epsilon and occurs in a complex with axin. The two protein kinases function sequentially: whereas CK1epsilon is required for early responses to Wnt3a stimulation, such as recruitment of Dishevelled 2 (Dvl-2), CK1alpha participates in the release of p120-catenin from the complex, which activates p120-catenin for further actions on this pathway. Another CK1, CK1gamma, acts at an intermediate level, since it is not necessary for Dvl-2 recruitment but for LRP5/6 phosphorylation at Thr1479 and axin binding. Therefore, our results indicate that CK1 isoforms work coordinately to promote the full response to Wnt stimulus. PMID- 21606195 TI - Opposing roles of FoxP1 and Nfat3 in transcriptional control of cardiomyocyte hypertrophy. AB - Cardiac homeostasis is maintained by a balance of growth-promoting and growth modulating factors. Sustained elevation of calcium signaling can induce cardiac hypertrophy through activation of Nfat family transcription factors. FoxP family transcription factors are known to interact with Nfat proteins and to modulate their transcriptional activities in lymphocytes. We investigated FoxP1 interaction with Nfat3 (Nfatc4) and their effects on transcription of hypertrophy associated genes in neonatal rat cardiomyocytes. FoxP1-Nfat3 complexes were visualized using bimolecular fluorescence complementation (BiFC) analysis. Calcineurin activation induced FoxP1-Nfat3 BiFC complex formation. Amino acid substitutions in the predicted interaction interface inhibited it. FoxP1 repressed hypertrophy-associated genes (Myh7, Rcan1, Cx43, Anf, and Bnp) and counteracted their activation by constitutively nuclear Nfat3 (cnNfat3). In contrast, FoxP1 activated genes that maintain normal heart functions (Myh6 and p57Kip2) and cnNfat3 counteracted their activation by FoxP1. Amino acid substitutions in FoxP1 or cnNfat3 that inhibited their interaction abrogated the activation of hypertrophy-associated gene transcription by cnNfat3 and the repression of these genes by FoxP1. FoxP1 and Nfat3 co-occupied the promoter regions of hypertrophy-associated genes in neonatal and adult heart tissue. FoxP1 counteracted hypertrophic cardiomyocyte growth, and connexin 43 mislocalization caused by cnNfat3 expression. These data suggest that the opposing transcriptional activities of FoxP1 and Nfat3 maintain cardiomyocyte homeostasis. PMID- 21606196 TI - ID1 facilitates the growth and metastasis of non-small cell lung cancer in response to nicotinic acetylcholine receptor and epidermal growth factor receptor signaling. AB - Expression of ID1 (inhibitor of differentiation) has been correlated with the progression of a variety of cancers, but little information is available on its role in non-small cell lung cancer (NSCLC). Here we show that ID1 is induced by nicotinic acetylcholine receptor (nAChR) and epidermal growth factor receptor (EGFR) signaling in a panel of NSCLC cell lines and primary cells from the lung. ID1 induction was Src dependent and mediated through the alpha7 subunit of nAChR; transfection of K-Ras or EGFR to primary cells induced ID1. ID1 depletion prevented nicotine- and EGF-induced proliferation, migration, and invasion of NSCLC cells and angiogenic tubule formation of human microvascular endothelial cells from lungs (HMEC-Ls). ID1 could induce the expression of mesenchymal markers such as vimentin and fibronectin by downregulating ZBP-89, a zinc finger repressor protein. ID1 levels were elevated in tumors from mice that were exposed to nicotine. Further, human lung tissue microarrays (TMAs) showed elevated levels of ID1 in NSCLC samples, with maximal levels in metastatic lung cancers. Quantitative reverse transcription-PCR (RT-PCR) performed on patient lung tumors showed that ID1 levels were elevated in advanced stages of NSCLC and correlated with elevated expression of vimentin and fibronectin, irrespective of smoking history. PMID- 21606197 TI - Two closely spaced tyrosines regulate NFAT signaling in B cells via Syk association with Vav. AB - Activated Syk, an essential tyrosine kinase in B cell signaling, interacts with Vav guanine nucleotide exchange factors and regulates Vav activity through tyrosine phosphorylation. The Vav SH2 domain binds Syk linker B by an unusual recognition of two closely spaced Syk tyrosines: Y342 and Y346. The binding affinity is highest when both Y342 and Y346 are phosphorylated. An investigation in B cells of the dependence of Vav phosphorylation and NFAT activation on phosphorylation of Y342 and Y346 finds that cellular response levels match the relative binding affinities of the Vav1 SH2 domain for singly and doubly phosphorylated linker B peptides. This key result suggests that the uncommon recognition determinant of these two closely spaced tyrosines is a limiting factor in signaling. Interestingly, differences in affinities for binding singly and doubly phosphorylated peptides are reflected in the on rate, not the off rate. Such a control mechanism would be highly effective for regulating binding among competing Syk binding partners. The nuclear magnetic resonance (NMR) structure of Vav1 SH2 in complex with a doubly phosphorylated linker B peptide reveals diverse conformations associated with the unusual SH2 recognition of two phosphotyrosines. NMR relaxation indicates compensatory changes in loop fluctuations upon binding, with implications for nonphosphotyrosine interactions of Vav1 SH2. PMID- 21606198 TI - A cytosolic ATM/NEMO/RIP1 complex recruits TAK1 to mediate the NF-kappaB and p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 responses to DNA damage. AB - In multiple tumor types, activation of the transcription factor NF-kappaB increases the resistance of tumor cells to anticancer therapies and contributes to tumor progression. Genotoxic stress induced by chemotherapy or radiation therapy triggers the ATM-dependent translocation of NF-kappaB essential modifier (NEMO), also designated IkappaB kinase gamma (IKKgamma), from the nucleus to the cytosol, resulting in IkappaB kinase activation by mechanisms not yet fully understood. RIP1 has been implicated in this response and found to be modified in cells with damaged DNA; however, the nature of the RIP1 modification and its precise role in the pathway remain unclear. Here, we show that DNA damage stimulates the formation of a cytosolic complex containing ATM, NEMO (IKKgamma), RIP1, and TAK1. We find that RIP1 is modified by SUMO-1 and ubiquitin in response to DNA damage and demonstrate that modified RIP1 is required for NF-kappaB activation and tumor cell survival. We show that ATM activates TAK1 in a manner dependent on RIP1 and NEMO. We also reveal TAK1 as a central mediator of the alternative DNA damage response pathway mediated by the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 (MAPKAP-2) kinases. These findings have translational implications and reveal RIP1 and TAK1 as potential therapeutic targets in chemoresistance. PMID- 21606199 TI - The Ric-8B gene is highly expressed in proliferating preosteoblastic cells and downregulated during osteoblast differentiation in a SWI/SNF- and C/EBPbeta mediated manner. AB - The Ric-8 gene encodes a guanine exchange factor (GEF) that modulates G protein mediated signaling, exhibiting a relevant role during regulation of cell division. In mammals, two Ric-8 homologues have been reported (Ric-8A and Ric 8B), and recent studies indicate equivalent roles for each protein. Here, we show that the Ric-8B gene is negatively regulated during osteoblast differentiation by the transcription factor C/EBPbeta. Only the larger C/EBPbeta isoform (C/EBPbeta LAP*) downregulates Ric-8B gene promoter activity in osteoblastic cells. Accordingly, knockdown of C/EBPbeta expression by small intefering RNA in osteoblastic cells results in a significant increase of Ric-8B gene expression. Transient overexpression of Brg1 or Brm, the catalytic subunits of the SWI/SNF chromatin-remodeling complex, inhibits Ric-8B promoter activity. Also, the presence of inactive SWI/SNF complexes in osteoblastic cells results in increased endogenous Ric-8B transcription, indicating that SWI/SNF activity negatively regulates Ric-8B expression. During osteoblast differentiation, Ric-8B gene repression is accompanied by changes in nucleosome placement at the proximal Ric 8B gene promoter and reduced accessibility to regulatory sequences. PMID- 21606200 TI - Mammalian Llgl2 is necessary for proper branching morphogenesis during placental development. AB - Cell polarity plays a critical role in the development of all metazoans; however, the mechanisms of cell polarity and the specific role of cell polarity pathways in mammalian organisms are still poorly understood. Lethal giant larvae (Lgl) is an apical-basal polarity gene identified in Drosophila, where it functions as a tumor suppressor controlling self-renewal and differentiation of progenitor cells. There are two orthologs of Lgl in mammalian genomes: Llgl1 and Llgl2. While mammalian Lgls are assumed to be tumor suppressor genes, little is known about their function in vivo. Here we report the functional analysis of murine Llgl2. We generated Llgl2(-/-) mice and found that Llgl2 functions as a polarity protein required for proper branching morphogenesis during placental development. Llgl2(-/-) pups are born as runts but quickly catch up in size and grow into normal-size adults. Surprisingly, no prominent phenotypes or spontaneous tumors were observed in adult Llgl2(-/-) mice. Analyses of placental trophoblasts reveal a critical role for Llgl2 in cell polarization and polarized cell invasion. We conclude that mammalian Llgl2 is required for proper polarized invasion of trophoblasts and efficient branching morphogenesis during placental development, but, unlike its Drosophila ortholog, it does not function as a canonical tumor suppressor gene. PMID- 21606201 TI - The sodium-dependent inorganic phosphate transporter SLC34A1 (NaPi-IIa) is not localized in the mouse brain: a case of tissue-specific antigenic cross reactivity. AB - The sodium-dependent inorganic phosphate transporter NaPi-IIa is expressed in the kidney. Here, the authors used a polyclonal antiserum raised against NaPi-IIa- and NaPi-IIa-deficient mice to characterize its expression in nervous tissue. Western blots showed that a NaPi-IIa immunoreactive band (~90 kDa) was only present in wild-type kidney membranes and not in kidney knockout or wild-type brain membranes. In the water-soluble fraction of wild-type and knockout brains, another band (~50 kDa) was observed; this band was not detected in the kidney. Light and electron microscopic immunohistochemistry using the NaPi-IIa antibodies showed immunolabeling of kidney tubules in wild-type but not knockout mice. In the brain, labeling of presynaptic nerve terminals was present also in NaPi-IIa deficient mice. This labeling pattern was also produced by the NaPi-IIa preimmune serum. The authors conclude that the polyclonal antiserum is specific toward NaPi IIa in the kidney, but in the brain, immunolabeling is caused by a cross-reaction of the antiserum with an unknown cytosolic protein that is not present in the kidney. This tissue-specific cross-reactivity highlights a potential pitfall when validating antibody specificity using knockout mouse-derived tissue other than the specific tissue of interest and underlines the utility of specificity testing using preimmune sera. PMID- 21606202 TI - The angiotensin-(1-7)/Mas receptor axis is expressed in sinoatrial node cells of rats. AB - The authors' previous studies have indicated that angiotensin(Ang)-(1-7) protects the heart against reperfusion arrhythmias. The aim of this study was to determine whether a functional angiotensin-converting enzyme2 (ACE2)/Ang-(1-7)/Mas receptor axis is present in the sinoatrial node (SAN) of Wistar rats. SAN cells were identified by Masson's trichrome staining, HCN4 expression, and lack of connexin43 expression. Immunohistochemistry technique was used to detect the expression of ACE2, Ang-(1-7), and Mas in the SAN. To evaluate the role of this axis in the SAN function, atrial tachyarrhythmias (ATs) were induced in isolated rat atria perfused with Krebs-Ringer solution (KRS) alone (control) or KRS containing Ang-(1-7). The specific Mas antagonist, A-779, was used to evaluate the role of Mas in the Ang-(1-7) effects. The findings showed that all components of the ACE2/Ang-(1-7)/Mas branch are present in the SAN of rats. Importantly, it was found that this axis is functional because perfusion of atria with Ang-(1-7) significantly reduced the duration of ATs. Additionally, this anti-arrhythmogenic effect was attenuated by A-779. No significant changes were observed in heart rate, contractile tension, or +/-dT/dt. These observations demonstrate that the ACE2/Ang-(1-7)/Mas axis is expressed in SAN cells of rats. They provide the morphological support to the anti-arrhythmogenic effect of Ang-(1-7). PMID- 21606203 TI - Estimation of immunohistochemical expression of VEGF in ductal carcinomas of the breast. AB - Vascular endothelial growth factor A (VEGF-A) is a very important growth factor in angiogenesis and holds potential as both a predictive marker for anti angiogenic cancer treatment and a prognostic variable. Consequently, reliable estimation of VEGF expression is crucial. Investigators immunostained whole tumor sections for VEGF-A, VEGF-B, and VEGFR-1 of invasive ductal carcinomas of the breast and scored the tumors manually with staining intensity as the only parameter and by a combination of qualitative and quantitative information. The investigators also introduce an automated method for analyzing VEGF expression (so-called AI score) using the same tumor sections. Analysis of 100% of the tumor area was performed and the results were compared with the reduced analysis of 25% of the tumor area. These analyses were performed at *5 and *10 magnification, and each analysis was repeated in a second run with a new delineation of the tumor area. The AI scores were correlated to the manual scoring of VEGF intensity, but reproducibility of manual IHC scores was rather poor. The AI scores were reproducible, and the restricted analysis of 25% of the tumor area at *5 magnifications was the most efficient considering time consumption and data load. PMID- 21606204 TI - Mitochondrial DNA mutations in disease and aging. AB - The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage. PMID- 21606205 TI - Global defects in collagen secretion in a Mia3/TANGO1 knockout mouse. AB - Melanoma inhibitory activity member 3 (MIA3/TANGO1) [corrected] is an evolutionarily conserved endoplasmic reticulum resident transmembrane protein. Recent in vitro studies have shown that it is required for the loading of collagen VII, but not collagen I, into COPII-coated transport vesicles. In this paper, we show that mice lacking Mia3 are defective for the secretion of numerous collagens, including collagens I, II, III, IV, VII, and IX, from chondrocytes, fibroblasts, endothelial cells, and mural cells. Collagen deposition by these cell types is abnormal, and extracellular matrix composition is compromised. These changes are associated with intracellular accumulation of collagen and the induction of a strong unfolded protein response, primarily within the developing skeleton. Chondrocyte maturation and bone mineralization are severely compromised in Mia3-null embryos, leading to dwarfism and neonatal lethality. Thus, Mia3's role in protein secretion is much broader than previously realized, and it may, in fact, be required for the efficient secretion of all collagen molecules in higher organisms. PMID- 21606206 TI - Disconnecting the Golgi ribbon from the centrosome prevents directional cell migration and ciliogenesis. AB - Mammalian cells exhibit a frequent pericentrosomal Golgi ribbon organization. In this paper, we show that two AKAP450 N-terminal fragments, both containing the Golgi-binding GM130-interacting domain of AKAP450, dissociated endogenous AKAP450 from the Golgi and inhibited microtubule (MT) nucleation at the Golgi without interfering with centrosomal activity. These two fragments had, however, strikingly different effects on both Golgi apparatus (GA) integrity and positioning, whereas the short fragment induced GA circularization and ribbon fragmentation, the large construct that encompasses an additional p150glued/MT binding domain induced separation of the Golgi ribbon from the centrosome. These distinct phenotypes arose by specific interference of each fragment with either Golgi-dependent or centrosome-dependent stages of Golgi assembly. We could thus demonstrate that breaking the polarity axis by perturbing GA positioning has a more dramatic effect on directional cell migration than disrupting the Golgi ribbon. Both features, however, were required for ciliogenesis. We thus identified AKAP450 as a key determinant of pericentrosomal Golgi ribbon integrity, positioning, and function in mammalian cells. PMID- 21606207 TI - Peroxisome reintroduction in Hansenula polymorpha requires Pex25 and Rho1. AB - We identified two proteins, Pex25 and Rho1, which are involved in reintroduction of peroxisomes in peroxisome-deficient yeast cells. These are, together with Pex3, the first proteins identified as essential for this process. Of the three members of the Hansenula polymorpha Pex11 protein family-Pex11, Pex25, and Pex11C only Pex25 was required for reintroduction of peroxisomes into a peroxisome deficient mutant strain. In peroxisome-deficient pex3 cells, Pex25 localized to structures adjacent to the ER, whereas in wild-type cells it localized to peroxisomes. Pex25 cells were not themselves peroxisome deficient but instead contained a slightly increased number of peroxisomes. Interestingly, pex11 pex25 double deletion cells, in which both peroxisome fission (due to the deletion of PEX11) and reintroduction (due to deletion of PEX25) was blocked, did display a peroxisome-deficient phenotype. Peroxisomes reappeared in pex11 pex25 cells upon synthesis of Pex25, but not of Pex11. Reintroduction in the presence of Pex25 required the function of the GTPase Rho1. These data therefore provide new and detailed insight into factors important for de novo peroxisome formation in yeast. PMID- 21606208 TI - Actin polymerization driven by WASH causes V-ATPase retrieval and vesicle neutralization before exocytosis. AB - WASP and SCAR homologue (WASH) is a recently identified and evolutionarily conserved regulator of actin polymerization. In this paper, we show that WASH coats mature Dictyostelium discoideum lysosomes and is essential for exocytosis of indigestible material. A related process, the expulsion of the lethal endosomal pathogen Cryptococcus neoformans from mammalian macrophages, also uses WASH-coated vesicles, and cells expressing dominant negative WASH mutants inefficiently expel C. neoformans. D. discoideum WASH causes filamentous actin (F actin) patches to form on lysosomes, leading to the removal of vacuolar adenosine triphosphatase (V-ATPase) and the neutralization of lysosomes to form postlysosomes. Without WASH, no patches or coats are formed, neutral postlysosomes are not seen, and indigestible material such as dextran is not exocytosed. Similar results occur when actin polymerization is blocked with latrunculin. V-ATPases are known to bind avidly to F-actin. Our data imply a new mechanism, actin-mediated sorting, in which WASH and the Arp2/3 complex polymerize actin on vesicles to drive the separation and recycling of proteins such as the V-ATPase. PMID- 21606209 TI - Management of radiation dermatitis in patients receiving cetuximab and radiotherapy for locally advanced squamous cell carcinoma of the head and neck: proposals for a revised grading system and consensus management guidelines. AB - BACKGROUND: Radiation dermatitis developing in patients receiving cetuximab concomitantly with radiotherapy for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) is now recognized to have different pathophysiological and clinical characteristics to the radiation dermatitis associated with radiotherapy or concomitant chemotherapy and radiotherapy. Current grading tools were not designed to grade this type of radiation dermatitis; their use may lead to misclassification of reactions and inappropriate management strategies, potentially compromising cancer treatment. PATIENTS AND METHODS: An advisory board of seven leading European specialists (three medical oncologists, three radiation oncologists and a dermatologist) with extensive experience of the use of cetuximab plus radiotherapy produced consensus guidelines for the grading and management of radiation dermatitis in patients receiving cetuximab plus radiotherapy. RESULTS: Modifications to the current, commonly used National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.3 for grading radiation dermatitis were proposed. Updated management guidelines, building on previously published guidelines from 2008, were also proposed. CONCLUSIONS: The proposed revisions to the grading system and updated management guidelines described here represent important developments toward the more appropriate grading and effective management of radiation dermatitis in patients receiving cetuximab plus radiotherapy for LA SCCHN. PMID- 21606210 TI - Verrucomicrobia in Brazilian Atlantic forest soil. PMID- 21606211 TI - Hebbian-type stimulation during robot-assisted training in patients with stroke. AB - BACKGROUND: Training-related improvements in motor function are associated with changes in movement representation of the primary motor cortex (M1). In healthy individuals, transcranial magnetic stimulation (TMS) of M1 delivered in a strict temporal relationship (Hebbian-type stimulation) during execution of movements enhances these effects and is superior to random stimulation. OBJECTIVE: The authors tested whether training combined with Hebbian-type M1 stimulation enhances M1 reorganization in patients with stroke. METHODS: Six patients with chronic stroke participated in the study. Patients executed robot-assisted wrist extension movements at 0.2 Hz frequency while subthreshold repetitive TMS was applied over M1 in a strict temporal relationship to the training movements. TMS was applied to either the affected hemisphere (contralateral M1) or the nonaffected hemisphere (ipsilateral M1) at 0.1 Hz. Intervention-related changes in motor maps and intracortical excitability were measured using TMS. RESULTS: Training alone or combined Hebbian-type stimulation of either M1 resulted in differential effects on motor maps and intracortical inhibition. Shifts in motor maps were associated with increases in intracortical excitability. In contrast to previous results for healthy participants, the inhibitory effect of ipsilateral M1 Hebbian-type stimulation was not present, and the facilitatory effect of contralateral M1 stimulation was more subtle. CONCLUSIONS: Hebbian-type stimulation is feasible in patients poststroke and induces map reorganization and associated decreases in GABAergic inhibition. However, because TMS protocols have a different effect on motor reorganization in the injured brain and may depend on location of the lesion, protocols need to be tailored to the patient's pathology. PMID- 21606212 TI - Psychological distress among nurses caring for victims of war in Sri Lanka. AB - OBJECTIVE: To determine prevalence and factors associated with psychological distress among nurses caring for war victims in Sri Lanka. METHODS: Descriptive, cross-sectional study design was used to collect data from 241 nurses from 2 hospitals with stratified random sampling according to workstation. Self administered 30-item General Health Questionnaire was used to detect psychological distress. RESULTS: The prevalence of psychological distress was 21%. Female sex was found to be the most significant predictor of psychological distress among nurses. Factors, such as being married, having children, or both, were found to be protective. High exposure to war victims, measured by the frequency with which a nurse tended to those patients, also resulted in less psychological distress. CONCLUSIONS: The prevalence of psychological distress is higheramong nurses in this study compared with that among the general population. Brief screening instruments, such as the General Health Questionnaire, can be used to identify individuals at risk for psychological distress. Results suggest that the presence of a social support network helped to psychologically buffer these nurses. Findings also imply the importance of promoting positive attitudes and beneficial stress (eustress) to complement a well-developed focus on distress prevention. PMID- 21606213 TI - Relationship between reactive pulmonary hypertension and mortality in patients with acute decompensated heart failure. AB - BACKGROUND: In patients with heart failure, pulmonary hypertension (PH) predicts higher risk for morbidity and mortality. However, few data are available on the prognostic implications of reactive (precapillary) PH superimposed on passive (postcapillary) PH. METHODS AND RESULTS: We performed a subgroup analysis of 242 patients with acute decompensated heart failure assigned to pulmonary artery catheter placement in the Vasodilation in the Management of Acute Congestive Heart Failure trial. Patients were classified into 3 groups, using the final (posttreatment) hemodynamic measurements: (1) no PH (mean pulmonary artery pressure <= 25 mm Hg; (2) passive PH (mean pulmonary artery pressure > 25, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance <= [corrected] Wood units); and (3) reactive PH (mean pulmonary artery pressure > 25, [corrected] pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance > 3 Wood units). Fifty-eight patients were classified as normal mean pulmonary artery pressure, 124 with passive PH and 60 with reactive PH. During follow-up of 6 months, 5 (8.6%), 27 (21.8%), and 29 (48.3%) deaths occurred in patients without PH, patients with passive PH, and with reactive PH, respectively (P<0.0001). After multivariable adjustments, reactive PH remained an independent predictor of death, with an adjusted hazard ratio of 4.8 compared with patients without PH, and 2.8 compared with patients with passive PH (95% confidence interval, 1.7 to 4.7, P=0.0001). Similar results were obtained when reactive PH was defined on the basis of transpulmonary gradient. CONCLUSIONS: Reactive PH is common among patients with acute decompensated heart failure after initial diuretic and vasodilator therapy. The adverse outcome associated with PH is predominantly due to increased mortality rates in the subgroup of patients with reactive PH. PMID- 21606214 TI - Stromal cell-derived factor-1 retention and cardioprotection for ischemic myocardium. AB - BACKGROUND: Stromal cell-derived factor-1 (SDF-1) is a chemoattractant of stem/progenitor cells, and several studies have shown that SDF-1 may improve ventricular function after infarction. SDF-1 is cleaved by proteases including matrix metalloproteinase-2 (MMP-2) and CD26/dipeptidylpeptidase-4 (DPP-4), which are activated in injured tissues. METHODS AND RESULTS: We investigated the biodistribution and functional roles of SDF-1 in experimental ischemia/reperfusion injury in rats. Radiolabeled SDF-1 given by intracoronary injection was selectively concentrated in ischemic myocardium. The enhanced uptake of SDF-1 in ischemic myocardium was not mediated by its receptor, CXCR4. Mass spectrometry and Western analyses showed that SDF-1 was cleaved by DPP-4 in plasma and myocardium, whereas a bioengineered MMP-2/DPP-4-resistant form of SDF 1, SSDF-1(S4V), was highly stable. A single dose of SSDF-1(S4V) exhibited greater potency for cardioprotection than wild-type SDF-1. SSDF-1(S4V) improved cardiac function in rats even after a 3-hour ischemic period. CONCLUSIONS: These results show that a single dose of protease-resistant SSDF-1(S4V) after myocardial infarction leads to dramatic improvement in angiogenesis and ventricular function even 3 hours after the onset of ischemia, revealing a simple, clinically feasible approach to prevention of heart failure. PMID- 21606215 TI - The allure of status: high-status targets are privileged in face processing and memory. AB - The current research tests the hypothesis that face processing is attuned to high status faces. Across three experiments, faces of high-status targets were better recognized than faces of low-status targets. In Experiment 2, this memory advantage for high-status targets also extended to an attentional bias toward high-status targets and to stronger sociospatial memory (identity-location link) for high-status targets. Finally, Experiment 3 finds that high-status faces received more expert-style holistic processing than did low-status faces. This suggests that high-status faces also benefit more from the strategic deployment of expert face processing resources than low-status faces. Taken together, these data indicate that perceivers strategically allocate face processing resources to targets perceived to be high in status. PMID- 21606216 TI - Learning inhibition in the Monty Hall problem: the role of dysfunctional counterfactual prescriptions. AB - Despite repeated trials, people consistently fail to learn the solution to the Monty Hall problem (MHP). This research examines the links between learning, counterfactual thinking, and memory for decision/outcome frequencies. Study 1 participants completed 60 MHP trials and listed their thoughts following losses. Results showed that participants tended to counterfactualize switch losses more than stick losses, adhered to the prescriptions of their counterfactuals more frequently following switch losses than any other decisions/outcomes, and were less likely to learn the solution as counterfactuals increased. Furthermore, memory for switch losses was significantly overestimated, and the relationship between counterfactuals and learning was mediated by misestimation of decision/outcome frequencies. In Study 2, counterfactual salience was manipulated. Learning was less likely to occur when counterfactual salience was high than when it was low, a relationship that was again mediated by memory of decision/outcome frequencies. Findings are discussed in light of their theoretical and applied implications. PMID- 21606217 TI - Off-target serine/threonine kinase 10 inhibition by erlotinib enhances lymphocytic activity leading to severe skin disorders. AB - Skin disorders are among the most common adverse events related to treatment with epidermal growth factor receptor (EGFR) kinase inhibitors, and of these, erlotinib is known to cause more frequent and severe skin disease than other agents in this class. Although previous reports have shown that cutaneous manifestations are triggered by the inhibition of multiple EGFR-related homeostatic functions of the skin, this mechanism alone cannot explain the differences in frequency and severity of skin disorders caused by different kinase inhibitors. In this study, we focused on the relationship between the off target kinase inhibition and aggravation of skin disorders. Based on calculations using reported K(d) values and plasma drug concentrations, serine/threonine kinase 10 (STK10) and Ste20-like kinase (SLK) were selected as candidates preferentially inhibited by erlotinib over gefitinib. In vitro experiments confirmed that STK10 and SLK kinase activity are inhibited by erlotinib at clinical concentrations, whereas only STK10 is slightly inhibited by gefitinib. It was also shown that erlotinib up-regulated lymphocytic responses such as interleukin (IL)-2 secretion and cell migration at clinical concentrations, whereas gefitinib did not affect lymphocyte activity. Moreover, small interfering RNA experiments revealed that STK10 plays a major role in up-regulation of the lymphocytic responses induced by erlotinib treatment. Finally, the role of erlotinib-induced lymphocyte activation was assessed in vivo using irritant hypersensitivity models. The results indicated that erlotinib aggravates cutaneous inflammatory reactions through the activation of lymphocytic responses such as IL-2 secretion and cell migration. These results demonstrated that off target inhibition of STK10 by erlotinib enhances lymphocytic responses, which lead to the aggravation of skin inflammation. PMID- 21606218 TI - Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. AB - Hyperglycemia plays an important role in the pathogenesis of type 2 diabetes mellitus, i.e., glucotoxicity, and it also is the major risk factor for microvascular complications. Thus, effective glycemic control will not only reduce the incidence of microvascular complications but also correct some of the metabolic abnormalities that contribute to the progression of the disease. Achieving durable tight glycemic control is challenging because of progressive beta-cell failure and is hampered by increased frequency of side effects, e.g., hypoglycemia and weight gain. Most recently, inhibitors of the renal sodium glucose cotransporter have been developed to produce glucosuria and reduce the plasma glucose concentration. These oral antidiabetic agents have the potential to improve glycemic control while avoiding hypoglycemia, to correct the glucotoxicity, and to promote weight loss. In this review, we will summarize the available data concerning the mechanism of action, efficacy, and safety of this novel antidiabetic therapeutic approach. PMID- 21606219 TI - Early to bed, early to rise?: an exploration of adolescent sleep hygiene practices. AB - Cognition, memory, safety, mental health, and weight are all affected by inadequate sleep. Biological studies indicate significant changes in sleep architecture during adolescence, such as changes in melatonin secretion, and a need for greater total sleep time. Yet, social contexts and cultural values impinge on these changing biological sleep needs making adolescents vulnerable to the dangers of insufficient sleep. Sleep hygiene practices are purported as potential mediating factors between biological sleep needs and the sociocultural context of sleep. The purpose of this literature review is to highlight biological and social factors contributing to insufficient sleep in adolescents, to explore the evidence of several recommended sleep hygiene practices, and to stimulate further research about how adolescents negotiate their shifting biological sleep needs amid increasing social demands. PMID- 21606220 TI - School wellness policies: opportunities for change. AB - School districts are required to comply with a 2004 federal mandate to guide nutrition and physical activity environments of schools by developing and implementing wellness policies. The purposes of this article are to (a) discuss the implications of the federal mandate and (b) analyze policies from nine school districts in one large suburban county in Minnesota to assess for compliance, comprehension, and strength. Policy analysis was guided by a coding system that reflected the federal mandate. Only one district met all federal requirements; policy statements from most districts analyzed were nonspecific. Evidence from this analysis supports previous research indicating that many school wellness policies are not comprehensive, lack strength, and do not fully comply with the intent of the federal mandate. School nurses, as stakeholders in school environments, must identify and utilize collaborative opportunities to impact policy development and implementation regarding school nutrition and physical activity environments. PMID- 21606221 TI - Visually storying living with HIV: bridging stressors and supports in accessing care. AB - This paper examines how visual narratives may bridge relational understandings between people living with HIV/AIDS (PLWH/A) and future oral health care providers. Borrowing from literature in participatory visual methods such as photo elicitation and photovoice, we explored how PLWH/A visually choose to represent their daily lives. This study uses a grounded theory action-oriented approach in examining the thematic analysis of 257 photos and 12 related reflective participant journals. Ten collaborative themes emerged from the participants' analysis of their photos. These themes of social support, places, family, staff, group, recovery tools, transportation, friends, medications and food exhibited the indivisible characteristics of stressors and supports commonly found in accessing care. Further researcher reflections also found three meta themes of stigmatization, maintenance of positive mental health and the development of pride in managing one's health. PLWH/A need to share these visual themes of supports and stressors with future dental providers so that they may hopefully acquire an understanding of chronic illness that is more personalized and relationship centered rather than merely numeric and detached. PMID- 21606222 TI - Correlation of daptomycin resistance in a clinical Staphylococcus aureus strain with increased cell wall teichoic acid production and D-alanylation. AB - Cell wall thickening is a common feature among daptomycin-resistant Staphylococcus aureus strains. However, the mechanism(s) leading to this phenotype is unknown. We examined a number of cell wall synthesis pathway parameters in an isogenic strain set of S. aureus bloodstream isolates obtained from a patient with recalcitrant endocarditis who failed daptomycin therapy, including the initial daptomycin-susceptible parental strain (strain 616) and two daptomycin-resistant strains (strains 701 and 703) isolated during daptomycin therapy. Transmission electron microscopy demonstrated significantly thicker cell walls in the daptomycin-resistant strains than in the daptomycin-susceptible strain, a finding which was compatible with significant differences in dry cell weight of strain 616 versus strains 701 to 703 (P < 0.05). Results of detailed analysis of cell wall muropeptide composition, the degree of peptide side chain cross-linkage, and the amount of the peptidoglycan precursor, UDP-MurNAc pentapeptide, were similar in the daptomycin-susceptible and daptomycin-resistant isolates. In contrast, the daptomycin-resistant strains contained less O acetylated peptidoglycan. Importantly, both daptomycin-resistant strains synthesized significantly more wall teichoic acid (WTA) than the parental strain (P < 0.001). Moreover, the proportion of D-alanylated WTA species was substantially higher in the daptomycin-resistant strains than in the daptomycin susceptible parental strain (P < 0.05 in comparing strain 616 versus strain 701). The latter phenotypic findings correlated with (i) enhanced tagA and dltA gene expression, respectively, and (ii) an increase in surface positive charge observed in the daptomycin-resistant versus daptomycin-susceptible isolates. Collectively, these data suggest that increases in WTA synthesis and the degree of its D-alanylation may play a major role in the daptomycin-resistant phenotype in some S. aureus strains. PMID- 21606223 TI - Comparative activities of tigecycline and other tetracyclines against nonfermenting Gram-negative bacilli, excluding Acinetobacter spp. PMID- 21606225 TI - More on identification of iron deficiency when it coexists with chronic inflammation. PMID- 21606224 TI - Emergence of quinolone resistance and cephalosporin MIC creep in Neisseria gonorrhoeae isolates from a cohort of young men in Kisumu, Kenya, 2002 to 2009. AB - We evaluated antimicrobial resistance in Neisseria gonorrhoeae isolated from men enrolled in a randomized trial of male circumcision to prevent HIV. Urethral specimens from men with discharge were cultured for N. gonorrhoeae. MICs were determined by agar dilution. Clinical and Laboratory Standards Institute (CLSI) criteria defined resistance: penicillin, tetracycline, and azithromycin MICs of >=2.0 MUg/ml; a ciprofloxacin MIC of >=1.0 MUg/ml; and a spectinomycin MIC of >=128.0 MUg/ml. Susceptibility to ceftriaxone and cefixime was shown by an MIC of <=0.25 MUg/ml. Additionally, PCR amplification identified mutations in parC and gyrA genes in selected isolates. From 2002 to 2009, 168 N. gonorrhoeae isolates were obtained from 142 men. Plasmid-mediated penicillin resistance was found in 65%, plasmid-mediated tetracycline resistance in 97%, and 11% were ciprofloxacin resistant (quinolone-resistant N. gonorrhoeae [QRNG]). QRNG appeared in November 2007, increasing from 9.5% in 2007 to 50% in 2009. Resistance was not detected for spectinomycin, cefixime, ceftriaxone, or azithromycin, but MICs of cefixime (P = 0.018), ceftriaxone (P < 0.001), and azithromycin (P = 0.097) increased over time. In a random sample of 51 men, gentamicin MICs were as follows: 4 MUg/ml (n = 1), 8 MUg/ml (n = 49), and 16 MUg/ml (n = 1). QRNG increased rapidly and alternative regimens are required for N. gonorrhoeae treatment in this area. Amid emerging multidrug-resistant N. gonorrhoeae, antimicrobial resistance surveillance is essential for effective drug choice. High levels of plasmid mediated resistance and increasing MICs for cephalosporins suggest that selective pressure from antibiotic use is a strong driver of resistance emergence. PMID- 21606226 TI - Mean corpuscular haemoglobin, referenced and resurrected. PMID- 21606228 TI - Oral glucose tolerance testing outcomes among women at high risk for gestational diabetes mellitus. AB - AIMS: This study aimed to determine the prevalence and relationships with known risk factors of gestational diabetes mellitus (GDM) at University College Hospital, Ibadan, Nigeria. METHODS: Records of all women referred for oral glucose tolerance testing at the metabolic research unit of the Hospital over a 2 year period were reviewed. Diagnosis of GDM was made in accordance with WHO criteria. GDM diagnosis was classified as early and late based on a gestational age <24 weeks and >24 weeks respectively. Body mass index (BMI) measurements were performed for women who presented in the first trimester. Various statistical tools including student t test and Pearson's coefficient of correlation were used. RESULTS: A total of 765 records were reviewed. The crude prevalence rate was 13.9%. The prevalence rate among women in the first trimester was highest at 17.4% although most of the diagnoses were made in the third trimester (55.7%). A positive family history and a family history of GDM were associated significantly with a higher fasting and 2 h post-load glucose values, irrespective of current GDM diagnosis. The most consistent associations with a diagnosis of GDM were a positive family history and a history of GDM. Age above 30 years at oral glucose testing also showed significant association. There was no BMI threshold associated with a significant risk of GDM for those women presenting in the first trimester. CONCLUSIONS: GDM is a common metabolic condition in Nigeria. Onset before the 24th week of pregnancy is not uncommon. PMID- 21606229 TI - Still waiting for predictive biomarkers in Barrett's oesophagus. AB - Barrett's oesophagus is important as a precursor of oesophageal adenocarcinoma via a metaplasia-dysplasia-carcinoma sequence. It is often detected on upper gastrointestinal endoscopy. In the absence of glandular dysplasia the risk of progression to cancer is low but ascertainment of dysplasia is not always straightforward. Sparse mucosal sampling may miss dysplasia, or reactive changes may be overinterpreted due to inter and intraobserver variation. Low-grade and even high-grade dysplasia do not necessarily progress, provided prevalent cancer has been rigorously excluded. This indeterminacy motivates an ongoing search for clinically useful predictive biomarkers. Although many genetic and epigenetic abnormalities have been associated with neoplastic progression in Barrett's mucosa no molecular tests have as yet been accepted into routine pathology practice. Challenges of assay definition remain and many marker studies lack statistical power or have other methodological flaws. Even where strong evidence of clinically relevant predictive value does exist (in the case of ploidy analysis by flow or image cytometry) adoption has been minimal, likely reflecting technological and possible reimbursement obstacles. Well designed multicentre studies are likely to be required to translate improved knowledge of Barrett's carcinogenesis into clinically significant progress on predictive testing, and will require a degree of cooperation not so far widely seen in the field. PMID- 21606230 TI - A prospective randomised study of a rotary powered device (OnControl) for bone marrow aspiration and biopsy. AB - INTRODUCTION: Bone marrow aspiration and biopsy is an invasive procedure associated with morbidity and mortality risk. We compared a powered bone marrow aspiration and biopsy device to the traditional method by relatively assessing pain scores, procedure times, biopsy capture rates, quality of material retrieved, and safety and operator satisfaction. METHODS: Two large academic medical centres participated in this trial. Patients were randomised to have procedures carried out using the powered system or the manual technique. A visual analogue scale pain score was recorded immediately following skin puncture and once again at the end of the procedure for each patient. Procedure time was measured from skin puncture to core specimen acquisition. Pathologic assessment of 30 randomised samples was carried out. Operator satisfaction with devices was measured on a scale of 0-10, with 10 as the highest rating. RESULTS: Five operators from two sites enrolled 50 patients (powered, n=25; manual, n=25). Groups were evenly matched, with no significant differences in the means for age, weight and height. The powered system was superior to the manual system with respect to patient perceived pain from needle insertion (2.6+/-2.0 vs 4.1+/-2.5, p=0.022) and procedural time (100.0+/-72.8 s vs 224.1+/-79.0 s, p<0.001). Overall pain scores at the end of both procedures were comparable (3.2+/-2.2 vs 3.8+/ 3.0, p=0.438). No complications were observed in either arm of the study. Blinded pathologic analysis of the specimens retrieved revealed that cores obtained using the powered system were longer and wider than those obtained using the manual technique (25.4+/-12.3 mm2 vs 11.9+/-5.6 mm2, p=0.001). For marrow aspiration, no difference was seen between groups for clot/particle spicules or smear spicules. Operator assessment favoured the use of the powered device. CONCLUSIONS: Results of this trial suggest that the use of a powered bone marrow biopsy device significantly reduces needle insertion pain and procedural time when compared to a manual technique. The superior size and overall quality of core specimens retrieved by the powered device provides more material for pathologic evaluation, thereby increasing diagnostic yield and reducing the need for repeat procedures. PMID- 21606231 TI - Evaluation of adjunct immunohistochemistry on reporting patterns of non-small cell lung carcinoma diagnosed histologically in a regional pathology centre. AB - Morphological sub-classification of non-small cell carcinoma in small biopsy specimens presents difficulties for pathologists and recent advances in chemotherapy have resulted in increased pressure to more robustly differentiate between squamous carcinoma and adenocarcinoma. The results of audits examining classification of non-small cell lung carcinoma by pathologists working in a specialist team within a regional centre and the effect of introducing adjunct immunohistochemistry into the reporting pathway are presented. It is concluded that the use of a limited immunohistochemical panel substantially reduces the number of cases when a specific cell type cannot be identified or 'favoured' (34% to 6%) and that the classification obtained correlates well with that found in subsequent resection specimens. In addition the introduction of immunohistochemistry substantially reduces the variability in reporting practice between pathologists. PMID- 21606232 TI - Intranuclear inclusions in epithelial cells of benign proliferative breast lesions. AB - AIM: To document and clarify the nature of intranuclear inclusions of luminal epithelium in benign proliferative breast lesions. METHODS AND RESULTS: Five benign breast lesions were selected which showed intranuclear inclusions within epithelial cells on light microscopy. Following confirmation of their luminal epithelial (non-myoepithelial) localisation by immunohistochemistry, ultrastructural examination was performed with the following observations: (1) presence of deep nuclear indentations occasionally verging on nuclear inclusions; (2) inclusions with features of helioid bodies; and (3) a morphological spectrum of helioid bodies and their focal coexistence. CONCLUSION: Intranuclear inclusions of breast epithelium are likely of cytoplasmic origin. Helioid bodies may be formed by a stepwise process, the nature of which needs further study. PMID- 21606233 TI - Influence of sampling on clustering and associations with risk factors in the molecular epidemiology of tuberculosis. AB - Molecular epidemiologic studies may use genotypic clustering of isolates as an indicator of recent transmission. It has been shown that missing cases lead to underestimating clustering, and modelling studies suggested that they may also lead to underestimating odds ratios for clustering. Using a national, comprehensive database from the Netherlands covering 15 years between 1993 and 2007 and including over 12,000 patients and their isolates, the authors determined the effects of sampling at random, in time, and by geographic area. As expected, sampling reduced the observed clustering percentages. However, sampling did not reduce the observed odds ratios for clustering. The main explanations for this discrepancy with model outcomes were that a substantial proportion of clustered cases were found in large clusters and that risk factors for clustering tended to be-among clustered cases-also risk factors for large clusters. The authors conclude that, in settings where risk factors for clustering may be interpreted as risk factors for recent transmission, these risk factors are also associated with larger cluster sizes. As a result, odds ratios would show limited sampling bias. PMID- 21606234 TI - Prediction model of Parkinson's disease based on antiparkinsonian drug claims. AB - Drug claims databases are increasingly available and provide opportunities to investigate epidemiologic questions. The authors used computerized drug claims databases from a social security system in 5 French districts to predict the probability that a person had Parkinson's disease (PD) based on patterns of antiparkinsonian drug (APD) use. Clinical information for a population-based sample of persons using APDs in 2007 was collected. The authors built a prediction model using demographic variables and APDs as predictors and investigated the additional predictive benefit of including information on dose and regularity of use. Among 1,114 APD users, 320 (29%) had PD and 794 (71%) had another diagnosis as determined by study neurologists. A logistic model including information on cumulative APD dose and regularity of use showed good performance (c statistic = 0.953, sensitivity = 92.5%, specificity = 86.4%). Predicted PD prevalence (among persons aged >=18 years) was 6.66/1,000; correcting this estimate using sensitivity/specificity led to a similar figure (6.04/1,000). These data demonstrate that drug claims databases can be used to estimate the probability that a person is being treated for PD and that information on APD dose and regularity of use improves models' performances. Similar approaches could be developed for other conditions. PMID- 21606235 TI - Urgent findings on portable chest radiography: what the radiologist should know- review. PMID- 21606236 TI - Imaging of Paget disease of bone and its musculoskeletal complications: review. PMID- 21606237 TI - MRI of nontumorous skeletal muscle disease: case-based review. PMID- 21606238 TI - Chronic recurrent multifocal osteomyelitis: review. PMID- 21606239 TI - Urgent findings on portable chest radiography: what the radiologist should know- self-assessment module. AB - The educational objectives for this self-assessment module are for the participant to exercise, self-assess, and improve his or her understanding of the spectrum of urgent findings on portable chest radiography. PMID- 21606240 TI - Radiological reasoning: imaging of a talar mass. PMID- 21606241 TI - Imaging of Paget disease of bone and its musculoskeletal complications: self assessment module. AB - The educational objectives for this self-assessment module are for the participant to exercise, self-assess, and improve his or her skills in diagnostic radiology with regard to imaging of Paget disease of bone and its musculoskeletal complications. PMID- 21606242 TI - MRI of nontumorous skeletal muscle disease: self-assessment module. AB - The educational objectives for this case-based self-assessment module are for the participant to exercise, self-assess, and improve skills in diagnostic radiology with regard to the interpretation of MRI examinations of nontumorous skeletal muscle disease. PMID- 21606243 TI - Imaging of chronic recurrent multifocal osteomyelitis: self-assessment module. AB - The educational objectives for this self-assessment module are for the participant to exercise, self-assess, and improve his or her understanding of both the imaging and clinical findings of chronic recurrent multifocal osteomyelitis (CRMO). PMID- 21606244 TI - Cystic and cystic-appearing lesions of the mandible: review. PMID- 21606245 TI - AJR teaching file: left neck mass evaluated by PET/CT. PMID- 21606246 TI - AJR teaching file: incidental breast cancer detected with 18F-FDG PET/CT. PMID- 21606247 TI - Involvement of tyrosine kinase-2 in both the IL-12/Th1 and IL-23/Th17 axes in vivo. AB - Tyrosine kinase-2 (Tyk2), a member of the Jak family of kinases, mediates the signals triggered by various cytokines, including type I IFNs, IL-12, and IL-23. In the current study, we investigated the in vivo involvement of Tyk2 in several IL-12/Th1- and IL-23/Th17-mediated models of experimental diseases, including methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis like skin inflammation, and dextran sulfate sodium- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis. In these disease models, Tyk2 deficiency influenced the phenotypes in immunity and/or inflammation. Our findings demonstrate a somewhat broader contribution of Tyk2 to immune systems than previously expected and suggest that Tyk2 may represent an important candidate for drug development by targeting both the IL-12/Th1 and IL-23/Th17 axes. PMID- 21606248 TI - IL-6 mediates the susceptibility of glycoprotein 130 hypermorphs to Toxoplasma gondii. AB - IL-6 and IL-27 are closely related cytokines that play critical but distinct roles during infection with Toxoplasma gondii. Thus, IL-6 is required for the development of protective immunity to this pathogen, whereas IL-27 is required to limit infection-induced pathology. Paradoxically, these factors both signal through gp130, but little is known about how the signals downstream of gp130 are integrated to coordinate the immune response to infection. To better understand these events, gp130 Y757F mice that have a mutation in gp130 at the binding site for suppressor of cytokine signaling 3, a critical negative regulator of gp130 signaling, were infected with T. gondii. These mutant mice were acutely susceptible to this challenge, characterized by an early defect in the production of IL-12 and IFN-gamma and increased parasite burdens. Consistent with the reduced IL-12 levels, IL-6, but not other gp130 cytokines, was a potent antagonist of IL-12 production by gp130 Y757F macrophages and dendritic cells in vitro. Moreover, in gp130 Y757F mice, blocking IL-6 in vivo, or administration of rIL-12, during infection restored IFN-gamma production and protective immunity. Collectively, these studies highlight that a failure to abbreviate IL-6-mediated gp130 signaling results in a profound anti-inflammatory signal that blocks the generation of protective immunity to T. gondii. PMID- 21606250 TI - Y-box binding protein-1 mediates profibrotic effects of calcineurin inhibitors in the kidney. AB - The immunosuppressive calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus are widely used in transplant organ recipients, but in the kidney allograft, they may cause tubulointerstitial as well as mesangial fibrosis, with TGF-beta believed to be a central inductor. In this study, we report that the cold-shock protein Y-box binding protein-1 (YB-1) is a TGF-beta independent downstream effector in CsA- as well as in tacrolimus- but not in rapamycin mediated activation of rat mesangial cells (rMCs). Intracellular content of YB-1 is several-fold increased in MCs following CNI treatment in vitro and in vivo in mice. This effect ensues in a time-dependent manner, and the operative concentration range encompasses therapeutically relevant doses for CNIs. The effect of CNI on cellular YB-1 content is abrogated by specific blockade of translation, whereas retarding the transcription remains ineffective. The activation of rMCs by CNIs is accomplished by generation of reactive oxygen species. In contrast to TGF-beta-triggered reactive oxygen species generation, hydrogen peroxide especially could be identified as a potent inductor of YB-1 accumulation. In line with this, hindering TGF-beta did not influence CNI-induced YB-1 upregulation, whereas ERK/Akt pathways are involved in CNI-mediated YB-1 expression. CsA-induced YB-1 accumulation results in mRNA stabilization and subsequent generation of collagen. Our results provide strong evidence for a CNI dependent induction of YB-1 in MCs that contributes to renal fibrosis via regulation of its own and collagen translation. PMID- 21606249 TI - Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. AB - IL-17 and IL-23 are known to be absolutely central to psoriasis pathogenesis because drugs targeting either cytokine are highly effective treatments for this disease. The efficacy of these drugs has been attributed to blocking the function of IL-17-producing T cells and their IL-23-induced expansion. However, we demonstrate that mast cells and neutrophils, not T cells, are the predominant cell types that contain IL-17 in human skin. IL-17(+) mast cells and neutrophils are found at higher densities than IL-17(+) T cells in psoriasis lesions and frequently release IL-17 in the process of forming specialized structures called extracellular traps. Furthermore, we find that IL-23 and IL-1beta can induce mast cell extracellular trap formation and degranulation of human mast cells. Release of IL-17 from innate immune cells may be central to the pathogenesis of psoriasis, representing a fundamental mechanism by which the IL-23-IL-17 axis mediates host defense and autoimmunity. PMID- 21606252 TI - Cystic lesions of the pancreas. PMID- 21606251 TI - Mass spectrometric characterization of circulating and functional antigens derived from piperacillin in patients with cystic fibrosis. AB - A mechanistic understanding of the relationship between the chemistry of drug Ag formation and immune function is lacking. Thus, mass spectrometric methods were employed to detect and fully characterize circulating Ags derived from piperacillin in patients undergoing therapy and the nature of the drug-derived epitopes on protein that can function as an Ag to stimulate T cells. Albumin modification with piperacillin in vitro resulted in the formation of two distinct haptens, one formed directly from piperacillin and a second in which the dioxopiperazine ring had undergone hydrolysis. Modification was time and concentration dependent, with selective modification of Lys(541) observed at low concentrations, whereas at higher concentrations, up to 13 out of 59 lysine residues were modified, four of which (Lys(190), Lys(195), Lys(432), and Lys(541)) were detected in patients' plasma. Piperacillin-specific T lymphocyte responses (proliferation, cytokines, and granzyme B release) were detected ex vivo with cells from hypersensitive patients, and analysis of incubation medium showed that modification of the same lysine residues in albumin occurred in situ. The antigenicity of piperacillin-modified albumin was confirmed by stimulation of T cells with characterized synthetic conjugates. Analysis of minimally modified T cell-stimulatory albumin conjugates revealed peptide sequences incorporating Lys(190), Lys(432), and Lys(541) as principal functional epitopes for T cells. This study has characterized the multiple haptenic structures on albumin in patients and showed that they constitute functional antigenic determinants for T cells. PMID- 21606253 TI - Complications of CT-guided percutaneous needle biopsy of the chest: prevention and management. AB - OBJECTIVE: The objective of this article is to describe potential complications of percutaneous needle biopsy of the chest, discuss the risk factors associated with the development of complications, and explain how to prevent complications and manage complications when they occur. CONCLUSION: Pneumothorax and pulmonary hemorrhage are the most common complications of percutaneous needle biopsy of the chest, whereas air embolism and tumor seeding are extremely rare. Attention to biopsy planning and technique and postprocedural care help to prevent or minimize most potential complications. PMID- 21606254 TI - Clinical applications of physical 3D models derived from MDCT data and created by rapid prototyping. AB - OBJECTIVE: In this article, we describe the production of physical models from CT data using rapid prototyping and present their clinical application. MDCT data acquisition of isotropic voxels and modern postprocessing techniques provide exquisite detail for clinicians and radiologists. CONCLUSION: In recent years, rapid prototyping technologies have provided new possibilities to visualize complex anatomic structures through the generation of physical models that can be used to assist with diagnosis, surgical planning, prosthesis design, and patient communication. PMID- 21606255 TI - X-ray crystallography and the elucidation of the structure of DNA. AB - OBJECTIVE: Since their discovery by Roentgen in 1895, x-rays have contributed to some of the most important advances in science. X-ray crystallography is an imaging technique that uses x-ray diffraction to evaluate the molecular structure of a crystalline solid. This article discusses the critical role played by x-ray crystallography in the elucidation of the structure of DNA. CONCLUSION: The story of DNA includes insights on molecular structure provided by x-rays and also lessons on scientific collaboration and innovation that can be applied to radiology today. PMID- 21606256 TI - Iodine quantification with dual-energy CT: phantom study and preliminary experience with renal masses. AB - OBJECTIVE: The purpose of this study was to validate the utility of dual-source dual-energy MDCT in quantifying iodine concentration in a phantom and in renal masses. MATERIALS AND METHODS: A series of tubes containing solutions of varying iodine concentration were imaged with dual-source dual-energy MDCT. Iodine concentration was calculated and compared with known iodine concentration. Single phase contrast-enhanced dual-source dual-energy MDCT data on 15 patients with renal lesions then were assessed independently by two readers. Dual-energy postprocessing was used to generate iodine-only images. Regions of interest were placed on the iodine image over the lesion and, as a reference, over the aorta, for recording of iodine concentration in the lesion and in the aorta. Another radiologist determined lesion enhancement by comparing truly unenhanced with contrast-enhanced images. Mixed-model analysis of variance based on ranks was used to compare lesion types (simple cyst, hemorrhagic cyst, enhancing mass) in terms of lesion iodine concentration and lesion-to-aorta iodine ratio. RESULTS: In the phantom study, there was excellent correlation between calculated and true iodine concentration (R(2) = 0.998, p < 0.0001). In the patient study, 13 nonenhancing (10 simple and three hyperdense cysts) and eight enhancing renal masses were evaluated in 15 patients. The lesion iodine concentration and lesion to-aorta iodine ratio in enhancing masses were significantly higher than in hyperdense and simple cysts (p < 0.0001). CONCLUSION: Iodine quantification with dual-source dual-energy MDCT is accurate in a phantom and can be used to determine the presence and concentration of iodine in a renal lesion. Characterization of renal masses may be possible with a single dual-source dual energy MDCT acquisition without unenhanced images or reliance on a change in attenuation measurements. PMID- 21606257 TI - Diffusion-attenuated MRI signal of renal allografts: comparison of two different statistical models. AB - OBJECTIVE: Contrast-enhanced MRI is considered problematic in renal allograft recipients because of the development of nephrogenic systemic fibrosis. Therefore, we assessed the clinical value of a monoexponential model and a distribution function model of diffusion-weighted imaging (DWI) in renal allografts. MATERIALS AND METHODS: A total of 23 patients were divided into three groups, as follows: group A, stable renal allograft function for at least 6 months; group B, transplantation within the past 30 days, with good renal allograft function; and group C, an acute deterioration or decrease in renal allograft function. T2-weighted axial, T1-weighted coronal, and a paracoronal DWI sequences with 16 b values (b = 0-750 s/mm(2)) were performed on a 1.5-T scanner. Region of interest-based analysis of the apparent diffusion coefficient (ADC) of the renal cortex was used. RESULTS: Monoexponential analysis showed mean (+/- SD) ADC values of 1932 +/- 98, 2095 +/- 246, and 1636 +/- 200 10-(6) mm(2)/s for patient groups A, B, and C, respectively. The distribution function revealed a mean ADC of 2487 +/- 185, 2850 +/- 325, and 2142 +/- 31410-(6) mm(2)/s for groups A, B, and C, respectively. The difference between groups A and B combined and group C (p < 0.005) was statistically significant for both models. R(2) yielded the best regression of mathematic fitting for the distribution function model (p < 0.0001). DISCUSSION: Unenhanced evaluation of renal allografts with DWI correlated well with renal function for both the monoexponential analysis and the distribution function model. There was no statistically significant difference in ADC values and renal allograft function between both types of analysis, but the distribution function showed the best regression. PMID- 21606258 TI - Adrenocortical carcinoma: the range of appearances on CT and MRI. AB - OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare, aggressive tumor arising from the adrenal cortex that typically presents late with a large mass. The increased use of cross-sectional imaging for unrelated reasons has led to a greater number of ACCs being detected incidentally at an earlier stage. Recognition of the typical clinical, biochemical, and imaging findings is imperative for rapid diagnosis, prompt intervention, and early use of the appropriate therapy. CONCLUSION: Cross-sectional imaging with CT and MRI is essential for determining the extent of local and distant tumor spread. Complete surgical resection is currently the only potentially curative treatment of ACC, and the information attained from CT and MRI is important to guide surgery and further patient management. PMID- 21606259 TI - Usefulness of prebiopsy multifunctional and morphologic MRI combined with free-to total prostate-specific antigen ratio in the detection of prostate cancer. AB - OBJECTIVE: The purpose of the study was to assess the predictive value for prostate cancer of MRI using morphologic (T2-weighted imaging [T2WI]) and functional (MR spectroscopy [MRS], diffusion-weighted imaging [DWI], and dynamic contrast-enhanced [DCE] MRI) sequences and the free-to-total prostate-specific antigen (PSA) ratio, alone and combined. MATERIALS AND METHODS: This retrospective study included 70 patients (PSA level, > 4 ng/mL; free-to-total PSA ratio, < 20%) who underwent endorectal 1.5-T MRI before biopsy. We graded the likelihood of cancer on a 5-point scale. Imaging data were compared with histologic results on biopsy or prostatectomy. Accuracies were estimated from the area under receiver operating characteristic using the hemiprostate as the unit of analysis. A p value less than 0.05 denoted statistical significance. RESULTS: The model combining all variables was more accurate than each variable alone (95.2% vs 73.5% for T2WI, 76.0% for MRS, 81.8% for DWI, 75.6% for DCE-MRI, and 78.8% for free-to-total PSA ratio). The complete model had accuracy similar to that of combining two imaging variables with free-to-total PSA ratio, especially free-to-total PSA ratio, T2WI, and DWI (94.0%); and free-to-total PSA ratio, DWI, and MRS (93.8%); with negative predictive values of 91.0% and 89.5%, respectively. The best models combining two imaging variables (MRS and DWI, 85.8%; T2WI and DWI, 84.8%) had accuracy that was similar to that of the combination of all imaging variables (87.3%) and higher than that of the best individual imaging variable (DWI, 81.8%), but lower than that of the complete model. CONCLUSION: The combination of at least one functional technique with free to-total PSA ratio is more accurate than combining only imaging variables in cancer detection. The use of more than two imaging variables does not increase the detection rate. Functional MRI has the potential to help avoid a large number of negative biopsies. PMID- 21606260 TI - Swine-origin influenza A (H1N1) viral infection: thoracic findings on CT. AB - OBJECTIVE: The purpose of this article is to illustrate and describe various CT manifestations of swine-origin influenza A (H1N1) viral infection. CONCLUSION: The imaging findings seen in patients with H1N1 infection include consolidations, ground-glass opacities, interlobular septal thickening, small nodules, and findings suggestive of small airways disease, among others. Definitive diagnosis is based on correlation of the CT findings with the clinical symptoms and laboratory test results. PMID- 21606261 TI - Coronary image quality of 320-MDCT in patients with heart rates above 65 beats per minute: preliminary experience. AB - OBJECTIVE: High heart rate may negatively influence the image quality of cardiac CT. The technical advances of 320-MDCT may overcome issues with poor image quality associated with high heart rate. This study aimed to evaluate the coronary image quality of 320-MDCT in patients with heart rates above 65 beats/min. MATERIALS AND METHODS: Patients who presented for cardiac CT were divided into two groups according to heart rate, either greater than 65 beats/min or less than or equal to 65 beats/min. Two radiologists were blinded to the patient groups and evaluated images of 15 coronary artery segments per patient using 320-MDCT with consensus agreement. The image quality was scored subjectively as 1 or 2 (diagnostic quality) or 3 (poor quality and nondiagnostic). RESULTS: There were no statistically significant differences between the two groups in terms of age, sex, and body mass index (p > 0.05). The median heart rate was 70 beats/min (range, 67-110 beats/min) for the group with heart rate greater than 65 beats/min and 60 beats/min (range, 48-65 beats/min) for the group with heart rate less than or equal to 65 beats/min (p < 0.001). In patients with heart rates greater than 65 beats/min, diagnostic quality images (scores of 1 or 2) were obtained in 95.6% of the analyzed segments, compared with 96.9% in the group with heart rate less than or equal to 65 beats/min (p = 0.7). CONCLUSION: Our initial evaluation suggests that coronary artery images of diagnostic quality can be obtained using 320-MDCT in most patients with heart rates greater than 65 beats/min, in percentages similar to those for patients with heart rates less than or equal to 65 beats/min. This finding may be the result of the inherent image acquisition and reconstruction technique of 320 MDCT. PMID- 21606262 TI - Hepatic steatosis in morbidly obese patients undergoing gastric bypass surgery: assessment with open-system 1H-MR spectroscopy. AB - OBJECTIVE: The purpose of this study was to assess, with histopathologic control, the use of open-system 1-T (1)H MR spectroscopy for the evaluation of hepatic steatosis in morbidly obese patients undergoing gastric bypass surgery. SUBJECTS AND METHODS: Patients underwent (1)H MR spectroscopy (MRS) for the assessment of steatosis before and 3 months after surgery. Liver biopsy was performed during surgery. Hepatic steatosis was expressed as the ratio of fat peak area to cumulative water and fat peak areas. Histopathologic percentage of steatosis was graded as none (0-5%), mild (5-33%), moderate (33-66%), or severe (> 66%). The accuracy of (1)H-MRS and Spearman correlation coefficient were calculated. Differences between groups were assessed with the Wilcoxon signed rank and Mann Whitney tests. RESULTS: The study included 38 patients (median age, 45.5 years; median body mass index, 47.7). Before surgery, median steatosis measured with (1)H-MRS was 5.8%. The accuracy of (1)H-MRS was 89% (32/36), and the (1)H-MRS findings correlated with the histopathologic assessment of steatosis (r = 0.85, p < 0.001). With (1)H-MRS, no steatosis was discriminated from mild steatosis (p = 0.011), mild was discriminated from moderate steatosis (p < 0.001), and moderate was discriminated from severe steatosis (p = 0.021). Three months after surgery, steatosis had decreased to 3.1% (p < 0.001). The prevalence of hepatic steatosis measured with (1)H-MRS decreased from 53% to 32%. CONCLUSION: In the care of morbidly obese patients undergoing assessment of hepatic steatosis and changes in steatosis after gastric bypass surgery, (1)H-MRS with an open 1-T MRI system is feasible. Measurements of hepatic fat with (1)H-MRS are accurate and correlate with clinical and histopathologic results. PMID- 21606263 TI - Low-dose MDCT and CT enterography of patients with Crohn disease: feasibility of adaptive statistical iterative reconstruction. AB - OBJECTIVE: The purpose of this study was to evaluate the image quality and diagnostic performance of low-dose MDCT and CT enterography with adaptive statistical iterative reconstruction (ASIR) in the evaluation of Crohn disease. SUBJECTS AND METHODS: Forty-eight patients (20 men, 28 women; mean age, 33.3 years; range, 17-83 years) with known or suspected Crohn disease who underwent low-dose MDCT and CT enterography with ASIR between December 2008 and December 2009 were included in the study. Twenty-seven patients had previously undergone standard-dose 64-MDCT and CT enterography with filtered back projection (FBP), and those images were used for comparison. The weight-based i.v. contrast protocol and scan parameters (120 kVp, 5-mm section thickness, 0.5-second rotation, pitch of 1.375, 64 * 0.625 mm detector configuration) were constant for the two techniques except for a higher noise index (*1.3) in the ASIR group. Two blinded readers reviewed 75 randomized MDCT-CT enterographic scans of 48 patients to assess image quality and diagnostic performance in the evaluation of Crohn disease, and the radiation dose for the studies was estimated. RESULTS: All 75 MDCT and CT enterographic scans had acceptable quality for diagnostic interpretation. Findings of Crohn disease were seen on 63 of 75 scans (84%). Low dose scans in the ASIR group had optimal image quality and were rated comparable to or better than standard-dose FBP images (mean score, 4.2 vs 3.87; p = 0.007). The subjective image noise score (mean, 1.43 vs 1.58; p = 0.2) and objective image noise measurements were lower for ASIR images (p < 0.001). Low-dose studies with ASIR allowed average dose reduction of 34.5% compared with standard-dose scans with FBP (volume CT dose index for ASIR, 7.7 +/- 2.1 mGy; for FBP, 12 +/- 5.5 mGy; p < 0.01). CONCLUSION: Low-dose MDCT and CT enterographic studies reconstructed with ASIR were of appropriate quality for confident evaluation of the manifestations of Crohn disease while allowing approximately 34% dose reduction in comparison with FBP technique. PMID- 21606264 TI - A phantom study comparing ultrasound-guided liver tumor puncture using new real time 3D ultrasound and conventional 2D ultrasound. AB - OBJECTIVE: The purpose of this study is to compare the accuracy of ultrasound guided puncture using new real-time 3D (4D) ultrasound and conventional 2D ultrasound for focal hepatic masses using a liver phantom. MATERIALS AND METHODS: A 4D ultrasound system equipped with a 5-MHz 4D probe displayed both axial and orthogonal images parallel to a puncture line plane. We used a liver phantom that contained four simulated spherical masses in an acrylic box (length * width * height, 300 * 299 * 150 mm) with two different sizes (15 and 30 mm in diameter) in two different positions (30 and 80 mm from the surface). Four inexperienced and four experienced physicians attempted punctures on these four simulated masses twice using 2D and 4D ultrasound guidance in a total of 128 punctures (eight operators, two techniques, and eight punctures per session). The error distance of the puncture was defined as the perpendicular distance from the center of a target mass (sphere) to the line of the puncture needle in the coronal plane of the target center, which was measured manually on the basis of the 3D volume data on off-line analysis. RESULTS: On each tumor model, the average error distance with 4D ultrasound was significantly smaller than that with 2D ultrasound, except for one tumor model that was 15 mm in diameter and 30 mm in depth. The average error distances for the experienced group tended to be smaller than those for the inexperienced group, with both techniques and on each tumor model, and there was a statistically significant difference between the two groups on one tumor model (30 mm in diameter and 80 mm in depth) on 4D ultrasound (p < 0.05). CONCLUSION: Four-dimensional ultrasound-guided puncture for liver tumors can markedly improve puncture accuracy for both experienced and inexperienced physicians compared with conventional 2D ultrasound guidance. PMID- 21606265 TI - Hypervascular hepatocellular carcinoma 1 cm or smaller in patients with chronic liver disease: characterization with gadoxetic acid-enhanced MRI that includes diffusion-weighted imaging. AB - OBJECTIVE: The purpose of this study was to determine the finding most predictive for characterizing hypervascular hepatocellular carcinoma (HCC) measuring 1 cm or less at gadoxetic acid-enhanced MRI that includes diffusion-weighted images. MATERIALS AND METHODS: In this retrospective study, between May 2008 and June 2009, 66 patients with 108 hypervascular HCCs 1 cm or smaller underwent gadoxetic acid-enhanced 3-T MRI that included diffusion-weighted images. The diagnosis of HCC was determined by surgical resection in 32 cases, percutaneous biopsy in three cases, or interval growth to larger than 1 cm on follow-up images in accordance with the American Association for the Study of Liver Diseases guidelines in 73 cases. MRI findings of HCC and 33 benign hypervascular lesions in a control group were analyzed by two radiologists in consensus. They based their assessments on the presence or absence of the following five findings: hyperintensity on T2-weighted images, hyperintensity on diffusion-weighted images with low b values, washout pattern, capsular enhancement, and hypointensity on gadoxetic acid-enhanced hepatobiliary phase images. The findings were compared by use of univariate and multivariate analyses. RESULTS: No HCC with capsular enhancement was found. Fifty-seven HCCs (52.8%) had four findings, 36 (33.3%) had three, nine (8.3%) had two findings, and six (5.6%) had one finding. Univariate analysis showed significant differences between the HCC and control groups with respect to four findings (p < 0.0001). Multivariate analysis showed that hyperintensity on T2-weighted (p < 0.0001) and diffusion-weighted (p = 0.0081) images were statistically significant MRI findings for predicting HCC. CONCLUSION: Hyperintensity on both T2- and diffusion-weighted images is helpful in the diagnosis of hypervascular HCC smaller than 1 cm in diameter. PMID- 21606266 TI - Hepatic elasticity in patients with ascites: evaluation with real-time tissue elastography. AB - OBJECTIVE: Transient elastography is a rapid, noninvasive, and reproducible approach to assessment of liver fibrosis by measurement of liver elasticity. However, transient elastographic measurements are of limited utility in patients with ascites or severe obesity. The aim of this study was to determine whether measurements of liver stiffness with real-time tissue elastography can be altered for patients with ascites. SUBJECTS AND METHODS: The subjects were 54 patients being treated at a university hospital between January and December 2009. In 42 patients, real-time tissue elastography to evaluate liver stiffness was performed before and after injection to produce artificial ascites for radiofrequency ablation. The other 12 patients had ascites due to cirrhosis, and liver stiffness was measured with real-time tissue elastography before and after control of ascites. RESULTS: Elastic ratios evaluated with real-time tissue elastography did not differ significantly before and after injection for artificial ascites or before and after control of ascites. This ratio was the same for patients with and those without cirrhosis and was unaffected by distance between the body surface and the targeted liver area. Stable values thus were measured with real time tissue elastography. CONCLUSION: Liver stiffness can be measured reproducibly with real-time tissue elastography even in patients with ascites. This method has the potential of being superior to transient elastography for assessment of liver stiffness, particularly in patients with decompensated cirrhosis. PMID- 21606267 TI - Decreased detection of hypovascular liver tumors with MDCT in obese patients: a phantom study. AB - OBJECTIVE: The purpose of this article is to assess the impact of large patient size on the detection of hypovascular liver tumors with MDCT and the effect of a noise filter on image quality and lesion detection in obese patients. MATERIALS AND METHODS: A liver phantom with 45 hypovascular tumors (diameters of 5, 10, and 15 mm) was placed into two water containers mimicking intermediate and large patients. The containers were scanned with a 64-MDCT scanner. The CT dataset from the large phantom was postprocessed using a noise filter. The image noise was measured and the contrast-to-noise ratio (CNR) of the tumors was calculated. Tumor detection was independently performed by three radiologists in a blinded fashion. RESULTS: The application of the noise filter in the large phantom yielded a reduction of image noise by 42% (p < 0.0001). The CNR values of the tumors in the nonfiltered and filtered large phantom were lower than that in the intermediate phantom (p < 0.05). In the non-filtered and filtered large phantom, 25% and 19% fewer tumors, respectively, were detected on average compared with the intermediate phantom (p < 0.01). CONCLUSION: The risk of missing hypovascular liver tumors with CT is substantially increased in large patients. A noise filter improves image quality in obese patients. PMID- 21606268 TI - Physician documentation of fluoroscopy time in voiding cystourethrography reports correlates with lower fluoroscopy times: a surrogate marker of patient radiation exposure. AB - OBJECTIVE: Radiation awareness has been advocated as a method of decreasing radiation exposure. For fluoroscopy, one indicator of radiation use is fluoroscopy time. We retrospectively reviewed fluoroscopy times on voiding cystourethrography (VCUG) studies performed at a major pediatric center, comparing the average fluoroscopy time of examinations with the fluoroscopy time documented in the report to the average time of those without documentation. MATERIALS AND METHODS: A database search of records for the period between June 1, 2002, and March 31, 2009, identified all VCUG examinations and their recorded fluoroscopy time in the radiology information system. Those examinations in which the fluoroscopy time was documented in the radiologist's report were also identified. Average fluoroscopy times were calculated for three groups: all VCUG examinations, examinations without the fluoroscopy time documented in the dictated report, and examinations including the fluoroscopy time in the dictated report. RESULTS: Over the 7-year study period, 10,594 VCUG examinations were performed. The average fluoroscopy time was 47 seconds for all examinations, 50 seconds for examinations without fluoroscopy time reported (n = 8484), and 32 seconds for examinations with fluoroscopy time reported (n = 1979). There was a statistically significant difference between examinations with and without fluoroscopy time reported by the radiologist (p < 0.0001). A decreasing trend in average fluoroscopy time for all VCUG examinations was identified over time (average fluoroscopy time: 65 seconds for 2002-2003 vs 29 seconds for 2008-2009). Radiologists also increasingly reported fluoroscopy time over time (fluoroscopy time reported in 1% of reports in 2002-2003 vs 82% in 2008-2009). CONCLUSION: Radiologist reporting of fluoroscopy time correlates with a decrease in fluoroscopy time, a surrogate indicator of radiation dose. Our findings suggest that the radiologist's documentation of fluoroscopy time in the report is part of a radiation awareness strategy leading to decreased fluoroscopy times. PMID- 21606269 TI - Automated extraction of radiation dose information from CT dose report images. AB - OBJECTIVE: The purpose of this article is to describe the development of an automated tool for retrieving texts from CT dose report images. CONCLUSION: Optical character recognition was adopted to perform text recognitions of CT dose report images. The developed tool is able to automate the process of analyzing multiple CT examinations, including text recognition, parsing, error correction, and exporting data to spreadsheets. The results were precise for total dose length product (DLP) and were about 95% accurate for CT dose index and DLP of scanned series. PMID- 21606270 TI - The retrodural space of Okada. AB - OBJECTIVE: The retrodural space of Okada is a potential space that can act as a conduit for the spread of inflammatory or infectious processes, connecting ipsilateral adjacent facet joints, contralateral adjacent facet joints, adjacent neural foramen, paraspinal musculature, and spinous process adventitial bursa (i.e., Baastrup disease). CONCLUSION: Awareness of these potential retrodural communications during diagnostic imaging interpretation and interventional spine injection procedures can play an important role in patient care and management. PMID- 21606271 TI - Whole-body diffusion-weighted MRI with apparent diffusion coefficient mapping for early response monitoring in multiple myeloma: preliminary results. AB - OBJECTIVE: The purpose of our study was to prospectively assess the feasibility of whole-body diffusion-weighted imaging (DWI) for short-term evaluation of response to treatment in multiple myeloma patients using a single-shot echo planar imaging DWI sequence with a Stejskal-Tanner diffusion encoding scheme and spectral fat suppression. SUBJECTS AND METHODS: Twelve consecutive patients (nine men and three women; mean age, 61.4 years; age range, 54-79 years) underwent whole-body DWI (b = 50, 400, and 800 s/mm(2)) both at baseline and 3 weeks (mean, 23 days) after onset of therapy. Bone marrow and extramedullary manifestations were evaluated by quantitative image analysis using measurements of the mean apparent diffusion coefficient (ADC). These parameters were correlated with myeloma response according to standard criteria and were evaluated parallel to MRI and continuously for more than 6 months afterward. RESULTS: Fifty-three myeloma lesions, 50 medullary (28 axial and 22 appendicular skeleton) and three extramedullary, were analyzed. Eleven patients were classified as responders and one as a nonresponder. DWI results accurately (100%) correlated with disease course according to standard clinical and laboratory criteria. All involved lesions showed restricted diffusion at baseline. ADC quantification yielded an increase of 63.9% (range, 8.7-211.3%) in responders and a decrease of 7.8% in the sole nonresponding patient during therapy. In parallel, M-gradient measurement showed a mean decrease of 45.1% (range, 19.6-88.8%) in responders and an increase of 21.8% in the nonresponder. Amplitude of response measured by the course of ADC values proved higher in the appendicular skeleton (99.8%) compared with the axial skeleton (54.3%) (p = 0.037). CONCLUSION: Whole-body DWI with ADC analysis represents a feasible diagnostic tool for assessment of short-term treatment response in myeloma patients. PMID- 21606272 TI - Assessment of calcified carotid plaque volume: comparison of contrast-enhanced dual-energy CT angiography and native single-energy CT. AB - OBJECTIVE: The purpose of this study was to compare estimates of calcified plaque volume in the carotid arteries based on contrast-enhanced dual-energy CT angiograms with volume estimates based on native CT scans. CONCLUSION: Detection of hard plaque in the carotid arteries with dual-energy CT angiography was successful in all patients. Estimates of calcified plaque volume based on dual energy CT angiograms correlated well with those based on native single-energy CT scans but at a lower attenuation threshold (130 HU as opposed to 180 HU) were underestimates compared with those on the native CT scans. PMID- 21606273 TI - CT and MR angiography features of traumatic vascular injuries of the neck. AB - OBJECTIVE: The objective of this article is to review the CT and MR angiography features of vascular injuries to the neck with special emphasis on the key diagnostic features of common and less common entities. CONCLUSION: CT and MR angiography are highly efficient for the diagnosis of most arterial and venous traumatic lesions in the acute setting and when patients develop delayed symptoms. Conventional angiography is recommended only for therapeutic purposes or when the diagnosis remains unclear after performing cross-sectional imaging techniques. PMID- 21606274 TI - MR enterography findings of inflammatory bowel disease in pediatric patients. AB - OBJECTIVE: The purpose of this article is to illustrate and describe the characteristic MR enterography findings in children with inflammatory bowel disease (IBD) and to present MR enterography as the first-choice imaging modality in this setting. CONCLUSION: Given its high sensitivity and specificity for IBD and lack of ionizing radiation, MR enterography is a valuable technique for examining children with IBD. PMID- 21606275 TI - Gray-scale and color Doppler ultrasound findings in children with cow's milk allergy. AB - OBJECTIVE: The objective of our study was to evaluate whether gray-scale and color Doppler ultrasound can reveal intestinal inflammation in infants with cow's milk allergy (CMA). SUBJECTS AND METHODS: This study evaluated the clinical findings and grayscale and color Doppler sonograms of 34 infants. Seventeen 0- to 6-month-old infants with suspected CMA and 17 nonsymptomatic age-matched infants were evaluated by a blinded investigator who determined the percentage of vessel density and the thickness of different parts of the bowel. Clinical and sonographic variables were evaluated in the same regions of bowel considering three time points: presentation, after 4 weeks of feeding only amino acid-based formula, and after challenge test. Likelihood ratios and receiver operating characteristic (ROC) curves were used to define a cutoff point for vascular density percentage. RESULTS: The difference in the percentage of vessel density between patients with CMA (mean, 28.1%) and control infants (mean, 7.77%) was statistically significant. ROC analysis showed that a cutoff point of 18.7% could differentiate between patients with CMA and control infants with 81.8% sensitivity and 94.1% specificity. The area under the curve was 0.941. We found statistical differences in bowel wall thickness between control patients and patients with CMA. CONCLUSION: There was a significant increase in vessel density in infants younger than 6 months with CMA compared with healthy age-matched infants. The most appropriate cutoff point for vessel density was 18.7%. The results of this study suggest that Doppler ultrasound could be used as a screening tool to diagnose CMA. PMID- 21606276 TI - Pulmonary CT angiography to evaluate for pulmonary embolism in children visiting adult-centered community hospitals. AB - OBJECTIVE: The objective of our study was to determine the rate of pulmonary embolism (PE) on pulmonary CT angiography (CTA) in children and adolescents visiting adult-centered community hospitals. We also investigated alternative diagnoses that may account for presenting symptoms. MATERIALS AND METHODS: We identified consecutive children and adolescents (age <= 19 years) who underwent pulmonary CTA during a 12- and 24-month period, respectively, at two community hospitals. Staff radiologists' clinical interpretations of pulmonary CTA studies were compared with interpretations performed by a blinded, subspecialty-trained thoracic radiologist, with a third tie-breaking interpretation performed in cases of discrepancy. A systematic review of pulmonary CTA studies for possible alternative diagnoses was completed. Diagnostic rates of PE on pulmonary CTA studies in adults at these hospitals were also reviewed for comparison. RESULTS: The study population consisted of 130 individuals (32 boys and 98 girls; median age, 18 years; age range, 11-19 years) who underwent 137 examinations, 11 as inpatients and 126 as outpatients. CTA studies were positive for PE in six patients (4.6%). CTA showed an important alternative diagnosis, such as pulmonary consolidation, in 27 patients (21%). By comparison, pulmonary CTA studies in adults at these two hospitals yielded a 16% positive rate for PE. CONCLUSION: The prevalence of PE in young ambulatory patients with clinically suspected PE at adult-centered community hospitals is substantially lower than in adults. Alternative diagnoses, such as pulmonary consolidation and pneumothorax, are discovered more frequently than PE on pulmonary CTA studies. Pulmonary CTA should be used with discretion in adolescents, especially when radiography may provide the necessary diagnosis. PMID- 21606277 TI - Tumor overgrowth after expandable metallic stent placement: experience in 583 patients with malignant gastroduodenal obstruction. AB - OBJECTIVE: The objective of our study was to assess the incidence, predictive factors, and treatment of tumor overgrowth after placement of expandable metallic dual stents in patients with malignant gastroduodenal obstruction. MATERIALS AND METHODS: Expandable metallic dual stents were inserted under fluoroscopic guidance in 583 patients with symptomatic malignant gastroduodenal obstruction. We retrospectively reviewed prospectively collected patient records to determine the incidence and treatment of tumor overgrowth after stent placement and used multivariate analysis to determine factors predicting tumor overgrowth. RESULTS: Tumor overgrowth occurred after stent placement in 22 of 583 patients (3.8%) (range, 41-634 days; mean, 179.0 days). Duodenal lesions (odds ratio [OR], 4.505; p = 0.002), longer survival time (OR, 1.003; p = 0.001), and length of obstruction (OR, 0.783; p = 0.035) were independent predictors of tumor overgrowth. Twenty of the 22 patients were successfully treated by placement of a second dual stent, whereas the other two patients refused placement of a second stent or other further treatment. Overall, 19 of 20 patients (95%) showed improvement in symptoms after second stent placement. Duodenal perforation occurred in one of the 20 patients 125 days after placement of a second stent and was treated surgically. CONCLUSION: Tumor overgrowth seems to be an uncommon complication of expandable metallic dual stent placement in patients with malignant gastroduodenal obstruction. Tumor overgrowth is associated with duodenal lesions, longer survival time, and shorter stricture length. Tumor overgrowth can be successfully managed by coaxial insertion of a second dual expandable metallic stent into the obstructed first stent. PMID- 21606278 TI - Distant infusion of saline may enlarge coagulation volume during radiofrequency ablation of liver tissue using cool-tip electrodes without impairing predictability. AB - OBJECTIVE: Our aim was to evaluate the capability of a Cool-tip electrode to create larger coagulation volumes combined with a low-flow (0.1 mL/min) perfusion of hypertonic saline at a distance of 2 mm (hybrid applicator) without reducing either predictability or sphericity of the coagulation zone. MATERIALS AND METHODS: A total of 48 radiofrequency ablations were performed on a total of 12 adult pigs: 24 with the Cool-tip (group 1) and 24 with the hybrid applicator (group 2). Volumes and diameters were assessed both macroscopically and with imaging techniques (ultrasound and MRI). Digital reconstruction techniques were also used. Reproducibility of the coagulations was assessed by means of the coefficient of variation. RESULTS: The macroscopic assessment showed a significantly larger coagulation zone in group 2 than in group 1, both with (19.40 +/- 11.38 cm(3) vs 9.16 +/- 5.62 cm(3); p < 0.001) and without (19.54 +/- 11.39 cm(3) vs 9.21 +/- 5.74 cm(3); p < 0.001) digital reconstruction. Differences were also significant in the MRI assessment. The minimum transverse diameter was also significantly (p < 0.01) larger in group 2 than group 1: 2.46 +/- 0.61 versus 1.86 +/- 0.55 cm for macroscopic assessment, 2.33 +/- 0.96 versus 1.69 +/- 0.53 cm for ultrasound, and 2.41 +/- 0.58 versus 1.8 +/- 0.52 cm for MRI. The coefficient of variation was similar in both groups. CONCLUSION: The results suggest that low-flow perfusion of hypertonic saline at 2 mm from a Cool tip electrode could increase coagulation zone volume without reducing predictability. PMID- 21606279 TI - Enhancing the case log by coding the level of trainee participation in vascular interventional radiology procedures. AB - OBJECTIVE: The purpose of this article is to describe a new method for coding trainee participation in vascular interventional radiology procedures. MATERIALS AND METHODS: From July 2008 through June 2009, all interventional radiology fellows maintained an enhanced case log at our institution; 748 unique cases were logged by procedure type, supervising physician, and level of participation in the case. Level of participation was classified on a 5-point scale that included designations for observation, first assistant, performance of basic techniques, performance of advanced techniques, and primary operation. Descriptive statistics of participation scores were calculated for each quarter and were analyzed by procedure type and by teaching faculty member. RESULTS: As expected, analysis by procedure type showed that average participation scores increased from one quarter to the next in most cases. By the fourth quarter, the modal participation score was 5, indicating primary operation or performance of multiple critical steps. Analysis by teaching faculty member revealed three patterns: those attending physicians facilitating increasing levels of participation in every quarter, those facilitating maximal growth within the first 6 months, and those with irregular trainee participation profiles. CONCLUSION: Data from a 5-point participation scale add information to the procedure case log that could be used to quantitatively track the technical progress of trainees while providing education quality feedback to both teaching physicians and program directors. PMID- 21606280 TI - Documenting instructions for follow-up imaging. PMID- 21606281 TI - Electronic communication of significant radiologic findings. PMID- 21606282 TI - Infectious complications after ultrasound-guided interventional procedures in the liver. PMID- 21606283 TI - Neuralgic amyotrophy. PMID- 21606285 TI - Imaging of urothelial cancers: what the urologist needs to know. AB - OBJECTIVE: Imaging is vital in the diagnosis, staging, and surveillance of urothelial carcinomas. In this review, we discuss what treating urologists need to know from radiologists to optimally identify disease, plan surgery, determine prognosis, and identify patients in need of multimodal or alternative treatment strategies. We identify key points that a radiologist should convey to the treating urologist, in writing, in order to be an active partner in the formulation of an effective course of care. CONCLUSION: Because imaging plays a crucial role in the diagnosis, staging, and surveillance of patients with tumors of the urinary tract, it is imperative that radiologists provide information about the anatomic features related to the primary tumor, the surrounding anatomy, and involvement or lack of involvement of known potential landing sites for metastases. A good understanding of the imaging features that affect management of the disease and a good relationship between the radiologist and the urologist are vital to the care of patients with urothelial cancers. PMID- 21606286 TI - Renal cell carcinoma: what the surgeon and treating physician need to know. AB - OBJECTIVE: The multimodality approach to treating both localized and metastatic renal cell carcinoma has led to a demand for improved imaging evaluation. We review the information needed from the radiologic studies used to determine treatment strategies. CONCLUSION: Adequate preoperative radiologic assessment provides the treating physician with information critical in determining the sequence of treatments, role of nephron-sparing surgery, surgical approach, and timing of systemic therapy for metastatic disease. PMID- 21606287 TI - Prostate cancer imaging: what surgeons, radiation oncologists, and medical oncologists want to know. AB - OBJECTIVE: The purpose of this article is to discuss the information that is important to note in imaging reports of patients with prostate cancer. CONCLUSION: Accurate staging through imaging is an integral part of prostate cancer management. Ultrasound, CT, bone scanning, and MRI are used for prostate cancer patients to assess the primary tumor, lymph node status, and bone metastasis. Accurate reporting of images is crucial for effective cancer treatment. PMID- 21606288 TI - Small renal mass: what the urologist needs to know for treatment planning and assessment of treatment results. AB - OBJECTIVE: Small renal mass is a new distinct clinical entity. Detection of these tumors has increased with increased use of imaging. CONCLUSION: We know that a proportion of these tumors are not renal cell carcinoma, and imaging-guided biopsy is being increasingly used for treatment planning. The objectives of this review are to provide an update on our current understanding of the biology of small renal masses and to review approaches to the diagnosis and treatment of these lesions. PMID- 21606289 TI - Nephrolithiasis: what surgeons need to know. AB - OBJECTIVE: In this article, we review the standard of care for imaging of nephrolithiasis as well as new technology and radiation concerns from the perspective of the urologic surgeon. CONCLUSION: Nephrolithiasis is a common cause of morbidity with a lifetime prevalence of 5-10% worldwide. Increasingly, diagnostic evaluation and planning for medical or surgical intervention have become reliant on imaging. PMID- 21606291 TI - Prospective randomized comparison of standard didactic lecture versus high fidelity simulation for radiology resident contrast reaction management training. AB - OBJECTIVE: The objective of our study was to assess whether high-fidelity simulation-based training is more effective than traditional didactic lecture to train radiology residents in the management of contrast reactions. SUBJECTS AND METHODS: This was a prospective study of 44 radiology residents randomized into a simulation group versus a lecture group. All residents attended a contrast reaction didactic lecture. Four months later, baseline knowledge was assessed with a written test, which we refer to as the "pretest." After the pretest, the 21 residents in the lecture group attended a repeat didactic lecture and the 23 residents in the simulation group underwent high-fidelity simulation-based training with five contrast reaction scenarios. Next, all residents took a second written test, which we refer to as the "posttest." Two months after the posttest, both groups took a third written test, which we refer to as the "delayed posttest," and underwent performance testing with a high-fidelity severe contrast reaction scenario graded on predefined critical actions. RESULTS: There was no statistically significant difference between the simulation and lecture group pretest, immediate posttest, or delayed posttest scores. The simulation group performed better than the lecture group on the severe contrast reaction simulation scenario (p = 0.001). The simulation group reported improved comfort in identifying and managing contrast reactions and administering medications after the simulation training (p <= 0.04) and was more comfortable than the control group (p = 0.03), which reported no change in comfort level after the repeat didactic lecture. CONCLUSION: When compared with didactic lecture, high fidelity simulation-based training of contrast reaction management shows equal results on written test scores but improved performance during a high-fidelity severe contrast reaction simulation scenario. PMID- 21606290 TI - Dual-energy dual-source CT with additional spectral filtration can improve the differentiation of non-uric acid renal stones: an ex vivo phantom study. AB - OBJECTIVE: The purpose of this study was to determine the ex vivo ability of dual energy dual-source CT (DSCT) with additional tin filtration to differentiate among five groups of human renal stone types. MATERIALS AND METHODS: Forty-three renal stones of 10 types were categorized into five primary groups on the basis of effective atomic numbers, which were calculated as the weighted average of the atomic numbers of constituent atoms. Stones were embedded in porcine kidneys and placed in a 35-cm water phantom. Dual-energy DSCT scans were performed at 80 and 140 kV with and without tin filtration of the 140-kV beam. The CT number ratio, defined as the ratio of the CT number of a given material in the low-energy image to the CT number of the same material in the high-energy image, was calculated on a volumetric voxel-by-voxel basis for each stone. Statistical analysis was performed, and receiver operating characteristic (ROC) curves were plotted to compare the difference in CT number ratio with and without tin filtration, and to measure the discrimination among stone groups. RESULTS: The CT number ratio of non-uric acid stones increased on average by 0.17 (range, 0.03-0.36) with tin filtration. The CT number ratios for non-uric acid stone groups were not significantly different (p > 0.05) between any of the two adjacent groups without tin filtration. Use of the additional tin filtration on the high-energy x-ray tube significantly improved the separation of non-uric acid stone types by CT number ratio (p < 0.05). The area under the ROC curve increased from 0.78 to 0.84 without fin filtration and to 0.89-0.95 with tin filtration. CONCLUSION: Our results showed better separation among different stone types when additional tin filtration was used on dual-energy DSCT. The increased spectral separation allowed a five-group stone classification scheme. Some overlapping between particular stone types still exists, including brushite and calcium oxalate. PMID- 21606292 TI - Pulmonary hypertension in patients with bronchiectasis: prognostic significance of CT signs. AB - OBJECTIVE: The purpose of this study was to evaluate the association between pulmonary hypertension estimated with CT and outcome among patients with bronchiectasis. MATERIALS AND METHODS: The cases of 91 patients with bronchiectasis were studied. CT signs of pulmonary hypertension examined were main pulmonary artery diameter, right and left main pulmonary artery diameters, and the ratio between the diameters of the main pulmonary artery and the ascending aorta. CT scans were scored for extent of bronchiectasis and presence of bronchial dilatation, bronchial wall thickening, mucous plugging, mosaicism, and emphysema. Univariate, bivariate, and multivariate Cox proportional hazards models were used to test the influence of CT signs on mortality. RESULTS: Average right and left main pulmonary artery diameter was the best predictor of mortality (hazard ratio, 1.24; 95% CI, 1.13-1.35; p < 0.0001) and was associated with outcome independent of CT signs of bronchiectasis. CONCLUSION: Pulmonary hypertension, reflected by pulmonary arterial enlargement on CT scans, is a highly significant prognostic indicator in the evaluation of patients with bronchiectasis. PMID- 21606293 TI - Diffuse cystic lung disease at high-resolution CT. AB - OBJECTIVE: This article will illustrate and describe the spectrum of diseases associated with air cysts at high-resolution CT (HRCT). CONCLUSION: HRCT is an important modality in the evaluation of interstitial lung disease to include cystic lung disease. Although most commonly associated with lymphangioleiomyomatosis or Langerhans cell histiocytosis, cystic lung disease is increasingly being recognized as a feature of other entities. Awareness of the spectrum of HRCT findings associated with these diseases may help the trained observer narrow the differential diagnosis. PMID- 21606294 TI - Correlation between contrast-enhanced intraoperative ultrasound using Sonazoid and histologic grade of resected hepatocellular carcinoma. AB - OBJECTIVE: Our aim was to accurately assess the correlation between findings of contrast-enhanced intraoperative ultrasound using Sonazoid and histologic grade of hepatocellular carcinoma (HCC). SUBJECTS AND METHODS: We enrolled 239 consecutive patients who were undergoing surgery for HCC for this study. Because 33 extensively necrotic HCCs were excluded, a total of 374 histologically proven HCCs were detected in all resected specimens and were the study subjects (71 well differentiated, 239 moderately differentiated, and 64 poorly differentiated HCCs). After a laparotomy and liver mobilization, contrast-enhanced intraoperative ultrasound in the harmonic mode was performed after a Sonazoid injection. The first minute was defined as the vascular phase, in which the vascularity of the 239 HCCs was assessed. After an approximately 15-minute delay, a thorough liver exploration was performed (Kupffer phase). Preoperative dynamic CT was routinely performed, and the findings were assessed for reference. RESULTS: The proportion of hypervascular tumors during the vascular phase tended to be lower among well-differentiated than among moderately and poorly differentiated HCCs (66% vs 80%, p = 0.058). The proportion of hypoechoic tumors during the Kupffer phase was significantly lower among well-differentiated than among moderately and poorly differentiated HCCs (54% vs 92%, p < 0.0001). In dynamic CT, the proportions of hypervascular tumors during the early phase and hypodense tumors during the late phase were significantly lower among well differentiated HCCs than among moderately and poorly differentiated HCCs, respectively (early phase, 51% vs 87%, p < 0.0001; late phase, 59% vs 85%, p < 0.0001). CONCLUSION: Contrast-enhanced intraoperative ultrasound using Sonazoid is useful for estimating the histologic grade of HCC. PMID- 21606295 TI - Abdominal CT at low peak tube potential settings brings promises, but new rules apply. PMID- 21606296 TI - Hepatocellular carcinoma in patients weighing 70 kg or less: initial trial of compact-bolus dynamic CT with low-dose contrast material at 80 kVp. AB - OBJECTIVE: The purpose of this study was to compare the diagnostic capability of hepatic dynamic CT with low-dose contrast material (420 mg I/kg body weight) at 80 kVp with that of the same modality performed with standard-dose contrast material at 120 kVp. SUBJECTS AND METHODS: We randomly assigned 111 patients (50 women, 61 men; mean age, 69.1 years) with known or suspected hepatocellular carcinoma and a body weight of 70 kg or less to one of two protocols. In the 80 kVp protocol, the contrast material (444 mg I/kg body weight) was delivered over 15 seconds at a tube voltage of 80 kVp. In the 120-kVp protocol, a contrast dose of 600 mg I/kg was delivered over 30 seconds at 120 kVp. Of the 111 patients, 38 had hypervascular hepatocellular carcinoma. Using the Mann-Whitney U test, we compared the two protocols for the contrast-to-noise ratio of the tumors (difference between tumor attenuation and liver attenuation divided by noise in the liver) and the figure of merit (square of contrast-to-noise ratio divided by effective dose) of the tumors during the arterial phase of imaging. Effective doses also were compared. RESULTS: The contrast-to-noise ratio of the tumors was significantly higher with the 80-kVp than with the 120-kVp protocol (median, 5.3 vs 4.2; p = 0.04). The figure of merit also was significantly higher with the 80 kVp than with the 120-kVp protocol (10.2 vs 5.3, p = 0.02). The effective dose was significantly lower with the 80-kVp than with the 120-kVp protocol (2.97 vs 3.41 mSv, p < 0.01). CONCLUSION: With 80-kVp acquisition, the contrast-to-noise ratio and figure of merit of tumors during the arterial phase improved despite the lower contrast dose and radiation exposure. PMID- 21606297 TI - Low-kilovoltage, high-tube-current MDCT of liver in thin adults: pilot study evaluating radiation dose, image quality, and display settings. AB - OBJECTIVE: The purpose of our study was to evaluate the effect of a low tube voltage-high tube current-time product technique for portal phase abdominal CT of thin adults. SUBJECTS AND METHODS: This study included 25 patients who had undergone portal phase abdominal CT at 120 kVp in the preceding 6 months. All were scanned using 80 kVp and high tube-current time products. We assessed the estimated effective dose (ED), image noise, attenuation, contrast-to-noise ratio (CNR), and figure of merit of the liver and portal vein. Two radiologists evaluated the quality of scans for image contrast and streak artifacts at 80 kVp, 120 kVp, and 80 kVp with wide window width display presets (W-80). RESULTS: The estimated ED was 33% lower at 80 than at 120 kVp. CNR of the portal vein was 36.8% higher at 80 than 120 kVp, and for the liver it was 17.7% higher at 80 than 120 kVp. The visual score of image contrast was significantly higher for W-80 than for 120 kVp; however, there was no significant difference in the visual score of streak artifacts. CONCLUSION: At portal phase abdominal CT, 80 kVp and a high tube current-time product setting significantly improved image quality and reduced the radiation dose compared with 120 kVp. PMID- 21606298 TI - Effective argumentation. PMID- 21606299 TI - Intravoxel incoherent motion in body diffusion-weighted MRI: reality and challenges. AB - OBJECTIVE: Diffusion-weighted MRI is increasingly applied in the body. It has been recognized for some time, on the basis of scientific experiments and studies in the brain, that the calculation of apparent diffusion coefficient by simple monoexponential relationship between MRI signal and b value does not fully account for tissue behavior. However, appreciation of this fact in body diffusion MRI is relatively new, because technologic advancements have only recently enabled high-quality body diffusion-weighted images to be acquired using multiple b values. There is now increasing interest in the radiologic community to apply more sophisticated analytic approaches, such as those based on the principles of intravoxel incoherent motion, which allows quantitative parameters that reflect tissue microcapillary perfusion and tissue diffusivity to be derived. CONCLUSION: In this review, we discuss the principles of intravoxel incoherent motion as applied to body diffusion-weighted MRI. The evidence for the technique in measuring tissue perfusion is presented and the emerging clinical utility surveyed. The requisites and challenges of quantitative evaluation beyond simple monoexponential relationships are highlighted. PMID- 21606300 TI - Utility of sonographic measurement of the common tensor tendon in patients with lateral epicondylitis. AB - OBJECTIVE: The purpose of this article is to evaluate prospectively the utility of sonographic measurements of the common extensor tendon for diagnosing lateral epicondylitis. SUBJECTS AND METHODS: Forty-eight patients with documented lateral epicondylitis and 63 healthy volunteers were enrolled and underwent ultrasound of the elbow joint. The common extensor tendon overlying the bony landmark was scanned transversely, and the cross-section area and the maximum thickness were measured. Clinical examination was used as the reference standard in the diagnosis of lateral epicondylitis. Data from the patient and control groups were compared with established optimal diagnostic criteria for lateral epicondylitis using receiver operating characteristic curves. Qualitative evaluation with grayscale ultrasound was also performed on patients and healthy volunteers. RESULTS: The common extensor tendon was significantly thicker in patients with lateral epicondylitis than in control subjects (p < 0.01). Tendon thickness greater than 4.2 mm (sensitivity, 78.4%; specificity, 95.2%; accuracy, 87.7%) and area larger than or equal to 32 mm(2) (sensitivity, 86.3%; specificity, 82.5%; accuracy, 84.2%) were highly predictive of lateral epicondylitis. For qualitative evaluation with gray-scale ultrasound, overall sensitivity, specificity, and accuracy values in the diagnosis of lateral epicondylitis were 76.5%, 76.2%, and 76.3%, respectively. CONCLUSION: The quantitative sonographic measurements had an excellent diagnostic performance for lateral epicondylitis, as well as good or excellent interreader agreement. A common extensor tendon cross-section area greater than or equal to 32 mm(2) and a thickness of 4.2 mm correlated well with the presence of lateral epicondylitis. However, further prospective study is necessary to determine whether quantitative ultrasound with these cutoff values can improve the accuracy of the diagnosis of lateral epicondylitis. PMID- 21606301 TI - Novel, portable, cassette-sized, and wireless flat-panel digital radiography system: initial workflow results versus computed radiography. AB - OBJECTIVE: The purpose of this article is to compare workflow efficiency between a conventional computed radiography (CR) system and a novel, portable, cassette sized, and wireless flat-panel digital radiography (DR) system. MATERIALS AND METHODS: Observational time-motion analyses were performed at one site at which CR and the new portable DR system are used concurrently. The workflow steps of both systems were identified and categorized to facilitate comparison. The times required for examination preparation, patient positioning, exposure, postacquisition processing, and the examination as a whole were recorded by a neutral observer. Timing differences between the CR and portable DR systems were compared, and all data were analyzed using commercially available statistical software. Nine general radiographic examination types were selected, with approximately 50 patients per examination type. RESULTS: A total of 941 examinations (CR, n = 474; portable DR, n = 467) were timed in this study. Total examination time differences between CR and portable DR system (mean, 26.44 seconds; median 26.99 seconds) were found to be statistically significant (p < 0.001), with DR proving faster than CR. The single largest contributor to the time difference between CR and portable DR was postacquisition processing (mean, 26.58 seconds; median, 25.91 seconds), which was a composite of multiple individual steps, including cassette transport (CR only, mean, 13.22 seconds; median, 12.74 seconds), cassette readout (mean, 10.15 seconds; median, 10.4 seconds), and postprocessing (mean, 3.21 seconds; median, 3.11 seconds). CONCLUSION: Overall radiographer time was significantly shorter when performing examination-related tasks with the novel, portable DR system than when performing comparable tasks with the CR system, a difference that appears to result largely from technology configuration. PMID- 21606302 TI - Perfusion CT of head and neck cancer: effect of arterial input selection. AB - OBJECTIVE: The purpose of this study is to evaluate the effect of arterial input selection on perfusion CT parameters of head and neck tumors. MATERIALS AND METHODS: Perfusion calculations were done for 50 cases using deconvolution-based software. Peak enhancement values of the ipsilateral internal carotid artery (ICA) and external carotid artery (ECA) were recorded. Blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability surface area product were calculated using ipsilateral ECA, ipsilateral ICA, and contralateral ICA as input arteries. Values were compared using Wilcoxon's matched pair test and Pearson's correlation coefficients (r). RESULTS: A highly significant correlation was observed between peak enhancement values of the ICA and ECA (r = 0.97; p < 0.0001). A high correlation was observed between perfusion calculations obtained using ipsilateral ICA and ECA (BF, r = 0.98; BV, r = 0.92; MTT, r = 0.91; and permeability surface area product, r = 0.89), ipsilateral and contralateral ICA (BF, r = 0.97; BV, r = 0.95; MTT, r = 0.93; and permeability surface area product, r = 0.89), as well as left and right ICA (BF, r = 0.97; BV, r = 0.95; MTT, r = 0.94; and permeability surface area product, r = 0.88). All correlations were statistically significant (p < 0.0001). No significant differences were observed between perfusion calculations obtained using ipsilateral ICA versus ECA, ipsilateral versus contralateral ICA, or left versus right ICA (p > 0.05). CONCLUSION: Arterial input selection has no significant effect on perfusion CT calculation of head and neck cancer. For standardization and simplification of postprocessing, we recommend the use of the ICA instead of the ECA as the arterial input because of its better visualization, perpendicular course, and larger caliber, all of which decrease partial volume effects. PMID- 21606303 TI - Transplanted neural stem cells promote nerve regeneration in acute peripheral nerve traction injury: assessment using MRI. AB - OBJECTIVE: The purpose of our study was to monitor neural stem cells (NSCs) transplanted in acute peripheral nerve traction injury and to use MRI to assess the ability of NSCs to promote nerve regeneration. MATERIALS AND METHODS: After labeling with gadolinium-diethylene triamine pentaacetic acid (gadopentetate dimeglumine) and fluorescent dye (PKH26), 5 * 10(5) NSCs were grafted to acutely distracted sciatic nerves in 21 New Zealand White rabbits. In addition, 5 * 10(5) unlabeled NSCs (n = 21) and vehicle alone (n = 21) subjects were injected as a control. Serial MRI was performed with a 1.5-T scanner to determine the distribution of grafted cells. Sequential T1 and T2 values of the nerves and functional recovery were measured over a 70-day follow-up period, with histologic assessments performed at regular intervals. RESULTS: The distribution and migration of labeled NSCs could be tracked with MRI until 10 days after transplantation. Compared with vehicle control, nerves grafted with labeled or unlabeled NSCs had better functional recovery and showed improved nerve regeneration but exhibited a sustained increase of T1 and T2 values during the phase of regeneration. CONCLUSION: Gadopentetate dimeglumine-based labeling allowed short-term in vivo MRI tracking of NSCs grafted in injured nerves. NSCs transplantation could promote nerve regeneration in acute peripheral nerve traction injury as shown by a prolonged increase of nerve T1 and T2 values. PMID- 21606304 TI - The utility of 11C-choline PET/CT for imaging prostate cancer: a pictorial guide. AB - OBJECTIVE: The objective of this article is to provide an illustrative tutorial showing the utility of (11)C-choline PET/CT for imaging prostate cancer. CONCLUSION: Carbon-11-labeled choline PET/CT is a powerful adjunct to the currently available imaging modalities for evaluating prostate cancer. As with any diagnostic method, false-positives and false-negatives occur. However, these diagnostic errors can be reduced if readers are familiar with the normal and abnormal patterns of (11)C-choline distribution in the body. PMID- 21606306 TI - Dual-energy CT for detection of endoleaks after endovascular abdominal aneurysm repair: usefulness of colored iodine overlay. AB - OBJECTIVE: The purpose of our study was to evaluate the value of dual-source dual energy CT with colored iodine overlay for detection of endoleaks after endovascular abdominal aortic aneurysm repair. We also calculated the potential dose reduction by using a dual-energy CT single-phase protocol. SUBJECTS AND METHODS: From November 2007 to November 2009, 74 patients underwent CT angiography 2-7 days after endovascular repair during single-energy unenhanced and dual-energy venous phases. By using dual-energy software, the iodine overlay was superimposed on venous phase images with different percentages ranging between 0 (virtual unenhanced images) and 50-75% to show the iodine in an orange color. Two blinded readers evaluated the data for diagnosis of endoleaks during standard unenhanced and venous phase images (session 1, standard of reference) and virtual unenhanced and venous phase images with colored iodine overlay images (session 2). We compared the effective dose radiation of a single-energy biphasic protocol with that of a single-phase dual-energy protocol. The diagnostic accuracy of session 2 was calculated. RESULTS: The mean dual-energy effective dose was 7.27 mSv. By using a dual-energy single-phase protocol, we obtained a mean dose reduction of 28% with respect to a single-energy biphasic protocol. The diagnostic accuracy of session 2 was: 100% sensitivity, 100% specificity, 100% negative predictive value, and 100% positive predictive value. Statistically significant differences in the level of confidence for endoleak detection between the two sessions were found by reviewers for scores 3-5. CONCLUSION: Dual-energy CT with colored iodine overlay is a useful diagnostic tool in endoleak detection. The use of a dual-energy single-phase study protocol will lower radiation exposure to patients. PMID- 21606305 TI - Abdominal ultrasound with scintigraphic and clinical correlates in infants with sickle cell anemia: baseline data from the BABY HUG trial. AB - OBJECTIVE: The purpose of this study is to perform and evaluate baseline abdominal ultrasound in infants with sickle cell anemia who participated in the BABY HUG multiinstitutional randomized placebo-controlled trial of hydroxyurea therapy and to examine the potential relationships among ultrasound results and clinical, nuclear medicine, and laboratory data. SUBJECTS AND METHODS: After local institutional review board approval and with informed guardian consent, 116 girls and 87 boys (age range, 7.5-18 months) with sickle cell anemia underwent standardized abdominal sonography at 14 institutions. Imaging was centrally reviewed by one radiologist who assessed and measured the spleen, kidneys, gallbladder, and common bile duct. Baseline physical assessment of spleen size, serum alanine aminotransferase and bilirubin levels, (99m)Tc sulfur colloid liver spleen scans, and (99m)Tc diethylenetriaminepentaacetic acid clearance glomerular filtration rates (GFRs) were obtained. Analysis of variance and the Student test were performed to compare sonographic findings to published results in healthy children and to clinical and laboratory findings. RESULTS: The mean (+/- SD) spleen volume (108 +/- 47 mL) was significantly greater than published normal control values (30 +/- 14 mL; p < 0.0001). There was no correlation between spleen volume and function assessed by liver-spleen scan. The mean GFR (125 +/- 34 mL/min/1.73 m(2)) was elevated compared with control GFRs (92 +/- 18 mL/min/1.73 m(2)). Renal volumes (right kidney, 29 +/- 8 mL; left kidney, 31 +/- 9 mL) were significantly greater than control volumes (right kidney, 27 +/- 3 mL; left kidney, 27 +/- 3 mL; p < 0.0001) and were positively correlated with GFR (p = 0.0009). Five percent of patients had sonographic biliary abnormalities (sludge, n = 6; dilated common bile duct, n = 2; and cholelithiasis and thickened gallbladder wall, n = 1 each). There was no correlation between biliary sonographic findings and laboratory results. CONCLUSION: In infants with sickle cell anemia, sonographic spleen volume does not reflect function, but increased renal volume correlates with GFR and is consistent with hyperfiltration. Sonographic biliary abnormalities can occur early in life, while remaining clinically silent. PMID- 21606307 TI - Percutaneous vertebroplasty for osteoporotic compression fractures: long-term evaluation of the technical and clinical outcomes. AB - OBJECTIVE: The purpose of this article is to evaluate the technical and clinical outcomes of 194 patients with 500 osteoporotic vertebral compression fractures (VCFs) consecutively treated by percutaneous vertebroplasty, to investigate the long-term efficacy of percutaneous vertebroplasty, and to determine the frequency of new VCFs after percutaneous vertebroplasty. MATERIALS AND METHODS: One hundred ninety-four patients (168 women and 26 men; mean age, 73.3 years; range, 44-89 years) with 500 VCFs (T5-L5) were enrolled in this study. Evaluation at each follow-up time point (1 day, 1 month, 4 months, 1 year, and then once yearly) included pain response by using a pain visual analog scale (VAS) and frontal and lateral radiographs of the thoracic and lumbar vertebrae regardless of the symptoms. RESULTS: The mean volume of cement injected was 3.3 mL (range, 0.5-12 mL) per level. Cement leakage was seen at 213 levels (42.6%). The mean follow-up time was 31 months (range, 1-97 months). The mean VAS score was 7.6 before percutaneous vertebroplasty and 3.1 at 1 day, 2.3 at 1 month, 1.7 at 4 months, 1.5 at 1 year, 1.2 at 2 years, 1.0 at 3 years, 1.1 at 4 years, 0.9 at 5 years, 0.9 at 6 years, and 1.0 at 7 years after percutaneous vertebroplasty. New VCFs were confirmed in 103 vertebrae in 65 patients (33.5%), affecting 65 adjacent vertebrae (63.1%) and 38 nonadjacent vertebrae (36.9%). CONCLUSION: Percutaneous vertebroplasty was effective in relieving the pain associated with osteoporosis induced VCFs, and the analgesic effect was long lasting when no new VCF occurred. However, radiologic follow-up observation showed that new VCFs occurred in approximately one-third of the patients. PMID- 21606308 TI - Mucocele-like tumors of the breast as cystic lesions: sonographic-pathologic correlation. AB - OBJECTIVE: The purpose of this study was to evaluate the differential radiologic findings of pure mucocele-like tumor and mucocele-like tumor associated with atypical ductal hyperplasia (ADH) or malignancy of the breast according to BI RADS and sonographic cystic mass classification. MATERIALS AND METHODS: During a 10-year period, 72 mucocele-like tumors in 68 women were diagnosed histologically at three institutions. We retrospectively reviewed the mammographic (n = 69) and ultrasound (n = 72) findings of the 72 lesions according to the BI-RADS lexicon. The radiologic findings were correlated with the pathologic results. RESULTS: Mammography showed 53 lesions had calcifications without (n = 39) or with (n = 14) a mass. Calcifications of intermediate concern or associated with higher probability of malignancy were found more frequently in mucocele-like tumors associated with ADH or malignancy than in pure mucocele-like tumors (92.3% vs 62.9%, p = 0.019). At ultrasound, 69 of the mucocele-like tumors (95.8%) were seen as a cystic mass. Cysts with thick septations, clustered cysts, and complex masses were more frequently seen in mucocele-like tumors associated with ADH or malignancy (89.7% vs 32.5%, p < 0.001). The positive predictive value for BI-RADS category 4 was 13.3% (95% CI, 6.9-24.2%) and was 50% for BI-RADS category 5 (95% CI, 15-85%). CONCLUSION: Mucocele-like tumors associated with ADH or malignancy were more frequently seen as clustered cysts, cysts with thick septations, and complex masses associated with calcifications of intermediate concern or higher probability of malignancy. BI-RADS can be used in the management of mucocele-like tumors. PMID- 21606309 TI - Comparison of uterine peristalsis before and after uterine artery embolization at 3-T MRI. AB - OBJECTIVE: The purpose of this article is to compare uterine peristalsis before and after uterine artery embolization (UAE) on a 3-T MRI system. SUBJECTS AND METHODS: MRI scans were prospectively performed for 20 women with symptomatic uterine fibroids (age range, 39-53 years) before and after UAE in the periovulatory phase with a 3-T scanner. Sagittal T2 turbo spin-echo sequences and a HASTE sequence were obtained. Sixty HASTE images were obtained for 3 minutes to display on cine mode. Two radiologists independently evaluated the datasets for the presence of uterine peristalsis using a 5-point rating scale. When peristalsis was present, the direction and frequency were recorded. The images were also evaluated for index fibroid location before and after UAE, index fibroid volume, uterine volume, and fibroid burden estimate. RESULTS: The presence and frequency of uterine peristalsis increased after UAE for both readers, but was significant only for the presence of uterine peristalsis. The majority of patients had peristalsis in the cervix-to-fundus direction. In six cases, uterine peristalsis emerged after UAE. Uterine volumes before UAE were significantly smaller in these six cases compared with the remaining 14 cases, though no significant difference was found in the reduction rate of the uterus or fibroid volumes. The index fibroid was intramural in three of the six cases with interval appearance of peristalsis. The fibroid was solitary in four of the six cases. CONCLUSION: Cine MRI at 3 T may show recovery of uterine peristalsis in some women with symptomatic fibroids after successful UAE. PMID- 21606310 TI - Full-field digital mammographic interpretation with prior analog versus prior digitized analog mammography: time for interpretation. AB - OBJECTIVE: The purpose of our study was to quantitatively compare the time for interpretation of screening full-field digital mammography (FFDM) images using prior analog film mammograms for comparison versus digitized prior analog mammograms. MATERIALS AND METHODS: Images from 100 FFDM studies were interpreted by four radiologists. All FFDM images had comparison analog mammograms obtained a minimum of 1 year earlier that were digitized using a 43-MUm film digitizer. Initially, the FFDM images were interpreted using the digitized prior mammogram on two, 5-megapixel monitors and PACS. All available PACS tools could be used. Four weeks later, the same 100 screening FFDMs were interpreted using the original analog mammograms on an alternator at 90 degrees to the monitors used to interpret the screening FFDMs. The interpretation times were recorded and compared. The results were compared and evaluated for statistical significance using statistical software, with statistical significance set at p < 0.05. RESULTS: For each radiologist, the mean reading time for FFDM with digitized priors was significantly shorter in length in comparison with the mean reading time calculated for interpreting FFDM using analog film priors. The differences in times recorded between digitized analog versus analog ranged from 11.31 to 74.18 seconds. The reading times for the four readers ranged from 17.32 to 185.94 seconds, with a mean of 58.56 seconds when using analog film prior mammograms. When using digitized analog prior mammograms, the reading times for the four readers ranged from 11.32 to 109.11 seconds with a mean of 39.76 seconds. The average difference in reading time was calculated to be 18.80 seconds, showing that there is a 32% increase in interpretation speed when using a digitized prior analog for comparison studies as opposed to an analog prior. CONCLUSION: There is a statistically significant 32.1% average improvement in interpretation time when FFDM screening mammograms use digitized analog comparison mammograms than if FFDM is interpreted with the original analog film mammograms. This should allow more FFDMs to be interpreted in the same amount of time if digitized prior analog mammograms are used. PMID- 21606311 TI - Does the type of intrauterine device affect conspicuity on 2D and 3D ultrasound? AB - OBJECTIVE: The objective of our study was to assess the conspicuity and position evaluation of intrauterine devices (IUDs) on 2D ultrasound and 3D ultrasound in nongravid patients. MATERIALS AND METHODS: Review of the ultrasound database for the period from July 2008 through June 2009 was performed for identification of patients with IUDs, of the type and position of the IUD, and of the patient's presenting symptoms. The conspicuity of the IUD on 2D sagittal and transverse planes and 3D coronal views was scored according to a 7-point scale. Data analysis was performed using the Student t test and the Pearson chi-square test. RESULTS: Of the 269 patients with IUDs who had undergone ultrasound during the study period, 180 patients had a copper IUD; 59, a levonorgestrel-releasing device; and three, a Lippes loop. Twenty-seven IUDs were excluded because they were not seen on ultrasound (n = 15) or the type of IUD was not identifiable (n = 12). Of the 239 IUDs identified, the conspicuity score for copper IUDs (mean score, 5.3 [SD, 1.4]) differed significantly from that for levonorgestrel releasing IUDs (mean, 3.1 [1.0]) on 2D ultrasound (p < 0.001). The difference in the conspicuity score for copper IUDs (mean, 6.6 [0.95]) versus that for levonorgestrel-releasing devices (mean, 6.2 [0.92]) on 3D ultrasound was marginally significant (p = 0.05). One hundred seventy-six IUDs (74%) were properly positioned within the endometrial cavity and 60 (25%) were malpositioned; proper positioning of three IUDs (1%) could not be confirmed. The indications for sonographic evaluation were pain (111/239, 46%), missing strings (91/239, 38%), and bleeding (34/239, 14%). Of the patients who presented with bleeding, the IUD was malpositioned in 13 (38%). CONCLUSION: The levonorgestrel releasing IUD is significantly less conspicuous than the copper IUD on 2D imaging. Three-dimensional ultrasound enhances the conspicuity of both types of IUD. PMID- 21606312 TI - Characterization of papillary projections in benign versus borderline and malignant ovarian masses on conventional and color Doppler ultrasound. AB - OBJECTIVE: The purpose of our study was to evaluate on endovaginal ultrasound the morphologic and color Doppler characteristics of papillary projections in benign compared with borderline and malignant epithelial stromal ovarian tumors. MATERIALS AND METHODS: A total of 283 women (mean age, 52 years; age range, 20-85 years) with 343 operated adnexal masses comprising 167 epithelial stromal tumors of the ovary with 76 tumors containing papillary projections at pathology were retrospectively studied on ultrasound. We systematically evaluated the topography of the papillary projections, the morphologic features of the largest papillary projection, and the presence or absence of color Doppler findings. All these findings were correlated with macroscopic and microscopic features. RESULTS: Ultrasound detected papillary projections in 78% of tumors. Papillary projections were disseminated in 33% of malignant, 20% of borderline, and 0% of benign tumors (p = 0.0049). The mean size of the papillary projections was 9.6, 15.7, and 35.3 mm in benign, borderline, and malignant tumors, respectively (p = 0.0007). An acute angle was present in 68% of benign tumors and an obtuse angle in 40% of borderline and 89% of malignant tumors (p = 0.0001). The surface was regular in 77% of benign tumors and irregular in 50% of borderline and 88% of malignant tumors (p = 0.0000). Calcifications were present only in benign tumors (18%). For papillary projections >= 10 mm, color flow was present in all malignant, in 86% of borderline, and absent in all benign tumors. CONCLUSION: Association of morphologic and vascular ultrasound findings can highly suggest the diagnosis of benign or malignant papillary projection. PMID- 21606313 TI - MRI findings of pure ductal carcinoma in situ: kinetic characteristics compared according to lesion type and histopathologic factors. AB - OBJECTIVE: The purposes of this study were to analyze the morphologic and kinetic characteristics of pure ductal carcinoma in situ on MR images and to compare the kinetic characteristics according to MRI lesion type, histopathologic factors, and mammographic and sonographic findings. MATERIALS AND METHODS: Sixty-seven patients with histologically proven pure ductal carcinoma in situ were included in this study. The MRI findings were analyzed according to the BI-RADS MRI lexicon without knowledge of the pathologic findings. The quantitative variables of the kinetic enhancement pattern calculated for each lesion were initial enhancement slope, peak enhancement, time to peak enhancement, and washout ratio. The histopathologic factors of nuclear grade, hormone receptor status, and c-erbB 2 expression status were reviewed. Mammographic and sonographic findings were reviewed independently without knowledge of the MRI findings. Kinetic characteristics were compared according to MRI lesion type, histopathologic factors, and mammographic and sonographic findings. RESULTS: The dominant morphologic appearance was a nonmass lesion with segmental and clumped or heterogeneous enhancement. The pure ductal carcinoma in situ lesions exhibited variable enhancement patterns consisting of persistent (34.3%), plateau (52.2%), and washout (13.4%) curves. The mean initial enhancement slope (p < 0.005) and time to peak enhancement (p < 0.05) correlated with MRI lesion type, and time to peak enhancement (p < 0.05) correlated with the sonographic findings. No statistically significant correlations were observed between the kinetic characteristics and histopathologic factors or mammographic findings (p > 0.05). CONCLUSION: Nonmass lesions and plateau curve enhancement were the dominant MRI findings of pure ductal carcinoma in situ. The lesions with mass appearance at MRI had more suspicious kinetic characteristics than did nonmass lesions. PMID- 21606314 TI - Ultrasound and MRI of fetuses with ventriculomegaly: can cortical development be used to predict postnatal outcome? AB - OBJECTIVE: The purpose of this study was to assess the conspicuity of brain cortical maturation with sonography and MRI of fetuses referred because of ventriculomegaly and to determine whether sulcal visualization can be used to predict postnatal outcome. SUBJECTS AND METHODS: Women with 374 fetuses referred because of ventriculomegaly underwent sonography and MRI. Four to six radiologists rated visualization of 19 fissures or sulci. Majority opinion regarding sulcal visualization was compared among fetuses categorized by CNS abnormality: normal, isolated ventriculomegaly, and ventriculomegaly with additional CNS abnormalities. Live-born infants were categorized as having normal or abnormal development. Logistic regression analysis was used to correlate sulcal visualization and postnatal development. A subanalysis was performed with fetuses who had been classified prenatally as having a normal brain or isolated ventriculomegaly. RESULTS: Cortical sulci were visualized more frequently and at an earlier gestational age with MRI than with ultrasound. In the entire cohort, the odds ratio of normal development ranged from 3.1 to 10.0 whenever the calcarine, parietooccipital, cingulate, superior temporal, precentral, or postcentral sulcus was seen on MR images. In fetuses categorized as having a normal brain or having isolated ventriculomegaly, the odds ratio of normal development ranged from 3.5 to 9.0 whenever the parietooccipital, cingulate, or superior temporal sulcus was seen. CONCLUSION: Visualization of the sulci in fetal brains depends on the imaging modality used and the gestational age at imaging. Information regarding sulcal visualization may aid in counseling patients carrying fetuses with ventriculomegaly. PMID- 21606316 TI - Soil microorganisms mediating phosphorus availability update on microbial phosphorus. PMID- 21606315 TI - Identification of an ARGONAUTE for antiviral RNA silencing in Nicotiana benthamiana. AB - ARGONAUTE proteins (AGOs) are known to be key components of the RNA silencing mechanism in eukaryotes that, among other functions, serves to protect against viral invaders. Higher plants encode at least 10 individual AGOs yet the role played by many in RNA silencing-related antiviral defense is largely unknown, except for reports that AGO1, AGO2, and AGO7 play an antiviral role in Arabidopsis (Arabidopsis thaliana). In the plant virus model host Nicotiana benthamiana, Tomato bushy stunt virus (TBSV) P19 suppressor mutants are very susceptible to RNA silencing. Here, we report that a N. benthamiana AGO (NbAGO) with similarity to Arabidopsis AGO2, is involved in antiviral defense against TBSV. The activity of this NbAGO2 is shown to be directly associated with anti TBSV RNA silencing, while its inactivation does not influence silencing of transiently expressed transgenes. Thus, the role of NbAGO2 might be primarily for antiviral defense. PMID- 21606317 TI - Phosphate utilization efficiency correlates with expression of low-affinity phosphate transporters and noncoding RNA, IPS1, in barley. AB - Genetic variation in phosphorus (P) efficiency exists among wheat (Triticum aestivum) and barley (Hordeum vulgare) genotypes, but the underlying mechanisms for the variation remain elusive. High- and low-affinity phosphate (Pi) PHT1 transporters play an indispensable role in P acquisition and remobilization. However, little is known about genetic variation in PHT1 gene expression and association with P acquisition efficiency (PAE) and P utilization efficiency (PUE). Here, we present quantitative analyses of transcript levels of high- and low-affinity PHT1 Pi transporters in four barley genotypes differing in PAE. The results showed that there was no clear pattern in the expression of four paralogs of the high-affinity Pi transporter HvPHT1;1 among the four barley genotypes, but the expression of a low-affinity Pi transporter, HvPHT1;6, and its close homolog HvHPT1;3 was correlated with the genotypes differing in PUE. Interestingly, the expression of HvPHT1;6 and HvPHT1;3 was correlated with the expression of HvIPS1 (for P starvation inducible; noncoding RNA) but not with HvIPS2, suggesting that HvIPS1 plays a distinct role in the regulation of the low-affinity Pi transporters. In addition, high PUE was found to be associated with high root shoot ratios in low-P conditions, indicating that high carbohydrate partitioning into roots occurs simultaneously with high PUE. However, high PUE accompanying high carbon partitioning into roots could result in low PAE. Therefore, the optimization of PUE through the modification of low-affinity Pi transporter expression may assist further improvement of PAE for low-input agriculture systems. PMID- 21606319 TI - Gene coexpression network alignment and conservation of gene modules between two grass species: maize and rice. AB - One major objective for plant biology is the discovery of molecular subsystems underlying complex traits. The use of genetic and genomic resources combined in a systems genetics approach offers a means for approaching this goal. This study describes a maize (Zea mays) gene coexpression network built from publicly available expression arrays. The maize network consisted of 2,071 loci that were divided into 34 distinct modules that contained 1,928 enriched functional annotation terms and 35 cofunctional gene clusters. Of note, 391 maize genes of unknown function were found to be coexpressed within modules along with genes of known function. A global network alignment was made between this maize network and a previously described rice (Oryza sativa) coexpression network. The IsoRankN tool was used, which incorporates both gene homology and network topology for the alignment. A total of 1,173 aligned loci were detected between the two grass networks, which condensed into 154 conserved subgraphs that preserved 4,758 coexpression edges in rice and 6,105 coexpression edges in maize. This study provides an early view into maize coexpression space and provides an initial network-based framework for the translation of functional genomic and genetic information between these two vital agricultural species. PMID- 21606318 TI - OsREC8 is essential for chromatid cohesion and metaphase I monopolar orientation in rice meiosis. AB - The successful transmission of chromosomes during mitosis and meiosis relies on the establishment and subsequent release of cohesion between replicated chromatids. Cohesion is mediated by a four-subunit structural maintenance of chromosome complex, called cohesins. REC8 is a key component of this meiotic cohesion complex in most model organisms studied to date. Here, we isolated and dissected the functions of OsREC8, a rice (Oryza sativa) REC8 homolog, using two null Osrec8 mutants. We showed that OsREC8 encodes a protein that localized to meiotic chromosomes from approximately meiotic interphase to metaphase I. Homologous pairing and telomere bouquet formation were abnormal in Osrec8 meiocytes. Furthermore, fluorescent in situ hybridization experiments on Osrec8 meiocytes demonstrated that the mutation eliminated meiotic centromeric cohesion completely during prophase I and also led to the bipolar orientation of the kinetochores during the first meiotic division and accordingly resulted in premature separation of sister chromatid during meiosis I. Immunolocalization analyses revealed that the loading of PAIR2, PAIR3, OsMER3, and ZEP1 all depended on OsREC8. By contrast, the presence of the OsREC8 signal in pair2, pair3, Osmer3, and zep1 mutants indicated that the loading of OsREC8 did not rely on these four proteins. These results suggest that OsREC8 has several essential roles in the meiotic processes. PMID- 21606320 TI - Genetic associations with sporadic neuroendocrine tumor risk. AB - Genetic risk factors for sporadic neuroendocrine tumors (NET) are poorly understood. We tested risk associations in patients with sporadic NET and non cancer controls, using a custom array containing 1536 single-nucleotide polymorphisms (SNPs) in 355 candidate genes. We identified 18 SNPs associated with NET risk at a P-value <0.01 in a discovery set of 261 cases and 319 controls. Two of these SNPs were found to be significantly associated with NET risk in an independent replication set of 235 cases and 113 controls, at a P value <=0.05. An SNP in interleukin 12A (IL12A rs2243123), a gene implicated in inflammatory response, replicated with an adjusted odds ratio (95% confidence interval) (aOR) = 1.47 (1.03, 2.11) P-trend = 0.04. A second SNP in defender against cell death, (DAD1 rs8005354), a gene that modulates apoptosis, replicated at aOR = 1.43 (1.02, 2.02) P-trend = 0.04. Consistent with our observations, a pathway analysis, performed in the discovery set, suggested that genetic variation in inflammatory pathways or apoptosis pathways is associated with NET risk. Our findings support further investigation of the potential role of IL12A and DAD1 in the etiology of NET. PMID- 21606323 TI - A clinic-based youth development program to reduce sexual risk behaviors among adolescent girls: prime time pilot study. AB - Multifaceted, sustained efforts are needed to reduce early pregnancy and sexually transmitted diseases among high-risk adolescents. An important area for research is testing youth development interventions offered through clinic settings, where access to high-risk adolescents is plentiful and few efforts have rigorously evaluated a dual approach of building protective factors while addressing risk. This article presents findings from a pilot study of Prime Time, a clinic-based youth development intervention to reduce sexual risk behaviors among girls at risk for early pregnancy. Girls aged 13 to 17 years meeting specified risk criteria were assigned to Prime Time treatment groups. The Prime Time intervention included a combination of case management services and peer leadership groups. Participants completed self-report surveys at baseline, 12 and 18 months following enrollment. At 12 months, the intervention group reported significantly fewer sexual partners than the control group. At 18 months, the intervention group reported significantly more consistent condom use with trends toward more consistent hormonal and dual method use. Dose-response analyses suggested that relatively high levels of exposure to a youth development intervention were needed to change contraceptive use behaviors among adolescents at risk for early pregnancy. Given promising findings, further testing of the Prime Time intervention is warranted. PMID- 21606321 TI - The role for estrogen receptor-alpha and prolactin receptor in sex-dependent DEN induced liver tumorigenesis. AB - Mice treated neonatally with diethylnitrosamine (DEN) develop liver tumors in a male-dominant manner, reflecting the male bias in human hepatocellular carcinoma. Evidence suggests that estrogen, androgen, prolactin (PRL) and growth hormone (GH) modify liver tumorigenesis. We determined the roles of estrogen receptor alpha (ERalpha) and prolactin receptor (PRLR) using receptor null mice, ERalphaKO (C57Bl/6J) and PRLR-KO (129Ola-X-C57BL/6), in the neonatal-DEN model of liver tumorigenesis. In both mouse strains, females had reduced tumorigenesis compared with males (P < 0.01), regardless of ERalpha or PRLR status. Tumorigenesis was not affected by ovariectomy in C57Bl/6J mice but it was increased by ovariectomy in the mixed strain, 129Ola-X-C57BL/6, regardless of PRLR status. ERalphaKO males had 47% fewer tumors than ERalpha wild-type males (P < 0.01). On the other hand, estradiol treatment protected against tumorigenesis in males only in the presence of ERalpha. As evidenced by liver gene expression, lack of ERalpha did not alter the pattern of GH secretion in males but resulted in the male GH pattern in females. These observations indicate that ERalpha is not required for lower tumorigenesis in females, but it is required for the protective effects of exogenously delivered estradiol. Unexpectedly, the results indicate that ERalpha plays a role in promotion of liver tumors in males. In addition, it can be concluded that sex differences in liver tumorigenesis cannot be explained by the sexually dimorphic pattern of GH secretion. The results also rule out PRL as the mediator of the protective effect of the ovaries. PMID- 21606322 TI - Visual masking in schizophrenia: overview and theoretical implications. AB - Visual masking provides several key advantages for exploring the earliest stages of visual processing in schizophrenia: it allows for control over timing at the millisecond level, there are several well-supported theories of the underlying neurobiology of visual masking, and it is amenable to examination by electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI). In this paper, we provide an overview of the visual masking impairment schizophrenia, including the relevant theoretical mechanisms for masking impairment. We will discuss its relationship to clinical symptoms, antipsychotic medications, diagnostic specificity, and presence in at-risk populations. As part of this overview, we will cover the neural correlates of visual masking based on recent findings from EEG and fMRI. Finally, we will suggest a possible mechanism that could explain the patterns of masking findings and other visual processing findings in schizophrenia. PMID- 21606324 TI - Kinetics of cyclobutane thymine dimer splitting by DNA photolyase directly monitored in the UV. AB - CPD photolyase uses light to repair cyclobutane pyrimidine dimers (CPDs) formed between adjacent pyrimidines in UV-irradiated DNA. The enzyme harbors an FAD cofactor in fully reduced state (FADH(-)). The CPD repair mechanism involves electron transfer from photoexcited FADH(-) to the CPD, splitting of its intradimer bonds, and electron return to restore catalytically active FADH(-). The two electron transfer processes occur on time scales of 10(-10) and 10(-9) s, respectively. Until now, CPD splitting itself has only been poorly characterized by experiments. Using a previously unreported transient absorption setup, we succeeded in monitoring cyclobutane thymine dimer repair in the main UV absorption band of intact thymine at 266 nm. Flavin transitions that overlay DNA based absorption changes at 266 nm were monitored independently in the visible and subtracted to obtain the true repair kinetics. Restoration of intact thymine showed a short lag and a biexponential rise with time constants of 0.2 and 1.5 ns. We assign these two time constants to splitting of the intradimer bonds (creating one intact thymine and one thymine anion radical T(?-)) and electron return from T(?-) to the FAD cofactor with recovery of the second thymine, respectively. Previous model studies and computer simulations yielded various CPD splitting times between < 1 ps and < 100 ns. Our experimental results should serve as a benchmark for future efforts to model enzymatic photorepair. The technique and methods developed here may be applied to monitor other photoreactions involving DNA. PMID- 21606325 TI - Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity. AB - Amyloid fiber formation is correlated with pathology in many diseases, including Alzheimer's, Parkinson's, and type II diabetes. Although beta-sheet-rich fibrillar protein deposits define this class of disorder, increasing evidence points toward small oligomeric species as being responsible for cell dysfunction and death. The molecular mechanism by which this occurs is unknown, but likely involves the interaction of these species with biological membranes, with a subsequent loss of integrity. Here, we investigate islet amyloid polypeptide, which is implicated in the loss of insulin-secreting cells in type II diabetics. We report the discovery of oligomeric species that arise through stochastic nucleation on membranes and result in disruption of the lipid bilayer. These species are stable, result in all-or-none leakage, and represent a definable protein/lipid phase that equilibrates over time. We characterize the reaction pathway of assembly through the use of an experimental design that includes both ensemble and single-particle evaluations. Complexity in the reaction pathway could not be satisfied using a two-state description of membrane-bound monomer and oligomeric species. We therefore put forward a three-state kinetic framework, one of which we conjecture represents a non-amyloid, non-beta-sheet intermediate previously shown to be a candidate therapeutic target. PMID- 21606326 TI - Interaction of a G protein with an activated receptor opens the interdomain interface in the alpha subunit. AB - In G-protein signaling, an activated receptor catalyzes GDP/GTP exchange on the G(alpha) subunit of a heterotrimeric G protein. In an initial step, receptor interaction with G(alpha) acts to allosterically trigger GDP release from a binding site located between the nucleotide binding domain and a helical domain, but the molecular mechanism is unknown. In this study, site-directed spin labeling and double electron-electron resonance spectroscopy are employed to reveal a large-scale separation of the domains that provides a direct pathway for nucleotide escape. Cross-linking studies show that the domain separation is required for receptor enhancement of nucleotide exchange rates. The interdomain opening is coupled to receptor binding via the C-terminal helix of G(alpha), the extension of which is a high-affinity receptor binding element. PMID- 21606327 TI - Recognition of the centromere-specific histone Cse4 by the chaperone Scm3. AB - A specialized nucleosome is a component of all eukaryotic kinetochores. The core of this nucleosome contains a centromere-specific histone, CENP-A (the Cse4 gene product in budding yeast), instead of the usual H3. Assembly of a centromeric nucleosome depends on a specific chaperone, called Scm3 in yeast and HJURP in higher eukaryotes. We describe here the structure of a complex formed by an N terminal fragment of Scm3 with the histone-fold domains of Cse4, and H4, all prepared as recombinant proteins derived from the budding yeast Kluyveromyces lactis. The contacts of Scm3 with Cse4 explain its selectivity for the centromere specific histone; key residues at the interface are conserved in HJURP, indicating a common mechanism for centromeric-histone deposition. We also report the structure of a (Cse4 : H4)(2) heterotetramer; comparison with the structure of the Scm3:Cse4:H4 complex shows that tetramer formation and DNA-binding require displacement of Scm3 from the nucleosome core. The two structures together suggest that specific contacts between the chaperone and Cse4, rather than an altered overall structure of the nucleosome core, determine the selective presence of Cse4 at centromeres. PMID- 21606328 TI - Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step. AB - Telomerases constitute a group of specialized ribonucleoprotein enzymes that remediate chromosomal shrinkage resulting from the "end-replication" problem. Defects in telomere length regulation are associated with several diseases as well as with aging and cancer. Despite significant progress in understanding the roles of telomerase, the complete structure of the human telomerase enzyme bound to telomeric DNA remains elusive, with the detailed molecular mechanism of telomere elongation still unknown. By application of computational methods for distant homology detection, comparative modeling, and molecular docking, guided by available experimental data, we have generated a three-dimensional structural model of a partial telomerase elongation complex composed of three essential protein domains bound to a single-stranded telomeric DNA sequence in the form of a heteroduplex with the template region of the human RNA subunit, TER. This model provides a structural mechanism for the processivity of telomerase and offers new insights into elongation. We conclude that the RNADNA heteroduplex is constrained by the telomerase TEN domain through repeated extension cycles and that the TEN domain controls the process by moving the template ahead one base at a time by translation and rotation of the double helix. The RNA region directly following the template can bind complementarily to the newly synthesized telomeric DNA, while the template itself is reused in the telomerase active site during the next reaction cycle. This first structural model of the human telomerase enzyme provides many details of the molecular mechanism of telomerase and immediately provides an important target for rational drug design. PMID- 21606329 TI - Relating domain size distribution to line tension and molecular dipole density in model cytoplasmic myelin lipid monolayers. AB - We fit the size distribution of liquid-ordered (L(o)) domains measured from fluorescence images of model cytoplasmic myelin monolayers with an equilibrium thermodynamic expression that includes the competing effects of line tension, lambda, dipole density difference, Deltam, and the mixing entropy. From these fits, we extract the line tension, lambda, and dipole density difference, Deltam, between the L(o) and liquid-disordered (L(d)) phases. Both lambda and Deltam decrease with increasing surface pressure, , although lambda/Deltam(2) remains roughly constant as the monolayer approaches the miscibility surface pressure. As a result, the mean domain size changed little with surface pressure, although the polydispersity increased significantly. The most probable domain radius was significantly smaller than that predicted by the energy alone, showing that the mixing entropy promotes a greater number of smaller domains. Our results also explain why domain shapes are stable; at equilibrium, only a small fraction of the domains are large enough to undergo theoretically predicted shape fluctuations. Monolayers based on the composition of myelin from animals with experimental allergic encephalomyelitis had slightly lower values of lambda and Deltam, and a higher area fraction of domains, than control monolayers at all . While it is premature to generalize these results to myelin bilayers, our results show that the domain distribution in myelin may be an equilibrium effect and that subtle changes in surface pressure and composition can alter the distribution of material in the monolayer, which will likely also alter the interactions between monolayers important to the adhesion of the myelin sheath. PMID- 21606330 TI - Photosynthetic electron partitioning between [FeFe]-hydrogenase and ferredoxin:NADP+-oxidoreductase (FNR) enzymes in vitro. AB - Photosynthetic water splitting, coupled to hydrogenase-catalyzed hydrogen production, is considered a promising clean, renewable source of energy. It is widely accepted that the oxygen sensitivity of hydrogen production, combined with competition between hydrogenases and NADPH-dependent carbon dioxide fixation are the main limitations for its commercialization. Here we provide evidence that, under the anaerobic conditions that support hydrogen production, there is a significant loss of photosynthetic electrons toward NADPH production in vitro. To elucidate the basis for competition, we bioengineered a ferredoxin-hydrogenase fusion and characterized hydrogen production kinetics in the presence of Fd, ferredoxin:NADP(+)-oxidoreductase (FNR), and NADP(+). Replacing the hydrogenase with a ferredoxin-hydrogenase fusion switched the bias of electron transfer from FNR to hydrogenase and resulted in an increased rate of hydrogen photoproduction. These results suggest a new direction for improvement of biohydrogen production and a means to further resolve the mechanisms that control partitioning of photosynthetic electron transport. PMID- 21606331 TI - Paul trapping of charged particles in aqueous solution. AB - We experimentally demonstrate the feasibility of an aqueous Paul trap using a proof-of-principle planar device. Radio frequency voltages are used to generate an alternating focusing/defocusing potential well in two orthogonal directions. Individual charged particles are dynamically confined into nanometer scale in space. Compared with conventional Paul traps working in frictionless vacuum, the aqueous environment associated with damping forces and thermally induced fluctuations (Brownian noise) exerts a fundamental influence on the underlying physics. We investigate the impact of these two effects on the confining dynamics, with the aim to reduce the rms value of the positional fluctuations. We find that the rms fluctuations can be modulated by adjusting the voltages and frequencies. This technique provides an alternative for the localization and control of charged particles in an aqueous environment. PMID- 21606332 TI - Side-chain hydrophobicity scale derived from transmembrane protein folding into lipid bilayers. AB - The transfer free energies of the twenty natural amino acid side chains from water to phospholipid bilayers make a major contribution to the assembly and function of membrane proteins. Measurements of those transfer free energies will facilitate the identification of membrane protein sequences and aid in the understanding of how proteins interact with membranes during key biological events. We report the first water-to-bilayer transfer free energy scale (i.e., a "hydrophobicity scale") for the twenty natural amino acid side chains measured in the context of a native transmembrane protein and a phospholipid bilayer. Our measurements reveal parity for apolar side-chain contributions between soluble and membrane proteins and further demonstrate that an arginine side-chain placed near the middle of a lipid bilayer is accommodated with much less energetic cost than predicted by molecular dynamics simulations. PMID- 21606333 TI - Helicase-DNA polymerase interaction is critical to initiate leading-strand DNA synthesis. AB - Interactions between gene 4 helicase and gene 5 DNA polymerase (gp5) are crucial for leading-strand DNA synthesis mediated by the replisome of bacteriophage T7. Interactions between the two proteins that assure high processivity are known but the interactions essential to initiate the leading-strand DNA synthesis remain unidentified. Replacement of solution-exposed basic residues (K587, K589, R590, and R591) located on the front surface of gp5 with neutral asparagines abolishes the ability of gp5 and the helicase to mediate strand-displacement synthesis. This front basic patch in gp5 contributes to physical interactions with the acidic C-terminal tail of the helicase. Nonetheless, the altered polymerase is able to replace gp5 and continue ongoing strand-displacement synthesis. The results suggest that the interaction between the C-terminal tail of the helicase and the basic patch of gp5 is critical for initiation of strand-displacement synthesis. Multiple interactions of T7 DNA polymerase and helicase coordinate replisome movement. PMID- 21606334 TI - Apolar surface area determines the efficiency of translocon-mediated membrane protein integration into the endoplasmic reticulum. AB - Integral membrane proteins are integrated cotranslationally into the membrane of the endoplasmic reticulum in a process mediated by the Sec61 translocon. Transmembrane alpha-helices in a translocating polypeptide chain gain access to the surrounding membrane through a lateral gate in the wall of the translocon channel [van den Berg B, et al. (2004) Nature 427:36-44; Zimmer J, et al. (2008) Nature 455:936-943; Egea PF, Stroud RM (2010) Proc Natl Acad Sci USA 107:17182 17187]. To clarify the nature of the membrane-integration process, we have measured the insertion efficiency into the endoplasmic reticulum membrane of model hydrophobic segments containing nonproteinogenic aliphatic and aromatic amino acids. We find that an amino acid's contribution to the apparent free energy of membrane-insertion is directly proportional to the nonpolar accessible surface area of its side chain, as expected for thermodynamic partitioning between aqueous and nonpolar phases. But unlike bulk-phase partitioning, characterized by a nonpolar solvation parameter of 23 cal/(mol . A(2)), the solvation parameter for transfer from translocon to bilayer is 6-10 cal/(mol . A(2)), pointing to important differences between translocon-guided partitioning and simple water-to-membrane partitioning. Our results provide compelling evidence for a thermodynamic partitioning model and insights into the physical properties of the translocon. PMID- 21606335 TI - Forces guiding assembly of light-harvesting complex 2 in native membranes. AB - Interaction forces of membrane protein subunits are of importance in their structure, assembly, membrane insertion, and function. In biological membranes, and in the photosynthetic apparatus as a paradigm, membrane proteins fulfill their function by ensemble actions integrating a tight assembly of several proteins. In the bacterial photosynthetic apparatus light-harvesting complexes 2 (LH2) transfer light energy to neighboring tightly associated core complexes, constituted of light-harvesting complexes 1 (LH1) and reaction centers (RC). While the architecture of the photosynthetic unit has been described, the forces and energies assuring the structural and functional integrity of LH2, the assembly of LH2 complexes, and how LH2 interact with the other proteins in the supramolecular architecture are still unknown. Here we investigate the molecular forces of the bacterial LH2 within the native photosynthetic membrane using atomic force microscopy single-molecule imaging and force measurement in combination. The binding between LH2 subunits is fairly weak, of the order of k(B)T, indicating the importance of LH2 ring architecture. In contrast LH2 subunits are solid with a free energy difference of 90 k(B)T between folded and unfolded states. Subunit alpha-helices unfold either in one-step, alpha- and beta polypeptides unfold together, or sequentially. The unfolding force of transmembrane helices is approximately 150 pN. In the two-step unfolding process, the beta-polypeptide is stabilized by the molecular environment in the membrane. Hence, intermolecular forces influence the structural and functional integrity of LH2. PMID- 21606336 TI - Dynamics of enzymatic digestion of elastic fibers and networks under tension. AB - We study the enzymatic degradation of an elastic fiber under tension using an anisotropic random-walk model coupled with binding-unbinding reactions that weaken the fiber. The fiber is represented by a chain of elastic springs in series along which enzyme molecules can diffuse. Numerical simulations show that the fiber stiffness decreases exponentially with two distinct regimes. The time constant of the first regime decreases with increasing tension. Using a mean field calculation, we partition the time constant into geometrical, chemical and externally controllable factors, which is corroborated by the simulations. We incorporate the fiber model into a multiscale network model of the extracellular matrix and find that network effects do not mask the exponential decay of stiffness at the fiber level. To test these predictions, we measure the force relaxation of elastin sheets stretched to 20% uniaxial strain in the presence of elastase. The decay of force is exponential and the time constant is proportional to the inverse of enzyme concentration in agreement with model predictions. Furthermore, the fragment mass released into the bath during digestion is linearly related to enzyme concentration that is also borne out in the model. We conclude that in the complex extracellular matrix, feedback between the local rate of fiber digestion and the force the fiber carries acts to attenuate any spatial heterogeneity of digestion such that molecular processes manifest directly at the macroscale. Our findings can help better understand remodeling processes during development or in disease in which enzyme concentrations and/or mechanical forces become abnormal. PMID- 21606337 TI - Structure of a bacterial cell surface decaheme electron conduit. AB - Some bacterial species are able to utilize extracellular mineral forms of iron and manganese as respiratory electron acceptors. In Shewanella oneidensis this involves decaheme cytochromes that are located on the bacterial cell surface at the termini of trans-outer-membrane electron transfer conduits. The cell surface cytochromes can potentially play multiple roles in mediating electron transfer directly to insoluble electron sinks, catalyzing electron exchange with flavin electron shuttles or participating in extracellular intercytochrome electron exchange along "nanowire" appendages. We present a 3.2-A crystal structure of one of these decaheme cytochromes, MtrF, that allows the spatial organization of the 10 hemes to be visualized for the first time. The hemes are organized across four domains in a unique crossed conformation, in which a staggered 65-A octaheme chain transects the length of the protein and is bisected by a planar 45-A tetraheme chain that connects two extended Greek key split beta-barrel domains. The structure provides molecular insight into how reduction of insoluble substrate (e.g., minerals), soluble substrates (e.g., flavins), and cytochrome redox partners might be possible in tandem at different termini of a trifurcated electron transport chain on the cell surface. PMID- 21606338 TI - Structural basis of photosensitivity in a bacterial light-oxygen-voltage/helix turn-helix (LOV-HTH) DNA-binding protein. AB - Light-oxygen-voltage (LOV) domains are blue light-activated signaling modules integral to a wide range of photosensory proteins. Upon illumination, LOV domains form internal protein-flavin adducts that generate conformational changes which control effector function. Here we advance our understanding of LOV regulation with structural, biophysical, and biochemical studies of EL222, a light-regulated DNA-binding protein. The dark-state crystal structure reveals interactions between the EL222 LOV and helix-turn-helix domains that we show inhibit DNA binding. Solution biophysical data indicate that illumination breaks these interactions, freeing the LOV and helix-turn-helix domains of each other. This conformational change has a key functional effect, allowing EL222 to bind DNA in a light-dependent manner. Our data reveal a conserved signaling mechanism among diverse LOV-containing proteins, where light-induced conformational changes trigger activation via a conserved interaction surface. PMID- 21606339 TI - p53 binding to nucleosomes within the p21 promoter in vivo leads to nucleosome loss and transcriptional activation. AB - It is well established that p53 contacts DNA in a sequence-dependent manner in order to transactivate its myriad target genes. Yet little is known about how p53 interacts with its binding site/response element (RE) within such genes in vivo in the context of nucleosomal DNA. In this study we demonstrate that both distal (5') and proximal (3') p53 REs within the promoter of the p21 gene in unstressed HCT116 colon carcinoma cells are localized within a region of relatively high nucleosome occupancy. In the absence of cellular stress, p53 is prebound to both p21 REs within nucleosomal DNA in these cells. Treatment of cells with the DNA damaging drug doxorubicin or the p53 stabilizing agent Nutlin-3, however, is accompanied by p53-dependent subsequent loss of nucleosomes associated with such p53 REs. We show that in vitro p53 can bind to mononucleosomal DNA containing the distal p21 RE, provided the binding site is not close to the diad center of the nucleosome. In line with this, our data indicate that the p53 distal RE within the p21 gene is located close to the end of the nucleosome. Thus, low- and high resolution mapping of nucleosome boundaries around p53 REs within the p21 promoter have provided insight into the mechanism of p53 binding to its sites in cells and the consequent changes in nucleosome occupancy at such sites. PMID- 21606340 TI - Reactive nanostructured membranes for water purification. AB - Many current treatments for the reclamation of contaminated water sources are chemical-intensive, energy-intensive, and/or require posttreatment due to unwanted by-product formation. We demonstrate that through the integration of nanostructured materials, enzymatic catalysis, and iron-catalyzed free radical reactions within pore-functionalized synthetic membrane platforms, we are able to conduct environmentally important oxidative reactions for toxic organic degradation and detoxification from water without the addition of expensive or harmful chemicals. In contrast to conventional, passive membrane technologies, our approach utilizes two independently controlled, nanostructured membranes in a stacked configuration for the generation of the necessary oxidants. These include biocatalytic and organic/inorganic (polymer/iron) nanocomposite membranes. The bioactive (top) membrane contains an electrostatically immobilized enzyme for the catalytic production of one of the main reactants, hydrogen peroxide (H(2)O(2)), from glucose. The bottom membrane contains either immobilized iron ions or ferrihydrite/iron oxide nanoparticles for the decomposition of hydrogen peroxide to form powerful free radical oxidants. By permeating (at low pressure) a solution containing a model organic contaminant, such as trichlorophenol, with glucose in oxygen-saturated water through the membrane stack, significant contaminant degradation was realized. To illustrate the effectiveness of this membrane platform in real-world applications, membrane-immobilized ferrihydrite/iron oxide nanoparticles were reacted with hydrogen peroxide to form free radicals for the degradation of a chlorinated organic contaminant in actual groundwater. Although we establish the development of these nanostructured materials for environmental applications, the practical and methodological advances demonstrated here permit the extension of their use to applications including disinfection and/or virus inactivation. PMID- 21606341 TI - Electronic phase diagram of high-temperature copper oxide superconductors. AB - In order to understand the origin of high-temperature superconductivity in copper oxides, we must understand the normal state from which it emerges. Here, we examine the evolution of the normal state electronic excitations with temperature and carrier concentration in Bi(2)Sr(2)CaCu(2)O(8+delta) using angle-resolved photoemission. In contrast to conventional superconductors, where there is a single temperature scale T(c) separating the normal from the superconducting state, the high-temperature superconductors exhibit two additional temperature scales. One is the pseudogap scale T(*), below which electronic excitations exhibit an energy gap. The second is the coherence scale T(coh), below which sharp spectral features appear due to increased lifetime of the excitations. We find that T(*) and T(coh) are strongly doping dependent and cross each other near optimal doping. Thus the highest superconducting T(c) emerges from an unusual normal state that is characterized by coherent excitations with an energy gap. PMID- 21606342 TI - Core unit of chemotaxis signaling complexes. AB - Bacterial chemoreceptors, histidine kinase CheA, and coupling protein CheW form clusters of chemotaxis signaling complexes. In signaling complexes kinase activity is enhanced several hundredfold and placed under receptor control. Activation is necessary to poise enzyme activity such that receptor control has physiologically relevant effects. Thus kinase activation can be considered the underlying core activity of signaling complexes. We defined the minimal physical unit that generates this activity using chemoreceptor Tar from Escherichia coli rendered water soluble by insertion into nanodiscs to (i) measure saturable binding of CheA and CheW to the smallest kinase-activating groups of receptor dimers and (ii) purify and characterize core units of signaling complexes. Purified complexes activated kinase almost as well as signaling complexes formed on arrays of receptors in isolated native membrane. Purified complexes contained two receptor trimers of dimers and two CheW for each CheA dimer, consistent with the approximately 1:1 CheACheW ratio determined by binding measurements. The 2:2:1 stoichiometry implied that CheA dimers, the enzymatically active form, connect two chemoreceptor trimers of dimers by interaction of one CheA protomer and a CheW with each trimer, an organization for which specific molecular interactions have previously been identified. The core unit associates six receptor dimers with a CheA dimer, providing sufficient capacity to account for much of the cooperativity and interdimer influence observed experimentally. We conclude that the 221 organization is the core structural and functional unit of chemotaxis signaling complexes and postulate that hexagonal arrays characteristic of signaling complexes are built from this unit. PMID- 21606343 TI - Naturally occurring aminoacyl-tRNA synthetases editing-domain mutations that cause mistranslation in Mycoplasma parasites. AB - Mycoplasma parasites escape host immune responses via mechanisms that depend on remarkable phenotypic plasticity. Identification of these mechanisms is of great current interest. The aminoacyl-tRNA synthetases (AARSs) attach amino acids to their cognate tRNAs, but occasionally make errors that substitute closely similar amino acids. AARS editing pathways clear errors to avoid mistranslation during protein synthesis. We show here that AARSs in Mycoplasma parasites have point mutations and deletions in their respective editing domains. The deleterious effect on editing was confirmed with a specific example studied in vitro. In vivo mistranslation was determined by mass spectrometric analysis of proteins produced in the parasite. These mistranslations are uniform cases where the predicted closely similar amino acid replaced the correct one. Thus, natural AARS editing domain mutations in Mycoplasma parasites cause mistranslation. We raise the possibility that these mutations evolved as a mechanism for antigen diversity to escape host defense systems. PMID- 21606344 TI - Impaired capacity for familiarity after hippocampal damage. AB - Recognition memory is thought to consist of two components: recollection and familiarity. Whereas it is widely agreed that the hippocampus supports recollection (remembering the episode in which an item was learned), there is uncertainty about whether it also supports familiarity (simply knowing that an item was encountered but without remembering the learning episode). We tested a counterintuitive prediction that follows from the idea that the hippocampus selectively supports recollection. Patients with hippocampal lesions should have strong experiences of familiarity as often as controls do; however, unlike controls, these experiences should not be accompanied by recollection. Accordingly, with methods that allow participants to report whether they remember an item as encountered previously or whether they simply know it is familiar, patients should express strong familiarity (in the absence of recollection) more often than controls. We indexed strong familiarity and recollection for previously studied words by obtaining confidence ratings together with Remember Know judgments. The result was that patients provided fewer high-confidence Know responses than controls rather than more. Furthermore, the number of Know responses made by patients was substantially less than was predicted if recollection were impaired. This was true regardless of whether the prediction was based on the assumption that recollection and familiarity are independent or dependent processes. These results suggest that hippocampal lesions impair both recollection and familiarity. Unlike many previous studies of these constructs, the prediction (and the result) is independent of any particular theoretical model, and it holds even if Remember-Know judgments are not process-pure indicators of recollection and familiarity. PMID- 21606345 TI - Targeting and imaging single biomolecules in living cells by complementation activated light microscopy with split-fluorescent proteins. AB - Single-molecule (SM) microscopy allows outstanding insight into biomolecular mechanisms in cells. However, selective detection of single biomolecules in their native environment remains particularly challenging. Here, we introduce an easy methodology that combines specific targeting and nanometer accuracy imaging of individual biomolecules in living cells. In this method, named complementation activated light microscopy (CALM), proteins are fused to dark split-fluorescent proteins (split-FPs), which are activated into bright FPs by complementation with synthetic peptides. Using CALM, the diffusion dynamics of a controlled subset of extracellular and intracellular proteins are imaged with nanometer precision, and SM tracking can additionally be performed with fluorophores and quantum dots. In cells, site-specific labeling of these probes is verified by coincidence SM detection with the complemented split-FP fusion proteins or intramolecular single pair Forster resonance energy transfer. CALM is simple and combines advantages from genetically encoded and synthetic fluorescent probes to allow high-accuracy imaging of single biomolecules in living cells, independently of their expression level and at very high probe concentrations. PMID- 21606346 TI - Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. AB - The SNP (c.1142G > A;p.R381Q) in the IL-23 receptor (IL23R) confers protection from multiple inflammatory diseases, representing one of the most significant human genetic polymorphisms in autoimmunity. We, therefore, sought to define the functional consequences of this clinically significant variant. We find that CD4+CD45RO+ and CD8+ T cells from healthy R381Q IL23R carriers show decreased IL 23-dependent IL-17 and IL-22 production relative to WT IL23R individuals. This was associated with a lower percentage of circulating Th17 and Tc17 cells. Furthermore, CD8+ T cells from R381Q IL23R individuals showed decreased IL-23 dependent expansion and signal transducer and activator of transcription 3 (STAT3) activation compared with WT CD8+ T cells. Importantly, cells transfected with the IL23R glutamine variant show decreased IL-23-mediated signaling compared with the IL23R arginine allele. Our results show that the R381Q IL23R variant leads to selective, potentially desirable, loss of function alterations in primary human CD4+ and CD8+ T cells, resulting in highly significant protection against autoimmunity. PMID- 21606347 TI - Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. AB - Despite encouraging clinical results with next generation drugs (MDV3100 and abiraterone) that inhibit androgen receptor (AR) signaling in patients with castration-resistant prostate cancer (CRPC), responses are variable and short lived. There is an urgent need to understand the basis of resistance to optimize their future use. We reasoned that a radiopharmaceutical that measures intratumoral changes in AR signaling could substantially improve our understanding of AR pathway directed therapies. Expanding on previous observations, we first show that prostate-specific membrane antigen (PSMA) is repressed by androgen treatment in multiple models of AR-positive prostate cancer in an AR-dependent manner. Conversely, antiandrogens up-regulate PSMA expression. These expression changes, including increased PSMA expression in response to treatment with the antiandrogen MDV3100, can be quantitatively measured in vivo in human prostate cancer xenograft models through PET imaging with a fully humanized, radiolabeled antibody to PSMA, (64)Cu-J591. Collectively, these results establish that relative changes in PSMA expression levels can be quantitatively measured using a human-ready imaging reagent and could serve as a biomarker of AR signaling to noninvasively evaluate AR activity in patients with CRPC. PMID- 21606348 TI - PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function. AB - Oxidative stress is caused by an imbalance between reactive oxygen species (ROS) production and the ability of an organism to eliminate these toxic intermediates. Mutations in PTEN-inducible kinase 1 (PINK1) link mitochondrial dysfunction, increased sensitivity to ROS, and apoptosis in Parkinson's disease. Whereas PINK1 has been linked to the regulation of oxidative stress, the exact mechanism by which this occurs has remained elusive. Oxidative stress with associated mitochondrial dysfunction leads to cardiac dysfunction and heart failure (HF). We hypothesized that loss of PINK1 in the heart would have deleterious consequences on mitochondrial function. Here, we observed that PINK1 protein levels are markedly reduced in end-stage human HF. We also report that PINK1 localizes exclusively to the mitochondria. PINK1(-/-) mice develop left ventricular dysfunction and evidence of pathological cardiac hypertrophy as early as 2 mo of age. Of note, PINK1(-/-) mice have greater levels of oxidative stress and impaired mitochondrial function. There were also higher degrees of fibrosis, cardiomyocyte apoptosis, and a reciprocal reduction in capillary density associated with this baseline cardiac phenotype. Collectively, our in vivo data demonstrate that PINK1 activity is crucial for postnatal myocardial development, through its role in maintaining mitochondrial function, and redox homeostasis in cardiomyocytes. In conclusion, PINK1 possesses a distinct, nonredundant function in the surveillance and maintenance of cardiac tissue homeostasis. PMID- 21606349 TI - QnAs with Eric S. Lander. Interview by Prashant Nair. PMID- 21606350 TI - Behavioral thermoregulation by turtle embryos. AB - Mobile ectothermic animals can control their body temperatures by selecting specific thermal conditions in the environment, but embryos--trapped within an immobile egg and lacking locomotor structures--have been assumed to lack that ability. Falsifying that assumption, our experimental studies show that even early stage turtle embryos move within the egg to exploit small-scale spatial thermal heterogeneity. Behavioral thermoregulation is not restricted to posthatching life and instead may be an important tactic in every life-history stage. PMID- 21606351 TI - Isotopic Ag-Cu-Pb record of silver circulation through 16th-18th century Spain. AB - Estimating global fluxes of precious metals is key to understanding early monetary systems. This work adds silver (Ag) to the metals (Pb and Cu) used so far to trace the provenance of coinage through variations in isotopic abundances. Silver, copper, and lead isotopes were measured in 91 coins from the East Mediterranean Antiquity and Roman world, medieval western Europe, 16th-18th century Spain, Mexico, and the Andes and show a great potential for provenance studies. Pre-1492 European silver can be distinguished from Mexican and Andean metal. European silver dominated Spanish coinage until Philip III, but had, 80 y later after the reign of Philip V, been flushed from the monetary mass and replaced by Mexican silver. PMID- 21606352 TI - Selectivity of terrestrial gastropod extinctions on an oceanic archipelago and insights into the anthropogenic extinction process. AB - Anthropogenic impacts have led to widespread extinctions of species on oceanic islands but the nature of many of these extinctions remains poorly known. Here we investigate extinction selectivities of terrestrial gastropods from the Ogasawara archipelago in the northwest Pacific, where anthropogenic threats have changed over time, shifting primarily from the effects of habitat loss to predation by a variety of different predators. Across all of the islands, extinct species had significantly smaller geographic ranges compared with species that are still alive, but among the surviving species, ranges of those that are currently declining due to human impacts do not differ significantly from those that are not threatened. Extinctions were selective with respect to spire index (SI) of shells, a trait of potential functional importance, but the relationship between body size and extinction vulnerability varied among extinction agents, some of which were strongly size selective, whereas others were not. Overall, whereas anthropogenic impacts have resulted in nonrandom losses of phenotypic diversity, the patterns of selectivity are complex, vary among islands, and with the type of threat. As extinction agents have changed historically, so has the pattern of loss. Because of the changing nature of anthropogenic impacts, resiliency to one type of threat does not guarantee long-term survival of species and future patterns of biodiversity loss on these islands are likely to be different from those in the past. PMID- 21606354 TI - QnAs with Peter H. Gleick by Phil Downey. PMID- 21606353 TI - Platelet gene therapy improves hemostatic function for integrin alphaIIbbeta3 deficient dogs. AB - Activated blood platelets mediate the primary response to vascular injury. Although molecular abnormalities of platelet proteins occur infrequently, taken collectively, an inherited platelet defect accounts for a bleeding diathesis in ~1:20,000 individuals. One rare example of a platelet disorder, Glanzmann thrombasthenia (GT), is characterized by life-long morbidity and mortality due to molecular abnormalities in a major platelet adhesion receptor, integrin alphaIIbbeta3. Transfusion therapy is frequently inadequate because patients often generate antibodies to alphaIIbbeta3, leading to immune-mediated destruction of healthy platelets. In the most severe cases allogeneic bone marrow transplantation has been used, yet because of the risk of the procedure it has been limited to few patients. Thus, hematopoietic stem cell gene transfer was explored as a strategy to improve platelet function within a canine model for GT. Bleeding complications necessitated the use of a mild pretransplant conditioning regimen; therefore, in vivo drug selection was used to improve engraftment of autologously transplanted cells. Approximately 5,000 alphaIIbbeta3 receptors formed on 10% of platelets. These modest levels allowed platelets to adhere to alphaIIbbeta3's major ligand (fibrinogen), form aggregates, and mediate retraction of a fibrin clot. Remarkably, improved hemostatic function was evident, with <=135-fold reduced blood loss, and improved buccal bleeding times decreased to 4 min for up to 5 y after transplant. One of four transplanted dogs developed a significant antibody response to alphaIIbbeta3 that was attenuated effectively with transient immune suppression. These results indicate that gene therapy could become a practical approach for treating inherited platelet defects. PMID- 21606355 TI - Rare gene capture in predominantly androgenetic species. AB - The long-term persistence of completely asexual species is unexpected. Although asexuality has short-term evolutionary advantages, a lack of genetic recombination leads to the accumulation over time of deleterious mutations. The loss of individual fitness as a result of accumulated deleterious mutations is expected to lead to reduced population fitness and possible lineage extinction. Persistent lineages of asexual, all-female clones (parthenogenetic and gynogenetic species) avoid the negative effects of asexual reproduction through the production of rare males, or otherwise exhibit some degree of genetic recombination. Another form of asexuality, known as androgenesis, results in offspring that are clones of the male parent. Several species of the Asian clam genus Corbicula reproduce via androgenesis. We compared gene trees of mitochondrial and nuclear loci from multiple sexual and androgenetic species across the global distribution of Corbicula to test the hypothesis of long-term clonality of the androgenetic species. Our results indicate that low levels of genetic capture of maternal nuclear DNA from other species occur within otherwise androgenetic lineages of Corbicula. The rare capture of genetic material from other species may allow androgenetic lineages of Corbicula to mitigate the effects of deleterious mutation accumulation and increase potentially adaptive variation. Models comparing the relative advantages and disadvantages of sexual and asexual reproduction should consider the possibility of rare genetic recombination, because such events seem to be nearly ubiquitous among otherwise asexual species. PMID- 21606356 TI - Cholinergic chemosensory cells in the trachea regulate breathing. AB - In the epithelium of the lower airways, a cell type of unknown function has been termed "brush cell" because of a distinctive ultrastructural feature, an apical tuft of microvilli. Morphologically similar cells in the nose have been identified as solitary chemosensory cells responding to taste stimuli and triggering trigeminal reflexes. Here we show that brush cells of the mouse trachea express the receptors (Tas2R105, Tas2R108), the downstream signaling molecules (alpha-gustducin, phospholipase C(beta2)) of bitter taste transduction, the synthesis and packaging machinery for acetylcholine, and are addressed by vagal sensory nerve fibers carrying nicotinic acetylcholine receptors. Tracheal application of an nAChR agonist caused a reduction in breathing frequency. Similarly, cycloheximide, a Tas2R108 agonist, evoked a drop in respiratory rate, being sensitive to nicotinic receptor blockade and epithelium removal. This identifies brush cells as cholinergic sensors of the chemical composition of the lower airway luminal microenvironment that are directly linked to the regulation of respiration. PMID- 21606357 TI - Polycomb repressive complex 2 is necessary for the normal site-specific O-GlcNAc distribution in mouse embryonic stem cells. AB - The monosaccharide addition of an N-acetylglucosamine to serine and threonine residues of nuclear and cytosolic proteins (O-GlcNAc) is a posttranslational modification emerging as a general regulator of many cellular processes, including signal transduction, cell division, and transcription. The sole mouse O GlcNAc transferase (OGT) is essential for embryonic development. To understand the role of OGT in mouse development better, we mapped sites of O-GlcNAcylation of nuclear proteins in mouse embryonic stem cells (ESCs). Here, we unambiguously identify over 60 nuclear proteins as O-GlcNAcylated, several of which are crucial for mouse ESC cell maintenance. Furthermore, we extend the connection between OGT and Polycomb group genes from flies to mammals, showing Polycomb repressive complex 2 is necessary to maintain normal levels of OGT and for the correct cellular distribution of O-GlcNAc. Together, these results provide insight into how OGT may regulate transcription in early development, possibly by modifying proteins important to maintain the ESC transcriptional repertoire. PMID- 21606358 TI - Systematic variation in the temperature dependence of physiological and ecological traits. AB - To understand the effects of temperature on biological systems, we compile, organize, and analyze a database of 1,072 thermal responses for microbes, plants, and animals. The unprecedented diversity of traits (n = 112), species (n = 309), body sizes (15 orders of magnitude), and habitats (all major biomes) in our database allows us to quantify novel features of the temperature response of biological traits. In particular, analysis of the rising component of within species (intraspecific) responses reveals that 87% are fit well by the Boltzmann Arrhenius model. The mean activation energy for these rises is 0.66 +/- 0.05 eV, similar to the reported across-species (interspecific) value of 0.65 eV. However, systematic variation in the distribution of rise activation energies is evident, including previously unrecognized right skewness around a median of 0.55 eV. This skewness exists across levels of organization, taxa, trophic groups, and habitats, and it is partially explained by prey having increased trait performance at lower temperatures relative to predators, suggesting a thermal version of the life-dinner principle-stronger selection on running for your life than running for your dinner. For unimodal responses, habitat (marine, freshwater, and terrestrial) largely explains the mean temperature at which trait values are optimal but not variation around the mean. The distribution of activation energies for trait falls has a mean of 1.15 +/- 0.39 eV (significantly higher than rises) and is also right-skewed. Our results highlight generalities and deviations in the thermal response of biological traits and help to provide a basis to predict better how biological systems, from cells to communities, respond to temperature change. PMID- 21606359 TI - Convergent transcription confers a bistable switch in Enterococcus faecalis conjugation. AB - Convergent gene pairs with head-to-head configurations are widespread in both eukaryotic and prokaryotic genomes and are speculated to be involved in gene regulation. Here we present a unique mechanism of gene regulation due to convergent transcription from the antagonistic prgX/prgQ operon in Enterococcus faecalis controlling conjugative transfer of the antibiotic resistance plasmid pCF10 from donor cells to recipient cells. Using mathematical modeling and experimentation, we demonstrate that convergent transcription in the prgX/prgQ operon endows the system with the properties of a robust genetic switch through premature termination of elongating transcripts due to collisions between RNA polymerases (RNAPs) transcribing from opposite directions and antisense regulation between complementary counter-transcripts. Evidence is provided for the presence of truncated RNAs resulting from convergent transcription from both the promoters that are capable of sense-antisense interactions. A mathematical model predicts that both RNAP collision and antisense regulation are essential for a robust bistable switch behavior in the control of conjugation initiation by prgX/prgQ operons. Moreover, given that convergent transcription is conserved across species, the mechanism of coupling RNAP collision and antisense interaction is likely to have a significant regulatory role in gene expression. PMID- 21606360 TI - Gain of chromosome band 7q11 in papillary thyroid carcinomas of young patients is associated with exposure to low-dose irradiation. AB - The main consequence of the Chernobyl accident has been an increase in papillary thyroid carcinomas (PTCs) in those exposed to radioactive fallout as young children. Our aim was to identify genomic alterations that are associated with exposure to radiation. We used array comparative genomic hybridization to analyze a main (n = 52) and a validation cohort (n = 28) of PTC from patients aged <25 y at operation and matched for age at diagnosis and residency. Both cohorts consisted of patients exposed and not exposed to radioiodine fallout. The study showed association of a gain on chromosome 7 (7q11.22-11.23) with exposure (false discovery rate = 0.035). Thirty-nine percent of the exposed group showed the alteration; however, it was not found in a single case from the unexposed group. This was confirmed in the validation set. Because only a subgroup of cases in the exposed groups showed gain of 7q11.22-11.23, it is likely that different molecular subgroups and routes of radiation-induced carcinogenesis exist. The candidate gene CLIP2 was specifically overexpressed in the exposed cases. In addition, the expression of the genes PMS2L11, PMS2L3, and STAG3L3 correlated with gain of 7q11.22-11.23. An enrichment of Gene Ontology terms "DNA repair" (PMS2L3, PMS2L5), "response to DNA damage stimulus" (BAZ1B, PMS2L3, PMS2L5, RFC2), and "cell-cell adhesion" (CLDN3, CLDN4) was found. This study, using matched exposed and unexposed cohorts, provides insights into the radiation related carcinogenesis of young-onset PTC and, with the exposure-specific gain of 7q11 and overexpression of the CLIP2 gene, radiation-specific molecular markers. PMID- 21606361 TI - CCCTC-binding factor (CTCF) and cohesin influence the genomic architecture of the Igh locus and antisense transcription in pro-B cells. AB - Compaction and looping of the ~2.5-Mb Igh locus during V(D)J rearrangement is essential to allow all V(H) genes to be brought in proximity with D(H)-J(H) segments to create a diverse antibody repertoire, but the proteins directly responsible for this are unknown. Because CCCTC-binding factor (CTCF) has been demonstrated to be involved in long-range chromosomal interactions, we hypothesized that CTCF may promote the contraction of the Igh locus. ChIP sequencing was performed on pro-B cells, revealing colocalization of CTCF and Rad21 binding at ~60 sites throughout the V(H) region and 2 other sites within the Igh locus. These numerous CTCF/cohesin sites potentially form the bases of the multiloop rosette structures at the Igh locus that compact during Ig heavy chain rearrangement. To test whether CTCF was involved in locus compaction, we used 3D-FISH to measure compaction in pro-B cells transduced with CTCF shRNA retroviruses. Reduction of CTCF binding resulted in a decrease in Igh locus compaction. Long-range interactions within the Igh locus were measured with the chromosomal conformation capture assay, revealing direct interactions between CTCF sites 5' of DFL16 and the 3' regulatory region, and also the intronic enhancer (EMU), creating a D(H)-J(H)-EMU-C(H) domain. Knockdown of CTCF also resulted in the increase of antisense transcription throughout the D(H) region and parts of the V(H) locus, suggesting a widespread regulatory role for CTCF. Together, our findings demonstrate that CTCF plays an important role in the 3D structure of the Igh locus and in the regulation of antisense germline transcription and that it contributes to the compaction of the Igh locus. PMID- 21606362 TI - Genetic and molecular analyses reveal an evolutionary trajectory for glycan synthesis in a bacterial protein glycosylation system. AB - Although protein glycosylation systems are becoming widely recognized in bacteria, little is known about the mechanisms and evolutionary forces shaping glycan composition. Species within the genus Neisseria display remarkable glycoform variability associated with their O-linked protein glycosylation (pgl) systems and provide a well developed model system to study these phenomena. By examining the potential influence of two ORFs linked to the core pgl gene locus, we discovered that one of these, previously designated as pglH, encodes a glucosyltransferase that generates unique disaccharide products by using polyprenyl diphosphate-linked monosaccharide substrates. By defining the function of PglH in the glycosylation pathway, we identified a metabolic conflict related to competition for a shared substrate between the opposing glycosyltransferases PglA and PglH. Accordingly, we propose that the presence of a stereotypic, conserved deletion mutation inactivating pglH in strains of Neisseria gonorrhoeae, Neisseria meningitidis, and related commensals, reflects a resolution of this conflict with the consequence of reduced glycan diversity. This model of genetic detente is supported by the characterization of pglH "missense" alleles encoding proteins devoid of activity or reduced in activity such that they cannot exert their effect in the presence of PglA. Thus, glucose containing glycans appear to be a trait undergoing regression at the genus level. Together, these findings document a role for intrinsic genetic interactions in shaping glycan evolution in protein glycosylation systems. PMID- 21606363 TI - Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. AB - Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM(+) HDL contained S1P, whereas ApoM(-) HDL did not. Moreover, HDL in Apom(-/-) mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-A structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM(+) HDL induced S1P(1) receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM(-) HDL did not. Importantly, lack of S1P in the HDL fraction of Apom(-/-) mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P(1) receptor on endothelial cells, is a vasculoprotective constituent of HDL. PMID- 21606364 TI - The DISABLED protein functions in CLATHRIN-mediated synaptic vesicle endocytosis and exoendocytic coupling at the active zone. AB - Members of the DISABLED (DAB) family of proteins are known to play a conserved role in endocytic trafficking of cell surface receptors by functioning as monomeric CLATHRIN-associated sorting proteins that recruit cargo proteins into endocytic vesicles. Here, we report a Drosophila disabled mutant revealing a novel role for DAB proteins in chemical synaptic transmission. This mutant exhibits impaired synaptic function, including a rapid activity-dependent reduction in neurotransmitter release and disruption of synaptic vesicle endocytosis. In presynaptic boutons, Drosophila DAB and CLATHRIN were highly colocalized within two distinct classes of puncta, including relatively dim puncta that were located at active zones and may reflect endocytic mechanisms operating at neurotransmitter release sites. Finally, broader analysis of endocytic proteins, including DYNAMIN, supported a general role for CLATHRIN mediated endocytic mechanisms in rapid clearance of neurotransmitter release sites for subsequent vesicle priming and refilling of the release-ready vesicle pool. PMID- 21606365 TI - Evolution of the knowledge system for agricultural development in the Yaqui Valley, Sonora, Mexico. AB - Knowledge systems-networks of linked actors, organizations, and objects that perform a number of knowledge-related functions that link knowledge and know how with action-have played a key role in fostering agricultural development over the last 50 years. We examine the evolution of the knowledge system of the Yaqui Valley, Mexico, a region often described as the home of the green revolution for wheat, tracing changes in the functions of critical knowledge system participants, information flows, and research priorities. Most of the knowledge system's key players have been in place for many decades, although their roles have changed in response to exogenous and endogenous shocks and trends (e.g., drought, policy shifts, and price trends). The system has been agile and able to respond to challenges, in part because of the diversity of players (evolving roles of actors spanning research-decision maker boundaries) and also because of the strong and consistent role of innovative farmers. Although the agricultural research agenda in the Valley is primarily controlled from within the agricultural sector, outside voices have become an important influence in broadening development- and production-oriented perspectives to sustainability perspectives. PMID- 21606366 TI - Transfer characteristics of a thermosensory synapse in Caenorhabditis elegans. AB - Caenorhabditis elegans is a compact, attractive system for neural circuit analysis. An understanding of the functional dynamics of neural computation requires physiological analyses. We undertook the characterization of transfer at a central synapse in C. elegans by combining optical stimulation of targeted neurons with electrophysiological recordings. We show that the synapse between AFD and AIY, the first stage in the thermotactic circuit, exhibits excitatory, tonic, and graded release. We measured the linear range of the input-output curve and estimate the static synaptic gain as 0.056 (<0.1). Release showed no obvious facilitation or depression. Transmission at this synapse is peptidergic. The AFD/AIY synapse thus seems to have evolved for reliable transmission of a scaled down temperature signal from AFD, enabling AIY to monitor and integrate temperature with other sensory input. Combining optogenetics with electrophysiology is a powerful way to analyze C. elegans' neural function. PMID- 21606367 TI - Enhancer-driven membrane markers for analysis of nonautonomous mechanisms reveal neuron-glia interactions in Drosophila. AB - Extrinsic factors and the interactions of neurons with surrounding tissues are essential for almost every aspect of neuronal development. Here we describe a strategy of gene expression with an independent enhancer-driven cellular marker (GEEM) for studying roles of cell-cell interactions and extrinsic factors in the development of the Drosophila nervous system. Key to this strategy is robust expression of enhancer-driven transgenic markers in specific neurons. To this end, we have created vectors to achieve bright and even labeling of neuronal processes, easy cloning of enhancer elements, and efficient and flexible generation of transgenic animals. We provide examples of enhancer-driven membrane markers for specific neurons in both the peripheral and central nervous systems and their applications in the study of neuronal projections and connections in the Drosophila brain. We further applied GEEM to examine the wrapping of sensory neuron somas by glia during embryonic and larval stages, and neuron-glia interaction during dendrite pruning in live animals, leading to the discovery that glia play critical roles in the severing and degradation of proximal dendrites. The GEEM paradigm should be applicable to the studies of both cell autonomous and nonautonomous regulations of any cell type. PMID- 21606368 TI - Stage-specific proteomic expression patterns of the human filarial parasite Brugia malayi and its endosymbiont Wolbachia. AB - Global proteomic analyses of pathogens have thus far been limited to unicellular organisms (e.g., protozoa and bacteria). Proteomic analyses of most eukaryotic pathogens (e.g., helminths) have been restricted to specific organs, specific stages, or secretomes. We report here a large-scale proteomic characterization of almost all the major mammalian stages of Brugia malayi, a causative agent of lymphatic filariasis, resulting in the identification of more than 62% of the products predicted from the Bm draft genome. The analysis also yielded much of the proteome of Wolbachia, the obligate endosymbiont of Bm that also expressed proteins in a stage-specific manner. Of the 11,610 predicted Bm gene products, 7,103 were definitively identified from adult male, adult female, blood-borne and uterine microfilariae, and infective L3 larvae. Among the 4,956 gene products (42.5%) inferred from the genome as "hypothetical," the present study was able to confirm 2,336 (47.1%) as bona fide proteins. Analysis of protein families and domains coupled with stage-specific expression highlight the important pathways that benefit the parasite during its development in the host. Gene set enrichment analysis identified extracellular matrix proteins and those with immunologic effects as enriched in the microfilarial and L3 stages. Parasite sex- and stage specific protein expression identified those pathways related to parasite differentiation and demonstrates stage-specific expression by the Bm endosymbiont Wolbachia as well. PMID- 21606369 TI - Community interactions govern host-switching with implications for host-parasite coevolutionary history. AB - Reciprocal selective effects between coevolving species are often influenced by interactions with the broader ecological community. Community-level interactions may also influence macroevolutionary patterns of coevolution, such as cospeciation, but this hypothesis has received little attention. We studied two groups of ecologically similar feather lice (Phthiraptera: Ischnocera) that differ in their patterns of association with a single group of hosts. The two groups, "body lice" and "wing lice," are both parasites of pigeons and doves (Columbiformes). Body lice are more host-specific and show greater population genetic structure than wing lice. The macroevolutionary history of body lice also parallels that of their columbiform hosts more closely than does the evolutionary history of wing lice. The closer association of body lice with hosts, compared with wing lice, can be explained if body lice are less capable of switching hosts than wing lice. Wing lice sometimes disperse phoretically on parasitic flies (Diptera: Hippoboscidae), but body lice seldom engage in this behavior. We tested the hypothesis that wing lice switch host species more often than body lice, and that the difference is governed by phoresis. Our results show that, where flies are present, wing lice switch to novel host species in sufficient numbers to establish viable populations on the new host. Body lice do not switch hosts, even where flies are present. Thus, differences in the coevolutionary history of wing and body lice can be explained by differences in host-switching, mediated by a member of the broader parasite community. PMID- 21606370 TI - Guanine nucleotide exchange factor Vav1 regulates perivascular homing and bone marrow retention of hematopoietic stem and progenitor cells. AB - Engraftment and maintenance of hematopoietic stem and progenitor cells (HSPC) depend on their ability to respond to extracellular signals from the bone marrow microenvironment, but the critical intracellular pathways integrating these signals remain poorly understood. Furthermore, recent studies provide contradictory evidence of the roles of vascular versus osteoblastic niche components in HSPC function. To address these questions and to dissect the complex upstream regulation of Rac GTPase activity in HSPC, we investigated the role of the hematopoietic-specific guanine nucleotide exchange factor Vav1 in HSPC localization and engraftment. Using intravital microscopy assays, we demonstrated that transplanted Vav1(-/-) HSPC showed impaired early localization near nestin(+) perivascular mesenchymal stem cells; only 6.25% of Vav1(-/-) HSPC versus 45.8% of wild-type HSPC were located less than 30 MUm from a nestin(+) cell. Abnormal perivascular localization correlated with decreased retention of Vav1(-/-) HSPC in the bone marrow (44-60% reduction at 48 h posttransplant, compared with wild-type) and a very significant defect in short- and long-term engraftment in competitive and noncompetitive repopulation assays (<1.5% chimerism of Vav1(-/-) cells vs. 53-63% for wild-type cells). The engraftment defect of Vav1(-/-) HSPC was not related to alterations in proliferation, survival, or integrin-mediated adhesion. However, Vav1(-/-) HSPC showed impaired responses to SDF1alpha, including reduced in vitro migration in time-lapse microscopy assays, decreased circadian and pharmacologically induced mobilization in vivo, and dysregulated Rac/Cdc42 activation. These data suggest that Vav1 activity is required specifically for SDF1alpha-dependent perivascular homing of HSPC and suggest a critical role for this localization in retention and subsequent engraftment. PMID- 21606371 TI - Glucocorticoids target suppressor of cytokine signaling 1 (SOCS1) and type 1 interferons to regulate Toll-like receptor-induced STAT1 activation. AB - Endogenous and pharmacologic glucocorticoids (GCs) limit inflammatory cascades initiated by Toll-like receptor (TLR) activation. A long-standing clinical observation has been the delay between GC administration and the manifestation of GC's anti-inflammatory actions. We hypothesized that the GCs would have inhibitory effects that target late temporal pathways that propagate proinflammatory signals. Here we interrogated signal transducer and activator of transcription 1 (STAT1) regulation by GC and its consequences for cytokine production during activation of macrophages with TLR-specific ligands. We found that robust STAT1 activation does not occur until 2-3 h after TLR engagement, and that GC suppression of STAT1 phosphorylation first manifests at this time. GC attenuates TLR4-mediated STAT1 activation only through induction of suppressor of cytokine signaling 1 (SOCS1), which increases throughout the 6-h period after treatment. Inhibition of TLR3-mediated STAT1 activation occurs via two mechanisms, impairment of type I IFN secretion and induction of SOCS1. Our data show that SOCS1 and type I interferons are critical GC targets for regulating STAT1 activity and may account for overall GC effectiveness in inflammation suppression in the clinically relevant time frame. PMID- 21606372 TI - Infection with a plant virus modifies vector feeding behavior. AB - Vector infection by some animal-infecting parasites results in altered feeding that enhances transmission. Modification of vector behavior is of broad adaptive significance, as parasite fitness relies on passage to a new host, and vector feeding is nearly always essential for transmission. Although several plant viruses infect their insect vectors, we have shown that vector infection by a plant virus alters feeding behavior. Here we show that infection with Tomato spotted wilt virus (TSWV), type member of the only plant-infecting genus in the Bunyaviridae, alters the feeding behavior of its thrips vector, Frankliniella occidentalis (Pergande). Male thrips infected with TSWV fed more than uninfected males, with the frequency of all feeding behaviors increasing by up to threefold, thus increasing the probability of virus inoculation. Importantly, infected males made almost three times more noningestion probes (probes in which they salivate, but leave cells largely undamaged) compared with uninfected males. A functional cell is requisite for TSWV infection and cell-to-cell movement; thus, this behavior is most likely to establish virus infection. Some animal-infecting members of the Bunyaviridae (La Crosse virus and Rift Valley fever virus) also cause increased biting rates in infected vectors. Concomitantly, these data support the hypothesis that capacity to modify vector feeding behavior is a conserved trait among plant- and animal-infecting members of the Bunyaviridae that evolved as a mechanism to enhance virus transmission. Our results underscore the evolutionary importance of vector behavioral modification to diverse parasites with host ranges spanning both plant and animal kingdoms. PMID- 21606373 TI - Hedgehog signaling is required for formation of the notochord sheath and patterning of nuclei pulposi within the intervertebral discs. AB - The vertebrae notochord is a transient rod-like structure that produces secreted factors that are responsible for patterning surrounding tissues. During later mouse embryogenesis, the notochord gives rise to the middle part of the intervertebral disc, called the nucleus pulposus. Currently, very little is known about the molecular mechanisms responsible for forming the intervertebral discs. Here we demonstrate that hedgehog signaling is required for formation of the intervertebral discs. Removal of hedgehog signaling in the notochord and nearby floorplate resulted in the formation of an aberrant notochord sheath that normally surrounds this structure. In the absence of the notochord sheath, small nuclei pulposi were formed, with most notochord cells dispersed throughout the vertebral bodies during embryogenesis. Our data suggest that the formation of the notochord sheath requires hedgehog signaling and that the sheath is essential for maintaining the rod-like structure of the notochord during early embryonic development. As notochord cells form nuclei pulposi, we propose that the notochord sheath functions as a "wrapper" around the notochord to constrain these cells along the vertebral column. PMID- 21606374 TI - Soil warming, carbon-nitrogen interactions, and forest carbon budgets. AB - Soil warming has the potential to alter both soil and plant processes that affect carbon storage in forest ecosystems. We have quantified these effects in a large, long-term (7-y) soil-warming study in a deciduous forest in New England. Soil warming has resulted in carbon losses from the soil and stimulated carbon gains in the woody tissue of trees. The warming-enhanced decay of soil organic matter also released enough additional inorganic nitrogen into the soil solution to support the observed increases in plant carbon storage. Although soil warming has resulted in a cumulative net loss of carbon from a New England forest relative to a control area over the 7-y study, the annual net losses generally decreased over time as plant carbon storage increased. In the seventh year, warming-induced soil carbon losses were almost totally compensated for by plant carbon gains in response to warming. We attribute the plant gains primarily to warming-induced increases in nitrogen availability. This study underscores the importance of incorporating carbon-nitrogen interactions in atmosphere-ocean-land earth system models to accurately simulate land feedbacks to the climate system. PMID- 21606375 TI - ES cell-derived renewable and functional midbrain dopaminergic progenitors. AB - During early development, midbrain dopaminergic (mDA) neuronal progenitors (NPs) arise from the ventral mesencephalic area by the combined actions of secreted factors and their downstream transcription factors. These mDA NPs proliferate, migrate to their final destinations, and develop into mature mDA neurons in the substantia nigra and the ventral tegmental area. Here, we show that such authentic mDA NPs can be efficiently isolated from differentiated ES cells (ESCs) using a FACS method combining two markers, Otx2 and Corin. Purified Otx2(+)Corin(+) cells coexpressed other mDA NP markers, including FoxA2, Lmx1b, and Glast. Using optimized culture conditions, these mDA NPs continuously proliferated up to 4 wk with almost 1,000-fold expansion without significant changes in their phenotype. Furthermore, upon differentiation, Otx2(+)Corin(+) cells efficiently generated mDA neurons, as evidenced by coexpression of mDA neuronal markers (e.g., TH, Pitx3, Nurr1, and Lmx1b) and physiological functions (e.g., efficient DA secretion and uptake). Notably, these mDA NPs differentiated into a relatively homogenous DA population with few serotonergic neurons. When transplanted into PD model animals, aphakia mice, and 6-OHDA-lesioned rats, mDA NPs differentiated into mDA neurons in vivo and generated well-integrated DA grafts, resulting in significant improvement in motor dysfunctions without tumor formation. Furthermore, grafted Otx2(+)Corin(+) cells exhibited significant migratory function in the host striatum, reaching >3.3 mm length in the entire striatum. We propose that functional and expandable mDA NPs can be efficiently isolated by this unique strategy and will serve as useful tools in regenerative medicine, bioassay, and drug screening. PMID- 21606376 TI - Structural basis for enabling T-cell receptor diversity within biased virus specific CD8+ T-cell responses. AB - Pathogen-specific responses are characterized by preferred profiles of peptide+class I MHC (pMHCI) glycoprotein-specific T-cell receptor (TCR) Variable (V)-region use. How TCRV-region bias impacts TCRalphabeta heterodimer selection and resultant diversity is unclear. The D(b)PA(224)-specific TCR repertoire in influenza A virus-infected C57BL/6J (B6) mice exhibits a preferred TCRV-region bias toward the TRBV29 gene segment and an optimal complementarity determining region (CDR3) beta-length of 6 aa. Despite these restrictions, D(b)PA(224) specific BV29(+) T cells use a wide array of unique CDR3beta sequences. Structural characterization of a single, TRBV29(+)D(b)P(A224)-specific TCRalphabeta-pMHCI complex demonstrated that CDR3alpha amino acid side chains made specific peptide interactions, but the CDR3beta main chain exclusively contacted peptides. Thus, length but not amino acid sequence was key for recognition and flexibility in Vbeta-region use. In support of this hypothesis, retrovirus expression of the D(b)PA(224)-specific TCRValpha-chain was used to constrain pairing within a naive/immune epitope-specific repertoire. The retrogenic TCRValpha paired with a diversity of CDR3betas in the context of a preferred TCRVbeta spectrum. Overall, these data provide an explanation for the combination of TCRV region bias and diversity within selected repertoires, even as they maintain exquisite pMHCI specificity. PMID- 21606377 TI - Flexible intuitions of Euclidean geometry in an Amazonian indigene group. AB - Kant argued that Euclidean geometry is synthesized on the basis of an a priori intuition of space. This proposal inspired much behavioral research probing whether spatial navigation in humans and animals conforms to the predictions of Euclidean geometry. However, Euclidean geometry also includes concepts that transcend the perceptible, such as objects that are infinitely small or infinitely large, or statements of necessity and impossibility. We tested the hypothesis that certain aspects of nonperceptible Euclidian geometry map onto intuitions of space that are present in all humans, even in the absence of formal mathematical education. Our tests probed intuitions of points, lines, and surfaces in participants from an indigene group in the Amazon, the Mundurucu, as well as adults and age-matched children controls from the United States and France and younger US children without education in geometry. The responses of Mundurucu adults and children converged with that of mathematically educated adults and children and revealed an intuitive understanding of essential properties of Euclidean geometry. For instance, on a surface described to them as perfectly planar, the Mundurucu's estimations of the internal angles of triangles added up to ~180 degrees, and when asked explicitly, they stated that there exists one single parallel line to any given line through a given point. These intuitions were also partially in place in the group of younger US participants. We conclude that, during childhood, humans develop geometrical intuitions that spontaneously accord with the principles of Euclidean geometry, even in the absence of training in mathematics. PMID- 21606378 TI - Using the Integrative Model to explain how exposure to sexual media content influences adolescent sexual behavior. AB - Published research demonstrates an association between exposure to media sexual content and a variety of sex-related outcomes for adolescents. What is not known is the mechanism through which sexual content produces this "media effect" on adolescent beliefs, attitudes, and behavior. Using the Integrative Model of Behavioral Prediction, this article uses data from a longitudinal study of adolescents ages 16 to 18 (N = 460) to determine how exposure to sexual media content influences sexual behavior. Path analysis and structural equation modeling demonstrated that intention to engage in sexual intercourse is determined by a combination of attitudes, normative pressure, and self-efficacy but that exposure to sexual media content only affects normative pressure beliefs. By applying the Integrative Model, we are able to identify which beliefs are influenced by exposure to media sex and improve the ability of health educators, researchers, and others to design effective messages for health communication campaigns and messages pertaining to adolescents' engaging in sexual intercourse. PMID- 21606379 TI - Psychological empowerment among urban youth: measure development and relationship to psychosocial functioning. AB - Although there are an increasing number of youth development programs that aim to empower young people, there is a dearth of psychometrically sound measures that can be used to assess flexible youth-led organizing and participatory research approaches that tackle a wide range of social and community problems. This study developed and tested measures of psychological empowerment (PE) and self-efficacy for research and action among a sample of 439 ethnically diverse adolescents primarily recruited from public high schools in an urban center. Items for the PE measure were generated through an iterative combination of conducting formative research with our target population while also drawing on existing theory and measures in the field. We conducted a confirmatory factor analysis of the PE measure, testing four factors: adolescents' motivation to influence their school and community settings; participatory behavior; sociopolitical skills; and perceived control. Psychometric analyses for the PE scales and their correlation with adolescents' report of self-esteem, academic achievement, caring relationships with adults at school, and social support from peers are reported; the implications of the present study for research and practice in the youth development and adolescent psychology field are considered. PMID- 21606380 TI - Monitoring of Renal Function among HIV-Infected Patients Receiving Tenofovir in a Resource-Limited Setting. AB - The use of tenofovir disoproxil fumarate (TDF) is supposed to be increased in a resource-limited setting due to the changing of the guidelines. TDF-associated renal function declines among HIV-infected patients were defined by an increase of serum creatinine (SCr) >1.5 times, a 25% decrease in calculated creatinine clearance (CCrCl), or an estimated glomerular filtration rate (eGFR) from the baseline. Of all, 99% were antiretroviral treatment (ART)-experienced patients. At the 30th month, 19 (5.3%), 53 (14.9%), and 63 (17.7%) patients had renal function decline as defined by the above criteria with an incidence of 4.5, 12.5, and 14.6/100 person-year. A proportion of patients with a renal function decline detected by CCrCl or eGFR criteria was not different (P = .301), whereas, it differed from that detected by SCr criteria (P < .001). In conclusion, we encourage either CCrCl or eGFR calculations in monitoring renal function decline among HIV-infected patients receiving TDF in resource-limited settings. PMID- 21606381 TI - Cortical and behavioral sensitivity to eccentric polar form. AB - Patterns composed of local features aligned relative to polar angle, yielding starbursts, concentric circles, and spirals, can inform the understanding of spatial form perception. Previous studies have shown that starburst and concentric form instantiated in Glass patterns are, relative to spirals, both more readily detected in noise and evoke higher levels of blood-oxygen level dependent (BOLD) signal, as measured with functional magnetic resonance imaging (fMRI), in the retinotopic cortex. However, such studies have typically presented the polar form at the center of gaze, which confounds the distribution of local orientations relative to fixation with variations in polar form. Here, we measure psychophysical detection thresholds and evoked BOLD signal to Glass patterns of varying polar orientation centered at eccentricity. We find an enhanced behavioral sensitivity to starburst and concentric form, consistent with previous studies. While visual areas V1, V2, V3, V3A/B, and hV4 showed elevated levels of BOLD activity to concentric patterns, V1 and V2 showed little to none of the increased activity to starburst patterns evident in areas V3, V3A/B, and hV4. Such findings demonstrate the anisotropic response of the human visual system to variations in polar form independent of variations in local orientation distributions. PMID- 21606382 TI - Inference for psychometric functions in the presence of nonstationary behavior. AB - Measuring sensitivity is at the heart of psychophysics. Often, sensitivity is derived from estimates of the psychometric function. This function relates response probability to stimulus intensity. In estimating these response probabilities, most studies assume stationary observers: Responses are expected to be dependent only on the intensity of a presented stimulus and not on other factors such as stimulus sequence, duration of the experiment, or the responses on previous trials. Unfortunately, a number of factors such as learning, fatigue, or fluctuations in attention and motivation will typically result in violations of this assumption. The severity of these violations is yet unknown. We use Monte Carlo simulations to show that violations of these assumptions can result in underestimation of confidence intervals for parameters of the psychometric function. Even worse, collecting more trials does not eliminate this misestimation of confidence intervals. We present a simple adjustment of the confidence intervals that corrects for the underestimation almost independently of the number of trials and the particular type of violation. PMID- 21606383 TI - Quantifying the benefit of early living-donor renal transplantation with a simulation model of the Dutch renal replacement therapy population. AB - BACKGROUND: Early living-donor transplantation improves patient- and graft survival compared with possible cadaveric renal transplantation (RTx), but the magnitude of the survival gain is unknown. For patients starting renal replacement therapy (RRT), we aimed to quantify the survival benefit of early living-donor transplantation compared with dialysis and possible cadaveric transplantation and to estimate the population benefit from increasing the early transplantation rate. METHODS: We used a decision-analytic computer-simulation model, with a lifetime time horizon, simulating patients starting RRT, using data from the Dutch End-Stage Renal Disease Registry and published data. We compared the (quality adjusted) life expectancy (LE) of 'early living-donor RTx' and 'dialysis' (with possible cadaveric RTx if available). RESULTS: LE and quality adjusted LE benefits of the early living-donor RTx compared with the dialysis strategy for 40-year-old patients ranged from 7.5 to 9.9 life years (LYs) [6.7 8.8 quality-adjusted life years (QALYs)] depending on the primary renal disease. For 70-year-old patients, the benefit was 4.3-6.0 LYs (4.3-6.0 QALYs). Increasing the early transplantation rate from currently 5.8 to 22.2% (the highest in Europe) would increase average LE by 1.2 LYs and total LE for annual incident cases in the Netherlands by >1800 LYs. CONCLUSIONS: Efforts to increase early living-donor RTx could potentially substantially increase LE for patients starting RRT, especially in younger patients. PMID- 21606384 TI - The Oxford classification as a predictor of prognosis in patients with IgA nephropathy. AB - BACKGROUND: In 2009, the Oxford classification was developed as a pathological classification system for immunoglobulin A nephropathy (IgAN) to predict the risk of disease progression. The aim of this retrospective study was to evaluate the clinical and pathologic relevance of the Oxford classification in Korean patients with a pathologic diagnosis of IgAN. PATIENTS AND METHODS: We reviewed the renal pathology archives from January 2000 to December 2006 at Seoul St Mary's Hospital in Korea and identified 273 patients, who were diagnosed as having IgAN. We enrolled 197 patients who were available for further clinicopathologic analysis. All cases of IgAN were categorized according to the WHO classification, the semiquantitative classification and the Oxford classification. These pathologic classifications were compared. The clinical and laboratory findings at the time of biopsy were compared with those at the end of the follow-up according to the Oxford classification. RESULTS: When three pathologic classifications were compared, M1, S1, E1, T1 or T2 were associated with a higher score in the activity index. S1, T1 or T2 were associated with a higher score in the chronicity index and a higher grade in the WHO classification. The clinical and laboratory findings were compared according to the Oxford classification. At the time of biopsy, the proteinuria in patients with M1 was more than that of M0 (P = 0.035). At the end of follow-up, the number of antihypertensive drugs taken among patients with M1 was greater than that of patients with M0 (P = 0.001). At the time of biopsy, the proteinuria of patients with S1 was greater than that of S0 patients (P = 0.009). At the end of follow-up, the number of patients who received immunosuppressants was increased as the grade of T increased (P = 0.000). At the end point of the follow-up, the estimated glomerular filtration rate (eGFR) decreased as the grade of T increased (P = 0.008). The time-average proteinuria after adjusting the initial proteinuria increased significantly with increasing degree of T (P = 0.000). Levels of tubular atrophy/interstitial fibrosis were predictive for survival from end-stage renal disease or of having a 50% reduction of eGFR. CONCLUSION: The pathologic variables of the Oxford classification correlated significantly with other classifications (the WHO classification and the semiquantitative classification). The Oxford classification is a simple method for predicting renal outcome and differentiating between active and chronic lesions. We suggest that the Oxford classification offers an advantage for determining treatment policy for patients with IgAN. PMID- 21606385 TI - Counselling the elderly between hope and reality. PMID- 21606386 TI - The QT and corrected QT interval in recovery after exercise in children. AB - BACKGROUND: Prolongation of the QT interval after exercise can be used to help diagnose long-QT syndrome, especially when the resting QT interval is borderline. The aim of this study was to determine the normal ranges for QT and corrected QT in the recovery phase after exercise in children. METHODS AND RESULTS: Ninety four volunteer boys and girls aged 8 to < 17 years without any history of heart disease underwent exercise testing and had a 12-lead ECG performed in the supine position for 10 minutes of recovery. The QT was measured using a standardized tangent method, with the baseline defined as the Q-Q line. The recovery QT was maximally short at 1 minute of recovery in 93 of 94 children then lengthened and stabilized at 4 to 5 minutes recovery. The recovery QT lengthens as heart rate decreases in an approximately linear fashion with a mean increase of 15 ms per 10 beat decrease in heart rate. The 98 th percentiles for the corrected QT using the Bazett formula during minutes 4 to 6 in recovery were from 482 to 491 ms. There was excellent intraobserver and interobserver reliability, with intraclass correlation coefficients of 0.95 and 0.88, respectively. CONCLUSIONS: There is substantial individual variability of the normal repolarization process in the postexercise recovery period in children. The study provides a reference for normal responses for similar populations using a specific measurement protocol that can be easily applied. PMID- 21606387 TI - Endothelial function and circulating biomarkers are disturbed in women and children after preeclampsia. AB - Preeclampsia is a long-term cardiovascular risk factor for the mother and possibly the offspring. Preeclampsia and cardiovascular diseases share common pathophysiological features, including endothelial dysfunction. We explored whether endothelial function, measured noninvasively, as well as circulating biomarkers reflecting lipid metabolism, angiogenesis, and inflammation, differed in paired mothers and offspring 5 to 8 years after delivery. Twenty-six mother and child pairs after pregnancies complicated by preeclampsia were compared with 17 mother and child pairs after uncomplicated pregnancies. In addition, we assessed whether concentrations of maternal circulating biomarkers at delivery predicted findings 5 to 8 years postpartum. We also included an assessment of early onset preeclampsia and specifically addressed the effects of small for gestational age. Endothelial function was significantly reduced in both mothers and children after preeclampsia when combined with a small-for-gestational-age infant compared with mothers and children after pregnancies without a small-for gestational-age infant (mothers: P<0.001; children: P<0.05). Postpartum maternal soluble fms-like tyrosine kinase 1 (P=0.05) and high-sensitivity C-reactive protein (P=0.02) were elevated in the preeclampsia group compared with controls. High concentrations of these maternal biomarkers both at delivery and 5 to 8 years postpartum were also more frequent in preeclampsia compared with controls (P<0.05). The novelty of our study is the parallel finding of reduced endothelial function in mother and child pairs 5 to 8 years after small-for-gestational-age preeclamptic pregnancies, accompanied by increased inflammatory and antiangiogenic maternal biomarkers. This finding supports the concept of transgenerational risk of cardiovascular disease after preeclampsia. PMID- 21606388 TI - Calcitonin gene-related peptide terminates long-lasting vasopressor responses to endothelin 1 in vivo. AB - Slow dissociation of endothelin 1 from its endothelin A receptors is responsible for the long-lasting vasoconstrictor effects of the peptide. We showed recently that calcitonin gene-related peptide selectively terminates long-lasting contractile responses to endothelin 1 in isolated rat mesenteric arteries. Here we assessed whether the antiendothelinergic effect of calcitonin gene-related peptide is vascular bed specific and may terminate long-lasting pressor responses to exogenous and locally produced endothelin 1 in vivo. Regional heterogeneity of the calcitonin gene-related peptide/endothelin A receptor cross-talk was explored in arteries isolated from various rat organs. Endothelin A receptor-mediated arterial contractions were terminated by calcitonin gene-related peptide in rat mesenteric, renal, and spermatic arteries but not in basilar, coronary, epigastric, gastric, splenic, and saphenous arteries. Endothelin A receptor antagonism only ended endothelin 1-induced contractions in spermatic arteries. In anesthetized rats, instrumented with Doppler flow probes to record regional blood flows, long-lasting pressor and vasoconstrictor responses to an intravenous bolus injection of endothelin 1 or big endothelin 1 were transiently reduced by sodium nitroprusside (NO donor) but terminated by intravenously administered calcitonin gene-related peptide. In conscious rats, calcitonin gene-related peptide but not sodium nitroprusside terminated prolonged (>60-minute) pressor responses to endothelin 1 but not those to intravenous infusion of phenylephrine. In conclusion, pressor responses to circulating and locally produced endothelin 1 that are resistant to endothelin receptor antagonism and NO can be terminated by a regionally selective effect of calcitonin gene-related peptide. Calcitonin gene related peptide receptor agonism may represent a novel strategy to treat endothelin 1-associated cardiovascular pathologies. PMID- 21606389 TI - Cardiovascular system during the postpartum state in women with a history of preeclampsia. AB - In subjects with previous preeclampsia, differences in cardiovascular and/or blood biochemical parameters are present in the nonpregnant state, and a simultaneous assessment of multiple derived indices better differentiates between women with or without previous preeclampsia. We examined 18 previous preeclamptic and 50 previous uncomplicated pregnancies, ~16 months postpartum. Cardiovascular assessment included the following: (1) systemic hemodynamics and mechanics (Doppler echocardiography, tonometry, and oscillometric sphygmomanometry); (2) endothelial function (plethysmography); (3) left ventricular properties (echocardiography); and (4) blood biochemical analyses. Compared to women with previous uncomplicated pregnancies, previous preeclamptics had higher mean (80+/ 1 versus 86+/-3 mm Hg; P=0.04) and diastolic (64+/-1 versus 68+/-2 mm Hg; P=0.04) pressures and total vascular resistance (1562+/-37 versus 1784+/-114 dyne . s/cm(5); P=0.03). Systolic blood pressure, arterial compliance, and left ventricular properties were not different. Although heart-to-femoral pulse wave velocity was not different, heart-to-brachial pulse wave velocity tended to be faster in previous preeclamptics (374+/-8 versus 404+/-20 cm/s; P=0.06). Stress induced increase in forearm blood flow was less in previous preeclamptics (245%+/ 21% versus 136%+/-22%; P=0.01), indicating impaired endothelial function. No significant differences were observed in markers of endothelial activation, dyslipidemia, or oxidative stress; previous preeclamptics tended to have higher glucose level (58.7+/-1.9 versus 95+/-5.2 mg/dL; P=0.06). Logistic regression analysis indicated that a simultaneous evaluation of multiple derived indices better discriminated between the 2 groups. The differences in the previous preeclamptic group are in directions known to be associated with greater cardiovascular disease risk later in life. PMID- 21606390 TI - Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. AB - BACKGROUND: With recognition of disease-causing genes in arrhythmogenic right ventricular cardiomyopathy, mutation analysis is being applied. METHODS AND RESULTS: The role of genotyping in familial assessment for arrhythmogenic right ventricular cardiomyopathy was investigated, including the prevalence of mutations in known causal genes, the penetrance and expressivity in genotyped families, and the utility of the 2010 Task Force criteria in clinical diagnosis. Clinical and molecular genetic evaluation was performed in 210 first-degree and 45 second-degree relatives from 100 families. In 51 families, the proband was deceased. The living probands had a high prevalence of ECG abnormalities (89%) and ventricular arrhythmia (78%) and evidence of more severe disease than relatives. Definite or probable causal mutations were found in 58% of families and 73% of living probands, of whom 28% had an additional desmosomal variant (ie, mutation or polymorphism). Ninety-three relatives had a causal mutation; 33% fulfilled the 2010 criteria, whereas only 19% satisfied the 1994 version (P=0.03). An additional desmosomal gene variant was found in 10% and was associated with a 5-fold increased risk of developing penetrant disease (odds ratio, 4.7; 95% confidence interval, 1.1 to 20.4; P=0.04). CONCLUSIONS: Arrhythmogenic right ventricular cardiomyopathy is a genetically complex disease characterized by marked intrafamilial phenotype diversity. Penetrance is definition dependent and is greater with the 2010 criteria compared with the 1994 criteria. Relatives harboring >1 genetic variant had significantly increased risk of developing clinical disease, potentially an important determinant of the phenotypic heterogeneity seen within families with arrhythmogenic right ventricular cardiomyopathy. PMID- 21606391 TI - Predictors of bleeding and time dependence of association of bleeding with mortality: insights from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel--Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). AB - BACKGROUND: The balance between benefit (ischemia protection) and risk (bleeding) is a key consideration in choosing the intensity of antiplatelet therapy for patients with acute coronary syndromes. The goals of this analysis were to identify baseline characteristics that independently predict bleeding and to determine how bleeding events impact the subsequent mortality in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel--Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). METHODS AND RESULTS: Multivariable Cox regression analyses adjusted for treatment, baseline, and procedural variables were used to determine the predictors for serious (TIMI major or minor) bleeding. To analyze the hazard ratio and time dependency of bleeding on mortality, we used iterative day-to-day landmark analyses after the bleed. From the 13 420 patients with acute coronary syndromes included in this analysis, 534 (4.0%) experienced a serious bleeding event. Variables with the highest strength of association with risk of serious bleeding were female sex, use of a glycoprotein IIb/IIIa inhibitor, duration of intervention, age, assignment to prasugrel, regional characteristics, admission diagnosis of ST elevation myocardial infarction, femoral access for angiography, creatinine clearance, hypercholesterolemia, and arterial hypertension. Serious bleeding was associated with a significantly increased adjusted hazard ratio of 5.84 (95% confidence interval 4.11 to 8.29) for mortality. However, the hazard ratio did not differ statistically from baseline risk by 40 days after the bleeding event. CONCLUSIONS: The major predictors of serious bleeding were a combination of patient and procedural characteristics and antiplatelet therapies. Although serious bleeding was strongly associated with mortality within the first month of the bleeding event, this association was not significant beyond 40 days. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrial.gov. Unique identifier NCT00097591. PMID- 21606392 TI - Role of pyruvate dehydrogenase inhibition in the development of hypertrophy in the hyperthyroid rat heart: a combined magnetic resonance imaging and hyperpolarized magnetic resonance spectroscopy study. AB - BACKGROUND: Hyperthyroidism increases heart rate, contractility, cardiac output, and metabolic rate. It is also accompanied by alterations in the regulation of cardiac substrate use. Specifically, hyperthyroidism increases the ex vivo activity of pyruvate dehydrogenase kinase, thereby inhibiting glucose oxidation via pyruvate dehydrogenase. Cardiac hypertrophy is another effect of hyperthyroidism, with an increase in the abundance of mitochondria. Although the hypertrophy is initially beneficial, it can eventually lead to heart failure. The aim of this study was to use hyperpolarized magnetic resonance spectroscopy to investigate the rate and regulation of in vivo pyruvate dehydrogenase flux in the hyperthyroid heart and to establish whether modulation of flux through pyruvate dehydrogenase would alter cardiac hypertrophy. METHODS AND RESULTS: Hyperthyroidism was induced in 18 male Wistar rats with 7 daily intraperitoneal injections of freshly prepared triiodothyronine (0.2 mg x kg(-1) x d(-1)). In vivo pyruvate dehydrogenase flux, assessed with hyperpolarized magnetic resonance spectroscopy, was reduced by 59% in hyperthyroid animals (0.0022 +/- 0.0002 versus 0.0055 +/- 0.0005 second(-1); P=0.0003), and this reduction was completely reversed by both short- and long-term delivery of dichloroacetic acid, a pyruvate dehydrogenase kinase inhibitor. Hyperpolarized [2-(13)C]pyruvate was also used to evaluate Krebs cycle metabolism and demonstrated a unique marker of anaplerosis, the level of which was significantly increased in the hyperthyroid heart. Cine magnetic resonance imaging showed that long-term dichloroacetic acid treatment significantly reduced the hypertrophy observed in hyperthyroid animals (100 +/- 20 versus 200 +/- 30 mg; P=0.04) despite no change in the increase observed in cardiac output. CONCLUSIONS: This work has demonstrated that inhibition of glucose oxidation in the hyperthyroid heart in vivo is mediated by pyruvate dehydrogenase kinase. Relieving this inhibition can increase the metabolic flexibility of the hyperthyroid heart and reduce the level of hypertrophy that develops while maintaining the increased cardiac output required to meet the higher systemic metabolic demand. PMID- 21606393 TI - Relationship between supranormal oxygen tension and outcome after resuscitation from cardiac arrest. AB - BACKGROUND: Laboratory and recent clinical data suggest that hyperoxemia after resuscitation from cardiac arrest is harmful; however, it remains unclear if the risk of adverse outcome is a threshold effect at a specific supranormal oxygen tension, or is a dose-dependent association. We aimed to define the relationship between supranormal oxygen tension and outcome in postresuscitation patients. METHODS AND RESULTS: This was a multicenter cohort study using the Project IMPACT database (intensive care units at 120 US hospitals). Inclusion criteria were age >17 years, nontrauma, cardiopulmonary resuscitation preceding intensive care unit arrival, and postresuscitation arterial blood gas obtained. We excluded patients with hypoxia or severe oxygenation impairment. We defined the exposure by the highest partial pressure of arterial oxygen (PaO(2)) over the first 24 hours in the ICU. The primary outcome measure was in-hospital mortality. We tested the association between PaO(2) (continuous variable) and mortality using multivariable logistic regression adjusted for patient-oriented covariates and potential hospital effects. Of 4459 patients, 54% died. The median postresuscitation PaO(2) was 231 (interquartile range 149 to 349) mm Hg. Over ascending ranges of oxygen tension, we found significant linear trends of increasing in-hospital mortality and decreasing survival as functionally independent. On multivariable analysis, a 100 mm Hg increase in PaO(2) was associated with a 24% increase in mortality risk (odds ratio 1.24 [95% confidence interval 1.18 to 1.31]. We observed no evidence supporting a single threshold for harm from supranormal oxygen tension. CONCLUSION: In this large sample of postresuscitation patients, we found a dose-dependent association between supranormal oxygen tension and risk of in-hospital death. PMID- 21606395 TI - Fire in the hole: carotid stenting versus endarterectomy. PMID- 21606394 TI - Myocardial infarction after carotid stenting and endarterectomy: results from the carotid revascularization endarterectomy versus stenting trial. AB - BACKGROUND: The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) found a higher risk of stroke after carotid artery stenting and a higher risk of myocardial infarction (MI) after carotid endarterectomy. METHODS AND RESULTS: Cardiac biomarkers and ECGs were performed before and 6 to 8 hours after either procedure and if there was clinical evidence of ischemia. In CREST, MI was defined as biomarker elevation plus either chest pain or ECG evidence of ischemia. An additional category of biomarker elevation with neither chest pain nor ECG abnormality was prespecified (biomarker+ only). Crude mortality and risk adjusted mortality for MI and biomarker+ only were assessed during follow-up. Among 2502 patients, 14 MIs occurred in carotid artery stenting and 28 MIs in carotid endarterectomy (hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.94; P=0.032) with a median biomarker ratio of 40 times the upper limit of normal. An additional 8 carotid artery stenting and 12 carotid endarterectomy patients had biomarker+ only (hazard ratio, 0.66; 95% confidence interval, 0.27 to 1.61; P=0.36), and their median biomarker ratio was 14 times the upper limit of normal. Compared with patients without biomarker elevation, mortality was higher over 4 years for those with MI (hazard ratio, 3.40; 95% confidence interval, 1.67 to 6.92) or biomarker+ only (hazard ratio, 3.57; 95% confidence interval, 1.46 to 8.68). After adjustment for baseline risk factors, both MI and biomarker+ only remained independently associated with increased mortality. CONCLUSIONS: In patients randomized to carotid endarterectomy versus carotid artery stenting, both MI and biomarker+ only were more common with carotid endarterectomy. Although the levels of biomarker elevation were modest, both events were independently associated with increased future mortality and remain an important consideration in choosing the mode of carotid revascularization or medical therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00004732. PMID- 21606397 TI - Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. AB - BACKGROUND: Recent studies have investigated alternatives to warfarin for stroke prophylaxis in patients with atrial fibrillation (AF), but whether these alternatives are cost-effective is unknown. METHODS AND RESULTS: On the basis of the results from Randomized Evaluation of Long Term Anticoagulation Therapy (RE LY) and other trials, we developed a decision-analysis model to compare the cost and quality-adjusted survival of various antithrombotic therapies. We ran our Markov model in a hypothetical cohort of 70-year-old patients with AF using a cost-effectiveness threshold of $50 000/quality-adjusted life-year. We estimated the cost of dabigatran as US $9 a day. For a patient with an average risk of major hemorrhage (~3%/y), the most cost-effective therapy depended on stroke risk. For patients with the lowest stroke rate (CHADS2 stroke score of 0), only aspirin was cost-effective. For patients with a moderate stroke rate (CHADS2 score of 1 or 2), warfarin was cost-effective unless the risk of hemorrhage was high or quality of international normalized ratio control was poor (time in the therapeutic range <57.1%). For patients with a high stroke risk (CHADS(2) stroke score >=3), dabigatran 150 mg (twice daily) was cost-effective unless international normalized ratio control was excellent (time in the therapeutic range >72.6%). Neither dabigatran 110 mg nor dual therapy (aspirin and clopidogrel) was cost-effective. CONCLUSIONS: Dabigatran 150 mg (twice daily) was cost-effective in AF populations at high risk of hemorrhage or high risk of stroke unless international normalized ratio control with warfarin was excellent. Warfarin was cost-effective in moderate-risk AF populations unless international normalized ratio control was poor. PMID- 21606396 TI - Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study. AB - BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ~50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. METHODS AND RESULTS: One hundred forty-nine ARVD/C index patients (111 male patients; age, 49+/-13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44+/-13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V(1) to V(3), especially in mutation-carrying relatives <20 years of age. In 45% of screened families, >=1 affected relatives were identified (90% with mutations). CONCLUSIONS: Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives. PMID- 21606398 TI - Circumstances and outcomes of sudden unexpected death in patients with high-risk myocardial infarction: implications for prevention. AB - BACKGROUND: Sudden death (SD) is a frequent catastrophic complication in patients after myocardial infarction. Circumstances of SD may affect strategies for prevention. METHODS AND RESULTS: We reviewed source documentation for 1067 patients who had SD in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) trial. We determined the circumstances of these events and assessed long-term mortality in patients who were resuscitated. Location of the SD event was available in 978 of 1067 patients, with 226 events occurring within the first 40 days. Although SD was more likely to occur at home (645 of 978, 66%) than in hospital (204 of 978, 21%), the proportion of in-hospital events was higher early on (99 of 226, 44%). Home events were less likely to be witnessed regardless of time frame. Preceding activity was known for 42% of patients with home arrest; of these, 52% were determined to be asleep at time of event, and these deaths were more likely to be unwitnessed. A majority of patients for whom initial ECG rhythm was reported had ventricular tachycardia/ventricular fibrillation (189 of 283, 67%). Of the 155 patients successfully resuscitated, 24% subsequently received an implantable cardioverter-defibrillator. Nineteen percent of those who received an implantable cardioverter-defibrillator subsequently died compared with 49% of patients who did not receive an implantable cardioverter-defibrillator (hazard ratio, 0.36; 95% confidence interval, 0.14 to 0.93; P=0.04). CONCLUSIONS: A high proportion of SD events after high-risk myocardial infarction occurred at home, but in-hospital events were more common early on. Patients who were asleep were more likely to have unwitnessed arrests. Alternative strategies for the prevention of SD in patients who are not candidates for implantable cardioverter defibrillator will need to take into account the circumstances of SD events. PMID- 21606399 TI - Phosphorylation of vasodilator-stimulated phosphoprotein prevents platelet neutrophil complex formation and dampens myocardial ischemia-reperfusion injury. AB - BACKGROUND: Recent work has suggested that the formation of platelet-neutrophil complexes (PNCs) aggravates the severity of inflammatory tissue injury. Given the importance of vasodilator-stimulated phosphoprotein (VASP) for platelet function, we pursued the role of VASP on the formation of PNCs and its impact on the extent of myocardial ischemia-reperfusion (IR) injury. METHODS AND RESULTS: In initial in vitro studies we found that neutrophils facilitated the movement of platelets across endothelial monolayers. Phosphorylation of VASP reduced the formation of PNCs and transendothelial movement of PNCs. During myocardial IR injury, VASP(-/ ) animals demonstrated reduced intravascular formation of PNCs and reduced presence of PNCs within the ischemic myocardial tissue. This was associated with reduced IR injury. Studies using platelet transfer and bone marrow chimeric animals showed that hematopoietic VASP expression was crucial for the intravascular formation of PNCs the presence of PNCs within ischemic myocardial tissue and the extent of myocardial IR injury. Furthermore, phosphorylation of VASP on Ser153 or Ser235 reduced intravascular PNC formation and presence of PNCs within ischemic myocardial tissue. This finding was associated with reduced myocardial IR injury. CONCLUSION: Previously unappreciated, the phosphorylation of VASP performs a key function for the formation of PNCs that is crucially important for the extent of myocardial IR injury. PMID- 21606400 TI - The relative cost-effectiveness of anticoagulants: obvious, except for the cost and the effectiveness. PMID- 21606401 TI - Percutaneous pulmonary vein isolation for atrial fibrillation ablation. PMID- 21606402 TI - Multiple fractures with pseudoaneurysm formation in a subclavian artery stent. PMID- 21606403 TI - Letter by Nabi regarding article, "attained educational level and incident atherothrombotic events in low- and middle-income compared with high-income countries". PMID- 21606404 TI - Letter by Lacout et Al regarding article, "prevalence, characteristics, and outcomes of patients presenting with cardiogenic unilateral pulmonary edema". PMID- 21606406 TI - Recent advances in preventive cardiology and lifestyle medicine: a themed series. PMID- 21606407 TI - Catheter ablation of ventricular tachycardia. PMID- 21606405 TI - Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. PMID- 21606408 TI - Longitudinal follow-up of a right atrial appendage aneurysm by cardiac magnetic resonance imaging. PMID- 21606409 TI - Cabozantinib in medullary thyroid carcinoma: time to focus the spotlight on this rare disease. PMID- 21606410 TI - Inflammatory lesions of the peritoneum mimic carcinomatosis after treatment with intravenous chemotherapy and intraperitoneal catumaxomab. PMID- 21606411 TI - Breast cancer tumor size, nodal status, and prognosis: biology trumps anatomy. PMID- 21606412 TI - Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. AB - PURPOSE: XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article. PATIENTS AND METHODS: A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses. RESULTS: Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC. CONCLUSION: Cabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing (ClinicalTrials.gov number NCT00215605). PMID- 21606413 TI - Cytarabine dose of 36 g/m2 compared with 12 g/m2 within first consolidation in acute myeloid leukemia: results of patients enrolled onto the prospective randomized AML96 study. AB - PURPOSE: To assess the optimal cumulative dose of cytarabine for treatment of young adults with acute myeloid leukemia (AML) within a prospective multicenter treatment trial. PATIENTS AND METHODS: Between 1996 and 2003, 933 patients (median age, 47 years; range 15 to 60 years) with untreated AML were randomly assigned at diagnosis to receive cytarabine within the first consolidation therapy at either a intermediate-dose of 12 g/m2 (I-MAC) or a high-dose of 36 g/m2 (H-MAC) combined with mitoxantrone. Autologous hematopoietic stem-cell transplantation or intermediate-dose cytarabine (10 g/m2) were offered as second consolidation. Patients with a matched donor could receive an allogeneic transplantation in a risk-adapted manner. RESULTS: After double induction therapy including intermediate-dose cytarabine (10 g/m2), mitoxantrone, etoposide, and amsacrine, complete remission was achieved in 66% of patients. In the primary efficacy analysis population, a consolidation with either I-MAC or H-MAC did not result in significant differences in the 5-year overall (30% v 33%; P = .77) or disease-free survival (37% v 38%; P = .86) according to the intention-to-treat analysis. Besides a prolongation of neutropenia and higher transfusion demands in the H-MAC arm, rates of serious adverse events were comparable in the two groups. CONCLUSION: In young adults with AML receiving intermediate-dose cytarabine induction, intensification of the cytarabine dose beyond 12 g/m2 within first consolidation did not improve treatment outcome. PMID- 21606414 TI - Hepatic macronodular tuberculoma mimics liver metastasis in a patient with locoregional advanced tongue cancer. PMID- 21606415 TI - Diffuse large B-cell lymphoma, not otherwise specified, associated with coinfection of human herpesvirus 6 and 8. PMID- 21606416 TI - Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study. AB - PURPOSE: Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma. PATIENTS AND METHODS: Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle. RESULTS: The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance. CONCLUSION: Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma. PMID- 21606418 TI - Advanced colorectal liver metastases and surgery after preoperative chemotherapy: is response-based selection enough? PMID- 21606417 TI - SLCO2B1 and SLCO1B3 may determine time to progression for patients receiving androgen deprivation therapy for prostate cancer. AB - PURPOSE: Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT. PATIENTS AND METHODS: A cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays. RESULTS: Three SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P < .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene gene interaction (P(interaction) = .041). CONCLUSION: Genetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer. PMID- 21606419 TI - Persistent, biologically meaningful prostate cancer after 1 year of androgen ablation and docetaxel treatment. AB - PURPOSE: Clinicians are increasingly willing to treat prostate cancer within the primary site in the presence of regional lymph node or even limited distant metastases. However, no formal study on the merits of this approach has been reported. We used a preoperative clinical discovery platform to prioritize pathways for assessment as therapeutic targets and to test the hypothesis that the primary site harbors potentially lethal tumors after aggressive treatment. PATIENTS AND METHODS: Patients with locally advanced or lymph node-metastatic prostate cancer underwent 1 year of androgen ablation and three cycles of docetaxel therapy, followed by prostatectomy. All specimens were characterized for stage by accepted criteria. Expression of select molecular markers implicated in disease progression and therapy resistance was determined immunohistochemically and compared with that in 30 archived specimens from untreated patients with high-grade prostate cancer. Marker expression was divided into three groups: intracellular signaling pathways, stromal-epithelial interaction pathways, and angiogenesis. RESULTS: Forty patients were enrolled, 30 (75%) of whom underwent prostatectomy and two (5%) who underwent cystoprostatectomy. Twenty-nine specimens contained sufficient residual tumor for inclusion in a tissue microarray. Immunohistochemical analysis showed increased epithelial and stromal expression of CYP17, SRD5A1, and Hedgehog pathway components, and modulations of the insulin-like growth factor I pathway. CONCLUSION: A network of molecular pathways reportedly linked to prostate cancer progression is activated after 1 year of therapy; biomarker expression suggests that potentially lethal cancers persist in the primary tumor and may contribute to progression. PMID- 21606421 TI - Celebrate or calibrate? We say calibrate. PMID- 21606420 TI - Case series of dermatologic events associated with the insulin-like growth factor receptor 1 inhibitor cixutumumab. PMID- 21606422 TI - Androgen-producing testicular germ cell tumors. PMID- 21606423 TI - Cardiotoxicity in patients treated with bevacizumab is potentially reversible. PMID- 21606424 TI - Effect of very small tumor size on cancer-specific mortality in node-positive breast cancer. AB - PURPOSE: Traditionally, larger tumor size and increasing lymph node (LN) involvement have been considered independent predictors of increased breast cancer-specific mortality (BCSM). We sought to characterize the interaction between tumor size and LN involvement in determination of BCSM. In particular, we evaluated whether very small tumor size may predict for increased BCSM relative to larger tumors in patients with extensive LN involvement. PATIENTS AND METHODS: Using Surveillance, Epidemiology and End Results registry data, we identified 50,949 female patients diagnosed between 1990 and 2002 with nonmetastatic T1/T2 invasive breast cancer treated with surgery and axillary LN dissection. Primary study variables were tumor size, degree of LN involvement, and their corresponding interaction term. Kaplan-Meier methods, adjusted Cox proportional hazards models with interaction terms, and a linear trend test across nodal categories were performed. RESULTS: Median follow-up was 99 months. In multivariable analysis, there was significant interaction between tumor size and LN involvement (P < .001). Using T1aN0 as reference, T1aN2+ conferred significantly higher BCSM compared with T1bN2+ (hazard ratio [HR], 20.66 v 12.53; P = .02). A similar pattern was seen among estrogen receptor (ER) -negative patients with T1aN2+ compared with T1bN2+ (HR, 24.16 v 12.67; P = .03), but not ER-positive patients (P = .52). The effect of very small tumor size on BCSM was intermediate among N1 cancers, between that of N0 and N2+ cancers. CONCLUSION: Very small tumors with four positive LNs may predict for higher BCSM compared with larger tumors. In extensive node-positive disease, very small tumor size may be a surrogate for biologically aggressive disease. These results should be validated in future database studies. PMID- 21606425 TI - Neuroprotection for oxaliplatin-induced neurotoxicity: what happened to objective assessment? PMID- 21606426 TI - Association between prescription co-payment amount and compliance with adjuvant hormonal therapy in women with early-stage breast cancer. AB - PURPOSE: Noncompliance with adjuvant hormonal therapy among women with breast cancer is common. Little is known about the impact of financial factors, such as co-payments, on noncompliance. PATIENTS AND METHODS: We conducted a retrospective cohort study by using the pharmacy and medical claims database at Medco Health Solutions. Women older than age 50 years who were taking aromatase inhibitors (AIs) for resected breast cancer with two or more mail-order prescriptions, from January 1, 2007, to December 31, 2008, were identified. Patients who were eligible for Medicare were analyzed separately. Nonpersistence was defined as a prescription supply gap of more than 45 days without subsequent refill. Nonadherence was defined as a medication possession ratio less than 80% of eligible days. RESULTS: Of 8110 women younger than age 65 years, 1721 (21.1%) were nonpersistent and 863 (10.6%) were nonadherent. Among 14,050 women age 65 years or older, 3476 (24.7%) were nonpersistent and 1248 (8.9%) were nonadherent. In a multivariate analysis, nonpersistence (ever/never) in both age groups was associated with older age, having a non-oncologist write the prescription, and having a higher number of other prescriptions. Compared with a co-payment of less than $30, a co-payment of $30 to $89.99 for a 90-day prescription was associated with less persistence in women age 65 years or older (odds ratio [OR], 0.69; 95% CI, 0.62 to 0.75) but not among women younger than age 65, although a co-payment of more than $90 was associated with less persistence both in women younger than age 65 (OR, 0.82; 95% CI, 0.72 to 0.94) and those age 65 years or older (OR, 0.72; 95% CI, 0.65 to 0.80). Similar results were seen with nonadherence. CONCLUSION: We found that higher prescription co-payments were associated with both nonpersistence and nonadherence to AIs. This relationship was stronger in older women. Because noncompliance is associated with worse outcomes, future policy efforts should be directed toward interventions that would help patients with financial difficulties obtain life-saving medications. PMID- 21606428 TI - Rectal cancer trials: no movement. PMID- 21606427 TI - Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. AB - PURPOSE: To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. PATIENTS AND METHODS: Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m(2)/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m(2) weekly * 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here. RESULTS: Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received >= 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014). CONCLUSION: Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points. PMID- 21606429 TI - Primary intrahepatic small-cell carcinoma arising from combined hepatocellular and cholangiocarcinomas. PMID- 21606430 TI - Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. AB - PURPOSE: To assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter, phase II study using DTIC alone as a control arm. PATIENTS AND METHODS: Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months. RESULTS: From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio [HR], 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects. CONCLUSION: The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients. PMID- 21606431 TI - Why do patients with cancer visit emergency departments? Results of a 2008 population study in North Carolina. AB - PURPOSE: Emergency departments (EDs) in the United States are used by patients with cancer for disease or treatment-related problems and unrelated issues. The North Carolina Disease Event Tracking and Epidemiologic Collection Tool (NC DETECT) collects information about ED visits through a statewide database. PATIENTS AND METHODS: After approval by the institutional review board, 2008 NC DETECT ED visit data were acquired and cancer-related visits were identified. Descriptive statistics and logistic regressions were performed. Of 4,190,911 ED visits in 2008, there were 37,760 ED visits by 27,644 patients with cancer. RESULTS: Among patients, 77.2% had only one ED visit in 2008, the mean age was 64 years, and there were slightly more men than women. Among visits, the payor was Medicare for 52.4% and Medicaid for 12.1%. More than half the visits by patients with cancer occurred on weekends or evenings, and 44.9% occurred during normal hours. The top three chief complaints were related to pain, respiratory distress, and GI issues. Lung, breast, prostate, and colorectal cancers were identified in 26.9%, 6.3%, 6%, and 7.7% of visits, respectively, with diagnosis. A total of 63.2% of visits resulted in hospital admittance. When controlling for sex, age, time of day, day of week, insurance, and diagnosis position, patients with lung cancer were more likely to be admitted than patients with other types of cancer. CONCLUSION: To the best of our knowledge, this is the first study to provide a population-based snapshot of ED visits by patients with cancer in North Carolina. Efforts that target clinical problems and specific populations may improve delivery of quality cancer care and avoid ED visits. PMID- 21606432 TI - Missense mutations located in structural p53 DNA-binding motifs are associated with extremely poor survival in chronic lymphocytic leukemia. AB - PURPOSE: There is a distinct connection between TP53 defects and poor prognosis in chronic lymphocytic leukemia (CLL). It remains unclear whether patients harboring TP53 mutations represent a homogenous prognostic group. PATIENTS AND METHODS: We evaluated the survival of patients with CLL and p53 defects identified at our institution by p53 yeast functional assay and complementary interphase fluorescence in situ hybridization analysis detecting del(17p) from 2003 to 2010. RESULTS: A defect of the TP53 gene was identified in 100 of 550 patients. p53 mutations were strongly associated with the deletion of 17p and the unmutated IgVH locus (both P < .001). Survival assessed from the time of abnormality detection was significantly reduced in patients with both missense (P < .001) and nonmissense p53 mutations (P = .004). In addition, patients harboring missense mutation located in p53 DNA-binding motifs (DBMs), structurally well defined parts of the DNA-binding domain, manifested a clearly shorter median survival (12 months) compared with patients having missense mutations outside DBMs (41 months; P = .002) or nonmissense alterations (36 months; P = .005). The difference in survival was similar in the analysis limited to patients harboring mutation accompanied by del(17p) and was also confirmed in a subgroup harboring TP53 defect at diagnosis. The patients with p53 DBMs mutation (at diagnosis) also manifested a short median time to first therapy (TTFT; 1 month). CONCLUSION: The substantially worse survival and the short TTFT suggest a strong mutated p53 gain of-function phenotype in patients with CLL with DBMs mutations. The impact of p53 DBMs mutations on prognosis and response to therapy should be analyzed in investigative clinical trials. PMID- 21606433 TI - Nodal status and clinical outcomes in a large cohort of patients with triple negative breast cancer. AB - PURPOSE: To evaluate the clinical outcomes and relationship between tumor size, lymph node status, and prognosis in a large cohort of patients with confirmed triple receptor-negative breast cancer (TNBC). PATIENTS AND METHODS: We reviewed 1,711 patients with TNBC diagnosed between 1980 and 2009. Patients were categorized by tumor size and nodal status. Kaplan-Meier product limit method was used to calculate overall survival (OS) and relapse-free survival (RFS). A Sidak adjustment was used for multiple group comparisons. Cox proportional hazards models were fit to determine the association of tumor size and nodal status with survival outcomes after adjustment for other patient and disease characteristics. RESULTS: Median age was 48 years (range, 21 to 87 years). At a median follow-up of 53 months (range, 0.7 to 317 months), there were 614 deaths and 747 recurrences. The 5-year OS was 80% for node-negative patients (N0), 65% for one to three positive lymph nodes (N1), 48% for four to nine positive lymph nodes (N2), and 44% for >= 10 positive lymph nodes (N3; P < .0001). The 5-year RFS rates were 67% for N0, 52% for N1, 36% for N2, and 33% for N3 (P < .0001). Pairwise comparison by nodal status showed that when comparing N0 with node positive disease, there was a significant difference in OS and RFS (P < .001 all comparisons). However, when comparing N1 with N2 and N3 disease regardless of tumor size, there were no significant differences in OS or RFS. CONCLUSION: In patients with TNBC, once there is evidence of lymph node metastasis, the prognosis may not be affected by the number of positive lymph nodes. PMID- 21606434 TI - Signet ring cell carcinoma of the ampulla of Vater with leptomeningeal metastases: a case report. PMID- 21606435 TI - Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs. AB - PURPOSE: The relationship between market pricing of new anticancer drugs and the magnitude of clinical benefit caused by them has not been reported. PATIENTS AND METHODS: Randomized clinical trials (RCTs) that evaluated approved new agents for solid tumors by the U.S. Food and Drug administration since the year 2000 were assessed. Hazard ratios (HRs) and 95% CIs were extracted for time-to-event end points described for each RCT. HRs were pooled for three groups: agents directed against a specific molecular target, for which the target population is selected by a biomarker (group A); less specific biologic targeted agents (group B); and chemotherapeutic agents (group C). Monthly market prices of these different drugs were compared. RESULTS: For overall survival (OS), the pooled HR was 0.69 (95% CI, 0.59 to 0.81) for group A (six drugs, six trials); it was 0.78 (95% CI, 0.74 to 0.83) for group B (seven drugs, 14 trials); and it was 0.84 (95% CI, 0.79 to 0.90) for group C (eight drugs, 12 trials). For progression-free survival (PFS), the pooled HR was 0.42 (95% CI, 0.36 to 0.49) for group A (six drugs, seven trials); it was 0.57 (95% CI, 0.51 to 0.64) for group B (seven drugs, 14 trials); and it was 0.75 (95% CI, 0.66 to 0.85) for group C (six drugs, 10 trials). Tests for heterogeneity between subgroups were highly significant for PFS (P < .001) and OS (P = .02). The median monthly prices for standard doses of drugs were $5375 for group A, $5644 for group B, and $6584 for group C (P = .87). CONCLUSION: New agents with specific molecular targets are clinically the most beneficial, but their monthly market prices are not significantly different from those of other anticancer agents. PMID- 21606436 TI - Vitamin D and cancer: uncertainty persists; research continues. PMID- 21606437 TI - Changes in European cross-border cancer research and treatment. PMID- 21606438 TI - Genome sequencing in patient care: preventing contamination is crucial. PMID- 21606439 TI - StatBite: Cancer rates in selected EU countries. PMID- 21606440 TI - Telomere research offers insight on stress-disease link. PMID- 21606441 TI - Novel proteasome inhibitors to overcome bortezomib resistance. AB - The proteasome is an intracellular enzyme complex that degrades ubiquitin-tagged proteins and thereby regulates protein levels within the cell. Given this important role in maintaining cellular homeostasis, it is perhaps somewhat surprising that proteasome inhibitors have a therapeutic window. Proteasome inhibitors have demonstrated clinical efficacy in the treatment of multiple myeloma and mantle cell lymphoma and are under evaluation for the treatment of other malignancies. Bortezomib is the first and only Food and Drug Administration approved proteasome inhibitor that inhibits this enzyme complex in a reversible fashion. Although bortezomib improves clinical outcomes when used as a single agent, most patients do not respond to this drug and those who do respond almost uniformly relapse. As such, efforts are underway to develop proteasome inhibitors that act through mechanisms distinct from that of bortezomib. Specifically, inhibitors that bind the active site of the proteasome and inhibit the complex irreversibly have been developed and are in advanced clinical trials. Inhibitors that act on sites of the proteasome outside of the catalytic center have also been identified and are in preclinical development. In this review, we discuss the structure and function of the proteasome. We then focus on the molecular biology, chemistry, and the preclinical and clinical efficacy of novel proteasome inhibitors as strategies to inhibit this target and overcome some forms of bortezomib resistance. PMID- 21606443 TI - Genetic structure of the European Charolais and Limousin cattle metapopulations using pedigree analyses. AB - Pedigree collected by the Interbeef service allowed genetic diversity to be assessed by using pedigree analyses for the European Charolais (CHA) and Limousin (LIM) cattle populations registered in national herdbooks in Denmark (DNK), France (FRA), Ireland (IRL), Sweden (SWE), and, solely for the LIM breed, the United Kingdom (UK). The CHA data set included 2,563,189 calves with weaning performance, of which 96.1% were recorded in FRA, 3.0% in SWE, 0.5% in IRL, and 0.4% in DNK. The LIM data set included 1,652,734 calves with weaning performance, of which 91.9% were recorded in FRA, 4.9% in UK, 1.8% in DNK, 0.9% SWE, and 0.5% in IRL. Pedigree files included 3,191,132 CHA and 2,409,659 LIM animals. Gene flows were rather limited between populations, except from FRA toward other countries. Pedigree completeness was good in all subpopulations for both breeds and allowed the pedigree to be traced back to the French population. A relatively high level of genetic diversity was assessed in each CHA and LIM subpopulation by estimating either effective population sizes (N(e) >244 and N(e) >345 in the CHA and LIM subpopulations, respectively), relationship coefficients within subpopulations (<1.3% in both breeds), or probability of gene origins. However, in each subpopulation, it was shown that founders and also ancestors had unbalanced genetic contributions, leading to a moderate but continuous reduction in genetic diversity. Analyses between populations suggested that all European CHA and LIM populations were differentiated very little. The Swedish CHA population was assessed as genetically more distant from the other CHA populations because of fewer gene flows from other countries and because of the use of North American sires to introgress the polled phenotype. In each European subpopulation, most of the main ancestors, which explained 50% of gene origin, were born in FRA. However, those main ancestors were different between countries. Moreover, in both breeds, the main ancestors, which explained 50% of the gene origin in DNK, IRL, SWE, and UK for the LIM breed, were found to be infrequently used in FRA. Those results were consistent with the low relationship coefficients estimated between subpopulations (<0.6% in both the CHA and LIM breeds). Therefore, in both breeds, each subpopulation may constitute a reservoir of genetic diversity for the other ones. PMID- 21606444 TI - Effect of prenatal stress on subsequent response to mixing stress and a lipopolysaccharide challenge in pigs. AB - Sows subjected to prenatal stress have been found to produce offspring that have altered responses to stress. Our objective was to determine if exposing a sow to stress would alter the response of the offspring to lipopolysaccharide (LPS) at 2 mo of age or their response to mixing stress at 4 mo of age. Sow treatments consisted of intravenous injections of ACTH (1 IU/kg of BW), exposure to rough handling for a 10-min duration (rough), or no treatment (control) once per week from d 42 to 77 of gestation. At 2 mo of age, pigs from each treatment, 1 per litter (n = 21, 17, and 15 for the ACTH, rough, and control treatments, respectively), were challenged with 2 MUg of LPS/kg of BW or saline, or served as a noninjected control. Their behavioral response to a human approach test and salivary cortisol were measured. At 4 mo of age, 1 pig from each treatment (n = 14, 14, and 15 for the ACTH, rough, and control treatments, respectively) was taken from its home pen and placed in a pen of unfamiliar pigs. At this time, a punch biopsy wound (6 * 6 mm) was created to measure the ability of the pig to heal the wound. At this same time, each pig received a 1-mL intramuscular injection of 20% ovine red blood cells (oRBC), and then a second injection of oRBC at 21 d postmixing. Blood samples were collected 3 times per week for 2 wk and then once a week for 4 more weeks. Blood samples were analyzed for cortisol, porcine corticosteroid-binding globulin, antibody response to oRBC, and nitric oxide production by macrophages. Behavior was recorded during the first 5 d after mixing. All pigs in the LPS challenge responded with characteristic sickness behavior; however, pigs in the rough treatment showed less sickness behavior than those in the other 2 treatments (P < 0.05). Maternal stress treatment did not affect (P < 0.43) salivary cortisol. Pigs from all treatments responded similarly to mixing stress with regard to cortisol, porcine corticosteroid-binding globulin, antibody titers, nitric oxide production, and hematology measures, and all pigs experienced the same amount of aggression in response to mixing. Without altering peripheral measures of stress responsivity, prenatal stress enhanced the ability of pigs to cope with a simulated immune challenge, which could prove to be an adaptation to challenging environments. PMID- 21606442 TI - Lung cancer risk prediction: Prostate, Lung, Colorectal And Ovarian Cancer Screening Trial models and validation. AB - INTRODUCTION: Identification of individuals at high risk for lung cancer should be of value to individuals, patients, clinicians, and researchers. Existing prediction models have only modest capabilities to classify persons at risk accurately. METHODS: Prospective data from 70 962 control subjects in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) were used in models for the general population (model 1) and for a subcohort of ever smokers (N = 38 254) (model 2). Both models included age, socioeconomic status (education), body mass index, family history of lung cancer, chronic obstructive pulmonary disease, recent chest x-ray, smoking status (never, former, or current), pack-years smoked, and smoking duration. Model 2 also included smoking quit-time (time in years since ever-smokers permanently quit smoking). External validation was performed with 44 223 PLCO intervention arm participants who completed a supplemental questionnaire and were subsequently followed. Known available risk factors were included in logistic regression models. Bootstrap optimism-corrected estimates of predictive performance were calculated (internal validation). Nonlinear relationships for age, pack-years smoked, smoking duration, and quit-time were modeled using restricted cubic splines. All reported P values are two-sided. RESULTS: During follow-up (median 9.2 years) of the control arm subjects, 1040 lung cancers occurred. During follow-up of the external validation sample (median 3.0 years), 213 lung cancers occurred. For models 1 and 2, bootstrap optimism-corrected receiver operator characteristic area under the curves were 0.857 and 0.805, and calibration slopes (model predicted probabilities vs observed probabilities) were 0.987 and 0.979, respectively. In the external validation sample, models 1 and 2 had area under the curves of 0.841 and 0.784, respectively. These models had high discrimination in women, men, whites, and nonwhites. CONCLUSION: The PLCO lung cancer risk models demonstrate high discrimination and calibration. PMID- 21606445 TI - Nonruminant Nutrition Symposium: nutrient and non-nutrient sensing and signaling in the gastrointestinal tract. PMID- 21606446 TI - Alpharma Beef Cattle Nutrition Symposium: parameterizing health and performance expectations of feedlot cattle. PMID- 21606447 TI - Yeast culture supplement during nursing and transport affects immunity and intestinal microbial ecology of weanling pigs. AB - The objectives of this study were to determine the influence of a Saccharomyces cerevisiae fermentation product on innate immunity and intestinal microbial ecology after weaning and transport stress. In a randomized complete block design, before weaning and in a split-plot analysis of a 2 * 2 factorial arrangement of yeast culture (YY) and transport (TT) after weaning, 3-d-old pigs (n = 108) were randomly assigned within litter (block) to either a control (NY, milk only) or yeast culture diet (YY; delivered in milk to provide 0.1 g of yeast culture product/kg of BW) from d 4 to 21. At weaning (d 21), randomly, one-half of the NY and YY pigs were assigned to a 6-h transport (NY-TT and YY-TT) before being moved to nursery housing, and the other one-half were moved directly to nursery housing (NY-NT and YY-NT, where NT is no transport). The yeast treatment was a 0.2% S. cerevisiae fermentation product and the control treatment was a 0.2% grain blank in feed for 2 wk. On d 1 before transport and on d 1, 4, 7, and 14 after transport, blood was collected for leukocyte assays, and mesenteric lymph node, jejunal, and ileal tissue, and jejunal, ileal, and cecal contents were collected for Toll-like receptor expression (TLR); enumeration of Escherichia coli, total coliforms, and lactobacilli; detection of Salmonella; and microbial analysis. After weaning, a yeast * transport interaction for ADG was seen (P = 0.05). Transport affected (P = 0.09) ADFI after weaning. Yeast treatment decreased hematocrit (P = 0.04). A yeast * transport interaction was found for counts of white blood cells (P = 0.01) and neutrophils (P = 0.02) and for the neutrophil-to-lymphocyte ratio (P = 0.02). Monocyte counts revealed a transport (P = 0.01) effect. Interactions of yeast * transport (P = 0.001) and yeast * transport * day (P = 0.09) for TLR2 and yeast * transport (P = 0.08) for TLR4 expression in the mesenteric lymph node were detected. Day affected lactobacilli, total coliform, and E. coli counts. More pigs were positive for Salmonella on d 7 and 14 than on d 4, and more YY-TT pigs were positive (P = 0.07) on d 4. The number of bands for microbial amplicons in the ileum was greater for pigs in the control treatment than in the yeast treatment on d 0, and this number tended to decrease (P = 0.066) between d 1 and 14 for all pigs. Similarity coefficients for jejunal contents were greater (P = 0.03) for pigs fed NY than for those fed YY, but pigs fed YY had greater similarity coefficients for ileal (P = 0.001) and cecal (P = 0.058) contents. The number of yeast * transport * day interactions demonstrates the complexity of the stress and dietary relationship. PMID- 21606448 TI - Farm factors associated with the use of antibiotics in pig production. AB - The aim of this study was to investigate farm-level economic and technical factors that are associated with the use of antibiotics on pig farms. Identification of such factors, like farm size and net farm result, may help to increase epidemiological knowledge and to specify farm advice and policy making to reduce inappropriate use of antibiotics. The study used over 300 farm-year records collected during 2004 to 2007 from pig farms in the Netherlands. Data included economic and technical factors as well as antibiotic administration. Data were statistically analyzed for factors associated with antibiotic use, both for fattening pig and sow farms (piglets only), separately. The response variable was the average number of daily dosages per average pig year. Statistical analysis was performed on 16 and 19 potential explanatory factors for the fattening pig and sow farms, respectively. The results showed that, both on the fattening pig and sow farms, the average use of antibiotics increased from 2004 to 2006, but decreased during 2007, but the effect of year was not significant (P > 0.05). Use of antibiotics varied between individual farms. Large farm repeatability for the use of antibiotics in the different years was found. Factors associated (P < 0.05) with the use of antibiotics included: farm system, number of pigs, and population density in the region of the farm (for sow farms only). As these factors are easy to collect and to register, they can be used to specify farm advice and investigation, as well as for policy making. The majority of the technical and economic factors were not significantly (P > 0.05) related to the on-farm use of antibiotics. Therefore, it is recommended to focus future research on the potential role of socioeconomic factors associated with antibiotic use on pig farms. PMID- 21606449 TI - International issues: tropical neurology in Vietnam. PMID- 21606450 TI - Teaching neuroImages: Schwannoma of the cauda equina. PMID- 21606451 TI - Progression of language decline and cortical atrophy in subtypes of primary progressive aphasia. AB - OBJECTIVES: To examine the longitudinal course of primary progressive aphasia (PPA) over a 2-year period and to offer quantitative ranges of expected change that could be used to guide the design and evaluation of therapeutic intervention trials. METHODS: Regional changes of cortical thickness and whole-brain cortical volume loss as well as neuropsychological language performance were assessed at baseline and 2 years later in 13 rigorously characterized patients who fulfilled research criteria for logopenic, agrammatic, and semantic PPA subtypes (6 PPA-L, 3 PPA-G, and 4 PPA-S). RESULTS: There was substantial progression of clinical deficits and cortical atrophy over 2 years. Neuropsychological language performance patterns lost the sharp distinctions that differentiated one PPA variant from another. Nonetheless, the subtype-specific differential impairment of word comprehension vs grammatical processing was largely maintained. Peak atrophy sites spread beyond the initial distinctive locations that characterized each of the 3 subtypes and displayed a more convergent distribution encompassing all 3 major components of the language network: the inferior frontal gyrus, the temporoparietal junction, and lateral temporal cortex. Despite the progression, overall peak atrophy remained lateralized to the left hemisphere. CONCLUSIONS: The results suggest that the unique features, which sharply differentiate the PPA variants at the early to middle stages, may lose their distinctiveness as the degeneration becomes more severe. Given the substantial atrophy over 2 years, PPA clinical trials may require fewer patients and shorter study durations than Alzheimer disease trials to detect significant therapeutic effects. PMID- 21606452 TI - Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. AB - OBJECTIVE: To investigate striatal adenosine A2A receptor availability in patients with Parkinson disease (PD) with and without levodopa-induced dyskinesias (LIDs). While providing effective relief from the motor symptoms of PD, chronic levodopa use is associated with development of LIDs. A2A receptors are expressed on the bodies of indirect pathway medium spiny striatal neurons and on dopamine terminals and play a role in modulating dopamine transmission. A2A antagonists have antiparkinsonian activity by boosting levodopa efficacy. We aimed to study A2A receptor availability in patients with PD with and without LIDs using PET and [11C]SCH442416, an A2A antagonist. METHODS: Six patients with PD with and 6 without LIDs were studied withdrawn 12 hours from medication. Their PET findings were compared with 6 age-matched healthy controls. Using spectral analysis, [11C]SCH442416 regional volumes of distribution (V(T)) were computed for the caudate, putamen, and thalamus and binding potentials (BP(ND)) reflecting the ratio of specific:nonspecific uptake were compared between groups. RESULTS: A2A binding in the caudate and putamen of subjects with PD with LIDs was far higher (p = 0.026 and p = 0.036, respectively) than that of subjects with PD without LIDs, which lay within the control range. Thalamic A2A availability was similar for all 3 groups. CONCLUSION: Patients with PD with LIDs show increased A2A receptor availability in the striatum. This finding is compatible with altered adenosine transmission playing a role in LIDs and provides a rationale for a trial of A2A receptor agents in the treatment of these motor complications. PMID- 21606453 TI - Final results from 18 years of the International Lamotrigine Pregnancy Registry. AB - OBJECTIVE: To monitor for a signal for major teratogenicity following in utero lamotrigine exposure. METHODS: Health care providers reported lamotrigine exposure during pregnancy, and subsequent outcomes, on a voluntary basis. Prospective reporting early in pregnancy was encouraged. Major congenital malformations (MCMs) were classified according to the Centers for Disease Control and Prevention (CDC) criteria and were reviewed by a pediatrician on the Registry's Scientific Advisory Committee. The proportion of infants with MCMs was calculated by trimester and therapy type and descriptively compared to population based reference estimates. RESULTS: Over an 18-year period, 35 infants with MCMs were observed among 1,558 first-trimester monotherapy exposures: 2.2%(95% confidence interval [CI] 1.6%-3.1%). This was similar to estimates from general population-based cohorts. The observed proportion of infants with MCMs among 150 lamotrigine/valproate polytherapy exposures was 10.7% (95% CI 6.4%-17.0%) and was 2.8% (95% CI 1.5%-5.0%) among 430 infants exposed to lamotrigine polytherapy without valproate. No consistent pattern of malformation type, or malformation frequency by dose, was observed. DISCUSSION: The Registry did not detect an appreciable increase in MCM frequency following first-trimester lamotrigine monotherapy exposure. With over 1,500 first-trimester monotherapy exposures, the Registry was powered to detect major teratogenicity. The proportion of infants with MCMs following lamotrigine/valproate polytherapy exposure was high, but similar to that previously reported with valproate monotherapy. The Registry failed to observe an increased MCM frequency with increasing lamotrigine dose. Monitoring of specific malformations among lamotrigine-exposed pregnancies will continue through case-control surveillance in the European Congenital Anomalies and Twins Registers network. PMID- 21606454 TI - Vitamin D in African Americans with multiple sclerosis. AB - OBJECTIVE: To evaluate whether vitamin D is associated with multiple sclerosis (MS) status and disease severity in African Americans. METHODS: Serum 25 hydroxyvitamin D was compared in a cross-sectional sample of 339 African Americans with MS and 342 African American controls. Correlations between disease severity (Multiple Sclerosis Severity Score [MSSS]) and 25-hydroxyvitamin D levels were sought. RESULTS: A total of 71% of controls and 77% of patients with MS were vitamin D deficient (<50 nmol/L; <20 ng/mL), and 93% of controls and 94% of patients with MS were vitamin D insufficient (<75 nmol/L; <30 ng/mL). Median unadjusted (29.7 vs 36.6 nmol/L, p = 0.0001) and deseasonalized (p = 0.0013) 25 hydroxyvitamin D levels were lower in the MS group. Multivariable analysis revealed that differences in latitude and ultraviolet index accounted for much of this association. The median (interquartile range) MSSS was 6.1 (4.8-8.1). There was no apparent association between the MSSS and vitamin D status. A greater proportion of European genetic ancestry, a measure of genetic admixture, was positively correlated with 25-hydroxyvitamin D (p = 0.007). CONCLUSIONS: Levels of 25-hydroxyvitamin D were lower in African Americans with MS than controls, an observation primarily explained by differences in climate and geography. There was no apparent association between vitamin D status and disease severity. These results are consistent with observations in other populations that lower 25 hydroxyvitamin D is associated with having MS, but also highlight the importance of climate and ancestry in determining vitamin D status. PMID- 21606455 TI - Diabetes mellitus and ischemic stroke in the young: clinical features and long term prognosis. AB - OBJECTIVE: To compare risk factors, stroke characteristics, and long-term prognosis between nondiabetic young ischemic stroke patients and similar patients having either type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) to provide information for patient management, counseling, and future research in these patient groups. METHODS: Our database comprised 1,008 consecutive patients aged 15 to 49 with first-ever ischemic stroke from 1994 to 2007. Primary outcome measures were 1) nonfatal or fatal recurrent ischemic stroke and 2) composite vascular endpoint (myocardial infarction, any stroke, revascularization, or vascular death). RESULTS: Compared with nondiabetic stroke patients (n = 904), patients with T1D (44) or T2D (60) were more likely to have hypertension and stroke attributable to small-vessel disease (SVD). In addition, when compared with nondiabetic patients, those with T1D more frequently had coronary heart disease and peripheral arterial disease (PAD) and those with T2D more often had obesity, PAD, history of TIA, and stroke attributable to large-artery atherosclerosis, and T2D patients were also more likely to be older and male than were the nondiabetic patients. Mean follow-up in survivors was 9.0 (+/-3.8) years. Cumulative recurrent ischemic stroke rate at 10 years was 40.9% for T1D (14 events), 29.7% for T2D (15), and 12.0% for nondiabetic patients (94). Corresponding rates for the composite vascular endpoint were 65.1% for T1D (25), 46.9% for T2D (28), and 19.3% for nondiabetic patients (153). CONCLUSIONS: Our findings suggest that ischemic stroke patients with T1D or T2D exhibit a distinct risk-factor and etiologic profile and a worse vascular prognosis than do nondiabetic patients. PMID- 21606457 TI - Floppy epiglottis as a contraindication of CPAP in patients with multiple system atrophy. PMID- 21606458 TI - No influence of KIF1B on neurodegenerative markers in multiple sclerosis. PMID- 21606460 TI - Fenestration of the internal carotid artery mimicking floating thrombus on CT and MR angiography. PMID- 21606461 TI - Open biopsy in patients with acute progressive neurologic decline and absence of mass lesion. PMID- 21606462 TI - Improving safety for the neurologic patient: evaluating medications, literacy, and abuse. PMID- 21606463 TI - Hyperglycemic Ins2AkitaLdlr-/- mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease. AB - Accelerated atherosclerosis is the leading cause of death in type 1 diabetes, but the mechanism of type 1 diabetes-accelerated atherosclerosis is not well understood, in part due to the lack of a good animal model for the long-term studies required. In an attempt to create a model for studying diabetic macrovascular disease, we have generated type 1 diabetic Akita mice lacking the low density lipoprotein receptor (Ins2(Akita)Ldlr-/-). Ins2(Akita)Ldlr-/- mice were severely hyperglycemic with impaired glucose tolerance. Compared with Ldlr-/ mice, 20-week-old Ins2(Akita)Ldlr-/- mice fed a 0.02% cholesterol AIN76a diet showed increased plasma triglyceride and cholesterol levels, and increased aortic root cross-sectional atherosclerotic lesion area [224% (P < 0.001) in males and 30% (P < 0.05) in females]. Microarray and quantitative PCR analyses of livers from Ins2(Akita)Ldlr-/- mice revealed altered expression of lipid homeostatic genes, including sterol-regulatory element binding protein (Srebp)1, liver X receptor (Lxr)alpha, Abca1, Cyp7b1, Cyp27a1, and Lpl, along with increased expression of pro-inflammatory cytokine genes, including interleukin (Il)1alpha, Il1beta, Il2, tumor necrosis factor (Tnf)alpha, and Mcp1. Immunofluorescence staining showed that the expression levels of Mcp1, Tnfalpha, and Il1beta were also increased in the atherosclerotic lesions and artery walls of Ins2(Akita)Ldlr /- mice. Thus, the Ins2(Akita)Ldlr-/- mouse appears to be a promising model for mechanistic studies of type 1 diabetes-accelerated atherosclerosis. PMID- 21606464 TI - CETP expression reverses the reconstituted HDL-induced increase in VLDL. AB - Human data suggest that reconstituted HDL (rHDL) infusion can induce atherosclerosis regression. Studies in mice indicated that rHDL infusion adversely affects VLDL levels, but this effect is less apparent in humans. This discrepancy may be explained by the fact that humans, in contrast to mice, express cholesteryl ester transfer protein (CETP). The aim of this study was to investigate the role of CETP in the effects of rHDL on VLDL metabolism by using APOE*3-Leiden (E3L) mice, a well-established model for human-like lipoprotein metabolism. At 1 h after injection, rHDL increased plasma VLDL-C and TG in E3L mice, but not in E3L mice cross-bred onto a human CETP background (E3L.CETP mice). This initial raise in VLDL, caused by competition between rHDL and VLDL for LPL-mediated TG hydrolysis, was thus prevented by CETP. At 24 h after injection, rHDL caused a second increase in VLDL-C and TG in E3L mice, whereas rHDL had even decreased VLDL in E3L.CETP mice. This secondary raise in VLDL was due to increased hepatic VLDL-TG production. Collectively, we conclude that CETP protects against the rHDL-induced increase in VLDL. We anticipate that studies evaluating the anti-atherosclerotic efficacy of rHDL in mice that are naturally deficient for CETP should be interpreted with caution, and that treatment of atherogenic dyslipidemia by rHDL should not be combined with agents that aggressively reduce CETP activity. PMID- 21606465 TI - Ultrasound biomicroscopy evaluation of anterior extension in retinoblastoma: a clinicopathological study. AB - BACKGROUND: Extension of retinoblastoma cells into the posterior chamber is a criterion for group E according to the international classification of intraocular retinoblastoma. Currently, the anterior extension of retinoblastoma is based on the presence of tumour cells in the anterior chamber assessed by biomicroscopy. AIM: To determine the value of ultrasound biomicroscopy (UBM) in the assessment of posterior chamber involvement in advanced retinoblastoma. METHODS: Retrospective review of all retinoblastoma cases enucleated at the Jules Gonin Eye Hospital from January 1996 to December 2009 for which UBM (35 MHz) evaluation was available. The patients' records were reviewed for patient and tumour features and histopathological findings. UBM findings were compared with histopathological features. RESULTS: UBM documentation was available in 31 cases. Retinoblastoma was detected by UBM in the posterior chamber in 18 cases and was absent in 13 cases while histopathological analysis demonstrated its presence in the posterior chamber in 22 cases and its absence in 9 cases. Among the 18 UBM positive cases, 7 had biomicroscopic detectable involvement of the anterior chamber. There was a significant correlation between echodensities consistent with retinoblastoma on UBM in the posterior chamber and histopathological tumorous involvement of the posterior chamber (p=0.0001). The sensitivity of UBM in the assessment of posterior chamber invasion by retinoblastoma was 81% and the specificity was 100%. CONCLUSION: In selected cases of advanced retinoblastoma, UBM appears to represent a valuable tool in the precise evaluation of anterior extension of disease, with good sensitivity and specificity for the assessment of posterior chamber involvement. UBM may provide useful criteria governing the indication for enucleation. PMID- 21606466 TI - Basement membrane changes in capillaries of the ageing human retina. AB - OBJECTIVES: The ultrastructural appearance of retinal capillaries can yield important information about disease mechanisms, but is not well characterised in human post mortem samples. We therefore aimed to create a baseline for the appearance of capillaries and establish how this is influenced by post mortem fixation delays and donor age. METHODS: Electron microscopy was used to characterise retinal capillaries in 20 anonymous donors (with no known eye diseases) of various ages and with various post mortem fixation delays. In addition, samples from six patients with conditions that are known to affect the retinal vasculature (four cases of type 2 diabetes without diabetic retinopathy, one case of diabetic retinopathy and one case of macular telangiectasia type 2) were analysed. RESULTS: Vacuoles were found in capillary basement membranes at the vessel-glia interface in all samples, from both the normal and disease cases. Vacuole frequency increased with donor age but was not influenced by post mortem fixation delays. CONCLUSION: Vacuoles in the basement membrane are a normal feature of adult human retinal capillaries and do not indicate disease. Their incidence increases with age and might be a contributing factor to late-onset pathologies of the retinal vasculature. PMID- 21606467 TI - Barriers to clinical uptake of tear osmolarity measurements. AB - AIM: The aim of the study was to examine the possibilities of measuring tear osmolarity in a general clinical setting, and to identify the barriers preventing the uptake of new methodologies for its measurement. METHODS: Five non-contact lens wearers were recruited to evaluate the diagnostic capability of the TearLab. Three osmolarity measurements were taken at 1 min intervals in the morning at 09:00, midday between 12:00 and 13:00 and afternoon at 16:00 for two consecutive days. Forty more osmolarity measurements were carried out at different times on one subject with low and one subject with high tear osmolarity over 4 months. The osmolarity of a standard solution, 290 mOsm/l, was measured 19 times alternatively with the TearLab by two examiners. RESULTS: Consecutive tear osmolarity readings in an individual varied up to 35 mOsm/l, but an average over three readings was found to be a reliable indicator of tear osmolarity at 95% confidence level. For population studies, a power analysis based on the variability of the data showed that three repeat measurements would be required to obtain reliable data for a study with <50 subjects, whereas one measurement would suffice for 490 or more subjects. There were no interobserver or interinstrumental differences, but readings obtained for the standard solution varied up to 89 mOsm/l. CONCLUSION: Three consecutive readings are required with the TearLab to obtain a reliable measure of tear osmolarity. The variation in recorded tear osmolarity makes it difficult to use the technique for the diagnosis of mild dry eye. PMID- 21606468 TI - Exposure to pesticides and risk of childhood cancer: a meta-analysis of recent epidemiological studies. AB - OBJECTIVES: The authors performed a meta-analysis of case-control and cohort studies to clarify the possible relationship between exposure to pesticides and childhood cancers. METHODS: Two cohort and 38 case-control studies were selected for the first meta-analysis. After evaluating homogeneity among studies using the Cochran Q test, the authors calculated a pooled meta-OR stratified on each cancer site. The authors then constructed a list of variables believed to play an important role in explaining the relation between parental exposure to pesticide and childhood cancer, and performed a series of meta-analyses. The authors also performed a distinct meta-analysis for three cohort studies with RR data. RESULTS: Meta-analysis of the three cohort studies did not show any positive links between parental pesticide exposure and childhood cancer incidence. However, the meta-analysis of the 40 studies with OR values showed that the risk of lymphoma and leukaemia increased significantly in exposed children when their mother was exposed during the prenatal period (OR=1.53; 95% CI 1.22 to 1.91 and OR=1.48; 95% CI 1.26 to 1.75). The risk of brain cancer was correlated with paternal exposure either before or after birth (OR=1.49; 95% CI 1.23 to 1.79 and OR=1.66; 95% CI 1.11 to 2.49). The OR of leukaemia and lymphoma was higher when the mother was exposed to pesticides (through household use or professional exposure). Conversely, the incidence of brain cancer was influenced by the father's exposure (occupational activity or use of household or garden pesticides). CONCLUSION: Despite some limitations in this study, the incidence of childhood cancer does appear to be associated with parental exposure during the prenatal period. PMID- 21606469 TI - Bicycle helmet wearing and the risk of head, face, and neck injury: a French case -control study based on a road trauma registry. AB - BACKGROUND: Previous case-control studies on bicycle helmet efficacy are mostly Anglo-Saxon, and based on data from the early 1990s when hard-shell helmets were common. METHODS: In France, the Rhone county (1.6 million inhabitants) is covered by a road trauma registry that includes emergency department visits, hospital admissions, and fatalities. Over the 1998-2008 period, 13,797 cyclist casualties were identified. The injuries sustained were coded using the Abbreviated Injury Scale (AIS) for injuries to the head (AIS1+ and AIS3+), face (AIS1+), or neck (AIS1+). The study uses a case-control design where the control group includes cyclists injured below the neck-that is, not injured in the region associated with the helmet. We first adjusted for age, gender, and type of crash, as in a previously published Cochrane review. Then we adjusted for injury severity based on non-head, face, or neck injury, and when relevant, for crash location: type of road, urban/rural area. RESULTS: The fully adjusted ORs of helmeted versus unhelmeted cyclists are: for AIS1+ head injuries, 0.69 (95% CI 0.59 to 0.81); for AIS3+ head injuries sustained in urban areas, 0.34 (95% CI 0.15 to 0.65), those sustained in rural areas, 0.07 (95% CI 0.02 to 0.23); for AIS1+ facial injuries, 0.72 (95% CI 0.62 to 0.83); and for AIS1+ neck injuries, 1.18 (95% CI 0.94 to 1.47). CONCLUSION: This study confirms the protective effect for head and facial injuries, even though soft-shell helmets have now become more common. The reduction of risk is greater for serious head injuries. The study is inconclusive about the risk for neck injuries. PMID- 21606470 TI - Social inequalities in road traffic deaths at age 16-20 years among all 611,654 Norwegians born between 1967 and 1976: a multilevel analysis. AB - BACKGROUND: Road traffic injury is a major cause of death among youths. AIMS: To estimate mortality differences in family socioeconomic position (SEP) and municipal disadvantage level. METHODS: Data on all Norwegians born in 1967-76, gathered from national registries, were linked by a unique national identification number. The 611 654 participants were followed-up for 5 years from age 16 years. Parental education level, father's income level, and proportion of high-income earners in the municipality served as SEP indicators. Associations between SEP and road traffic deaths were analysed by multilevel Poisson regression. Results Road traffic deaths (n=676, rate 22.2 per 100 000 person years) constituted a major cause of death, of which 91.9% were motor vehicle occupants. SEP distributions differed according to gender and type of motor vehicle crash (collision, non-collision). There was an inverse relationship between municipal proportions of high-income earners and mortality (population attributable fraction (PAF) 0.43, 95% CI 0.30 to 0.53) in all categories of gender-specific crash types. Family SEP gradients were not found except for male non-collision deaths, where increasing mortality was found in association with decreasing parental education level (PAF 0.94, 95% CI 0.59 to 0.99) and increasing paternal income (PAF 0.25, 95% CI 0.06 to 0.40). CONCLUSION: The different SEP patterns for road traffic deaths across gender and motor vehicle crash type illustrate that heterogeneity of social inequalities in health can be found even within narrow age bands and for similar causes of death. PMID- 21606471 TI - Paediatrician knowledge, attitudes, and counselling patterns on teen driving. AB - BACKGROUND: Motor vehicle crashes (MVCs) are the leading cause of death among teenagers. Little is known about the content of US paediatrician counselling about teen driving. OBJECTIVE: To examine US paediatrician knowledge, attitudes, and counselling patterns regarding teen driving. METHODS: A random sample questionnaire was mailed to American Academy of Pediatrics members in 2009 (n=1606; response=875 (55%)). Analysis was limited to 596 paediatricians who provide adolescent checkups. Questions addressed counselling and attitudes towards roles in promoting safe driving. Logistic regression assessed the relationship between counselling topics and practice characteristics. RESULTS: Most (89%) respondents provide some counselling about driving. Two topics commonly discussed by paediatricians were seatbelts (87%) and alcohol use (82%). Less frequently discussed were: cell phones (47%), speeding (43%), and dangers of transporting teen passengers (41%). Topics rarely discussed were: night driving (21%), graduated driver licensing laws (13%), safe cars (9%), driver education (9%), fatigue (25%), and parental limit setting (23%). Only 10% ever recommend a parent-teen driver agreement. Paediatricians who had a patient injured or killed in an MVC were more likely to discuss night driving (OR=2.86). Physicians caring for a high proportion of adolescents (OR=1.83) or patients with private insurance (OR=1.85) counsel more about the risks of driving with teen passengers. CONCLUSIONS: Paediatricians in the USA support counselling on teen driving during routine office visits, but omit many important risk factors. Few recommend parent teen driver agreements. Methods that help clinicians efficiently and effectively counsel families about teen driving should be developed. PMID- 21606472 TI - Opportunities and challenges in creating an international centralised knowledge base for clinical decision support systems in ePrescribing. AB - Prescribing errors cause substantial potentially avoidable patient harm. There is increasing evidence that the implementation of clinical decision support systems to support prescribing may reduce the risk of such errors. Efforts have thus far concentrated on the implementation of these systems within local health communities. However, considerable potential benefit exists in sharing the content of these prescribing decision support systems across geographical boundaries, including the sharing of experiences and expertise and cost reduction, which could in turn potentially increase accessibility to low resource settings. Technical, commercial and regulatory issues would however first need to be overcome in order to facilitate such a development. In this paper, the authors reflect on some of the opportunities and challenges inherent in trying to develop an internationally agreed and shared computerised decision support system aiming to enhance prescribing safety. PMID- 21606473 TI - Barriers and strategies for improving communication between inpatient and outpatient mental health clinicians. AB - OBJECTIVES: To explore hospital leaders' perceptions of organisational factors as barriers and/or facilitators in improving inpatient-outpatient (IP-OP) communication. DESIGN: Semistructured in-person interviews. ANALYSIS: Constant comparative method of qualitative data. SETTING: Inpatient psychiatry units in 33 general medical/surgical and specialty psychiatric hospitals in California and Massachusetts (USA). PARTICIPANTS: Psychiatry chair/chief, service director or medical director. VARIABLES: Importance to leadership, resources, organisational structure and culture. RESULTS: A majority of hospital leaders rated the IP-OP communication objective as highly or moderately important. Hospitals with good IP OP communication had structures in place to support communication or had changed/implemented new procedures to enhance communication, and anticipated clinicians would 'buy in' to the goal of improved communication. Hospitals reporting no improvement efforts were less likely to have structures supporting IP-OP communication, anticipated resistance among clinicians and reported a need for technological resources such as electronic health records, integrated IT and secure online communication. Most leaders reported a need for additional staff time and information, knowledge or data. CONCLUSIONS: For many hospitals, successfully improving communication will require overcoming organisational barriers such as cultures not conducive to change and lack of resources and infrastructure. Creating a culture that values communication at discharge may help improve outcomes following hospitalisation, but changes in healthcare delivery in the past few decades may necessitate new strategies or changes at the systems level to address barriers to effective communication. PMID- 21606474 TI - Local and systemic adverse effects to topical imiquimod due to systemic immune stimulation. PMID- 21606475 TI - Preventing onward HIV transmission in routine HIV care: low levels of evaluation of risk behaviour in HIV-infected patients. PMID- 21606477 TI - Coronary artery fistula: recanalisation after complete transcatheter coil occlusion. PMID- 21606478 TI - Muscle weakness in extremities and diffuse centrilobular nodules in lungs. HTLV-1 associated bronchiolo-alveolar disorder. PMID- 21606476 TI - EP4 receptor as a new target for bronchodilator therapy. AB - BACKGROUND: Asthma and chronic obstructive pulmonary disease are airway inflammatory diseases characterised by airflow obstruction. Currently approved bronchodilators such as long-acting beta(2) adrenoceptor agonists are the mainstay treatments but often fail to relieve symptoms of chronic obstructive pulmonary disease and severe asthma and safety concerns have been raised over long-term use. The aim of the study was to identify the receptor involved in prostaglandin E(2) (PGE(2))-induced relaxation in guinea pig, murine, monkey, rat and human airways in vitro. METHODS: Using an extensive range of pharmacological tools, the relaxant potential of PGE(2) and selective agonists for the EP(1-4) receptors in the presence and absence of selective antagonists in guinea pig, murine, monkey, rat and human isolated airways was investigated. RESULTS: In agreement with previous studies, it was found that the EP(2) receptor mediates PGE(2)-induced relaxation of guinea pig, murine and monkey trachea and that the EP(4) receptor mediates PGE(2)-induced relaxation of the rat trachea. These data have been confirmed in murine airways from EP(2) receptor-deficient mice (Ptger2). In contrast to previous publications, a role for the EP(4) receptor in relaxant responses in human airways in vitro was found. Relaxant activity of AH13205 (EP(2) agonist) was also demonstrated in guinea pig but not human airway tissue, which may explain its failure in clinical studies. CONCLUSION: Identification of the receptor mediating PGE(2)-induced relaxation represents a key step in developing a novel bronchodilator therapy. These data explain the lack of bronchodilator activity observed with selective EP(2) receptor agonists in clinical studies. PMID- 21606479 TI - Notch-Hes1 pathway is required for the development of IL-17-producing gammadelta T cells. AB - Unlike conventional T cells, which are exported from the thymus as naive cells and acquire effector functions upon antigen encounter in the periphery, a subset of gammadelta T cells differentiates into effectors that produce IL-17 within the fetal thymus. We demonstrate here that intrathymic development of the naturally occurring IL-17-producing gammadelta T cells is independent of STAT3 and partly dependent on RORgammat. Comparative gene-expression analysis identified Hes1, one of the basic helix-loop-helix proteins involved in Notch signaling, as a factor specifically expressed in IL-17-producing gammadelta T cells. Hes1 is critically involved in the development of IL-17-producing gammadelta T cells, as evidenced by their severe decrease in the thymi of Hes1-deficient fetal mice. Delta-like 4 (Dll4)-expressing stromal cells support the development of IL-17-producing gammadelta T cells in vitro. In addition, conditional Hes1 ablation in peripheral gammadelta T cells decreases their IL-17 production but not their IFN-gamma production. These results reveal a unique differentiation pathway of IL-17 producing gammadelta T cells. PMID- 21606481 TI - Blood consult: resistant and progressive essential thrombocythemia. PMID- 21606480 TI - Perforin is a critical physiologic regulator of T-cell activation. AB - Individuals with impaired perforin-dependent cytotoxic function (Ctx(-)) develop a fatal inflammatory disorder called hemophagocytic lymphohistiocytosis (HLH). It has been hypothesized that immune hyperactivation during HLH is caused by heightened infection, defective apoptosis/responsiveness of Ctx(-) lymphocytes, or enhanced antigen presentation. Whereas clinical and experimental data suggest that increased T-cell activation drives HLH, potential abnormalities of T-cell activation have not been well characterized in Ctx(-) hosts. To define such abnormalities and to test these hypotheses, we assessed in vivo T-cell activation kinetics and viral loads after lymphocytic choriomeningitis virus (LCMV) infection of Ctx(-) mice. We found that increased T-cell activation occurred early during infection of Ctx(-) mice, while they had viral burdens that were identical to those of WT animals, demonstrating that T-cell hyperactivation was independent of viral load. Furthermore, cell transfer and signaling studies indicated that increased antigenic stimulation, not a cell-intrinsic defect of responsiveness, underlay heightened T-cell activation in vivo. Finally, direct measurement of viral antigen presentation demonstrated an increase in Ctx(-) mice that was proportional to abnormal T-cell activation. We conclude that perforin dependent cytotoxicity has an immunoregulatory role that is distinguishable from its pathogen clearance function and limits T-cell activation in the physiologic context by suppressing antigen presentation. PMID- 21606482 TI - RAC2, AEP, and ICAM1 expression are associated with CNS disease in a mouse model of pre-B childhood acute lymphoblastic leukemia. AB - We developed a murine model of CNS disease to obtain a better understanding of the pathogenesis of CNS involvement in pre-B-cell acute lymphoblastic leukemia (ALL). Semiquantitative proteomic discovery-based approaches identified unique expression of asparaginyl endopeptidase (AEP), intercellular adhesion molecule 1 (ICAM1), and ras-related C3 botulinum toxin substrate 2 (RAC2), among others, in an invasive pre-B-cell line that produced CNS leukemia in NOD-SCID mice. Targeting RAC2 significantly inhibited in vitro invasion and delayed disease onset in mice. Induced expression of RAC2 in cell lines with low/absent expression of AEP and ICAM1 did not result in an invasive phenotype or murine CNS disease. Flow cytometric analysis identified an enriched population of blast cells expressing ICAM1/lymphocyte function associated antigen-1 (LFA-1)/CD70 in the CD10(+)/CD19(+) fraction of bone marrow aspirates obtained from relapsed compared with normal controls and those with primary disease. CD10(+)/CD19(+) fractions obtained from relapsed patients also express RAC2 and give rise to CNS disease in mice. Our data suggest that combinations of processes are involved in the pathogenesis of CNS disease in pre-B-cell ALL, support a model in which CNS disease occurs as a result of external invasion, and suggest that targeting the processes of adhesion and invasion unique to pre-B cells may prevent recurrences within the CNS. PMID- 21606483 TI - Human T cells expressing affinity-matured TCR display accelerated responses but fail to recognize low density of MHC-peptide antigen. AB - We have tested whether affinity-matured TCRs that retain peptide specificity improve the ability of primary human CD8(+) T cells to mount antigen-specific responses. We found that TCR affinity correlated with the speed of T-cell responses. High affinity TCR-antigen interactions rapidly initiated T-cell responses, but low affinity TCR/antigen interactions required longer time periods to elicit the same responses. Within the "natural" affinity range, increased TCR to-antigen affinity correlated with improved ability of T cells to recognize low concentration of antigen. However, affinity-matured TCR with 700-fold enhanced affinity for MHC-to-antigen required 100-fold higher antigen-density to initiate T-cell responses than did wild-type TCR. Using modified peptides to reduce the affinity of TCR-to-antigen interaction, we demonstrate that affinity-matured TCRs are not defective, being superior to wild-type TCR in recognizing low concentration of modified peptides. These data indicate that enhancing TCR affinity can accelerate the speed of T-cell activation and reduce the ability to recognize low density of MHC-to-peptide antigen. We predict that future studies of the human T-cell repertoire will reveal 2 types of low avidity T cells: fast and slow responders, with high-affinity and low-affinity TCR, respectively. PMID- 21606484 TI - Biochemical characterization of major bone-matrix proteins using nanoscale-size bone samples and proteomics methodology. AB - There is growing evidence supporting the need for a broad scale investigation of the proteins and protein modifications in the organic matrix of bone and the use of these measures to predict fragility fractures. However, limitations in sample availability and high heterogeneity of bone tissue cause unique experimental and/or diagnostic problems. We addressed these by an innovative combination of laser capture microscopy with our newly developed liquid chromatography separation methods, followed by gel electrophoresis and mass spectrometry analysis. Our strategy allows in-depth analysis of very limited amounts of bone material, and thus, can be important to medical sciences, biology, forensic, anthropology, and archaeology. The developed strategy permitted unprecedented biochemical analyses of bone-matrix proteins, including collagen modifications, using nearly nanoscale amounts of exceptionally homogenous bone tissue. Dissection of fully mineralized bone-tissue at such degree of homogeneity has not been achieved before. Application of our strategy established that: (1) collagen in older interstitial bone contains higher levels of an advanced glycation end product pentosidine then younger osteonal tissue, an observation contrary to the published data; (2) the levels of two enzymatic crosslinks (pyridinoline and deoxypiridinoline) were higher in osteonal than interstitial tissue and agreed with data reported by others; (3) younger osteonal bone has higher amount of osteopontin and osteocalcin then older interstitial bone and this has not been shown before. Taken together, these data show that the level of fluorescent crosslinks in collagen and the amount of two major noncollagenous bone matrix proteins differ at the level of osteonal and interstitial tissue. We propose that this may have important implications for bone remodeling processes and bone microdamage formation. PMID- 21606486 TI - Insights into the composition and assembly of the membrane arm of plant complex I through analysis of subcomplexes in Arabidopsis mutant lines. AB - NADH-ubiquinone oxidoreductase (Complex I, EC 1.6.5.3) is the largest complex of the mitochondrial respiratory chain. In eukaryotes, it is composed of more than 40 subunits that are encoded by both the nuclear and mitochondrial genomes. Plant Complex I differs from the enzyme described in other eukaryotes, most notably due to the large number of plant-specific subunits in the membrane arm of the complex. The elucidation of the assembly pathway of Complex I has been a long standing research aim in cellular biochemistry. We report the study of Arabidopsis mutants in Complex I subunits using a combination of Blue-Native PAGE and immunodetection to identify stable subcomplexes containing Complex I components, along with mass spectrometry analysis of Complex I components in membrane fractions and two-dimensional diagonal Tricine SDS-PAGE to study the composition of the largest subcomplex. Four subcomplexes of the membrane arm of Complex I with apparent molecular masses of 200, 400, 450, and 650 kDa were observed. We propose a working model for the assembly of the membrane arm of Complex I in plants and assign putative roles during the assembly process for two of the subunits studied. PMID- 21606487 TI - A xylosylphosphotransferase of Cryptococcus neoformans acts in protein O-glycan synthesis. AB - Cryptococcal meningoencephalitis is an AIDS-defining illness caused by the opportunistic pathogen Cryptococcus neoformans. This organism possesses an elaborate polysaccharide capsule that is unique among pathogenic fungi, and the glycobiology of C. neoformans has been a focus of research in the field. The capsule and other cellular glycans and glycoconjugates have been described, but the machinery responsible for their synthesis remains largely unexplored. We recently discovered Xpt1p, an enzyme with the unexpected activity of generating a xylose-phosphate-mannose linkage. We now demonstrate that this novel activity is conserved throughout the C. neoformans species complex, localized to the Golgi apparatus, and functions in the O-glycosylation of proteins. We also present the first survey of O-glycans from C. neoformans. PMID- 21606489 TI - Uniform distribution of elongating RNA polymerase II complexes in transcribed gene locus. AB - The intensity of gene transcription is generally reflected by the level of RNA polymerase II (RNAPII) recruitment to the gene. However, genome-wide studies of polymerase occupancy indicate that RNAPII distribution varies among genes. In some loci more polymerases are found in the 5' region, whereas in other loci, in the 3' region of the gene. We studied the distribution of elongating RNAPII complexes at highly transcribed GAL-VPS13 locus in Saccharomyces cerevisiae and found that in the cell population the amount of polymerases gradually decreased toward the 3' end of the gene. However, the conventional chromatin immunoprecipitation assay averages the signal from the cell population, and no data on single cell level can be gathered. To study the spacing of elongating polymerases on single chromosomes, we used a sequential chromatin immunoprecipitation assay for the detection of multiple RNAPII complexes on the same DNA fragment. Our results demonstrate uniform distribution of elongating polymerases throughout all regions of the GAL-VPS13 gene. PMID- 21606488 TI - Bioinformatic prediction and confirmation of beta-adducin as a novel substrate of glycogen synthase kinase 3. AB - It is important to identify the true substrates of protein kinases because this illuminates the primary function of any kinase. Here, we used bioinformatics and biochemical validation to identify novel brain substrates of the Ser/Thr kinase glycogen synthase kinase 3 (GSK3). Briefly, sequence databases were searched for proteins containing a conserved GSK3 phosphorylation consensus sequence ((S/T)PXX(S/T)P or (S/T)PXXX(S/T)P), as well as other criteria of interest (e.g. brain proteins). Importantly, candidates were highlighted if they had previously been reported to be phosphorylated at these sites by large-scale phosphoproteomic studies. These criteria identified the brain-enriched cytoskeleton-associated protein beta-adducin as a likely substrate of GSK3. To confirm this experimentally, it was cloned and subjected to a combination of cell culture and in vitro kinase assays that demonstrated direct phosphorylation by GSK3 in vitro and in cells. Phosphosites were mapped to three separate regions near the C terminus and confirmed using phosphospecific antibodies. Prior priming phosphorylation by Cdk5 enhanced phosphorylation by GSK3. Expression of wild type, but not non-phosphorylatable (GSK3 insensitive), beta-adducin increased axon and dendrite elongation in primary cortical neurons. Therefore, phosphorylation of beta-adducin by GSK3 promotes efficient neurite outgrowth in neurons. PMID- 21606490 TI - Human interleukin-1 receptor-associated kinase-2 is essential for Toll-like receptor-mediated transcriptional and post-transcriptional regulation of tumor necrosis factor alpha. AB - Toll-like receptors (TLRs) are pattern-recognition receptors that recognize microbial ligands and subsequently trigger intracellular signaling pathways involving transcription factors such as NFkappaB and MAPKs such as p38. TLR signaling can regulate both transcriptional and post-transcriptional events leading to altered gene expression and thus appropriate immune responses. The interleukin-1 receptor-associated kinase (IRAK) family comprises four kinases that regulate TLR signaling. However, the role of IRAK-2 has remained unclear, especially in human cells. Recent studies using cells from in-bred Irak2(-/-) mice showed that murine IRAK-2 was not required for early TLR signaling events but had a role in delayed NFkappaB activation and in cytokine production. IRAK-2 in mice has four splice variants, two of which are inhibitory, whereas human IRAK 2 has no splice variants. Thus IRAK-2 in mice and humans may function differently, and therefore we analyzed the role of IRAK-2 in TLR responses in primary human cells. siRNA knockdown of IRAK-2 expression in human peripheral blood mononuclear cells showed a role for human IRAK-2 in both TLR4- and TLR8 mediated early NFkappaB and p38 MAPK activation and in induction of TNF mRNA. These data conflict with findings from the in-bred Irak2(-/-) mice but concur with what has been seen in wild-derived mice for TLR2. Moreover, human IRAK-2 was required for regulating MyD88-dependent TNFalpha mRNA stability via the TNF 3'UTR. Collectively, these data demonstrate for the first time an essential role for IRAK-2 in primary human cells for both transcriptional and post transcriptional TLR responses. PMID- 21606491 TI - Autoacetylation of the histone acetyltransferase Rtt109. AB - Rtt109 is a yeast histone acetyltransferase (HAT) that associates with histone chaperones Asf1 and Vps75 to acetylate H3K56, H3K9, and H3K27 and is important in DNA replication and maintaining genomic integrity. Recently, mass spectrometry and structural studies of Rtt109 have shown that active site residue Lys-290 is acetylated. However, the functional role of this modification and how the acetyl group is added to Lys-290 was unclear. Here, we examined the mechanism of Lys-290 acetylation and found that Rtt109 catalyzes intramolecular autoacetylation of Lys 290 ~200-times slower than H3 acetylation. Deacetylated Rtt109 was prepared by reacting with a sirtuin protein deacetylase, producing an enzyme with negligible HAT activity. Autoacetylation of Rtt109 restored full HAT activity, indicating that autoacetylation is necessary for HAT activity and is a fully reversible process. To dissect the mechanism of activation, biochemical, and kinetic analyses were performed with Lys-290 variants of the Rtt109-Vps75 complex. We found that autoacetylation of Lys-290 increases the binding affinity for acetyl CoA and enhances the rate of acetyl-transfer onto histone substrates. This study represents the first detailed investigation of a HAT enzyme regulated by single site intramolecular autoacetylation. PMID- 21606492 TI - Dependence on endocytic receptor binding via a minimal binding motif underlies the differential prognostic profiles of SerpinE1 and SerpinB2 in cancer. AB - Tumor overexpression of urokinase-type plasminogen activator (uPA) and its specific inhibitor SerpinE1 (plasminogen activator inhibitor type-1) correlates with poor prognosis and increased metastatic potential. Conversely, tumor expression of uPA and another specific inhibitor, SerpinB2 (plasminogen activator inhibitor type-2), are associated with favorable outcome and relapse-free survival. It is not known how overexpression of these uPA inhibitors results in such disparate outcomes. A possible explanation may be related to the presence of a proposed low density lipoprotein receptor (LDLR)-binding motif in SerpinE1 responsible for mitogenic signaling via ERK that is absent in SerpinB2. We now show that complementation of such a LDLR-binding motif in SerpinB2 by mutagenesis of two key residues enabled high affinity binding to very LDLR (VLDLR). Furthermore, the VLDLR-binding SerpinB2 form behaved in a manner indistinguishable from SerpinE1 in terms of enhanced uPA-SerpinB2 complex endocytosis and subsequent ERK phosphorylation and cell proliferation; that is, the introduction of the LDLR-binding motif to SerpinB2 was necessary and sufficient to allow it to acquire characteristics of SerpinE1 associated with malignancy. In conclusion, this study defines the structural elements underlying the distinct interactions of SerpinE1 versus SerpinB2 with endocytic receptors and how differential VLDLR binding impacts on downstream cellular behavior. This has clear relevance to understanding the paradoxical disease outcomes associated with overexpression of these serpins in cancer. PMID- 21606493 TI - Rho signaling regulates pannexin 1-mediated ATP release from airway epithelia. AB - ATP released from airway epithelial cells promotes purinergic receptor-regulated mucociliary clearance activities necessary for innate lung defense. Cell swelling induced membrane stretch/strain is a common stimulus that promotes airway epithelial ATP release, but the mechanisms transducing cell swelling into ATP release are incompletely understood. Using knockdown and knockout approaches, we tested the hypothesis that pannexin 1 mediates ATP release from hypotonically swollen airway epithelia and investigated mechanisms regulating this activity. Well differentiated primary cultures of human bronchial epithelial cells subjected to hypotonic challenge exhibited enhanced ATP release, which was paralleled by the uptake of the pannexin probe propidium iodide. Both responses were reduced by pannexin 1 inhibitors and by knocking down pannexin 1. Importantly, hypotonicity-evoked ATP release from freshly excised tracheas and dye uptake in primary tracheal epithelial cells were impaired in pannexin 1 knockout mice. Hypotonicity-promoted ATP release and dye uptake in primary well differentiated human bronchial epithelial cells was accompanied by RhoA activation and myosin light chain phosphorylation and was reduced by the RhoA dominant negative mutant RhoA(T19N) and Rho and myosin light chain kinase inhibitors. ATP release and Rho activation were reduced by highly selective inhibitors of transient receptor potential vanilloid 4 (TRPV4). Lastly, knocking down TRPV4 impaired hypotonicity-evoked airway epithelial ATP release. Our data suggest that TRPV4 and Rho transduce cell membrane stretch/strain into pannexin 1 mediated ATP release in airway epithelia. PMID- 21606494 TI - Soluble amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells. AB - Human embryonic stem cells (hESCs) offer tremendous potential for not only treating neurological disorders but also for their ability to serve as vital reagents to model and investigate human disease. To further our understanding of a key protein involved in Alzheimer disease pathogenesis, we stably overexpressed amyloid precursor protein (APP) in hESCs. Remarkably, we found that APP overexpression in hESCs caused a rapid and robust differentiation of pluripotent stem cells toward a neural fate. Despite maintenance in standard hESC media, up to 80% of cells expressed the neural stem cell marker nestin, and 65% exhibited the more mature neural marker beta-3 tubulin within just 5 days of passaging. To elucidate the mechanism underlying the effects of APP on neural differentiation, we examined the proteolysis of APP and performed both gain of function and loss of function experiments. Taken together, our results demonstrate that the N terminal secreted soluble forms of APP (in particular sAPPbeta) robustly drive neural differentiation of hESCs. Our findings not only reveal a novel and intriguing role for APP in neural lineage commitment but also identify a straightforward and rapid approach to generate large numbers of neurons from human embryonic stem cells. These novel APP-hESC lines represent a valuable tool to investigate the potential role of APP in development and neurodegeneration and allow for insights into physiological functions of this protein. PMID- 21606495 TI - Protein kinase C promotes N-methyl-D-aspartate (NMDA) receptor trafficking by indirectly triggering calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation. AB - Regulation of neuronal NMDA receptor (NMDAR) is critical in synaptic transmission and plasticity. Protein kinase C (PKC) promotes NMDAR trafficking to the cell surface via interaction with NMDAR-associated proteins (NAPs). Little is known, however, about the NAPs that are critical to PKC-induced NMDAR trafficking. Here, we showed that calcium/calmodulin-dependent protein kinase II (CaMKII) could be a NAP that mediates the potentiation of NMDAR trafficking by PKC. PKC activation promoted the level of autophosphorylated CaMKII and increased association with NMDARs, accompanied by functional NMDAR insertion, at postsynaptic sites. This potentiation, along with PKC-induced long term potentiation of the AMPA receptor mediated response, was abolished by CaMKII antagonist or by disturbing the interaction between CaMKII and NR2A or NR2B. Further mutual occlusion experiments demonstrated that PKC and CaMKII share a common signaling pathway in the potentiation of NMDAR trafficking and long-term potentiation (LTP) induction. Our results revealed that PKC promotes NMDA receptor trafficking and induces synaptic plasticity through indirectly triggering CaMKII autophosphorylation and subsequent increased association with NMDARs. PMID- 21606496 TI - Glycosylation affects ligand binding and function of the activating natural killer cell receptor 2B4 (CD244) protein. AB - 2B4 (CD244) is an important activating receptor for the regulation of natural killer (NK) cell responses. Here we show that 2B4 is heavily and differentially glycosylated in primary human NK cells and NK cell lines. The differential glycosylation could be attributed to sialic acid residues on N- and O-linked carbohydrates. Using a recombinant fusion protein of the extracellular domain of 2B4, we demonstrate that N-linked glycosylation of 2B4 is essential for the binding to its ligand CD48. In contrast, sialylation of 2B4 has a negative impact on ligand binding, as the interaction between 2B4 and CD48 is increased after the removal of sialic acids. This was confirmed in a functional assay system, where the desialylation of NK cells or the inhibition of O-linked glycosylation resulted in increased 2B4-mediated lysis of CD48-expressing tumor target cells. These data demonstrate that glycosylation has an important impact on 2B4-mediated NK cell function and suggest that regulated changes in glycosylation during NK cell development and activation might be involved in the regulation of NK cell responses. PMID- 21606497 TI - Tristetraprolin mediates anti-inflammatory effects of nicotine in lipopolysaccharide-stimulated macrophages. AB - Nicotine inhibits the release of TNF-alpha from macrophage through activation of STAT3. Tristetraprolin (TTP) is known to destabilize pro-inflammatory transcripts containing AU-rich elements (ARE) in 3'-untranslated region (3'-UTR). Here we show that in LPS-stimulated human macrophages the anti-inflammatory action of nicotine is mediated by TTP. Nicotine induced activation of STAT3 enhanced STAT3 binding to the TTP promoter, increased TTP promoter activity, and increased TTP expression resulting in the suppression of LPS-stimulated TNF-alpha production. Overexpression of a dominant negative mutant of STAT3 (R382W) or down-regulation of STAT3 by siRNA abolished nicotine-induced TTP expression and suppression of LPS-stimulated TNF-alpha production. Nicotine enhanced the decay of TNF-alpha mRNA and decreased luciferase expression of a TNF-alpha 3'-UTR reporter plasmid in U937 cells. However, siRNA to TTP abrogated these effects of nicotine. In this experiment, we are reporting for the first time the involvement of TTP in the cholinergic anti-inflammatory cascade consisting of nicotine-STAT3-TTP-dampening inflammation. PMID- 21606498 TI - Breaking the light and heavy chain linkage of human immunoglobulin G1 (IgG1) by radical reactions. AB - We report that the production of hydrogen peroxide by radical chain reductions of molecular oxygen into water in buffers leads to hinge degradation of a human IgG1 under thermal incubation conditions. The production of the hydrogen peroxide can be accelerated by superoxide dismutase or redox active metal ions or inhibited by free radical scavengers. The hydrogen peroxide production rate correlates well with the hinge cleavage. In addition to radical reaction mechanisms described previously, new degradation pathways and products were observed. These products were determined to be generated via radical reactions initiated by electron transfer and addition to the interchain disulfide bond between Cys(215) of the light chain and Cys(225) of the heavy chain. Decomposition of the resulting disulfide bond radical anion breaks the C-S bond at the side chain of Cys, converting it into dehydroalanine and generating a sulfur radical adduct at its counterpart. The hydrolysis of the unsaturated dehydropeptides removes Cys and yields an amide at the C terminus of the new fragment. Meanwhile, the competition between the carbonyl (-C(alpha)ONH-) and the side chain of Cys allows an electron transfer to the alpha carbon, forming a new intermediate radical species ( (.)C(alpha)(O(-))NH-) at Cys(225). Dissociative deamidation occurs along the N C(alpha) bond, resulting in backbone cleavage. Given that hydrogen peroxide is a commonly observed product of thermal stress and plays a role in mediating the unique degradation of an IgG1, strategies for improving stability of human antibody therapeutics are discussed. PMID- 21606499 TI - Flanking V and J sequences of complementary determining region 3 of T cell receptor (TCR) delta1 (CDR3delta1) determine the structure and function of TCRgamma4delta1. AB - The gammadelta T cell receptor (TCR) differs from immunoglobulin and alphabeta TCR in its overall binding mode. In human, genes delta1, delta2, and delta3 are used for TCRdelta chains. Previously, we have studied antigen binding determinants of TCRdelta2 derived from dominant gammadelta T cells residing in peripheral blood. In this study we have investigated the critical determinants for antigen recognition and TCR function in TCRdelta1 originated from gastric tumor-infiltrating gammadelta T lymphocytes using three independent experimental strategies including complementary determining region 3 (CDR3) of TCRdelta1 (CDR3delta1)-peptide mediated binding, CDR3delta1-grafted TCR fusion protein mediated binding, and TCRgamma4delta1- and mutant-expressing cell-mediated binding. All three approaches consistently showed that the conserved flanking V and J sequences but not the diverse D segment in CDR3delta1 determine the antigen binding. Most importantly, we found that mutations in the V and J regions of CDR3delta1 also abolish the assembly of TCR and TCR-CD3 complexes in TCRgamma4delta1-transduced J.RT3-T3.5 cells. Together with our previous studies on CDR3delta2 binding, our finding suggests that both human TCRdelta1 and TCRdelta2 recognize antigen predominately via flanking V and J regions. These results indicate that TCRgammadelta recognizes antigens using conserved parts in their CDR3, which provides an explanation for a diverse repertoire of gammadeltaTCRs only recognizing a limited number of antigens. PMID- 21606500 TI - Maspin, the molecular bridge between the plasminogen activator system and beta1 integrin that facilitates cell adhesion. AB - Maspin is a non-inhibitory serine protease inhibitor (serpin) that influences many cellular functions including adhesion, migration, and invasion. The underlying molecular mechanisms that facilitate these actions are still being elucidated. In this study we determined the mechanism by which maspin mediates increased MCF10A cell adhesion. Utilizing competition peptides and mutation analyses, we discovered two unique regions (amino acid residues 190-202 and 260 275) involved in facilitating the increased adhesion function of maspin. In addition, we demonstrate that the urokinase-type plasminogen activator (uPA)/uPA receptor (uPAR) complex is required for the localization and adhesion function of maspin. Finally, we showed that maspin, uPAR, and beta1 integrin co immunoprecipitate, suggesting a novel maspin-uPA-uPAR-beta1 integrin mega-complex that regulates mammary epithelial cell adhesion. PMID- 21606501 TI - Production and characterization of a humanized single-chain antibody against human integrin alphav beta3 protein. AB - Anti-angiogenesis therapy is an emerging strategy for cancer treatment. This therapy has many advantages over existing treatments, such as fewer side effects, fewer resistance problems, and a broader tumor type spectrum. Integrin alphavbeta3 is a heterodimeric transmembrane glycoprotein that has been demonstrated to play a key role in tumor angiogenesis and metastasis. We have used a phage antibody display to humanize a mouse monoclonal antibody (mAb E10) against human integrin alphavbeta3 with a predetermined CDR3 gene. Three human phage antibodies were developed. Analysis of the humanized phage antibodies by phage ELISA revealed that the antibodies retained high antigen-binding activity and detected the same epitope as the parent mAb E10. A humanized single chain Fv (scFv) antibody was expressed in Escherichia coli in a soluble form. Analysis of the purified scFv indicated that it has the same specificity and affinity as the original mAb. Cell viability assays and xenograft model results suggested that the humanized scFv possesses anti-tumor growth activity in vitro and in vivo. This successful production of a humanized scFv with the ability to inhibit alphavbeta3-mediated cancer cell growth may provide a novel candidate for integrin alphavbeta3-targeted therapy. PMID- 21606502 TI - Investigation of the reciprocal relationship between the expression of two gap junction connexin proteins, connexin46 and connexin43. AB - Connexins are the transmembrane proteins that form gap junctions between adjacent cells. The function of the diverse connexin molecules is related to their tissue specific expression and highly dynamic turnover. Although multiple connexins have been previously reported to compensate for each other's functions, little is known about how connexins influence their own expression or intracellular regulation. Of the three vertebrate lens connexins, two connexins, connexin43 (Cx43) and connexin46 (Cx46), show reciprocal expression and subsequent function in the lens and in lens cell culture. In this study, we investigate the reciprocal relationship between the expression of Cx43 and Cx46. Forced depletion of Cx43, by tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate, is associated with an up-regulation of Cx46 at both the protein and message level in human lens epithelial cells. An siRNA-mediated down-regulation of Cx43 results in an increase in the level of Cx46 protein, suggesting endogenous Cx43 is involved in the regulation of endogenous Cx46 turnover. Overexpression of Cx46, in turn, induces the depletion of Cx43 in rabbit lens epithelial cells. Cx46 induced Cx43 degradation is likely mediated by the ubiquitin-proteasome pathway, as (i) treatment with proteasome inhibitors restores the Cx43 protein level and (ii) there is an increase in Cx43 ubiquitin conjugation in Cx46-overexpressing cells. We also present data that shows that the C-terminal intracellular tail domain of Cx46 is essential to induce degradation of Cx43. Therefore, our study shows that Cx43 and Cx46 have novel functions in regulating each other's expression and turnover in a reciprocal manner in addition to their conventional roles as gap junction proteins in lens cells. PMID- 21606503 TI - Enhanced biosynthesis of coagulation factor VIII through diminished engagement of the unfolded protein response. AB - Human and porcine coagulation factor VIII (fVIII) display a biosynthetic efficiency differential that is being exploited for the development of new protein and gene transfer-based therapies for hemophilia A. The cellular and/or molecular mechanism(s) responsible for this phenomenon have yet to be uncovered, although it has been temporally localized to post-translational biosynthetic steps. The unfolded protein response (UPR) is a cellular adaptation to structurally distinct (e.g. misfolded) or excess protein in the endoplasmic reticulum and is known to be induced by heterologous expression of recombinant human fVIII. Therefore, it is plausible that the biosynthetic differential between human and porcine fVIII results from differential UPR activation. In the current study, UPR induction was examined in the context of ongoing fVIII expression. UPR activation was greater during human fVIII expression when compared with porcine fVIII expression as determined by ER response element (ERSE)-luciferase reporter activity, X-box-binding protein 1 (XBP1) splicing, and immunoglobulin-binding protein (BiP) up-regulation. Immunofluorescence microscopy of fVIII expressing cells revealed that human fVIII was notably absent in the Golgi apparatus, confirming that endoplasmic reticulum to Golgi transport is rate limiting. In contrast, a significant proportion of porcine fVIII was localized to the Golgi indicating efficient transit through the secretory pathway. Overexpression of BiP, an integral UPR protein, reduced the secretion of human fVIII by 50%, but had no effect on porcine fVIII biosynthesis. In contrast, expression of BiP shRNA increased human fVIII expression levels. The current data support the model of differential engagement of UPR by human and porcine fVIII as a non-traditional mechanism for regulation of gene product biosynthesis. PMID- 21606504 TI - Flanking residues help determine whether a hydrophobic segment adopts a monotopic or bitopic topology in the endoplasmic reticulum membrane. AB - Proteins interacting with membranes via a single hydrophobic segment can be classified as either monotopic or bitopic. Here, we probe the topology of a membrane-attached enzyme, the epsilon isoform of human diacylglycerol kinase (DGKepsilon), when inserted into rough microsomes and compare it with the monotopic membrane protein mouse caveolin-1. In contrast to previous findings, the N-terminal hydrophobic stretch in DGKepsilon attains a bitopic rather than a monotopic topology in our experimental system. In addition, we find that charged flanking residues as well as proline residues embedded in the hydrophobic segment are important determinants of monotopic versus bitopic topology. PMID- 21606505 TI - Platelet activation attracts a subpopulation of effector monocytes to sites of Leishmania major infection. AB - Leishmania species trigger a brisk inflammatory response and efficiently induce cell-mediated immunity. We examined the mechanisms whereby leukocytes were recruited into lesions after Leishmania major infection of mice. We found that a subpopulation of effector monocytes expressing the granulocyte marker GR1 (Ly6C) is rapidly recruited into lesions, and these monocytes efficiently kill L. major parasites. The recruitment of this subpopulation of monocytes depends on the chemokine receptor CCR2 and the activation of platelets. Activated platelets secrete platelet-derived growth factor, which induces the rapid release of CCL2 from leukocytes and mesenchymal cells. This work points to a new role for platelets in host defense involving the selective recruitment of a subpopulation of effector monocytes from the blood to efficiently kill this intracellular parasite. PMID- 21606506 TI - Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia. AB - As STAT5 is critical for the differentiation, proliferation, and survival of progenitor B cells, this transcription factor may play a role in acute lymphoblastic leukemia (ALL). Here, we show increased expression of activated signal transducer and activator of transcription 5 (STAT5), which is correlated with poor prognosis, in ALL patient cells. Mutations in EBF1 and PAX5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL, we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1, but this had little effect on most EBF1 or PAX5 target genes. Only a subset of target genes was deregulated; this subset included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL. PMID- 21606511 TI - Our first century. PMID- 21606508 TI - T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. AB - The ability of antigen receptors to engage self-ligands with varying affinity is crucial for lymphocyte development. To further explore this concept, we generated transgenic mice expressing GFP from the immediate early gene Nr4a1 (Nur77) locus. GFP was up-regulated in lymphocytes by antigen receptor stimulation but not by inflammatory stimuli. In T cells, GFP was induced during positive selection, required major histocompatibility complex for maintenance, and directly correlated with the strength of T cell receptor (TCR) stimulus. Thus, our results define a novel tool for studying antigen receptor activation in vivo. Using this model, we show that regulatory T cells (T(reg) cells) and invariant NKT cells (iNKT cells) perceived stronger TCR signals than conventional T cells during development. However, although T(reg) cells continued to perceive strong TCR signals in the periphery, iNKT cells did not. Finally, we show that T(reg) cell progenitors compete for recognition of rare stimulatory TCR self-ligands. PMID- 21606512 TI - Reflections on the past as prologue. PMID- 21606507 TI - Polyubiquitin binding to ABIN1 is required to prevent autoimmunity. AB - The protein ABIN1 possesses a polyubiquitin-binding domain homologous to that present in nuclear factor kappaB (NF-kappaB) essential modulator (NEMO), a component of the inhibitor of NF-kappaB (IkappaB) kinase (IKK) complex. To address the physiological significance of polyubiquitin binding, we generated knockin mice expressing the ABIN1[D485N] mutant instead of the wild-type (WT) protein. These mice developed all the hallmarks of autoimmunity, including spontaneous formation of germinal centers, isotype switching, and production of autoreactive antibodies. Autoimmunity was suppressed by crossing to MyD88(-/-) mice, demonstrating that toll-like receptor (TLR)-MyD88 signaling pathways are needed for the phenotype to develop. The B cells and myeloid cells of the ABIN1[D485N] mice showed enhanced activation of the protein kinases TAK, IKK alpha/beta, c-Jun N-terminal kinases, and p38alpha mitogen-activated protein kinase and produced more IL-6 and IL-12 than WT. The mutant B cells also proliferated more rapidly in response to TLR ligands. Our results indicate that the interaction of ABIN1 with polyubiquitin is required to limit the activation of TLR-MyD88 pathways and prevent autoimmunity. PMID- 21606513 TI - Chestnut Lodge and the psychoanalytic approach to psychosis. AB - The study of psychosis has a long history in psychoanalysis, as does the debate over the suitability of psychoanalysis for treating schizophrenia. For decades, Chestnut Lodge was not only a hospital but also a clinical research and educational institution. A unique patient-staff ratio--about twenty analytic therapists for a hundred patients--made possible prolonged and intense clinical work with schizophrenic and other severely disturbed patients. Interstaff discussions were encouraged and facilitated. This quasi-academic approach to in depth individual case studies led to clinical findings and theoretical formulations that had a significant impact on developments in psychoanalysis, both here and abroad. Many of these findings and theoretical formulations are relevant to current studies and treatments of psychotic and nonpsychotic patients. PMID- 21606514 TI - The psychoanalytic approach to psychosis: commentary on Kafka. PMID- 21606515 TI - Psychoanalysis and the psychoses: commentary on Kafka. PMID- 21606516 TI - Psychoanalytic institutions and treatment resistance: commentary on Kafka. PMID- 21606518 TI - Common ground between psychoanalysis and art: introduction to Wilson and Miller. PMID- 21606519 TI - Light and shadow in the life and work of Louise Nevelson. AB - The life and work of the artist Louise Nevelson are examined through the lens of her ideas about light and shadow. Nevelson developed several ways of dealing with a basic fault established in childhood. Some ideas of Christopher Bollas are used in understanding the artist's relationships with art dealers who served her as transformational objects. The artist became the grandmother of environmental sculpture in America and saw her work as a bridge between the third and the fourth dimension--an idealized realm and a popular concept in twentieth-century art that she related directly to light and shadow. Colette Roberts, a dealer with whom she worked, allowed Nevelson to arrive at a signature style. Arne Glimcher, who represented her for twenty-four years, provided the material and psychological comfort that allowed Nevelson to explore new materials and new styles and to arrive at aesthetic solutions of remarkable power and sophistication through her eighty-ninth year. From the time she met Roberts in 1953 until the end of her life thirty-five years later, Nevelson's ideas about light and shadow expressed not only her thoughts about visual perception but her experience of her mother as her original transformational object and unthought known. PMID- 21606520 TI - More than meets the eye: Morandi's art and analytic listening. AB - This study of Giorgio Morandi, the great twentieth-century Italian painter, departs from the model of Freud's essay on Leonardo, in which he creates a psychodynamic hypothesis by linking the art with facts and conjecture about the artist's life. Because personal information about Morandi is remarkably scarce, we can make few connections between his art and his individual psychology. But Morandi's works can inform psychoanalysis and enhance analytic listening when we reflect on the paintings themselves, our responses to them, and the responses of art critics. This approach to his art evokes core principles of clinical theory, demonstrates the overlap between the creative process in art and analysis, and exemplifies the value of interdisciplinary study for analytic education. PMID- 21606521 TI - More than enough guilt to go around: oedipal guilt, survival guilt, separation guilt. AB - The concepts of oedipal guilt, survivor guilt, and separation guilt are examined using clinical material from a child case to demonstrate the intermingling of these constructs. A brief review of their evolution in the psychoanalytic literature reveals a frequent conflation of the terms guilt and fear, the former at times standing in for both meanings. The fear/guilt distinction and the subsequent differentiation of guilt into oedipal, survivor, and separation guilt have implications for how analysts understand and interpret particular kinds of clinical material. Two sets of adult clinical data are next presented: the first illustrates a shift from interpreting a patient's fear of retribution for forbidden desires to interpreting guilt over pursuing those desires. The second vignette illustrates a common dynamic in which a patient's fear/anxiety regarding the ability to lead an independent life defends against deeper feelings of guilt over this same desire. This latter dynamic can play an important role in negative therapeutic reactions and interminable analyses. Developmental research suggests that toward the end of the first year of life, infants' capacity to attribute independent mental states and intentionality to self and others allows for the rudimentary experience of guilt. PMID- 21606522 TI - The Psychodynamic Diagnostic Manual (PDM): rationale, conception, and structure. AB - The declaredly atheoretical DSM-III (and its successors), the diagnostic manual of the American Psychiatric Association, was created to enhance diagnostic reliability for research, epidemiological survey, and governmental and insurance categorization and reimbursement purposes. It has, however, exhibited many inadequacies for psychodynamic diagnosis and case formulation for treatment planning and outcome assessment, and its claimed diagnostic reliability has turned out to be less than originally projected. The psychoanalytically sponsored Psychodynamic Diagnostic Manual (PDM) marks a return to a theoretically (psychoanalytically) based diagnostic frame and was created as a supplement to, or replacement for, DSM (depending on the precise clinical need), for use in psychodynamic diagnosis and treatment planning. PMID- 21606524 TI - Psychoanalysis and Surrealism: Andre Breton and Sigmund Freud. PMID- 21606526 TI - Influenza and acute myocardial infarction. PMID- 21606527 TI - Increasing clarity on bone loss associated with antiretroviral initiation. PMID- 21606528 TI - Another step down the development pipeline for the novel tuberculosis vaccine MVA 85A. PMID- 21606529 TI - Circulating influenza virus, climatic factors, and acute myocardial infarction: a time series study in England and Wales and Hong Kong. AB - BACKGROUND: Previous studies identifying associations between influenza and acute cardiac events may have been confounded by climatic factors. Differing seasonal patterns of influenza activity in Hong Kong and England and Wales provide a natural experiment to examine associations with myocardial infarction (MI) independent of cold weather effects. METHODS: Weekly clinical and laboratory influenza surveillance data, environmental temperature and humidity data, and counts of MI-associated hospitalizations and deaths were obtained for England and Wales and for Hong Kong for the period 1998-2008. We used Poisson regression models that included environmental and seasonal variables to investigate the relationship between influenza and MI. RESULTS: There were >=1.2 million MI associated hospitalizations and 410,204 MI-associated deaths in England and Wales, with a marked peak in the winter season. In Hong Kong, the incidence of MI, on the basis of 65,108 hospitalizations and 18,780 deaths, had a large winter and smaller summer peak, mirroring patterns of influenza activity. There was strong evidence for a link between influenza and MI both in England and Wales, where 3.1%-3.4% of MI-associated deaths (P < .001) and 0.7%-1.2% of MI-associated hospitalizations (P < .001) were attributable to influenza, and in Hong Kong, where the corresponding figures were 3.9%-5.6% (P = .018) and 3.0%-3.3% (P = .002). CONCLUSIONS: Influenza was associated with an increase in MI-associated deaths and hospitalizations in 2 contrasting settings. PMID- 21606530 TI - Combined, concurrent, and sequential administration of seasonal influenza and MF59-adjuvanted A/H5N1 vaccines: a phase II randomized, controlled trial of immunogenicity and safety in healthy adults. AB - OBJECTIVE: We performed a phase II randomized, controlled, open-label, single center study (Centros de Estudios de Infectologia Pediatrica, Colombia) to examine the feasibility of combined administration of seasonal and MF59 adjuvanted A/H5N1 influenza vaccines using extemporaneous mixing or simultaneous administration. METHODS: The primary objective of the study was to assess the immunogenicity of seasonal influenza and A/H5N1 vaccines using European licensure criteria (Committee for Medicinal Products for Human Use [CHMP]); the secondary objective was to assess vaccine reactogenicity and safety. RESULTS: In 401 healthy 18-40-year-old subjects, both vaccines were immunogenic in all settings; the vaccine for seasonal influenza met all CHMP criteria, unaffected by coadministration of A/H5N1 vaccine in separate or mixed injections. Likewise, the immunogenicity of A/H5N1 vaccine was unaffected by seasonal influenza vaccination, with hemagglutination inhibition seroprotection rates of 28%-40% after 1 dose and 67%-80% after 2 doses, sufficient to meet CHMP criteria. Solicited local and systemic adverse events were mainly mild to moderate. No vaccine-related serious adverse events were reported during the study period. CONCLUSIONS: These data demonstrate that seasonal and MF59-adjuvanted A/H5N1 influenza vaccines can be given as a mixed injection or by simultaneous separate injections without affecting immunogenicity or safety, supporting the feasibility of incorporating prepandemic MF59-adjuvanted A/H5N1 vaccines into seasonal influenza vaccination programs and the development of tetravalent influenza vaccines, including pandemic strains. Clinical Trials Registration. NCT00481065. PMID- 21606531 TI - Dose-sparing H5N1 A/Indonesia/05/2005 pre-pandemic influenza vaccine in adults and elderly adults: a phase III, placebo-controlled, randomized study. AB - BACKGROUND: Highly pathogenic avian influenza H5N1 viruses remain a threat to human health, with potential to become pandemic agents. METHODS: This phase III, placebo-controlled, observer-blinded study evaluated the immunogenicity, cross reactivity, safety, and lot consistency of 2 doses of oil-in-water (AS03(A)) adjuvanted H5N1 A/Indonesia/05/2005 (3.75 MUg hemagglutinin antigen) prepandemic candidate vaccine in 4561 adults aged 18-91 years. RESULTS: Humoral antibody responses in the H5N1 vaccine groups fulfilled US and European immunogenicity licensure criteria for pandemic vaccines in all age strata 21 days after the second dose. At 6 months after the administration of the primary dose, serum antibody seroconversion rates continued to fulfill licensure criteria. Neutralizing cross-clade immune responses were demonstrated against clade 1 A/Vietnam/1194/2004. Consistency was demonstrated for 3 consecutive H5N1 vaccine lots. Temporary injection-site pain was more frequent with H5N1 vaccine than placebo (89.3% and 70.7% in the 18-64 and >=65 years strata vs 22.2% and 14.4% in the placebo groups). Unsolicited adverse event frequency, including medically attended and serious events, was similar between groups through day 364. CONCLUSIONS: In adults and elderly adults, AS03(A)-adjuvanted H5N1 candidate vaccine was highly immunogenic for A/Indonesia/05/2005, with cross-reactivity against A/Vietnam/1194/2004. Temporary injection site reactions were more frequent with H5N1 vaccine than placebo, although the H5N1 vaccine was well tolerated overall. Clinical Trials Registration. NCT00616928. PMID- 21606532 TI - Complications and outcomes of pandemic 2009 Influenza A (H1N1) virus infection in hospitalized adults: how do they differ from those in seasonal influenza? AB - BACKGROUND: It is unclear whether pandemic 2009 influenza A (pH1N1) infection caused more significant disease among hospitalized adults than seasonal influenza. METHODS: A prospective, observational study was conducted in adults hospitalized with polymerase chain reaction-confirmed pH1N1 infection in 2 acute care general hospitals from June 2009 to May 2010 (n = 382). Complications and outcomes were described and compared with those in a seasonal influenza cohort (2007-2008, same hospitals; n = 754). RESULTS: Hospitalized patients with pH1N1 influenza were younger than those with seasonal influenza (mean age +/- standard deviation, 47 +/- 20 vs 70 +/- 19 years) and fewer had comorbid conditions (48% vs 64%). The rate of positive immunofluorescence assay results was low (54% vs 84%), and antiviral use was frequent (96% vs 52%). Most patients in both cohorts developed complicated illnesses (67.8% vs 77.1%), but patients with pH1N1 influenza had higher rates of extrapulmonary complications (23% vs 16%; P = .004) and intensive care unit admission and/or death (patient age <35 years, 2.3% vs 0%; 35-65 years, 12.4% vs 3.2%; >65 years, 13.5% vs 8.5%; adjusted odds ratio [OR] 2.13; 95% confidence interval [CI], 1.25-3.62; P = .005). Patients who received antiviral treatment within 96 h after onset had better survival (log rank test, P < .001). However, without timely treatment, the mortality risk was higher with pH1N1 infection (9.0% vs 5.8% for seasonal influenza; adjusted OR, 6.85; 95% CI, 1.64-28.65; P = .008]. Bacterial superinfection worsened outcomes. CONCLUSIONS: Adults hospitalized for pH1N1 influenza had significant complications and mortality despite being younger than patients with seasonal influenza. Antiviral treatment within 96 h may improve survival. PMID- 21606533 TI - Interleukin 28B gene variation at rs12979860 determines early viral kinetics during treatment in patients carrying genotypes 2 or 3 of hepatitis C virus. AB - Single-nucleotide polymorphisms upstream of the interleukin 28B (interferon lambda3) gene (IL28B) strongly influence treatment efficacy in patients carrying hepatitis C virus (HCV) of genotype 1. In patients receiving 12 or 24 weeks of interferon-ribavirin therapy for infection with genotype 2 or 3 (n = 341), we found that rs12979860 strikingly determined the first phase of viral elimination (P < .001). In patients treated for 24 weeks, rs12979860 also predicted the rate of sustained virologic response (P = .02), especially among those with high baseline HCV RNA levels (P = .002) or older than 45 years (P = .01). Patients carrying CC(rs12979860) had higher baseline HCV RNA levels (P < .001) and did not, when treated for 12 weeks, achieve sustained virologic response more often than those carrying CT(rs1297986) or TT(rs1297986). The results indicate that IL28B gene testing may identify patients carrying genotype 2 or 3 who could benefit from extended treatment. PMID- 21606535 TI - Impairment of CD4+ T cell polarization by dengue virus-infected dendritic cells. AB - BACKGROUND: The production of type I interferon alpha/beta (IFN-alpha/beta) is crucial to viral clearance during dengue virus (DENV) infection; however, in vitro-infected dendritic cells (DCs) exhibit a decreased capacity to respond to IFN-alpha/beta stimulation, and antigen-presenting cells (APCs) isolated from patients with acute DENV infection exhibit defects in T cell priming. METHODS: In order to ascertain the stimulatory capacity of primary human monocyte-derived DCs infected with wild-type DENV isolates, representing a range of genotypes and disease outcomes, we cocultured infected DCs with allogeneic-naive CD4(+) T cells. The gene expression patterns of IFN-alpha/beta sensitive genes were quantitated to determine if the infected DCs displayed a blunted IFN-alpha/beta response. RESULTS: DENV-infected DCs induced the initial proliferation of naive CD4(+) T cells but they remained nonpolarized in effector function. The expression of IFN-alpha/beta-stimulated genes was downregulated, revealing that the inhibition of IFN-alpha/beta signaling is conserved among endemic DENV serotype 2 strains. CONCLUSIONS: The failure of naive CD4(+) T cells to differentiate into IFN gamma-producing effector T cells when primed by DENV infected DCs cannot be explained solely by a block in IFN-alpha/beta signaling, suggesting that the ability of DENV to evade the early host response is multifaceted. PMID- 21606534 TI - Hepatitis C virus infection and hepatic stellate cell activation downregulate miR 29: miR-29 overexpression reduces hepatitis C viral abundance in culture. AB - BACKGROUND: Chronic hepatitis C virus (HCV)-induced liver fibrosis involves upregulation of transforming growth factor (TGF)-beta and subsequent hepatic stellate cell (HSC) activation. MicroRNAs (miRNAs) regulate HCV infection and HSC activation. METHODS: TaqMan miRNA profiling identified 12 miRNA families differentially expressed between chronically HCV-infected human livers and uninfected controls. To identify pathways affected by miRNAs, we developed a new algorithm (pathway analysis of conserved targets), based on the probability of conserved targeting. RESULTS: This analysis suggested a role for miR-29 during HCV infection. Of interest, miR-29 was downregulated in most HCV-infected patients. miR-29 regulates expression of extracellular matrix proteins. In culture, HCV infection downregulated miR-29, and miR-29 overexpression reduced HCV RNA abundance. miR-29 also appears to play a role in HSCs. Hepatocytes and HSCs contribute similar amounts of miR-29 to whole liver. Both activation of primary HSCs and TGF-beta treatment of immortalized HSCs downregulated miR-29. miR-29 overexpression in LX-2 cells decreased collagen expression and modestly decreased proliferation. miR-29 downregulation by HCV may derepress extracellular matrix synthesis during HSC activation. CONCLUSIONS: HCV infection downregulates miR-29 in hepatocytes and may potentiate collagen synthesis by reducing miR-29 levels in activated HSCs. Treatment with miR-29 mimics in vivo might inhibit HCV while reducing fibrosis. PMID- 21606536 TI - Lectin switching during dengue virus infection. AB - Dengue virus receptors are relatively poorly characterized, but there has been recent interest in 2 C-type lectin molecules, dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) and its close homologue liver/lymph node-specific ICAM-3-grabbing integrin (L-SIGN), which can both bind dengue and promote infection. In this report we have studied the interaction of dengue viruses produced in insect cells, tumor cell lines, and primary human dendritic cells (DCs) with DC-SIGN and L-SIGN. Virus produced in primary DCs is unable to interact with DC-SIGN but remains infectious for L-SIGN expressing cells. Skin-resident DCs may thus be a site of initial infection by insect-produced virus, but DCs will likely not participate in large-scale virus replication during dengue infection. These results reveal that differential glycosylation of dengue virus envelope protein is highly dependent on cell state and suggest that studies of virus tropism using virus prepared in insect cells or tumor cell lines should be interpreted with caution. PMID- 21606537 TI - Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. AB - BACKGROUND: Long-term effects of abacavir (ABC)-lamivudine (3TC), compared with tenofovir (TDF)-emtricitabine (FTC) with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r), on bone mineral density (BMD) have not been analyzed. METHODS: A5224s was a substudy of A5202, in which HIV-infected treatment-naive participants were randomized and blinded to receive ABC-3TC or TDF-FTC with open label EFV or ATV/r. Primary bone end points included Dual-emission X-ray absorbtiometry (DXA)-measured percent changes in spine and hip BMD at week 96. Primary analyses were intent-to-treat. Statistical tests used the factorial design and included linear regression, 2-sample t, log-rank, and Fisher's exact tests. RESULTS: Two hundred sixty-nine persons randomized to 4 arms of ABC-3TC or TDF-FTC with EFV or ATV/r. At baseline, 85% were male, and 47% were white non Hispanic; the median HIV-1 RNA load was 4.6 log(10) copies/mL, the median age was 38 years, the median weight was 76 kg, and the median CD4 cell count was 233 cells/MUL. At week 96, the mean percentage changes from baseline in spine and hip BMD for ABC-3TC versus TDF-FTC were -1.3% and -3.3% (P = .004) and -2.6% and 4.0% (P = .024), respectively; and for EFV versus ATV/r were -1.7% and -3.1% (P = .035) and -3.1% and -3.4% (P = .61), respectively. Bone fracture was observed in 5.6% of participants. The probability of bone fractures and time to first fracture were not different across components. CONCLUSIONS: Compared with ABC 3TC, TDF-FTC-treated participants had significantly greater decreases in spine and hip BMD, whereas ATV/r led to more significant losses in spine, but not hip, BMD than EFV. Clinical Trials Registration. NCT00118898. PMID- 21606538 TI - Concomitant highly active antiretroviral therapy leads to smaller decline and faster recovery of CD4+ cell counts during and after pegylated interferon plus ribavirin therapy in HIV-hepatitis C virus coinfected patients. AB - INTRODUCTION: The impact of highly active antiretroviral therapy (HAART) on CD4+ cell course during treatment with pegylated interferon plus ribavirin (PegIFN RBV) in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is unknown. METHODS: We determined CD4(+) cell count in 94 HIV-HCV coinfected patients undergoing treatment with pegylated interferon plus RBV at baseline, treatment weeks 4-48 (W4-W48), and months 1, 3, and 6 of follow-up. Of the 94 patients, 70 underwent concomitant HAART (group A) and 24 did not (group B). RESULTS: Group A showed smaller CD4(+) cell decreases from W24-W48 (P = .027) and greater CD4(+) cell increases after cessation of pegylated interferon plus ribavirin therapy (P = .002) than group B showed. CONCLUSIONS: Concomitant HAART leads to smaller decreases and faster recovery of CD4(+) cells during and after pegylated interferon plus RBV therapy. PMID- 21606539 TI - The relation of HLA genotype to hepatitis C viral load and markers of liver fibrosis in HIV-infected and HIV-uninfected women. AB - BACKGROUND: Human leukocyte antigen (HLA) class I and II genotype is associated with clearance of hepatitis C virus (HCV) infection, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection. METHODS: High-resolution HLA class I and II genotyping was conducted in a prospective cohort of 519 human immunodeficiency virus (HIV)-seropositive and 100 HIV-seronegative women with persistent HCV infection. The end points were baseline HCV viral load and 2 noninvasive indexes of liver disease, fibrosis-4 (FIB-4), and the aspartate aminotransferase to platelet ratio index (APRI), measured at baseline and prospectively. RESULTS: DQB1*0301 was associated with low baseline HCV load (beta = -.4; 95% confidence interval [CI], -.6 to -.3; P < .00001), as well as with low odds of FIB-4-defined (odds ratio [OR], .5; 95% CI, .2-.9; P = .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3-1.0; P = .06) at baseline and/or during follow-up. Most additional associations with HCV viral load also involved HLA class II alleles. Additional associations with FIB-4 and APRI primarily involved class I alleles, for example, the relation of B*1503 with APRI-defined fibrosis had an OR of 2.0 (95% CI, 1.0-3.7; P = .04). CONCLUSIONS: HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies. PMID- 21606540 TI - Long-term durability of immune responses after hepatitis A vaccination among HIV infected adults. AB - BACKGROUND: Vaccination provides long-term immunity to hepatitis A virus (HAV) among the general population, but there are no such data regarding vaccine durability among human immunodeficiency virus (HIV)-infected adults. METHODS: We retrospectively studied HIV-infected adults who had received 2 doses of HAV vaccine. We analyzed blood specimens taken at 1 year, 3 years, and, when available, 6-10 years postvaccination. HAV immunoglobulin G (IgG) values of >=10 mIU/mL were considered seropositive. RESULTS: We evaluated specimens from 130 HIV infected adults with a median age of 35 years and a median CD4 cell count of 461 cells/mm(3) at or before time of vaccination. Of these, 49% had an HIV RNA load <1000 copies/mL. Initial vaccine responses were achieved in 89% of HIV-infected adults (95% confidence interval [CI], 83%-94%), compared with 100% (95% CI, 99% 100%) of historical HIV-uninfected adults. Among initial HIV-infected responders with available specimens, 90% (104 of 116; 95% CI, 83%-95%) remained seropositive at 3 years and 85% (63 of 74; 95% CI, 75%-92%) at 6-10 years. Geometric mean concentrations (GMCs) among HIV-infected adults were 154, 111, and 64 mIU/mL at 1, 3, and 6-10 years, respectively, compared with 1734, 687, and 684 mIU/mL among HIV-uninfected persons. Higher GMCs over time among HIV-infected adults were associated with lower log(10) HIV RNA levels (beta = -.12, P = .04). CONCLUSIONS: Most adults with well-controlled HIV infections had durable seropositive responses up to 6-10 years after HAV vaccination. Suppressed HIV RNA levels are associated with durable HAV responses. PMID- 21606542 TI - Dose-finding study of the novel tuberculosis vaccine, MVA85A, in healthy BCG vaccinated infants. AB - BACKGROUND: BCG, the only licensed tuberculosis vaccine, affords poor protection against lung tuberculosis in infants and children. A new tuberculosis vaccine, which may enhance the BCG-induced immune response, is urgently needed. We assessed the safety of and characterized the T cell response induced by 3 doses of the candidate vaccine, MVA85A, in BCG-vaccinated infants from a setting where tuberculosis is endemic. METHODS: Infants aged 5-12 months were vaccinated intradermally with either 2.5 * 10(7), 5 * 10(7), or 10 * 10(7) plaque-forming units of MVA85A, or placebo. Adverse events were documented, and T-cell responses were assessed by interferon gamma (IFN-gamma) enzyme-linked immunospot assay and intracellular cytokine staining. RESULTS: The 3 MVA85A doses were well tolerated, and no vaccine-related serious adverse events were recorded. MVA85A induced potent, durable T-cell responses, which exceeded prevaccination responses up to 168 d after vaccination. No dose-related differences in response magnitude were observed. Multiple CD4 T cell subsets were induced; polyfunctional CD4 T cells co expressing T-helper cell 1 cytokines with or without granulocyte-macrophage colony-stimulating factor predominated. IFN-gamma-expressing CD8 T cells, which peaked later than CD4 T cells, were also detectable. CONCLUSIONS: MVA85A was safe and induced robust, polyfunctional, durable CD4 and CD8 T-cell responses in infants. These data support efficacy evaluation of MVA85A to prevent tuberculosis in infancy. Clinical Trials Registration. NCT00679159. PMID- 21606541 TI - Nef inhibits glucose uptake in adipocytes and contributes to insulin resistance in human immunodeficiency virus type I infection. AB - Human immunodeficiency virus (HIV) infection is associated with insulin resistance. HIV type 1 Nef downregulates cell surface protein expression, alters signal transduction, and interacts with the cytoskeleton and proteins involved in actin polymerization. These functions are required for glucose uptake by insulin stimulated adipocytes. We sought to determine whether Nef alters adipocyte glucose homeostasis. Using radiolabeled glucose, we found that adipocytes exposed to recombinant Nef took in 42% less glucose after insulin stimulation than did control cells. This reduction resulted from a Nef-dependent inhibition of glucose transporter 4 (GLUT4) trafficking, as assessed by means of immunofluorescence microscopy. Immunoblot analysis revealed a decrease in phosphorylation of signal transducing proteins after Nef treatment, and fluorescence microscopy showed a dramatic alteration in cortical actin organization. We conclude that Nef interferes with insulin-stimulated processes in adipocytes. We have identified HIV Nef, which is detectable and antigenic in serum samples from HIV-infected people, as a novel contributor to the development of insulin resistance. PMID- 21606543 TI - Osteopontin impairs host defense during pneumococcal pneumonia. AB - BACKGROUND: Streptococcus pneumoniae is the most frequently isolated pathogen responsible for community-acquired pneumonia. Osteopontin is involved in inflammation during both innate and adaptive immunity. METHODS: To determine the role of osteopontin in the host response during pneumococcal pneumonia, osteopontin knockout (KO) and normal wild-type (WT) mice were intranasally infected with viable S. pneumoniae. RESULTS: Pneumonia was associated with a rapid increase in pulmonary osteopontin concentrations in WT mice from 6 h onward. Osteopontin KO mice showed a prolonged survival relative to WT mice, which was accompanied by diminished pulmonary bacterial growth and reduced dissemination to distant body sites. In addition, at 48 h after infection pulmonary inflammation was decreased in osteopontin KO mice as reflected by lower inflammation scores and reduced chemokine concentrations. In contrast to pneumococcal pneumonia, osteopontin deficiency did not influence bacterial growth in primary pneumococcal sepsis induced by direct intravenous infection, suggesting that the detrimental effect of osteopontin on antibacterial defense during pneumonia primarily is exerted in the pulmonary compartment. Moreover, recombinant osteopontin stabilized S. pneumoniae viability in vitro. CONCLUSIONS: These results suggest that the pneumococcus misuses osteopontin in the airways for optimal growth and to cause invasive disease after entering the lower airways. PMID- 21606544 TI - A Haemophilus ducreyi CpxR deletion mutant is virulent in human volunteers. AB - Haemophilus ducreyi 35000HP contains a homolog of the CpxRA 2-component signal transduction system, which controls the cell envelope stress response system in other gram-negative bacteria and regulates some important H. ducreyi virulence factors. A H. ducreyi cpxR mutant was compared with its parent for virulence in the human challenge model of experimental chancroid. The pustule formation rate in 5 volunteers was 33% (95% confidence interval [CI], 1.3%-65.3%) at 15 parent sites and 40% (95% CI, 18.1%-61.9%) at 15 mutant sites (P = .35). Thus, the cpxR mutant was not attenuated for virulence. Inactivation of the H. ducreyi cpxR gene did not reduce the ability of this mutant to express certain proven virulence factors, including the DsrA serum resistance protein and the LspA2 protein, which inhibits phagocytosis. These results expand our understanding of the involvement of the CpxRA system in regulating virulence expression in H. ducreyi. PMID- 21606545 TI - Regarding "type 2 vaccine-derived poliovirus from patients with acute flaccid paralysis in China: current immunization strategy effectively prevented its sustained transmission". PMID- 21606547 TI - IL-6 -174 c/c genotype is not conclusively a low IL-6 production phenotype. PMID- 21606549 TI - Predicting metal-binding sites from protein sequence. AB - Prediction of binding sites from sequence can significantly help toward determining the function of uncharacterized proteins on a genomic scale. The task is highly challenging due to the enormous amount of alternative candidate configurations. Previous research has only considered this prediction problem starting from 3D information. When starting from sequence alone, only methods that predict the bonding state of selected residues are available. The sole exception consists of pattern-based approaches, which rely on very specific motifs and cannot be applied to discover truly novel sites. We develop new algorithmic ideas based on structured-output learning for determining transition metal-binding sites coordinated by cysteines and histidines. The inference step (retrieving the best scoring output) is intractable for general output types (i.e., general graphs). However, under the assumption that no residue can coordinate more than one metal ion, we prove that metal binding has the algebraic structure of a matroid, allowing us to employ a very efficient greedy algorithm. We test our predictor in a highly stringent setting where the training set consists of protein chains belonging to SCOP folds different from the ones used for accuracy estimation. In this setting, our predictor achieves 56 percent precision and 60 percent recall in the identification of ligand-ion bonds. PMID- 21606551 TI - A multi-slot surface coil for MRI of dual-rat imaging at 4 T. AB - A slotted surface coil inspired by the hole-and-slot cavity magnetron was developed for magnetic resonance imaging of obese rats at 4 T. Full-wave analysis of the magnetic field was carried out at 170 MHz for both the slotted and circular-shaped coils. The noise figure values of two coils were investigated via the numerical calculation of the quality factors. Fat simulated phantoms to mimic overweight rats were included in the analysis with weights ranging from 300 to 900 g. The noise figures were 1.2 dB for the slotted coil and 2.4 dB for the circular coil when loaded with 600 g of simulated phantom. A slotted surface coil with eight circular slots and a circular coil with similar dimensions were built and operated in the transceiver mode, and their performances were experimentally compared. The imaging tests in phantoms demonstrated that the slotted surface coil has a deeper RF-sensitivity and better field uniformity than the single-loop RF-coil. High quality images of two overweight Zucker rats were acquired simultaneously with the slotted surface coil using standard spin-echo pulse sequences. Experimental results showed that the slotted surface coil outperformed the circular coil for imaging considerably overweight rats. Thus, the slotted surface coil can be a good tool for MRI experiments in rats on a human whole-body 4 T scanner. PMID- 21606552 TI - Thermal drift reduction with multiple bias current for MOSFET dosimeters. AB - New thermal compensation methods suitable for p-channel MOSFET (pMOS) dosimeters with the usual dose readout procedure based on a constant drain current are presented. Measuring the source-drain voltage shifts for two or three different drain currents and knowing the value of the zero-temperature coefficient drain current, I(ZTC), the thermal drift of source-drain or threshold voltages can be significantly reduced. Analytical expressions for the thermal compensation have been theoretically deduced on the basis of a linear dependence on temperature of the parameters involved. The proposed thermal modelling has been experimentally proven. These methods have been applied to a group of ten commercial pMOS transistors (3N163). The thermal coefficients of the source-drain voltage and the threshold voltage were reduced from -3.0 mV degrees C(-1), in the worst case, down to -70 uV degrees C(-1). This means a thermal drift of -2.4 mGy degrees C(-1) for the dosimeter. When analysing the thermal drifts of all the studied transistors, in the temperature range from 19 to 36 degrees C, uncertainty was obtained in the threshold voltage due to a thermal drift of +/-9 mGy (2 SD), a commonly acceptable value in most radiotherapy treatments. The procedures described herein provide thermal drift reduction comparable to that of other technological or numerical strategies, but can be used in a very simple and low cost dosimetry sensor. PMID- 21606554 TI - Performance evaluation of a pixellated Ge Compton camera. AB - An ongoing project is being carried out to develop a high purity germanium (HPGe) Compton camera for medical applications. The Compton camera offers many potential advantages over the conventional gamma camera. The camera reported in this paper comprises two pixellated germanium detector planes housed 9.6 cm apart in the same vacuum housing. The camera has 177 pixels, 152 in the scatter detector and 25 in the absorption detector. The pixels are 4 * 4 mm(2) with a thickness of 4 mm in the scatter detector and 10 mm in the absorption detector. Images have been taken for a variety of test objects including point sources, a ring source and a Perspex phantom. The measured angular resolution is 9.4 degrees +/- 0.4 degrees for a 662 keV gamma-ray source at 3 cm. Due to the limited number of readout modules a multiple-view technique was used to image the source distributions from different angles and simulate the pixel arrangement in the full camera. PMID- 21606555 TI - Microbubble-based synchrotron radiation phase contrast imaging: basic study and angiography applications. AB - The purpose of the study was to evaluate the feasibility of microbubbles as phase contrast imaging (PCI) agents for angiography applications. The hypothesis was that the introduction of microbubbles into tissue produces a significant change in the refractive index and highlights the lumen of the vessel in PCI. The absorption and phase contrast images of commercially available microbubbles were obtained and compared in vitro. A further increase in contrast was observed in PCI. Microbubbles highlighted the lumen of the renal microvessels, acting as a positive contrast medium in ex vivo imaging. In addition, home-made microbubbles with larger diameters were introduced for image contrast enhancement in living tumor-bearing mice, demonstrating the feasibility of microbubble-based x-ray phase-contrast imaging for tumor vasculature in vivo. PMID- 21606553 TI - Limited-angle x-ray luminescence tomography: methodology and feasibility study. AB - X-ray luminescence tomography (XLT) has recently been proposed as a new imaging modality for biological imaging applications. This modality utilizes phosphor nanoparticles which luminesce near-infrared light when excited by x-ray photons. The advantages of this modality are that it uniquely combines the high sensitivity of radioluminescent nanoparticles and the high spatial localization of collimated x-ray beams. Currently, XLT has been demonstrated using x-ray spatial encoding to resolve the imaging volume. However, there are applications where the x-ray excitation may be limited by geometry, where increased temporal resolution is desired, or where a lower dose is mandatory. This paper extends the utility of XLT to meet these requirements by incorporating a photon propagation model into the reconstruction algorithm in an x-ray limited-angle (LA) geometry. This enables such applications as image-guided surgery, where the ability to resolve lesions at depths of several centimeters can be the key to successful resection. The hybrid x-ray/diffuse optical model is first formulated and then demonstrated in a breast-sized phantom, simulating a breast lumpectomy geometry. Both numerical and experimental phantoms are tested, with lesion-simulating objects of various sizes and depths. Results show localization accuracy with median error of 2.2 mm, or 4% of object depth, for small 2-14 mm diameter lesions positioned from 1 to 4.5 cm in depth. This compares favorably with fluorescence optical imaging, which is not able to resolve such small objects at this depth. The recovered lesion size has lower size bias in the x-ray excitation direction than the optical direction, which is expected due to the increased optical scatter. However, the technique is shown to be quite invariant in recovered size with respect to depth, as the standard deviation is less than 2.5 mm. Sensitivity is a function of dose; radiological doses are found to provide sufficient recovery for ug ml(-1) concentrations, while therapy dosages provide recovery for ng ml(-1) concentrations. Experimental phantom results agree closely with the numerical results, with positional errors recovered within 8.6% of the effective depth for a 5 mm object, and within 5.2% of the depth for a 10 mm object. Object size median error is within 2.3% and 2% for the 5 and 10 mm objects, respectively. For shallow-to-medium depth applications where optical and radio emission imaging modalities are not ideal, such as in intra-operative procedures, LAXLT may be a useful tool to detect molecular signatures of disease. PMID- 21606556 TI - X-ray properties of an anthropomorphic breast phantom for MRI and x-ray imaging. AB - The purpose of this study is to characterize the x-ray properties of a dual modality, anthropomorphic breast phantom whose MRI properties have been previously evaluated. The goal of this phantom is to provide a platform for optimization and standardization of two- and three-dimensional x-ray and MRI breast imaging modalities for the purpose of lesion detection and discrimination. The phantom is constructed using a mixture of lard and egg whites, resulting in a variable, tissue-mimicking structure with separate adipose- and glandular mimicking components. The phantom can be produced with either a compressed or uncompressed shape. Mass attenuation coefficients of the phantom materials were estimated using elemental compositions from the USDA National Nutrient Database for Standard Reference and the atomic interaction models from the Monte Carlo code PENELOPE and compared with human values from the literature. The image structure was examined quantitatively by calculating and comparing spatial covariance matrices of the phantom and patient mammography images. Finally, a computerized version of the phantom was created by segmenting a computed tomography scan and used to simulate x-ray scatter of the phantom in a mammography geometry. Mass attenuation coefficients of the phantom materials were within 20% and 15% of the values for adipose and glandular tissues, respectively, which is within the estimation error of these values. Matching was improved at higher energies (>20 keV). Tissue structures in the phantom have a size similar to those in the patient data, but are slightly larger on average. Correlations in the patient data appear to be longer than those in the phantom data in the anterior-posterior direction; however, they are within the error bars of the measurement. Simulated scatter-to-primary ratio values of the phantom images were as high as 85% in some areas and were strongly affected by the heterogeneous nature of the phantom. Key physical x-ray properties of the phantom have been quantitatively evaluated and shown to be comparable to those of breast tissue. Since the MRI properties of the phantom have been previously evaluated, we believe it is a useful tool for quantitative evaluation of two- and three dimensional x-ray and MRI breast imaging modalities for the purpose of lesion detection and characterization. PMID- 21606557 TI - Line plus arc source trajectories and their R-line coverage for long-object cone beam imaging with a C-arm system. AB - Cone-beam imaging with C-arm systems has become a valuable tool in interventional radiology. Currently, a simple circular trajectory is used, but future applications should use more sophisticated source trajectories, not only to avoid cone-beam artifacts but also to allow extended volume imaging. One attractive strategy to achieve these two goals is to use a source trajectory that consists of two parallel circular arcs connected by a line segment, possibly with repetition. In this work, we address the question of R-line coverage for such a trajectory. More specifically, we examine to what extent R-lines for such a trajectory cover a central cylindrical region of interest (ROI). An R-line is a line segment connecting any two points on the source trajectory. Knowledge of R line coverage is crucial because a general theory for theoretically exact and stable image reconstruction from axially truncated data is only known for the points in the scanned object that lie on R-lines. Our analysis starts by examining the R-line coverage for the elemental trajectories consisting of (i) two parallel circular arcs and (ii) a circular arc connected orthogonally to a line segment. Next, we utilize our understanding of the R-lines for the aforementioned elemental trajectories to determine the R-line coverage for the trajectory consisting of two parallel circular arcs connected by a tightly fit line segment. For this trajectory, we find that the R-line coverage is insufficient to completely cover any central ROI. Because extension of the line segment beyond the circular arcs helps to increase the R-line coverage, we subsequently propose a trajectory composed of two parallel circular arcs connected by an extended line. We show that the R-lines for this trajectory can fully cover a central ROI if the line extension is long enough. Our presentation includes a formula for the minimum line extension needed to achieve full R-line coverage of an ROI with a specified size, and also includes a preliminary study on the required detector size, showing that the R-lines added by the line extension are not constraining. PMID- 21606558 TI - An MR-compliant phased-array HIFU transducer with augmented steering range, dedicated to abdominal thermotherapy. AB - A novel architecture for a phased-array high intensity focused ultrasound (HIFU) device was investigated, aiming to increase the capabilities of electronic steering without reducing the size of the elementary emitters. The principal medical application expected to benefit from these developments is the time effective sonication of large tumours in moving organs. The underlying principle consists of dividing the full array of transducers into multiple sub-arrays of different resonance frequencies, with the reorientation of these individual emitters, such that each sub-array can focus within a given spatial zone. To enable magnetic resonance (MR) compatibility of the device and the number of output channels from the RF generator to be halved, a passive spectral multiplexing technique was used, consisting of parallel wiring of frequency shifted paired piezoceramic emitters with intrinsic narrow-band response. Two families of 64 emitters (circular, 5 mm diameter) were mounted, with optimum efficiency at 0.96 and 1.03 MHz, respectively. Two different prototypes of the HIFU device were built and tested, each incorporating the same two families of emitters, but differing in the shape of the rapid prototyping plastic support that accommodated the transducers (spherical cap with radius of curvature/aperture of 130 mm/150 mm and, respectively, 80 mm/110 mm). Acoustic measurements, MR-acoustic radiation force imaging (ex vivo) and MR-thermometry (ex vivo and in vivo) were used for the characterization of the prototypes. Experimental results demonstrated an augmentation of the steering range by 80% along one preferentially chosen axis, compared to a classic spherical array of the same total number of elements. The electric power density provided to the piezoceramic transducers exceeded 50 W cm(-2) CW, without circulation of coolant water. Another important advantage of the current approach is the versatility of reshaping the array at low cost. PMID- 21606559 TI - Oscillatory dynamics of vasoconstriction and vasodilation identified by time localized phase coherence. AB - We apply wavelet-based time-localized phase coherence to investigate the relationship between blood flow and skin temperature, and between blood flow and instantaneous heart rate (IHR), during vasoconstriction and vasodilation provoked by local cooling or heating of the skin. A temperature-controlled metal plate (approximately 10 cm2) placed on the volar side of the left arm was used to provide the heating and cooling. Beneath the plate, the blood flow was measured by laser Doppler flowmetry and the adjacent skin temperature by a thermistor. Two 1 h datasets were collected from each of the ten subjects. In each case a 30 min basal recording was followed by a step change in plate temperature, to either 24 degrees C or 42 degrees C. The IHR was derived from simultaneously recorded ECG. We confirm the changes in the energy and frequency of blood flow oscillations during cooling and heating reported earlier. That is, during cooling, there was a significant decrease in the average frequency of myogenic blood flow oscillations (p < 0.05) and the myogenic spectral peak became more prominent. During heating, there was a significant (p < 0.05) general increase in spectral energy, associated with vasodilation, except in the myogenic interval. Weak phase coherence between temperature and blood flow was observed for unperturbed skin, but it increased in all frequency intervals as a result of heating. It was not significantly affected by cooling. We also show that significant (p < 0.05) phase coherence exists between blood flow and IHR in the respiratory and myogenic frequency intervals. Cooling did not affect this phase coherence in any of the frequency intervals, whereas heating enhanced the phase coherence in the respiratory and myogenic intervals. This can be explained by the reduction in vascular resistance produced by heating, a process where myogenic mechanisms play a key role. We conclude that the mechanisms of vasodilation and vasoconstriction, in response to temperature change, are oscillatory in nature and are independent of central sources of variability. PMID- 21606560 TI - A bio-telemetric device for measurement of left ventricular pressure-volume loops using the admittance technique in conscious, ambulatory rats. AB - This paper presents the design, construction and testing of a device to measure pressure-volume loops in the left ventricle of conscious, ambulatory rats. Pressure is measured with a standard sensor, but volume is derived from data collected from a tetrapolar electrode catheter using a novel admittance technique. There are two main advantages of the admittance technique to measure volume. First, the contribution from the adjacent muscle can be instantaneously removed. Second, the admittance technique incorporates the nonlinear relationship between the electric field generated by the catheter and the blood volume. A low power instrument weighing 27 g was designed, which takes pressure-volume loops every 2 min and runs for 24 h. Pressure-volume data are transmitted wirelessly to a base station. The device was first validated on 13 rats with an acute preparation with 2D echocardiography used to measure true volume. From an accuracy standpoint, the admittance technique is superior to both the conductance technique calibrated with hypertonic saline injections, and calibrated with cuvettes. The device was then tested on six rats with 24 h chronic preparation. Stability of animal preparation and careful calibration are important factors affecting the success of the device. PMID- 21606561 TI - An audiovisual feedback device for compression depth, rate and complete chest recoil can improve the CPR performance of lay persons during self-training on a manikin. AB - This study aims to contribute to the scarce data available about the abilities of untrained lay persons to perform hands-only cardio-pulmonary resuscitation (CPR) on a manikin and the improvement of their skills during training with an autonomous CPR feedback device. The study focuses on the following questions: (i) Is there a need for such a CPR training device? (ii) How adequate are the embedded visual feedback and audio guidance for training of lay persons who learn and correct themselves in real time without instructor guidance? (iii) What is the achieved effect of only 3 min of training? This is a prospective study in which 63 lay persons (volunteers) received a debriefing to basic life support and then performed two consecutive 3 min trials of hands-only CPR on a manikin. The pre-training skills of the lay persons were tested in trial 1. The training process with audio guidance and visual feedback from a cardio compression control device (CC-Device) was recorded in trial 2. After initial debriefing for correct chest compressions (CC) with rate 85-115 min(-1), depth 3.8-5.4 cm and complete recoil, in trial 1 the lay persons were able to perform CC without feedback at mean rate 95.9 +/- 18.9 min(-1), mean depth 4.13 +/- 1.5 cm, with low proportions of 'correct depth', 'correct rate' and 'correct recoil' at 33%, 43%, 87%, resulting in the scarce proportion of 14% for compressions, which simultaneously fulfill the three quality criteria ('correct all'). In trial 2, the training process by the CC-Device was established by the significant improvement of the CC skills until the 60th second of training, when 'correct depth', 'correct rate' and 'correct recoil' attained the plateau of the highest quality at 82%, 90%, 96%, respectively, resulting in 73% 'correct all' compressions within 3 min of training. The training was associated with reduced variance of the mean rate 102.4 +/- 4.7 min(-1) and mean depth 4.3 +/- 0.4 cm, indicating a steady CC performance achieved among all trained participants. Multivariable linear regression showed that the compression depth, rate and complete chest recoil did not strongly depend on lay person age, gender, height, weight in pre-training and training stage (correlation coefficient below 0.54). The study confirmed the need for developing CPR abilities in untrained lay persons via training by real-time feedback from the instructor or CC-Device. The CC-Device embedded feedback was shown to be comprehensible and easy to be followed and interpreted. The high quality of the CC-Device-assisted training process of lay persons was confirmed. Thus learning or refresher courses in basic life support could be organized for more people trained at the same time with fewer instructors needed only for the initial debriefing and presentation of the CC-Device. PMID- 21606562 TI - Very low frequency oscillations in the power spectra of heart rate variability during dry supine immersion and exposure to non-hypoxic hypobaria. AB - The origin of very low frequency (VLF) oscillations in the power spectra of heart rate variability (HRV) is controversial with possible mechanisms involving thermoregulation and/or renin-angiotensin-aldosterone system. Recently, a major contribution from vagal influences has been suggested. The present study investigated the behaviour of VLF (0.004-0.040 Hz) components of HRV power spectra in a group of healthy male volunteers during their exposure to (1) dry, supine, immersion in thermo-neutral water for 6 h (n = 7) and (2) non-hypoxic hypobaria (breathing 40-60% oxygen at 15,000' simulated in a decompression chamber) for 5 h (n = 15). The two manoeuvres are established to increase vagal outflow. During both the manoeuvres, all the frequency domain indices of HRV exhibited a significant increase. Increase in HRV was much more than that in the R-R interval. At 6 h of immersion, the R-R interval increased by ~ 15% but the total power increased ~ fourfold. Similarly, at 5 h of exposure to hypobaria, total power increased ~ twofold with a very modest increase in an R-R of ~ 9%. Increase in spectral power was appreciable even after normalization with mean R R(2). Increase in VLF during immersion was more than reported during enalaprilat blockade of angiotensin convertase enzyme. Plasma renin activity did not vary during hypobaria. There was a significant increase in pNN50, an established marker of cardiac vagal activity. Centre frequencies of the spectra and slope (beta) of the relation between log(PSD) and log(frequency) did not change. Results were supportive of the notion that the parasympathetic system is pre potent to influence slower (than respiratory) frequency components in HRV spectrum. Additionally, such an effect was without a change in the time constant of effector responses or pacemaker frequencies of VLF and LF periodicities and HRV was not a simple linear surrogate for cardiac vagal effects. An invariance of spectral exponent (beta) ruled out contamination of VLF and LF spectra from fractal power as an alternate explanation. PMID- 21606563 TI - Structural and magnetic characterization of batch-fabricated nickel encapsulated multi-walled carbon nanotubes. AB - We report on the growth and fabrication of Ni-filled multi-walled carbon nanotubes (Ni-MWNTs) with an average diameter of 115 nm and variable length of 400 nm-1 um. The Ni-MWNTs were grown using template-assisted electrodeposition and low pressure chemical vapor deposition (LPCVD) techniques. Anodized alumina oxide (AAO) templates were fabricated on Si using a current controlled process. This was followed by the electrodeposition of Ni nanowires (NWs) using galvanostatic pulsed current (PC) electrodeposition. Ni NWs served as the catalyst to grow Ni-MWNTs in an atmosphere of H2/C2H2 at a temperature of 700 degrees C. Time dependent depositions were carried out to understand the diffusion and growth mechanism of Ni-MWNTs. Characterization was carried out using scanning electron microscopy (SEM), focused ion beam (FIB) milling, transmission electron microscopy (TEM), Raman spectroscopy and energy dispersive x-ray spectroscopy (EDX). TEM analysis revealed that the Ni nanowires possess a fcc structure. To understand the effects of the electrodeposition parameters, and also the effects of the high temperatures encountered during MWNT growth on the magnetic properties of the Ni-MWNTs, vibrating sample magnetometer (VSM) measurements were performed. The template-based fabrication method is repeatable, efficient, enables batch fabrication and provides good control on the dimensions of the Ni-MWNTs. PMID- 21606564 TI - Lipid nanocarriers (GeluPearl) containing amphiphilic lipid Gelucire 50/13 as a novel stabilizer: fabrication, characterization and evaluation for oral drug delivery. AB - PURPOSE: To evaluate the ability of Gelucire 50/13 (an amphiphilic lipid excipient) to act as a stabilizer for lipid nanocarriers such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and to establish the ability of Gelucire 50/13 based lipid nanocarriers to improve oral delivery of hydrophobic drugs using repaglinide (RPG) as a model drug. METHODS: The ability of Gelucire 50/13 to nanosize various solid lipids was evaluated. The ability of Gelucire 50/13 to yield NLC was evaluated by using Precirol ATO 5 as a model solid lipid and various liquid lipids (oils). Gelucire 50/13 based NLC (GeluPearl) were evaluated for their ability to improve the efficacy of RPG on oral administration in comparison to RPG tablets. The short term stability of RPG GeluPearl was evaluated at 25 degrees C/60% RH. RESULTS: Gelucire 50/13 could successfully yield SLN and NLC of various solid lipids, demonstrating its potential to act as a novel stabilizer. DSC studies indicated that Gelucire 50/13 interacts with Precirol ATO 5 and this interaction suppresses polymorphic transitions of both the components. RPG-GeluPearl exhibited significantly higher anti-diabetic activity compared to marketed RPG tablets. RPG-GeluPearl demonstrated good colloidal and chemical stability at the end of 1 month. PMID- 21606565 TI - RF-sputtering preparation of gold-nanoparticle-modified ITO electrodes for electrocatalytic applications. AB - The preparation of gold-nanoparticle (AuNPs)-modified indium tin oxide (ITO) electrodes (AuNPs/ITO) was performed by radio-frequency (RF) sputtering from Ar plasmas at temperatures as low as 60 degrees C, tailoring the AuNP morphology and content as a function of the sole sputtering time. The latter parameter was varied from 5 to 20 min in order to investigate the influence of gold amount and distribution on the electrochemical performances of the resulting AuNPs/ITO systems. The electrodes were characterized using field emission-scanning electron microscopy (FE-SEM), UV-vis absorption and x-ray photoelectron spectroscopies (XPS); moreover variable scan rate cyclic voltammetry (CV) studies were performed to examine their electrochemical behavior. The electrocatalytic activity of the nanostructured AuNPs/ITO electrodes toward methanol oxidation was investigated and compared with a continuous gold film (Aufilm/ITO). The catalytic efficiency of the AuNPs/ITO systems was found to increase with the gold content and the AuNPs-support boundary region in the corresponding samples. For the longest sputtering time (i.e. 20 min) the performances of the nanostructured electrode were better than the Aufilm/ITO reference, despite the much lower catalyst amount. Furthermore, conversely from the AuNPs/ITO samples, in the Au(film)/ITO case the gold film displayed a poor adhesion to the substrate and the electrode could be used only for a limited number of electrochemical cycles. PMID- 21606566 TI - Diameter-dependent coloration of silver nanowires. AB - Silver nanowires were synthesized with a green method and characterized with microscopic and diffractometric methods. The correlation between the colors of the nanowires deposited on a solid substrate and their diameters was explored. Silver nanowires that appear similar in color in the optical micrographs have very similar diameters as determined by atomic force microscopy. We have summarized the diameter-dependent coloration for these silver nanowires. An optical interference model was applied to explain such correlation. In addition, microreflectance spectra were obtained from individual nanowires and the observed spectra can be explained with the optical interference theory. This work provides a cheap, quick and simple screening method for studying the diameter distribution of silver nanowires, as well as the diameter variations of individual silver nanowires, without complicated sample preparation. PMID- 21606567 TI - Long-term stability of Alzheimer's disease biomarker proteins in cerebrospinal fluid. AB - The quantitative analysis of peptides in human cerebrospinal fluid (CSF) has become an important step in the early diagnosis of dementia, e.g., Alzheimer's disease. In search of new biomarkers for early detection and differential diagnosis of chronic neurodegenerative diseases, "biobanking" and long-term storage of human samples is increasingly important. The German Dementia Competence Network (DCN) has accomplished one of the largest biomaterial banks in this field, comprising CSF from several hundreds of patients. Since little is known about long-term stability of biomarker proteins in frozen CSF, we investigated the reliability of quantitative analysis in a total of 56 CSF samples that had been frozen for up to six years. Here, we compare a second quantitative analysis of Abeta40, Abeta42, and the total-tau protein after several years of storage at -80 degrees C with initial results obtained within six months after lumbar puncture. The second analysis was done using standard ELISAs or the newly developed Mesocale System. We found that regarding Abeta42 and total-tau, the results highly correlate with correlation coefficients of c = 0.73 and c = 0.82 respectively, while for Abeta40 the correlation coefficient was lower (c = 0.53), suggesting that Abeta40 is more vulnerable to degradation. We conclude that the quantitative analysis of the concentration of Abeta42, as well as for total-tau, in CSF in samples that have been stored for years is reliable. The determination of these biomarkers and potentially new biomarkers in CSF samples stored in large biomaterial banks assembled over many years is feasible. PMID- 21606568 TI - Cessation versus continuation of galantamine treatment after 12 months of therapy in patients with Alzheimer's disease: a randomized, double blind, placebo controlled withdrawal trial. AB - Galantamine improved symptoms in Alzheimer's disease (AD) patients after 5 to 6 months of treatment. To examine long-term outcomes, this study assessed if continuing of galantamine treatment beyond 12 months delayed further cognitive deterioration. It consisted of two phases: an open label (OL) phase (12 months), followed by a double blind, randomized, placebo controlled withdrawal phase (up to 24 months). Subjects with mild to moderate AD were included in the study and titrated up to 16 mg/day of galantamine. Subjects were eligible to enter the double blind phase if a cognitive decline of <4 points on AD Assessment Scale cognitive subscale (ADAS-cog)/11 was recorded at the end of the OL phase. The differences between galantamine and placebo in time to dropout were estimated using the Cox proportional hazard model. 47.4% of galantamine and 31.7% of placebo subjects completed the double blind phase. Placebo subjects were more likely to discontinue prematurely than galantamine subjects for any reason (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.10-2.81, p = 0.02), or lack of efficacy (HR 1.80, 95% CI 1.02-3.18, p = 0.04); no statistically significant difference was seen for a change in ADAS-cog >= 4 between treatment groups (HR 1.66, 95% CI 0.78-3.54, p = 0.19). Subjects who responded to 12 months of galantamine treatment benefited from continued drug therapy for up to 36 months. Galantamine was effective in delaying time to cognitive deterioration in subjects with mild to moderate AD. Treatment was generally safe and well tolerated. PMID- 21606569 TI - Hippocampal volume differences between healthy young apolipoprotein E epsilon2 and epsilon4 carriers. AB - The apolipoprotein E (APOE) epsilon4 allele is the major genetic risk factor for the development of late-onset Alzheimer's disease (AD), whereas the presence of the APOE epsilon2 allele seems to confer protection. Here, we report that healthy young APOE epsilon4 carriers have statistically significantly smaller hippocampal volumes than APOE epsilon2 carriers, while no differences were detected between the two groups in memory performance. The difference in hippocampal morphology is cognitively/clinically silent in young adulthood, but could render APOE epsilon4 carriers more prone to the later development of AD possibly due to lower reserve cognitive capacity. PMID- 21606570 TI - CSF tau levels influence cortical plasticity in Alzheimer's disease patients. AB - Alzheimer's disease (AD) is a neurodegenerative process characterized by progressive neuronal degeneration, reduced levels of neurotransmitters, and altered forms of synaptic plasticity. In animal models of AD, amyloid-beta (Abeta) and tau proteins are supposed to interfere with synaptic transmission. In the current study, we investigated the correlation between motor cortical plasticity, measured with 1 Hz repetitive transcranial magnetic stimulation (rTMS), and the levels of Abeta1-42, total tau (t-Tau), and phosphorylated tau (p Tau) detected in cerebrospinal fluid (CSF) of AD patients. We found that the overall rTMS after effects were milder in AD patients in comparison with controls. In AD patients the amount of rTMS-induced inhibition correlated with CSF t-Tau, but not with Abeta1-42 CSF levels. Surprisingly, higher CSF t-Tau levels were associated to a stronger inhibition of the motor evoked potentials, implying that the expected effects of the 1 Hz rTMS protocol were more evident in patients with more pathological t-Tau CSF levels. These data could be interpreted as the consequence of CSF t-Tau mediated abnormal excitatory activity and could suggest that CSF t-Tau may impact mechanisms of cortical plasticity. PMID- 21606571 TI - Imatinib mesylate alters the expression of genes related to disease progression in an animal model of uveal melanoma. AB - Imatinib mesylate (IM) is a compound that inhibits both BCR-ABL tyrosine kinase and c-kit receptors. Tyrosine kinases are important in cellular signaling and mediate major cellular processes such as proliferation, differentiation, apoptosis, attachment, and migration. Twenty-six albino rabbits were injected with 1 * 10(6) human uveal melanoma (UM) cells (92.1) into the suprachoroidal space. Animals were immunosuppressed (cyclosporin A) over the course of the 12 week experiment and divided into two groups (n = 13). The experimental group received IM once daily by gavage while the control group received a placebo. One animal per group was sacrificed every week after the 2nd week. Upon necropsy, organs were harvested for histopathological examination. Cells from the primary tumors were recultured and tested in proliferation and invasion assays. A PCR array was used to investigate the differences in expression of 84 genes related to tumor metastasis. In the treated group, 4 rabbits developed intraocular tumors, with an average largest tumor dimension (LTD) of 2.5 mm and 5 animals reported metastatic disease. Whereas 6 rabbits in the control group developed intraocular tumors, with an average LTD of 5.8 mm and 6 animals reported metastatic disease. The recultured cells from the treated group demonstrated lower proliferation rates and were less invasive (p < 0.001). The PCR array showed differences in expression of genes related to metastasis. Notably, there was 290-fold increase in SERPINB5, a tumor suppressor gene, and a 10-fold higher expression of KISS1, a metastasis suppressor gene, in the treated group. Proangiogenic genes such as VEGFA, PDGFA and PDGFB were downregulated in the treated group. To the best of our knowledge, this is the first report detailing the altered expression of specific genes in UM cells after treatment with IM. PMID- 21606572 TI - Cerebral perfusion in chronic stroke: implications for lesion-symptom mapping and functional MRI. AB - Lesion-symptom mapping studies are based upon the assumption that behavioral impairments are directly related to structural brain damage. Given what is known about the relationship between perfusion deficits and impairment in acute stroke, attributing specific behavioral impairments to localized brain damage leaves much room for speculation, as impairments could also reflect abnormal neurovascular function in brain regions that appear structurally intact on traditional CT and MRI scans. Compared to acute stroke, the understanding of cerebral perfusion in chronic stroke is far less clear. Utilizing arterial spin labeling (ASL) MRI, we examined perfusion in 17 patients with chronic left hemisphere stroke. The results revealed a decrease in left hemisphere perfusion, primarily in peri infarct tissue. There was also a strong relationship between increased infarct size and decreased perfusion. These findings have implications for lesion-symptom mapping studies as well as research that relies on functional MRI to study chronic stroke. PMID- 21606573 TI - Visuo-spatial imagery impairment in posterior cortical atrophy: a cognitive and SPECT study. AB - This study investigated the cognitive profile and the cerebral perfusion pattern in a highly educated 70 year old gentleman with posterior cortical atrophy (PCA). Visuo-perceptual abilities, spatial memory, spatial representation and navigation, visuo-spatial mental imagery, semantic and episodic-autobiographical memory were assessed. Regional cerebral blood flow (rCBF) was imaged with SPECT. Cognitive testing showed visual-perceptual impairment, apperceptive visual and landmark agnosia, topographical disorientation with way-finding deficits, impaired map learning and poor mental image generation. Semantic memory was normal, while episodic-autobiographical memory was impaired. Reduced rCBF was found mainly in the right hemisphere, in the precentral gyrus, posterior cingulate and middle temporal gyri, cuneus and precuneus, in the left superior temporal and lingual gyri and in the parahippocampus bilaterally. Hypoperfusion in occipito-parietal regions was associated with visuo-spatial deficits, whereas deficits in visuo-spatial mental imagery might reflect dysfunction related to hypoperfusion in the parahippocampus and precuneus, structures which are responsible for spatial and imagery processing. Dissociating performance between preserved semantic memory and poor episodic-autobiographical recall is consistent with a pattern of normal perfusion in frontal and anterior temporal regions but abnormal rCBF in the parahippocampi. The present findings indicate that PCA involves visuo-spatial imagery deficits and provide further validation to current neuro-cognitive models of spatial representation and topographical disorientation. PMID- 21606574 TI - Side of onset in Parkinson's disease and alterations in religiosity: novel behavioral phenotypes. AB - Behavioral neurologists have long been interested in changes in religiosity following circumscribed brain lesions. Advances in neuroimaging and cognitive experimental techniques have been added to these classical lesion-correlational approaches in attempt to understand changes in religiosity due to brain damage. In this paper we assess processing dynamics of religious cognition in patients with Parkinson's disease (PD). We administered a four-condition story-based priming procedure, and then covertly probed for changes in religious belief. Story-based priming emphasized mortality salience, religious ritual, and beauty in nature (Aesthetic). In neurologically intact controls, religious belief-scores significantly increased following the Aesthetic prime condition. When comparing effects of right (RO) versus left onset (LO) in PD patients, a double dissociation in religious belief-scores emerged based on prime condition. RO patients exhibited a significant increase in belief following the Aesthetic prime condition and LO patients significantly increased belief in the religious ritual prime condition. Results covaried with executive function measures. This suggests lateral cerebral specialization for ritual-based (left frontal) versus aesthetic based (right frontal) religious cognition. Patient-centered individualized treatment plans should take religiosity into consideration as a complex disease associated phenomenon connected to other clinical variables and health outcomes. PMID- 21606575 TI - Cognitive impairment in patients with Pseudotumor Cerebri Syndrome. AB - INTRODUCTION: Patients with Pseudotumor Cerebri Syndrome (PTCS) may complain of difficulty in thinking or concentrating; however there has been little formal cognitive evaluation in this population. OBJECTIVE: To evaluate the characteristics and nature of cognitive impairment in patients with PTCS. METHODS: We retrospectively reviewed records of 10 patients diagnosed with PTCS who were cognitively tested at presentation. In each cognitive test, "Borderline deficit" (BD) was defined as a score more than 1 standard deviation (SD) below and "Definite Deficit" (DD) as a score more than 2 SD below the mean for age, sex and education. In each cognitive domain, impairment was defined as a single test score more than 2 SD below the mean, or scores of more than 1 SD below the mean for age, sex and education in > 50% of tests. RESULTS: Mean age of patients was 43.4 +/- 13.5 years. 8/10(80%) patients were female. 3/10(30%) had papilledema; 3/10(30%) had significant cerebral venous outflow obstruction. Impairment was most commonly seen and was most severe in the WMS logical memory I (BD-44%, DD 44%), WMS logical memory II (BD-37.5%, DD-50%), RAVLT delayed recall (BD-30%, DD 40%) and RAVLT retention(BD-40%, DD-30%) tests. Evaluation of cognitive domains revealed impairment in memory and learning (80%), executive function (10%), visuo spatial skills (30%), and language (30%). CONCLUSION: Our results indicate that patients with PTCS can have significant cognitive impairment, particularly in learning and memory. The prevalence needs to be studied in a larger cohort. The relationship of cognitive impairment with chronically elevated intracranial pressures and its role in contributing to patient morbidity needs to be investigated further. PMID- 21606576 TI - Tower of London test: a comparison between conventional statistic approach and modelling based on artificial neural network in differentiating fronto-temporal dementia from Alzheimer's disease. AB - The early differentiation of Alzheimer's disease (AD) from frontotemporal dementia (FTD) may be difficult. The Tower of London (ToL), thought to assess executive functions such as planning and visuo-spatial working memory, could help in this purpose. Twentytwo Dementia Centers consecutively recruited patients with early FTD or AD. ToL performances of these groups were analyzed using both the conventional statistical approaches and the Artificial Neural Networks (ANNs) modelling. Ninety-four non aphasic FTD and 160 AD patients were recruited. ToL Accuracy Score (AS) significantly (p < 0.05) differentiated FTD from AD patients. However, the discriminant validity of AS checked by ROC curve analysis, yielded no significant results in terms of sensitivity and specificity (AUC 0.63). The performances of the 12 Success Subscores (SS) together with age, gender and schooling years were entered into advanced ANNs developed by Semeion Institute. The best ANNs were selected and submitted to ROC curves. The non-linear model was able to discriminate FTD from AD with an average AUC for 7 independent trials of 0.82. The use of hidden information contained in the different items of ToL and the non linear processing of the data through ANNs allows a high discrimination between FTD and AD in individual patients. PMID- 21606577 TI - A functional neuroimaging analysis of the Trail Making Test-B: implications for clinical application. AB - Recent progress has been made using fMRI as a clinical assessment tool, often employing analogues of traditional "paper and pencil" tests. The Trail Making Test (TMT), popular for years as a neuropsychological exam, has been largely ignored in the realm of neuroimaging, most likely because its physical format and administration does not lend itself to straightforward adaptation as an fMRI paradigm. Likewise, there is relatively more ambiguity about the neural systems associated with this test than many other tests of comparable clinical use. In this study, we describe an fMRI version of Trail Making Test-B (TMTB) that maintains the core functionality of the TMT while optimizing its use for both research and clinical settings. Subjects (N=32) were administered the Functional Trail Making Test-B (f-TMTB). Brain region activations elicited by the f-TMTB were consistent with expectations given by prior TMT neurophysiological studies, including significant activations in the ventral and dorsal visual pathways and the medial pre-supplementary motor area. The f-TMTB was further evaluated for concurrent validity with the traditional TMTB using an additional sample of control subjects (N=100). Together, these results support the f-TMTB as a viable neuroimaging adaptation of the TMT that is optimized to evoke maximally robust fMRI activation with minimal time and equipment requirements. PMID- 21606578 TI - From narcissistic personality disorder to frontotemporal dementia: a case report. AB - Premorbid personality characteristics could have a pathoplastic effect on behavioral symptoms and personality changes related to neurodegenerative diseases. Patients with personality disorders, in particular of the dramatic cluster, may present functional frontolimbic abnormalities. May these neurobiological vulnerabilities linked to a premorbid personality disorder predispose or represent a risk factor to subsequently develop a neurodegenerative disorder? Are subjects with personality disorders more at risk to develop a dementia than mentally healthy subjects? This topic is discussed presenting the clinical case of a patient who suffered of a probable Narcissistic Personality Disorder and subsequently developed a clinically diagnosed Frontotemporal Dementia. PMID- 21606579 TI - GPU-based fast low-dose cone beam CT reconstruction via total variation. AB - X-ray imaging dose from serial Cone-beam CT (CBCT) scans raises a clinical concern in most image guided radiation therapy procedures. The goal of this paper is to develop a fast GPU-based algorithm to reconstruct high quality CBCT images from undersampled and noisy projection data so as to lower the imaging dose. The CBCT is reconstructed by minimizing an energy functional consisting of a data fidelity term and a total variation regularization term. We develop a GPU friendly version of a forward-backward splitting algorithm to solve this problem. A multi-grid technique is also employed. We test our CBCT reconstruction algorithm on a digital phantom and a head-and-neck patient case. The performance under low mAs is also validated using physical phantoms. It is found that 40 x ray projections are sufficient to reconstruct CBCT images with satisfactory quality for clinical purposes. Phantom experiments indicate that CBCT images can be successfully reconstructed under 0.1 mAs/projection. Comparing with the widely used head-and-neck scanning protocol of about 360 projections with 0.4 mAs/projection, an overall 36 times dose reduction has been achieved. The reconstruction time is about 130 sec on an NVIDIA Tesla C1060 GPU card, which is estimated ~ 100 times faster than similar regularized iterative reconstruction approaches. PMID- 21606580 TI - Reconstruction from truncated projections using mixed extrapolations of exponential and quadratic functions. AB - In computer tomography (CT), truncated projections are produced due to scanning large objects with a detector that is limited in width. Applying filtered back projection(FBP) method directly to truncated projections, the reconstructed image will contain truncation artifacts - bright rings on the boundary of region of interest (ROI). Extrapolation algorithms can be used to reduce the truncation artifacts; however extrapolations are usually double the length of the projection data; resulting in an increased calculation time. This paper introduces mixed extrapolation, which is a combination of exponential and quadratic extrapolation. It is proven that doubling the length of the projection data for the mixed extrapolation can be avoided. The projections were extrapolated according to the boundary values and their derivatives. The algorithm achieves equivalence to the extrapolation approach with negligible increased calculation time. Supplementary functions are introduced in order to simplify the calculations. These functions can be calculated prior to extrapolation process, hence the calculation time is significantly reduced. The calculation times are compared between fast extrapolation introduced in this paper and normal extrapolation with doubling the length of projection data. PMID- 21606581 TI - CT gradient image reconstruction directly from projections. AB - An algorithm is proposed to directly reconstruct a CT gradient image in a region of interest(ROI). First, the central slice theorem is generalized and a differential constraint condition (DCC) is introduced in parallel-beam geometry. Then, an algorithm is developed to reconstruct the gradient images in both Cartesian and polar coordinate systems based on a two-step Hilbert transform method. Finally, the reconstruction algorithm is extended into the equi-distant fan-beam geometry. Meanwhile, a conditional truncation for projection data acquisition is permitted by using a one-dimensional(1-D) finite Hilbert transform in image domain. Because the reconstructed gradient image is in terms of local operator, it have a better performance in CT image analysis and other CT applications compared to the global Calderon operator in Lambda Tomography. PMID- 21606582 TI - The perspectives of users and developers in designing and developing O-arm imaging system. AB - A questionnaire survey was performed to investigate the different knowledge of radiation exposure, awareness and expectation for O-arm imaging system between the users (orthopaedic surgeons) and the developers (engineers). A total of 93 orthopaedic surgeons and 19 engineers participated and answered the questionnaire consisting of 18 items designed for this study. The items were focused on knowlege, awareness, and expectation. Orthopaedic surgeons had higher scores for items of knowledge domains regarding radiation exposure than the engineers while the engineers were more sensitive to radiation hazards and adopted higher levels of radiation protection than orthopaedic surgeons in the awareness domain. Most engineers and orthopaedic surgeons answered that the requirements of diagnostic and intraoperative imaging systems differ. Image resolution, a low radiation exposure, and the time required for image acquisition was the top three requirements of O-arm selected by engineers. On the other hand, the top three requirements according to orthopaedic surgeons were; image resolution, expediency, and spatial occupancy. User requirements need to be reflected in developing O-arm along with basic requirements such as image resolution and low radiation exposure. PMID- 21606583 TI - Auto-tracking system for human lumbar motion analysis. AB - Previous lumbar motion analyses suggest the usefulness of quantitatively characterizing spine motion. However, the application of such measurements is still limited by the lack of user-friendly automatic spine motion analysis systems. This paper describes an automatic analysis system to measure lumbar spine disorders that consists of a spine motion guidance device, an X-ray imaging modality to acquire digitized video fluoroscopy (DVF) sequences and an automated tracking module with a graphical user interface (GUI). DVF sequences of the lumbar spine are recorded during flexion-extension under a guidance device. The automatic tracking software utilizing a particle filter locates the vertebra-of interest in every frame of the sequence, and the tracking result is displayed on the GUI. Kinematic parameters are also extracted from the tracking results for motion analysis. We observed that, in a bone model test, the maximum fiducial error was 3.7%, and the maximum repeatability error in translation and rotation was 1.2% and 2.6%, respectively. In our simulated DVF sequence study, the automatic tracking was not successful when the noise intensity was greater than 0.50. In a noisy situation, the maximal difference was 1.3 mm in translation and 1 degrees in the rotation angle. The errors were calculated in translation (fiducial error: 2.4%, repeatability error: 0.5%) and in the rotation angle (fiducial error: 1.0%, repeatability error: 0.7%). However, the automatic tracking software could successfully track simulated sequences contaminated by noise at a density <= 0.5 with very high accuracy, providing good reliability and robustness. A clinical trial with 10 healthy subjects and 2 lumbar spondylolisthesis patients were enrolled in this study. The measurement with auto tacking of DVF provided some information not seen in the conventional X-ray. The results proposed the potential use of the proposed system for clinical applications. PMID- 21606584 TI - X-ray scattering tomography for biological applications. AB - The conventional attenuation contrast imaging does not yield satisfactory sensitivity and specificity for weakly absorbing media, such as biological soft tissues. The x-ray scattering offer an important contrast mechanism to reveal structural features and density fluctuation within an object. This scattering signal carries information at the molecular and supra-molecular level, and has a tremendous implication for biomedical and other applications. In this paper, we develop a scattering imaging approach to reconstruct the electron density distribution of an object and demonstrate its feasibility in the numerical simulation. PMID- 21606585 TI - A 2D multiresolution image reconstruction method in X-ray computed tomography. AB - We propose a multiresolution X-ray imaging method designed for non-destructive testing/evaluation (NDT/NDE) applications which can also be used for small animal imaging studies. Two sets of projections taken at different magnifications are combined and a multiresolution image is reconstructed. A geometrical relation is introduced in order to combine properly the two sets of data and the processing using wavelet transforms is described. The accuracy of the reconstruction procedure is verified through a comparison to the standard filtered backprojection (FBP) algorithm on simulated data. PMID- 21606586 TI - Application of XANES profiles to X-ray spectromicroscopy for biomedical specimens: Part I. Discrimination of macromolecules with sulfur atoms. AB - XANES spectra of biomacromolecules such as histone, hemoglobin or bovine serum albumin (BSA) were measured in transmission at the S-K absorption edge for comparison with those of sulfur containing low-molecular weight biomolecules with special reference to the dependence on the chemical environment of sulfur. The spectra of dry histone and hemoglobin exhibited a prominent peak at the same energy as that of cysteine and glutathione (GSH), while the BSA spectrum showed an additional peak at a lower energy, which coincided with that of cystine and glutathione disulfide (GSSG). XANES peaks were found at the same energy even in a mammalian cell dry pellet. Spectra in the hydrated state exhibited similar profiles except for a very slight shift of resonance peaks to the lower energy. These results indicate that XANES profiles could be applicable to the mapping of S-C and S-S bonds in dry/hydrated biological systems using a spectromicroscopic technique. In addition, mass absorption coefficients of GSH and GSSG were determined. PMID- 21606588 TI - Noncovalent functionalization of single-walled carbon nanotubes by indocyanine green: Potential nanocomplexes for photothermal therapy. AB - Indocyanine green (ICG) is a functional dye with a variety of unique photomechanical, photochemical and photobiological properties. Single-walled carbon nanotubes (SWNTs) are promising new materials being used in biological and medical fields. In this paper, we reveal that ICG can directly dissolve SWNTs without covalent chemical functionalization of the tubes or the use of surfactants in aqueous solution. The ICG-SWNT complexes have been characterized with absorption, fluorescence and Raman spectroscopy. It is demonstrated that ICG molecules that affect nanotubes properties are also altered by the presence of the SWNTs. These results provide an important evidence to better understand the pi-pi interactions between aromatic molecules and sidewalls of nanotubes. The broad absorption spectrum of ICG-SWNT complexes ranging from the UV to the near infrared (NIR) regions opens this novel nanosystem to potential applications in the cancer photothermal therapy. PMID- 21606589 TI - Immunostimulatory properties of glycated chitosan. AB - Glycated chitosan (GC) is a new compound derived from chitosan by attaching galactose molecules to the chitosan molecules. GC was designed for immune stimulations in combination with phototherapies in the cancer treatment. The future clinical applications require a thorough understanding of the properties of GC. Murine macrophage cells (RAW264.7) were used to investigate NO formation and TNFalpha secretion stimulated by GC. Murine mammary tumor cells (EMT6) were treated in vitro and in vivo by laser irradiation with 980 nm in combination with GC stimulation. Here is the first in a series of studies designed to understand the immunological mechanisms of GC. Our in vitro results show that GC could enter into macrophages to stimulate NO generation and TNFalpha secretion. GC could further enhance the TNFalpha secretion of macrophages stimulated by laser treated tumor cells. Our in vivo results also show immunological effects of GC, particularly in inducing tumor-specific immune responses. Our results indicated that GC was a strong immunological stimulant for cancer treatment, particularly when combined with laser phototherapies. PMID- 21606590 TI - Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. AB - Angiopoietin-1/Tek signaling is a critical regulator of blood vessel development, with conventional knockout of angiopoietin-1 or Tek in mice being embryonically lethal due to vascular defects. In addition, angiopoietin-1 is thought to be required for the stability of mature vessels. Using a Cre-Lox conditional gene targeting approach, we have studied the role of angiopoietin-1 in embryonic and adult vasculature. We report here that angiopoietin-1 is critical for regulating both the number and diameter of developing vessels but is not required for pericyte recruitment. Cardiac-specific knockout of angiopoietin-1 reproduced the phenotype of the conventional knockout, demonstrating that the early vascular abnormalities arise from flow-dependent defects. Strikingly, deletion in the entire embryo after day E13.5 produced no immediate vascular phenotype. However, when combined with injury or microvascular stress, angiopoietin-1 deficiency resulted in profound organ damage, accelerated angiogenesis, and fibrosis. These findings redefine our understanding of the biological roles of angiopoietin-1: it is dispensable in quiescent vessels but has a powerful ability to modulate the vascular response after injury. PMID- 21606591 TI - Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. AB - Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy. PMID- 21606592 TI - Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism. AB - Probiotic bacteria can potentially have beneficial effects on the clinical course of several intestinal disorders, but our understanding of probiotic action is limited. We have identified a probiotic bacteria-derived soluble protein, p40, from Lactobacillus rhamnosus GG (LGG), which prevents cytokine-induced apoptosis in intestinal epithelial cells. In the current study, we analyzed the mechanisms by which p40 regulates cellular responses in intestinal epithelial cells and p40's effects on experimental colitis using mouse models. We show that the recombinant p40 protein activated EGFR, leading to Akt activation. Activation of EGFR by p40 was required for inhibition of cytokine-induced apoptosis in intestinal epithelial cells in vitro and ex vivo. Furthermore, we developed a pectin/zein hydrogel bead system to specifically deliver p40 to the mouse colon, which activated EGFR in colon epithelial cells. Administration of p40-containing beads reduced intestinal epithelial apoptosis and disruption of barrier function in the colon epithelium in an EGFR-dependent manner, thereby preventing and treating DSS-induced intestinal injury and acute colitis. Furthermore, p40 activation of EGFR was required for ameliorating colon epithelial cell apoptosis and chronic inflammation in oxazolone-induced colitis. These data define what we believe to be a previously unrecognized mechanism of probiotic-derived soluble proteins in protecting the intestine from injury and inflammation. PMID- 21606593 TI - Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling. AB - The adipocyte-derived hormone adiponectin signals from the fat storage depot to regulate metabolism in peripheral tissues. Inversely correlated with body fat levels, adiponectin reduction in obese individuals may play a causal role in the symptoms of metabolic syndrome. Adiponectin lowers serum glucose through suppression of hepatic glucose production, an effect attributed to activation of AMPK. Here, we investigated the signaling pathways that mediate the effects of adiponectin by studying mice with inducible hepatic deletion of LKB1, an upstream regulator of AMPK. We found that loss of LKB1 in the liver partially impaired the ability of adiponectin to lower serum glucose, though other actions of the hormone were preserved, including reduction of gluconeogenic gene expression and hepatic glucose production as assessed by euglycemic hyperinsulinemic clamp. Furthermore, in primary mouse hepatocytes, the absence of LKB1, AMPK, or the transcriptional coactivator CRTC2 did not prevent adiponectin from inhibiting glucose output or reducing gluconeogenic gene expression. These results reveal that whereas some of the hormone's actions in vivo may be LKB1 dependent, substantial LKB1-, AMPK-, and CRTC2-independent signaling pathways also mediate effects of adiponectin. PMID- 21606595 TI - Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice. AB - Leptin is an adipose-derived hormone that signals to inform the brain of nutrient status; loss of leptin signaling results in marked hyperphagia and obesity. Recent work has identified several groups of neurons that contribute to the effects of leptin to regulate energy balance, but leptin receptors are distributed throughout the brain, and the function of leptin signaling in discrete neuronal populations outside of the hypothalamus has not been defined. In the current study, we produced mice in which the long form of the leptin receptor (Lepr) was selectively ablated using Cre-recombinase selectively expressed in the hindbrain under control of the paired-like homeobox 2b (Phox2b) promoter (Phox2b Cre Lepr(flox/flox) mice). In these mice, Lepr was deleted from glucagon-like 1 peptide-expressing neurons resident in the nucleus of the solitary tract. Phox2b Cre Lepr(flox/flox) mice were hyperphagic, displayed increased food intake after fasting, and gained weight at a faster rate than wild type controls. Paradoxically, Phox2b Cre Lepr(flox/flox) mice also exhibited an increased metabolic rate independent of a change in locomotor activity that was dependent on food intake, and glucose homeostasis was normal. Together, these data support a physiologically important role of direct leptin action in the hindbrain. PMID- 21606594 TI - Adenovirus-mediated HIF-1alpha gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection. AB - Chronic rejection, manifested as small airway fibrosis (obliterative bronchiolitis [OB]), is the main obstacle to long-term survival in lung transplantation. Recent studies demonstrate that the airways involved in a lung transplant are relatively hypoxic at baseline and that OB pathogenesis may be linked to ischemia induced by a transient loss of airway microvasculature. Here, we show that HIF-1alpha mediates airway microvascular repair in a model of orthotopic tracheal transplantation. Grafts with a conditional knockout of Hif1a demonstrated diminished recruitment of recipient-derived Tie2+ angiogenic cells to the allograft, impaired repair of damaged microvasculature, accelerated loss of microvascular perfusion, and hastened denudation of epithelial cells. In contrast, graft HIF-1alpha overexpression induced via an adenoviral vector prolonged airway microvascular perfusion, preserved epithelial integrity, extended the time window for the graft to be rescued from chronic rejection, and attenuated airway fibrotic remodeling. HIF-1alpha overexpression induced the expression of proangiogenic factors such as Sdf1, Plgf, and Vegf, and promoted the recruitment of vasoreparative Tie2+ cells. This study demonstrates that a therapy that enhances vascular integrity during acute rejection may promote graft health and prevent chronic rejection. PMID- 21606596 TI - Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice. AB - The mutations that cause Leber congenital amaurosis (LCA) lead to photoreceptor cell death at an early age, causing childhood blindness. To unravel the molecular basis of LCA, we analyzed how mutations in LCA5 affect the connectivity of the encoded protein lebercilin at the interactome level. In photoreceptors, lebercilin is uniquely localized at the cilium that bridges the inner and outer segments. Using a generally applicable affinity proteomics approach, we showed that lebercilin specifically interacted with the intraflagellar transport (IFT) machinery in HEK293T cells. This interaction disappeared when 2 human LCA associated lebercilin mutations were introduced, implicating a specific disruption of IFT-dependent protein transport, an evolutionarily conserved basic mechanism found in all cilia. Lca5 inactivation in mice led to partial displacement of opsins and light-induced translocation of arrestin from photoreceptor outer segments. This was consistent with a defect in IFT at the connecting cilium, leading to failure of proper outer segment formation and subsequent photoreceptor degeneration. These data suggest that lebercilin functions as an integral element of selective protein transport through photoreceptor cilia and provide a molecular demonstration that disrupted IFT can lead to LCA. PMID- 21606597 TI - mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. AB - Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was enhanced in the podocytes of diabetic animals. Further, podocyte-specific mTORC1 activation induced by ablation of an upstream negative regulator (PcKOTsc1) recapitulated many DN features, including podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in nondiabetic young and adult mice. Abnormal mTORC1 activation caused mislocalization of slit diaphragm proteins and induced an epithelial-mesenchymal transition-like phenotypic switch with enhanced ER stress in podocytes. Conversely, reduction of ER stress with a chemical chaperone significantly protected against both the podocyte phenotypic switch and podocyte loss in PcKOTsc1 mice. Finally, genetic reduction of podocyte-specific mTORC1 in diabetic animals suppressed the development of DN. These results indicate that mTORC1 activation in podocytes is a critical event in inducing DN and suggest that reduction of podocyte mTORC1 activity is a potential therapeutic strategy to prevent DN. PMID- 21606598 TI - The human visual cortex responds to gene therapy-mediated recovery of retinal function. AB - Leber congenital amaurosis (LCA) is a rare degenerative eye disease, linked to mutations in at least 14 genes. A recent gene therapy trial in patients with LCA2, who have mutations in RPE65, demonstrated that subretinal injection of an adeno-associated virus (AAV) carrying the normal cDNA of that gene (AAV2 hRPE65v2) could markedly improve vision. However, it remains unclear how the visual cortex responds to recovery of retinal function after prolonged sensory deprivation. Here, 3 of the gene therapy trial subjects, treated at ages 8, 9, and 35 years, underwent functional MRI within 2 years of unilateral injection of AAV2-hRPE65v2. All subjects showed increased cortical activation in response to high- and medium-contrast stimuli after exposure to the treated compared with the untreated eye. Furthermore, we observed a correlation between the visual field maps and the distribution of cortical activations for the treated eyes. These data suggest that despite severe and long-term visual impairment, treated LCA2 patients have intact and responsive visual pathways. In addition, these data suggest that gene therapy resulted in not only sustained and improved visual ability, but also enhanced contrast sensitivity. PMID- 21606599 TI - The targeted podocyte. AB - The podocyte plays a key role both in maintenance of the glomerular filtration barrier and in glomerular structural integrity. Podocyte injury and loss contribute to proteinuria and progressive sclerosis. Inhibitors of mammalian target of rapamycin (mTOR) have variably decreased or caused proteinuria and sclerosis in human disease and experimental settings. In this issue of the JCI, two interesting studies of podocyte-specific manipulation of the mTOR system shed light on the complexity of this pathway in the podocyte. PMID- 21606600 TI - The yin, the yang, and the angiopoietin-1. AB - Twenty years after the discovery of the vascular endothelial Tie receptor tyrosine kinases and 15 years after the discovery of the Tie2 ligand, angiopoietin-1 (Angpt1, also known as Ang1), a study published in the current issue of the JCI reveals an unexpected loss-of-function phenotype of mice conditionally deleted of the Angpt1 gene. The results suggest that Angpt1 is needed as a vascular stabilizing factor that organizes and limits the angiogenesis response and protects from pathological consequences, such as tissue fibrosis. PMID- 21606601 TI - Spotlight on childhood blindness. AB - Leber congenital amaurosis (LCA) is a rare disease that severely affects vision in early life. It is characterized by genetic and clinical heterogeneity due to complex and not fully understood pathogenetic mechanisms. It is also now widely known as a disease model for gene therapy. In this issue of the JCI, two independent research groups report valuable new data on LCA. Specifically, they provide important insights into the pathophysiological mechanisms of LCA and offer strong hope that the outcome of gene therapy for retinal degenerative diseases will be successful. PMID- 21606602 TI - Neuroanatomy of body weight control: lessons learned from leptin. AB - Rather than arising from the passive accumulation of excess calories, obesity is a state in which the biologically defended level of body fat stores increases due to defects in the homeostatic process that matches food intake and energy expenditure over time. By deleting leptin receptors from distinct brain regions and neuronal subsets, researchers are beginning to identify the neuroanatomical substrates responsible for this regulation. In this issue of the JCI, Scott et al. demonstrate that loss of leptin receptors in a subset of hindbrain neurons increases food intake in mice, but, unlike what is observed when leptin receptors are deleted from hypothalamic neurons, these mice compensate by increasing energy expenditure and hence do not become obese. Although many brain areas can regulate energy intake and/or energy expenditure, it is likely that only a small subset of neurons actively matches the two over time. It is vital to clarify how this works if we are to improve our understanding of obesity pathogenesis and options available for its treatment. PMID- 21606603 TI - Chronic lung allograft rejection and airway microvasculature: is HIF-1 the missing link? AB - Chronic lung allograft rejection, known as obliterative bronchiolitis (OB), is the leading cause of death in lung transplant patients. Although OB pathogenesis is not fully understood, in this issue of the JCI, Jiang and colleagues report that tissue hypoxia resulting in dysfunctional airway microvasculature precedes the airway fibrosis characteristic of OB. In addition, a relative deficiency of allograft endothelial cell-derived HIF-1alpha contributes to this process. Data showing that overexpressing HIF-1alpha restores the microvascular airway normoxia and prevents airway fibrosis highlight a novel role for vascular biology in OB pathogenesis. PMID- 21606604 TI - From probiotics to therapeutics: another step forward? AB - Preclinical studies with probiotics continue to unravel mechanisms of cytoprotection and suggest that approaches utilizing microbial products as therapeutics in acute and chronic gastrointestinal disorders could be effective. However, clinical trials using these bacteria have thus far been inconsistent. In this issue of the JCI, Yan et al. describe a novel mechanism of cytoprotection by p40, a soluble product of Lactobacillus rhamnosus GG, mediated via EGFR. The efficacy of p40 in three models of chemically induced colitis indicates tremendous therapeutic potential, though this finding will need to be verified in human patients. PMID- 21606605 TI - Prediction of human pharmacokinetics of therapeutic monoclonal antibodies from simple allometry of monkey data. AB - Interspecies allometric scaling is a useful tool for calculating human pharmacokinetic (PK) parameters from data in animals. In this study, in order to determine the scaling exponent in a simple allometric equation that can predict human clearance (CL) and distribution volume at steady state (Vss) of monoclonal antibodies (mAbs) from monkey data alone, PK data of 24 mAbs were collected and analyzed according to the types of targeted antigens (soluble or membrane-bound antigens). Based on the observed PK data in humans (at clinical doses) and monkeys (at >1 mg/kg), where the PK is expected to be linear, the mean scaling exponents in the allometric equation for CL and Vss, respectively, against body weight were calculated to be 0.79 and 1.12 [95% confidence intervals (CIs): 0.69 0.89 and 0.96-1.28] for soluble antigens, and 0.96 and 1.00 (95% CIs: 0.83-1.09 and 0.87-1.13) for membrane-bound antigens. Using these exponents and monkey PK data (at >1 mg/kg) alone, both human CL and Vss of mAbs can be predicted with reasonable accuracy, i.e., within 2-fold of the observed values. Compared with traditional allometric scaling using PK data from three or more preclinical species, this approach is simple, quick, resource-saving, and useful in drug discovery and development. PMID- 21606606 TI - Novel single nucleotide polymorphism of the CYP2A13 gene in Japanese individuals. AB - Cytochrome P450 2A13 (CYP2A13) is a human CYP enzyme that is selectively expressed in the respiratory tract. It plays an active role in the metabolic activation of a tobacco-specific procarcinogen. In this study, the entire coding sequence and the exon-intron junctions of the CYP2A13 gene obtained from 395 Japanese individuals were screened for genetic polymorphisms. Eight genetic polymorphisms were found, of which seven gave rise to known variant alleles: CYP2A13*2, CYP2A13*3, CYP2A13*4, CYP2A13*6, and CYP2A13*7. We identified a novel single nucleotide polymorphism (SNP), 5792T>C, in exon 7 that caused an amino acid substitution (Ile331Thr). One of the 395 individuals included in the study was heterozygous for the variant allele, and therefore, the frequency of the allele in the study population was 0.13%. PMID- 21606607 TI - Predictive power of self-rated health for subsequent mortality risk during old age: analysis of data from a nationally representative survey of elderly adults in Taiwan. AB - BACKGROUND: Previous research has investigated differences in the predictive power of self-rated health (SRH) for mortality based on socioeconomic status (SES). However, these studies mainly assessed adults in the general population and did not focus specifically on elderly adults. In addition, this predictive power has never been evaluated using subjective SES, which is an important measure of SES in elderly adults. METHODS: This study used data from the Survey of the Health and Living Status of the Middle Aged and the Elderly in Taiwan (SHLS) conducted by the Bureau of Health Promotion, Taiwan. The SHLS is a 15-year longitudinal survey based on a nationally representative sample. It was initiated in 1989 with 4049 respondents aged 60 years or older. Both education and subjective financial satisfaction were used as SES measures in the present study. A Cox regression model was used to estimate the interaction between SRH and SES for 3829 individuals without missing data. RESULTS: As compared with those who reported their health as good, those who reported their health as poor and their education as high had a higher hazard ratio (hazard ratio = 1.97, 95% confidence interval = 1.35-2.88) for 6-15-year mortality, after adjusting for depressive symptoms, activities of daily living, and instrumental activities of daily living. This HR was significantly higher than those for adults with middle (1.16, 0.93-1.44) and low (1.27, 1.05-1.54) education, based on the chi(2) test (P < 0.05 for both comparisons). A similar pattern was observed when financial satisfaction was used as the SES measure. However, the pattern was attenuated when using 5-year mortality from baseline. CONCLUSIONS: The use of SRH as a single health measure in elderly adults may yield inconsistent results across different SES groups, especially when used as a predictor of a longer-term mortality. This is true regardless of whether objective or subjective measures of SES are used, where both are important measures of SES in elderly adults. PMID- 21606608 TI - Three novel species of the anamorphic yeast genus Candida in the Candida intermedia clade found in Japan, Thailand and Taiwan. AB - Four strains of yeasts isolated in Japan, Thailand and Taiwan were found to represent three novel species of the genus Candida. The three species are located in a clade including Candida tsuchiyae, Candida thailandica and Candida akabanensis in a tree based on the D1/D2 domain sequences of the large subunit rRNA genes but clearly differentiated from these relative species. Three novel species are proposed for these strains, i. e., Candida berkhoutiae sp. nov., for strains ST-49(T) (=BCC 7749(T)=NBRC 106733(T)=CBS 11722(T)) isolated from insect frass in Thailand and SA13S01 (=NBRC 106053) isolated from soil in Taiwan, Candida ezoensis sp. nov., for strain Y07-1601-2(T) (=NBRC 105019(T)=CBS 11753(T)) isolated from forest soil in Japan, and Candida inulinophila sp. nov., for ST-369(T) (=BCC 15081(T)=NBRC 106735(T)=CBS 11725(T)) isolated from an unidentified wild mushroom from Thailand. PMID- 21606609 TI - Geobacillus thermodenitrificans subsp. calidus, subsp. nov., a thermophilic and alpha-glucosidase producing bacterium isolated from Kizilcahamam, Turkey. AB - An alpha-glucosidase producing, thermophilic, facultatively anaerobic, and endospore-forming, motile, rod-shaped bacterial strain F84b(T) was isolated from a high temperature well-pipeline sediment sample in Kizilcahamam, Turkey. The growth occurred at temperatures, pH and salinities ranging from 45 to 69oC (optimum 60oC), 7.0 to 8.5 (optimum 8.0) and 0 to 5% (w/v) (optimum 3.5%), respectively. Strain F84b(T) was able to grow on a wide range of carbon sources. Starch and tyrosine utilization, amylase, catalase and oxidase activities, nitrate reduction, and gas production from nitrate were all positive. The G+C content of the genomic DNA was 49.6 mol%. The menaquinone content was MK-7. The dominant cellular fatty acids were iso-C17:0, iso-C15:0, and C16:0. In phylogenetic analysis of 16S rRNA gene sequence, strain F84b(T) showed high sequence similarity to Geobacillus thermodenitrificans (99.8%) and to Geobacillus subterraneus (99.3%) with DNA hybridization values of 74.3% and 29.1%, respectively. In addition, the Rep-PCR and the intergenic 16S-23S rRNA gene fingerprinting profiles differentiated strain F84b(T) from the Geobacillus species studied. The results obtained from the physiological and biochemical characters, the menaquinone contents, the borderline DNA-DNA hybridization homology, and the genomic fingerprinting patterns had allowed phenotypic, chemotaxonomic and genotypic differentiation of strain F84b(T) from G. thermodenitrificans. Therefore, strain F84b(T) is assigned to be a new subspecies of G. thermodenitrificans, for which the name Geobacillus thermodenitrificans subsp. calidus, subsp. nov. is proposed (The type strain F84b(T) = DSM 22629(T) = NCIMB 14582(T)). PMID- 21606610 TI - Saccharopolyspora pathumthaniensis sp. nov., a novel actinomycetes isolated from termite guts (Speculitermes sp.). AB - Morphological and chemotaxonomic characterization of actinomycete strain S582 isolated from the gut of a termite (Speculitermes sp.) in Pathum Thani Province, Thailand, clearly demonstrated that this strain is a member of the genus Saccharopolyspora. 16S rDNA sequence analysis for the strain supported the assignment of the strain to the genus Saccharopolyspora. The similarity value of sequences between this strain and the closely related species Saccharopolyspora endophytica was 99.5%. The DNA G+C content was 70.2 mol%. DNA-DNA hybridization results (53.3%) and some physiological and biochemical properties indicated that strain S582(T) was distinguished from the phylogenetically closest relatives. Based on these genotypic and phenotypic data, strain S582(T) should be a new species in the genus Saccharopolyspora and the name Saccharopolyspora pathumthaniensis sp. nov. is proposed for the strain. The type strain is S582(T) (=NBRC 104112(T) =BCC 28624(T)). PMID- 21606611 TI - Genetic and functional heterogeneities among fluorescent Pseudomonas isolated from environmental samples. AB - Fluorescent Pseudomonas from diverse environmental samples including wastes were identified and screened for the solubilization of tricalcium phosphate, indole-3 acetic acid (IAA), production and inhibition of extracellular N-acylhomoserine lactone (AHLs) and characterized for their siderophores. Genotypic analysis by amplified rDNA restriction analysis (ARDRA) and BOX-A1R-based repetitive extragenic palindromic-PCR (BOX-PCR) typing resulted respectively in 14 ARDRA types and 24 different BOX-types with diverse incidence among the analyzed strains. Based on 16S rRNA sequence analysis the isolates were assigned to P. aeruginosa, P. otitidis, P. plecoglossicida, P. mosselii, P. monteilii, P. koreensis, P. taiwanenesis, P. frederiksbergensis and P. graminis. Of the 66 isolates, 56 (84.85%) isolates solubilized tri-calcium phosphate (TCP), 53 (80.30%) isolates produced plant growth hormone IAA, 62 (94%) produced bacteriocin and 34 (52%) isolates produced extracellular N-acylhomoserine lactone while 30 (45%) isolates were able to interfere with N-acylhomoserine lactone. Isolates were clustered into 17 siderotypes and (59)Fe cross-incorporation experiments permitted assignment of all siderotypes but two into well-defined siderovars. PMID- 21606613 TI - Nanoarchaeum equitans failed to maintain the balance between DNA stability and melting potential. PMID- 21606612 TI - Salmonella typhimurium harboring plasmid expressing interleukin-12 induced attenuation of infection and protective immune responses. AB - IL-12 is known to be an essential cytokine which appears to provide protective immunity against intracellular bacteria, such as Salmonella. In this study, we investigated the possibility of developing a vaccine using IL-12 against virulent Salmonella. We used the host defense system activated by cytokine IL-12. The highly virulent Salmonella strain (Salmonella typhimurium UK-1) was transformed with cytokine-expressing plasmids. These live, wild-type pathogens were used as vaccine strains without undergoing any other biological or genetic attenuating processes. The newly developed strains induced partial protection from infections (30-40%). Of note, the interleukin-12-transformed pathogen was safe upon immunization with low doses (10(3) cfu), induced IgG responses, and stimulated protective immune responses against Salmonella typhimurium in mice (80-100%). These results suggest that IL-12 induced attenuation of wild-type Salmonella in the host infection stage and vaccine development using the wild-type strain harboring plasmid-secreting IL-12 may be considered as an alternative process for intracellular bacterial vaccine development without the inconvenience of time consuming attenuation processes. PMID- 21606614 TI - Enzymatic synthesis of capric acid-rich structured lipids (MUM type) using Candida antarctica lipase. AB - The objective of the work was to produce capric acid rich structured lipids starting from various Indian indigenous vegetable oils, such as rice bran, ground nut and mustard oils. Acidolysis reaction between individual vegetable oils and capric acid in one is to three molar ratios at 45 degree centigrade temperature was carried out using position specific Candida antarctica lipase so as to protect the Sn-2 position of the oils which are rich in unsaturated fatty acids. The incorporation of capric acid depended on the reaction time showing 6 % within 6 h and 30.8 % in 72 h with rice bran oil. Similarly, in ground nut oil incorporation of capric acid was 34.2 % in 72 h compared to 5.3 % in 6 h. Thus mustard oil showed much lower incorporation than the other two oils, with 3.3 % and 19.5 % in 6 and 72 h respectively. The incorporation of capric acid was influenced by the nature of the fatty acids present in the original oil. The fatty acid composition of Sn-2 position of the structured triacylglycerols of the three oils revealed that capric acid was mainly replacing the fatty acids occupying the Sn-1 and 3 positions of the triglyceride molecule. PMID- 21606615 TI - Enzymatic synthesis of phenyl fatty hydroxamic acids from canola and palm oils. AB - Phenyl fatty hydroxamic acids (PFHAs) were synthesized from canola or palm oils and phenyl hydroxylamine (FHA) catalyzed by Lipozyme TL IM or RM IM. The reaction was carried out by shaking the reaction mixture at 120 rpm. The optimization was carried out by changing the reaction parameters, namely; temperature, organic solvent, amount and kind of enzyme, period of reaction and the mol ratio of reactants. The highest conversion was obtained when the reaction was carried out under the following conditions: temperature, 39 degrees C; solvent, petroleum ether; kind and amount of lipase, 80 mg Lipozyme TL IM/mmol oil; reaction period, 72 h and FHA-oil ratio, 7.3 mmol FHA/ mmol oil. The highest conversion percentage of phenyl hydroxylaminolysis of the Ladan and Kristal brands commercial canola oils, palm stearin and palm kernel oils were 55.6, 52.2, 51.4 and 49.7 %, respectively. PMID- 21606616 TI - Crystallization of fully hydrogenated and interesterified fat and vegetable oil. AB - Owing to public concern regarding the adverse health effects of trans fatty acids, an alternative technology to trans fats has recently become an important issue. The interesterification of fully hydrogenated vegetable oil and liquid oil blends is one of the most versatile options. This paper reports a physical analysis of high-melting fat (HMF) prepared through the interesterification of fully hydrogenated soybean oil and regular soybean oil, and through fractionation. The thermal and structural properties of the HMF blended with salad oil at a mass ratio of 4:1 (called the HMF blend, hereafter), which was prepared as a model fat blend for margarine, were assessed using X-ray diffraction (XRD), differential scanning calorimetry (DSC), and polarized light microscopy (POM). To observe the polymorphic transformation, all samples were aged after crystallization, and the development of granular crystals during the aging process was observed. We found that the granular crystals are made of SOS/SSO, POS/PSO, and (SOS+POS)/(SSO+PSO) molecular compounds, all of which easily transform into beta form with a double-chain-length structure. PMID- 21606617 TI - Esterification of fatty acid over Tunisian acid activated clay: kinetic study. AB - Tunisian acid activated clay was investigated as catalyst in the esterification of stearic acid with ethyl alcohol, carried out in a semi-continuous reactor. Kinetic study shows that the reaction is first order with respect to acid concentration. The activation energy found was 21 kJ/mol. This result suggests that the reaction process was controlled by a diffusional step. A kinetic model, giving the apparent constant rate as a function of temperature and catalyst concentration, has been established. This equation has been then successfully applied for a complex mixture of fatty acid. PMID- 21606618 TI - Genetic variation in Mexican Jatropha curcas L. estimated with seed oil fatty acids. AB - The genetic diversity of Mesoamerican populations of the biofuel plant Jatropha curcas, using the fatty acids of the seeds as chemical markers was studied. The oil content of the whole seed in 135 accessions from 38 sites varied between 8.020% and 54.28%. The prevalent fatty acids were oleic acid (18:1) and linoleic acid (18:2), and the proportion of unsaturated fatty acids varied between 74.5% and 83.7%. A study with cloned plants grown in common garden showed that both the content of oil as well as the proportion of fatty acids are highly inheritable, therefore these chemical markers are valid for estimating the genetic diversity of the species. An analysis of principal components showed that the fatty acids that contribute more to the variance are stearic, oleic, linoleic, methylpalmitic, gadoleic and ricinoleic. The populations were classified in ten groups when the data were analyzed for fatty acids by analysis of clusters, showing the elevated genetic variation in natural populations of this native species of Mesoamerica. A discriminant analysis separated the populations in accordance with their geographic origin, which was verified with a Mantel test. Using the Monmonier's algorithm two genetic barriers between the populations were identified. The results are discussed in light of their microevolutionary significance. PMID- 21606619 TI - Stability of sucrose fatty acid esters under acidic and basic conditions. AB - The stability of sucrose fatty acid monoesters toward hydrolysis under acidic and basic conditions was evaluated. Mass spectrometric analysis of hydrolysates showed that the glycosidic bond was preferentially hydrolyzed under acidic conditions, whereas the ester bond was selectively hydrolyzed under basic conditions. Under both conditions, the rate of hydrolysis depended on the pH of the solution, the concentration of sucrose monoesters, and the acylated position of the sucrose monoesters. The hydrolysis of the glycosidic bond under acidic conditions was shown to be a first-order process. The rate constants for hydrolysis at various temperatures were measured, and the activation energies were calculated from the slope of the Arrhenius plots. The lifetime of sucrose monoesters estimated from the first-order rate constant for the hydrolysis reaction revealed that the sucrose monoesters have excellent long-term stability over a pH range of 5 to 7 at room temperature. PMID- 21606620 TI - Inhibitory effect of topical maize glucosylceramide on skin photoaging in UVA irradiated hairless mice. AB - We investigated the effect of topical application of the glucosylceramide prepared from maize on photoaged mice. Six-week-old hairless female mice were swabbed on the back with glucosylceramide solution or vehicle, following UVA irradiation for 9 weeks. Wrinkle formation was evaluated at 3, 6, and 9 weeks by skin replica analysis by using a three-dimensional (3-D) imaging system. Moreover, epidermal thickness was analyzed at the end of the experiment. Topical application of glucosylceramide significantly reduced UVA-induced wrinkle formation in the skin as well as epidermal hypertrophy. These results suggest that topical glucosylceramide has an inhibitory effect on UVA-induced photoaging. PMID- 21606621 TI - Synthesis and evaluation of dioleoyl glyceric acids showing antitrypsin activity. AB - Previously, Lesova et al. reported the isolation and identification of metabolite OR-1, showing antitrypsin activity, produced during fermentation by Penicillium funiculosum. The structure of OR-1 was a mixture of glyceric acid (GA), esterified with C(14)-C(18) fatty acids, and oleic acid (C18:1) as the most predominant fatty acid (Folia Microbiol. 46, 21-23, 2001). In this study, dioleoyl D-GA and dioleoyl L-GA were synthesized via diesterification with oleoyl chloride, and their antitrypsin activities were evaluated using both a disk diffusion method and spectral absorption measurements. The results show that both compounds and their equivalent mixtures possess antitrypsin activities; however, their IC(50) values (approximately 2 mM) are much higher than that of OR-1 (4.25 uM), suggesting that dioleoyl GA does not play a major role in the OR-1 antitrypsin activity. PMID- 21606622 TI - Neuropsychotoxic and neuroprotective potentials of dextromethorphan and its analogs. AB - Dextromethorphan (3-methoxy-17-methylmorphinan) has complex pharmacologic effects on the central nervous system. Although some of these effects are neuropsychotoxic, this review focuses on the neuroprotective effects of dextromethorphan and its analogs. Some of these analogs, particularly dimemorfan (3-methyl-17-methylmorphinan) and 3-hydroxymorphinan, have promising neuroprotective properties with negligible neuropsychotoxic effects. Their neuroprotective effects, the mechanisms underlying these effects, and their therapeutic potential for the treatment of diverse neurodegenerative disorders are discussed. PMID- 21606623 TI - Neuroprotective and ameliorative actions of polyunsaturated fatty acids against neuronal diseases - evidence from basic to clinical studies: preface. PMID- 21606624 TI - Anti-osteoporosis effect of 5-bromo-2-(4-chlorobenzoyl)-(Z)-3-(2-cyano-3 hydroxybut-2-enonyl)aminobenzo[b]furan: a novel selective estrogen receptor modulator. AB - The benzo[b]furan derivative MU314 inhibits in vitro bone resorption as potently as beta-estradiol (E(2)). Here, we examined the point of action on the anti osteoporotic effects of MU314. MU314 (10 nM) suppressed lacunae formation by osteoclastic cells and ICI-182,780, a pure E(2) antagonist, inhibited this effect. Specifically, we ovariectomized (OVX) Wistar female rats and subcutaneously injected them with either MU314 (30 or 100 ug/kg) or E(2) (100 ug/kg) over an 8-week period. Bone mineral content (BMC) in the proximal end of the tibia was significantly decreased (14%) in OVX rats, and MU314 (100 ug/kg) and E(2) significantly suppressed the decline in BMC. OVX rats exhibited decreased cancellous bone in the proximal end of the tibia and induced destruction of its trabecular structure. MU314 suppressed these changes. OVX also reduced the mechanical strength of the femoral neck, which was also recovered by MU314 and E(2). E(2) completely protected against OVX-induced uterine atrophy, but MU314 had no effect. These results strongly indicate that MU314 acts as a selective estrogen receptor modulator. PMID- 21606625 TI - Effects of flavonoids on matrix metalloproteinase-13 expression of interleukin 1beta-treated articular chondrocytes and their cellular mechanisms: inhibition of c-Fos/AP-1 and JAK/STAT signaling pathways. AB - To identify the therapeutic potential for cartilage degradation and its action mechanisms, the effects of naturally-occurring flavonoids on matrix metalloproteinase-13 (MMP-13) induction were examined in the human chondrocyte cell line SW1353. Flavones including apigenin and wogonin strongly inhibited MMP 13 induction in interleukin (IL)-1beta-treated SW1353 cells, while flavonols such as kaempferol, quercetin, and flavanone (naringenin) did not at 5 - 25 uM. Apigenin and wogonin primarily inhibit MMP-13 by blocking the c-Fos / activator protein-1 (AP-1) and Janus kinase 2 (JAK2) / signal transducer and activator of transcription 1/2 (STAT1/2) pathways, but not nuclear factor-kappaB (NF-kappaB) signaling. Apigenin was also shown to inhibit extracellular matrix degradation in rabbit cartilage culture. The following study using some synthetic flavones demonstrated that A-ring C-5,7-dihydroxyl and B-ring dihydroxyl substitution at C 2,3, C-2,4, or C-3,4 are important for the suppression of MMP-13 expression. Among these flavones, 2',3',5,7-tetrahydroxyflavone also inhibited both the c Fos/AP-1 and STAT1/2 pathways. Taken together, these results indicate that certain flavonoids, especially flavones, inhibit MMP-13 expression in IL-1beta treated chondrocytes, at least in part, by suppressing the c-Fos/AP-1 and JAK2/STAT1/2 pathways. Furthermore, these findings suggest that some flavonoids have the potential for protecting against collagen matrix breakdown in the cartilage of diseased tissues such as those found in arthritic disorders. PMID- 21606626 TI - Neuroprotective and ameliorative actions of polyunsaturated fatty acids against neuronal diseases: implication of fatty acid-binding proteins (FABP) and G protein-coupled receptor 40 (GPR40) in adult neurogenesis. AB - Adult neurogenesis in the mammalian brain is well-known to occur in the subgranular zone of the hippocampus. As the hippocampus is related to learning, memory, and emotions, adult hippocampal neurogenesis possibly contributes to these functions. Adult neurogenesis is modulated by polyunsaturated fatty acids (PUFA) such as docosahexaenoic and arachidonic acids that are essential for normal brain development, maintenance, and function. They are reported to improve spatial learning and memory in rodents and cognitive functions in humans. However, detailed mechanisms of PUFA effects still remain obscure. PUFA are functionally linked with chaperons called fatty acid-binding proteins (FABP). FABP uptake and transport PUFA to different intracellular organelles. Intriguingly, PUFA were determined as ligands for G protein-coupled receptor 40 (GPR40), a cell membrane receptor abundantly expressed in the brain and the pancreas of primates. While the role of GPR40 in pancreatic beta-cells is associated with insulin secretion, its role in the brain is not yet clarified presumably because of its absence in the rodent brain. The purpose of this review is to discuss the role of PUFA in adult neurogenesis, considering the role of GPR40 and FABP in the hippocampal neurogenic niche. Here, the authors would like to introduce a PUFA-GPR40 signaling pathway that is specific for the primate brain. PMID- 21606627 TI - Neuroprotective and ameliorative actions of polyunsaturated fatty acids against neuronal diseases: beneficial effect of docosahexaenoic acid on cognitive decline in Alzheimer's disease. AB - Docosahexaenoic acid (DHA, C22:6 n-3), the most abundant n-3 polyunsaturated fatty acid in the brain, is essential for brain growth and development. Recent evidence has indicated the potential health benefits of DHA for managing Alzheimer's disease (AD). For example, dietary administration of DHA considerably protects against and ameliorates the impairment of learning ability in amyloid beta (Abeta)(1-40)-infused AD-model rats, with concurrent increases in DHA levels and decreases in the levels of lipid peroxide and reactive oxygen species in the cortico-hippocampal tissues. In addition, dietary DHA helps in eliminating the amyloid burden from the brains of AD-model rats. In vitro studies have revealed that DHA substantially inhibits Abeta fibrillation. Furthermore, DHA reduces amyloid-induced toxicity in cell culture. These in vitro data support the hypothesis that DHA can ameliorate the cognitive deficits of AD in vivo by limiting Abeta polymerization in the brains. Therefore, it might be a useful therapeutic agent to prevent and/or delay cognitive impairment in mild cases of AD. PMID- 21606628 TI - Epigenetic assessment of environmental chemicals detected in maternal peripheral and cord blood samples. AB - Epigenetic alteration is an emerging paradigm underlying the long-term effects of chemicals on gene functions. Various chemicals, including organophosphate insecticides and heavy metals, have been detected in the human fetal environment. Epigenetics by DNA methylation and histone modifications, through dynamic chromatin remodeling, is a mechanism for genome stability and gene functions. To investigate whether such environmental chemicals may cause epigenetic alterations, we studied the effects of selected chemicals on morphological changes in heterochromatin and DNA methylation status in mouse ES cells (ESCs). Twenty-five chemicals, including organophosphate insecticides, heavy metals and their metabolites, were assessed for their effect on the epigenetic status of mouse ESCs by monitoring heterochromatin stained with 4c,6-diamino-2-phenylindole (DAPI). The cells were surveyed after 48 or 96 h of exposure to the chemicals at the serum concentrations of cord blood. The candidates for epigenetic mutagens were examined for the effect on DNA methylation at genic regions. Of the 25 chemicals, five chemicals (diethyl phosphate (DEP), mercury (Hg), cotinine, selenium (Se) and octachlorodipropyl ether (S-421)) caused alterations in nuclear staining, suggesting that they affected heterochromatin conditions. Hg and Se caused aberrant DNA methylation at gene loci. Furthermore, DEP at 0.1 ppb caused irreversible heterochromatin changes in ESCs, and DEP-, Hg- and S-421-exposed cells also exhibited impaired formation of the embryoid body (EB), which is an in vitro model for early embryos. We established a system for assessment of epigenetic mutagens. We identified environmental chemicals that could have effects on the human fetus epigenetic status. PMID- 21606629 TI - DNA methylation-dependent modulator of Gsg2/Haspin gene expression. AB - The Gsg2 (Haspin) gene encodes a serine/threonine protein kinase and is predominantly expressed in haploid germ cells. In proliferating somatic cells, Gsg2 is shown to be expressed weakly but plays an essential role in mitosis. Although the Gsg2 minimal promoter recognized by the spermatogenic cell-specific nuclear factor(s) has been found, to date, the molecular mechanism that differentially controls Gsg2 expression levels in germ and somatic cells remains to be sufficiently clarified. In this study, we analyzed the DNA methylation status of the upstream region containing the Gsg2 promoter. We found a tissue dependent and differentially methylated region (T-DMR) upstream (-641 to -517) of the authentic promoter that is hypomethylated in germ cells but hypermethylated in other somatic tissues. Profiling of Gsg2 expression and DNA methylation status at the T-DMR in spermatogenic cells indicated that the hypomethylation of the T DMR is maintained during spermatogenesis. Using the reporter assay, we also demonstrated that DNA methylation at the T-DMR of Gsg2 reduced the promoter activity by 60-80%, but did not fully suppress it. Therefore, the T-DMR functions as a modulator in a DNA methylation-dependent manner. In conclusion, Gsg2 is under epigenetic control. PMID- 21606630 TI - Effects of exposure to zearalenone on porcine oocytes and sperm during maturation and fertilization in vitro. AB - The influence of acute exposure to zearalenone (ZEN) on porcine oocyte maturation, fertilization or sperm penetration ability during both in vitro maturation and fertilization was evaluated. First, oocytes were cultured in ZEN containing (0-1000 ug/l) maturation medium and then fertilized. The oocytes maturing in vitro without ZEN were then fertilized in ZEN-containing fertilization medium. The maturation rates of oocytes and penetration ability of sperm decreased significantly in the presence of 1000 ug/l of ZEN. However, neither increases in the rates of degeneration and DNA fragmentation of oocytes nor reductions in normal and polyspermic fertilization were observed. ZEN did not affect the sperm penetration rates; however, 1000 ug/l ZEN had positive effects on normal and polyspermic fertilization rates. Therefore, it can be suggested that an acute exposure of porcine oocytes during maturation and of oocytes and sperm during fertilization to ZEN up to 1000 ug/l may not affect the fertility of the oocytes. PMID- 21606631 TI - Regulation of trophoblast-specific factors by GATA2 and GATA3 in bovine trophoblast CT-1 cells. AB - Numerous transcription factors that regulate trophoblast developmental processes have been identified; however, the regulation of trophoblast-specific gene expression has not been definitively characterized. While a new role of Gata3 in trophoblast development was being demonstrated in mice, we examined effects of GATA transcription factors on conceptus interferon tau (IFNT), a major trophectoderm factor in ruminants. In this study, expression patterns of trophoblast ASCL2, CDX2, CSH1, ELF5, HAND1, IFNT, and TKDP1 mRNAs were initially examined, from which ASCL2, CDX2, IFNT, and TKDP1 mRNAs were found to be similar to those of GATA2 and GATA3 in days 17, 20, and 22 (day 0=day of estrus) bovine conceptuses. A chromatin immunoprecipitation (ChIP) assay revealed that endogenous GATA2 and GATA3 occupied GATA binding sites on the upstream regions of CSH1, IFNT, and TKDP1 genes and on the intron 1 region of CDX2 gene in bovine trophoblast CT-1 cells. In transient transfection analyses of the upstream region of bovine CSH1, and IFNT or the intron 1 region of CDX2 gene, over-expression of GATA2 induced transactivation of these trophoblast-specific genes in bovine non trophoblast ear fibroblast EF cells, but over-expression of GATA3 did not substantially affect their transactivation. In CT-1 cells, endogenous CDX2 and IFNT mRNAs were down-regulated by GATA2 siRNA, while endogenous ASCL2 and CDX2 mRNAs were down-regulated by GATA3 siRNA. Our results indicate that in addition to trophectoderm lineage specification, GATA2 and/or GATA3 are involved in the regulation of trophoblast-specific gene transcription in bovine trophoblast CT-1 cells. PMID- 21606632 TI - Assisted hatching of poor-quality bovine embryos increases pregnancy success rate after embryo transfer. AB - Embryos of good, fair and poor quality were collected from superovulated cows and subjected to zona cutting (ZC) treatment using a needle under either an inverted microscope or a stereomicroscope. One (single transfer) or 2 (twin transfer) embryos with or without prior ZC treatment were transferred nonsurgically to recipients. Without the ZC treatment, lower embryonic quality resulted in lower pregnancy success rates. However, the ZC treatment increased the pregnancy success rate following transfer of poor-quality embryos, but not the pregnancy rate after transfer of good- or fair-quality embryos. No differences were observed between the pregnancy success rates after the transfer of embryos treated under the inverted microscope and those after transfer of embryos treated under the stereomicroscope, and this was the same after single and twin transfer. Moreover, ZC treatment of embryos prior to transfer did not result in an increased abortion rate, irrespective of the number of transferred embryos. In conclusion, ZC treatment improves pregnancy success rates following transfer of poor-quality embryos. Moreover, the results indicate that ZC treatment by using a stereomicroscope is practical for on-farm application. PMID- 21606633 TI - Reproductive cycle observation of the Okinawa rail (Gallirallus okinawae) in the wild. AB - The captive breeding program of the Okinawa rail started in 2008. For successful captive breeding, information related to reproduction, such as age at sexual maturity, testicular cycles and ovulatory cycles, is essential to predict when reproduction is possible and when certain reproductive behaviors are most likely to occur. We made gross and histological observations of the reproductive organs of Okinawa rails to gain understanding of sexual maturity, the testicular cycle and the ovulatory cycle. We found that the weight of the testis was smallest in December and largest in March. Changes in the diameter of the seminiferous tubule showed the same pattern. Mature sperm were observed from March to June. The heaviest ovary was observed in April. A single peak of reproduction, from March to April, was observed in males and females. Our observations suggested that the Okinawa rail is a seasonal breeder. Establishing suitable breeding pairs will be critical to ensure success of the Okinawa rail captive breeding program. Our results suggested that pairing must be started before March. If supportive breeding is used, semen should be collected from March to June and artificial insemination conducted in April. PMID- 21606634 TI - Analgesic efficacy of forced coughing versus local anesthesia during cervical punch biopsy. AB - BACKGROUND/AIMS: To compare local anesthesia and forced coughing in terms of subjective pain perception during cervical punch biopsy. METHODS: In this randomized controlled trial, 114 patients (mean age: 38.9 +/- 9.0 years) scheduled for colposcopically directed cervical punch biopsy were randomly assigned to local anesthesia (n = 39), forced coughing (n = 39) and control (n = 36) groups. Pain perception was measured on a 10-cm visual analog scale (VAS) during the insertion of the speculum, injection of the local anesthetic to the cervix and the taking of the first cervical biopsy, as well as for the overall pain perceived during the entire procedure. RESULTS: Experimental groups were similar in age, gravidity, parity and prior curettage. The pain score obtained during the first cervical biopsy was significantly lower if local anesthesia was applied (p = 0.016). Groups were similar in other pain subscores. The duration of the entire procedure was significantly longer (p < 0.001) in the local anesthesia group, while it was not significantly different in forced coughing patients compared to controls. CONCLUSION: Local anesthesia, but not forced coughing, provides significant pain relief during cervical biopsy. Based on similarity to control data in terms of pain relief and shortening of the operation, forced coughing per se seems related neither to pain relief nor a faster cervical biopsy. PMID- 21606635 TI - Hearing evaluation in preeclamptic patients. AB - OBJECTIVE: To evaluate the pathological effects of preeclampsia on hearing levels in pregnant women by pure-tone audiometry and brainstem auditory-evoked potentials (BAEPs). METHODS: Both ears in 30 preeclamptic patients and 38 women with uncomplicated pregnancy matched by maternal age and gestational age were investigated based on BAEPs and pure-tone audiometry. Hearing thresholds were within the normal ranges in all subjects prior to pregnancy. We compared the results of hearing levels and auditory pathway functions between the two groups. RESULTS: Statistically significant differences in pure-tone audiometry results were found between the two groups (p < 0.05). However, these results were not clinically significant because all pure-tone thresholds were lower than 20 dB (normal hearing abilities). The differences between BAEPs were not statistically significant (p > 0.05). CONCLUSION: This study suggests that preeclampsia does not markedly affect hearing function unless it causes secondary vascular occlusion of microcirculation related to hearing. PMID- 21606636 TI - Psychological factors in chronic pelvic pain due to endometriosis: a comparative study. AB - BACKGROUND/AIMS: This study compared women suffering chronic pelvic pain (CPP) secondary to endometriosis (n = 30) with women experiencing CPP due to either myofascial abdominal/pelvic pain (n = 70) or pelvic adhesions (n = 38) to determine if there are specific psychological variables uniquely associated with endometriosis. METHODS: This is a cross-sectional study of 138 women drawn from a convenience sample of 192 consecutive women with CPP presenting for evaluation to a university hospital chronic pain clinic. Subjects were categorized into groups based on their CPP diagnosis. Each subject completed a battery of validated inventories assessing demographic status, pain experience and other pain-related symptoms, pain disability, frequency of depressive symptoms, level of affective distress, satisfaction with pain treatment and satisfaction with their marital relationship. RESULTS: No differences were obtained across the three groups for any of the outcome measures. Effect size computation supported the absence of clinical differences across the groups for these measures. CONCLUSION: These findings fail to support the presence of a unique psychological profile or disproportionate psychological disturbance for women with CPP due to endometriosis. These data illustrate the importance of considering control groups that include chronic pain when exploring psychological contributions to specific chronic pain conditions. PMID- 21606637 TI - Clinical characteristics and type of thrombophilia in women with pregnancy related venous thromboembolic disease. AB - BACKGROUND: Normal pregnancy is characterized by numerous changes in the hemostatic system, creating the hypercoagulable state which increases the risk of venous thromboembolic event (VTE) occurrence. The risk is further increased by the presence of inherited or acquired thrombophilia. OBJECTIVE: In this study, we aimed to determine the prevalence of different types of thrombophilia in women with pregnancy-related VTE, and to investigate the possible connection between the type of thrombophilia and localization of VTE as well as the gestational age of VTE occurrence. PARTICIPANTS AND METHODS: Two hundred and two women with the first episode of pregnancy-related VTE and 130 controls were investigated. The antithrombin, protein C and protein S activity, APC resistance, FVG1691A, and FIIG20210A were determined. None of the investigated women was pregnant at the time of thrombophilia testing, and none was using oral contraceptives. RESULTS: Thrombophilia was diagnosed in 95 patients (47%) and 7 controls (5.4%). The prevalence of FV Leiden, FIIG20210A mutations, antithrombin, PC and PS deficiencies taken together and combined thrombophilia was 22.3, 10.4, 6.9 and 6.9%, respectively. Significantly more frequent antepartum occurrence of VTE (11 vs. 3, p < 0.05) was found in women with natural coagulation inhibitor deficiency. Pulmonary embolism occurred more frequently in nonthrombophilic women (25 vs. 3, p < 0.001). CONCLUSION: Inherited thrombophilia was found to be considerably more frequently present in women with pregnancy- and puerperium related VTE compared to healthy controls. Women with thrombophilia are at higher risk of developing thromboses localized in the iliacofemoral region, and women without thrombophilia are at higher risk of developing pulmonary embolism. Deficiency in natural coagulation inhibitors is associated with antepartum VTE occurrence. PMID- 21606638 TI - Safety of tumescent liposuction under local anesthesia in a series of 4,380 patients. AB - BACKGROUND: Liposuction is increasingly performed under local anesthesia and in an outpatient setting. The term 'tumescent liposuction' has been used in the literature in patients receiving other forms of anesthesia as well, hence the confusion regarding the safety profile of liposuction performed under local anesthesia alone. OBJECTIVE: To analyze the safety of tumescent liposuction performed under local anesthesia in a larger group of patients. METHODS: Between 2003 and 2010, 4,380 consecutive patients underwent tumescent liposuction by the same surgeon. The occurrence of complications was recorded in detail. RESULTS: There were no serious complications requiring hospitalization. There were no injuries, no nerve damage or permanent lymphedema, no deep venous thrombosis or seroma. Seven patients needed closer follow-up due to large hematoma (n = 3; no drainage needed), allergic drug reaction to doxycycline (n = 2), erysipelas (n = 1) and generalized edema (n = 1). CONCLUSIONS: Tumescent liposuction under local anesthesia is a safe method, providing it is performed by an experienced surgeon and the guidelines of care for liposuction are strictly followed. PMID- 21606639 TI - Two atypical cases of cutaneous gamma/delta T-cell lymphomas. AB - Cutaneous gamma/delta T-cell lymphoma (CGD-TCL) is a recent entity described in the newly revised World Health Organization-European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas, and is characterized by the gamma/delta T-cell receptor expression on atypical lymphocytes. Only a few cases of primary CGD-TCL have been reported, with an extremely aggressive course (median survival time of 15 months). We describe 2 atypical cases of CGD-TCL. The first case was initially misdiagnosed as an inflammatory panniculitis due to the granulomatous infiltrate on the skin biopsy specimen. Diagnosis was confirmed using delta PCR that revealed gamma/delta T cell clonal expansion. The evolution was marked by predominant gamma/delta T-cell infiltrate with diffuse body fat involvement as seen on positron emission tomography-computed tomography. The second case is the first described Epstein Barr virus (EBV)-associated CGD-TCL with a rapidly fatal evolution. CGD-TCL is also a heterogeneous entity and delta PCR and EBV-encoded RNA probe to detect an EBV latent infection may help diagnose and characterize these cutaneous lymphomas. PMID- 21606640 TI - Different isoforms of nitric oxide synthase are involved in angiotensin-(1-7) mediated plasticity changes in the amygdala in a gender-dependent manner. AB - BACKGROUND: The amygdala receives afferent sensory input and processes information related to hydromineral balance. Angiotensin acts on and through the amygdala to stimulate thirst and sodium appetite. In addition, different angiotensins seem to play a role in cognition and learning mechanisms by acting on and through the amygdala. Recently, we showed that angiotensin-(1-7) (Ang-(1 7)) enhances the magnitude of long-term potentiation (LTP) in the lateral nucleus of the amygdala (LA) via the Mas receptor. METHODS: Extracellular field potentials were measured in the LA. RESULTS: LA-LTP induced by stimulation of the external capsule was nitric oxide (NO)-dependent because the NO synthase (NOS) inhibitor L-NAME reduced LA-LTP. The LA-LTP was also reduced in both male and female nNOS and eNOS knockout mice. In male eNOS(-/-) mice, Ang-(1-7) enhanced LA LTP, whereas the LTP-enhancing effect of Ang-(1-7) was missing in female eNOS(-/ ) mice. Therefore, the LTP-enhancing effect of Ang-(1-7) was mediated by eNOS in females. In contrast, Ang-(1-7) strongly enhanced the LTP in nNOS(-/-) females, whereas the effect of Ang-(1-7) was missing in nNOS(-/-) males. Thus, Ang-(1-7) induced an increase in the magnitude of LTP via the involvement of nNOS in males. CONCLUSION: Our data support not only the hypothesis that NO contributes to plasticity changes in the lateral amygdala, but also show for the first time a gender-dependent involvement of different isoforms of NOS in the mediation of Ang (1-7) on LTP in the amygdala. PMID- 21606641 TI - Progesterone level predicts serotonin-1a receptor binding in the male human brain. AB - BACKGROUND: Progesterone (P) is thought to influence mood and affective states. Alterations of the inhibitory serotonin-1A (5-HT(1A)) receptor distribution are associated with depression and anxiety. This study evaluates the influence of plasma P levels on the 5-HT(1A) receptor binding in healthy male subjects. METHODS: Molecular neuroimaging of the 5-HT(1A) receptor distribution using positron emission tomography and hormone assays for total plasma P and cortisol were done in a sample of 18 healthy men. RESULTS: Plasma P levels explained up to 65% of the variability in 5-HT(1A) receptor binding in limbic regions including the amygdala, orbitofrontal cortex and retrosplenial cortex. When controlling for cortisol in the model, there was an expected decline in explained variances of 5 HT(1A) binding attributed to P. CONCLUSIONS: The results of this study provide further support for the effect of P on 5-HT(1A) receptor expression and raise the possibility that P mediates the vulnerability to mood disorders by affecting the serotonergic system. PMID- 21606642 TI - Quantitative magnetic resonance imaging evaluation of the olfactory system in Kallmann syndrome: correlation with a clinical smell test. AB - OBJECTIVES: To measure olfactory bulbs and sulci using dedicated magnetic resonance imaging (MRI) sequences and specific measurement tools in Kallmann syndrome (KS) patients with a well-established genotype and phenotype, as well as correlate MRI findings with a clinical smell test. METHODS: MRI was performed in 21 patients with KS and 16 healthy volunteers; olfactory dysfunction was assessed using the Smell Identification Test (UPSIT), a qualitative suprathreshold olfaction test. Coronal turbo spin echo T2-weighted and volumetric T1-weighted gradient echo sequences were acquired in a 1.5T system. ImageJ software was used to obtain olfactory bulb volumes and olfactory sulcus depths and lengths. Data were analyzed with SPSS 15.0 and the Kappa index was used to evaluate the agreement between the UPSIT and MRI. RESULTS: The UPSIT showed 14 patients with anosmia and 6 with moderate hyposmia. Eighteen patients (85%) presented altered rhinencephalon structures in the MRI. Sixteen patients (76%) presented olfactory bulb aplasia (14/16 bilaterally), and these patients presented a total of 16 aplastic sulci. There was moderate agreement between the MRI quantitative evaluation and the UPSIT (overall Kappa = 0.55), but when considering the presence of aplastic bulbs and anosmia, we found almost perfect agreement (Kappa = 0.87). Three patients had normal rhinencephalon structures, including one with a KAL1 gene mutation. CONCLUSION: Olfactory bulb and sulcus aplasia were the most common findings in KS patients. We objectively demonstrated agreement between MRI findings and the smell test, especially the presence of bulb aplasia and anosmia. Therefore, our findings help ascertain MRI accuracy in the diagnosis of KS, differentiating patients with hypogonadotropic hypogonadism with an apparently normal or difficult to evaluate sense of smell. PMID- 21606643 TI - The role of high-mobility group box-1 protein in the development of diabetic nephropathy. AB - BACKGROUND/AIMS: The purpose of the experiment reported here was to assess the involvement of high-mobility group box-1 (HMGB1), receptor for advanced glycation end products (RAGE) and nuclear factor (NF)-kappaB signaling pathway in the development of rat diabetic nephropathy. METHODS: Diabetes was induced by intraperitoneal streptozotocin injection in 7-week-old male rats. At 20 weeks of age, renal expression of HMGB1 was detected by immunohistochemistry. The expression of RAGE and NF-kappaB activity was studied by Western blot and electrophoretic mobility shift assay in renal tissues of normoglycemic and diabetic rats, respectively. RESULTS: HMGB1 was highly expressed in both the cytoplasmic and nuclear patterns in diabetic renal glomerular cells and tubular epithelial cells, although in normal rats, HMGB1 was expressed only in the cell nuclei. The expression of RAGE, a potential receptor for HMGB1, and NF-kappaB activity were also greater in diabetic than in normal rats. Moreover, diabetes increased the binding of NF-kappaB to the RAGE promoter. CONCLUSION: These findings suggest that hyperglycemia-induced HMGB1 release may induce the renal injury in diabetic rats, and that the pathogenic role of HMGB1 might be dependent on RAGE and through activation of NF-kappaB. PMID- 21606644 TI - Donor effect on cortical perfusion intensity in renal allograft recipients: a paired kidney analysis. AB - BACKGROUND: The contributions of donor- and recipient-related factors to renal allograft hemodynamics are difficult to dissect due to methodological reasons. We analyzed 28 pairs of kidneys (each pair from the same donor) transplanted to 56 different recipients in order to define the contributions of the donor and the recipient to allograft hemodynamics. METHODS: Two different techniques based on color-coded duplex ultrasound were used: renal resistance index (RI; measured in 3 different segmental arteries) and cortical perfusion intensity (PI; calculated as the average PI of selected cortical parenchymal regions during one heart cycle in standardized registered and processed ultrasound videos). All measurements were performed during the same study visit. RESULTS: Donor age was 56 years (median, range 17-78) and recipient age at examination 54 years (range 30-77). Median time after transplant (at the date of examination) was 2.4 years (range 0.7-5.5). RI correlated with pulse pressure (r = 0.64; p < 0.001) and recipient age (r = 0.42; p < 0.03), but not with donor age or transplant function expressed as estimated glomerular filtration rate (eGFR) or PI. In within- and between pairs ANOVA, donor-derived factors determined eGFR (p < 0.02) and cortical PI (p < 0.03), but not RI. CONCLUSIONS: Intrinsic donor-derived factors are associated with GFR and cortical parenchymal perfusion intensity, but not the RI of segmental arteries in renal allografts. PMID- 21606645 TI - Dendrin location in podocytes is associated with disease progression in animal and human glomerulopathy. AB - BACKGROUND: Adriamycin (ADR) nephrosis in mice has been extensively studied and has enabled a greater understanding of the processes underlying the progression of renal injury. Dendrin is a novel component of the slit diaphragm with proapoptotic signaling properties, and it accumulates in the podocyte nucleus in response to glomerular injury in mice. The present study re-evaluated chronic progressive nephropathy in ADR mice and the localization of dendrin in mice and in human glomerulopathy. METHODS: To investigate the localization of dendrin, a mouse model of nephrosis and glomerulosclerosis was used, in which ADR was injected once. WT-1-positive cells and apoptotic cells were counted in vivo and in vitro. To check the expression of dendrin in ADR mice, immunostaining and Western blot were performed. A survey of dendrin staining was performed on human kidney biopsy specimens. RESULTS: The injection of ADR induced proteinuria, podocyte loss and glomerulosclerosis. It also caused the relocation of dendrin from the slit diaphragm to the podocyte nucleus. We demonstrated the location of dendrin to podocyte nuclei in several cases of human glomerulopathy. The mean occurrence of dendrin-positive nucleus per glomerulus increased in several cases of human glomerulopathy. CONCLUSIONS: These findings suggest that the relocation of dendrin to the podocyte nuclei is useful as a novel marker of podocyte injury in human glomerulopathy. PMID- 21606646 TI - Electric-acoustic stimulation of the auditory system: a review of the first decade. AB - Electric-acoustic stimulation (EAS) was developed for individuals with a profound hearing loss in the high frequencies and a substantial residual low-frequency hearing (LFH). For this group of candidates, conventional hearing aids often neither provided sufficient amplification nor were they considered suitable for cochlear implantation due to the possible destruction of residual hearing capabilities. With EAS, combining electric stimulation with an ipsilateral acoustic stimulation, preservation of residual LFH and the development of a new speech processor uniting both strategies became essential. Over the last years, EAS has developed further and advanced in electrode design and surgery techniques. This paper summarizes the history of EAS and acknowledges the tremendous work of the many research groups who contributed to the success of EAS. PMID- 21606647 TI - Effect of ZP123, a gap junction modifier, on prolonged ventricular fibrillation in swine. AB - OBJECTIVES: It was the aim of this study to investigate the effect of ZP123 on prolonged ventricular fibrillation (VF) in swine. METHODS: VF was electrically induced in 20 pigs. The animals randomly received either ZP123 or saline control infusion before VF. After 8 min of untreated VF, cardiopulmonary resuscitation and biphasic defibrillation shocks were applied. VF mean frequency (VF(mf)) and mean amplitude (VF(ma)), hemodynamics, outcome of defibrillation and the rate of return of spontaneous circulation (ROSC) were analyzed. RESULTS: Compared with the control group, VF(mf) was higher but VF(ma) lower during the 8 min of VF in the drug group (11.8 +/- 2.1 vs. 10.4 +/- 2.0 Hz and 0.24 +/- 0.10 vs. 0.31 +/- 0.16 mV, respectively; p < 0.05). Hemodynamic variables in the 2 groups were comparable (p > 0.05). The defibrillation threshold was lower and the rate of successful defibrillation was higher in the drug group compared with the control group (92.2 +/- 26.4 vs. 133.3 +/- 28.9 J and 90 vs. 30%, respectively; p < 0.05). The rate of ROSC was not different between the 2 groups (40 vs. 30%; p > 0.05). CONCLUSION: In prolonged VF, ZP123 could decrease the defibrillation threshold and improve the rate of successful defibrillation. However, it could not improve the rate of ROSC - which may be due to its side effect of decreasing VF(ma). PMID- 21606648 TI - Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double blind placebo-controlled pilot study. AB - Relapse is the rule rather than the exception in smokers aiming to quit smoking. Recently, evidence has emerged that glutamate transmission plays an important role in relapse. N-acetylcysteine (NAC), a cysteine prodrug, restores glutamate homeostasis and appears to be a potential new treatment for substance dependence. In the current pilot study, the effects of NAC on short-term abstinence of smoking were investigated. Subjects were heavy smokers randomized to receive placebo (n = 12) or NAC 3,600 mg/day (n = 10) in a double-blind fashion during 3.5 days. Subjects were asked to stop smoking and report on nicotine craving, nicotine withdrawal symptoms, and cigarette smoking during treatment. At the end of the treatment, subjects were invited to smoke a cigarette and to rate the rewarding effect of this cigarette. There was no significant effect of NAC on craving (p = 0.23, d = 0.52) and only a statistical trend towards fewer withdrawal symptoms in the NAC condition (p = 0.07, d = 0.80). Interestingly, subjects receiving NAC rated the first cigarette after the abstinence period of 3.5 days as significantly less rewarding than subjects on placebo (p = 0.04, d = 0.85). It is concluded that the results of this pilot study are encouraging and suggest that NAC might be a promising new treatment option for relapse prevention in nicotine dependence. PMID- 21606649 TI - Attention shift towards smoking cues relates to severity of dependence, smoking behavior and breath carbon monoxide. AB - The aim of this study was to assess the severity of dependence as a factor affecting the attentional bias of smokers towards smoking-related stimuli and to clarify contradictory results of previous studies. A visual dot probe task was administered to 51 smokers and 41 nonsmokers to assess the attentional bias. Smokers were classified into a group of less severely dependent and a group of more severely dependent smokers according to the Fagerstrom Test for Nicotine Dependence, the number of cigarettes smoked per day or the CO concentration in the expired air. Nicotine craving was assessed as well. The more severely dependent smokers displayed an attentional bias towards smoking-related stimuli, while smokers with less severe nicotine dependence showed a negative attentional bias which was also observed in nonsmokers. A multiple linear regression indicated that CO concentration was the only significant predictor of attentional bias. In the total group of smokers we found a positive association between attentional bias and craving for the rewarding effects of nicotine. Future studies are warranted to further enhance our understanding of factors that affect attentional bias as appetitive responses towards smoking-related stimuli might be an important target for therapeutic interventions. PMID- 21606650 TI - Writing error may be a predictive sign for impending brain atrophy progression in amyotrophic lateral sclerosis: a preliminary study using X-ray computed tomography. AB - AIM: To investigate whether writing errors are predictive of longitudinal brain atrophy progression in patients with amyotrophic lateral sclerosis (ALS). METHODS: The frequency of writing errors in 6 ALS patients without dementia was compared with longitudinal changes in lateral ventricular areas of the bilateral anterior and inferior horns on X-ray computed tomography scans. The increase in area per month for the anterior and inferior horns was used as a measure of longitudinal brain atrophy progression, and was calculated as: (area on the initial scan - area on the follow-up scan)/scan interval (month). RESULTS: The longitudinal rate of increase in the area of the anterior horns showed significant associations with the rates of total writing errors (r = 0.886, p = 0.0152), kana errors (r = 0.887, p = 0.0148) and kana omission (r = 0.856, p = 0.0268), whereas that for the inferior horns size showed no significant association with any writing errors. CONCLUSION: The increased area of the anterior horns indicates frontal-lobar atrophy, and writing errors may be a predictive sign for impending brain atrophy progression in the frontal lobes, which reflects the development of anterior-type dementia. PMID- 21606651 TI - Intraperitoneal administration of bevacizumab intraoperatively does not affect abdominal wound healing in rats. AB - BACKGROUND: Bevacizumab is a monoclonal antibody targeted at vascular endothelial growth factor (VEGF) to treat advanced colorectal cancer as well as other malignancies, but the ideal time point for its administration in patients scheduled for surgery is not well defined due to serious concerns regarding possible side effects on wound healing. Therefore, we conducted an experimental study in rats to clarify this issue. METHODS: Four groups of 10 Wistar rats each underwent a 4-cm midline laparotomy and closure of the wound in 2 layers. In the treatment groups (A and B), bevacizumab (Avastin((r))) received a single dose of 5 mg/kg i.p., and an equal amount of saline was given to the control groups (C and D). Groups A and C were sacrificed on the 7th postoperative day, and groups B and D on the 14th postoperative day. Wounds were inspected by two independent observers upon sacrifice and results were recorded; wound tissues were sent for histology to assess the degree of fibrosis and measurement of tissue hydroxyproline levels. Serum levels of endothelin-1, C-reactive protein, pro oxidant/antioxidant balance and carbonylated proteins were also determined. For statistical analysis, the Mann-Whitney U test was used. RESULTS: Wound healing did not differ among groups both on the 7th and the 14th postoperative days, and there was also no significant difference regarding the degree of inflammation, fibroblast proliferation and collagen synthesis, as well as hydroxyproline and biochemical marker levels among the groups. CONCLUSIONS: Intraperitoneal bevacizumab administered intraoperatively does not significantly affect abdominal wound healing in rats. PMID- 21606652 TI - Moderate intrarenal vasoconstriction after high pressor doses of norepinephrine in the rat: comparison with effects of angiotensin II. AB - AIMS: Treatment of arterial hypotension with norepinephrine (NE) is associated with renal vasoconstriction and may lead to ischemic kidney injury; the risk involved is still a matter of debate. METHODS: In anesthetized, acutely uninephrectomized rats, we examined changes in intrarenal hemodynamics induced by intravenous infusion of NE and angiotensin II (Ang II), at doses that increased arterial pressure by ~25 mm Hg (20%). Renal blood flow (RBF) was determined using a Transonic probe, and superficial cortical, outer and inner medullary flows (CBF, OMBF, IMBF) as laser-Doppler fluxes. RESULTS: NE decreased regional intrarenal perfusion similarly, by 16, 15 and 16% for RBF, OMBF and IMBF, respectively (all changes significant). The respective decreases after Ang II were significantly greater and clearly differentiated: 45, 32 and 22%, respectively. The renal vascular resistance increased 47 +/- 4% after NE and 131 +/- 11% after Ang II, indicating that the latter drug induces much more pronounced renal vasoconstriction. CONCLUSION: An ~15% decrease of renal perfusion may be taken as an indication of an impairment of renal circulation during antihypotensive NE therapy. While superiority of NE over Ang II is obvious, a further search for drugs even less harmful to renal perfusion and function is desirable. PMID- 21606653 TI - Determining the burden of neurological disorders in populations living in tropical areas: who would be questioned? Lessons from a Mexican rural community. AB - BACKGROUND: The best approach to determine the burden of neurological disorders in developing countries is to perform population-based studies. Our objectives were to determine the prevalence of neurological disorders in a Mexican rural community and assess the usefulness of a household screening questionnaire. METHODS: The survey took place in a Mexican rural community of Puebla State in Mexico. This was a cross-sectional, population-based, 2-phase study including a comparison of the usefulness levels of the individual (IQ) and household (HQ) questionnaires. RESULTS: A total of 4,008 individuals participated in the prevalence study using the IQ; of these, 280 neurological examinations allowed to identify 127 individuals suffering from at least 1 neurological disease. The most frequent ailments were headache (22.4/1,000, 95% confidence interval, CI: 17.7 28.2), neuropathy (7.1/1,000, CI 95%: 4.4-11.3) and epilepsy (3.9/1,000, CI 95%: 2.3-6.5). The HQ, used in parallel with the IQ, detected significantly fewer neurological cases. This result was mainly due to the low capacity of the HQ to detect headache. CONCLUSIONS: Results of the prevalence study are discussed emphasizing their relevance in adequately allocating resources. The usefulness of the HQ for screening neurological disorders in general was low, but could be adequate for specific neurological disorders. PMID- 21606654 TI - The influence of design and definition on the proportion of general epilepsy cohorts with remission and intractability. AB - Remission while on anti-epileptic drug (AED) therapy and remission off AED are the only prognostic criteria defined by the International League against Epilepsy (ILAE), defining remission as 5 seizure-free years. Prognosis studies in epilepsy have investigated other prognostic categories using different designs and definitions. This systematic review explores factors that explain discrepancies in the proportion of patients reported with commonly studied prognostic categories in general epilepsy cohorts. Thirty publications (reporting 37 studies) were included. The outcome categories were classified as immediate remission (5 studies), remission off medication (7 studies), remission on or off medication (15 studies), intractability (9 studies) and no remission after relapse (1 study). The findings show the importance of qualifying estimates specifically by how they were defined in each study, study design, setting and patient population as these have implications for patient management and counselling. The ILAE should define the outcome measures and terminology to which researchers should be required to adhere in subsequent updates of their guidelines on research related to remission and intractability. PMID- 21606655 TI - Urine proteomics and biomarkers in renal disease. AB - The application of urine proteomics is a useful approach to the study of the proteins involved in healthy and diseased kidneys and may provide a noninvasive approach to assess disease activity and to monitor clinical response in patients with renal diseases. This technique may provide an additional tool in clinical trials and for the assessment of prognosis for patients. Both soluble proteins and membrane-bound (exosomal) proteins may be studied, and multiple approaches are available. Discovery proteomics is an unbiased approach to detect novel proteins in urine samples. Mass spectrometry (MS) is often needed to identify specific protein fragments. Targeted proteomics often involves specific immunoassays or modified MS, which enables a hypothesis-based design. These approaches may be integrated. For example, specific proteins may be identified by the discovery approach or laboratory study of disease mechanisms. These proteins will then be studied further by targeted proteomics. In order to translate to clinical practice, the specific assays need vigorous validation by means of sufficiently statistically powered clinical trials. PMID- 21606656 TI - Inflammatory gene expression in OVE26 diabetic kidney during the development of nephropathy. AB - AIM: To define renal gene expression during the development of severe albuminuria in OVE26 diabetic mice. METHODS: Kidney microarray analysis was performed at 2, 4 and 8 months. Data were validated by RT-PCR, in situ hybridization and immunohistochemistry. RESULTS: Gene expression differences between control and diabetic mice increased 10-fold from 2 to 8 months. This change was most obvious for inflammatory genes. Three inflammatory genes, complement C3, VCAM1 and CD44 were upregulated more than 4-fold. Inflammatory gene expression correlated with albuminuria and C3 and CD44 increased in tubules that accumulated albumin. VCAM1 was induced in different tubules that were neither dilated nor accumulated albumin. Six of 8 genes previously reported to be markers of human advanced diabetic nephropathy and the NF-kappaB_IFN_x promoter module were elevated in the oldest diabetic mice. Vitamin D inhibits diabetic renal inflammation. Vitamin D and mRNA for vitamin D synthetic enzyme CYP2B1 were elevated in kidneys of young OVE26 mice. CONCLUSIONS: OVE26 mice induce inflammatory genes consistent with advanced renal disease, associated with severe albuminuria and to a greater extent than reported in other diabetic models. They provide an excellent model of diabetic nephropathy to assess the effect of induction of inflammatory proteins. PMID- 21606657 TI - Reward-related genes and personality traits in alcohol-dependent individuals: a pilot case control study. AB - Components of the brain reward system, i.e. the mesolimbic dopamine, laterodorsal cholinergic and ghrelin signaling systems, have been implicated in alcohol reward in preclinical studies. Genetic variants of these systems have previously been linked to alcohol dependence. Here, we genotyped 31 single nucleotide polymorphisms (SNPs): 1 SNP in the dopamine D2 receptor (DRD2) gene, 20 SNPs in 5 different nicotinic acetylcholine receptor subunit (CHRN*) genes, and 10 SNPs in the genes encoding pro-ghrelin (GHRL) and its receptor (GHSR), in a pilot study of type 1 alcoholics (n = 84) and healthy controls (n = 32). These individuals were characterized using the Temperament and Character Inventory. None of the SNPs were associated with risk of alcohol dependence in this population. The GG genotype of SNP rs13261190 in the CHRNB3 was associated with increased novelty seeking, while SNPs of the ghrelin signaling system were associated with decreased self-directedness (AA of rs495225, GHSR) and alterations in self transcendence (AA of both rs42451 and rs35680, GHRL). In conclusion, this pilot study suggests that reward-related genes are associated with altered personality scores in type 1 alcohol dependence, which warrants future studies of these associations in larger study samples. PMID- 21606658 TI - The role of the right hemisphere for processing of social interactions in normal adults using functional magnetic resonance imaging. AB - OBJECTIVE: The main purpose of this study was to evaluate whole-brain and hemispheric activation in normal adult volunteers to videos depicting positive and negative social encounters. There are few studies that have utilized dynamic social stimuli to evaluate brain activation. METHOD: Twenty young adults viewed videotaped vignettes during an functional magnetic resonance imaging procedure. The vignettes included positive and negative interaction scenes of social encounters. RESULTS: Significant right greater than left activation for positive and negative conditions was found for the social interaction videos in the amygdaloid complex, the inferior frontal gyrus, the fusiform gyrus, and the temporal gyri (p < 0.0001). CONCLUSION: These findings support the hypothesis that the regions of the right hemisphere are more active in the interpretation of social information processing than those regions in the left hemisphere. This study is a first step in understanding processing of dynamic stimuli using ecologically appropriate stimuli that approximate the real-time social processing that is appropriate for use with populations who experience significant social problems. PMID- 21606659 TI - Differences and similarities on neuronal activities of people being happily and unhappily in love: a functional magnetic resonance imaging study. AB - BACKGROUND: Brain activity was studied in grief following frustrated love compared to romantic love, and it was hypothesized that unhappy lovers compared to happy lovers would have decreased brain activity in regions specific to emotional and reward circuits, such as frontal brain areas, anterior cingulate cortex (ACC), bilateral insula or posterior cingulate cortex (PCC). METHODS: Twelve volunteers intensely in love and 12 volunteers recently separated from their romantic partners were scanned performing 3 runs of functional magnetic resonance imaging acquisition. Subjects viewed partner pictures versus erotic pictures during the first run of the scanning process, autobiographical pictures versus neutral pictures during the second and autobiographical texts versus neutral texts during the third run. The Passionate Love Scale (PLS) and the Beck Depression Inventory (BDI) were additionally recorded. RESULTS: Decreased brain activity in unhappy lovers compared to happy lovers occurred in frontal areas, ACC and PCC and bilateral insula. Unhappy lovers also revealed clinical depressive symptoms in the BDI. CONCLUSION: Unhappy lovers compared to happy lovers exhibited clinical depressive symptoms and reduced blood oxygen level dependency changes in a brain network which has been described as being involved in major depression. This might be a cue for the close relationship between grief and depression. PMID- 21606660 TI - Analysis of prognostic factors of pediatric-type sarcomas in adult patients. AB - OBJECTIVE: Pediatric-type sarcomas such as Ewing's sarcoma (EWS)/primitive neuroectodermal tumor family and rhabdomyosarcoma are relatively uncommon in adult patients. Optimal treatment strategies for this population and prognosis in adult patients compared with pediatric patients remain controversial. METHODS: We retrospectively reviewed pediatric-type sarcoma patients older than 15 years at a single institution. RESULTS: A total of 84 consecutive patients between 1995 and 2009 were identified at the Samsung Medical Center, Seoul, Korea. Median age was 30 years with a range of 15-74 years. Forty-seven patients (56.0%) were diagnosed with Ewing's sarcoma/primitive neuroectodermal tumor family, 34 (40.5%) with rhabdomyosarcoma and 3 (3.6%) with desmoplastic round-cell tumor. Median follow up duration was 5.9 years. Median overall survival for all patients was 33.1 months (95% CI 13.5-52.7) and median event-free survival for all patients was 14.4 months (95% CI 5.9-22.9 months). Multivariate analysis revealed that localized disease was a significant independent prognostic factor for longer overall survival (hazard ratio 0.30, 95% CI 0.14-0.66, p = 0.003), and favorable primary tumor sites were associated with longer event-free survival (hazard ratio 0.33, 95% CI 0.11-0.98, p = 0.045). CONCLUSION: We identified the prognostic variables which may facilitate risk-adapted therapies for this rare adult sarcoma group, which should be further investigated. PMID- 21606661 TI - Self-reported compliance with capecitabine: findings from a prospective cohort analysis. AB - OBJECTIVES: While oral anticancer treatment has increased the convenience for patients with no risk of venous access complications compared to intravenous drug administration, a high level of compliance cannot always be assumed. The aim of the present report was to evaluate real-life drug adherence in a prospective cohort analysis of patients with gastrointestinal or breast cancer treated with capecitabine-based chemotherapy. METHODS: Twenty-nine Swiss oncologists recruited patients receiving capecitabine, either as monotherapy or in combination with other chemotherapeutic agents, in a prospective fashion. Patients recorded both their capecitabine intake and any adverse effects each day in patient diaries. RESULTS: A total of 177 patients were included, 143 (81%) with gastrointestinal tumours and 34 (19%) with breast cancer. Overall, 161 patients (91%) were considered as fully compliant, while 16 patients (9%) reported some kind of compliance error. Reasons for non-compliance included forgetting to take treatment (n = 9), side effects (n = 4) and misunderstanding instructions (n = 3). Self-reported compliance was not influenced by age or Eastern Cooperative Oncology Group performance status, but there was a trend towards better compliance with capecitabine therapy if fewer adverse effects occurred (p = 0.07, simple logistic regression). CONCLUSIONS: Self-reported compliance with capecitabine-based therapy in clinical practice is high and seems to be adversely affected by side effects. PMID- 21606662 TI - Efficacy of temsirolimus after previous treatment with sunitinib, sorafenib or everolimus in advanced renal cell cancer. AB - OBJECTIVE: Temsirolimus inhibits the mammalian target of rapamycin with demonstrated efficacy in patients with advanced renal cell cancer. PATIENTS AND METHODS: We present a retrospective analysis of our single-center experience with temsirolimus in patients pretreated with sunitinib, sorafenib or everolimus. Sixteen patients were treated within our center starting in December 2006 until September 2009. The majority of patients (14 of 16) had received a prior antiangiogenic pretreatment. We further analyzed the efficacy of subsequent treatment with temsirolimus in these patients. RESULTS: Stable disease could be achieved in 8 of 14 pretreated patients (57%). The duration of median progression free survival was 10 weeks (range 1-43). Especially patients with a good response to previous antiangiogenic treatment, a good overall condition and a low Memorial Sloan Kettering Cancer Center (MSKCC) score benefited from subsequent treatment with temsirolimus. We did not see any complete or partial response meeting the World Health Organization criteria. Temsirolimus was well tolerated. CONCLUSION: Temsirolimus appears to be an effective and well-tolerated substance in the treatment of patients with a good performance status, low MSKCC score and stable disease under previous antiangiogenic treatment in advanced renal cell cancer. However, its use is highly questionable in pretreated patients with a poor performance score and a high MSKCC score. PMID- 21606663 TI - Incidence of non-AIDS-defining cancer in antiretroviral treatment-naive subjects after antiretroviral treatment initiation: an ACTG longitudinal linked randomized trials analysis. AB - BACKGROUND: Prospective data on factors associated with the non-AIDS-defining cancer (NADC) incidence in HIV-infected individuals are limited. METHODS: We examined the NADC incidence in 3,158 antiretroviral treatment (ART)-naive subjects after ART initiation in AIDS Clinical Trials Group trials; extended follow-up was available for 2,122 subjects. Poisson regression was used to examine the associations between covariates and incident NADC. RESULTS: At ART initiation, subjects (median age 37 years) were 40% non-Hispanic whites, and 82% were male; 23% had CD4+ T cell count <= 50 cells/mm3 and 25% had CD4 >350 cells/mm3. Median follow-up was 3.8 years. Among 64 incident NADCs, the most common were 8 anal cancers, 8 basal cell carcinomas, 8 Hodgkin's disease, and 6 lung cancers. In univariate models, age, smoking and recent (time-updated) CD4 were associated with incident NADC. There was no association between initial ART drug class (protease inhibitor, nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor) and NADC. After adjusting for age, race and sex: smoking [relative risk = 2.12 (95% CI = 1.1-4.08)] and recent CD4 (<= 50 cells/mm3: 3.58, 1.22-10.45; 51-200 cells/mm3: 2.54, 1.30-5.0; 201-350 cells/mm3: 2.37, 1.32-4.26 vs. >350 cells/mm3) were associated with NADC. CONCLUSION: Smoking and lower recent CD4 levels, but not initial ART drug class, were associated with NADC. Strategies for maintaining higher CD4 cell counts and successful smoking cessation may reduce the NADC incidence in the HIV-infected population. PMID- 21606664 TI - Defective polysialylation and sialylation induce opposite effects on gating of the skeletal Na+ channel NaV1.4 in Chinese hamster ovary cells. AB - Polysialic acid (polySia) is a large, negatively charged homopolymer of 2,8 linked N-acetylneuraminic acid residues resulting from remodeling and extension of protein-bound sialic acid (Sia) residues and seems to have a key role in regulating neural cell development and function. The aim of this study was to explore and compare the effects of polySia and sialylation on gating of voltage gated sodium channels. The skeletal muscle alpha-subunit NaV1.4 was transiently expressed in wild-type Chinese hamster ovary (CHO) cells or in mutant CHO cells with deficits in their capacity to produce sialylated or polysialylated membrane components. Expression in both mutant cell lines resulted in larger peak current amplitudes as compared to wild-type CHO cells. Loss of Sia and polySia also resulted in significant shifts of voltage-dependent activation and steady-state inactivation, however, in opposite directions. Furthermore, only the loss of Sia had a significant effect on recovery from fast inactivation. Our data demonstrate for the first time that gating of voltage-gated sodium channels seems to be differentially regulated by polySia and Sia. PMID- 21606665 TI - Effects of fear of falling on muscular coactivation during walking. AB - BACKGROUND AND AIMS: Increased fear of falling is associated with greater muscular coactivation during standing postural control. Excessive muscular coactivation reduces the performance of agonist muscles. Although several recent studies have observed increased muscular coactivation during walking in older adults, little is known about the relationship between fear of falling and muscular coactivation during walking. The purpose of this study was to compare muscular coactivation during walking between older adults with fear of falling and older adults without fear of falling. METHODS: Thirty-eight healthy older adults (82.3 +/- 6.8 years) participated in this study. Walking speed and step length were measured. Electromyography (EMG) data were collected from the tibialis anterior and soleus during walking to calculate the co-contraction index (CI). Subjects were divided into those with fear of falling and those without fear of falling, on the basis of a modified Falls Efficacy Scale (FES). Stepwise multiple regression analysis was used, with CI as the dependent variable, and fear of falling, experience of falling (during the past year), walking speed, step length, and age as independent variables. RESULTS: Mean values of CI during walking, walking speed, and step length were 51.9 +/- 11.7%, 0.90 +/- 0.40 m/s, and 0.43+/-0.11 m, respectively. Eight subjects (21.1%) had fallen within the past year, and 19 subjects (50.0%) had fear of falling. All subjects without fear of falling had FES scores of 10 (maximum score). Subjects with fear of falling had a median FES score of 17 (interquartile range, 13 to 25). Stepwise multiple regression analysis revealed that fear of falling remained significantly associated with CI (p<0.01): CIs for subjects with fear and those without fear were 59.5 +/- 12.2% and 46.7 +/- 8.5%, respectively. CONCLUSION: Individuals with a fear of falling have increased muscular co-activation at the ankle joint during walking, at least in a certain subgroup of older adults. Further research is needed to clarify negative and positive effects of muscular coactivation during walking in fearful subjects. PMID- 21606666 TI - Resumption of menses after 32 years in anorexia nervosa. AB - In anorexia nervosa estrogen deficient amenorrhea is associated with reduced bone mineral density and increased fracture risk. We report a case of a 53 years old female patient affected with AN since the age of 17 years when also amenorrhea started. During the subsequent 31 years she refused to modify her body weight, she always remained with a BMI below 17, and amenorrhea persisted throughout all the period. In November 2005, when she was 48 years old (BMI 15.6 kg/m2), she came to the Eating Disorder Unit of Niguarda Hospital to treat surgical complication of lower limb wound persisting after two operation; she also presented a marked reduction of bone density. After 6 months of intensive day hospital treatment she got a normal body weight and resumption of menses; in the following four years she has still been well and with normal menses, and bone density showed an improvement. PMID- 21606668 TI - Frequency of glycated hemoglobin monitoring was inversely associated with glycemic control of patients with Type 2 diabetes mellitus. AB - BACKGROUND: The frequency of monitoring glycated hemoglobin (HbA(1c)) and its impact on glycemic control of Chinese Type 2 diabetes mellitus (T2DM) patients have not been well understood. AIM: To explore the current status of the glycemic control, the frequency of HbA(1c) monitoring, and their relationship in T2DM outpatients in urban China. SUBJECTS AND METHODS: A cross-sectional study was carried out in 15 hospitals purposely sampled from 4 cities of China. T2DM outpatients were consecutively recruited, and underwent a face-to-face interview in outpatient consulting rooms using a self-developed structured questionnaire to collect information. All consented patients were invited to have a free HbA(1c) test. RESULTS: Among 1511 subjects, the average level of HbA(1c) was 8.1+/-1.6% with the ideal percents of 13.6% and 24.8% (HbA(1c)<6.5% and <7.0%, respectively). Less than 1/3 (339/1157) had received 2 or more HbA(1c) tests per yr, and they had a significantly lower average of HbA(1c) than those having only 1 or no test per yr (F=5.012, p=0.007). After adjustment for possible confounders including age, gender, and city, there was a significantly inverse association with adjusted odds ratios of 2.56 [95% confidence interval (CI): 1.71, 3.86] and 1.67 (95% CI: 1.11, 2.50), respectively, between the frequency of monitoring HbA(1c) (null, once vs >=2 times per yr) and worse glycemic control (HbA(1c)>=7.0%). CONCLUSIONS: Glycemic control of T2DM outpatients was poor in urban China. Frequency of HbA(1c) monitoring is seriously insufficient in majority of patients. Lower frequency of HbA(1c) monitoring is significantly associated with poor glycemic control. PMID- 21606669 TI - Defining vitamin D status by secondary hyperparathyroidism in the U.S. population. AB - BACKGROUND: Vitamin D is associated with a variety of health outcomes, but the exact definition of vitamin D sufficiency remains controversial. AIM: We sought to define skeletal-related vitamin D sufficiency by estimating maximum PTH suppression in the U.S. population. METHODS: We performed a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES), 2003 2006. We examined the association between serum 25-hydroxyvitamin D (25OHD) level and serum PTH level in 14,681 participants aged >=6 yr. We also evaluated the 25OHD-PTH association using 2 thresholds of hyperparathyroidism: PTH>=45 pg/ml and >=75 pg/ml. RESULTS: The mean 25OHD level was 24 ng/ml and mean PTH was 42 pg/ml. PTH>=45 pg/ml was present in 35% of the population, while PTH>=75 pg/ml was present in 7%. The prevalence of 25OHD levels <40 ng/ml and <30 ng/ml was 95% and 77%, respectively. In both unadjusted and adjusted models, there was a strong inverse relationship between 25OHD and PTH. Compared to 25OHD>=40 ng/ml, the 25OHD-PTH association was 2.36 [95% confidence interval (CI), 2.08-2.67] times greater for 25OHD<5 ng/ml and 1.12 (95%CI, 1.07-1.17) times greater for 25OHD 30 39.9 ng/ml. Compared to 25OHD>=40 ng/ml, 25OHD levels of 20- 29.9 ng/ml [odds ratio (OR) 2.0 (95%CI, 1.4-2.8)] but not 30- 39.9 ng/ml [OR 1.1 (95%CI, 0.8-1.6)] were independently associated with PTH>=45 pg/ml. CONCLUSIONS: Optimal vitamin D status, defined by estimated maximum PTH suppression, does not occur until at least 25OHD levels >=40 ng/ml. Using these thresholds, most of the U.S. population needs more vitamin D. Large, prospective studies are needed to determine optimal vitamin D supplementation. PMID- 21606667 TI - Understanding polycystic ovarian syndrome pathogenesis: an updated of its genetic aspects. AB - Polycystic ovary syndrome (PCOS) is the most frequent cause of female infertility. It is also characterized by metabolic defects that raise the risk for cardiovascular disease. Despite the progress in the definition of the clinical aspects of the syndrome, only very few definite data are available about the ethiopathogenetic mechanisms that subtend PCOS. It is likely that the PCOS phenotype derives from the interaction between environmental and genetic factors. While environmental factors have easily been investigated, the individuation of the genetic factors seem to be more complex. Indeed, PCOS appears to be inherited as a complex, polygenic trait. Several family studies have been conducted with the aim to clarify the genetic aspects of PCOS, but their findings are often conflicting and not conclusive.Moreover, it is difficult to establish with certainty which genes are involved and their effective role in the development of the syndrome because in PCOS, genetic analysis is hampered by low fecundity, lack of a male phenotype, absence of an animal model, and dissimilarity of the diagnostic criteria used to select the patients. Since multiple biochemical pathways are implicated in PCOS pathogenesis, genes of steroid hormone metabolism, gonadotropin release and action, insulin secretion and action, adipose tissue metabolism and others have been investigated. Nevertheless, none of them seems to play a key role in the ethiopathogenesis of PCOS. This article reviews the large body of literature generated to support the presence of genetic abnormalities in PCOS women by taking in consideration the most important studies regarding PCOS candidate genes. PMID- 21606670 TI - Association between circulating levels of adiponectin and indices of bone mass and bone metabolism in middle-aged post-menopausal women. AB - BACKGROUND: Adiponectin, a fat derived cytokine, is a potential independent contributor to bone mineral density (BMD); however, its action on bone metabolism in humans is still unclear. AIM: The aim of this study was to investigate the relationship of adiponectin with bone mass indices and bone metabolic markers in middle-aged post-menopausal women without diabetes. SUBJECTS AND METHODS: A random sample consisted of 81 post-menopausal women (age range 45-61 yr, osteopenic/osteoporotic no.=43) was studied. Lumbar-spine BMD (BMD(L2-L4)) and total-body bone mineral content (TBBMC) were measured with dual X-ray absorptiometry. Plasma levels of total and high-molecular weight (HMW) adiponectin, osteoprotegerin (OPG), soluble receptor activator of nuclear factor kappaB ligand (sRANKL) and IGF-I were determined. RESULTS: No association was observed between total or HMW adiponectin and BMD(L2-L4) or TBBMC. On the contrary, adiponectin levels were positively associated with OPG levels (partial r=0.276, p=0.015) and negatively with IGF-I (partial r=-0.438, p<0.001), in multiple regression models after adjustment for potential confounders. HMW adiponectin showed a negative association with IGF-I (partial r=-0.266, p=0.049) in the multiple regression models but not with OPG, TBBMC or BMD(L2-L4). CONCLUSIONS: Although we failed to show statistically significant association between circulating adiponectin levels and indices of bone mass in women during the postmenopausal period, we showed significant associations with OPG and IGF-I levels, suggesting an anabolic role of adiponectin, which may contribute in the understanding of the interplay between adipose tissue-derived hormones and bone metabolism. PMID- 21606671 TI - Effects of highly purified follicle-stimulating hormone on sperm DNA damage in men with male idiopathic subfertility: a pilot study. AB - BACKGROUND: Gonadotropins administration have been demonstrated effective for the treatment of idiopathic male infertility, even if no clear data regarding their specific mechanism of action on semen quality are at the moment available. AIM: To evaluate the effect of highly purified FSH (hpFSH) administration on standard semen parameters, sperm oxidative stress, and sperm chromatin structure and DNA fragmentation. MATERIAL AND METHODS: In the current prospective baseline controlled study, 36 subjects with male idiophatic infertility were enrolled. Baseline clinical and biochemical data were evaluated. Before and after 3 months of treatment with hpFSH, sperm samples were collected and standard semen analysis, reactive oxygen species (ROS) assessment and sperm DNA fragmentation were evaluated. RESULTS: A significant (p<0.05) improvement from baseline in standard seminal parameters was observed. A significant (p<0.05) reduction in sperm ROS levels and DNA fragmentation was observed. Statistically significant (p<0.05) correlations between variation in ROS levels and both seminal parameters and DNA fragmentation variations were detected. CONCLUSIONS: Three months of hpFSH administration seems to reduce ROS and DNA damage in subjects with male idiopathic subfertility improving semen parameters. Further evidences from well designed randomized double-blind placebo- controlled studies are needed in order to confirm our preliminary results. PMID- 21606672 TI - Insulitis in human type 1 diabetes: The quest for an elusive lesion. AB - The histopathology of type 1 diabetes is defined by a decreased beta-cell mass in association with insulitis, a characteristic lymphocytic infiltration limited to the islets of Langerhans and prominent in early stage disease in children. A cytotoxic T-cell mediated destruction of insulin-producing beta-cells is thought to be initiated by an unknown (auto)antigen, leading to the destruction > 75% of beta-cell mass at clinical diagnosis. Although considered to be pathognomonic for recent onset disease, insulitis has only been described in approximately 150 cases over the past century. This review describes the quest for this elusive lesion and gives its incidence in various patient subpopulations stratified for age of onset and duration of the disease. It discusses recent new insights into the regenerative capacity of the beta-cell mass in the pre-clinical stages of the disease and relates these findings to the inflammatory processes within the islet tissue. PMID- 21606673 TI - Histopaque provides optimal mouse islet purification kinetics: comparison study with Ficoll, iodixanol and dextran. AB - Islet transplantation has become a very promising treatment for type 1 diabetes. To facilitate further clinical improvements in this exciting field, rodent islets are used to evaluate new strategies and modifications. One method to purify islets is on a density gradient, although the optimal gradient component can be debated. N=6 separate mouse islet isolations were used and the resulting islets were separated and purified on either a Ficoll, Histopaque, Dextran or Iodixanol gradient. Islets were assessed for recovery, viability, purity and in vitro functionality. Aliquots were transplanted into diabetic mice to assess in vivo functionality and survival. There was no difference in the number of islets recovered across groups nor in the size of recovered islets. Use of a Ficoll or Histopaque gradient led to the most pure and viable islets in comparison to Dextran and Iodixanol. Functionally, islets isolated on a Ficoll gradient had the highest glucose-stimulated insulin release in vitro while performing equally to Histopaque and Dextran gradients in vivo. Using a Ficoll gradient, however, comes at a higher monetary cost. We recommend using a Histopaque gradient, which led to the isolation of viable and functional islets with a reduced cost as compared to a Ficoll gradient. PMID- 21606674 TI - Inhibition of the EGF receptor and ERK1/2 signaling pathways rescues the human epidermoid carcinoma A431 cells from IFNgamma-induced apoptosis. AB - Interferon gamma (IFNgamma) has been demonstrated to inhibit tumor growth in vivo as well as proliferation of multiple types of cultured transformed cells. In this study, we showed that IFNgamma promoted progressive death in A431 cells, overexpressing EGF receptor (EGFR). Based on the data provided by evaluating cell morphology, MTT assay, FACS analysis, and cleaved caspase-3 staining we concluded that the major cause of IFNgamma-induced A431 cell growth inhibition was not cell cycle arrest, but apoptosis. We investigated a role for the EGFR and ERK1/2 MAPK signaling pathways in IFNgamma-induced apoptosis of A431 cells. IFNgamma-induced cell death was accompanied by both an increase of the ERK1/2 MAPK activation and a simultaneous reduction of the EGFR activation. Activation of ERK1/2 was crucial for IFNgamma-induced cell death because MEK1/2 inhibitors, PD0325901 and U0126 efficiently protected cells from apoptosis by suppressing caspase-3 activation. Even though EGFR tyrosine kinase inhibitor AG1478 also rescued A431 cells from IFNgamma-induced apoptosis, unlike MEK1/2 inhibitors, it initiated G 1 arrest. Together, these results suggest that sustained inhibition of both EGFR and ERK1/2 leads to significant protection of the cells from IFNgamma-induced apoptosis, indicating important roles for the EGFR tyrosine kinase and ERK1/2 MAP-kinases in regulating A431 cell death. PMID- 21606675 TI - Limited role of Sirt1 in cancer protection by dietary restriction. AB - Dietary restriction (DR) has multiple beneficial effects, the two most prominently studied being an increased longevity and an increased cancer protection. Mammalian Sirt1 is a protein deacetylase that has been linked to DR. To explore the relation between Sirt1 and DR, we have examined here DR-induced cancer protection in mice overexpressing Sirt1 (2-3 fold) under its own regulatory elements (Sirt1-tg mice). In particular, we have subjected p53 deficient mice, carrying or not the Sirt1-tg allele, to every-other-day fasting (EOD), which is a type of DR that significantly delays cancer onset. As expected, EOD extended the survival of p53-heterozygous (p53 (+/-) ) mice. However, the extension of survival of p53-heterozygous mice by EOD was the same in the presence or absence of the Sirt1-tg allele. These results suggest that Sirt1 has a limited role in mediating cancer protection by DR in mammals. PMID- 21606676 TI - A herpesvirus kinase that masquerades as Akt: you don't have to look like Akt, to act like it. AB - The cellular protein synthesis machinery is tightly regulated and capable of rapid reaction to a variety of physiological inputs critical in stress-response, cell cycle control, cancer biology, and virus infection. One important strategy for stimulating protein synthesis involves the ser/thr kinase Akt, which subsequently triggers inactivation of the cap-dependent translational repressor 4E-BP1 by an mTOR-containing protein complex (mTORC1). A recent paper demonstrated that herpes simplex virus utilizes a remarkable tactic to activate mTOR in infected cells. Instead of using the cellular Akt, the virus produces a ser / thr kinase called Us3 that doesn't look like Akt, but masquerades as Akt. By making the Akt-like protein unrecognizable, this disguise allows it to bypass the strict limits normally imposed on the real cellular Akt. Importantly, preventing the virus Akt-imposter from triggering mTORC1 inhibited viral growth, suggesting a new way to block herpes simplex virus. This study also raises the possibility that other Akt-impersonators may lurk hidden in our own genomes, possibly contributing to diseases ranging from diabetes to cancer. PMID- 21606678 TI - Signaling at the gate: phosphorylation of the mitochondrial protein import machinery. AB - Protein import into mitochondria is an essential process in every eukaryotic organism. While most of the components of the import machinery have been identified and are mechanistically quite well understood, regulation of this process had been a largely neglected area of research in the past. Recently, we demonstrated for the first time that the translocase of the outer mitochondrial membrane (TOM) is phosphorylated and regulated by several cytosolic protein kinases. Among these, casein kinase 2 (CK2) governs the assembly of TOM complexes, while protein kinase A (PKA) controls translocase function. Here, we outline the current model of protein import regulation, together with additional mitochondrial functions of CK2 and PKA. We also reflect the data on mitochondria associated protein kinases and phosphatases in the model organism baker's yeast. PMID- 21606677 TI - Mouse chimeras as a system to investigate development, cell and tissue function, disease mechanisms and organ regeneration. AB - Chimeras are organisms composed of at least two genetically distinct cell lineages originating from different zygotes. In the laboratory, mouse chimeras can be produced experimentally; various techniques allow combining different early stage mouse embryos with each other or with pluripotent stem cells. Identification of the progeny of the different lineages in chimeras permits to follow cell fate and function, enabling correlation of genotype with phenotype. Mouse chimeras have become a tool to investigate critical developmental processes, including cell specification, differentiation, patterning, and the function of specific genes. In addition, chimeras can also be generated to address biological processes in the adult, including mechanisms underlying diseases or tissue repair and regeneration. This review summarizes the different types of chimeras and how they have been generated and provides examples of how mouse chimeras offer a unique and powerful system to investigate questions pertaining to cell and tissue function in the developing and adult organism. PMID- 21606679 TI - A critical role for UVRAG in apoptosis. AB - Autophagy and apoptosis are tightly regulated biological processes that are crucial for cell growth, development and tissue homeostasis. UVRAG (UV radiation resistance-associated gene), a mammalian homolog of yeast Vps38, activates the Beclin 1/PtdIns3KC3 (class III phosphatidylinositol-3-kinase) complex, which promotes autophagosome formation. Moreover, UVRAG promotes autophagosome maturation by recruiting class C Vps complexes (HOPS complexes) and Rab7 of the late endosome. We found that UVRAG has anti-apoptotic activity during tumor therapy through interactions with Bax. UVRAG inhibits Bax translocation from the cytosol to mitochondria during chemotherapy- or UV irradiation-induced apoptosis of human tumor cells. Moreover, deletion of the UVRAG C2 domain abolishes Bax binding and anti-apoptotic activity. These results suggest that, in addition to its previously recognized pro-autophagy activity in response to starvation, UVRAG has cytoprotective functions in the cytosol that control the localization of Bax in tumor cells exposed to apoptotic stimuli. PMID- 21606680 TI - Simultaneous assessment of autophagy and apoptosis using multispectral imaging cytometry. AB - Multiple stress pathways result in the induction of autophagy and apoptosis. Current methods (e.g., protein gel blot, microscopy) do not offer quantitative single-cell resolution, thus making it difficult to discern if these pathways are mutually exclusive or, in some situations, cooperative in executing cell death. We report a novel method that enables high-throughput, high-content assessment of LC3 puncta and caspase-3 cleavage at the single cell level. PMID- 21606681 TI - Leucine-rich repeat (LRR) proteins: integrators of pattern recognition and signaling in immunity. AB - The leucine-rich repeats (LRR)-containing domain is evolutionarily conserved in many proteins associated with innate immunity in plants, invertebrates and vertebrates. Serving as a first line of defense, the innate immune response is initiated through the sensing of pathogen-associated molecular patterns (PAMPs). In plants, NBS (nucleotide-binding site)-LRR proteins provide recognition of pathogen products of avirulence (AVR) genes. LRRs also promote interaction between LRR proteins as observed in receptor-coreceptor complexes. In mammals, toll-like receptors (TLRs) and NOD-like receptors (NLRs) through their LRR domain, sense molecular determinants from a structurally diverse set of bacterial, fungal, parasite and viral-derived components. In humans, at least 34 LRR proteins are implicated in diseases. Most LRR domains consist of 2-45 leucine rich repeats, with each repeat about 20-30 residues long. Structurally, LRR domains adopt an arc or horseshoe shape, with the concave face consisting of parallel beta-strands and the convex face representing a more variable region of secondary structures including helices. Apart from the TLRs and NLRs, most of the 375 human LRR proteins remain uncharacterized functionally. We incorporated computational and functional analyses to facilitate multifaceted insights into human LRR proteins and outline a few approaches here. PMID- 21606682 TI - The protective role of autophagy against aging and acute ischemic injury in kidney proximal tubular cells. AB - In kidney, proximal tubules consume a large amount of energy in the process of electrolyte reabsorption. These tubules contain large quantities of mitochondria which provide the energy for this reabsorption. Proximal tubules are susceptible to many kinds of insults such as ischemia-reperfusion injury and nephrotoxic substrates, but little is known of the factors that counteract cellular stress signaling pathways. Autophagy mediates bulk degradation and recycling of cytoplasmic constituents to maintain cellular homeostasis. We demonstrated the critical role of autophagy in normal proximal tubule function and protection against acute tubular injury. PMID- 21606683 TI - Bacterial toxins can inhibit host cell autophagy through cAMP generation. AB - Autophagy plays a significant role in innate and adaptive immune responses to microbial infection. Some pathogenic bacteria have developed strategies to evade killing by host autophagy. These include the use of 'camouflage' proteins to block targeting to the autophagy pathway and the use of pore-forming toxins to block autophagosome maturation. However, general inhibition of host autophagy by bacterial pathogens has not been observed to date. Here we demonstrate that bacterial cAMP-elevating toxins from B. anthracis and V. cholera can inhibit host anti-microbial autophagy, including autophagic targeting of S. Typhimurium and latex bead phagosomes. Autophagy inhibition required the cAMP effector protein kinase A. Formation of autophagosomes in response to rapamycin and the endogenous turnover of peroxisomes was also inhibited by cAMP-elevating toxins. These findings demonstrate that cAMP-elevating toxins, representing a large group of bacterial virulence factors, can inhibit host autophagy to suppress immune responses and modulate host cell physiology. PMID- 21606684 TI - Development of p97 AAA ATPase inhibitors. AB - Specific p97 inhibitors are valuable research tools to carry out mechanistic and cellular investigations of p97 biology. p97 is an abundant, ubiquitin-selective chaperone that has multiple functions and is essential for life. Therefore, genetic methods that require long incubations like siRNA or expression of dominant-negative p97 mutants are likely to generate complicated outcomes due to secondary consequences that arise upon slow depletion of p97 activity. We recently identified a small molecule p97 inhibitor, N ( 2) ,N ( 4) dibenzylquinazoline-2,4-diamine (DBeQ), and documented its effects on blocking autophagic degradation of LC3-II and proteasomal degradation of a p97-dependent ubiquitin-proteasome system (UPS) substrate. What distinguishes DBeQ from conventional proteasome inhibitors is that DBeQ affects both the UPS and autophagic protein degradation pathways and rapidly activates cell death. Whether DBeQ activates autophagic and/or apoptotic cell death will require further work to evaluate its detailed mechanism of action. An exciting goal for the future will be to generate p97 inhibitors that affect one or the other pathway. We propose that generation of 'separation of function' inhibitors will be a challenging adventure for chemical biologists but will yield extremely powerful tools to study p97 and enable evaluation of the therapeutic potential of targeting distinct p97 complexes. PMID- 21606685 TI - Economic evaluation of a vaccine for the prevention of herpes zoster and post herpetic neuralgia in older adults in Switzerland. AB - BACKGROUND: A life-attenuated vaccine aimed at preventing herpes zoster (HZ) and its main complication, post-herpetic neuralgia (PHN), will soon be available in Europe. The study's objective was to assess the clinical and economic impact of a vaccination program for adults aged 70-79 years in Switzerland. RESULTS: A vaccination strategy compared to a no-vaccination resulted in lifetime incremental cost-effectiveness ratios (ICERs) of 25,538 CHF (23,646 USD) per QALY gained, 6,625 CHF (6,134 USD) per HZ case avoided, and 15,487 CHF (14,340 USD) per PHN3 case avoided under the third-party payer perspective. Sensitivity analyses showed that the model was most sensitive to the discount rates, HZ epidemiological data and vaccine price used. METHODS: A Markov model, simulating the natural history of HZ and PHN and the lifetime effects of vaccination, previously developed for the UK was adapted to the Swiss context. The model includes several health states including good health, HZ, PHN, and death. HZ and PHN states reflected pain severity. CONCLUSION: The model predicts clinical and economic benefits of vaccination in the form of fewer HZ and PHN cases and reductions in healthcare resource use. ICERs were within the commonly accepted thresholds in Switzerland, indicating that a HZ vaccination program would be considered a cost-effective strategy in the Swiss setting. PMID- 21606686 TI - Correlates of immune protection: Standardized and automated assays to interrogate correlates of immunity--Phacilitate Vaccine Forum Washington 2011. The Grand Hyatt, Washington, DC January 24-26, 2011. AB - The utility of functional cell mediated immune assays in the assessment of immune response or immunogenicity is increasing significantly as we search for surrogates to determine vaccine efficacy or therapeutic response. No definitive reports to date have demonstrated that CMI assays in human clinical trials correlate with clinical outcome, although animal and non human primate studies have reported surrogacy in varying degrees. This report discusses the approaches identified, their advantages and disadvantages, and their justification for inclusion in the clinical trial setting. PMID- 21606689 TI - The self and Asperger syndrome. PMID- 21606687 TI - Plant NBR1 is a selective autophagy substrate and a functional hybrid of the mammalian autophagic adapters NBR1 and p62/SQSTM1. AB - (Macro)autophagy encompasses both an unselective, bulk degradation of cytoplasmic contents as well as selective autophagy of damaged organelles, intracellular microbes, protein aggregates, cellular structures and specific soluble proteins. Selective autophagy is mediated by autophagic adapters, like p62/SQSTM1 and NBR1. p62 and NBR1 are themselves selective autophagy substrates, but they also act as cargo receptors for degradation of other substrates. Surprisingly, we found that homologs of NBR1 are distributed throughout the eukaryotic kingdom, while p62 is confined to the metazoans. As a representative of all organisms having only an NBR1 homolog we studied Arabidopsis thaliana NBR1 (AtNBR1) in more detail. AtNBR1 is more similar to mammalian NBR1 than to p62 in domain architecture and amino acid sequence. However, similar to p62, AtNBR1 homo-polymerizes via the PB1 domain. Hence, AtNBR1 has hybrid properties of mammalian NBR1 and p62. AtNBR1 has 2 UBA domains, but only the C-terminal UBA domain bound ubiquitin. AtNBR1 bound AtATG8 through a conserved LIR (LC3-interacting region) motif and required co expression of AtATG8 or human GABARAPL2 to be recognized as an autophagic substrate in HeLa cells. To monitor the autophagic sequestration of AtNBR1 in Arabidopsis we made transgenic plants expressing AtNBR1 fused to a pH-sensitive fluorescent tag, a tandem fusion of the red, acid-insensitive mCherry and the acid-sensitive yellow fluorescent proteins. This strategy allowed us to show that AtNBR1 is an autophagy substrate degraded in the vacuole dependent on the polymerization property of the PB1 domain and of expression of AtATG7. A functional LIR was required for vacuolar import. PMID- 21606690 TI - Thrombocytosis in patients with polycystic ovary syndrome: reactive or culpable? PMID- 21606691 TI - Hydatid cyst disease revisited: optimal management of complex liver disease. PMID- 21606692 TI - Is it time for carotid artery stenting in low-risk patients? PMID- 21606693 TI - Protected carotid artery stenting in patients at high risk for carotid endarterectomy. AB - OBJECTIVES: To compare the 30-day, six-month, and one-year outcomes of carotid artery stenting (CAS) and carotid endarterectomy (CEA) in male veterans, and to identify any predictors of adverse outcomes. CAS has been shown to be non inferior to CEA in patients at high-risk for CEA. The outcome of CAS compared to low-risk CEA is less clear. METHODS: Retrospective analysis of 96 consecutive patients who underwent CAS (N = 31) or CEA (N = 65). The cumulative 30-day, six month, and one-year incidence of ipsilateral transient ischemic attack (TIA) or stroke, restenosis or reocclusion, need for target vessel revascularization, non fatal myocardial infarction (MI), and death were compared. RESULTS: All patients in the CAS group were at high risk for CEA. Among the CEA group, 50 (76.9%) were at high risk and the remaining 15 (23.1%) were considered to be at low risk. The cumulative incidence of adverse outcomes with CAS and CEA, respectively, at 30 days (3.2% vs 9.2%, P = ns), six months (3.2 vs 18.5%, P = 0.047), and one year (9.7% vs 18.5%, P = ns) favored CAS. This difference was primarily due to adverse events in the high-risk CEA patients. There was no significant difference in outcome between the CAS and low-risk CEA groups. The independent significant predictors for adverse outcomes within six months were the group (P = 0.047) and number of risk factors (P = 0.01). Interestingly, the use of angiotensin converting enzyme inhibitors (ACE-I) predicted adverse outcomes within one year (P = 0.01). CONCLUSION: CAS may be superior to high-risk CEA with better six month outcomes. The outcomes with CAS were not significantly different compared to low-risk CEA, suggesting that CAS may be non-inferior to low-risk CEA. PMID- 21606694 TI - Asperger disorder in adults. AB - Asperger disorder was first described in 1944 by the Austrian pediatrician, Hans Asperger. It was introduced as a separate diagnostic category from autistic disorder in DSM-IV and ICD-10. The pattern of comorbidity in Asperger disorder is different from autistic disorder, with a higher level of psychosis, violent behavior, anxiety, and mood disorders. We present three cases of Asperger disorder diagnosed for the first time in adulthood, with psychosis being the predominant reason for the referral. In each case, the psychosis improved with antipsychotic treatment, although core autistic symptoms remained the same. PMID- 21606695 TI - Diffuse alveolar hemorrhage. AB - Diffuse alveolar hemorrhage (DAH) is a life-threatening disorder characterized clinically by the presence of hemoptysis, falling hematocrit, diffuse pulmonary infiltrates and hypoxemic respiratory failure. It refers to bleeding that originates in the pulmonary microvasculature instead of the parenchyma or bronchial circulation. DAH should be considered a medical emergency due to the morbidity and mortality associated with failure to treat the disorder promptly. Pulmonary renal syndromes, connective tissue disorders and drugs make up the majority of the cases of DAH. The treatment of DAH ranges from supportive care and withdrawal of offending drugs to high-dose steroids, immunosuppresents and plasmapharesis. The following review will discuss the clinical, radiographic and pathologic findings in a variety of disorders that cause DAH. Standard treatment options, as well as new treatment options will also be discussed. PMID- 21606696 TI - Diffuse alveolar hemorrhage. PMID- 21606697 TI - Isolated unilateral absence of the right pulmonary artery. AB - Isolated unilateral absence of the right pulmonary artery is an uncommon congenital disorder that may remain undiagnosed for prolonged periods of time. A brief overview of isolated unilateral absence of the right pulmonary artery is presented with a description of the typical clinical and radiographic findings associated with this anomaly. PMID- 21606698 TI - Gastrointestinal Kaposi sarcoma with appendiceal involvement. AB - Kaposi sarcoma is a vascular tumor manifesting as nodular lesions on skin, mucous membranes, or internal organs. This is a case of a 42-year-old human immunodeficiency virus- (HIV) positive bisexual male, not on highly active antiretroviral therapy (HAART) since diagnosis four years ago. He presented with a three-day history of abdominal pains, fever, vomiting, and a one-week history of melena stools. Endoscopy revealed Kaposi sarcoma in the stomach and duodenum. Postendoscopy, he developed acute abdomen. Exploratory laparotomy revealed extensive Kaposi sarcoma of the gastrointestinal tract with appendiceal involvement. The patient underwent appendectomy and had an uneventful recovery. A review of the literature discusses appendiceal Kaposi sarcoma with appendicitis, a rare but critical manifestation of gastrointestinal Kaposi sarcoma. PMID- 21606699 TI - Constrictive-like physiology in severe pulmonary hypertension: the effect of the Valsalva maneuver. AB - We describe the case of a 37-year-old female with severe pulmonary hypertension on intravenous Remodulin and Tracleer who experienced presyncope following a six minute walk. A transthoracic echocardiogram, in addition to showing the usual findings of chronic pulmonary hypertension, also demonstrated a noticeable increase in both mitral annular systolic and early diastolic (E') velocities while performing the Valsalva maneuver. Most importantly, a significant increase in the propagation velocity to an almost perpendicular tilt was noted with Valsalva, resembling the propagation velocity profile that has only been previously described in cases of constrictive pericarditis. The clinical relevance of this finding and the pathophysiologic implications are reviewed and discussed. PMID- 21606700 TI - Constrictive-like physiology in severe pulmonary hypertension: the effect of the Valsalva maneuver. PMID- 21606701 TI - Thrombocytopenia following 90Yttrium glass microsphere liver radioembolization. PMID- 21606702 TI - Duloxetine-induced tako-tsubo cardiomyopathy: implications for preventing a broken heart. PMID- 21606703 TI - Metastatic Staphylococcus aureus bloodstream infections: don't dare not to show respect. PMID- 21606704 TI - Surgical intervention for peritoneal dialysis associated refractory Pseudomonas peritonitis: using water to put out a forest fire. PMID- 21606705 TI - Food allergy: an overdiagnosed but underappreciated problem. PMID- 21606706 TI - Comparing the aspartate aminotransferase (AST) to platelet ratio index (APRI) between African American and White veterans with chronic hepatitis C. AB - OBJECTIVES: The study of noninvasive markers of fibrosis, such as aspartate aminotransferase (AST) to platelet ratio index (APRI), have been limited in African American populations. Given the disparate outcomes of chronic hepatitis C in African American populations, comparative analyses of the APRI score should be undertaken. Compare the diagnostic accuracy of the APRI score for significant fibrosis and cirrhosis in a sample of African American and white veterans with chronic hepatitis C in the southeastern United States. METHODS: We identified 268 veterans with chronic hepatitis C who had received a liver biopsy. The APRI score was calculated using laboratory values obtained within 180 days of liver biopsy and compared to the fibrosis stage (F0-F4). Performance characteristics of the APRI score for determining stages of fibrosis were compared in African American (n = 142) and white (n = 117) individuals. RESULTS: An APRI score of 0.99 had a comparably high negative predictive value for significant fibrosis (F3-F4) in African American 0.90 and white veterans (0.83). For cirrhosis (F4), an APRI score of 1.0 provided a negative predictive value of 0.96 in the African American subset and 0.94 in the white subset. We did not detect any difference in the performance of the APRI score for predicting stages of fibrosis between the two groups. CONCLUSION: The APRI score displayed similar performance in African Americans and whites. A threshold of 1.0 can reliably exclude cirrhosis in African American veterans with chronic HCV infection. PMID- 21606707 TI - Impact of tracheal mucosa involvement on clinical characteristics of sarcoidosis. AB - OBJECTIVES: To investigate the impact of tracheal mucosa involvement on the clinical features of sarcoidosis. METHODS: The clinical data of sarcoidosis patients with (Group A, n = 26) and without (Group B, n = 61) tracheal mucosa involvement were evaluated retrospectively. RESULTS: The proportion of patients suffering from cough in Group A was 92.3%, which was significantly higher than that in Group B (49.2%). The level of serum angiotensin-converting enzyme I (SACE) in Group A (60.7 +/- 27.8 IU/L) was significantly higher than that in Group B (44.5 +/- 31.9 IU/L). The proportion of lymphocytes in the bronchoalveolar lavage fluid (BALF) in Group A was significantly higher than that of Group B (45.3 +/- 16.8% and 36.7 +/- 15.1%, respectively; P = 0.047). The ratio of CD4 to CD8 in Group A was significantly higher than that in Group B (7.6 +/- 5.4 and 3.1 +/- 3.2, respectively; P = 0.005). In Group A, 84.6% patients received drug treatment, with a spontaneous remission rate of 15.4%. In Group B, 50.2% patients received drug treatment and the spontaneous remission rate was as high as 49.2%. CONCLUSIONS: Sarcoidosis with tracheal mucosa involvement that can lead to cough and other respiratory symptoms, may be a manifestation of sarcoidosis activity, and usually requires drug treatment (including corticosteroid treatment). PMID- 21606708 TI - Association of Chlamydia pneumoniae serology and ischemic stroke. AB - BACKGROUND: Stroke is one of the major causes of morbidity and mortality throughout the world. Reports about the role of Chlamydia pneumoniae infection in the development of atherosclerosis have been reported in many studies. The aim of the study was to evaluate the association between Chlamydia pneumoniae infection and ischemic stroke. METHODS: We evaluated 50 patients with ischemic stroke (32 males and 18 females) and 40 control subjects (22 males and 18 females). They were age- and sex-matched. All enrolled subjects underwent an enzyme-linked immunosorbent assay (ELISA) serologic test for IgG and IgA antibodies for Chlamydia pneumoniae. RESULTS: Eighteen (36%) patients with ischemic stroke have positive IgA, in comparison with 6 (15%) among the control group (OR 3.18; CI 1.12-9.04; P = 0.03). This translates into the fact that there was a more than three-fold risk of developing ischemic stroke in those with Chlamydia pneumoniae infection compared to those who without. The IgG seropositivity was increased in patients with ischemic stroke, but it did not reach statistical significance (OR = 2.32; CI = 0.97-5.58; P = 0.078). CONCLUSIONS: Chronic Chlamydia pneumoniae infection demonstrated by positive IgA-type antibody can be considered a significant risk for ischemic stroke. PMID- 21606709 TI - Hospitalizations of children and young adults from peanut-induced anaphylaxis in Texas. AB - OBJECTIVE: Population-based studies of peanut anaphylaxis in Texas children and young adults are lacking. The objective of this investigation was to report the clinical and demographic features of children discharged throughout Texas with a diagnosis of anaphylaxis triggered by peanut consumption and calculate the peanut anaphylaxis hospitalization rate by age group. METHODS: Public-use statewide Texas hospital discharge data for the years 2004 through 2007 were analyzed. Patients under the age of 25 years who were Texas residents were included in the study if their principal or secondary diagnosis was anaphylactic shock due to peanut, ICD-9-CM code 995.61. Clinical and demographic features were summarized. Peanut anaphylaxis hospitalization rates were calculated by dividing the number of hospitalizations in a particular age group by the appropriate Texas resident population estimate. RESULTS: Thirty-four patients were identified, 23 of whom (67.7%) were male. The majority (91%) of the patients were emergency or urgent admissions. After controlling for patient sex and whether or the not patient was self-pay, asthmatics were more likely than non-asthmatics to have received mechanical ventilation (adjusted exact odds ratio = 15.98, P = 0.01). The highest risk of peanut anaphylaxis hospitalization was in the youngest age group, children under five years 1.9/1 million. CONCLUSION: Epidemiologic analysis of a statewide hospital discharge database revealed that the highest risk of peanut anaphylaxis hospitalization in Texas children and young adults was in children under five years. Asthmatics were significantly more likely than non-asthmatics to receive mechanical ventilation during their hospitalization. PMID- 21606710 TI - Vitamin D deficiency in patients with congestive heart failure: mechanisms, manifestations, and management. AB - Recent research suggests that vitamin D may play a role in cardiovascular (CV) health. Although its exact role is still debated and is a matter of controversy, vitamin D deficiency has been linked to increased prevalence of CV risk factors and events. Factors that predispose persons with congestive heart failure (CHF) to hypovitaminosis D include nutritional deficiency, decreased skin production, reduced intestinal absorption, and hepatorenal disease. It is possible that low vitamin D can in turn aggravate CHF. The extent of deficiency can be severe enough to cause hypocalcemia, secondary hyperparathyroidism, osteomalacia, and decreased bone density. No clear data exist showing improvement in CV clinical outcomes with vitamin D replacement. Screening is advocated in most patients, although benefits of replacement are most likely to accrue in those with severe lack or with abnormalities of calcium-parathyroid-bone metabolism. According to current guidelines and research, vitamin D goals of >20 ng/ml in most patients with CHF and >30 ng/ml in those with secondary hyperparathyroidism seem to be appropriate to aim for. Further research is needed to fully unravel the association among CV risk, CHF and hypovitaminosis D, and translate this knowledge into clinically meaningful management recommendations. PMID- 21606711 TI - Protean manifestations of vitamin D deficiency, part 1: the epidemic of deficiency. AB - Just when vitamin deficiencies were thought to be a "thing of the past" a new vitamin deficiency-that of vitamin D has developed over the past 20 years. Vitamin D works like a hormone being produced primarily in one organ (the kidney) before circulating through the bloodstream to multiple organs where it has multiple effects. The increased prevalence of vitamin D deficiency is due to changes in modern lifestyle-mainly lack of exposure to sunlight and the increased prevalence of obesity that, results in sequestration of this fat-soluble vitamin in adipose tissue. Distance from the Equator and increasing age and skin pigmentation are additional risk factors. In pregnancy vitamin D deficiency can result in low birth weight, pre-term labor, pre-term birth, infections, and pre eclamptic toxemia. While vitamin D deficiency is classically associated with rickets and osteomalacia, its effects are much more protean. PMID- 21606712 TI - Protean manifestations of vitamin D deficiency, part 2: deficiency and its association with autoimmune disease, cancer, infection, asthma, dermopathies, insulin resistance, and type 2 diabetes. AB - Vitamin D deficiency is epidemic and its manifestations are protean. Vitamin D deficiency is associated with autoimmune diseases (particularly multiple sclerosis and type 1 diabetes) and has been associated with infection, allergy, asthma, and dermopathies (particularly psoriasis). Asthma may be worsened by vitamin D deficiency and correction of the deficiency has been shown to improve the manifestations of asthma. Vitamin D deficiency has been associated with multiple cancers, including those of the breast, colon, ovary, and prostate. Due mainly to increased insulin resistance but also to an impairment in insulin release, vitamin D deficiency is associated with the development of type 2 diabetes. In addition, the complications of diabetes may be worsened by vitamin D deficiency. PMID- 21606713 TI - Protean manifestations of vitamin D deficiency, part 3: association with cardiovascular disease and disorders of the central and peripheral nervous systems. AB - Vitamin D deficiency is associated with the risk factors of inflammation, insulin resistance and endothelial dysfunction, and left ventricular hypertrophy. As a result there is an increase in cardiovascular events (CVEs) associated with vitamin D deficiency. Vitamin D deficiency itself or secondary hyperparathyroidism or both may be responsible for the increase in CVEs. Correction of vitamin D deficiency may decrease the incidence of CVEs. Vitamin D deficiency is also associated with Alzheimer disease, schizophrenia, depression, and chronic pain and muscle weakness. Vitamin D deficiency is early treated with oral vitamin D supplements which may improve the manifestations of the diseases associated with vitamin D deficiency. PMID- 21606714 TI - "Tako-tsubo" cardiomyopathy and duloxetine use. AB - We report the case of a 68-year-old woman in whom the use of duloxetine, a potent serotonin and norepinephrine reuptake inhibitor, was associated with "tako-tsubo" cardiomyopathy (TTC). Although several pathophysiological mechanisms for TTC have been proposed, available evidence suggests that an excess of catecholamines may play a major role. Our patient had a history of myocardial infarction with normal coronary arteries, probably the first manifestation of TTC. We speculate that duloxetine may have precipitated TTC by increasing plasma catecholamine concentration in a predisposed patient. PMID- 21606715 TI - Tumor-induced osteomalacia (TIO): atypical presentation. AB - Tumor-induced osteomalacia is a rare acquired condition characterized by phosphaturia, hypophosphatemia and osteomalacia. We report an unusual presentation in a 15-year-old healthy male with a two-week history of cough and chest pain. The chest radiograph showed right middle lobe opacity and chest CT revealed a mass in the extra pleural space. A biopsy showed chondro-myxoidstroma with osteoid formation. Diagnosis was confirmed with the above findings and hypophosphatemia. The patient's symptoms resolved after complete surgical excision of the mass. Tumor-induced osteomalacia, although a rare disorder, can be a diagnostic challenge, especially in patients presenting with atypical symptoms. PMID- 21606716 TI - Large blood transfusion as a rare cause of ventricular fibrillation. AB - Large blood transfusions are common in clinical practice. Though several complications have been described with this procedure, cardiac arrhythmias occur uncommonly in this setting. We describe a case of a previously healthy 17-year old girl who developed wide-complex ventricular tachycardia rapidly culminating in a ventricular fibrillation cardiac arrest several hours following an uneventful large-volume blood transfusion. Hypomagnesemia was detected on postcardiac arrest investigations. A review of this life-threatening complication and discussion on the ways to prevent it are presented. PMID- 21606717 TI - Giant mediastinal mass: thymolipoma. AB - A 26-year-old man presented with shortness of breath on exertion that was gradually getting worse. His history revealed a mass in the left hemithorax that had been growing on follow-ups. Physical examination only showed that the respiratory sounds were fainter on the left. Thoracic computerized tomography was performed to elucidate the left hemithorax lesion seen on chest x-ray and a giant mass of lipid density extending from the anterior mediastinum to the diaphragm and filling almost the entire left hemithorax was observed. Total excision of the 25 * 21 * 8 cm mass weighing 1580 g was performed with a left thoracotomy. The histopathology investigation of the mass was reported as thymolipoma. The case was presented because it is a rare mediastinal mass. PMID- 21606718 TI - Metastatic methicillin-sensitive Staphylococcus aureus infection. AB - Staphylococcus aureus bacteremia (SAB) is a common and increasingly recognized hospital- and community-acquired infection. To minimize morbidity and mortality, it is essential to determine which patients are at high risk for metastatic SAB. The risk-scoring system described by Fowler et al and the APACHE II scoring system can be helpful in identifying the clinical predictors of metastatic SAB. Herein we describe a case of metastatic methicillin-sensitive SAB in a previously healthy 19-year-old woman that was complicated by a disseminated pneumonia, an ischemic toe, and an acute intracranial hemorrhage. We also discuss the clinical factors associated with increased risk for complications from SAB and the currently available treatment options. PMID- 21606719 TI - Pelvic tuberculosis and shock in the puerperium. AB - Pelvic tuberculosis (TB) in pregnancy and puerperium is rare. Its atypical presentation as puerperal shock is more rare. We describe a case of pelvic TB that manifested as shock in a teenager who was two weeks postpartum. She failed to respond to antibiotics. Ziehl-Neelsen staining of aspirated pus from the left fossa collection in the abdominal cavity was positive for mycobacterium TB. Prompt treatment with antitubercular therapy could save patients from this life threatening condition. PMID- 21606720 TI - Fever of unknown origin from a left atrial myxoma: an immunologic basis and cytokine association. AB - Myxoma is the most common primary tumor of the heart. The typical presentations include a triad of embolic phenomena, intracardiac flow obstruction, and constitutional symptoms. We report a case of cardiac myxoma presenting as prolonged fever. Leukocytosis with a left shift, anemia, and elevated C-reactive protein were noted. A large left atrial myxoma was found incidentally by chest computed tomography. The fever subsided after surgical removal of the myxoma. His elevated serum interleukin-4 (IL-4), IL-6, IL-12 p70, interferon-gamma, and tumor necrosis factor-alpha returned to undetectable levels four days after surgery. Cardiac myxomas should be included in the differential diagnosis of prolonged fever, even though no typical symptoms could be found. PMID- 21606721 TI - Cryptococcal endocarditis. AB - Fungal infections of the heart are increasingly described especially in immunocompromised patients. Cardiac involvement can present with myocarditis, pericarditis or endocarditis. Cryptococcal endocarditis is extremely rare, with only four reported cases in the literature. The prognosis, natural history and the optimal management for cryptococcal endocarditis are not well described because of paucity of cases. We report the case of a patient with prosthetic aortic valve endocarditis due to C. neoformans. The diagnosis was confirmed with transthoracic and transesophageal echocardiogram, blood cultures that were positive for C. neoformans and high titers of cryptococcal antigen in the serum. The patient was successfully treated with liposomal amphotericin without surgical intervention. PMID- 21606722 TI - Chylous ascites as a rare complication after abdominal aortic aneurysm surgery. AB - Chylous ascites is a rare complication, and the treatment, which includes conservative and surgical strategies, is controversial. We describe two cases of chylous ascites that occurred after abdominal aortic aneurysm surgery. The first patient died of underlying diseases despite conservative treatment, while in the second patient, chylous ascites resolved with conservative treatment. In this article, we will discuss the management of chylous ascites, which vascular surgeons may face as a complication after abdominal aortic aneurysm surgery. PMID- 21606723 TI - Acquired factor VIII inhibitor (acquired hemophilia A) presenting as spontaneous blood-filled scrotum. AB - Acquired hemophilia A, also known as acquired factor VIII deficiency, is an exceedingly rare bleeding diathesis that does not require any personal or family history of bleeding or clotting disorder. Because treatment is available, misdiagnosing or completely missing this diagnosis can be life threatening for patients. Clinicians should be aware that acquired forms of hemophilia do exist and are associated with high morbidity and mortality in elderly adults. We present a case of a 74-year-old man who was diagnosed with acquired factor VIII inhibitor during an admission for community-acquired pneumonia. PMID- 21606724 TI - Acute lithium intoxication: properly directing an index of suspicion. AB - Lithium is known for its efficacy and toxicity. Toxic effects have been characterized even with therapeutic levels. Most physicians will at some point be faced with a patient with altered mental status and no records of his or her history. The differential diagnosis of altered mental status is long, and further lengthens in a patient with a psychiatric history. Since several life-threatening complications of psychotropic medications exist, physicians must be astute with their diagnoses. Lithium toxicity, neuroleptic malignant syndrome, and the serotonin syndrome can present similarly and require rapid recognition. We present a case of lithium toxicity in a patient who presented with altered mental status and a paucity of history information. PMID- 21606725 TI - Early surgical intervention of peritoneal dialysis catheter-related Pseudomonas peritonitis. AB - We present two cases of peritoneal dialysis (PD) catheter-related Pseudomonas peritonitis that were poorly responsive to treatment guidelines of antibiotics and early catheter removal, and uncommonly complicated with ongoing intractable infections. An emergency exploratory laparotomy with extensive intraoperative peritoneal lavage and drainage was performed. The patients recovered dramatically and were transferred to hemodialysis permanently. These unusual cases show the possibility of persistent intra-abdominal infection that may extend extra abdominally. Early diagnosis of persistent infection, timely surgical intervention, and concept of source control are of utmost importance. PMID- 21606726 TI - Isolated septic discitis associated with Streptococcus bovis bacteremia. AB - Streptococcus bovis is a Gram-positive coccus that can be found in the intestinal flora of healthy people; it is also associated with colon cancer and infective endocarditis. We report on a 79-year-old male who initially presented with acute onset lower back pain. Streptococcus bovis was detected in repeated blood cultures, and magnetic resonance imaging of the lumbar spine revealed septic discitis of the L2-L3 intervertebral disc. Excision and debridement of the intervertebral disc was performed and a tissue culture tested positive for S. bovis. Repeat echocardiography and colonoscopy showed no signs of vegetation or tumor lesions, respectively. We diagnosed the patient with isolated septic discitis caused by S. bovis-induced bacteremia. The patient was discharged after six weeks of antibiotic therapy. PMID- 21606727 TI - Multiorgan failure following mass wasp stings. AB - Wasp bites usually bring temporary discomfort and pain, but on occasion, they can cause serious infections and fatal allergic reactions. We report on a patient who experienced massive wasp stings and developed multiple organ failure, including acute kidney, hepatic failure, and circulatory collapse 4 days later. He was treated with aggressive fluid resuscitation, inotropic agent, intravenous injection of steroids, broad-spectrum antibiotics, and hemodialysis. After intensive treatment, his liver function recovered one month later. Recovery of renal function was delayed, and the patient needed temporary regular hemodialysis. The pathology of kidney biopsy showed acute tubulointerstitial nephritis. This case shows that toxic reactions following massive wasp attacks may happen several days after the fact and result in severe, multiorgan system dysfunction. PMID- 21606728 TI - Internal medicine resident physicians may be uncomfortable with managing irritable bowel syndrome at the completion of residency. PMID- 21606729 TI - Resolution of statin-induced myalgias by correcting vitamin D deficiency. PMID- 21606730 TI - Pediatric diabetes and neuropsychiatry disorder. PMID- 21606736 TI - What's an obstetrician-gynecologist to do? PMID- 21606737 TI - Take the high road and choose to dance. PMID- 21606738 TI - Term pregnancy: a period of heterogeneous risk for infant mortality. AB - OBJECTIVE: To estimate the trend of maternal racial and ethnic differences in mortality for early-term (37 0/7 to 38 6/7 weeks of gestation) compared with full term births (39 0/7 to 41 6/7 weeks of gestation). METHODS: We analyzed 46,329,018 singleton live births using the National Center for Health Statistics U.S. period-linked birth and infant death data from 1995 to 2006. Infant mortality rates, neonatal mortality rates, and postneonatal mortality rates were calculated according to gestational age, race and ethnicity, and cause of death. RESULTS: Overall, infant mortality rates have decreased for early-term and full term births between 1995 and 2006. At 37 weeks of gestation, Hispanics had the greatest decline in infant mortality rates (35.4%; 4.8 per 1,000 to 3.1 per 1,000) followed by 22.4% for whites (4.9 per 1,000 to 3.8 per 1,000); blacks had the smallest decline (6.8%; 5.9 per 1,000 to 5.5 per 1,000) as a result of a stagnant neonatal mortality rate. At 37 weeks compared with 40 weeks of gestation, neonatal mortality rates increase. For Hispanics, the relative risk is 2.6 (95% confidence interval [CI] 2.0-3.3); for whites, the relative risk is 2.6 (95% CI 2.2-3.1); and for blacks, the relative risk is 2.9 (95% CI 2.2-3.8). Neonatal mortality rates are still increased at 38 weeks of gestation. At both early- and full-term gestations, neonatal mortality rates for blacks are 40% higher than for whites and postneonatal mortality rates 80% higher, whereas Hispanics have a reduced postneonatal mortality rate when compared with whites. CONCLUSION: Early-term births are associated with higher neonatal, postneonatal, and infant mortality rates compared with full-term births with concerning racial and ethnic disparity in rates and trends. PMID- 21606739 TI - Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors. AB - OBJECTIVE: To compare the effectiveness of physician assessment with a new multivariate index assay in identifying high-risk ovarian tumors. METHODS: The multivariate index assay was evaluated in women scheduled for surgery for an ovarian tumor in a prospective, multi-institutional trial involving 27 primary- care and specialty sites throughout the United States. Preoperative serum was collected, and results for the multivariate index assay, physician assessment, and CA 125 were correlated with surgical pathology. Physician assessment was documented by each physician before surgery. CA 125 cutoffs were chosen in accordance with the referral guidelines of the American College of Obstetricians and Gynecologists. RESULTS: The study enrolled 590 women, with 524 evaluable for the multivariate index assay and CA 125, and 516 for physician assessment. Fifty three percent were enrolled by nongynecologic oncologists. There were 161 malignancies and 363 benign ovarian tumors. Physician assessment plus the multivariate index assay correctly identified malignancies missed by physician assessment in 70% of nongynecologic oncologists, and 95% of gynecologic oncologists. The multivariate index assay also detected 76% of malignancies missed by CA 125. Physician assessment plus the multivariate index assay identified 86% of malignancies missed by CA 125, including all advanced cancers. The performance of the multivariate index assay was consistent in early- and late stage cancers. CONCLUSION: The multivariate index assay demonstrated higher sensitivity and lower specificity compared with physician assessment and CA 125 in detecting ovarian malignancies. PMID- 21606740 TI - Differences in primary compared with secondary vestibulodynia by immunohistochemistry. AB - OBJECTIVE: To assess whether primary and secondary vestibulodynia represent different pathologic pathways. METHODS: This was an analysis of archived vestibulectomy specimens from 88 premenopausal women with vestibulodynia (2002 2008). Patient records were reviewed to classify the type of vestibulodynia, duration of symptoms, and hormone status. Histologic sections were stained for hematoxylin and eosin to grade inflammation, S100 to highlight nerves, CD117 for mast cells, estrogen receptor alpha, and progesterone receptor. Differences between primary and secondary vestibulodynia were tested by t tests, chi-square analysis, and linear and logistic regression. RESULTS: Primary vestibulodynia showed significant neural hypertrophy and hyperplasia (P=.02, adjusted odds ratio [OR] 3.01, 95% confidence interval [CI] 1.2-7.6) and increased progesterone receptor nuclear immunostaining (P=.004, adjusted OR 3.94, CI 1.6-9.9) compared with secondary vestibulodynia. Estrogen receptor alpha expression was also greater in primary vestibulodynia when symptom diagnosis was less than 5 years (P=.004, adjusted OR 5.53 CI 1.71-17.91). CONCLUSION: Primary and secondary vestibulodynia have significantly different histologic features, suggesting that they may have separate mechanistic pathways. Clinically, this may mean the discovery of distinct conditions. PMID- 21606741 TI - Risk of first-stage and second-stage cesarean delivery by maternal body mass index among nulliparous women in labor at term. AB - OBJECTIVE: To estimate in a cohort of nulliparous women in labor at term whether cesarean delivery rates are increased in first and second stages of labor in overweight and obese women and whether being overweight or obese is an independent risk factor for cesarean delivery. METHODS: Nulliparous women recruited to the prospective Screening for Pregnancy Endpoints study who went into labor after 37 weeks of gestation were categorized according to ethnicity specific body mass index (BMI) criteria as normal, overweight, or obese. Normal BMI was the referent. Multivariable analysis, adjusting for known confounders for obesity and cesarean delivery, was performed to estimate if being overweight or obese was associated with an increased risk of cesarean in labor (all cesarean deliveries and in first stage of labor). RESULTS: Of 2,629 participants, 1,416 (54%) had normal BMIs, 773 (29%) were overweight, and 440 (17%) were obese. First stage cesarean delivery was increased in overweight (n=149 [19%]) and obese (n=137 [31%]) women compared with normal-weight women (n=181 [13%; P<.001), whereas second-stage cesarean delivery was similar (normal BMI 76 [6.2%], overweight 45 [7.2%], obese 23 [7.6%], P=.87). Being overweight or obese was an independent risk factor for all cesarean deliveries in labor with adjusted odds ratio (OR) of 1.34 (95% confidence interval [CI] 1.07-1.67) and 2.51 (95% CI 1.94 3.25), respectively. Similarly, being overweight (adjusted OR 1.39; 95% CI 1.09 1.79) or obese (adjusted OR 2.89; 95% CI 2.19-3.80) was associated with increased cesarean delivery during the first stage. Risks of cesarean delivery were similar regardless of whether ethnicity-specific or World Health Organization (WHO) BMI criteria were used. CONCLUSION: Among nulliparous women in labor at term, being overweight or obese by either WHO or ethnicity-specific BMI criteria is an independent risk factor for cesarean delivery in the first stage but not the second stage of labor. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, www.anzctr.org.au, ACTRN12607000551493. PMID- 21606742 TI - Change in body mass index between pregnancies and the risk of gestational diabetes in a second pregnancy. AB - OBJECTIVE: To estimate the association between interpregnancy change in body mass index (BMI) and the risk of gestational diabetes mellitus (GDM) in a second pregnancy. METHODS: In a retrospective cohort analysis of 22,351 women, logistic regression models provided adjusted estimates of the risk of GDM in women gaining 3.0 or more 2.0-2.9, and 1.0-1.9 BMI units, or losing 1.0-2.0 and more than 2.0 units between pregnancies (one BMI unit corresponds to 5.9 pounds for the average height [5 feet 4 inches] of the study population). Women with stable BMIs (+/-1.0 BMI unit) comprised the reference. RESULTS: For those with GDM in the first pregnancy, the age-adjusted risk of GDM in the second pregnancy was 38.19% (95% confidence interval [CI] 34.96-41.42); for those whose first pregnancy was not complicated by GDM, the risk was 3.52% (95% CI 3.27-3.76). Compared with women who remained stable, interpregnancy BMI gains were associated with an increased risk of GDM in the second pregnancy (odds ratio [OR] 1.71 [95% CI 1.42-2.07] for gaining 1.0-1.9 BMI units; OR 2.46 [95% CI 2.00-3.02] for 2.0-2.9 BMI units; and OR 3.40 [95% CI 2.81-4.12] for 3.0 or more BMI units). The loss of BMI units was associated with a lower risk of GDM only among women who were overweight or obese in the first pregnancy (OR 0.26 [95% CI 0.14-0.47] for the loss of at least 2.0 BMI units). In overweight and obese women, those with GDM in the first pregnancy that did not develop the condition again gained fewer BMI units than those experiencing recurrent GDM (mean change 0.66 [95% CI 0.25-1.07] compared with 2.00 [95% CI 1.56-2.43] BMI units, respectively). CONCLUSION: Interpregnancy increases in BMI between the first and second pregnancy increases a woman's risk of GDM pregnancy. PMID- 21606743 TI - Comparative efficiency of measures of early fetal growth restriction for predicting adverse perinatal outcomes. AB - OBJECTIVE: To estimate the comparative efficiency of first-trimester fetal growth restriction, second-trimester fetal growth restriction, and first-to-second trimester growth lag for predicting adverse perinatal outcomes. METHODS: This is a retrospective cohort study of pregnancies with reliable dating based on last menstrual periods and first-trimester ultrasound examinations. Pregnancies with multiple fetuses, aneuploidy, and major structural anomalies were excluded. Fetal crown-rump lengths at 10-14 weeks, estimated fetal weights based on fetal biometry at 18-22 weeks, and interval growth were measured and converted to gestational age-adjusted Z-scores. The primary outcome was small for gestational age (SGA) at delivery. Secondary outcomes were low birth weight, preterm delivery, stillbirth, and preeclampsia. Receiver-operating characteristics curves were used to identify the optimal definitions of early fetal growth restriction associated with SGA and to compare screening efficiencies. Multivariable logistic regression was used to adjust for confounders. RESULTS: Among 8,978 pregnancies meeting inclusion criteria, 551 (6.5%) neonates were SGA. Crown-rump length Z score less than -1.0, estimated fetal weights Z-score less than -1.0, and growth Z-score less than -1.0 were identified as the optimal definitions of early fetal growth restriction associated with SGA (adjusted odds ratio 1.41 [95% confidence interval (CI) 1.13-1.74], 3.44 [95% CI 2.85-4.15] and 2.61 [95% CI 2.09-3.25], respectively). The sensitivity and specificity of first- and second-trimester fetal growth restriction for predicting SGA were 21.4% and 83.4%, and 37.2% and 85.5%, respectively. The area under the receiver-operating characteristics curve for second-trimester fetal growth restriction was greater than that for first trimester fetal growth restriction and first-to-second-trimester growth lag (0.70 compared with 0.59 and 0.66, P<.001). CONCLUSION: Second-trimester fetal growth restriction is superior to first-trimester fetal growth restriction and first-to second-trimester growth lag for predicting SGA. PMID- 21606744 TI - Echogenic bowel on second-trimester ultrasonography: evaluating the risk of adverse pregnancy outcome. AB - OBJECTIVE: To estimate if echogenic bowel diagnosed on second-trimester ultrasonography has an independent risk association with intrauterine growth restriction (IUGR) and intrauterine fetal demise. METHODS: This is a retrospective cohort study of all patients with singleton gestations who presented to our institution for second-trimester ultrasonography between 1990 and 2008. Study groups were defined by the presence or absence of echogenic bowel. Primary outcomes were IUGR, defined as birth weight less than the 10th percentile for gestational age and intrauterine fetal demise at 20 weeks or more of gestation. Univariable and multivariable logistic regression analyses were used to estimate the risk of intrauterine fetal demise and IUGR in fetuses with echogenic bowel. Analyses were repeated after excluding cases of aneuploidy, cytomegalovirus (CMV) infection, other major congenital anomalies, and abnormal second-trimester serum screening results. RESULTS: Of 64,048 patients, the incidence of echogenic bowel was 0.4%. Of these, echogenic bowel was an isolated finding in 188 (72.3%) cases. There were 579 (0.9%) cases of intrauterine fetal demise and 8,173 (12.8%) cases of IUGR in the entire cohort. After excluding cases of aneuploidy and CMV infection, the incidence of intrauterine fetal demise was 7.3% in the echogenic bowel group compared with 0.9% in the nonechogenic bowel group, translating to an absolute risk increase of 6.4%. The incidence of IUGR in the echogenic bowel group was 19.5% compared with 12.9% in the nonechogenic bowel group (absolute risk increase, 6.6%). After controlling for potential confounders, echogenic bowel was significantly associated with both intrauterine fetal demise (adjusted odds ratio [OR] 9.6, 95% confidence interval [CI] 5.8-15.9) and IUGR (adjusted OR 2.1, 95% CI 1.5-2.9). This risk association remained significant even when evaluating echogenic bowel as an isolated sonographic finding. CONCLUSION: The presence of echogenic bowel on ultrasonography is independently associated with an increased risk for both IUGR and intrauterine fetal demise. Serial growth assessment and antenatal testing may be warranted in these patients. PMID- 21606745 TI - Characteristics of women in the United States who use long-acting reversible contraceptive methods. AB - OBJECTIVE: To examine characteristics of U.S. women that are associated with use of long-acting reversible contraception and changes in these characteristics between 2002 and 2006-2008. METHODS: We analyzed data from two nationally representative samples of women aged 15-44 in the National Survey of Family Growth, including 7,643 women in 2002 and 7,356 women in 2006-2008. We conducted simple and multinomial logistic regression analyses to identify demographic and reproductive health characteristics associated with use of long-acting reversible contraception. RESULTS: Long-acting reversible contraception (intrauterine devices and subdermal implants) use among U.S. women using contraception increased from 2.4% in 2002 to 5.6% in 2006-2008. The largest increases in long acting reversible contraception use during this time occurred among the youngest and oldest age groups, non-Hispanic white and non-Hispanic African American women, foreign-born women, and those in the highest income group. High prevalence of long-acting reversible contraception use in 2006-2008 was seen among women who had given birth once or twice (10%), foreign-born women (8.8%), and Hispanic women (8.4%). After adjusting for key demographic and reproductive health characteristics, in comparison with users of other contraceptive methods and with those not using contraception who were at risk for unintended pregnancy, foreign born women and women who experienced coitarche before age 18 were approximately twice as likely to be using long-acting reversible contraception as women without those characteristics. CONCLUSION: A more diverse population of women used long acting reversible contraception in 2006-2008 compared with 2002. However, there is likely more potential for increased uptake, especially among populations historically not considered to be candidates for these methods. PMID- 21606746 TI - Changes in abortion rates between 2000 and 2008 and lifetime incidence of abortion. AB - OBJECTIVE: To estimate abortion rates among subpopulations of women in 2008, assess changes in subpopulation abortion rates since 2000, and estimate the lifetime incidence of abortion. METHODS: We combined secondary data from several sources, including the 2008 Abortion Patient Survey, the Current Population Surveys for 2008 and 2009, and the 2006-2008 National Survey of Family Growth, to estimate abortion rates by subgroup and lifetime incidence of abortion for U.S. women of reproductive age. RESULTS: The abortion rate declined 8.0% between 2000 and 2008, from 21.3 abortions per 1,000 women aged 15-44 to 19.6 per 1,000. Decreases in abortion were experienced by most subgroups of women. One notable exception was poor women; this group accounted for 42.4% of abortions in 2008, and their abortion rate increased 17.5% between 2000 and 2008 from 44.4 to 52.2 abortions per 1,000. In addition to poor women, abortion rates were highest for women who were cohabiting (52.0 per 1,000), aged 20-24 (39.9 per 1,000), or non Hispanic African American (40.2 per 1,000). If the 2008 abortion rate prevails, 30.0% of women will have an abortion by age 45. CONCLUSION: Abortion is becoming increasingly concentrated among poor women, and restrictions on abortion disproportionately affect this population. PMID- 21606747 TI - Venous thromboembolism and use of prophylaxis among women undergoing laparoscopic hysterectomy. AB - OBJECTIVE: To examine the risk of venous thromboembolism and the use of venous thromboembolism prophylaxis in women undergoing laparoscopic hysterectomy. METHODS: Results of women recorded in a health outcomes, resource utilization, and quality database from 2003 to 2007 who underwent laparoscopic hysterectomy were analyzed. The rate and predictors of venous thromboembolism as well as patterns of venous thromboembolism prophylaxis were examined. Multivariable logistic regression models were developed to determine the incidence of venous thromboembolism and use of any prophylaxis, as well as pharmacologic prophylaxis. RESULTS: Among 60,013 women, a total of 579 (1.0%) venous thromboembolism events were noted. Venous thromboembolism was diagnosed in 2.1% of women aged 60 years or older and in 2.3% of those with cancer. Women older than 60 years (OR 1.64, 95% CI 1.19-2.26) and with more medical comorbidities (OR 3.07, 95% CI 2.23-4.23) were most likely to have a venous thromboembolism develop. A total of 23,562 (39.3%) patients received no venous thromboembolism prophylaxis, 29,288 (48.8%) received mechanical prophylaxis, and 7,163 (11.9%) received pharmacologic prophylaxis. Women aged 60 years or older (OR 1.56, 95% CI 1.41-1.73), women with more medical comorbidities (OR 1.93, 95% CI 1.71-2.17), those with cancer (OR 3.08, 95% CI 2.75-3.45), and patients treated by high-volume surgeons (OR 1.42, 95% CI 1.33-1.52) were more likely to receive pharmacologic prophylaxis. CONCLUSION: Whereas patients undergoing laparoscopic hysterectomy are overall at low risk for venous thromboembolism, older women, those with medical comorbidities, and women with cancer are at substantial risk. Venous thromboembolism prophylaxis is highly variable and often not utilized. PMID- 21606748 TI - Angiogenic response of placental villi to heparin. AB - OBJECTIVE: To estimate the angiogenic effect of heparin on human umbilical vein endothelial cells cultured in conditioned media from normal and severely pre eclamptic human placental villi. METHODS: Normal first- and second-trimester floating placental villi were explanted in control conditions and increasing concentrations of heparin (unfractionated and low molecular weight heparin) across the clinical prophylactic and therapeutic range (0.025-25 units/mL). At 96 hours, the placenta-conditioned media was tested for angiogenic activity in a human umbilical vein endothelial cell in vitro angiogenesis assay. Total capillary-like tube length and number of branch points were determined from photographs that did not contain information about experimental conditions. The response of placenta-conditioned media from preterm severely preeclamptic pregnant women exposed to low molecular weight heparin also was assessed and compared with both preterm and term control groups. RESULTS: Unfractionated heparin significantly promoted angiogenesis (0.25 units/mL compared with control: relative branch points 185+/-32% [mean+/-standard error of the mean], P<.05), whereas low molecular weight heparin had no significant effect. Addition of unfractionated or low molecular weight heparin to first- and second-trimester placenta-conditioned media significantly promoted angiogenesis with the response to low molecular weight heparin more than double that of unfractionated heparin (low molecular weight compared with unfractionated heparin at 2.5 units/mL: relative branch points 930+/-158% compared with 398+/-90%, P<.05). Placenta conditioned media from pregnancies with severe preeclampsia arrested angiogenesis in comparison with both preterm and term pregnancies and was not significantly restored by the addition of low molecular weight heparin. CONCLUSION: Unfractionated and low molecular weight heparin promote in vitro angiogenesis in healthy first- and second-trimester placenta-conditioned media. The nonanticoagulant actions of heparin may be relevant to the prevention of severe preeclampsia. PMID- 21606749 TI - Contribution of fetal tricuspid regurgitation in first-trimester screening for major cardiac defects. AB - OBJECTIVE: To estimate the potential value of fetal assessment for tricuspid regurgitation at 11-13 weeks of gestation in the prediction of major cardiac defects. METHODS: We screened for aneuploidies by measuring fetal nuchal translucency thickness as well as assessing blood flow across the tricuspid valve for evidence of tricuspid regurgitation and in the ductus venosus for evidence of reversed A-wave at 11 0/7 to 13 6/7 weeks of gestation. The estimated performance of different combinations of increased fetal nuchal translucency, tricuspid regurgitation, and ductus venosus reversed A-wave in screening for major cardiac defects was examined. RESULTS: The study population of euploid fetuses included 85 cases with major cardiac defects and 40,905 with no cardiac defects. Fetal nuchal translucency above the 95th percentile, tricuspid regurgitation, or ductus venosus reversed A-wave was observed in 30 (35.3%), 28 (32.9%), and 24 (28.2%) of the fetuses with cardiac defects, respectively, and in 1,956 (4.8%), 516 (1.3%), and 856 (2.1%) of those without cardiac defects. Any one of the three markers was found in 49 of the fetuses with cardiac defects (57.6%, 95% confidence interval [CI] 47.0-67.6%) and in 3,265 of those without cardiac defects (8.0%, 95% CI 7.7 8.2%). CONCLUSION: Assessment of flow across the tricuspid valve improves the performance of screening for major cardiac defects by fetal nuchal translucency and ductus venosus flow. PMID- 21606750 TI - Society for Women's Health Oversight: Establishing equality in the profession of obstetrics and gynecology. PMID- 21606751 TI - Addressing global health, economic, and environmental problems through family planning. AB - Although obstetrician-gynecologists recognize the importance of managing fertility for the reproductive health of individuals, many are not aware of the vital effect they can have on some of the world's most pressing issues. Unintended pregnancy is a key contributor to the rapid population growth that in turn impairs social welfare, hinders economic progress, and exacerbates environmental degradation. An estimated 215 million women in developing countries wish to limit their fertility but do not have access to effective contraception. In the United States, half of all pregnancies are unplanned. Voluntary prevention of unplanned pregnancies is a cost-effective, humane way to limit population growth, slow environmental degradation, and yield other health and welfare benefits. Family planning should be a top priority for our specialty. PMID- 21606752 TI - Adding strength training, exercise intensity, and caloric expenditure to exercise guidelines in pregnancy. AB - Several versions of exercise guidelines for pregnancy have been published, the latest 9 years ago. These guidelines recommend 30 minutes or more of moderate exercise on most if not all days of the week for pregnant women in the absence of medical or obstetric complications. However, moderate-intensity exercise was not defined. In addition, the specific weekly energy expenditure of physical activity was not suggested. Recent research has determined that, compared with less vigorous activities, exercise intensity that reaches at least 60% of the heart rate reserve during pregnancy while gradually increasing physical-activity energy expenditure reduces the risk of gestational diabetes. To achieve the minimum expenditure of 16 metabolic equivalent task-h/wk, one could walk at 2 miles/h for 6.4 h/wk (2.5 metabolic equivalent task-hours, light intensity) or, preferably, exercise on a stationary bicycle for 2.7 h/wk (6 to 7 metabolic equivalent task hours, vigorous intensity). To achieve the target expenditure of 28 metabolic equivalent task-hours per week, one could walk at 2.0 miles/h for 11.2 h/wk (2.5 metabolic equivalent task-hours, light intensity) or, preferably, exercise on a stationary bicycle for 4.7 h/wk (6 to 7 metabolic equivalent task-hours, vigorous intensity). The more vigorous the exercise, the less total exercise time is required. Light muscle strengthening performed during the second and third trimesters of pregnancy has minimal effect on newborn body size and overall health. On the basis of this and other information, updated recommendations for exercise in pregnancy are suggested. PMID- 21606753 TI - Clinical research education study teams: a research curriculum for obstetric and gynecology residents. AB - Research education is a requirement for obstetrics and gynecology residents. Most obstetrics and gynecology residencies struggle with barriers to efficient, effective research education and productivity for their residents. These barriers include constraints on faculty time, lack of intrinsic desire within individual residents, and lack of relevant outcome measures. We developed an efficient, novel research education curriculum that overcomes many of these barriers and provides obstetrics and gynecology residents with a structured format that maximizes the likelihood of a successful, positive research experience. Since the start of the Clinical Research Education Study Team program, the graduating resident cohorts reliably complete and present prospective research projects, including three registered randomized trials. Residency-wide support for other team research has grown dramatically. The residents' work was acknowledged with several research awards, which further reinforces the positive perception of the program. The certainty of completion of their research requirement relieved our residents of the anxiety commonly reported by residents nearing graduation. The Clinical Research Education Study Team program's team design makes efficient use of faculty time. In addition, Clinical Research Education Study Team mentors also have incorporated junior faculty members who wish to improve their own research education skills. We offer our experience with this program in hopes that it may be of value to other programs that wish to improve their resident research education curriculum. It remains important for residents to acquire research skills before continuing into practice or fellowship. The Clinical Research Education Study Team program facilitates this education in an efficient, organized manner. PMID- 21606754 TI - Management of the adnexal mass. AB - Adnexal masses are commonly encountered in gynecologic practice and often present both diagnostic and management challenges. This is partly because of the fact that the majority of adnexal masses that are identified represent benign entities that do not necessarily require active intervention, yet a small subset will represent malignant processes that require both timely and appropriate surgical intervention for optimal outcome. To determine the best diagnostic and management strategies in this setting, physicians must effectively triage risk for malignancy by having a thorough understanding of the entities on the differential diagnosis and carefully considering the clinical context for each individual patient. Optimal selection and interpretation of diagnostic tests are enhanced by both an accurate clinical risk assessment and an understanding of the inherent accuracy of diagnostic tests considered in this setting. The purpose of this document is to provide clinicians with a practical strategy for distinguishing benign and malignant masses in the nonpregnant woman. Our approach addresses the critical elements of accurate risk stratification, reviews the performance of diagnostic tests for identifying malignancy, and offers evidence-based management algorithms to optimize outcomes for women with adnexal masses. PMID- 21606755 TI - Microscopic hematuria in women. PMID- 21606756 TI - Trocar-guided mesh compared with conventional vaginal repair in recurrent prolapse: a randomized controlled trial. PMID- 21606758 TI - Clinical significance of borderline amniotic fluid index and oligohydramnios in preterm pregnancy. PMID- 21606761 TI - Timing of elective repeat cesarean delivery at term and maternal perioperative outcomes. PMID- 21606763 TI - Clinical importance of appearance of cesarean hysterotomy scar at transvaginal ultrasonography in nonpregnant women. PMID- 21606765 TI - Breast milk hydrocodone and hydromorphone levels in mothers using hydrocodone for postpartum pain. PMID- 21606770 TI - ACOG Practice Bulletin No. 120: Use of prophylactic antibiotics in labor and delivery. PMID- 21606771 TI - ACOG Committee Opinion No. 494: Sulfonamides, nitrofurantoin, and risk of birth defects. AB - The evidence regarding an association between the nitrofuran and sulfonamide classes of antibiotics and birth defects is mixed. As with all patients, antibiotics should be prescribed for pregnant women only for appropriate indications and for the shortest effective duration. During the second and third trimesters, sulfonamides and nitrofurantoins may continue to be used as first line agents for the treatment and prevention of urinary tract infections and other infections caused by susceptible organisms. Prescribing sulfonamides or nitrofurantoin in the first trimester is still considered appropriate when no other suitable alternative antibiotics are available. Pregnant women should not be denied appropriate treatment for infections because untreated infections can commonly lead to serious maternal and fetal complications. PMID- 21606772 TI - Technology assessment No. 7: Hysteroscopy. AB - Hysteroscopy is performed to view and treat pathology within the uterine cavity and endocervix. Diagnostic hysteroscopy allows visualization of the endocervical canal, endometrial cavity, and fallopian tube ostia. Operative hysteroscopy incorporates the use of mechanical, electrosurgical, or laser instruments to treat intracavitary pathology and perform hysteroscopic sterilization procedures. Selection of a distending medium requires consideration of the advantages, disadvantages, and risks associated with various media as well as their compatibility with electrosurgical or laser energy. A preoperative consultation allows the patient and physician to discuss the hysteroscopic procedure, weigh its inherent risks and benefits, review the patient's medical history for any comorbid conditions, and exclude pregnancy. Known pregnancy, genital tract infections, and active herpetic infection are contraindications to hysteroscopy. The most common perioperative complications associated with operative hysteroscopy are hemorrhage, uterine perforation, and cervical laceration. The procedure is minimally invasive and can be used with a high degree of safety. PMID- 21606773 TI - A full spectrum. PMID- 21606774 TI - Early controlled passive motion regime for zone II extensor tendon injury--a case report. AB - Zone II extensor tendon injuries are often associated with sharp laceration and saw injuries. These injuries are usually been immobilized for 4 to 6 weeks with static splint followed with gradual increment in ROM at distal interphalangeal (DIP) joint. Zone II injuries are usually associated with stiff DIP joint. Any effects taken to improve the DIP joint flexion aggravates the extensor lag at DIP joint. We report a dynamic passive mobilization regime for treating zone II extensor tendon injuries. We found dynamic passive mobilization program was effective in managing these injuries in preventing the DIP joint stiffness. PMID- 21606775 TI - Swiss roll technique for treatment of paronychia. AB - Management of paronychia should primarily be aimed at preventing any activity that results in impairment of the natural barrier function of the nail fold. Surgical treatments aim to cure paronychia by exposing the inflamed germinal matrix to permit unrestricted drainage. We describe a Swiss roll technique for treatment of chronic and severe acute paronychia. PMID- 21606776 TI - Parachute technique: a complimentary method in zone II tendon repair. AB - Flexor tendon lacerations still represent a challenging problem for the hand and the plastic surgeon, particularly in zone II. Many techniques have been devised accordingly to make the surgery of this zone easier. Hence, we too have devised an added complementary technique (ie, the parachute technique) to the common surgical techniques of the tendon repair to ease the repairing process and improve the outcomes. In this study, 79 patients, from whom 21 patients had 2 injured fingers, with flexor tendon injury in zone II (ie, 100 fingers) underwent this new technique. Finally, the results were hopeful. Thus, this complementary parachute technique combined with an early active mobilization with almost full range of flexion and extension, starting on the first postoperative day, resulted in improved outcomes compared with both passive mobilization and gentle active mobilization with a limited range of motion (ie, "controlled"). The Strickland formula (total active motion) system was used to evaluate the functional results of the flexor tendon repair. Finally, this technique is applicable for tendon repairs, and is shown to produce good results in their hands. PMID- 21606777 TI - Refinement of a simple technique with new relevance for exsanguination of the upper limb. AB - Many techniques have been described for exsanguination of the upper limb before the application of a pneumatic tourniquet. These require additional equipment such as the Esmarch bandage, the Urias bag, the Pomidor roll-cuff, the Northwick Park exsanguinator, or the Rhys-Davies exsanguinator. At a time of increasing demand on scarce resources and increasing medico-legal claims, these techniques have a number of disadvantages: increasing tourniquet and theater time, having cost implications, posing a risk of transmission of infection such as methicillin resistant Staphylococcus aureus and Group A Streptococcus, being contraindicated in certain upper limb pathologies, and causing potential injury or even fatal pulmonary embolism. Some of these techniques continue to be in common usage but a review of the literature suggests that they may be unnecessary in routine practice, and should be reserved for select situations. The present article describes the formalization and refinement of a simple technique with new relevance, 101 years after Bier first mentioned it in the literature, where the brachial artery is compressed in the cubital fossa before elevation of the arm and then the tourniquet is inflated. This method is simple, cost-effective, time saving, and most importantly safe and fomite free. PMID- 21606778 TI - Full-thickness skin graft after nail complex resection for malignant tumors. AB - Melanoma in situ and early squamous cell carcinoma can be treated successfully with excision with narrow margins. However, as the extent of disease is known only after pathologic examination of the entire lesion, the appropriate initial surgical margin is a dilemma. Lesions that involve the nail complex present an additional challenge for surgeons-whether to excise the nail complex partially or completely. The ideal form of reconstruction is also in question. We elect to completely excise the nail complex with immediate reconstruction using a full thickness skin graft, allowing complete tumor clearance and preserving the distal phalanx. We retrospectively reviewed records of patients who had undergone complete nail complex excision and immediate skin grafting. We assessed the need for additional procedures for positive resection margins, full-thickness skin graft take on the bare bone of the distal phalanx, and final aesthetic appearance. Our study included 9 patients who had surgery on a total of 10 digits. One patient underwent repeat resection with distal phalanx disarticulation after pathologic assessment revealed a positive margin for an invasive tumor No patients had a local recurrence. Two patients required a second procedure-one for excision of a nail remnant and another for excision of an epidermal inclusion cyst. All patients were satisfied with the results, with none wanting further nail reconstruction, and all returned to presurgery use of the hand. This technique is effective for managing melanoma in situ and early squamous cell carcinoma that affect the nail complex. PMID- 21606779 TI - Surgical reconstruction of PIP joint collateral ligament in chronic instability in a high performance athlete: case report and description of technique. AB - We present a case report describing the surgical technique for the reconstruction of the proximal interphalangeal (PIP) joint collateral ligament using autograft palmaris longus tendon graft. We accomplished this successfully in a high performance professional athlete presenting with chronic instability of the PIP joint. Our surgical reconstructive technique recreated anatomic ligament position, while correcting multidirectional instability without disruption of the other dynamic anatomic structures of the PIP joint. Our results demonstrated excellent clinical and functional results, and we offer our technique as an alternative to tenodesis procedures for individuals with professions that demand PIP motion. PMID- 21606780 TI - New transfer for correction of thumb metacarpophalangeal hyperextension in cases with associated surgery for basal thumb osteoarthritis (transfer of the volar half of the abductor pollicis brevis). AB - We present a new technique for the correction of thumb metacarpophalangeal joint hyperextension in patients with concomitant basal thumb osteoarthritis. For consistent result with trapeciometacarpal arthroplasty both pathologies should be treated at the same time. INDICATION: Cases with passively reducible metacarpophlangeal joint (without osteoarthritis or severe medial instability). We use a midlateral approach to transfer the volar half of the abductor pollicis brevis to the radial insertion of the A1 pulley distal to the MP joint. The transfer should be with maximum tension with the joint in 20 degrees of flexion. We protect this transfer with immobilization for 1 month. PMID- 21606781 TI - Purse-string suture as a complementary technique with conventional flaps in repairing fingertip amputation. AB - The main aim of the treatment in fingertip amputations is to establish the functional and aesthetic construction of the fingertip. The aim of this study is to discuss how to use purse-string suture as a complementary technique accompanying conventional flaps repair in fingertip amputation. Fifty-four patients with fingertip amputations on the nail bed referred to our center for fingertip reconstruction. From which 41 patients who had at least one-third of their nail remained (to preserve the nail) were chosen to undergo this new technique. Patient's satisfaction of the achieved functional results (in case of pain and motion) was as follows: 32 responded excellent, 8 good, and 1 fair. Also, patient's satisfaction of the achieved aesthetic results were Excellent = 7 and Good = 2 in females (n = 9) and Excellent = 19, Good = 7 and Fair = 6 in males (n = 32). 93% (38 patients) of the patients had two-point discriminationof less than 3 mm. No flap necrosis was observed in this study. The flap donor site was covered by primary closure (in 24 cases), secondary intention (in 11 cases), and skin graft (in 6 cases). The nail and finger contour are important for achieving a satisfying aesthetic and functional result. We believe that this new complementary technique could be an easy way for reaching this end. It is recommended that this technique be applied to all fingertip injuries to preserve the nail. PMID- 21606782 TI - Four-corner fusion and scaphoid excision using headless compression screws for SLAC and SNAC wrist deformities. AB - Scapholunate advanced collapse and scaphoid nonunion advanced collapse wrist deformities are the most common causes of traumatic arthritis of the wrist. Four corner fusion and scaphoid excision has proven to be an effective procedure for relieving pain and preserving range of motion in the wrist joint. Several methods for providing fixation of the midcarpal joint during fusion have been used, including K-wires, staples, and the Spider plate. K-wire fixation has proven effective, but requires a period of cast immobilization to protect the fusion mass. The Spider plate was promising, but has not been without complications. The development and improvements in cannulated headless compression screws has resulted in increased indications for their use, including fixation for 4-corner fusion. We review the technique and tips developed by the senior author over the last several years using headless compression screws for fixation of the midcarpal joint. Acutrak 2 Standard implants were used. This technique has allowed for early range of motion with reliable fusion rates. PMID- 21606783 TI - Custom subatmospheric dressing for fingertip injuries. AB - Fingertip injuries are difficult to treat. Although the best way is to cover the wound with flap or graft without finger shortening, coverage of the wound with flap or graft cannot be suitable in each case. For some cases, secondary wound healing can be an alternative treatment. In the secondary healing process, to promote the granulation tissue and to reduce wound-healing time, subatmospheric dressing (vacuum dressing) can be a useful method. In this study, a new custom made subatmospheric dressing method designed for fingertip injuries has been described. PMID- 21606784 TI - Management of comminuted proximal ulna fracture-dislocations using a multiplanar locking intramedullary nail. AB - Intramedullary nails have been used for the fixation of olecranon fractures in an attempt to reduce the soft tissue irritation and resulting need for hardware removal seen with plating and tension banding. Further benefits include preservation of vascular supply, and increase stability and improved compression over some alternative techniques. Most intramedullary nails have been limited to simple olecranon fractures or osteotomies. One novel multiplanar, locking intramedullary nail, however, is indicated to stabilize all fracture patterns of the proximal ulna, including the coronoid. This particular locking nail has screws that radiate in multiple planes and form a fixed-angle lattice throughout the bone. The nail also has fixed-angle screws dedicated to the 3 parts of the coronoid: process tip, medial facet, and medial wall. This allows the nail to secure multiple fragments regardless of the fracture pattern's extent of instability. The objective of this article is to illustrate the recommended steps in reducing and stabilizing a comminuted proximal ulna fracture-dislocation using this multiplanar locking intramedullary nail. PMID- 21606785 TI - Thumb carpometacarpal arthroplasty using an absorbable interference screw for flexor carpi radialis ligament reconstruction. AB - Few surgical techniques that address advanced thumb carpometacarpal osteoarthrosis specifically allow early mobilization postoperatively. After trapeziectomy, we carry out a ligament reconstruction using an absorbable interference screw to secure a flexor carpi radialis tendon autograft within the first metacarpal base. Theoretically, superior tendon graft fixation strength allows early mobilization within 2 weeks postoperatively. We have retrospectively compared our clinical results using this technique with another group of patients who underwent traditional ligament reconstruction and tendon interposition as described by Burton and Pellegrini. There were no differences in the verbal pain score, satisfaction rating, or DASH scores between groups. There was a statistically significant decrease in trapezial space ratio both at rest and with stress for the experimental group. Although the clinical significance of this finding is largely unknown, it did not correlate with clinical outcome in our patients. Although no conclusions could be drawn regarding early mobilization after thumb carpometacarpal arthroplasty, further studies are planned to investigate this intriguing aspect of postoperative care. In this article, we present the details of the surgical technique and postoperative rehabilitation. PMID- 21606786 TI - Treatment of hyperextension deformity of the thumb metacarpophalangeal joint in basal joint arthritis: a novel technique based on an anatomic study. AB - Advanced stages of basal joint arthritis are sometimes characterized by an adduction deformity of the first metacarpal and a hyperextension deformity of the unstable metacarpophalangeal (MCP) joint. Stabilizing the MCP joint in these patients is critical to ensure a pain-free repair and efficient pinch mechanism. This study presents the anatomic basis for a novel capsulodesis technique using the volar plate that can be incorporated into any reconstructive basal joint procedure when clinically indicated. Eleven normal cadavers were dissected to expose the volar plate. The dimensions of the volar plate, relationship of the sesamoid bones to the oblique pulley, and the distance from the sesamoids to the base of the proximal phalanx were compared between specimens. The radial border of the volar plate measured 8.5 +/- 1.3 mm, ulnar border 8.8 +/- 1.0 mm, proximal border 7.5 +/- 1.0 mm, and distal border 7.8 +/- 0.6 mm. The distance between the ulnar sesamoid bone and the oblique pulley measured 12.1 +/- 1.1 mm and from the radial sesamoid to the oblique pulley measured 16.6 +/- 0.2 mm. The distance between the sesamoids and the base of the phalanx measured 2.2 +/- 0.2 mm. The anatomic studies provide a foundation on which the surgeon can understand the complex nature of the MCP joint. This study describes a novel technique for MCP capsulodesis of the thumb in which volar plate flaps are imbricated to provide stability to the MCP joint, obviating the need for suture anchors and tendon grafts. PMID- 21606787 TI - Technique for and an anatomic guide to forearm tendon repair. AB - Forearm lacerations involving muscle bellies are usually treated by repairing muscle fascia. Repair of tendons themselves is stronger and restores normal muscle anatomy better. Tendon repair requires good knowledge of forearm muscle and tendon anatomy. We have made cadaver measurements to produce graphical maps of locations of individual muscles tendons of origin and insertion, some practical guides for finding tendon ends and a simple grasping stitch for intramuscular tendons. PMID- 21606788 TI - Comments from the editor. PMID- 21606789 TI - Pathologic continuum of acute appendicitis: sonographic findings and clinical management implications. AB - Appendicitis is one of the most common causes of the acute abdomen often requiring emergent surgery. Delayed diagnosis leads to the progression of uncomplicated appendicitis to complicated (gangrenous, perforated) appendicitis, often changing clinical management. Computed tomography and ultrasound are imaging modalities of choice to preoperatively diagnose appendicitis. Recent concerns of radiation exposure and cost have renewed interest in using ultrasound as an initial, diagnostic study. A sonographic pictorial and histopathologic review of the continuum of appendicitis is presented. A comprehensive sonographic examination of the appendix should investigate the size (maximal diameter), the echogenic submucosal layer integrity, the mural color Doppler signature, the presence of a fecalith, and the periappendiceal changes. Features of an uncomplicated appendicitis include size greater than 6 to 7 mm, hyperemia on color Doppler, mural thickening, and an intact echogenic submucosal layer. Gangrenous appendicitis is characterized by loss of the echogenic submucosal layer with absent color Doppler flow. Loculated pericecal fluid, prominent pericecal fat, and circumferential loss of the submucosal layer are suggestive of perforation. Sonographic staging can triage management of appendicitis by directing urgent laparoscopic appendectomy for uncomplicated appendicitis, open appendectomy for complicated appendicitis, and conservative management (antibiotics with percutaneous drainage) for perforated appendicitis with abscess formation. PMID- 21606790 TI - Carotid and vertebral artery Doppler ultrasound waveforms: a pictorial review. AB - Carotid and vertebral artery spectral Doppler ultrasound waveforms can be affected by many types of local lesions, proximal cardiovascular disease, and devices, as well as distal cerebrovascular disease. Recognizing abnormal spectral Doppler ultrasound waveforms and their significance is important for proper management. Examples of normal and abnormal carotid and vertebral artery spectral Doppler ultrasound waveforms are reviewed and illustrated in this pictorial review. PMID- 21606791 TI - Endoanorectal ultrasonography. AB - Endoanorectal ultrasonography (EARUS) may be used for diagnosing various anorectal disorders. EARUS is easy to perform, has a short learning curve, and causes less discomfort than routine digital examination. Anal sphincters can be clearly visualized, and one can easily distinguish between the internal (hypoechoic) and external (hyperechoic) anal sphincters. Other pelvic floor structures, like the puborectalis muscle, can also be visualized. The use of contrast agents can increase the accuracy of EARUS in the assessment of perianal fistulae. In addition, EARUS is an excellent alternative to expensive magnetic resonance imaging. Besides its use in incontinence and perianal sepsis, the presence of slight or massive submucosal invasion in early rectal cancer may be imaged in greater detail. With 3-dimensional EARUS, it is possible to diagnose the anorectal diseases, in multiplane, with high spatial resolution, adding important information about the therapeutic decision. The normal sonographic anatomy of the anorectum, sonographic findings of anorectal diseases, and indications and limitations of endosonography with complementary techniques such as transvaginal and transperineal ultrasound are reviewed in this article. PMID- 21606792 TI - Ultrasound-guided fine needle aspiration of major salivary gland masses and adjacent lymph nodes. AB - Ultrasound has an established role in the detection of masses in the major salivary glands and potentially malignant adjacent lymph nodes. Because there is overlap in their sonographic features, tissue diagnosis plays an important role in management. This review assesses ultrasound-guided fine needle aspiration biopsy as a diagnostic tool in the characterization of these lesions. The literature, and the authors' experience, suggests that ultrasound-guided fine needle aspiration is a safe and accurate technique, with definable implications for management, when performed in conjunction with cytopathologic expertise. PMID- 21606814 TI - Testicular torsion/detorsion. PMID- 21606813 TI - Lack of utility of transabdominal ultrasound in the detection of gastroesophageal reflux disease-induced esophagitis in comparison with endoscopy. AB - BACKGROUND: Although upper gastrointestinal (GI) tract endoscopy is the investigation of choice for patients with suspected gastroesophageal reflux disease (GERD)-induced esophagitis, it is associated with complications and significant patient discomfort. The aim of the current study was to compare the accuracy of transabdominal ultrasonography with upper GI tract endoscopy in the detection of GERD-induced esophagitis. MATERIALS AND METHODS: In this descriptive study, 350 patients (mean age, 41.41 +/- 14.52 years) referred to a gastroenterologist with symptoms suggestive of GERD were enrolled. The esophageal wall thickness was measured with transabdominal ultrasonography, and patients were subsequently assessed by upper GI endoscopy, representing the criterion standard in the diagnostic evaluation for GERD-induced esophagitis. RESULTS: Endoscopic evaluation identified 100 patients with esophagitis (case group), and 250 subjects were reported to have normal endoscopic findings (control group). The wall thickness was significantly higher in the case group compared with the control (P < 0.0001).In the receiver operating characteristic analysis, only 2 cutoff points had a positive predictive value (PPV) greater than 50%. The cutoff point of 2.7 mm had 38% sensitivity, 91% specificity, 63% PPV, and 79% negative predictive value in the detection of GERD. Its positive and negative likelihood ratios were 4.32 and 0.68, respectively. CONCLUSIONS: According to the identified sensitivity/specificity, low PPV and positive likelihood ratio, and relatively high negative likelihood ratio, we failed to find the transabdominal ultrasound effective in the detection of GERD-induced esophagitis. PMID- 21606815 TI - Superior mediastinal venous obstruction. PMID- 21606816 TI - Uterine lipoleiomyoma. PMID- 21606817 TI - Hemimegalencephaly. PMID- 21606818 TI - ACR appropriateness Criteria(r) pretreatment evaluation and follow-up of endometrial cancer of the uterus. AB - Endometrial cancer is one of the common malignancies in the female genital tract. Imaging in pretreatment evaluation may play an important role in an assessment of morphological prognostic factors including tumor size, depth of myometrial invasion, endocervical extent, and lymph node status. Imaging is also useful in posttreatment evaluation of patients with clinically suspected recurrence. Various modalities including MRI, CT ultrasound and FDG PET-CT-CT have been used for evaluation of the endometrial cancer in both before and after treatment settings. Literature on the indications and usefulness of these imaging studies for endometrial cancer is reviewed. PMID- 21606819 TI - ACR appropriateness criteria pretreatment evaluation and follow-up of endometrial cancer of the uterus: commentary. PMID- 21606820 TI - Safety and efficacy of adjuvant chemoradiation therapy with capecitabine after resection of pancreatic ductal adenocarcinoma: a retrospective review. AB - PURPOSE: To evaluate clinical outcomes and safety of adjuvant chemoradiation therapy (CRT) with capecitabine after resection of pancreatic adenocarcinoma at a single institution. PATIENTS AND METHODS: A retrospective analysis of patients undergoing adjuvant CRT with capecitabine after resection of pancreatic ductal adenocarcinoma between 2004 and 2007 yielded a total of 55 patients. Capecitabine was administered at 850 mg/m(2) twice daily every day per week radiotherapy (45 Gy in 25 fractions) over the 5 weeks. Sixteen percent of patients (N=9) went on to receive gemcitabine. RESULTS: Of 55 patients, 42 had curative (R0) resection and 13 had incomplete resection (R1). Median overall survival (OS) and progression free survival were 18.3 and 8.0 months for all patients, respectively. Patients receiving additional gemcitabine after adjuvant CRT with capecitabine showed better OS and progression free survival than those not receiving additional gemcitabine (P<0.05). In multivariate analysis, lymphovascular invasion (present vs. absent) and addition gemcitabine therapy (yes vs. no) were significant independent prognostic factors for OS (P<0.05). Local recurrence was observed in 10 patients, and distant recurrence in 26 patients, synchronously accounting for 6 recurrences. Ten patients (18.2%) had severe grade 3 toxicities. CONCLUSIONS: Capecitabine-based CRT after resection of pancreatic adenocarcinoma showed favorable outcomes and tolerable toxicity profiles. PMID- 21606821 TI - Treatment outcome of elderly patients with glioblastoma who received combination therapy. AB - OBJECTIVES: Large population-based registries in Western countries show that the treatment strategy for glioblastoma multiforme (GBM) in elderly patients is likely less intensive. The purpose of this study was to clarify the treatment outcome of elderly patients with GBM and to explore appropriate treatment strategies. METHODS: We analyzed records from 86 patients (median age, 59 y; range, 9 to 77 y) diagnosed and histologically confirmed to have GBM, between January 1991 and June 2006 at our institutions; 14 elderly patients (range, 71 to 77 y) and 72 younger patients (range, 9 to 70 y). Fifty-two patients underwent total or subtotal resection and 34 patients underwent partial resection or biopsy. The median radiation dose was 54 Gy and 79 patients (92%) received anticancer agents. RESULTS: Among the 51 patients in recursive partitioning analysis (RPA) classes 5 and 6, the median survival time of the 12 elderly and 39 younger patients were 10.5 months [95% confidence interval, 5.8-12.8] and 11.7 months (95% confidence interval, 9.3-13.0), respectively (P = 0.32). Multivariate analysis showed only RPA class as an independent prognostic factor for overall survival rate (P = 0.009), whereas age (P = 0.85), total radiation dose (P = 0.052), and treatment with anticancer agents (P = 0.32) were not. CONCLUSIONS: After adjustment for RPA class, the treatment outcome of patients aged >70 years was equal to that of younger patients. Definitive treatment should not be withheld based on age alone. PMID- 21606822 TI - Biomarkers for cognitive decline: opportunities and challenges. PMID- 21606823 TI - Mesonephric remnant hyperplasia involving prostate and periprostatic tissue: findings at radical prostatectomy. AB - Mesonephric remnant hyperplasia is a very rare benign mimicker of prostate adenocarcinoma. As most reported cases are from transurethral resection specimens, the anatomic location and histologic spectrum of this entity have not been fully elucidated. Its immunohistochemical profile using current prostatic diagnostic markers has also not been well studied. In this study, we retrospectively characterized 10 cases of mesonephric remnant hyperplasia involving the prostate and periprostatic tissue, including 8 cases seen in radical prostatectomy specimens, with emphasis on the histopathologic and immunohistochemical features. Patients ranged in age from 48 to 70 years (average, 60 y). Seven of them had concurrent prostatic adenocarcinoma and underwent radical prostatectomy; one patient underwent prostatectomy because of the misdiagnosis of mesonephric remnant hyperplasia on transurethral resection as carcinoma; 2 patients had transurethral resection for urinary obstruction. The distribution of prostatic mesonephric hyperplasia was concentrated in 2 areas: one was in the anterior fibromuscular stroma and adjacent anterolateral periprostatic tissue (n=6 of 8); the other was located toward the base posteriorly and posterolaterally either within or exterior to the prostate and around the seminal vesicle (n=4 of 8). Histologic patterns observed included the following: small-to-medium-sized acini or tubules with a lobular distribution (n=10 of 10); cysts either in clusters or scattered containing secretions (n=8 of 10); small or ill-formed glands with an infiltrative growth (n=7 of 10); glands with papillary infoldings or micropapillary tufts (n=4 of 10); and 2 cases exceptionally displayed nodules of ill-formed small glands intermixed with spindle cells, mimicking sclerosing adenosis or Gleason pattern 5 prostate cancer. Most cases (7 of 10) had florid hyperplasia and harbored 3 or more growth patterns. All cases were negative for prostate-specific antigen. Cytokeratin 34betaE12 was diffusely positive in 4 of 9 cases, and showed focal immunoreactivity in the remaining 5 cases. Except for focal positivity seen in 4 of 7 cases, p63 was largely negative. Racemase was focally positive in 4 of 7 cases. Small glands with an infiltrative growth pattern, the most difficult to distinguish from cancer, were negative (n=3 of 6) or only focally positive (n=3 of 6) for 34betaE12, negative for p63 (n=6 of 6), and focally positive for racemase (n=4 of 6). All cases examined in the study were diffusely positive for PAX8. In conclusion, mesonephric remnant hyperplasia not only involves the bladder neck and base of the prostate as previously described, but may also present as a florid growth in the anterior fibromuscular stroma from the apex to the base, closely mimicking prostate cancer. Although basal cell marker and racemase expression overlaps with prostate cancer, mesonephric hyperplasia's unique morphology along with distinctive immunohistochemical expression of PAX8 and lack of prostate-specific antigen can help in distinguishing this benign entity from prostatic adenocarcinoma. PMID- 21606824 TI - Gastroesophageal junction hyperplastic (inflammatory) polyps: a clinical and pathologic study of 46 cases. AB - Hyperplastic (inflammatory) polyps (HPs) of the gastric corpus and antrum typically develop in association with chronic gastritis. However, little is known regarding the etiology, pathologic features, and natural history of HPs of the gastroesophageal junction (GEJ). We have noted, anecdotally, that GEJ HPs often occur in patients without gastric pathology. The aim of this study was to evaluate the clinical, pathologic, and outcome features of patients with HPs of the GEJ, and to compare the data with a control group of individuals with HPs in the gastric corpus or antrum. One hundred thirty-four consecutive polyps of the GEJ were identified by a 5-year search through the pathology files of a major tertiary-care hospital. Of these, 46 (36%) polyps from 46 patients met the pathologic criteria for HPs and formed the basis of this study. The 46 study patients, and their polyps, were evaluated for a wide variety of clinical, endoscopic, and pathologic features including outcome on follow-up endoscopy. The findings were compared with 46 HPs from 46 patients of the distal stomach (antrum or corpus) that were obtained randomly from the same 5-year period. Compared with patients with gastric antral or corpus HPs, patients with HPs of the GEJ were significantly younger in age (mean age, 55.9 y vs. 63.0 y; P=0.04). Pathologically, GEJ HPs showed a significantly higher rate of multilayered epithelium (P=0.06) and association with Barrett esophagus (BE) (P=0.0001) compared with distal gastric HPs. All BE-associated GEJ HPs were associated with either ultrashort (<1 cm) or short segment (1 to 3 cm) BE. All other pathologic variables, including intestinal metaplasia, were similar to those of distal gastric HPs. In a subanalysis, BE-associated GEJ HPs (33% of all GEJ HPs) showed a higher male to female ratio and a higher rate of intestinal metaplasia compared with all other HPs. Furthermore, none of the BE-associated GEJ HPs were associated with chronic active gastritis versus the non-BE-associated GEJ HPs, although this was not statistically significant. Only 1 HP (from the GEJ) from both the study and control groups was associated with a neoplasm (signet-ring cell carcinoma). On follow-up, 1 patient with a GEJ HP and 4 with distal gastric HPs developed recurrent HPs and none of the patients from either patient group developed dysplasia or carcinoma. In conclusion, unlike HPs of the gastric corpus or antrum, a significant proportion of HPs of the GEJ arise in association with BE and without gastric pathology. In patients with BE, the columnar-lined segment is often ultrashort, and thus, an HP may be the first clinical/endoscopic manifestation of that disorder. PMID- 21606825 TI - Thoracic epidural analgesia and acute pain management. PMID- 21606826 TI - Changing healthcare providers' behavior during pediatric inductions with an empirically based intervention. AB - BACKGROUND: Each year more than 4 million children experience significant levels of preoperative anxiety, which has been linked to poor recovery outcomes. Healthcare providers (HCPs) and parents represent key resources for children to help them manage their preoperative anxiety. The current study reports on the development and preliminary feasibility testing of a new intervention designed to change HCP and parent perioperative behaviors that have been reported previously to be associated with children's coping and stress behaviors before surgery. METHODS: An empirically derived intervention, Provider-Tailored Intervention for Perioperative Stress, was developed to train HCPs to increase behaviors that promote children's coping and decrease behaviors that may exacerbate children's distress. Rates of HCP behaviors were coded and compared between preintervention and postintervention. In addition, rates of parents' behaviors were compared between those that interacted with HCPs before training to those interacting with HCPs after the intervention. RESULTS: Effect sizes indicated that HCPs who underwent training demonstrated increases in rates of desired behaviors (range: 0.22-1.49) and decreases in rates of undesired behaviors (range: 0.15-2.15). In addition, parents, who were indirectly trained, also demonstrated changes to their rates of desired (range: 0.30-0.60) and undesired behaviors (range: 0.16 0.61). CONCLUSIONS: The intervention successfully modified HCP and parent behaviors. It represents a potentially new clinical way to decrease anxiety in children. A multisite randomized control trial funded by the National Institute of Child Health and Development will examine the efficacy of this intervention in reducing children's preoperative anxiety and improving children's postoperative recovery. PMID- 21606827 TI - Consequences of succinylcholine administration to patients using statins. AB - BACKGROUND: Statins cause structural changes in myocytes and provoke myotoxicity, myopathy, and myalgias. Thus, patients taking statins may be especially susceptible to succinylcholine-induced muscle injury. The authors tested the hypothesis that succinylcholine increases plasma concentrations of myoglobin, potassium, and creatine kinase more in patients who take statins than in those who do not and that succinylcholine-induced postoperative muscle pain is aggravated in statin users. METHODS: Patients who took statins for at least 3 months and those who had never used statins were enrolled. General anesthesia was induced and included 1.5 mg/kg succinylcholine for intubation. The incidence and degree of fasciculation after succinylcholine administration were recorded. Blood samples were obtained before induction and 5 and 20 min and 24 h after succinylcholine administration. Patients were interviewed 2 and 24 h after surgery to determine the degree of myalgia. RESULTS: The authors enrolled 38 patients who used statins and 32 who did not. At 20 min, myoglobin was higher in statin users versus nonusers (ratio of medians 1.34 [95% CI: 1.1, 1.7], P = 0.018). Fasciculations in statin users were more intense than in nonusers (P = 0.047). However, plasma potassium and creatine kinase concentrations were similar in statin users and nonusers, as was muscle pain. CONCLUSIONS: The plasma myoglobin concentration at 20 min was significantly greater in statin users than nonusers, although the difference seems unlikely to be clinically important. The study results suggest that the effect of succinylcholine given to patients taking statins is likely to be small and probably of limited clinical consequence. PMID- 21606828 TI - Nonselective and NR2B-selective N-methyl-D-aspartic acid receptor antagonists produce antinociception and long-term relief of allodynia in acute and neuropathic pain. AB - BACKGROUND: At low dose, the nonselective N-methyl-D-aspartate receptor antagonist ketamine produces potent analgesia. In humans, psychedelic side effects limit its use. To assess whether other N-methyl-D-aspartate receptor antagonist have an improved therapeutic utility index, we compared antinociceptive, side effect, and locomotor activity of three N-methyl-D aspartate receptor antagonists. METHODS: Ketamine, its active metabolite norketamine, and the NR2B-selective antagonist traxoprodil (CP-101,606) were tested in rat models of acute antinociception (paw-withdrawal response to heat) and chronic neuropathic pain (spared nerve injury). Side effects (stereotypical behavior, activity level) were scored and locomotor function of the nerve-injured paw was assessed using computerized gait analysis. In the chronic pain model, treatment was given 7 days after surgery, for 3 h on 5 consecutive days. RESULTS: All three N-methyl-D-aspartate receptor antagonists caused dose-dependent antinociception in the acute pain model and relief of mechanical and cold allodynia for 3-6 weeks after treatment in the chronic pain model (P < 0.05 vs. saline). In both tests, ketamine was most potent. Norketamine was as much as two times less potent and traxoprodil was up to 8 times less potent than ketamine (based on area under the curve measures). Nerve injury caused an inability to use the affected paw that either did not improve after treatment (ketamine, traxoprodil) or showed only a limited effect (norketamine). Traxoprodil, but not ketamine or norketamine, showed clear separation between effect and side effect. CONCLUSIONS: The observation that traxoprodil causes relief of chronic pain outlasting the treatment period with no side effects makes it an attractive alternative to ketamine in the treatment of chronic neuropathic pain. PMID- 21606829 TI - Two complications of tracheal intubation in a neonate: gastric perforation and lung collapse. PMID- 21606830 TI - Clinical translation of remote ischemic preconditioning of the liver. PMID- 21606831 TI - Remote ischemic preconditioning by hindlimb occlusion prevents liver ischemic/reperfusion injury. PMID- 21606832 TI - Elective sigmoid colectomy for diverticulitis: to operate or not? PMID- 21606833 TI - Mechanistic links in trauma-induced coagulopathy: a tale of two cities. PMID- 21606834 TI - Improving cutaneous scar formation by controlling the mechanical environment: large animal and phase I studies. AB - OBJECTIVE: To test the hypothesis that the mechanical environment of cutaneous wounds can control scar formation. BACKGROUND: Mechanical forces have been recognized to modulate myriad biologic processes, but the role of physical force in scar formation remains unclear. Furthermore, the therapeutic benefits of offloading cutaneous wounds with a device have not been rigorously tested. METHODS: A mechanomodulating polymer device was utilized to manipulate the mechanical environment of closed cutaneous wounds in red Duroc swine. After 8 weeks, wounds subjected to different mechanical stress states underwent immunohistochemical analysis for fibrotic markers. In a phase I clinical study, 9 human patients undergoing elective abdominal surgery were treated postoperatively with a stress-shielding polymer on one side whereas the other side was treated as standard of care. Professional photographs were taken between 8 and 12 months postsurgery and evaluated using a visual analog scale by lay and professional panels. This study is registered with ClinicalTrials.gov, number NCT00766727. RESULTS: Stress shielding of swine incisions reduced histologic scar area by 6- and 9-fold compared to control and elevated stress states, respectively (P < 0.01 for both) and dramatically decreased the histologic expression of profibrotic markers. Closure of high-tension wounds induced human-like scar formation in the red Duroc, a phenotype effectively mitigated with stress shielding of wounds. In the study on humans, stress shielding of abdominal incisions significantly improved scar appearance (P = 0.004) compared with within-patient controls. CONCLUSIONS: These results indicate that mechanical manipulation of the wound environment with a dynamic stress-shielding polymer device can significantly reduce scar formation. PMID- 21606835 TI - Pancreatic cancer surgery in the new millennium: better prediction of outcome. AB - BACKGROUND: Surgery is the only therapy with potentially curative intention in pancreatic cancer. This analysis aimed to determine prognostic parameters in a patient cohort with resected pancreatic adenocarcinoma with a special focus on the revised R1-definition. METHODS: Between October 2001 and August 2009, data from 1071 consecutively resected patients with pancreatic adenocarcinoma were prospectively collected in an electronical database. Parameters tested for survival prediction in univariate analysis included patient, tumor, and resection characteristics as well as adjuvant therapy. The parameters with significant results were used for multivariate survival analysis. Identified parameters with positive or negative prognostic effect were used to define risk groups and to assess the effects on patient survival. RESULTS: Age, ASA-score, CEA and CA19-9 levels, preoperative insulin-dependent diabetes mellitus, T-, N-, M-, R-, G-tumor classification, advanced disease, and LNR were all significant in univariate analysis, whereas gender, NYHA score, BMI, insurance status, type of surgical procedure, and adjuvant therapy were not. In multivariate analysis, age >=70 years, preoperative insulin-dependent diabetes, CA19-9 >=400 U/mL, T4-, M1- or G3 status, and LNR > 0.2 were independent negative predictors, whereas Tis/T1/T2 status, G1-differentiation, and R0-status (revised definition) were independently associated with good prognosis. Using these risk factors, patients were stratified into 4 risk-groups with significantly different prognosis; 5-year survival varied between 0% and 54.5%. Risk stratification resulted in improved survival prognostication within the predominant AJCC IIA and AJCC IIB stages. CONCLUSIONS: A newly defined prognostic profiling including the revised R1 definition discriminates survival of patients with resectable pancreatic adenocarcinoma better than the AJCC staging system, and may be of particular relevance for patient-adjusted therapy in the heterogeneous group of AJCC stage II tumors. PMID- 21606836 TI - Percutaneous radiofrequency ablation as first-line treatment in patients with early colorectal liver metastases amenable to surgery: is it justified? PMID- 21606837 TI - Triple positive tumor markers for hepatocellular carcinoma are useful predictors of poor survival. AB - OBJECTIVE: To determine the importance of the expression pattern of multiple tumor markers for hepatocellular carcinoma (HCC) with regard to the tumor malignancy and patient survival. BACKGROUND: Several studies have indicated that HCC tumor markers, including alpha-fetoprotein (AFP), Lens culinaris agglutinin reactive fraction of AFP and des-gamma-carboxy prothrombin were predictors of HCC malignancy. However, few reports have shown the relevance of the expression pattern of these 3 tumor markers with regard to patient prognosis. We herein reported the influence of the expression pattern of these 3 tumor markers on HCC malignancy and patient prognosis. METHODS: This retrospective study analyzed 185 patients who underwent hepatectomy for HCC between January 1999 and May 2009. The relationships between clinical parameters and these 3 tumor markers were analyzed. Cox proportional hazards regression analyses were performed to estimate risk factors for recurrence and survival. Furthermore, the relationships between pathological parameters and the expression patterns of the 3 tumor markers were analyzed. RESULTS: From clinical parameters, expression patterns of 3 tumor markers were related to maximum tumor size and macrovascular invasion in image findings. Multivariate analyses revealed independent risk factors for recurrence or survival to be the Child-Pugh score, the presence of multiple tumors, and triple positive tumor marker expression. From pathological findings, microvascular invasion and an Edmondson-Steiner classification of III or IV were related to the expression patterns of the 3 tumor markers. CONCLUSIONS: Triple positive tumor markers for HCC showed poor prognosis and invasive characteristics in pathological findings. Examination of these markers would be useful for predicting the degree of HCC malignancy. PMID- 21606838 TI - A multivariate analysis of pre-, peri-, and post-transplant factors affecting outcome after pediatric liver transplantation. AB - OBJECTIVE: The purpose of this study was to identify significant, independent factors that predicted 6 month patient and graft survival after pediatric liver transplantation. SUMMARY BACKGROUND DATA: The Studies of Pediatric Liver Transplantation (SPLIT) is a multicenter database established in 1995, of currently more than 4000 US and Canadian children undergoing liver transplantation. Previous published analyses from this data have examined specific factors influencing outcome. This study analyzes a comprehensive range of factors that may influence outcome from the time of listing through the peri- and postoperative period. METHODS: A total of 42 pre-, peri- and posttransplant variables evaluated in 2982 pediatric recipients of a first liver transplant registered in SPLIT significant at the univariate level were included in multivariate models. RESULTS: In the final model combining all baseline and posttransplant events, posttransplant complications had the highest relative risk of death or graft loss. Reoperation for any cause increased the risk for both patient and graft loss by 11 fold and reoperation exclusive of specific complications by 4 fold. Vascular thromboses, bowel perforation, septicemia, and retransplantation, each independently increased the risk of patient and graft loss by 3 to 4 fold. The only baseline factor with a similarly high relative risk for patient and graft loss was recipient in the intensive care unit (ICU) intubated at transplant. A significant center effect was also found but did not change the impact of the highly significant factors already identified. CONCLUSIONS: We conclude that the most significant factors predicting patient and graft loss at 6 months in children listed for transplant are posttransplant surgical complications. PMID- 21606839 TI - Quantification of immune deposits in renal diseases. AB - In this series of renal diseases, in addition to semiquantitative scoring of direct immunofluorescein images, the immune deposits were quantified by image analysis. The aim of this study was to evaluate quantitative measurements for diagnosis and prognosis of renal immune complex diseases. Immunoglobulin A (IgA) nephropathy (n=27, 54%), membranous nephropathy (n=8, 16%), membranoproliferative glomerulonephritis (n=8, 16%), and systemic lupus erithematosus nephritis cases (n=7, 14%) were evaluated by semiquantitative scores (SS) for IgG, IgA, IgM, C3, C1q, lambda, and kappa. The quantitative measures, intensity, mean and total optical density (MOD and TOD) were determined by image analysis software. There was positive correlation between SS; and intensity as well as TOD for 199 positive stained images, but not between SS and MOD. TOD was important for determining SS by linear regression. When all of the cases were considered, creatinin at the time of biopsy was only slightly correlated with intensity and TOD of IgM. Intensity and TOD, but not SS of IgA was significantly increased in IgA nephropathy cases with adverse histopathologic prognostic features. In 4 cases (8%) only TOD allowed identification of the predominantly deposited antibody. TOD and intensity seems to have better correlation with prognostic histopathologic features than SS. TOD may be useful for determining predominant immune deposit, a feature important for diagnosis. PMID- 21606840 TI - A mixed polyunsaturated fatty acid diet normalizes hippocampal neurogenesis and reduces anxiety in serotonin transporter knockout rats. AB - The aim of this study was to investigate the effects of a mixed dietary intervention on behavioral symptoms in serotonin transporter knockout (5-HTT-/-) rats modeling the human 5-HTT length polymorphic region short-allele. Twenty female 5-HTT-/- and 19 wild-type (5-HTT+/+) rats were fed for 3 months on a mixed polyunsaturated fatty acid (PUFA) diet comprising n-3 PUFAs, B vitamins and phospholipids, or an isocaloric control diet, and a subgroup was subsequently tested in an array of anxiety-related behavioral tests. All brains were harvested and immunostained for doublecortin, a neurogenesis marker. In addition, hippocampal volume was measured. 5-HTT-/- rats on the control diet displayed increased anxiety-related behavioral responses, and impaired fear extinction. These effects were completely offset by the mixed PUFA diet, whereas this diet had no behavioral effect in 5-HTT+/+ rats. In parallel, dentate gyrus doublecortin immunoreactivity was increased in 5-HTT-/- rats fed on the control diet, which was reversed by the mixed PUFA diet. Hippocampal volume was unaffected by the mixed PUFA diet in 5-HTT-/- subjects, whereas it increased in 5 HTT+/+ rats. We conclude that a mixed n-3 PUFA diet ameliorates anxiety-related symptoms in a genotype-dependent manner, potentially by normalizing neurogenesis. We suggest that such a mixed diet may serve as an attractive adjuvant to treat anxiety in 5-HTT length polymorphic region short-allele carriers. PMID- 21606841 TI - Matrix metalloproteinase-1 and matrix metalloproteinase-12 gene polymorphisms and the outcome of coronary artery disease. AB - OBJECTIVES: In this study, we investigated the association between matrix metalloproteinase-1 (MMP-1) G-1607GG, MMP-12 A-82G and MMP-12 A1082G genotypes and haplotypes and the prognosis of coronary artery disease (CAD). METHODS: A total of 129 Tunisian patients with CAD were followed prospectively for a median of 2.5 years. Genotypes were determined by a PCR-based restriction fragment length polymorphism. Two endpoints were considered: restenosis and incidence of clinical vascular events (restenosis, myocardial infarction, stroke, cardiac death). RESULTS: Genotypes of MMP-1 G-1607GG, MMP-12 A-82G and MMP-12 A1082G were not associated with the incidence of restenosis or clinical events. Analysis of haplotypes consisting of alleles of MMP-1 G-1607GG and MMP-12 A1082G showed that the rate of clinical events was significantly higher in patients carrying the GG A haplotype than those with other haplotypes (0.637 vs. 0.424, respectively, odds ratio=1.45; 95% confidence interval=1.04-2.04; P<0.05; P adjusted for multiple risk factors). However, after Bonferroni correction for multiple comparisons, this difference did not reach statistical significance (P=0.093), showing that there was a tendency for the association between the GG-A haplotype and future clinical events in patients with CAD. CONCLUSION: These findings showed a trend of the GG-A haplotype of MMP-1 G-1607GG/MMP-12 A1082G towards the prediction of future clinical events in patients with CAD and suggested a possible importance of these loci in the prediction of the prognosis of CAD. Studies with large sample size are warranted to better investigate this association, as MMP genotyping could aid in identifying patients who are likely to have unfavourable prognosis. PMID- 21606842 TI - Is there a difference in the diagnostic accuracy of computed tomography coronary angiography between women and men? AB - OBJECTIVE: To assess the influence of sex on the diagnostic performance of computed tomography coronary angiography (CTCA). METHODS: A total of 916 symptomatic patients (30.5% women) without earlier history of coronary artery intervention underwent both CTCA and invasive coronary angiography. Descriptive diagnostic parameters, to detect obstructive coronary artery disease (CAD; >= 50% lumen diameter narrowing) on CTCA, were compared between women and men on a per patient, per-vessel, and per-segment level. Adjusted values were calculated for clustered segments and differences in sex variables using logistic multivariate regression models in general estimated equations. RESULTS: Women were older, had less typical chest complaints, and had a lower prevalence, extent, and severity of CAD compared with men. Multivariate analysis on a per-patient level revealed no difference in sensitivity (98 vs. 99%, P=0.15), specificity (78 vs. 82%, P=0.65), positive predictive value (PPV; 87 vs. 95%, P=0.10), negative predictive value (NPV; 97 vs. 98%, P=0.63), and diagnostic odds ratio (DOR; 198 vs. 721, P=0.07). No difference was found on per-vessel level analysis (sensitivity 95 vs. 97%, P=0.14; specificity 89 vs. 87%, P=0.93; PPV 73 vs. 79%, P=0.06; NPV 98 vs. 98%, P=0.72; and DOR 143 vs. 240, P=0.08). Per-segment analysis revealed a lower sensitivity (88 vs. 94%, P<0.001) and DOR (163 vs. 302, P=0.002) in women compared with men, without a difference in specificity (96 vs. 95%, P=0.19), PPV (64 vs. 69%, P=0.07), and NPV (99 vs. 99%, P=0.08). CONCLUSION: CTCA can accurately rule out obstructive CAD in both women and men. CTCA is less accurate in women to detect individual obstructive disease. PMID- 21606843 TI - Obesity and familial obesity and risk of cancer. AB - Obesity is associated with a risk of at least 20 different cancers. We aimed at defining cancer risks in prospectively recruited patients with a novel subgroup, those with a family history of obesity. We defined a cohort of 30 020 patients who had been hospitalized since 1964. Cancer risks in these patients were followed through 2006. Standardized incidence ratios were calculated for cancer using those not hospitalized for obesity as a reference population. We could also identify persons who had been hospitalized for type 2 diabetes. A total of 1721 patients were diagnosed with cancer after hospitalization for obesity, showing an increased risk for 12 cancers and a decrease for breast cancer. The largest increases were found for nervous system hemangioma (13.64, 95% confidence interval 2.57-40.37) and other male genital (3.94, 1.24-9.26), bone (3.41, 1.23 7.47), small intestinal (2.93, 1.60-4.93), kidney (2.46, 1.97-3.02), and endometrial (2.32, 2.01-2.66) cancers. Among endocrine cancers, adrenal tumors showed the highest risk, of 3.74 (1.86-6.72). The overall risk was 1.19 (1.13 1.25). Family history of obesity was associated with formerly unrecognized increased risks of gallbladder and colon cancers and ocular melanoma. Cancer risks in this relatively young obese population differed quantitatively from those found after type 2 diabetes. The novel findings included rare and relatively benign tumors, probably found in endocrinological and other medical examinations for obesity and related conditions. Similarly, male genital cancer may be related to sexual behavior, and bone cancers, found in old individuals, could be related to propensity for fractures. PMID- 21606844 TI - Responding to the National HIV/AIDS Strategy-setting the research agenda. PMID- 21606846 TI - Readability of 3 heart disease health-related quality of life questionnaires. AB - PURPOSE: To compare the readability of the English language versions of 3 heart disease health-related quality of life questionnaires, the Minnesota Living with Heart Failure (MLHF) Questionnaire, the Seattle Angina Questionnaire (SAQ), and the MacNew Heart Disease Health-Related Quality of Life (MacNew) Questionnaire. METHODS: The readability of the MLHF, the SAQ, and the MacNew was calculated using 6 different readability formulas; the FOG Index, the Fry Readability Formula for Short Passages, the Harris-Jacobson, the Flesch, the New Dale-Chall, and the SMOG. RESULTS: The reading grade level of the MacNew averaged between the fifth and sixth grades. Readability of the MLHF and the SAQ averaged between the seventh and eighth grade levels. CONCLUSIONS: These findings suggest that care should be taken to select heart disease health-related quality of life instruments that match closely the reading level of the target population as the ease of reading these 3 heart disease health-related quality of life instruments varies. PMID- 21606845 TI - Incremental exercise using progressive versus constant pedaling rates: a study in cardiac patients. AB - PURPOSE: Cardiopulmonary exercise testing is widely used in clinical assessment and exercise prescription. However, significant differences in physiological responses can occur depending on testing protocol. The aim of this study was to evaluate the cardiopulmonary responses to different incremental cycle pedaling cadences in cardiac patients. METHODS: Eleven men with coronary artery disease (CAD) and 12 men with chronic heart failure (CHF) performed 2 maximal cycle tests at constant cadence (60-70 rpm, at fixed cadence) and at progressive cadence. Peak values for oxygen uptake (V(O(2)peak)), workload (W(peak)), and heart rate (HR(peak)); ventilatory threshold (VT); and the oxygen uptake (VO2) per unit work rate (WR) increment (DeltaV(O(2))/DeltaWR) obtained using 2 protocols were determined. RESULTS: V(O(2)peak) and W(peak), respectively, were higher during increasing cadence (INCR) compared with fixed cadence (FIX) protocol both in patients with CAD (32.7 +/- 5.4 vs 28.1 +/- 7.0 mL . kg(-1) . min(-1), P = .01; 214 +/- 42 vs 150 +/- 28 W, P = .001) and in patients with CHF (20.3 +/- 7.4 vs 17.2 +/- 5.5 mL . kg(-1) . min(-1), P = .006; 133 +/- 45 vs 104 +/- 33 W, P = .005). No differences were seen in HR(peak). Both in patients with CAD and in patients with CHF, V(O(2)) (21.7 +/- 5.5 vs 16.8 +/- 5.3 and 12.3 +/- 7.4 vs 9.3 +/- 2.8 mL . kg(-1) . min(-1)) and HR (114 +/- 14 vs 98 +/- 13 and 92 +/- 17 vs 80 +/- 17 bpm) at VT were significantly higher in INCR than in FIX protocol. No differences were seen in workload at VT. DeltaV(O(2))/DeltaWR during INCR protocol were higher in patients with CAD (13.4 +/- 1.8 vs 9.5 +/- 2.6 mL . kg( 1) . W(-1), P = .006) and patients with CHF (13.6 +/- 4.1 vs 8.7 +/- 1.9 mL . kg( 1) . W(-1), P = .006). DISCUSSION: These findings indicate that in tests at fixed cadence, there occurs an earlier activation of the anaerobic mechanisms leading to a premature exhaustion before a cardiopulmonary endpoint has been achieved. PMID- 21606847 TI - Overview of current toxicological knowledge of engineered nanoparticles. AB - OBJECTIVE: Nanotechnology is the manipulation of matter on a near-atomic scale to produce nanoparticles with unique properties, allowing new commercial applications. Since nanoparticles exhibit unique physicochemical properties, they are likely to exhibit biological activity significantly different from fine-sized particles of the same chemical composition. Therefore, evaluation of the biological effects of nanoparticles is critical. METHODS: The article lists the major objectives of nanotoxicology and briefly reviews the literature concerning biological responses to pulmonary exposure. RESULTS: Interactions of nanoparticles with biological systems depend on particle size, shape, oxidant generation, surface functionalization, and rate of dissolution. Pulmonary, cardiovascular, and central nervous system responses to pulmonary exposure to nanotitanium dioxide and carbon nanotubes are described. CONCLUSIONS: Significant biological responses occur in animal models after pulmonary exposure to certain nanoparticles. Control of exposure appears prudent to protect worker health. CLINICAL SIGNIFICANCE: Nanotechnology is synthesizing a wide range of nanoparticles, which exhibit unique physicochemical properties. These unique properties make unique biological activity likely. If certain nanoparticles induce adverse effects in vitro or in animal models, then occupational health surveillance and exposure control may be prudent steps in the protection of worker health. PMID- 21606848 TI - General principles of medical surveillance: implications for workers potentially exposed to nanomaterials. AB - OBJECTIVE: As potential occupational exposure to nanomaterials becomes more prevalent, it is important that the principles of medical surveillance be considered for workers in the nanotechnology industry. METHODS: The principles of medical surveillance are reviewed to further the discussion of occupational health surveillance for workers exposed to nanomaterials. RESULTS: Because of the rapid evolution of nanotechnology, information may not be available to make a well-informed determination of all factors needed to evaluate risk of health effects from occupational exposure to nanomaterials. CONCLUSION: Every workplace dealing with engineered nanomaterials should conduct hazard and exposure assessments as part of an overall surveillance needs assessment for nanotechnology workers. In workplaces where risk is felt to be present, or at least cannot be ruled out, initiation of medical surveillance is prudent to protect workers' health. PMID- 21606849 TI - Role of medical surveillance in risk management. AB - OBJECTIVE: Occupational physicians face increasing pressure by health authorities, employers, and employees to provide practical, targeted, and meaningful medical surveillance to workers handling nanoparticles. METHODS: On the basis of experience and literature review, examples were identified for successful medical surveillance activities. Consideration was given to the respective context in which they provide benefit, and whether these examples may be extrapolated to the present situation with nanoparticles. RESULTS: Occupational medical surveillance based on existing knowledge of hazards and potentially associated health effects is both feasible and useful. In the absence of sufficient knowledge, results from surveillance programs may still provide new insights into exposure-response relationships or help to identify new hazards. In some situations, however, medical surveillance may also produce harm. CONCLUSIONS: Medical surveillance provides benefits on the individual, company, and societal level, provided that it is planned and performed with its limitations in mind. PMID- 21606850 TI - National Institute for Occupational Safety and Health Nanomaterials and Worker Health Conference--medical surveillance session summary report. AB - OBJECTIVES: The goal of these sessions was to identify current practices and recommendations regarding medical surveillance for nanomaterial workers. METHODS: Conference participants met in three discussion groups. RESULTS: There were few existing programs directed to nanomaterial workers. Participants expressed a range of views, from feeling that comprehensive medical surveillance is important currently to suggesting that targeted medical surveillance will become important when more complete data are available to assess risks. CONCLUSIONS: Results of health outcomes research for ultrafine air pollution and toxicological information about specific nanomaterials should inform the design of medical surveillance programs. Groups with high exposures should be identified and targeted. Overall, because of uncertainties in the health effects of concern, investments in control measures, exposure assessment efforts, and exposure registries are currently most likely to be important prevention strategies. PMID- 21606851 TI - Subtotal splenic embolization is a safe and effective treatment for isolated splenic vascular tumors associated with consumptive coagulopathy. AB - Consumptive coagulopathy is a known complication of large vascular tumors. We describe 2 episodes of consumptive coagulopathy in young children, which were secondary to isolated splenic vascular tumors. One child was successfully treated by subtotal embolization of the spleen, whereas the second child required splenectomy after an initial embolization improved--but did not fully control- his consumptive coagulopathy. PMID- 21606852 TI - A case of spontaneous hip dislocation that occurred during radiation therapy. AB - Currently, radiation therapy is widely used for the treatment and palliation of metastatic bone disease in both adults and children. Recent advances in radiation therapy, such as intensity-modulated radiation therapy, have led to more focused treatments and fewer adverse effects. Although radiation therapy has been associated with several musculoskeletal effects in the growing child, hip dislocation during a course of radiation therapy has not been reported. We report a case of a 12-year-old girl who presented with metastatic bone disease, and developed a hip dislocation during radiation therapy. Possible causes are discussed in detail and a thorough literature review is presented. PMID- 21606853 TI - Cannulated screw fixation of fracture neck of femur in children with osteogenesis imperfecta. AB - Osteogenesis imperfecta is a disorder of abnormality in collagen metabolism due to genetic defects, which causes fragility fracture in children. Fragility fracture of the neck of femur can be difficult to treat in adults. The difficulties increase exponentially in children. The challenge becomes more severe when there is an intramedullary rod in situ in the femoral shaft. It is a technically demanding work to fix fracture caused by osteogenesis imperfecta. There is hardly any published study on the difficult fixation of fracture neck of femur in osteogensis imperfecta. Therefore, we present two cases using cannulated screw fixation for this type of fracture for the benefit of other orthopaedic surgeons. PMID- 21606854 TI - Intracapsular hip pressures in a porcine model: does position and volume matter? AB - This study outlines a relationship between joint volume, positioning, and intracapsular pressure in a healthy hip. After measuring the native intracapsular pressure in 12 porcine specimens, each joint was injected with radio-opaque colored saline as pressures were measured. At 20 mmHg, the hip was placed in its position of ease and then in differing positions while pressures were recorded. Position significantly altered pressures, with the lowest values in neutral and the highest in hyperextension (P<0.001). Extreme hip positions may be detrimental because of high pressures created within the joint, possibly explaining complications associated with some hip diagnostic and treatment methods. PMID- 21606855 TI - Lumbarized sacrum as a relative contraindication for lateral transpsoas interbody fusion at L5-6. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To determine if lumbarized sacra at the L5-6 level (functional L4-5) are a contraindication to a lateral transpsoas approach. SUMMARY OF BACKGROUND DATA: Transitional vertebrae at the lumbosacral junction present mechanical and morphologic changes, though these changes have not been characterized with respect to the feasibility of a lateral transpsoas approach. METHODS: Three hundred fifty-one patients were scheduled for lumbar interbody fusion using a mini-open lateral transpsoas approach (XLIF) at L4-5 from 2004 to 2008 at a single institution. In patients with 6 lumbar vertebrae, accessibility, based on neuromonitoring, of the L5-6 level (functional L4-5) was reviewed. Qualitative assessments using axial magnetic resonance imaging (MRI) were performed and compared with a sample of patients with normal anatomy treated at L4-5. RESULTS: Of the 351 patients scheduled for treatment at L4-5, 10 (2.8%) were determined to have 6 lumbar vertebrae with the symptomatic level at L5-6. Of those 10, 2 (20%) could be treated using a lateral transpsoas approach, and 8 (80%) were converted to another approach after a corridor through the psoas muscle was not found, based on neuromonitoring feedback. Review of axial MRI showed a teardrop-shaped psoas detached from the lateral border of the disc space in patients with transitional anatomy unapproachable at L5-6, resemblant of L5-S1 in normal anatomy. In the 2 patients who could be safely approached, the psoas anatomy at L5-6 was similar to a normal L4-5 level, with a domed/helmet shape, attached laterally to the disc space. CONCLUSIONS: Treating the L5-6 level using a lateral transpsoas approach in individuals with lumbarized sacra can be challenging due to anatomy more similar to the L5-S1 level in normal patients. Preoperative planning using axial MRI and intraoperative adherence to advanced neuromonitoring can aid in identifying and avoiding injury in these rare patients. PMID- 21606856 TI - Gonadal function in male mountain bikers. AB - Some studies reported testicular disorders associated with biking in mountain cyclists, which include injuries, erectile dysfunction, and higher scrotal temperatures. But none of these studies evaluated gonadal function. Therefore, the aim of this study was to evaluate gonadal function in male mountain bikers. Twenty-two male professional mountain bikers and 30 healthy noncyclist controls were included in the study. The mean age and body mass index were similar in both groups. Fasting blood samples for the measurement of the levels of total testosterone (TT), sex-hormone binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were obtained from all study participants before any physical activity. In addition, because insulin sensitivity and leptin modulate gonadal function, the concentrations of insulin, glucose, and leptin were also measured in the same samples. Calculated free testosterone (cFT) and bioavailable testosterone (bioT) were calculated from SHBG and TT. Basal hormonal levels including insulin, leptin, LH, FSH, SHBG, TT, glucose, and homeostasis model assessment scores were similar between the groups. However, bioT and cFT levels were significantly lower (p <= 0.05) in the mountain bikers than those in the controls. Despite the lower mean testosterone levels in the study group, the levels of LH and FSH were similar to controls. Insulin and leptin do not contribute to lower testosterone levels. In conclusion, male mountain bikers have lower testosterone concentrations compared to controls. This alteration cannot solely be explained by testicular dysfunction. The etiology of lower testosterone levels in cyclists appears to be complex and requires further research. The influence of such a decline on the athlete's performance, quality of life, and muscle strength is not known as yet. PMID- 21606857 TI - Muscular hypertrophy and changes in cytokine production after eccentric training in the rat skeletal muscle. AB - We investigated the time course effects of eccentric training on muscular size, strength, and growth factor/cytokine production by using an isokinetic-exercise system for rats. Male Wistar rats (n = 34) were randomly assigned into 4 groups: 5 session eccentric-training group (ECC5S, n = 10); 5 session sham-operated group (CON5S, n = 10); 10 session eccentric-training group (ECC10S, n = 7); 10 session sham-operated group (CON10S, n = 7). In each group, a session of either training or sham operation was performed every 2 days. The training consisted of 4 sets of forced dorsiflexion (5 repetitions) combined with electric stimulation of plantar flexors. The wet weight of medial gastrocnemius muscle did not increase significantly after 5 sessions of training, whereas that after 10 sessions of training significantly increased with a concomitant increase in the cross sectional area (CSA) of muscle fibers (weight, p < 0.05; fiber CSA, p < 0.001). Interleukin (IL)-6 in ECC5S and ECC10S groups showed significant increases (p < 0.01), whereas those of tumor necrosis factor (TNF)-alpha and IL-10 did not. The phospho-stat-3 showed a significant increase in ECC10S (p < 0.001) but not in ECC5S. Myostatin and follistatin also showed significant differences only between ECC10S and CON10S (p < 0.05). The results showed that repeated sessions of eccentric training for 20 days cause increases in muscular size and strength associated with increases in IL-6, follistatin, phospho-stat-3, and a decrease in myostatin. The delayed responses of IL-6, myostatin, phospho-stat-3, and follistatin would be due to the chronic effects of repeated training and possibly important for muscular hypertrophy. PMID- 21606858 TI - Effects of a heart rate-based recovery period on hormonal, neuromuscular, and aerobic performance responses during 7 weeks of strength training in men. AB - The purpose of this study was to compare hormonal, neuromuscular, and aerobic performance changes between a constant 2-minute interset recovery time and an interset recovery time based on individual heart rate (HR) responses during a 7 week (3 sessions per week, 3 * 10 repetition maximum [RM]) hypertrophic strength training period. The HR-dependent recovery time was determined with a Polar FT80 HR monitor, whereas the control groups used constant 2-minute periods between sets. From 24 male subjects who were divided in 2 equal groups, 21 completed the study (FT80, n = 12; CONTROL, n = 9). Serum blood samples analyzed for testosterone (TES) and cortisol (COR) were taken before and after the 7-week training period at rest. Concentric knee extension 1RM was measured before, after 4 weeks, and at the end of the training period. Concentric knee extension and knee flexion 10RM, central activation ratio (CAR), and maxVO2 were measured before and after the training. Serum TES concentrations were significantly higher after the training period in FT80 (p < 0.001), whereas no significant changes were observed in the CONTROL. Serum COR and maxVO2 were unchanged in both groups. In FT80 (p < 0.001), the increase in 10RM was higher (p < 0.05) than in CONTROL (p < 0.001). Central activation ratio increased in both groups, with the significant increase observed in FT80 (p < 0.05). The higher TES responses, 10RM, and CAR development in FT80 suggest that an HR-based recovery period system of the FT80 may be more efficient in this type of hypertrophic strength training (3 * 10RM). The protocol in this study may be considered as a metabolic training cycle that coaches and trainers can use within a longer periodized training program. PMID- 21606859 TI - Effects of 24 weeks of progressive resistance training on knee extensors peak torque and fat-free mass in older women. AB - This study examined the effects of resistance training (RT) on knee extensor peak torque (KEPT) and fat-free mass (FFM) in older women. Seventy-eight volunteers (67.1 +/- 5.9 years old) underwent 24 weeks of progressive RT (RTG) while 76 (67.4 +/- 5.9 years old) were studied as controls (CG). Dominant knee extension peak torque was assessed using an isokinetic dynamometer (Biodex System 3) and FFM measurements were performed by dual-energy x-ray absorptiometry. Muscle strength and FFM were evaluated before and after the intervention in all volunteers. Participants in the RTG trained major muscle groups 3 times per week during 24 weeks. Training load was kept at 60% of 1 repetition maximum in the first 4 weeks, 70% in the following 4 weeks, and 80% in the remaining 16 weeks, with repetitions, respectively, decreasing from 12, 10, and 8. A Split-plot analysis of variance was performed to examine between- and within-group differences, and the level of significance was accepted at p <= 0.05. It was observed that the RTG showed significant increases in KEPT (from 89.9 +/- 21.8 to 102.8 +/- 22.6 N.m; p < 0.05) and FFM (from 36.4 +/- 4.0 to 37.1 +/- 4.2 kg, p < 0.05). Appendicular FFM was also significantly increased after the intervention period in the RTG (13.9 +/- 1.8 to 14.2 +/- 1.9 kg, p < 0.05). None of these changes were observed for the CG. Consistent with the literature, it is concluded that a progressive RT program promotes not only increases in muscle strength, as evaluated by an isokinetic dynamometer, but also in FFM as evaluated by the DXA, in elderly women. PMID- 21606860 TI - Physiological and perceived exertion responses at intermittent critical power and intermittent maximal lactate steady state. AB - The aim of this study was to compare the power outputs of the intermittent critical power (CPi) with the intermittent maximal lactate steady state (MLSSi) and to compare the physiological and perceptual responses exercising at CPi and MLSSi. Ten subjects performed intermittent trials on a cycle ergometer to determine CPi and MLSSi using 30:30 seconds of effort and pause. The oxygen uptake (&OV0312;o2), heart rate (HR), blood lactate concentration ([Lac]), and rating of perceived exertion (RPE) responses were compared during 30-minute cycling at CPi and MLSSi. The CPi (267 +/- 45 W) was similar to MLSSi (254 +/- 39 W), and they were correlated (r = 0.88; p < 0.05). The &OV0312;o2 and HR responses stabilized throughout exercising at CPi (2.52 +/- 0.52 L.min; 156 +/- 8 b.min) and MLSSi (2.41 +/- 0.32 L.min; 152 +/- 10 b.min). These physiological variables were similar between conditions. However, the [Lac] and RPE were higher from the middle to the end of exercise duration at CPi ([Lac] = 6.9 +/- 2.6 mM; RPE = 17.1 +/- 2.1 a.u.) compared to MLSSi ([Lac] = 5.1 +/- 0.9 mM; RPE = 15.7 +/ 1.8 a.u.). Therefore, CPi intensity determined from 30:30 seconds of effort and rest periods on a cycle ergometer is equivalent to the MLSSi, and there is a physiological steady state throughout both exercise intensities, although the [Lac] and RPE responses at CPi are higher than at MLSSi. Thus, the CPi and MLSSi may be used as tools for intermittent training evaluation and prescription. PMID- 21606861 TI - Adjunctive use of noncontact low-frequency ultrasound for treatment of suspected deep tissue injury: a case series. AB - PURPOSE: We lack a clear understanding of the mechanisms of damage associated with suspected deep tissue injuries (SDTI) and sufficient evidence to determine the efficacy of various preventive interventions. The purpose of this article is to evaluate noncontact low-frequency ultrasound (NLFU) as one component of a preventive program designed for preventing SDTI from progressing to higher-stage pressure ulcers. CASES: In March 2009, we added NLFU treatments daily for 5 days, then every other day until healed, to our prevention protocol in order to prevent progression of SDTI to a higher-stage pressure ulcer. We report the course and outcomes of 6 SDTIs that were treated adjunctively with NLFU. Treatment was limited to patients with an SDTI identified within 3 to 4 days of onset. CONCLUSION: Following the addition of NLFU to the SDTI plan of care, these 6 cases of SDTI did not progress to advanced-stage pressure ulcers. These initial findings suggest that the addition of NLFU to SDTI identified within 3 to 4 days of onset may be effective for preventing progression to higher-stage pressure ulcers. PMID- 21606862 TI - Calciphylaxis: no longer rare; no longer calciphylaxis? A paradigm shift for wound, ostomy and continence nursing. AB - This article challenges conventional wisdom that calciphylaxis is a rare condition. Rather, emerging evidence suggests that calciphylaxis is neither rare nor uncommon. In addition, the term calciphylaxis is questioned because misrepresents the underlying etiology of the condition. Multiple researchers and clinicians advocate abandoning the use of the term, but nursing literature has not yet followed suit. This article reviews the epidemiology, clinical manifestations, diagnosis, prevention, and treatment of this condition and associated wounds, and suggests areas for future research. The WOC nurse's role as an educator, leader, researcher, clinical expert, and patient advocate is summarized. PMID- 21606863 TI - Negative pressure wound therapy for recurrent pilonidal disease: a review of the literature. AB - Pilonidal disease arises from hair follicles of the gluteal cleft and may result in a chronic exudative disorder. The management of pilonidal disease following surgical excision remains controversial, despite an abundance of research into different treatment options. Negative pressure wound therapy is an emerging treatment option for complex or recurrent pilonidal disease. We performed a comprehensive literature search, using the electronic databases MEDLINE, Cochrane library, CINAHL, PubMed, and Web of Knowledge. All studies, case reports, and multiple case series evaluating the use of negative pressure wound therapy for treatment of pilonidal disease were included. Despite the breadth of our search parameters, we identified limited studies addressing this issue; all were published between 2003 and 2007. Findings of 5 case reports or multiple case series tentatively suggest that negative pressure wound therapy may be an emerging treatment option for pilonidal disease management. However, we recommend that more rigorous research, including randomized controlled trials, be conducted before implications can be drawn for evidence-based practice. PMID- 21606864 TI - A prospective study of the PUSH tool in diabetic foot ulcers. AB - PURPOSE: The purpose of this study was to examine the predictive validity of Pressure Ulcer Scale for Healing (PUSH; v. 3.0) in monitoring healing of neuropathic foot ulcers in patients with diabetes mellitus. DESIGN: This is a 13 week descriptive, prospective study describing the trajectory of change over time and the time-to-heal associated with PUSH scores. The study monitored a convenience sample of 18 subjects with Wagner 2 or greater neuropathic, nonischemic ulcers on the plantar surface of the foot, which healed completely over a 13-week follow-up period. Every 2 weeks, the study ulcers were evaluated via PUSH. Healing was defined as complete reepithelialization. RESULTS: PUSH scores were modeled using a piecewise linear regression. PUSH values decreased significantly (P < .0001) at a rate of 0.6656 per week, until 2 weeks before healing, and then decreased significantly (P < .0001) at a rate of 2.2496 per week for the last 2 weeks of healing. Conversely, the time-to-heal (in weeks) increased significantly (P < .0001), at a rate of 0.6412 per each unit increase in PUSH for PUSH values of 4 or less, and then significantly (P < .0001) increased at a rate of 1.072 for PUSH values greater than 5. In predicting time to-heal, the subitem of length * width alone (R = 0.81) is comparable to the total PUSH score (R = 0.76). Individually, exudate (R = 0.36) and tissue type (R = 0.42) are not nearly as useful as length * width. CONCLUSION: Our findings indicate that PUSH scores significantly decrease over time in healing neuropathic diabetic foot ulcers (DFUs) that have no arterial etiologic component. Findings also suggest that total PUSH scores predict time-to-heal for DFU. We showed that a DFU with a PUSH score of 10 would be expected to heal in 8.8 weeks (95% CI: 7.4 10.2) and a DFU with a PUSH score of 4 in 2.6 weeks (95% CI: 1.88-3.25). Finally, measurements of size alone predict healing time for neuropathic DFU. This finding could greatly simplify clinical assessments. PMID- 21606865 TI - Reliability analysis of the 3-min all-out exercise test for cycle ergometry. AB - The 3-min all-out exercise test (3 MT) is purported to estimate critical power (CP) and anaerobic work capacity (W') and serve as an exercise mode for measuring maximum oxygen uptake (VO(2max)). Reliability analysis of the 3 MT has been confined to CP, not W', and verification of "true" VO(2max)was exclusive to a graded exercise test (GXT). PURPOSE: We conducted a reliability analysis of the 3 MT and compared VO(2max)values from the 3 MT with a GXT and an exhaustive square wave verification bout. METHODS: Upon completion of a custom GXT and square-wave verification protocol, 11 subjects of various aerobic powers completed two 3 MTs (separate visits). CP, W', average power during 150 s from the 3 MT, and VO(2max)values were assessed using typical error (TE), coefficient of variation (CV), and intraclass correlation (alpha). RESULTS: CP (W) (trial 1 = 206 +/- 47, trial 2 = 206 +/- 42) did not differ between 3 MT trials (P = 0.37) and was reliable (TE = 15 W, CV = 7%, alpha = 0.93). W' was less reliable (TE = 2864 J, CV = 28%, alpha = 0.76) but did not alter power-duration estimates from the two 3 MTs (P > 0.05). Variability for VO(2max)(TE (mL.kg(-1).min(-1)) between the GXT and the verification bout (1.16) was more consistent than the first (2.03) or second (2.69) 3 MT. CONCLUSIONS: The 3 MT yields reliable estimates of CP and consistent estimates of the power-duration relationship. Power for 150 s, in comparison with W', is a more reliable metric of short-term power performance. The square-wave protocol is recommended over the 3 MT for verifying true VO(2max). PMID- 21606866 TI - Quercetin and endurance exercise capacity: a systematic review and meta-analysis. AB - Quercetin is a dietary flavonoid purported to improve human endurance exercise capacity. However, published findings are mixed. PURPOSE: The study's purpose was to perform a systematic review of the literature and meta-analysis to examine whether quercetin ingestion increases endurance exercise capacity. METHODS: A search of the literature was conducted using the key words quercetin, performance, exercise, endurance, and aerobic capacity. Eleven studies were identified as meeting the inclusion criteria providing data on 254 human subjects. Across all studies, subject presupplementation VO(2max) ranged from 41 to 64 mL.kg(-1).min(-1) (median = 46), and median treatment duration was 11 d with a median dosage of 1000 mg.d(-1). Effect sizes (ES) were calculated as the standardized mean difference, and meta-analyses were completed using a random effects model. RESULTS: The ES calculated for all studies combining VO(2max) and endurance performance measures indicates a significant effect favoring quercetin over placebo (ES = 0.15, P = 0.021, 95% confidence interval = 0.02-0.27), but the magnitude of effect is considered between trivial and small, equating to a ~2% [corrected] improvement of quercetin over placebo. Using a subgroup meta-analysis comparing quercetin's effect on endurance exercise performance versus VO(2max), no significant difference was found (P = 0.69). Meta-regression of study ES relative to subjects' fitness level or plasma quercetin concentration achieved by supplementation was also not significant. CONCLUSIONS: On average, quercetin provides a statistically significant benefit in human endurance exercise capacity (VO(2max) and endurance exercise performance), but the effect is between trivial and small. Experimental factors that explain the between-study variation remain to be elucidated. PMID- 21606867 TI - Cerebrovascular reactivity impairment after sport-induced concussion. AB - PURPOSE: This study evaluated cerebrovascular reactivity (CVR) after a sport induced concussion, also called mild traumatic brain injury (mTBI), by monitoring middle cerebral artery blood velocity (vMCA) with transcranial Doppler ultrasonography and simultaneous end-tidal carbon dioxide (PETCO(2)) measurements. METHODS: Thirty-one athletes (16-25 yr old) participated in this study. The participants were divided into two groups-healthy (n = 21) and mTBI (n = 10). Participants in the mTBI group suffered an mTBI within the last 7 d (x- = 4.5 +/- 1.1 d). Outcome measures included vMCA and PETCO(2) in response to breath holding (5 * 20 s, 40-s rest) and hyperventilation (5 * 20 s, 40-s rest). RESULTS: Resting vMCA values between groups were not significantly different. Percentage change of vMCA was significantly different after the recovery period of the second hyperventilation (P = 0.034). mTBI subjects failed to return to resting levels after each breath hold. PETCO(2) changes mirrored the vMCA changes. CONCLUSIONS: These data suggest that normal CVR responses may be disrupted in the days immediately after occurrence of mTBI. Transcranial Doppler ultrasonography combined with expired gas measurements provides a useful method for assessing CVR impairment after mTBI. Further research, including serial monitoring after mTBI and analysis of CVR response to exercise, is warranted before any firm conclusions can be drawn. PMID- 21606868 TI - Pacing strategy from high-frequency field data: more evidence for neural regulation? AB - INTRODUCTION: We demonstrate a methodology that uncovers an athlete's true pacing strategy from high-frequency (<=1 km) split field data, even if affected by high gradient variation on course. The method thus opens up the analysis of many previously opaque but popular undulating professional and amateur races to scientific scrutiny. METHODS: The method is relatively simple to use in any standard statistical package, and execution only requires the addition of the altitude-distance trace of the event to a runner's split times (e.g., as automatically collected by a modern Global Positioning System-enabled wristwatch). In addition, as opposed to assuming a pacing function (e.g., "J shaped," "U shaped," "all-out") and testing this function on the data, the method uses a preliminary discovery step to suggest the most appropriate pacing function(s) to test on the data (if any). RESULTS: The method is demonstrated with two novel case studies: Gebrselassie's world-record Berlin marathon (September 2008) and a unique data set taken from several years of the Six Foot Track Ultramarathon (45 km, Sydney, Australia). CONCLUSIONS: In both cases, the method reveals highly variable pacing strategies on a microscale despite remarkable symmetry on a macroscale in one case adding weight to the recent complex system perspective of the neural regulator. PMID- 21606869 TI - Repeatability of aerobic capacity measurements in Parkinson disease. AB - PURPOSE: Maximal or peak aerobic capacity (VO(2peak)) during a maximal-effort graded exercise test is considered by many to be the "gold standard" outcome for assessing the effect of exercise training on cardiorespiratory fitness. The reliability of this measure in Parkinson disease (PD) has not been established, where the degree of motor impairment can vary greatly and is influenced by medications. This study examined the reliability of VO(2peak) during a maximal effort graded exercise test in subjects with PD. METHODS: Seventy healthy middle aged and older subjects with PD Hoehn and Yahr stage 1.5-3 underwent a screening/acclimatization maximal-effort treadmill test followed by two additional maximal-effort treadmill tests with repeated measurements of VO(2peak). A third VO(2peak) test was performed in a subset of 21 subjects. RESULTS: The mean VO(2peak) measurement was 2.4% higher in the second test compared with the first test (21.42 +/- 4.3 vs 21.93 +/- 4.50 mL.kg(-1).min(-1), mean +/- SD, P = 0.03). The intraclass correlation coefficients (ICC) for VO(2peak) expressed either as milliliters per kilogram per minute or as liters per minute were highly reliable, with ICC of 0.90 and 0.94, respectively. The maximum HR (ICC of 0.91) and final speed achieved during the tests (ICC of 0.94) were also highly reliable, with the respiratory quotient being the least reliable of the parameters measured (ICC of 0.65). CONCLUSIONS: Our results demonstrate that measurement of VO(2peak) is reliable and repeatable in subjects with mild to moderate PD, thereby validating use of this parameter for assessing the effects of exercise interventions on cardiorespiratory fitness. PMID- 21606870 TI - Maximal sustained levels of energy expenditure in humans during exercise. AB - Migrating birds have been able to sustain an energy expenditure (EE) that is five times their basal metabolic rate. Although humans can readily reach these levels, it is not yet clear what levels can be sustained for several days. PURPOSE: The study's purposes were 1) to determine the upper limits of human EE and whether or not those levels can be sustained without inducing catabolism of body tissues and 2) to determine whether initial body weight is related to the levels that can be sustained. METHODS: We compiled data on documented EE as measured by doubly labeled water during high levels of physical activity (minimum of five consecutive days). We calculated the physical activity level (PAL) of each individual studied (PAL = total EE / basal metabolic rate) from the published data. Correlations were run to examine the relationship between initial body weight and body weight lost with both total EE and PAL. RESULTS: The uppermost limit of EE was a peak PAL of 6.94 that was sustained for 10 consecutive days of a 95-d race. Only two studies reported PALs above 5.0; however, significant decreases in body mass were found in each study (0.45-1.39 kg.wk(-1) of weight loss). To test whether initial weight affects the ability to sustain high PALs, we found a significant positive correlation between TEE and initial body weight (r = 0.46, P < 0.05) but no correlation between PAL and body weight (r = 0.27, not statistically significant). CONCLUSIONS: Some elite humans are able to sustain PALs above 5.0 for a minimum of 10 d. Although significant decreases in body weight occur at this level, catabolism of body tissue may be preventable in situations with proper energy intake. Further, initial body weight does not seem to affect the sustainability of PALs. PMID- 21606871 TI - Aerobic training effects on glucose tolerance in prediabetic and normoglycemic humans. AB - INTRODUCTION: It is generally accepted that if prediabetic individuals adopt healthy lifestyle habits, the progression to type 2 diabetes mellitus can be prevented or delayed. However, the role of exercise training independent of other lifestyle factors has not been determined. Furthermore, patients with type 2 diabetes mellitus have been shown to experience greater training-induced changes in glucose and insulin metabolism compared with healthy subjects, but the adaptations of prediabetic individuals have not been adequately examined. We hypothesized that (i) prediabetic subjects would have greater endurance training induced changes in plasma glucose and insulin responses to an oral glucose challenge compared with age- and body mass index-matched normoglycemic subjects and (ii) training would completely reverse the abnormal glucose metabolism of prediabetic subjects. METHODS: Plasma glucose and insulin responses to oral glucose tolerance tests (OGTTs) were examined in normoglycemic (n = 119) and prediabetic (n = 47) older men and women before and after a 6-month standardized endurance exercise training program. RESULTS: Prediabetic subjects had greater glucose and insulin OGTT responses than normoglycemic subjects both before and after training (P < 0.05). Prediabetic subjects had greater training-induced changes in glucose and insulin areas under the glucose tolerance curve, as well as greater changes in glucose and insulin concentrations at several points of the OGTT. However, these changes did not eliminate the baseline differences in glucose tolerance between normoglycemic and prediabetic subjects. The between group differences in changes in glucose and insulin variables were largely independent of changes in body weight or composition. CONCLUSIONS: Our data indicate that prediabetes is associated with greater training-induced changes in glucose tolerance. However, 6 months of endurance training alone was not sufficient to completely reverse prediabetes. PMID- 21606872 TI - Insulin-like growth factor I signaling for brain recovery and exercise ability in brain ischemic rats. AB - PURPOSE: Exercise increases neuron survival and plasticity in the adult brain by enhancing the uptake of insulin-like growth factor I (IGF-I). Exercise also reduces the infarct volume in the ischemic brain and improves motor function after such a brain insult. However, the underlying mechanisms are not fully known. The purpose of this study was to investigate the involvement of IGF-I signaling in neuroprotection after exercise. METHOD: Rats were assigned to one of four groups: middle cerebral artery occlusion (MCAO) without exercise training (MC), MCAO with exercise training (ME), MCAO with IGF-I receptor inhibitor and without exercise training (MAg), and MCAO with IGF-I receptor inhibitor and exercise training (MEAg). Rats in the ME and MEAg groups underwent treadmill training for 14 d, and rats in the MC and MAg groups served as controls. After the final intervention, rats were sacrificed under anesthesia, and samples were collected from the affected motor cortex, striatum, and plasma. RESULTS: IGF-I and p-Akt levels in the affected motor cortex and the striatum of the ME group were significantly higher than those in the MC group, with significant decreases in infarct volume and improvements in motor function. However, IGF-I receptor inhibitor eliminated these effects and decreased the exercise ability. The brain IGF-I signaling strongly correlated with exercise ability. CONCLUSIONS: Exercise enhanced IGF-I entrance into ischemic brain and IGF-I signaling was related to exercise-mediated neuroprotection. IGF-1 signaling also affected the ability to exercise after brain ischemia. PMID- 21606873 TI - Exercise in a child with systemic lupus erythematosus and antiphospholipid syndrome. AB - Exercise training has emerged as a potential therapeutic strategy to counteract the decline in physical function and aerobic capacity in pediatric rheumatic disease. PURPOSE: We report for the first time on the effects of exercise training in juvenile systemic lupus erythematosus (JSLE) and antiphospholipid syndrome (APS). METHODS: A 15-yr-old boy with JSLE and APS treated with warfarin, azathioprine, and prednisone underwent a 12-wk aerobic exercise training program to improve his physical capacity and functioning. Before and after the 12-wk exercise program, the patient was submitted to incremental cardiopulmonary tests to determine VO(2peak), peak and submaximal exercise intensity, and time to exhaustion. In addition, a 6-min square-wave test was performed for assessing metabolic parameters. Functioning was assessed by using the visual analog scale. Laboratory parameters of inflammation were also assessed at baseline and 48 h after the last training session. RESULTS: All the cardiopulmonary parameters (e.g., VO(2max) = +36.0%, time to exhaustion = +67.8%, peak exercise intensity = +16.7%) and the metabolic cost of movement (e.g., energy expenditure = -28.3% to 33.3%, VO(2) = -29.3% to -33.4%) were improved. Both disease activity and cumulative damage scores did not change after the intervention, and no evidence of exercise-induced exacerbation of inflammation was observed. Visual analog scale scores were also improved according to the patients' evaluation (before intervention = 8 vs after intervention = 10), parents' evaluation (before intervention = 8 vs after intervention = 10), and physicians' evaluation (before intervention = 6 vs after intervention = 9). CONCLUSIONS: This is the first evidence that a 12-wk supervised aerobic training program can be safe and effective in improving aerobic conditioning and physical function in a patient with JSLE and APS. In light of these findings, the therapeutic effects of exercise training in pediatric rheumatic diseases merit further investigations. PMID- 21606875 TI - Trunk strength effect on track wheelchair start: implications for classification. AB - PURPOSE: The T54 wheelchair racing class comprises athletes with normal arm muscle strength and trunk strength ranging from partial to normal. Paralympic sports classes should comprise athletes who have impairments that cause a comparable degree of activity limitation. On the basis of this criterion, the purpose of this study was to determine whether the T54 class is valid by assessing the strength of association between trunk strength and wheelchair acceleration. METHODS: Participants were 10 male and 3 female international wheelchair track athletes with normal arm strength. Six were clinically assessed as having normal trunk strength, and seven had impaired trunk strength. Measures included isometric arm and trunk strength and distance covered at 1, 2, and 3 s in an explosive start from standstill on a regulation track, as well as on a custom-built ergometer with four times normal rolling resistance. RESULTS: No significant differences were observed between male athletes with and without full trunk strength in distance covered after 1, 2, and 3 s. Correlations between isometric trunk strength and wheelchair track acceleration were nonsignificant and low (0.27-0.32), accounting for only 7%-10% of variance in performance. Correlations between trunk strength and distance pushed under high resistance were also nonsignificant, although values were almost double (r = 0.41-0.54), accounting for 18%-28% of the variance in performance. CONCLUSIONS: These results provide evidence that impairment of trunk strength has minimal effect on wheelchair acceleration and indicate the T54 class is valid. Results do not infer that athletes with no trunk strength should compete with those who have partial or full trunk strength. PMID- 21606874 TI - Exercise, amino acids, and aging in the control of human muscle protein synthesis. AB - In this review, we discuss recent research in the field of human skeletal muscle protein metabolism characterizing the acute regulation of mammalian target of rapamycin complex (mTORC) 1 signaling and muscle protein synthesis (MPS) by exercise, amino acid nutrition, and aging. Resistance exercise performed in the fasted state stimulates mixed MPS within 1 h after exercise, which can remain elevated for 48 h. We demonstrate that the activation of mTORC1 signaling (and subsequently enhanced translation initiation) is required for the contraction induced increase in MPS. In comparison, low-intensity blood flow restriction (BFR) exercise stimulates MPS and mTORC1 signaling to an extent similar to traditional, high-intensity resistance exercise. We also show that mTORC1 signaling is required for the essential amino acid (EAA)-induced increase in MPS. Ingestion of EAAs (or protein) shortly after resistance exercise enhances MPS and mTORC1 signaling compared with resistance exercise or EAAs alone. In older adults, the ability of the skeletal muscle to respond to anabolic stimuli is impaired. For example, in response to an acute bout of resistance exercise, older adults are less able to activate mTORC1 or increase MPS during the first 24 h of postexercise recovery. However, BFR exercise can overcome this impairment. Aging is not associated with a reduced response to EAAs provided the EAA content is sufficient. Therefore, we propose that exercise combined with EAA should be effective not only in improving muscle repair and growth in response to training in athletes, but that strategies such as EAA combined with resistance exercise (or BFR exercise) may be very useful as a countermeasure for sarcopenia and other clinical conditions associated with muscle wasting. PMID- 21606876 TI - Functional movement screening: predicting injuries in officer candidates. AB - PURPOSE: Functional movement screening (FMS) is a musculoskeletal assessment method that incorporates seven movements and yields an overall score based on movement quality. The objectives of this study were to document the distribution of scores and to determine whether FMS scores could predict injury in a large military cohort. METHODS: A cohort of 874 Marine officer candidates were recruited, consented, completed demographic questionnaires, and had FMS performed during medical in-processing. Candidates were enrolled in either long-cycle (LC: 68 d; n = 427) or short-cycle (SC: 38 d; n = 447) training and followed up for injuries occurring in training. RESULTS: The mean FMS score (score range = 0-21) among all candidates was 16.6 +/- 1.7; approximately 10% of candidates had FMS scores <=14. A score of <=14 on the FMS predicted any injury with a sensitivity of 0.45 and a specificity of 0.71 and serious injury with a sensitivity of 0.12 and a specificity of 0.94. Both LC and SC cohorts demonstrated higher injury risk among candidates who had scores <=14 compared with those with scores >14 (LC: risk ratio (RR) = 1.65, 95% confidence interval = 1.05-2.59, P = 0.03; SC: RR = 1.91, 95% confidence interval = 1.21-3.01, P < 0.01). Overall, 79.8% of persons with scores <=14 were in the group with fitness scores <280 (/300), whereas only 6.6% of candidates in the group with fitness scores >=280 had scores <=14. CONCLUSIONS: This was the first large-scale study performed in an active-duty military cohort to examine the utility of FMS during medical in-processing. Further work is warranted to evaluate FMS and the potential for injury prediction and prevention. PMID- 21606877 TI - Neck cooling and running performance in the heat: single versus repeated application. AB - PURPOSE: This study aimed to evaluate the effect of sustained neck cooling during time trial running in a hot environment. METHODS: Seven nonacclimated, familiarized males completed three experimental 90-min preloaded time trials in the heat (30.4 degrees C +/- 0.1 degrees C and 53% +/- 2% relative humidity). During one of the trials, the, participants wore a cooling collar from the start (CC); in another, they wore a collar from the start which was replaced at 30-min intervals (CC(replaced)); and in the last trial, they wore no collar (NC). Participants ran for 75 min at 60% VO(2max) and then performed a 15-min time trial blinded from the distance ran. Distance ran, rectal temperature, neck skin temperature, HR, fluid loss and consumption, peripheral lactate, glucose, dopamine, serotonin and cortisol, RPE, thermal sensation, and feeling scales were recorded. Significance was set a priori at the P < 0.05 level. RESULTS: Participants ran further in CC (2779 +/- 299 m) compared with NC (2597 +/- 291 m, P = 0.007; d = 0.67) and in CC(replaced) (2776 +/- 331 m) compared with NC (P = 0.008; d = 0.62). There was no difference in the distance covered in CC compared with that in CC(replaced) (P = 0.998). The collar lowered neck temperature (P < 0.001) and the thermal sensation of the neck region (P < 0.001) but had no effect on any of the other physiological, endocrinological, or perceptual variables. CONCLUSIONS: Cooling the surface of the neck improves time trial performance in a hot environment without altering physiological or neuroendocrinological responses. Maintenance of a lower neck temperature via the replacement of a CC has no additional benefit to an acute cooling intervention. PMID- 21606878 TI - Human muscle proteome modifications after acute or repeated eccentric exercises. AB - INTRODUCTION: Delayed-onset muscle soreness (DOMS), a condition triggered by eccentric exercise, affects muscle cells at a biochemical level in a poorly understood fashion. The objective of the present study was to examine human muscle proteome modifications induced by strenuous eccentric exercises after a specific training aimed to prevent DOMS. METHODS: Biopsy samples of the rectus femoris were obtained from healthy human volunteers in three successive conditions: 1) at rest, 2) 24 h after an injuring exercise protocol consisting of three series of 30 maximal contractions of the quadriceps on an isokinetic dynamometer, and 3) 24 h after a similar exercise bout preceded either by five eccentric training sessions or by no training. RESULTS: Muscle damage was assessed before and 1 d after each maximal eccentric test by comparing three indirect markers: plasma activity of creatine kinase, muscle stiffness, and subjective pain intensity. Compared with the first eccentric test, those markers were reduced after the second test and further reduced if this second test followed the eccentric training, thus confirming the protective effect of such training. Muscle protein extracts were subjected to a two-dimensional difference gel electrophoresis proteomic analysis coupled with matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry protein identification. Surprisingly, we observed that myosin heavy chains decreased after the first eccentric test and were reduced further with other contractile proteins after the second test. Furthermore, the expression of several glycolytic enzymes decreased only after the second test, which was preceded by a specific training. CONCLUSIONS: These findings suggest that the eccentric training resulted in a switch to oxidative metabolism, which may be associated with protection from DOMS. PMID- 21606879 TI - Simple change in initial standing position enhances the initiation of gait. AB - PURPOSE: Older adults and individuals with Parkinson's disease exhibit impaired gait initiation performance with less effective anticipatory postural adjustments (APA) and less dynamic stepping characteristics. These observations may reflect impaired interactions between the postural and locomotor components of this task. The purpose of this study was to evaluate the effectiveness of altering the stance position of the initial swing limb on improving APA characteristics and stepping performance. METHODS: Three groups (healthy young adults, individuals with Parkinson's disease, and age-matched older adults) of 12 participants initiated gait from three initial stance conditions: normal, backward displaced swing limb, and forward displaced swing limb. Ground reaction forces and whole body kinematics were recorded to characterize the APA and step parameters. RESULTS: Initiating gait from the back condition produced more forceful weight shifting (P < 0.001), greater propulsive forces (P < 0.001), and faster center-of mass velocities throughout the stepping phases (P < 0.05). CONCLUSIONS: Translating the swing limb 0.5-ft-length backward seems to enhance the interaction between posture and locomotion, which may have therapeutic potential for improving gait initiation performance. PMID- 21606880 TI - Use of integrative epigenetic and cytogenetic analyses to identify novel tumor suppressor genes in malignant melanoma. AB - The objective of this study was to identify novel tumor-suppressor genes in melanoma, using an integrative genomic approach. Data from: (i) earlier reports of DNA loss and gain in malignant melanoma accompanied by comparative genomic hybridization high-definition array data of the entire human genome; (ii) microarray expression data from melanoma-derived cell lines identifying genes with significantly increased expression due to methylation using a pharmacologic demethylating strategy; and (iii) publicly available RNA expression microarray data of primary tumors and benign nevi were integrated using statistical tools to define a population of candidate tumor-suppressor genes. Twenty-seven genes were identified in areas of deletion that demonstrated diminished expression in primary melanomas relative to benign nevi and were significantly increased in expression by 5-Aza treatment. Seven genes of these 27 genes demonstrated methylation and deletion in a validation cohort of 14 separate primary tumors. These were: CHRDL1, SFRP1, TMEM47, LPL, RARRES1, PLCXD1, and KOX15. All of these genes demonstrated growth-suppressive properties with transfection into melanoma derived cell lines. Seven putative tumor-suppressor genes in malignant melanoma were identified using a novel integrative technique. PMID- 21606881 TI - Anabolic steroids and head injury. AB - BACKGROUND: The suggestion has been made that neurological changes seen in the syndrome of chronic traumatic encephalopathy may be due to exogenous anabolic steroid use rather than traumatic brain injury. OBJECTIVE: To determine whether administration of anabolic steroids alters the pathophysiology of traumatic brain injury. METHODS: Sixty adult male Sprague-Dawley rats and a linear acceleration model of traumatic brain injury were used. Experimental groups were (1) preinjury anabolic steroids, (2) preinjury placebo carrier, (3) anabolic steroids without injury, (4) no steroids and no injury, (5) postinjury placebo carrier, and (6) postinjury anabolic steroids. Following a 30-day recovery, rats were euthanized, and brainstem white matter tracts underwent fluorescent immunohistochemical processing and labeling of beta-amyloid precursor protein (APP), a marker of axonal injury. Digital imaging and statistical analyses were used to determine whether anabolic steroid administration resulted in a significant change in the number of injured axons. RESULTS: There was no statistically significant difference in number of APP-positive axons by immunohistochemical analysis between respective anabolic steroid and placebo groups. CONCLUSION: Using a standard acceleration-deceleration model of mild traumatic brain injury, we have shown successful visualization of traumatically injured axons with antibody staining of APP. Our results indicate no statistically significant effect of anabolic steroids on the number of APP-positive axons. With the use of this model, and within its limitations, we see no adverse effect or causative role of anabolic steroid administration on the brain following mild traumatic brain injury using APP counts as a marker for anatomic injury. PMID- 21606882 TI - Posterior epidural migration of sequestrated lumbar disc fragments into the bilateral facet joints: case report. AB - BACKGROUND AND IMPORTANCE: Symptomatic lumbar disc herniation is common. Migration of a free disc fragment is usually found in rostral, caudal, or lateral directions. Posterior epidural migration is very rare. We report the first case with posterior epidural migration and sequestration into bilateral facet joints of a free disc fragment. CLINICAL PRESENTATION: A 78-year-old female presented with low back pain and right leg pain. Plain radiographs showed lumbar spondylolisthesis. Magnetic resonance imaging revealed a posterior epidural mass and intrafacet mass, which was hypointense on T1-weighted images and hyperintense on T2-weighted images. The lesion in the left L3-4 facet joint had rim enhancement, whereas the right one was not contrasted after gadolinium injection. Preoperative differential diagnosis included abscess, tumor, hematoma, or synovial cyst. An interbody cage fusion at L3-4 and L4-5 for spondylolisthesis was performed, and a hybrid technique was applied with the Dynesys flexible rod system at L3-S1 for multisegment degenerative disc disease. The lesion proved to be an epidural disc fragment with sequestration into bilateral facet joints. CONCLUSION: A free disc fragment should be considered in the differential diagnosis of posterior epidural lesions, and even in the facet joint. PMID- 21606883 TI - Results of a national neurosurgery resident survey on duty hour regulations. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) duty hour standards that began July 2011 will further limit resident duty hours. OBJECTIVE: To survey neurosurgery residents in the United States on duty hour violations under the current system and the predicted effects on education and patient safety of the new regulations. METHODS: Surveys were mailed to every neurosurgery training program in the United States and Puerto Rico. Program directors and coordinators were asked to distribute surveys to their residents. RESULTS: Three hundred seventy-seven neurosurgery residents mailed surveys back to the study center (34% response rate). More than one-third of respondents reported violating the 80-hour rule occasionally or frequently (36%). Thirty-one residents (8%) reported having been involved in a motor vehicle collision or life threatening event and 20 (6%) reported having made a medical error resulting in patient harm after an extended shift. Eighty-three percent disagreed with the 16 hour proposed regulation for postgraduate year 1. The majority of respondents thought that the new standards will have a negative or strongly negative effect on their residency training (72%). CONCLUSION: This national duty hour survey of neurosurgical residents reveals considerable concern over the new ACGME proposed standards. The majority of respondents believe that the new standards will have a negative effect on their residency training. Furthermore, this survey indicates an overwhelming negative attitude toward mandated duty hour regulations among neurosurgical residents. Duty hour violations reported in this survey may be a more honest depiction of true violations than previous surveys and are higher than expected. PMID- 21606884 TI - Cardiac fatty acid metabolism and ischemic memory imaging with nuclear medicine techniques. AB - There has been a dramatic improvement in the clinical management of myocardial diseases with the advent of cardiac metabolic and molecular imaging. Although both myocardial perfusion and metabolic imaging provide insight of myocardium at risk for infarction or ischemia, it is known that metabolic derangements precede perfusion abnormalities, especially after reperfusion therapy. Deranged myocyte loses its flexibility of choosing the right substrate for energy production and it switches its substrate, especially between fatty acid (FA) and glucose depending on disease condition; for example, predominance of FA metabolism is noted in diabetic heart disease, whereas glucose metabolism is enhanced in pressure overload conditions such as left ventricular hypertrophy. We thus hypothesize that with better technological advancements and different substrates, the metabolic footprint of various heart diseases can be charted out in future to help in the optimization of patient management. This review attempts to discuss the importance of radionuclide-labeled FAs in cardiac metabolic and ischemic memory imaging. PMID- 21606885 TI - Relationship between clinicopathological factors and fluorine-18 fluorodeoxyglucose uptake in patients with papillary thyroid cancer. AB - OBJECTIVE: To examine the relationship between clinicopathological factors and fluorine-18-fluorodeoxyglucose (F-FDG) uptake in patients with papillary thyroid cancer (PTC). MATERIALS AND METHODS: Fifty-four patients were included in this study.F-FDG positron emission tomography was performed before surgery. Immunohistochemistry of glucose transporter (GLUT) was performed using postoperative histopathological specimens. We investigated the relationship between maximum standardized uptake value (SUVmax) and GLUT-1, GLUT-3, and GLUT-4 expression/SUVmax and prognostic risk factors {tumor size, age, sex, extrathyroidal extension, and lymph node metastasis [ly (+)]}. RESULTS: GLUT-3 and GLUT-4 expressions significantly correlated with SUVmax (GLUT-3: r=0.38, P=0.008; GLUT-4: r=0.46, P=0.001), but GLUT-1 did not (r=0.21, P=0.147). The tumor size correlated with SUVmax (r=0.5, P<0.001), but GLUT-1, GLUT-3, and GLUT 4 did not (GLUT-1: r=0.006, P=0.681; GLUT-3: r=0.05, P=0.705; GLUT-4: r=-0.17, P=0.217). Both SUVmax and GLUT-4 expressions were statistically significant with ly (+) (SUVmax: P=0.012; GLUT-4: P=0.018), but GLUT-1 and GLUT-3 expressions were not (GLUT-1: P=0.165; GLUT-3: P=0.499). There was no significant difference between other clinicopathological factors and SUVmax or any GLUT expressions. CONCLUSION: F-FDG uptake in PTC may be determined by GLUT-3 and GLUT-4 expressions and may be related to tumor size and lymph node metastasis of PTC. F FDG uptake may reflect tumor progression of PTC. PMID- 21606886 TI - Successful tenofovir treatment for fulminant hepatitis B infection in an infant. AB - Fulminant hepatic failure is defined by the presence of severe impairment of liver function, with or without encephalopathy, in patients with no underlying chronic liver disease. We report the case of a 4-month-old infant who developed fulminant hepatitis B infection and recovered concomitant with tenofovir therapy without liver transplantation. PMID- 21606887 TI - Primary retinal detachment repair: comparison of 1-year outcomes of four surgical techniques. AB - PURPOSE: To compare functional and anatomical outcomes of modern methods of repair of primary retinal detachment. MATERIALS AND METHODS: Retrospective interventional comparative case series. A total of 1,226 patients with primary retinal detachment were included in the study. All patients completed 1-year follow-up and were divided into 4 groups: 322 patients underwent scleral buckling surgery, 442 patients underwent pars plana vitrectomy surgery, 316 patients underwent a combination of scleral buckling and vitrectomy surgery, and 56 patients underwent pneumatic retinopexy surgery for the primary repair of retinal detachment. Reattachment success rates, pre- and postoperative visual acuity, complications, and change in refractive error were reviewed. RESULTS: Initial success rate for retinal reattachment was 86% for scleral buckling only, 90% for vitrectomy only, 94% for the combination of scleral buckling and vitrectomy, and 63% for pneumatic retinopexy surgery. Although patients undergoing pneumatic retinopexy had a lower initial success rate, there was no statistically significant difference in initial reattachment rates between the other three groups. There was no statistically significant difference in final visual acuity between the four groups. Complication rates varied among the techniques used. CONCLUSION: Postoperative visual acuity at 1 year did not differ among the various techniques used to repair primary rhegmatogenous retinal detachments. However, scleral buckling, vitrectomy, or a combination of both resulted in an initially better anatomical success rate and fewer operative procedures than pneumatic retinopexy. PMID- 21606888 TI - Association between foveal microstructure and visual outcome in age-related macular degeneration. AB - PURPOSE: To investigate the correlation between foveal photoreceptor integrity and final visual acuity after treatment of eyes with neovascular age-related macular degeneration, and to determine the visual prognostic factors. METHODS: We retrospectively studied 40 eyes of 40 patients with neovascular age-related macular degeneration who were treated successfully with intravitreal anti vascular endothelial growth factor injection. Using spectral-domain optical coherence tomography, the eyes were categorized into three groups at the final visit, the V group with a completely visible photoreceptor inner and outer segment junction (IS/OS), the P group with a partially detected IS/OS, and the I group with an invisible IS/OS. The length of disrupted IS/OS and external limiting membrane, central macular thickness, and choroidal neovascularization size at the initial and final visits were measured. Retinal pigment epithelium regularity and outer nuclear layer thickness at the final visit were also evaluated. RESULTS: Final visual acuity was closely associated with IS/OS integrity at the final visit. Final visual acuity (logarithm of minimum angle of resolution) in the V group (0.13 +/- 0.10) was better than that in the P group (0.41 +/- 0.31), and final visual acuity in the P group was better than that in the I group (0.97 +/- 0.51) (P < 0.001). Shorter disrupted IS/OS and external limiting membrane length at the final visit were closely associated with better final visual acuity. Preservation of the IS/OS and external limiting membrane, thinner central macular thickness, and shorter choroidal neovascularization height before treatment were associated with intact photoreceptor integrity after resolution of exudation. However, central macular thickness, outer nuclear layer thickness, and retinal pigment epithelium regularity at the final visit had no significant correlation with photoreceptor integrity. CONCLUSION: Foveal photoreceptor integrity was closely associated with final visual acuity in neovascular age-related macular degeneration after treatment. Initial visual acuity, IS/OS and external limiting membrane integrity, central macular thickness, and choroidal neovascularization height were correlated with final photoreceptor integrity, and they would be visual prognostic factors after resolution of exudation. PMID- 21606889 TI - Intravitreally implantable voriconazole delivery system for experimental fungal endophthalmitis. AB - PURPOSE: To investigate the therapeutic efficacy and optimal drug dose of an intravitreally implantable voriconazole (VCZ) drug delivery system (DDS) in experimental endophthalmitis of Aspergillus fumigatus. METHODS: Vitrectomy was performed in albino rabbits with intravitreal inoculation of susceptible A. fumigatus. The animals were randomized into groups of control, polylactic-co glycolic acid implantation, VCZ injection, and intravitreal VCZ DDS containing 0.5, 0.9, and 1.2 mg of VCZ, respectively. The therapeutic effect was assessed by clinical observation, histology, and microbiology. RESULTS: The inflammation in the VCZ injection and DDS groups was milder than the untreated and polylactic-co glycolic acid groups (P <= 0.046). The 0.9-mg and 1.2-mg DDS groups presented milder anterior chamber and vitreous inflammation than the injection group during the first 3 weeks (P <= 0.044), but only the 1.2-mg DDS group had clearer vitreous thereafter (P <= 0.037). Smear and fungal culture showed negative results in all DDS groups. Normal histologic structure of the retina was observed in the eyes recovering from endophthalmitis. CONCLUSION: The therapeutic effect of intravitreal VCZ DDS on fungal endophthalmitis appears to be significantly better than intravitreal injection of VCZ. The optimal dose of VCZ in the DDS in this study was 1.2 mg. PMID- 21606890 TI - Outcomes of 20-gauge transconjunctival sutureless vitrectomy. AB - PURPOSE: To assess the effectiveness and safety of the 20-gauge transconjunctival sutureless vitrectomy system in vitreoretinal surgeries. METHODS: The charts of 102 consecutive patients who underwent 20-gauge transconjunctival sutureless vitrectomy by 1 surgeon were retrospectively reviewed. The main outcome measures were intraoperative and postoperative complications and postoperative intraocular pressure and Snellen visual acuity relative to preoperative values. Patients were evaluated before surgery and 1 day, 1 week, 1 month, and 3 months postoperatively. RESULTS: No trocar-related intraoperative complications were recorded. Two patients (2%) each required suturing of 1 sclerotomy because of leakage at completion of surgery. Mean preoperative visual acuity (in logarithm of the minimum angle of resolution units) was 1.1 +/- 0.6. By 3 months after surgery, the mean visual acuity had improved to 0.8 +/- 0.5 (P < 0.001). Mean preoperative intraocular pressure was 14.7 +/- 5.1 mmHg. Mean postoperative intraocular pressure was 14.2 +/- 5.5 mmHg (P = 0.48) at Day 1 and 14.6 +/- 4.3 mmHg (P = 0.82) at Day 7 after surgery. Hypotony was present in 3 patients (3%) on the first postoperative day, but their intraocular pressure normalized spontaneously within 1 week. None of the patients developed postoperative endophthalmitis or retinal detachment. CONCLUSION: Twenty-gauge transconjunctival sutureless vitrectomy is a safe and effective technique for the surgical treatment of a variety of vitreoretinal pathologies. PMID- 21606891 TI - Macular holes after rhegmatogenous retinal detachment repair: surgical management and functional outcome. AB - PURPOSE: To review the surgical management and functional outcome of macular holes (MHs) developing after rhegmatogenous retinal detachment repair. METHODS: Retrospective, interventional, noncomparative case series. Twenty patients with MH developing after rhegmatogenous retinal detachment repair were included. Pars plana vitrectomy with internal limiting membrane peeling and gas tamponade was performed. Macular attachment status and number of best-corrected visual acuity lines of improvement after MH repair were evaluated. RESULTS: The fovea had been detached in all eyes at the time of rhegmatogenous retinal detachment repair. Six MHs developed after scleral buckling surgery and 14 MHs after vitrectomy with an encircling band. In 5 of the 20 patients, >= 2 operations had been required to achieve retinal reapplication. The mean time to MH diagnosis was 38 weeks. Preoperative best-corrected visual acuity was <= 20/100 in all but one case. Single-operation MH closure rate was 100%, with a mean of 4 Early Treatment Diabetic Retinopathy Study lines of visual improvement (P < 0.001). Mean postoperative Snellen best-corrected visual acuity was 20/70 (+/- 0.15) (P < 0.001). CONCLUSION: In this small retrospective study, standard surgical treatment for idiopathic MH was effective in achieving anatomical closure of these secondary MHs, but visual acuity gain was limited by the previous macula involving rhegmatogenous retinal detachment status. PMID- 21606892 TI - Efficacy of vitrectomy in improving the outcome of Bacillus cereus endophthalmitis. AB - PURPOSE: To evaluate the efficacy of vitrectomy with vancomycin for the treatment of experimental Bacillus cereus endophthalmitis. METHODS: Endophthalmitis was initiated in rabbits via intravitreal injection of 100 colony-forming unit B. cereus. Treatment groups included 25-gauge transconjunctival sutureless vitrectomy with intravitreal vancomycin (1 mg) or vancomycin alone. Groups were treated at 4, 5, or 6 hours after infection. At 48 hours (for 4-hour and 5-hour groups) or 36 hours (for the 6-hour group) after infection, eyes were analyzed by electroretinography, histology, and inflammatory cell counts. RESULTS: Treatment with vitrectomy/vancomycin at 4 hours resulted in significantly greater retinal function compared with that of vancomycin alone. Intraocular inflammation after treatment at 4 hours was minimal for both the treatment groups. Treatment with vitrectomy/vancomycin or vancomycin alone at 5 hours or 6 hours after infection resulted in similar levels of retinal function loss (i.e., >90%) and significant intraocular inflammation. CONCLUSION: These results demonstrate that vitrectomy may be of therapeutic benefit in the treatment of B. cereus endophthalmitis but only during the early stages of infection. PMID- 21606893 TI - A restudy of the surgical anatomy of the posterior aspect of the globe: an essential topography for exact macular buckling. AB - PURPOSE: To study the anatomy of the posterior aspect of the globe comparing it with previous textbook descriptions, to find constant anatomical landmarks for macular buckling surgery. DESIGN: This is an anatomical study on cadaver eyes with additional in vivo measurements during the macular buckling procedure. METHODS: Twelve cadaver eyes were carefully dissected identifying important structures on the posterior aspect of the globe and measuring their cross diameters and relative distances. The distance of the medial end of inferior oblique insertion from the foveal position projected on the scleral surface and the border of the optic nerve sheath were measured. The intrascleral course of temporal long posterior ciliary artery was identified and measured, and its distance from the optic nerve sheath was also measured. RESULTS: The macula consistently lies on the horizontal meridian (foveal horizontal meridian) defined by the course of the long posterior ciliary arteries, which cross the optic nerve somewhere between its center and its lower border. CONCLUSION: The horizontal meridian (foveal horizontal meridian), defined by the entry site and course of the long posterior ciliary arteries, serves as an important surgical landmark if precise external scleral buckling of the fovea is the objective. For practical purposes, foveal horizontal meridian, geometrical horizontal meridian, and optic nerve horizontal meridian need to be distinguished. PMID- 21606894 TI - Lung transplantation: the Yin and Yang of mesenchymal stem cells. PMID- 21606895 TI - Does caregiver burden mediate the effects of behavioral disturbances on nursing home admission? AB - OBJECTIVES: The primary objective of this study was to determine whether caregiving burden mediated the relationship between specific behavior disturbances and time to nursing home admission (NHA) for persons with dementia (i.e., Alzheimer disease or a related disorder). DESIGN: The study used secondary longitudinal data from the Medicare Alzheimer's Disease Demonstration, a Medicare covered home care benefit and case management program for family caregivers of persons with dementia. Primary caregivers of persons with dementia were assessed via in-person and telephone interviews every 6 months over a 3-year period. SETTING: Dementia caregivers were recruited from eight catchment areas throughout the United States. PARTICIPANTS: The baseline sample included 5,831 dementia caregivers. Just more than 40% (43.9%; N = 2,556) of persons with dementia permanently entered a nursing home during the 3-year study period. MEASUREMENTS: Individual behavior problems were measured with the Memory and Behavior Problem Checklist. Caregiving burden was assessed with a short version of the Zarit Burden Inventory. Key covariates, including sociodemographic background, functional status, and service utilization, were also considered. RESULTS: Event history analyses revealed that time-varying measures of caregiver burden fully mediated the relationship between four behavioral disturbances (episodes of combativeness, property destruction, repetitive questions, and reliving the past) and NHA. CONCLUSIONS: The findings highlight the multifaceted, complex pathway to NHA for persons with dementia and their family caregivers. The results emphasize the need for comprehensive treatment approaches that incorporate the burden of caregivers and the behavioral/psychiatric symptoms of persons with dementia simultaneously. PMID- 21606896 TI - Progression of cognitive, functional, and neuropsychiatric symptom domains in a population cohort with Alzheimer dementia: the Cache County Dementia Progression study. AB - OBJECTIVES: Progression of Alzheimer dementia (AD) is highly variable. Most estimates derive from convenience samples from dementia clinics or research centers where there is substantial potential for survival bias and other distortions. In a population-based sample of incident AD cases, we examined progression of impairment in cognition, function, and neuropsychiatric symptoms, and the influence of selected variables on these domains. DESIGN: Longitudinal, prospective cohort study. SETTING: Cache County (Utah). PARTICIPANTS: Three hundred twenty-eight persons with a diagnosis of possible/probable AD. MEASUREMENTS: Mini-Mental State Exam (MMSE), Clinical Dementia Rating sum-of boxes (CDR-sb), and Neuropsychiatric Inventory (NPI). RESULTS: Over a mean follow up of 3.80 (range: 0.07-12.90) years, the mean (SD) annual rates of change were 1.53 (2.69) scale points on the MMSE, 1.44 (1.82) on the CDR-sb, and 2.55 (5.37) on the NPI. Among surviving participants, 30% to 58% progressed less than 1 point per year on these measures, even 5 to 7 years after dementia onset. Rates of change were correlated between MMSE and CDR-sb (r = -0.62, df = 201, p < 0.001) and between the CDR-sb and NPI (r = 0.20, df = 206, p < 0.004). Female subjects (LR chi = 8.7, df = 2, p = 0.013) and those with younger onset (likelihood ratio [LR] chi = 5.7, df = 2, p = 0.058) declined faster on the MMSE. Although one or more apolipoprotein E epsilon 4 alleles and ever use of FDA-approved antidementia medications were associated with initial MMSE scores, neither was related to the rate of progression in any domain. CONCLUSIONS: A significant proportion of persons with AD progresses slowly. The results underscore differences between population-based versus clinic-based samples and suggest ongoing need to identify factors that may slow the progression of AD. PMID- 21606897 TI - Grief among family members of nursing home residents with advanced dementia. AB - OBJECTIVES: To describe preloss and postloss grief symptoms among family members of nursing home (NH) residents with advanced dementia, and to identify predictors of greater postloss grief symptoms. DESIGN: Prospective cohort study. SETTING: 22 NHs in the greater Boston area. PARTICIPANTS: 123 family members of NH residents who died with advanced dementia. MEASUREMENTS: Preloss grief was measured at baseline, and postloss grief was measured 2 and 7 months postloss using the Prolonged Grief Disorder Scale. Independent variables included resident and family member sociodemographic characteristics, resident comfort, acute illness, acute care prior to death, family member depression, and family member understanding of dementia and of resident's prognosis. RESULTS: Levels of preloss and postloss grief were relatively stable from baseline to 7 months postloss. Feelings of separation and yearning were the most prominent grief symptoms. After multivariable adjustment, greater preloss grief and the family member having lived with the resident prior to NH admission were the only factors independently associated with greater postloss grief 7 months after resident death. CONCLUSIONS: The pattern of grieving for some family members of NH residents with advanced dementia is prolonged and begins before resident death. Identification of family members at risk for postloss grief during the preloss period may help guide interventions aimed at lessening postloss grief. PMID- 21606898 TI - Diagnostic criteria for depression in Alzheimer disease: a study of symptom patterns using latent class analysis. AB - CONTEXT: Although depression in Alzheimer disease (AD) has a negative emotional and functional impact on patients and caregivers, specific criteria to diagnose depression in AD are still to be validated. OBJECTIVE: To validate a set of diagnostic criteria for major depression in AD. DESIGN: Cross-sectional design using latent cluster analysis (LCA). SETTING: Participants were recruited from consecutive referrals to a Memory Clinic of a tertiary hospital. PARTICIPANTS: A consecutive series of 971 outpatients with probable AD. MAIN OUTCOME MEASURE: Clusters of patients with or without major depression as determined with LCA. RESULTS: A LCA demonstrated three clusters that were considered to represent major depression, minor depression, and no depression. All nine Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for major depression were significantly associated with the major depression cluster. Although a diagnosis of generalized anxiety disorder (GAD) and apathy were also associated with the major depression cluster, irritability was not. CONCLUSIONS: The DSM-IV criteria for major depression should be used unmodified to diagnose depression in AD. Future studies should determine whether GAD should be included as an additional diagnostic criterion. PMID- 21606900 TI - Cognitive function is associated with the development of mobility impairments in community-dwelling elders. AB - OBJECTIVE: To examine the association of cognitive function with the risk of incident mobility impairments and the rate of declining mobility in older adults. DESIGN: Prospective, observational cohort study. SETTING: Retirement communities across metropolitan Chicago. PARTICIPANTS: A total of 1,154 ambulatory elders from two longitudinal studies without baseline clinical dementia or history of stroke or Parkinson disease. MEASUREMENTS: All participants underwent baseline cognitive testing and annual mobility examinations. Mobility impairments were based on annual timed walking performance. A composite mobility measure, which summarized gait and balance measures, was used to examine the annual rate of mobility change. RESULTS: During follow-up of 4.5 years, 423 of 836 (50.6%) participants developed impaired mobility. In a proportional hazards model controlled for age, sex, education, and race, each 1-unit higher level of baseline global cognition was associated with a reduction to about half in the risk of mobility impairments (hazard ratio = 0.51, 95% confidence interval: 0.40 0.66) and was similar to a participant being about 13 years younger at baseline. These results did not vary by sex or race and were unchanged in analyses controlling for body mass index, physical activity, vascular diseases, and risk factors. The level of cognition in five different cognitive abilities was also related to incident mobility impairment. Cognition showed similar associations with incident loss of the ability to ambulate. Linear mixed-effects models showed that global cognition at baseline was associated with the rate of declining mobility. CONCLUSIONS: Among ambulatory elders, cognition is associated with incident mobility impairment and mobility decline. PMID- 21606899 TI - A 35-year longitudinal assessment of cognition and midlife depression symptoms: the Vietnam Era Twin Study of Aging. AB - OBJECTIVE: To determine whether early adult cognitive ability is a risk factor for depressive symptoms in midlife and how genetic and environmental influences explain the association and to examine cross-sectional relationships between depressive symptoms and specific cognitive abilities at midlife. DESIGN: A 35 year longitudinal and cross-sectional twin study of cognitive aging. SETTING: Large multicenter study in the United States. PARTICIPANTS: One thousand two hundred thirty-seven male twins aged 51 to 60 years. MEASUREMENTS: At the age of 20 years and midlife, participants completed the same version of a general cognitive ability test (Armed Forces Qualification Test [AFQT]). Midlife testing included an extensive neurocognitive protocol assessing processing speed, verbal memory, visual-spatial memory, working memory, executive function, and visual spatial ability. Participants completed the Center for Epidemiologic Studies Depression Scale before cognitive testing and provided health and life style information during a medical history interview. RESULTS: Lower age 20 AFQT scores predicted higher levels of depressive symptoms at age 55 years (r = -0.16,p <0.001). In bivariate twin modeling, 77% of the correlation between early cognitive ability and midlife depressive symptoms was due to shared genetic influences. Controlling for current age, age 20 AFQT, and nonindependence ofobservations, depressive symptoms were associated with worse midlife AFQT scores and poorer performance in all cognitive domains except verbal memory. CONCLUSION: Results suggest that low cognitive ability is a risk factor for depressive symptoms; this association is partly due to shared genetic influences. Crosssectional analyses indicate that the association between depressive symptoms and performance is not linked to specific cognitive domains. PMID- 21606901 TI - Successful aging: definitions and prediction of longevity and conversion to mild cognitive impairment. AB - OBJECTIVES: To examine alternative models of defining and characterizing successful aging. DESIGN: A retrospective cohort study. SETTING: Olmsted County, MN. PARTICIPANTS: Five hundred sixty community-dwelling nondemented adults, aged 65 years and older. MEASUREMENTS: Three models were developed. Each model examined subtests in four cognitive domains: memory, attention/executive function, language, and visuospatial skills. A composite domain score was generated for each of the four domains. In Model 1, a global z score was further generated from the four cognitive domains, and subjects with mean global z score in the top 10% were classified as "successful agers," whereas those in the remaining 90% were classified as "typical agers." In Model 2, subjects with all four domain scores above the 50th percentile were classified as "successful agers." In Model 3, a primary neuropsychological variable was selected from each domain, and subjects whose score remained above - 1 standard deviation compared with norms for young adults were labeled successful agers. Validation tests were conducted to determine the ability of each model to predict survival and conversion to mild cognitive impairment (MCI). RESULTS: Model 1 showed 65% lower mortality in successful agers compared with typical agers and also a 25% lower conversion rate to MCI. CONCLUSION: Model 1 was most strongly associated with longevity and cognitive decline; as such, it can be useful in investigating various predictors of successful aging, including plasma level, APOE genotype, and neuroimaging measurements. PMID- 21606902 TI - Validation of a brief seven-item response bias-free geriatric depression scale. AB - OBJECTIVE: Shortened versions of various depression scales have typically been based on conventional techniques such as factor analysis, without simultaneously considering the removal of culturally biased items that show differential item functioning (DIF). The authors recently showed that eight items in the 15-item Geriatric Depression Scale (GDS-15) evidenced DIF, associated with gender, age, ethnicity, and chronic illnesses. By selecting out these items, the authors derived a shortened 7-item GDS and compared it with derivations based on conventional factor analysis and logistic regression techniques and validated its test performance in Asian elderly. METHODS: The GDS-15 and Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder (MDD) was independently administered by interviewers to 4,253 noninstitutionalized community-living elderly subjects aged 60 years and older. Concurrent methods of data reduction and item selection included factor analyses and logistic regression modeling. The GDS-7 was compared with GDS-15 test performance using Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders diagnosis of MDD as gold standard criterion and receiver operating characteristics analysis. RESULTS: After removal of eight DIF items, the derivation was consistent with and complements the results from factor analysis and logistic regression analyses. The short GDS-7 fit a unidimensional model with high explained total variance and demonstrated high sensitivity (0.93) and specificity (0.91) at a cutoff of one half that was comparable with GDS-15. CONCLUSIONS: By removing items with culturally based response bias, the GDS-7 showed excellent scaling and test performance for screening MDD in an Asian elderly population. PMID- 21606903 TI - The relationships between quality of life, psychiatric illness, and suicidal ideation in geriatric veterans living in a veterans' home: a structural equation modeling approach. AB - OBJECTIVE: This study tested a structural model and examined the relationships between age, suicidal ideation, and scores on the 5-item Brief Symptom Rating Scale (BSRS-5), the 15-item Geriatric Depression Scale (GDS-15), and the Medical Outcome Study Short Form-12 (MOS SF-12) in a sample of veterans' home residents. METHODS: Of the 266 individuals recruited, 226 completed the questionnaires, resulting in a response rate of 84.9%. Participants completed the BSRS-5, GDS-15, MOS SF-12, and a demographic survey. Analysis of Moment Structures, Version 7.0, was used to test the structural relationships of the model with a structural equation modeling analysis and a maximum likelihood ratio estimation. Patient subitem scores, which ranked their feelings of depression, hostility, and inferiority, were summed to determine their 3-BSRS-subitem sum scores. RESULTS: The measures of model fitness were as follows: goodness-of-fit (chi = 12.03, df = 7, p = 0.1), goodness-of-fit index (0.98), adjusted goodness-of-fit index (0.95), comparative fit index (0.99), parsimony ratio (0.47), and root mean square error of approximation (0.06). All indices suggested that the final model fit the data well. Age was inversely related to physical component summary, which was inversely related to the 3-BSRS-subitem sum score. Mental component summary was inversely related to the 3-BSRS-subitem sum score and the GDS-15. Physical component summary was inversely related to the GDS-15. The 3-BSRS-subitem sum score correlated with suicidal ideation. CONCLUSIONS: The data reveal a significant relationship between quality of life and suicidal ideation, which may be affected more by the 3-BSRS-subitem sum score than by the GDS-15. The proposed model has the potential to help healthcare professionals effectively design and implement their suicide prevention programs. PMID- 21606904 TI - Factor structure of the National Alzheimer's Coordinating Centers uniform dataset neuropsychological battery: an evaluation of invariance between and within groups over time. AB - The neuropsychological battery from the National Alzheimer's Disease Coordinating Center is designed to provide a sensitive assessment of mild cognitive disorders for multicenter investigations. Comprising 8 common neuropsychological tests (12 measures), the battery assesses cognitive domains affected early in the course of Alzheimer disease. We examined the factor structure of the battery across levels of cognition [normal, mild cognitive impairment, dementia] based on Clinical Dementia Rating scores to determine cognitive domains tapped by the battery. Using data pooled from 29 Alzheimer's Disease Centers funded by National Institute on Aging, exploratory factor analysis was used to derive a general model using half of the sample; 4 factors representing memory, attention, executive function, and language were identified. Confirmatory factor analysis was used on the second half of the sample to evaluate invariance between groups and within groups over 1 year. Factorial invariance testing included systematic addition of constraints and comparisons of nested models. The general confirmatory factor analysis model had a good fit. As constraints were added, model fit deteriorated slightly. Comparisons within groups showed stability over 1 year. In a range of cognition from normal to dementia, factor structures and factor loadings will vary little. Further work is needed to determine whether domains become more or less distinct in severely cognitively compromised individuals. PMID- 21606905 TI - Dietary inflammation factor rating system and risk of Alzheimer disease in elders. AB - It has been suggested that inflammation is involved in Alzheimer disease (AD) pathogenesis. The aim of this study is to evaluate the association between inflammatory aspects of diet and incident AD risk. About 2258 nondemented elderly (age >= 65) in New York who provided dietary information at baseline were followed-up prospectively for AD development. We examined the composite total Inflammation Factor Rating (tIFR), as a measure of inflammatory impact of foods, in relation with (i) serum level of high-sensitivity C-reactive protein (hsCRP) and (ii) risk of incident AD using Cox proportional hazard model. The tIFR was not associated with serum hsCRP level. After an average of 4.0 years of follow up, 262 participants developed incident AD. The tIFR was not associated with AD risk: compared with the lowest tertile of tIFR (most proinflammatory), hazard ratios (95% confidence interval) for the highest tertile (most anti-inflammatory) was 0.97 (0.69-1.35) (P-for-trend=0.71), in the adjusted model. We conclude that tIFR might not be a biologically relevant measure of the inflammatory impact of the diet. In addition, although it remains possible that tIFR might be related with some other aspects of inflammation not captured by hsCRP, lack of association with AD risk suggests its limited clinical utility. PMID- 21606907 TI - Is elevated PCWP during exercise sufficient to reduce exercise capacity in diabetics? PMID- 21606906 TI - Management of behavioral and psychological symptoms of dementia in a dedicated psychogeriatric unit: a pilot experience. AB - BACKGROUND: The French government gave a consensual definition of reinforced care units for Behavioral and Psychological Symptoms in Dementia (BPSD) within the project "Plan Alzheimer 2008/2012." These Cognitive and Behavioral Units (CBU) differ in resources from the traditional reference units for BPSD management, the Acute Psychogeriatric Units (APU). However, a better understanding of their operational specificities may enhance the CBU and APU synergies. OBJECTIVES: To describe one of the first CBU experiments, with regard to preexisting BPSD management in an APU in the same geriatric hospital. PARTICIPANTS: A total of 129 patients with BPSD, 35 from the CBU and 94 admitted to the APU before opening the colocated CBU. RESULTS: Patients from the CBU often showed comorbidities and a lower nutritional status, but these conditions were more frequent in the APU (P <= 10(-4)). Severe dementia, night time and aberrant motor behavior, and agitation were more frequent in the CBU (P <= 0.0015). In both the units, about 80% of patients were improved without increased use of psychotropic medications and there was a high discharge rate back home of about 30%. CONCLUSIONS: These findings that are still preliminary support a particular role for the CBU for elderly patients showing the most advanced dementia and disruptive BPSD. Colocated APU and CBU may allow for more effective integration of medical and psychiatric care in elderly patients with BPSD with frequent comorbidities. PMID- 21606909 TI - Bone health in cyclists: discrepancies between the axial and peripheral skeletons. PMID- 21606911 TI - Epigenetic regulation of estrogen receptor beta expression in the rat cortex during aging. AB - During aging, there is an increase in neurodegenerative diseases and a decrease in cognitive performance. Postmenopausal women are more vulnerable as their estrogen levels decline, but most hormone replacement therapies do not prevent cognitive decline. One potential reason is that the timing of hormone replacement is critical and changes in the estrogen receptor expression may over-ride hormonal intervention. In rodents, estrogen receptor beta (ERbeta) mRNA decreases in the cortex with age. One mechanism by which ERbeta mRNA could be regulated is by epigenetic modification of ERbeta promoter. Here, we show an increase in methylation of ERbeta promoter corresponding to decrease in ERbeta mRNA in the cortex of an aging female. PMID- 21606912 TI - [Clinical cases: an unusual pulmonary mass]. PMID- 21606913 TI - [Pelvic ostheomyelitis: diagnostics and treatment]. AB - Results of treatment of 223 patients with ostheomyelitis of various etiology and localization were analyzed. Such aspects as diagnostic difficulties, polifocal type of the disease, sepsis development on the background of pelvic ostheomyelitis were discussed. Ostheoscintygraphy, magnetic resonance imaging and computed tomography proved to be of highest diagnostic value by pelvic ostheomyelitis. The original method of surgical treatment of purulent sacroileitis with the use of combined (pelvic and extrapelvic) access was represented. PMID- 21606914 TI - [Surgical mistakes in treatment of patients with lower limbs' critical ischemia]. AB - The immediate and long-term results of the operative treatment of 473 patients with lower limbs' critical ischemia were analyzed. The ischemia was caused by vascular damage under the level of Pupart ligament. All patients overcame direct and indirect surgical revascularization procedures. The results of the reconstructive operations depended directly upon the transplant permeability both in early and long-term periods. Thus, the shunt thrombosis by femoral-popliteal bypass above the popliteal joint space was 7.5-10.7%, not depending on the operative technique. Whereas, the shunt thrombosis by femoral-popliteal bypass below the popliteal joint space was 8.5-37.0%, directly depending on the operative technique. The thrombosis frequency after femoral-tibial bypass was in between 28.3-100.0%. The comparative analysis proved obvious advantages of direct and combined revascularisations. PMID- 21606915 TI - [Prevention of complications after surgery in patients with upper limbs' lymphedema]. AB - The results of surgical treatment of patients with the fourth stage of the upper limbs' lymphedema was studied. Of all 170 patients with lymphedema, 16 (9.4%) had the fourth stage of the disease. The debulking procedures were performed in 15 patients (8 had standart operations, 7 - simultaneous rwo-stage operations). Beeing a preliminary stage of the radical surgical excision of lymphoedematously changed tissues, the liposuction allows a more precisional hemostasis for the accurate vessel visualization. It led to the 4,4 times decrease of the postoperative morbidity rate and shortened the time of the operation. PMID- 21606916 TI - [Intra-operative complications and causes of conversion during aortofemoral reconstruction through mini-laparotomy]. AB - Results of 269 reconstructive operations on infrarenal aorta (among them 30 - for aneurysms) applied using mini-laparotomy (abdominal midsection 5-10 cm) were analyzed. Complexities during the operation occurred in 12,6% of patients; among them complications were observed in 4.8%. In 7.1% of cases it resulted in conversion of access. With accumulation of experience frequency of complications decreased from 6.1 to 3.8% (p=0,616) and frequency of conversions - from 12.2 to 3.2% (p=0.017). Comparison with group of 162 patients operated using standard laparotomy showed that despite rather more frequent complexities with infrarenal aorta reconstruction from mini-access (12.6% against 9.4%, p=0.505) amount of complications didn't differ significantly (4.8% and 5.6% respectively, p=0.930). Authors consider abdominal aorta reconstruction from mini-access to be a safe operation. PMID- 21606917 TI - [Sonoelastography in differential diagnosis of thyroid nodes]. AB - The study was aimed to assess the diagnostic possibilities of the new method of sonoelastography. 68 patients with different thyroid nodes were studied. Sonoelastography increased the sensitivity of the routine ultrasound investigation from 89 to 94.8%, the specificity from the 83 to 93%, and the accuracy of the method from 76 to 89%. The method assignes the information of the structural changes of the thyroid, unavailable by the routine ultrasound investigation. PMID- 21606918 TI - [Topographically oriented mobilization of the thyroid]. AB - The analysis of clinical experience of the operative treatment of 600 patients with a thyroid pathology has allowed to develop technics of allocation of a return laryngeal nerve depending on the type of an anatomic structure of a gland. It gave the opportunities for the extrafascial removal of a share of a thyroid gland, the more accurate visualization and preservation of the parathyroid glands, located near the nerve and safe central lymphadenectomy. PMID- 21606919 TI - [Principles of diagnostics and treatment of chronic appendicitis]. AB - Treatment results of 101 patients, operated on with the diagnosis of the chronic appendicitis, were analyzed. Of them, 55 had periodic right iliac pain syndrome, the rest 46 had a history of appendicular abscess or infiltrate. 58 patients were operated on laparoscopically, the rest had traditional open appendectomy. The use of ultrasound and roentgen diagnostics proved to be non-effective. The reliable laparoscopic symptoms of chronic appendicitis were singled out. The laparoscopy provided the correct diagnosis in 93.3% of patients and allowed avoiding the groundless appendectomy in 31.2%. The intraoperative ultrasound is helpful in questionable cases. The diagnostic and treatment algorithm for chronic appendicitis, based on laparoscopic methods, was worked out. PMID- 21606920 TI - [The improved method of portal decompression by liver cirrhosis in vivo]. AB - The experimental study of liver cirrhosis with portal hypertension syndrome, modeled in 38 dogs, has been performed. Surgical treatment aimed on the portal decompression consisted of the implantation of the Celsite port-system. The reliable portal pressure decrease was observed in the first week of the experiment (from 269.3+/-17.8 to 157.4+/-26.5 millimeter of water). Portal decompression reasonably led to the improvement of the general state of the animals. PMID- 21606921 TI - [The combined abdomenotranssacral access for the extralevator rectum extirpation]. AB - Technique of the extralevator abdomenoperineal rectum extirpation with the use of the combined abdomenotranssacral access is thoroughly described in the article. The radicality of the procedure and the immediate results has been evaluated in 27 patients with the lower ampullary rectum and anal canal cancer. The average blood loss was 625+/-288 (300-3500) ml. The soft tissue defect was replaced with the use of unilateral rotated gluteus maximus muscle (n=21), bilateral rotated gluteus maximus muscle (n=6). Tumor-free resection line was registered by the morphological investigation of the resected tissues in 25 cases. Long-term results (13.2+/-3.1) (2-22 months)) were obtained in 24 patients. The obtained results of the postoperative morbidity and survival rates allow to consider the described method as a safe and appropriate surgical procedure. PMID- 21606922 TI - [The homeostasis assessment by hemorrhagic shock]. AB - The comparative analysis of different protocols of infusion therapy of the hemorrhagic shock stage III was performed. The infusion of the colloid solution of hydroxiethylstarch 200/0.5 and non-balanced crystalloid 0.9% solution of natrium chloride leads to the development of negative changes in homeostasis. Whereas infusion of the 4% solution of the modified gelatin and balanced crystalloid solition (sterofundin) allows to avoid the registered changes in electrolyte and alkaline balance. PMID- 21606923 TI - Development of an in vitro model of myotube ischemia. AB - Critical limb ischemia causes severe damage to the skeletal muscle. This study develops a reproducible model of myotube ischemia by simulating, in vitro, the critical parameters that occur in skeletal muscle ischemia. Monolayers of C2C12 myoblasts were differentiated into mature myotubes and exposed to nutrition depletion, hypoxia and hypercapnia for variable time periods. A range of culture media and gas mixture combinations were used to obtain an optimum ischemic environment. Nuclear staining, cleaved caspase-3 and lactate dehydrogenase (LDH) release assay were used to assess apoptosis and myotube survival. HIF-1alpha concentration of cell lysates, pH of conditioned media as well as partial pressures of oxygen (PO2) and carbon dioxide (PCO2) in the media were used to confirm ischemic simulation. Culturing myotubes in depleted media, in a gas mixture containing 20% CO+80% N2 for 6-12 h increased the PCO2 and decreased the pH and PO2 of culture media. This attempts to mimic the in vivo ischemic state of skeletal muscle. These conditions were used to study the potential tissue protective effects of erythropoietin (EPO) in C2C12 myotubes exposed to ischemia. EPO (60 ng/ml) suppressed LDH release, decreased cleaved caspase-3 and reduced the number of apoptotic nuclei, suggesting significantly decreased ischemia induced apoptosis in myotubes (P<0.01) and a potential role in tissue protection. Additional therapeutic agents designed for tissue protection can also be evaluated using this model. PMID- 21606924 TI - Post liver transplantation acute kidney injury in a rat model of syngeneic orthotopic liver transplantation. AB - Acute kidney injury (AKI) is a frequent complication after liver transplantation (LT). The mechanism of post-LT AKI remains unclear. We used the rat model of syngeneic orthotopic LT (SOLT) to investigate the mechanism of post-LT AKI. We hypothesized that the condition of the graft, rather than intraoperative hemodynamic instability, has an important role in post-LT AKI in the SOLT model. Rats were randomly assigned into four groups: sham-operated group; vessel-clamped group; full-size LT group; and reduced-size LT group. We identified AKI in both full-size and reduced-size LT groups. In addition to renal tubular necrosis and apoptosis, renal peritubular capillary injury was also present. Pathological changes were more severe in the reduced-size than in the full-size LT group. We found that the systemic inflammatory response induced by LT was the initiating factor in post-LT AKI. This is the first study to investigate the pathological mechanism of AKI in an animal model of SOLT. Our results demonstrate that protection of the liver graft and inhibition of the systemic inflammatory response are vital in reducing the risk of post-LT AKI. PMID- 21606925 TI - Epidermal growth factor protects the apical junctional complexes from hydrogen peroxide in bile duct epithelium. AB - The tight junctions of bile duct epithelium form a barrier between the toxic bile and liver parenchyma. Disruption of tight junctions appears to have a crucial role in the pathogenesis of various liver diseases. In this study, we investigated the disruptive effect of hydrogen peroxide and the protective effect of epidermal growth factor (EGF) on the tight junctions and adherens junctions in the bile duct epithelium. Oxidative stress in NRC-1 and Mz-ChA-1 cell monolayers was induced by administration of hydrogen peroxide. Barrier function was evaluated by measuring electrical resistance and inulin permeability. Integrity of tight junctions, adherens junctions and the actin cytoskeleton was determined by imunofluorescence microscopy. Role of signaling molecules was determined by evaluating the effect of specific inhibitors. Hydrogen peroxide caused a rapid disruption of tight junctions and adherens junctions leading to barrier dysfunction without altering the cell viability. Hydrogen peroxide rapidly increased the levels of p-MLC (myosin light chain) and c-Src(pY418). ML-7 and PP2 (MLCK and Src kinase inhibitors) attenuated hydrogen peroxide-induced barrier dysfunction, tight junction disruption and reorganization of actin cytoskeleton. Pretreatment of cell monolayers with EGF ameliorated hydrogen peroxide-induced tight junction disruption and barrier dysfunction. The protective effect of EGF was abrogated by ET-18-OCH(3) and the Ro-32-0432 (PLCgamma and PKC inhibitors). Hydrogen peroxide increased tyrosine phosphorylation of ZO-1, claudin-3, E cadherin and beta-catenin, and pretreatment of cells with EGF attenuated tyrosine phosphorylation of these proteins. These results demonstrate that hydrogen peroxide disrupts tight junctions, adherens junctions and the actin cytoskeleton by an MLCK and Src kinase-dependent mechanism in the bile duct epithelium. EGF prevents hydrogen peroxide-induced tight junction disruption by a PLCgamma and PKC-dependent mechanism. PMID- 21606926 TI - A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD. AB - In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 * 10(-8)) and 11q and 17p (P<1 * 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome. PMID- 21606927 TI - SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism. AB - Genetic mutations of SHANK3 have been reported in patients with intellectual disability, autism spectrum disorder (ASD) and schizophrenia. At the synapse, Shank3/ProSAP2 is a scaffolding protein that connects glutamate receptors to the actin cytoskeleton via a chain of intermediary elements. Although genetic studies have repeatedly confirmed the association of SHANK3 mutations with susceptibility to psychiatric disorders, very little is known about the neuronal consequences of these mutations. Here, we report the functional effects of two de novo mutations (STOP and Q321R) and two inherited variations (R12C and R300C) identified in patients with ASD. We show that Shank3 is located at the tip of actin filaments and enhances its polymerization. Shank3 also participates in growth cone motility in developing neurons. The truncating mutation (STOP) strongly affects the development and morphology of dendritic spines, reduces synaptic transmission in mature neurons and also inhibits the effect of Shank3 on growth cone motility. The de novo mutation in the ankyrin domain (Q321R) modifies the roles of Shank3 in spine induction and morphology, and actin accumulation in spines and affects growth cone motility. Finally, the two inherited mutations (R12C and R300C) have intermediate effects on spine density and synaptic transmission. Therefore, although inherited by healthy parents, the functional effects of these mutations strongly suggest that they could represent risk factors for ASD. Altogether, these data provide new insights into the synaptic alterations caused by SHANK3 mutations in humans and provide a robust cellular readout for the development of knowledge-based therapies. PMID- 21606929 TI - Association of spasticity and life satisfaction after spinal cord injury. AB - STUDY DESIGN: Cross-sectional survey; secondary analysis of existing data by linear regression analysis between spasticity and quality of life. OBJECTIVE: To identify the relationship between spasticity and life satisfaction as measured by three multi-item factor scales and a rating of overall quality of life among participants with spinal cord injury (SCI). SETTING: Large specialty hospital in the Southeastern United States. METHODS: Participants included 1549 adults with traumatic spinal cord injuries, at least 18 years of age and a minimum of 1-year post-injury at survey. Outcome measures included: (1) home life satisfaction, (2) global satisfaction, (3) vocational satisfaction, (4) overall quality of life and (5) three subscales from the Patient Reported Impact of Spasticity Measure. RESULTS: Three aspects of spasticity (daily activities, positive impact and spasticity at its worst) all were negatively correlated with home life satisfaction, global satisfaction and overall quality of life. Only the daily activities scale and the spasticity at its worst rating had a significant negative correlation with vocational satisfaction. CONCLUSION: Spasticity is negatively associated with quality of life after SCI. These negative outcomes need to be considered in an individual's rehabilitation and treatment methods. PMID- 21606928 TI - MicroRNAs in addiction: adaptation's middlemen? AB - A central question in addiction is how drug-induced changes in synaptic signaling are converted into long-term neuroadaptations. Emerging evidence reveals that microRNAs (miRNAs) have a distinct role in this process through rapid response to cellular signals and dynamic regulation of local mRNA transcripts. Because each miRNA can target hundreds of mRNAs, relative changes in the expression of miRNAs can greatly impact cellular responsiveness, synaptic plasticity and transcriptional events. These diverse consequences of miRNA action occur through coordination with genes implicated in addictions, the most compelling of these being the neurotrophin BDNF, the transcription factor cAMP-responsive element binding protein (CREB) and the DNA-binding methyl CpG binding protein 2 (MeCP2). In this study, we review the recent progress in the understanding of miRNAs in general mechanisms of plasticity and neuroadaptation and then focus on specific examples of miRNA regulation in the context of addiction. We conclude that miRNA mediated gene regulation is a conserved means of converting environmental signals into neuronal response, which holds significant implications for addiction and other psychiatric illnesses. PMID- 21606930 TI - Non-conventional hemostatic risk factors for coronary heart disease in individuals with spinal cord injury. AB - STUDY DESIGN: Review. OBJECTIVES: In subjects with spinal cord injury (SCI), there is strong evidence for platelet hyperactivity, which may stimulate atherosclerosis and coronary heart disease (CHD). The literature was reviewed. BACKGROUND: Individuals with SCI develop premature CHD. In addition to the conventional risk factors associated with CHD, there are pathologic hematological factors involved in atherogenesis that are similar to those that have been demonstrated in individuals with diabetes, and these hematological factors might affect individuals with SCI. One such hematological factor, platelet aggregation, is essential for the development of CHD, which results from thrombus formation in the coronary vasculature. Prostacyclin (PGI(2)) is a potent inhibitor of platelet aggregation and is thought to have a beneficial role in inhibiting atherogenesis; therefore, it is possible that individuals with SCI have impaired PGI(2) receptor function. METHODS: We reviewed the literature by conducting a search using PubMed (1970-2007). RESULTS: Acute thrombosis is emerging as an important factor in the etiology of CHD and therefore could mediate the risk of CHD in persons with SCI, in addition to previously known risk factors such as hyperlipidemia, hypertension, hyperlipidemia, diabetes mellitus and hyperinsulinemia. Because PGI(2) may retard atherogenesis through its inhibitory effects on platelet function, we discuss the effects of PGI(2) on platelets in persons with SCI in this review. CONCLUSIONS: Subjects with chronic SCI develop abnormal platelet function, resulting in the production of atherogenic and thrombogenic factors for the following reasons: (1) the PGI(2) and insulin receptors on their platelets are impaired; (2) thrombin generation and platelet-derived growth factor release are elevated; (3) insulin-induced nitric oxide production by platelets is markedly impaired; and (4) a circulating antibody (immunoglobulin G (IgG)) blocks the antithrombotic effect of both insulin and PGI(2) receptors. Thus, this IgG molecule is thought to be one of the pathological mediators of the increased incidence of CHD in individuals with SCI. PMID- 21606931 TI - Intrathecal transplantation of stem cells by lumbar puncture for thoracic spinal cord injury in the rat. AB - STUDY DESIGN: Experimental investigation of intrathecal transplantation of stem cells by lumbar puncture (LP) in a rat model that simulates human thoracic spinal cord injury (SCI). OBJECTIVES: To examine the distribution and phenotype of spinal cord-derived neural stem/progenitor cells (NSPCs) and bone marrow-derived mesenchymal stromal cells (BMSCs) following LP transplantation in SCI rats. SETTING: Toronto Western Research Institute, Toronto, Ontario, Canada. METHODS: NSPCs or BMSCs were transplanted via LP at level L3-5 1 week after compression SCI at T8. Rats were killed at 3, 17 and 27 days after LP transplantation and the relative distribution of cells at C4, T8 and L3-5 was quantitated. The phenotype of the NSPC and BMSC was assessed with immunocytochemistry in vitro and following LP transplantation. RESULTS: By 4 weeks, more NSPC migrated to the lesion site relative to BMSC and uninjured animals. However, there was no preferential homing of either of these types of cells into the parenchyma of the injury site, and most of the transplanted cells remained in the intrathecal space. In vitro, spinal cord-derived NSPC proliferated and expressed nestin, but after LP transplantation, NSPC became post-mitotic and primarily expressed oligodendrocyte markers. In contrast, BMSC did not express any neural antigens in vivo. CONCLUSION: LP is a minimally invasive method of cell transplantation that produces wide dissemination of cells in the subarachnoid space of the spinal cord. This is the first study to report and quantify the phenotype and spatial distribution of LP transplanted NSPC and BMSC in the intact and injured spinal cord. PMID- 21606932 TI - Interview by David Page. PMID- 21606933 TI - Leukaemia: Notch has commitment issues. PMID- 21606935 TI - Prostate cancer: Studying the classics. PMID- 21606937 TI - Gist natural killers. PMID- 21606938 TI - Molecular profiling: a double agent. PMID- 21606939 TI - Pathology: Two of a kind. PMID- 21606940 TI - Hypoxia: HIF switch. PMID- 21606943 TI - A proposal for a simple and inexpensive therapeutic cancer vaccine. AB - In this essay, I propose a new method of treating tumours, using an old and inexpensive preparation, that I contend would be of considerable benefit to patients and their cancer management. My rationale for this treatment initially arose from recent advances in the understanding of dendritic cell function. (Dendritic cells are key cells of the immune system that are able to either turn on or turn off T-cell responses.) Evidence to support this approach is found in 100-year-old studies on the immunotherapy of cancer. Also, I draw on some remarkable, but little-known studies from the 1960s-1990s, demonstrating that the preparation has already been trialled in humans (although not intratumourally, as I propose), and is considered sufficiently safe to proceed with clinical trials in cancer volunteers. PMID- 21606941 TI - Targeting hypoxia in cancer therapy. AB - Hypoxia is a feature of most tumours, albeit with variable incidence and severity within a given patient population. It is a negative prognostic and predictive factor owing to its multiple contributions to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, resistance to cell death, altered metabolism and genomic instability. Given its central role in tumour progression and resistance to therapy, tumour hypoxia might well be considered the best validated target that has yet to be exploited in oncology. However, despite an explosion of information on hypoxia, there are still major questions to be addressed if the long-standing goal of exploiting tumour hypoxia is to be realized. Here, we review the two main approaches, namely bioreductive prodrugs and inhibitors of molecular targets upon which hypoxic cell survival depends. We address the particular challenges and opportunities these overlapping strategies present, and discuss the central importance of emerging diagnostic tools for patient stratification in targeting hypoxia. PMID- 21606942 TI - Interleukin-2 is present in human blood vessels and released in biologically active form by heparanase. AB - Interleukin-2 (IL-2) is a multifaceted cytokine with immunostimulatory and immunosuppressive properties. Our laboratory recently demonstrated that the availability of IL-2 is regulated, in part, by association with perlecan, a heparan sulfate proteoglycan. Given the abundance of perlecan in blood vessels, we asked whether IL-2 is present in vessel walls. Our results indicate that IL-2 is associated with endothelial and smooth muscle cells within the human arterial wall. This IL-2 is released by heparanase, and promotes the proliferation of an IL-2-dependent cell line. Given the presence of IL-2 in human arteries, we asked whether the large vessels of IL-2-deficient mice were normal. The aortas of IL-2 deficient mice exhibited a loss of smooth muscle cells, suggesting that IL-2 may contribute to their survival. In their entirety, these results suggest a here-to fore unrecognized role of IL-2 in vascular biology, and have significant implications for both the immune and cardiovascular systems. PMID- 21606944 TI - Regulatory T cells fulfil their promise? PMID- 21606945 TI - HIV-specific CD8+ T-cell proliferation is prospectively associated with delayed disease progression. AB - Human immunodeficiency virus (HIV)-specific CD8(+) T-cell proliferation is consistently correlated with enhanced host HIV immune control, but whether proliferative responses are a cause or consequence of immune protection is unclear. We measured Env-specific CD8(+) T-cell proliferation and interferon (IFN)-gamma secretion in HIV-infected participants with CD4 counts >200, who then completed 121 person-years of prospective follow-up to monitor HIV disease progression. In all, 13 of 31 participants (42%) reached end point during longitudinal follow-up. Strong Env-specific CD8(+) T-cell proliferation (>10% of CD8(+) T cells) was observed in 14/31 participants at baseline, and this was associated with a longer time to HIV disease progression end point, stratified baseline CD4 count (P=0.016). No associations were observed for IFN-gamma ELISPOT responses and progression (P>0.2). Strong proliferation remained significant in multivariate Cox regression analyses (P=0.044) as an independent predictor of delayed HIV disease progression, along with baseline CD4 count (P=0.04). Duration of HIV infection was associated with more rapid progression in univariate, but not multivariate, analysis (P=0.112). Age and baseline viral load were not predictive of progression. HIV-specific CD8(+) T-cell proliferation was a correlate of protective immunity in this prospective study; such responses may be important for HIV vaccine protection. PMID- 21606946 TI - Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia. AB - Multidrug resistance-related proteins (MRPs) 2, 3 and 5 are involved in the efflux of drugs used in acute lymphoblastic leukemia (ALL) treatment. Polymorphisms of these genes were investigated for an association with treatment responses in 273 childhood ALL patients. The MRP3 A-189 allele of the regulatory AT polymorphism was associated with reduced event-free survival (P=0.01). The results remained significant after adjustment for multiple comparisons and in the multivariate analysis. Among patients with an event, the A-189 carriers had significantly higher methotrexate plasma levels (P=0.03). MRP3 A-189 also conferred four times higher risk of a relapse in central nervous system (P=0.01). Patients with this allele tended to have lower frequency of thrombocytopenia grade 2 (P=0.06). Gene reporter assay showed that the haplotype tagged by the A 189 had higher promoter activity (P<=0.01). In conclusion, MRP3 A-189 T polymorphism was associated with treatment responses in ALL, likely due to the change in MRP3 efflux. PMID- 21606947 TI - Sequencing of Lp-PLA2-encoding PLA2G7 gene in 2000 Europeans reveals several rare loss-of-function mutations. AB - Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency <0.1%). Lp-PLA2 activity was significantly lower in rare nsSNP carriers compared with non-carriers (167.8+/-63.2 vs 204.6+/-41.8, P=0.01) and seven variants had enzyme activities consistent with a null allele. The cumulative frequency of these null alleles was 0.25%, so <1 in 10,000 Europeans would be expected to be homozygous, and thus not potentially benefit from treatment with an Lp-PLA2 inhibitor. PMID- 21606948 TI - Varenicline for smoking cessation: nausea severity and variation in nicotinic receptor genes. AB - This study evaluated association between common and rare sequence variants in 10 nicotinic acetylcholine receptor subunit genes and the severity of nausea 21 days after initiating the standard, Food and Drug Administration-approved varenicline regimen for smoking cessation. A total of 397 participants from a randomized clinical effectiveness trial with complete clinical and DNA resequencing data were included in the analysis (mean age=49.2 years; 68.0% female). Evidence for significant association between common sequence variants in CHRNB2 and nausea severity was obtained after adjusting for age, gender and correlated tests (all P(ACT)<0.05). Individuals with the minor allele of CHRNB2 variants experienced less nausea than did those without the minor allele, consistent with previously reported findings for CHRNB2 and the occurrence of nausea and dizziness as a consequence of first smoking attempt in adolescents, and with the known neurophysiology of nausea. As nausea is the most common reason for discontinuance of varenicline, further pharmacogenetic investigations are warranted. PMID- 21606949 TI - Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design. AB - The risk of venous thromboembolism (VTE) is higher after the total hip or knee replacement surgery than after almost any other surgical procedure; warfarin sodium is commonly prescribed to reduce this peri-operative risk. Warfarin has a narrow therapeutic window with high inter-individual dose variability and can cause hemorrhage. The genetics-informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT) is a 2 * 2 factorial-design, randomized controlled trial designed to compare the safety and effectiveness of warfarin-dosing strategies. GIFT will answer two questions: (1) does pharmacogenetic (PGx) dosing reduce the rate of adverse events in orthopedic patients; and (2) is a lower target international normalized ratio (INR) non-inferior to a higher target INR in orthopedic participants? The composite primary endpoint of the trial is symptomatic and asymptomatic VTE (identified on screening ultrasonography), major hemorrhage, INR >= 4, and death. PMID- 21606950 TI - Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase. AB - Cytosine methylation of genomic DNA controls gene expression and maintains genome stability. How a specific DNA sequence is targeted for methylation by a methyltransferase is largely unknown. Here, we show that histone H3 tails lacking lysine 4 (K4) methylation function as an allosteric activator for methyltransferase Dnmt3a by binding to its plant homeodomain (PHD). In vitro, histone H3 peptides stimulated the methylation activity of Dnmt3a up to 8-fold, in a manner reversely correlated with the level of K4 methylation. The biological significance of allosteric regulation was manifested by molecular modeling and identification of key residues in both the PHD and the catalytic domain of Dnmt3a whose mutations impaired the stimulation of methylation activity by H3 peptides but not the binding of H3 peptides. Significantly, these mutant Dnmt3a proteins were almost inactive in DNA methylation when expressed in mouse embryonic stem cells while their recruitment to genomic targets was unaltered. We therefore propose a two-step mechanism for de novo DNA methylation - first recruitment of the methyltransferase probably assisted by a chromatin- or DNA-binding factor, and then allosteric activation depending on the interaction between Dnmt3a and the histone tails - the latter might serve as a checkpoint for the methylation activity. PMID- 21606951 TI - TLR-induced activation of Btk -- role for endosomal MHC class II molecules revealed. PMID- 21606953 TI - Increased IL-1beta activation, the culprit not only for defective insulin secretion but also for insulin resistance? PMID- 21606952 TI - Wnt signaling through T-cell factor phosphorylation. AB - Embryonic signaling pathways often lead to a switch from default repression to transcriptional activation of target genes. A major consequence of Wnt signaling is stabilization of beta-catenin, which associates with T-cell factors (TCFs) and 'converts' them from repressors into transcriptional activators. The molecular mechanisms responsible for this conversion remain poorly understood. Several studies have reported on the regulation of TCF by phosphorylation, yet its physiological significance has been unclear: in some cases it appears to promote target gene activation, in others Wnt-dependent transcription is inhibited. This review focuses on recent progress in the understanding of context-dependent post translational regulation of TCF function by Wnt signaling. PMID- 21606956 TI - Maximizing target protein ablation by integration of RNAi and protein knockout. PMID- 21606955 TI - Coordinate activation of inflammatory gene networks, alveolar destruction and neonatal death in AKNA deficient mice. AB - Gene expression can be regulated by chromatin modifiers, transcription factors and proteins that modulate DNA architecture. Among the latter, AT-hook transcription factors have emerged as multifaceted regulators that can activate or repress broad A/T-rich gene networks. Thus, alterations of AT-hook genes could affect the transcription of multiple genes causing global cell dysfunction. Here we report that targeted deletions of mouse AKNA, a hypothetical AT-hook-like transcription factor, sensitize mice to pathogen-induced inflammation and cause sudden neonatal death. Compared with wild-type littermates, AKNA KO mice appeared weak, failed to thrive and most died by postnatal day 10. Systemic inflammation, predominantly in the lungs, was accompanied by enhanced leukocyte infiltration and alveolar destruction. Cytologic, immunohistochemical and molecular analyses revealed CD11b(+)Gr1(+) neutrophils as major tissue infiltrators, neutrophilic granule protein, cathelin-related antimicrobial peptide and S100A8/9 as neutrophil-specific chemoattracting factors, interleukin-1beta and interferon gamma as proinflammatory mediators, and matrix metalloprotease 9 as a plausible proteolytic trigger of alveolar damage. AKNA KO bone marrow transplants in wild type recipients reproduced the severe pathogen-induced reactions and confirmed the involvement of neutrophils in acute inflammation. Moreover, promoter/reporter experiments showed that AKNA could act as a gene repressor. Our results support the concept of coordinated pathway-specific gene regulation functions modulating the intensity of inflammatory responses, reveal neutrophils as prominent mediators of acute inflammation and suggest mechanisms underlying the triggering of acute and potentially fatal immune reactions. PMID- 21606957 TI - The absolute monocyte and lymphocyte prognostic score predicts survival and identifies high-risk patients in diffuse large-B-cell lymphoma. AB - Despite the use of modern immunochemotherapy regimens, almost 50% of patients with diffuse large-B-cell lymphoma will relapse. Current prognostic models, including the International Prognostic Index, incorporate patient and tumor characteristics. In contrast, recent observations show that variables related to host adaptive immunity and the tumor microenvironment are significant prognostic variables in non-Hodgkin lymphoma. Therefore, we retrospectively examined the absolute monocyte and lymphocyte counts as prognostic variables in a cohort of 366 diffuse large-B-cell lymphoma patients who were treated between 1993 and 2007 and followed at a single institution. The absolute monocyte and lymphocyte counts in univariate analysis predicted progression-free and overall survival when analyzed as continuous and dichotomized variables. On multivariate analysis performed with factors included in the IPI, the absolute monocyte and lymphocyte counts remained independent predictors of progression-free and overall survival. Therefore, the absolute monocyte and lymphocyte counts were combined to generate a prognostic score that identified patients with an especially poor overall survival. This prognostic score was independent of the IPI and added to its ability to identify high-risk patients. PMID- 21606958 TI - The immunoglobulin heavy chain gene 3' enhancers induce Bcl2 deregulation and lymphomagenesis in murine B cells. AB - Human follicular B-cell lymphoma is associated with the t(14;18) chromosomal translocation that juxtaposes the Bcl2 proto-oncogene with the immunoglobulin heavy chain (Igh) locus, resulting in the deregulated expression of Bcl2. Our previous studies have shown that the Igh 3' enhancers deregulate the Bcl2 expression in vitro. However, the effects of the Igh 3' enhancer elements on Bcl2 expression in vivo are not known. To investigate the role of the Igh 3' enhancers in Bcl2 deregulation, we used gene targeting to generate knock-in mice in which four DNase I-hypersensitive regions from the murine Igh 3' region were integrated 3' of the Bcl2 locus. Increased levels of Bcl2 mRNA and protein were observed in the B cells of Igh-3'E-bcl2 mice. B cells from Igh-3'E-bcl2 mice showed an extended survival in vitro compared with B cells from wild-type (Wt) mice. The Bcl2 promoter shift from P1 (the 5' promoter) to P2 (the 3' promoter) was observed in B cells from Igh-3'E-bcl2 mice, similar to human t(14;18) lymphomas. The IgH-3'E-bcl2 mice developed monoclonal B-cell follicular lymphomas, which were slowly progressive. These studies show that the Igh 3' enhancers have an important role in the deregulation of Bcl2 and B-cell lymphomagenesis in vivo. PMID- 21606959 TI - Translocation t(1;16)(p31;q24) rearranging CBFA2T3 is specific for acute erythroid leukemia. PMID- 21606961 TI - Discovery of new microRNAs by small RNAome deep sequencing in childhood acute lymphoblastic leukemia. AB - MicroRNAs (miRNAs) relevant to acute lymphoblastic leukemia (ALL) in children are hypothesized to be largely unknown as most miRNAs have been identified in non leukemic tissues. In order to discover these miRNAs, we applied high-throughput sequencing to pooled fractions of leukemic cells obtained from 89 pediatric cases covering seven well-defined genetic types of ALL and normal hematopoietic cells. This resulted into 78 million small RNA reads representing 554 known, 28 novel and 431 candidate novel miR genes. In all, 153 known, 16 novel and 170 candidate novel mature miRNAs and miRNA-star strands were only expressed in ALL, whereas 140 known, 2 novel and 82 candidate novel mature miRNAs and miRNA-star strands were unique to normal hematopoietic cells. Stem-loop reverse transcriptase (RT) quantitative PCR analyses confirmed the differential expression of selected mature miRNAs in ALL types and normal cells. Expression of 14 new miRNAs inversely correlated with expression of predicted target genes (-0.49 <= Spearman's correlation coefficients (Rs)<= -0.27, P <= 0.05); among others, low levels of novel sol-miR-23 associated with high levels of its predicted (antiapoptotic) target BCL2 (B-cell lymphoma 2) in precursor B-ALL (Rs -0.36, P = 0.007). The identification of >1000 miR genes expressed in different types of ALL forms a comprehensive repository for further functional studies that address the role of miRNAs in the biology of ALL. PMID- 21606960 TI - Risk factors for tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. AB - Tumor lysis syndrome (TLS) has been described in over 40% of patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. We conducted a retrospective analysis to determine predictive factors for TLS. In 116 patients, the incidence of TLS was 46% (95% CI: 36-55%). In univariable analysis, female gender, greater number of prior therapies, Rai stages III-IV, adenopathy >= 10 cm, splenomegaly, del(11q), decreased albumin and increased absolute lymphocyte count, white blood cell count (WBC), beta2 microglobulin, and lactate dehydrogenase were associated (P < 0.05) with TLS. In multivariable analysis, female gender, adenopathy >= 10 cm, elevated WBC, increased beta2-microglobulin, and decreased albumin were associated with TLS (P < 0.05). With respect to patient outcomes, 49 and 44% of patients with and without TLS, respectively, responded to flavopiridol (P = 0.71). In a multivariable analysis, controlling for number of prior therapies, cytogenetics, Rai stage, age and gender, progression-free survival (PFS) was inferior in patients with TLS (P = 0.01). Female patients and patients with elevated beta2 microglobulin, increased WBC, adenopathy >= 10 cm and decreased albumin were at highest risk and should be monitored for TLS with flavopiridol. TLS does not appear to be predictive of response or improved PFS in patients receiving flavopiridol. PMID- 21606962 TI - Somatic mutations in acute promyelocytic leukemia (APL) identified by exome sequencing. PMID- 21606963 TI - Importance of c-kit mutation detection method sensitivity in prognostic analyses of t(8;21)(q22;q22) acute myeloid leukemia. AB - Recently, c-kit mutations have been reported as a novel adverse prognostic factor of acute myeloid leukemia with t(8;21)(q22;q22) translocation (t(8;21) AML). However, much remains unclear about its clinical significance. In this study, we developed a highly sensitive mutation detection method known as mutation-biased PCR (MB-PCR) and investigated the relationship between c-kit mutations and prognosis. When c-kit mutations were analyzed for 26 cases of t(8;21) AML using the direct sequence (DS) and MB-PCR, the latter had a much higher detection rate of c-kit mutations at initial presentation (DS 5/26(19.2%) vs MB-PCR 12/26(46.2%)). Interestingly for the three cases, in which c-kit mutations were observed only at relapse with the DS, c-kit mutations were detected at initial presentation using the MB-PCR. This result suggests that a minor leukemia clone with c-kit mutations have resistance to treatment and are involved in relapse. In univariate analyses, the presence of a c-kit mutation using DS was not an adverse prognostic factor (P = 0.355), but was a factor when using MB-PCR (P = 0.014). The presence of c-kit mutations with MB-PCR was also an independent adverse prognostic factor by multivariate analyses (P = 0.006). We conclude that sensitivity of c-kit mutation detection method is important to predict prognosis for t(8;21) AML. PMID- 21606964 TI - Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL. AB - Chronic lymphocytic leukemia (CLL) cells require complex microenvironmental and immunologic interactions to survive and proliferate. Such interactions might be best recreated in animal models; however, this needs extensive verification. We therefore investigated the composition of the T-cell compartment in the EMU-TCL1 transgenic mouse, currently the most widely used murine model for CLL. Immunophenotyping and transplant approaches were used to define T-cell subsets at various stages of CLL. Analogous to human CLL, we observed a skewing of T-cell subsets from naive to antigen-experienced memory T cells that was more pronounced in lymph nodes than in blood. Transplantation of CLL into non-transgenic recipients was feasible without immunosuppression in a pure C57BL/6 background and resulted in the prominent skewing of the T cells of the recipient mice. Both in spontaneously developed CLL and in the transplantation setting, a loss in T cell receptor diversity was observed, with a relevant number of clonal T-cell populations arising. This suggests that antigen-dependent differentiation toward the T memory pool is initiated by murine CLL cells. In summary, we validate the TCL1 transgenic mouse model for analysis of T-cell phenotypes and suggest a CLL dependent antigen-driven skewing of T cells in these mice. PMID- 21606965 TI - Predictive impact of allele-matching and EBMT risk score for outcome after T-cell depleted unrelated donor transplantation in poor-risk acute leukemia and myelodysplasia. AB - Many parameters predict for outcome after unrelated donor (URD) allogeneic hematopoietic stem cell transplantation (alloSCT). High-resolution HLA-matching significantly impacts outcome and also the European Group of Blood and Marrow Transplantation (EBMT) risk score, based on patient age, disease stage, donor type, time from diagnosis to SCT and gender combination, may predict for non relapse mortality and overall survival (OS). We evaluated the individual and combined effects of allele-matching and the EBMT risk score in 327 patients with poor-risk acute leukemia or myelodysplasia, who received a T-cell depleted URD alloSCT. Matching for HLA-A, -B, -C and -DRB1 alleles (8/8 match) was associated with a 5-year OS of 40% compared with 30% for mismatched (<=7/8) pairs (P=0.02). Patients with EBMT risk scores of 1-2, 3, 4 and 5-7 had 5-year OS estimates of 53, 43, 30 and 20%, respectively (P<0.001). The favorable prognostic impact of an 8/8 donor was most pronounced if the EBMT risk score was low (1-2). Five-year OS was 74+/-8% vs 39+/-11% for fully matched patients with a low-risk EBMT score as compared with EBMT low-risk patients with <=7/8 donors. These data underscore the importance of incorporating both the EBMT risk score and the degree of high resolution HLA-matching in the risk assessment prior to URD alloSCT. PMID- 21606966 TI - Heart failure: poor health literacy increases mortality. PMID- 21606967 TI - Device therapy: risk assessment to improve patient care following cardioverter defibrillator implantation. PMID- 21606968 TI - BRAF targeted therapy changes the treatment paradigm in melanoma. AB - After decades of stagnation, recent therapeutic advances in melanoma seem on the horizon. The discovery of the genetic underpinnings of this historically refractory disease has exposed potential targets for therapy, BRAF mutations being principal among them. In the 8 years following the discovery of BRAF mutations in 50-60% of advanced melanomas, only recently have potent and selective inhibitors of this intracellular signaling molecule shown efficacy from early clinical testing. Vemurafenib (PLX4032) and GSK2118436, two orally available and well tolerated agents are on the verge of transforming the landscape of melanoma therapy based on the promising results of their respective phase I, II, and III trials. PMID- 21606969 TI - Hematology: Allografting offers better outcomes than autografting for patients with myeloma. PMID- 21606971 TI - Immunotherapy for the treatment of prostate cancer. AB - Failure of immune surveillance has a prominent role in tumorigenesis. Cancerous cells can evade T-cell responses to tumor-associated antigens by multiple mechanisms. Active immunotherapy aims to stimulate the immune response against cancer cells. Unlike normal prostate tissue, prostate cancer is not ignored by the immune system, as shown by the presence of tumor infiltrating lymphocytes. This characteristic renders prostate cancer particularly suitable for immunotherapy. The existence of well-defined antigens, largely limited to prostate tissue, allows prostate cancer cells to be targeted without the risk of systemic autoimmune reactions, as autoimmunity specifically directed at the prostate is the goal of prostate cancer immunotherapy. Active immunotherapy directed towards prostate cancer can be conducted using multiple strategies, involving dendritic cells, whole-cell vaccines, viral vectors, DNA-based and peptide-based agents, as well as immunostimulatory agents. The only FDA-approved immunotherapy for prostate cancer is the dendritic-cell-based agent Sipuleucel-T, which yielded an advantage in overall survival, but not in progression-free survival in a phase III trial. We present the clinical developments in the field of immunotherapy and critically analyze methodological issues related to the evaluation of tumor responses to immunotherapy, trial design, and surrogate end points. PMID- 21606970 TI - The role of local therapy in the management of lung and liver oligometastases. AB - Despite recent advances in oncologic therapy, an important proportion of patients with primary cancer will develop distant metastasis. The standard therapy for metastatic cancer is systemic therapy, which typically does not yield excellent response rates for most solid tumors. Data in the literature support the existence of a state of limited metastasis or oligometastasis. Favorable outcomes have been observed in selected patients with oligometastases that are treated with local ablative therapies, which include surgical extirpation, stereotactic body radiation therapy, and radiofrequency ablation. Lung and liver are the two most common sites of oligometastases considered for local ablative therapy and this Review will focus on the role of local therapy in oligometastases that arise in these organs. PMID- 21606972 TI - The role of lymphadenectomy for upper tract urothelial carcinoma. AB - Regional lymphadenectomy, with both its diagnostic and therapeutic roles, serves as an integral component of the management of many malignancies. Extended pelvic lymph node dissection (LND) is the standard of care for urothelial carcinoma of the bladder, with the extent of lymphadenectomy correlating positively with cancer-related outcomes. Given their histologic similarities with bladder cancer, it is reasonable to hypothesize that a similar relationship exists for upper tract urothelial carcinomas (UTUCs). However, the data published to date have failed to consistently demonstrate a therapeutic benefit of regional LND for UTUC. As a consequence, utilization of regional lymphadenectomy remains at the discretion of the surgeon, the extent of LND lacks standardization, and its clinical utility continues to be debated. In order to better clarify the existing data, we present a review of the role of regional lymphadenectomy in patients with UTUC. PMID- 21606973 TI - Bladder cancer: improvements in clinical staging of muscle-invasive bladder cancer. PMID- 21606974 TI - A randomized placebo-controlled phase IIb trial of a3309, a bile acid transporter inhibitor, for chronic idiopathic constipation. AB - OBJECTIVES: A3309 is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor. We conducted an 8-week, multicenter, randomized, double-blind, placebo controlled, parallel group, phase IIb study, which evaluated A3309 in patients with chronic idiopathic constipation (CIC). METHODS: Patients with CIC (modified Rome III criteria and <3 complete (CSBM) spontaneous bowel movements (SBMs)/week during the 2-week baseline) were randomized to 5, 10, or 15 mg A3309 or placebo once daily. The primary end point was change in SBM number during week 1 compared with baseline. Other bowel and abdominal symptoms were assessed as secondary end points. Serum 7alphaC4 and lipids were evaluated as biomarkers of BA synthesis/loss. RESULTS: In all, 190 patients (mean 48 years, 90% female) were randomized. Mean increase (95% confidence interval) in SBM for week 1 were 1.7 (0.7-2.8) for placebo vs. 2.5 (1.5-3.5), 4.0 (2.9-5.0), and 5.4 (4.4-6.4) for 5 mg, 10 mg (P<0.002), and 15 mg (P<0.001) A3309, respectively. Increased stool frequency was maintained over 8 weeks. Time to first SBM and CSBM were significantly reduced in the 10- and 15-mg A3309 groups compared with placebo. Straining and bloating decreased with A3309 compared with placebo (P<0.05). Increased 7alphaC4 and reduced low-density lipoprotein cholesterol with A3309 suggested increased BA synthesis and BA loss. The most common adverse events (AEs) were abdominal pain and diarrhea, which occurred most commonly in the 15-mg A3309 group. No drug-related serious AEs were observed. CONCLUSIONS: A3309 increased stool frequency and improved constipation-related symptoms in CIC; effects were maintained over 8 weeks of treatment. PMID- 21606975 TI - Serum miR-122 as a biomarker of necroinflammation in patients with chronic hepatitis C virus infection. AB - OBJECTIVES: The liver contains large amounts of microRNA-122 (miR-122), whereas other tissues contain only marginal amounts of this miRNA. MicroRNAs have also been found to circulate in the blood in a cell-free form; their potential as readily accessible disease markers is currently evaluated. Here, we investigated if the serum levels of miR-122 might be useful as disease parameter in patients with chronic hepatitis C virus (HCV) infection. METHODS: RNA was extracted from sera of patients with chronic HCV infection (CHC) and healthy controls and was analyzed for miR-22 content by quantitative real-time reverse-transcription polymerase chain reaction. miR-122 serum levels were correlated with standard parameters of liver function. Liver biopsies from the same patients were examined for the histologic activity index (HAI) and the degree of fibrosis. RESULTS: Sera from patients with CHC contained higher levels of miR-122 than sera from healthy controls. Serum miR-122 levels correlated well with markers of liver inflammatory activity, that is, the serum levels of alanine leucine transaminase (ALT) and aspartate transaminase, and the HAI score. In patients with persistently normal ALT levels, serum miR-122 levels did not differ from healthy controls. There was no correlation of serum miR-122 levels with serum albumin, international normalized ratio, liver fibrosis, or serum HCV RNA. CONCLUSIONS: The serum level of miR-122 strongly correlates with serum ALT activity and with necroinflammatory activity in patients with CHC and elevated ALT levels, but not with fibrosis stage and functional capacity of the liver. PMID- 21606976 TI - Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis. AB - OBJECTIVES: Chronic idiopathic constipation (CIC) is a common functional gastrointestinal disorder in the community, yet no previous systematic review and meta-analysis has estimated the global prevalence, or potential risk factors for the condition. METHODS: MEDLINE, EMBASE, and EMBASE Classic were searched (up to December 2010) to identify population-based studies reporting the prevalence of CIC in adults (>=15 years), according to self-report, questionnaire, or specific symptom-based criteria. The prevalence of CIC was extracted for all studies, and according to country, age, gender, socioeconomic status, and presence or absence of irritable bowel syndrome (IBS) where reported. Pooled prevalence overall, and according to study location and certain other characteristics, as well as odds ratios (ORs), with 95% confidence intervals (CIs) were calculated. RESULTS: Of the 100 papers evaluated, 45 reported the prevalence of CIC in 41 separate study populations, containing 261,040 subjects. Pooled prevalence of CIC in all studies was 14% (95% CI: 12-17%). The prevalence of CIC was lower in South East Asian studies, and in studies using the Rome II or III criteria. The prevalence of CIC was higher in women (OR: 2.22; 95% CI: 1.87-2.62), and increased with age and lower socioeconomic status. The prevalence was markedly higher in subjects who also reported IBS (OR: 7.98; 95% CI: 4.58-13.92), suggesting common pathogenic mechanisms. CONCLUSIONS: Pooled prevalence of CIC in the community was 14%, and of similar magnitude in most geographical regions. Rates were higher in women, older individuals, and those of lower socioeconomic status. Presence of IBS was strongly associated with CIC. PMID- 21606977 TI - Mortality from acute upper gastrointestinal bleeding in the United kingdom: does it display a "weekend effect"? AB - OBJECTIVES: An increased mortality in patients presenting to hospital at weekends has been observed for several medical conditions. The aim of this study is to examine the relationship between weekend presentation to hospital following acute upper gastrointestinal bleeding and mortality. METHODS: Data were collected on 6,749 patients presenting to 212 UK hospitals. A logistic regression model was used to examine the relationship between weekend presentation to hospital and mortality. RESULTS: Patients presenting at the weekend were more likely to present with shock (39% vs. 36%), hematemesis (41% vs. 38%), and receive red cell transfusion (42% vs. 39%). Only 38% of those presenting at weekends underwent endoscopy within 24 h compared with 55% admitted on weekdays (adjusted odds ratio (OR)=0.47, 95% confidence interval (CI)=0.41-0.54), although the proportion of all patients receiving endoscopic therapy was identical at weekends compared with weekdays (24%). After adjustment for confounders, there was no evidence of a difference between weekend and weekday mortality (OR=0.93; 95% CI=0.75-1.16). Similar results were seen when restricting the analysis to those patients who underwent endoscopy (n=5,004) (OR=0.87, 95% CI=0.65-1.16). There was no difference in the OR for mortality for weekend compared with weekday presentation between patients presenting to hospitals with an out-of-hours (OOH) endoscopy rota compared with those presenting to hospitals without such a facility. CONCLUSIONS: In this large prospective study of acute upper gastrointestinal bleeding in the United Kingdom, there was no increase in mortality for weekend vs. weekday presentation despite patients being more critically ill and having greater delays to endoscopy at weekends. Provision of an OOH endoscopy service at weekends in the remaining UK hospitals may not lead to further reductions in case fatality, although a reduction in OOH endoscopy provision from current levels could lead to an increase in mortality at weekends. PMID- 21606978 TI - A prospective study of duodenal bulb biopsy in newly diagnosed and established adult celiac disease. AB - OBJECTIVES: Recent reports suggest that the duodenal bulb may be the only site to demonstrate villous atrophy (VA) in celiac disease. However, there is a paucity of data from newly diagnosed adult celiac patients and no data from those patients with established celiac disease. The objective of this study was to compare the histological findings in the duodenal bulb and distal duodenum of patients with adult celiac disease (newly diagnosed or established) against controls. METHODS: A total of 461 patients were prospectively recruited. Biopsies were graded using the Marsh criteria. RESULTS: In all, 461 patients (300 females and 161 males) with median age 51 years were analyzed. In all, 126 had newly diagnosed celiac disease, 85 established celiac disease, and 250 controls. New diagnosis celiac disease (9%, P<0.0001) and established celiac disease (14%, P<0.0001) were more likely than controls to have VA in the bulb alone. Overall, when comparing the histological lesion of the bulb against the distal duodenum, 31/85 with established celiac disease (P<0.0001) and 21/126 newly diagnosed (P=0.0067) had a discrepancy in the severity of the lesion between the two sites compared with 18/250 controls. In all, 24/31 with established celiac disease and 16/21 newly diagnosed had the more severe lesion in the bulb. CONCLUSIONS: VA may be present only in the duodenal bulb. This study suggests that the optimal assessment of patients in whom celiac disease is suspected (with positive serology) and those with established celiac disease requires a duodenal bulb biopsy in addition to distal duodenal biopsies. PMID- 21606979 TI - [What is a physician?]. PMID- 21606980 TI - [Calve-Legg-Perthes disease]. PMID- 21606981 TI - [The significance of clinical competence]. PMID- 21606982 TI - [Depressing about tobacco in a commentary from SIRUS]. PMID- 21606984 TI - [Teleradiology in Norway]. PMID- 21606985 TI - [Religious coping in medical treatment]. PMID- 21606986 TI - [Osteoporosis patients are disfavorized by the subsidized prescription system]. PMID- 21606988 TI - [Internship is sick and needs treatment]. PMID- 21606987 TI - [Treatment of stroke--an interdisciplinary challenge]. PMID- 21606989 TI - [Cream skimmers entry]. PMID- 21606990 TI - [Communication about drug use in referrals, acute admissions and discharge letters]. AB - BACKGROUND: It is critical to communicate properly about drug use across health care levels, to avoid adverse drug effects and medication errors. We have investigated communication about drug use between a hospital and the primary health care services through an assessment of referrals and discharge letters. MATERIAL AND METHODS: At Innlandet Hospital Trust Gjovik, all elective referrals to the medical outpatient clinic and discharge letters from the medical department during two periods (in 2009) were copied and anonymised. The documents were searched for information about drug use and for completeness of that information. We also assessed whether admission letters for acute admissions to the medical department included a medication list. RESULTS: 92 (47%) of 194 of elective referrals, and 167 (91%) of 184 of discharge letters, contained complete information about drug use. In 61 (49%) of 125 of discharge letters that contained information about altered drug use, these changes were not discussed in the medication list. Among 196 acutely admitted patients who used drugs, medication lists were missing in 76 (39%). When the admitting doctor was a regular GP the lists were missing in 10 (16%) of 63 of admissions. INTERPRETATION: Proper communication about drug use seems to have low priority and patients are often admitted to and discharged from the hospital with insufficient information. Patients should have a paper version of their medication list until such information is available electronically. PMID- 21606991 TI - [Legg-Calve-Perthes disease]. AB - BACKGROUND: Legg-Calve-Perthes disease is characterized by avascular necrosis of the head of the femur. This article deals with the epidemiology, possible causes, treatment and prognostic factors connected with the disease. MATERIAL AND METHOD: The article is based on a non-systematic literature search and own clinical practice, with special emphasis on a Norwegian countrywide study of children with Legg-Calve-Perthes disease. RESULTS: The incidence of Legg-Calve-Perthes disease varies in different countries and regions. Those who are older than six years at the time of diagnosis and have over 50% femoral head necrosis have a worse prognosis than younger children where the necrosis is less extensive. Treatment has been discussed extensively over the past 100 years, and still varies considerably. The Norwegian countrywide investigation showed that the results in children who were over six years at the time of diagnosis and had more than 50% femoral head necrosis were significantly better after varus femoral osteotomy than after physiotherapy or orthosis. This agrees with the only other prospective study that has been published. INTERPRETATION: Operative treatment should be considered in children who are six years old or older and have over 50% femoral head necrosis when the diagnosis Legg-Calve-Perthes disease is made. Those who are younger than six years at the time of diagnosis or who have less than 50% femoral head necrosis should be treated symptomatically. Abduction orthosis has no place in the treatment of Legg-Calve-Perthes disease. PMID- 21606992 TI - [Acquired Horner's syndrome]. AB - BACKGROUND: Horner's syndrome is characterized by the classic triad of eyelid ptosis, miosis and facial anhidrosis and is caused by an interruption of the oculosympathetic nerve pathway somewhere between its origin in the hypothalamus and the eye. MATERIAL AND METHODS: This review is based on own experiences and a discretionary selection of articles found through non-systematic searches in PubMed. Cases from own practice serve as examples. RESULTS: Based on localization of the nerve pathway interruption, a Horner's syndrome is often classified as central, pre- or postganglionic. For the central type the syndrome is associated with other symptoms and signs from the central nervous system. The preganglionic type is most often caused by a tumor or trauma. The postganglionic type is often associated with pain/headache; most frequently it is seen as a consequence of carotid artery dissection or during cluster headache. Anhidrosis is rarely prominent, and in the postganglionic subtype it is virtually absent. Pharmacological tests can be used in diagnostics. Apraclonidine seems to be a good alternative to cocaine to confirm Horner's syndrome. MRI is generally recommended in the evaluation, if necessary with special sequences. INTERPRETATION: The path of the long oculosympathetic fibers is complex and not fully understood. Topographic diagnostics may be challenging, but in most cases a specific cause is identified. PMID- 21606993 TI - [Meeting with Auditorium 13]. PMID- 21606994 TI - [Drug therapy of menstruation related complaints]. PMID- 21606995 TI - [A man with acutely starting pain in the right hip and thigh]. PMID- 21606996 TI - [When red flag flips, but blood tests and MR are normal]. PMID- 21606997 TI - [Limits, price and alternatives of normality--disability as experienced reality]. PMID- 21606998 TI - [When is cancer work-connected?]. PMID- 21606999 TI - [Who discovered insulin?]. PMID- 21607000 TI - [When the patient threatens or attacks]. PMID- 21607001 TI - [Information about hereditary disposition in connection with health insurance application]. PMID- 21607002 TI - [The role of multidetector CT in cardiovascular diagnosis: the CT coronary angiography. Current applications]. AB - Currently, computed tomographic (CT) imaging of the heart is mainly used for the quantification of coronary artery calcification as an indirect measure of coronary plaque burden and, less frequently, for minimally invasive coronary angiography. Recently, so-called multislice spiral computed tomographic (MSCT) scanners with gantry rotation speeds fast enough to produce diagnostic images of the heart under certain conditions have become widely available. As a consequence, cardiac CT imaging, most often performed for the purpose of calcium scoring, is increasingly applied. In this paper we provide a discussion of technical issues, applications, advantages, and limitations, after which we offer recommendations for current and future uses. To accomplish this, we conducted a comprehensive review of a study (Stacul et al. 2009) that was done to analyse the costs of 64-slice computed tomography (CT) coronary angiography and conventional coronary angiography and determine the cost-effectiveness of the two modalities. PMID- 21607003 TI - [Treatment of levator ani syndrome: update and future developments]. AB - Chronic proctalgia is defined by chronic or recurrent episodes of rectal pain or aching lasting at least 20 minutes in the absence of structural or systemic disease explanation for the pain syndrome. Digital rectal examination distinguishes between levator ani syndrome where the patient reports tenderness on palpation of the pubo-rectalis muscle and unspecified functional anorectal pain where no pain can be elicited. There is no consensus on its etiology, but chronic tension of the pelvic floor muscles is the most common view. Diagnosis is focused on excluding organic diseases potentially responsible for the pain. A number of small sized, non-controlled trials have evaluated different treatments for chronic proctalgia with frustrating results for both patients and physicians. A recent well designed, prospective, randomized, controlled trial has evaluated the three most commonly prescribed treatments to relax pelvic floor muscles in chronic proctalgia: biofeedback, electrogalvanic stimulations and digital massage of the levator ani. The study has provided unequivocal evidence that biofeedback is effective treatment for chronic proctalgia, but its efficacy is limited to levator ani syndrome. In these patients a paradoxical contraction of the pelvic floor muscles on attempted defecation has been documented in most cases and its therapeutic reversal do correlate with clinical benefit. Similar data have been also reported in constipation secondary to obstructed defecation. Electrogalvanic stimulation is somewhat effective and may be considered where high biofeedback expertise is not available. No treatment has been proven effective in unspecified functional anorectal pain where analgesic and antidepressant drugs retain a role in the absence of randomized, controlled trials. PMID- 21607004 TI - [Adrenal pheochromocytoma associated with "tako-tsubo" syndrome]. AB - "Tako-tsubo" cardiomyopathy is a condition characterized by a transitory left ventricular asinergia, induced by physical and emotional stress. In literature there are few cases of association between cardiomyopathy and pheochromocytoma. We described a case of a 72 year-old woman admitted in Emergency Room for chest pain associated with high blood pressure: the ECG showed non-ST elevation in leads III, AVF and V1. An echocardiogram showed global reduction in contractility (EF 40%) with apical akinesia. The coronary angiography showed coronary without stenosis while left ventriculography showed an average apical akinesia of the anterior wall with enhanced contractility of basal segments. Subsequently, the patient continued to present episodes of tremors associated with high blood pressure and therefore was made the determination of urinary metanephrines and urinary vanilmandelic acid that were both high. A subsequent abdomen MRI showed a 32 mm left adrenal lesion with arterial phase impregnation. The diagnosis of left adrenal pheochromocytoma was made and the tumor, after appropriate preoperative pharmacological preparation with alpha-blockers, was removed surgically. In conclusion, the unexplained transitory left ventricular asinergia alert the clinician of an underlying disorder, such as pheochromocytoma, the early detection of which is crucial to the prognosis. PMID- 21607005 TI - [Heart recruiment of elderly donors by pharmacological echostress]. AB - BACKGROUND: The heart transplant is a treatment of the heart failure, which is not responding to medications. To counteract heart donor shortage, we should screen aged potential donor hearts for initial cardiomyopathy and functionally significant coronary artery disease, in order to exclude donors with a history of cardiac disease. A simple way to evaluate this should be stress echocardiography. CASE REPORT: A marginal donor (a 57 year old woman meeting legal requirements for brain death) underwent a transesophageal (TE) dipyridamole stress echo (6 minutes accelerated protocol) to rule out moderate or severe heart and coronary artery disease. Wall motion was normal at baseline and at peak stress, without signs of stress inducible ischemia, and there was no latent myocardial dysfunction. The marginal donor heart was transplanted to a recipient marginal for co-morbidity (a 63 year old man with multiple myeloma and cardiac amyloidosis , chronic severe heart failure, NYHA class IV). The transplanted heart was assessed normal for dimensions and ventricular function at transthoracic (TT) echocardiography on post-transplant day 7. Coronary artery disease was ruled out at coronary angiography one month after transplant. CONCLUSION: For the first time stress echo was successfully used for the selection of hearts "too good to die", representing a critical way to solve the mismatch between donor need and supply. PMID- 21607006 TI - [Restless legs syndrome and diabetes mellitus: an accidental association?]. AB - Although limited in number, several studies have documented an increased prevalence of Restless Legs Syndrome (RLS) in type 2 diabetes. Polyneuropathy only partially explains the relation between the two disorders. This association could be due to the effects of a prolonged sleep loss: in increasing the probability of developing insulin-resistance and metabolic disturbances. PMID- 21607007 TI - [AGREE II: assessing the quality of practice guidelines]. AB - Clinical practice guidelines (CPG) are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. Rigorous methodologies in the CPG development process are crucial for their successful implementation, but the quality of guidelines can be extremely variable and sometimes it is very low. The Appraisal of Guidelines for Research & Evaluation (AGREE) instrument was published in 2001 to address the issue of variability in guideline quality. The AGREE Next Step Consortium refined the instrument with the publication of the new AGREE II, including a new User's Manual. GIMBE Foundation supported the Italian translation of AGREE II. PMID- 21607009 TI - Modeling Genetic and Environmental Factors in Biological Systems Using Structural Equation Modeling: An Application to Energy Balance. AB - To improve our understanding of the role(s) that genes and environmental factors play in a complex disease, we need statistical approaches that model multiple factors simultaneously in a hierarchical manner that aims to reflect the underlying biological system(s). We present an approach that models genes as latent constructs, defined by multiple variants (single nucleotide polymorphisms, SNPs) within each gene, using the multivariate statistical framework of structural equation modeling (SEM) to model multiple, putative genetic and environmental factors involved in energy imbalance ('obesity') using subjects from a colon polyp case-control study. We found that modeling constructs for the leptin receptor (LEPR) gene (defined by SNPs rs1137100, rs1137101, rs1805096, rs6588147) and the fat mass-and-obesity-associated (FTO) gene (defined by SNPs rs9939609, rs1421085, rs8044769) together with demographic (age, race, gender), physical activity, diet and sleep variables increased the strength of the association (beta(std)=-0.13 +/- 0.06; p=0.03) between the FTO and obesity constructs compared to that observed in a reduced model with only the FTO and LEPR constructs and demographic variables (beta(std)=-0.05 +/- 0.03; p=0.08). Several indirect paths, including an association between the LEPR and physical activity constructs (beta(std)=-0.15 +/- 0.04; p=0.01), were found. Interestingly, removing FTO revealed a marginal association between the LEPR and obesity constructs (beta(std)=0.24 +/- 0.14; p=0.09), which was not present when FTO was in the model. These results illustrate the importance of modeling multiple relevant genes and other factors in the same model, which is a major strength of this approach. Moreover, our latent gene construct approach exploits the correlation structure between SNPs while capturing overall effects of variation in that gene, which will enable better utilization of candidate gene and genome-wide SNP array data. PMID- 21607008 TI - [Neuropathic pain in oncology. Novel evidence for clinical practice]. AB - Neuropathic pain is usually considered an "hard pain" both for the intrinsic difficulties in a correct diagnosis, and for the modest efficacy of the most part of conventional treatments. The most frequently used drugs in clinical practice are tricyclic antidepressants and anticonvulsants, while a minor role is reserved to NSAIDs or to strong opiates. Aim of our work was to systematically analyze all the evidences of literature about the treatment options against neuropathic pain in oncology, focusing our attention upon the efficacy and the safety of the different therapeutic options assessed as Number-Needed-to-Treat (NNT) and Number Needed-to-Harm (NNH). A critical analysis of literature was finally performed using the GRADE system. On the basis of our review and the NNT and NNH ratio, gabapentin, pregabalin and strong opiates seem to be the most effective and well tolerated options against neuropathic pain in oncology, while carbamazepine, amitryptiline, tramadol and NSAIDs do not seem to be valid options in front line approach against oncologic neuropathic pain, either for a minor efficacy or for an unfavorable safety profile. Further trials comparing the different effective options are needed to better define the correct approach against neuropathic pain in oncology. PMID- 21607010 TI - Evaluating the Impact of a Pragmatic Nutrition Awareness Program for Expectant Mothers upon Birth Weight of the Newborn. AB - Poor maternal nutritional status and substandard antenatal care, which result in increased women's risk, low birth weight and stillbirth, afflict many countries with weak or emerging economies even today. Studies that address the effect of extending nutrition awareness among pregnant women to the net outcome of pregnancy remain scarce. We aimed to compare and contrast the effect of a pragmatic nutrition awareness program for expectant mothers (NAPEM) on birth weight of the newborn with a control group who received no such nutrition awareness activity. The effect of variables of mode of newborn delivery, associated complications at birth, and APGAR score of the newborn were also assessed. A pragmatic intervention trial of an antenatal care (ANC) program that consisted in nutrition awareness was conducted involving 53 pregnant women. Awareness was given through one-to-one interview and through informational literature provided to the participants in the local language. A hospital registry for deliveries undertaken during the study period was screened for identification of variables. A control group of matched pregnant women (n = 53) was obtained from the same hospital registry from preceding years, when the nutrition awareness program was not executed. A statistically significant improvement in birth weight of the newborn was observed in the intervention group, where expectant mothers were made aware about desired nutrition during pregnancy. A reduced incidence of complications associated with pregnancy was also observed in the intervention group. Providing awareness about nutritional requirements during pregnancy and suggesting the pragmatic ways to meet them was shown to be one possible effective measure to deal with pregnancy-related undernutrition. We show the efficacy of the intervention for underprivileged regions of India marked by inadequate health care delivery and lower socio economical standards. We discuss our findings in the context of available evidence-based guidelines. PMID- 21607011 TI - Preventive effect of pine bark extract (flavangenol) on metabolic disease in Western diet-loaded tsumura suzuki obese diabetes mice. AB - It is known that the metabolic syndrome has a multi-factorial basis involving both genetic and environmental risk factors. In this study, Tsumura Suzuki Obese Diabetes (TSOD) mice, a mouse model of multi-factorial, hereditary, obese type II diabetes, were given a Western diet (WTD) as an environmental factor to prepare a disease model (TSOD-WTD) and to investigate the preventive effects of Pine bark extract (Flavangenol) against obesity and various features of metabolic disease appearing in this animal model. In contrast to control Tsumura Suzuki Non-obesity (TSNO) mice, TSOD mice were obese and suffered from other metabolic complications. WTD-fed TSOD mice developed additional features such as hyperinsulinemia, abnormal glucose/lipid metabolism and fatty liver. The treatment with Flavangenol had a suppressive effect on increase in body weight and accumulation of visceral and subcutaneous fat, and also showed preventive effects on symptoms related to insulin resistance, abnormal glucose/lipid metabolism and hypertension. Flavangenol also increased the plasma concentration of adiponectin and decreased the plasma concentration of TNF-alpha. We next investigated the effect of Flavangenol on absorption of meal-derived lipids. Flavangenol suppressed absorption of neutral fat in an olive-oil-loading test (in vivo) and showed an inhibitory effect on pancreatic lipase (in vitro). The above results suggest that Flavangenol has a preventive effect on severe metabolic disease due to multiple causes that involve both genetic and environmental risk factors. The mechanism of action might involve a partial suppressive effect of meal-derived lipids on absorption. PMID- 21607012 TI - Antifungal Activity of Brazilian Propolis Microparticles against Yeasts Isolated from Vulvovaginal Candidiasis. AB - Propolis, a resinous compound produced by Apis mellifera L. bees, is known to possess a variety of biological activities and is applied in the therapy of various infectious diseases. The aim of this study was to evaluate the in vitro antifungal activity of propolis ethanol extract (PE) and propolis microparticles (PMs) obtained from a sample of Brazilian propolis against clinical yeast isolates of importance in the vulvovaginal candidiasis (VVC). PE was used to prepare the microparticles. Yeast isolates (n = 89), obtained from vaginal exudates of patients with VVC, were exposed to the PE and the PMs. Moreover, the main antifungal drugs used in the treatment of VVC (Fluconazole, Voriconazole, Itraconazole, Ketoconazole, Miconazole and Amphotericin B) were also tested. Minimum inhibitory concentration (MIC) was determined according to the standard broth microdilution method. Some Candida albicans isolates showed resistance or dose-dependent susceptibility for the azolic drugs and Amphotericin B. Non-C. albicans isolates showed more resistance and dose-dependent susceptibility for the azolic drugs than C. albicans. However, all of them were sensitive or dose dependent susceptible for Amphotericin B. All yeasts were inhibited by PE and PMs, with small variation, independent of the species of yeast. The overall results provided important information for the potential application of PMs in the therapy of VVC and the possible prevention of the occurrence of new symptomatic episodes. PMID- 21607013 TI - Bacopa monniera Attenuates Scopolamine-Induced Impairment of Spatial Memory in Mice. AB - Scopolamine, an anticholinergic, is an attractive amnesic agent for discerning the action of candidate antiamnesic drugs. Bacopa monniera Linn (Syn. Brahmi) is one such antiamnesic agent that is frequently used in the ancient Indian medical system. We have earlier reported the reversal of diazepam-induced amnesia with B. monniera. In this study we wanted to test if scopolamine-induced impairment of spatial memory can also be ameliorated by B. monniera using water maze mouse model. The objective of study was to study the effect of B. monniera on scopolamine-induced amnesia. We employed Morris water maze scale to test the amnesic effect of scopolamine and its reversal by B. monniera. Rotarod test was conducted to screen muscle coordination activity of mice. Scopolamine significantly impaired the acquisition and retrieval of memory producing both anterograde and retrograde amnesia. Bacopa monniera extract was able to reverse both anterograde and retrograde amnesia. We propose that B. monniera's effects on cholinergic system may be helpful for developing alternative therapeutic approaches for the treatment of Alzheimer's disease. PMID- 21607015 TI - Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the Surveillance, Epidemiology and End Results Program. AB - BACKGROUND: The role of histology in the targeted management of nonsmall cell lung cancer (NSCLC) has garnered renewed attention in recent years. We provide contemporary population-based estimates of survival and an assessment of important prognostic factors in stage IV NSCLC by major histologic subtype. METHODS: Using data from the Surveillance, Epidemiology and End Results (SEER) Program, we stratified 51,749 incident stage IV NSCLC patients (1988-2003 with follow-up through 2006) by major histologic subtype. We used Kaplan-Meier and Cox proportional hazards methods to describe overall survival and the prognostic influence of select patient, tumor, and treatment characteristics for each histologic subgroup. RESULTS: Survival was highest in patients with bronchioloalveolar adenocarcinoma (1-year survival: 29.1%) and lowest in those with large cell tumors (1-year survival: 12.8%). Diagnosis in later years, female gender, younger age, either Asian/Pacific Islander or Hispanic race/ethnicity, lower tumor grade, and surgery or beam radiation as part of first-line treatment were generally independently associated with a decreased risk of death, but the prognostic significance of some of these factors (age, ethnicity, tumor grade) varied according to histologic subtype. CONCLUSION: Findings demonstrate a poor prognosis across histologic subtypes in stage IV NSCLC patients but highlight differences in both absolute survival and the relative importance of select prognostic factors by histologic subclassification. More research using other sources of population-based data could help clarify the role of histology in the presentation, management, and prognosis of late-stage NSCLC. PMID- 21607016 TI - Use of prescribed drugs among primiparous women: an 11-year population-based study in Denmark. AB - PURPOSE: To describe patterns of prescribed drug use over time among primiparous women in Denmark. METHODS: Through the Danish Medical Birth Registry, we identified all primiparous women giving live birth or stillbirth at >= 22 gestational weeks in northern Denmark, from 1999 to 2009. From the Aarhus University Prescription Database we obtained information on the women's prescriptions for reimbursed drugs filled from 30 days before conception until delivery. RESULTS: Among 85,710 primiparous women, 47,982 (56.0%) redeemed at least one prescription from 30 days before conception until delivery. Women aged 35 years and older had the highest overall prevalence of prescription drug use (61.1%). Age-standardized prevalence of drug use was 54.7% in 1999 and 61.2% in 2009, prevalence ratio (PR) of 1.13 (95% confidence interval 1.10; 1.16), adjusted for age and smoking. CONCLUSION: Over the 11-year period from 1999 to 2009, we found a modest increase in overall use of drugs by primiparous women in Denmark. This increase was not, however, explained by an increasing proportion of older first-time mothers. We noted changes in patterns of use of anti-infective drugs and antidepressants. PMID- 21607017 TI - Appraising relative and excess mortality in population-based studies of chronic diseases such as end-stage renal disease. AB - PURPOSE: Modeling excess and relative mortality represents two ways of considering general population mortality rates (ie, background mortality) in cohort studies. Excess mortality is obtained by subtracting the expected mortality from the observed mortality (additive hazard model). Relative mortality is obtained by dividing the observed mortality by the expected mortality (multiplicative hazard model). Our first objective was to compare the results of these two models in a population-based cohort including 5115 dialyzed patients older than 70 years (mean age 79 years, range 70-97 years). Our second objective was to explore an alternative model combining both excess and relative mortality. PATIENTS AND METHODS: Effects of covariates on excess mortality and relative mortality were assessed using a generalized linear model and a Cox model, respectively. The model, combining both excess and relative mortality, is derived from the Aalen model. RESULTS: The effect of age and sex was different according to the additive or multiplicative model used, whereas the effect of the first modality of dialysis or the primary nephropathy was similar. Because there was no evidence of lack of fit, the choice of one of these two models was not obvious. The combined model showed that the two components, additive and multiplicative, had to be kept. In this case, the combined model led to results similar to the pure additive and multiplicative univariate models, except for the method of dialysis, which did not exert an effect on both excess and relative mortality. CONCLUSION: We underlined the complementary interest of modeling excess and relative mortality in looking for factors associated with mortality related to end-stage renal disease. The combined model appeared attractive in offering the possibility of reducing the model to the most appropriate one. When both components have to be retained, it better describes the effect of covariates on excess and relative mortality. PMID- 21607018 TI - Targeting nicotine addiction: the possibility of a therapeutic vaccine. AB - Cigarette smoking is the primary cause of lung cancer, cardiovascular diseases, reproductive disorders, and delayed wound healing all over the world. The goals of smoking cessation are both to reduce health risks and to improve quality of life. The development of novel and more effective medications for smoking cessation is crucial in the treatment of nicotine dependence. Currently, first line smoking cessation therapies include nicotine replacement products and bupropion. The partial nicotinic receptor agonist, varenicline, has recently been approved by the US Food and Drug Administration (FDA) for smoking cessation. Clonidine and nortriptyline have demonstrated some efficacy, but side effects may limit their use to second-line treatment products. Other therapeutic drugs that are under development include rimonabant, mecamylamine, monoamine oxidase inhibitors, and dopamine D3 receptor antagonists. Nicotine vaccines are among newer products seeking approval from the FDA. Antidrug vaccines are irreversible, provide protection over years and need booster injections far beyond the critical phase of acute withdrawal symptoms. Interacting with the drug in the blood rather than with a receptor in the brain, the vaccines are free of side effects due to central interaction. For drugs like nicotine, which interacts with different types of receptors in many organs, this is a further advantage. Three anti nicotine vaccines are today in an advanced stage of clinical evaluation. Results show that the efficiency of the vaccines is directly related to the antibody levels, a fact which will help to optimize the vaccine effect. The vaccines are expected to appear on the market between 2011 and 2012. PMID- 21607019 TI - Emerging strategies and therapies for treatment of Paget's disease of bone. AB - Paget's disease of bone (PDB) is a progressive monostotic or polyostotic metabolic bone disease characterized by focal abnormal bone remodeling, with increased bone resorption and excessive, disorganized, new bone formation. PDB rarely occurs before middle age, and it is the second most frequent metabolic bone disorder after osteoporosis, affecting up to 3% of adults over 55 years of age. One of the most striking and intriguing clinical features is the focal nature of the disorder, in that once the disease is established within a bone, there is only local spread within that bone and no systemic dissemination. Despite many years of intense research, the etiology of PDB has still to be conclusively determined. Based on a detailed review of genetic and viral factors incriminated in PDB, we propose a unifying hypothesis from which we can suggest emerging strategies and therapies. PDB results in weakened bone strength and abnormal bone architecture, leading to pain, deformity or, depending on the bone involved, fracture in the affected bone. The diagnostic assessment includes serum total alkaline phosphatase, total body bone scintigraphy, skull and enlarged view pelvis x-rays, and if needed, additional x-rays. The ideal therapeutic option would eliminate bone pain, normalize serum total alkaline phosphatase with prolonged remission, heal radiographic osteolytic lesions, restore normal lamellar bone, and prevent recurrence and complications. With the development of increasingly potent bisphosphonates, culminating in the introduction of a single intravenous infusion of zoledronic acid 5 mg, these goals of treatment are close to being achieved, together with long-term remission in almost all patients. Based on the recent pathophysiological findings, emerging strategies and therapies are reviewed: ie, pulse treatment with zoledronic acid; denosumab, a fully human monoclonal antibody directed against RANK ligand; tocilizumab, an interleukin-6 receptor inhibitor; odanacatib, a cathepsin K inhibitor; and proteasome and Dickkopf-1 inhibitors. PMID- 21607021 TI - Five-year extension of a clinical trial comparing the EX-PRESS glaucoma filtration device and trabeculectomy in primary open-angle glaucoma. AB - BACKGROUND: This study compared the efficacy of the EX-PRESS((r)) glaucoma filtration device and trabeculectomy in primary open-angle glaucoma up to five years after surgery. METHODS: Patients from a previously reported randomized, open-label, parallel-arm clinical trial in which 78 patients received either the EX-PRESS glaucoma filtration device or underwent a trabeculectomy were followed for up to an additional four years (five total) beyond the original study (39 eyes per treatment group). Risk-benefit data were obtained for up to five years after glaucoma surgery. Outcome variables were intraocular pressures and intraocular pressure medications. Complete success was denoted by intraocular pressure values <= 18 mmHg without medication. RESULTS: The EX-PRESS glaucoma filtration device controlled intraocular pressure more effectively without medication for more patients from year 1 (86.8% versus 61.5%, P = 0.01) to year 3 (66.7% versus 41.0%, P = 0.02) than trabeculectomy. At year 1, only 12.8% of patients required intraocular pressure medication after EX-PRESS implantation, compared with 35.9% after trabeculectomy. The proportions became closer at year 5 (41% versus 53.9%). The responder rate was higher with EX-PRESS and time to failure was longer. In addition, surgical interventions for complications were fewer after EX-PRESS implantation. CONCLUSION: This five-year analysis confirmed and extended the results reported after one year. Compared with trabeculectomy, EX-PRESS provided better intraocular pressure control in the first three years, and patients required fewer intraocular pressure medications and fewer surgical interventions during the five-year study period. For patients with primary open angle glaucoma, the EX-PRESS glaucoma filtration device, implanted under a superficial scleral flap, produced significantly higher success rates than trabeculectomy. EX-PRESS is an effective device for long-term treatment of primary open-angle glaucoma. PMID- 21607020 TI - Available and emerging treatments for Parkinson's disease: a review. AB - Parkinson's disease is a commonly encountered neurodegenerative disorder primarily found in aged populations. A number of medications are available to control symptoms, although these are less effective in advanced disease. Deep brain stimulation provides a practicable alternative at this stage, although a minority of patients meet the strict criteria for surgery. Novel medications that provide enhanced symptomatic control remain in developmental demand. Both gene and cell-based therapies have shown promise in early clinical studies. A major unmet need is a treatment that slows or stops disease progression. PMID- 21607022 TI - A case of oculomotor nerve palsy associated with antimitotic spindle apparatus. AB - In this case report, we describe a case of isolated oculomotor nerve palsy associated with antibodies to mitotic spindle apparatus (anti-MSA). A 28-year-old female patient had acute, painful vertical diplopia. She had limited depression and adduction in the right eye. There was no relative afferent pupillary defect. Brain magnetic resonance imaging showed no abnormal findings. Laboratory tests were all negative, with the exception of positive anti-MSA, She had an excellent and rapid response to treatment with corticosteroids, and completely recovered after two weeks of steroid pulse therapy. PMID- 21607023 TI - Tumor necrosis factor-alpha (TNF-alpha) levels in aqueous humor of primary open angle glaucoma. AB - PURPOSE: Tumor necrosis factor alpha (TNF-alpha), a macrophage/monocyte derived pluripotent cytokine is associated with tissue ischemia, neuronal damage and remodeling. The physiological level of TNF-alpha in aqueous humor of normal and glaucomatous eyes is unknown. In this study, we evaluated the TNF-alpha levels in aqueous in patients with primary open angle glaucoma (POAG) and compared them to controls. METHODS: 50-100 MUL of undiluted aqueous humor samples were obtained from eyes of 32 POAG patients who underwent cataract extraction, trabeculectomy or aqueous shunt implantation. Controls were obtained from 32 normal subjects who underwent routine cataract surgery. TNF-alpha levels were quantified using singleplex bead immunoassay analysis. RESULTS: The average TNF-alpha level in POAG samples was 2.72 +/- 1.5 pg/mL (mean +/- SD). The average TNF-alpha level in normal samples was 1.59 +/- 0.46 pg/mL (mean +/- SD). Significant increase of TNF alpha levels in POAG samples was noted in comparison to normal samples (P < 0.001). CONCLUSION: TNF-alpha levels are elevated in aqueous in patients with POAG compared to normal subjects based on highly sensitive Luminex((r)) bead immunoassay and may be a reliable biomarker in the progression of glaucoma. PMID- 21607024 TI - Usher syndrome associated with Fuchs' heterochromic uveitis: a case report. AB - We report a case of Usher syndrome in association with unilateral Fuchs' heterochromic uveitis. PMID- 21607025 TI - Indications for destructive eye surgeries at the Yaounde Gynaeco-Obstetric and Paediatric Hospital. AB - OBJECTIVE: To determine the indications and rate of acceptance for destructive eye surgeries at the ophthalmology unit of the Yaounde Gynaeco-Obstetric and Paediatric Hospital. METHODS: A retrospective consecutive case series in which the medical records of all patients consulting in this unit over a 9-year period (2002 to 2010) were reviewed. Records in which destructive surgery was recommended were retained. Information collected included demographic data, eye affected, clinical diagnosis, acceptance or refusal of surgery, and the outcome in those in whom surgery was performed. RESULTS: A total of 48 patients had a recommendation for destructive eye surgery, of whom 30 (62.5%) were males and 18 (37.5%) were females. Mean age was 43.78 (SD = 28.11; range 1 month to 91 years). Children <10 years comprised 23.10%. The leading causes were endophthalmitis/panophthalmitis (47.9%), neoplasm (20.8%), and absolute glaucoma (14.6%). Surgery was done in 20 cases (41.7%). Evisceration was the most performed surgical procedure (50%), with endophthalmitis/panophthalmitis and neoplasm combined accounting for 65% of surgeries. CONCLUSION: The high rate of refusal is an indication of the psychological devastation undergone by patients or the families of children in whom eye removal is recommended. Awareness should be raised on preventive measures and the need to rapidly seek eye care. PMID- 21607026 TI - Electrophysiologic changes after intravitreal ranibizumab injection for the treatment of choroidal neovascular membrane (CNVM). AB - PURPOSE: To determine the pattern of electroretinographic change after an intravitreal ranibizumab (Lucentis((r))) injection for the treatment of choroidal neovascular membrane (CNVM). PATIENTS AND METHODS: A prospective interventional case series of patients treated by intravitreal ranibizumab injection. Best corrected visual acuity, optical coherence tomography (OCT), and multifocal electroretinography (mfERG) were assessed prior to treatment, and 2 weeks, 1 and 3 months after treatment. Primary outcome was the functional change in amplitude and implicit time by mfERG and secondary outcome was the structural change in macular thickness by optical coherence tomography (OCT). RESULTS: Twenty-six eyes from 25 consecutive patients were enrolled. At 3 months after treatment, the mean visual acuity (VA) improved from 1.06 to 0.84 logMAR (P = 0.034) and the mean macular thickness decreased from 389.7 to 264.4 microns (P = 0.003). The mean implicit time of the central zone showed an improvement at 3 months after treatment when compared with the response at baseline (P = 0.024) and at 1 month (P = 0.013) but the mean amplitude showed no significant change. In subgroup analysis, the eyes with initial visual acuity (VA) >= 20/200 had a significant improvement in mean implicit time of the peripheral zone at 2 weeks after treatment (P = 0.028). The OCT revealed a significant decrease (P < 0.003) in macular thickness at 1 and 3 months postoperatively. CONCLUSION: The mean implicit time of the central zone improved significantly at 3 months after treatment, whereas the mean amplitude showed no significant change. The macular thickness decreased significantly after the treatment, while VA improved to a lesser extent. PMID- 21607027 TI - Cerebellar ataxia with complete clinical recovery and resolution of MRI lesions related to central pontine myelinolysis: case report and literature review. AB - There are several reports of central pontine myelinolysis (CPM) in a setting of malnutrition, alcoholism, and chronic debilitating illness associated with electrolyte abnormalities, especially hyponatremia. The cause of myelinolysis is still under debate, and, although osmotic effects are thought to be responsible in most cases, alternative pathological factors should be considered [King et al.: Am J Med Sci 2010;339:561-567]. We report a case of CPM in a patient with recent chemotherapy for colon cancer without electrolyte unbalance and otherwise unexplained causes. Moreover, the present case is an example of the unusual clinical ataxic variant, followed by complete recovery without any specific treatment. The diagnosis was confirmed by MRI, which showed a characteristic hyperintense signal abnormality in the central part of the pons with an unaffected outer rim. One month later, we observed complete resolution of clinical and radiological symptoms. PMID- 21607028 TI - A new paradigm in the treatment of the cardiovascular disease continuum: focus on prevention. AB - The cardiovascular disease continuum (CVDC) is a sequence of cardiovascular events, which begins from a cluster of cardiovascular risk factors consisting of diabetes mellitus, dyslipidemia, hypertension, smoking and visceral obesity. If these factors are not intervened with early, they will, inexorably, progress to atherosclerosis, coronary artery disease, myocardial infarction, left ventricular hypertrophy, left ventricular dilatation leading to left ventricular diastolic or systolic dysfunction and eventually end stage heart failure and death. For this concise review, a Medline search of the English language literature between the years 2000 and 2009 was conducted and 33 pertinent publications were selected. Based on the evidence contained in these publications, it is possible that early intervention and treatment of the various cardiovascular risk factors, which initiate and perpetuate the CVDC, could prevent it or arrest its further progress. Therefore, this concise review will emphasize the early detection and treatment of the various cardiovascular risk factors, which initiate and perpetuate the CVDC. PMID- 21607030 TI - Adipogenesis and osteoblastogenesis: trans-differentiation in the pathophysiology of bone disorders. AB - Mesechymal stem cells as pluripotent cells are involved in the differentiation of adipocytes under regulation of genes and transcription factors. The plasticity observed between adipocytes and osteoblasts differentiation is the basis of transdifferentiation, observed in both experimental and clinical level. This review analyzes not only the adipose tissue as an endocrine organ but also the underlying mechanism of trans-differentiation between adipocytes and osteoblasts. Fat and bone tissue interaction is altered by activation or silencing of genes, signaling molecules and transcription factors. Disorders of this interaction include ectopic ossification syndromes and other bone disorders like osteoporosis and multiple myeloma. Further research will reveal the instinct mechanisms of this imbalance in the pathophysiology of many metabolic disorders such as diabetes mellitus, atherogenesis e.t.c. PMID- 21607029 TI - Infections in hemodialysis: a concise review - Part 1: bacteremia and respiratory infections. AB - Hemodialysis (HD) patients are particularly predisposed to infections. It seems that the HD procedure per se as well as disturbances in both innate and adaptive immunity significantly contribute to this susceptibility. Infections are the major cause of morbidity and the second cause of death following cardiovascular events in HD patients. Episodes of bacteremia and pneumonia account for the majority of severe infections in this population. In addition to these bacterial infections another common problem in HD units is the blood transmitted viral infections, particularly infections caused by hepatitis B virus, hepatitis C virus and Human immunodeficiency virus. A number of safety concerns exist for limiting the spread of these viral infections among HD patients and the staff of the unit. The aim of the present review is to present in a concise albeit practical form the difficult aspect of infections in HD. For practical reasons the review is separated in two parts. The present first part covers bacteremia and respiratory infections, while the second part will cover blood transmitted viral infections. PMID- 21607031 TI - Oscillating LDL accumulation in normal human aortic arch - shear dependent endothelium. AB - OBJECTIVE: Abnormal mass transfer of blood components to the arterial walls initiates atherosclerosis. Understating the role of mass transfer within the arterial walls requires quantitative analysis. The oscillating lipid accumulation in the aortic wall is examined in the normal human aortic arch with shear dependent endothelium properties. METHODS: A semi-permeable nature of the arterial wall computational model, applied in the normal human aortic arch under unsteady normal flow and mass conditions, is incorporated with hydraulic conductivity and permeability treated as wall shear stress dependent. The coupling of fluid dynamics and solute dynamics at the endothelium was achieved by the Kedem-Katchalsky equation. A typical aortic arch blood flow waveform at resting conditions and lasting 800 msec is applied. RESULTS: With constant values of water infiltration and endothelial permeability the surface vertex average normalized luminal concentration is 4.25 % higher than that at the entrance. With shear dependent values the surface vertex average normalized luminal concentration is 7.3 % higher than at the entrance. The luminal surface concentration at the arterial wall is flow-dependent with local variations due to geometric features. Concave sides of the aortic arch exhibit, relatively to the convex ones, elevated low density lipoprotein at all time steps. CONCLUSIONS: The degree of elevation in luminal surface LDL concentration is mostly affected from the water infiltration velocity at the vessel wall. Shear dependent endothelial values must be taken into account whenever fluid and mass flow within the arterial system is incorporated. PMID- 21607032 TI - Significant epidemiological changes in chronic hepatitis C infection: results of the nationwide HEPNET-GREECE cohort study. AB - BACKGROUND AND AIMS: Hepatitis C virus (HCV) infection is an important health problem worldwide. The aim of the study is to describe the baseline characteristics and possible epidemiological changes of the patients with chronic HCV infection included in a nationwide Greek study. PATIENTS AND METHODS: two thousand eight hundred seventeen (2817) patients, followed-up at 20 hepatology centres throughout Greece between the years 1997 and 2006 were enrolled in the study. RESULTS: Intravenous drug use (IDU) and history of blood transfusion prior to 1992 was reported in 30.7% and 22.6% of our patients, respectively. In 1865 (66.2%) patients with known genotypes, the distribution for genotype 1, 2, 3 and 4 was 45.1%, 7%, 34% and 13.9% respectively. Genotype 1 was more common in older people, in women (55.9% p<0.001) and patients with transfusion-related hepatitis (61.6% p<0.001). Genotype 3 was more common in younger patients, in men (43% p<0.001) and in IDUs (63.3% p<0.001). A significant reduction of transfusion related hepatitis C incidence (p<0.001) in conjunction with the proportion of genotype 1 (p<0.001) was observed during the last three decades while an increase in IDU infected patients and genotype 3 was detected. CONCLUSIONS: Our study showed a significant change in HCV genotype distribution and source of HCV infection during the last three decades and under that scope, urgent actions are needed in order to control the spread of HCV infection. PMID- 21607033 TI - Analysis of fatal motor vehicle collisions: evidence from Central Macedonia, Greece. AB - BACKGROUND: The objective of this study was to assess the factors associated with the traffic mortality in the region of Central Macedonia in order to produce evidence in building up preventive policies. MATERIAL AND METHODS: This study is a descriptive survey covering a three-year period (from 01-01-2006 to 31-12- 2008). The data used were supplied by the regional Road Traffic Police Service in Thessaloniki. RESULTS: A total of 280 fatal vehicle collisions were recorded in three years, in which 312 people died. 266 (85.26%) of the 312 people who died were men and 46 (14.74%) were women. The victims were between 1 and 91 years of age (mean +/- SD, 42.00 +/- 20.36 years). More fatal vehicle collisions were recorded on weekends and holidays than weekdays. Regarding the type of the vehicle, occupants of two-wheeled motor vehicles were in greater risk for dying compared to heavy duty vehicle passengers, who are considered to be protected by the vehicle. Among the 312 fatalities, alcohol was detected in 87 (28%) of the drivers who were responsible for the collision. Most of them (56/86, 64.4%) were between 15 and 44 years of age. In 6 (1.9%) cases, all of them drivers, illicit substances were detected. Vehicle collisions with younger victims were recorded during the early morning hours, whereas older people died more frequently during daytime. CONCLUSIONS: The findings of this study are providing evidence for the design and implementation of concrete and urgently needed preventive strategies in order to control the almost completely preventable fatalities of the road crashes. PMID- 21607034 TI - Radionuclide imaging with human polyclonal immunoglobulin (Tc-HIG) and bone scan in patients with rheumatoid arthritis and serum-negative polyarthritis. AB - BACKGROUND AND AIM: Rheumatoid arthritis (RA) is a chronic polyarthritic syndrome in which actively inflamed joints coexist with others being in remission. Compatible bone scan (BS) reveals joints with increased activity due to degenerative alterations, whilst scanning with human polyclonal immunoglobulin (HIG) is capable to show which of the joints present active inflammation of the synovial membrane. The aim of the study is to investigate the utility of molecular imaging with HIG in patients suffering from RA. PATIENTS AND METHODS: Forty patients (9 males plus 31 females), suffering from painful polyarthritic syndrome, with a mean age 45.3+/-7 years and a duration of disease 18.3+/-4.2 months were enrolled in the study. Twenty-six of the patients were serum positive to RA factor, considered as suffering from RA, whilst fourteen of them were RA factor negatives and they were considered as patients with serum-negative polyarthritis. All patients were submitted to x-rays and ultrasound examination (US) in joints of interest, plus whole body BS with (99m)Tc-MDP and finally scan with (99m)Tc-HIG. RESULTS: A total of 1680 joints have been evaluated. In 6 of the patients-two with serum negative RA (252 joints), radionuclide imaging with HIG was within normal limits, despite the fact that in compatible bone scan degenerative alterations have been mentioned in 30 joints. In all these patients disease was evaluated as inactive ("arthrotic changes"). In the remaining 34 patients-12 with serum negative RA (1428 joints), increased accumulation of HIG, concerning serum positive patients, has been mentioned to 163 joints ("arthritic changes"), whilst in the same group, BS revealed degenerative changes to 265 joints. Concerning serum negative patients, the respective results were 64 versus 190 joints. Increased uptake of HIG has been found in 189/226 swollen and painful joints (overall sensitivity according to clinical criteria 83.3%) and in 38 joints without any clinical evidence of inflammation, with clinical active inflammation presented after follow-up to 35 of them, yielding thus specificity at the level of 92%. Matched findings between these two methods have been mentioned to 185 out of 227 joints with an abnormal scan with HIG. Abnormal x rays and US findings have been mentioned in 67 of the joints. CONCLUSIONS: According to the above mentioned, BS in RA reveals joints being actively inflamed or not, whilst radionuclide study with HIG is capable to distinguish actively inflamed joints, even in patients with serum negative RA, in a greater extent than anatomical imaging modalities. PMID- 21607035 TI - Alterations of bone mineral metabolism of children with different cell lineage types of acute lymphoblastic leukaemia under chemotherapy. AB - BACKGROUND: Children with haematological malignancies such as acute lymphoblastic leukaemia (ALL) may have alteration of bone mineral metabolism therefore increased risk for osteopenia and osteoporosis. PATIENTS AND METHODS: The purpose of this study was to examine the alterations of bone mineral metabolism in two groups of children (n=42) according to immunophenotyping (B-cell type, T-cell type) both quantitative (bone mineral density z-scores) and qualitative (serum osteocalcin - OC and carboxyl-terminal telopeptide of human type I collagen - ICTP) during diagnosis (T=0), after the intensified chemotherapy period (T=0.5) and the consolidation period (T=1). RESULTS: According to our results 15 patients had osteopenia and 1 child developed osteoporosis at T=0.5 and 13 patients had osteopenia at T=1. Mean BMD z-score was significantly decreased in both groups during chemotherapy and especially statistically significant decline of T-cell type ALL group compared with B-cell type ALL patients. OC mean level remains in low levels for both groups reaching in plateau during chemotherapy and ICTP level was increased in T-cell type ALL group of patients compared with B-cell type in both periods of chemotherapy. CONCLUSIONS: It seems that not only the combination of chemotherapeutic agents but also the cell lineage of ALL are important parameters of altering bone mineral metabolism. PMID- 21607036 TI - Prevalence of overweight and abdominal obesity in Greek children 6-12 years old: Results from the National Epidemiological Survey. AB - OBJECTIVE: To provide estimates of overweight (OW), obesity (OB) and abdominal obesity (AO) in a sample of children throughout the whole of Greece. MATERIAL AND METHODS: This epidemiological, cross-sectional survey examined 3,140 children aged 6-12 y (1,589 boys and 1,551 girls) who were selected by stratified sampling through household family members of Greek adolescents attending school. Participants reported data on height, weight and waist circumference (WC). BMI and Waist-to-Height ratio (WHtR) were calculated. AO was estimated using WC and WHtR. RESULTS: Overall prevalence of OW including OB was 31.2% in boys and 26.5% in girls, while OB prevalence was 9.4% and 6.4% respectively. The prevalence of AO based on WC (AO-WC), was similar in girls (14.2%) and boys (12.5%) while the prevalence of AO, based on WHtR (AO-WHtR), was higher in boys than in girls (25.6% vs 20.0%, p<0.0001). With increasing age, the prevalence of OW and OB decreases in both genders, and AO-WHtR only in girls. Rates of OW were significantly more prevalent in Greeks than in immigrants. CONCLUSIONS: Overweight and obesity in Greek children is very prevalent, particularly in boys, comparable with that reported for Mediterranean European countries. Abdominal obesity also appears high. Preventive and treatment strategies are urgently needed to combat this national epidemic. PMID- 21607037 TI - Factors influencing bone loss in paraplegia. AB - BACKGROUND AND AIM: Significant bone loss develops in the first months and continues years after spinal cord injury. A cross - sectional comparative study was performed to evaluate factors influencing bone loss in spinal cord injured men with paraplegia. PATIENTS AND METHODS: We studied 31 paraplegic men in chronic stage (>1.5 years) in comparison with 30 able-bodied men of similar age, height, and weight. The paraplegic men were allocated into 2 subgroups based on the neurological level of injury; high paraplegics (n=16, T4-T7 neurological level of injury) and low paraplegics (n=15, T8-T12 neurological level of injury). The influence of positive and negative factors (spasticity, standing-therapeutic walking, and duration of paralysis) on bone structures was evaluated by pQCT measurement of the total, trabecular and cortical bone mineral density (BMDtot, BMDtrab, BMDcort, respectively) and cortical thickness (THIcort) at the distal tibial epiphysis and the tibial diaphysis at 4% and 38% proximal to the distal end of the tibia. The stress strain index (SSI) was measured at 14% (SSI(2)) and at 38% (SSI(3)) of the tibial diaphysis, and the difference SSI(3) - SSI(2) (deltaSSI(3-2)) was calculated. RESULTS: In all paraplegics, bone mineral density parameters were significantly reduced compared to the control group (BMDtot: p<0.0005, BMDtrab: p<0.0005, BMDcort: p=0.029, THIcort: p=0.019, SSI(2): p=0.009, SSI(3): p=0.003, respectively). Paraplegics who used standing frames or long brace orthoses had statistically significant higher bone mass and geometric parameters (BMDtrab: p=0.03, BMDtot: p=0.01, THIcort: p=0.013, respectively), while spasticity did not protect bone. The duration of paralysis was significantly related to trabecular bone loss (r=-0.5, p=0.05) and cortical thickness (r=-0.6, p=0.006) in high paraplegics and to deltaSSI(3-2) in low paraplegics (r=0.534, p=0.03). CONCLUSIONS: The neurological level of injury adversely affects bone strength in paralyzed lower extremities such as the distal tibia. Standing or therapeutic walking could possibly have a positive effect in cortical and trabecular bone in paraplegia. PMID- 21607038 TI - Clinical applications of intravascular ultrasound (IVUS): experience from an academic high volume centre of Northern Greece. AB - BACKGROUND: Intravascular ultrasound (IVUS) has become a valuable tool adjunctive to coronary angiography due to its ability to directly image atheroma and the vessel wall. We aimed to evaluate the use of IVUS during diagnostic angiography and coronary interventions in a coronary intervention academic high volume center of northern Greece. PATIENTS AND METHODS: IVUS studies have been retrospectively retrieved from 2005 to 2008 from the archives of the catheterization laboratory of our department. IVUS was performed in 403 patients (294 male) of mean age 62+/ 6 years. Indications for coronary angiography +/- intervention were acute coronary syndromes (49%), stable angina (46%) and previous coronary angioplasty evaluation (5%). RESULTS: Forty eight per cent of the IVUS studies were performed in left anterior descending artery (LAD), 25% in right coronary artery (RCA), 18% in left circumflex artery (LCx), and the rest (9%) in left main coronary artery (LMCA) or in coronary branches. Indications for performing an IVUS study were assessment of intermediate lesions (60%), evaluation of stent placement (36.5%), and determination of stent restenosis aetiology (3.5%). Among studies performed for assessment of intermediate lesions, 63% showed a non critical stenosis. IVUS after coronary stenting revealed a suboptimal stent placement in 77% of the cases, while in cases of stent restenosis, IVUS showed inadequate initial stent deployment in 43% of the patients. CONCLUSIONS: The use of IVUS in our department has contributed to the optimization of intervertional treatment of coronary lesions by means of evaluating borderline lesions, stenting placement and stent restenosis. PMID- 21607039 TI - Contractility evaluation by 2 dimensional echocardiography and gated SPECT myocardial perfusion scintigraphy in hypertensive patients with clinical presentation of atypical chest pain. AB - BACKGROUND: Hypertension (HT) is a growing health problem in the population and associated with increased cardiovascular event risk and mortality. In hypertensive patients, progressive left ventricular (LV) contractility deterioration is detectable by gated single photon emission computed tomography (SPECT) myocardial perfusion scintigraphy9. We planned this study to explore the agreement in ejection fraction (EF) determination between 2 dimensional echocardiography and gated SPECT analysis in selected group of patients with hypertension. PATIENTS AND METHODS: We studied 26 consecutive patients (mean age 56.5 +/- 8.8 years; 6 men) with hypertension. Quantitative contractility analysis by both echocardiography and SPECT at rest was performed to investigate the agreement between two diagnostic tests. RESULTS: EF at rest was greater than 55 % in all patients. All patients had a clinical presentation of atypical chest pain. Therefore, in addition to quantitative contractility analysis at rest by echocardiography and myocardial SPECT perfusion scintigraphy, we examined ischemia by stress induction and determined that 10 patients had ischemic finding (38.4 %). The mean value of EF calculated by echocardiography was 67.5 +/- 5.7 %, while EF by gated SPECT was 72.8 +/- 8.5 %. We documented an acceptable agreement in EF determination between these 2 diagnostic tests by meaningful correlation (r = 0.556, p = 0.003). There was no regional contractility deterioration despite existence of ischemia in 10 patients of the study group. CONCLUSIONS: We observed that both echocardiography and gated SPECT can be used for quantification of EF in the hypertensive patients with an acceptable agreement. PMID- 21607040 TI - Comparison between low flow sevoflurane anesthesia and total intravenous anesthesia during intermediate-duration surgery: effects on renal and hepatic toxicity. AB - BACKGROUND: Renal and hepatic dysfunction or injury might be involved by ether based anesthetic and intravenous anesthetic drug or surgical stress. The purpose of this study is to compare the effect of moderate duration low-flow sevoflurane versus total intravenous anesthesia on renal and hepatic functions. PATIENTS AND METHODS: Eighty (80) patients between the ages of 25-70 scheduled for elective lumbar disc herniotomy, with an expected operation time of 120-240 min, were enrolled in the study. Anesthesia was induced using remifentanil, propofol and atracurium. Patients were randomly divided into two groups. After intubation, Group S (n=40) received sevoflurane and Group T (n=40) received total intravenous anesthesia with propofol in oxygen and air with a fresh gas flow of 5 L min(?1). Ten minutes after induction the fresh gas flow was decreased to 1L min(?1) in both groups. Serum BUN, creatinine, ALT, AST, LDH and 24 hours excretion of glucose, protein, and creatinine in urine were measured preoperatively and the first three postoperative days. RESULTS: Serum BUN at 48 hours, creatinine at 24, 48. hours, and urine glucose at 24, and 48 hours were significantly higher from the preoperative values in Group S (p<0.05). However, serum BUN and creatinin, urine glucose were within the normal range. There were no significant differences in the renal and hepatic function tests between the groups. CONCLUSIONS: These results show that the renal and hepatic effect of moderate duration low-flow sevoflurane and total intravenous anesthesia is similar. PMID- 21607041 TI - The role of tumor size and patient's age as prognostic factors in laryngeal cancer. AB - BACKGROUND AND AIM: The loco-regional recurrence of laryngeal carcinoma in patients who underwent total laryngectomy is related to numerous factors. Aim of the present study was to investigate the role of patient's age and tumor size in the recurrence rate of patients. Additional aim of the current study was to investigate the possible associations between the size of the tumor and other characteristics. PATIENTS AND METHODS: In 1st Department of Otorhinolaryngology of AHEPA University Hospital, from 1992 to 2007, 255 patients with laryngeal carcinoma underwent total laryngectomy. Accurate data regarding the size of the tumor were obtained. Total laryngectomy was the initial treatment in 212 patients, while in the remaining 43 patients was performed as salvage surgery after recurrence. RESULTS: The median tumor size was 2.74 cm (0.8-5.5 cm). There was no significant difference in the median tumor size between the patients who had recurrence (2.87 cm) and the disease free patients (2.69 cm). The median size of glottic tumors (2.47 cm) was smaller than that of supraglottic (2.95 cm) and of subglottic tumors (3.27 cm) (p<0.05). Among the 255 patients, recurrence of the tumor occurred in 73 (28.7%). Statistical analysis of the data showed that the tumor size was affecting the recurrence rate in a different manner, according the stage of the tumor. The recurrence rate in T3 neoplasms was higher in larger tumors than in smaller (13.2% for tumors<2cm, 62% for tumors>4cm), while T4 carcinomas appeared to have the opposite behavior (66.5% for tumors <2cm, 23% for tumors >4cm). The median tumor size in T4 patients that recurred was smaller than in those with no recurrence (2.8 cm Vs 3.3 cm). This behavior was observed in T4 tumors from all sites. Patients who experienced recurrence and had positive neck lymph nodes at the time of the initial diagnosis appeared to have smaller laryngeal tumors (2.7 cm), compared to with the same group of patients with no recurrence (3.5 cm). Supraglottic location and advanced T stage showed a statistically significant impact on disease free survival, based on Cox regression model. CONCLUSIONS: Smaller sized tumors in patients with locally advanced laryngeal cancer (T4) or regionally (N+) appear to have more aggressive behavior and higher recurrence rate. Thus, the small tumor size could be regarded as an unfavorable prognostic factor for those laryngeal cancer cases. PMID- 21607042 TI - Use of propranolol in infantile haemangiomas: report of five cases and review of the literature. AB - Infantile haemangiomas are common benign tumours that do not require treatment unless they cause significant functional impairment or disfigurement. We report our experience with the off-label use of propranolol in 5 children with haemangiomas and review the relevant literature. PMID- 21607043 TI - Breast ductal carcinoma and metastatic lymphoma to the contralateral breast in patient with cutaneous non-Hodgkin lymphoma. AB - Breast lymphoma is a rare condition, both as a primary and a metastatic manifestation. The primary form has an incidence ranging from 0.04% to 0.5% of all breast neoplasms, whereas the metastatic form has an incidence of 0.07%. We hereby report a clinical case of a patient who presented with cutaneous non Hodgkin lymphoma (NHL) in the left scapulohumeral region treated with surgery followed by radiotherapy (40 Gy total). Three years following radiotherapy, the patient was diagnosed with a left breast infiltrating ductal carcinoma, treated with conservative surgery and adjuvant therapy. The following year, i.e. four years after the initial diagnosis of NHL, two lymphoproliferative relapses occurred: in the left cutaneous scapulohumeral region at the original site of disease, and in the right breast. The aim of this paper is to highlight an uncommon oncologic disorder such as breast lymphoma, highlighting its clinical and radiological manifestations. Some studies reported a possible aetiological role of radiotherapy in the development of breast cancer following treatment of NHL, and in the development of breast cancer following treatment of Hodgkin lymphoma, which could potentially explain our findings. PMID- 21607044 TI - Imaging of an unusually located aggressive osteoblastoma of the pelvis: a case report. AB - INTRODUCTION: We present a case of an aggressive osteoblastoma involving the posterior acetabular column and the ischium, which is very rare location for the tumor. CASE PRESENTATION: A 21-year-old man presented with a persistent pain on the left buttock which extended on the rear surface of the thigh and the front surface of the left hip. A plain radiograph, a CT and MRI examinations were performed. The tumor was radically excised and histologically it proved to be an aggressive osteoblastoma. CONCLUSIONS: Although aggressive osteoblastoma is a rare entity it should be considered in the differential diagnosis of bone tumors. Our purpose is to reveal the radiographic presentation of this rare tumor. PMID- 21607045 TI - Atypical hemolytic-uremic syndrome (HUS) with recovery after a long-lasting anuria: a case report. AB - We report a case of a seven-year-old girl who suffered from atypical Hemolytic Uremic Syndrome (aHUS) complicated by septicaemia, central nervous system involvement, and cholangiitis. She remained anuric requiring treatment with peritoneal dialysis (PD) for a five-month period. In addition to conventional therapeutic measures including fresh frozen plasma (FFP) and blood cells transfusions she also underwent to plasma exchange (PE) treatment. Following a stormy hospitalization period of 17 weeks, the patient finally regained renal function and three years later she remains well on antihypertensive treatment and free of dialysis. PMID- 21607046 TI - Bolus fluorouracil induced syncope and pulseless ventricular tachycardia: a case report. AB - 5-fluorouracil is an anti-cancer drug commonly used in oncology practice. Typical side effects are myelosupression, nausea, vomiting, diarrhea and stomatitis. Cardiotoxicity is the other toxicity. Cardiac side effects are ST segment changes, rhythm abnormalities, supraventricular and ventricular dysrhytmias. Pulseless ventricular tachycardia and ventricular fibrillation releated with bolus fluorouracil were not detected in the literature. Here we discussed a 46 year-old male patient that has no known cardiac history. After bolus fluorouracil administration, syncope and pulseless ventricular tachycardia developed in this patient. There are a few explanations about the cardiotoxicity of fluorouracil. One of these is the effect on nitric oxide. It causes a reduction in the levels of endothelial NO and this leads coronary vasospasm. Another explanation is protein kinase C mediated vasospasm. In animal studies toxic myocarditis like lesions were detected with fluorouracil infusions. Finally both myocardit and vasospasm may lead cardiac problems like sudden cardiac deaths. Bolus 5 fluorouracil is as cardiotoxic as 5-fluorouracil infusion and we must be careful about the arrhytmia after the bolus administration. PMID- 21607047 TI - J Young Pharm. 2011: What are we aiming at? PMID- 21607048 TI - Design and evaluation of self-nanoemulsifying drug delivery system of flutamide. AB - Flutamide (FLT) is an antiandrogen drug for the treatment of prostate cancer. It has the drawback of poor water solubility and needs enhancement of its dissolution rate in simulated gastric fluids. Hence, it is prepared as self nanoemulsifying drug delivery systems (SNEDDS) with an aim to enhance its dissolution rate. The objectives of the study are to develop SNEDDS of FLT and to characterize for particle size, self-nanoemulsification, and dissolution enhancement. Solubility of FLT was determined in various oils, surfactants, and cosurfactants. Sesame oil was selected as an oil phase, Tween 20 as surfactant, and PEG400 as cosurfactant due to their higher solubilization effect. Various formulations were prepared by simple mixing followed by vortexing. From studies, the optimized SNEDDS formulation was composed of FLT (8.04% w/w), sesame oil (24.12% w/w), Tween 20 (53.38% w/w), and PEG400 (14.46% w/w). The selected SNEDDS could be self-emulsified without precipitation upon simple mixing. The mean particle size of the SNEDDS was 148.7 nm and percent drug content was 99.66. The dissolution rate of FLT from SNEDDS was faster and higher in three different dissolution media such as 2% sodium lauryl sulfate (97.85%), simulated gastric fluid (0.1 N HCl containing 0.5% Tween 20) (95.71%), and simulated intestinal fluid (pH 6.8 buffer) (96.21%). PMID- 21607049 TI - Biodegradable chitosan-based ambroxol hydrochloride microspheres: effect of cross linking agents. AB - The objective of this study was to investigate the influence of type of cross linking method used on the properties of ambroxol hydrochloride microspheres such as encapsulation efficiency, particle size, and drug release. Microspheres were prepared by solvent evaporation technique using chitosan as a matrix-forming agent and cross-linked using formaldehyde and heat treatment. Morphological and physicochemical properties of microspheres were then investigated by scanning electron microscopy (SEM), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FTIR) spectroscopy. The cross-linking of chitosan takes place at the free amino group because of formation of imine bond as evidenced by FTIR. The DSC, XRD, and FTIR analysis showed that chitosan microspheres cross linked by heating were superior in properties and performance as compared to the microspheres cross-linked using formaldehyde. SEM results revealed that heat-treated microspheres were spherical, discrete having smooth, and porous structure. The particle size and encapsulation efficiencies of the prepared chitosan microspheres ranged between 10.83-24.11 MUm and 39.73MU80.56%, respectively. The drug release was extended up to 12 h, and the kinetics of the drug release was obeying Higuchi kinetic proving diffusion controlled drug release. PMID- 21607050 TI - Six sigma: process of understanding the control and capability of ranitidine hydrochloride tablet. AB - The process of understanding the control and capability (PUCC) is an iterative closed loop process for continuous improvement. It covers the DMAIC toolkit in its three phases. PUCC is an iterative approach that rotates between the three pillars of the process of understanding, process control, and process capability, with each iteration resulting in a more capable and robust process. It is rightly said that being at the top is a marathon and not a sprint. The objective of the six sigma study of Ranitidine hydrochloride tablets is to achieve perfection in tablet manufacturing by reviewing the present robust manufacturing process, to find out ways to improve and modify the process, which will yield tablets that are defect-free and will give more customer satisfaction. The application of six sigma led to an improved process capability, due to the improved sigma level of the process from 1.5 to 4, a higher yield, due to reduced variation and reduction of thick tablets, reduction in packing line stoppages, reduction in re-work by 50%, a more standardized process, with smooth flow and change in coating suspension reconstitution level (8%w/w), a huge cost reduction of approximately Rs.90 to 95 lakhs per annum, an improved overall efficiency by 30% approximately, and improved overall quality of the product. PMID- 21607051 TI - Effects of Cynodon dactylon on Stress-Induced Infertility in Male Rats. AB - Cynodon dactylon (Family: Poaceae) is known to be a tackler in Indian mythology and is offered to Lord Ganesha. It is found everywhere, even on waste land, road side, dry places, and spreads vigorously on cultivated ground. This study was carried out with an objective to test if the constituents of this plant are useful in coping stress-induced sexual In this study, we considered immobilization stress to induce male infertility and the effect of C. dactylon in restoration of the dysfunction was evaluated by considering sexual behavioral observations, sexual performance, fructose content of the seminal vesicles, epididymal sperm concentration and histopathological examinations as parameters. Treatment of rats under stress with methanolic extract of C. dactylon has shown a promising effect in overcoming stress-induced sexual dysfunction, sexual performance, fructose content, sperm concentration and its effect on accessory sexual organs and body weight. We conclude that active constituents of C. dactylon present in methanolic extract have a potent aphrodisiac and male fertility activity. PMID- 21607052 TI - Antiurolithiatic Activity of Whole-Plant Hydroalcoholic Extract of Pergularia daemia in Rats. AB - The whole-plant, Pergularia daemia (Family: Asclepediaceae), extract (50% alcohol) was investigated for its antiurolithiatic and diuretic activity. Ethylene glycol (0.75% in water) feeding resulted in hyperoxaluria as well as increased renal excretion of calcium and phosphate. Alcoholic extract (400 mg/kg) of P. daemia was given orally in curative and preventive regimens over a period of 28 days. Supplementation with extract significantly (P < 0.001) lowered the urinary excretion and kidney retention levels of oxalate, calcium and phosphate. Furthermore, high serum levels of urea nitrogen, creatinine and uric acid were significantly (P < 0.001) reduced by the extract. The results were comparable with the standard drug, cystone (750 mg/kg). The reduction of stone-forming constituents in urine and their decreased kidney retention reduces the solubility product of crystallizing salts such as calcium oxalate and calcium phosphate, which could contribute to the antiurolithiatic property of the extract. The extract exhibited significant diuretic activity at dose of 400 mg/kg body weight as evidenced by increased total urine volume and the urine concentration of Na(+), and K(+). These findings affirm assertions made regarding the effectiveness of the extract of this plant against urinary pathologies in the Indian folk medicine. PMID- 21607053 TI - Evaluation of Effect of Taxus baccata Leaves Extract on Bronchoconstriction and Bronchial Hyperreactivity in Experimental Animals. AB - The present investigation was undertaken to evaluate the bronchodilating effect and bronchial hyperreactivity of alcoholic extract of Taxus baccata Linn. (AET) leaves in experimental animals. Bronchodilator activity of AET was studied on the histamine and acetylcholine aerosol induced bronchospasm in guinea pigs and bronchial hyperreactivity was studied on bronchoalveolar lavage fluid (BALF) in the egg albumin sensitized guinea pigs and by histopathological studies. In vitro mast cell stabilizing activity was studied using compound 48/80 as a degranulating agent. Treatment with AET (200 and 400 mg/kg, p.o., for 7 days) showed significant protection against histamine and acetylcholine aerosol induced bronchospasm in guinea pigs. Significant decrease in the total leukocyte and differential leukocyte count in the BALF of the egg albumin sensitized guinea pigs was observed by administration of AET (200 and 400 mg/kg, p.o., for 15 days). AET dose dependently protected the mast cell disruption induced by compound 48/80. These results suggest that AET not only has bronchodilating activity but also decreases bronchial hyperreactivity by decreasing the infiltration of inflammatory cells in the airway and inhibiting the release of histamine like mediators from the mast cell by stabilizing it. PMID- 21607054 TI - Anticancer Evaluation of Adiantum venustum Don. AB - Cancer is a malignant disease that is characterized by rapid and uncontrolled formation of abnormal cells which may mass together to form a growth or tumor, or proliferate throughout the body. Next to heart disease, cancer is a major killer of mankind. This study aims at a preliminary phytochemical screening and anticancer evaluation of Adiantum venustum Don against Ehrlich Ascites Carcinoma in animal model. The findings indicate that ethanolic extract of A. venustum Don possesses significant anticancer activity and also reduces elevated level of lipid peroxidation due to the presence of terpenoids and flavonoids. Thus, ethanolic extract of A. venustum Don could have vast therapeutic application against cancer. PMID- 21607056 TI - A study of practical parameters and their relative importance as perceived by various stakeholders in clinical trials. AB - A contract research organization (CRO) is a company which conducts a Good Clinical Practice (GCP) in clinical trial. There are literally hundreds of CROs worldwide employing a workforce of nearly 100,000 professionals. The project proposes the study of practical parameters and their relative importance as perceived by the various stakeholders in clinical trials. The survey was conducted in Bangalore and New Delhi. Primary market data was obtained by primary market research which included 80 clinical trial stakeholders by having a preliminary communication with them, followed by administering a questionnaire along with prior permission. There were 15 Sponsors/ CROs, 27 Investigators /Monitors and 38 Ethics committee members involved in the study. It was shown from the study that a clinical investigator involved in a clinical trial is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of the subjects under the investigator's care; and for the control of drugs under investigation. It was also shown from the study that the sponsors of a clinical trial carry the ultimate responsibility for the initiation, management and financing of the clinical trial. The study has identified a specific training need at the level of the individual stakeholder to perform a particular job function and to identify the actual practical parameters in the Indian context important for the conduction of clinical trials (GCP) with respect to the different stakeholders, to determine the relative importance of these parameters as perceived by various stakeholders involved in clinical trials, and to identify the relative contributions of different stakeholders to the success/ satisfactory conduct of a clinical trial. PMID- 21607055 TI - A validated densitometric method for analysis of atorvastatin calcium and metoprolol tartarate as bulk drugs and in combined capsule dosage forms. AB - A simple, accurate and precise high-performance thin-layer chromatographic method has been developed for the estimation of Atorvastatin Calcium and Metoprolol Tartarate simultaneously from a capsule dosage form. The method employed Silica gel 60F (254s)precoated plates as stationary phase and a mixture of Chloroform: Methanol: Glacial acetic acid (dil.) :: (9:1.5:0.2 ml %v/v) as mobile phase. Densitometric scanning was performed at 220 nm using Camag TLC scanner 3. The method was linear in the drug concentrations' range of 500 to 2500 ng/spot for Atorvastatin Calcium, also for Metoprolol Tartarate with correlation coefficient of 0.984 for Atorvastatin Calcium and 0.995 for Metoprolol Tartarate respectively. The retention factor for Atorvastatin Calcium was 0.45 +/- 0.04 and for Metoprolol Tartarate was 0.25 +/- 0.02. The method was validated as per ICH (International Conference on Harmonisation) Guidelines, proving its utility in estimation of Atorvastatin Calcium and Metoprolol Tartarate in combined dosage form. PMID- 21607057 TI - Effect of a diabetes counseling programme on knowledge, attitude and practice among diabetic patients in Erode district of South India. AB - The prevalence of diabetes in India has grown over the past decade. Diabetic patients develop complications due to poor awareness regarding the disease and inadequate glycemic control. Patient education is the most effective way to lessen the complications of diabetes and its management. A total of 207 (85 males and 122 females) type 2 diabetes mellitus patients were enrolled and randomized into test and control groups. Patients in the test group received counseling at each visit and information leaflets from the pharmacist; the control group patients received counseling and information leaflets only at the end of the study. A validated knowledge, attitude, and practice (KAP) questionnaire was administered to both test and control group patients at baseline and at final follow-up to assess awareness regarding disease management. Glucose and lipid levels were also evaluated at baseline and final follow-up in both the groups. At the end of the study, the KAP score of test group patients improved significantly (P<0.0001), whereas no significant changes were observed in control group patients. The postprandial blood glucose (PPBG) levels decreased significantly in the test group. Total cholesterol (TC), triglycerides (TGL), and low density lipoprotein levels (LDL) also showed a decrease in the test group. Thus, our study reveals that pharmacist counseling might be an important element in diabetes management programs. PMID- 21607058 TI - Cardiovascular and smooth muscle pharmacology in the next decade. PMID- 21607059 TI - Gastrointestinal pharmacology: challenges ahead. PMID- 21607060 TI - Defining pharmacology of natural products in the 21st century - challenge on multiple fronts. PMID- 21607061 TI - Applicability of Generic Assays Based on Liquid Chromatography-Electrospray Mass Spectrometry to Study in vitro Metabolism of 55 Structurally Diverse Compounds. AB - Liquid chromatography-mass spectrometry (LC-MS) with generic gradient elution for a large number of chemically different compounds is a common approach in drug development, used to acquire a large amount of data in a short time frame for drug candidates. The analysis with non-optimized parameters however may lead to a poor method performance for many compounds, and contains a risk of losing important information. Here, generic electrospray time of flight (ESI-TOF) MS methods in various pH conditions were tested for 55 chemically diverse compounds (10 acids, 25 bases, 17 neutrals, and 3 amphoterics), aiming to find best analytical conditions for each compound, for studies of in vitro metabolic properties in liver preparations. The effect of eluent pH and elution gradient strength on chromatographic performance and electrospray MS ionization efficiency were examined for each compound. The data are evaluated how well the best generic approach could cover the analysis of test compounds and how many compounds would still need completely different analytical conditions after that. Aqueous mobile phase consisting of 0.05% acetic acid and 5 mM ammonium acetate (pH 4.4) showed the best general suitability for the analyses, showing adequate performance for metabolite profiling for 41 out of 55 compounds either in positive or negative ion mode. In positive ion mode, the main limitation of performance in various pH conditions was generally not the lack of ionization, but rather the poor chromatographic performance (inadequate retention or poor peak shape), suggesting that more emphasis should be put in finding conditions providing best chromatographic performance, rather than highest ionization properties. However, a single generic approach for a large number of different compounds is not likely to produce good results for all compounds. Preferably, at least two or three different conditions are needed for the coverage of a larger number of structurally diverse compounds. PMID- 21607063 TI - Pharmacogenetics - challenges and opportunities ahead. PMID- 21607062 TI - Magnesium Lithospermate B Protects Cardiomyocytes from Ischemic Injury Via Inhibition of TAB1-p38 Apoptosis Signaling. AB - Danshen has been used in traditional Chinese medicine for hundreds of years to treat cardiovascular diseases. However, its precise cardioprotective components and the underlying mechanism are still unclear. In the present study, we demonstrated that in a rat model of acute myocardial infarction, the treatment with magnesium lithospermate B (MLB), the representative component of phenolic acids in Danshen, significantly reduced the infarct size and the blood lactate dehydrogenase level. In contrast, tanshinone IIA, the representative component of lipophilic tanshinones in Danshen, had no such protective effects. Moreover, in the simulated ischemia cell model, MLB treatment considerably increased the cell viability and reduced the sub-G1 population and the apoptotic nuclei, indicating its anti-apoptotic effect. Further mechanism study revealed that the ischemia induced p38 phosphorylation was abolished by MLB treatment. Interestingly, MLB specifically inhibited the TGFbeta-activated protein kinase 1-binding protein 1 (TAB1) mediated p38 phosphorylation through disrupting the interaction between TAB1 and p38, but it did not affect the mitogen-activated protein kinase 3/6 mediated p38 phosphorylation. In conclusion, the present study identifies MLB as an active component of Danshen in protecting cardiomyocytes from ischemic injury through specific inhibition of TAB1-p38 apoptosis signaling. These results indicate TAB1-p38 interaction as a putative drug target in treating ischemic heart diseases. PMID- 21607064 TI - Grand challenge for ion channels: an underexploited resource for therapeutics. PMID- 21607066 TI - How to assess the value of medicines? AB - This study aims to discuss approaches to assessing the value of medicines. Economic evaluation assesses value by means of the incremental cost-effectiveness ratio (ICER). Health is maximized by selecting medicines with increasing ICERs until the budget is exhausted. The budget size determines the value of the threshold ICER and vice versa. Alternatively, the threshold value can be inferred from pricing/reimbursement decisions, although such values vary between countries. Threshold values derived from the value-of-life literature depend on the technique used. The World Health Organization has proposed a threshold value tied to the national GDP. As decision makers may wish to consider multiple criteria, variable threshold values and weighted ICERs have been suggested. Other approaches (i.e., replacement approach, program budgeting and marginal analysis) have focused on improving resource allocation, rather than maximizing health subject to a budget constraint. Alternatively, the generalized optimization framework and multi-criteria decision analysis make it possible to consider other criteria in addition to value. PMID- 21607065 TI - Neuropeptides in the gonads: from evolution to pharmacology. AB - Vertebrate gonads are the sites of synthesis and binding of many peptides that were initially classified as neuropeptides. These gonadal neuropeptide systems are neither well understood in isolation, nor in their interactions with other neuropeptide systems. Further, our knowledge of the control of these gonadal neuropeptides by peripheral hormones that bind to the gonads, and which themselves are under regulation by true neuropeptide systems from the hypothalamus, is relatively meager. This review discusses the existence of a variety of neuropeptides and their receptors which have been discovered in vertebrate gonads, and the possible way in which such systems could have evolved. We then focus on two key neuropeptides for regulation of the hypothalamo pituitary-gonadal axis: gonadotropin-releasing hormone (GnRH) and gonadotropin inhibitory hormone (GnIH). Comparative studies have provided us with a degree of understanding as to how a gonadal GnRH system might have evolved, and they have been responsible for the discovery of GnIH and its gonadal counterpart. We attempt to highlight what is known about these two key gonadal neuropeptides, how their actions differ from their hypothalamic counterparts, and how we might learn from comparative studies of them and other gonadal neuropeptides in terms of pharmacology, reproductive physiology and evolutionary biology. PMID- 21607068 TI - Grand challenge of psychopathology in the years to come. PMID- 21607067 TI - PG F(2alpha) Receptor: A Promising Therapeutic Target for Cardiovascular Disease. AB - Prostaglandins (PGs), a group of key lipid mediators, are involved in numerous physiological and pathological processes including inflammation and cardiovascular homeostasis. Each PG acts on its specific and distinct cell surface G protein-coupled receptors (GPCRs) or peroxisome proliferator-activated receptors (PPARs). Prostaglandin F(2alpha) receptor (FP) is required for female reproductive function such as luteolysis and parturition. It has recently been implicated in blood pressure regulation, atherosclerosis and other inflammation related disorders. The emerging role of FP in cardiovascular diseases is highlighted and potential therapeutic translation is discussed in the current review. PMID- 21607069 TI - The grand challenge for psychology: integrate and fire! PMID- 21607070 TI - Sexual orientation biases attentional control: a possible gaydar mechanism. AB - Homosexuals are believed to have a "sixth sense" for recognizing each other, an ability referred to as gaydar. We considered that being a homosexual might rely on systematic practice of processing relatively specific, local perceptual features, which might lead to a corresponding chronic bias of attentional control. This was tested by comparing male and female homosexuals and heterosexuals - brought up in the same country and culture and matched in terms of race, intelligence, sex, mood, age, personality, religious background, educational style, and socio-economic situation - in their efficiency to process global and local features of hierarchically-constructed visual stimuli. Both homosexuals and heterosexuals showed better performance on global features - the standard global precedence effect. However, this effect was significantly reduced in homosexuals, suggesting a relative preference for detail. Findings are taken to demonstrate chronic, generalized biases in attentional control parameters that reflect the selective reward provided by the respective sexual orientation. PMID- 21607071 TI - Language across the mind and brain. PMID- 21607072 TI - An entropy model for artificial grammar learning. AB - A model is proposed to characterize the type of knowledge acquired in artificial grammar learning (AGL). In particular, Shannon entropy is employed to compute the complexity of different test items in an AGL task, relative to the training items. According to this model, the more predictable a test item is from the training items, the more likely it is that this item should be selected as compatible with the training items. The predictions of the entropy model are explored in relation to the results from several previous AGL datasets and compared to other AGL measures. This particular approach in AGL resonates well with similar models in categorization and reasoning which also postulate that cognitive processing is geared towards the reduction of entropy. PMID- 21607073 TI - Using time-varying covariates in multilevel growth models. AB - This article provides an illustration of growth curve modeling within a multilevel framework. Specifically, we demonstrate coding schemes that allow the researcher to model discontinuous longitudinal data using a linear growth model in conjunction with time-varying covariates. Our focus is on developing a level-1 model that accurately reflects the shape of the growth trajectory. We demonstrate the importance of adequately modeling the shape of the level-1 growth trajectory in order to make inferences about the importance of both level-1 and level-2 predictors. PMID- 21607074 TI - Fixation patterns during recognition of personally familiar and unfamiliar faces. AB - Previous studies recording eye gaze during face perception have rendered somewhat inconclusive findings with respect to fixation differences between familiar and unfamiliar faces. This can be attributed to a number of factors that differ across studies: the type and extent of familiarity with the faces presented, the definition of areas of interest subject to analyses, as well as a lack of consideration for the time course of scan patterns. Here we sought to address these issues by recording fixations in a recognition task with personally familiar and unfamiliar faces. After a first common fixation on a central superior location of the face in between features, suggesting initial holistic encoding, and a subsequent left eye bias, local features were focused and explored more for familiar than unfamiliar faces. Although the number of fixations did not differ for un-/familiar faces, the locations of fixations began to differ before familiarity decisions were provided. This suggests that in the context of familiarity decisions without time constraints, differences in processing familiar and unfamiliar faces arise relatively early - immediately upon initiation of the first fixation to identity-specific information - and that the local features of familiar faces are processed more than those of unfamiliar faces. PMID- 21607076 TI - Are psychological quantities and measurement relevant in the 21st century? PMID- 21607075 TI - Key visual features for rapid categorization of animals in natural scenes. AB - In speeded categorization tasks, decisions could be based on diagnostic target features or they may need the activation of complete representations of the object. Depending on task requirements, the priming of feature detectors through top-down expectation might lower the threshold of selective units or speed up the rate of information accumulation. In the present paper, 40 subjects performed a rapid go/no-go animal/non-animal categorization task with 400 briefly flashed natural scenes to study how performance depends on physical scene characteristics, target configuration, and the presence or absence of diagnostic animal features. Performance was evaluated both in terms of accuracy and speed and d' curves were plotted as a function of reaction time (RT). Such d' curves give an estimation of the processing dynamics for studied features and characteristics over the entire subject population. Global image characteristics such as color and brightness do not critically influence categorization speed, although they slightly influence accuracy. Global critical factors include the presence of a canonical animal posture and animal/background size ratio suggesting the role of coarse global form. Performance was best for both accuracy and speed, when the animal was in a typical posture and when it occupied about 20 30% of the image. The presence of diagnostic animal features was another critical factor. Performance was significantly impaired both in accuracy (drop 3.3-7.5%) and speed (median RT increase 7-16 ms) when diagnostic animal parts (eyes, mouth, and limbs) were missing. Such animal features were shown to influence performance very early when only 15-25% of the response had been produced. In agreement with other experimental and modeling studies, our results support fast diagnostic recognition of animals based on key intermediate features and priming based on the subject's expertise. PMID- 21607077 TI - Confidence intervals permit, but do not guarantee, better inference than statistical significance testing. AB - A statistically significant result, and a non-significant result may differ little, although significance status may tempt an interpretation of difference. Two studies are reported that compared interpretation of such results presented using null hypothesis significance testing (NHST), or confidence intervals (CIs). Authors of articles published in psychology, behavioral neuroscience, and medical journals were asked, via email, to interpret two fictitious studies that found similar results, one statistically significant, and the other non-significant. Responses from 330 authors varied greatly, but interpretation was generally poor, whether results were presented as CIs or using NHST. However, when interpreting CIs respondents who mentioned NHST were 60% likely to conclude, unjustifiably, the two results conflicted, whereas those who interpreted CIs without reference to NHST were 95% likely to conclude, justifiably, the two results were consistent. Findings were generally similar for all three disciplines. An email survey of academic psychologists confirmed that CIs elicit better interpretations if NHST is not invoked. Improved statistical inference can result from encouragement of meta-analytic thinking and use of CIs but, for full benefit, such highly desirable statistical reform requires also that researchers interpret CIs without recourse to NHST. PMID- 21607078 TI - The grand challenges to cellular and infection microbiology. PMID- 21607079 TI - Human food chain and microorganisms: a case of co-evolution. PMID- 21607081 TI - Genomic polymorphisms as inherent watermarks for tracking infectious agents. PMID- 21607080 TI - Mammalian MicroRNAs: Post-Transcriptional Gene Regulation in RNA Virus Infection and Therapeutic Applications. AB - RNA silencing mediated by microRNAs (miRNAs) is a recently discovered gene regulatory mechanism involved in various aspects of biology, such as development, cell differentiation and proliferation, and innate immunity against viral infections. miRNAs, which are a class of small (21-25 nucleotides) RNAs, target messenger RNA (mRNA) through incomplete base-pairing with their target sequences resulting in mRNA degradation or translational repression. Although studies of miRNAs have led to numerous sensational discoveries in biology, many fundamental questions about their expression and function still remain. In this review, we discuss the dynamics of the mammalian miRNA machinery and the biological function of miRNAs, focusing on RNA viruses and the various therapeutic applications of miRNAs against viral infections. PMID- 21607082 TI - A Functional Slow Recycling Pathway of Transferrin is Required for Growth of Chlamydia. AB - An inhibitor of host cell lysophospholipid acyltransferase, an enzyme involved in lipid metabolism blocked growth of the obligate intracellular pathogen Chlamydia through its action on the transport of transferrin (Tf) via the slow pathway of recycling. A detailed characterization of this inhibition revealed that Tf accumulated in vesicles positive for Rab11, with a concomitant reduction in the level of Tf found within the transport intermediate Rab4/11 hybrid vesicles. The net result was the failure to be recycled to the plasma membrane. In chlamydiae infected cells, the Tf-containing Rab11-positive vesicles were typically found intimately associated with the inclusion, and treatment with the inhibitor caused their accumulation, suggesting that the timely progression and completion of Tf recycling was necessary for proper chlamydial growth. Growth inhibition by the compound could be negated by the simple removal of the Tf-containing fraction of the serum, a further indication that accumulation of Tf around the chlamydial inclusion was deleterious to the pathogen. Thus, it appears that manipulating the slow recycling pathway can have biological consequences for Chlamydia and implies the need to regulate carefully the interaction of the inclusion with this host trafficking pathway. PMID- 21607083 TI - AMPylation: Something Old is New Again. AB - The post-translational modification AMPylation is emerging as a significant regulatory mechanism in both prokaryotic and eukaryotic biology. This process involves the covalent addition of an adenosine monophosphate to a protein resulting in a modified protein with altered activity. Proteins capable of catalyzing AMPylation, termed AMPylators, are comparable to kinases in that they both hydrolyze ATP and reversibly transfer a part of this primary metabolite to a hydroxyl side chain of the protein substrate. To date, only four AMPylators have been characterized, though many more potential candidates have been identified through amino acid sequence analysis and preliminary in vitro studies. This modification was first discovered over 40 years ago by Earl Stadtman and colleagues through the modification of glutamine synthetase by adenylyl transferase; however research into this mechanism has only just been reenergized by the studies on bacterial effectors. New AMPylators were revealed due to the discovery that a bacterial effector having a conserved Fic domain transfers an AMP group to protein substrates. Current research focuses on identifying and characterizing various types of AMPylators homologous to Fic domains and adenylyl transferase domains and their respective substrates. While all AMPylators characterized thus far are bacterial proteins, the conservation of the Fic domain in eukaryotic organisms suggests that AMPylation is omnipresent in various forms of life and has significant impact on a wide range of regulatory processes. PMID- 21607084 TI - Site-Directed Mutagenesis of HIV-1 vpu Gene Demonstrates Two Clusters of Replication-Defective Mutants with Distinct Ability to Down-Modulate Cell Surface CD4 and Tetherin. AB - HIV-1 Vpu acts positively on viral infectivity by mediating CD4 degradation in endoplasmic reticulum and enhances virion release by counteracting a virion release restriction factor, tetherin. In order to define the impact of Vpu activity on HIV-1 replication, we have generated a series of site-specific proviral vpu mutants. Of fifteen mutants examined, seven exhibited a replication defect similar to that of a vpu-deletion mutant in a lymphocyte cell line H9. These mutations clustered in narrow regions within transmembrane domain (TMD) and cytoplasmic domain (CTD). Replication-defective mutants displayed the reduced ability to enhance virion release from a monolayer cell line HEp2 without exception. Upon transfection with Vpu expression vectors, neither TMD mutants nor CTD mutants blocked CD4 expression at the cell surface in another monolayer cell line MAGI. While TMD mutants were unable to down-modulate cell surface tetherin in HEp2 cells, CTD mutants did quite efficiently. Confocal microscopy analysis revealed the difference of intracellular localization between TMD and CTD mutants. In total, replication capability of HIV-1 carrying vpu mutations correlates well with the ability of Vpu to enhance virion release and to impede the cell surface expression of CD4 but not with the ability to down-modulate cell surface tetherin. Our results here suggest that efficient viral replication requires not only down-regulation of cell surface tetherin but also its degradation. PMID- 21607085 TI - The Vibrio Cholerae Type VI Secretion System: Evaluating its Role in the Human Disease Cholera. AB - Vibrio cholerae, the marine bacterium responsible for the diarrheal disease cholera, utilizes a multitude of virulence factors to cause disease. The importance of two of these factors, the toxin co-regulated pilus (TCP) and cholera toxin (CT), has been well documented for pandemic O1 and epidemic O139 serogroups. In contrast, endemic non-O1 and non-O139 serogroups can cause localized outbreaks of cholera-like illness, often in the absence of TCP and CT. One virulence mechanism used by these strains is the type VI secretion system (T6SS) to export toxins across the cell envelope and confer toxicity toward eukaryotic and prokaryotic organisms. The V. cholerae strain V52 (an O37 serogroup strain) possesses a constitutively active T6SS and was responsible for an outbreak of gastroenteritis in Sudan in 1968. To evaluate a potential role of the T6SS in the disease cholera, we compared the T6SS clusters of V. cholerae strains with sequenced genomes. We found that the majority of V. cholerae strains, including one pandemic strain, contain intact T6SS gene clusters; thus, we propose that the T6SS is a conserved mechanism that allows pandemic and endemic V. cholerae to persist both in the host and in the environment. PMID- 21607086 TI - Genetic manipulation of francisella tularensis. AB - Francisella tularensis is a facultative intracellular pathogen that causes the disease tularemia. F. tularensis subsp. tularensis causes the most severe disease in humans and has been classified as a Category A select agent and potential bioweapon. There is currently no vaccine approved for human use, making genetic manipulation of this organism critical to unraveling the genetic basis of pathogenesis and developing countermeasures against tularemia. The development of genetic techniques applicable to F. tularensis have lagged behind those routinely used for other bacteria, primarily due to lack of research and the restricted nature of the biocontainment required for studying this pathogen. However, in recent years, genetic techniques, such as transposon mutagenesis and targeted gene disruption, have been developed, that have had a dramatic impact on our understanding of the genetic basis of F. tularensis virulence. In this review, we describe some of the methods developed for genetic manipulation of F. tularensis. PMID- 21607088 TI - Cervical adenocarcinoma in situ with negative conization margin: negligible or not? PMID- 21607087 TI - Innate immune recognition and inflammasome activation in listeria monocytogenes infection. AB - Listeria monocytogenes is an intracellular, Gram-positive bacterium that can cause life-threatening illness especially in immunocompromised individuals and newborns. The pathogen propagates within the cytosol of various host cells after escaping from the phagosomal compartment depending on the cytolysin listeriolysin O. While L. monocytogenes can manipulate the endocytic and many host-cell signaling cascades to its advantage, host cells are however capable of detecting Listeria infection at different cellular compartments by expressing innate immune receptors that trigger antibacterial defense pathways. These receptors include the Toll-like receptors, NOD-like receptors (NLRs), and cytosolic DNA sensors. Some NLRs as well as the DNA sensor AIM2 form multiprotein complexes called inflammasomes. Inflammasomes regulate caspase-1-dependent production of the key inflammatory cytokines IL-1beta and IL-18 as well as pyroptotic cell death in L. monocytogenes-infected cells. This review describes the current knowledge about innate immune sensing and inflammasome activation in Listeria infection. PMID- 21607089 TI - Multivariate survival analysis of the patients with recurrent endometrial cancer. AB - OBJECTIVE: Few studies on the prognosticators of the patients with recurrent endometrial cancer after relapse have been reported in the literature. The aim of this study was to determine the prognosticators after relapse in patients with recurrent endometrial cancer who underwent primary complete cytoreductive surgery and adjuvant chemotherapy. METHODS: Thirty-five patients with recurrent endometrial cancer were included in this retrospective analysis. The prognostic significance of several clinicopathological factors including histologic type, risk for recurrence, time to relapse after primary surgery, number of relapse sites, site of relapse, treatment modality, and complete resection of recurrent tumors were evaluated. Survival analyses were performed by Kaplan-Meier curves and the log-rank test. Independent prognostic factors were determined by multivariate Cox regression analysis. RESULTS: Among the clinicopathological factors analyzed, histologic type (p=0.04), time to relapse after primary surgery (p=0.03), and the number of relapse sites (p=0.03) were significantly related to survival after relapse. Multivariate analysis revealed that time to relapse after primary surgery (hazard ratio, 6.8; p=0.004) and the number of relapse sites (hazard ratio, 11.1; p=0.002) were independent prognostic factors for survival after relapse. Survival after relapse could be stratified into three groups by the combination of two independent prognostic factors. CONCLUSION: We conclude that time to relapse after primary surgery, and the number of relapse sites were independent prognostic factors for survival after relapse in patients with recurrent endometrial cancer. PMID- 21607090 TI - Early stage (IA-IB) primary carcinoma of the fallopian tube: case-control comparison to adenocarcinoma of the ovary. AB - OBJECTIVE: Early stage primary carcinoma of the fallopian tube (PCFT) is an uncommon condition when strict criteria are applied. The aim of this study was to compare the outcome stage IA-IB PCFT to a matched group of ovarian cancer (OC). METHODS: Between 1990 and 2008, 32 patients with stage IA-IB of PCFT were recorded in the database of three French Institutions. A control group of patients with OC was constituted. RESULTS: Eleven eligible PCFT cases and 29 OC controls fulfilled the stringent inclusion criteria. Median follow-up was 70.2 months. Five-year overall survival was 83.3% (95% confidence interval [CI], 27.3 to 97.5) for PCFT and 88.0% (95% CI, 66.9 to 96.0) for OC (p=0.93). In the subgroup of patients with grade 2-3, the outcome was similar in PCFT compared to OC patients (p=0.75). Five-year relapse-free survival was respectively 62.5% (95% CI, 22.9 to 86.1) and 85.0% (95% CI, 64.6 to 94.2) in the PCFT and OC groups (p=0.07). In the subgroup of patients (grade 2-3), there was no difference between PCFT and OC (p=0.65). CONCLUSION: The findings did not reveal any difference in prognosis between early stage of PCFT and OC when grade is taken into account. Management of PCFT should mirror that of ovarian carcinoma. PMID- 21607091 TI - Differences in perioperative outcomes after laparoscopic management of benign and malignant adnexal masses. AB - OBJECTIVE: To compare the feasibility and safety of the laparoscopic management of adnexal masses appearing preoperatively benign with those suspicious for malignancy. METHODS: Retrospective study of 694 women that underwent laparoscopic management of an adnexal mass. RESULTS: Laparoscopic management of an adnexal mass was completed in 678 patients. Six hundred and thirty five patients had benign pathology (91.5%) and 53 (7.6%) had primary ovarian cancers. Sixteen patients (2.3%) were converted to laparotomy; there were 13 intraoperative (1.9%) and 16 postoperative complications (2.3%). Patients divided in 2 groups: benign and borderline/malignant tumors. Patients in the benign group had a higher incidence of ovarian cyst rupture (26% vs. 8.7%, p<0.05). Patients in the borderline/malignant group had a statistically significant higher conversion rate to laparotomy (0.9% vs. 16.9%, p<0.001), postoperative complications (1.9% vs. 12.2%, p<0.05), blood loss, operative time, and duration of hospital stay. The incidence of intraoperative complications was similar between the 2 groups. CONCLUSION: Laparoscopic management of masses that are suspicious for malignancy or borderline pathology is associated with an increased risk in specific intra operative and post-operative morbidities in comparison to benign masses. Surgeons should tailor the operative risks with their patients according to the preoperative likelihood of the mass being carcinoma or borderline malignancy. PMID- 21607092 TI - The safety of conization in the management of adenocarcinoma in situ of the uterine cervix. AB - OBJECTIVE: To evaluate the occurrence of residual or recurrent disease after conization for adenocarcinoma in situ (AIS) of the uterine cervix. METHODS: Medical records of 99 patients with a histologically diagnosis of AIS of the uterine cervix by conization between 1991 and 2008 were reviewed retrospectively. RESULTS: Seventy eight of 99 patients (78.8%) had negative and 18 (18.2%) had positive resection margins of the conization specimen, and 3 (3.0%) had unknown margin status. Of the 78 patients with negative margins, 45 underwent subsequent hysterectomy and residual AIS were present in 4.4% (2/45) of patients. Ten of the 18 patients with positive margins received subsequent hysterectomy and 3 patients (30%) had residual AIS. Twenty-eight patients had conservative treatment and during the median follow-up time of 23.5 months (range, 7 to 124 months), only one patient (3.6%) had recurrent AIS and was treated with a simple hysterectomy. Eight patients became pregnant after conization, 4 of them delivered healthy babies, one had a spontaneous abortion and 3 were ongoing pregnancies. CONCLUSION: Patients with positive resection margins after conization for AIS of the uterine cervix are significantly more likely to have residual disease. However, negative resection margin carries a lower risk for residual AIS, therefore conservative management with careful surveillance seems to be feasible in women who wish to preserve their fertility. PMID- 21607093 TI - Is human papillomavirus genotype an influencing factor on radiotherapy outcome? Ambiguity caused by an association of HPV 18 genotype and adenocarcinoma histology. AB - OBJECTIVE: To evaluate whether human papillomavirus (HPV) genotype is associated with poor prognosis of uterine cervical cancer treated primarily with radiotherapy. METHODS: HPV genotyping was performed in 181 radiotherapy patients using SPF10 polymerase chain reaction and HPV reverse hybridization line probe assay. Univariate and multivariate Cox regression analysis was performed to explore the prognostic factors. Bivariate analysis was performed to investigate any association between HPV genotype and the rest of the prognostic factors. RESULTS: HPV type 18 was associated with poor disease-free survival on univariate analysis but the statistical significance was abolished when multivariate analysis was applied. Bivariate analysis was performed to examine the possible confounding factors influencing the effect of HPV 18 on prognosis. As a result, adeno/adenosquamous carcinoma histology reduced the prognostic importance of HPV 18 by 66% (2.4 to 1.6), and was the only factor which reduced the hazard ratio of HPV 18. When compared to non-18 squamous cell carcinoma, type 18 increased the risk of recurrence up to 4-fold in adeno/adenosquamous/HPV 18 and 3.7 in adeno/adenosquamous/non-18, and to 2-fold in squamous carcinoma/HPV 18, respectively. CONCLUSION: Our data suggest that the prognostic significance of HPV 18 genotype is substantial on radiotherapy outcome, but can be underestimated because of the close association of the HPV 18 and adenocarcinoma/adenosquamous carcinoma histology. Both HPV 18 and histologic type should be regarded as strong prognostic factors in considering the treatment outcome of the uterine cervical cancer. PMID- 21607094 TI - Pap smear screening for small cell carcinoma of the uterine cervix: a case series and review of the literature. AB - OBJECTIVE: Small cell carcinoma of the uterine cervix (SMCC) is extremely rare, and an aggressive disease that proliferates rapidly. It was often reported that the diagnostic accuracy of cytologic smears in diagnosing SMCC was low. This is a report of the Severance Hospital experience with the patients suffering from SMCC. METHODS: Twenty-seven patients with small cell carcinoma of the uterine cervix were diagnosed and treated at the Severance Hospital from November 1991 to January 2010. The data were analyzed retrospectively, based on the available charts and pathology reports. Various fields, such as chief complaints and symptoms present at first clinic visit, age, International Federation of Obstetrics and Gynecology (FIGO) clinical stage, treatment modality, the 5-year overall survival rate, and recurrence rate were investigated. RESULTS: Among the 27 patients diagnosed with small cell carcinoma of the uterine cervix, 18 of them (66.7%) presented with symptoms, including vaginal bleeding, at the first clinic visit, and the remaining 9 patients (33.3%) showed abnormal Pap smear screening in the process of their routine health check-up. The median age of the patients was 54 years (range, 24 to 77 years). FIGO stage IIB was the most common stage (11 of 27 patients). The 5-year overall survival rate of 21 patients, who could be followed up, was 57.2%. Six patients showed recurrence after remission, and the mean disease free interval of them was 9.2 months (range, 6 to 11 months). Abnormal Pap smear screening results of 9 patients was investigated, and the diagnostic accuracy of the cytologic findings was 22.2%. CONCLUSION: Our study was consistent with the concept that Pap smear screening might not be helpful in early diagnosis of SMCC considering its low diagnostic accuracy. Further large scale multicenter prospective studies are definitely needed in order to produce abundant information about optimal therapy and diagnosis. PMID- 21607095 TI - Clinical significance of HIF-2alpha immunostaining area in radioresistant cervical cancer. AB - OBJECTIVE: Hypoxia has been established as a key factor influencing the pathophysiology of malignant growth. Hypoxia-induced changes in gene expression are coordinated primarily by hypoxia inducible factor-1 alpha (HIF-1alpha) and HIF-2alpha. The purpose of this study was to determine whether or not HIF-2alpha expression is associated with survival and response to radiation in patients with cervical cancer. METHODS: After reviewing the medical records of 119 patients treated in our institution by primary therapy for stage IIB-IVA cervical cancer, we performed a case-control study. Cases (n=12) were selected from patients with local recurrence or radiation failure after primary radiation therapy with or without concurrent chemoradiation. For each case, we selected two controls from patients who had no evidence of local recurrence. Using pre-treatment paraffin embedded tissues, we evaluated the expression of HIF-2alpha by immunohistochemistry. Staining was scored based on intensity (intensity score [IS], 0-3) and proportion (proportion score [PS], 0-100). The results were analyzed by the Student t-test, Mann-Whitney U test, Fisher's exact test, and Cox proportional hazards regression model. RESULTS: Cytoplasmic expression of HIF 2alpha, representing the degree of hypoxia, had a relationship with poor response to radiotherapy. The hazard ratio of recurrence was 1.71 for the HIF-2alpha IS (p=0.110) and 1.04 for the HIF-2alpha PS (p<0.001), indicating that the HIF 2alpha staining area correlates weakly with the risk for recurrence. CONCLUSION: The HIF-2alpha expression area may have an important role in radioresistance in patients with locally advanced cervical cancer. We conclude that a wider area of hypoxia predicts an increased probability of radioresistance. PMID- 21607096 TI - Guideline adherence to chemotherapy administration safety standards: a survey on nurses in a single institute. AB - OBJECTIVE: Little is known about the guideline adherence of nurses to chemotherapy administration guidelines. We determined the guideline adherence of nurses to the Chemotherapy Administration Safety Standards and the relationship between demographic characteristics and guideline adherence. METHODS: Survey sheets containing two questions on demographic characteristics and 16 questions on the guideline adherence of nurses regarding chemotherapy administration were distributed to all in-patient departments in our hospital in which chemotherapy was performed. All clinical nurses in the department were recommended to respond. RESULTS: Of 202 nurses, 123 responses were collected (61% response rate). The guideline adherence rate was >70% for 15 of 16 questions, but 55% of respondents indicated that there was no competency monitoring for nurses. Nurses with >7 years of clinical nursing experience felt more competent in performing cardiopulmonary resuscitation (CPR) than nurses with <7 years of clinical nursing experience (p=0.032). CONCLUSION: The guideline adherence rate of nurses with respect to chemotherapy administration was high, with the exception of the absence of a competency monitoring for nurses. A significant number of nurses with <7 years of clinical nursing experience felt incompetent in performing CPR. PMID- 21607097 TI - A case of minimal uterine serous carcinoma with distant lymph node metastasis without peritoneal dissemination. AB - A 61-year old woman underwent total abdominal hysterectomy and pelvic lymph node dissection under the diagnosis of endometrial cancer. Although pelvic lymph nodes were positive for adenocarcinoma with psamomma bodies, no other lesion that was a primary lesion was verified. A postoperative study revealed the existence of para aortic lymph node and supraclavicular lymph node metastases. Therefore, the endometrial biopsy specimen was reviewed. With the findings of p53 positivity by immunohistochemistry in the papillary part, the final histopathological diagnosis was changed to endometrial serous adenocarcinoma. Postoperative chemotherapy followed by radiotherapy for supraclavicular lymph node metastasis achieved complete response. This type of tumor must be considered in a differential diagnosis when metastatic papillary serous carcinoma is detected, but the primary site remains unknown. PMID- 21607098 TI - Early port-site metastasis during neoadjuvant chemotherapy in advanced stage ovarian cancer: report of two cases. AB - Port-site metastases in gynecological malignancies subsequent to laparoscopy have been reported with an incidence of 1.1-16%. These metastases tend to be disappearing after primary debulking surgery and subsequent primary chemotherapy. Local resection, chemotherapy and/or radiotherapy have been defined in the management of these metastases with enhanced clinical success. However, in extremely rare cases these metastases were also defined very early during neoadjuvant chemotherapy. Herein, we present two ovarian cancer cases which are clinically diagnosed with port site metastasis during neoadjuvant chemotherapy following diagnostic laparoscopy. Although neoadjuvant chemotherapy is sometimes needed in cases of fully advanced ovarian cancers, port-site metastasis may be encountered during neoadjuvant chemotherapy. The possible poor prognosis of these patients, especially those who have ascites, should make us careful in performing diagnostic laparoscopy with preventive measures for port-site metastasis and to start the chemotherapy immediately. PMID- 21607099 TI - Chylous ascites following robotic lymph node dissection on a patient with metastatic cervical carcinoma. AB - Chylous ascites is an uncommon postoperative complication of gynecological surgery. We report a case of chylous ascites following a robotic lymph node dissection for a cervical carcinoma. A 38-year-old woman with IB2 cervical adenocarcinoma with a palpable 3 cm left external iliac lymph node was taken to the operating room for robotic-assisted laparoscopic pelvic and para-aortic lymph node dissection. Patient was discharged on postoperative day 2 after an apparent uncomplicated procedure. The patient was readmitted the hospital on postoperative day 9 with abdominal distention and a CT-scan revealed free fluid in the abdomen and pelvis. A paracentesis demonstrated milky-fluid with an elevated concentration of triglycerides, confirming the diagnosis of chylous ascites. She recovered well with conservative measures. The risk of postoperative chylous ascites following lymph node dissection is still present despite the utilization of new technologies such as the da Vinci robot. PMID- 21607100 TI - What is the purpose of launching World Journal of Stem Cells? AB - The first issue of World Journal of Stem Cells (WJSC), whose preparatory work was initiated on September 27, 2008, will be published on December 31, 2009. The WJSC Editorial Board has now been established and consists of 281 distinguished experts from 28 countries. Our purpose of launching WJSC is to publish peer reviewed, high-quality articles via an open-access online publishing model, thereby acting as a platform for communication between peers and the wider public, and maximizing the benefits to editorial board members, authors and readers. PMID- 21607101 TI - Microenvironment at tissue injury, a key focus for efficient stem cell therapy: A discussion of mesenchymal stem cells. AB - Stem cell therapy is not a new field, as indicated by the success of hematopoietic stem cell reconstitution for various hematological malignancies and immune-mediated disorders. In the case of tissue repair, the major issue is whether stem cells should be implanted, regardless of the type and degree of injury. Mesenchymal stem cells have thus far shown evidence of safety, based on numerous clinical trials, particularly for immune-mediated disorders. The premise behind these trials is to regulate the stimulatory immune responses negatively. To apply stem cells for other disorders, such as acute injuries caused by insults from surgical trauma and myocardial infarction, would require other scientific considerations. This does not imply that such injuries are not accompanied by immune responses. Indeed, acute injuries could accompany infiltration of immune cells to the sites of injuries. The implantation of stem cells within a milieu of inflammation will establish an immediate crosstalk among the stem cells, microenvironmental molecules, and resident and infiltrating immune cells. The responses at the microenvironment of tissue injury could affect distant and nearby organs. This editorial argues that the microenvironment of any tissue injury is a key consideration for effective stem cell therapy. PMID- 21607102 TI - Tumor initiating cells in pancreatic cancer: A critical view. AB - Emerging evidence points to the existence of pancreatic cancer stem cells (CSC) as the culprit in the initiation, maintenance, metastasis, and treatment resistance of pancreatic cancer. The existence of such a cell population would have an important impact on the design of novel therapies against this devastating disease. However, no in vivo validation or rebuttal of the pancreatic CSC hypothesis exists. Major backlashes in the discussion on CSC are firstly, the confusion between the terms CSC and cell of origin of pancreatic ductal adenocarcinoma (PDAC), secondly the ambiguity of the cell of origin itself and thirdly, the fact that the CSC hypothesis is based on cell sorting and xenografting experiments; the latter of which often precludes solid conclusions because of the lack of a natural microenvironment and differences in drug delivery. Nonetheless, recent studies in other cancers partially support the CSC hypothesis by demonstrating a link between epithelial-to-mesenchymal transdifferentiation/transition (EMT) and CSC properties. Such a link is again open to dispute as EMT is a reversible process which is highly dependent on major oncogenic pathways in PDAC [e.g. K-Ras, transforming growth factor-beta (TGF beta)] rather than on presumed cancer stem cell pathways. Hence, the available evidence does not robustly support the CSC concept in PDAC and a thorough validation of this hypothesis in well-defined genetically engineered mouse models of pancreatic cancer is required. PMID- 21607103 TI - Embryoid body formation from embryonic and induced pluripotent stem cells: Benefits of bioreactors. AB - Embryonic stem (ES) cells have the ability to differentiate into all germ layers, holding great promise not only for a model of early embryonic development but also for a robust cell source for cell-replacement therapies and for drug screening. Embryoid body (EB) formation from ES cells is a common method for producing different cell lineages for further applications. However, conventional techniques such as hanging drop or static suspension culture are either inherently incapable of large scale production or exhibit limited control over cell aggregation during EB formation and subsequent EB aggregation. For standardized mass EB production, a well defined scale-up platform is necessary. Recently, novel scenario methods of EB formation in hydrodynamic conditions created by bioreactor culture systems using stirred suspension systems (spinner flasks), rotating cell culture system and rotary orbital culture have allowed large-scale EB formation. Their use allows for continuous monitoring and control of the physical and chemical environment which is difficult to achieve by traditional methods. This review summarizes the current state of production of EBs derived from pluripotent cells in various culture systems. Furthermore, an overview of high quality EB formation strategies coupled with systems for in vitro differentiation into various cell types to be applied in cell replacement therapy is provided in this review. Recently, new insights in induced pluripotent stem (iPS) cell technology showed that differentiation and lineage commitment are not irreversible processes and this has opened new avenues in stem cell research. These cells are equivalent to ES cells in terms of both self-renewal and differentiation capacity. Hence, culture systems for expansion and differentiation of iPS cells can also apply methodologies developed with ES cells, although direct evidence of their use for iPS cells is still limited. PMID- 21607104 TI - Germline competence of mouse ES and iPS cell lines: Chimera technologies and genetic background. AB - In mice, gene targeting by homologous recombination continues to play an essential role in the understanding of functional genomics. This strategy allows precise location of the site of transgene integration and is most commonly used to ablate gene expression ("knock-out"), or to introduce mutant or modified alleles at the locus of interest ("knock-in"). The efficacy of producing live, transgenic mice challenges our understanding of this complex process, and of the factors which influence germline competence of embryonic stem cell lines. Increasingly, evidence indicates that culture conditions and in vitro manipulation can affect the germline-competence of Embryonic Stem cell (ES cell) lines by accumulation of chromosome abnormalities and/or epigenetic alterations of the ES cell genome. The effectiveness of ES cell derivation is greatly strain dependent and it may also influence the germline transmission capability. Recent technical improvements in the production of germline chimeras have been focused on means of generating ES cells lines with a higher germline potential. There are a number of options for generating chimeras from ES cells (ES chimera mice); however, each method has its advantages and disadvantages. Recent developments in induced pluripotent stem (iPS) cell technology have opened new avenues for generation of animals from genetically modified somatic cells by means of chimera technologies. The aim of this review is to give a brief account of how the factors mentioned above are influencing the germline transmission capacity and the developmental potential of mouse pluripotent stem cell lines. The most recent methods for generating specifically ES and iPS chimera mice, including the advantages and disadvantages of each method are also discussed. PMID- 21607105 TI - Recent advances in stem cell research for the treatment of diabetes. AB - The success achieved over the last decade with islet transplantation has intensified interest in treating diabetes, not only by cell transplantation, but also by stem cells. The formation of insulin-producing cells from pancreatic duct, acinar, and liver cells is an active area of investigation. Protocols for the in vitro differentiation of embryonic stem (ES) cells based on normal developmental processes, have generated insulin-producing cells, though at low efficiency and without full responsiveness to extracellular levels of glucose. Induced pluripotent stem cells, which have been generated from somatic cells by introducing Oct3/4, Sox2, Klf4, and c-Myc, and which are similar to ES cells in morphology, gene expression, epigenetic status and differentiation, can also differentiate into insulin-producing cells. Overexpression of embryonic transcription factors in stem cells could efficiently induce their differentiation into insulin-expressing cells. The purpose of this review is to demonstrate recent progress in the research for new sources of beta-cells, and to discuss strategies for the treatment of diabetes. PMID- 21607106 TI - The famous versus the inconvenient - or the dawn and the rise of 3D-culture systems. AB - One of the greatest impacts on in vitro cell biology was the introduction of three-dimensional (3D) culture systems more than six decades ago and this era may be called the dawn of 3D-tissue culture. Although the advantages were obvious, this field of research was a "sleeping beauty" until the 1970s when multicellular spheroids were discovered as ideal tumor models. With this rebirth, organotypical culture systems became valuable tools and this trend continues to increase. While in the beginning, simple approaches, such as aggregation culture techniques, were favored due to their simplicity and convenience, now more sophisticated systems are used and are still being developed. One of the boosts in the development of new culture techniques arises from elaborate manufacturing and surface modification techniques, especially micro and nano system technologies that have either improved dramatically or have evolved very recently. With the help of these tools, it will soon be possible to generate even more sophisticated and more organotypic-like culture systems. Since 3D perfused or superfused systems are much more complex to set up and maintain compared to use of petri dishes and culture flasks, the added value of 3D approaches still needs to be demonstrated. PMID- 21607107 TI - Targeting leukemia stem cells: The new goal of therapy in adult acute myeloid leukemia. AB - The most popular view of hematopoietic cell lineage organization is that of complex reactive or adaptative systems. Leukemia contains a subpopulation of cells that display characteristics of stem cells. These cells maintain tumor growth. The properties of leukemia stem cells indicate that current conventional chemotherapy, directed against the bulk of the tumor, will not be effective. Leukemia stem cells are quiescent and do not respond to cell cycle-specific cytotoxic agents used to treat leukemia and thus contribute to treatment failure. New strategies are required that specifically target this malignant stem cell population. PMID- 21607109 TI - Advances in stem cell therapy for the lower urinary tract. AB - Lower urinary tract diseases are emotionally and financially burdensome to the individual and society. Current treatments are ineffective or symptomatic. Conversely, stem cells (SCs) are regenerative and may offer long-term solutions. Among the different types of SCs, bone marrow SCs (BMSCs) and skeletal muscle derived SCs (SkMSCs) have received the most attention in pre-clinical and clinical trial studies concerning the lower urinary tract. In particular, clinical trials with SkMSCs for stress urinary incontinence have demonstrated impressive efficacy. However, both SkMSCs and BMSCs are difficult to obtain in quantity and therefore neither is optimal for the eventual implementation of SC therapy. On the other hand, adipose tissue-derived SCs (ADSCs) can be easily and abundantly obtained from "discarded" adipose tissue. Moreover, in several head-on comparison studies, ADSCs have demonstrated equal or superior therapeutic potential compared to BMSCs. Therefore, across several different medical disciplines, including urology, ADSC research is gaining wide attention. For the regeneration of bladder tissues, possible differentiation of ADSCs into bladder smooth muscle and epithelial cells has been demonstrated. For the treatment of bladder diseases, specifically hyperlipidemia and associated overactive bladder, ADSCs have also demonstrated efficacy. For the treatment of urethral sphincter dysfunction associated with birth trauma and hormonal deficiency, ADSC therapy was also beneficial. Finally, ADSCs were able to restore erectile function in various types of erectile dysfunction (ED), including those associated with diabetes, hyperlipidemia, and nerve injuries. Thus, ADSCs have demonstrated remarkable therapeutic potentials for the lower urinary tract. PMID- 21607108 TI - Effects of nanotopography on stem cell phenotypes. AB - Stem cells are unspecialized cells that can self renew indefinitely and differentiate into several somatic cells given the correct environmental cues. In the stem cell niche, stem cell-extracellular matrix (ECM) interactions are crucial for different cellular functions, such as adhesion, proliferation, and differentiation. Recently, in addition to chemical surface modifications, the importance of nanometric scale surface topography and roughness of biomaterials has increasingly becoming recognized as a crucial factor for cell survival and host tissue acceptance in synthetic ECMs. This review describes the influence of nanotopography on stem cell phenotypes. PMID- 21607110 TI - The bad and the good of mesenchymal stem cells in cancer: Boosters of tumor growth and vehicles for targeted delivery of anticancer agents. AB - In cancer biology, mesenchymal stem cells (MSCs) display aspects that can appear contradictory. On one hand, these cells possess several features which give them the ability to specifically target and then sustain cancer cells in their ability to survive the multifaceted host response against cancer. On the other hand, due to this excellent aptitude to home-in on tumor tissues, regardless their location in the host's body, MSCs are considered to be extremely selective vehicles to reach cancer cells specifically. Recently, MSC sustainment of cancer cell growth is a hot research topic. Indeed, these cells are known to sustain tumor angiogenesis and metastasis formation, to create a microenvironment favorable for cancer cell growth and to down-modulate the immune system capabilities in the host organism. On the other hand, since scientists became able to take advantage of their extremely selective capability to target cancer cells, MSCs are now also thought of in a different light. Indeed, MSCs are now considered a promising vehicle for local expression or delivery of even particularly toxic anticancer agents, ranging from Herpes Simplex Virus to locally-acting antineoplastic drugs. On this basis, investigation is now focused on how to impair the pro-neoplastic features of MSCs on one hand whilst taking advantage of their specific tropism toward cancer cells, on the other. As with the two faces of Janus, this review will concisely explore the research activity in these two apparently conflicting fields. PMID- 21607111 TI - Mesenchymal stem cells: From bench to bedside. AB - Human mesenchymal stem cells (hMSCs) have tremendous promise for use in a variety of clinical applications. The ability of these cells to self-renew and differentiate into multiple tissues makes them an attractive cell source for a new generation of cell-based regenerative therapies. Encouraging results from clinical trials have also generated growing enthusiasm regarding MSC therapy and related treatment, but gaps remain in understanding MSC tissue repair mechanisms and in clinical strategies for efficient cell delivery and consistent therapeutic outcomes. For these reasons, discoveries from basic research and their implementation in clinical trials are essential to advance MSC therapy from the laboratory bench to the patient's bedside. PMID- 21607112 TI - Hematopoietic stem cells in research and clinical applications: The "CD34 issue". AB - In this paper, experimental findings concerning the kinetics of hematopoietic reconstitution are compared to corresponding clinical data. Although not clearly apparent, the transplantation practice seems to confirm the basic proposals of experimental hematology concerning hematopoietic reconstitution resulting from successive waves of repopulation stemming from different subpopulations of progenitor and stem cells. One of the "first rate" parameters in clinical transplantations in hematology; i.e. the CD34+ positive cell dose, has been discussed with respect to the functional heterogeneity and variability of cell populations endowed by expression of CD34. This parameter is useful only if the relative proportion of stem and progenitor cells in the CD34+ cell population is more or less maintained in a series of patients or donors. This proportion could vary with respect to the source, pathology, treatment, processing procedure, the graft ex vivo treatment and so on. Therefore, a universal dose of CD34+ cells cannot be defined. In addition, to avoid further confusion, the CD34+ cells should not be named "stem cells" or "progenitor cells" since these denominations only concern functionally characterized cell entities. PMID- 21607114 TI - Application of human umbilical cord blood-derived mesenchymal stem cells in disease models. AB - Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) are regarded as an alternative source of bone marrow-derived mesenchymal stem cells because collection of cord blood is less invasive than that of bone marrow. hUCB MSCs have recently been studied for evaluation of their potential as a source of cell therapy. In this review, the general characteristics of hUCB-MSCs and their therapeutic effects on various diseases in vitro and in vivo will be discussed. PMID- 21607115 TI - A General Purpose Q-Measuring Circuit Using Pulse Ring-Down. AB - A general purpose pulsed microwave circuit was developed for the purpose of measuring resonator Q by the pulse ring-down method in EPR spectrometers without pulse capability. The circuit was installed and tested in a Bruker X-band EPR bridge. This method and circuit could be adapted for use in a variety of spectrometers operating at various microwave frequencies. PMID- 21607113 TI - Human pluripotent stem cells: from biology to cell therapy. AB - Human pluripotent stem cells (PSCs), encompassing embryonic stem cells and induced pluripotent stem cells, proliferate extensively and differentiate into virtually any desired cell type. PSCs endow regenerative medicine with an unlimited source of replacement cells suitable for human therapy. Several hurdles must be carefully addressed in PSC research before these theoretical possibilities are translated into clinical applications. These obstacles are: (1) cell proliferation; (2) cell differentiation; (3) genetic integrity; (4) allogenicity; and (5) ethical issues. We discuss these issues and underline the fact that the answers to these questions lie in a better understanding of the biology of PSCs. To contribute to this aim, we have developed a free online expression atlas, Amazonia!, that displays for each human gene a virtual northern blot for PSC samples and adult tissues (http://www.amazonia.transcriptome.eu). PMID- 21607116 TI - Structure-activity relationships of ustiloxin analogues. AB - Four novel ustiloxin D analogues were synthesized focusing on the size of the macrocyclic core, the stereochemistry at the bridgehead ether, and the enantiomer of ustiloxin D. All four were subjected to biological evaluation testing the inhibition of tubulin polymerization. Only 2,2-dimethyl-ustiloxin D retained any activity. PMID- 21607117 TI - Studies of RF Shimming Techniques with Minimization of RF Power Deposition and Their Associated Temperature Changes. AB - In ultrahigh field (UHF), human magnetic resonance imaging (MRI) concerns related to the homogeneity of the B1+ field [the radiofrequency (RF) magnetic field component responsible for the excitation of the spins] and the local/average specific absorption rate (SAR) are highly evident. In this work, through RF shimming techniques, a full-wave electromagnetic model that treats a coupled-RF coil and the load (an 18-tissue anatomically detailed human head model) as a single system is utilized to simultaneously (1) improve the homogeneity of B1+ field in various regions of interest across the volume of the human head and (2) minimize the total RF power deposition at 7 and 9.4 T. The numerical results illustrate that the B1+ field homogeneity (evaluated by the coefficient of variance) can be greatly improved in 3D slabs that vary in orientations and sizes, in the brain, and in the entire head volume without increasing the total RF power deposition in the head to exceed that obtained with quadrature excitation. The RF shimming simulation results are experimentally validated (by performing RF shimming without experimental B(1) measurements) on a head-sized phantom using a 7-T human MRI scanner equipped with a transmit array excitation system. The SAR and associated temperature changes under quadrature and RF shimming excitation conditions are calculated and compared. PMID- 21607118 TI - A Fluctuating Pattern of Over- and Under-Adherence for HAART: A Case Study from a Videophone Intervention Project. AB - Highly Active Antiretroviral Therapy (HAART) has transformed HIV from a terminal illness to a chronic condition. While disagreement remains regarding the level of medication adherence required to achieve and maintain viral suppression, the highest possible rate is preferable. This article discusses the case study of "Bob," a 54 year-old man living with HIV for 25 years. At baseline, Bob evinced fluctuating patterns of medication over- and under-adherence and reported numerous negative side effects. Bob participated in eight videophone-administered adherence intervention sessions. His adherence improved to a high of 97.9% at one month follow-up; his negative treatment side effects subsided considerably. This case study demonstrates that videophone technology is a potential medium by which to assess and intervene upon HIV medication adherence. PMID- 21607119 TI - Pterin chemistry and its relationship to the molybdenum cofactor. AB - The molybdenum cofactor is composed of a molybdenum coordinated by one or two rather complicated ligands known as either molybdopterin or pyranopterin. Pterin is one of a large family of bicyclic N-heterocycles called pteridines. Such molecules are widely found in Nature, having various forms to perform a variety of biological functions. This article describes the basic nomenclature of pterin, their biological roles, structure, chemical synthesis and redox reactivity. In addition, the biosynthesis of pterins and current models of the molybdenum cofactor are discussed. PMID- 21607120 TI - FOCUS SPLITTING ASSOCIATED WITH PROPAGATION OF FOCUSED ULTRASOUND THROUGH THE RIB CAGE. AB - The effect of focus splitting after propagation of focused ultrasound through a rib cage is investigated theoretically. It is shown that the mechanism of this effect is caused by the interference of waves from two or more spatially separated sources, such as intercostal spaces. Analytical estimates of the parameters of splitting are obtained, i.e., the number of foci, their amplitudes, diameter, and the distance between them, depending on the transducer parameters, as well as the dimensions of the rib cage and position of ribs relative to the radiator. Various configurations of the relative positioning of ribs and radiator are considered; it is shown which of them are the most effective for real surgical operations. PMID- 21607121 TI - Vessel-associated stem cells from skeletal muscle: From biology to future uses in cell therapy. AB - Over the last years, the existence of different stem cells with myogenic potential has been widely investigated. Besides the classical skeletal muscle progenitors represented by satellite cells, numerous multipotent and embryologically unrelated progenitors with a potential role in muscle differentiation and repair have been identified. In order to conceive a therapeutic approach for degenerative muscle disorders, it is of primary importance to identify an ideal stem cell endowed with all the features for a possible use in vivo. Among all emerging populations, vessel-associated stem cells are a novel and promising class of multipotent progenitors of mesodermal origin and with high myogenic potential which seem to best fit all the requirements for a possible cell therapy. In vitro and in vivostudies have already tested the effectiveness and safety of vessel-associated stem cells in animal models. This leads to the concrete possibility in the future to start pilot human clinical trials, hopefully opening the way to a turning point in the treatment of genetic and acquired muscle disorders. PMID- 21607122 TI - Immunological properties of embryonic and adult stem cells. AB - The possibility of treating degenerative diseases by stem cell-based approaches is a promising therapeutical option. Among major concerns for the clinical application of stem cells, some derive from the possibility that stem cells may be rejected by the immune system as a consequence of histoincompatibility and that stem cells themselves may interfere with the normal functions of host immune response. Therefore, the immunogenicity and the immunomodulatory properties of stem cells must be carefully addressed. Although these properties are common features of different stem cell types, some peculiarities can be recognized and characterized for their proper clinical use. PMID- 21607125 TI - A novel strategy for engineering vascularized grafts in vitro. AB - Tissue engineering is an interdisciplinary field promising new therapeutic means for replacing lost or severely damaged tissues or organs. However, the fabrication of complex engineered tissues has been hampered due to the lack of vascularization to provide sufficient blood supply after implantation. In this article, we propose using rapid prototyping technology to prefabricate a scaffold with an inside hollowed vascular system including an arterial end, a venous end and capillary networks between them. The scaffold will be ''printed'' layer by layer. When printing every layer, a ''low-melting point'' material will be used to form a blood vessel network and a tissue-specific material will be used outside it. Hereafter the 'low-melting point' material will be evacuated by vaporization to ensure a hollowed vessel network. Then the inside hollowed capillary network can be endothelialized by using autologous endothelial cells in a cycling bioreactor while the outside material can be embedded with tissue special cells. In the end, the new vascularized autologous grafts could be transferred to the defect site by using microsurgical techniques to connect the grafts with the host artery and vein. The strategy would facilitate construction of complex tissue engineering if the hypothesis proved to be practical. PMID- 21607123 TI - Mesenchymal stem cells: Molecular characteristics and clinical applications. AB - Mesenchymal stem cells (MSCs) are non-hematopoietic stem cells with the capacity to differentiate into tissues of both mesenchymal and non-mesenchymal origin. MSCs can differentiate into osteoblastic, chondrogenic, and adipogenic lineages, although recent studies have demonstrated that MSCs are also able to differentiate into other lineages, including neuronal and cardiomyogenic lineages. Since their original isolation from the bone marrow, MSCs have been successfully harvested from many other tissues. Their ease of isolation and ex vivo expansion combined with their immunoprivileged nature has made these cells popular candidates for stem cell therapies. These cells have the potential to alter disease pathophysiology through many modalities including cytokine secretion, capacity to differentiate along various lineages, immune modulation and direct cell-cell interaction with diseased tissue. Here we first review basic features of MSC biology including MSC characteristics in culture, homing mechanisms, differentiation capabilities and immune modulation. We then highlight some in vivo and clinical evidence supporting the therapeutic roles of MSCs and their uses in orthopedic, autoimmune, and ischemic disorders. PMID- 21607126 TI - Epigenetic states and expression of imprinted genes in human embryonic stem cells. AB - AIM: To investigate the epigenetic states and expression of imprinted genes in five human embryonic stem cell (hESC) lines derived in Taiwan. METHODS: The heterozygous alleles of single nucleotide polymorphisms (SNPs) at imprinted genes were analyzed by sequencing genomic DNAs of hESC lines and the monoallelic expression of the imprinted genes were confirmed by sequencing the cDNAs. The expression profiles of 32 known imprinted genes of five hESC lines were determined using Affymetrix human genome U133 plus 2.0 DNA microarray. RESULTS: The heterozygous alleles of SNPs at seven imprinted genes, IPW, PEG10, NESP55, KCNQ1, ATP10A, TCEB3C and IGF2, were identified and the monoallelic expression of these imprinted genes except IGF2 were confirmed. The IGF2 gene was found to be imprinted in hESC line T2 but partially imprinted in line T3 and not imprinted in line T4 embryoid bodies. Ten imprinted genes, namely GRB10, PEG10, SGCE, MEST, SDHD, SNRPN, SNURF, NDN, IPW and NESP55, were found to be highly expressed in the undifferentiated hESC lines and down-regulated in differentiated derivatives. The UBE3A gene abundantly expressed in undifferentiated hESC lines and further up regulated in differentiated tissues. The expression levels of other 21 imprinted genes were relatively low in undifferentiated hESC lines and five of these genes (TP73, COPG2, OSBPL5, IGF2 and ATP10A) were found to be up-regulated in differentiated tissues. CONCLUSION: The epigenetic states and expression of imprinted genes in hESC lines should be thoroughly studied after extended culture and upon differentiation in order to understand epigenetic stability in hESC lines before their clinical applications. PMID- 21607124 TI - Mesenchymal stromal cells from human perinatal tissues: From biology to cell therapy. AB - Cell-based regenerative medicine is of growing interest in biomedical research. The role of stem cells in this context is under intense scrutiny and may help to define principles of organ regeneration and develop innovative therapeutics for organ failure. Utilizing stem and progenitor cells for organ replacement has been conducted for many years when performing hematopoietic stem cell transplantation. Since the first successful transplantation of umbilical cord blood to treat hematological malignancies, non-hematopoietic stem and progenitor cell populations have recently been identified within umbilical cord blood and other perinatal and fetal tissues. A cell population entitled mesenchymal stromal cells (MSCs) emerged as one of the most intensely studied as it subsumes a variety of capacities: MSCs can differentiate into various subtypes of the mesodermal lineage, they secrete a large array of trophic factors suitable of recruiting endogenous repair processes and they are immunomodulatory.Focusing on perinatal tissues to isolate MSCs, we will discuss some of the challenges associated with these cell types concentrating on concepts of isolation and expansion, the comparison with cells derived from other tissue sources, regarding phenotype and differentiation capacity and finally their therapeutic potential. PMID- 21607127 TI - Adipose tissue-derived progenitor cells and cancer. AB - Recruitment of stem cells and partially differentiated progenitor cells is a process which accompanies and facilitates the progression of cancer. One of the factors complicating the clinical course of cancer is obesity, a progressively widespread medical condition resulting from overgrowth of white adipose tissue (WAT), commonly known as white fat. The mechanisms by which obesity influences cancer risk and progression are not completely understood. Cells of WAT secret soluble molecules (adipokines) that could stimulate tumor growth, although there is no consensus on which cell populations and which adipokines are important. Recent reports suggest that WAT-derived mesenchymal stem (stromal) cells, termed adipose stem cells (ASC), may represent a cell population linking obesity and cancer. Studies in animal models demonstrate that adipokines secreted by ASC can promote tumor growth by assisting in formation of new blood vessels, a process necessary for expansion of tumor mass. Importantly, migration of ASC from WAT to tumors has been demonstrated, indicating that the tumor microenvironment in cancer may be modulated by ASC-derived trophic factors in a paracrine rather than in an endocrine manner. Here, we review possible positive and adverse implications of progenitor cell recruitment into the diseased sites with a particular emphasis on the role in cancer progression of progenitors that are expanded in obesity. PMID- 21607128 TI - Spontaneous immortalization of human dermal microvascular endothelial cells. AB - AIM: To establish and characterize a spontaneously immortalized human dermal microvascular endothelial cell line, iHDME1. METHODS: We developed a spontaneous immortalization method. This approach is based on the application of optimized culture media and culture conditions without addition of any exogenous oncogenes or carcinogens. Using this approach, we have successfully established a microvascular endothelial cell line, iHDME1, from primary human dermal microvascular endothelial cells. iHDME1 cells have been maintained in culture dishes for more than 50 passages over a period of 6 mo. Using a GFP expressing retrovirus, we generated a GFP-stable cell line (iHDME1-GFP). RESULTS: iHDME1 retain endothelial morphology and uniformly express endothelial markers such as VEGF receptor 2 and VE-cadherin but not alpha-smooth muscle actin (alpha-SM actin) and cytokeratin 18, markers for smooth muscle cells and epithelial cells respectively. These cells retain endothelial properties, migrate in response to VEGF stimulation and form 3-D vascular structures in Matrigel, similar to the parental cells. There is no significant difference in cell cycle profile between the parental cells and iHDME1 cells. Further analysis indicates enhanced stemness in iHDME1 cells compared to parental cells. iHDME1 cells display elevated expression of CD133 and hTERT. CONCLUSION: iHDME1 cells will be a valuable source for studying angiogenesis. PMID- 21607129 TI - Histone acetylation and its role in embryonic stem cell differentiation. AB - The understanding of mechanisms leading to cellular differentiation is the main aim of numerous studies. Accessibility of DNA to transcription factors depends on local chromatin structure and chromatin compaction inhibits gene transcription. Histone acetylation correlates with an open chromatin structure and increased gene expression. Gene transcription levels are changed in early embryonic stem cells differentiation in a tissue-specific manner and epigenetic marks are modified, including increased global acetylation levels. Manipulation of histone deacetylases activity might be an interesting tool to generate populations of specific cell types for transplantation purposes. Thus, this review aims to show recent findings on histone acetylation, a post translational modification and its manipulation in embryonic stem cells differentiation. PMID- 21607130 TI - Gene targeting and Calcium handling efficiencies in mouse embryonic stem cell lines. AB - AIM: To compare gene targeting efficiencies, expression profiles, and Ca(2+) handling potentials in two widely used mouse embryonic stem cell lines. METHODS: The two widely used mouse embryonic stem cell lines, R1 and HM-1, were cultured and maintained on Mitomycin C treated mouse embryonic fibroblast feeder cell layers, following standard culture procedures. Cells were incubated with primary and secondary antibodies before fluorescence activated cell sorting analysis to compare known pluripotency markers. Moreover, cells were harvested by trypsinization and transfected with a kinase-inactive murine Tyk2 targeting construct, following the BioRad and Amaxa transfection procedures. Subsequently, the cells were cultured and neomycin-resistant cells were picked after 13 d of selection. Surviving clones were screened twice by polymerase chain reaction (PCR) and finally confirmed by Southern blot analysis before comparison. Global gene expression profiles of more than 20 400 probes were also compared and significantly regulated genes were confirmed by real time PCR analysis. Calcium handling potentials of these cell lines were also compared using various agonists. RESULTS: We found significant differences in transfection efficiencies of the two cell lines (91% +/- 6.1% vs 75% +/- 4.2%, P = 0.01). Differences in the targeting efficiencies were also significant whether the Amaxa or BioRad platforms were used for comparison. We did not observe significant differences in the levels of many known pluripotency markers. However, our genome-wide expression analysis using more than 20 400 spotted cDNA arrays identified 55 differentially regulated transcripts (P < 0.05) implicated in various important biological processes, including binding molecular functions (particularly Ca(2+) binding roles). Subsequently, we measured Ca(2+) signals in these cell lines in response to various calcium agonists, both in high and low Ca(2+) solutions, and found significant differences (P < 0.05) in the regulation of Ca(2+) homeostasis between the investigated cell lines. Then we further compared the detection and expression of various membrane and intracellular Ca(2+) receptors and similarly found significant (P < 0.05) variations in a number of calcium receptors between these cell lines. CONCLUSION: Results of this study emphasize the importance of considering intrinsic cellular variations, during selection of cell lines for experiments and interpretations of experimental results. PMID- 21607131 TI - Immune regulatory properties of multipotent mesenchymal stromal cells: Where do we stand? AB - Multipotent mesenchymal stromal cells (MSC) can be isolated and efficiently expanded from almost every single body tissue and have the ability of self renewal and differentiation into various mesodermal cell lineages. Moreover, these cells are considered immunologically privileged, related to a lack of surface expression of costimulatory molecules required for complete T cell activation. Recently, it has been observed that MSC are capable of suppressing the immune response by inhibiting the maturation of dendritic cells and suppressing the function of T lymphocytes, B lymphocytes and natural killer cells in autoimmune and inflammatory diseases as a new strategy for immunosuppression. The understanding of immune regulation mechanisms by MSC is necessary for their use as immunotherapy in clinical applications for several diseases. PMID- 21607132 TI - Progenitor cells as remote "bioreactors": neuroprotection via modulation of the systemic inflammatory response. AB - Acute central nervous system (CNS) injuries such as spinal cord injury, traumatic brain injury, autoimmune encephalomyelitis, and ischemic stroke are associated with significant morbidity, mortality, and health care costs worldwide. Preliminary research has shown potential neuroprotection associated with adult tissue derived stem/progenitor cell based therapies. While initial research indicated that engraftment and transdifferentiation into neural cells could explain the observed benefit, the exact mechanism remains controversial. A second hypothesis details localized stem/progenitor cell engraftment with alteration of the loco-regional milieu; however, the limited rate of cell engraftment makes this theory less likely. There is a growing amount of preclinical data supporting the idea that, after intravenous injection, stem/progenitor cells interact with immunologic cells located in organ systems distant to the CNS, thereby altering the systemic immunologic/inflammatory response. Such distant cell "bioreactors" could modulate the observed post-injury pro-inflammatory environment and lead to neuroprotection. In this review, we discuss the current literature detailing the above mechanisms of action for adult stem/progenitor cell based therapies in the CNS. PMID- 21607133 TI - Functional ion channels in stem cells. AB - Bioelectrical signals generated by ion channels play crucial roles in excitation genesis and impulse conduction in excitable cells as well as in cell proliferation, migration and apoptosis in proliferative cells. Recent studies have demonstrated that multiple ion channels are heterogeneously present in different stem cells; however, patterns and phenotypes of ion channels are species- and/or origin-dependent. This editorial review focuses on the recent findings related to the expression of functional ion channels and the roles of these channels in regulation of cell proliferation in stem cells. Additional effort is required in the future to clarify the ion channel expression in different types of stem cells; special attention should be paid to the relationship between ion channels and stem cell proliferation, migration and differentiation. PMID- 21607135 TI - Non-random tissue distribution of human naive umbilical cord matrix stem cells. AB - AIM: To determine the tissue and temporal distribution of human umbilical cord matrix stem (hUCMS) cells in severe combined immunodeficiency (SCID) mice. METHODS: For studying the localization of hUCMS cells, tritiated thymidine labeled hUCMS cells were injected in SCID mice and tissue distribution was quantitatively determined using a liquid scintillation counter at days 1, 3, 7 and 14. Furthermore, an immunofluorescence detection technique was employed in which anti-human mitochondrial antibody was used to identify hUCMS cells in mouse tissues. In order to visualize the distribution of transplanted hUCMS cells in H&E stained tissue sections, India Black ink 4415 was used to label the hUCMS cells. RESULTS: When tritiated thymidine-labeled hUCMS cells were injected systemically (iv) in female SCID mice, the lung was the major site of accumulation at 24 h after transplantation. With time, the cells migrated to other tissues, and on day three, the spleen, stomach, and small and large intestines were the major accumulation sites. On day seven, a relatively large amount of radioactivity was detected in the adrenal gland, uterus, spleen, lung, and digestive tract. In addition, labeled cells had crossed the blood brain barrier by day 1. CONCLUSION: These results indicate that peripherally injected hUCMS cells distribute quantitatively in a tissue-specific manner throughout the body. PMID- 21607134 TI - Adipose-derived stromal cells: Their identity and uses in clinical trials, an update. AB - In adults, adipose tissue is abundant and can be easily sampled using liposuction. Largely involved in obesity and associated metabolic disorders, it is now described as a reservoir of immature stromal cells. These cells, called adipose-derived stromal cells (ADSCs) must be distinguished from the crude stromal vascular fraction (SVF) obtained after digestion of adipose tissue. ADSCs share many features with mesenchymal stem cells derived from bone marrow, including paracrine activity, but they also display some specific features, including a greater angiogenic potential. Their angiogenic properties as well as their paracrine activity suggest a putative tumor-promoting role for ADSCs although contradictory data have been published on this issue. Both SVF cells and ADSCs are currently being investigated in clinical trials in several fields (chronic inflammation, ischemic diseases, etc.). Apart from a phase III trial on the treatment of fistula, most of these are in phase I and use autologous cells. In the near future, the end results of these trials should provide a great deal of data on the safety of ADSC use. PMID- 21607136 TI - What is the purpose of launching World Journal of Gastrointestinal Pathophysiology? AB - The first issue of World Journal of Gastrointestinal Pathophysiology (WJGP), whose preparatory work was initiated in June, 2009, is published on April 15, 2010. The WJGP Editorial Board has now been established and consists of 154 distinguished experts from 27 countries. Our purpose of launching WJGP is to publish peer-reviewed, high-quality articles via an open-access online publishing model, thereby acting as a platform for communication between peers and the wider public, and maximizing the benefits to editorial board members, authors and readers. PMID- 21607137 TI - Integrin alpha6beta4 in colorectal cancer. AB - The ability of cells to interact with extracellular matrix macromolecules is at the forefront of the regulation of cell phenotype and organization. Indeed most if not all cells bear specific cell surface receptors for these molecules, namely the integrins, which are specific for the ligation of various macromolecules such as the laminins, fibronectins and tenascins. It is now well established that integrins can regulate a variety of biological activities, most notably cell cycle and tissue-specific gene expression. In the intestine, several observations suggest functional roles for cell-matrix interactions in the regulation of epithelial cell functions. This article focuses on integrin alpha6beta4 as a paradigm to illustrate the importance as well as the complexity of integrins in the mediation of cell-matrix interactions. Indeed, alpha6beta4 has been well characterized for its involvement as a link between the cytoskeleton and extracellular matrix molecules as well as in the activation of a variety of intracellular signalization processes in cooperation with growth factor receptors. Furthermore, recent studies show that distinct forms of alpha6 and beta4 subunits are expressed in the human intestine and, more importantly, recent work provides experimental evidence that various forms of alpha6beta4 can differentially regulate intestinal epithelial cell functions under both normal and pathological conditions. For instance, it has been discovered that colorectal cancer cells express a hybrid form of alpha6beta4 that is never seen in normal cells. Although further work is needed, integrin alpha6beta4 is emerging as a key regulator of intestinal functions in both intestinal health and disease. PMID- 21607138 TI - Molecular mechanisms of cholangiocarcinoma. AB - Cholangiocarcinoma (CC), the malignant tumor of the epithelial cells lining the biliary ducts, has undergone a worldwide increase in incidence and mortality. The malignant transformation of the biliary cells originates from a multistep process evolving through chronic inflammation of the biliary tract to CC. In the last few years several advances have been towards understanding and clarifying the molecular mechanisms implicated in the cholangiocarcinogenesis process. However, many pathophysiologic aspects governing the growth of CC are still undefined. The poor prognosis of this tumor underlines the urgent need to codify the underlying molecular mechanisms involved in the growth and progression of CC in order to design effective preventive measures and valid treatment regimens. This review reports on progresses made in the last few years in clarifying the molecular pathways involved in the process of cholangiocarcinogenesis. PMID- 21607139 TI - Aberrant DNA methylation profile in cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a notoriously lethal epithelial cancer originating from the biliary system. As radical resection offers a poor success rate and limited effective adjuvant modalities exist in its advanced stage, the disease leads to a fairly poor prognosis. As the incidence of CCA is increasing, although the mortality rate remains stable, and few other definite etiologies have yet to be established, renewing our knowledge of its fundamental carcinogenesis is advisable. The latest advances in molecular carcinogenesis have highlighted the roles of epigenetic perturbations and cancer-related inflammation in CCA. This review focuses on the reciprocal effects between aberrant DNA methylation and inflammatory microenvironment in CCA. PMID- 21607140 TI - Involvement of cholangiocyte proliferation in biliary fibrosis. AB - Cholangiocytes are the epithelial cells that line the biliary tree. In the adult liver, they are a mitotically dormant cell population, unless ductular reaction is triggered by injury. The ability of cholangiocytes to proliferate is important in many different human pathological liver conditions that target this cell type, which are termed cholangiopathies (i.e. primary biliary cirrhosis, primary sclerosing cholangitis and biliary atresia). In our article, we provide background information on the morphological and functional heterogeneity of cholangiocytes, summarize what is currently known about their proliferative processes, and briefly describe the diseases that target these cells. In addition, we address recent findings that suggest cholangiocyte involvement in epithelial-to-mesenchymal transformation and liver fibrosis, and propose directions for future studies. PMID- 21607141 TI - Histamine regulation of hyperplastic and neoplastic cell growth in cholangiocytes. AB - Histamine has long been known to be involved in inflammatory events. The discovery of antihistamines dates back to the first half of the 20(th) century when a Swiss-Italian pharmacologist, Daniel Bovet began his work. In 1957 he was awarded a Nobel Prize for his production of antihistamines for allergy relief. Since that time, histamine has been found to play a role in other events besides allergic reaction. Possibly unbelievable to Bovet and his peers, histamine has now been marked as playing a role in liver pathologies including hepatobiliary diseases. PMID- 21607143 TI - Biogenic amines serotonin and dopamine regulate cholangiocyte hyperplastic and neoplastic growth. AB - Biogenic amines, such as serotonin and dopamine, regulate a multitude of cellular responses. A great deal of effort has been invested into understanding the effects of these molecules and their corresponding receptor systems on cholangiocyte and cholangiocarcinoma secretion, apoptosis and growth. This review summarizes the results of these efforts and highlights the importance of these regulatory molecules on the physiology and pathophysiology of cholangiocytes. Specifically we have focused on the recent findings into the effects of serotonin and dopamine on cholangiocyte hyperplasia and neoplastic growth. PMID- 21607142 TI - Role of sex hormones in the modulation of cholangiocyte function. AB - Over the last years, cholangiocytes, the cells that line the biliary tree, have been considered an important object of study for their biological properties which involves bile formation, proliferation, injury repair, fibrosis and angiogenesis. Cholangiocyte proliferation occurs in all pathologic conditions of liver injury where it is associated with inflammation and regeneration. During these processes, biliary cells start to secrete different cytokines, growth factors, neuropeptides and hormones which represent potential mechanisms for cross talk with other liver cells. Several studies suggest that hormones, and in particular, sex hormones, play a fundamental role in the modulation of the growth of this compartment in the injured liver which functionally conditions the progression of liver disease. Understanding the mechanisms of action and the intracellular pathways of these compounds on cholangiocyte pathophysiology will provide new potential strategies for the management of chronic liver diseases. The purpose of this review is to summarize the recent findings on the role of sex hormones in cholangiocyte proliferation and biology. PMID- 21607145 TI - Pancreatic secretory trypsin inhibitor: More than a trypsin inhibitor. AB - Kazal-type serine protease inhibitor is one of the most important and widely distributed protease inhibitor families. Pancreatic secretory trypsin inhibitor (PSTI), also known as serine protease inhibitor Kazal type I(SPINK1), binds rapidly to trypsin, inhibits its activity and is likely to protect the pancreas from prematurely activated trypsinogen. Therefore, it is an important factor in the onset of pancreatitis. Recent studies found that PSTI/SPINK1 is also involved in self-regulation of acinar cell phagocytosis, proliferation and growth of a variety of cell lines. In addition, it takes part in the response to inflammatory factor or injury and is highly related to adult type II citrullinemia. PMID- 21607146 TI - Metabolic syndrome and gastro-esophageal reflux: A link towards a growing interest in developed countries. AB - The aim of this Editorial is to describe the growing possibility of a link between gastro-esophageal reflux disease (GERD) and metabolic syndrome on the light of recent epidemiological and pathophysiological evidence. The state of the art of GERD is described, based on recent definitions, pathophysiological evidence, epidemiology in developed countries, clinical subtypes together with a diagnostic approach specifically focussed on the appropriateness of endoscopy. Metabolic syndrome is accurately defined and the pivotal role of insulin resistance is emphasized. The strong relationship between GERD and metabolic syndrome has been pathophysiologically analyzed, taking into account the role of obesity, mechanical factors and metabolic changes. Data collected by our group regarding eating habits and GERD are briefly summarized at the end of a pathophysiological analysis. The literature on the subject strongly supports the possibility that lifestyle and eating habits may be involved in both GERD and metabolic syndrome in developed countries. PMID- 21607144 TI - Paediatric cholestatic liver disease: Diagnosis, assessment of disease progression and mechanisms of fibrogenesis. AB - Cholestatic liver disease causes significant morbidity and mortality in children. The diagnosis and management of these diseases can be complicated by an inability to detect early stages of fibrosis and a lack of adequate interventional therapy. There is no single gold standard test that accurately reflects the presence of liver disease, or that can be used to monitor fibrosis progression, particularly in conditions such as cystic fibrosis. This has lead to controversy over how suspected liver disease in children is detected and diagnosed. This review discusses the challenges in using commonly available methods to diagnose hepatic fibrosis and monitor disease progression in children with cholestatic liver disease. In addition, the review examines the mechanisms hypothesised to be involved in the development of hepatic fibrogenesis in paediatric cholestatic liver injury which may ultimately aid in identifying new modalities to assist in both disease detection and therapeutic intervention. PMID- 21607148 TI - Colo-renal fistula: An unusual cause of hematochezia. AB - A 76 year old woman with bloody stools and symptomatic anemia presented to the Emergency Department approximately 2 wk after computed tomography (CT)-guided cryoablation to a 4.5 cm renal cell carcinoma on her left posterior kidney. The patient was initially prepped for a colonoscopy to view possible causes of lower gastrointestinal bleeding. However, the patient had a CT with PO contrast that revealed a variation of a renoalimentary fistula. The patient was subsequently brought to the operating room, and it was discovered that a colo-renal fistula had formed, with transmural perforation of the posterior descending colon. A left nephrectomy, left colectomy with colostomy and Hartmann's pouch was performed. PMID- 21607147 TI - Low-grade inflammation plays a pivotal role in gastrointestinal dysfunction in irritable bowel syndrome. AB - The pathogenesis of irritable bowel syndrome (IBS) is considered to be multifactorial and includes psychosocial factors, visceral hypersensitivity, infection, microbiota and immune activation. It is becoming increasingly clear that low-grade inflammation is present in IBS patients and a number of biomarkers have emerged. This review describes the evidence for low-grade inflammation in IBS and explores its mechanism with particular focus on gastrointestinal motor dysfunction. Understanding of the immunological basis of the altered gastrointestinal motor function in IBS may lead to new therapeutic strategies for IBS. PMID- 21607149 TI - Isolated splenic tuberculosis: A case report. AB - We present a rare case of a 36 year old man who presented with recurrent fever but no other symptoms. Laboratory data provided no specific information for diagnosis. Abdominal ultrasonography revealed splenomegaly with multiple small hypoechoic lesions within the spleen. Computed tomography of abdomen showed a hypodense diffuse lesion. A diagnosis of isolated splenic tuberculosis was confirmed after a splenic puncture and histopathological examination. PMID- 21607150 TI - Syphilitic proctitis mimicking rectal cancer: A case report. AB - Syphilitic proctitis is a rare disease. It usually presents as proctitis, ulcer and neoplasm but lacks pathognomonic clinical symptoms. It is, therefore, difficult to diagnose and is occasionally treated inappropriately. We report the case of a 51-year-old man who had a hard, ulcerated mass, which occupied the circumference of the rectal wall and which mimicked a rectal tumor. Fortunately, positive finding from routine toluidine red unheated serum test and treponema pallidum particle agglutination tests made us reevaluate the patient and led us to suspect syphilitic proctitis. This diagnosis was finally confirmed after successful penicillin G benzathine therapy which made surgery unnecessary. PMID- 21607151 TI - Emerging roles of connexin hemichannels in gastrointestinal and liver pathophysiology. AB - Connexin hemichannels have long been considered as mere structural precursors for gap junctions. In the last decade, it has become clear that they also act as individual channels, connecting the intracellular compartment and the extracellular environment. Impairement of connexin hemichannel functionality may result in disturbance of homeostasis, as exemplified in the current paper for the intestine and the liver. Research in this field still has a number of shortcomings, of which some are also discussed here. PMID- 21607152 TI - Immune-mediated bile duct injury: The case of primary biliary cirrhosis. AB - Autoimmune cholangitis would be the appropriate name to define the immune mediated bile duct injury following the breakdown of tolerance to mitochondrial proteins and the appearance of serum autoantibodies and autoreactive T cells. Nevertheless, the condition is universally named primary biliary cirrhosis (PBC). The disease etiology and pathogenesis remain largely unknown despite the proposed lines of evidence. One twin study and numerous epidemiology reports suggest that both a susceptible genetic background and environmental factors determine disease onset while a recent genome-wide association study proposed highly significant associations with several common genetic polymorphisms in subgroups of patients. Specific infectious agents and chemicals may contribute to the disease onset and perpetuation in a genetically susceptible host, possibly through molecular mimicry. Importantly, several murine models have been proposed and include strains in which PBC is genetically determined or induced by immunization with chemicals and bacteria. From a pathogenetic standpoint, new exciting data have demonstrated the unique apoptotic features of bile duct cells that allow the mitochondrial autoantigens to be taken up in their intact form within apoptotic blebs. We are convinced that the application of the most recent molecular techniques will soon provide developments in PBC etiology and pathogenesis with likely implications in diagnostics and therapeutics. PMID- 21607153 TI - Protein induced by vitamin K absence or antagonist II-producing gastric cancer. AB - Protein induced by vitamin K absence or antagonist II (PIVKA-II) is a putative specific marker of hepatocellular carcinoma (HCC), but it may also be produced by a small number of gastric cancers. To date, 16 cases of PIVKA-II-producing gastric cancer have been reported, 2 of which were reported by us and all of which were identified in Japan. There are no symptoms specific to PIVKA-II producing gastric cancer, and the representative clinical symptoms are general fatigue, appetite loss, and upper abdominal pain. Serum alpha-fetoprotein (AFP) levels are also increased in almost all cases. Liver metastasis is observed in approximately 80% of cases and portal vein tumor thrombus is observed in approximately 20% of cases. Differential diagnosis between metastatic liver tumor and HCC is often difficult. Grossly, almost all cases appear as advanced gastric cancer. Histologically, a hepatoid pattern is observed in many cases, in addition to a moderately to poorly differentiated adenocarcinoma component. The production of PIVKA-II and AFP is usually confirmed using immunohistochemical staining. Treatment and prognosis largely depends on the existence of liver metastasis, and the prognosis of patients with liver metastasis is very poor. PIVKA-II may be produced during the hepatocellularmetaplasia of the tumor cells. PMID- 21607154 TI - Ischemic post-conditioning to counteract intestinal ischemia/reperfusion injury. AB - Intestinal ischemia is a severe disorder with a variety of causes. Reperfusion is a common occurrence during treatment of acute intestinal ischemia but the injury resulting from ischemia/reperfusion (IR) may lead to even more serious complications from intestinal atrophy to multiple organ failure and death. The susceptibility of the intestine to IR-induced injury (IRI) appears from various experimental studies and clinical settings such as cardiac and major vascular surgery and organ transplantation. Whereas oxygen free radicals, activation of leukocytes, failure of microvascular perfusion, cellular acidosis and disturbance of intracellular homeostasis have been implicated as important factors in the pathogenesis of intestinal IRI, the mechanisms underlying this disorder are not well known. To date, increasing attention is being paid in animal studies to potential pre- and post-ischemia treatments that protect against intestinal IRI such as drug interference with IR-induced apoptosis and inflammation processes and ischemic pre-conditioning. However, better insight is needed into the molecular and cellular events associated with reperfusion-induced damage to develop effective clinical protection protocols to combat this disorder. In this respect, the use of ischemic post-conditioning in combination with experimentally prolonged acidosis blocking deleterious reperfusion actions may turn out to have particular clinical relevance. PMID- 21607155 TI - Granulocytic sarcoma of the rectum: Report of one case that presented with rectal bleeding. AB - Granulocytic sarcoma is an uncommon and localized extramedullary tumor composed of immature granulocytic cells. It may present in association with acute myeloid leukaemia, myelodysplastic syndrome and chronic myelogenous leukaemia. Granulocytic sarcoma may occur in any anatomical site but involvement of the gastrointestinal tract is rare, especially in the rectum. We report on the case of a 17 year old female who presented with rectal bleeding, abdominal pain and weight loss one mo prior to admission. Rectosigmoidoscopy revealed a rectal polypoid and ulcerated mass. The histological examination of the mass showed granulocytic sarcoma. Bone marrow examination was compatible with acute promyelocytic leukaemia (FAB type M3). This case report is a reminder of this peculiar sign of tumoral syndrome in acute myeloid leukaemia. We also discuss diagnostic methods and analyze the disease course. PMID- 21607156 TI - Fatty acid binding receptors in intestinal physiology and pathophysiology. AB - Free fatty acids are essential dietary components and recognized as important molecules in the maintenance of cellular homeostasis. In the last decade, the molecular pathways for free fatty acid sensing in the gastrointestinal tract have been further elucidated by molecular identification and functional characterization of fatty acid binding receptors. These sensing molecules belong to the family of G protein-coupled receptors. In the intestine, four important receptors have been described so far. They differ in molecular structure, ligand specificity, expression pattern, and functional properties. In this review, an overview of intestinal fatty acid binding receptors and their role in intestinal physiology and pathophysiology is given. PMID- 21607157 TI - Histamine 3 receptor activation mediates inhibition of acid secretion during Helicobacter-induced gastritis. AB - AIM: To test the hypothesis that histamine 3 receptor (H3R) activation during Helicobacter infection inhibits gastric acid secretion in vivo and in vitro. METHODS: Helicobacter felis (H. felis) infected and uninfected C57Bl/6 mice were infused with either PBS or the H3 receptor antagonist thioperamide (THIO) for 12 wk. After treatment, mice were analyzed for morphological changes and gastric acid content. Total RNA was prepared from the stomachs of each group and analyzed for changes in somatostatin and gastrin mRNA abundance by real time-polymerase chain reaction (RT-PCR). Location of H3 receptors in the stomach was analyzed by co-localization using antibodies specific for the H3 receptor and parietal cell marker H(+), K(+)-ATPase beta subunit. RESULTS: Inflammation and parietal cell atrophy was observed after 12 wk of H. felis infection. Interestingly, treatment with the H3R antagonist thioperamide (THIO) prior to and during infection prevented H. felis-induced inflammation and atrophy. Compared to the uninfected controls, infected mice also had significantly decreased gastric acid. After eradication of H. felis with THIO treatment, gastric acidity was restored. Compared to the control mice, somatostatin mRNA abundance was decreased while gastrin gene expression was elevated during infection. Despite elevated gastric acid levels, after eradication of H. felis with THIO, somatostatin mRNA was elevated whereas gastrin mRNA was suppressed. Immunofluorescence revealed the presence of H3 receptors on the parietal cells, somatostatin-secreting D-cells as well as the inflammatory cells. CONCLUSION: This study shows that during H. felis infection, gastric acidity is suppressed as a consequence of an inhibitory effect on the parietal cell by H3R activation. The stimulation of gastric mucosal H3Rs increases gastrin expression and release by inhibiting release of somatostatin. PMID- 21607158 TI - Eosinophilic ascites, an unusual presentation of eosinophilic gastroenteritis: A case report and review. AB - Eosinophilic ascites (EA) is a rare disorder of unknown etiology that has been reported in both adult and pediatric patients. It is a part of the syndrome of eosinophilic gastroenteritis, which is characterized by eosinophilic infiltration of any or all layers of the gut wall and may involve any segment of the gastrointestinal tract. Peripheral eosinophilia may or may not be present. We report a case of EA that developed post partum. PMID- 21607159 TI - Retroperitoneal cystic lymphangioma in an adult: A case report and review of the literature. AB - Lymphangiomas are rare benign cystic tumors of the lymphatic system. Retroperitoneal lymphangiomas account for 1% of all lymphangiomas, and approximately 186 cases have been reported. They may clinically present as a palpable abdominal mass and can cause diagnostic dilemmas with other retroperitoneal cystic tumors, including those arising from the liver, kidney and pancreas. This report describes the rare case of a cystic retroperitoneal lymphangioma in a 54-year-old male patient. The lymphangioma had progressed to the point of inducing clinical symptoms of abdominal distention, abdominal pain, anorexia, fever, nausea and diarrhea. Radiological imaging revealed a large multiloculated cystic abdominal mass with enhancing septations involving the upper retroperitoneum and extending into the pelvis. Surgical removal of the cyst was accomplished without incident. A benign cystic retroperitoneal lymphangioma was diagnosed on histology and confirmed with immunohistochemical stains. PMID- 21607161 TI - Right colon cancer presenting as hemorrhagic shock. AB - A 67-year-old man visited our hospital with a history of continuous hematochezia leading to hemorrhagic shock. An abdominal computed tomography scan revealed a large mass in the ascending colon invading the duodenum and pancreatic head as well as extravasation of blood from the gastroduodenal artery (GDA) into the colon. Colonoscopy revealed an irregular ulcerative lesion and stenosis in the ascending colon. Therefore, right hemicolectomy combined with pylorus-preserving pancreaticoduodenectomy was performed. Histologically, the tumor was classified as a moderately differentiated adenocarcinoma. Moreover, cancer cells were mainly located in the colon but had also invaded the duodenum and pancreas and involved the GDA. Immunohistochemically, the tumor cells were positive for cytokeratin (CK)20 and carcinoembryonic antigen (CEA) but not for CK7 and carbohydrate antigen (CA)19-9. The patient died 23 d after the surgery because he had another episode of arterial bleeding from the anastomosis site. Although En bloc resection of the tumor with pancreaticoduodenectomy and colectomy performed for locally advanced colon cancer can ensure long-term survival, patients undergoing these procedures should be carefully monitored, particularly when the tumor involves the main artery. PMID- 21607160 TI - Therapeutic potential of curcumin in gastrointestinal diseases. AB - Curcumin, also known as diferuloylmethane, is derived from the plant Curcuma longa and is the active ingredient of the spice turmeric. The therapeutic activities of curcumin for a wide variety of diseases such as diabetes, allergies, arthritis and other chronic and inflammatory diseases have been known for a long time. More recently, curcumin's therapeutic potential for preventing and treating various cancers is being recognized. As curcumin's therapeutic promise is being explored more systematically in various diseases, it has become clear that, due to its increased bioavailability in the gastrointestinal tract, curcumin may be particularly suited to be developed to treat gastrointestinal diseases. This review summarizes some of the current literature of curcumin's anti-inflammatory, anti-oxidant and anti-cancer potential in inflammatory bowel diseases, hepatic fibrosis and gastrointestinal cancers. PMID- 21607162 TI - MAPKs represent novel therapeutic targets for gastrointestinal motility disorders. AB - The number of patients suffering from symptoms associated with gastrointestinal (GI) motility disorders is on the rise. GI motility disorders are accompanied by alteration of gastrointestinal smooth muscle functions. Currently available drugs, which can directly affect gastrointestinal smooth muscle and restore altered smooth muscle contractility to normal, are not satisfactory for treating patients with GI motility disorders. We have recently shown that ERK1/2 and p38MAPK signaling pathways play an important role in the contractile response not only of normal intestinal smooth muscle but also of inflamed intestinal smooth muscle. Here we discuss the possibility that ERK1/2 and p38MAPK signaling pathways represent ideal targets for generation of novel therapeutics for patients with GI motility disorders. PMID- 21607164 TI - Purinergic signaling in the gastrointestinal tract. AB - Geoffrey Burnstock completed a BSc at King's College London and a PhD at University College London. He held postdoctoral fellowships with Wilhelm Feldberg (National Institute for Medical Research), Edith Bulbring (University of Oxford) and C. Ladd Prosser (University of Illinois). He was appointed to a Senior Lectureship in Melbourne University in 1959 and became Professor and Chairman of Zoology in 1964. In 1975 he became Head of Department of Anatomy and Developmental Biology at UCL and Convenor of the Center of Neuroscience. He has been Director of the Autonomic Neuroscience Institute at the Royal Free Hospital School of Medicine since 1997. He was elected to the Australian Academy of Sciences in 1971, the Royal Society in 1986, the Academy of Medical Sciences in 1998 and an Honorary Fellow of the Royal College of Surgeons and the Royal College of Physicians in 1999 and 2000. He was awarded the Royal Society Gold Medal in 2000. He is editor-in-chief of the journals Autonomic Neuroscience and Purinergic Signalling and on the editorial boards of many other journals. Geoffrey Burnstock's major research interest has been autonomic neurotransmission and he is best known for his seminal discovery of purinergic transmission and receptors, their signaling pathways and functional relevance. He has supervised over 100 PhD and MD students and published over 1400 original papers, re-views and books. He was first in the Institute of Scientific Information list of most cited scientists in Pharmacology and Toxicology from 1994-2004 [59.083 citations (March 2011) and an h-index of 109]. PMID- 21607163 TI - Primary hepatic gastrinoma: Report of a case and review of literature. AB - Primary hepatic gastrinoma is a very rare ectopic gastrinoma with less than 20 cases reported worldwide. We report the case of a patient with hypergastrinemia who was subjected to exhaustive preoperative and intraoperative imaging and also careful surgical exploration of the duodenum and pancreas which failed initially to identify the primary tumour. Eventually the patient was subjected to left liver lobectomy, as a small palpable lesion was noted intraoperatively. The diagnosis of gastrinoma requires a high index of clinical suspicion and the flawless cooperation of many specialties. PMID- 21607166 TI - Non-dipper and inappropriate left ventricular mass in hypertensive patients. PMID- 21607165 TI - Evidence of lung function for stratification of cardiovascular disease risk. AB - Among adults in the United States, the prevalence of reduced lung function including obstructive and restrictive lung disease is about 20%, representing an over 40 million adults. Persons with reduced lung function often demonstrate chronic systemic inflammation, such as from elevated levels of C-reactive protein. Substantial data suggests that inflammation may have a significant role in the association between reduced lung function and cardiovascular disease (CVD); however, how reduced lung function predicts CVD as risk modification remains largely unknown. Poor lung function has been shown to be a better predictor of all-cause and cardiac-specific mortality than established risk factors such as serum cholesterol, and CVD is the leading cause of mortality among those with impaired lung function. The exact mechanism of atherosclerosis is not clear, but persistent low grade inflammation is considered as one of the culprits in clot formation. The initial presentation of coronary heart disease is either myocardial infarction or sudden death in approximately half of the individuals. Unfortunately, conventional risk factor assessment predicts only 65 80% of future cardiovascular events, leaving many middle-aged and older individuals to manifest a major cardiovascular event despite being classified low risk by the Framingham risk estimates. PMID- 21607167 TI - Association between plaque thickness of the thoracic aorta and recurrence of atrial fibrillation after ablation. AB - BACKGROUND AND OBJECTIVES: Several predictors of recurrence of atrial fibrillation (AF) after ablation have been identified, including age, type of AF, hypertension, left atrial diameter and impaired left ventricular ejection fraction. The aim of this study was to investigate whether the atherosclerotic plaque thickness of the thoracic aorta is associated with a recurrence of AF after circumferential pulmonary vein ablation (CPVA). SUBJECTS AND METHODS: Among patients with drug-refractory paroxysmal or persistent AF, 105 consecutive (mean age 58+/-11 years, male : female=76 : 29) patients who underwent transesophageal echocardiography and CPVA were studied. The relationships between the recurrence of AF and variables, including clinical characteristics, plaque thickness of the thoracic aorta, laboratory findings and echocardiographic parameters were evaluated. RESULTS: A univariate analysis showed that the presence of diabetes {hazard ratio (HR)=3.425; 95% confidence interval (CI), 1.422-8.249, p=0.006}, ischemic heart disease (HR=4.549; 95% CI, 1.679-12.322, p=0.003), duration of AF (HR=1.010; 95% CI, 1.001-1.018, p=0.025), type of AF (HR=2.412, 95% CI=1.042 5.584, p=0.040) and aortic plaque thickness with >=4 mm (HR=9.514; 95% CI, 3.419 26.105, p<0.001) were significantly associated with the recurrence of AF after ablation. In Cox multivariate regression analysis, only the aortic plaque thickness (with >=4 mm) was an independent predictor of recurrence of AF after ablation (HR=7.250, 95% CI=1.906-27.580, p=0.004). CONCLUSION: Significantly increased aortic plaque thickness can be a predictable marker of recurrence of AF after CPVA. PMID- 21607168 TI - Decreased Glomerular Filtration Rate is an Independent Predictor of In-Hospital Mortality in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. AB - BACKGROUND AND OBJECTIVES: Patients with renal dysfunction (RD) experience worse prognosis after myocardial infarction (MI). The aim of the present study was to investigate the impact of admission estimated glomerular filtration rate (eGFR) on clinical outcomes of patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation MI (STEMI). SUBJECTS AND METHODS: We retrospectively evaluated 4,542 eligible patients from the Korea Acute Myocardial Infarction Registry (KAMIR). Patients were divided into three groups according to eGFR (mL/min/1.73 m(2)): normal renal function (RF) group (eGFR >=60, n=3,515), moderate RD group (eGFR between 30 to 59, n=894) and severe RD group (eGFR <30, n=133). Baseline characteristics, angiographic and procedural results, and in hospital outcomes between the three groups were compared. RESULTS: Age, gender, Killip class >=3, hypertension, diabetes, congestive heart failure, peak creatine kinase-MB, high sensitivity C-reactive protein, B-type natriuretic peptide, left ventricle ejection fraction, multivessel disease, infarct-related artery and rate of successful PCI were significantly different between the 3 groups (p<0.05). With decline in RF, in-hospital complications developed with an increasing frequency (14.1% vs. 31.8% vs. 45.5%, p<0.0001). In-hospital mortality rate was significantly higher in the moderate and severe RD groups as compared to the normal RF group (2.3% vs. 13.9% vs. 25.6%, p<0.0001). Using multivariate logistic regression analysis, adjusted odds ratio for in-hospital mortality was 2.67 {95% confidence interval (CI) 1.44-4.93, p=0.002} in the moderate RD group, and 4.09 (95% CI 1.48-11.28, p=0.006) in the severe RD group as compared to the normal RF group. CONCLUSION: Decreased admission eGFR was associated with worse clinical courses and it was an independent predictor of in-hospital mortality in STEMI patients undergoing primary PCI. PMID- 21607169 TI - Non-Dipper Pattern is a Determinant of the Inappropriateness of Left Ventricular Mass in Essential Hypertensive Patients. AB - BACKGROUND AND OBJECTIVES: Inappropriately high left ventricular mass (iLVM) is known to be related to cardiovascular prognosis. A non-dipper pattern has a greater mean left ventricular (LV) mass than the dipper pattern in hypertensive patients. However, the appropriateness of LV mass in dipper or non-dipper patterns has not been adequately investigated. The aim of this study was to define the relationship between nocturnal dipping and the appropriateness of LV mass. SUBJECTS AND METHODS: Using the ambulatory blood pressure monitoring (ABPM) database, the data of 361 patients who underwent ABPM and echocardiography was analyzed retrospectively. Appropriateness of LV mass was calculated as observed/predicted ratio of LV mass (OPR) using a Korean-specified equation. Nocturnal dipping was expressed as percent fall in systolic blood pressure (BP) during the night compared to the day. RESULTS: Daytime, nighttime and 24 hours BP in hypertensive patients was 140.4+/-14.8 mmHg, 143.7+/-15.2 mmHg and 129.4+/ 20.0 mmHg, respectively. OPR was 106.3+/-19.9% and nocturnal dipping was 10.2+/ 10.9 mmHg. In a multiple linear regression model, 24 hours systolic BP (beta=0.097, p=0.043) and nocturnal dipping (beta=-0.098, p=0.046) were independent determinants of OPR as well as age (beta=0.130, p=0.025) and body mass index (BMI) (beta=0.363, p<0.001). Odds ratio of the non-dipper pattern was 2.134 for iLVM (p=0.021) and 3.694 for obesity (p<0.001; BMI >25 kg/m(2)). CONCLUSION: The non-dipper pattern is independently associated with iLVM in hypertensive patients as well as obesity. PMID- 21607170 TI - Relationship between plasma adiponectin, retinol-binding protein 4 and uric Acid in hypertensive patients with metabolic syndrome. AB - BACKGROUND AND OBJECTIVES: Adipokines have been suggested for their potential use in tracking the clinical progress in the subjects with metabolic syndrome (MS). To investigate the relationship between the serum levels of adipokines {adiponectin and retinol-binding protein 4 (RBP4)} and the serum level of uric acid in hypertensive (HTN) patients with MS. SUBJECTS AND METHODS: In this study, 38 totally untreated HTN patients were enrolled. Anthropometric measurements, blood pressure (BP) were taken in the 12 HTN patients without MS and the 26 HTN patients with MS. Fasting blood samples were collected for measurement of adiponectin, RBP4, nitric oxide (NO), glucose, creatinine, uric acid, lipid profile and insulin. RESULTS: The HTN with MS group had significant higher values of body mass index, waist length, serum uric acid and triglyceride levels than the HTN without MS group. Compared to the HTN without MS group, the HTN with MS group showed significantly lower adiponectin (p=0.030), NO (p=0.003) and high density lipoprotein levels (p<0.001). Serum adiponectin levels negatively correlated with insulin level (R=-0.453, p=0.026) and uric acid level (R=-0.413, p=0.036), and serum RBP4 levels positively correlated with uric acid level (R=0.527, p=0.006) in the HTN with MS group. Multiple linear regression analysis using RBP4 and adiponectin levels as the dependent variables showed that uric acid level correlated with serum RBP4 level (p=0.046) and adiponectin level (p=0.044). CONCLUSION: The HTN with MS group showed a correlation with two types of adipokines (adiponectin, RBP4) and uric acid. Adiponectin, RBP4 and uric acid may be important components associated with MS, especially when associated with hypertension. PMID- 21607171 TI - Change in blood pressure and pulse pressure in preterm infants after treatment of patent ductus arteriosus with indomethacin. AB - BACKGROUND AND OBJECTIVES: Patent ductus arteriosus (PDA) is associated with increased morbidity and mortality in premature infants. Therefore, an early diagnosis and treatment of a hemodynamically significant PDA are very important. A widened pulse pressure is considered to be a well known clinical sign of a PDA in older infants and children; however, whether this is also applicable in the case of preterm infants remains to be confirmed. The aims of this study were to investigate the change in blood pressure (BP) before and after medical treatment of a PDA with indomethacin and to evaluate if the change in the pulse pressure in preterm infants with a medically treated PDA could be used as a reliable clinical predictor of a hemodynamically significant PDA. SUBJECTS AND METHODS: Between January 2005 and June 2009, a retrospective analysis was performed in preterm infants with a hemodynamically significant PDA (PDA group, n=72) and preterm infants without a PDA (control group, n=72) at the Chonnam National University Hospital Neonatal Intensive Care Unit. The PDA was closed by treatment with indomethacin. The BP was compared between the two groups over the seven days after the first dose of indomethacin. RESULTS: In preterm infants with a hemodynamically significant PDA, the mean systolic (55.1+/-6.0 mmHg) and diastolic BPs (31.4+/-6.2 mmHg) were lower than those in the controls (mean systolic BP 58.0+/-6.4 mmHg, mean diastolic BP 34.7+/-6.0 mmHg) before indomethacin treatment. When the ductus arteriosus was successfully closed by indomethacin treatment, there was a gradual increase in both the systolic and diastolic BPs without any change in the pulse pressure. CONCLUSION: The results of this study show that a widened pulse pressure is not a useful clinical sign of a hemodynamically significant PDA in preterm infants. However, low systolic and diastolic BPs may be useful clinical signs of a hemodynamically significant PDA in preterm infants. If the systolic and diastolic BP is low, a PDA should be considered and echocardiography should be performed for early diagnosis and treatment. PMID- 21607172 TI - A case of a senile systemic amyloidosis patient presenting with angina pectoris and dilated cardiomyopathy. AB - A 77-year-old man visited our hospital complaining of aggravated exertional chest pain. He was diagnosed with syndrome X 7 years ago and underwent medical treatment in a regional hospital. Coronary angiography and echocardiography did not show any significant abnormalities. On the seventh in-hospital day, cardiogenic shock developed and echocardiography showed a dilated left ventricular (LV) cavity and severe LV systolic dysfunction. We thus inserted an intra-aortic balloon pump for hemodynamic support and were forced to maintain it because of weaning failure several times. Finally, heart transplantation was the decided necessary procedure. After successful heart transplantation, the biopsy specimen revealed a wild-type transthyretin deposition indicating senile systemic amyloidosis in the intramuscular coronary vessels and interstitium. Cardiac biopsy at the 4-year follow-up showed no recurrence of amyloid deposition. PMID- 21607173 TI - Dual fistulas of ascending aorta and coronary artery to pulmonary artery. AB - Coronary artery fistula to pulmonary artery is common. However, to the best of our knowledge, a case of coronary artery fistula to pulmonary artery associated with aortopulmonary fistula remains unreported. We herein report a 64-year-old female with a left anterior descending coronary artery and ascending aorta to pulmonary artery fistulas, and conduct a brief review of the literature. PMID- 21607174 TI - An Atypical Mitral Valve Prolapse in a Patient With Behcet's Disease. AB - We report the case of a 42-year-old male who was admitted to the hospital with progressive dyspnea. Cardiomegaly and diffuse pulmonary edema were visible on chest X-ray and multiple oral and genital ulcers on physical examination. On admission, echocardiography revealed mitral valve prolapse (MVP) predominantly involving a basal portion of the posterior leaflet, with severe mitral regurgitation. A successful mitral valve replacement with St. Jude #29 was performed, after pre-treatment with prednisolone for 2 weeks. Fifteen months following the operation, the patient expired from severe pulmonary edema and secondary pneumonia. This case demonstrates, for the first time in the literature, an unusual feature of mitral prolapse in the basal portion with severe mitral regurgitation in a patient with Behcet's disease. As suggested by this case, we should consider an atypical type of MVP as a possible inflammatory involvement of the heart in patients with Behcet's disease. PMID- 21607175 TI - A case of variant angina developing transient collateral circulation during vasospasm. AB - Variant angina is characterized by spontaneous episodes of angina, usually occurring in the morning and having ST segment elevation on the electrocardiogram. However, in the case presented here, vasospasm and angina was shown by ergonovine without ST elevation. The patient was a 60-year-old man who presented with a 2-year history of frequent chest pain. There were no abnormalities in coronary angiography. When ergonovine (100 ug) was injected, total occlusion of the proximal right coronary artery was seen, without ST elevation at the electrocardiogram. The cause was collateral from left anterior descending artery to distal right coronary artery at the left coronary angiography. Therefore, in a patient with variant angina without ST elevation, a transient collateral circulation during vasospasm should be considered. PMID- 21607176 TI - Asymptomatic left ventricular pseudoaneurysm evaluated with multimodality cardiac imaging. PMID- 21607177 TI - Neuroprotective effect of anthocyanin on experimental traumatic spinal cord injury. AB - OBJECTIVE: We investigated the neuroprotective effect of anthocyanin, oxygen radical scavenger extracted from raspberries, after traumatic spinal cord injury (SCI) in rats. METHODS: THE ANIMALS WERE DIVIDED INTO TWO GROUPS : the vehicle treated group (control group, n=20) received an oral administration of normal saline via stomach intubation immediately after SCI, and the anthocyanin-treated group (AT group, n=20) received 400 mg/kg of cyanidin 3-O-beta-glucoside (C3G) in the same way. We compared the neurological functions, superoxide expressions and lesion volumes in two groups. RESULTS: At 14 days after SCI, the AT group showed significant improvement of the BBB score by 16.7+/-3.4%, platform hang by 40.0+/ 9.1% and hind foot bar grab by 30.8+/-8.4% (p<0.05 in all outcomes). The degree of superoxide expression, represented by the ratio of red fluorescence intensity, was significantly lower in the AT group (0.98+/-0.38) than the control group (1.34+/-0.24) (p<0.05). The lesion volume in lesion periphery was 32.1+/-2.4 uL in the control and 24.5+/-2.3 uL in the AT group, respectively (p<0.05), and the motor neuron cell number of the anterior horn in lesion periphery was 8.3+/-5.1 cells/HPF in the control and 13.4+/-6.3 cells/HPF in the AT group, respectively (p<0.05). CONCLUSION: Anthocyanin seemed to reduce lesion volume and neuronal loss by its antioxidant effect and these resulted in improved functional recovery. PMID- 21607178 TI - New technical tip for anterior cervical plating : make hole first and choose the proper plate size later. AB - OBJECTIVE: It is well known that plate-to-disc distance (PDD) is closely related to adjacent-level ossification following anterior cervical plate placement. The study was undertaken to compare the outcomes of two different anterior cervical plating methods for degenerative cervical condition. Specifically, the new method involves making holes for plate screws first with an air drill and then choosing a plate size. The other method was standard, that is, decide on the plate size first, locate the plate on the anterior vertebral body, and then drilling the screw holes. Our null hypothesis was that the new technical tip may increase PDD as compared with the standard anterior cervical plating procedure. METHODS: We retrospectively reviewed 49 patients who had a solid fusion after anterior cervical arthrodesis with a plate for the treatment of cervical disc degeneration. Twenty-three patients underwent the new anterior cervical plating technique (Group A) and 26 patients underwent the standard technique (Group B). PDD and ratios between PDD to anterior body heights (ABH) were measured using postoperative lateral radiographs. In addition, operating times and clinical results were reviewed in all cases. RESULTS: The mean durations of follow-up were 16.42+/-5.99 (Group A) and 19.83+/-6.71 (Group B) months, range 12 to 35 months. Of these parameters mentioned above, cephalad PDD (5.43 versus 3.46 mm, p=0.005) and cephalad PDD/ABH (0.36 versus 0.23, p=0.004) were significantly greater in the Group A, whereas operation time for two segment arthrodesis (141.9 versus 170.6 minutes, p=0.047) was significantly lower in the Group A. There were no significant difference between the two groups in caudal PDD (5.92 versus 5.06 mm), caudal PDD/ABH (0.37 versus 0.32) and clinical results. CONCLUSION: The new anterior cervical plating method represents an improvement over the standard method in terms of cephalad plate-to-disc distance and operating time. PMID- 21607179 TI - Endoscopic third ventriculostomy in patients with shunt malfunction. AB - OBJECTIVE: This paper presents data from a retrospective study of endoscopic third ventriculostomy (ETV) in patients with shunt malfunction and proposes a simple and reasonable post-operative protocol that can detect ETV failure. METHODS: We enrolled 19 consecutive hydrocephalus patients (11 male and 8 female) who were treated with ETV between April 2001 and July 2010 after failure of previously placed shunts. We evaluated for correlations between the success rate of ETV and the following parameters : age at the time of surgery, etiology of hydrocephalus, number of shunt revisions, interval between the initial diagnosis of hydrocephalus or the last shunt placement and ETV, and the indwelling time of external ventricular drainage. RESULTS: At the time of ETV after shunt failure, 14 of the 19 patients were in the pediatric age group and 5 were adults, with ages ranging from 14 months to 42 years (median age, 12 years). The patients had initially been diagnosed with hydrocephalus between the ages of 1 month 24 days and 32 years (median age, 6 years 3 months). The etiology of hydrocephalus was neoplasm in 7 patients; infection in 5; malformation, such as aqueductal stenosis or megacisterna magna in 3; trauma in 1; and unknown in 3. The overall success rate during the median follow-up duration of 1.4 years (9 days to 8.7 years) after secondary ETV was 68.4%. None of the possible contributing factors for successful ETV, including age (p=0.97) and the etiology of hydrocephalus (p=0.79), were statistically correlated with outcomes in our series. CONCLUSION: The use of ETV in patients with shunt malfunction resulted in shunt independence in 68.4% of cases. Age, etiology of hydrocephalus, and other contributing factors were not statistically correlated with ETV success. External ventricular drainage management during the immediate post-ETV period is a good means of detecting ETV failure. PMID- 21607180 TI - Surgical obliteration in superior petrosal sinus dural arteriovenous fistula. AB - Superior petrosal sinus (SPS) dural arteriovenous fistula (DAVF) is one of tentorial DAVFs with significant morbidity, which usually drains into the petrosal vein and its tributaries. Unless there is a connection with venous sinus, surgical obliteration is required. We present two cases of SPS DAVF which were successfully treated with the presigmoid retrolabyrinthine approach. PMID- 21607181 TI - Direct carotid cavernous fistula of an adult-type persistent primitive trigeminal artery with multiple vascular variations. AB - We report a case of spontaneous right carotid-cavernous fistula (CCF) in a proximal segment of persistent primitive trigeminal artery (PPTA) and combined vascular anomalies such as left duplicated hypoplastic proximal posterior cerebral arteries and a variation of anterior choroidal artery supplying temporal and occipital lobe. A 45-year-old male presented with progressive right exophthalmos, diplopia, and ocular pain. With manual compression of the internal carotid artery, a cerebral angiography revealed a right CCF from a PPTA. Treatment involved the placement of detachable non-fibered and fibered coils, and use of a hyperglide balloon to protect against coil herniation into the internal carotid artery. A final angiograph revealed complete occlusion of PPTA resulted in no contrast filling of CCF. PMID- 21607182 TI - Bilateral visual loss as a sole manifestation complicating carotid cavernous fistula. AB - Visual loss is one of the ocular symptoms resulting from a carotid cavernous fistula (CCF), but has rarely been reported as the sole manifestation in CCF. Visual impairment is known to be associated with a poor outcome unless timely intervention is employed. Herein, the authors report a patient with bilateral rapid progressing visual loss as a sole manifestation in CCF. Vision was successfully restored by transarterial embolization. The authors discuss the necessity of urgent fistula obliteration in patients with visual loss. PMID- 21607183 TI - Chronic Spinal Epidural Hematoma Related to Kummell's Disease. AB - Chronic spinal epidural hematoma related to Kummell's disease is extremely rare. An 82-year-old woman who had been managed conservatively for seven weeks with the diagnosis of a multi-level osteoporotic compression fracture was transferred to our institute. Lumbar spine magnetic resonance images revealed vertebral body collapse with the formation of a cavitary lesion at L1, and a chronic spinal epidural hematoma extending from L1 to L3. Because of intractable back pain, a percutaneous vertebroplasty was performed. The pain improved dramatically and follow-up magnetic resonance imaging obtained three days after the procedure showed a nearly complete resolution of the hematoma. Here, we present the rare case of a chronic spinal epidural hematoma associated with Kummell's disease and discuss the possible mechanism. PMID- 21607184 TI - Leg weakness in a patient with lumbar stenosis and adrenal insufficiency. AB - Lumbar spinal stenosis (LSS) is a common spinal disease in the elderly. The cardinal symptom of LSS is neurogenic claudication, but not all patients present with such typical symptom. The clinical symptoms are often confused with symptoms of peripheral neuropathy, musculo-skeletal disease and other medical conditions in elderly patients. In particular, LSS presenting with rapid progression of leg weakness must be distinguished from other combined diseases. We report a case of rapid progressive leg weakness in a patient with LSS and iatrogenic adrenal insufficiency that was induced by obscure health supplement. PMID- 21607186 TI - Sparganosis in the lumbar spine : report of two cases and review of the literature. AB - Sparganosis is a rare parasitic infection affecting various organs, including the central nervous system, especially the lumbar epidural space. This report describes the identification of disease and different strategies of treatments with preoperative information. A 42-year-old man presented with a 2-year history of urinary incontinence and impotence. He had a history of ingesting raw frogs 40 years ago. Magnetic resonance (MR) imaging showed an intramedullary nodular mass at conus medullaris and severe inflammation in the cauda equina. A 51-year-old woman was admitted with acute pain in the left inguinal area. We observed a lesion which seemed to be a tumor of the lumbar epidural space on MR imaging. She also had a history of ingesting inadequately cooked snakes 10 years ago. In the first patient, mass removal was attempted through laminectomy and parasite infection was identified during intra-operative frozen biopsy. Total removal could not be performed because of severe arachnoiditis and adhesion. We therefore decided to terminate the operation and final histology confirmed dead sparganum infection. We also concluded further surgical trial for total removal of the dead worm and inflammatory grannulation totally. However, after seeing another physician at different hospital, he was operated again which resulted in worsening of pain and neurological deficit. In the second patient, we totally removed dorsal epidural mass. Final histology and enzyme-linked immunosorbent assay (ELISA) confirmed living sparganum infection and her pain disappeared. Although the treatment of choice is surgical resection of living sparganum with inflammation, the attempt to remove dead worm and adhesive granulation tissue may cause unwanted complications to the patients. Therefore, the result of preoperative ELISA, as well as the information from image and history, must be considered as important factors to decide whether a surgery is necessary or not. PMID- 21607185 TI - A ganglion cyst in the second lumbar intervertebral foramen. AB - Ganglion cysts usually arise from the tendon sheaths and tissues around the joints. It is usually associated with degenerative arthritic changes in older people. Ganglion cyst in the spine is rare and there is no previous report on case that located in the intervertebral foramen and compressed dorsal root ganglion associated severe radiculopathy. A 29-year-old woman presented with severe left thigh pain and dysesthesia for a month. Magnetic resonance imaging revealed a dumbbell like mass in the intervertebral foramen between second and third lumbar vertebrae on the left side. The lesion was removed after exposure of the L2-L3 intervertebral foramen. The histological examination showed fragmented cystic wall-like structure composed of fibromyxoid tissue but there was no lining epithelium. A ganglion cyst may compromise lumbar dorsal root ganglion when it located in the intervertebral foramen. Although it is very rare location, ganglion cyst should be included in the differential diagnosis for intervertebral foraminal mass lesions. PMID- 21607187 TI - Postoperative systemic dissemination of injected elemental mercury. AB - There were only a few reports of mercury on pulmonary artery. However, there is no data on surgery related mercury dissemination. The objective of the present article is to describe one case of postoperative injected mercury dissemination. A 19-year-old man presented severe neck pain including meningeal irritation sign and abdominal pain after injection of mercury for the purpose of suicide. Radiologic study showed injected mercury in the neck involving high cervical epidural space and subcutaneous layer of abdomen. Partial hemilaminectomy and open mercury evacuation of spinal canal was performed. For the removal of abdominal subcutaneous mercury, C-arm guided needle aspiration was done. After surgery, radiologic study showed disseminated mercury in the lung, heart, skull base and low spinal canal. Neck pain and abdominal pain were improved after surgery. During 1 month after surgery, there was no symptom of mercury intoxication except increased mercury concentration of urine, blood and hair. We assumed the bone work during surgery might have caused mercury dissemination. Therefore, we recommend minimal invasive surgical technique for removal of injected mercury. If open exposures are needed, cautious surgical technique to prohibit mercury dissemination is necessary and normal barrier should be protected to prevent the migration of mercury. PMID- 21607188 TI - Robot-assisted transoral odontoidectomy : experiment in new minimally invasive technology, a cadaveric study. AB - OBJECTIVE: In the field of spinal surgery, a few laboratory results or clinical cases about robotic spinal surgery have been reported. In vivo trials and development of related surgical instruments for spinal surgery are required before its clinical application. We investigated the use of the da Vinci(r) Surgical System in spinal surgery at the craniovertebral junction in a human cadaver to demonstrate the efficacy and pitfalls of robotic surgery. METHODS: Dissection of pharyngeal wall to the exposure of C1 and odontoid process was performed with full robotic procedure. Although assistance of another surgeon was necessary for drilling and removal of odontoid process due to the lack of appropriate end-effectors, successful robotic procedures for dural sutures and exposing spinal cord proved its safety and dexterity. RESULTS: Robot-assisted odontoidectomy was successfully performed in a human cadaver using the da Vinci(r) Surgical System with few robotic arm collisions and minimal soft tissue damages. Da Vinci(r) Surgical System manifested more dexterous movement than human hands in the deep and narrow oral cavity. Furthermore, sutures with robotic procedure in the oral cavity demonstrated the advantage over conventional procedure. CONCLUSION: Presenting cadaveric study proved the probability of robot assisted transoral approach. However, the development of robotic instruments specific to spinal surgery must first precede its clinical application. PMID- 21607189 TI - One laser for a cosmetic/dermatologic practice. PMID- 21607190 TI - In-vivo Effectiveness of Adapalene 0.1%/Benzoyl Peroxide 2.5% Gel on Antibiotic sensitive and Resistant Propionibacterium acnes. AB - BACKGROUND: A gel combination treatment containing a retinoid (adapalene 0.1%) and an antimicrobial (benzoyl peroxide 2.5%) has been shown to be an effective treatment for acne vulgaris, addressing three of the four pathogenic factors (hyperkeratinization, Propionibacterium acnes proliferation, inflammation) without contributing to the incidence of Propionibacterium acnes antibiotic resistance as neither the retinoid nor benzoyl peroxide creates selective pressure for resistance. OBJECTIVE: To evaluate the effectiveness of an adapalene benzoyl peroxide gel combination in reducing antibiotic-sensitive and resistant strains of Propionibacterium acnes on the facial skin of volunteers. METHODS: This four-week, open-label, single-center study included 30 healthy adults with high facial Propionibacterium acnes populations [>10(4) colony-forming units per square centimeter of skin (CFU/cm(2))] and presence of subpopulations resistant to erythromycin, tetracycline, and clindamycin. The gel was applied once daily to the forehead. Cultures for total and antibiotic-resistant Propionibacterium acnes were obtained from the forehead area at screening, Baseline, Week 2, and Week 4. RESULTS: Total Propionibacterium acnes counts decreased by 1.1 log(10) CFU/cm(2) after two weeks of treatment, and by 1.6 log10 CFU/cm(2) after four weeks. All subjects had strains resistant to each of the five antibiotics at baseline. Mean counts of erythromycin and clindamycin resistant Propionibacterium acnes were high at baseline (5.37 and 5.28 log(10) CFU/cm(2), respectively) and decreased by >=2.1 log(10) by Week 4 (P<0.001). Mean counts of strains resistant to tetracyclines were lower at baseline (3.8 to 4.2 CFU/cm(2)) and decreased by 1.9 (tetracycline), 2.4 (minocycline), and 1.3 (doxycycline) log(10) CFU/cm(2) by Week 4 (P<0.001). LIMITATIONS: Although limited in scope, the results of the present study demonstrate that the fixed-dose combination gel containing adapalene 0.1% and benzoyl peroxide 2.5% effectively inhibited both antibiotic susceptible and antibiotic-resistant Propionibacterium acnes. In addition to reducing population densities, therapy with adapalene-benzoyl peroxide eradicated some resistant strains entirely in some individual subjects. CONCLUSION: Topical adapalene-benzoyl peroxide gel effectively reduced skin colonization by antibiotic-sensitive and antibiotic-resistant Propionibacterium acnes after four weeks. This trial was registered with ClinicalTrials.gov (http://clinicaltrials.gov/), registry number NCT00907101. PMID- 21607191 TI - Microsphere technology: hype or help? AB - Initiation of effective topical therapy as early as possible within the disease course is associated with improved patient experiences and better therapeutic outcomes in most dermatological diseases. Additionally, patient adherence is associated with better outcomes and lower long-term treatment costs, while poor adherence is directly linked to poor treatment results and patient dissatisfaction. Local cutaneous irritation associated with topical drug formulations has been an historical challenge to therapy initiation and adherence. Retinoids and benzoyl peroxide-essential elements of topical acne treatment-are two of the drugs most commonly associated with application-site adverse events. Novel approaches to product formulation incorporating microsphere technology may improve treatment tolerability, encourage adherence, and contribute to better long-term therapeutic outcomes. Microsphere technology eliminates the rapid delivery of high concentrations of active drug to the application site and instead facilitates controlled release of potentially irritating drugs. It is associated with improved treatment outcomes and minimal irritation. Microsphere formulations of topical tretinoin and benzoyl peroxide currently on the market have demonstrated good efficacy and tolerability and are expected to encourage adherence and long-term therapeutic benefit. PMID- 21607192 TI - Adult seborrheic dermatitis: a status report on practical topical management. AB - Seborrheic dermatitis is a common chronic-recurrent inflammatory disorder that most commonly affects adults; however, a more transient infantile form also occurs. The definitive cause of seborrheic dermatitis is unknown. However, proliferation of Malassezia species has been described as a contributing factor. The adult form of seborrheic dermatitis affects up to approximately five percent of the general population. The disorder commonly affects the scalp, face, and periauricular region, with the central chest, axillae, and genital region also involved in some cases. Pruritus is not always present and is relatively common, especially with scalp disease. A variety of treatments are available including topical corticosteroids, topical antifungal agents, topical calcineurin inhibitors, and more recently, a nonsteroidal "device "cream. This article reviews the practical topical management of seborrheic dermatitis in the United States, focusing on the adult population. PMID- 21607193 TI - Treatment of Basal cell carcinoma with curettage followed by imiquimod 3.75% cream. AB - Basal cell carcinoma is the most common form of nonmelanoma skin cancer in the United States. Treatment modalities include both surgical, medical, or combination therapy. In the following case, the authors report the successful treatment of a basal cell carcinoma on the nose with curettage followed by topical imiquimod 3.75% cream. PMID- 21607194 TI - Filler cheeks: a bright idea? The "eyes" have it. AB - The evolving field of facial volume restoration is changing our concept of facial rejuvenation. The older concept that "tighter is better" has been largely supplanted by a philosophy recognizing the importance of volume distribution as a defining characteristic of a more youthful face. It is well recognized that restoration of volume in the upper face can lessen or reverse the bottom-heavy, deflated appearance of the aging face. Perhaps of equal or greater importance is the change in light-reflectance patterns that illuminate the upper cheeks and the eyes. The resultant brighter and "perkier" cheeks can change the objective appearance and the patient's self perception of youthfulness. In this commentary, the author describes techniques to enhance outcomes and patient satisfaction and presents the results of a patient self-report pilot study assessing patient post injection mood state and functioning. PMID- 21607195 TI - Investigating Drinking via the Social Investment Hypothesis: Committed Relationship Status Moderates the Association between Educational Investment and Excessive Alcohol Consumption among College Students. AB - A sample of 18- to 23-year-old college students (N = 183) with a heterogeneous prevalence of alcohol dependence (AD) was used to examine the relationship between normative investment and alcohol consumption. Consistent with the social investment hypothesis, AD students reported lower educational investment and less participation in committed relationships than non-AD students. The sample-wide relationship between educational investment and alcohol use was moderated by relationship status, such that students in relationships who reported high educational investment were likely to drink more than single students who reported high educational investment. This interactive effect held when controlling for sex, IQ, and a measure of self-control. The results suggest normative investment is a candidate risk factor for excessive alcohol consumption for both highly "under-committed" and "over-committed" students. PMID- 21607196 TI - Socialization of Emotion and Offspring Internalizing Symptoms in Mothers with Childhood-Onset Depression. AB - This study examines how mothers with and without a history of childhood-onset depression respond to their 3-9 year-old children's emotions. Mother-child dyads included 55 offspring of mothers with a history of childhood-onset depressive disorders and 57 offspring of never-depressed mothers. Mothers with a history of childhood depression were less likely than were control mothers to respond in supportive ways to their children's negative emotions and were more likely to magnify, punish, or neglect their children's negative emotions. Magnification, neglect, and punishment of children's negative emotions were concurrently associated with children's internalizing symptoms, and neglect and punishment were associated with internalizing over a one year follow-up. Maternal neglect of children's negative emotion was positively associated with later internalizing symptoms for children who already had higher internalizing symptoms at the initial assessment. Findings suggest that atypical socialization of emotion may be one mechanism in the development of internalizing disorders. PMID- 21607197 TI - Attitude Toward Own Aging and Mental Health in Post-menopausal Women. AB - INTRODUCTION: Attitudes toward own aging (ATOA) refers to expectations about the personal experience of aging. As of now, there is limited literature that addresses the impact of ATOA on indicators of psychological, physical, and social health. In this study, we examine associations between ATOA and several measures associated with successful aging. METHODS: A detailed cross-sectional survey questionnaire on successful aging was completed by 1,973 older women enrolled in the San Diego site of the Women's Health Initiative study. ATOA was measured using the Philadelphia Geriatric Morale Scale (PGMS) RESULTS: The final sample consisted of 1151 women. The mean ATOA score was 3.8 indicating generally positive ATOA. Positive ATOA score was significantly associated with younger age, lower income, being married, higher SF-36 Physical Composite scores, higher SF-36 Mental composite scores, lower depression scores, and higher resilience scores. Approximately 40% of variance in ATOA scores was explained by successful aging related domain scores. CONCLUSIONS: Better physical and emotional functioning, greater resilience and lower depression are associated with more positive ATOA. Associations with sociodemographic traits are complex. Modifying ATOA may have potential to impact a broad range of health and successful aging related outcomes. PMID- 21607199 TI - ATTITUDES TOWARDS ECONOMIC RISK AND THE GENDER PAY GAP. PMID- 21607198 TI - Top-Down Analysis of Small Plasma Proteins Using an LTQ-Orbitrap. Potential for Mass Spectrometry-Based Clinical Assays for Transthyretin and Hemoglobin. AB - Transthyretin (TTR) amyloidosis and hemoglobinopathies are the archetypes of molecular diseases where point mutation characterization is diagnostically critical. We have developed a Top-down analytical platform for variant and/or modified protein sequencing and are examining the feasibility of using this platform for the analysis of hemoglobin/TTR patient samples and evaluating the potential clinical applications. The platform is based on a commercial high resolution hybrid orbitrap mass spectrometer (LTQ-Orbitrap(TM)) with automated sample introduction; automated data analysis is performed by our own software algorithm (BUPID topdown).The analytical strategy consists of iterative data capture, first recording a mass profile of the protein(s). The presence of a variant is revealed by a mass shift consistent with the amino acid substitution. Nozzle-skimmer dissociation (NSD) of the protein(s) yields a wide variety of sequence-defining fragment ions. The fragment ion containing the amino acid substitution or modification can be identified by searching for a peak exhibiting the mass shift observed in the protein mass profile. This fragment ion can then be selected for MS/MS analysis in the ion trap to yield sequence information permitting the identification of the variant. Substantial sequence coverage has been obtained in this manner. This strategy allows for a stepwise MS/MS analysis of the protein structure. The sequence information obtained can be supplemented with whole protein NSD fragmentation and MS/MS analysis of specific protein charge states. The analyses of variant forms of TTR and hemoglobin are presented to illustrate the potential of the method. PMID- 21607200 TI - Grammatical Evolution for Features of Epileptic Oscillations in Clinical Intracranial Electroencephalograms. AB - This paper presents grammatical evolution (GE) as an approach to select and combine features for detecting epileptic oscillations within clinical intracranial electroencephalogram (iEEG) recordings of patients with epilepsy. Clinical iEEG is used in preoperative evaluations of a patient who may have surgery to treat epileptic seizures. Literature suggests that pathological oscillations may indicate the region(s) of brain that cause epileptic seizures, which could be surgically removed for therapy. If this presumption is true, then the effectiveness of surgical treatment could depend on the effectiveness in pinpointing critically diseased brain, which in turn depends on the most accurate detection of pathological oscillations. Moreover, the accuracy of detecting pathological oscillations depends greatly on the selected feature(s) that must objectively distinguish epileptic events from average activity, a task that visual review is inevitably too subjective and insufficient to resolve. Consequently, this work suggests an automated algorithm that incorporates grammatical evolution (GE) to construct the most sufficient feature(s) to detect epileptic oscillations within the iEEG of a patient. We estimate the performance of GE relative to three alternative methods of selecting or combining features that distinguish an epileptic gamma (~65-95 Hz) oscillation from normal activity: forward sequential feature-selection, backward sequential feature-selection, and genetic programming. We demonstrate that a detector with a grammatically evolved feature exhibits a sensitivity and selectivity that is comparable to a previous detector with a genetically programmed feature, making GE a useful alternative to designing detectors. PMID- 21607201 TI - On influences of global and local cues on the rate of synchronization of oscillator networks. AB - Synchronization of connected oscillator networks under global and local cues is ubiquitous in both science and engineering. Over the last few decades, enormous attention has been paid to study synchronization conditions of connected oscillators in chemistry, physics, mechanics, and particularly in biology. However, the influences of global and local cues on the rate of synchronization have not been fully studied. It is widespread that synchronization is achieved in the simultaneous presence of both global and local cues, such as intercellular coupling signals and external entrainment signals in terms of biological oscillators, and inter-neighbor coupling signals between follower nodes and central guiding signals in terms of groups of mobile autonomous agents. We prove in this paper that strength of the global cue is the only determinant of the rate of synchronization. More specifically, we prove that a stronger global cue means a faster rate of synchronization whereas a stronger local cue does not necessarily make the synchronization rate faster. Our results not only apply to the noise free case, but also apply to the case that the oscillator natural frequencies are subject to white noise. The analysis does not require the interplay to be symmetric or balanced. Simulation results are given to illustrate the proposed results. PMID- 21607202 TI - Management of Non-STEMI and suspected Acute Coronary Syndrome. AB - 1. Patients presenting with ACS are at high risk of subsequent events and if ischaemic sounding chest pain is associated with either a raised troponin, dynamic ECG changes or other high risk features, inpatient coronary angiography should be arranged within 72 hours. 2. Patients with either ongoing chest pain and ECG changes despite medical treatment, ventricular arrythmias, or cardiogenic shock / haemodynamic compromise require emergency coronary angiography. 3. For patients with suspected ACS but no high risk features (Table 4) a non invasive test for myocardial ischaemia prior to discharge is recommended 4. In patients with renal impairment (creatinine .220) and chronically elevated troponin in whom an acute coronary syndrome is suspected additional cardiac markers such as CK or CK-MB as well as consecutive troponin measurements on admission and 12 hours are helpful to identify whether the patient sustained acute cardiac damage. PMID- 21607203 TI - Acute asthma in adults controversies and best practice. AB - Asthma in the emergency care setting is common and may be life-threatening. Last year the British Thoracic Society updated their guidelines for the management of asthma, however some treatments remain controversial and there is variation in adherence to these and other national and international guidelines. PMID- 21607204 TI - Poisoning and toxicological emergencies - current trends and practice. AB - Poisoning is a common presentation to hospital acute medical units, and can produce a variety of clinical scenarios. This review discusses the epidemiology of poisoning, a framework for managing patients with drug toxicity and considerations in the diagnosis of toxicity with unknown substances. The commonest substances seen in toxicity in the UK - paracetamol, antidepressants, sedatives and opioids are discussed in more detail. PMID- 21607205 TI - Internal Carotid Artery dissection presenting as Isolated Hypoglossal nerve palsy. AB - Internal carotid dissection most commonly presents as headache, focal neurological deficits or stroke. Rarely it can manifest itself by causing a palsy of the lower cranial nerves (IX, X, XI, XII). The reported incidence of isolated cranial nerve palsies is rare. We report a case of an internal carotid artery dissection manifesting as isolated XII (hypoglossal) cranial nerve palsy. PMID- 21607206 TI - Acute abdominal pain: An unusual medical cause. AB - Lyme disease is an infectious illness that arises from the spirochete, Borrelia burgdorferi transmitted via a bite by Ixodid ticks. There were 768 cases in the United Kingdom (incidence 1.46/100,000) identified by the Health Protection Agency in 2006. Clinical manifestations of Lyme disease can be multi-systemic. It is important for the acute physician to be aware of this condition. Its relative infrequency and unusual presentation can result in delayed diagnosis with potential for suboptimal outcome. Here, we present a case of Lyme disease presenting with abdominal pain and intestinal dysmotility. PMID- 21607207 TI - A case of postural orthostatic tachycardia syndrome on the acute medical unit. AB - We describe a case of postural orthostatic tachycardia syndrome (POTS) in a young female, presenting several weeks after neurosurgery, to the Medical Admissions Unit. The diagnosis is discussed with reference to differential diagnosis, diagnostic criteria, pathophysiology and treatment. PMID- 21607208 TI - Assessment of clinical risk in the out of hours hospital prior to the introduction of Hospital at Night. AB - Overnight medical cover in hospital is less than during daylight hours. We aimed to quantify the numbers of patients deteriorating overnight and their clinical outcome. Data was collected in real time on use of the Standardised Early Warning Score (SEWS), 'time to doctor', seniority of medical review and clinical outcome. 136 incidents of clinical concern were noted on the general wards with a median response time of 5 minutes for SEWS>4 and 10 minutes if SEWS<4. 159 incidents were recorded in critical care. There was significant inter-speciality variation in median response times and seniority of responding staff, particularly within critical care, which recorded the slowest times across the hospital. This will be reassessed following the establishment of Hospital at Night. PMID- 21607209 TI - SAM Acute Medicine Trainees Skills Survey 2009. AB - Specialist trainees in Acute Medicine have expressed concerns over skills training in the curriculum, compared with skills training in practice. Thus, an online survey was conducted in 2009 to investigate these comments in detail. The responses from 132 trainees were analysed. The results show that the majority of practical skills are being performed by trainees who feel that they have reached a level of competence sufficient to enable them to teach the skill to others. The major causes for concern were highlighted as temporary cardiac pacing, endotracheal intubation and Sengstaken Blakemore tubes. We recommend that these skills should be taught via simulation where not available in practice, but true competence cannot be expected for the majority. PMID- 21607210 TI - A retrospective analysis of alcohol intake and management on the medical assessment unit. AB - A retrospective case note analysis of 100 consecutive admissions to a Medical Assessment Unit to (a) review the current impact of alcohol, and (b) assess the quality of clinical management and adherence to local and national guidelines. PMID- 21607211 TI - Dysphagia: Aspects of assessment and management for the Acute Physician. AB - The term Dysphagia originates from a Greek word meaning disordered eating. It is defined as difficulty in swallowing. Dysphagia should not be confused with globus senstation, a feeling of having a lump in the throat, which is unrelated to swallowing and occurs without impaired transit (see below). Although odynophagia (painful swallowing) and phagophobia (fear of swallowing) are symptoms that may be associated with dysphagia it is important to distinguish this in the history. PMID- 21607212 TI - Tuberculosis of the central nervous system: recognition, diagnosis and treatment in a low-prevalence country. AB - Tuberculosis (TB) is one of the greatest threats to global public health, with 9.2 million new cases in 20061 and has become increasingly common in the UK. Central nervous system (CNS) infection with Mycobacterium tuberculosis (MTB) is relatively rare but is associated with a serious risk of neurological morbidity or death. Delays in diagnosis worsen prognosis and even with anti-tuberculous therapy up to 30% of tuberculous meningitis (TBM) patients may die.2 TBM and tuberculomas can mimic other CNS pathologies. Careful analysis of the clinical features, CSF examination and pragmatic use of diagnostic tests can aid the diagnosis. Prolonged anti-tuberculous treatment is required and presumptive treatment should not be delayed for microbiological confirmation of the disease. PMID- 21607213 TI - Acute painless jaundice: assessment and management. AB - The most common presentation of liver and biliary disease is jaundice, and most acute medical teams will encounter several jaundiced patients over time. Some of these patients will be extremely unwell, and a systematic approach will enable all doctors to manage such patients correctly. Key questions should be addressed during initial assessment: i. Is the patient critically ill? ii. Does the patient have fulminant hepatic failure? iii. Is the jaundice secondary to an intra- or extrahepatic cause? This article aims to provide a guide to the assessment and management of the acutely jaundiced patient in the emergency setting. PMID- 21607214 TI - Cerebral Nocardiosis in a patient with Waldenstrom's Macroglobulinaemia. AB - Nocardiosis is caused by nocardia species, a Gram positive aerobic filamentous bacillus. It is ubiquitous in the environment and often presents as pulmonary disease in more than 70% of patients.1 Dissemination of the disease may manifest as brain abscesses, and is reported to account for approximately 2% of all brain abscesses.2,3 We present a case of cerebral nocardiosis in a patient with Waldenstrom's macroglobulinaemia, previously unreported in the literature. PMID- 21607215 TI - What becomes of the broken-hearted? A typical case of Takotsubo cardiomyopathy. AB - Takotsubo cardiomyopathy (TC), or apical ballooning syndrome (ABS), is becoming an increasingly recognised entity. Usually preceded by emotional stress, it is characterised by chest pain associated with ST-segment elevation on the 12-lead electrocardiogram (ECG), elevated cardiac biomarkers, and reversible left ventricular (LV) apical hypokinesia, making it an important differential diagnosis for ST-segment elevation myocardial infarction (STEMI). We present a typical case of TC initially misdiagnosed and treated as a STEMI, fortunately with no adverse consequences. PMID- 21607216 TI - Acute Intermittent Porphyria: Some Diagnoses are Only Made If Thought of. AB - A 20-year-old Asian, female, student nurse of thin body habitus (Body Mass Index 16.5) but otherwise previously well had numerous admissions to our centre under a variety of surgical sub-specialities over a 5-month period. Each month, coinciding with menses, she complained of non-specific abdominal discomfort in the absence of any other symptoms. With the exception of the presence of a sinus tachycardia coupled with incidental hyponatraemia full physical examinations and routine baseline investigations were unremarkable. PMID- 21607217 TI - An uncommon cause of pyrexia of unknown origin. AB - Prolonged unexplained fever is one of the most challenging problems encountered in clinical medicine. We report the case of a patient with an uncommon cause of Pyrexia of Unknown Origin (PUO). PMID- 21607218 TI - Picture quiz: a case of acute hepatitis. AB - A 19 year old male with no previous medical history presented to hospital with an eight day history of jaundice and general malaise. PMID- 21607219 TI - Acute Medicine: A Practical guide to the management of medical emergencie. AB - Any junior doctor navigating the early stages of training will recognise the need to develop the ability to crystallise the essence of a clinical case with a few succinct questions and directed examination, enabling subsequent investigations and treatments to be well directed. Whilst the acquisition of this experience requires hard yards on the shop floor, this book makes an excellent companion for the junior doctor in the Emergency Department or the Admissions Unit. It offers an accessible and concise guide to the management of acute medical problems, with succinct 'aide memoires' for focussed assessment. PMID- 21607220 TI - Picture quiz: a case of acute hepatitis - answers. AB - All other screening tests (including viral hepatitisand HIV test) were unremarkable, hence a diagnosis of secondary syphilis causing hepatitis was made. Further examination revealed a healing chancre on the shaft of his penis and pustules around the anus. PMID- 21607221 TI - British society of echocardiography accreditation - the 'gold standard' for acute medicine. AB - We read with interest to the article written by Kevin Fox1 and wholly support the notion that acute medical trainees who wish to undertaken echocardiography within the medical admissions unit (MAU) should achieve British Society of Echocardiography (BSE) accreditation. I was one of the first trainees in acute medicine to undertake training in echocardiography; despite considerable competition from cardiology registrars as well as resistance from the physiology department I am now close to attaining the BSE Trans Thoracic Echocardiography accreditation. PMID- 21607222 TI - The management of community acquired pneumonia. AB - Community acquired pneumonia (CAP) is a common cause of hospital admission. The first 24-48 hours are crucial in the correct diagnosis and management of CAP. In this article we highlight the pitfalls in diagnosis and the important management steps. The correct assessment of severity with CURB65 scoring, proper supportive measures and appropriate antibiotics are key to effective treatment of CAP. PMID- 21607223 TI - Prescribing at the coalface in the era of antimicrobial resistance. AB - Antimicrobial resistance is of increasing concern to patients, physicians and policy-makers alike. The challenge for the clinician at the coalface, however, is to avoid the undertreatment of seriously ill patients whilst minimising the evolution of antimicrobial resistance. Difficult decisions about the most appropriate antibiotic to prescribe can be supported by careful risk factor and prognostic assessment. PMID- 21607224 TI - Management of Exacerbation of COPD. AB - COPD is a progressive debilitating lung condition the clinical course of which is punctuated by acute severe increases in symptoms (exacerbations). These can be life threatening and are a considerable cause of morbidity and mortality as well as frequently requiring hospital admission. The aims of treatment are to prevent attacks through vaccination, smoking cessation, appropriate medication, the provision of pulmonary rehabilitation and also patient education. During an attack treatment should be provided in the most suitable place for the individual (home or hospital) and consists of an accurate diagnosis, clinical assessment and the provision of bronchodilators, corticosteroids and antibiotics where appropriate. More severe attacks necessitating hospital assessment and admission may require ventilatory support and even intensive care. Where possible patients should be involved in decision making, particularly with regard to treatment and a possible ceiling of care. PMID- 21607225 TI - Cocaine abuse: acute medical manifestations and current recommended management strategies. AB - Recreational cocaine use in the UK is steadily rising. This review summarises some of the common clinical manifestations of cocaine use which may be encountered by acute physicians and discusses the available treatment options. PMID- 21607226 TI - Osteomyelitis as the cause of acute leg pain on the MAU. AB - An acutely painful swollen leg is a common presentation to Medical assessment units, typically secondary to cellulitis or deep vein thrombosis, although alternative diagnoses should to be considered in the presence of atypical features or inconclusive investigations. PMID- 21607227 TI - Spontaneous pneumomediastinum after oral ingestion of ecstasy. AB - We describe a 23 year old male who presented with sudden onset of facial swelling, nasal tone of voice and shortness of breath after taking eight tablets of ecstasy. He was found to have surgical emphysema and pneumomediastinum. Though spontaneous pneumomediastinum is well known in inhalation drug users who try to enhance alveolar resorbtion with repeated Valsalva manouvre, it is rather unusual to see it after oral ingestion of ecstasy. The probable causative event is the prolonged and excessive physical exertion involved in dancing at a "rave". Acute physicians should be aware of the association and of its usually benign nature. PMID- 21607228 TI - A case of fatal felodipine overdose. AB - A 54 year gentleman was admitted to hospital within four hours of taking an overdose of modified release felodipine tablets, with a total dose of approximately 250 mg. The initial management comprised fluid resuscitation, calcium chloride and glucagon. He remained hypotensive and was commenced on hyperinsulinaemia-euglycaemic therapy. Hypotension persisted with the development of progressive metabolic acidosis despite increasing inotropic support, haemofiltration and high dose insulin-dextrose infusions. The patient died 60 hours post overdose. The case highlights the profound, refractory circulatory collapse and lethal consequences of significant calcium channel blocker overdose and also reviews potential management strategies to attempt to reverse these changes. Despite the lack of evidence of whole bowel irrigation in overdose per se, its role in the removal of modified release compounds has not been studied. We would strongly urge emergency departments to consider this therapeutic modality, especially in overdoses involving delayed release preparations of calcium channel blockers, which are extremely toxic in overdose and are associated with very high mortality. PMID- 21607229 TI - Stroke due to Thromboembolism from Congenital Aneurysm of Ventricular Septum. AB - We describe the case of a 46-year-old female who presented with recurrent episodes of cerebrovascular events. She had an unremarkable family history and no risk factors for stroke, apart from smoking. A transthoracic echocardiogram with 'bubble' contrast was normal. However transoesophageal echocardiography demonstrated an aneurysm of the membranous part of the ventricular septum, representing the likely source of thrombo-embolisation. This case highlights the need for a systematic and rigorous approach to the investigation of young patients with stroke. PMID- 21607230 TI - A severe rash. AB - A fifty-one-year-old man with history of treated hypertension and seronegative rheumatoid arthritis presented to hospital with a three day history of a rash affecting the whole body and general malaise. He had been commenced on sulfasalazine 2 weeks ago to control his rheumatoid arthritis, which the patient had discontinued taking three days prior to admission. On examination, he was comfortable with a temperature of 39 degrees C and a widespread erythematous maculopapular rash. Investigations revealed a normal FBC, UEs, LFTs but high inflammatory markers with a CRP 125.9 and ESR 52. One day later the patient developed odynophagia and blisters on his lips and mouth shown in the picture below (Figure 1 and 2). PMID- 21607231 TI - Acute Medicine and Emergency Medicine are not (Yet?) The Same. AB - The acquisition of "Level 3" competencies in the setting of the Emergency Room from StR in Acute Medicine raises the question of the boundaries and competences of Acute Medicine and Emergency Medicine. The possibility that phisycians with a training both in Emergency Medicine and Acute Medicine will be involved in the management of Emergency Admission Units and Emergency Medicine Departments in the future is herein considered. PMID- 21607232 TI - 'Picture Quiz Answers: A severe rash. AB - This patient was diagnosed as having Stevens-Johnson Syndrome. The most likely cause was the sulfasalazine, which had been started recently. This drug was stopped. He was reviewed by a dermatologist, who confirmed the diagnosis and recommended treatment with oral corticosteroids. He was commenced on prednisolone 30 mg daily and discharged 2 days after his admission. He was reviewed in the rapid access clinic the following week and his rash was resolving well and his fever had subsided. The patient was discharged back to the care of the rheumatologists. PMID- 21607234 TI - 2nd International Conference The Society for Acute Medicine IMPERIAL COLLEGE, LONDON, 28TH-30TH SEPTEMBER 2008. PMID- 21607233 TI - The Society for Acute Medicine (UK) Acute Medicine Training Survey 2007. AB - An online survey of training in Acute Medicine was conducted to assemble a true picture of the current situation in the UK. The specialty is flourishing, with over 60 trainees having predicted CCT dates in Acute Medicine in 2010 and 2011 alone. 128 respondents highlighted a multitude of issues, including the need for improvements in management and special skills training and part time opportunities. We have used the results of this survey to suggest action points for Deaneries, Training Programme Directors, the Society for Acute Medicine (UK) and those involved in workforce planning. PMID- 21607235 TI - Construction of heterostructure materials toward functionality. AB - One- and zero-dimensional organic/inorganic heterostructure materials have been attracting considerable attention in materials science because of their outstanding optical and electrical properties and high tailorability in terms of composition, structure, and morphology. Strong interactions between the organic and inorganic units can lead to novel or improved physical or chemical performance relative to that of the individual components, thereby realizing synergistic ("1 + 1 > 2") performance. In this tutorial review, we discuss the synthetic methods available for preparing heterostructures incorporating diverse components; the functionality of the heterostructure materials; and their potential applications in the fields of electronics, optics, biology, and catalysis. The future development of such heterostructure materials will require deeper understanding of organic-inorganic or organic-organic interfaces on the nanoscale, collective phenomena, and interparticle coupling. PMID- 21607236 TI - Synthesis of a D3-symmetric "trefoil" knotted cyclophane. AB - A D(3)-symmetric knotted cyclophane, with a subgraph of trefoil topology, was synthesized by cyclization of a D(3)-symmetric scaffold. Control of configuration at the three metal-based stereocenters arises from a bascule/pivot mechanism. PMID- 21607238 TI - A new in situ synchrotron X-ray diffraction technique to study the chemical delithiation of LiFePO4. AB - We report a new synchrotron based in situ X-ray diffraction (XRD) technique to study the chemical delithiation of LiFePO(4). This technique provides a new powerful tool to study chemical reactions with excellent time-resolving power for dynamic studies. PMID- 21607239 TI - A carbon nanotube structured biomimetic catalyst for polysaccharide degradation. AB - A unique artificial catalyst that mimics the structure of active sites in real enzymes using functionalized carbon nanotubes is presented. This concept will allow for the potential construction of a library of biomimetic catalysts for enzyme active centers, for which the structure-catalysis relationships are well defined. PMID- 21607240 TI - A delafossite-based copper catalyst for sustainable Cl2 production by HCl oxidation. AB - A copper catalyst based on a delafossite precursor (CuAlO(2)) displays high activity and extraordinary lifetime in the gas-phase oxidation of HCl to Cl(2), representing a cost-effective alternative to RuO(2)-based catalysts for chlorine recycling. PMID- 21607241 TI - Functionalized magnetic nanoparticles as chemosensors and adsorbents for toxic metal ions in environmental and biological fields. AB - Functionalized magnetic nanoparticles, composed of both inorganic and organic components, have recently been examined as promising platforms for detection and separation applications. This unique class of nanomaterials can retain not only beneficial features of both the inorganic and organic components, but can also provide the ability to systematically tune the properties of the hybrid materials through the combination of appropriate functional components. This tutorial review focuses on the recent development of functionalized magnetic nanoparticles for use in biological and environmental applications, in which these chromogenic and fluorogenic chemosensors can selectively detect and separate specific toxic metal ions. PMID- 21607242 TI - Hydrogen bond assisted activation of a dinitrile towards nucleophilic attack. AB - The possibility of tunable regioselective activation of a dinitrile towards nucleophilic attack was demonstrated. For that, a sulfo-arylhydrazone unit was introduced into malononitrile and the thus formed intramolecular hydrogen bond systems assisted specific nucleophilic attacks to the cyano moieties leading to a variety of amidines, carboxamides and iminoesters depending on the nucleophiles and conditions used. PMID- 21607243 TI - Characterization of ambient black carbon and wood burning particles in two urban areas. AB - Previously it has been suggested that certain organic aerosol components of wood smoke have enhanced ultraviolet absorption at 370 nm relative to 880 nm in two wavelength aethalometer measurements. This enhanced absorption could serve as an indicator of wood burning particles. Two-wavelength (370 nm and 880 nm) aethalometer measurements were made at urban sites in Rochester, New York and Laredo, Texas from August 1 to December 31, 2009 and from December 23, 2007 to January 2, 2008, respectively. In Rochester, Delta-C (UVBC(370 nm)- BC(880 nm)) values were higher by a factor of 3 during the night than during the day in November and December when residential wood burning was common. In Laredo, particularly high Delta-C values were observed on Christmas Eve and New Year's Eve and were attributed to biomass burning and firework emissions. Exponential decay was found to be a good estimator for predicting BC concentrations at different wind speeds regardless of wind directions. PMID- 21607244 TI - SnO2 nanosheets grown on graphene sheets with enhanced lithium storage properties. AB - We demonstrate a new hydrothermal method to directly grow SnO(2) nanosheets on a graphene oxide support that is subsequently reduced to graphene. This unique SnO(2)/graphene hybrid structure exhibits enhanced lithium storage properties with high reversible capacities and good cycling performance. PMID- 21607237 TI - Rational chemical design of the next generation of molecular imaging probes based on physics and biology: mixing modalities, colors and signals. AB - In recent years, numerous in vivo molecular imaging probes have been developed. As a consequence, much has been published on the design and synthesis of molecular imaging probes focusing on each modality, each type of material, or each target disease. More recently, second generation molecular imaging probes with unique, multi-functional, or multiplexed characteristics have been designed. This critical review focuses on (i) molecular imaging using combinations of modalities and signals that employ the full range of the electromagnetic spectra, (ii) optimized chemical design of molecular imaging probes for in vivo kinetics based on biology and physiology across a range of physical sizes, (iii) practical examples of second generation molecular imaging probes designed to extract complementary data from targets using multiple modalities, color, and comprehensive signals (277 references). PMID- 21607245 TI - Cooperative spin transition in a lipid layer like system. AB - A novel iron(II) mononuclear spin transition complex [FeL(py)(2)] displays an abrupt spin transition around 225 K accompanied by a very wide thermal hysteresis loop (~50 K) that spreads out over 100 K. Crystal structure analysis in both low spin and high-spin states reveals a lipid layer-like arrangement of the complex molecules and provides insights into the spin switching mechanism. PMID- 21607246 TI - Real-time PCR of single bacterial cells on an array of adhering droplets. AB - Real-time PCR at the single bacterial cell level is an indispensable tool to quantitatively reveal the heterogeneity of isogenetic cells. Conventional PCR platforms that utilize microtiter plates or PCR tubes have been widely used, but their large reaction volumes are not suited for sensitive single-cell analysis. Microfluidic devices provide high density, low volume PCR chambers, but they are usually expensive and require dedicated equipment to manipulate liquid and perform detection. To address these limitations, we developed an inexpensive chip level device that is compatible with a commercial real-time PCR thermal cycler to perform quantitative PCR for single bacterial cells. The chip contains twelve surface-adhering droplets, defined by hydrophilic patterning, that serve as real time PCR reaction chambers when they are immersed in oil. A one-step process that premixed reagents with cell medium before loading was applied, so no on-chip liquid manipulation and DNA purification were needed. To validate its application for genetic analysis, Synechocystis PCC 6803 cells were loaded on the chip from 1000 cells to one cell per droplet, and their 16S rRNA gene (two copies per cell) was analyzed on a commercially available ABI StepOne real-time PCR thermal cycler. The result showed that the device is capable of genetic analysis at single bacterial cell level with C(q) standard deviation less than 1.05 cycles. The successful rate of this chip-based operation is more than 85% at the single bacterial cell level. PMID- 21607247 TI - Rational redesign of Candida antarctica lipase B for the ring opening polymerization of D,D-lactide. AB - Based on molecular modelling, the enzyme Candida antarctica lipase B was redesigned as a catalyst for the ring opening polymerization of D,D-lactide. Two mutants with 90-fold increased activity as compared to the wild-type enzyme were created. In a preparative synthesis of poly(D,D-lactide) the mutants greatly improved the rate and the degree of polymerization. PMID- 21607248 TI - Highly efficient iodine species enriching and guest-driven tunable luminescent properties based on a cadmium(II)-triazole MOF. AB - The first example of highly efficient iodine enrichment based on a Cd(II) triazole MOF (1) via both molecular sorption and ion-exchange approaches is reported. PMID- 21607249 TI - Supramolecular polymer nanofibers via electrospinning of a heteroditopic monomer. AB - Driven by the benzo-21-crown-7/secondary ammonium salt recognition motif, a linear supramolecular polymer was formed from self-organization of a low molecular-weight self-complementary monomer in chloroform. From this supramolecular polymer, nanofibers were obtained successfully via electrospinning. PMID- 21607250 TI - A strategy for fabricating single layer graphene sheets based on a layer-by-layer self-assembly. AB - A novel approach to synthesize graphene nanosheet is explored on the basis of the layer-by-layer (LbL) self-assembly of polyallylamine (PAA) and poly(styrene sulfonate) (PSS) multi-layer with a metallic dopant. PMID- 21607251 TI - Photochemically amplified detection of molecular recognition events: an ultra sensitive fluorescence turn-off binding assay. AB - Amplified fluorescence quenching methodology based on massive autocatalytic photo unmasking of a dual function sensitizer-quencher is developed and adopted for photoassisted ultra-sensitive detection of molecular recognition events. The resulting binding assay, based on a molecular recognition-triggered photo amplified cascade with concomitant decrease of fluorescence is validated with the biotin-avidin pair, achieving attomolar detection. PMID- 21607252 TI - A rigid lanthanide binding tag for NMR structural analysis of carbohydrates. AB - The first synthesis of a carbohydrate molecule covalently bound to a rigid lanthanide binding tag is reported. This derivative has been designed as a new tool to provide long-range restraints for structural elucidation and molecular recognition studies of carbohydrates, thus extending the methodology already developed for proteins. PMID- 21607253 TI - Infrared photochromism in a quantum crystal: laser pumping and probing in solid para-H2 doped with CH3F. AB - Solid para-H(2) doped with CH(3)F at 1.8 K is studied in the nu(3) region (~1040 cm(-1)) using a quantum cascade laser source. Residual ortho-H(2) gives rise to distinct spectral features due to CH(3)F-(ortho-H(2))(N) clusters with N = 0, 1, 2, etc. The laser power (~30 mW) is sufficient to significantly affect the sample, enabling novel photochromism experiments to be performed on a solid para H(2) matrix-isolated sample. It is found that population can be reversibly transferred between the N = 1 line and satellite features close to the N = 0 line. PMID- 21607266 TI - Well dispersed single-walled carbon nanotubes with strong visible fluorescence in water for metal ions sensing. AB - A novel and simple method to prepare well dispersed single-walled carbon nanotubes with strong visible fluorescence in water is reported. The visible fluorescence was found to be responsive to pH value and metal ions, and tunable emission ability of oxidized SWCNTs depending on the excitation wavelength and a novel self-excitation and emission process were found. PMID- 21607267 TI - Three-component coupling using arynes and DMF: straightforward access to coumarins via ortho-quinone methides. AB - ortho-Quinone methides, arising from a formal [2+2] cycloaddition between arynes and DMF, were found to facilely undergo a [4+2] cycloaddition with ester enolates or ketenimine anions to produce diverse coumarins in a straightforward manner. PMID- 21607268 TI - In situ enhancement of the blue photoluminescence of colloidal Ga2O3 nanocrystals by promotion of defect formation in reducing conditions. AB - We demonstrate redox control of defect-based photoluminescence efficiency of colloidal gamma-Ga(2)O(3) nanocrystals. Reducing environment leads to an increase in photoluminescence intensity by enhancing the concentration of oxygen vacancies, while the blue emission is suppressed in oxidative conditions. These results enable optimization of nanocrystal properties by in situ defect manipulation. PMID- 21607269 TI - Elegant approach to spacer arranged silagermylene and bis(germylene) compounds. AB - Herein we report on the reactions of the stable LSiCl (1) and LGeCl (2) [L = PhC(NtBu)(2)] with L(1)Ge, [L(1) = CH{(C[double bond, length as m dash]CH(2))(CMe)(2,6-iPr(2)C(6)H(3)N)(2)}] (3) to yield 1-sila-5-germylene (4) and a 1,5-bis(germylene) (5). The reactions proceed through the 1,4 nucleophilic addition of the M-Cl (M = Si or Ge) to 3 without any modification of the oxidation state although the change of the oxidation state is thermodynamically more favorable. Compounds 4 and 5 were investigated by single crystal X-ray structural analyses, multi-nuclear NMR spectroscopy, and micro-analysis. Treatment of L(1)AlMe.thf (6) with 1 resulted in the formation of the 1-sila-5 aluminium complex (7). The complex contains a Si(II) and an Al(III) atom in the molecule. All reported reactions proceed without changing the oxidation states at the metal centers. PMID- 21607270 TI - Monofunctionalized pillar[5]arenes: synthesis and supramolecular structure. AB - The first synthesis of a monohydroxy pillar[5]arene has been carried out, by controlling the de-O-methylation of per-methylated pillar[5]arene. Using monohydroxy pillar[5]arene as an intermediate, mono-guest-functionalized pillar[5]arene was prepared. It formed a self-inclusion complex in CDCl(3) whereas in acetone-d(6) dethreading of the guest moiety took place. PMID- 21607271 TI - The electro-oxidation of formate ions at a polycrystalline Pt electrode in alkaline solution: an in situ FTIR study. AB - This paper reports in situ FTIR studies on the oxidation of formate at polycrystalline Pt in aqueous KOH. Data are presented which show that hydroxyl species play a major role in the electro-oxidation of small organic molecules under alkaline conditions at polycrystalline Pt, and that a number of possible mechanistic pathways are possible. Small changes in experimental conditions appear to be able to cause the reaction to flick between these pathways; for example, the presence of oxygen has a marked effect upon the observed electrochemistry. In contrast to acid solution, our postulated model includes the formation of intermediates bonded through O atoms, rather than C, as being an important option in alkaline solution. Finally, the pH distribution across the reflective electrode in external reflectance IR is modelled and significant variations in pH across the electrode surface in FTIR cells predicted and confirmed experimentally. PMID- 21607272 TI - Mononuclear copper(II) complexes with 3,5-substituted-4-salicylidene-amino-3,5 dimethyl-1,2,4-triazole: synthesis, structure and potent inhibition of protein tyrosine phosphatases. AB - Six copper complexes of Schiff base ligands containing 3,5-substituted-4 salicylideneamino-3,5-dimethyl-1,2,4-triazole have been synthesized and well characterized. The structures of complexes 1 and 2 were determined by X-ray crystal analysis. Fluorescence and potentiometric study indicated that in the physiological pH range, one ligand was dissociated from the complexes to form 1:1 mononucleus copper complexes. The complexes potently inhibit protein tyrosine phosphatase 1B (PTP1B), T-cell protein tyrosine phosphatase (TCPTP), megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2) and Src homology phosphatase 1 (SHP-1) with 3-4 fold selectivity against PTP1B over TCPTP and PTP MEG2, and 3-9 fold over SHP-1, but display almost no inhibition against Src homology phosphatase 2 (SHP-2). Complex 1 inhibits PTP1B with a competitive model with K(i) of 30 nM. Substitution with small groups at the phenyl of the ligand does not obviously influence the inhibitory ability of the complexes. PMID- 21607273 TI - Density functional studies on diimine chelated palladium complex catalyzed Suzuki Miyaura cross-coupling reaction: the impact of Lewis base employed in transmetallation process. AB - The transmetallation processes of disubstituted diimine (RN=CH-CH=NR) chelated palladium complexes catalyzed Suzuki-Miyaura cross-coupling reactions of phenyl chloride (PhCl) and phenylboronic acid [B(OH)(2)Ph] in the presence of diverse Lewis bases (OH(-), F(-), O(t)Bu(-), CO(3)(2-) and PO(4)(3-)) were studied by DFT methods with the B3LYP functional. Activation strain model has also been employed to investigate the extent of deformation of the reactants including the catalyst in the transition state. The transmetallation processes for all the cases are exothermic. The energy barriers for the process with multivalent bases are smaller than that of univalent cases, while, the amounts of the released energies are on the opposite course. The high valent oxoanions such as CO(3)(2-) and PO(4)(3-) provide more versatile bonding modes in the processes. The flexibility of diimine either as mono- or bi-dentate ligand in the mechanism provides a valuable channel for lowering the energy barriers of this process. The simplicity and efficiency of this type of ligand make it a potential alternation to the most commonly used phosphine. PMID- 21607274 TI - Hybrid dibismuthines and distibines as ligands towards transition metal carbonyls. AB - The hybrid dibismuthines O(CH(2)CH(2)BiPh(2))(2) and MeN(CH(2)-2 C(6)H(4)BiPh(2))(2) react with [M(CO)(5)(thf)] (M = Cr or W) to form [{M(CO)(5)}(2){O(CH(2)CH(2)BiPh(2))(2)}] and [{Cr(CO)(5)}(2){MeN(CH(2)-2 C(6)H(4)BiPh(2))(2)}] containing bridging bidentate (Bi(2)) coordination. The unsymmetrical tertiary bismuthine complexes [M(CO)(5){BiPh(2)(o-C(6)H(4)OMe)}] are also described. Depending upon the molar ratio, the hybrid distibines O(CH(2)CH(2)SbMe(2))(2) and MeN(CH(2)-2-C(6)H(4)SbMe(2))(2) react with [M(CO)(5)(thf)] to give the pentacarbonyl complexes [{M(CO)(5)}(2){O(CH(2)CH(2)SbMe(2))(2)}] and [{Cr(CO)(5)}(2){MeN(CH(2)-2 C(6)H(4)SbMe(2))(2)}] or tetracarbonyls cis-[M(CO)(4){O(CH(2)CH(2)SbMe(2))(2)}] and cis-[M(CO)(4){MeN(CH(2)-2-C(6)H(4)SbMe(2))(2)}]. The latter can also be obtained from [Cr(CO)(4)(nbd)] or [W(CO)(4)(pip)(2)], and contain chelating bidentates (Sb(2)-coordinated) as determined crystallographically. S(CH(2)-2 C(6)H(4)SbMe(2))(2) coordinates as a tridentate (SSb(2)) in fac-[M(CO)(3){S(CH(2) 2-C(6)H(4)SbMe(2))(2)}] (M = Cr or Mo) and fac-[Mn(CO)(3){S(CH(2)-2 C(6)H(4)SbMe(2))(2)}][CF(3)SO(3)]. Fac-[Mn(CO)(3){MeN(CH(2)-2 C(6)H(4)SbMe(2))(2)}][CF(3)SO(3)] contains NSb(2)-coordinated ligand in the solid state, but in solution a second species, Sb(2)-coordinated and with a kappa(1) CF(3)SO(3) replacing the coordinated amine is also evident. X-ray crystal structures were also determined for fac-[Cr(CO)(3){S(CH(2)-2 C(6)H(4)SbMe(2))(2)}], fac-[Mn(CO)(3){S(CH(2)-2-C(6)H(4)SbMe(2))(2)}][CF(3)SO(3)] and fac-[Mn(CO)(3){MeN(CH(2)-2-C(6)H(4)SbMe(2))(2)}] [CF(3)SO(3)]. Hypervalent N...Sb interactions are present in cis-[M(CO)(4){MeN(CH(2)-2 C(6)H(4)SbMe(2))(2)}] (M = Mo or W), but absent for M = Cr. PMID- 21607275 TI - Effectiveness of amendments on re-acidification and heavy metal immobilization in an extremely acidic mine soil. AB - Previous studies have shown that the application of soil amendments is efficient in reducing acidity and heavy metal bioavailability in mine soils. However, it remains a challenge for environmentalists to predict accurately and control economically the re-acidification in re-vegetated mine soils. In this study, net acid generation (NAG) test and bioassay technique were employed to assess the effectiveness of the amendments [including lime, N-P-K (nitrogen, phosphorous and potassium) fertilizer, phosphate and river sediment] on re-acidification and heavy metal immobilization in an extremely acid (pH < 3) mine soil. Our results suggested that NAG test was a rapid and accurate approach to assess the effectiveness of the amendments on re-acidification potential of the mine soil. Interestingly, it was found that phosphate and river sediment played quite specific roles in preventing the re-acidification in the mine soil. In addition, the results also indicated that the addition of 25 t ha(-1) lime combined with river sediment (30%) might be an economical method to successfully control the acidification and re-acidification in the extremely acid mine soil, allowing the re-establishment of the plants. Collectively, our results implied that the combined use of NAG test and bioassay assessment was effective in evaluating a reclamation strategy for extremely acidic mine soils. PMID- 21607276 TI - Elaboration of vinblastine hybrids using a reactive in situ generated N carboxyanhydride. AB - Hybrids of vinblastine and phomopsin, designed by a molecular modelling study, were elaborated in order to target tubulin. The key step of the synthesis (fragmentation and insertion of vindoline) was mediated by an internal N carboxyanhydride (or O-acylcarbamate). This reaction was diastereospecific and addition of silver salts could reverse the diastereoselectivity. Even if the synthesized compounds are inactive, this synthesis represents an original example of a C-N fragmentation mediated by a N-carboxyanhydride. PMID- 21607277 TI - A regioselective synthesis of poly-substituted aryl triflones through self promoting three component reaction. AB - In the absence of any additional catalysts, the reactions of (CF(3)SO)(2)CH(2), aldehydes, and 1,3-dienes gave gem-bis(triflyl)cyclohexenes in excellent yields with high regioselectivity. gem-Bis(triflyl)cyclohexene products can be easily converted to the corresponding aryl trifluoromethyl sulfones. PMID- 21607278 TI - Promotion of hydrogen release from ammonia borane with magnesium nitride. AB - Hydrogen release from ammonia borane (NH(3)BH(3), AB) can be greatly promoted by mechanical milling with magnesium nitride (Mg(3)N(2)). For example, a post-milled 6AB/Mg(3)N(2) sample started to release hydrogen from ~65 degrees C and gave a material-based hydrogen capacity of ~11 wt% upon heating to 300 degrees C. In addition to the improved dehydrogenation kinetics, the 6AB/Mg(3)N(2) sample also showed satisfactory performance in suppressing the volatile byproducts. X-ray diffraction, Fourier transform infrared spectroscopy and solid-state (11)B MAS NMR, as well as a series of designed experiments, were carried out to gain mechanistic understanding of the property improvements that arise from addition of Mg(3)N(2). Our study found that the formation of 3Mg(NH(2)BH(3))(2).2NH(3), which is in single or mixed amidoborane ammoniate phases in nature, is an important mechanistic step in the dehydrogenation process of the 6AB/Mg(3)N(2) sample. PMID- 21607279 TI - Delineating similarities and dissimilarities in the use of metal organic frameworks and zeolites as heterogeneous catalysts for organic reactions. AB - This perspective article is aimed at providing a comparison of similarities and dissimilarities between the catalytic properties of zeolites and metal organic frameworks (MOFs). In the first part of the paper, we comment the general characteristics of MOFs with relevance to catalysis, making emphasis of how the properties of MOFs can serve to compliment those of zeolites as catalysts. The lower chemical and thermal stability of MOFs compared to zeolites is commented and correlated to the requirements for some liquid-phase reactions conducted under mild conditions. In the second part, we discuss the behaviour of zeolites and MOFs for four types of general organic reactions (acid catalysed, base catalysed, oxidation and hydrogenations). Particular attention is paid to provide critical comments on how MOFs could be adapted by design or can be modified by post-synthetic treatments to give well performing catalysts. PMID- 21607280 TI - Chemistry of 11-vertex rhodathiaboranes: reactions with monodentate phosphines. AB - The reaction of [8,8-(PPh(3))(2)-nido-8,7-RhSB(9)H(10)] (1) with PR(3) in a 1:2 ratio affords mixtures that contain the mono-substituted bis-PR(3)-ligated rhodathiaboranes [8,8-(PPh(3))(L)-nido-8,7-RhSB(9)H(10)] [L = PMe(2)Ph (5), PMe(3) (6)] and the corresponding tris-PR(3)-ligated compounds [8,8,8-(L)(3)-nido 8,7-RhSB(9)H(10)] [L = PMe(2)Ph (7), PMe(3) (8)]. These latter species are more conveniently prepared from the reaction of 1 with three equivalents of the monodentate phosphines, PMe(2)Ph and PMe(3). Reaction between 1 and PMePh(2) in a 1:2 ratio yields the disubstituted rhodathiaborane [8,8-(PMePh(2))(2)-nido-8,7 RhSB(9)H(10)] (4), whereas the use of three equivalents of phosphine leads to the formation of B-ligated eleven-vertex [8,8,8-(PMePh(2))(2)(H)-nido-8,7-RhSB(9)H(9) 9-(PMePh(2))] (9). Compounds 4-9 have been characterized by NMR spectroscopy, and the structures of 8 and 9 confirmed by X-ray diffraction analyses. The characterization of the cluster compounds has been aided by the use of DFT calculations on some of the species. Variable-temperature NMR studies have demonstrated a lability of the PMePh(2) ligands in compounds 4 and 9, providing mechanistic insights about the ligand substitutional chemistry in these eleven vertex rhodathiaboranes. PMID- 21607281 TI - Doped amorphous silica nanoparticles as enhancing agents for surface-assisted time-of-flight mass spectrometry. AB - This article examines the use of doped amorphous silica nanoparticles for surface assisted laser desorption/ionisation-time of flight-mass spectrometry (SALDI-TOF MS) of hydrophilic and hydrophobic compounds. A range of particles with surface aliphatic carboxylic, aminophenyl, phenyl or aminopropyl groups have been produced and these have been doped with carbon black, polyaniline or graphite. The effects of surface groups and dopants on the laser desorption/ionisation process were studied. The key factor in effective LDI was the presence of carbon black dopant carrying carboxyphenyl or phenyl residues for positive and negative ion formation. The second key factor was the presence of hydrophilic surface functional groups for hydrophilic amino acid analytes for their detection in positive or negative mode as protonated or de-protonated species respectively whereas hydrophobic surfaces were need for ionisation via cationisation for the hydrophobic analyte squalene. The mechanism for LDI of these particles appears to involve initial adsorption of the analyte onto the surface of the particle, formation of primary ions via adsorption of laser UV irradiation by carboxyphenyl residues attached to the carbon black network which act in an equivalent way to the matrix in matrix-assisted LDI. This is followed by reaction of the primary ions with neighbouring adsorbed analyte molecules. The latter are then released possibly via thermal desorption following proton donation or acceptance from/to via surface residues such carboxylate groups associated with the carbon black within the dopant. Alternatively in the absence of such proton donor/acceptor residues as with hydrophobic particles, the primary ions are released from the particles during desorption and form cation adducts as sodiated and potassiated species in the gas phase above the surface. PMID- 21607282 TI - Volatilisation of ferrocene from ionic liquids: kinetics and mechanism. AB - The evaporation of dissolved ferrocene from non-volatile ionic liquids under a flow of nitrogen gas has been monitored voltammetrically and modelled mathematically. The rate of volatilisation was found to depend on the surface tension of the ionic liquid, and a model is presented. PMID- 21607283 TI - Sample stacking microemulsion electrokinetic capillary chromatography induced by reverse migrating pseudostationary phase for the quantification of phenobarbital and its p-hydroxyphenobarbital metabolite in rat urine. AB - For the first time, a capillary electrophoretic (CE) method with sample stacking induced by a reverse migrating pseudostationary phase (SRMP) technique has been developed and validated for sensitive determination of phenobarbital (PB) and its p-hydroxyphenobarbital (PHPB) metabolite in rat urine samples. Separation and determination were optimized on a fused-silica capillary with a total length of 50 cm (effective length 40 cm) and 75 MUm ID. The microemulsion background electrolyte consisted of 0.8% (v/v) ethyl acetate, 6.6% (v/v) butan-2-ol, 1.0% (v/v) acetonitrile, 2.0% (w/v) sodium n-dodecyl sulfate (SDS), and 89.6% (v/v) of 7.5 mM ammonium formate at pH 8. When this preconcentration technique was used, the sample stacking and the separation processes took place successively with changing the voltage with an intermediate polarity switching step. For practical application, a solid-phase extraction (SPE), C(18) sorbent with n-hexane/ethyl acetate (1 : 1%, v/v) as the elution solvent was used for sample purification and concentration. The SPE method gave good extraction yields for all the analytes, with absolute recovery values of 96.9% and 99.1% for PB and PHPB, respectively. The regression equations for PB and PHPB showed excellent linearity over a concentration range of 55-1386 ng mL(-1) for PB and PHPB (r = 0.998). The developed microemulsion electrokinetic capillary chromatography (MEEKC) method for separation of the studied compounds with SRMP as the electrophoretic preconcentration technique allowed detection limits in urine samples at 16.8 ng mL(-1) for PB and PHPB which are 15-fold lower than the reported CE method in the literature. The precision results, expressed by the intra-day and inter-day relative standard deviation (RSD) values range from 3.6 to 7.1% (repeatability) and from 3.2 to 7.2% (intermediate precision) for PB and PHPB, respectively, which were in line with Food and Drug Administration (FDA) criteria. PMID- 21607284 TI - Establishment of trace determination method of pyrethroid pesticides with TiO2 nanotube array micro-solid phase equilibrium extraction combined with GC-ECD. AB - This paper described a new method for the enrichment and determination of pyrethroid pesticides from environmental water samples with ordered TiO(2) nanotube array micro-solid phase equilibrium extraction (MU-SPEE) prior to gas chromatography (GC) with electron capture detection (ECD). Several factors such as the anodization voltage, the kind of organic solvents, sample pH, equilibrium extraction time, desorption time and salting-out effect were optimized. Under the optimal conditions, ordered TiO(2) nanotube arrays demonstrated excellent merits on the preconcentration of pyrethroid pesticides and good detection limits were achieved as 0.018, 0.020, 0.031, 0.041, and 0.070 MUg L(-1) for bifenthrin, fenpropathrin, cyhalothrin, fenvalerate, and deltamethrin, respectively. Four real water samples were used to validate the proposed method and the spiked recoveries were over the range of 81.9-110.6%. Compared to conventional solid phase extraction (SPE), the present method showed better recoveries and good reproducibility. These results showed that this MU-SPEE technique could be an important alternative to multistep SPE for the extraction and determination of such analytes in complex samples and become a useful tool in monitoring such analytes in the environment. PMID- 21607285 TI - Templating a polymer-scaffolded dynamic combinatorial library. AB - A water soluble polymer-scaffolded dynamic combinatorial library whose members can interconvert through acylhydrazone exchange was prepared and shown to re equilibrate in the presence of macromolecular templates. PMID- 21607286 TI - Rapamycin ameliorates dystrophic phenotype in mdx mouse skeletal muscle. AB - Duchenne muscular dystrophy (DMD) is an X-linked, lethal, degenerative disease that results from mutations in the dystrophin gene, causing necrosis and inflammation in skeletal muscle tissue. Treatments that reduce muscle fiber destruction and immune cell infiltration can ameliorate DMD pathology. We treated the mdx mouse, a model for DMD, with the immunosuppressant drug rapamycin (RAPA) both locally and systemically to examine its effects on dystrophic mdx muscles. We observed a significant reduction of muscle fiber necrosis in treated mdx mouse tibialis anterior (TA) and diaphragm (Dia) muscles 6 wks post-treatment. This effect was associated with a significant reduction in infiltration of effector CD4(+) and CD8(+) T cells in skeletal muscle tissue, while Foxp3(+) regulatory T cells were preserved. Because RAPA exerts its effects through the mammalian target of RAPA (mTOR), we studied the activation of mTOR in mdx TA and Dia with and without RAPA treatment. Surprisingly, mTOR activation levels in mdx TA were not different from control C57BL/10 (B10). However, mTOR activation was different in Dia between mdx and B10; mTOR activation levels did not rise between 6 and 12 wks of age in mdx Dia muscle, whereas a rise in mTOR activation level was observed in B10 Dia muscle. Furthermore, mdx Dia, but not TA, muscle mTOR activation was responsive to RAPA treatment. PMID- 21607287 TI - STATus and Context within the Mammalian Nervous System. AB - Effective manipulation of human disease processes may be achieved by understanding transcriptional, posttranscriptional and epigenetic events that orchestrate cellular events. The levels of activation of specific molecules, spatial distribution and concentrations of relevant networks of signaling molecules along with the receptiveness of the chromatin to these signals are some of the parameters which dictate context. Effects elicited by the transcription factor signal transducers and activator of transcription 3 (Stat3) are discussed with respect to the context within which Stat3-mediated effects are elicited within the developing and adult mammalian nervous system. Stat3 signals are pivotal to the proliferation and differentiation of neural stem cells. They also participate in neuronal regeneration and cancers of the nervous system. An analysis of the context in which Stat3 activation occurs in these processes provides a potential predictive paradigm with which novel methods for intervention may be designed. PMID- 21607290 TI - B-cell subsets in the joint compartments of seropositive and seronegative rheumatoid arthritis (RA) and No-RA arthritides express memory markers and ZAP70 and characterize the aggregate pattern irrespectively of the autoantibody status. AB - The aim of the present study was to determine whether different subsets of B cells characterize synovial fluid (SF) or synovial tissue (ST) of seropositive or seronegative rheumatoid arthritis (RA) with respect to the peripheral blood (PB). PB, SF and ST of 14 autoantibody (AB)-positive (rheumatoid factor [RF]-IgM, RF IgA, anti-citrullinated peptide [CCP]), 13 negative RA and 13 no-RA chronic arthritides were examined for B-cell subsets (Bm1-Bm5 and IgD-CD27 classifications), zeta-associated protein kinase-70 (ZAP70) expression on B cells and cytokine levels (interleukin [IL]-1beta, tumor necrosis factor [TNF]-alpha, IL-6, IL-8 and monocyte chemotactic protein [MCP]-1). Synovial tissues were classified as aggregate and diffuse patterns. No differences were found in B-cell percentages or in subsets in PB and SF between AB(+) and AB(-) RA and no-RA. In both AB(+) and AB(-) RA (and no-RA), the percentage of CD19(+)/ZAP70(+) was higher in SF than in PB (AB(+): P = 0.03; AB(-): P = 0.01; no-RA: P = 0.01). Moreover, SF of both AB(+) and AB(-) RA (and no-RA) patients was characterized by a higher percentage of IgD-CD27(+) and IgD-CD27(-) B cells and lower percentage of IgD(+)CD27(-) (P < 0.05) B cells compared to PB. In SF, ZAP70 positivity is more represented in B cell CD27(+)/IgD(-)/CD38(-). The aggregate synovitis pattern was characterized by higher percentages of Bm5 cells in SF compared with the diffuse pattern (P = 0.05). These data suggest that no difference exists between AB(+) and AB(-) in B-cell subset compartmentalization. CD27(+)/IgD( )/ZAP70(+) memory B cells accumulate preferentially in the joints of RA, suggesting a dynamic maturation of the B cells in this compartment. PMID- 21607289 TI - Cordycepin blocks lung injury-associated inflammation and promotes BRCA1 deficient breast cancer cell killing by effectively inhibiting PARP. AB - Cordycepin has been shown to interfere with a myriad of molecular processes from RNA elongation to kinase activity, and prevents numerous inflammatory processes in animal models. Here we show in a mouse model of LPS-induced acute lung injury that cordycepin prevents airway neutrophilia via a robust blockade of expression of several inflammatory genes, including the adhesion molecule ICAM-1 and VCAM-1, the cytokine/chemokine MCP-1, MIP-1alpha, MIP-2 and KC, and the chemokine receptor CXCR2. Such a blockade appears to be related to a severe reduction in TNF-alpha expression. Interestingly, in an in vitro system of A549 epithelial cell inflammation, cordycepin effectively blocked LPS-induced, but not TNF-alpha induced, VCAM-1 expression. Such effects correlated with a marked reduction in p65-NF-kappaB activation as assessed by its phosphorylation at serine-536 but without an apparent effect on its nuclear translocation. The effects of cordycepin on the expression of VCAM-1 and ICAM-1, and of NF-kappaB activation and nuclear translocation upon TNF-alpha stimulation resembled the effects achieved upon poly(ADP-ribose) polymerase (PARP) inhibition, suggesting that cordycepin may function as a PARP inhibitor. Indeed, cordycepin blocked H(2)O(2) induced PARP activation in A549 cells. In a cell-free system, cordycepin inhibited PARP-1 activity at nanomolar concentrations. Similar to PARP inhibitors, cordycepin significantly induced killing of breast cancer susceptibility gene (BRCA1)-deficient MCF-7 cells, supporting its therapeutic use for the treatment of BRCA-deficient breast cancers. With added antiinflammatory characteristics, therapies that include cordycepin may prevent potential inflammation triggered by traditional chemotherapeutic drugs. Cordycepin, to the best of our knowledge, represents the first natural product possessing PARP inhibitory traits. PMID- 21607288 TI - Frequent gene products and molecular pathways altered in prostate cancer- and metastasis-initiating cells and their progenies and novel promising multitargeted therapies. AB - Recent gene expression profiling analyses and gain- and loss-of-function studies performed with distinct prostate cancer (PC) cell models indicated that the alterations in specific gene products and molecular pathways often occur in PC stem/progenitor cells and their progenies during prostate carcinogenesis and metastases at distant sites, including bones. Particularly, the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/beta catenin, Notch, hyaluronan (HA)/CD44 and stromal cell-derived factor-1 (SDF 1)/CXC chemokine receptor 4 (CXCR4) during the epithelial-mesenchymal transition (EMT) process may provide critical functions for PC progression to locally invasive, metastatic and androgen-independent disease states and treatment resistance. Moreover, an enhanced glycolytic metabolism in PC stem/progenitor cells and their progenies concomitant with the changes in their local microenvironment, including the induction of tumor hypoxia and release of diverse soluble factors by tumor myofibroblasts, also may promote the tumor growth, angiogenesis and metastases. More particularly, these molecular transforming events may cooperate to upregulate Akt, nuclear factor (NF)-kappaB, hypoxia inducible factors (HIFs) and stemness gene products such as Oct3/4, Sox2, Nanog and Bmi-1 in PC cells that contribute to their acquisition of high self-renewal, tumorigenic and invasive capacities and survival advantages during PC progression. Consequently, the molecular targeting of these deregulated gene products in the PC- and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients. PMID- 21607291 TI - A nonerythropoietic peptide that mimics the 3D structure of erythropoietin reduces organ injury/dysfunction and inflammation in experimental hemorrhagic shock. AB - Recent studies have shown that erythropoietin, critical for the differentiation and survival of erythrocytes, has cytoprotective effects in a wide variety of tissues, including the kidney and lung. However, erythropoietin has been shown to have a serious side effect-an increase in thrombovascular effects. We investigated whether pyroglutamate helix B-surface peptide (pHBSP), a nonerythropoietic tissue-protective peptide mimicking the 3D structure of erythropoietin, protects against the organ injury/ dysfunction and inflammation in rats subjected to severe hemorrhagic shock (HS). Mean arterial blood pressure was reduced to 35 +/- 5 mmHg for 90 min followed by resuscitation with 20 mL/kg Ringer Lactate for 10 min and 50% of the shed blood for 50 min. Rats were euthanized 4 h after the onset of resuscitation. pHBSP was administered 30 min or 60 min into resuscitation. HS resulted in significant organ injury/dysfunction (renal, hepatic, pancreas, neuromuscular, lung) and inflammation (lung). In rats subjected to HS, pHBSP significantly attenuated (i) organ injury/dysfunction (renal, hepatic, pancreas, neuromuscular, lung) and inflammation (lung), (ii) increased the phosphorylation of Akt, glycogen synthase kinase-3beta and endothelial nitric oxide synthase, (iii) attenuated the activation of nuclear factor (NF)-kappaB and (iv) attenuated the increase in p38 and extracellular signal-regulated kinase (ERK)1/2 phosphorylation. pHBSP protects against multiple organ injury/dysfunction and inflammation caused by severe hemorrhagic shock by a mechanism that may involve activation of Akt and endothelial nitric oxide synthase, and inhibition of glycogen synthase kinase-3beta and NF-kappaB. PMID- 21607294 TI - Absence of functional mutations in the ferroportin-encoding SLC40A1 gene in porphyria cutanea tarda: a series of 37 cases from southern France. PMID- 21607292 TI - Restoring the balance of the autonomic nervous system as an innovative approach to the treatment of rheumatoid arthritis. AB - The immunomodulatory effect of the autonomic nervous system has raised considerable interest over the last decades. Studying the influence on the immune system and the role in inflammation of the sympathetic as well as the parasympathetic nervous system not only will increase our understanding of the mechanism of disease, but also could lead to the identification of potential new therapeutic targets for chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). An imbalanced autonomic nervous system, with a reduced parasympathetic and increased sympathetic tone, has been a consistent finding in RA patients. Studies in animal models of arthritis have shown that influencing the sympathetic (via alpha- and beta-adrenergic receptors) and the parasympathetic (via the nicotinic acetylcholine receptor alpha7nAChR or by electrically stimulating the vagus nerve) nervous system can have a beneficial effect on inflammation markers and arthritis. The immunosuppressive effect of the parasympathetic nervous system appears less ambiguous than the immunomodulatory effect of the sympathetic nervous system, where activation can lead to increased or decreased inflammation depending on timing, doses and kind of adrenergic agent used. In this review we will discuss the current knowledge of the role of both the sympathetic (SNS) and parasympathetic nervous system (PNS) in inflammation with a special focus on the role in RA. In addition, potential antirheumatic strategies that could be developed by targeting these autonomic pathways are discussed. PMID- 21607295 TI - Do patient-reported outcome measures in hip and knee arthroplasty rehabilitation have robust measurement attributes? A systematic review. AB - OBJECTIVE: The aim of this study was to systematically review and compare the measurement attributes of multidimensional, patient-reported outcome measures used in hip and knee arthroplasty rehabilitation. METHODS: A search of PubMed, CINAHL, Cochrane Central Registry, SCOPUS and PEDro databases up to December 2009 identified the validation studies. The quality of the measurement properties were assessed based on the Terwee and Bot criteria, and Scientific Advisory Committee of the Medical Outcomes Trust guidelines. RESULTS: A total of 68 studies examining 28 instruments were identified. Three instruments had positive ratings for content validity. None of the instruments satisfied both factor analysis and Cronbach's alpha criteria for internal consistency. Four measures were positively rated for agreement. Nine tools had positive ratings for construct validity. Twenty-four of the instruments had indeterminate ratings for responsiveness to clinical change. Only certain subscales of 2 instruments were positively-rated for responsiveness to clinical change. CONCLUSION: A wide variety of multidimensional patient-reported instruments has been used to assess rehabilitation outcomes after hip and knee arthroplasty, but information about their measurement attributes in these populations is inadequate. More data are needed to clarify their reproducibility and responsiveness to clinical change. : PMID- 21607293 TI - Deptor knockdown enhances mTOR Activity and protein synthesis in myocytes and ameliorates disuse muscle atrophy. AB - Deptor is an mTOR binding protein that affects cell metabolism. We hypothesized that knockdown (KD) of Deptor in C2C12 myocytes will increase protein synthesis via stimulating mTOR-S6K1 signaling. Deptor KD was achieved using lentiviral particles containing short hairpin (sh)RNA targeting the mouse Deptor mRNA sequence, and control cells were transfected with a scrambled control shRNA. KD reduced Deptor mRNA and protein content by 90%, which increased phosphorylation of mTOR kinase substrates, 4E-BP1 and S6K1, and concomitantly increased protein synthesis. Deptor KD myoblasts were both larger in diameter and exhibited an increased mean cell volume. Deptor KD increased the percentage of cells in the S phase, coincident with an increased phosphorylation (S807/S811) of retinoblastoma protein (pRb) that is critical for the G(1) to S phase transition. Deptor KD did not appear to alter basal apoptosis or autophagy, as evidenced by the lack of change for cleaved caspase-3 and light chain (LC)3B, respectively. Deptor KD increased proliferation rate and enhanced myotube formation. Finally, in vivo Deptor KD (~50% reduction) by electroporation into gastrocnemius of C57/BL6 mice did not alter weight or protein synthesis in control muscle. However, Deptor KD prevented atrophy produced by 3 d of hindlimb immobilization, at least in part by increasing protein synthesis. Thus, our data support the hypothesis that Deptor is an important regulator of protein metabolism in myocytes and demonstrate that decreasing Deptor expression in vivo is sufficient to ameliorate muscle atrophy. PMID- 21607296 TI - Participation and health-related quality of life of Dutch children and adolescents with congenital lower limb deficiencies. AB - OBJECTIVES: To describe participation and health-related quality of life of Dutch children and adolescents with congenital lower limb deficiencies in comparison with typically developing children, and to explore differences between various degrees of limb loss and between parental reports and self-reports on health related quality of life. DESIGN: Cross-sectional study. METHODS: Participation was assessed with the Children's Assessment of Participation and Enjoyment questionnaire, and health-related quality of life with the KIDSCREEN-52 questionnaire, both as parental reports and self-reports, for 56 children and adolescents with congenital lower limb deficiencies, aged 8-18 years. RESULTS: Participation and health-related quality of life of children and adolescents with lower limb deficiencies (age range 8-18 years) did not differ from those of the reference group, except that the adolescents with lower limb deficiencies (age range 12-18 years) reported significantly (p < 0.05) less diversity and lower intensity of social and skill-based activities. Degree of limb loss did not affect participation or health-related quality of life. Differences (p < 0.05) between parental reports and self-reports for health-related quality of life were found for the "physical well-being", "moods and emotions" and "self-perception" domains. While parental reports were comparable to the adolescents' self-ratings, parents reported lower health-related quality of life in the "moods and emotions", "self-perception" and "autonomy" domains for their younger children. CONCLUSION: While the participation and perceived health-related quality of life of Dutch children with lower limb deficiencies do not differ from those among typically developing children, the participation of adolescents with lower limb deficiencies is characterized by less diversity, with less interaction in social and skill-based activities. PMID- 21607298 TI - Quantification of intratumoral vascularization predicts metastasis in human invasive solid tumors (review). AB - There is experimental evidence that tumour invasiveness, progression and metastasis of most solid tumours are angiogenesis-dependent. The onset of the angiogenic tumour cell phenotype behaves as an independent event during malignancy, and the switch from a prevascular to a vascular phase may be achieved by several mechanisms. From experimental data it is reasonable to think that determination of angiogenic activity is a marker of tumour aggressiveness and metastasis in human solid tumours. In particular, determination of tumour angiogenesis seems to be a potential new marker for prognosis, to recognize low versus high risk patients. On the above basis, recently, several clinical studies have been done to correlate the degree of intratumoral vascularisation, detected by immunocytochemical methods, with metastasis and/or prognosis. Overall, the majority of these studies found a significant correlation between microvessel density of the primary tumour and presence of metastasis in the human rumours tested (breast, non-small cell lung, prostatic and head and neck cancers and skin melanoma). Much experience has been obtained for early-stage breast carcinoma. In this tumour, vascular index is emerging as a novel important prognostic tool, particularly useful in identifying high risk node-negative patients eligible for systemic adjuvant therapy. Because angiogenesis-inhibitor drugs are beginning to be used in clinical trials, the knowledge of the individual angiogenic activity of the tumours may be used in the future also as a marker to predict response to such a novel therapeutic approach. The methods to assess tumour vascularisation, clinical results, open questions and future perspectives are presented and discussed. PMID- 21607297 TI - Cross-cultural validity of a naturalistic observational assessment of children's hand skills: a study using Rasch analysis. AB - OBJECTIVE: To investigate cross-cultural validity of a newly developed Assessment of Children's Hand Skills (ACHS) in children with and without disabilities. SUBJECTS: One group of 138 Australian children and 134 Taiwanese children, age range 2-12 years (a total of 149 typically developing children and 123 children with disabilities). METHODS: Rasch model analysis was used to evaluate rating scale performance, person-fit, and item unidimensionality of pooled data from the ACHS. Rasch-based differential item functioning was used to evaluate differences in item difficulties between cultural groups. RESULTS: The appropriateness of the ACHS 6-level rating scale was confirmed in the pooled analysis. All 22 activity items and 19 of 20 hand skill items in the ACHS formed a unidimensional scale. The ACHS exhibited reasonable response patterns when applied to the composite sample of Australian and Taiwanese children. Differential item functioning was found in 7 activity items and 7 hand skill items. CONCLUSION: The ACHS can be used to assess and compare children's hand skills across Australian and Taiwanese cultural contexts with confidence. Adjustment for differential item functioning may be used when pooling or comparing ACHS data from these cultural groups. PMID- 21607299 TI - Shedding of tnf-receptor and soluble icam-1 molecules in response to treatment with recombinant tnf-alpha and IFN-gamma in patients with colorectal-cancer. AB - Intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor alpha receptor (TNF-R) have been detected in soluble forms in the serum of cancer patients. sICAM-1 can abrogate non MHC-restricted cytotoxicity mediated by NK and lymphokine-activated killer cells. Soluble TNF-alpha receptors have been shown to neutralize the cytopathic activity of recombinant TNF-alpha. Both mechanisms can facilitate neoplastic cells to escape immunosurveillance. Serum levels of sTNF-R and sICAM-1 were determined during a phase II combination trial with TNF-alpha and IFN-gamma in eight patients with colorectal cancer. Serum concentrations of sTNF-R and sICAM-1 increased significantly during the treatment period. Shedding of ICAM-1 and TNF-R induced by TNF-alpha and IFN-gamma could be responsible for the ineffectivity of TNF-alpha based treatment regimens. PMID- 21607300 TI - Differential regulation of glucose-transporter expression in hematopoietic-cells by oncogenic transformation and cytokine stimulation. AB - Malignant transformation by the v-src oncogene and mitogenic stimulation by interleukin-3 (IL-3) both increased glucose transport into a hematopoietic cell line. These increases were additive and correlated with elevations in the level of GLUT1 mRNA. Glucose transport and GLUT1 mRNA were dependent on the presence of a functional v-src gene product in the absence of IL-3. Nuclear run-on analyses and mRNA turnover experiments demonstrated that GLUT1 gene transcription was enhanced by v-src while IL-3 stabilized GLUT1 mRNA. Introduction of retroviruses overexpressing GLUT1 into factor-dependent cells did not abrogate factor dependency. Thus, GLUT1 induction is necessary but not sufficient for mitogenesis. PMID- 21607301 TI - Intraarterial Cisplatin and caffeine with/without Doxorubicin for musculoskeletal high-grade spindle-cell sarcoma. AB - We report on the effects of intraarterial cisplatin and caffeine with/without doxorubicin on high-grade spindle cell sarcomas of bone and soft tissue based on the fact that caffeine enhances cytocidal effects of DNA-damaging agents. Intraarterial cisplatin and caffeine with/without doxorubicin was preoperatively given three times to ail patients and two courses of high-dose methotrexate with the citrovorum factor and vincristine were administered to the patients with skeletal spindle cell sarcoma. Tumor response was assessed radiographically and histologically. Seventeen (90%) of 19 patients with bone sarcoma and 7 (70%) of 10 patients with soft-tissue sarcoma showed good response. All patients with osteosarcoma demonstrating good radiological response underwent marginal excision without subsequent local tumor recurrence. Histologically, there were no viable cells in resected specimen of 14 patients with bone sarcoma. Other 8 cases with soft-tissue sarcoma treated by unplanned surgery were included to assess side effects. Twenty-five out of 37 patients are still free of disease. There was local tumor recurrence in 2 patients who did not respond to the chemotherapy. Toxic effects noted in the clinical study included moderate myelosuppression, nausea and vomiting, renal insufficiency and cutaneous injury. No toxic effects were directly attributable to 1.2-1.5 g/m(2) caffeine. The intraarterial infusion of cisplatin and caffeine combined with/without doxorubicin was tolerable in all patients and led to good response in high-grade spindle cell sarcomas. In patients with good response, limb-salvage surgery can be conducted safely without local relapse and good limb function is preserved by chemotherapy and marginal excision. PMID- 21607302 TI - The microfocus assay system (mfas) - a simple quantitative assay to identify inhibitory drugs targeted against specific oncogenes. AB - We have developed an assay, the microfocus assay system (MFAS), that enables the quantitative assessment of anticancer drugs and their ability to specifically target and inhibit cellular oncogenes. Analysis of three chemotherapeutic reagents showed a differential negative effect against the ability of transformed cells containing either the oncogenic rat neu, human H-ras, or v-mos oncogene to form transformed foci on a background of normal fibroblasts. Though these drugs have not been examined previously for targeting against specific oncogenes, our results with the MFAS indicate preferential inhibitory effects against cells transformed with different oncogenes. Therefore, the MFAS should enable the large scale screening of anti-cancer drugs specifically targeted against known oncogenes and provide a quantitative measurement of their effectiveness. PMID- 21607303 TI - Proliferating activity of gastric-carcinoma invading the muscularis propria and metastasis to lymph-nodes. AB - From 1965 to 1987, 126 patients who had gastric cancer invading the muscularis propria (pm) were treated with curative resection in the Department of Surgery II, Kyushu University. We examined the correlation between the proliferating activity of the tumor by staining the tissue for proliferating cell nuclear antigen (PCNA) and the occurrence of lymph node metastasis present in 46.8% (59/126) of the patients. Undifferentiated carcinoma was more frequent in these patients and lymphatic and vascular involvement was prominent. Patients with a lymph node metastasis had a higher level of PCNA staining in the tumors than did those without lymph node metastasis (labeling index: 36.5 +/- 9.6% vs. 25.3 +/- 8.3%) (P < 0.01). The survival rate for patients with lymph node metastasis was lower than that for those without this metastasis (P < 0.01). The 10-year survival rate was 63.6% for the patients with lymph node metastasis and 86.8% for those without lymph node metastasis. Thus, the presence of lymph node metastasis is associated with a high growth potential of tumor cells in pm gastric cancer. Close follow-up and adjuvant chemotherapy in the postoperative period is recommended for these patients. PMID- 21607304 TI - Treatment of patients with metastatic gastric-cancer by continuous-infusion of 5 Fluorouracil, Cisplatin and Etoposide. AB - The therapeutic effectiveness of continuous infusion of 5-fluorouracil and cisplatin, and etoposide (FEP) for treatment of metastatic gastric cancer was examined. Studies were made on 17 patients with gastric cancer with distant metastases. 5-fluorouracil (300 mg/m(2)/day) and cisplatin (80 mg/m(2)/day) were administered by continuous intravenous infusion for 120 and 24 hours, respectively; etoposide (60 mg/m(2)/day) was injected intravenously over a 2 hour period on days 2, 3 and 4. These chemotherapy treatments were repeated every 28 days. Partial, but not complete, remission was seen in four patients (24%). The treatment increased the survival times of patients with differentiated or Borrmann 2 or 3 type cancer, but not significantly. In many cases the treatment caused myelosuppression, but side effects were usually mild or moderate. It is concluded that infusion of 5-fluorouracil, etoposide and cisplatin is effective and well tolerated. PMID- 21607305 TI - Vitamin-k-3 induces cell-death via apoptosis in human cervical-carcinoma tsgh8302 cells. AB - Vitamin K-3 (VK3) exhibits antitumor activity in rodent and human cancer cells. The relationship between VK3-induced cytotoxicity, and morphological changes in human cervical carcinoma TSGH8302 cells were studied. Cell viability was analyzed by sulforhodamine B protein binding and clonogenic assays. Inhibition of cell growth by VK3 was cell density dependent as measured by IC50 values, which were 17 mu M at 0.5 x 10(4) cells/well and 36 mu M at 1.0 x 10(4) cells/well. Treatment of 10(6) cells with VK3 (5-100 mu M) for 1 h followed by recovery for 24 h caused depletion of the reduced glutathione pool. Under light, fluorescence and scanning electron microscopes, cells showed morphological changes after 1-h treatment with 25 mu M VK3, followed by a 4-h or 12-h recovery. The cells appeared retracted with blebs but no surface microvilli. They exhibited chromatin condensation and DNA fragmentation. Since these phenomena are characteristics of apoptosis, VK3-induced cell death appears to be mediated by apoptosis. PMID- 21607306 TI - Adjuvant tamoxifen in breast-cancer-treatment in postmenopausal women - occurrence of thromboembolic complications. AB - Of 441 postmenopausal breast cancer patients who received adjuvant tamoxifen, 19 had thromboembolic accidents (4.3%). All were in remission when thrombosis occurred. One patient died of bilateral pulmonary embolism. In the other cases, thromboembolic disorders were found to be reversible after the withdrawal of tamoxifen and anticoagulant treatment. Some patients had a history of vascular disorders, and others required prolonged bed rest which may have contributed as an aggravating circumstance to thrombotic events. Our study suggests that thromboembolic risk factors as well as potential vascular disorders induced by aggravating conditions have to be carefully examined in postmenopausal patients treated by adjuvant tamoxifen therapy. This is especially true in women with lobular breast cancer and aged more than 60 years. PMID- 21607307 TI - DNA-ploidy and proliferative activity in uterine-tumors - an in-vivo study using bromodeoxyuridine and flow-cytometry. AB - We have studied the DNA ploidy and the proliferative activity in 102 patients with endometrial and cervical carcinoma, by flow cytometry. Samples were excised 1 hour after bromodeoxyuridine (BrdU, 250 mg/) e.v. infusion and fixed in 70% ethanol. Nuclear DNA content and BrdU incorporation, were simultaneously determined to obtain ploidy (DNA index) and proliferative activity (BrdU-labeling index, LI). No acute toxicity or side effects related to BrdU injection were recorded. The overall feasibility of the determinations was higher than 90% (93/102). Twenty-two out of 59 (37.2%) endometrial neoplasms and 23 out of 34 (67.6%) cervical neoplasms were aneuploid, with a median DNA-index of the aneuploid peak of 1.3 and 1.4, respectively. Overall median BrdU LIs were 4.8% and 7.2%. Proliferative activity was found to be higher in aneuploid tumors (p<.05). DNA ploidy and/or BrdU-LI were not significantly related either with the clinical stage or the histopathologic grading in either tumor type. The BrdU in vivo administration coupled with bivariate FCM for measurement is a simple method that can be performed in clinical settings to better evaluate the prognostic significance of proliferative parameters in gynecological tumors. PMID- 21607308 TI - Quantitative-analysis of immunohistochemical androgen receptor and ki-67 in prostatic-carcinoma and its relationship to histologic grade. AB - Androgen receptor and Ki-67 were immunohistochemically investigated in biopsy specimens taken from 50 cases of prostatic carcinoma and the correlation between histologic grade and AR and Ki-67 was examined using a computer-assisted image analysis system. When the immunoreactive intensity of AR of tumor cells was the same or stronger than that of stromal cells in the same section, the tumor cells were defined AR-positive. An immunohistochemical study revealed that AR positive cases-were significantly higher in well differentiated type (86%) and moderately differentiated type (85%) than in poorly (38%) differentiated type. The expression of Ki-67 was significantly higher in poorly and moderately differentiated types than in well, differentiated type. There was a significant correlation between the histologic grade, and AR and Ki-67; however, there was no correlation between the clinical stage and AR or Ki-67. PMID- 21607309 TI - Suppression of tumorigenesis and tumor-growth of mouse mammary-glands by a traditional chinese herbal medicine, sho-saiko-to. AB - Hyperplastic alveolar nodule (HAN) is a representative preneoplastic state in mammary glands of mice. We investigated the effect of Sho-saiko-to (SST; a Japanese modified traditional Chinese herbal medicine containing seven medicinal plants) on the formation and growth of HAN and mammary tumour growth in SHN virgin mice which showed a high incidence of spontaneous mammary tumours. Chronic oral administration of SST reduced the number and the area of HAN and mammary thymidylate synthetase (TS) activity with slight decrease of serum prolactin level. In the established mammary tumours of mice, 20-day administration of SST reduced the activity of TS and thymidine kinase (TK) with slight reduction of serum prolactin level, though the significant change of mammary-tumour growth was not observed. These results indicate that SST may prevent the mammary tumourigenesis by suppression of the de novo pathway for pyrimidine nucleotide synthesis and the mammary tumour growth by suppression of the salvage pathway as well as the de novo pathway in mice. PMID- 21607310 TI - Clonality of malignant-tumors (review). AB - Heterogeneous descendants are continuously produced in tumor cell evolution, although the first step of carcinogenesis may involve a single clone. From the data obtained by molecular biology, we have to recognize that the 'clonality of tumor' proliferated from a single clone does not confirm the genetic identity of tumor cell society. The so-called 'multi-hit hypothesis' can not explain this heterogeneity, since this hypothesis only describes serial changes of genes in carcinogenesis. However, genetic alterations actually accumulate progressively after carcinogenesis until the end of total cell death. Genetic alterations in tumor evolution are a stochastic process rather than a non-stochastic one, since 'neutral evolution' in molecules occurs in micro-environments, It is an essential concept that retrospective analysis can never demonstrate the clonal origin of tumors, because the genetic pool of tumor cell society is unstable and changes proliferation-dependently. PMID- 21607311 TI - Chemotherapy of advanced malignant-melanoma (review). AB - The role of medical treatment in advanced or metastatic malignant melanoma is still controversial, and there is no standard systemic therapy. Dacarbazine has been the most widely used single drug, despite its response rate range of 10-25%. A number of new drugs, polychemo-therapeutic regimens and combined modalities have been explored. Fotemustine, a new chloronitrosourea, is one of the most promising, and is active against disseminated malignant melanoma, in particular against brain metastases. Cisplatin has modest activity as single agent but positive results have been reported when it is combined with dacarbazine. Modulation of the activity of cisplatin and dacarbazine by tamoxifen has recently been postulated. The results of the few clinical trials in malignant melanoma are interesting but controversial. Interleukin-2 and interferon are active in this disease, but no more so than individual chemotherapeutic drugs. However, despite their high cost, combinations of immuno- and chemotherapeutic agents have been extensively investigated in order to evaluate possible synergisms. The above mentioned efforts have produced contradictory results that are partly related to the difficulty in establishing whether a positive or negative treatment outcome is due to the chosen therapy or patient selection. For these reasons, patients with advanced malignant melanoma should be treated according to research protocols in specialized centers until an effective approach is developed. PMID- 21607312 TI - Rhabdomyoblastic differentiation after chemotherapy in malignant triton tumor - a case-report. AB - A case of malignant Triton tumor which consists of a malignant schwannoma accompanied by rhabdomyo-sarcomatous elements is reported. Only a small number is known in literature. The patient survived for four years without any sign of local recurrence or metastasis although an extremely poor prognosis for this neoplasm is reported. The therapy consisted of wide resection, irradiation and pre-and postoperative combination chemotherapy. The effect of multi-agent antineoplastic drugs on the differentiation of rhabdomyosarcoma cells and the relevant literature is discussed. PMID- 21607313 TI - 2 cases of gastric-cancer remarkably reduced with a combined dosage of irsogladine maleate preparation and uft. AB - Irsogladine Maleate intensifies the degree of intercellular contact so we expected that a combination of Irsogladine Maleate and UFT would cause tumor reducing effect and normalization of the malignant cells. A combination of Irsogladine Maleate and UFT was administered to 2 patients with inoperable gastric cancer (Case 1: An 83-year-old male: Borrmann type I, Case 2: A 93-year old female: A relatively wide early gastric cancer), marked tumor reduction was obtained in both cases. The doses administered were 4 mg/day of Irsogladine Maleate and 200 mg/day of UFT. PMID- 21607314 TI - Uterine metastases from primary breast-cancer - report of 2 cases. AB - The authors report on 2 cases of uterine dissemination from primary breast carcinoma. Special emphasis is made on this atypical site of metastases and on the necessity of a gynecological work-up in patients previously treated for breast cancer. PMID- 21607315 TI - Immunohistochemistry of eccrine porocarcinoma. AB - The eccrine porocarcinoma is a rare adnexal tumor of human skin. It has been related to the acrosyringeum of the sweat gland. An immunohistochemical study on paraffin sections of eight porocarcinomas and a control group of 29 poromas was conducted to investigate the differentiation of porocarcinomas. Antibodies against (neuro-) glandular antigens and selected intermediate filaments were used for indirect immunoperoxidase staining with amino ethyl carbazole. Porocarcinomas disclosed variable amounts of cells labeled with CEA, S100A, LS59, NKI/C-3, Cam 5.2, Vim9(1), and wide spectrum keratin. Cellular phenotypes showed greater variability than the benign poromas. The immunostaining patterns of porocarcinomas suggest a differentiation program towards inner duct cells and myoepithelium thereby questioning their classification as acrosyringeal neoplasms. PMID- 21607316 TI - Expression of ras p21 in benign and malignant thyroid lesions. AB - It is now widely accepted that human neoplasms arise as a result of a sequence of mutations affecting the structure of genes involved in growth control. Identifying the nature of such genetic mutations in thyroid neoplasms and their prevalence in the various tumor phenotypes is critical to the understanding of their pathogenesis. Mutational activation of ras oncogenes has been associated with human thyroid neoplasia. We examined the expression of ras oncogene in benign hyperplastic or inflamatory lesions of the goiter, as well as in benign and malignant thyroid tumors. Although no significant differences of ras oncogene expression was found between benign and malignant lesions, the overexpression in proliferative areas generally suggests the possible involvement of ras oncogene in the trophic hormone control of the thyroid. PMID- 21607317 TI - Higher frequency of ras oncogene activation in gastric stump carcinomas due to special conditions in the gastric remnant. AB - Gastric stump carcinoma is now widely recognized to be due to special conditions in the gastric remnant. To examine whether the mechanism of carcinogenesis is different in gastric stump carcinoma from other gastric carcinoma, we analyzed ras mutation in 62 gastric carcinomas. The ras mutation frequency was 4/17 (23.5%) in stump carcinomas, 2/25 (8.0%) in other remnant carcinomas and 1/20 (5.0%) in proximal carcinomas. The mutation frequency in stump carcinomas was much higher than that in other gastric carcinomas. These results suggest that the mechanism of carcinogenesis in gastric stump carcinomas may be different from other gastric carcinomas. PMID- 21607318 TI - Radiotherapy for roentgenographically-negative lung-cancer. AB - Ten roentgenographically-negative lung cancers were treated with radiation. All of the patients in this study were selected in a mass screening for lung cancer using sputum cytology, and their cancerous cells were confirmed as squamous cell carcinoma by bronchoscopic biopsy. Three tumors were proved to be multi-centric. Five patients were unresectable for medical reasons, three for the multi-centric occurrence, one for another advanced carcinoma and one for the refusal of surgery. The radiation field was confined into the primary tumor only, and a total dose of 6000cGy with a fraction size of 200cGy was delivered. Relapse was found in four patients; two inside the field and two outside the field. Local control rate was 75% of eight patients who were followed for more than 26 months. There was no mediastinal lymph node metastasis in seven patients. The radiation field for the roentgenographically-negative lung cancer may be confined at the primary tumor alone. However, careful follow-up should be continued because of the high incidence of multi-centric occurrence and subsequent additional lung cancer. PMID- 21607319 TI - Low activity of circadian continuous fluorodeoxyuridine (fudr) chemotherapy in poor-prognosis metastatic renal-cancer. AB - Thirteen patients with progressive metastatic renal cell carcinoma were treated with circadian continuous Fluorodeoxyuridine (FUDR) infusions. The drug was delivered according to the variable rate infusion of Hrushesky protocol. All patients had previously received and failed systemic treatment and presented more than one metastatic site. The toxicity was low, however, no objective responses were observed. Despite previous reports of activity of FUDR in metastatic renal cancer, we suggest that the present regimen cannot be recommended in poor prognosis metastatic renal cancer. PMID- 21607320 TI - Streamline phenomena in liver metastasis of gastrointestinal tumor - an experimental-study using rats. AB - The establishment of liver metastasis from gastrointestinal tumor is mainly considered to be via the portal vein, but its precise mechanism is still unknown. The purpose of this study is to evaluate the significance-of 'streamline' phenomena in liver metastasis of gastrointestinal tumor by means of an experimental model. An animal model for the metastatic liver tumor was made in the Donryu rat. Five million cells of AH-66 strain, alpha-fetoprotein (AFP) producing hepatoma cells maintained as an ascites type strain, were administered via portal vein. The superior mesenteric vein (group A), the inferior mesenteric vein (group B) and the splenic vein (group C) were used as the sites of injection. In every group, serum AFP levels were elevated after administration of AH-66 cells and no significant differences were revealed between each group. In the pathological specimens of the liver taken after 7 days, many tumorous lesions were seen microscopically with islet formations, but no definitive difference was seen in each lobe. The serum AFP concentration in group A was significantly higher than that in group C. The tissue AFP concentrations of the right lobe were significantly higher than those of the left in groups A and B, but significantly lower than those of the left lobe in group C. The results indicate that the distribution and proliferation of tumor cells administered via portal vein differed depending upon the site of tumor injection in accordance with the 'streamline' phenomena. PMID- 21607321 TI - Use of long-acting somatostatin analog, lanreotide, in neuroendocrine tumors. AB - Somatostatin and its analogues have been reported highly effective in reducing the clinical syndrome in endocrine tumours. The effects of a long-acting analogue of somatostatin, lanreotide, were evaluated in 10 patients with neuroendocrine tumours. In patients with carcinoid tumour, a relief of flushing was achieved in 7 of 8 patients, of diarrhoea in 7 of 7 patients and of bronchoconstriction in 2 of 2 patients. In 5 of 8 patients there was a decrease of more than 50% of 5 hidroxyindolacetic acid excretion. The activity on tumour size was assessed in all the patients. No objective responses were observed. The tolerance to lanreotide was excellent. For the high symptomatic effect and mild toxicity lanreotide seems to be an appropriate treatment in symptomatic patients. PMID- 21607322 TI - P53 and rb alterations in operable breast-cancer. AB - We analyzed association between p53 and/or Rb expression and clinicopathologic variables or Ag-NOR counts, and then ascertained whether p53 and/or Rb expression would be useful for estimating prognosis in 81 breast cancer patients. Positive p53 expression was significantly associated with post-menopausal status, axillary lymph node metastases and Ag-NOR counts, whereas low level Rb expression was significantly associated with tumor size. Moreover, the combination of p53 and Rb expression was significantly associated with Ag-NOR counts, although there was no significant association between p53 and Rb expression. In the univariate study, p53 expression as well as age and axillary lymph node metastases were significantly associated with survival, whereas Rb expression was not. In the multivariate study, p53 and/or Rb expression did not provide independent prognostic information, although axillary lymph node metastases was an important factor affecting survival. Our findings suggest that p53 and/or Rb expression may reflect tumor proliferation of breast cancer, but the prognostic value of such assays is limited. PMID- 21607323 TI - Altered binding of the ap-1 protein on a negative regulatory element of C-myc is correlated with the progression of the malignancy of the lung and may contribute to C-myc expression. AB - The binding activity of the AP-1 (FOS/JUN) complex to a negative regulatory element on the c-myc promoter was investigated in 7 tumour- versus normal lung specimens and it correlated with c-myc expression. AP-1 levels were found elevated in two samples representing stage I progression of the disease, while in three stage III tumour samples, the AP-1 binding activity was equal or slightly elevated compared with their normal adjacent tissue. Southern blot analysis revealed amplified c-myc in all three cases of stage III tumours. These results suggest that there is a negative correlation between FOS/JUN binding on c-myc promoter and the expression of c-myc during the progression of the disease, further supporting the fundamental role of AP-1 on c-myc regulation. PMID- 21607324 TI - Histopathologic prognostic factors for ductal carcinoma of the head of the pancreas. AB - To establish useful prognostic factors for carcinoma of the head of the pancreas a retrospective analysis of histopathologic factors was performed for 44 patients treated with resection. Overall survival rates after 1, 2, 3 and 5 years were 63.6%, 34.5%, 26.9% and 23.9%, respectively. Eight patients lived for 5 years. The significant factors affecting survival were nodal involvement (n), retroperitoneal invasion (rp), and the degree of cancer cell invasion to the exposed cut surface (ew). Tumor size (t), serosal invasion (s) and histologic type did not influence survival by univariate analysis. According to the Cox multiregression analysis, nodal involvement is the only useful prognostic factor. Lymph node metastasis is the most important prognostic factor. To improve the prognosis of pancreatic cancer it is necessary to perform extended lymph node dissection. PMID- 21607325 TI - Programmed cell-death and its control in the development of adult T-cell leukemia - hypothesis. AB - Despite the progress in virological and molecular studies on human T-cell leukaemia virus (HTLV-1), there still exist enigmas in biological and clinical features of adult T-cell leukaemia/lymphoma (ATL). They include the way of the development of ATL clones, the role of interleukin-2 (IL-2) receptors on the tumour cells and spontaneous fluctuation of the clinical activity frequently observed in chronic type of the disease. To elucidate these enigmas, based on our recent experimental data, we would like to present a model of the development of ATL clones from: the view point of programmed cell death (PCD) and its control. PMID- 21607326 TI - Skeletal metastases from unknown primaries - consideration of 71 cases. AB - Seventy-one cases of metastatic bone disease from unknown primary were analyzed retrospectively to assess diagnostic and therapeutic options. Forty-eight were male, and 23 female; average age 56.4 years (range 24-80). The main presenting symptom was pain. Fifty per cent of patients died within 14 months of symptoms onset and 22.7% were alive after 2 years. Although the prognosis is grave and unaffected by the treatment given, an assiduous diagnostic work-up can anticipate problems and indicate appropriate treatment to substantially improve the patient's quality of life and attitude to his disease. PMID- 21607327 TI - Helix-pomatia lectin and C-erbb-2 expression versus axillary and internal mammary lymph-node metastases in prognostic assessment of breast-cancer. AB - The relationship between Helix pomatia lectin (HPA) staining, c-erbB-2 expression, and other prognostic factors in breast cancer, i.e., axillary (AX) and internal mammary lymph node (IMN) metastases was assessed. The prognostic value of HPA staining and c-erbB-2 expression in combination was analyzed. HPA status was found to be significantly correlated with tumor size, and with AX and IMN metastases, whereas c-erbB-2 was significantly correlated only with AX and IMN metastases. A univariate study revealed that disease-free and overall survival were correlated significantly with tumor size, with AX and IMN metastases, and with HPA and c-erbB-2 status. Moreover, c-erbB-2 status was predictive of a poorer prognosis in both HPA+ and HPA- groups, and HPA+/c-erB-2+ patients had the worst prognosis when compared to the other subgroups. In a multivariate study, however, only AX and IMN metastases were significant prognostic factors. A combination of HPA staining and c-erbB-2 expression failed to provide any additional prognostic information. In patients in whom regional lymph node dissection has not been performed, however, one should take into account not only HPA binding status, but also c-erbB-2 oncoprotein status to discriminate more precisely those sub-populations with a high recurrence risk and predicted short survival who would be candidates for more aggressive therapy. PMID- 21607328 TI - Combinative growth-inhibitory effects of interferon-alpha and Doxorubicin on multidrug-resistant tumor-cell lines. AB - The antiproliferative effects of interferon-alpha (IFN-alpha) and of its combination with doxorubicin (DXR) were studied on three tumor cell lines, the mouse B16 melanoma and Friend erythroleukemia and the human K562 erythroleukemia, both as DXR-sensitive (B16, FLC, K562) and resistant (B16-DXR, FLC-DXR, K562-DXR) variants; the latter lines were endowed with typical multidrug resistance (MDR). Growth inhibition by IFN-alpha was greater in B16-DXR and FLC-DXR than in their chemosensitive counterparts and was superimposable in K562 and K562-DXR. On the other hand, the combination of IFN-alpha and DXR turned out to be merely additive in B16, B16-DXR, K562 and K562-DXR; it was synergistic in FLC and antagonistic in FLC-DXR. Our results and those of others seem to indicate that synergy between IFN-alpha and DXR may occur rarely in MDR cells. PMID- 21607329 TI - Comparison of geniposide and its acetylated derivative for the inhibition of aflatoxin b1-induced DNA-repair synthesis in rat primary hepatocyte. AB - Our previous studies showed that geniposide (GP) inhibits aflatoxin B1 (AFB1) induced hepatoxicity in rats, and that DNA repair synthesis in vitro and penta acetyl geniposide ((Ac)5-GP) inhibits AFB1-induced genotoxicity in C3H10T1/2 cells. One possible mechanism for GP is the enhancement of the enzyme activity of glutathione S-transferase (GST) and GSH-peroxidase (GSH-Px) in AFB1-treated hepatocyte culture. But the mechanism is unknown for (Ac)5-GP. The present study demonstrated that (Ac)5-GP was more potent in inhibiting AFB1-induced unscheduled DNA synthesis in rat primary hepatocyte. The action of GP and (Ac)S-GP may be related to their ability to induce the activity of phase II enzymes. PMID- 21607330 TI - Carboplatin associated anemia treated with subcutaneous erythropoietin - a pilot study. AB - In nineteen patients with carboplatin-induced anemia (hemoglobin less than 90 g/l), recombinant human erythropoietin was administered subcutaneously three times a week on an outpatient basis. The initial dose was 50 Units/kg of body weight. If response was not achieved within 3 weeks, dose was increased to 75 Units/kg. Using the same criteria further escalations to 100 and 150 Units/kg were performed. If there was no response erythropoietin was terminated. Two patients obtained an increase of hemoglobin levels greater than 100 g/l, which was considered as a clinical response in this study, with a dose of 75 U/kg; eleven patients needed an erythropoietin dose of 100 U/kg and three a dose of 150 U/kg. The other three patients required hemotransfusions and were considered non responders. Hemoglobin increases occurred despite continuation of carboplatin chemotherapy. In conclusion, subcutaneous eryhtropoietin is effective and safe in the treatment of carboplatin-induced anemia. PMID- 21607331 TI - The tris formulation of Fluorouracil is more cardiotoxic than the sodium-salt formulations. AB - The cardiotoxicity of 5-fluorouracil (FU) was attributed to degradation compounds present in the injected vials, fluoroacetaldehyde (Facet) and fluoromalonaldehydic acid (FMald). FU-NaOH vials were much less cardiotoxic than FU-Tris vials on the isolated perfused rabbit heart model since Facet and FMald are stored in stable depot forms in FU-Tris vials whereas, in FU-NaOH vials, they are extensively transformed. Cardiotoxic fluoroacetate (FAG), coming from Facet metabolization, was found in urine of patients, with a ratio FAC /FU catabolites 10-30 fold lower in patients treated with FU-NaOH than in those treated with FU Tris. PMID- 21607332 TI - In-vivo experimental demonstration that hyperhistaminism counteracts tumor growth. AB - Induction of hyperhistaminism in peritoneum of rats by daily intraperitoneal supply of 0.005 mu g of histamine, counteracts the growth of 10(3) Yoshida ascite sarcoma cells only if administration precedes inoculation of tumor cells and has a long duration. Treating animals for two weeks before tumor cell inoculation we observed significant 70% survival, that was increased to 80% continuing the supply for 20-days after the inoculation; treatment for 3 days before or 20 days after the inoculation did not show significant results. The condition created in rat peritoneum is similar to that in allergic people, and our data in animals confirm statistical data observed in allergic people showing decreased incidence of neoplastic disease due to histamine, that appears to be integrated in a highly potent immunoregulatory circuit. PMID- 21607333 TI - Differential-effects of max proteins (long and short) on growth and differentiation of murine erythroleukemia-cells. AB - The myc gene product belongs to a family of basic, Helix-Loop-Helix, Leucine Zipper (b-HLH-LZ) proteins involved in cell growth, differentiation and tumorigenesis. The Max protein dimerizes with Myc to form a complex which binds to DNA and promotes transcription of target genes. Max exists in two major forms, Max-9 (long) and Max (short), which differ by 9 amino acids just amino to the basic region. We compared the in vivo behavior of the two forms in stable transfectants of long and short wild type (Lwt, Swt) and basic region mutants (Lbm, Sbm). While both Lwt-max and Swt-max clones exhibit delays in cell growth and differentiation, these delays are far more pronounced in the Lwt-max clones. In contrast, no difference is noted between Lbm-Max and Sbm-Max in their observed ability to delay growth, to accelerate HMBA-induced differentiation and to induce spontaneous differentiation. We suggest that a difference in affinity for DNA underlies the differential activities of Lwt- and Swt-Max. PMID- 21607334 TI - Transformation of primary chick-embryo fibroblasts by virally-expressed C-jun requires no mutation in the protein when a sufficient level of C-jun protein is reached. AB - Proto-oncogene c-jun transforms primary chick embryo fibroblasts as a single gene when expressed from the replication competent retrovirus R (or RCAS). We have investigated whether transformation is caused by accumulating mutations within the proto-oncogene sequence during the retrotranscription process. c-jun coding sequences carried by three independently isolated R-cJUN viruses have been cloned and entirely sequenced. Two of these-were shown to carry no mutation demonstrating that deregulated expression of a normal c-Jun product is sufficient for transformation. On the contrary when expressed from non replicative Rneo vector lacking gag and pol sequences, the avian c-jun no longer transformed. This difference is correlated with weaker c-Jun accumulation in the second case. When expressed from the same Rneo vector, low level of v-Jun or of the heterologous mouse c-Jun still transform. Taken together, these data strongly suggest that a threshold level of c-Jun product is required for transformation and that this critical level can be lowered by mutations in c-jun or by the synthesis of an heterologous protein. PMID- 21607335 TI - Low-dose rate telecobalt-therapy as a boost against brain-tumors. AB - We applied low-dose rate telecobalt therapy (LDRT) as a boost for 26 brain tumors (17 malignant gliomas, 4 pontine gliomas and 5 others). Eleven of those cases were recurrent. The LDRT; 1 Gy per hour, 7 Gy per day, a total dose of 14 Gy in two successive days, was boosted after a conventional irradiation. In malignant glioma, the local control rate and the survival rate were not improved, compared with those of the control group. The treatment results of other brain tumors were also unsatisfactory. The incidence of brain necrosis was higher in the LDRT group. The benefits of the LDRT as a boost for radioresistant brain tumors seem to be small. PMID- 21607336 TI - Oncogenic alterations in primary human lung-tumors (review). AB - Lung cancer is the leading cause of death from cancer in Western countries. For improved diagnosis and refined therapeutical approaches it is of major importance to understand by what mechanisms carcinoma of the lung develop. The analysis of primary lung cancer revealed specific chromosomal alterations and allelic losses of the short arm of chromosome 3. Genetic aberrations have been observed in proto oncogenes such as H-ras, K-ras, C-myc and raf-1 as well as in the tumor suppressor genes Rb and p53. Rearrangement of rlf and elevated expression in certain lung tumors have also been reported. The development of lung cancer also involves the altered activation of genes coding for growth factors such as TGF beta 2 and certain growth factor receptor genes such as c-erbB-2, HEK2 and FGFR 4. PMID- 21607337 TI - Differential expression of pancreatic trypsinogen and cathepsin-B in human scirrhous-type and intestinal-type gastric carcinomas. AB - Pancreatic trypsinogen and cathepsin B expression was evaluated in 44 surgically resected gastric carcinomas by immunohistochemical analysis. Carcinomatous tissues were subjected to immunohistochemical staining with a monoclonal antibody against human pancreatic trypsinogen and a polyclonal antibody against human cathepsin B. As a result, twenty-two of 24 scirrhous-type gastric carcinomas (92%) expressed pancreatic trypsinogen intensely and diffusely in a fine granular pattern over the entire cytoplasm of carcinoma cells. In contrast, only 5 of 20 intestinal-type gastric carcinomas (25%) reacted with the trypsinogen specific antibody and then only focally, in a fine granular pattern in the supra-nuclear cytoplasm of carcinoma cells. Cathepsin B expression was detected in 20 of 24 scirrhous-type gastric carcinomas (84%) in a fine, diffuse, granular pattern in the cytoplasm of carcinoma cells, while only 2 of 20 intestinal-type gastric carcinomas (10%) had detectable cathepsin B. From these results, we find that scirrhous-type gastric carcinomas express abundant quantities of pancreatic trypsinogen and cathepsin B immunoreactive peptides. PMID- 21607338 TI - Adjuvant chemotherapy of stage-ii nonseminomatous testicular cancer. AB - 85 patients with resected stage II non-seminomatous testicular cancer were treated with adjuvant cisplatin-based chemotherapy. Only one patient developed a relapse 14 months after discontinuation of adjuvant chemotherapy, which was successfully treated with salvage chemotherapy. One patient developed a contralateral testicular tumor 6 years after primary therapy. After a median observation time of 6 years (range 2 months to 13 years) 84 patients are alive without evidence of testicular cancer; one died from an unrelated cause. In conclusion, adjuvant cisplatin-based chemotherapy for resected stage Il nonseminomatous testicular cancer almost always prevents relapse. PMID- 21607339 TI - Phase-I trial of Thiotepa, granulocyte-macrophage colony-stimulating factor and prednisone or pentoxifylline in patients with refractory solid tumors. AB - In a phase I trial, 13 patients with refractory solid tumors received thiotepa, granulocyte-macrophage colony-stimulating factor (GM-CSF), and either prednisone or pentoxifylline (PTX) on alternate cycles. The prednisone and PTX were administered in an attempt to ameliorate toxicity related to GM-CSF. Of the first six patients treated at a thiotepa dose of 60 mg/m(2), five experienced grade 3 or 4 thrombocytopenia and four grade 2 or greater leukopenia. One of these patients died secondary to E. coli sepsis. Seven patients received a thiotepa dose of 50 mg/m(2), with one experiencing grade 3 thrombocytopenia and another grade 3 leukopenia. The latter patient died secondary to presumed sepsis. The five remaining patients at the 50 mg/m(2) dose did not experience greater than grade 1 hematologic toxicity. Serum tumor necrosis factor levels were not increased by GM-CSF. Patients in this trial were not evaluable for amelioration of GM-CSF toxicity as too few received a second cycle of treatment. We conclude that thiotepa doses greater than 50 mg/m(2) are not tolerated due to severe thrombocytopenia which is not diminished by the administration of GM-CSF. PMID- 21607340 TI - Serum intracellular adhesion molecule-1 (sicam-1) and soluble hla class-1 antigens in breast-cancer patients in relation to tumor burden. AB - sICAM-1 and beta-2 microglobulin (beta-2M) serum levels were measured in 143 breast cancer patients and 43 controls. The patients were divided into three groups. A: new patients; B: patients on long term follow-up and C: metastatic patients. In all patients the mean +/-1SD sICAM-1 and beta-2M serum levels were significantly higher than normal controls (p <0.001 and p <0.0001, respectively). Analysis of the three groups showed that for both sICAM-1 and beta-2M, Groups A and C had similar serum levels, which differed significantly from Group B. sICAM 1 of Group B was similar to controls, while beta-2M of Group B was significantly higher than controls. During the study 20 patients relapsed. Initial high levels of sICAM-1 were observed in 20% and beta-2M in 50% of patients. These data suggest that sICAM-1 and beta-2M level indicate host cell-mediated immunity against tumor. PMID- 21607341 TI - Pitfalls of the tnm classification of head and neck tumors. AB - Any TNM system has to be a reproducible description for the anatomic extent of the tumor. In addition, the TNM should reflect the biology of the disease in a specific site in cancer patients at a specific time in the Life history of the cancer. A modified TNM classification for the head and neck cancers is proposed considering available data on: (i) survival rate vs level of involvement; (ii) lymphatic drainage patterns; (iii) embryological development of the neck lymphatics. The modified TNM definitions contain the old 'T','M' and new 'N1', 'N2', 'N3' and 'M1(lymph)' descriptions. The involvement of the supraclaviclar lymph nodes is described by 'M1(lymph)' since the biological significance is that of a distant metastases. PMID- 21607342 TI - Adjuvant treatment of colon-cancer - a plea for a large-scale European trial. AB - The is now compelling evidence that systemic adjuvant 5-fluorouracil (5-FU) based chemotherapy can delay or reduce recurrence after resection of high-risk (Dukes' C or TNM stage III) colon cancer. A meta-analysis of performed adjuvant studies with intraportal 5-FU suggests that an equal advantage can be obtained with this treatment modality. This might be related to the timing of chemotherapy rather than to the route. In the US large-scale cooperative studies are ongoing or completed that will answer important additional questions such as the more optimal systemic chemotherapy and the duration of treatment. The European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cooperative Group has initiated a large-scale study that compares the combination of 'early' postoperative locoregional directed chemotherapy plus 'late' systemic chemotherapy with systemic chemotherapy only. A plea is made for participation in this European trial that requires 2000 patients. PMID- 21607343 TI - Cathepsin-d in breast carcinomas - the role of the stromal cell component. AB - Cathepsin D was initially identified as being an oestrogen responsive protein in breast cancer cell lines. Subsequent studies have shown a role for this lysosomal enzyme in invasion and metastasis. Immunoassay and blotting studies have demonstrated a relationship between high cathepsin D levels in breast carcinomas and poor prognosis, but the converse or no relationship has been found in immunohistochemical studies. Cathepsin D from stromal cells, which will be included in tumour homogenates, may account for this difference. This immunohistochemical study of 145 breast carcinomas has used two monoclonal antibodies to cathepsin D, and considered staining of stromal cells as well as tumour cells. Some differences were found in the reactivities of the two antibodies. No relationship has been found between tumour cell reactivity and node status, grade, oestrogen receptor status and prognosis. Up to one third of carcinomas had no staining of tumour cells but a diffuse stromal cell infiltrate. Prominent stromal cell reactivity was associated with poorer survival but these tumours were predominantly poorly differentiated. However, stromal cell reactivity cannot account alone for the differences reported between different studies in relation to cathepsin D land prognosis. Other factors may include differences in detection of the different molecular weight forms, as well as quantification. PMID- 21607344 TI - Aztreonam in association with piperacillin as an empirical antibiotic-treatment in febrile granulocytopenic patients with solid tumors. AB - Forty-one patients with a total of 46 febrile episodes during granulocytopenia were included in a study to evaluate the efficacy of the association of aztreonam (2 g/6 hours iv) and piperacillin (4 g/6 hours iv) as an empirical antibiotic treatment. Forty-four episodes were evaluable for efficacy and toxicity. In 24 episodes (54.5%) response to treatment (disappearance of fever and improvement in the clinical signs of infection in the first 72 hours) was observed. In the subgroup of the microbiologically documented infections, 4 out of 12 episodes (33.3%) showed response to treatment. Gram-positive microorganisms were present in 7 of these 12 episodes (58.3%). Vancomycin rescue treatment obtained a response in the majority of episodes which initially had failed. Overall survival of the treated group was 93.2%. Toxicity of the antibiotic treatment was minimal. In 5 cases there was an increase in the prothrombin time (not clinically significant). Three cases showed cutaneous rash. Two cases presented diarrhoea due to dysbacteriosis and one case presented with raised blood bilirubin levels and renal impairment. Some of these manifestations coincided with modifications in the initial treatment regimen. The association of aztreonam and piperacillin may be a useful alternative to classical empirical antibiotic treatment in patients with granulocytopenia and fever. Initial addition of vancomycin is recommended especially in centres with a high incidence of infections due to Gram positive micro-organisms or in patients with venous catheters. PMID- 21607345 TI - The genes of the alpha-chain and Beta-chain of the gm-csp receptor are not rearranged in patients with aml. AB - Recently alterations in growth factor receptors, e.g. the erythropoietin receptor, have been described which cause increased sensitivity to growth factors or even autonomous growth independent from exogenous stimuli. We therefore investigated the gene structure of the alpha and beta chains of the GM-CSF receptor using Southern blots. EcoRI and HindIII digested DNA from peripheral blood samples from 34 consecutive patients with AML were hybridized with probes specific for the GM-CSF receptor alpha and beta chains. No abnormal DNA was detected. RNA expression was investigated by Northern blots in 32 patients. Expression of the beta chain was found in 30 of 32 patients. No messenger RNAs of aberrant size were detected. PCR reactions were performed with oligonucleotide primers specific for the alpha chain; c-DNAs were identified in all 10 patients studied. Thus we conclude that gene structure and expression of both chains of the GM-CSF receptor are not altered in AML. PMID- 21607346 TI - A safe procedure for transporting bone-marrow for purging in a central laboratory. AB - A central facility for ex vivo removal of neuroblastoma cells from bone marrow, to be used for autologous reinfusion after myeloablative treatment, was established and a study was designed to compare the survival time and the rate of bone marrow engraftment between local marrows obtained and processed at the University of Florida (UF) and marrow transported for purging from out of state, participating Pediatric Oncology Group (FOG) centers. Marrow harvest from patients either at UF or at participating centers, was done under a similar protocol. Marrows from participating centers were transported by air, to UF and purged using the immunomagnetic technique. The purged marrows were returned in liquid nitrogen for reinfusion before myeloablative treatment. Marrows were purged between 1985 to 1992 from 169 POG patients, of whom 164 were evaluable for this study (UF 29 and 135 transported). Statistical analysis of survival time and engraftment rate found no significant differences in survival time (p=0.2463) and engraftment rate (0.3259) between marrows shipped from other institutions to marrows harvested and processed at UF. PMID- 21607347 TI - Immunoregulation of T-lymphocytes by autologous serum in oral-cancer. AB - Autologous sera from 130 patients with squamous cell carcinoma of the buccal mucosa were evaluated for its immunoregulatory effect on the different sheep erythrocyte resetting populations of the patients. All the T cell populations were significantly reduced in oral cancer patients. The patient sera could be classified into blockers (0.5%-80% inhibition) and enhancers (0.5 to 130% enhancement) based on their activity on rosette formation. The degree of blocking and enhancement showed strong correlation with the severity of the disease with enhancers dominating the lower grades and blockers dominating the severe grades of the cancer. The dominance of enhancer sera in groups with better clinical prognosis suggest the ser;um enhancing activity to be related to good prognosis. PMID- 21607348 TI - In-vivo and in-vitro evaluations for the effect of cyclophosphamide on the carcinogen metabolizing system of mouse-liver microsomes. AB - The effect of the antineoplastic immunosuppressive alkylating agent cyclophosphamide (CPhA) on the modification of the carcinogen-metabolizing capacity was studied in vivo in mouse liver microsomes at different durations of treatment, from one to six consecutive days. The in vitro effect of increasing concentrations of the drug upon this enzyme system was also investigated. Following the administration of CPhA, a significant time-dependent decrease was observed in the activity of the low substrate level of the hepatic microsomal N nitrosodimethylamine demethylase (NDMAdII). The high substrate level of the enzyme (NDMAdII) also exhibited a similar decrease which was not a subject for the treatment intervals where the greatest decrease (-60%; p<0.05) emerged at day 3 of the administration-point. The activity of the aryl hydrocarbon (benzo(alpha)pyrene) hydroxylase (AHH) revealed a significant increase at the single dose of CPhA, while at the repeated dose treatment (for 3 days) no alteration was noticed in the enzyme activity. This figure of expression in AHH was reversed to a significant inhibition at the 6 day-repeated dose, the time point at which an almost identical effect was also observed in the hepatic content of cytochrome P450. The alterations in the metabolism of NDMA and benzo(alpha)pyrene which had been seen in the in vivo assays was further confirmed by the results of the in vitro experiment. PMID- 21607349 TI - Hormones in male-patients with advanced esophageal-carcinoma. AB - Hormones are believed to play a dominant role as promoters in the growth and development of hormone-dependent cancers. Much less is known about the circulating hormones in male patients with oesophageal cancer. This lack of attention led us to evaluate the role of peptide and steroid hormones (by RIA) in male patients with oesophageal cancer (n=49). Blood samples of patients were collected pretherapeutically and data was compared with age matched controls (n=25). In this retrospective study, significantly high levels of FSH (P<0.02), LH (P<0.001) and prolactin (P<0.001) were observed with concomitant low levels of estradiol (P<0.001), DHEA-S (P<0.02) and testosterone (P<0.001) in patients when compared with respective controls. The patients when grouped according to anatomical site and histological type of the tumor, intergroup variation was not observed in these hormones. From our, study, it seems that hormonal imbalance or altered ratio of peptide and steroid hormones might be playing a significant role in the development and/or progression of oesophageal carcinoma in men. PMID- 21607350 TI - Progress in radioimmunotherapy of head and neck-cancer (review). AB - There is an urgent need for an effective adjuvant systemic therapy for the treatment of patients with advanced head and neck cancer. This study shows that therapy based on the use of monoclonal antibodies (MAbs) is developing to a realistic option. A few years ago the first MAbs with specificity for squamous cell carcinoma of the head and neck (HNSCC) were produced, among which was MAb E48. In animal and patient studies, in which localization of radiolabelled MAb E48 was analysed qualitatively and quantitatively, it was demonstrated that a high percentage of the injected dose accumulated selectively in the tumour. These targeting properties, when exploited for delivery of toxic agents to the tumour, give MAb E48 potential for tumour therapy. Especially the application of MAb E48 in radioimmunotherapy (RIT) seems to be attractive due to the intrinsic radiosensitivity of HNSCC. Armed with 186-Rhenium, a radionuclide recently introduced in the field of RIT, MAb E48 IgG was shown to be highly capable of eradicating established HNSCC tumours in nude mice. Complete ablation of small HNSCC was observed in this animal model by a single bolus injection. In an effort to make MAb E48 less antigenic for human application a chimeric human/mouse MAb (cMAb) has been constructed by use of recombinant DNA techniques. This modification strongly improved the capacity of MAb E48 for mediating antibody dependent cellular cytotoxicity (ADCC). When using this cMAb E48 for RIT of minimal residual disease it can be anticipated that ADCC activity may be supportive to irradiation, especially in the ablation of single disseminated cells or small cell aggregates. Extrapolating results obtained in nude mice to patients and taking into account the good targeting in patients, RIT with E48 IgG seems to have potential for the elimination of minimal residual disease. Based on this encouraging progress, preparations are being made to evaluate the efficacy of Re-186-labelled cMAb E48 as an adjuvant in a phase III study for the treatment of patients who are at high risk for developing distant metastases. PMID- 21607351 TI - The addition of mesna to hyperhydration does not decrease the incidence of hemorrhagic cystitis in patients receiving high-dose cyclophosphamide. AB - To assess the efficacy of hyperhydration Versus hyperhydration plus mesna in preventing cyclophosphamide induced hemorrhagic cystitis a retrospective analysis was conducted of 110 patients who received hyperhydration alone (baseline intravenous intake of at least 3.6 1/m(2)/day) and 107 patients who received hyperhydration plus mesna (120% of daily cyclophosphamide dose) while receiving cyclophosphamide (total dose 150-200 mg/kg) as part of a dose intensive regimen. Macroscopic hematuria was noted in 17 (16%) and 9 (8%) patients who received hyperhydration with or without mesna, respectively (p=0.08). This analysis failed to demonstrate a benefit in adding mesna to hyperhydration alone in preventing cyclophosphamide induced hemorrhagic cystitis. PMID- 21607352 TI - Primary small-cell carcinoma of the stomach. AB - Primary small cell carcinoma of the stomach is an extremely rare tumor with only nine previously reported cases in the literature. Clinical behavior and prognosis are similar to small cell carcinomas of pulmonary origin. An additional case of a BI-year-old man with a gastric small cell carcinoma confined to the stomach is reported. The patient presented with an upper gastrointestinal bleed. A five centimeter ulcerated mass in the antrum was seen endoscopically and biopsied. At surgery the tumor appeared to be confined to the stomach and a subtotal gastrectomy was performed. The patient remains disease-free at 22 months. A review of nine other cases of small cell carcinoma of gastric origin reveals that most behave like their counterparts in the lung with rapid dissemination and death. However, like this patient, the only survivors for greater than one year are those amenable to surgical resection, implying that surgery has a roll in localized disease. PMID- 21607353 TI - Comparison of placental glutathione-s-transferase with gamma-glutamyl transpeptidase as tumor-markers during hamster pouch carcinogenesis. AB - This study investigated the expression of placental glutathione S-transferase (GST-P) in late squamous cell carcinomas and its expression after withdrawal of short term carcinogen treatment using the hamster buccal pouch mucosa (HBPM) model, and compared the activity of GST-P with that of gamma-glutamyl transpeptidase (GGT). 25 of 32 (78%) tumors induced by an 18-week treatment with 0.5% dimethylbenz(a)anthracene (DMBA) stained positive with GST-P while only 2 (6%) tumors were positive for GGT. Numerous GST-P positive foci were present in the pouch epithelium with 3 weeks of DMBA treatment. At week 6, after 3-week discontinuation of the carcinogen treatment, the average number of GST-P foci was not significantly less than that of week 3. Numerous GST-P foci were still evident at week 9 after 6-week discontinuation of the carcinogen treatment, although the number was significantly less than those of weeks 3 and 6. In contrast, GGT foci were hardly identifiable after discontinuation of the carcinogen treatment and the number of GGT foci at both weeks 6 and 9 was significantly less than that of week 3. The results suggest that GST-P may be a more persistent and stable tumor marker than GGT in the HBPM model. PMID- 21607354 TI - Differential-effects of tumor promoters and cytokines on protooncogene expression in a hematopoietic cytokine-dependent cell-line. AB - In order to investigate the mechanisms by which cytokines and tumor promoters stimulate cell growth, the expression of genes implicated in the regulation of cellular proliferation were examined in an interleukin-3 (IL-3) dependent hematopoietic cell line. Upon stimulation of factor-deprived cells with IL-3, mRNA transcripts encoding the immediate-early genes: c-myc, jun-B, krox-20, beta actin, and the cytokine genes: IL-4 and IL-6 were detected within 1 h. In contrast mRNA transcripts encoding the delayed-early genes: ornithine decarboxylase, p53, the IL-2 receptor-alpha, IL-4 receptor, and the T cell receptor c-gamma chains were observed at highest levels later. The tumor promoter, phorbol 12-myristate 13-acetate also stimulated the expression of many immediate-early genes, however, c-myc and the delayed-early genes were only detected when IL-3 was present. We conclude that cytokines and tumor promoters have distinct effects on proto-oncogene expression in hematopoietic cells which may affect the ability of these agents to promote cellular growth versus differentiation. PMID- 21607355 TI - The tumor-suppressor protein p53 - relationship of structure to function (review). AB - Point mutations and/or rearrangements in the tumor suppressor gene p53 are the most common genetic alterations in human cancers. Recent observations indicate that the sum and substance of p53 protein function is the prevention of tumor formation by preservation of genetic stability. This review summarizes and critically discusses various biochemical activities of p53 in relation to the known structural properties of this molecule. It will become apparent that several of the well-accepted biochemical activities of p53 such as p53 oligomerization, p53-protein interactions, and its association with nucleic acids are difficult to reconcile with the known structural features of the p53 polypeptide. More knowledge about the structure-function relationship is thus a critical issue for understanding the biological function of p53 at the molecular level. PMID- 21607356 TI - Preventive effect of whole peptidoglycan (wpg) on the occurrence of rat mammary tumors induced by 7,12-dimethylbenz(a)anthracene (dmba). AB - The preventive effect of purified cell wall of Bifidobacterium infantis, Whole Peptidoglycan (WPG), on the occurrence of mammary tumor induced by 7,12 dimethylbenz(a)anthracene (DMBA) in SD strain female rats was investigated. Rats were given p.o. with 20 mg of DMBA and then received s.c. 200 mu g of WPG weekly for 20 weeks starting on the day of DMBA administration or for 22 weeks, 2 weeks prior to DMBA administration. In the control group, the first tumors appeared 9 weeks after DMBA administration and the cumulative tumor incidence reached 100% within 17 weeks. Subcutaneous injections with WPG weekly for 20 or 22 weeks significantly protected animals from tumor development. The final tumor incidence in the WPG-treated groups was 60-72% at 20 weeks following DMBA administration. On the other hand, WPG was not effective on the delay of the date of first tumor appearance and the growth of tumors once developed. These results suggest that the preventive effect of WPG on the tumor development greatly depends upon the physiological conditions of the hosts in the system of DMBA-SD female rats. PMID- 21607357 TI - Intracavital chemotherapy for peritoneal and pleural carcinomatosis with lipid formulated anticancer agents. AB - A clinical pilot study of intracavital chemotherapy with anticancer agents dissolved in lipids for malignant effusion in pleural and peritoneal cavity was performed. Seven patients with pleural or peritoneal metastases were treated with a cocktail of anticancer agents dissolved in Lipiodol individually administered via the intracavitary route. All the patients revealed cytological and physical improvement. Five patients responded completely and two responded partially; four patients were able to be discharged from hospital and no serious side effects were observed. Thus, this therapeutic tactic of using oily anticancer agents appeares to be promising for control of pleural and peritoneal carcinomatoses. PMID- 21607358 TI - Primary branchiogenic carcinoma - immunohistochemical and ultrastructural features - a case-report and review of the literature. AB - A case with histological evidence of malignancy developed in a branchial cleft cyst (BCC), which conforms with the criteria for primary branchiogenic carcinoma (PBC) was analyzed by electron microscopy and immunchistochemistry; our findings reveal peculiar analogies between PBC and BBC, further supporting the primitive nature of the lesion. PMID- 21607359 TI - Immunohistochemical expression of keratin proteins in keratoacanthomas of the skin. AB - Keratin expression in eight cases of keratoacanthoma was examined immunohistochemically using a panel of seven monoclonal antibodies to either single or a few subsets of keratin polypeptides, and compared with normal surrounding skin to evaluate their cell phenotypes. Six cases of squamous cell carcinoma of the skin were also examined. In outer root sheath cells of normal hair follicles, all the cells were immunopositive with E3, CK8.12 and 312C8-1 antibodies, limited reactivity was seen at the level of sebaceous duct insertion with 34 beta B4, and restricted expression was seen at the early anagen stage with KS-1A3, while all cells were totally immunonegative with RPN1165 and CK4.62. In all eight keratoacanthomas studied, 312C8-1 immunorectivity was seen in peripheral basaloid cells of the endophytic lobules, E3, CK8.12 and 34 beta 4 immunoreactivity was found in centrally located cells with glassy appearance, while RPN1165 and CK4.62 gave no immunoreaction. In one case, glassy type cells were positive with KS-1A3. These results suggest that keratin expression in keratoacanthomas resembles that in the upper part of the outer root sheath cells of the hair follicle, and suggest the possible origin of keratoacanthoma cells from those of the outer root sheath. However, similar keratin expression was found in squamous cell carcinomas of the skin and we were unable to distinguish these two conditions from their keratin reactivity. PMID- 21607360 TI - Non-teleological differentiation of malignancy (review). AB - So-called 'de-differentiation' of malignant tumors is not identical with 'retro differentiation' of normal cells, although induction of differentiation of tumor cells seems to be successful. De-differentiation of tumor cells is a more stochastic process than the reversion of serial developmental lineage in normal differentiation. After retro-differentiation, re-differentiation of normal cells includes serial expression of negative regulators programmed a priori, and a teleological explanation of differentiation is possible. However, 'fragmented' gene expression is generally observed in tumor-cell differentiation. In tumor cells, it is more important that they cannot maintain a differentiated state under normal microenvironments than that they can be induced to differentiate by artificial agents. Induction of differentiation of tumor cells should be different from that of their normal counterparts since loss of regulatory mechanisms could not be restored by the inducers. Phenomenological homology between tumor cells and their normal counterparts in the differentiation may be only an experimental artifact, since the genetic information of development is generally damaged or lost in tumor cells. Loss of teleology in tumor cells is essentially correlated with their selfish behavior. Differentiation is not necessary for tumor cells, since they are 'selfish cells' in the altruistic somatic cell society. The differentiation program of tumor cells should be considered as a remnant of the normal one with loss of teleology. PMID- 21607361 TI - Cardiovascular monitoring of drug-resistant lymphoma patients treated with epoch chemotherapy plus high-dose verapamil in continuous-infusion. AB - High dose Verapamil (VP) infusion has been incorporated into cytotoxic chemotherapy in order to circumvent tumor cell drug-resistance. We have evaluated the cardiovascular side-effects produced by high dose VP associated to EPOCH chemotherapy in 12 patients with chemorefractory lymphoma. Continuous monitoring of right ventricular and pulmonary pressure and cardiac index was performed in three patients by a Swan-Ganz catheter. A slight reduction in cardiac index was observed 6 h after the beginning of VP infusion and was followed by spontaneous recovery within 12 h. First degree atrioventricular (AV) block was detected in 6/12 patients. Premature Ventricular Beats (PVB) occurred in one patient, and promptly disappeared after xylocaine administration. All patients experienced mild and transient hypotension, while severe hypotension was observed only in 1 patient, who promptly recovered when VP administration was discontinued. Hypokalemia was detected in 6 patients possibly as a consequence of transient activation of the renin-angiotensin system. PMID- 21607362 TI - The m1g8 monoclonal-antibody - a comparison between paraffin-embedded and frozen sections from breast-cancer. AB - Till now the immunohistochemical studies on the procathepsin D expression in breast cancer have been performed using polyclonal antibodies on paraffin embedded sections because the monoclonal ones were considered effective only on frozen sections. In this study we compared the MAb M1G8 reactivity, which recognizes the 52 Kd procathepsin D, on a series of frozen and paraffin-embedded sections of the same specimen from 22 breast cancers, using the immunohistochemical method. This methodological choice was due to the necessity to perform further studies with monoclonal antibodies using archival material to clarify the procathepsin D prognostic role. MAb M1G8 was clearly positive with a 100% concordance rate both in frozen and paraffin sections of the same specimen. PMID- 21607363 TI - Immunohistochemical expression of p53 paraffin sections from colon-cancer specimens - comparison between 2 new monoclonal-antibodies. AB - The early monoclonal antibodies (MAbs) to p53 are considered reliable only on frozen sections. We examined the immunohistochemical expression of p53 in 40 paraffin-embedded samples obtained from colon carcinomas using the two new MAbs DO-1 and DO-7. Thirty-one frozen samples were obtained from the same surgical specimens and were stained using MAb PAb 1801 which has a high specificity to p53. Fifty-five percent of 40 paraffin-embedded samples was positively stained with both MAbs DO series and showed a 100% concordance rate while 52% of 31 frozen samples was positively stained with MAb PAb 1801. The concordance rate between the reactivity of MAbs DO series and that of MAb PAb 1801 was 98%. Therefore, the reactivity of MAbs DO Series in paraffin-embedded material is similar and reflects accurately the overexpression of p53 when compared with the reactivity of MAb PAb 1801. Further investigations, moreover, can be performed using the MAbs DO series on archival material for a full understanding of the p53 involvement in human cancer. PMID- 21607364 TI - C-jun oncogene expression in nonsmall cell lung-cancer. AB - Primary lung cancer specimens of the non-small cell (NSC) types were examined for expression of the c-jun gene at the protein level by immunocytochemistry using the polyclonal antibody c-jun 890. The results obtained revealed that the c-jun p39 protein was expressed in 82% (18/22) of squamous cell carcinomas, 77% (10/15) of adenocarcinomas and 40% (2/5) of large cell anaplastic carcinomas, but no staining was seen in the non-cancer cases. Positive immunostaining was also seen in 16.7% (3/18) of the nonneoplastic bronchial cells of positively stained squamous cell carcinomas and in 40% (4/10) of adenocarcinomas. We suggest that elevated expression df c-jun p39 protein which was seen in a total of 75% (30/40) of the NSCLC, plays a role in lung cancer. PMID- 21607365 TI - Osseous metastatic pattern in breast-cancer - relation between anatomical distribution and ulterior visceral involvement. AB - The development of ultimate visceral metastases and the visceral metastases-free time interval was evaluated in patients with breast carcinoma bearing bone-only metastases. Ninety patients were identified and were subdivided into three groups according to the anatomic distribution of osseous lesions: group A with osseous involvement cranial to the lumbosacral junction, group B caudal to this, and group C with lesions in both areas. The purpose of this subdivision was to evaluate if there is any correlation between bone-metastases distribution and probability of developing visceral lesions. All patients received systemic therapy consisting of hormonal therapy, chemotherapy or both. The median survival for the whole group was 28 months, whereas it was 33, 43 and 26 months for patients in groups A, B and C, respectively (p=NS). No differences in subsequent visceral involvement and visceral-free time interval were observed among the three groups of patients regardless of tumor burden. In conclusion, our analyses did not show significant differences in the incidence of visceral metastases, visceral metastases-free time interval and overall survival in patients with breast cancer with bone-only lesions independently of anatomic distribution. PMID- 21607366 TI - Analysis of C-myc amplification by the differential polymerase chain-reaction (d PCR), study in breast-cancer. AB - c-myc proto-oncogene amplification seems to have a prognostic value in breast cancer. In this study, quantitative analysis of c-myc amplification was carried out by differential polymerase chain reaction technique (d-PCR) using beta-globin as the reference gene. d-PCR assessment showed coampIification products of c-myc and beta-globin depend on variations in reaction factors such as the genomic DNA concentration, the relative concentrations of the various amplimers, the thermostable DNA polymerase concentration and the number of cycles. However, amplification of c-myc can be estimated quantitatively. In addition, results of individual sets of d-PCR can be expressed on a standard reference scale. A clinical study of 309 patients with breast cancer found c-myc amplification, respectively in 19% (45/236) of primary tumour tissues, 21% (4/19) of subsequent second primary cancers, 36% (4/11) of tumours of patients with bilateral lesions, 40% (8/20) of local recurrence tumours and 22% (5/23) of metastatic lesions. Amplification of c-myc was observed more frequently in histological grades 2-3 (p<0.02), in ER negative (p<0.01) and PgR negative tumours (p<0.02), but was not associated with age, tumour size, nodal status, histology, cytosolic cathepsin D or pS2. d-PCR appears amenable to automation and should facilitate large scale, inter laboratory gene amplification studies. PMID- 21607367 TI - Quantitative-analysis of silver staining nucleolar organizer regions (AgNORs) in human tongue carcinoma cell-lines. AB - Six morphometric parameters related to nuclear size, number of AgNORs, and area of AgNORs in two tongue carcinoma cell lines were analyzed by an image analyzing system. It was discovered that AgNOR numbers, the area of all AgNORs in the nucleus, the ratio of mean area and size, and nuclear size are the parameters demonstrating the most consistent pattern of change against passage numbers in T1 and T2 human tongue carcinoma cells. These changes may be related to 'dedifferentiation' of tumor cells in prolonged culture. PMID- 21607368 TI - Benign cystic teratoma of the mediastinum presenting as recurrent pneumonia and simulating malignancy. AB - We describe a case in whom recurrent pneumonia was the presenting manifestation of a benign cystic teratoma of the mediastinum. Although the symptoms had developed over a 15-year period, the mass was not identified on the chest roentgenograrns up to the age of 22 years. CT demonstrated the extent of the mass, but failed in clarifying the cystic nature of the tumor and in providing diagnosis. The lesion could be safely approached through an antero-lateral thoracotomy, saving major chest wall muscles. However, surgical removal of the mass was difficult because of firm adherence to surrounding structures. PMID- 21607369 TI - Reactivity of axillary lymph-nodes draining invasive breast carcinomas - immunohistochemical evidence of tumor-associated reactions of B-region and T region. AB - The B and T regions in 495 axillary lymph nodes (TU-LN) draining 104 invasive breast carcinomas and 34 non-tumor-draining axillary/cervical lymph nodes (R-LN) were investigated immunohistochernically in frozen sections. The extents of the B regions and T regions were evaluated by staining with TO15 (CD22) and Leu-1 (CD5), respectively. Staining with Ki-M4, which specifically recognizes follicular dendritic cells, enabled determination of the number of lymphatic follicles. The germinal-center index (GCI), the numerical ratio of primary to secondary follicles, was determined to quantify the reactivity of the B regions. The number of Ki-67+ proliferating lymphoid cells per 0.5 mm(2) T region (PCT) was assessed as an index of the reactivity of the T regions. (i) In the TU-LN, the median GCI and PCT (0.1 and 18, respectively) were significantly lower than in the R-LN (0.6 and 26, respectively; both p<0.01). (ii) Greater TU-LN volumes were found to be associated with predominance of the T regions, high GCIs, and high PCTs. (iii) Higher GCIs and PCTs were associated with predominance of the T regions in TU-LN in general, but TU-LN partially destroyed by tumor metastases exhibited higher GCIs and PCTs when there was predominance of the B regions. The findings of the study show that LN draining breast carcinomas and reactive LN with signs of chronic nonspecific lymphadenitis exhibit significant immunohistochemical differences but it remains open to speculation whether the malignant tumor exerts suppressive effects on the lymphoreticular tissue or whether its antigenicity is low, particularly when compared with common, mostly infectious stimuli leading to chronic lymphadenitis. PMID- 21607370 TI - Immunohistochemical study of epidermal growth-factor and epidermal growth-factor receptor in breast-carcinoma. AB - We examined the relationship between epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) with clinicopathologic variables and silver-stained nuclear organizer region (Ag-NOR) counts in 93 patients with breast cancer. EGFR expression was significantly associated with axillary lymph node metastases, whereas EGF expression was not significantly associated with any of the clinicopathologic variables. Ag-NOR counts were not significantly different among groups of tumors categorized by EGF and EGFR expression, but a significant correlation was observed between clinical stage and synchronous expression of EGF and EGFR. However, EGF and EGFR expression did not appear to be independent prognostic factors as determined by multivariate analysis in which axillary lymph node metastases were included. We therefore conclude that EGF and EGFR expression may play a role in tumor progression rather than in tumor proliferation, but their expression was not useful in predicting the prognosis of patients with breast cancer. PMID- 21607371 TI - The mode of action of the antitumor agent lonidamine involves calcium-associated actin filament rounding. AB - The action of Lonidamine (LND), a dichlorinated derivative of indazole-3 carboxylic acid, on the membrane and cytoskeleton of Ehrlich tumor cells was investigated. A remarkable alteration in the molecular organization of the plasma membrane was observed. In particular, changes of plasma membrane and mitochondrial membrane protein distribution were induced by the drug. These membrane alterations were positively related to a rearrangement of microfilaments. In particular, characteristic ring-like structures of actin filaments were observed after 8 h of LND treatment. Intracellular calcium imbalance appeared-to be necessary to produce such peculiar structures. In fact, the administration of a calcium ionophore prevented the actin modifications induced by LND treatment while the simultaneous exposure to the antineoplastic drug verapamil, also considered a calcium channel blocker, was ineffective. The results reported herein suggest that the cytoskeleton as well as cell membranes might be involved in the cytotoxic action of LND and that they could share a common mechanism related to the calcium homeostasis. Moreover, Ehrlich tumor cells display a specific, peculiar rearrangement of F-actin filaments which can be considered as a marker effect of LND. PMID- 21607372 TI - Allelic loss at chromosome 8p in human breast-cancer. AB - Loss of heterozygosity (LOH) at loci from the short arm of chromosome 8 has been shown to occur in several types of carcinomas. The consensus deletion region has been recently mapped at 8p21-p22, distal to D8S283 and NEFL loci, and proximal to LPL and D8S265 loci. We report LOH at D8S133, a marker located in this consensus region, in a panel of breast tumor samples. LOH at this locus was observed in about 20% of the tumors. PMID- 21607373 TI - Ap-1 recognizes sequence elements on hiv-1 LTR in human epithelial tumor-cell lines. AB - Investigation of the nucleotide sequence of the HIV-1 LTR showed the presence of four novel short DNA regions which are homologous to the recognition site for the cellular transcription factor AP-1. Four short oligonucleotide hybrids containing these potential AP-1 sites were constructed and used in gel retardation assays and in competition experiments in order to determine the role of the AP-L protein in the regulation of HIV-1 expression. The breast MDA MB 468 and cervical HeLa turner cell lines, which are known to overexpress the AP-1 protein were used in a gel retardation assay as a control to study the affinity of the AP-1 to synthesized oligonucleotide sequences. We have observed specific binding of nuclear factor AP-1 to three of these oligonucleotide hybrids. These results demonstrate the presence of three novel AP-1 binding sites on HIV-1 LTR, one of which was found within the TAR element and in the Tat protein binding region. Moreover, they suggest that AP-1 could be contributing to HIV-1 transcriptional regulation through its interaction with the AP-1 binding sites of HIV-1 LTR. PMID- 21607374 TI - Human lung, bladder and head and neck tumors as compared to their adjacent normal tissues have elevated ap-1 activity and recognize sequence elements of hiv-1 LTR. AB - We have previously reported the specific binding of nuclear factor AP-1 isolated from human breast MDA MB 468 and HeLa cervical tumor cell lines to oligonucleotides complementary to three newly elucidated sequences within the HIV 1 LTR. These synthesized oligonucleotides, which bear high homology to the AP-1 recognition sequence, were used in the present study in gel retardation assays together with unfractionated nuclear protein extracts from human lung, bladder and head and neck tumors and adjacent normal tissue to study the role of the AP-1 protein in the regulation of HIV-1 expression. We found increased binding of AP-1 to these oligonucleotides in 9/12 lung tumors, 9/14 bladder tumors and 7/7 head and neck tumors as compared to adjacent normal tissues. This confirms previous results obtained when using MDA MB 468 and HeLa nuclear protein extracts. These results indicate that, AP-1 could be contributing to the HIV-1 transcriptional regulation through its interaction with the AP-I binding sites of HIV-I LTR. PMID- 21607375 TI - Expression of NK-associated surface-antigens cd-56 and cd-16 on aml-cells. AB - Monoclonal antibodies Leu 11a (CD16) and Leu 19 (CD56) were tested for reactivity with cells from 36 patients with acute myelogenous leukemia (AML) using two colour flow cytometry. Blast cells were identified by a broad panel of monoclonal antibodies. In 33% (12/36) the monoclonal antibody Leu 19, which has been demonstrated to bind to the 140 kD isoform of the human neural cellular adhesion molecule N-CAM, found on peripheral natural killer (NK)-cells, neuroectodermal cells, activated T-cells, and myeloma cells, was shown to bind strongly to the leukemic cells. The monoclonal antibody Leu 11a, which recognizes a surface differentiation antigen associated with the low affinity FcRIII for IgG, expressed on NK-cells, granulocytes and macrophages were found to bind to leukemic cells of four of the 12 Leu-19 positive cases. 50% (6/12) of Leu-19 positive patients were classified as having M4 according to the French-American British (FAB) morphology criteria. The potential diagnostic and clinical importance of CD 56 and/or CD 16 expression in acute myelogenous leukemia is presently under investigation. PMID- 21607376 TI - Chemotherapeutic treatment in unresectable nonsmall cell lung-cancer (nsclc) - a further attempt to modulate Cisplatin, vinblastine and mitomycin-C (pvm) schedule. AB - Searching for a more appropriate PVM (cisplatin, vinblastine and mitomycin-C) schedule against NSCLC, we treated 62 patients with unresectable NSCLC (49 males and 13 females), with the following regimen: high-dose cisplatin, 120 mg/m(2) i.v., day 1; common-dose vinblastine, 6 mg/m(2) i.v., day 1, and low-dose mitomycin-C, 6 mg/m(2) i.v., day 1, repeated every 3 weeks, until progression or tolerance. Following a minimum of 2 courses, responses, by extent of disease, were as follows: in 16 patients with stage IIIB: 2 CR, 5 PR (total response rate, 44%), 8 SD and 1 PD; in 42 patients with stage IV: no CR, 15 PR (total response rate, 33%), 18 SD and 13 PD. Overall response rate was 35% with (95%) confidence limit range 23%-47%. In all the series, median duration of response was 17 weeks (range, 4-98 wks) and median time to progression 26 weeks (range, 7-111 wks). Drug related toxicity was WHO grade III and IV, leucopenia: in 30% and 11% of patients, thrombocytopenia in 27% and 10% of patients, respectively. Twelve patients (19%) developed severe anemia requiring transfusions. Three out of 5 patients dismissed treatment due to irreversible nephrotoxicity. No pulmonary toxic effect was recorded and no drug related death occurred. Fifty out of 62 patients (81%) received full doses as scheduled and 12 (19%) required cisplatin dose reduction alone from 30% to 50%. Median duration of survival, in overall patients, was 27 weeks (range, 2-144 wks). Our results were in line with those of literature; this schedule with low-dose mitomycin-C and a single-dose vinblastine per course, seemed well feasible and safe. However, we recommend a cisplatin dose reduction to 80-90 mg/m(2) to optimise this schedule. PMID- 21607377 TI - Relevance of immunological parameters in progression of colorectal-carcinoma. AB - The long-term influence on the immunological stage from surgery and/or adjuvant or palliative therapy of 23 patients with metastatic colorectal carcinoma was investigated by performing regular phenotyping and functional analysis of peripheral blood lymphocytes (PBL). The following groups were chosen: A (n=6); patients after resection of primary tumor and liver-metastases without chemotherapy. B (n=3); patients with catheter implantation after resection of primary tumor and liver metastases receiving an adjuvant arterial chemotherapy with 5-fluorouracil (5-FU) and folinic acid (5-formyltetrahydrofolic acid, FA). C (n=7); patients with non-resectable liver-metastases, receiving arterial or systemic chemotherapy after catheter implantation. D (n=7); patients with extrahepatic filiae receiving systemic palliative chemotherapy. Lymphocytes of 10 healthy volunteers served as controls. Furthermore, we were able to show effects of 5-FU and FA on the immune system. PMID- 21607378 TI - Inhibition of vascular endothelial growth-factor induced cell-growth by an angiogenesis inhibitor agm-1470 in capillary endothelial-cells. AB - It is known that an anti-angiogenic compound AGM-1470 inhibits cells in vitro and in vivo, on mitogen-induced cell growth in capillary endothelial cells. In monolayer cultures, 1 ng/ml AGM-1470 completely inhibited both basic fibroblast growth factor (bFGF) induced cell growth and vascular endothelial growth factor (VEGF) induced cell growth in a cytostatic manner. IC50 was 85 pg/ml and 55 pg/ml for bFGF and VEGF induced cell growth, respectively. Moreover, in collagen gels, AGM-1470 suppressed the colony formation induced by bFGF and by VEGF in a dose dependent manner. Few colonies appeared 25 days after co-culuture with I ng/ml AGM-1470 and either 1 ng/ml bFGF or 5 ng/ml VEGF. It is suggested that a potent; inhibition of growth signals of more than one growth factor for endothelial cells might be involved in anti-angiogenic activity of AGM-1470. PMID- 21607379 TI - Prognostic value of nuclear volume in adenoid cystic carcinoma of the head and neck. AB - Modem stereologic techniques enable unbiased, objective and reproducible assessment of histologic parameters. The purpose of this study was to investigate the prognostic impact of the volume-weighted mean volume of tumor nuclei (nuclear (V) over bar v) in 62 patients with adenoid cystic carcinoma (ACC) and to correlate nuclear (V) over bar v and some traditional prognostic parameters with treatment failures. The observation time of the patients ranged from 2 to 11 years. Disregarding the well known histopathological subtypes of ACC and using random sampling it was found that treatment failures, i.e. inability to eradicate the disease and recurrences, were more often seen in specimens with small nuclear (V) over bar v when-compared to non-failures. Using a cut-off point of 250 mu m(3) the prognostic significance of nuclear (V) over bar v was 0.0177 by log rank analysis. For tumor stage vs. treatment failures/nonfailures log rank analysis revealed p=0.0147. Cox regression analysis left only the nuclear (V) over bar v (p=0.0234) as a prognostic factor. Estimations of nuclear (V) over bar v appears to be a reliable indicator of short term treatment failures in ACC. PMID- 21607380 TI - Mast-cell frequency within tumor correlates to the stage of tongue cancer. AB - Hydrolytic enzymes and angiogenic signals produced from mast cells have been suggested to be involved in the ability of tumours to invade normal tissues. In an approach to further test the hypothesis of the potential importance of mast cells in tumour growth we have compared the frequency of mast cells in tumour specimens from squamous cell carcinoma of the tongue stage T1 and T4. The results demonstrated a correlation of the frequency of mast cells within tumour with the stage of tongue cancer. No statistical correlation were found between mast cell frequency and grade of malignancy or spread to lymph nodes. Thus, further studies regarding the importance of mast cells in malignancy are of interest. PMID- 21607381 TI - Induction of breast and lung neoplastic lesions in mice by alpha-ecdysone. AB - Alpha ecdysone is naturally present in the leaves of some plants, including the carcinogenic plant bracken fern (Pteris aquilina). Feeding mice with alpha ecdysone at a dose level of 3 ppm/25 g body weight, 2 times per week for 22 months induced a significant increase in the body weight of the animals. Breast and lung tumors developed in the experimental mice. Other pathological changes such as fibrocystic disease of the breast and bronchocentric granulomas appeared in these animals. The results of this study proved that alpha-ecdysone may be one of the active carcinogens in bracken fern plant which was responsible for induction of tumors in different animals investigated by previous authors. PMID- 21607382 TI - Natural-killer-cell and antibody-dependent cellular cytotoxicity in gastric carcinoma patients - modulatory effects of IL-2 and 5-Fluorouracil. AB - Non-adherent peripheral blood mononuclear cells (PBMC) from 15 patients with carcinoma of the stomach and 6 normal healthy controls were assessed for natural killer cell mediated cytotoxicity (NKCMC) and antibody dependent cellular cytotoxicity (ADCC) in a 4 hour (51)Chromium release assay against target cells, K-562 and sensitized chicken red blood cells (CRBC), respectively. NKCMC and ADCC were significantly reduced in patients with respect to normal controls. However, significant enhancement in NKCMC and ADCC was observed when PBMC from patients were cultured in RPMI-1640 containing 200 IU/ml of Interleukin-2 (IL-2) for 4 days in 5% CO2 atmosphere at 37 degrees C. Augmentation of NKCMC and ADCC was also detected when a follow-up study of the patients was conducted after one month following initial trial of chemotherapy with 5-fluorouracil (5-Fu). Patients, who had undergone clinical trial with 5-Fu were better responders of IL 2 activation as reflected on NK cell and ADCC potential of these patients. Our investigations highlight the synergistic effect of 5-Fu and IL-2 on effecters of natural immunity in patients with carcinoma of the stomach, Judicious modulation of effecters may be beneficial in killing residual cancer cells in vivo. PMID- 21607383 TI - Unresectable colorectal-carcinoma - 10 years experience with patients treated with radical or palliative external-beam radiotherapy in Greece. AB - Our analysis presents a group of 86 patients with unresectable colorectal cancer who were treated with radical or palliative external beam radiotherapy from 1979 1990 at the Radiation Oncology Department of Greek Anticancer Institute, St. Savvas Hospital, Athens. The dose applied to the tumor area was 20-50 Gy in 2-6 weeks. A CAT-scan guided boost field portal to the primary tumor bed and immediately adjacent nodes was also used. Irradiation was given with a Co-60 unit or a 6 MeV Linear Accelerator using a two, three or 4-field technique. Complete symptomatic relief was achieved in 90% of patients with rectal bleeding, 63% with pain and 37% with mucous discharge. Although the majority of our patients received a higher than 40Gy radiation dose, we have seen symptomatic relief in up to 90% of patients treated with 20-30 Gy in 2-3 weeks. However, the duration of improvement in symptomatic relief of our patients was better for those who had been given higher doses of radiation therapy. The radiation dose was sufficient to relieve symptoms in 40 patients (46.5%) for more than 12 months and in 20 patients (23.2%) for 8-12 months. PMID- 21607384 TI - A descriptive study of uterine sarcomas. AB - A descriptive study of 67 patients with uterine sarcoma reveals the patients to be elderly (mean age 73 years) with significant co-existent medical problems. Despite this, primary surgical therapy is associated with minimal morbidity. Overall, survival is 63% for disease confined to the uterine corpus, and considerably less for more extensive disease. Nodal status, depth of myometrial invasion, peritoneal washings, cervical involvement, histologic type of sarcoma and treatment do not accurately predict survival. Patients alive 26 months after treatment are likely to survive their disease. PMID- 21607385 TI - Diagnostic-significance of liver-failure after newly-appeared serum fractions following liver surgery. AB - We investigated a serum marker suggesting postoperative liver failure based on basic research. In diseased Long Evans Cinnamon rat with spontaneous development of hepatitis and hepatocellular carcinoma, the specific fractions, Fr 43 (peak-1) and Fr 58-60 (peak-2), newly appeared in the eluted serum following highperformance liquid chromatography. Peak-1 was associated with progressing Liver damage or failure. We applied this theory to five patients undergoing liver surgery and our expectations were realized. Peak-1 was probably a certain hepatic regenerating factor recognized in a previous study and we suspected that the exessive production of a liver regenerating factor signified an ongoing liver failure. PMID- 21607386 TI - Circulating hormones in patients with tongue cancer. AB - Serum FSH, LH, prolactin and plasma estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) were estimated by RIA method in male patients with tongue cancer (N=110) and in healthy age-matched male controls (N=25). In this retrospective study, there was a trend towards higher levels of FSH (P<0.01), LH (P<0.01), prolactin (P<0.001), estradiol (P<0.0001), progesterone (P<0.0001) and DHEA (P<0.01) with concomitant lower levels of testosterone (P<0.001) and DHEA-S (P<0.02) in patients with tongue cancer compared to controls. We did not find significant difference in hormone levels when grouped according to the site of the tumor and stage of the disease. Patients below 40 years of age had significantly higher levels of DHEA and DHEA-S and lower levels of FSH than their counterparts. We observed a decreased ratio of testosterone: estradiol and increased levels of FSH, LH and prolactin in tongue cancer patients. These hormonal abnormalities clearly suggest a disturbance in the pituitary-adrenal-testicular axis. Based on our previous work and from these results, we suggest that prolactin might be playing an important role in the development and progression of tongue cancer. PMID- 21607387 TI - Oncogenesis and genome duplication maps (commentary). AB - Examples of activation of putative cancer genes belonging to multigene families are given. Their structure and chromosomal location helps in identifying genome duplications. Reciprocally, genome duplication maps may help in predicting the location and behaviour of putative cancer genes. PMID- 21607388 TI - Cytodifferentiation inducers as anticancer agents (review). AB - Several successful applications of differentiating agents in leukemic diseases, led to a regained interest in differentiation therapy. In this report we focus on novel classes of natural and synthetic compounds, which were not extensively reviewed and have a promising potential as anticancer agents e.g. protein kinase analogues, butyric acid, vitamin D-3 and purine and pyrimidine derivatives. The biological activities, preclinical and clinical studies of these agents are described. PMID- 21607389 TI - Tumor-growth and drug-resistance - lessons from the treatment of hodgkins-disease (review). AB - The resistance of cancer cells to anti-neoplastic agents is a major attribute of malignancy. Kinetic drug resistance develops as the tumor burden increases, and is reversible when the cell mass can be reduced. Genetic drug resistance, in contrast, results in the acquisition of possibly irreversible resistance by random cell mutation. The latter mechanism, and one of its corollaries, that rapidly alternating drug regimens could prevent the advent of new resistant cell lines, have been the subject of many studies in the last decade. The endpoint to evaluate in such studies should be an increase in failure-free survival, since such prevention cannot have any influence in the complete remission rates. A review of the clinical trials in Hodgkin's disease suggests that failure-free survival rates are in fact improved with the alternating schedules. On the other hand, dose-intensification is presently under study as a means of overcoming kinetic drug resistance, thereby increasing the complete remission rates, and has recently proved effective in the prolongation of survival in different malignancies. Further understanding of the mechanisms of drug resistance and the prospective appraisal of the combination of both high-dose therapy and alternating drug treatments should result in a better outcome, mostly for patients with large tumor burdens or other high risk factors. PMID- 21607390 TI - Coamplification of cyclin-d, hst-1 and int-2 genes is a good biological marker of high malignancy for human esophageal carcinomas. AB - In order to elucidate whether the amplification of cyclin D gene, hst-1 and int-2 genes might be a good biological marker of high malignancy for human esophageal carcinomas, we analyzed the coamplification of these genes by slot blot analysis using DNAs from formalin fixed paraffin embedded tissues of 18 dysplastic lesions, 100 primary esophageal carcinomas after surgical resection and 18 metastatic carcinomas of esophagus taken at autopsy. No amplification was detected in dysplasia, while it was detected in 41 cases (41%) of primary tumors and 100% of metastatic carcinomas, respectively. The amplification of these genes correlated to tumor staging and depth of tumor invasion. Moreover, the prognosis of patients with gene amplification was poorer than those without gene amplification. Interestingly, distant metastasis and local recurrence, were often observed in cases with gene amplification. These results indicate that amplification of cyclin D, hst-1 and int-2 genes might play an important role for tumor progression and patient prognosis for human esophageal carcinomas. PMID- 21607391 TI - The influence of intestinal metaplasia on development of gastric tumors in wistar rats receiving x-rays and mnng, mnu or dmh. AB - Five-week-old male Wistar:Crj rats received two 10 Gy doses of X-rays to the gastric region at a 3-day interval. Two months thereafter the animals were treated with 100 mg/liter of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 4 months in their drinking water, N-methyl-N-nitrosourea (MNU) 2 mg/l ml/weekly/ for a total of 10 times by gastric intubation, or dimethylhydrazine (DMH) 20 mg/kg i.m./weekly/20 times. After 1 year, the animals were sacrificeded. There was thus no direct evidence of a histogenetic link between intestinal metaplasia and gastric carcinogenesis in the present results. PMID- 21607392 TI - Dephosphorylation of retinoblastoma protein-induced by gamma-radiation correlates with cell-cycle perturbation. AB - Gamma radiation is a well-known antiproliferative agent, yet its mechanism of inhibiting tumor cell growth is not fully understood. Human oral epidermoid carcinoma KB cells were irradiated with various doses of Co-60 gamma-rays and harvested for analysis of the phosphorylation status of retinoblastoma protein (Rb) by SDS-polyacrylamide gel electrophoresis and analysis of their DNA content by flow cytometry. Dephosphorylation of Rb, which coincided with S and G2 arrest was observed in the lethal dose range of 750-1500 cGy. Both effects could be reversed by 1 mM caffeine, an inhibitor of tyrosine kinase and DNA repair enzymes. These results suggest that gamma-radiation, like many other antiproliferative agents, induces cell cycle arrest and growth inhibition in which dephosphorylation or reactivation of Rb plays an important role. PMID- 21607393 TI - Origin of heterogeneity of interleukin-6 (IL-6) levels in malignant pleural effusions. AB - We measured interleukin-6 (IL-6) concentrations from 48 malignant pleural effusions by an enzyme immunoassay and found a marked heterogeneity of the concentrations. The histological type of the malignant cells and total counts or differentials of the cells in effusions could not account for the heterogeneity. We newly established five malignant cell lines and found that the amounts of IL-6 produced by them were well correlated with IL-6 concentrations of the effusions from which these lines were derived (r=0.96; p<0.01). These results suggest that a marked heterogeneity of IL-6 concentrations in malignant effusions reflects the differential production of IL-6 by malignant cells in pleural space. PMID- 21607394 TI - Aneuploid cells in benign breast-lesions monitored by flow-cytometry. AB - It has been observed that various types of benign breast disease are associated to an increased risk of breast cancer. The biological significance of this association remains unclear: both benign and malignant lesions could independently have a common set of risk factors. The cellular DNA content of biopsy samples from 47 breast benign lesions was analyzed by flow cytometry. Flow cytometric measurements evidenced that 11/47 cases showed at least one aneuploid cell subpopulation. The presence of aneuploid subpopulations in benign lesions could be related to an unknown cellular alteration predisponding the developement of benign and malignant lesions independently. PMID- 21607395 TI - Tps in serum and urine of egyptian bladder-cancer patients. AB - TPS levels were determined in the serum and urine of 136 Egyptian patients with infiltrating bladder cancer and compared with the levels in 45 normal controls and 45 patients with urinary tract Bilharziasis. At 95% specificity the sensitivy in bladder cancer patients in serum and urine was 34.6% and 96.3%, respectively. Elevated TPS levels did not correlate with histological type, staging, grade, lymph node involvement or Bilharziasis. The determination of urinary TPS could probably be a useful tool in the follow-up of patients with superficial transitional cell carcinoma of the bladder. This urine test is less invasive and cheaper than cystoscopy and could, eventually, in combination with cytological examination of the urine, indicate the need of less frequent cystoscopy. PMID- 21607396 TI - Nm23 and C-erbb-2 expression in invasive breast-cancer. AB - We investigated whether nm23 and/or c-erbB-2 expression are useful for estimating the prognosis of invasive breast cancer patients. nm23 expression was significantly correlated with axillary (AX) and internal mammary lymph node (IMN) metastases, whereas c-erbB-2 expression was significantly correlated only with AX metastases. However, a univariate study revealed that survival was correlated significantly with tumor size, AX and IMN metastases, and c-erbB-2 expression, whereas nm23 expression was not an important prognostic factor. In a multivariate study, only AX and IMN metastases were significant prognostic factors. When AX and IMN metastases were excluded from the Cox model, only c-erbB-2 expression had independent prognostic value for survival. Therefore, we conclude that nm23 and/or c-erbB-2 expression may reflect the metastatic potential of breast cancer, but their prognostic value in combination is limited. PMID- 21607397 TI - Comparative-studies on the anti-invasive effects of retinoic Acid and staurosporine. AB - Retinoic acid and the protein kinase C inhibitor staurosporine have been reported to inhibit the invasiveness of tumor cells and may potentially be used to prevent metastatic disease. We report that retinoic acid reduced the invasiveness of 6 of 6 ras-transformed rat fibroblast cell lines and that inhibition did not require expression of the c-Jun component of AP-1. In contrast, staurosporine reduced the invasiveness of only 1 of 4 ras-transformed cell lines. The effect of staurosporine on the invasiveness of human tumor cell lines varied with cell type and length of treatment. We conclude that retinoic acid, but not necessarily staurosporine, decreases the invasiveness of ras-transformed fibroblasts. PMID- 21607398 TI - Regulation of the rb gene by normal and mutated ras, tpa and EGF. AB - Complete inactivation of the human retinoblastoma gene is believed to be an essential step in tumorigenesis of several different cancers. Using the plasmid pRbCAT2 that contains the Rb promoter region was tested for its ability to promote transcription of the bacterial chloramphenicol acetyltransferase (CAT) gene in a transient expression assay. This plasmid was co-transfected in a short term transfections with the plasmids pHO6T1 and pHO6N1 that contains the mutant and normal H-ras gene respectively, into the human cell line HeLa, by the calcium phosphate technique. It was found that the mutant H-ras gene enhances the activity of the Rb gene promoter in contrast to the normal H-ras gene that inhibits it. The expression of the CAT gene in stable clones of HeLa cells carrying the promoter of Rb gene after treatment with TPA and EGF respectively, was also investigated, whereas TPA enhanced, EGF had no effect on the activity of the Rb gene promoter. PMID- 21607399 TI - Mucin production and subsequent interstitial fibrosis in gastric-cancer with signet-ring cells. AB - The relation between the mucin production and the fibrous reaction was examined in 28 cases of gastric cancer with signet ring cells. Six of twelve cases had tubular adenocarcinomas in the group that the staining intensity ratio of Alcian blue to PAS(A-B/PAS) was less than 0.5. Of the sixteen cases eight had poorly differentiated adenocarcinomas and seven had signet ring cell carcinomas in the group that A-B/PAS was over 0.5. After mucosal replacement by tumour cells, four of six cases showed no fibrosis in the former group and five of seven cases showed submucosal fibrosis in the latter group. Signet ring cells were characterized by their destruction of mucosal architectures. Subsequent submucosal invasion and fibrosis depended on the types of tumour cells; tumour cells having the potential ability to form a gland invaded medullary with scarce fibrosis and those of weak intercellular adhesion invaded separately with interstitial fibrosis. PMID- 21607400 TI - Immunohistochemical study on cathepsin-B and cathepsin-d in pancreatic-cancer. AB - Lysosomal enzymes, cathepsin B and D, have been studied in their possible relationship to the ability of malignant cells to invade and metastasize. In the current investigation, these cathepsins were detected immunohistochemically using avidin-biotin-peroxidase complex method in the pancreatic cancer cells of 21 patients. The positive rate of identification of cathepsin B and D was 43% and 81%, respectively. Cathepsin D stained more strongly than cathepsin B and the plasma membrane stained quite strongly in two instances. A correlation between the presence of cathepsin B or D in cancer cells and the degree of metastasis to lymph nodes, liver, or lung was not recognized. PMID- 21607401 TI - Activating mutations in the k-ras gene in ulcerative-colitis and crohns-disease. AB - Patients with ulcerative colitis (UC) and Crohn's disease have an increased risk for developing cancer of the colon. Mutations in the K-ras gene are relatively frequent in specimens from patients with sporadic colon cancer, but less frequent in cases of cancer complicating ulcerative colitis. In order to study the problem further we used the polymerase chain reaction (PCR) technique followed by a restriction fragment length polymorphism (RFLP) assay, to detect mutations at codon 12 of K-ras in biopsy specimens from patients with UC or Crohn's disease. Six among 27 patients (22.2%) with UC and 2 of the 19 patients (10.5%) with Crohn's disease examined, carried a mutation at codon 12 of K-ras. Our results indicate that mutations in K-ras may be a genetic marker that would reveal the predisposition to colon cancer among this group of patients. PMID- 21607402 TI - Characteristic changes in protein-kinase-C activity and isoforms in ah66 cells during the acquisition of multidrug-resistant phenotype. AB - Changes in enzyme activity and the isoform pattern of protein kinase C (PKC) during the process of acquiring of drug resistance to doxorubicin (DXR) was examined in rat ascites hepatoma AH66 parental cells (AH66P) and several established clones of DXR-resistant AH66DR cells. In the weakly resistant cell line, AH66DR-0.3, which was resistant to DXR at the concentration of 0.3 mu M, reduced PKC activity and significantly decreased expression of its isoforms (alpha, delta and zeta) were observed. By contrast, AH66DR-30, the clone with the highest resistance, showed increased PKC activity, which was mainly either Ca2+ independent and phospholipid-dependent or Ca2+-independent and phospholipid independent. PKC-isoform analysis of the AH66DR-30 cells disclosed high levels of PKC-delta and -zeta and a quite low level of PKC-alpha relative to that of the AH66P cells. In both cell lines, phosphorylation of P-glycoprotein (Pgp), which is known as a drug efflux pump, was induced by PKC not only with Ca2+-dependent, but also with Ca2+-independent reactions. These results indicate that the expression of one or more specific isoform(s) of PKC, particularly the Ca2+ independent type, may be necessary for expression as well as activation of the function of Pgp. PMID- 21607403 TI - A case of ductal adenoma of the breast which contains high-concentration of steroid-hormone receptors. AB - A case of ductal adenoma of the breast in a 64-year-old Japanese woman is reported. The patient presented with a well-defined, 0.9 cm, firm mass in the right breast. Histological examination of the excised tumor revealed small and medium-sized ductules forming a nodular pattern partly surrounded by a thin layer of mature collagenous fibers. A few hyalinized fibers were also observed among the ductules, which had a clearly defined basement membrane, diagnosed as ductal adenoma of the breast. Determination of steroid hormone receptor by a dextran coated charcoal method revealed that the ductal adenoma contained high concentration of estrogen receptor (ER) and progesterone receptor (PgR) (280 and 105 fmol/mg protein, respectively). The patient had a previous history of invasive ductal carcinoma of the left breast and had undergone a modified radical mastectomy 4 years earlier. The contralateral breast cancer was also positive for both ER and PgR (350 and 78 fmol/mg protein, respectively). PMID- 21607404 TI - Cytogenetical and fish analysis on a salivary sebaceous lymphadenoma. AB - Chromosomal studies of a cultured parotid sebaceous lymphadenoma showed two abnormal cell groups, one with trisomy 9 (15% of the metaphases) and one with inconsistent structural deviations (10%). FISH analysis showed that the trisomic clone was actually larger (36%) than that revealed by chromosomal studies. The sebaceous lymphadenoma represents the fourth type of benign salivary gland tumor to show clonal chromosomal deviations. PMID- 21607405 TI - Expression of C-erbb-2 and epidermal growth-factor receptor in breast-carcinoma - prognostic value and correlation with clinicopathological and biological variables. AB - We examined epidermal growth factor receptor (EGFR) and/or c-erbB-2 expression, clinicopathological variables, silver-stained nuclear organizer region (Ag-NOR) counts, and their prognostic values in 93 patients with operable breast carcinoma. There was no significant correlation between c-erbB-2 and EGFR expression. Increased Ag-NOR counts were significantly associated with positive c erbB-2 expression, but not with positive EGFR expression. However, co-expression of both proteins was significantly correlated with axillary lymph node metastases. Significant differences in survival were found between groups of patients stratified by tumor size, histological grade, axillary lymph node metastases, c-erbB-2, and EGFR expression by univariate analysis. In addition, c erbB-2 and EGFR expression in combination was strongly correlated with decreased survival. However, only axillary lymph node metastases and age appeared to be independent prognostic factors by multivariate analysis. We therefore conclude that the prognostic value of c-erbB-2 and EGFR expression is limited in breast carcinoma. PMID- 21607407 TI - Cellular and molecular analysis of tumor-infiltrating T-lymphocytes from human breast-cancer at clonal level. AB - 51 T cell lines/clones were established from tumor-infiltrating lymphocytes of nine breast tumors by limiting dilution. All the lines/clones were exclusively CD3+ and expressed either CD4 (57%) or CD8 (26%) phenotype. In addition, 17% of the lines/clones displayed a dual expression of CD4+CD8+ antigens. No CD3-CD16+ NK clones were obtained. A vast majority of the T cell lines and clones (84%) exhibited cytolytic activity in a lectin-dependent assay which allows the detection of cytolytic T cells of any antigen specificity. 17% of the lines/clones lysed two allogeneic breast tumor cell lines, MCF-7 and HBL-100. 11% of the cells showed NK-like cytolysis by lysing an NK-sensitive cell line K562. Of the 17 lines tested against autologous tumor cells, only two exhibited cytolytic activity via T cell receptor and CD3 molecule in an MHC-restricted manner. Southern blot analysis of T cell receptor of 39 lines/clones revealed a limited heterogeneity of TCR-B chain gene rearrangements, which suggests oligoclonal expansion of T cells infiltrating into the tumor. PMID- 21607406 TI - Ras gene-mutations are a rare event in human uveal and cutaneous melanomas. AB - Melanomas are malignant tumours with high metastatic potential. The genetic alterations which lead to the transformation and progression of melanocytes to malignant melanoma remain obscure. Mutations in the ras gene family have been described, however their role in melanoma pathogenesis is still controversial. In this study we examined the incidence of H-, K- and N-ras mutations in 47 DNA samples isolated from paraffin-embedded 25 cutaneous and 22 uveal malignant melanoma tissues and a MeWo melanoma cell line using the Restriction Fragment Length Polymorphism (RFLP) analysis of PCR products. Only one mutation in codon 61 of the N-ras gene was found suggesting that the importance of ms mutations in melanoma tumourigenesis may be limited. PMID- 21607408 TI - Immunohistochemical expression of ps2 and cathepsin-d in breast-cancer - relationship with er, pgr immunostainings and clinicopathological aspects. AB - Fifty patients with breast cancer were studied to examine the relationship between the immunohistochemical tumour expression of pS2 and 52 kilodalton cathepsin D (52K-CD) proteins and several biological and clinical parameters. Our aim was to verify whether these two proteins may provide additional information for the management of breast cancer patients. By using a cut-off point of 10% for pS2 and 15% for 52K-CD valuations, we found that 24 of 50 (48%) carcinomas were pS2+ and 26 of 50 (52%) were 52K-CD+. A statistically significant positive association was found between pS2 positivity and ER presence (p=0.05), though 36% of ER-patients were pS2+. We did not find any correlation between the 52K-CD expression and other parameters studied, neither pS2. Although our findings confirm previous data correlating significantly the ER presence with pS2+ cases, we emphasise the necessity to standardize the use of a clinically significant cut off point in further immunohistochemical studies to evaluate this protein and, therefore, to explain its role also in tumours lacking ER. As regard the 52K-CD, our results agree with those of other studies, though the association of this enzyme with ER status is controversial in both cytosol and immunohistochemical studies, the use of monoclonal antibodies on frozen sections and polyclonal antibodies on paraffin section can explain this controversy. Our experience indicate the use of an immunohistochemical method in detection of this enzyme and the use of M1G8 (morioclonal antibody) on paraffin sections to make clear the possible role of 52K-CD in breast cancer. PMID- 21607409 TI - Accelerated chemotherapy with mitoxantrone plus g-csf in heavily pretreated patients with metastatic breast-cancer. AB - Twenty-two women with metastatic breast cancer, previously submitted to one or more lines of chemotherapy, were treated with mitoxantrone as single agent delivered at full dosage (14 mg/m(2)) every other week (accelerated chemotherapy). This dose was possible with concomitant subcutaneous administration of granulocyte colony stimulating factor (G-CSF) on days 5 to 12 of each 14 day cycle. Although grade III-IV leukopenia, anemia and thrombocytopenia were observed in 50%, 13%, and 27% of cases, respectively, a complete recovery of neutrophils, due to G-CSF administration, permitted on time cycle delivery in the majority of cases. Partial response was observed in 6/22 patients (27%). In conclusion, accelerated chemotherapy with mithoxantrone plus G CSF is both feasible and effective for patients with previously treated breast cancer. PMID- 21607410 TI - Swallowing function following multispecialty organ preservation treatment of advanced head and neck-cancer. AB - Swallowing function was studied in twenty-two patients before, during and after multispecialty (surgical, medical, radiation oncology) organ preservation treatment of advanced pharyngeal and laryngeal carcinoma. Video-fluorographic oropharyngeal motility (OPM) studies were performed at three stages during treatment. Swallowing function was rated according to the Swallowing Performance Status Scale (SPSS). Swallowing function significantly declined after surgery compared to presurgical status but improved significantly after post-surgical concomitant chemoradiotherapy. Swallowing function without need for enteral feeding support was maintained after completion of treatment in 18 of 22 patients (82%). The findings support the need for systematic evaluation of swallowing function throughout the treatment process for patients at risk for pharyngeal dysphagia. PMID- 21607411 TI - Immunohistochemically demonstrable pp60(c-SRC) in human breast-cancer. AB - Both elevated protein-tyrosine kinase activity of pp60(c-src) and the association of its high activity with a short disease-free period have been reported in patients with human breast cancer. In another human malignancy, colon cancer, tyrosine kinase activity and a protein level of pp60(c-src) have been observed to be correlated directly with the malignancy grade of tumors. In the present work, pp60(c-src) was demonstrated immunohistochemically in 48 human breast cancers, and the level demonstrated in this way was compared with prognostic histopathological factors. A weakly positive granular reaction product was detected in the plasma membrane of normal ductal epithelial cells and of cancer cells in 40% of cases of infiltrating breast cancer. In 60% of breast cancers, the pp60(c-src) level was increased, the reaction intensity was elevated, and a positive reaction was seen in cytoplasma and in the nuclear area. When the cancers with a low level of pp60(c-src) were compared with those showing an increased level with respect to prognostic factors (tumor size, axillary metastases and histopathological maligancy grade), no statistically significant differences were found. It seems that although pp60(c-src) is not primarily associated with the malignant growth of all human breast cancers, it may contribute to malignant cell proliferation in many of them. PMID- 21607412 TI - Expression of the carcinoma-associated le(a)-le(x) oligosaccharide in vertebrate endoderm and its fetal derivatives. AB - The extended Le(a)-Le(x) oligosaccharide, expressed as a cell surface antigen by human squamous lung carcinomas marks cancer cells of tumors having poor prognosis. In order to see if the extended Le(a)-Le(x) also has a precisely controlled pattern of expression during embryogenesis, a survey of representative vertebrate embryos and fetuses in various stages was undertaken. Embryonic and fetal cells which express the epitope are derived from embryonic endoderm. No. epitope expression was demonstrated in tissues of ectodermal or mesodermal origin. Vertebrate conservation of this endodermal cell surface carbohydrate suggests function necessary for normal growth and development with inappropriate re-expression during carcinogenesis. PMID- 21607413 TI - The effect of weight-loss on estimated breast-cancer risk and sex-hormone levels. AB - The effect of weight loss on estimated breast cancer risk, sex hormone binding globulin (SHBG), total and free estradiol levels was evaluated. Increasing weight loss reduced upper body fat distribution progressively. Women with a family history of breast cancer who lost more than 7.0 kilograms decreased their estimated breast cancer risk by 25.7% while women without such a family history decreased their risk by 42.8%. A significant (P<0.001) increase in SHBG with a 4.0 to 7.4 kg weight loss was seen in both pre and postmenopausal women (P<0.05). No significant change in total or free estradiol levels was observed. PMID- 21607414 TI - Distinct spectrum of N-ras mutations in aml and mds patients in yugoslavia. AB - Mutations that activate ras genes were demonstrated to be associated with certain types of malignancies. Multiple point mutations were predominantly found in the N ras and occasionally in the K-ras genes. The analysis of 4 MDS, 23 AML and 11 CML patients from Yugoslavia revealed the prevalence of the N-ras mutation (83%) over K-ras mutations (17%). Although the frequencies of the N- and K-ras mutations in these patients were similar to the ones reported for patients from USA and Japan, the N-ras mutational spectra considerably differed. The prevailing type of mutation in patients from Yugoslavia was G-to-T transversion at the first position in the codon 12 of the N-ras gene. This study supports a hypothesis that different geographical and environmental factors may cause the accumulation of different type of point mutations in the same target gene. PMID- 21607415 TI - P(185/Her2) and ps2 protein overexpression in breast-cancer specimens - improvement for prediction of response to endocrine therapy. AB - Simultaneous analyses of p(185/Her2) and pS2 protein expression in breast cancer is discussed to add information about prognosis and response to endocrine treatment. In a retrospective study, expression of p(185/Her2) and pS2 protein were detected by immunohistochemistry in paraffinembedded, formalin-fixed sections of 219 primary breast cancers. Median age was 56.6 years, median follow up 168 months. Results were correlated with clinical parameters and steroid receptor status. ER was positive in 55%, PgR in 54% of the tumors. ER correlated inversely with tumor size, and with tumor grade. pS2 was detected in 54% of the tumors, but showed no correlations with other parameters. p(185/Her2) was present in 24% of the tumors and correlated positively with tumor size. pS2 and ER or PgR status correlated (p<0.001). In the sub-group of negative steroid receptors and positive pS2 a qualitative significant difference for p(185/Her2) expression was seen. ER, pS2 and p(185/Her2) status had no prognostic impact on disease-free or overall survival; PgR status correlated with clinical outcome. PMID- 21607416 TI - Comparison of Ifosfamide versus cyclophosphamide in combination with Cisplatin and Doxorubicin (adriamycin), as first-line therapy for advanced epithelial ovarian-cancer - report of a pilot-study. AB - Cisplatin induction therapy followed by combination chemotherapy employing cisplatin, doxorubicin, and ifosfamide was administered to 25 consecutive patients with FIGO stage III:or IV epithelial ovarian cancer as first-line therapy following cytoreductive surgery. A median of seven (3-10) courses of combination chemotherapy were administered. Myelotoxicity necessitated dose attenuation in 20 (80%) patients. Microscopic hematuria was observed in one (4%) patient. Serious central neurotoxicity occurred in two (8%) patients. A surgically documentable response to therapy was observed in 16 of 19 (84%) patients who underwent second-look laparotomy. Thirteen (68%) patients had a surgical complete response, three (12%) patients had a surgical partial response, and three (12%) patients demonstrated progression of disease. The estimated two year survival for the study population was 81%. The results observed in the current study were compared to those reported for a population of 40 patients with advanced ovarian cancer treated with cisplatin, doxorubicin, and cyclophosphamide (PAC). Patients treated with PAI had significantly (p=0.04) fewer episodes of sepsis, a significantly (p=0.02) greater percentage of patients requiring dose reduction secondary to myelotoxicity, and a significantly (p=0.02) higher surgical complete response rate. The two-year survival for patients treated with PAI of 81% and that for patients treated with PAC of 68%, do not differ significantly (p=0.39). The two-year disease-free survival for patients treated with PAI of 34% and the two-year disease-free survival of 55% for patients treated with PAC do not differ significantly (p=0.99). The combination of cisplatin, doxorubicin, and ifosfamide is effective as first-line therapy in the treatment of advanced epithelial ovarian cancer, but a significant advantage over the less costly standard regimen which employs cisplatin, doxorubicin and cyclophosphamide is not demonstrable in the current study. PMID- 21607417 TI - Clonality of head and neck-carcinoma and adjacent mucosa. AB - Upper aerodigestive tract squamous cell carcinoma (UADT SCC) is associated with exposure to tobacco and ethanol and there is a high incidence of multifocal dysplasia, synchronous/metachronous lesions and local recurrence. These observations led to a 'field cancerization' hypothesis which proposes that the entire expanse of carcinogen-exposed mucosa is predisposed to neoplasia. This hypothesis implies that UADT SCC arises from multiple sites and is therefore polyclonal. To test this hypothesis, eight paired tumor and blood samples and 4 specimens of adjacent normal mucosa were tested for clonality by molecular X chromosome inactivation analysis. While tumor specimens were clonal, normal mucosa and blood were polyclonal. These findings demonstrate that UADT SCC is a clonal neoplasm that arises from polyclonal mucosa and supports an alternative interpretation of the 'field cancerization' theory which states that multiple sites are at risk and each neoplasm arising from these different sites is monoclonal. PMID- 21607418 TI - None of the known different fibroblast growth-factor receptor-2 carboxy-terminal tails are restricted to cancer-cells. AB - Fibroblast growth factor receptor-2 cDNAs derived from healthy tissues code for proteins with a 63 amino acid carboxy-terminal tail. Some cDNAs isolated from human tumour cDNA libraries code for receptors with 11, 15 or 29 amino acid carboxy-terminal tails. However, the important issue as to whether these latter tails are tumour specific markers has remained unresolved. We show that mRNAs coding for FGFR-2 proteins with carboxy-terminal tails of 11, 29 and 63 amino acids are co-expressed not only in many tumour tissues but also in normal human tissues, while the 15 amino acid tail appears to reflect a cloning artefact. PMID- 21607419 TI - Morphometric study of adenomatoid hyperplasia of the liver by image-analysis technology. AB - Seven nuclear morphometric parameters in adenomatoid hyperplasia of the liver (AHL), compared with normal liver cells (NLC) and hepatocellular carcinoma (HCC), were analyzed quantitatively by measuring the area (AREA), perimeter (PERIM), maximum diameter (DMAX), minimum diameter (DMIN), the equivalent circle diameter (DCIRCLE), circularity shape factor (FCIRCLE) and shape factor (FSHAPE) using image analysis technology (IAT). HCC could be subclassified into two groups according to the variation degree of FCIRCLE. All of above seven parameters in AHL and HCC were statistically different from NLC; AREA, PERIM, DCIRCLE and FCIRCLE in AHL were different from HCC. The degree of nuclear atypism of AHL was intermediate between NLC and HCC. The results indicate that AHL is not part of normal hepatocytic population morphometrically, but is a group of abnormal liver cells with somewhat nuclear atypia. As AHL has almost the same Value of parameters related to both the nuclear geometry and shapes to those of HCC, especially group 1 of HCC, as well as its frequently malignant transformation, AHL should be considered as an important precancerous lesion of human HCC. PMID- 21607420 TI - Alteration in the capacities of carcinogen metabolizing system of mouse-livers during pretreatment with various antineoplastic agents. AB - The effect of treatment with antineoplastic drugs on the modification of the carcinog en-metabolizing capacity was studied in mice liver microsomes at different durations as a single and as a repeated dose treatment. It is generally demonstrated that there is a commonality of influence for each specific antineoplastic group on the expression of the mixed function mono-oxygenases. The antineoplastic alkylating agents (chlorambucil, melphalan and busulfan) significantly increased the activity of carcinogen metabolizing enzymes in contrary to the effects observed for the antibiotic actinomycin-D. The antimetabolite agents (5-flourouracil and methotrexate), on the other hand, although decreased these activities when administered as a single dose, a pronounced increase was observed at the repeated dose treatment. Significant increases in the activity of N-nitrosodimethylamine demethylases I and II and aryl hydrocarbon (benzo[alpha]pyrene) hydroxylase were observed with chlorambucil when administered as a single or repeated doses. Similar effects was observed when the animals were treated with repeated doses of melphalan, busulfan and 5 flourouracil. Contrary to these effects, inhibition in the enzyme activity was exhibited when actinomycin-D was administered for either single or repeated dose treatment. The hepatic content of cytochrome P450 was significantly increased with all the administered drugs, except busulfan, when applied repeatedly. The implication of such alterations in the capacities of carcinogen metabolizing enzymes for antitumour-induced toxicity and carcinogenicity are discussed. PMID- 21607421 TI - Difficulties in the management of a parathyroid carcinoma - case-report. AB - The case of a parathyroid carcinoma in a 61-year-old woman is described. The patient was referred to our hospital, with the diagnosis of medullary thyroid carcinoma, after a prior thyroidectomy performed at another hospital. On admission, serum calcium was 3.92 mmol/l (n.r. 2.2-2.5), PTH level was 320 ng/l (n.r. 10-65), urinary cAMP was 508.9 mmol/mmol creatinine (n.r. 330- 630) and serum calcitonin was 2.1 ng/l (n.r.<10). The patient was then submitted to a complete neck exploration and multiple nodules were removed. Histopathological diagnosis of parathyroid carcinoma was made by local recurrence and retrospectively upon closer examination of the original specimen. After surgery, normocalcemia was achieved and maintained for about four months. Serum PTH decreased to 28.8 ng/l after surgery but increased quickly to 75.6 ng/l ten days later. Three months later, there was both biochemical and clinical evidence of disease. In the following eight months, calcium levels ranged from 2.99 mmol/l to 4-24 mmol/l and PTH from 135 ng/l to 1431 ng/l. However no distant metastases were found. To Control hypercalcemia, the patient was treated with bisphosphonates but normocalcemia was never achieved. A slight and transient reduction in serum calcium as response to an acute administration of octreotide, made us not to consider this eventual modality of therapy. Sonographically guided percutaneous injection of ethanol was performed but the treatment was not found to be effective. Finally, the use of chemotherapy with 5-fluorouracil, cyclophosphamide and dacarbazine was also unsuccessful. The patient died two years after the initial diagnosis. PMID- 21607422 TI - Incomplete axillary dissection in early breast-cancer and the risk of erroneous staging. AB - Maximum control of local disease in early breast cancer is obtained by breast conserving surgery, minimally invasive surgery of the axilla and consecutive selection for adjuvant therapy based on the number of involved axillary level I nodes. The answer to the question what is a 'node negative' patient? by defining the number of lymph nodes excised at operation exclusively, and the number of involved nodes found by the pathologist is given. Based on the data of Veronesi et al (Eur J Surg Oncol 16: 127-133, 1990) on 1446 complete axillary dissections performed between 1983-1986, the mathematical basis of the incomplete axillary dissection of the axilla in early breast cancer is presented: (i) To achieve a degree of confidence of 90% of the entire axilla being negative, histological examination of 10 level I nodes for a T1 tumor and 11 level I nodes for a T2 primary are necessary. In order to obtain these lymph nodes a total en bloc dissection of level I is indicated. (ii) The axillary status was considered negative if 10 or more lymph nodes for T1 or 11 or more in T2 tumors were found and were negative. (iii) The axillary status was considered positive, if <10 lymph nodes in T1 or <11 nodes in T2 tumors were found, even if they all were negative. If positive lymph nodes are left or estimated in the axilla after incomplete dissection, surgical treatment of the axilla is mandatory. PMID- 21607424 TI - Growth-factor regulation of mdm-2 messenger-RNA expression. AB - We have investigated the growth factor regulation of mdm-2 mRNA levels in mouse embryo fibroblasts, whose growth is controlled by platelet-derived growth factor (PDGF) and insulin-like growth factor I (IGF-I). We find that both growth factors up-regulate the expression of mdm-2 mRNA, independently of each other. PMID- 21607423 TI - Regulation of ras proteins and their involvement in signal-transduction pathways (review). AB - Albeit the exciting new developments in the last few years in the field of the growth factors and oncogene research, there are still many dark points in the pathways that lead to cell growth which makes future research even more interesting. The complexity of the network of proteins and messengers which are known to be involved, as well as the new discoveries indicating that new members of the cascade are yet to be discovered, gives the impression that we have to be more open minded than previously. Thus, a comprehensive look to the multiple pathways affected by some of the key molecules involved in regulating cell growth and differentiation is becoming more an obligation than a preference. Guided by this our review brings together most of the elements which seems to be relevant for the function of Ras proteins with special attention to the phospholipid metabolism alterations. We hope that it would stimulate stronger interaction among specialists working in different areas of the signal transduction pathways. PMID- 21607425 TI - Does informed adjuvant placebo chemotherapy for breast-cancer elicit immune changes. AB - To study psychological effects on the immune system, a saline infusion was administered to 24 fully informed patients who previously had received adjuvant chemotherapy for breast cancer. Blood samples were drawn before and after treatment, and compared to samples obtained at home two days earlier. Patients displayed a rise in natural killer-cell activity and a tendency to lowered percentage of suppressor/cytotoxic cells when assessed before treatment as compared to at home. Trait anxiety was associated with numbers of leukocytes. It is concluded that immune status partly reflects psychological factors. PMID- 21607426 TI - Molecular-cloning of the human cycg1 gene encoding a g-type cyclin - overexpression in human osteosarcoma cells. AB - Cyclins constitute a growing family of regulatory proteins that complex with, and activate, protein kinases involved in cell cycle control. Dysregulation of cyclin expression and/or cyclin-dependent kinase (cdk) activities may play a pivotal role in oncogenesis. In this report, we characterize a novel human cyclin gene by molecular cloning. This gene, designated CYCG1, encodes a human homologue of the rat G-type cyclin, exhibiting structural features and conserved sequence motifs of identified G(1) cyclins. The CYCG1 gene is expressed constitutively in synchronized human WI-38 fibroblasts and MG-63 osteosarcoma cells, which is reminiscent of CLN3 in Saccharomyces cerevisiae. Marked overexpression of CYCG1 is observed in a subset of human osteosarcoma cells, providing a potential link to cancer. PMID- 21607427 TI - Cyclophosphamide, epidoxorubicin and Carboplatin as treatment for advanced carcinoma of the bladder - a phase-ii study. AB - In advanced carcinoma of the bladder, the M-VAC chemotherapy schedule can yield positive results, but at the cost of very high toxicity. Recent studies have shown epidoxorubicin and to a lesser degree, carboplatin to be active against urothelial tumors, with cardiac, haematological and renal toxicity lower than that observed with CISCA or M-VAC chemotherapy regimens. In this study, we determined the toxicity and efficacy of cyclophosphamide 400 mg/m(2), epidoxorubicin 75 mg/m(2) and carboplatin 300 mg/m(2) in a 28-day course. From February 1990 to December 1991, we enrolled 33 advanced bladder cancer patients (25 males, 8 females), mean age 63 years. 31 patients were evaluable for toxicity and response. The major disease localizations were: locoregional 15 (48%), lymph nodes 6 (20%), liver 5 (16%), lung 3 (10%) and bone 2 (6%). A total of 186 cycles of therapy were administered, with a mean of 5.4 per patient. Six patients (19%) had a complete response (CR): 2 locoregional, 3 lymph node and 1 lung. Eleven patients (36%) had a partial response (PR), for an overall response rate of 55%. The median duration of response was 53 weeks and median survival for the entire group of patients was 40 weeks. No delays or interruptions due to sepsis occurred during therapy; haematological, cardiac and renal toxicity were below WHO grade 3. The efficacy of this chemotherapy regimen proved to be comparable to that of more aggressive schedules, while its toxicity was markedly lower. PMID- 21607428 TI - Inhibition by calmodulin antagonist trifluoperazine of experimental carcinogenesis in rat colon induced by azoxymethane. AB - The effects of the calmodulin antagonist trifluoperazine on the development of colon tumors induced by azoxymethane (AOM), and on the labeling index of the colon mucosa and the activity of ornithine decarboxylase (ODC) in the colon wall were investigated in Wistar rats. Prolonged administration of trifluoperazine significantly reduced the number of colon tumors in week 35. Administration of trifluoperazine caused a significant decrease in the labeling index of the colon mucosa and the AOM-induced ODC activity in the colon wall during administration of the carcinogen, but not after its cessation. A possible mechanism of inhibition of colon carcinogenesis by trifluoperazine could be its inhibition of AOM-induced increase in ODC activity of the colon wall with consequent suppression of cell proliferation in the colon. PMID- 21607429 TI - 90k is a serum marker of poor-prognosis in non-hodgkins-lymphoma patients. AB - Monoclonal antibody SP-2, which binds to a 90,000 daltons tumor-associated antigen termed 90K, was generated by mouse immunization with proteins released by human breast cancer cells into the culture medium (Iacobelli et al: Cancer Res 46: 3005-3010, 1986). Elevated 90K levels have been previously reported in the serum of patients with various malignancies. We investigated whether the circulating levels of 90K antigen might be related to prognosis of patients with Non-Hodgkin's Lymphomas (NHL). Serum samples were obtained from 50 apparently healthy blood donors and 81 patients with NHL. Circulating serum 90K concentrations (U/ml) were determined by a solid-phase immunoradiometric assay (IRMA) by a two-step procedure. Serum 90K levels were significantly higher in patients with NHL than in healthy controls (p=0.004). The Kaplan-Meier analysis of overall survival showed that patients with 90K-negative (serum 90K levels less than or equal to 16 U/ml) survived longer than patients with 90K-positive sera (less than or equal to 16 U/ml) (p=0.004). Multivariate regression analysis revealed that serum levels of LDH and 90K were the two independent prognostic variables for predicting overall survival. We propose that an elevated 90K antigen level in sera is a predictor of poor prognosis in NHL. PMID- 21607430 TI - Inhibitory effects of combined administration of uft and krestin on intraperitoneal metastases in mice. AB - In this study we investigated the effect of combined administration of UFT and Krestin (PSK) on the growth of intraperitoneal metastasis and temporal changes in the immune-endocrine system under this immunochemotherapy. At 7 days, Plasma ACTH levels of the PSK group were significantly lower than that of the control group (p<0.01). At 14 days, the tumor weight in the combined and the PSK alone group was significantly decreased, compared to the control group (p<0.05). Serum IAP levels of the UFT group were significantly lower than that of the control group (p<0.05). Serum cortisol levels of the combined group were lower than that of the other groups. PMID- 21607431 TI - Sialyl-lewis-x antigen immunoreaction of colorectal-cancer and its relationship to hematogenous metastasis. AB - The adhesion of cancer cells to endothelial cells of the target organ is one of the most important steps of hematogenous metastasis. Especially, sialyl Le(X) plays an important role in defining the metastasis. The expression of sialyl Le(X) antigen in colorectal cancer and its usefulness not only as an indicator of metastatic potential but also as a prognostic factor was studied immunohistochemically. Fifty-five (32.4%) sialyl Le(X) antigen-positive tumors were found in 170 colorectal cancers. There was a significant correlation between the expression of sialyl Le(X) antigen and the histological tumor type, venous invasion, lymph node metastasis, as well as liver metastasis. Hematogenous metastases were significantly more frequent in patients with sialyl Le(X) positive tumor than in those with sialyl Le(X)-negative tumor; and prognosis was significantly poorer in the former. The results suggest that sialyl Le(X) antigen plays a role in hematogenous metastasis of colorectal cancer, and that the expression of sialyl Le(X) is associated with poor prognosis. PMID- 21607432 TI - The enhanced antitumor-activity of DNA topoisomerase ii-trapping drugs by natural human tumor-necrosis-factor against human glioma cell-lines in-vitro. AB - We investigated the antitumor activity of human natural tumor necrosis factor (n TNF) either alone or in combination with chemotherapeutic drugs on human glioma cell lines in vitro. Although the cytotoxic effect of n-TNF alone did not exceed 30%, n-TNF, in combination with topoisomerase II-trapping drugs, such as actinomycin D (ACD) and daunomycin (DAM), demonstrated a striking synergistic enhancement of the cytotoxicity, and reached a level of more than 80%, against all the tested cell lines. Thus this new combination therapy is considered to be a promising candidate in developing a new treatment approach to glioma patients. PMID- 21607433 TI - Multiparametric assessment of the cell-cycle effects of tamoxifen on mcf-7 human breast-cancer cells. AB - Tamoxifen (TAM)-induced changes in proliferation kinetics of the human breast cancer cell line MCF-7 were investigated using dual parameter flow cytometry (FCM) of bromodeoxyuridine (BrdU) immunolabelling and of the expression of cell cycle related proteins (the proliferating cell nuclear antigen, PCNA, and the non proliferation-specific protein, Statin), versus the DNA content. Single-parameter FCM DNA histograms confirmed that after 96 hours of treatment with 10(-7) M TAM the fraction of S-phase cells decreased significantly, with a simultaneous accumulation of cells in the G(0)/G(1) range of DNA content. In dual-parameter FCM cytograms, the fraction of BrdU-positive cells after TAM exposure was significantly lower than in the controls, and no unlabeled S-phase cells were found. The TAM-induced block in G(0)/G(1) phase was paralleled by a decrease in the number of cells with a DNA content typical of the S-phase expressing PCNA, and by an increase in Statin-positive (G(0)) cells. Upon readdition of 10(-9) M 17 beta-estradiol (E2) to the TAM-treated cultures, BrdU-labelling as well as PCNA expression levels increased significantly, whereas the fraction of Statin positive cells remained higher than in the controls. The results obtained confirm that the TAM-induced inhibition of cell growth is associated with major changes in the cell cycle parameters of MCF-7 cells, and provide experimental evidence that two main mechanisms are operating: the accumulation of cells in G(1), before the onset of S-phase, and the exit of some cells from the cycling compartment; however, some of those that are blocked at G(0); cannot be totally reversed by estrogens and may be permanent; These data should be taken into account in the attempt to combine the antiestrogen treatment with chemotherapy more effectively. PMID- 21607434 TI - Cytosol and serum concentration of cytokeratin subunit-19 fragment (cyfra-21-1) in breast-cancer. AB - Cytokeratin 19 is a subunit of cytokeratin intermediate filament. CYFRA 21-1 is a new tumor marker using monoclonal antibodies which recognize a fragment of cytokeratin 19. CYFRA 21-1 was measured in cytosol of breast cancer tissues or in sera of patients with breast cancer or benign breast diseases to study the significance of this protein as a tumor marker. The cytosol concentration of CYFRA 21-1 was elevated in cancerous tissue compared to that in adjacent noncancerous tissue, and correlated with the tumor stage or the estrogen receptor status. In the serum, the mean value and positive rate for CYFRA 21-1 (assuming 2.2 ng/ml as the cut-off value) were 0.61 ng/ml (0%) in benign breast diseases, 0.98 ng/ml (6.7%) in stage I/II primary breast cancer, 75.67 ng/ml (60.0%) in stage III/IV primary breast cancer, 45.28 ng/ml (60.0%) in recurrent breast cancer, and 0.64 ng/ml (2.6%) in those with no evidence of recurrence. From the above, we concluded that CYFRA 21-1 could be a tumor marker with high specificity in breast cancer. PMID- 21607435 TI - Isolation of tumor-associated protein from sera of colon tumor-bearing rats using polyclonal antibodies entrapped in gel fiberglass columns. AB - A new, effective support for the isolation of proteins has been invented utilizing a gel fiberglass (GFG) (R. Zusman, Patent application 1992, 1993). We describe the utilization of this support to isolate tumor-associated proteins (TAP) from sera of colon tumor-bearing rats. Sera were percolated through GFG columns with entrapped anti-rat colon cancer IgG from rabbits. TAP were eluted in a large amount, up to 3 mg/ml sera/column. Their affinity to antitumorous polyclonal antibodies was detected by ELISA. Western immunoblotting with commercial monoclonal antibodies has identified the isolated antigens as p21 and p53. Their concentrations were much higher (up to 1,000 times) in sera from tumor bearing rats compared to control rats. The method was highly reproducible. It is suggested that data obtained can be considered as a basis for the further improving of quantitative methods of diagnosis. PMID- 21607436 TI - Double alternate modulation of high-dose 5-Fluorouracil by interferon-alpha-2b and phosphonacetyl-L-aspartic Acid in patients with advanced colorectal-cancer. AB - We conducted a multicenter phase II trial in patients with advanced colorectal cancer to investigate the antitumor efficacy of double alternate modulation of high-dose infusional 5-fluorouracil (5FU) (60 mg/kg/48 h = 2400 mg/m(2)/48 h) by interferon alpha-2b (IFN alpha) (10 MU/dose s.c. prior to and halfway 5FU, uneven cycles) and phosphonacetyl-L-aspartic acid (PALA) (250 mg/m(2) i.v. 24 h before 5FU, even cycles). Cycles were given weekly for 4 weeks and once every 2 weeks thereafter. Twenty one patients with progressive or symptomatic disease were treated ambulatory. Two patients (10%, 95% confidence interval 1-30%) achieved a partial response. Therefore, this schedule of double alternate modulation of 5FU is unlikely to be superior to single modulation of 5FU in patients with advanced colorectal cancer. Since no grade III/IV toxicity (WHO) occurred during 251 cycles, which is in contrast to our previous studies using the same 5FU schedule, it might be possible that alternate modulation allows more intense 5FU schedules compared to single or double modulation schedules. PMID- 21607437 TI - Expression of pancreatic trypsinogen in human extrapancreatic gastrointestinal carcinomas. AB - Pancreatic trypsinogen expression in 149 surgically resected extrapancreatic gastrointestinal neoplasms was evaluated immunohistochemically. Immunohistochemistry was performed using a monoclonal antibody against human pancreatic trypsinogen. Pancreatic trypsinogen expression was detected in 28 of 55 gastric carcinomas (50.9%), 22 of 44 colorectal cancers (50%), 12 of 20 gallbladder cancers (60%), nine of 10 extrahepatic bile duct cancers (90%), and none of 20 hepatocellular carcinomas. The intensity of immunoreactivity in the tumor area varied from specimen to specimen, and from area to area within the same specimen. In most cases, however, immunoreactivity was more pronounced at the infiltrative margin of the tumor. Additionally, the highly differentiated carcinoma cells tended to display a focal, fine granular immunoreactive pattern, usually present in the supranuclear cytoplasm, while the poorly differentiated carcinoma cells displayed a fine granular pattern, usually present over the entire cytoplasm. These findings suggest that some extrapancreatic gastrointestinal neoplasms express pancreatic trypsinogen immunoreactive peptides, raising the possibility that secreted pancreatic trypsinogen plays a role in carcinoma invasion and metastasis, as has been shown for other classes of proteases. PMID- 21607439 TI - Hiv-1 tat protein suppresses the nerve growth-factor (ngf)-mediated differentiation of PC12 rat pheochromocytoma cell-line. AB - In order to evaluate the effect of the regulatory human immunodeficiency virus type 1 (HIV-1) Tat protein on the process of neuronal differentiation, two tat transfected and mock-transfected PC12 cell lines were cultured in the absence or presence of 100-1000 ng/ml of nerve growth factor (NGF). As expected, NGF was able to induce a clearcut morphological differentiation of mock-transfected PC12 into sympathetic-like neurons, also reducing the percentage of cells in S phase. On the other hand, NGF was unable to reduce the percentage of PC12-tat cells in S phase and/or to induce their neuronal differentiation. Only the addition in culture of 5 mu g/ml neutralizing anti-Tat antibody plus 1000 ng/ml NGF was effective in decreasing the percentage of PC12-tat in S phase and inducing partial signs of neuronal differentiation in serum-free cultures. The ability of Tat protein to suppress the neuronal differentiation pathway controlled by NGF further contribute to the definition of its role in tumor promotion during the course of HTV-1 disease. PMID- 21607438 TI - Prognostic value of urokinase-type plasminogen activators in gastric-cancer. AB - To elucidate the relation between urokinase-type plasminogen activator (U-PA) and metastasis in gastric cancer, we examined U-PA tissue status immunohistochemically. Ninety-eight primary gastric cancer, prepared by AMeX method, were analyzed with anti-U-PA and anti-proliferating cell nuclear antigen (PCNA) monoclonal antibody. In addition, DNA ploidy patterns were determined by cytofluorometer after staining with propidium iodide. U-PA immunoreactivity can be observed as diffuse cytoplasmic staining, as intensely outlined luminal borders or in desquameted cells in the lumens. U-PA expression-positive tumors showed higher incidence of serosal invasion, lymph node involvement or larger tumors than did U-PA negative ones. There was no correlation between U-PA tissue status and PCNA labeling rates or DNA ploidy patterns. Patients with a U-PA positive tumor survived significantly shorter than those with U-PA negative ones. These results may indicate that U-PA tissue status is a useful biological prognostic indicator in gastric cancer. The high malignant potential of U-PA positive tumors may be associated with a rapid infiltrating capacity through gastric wall but not with a high proliferative activity. PMID- 21607440 TI - Cea and ca-19.9 as markers of colorectal neoplasms during chemotherapeutic treatment. AB - Carcinoembryonic antigen and CA 19.9 are markers of colorectal neoplasms, often related to tumor burden. Elevated pre-operative levels parallel disease extent and may foresee adverse prognosis. CEA and CA 19.9 may increase post-operatively, indicating tumor recurrence. Only limited data are available on the influence of chemotherapeutic treatments on these two markers, to detect chemotherapy-induced cytolysis. We measured CEA and CA 19.9 before and after a chemotherapy regimen of five days consisting of folinic acid and 5-fluorouracil in forty patients with colorectal cancer. No consistent fluctuation was detected, the examined tumor markers being related in a given patient only to tumor burden. PMID- 21607441 TI - Elevated protein-tyrosine-phosphatase activity in human colon-carcinoma. AB - We have examined the activity of protein tyrosine phosphatase in various tumor cell lines and surgically resected human colon carcinoma specimens. The protein tyrosine phosphatase activity of rat fibroblasts increases with the transformation by v-src gene. Likewise human colon carcinoma and human neuroblastoma cell lines, in which the activation of c-src tyrosine kinase was reported, show elevated protein tyrosine phosphatase activity in most cases. We compared the protein tyrosine phosphatase activity of eight human colon cancer tissues with that of normal mucosa of the same patient. The results show that the protein tyrosine phosphatase activity in tumor tissue was increased, suggesting the biological significance of protein tyrosine phosphatase in colon cancer. PMID- 21607442 TI - The prognostic-significance of cathepsin-d in breast carcinomas - an immunohistochemical study. AB - Cathepsin D, a lysosomal protease, was examined by immunohistochemistry in 481 breast carcinomas. The immunoreactivity for cathepsin D was registered in the tumour cells, in the surrounding stroma, and in the macrophages and correlated with clinicopathological parameters. In univariate analysis of survival data, less than 25% positive tumour cells, any positivity in the stroma, and moderate or strong positivity in the macrophages were poor prognostic parameters. In multivariate analysis, all three parameters were of independent prognostic significance; therefore a cathepsin D index was constructed. In multivariate analysis the cathepsin D index was also found to be of independent poor prognostic significance both in patients with and without lymph node metastases. Progesterone receptor status was an independent prognostic parameter in patients with lymph node metastases. From the present study we concluded that the cathepsin D index was a independent poor prognostic parameter. PMID- 21607443 TI - Relationship between nm23 expression and axillary and internal mammary lymph-node metastases in invasive breast-cancer. AB - We examined the relationship between nm23 expression and clinicopathological variables in 144 patients with invasive breast cancer to assess the role of nm23 expression in estimating prognosis. Expression of nm23 was significantly associated with axillary lymph node (AX) metastases (p=0.0359) and internal mammary lymph node (IMN) metastases (p=0.0146), but not with age, menopausal status, histological type or grade, or tumor size. A univariate study revealed that survival significantly correlated with tumor size, AX and IMN metastases, whereas nm23 expression did not appear to be a significant prognostic factor. Among patients with negative AX, however, survival in patients without nm23 expression was lower than in those with nm23 expression (p=0.0778). Survival in patients with IMN metastases was significantly lower than those without IMN metastases among patients with positive AX (p=0.0073). In a multivariate study, AX and IMN metastases, and nm23 expression appeared to be significant prognostic factors for survival. This study suggests that nm23 expression may be an additional prognostic factor in patients with negative AX, while IMN metastases are an additional prognostic factor in those with positive AX. PMID- 21607444 TI - Eyelid metastasis originated from gastric-cancer. AB - The incidence of cutaneous metastasis from neoplasms of internal organs is uncommon, and in particular eyelid metastasis from gastric cancer is extremely rare. We report on such a case together with a review of a total of 6 cases. Of the 6 cases, 5 were males and 4 were pathologically low-grade differentiated adenocarcinoma. The presentation of eyelid mass was 3 nodular, 2 diffuse and one ulcerative without characteristics of its location. All the cases involved systemic disease and the effective treatment was not performed. We consider that the number of cases with eyelid metastasis from gastric cancer is actually much higher and that gastroenterologists should pay more attention to such cases in order to adequately grasp the pathogenesis. PMID- 21607445 TI - Detection of human cytomegalovirus by the polymerase chain-reaction in immunosuppressed and immunocompromised patients. AB - Infections caused by Human Cytomegalovirus (HCMV) are very common in patients who undergo immunosuppression or immunocompromisation. The techniques used for routine HCMV detection are time-consuming and lack specificity and sensitivity. The ability of the Polymerase Chain Reaction (PCR) to amplify HCMV DNA from clinical samples of the patients is a valuable diagnostic tool for the detection of HCMV in the early stages of the infection. We used a pair of primers to amplify a 435 bp region of the immediate early-1 gene, to detect HCMV DNA in clinical samples from patients at high risk for HCMV infection. We found HCMV in the following type of patients: 6 out of 20 in immunosuppressed, 11 out of 31 in immunocompromised, 5 out of 8 in pregnant women, 4 out of 25 in patients with high anti-CMV IgM and IgG titres, 1 out of 2 in patients with kidney failure, and 6 out of 14 in patients with opthalmic disorders. Sixty-seven specimens, which were found to be negative for CMV by the PCR technique, were used to inoculate human fibroblast monolayer cultures and PCR was performed to the DNA extracted from the cultured cells. Only in 1 out of the 67 cases HCMV DNA was detected. PMID- 21607446 TI - Detection of the epstein-barr-virus by the polymerase chain-reaction in immunosuppressed and immunocompromised patients. AB - DNA extracted from the blood of immunosuppressed and immunocompromised individuals and from patients with infectious mononucleosis, leukaemias and lymphomas were studied using the Polymerase Chain Reaction (PCR) technique. The oligonucleotide primers used for the detection of the Epstein-Barr virus (EBV) amplify a 375bp sequence from the EcoRI B fragment of the viral genome. EBV specific sequences were amplified from the blood samples of 18 out of 65 patients, most of which were transplant patients (9 out of 31). The results confirmed the association of EBV with clinical disorders in immunodeficient and immunocompromised patients and the importance of PCR method in routine diagnosis. PMID- 21607447 TI - Detection of human cytomegalovirus and epstein-barr-virus by the polymerase chain reaction in patients with Beta-thalassemia. AB - Infections caused by Human Cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) are common in multiple transfused patients, such as patients with beta thalassaemia. The ability of the Polymerase Chain Reaction (PCR) to amplify HCMV and EBV DNA from blood and other samples makes this technique a valuable diagnostic tool for the detection of both viruses in the early stages of the infection. PCR was used for the amplification of a 435 bp region of the immediate early-1 (IE-1) gene of HCMV and a 375 bp sequence from the EcoRI B fragment of EBV genome. Blood samples from 80 patients with beta-thalassaemia were examined. HCMV was found in 14 and EBV in 12 patients. The results obtained confirm the implications of HCMV and EBV in the diagnosis of viral infections in multiple transfused patients as well as the importance of PCR technique as a valuable diagnostic tool. PMID- 21607448 TI - Fenretinide in breast-cancer chemoprevention (review). AB - Fenretinide (4-HPR), a synthetic amide derivative of retinoic acid, has proven effective in preventing chemically induced mammary carcinoma in rodents. During the past years, our group has made a particular effort with regard to this molecule in clinical studies aimed at evaluating its pharmacology, toxicity and efficacy in breast cancer prevention. We have demonstrated that 4-HPR blood levels remain constant during administration for as long as 5 years, that the drug accumulates in the human breast, and that it induces a significant decline of plasma retinol and insulinlike growth factor-I (IGF-I) levels. Accrual of the phase III study was closed on July 31, 1993 including 2,972 Stage I breast cancer patients. The aim is to evaluate the efficacy of a 5-year administration of 4-HPR to prevent new contralateral primary breast cancers. Compliance to protocol and treatment is high and tolerability of the drug is good; only 51 women out of 1,397 (3.6%) have interrupted drug intake due to toxicity. The only remarkable adverse effect of 4-HPR administration is diminished dark adaptation, which occurs in about one-fourth of the patients and is dependent on the decline of plasma retinol below the threshold level of 100 ng/ml. However, about 50% of the patients with altered dark-adaptometry are asymptomatic and the alterations of dark adaptation are promptly reversible upon drug discontinuation. Plasma level of N-(4-methoxyphenyl) retinamide (4-MPR), the principal metabolite of 4-HPR, which tends to be higher in women over 55 years with a high percentage of adipose tissue, is the major determinant of both retinol and IGF-I decrease. Since the combination of 4-HPR with the antioestrogen tamoxifen has shown a synergistic activity in preclinical models, it is currently an important avenue of clinical investigation in an attempt to prevent breast cancer. Moreover, a dose reduction of one or both agents in an effort to minimise toxicity while maintaining activity, would represent a major improvement in cancer chemoprevention. PMID- 21607449 TI - Malignant fibrous histiocytoma of the spleen - report on a case presenting as emergency. AB - Among the primary malignant tumours of the spleen, fibrous histiocytoma (MFH) is extremely rare and only six cases have been reported in the literature. A splenectomy was carried out in a 22-year-old woman presenting with an acute abdomen. Imaging procedures showed a 5 cm round, heterogeneous mass in the spleen. At light microscopy the infiltrating cell population was arranged in nests or bundles with a storiform pattern. At higher magnification, most neoplastic elements were medium-sized, round or spindle-shaped, with acidophilic cytoplasm and oval or round nucleus. Mitotic figures were numerous; reactive foamy macrophages could be seen. At immunohistochemistry, in paraffin sections, there was strong positivity with the reagents against CD45, CD68, alfa-1 antichymotrypsin and vimentin. In frozen sections there was a clear-cut positivity with the antibodies EBM11 (CD68), KP1 (CD68), Ber Mac 3, anti-lysozyme and anti-vimentin. The case reported revealed morphological and immunohistochemical features consistent with MFH, of the storiform-pleomorphic variant. The clear-cut positivity for macrophage-associated molecules and for leucocyte common antigen would seem to suggest a histiocytic origin. MFH is considered an aggressive tumour, with a frequent recurrence and metastasis but our patient is alive and free of disease three years from surgery. PMID- 21607450 TI - Interrelationship between the expression of h-ras p21, C-myc and p53 proteins, and the infection of high-risk human papillomaviruses in Japanese patients with esophageal squamous-cell carcinoma. AB - The presence and distribution of increased expression of H-ras p21 protein, c-myc protein and p53 protein, or of human papillomavirus (HPV) DNA were investigated in 42 Japanese patients with esophageal squamous cell carcinoma (SCC) by immunohistochemical techniques using each protein antibody, and by in situ hybridization with fluorescein isothiocyanate (FITC)-labelled DNA. probes for HPV 16 and HPV-18. Eighteen cases were positive with H-ras p21 antibody, but only one with c-myc protein antibody. Positive reaction of the cancer cell nuclei with p53 antibody was found in 14 cases. Among these positive cases with H-ras p21 or p53 antibody, 7 were double positive. In addition, we found positive results in 7 cases with HPV-16, and 8 cases with HPV-18, including 2 double positive cases. Among them, 6 cases were also positive with H-ras p21. Only HPV infection or p53 overexpression was detected each in 7 cases. All of HPV-positive tumors were negative with p53 antibody. Moreover, among the cases with the expression of I-I ins p21, combined cases with overexpressed p53 protein or HPV infection counted for more than 50%. Statistically, these combined cases showed worse survival rate than only H-ras p21 positive ones. Judging from these results obtained in the present study, the increased expression of H-ras p21 protein as well as p53 and/or HPV may be involved in the carcinogenesis of this kind of disease, and become apparent, when the function of p53 as a tumor suppressor gene is inhibited with overexpressed p53 protein or HPV oncoprotein, resulting in a poor prognostic indicator. PMID- 21607451 TI - A complex translocation t(1-12-11) in a patient with hodgkins-disease. AB - A new complex translocation t(1;12;11) (p32;q24;q23) was found as the sole abnormality in spleen cells from a patient with lymphocyte predominant subtype of Hodgkin's disease. The patient is in complete remission 4.5 years after diagnosis. PMID- 21607452 TI - Node-positive breast-cancer - prognostic-significance of the plasma prolactin compared with steroid-receptors and clinicopathological features. AB - The value of plasma prolactin (PRL), estrogen-receptor (ER) and progesterone receptor (PR) determinations in predicting overall survival was evaluated in a group of 151 breast cancer patients. The patients were enrolled at The Gujarat Cancer and Research Institute, Ahmedabad and were followed for a period of three years. As 85% patients had node-positive disease (N=129), the results were analyzed only for this group of patients. Of the 129 node-positive breast cancer patients, 61% had hyperprolactinemia (PRL >20.0 ng/ml plasma), and ER+ tumors. 67% of the tumors were PR+. Significant correlation was not observed between age, menopausal status and clinicopathological features and ER and PR content. When the patients were subgrouped according to the cut-off levels for the three prognostic indicators i.e. PRL, ER and PR, the difference between the two subgroups of PRL was statistically significant for overall survival (P<0.02). ER+ and PR+ patients had better overall survival than their counterparts. However, the differences were statistically non-significant for both the subgroups. Moreover, ER- hyperprolactinemic patients had unfavourable prognosis (P<0.02) compared to their counterparts. This study suggest that hyperprolactinemia is an important indicator of unfavourable prognosis in node-positive breast cancer patients, both when evaluated singly and in conjunction with steroid receptors, ER-hyperprolactinemic patients had poor prognosis. PMID- 21607453 TI - Oncogene-related sequences in amphibian genomes. AB - In this investigation the presence of oncogene-related sequences in amphibian genomes was examined by means of Southern hybridization. Our studies show presence of these sequences in urodele and anura amphibia. In addition, it seems that copies of some cross-hybridized sequences were increased in species with more DNA per haploid nucleus. This provides evidence that the higher complexity of genomes in some amphibians does correlate with duplication of structural genes. PMID- 21607454 TI - The value of the lysosomal protease cathepsin-d in egyptian bladder-cancer. AB - Cathepsin D was measured in cytosols of 60 malignant bladder specimens and normal tissue from the same bladder at safety margin 5 cm of the tumor. Significant elevation in cathepsin D level (50 +/- 3.5 pmol/mg protein) in bladder carcinoma compared to normal tissue (12.7 +/- 1.58 pmol/mg protein) was found. At 100% specificity, cathepsin D sensitivity was 78%. The positivity rate of cathepsin D increased in the presence of lymph node metastasis. The higher concentration of cathepsin D in malignant bladder tissue vs. normal tissue and its correlation with lymph node metastasis could reflect its importance as a marker of metastatic potentiality of primary bladder cancer. PMID- 21607455 TI - Influence of inflammatory reaction in primary fallopian-tube carcinoma (stage-I and stage-ii). AB - A retrospective evaluation of 68 Fallopian tube carcinomas (FTC) of a period of ten years (1980-1990) in stage I and II was performed. The aim of this study was to evaluate the prognostic impact of various factors. 68 cases were investigated for the prognostic influence of mitotic activity, degree of nuclear anaplasia and inflammatory reaction. Histological grading (p=0.08), and inflammatory reaction (p=0.003) showed to have a prognostic impact for survival in univariate analysis. Whereas, mitotic activity did not show any statistically significant influence. 47 (69%) tissue samples showed a positive inflammatory reaction which correlated with a significantly better outcome compared with tumors without this feature. However, this influence was proved in multivariate analysis for inflammatory reaction only (p=0.01). Although no data on the influence of the inflammatory reaction on prognosis in FTC has been published up to now, we can state that the determination of this factor can be useful for prognosis in this rare but highly aggressive tumor. PMID- 21607456 TI - Chloramphenicol and actinomycin-d-induced modifications in the carcinogen metabolizing capacities of mouse-liver microsomes. AB - The effect of antibiotics chloramphenicol (CML) and actinomycin-D (AMD) on the modification of the carcinogen metabolizing capacity was studied in vivo in mouse liver microsomes at different durations of treatment, for one day and three and six consecutive days. Following the administration of CML, a significant increase was observed in the activity of the low and high substrate levels of the hepatic microsomal N-nitrosodimethylamine demethylases (NDMAd I and II, respectively). On the contrary, AMD reduced the activity of NDMAd I and II in a time-dependent manner up to 3 days of treatment while no effect was observed when the drug was administered for 6 consecutive days. No effect was observed in the activity of the arylhydrocarbon (benzo(alpha)pyrene) hydroxylase either at the single or the repeated doses of CML only for 6 days of treatment with AMD. The expression of the hepatic content of cytochrome P450 revealed a significant induction at the various treatment intervals with CML. AMD, however, reduced the cytochrome P450 at 1 and 6 days treatment with induction at 3 days of repeated treatment. PMID- 21607457 TI - Topological and quantitative-analyses of early events in tumor-formation using histochemically-tagged transformed 3t3 cells. AB - Human EJ H-ras or c-sis oncogene-transformed Balb/c 3T3 cells were investigated to discern the oncogene dependence of earliest events of primary tumor development by utilizing bacterial lacZ or human alkaline phosphatase histochemical marker genes. The locations and morphologies of transformed or untransformed Balb/c 3T3 cells, also transfected with either marker gene, were monitored in situ by visual, histochemical staining of skin after subcutaneous injection. Cell numbers remaining in the subcutaneous space were quantitated through newly-developed assays maximizing enzymatic detection of the transfected marker gene-encoded enzymes using luminescent substrates. Either oncogene was effective at facilitating cell establishment within the subcutaneous space while parental 3T3 cells were cleared efficiently. Quantitation by enzymatic assays revealed that the rates of cell loss and establishment differed for the two transformants. Ras-transformed cells exhibited a spindled-shaped morphology within the subcutis. In contrast, sis-transformed cells established a dichotomous morphology, with one subpopulation spreading modestly and another remaining rounded. 3T3 cells which established transiently became well-spread in a manner reminiscent of cells in culture. In conclusion, ras and sis oncogenes aid the parental 3T3 cells to overcome the clearance mechanisms at the subcutaneous injection site and modify 3T3 cell morphology as visualized in situ. PMID- 21607458 TI - Disseminated intravascular coagulation in a man with metachronous bone metastasis from gastric-cancer - case-report. AB - We report on a case of multiple bone metastasis and disseminated intravascular coagulation (DIG) in a 49-year-old Japanese man. He underwent total gastrectomy for advanced gastric cancer in July 1992, He was diagnosed as a case of multiple bone metastasis in August 1993. Severe anemia, thrombocytopenia, and elevated fibrinogen degradative products were indicative of DIG. He was treated with sequential i.v. administration of methotrexate (MTX) and 5-fluorouracil (5-FU) and continuous i.v. infusion of heparin and gabexate mesilate. After two weeks of treatment with MTX combined with 5-FU, the findings of DIC disappeared and his general condition improved dramatically. PMID- 21607459 TI - Involvement of 22q13.3 in chromosomal-anomalies. AB - In a series of neoplasms involvement of chromosome 22, mainly concerning loci within bands 22q11-q12 has been reported. Yet, little is known about chromosomal anomalies in 22q13. As loss of heterozygosity in two neurofibromatosis type 2 patients was described in a 22q13.3 locus and deletions in the 22q13.3 chromosomal region were noted in a set of 7 patients, we decided to apply several newly isolated cosmids from 22q13 to analyse additional cases with chromosome 22 anomalies. In addition, the study was aided by centromeric probes and chromosome 22 painting. Fluorescent in situ hybridization with new cosmids mapping to 22q13.1 and 22q13.3 did not indicate deletions or rearrangements in one neurofibromatosis type 2 case [r(22)], a bisatellited chromosome 22 and in a translocation case [t(Y;22)]. PMID- 21607460 TI - P53 expression in human small-intestinal tumors. AB - Expression of the tumor supressor gene product p53 in thirteen human small intestinal tumors was examined employing an immunohistochemical technique. The level of p53 was analysed using the monoclonal antibody pAb240. Six out of thirteen tumors (46%) including one lymphoma, one angiosarcoma of the jejunum, one leiomyosarcoma, one adenocarcinoma of the small intestine and two metastatic adenocarcinomas of the colon were found to have p53 overexpression. This is the first demonstration of p53 expression in small intestinal tumors. These results indicate that the p53 gene may be involved in the pathogenesis of small intestinal tumors. PMID- 21607461 TI - Inducible h-ras gene-expression controlled by an allosterically regulated transactivator. AB - Inducible promoters have been employed widely to control the transcription of specific genes and thus to elucidate their role. We constructed a plasmid in which three lac operator sequences and the SV40 early promoter were placed upstream of the T24 H-ras1 gene. This plasmid was co-introduced in rat fibroblasts with a plasmid coding for a fusion protein containing the DNA binding domain of the lac repressor protein and the transactivation domain VP16 from HSV1. In the clones derived from this co-transfection, the transcription of the exogenous H-ras1 gene is dependent on the interaction between the transactivator protein and the lac operators. Given that this interaction is inhibited by IPTG, such a cell line overexpresses the H-ras gene encoded protein ras p21 and the addition of isopropyl beta-D-thiogalactopyranoside (IPTG) into the culture medium diminishes overexpression. The decrease of ms expression levels after the addition of IPTG was confirmed by Western blot analysis and by quantitative Reverse Transcription PCR based on comparison of amplification levels between the target cellular H-ras1 gene transcript and an in vitro produced deletion mutant H ras reference transcript. PMID- 21607462 TI - Suppressed autophosphorylation and tyrosine kinase-activity in revertant cell lines expressing rat Neu oncogene. AB - The revertants of neu oncogene-transformed cell lines, neu-R1 and neu-R2, have been shown previously to be phenotypically and morphologically nontransformed, yet both expressed the rat neu oncogene. In both cell lines the rat neu lacked significant tyrosine phosphorylation. We show that the intrinsic tyrosine kinase activity of neu-encoded p185 protein of both revertants was suppressed as well, and the p185 neu protein contained extracellular conformational changes that may inhibit receptor activity. Five other revertant cell lines that lost neu upon reversion were transfected with a rat neu oncogenic construct. They remained nontransforned but expressed the oncogene. Like neu-R1 and neu-R2, the transfectants expressed p185 that lacked receptor tyrosine phosphorylation. The inability of neu to induce transformation in these cell lines may be through a common mechanism that suppresses receptor autophosphorylation and tyrosine kinase activity. PMID- 21607463 TI - Effects of ethanol on the DNA-damage induced by 2 carcinogenic nitrosamines. AB - We studied the DNA single-strand breaks (DNA SSBs) induced by two nitrosamines using rat hepatocytelin situ nick translation assay. In the hepatocytes treated with 20 mu M of N-nitrosodimethylamine (NDMA), 100 mM ethanol enhanced DNA SSBs 3 times higher than those of control. However, there was no significant difference between the DNA SSBs with and without ethanol in 300 mu M of N nitrosodiethylamine (NDEA) treated groups. Pretreatment of 100 mM ethanol increased P450IIE1 levels determined by Western blotting, whereas the amount of total P450 was not affected. Although NDMA is possibly activated by P450IIE1, there could be other isozymes responsible for the activation of NDEA. Phenobarbital inducible isozymes such as P450IIB1 and IIB2, or P450IIA3 may be primarily responsible. PMID- 21607464 TI - Levels of messenger-RNA coding for DNA topoisomerase-ii isoforms do not correlate with in-vitro drug-sensitivity. AB - The relationship between cellular levels of mRNA coding for DNA topoisomerase II, both the alpha and beta isoforms, and in vitro sensitivity to anticancer drugs were evaluated. Using a sensitive RNA-polymerase chain reaction technique, the levels of mRNA coding for the alpha and beta isoforms of topoisomerase II were estimated relative to beta-actin mRNA. A relatively narrow range of expression was observed across a broad range of approximately 60 human tumor cell lines representing eight major histological types which have been characterized in detail with respect to their in vitro sensitivity to standard anticancer drugs. No significant correlations were observed between mRNA level and cellular response to drugs thought to inhibit topoisomerase II or any of the other drugs studied. These results suggest that predictive tests for response to topoisomerase II-related drugs can not be based on estimation of levels of mRNA. PMID- 21607465 TI - In-vivo stimulation of cell-proliferation of 2 human tumor xenograft lines by granulocyte-macrophage colony-stimulating factor (gm-csf). AB - In the present work the effect of a colony stimulating factor (CSFs), i.e. recombinant human granulocyte-macrophage colony stimulating factor (rhGMCSF), on tumor cell proliferation of a human renal cell carcinoma (RCC) and a squamous cell carcinoma (SCC) xenotransplanted into nude mice was studied. The measurement of the H-3-thymidine labeling index and the mitotic index of the tumor cells of both tumor lines as a function of the GM-CSF dose (0.05-1.00 mu g/g body weight) showed that the cell proliferation in both tumor types increases at low doses (p<0.05). Furthermore, the course of the dose dependent stimulation of cell proliferation is somewhat different for each tumor line. This possible growth stimulating effect of the rhGM-CSF found in the present work for both xenotransplanted tumor types should be considered, when this substance is applied within therapeutic regimens. Intertumoral differences should also be regarded. PMID- 21607466 TI - Hyperfibrotic myelodysplasia - a possible new entity (review). AB - Fibrosis of the bone marrow may be present in various hematologic diseases such as myeloproliferative diseases (MPD) and acute myeloid leukemias (AML). In primary myelodysplastic syndromes (MDS) myelofibrosis is a relatively rare event. Patients affected by MDS with myelofibrosis (H-MDS) present intriguing features that give rise to the hypothesis that H-MDS might represent a new entity. The purpose of this concise review is to summarize the contrasting opinions of the authors who have described some series of H-MDS patients. Many characteristics induce one to distinguish H-MDS from classical MDS, so that the former has been considered each time as a transitional stage between MDS and MPD, an acute transformation of an MPD, or an AML from the beginning. The pathogenetic mechanism of the fibrosis of the bone marrow may be similar to sic sic of the MPD in which a stimulus to secrete reticuline or collagen derives from abnormal marrow megakaryocytes. Importance of karyotype abnormalities are discussed. Clinical features of the syndrome are rather heterogeneous; evaluation of the survival of the described single cases reveals that mean survival is not significantly different from classical MDS. Finally, trephine biopsy and the cytogenetic study are necessary to permit the diagnosis of H-MDS. However, because of the relatively low number of cases, series of patients are necessary to correctly classify this syndrome. PMID- 21607467 TI - Anaplastic thyroid-carcinoma - a retrospective clinical and immunohistochemical study. AB - We reviewed 34 patients with histologically proven anaplastic thyroid carcinoma, representing 3.1% of all thyroid carcinomas treated from 1970 to 1992 in our Institution. Mean age at diagnosis was 63.1+/-10.3 years. Initial treatment consisted of near total thyroidectomy in 14 patients, partial thyroidectomy in 6 and no more than a biopsy in 14. After surgery 11 patients received external radiotherapy associated with chemotherapy (R+C), 8 patients had only chemotherapy (C), and 11 patients had only radiotherapy (R). Two patients, both in the group treated with R+C, are still alive, with a survival from the diagnosis of 23 and 26 months, respectively. Mean survival of the group treated with R+C (16.1+/-8.2 months) was significantly higher than that of patients treated only with C (6.2+/ 4.4 months; p<0.01) or only with R (5.1+/-2.6 months; p<0.0004). In the group treated with R+C, patients submitted to near total or partial thyroidectomy had a mean survival of 15.0+/-8.8 months, similar to that of patients who had only a biopsy (17.2+/-7.9 months), suggesting that the outcome was affected by post surgical therapy rather than by surgery per se. Twenty-two tumors were also assayed by immunohistochemistry for p53 and PCNA expression. p53 was expressed in 16/22 (72.2%) cases, with no correlation with sex, age, presence of differentiated component or survival. Comparing tumors with <30% or >30% p53 positive cells a tendency to longer (but not significant) survival was found in tumors with lower p53 expression. PCNA was expressed in all cases, with a percentage of positive cells ranging from 15% to 90%, and was not correlated with sex, age, differentiation, or survival. A positive correlation was found between PCNA and p53 expression (r=0.58; p=0.0039). In conclusion, our data indicate that in anaplastic thyroid carcinoma the use of combined R+C has some advantages with respect to single therapy. As in other aggressive malignancies; p53 and PCNA expression is increased irrespective of the response to therapy or the outcome. PMID- 21607468 TI - The role of p-glycoprotein, glutathione-s-transferase-pi, thymidylate synthase and metallothionein in the expression of differential sensitivities to antitumor agents in human tumor xenografts. AB - Expression of P-glycoprotein (P-gp), glutathione S-transferase-pi (GST-pi), thymidylate synthase (TS) and metallothionein (MT) was studied in a series of different human tumors growing in nude mice and expressing a range of in vivo sensitivities to certain antitumor agents. Quantitative relationships between resistance parameters and sensitivities to seven clinically used antitumor drugs in vivo, as judged by specific growth delay, were determined by Wilcoxon test. A positive relationship was identified between expression of GST-pi and TS and sensitivities to cyclophosphamide, doxorubicin, and 5-fluorouracil. No relationship was noted between MT expression and P-gp expression and any of these drug sensitivities in this series of tumors. PMID- 21607469 TI - The alpha-anomers and Beta-anomers of 1-o-hexadecyl-2-o-methyl-3-s-thioglucosyl sn-glycerol inhibit the proliferation of epithelial cancer cell-lines. AB - Previous studies have shown that the alpha anomer of 1-O-hexadecyl-2-O-methyl-3-S (D-1'-thioglucopyranosyl-sn-glycerol) inhibits the proliferation of leukaemic cell lines while the beta anomer was without any effect. In the present study both the alpha and beta anomers inhibited the proliferation of MCF-7, A427, A549 and T84 cells in a dose dependent manner. These results suggest that the mechanism of action of the ether thioglycolipids in epithelial and leukemic cells may be different. Our studies also revealed that A549, which was the most resilient of the four cell lines to the inhibitory effects of 1-O-alkyl-2-O methyl-glycerophosphocholine (ET18-OCH3), was the most susceptible to the effects of the ether thioglycolipids. Hence the mechanisms of action of the thioglycolipids appear to be distinct from those of ET18-OCH3. The above ether linked thioglycolipids may therefore be prototypes of a new class of antitumour ether lipids. PMID- 21607470 TI - Combined treatment of radiofrequency capacitive hyperthermia for urological malignancies. AB - During the period from April 1984 to July 1993, we investigated the clinical efficacy of local hyperthermia used to treat 110 patients with urological malignancies. We investigated the long-term outcome of 40 (36.4%) responders who exhibited an immediate, partial or better response to the therapy. The one-year survival rate was 75% for retroperitoneal tumor, 65% for bladder cancer, 33% for each of renal cell carcinoma and prostatic cancer and 29% for renal pelvic and ureteral cancer. The 5-year survival rate was 48% for bladder cancer, 29% for renal pelvic and ureteral cancer, 25% for retroperitoneal tumor, and 0% for renal cell carcinoma and prostatic cancer. Subsidence of intolerable pain caused by cancer invasion was achieved in 29 of 42 patients (69.0%), indicating an improvement in patient's quality of life through pain relief. PMID- 21607471 TI - Elevation of interleukin-2 production in peripheral-blood lymphocytes by recombinant human granulocyte-colony-stimulating factor in ovarian-cancer patients during combination chemotherapy. AB - Interleukin-2 (IL-2) production and peripheral blood lymphocyte (PBL) subsets were measured in ovarian cancer patients who received cis-platinum based chemotherapy with or without recombinant human granulocyte colony stimulating factor (rhG-CSF). Additional treatment with rhC-CSF resulted in significant elevation of IL-2 production and highly differentiated natural killer (NK) cell counts, indicating that rhG-CSF may be helpful for enhancement of the cellular immunity in ovarian cancer patients. PMID- 21607472 TI - Medullary-thyroid carcinoma - clinical-evaluation of 19 cases. AB - Medullary thyroid carcinoma (MTC) accounts for 5-10% of thyroid malignancies and occurs either as a sporadic or as a familial form. The familial form is inherited in an autosomal dominant pattern, and it is clinically expressed as multiple endocrine neoplasia (MEN), types IIa and IIb or as familial MTC alone. It is possible to make an early diagnosis in patients who have the familial form of the disease as well as to perform an organ specific localisation regarding possible spread of the disease. Calcitonin is a major product of MTC cells and represent the most used tumour marker for diagnosis and evaluation of prognosis. The purpose of this investigation is to analyse our experience with patients treated for MTC in the period 1980-1993. PMID- 21607473 TI - Intradermal transplantation of hepatoma-cells in Guinea-pigs - a model of early cancer. AB - Small numbers of hepatoma cells were transplanted intradermally in the flanks of strain-2 guinea pigs to study the course of growth when the size of the transplant was comparable to an early stage of spontaneous cancer. The incidence of positive transplants and the time for the appearance of the tumor were related to the number of cells transplanted. When 40,000 or 80,000 cells were transplanted, tumor developed at 98-100% of the sites, but only 60% of the sites that received 5,000 cells developed tumors. When 40,000 or 80,000 cells were injected, a measurable tumor appeared within 10 to 12 days, whereas when 20,000 cells were injected, 20 days were required. The size of the tumor was determined by measuring the average diameter, (length + width)/2, of the tumor. The growth rate of the developed tumor is independent of the number of cells transplanted. The initial growth rate of the tumors was 0.32 mm/day. When the diameter of the tumor was between 14 and 20 mm, the growth rate decreased to 0.26 mm/day; and regression began when the tumor diameter reached 20 mm. PMID- 21607474 TI - Increase of endo-peptidases and exo-peptidases in thyroid-tumors. AB - Production of proteolytic enzymes is important for the invasive properties of malignant tumours. In this series of 43 cases of various non-neoplastic and neoplastic thyroid lesions, the activity of dipeptidyl peptidase I and dipeptidyl peptidase IV was increased in papillary carcinomas. In addition, cathepsin B and cathepsin L were markedly elevated in 2 of 3 follicular carcinomas, and tryptase, which is a marker of mast cells, was also significantly elevated in follicular carcinomas. Our results indicate that proteolytic proteins are important in thyroid carcinomas, and in addition there seem to be some differences between papillary and follicular tumours. Larger studies are needed to confirm these findings. PMID- 21607475 TI - A phase-ii trial of neoadjuvant chemotherapy and concomitant chemoradiotherapy for the treatment of locally advanced nonsmall cell lung-cancer. AB - Treatment strategies for locally advanced nonsmall cell lung cancer have failed to significantly alter the survival of most patients. Treatment strategies utilizing, neoadjuvant chemotherapy and concurrent chemotherapy/radiation therapy have shown promise in some reports. Twenty-six consecutive patients with stage III, non-small cell lung cancer were treated over a 3 year period according to a strategy involving neoadjuvant chemotherapy (mitomycin, vinblastine, cisplatin [MVP]) followed by reassessment for surgical resection, followed by treatment with concomitant radiation therapy and chemotherapy (hydroxyurea [HU], 5 fluorouracil [5-FU]). Staging revealed stage IIIa disease in 15 patients and stage IIIb disease in 11 patients. Nine of 18 evaluable patients responded to MVP (50%) with 1 CR and 8 PRs. Only one of nine responders underwent surgical resection. Eleven of 19 patients receiving concomitant 5-FU, HU, and radiation therapy were evaluable for response. Two of 11 patients were converted to clinical CRs, and the remaining 9 patients had stable disease. Myelosuppression, mucositis and hand-foot syndrome were observed with 5-FU/HU/RT. Median survival for all patients is 10.5 months. One and 2-year survival is estimated at 36% and 27%, respectively. This clinical trial combining neoadjuvant chemotherapy with concurrent chemotherapy/radiation therapy is feasible. Select patients appeared to have a survival benefit however most patients failed to derive an improvement in clinical endpoints. PMID- 21607476 TI - Differential phorbol ester growth modulation and protein-kinase-C isoenzyme expression in rat hepatoma-cells vs non neoplastic rat hepatocytes. AB - In the present study the expression of protein kinase C (PKC) isoenzymes and the growth modulation caused by phorbol esters were studied in two rat hepatic cell lines: the neoplastic MH1C1 hepatoma and the syngeneic immortalized non neoplastic BRL3A cell line. Western blot analysis revealed that MH1C1 rat hepatoma cells express the a isoenzyme as the only isoform of PKC, whereas BRL3A cells showed immunoreactivity for alpha, delta and epsilon PKC. Immunoblot analysis showed that in both cell lines phorbol 12-myristate 13-acetate (PMA) caused a persistent, marked down-regulation of all expressed PKC isoenzymes. In MH1C1 cells, PMA also induced a reversible, marked dose-dependent growth inhibition, whereas a minimal impairment of cell proliferation was observed in BRL cells. The observed selective mitoinhibitory effect of PMA on tumor cells indicates PKC as an interesting target for innovative antiproliferative strategies based on the modulation of specific isoenzymes. PMID- 21607477 TI - Alterations of microsatellite repeats in bladder-cancer. AB - Investigation of the genomic instability of microsatellite repeats indicates a new mechanism for human carcinogenesis. This study was conducted to determine whether such alterations in microsatellite repeats are associated with the onset of bladder cancer. Thirty-two primary bladder cancer DNA samples were examined for genomic instability at (CA)n repeats on human chromosomes 5q (D5S107), 17p (D17S261) and 18q (DCC) by polymerase chain reaction (PCR) assay. Differences in unrelated microsatellites for tumor and normal DNA were detected in 6 of the 32 (18.8%) tumors examined. These six tumors were beyond grade 2 and stage pT2 invasive bladder tumors. However, only one of 32 (3.1%) showed alterations with more than 2 microsatellite probes. It follows that alterations of (CA)n microsatellite instability may be infrequent in the tumorigenesis of bladder cancer. PMID- 21607478 TI - Long-term survival after right nephrectomy, caval prosthesis and failed left renal-vein reconstruction, in managing an enormous retroperitoneal tumor. AB - The left renal vein is endowed with a rich network of collaterals, therefore distal division does not jeopardize global renal function and this is true under particularly favourable conditions, even if the right kidney is missing. A woman presented with an enormous retroperitoneal liposarcoma and a carcinoma of the breast. She underwent a radical mastectomy and the resection of a 13 kg retroperitoneal tumor which required a right nephrectomy, segmental resection of the involved vena cava and reconstruction with a prosthesis joined to the left renal vein by a bovine carotid graft. This graft thrombosed shortly after surgery, without causing apparent damage to the residual kidney. The patient died 77 months after the operation, from diffuse recurrences of the breast cancer while renal function was never impaired. The left renal vein may be interrupted distally for many pathologies and then reconstructed or ligated definitively without renal function failure, even in monorenal patients if collaterals are well developed. PMID- 21607479 TI - The novel regulation system of plasma unbound estradiol concentration in normal premenopausal women. AB - SHBG titer (maximum binding capacity of sex hormone binding globulin for 17 beta estradiol), percentage of plasma unbound estradiol, plasma unbound estradiol concentration, plasma total estradiol concentration and total testosterone concentrations were determined in ten normal premenopausal women to study the regulation mechanism of plasma unbound estradiol concentration and the physiological role of SHBG in the mechanism. The percent of unbound estradion was 1.48+/-0.37 (mean+/-standard deviation). The unbound estradiol concentration was 1.24+/-0.74 pg/ml. The total estradiol and testosterone concentrations were 84+/ 50 pg/ml and 0.8+/-0.09 ng/ml. SHBG titer was 42+/-15 pmol/ml. SHBG-testosterone ratio was 51+/-11.9. There was a significantly positive correlation between total estradiol concentration and unbound estradiol concentration (r=0.95, p<0.005, y=64X+4.6). A positive correlation between unbound estradiol and bound estradiol concentration (r=0.94, p<0.005, y=0.08+0.014X) was also observed. On the other hand, there was a significant inverse relationship between unbound estradiol concentration and SHBG-testosterone ratio (r=-0.88, p<0.005, y=78-23X). These data indicate that total estradiol and testosterone and SHBG-testosterone ratio play an important role in the regulation system of unbound estradiol. PMID- 21607480 TI - Alterations of the in-vivo growth-pattern of xenotransplanted human-malignant melanomas after suramin treatment in nude-mice. AB - The effect of suramin on the in vivo growth of 4 human malignant melanoma xenotransplantation lines in nude mice was studies. The drug (multiple i.p. injections of 80 mg/kg) was well tolerated by the animals, however, no tumor regressions were seen. All 8 different sets of tumor growth data (4 treated and 4 control groups of 8 tumor-bearing animals each) fitted well to the Gompertz difference equation, which enables to precisely analyse the pattern of tumor growth. The results show that suramin treatment leads to a statistically significant inhibition of the intrinsic growth rate of all tumors and also a simultaneous partial inhibition of the growth deceleration rate in three of the 4 tumor lines. As result of this complex alteration the growth of most melanoma lines presently studied is ultimately stimulated by suramin treatment in vivo. However, one recently established line is an exception: in this tumor suramin did not significantly affect growth retardation and thus, led to an overall growth inhibition. One possible interpretation might be, that suramin simultaneously inhibits both the positive and the negative growth regulatory mechanisms of the tumors to different degrees leading to a new balance between them, which is expressed in a different growth pattern. PMID- 21607481 TI - Oncogenes and tumor-suppressor genes - 2 different looks of the same gene. AB - Dominant oncogenes and recessive tumor suppressor genes are widely implicated in the pathogenesis of human neoplasia. Several recent experimental findings suggested that an oncogene and a tumor suppressor gene can share a similar ontogeny from the parental normal 'in vivo' gene. At least three mechanisms have been demonstrated to be responsible for this ambivalent expression: the mutations located in different regions of the gene, transcriptional and post transcriptional events (especially alternative splicing) and cell- and/or time dependent control of gene expression. There are also evolutionary explanations for the existence of such genes with ambivalent expression. PMID- 21607482 TI - Cancer-patients - the survival and expense of traditional care and hospice care. AB - Hospice care is a reasonable treatment strategy for those cancer patients whose disease process is no longer responsive to standard treatment regimens or who are unable to tolerate the adverse side effects of continued aggressive therapy. A 1:1 matched case-control study design that designated those patients selecting the hospice model of care as controls and those receiving acute care as cases was utilized. Data was abstracted from medical records and financial billing statements. The difference between total hospital charges plus hospice charges during the last 6 months of life for the hospice patients ($35,625) compared to the non-hospice patients ($50,152) was statistically significant. The hospice model of care may be a less costly option for those cancer patients where palliation is the objective. PMID- 21607483 TI - Variability of serum tumor-associated antigens and their significance in cancer diagnosis (review). AB - The significance of serum tumor markers in the diagnosis of several of the most widespread types of cancer (lung, gastric, colorectal, breast, endometrial and ovarian) has been reviewed. The high heterogeneity of obtained results demonstrated in this review suggests that none of the present markers can be utilized alone as a significant marker of neoplasia and that only their combined use can give objective information. The role of individual variability of various markers in the detection of different stages of neoplastic transformations has also been revised. It was concluded that none of the markers studied can be absolutely positive without false results, and that objective information regarding early stages of malignancy may be obtained only with a combined analysis utilizing many laboratory methods. A new approach should be developed in oncological diagnostic practice. PMID- 21607484 TI - Molecular-genetic mechanisms underlying oral oncogenesis (review). AB - The exceptionally high incidence of oral cancer in India poses a major health problem. Despite advancement in various treatment modalities, prognosis for many of the oral cancer patients is grave, mainly because of late diagnosis. Even though several etiological agents have been associated with oral cancer, the molecular mechanisms underlying oral oncogenesis is still an enigma. Oral carcinogenesis is considered to be a multi-hit process which involves a number of aberrant genetic events culminating in malignant transformation. Aberrations of two major classes of genes oncogene and tumour suppressor genes - are presumed to be involved in the genesis and progression of oral cancer. The molecular evidence relating to these genes is reviewed. PMID- 21607485 TI - Establishment and characterization of a hepatoblastoma cell-line from a patient with secondary acute myeloid-leukemia. AB - A girl who had been treated, apparently successfully, with surgery and chemotherapy for a hepatoblastoma, fell ill two years later with what was diagnosed as an AMF M(4). A cell line was established from her peripheral blood. This cell line had epithelial morphology and grew both in suspension culture and as a monolayer. The cells were positive for epithelial surface markers, including the liver-specific alpha-fetoprotein, but not for leukocyte markers. The cell line's karyotype was markedly abnormal. It did not have any specific aneuploidies or any other aberrations characteristic of leukemias; instead it had gains of 2q and chromosome 20, the most common cytogenetic changes in hepatoblastoma. It is most likely that the patient had a relapse of hepatoblastoma with massive seeding of the blood leading to a leukemia-like picture without, of course, excluding other possibilities. PMID- 21607486 TI - O-6-alkylguanine-DNA alkyltransferase activity in tissues of mice treated with antischistosomal agents. AB - The activity of O-6-alkylguanine-DNA alkyl transferase (ATase), the enzyme responsible for repairing promutagenic methylation damage in DNA, was measured at various time intervals in tissue extracts of mice administered (in vivo) a single therapeutic dose of the antischistosomal agents hycanthone, oxaminiquine and metrifonate. In control animals, liver contained the highest levels of ATase activity (15.8+/-1.8 fmole ATase/mu g DNA) followed by spleen (11.0+/-1.7 fmole/mu g DNA), intestine (2.3+/-0.3 fmole/mu g DNA) and bladder (0.22+/-0.04 fmole/mu g DNA). With hycanthone, ATase activity was reduced by 6 and 24 h post treatment to 74% and 27% below the control value, respectively. Bladder exhibited a 25% inactivation in the ATase level at 6 h time point. Spleen and bladder did not show any alteration in the ATase activity. In animals administered oxaminiquine, liver and bladder had a near identical pattern to that observed for hycanthone. Spleen and intestine, however, revealed activation in ATase by 50% and 42%, respectively after 6 h of treatment. This activation was also observed in the bladder of metrifonate-treated mice. In a previous study (Badawi et al, Cancer Lett 75: 167, 1993), DNA-alkylation damage (O-6-methyldeoxyguanosine; O-6 MedG) was evaluated in these tissues and there was an inverse correlation between the levels of methylation damage and ATase activity in liver (r=-0.85, p<0.01), intestine (r=-0.62, p<0.01) and bladder (r=-0.59, p<0.05). PMID- 21607487 TI - Influence of surgical insults for colorectal cancers on neuroendocrine and immune parameters. AB - In surgery for colorectal cancer, a tendency of immune suppression was noted as seen in surgery for other types of gastro-intestinal cancer. This tendency was also found in the biological response, and it was related to the operative procedures and insults for rectal cancer. The degree of immunosuppression was milder in patients who underwent procedures that preserve the natural sphincter than in those who underwent colostomy. It is important for surgeons to avoid postoperative immunosuppression in order to prevent recurrence and improve prognosis. Given similar degrees of operative insult and stage of cancer, an operative procedure which causes as little immunosuppression as possible should be selected. PMID- 21607488 TI - Prognostic-significance of multifocality in primary breast-cancer. AB - The impact of multicentricity in primary breast cancer on relapse or death after radical or modified radical mastectomy was evaluated in 1336 consecutive patients. Multiple tumor foci were found in 11.7% of breast cancers: in 8.4% multicentricity was infiltrating, while in 3.3% of cases an in situ growth pattern was observed. There was a statistically significant association between multicentric primaries and lobular infiltrating carcinoma, age less than or equal to 50 years, large tumors and metastatic axillary nodes, while no relationship was observed with histological grade. Both 5-year disease-free survival and overall survival were shorter in patients with infiltrating multicentric primary tumors. Multivariate analysis confirmed the prognostic role of infiltrating multicentric tumors after adjusting for nodal status, tumor size, age and adjuvant therapy. PMID- 21607489 TI - Significance of hepatitis-B and hepatitis-C viral sequences frequently detected in hepatocellular-carcinoma tissues. AB - Serum HBsAg or anti-HCV were identified in over 90% of hepatocellular carcinoma (HCC) patients in Japan with positive rates approximately 20% and 70%, respectively. In this study, we detected HBV DNA and HCV RNA sequences in tumor or non-tumor tissues obtained from 16 hepatectomized HCC cases, using the polymerase chain reaction (PCR) method for HBV x gene and reverse transcription (RT)-PCR for HCV RNA. Only 3 cases were positive of HBsAg in serum, however, HBV x gene could be detected in the tumor or non-tumor tissues of 13 cases among 16 HCC patients. In two cases, HBV x gene was detected exclusively in tumor or non tumor tissues. Whereas HCV RNA was detected in both tumor and non-tumor in 9 cases, which results coincided with the anti-HCV testing in sera. These results indicate that HBV x gene might be detected as the integrated form in the liver genomic DNA, while HCV RNA as viremia. The frequent detection of HBV DNA suggests that HBV may be associated with the development of HCC predominantly or cooperatively with HCV. PMID- 21607490 TI - High-concentration of epidermal growth-factor induces apoptosis in breast and esophageal cancer-cells transplanted into nude-mice. AB - We found that p53 tumor suppressor gene is the key gene that is involved in the signal transduction of the epidermal growth factor (EGF). In this study, we investigated apoptosis induced by high concentration of EGF and modulation of cell cycle progression by high concentration of EGF in breast and esophageal cancer cells transplanted into nude mice. In situ apoptosis detection was performed using Apop Tag(TM) in situ apoptosis detection kit peroxidase. DNA fragmentation analysis was also performed to detect apoptosis. Modulation of cell cycle progression was detected through PCNA immunostaining. Two mu g of EGF induced apoptosis in ES-4 esophageal cancer cells and MX-1 breast cancer cells after increased accumulation of p53 induced by 2 mu g of EGF. At the same time, there was negative PCNA immunostaining in these cells. On the other hand, using UM-1 breast cancer cells, we inhibited p53 expression by 2 mu g of TGF-beta 1 and detected apoptosis and PCNA immunostaining. We detected no apoptosis, however, strong positive PCNA immunostaining was detected in these cells. The evidence demonstrates that high concentration of EGF induces apoptosis in MX-1 human breast cancer and ES-4 human esophageal cancer transplanted into nude mice and indicates that there is a signal pathway of EGF that induces apoptosis. PMID- 21607491 TI - Malignant myoepithelioma of the breast - a case-history and review of literature. AB - A malignant myoepithelioma, mainly intraductally growing, of the breast was studied, emphasizing the immunohistological features of such tumors, in comparison with the more common, architecturally similar, infiltrating ductal carcinoma with intraductal component. Immunohistochemically, cell population of the tumor studied expressed intense reaction to alpha-SM-actin, cytokeratin 14, vimentin, S-100 protein and collagen IV antibodies, confirming myoepithelial differentiation. Since myoepitheliomas of the breast are very rare, complete knowledge of these neoplasms has not been attained. Nevertheless, histogenetic investigations may be useful in differentiating this type of tumor, from the above one, which is known to be characterized by severe clinical and prognostic implications. PMID- 21607492 TI - Amplification on chromosomes 1p31, 1q21-24, 5p13-14, and 11p12-14 in ovarian carcinoma detected by reverse chromosome painting. AB - Recently, amplifications of several genes including c-myc, HER-2/neu, and FGF-3 (int-2) have been identified in ovarian carcinomas. We analyzed Il tumor samples from ovarian carcinoma for gene amplification using reverse chromosome painting and standard Southern blot analysis. Reverse chromosome painting detected four amplified domains on chromosome bands 1p31, 1q21-24, 5p13-14, and 11p12-14. None of the amplified domains contained genes previously reported to be amplified in ovarian carcinomas. Southern blot analysis revealed amplifications of genes HER2/neu, N-ras and H-ras. Tumor T3711 showed three independent amplifications including chromosome bands 1p31, 11p12-14 and the HER-2/neu gene (17q11.2-12). PMID- 21607493 TI - Gastric-cancer associated with pregnancy - a case-report. AB - We treated a 27-year-old pregnant woman with Borrmann type IV gastric cancer and immunohistochemically detected micrometastasis of cancer cells in the bone marrow. Total gastrectomy combined with splenectomy was followed by postoperative chemotherapy. Despite intensive treatment, she died with tumor progression 6 months later. When malignant cells are present in the bone marrow, the prognosis is poor. The literature on gastric cancer associated pregnancy is reviewed. PMID- 21607494 TI - Induction of breast neoplasia and lung granulomas in mice by an antifungal drug (griseofulvin). AB - Infiltrating duct carcinomas were induced in the mammary glands of 7 out of 60 experimental female mice force-fed with the antifungal drug griseofulvin, at a daily dose lever of 0.3 mg/30g body weight, for 12 months. The first mammary gland tumor appeared 8 months after the initiation of feeding. Other pathological changes such as bronchocentric granulomas appeared in some male and female treated animals (16.5%). PMID- 21607495 TI - Immunohistochemical characteristics of breast-carcinoma in patients receiving neuroleptic therapy. AB - The immunohistochemical characteristics of 17 cases of breast carcinoma in patients treated with neuroleptics (prolactin-releasing drug) are reported. Sixteen of the patients were female and one was male. Sixteen tumors in thirteen patients were invasive ductal carcinoma, two tumors in two patients were lipid secreting carcinoma, one tumor was apocrine carcinoma, and two tumors in one patient were mucinous carcinoma. Elevated serum prolactin (Prl) levels (>15.0 ng/ml) were seen in all 7 patients whose preoperative serum prolactin levels had been determined. Immunohistochemical staining showed that 71% (15/21) of the carcinomas reacted positively for prolactin receptor (PrlR), while immunoreactive Prl was totally negative. Fourteen tumors were estrogen receptor (ER)-positive (67%; 14/21), and 12 were progesterone receptor (PgR)-positive (57%; 12/21). These results suggest that Prl secreted from the pituitary gland may interact with PrlR present on the cancer cells, but there was no evidence of de novo synthesis or uptake of Prl by cancer cells. ER and PgR status showed no characteristic immunoreactivity compared with unselected breast carcinoma patients not related to neuroleptic use. PMID- 21607496 TI - Scarff-bloom-richardson histoprognostic grading correlates with the immunohistochemical expressions of genomic alterations in infiltrating ductal carcinomas (nos) of the breast. AB - The Scarff-Bloom-Richardson (SBR) multiparametric histological grading has been correlated with the immunohistochemical expression of EGF-R, c-erbB-2 and p53 oncoproteins, with the growth fraction (Ki67 antibody) and with the receptor status (ER, PgR) in 365 infiltrating ductal carcinomas of the breast (IDC-NOS). Specimens of carcinomas after surgery were sectioned and a section of each lesion was formalin-fixed and paraffin-embedded, and stained by hematoxylin-eosin in order to classify and grade cases. Another section was liquid nitrogen frozen, cryostatcut and immunostained using monoclonal antibodies against EGF-R (455 and 528 clones), c-erbB-2 (3B5 clone), p53 (Pab 1801 clone) and Ki67 antigen. An ABC peroxidase was used after incubation with biotinylated antimouse antibody. Colour was developed using a DAB solution. ER-ICA and PgR-ICA Kits (Abbott) served to detect the hormonal receptor status. A significant direct correlation between SBR and the immuno-histochemical markers (EGF-R, c-erbB-2, p53, Ki67 growth fraction) was found. An inverse relationship of grade to ER and a weaker one to PgR was evident. An increasing histological grade was found parallel with the progressive appearance of one, two or three immunohistochemical markers in the same tumour. PMID- 21607497 TI - Different chemosensitivity of pre and postmenopausal breast-cancer cells. AB - In order to refine our adjuvant chemotherapy against locally advanced breast cancer, an anticancer drug sensitivity test, using the MTT assay was conducted with biopsy specimens of human breast cancer obtained prior to therapy. Dose dependent sensitivity was observed with all tested agents: cisplatinum, mitomycin C, methotrexate and doxorubicin. The sensitivity of the premenopausal specimens to the effects of mitomycin C and doxorubicin varied widely. When selecting chemotherapeutic agents to combat breast cancer, this variation in drug sensitivity based on menopausal status and patient age should be considered. PMID- 21607498 TI - Ttf1 gene-expression in human proliferating thyroid-diseases. AB - TTF1 mRNA expression in the thyroid gland from 30 patients with thyroid proliferating diseases and 4 healthy donors used as normal controls was investigated using Northern blot analysis. Six patients affected by malignant thyroid carcinomas and six patients with adenoma were examined; moreover 18 patients with non malignant proliferating disease such as multinodular goiters were investigated. Determination of TTF1 mRNA revealed a significant decrease of the steady state mRNA levels in carcinomas and adenomas as compared to normal tissues. On the contrary, in patients affected by multinodular goiters variations were observed that seemed not to be directly associated with the pathological conditions. PMID- 21607499 TI - Quinolone prophylaxis in neutropenic patients - efficacy versus resistance. AB - To assess the efficacy of quinolones in the prophylaxis of infections in neutropenic patients with acute non-lymphocytic leukemia, and to evaluate the emergence of quinolone resistance in two University Hospitals in Brazil, we retrospectively compared 101 consecutive episodes of neutropenia managed with quinolone prophylaxis between 1989 and November 1993, and 26 previous episodes without prophylaxis, and reviewed the results of in vitro sensitivity of Gram negative strains to quinolones in the same period. Prophylaxis with quinolones resulted in less episodes of bacteremias (21% vs. 69%, p=10(-7)), including Gram negative bacteremias (6% vs. 38%, p=10(-5)), with no statistically significant difference in the death rate (18% vs. 31%, p=0.14, 95% confidence interval -6 32). The resistance of Gramnegative strains to quinolones rose from 7% to 18% between 1990 and 1993 (p=10(-5)). The resistance against ceftazidime and amikacin, the agents used in the empirical antibiotic therapy, increased in the same proportion as the quinolones. Given the limited benefit of quinolones as prophylaxis and the increasing number of quinolone-resistant Gram-negative strains observed in our hospitals, the use of quinolones as prophylaxis must be seriously questioned. A stricter control of the use of quinolones in these hospitals might decrease resistance. PMID- 21607500 TI - Difference in the distribution of low-molecular-weight peptides and amino-acids in normal and malignant-cells and tissues. AB - The amount of low molecular weight amino acids and peptides measured in the form amino acids released by hydrolysis was found to be very low in malignant tissues and cell lines compared to normal tissues and cell lines. The ratios of acid soluble proteins to these low molecular weight compounds were statistically different in normal and malignant cells. The difference may reflect faster growth, greater membrane permeability or other aspects of the malignant process itself. PMID- 21607501 TI - Retrovirus-mediated gene-transfer of tnf receptor for treatment of cancer. AB - Tumor necrosis factor-alpha receptor cDNA (TNFR-1 or TNFR-2) was inserted into a retrovirus derived vector. Recombinant vector was transfected into packaging cell line. The transfectants producing high titer of virus containing TNFR-1 or TNFR-2 cDNA were obtained. Human stomach cancer cells that poorly expressed TNFR-1 or TNFR-2 were infected with this virus as an in vitro model experiment of gene therapy. The stomach cancer cells that were infected with recombinant virus expressed TNFR-1 or TNFR-2 and were effectively killed by recombinant TNF. PMID- 21607502 TI - Effects of delta(7)-prostaglandin a(1) methyl-ester on human ovarian-cancer cell growth in-vitro and in nude-mice. AB - The antitumor activities of Delta(7)-prostaglandin A(1) methyl ester (Delta(7) PGA(1)) and Delta(7)-PGA(1) emulsified in lecithin oil (lipo Delta(7)-PGA(1)) were studied in nude mice models with ascites or solid tumors formed by i.p. or s.c. inoculation of human ovarian cancer cells (HRA). Inhibitory effects of Delta(7)-PGA(1), on the HRA cell proliferation in vitro were about 3.8-fold higher than those of lipo Delta(7)-PGA(1). In the ascites tumor model, the median survival in a CDDP alone treated group among alone treated groups was longest and followed by a Delta(7)-PGA(1) alone treated group. A combination of CDDP and Delta(7)-PGA(1) resulted in a significant (p<0.05) prolongation of the median survival, compared to that in any alone treated group, while even when CDDP was combined with lipo Delta(7)-PGA(1) the survival was not improved, compared to that in a CDDP alone treated group. In addition, analyses of the survival curve revealed that a combination of CDDP with Delta(7)-PGA(1) resulted in higher survival rate than with lipo Delta(7)-PGA(1). On the other hand, in the s.c. tumor model lipo Delta(7)-PGA(1) (but not Delta(7)-PGA(1)) significantly (p<0.05) inhibited the tumor growth. When combining lipo Delta(7)-PGA(1) with CDDP, its inhibitory effect was further enhanced. Subsequently, the survival time in a lipo Delta(7)-PGA(1)+CDDP treated group was longest and 3 out of 9 mice survived more than 100 days. Taken together, we conclude that Delta(7)-PGA(1) might be suitable for local treatment in i.p, ascites tumors while lipo Delta(7)-PGA(1) is useful for remote treatment in s.c. solid tumors. PMID- 21607503 TI - Overexpression of C-erbb-2 protein in endometrial carcinoma is associated with advanced-stage disease. AB - Expression of the c-erbB-2 product (p185(c-erbB-2)) was examined in plasma membrane isolations from 14 uterine endometrial carcinomas and 3 normal endometrial tissues. Overexpression of p185(c-erbB-2) was found in 8 of 9 endometrial carcinomas of stages III and IV and in none of 5 early stage specimens, when compared with the level in normal endometrial tissues. The expression of p185(c-erbB-2) was independent of histological grade. When the p185(c-erbB-2) immunoprecipitated with anti-p185(c-erbB-2) antibodies was exposed to adenosine triphosphate, enhanced self-phosphorylation occurred more frequently in specimens from the tumors carrying p185(c-erbB-2) overexpression. These findings demonstrated positive correlation between disease spread, p185(c-erbB-2) expression and autophosphorylation of p185(c-erbB-2) in human endometrial carcinoma. The prognostic value of these observations awaits continued study. PMID- 21607504 TI - Medroxyprogesterone acetate (mpa) increases pai-1 secretion from huvec and elevates the plasma-levels of pai-I in-vivo. AB - Plasma levels of tissue type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in patients administered with medroxyprogesterone acetate (MPA) (800 mg/day) or tamoxifen (20 mg/day) were assayed. Active free PAI 1 levels of patients given MPA were significantly higher than those either given tamoxifen or post adjuvant therapy, t-PA antigen levels were not different among the three groups. In in vitro study, treatment of cultured human umbilical vein endothelial cells (HUVEC) with MPA (10(-6)-10(-8) M) decreased PAI-1 levels significantly with a trend to decrease in t-PA levels. PMID- 21607505 TI - Figo clinical stage IIb carcinoma of the uterine cervix and surgical staging. AB - Postsurgical precise correlation was examined in 48 patients with an invasive carcinoma of the cervix in International Federation of Gynecology and Obstetrics (FIGO) clinical stage IIb. Of the 48 cases, 18 cases were overestimated; in which inflammatory parametrial changes and endophytic tumor growth were seen. Six lesions clinically underestimated were associated with superficial invasion into the rectal or bladder muscle. Resultant precise correlation was available in the remainder (24 cases). PMID- 21607506 TI - A short-term infusion regimen of Cisplatin, 5-Fluorouracil and L-folinic Acid in advanced head and neck-carcinoma. AB - Treatment of advanced head and neck cancer is still a matter of controversy. Although current chemotherapy regimens are able to induce high response rates, they have not shown improved survival. We employed a combination of cisplatin (CDDP), 5-fluorouracil (5FU) and 1-folinic acid (1-FA) in a 6-hour infusion schedule easy to administer on an outpatient basis. 49 patients have been included to date. The treatment plan consists of 5-FU (375 mg/m(2)) plus 1-FA (100 mg/m(2)) in a 4-hour i.v. infusion followed by a 2-hour i.v. administration of CDDP (20 mg/m(2)). This therapy was repeated for five consecutive days and recycled every 3-4 weeks. Out of 46 evaluable patients there were 6 complete responses (CR) and 23 partial responses (PR) for an overall response rate of 63%. Overall survival was 10.2 months (mean). Untreated patients had a higher probability of response as well as patients with naso-oropharyngeal primary tumor. Toxicity was generally mild with leukopenia, anemia and vomiting being the most frequent side effects. In conclusion, this combination appears well tolerated and active in the palliation of advanced head and neck cancer. However we think that increasing dose intensity of standard regimens and experimental new therapeutic approaches are needed to improve the clinical outcome of this disease. PMID- 21607507 TI - Cancer chemoprevention by natural-products (review). AB - Cancer chemoprevention is based on a number of experimental and epidemiological evidence that our environment could contain not only carcinogenic compounds but also natural or synthetic substances able to inhibit or reverse the process of carcinogenesis. More than 600 potential chemopreventives have been identified and approximately 30 of them have been or are being tested in humans. These include naturally occurring substances present in human foods and synthetic chemicals. In this review natural products possessing chemopreventive potential are introduced with experimental evidence of their mechanisms of action, although other natural chemopreventives are under investigation with regard to their spectra of activity and their possible relevance to prophylaxis of human cancer. PMID- 21607508 TI - Prognostic factors in breast-cancer and their controversies (review). AB - The status of the axillary lymph nodes (AX) is widely accepted as the most significant prognostic factor in breast cancer. Nevertheless, there are large differences in the clinical outcomes of patients with the same AX status, which suggest that we should seek further prognostic variables. At present, several biologic factors, such as DNA ploidy, c-erbB-2 expression, EGFR, p53 alteration, and HPA staining, have been proposed. However, their value as prognostic indicators remains undetermined. Whether these factors are independent prognostic factors, or merely related to other variables, such as AX metastasis, is unclear. A clear need for a new biologic markers to serve as more reliable prognostic factors exists. PMID- 21607509 TI - Interferon-alpha-2b alone and combined with octreotide in primary carcinoid cell cultures. AB - Interferon and octreotide are two main therapeutic options in metastatic carcinoid disease. In primary cell cultures prepared from 26 previously untreated carcinoid patients interferon-alpha 2b (alpha-INF), alone and combined with octreotide, significantly reduced medium serotonin (5-HT). The amines were measured with reversed phase HPLC and electrochemical detection, total DNA with a photometric method. Interferon lowered the medium concentration of serotonin to 53% (range 42-79%), octreotide alone to 44% (range 23-48%). Neither interferon, octreotide nor the combined treatment decreased DNA content. Octreotide had no effect on intracellular 5-HT. Both interferon alone and combined with octreotide lowered intracellular 5-HT concentrations significantly. This may represent a direct biochemical effect of interferon on tryptophan metabolism. PMID- 21607510 TI - Arterial chemoembolization with epirubicin in unresectable hepatocellular carcinoma in cirrhosis. AB - No reliable therapy has yet been established for unresectable hepatocellular carcinoma (HCC). Encouraging data in terms of response rate and survival have been reported with intra-arterial chemotherapy combined with venooclusive materials, specifically ethiodized oil and gelatin sponge. To evaluate the activity and tolerance of a new chemoembolization protocol in cirrhotic patients with HCC, 22 patients were treated with epirubicin (50 mg) and ethiodized oil (10 15 ml), administered through hepatic arterial catheters, followed by gelatin sponge. Patient characteristics were: median age 70 years (range, 59-77); ECOG performance status 0-1 in 15 and 2 in 7 cases; Child's A disease in 11 and B in 11; TNM stage II in 9, stage III in 3 and stage IVA in 10 cases. Histologically documented cirrhosis was present in all cases. A total of 53 courses of therapy has been delivered. All patients were evaluable for response and toxicity. Three partial remissions (13%), 2 stabilizations of disease and 17 progressions have been observed. Median time to progression was 4 months, with a median survival of 7.6 months (range, 1-26+ months). Significant differences in survival (p = 0.001) have been observed between patients at stage II-III (21 months) and those at stage IVA (3 months), and between patients with Child's A disease (10 months) and Child's B disease (4 months) (p= 0.02). The treatment was well tolerated, with only 2 cases of WHO grade I pain and 2 cases of grade I fever. In conclusion, our results indicate that the schedule has only limited activity and does; not seem to offer any sure advantage over other treatments modalites in HCC. PMID- 21607511 TI - Proliferation and oxygenation status of widr spheroids in different lactate and oxygen environments. AB - Human colon adenocarcinoma cells WiDr were cultured as monolayers or multicellular spheroids in 5% or 20% (v/v) oxygen and in various external lactate concentrations of 0-20 mM. Doubling times and H-3-thymidine labeling indices of exponential monolayer cells indicated that there was no difference in growth behavior between the two oxygen environments, yet these parameters reflected a growth retardation upon elevation of lactate. Growth of WiDr spheroids was retarded in both low oxygen and high lactate concentrations. There was a tendency towards a decrease in the thickness of the viable cell rim with increasing lactate in 20% O-2, whereas the width of the viable rim increased significantly as a function of external lactate in 5% O-2. Intraspheroidal oxygen tensions (Po 2) measured with microelectrodes were less in 5% O-2 than in 20% O-2, yet did not vary systematically as a function of external lactate. Po-2 values in the spheroid center dropped to 0 mm Hg prior to the emergence of central necrosis under all conditions investigated. Unlike numerous other spheroid types investigated up to now, WiDr spheroids mimic tumor microregions with hypoxia induced necrosis and with nonproliferating cells at very low oxygen pressure. PMID- 21607512 TI - Primary tumor levels of interleukin-6 in relation to tumor burden in human breast cancer. AB - To examine whether tissue levels of interleukin 6 (IL-6) are associated with the clinicopathologic status in human breast cancer, immunoreactive IL-6 concentration was measured in tumor extracts of 75 breast cancer patients. IL-6 was detectable in 69 of 75 tumor extracts by enzyme-linked immunosorbent assay, the concentration ranging from 10 to 10.690 pg/mg protein. When breast cancer specimens were categorized into four groups in terms of clinical stage of disease at diagnosis, IL-6 concentration (mean +/- SE) in tissue extracts was significantly higher in stage IV patients (2859 +/- 840 pg/mg protein) than in stage I-III patients (344 +/- 117, 350 +/- 150 and 564 +/- 230 pg/mg protein, respectively). Correlation analyses between IL-6 concentration and clinicopathologic factors showed that tissue levels of IL-6 were significantly higher in patients with distant metastasis compared with those without. Furthermore, IL-6 concentration was significantly higher in tumors of more than 5.0 cm in size as compared to less than 5.0 cm. However, no significant association was found between IL-6 concentration and age, histological type, histological grade, lymph node involvement, or hormone receptor status. These results suggest that primary tumor levels of IL-6 are closely associated with clinical stage in human breast cancer. PMID- 21607513 TI - 3 cases of destructive facial granulocytic sarcoma in childhood - acute myeloid leukemia expressing lymphoid associated antigens. AB - Three children, two from the Middle East and one from Greece, presented to this clinic for treatment of malignant facial tumours destroying bone. In each case biopsy histology led to an initial diagnosis of 'lymphoma'. Further characterisation of the tumour cells by cytochemistry and immunophenotyping established diagnoses of acute myeloid leukaemia, with myeloblasts in all three cases expressing lymphoid associated cell surface antigens. The possibility of granulocytic sarcoma should be considered in the differential diagnosis of facial tumours showing 'lymphomatous' morphology. The prognostic significance of this presentation 'syndrome' is discussed. PMID- 21607514 TI - T24 h-ras gene-expression increases the activity of phosphoglycerate kinase, enolase and pyruvate-kinase and decreases the activity of adenosine-deaminase in fibroblast cells. AB - We examined the possible implication of ras in the regulation of the activity of several metabolic enzymes by employing an inducible H-ras expression system (RFLSVrasLAP cell line), in which the addition of IPTG decreases the levels of ras p21 3-fold. We measured the activity of hexokinase (E.C. 2.7.1.1.), glucose phosphate isomerase (E.C. 5.3.1.9), phospho-fructokinase (E.C. 2.7.1.11), aldolase (E.C. 4.1.2.13), phosphoglycerate kinase (E.C. 2.7.2.3), enolase (E.C. 4.2.1.11), pyruvate kinase (E.C. 2.7.1.40), lactate dehydrogenase (E.C. 1.1.1.27), adenosine deaminase (E.C. 3.5.4.4) and purine nucleoside phosphorylase (E.C. 2.4.2.1) from cells grown in the presence and absence of IPTG. We found that the addition of IPTG to RFLSVrasLAP cells led to lower activity of phosphoglycerate kinase (p=0.004), enolase (p=0.027) and pyruvate kinase (p=0.031). Enolase mRNA levels were found to be increased in cells overexpressing either the normal or mutant H-ras. The total rate of glycolysis was not affected by H-ras expression indicating that the implication of H-ras in the activity of phosphoglycerate kinase, enolase and pyruvate kinase may be associated with glycolysis-independent functions of these enzymes. Adenosine deaminase activity was found to increase after IPTG addition (P=0.009), indicating also a possible role for H-ras in the control of the purine nucleotide salvage pathway. PMID- 21607515 TI - Increase in the circulating level of hepatocyte growth-factor in breast-cancer patients with distant metastases. AB - Hepatocyte growth factor (HGF) is known to be a potent mitogen not only for hepatocytes but also for a variety of cell types including tumor cells and endothelial cells. However, still little is known about the circulating level of HGF in cancer patients. We measured the HGF level in sera in 61 breast cancer patients including 31 primary breast cancer patients and 30 recurrent breast cancer patients by an enzyme linked immunosorbent assay system. In 10 (32.3%) out of 31 primary breast cancer patients and in 25 (83.3%) out of 30 recurrent breast cancer patients, the circulating level of HGF was increased to over 0.4 ng/ml. In particular, the increase in the level of HGF was marked in patients with liver metastases (mean+/-SD: 1.286+/-0.557 ng/ml) compared to those with recurrence of other sites (mean+/-SD: 0.635+/-0.277 ng/ml). It was suggested that the increase in HGF level in sera might be associated with tumor progression, particularly with liver metastases, in human breast cancer. PMID- 21607516 TI - Radical treatment of brain metastasis of colorectal-cancer. AB - Among 15 patients with brain metastases from colorectal cancer, the eight patients treated by open surgery+whole brain irradiation (35-45 Gy) or gamma knife surgery had significant improvement in their neurologic symptoms and were able to return to their daily life. Survival from the time of diagnosis of brain metastases to death averaged 7.6 months in these radically-treated patients compared to 1.7 months in the conventional group (p<0.05). If performance status permits, aggressive treatment such as open surgery or gamma-knife surgery should be an option for treatment of brain metastasis of colorectal cancer. PMID- 21607517 TI - Detection of hsv, CMV and ebv by the polymerase chain-reaction technique in patients with inflammatory eye-diseases. AB - Herpes simplex virus (HSV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) have been recognized as pathogenic agents of intraocular inflammatory conditions. The ability of the Polymerase Chain Reaction (PCR) technique to amplify HSV, CMV and EBV DNA from aqueous specimens makes this technique a valuable diagnostic tool for the detection of these viral pathogens in patients with ophthalmic lesions. We used PCR for the amplification of a 476 bp long sequence from the pol I gene of HSV genome, a 435 bp region of the immediate early-1 (IE-1) gene of CMV and a 375 bp sequence from the EcoRI B fragment of EBV genome. We examined 22 aqueous humour specimens from patients with uveitis and retinitis, inflammatory eye diseases, diagnosed clinically. We found HSV in 4 (18.2%), CMV in 6 (27.3%) and EBV in 1 (4.5%) out of the 22 examined patients. None of the 22 examined samples was found to be infected with more than one of the examined viral pathogens. These data confirm the implications of the members of Herpesvirus family in inflammatory inner eye diseases and the importance of PCR technique as a diagnostic tool in clinical virology. PMID- 21607518 TI - Neutropenic enteritis - a 2-case report and literature-review. AB - In the last decade, clinical management of neutropenic enteritis has been most controversial due to the large variability in the clinical manifestations and evolution. In this work, two-case report are presented showing the broad spectrum of symptoms and prognosis. Intestinal perforation, abscess, obstruction and pneumatosis are factors associated with poor prognosis referred in the literature, and all of which indicate an early surgical intervention. In its absence, a close medical control with hematological support and broad spectrum antibiotic therapy could be indicated. In this case, surgery should be the approach for patients with a rapidly progressive evolution or massive or continuous intestinal bleeding, in spite of the conservative therapy. PMID- 21607519 TI - Phase-ii evaluation of single-agent Carboplatin in advanced thyroid-carcinoma. AB - Single agent carboplatin was used in a phase II trial to treat patients with metastatic thyroid cancer who had failed surgery, radiation therapy, or radioactive iodine. Carboplatin was administered at a dose of 400 mg/m(2) every 28 days on an outpatient basis. Eight patients with a variety of tumor histologies were enrolled. No patient had a response to treatment and the average time to disease progression while on treatment was 5.4 months. Toxicity was mild and included hearing loss in one patient. There have been few studies using newer agents in patients with metastatic thyroid cancer who failed surgery and radioactive iodine. These results underline the need for larger intergroup trials with newer agents. PMID- 21607520 TI - Absence of over-expression of p53 protein in benign and malignant paragangliomas. AB - Expression of abnormally stable mutant forms of the protein encoded by the gene known as p53 is an extremely common event in human neoplasms, a fact reflecting its crucial role in the regulation of cell turnover. Although widely investigated in a range of tumours from a variety of sites, there do not, to our knowledge, appear to have been any studies of its expression in paragangliomas. Abnormal expression of p53 protein was absent from 15 morphologically typical adrenal (2) and extra-adrenal(13) paragangliomas, 3 were overtly malignant, when sought for using the DO-7 antibody (Dako), whilst colon adenocarcinomas known to abnormally express the protein and used as controls were consistently positive. These results suggest that the mechanism of any dysfunction of the p53 encoding gene in paragangliomas might differ from that in tumours from other sites such that its detectable overexpression does not result. PMID- 21607521 TI - Alterations of the p53 tumor-suppressor gene and ki-ras oncogene in human pancreatic cancer-derived cell-lines with different metastatic potential. AB - Alterations of the p53 and Ki-ras genes were examined in 12 human pancreatic cancer-derived cell lines with different metastatic potential. Point mutations of the Ki-ras gene at codon 12 were found in 10 out of 12 cell lines (83%), while abnormalities of the p53 gene were identified in 8 out of 12 cell lines (67%) which included point mutations (n=7) and one base deletion (n=1). The comparison between alterations of the p53 and Ki-ras genes showed that all the 12 cell lines revealed alterations of both genes or one of these genes regardless of the metastatic potential. Further, same alterations of the Ki-ras gene or p53 gene were noted among the cell lines with increased metastatic potential and their parental cell lines. These findings suggest that alterations of the p53 gene, like the Ki-ras gene is a frequent event in pancreatic cancer, and could contribute cooperatively in the oncogenic steps of pancreatic cancer. It is also suggested that the genetic changes of the p53 and Ki-ras genes are not substantially associated with the metastatic potential in pancreatic cancer. PMID- 21607522 TI - Correlation among [h-3] thymidine, flow-cytometry and proliferating cell nuclear antigen indexes in colorectal tumors. AB - In colorectal cancer and other tumors, proliferating cell nuclear antigen (PCNA) has been found to be a useful marker in immunohistochemical studies of cell proliferation, The presence of a correlation among PCNA labeling index (PCNA LI) and values of cell proliferation expressed by [H-3]thymidine labeling index (TLI) and flow cytometry (FC), the most common techniques used in the evaluation of proliferative activity in colorectal cancer were studied. In 50 operable colorectal cancer patients, TLI, PCNA LI and determination of S-phase fraction by FC were carried out in order to evaluate the correlation among these three indices. A good correlation was obtained between PCNA LI and both TLI (r=0.667; P=0.0001) and percent of cells in S-phase as determined by FC (r=0.819; P=0.0001). It is concluded that PCNA immunohistochemistry can be a reliable marker of the proliferative activity in colorectal rumours. Furthermore, because of its technical simplicity and lower cost it can be more advantageous than TLI or FC. PMID- 21607523 TI - Etoposide pharmacokinetics in a jaundiced infant with letterer-siwe variant of langerhans cell histiocytosis. AB - An infant with hepatocellular jaundice due to Langerhans cell histiocytosis was treated and responded well to intravenous etoposide. Pharmacokinetics demonstrated similar clearance and AUC data in both the jaundiced and non jaundiced states but myelosuppression was greater when the infant was jaundiced. Children with hepatocellular jaundice require dose reductions of etoposide, despite the similar drag pharmacokinetics to the non-jaundiced state. The mechanisms involved are discussed. PMID- 21607524 TI - Supraclavicular lymph-node recurrence of breast-cancer. AB - To describe prognosis and outcome of patients with a recurrence in the supraclavicular fossa (SCLNR) and to evaluate the role of different therapeutic options for recurrence on the outcome of these patients, clinical and pathological characteristics, treatment and time course of 55 patients with supraclavicular recurrence as their first relapse of disease were analysed. Thirty-nine patients had an isolated recurrence, i.e. no distant metastases were known at the time of supraclavicular recurrence. Median follow-up was 20.4 months from supraclavicular recurrence and 58.8 months from primary diagnosis. For evaluation of treatment only the 39 patients without distant disease before or simultaneous with supraclavicular recurrence were analysed. Mean age of the 55 patients at primary diagnosis and at diagnosis of recurrence was 56.7 and 61.2 years respectively. The majority of patients developing such a recurrence was younger than 60 years at the time of primary diagnosis, Evaluation of patient characteristics showed a high proportion of positive axillary status (65%) at the time of primary diagnosis with a mean number of 7.5 involved nodes. Tumor was located in the medial or central part of the breast in 53% of patients in whom primary tumor location was known. About 80% of patients developed their recurrence in the first 5 years from primary diagnosis of breast cancer. Global survival after SCLNR was poor. Survival rate from recurrence was 65% at 2 years and only 16% at 5 years. Among the 39 patients with an isolated SCLNR 88% developed distant metastases within 5 years from recurrence. The evaluation of different therapeutic options for a SCLNR (radiotherapy, surgery, systemic therapy) revealed no significant influences on survival rates. When local regional control was obtained, a trend towards improved survival was noted. Patients aged younger than 60 years at primary diagnosis, with high positive primary axillary status or tumor of the medial or central part of the breast seem to be at higher risk for developing SCLNR and internal mammary lymphatic route may be a more probable pathway to the supraclavicular nodes besides the common axillary route. SCLNR carries a grave prognosis. Most patients develop distant disease within short time, with only a small section surviving more than 5 years from the onset of recurrence. Survival rate of patients with SCLNR is clearly inferior to patients with local or regional axillary recurrence. From this we conclude that SCLNR should be considered as an indicator of systemic disease despite its lymphogenous genesis and not as regional recurrence. Local therapy of SCLNR is to be defined with palliative intent in most cases. Systemic therapy has to be applied additionally even if no other distant disease is known. Further prospective analyses will have to evaluate the role of systemic treatment for solitary supraclavicular recurrences. PMID- 21607525 TI - Immunohistochemical detection of cathepsin-d expression in prostate-cancer. AB - Lysosomal proteases may be involved in facilitating cancer invasion and metastatic spread by degradation of basement membranes and intercellular matrix. Overexpression of cathepsin D, a lysosomal aspartyl protease, has been reported in different tumours and seems to constitute a prognostic factor for survival in patients with breast cancer. The current study investigates immunohistochemical staining using anti-cathepsin D monoclonal antobodies (M1G8) in prostate cancer specimens and tissue from patients with benign prostatic hyperplasia (BPH). Among 41 tumours expression of cathepsin D was observed in 14 of 26 (54%) low stage and grade tumours (T-1-2/G(1-2)) and in 12 of 15 (86%) high stage and grade tumours (T-3, G(3)). Cathepsin D positivity was found within the cytoplasm and at the surface of tumour cells localized in glandular structures and in single cells invading the prostatic stroma, while no staining was observed in normal prostatic tissue and in mesenchymal cells. Two of ten specimens from patients with benign prostatic hyperplasia showed a weakly positive staining reaction within glandular structures. The clinical course of localized prostate cancer appears to be highly variable and the different treatment strategies (radical prostatectomy, radiation therapy or surveillance) have come under debate. For the determination of the biological aggressiveness of prostate cancer in the individual patient easily available biological prognostic factors are needed. This report demonstrates overexpression of cathepsin D in prostate cancer specimens with increasing frequency in patients with tumours of high grade and stage. The usefulness of cathepsin D immunohistochemistry as a prognostic factor should be prospectively evaluated. PMID- 21607526 TI - Cytotoxicity of new aza-alkyl lysophospholipids against drug-sensitive and resistant human ovarian tumor-cell lines - role of free-radicals and potentiation of cytotoxicity by tnf-alpha and cddp. AB - Three aza-alkyl lysophospholipids (AALP) with related chemical structures (BN52205, BN52218, BN52227) were examined for their anti-tumor cytotoxic activity when used alone or in combination with TNF-alpha or CDDP. The three compounds were cytotoxic, though to a different degree, against a battery of human ovarian tumor cell lines. The compounds were cytotoxic to both drug sensitive and drug resistant lines and were also cytotoxic to an MDR(+) tumor cell line. BN52205 was the most potent cytotoxic AALP and differed from the least cytotoxic compound BN52227 by a substitution of a methoxy group for an ethoxy group at position 1. The AALP-mediated cytotoxicity was found to be mediated in large part by free radicals as: i) treatment of the tumor cells with an inhibitor of glutathione biosynthesis, buthionine sulfoximine (BSO), augmented cytotoxicity and often resulted in synergy and ii) the addition of the anti-oxidant glutathione inhibited cytotoxicity. Since free radicals have also been involved in both TNF alpha and CDDP-mediated cytotoxicity, we examined the potentiating effect of combination treatment of AALP with these cytotoxic agents. Depending on the cell line, there was either an additive or a synergistic activity by the combination treatment. Furthermore, combination of BN52205 and TNF-alpha resulted in a synergistic activity against the MDR(+) ovarian line, AD10, and the cis-platinum resistant line, C30. These results demonstrate that AALP are cytotoxic to tumor cell lines and can overcome drug resistance. Further, low concentrations of AALP and TNF-alpha/drug/BSO result in additive or synergistic cytotoxic activity. These findings suggest that combination treatment can be effective in the therapy of drug resistant ovarian tumors and can achieve reduced overall toxicity. PMID- 21607527 TI - Modeling the development of in-situ breast-cancer - a clonal evolutionary approach. AB - We present a speculative hypothesis based on the assumption that a morphological parameter of a tumour in this case the nuclear area as assessed by computerised image analysis can be utilised to predict the number of specific events occurring at a gene or chromosomal level within a tumour given the assumption that the tumour morphology is predictive of the clonal evolution of a tumour and clonal progression of neoplasia. Assuming that the phenotype of the tumour is truly determined by the genotype and that morphological variations within a tumour are not due to other factors such analogous to biotypic or ecotypic diversity in animal species we argue that this may be a valuable model to approach the understanding of tumour biology and clonal evolution of tumour cell populations. Such analyses could in future be important in cytogenetic or microdissection studies of DCIS, and could be applicable to studies of clonal evolution in DCIS and other neoplasms using fluorescent in situ hybridisation. PMID- 21607528 TI - Immunohistochemical detection of the p53 gene-product in gastric-cancer patients aberrant expression but no prognostic-significance. AB - The aim of the present study was to examine whether immunohistochemical p53 expression could be identified as an independent predictor for disease recurrence and survival and to assess any relation to tumour type, metastatic potential and response to different therapeutic regimens. We examined gastric carcinomas from 125 patients using a mouse monoclonal antibody (DO7). Seventy two of the tumours showed positive nuclear staining. No special relation was observed either according to tumour type, grade or stage classification of the tumours nor to the lymph node status. Survival analysis showed no significant advantage of the p53 negative patients. Expression of p53 in our series did not prove to be a valuable prognostic marker for survival nor did it correlate with other standard prognostic markers. PMID- 21607529 TI - Human and Xenopus mo15 messenger-RNA are highly conserved but show different patterns of expression in adult tissues. AB - Phosphorylation of human p34(cdc2) at Thr 161 seems to be necessary for its catalytic activity. CAK (cdk activating kinase) containing p40(MO15) from Xenopus egg extracts phosphorylates and activates p34(cdc2) in a cyclin dependent manner at Thr 161. We describe the cDNA sequence coding for human MO15, which predicts a serine/threonine kinase of 346 aa. Despite the high homology of 91% between the human and Xenopus proteins we observed a rather different mRNA distribution in adult tissues: In contrast to ubiquitously expressed human MO15-transcripts MO15 mRNA expression in Xenopus is restricted to oocytes indicating a different cellular role in these two phylogenetically distant species. By virtue of the homology to members of the family of cell cycle kinase genes we examined MO15 mRNA expression for its correlation to the proliferative activity of cells. Stimulation of lymphocytes showed MO15 mRNA expression to be independent of mitotic activity. PMID- 21607530 TI - A clinical-study of immunotherapy versus endocrine therapy versus chemotherapy in the treatment of advanced pancreatic adenocarcinoma. AB - The advanced carcinoma of pancreas still remains an untreatable disease. Both chemotherapy and hormono-therapy seem not to prolong the survival time. Also immunotherapy with IL-2 has been shown to have no efficacy. Our experimental studies suggested the possibility of enhancing the antitumor activity of IL-2 by the administration of immunomodulating neurohormones, such as melatonin (MLT). This study was carried out to evaluate the efficacy of IL-2 plus MLT in advanced cancer of the pancreas. Fifty patients, with advanced adenocarcinoma of the pancreas, were randomized to receive chemotherapy consisting of 5-FU plus folates, endocrine therapy with LHRH and somatostatin analogues, supportive care alone or immunotherapy with subcutaneous low-dose IL-2 plus MLT. A partial response was obtained in 1/13 patients treated with chemotherapy and in 2/12 patients receiving immunotherapy; no tumor regression was seen in the other groups. The percent of survival at 1 year achieved in patients treated with immunotherapy was significantly higher than in the other groups tested (3/12 vs 1/38; p<0.02). This preliminary study would suggest that the immunotherapy with IL-2 plus MLT may represent a new promising treatment of advanced pancreatic adenocarcinoma. PMID- 21607531 TI - The UTCI-clothing model. AB - The Universal Thermal Climate Index (UTCI) was conceived as a thermal index covering the whole climate range from heat to cold. This would be impossible without considering clothing as the interface between the person (here, the physiological model of thermoregulation) and the environment. It was decided to develop a clothing model for this application in which the following three factors were considered: (1) typical dressing behaviour in different temperatures, as observed in the field, resulting in a model of the distribution of clothing over the different body segments in relation to the ambient temperature, (2) the changes in clothing insulation and vapour resistance caused by wind and body movement, and (3) the change in wind speed in relation to the height above ground. The outcome was a clothing model that defines in detail the effective clothing insulation and vapour resistance for each of the thermo physiological model's body segments over a wide range of climatic conditions. This paper details this model's conception and documents its definitions. PMID- 21607532 TI - Percutaneous mitral valve repair using the MitraClip in acute cardiogenic shock. PMID- 21607533 TI - Large necrosis: a rare complication of medial thighplasty. AB - Obesity is a major public health problem in Western societies. After failure of diet and exercise, patients can have bariatric surgery. Weight loss causes excess skin on the body, including the thighs. This leads to difficulty walking and psychological disorders such as devalued self-image. Medial thighplasty is an intervention to reduce excess skin and fat in the thighs. The main complications are scar migration, scar infection, hematoma, lymphedema, gaping vulva, and, rarely, skin necrosis. We describe a case of flap necrosis after a reoperation of medial thighplasty. Treatment included debridement of necrotic tissue and healing of the wound by secondary intention (vacuum-assisted closure and dressings with calcium alginate). Complete healing was achieved in 4 months. As the patient refused any new procedure, skin grafting was not performed. The aesthetic results of plastic surgery procedures are often imperfect. Patients should be clearly prepared and informed about the results expected from the operation. Surgeons should know contraindications for reoperation. PMID- 21607534 TI - Utilizing muscle-derived stem cells to enhance long-term retention and aesthetic outcome of autologous fat grafting: pilot study in mice. AB - Autologous fat grafting has been regarded as the ideal soft tissue filler for more than a century. Low long-term retention rate and unpredictability limit it from widespread clinical practice. Many theories for this have been proposed: lack of sufficient blood supply and subsequent necrosis is the most accepted. In this pilot study, we showed both macroscopically and microscopically the viability of muscle-derived stem cells (MDSCs) cotransplanted with fat placed intramuscularly for 3 months. MRI scanning showed a stronger fat signal in the MDSC-treated group than that of the control group. Moreover, histological evaluation exhibited well-preserved and intact fat cells in the MDSC-treated group. In contrast, the control group showed extensive fibrosis and fat graft loss. Furthermore, the MDSC-treated group possessed almost threefold greater capillary density than the control group. We conclude that cotransplantation of muscle-derived stem cells and autologous fat tissue improves the long-term survival of intramuscular fat transplants by promoting neovascularization. PMID- 21607535 TI - A modified and accurately designed Z-epicanthoplastic technique. AB - Surgical creation of a supratarsal crease has been by far the most common cosmetic procedure in China. To gain a pleasing eye appearance, double-eyelid surgery usually is performed in combination with epicanthoplasty. Currently, many epicanthoplastic techniques are described. Essentially, among the various epicanthoplasties, quite a few procedures are different designs of the Z-plastic or Y-V technique. In the authors' opinion, a better cosmetic result depends on a specific design more than the procedure itself. This report describes a modified Z-epicanthoplastic technique with accurate design and different types of tissue flaps raised. The authors performed epicanthoplasties with the Z-plastic technique for 163 patients from December 2006 to December 2010. Interepicanthal distances longer than a palpebral fissure and lacrimal caruncles obviously covered by epicanthic folds were considered an indication for performing epicanthoplasty. The follow-up period ranged from 4 months to 4 years. A good result was obtained, with natural fine creases of the upper eyelids and complete caruncle exposure at the near inner canthus. There was no shadow or local depressed deformity, visible scar in the inner canthus, or recurrence, and most of the patients showed slight westernizations of the medial eye architecture rather than wide and prominent western upper eyelid creases at the medial eyelids. Three patients had slight asymmetric exposure of the lacrimal caruncle, which was corrected by a second surgery. In conclusion, the modified and accurately designed Z-epicanthoplasty can avoid some complications such as local depressed deformity, displeasing appearance, and excessive westernized architecture at the inner canthus. A predictable shape in the medial corner can be obtained by developing and accurately designing different types of flaps. PMID- 21607536 TI - Use of deepithelialized flap in mammoplasties: simple method with excellent results. AB - BACKGROUND: A deepithelialized flap is used in almost all surgical fields, particularly in plastic, reconstructive, and aesthetic surgery. This article describes several operating techniques using deepithelialized flaps that in specific cases can improve silicone breast implant coverage. METHODS: All the patients underwent surgery in our department. The operations described are subcutaneous mastectomies with immediate reconstruction using silicone implants, mastopexy with immediate augmentation using silicone implants in a patient with very thin skin, and reaugmentation with mastopexy and reimplantation of silicone implants in a patient with very thin skin and extremely thin pectoral muscles. In all the described operations, we used a superolaterally based deepithelialized flap from the lower part of the breast that we fixed to the thoracic wall to cover the inferior part of the implant. RESULTS: The authors have extensive experience using this flap in such specific cases. To date, they have performed more than 30 operations using this technique. Each patient was followed for 2-7 years, and the findings show excellent postoperative results. None of the patients had implant extrusions, flap extrusions, or infections. The long-term cosmetic results were outstanding. CONCLUSION: The use of deepithelialized flaps in patients with very thin skin or pectoral muscles is a safe and easy way to improve implant coverage and prevent implant extrusion. This technique provides an alternative surgical option that can be beneficial in certain mammary cases. PMID- 21607537 TI - Acellular dermal matrix masking detection of recurrent breast carcinoma: a novel complication. AB - Acellular dermal matrix (ADM) use in prosthetic breast reconstruction has become increasingly popular. Several benefits have been reported with this technique including diminished donor-site morbidity and improved aesthetic outcomes. Recently, in an effort to ascertain the overall safety and efficacy of this approach, an emphasis has been placed on identifying potential postoperative complications. This report describes a unique complication experienced with ADM use in which ADM conceals the detection of recurrent breast carcinoma. PMID- 21607538 TI - [Rehabilitation and sport following total hip replacement]. AB - The number of total hip replacement (THR) surgeries has increased significantly over the last few years and patients undergoing surgery are of decreasing age. In consequence the question of the influencing factors for the survival of artificial hip joints becomes more and more urgent. The expected survival time of an implant is nowadays 15-20 years and it seems that factors for a shorter lifetime are female gender, overweight, younger age and certain indications which led to surgery, such as rheumatoid arthritis or fractures. In the early phase of rehabilitation, measures against dislocation including training of the abductor muscles are most important. Starting rehabilitation programs early after surgery has positive effects on outcome, especially when strengthening programs are included. There are different opinions concerning the question how the lifetime of a THR is influenced by sports activities. However, it seems to have been demonstrated that suitable sports activities have a positive effect and do not necessarily correlate with higher loosening rates after THR. In general, high impact sports should be avoided. Recommended activities are cycling, swimming, aquajogging, hiking, rowing and dancing. PMID- 21607539 TI - [Antibiotic prophylaxis in primary and revision hip arthroplasty: what is the evidence?]. AB - Advances in the perioperative and postoperative management of total joint replacement have led to a steady decrease in the infection rate, which in the case of total hip replacement presently lies between 0.25 and 1%. Unfortunately there is disparity in current practice nationally and internationally, regarding duration, time of application and choice of antibiotics. Currently there are only Level 1a recommendations for primary hip arthroplasty, whereas, due to the heterogeneity and complexity of most revision cases as well as a lack of randomized controlled trials, antibiotic prophylaxis for hip revision arthroplasty is mostly based on the surgeon's preference. In this article the current literature is reviewed and scientifically sound data and recommendations are summarized. PMID- 21607540 TI - Gene expression differences between stroke-associated and asymptomatic carotid plaques. AB - Atherosclerotic carotid stenosis is an important risk factor for stroke. Carotid plaques (CPs) causing stroke may present a distinct type of molecular pathology compared with transient ischemic attack (TIA)-associated or asymptomatic plaques. We compared the gene expression profiles of CPs from stroke patients (n = 12) and asymptomatic patients (n = 9), both with similar risk factors and severity of carotid stenosis (>70%). Sixty probes showed over 1.5-fold expression difference at 5% false discovery rate. Functional clustering showed enrichment of genes in 51 GO categories and seven pathways, the most significant of which relate to extracellular-matrix interaction, PPAR gamma signaling, scavanger receptor activity, and lysosomal activity. Differential expression of ten genes was confirmed in an extended replication group (n = 43), where the most significant expression differences were found in CD36 (2.1-fold change, p = 0.005), CD163 (1.7-fold change, p = 0.007) and FABP4 (2.2-fold change, p = 0.015). These include four genes not previously linked to plaque destabilization: GLUL (2.2 fold change, p = 0.016), FUCA1 (2.2-fold change, p = 0.025), IL1RN (1.6-fold change, p = 0.034), and S100A8 (2.5-fold change, p = 0.047). Strong correlations were found to plaque ulceration, plaque hemorrhage, and markers of apoptosis and proliferation (activated caspase 3, TUNEL, and Ki67). Protein expression of these genes was confirmed by immunohistochemistry and was found in the atheromatous areas of CPs critical for plaque destabilization. This study presents a comprehensive transcriptional analysis of stroke-associated CPs and demonstrates a significant transcriptome difference between stroke-associated and asymptomatic CPs. Follow-up studies on the identified genes are needed to define whether they could be used as biomarkers of symptomatic CPs or have a role in plaque destabilization. PMID- 21607541 TI - Connecting the renin-angiotensin-aldosterone system with sudden death. PMID- 21607542 TI - Identification of a coronary stem cell in the human heart. AB - Human ischemic cardiomyopathy is characterized by de novo cardiomyogenesis, which is limited to the surviving portion of the ventricle, and by organ hypertrophy that develops as a chronic response to ischemic injury. Although myocyte hypertrophy and myocyte regeneration restore the original myocardial mass, the coronary vasculature remains defective and the extent and regulation of myocardial perfusion are severely impaired. Recently, vascular stem cells (VSCs) have been identified in the coronary circulation. VSCs express c-kit and the vascular endothelial growth factor receptor-2, KDR. These cells are self renewing, clonogenic, and multipotent in vitro and in vivo. In animal models of critical coronary artery stenosis, VSCs form large conductive coronary arteries and their distal branches. This degree of vasculogenesis replaces partly the function of the occluded coronary artery improving myocardial perfusion and positively interfering with the development of the post-infarction myopathy. Cell therapy directed to the restoration of the integrity of the coronary circulation, the replacement of atherosclerotic coronary vessels, or both, would change dramatically the goal of cell therapy for the ischemic heart: the prevention of myocardial injury would become the end-point of cell therapy rather than the partial recovery of established damage. PMID- 21607543 TI - The importance of chitin in the marine environment. AB - Chitin is the most abundant renewable polymer in the oceans and is an important source of carbon and nitrogen for marine organisms. The process of chitin degradation is a key step in the cycling of nutrients in the oceans and chitinolytic bacteria play a significant role in this process. These bacteria are autochthonous to both marine and freshwater ecosystems and produce chitinases that degrade chitin, an insoluble polysaccharide, to a biologically useful form. In this brief review, a description of the structure of chitin and diversity of chitinolytic bacteria in the oceans is provided, in the context of the significance of chitin degradation for marine life. PMID- 21607545 TI - Multigene barcoding and phylogeny of geographically widespread muricids (Gastropoda: Neogastropoda) along the coast of China. AB - The identification and phylogeny of muricids have been in a state of confusion for a long time due to the morphological convergence and plasticity. DNA-based identification and phylogeny methods often offer an analytically powerful addition or even an alternative. In this study, we employ a DNA barcoding method to identify 17 known and easily confused muricid species (120 individuals) from the whole China coast based on mitochondrial cytochrome c oxidase subunit I (COI) and 16S rRNA sequences, and nuclear ITS-1 and 28S rRNA sequences. The phylogeny of muricid subfamilies is also analysed based on all mitochondrial and nuclear sequences. The universal COI and 16S rRNA primers did not work broadly across the study group, necessitating the redesign of muricid specific COI and 16S rRNA primers in this paper. Our study demonstrates that COI gene is a suitable marker for barcoding muricids, which can distinguish all muricid species studied. Phylogenetic analysis of 16S rRNA, ITS-1 and 28S rRNA data also provide good support for the species resolution observed in COI data. The relationships of muricid subfamilies are resolved based on the separate and combined gene data that showed the monophyly of each the subfamilies Ergalataxinae, Rapaninae, Ocenebrinae and Muricinae, especially that Ergalataxinae did not fall within Rapaninae. PMID- 21607544 TI - Hepatocyte nuclear factor 4alpha transactivates the mitochondrial alanine aminotransferase gene in the kidney of Sparus aurata. AB - Alanine aminotransferase (ALT) plays an important role in amino acid metabolism and gluconeogenesis. The preference of carnivorous fish for protein amino acids instead of carbohydrates as a source of energy lead us to study the transcriptional regulation of the mitochondrial ALT (mALT) gene and to characterize the enzyme kinetics and modulation of mALT expression in the kidney of gilthead sea bream (Sparus aurata) under different nutritional and hormonal conditions. 5'-Deletion analysis of mALT promoter in transiently transfected HEK293 cells, site-directed mutagenesis and electrophoretic mobility shift assays allowed us to identify HNF4alpha as a new factor involved in the transcriptional regulation of mALT expression. Quantitative RT-PCR assays showed that starvation and the administration of streptozotocin (STZ) decreased HNF4alpha levels in the kidney of S. aurata, leading to the downregulation of mALT transcription. Analysis of the tissue distribution showed that kidney, liver, and intestine were the tissues with higher mALT and HNF4alpha expression. Kinetic analysis indicates that mALT enzyme is more efficient in catalyzing the conversion of L: -alanine to pyruvate than the reverse reaction. From these results, we conclude that HNF4alpha transactivates the mALT promoter and that the low levels of mALT expression found in the kidney of starved and STZ-treated fish result from a decreased expression of HNF4alpha. Our findings suggest that the mALT isoenzyme plays a major role in oxidazing dietary amino acids, and points to ALT as a target for a biotechnological action to spare protein and optimize the use of dietary nutrients for fish culture. PMID- 21607546 TI - Protection of endothelial cells, inhibition of neointimal hyperplasia by beta elemene in an injured artery. AB - AIMS: It is generally accepted that the oxidative stress and the proliferative activity of vascular smooth muscle cells (VSMCs) contribute to the pathogenesis of neointimal hyperplasia after vascular injury. Although beta-elemene (beta-1 methyl-1-vinyl-2, 4-diisopropenyl-cyclohexane) has been used as an antitumour drug, its therapeutic effect on vascular diseases has not yet been determined. In this study, we investigated whether beta-elemene could inhibit oxidative damage of vascular endothelial cells, suppress VSMCs growth and prevent neointimal hyperplasia. METHODS AND RESULTS: beta-elemene can increase the survival rate of human umbilical vein endothelial cells in vitro. By measuring the malondialdehyde content, total antioxidant capacity, superoxide dismutase activity, catalase activity, glutathione peroxidase activity and nitric oxide levels, we assessed the protective effect of beta-elemene in the vascular endothelium model against oxidant-induced injury. MUoreover, beta-elemene inhibited cell proliferation and induced apoptosis in cultured VSMCs. In a flow culture system, beta-elemene reduced the migration distance of VSMCs. By transwell migration assay, beta elemene was found to reduce the migration cell number of VSMCs, but not affect the HUVECs migration. In a rat carotid artery balloon injury model, administration of beta-elemene significantly reduced the ratio of intimal area to medial area and neointima formation. CONCLUSIONS: Our results indicate that beta elemene is effective in protecting the endothelial cells from injury induced by hydrogen peroxide in vitro, inhibiting smooth muscle cell proliferation/migration and inhibiting neointima formation in vivo after vascular injury. PMID- 21607547 TI - Supporting performance in the face of age-related neural changes: testing mechanistic roles of cognitive reserve. AB - Age impacts multiple neural measures and these changes do not always directly translate into alterations in clinical and cognitive measures. This partial protection from the deleterious effects of age in some individuals is referred to as cognitive reserve (CR) and although linked to variations in intelligence and life experiences, its mechanism is still unclear. Within the framework of a theoretical model we tested two potential mechanistic roles of CR to maintain task performance, neural reserve and neural compensation, in young and older adults using functional and structural MRI. Neural reserve refers to increased efficiency and/or capacity of existing functional neural resources. Neural compensation refers to the increased ability to recruit new, additional functional resources. Using structural and functional measures and task performance, the roles of CR were tested using path analysis. Results supported both mechanistic theories of CR and the use of our general theoretical model. PMID- 21607548 TI - Prognostic clinicopathological factors after curative resection of small bowel adenocarcinoma. AB - PURPOSE: Small bowel adenocarcinoma is a relatively uncommon neoplasm that accounts for approximately 0.3% to 2.4% of digestive cancers. In comparison with carcinomas of the other areas of the gastrointestinal tract, the prognosis for small bowel adenocarcinoma is generally worse. The prognostic factors of small bowel adenocarcinoma were analyzed retrospectively, and the significance of operative procedure, lymphadenectomy, and adjuvant chemotherapy was evaluated. METHODS: From 1990 to 2009, 30 patients with small bowel adenocarcinoma who underwent surgery at Osaka Medical College Hospital were analyzed with respect to tumor extent, operation method, and prognosis. RESULTS: Overall 5-year survival was 52.5%, and the median survival time was 27.0 months. On univariate and multivariate analyses, the location (duodenum vs. jejunum and ileum), size (greater or less than 70 mm), and tumor, nodes, and metastasis (TNM) stage (stage 0 + I + II vs. III + IV) of the tumor were the significant prognostic factors. No differences in survival and recurrence rates were observed between patients undergoing pancreaticoduodenectomy and those undergoing partial resection, between those undergoing mural lymphadenectomy and those undergoing extended lymphadenectomy, or between those with and without adjuvant chemotherapy. The combination of surgery and adjuvant chemotherapy did not control recurrence or improve the prognosis. CONCLUSIONS: In small bowel adenocarcinoma, location, size, and TNM stage of the tumors were the independent prognostic factors after curative resections. Partial resection with mural lymphadenectomy may be recommended as optimal surgery for small bowel adenocarcinoma. PMID- 21607549 TI - Genomic analysis of Acidianus hospitalis W1 a host for studying crenarchaeal virus and plasmid life cycles. AB - The Acidianus hospitalis W1 genome consists of a minimally sized chromosome of about 2.13 Mb and a conjugative plasmid pAH1 and it is a host for the model filamentous lipothrixvirus AFV1. The chromosome carries three putative replication origins in conserved genomic regions and two large regions where non essential genes are clustered. Within these variable regions, a few orphan orfB and other elements of the IS200/607/605 family are concentrated with a novel class of MITE-like repeat elements. There are also 26 highly diverse vapBC antitoxin-toxin gene pairs proposed to facilitate maintenance of local chromosomal regions and to minimise the impact of environmental stress. Complex and partially defective CRISPR/Cas/Cmr immune systems are present and interspersed with five vapBC gene pairs. Remnants of integrated viral genomes and plasmids are located at five intron-less tRNA genes and several non-coding RNA genes are predicted that are conserved in other Sulfolobus genomes. The putative metabolic pathways for sulphur metabolism show some significant differences from those proposed for other Acidianus and Sulfolobus species. The small and relatively stable genome of A. hospitalis W1 renders it a promising candidate for developing the first Acidianus genetic systems. PMID- 21607550 TI - Bacterial diversity in five Icelandic geothermal waters: temperature and sinter growth rate effects. AB - The microbial ecology associated with siliceous sinters was studied in five geochemically diverse Icelandic geothermal systems. Bacterial 16S rRNA clone libraries were constructed from water-saturated precipitates from each site resulting in a total of 342 bacterial clone sequences and 43 species level phylotypes. In near-neutral, saline (2.6-4.7% salinity) geothermal waters where sinter growth varied between 10 and ~300 kg year(-1) m(-2), 16S rRNA gene analyses revealed very low (no OTUs could be detected) to medium (9 OTUs) microbial activity. The most dominant phylotypes found in these waters belong to marine genera of the Proteobacteria. In contrast, in alkaline (pH = 9-10), meteoric geothermal waters with temperature = 66-96 degrees C and <1-20 kg year( 1)m(-2) sinter growth, extensive biofilms (a total of 34 OTUs) were observed within the waters and these were dominated by members of the class Aquificae (mostly related to Thermocrinis), Deinococci (Thermus species) as well as Proteobacteria. The observed phylogenetic diversity (i.e., number and composition of detected OTUs) is argued to be related to the physico-chemical regime prevalent in the studied geothermal waters; alkaliphilic thermophilic microbial communities with phylotypes related to heterotrophic and autotrophic microorganisms developed in alkaline high temperature waters, whereas halophilic mesophilic communities dominated coastal geothermal waters. PMID- 21607551 TI - A 13-week, multicenter, randomized, double-blind study of lumiracoxib in hip osteoarthritis. AB - The aim of this 13-week, multicenter, randomized, double-blind, double-dummy, placebo- and positive-internal (celecoxib)-controlled, parallel-group study was to demonstrate the efficacy, safety, and tolerability of lumiracoxib in primary hip osteoarthritis (OA) patients. Eligible patients (n = 1,262; ACR criteria) were randomized (1:1:1) to receive lumiracoxib 100 mg once daily (o.d.) (n = 427), celecoxib 200 mg o.d. (n = 419), or matching placebo o.d. (n = 416) administered orally. The primary objective was to compare lumiracoxib 100 mg o.d. and placebo with respect to three co-primary efficacy variables: the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index Likert version 3.1 (WOMACTM LK 3.1) questionnaire, the function subscale of the WOMACTM LK 3.1 questionnaire, and patient's global assessment of disease activity (100-mm visual analog scale (VAS)) after 13 weeks of treatment. Of the 1,262 randomized patients, 951 completed the study. All randomized patients were included in the intention-to-treat and safety populations. Lumiracoxib was superior to the placebo (p < 0.001) after 13 weeks for all three co-primary endpoints. By week 13, the patient's global assessment of disease activity (100 mm VAS) improved by 23.3 mm (+/-SD, 27.83 mm) with lumiracoxib and 13.3 mm (+/ 26.71 mm) with placebo. The WOMACTM function score decreased by 10.4 (+/-13.56) with lumiracoxib and 6.8 (+/-12.55) with placebo. The WOMACTM pain scores decreased by 3.4 (+/-4.16) with lumiracoxib and 2.2 (+/-3.94) with placebo at week 13. Similar results were observed for secondary endpoints: OA pain intensity and WOMACTM total score. Lumiracoxib was similar to celecoxib for all three co primary endpoints. All treatments were well tolerated. In conclusion, lumiracoxib is effective in reducing pain and improving function in hip OA patients. PMID- 21607552 TI - Current smoking status is associated to a non-ACR 50 response in early rheumatoid arthritis. A cohort study. AB - The purpose of this study is to determine factors associated with a non-ACR 50 response at 6 months of follow-up, in a cohort of patients with early rheumatoid arthritis (RA). Early RA patients (symptom duration <1 year), treated with the same combination treatment (methotrexate and sulfasalazine), were included. Demographic characteristics of the patients including current smoker status (defined as a patient that smokes at least one cigarette per day), years of formal education, a 28-joint count for swelling and tenderness were registered. A basal HAQ questionnaire, visual scales for global assessment, and pain were answered by all patients, and a CDAI basal score was calculated. The ACR 50 response was determined at 6 months follow-up. Multivariable logistic regression analysis was used to calculate adjusted ORs. Two hundred twenty-five patients were evaluated, but only 144 had a complete follow-up, 43% of the latter did not reach an ACR 50 response. The only factor associated with this outcome was current smoking (OR 3.58, P < 0.008, 95% CI 1.23-11.22). Low level of formal education (<=6 years) had a tendency towards a statistical difference (P < 0.08). After controlling with low level of formal education, sex, age in years, and CDAI baseline value with multivariable logistic regression analysis, current smoking status had an adjusted OR of 3.91 (P < 0.009, 95% CI 1.41-10.81). Smoking is associated with a non-ACR 50 response in early rheumatoid arthritis in patients treated with a combination therapy with methotrexate and sulfasalazine. PMID- 21607553 TI - Serum and urine responses to the aquaretic agent tolvaptan in hospitalized hyponatremic patients. AB - Tolvaptan, an oral, selective arginine vasopressin (AVP) V2 receptor antagonist has been approved for the treatment of euvolemic and hypervolemic hyponatremia in the United States. This report summarizes our center's experience with thirteen patients treated for hyponatremia with one 15-mg dose of tolvaptan. The patients had euvolemic or hypervolemic hyponatremia with decreased serum osmolality and serum sodium (SNa) levels less than 129 mEq/L. Eight patients had a diagnosis of the syndrome of inappropriate antidiuretic hormone (SIADH), and five patients had a diagnosis of congestive heart failure (CHF). Results revealed an increase in SNa in all patients from 122.5 +/- 4.2 to 128.9 +/- 4.1 mEq/L (P < 0.05). The mean increase in SNa of 6.4 mEq/L (range 2-10 mEq/L) 24 h post-tolvaptan was not different in the two groups of patients, but SIADH patients had higher pre and post-tolvaptan SNa levels than CHF patients. Urine osmolalities (UOsm) decreased in all patients, and the patients with SIADH had significantly higher baseline UOsm and a larger decrease in UOsm 12 h post-tolvaptan administration when compared with the CHF patients. AVP levels did not change post-tolvaptan administration. However, the magnitude of increase in SNa levels was inversely related to pretolvaptan AVP levels in the SIADH subgroup (r = -0.7, P = 0.01). Three SIADH patients received small amounts of D5W to attenuate changes in SNa. No significant changes in mean arterial pressure, serum potassium, serum glucose, and blood urea nitrogen or serum creatinine were observed. The data show that tolvaptan is effective for the treatment of hyponatremia and may produce differing responses in disparate patient groups. PMID- 21607554 TI - Meta-analysis of docetaxel-based doublet versus docetaxel alone as second-line treatment for advanced non-small-cell lung cancer. AB - PURPOSE: To compare docetaxel-based doublet with single-agent docetaxel as second line treatment in non-small-cell lung cancer (NSCLC). METHODS: We systematically searched for randomized clinical trials that compared docetaxel-based doublet with single-agent docetaxel in patients with histologically proven non-small-cell lung cancer. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, 1-year survival rate, and grade 3 or 4 toxicity. Data were extracted from the studies by two independent reviewers. The meta-analysis was performed by Stata version 10.0 software (Stata Corporation, College Station, TX, USA). RESULTS: Eight randomized clinical trials (totally 2,126 patients) were eligible. Meta-analysis showed that there was significant improvement in PFS (HR 0.81, 95% CI 0.69-0.96, P = 0.013) and overall response rate (OR 1.42, 95% CI 1.13-1.80, P = 0.03) in docetaxel based doublet group, compared with docetaxel alone, though the pooled HR for overall survival (HR 0.93, 95% CI 0.80-1.07, P = 0.308) showed no significant difference between the two groups. However, there were more incidences of grade 3 or 4 neutropenia (OR 1.2, 95% CI 1.00-1.45, P = 0.05), thrombocytopenia (OR 4.53, 95% CI 1.75-11.75, P = 0.002), and diarrhea (OR 1.78, 95% CI 1.16-2.74, P = 0.008) in docetaxel-based doublet group. With regard to the risk of grade 3 or 4 anemia (OR 1.95, 95% CI 0.62-6.17, P = 0.25), fatigue (OR 1.09, 95% CI 0.75-1.59, P = 0.66), and nausea and vomiting (OR 1.75, 95% CI 0.78-3.91, P = 0.17), there was no significant difference between the two groups. CONCLUSIONS: This was the first meta-analysis of docetaxel-based doublet versus single-agent docetaxel as second-line therapy in the treatment of non-small-cell lung cancer. The results indicated that docetaxel-based doublet therapy did not gain any benefit in survival but significantly improved PFS and better ORR versus single-agent docetaxel. However, more incidences of grade 3 or 4 neutropenia, thrombocytopenia, and diarrhea were observed in docetaxel-based doublet group. PMID- 21607555 TI - Modification of uptake and subcellular distribution of doxorubicin by N acylhydrazone residues as visualised by intrinsic fluorescence. AB - PURPOSE: Doxorubicin (1) is commonly used in the treatment of a wide range of cancers. Some N-acylhydrazones of 1 were previously found to have an improved tumour and organ selectivity. In order to clarify the molecular basis for this effect, the cellular uptake into various cancer cells and the localisation in PtK(2) potoroo kidney cells of 1 and its N-acylhydrazones derived from heptadecanoic acid (2) and 11-(menthoxycarbonyl)undecanoic acid (3) were studied drawing on their intrinsic fluorescence. METHODS: The uptake of compounds 1-3 into human cells of HL-60 leukaemia, 518A2 melanoma, HT-29 colon, and resistant KB-V1/Vbl and MCF-7/Topo breast carcinomas was determined fluorometrically from their residual amounts in the supernatant. Their time-dependent accumulation in PtK(2) potoroo kidney cells was visualised by fluorescence microscopy. RESULTS: The uptake, though not the cytotoxicity, of 2 in multi-drug resistant MCF-7/Topo breast cancer cells was conspicuously greater than that of 1 and 3, probably due to an attractive lipophilic interaction with the lipid-rich membranes of these cells. In non-malignant PtK(2) cells, both 1 and 3 accumulated initially in the nuclei. Upon prolonged incubation, their fluorescent metabolites were visualised in lysosomes neighbouring the nuclei. In contrast, conjugate 2 was not observed in the nuclei at any time. After 2 h, it had accumulated in vesicles scattered all over the cells, and upon prolonged incubation, its fluorescent metabolites were concentrated in the cellular membrane. CONCLUSIONS: Long unbranched fatty acyl residues when attached to doxorubicin via a hydrazone can act as lipophilic membrane anchors. This allows an increased uptake of such derivatives into lipid rich membranes especially of multi-drug resistant cancer cells, a retarded release from there into the cytosol and the eventual storage of their metabolites again in the cell membrane rather than in lysosomes. PMID- 21607556 TI - Combining capecitabine, oxaliplatin, and gemcitabine (XELOXGEM) for colorectal carcinoma patients pretreated with irinotecan: a multicenter phase I/II trial. AB - PURPOSE: Capecitabine plus oxaliplatin (XELOX) is an effective second-line regimen for advanced colorectal carcinoma (CRC) patients pretreated with irinotecan. Previous studies have shown supra-additive anti-tumor activity of gemcitabine (GEM) when administered with oxaliplatin. We investigated the dose, toxicity, and efficacy of a second-line XELOXGEM regimen in CRC patients pretreated with irinotecan. METHODS: Patients with metastatic or recurrent CRC who failed after a first-line irinotecan-containing regimen received escalating doses of gemcitabine (600, 800, 1,000 mg/m(2) d1, d8) followed by capecitabine (1,000 mg/m(2) b.i.d d1-14) and oxaliplatin (100 mg/m(2) d1) on a 21-day cycle. RESULTS: A total of 38 patients were treated. At 800 mg/m(2), two of six patients experienced dose-limiting toxicities (diarrhea and thrombocytopenia). Therefore, the clinically recommended dose was defined as 600 mg/m(2) gemcitabine (d1, d8) followed by 1,000 mg/m(2) capecitabine (b.i.d dl-14) and 100 mg/m(2) oxaliplatin (d1). The most common grade 3/4 toxicities were neutropenia (32%), thrombocytopenia (13%), anemia (11%), and peripheral neuropathy (11%). Ten (26.3%) and 23 (60.5%) patients experienced partial response and stable disease, respectively. The median progression-free survival and overall survival were 5.4 months (95% CI 3.8-6.9 months) and 17.7 months (95% CI 8.4-26.9 months), respectively. CONCLUSIONS: The XELOXGEM triplet combination is an active and safe second-line regimen for advanced CRC patients pretreated with irinotecan. PMID- 21607557 TI - Gemcitabine enhances Wilms' tumor gene WT1 expression and sensitizes human pancreatic cancer cells with WT1-specific T-cell-mediated antitumor immune response. AB - Wilms' tumor gene (WT1), which is expressed in human pancreatic cancer (PC), is a unique tumor antigen recognized by T-cell-mediated antitumor immune response. Gemcitabine (GEM), a standard therapeutic drug for PC, was examined for the regulation of WT1 expression and the sensitizing effect on PC cells with WT1 specific antitumor immune response. Expression of WT1 was examined by quantitative PCR, immunoblot analysis, and confocal microscopy. Antigenic peptide of WT1 presented on HLA class I molecules was detected by mass spectrometry. WT1 specific T-cell receptor gene-transduced human T cells were used as effecter T cells for the analysis of cytotoxic activity. GEM treatment of human MIAPaCa2 PC cells enhanced WT1 mRNA levels, and this increase is associated with nuclear factor kappa B activation. Tumor tissue from GEM-treated MIAPaCa2-bearing SCID mice also showed an increase in WT1 mRNA. Some human PC cell lines other than MIAPaCa2 showed up-regulation of WT1 mRNA levels following GEM treatment. GEM treatment shifted WT1 protein from the nucleus to the cytoplasm, which may promote proteasomal processing of WT1 protein and generation of antigenic peptide. In fact, presentation of HLA-A*2402-restricted antigenic peptide of WT1 (CMTWNQMNL) increased in GEM-treated MIAPaCa2 cells relative to untreated cells. WT1-specific cytotoxic T cells killed MIAPaCa2 cells treated with an optimal dose of GEM more efficiently than untreated MIAPaCa2 cells. GEM enhanced WT1 expression in human PC cells and sensitized PC cells with WT1-specific T-cell mediated antitumor immune response. PMID- 21607558 TI - Sonographic assessment of carpal tunnel syndrome in rheumatoid arthritis: prevalence and correlation with disease activity. AB - Carpal tunnel syndrome (CTS) is one of the most frequent extra-articular manifestations of rheumatoid arthritis (RA). High frequency ultrasonography (US) is a sensitive and specific method in diagnosis of CTS. This study is aimed to: firstly assess diameter frequency of CTS in RA with US and compare with a control group; secondly, investigate relationship of CTS with disease activity. One hundred consecutive RA patients (women/men: 78/22) fulfilling ACR 1987 RA criteria and 45 healthy controls (women/control: 34/11) were enrolled into study. Disease activity parameters, RA and CTS patient global assessment and health assessment questionnaire (HAQ-DI) were recorded. Both patient and control group were questioned about secondary causes of CTS, and Katz hand diagram, Boston CTS questionnaire and Phalen ve Tinel tests were applied once for each hand. Wrist joint and carpal tunnel were assessed with US grey scale and power Doppler US, then cross-sectional area of median nerve (CSA) was calculated. Patients with median nerve CSA between 10.0 and 13.0 mm(2) were evaluated with electromyography (EMG). CTS was diagnosed if CSA of median nerve >13.0 mm(2) or CTS was shown with NCS. Although there was no difference between RA patients and controls in age, sex, history of DM (+) and goitre, CTS was more frequent in RA group (respectively, 17.0% vs. 4.4%, P = 0.038). In RA group with CTS, age, history of DM, disease duration, HAQ-DI score, CTS patient global score, Boston symptom severity and functional status scores were elevated compared to without CTS [respectively, 57 (36-73) vs. 50 (24-76), P = 0.041; 35.3% vs. 6.0%, P < 0.001; 108 (12-396) months vs. 72 (6-360) months, P = 0.036; 1.93 (0.75-2.87) vs. 1.125 (0-2.75), P = 0.013; 52 (1-97) vs. 25 (0-91), P = 0.001; 2.81 (1.18-4.17) vs. 2.0 (1.0-4.01), P = 0.01; 3.37 (1.37-5.0) vs. 2.25 (1.0-5.0), P = 0.008]. No difference was found between CTS (+) and (-) RA patients in acute phase reactants, disease activity and US findings (P > 0.05). Sensitivity of Katz hand diagram was higher than Tinel and Phalen tests (respectively, 100, 60.0, 66.7%). Boston symptom and functional scores of RA patients with CTS diagnosed by EMG were increased than patients CTS (-) by EMG [respectively, 3.05 (1.90-4.27) vs. 1.55 (1.0-2.90), P = 0.002; 3.25 (1.73-3.82) vs. 1.12 (1.0-2.10), P = 0.008]. CTS frequency in RA was found higher than normal population, especially in patients with additional risk factors of CTS. There was no relationship between CTS and disease activity. CTS group had long disease duration and worse functional status. CTS could be a result of the chronic course in RA. In patient with CSA between 10 and 13 mm(2), Boston CTS questionnaire might give additional idea about CTS. PMID- 21607559 TI - Serum levels of macrophage migration inhibitory factor are associated with rheumatoid arthritis course. AB - Rheumatoid arthritis (RA) is an inflammatory autoimmune disease of unknown etiology. Many cytokines have been found to be associated with RA pathogenesis and among them is macrophage migration inhibitory factor (MIF). The aim of this study was to determine whether MIF serum levels are associated with RA course, clinical activity, and clinical biomarkers of the disease. MIF levels were determined in serum samples of 54 RA patients and 78 healthy subjects (HS) by enzyme-linked immunosorbent assay (ELISA). Disease activity was evaluated using the DAS28 score. Patients were subgrouped according to disease activity and years of evolution of disease. Statistical analysis was carried out by SPSS 10.0 and GraphPad Prism 5 software. RA patients presented increased levels of MIF as compared to HS. MIF levels were raised on early stages of RA and tend to decrease according to years of evolution. Moreover, MIF levels positively correlated with rheumatoid factor in RA patients and with C reactive protein in all individuals studied. Our findings suggest that MIF plays a role in early stages of RA. PMID- 21607560 TI - Secondary neuropsychiatric manifestations caused by Epstein-Barr virus encephalitis in a new onset systemic lupus erythematosus patient. AB - Abnormal manifestations of central nervous system in system lupus erythematosus (SLE) patients are mainly caused by primary neuropsychiatric SLE (NP-SLE). We reported a new onset SLE patient who had secondary neuropsychiatric manifestations caused by Epstein-Barr virus (EBV) encephalitis. Although EBV has an uncertain association with SLE, Epstein-Barr virus encephalitis occurred in active SLE patients was not reported previously. Our report may be the first case about EBV encephalitis occurred in active SLE. PMID- 21607561 TI - Eponym : Grisel syndrome. AB - Grisel syndrome or atlantoaxial non-traumatic subluxation is a rare entity, poorly described in pediatric literature, although it is a pathology that usually appears in young children. The typical presentation is a torticollis with a previous surgical antecedent (mainly a surgery of the ear, nose, and throat area like adenoidectomy) or after an upper tract respiratory infection. A prompt diagnosis is essential for a successful evolution, and the treatment in most cases is conservative. We report a case of an 8-year-old girl with a typical evolution of this unusual complication. In our case, the most important element for diagnosis was the 3D CT scanner, and the treatment was conservative with a successful outcome. Pediatricians should be aware of this rare but potentially serious entity to establish the correct treatment and avoid complications. PMID- 21607562 TI - Feasibility of transcutaneous electrical muscle stimulation in acute exacerbation of COPD. AB - Transcutaneous electrical muscle stimulation is a well-established intervention for rehabilitation of clinically stable patients with chronic obstructive pulmonary disease. This study investigated feasibility and safety of this method during acute exacerbation of chronic obstructive pulmonary disease. We included 19 patients (71 +/- 6 years, 76% men) who underwent two sessions/day during hospitalization (15 +/- 1 training sessions). They reported good tolerability and excellent safety profile of transcutaneous electrical muscle stimulation. Our results set the stage for future research to determine specific benefit of transcutaneous electrical muscle stimulation, either alone or in combination with nutritional support and pharmacological therapy. PMID- 21607563 TI - Craving in response to stress induction in a human laboratory paradigm predicts treatment outcome in alcohol-dependent individuals. AB - RATIONALE: Alcohol dependence is associated with high rates of recidivism. Stress has been shown to increase alcohol craving in alcohol-dependent individuals, but the association between stress-induced craving and alcoholism treatment outcome is not well understood. OBJECTIVE: The aim of the present study was to examine the relationship between strength of stress-induced alcohol craving in the human laboratory and subsequent drinking in a cohort of treatment-seeking, alcohol dependent adults. MATERIALS AND METHODS: This is a prospective study assessing stress-induced craving in the lab and subsequent treatment outcomes in alcohol dependent subjects enrolled in a 12-week outpatient study. Stress was induced using a previously developed, individualized, audio recorded stress script and validated with objective (salivary cortisol) and subjective measures of distress. In vivo craving for alcohol was measured pre- and post-challenge using VAS. RESULTS: Subjects were 28 (16 male, 12 female) alcohol-dependent outpatients. Greater stress-induced craving was associated with a blunted salivary cortisol response, significantly shorter time to alcohol relapse, higher mean drinks per week, fewer percent days abstinent, and lower rates of complete abstinence over the study duration (all p's < 0.05). Conversely, no demographic or baseline variables were significant predictors of any outcome variable. CONCLUSIONS: These results suggest that greater stress-related increases in alcohol craving are associated with poorer alcohol treatment outcomes. The findings support the use of stress-induced craving as a predictor of alcohol relapse propensity. Furthermore, treatments that address high stress levels and the associated high levels of alcohol craving are likely to improve treatment outcomes in alcohol dependence. PMID- 21607564 TI - Role of gonadal hormones on mu-opioid-stimulated [35S]GTPgammaS binding and morphine-mediated antinociception in male and female Sprague-Dawley rats. AB - RATIONALE: Male rats are more sensitive to morphine-mediated antinociception than female rats. A role for gonadal hormones in this sex difference has not been clearly defined. OBJECTIVES: To test the hypothesis that in vivo manipulation of gonadal hormones alters morphine-mediated G protein activation and leads to changes in morphine-mediated antinociception. METHODS: Adult male and female rats were gonadectomized and treated with either estradiol or testosterone in the females or testosterone in the male for up to 10 days. The ability of morphine and the peptidic mu-opioid agonist [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) to stimulate [(35)S]GTPgammaS binding was measured in brain slices. In separate groups of identically treated rats, the antinociceptive response to morphine was determined using the warm-water tail-withdrawal assay. RESULTS: In the thalamus, morphine- and DAMGO-stimulated [(35)S]GTPgammaS binding was reduced by estradiol treatment of gonadectomized females compared to gonadectomized females treated with vehicle or testosterone. In the nucleus accumbens, the morphine-stimulated [(35)S]GTPgammaS binding was increased by estradiol treatment of gonadectomized females. In males, castration caused an increase in agonist stimulated binding in the thalamus and a reduction in the amygdala compared with intact males. No significant changes were seen in mu-opioid agonist-stimulated [(35)S]GTPgammaS binding in other brain regions. There was no difference in antinociception following the systemic administration of morphine across the different hormonal manipulation conditions and the greater sensitivity of males was maintained irrespective of the treatment conditions. CONCLUSIONS: The modulation of mu-opioid receptor activation of G proteins by manipulation of sex hormones is region-specific and not reflected in antinociceptive responsiveness to morphine. PMID- 21607565 TI - Imaging of diabetic retinopathy and diabetic macular edema. AB - Imaging of the retinal complications of diabetes mellitus is rapidly changing from the emergence of new technology such as optical coherence tomography. In particular, the characterization of diabetic macular edema is much easier for the clinician and there are new, more sensitive clinical research end points. However, our understanding of structure-functional relationships remains suboptimal and the classification of macular edema by optical coherence tomography continues to evolve. The classification of diabetic retinopathy severity continues to rely upon fundus photography, although the transition from film to digital photography presents both challenges and advantages. PMID- 21607566 TI - Distribution and changes of serotonin and dopamine levels in the central nervous system and ovary of the Pacific white shrimp, Litopenaeus vannamei, during ovarian maturation cycle. AB - We investigated changes in serotonin (5-HT) and dopamine (DA) levels and in their distribution patterns in the central nervous system (CNS) and ovary during the ovarian maturation cycle in the Pacific white shrimp, Litopenaeus vannamei. The concentrations of these two neurotransmitters were determined by using high performance liquid chromatography with electrochemical detection. The 5-HT concentration exhibited a gradual increase in the brain and thoracic ganglia during early ovarian stages I, II, and III, reaching a maximum at the mature ovarian stage IV, whereas DA showed its highest concentration at ovarian stage II in the brain and thoracic ganglia and then declined to its lowest concentration at ovarian stage IV. In the ovaries, 5-HT was lowest at ovarian stage I and gradually increased to a peak at ovarian stage IV. Conversely, the concentration of DA was highest at ovarian stages I and II and lowest at ovarian stage IV. In the brain, 5-HT immunoreactivity (-ir) from stage IV and DA-ir from stage II were distributed extensively in neurons of clusters 6, 11, and 17, in fibers, and in the anterior and posterior medial protocerebral, olfactory, antenna II, and tegumentary neuropils. In the circumesophageal, subesophageal, thoracic, and abdominal ganglia, both 5-HT-ir and DA-ir were detected in neuropils and surrounding neurons and fibers. 5-HT-ir and DA-ir were more intense in the thoracic ganglia than in other parts of the CNS. In the ovary, 5-HT-ir exhibited high intensity in late oocytes, whereas DA-ir was more intense in early oocytes. Thus, opposing changes occur in the levels of these two neurotransmitters and in their specific localizations in the CNS and ovary during ovarian maturation, indicating their important involvement in female reproduction. PMID- 21607567 TI - Load-bearing capacity of artificially aged zirconia fixed dental prostheses with heterogeneous abutment supports. AB - Aim of this in vitro study was to investigate the effect of artificial ageing and differential abutment support on the load-bearing capacity of zirconia posterior four-unit fixed dental prostheses (FDPs). Thirty-six FDPs were fabricated using CAD/CAM technology and divided into three groups. Specimens in the first group were cemented onto tooth analogues with simulated periodontal resilience, in the second group onto a dental implant and a tooth analogue, but in the third group only onto implants. Half of the samples in each group underwent artificial ageing. Afterwards, all FDPs were loaded until bulk fracture in a universal testing machine. Load-displacement curves and forces at fracture were recorded and results were statistically analysed using ANOVA. Load-bearing capacities within the different test groups averaged as follows (control/artificially aged): tooth-tooth supported (2,009/1,751 N), tooth-implant supported (2,144/1,935 N) and implant-implant supported (2,689/2,484 N). Artificial ageing as well as differential abutment support did have a significant influence on the fracture strength of the zirconia FDPs. Implant-retained prostheses demonstrated the highest load-bearing capacity, while resilient support was demonstrated to be unfavourable. According to these in vitro results, zirconia four-unit prostheses may be promising for application in posterior areas with all three support scenarios (implant-assisted, tooth-retained, or implant-tooth-interconnected prostheses). However, the restorations' mechanical strength may expected to be significantly influenced in situ by ageing of the material on the long term. PMID- 21607568 TI - Efficacy of taurolidine against periodontopathic species--an in vitro study. AB - The antimicrobial effect of taurolidine was tested against periodontopathic species in comparison to chlorhexidine digluconate in the presence or absence of serum. Minimal inhibitory concentrations (MIC), microbiocidal concentrations (MBC), as well as killing were determined against 32 different microbial strains including 3 Porphyromonas gingivalis, 3 Aggregatibacter actinomycetemcomitans, and 15 potentially superinfecting species with and without 25% v/v human serum. The MIC(50) of taurolidine against the tested microbial strains was 0.025% and the MIC(90) 0.05%. The respective values for the MBCs were 0.05% and 0.1%. Addition of 25% serum (heat-inactivated) did not change the MIC and MBC values of taurolidine. In contrast, MICs and MBCs of chlorhexidine (CHX) increased by two steps after addition of serum. Taurolidine killed microorganisms in a concentration and time-dependent manner, the killing rate of 1.6% taurolidine was 99.08% +/- 2.27% in mean after 2 h. Again, killing activity of taurolidine was not affected if serum was added, whereas addition of inactivated serum clearly reduced the killing rate of all selected bacterial strains by CHX. Therefore, taurolidine possesses antimicrobial properties which are not reduced in the presence of serum as a main component in gingival crevicular fluid and wound fluid. Taurolidine may have potential as an antimicrobial agent in non-surgical and surgical periodontal treatment. PMID- 21607571 TI - Histologic evaluation of absorbable and non-absorbable barrier coated mesh secured to the peritoneum with fibrin sealant in a New Zealand white rabbit model. AB - PURPOSE: The purpose of this study is to evaluate the histologic response to fibrin sealant (FS) as an alternative fixation method for laparoscopic ventral hernia repair. METHODS: One non-absorbable barrier mesh (ComposixTM) and three absorbable barrier meshes (SeprameshTM, ProceedTM, and ParietexTM Composite) were used for the study, with uncoated macroporous polypropylene mesh (ProLite UltraTM) as the control. Three methods of fixation were used: #0-polypropylene suture + FS (ARTISSTM, Baxter Healthcare Corp.), FS alone (ARTISSTM), or tacks alone (n = 10 for each group). Two pieces of mesh (of dimensions 4 * 4-cm) were secured intraperitoneally in 75 New Zealand white rabbits. After 8 weeks, hematoxylin and eosin (H&E)-stained specimens were evaluated for host tissue response. Statistical significance (P < 0.05) was determined using a one-way analysis of variance (ANOVA) with Fisher's least significant difference (LSD) post hoc test. RESULTS: ComposixTM with FS only showed significantly greater cellular infiltration than with suture + FS (P = 0.0007), ProceedTM with FS only had significantly greater neovascularization than with suture + FS (P = 0.0172), and ProLite UltraTM with suture + FS had significantly greater neovascularization than with tacks only (P = 0.046). Differences due to mesh type showed that ComposixTM exhibited less extensive cellular infiltration (P <= 0.0032), extracellular matrix (ECM) deposition, and neovascularization, and demonstrated less inflammatory cells and more fibroblasts compared to the other meshes (P < 0.05). CONCLUSIONS: FS did not have a significant histologic effect compared to tacks when utilized for the fixation of mesh to the peritoneum of New Zealand White rabbits. However, the mesh type did have a significant histologic effect. The permanent barrier mesh (ComposixTM) was associated with less histologic incorporation than absorbable barrier and macroporous meshes, as evidenced by lower levels of cellular infiltration, ECM deposition, and neovascularization, independent of the fixation method used. PMID- 21607569 TI - The role of the precursor structure in the biogenesis of microRNA. AB - The human genome contains more than 1,000 microRNA (miRNA) genes, which are transcribed mainly by RNA polymerase II. The canonical pathway of miRNA biogenesis includes the nuclear processing of primary transcripts (pri-miRNAs) by the ribonuclease Drosha and further cytoplasmic processing of pre-miRNAs by the ribonuclease Dicer. This review discusses the issue of miRNA end heterogeneity generated primarily by Drosha and Dicer cleavage and focuses on the structural aspects of the Dicer step of miRNA biogenesis. We examine the structures of miRNA precursors, both predicted and experimentally determined, as well as the influence of various motifs that disturb the regularity of pre-miRNA structure on Dicer cleavage specificity. We evaluate the structural determinants of the length diversity of miRNA generated by Dicer from different precursors and highlight the importance of asymmetrical motifs. Finally, we discuss the impact of Dicer protein partners on cleavage efficiency and specificity and propose the contribution of pre-miRNA structural plasticity to the dynamics of the dicing complex. PMID- 21607572 TI - Low-cost mesh for inguinal hernia repair in resource-limited settings. AB - INTRODUCTION: Hernia repair is one of the most frequently performed surgical procedures worldwide, yet more than half of hernias may be untreated in African countries that lack adequate and affordable surgical care. Although this disease burden can be effectively reduced by surgical repair, public health efforts to promote repair have been sparse because of the presumed high cost of surgery. OBJECTIVE: To review the epidemiology and treatment of hernias in African countries and to assess the efficacy and safety of using low-cost mesh for repair in resource-limited settings. METHODS: An extensive literature search was performed using PubMed and the Cochrane Library to locate pertinent background information and studies that used low-cost alternatives to commercial mesh. RESULTS: Most hernia repairs in Africa are performed as high-risk emergency procedures. When treatment is provided, fewer than 5% are repaired using implanted mesh because of its high cost, despite the demonstrated improvement in clinical outcomes with tension-free repair. A total of four studies using low cost mesh were reviewed. Three of the studies compared postoperative outcomes for repairs using sterile mosquito nets with those using commercial surgical mesh. The fourth study randomized patients to receive either an indigenous bilayer device or the Prolene Hernia System. No significant differences in recurrence or in incidence of wound complications between repairs using low-cost and commercial mesh were observed. The price of low-cost mesh was generally less than 1/1,000 the price of commercial mesh. CONCLUSIONS: There were no significant differences in outcomes between repairs using low-cost and commercial mesh. While the size of the study populations and the limited time for follow-up preclude conclusive measures of effectiveness, recurrence, and long-term complications, these studies demonstrate that providing an improved standard of surgical care need not be prohibitively expensive. PMID- 21607573 TI - Subarachnoid hemorrhage and negative angiography: clinical course and long-term follow-up. AB - The aim of this study was to investigate the long-term natural history of nontraumatic angiogram-negative subarachnoid hemorrhage with typical pretruncal (P-SAH) and diffuse (D-SAH) pattern of hemorrhage. A retrospective review of 102 patients who experienced angiographically negative SAH at our institution was undertaken (11.6% of 882 spontaneous SAH). Follow-ups were obtained at 7.9 to 16 years. In the D-SAH group, 11 patients (13.9%) out of 79 had an aneurysm, and four (5.1%) had rebleeding episodes. In the P-SAH group, the second angiography was negative in all of the 23 cases, and no rebleeding episodes were recorded. The long-term follow-up confirms that P-SAH is a benign disease. A second angiography could not be necessary. D-SAH is probably due to an aneurysm that thrombose early after the bleeding. At short-term follow-up, the sack could frequently recanalize and rebleed, whereas a late follow-up shows that rebleeding is very rare. PMID- 21607574 TI - No need for systemic heparinization during laparoscopic donor nephrectomy with short warm ischemia time. AB - PURPOSE: Systemic heparin administration during laparoscopic donor nephrectomy (LDN) may prevent microvascular thrombus formation following warm ischemia. We herein present our experience with and without systemic heparinization during LDN. METHODS: We retrospectively reviewed donor complications and graft outcomes in 119 consecutive live donor kidney transplantations between January 2005 and December 2009. Systemic heparin was administered to the first 65 donors. LDN was carried out by 2 surgeons using a pure laparoscopic technique. RESULTS: Total operating time for LDN was significantly longer in the heparin group (202 vs. 157 min). The incidence of renal artery multiplicity was significantly higher in the heparin group. Mean warm ischemia time was 160 s, and mean hospital stay was 5 days with no differences between groups. Postoperative hemorrhage occurred in 3 donors with systemic heparinization and in 1 without heparinization. Two donors received blood transfusions, and 2 underwent laparoscopic reexploration. Three grafts were lost in the heparin group and 1 in the non-heparin group. Graft loss was due to early vascular thrombosis (n = 3) and due to acute rejection (n = 1). Overall, 1-year graft survival was 96.6%, and 1-year serum creatinine was 1.41 mg/dl (P = n. s. between groups). CONCLUSIONS: Abandoning systemic donor heparinization in LDN with short warm ischemia has a low complication rate without adverse effects on short- and long-term graft outcomes. PMID- 21607576 TI - Role of US in acute scrotal pain. AB - BACKGROUND: The acute scrotum is a common emergency department (ED) presentation and can be defined as any condition of the scrotum or intrascrotal contents requiring emergent medical or surgical intervention. Although rarely fatal, acute scrotal pathology can result in testicle infarction and necrosis, testicular atrophy, infertility, and significant morbidity. METHODS: Scrotal US is best performed with a linear 7.5- to 12-MHz transducer. In addition to imaging in the longitudinal and transverse planes, it is helpful to obtain simultaneous images of both testes for comparison. Color Doppler is used to evaluate for abnormalities of flow and to differentiate vascular from nonvascular lesions. Attention to appropriate color Doppler settings to optimize detection of slow flow is critical. RESULTS: The evaluation of acute scrotal pain can be challenging for the clinician initially examining and triaging the patient. Acute scrotal conditions due to traumatic, infectious, vascular, or neoplastic etiologies can all present with pain as the initial complaint. Additionally, the laboratory and physical examination findings in such conditions may overlap; this, coupled with potential patient guarding and lack of collaboration, may result in a limited, non-specific physical examination. Therefore, scrotal ultrasound has emerged to play a central role in the evaluation of the patient presenting with acute scrotal pain. CONCLUSIONS: In conclusion, we are firmly convinced that a scrotal ultrasound should always be performed in the presence of acute scrotal pain. Moreover, urologist should be able to perform a scrotal ultrasound but, if imaging does not supply a clear diagnosis, surgical exploration is still mandatory. PMID- 21607575 TI - Color Doppler ultrasound imaging in varicoceles: is the venous diameter sufficient for predicting clinical and subclinical varicocele? AB - PURPOSE: Investigating the diagnostic value of color Doppler ultrasound for defining the varicocele grade according to WHO criteria. METHODS: A total of 217 men (129 with clinical varicocele and 88 without clinical varicocele) were investigated by physical examination and color Doppler ultrasound and categorized according to WHO varicocele criteria (0, subclinical, I, II, and III). Diameter and reflux of the largest vein in the pampiniform plexus were measured bilaterally with the patient in the supine position in rest and during the Valsalva maneuver. To assess the possibility of differentiating varicocele grade by venous diameter, optimal cut-point values were determined by receiver-operator characteristic (ROC) analysis. RESULTS: With increased varicocele grade, a larger vein diameter was more significant in rest and during Valsalva (in all cases P < 0.05), except between grade I and grade II. Retrograde peak flow velocities were similar in every group (in all cases P > 0.1). Only grade III varicoceles demonstrated significantly increased peak flow values compared with all other grades (P < 0.001). There were no side-related differences when comparing identical varicocele grades (in all cases P > 0.1). Venous diameters above 2.45 mm in rest (sensitivity 84%, specificity 81%) or 2.95 mm during Valsalva (sensitivity 84%, specificity 84%) predicted the presence of a clinical varicocele. CONCLUSIONS: Our findings support the hypothesis that clinical varicoceles can be predicted with high accuracy based only on the diameter of testicular veins using cut-point values of >2.45 mm in rest or >2.95 mm during Valsalva maneuver in the supine position. PMID- 21607577 TI - Management of complication from temporal bone fractures. AB - The objective of the study is to review clinical findings and outcomes in patients with temporal bone fractures, and to show an incidence and management of complications. It is the retrospective clinical study and the study took place at tertiary referral center. Fifty-two patients with temporal bone fractures. Data were collected from patients' charts and clinical review. Patients were classified into five groups according to the CT scan. The primary endpoint of study was to show management of possible complication from temporal bone fractures and to analyze association with intracranial injuries. The second endpoint was to show incompleteness of traditionally classification of fracture type. Of the 52 patients with 54 fractures, 27 (50%) had longitudinal fractures, 4 (7.4%) had transverse fractures, 17 (31.5%) had temporal squama-mastoid fractures, 4 (7.4%) had mixed fractures and 2 (3.7%) had isolated meatal fracture. Fifty-eight percent of patients had at least one intracranial pathologic finding, of which 11% had two or more. Persistent conductive hearing loss was noted in 8 of 16 affected patients. The facial paralysis occurred in seven patients. One patient had benign paroxysmal positional vertigo developed 3 weeks after injury. In conclusion, rarely temporal bone fractures are isolated injures. The squama-mastoid fracture in most cases associated with intracranial injuries. Coordination between the neurosurgeon and otologist is essential in the care of such patients. Further large studies will be done to give a more complete classification of temporal bone fractures which will include all fracture patterns and predict clinical outcome. PMID- 21607578 TI - Clinical impact of cervical lymph node involvement and central neck dissection in patients with papillary thyroid carcinoma: a retrospective analysis of 368 cases. AB - The impact of cervical lymph node metastases and the optimal surgical management of the neck in patients with papillary thyroid carcinoma (PTC) remain controversial. The objectives of this retrospective study were to determine, in patients with PTC, the predictive factors and the impact on tumor recurrence rate of cervical lymph node involvement, and to evaluate the oncologic results and the morbidity of central neck dissection (CND). We reviewed the records of patients who had undergone surgical treatment for PTC at our institution between 1990 and 2000. A total of 368 patients (86 men and 282 women) were included in this study. Young age (p = 0.02), tumor size (p = 0.001) and extrathyroidal tumor extension (p = 0.003) were significant predictive factors of cervical lymph node metastatic involvement (multivariate analysis). Initial metastatic cervical lymph node involvement was identified as an independent risk factor of tumor recurrence (multivariate analysis, p = 0.01). Metastatic lymph node(s) were found in prophylactic CND specimens in 31% of the patients. CND increased the risk of postoperative hypocalcemia (p = 0.008) and of permanent hypoparathyroidism (p = 0.002). In conclusion, cervical lymph node metastatic involvement at the time of initial surgery is an independent risk factor of tumor recurrence. CND provided an up-staging of more than 30% of patients with a clinically N0 neck, but was associated with significant morbidity regarding parathyroid function. PMID- 21607579 TI - Transnasal endoscopic marsupialization of postoperative maxillary mucoceles: middle meatal antrostomy versus inferior meatal antrostomy. AB - The aim of this study was to evaluate the efficacy of transnasal endoscopic marsupialization as a treatment modality in patients with postoperative maxillary mucoceles and to compare the efficacy of marsupialization via middle meatal antrostomy with that of marsupialization via inferior meatal antrostomy. The study design was a retrospective clinical series and the setting was a tertiary referral center. After obtaining approval from the local ethics committee, we reviewed the medical records of 39 consecutive patients with postoperative maxillary mucoceles who were diagnosed and treated at the Department of Otolaryngology, Chang Gung Memorial Hospital, Taiwan, from 2004 to 2009. Transnasal endoscopic marsupialization was performed on 32 patients (34 sides) with postoperative maxillary mucoceles. All patients were followed for more than 12 months after surgery, and recurrence was noted in five patients (14.9%). Recurrence was experienced by five patients who underwent inferior meatal antrostomy and zero patients who underwent middle meatal antrostomy; thus, a statistically significant difference (p = 0.04) was observed. Transnasal endoscopic marsupialization is an effective modality for postoperative maxillary mucoceles and results in reduced morbidity. The use of middle meatal antrostomy in particular is preferred. PMID- 21607580 TI - Choanal adenoid in adults with persistent nasal symptoms: endoscopic management to avoid misdiagnosis and unsuccessful surgeries. AB - Our objective was to confirm the necessity of nasal endoscopy in the diagnosis and treatment of choanal adenoid in adult patients with persistent bilateral nasal obstruction and recurrent nasal infections that may lead to repeated unsuccessful medical and surgical procedures. We present a series of 64 adult patients (18-37 years: 40 males, 24 females). All patients had persistent bilateral nasal obstruction and recurrent nasal infections. There was history of repeated medical and surgical unsuccessful procedures. Choanal adenoid was confirmed by nasal endoscopy and CT scanning. Absence of adenoid tissues in the nasopharynx was confirmed in all cases. Surgical removal of choanal adenoids was undertaken in all cases endoscopically. Some other surgical procedures like straightening of a deviated septum or reduction of a hypertrophied turbinate were undertaken in some indicated cases. Most of the cases experienced complete relief from obstruction and return of a patent nasal airway, and improvement of associated complaints such as dry mouth and persistent cough. A thorough review of this phenomenon and its clinical relevance, and methods of diagnosis and management are presented. We recommend a thorough nasal endoscopy as a routine in cases of persistent nasal obstruction even in the presence of an apparent cause of obstruction. PMID- 21607581 TI - The semisolid bolus swallow test for clinical diagnosis of oropharyngeal dysphagia: a prospective randomised study. AB - Contrary to clinical experience, clinical swallow tests are predominantly performed using water (water swallow tests, WST). In this study, we examine whether swallow tests performed using a bolus of semisolid food (bolus swallow test, BST) offer benefits. In a prospective, randomised, blind study, the results of a standardised saliva swallow test (SST), WST, BST, combinations of these tests and an endoscopic swallow test (FEES) in patients with oropharyngeal swallowing disorders of neurological (NEU) and non-neurological (NNEU) origin were compared. Sensitivity, specificity, test accuracy and inter-rater reliability were analysed. 62 patients (mean age = 64.68; range = 22-84) were included in the study (NEU = 40; NNEU = 22). A sensitivity of 70.7% (NEU = 70.3%, NNEU = 71.4%) and specificity of 82.5% (NEU = 92.3%; NNEU = 100%) were determined for the WST. The BST + SST was found to have a sensitivity of 89.6% (NEU = 66.7%; NNEU = 90.9%) and a specificity of 72.7% (NEU = 87.5%; NNEU = 90.9%). Analysis of test accuracy showed a statistically significant correlation between FEES and BST + SST. Only BST + SST exhibited statistically significant inter-rater reliability. BST in combination with SST was the sensitive clinical instrument for detecting aspiration both over the patient population as a whole and over the two sub-populations. Inter-rater reliability was found to be statistically significant. The results presented here demonstrate the benefit of semisolid food in investigating clinical dysphagia. PMID- 21607582 TI - Two patients with germline mutations in both BRCA1 and BRCA2 discovered unintentionally: a case series and discussion of BRCA testing modalities. AB - When a family is known to have a BRCA mutation, genetic testing for family members is typically limited to single site analysis of the known mutation. The exception to this is in Ashkenazi Jewish families, where testing for the three common Ashkenazi Jewish BRCA mutations is recommended. We report two cases, one without Ashkenazi Jewish ancestry and one with maternal Ashkenazi Jewish ancestry, who underwent Comprehensive BRACAnalysis testing despite known BRCA1 mutations in family members. Testing identified the BRCA1 mutation previously identified, and a second mutation in BRCA2. These cases raise the question of whether or not Single Site BRACAnalysis for a known familial BRCA mutation is always the appropriate test when testing an affected individual. The implications of missing a second mutation are discussed. PMID- 21607584 TI - Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer. AB - Mitotic regulatory pathways insure proper timing of mitotic entry, sister chromatid cohesion and separation, and cytokinesis. Disruption of this process results in inappropriate chromosome segregation and aneuploidy, and appears to contribute to cancer. Specifically, disregulation and somatic mutation of mitotic regulators has been observed in human cancers, and overexpression of mitotic regulators is common in aggressive and late stage tumors. However, the role of germline variation in mitotic pathways and risk of cancer is not well understood. We tested 1,084 haplotype-tagging and functional variants from 164 genes in mitotic regulatory pathways in 791 Caucasian women with breast cancer and 843 healthy controls for association with risk of overall and high grade breast cancer. Sixty-one single nucleotide polymorphisms (SNPs) from 40 genes were associated (P < 0.05) with risk of breast cancer in a log-additive model. In addition, 60 SNPs were associated (P < 0.05) with risk of high grade breast cancer. However, none of these associations were significant after Bonferroni correction for multiple testing. In gene-level analyses, CDC25C, SCC1/RAD21, TLK2, and SMC6L1 were associated (P < 0.05) with overall breast cancer risk, CDC6, CDC27, SUMO3, RASSF1, KIF2, and CDC14A were associated with high grade breast cancer risk, and EIF3S10 and CDC25A were associated with both. Further investigation in breast and other cancers are needed to understand the influence of inherited variation in mitotic genes on tumor grade and cancer risk. PMID- 21607583 TI - Estrogen receptor-alpha and sex steroid hormones regulate Toll-like receptor-9 expression and invasive function in human breast cancer cells. AB - Toll-like receptor 9 (TLR9) is a cellular DNA-receptor, which is widely expressed in cancer. Synthetic TLR9-ligands induce cancer cell invasion in vitro, but the role of TLR9 in cancer pathophysiology remains unclear. Increased TLR9 expression has been, however, detected in estrogen receptor negative (ER-) breast cancers. In this study, we investigated the effects of ERalpha expression and sex steroid hormones on TLR9 expression in human ER+ (MCF-7, T47-D) and ER- (MDA-MB-231) breast cancer cell lines in vitro. We also studied TLR9 mRNA expression in archival breast cancer specimens (n = 12) with qRT-PCR, using primer sets that detect only the TLR9A isoform or the isoforms A and B (TLR9A/B). The TLR9 mRNA expression was detected in 10/12 specimens with both primer sets, and in 1/12 with only the TLR9A or the TLR9A/B primer sets. The basal TLR9 mRNA expression levels were significantly lower in the ER+ cell lines as compared with the ER- MDA-MB-231 cells. The transfection of ERalpha cDNA into MDA-MB-231 cells also resulted in down-regulation of TLR9 expression. While sex steroids had no effect on TLR9 expression in MCF-7 cells, testosterone (10(-8) M) induced TLR9 expression in MDA-MB-231 and T47-D cells. Although bicalutamide blocked this testosterone effect in MDA-MB-231 cells, in T47-D cells bicalutamide increased TLR9 expression and only partially blocked the testosterone effects. Estradiol (10(-8) M) induced TLR9 expression in T47-D cells. The invasive effects of synthetic TLR9-ligands were augmented by testosterone in vitro. This effect was lost in TLR9 siRNA MDA-MB-231 cells and also decreased by over-expression of ERalpha, which also inhibited NF-kappaB activation by TLR9-ligands. In conclusion, expression of TLR9 isoforms A and B can be detected in clinical breast cancer specimens. The ERalpha and sex steroid hormones regulate TLR9 expression and invasive effects in the breast cancer cells. Also, the commonly used hormonal cancer therapy bicalutamide affects TLR9 expression. PMID- 21607585 TI - Simultaneous measurement of ERalpha, HER2, and phosphoERK1/2 in breast cancer cell lines by flow cytometry. AB - The activation of human epidermal growth factor receptor-2 (HER2) results in the activation of the mitogen-activated protein kinase (MAPK) cascade that may lead to the resistance to anti-estrogen therapy in estrogen receptor (ERalpha) expressing breast cancer by means of phosphorylation of ERalpha in the N-terminal region by phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and by means of decreasing ERalpha expression. Immunohistochemistry is the most widely used technique for the detection of ERalpha and HER2 in breast cancer specimens, however, is inadequate in its ability to assess the relationship between ERalpha, HER2, and MAPK cascade at the single cell level. To clear this major hurdle, we devised a novel flow cytometric method to quantify the expression of ERalpha, HER2, and the activation of MAPK cascade simultaneously in single cells. The method was validated by concurrent Western blotting in established cell lines: MDA-231 (ERalpha and HER2-negative), MCF-7 (ERalpha positive, HER2-negative), MCF-7 cells overexpressing ERalpha after long-term incubation in estrogen-free medium, and HER2 transfected MCF7 cells. Using the flow cytometry method, we confirmed the previous finding that ERalpha expression is down-regulated upon epidermal growth factor mediated ERK1/2 phosphorylation in EGFR/MCF-7 cells. To our knowledge, this is the first such assay to incorporate simultaneous single cell measurement for all of these pathways, which may prove useful to determine the intratumoral heterogeneity in breast tumors or the receptor status in circulating tumor cells. PMID- 21607586 TI - G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer. AB - Recently, we have shown that the new G-protein-coupled estrogen receptor GPR30 plays an important role in the development of tamoxifen resistance in vitro. This study was undertaken to evaluate the correlation between GPR30 and tamoxifen resistance in breast cancer patients. GPR30 protein expression was evaluated by immunohistochemical analysis in 323 patients with primary operable breast cancer. The association between GPR30 expression and tamoxifen resistance was confirmed in a second cohort of 103 patients treated only with tamoxifen. Additionally, we evaluated GPR30 expression in 33 primary tumors and in recurrent tumors from the same patients. GPR30 expression was detected in 56.7% of the breast cancer specimens investigated and it correlated with overexpression of HER-2 (P = 0.021), EGFR (P = 0.024) and lymph node status (P = 0.047). In a first cohort, survival analysis showed that GPR30 was negatively correlated with relapse-free survival (RFS) only in patients treated with tamoxifen (tamoxifen with or without chemotherapy). GPR30 expression was associated with shorter RFS (HR = 1.768; 95% CI, 1.156-2.703; P = 0.009). In a subset of patients treated only with tamoxifen, multivariate analysis revealed that GPR30 expression is an independent unfavorable factor for RFS (HR = 4.440; 95% CI, 1.408-13.997; P = 0.011). In contrast, GPR30 tended to be a favorable factor regarding RFS in patients who did not receive tamoxifen. In 33 paired biopsies obtained before and after adjuvant therapy, GPR30 expression significantly increased only under tamoxifen treatment (P = 0.001). GPR30 expression in breast cancer independently predicts a poor RFS in patients treated with tamoxifen. PMID- 21607587 TI - Clinical usefulness of pit patterns for detecting colonic lesions requiring surgical treatment. AB - BACKGROUND: The number of patients suffering from colorectal cancer is increasing. According to Japanese guidelines, lesions with a submucosal invasive depth >1,000 MUm should be treated with radical proctocolectomy. We propose and evaluate a new clinical classification for pit patterns that uses endoscopy to assess lesion depth for determination of the appropriate therapeutic approach for early colorectal cancers and adenomas. METHODS: Endoscopic images of colorectal adenomas and early cancer cases with type V(I) pit pattern, resected surgically or endoscopically from April 2002 to April 2007 at Showa University Yokohama Northern Hospital, were utilized for analysis. Each image was retrospectively analyzed for (A) pit narrowness, (B) irregular pit margins, and (C) indistinct stromal staining. Sensitivity, specificity, and predictive value were evaluated as major outcomes, using pathological results as the standard. RESULT: In total, 186 cases were assessed. With all features considered (A, B, and C), the sensitivity, specificity, and positive and negative predictive values were 47.8%, 86.3%, 66.0%, and 74.2%, respectively. When limited to two features (A and B), these values were 75.3%, 81.2%, 70.2%, and 84.8%, respectively. CONCLUSION: Our results suggest that the established criteria can, to a certain degree, distinguish between high and low irregularity in colorectal lesions with V(I) pit pattern indicating submucosal cancer infiltration of more or less than 1,000 MUm with the clinical consequence of surgery versus endoscopic mucosal resection/endoscopic mucosal dissection. PMID- 21607588 TI - Papillary thyroid carcinoma does not have standard course in children. AB - BACKGROUND AND PURPOSE: Papillary thyroid carcinoma has a favorable outcome in children. Recent experience with young children cases with early recurrences, after the total thyroidectomy and excision of palpable lymph nodes, in contrast to usual course of disease in adolescent cases, prompted us to review our experience on papillary carcinoma surgery. MATERIALS AND METHODS: Sixteen children who underwent surgery for papillary carcinoma between 1997 and 2010 were included. The charts and surgery notes were evaluated retrospectively and age, sex, complaints and physical findings at presentation, past medical history, results of laboratory tests, imaging findings, aspiration biopsy, extent of disease, details of surgery, complications and postoperative course were noted. RESULTS: Male to female ratio was 3:1. The mean age was 10.9 years (range, 5-16). The presenting symptom was palpable swelling in the neck (n = 12) or asymptomatic nodule was detected incidentally (n = 4). Physical examination findings were palpable nodule (n = 7), lymphadenopathy (n = 6) or both (n = 4). Thyroid ultrasound (US) revealed nodule (n = 9), heterogenisity of the parenchyma and enlargement of thyroid (n = 9), and microcalcifications (n = 5). Fine-needle aspiration biopsy was performed in 12 patients and was suggestive for malignancy in most cases (91%). Pulmonary metastasis was detected at presentation in two patients and appeared after thyroidectomy in one patient. Complementary thyroidectomy was performed in nine patients because the total thyroidectomy with or without cervical lymph node dissection was the treatment of choice (n = 15). Iodine scan was performed 4 weeks later following thyroidectomy. Radioactive iodine ablation (RIA) therapy was given to 11 patients who had residual or recurrent disease. Postoperative complications were permanent hypoparathyroidism (n = 4), recurrent laryngeal nerve injury (n = 3), lymphorea (n = 1) and Horner's syndrome (n = 1). CONCLUSION: Total thyroidectomy and excision of affected lymph nodes is the current mode of surgical management for thyroid papillary carcinoma in children. However, especially in young children (<10 years), modified lymph node dissection should be added to total thyroidectomy in order to avoid leaving the residual tumor foci which can impair the efficacy of the ablation therapy. PMID- 21607589 TI - Chemometric analysis of excitation emission matrices of fluorescent nanocomposites. AB - The performance of multivariate curve resolution (MCR-ALS) to decompose sets of excitation emission matrices of fluorescence (EEM) of nanocomposite materials used as analytical sensors was assessed. The two fluorescent nanocomposite materials were: NH(2)-polyethylene glycol (PEG200) functionalized carbon dots, sensible to aqueous Hg(II) (CD); and, CdS quantum dots attached to the dendrimer DAB, sensible to the ionic strength of the aqueous medium (CdS-DAB). The structures of these sets of EEM, obtained as function of the Hg(II) concentration and ionic strength, are characterized by collinear properties (CD) and non-linear spectral variations (CdS-DAB). MCR-ALS was able to detect that the source of the collinearities is the presence of different size CD that show similar affinity towards Hg(II). Moreover, MCR-ALS was able to model the non-linear spectral variations of the CdS-DAB that are induced by varying ionic strength. The chemometric pre-processing of the fluorescent data sets using soft-modelling multivariate curve resolution like MCR-ALS is a critical step to transform these nanocomposites with interesting fluorescent proprieties into analytical useful nanosensors. PMID- 21607590 TI - Alcohol and tobacco, and the risk of cancers of the upper aerodigestive tract in Latin America: a case-control study. AB - BACKGROUND: Cancers of the upper aerodigestive tract (UADT; including oral cavity, pharynx, larynx and oesophagus) have high incidence rates all over the world, and they are especially frequent in some parts of Latin America. However, the data on the role of the major risk factors in these areas are still limited. METHODS: We have evaluated the role of alcohol and tobacco consumption, based on 2,252 upper aerodigestive squamous-cell carcinoma cases and 1,707 controls from seven centres in Brazil, Argentina, and Cuba. RESULTS: We show that alcohol drinkers have a risk of UADT cancers that is up to five times higher than that of never-drinkers. A very strong effect of aperitifs and spirits as compared to other alcohol types was observed, with the ORs reaching 12.76 (CI 5.37-30.32) for oesophagus. Tobacco smokers were up to six times more likely to develop aerodigestive cancers than never-smokers, with the ORs reaching 11.14 (7.72 16.08) among current smokers for hypopharynx and larynx cancer. There was a trend for a decrease in risk after quitting alcohol drinking or tobacco smoking for all sites. The interactive effect of alcohol and tobacco was more than multiplicative. In this study, 65% of all UADT cases were attributable to a combined effect of alcohol and tobacco use. CONCLUSIONS: In this largest study on UADT cancer in Latin America, we have shown for the first time that a prevailing majority of UADT cancer cases is due to a combined effect of alcohol and tobacco use and could be prevented by quitting the use of either of these two agents. PMID- 21607591 TI - Coexpression of SGLT1 and EGFR is associated with tumor differentiation in oral squamous cell carcinoma. AB - Overexpression of epidermal growth factor receptor (EGFR) is associated with resistance to chemotherapy and radiotherapy, advanced tumor stage, invasion, metastasis and poor prognosis in malignant tumors. EGFR, therefore, has been an attractive molecular target for chemotherapy. However, the results of clinical studies using inhibitors of its kinase activity have not been promising because the response rates were at most 20%. Sodium-glucose co-transporter 1 (SGLT1) is a membrane protein that mediates the transport of glucose across cellular membranes. EGFR physically associates with and stabilizes SGLT1 to promote glucose uptake into cancer cells through a kinase-independent process. The purpose of this study was to investigate the coexpression of SGLT1 and EGFR and its relationships with clinicopathological features in oral squamous cell carcinoma (OSCC). SGLT1 and EGFR were detected in all OSCC cell lines, and the expression levels of SGLT1 were significantly correlated with those of EGFR. Pearson product-moment correlation coefficient of SGLT1 and EGFR was 0.89 (P = 0.016). The immunohistochemical study using the surgical specimens in 52 patients with tongue SCC also showed a significant correlation between SGLT1 and EGFR. Moreover, SGLT1/EGFR expression was inversely related to tumor differentiation among the 5 clinicopathological factors (P = 0.004). SGLT1/EGFR coexpression might be required in the de-differentiation of OSCC, but further study is needed to clarify the implication of these proteins in the manifestation of malignancy and clinical significance. PMID- 21607592 TI - Mutational analysis of HRAS and KRAS genes in oral carcinoma cell lines. AB - RAS overexpression and its active mutations are involved in malignant tumorigenesis. However, the mutation rates in oral carcinoma cells differ between populations. In the present study, genomic DNA of oral carcinoma cells (HOC313, TSU, HSC2, HSC3, KOSC2, KOSC3, SCCKN, OSC19, Ca9.22, and Ho1u1 cells) or normal gingival fibroblasts (GF12 cells) derived from a Japanese population were amplified by polymerase chain reaction using primer sets, spanning HRAS and KRAS exons. Nucleotide substitutions were analyzed by single strand conformation polymorphism. In contrast to no substitutions in KRAS, nine different substitutions were detected in HRAS. Of the nine, six substitutions were located at intron 1 (HSC2 and HSC3 cells) or intron 2 (HSC3, SCCKN and Ca9.22 cells), and one each of exon 1 (all cells), exon 2 (HOC313, TSU, HSC2 and HSC3 cells) and the 5' upstream region (all cells). Substitutions at exons 1 and 2 did not affect the amino acid sequence; the exon 1 substitution was positioned at the 5' untranslated region, which may be a single nucleotide polymorphism (SNP) sequence because all the cells were isolated from a Japanese population, and the mutations at exon 2 was a silent mutation. A substitution at the 5' upstream region was an SNP. These data demonstrate that SNPs and point mutations observed in HRAS do not change the amino acid sequence, and suggest that the mutations affecting the amino acid sequence may be a rare event in oral carcinomas of the Japanese population. PMID- 21607593 TI - Hybridization morphology and dentin bond stability of self-etch primers with different ethanol/water ratios. AB - This study evaluated the influence of ethanol/water ratios on the bond strength to dentin of experimental two-step, self-etch adhesive systems. Self-etch primers were prepared with constant 40 mass % of solvents. The ethanol/water ratios tested were 7:1 (P1), 3:1 (P2), and 1:1 (P3); primers with only ethanol (PE) or water (PW) as solvent were also tested. The bond strength to the dentin was investigated through a microtensile bond strength test. Resin-dentin beam-shaped specimens were obtained and tested after 24 h, 6 months, and 1 year of storage in water at 37 degrees C. The hybridization morphology was analyzed using SEM. For bond strength at 24 h, PE = P1, P1 = P2, and P2, P3 and PW > PE. After 6 months, PE = P1 < P2, P3 and PW. After 1 year, no significant differences among the materials were detected. No significant differences among the periods were detected for PE. For P1, 24 h > 6 months = 1 year. For P2, P3 and PW, 24 h = 6 months > 1 year. For PE and P1, adhesive failures were predominant at 24 h, mixed or adhesive failures after 6 months, and premature debonding was predominant after 1 year. For P2, mixed failures were predominant at 24 h and 6 months, and premature debonding after 1 year. For P3 and PW, mixed failures were predominant at all storage periods. The SEM analysis revealed no clear differences in the hybridization patterns yielded by the water-based primers; PE showed formation of irregular resin tags. PMID- 21607594 TI - Oral lipoma extending superiorly from mandibular gingivobuccal fold to gingiva: a case report and analysis of 207 patients with oral lipoma in Japan. AB - Lipoma is relatively uncommon in the oral cavity. Among the intraoral regions, lipoma involving the gingiva or gingivobuccal fold is relatively infrequent. We report the case of a patient with lipoma extending superiorly from the mandibular gingivobuccal fold to the gingiva. In addition to the case report, we retrospectively reviewed 207 patients with intraoral lipoma reported in Japan from 1987 to 2004. The most frequent site of development was the buccal mucosa (40.6%), followed by the tongue (17.9%), lip (12.6%), gingiva (8.7%), oral floor (6.8%), gingivobuccal fold and palate (4.8%), and others (3.9%). Occurrence tended to be more frequent in males (57.5%) than in females (42.5%). Relative to age, frequency peaked among patients in the 7th (27.3%) and 6th decades (25.1%), respectively, followed in descending order by the 5th (14.8%) and 8th decades (13.1%). The majority of patients (86.3%) were at least 40 years. The most frequent size was 10-19 mm (37.5%), followed by 0-9 mm (27.8%) and 20-29 mm (14.6%), and tumors 30 mm or larger were relatively infrequent. Histopathological types in order of descending frequency were lipomas (69.0%), fibrolipomas (27.4%), and others (3.5%). The male:female ratio was 1.7:1 for lipoma and 1:1.6 for fibrolipoma. PMID- 21607595 TI - Accurate localization of the position of the tip of a naso/orogastric tube in children; where is the location of the gastro-esophageal junction? AB - BACKGROUND: Abdominal radiographs are used to determine the location of the tip of a newly placed nasogastric tube. The precise location of the gastroesophageal junction has not been well described in the radiology literature. OBJECTIVE: To improve interpretation of radiographs taken to evaluate the location of the tip of a nasogastric tube. Using UGI barium studies, we determined the anatomical location and variability of the position of the gastroesophageal (GE) junction and the pylorus MATERIALS AND METHODS: We reviewed 200 upper gastrointestinal barium studies (50 in each of 4 age groups). We measured the vertebral levels and distance of the gastroesophageal junction and the pylorus from the spine, the vertical distance of the gastroesophageal junction from the dome of the diaphragm and the distance from the gastroesophageal junction to the pylorus. RESULTS: There is a constant location of the GE junction with no significant variation between age groups. There is a moderately constant location of the pylorus. The other measurements were very variable. CONCLUSION: The location of the GE junction is very constant, irrespective of age. Tube tips below the level of the vertebral disc between the 11th and 12th thoracic vertebra and/or more than 16 mm from the left side of the spine lie in the stomach and not the lower esophagus. Our results should help in accurate radiographic description of the location of the tip of an NG tube. PMID- 21607596 TI - Radiological evaluation of dysmorphic thorax of paternal uniparental disomy 14. AB - BACKGROUND: The "coat-hanger" sign of the ribs with a bell-shaped thorax has been known as a radiological hallmark of the paternal uniparental disomy 14 (upd(14)pat). OBJECTIVE: To quantitatively determine the differences in thoracic deformity between upd(14)pat and other bone diseases with thoracic hypoplasia and to establish the age-dependent evolution. MATERIALS AND METHODS: The subjects comprised 11 children with upd(14)pat. The angle between the 6th posterior rib and the horizontal axis was measured (coat hanger angle; CHA). The ratio of the mid- to widest thorax diameter (M/W ratio) was calculated for the bell-shaped thorax. RESULTS: CHA ranged from +28.5 to 45 degrees (mean; 35.1 degrees +/- 5.2) in upd(14)pat, and from -19.8 to 21 degrees (-3.3 +/- 13 degrees ) in bone dysplasias (p < 0.01). The M/W ratio ranged from 58% to 93% (75.4 +/- 10) in upd(14)pat, and from 80% to 92% (86.8 +/- 3.3) in bone dysplasias (p < 0.05). Serial radiographs revealed that CHA remained constant during early childhood, while the M/W ratio gradually increased with age. CONCLUSION: The "coat-hanger" sign of upd(14)pat provides a distinctive radiological gestalt that makes it possible to differentiate the disorder from other skeletal dysplasias. By contrast, the bell-shaped thorax is significant only in the neonatal period. PMID- 21607597 TI - Pediatric intestinal transplantation: normal radiographic appearance and complications. AB - We present a pictorial essay on pediatric intestinal transplantation that describes the indications for pediatric intestinal transplantation, surgical technique, and the role of imaging in the pre-transplant work-up and detection of post-transplant complications. We illustrate the normal post-transplant imaging appearance and common complications, including rejection, infection, post transplant lymphoproliferative disease (PTLD), mechanical dysfunction and vascular complications. We conclude with an imaging algorithm for suspected post transplant complications based on clinical scenarios. PMID- 21607598 TI - Hemangiomas revisited: the useful, the unusual and the new. Part 2: endangering hemangiomas and treatment. AB - Hemangiomas, although benign tumors, can when located in particular regions threaten vital structures or in certain clinical circumstances be associated with other abnormalities, carrying significant morbidity and mortality. We review these endangering hemangiomas. We also discuss briefly the treatment with emphasis on the recent use of propranolol. PMID- 21607599 TI - Hydatid cysts of the liver in children: percutaneous treatment with ultrasound follow-up. AB - BACKGROUND: Hydatid disease is a serious public health problem in endemic areas. Percutaneous treatment is an effective alternative to surgical and medical therapy in hydatid liver disease (HLD). OBJECTIVE: To present clinical and radiological results of percutaneous treatment of HLD in children. MATERIALS AND METHODS: Twenty-five children (16 males; age range, 5-15 years; mean age, 9.6 years) with a total of 30 hydatid cysts of the liver underwent ultrasound US guided percutaneous treatment using hypertonic saline as the scolicidal agent. RESULTS: The percutaneous procedure was successful in all patients. All children were asymptomatic at follow-up. A hypersensitivity reaction occurred in one child (4%) during the procedure. No other complications occurred. The reduction in cyst volume was 14-100% (mean, 64%) at follow-up (mean 13.8 months). On US at follow up, the treated cysts were semisolid with a heterogeneous echo pattern (n = 17), solid hypoechoic (n = 10) or solid with calcification (n = 2). One treated cyst disappeared sonographically. CONCLUSION: Percutaneous treatment of HLD is effective, safe and well-tolerated in children. PMID- 21607600 TI - Limitations of using logarithmic transformation and linear fitting to estimate relaxation rates in iron-loaded liver. AB - BACKGROUND: MRI is being increasingly used to evaluate tissue relaxation in the setting of iron overload. Diagnostic accuracy is strongly dependent upon the acquisition and analysis methods employed. Typically, a multi-echo train of relaxation data is acquired, the resulting curve is fit using a non-linear (exponential) function, and the derived relaxation time is converted to iron concentration by a calibration formula derived from paired MRI-biopsy samples. A theoretically valid processing alternative is to fit a straight line to the relaxation data after logarithmic transformation (log-linear). This log-linear method is more computationally efficient, allowing a full relaxation map to be generated in near real time. This method is present on all scanner platforms and has been published for use in assessing iron concentration. These factors imply methodological validity. OBJECTIVE: To use in vivo and simulation data to show that log-linear fitting can generate highly erroneous relaxation results in iron loaded tissues. MATERIALS AND METHODS: After IRB approval, exponential and linear fitting were compared in a cohort of 20 patients being evaluated for hepatic iron overload. Simulation analyses were performed to characterize the main factors impacting derived results. RESULTS: In human subjects, log-linear analyses demonstrated gross deviation from exponential results at a moderate relaxation shortening (T2* ~5 ms). Simulation analyses demonstrated that the discrepancy was caused by noise effects and additional signal components violating mono exponential function shape. CONCLUSION: Log-linear processing results in increasingly erroneous estimation of T2* with iron-loading. Therefore, this method should not be employed for measurement of relaxation behavior in clinical samples. PMID- 21607601 TI - Postmortem gastric perforation (gastromalacia) mimicking abusive injury in sudden unexplained infant death. AB - Gastromalacia is a postmortem autolysis of gastric tissue that can culminate in gastric perforation. This entity is well-recognized by pathologists but is rarely encountered by diagnostic radiologists. We are reporting a case of sudden unexplained infant death (SUID) in which a boy was found to have pneumoperitoneum on postmortem radiographs, subsequently proved by autopsy to be caused by postmortem gastric perforation resulting from gastromalacia. It is important for radiologists to recognize this entity so as not to mistake it for bowel perforation caused by antemortem pathology, including inflicted trauma. PMID- 21607602 TI - Syringocoele of the bulbourethral duct with additional lower genito-urinary anomalies. AB - The ultrasonographic (US) appearance of a syringocoele of the bulbourethral (Cowper) duct, with correlative urethrocystoscopic images, is demonstrated. An infant boy, 5 weeks of age, who presented with E. coli infection of the urinary tract also had bilateral hydroureteronephrosis, small bilateral simple ureterocoeles, and posterior urethral valve leaflets. PMID- 21607604 TI - Cystic dysplasia of the testis: spontaneous regression. AB - Cystic dysplasia of the testis is a rare disorder, characterized by irregular cystic spaces within the mediastinum or rete testis. Ipsilateral renal defects are seen in many patients with cystic dysplasia of the testis. Although cystic dysplasia of the testis is considered a benign lesion, it has typically been treated with orchiectomy. We report a child with cystic dysplasia of the testis in whom spontaneous regression of the US findings occurred. This suggests that conservative management, through regular observation with US, may be the more desirable initial course of treatment for patients with this disorder. PMID- 21607603 TI - SPECT/CT imaging in children with papillary thyroid carcinoma. AB - BACKGROUND: SPECT/CT improves localization of single photon-emitting radiopharmaceuticals. OBJECTIVE: To determine the utility of SPECT/CT in children with papillary thyroid carcinoma. MATERIALS AND METHODS: 20 SPECT/CT and planar studies were reviewed in 13 children with papillary thyroid carcinoma after total thyroidectomy. Seven studies used I-123 and 13 used I-131, after elevating TSH by T4 deprivation or intramuscular thyrotropin alfa. Eight children had one study and five children had two to four studies. Studies were performed at initial post total thyroidectomy evaluation, follow-up and after I-131 treatment doses. SPECT/CT was performed with a diagnostic-quality CT unit in 13 studies and a localization-only CT unit in 7. Stimulated thyroglobulin was measured (except in 2 cases with anti-thyroglobulin antibodies). RESULTS: In 13 studies, neck activity was present but poorly localized on planar imaging; all foci of uptake were precisely localized by SPECT/CT. Two additional foci of neck uptake were found on SPECT/CT. SPECT/CT differentiated high neck uptake from facial activity. In six studies (four children), neck uptake was identified as benign by SPECT/CT (three thyroglossal duct remnants, one skin contamination, two by precise anatomical CT localization). In two children, SPECT/CT supported a decision not to treat with I-131. When SPECT/CT was unable to identify focal uptake as benign, stimulated thyroglobulin measurements were valuable. In three of 13 studies with neck uptake, SPECT/CT provided no useful additional information. CONCLUSION: SPECT/CT precisely localizes neck iodine uptake. In small numbers of patients, treatment is affected. SPECT/CT should be used when available in thyroid carcinoma patients. PMID- 21607605 TI - Functional imaging of infection: conventional nuclear medicine agents and the expanding role of 18-F-FDG PET. AB - A growing body of literature suggests that 18-fluorine fluorodeoxyglucose positron emission tomography ((18)F-FDG PET), particularly when combined with CT, is a useful tool for the detection of infectious and inflammatory disease processes. This article will briefly review the data to date on the use of FDG PET in diagnosing musculoskeletal infections and fever of unknown origin, comparing it to conventional scintigraphic techniques in both adults and, when available, in children. PMID- 21607606 TI - Physeal injuries of the proximal humerus: long-term results in seventy two patients. AB - PURPOSE: The aim of this study was to evaluate our treatment methods of proximal humeral physeal injuries retrospectively and elucidate the relationship between the trauma mechanism, the radiographic injury pattern, the consequent therapy and the functional outcome, and to further deduct and verify prognostic criteria. METHODS: At our Department of Trauma Surgery, 303 children and adolescent patients with fractures of the proximal humeral epiphysis were treated from 1992 to 2009. 72 cases were diagnosed as physeal fractures according to the Salter Harris classification and were included in our study. RESULTS: 15 physeal fractures of the proximal humerus were reconstructed anatomically by open or closed reduction and produced 93.3% excellent results. 57 physeal fractures were treated in a conservative way and produced 94.7% excellent results. CONCLUSION: We state that epiphyseal injuries should to be treated depending on the age of the patient. This is the only way to decrease the rate of posttraumatic epiphysiodesis with consequent problems, including limb-length discrepancy and/or angular deformities. PMID- 21607607 TI - Taylor spatial frame in severe foot deformities using double osteotomy: technical approach and primary results. AB - PURPOSE: The treatment of severe foot deformities in children or adolescents is complex and demanding to the surgeon. This paper describes the technical strategy of using a Taylor spatial frame and reports on the functional outcome. METHODS: The Taylor spatial frame was used by a single surgeon in patients with severe foot deformities. Seven patients with eight severe deformities were treated. Mean patient age at surgery was 15.1 (9-29) years. A double Taylor spatial frame reconstruction was mounted to the limb. All patients had a midtarsal osteotomy and an additional inverse dome-shaped calcaneus osteotomy. Assessed measures were pre- and postoperative deformity and associated complications and clinical results according to Ferreira et al. RESULTS: Mean follow-up was 576.5 (359-987) days. The final functional outcome according to Ferreira was good in seven cases, fair in none, and poor in one. Early complications included pin-tract infection, temporary hypoesthesia, and temporary shortening of the tendon of the M. flexor digitorum. At follow-up there was no deformity recurrence. CONCLUSION: In children or adolescents, the innovative treatment using the Taylor spatial frame and a double osteotomy allows joint-preserving correction of severe foot deformities. However, the complication rate is relatively high due to the severely deformed feet. Furthermore, the Taylor spatial frame is expensive. Thus, this treatment is only recommended for severe foot deformities and should be handled by experienced orthopedic surgeons. PMID- 21607608 TI - Toll-like receptor mRNA expression, iNOS gene polymorphism and serum nitric oxide levels in indigenous chickens. AB - Toll-like receptor (TLR) family is one of the important members of innate immune system that recognizes conserved microbial patterns and induces innate immune response. They also act as a link to adaptive immune response. Nitric oxide (NO) is a multi-functional mediator with diverse physiological and immunological roles. In the present study TLR mRNA expression in heterophils, serum nitric oxide level and iNOS (inducible Nitric Oxide Synthase) gene polymorphism were investigated in cockerels of two Indian native chicken breeds, Aseel and Kadaknath. TLR (4 and 5) mRNA expression as quantified by real time RT-PCR revealed Kadaknath males expressed significantly (P < 0.01) higher TLR4 mRNA than Aseel males. iNOS gene polymorphism analyzed by PCR-RFLP method revealed difference in allele frequency. Kadaknath males had higher allele B frequency (0.81) than Aseel males (0.56). However, there were no genotype and breed effect on serum nitric oxide level. Based on the present study we conclude that Kadaknath has comparatively higher innate immunity levels than Aseel, however further investigations are needed. PMID- 21607609 TI - Determination of heavy metals in two barbs, Barbus grypus and Barbus xanthopterus in Karoon and Dez Rivers, Khoozestan, Iran. AB - Cadmium, lead, nickel and mercury were contamination in gill, liver and muscle of B. grypus and B. xanthopterus in Karoon and Dez Rivers. Significant variations in metal values were evaluated using student's t test at p < 0.05. In B. grypus high levels of cadmium, lead, nickel and mercury were measured in gill (1.49, 2.25, 1.02 and 0.89 mg kg(-1) dw) except for mercury (1.06 mg kg(-1) dw) in B. grypus in Dez River was high in liver. In B. xanthopterus high levels of cadmium, lead, nickel and mercury were measured in gill (2.17, 2.91 and 1.43 mg kg(-1) dw) except for mercury (1.42 mg kg(-1) dw) high levels were measured in liver. PMID- 21607610 TI - Neurotoxic effect of the complex of the ovine prion protein (OvPrP(C)) and RNA on the cultured rat cortical neurons. AB - Prion diseases are conformational diseases, many factors are involved in altering the conformation of prion, such as RNA, DNA, pH, and copper etc. However the neurotoxic mechanism of prion diseases is not clear yet. The aim of this study is to investigate the effect of the nucleoprotein complex of RNA and recombinant ovine prion protein (OvPrP(C)) on the cultured rat cortical neurons in vitro. Our previous study revealed that the nucleoprotein complex (OvPrP(C)-RNA) is characterized with high beta sheet conformation and proteinase K resistance. Here we found that the OvPrP(C)-RNA induced marked neuronal cell death by the MTT (3 (4,5-dimethyl-thiazole -2-yl)-2,5-diphenyl -tetrazolium bromide) and TUNEL (TdT mediated biotin-dUTP nicked-end labeling) assay, and the neurotoxic effects were confirmed by testing the content of Bcl-2 Associated X protein (Bax) in the immunoprecipitation assay and Western blot assay. Compared to the control group, there is no significant difference of active Bax or total Bax after RNA alone treatment or OvPrP(C) alone treatment, but the OvPrP(C)-RNA induced significant increases of active Bax level, while the contents of total Bax had no obvious changes after OvPrP(C)-RNA treatment. The results suggested that OvPrP(C)-RNA is neurotoxic in vitro, which added further evidence to the current understanding of mechanism of cellular injury by RNA molecules for transformation of the PrP(C) to PrP(Sc). PMID- 21607611 TI - Purification and structural characterization of fengycin homologues produced by Bacillus subtilis LSFM-05 grown on raw glycerol. AB - Raw glycerol is a byproduct of biodiesel production that currently has low to negative value for biodiesel producers. One option for increasing the value of raw glycerol is to use it as a feedstock for microbial production. Bacillus subtilis LSFM 05 was used for the production of fengycin in a mineral medium containing raw glycerol as the sole carbon source. Fengycin was isolated by acid precipitation at pH 2 and purified by silica gel column chromatography and characterized using electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS) with collision-induced dissociation (CID). The mass spectrum revealed the presence of the ions of m/z 1,435.7, 1,449.9, 1,463.8, 1,477.8, 1,491.8 and 1,505.8, which were further fragmented by ESI-MS/MS. The CID profile showed the presence of a series of ions (m/z 1,080 and 966) and (m/z 1,108 and 994) that represented the different fengycin homologues A and B, respectively. Fengycin homologues A and B are variants that differ at position 6 of the peptide moiety, having either Ala or Val residues, respectively. Mass spectrometry analyses identified four fengycin A and three fengycin B variants with fatty acid components containing 14-17 carbons. These results demonstrate that raw glycerol can be used as feedstock to produce fengycin, and additional work should focus on the optimization of process conditions to increase productivity. PMID- 21607612 TI - Location, location, location: genetic regulation of neural sex differences. AB - Sex differences in many behaviors such as cognition, mood, and motor skills are well-documented in animals and humans and are regulated by many neural circuits. Sexual dimorphisms within cell populations in these circuits play critical roles in the production of these behavioral dichotomies. Here we focus on three proteins that have well described sexual dimorphisms; calbindin-D28k, a calcium binding protein, tyrosine hydroxylase, the rate limiting enzyme involved in dopamine synthesis and vasopressin, a neuropeptide with central and peripheral sites of action. We describe the sex differences in subpopulations of these proteins, with particular emphasis on laboratory mice. Our thrust is to examine genetic bases of sex differences and how the use of genetically modified models has advanced our understanding of this topic. Regional sex differences in the expression of these three proteins are driven by sex chromosome complement, steroid receptors or in some instances both. While studies of sex differences attributable to sex chromosome genes are still few in number it is exciting to note that this variable factors into expression differences for all three of these proteins. Different genetic mechanisms, which elaborate sex differences, may be employed stochastically in different cell populations. Alternately, general patterns involving the timing of differentiation of the sex differences, relative to the "critical period" in hormonal differences between males and female neonates may emerge. In conclusion, future directions in this area should include examination of the importance of location, timing, steroidal receptor/sex chromosome gene synergy and epigenetics in molding neural sex differences. PMID- 21607613 TI - Safety and efficacy of contraception--Why should the obese woman be any different? AB - The public health impact of obesity and unintended pregnancy is profound with far reaching consequences. Obese women are less likely to use contraception due to a variety of self-induced and systems-based barriers but their risk of becoming pregnant is similar to their normal weight counterparts. However, pregnancy associated risks for obese women are higher than that of normal weight women and thus, pregnancy generally outweighs the risks of contraceptive use. Adequate counselling to prevent and/or plan for pregnancy is imperative for these women. Research that investigates the relationship between obesity and contraceptive use is urgently needed. PMID- 21607614 TI - Maternal prenatal depressive symptoms, nicotine addiction, and smoking-related knowledge, attitudes, beliefs, and behaviors. AB - Maternal smoking is a key preventable cause of poor pregnancy outcomes, such as low birthweight. In many areas of the United States, including Eastern North Carolina, rates of prenatal smoking are high. Prenatal depressive symptoms are associated with maternal smoking, but there remains much to learn about this relationship, especially among Black women, who have double the risk of poor pregnancy outcomes of White women. In the study reported in this paper, we investigated the relationship between maternal prenatal depressive symptoms with smoking behaviors, beliefs and attitudes, environmental factors which promote smoking and nicotine addiction. Pregnant women were enrolled in the study at the first prenatal visit to the clinics of the Departments of Obstetrics and Gynecology and Family Medicine of the Brody School of Medicine, East Carolina University. An interviewer administered a questionnaire to each woman about smoking, smoking-related attitudes, knowledge, beliefs and behaviors, nicotine addiction, and home environmental factors that encourage smoking. The CES-D was used to measure depressive symptoms. We used the cut-point score of 23 or greater to indicate elevated depressive symptoms, which is thought to represent major depressive disorder. The sample consisted of 810 Black women, of whom 18% were smokers. CES-D score was associated with nicotine addiction, not thinking of quitting smoking, and not expecting support from family and friends if they decided to quit. Prenatal depressive symptoms may be a barrier to smoking cessation. PMID- 21607615 TI - p53 codon 72 polymorphism is associated with susceptibility to hepatocellular carcinoma in the Turkish population: a case-control study. AB - The tumor suppressor p53 gene plays a crucial role in preventing carcinogenesis through its ability to induce cell cycle arrest and apoptosis following DNA damage and oncogene activation. A guanine (G)/cytosine (C) common single nucleotide polymorphism (SNP) at second position of codon 72 in exon 4 of p53 gene determines a arginine (Arg) to proline (Pro) (Arg72Pro) aminoacidic substitution within the proline-rich domain of p53 protein. Arg72 and Pro72 allele are different from a biochemical and biological point of view and many reports suggest that they can modulate individual cancer susceptibility. To determine the association of the p53 Arg72Pro polymorphism with the risk of hepatocellular carcinoma (HCC) development in a Turkish population, a hospital based case-control study was designed consisting of 119 subjects with HCC and 119 cancer-free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the p53 Arg72Pro polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Our data shows that the Pro/Pro genotype of the p53 Arg72Pro polymorphism is associated with increased risk of HCC development in this Turkish population (OR = 3.20, 95% CI: 1.24-8.22, P = 0.02). Furthermore, according to stratified analysis, a significant association was observed between the homozygote Pro/Pro genotype and HCC risk in the subgroups of male gender (OR = 3.01, 95% CI: 1.14 7.97, P = 0.03) and patients with hepatitis B virus (HBV)-related HCC (OR = 4.04, 95% CI: 1.46-11.15, P = 0.007). Because our results suggest for the first time that the Pro/Pro homozygote of p53 Arg72Pro polymorphism may be a genetic susceptibility factor for HCC (especially in the male gender and HBV-infected patients) in the Turkish population, further independent studies are required to validate our findings in a larger series, as well as in patients of different ethnic origins. PMID- 21607616 TI - A proteomic approach to analyze nitrogen- and cytokinin-responsive proteins in rice roots. AB - Nitrogen plays a central role in rice growth and development because it modulates a wide variety of processes, including cytokinin (CK) metabolism. CK-mediated signaling is also related to nitrogen metabolism. The functional relation between nitrogen and CK are extremely complex and unclear. In this study, a comparative proteomic analysis was carried out to analyze proteins regulated by nitrogen and CK in rice roots. Proteins extracted from rice roots are separated by two dimensional polyacrylamide gel electrophoresis. Thirty-two protein spots that expressed similarly by nitrogen and CK treatments are selected for identification by mass spectrometry. Of these spots, 28 are successfully identified. These proteins were categorized into classes related to energy, metabolism, disease/defense, protein degradation, signal transduction, transposons, and unclear classification. Energy gives the largest functional category, suggesting that the glycolysis (two enzymes detected) and tricarboxylic acid cycle (six enzymes detected) are accurately regulated by nitrogen and CK, thus promoting the synthesis of amino acid. The identification of novel proteins provides new insights into the coordination of nitrogen and CK in rice. The possible role of these proteins is discussed. PMID- 21607617 TI - Combined point mutations in codon 12 and 13 of KRAS oncogene in prostate carcinomas. AB - Prostate cancer is a common malignancy that develops by structural mutation(s) and/or other genetic alterations in specific genes.The G to T transversions in codon 12 and C to T transitions in codon 13 of KRAS proto-oncogene are predominant point mutations that occur in about 20% of different cancers in human. In the current study it was aimed to investigate the prevalence and predictive significance of KRAS mutations in patients with prostate carcinomas. In a total of 30 fresh tumoural tissue specimens were investigated in patients with prostate carcinoma. All tumoural specimens were histo-pathologically diagnosed and genotyped for codon 12, 13 KRAS point mutations by reverse hybridisation and direct sequencing methods. KRAS mutations were found in 12 (40%) samples with 29 samples deriving from adenocarcinomas and 1 sample was small cell prostate carcinoma. In 1 (3.44%) sample codon 12 was found to be mutated and in 2 (6.8%) samples codon 13 and in 9 (31%) samples combined codon 12 and 13 were found to be mutated particularly in higher grade of tumoural tissues. Our study, based on representative collection of human prostate tumours, indicates that combined mutations in codons 12 and 13 KRAS are relatively infrequent and most commonly occur in prostate carcinomas. PMID- 21607618 TI - Molecular characterization, expression pattern, polymorphism and association analysis of bovine ADAMTSL3 gene. AB - A disintegrin-like and metalloprotease domain with thrombospondin type I motifs like 3 (ADAMTSL3) is an important candidate gene for body measurement traits through marker-assisted selection (MAS). The objective of this study was to analyze SNP of bovine ADAMTSL3 gene and its specific expression in tissues to explore its possible correlation with body measurement traits in Bos taurus. Our genomic structural analysis showed that bovine ADAMTSL3 shares much similarity with human ADAMTSL3. Gene expression analysis indicated that the order of specific tissue expression patterns of bovine ADAMTSL3 was the testis, heart, fat, stomach, small intestine, liver, lung, trachea, kidney, spleen, large intestine and muscle. Allele frequencies demonstrated significant variance in different local cattle breeds. Also, the T1532C SNP in exon 13 and C1899T SNP in exon 15 were significantly correlated with Body Length (BL), Chest Depth (CD), Heart Girth (HG) and Pin Bone Width (PBW). Furthermore, C1899T SNP marker had significant correlation with the PBW (P = 0. 0235) based on 867 individual analysis. In the total population, combination of T1532C and C1899T SNPs significantly affected on the BL (P = 0.0028), CD (P < 0.0001), HG (P = 0.0002) and PBW (P = 0.0049). These results suggest that the ADAMTSL3 gene, as one of target genes for body measurement traits in cattle breeds, could be used as a genetic marker to select excellent body type of cattle population in the animal breeding program. PMID- 21607619 TI - Gametic phase disequilibrium between the syntenic multiallelic HTG4 and HMS3 markers widely used for parentage testing in Thoroughbred horses. AB - Validation of parentage and horse breed registries through DNA typing relies on estimates of random match probabilities with DNA profiles generated from multiple polymorphic loci. Of the twenty-seven microsatellite loci recommended by the International Society for Animal Genetics for parentage testing in Thoroughbred horses, eleven are located on five chromosomes. An important aspect in determining combined exclusion probabilities is the ascertainment of the genetic linkage status of syntenic markers, which may affect reliable use of the product rule in estimating random match probabilities. In principle, linked markers can be in gametic phase disequilibrium (GD). We aimed at determining the extent, by frequency and strength, of GD between the HTG4 and HMS3 multiallelic loci, syntenic on chromosome 9. We typed the qualified offspring (n (1) = 27; n (2) = 14) of two Quarter Bred stallions (registered by the Brazilian Association of Quarter Horse Breeders) and 121 unrelated horses from the same breed. In the 41 informative meioses analyzed, the frequency of recombination between the HTG4 and HMS3 loci was 0.27. Consistent with genetic map distances, this recombination rate does not fit to the theoretical distribution for independently segregated markers. We estimated sign-based D' coefficients as a measure of GD, and showed that the HTG4 and HMS3 loci are in significant, yet partial and weak, disequilibrium, with two allele pairs involved (HTG4 M/HMS3 P, D'(+) = 0.6274; and HTG4 K/HMS3 P, D'(-) = -0.6096). These results warn against the inadequate inclusion of genetically linked markers in the calculation of combined power of discrimination for Thoroughbred parentage validation. PMID- 21607620 TI - Association between two genetic polymorphisms of the renin-angiotensin aldosterone system and diabetic nephropathy: a meta-analysis. AB - The widely studied candidate genes of the renin-angiotensin-aldosterone system, angiotensinogen (AGT), and angiotensin II receptor type 1 (AGTR1), are implicated in the development of diabetic nephropathy (DN). A number of studies have evaluated the association between the functional polymorphisms, AGT M235T and AGTR1 A1166C, and DN risk with conflicting results. The present meta-analysis was performed to estimate the overall risk of these polymorphisms associated with DN on 4,377 DN cases and 4,905 controls from 34 published case-control studies by searching electronic databases and reference lists of relevant articles. We examined the association between each polymorphism and the risk of DN by odds ratio (OR) with 95% confidence intervals (95% CI) and calculated the ORs for different genetic model. In addition, stratification analysis by ethnicity and diabetes mellitus (DM) type was conducted. In this meta-analysis, we failed to find any significant main effects in both overall analysis and stratified analysis for the AGT M235T. However, the overall analysis detected a significant association between the AGTR1 A1166C and the risk of DN for the CC compared with the AA and dominant genetic model (CC vs. AA: OR = 2.10, 95% CI: 1.00-4.44; dominant model: OR = 2.11, 95% CI: 1.06-4.23). In subgroup analysis, only patients with T2DM showed significant association for CC vs. AA model and dominant model (CC vs. AA: OR = 3.31, 95% CI: 1.21-9.08; dominant model: OR = 3.50, 95% CI: 1.41-8.69). This study suggests that the AGTR1 A1166C polymorphism may contribute to DN development, particularly in T2DM patients. PMID- 21607621 TI - Genetic variants of SDF-1 and CXCR4 genes in endometrial carcinoma. AB - In this study, we aimed to investigate a possible association between the Stromal cell-derived factor-1 (SDF-1) and CXCR4 polymorphisms and the risk of developing endometrial carcinoma. SDF-1 3'A and CXCR4 gene polymorphisms was performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism in 139 healthy individuals and 113 patients with endometrial carcinoma. In our study groups SDF-1 3'A AA genotype frequency was higher in patients that of controls and individuals who had AA genotype showed a 2.6-fold increased risk for endometrial cancer. The carriers of CXCR4 T allele were higher in patients compared with controls and individuals who had TT genotype had a 2.5-fold high risk for endometrial carcinoma. Our finding suggest that there was no significant association between the (SDF-1) and CXCR4 polymorphisms and endometrium cancer risk. Further studies in a larger population are needed to better elucidate the role of (SDF-1) and CXCR4 gene polymorphisms in the risk of endometrial carcinogenesis. To the best of our knowledge, this is the first study to show such an association. PMID- 21607622 TI - Expression of antioxidant genes in renal cortex of PTU-induced hypothyroid rats: effect of vitamin E and curcumin. AB - The present study was undertaken to investigate the effect of vitamin E and curcumin on the expression of antioxidant genes in 6-propyl-2-thiouracil (PTU) induced hypothyroid rat renal cortex. The levels of lipid peroxidation and protein carbonylation were increased in hypothyroid rat kidney. Co-administration of vitamin E and curcumin to hypothyroid rats resulted in amelioration of lipid peroxidation level, whereas curcumin alone alleviated the protein carbonylation level. The mRNA levels of SOD1 and SOD2 were decreased in hypothyroid rats. Decreased level of SOD1 transcripts was observed in hypothyroid rats supplemented with curcumin alone or co-administrated with vitamin E. Translated products of SOD1 and SOD2 in hypothyroid rats was elevated in response to supplementation of both the antioxidants. Decreased SOD1 and SOD2 activities in hypothyroid rats compared to control were either unaltered or further decreased in response to the antioxidants. Expressions of CAT at transcript and translate level along with its activity were down regulated in hypothyroid rats. Administration of vitamin E to hypothyroid rats resulted in elevated CAT mRNA level. In contrast, expression of CAT protein was elevated in response to both the antioxidants. However, CAT activity was unaltered in response to vitamin E and curcumin. GPx1 and GR mRNA level and the activity of glutathione peroxidase (GPx) were not affected in response to induced hypothyroidism. The activity of GPx was increased in response to vitamin E treatment, whereas decreased GR activity in hypothyroid rats was further declined by the administration of antioxidants. The over all results suggest that vitamin E and curcumin differentially modulate the altered antioxidant defence mechanism of rat kidney cortex under experimental hypothyroidism. PMID- 21607623 TI - Anti-apoptotic and antioxidant effect of leptin on CCl4-induced acute liver injury in rats. AB - The aim of this study is to investigate the effect of leptin in rats on carbon tetrachloride (CCl(4)) induced acute liver damage using immunohistochemical methods for apoptosis and biochemical parameters. In this experimental study, 18 Spraque-Dawley rats were divided into three groups viz; control, CCl(4) and CCl(4)+leptin treatment. 0.8 ml/kg olive oil was administered intraperitoneally (i.p.) to the control group and 0.8 ml/kg CCl(4) (1:1 dissolved in olive oil) was administered i.p. to the CCl(4) and CCl(4)+leptin treatment groups, respectively. After 6 h of administrating CCl(4), CCl(4)+leptin treatment group was given i.p. leptin (10 MUg/kg). Twenty-four hours after administrating CCl(4) all of the groups were euthanized. Biochemical assessments were performed using serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), plasma tumor necrosis factor alpha (TNF-alpha) levels and tissue malondialdehyde (MDA), and TNF-alpha levels. Histological assessments were then performed using Hematoxylin&Eosin (H&E) staining in light microscope and apoptosis assessment using Terminal Transferase dUTP Nick End Labeling (TUNEL) staining. Serum AST, ALT, ALP and plasma TNF-alpha levels, tissue MDA and TNF alpha levels had all increased in CCl(4) group, but were found to be significantly decreased in CCl(4)+leptin treatment group. Moreover, TUNEL positive cell counts in liver had significantly increased in CCl(4) group, but decreased in CCl(4)+leptin treatment group (P < 0.05). The results of our study the biochemical, histological and TUNEL-staining showed that leptin has treatment effects on liver CCl(4) induced injury. It plays a role as a potent free radical scavenger, a powerful antioxidant and it also has anti-apoptotic effects. PMID- 21607624 TI - Association of SCD1 and DGAT1 SNPs with the intramuscular fat traits in Chinese Simmental cattle and their distribution in eight Chinese cattle breeds. AB - Intramuscular fat (IMF) is a key parameter for evaluation of nutritional quality of beef, with its endogenous synthesis regulated by stearoyl CoA desaturase (SCD1) and diacylglycerol-acyl transferase 1 (DGAT1) genes in cattle. The object of this research was to evaluate the effect of SCD1 and DGAT1 polymorphisms on IMF trait in beef cattle and to estimate the frequency distribution of SNPs in the two genes in Chinese cattle populations. The SCD1 and DGAT1 polymorphisms were detected by PCR-single strand conformation polymorphism (PCR-SSCP) method in Chinese Simmental cattle and their associations with IMF traits were analyzed using the general linear model (GLM). The frequency distribution of SNPs in SCD1 and DGAT1 genes were detected by PCR-SSCP method and analyzed in seven other cattle populations. The results showed significant associations of SNPs SCD1-878, SCD1-762, and DGAT1 10433 and 10434 with IMF (%) and shearing force values (SFV; kg) in Chinese Simmental cattle. A haplotype combining SCD1-878C, SCD1-762T, and DGAT1 10433 and 10434-GC had the highest IMF, marbling score and shearing force. The polymorphic investigation indicated that the frequency of SCD1-878C or SCD1 762T was significantly higher in Chinese southern cattle (Leiqiong, Yunnan High pump, BMY or Minnan Cattle) than in Chinese northern cattle (Chinese Simmental, Luxi Cattle, Bohai Black or Chinese Holstein), while the frequency of DGAT1 10433 and 10434-GC in Chinese indigenous breed (Leiqiong, Yunnan High pump, BMY, Luxi Cattle, Bohai Black, or Minnan Cattle) was significantly lower than breeds with imported blood (Chinese Simmental or Chinese Holstein). These findings demonstrated that both the SCD1 and DGAT1 SNPs were prospect genetic markers for IMF traits, and the SCD1 SNPs could be used as a genetic marker for southern or northern blood in Chinese cattle. PMID- 21607625 TI - RNA interference and ischemic injury. AB - In the early period of 21st century, RNA interference (RNAi) had emerged as one of the most important discoveries. This highly conserved endogenous gene silencing mechanism has been largely exploited as a powerful tool to determine biological functions of each gene. Both direct introduction of chemically synthesized small interference RNA (siRNA) and a plasmid or viral vectors encoding for siRNA can allow especially stable RNA knockdown. Recently, it has been widely used in the production of therapeutic drugs against hepatitis or immuno-deficiency viruses in human beings. Here, we provide a brief overview of the RNAi mechanism and the technology of RNAi on ischemic injury. PMID- 21607627 TI - Alpha-tocopherol prevents intrauterine undernutrition-induced oligonephronia in rats. AB - The role of alpha-tocopherol during nephrogenesis was investigated in rats subjected to maternal undernutrition, which reduces the number of nephrons. alpha tocopherol (350 mg/kg, p.o.) was administered daily to well-nourished or malnourished Wistar dams during pregnancy, or to prenatal undernourished rats during lactation. The kidneys of 1- and 25-day-old offspring were removed to evaluate expression of angiotensin II (Ang II) and to correlate this with expression of proliferating cell nuclear antigen, alpha-smooth muscle actin, fibronectin and vimentin in the glomeruli and tubulointerstitial space. One-day old prenatally undernourished rats had reduced expression of Ang II and of kidney development markers, and presented with an enlarged nephrogenic zone. Maternal administration of alpha-tocopherol restored the features of normal kidney development in undernourished rats. Twenty-five-day-old prenatally undernourished progeny had fewer glomeruli than the control group. Conversely, animals from mothers that received alpha-tocopherol during lactation presented with the same number of glomeruli and the same glomerular morphometrical profile as the control group. Analyzing the levels of thiobarbituric acid reactive substances in the liver in conjunction with kidney development markers, it is plausible that alpha tocopherol had antioxidant and non-antioxidant actions. This study provides evidence that alpha-tocopherol treatment restored Ang II expression, and subsequently restored renal structural development. PMID- 21607629 TI - Congenital nephrotic syndrome with acute renal failure: questions. PMID- 21607626 TI - Anoctamins. AB - Endogenous Ca(2+)-activated Cl(-) channels (CaCC) demonstrate biophysical and pharmacological properties that are well represented in cells overexpressing anoctamin 1 (Ano 1, TMEM16A), a protein that has been identified recently as CaCC. Proteins of the anoctamin family (anoctamin 1-10, TMEM16A-K) are widely expressed. The number of reports demonstrating their physiological and clinical relevance is quickly rising. Anoctamins gain additional interest through their potential role in cell volume regulation and malignancy. Available data suggest that Ano 1 forms stable dimers and probably liaise with accessory proteins such as calmodulin or other anoctamins. In order to understand how anoctamins produce Ca(2+)-activated Cl(-) currents, it will be necessary to obtain better insight into their molecular structure, interactions with partner proteins, and mode of activation. PMID- 21607630 TI - Impact of primary PCI volume on hospital mortality in STEMI patients: does time to-presentation matter? AB - The exact relationship between primary percutaneous coronary intervention (PCI) volume and mortality remains unclear. No data are available on how this relationship could be affected by time-to-presentation. The primary aim of this study was to evaluate the impact of hospital primary PCI volume on in-hospital mortality in ST-elevation myocardial infarction (STEMI) patients depending on time-to-presentation. The impact of primary PCI volume on in-hospital mortality was investigated in a prospective registry of the Lombardy region in Northern Italy, deriving data on mortality rates and number of primary PCIs from a cohort of 2,558 patients. We also explored this relationship at different times-to presentation (<=90 min, >90 min-180 min, >180 min) and risk profiles assessed with the TIMI Risk Index. A strong inverse relationship was found between primary PCI hospital volume and risk-adjusted mortality (r = -0.9; P < 0.001). High primary PCI volumes best predicted the improvement of survival when the time-to presentation was <=90 min (area under the curve = 0.73, P < 0.0001). At this time, the best primary PCI threshold to provide benefit was >66 primary PCIs/year (OR = 0.21 [95% CI 0.10-0.47], P < 0.001) and those with high TIMI Risk Index achieved the greatest benefit (P < 0.001). At >90 min-180 min, the model was less significant (P = 0.02) with a higher threshold of procedures (>145 primary PCIs/year) required to provide benefits. The model was not predictive of survival for time-to-presentation >180 min (P = 0.30). The reduction of mortality of STEMI patients treated at high-volume primary PCI centers is time-dependent and affected by risk profile. The greatest benefit was observed in high-risk patients presenting within 90 min from symptoms onset. PMID- 21607631 TI - Soluble receptor for AGE (RAGE) is a novel independent predictor of all-cause and cardiovascular mortality in type 1 diabetes. AB - AIMS/HYPOTHESIS: Activation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes. In this study, we explore factors and mortality outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide cohort of Finnish adults with type 1 diabetes. METHODS: Baseline sRAGE concentrations were estimated in 3,100 adults with type 1 diabetes. Clinical and biological variables independently associated with sRAGE were identified using multivariate regression analysis. Independent predictors of mortality were determined using Cox and Fine-Gray proportional-hazards models. RESULTS: The main independent determinants of sRAGE concentrations were estimated glomerular filtration rate, albuminuria, body mass index, age, duration of diabetes, HbA(1c) and insulin dose (all p < 0.05). During a median of 9.1 years of follow-up there were 202 deaths (7.4 per 1,000 patient years). sRAGE was independently associated with all-cause (Cox model: HR 1.03) and cardiovascular mortality (Fine-Gray competing risks model: HR 1.06) such that patients with the highest sRAGE concentrations had the greatest risk of mortality, after adjusting for age, sex, macrovascular disease, HDL-cholesterol, HbA(1c), triacylglycerol, high-sensitivity C-reactive protein (hsCRP) and the presence and severity of chronic kidney disease. Although polymorphisms in the gene coding for RAGE were significantly associated with sRAGE concentrations, none were associated with mortality outcomes. CONCLUSIONS/INTERPRETATION: Increased concentrations of sRAGE are associated with increased all-cause and cardiovascular mortality in type 1 diabetes, potentially reflecting the activation and production of RAGE in the context of accelerated vascular disease. These novel findings highlight the importance of the RAGE activation in the prevention and management of diabetic complications. PMID- 21607632 TI - Inpatient costs for people with type 1 and type 2 diabetes in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. AB - AIMS/HYPOTHESIS: The rising prevalence of diabetes worldwide has increased interest in the cost of diabetes. Inpatient costs for all people with diabetes in Scotland were investigated. METHODS: The Scottish Care Information-Diabetes Collaboration (SCI-DC), a real-time clinical information system of almost all diagnosed cases of diabetes in Scotland, UK, was linked to data on all hospital admissions for people with diabetes. Inpatient stay costs were estimated using the 2007-2008 Scottish National Tariff. The probability of hospital admission and total annual cost of admissions were estimated in relation to age, sex, type of diabetes, history of vascular admission, HbA(1c), creatinine, body mass index and diabetes duration. RESULTS: In Scotland during 2005-2007, 24,750 people with type 1 and 195,433 people with type 2 diabetes were identified, accounting for approximately 4.3% of the total Scottish population (5.1 million). The estimated total annual cost of admissions for all people diagnosed with type 1 and type 2 diabetes was L26 million and L275 million, respectively, approximately 12% of the total Scottish inpatient expenditure (L2.4 billion). Sex, increasing age, serum creatinine, previous vascular history and HbA(1c) (the latter differentially in type 1 and type 2) were all associated with likelihood and total annual cost of admission. CONCLUSIONS/INTERPRETATION: Diabetes inpatient expenditure accounted for 12% of the total Scottish inpatient expenditure, whilst people with diabetes account for 4.3% of the population. Of the modifiable risk factors, HbA(1c) was the most important driver of cost in type 1 diabetes. PMID- 21607634 TI - Correct method for statistical analysis of stereopsis in ophthalmology research. PMID- 21607635 TI - Intraoperative conversion rate to a large, limbal opening in minimally invasive strabismus surgery (MISS). AB - BACKGROUND: To evaluate which factors predispose to an intraoperative conversion to the usual limbal approach in minimally invasive strabismus surgery (MISS). METHODS: This study included 451 consecutive patients operated on by one surgeon at Kantonsspital St Gallen, Switzerland, with minimally invasive rectus muscle surgery between February 2003 and December 2007. We evaluated the intraoperative conversion rate to the usual limbal approach over time, and performed a retrospective determination of date of surgery, age of patient, motility of the eye, primary or revision surgery, and the type and dose of surgery in 982 consecutive rectus muscle procedures. RESULTS: In 3.6% (35/982) of MISS procedures, an intraoperative conversion to a large, limbal approach was necessary. The overall conversion rate decreased over time, from 8.4% in 2003 to 0.4% in 2007. The multivariate regression analysis showed a significant negative influence between the date of surgery and the conversion rate (p < 0.005). Muscle resections were associated with a higher conversion rate (p < 0.001). The other evaluated factors had no significant influence on an intraoperative enlargement of the conjunctival opening. CONCLUSIONS: This study confirms the reliability of the new MISS technique, and shows a low conversion rate to the usual limbal approach. The conversion rate decreased over time with increasing surgical experience. Muscle resections were associated with a higher conversion rate, while the age of the patient, the motility of the eye, revision surgery and the dose of surgery had no significant influence on an intraoperative conversion. PMID- 21607636 TI - Corneal intrastromal tissue modeling with the femtosecond laser. AB - PURPOSE: To determine whether central corneal thinning and flattening can be achieved by intrastromal photodisruption using a femtosecond (fs) laser. SETTING: Institute of Clinical Neuroanatomy, Goethe-University, Frankfurt am Main, Germany. METHODS: Fourteen horizontal, parallel intrastromal cuts were performed on rabbit eyes using a fs laser. Full-grown rabbits (group 1; ten eyes) received bilateral treatment. Growing rabbits (group 2) received unilateral treatment (four eyes). Slit-lamp examination, pachymetry, and keratometry were performed on day 9, 31 and 86 (group 1) or on day 12, 29, 69, 176 and 318 (group 2) after surgery. RESULTS: Nine days after treatment, corneal swelling was present and a slight increase of mean corneal thickness (group 1: +4.40 +/- 5.56 MUm) as well as a steeper mean corneal curvature (group 1: -0.18 +/- 0.02 mm) were observed. In contrast, 1 month after tissue photodisruption corneas showed an average decrease of thickness (group 2: -21.0 +/- 2.5 MUm). By 6 months post-treatment, a further decrease (group 2: -36.3 +/- 6.9 MUm) was seen that remained stable for the rest of the observation period. At 176 days post-treatment, a decrease of corneal curvature (group 2: -0.21 +/- 0.10 mm) was found. Slit-lamp examination revealed a transparent cornea. At the site of intrastromal photodisruption a narrow band of increased reflectivity could be detected. CONCLUSIONS: Corneal thinning can be reliably achieved using intrastromal tissue modeling with a fs laser. Tissue modeling was accompanied by a transient opacity and irregularity of the corneal surface. PMID- 21607637 TI - Catheter ablation of non-inducible atrial tachycardia after surgical repair of heart disease. AB - We present a patient with non-inducible atrial tachycardia (AT) after atriotomy for surgical repair of heart disease who underwent ablation successfully. Using a 3-D mapping system, we presumed the atriotomy site on the lateral right atrial wall by searching for linear double potentials (DP) during sinus/paced rhythm from the coronary sinus, but it was evaluated incompletely. We could verify the edges of the atriotomy scar precisely by pacing from close to the linear DP lesion and the opposite site. After ablation between the presumed atriotomy scar and the inferior vena cava and cavotricuspid isthmus, no AT recurred without anti arrhythmic drugs. PMID- 21607638 TI - Fiber tractography assessment in double cortex syndrome. AB - INTRODUCTION: Subcortical band heterotopia (SBH) or double cortex syndrome is a malformation of cortical development that may be related to intractable epilepsy and severe mental retardation or to mild epilepsy and slight mental delay or normal cognitive functions. Several studies have been performed using neuroradiological or neurophysiological techniques, like SPECT, PET, MRS, fMRI, and MEG, in attempt to better characterize this neuronal migration disorder. Recently, also diffusion tensor imaging (DTI) and fiber tracking (FT) have been used to investigate on white matter anomalies in SBH, adding more information about such gray matter anomaly. METHODS: We report on three cases of SBH, evaluated with MRI, DTI, and FT. CONCLUSIONS: The data gathered from DTI and TF allow us to hypothesize a new functional role for heterotopic gray matter. PMID- 21607639 TI - Pure endoscopic removal of pineal region tumors. AB - PURPOSE: Endoscopic resection of pineal tumors using an endoscope with a mounted rigid suction that allows bimanual handling of the tumor for resection. This contrasts to the established method of biopsy of pineal tumors through intraventricular approach. METHODS: Two patients, one with a cystic lesion in the pineal region and one with a large pineal tumor, were operated in sitting position through a subtorcular approach. Endoscope was held in the left hand with suction tip extending beyond the tip through its instrument channel. Regular microsurgical instrumentation/CUSA/Nico Aspirator was used with the right hand for dissection, cutting, and removing the tumor under endoscopic vision. RESULT: Surgeon comfort was superior to when microscope is used in sitting position. Complete resection was achieved in all cases. CONCLUSION: The two-handed endoscopic technique using a mounted suction on the endoscope as described is a safe and effective strategy for resecting pineal region tumors. PMID- 21607640 TI - Frameless stereotactic endoscope-assisted transoccipital hippocampal depth electrode placement: cadaveric demonstration of a new approach. AB - PURPOSE: Hippocampal recording using depth electrodes is indicated in a small subgroup of patients with medically intractable seizures. There are several conventional techniques for implantation of hippocampal depth electrodes. We describe a new method for hippocampal depth electrode placement using an image guided endoscopic transoccipital route. This technique is simple and effective, eliminating several drawbacks of conventional techniques. METHODS: One silicone injected cadaver head was used. A rigid endoscope sheath was inserted through a transoccipital corridor into the atrium of the lateral ventricle and then advanced to the temporal horn. Each of the hemispheres was cannulated. The hippocampus was identified visually, and a depth electrode was inserted into the substance of the hippocampus along its long axis under direct vision. RESULTS: In both hemispheres we were able to successfully implant the depth electrode within the hippocampus. The advantages of our technique over conventional approaches are (1) there is no need for frame-based stereotaxy, thus reducing operating time and patient discomfort, (2) the electrodes are inserted into the hippocampus under direct endoscopic visualization, reducing the chance of injury to vascular structures, (3) there is no need to insert a larger cannula into the hippocampus before placement of the electrodes, reducing trauma to the hippocampus, and (4) the number of electrodes within the hippocampus can be assessed at the end of the procedure, reducing malposition. CONCLUSION: We believe that image-guided endoscopic transoccipital hippocampal depth electrode placement can be performed with precision equal or superior to conventional techniques but without their major disadvantages. PMID- 21607641 TI - Neurosurgical treatment of tuberous sclerosis complex lesions. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited syndrome. Renal disease is the main cause of death. Brain disorders are the origin of more frequent and severe problems, such as tumors, epilepsy, and mental retardation. Participation of neurosurgeons in the study and especially in the treatment of TSC patients is often required. MATERIALS AND METHODS: Two types of pathological conditions mainly require neurosurgical interventions in TSC: subependymal giant cell astrocytomas (SGCA) and cortical tubers. SGCA are located in the cerebral region close to the foramina of Monroe, uni- or bilaterally, and originate in hamartomas that can grow slowly as well as rapidly, even suddenly, especially in cases with intratumoral cyst, causing increased intracranial pressure (ICP) with severe risk for visual loss and life. Neurosurgeons have to participate in the follow-up of the patients as soon as the risk of ICP exists to remove the tumor when the criteria of SGCA growth are present. The other intracranial lesions that require neurosurgical intervention by are the cortical tubers. CONCLUSION: These dysplastic lesions are associated with TSC in almost the 100% of affected persons and are the cause of epilepsy in most patients. The seizures can be resistant to antiepileptic medication in many cases in which a tuber is identified as the origin of the focal seizures after functional studies, such as EEG, MR, PET, etc. In these cases, only surgical removal of the tuber and the perituberal epileptogenic foci can cure the epilepsy. Large tubers are more epileptogenic than smaller ones. PMID- 21607642 TI - Determinants associated with the utilization of primary and specialized mental health services. AB - The study aims to compare variables associated with the exclusive and joint use of primary and specialized care for mental health reasons by individuals diagnosed with a mental disorder in a Montreal/Canadian catchment area. Data were collected from a random sample (2,443 individuals). Among 406 people, diagnosed with a mental disorder 12 months pre-interview, 212 (52%) reported having used healthcare services. Compared to users of primary care only, people who sought both primary and specialized care presented more mental disorders and lower quality of life. People using only specialized healthcare received significantly less social support than persons using primary care exclusively and lived in neighborhoods with a high proportion of rental housing. Healthcare service provision should favor social networking and enable social cohesion and integration, particularly in neighborhoods with a high proportion of rental housing. Shared care and enhanced collaboration with other public and community based resources should be encouraged. PMID- 21607643 TI - High-risk behaviors associated with injection drug use among recently HIV infected men who have sex with men in San Diego, CA. AB - The contribution of injection drug use to HIV risk among men who have sex with men (MSM) is understudied. MSM infected with HIV within the prior 12 months completed a questionnaire assessing sociodemographic, sexual, drug use, and social factors. Analyses were performed to identify factors associated with lifetime history of injection drug use. Among 212 participants, the mean age was 33.8 years, 72% were White, 89% had attended college, and 9.4% reported ever injecting drugs. In multivariable logistic regression analysis, ever trading sex and using methamphetamine during sex with at least one of their last three partners were associated with injection drug use. Adjusting for these variables, in separate models, ever perpetrating violence against others (Adjusted Odds Ratio [AOR] = 3.16), having physically abusive sexual partners (AOR = 3.08), or physically abusing sexual partners (AOR = 10.17) were significantly (P < 0.05) associated with injection drug use. These findings suggest that violence is more common among MSM who inject drugs, which should be considered in HIV prevention efforts. PMID- 21607644 TI - Failure of knee osteotomy in a case of neuropathic arthropathy of the knee. AB - Neuropathic arthropathy (Charcot's joint) is a degenerative process that affects peripheral or vertebral joints as a consequence of a disturbance in proprioception and pain perception. The knee is one of the most frequently affected joints, but even when the diagnosis is made at an early stage there is no consensus on the best treatment options. An early diagnosis of neurosyphilis was made in a 55-year-old woman presenting a delayed union of an asymptomatic Schatzker type IV fracture of the proximal tibia. A medial opening wedge tibial osteotomy was performed to achieve fracture healing, to correct the medial depression of the articular surface, and possibly to avoid an early arthritis typical of the disease. To our knowledge, a knee osteotomy has never been reported at an early stage of neuropathic arthropathy. Even though the clinical and radiographic evaluation performed at 4 months follow-up showed a good stage of healing of the osteotomy and no typical features of neuropathic joint degeneration, at 8 months follow-up the knee was markedly deranged. PMID- 21607645 TI - Neuroprotective mechanisms of peroxisome proliferator-activated receptor agonists in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common causes of dementia accounting for 50 60% of all cases. The pathological hallmarks of AD are the formation of extracellular plaques consisting of amyloid-beta protein, intracellular neurofibrillary tangles of hyperphosphorylated tau proteins and presence of chronic neuroinflammation causing progressive decline in memory and cognitive functions. The current therapeutic strategies to improve memory deficits aim at preventing the formation and accumulation of amyloid-beta and tau phosphorylation. Beyond the plaque and tangle-related targets, other aspects of pathophysiology including molecular transport mechanism, oxidative damage, inflammation and glucose and lipid metabolism may also provide opportunities to slow down the progression of memory loss. A novel therapeutic approach to the treatment of AD is through the exploration of nuclear receptor agonists, peroxisome proliferator-activated receptors (PPARs), which have been clinically used as antidiabetic and dyslipidemic agents. The findings that PPAR agonists may possess antiamyloidogenic, anti-inflammatory, insulin-sensitizing, and cholesterol-lowering potential suggest that they could be interesting candidates for AD drugs. Through this review, we will discuss the probable pathophysiological mechanisms that may elicit the defending role of these receptors in brains of AD patients. PMID- 21607646 TI - Understanding protein kinase CK2 mis-regulation upon F508del CFTR expression. AB - We review areas of overlap between nucleoside diphosphate kinase (NDPK; nm23) and two proteins manifesting an equivalent diversity of action, each with many thousands of publications. The first is a constitutively active protein kinase, CK2 (formerly casein kinase 2), that includes NDPK amongst its hundreds of targets. The second is an enigmatic member of the ATP-binding cassette (ABC) family of membrane pumps that normally hydrolyse ATP to transport substrates. Yet our unusual family member (ABCC7) is not a pump but, uniquely, acts as a regulated anion channel. ABCC7 is the cystic fibrosis transmembrane conductance regulator (CFTR), and we discuss the highly prevalent CFTR mutation (F508del CFTR) in terms of the uncertainties surrounding the molecular basis of cystic fibrosis that cloud approaches to corrective therapy. Using lysates from cells stably expressing either wild-type or F508del CFTR, incubated with the CK2 substrate GTP, we show that the phosphoproteome of F508del CFTR-expressing cells both differs from wild-type CFTR-expressing cells and is significantly enhanced in intensity by ~1.5-fold (p < 0.05, paired t test with Bonferroni correction, n = 4). Phosphorylation is about 50% attenuated with a specific CK2 inhibitor. We propose that a new function may exist for the CFTR region that is commonly mutated, noting that its sequence (PGTIKENIIF(508)GVSYDEYRYR) is not only highly conserved within the C sub-family of ABC proteins but also a related sequence is found in NDPK. We conclude that a latent path may exist between mutation of this conserved sequence, CK2 hyperactivity and disease pathogenesis that might also explain the heterozygote advantage for the common F508del CFTR mutant. PMID- 21607647 TI - Identification and molecular properties of SUMO-binding proteins in Arabidopsis. AB - Reversible conjugation of the small ubiquitin modifier (SUMO) peptide to proteins (SUMOylation) plays important roles in cellular processes in animals and yeasts. However, little is known about plant SUMO targets. To identify SUMO substrates in Arabidopsis and to probe for biological functions of SUMO proteins, we constructed 6xHis-3xFLAG fused AtSUMO1 (HFAtSUMO1) controlled by the CaMV35S promoter for transformation into Arabidopsis Col-0. After heat treatment, an increased sumoylation pattern was detected in the transgenic plants. SUMO1 modified proteins were selected after two-dimensional gel electrophoresis (2-DE) image analysis and identified using matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). We identified 27 proteins involved in a variety of processes such as nucleic acid metabolism, signaling, metabolism, and including proteins of unknown functions. Binding and sumoylation patterns were confirmed independently. Surprisingly, MCM3 (At5G46280), a DNA replication licensing factor, only interacted with and became sumoylated by AtSUMO1, but not by SUMO1DeltaGG or AtSUMO3. The results suggest specific interactions between sumoylation targets and particular sumoylation enzymes. PMID- 21607648 TI - Effects of transient receptor potential channel blockers on pacemaker activity in interstitial cells of Cajal from mouse small intestine. AB - The interstitial cells of Cajal (ICCs) are pacemakers in the gastrointestinal tract and transient receptor potential melastatin type 7 (TRPM7) is a candidate for pacemaker channels. The effect of the 5-lipoxygenase (5-LOX) inhibitors NDGA, AA861, MK886 and zileuton on pacemaking activity of ICCs was examined using the whole cell patch clamp technique. NDGA and AA861 decreased the amplitude of pacemaker potentials in ICC clusters, but the resting membrane potentials displayed little change, respectively. Also, perfusing NDGA and AA861 into the bath reduced both inward current and outward current in TRPM7-like current in single ICC, respectively. But, they had no effects on Ca(2+) activated Cl(-) currents. The 5-LOX inhibitors MK886 and zileuton were, however, ineffective in pacemaker potentials in ICC clusters and in TRPM7-like current in single ICC, respectively. A specific TRPC3 inhibitor, pyrazole compound (Pyr3), and a specific TRPM4 inhibitor, 9-phenanthrol, had no effects in pacemaker potentials in ICC clusters and in TRPM7-like current in single ICC. These results suggest that, among the tested 5-LOX inhibitors, NDGA and AA861 modulate the pacemaker activities of the ICCs, and that the TRPM7 channel can affect intestinal motility. PMID- 21607649 TI - Claudin-18 in biliary neoplasms. Its significance in the classification of intrahepatic cholangiocarcinoma. AB - Claudin-18 (CLDN18), a tight junction protein specific to stomach and lung, is aberrantly expressed in preinvasive and invasive neoplasms of the pancreas. To investigate the significance of CLDN18 expression in biliary neoplasms, immunohistochemical analysis was performed. CLDN18 expression was frequently observed in the epithelial cells of extrahepatic bile duct carcinomas (90%, n = 99), intrahepatic intraductal papillary neoplasms of the bile duct (IPNBs, 100%, n = 11), and extrahepatic IPNBs (89%, n = 9), while it was less frequent in intrahepatic cholangiocarcinomas (ICCs, 43%, n = 83). Interestingly, CLDN18 expression was also frequently observed in precancerous lesions such as biliary intraepithelial neoplasias (78%, n = 18). Among ICCs, CLDN18-positive cases showed higher frequencies of periductal infiltrative growth, perineural invasion, and lymph node metastasis. Multivariable analysis demonstrated that positive CLDN18 expression was an independent risk factor for lymph node metastasis in ICCs. Furthermore, CLDN18 expression was associated with poor overall survival by univariable analysis, as well as lymph node metastasis. These results suggest that CLDN18 may play an important role in biliary carcinogenesis, and especially in ICCs, it is associated with aggressive behavior and serves as a useful marker for the classification of ICC. PMID- 21607650 TI - Beyond aspirin and clopidogrel: is there a need for additional antiplatelet therapy in ACS? AB - Dual antiplatelet therapy with aspirin and clopidogrel is a well-established standard of care for patients with acute coronary syndromes. Whether there are other drug strategies or therapies that will achieve fewer ischemic events, and at the same time be associated with fewer bleeding complications, is a question recurrently asked. Finding the appropriate pharmacologic calibration of antiplatelet potency and applying such a pharmacodynamic effect to all patients has only been partially successful. The shadow of this one-size-fits-all dilemma is now being recast with the arrival of newer antiplatelet agents, which are attempting to decouple antithrombotic potency from bleeding liability. Novel antiplatelet agents that act faster and have more consistent pharmacokinetics and higher potency are steadily emerging. Additionally, newer agents that target unique sites, such as the thrombin receptor on platelets, are being studied in large-scale clinical trials. Each of these new agents has the potential to extend net clinical benefits beyond those provided by aspirin and clopidogrel. PMID- 21607652 TI - Acute pancreatitis: should we use antibiotics? AB - Acute pancreatitis is a common cause of hospitalization and a major source of morbidity worldwide. When it is severe, and especially when it progresses to include necrosis of the pancreas, the risk of infection rises and mortality increases. Early reports suggested prophylactic antibiotics given in severe pancreatitis prevent infection and death. More recent clinical trials do not support this benefit, and meta-analyses on the topic offer conflicting recommendations. In this article, we evaluate the body of published literature examining the use of antibiotics as a preventive measure in acute pancreatitis. The highest quality, currently available data fail to support prophylactic use of antibiotics, which should be added to treatment regimens only where infection has been proven. PMID- 21607651 TI - Appropriate protein and specific amino acid delivery can improve patient outcome: fact or fantasy? AB - Protein utilization and requirements in critical illness are much researched and debated topics. The enhanced turnover and catabolism of protein in the setting of critical illness is well described and multifactorial in nature. The need to preserve lean body mass and enhance nitrogen retention in this state to improve immunologic function and reduce morbidity is well described. Debates as to the optimum amount of protein to provide in such states still exist, and a significant amount of research has contributed to our understanding of not only how much protein to supply to these patients, but how best to do so. Small peptide formulations, intact protein formulations, branched chain amino acids, and specialty formulas all exist, and their benefits, drawbacks, and potential uses have been investigated. Specific amino acid therapy has become part of the concept of immunonutrition, or the modification and enhancement of the immune response with specific nutrients. In this article, we describe the changes in outcomes demonstrated through the provision of protein, both as a macronutrient and as specific amino acids. PMID- 21607653 TI - Sexual behavior, cannibalism, and mating plugs as sticky traps in the orb weaver spider Leucauge argyra (Tetragnathidae). AB - Unpublished field observations in Leucauge argyra, a tropical orb weaver spider, suggest the occurrence of conspicuous mating plugs that could reduce or prevent remating attempts. Otherwise, the sexual behavior of this species remains unknown. The aims of this study were to describe the courtship behavior and copulation in L. argyra and investigate mating plug formation in this species. Fourteen virgin females and 12 plugged females were exposed to up to three males and checked for mating plug formation. Of the 12 virgins that copulated, nine produced plugs (five immediately after copulation), and the five plugged females that copulated produced another mating plug immediately after copulation. We did not detect the transfer of any male substance during copulation but observed a whitish liquid emerging from female genital ducts. Plug formation was positively associated with male twanging during courtship. One virgin and four plugged females cannibalized males. In seven trials with virgins and in three trials with plugged females, the male's palp adhered to a substance that emerged from female genital ducts and spread on her genital plate. The male had to struggle energetically to free his glued palp; two of these males were cannibalized while trying to release their palps. Females seem to determine copulation duration by altering the timing of mating plug formation and through sexual cannibalism. This is the first case reported of a mating plug as a sticky trap for males. PMID- 21607654 TI - Ocular palsy associated with aggressive NK-cell leukemia. PMID- 21607655 TI - Stromal-derived factor-1 deficiency in the bone marrow of acute myeloid leukemia. AB - Chemokine stromal-derived factor-1 (SDF-1) and its receptor CXCR4 have been shown to play an important role in the migration and homing of the transplanted hematopoietic stem cells (HSCs). Mesenchymal stem cells (MSCs) express these molecules. This study is to test the hypothesis that acute myeloid leukemia (AML) alters the expression of SDF-1/CXCR4 in human bone marrow MSCs. Expression of both CXCR4 and SDF-1 was found to be increased, but excessively retained, in the MSCs in AML. In contrast, the SDF-1 level in bone marrow plasma and supernatant of cultured MSCs from AML patients were reduced, while the SDF-1 was able to efficiently induce a dose-dependent migration of MSCs in vitro. Our results demonstrate that altered expression and distribution of SDF-1/CXCR4 in MSCs may contribute to SDF-1 deficiency in the plasma of AML patients. The migration of MSCs may be negatively affected by the SDF-1 deficiency. PMID- 21607656 TI - Small RNAs as regulators of primary and secondary metabolism in Pseudomonas species. AB - Small RNAs (sRNAs) exert important functions in pseudomonads. Classical sRNAs comprise the 4.5S, 6S, 10Sa and 10Sb RNAs, which are known in enteric bacteria as part of the signal recognition particle, a regulatory component of RNA polymerase, transfer-messenger RNA (tmRNA) and the RNA component of RNase P, respectively. Their homologues in pseudomonads are presumed to have analogous functions. Other sRNAs of pseudomonads generally have little or no sequence similarity with sRNAs of enteric bacteria. Numerous sRNAs repress or activate the translation of target mRNAs by a base-pairing mechanism. Examples of this group in Pseudomonas aeruginosa are the iron-repressible PrrF1 and PrrF2 sRNAs, which repress the translation of genes encoding iron-containing proteins, and PhrS, an anaerobically inducible sRNA, which activates the expression of PqsR, a regulator of the Pseudomonas quinolone signal. Other sRNAs sequester RNA-binding proteins that act as translational repressors. Examples of this group in P. aeruginosa include RsmY and RsmZ, which are central regulatory elements in the GacS/GacA signal transduction pathway, and CrcZ, which is a key regulator in the CbrA/CbrB signal transduction pathway. These pathways largely control the extracellular activities (including virulence traits) and the selection of the energetically most favourable carbon sources, respectively, in pseudomonads. PMID- 21607658 TI - Manipulating RuBisCO accumulation in the green alga, Chlamydomonas reinhardtii. AB - The nuclear factor, Maturation/stability of RbcL (MRL1), regulates the accumulation of the chloroplast rbcL gene transcript in Chlamydomonas reinhardtii by stabilising the mRNA via its 5' UTR. An absence of MRL1 in algal mrl1 mutants leads to a complete absence of RuBisCO large subunit protein and thus a lack of accumulation of the RuBisCO holoenzyme. By complementing mrl1 mutants by random transformation of the nuclear genome with the MRL1 cDNA, different levels of rbcL transcript accumulate. We also observe that RuBisCO Large Subunit accumulation is perturbed. Complemented strains accumulating as little as 15% RuBisCO protein can grow phototrophically while RuBisCO in this range is limiting for phototrophic growth. We also observe that photosynthetic activity, here measured by the quantum yield of PSII, appears to be a determinant for phototrophic growth. In some strains that accumulate less RuBisCO, a strong production of reactive oxygen species is detected. In the absence of RuBisCO, oxygen possibly acts as the PSI terminal electron acceptor. These results show that random transformation of MRL1 into mrl1 mutants can change RuBisCO accumulation allowing a range of phototrophic growth phenotypes. Furthermore, this technique allows for the isolation of strains with low RuBisCO, within the range of acceptable photosynthetic growth and reasonably low ROS production. MRL1 is thus a potential tool for applications to divert electrons away from photosynthetic carbon metabolism towards alternative pathways. PMID- 21607657 TI - MicroRNAs as regulators of root development and architecture. AB - MicroRNAs (miRNAs) are post-transcriptional regulators of growth and development in both plants and animals. In plants, roots play essential roles in their anchorage to the soil as well as in nutrient and water uptake. In this review, we present recent advances made in the identification of miRNAs involved in embryonic root development, radial patterning, vascular tissue differentiation and formation of lateral organs (i.e., lateral and adventitious roots and symbiotic nitrogen-fixing nodules in legumes). Certain mi/siRNAs target members of the Auxin Response Factors family involved in auxin homeostasis and signalling and participate in complex regulatory loops at several crucial stages of root development. Other miRNAs target and restrict the action of various transcription factors that control root-related processes in several species. Finally, because abiotic stresses, which include nutrient or water deficiencies, generally modulate root growth and branching, we summarise the action of certain miRNAs in response to these stresses that may be involved in the adaptation of the root system architecture to the soil environment. PMID- 21607659 TI - Attention network performance and psychopathic symptoms in early adolescence: an ERP study. AB - Reaction time (RT) and event-related potential (ERP) measures were used to examine the relationships between psychopathic symptoms and three major attention networks (alerting, orienting, and executive attention) among a community sample of youth. Antisocial Process Screening Device (APSD; Frick and Hare 2001) total and subscale scores were negatively correlated with ERP measures of attentional alerting, indicating that youth with psychopathic symptoms had difficulty using warning cues to prepare for upcoming targets. APSD total scores were not related to performance on measures of orienting or executive attention, although weaker executive attention was found among youth with higher scores on the Impulsivity subscale. These findings support attention-based models of psychopathy and provide evidence of specific deficits in attentional alerting among youth with psychopathic traits. Deficiencies in attentional alerting may be related to noradrenergic functioning and may have cascading effects on higher order cognitive and affective processing. PMID- 21607660 TI - The moderating role of verbal aggression on the relationship between parental feedback and peer status among children with ADHD. AB - We examined associations between children's sociometric status and (a) observed parental feedback as well as (b) child aggression. Participants were 94 children ages 6-10 (64 male; 44 with ADHD) and their parents. Children's peer status, parental feedback to their children, and child aggression were all assessed during lab-based playgroups of four children and their parents. Parent criticism in front of the child's peers was associated with the child receiving more negative ("disliked") and fewer positive ("liked") nominations, but only for children who displayed aggression; this interaction applied almost exclusively to children with ADHD. Parent praise in front of peers was associated with fewer negative nominations when children displayed low levels of aggression, but more at higher levels. Additional analyses revealed that relationships did not exist in the full sample between privately-given parental feedback and children's peer status. Processes by which peers use overheard adult feedback to inform their assessments of children are discussed. PMID- 21607661 TI - [Virological aspects of HTLV-1 infection and new therapeutical concepts]. AB - HTLV-1 was the first human oncogenic retrovirus to be discovered. It is the etiological agent of adult T leukemia/lymphoma (ATLL) and of tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM), two diseases that develop after a long latency period. Importantly, HTLV-1 does not cause ATLL through insertional mutagenesis. Apart from the gag, pro, pol and env genes, which are common to all retroviruses, HTLV-1 genome also encodes regulatory and auxiliary viral proteins. Among the former, Tax promotes cell transformation and HBZ is involved in the leukemic cells proliferation and in the maintenance of the transformed phenotype. Anti-ATLL therapies have lately made significant progress with an efficient antiviral treatment against the chronic and smoldering forms of this leukemia, but an efficient treatment of TSP/HAM patients is still lacking. Results from a recent study associating histone acetylase inhibitor with an anti viral drug will be discussed here. While an increase in proviral load is considered a marker for disease progression, this treatment allows a significant drop of the proviral load in asymptomatic carriers. PMID- 21607662 TI - [Conjonctival human myiasis by Oestrus ovis in Northern Africa]. AB - Following the publication of a paper on Conjonctival human myiasis by Oestrus ovis in southern Tunisia by Anane and Ben Hssine (Bull Soc Pathol Exot (2010) 103(5):299-304), the author reminds that the discovery of this disease was made in Algeria, in 1907 by Edmond and Etienne Sergent. PMID- 21607664 TI - Cloning and expression of one chloroplastic ascorbate peroxidase gene from Nelumbo nucifera. AB - A novel ascorbate peroxidase (APX) cDNA was obtained from Nelumbo nucifera (Elian). The phylogenetic analysis indicated that N. nucifera APX grouped together with chloroplastic APX of high plants. The recombinant protein expressed by PET-30a vector showed APX activity (0.04 mM ascorbate min(-1) mg(-1) protein). The APX mRNA was expressed in young leaves, roots, terminal buds, and leafstalks. Synergistic expression of N. nucifera APX and MnSOD mRNA was indicated in the short-term response to mechanical wounding. PMID- 21607665 TI - Identification of differentially expressed genes during the brachyurization of the Chinese mitten crab Eriocheir japonica sinensis. AB - Expressed sequence tags (ESTs) obtained from two-directional suppression subtractive hybridization (SSH) of cDNA libraries derived from the pleon of the Chinese mitten crab were analyzed using mRNA subtractive hybridization. After cDNA cloning and sequencing, gene expression profiles were examined, focusing on brachyurization. We assembled 211 non-redundant ESTs from SSH library 1 (yielding 130 unique transcripts: 25 consensi, 105 singletons) and 669 from SSH library 2 (195: 51 consensi, 144 singletons). Functional analysis shows that these genes are putatively involved in various cellular processes (33%), ribosomal RNA/proteins (30%), molting (12%), signal transduction (6%), immune factor and stress proteins (6%), development (4%), energy metabolism (3%), and mitochondrial membrane protein, hormone metabolizing, and chaperone (1% each) of other organisms. Some 3% are of unknown function in SSH library 1. The results facilitate the functional study of candidate genes involved in early developmental processes, especially the regulation of brachyurization in this crab. PMID- 21607666 TI - Molecular cloning, characterization, polymorphism, and association study of the interleukin-2 gene in Indian crossbred cattle. PMID- 21607667 TI - The combined effects of oncolytic reovirus plus Newcastle disease virus and reovirus plus parvovirus on U87 and U373 cells in vitro and in vivo. AB - Previous results had documented oncolytic capacity of reovirus, parvovirus and Newcastle disease virus (NDV) on several tumor cell types. To test whether combinations of these viruses may increase this capacity, human U87- and U373 glioblastoma cells, in vitro or xenografted into immuno-compromised mice, were subjected to simultaneous double infections and analyzed. Our results show that reovirus (serotype-3) plus NDV (Hitcher-B1) and reovirus plus parvovirus-H1 lead to a significant increase in tumor cell killing in vitro in both cell lines (Kruskal-Wallis test, P < 0.01) and in vivo. Immunofluorescence and flow cytometry analyses demonstrated the simultaneous replication of the viruses in nearly all cells (>95%) after combined infection. These data thus indicate that a synergistic anti-tumor effect can be achieved by the combined infection with oncolytic viruses. PMID- 21607668 TI - What is intrinsic atopic dermatitis? AB - Many authors favor a distinction between the extrinsic and intrinsic forms of atopic dermatitis. In this review, the controversy is discussed and several definitions are presented. After reviewing many papers on this topic, it is our opinion that it is useful to separate the intrinsic and extrinsic forms of atopic dermatitis or atopic eczema and atopiform dermatitis because the pathophysiology appears to be different between them. However, these terms require concrete definition and clarification of the distinction between these two concepts. This debate is a new step in the history of atopic dermatitis. It is possible that a single patient could suffer from one form and then from another but genetic differences suggest that two types could really exist. PMID- 21607669 TI - New therapeutics in C1INH deficiency: a review of recent studies and advances. AB - Hereditary angioedema (HAE) is a genetic condition causing a significant burden of illness for affected individuals. Episodes of angioedema involving the skin, gastrointestinal tract, as well as the larynx and oropharynx are often unpredictable and cause significant morbidity and mortality. Isolation of the underlying protein deficiency, specifically the serine protease C1 inhibitor, and further description of its role in multiple physiologic cascades has led to the development of several specific therapies for HAE. This report provides a brief overview of HAE but focuses primarily on reviewing recently published clinical studies of therapeutics developed for medical management of the condition. PMID- 21607670 TI - The morphological characteristics of corticostriatal and thalamostriatal neurons and their intrastriatal terminals in rats. AB - PURPOSE: The glutamatergic projection from the cerebral cortex and the thalamus extensively innervates the neostriatal neurons. However, some conflicts in the published literatures about cortical and thalamic intrastriatal synaptic terminals still need to be resolved. The present study intends to further elucidate the morphological characteristics of these two types of the terminals and their neurons. METHODS: The corticostriatal and thalamostriatal terminals were immunolabeled for vesicular glutamate transporter type 1 (VGluT1) and 2 (VGluT2), respectively, and their neurons were retrograde labeled by biotinylated dextran amine 3,000 molecular weight (BDA3k) injection into the dorsolateral striatum of rats. The characteristics of the corticostriatal and thalamostriatal terminals were observed at the LM and EM levels, and the data were statistically analyzed with SPSS10.0 software. RESULTS: We observed that 63.53% of VGluT1+ terminals synapsed on dendritic spines, which was different from VGluT2+ terminals with the equal percentage of synapses on spines and dendrites (14.88 and 17.86%, respectively). Notably, VGluT1+ axospinous synaptic terminals were remarkably larger than VGluT2+ axospinous synaptic terminals. Terminal size frequency distribution analysis showed that VGluT1+ terminals were within the size ranges of 0.4-0.5 and 0.8-0.9 MUm, and VGluT2+ terminals were in the ranges of 0.4-0.5 and 0.6-0.7 MUm. Perforated-postsynaptic densities (-PSDs) were more frequently found in VGluT1+ axospinous synaptic terminals than in VGluT2+ axospinous terminals. Furthermore, BDA3k-labeled corticostrital neurons were larger in perikaryal diameter than the thalamostriatal neurons, and they were also categorized as the two main populations based on their size-frequency distribution. CONCLUSIONS: The morphological characteristics of corticostriatal and thalamostriatal terminals and neurons have implications for understanding the roles of synaptic plasticity in adaptive motor control by the basal ganglia, and they have facilitations for understanding the complexities of basal ganglia function. PMID- 21607672 TI - Unusual twiddler syndrome: movement ties the knot. PMID- 21607671 TI - Population density and phenotypic attributes influence the level of nematode parasitism in roe deer. AB - The impact of parasites on population dynamics is well documented, but less is known on how host population density affects parasite spread. This relationship is difficult to assess because of confounding effects of social structure, population density, and environmental conditions that lead to biased among population comparisons. Here, we analyzed the infestation by two groups of nematodes (gastro-intestinal (GI) strongyles and Trichuris) in the roe deer (Capreolus capreolus) population of Trois Fontaines (France) between 1997 and 2007. During this period, we experimentally manipulated population density through changes in removals. Using measures collected on 297 individuals, we quantified the impact of density on parasite spread after taking into account possible influences of date, age, sex, body mass, and weather conditions. The prevalence and abundance of eggs of both parasites in females were positively related to roe deer density, except Trichuris in adult females. We also found a negative relationship between parasitism and body mass, and strong age and sex dependent patterns of parasitism. Prime-age adults were less often parasitized and had lower fecal egg counts than fawns or old individuals, and males were more heavily and more often infected than females. Trichuris parasites were not affected by weather, whereas GI strongyles were less present after dry and hot summers. In the range of observed densities, the observed effect of density likely involves a variation of the exposure rate, as opposed to variation in host susceptibility. PMID- 21607673 TI - Traumatic myocardial infarction visualised by computed tomography angiography. PMID- 21607674 TI - Giant coronary aneurysms: three-dimensional reconstruction. AB - A 31 year old man was referred for the evaluation of chest pain. Cardiac CT reconstruction revealed multiple calcified giant coronary aneurysms. Most likely this patient suffered from subclinical Kawasaki's disease in his childhood. PMID- 21607675 TI - A rare case of massive papillary fibroelastoma of the right ventricular free wall. PMID- 21607676 TI - [Not Available]. PMID- 21607677 TI - In the company of men: quality of life and social support among the Ariaal of northern Kenya. AB - To determine the age-related pattern of well-being among men and its predictors in a subsistence society, we collected anthropometric and questionnaire data among Ariaal pastoral nomads of northern Kenya. The sample consisted of 102 settled and 103 nomadic men ages 20 to 60+ stratified by 10 year age groups. Measures included questions from the WHO quality of life questionnaire (WHOQOL), anthropometrics, and hand grip strength, as well as questions about the number of friends and kin who gave material and emotional support. Results show that while reported quality of life declined significantly across age groups in both sub populations, nomadic males reported significantly higher overall quality of life than did settled males. Support from other males, but not marital status, was a significant predictor of quality of life, controlled for age group and residence. Among the physical measures, % body fat was positively related to quality of life among the nomads, while grip strength was not related to quality of life. In a multivariate model, male support was the strongest predictor of quality of life. These results provide the first clear demonstration of age-related declines in male quality of life and the importance of social support to men's quality of life in a subsistence population. PMID- 21607678 TI - Detection of liposome lysis utilizing an enzyme-substrate system. AB - A novel optical reporter system was developed to verify encapsulation and subsequent release of a foreign molecule in liposomes. The protocol utilizes a single enzyme and substrate. We encapsulate o-nitrophenyl-beta,D: galactopyranoside (ONPG) and measure its release by detecting the levels of o nitrophenol created when the encapsulated ONPG is released and hydrolyzed by beta galactosidase. Using this method, liposome formation and subsequent lysis with Triton X-100 were verified. This new protocol eliminates the complications of multiple reaction enzyme detection methods, along with the chance for false negatives and unreliable data seen when using fluorescent particles as reporters. PMID- 21607679 TI - Bone cross-sectional geometry in male runners, gymnasts, swimmers and non athletic controls: a hip-structural analysis study. AB - Loading of the skeleton is important for the development of a functionally and mechanically appropriate bone structure, and can be achieved through impact exercise. Proximal femur cross-sectional geometry was assessed in the male athletes (n = 55) representing gymnastics, endurance running and swimming, and non-athletic controls (n = 22). Dual energy X-ray absorptiometry (iDXA, GE Healthcare, UK) measurements of the total body (for body composition) and the left proximal femur were obtained. Advanced hip structural analysis (AHA) was utilised to determine the areal bone mineral density (aBMD), hip axis length (HAL), cross-sectional area (CSA), cross-sectional moment of inertia (CSMI) and the femoral strength index (FSI). Gymnasts and runners had greater age, height and weight adjusted aBMD than in swimmers and controls (p < 0.05). Gymnasts and runners had greater resistance to axial loads (CSA) and the runners had increased resistance against bending forces (CSMI) compared to swimmers and controls (p < 0.01). Controls had a lower FSI compared to gymnasts and runners (1.4 vs. 1.8 and 2.1, respectively, p < 0.005). Lean mass correlated with aBMD, CSA and FSI (r = 0.365-0.457, p < 0.01), particularly in controls (r = 0.657-0.759, p < 0.005). Skeletal loading through the gymnastics and running appears to confer a superior bone geometrical advantage in the young adult men. The importance of lean body mass appears to be of particular significance for non-athletes. Further characterisation of the bone structural advantages associated with different sports would be of value to inform the strategies directed at maximising bone strength and thus, preventing fracture. PMID- 21607680 TI - Cardiovascular adjustments in breath-hold diving: comparison between divers and non-divers in simulated dynamic apnoea. AB - The diving response is the sequence of cardiovascular, respiratory and metabolic adjustments produced by apnoea and further strengthened by cooling of the facial area and/or hypoxia. This study aimed at comparing the cardiovascular response to diving of trained divers with that of a control group. In this order, 14 trained divers were compared with 14 non-divers. By means of impedance cardiography and continuous monitoring of arterial pressure, hemodynamic data were collected during three different experimental sessions. Each session included a cycle ergometer exercise against a workload of 0.5 W kg(-1) of body mass, pedalling in a steady-state condition. During exercise, each subject randomly accomplished 40 s of breath-hold exercise with face immersion (test A) or in air (test B). A control exercise test with normal breathing (test C) was also performed. Divers showed a faster onset of bradycardic response (ANOVA, P < 0.01) and a faster adjustment in systemic vascular resistance (P < 0.001 for divers vs. controls) than did non-divers. Moreover, cardiac output decreased only in divers during the first phase of test A (P < 0.01 for divers vs. controls). The most striking findings were that divers showed a more rapid cardiovascular adjustment with respect to controls, in particular in heart rate and systemic vascular resistance; moreover, with continued apnoea, a delayed increase in myocardial performance and stroke volume occurred and obscured the cardiovascular effects of the diving response. PMID- 21607682 TI - Genotoxic effects of the cyanobacterial hepatotoxin cylindrospermopsin in the HepG2 cell line. AB - The cyanobacterial alkaloid cylindrospermopsin (CYN) is being increasingly identified in drinking water supplies worldwide. It is a potent protein synthesis inhibitor and causes human intoxications and animal mortality. The few genotoxicity studies available indicate that CYN is genotoxic, generally implying that it is pro-genotoxic. We evaluated CYN genotoxicity in the human hepatoma cell line, HepG2, analyzing the induction of DNA strand breaks, with the alkaline comet assay, and micronuclei (MNi), nuclear bud (NBUD), and nucleoplasmic bridge (NPB) formation, with the cytokinesis block micronucleus (CBMN) assay. In addition, changes in the expression of genes involved in the response to DNA damage (P53, CDKN1A, GADD45alpha, and MDM2) and genes presumably involved in CYN metabolism (genes from the Cytochrome P450 family: CYP1A1 and CYP1A2) were determined, using quantitative real-time PCR. Non-cytotoxic concentrations of CYN induced increased DNA damage after 12 and 24 h of exposure and increased the frequency of MNi, NBUDs, and NPBs after 24 h exposure. Moreover, CYN up-regulated the expression of the CYP1A1 and CYP1A2 genes. Although no changes in the expression of the P53 tumor-suppressor gene were found, CYN up-regulated the expression of the P53 downstream-regulated genes CDKN1A, GADD45alpha, and MDM2. Our results provide new evidence that CYN is genotoxic and strongly suggest that it needs to be considered in the human health risk assessment. PMID- 21607681 TI - Alternatives to animal testing: current status and future perspectives. AB - On the occasion of the 20th anniversary of the Center for Alternative Methods to Animal Experiments (ZEBET), an international symposium was held at the German Federal Institute for Risk Assessment (BfR) in Berlin. At the same time, this symposium was meant to celebrate the 50th anniversary of the publication of the book "The Principles of Humane Experimental Technique" by Russell and Burch in 1959 in which the 3Rs principle (that is, Replacement, Reduction, and Refinement) has been coined and introduced to foster the development of alternative methods to animal testing. Another topic addressed by the symposium was the new vision on "Toxicology in the twenty-first Century", as proposed by the US-National Research Council, which aims at using human cells and tissues for toxicity testing in vitro rather than live animals. An overview of the achievements and current tasks, as well as a vision of the future to be addressed by ZEBET@BfR in the years to come is outlined in the present paper. PMID- 21607683 TI - Identification of biomarkers of chemically induced hepatocarcinogenesis in rasH2 mice by toxicogenomic analysis. AB - Toxicogenomic approaches have been applied to chemical-induced heptocarcinogenesis rodent models for the identification of biomarkers of early stage hepatocarcinogenesis and to help clarify the underlying carcinogenic mechanisms in the liver. In this study, we used toxiciogenomic methods to identify candidate biomarker genes associated with hepatocarcinogenesis in rasH2 mice. Blood chemical, histopathologic, and gene expression analyses of the livers of rasH2 mice were performed 7 and 91 days after the administration of the genotoxic hepatocarcinogens 2-acetylaminofluorene (AAF) and diethylnitrosoamine (DEN), the genotoxic carcinogen melphalan (Mel), and the nongenotoxic noncarcinogen 1-naphthylisothiocynate (ANIT). Histopathologic lesions and a rise in accompanying serum marker levels were found in the DEN-treated rasH2 mice, whereas no neoplastic lesions were observed in the rasH2 mice. However, biological functional analysis using Ingenuity Pathways Analysis (IPA) software revealed that genes with comparable molecular and cellular functions were similarly deregulated in the AAF- and DEN-treated rasH2 mice. We selected 68 significantly deregulated genes that represented a hepatocarcinogen-specific signature; these genes were commonly deregulated in both the AAF- and DEN-treated rasH2 mice on days 7 and 91. Hierarchical clustering analysis indicated that the expression patterns of the selected genes in the hepatocarcinogen (AAF and DEN) groups were distinctive from the patterns in the control, Mel, and ANIT groups. Biomarker filter analysis using IPA software suggested that 28 of the 68 signature genes represent promising candidate biomarkers of cancer. Quantitative real-time PCR analysis confirmed that the deregulated genes, which exhibited sustained up- and down-regulation up to day 91, are likely involved in early stage hepatocarcinogenesis. In summary, the common and significant gene expression changes induced by AAF and DEN may reflect early molecular events associated with hepatocarcinogenesis, and these "signature" genes may be useful as biomarkers of hepatocarcinogenesis in mice. PMID- 21607684 TI - Does home range use explain the relationship between group size and parasitism? A test with two sympatric species of howler monkeys. AB - Group size is related to parasite infections in primates. This relationship probably reflects the fact that group size is associated with body contact between group members and with contact with contaminated items in the environment. The latter is highly associated with range use. In the present study we hypothesized that if infection by directly transmitted parasites (DTP) is mainly determined by the exposure of individuals to parasites that accumulate in the environment, and group size correlates negatively with the intensity of home range use, then smaller groups should be more infected by DTP. Additionally, groups that share a higher proportion of their home range with other groups should be more infected. To test our hypothesis we observed and collected fecal samples of two groups of Alouatta palliata (large group size) and two groups of A. pigra (small group size) that live sympatrically in a forest fragment located in Macuspana (Mexico). Group size was positively correlated with range area size and negatively correlated with the intensity of home range use. Range use variables were not related to either DTP prevalence or load. However, there were significant differences in DTP loads between groups, which were positively correlated with group size. Our results suggest that the intensity of home range use is a poor predictor of DTP infection parameters in groups with marked differences in size. Therefore, it is possible that the individual or combined effects of other ecological (e.g., microclimate), social (e.g., contact rate), or physiological (e.g., immune function) factors are more important in the dynamics of DTP in free-ranging primates. PMID- 21607685 TI - Negative correlation between aqueous vascular endothelial growth factor levels and axial length. AB - PURPOSE: The aim of this study was to evaluate the relationship between the concentrations of vascular endothelial growth factor (VEGF) in the aqueous humor and axial length. METHODS: Aqueous humor samples were obtained from 60 eyes of 60 patients without ocular diseases other than cataracts. No patients with diabetes mellitus were included. The VEGF concentration in the aqueous humor was measured using an enzyme-linked immunosorbent assay. RESULTS: The VEGF concentrations in the aqueous humor samples ranged from 25 to 241 pg/ml [mean +/- standard deviation (SD), 116.6 +/- 46.7 pg/ml]. The axial lengths ranged from 20.98 to 31.95 mm (mean +/- SD, 24.09 +/- 2.06 mm). The VEGF concentrations in the aqueous humor samples were correlated with axial length (Pearson product moment correlation test, rho = -0.373; P = 0.003). CONCLUSIONS: The concentration of VEGF in the aqueous humor is negatively correlated with axial length. PMID- 21607686 TI - Conjunctival swabs and corneoscleral rim cultures from corneal transplantation donors as possible early indicators for posttransplant endopthalmitis. AB - PURPOSE: To determine by microbiological examinations the rate of conjunctiva and corneoscleral rim contamination of cadaver donor tissues. METHODS: A prospective review of culture results for 98 cadaver donor conjunctival swabs [mean age 76.4 +/- 12.9 years (+/-SD)]. Transplant patients were evaluated both before and after disinfection with gentamicin. Individual parameters evaluated included detection rates of bacteria, variety of detected bacteria, time interval from donor death to tissue harvest and age of donors. RESULTS: Before disinfection, 60 out of 98 conjunctival swabs exhibited microbial growth, while only 36 out of 98 exhibited growth after disinfection (p = 0.0006). Longer intervals between death and tissue harvest were associated with higher positive microbial growth rates. Prior to disinfection, culture-positive donors (74.1 +/- 13.6 years) were significantly younger than culture-negative donors (79.8 +/- 10.8 years) (p = 0.024). Positive donor rim cultures were noted in 2 out of the 22 corneal transplantations. Microorganisms isolated from the corneal grafts matched those found in the conjunctiva. CONCLUSIONS: It is recommended that the corneoscleral buttons be removed as soon as possible. Cultures of conjunctival swabs collected from donors after disinfection may be useful in determining treatment for postoperative infections occurring after corneal transplantation. PMID- 21607687 TI - CD4 + CD25high regulatory T cell numbers and FOXP3 mRNA expression in patients with advanced esophageal cancer before and after chemotherapy. AB - We evaluated the changes in CD4 + CD25(high) regulatory T (Treg) cells and FOXP3 mRNA expression in patients with advanced esophageal cancer as well as its clinical significance. For this purpose, the frequencies of peripheral blood Treg cells in 68 patients with advanced esophageal cancer and 40 healthy controls were determined by flow cytometry, and FOXP3 mRNA expression in Treg cells of 40 patients was determined by RT-PCR. The data show that Treg cell numbers were significantly higher (P < 0.01) in esophageal cancer patients (1.82 +/- 0.54% of CD4 + T cells) as compared with healthy controls (1.52 +/- 0.70% of CD4(+) T cells). Treg cell numbers in the patients were significantly higher (P < 0.05) before chemotherapy (1.82 +/- 0.54% of CD4 + T cells) than after chemotherapy (1.66 +/- 0.58% of CD4 + T cells). Expression of the FOXP3 mRNA in the patients was significantly lower (P < 0.05) after chemotherapy (0.266 +/- 0.028% of CD4 + T cells) than before chemotherapy (0.318 +/- 0.027% of CD4 + T cells). It was, therefore, concluded that Treg cell numbers as well as FOXP3 mRNA expression in advanced esophageal cancer patients were significantly decreased after chemotherapy. Notably, FOXP3 gene may thus be involved in regulating the numbers and function of Treg cells in advanced esophageal cancer patients receiving chemotherapy. PMID- 21607688 TI - Detection of Cryptosporidium parvum and Cryptosporidium hominis in human patients in Cairo, Egypt. AB - Cryptosporidium is a significant cause of diarrheal disease in developing and industrialized nations. Cryptosporidium hominis and Cryptosporidium parvum are the main agents of cryptosporidiosis in humans. In Egypt, very little is known about genetic structure of Cryptosporidium spp. Therefore, this study was designed to examine samples from sporadic cases of cryptosporidiosis in Egyptians in order to identify the species involved in infection as well as the transmission dynamics and distribution of the parasite in the Great Cairo area. A total of 391 human faecal samples were collected, between May 2008 and March 2009, from ten public hospitals in Great Cairo. Initial screening by immunochromatographic detection kit "the Stick Crypto-Giardia; Operon" showed 23 possible positive cases. Twenty of them were confirmed by microscopic examination. PCR was performed by amplification of the oocyst wall protein (COWP) gene where 18 out of 23 samples were positive, one not detected by microscopy. Cryptosporidium genotyping was performed by RFLP analysis of PCR products of the diagnosis PCR. Only 15 samples rendered a digestion pattern. The genotyping distribution was nine cases showing C. hominis genotype, three showing C. parvum genotype and three showing mixed infection by C. hominis and C. parvum. The data showed an elevated prevalence of C. hominis (80.0%), the most anthroponotic species, suggesting a human-human transmission. Furthermore, the presence of up to 40% of samples infected with C. parvum shows that further investigations are required to determine the subgenotypes of C. parvum to clarify the mode of transmission in order to improve the control measures. PMID- 21607689 TI - Transcriptional differences between hypobiotic and non-hypobiotic preadult larvae of the bovine lungworm Dictyocaulus viviparus. AB - The survival of the bovine lungworm Dictyocaulus viviparus, one of the most important parasites in cattle, inside the host is ensured by arrested development during adverse environmental conditions, commonly referred to as hypobiosis. In the present study, a subtractive hybridization approach was used to compare the transcription profiles of hypobiotic and non-hypobiotic larvae (L5hyp and L5, respectively). Thereby, 75 L5hyp-enriched and 58 L5-enriched representative ESTs (rESTs) were identified. Subsequent sequence similarity search revealed that 28 L5hyp-rESTs and 11 L5-rESTs were homologous to known transcripts, whereas 47 L5hyp-rESTs and 47 L5-rESTs showed no homologies with published sequences, thus possibly representing parasitic or even Dictyocaulus-specific genes. The differential transcripts were predicted to be involved in nucleic acid synthesis, DNA binding, metabolic pathways and signal transduction. Overall, data presented in this paper provide a first basis for further characterization and analysis of genes driving normal as well as arrested (hypobiotic) parasite development. PMID- 21607690 TI - Revisiting caryophyllidean type of spermiogenesis in the Eucestoda based on spermatozoon differentiation and ultrastructure of Caryophyllaeus laticeps (Pallas, 1781). AB - Spermiogenesis of the monozoic cestode Caryophyllaeus laticeps (Pallas, 1781) (Caryophyllidea: Caryophyllaeidae), a parasite of Abramis brama (Pisces: Cyprinidae), has been investigated by means of transmission electron microscopy and cytochemical staining with periodic acid-thiosemicarbazide-silver proteinate for glycogen. The process of spermatozoon formation corresponds in the basic pattern to that of Khawia armeniaca as described by Brunanska and Poddubnaya (Parasitol Res 99:449-454, 2006). The dense material at the early stages of spermiogenesis, an intercentriolar body, the formation of a free flagellum and flagellar bud, the penetration of the nucleus into the spermatid body when the fusion of the free flagellum with the median cytoplasmic process has started, and a complete proximodistal fusion have been determined. In contrast to previous data on the caryophyllidean type spermiogenesis, the latter more recent observations show the presence and the rotation of a free flagellum and a flagellar bud. This pattern indicates clearly a derived stage of spermiogenesis in the Caryophyllidea, when the second shorter flagellum is greatly reduced comparing with that in the Spathebothriidea, Diphyllobothriidea, or Bothriocephalidea, thus forming a flagellar bud. The flagellar bud occurs in all stages of spermiogenesis and represents an evolved character in the Caryophyllidea. The mature spermatozoon of C. laticeps consists of one axoneme of the 9 + "1" trepaxonematan structure, parallel cortical microtubules, and a nucleus. Cell components are situated in a moderately electrondense cytoplasm, containing glycogen in the principal regions (II, III, and IV) of the spermatozoon. A crested body is absent. Similarities and differences between spermatozoa of caryophyllideans as well as other Eucestoda are discussed. PMID- 21607691 TI - In vivo validation of Aloe ferox (Mill). Elephantorrhiza elephantina Bruch. Skeels. and Leonotis leonurus (L) R. BR as potential anthelminthics and antiprotozoals against mixed infections of gastrointestinal nematodes in goats. AB - Aloe ferox (Mill)., Elephantorrhiza elephantina Bruch. Skeels. and Leonotis leonurus (L) R. BR. are some of the plants used by farmers in the Eastern Cape Province to control worms in goats, but information on their efficacy is lacking. The study was conducted to determine efficacy of these plants on gastrointestinal nematodes in natural mixed infections in goats. Forty-eight male goats aged 8-12 months were divided into eight groups (Treatments A-H) of six animals each, balanced in terms of liveweight and worm egg count. Treatments A to F received plant extracts, three animals in each group receiving doses of 250 mg/kg and the other three receiving 500 mg/kg at concentration of 100 mg/ml, while those in G and H received Valbazen(r) (11.36% albendazole) at 10 mg/kg, and 0.5 ml/kg distilled water, respectively per os. Faecal samples were collected on days 0, 3, 6 and 9 for faecal egg counts (FEC), and body weights recorded on days 1 and 9. Results showed significant reductions (P < 0.05) in strongyle eggs by A. ferox extract at dose levels of 500 mg/kg on days 3, 6 and 9, while reductions in Eimeria spp. oocysts were observed on days 3, 6 and 9 for animals that received 500 mg/kg doses. E. elephantina caused significant reduction (P < 0.05) of Trichuris spp. eggs on days 3 and 6, respectively at 250 mg/kg dose level, whereas L. leonurus also caused significant reduction (P < 0.05) in FEC of Trichuris spp. and Eimeria spp. oocysts at 250 mg/kg dose level on day 9. Albendazole caused reductions (P < 0.05) in strongyle eggs on days 3 and 6, Trichuris spp. on days 3, 6 and 9, and on coccidia, it caused a reduction (P > 0.05) on day 1, whereas on days 6 and 9, there was an increase. On total mixed infections, highest FECR% were observed with the extract of A. ferox on days 3 (53%), 6 (54%) and 9 (58%) at 500 mg/kg,whereas albendazole had efficacy levels of 39%, 44% and 29% on days 3, 6 and 9, respectively. Body weight of goats from days 1 to 9 were not significant different from the control. The study revealed efficacy of A. ferox, E. elephantina and L. leonurus against gastrointestinal parasites at high doses (500 mg/kg), showing that the plants have the potential to be used as anthelminthics. PMID- 21607692 TI - Molecular characterization of Hepatozoon sp. in cats from Sao Luis Island, Maranhao, Northeastern Brazil. AB - Few molecular studies have been done concerning the molecular characterization of Hepatozoon species among domestic and wild felids. The present work aimed to characterize molecularly the presence of Hepatozoon sp. DNA in cat blood samples from Sao Luis Island, Maranhao state, Northeastern Brazil. EDTA-whole blood samples were collected from 200 domestic cats with outdoor and wood areas access from Sao Luis, Maranhao, Brazil. Each sample of extracted DNA was used as a template in PCR reactions aiming to amplify a partial sequence of 18S rRNA of Hepatozoon spp. We also performed sequence alignment to establish the identity of the parasite species infecting these animals using DNA sequences based on 18S rRNA. From 200 sampled cats, Hepatozoon DNA was only found in one animal (0.5%). The found Hepatozoon DNA showed 97% of identity with Hemobartonella felis isolates 1 and 2 from Spain. When analyzing the phylogenetic tree, the found Hepatozoon DNA was in the same clade than H. felis isolates. Our findings suggest that more than one species of Hepatozoon could infect felids in Brazil. PMID- 21607693 TI - The characteristics of allelic polymorphism in killer-immunoglobulin-like receptor framework genes in African Americans. AB - The frequencies of alleles of killer cell immunoglobulin-like receptor genes, KIR3DL3 and KIR3DL2, and the carrier frequency of KIR2DL4 alleles have been determined from a population of African Americans (n = 100) by DNA sequencing of the coding regions. Fifty alleles of KIR3DL3 were observed with the most frequent, KIR3DL3*00901 (13%). KIR3DL2 was also diverse; 32 alleles with KIR3DL2*00103 the most frequent (17%). For KIR2DL4, of the 18 alleles observed, one allele, KIR2DL4*00103, was found in 64 of the 100 individuals. Thirty-six novel alleles encoding a total of 28 unique receptors are described. Pairwise comparisons among all of the alleles at each locus suggest a predominance of synonymous substitutions. The variation at all three framework loci fits a neutral model of evolution. PMID- 21607695 TI - Comparative antimicrobial activity and mechanism of action of bovine lactoferricin-derived synthetic peptides. AB - Lactoferricin B (LfcinB), a 25 residue peptide derived from the N-terminal of bovine lactoferrin (bLF), causes depolarization of the cytoplasmic membrane in susceptible bacteria. Its mechanism of action, however, still needs to be elucidated. In the present study, synthetic LfcinB (without a disulfide bridge) and LfcinB (C-C; with a disulfide bridge) as well as three derivatives with 15-, 11- and 9-residue peptides were prepared to investigate their antimicrobial nature and mechanisms. The antimicrobial properties were measured via minimum inhibitory concentration (MIC) determinations, killing kinetics assays and synergy testing, and hemolytic activities were assessed by hemoglobin release. Finally, the morphology of peptide-treated bacteria was determined by atomic force microscopy (AFM). We found that there was no difference in MICs between LfcinB and LfcinB (C-C). Among the derivatives, only LfcinB15 maintained nearly the same level as LfcinB, in the MIC range of 16-128 MUg/ml, and the MICs of LfcinB11 (64-256 MUg/ml) were 4 times more than LfcinB, while LfcinB9 exhibited the lowest antimicrobial activity. When treated at MIC for 1 h, many blebs were formed and holes of various sizes appeared on the cell surface, but the cell still maintained its integrity. This suggested that LfcinB had a major permeability effect on the cytoplasmic membrane of both Gram-positive and Gram negative bacteria, which also indicated it may be a possible intracellular target. Among the tested antibiotics, aureomycin increased the bactericidal activity of LfcinB against E. coli, S. aureus and P. aeruginosa, but neomycin did not have such an effect. We also found that the combination of cecropin A and LfcinB had synergistic effects against E. coli. PMID- 21607694 TI - Characterization of MHC class I and II genes in a subantarctic seabird, the blue petrel, Halobaena caerulea (Procellariiformes). AB - The great polymorphism observed in the major histocompatibility complex (MHC) genes is thought to be maintained by pathogen-mediated selection possibly combined with MHC-disassortative mating, guided by MHC-determined olfactory cues. Here, we partly characterize the MHC class I and II B of the blue petrel, Halobaena caerulea (Procellariiformes), a bird with significant olfactory abilities that lives under presumably low pathogen burdens in Subantarctica. Blue petrels are long-lived, monogamous birds which suggest the necessity of an accurate mate choice process. The species is ancestral to songbirds (Passeriformes; many MHC loci), although not to gamefowls (Galliformes; few MHC loci). Considering the phylogenetic relationships and the low subantarctic pathogen burden, we expected few rather than many MHC loci in the blue petrel. However, when we analysed partial MHC class I and class II B cDNA and gDNA sequences we found evidence for as many as at least eight MHC class I loci and at least two class II B loci. These class I and II B sequences showed classical MHC characteristics, e.g. high nucleotide diversity, especially in putative peptide binding regions where signatures of positive selection was detected. Trans species polymorphism was found between MHC class II B sequences of the blue petrel and those of thin-billed prion, Pachyptila belcheri, two species that diverged ~25 MYA. The observed MHC allele richness in the blue petrel may well serve as a basis for mate choice, especially since olfactory discrimination of MHC types may be possible in this species. PMID- 21607696 TI - A role of both NF-kappaB pathways in expression and transcription regulation of BAFF-R gene in multiple myeloma cells. AB - B-lymphocyte stimulator (BAFF) is a recently recognized member of the tumor necrosis factor ligand family (TNF) and a potent cell-survival factor expressed in many hematopoietic cells. BAFF regulates B-cell survival, differentiation, and proliferation by binding to three TNF receptors: TACI, BCMA, and BAFF-R. The mechanism involved in BAFF-R gene expression and regulation remains elusive. In this study, we examined BAFF-R gene expression, function, and regulation in multiple myeloma (KM3) cells. It was found that BAFF-BAFF-R induced cell survival by activating NF-kappaB1 pathway and NF-kappaB2 pathway. It was also found that NF-kappaB was an important transcription factor involved in regulating BAFF-R expression through one NF-kappaB binding site in the BAFF-R promoter, suggesting that inhibiting NF-kappaB could decrease the expression of BAFF-R mRNA and protein, and promote activity of BAFF-R gene. Our findings indicate that both NF kappaB pathways are involved in the regulation of BAFF-R gene and the NF-kappaB binding site of BAFF-R may be a new therapeutic target in this disease. PMID- 21607697 TI - New insights into the function of the iron deficiency-induced protein C from Synechococcus elongatus PCC 7942. AB - Iron limitation has a strong impact on electron transport reactions of the unicellular fresh water cyanobacterium Synechococcus elongatus PCC 7942 (thereafter referred to as S. elongatus). Among the various adaptational processes on different cellular levels, iron limitation induces a strongly enhanced expression of IdiC (iron-deficiency-induced protein C). In this article, we show that IdiC is loosely attached to the thylakoid and to the cytoplasmic membranes and that its expression is enhanced during conditions of iron starvation and during the late growth phase. The intracellular IdiC level was even more increased when additional iron was replenished in the late growth phase. On the basis of its amino acid sequence and of its absorbance spectrum, IdiC can be classified as a member of the family of thioredoxin (TRX)-like (2Fe 2S) ferredoxins. The presence of an iron cofactor in IdiC was detected by inductive coupled plasma optical emission spectrometry (ICP-OES). Comparative measurements of electron transport activities of S. elongatus wild type (WT) and an IdiC-merodiploid mutant called MuD, which contained a strongly reduced IdiC content under iron-sufficient as well as iron-deficient growth conditions, were performed. The results revealed that MuD had a strongly increased light sensitivity, especially under iron limitation. The measurements of photosystem II (PS II)-mediated electron transport rates in WT and MuD strain showed that PS II activity was significantly lower in MuD than in the WT strain. Moreover, P(700) (+) re-reduction rates provided evidence that the respiratory activities, which were very low in the MuD strain in the presence of iron, significantly increased in iron-starved cells. Thus, an increase in respiration may compensate for the drastic decrease of photosynthetic electron transport activity in MuD grown under iron starvation. Based on the similarity of the S. elongatus IdiC to the NuoE subunit of the NDH-1 complex in Escherichia coli, it is likely that IdiC has a function in the electron transport processes from NAD(P)H to the plastoquinone pool. This is in agreement with the up-regulation of IdiC in the late growth phase as well as under stress conditions when PS II is damaged. As absence or high reduction of the IdiC level would prevent or reduce the formation of functional NDH-1 complexes, under such conditions electron transport routes via alternative substrate dehydrogenases, donating electrons to the plastoquinone pool, can be assumed to be up-regulated. PMID- 21607698 TI - Efficacy of anterior odontoid screw fixation in the elderly patient: a CT-based biometrical analysis of odontoid fractures. AB - In the elderly population, reported union rates with anterior odontoid screw fixation (AOSF) for odontoid fracture (OF) treatment vary between 23 and 93% when using plain radiographs. However, recent research revealed poor interobserver reliability for fusion assessment using plain radiographs compared to CT scans. Therefore, union rates in patients aged >=60 years treated with AOSF have to be revisited using CT scans and factors for non-union to be analysed. Prospectively gathered consecutively treated patients using AOSF for odontoid fracture with age >=60 years were reviewed. Medical charts were assessed for demographics, clinical outcomes and complications. Patients' preoperative radiographs and CT scans were analysed to characterize fracture morphology and type, fracture displacement, presence of atlanto-dental osteoarthritis as well as a detailed morphometric assessment of fracture surfaces (in mm(2)). CT scans performed after a minimum of 3 months postoperatively were analysed for fracture union. Those patients not showing CT-based evidence of completely fused odontoid fracture were invited for radiographic follow-up at a minimum of 6 months follow-up. Follow-up CT-scan were studied for odontoid union as well as the number of screws used and the square surface of screws used for AOSF and the related corticocancellous osseous healing surface of the odontoid fragment (in %) were calculated. Patients were stratified whether they achieved osseous union or fibrous non-union. Patients with a non union were subjected to flexion-extension lateral radiographs and the non-union defined as stable if no motion was detected. The sample included 13 male (72%) and 5 female (18%) patients. The interval from injury to AOSF was 4.1 +/- 5.3 days (0-16 days). Age at injury was 78.1 +/- 7.6 years (60-87 years) and follow up was 75.7 +/- 50.8 months (4.2-150.2 months). 10 patients had dislocated fractures, 14 had Type II and 4 "shallow" Type III fractures according to the Anderson classification, 2 had stable C1-ring fractures, 8 had displayed atlanto dental osteoarthritis. Fracture square surface was 127.1 +/- 50.9 mm(2) (56.3 215.9 mm(2)) and osseous healing surface was 84.0 +/- 6.8% (67.6-91.1%). CT-based analysis revealed osseous union in 9 (50%) and non-union in 9 patients (50%). Union rates correlated with increased fracture surface (P = 0.02). Statistical analysis revealed a trend that the usage of two screws with AOSF correlates with increased fusion rates (P = 0.06). Stability at C1-2 was achieved in 89% of patients. CT scans are accepted as the standard of reference to assess osseous union. The current study offers an objective insight into the union rates of odontoid fractures treated with AOSF using CT scans in consecutive series of 18 patients >=60 years. Literature serves evidence that elderly patients with unstable OF benefit from early surgical stabilization. However, although using AOSF for unstable OF yields segmental stability at C1-2 in a high number of patients as echoed in the current study, our analysis stressed that using follow up CT scans in comparison to biplanar radiographs dramatically reduces osseous union rates compared to those previously reported for AOSF. PMID- 21607699 TI - Does computer use affect the incidence of distal arm pain? A one-year prospective study using objective measures of computer use. AB - PURPOSE: To study how objectively recorded mouse and keyboard activity affects distal arm pain among computer workers. METHODS: Computer activities were recorded among 2,146 computer workers. For 52 weeks mouse and keyboard time, sustained activity, speed and micropauses were recorded with a software program installed on the participants' computers. Participants reported weekly pain scores via the software program for elbow, forearm and wrist/hand as well as in a questionnaire at baseline and 1-year follow up. Associations between pain development and computer work were examined for three pain outcomes: acute, prolonged and chronic pain. RESULTS: Mouse time, even at low levels, was associated with acute pain in a similar way for all the examined regions. There were no exposure-response threshold patterns. Keyboard time had no effect. Mouse and keyboard sustained activity, speed and micropauses were not risk factors for acute pain, nor did they modify the effects of mouse or keyboard time. Computer usage parameters were not associated with prolonged or chronic pain. A major limitation of the study was low keyboard times. CONCLUSION: Computer work was not related to the development of prolonged or chronic pain. Mouse time was associated with acute distal arm pain, but the impact was quite small. PMID- 21607700 TI - Compulsory teaching of occupational health: impact on attitude of medical students in Brazil and Germany. AB - PURPOSE: To assess medical students' attitude toward occupational health (OH) in Brazil and Germany before and after a compulsory OH course. METHODS: A questionnaire regarding the attitude toward OH was completed by medical students at the beginning of the OH teaching term at the Federal University of Parana in Curitiba, Brazil (n = 79), and at both medical schools in Munich, Germany (n = 266), in 2009/2010. The change in the assessed qualities over the course period was measured repeating the survey at the end of the teaching term (n = 193; 56%). RESULTS: Overall, attitude toward OH was relatively low in both countries (mean 3.0 +/- SD 1.2 on a scale from 1 = very low to 6 = very high) and students did not consider OH as a career option. However, Brazilian medical students rated the importance of OH statistically significantly higher than German medical students. Students in both countries considered their knowledge of OH low (2.2 +/- 0.9). Not only self-assessed knowledge of OH (mean difference 1.5; 95% confidence interval 1.3-1.6) but also interest in OH (mean difference 0.2; 95% CI 0.06-0.4) improved statistically significantly over the teaching term. CONCLUSIONS: A negative attitude toward OH accompanied by little knowledge of OH seems to be a global problem. However, we have shown that this might be improved through adequate training in OH. The long-term effect still needs to be evaluated. Nevertheless, our results are promising and should encourage medical schools around the globe to include OH as a compulsory subject in medical training. PMID- 21607701 TI - Inhibition of contralateral premotor cortex delays visually guided reaching movements in men but not in women. AB - The premotor-parietal network for preparation of visually guided reaching demonstrates activity mainly contralateral to the reaching arm in men but bilaterally in women. These sex differences are most prominent in the dorsal premotor cortex (PMd); however, the functional implications of these differences remain unclear. Therefore, in the experiments described here, we used continuous theta burst stimulation (cTBS) to test hypotheses regarding the roles of PMd both contralateral and ipsilateral to the reaching arm in men and in women. Inhibitory cTBS of the ipsilateral PMd did not have a significant effect on reaction time in either men or women. However, cTBS of the contralateral PMd resulted in a slowed mean reaction time in men but not in women. Movement times were unaffected by stimulation applied to either hemisphere. These results suggest the presence of sex differences in processing within the left PMd during visually guided reaching movements using the right arm. Further, when taken together, the results suggest that ipsilateral PMd activity in women may not be functionally necessary for reaching movements. Rather, this ipsilateral activity may provide a protective redundancy that can compensate for decreased activity from the contralateral PMd. The observation of sex differences in reaction times but not in movement times following cTBS to the contralateral hemisphere suggests that these sex differences are more strongly associated with movement planning than with motor execution. PMID- 21607702 TI - Vasodilator phosphostimulated protein (VASP) protects endothelial barrier function during hypoxia. AB - The endothelial barrier controls the passage of solutes from the vascular space. This is achieved through active reorganization of the actin cytoskeleton. A central cytoskeletal protein involved into this is vasodilator-stimulated phosphoprotein (VASP). However, the functional role of endothelial VASP during hypoxia has not been thoroughly elucidated. We determined endothelial VASP expression through real-time PCR (Rt-PCR), immunhistochemistry, and Western blot analysis during hypoxia. VASP promoter studies were performed using a PGL3 firefly luciferase containing plasmid. Following approval by the local authorities, VASP ( -/- ) mice and littermate controls were subjected to normobaric hypoxia (8% O(2), 92% N(2)) after intravenous injection of Evans blue dye. In in vitro studies, we found significant VASP repression in human microvascular and human umbilical vein endothelial cells through Rt-PCR, immunhistochemistry, and Western blot analysis. The VASP promoter construct demonstrated significant repression in response to hypoxia, which was abolished when the binding of hypoxia-inducible factor 1 alpha was excluded. Exposure of wild-type (WT) and VASP ( -/- ) animals to normobaric hypoxia for 4 h resulted in an increase in Evans blue tissue extravasation that was significantly increased in VASP ( -/- ) animals compared to WT controls. In summary, we demonstrate here that endothelial VASP holds significant importance for endothelial barrier properties during hypoxia. PMID- 21607703 TI - A double-blind, placebo-controlled pilot study to evaluate the effect of calcium fructoborate on systemic inflammation and dyslipidemia markers for middle-aged people with primary osteoarthritis. AB - The objective of this pilot study was to determine whether 15 days of dietary supplementation with calcium fructoborate could acutely modulate inflammatory and lipid blood markers in individuals diagnosed with primary osteoarthritis. During 2 weeks, a placebo-controlled, randomized, double-blind study was conducted on 116 subjects that were initially recruited. Seventy-two subjects started the study, being divided into four groups, and only 60 completed the study as designed. The aim was to compare the effects of calcium fructoborate to placebo on subjects diagnosed with knee primary osteoarthritis. The obtained outcomes were inflammation biomarkers (C-reactive protein, fibrinogen, and erythrocyte sedimentation rate) and lipid markers (triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol). No serious adverse events were reported. The calcium fructoborate showed beneficial effect on the inflammatory markers for all groups subjected to the treatment when compared with the placebo group and slight changes in the lipid metabolism. This study suggests that short-term (2 weeks) calcium fructoborate supplementation in patients with osteoarthritis symptoms has a favorable prognosis on inflammation diseases. PMID- 21607704 TI - Effects of chronic light/dark cycle on iron zinc and copper levels in different brain regions of rats. AB - In this study, we aimed to investigate whether chronic shift in light/dark cycle alters brain trace element concentrations. For this purpose, 20 male Wistar albino adult rats were weighed and randomly divided into three groups. The first group (n = 6) was the control and had been subjected to 12/12-h light/dark cycle for 30 days. The second group (n = 7) was subjected to 6/18-h light/dark cycle for 15 days, and the third group (n = 7) was also subjected to 6/18-h light/dark cycle for 15 days and then returned to normal 12/12-h light/dark cycle for 15 days. When light/dark cycle protocols were completed, tissue specimens of the frontal lobe, temporal lobe, and brain stem were collected. Iron (Fe), zinc (Zn), and copper (Cu) concentrations of the frontal lobe, temporal lobe, and brain stem were determined by an atomic absorption spectrophotometer. When compared with controls, Fe levels of the temporal lobe significantly increased in 6/18-h light/dark cycle group (p < 0.05), whereas it was statistically unchanged in rats which were exposed to 6/18-h light/dark cycle then returned to the normal 12/12-h light/dark cycle period. Our results show that chronic shift in light/dark cycle affects trace element concentrations of the brain, especially Fe level in the temporal lobe, and these changes are reversible. PMID- 21607705 TI - Low concentrations of selenium and zinc in nails are associated with childhood asthma. AB - The purpose of this study was to investigate possible associations between Zn, Se, Cu, Mn, and Co concentrations in nails and asthma in a young population from a Southern Brazil city. Additionally, correlations between these chemical elements among asthmatic and non-asthmatic children were evaluated. Before nail collection (n = 165), children were asked to complete the International Study of Asthma and Allergies in Childhood questionnaire. The concentrations of trace elements were determined by inductively coupled plasma mass spectrometry. The chi square test was used to evaluate the association between element concentrations in nails and the respiratory outcome. To evaluate correlations between the elements, we used the Spearman correlation test. For all tests, the significance level was set at 95% (P <= 0.05). Children included in the highest quartile of nail Se and Zn concentration presented a fivefold decrease in the prevalence ratio of asthma while children in the lowest Se range presented an almost 2.5 fold increase in the asthma prevalence ratio. There were weak to strong correlations between Cu vs. Zn, Cu vs. Co, Cu vs. Se, Zn vs. Se, Zn vs. Mn, and Mn vs. Co in both asthmatic and non-asthmatic children. Interestingly, non asthmatics also presented correlations between Co vs. Se and Zn. Taken together, our results clearly demonstrated an association between concentrations of selenium and zinc and childhood asthma and the usefulness of nail as a noninvasive matrix to detect minerals imbalance in asthma patients. PMID- 21607706 TI - Editorial for special issue: ACM IHI 2010 best papers. PMID- 21607707 TI - Toward effective vaccine deployment: a systematic study. AB - Vaccination is a commonly-used epidemic control strategy based on direct antiviral immunization and indirect reduction of virus transmissibility. There exist three factors related to the efficacy of vaccine deployment; they are: (1) vaccine coverage, (2) releasing time, and (3) deployment method. Yet, the exact impacts of these factors still remain to be systematically studied. In our work, we examine the effectiveness of vaccination-based epidemic control in adjusting the composition of susceptible and infectious individuals (referred to as composite structure) in a host population. We develop a modified compartmental infection model for characterizing virus spreading dynamics in several age specific host populations (one host population for each age group). We consider vaccine deployment schedules that correspond to different settings of the three deployment factors. Based on our simulation-based experiments, we evaluate the impacts of deployment factors on virus spreading dynamics as well as their implications for an effective vaccination strategy. PMID- 21607708 TI - A low-cost reader for automatically collecting vital signs in hospitals. AB - Nowadays, the use of medical sensors with embedded communication modules provides accurate number reading and automatic recording. However, such readers are usually more expensive than similar devices without an embedded communication module. Further, different vendors define proprietary communication protocols and data formats for their own medical sensors. Due to the twin issues of high cost and diversity of standards, the automatic collection of patients' vital signs is not common in hospitals, meaning that medical staff need to periodically collect all patients' vital signs. This may cause further problems in caring for patients. We propose a low-cost reader using a cheap web camera to automatically read vital sign monitors in hospitals. The reader uses a high-resolution web camera to take a series of pictures of vital sign monitors and recognizes vital signs in electronic form and then forwards that information to hospital information systems. Its major benefit is that different sensors equipped with vital sign monitors, whether they include a computer communications module, can be digital-number recognized. It saves time in recording monitored vital signs of patients widely located in hospitals. In sum medical staff care of patients may be usefully assisted by the proposed reader which automatically collects all patients' vital signs, significantly improving patient care. PMID- 21607709 TI - On mending the genome and mentoring the epigenome. PMID- 21607710 TI - Induction of clinical remission with adalimumab-methotrexate combination therapy in a patient with rheumatoid arthritis and concomitant hepatitis C virus infection. AB - The patient described here is a 49-year-old woman who had hepatitis C virus (HCV) infection and rheumatoid arthritis (RA). Her RA had been successfully managed with methotrexate for about 10 years. After a sustained virological response was achieved with interferon therapy, treatment with adalimumab was instituted. This resulted in a rapid and sustained remission that lasted for more than a year, without HCV reactivation. The results in this case suggest that a sequential strategy, with initial HCV clearance followed by the targeting of remission with biologics, may be a favorable option in patients with RA and concomitant HCV infection. PMID- 21607711 TI - A trans-ethnic genetic study of rheumatoid arthritis identified FCGR2A as a candidate common risk factor in Japanese and European populations. AB - Rheumatoid arthritis (RA) is a common systemic autoimmune disease and its onset and prognosis are controlled by genetic, immunological, and environmental factors. The HLA locus, particularly HLA-DRB1, is its strongest genetic risk determinant across ethnicities. Several other genes, including PTPN22 and PADI4, show modest association with RA. However, they cover only a part of its genetic components and their relative contribution is different between populations. To identify novel genetic determinants, we took a candidate gene approach in a trans ethnic manner. After critical selection of 169 genes based on their immunological function, we performed SNP discovery of these genes by the resequencing of exons and surrounding areas using European and Japanese DNAs. We then generated a panel of 1,509 SNPs for case-control association study in both populations. The DerSimonian-Laird test for meta-analysis, using the combined results of the two populations, identified rs7551957 at the 5'-flanking region of the low-affinity Fc-gamma receptor IIa (FCGR2A) gene as the strongest candidate for the association (p = 8.6 * 10(-5), odds ratio = 1.58 with 95%CI 1.25-1.99). Suggestive signals were also obtained for three SNPs in the dihydropyrimidine dehydrogenase (DPYD) gene (rs6685859; p = 1.3 * 10(-4), rs7550959; p = 1.5 * 10( 4) and rs7531138; p = 1.7 * 10(-4)) and an intronic SNP, rs2269310, of the erythrocytic spectrin beta (SPTB) gene (p = 7.9 * 10(-4)). PMID- 21607712 TI - Elevated serum levels of macrophage migration inhibitory factor and their significant correlation with rheumatoid vasculitis disease activity. AB - Macrophage migration inhibitory factor (MIF) is recognized to be an important mediator in several inflammatory disorders, including rheumatoid arthritis (RA) and vasculitis. To evaluate the role of MIF in rheumatoid vasculitis (RV), we determined serum levels of MIF by enzyme-linked immunosorbent assay in RA patients with and without vasculitis and assessed their relationship to disease activity. Serum was obtained from 95 RA patients during active disease states [49 without vasculitis, 35 with extra-articular manifestations without histologically proven vasculitis, and 11 with histologically proven vasculitis] and from 22 healthy individuals. Vasculitis disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). MIF levels were significantly higher in RA patients than in controls. Moreover, MIF levels were significantly higher in RA patients with vasculitis than in those without vasculitic complications. In all RA patients, a statistically significant positive correlation was observed between serum MIF levels and each of the following: serum levels of C-reactive protein, rheumatoid factor, and thrombomodulin; and the erythrocyte sedimentation rate. In the RV group, the elevation of MIF levels correlated with the BVAS. Our findings suggest that MIF may serve as an additional serologic inflammatory marker of disease activity in RV, and it may be implicated in the pathogenesis of RV. PMID- 21607713 TI - The 894G > T (Glu298Asp) variant in the endothelial NOS gene and MTHFR polymorphisms influence homocysteine levels in patients with cognitive decline. AB - The presence and severity of cerebrovascular pathological findings have been shown to increase the risk and stage of cognitive decline observed in Alzheimer's disease and vascular dementia. Thus, the modification of vascular risk factors seems useful to reduce the risk of dementia regardless of type. Hyperhomocysteinemia has long been known as a major independent risk factor for vascular dysfunction. In this study, we evaluated the relationships between plasma homocysteine levels and genetic risk factors for hyperhomocysteinemia, i.e., the presence of gene variants for methylenetetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase (eNOS) in patients with cognitive impairment. Genotyping for MTHFR C677T and eNOS 894G > T polymorphisms was carried out in 69 patients with probable diagnosis of AD and anamnestic mild cognitive impairment, matched for age and gender with 69 healthy volunteers. Patients with MTHFR TT677 genotype showed higher plasma Hcy levels than controls, even after adjustment for folate levels (P < 0.05). Moreover, Hcy plasma levels were higher in cases than controls for any given eNOS genotype. In particular, the presence of eNOS TT894 genotype in patients with cognitive decline resulted significantly associated with increased plasma Hcy levels when compared with controls having the same genotype or patients having other eNOS genotypes (P = 0.02). These data suggest that both MTHFR C677T and eNOS G894T variants should be regarded as genetic risk factors for hyperhomocysteinemia in patients with cognitive decline. PMID- 21607714 TI - Ballistic parameters and trauma potential of direct-acting, powder-actuated fastening tools (nail guns). AB - Since their introduction in the 1950s in the construction and building trade, powder-actuated fastening tools (nail guns) are of forensic and traumatological importance. There are countless reports on both accidental and intentional injuries and fatalities caused by these tools in medical literature. While the ballistic parameters of so-called low-velocity fastening tools, where the expanding gases act on a captive piston that drives the fastener into the material, are well known, ballistic parameters of "high-velocity" tools, which operate like a firearm and release the energy of the propellant directly on the fastener, are unknown. Therefore, it was the aim of this work to investigate external ballistic parameters of cal. 9 and 6-mm fastening bolts discharged from four different direct-acting nail guns (Type Ideal, Record Piccolo S, Rapid Hammer R300, Titan Type 1). Average muzzle velocity ranged from 400 to 580 m/s, while average kinetic energy of the projectiles ranged from 385 to 547 J. Mean energy density of the projectiles ranged from 9 to 18 J/mm(2). To conclude, this work demonstrates that the muzzle velocity of direct-acting high-velocity tools is approximately five times higher than the muzzle velocity of piston-type tools. Hence, the much-cited comparison to the ballistic parameters of a cal. 22 handgun might be understated and a comparison to the widespread and well-known cal. 9 mm Luger might be more appropriate. PMID- 21607715 TI - Striated abrasions from a knife with non-serrated blade--identification of the instrument of crime on the basis of an experiment with material evidence. AB - This paper presents an experiment with a knife seized as material evidence in a homicide case. The reason for the experiment was the necessity to determine whether the injuries of the deceased could have been inflicted with this instrument since in the course of the investigation doubt arose as to the origin of linear, parallel scratches around one of the wounds and on the abdominal integuments suggesting a serrated blade. The knife found near the crime scene had a smooth blade and small serrations only on the borderline between its blade and hilt. However, the performed experiment showed that if the knife is directed towards the integuments of the body in a special way, its serrations, even though not located on the blade itself, may leave such striated marks on the body, as those found during the autopsy, suggesting their origin from a serrated blade. PMID- 21607716 TI - The examination and identification of bite marks in foods using 3D scanning and 3D comparison methods. AB - Bite mark analysis offers the opportunity to identify the biter based on the individual characteristics of the dentitions. Normally, the main focus is on analysing bite mark injuries on human bodies, but also, bite marks in food may play an important role in the forensic investigation of a crime. This study presents a comparison of simulated bite marks in different kinds of food with the dentitions of the presumed biter. Bite marks were produced by six adults in slices of buttered bread, apples, different kinds of Swiss chocolate and Swiss cheese. The time-lapse influence of the bite mark in food, under room temperature conditions, was also examined. For the documentation of the bite marks and the dentitions of the biters, 3D optical surface scanning technology was used. The comparison was performed using two different software packages: the ATOS modelling and analysing software and the 3D studio max animation software. The ATOS software enables an automatic computation of the deviation between the two meshes. In the present study, the bite marks and the dentitions were compared, as well as the meshes of each bite mark which were recorded in the different stages of time lapse. In the 3D studio max software, the act of biting was animated to compare the dentitions with the bite mark. The examined food recorded the individual characteristics of the dentitions very well. In all cases, the biter could be identified, and the dentitions of the other presumed biters could be excluded. The influence of the time lapse on the food depends on the kind of food and is shown on the diagrams. However, the identification of the biter could still be performed after a period of time, based on the recorded individual characteristics of the dentitions. PMID- 21607717 TI - Attractiveness of constitutive and herbivore-induced sesquiterpene blends of maize to the parasitic wasp Cotesia marginiventris (Cresson). AB - Plant volatile compounds induced by herbivore attack have been demonstrated to provide a signal to herbivore enemies such as parasitic wasps that use these volatiles to locate their hosts. However, in addition to herbivore-induced volatiles, plants often release volatiles constitutively. We assessed the interaction between herbivore-induced and constitutively released volatiles of maize in the attraction of the wasp Cotesia marginiventris that parasitizes herbivorous lepidopteran larvae feeding on maize. Experiments were carried out with olfactometers in which the sources of volatiles were transgenic Arabidopsis thaliana plants overexpressing maize sesquiterpene synthases that produce blends of herbivore-induced or constitutive compounds. We found that the constitutive volatiles of maize terpene synthase 8 (TPS8) were attractive to C. marginiventris, just like the herbivore-induced volatiles of TPS10 studied earlier. A mixture of both the TPS8 and TPS10 volatile blends, however, was more effective in parasitoid attraction, indicating that constitutively released sesquiterpenes enhance the attraction of those induced by herbivores. While C. marginiventris did not distinguish among the volatiles of TPS8, TPS10, nor those of another maize sesquiterpene synthase (TPS5), when these blends were combined, their attractiveness to the wasp appeared to increase with the complexity of the blend. PMID- 21607718 TI - Gemcitabine-loaded chitosan microspheres. Characterization and biological in vitro evaluation. AB - This study investigates the potential of chitosan microspheres as delivery systems for the anticancer drug gemcitabine. The microspheres were obtained by spray-drying chitosan-gemcitabine solutions containing different amounts of the polyanion dextran sulphate. Morphological characterization by SEM and FIB analyses showed the presence of porous spherical particles having sizes ranging from about 1 to 5 MUm. Dextran sulphate improves the technological parameters of the systems by producing very high encapsulation efficiency (about 96%, w/w) and by influencing the in vitro release of gemcitabine. The immediate drug release observed in the system prepared without dextrane sulphate (complete drug release within 30 min) was somewhat reduced by the polyanion (immediate release of 70% (w/w) of the encapsulated drug within 30 min, and subsequent continued release of the remaining 30% of the drug for over 4 days). The anti-tumoral efficacy of the various formulations was tested in vitro on human lung cancer cells (A549) comparing the effects with those of the free drug or drug/dextran sulfate complex. The carriers improved the cytotoxic activity of the drug, particularly the formulation containing the lowest amount of dextran sulphate after 72 h incubation. PMID- 21607719 TI - Food insufficiency and medication adherence among people living with HIV/AIDS in urban and peri-urban settings. AB - Food insufficiency is associated with medication non-adherence among people living with HIV/AIDS. The current study examines the relationship between hunger and medication adherence in a US urban and peri-urban sample of people living with HIV/AIDS. Men (N=133) and women (N=46) living with HIV/AIDS were recruited using snowball sampling and small media in Atlanta, Georgia. Participants completed computerized behavioral interviews that included measures of demographics, food insufficiency, social support, depression, and substance use, and provided blood specimens to determine HIV viral load. Participants also completed monthly unannounced pill counts to prospectively monitor medication adherence over 8 months. Results indicated that 45% of participants were less than 85% adherent to their medications and that food insufficiency was related to non-adherence; nearly half of non-adherent participants reported recent hunger. Geocoding of participant residences showed that 40% lived more than 5 miles from the city center. Multivariable logistic regression controlling for demographics and common factors associated with adherence showed that the interaction between distance from downtown and experiencing hunger significantly predicted non adherence over and above all other factors. Medication adherence interventions should address access to food, particularly for people living outside of urban centers. PMID- 21607720 TI - Brainstem congestion due to carotid-cavernous fistula via a shunt from the external carotid artery. PMID- 21607721 TI - Neural substrates of good and poor recovery after hemiplegic stroke: a serial PET study. AB - In this study, we used positron emission tomography (PET) at two different time points to study the temporal evolution of reorganization in patients with good and those without motor recovery from hemiplegia after the occurrence of a stroke. Ten hemiplegic patients with a first subcortical stroke and five healthy control subjects were scanned during passive and active movements at an interval of 8 weeks. PET1 was performed 22.8 +/- 7.8 days after the index stroke. At PET2, 8 weeks later, patients were dichotomized to either good recovery or no recovery according to the upper extremity motor component of the Fugl-Meyer score. Increases of regional cerebral blood flow (rCBF) and comparison between groups at PET1 and PET2 were assessed using statistical parametric mapping. At PET 1, activation was found bilaterally in the inferior parietal cortex. Eight weeks later, patients with good recovery showed maximum activation in the contralateral primary somatosensory cortex and overactivation of the contralateral inferior parietal cortex. Patients with poor recovery showed bilateral activation with a maximum in the somatosensory cortex. Studies correlating activation patterns with quality of recovery may identify the neuroanatomical substrates that subserve improved motor function. Such studies may also guide the development of more effective rehabilitative interventions after the occurrence of stroke. PMID- 21607722 TI - TDP-43 variants of frontotemporal lobar degeneration. AB - It has been only 5 years since the identification of TDP-43 as the major protein component of the ubiquitinated inclusions in FTLD-U. At that time, there were approximately a dozen papers about TDP-43; today, a "TDP-43" search reveals almost 600 papers. It is now clear that the majority of FTLD cases containing tau and alpha-synuclein-negative, ubiquitin-positive inclusions (FTLD-U) are FTLD TDP. The spectrum of TDP-43 proteinopathies includes FTLD-TDP with or without ALS, with or without mutations in GRN, VCP, or TARDBP, with or without chromosome 9p linkage, and sporadic and non-SOD1 familial ALS with or without FTLD-TDP. There are four sub-types of FTLD-TDP, and these correlate with specific clinical and genetic profiles. Sub-types are determined by the presence, predominance, and distribution of the various TDP-43 immunopositive insoluble aggregates-neuronal cytoplasmic inclusions, neuronal intranuclear inclusions, and dystrophic neurites. In this paper, FTLD-TDP pathologic sub-types will be described, and examples of each sub-type will be shown, and implications for future research will be discussed. PMID- 21607723 TI - Spontaneous recurrent hemarthrosis of the knee joint in the elderly: a report of two cases. PMID- 21607724 TI - Severe genu valgum deformity and slipped capital femoral epiphysis with renal osteodystrophy: a report of two cases. PMID- 21607725 TI - A case of thoracic myelopathy secondary to alkaptonuric spondylosis. PMID- 21607726 TI - Respiratory compensation improves the accuracy of electroanatomic mapping of the left atrium and pulmonary veins during atrial fibrillation ablation. AB - BACKGROUND: The creation of accurate electroanatomic maps (EAM) of the left atrium and pulmonary veins is important for atrial fibrillation (AF) ablation to guide ablative lesions and improve the safety and efficacy of the procedure. Respiratory motion of the heart and the pulmonary veins affects the accuracy of these maps. PURPOSE: This study aims to assess changes in the left atrial and pulmonary venous anatomy due to respiration and to evaluate their implication for EAM acquisition. METHODS: Two separate EAM were created using the CARTO 3 mapping system in 22 consecutive patients (63% males; mean age, 63 +/- 8 years) undergoing AF ablation at our center: a non-respiratory compensation (RC) map in which endocardial points were collected irrespective of respiratory phase and an RC map in which the points were collected during end expiration only. These maps were compared to pre-procedural cardiac CT/MRI images. RESULTS: Non-RC mapping required 3.2 +/- 1.0 min versus 7.8 +/- 2.1 min for the maps with RC. In comparison to the pre-procedural CT/MRI images, maps without RC significantly overestimated the dimensions of the pulmonary veins' ostia compared to maps with RC in both long and short axes. Distances between the pulmonary veins were not significantly different when comparing non-RC to RC mapping at the left atrial roof or floor. CONCLUSIONS: Respiratory compensation at the time of EAM acquisition during AF ablation more accurately represents the true anatomical dimensions of the pulmonary vein ostia. The resulting more accurate maps may improve the safety and efficacy of atrial fibrillation ablation. PMID- 21607727 TI - Influence of sintering temperature on the characteristics of shale brick containing oil well-derived drilling waste. AB - INTRODUCTION: The influence of sintering temperature on the physico-mechanical characteristics (such as water absorption, apparent porosity, bulk density, weight loss on ignition, firing shrinkage, and compressive strength), leachability, and microstructure of shale brick containing oil well-derived drilling waste (DW) was investigated. METHODS: The experiments were conducted at a temperature ranging from 950 degrees C to 1,050 degrees C with 30% DW addition. RESULTS: The results indicate that increasing the sintering temperature decreases the water absorption and apparent porosity and increases the shrinkage, density, and compressive strength of sintered specimens. Moreover, the physico-mechanical properties of samples sintered at 1,050 degrees C meet the requirements of the MU20 according to GB/T 5101-2003 (in China). The heavy metal concentrations of the leachate are much lower than the current regulatory limits according to GB16889-2008. CONCLUSION: The results from XRD and SEM show that increasing sintering temperature results in an increase of the high temperature liquid phase, which may have a significant effect on the densification process of the samples. PMID- 21607728 TI - Organic matter compounds as source indicators and tracers for marine pollution in a western Mediterranean coastal zone. AB - INTRODUCTION: Complex organic compounds found in oil and sediments linked with a particular source (such as algae, bacteria or vascular plants) are defined as biomarkers and are useful dating indicators in organic geochemistry. METHODS AND RESULTS: This paper presents the composition of the organic matter (OM) on marine surface sediments from a degraded Tunisian coast analysed by pyrolysis and gas chromatography-mass spectrometry (GC-MS). High total OM contents (0.3-4.2%) were detected with high levels of saturated linear hydrocarbons. The aliphatic lipids had contributed with up to 11.7% of the total OM, and their distribution had consisted of resolved compounds (n-alkanes and fatty acid (FAs)) and an unresolved complex mixture. Hydrocarbons, primarily n-alkanes, were ranged from 368 to 3,886 MUg g(-1). The FAs (674-2,568 MUg g(-1)) were dominated by derived primary production, and the short chain FAs (C16 and C18) were the most abundant throughout. The ubiquitous presence of petroleum contamination, mainly from offshore oil exploration, discharge of pollutants from rivers, shipping activities and atmospheric deposition was found in all samples. The Gabes littoral seems to be quite to very polluted near the industrial zone of Ghannouch. The C/H ratio (generally around 5.9), the thermal analysis and GC-MS of n-alkanes and FAs showed that the OM in the studied area was composed of anthropogenic/petrogenic, marine and continental sources. CONCLUSIONS: Our study represents an innovative approach to assessing environmental pollution. The evaluation of organic matter by examination of sterols, alkanes and fatty acids allows the identification of source, both anthropogenic and natural. PMID- 21607729 TI - Uranium biosorption by Padina sp. algae biomass: kinetics and thermodynamics. AB - INTRODUCTION: Kinetic, thermodynamic, and equilibrium isotherms of the biosorption of uranium ions onto Padina sp., a brown algae biomass, in a batch system have been studied. DISCUSSION: The kinetic data were found to follow the pseudo-second-order model. Intraparticle diffusion is not the sole rate controlling factor. The equilibrium experimental results were analyzed in terms of Langmuir isotherm depending with temperature. Equilibrium data fitted very well to the Langmuir model. The maximum uptakes estimated by using the Langmuir model were 434.8, 416.7, 400.0, and 370.4 mg/g at 10 degrees C, 20 degrees C, 30 degrees C, and 40 degrees C, respectively. Gibbs free energy was spontaneous for all interactions, and the adsorption process exhibited exothermic enthalpy values. Padina sp. algae were shown to be a favorable biosorbent for uranium removal from aqueous solutions. PMID- 21607730 TI - Familial neuralgia of occipital and intermedius nerves in a Chinese family. AB - Cranial nerve neuralgia usually occurs sporadically. Nonetheless, familial cases of trigeminal neuralgia are not uncommon with a reported incidence of 1-2%, suggestive of an autosomal dominant inheritance. In contrast, familial occipital neuralgia is rarely reported with only one report in the literature. We present a Chinese family with five cases of occipital and nervus intermedius neuralgia alone or in combination in three generations. All persons afflicted with occipital neuralgia have suffered from paroxysmal 'electric wave'-like pain for years. In the first generation, the father (index patient) was affected, in the second generation all his three daughters (with two sons spared) and in the third generation a daughter's male offspring is affected. This familial pattern suggests an X-linked dominant or an autosomal dominant inheritance mode. PMID- 21607731 TI - Interaction of carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) with lipid membrane systems: a biophysical approach with relevance to mitochondrial uncoupling. AB - FCCP (carbonylcyanide p-trifluoromethoxyphenylhydrazone), a classical uncoupler of mitochondrial oxidative phosphorylation, is used in this study as a model to clarify how interactions of uncouplers with membrane lipid bilayers may influence membrane biophysics and their protonophoric activity itself. In order to disclose putative effects that may be important when considering using uncouplers for pharmacological purposes, an extensive characterization of FCCP membrane lipid interactions using accurate biophysical approaches and simple model lipid systems was carried out. Differential scanning calorimetry studies showed that FCCP molecules disturb lipid bilayers and favor lateral phase separation in mixed lipid systems. (31)P NMR assays indicated that FCCP alters the curvature elastic properties of membrane models containing non-bilayer lipids, favoring lamellar/H(II) transition, probably by alleviation of hydrocarbon-packing constraints in the inverted hexagonal phase. Taking advantage of FCCP quenching effects on the fluorescent probes DPH (1,6-diphenyl-1,3,5-hexatriene) and DPH-PA (3-(p-(6-phenyl)-1,3,5-hexatrienyl)phenylpropionic acid), it is demonstrated that FCCP distributes across the bilayer thickness in both a single and a ternary lipid system mimicking the inner mitochondrial membrane. This behavior is consistent with the ability of the compound to migrate through the thickness of the inner mitochondrial membrane, an event required for its protonophoric activity. Finally, the study of the membrane fluidity in different lipid systems, as reported by the rotational correlation time (theta) of DPH or DPH-PA, showed that the extension at which FCCP disturbs membrane properties associated with the dynamics and the order of lipid molecules depends on the lipid composition of the model lipid system assayed. PMID- 21607732 TI - Effect of zinc supplementation on the distribution of various elements in the serum of diabetic rats subjected to an acute swimming exercise. AB - The present study aims to examine the effect of supplementation of zinc on the distribution of various elements in the sera of diabetic rats subjected to an acute swimming exercise. A total of 80 Sprague-Dawley-type adult male rats were equally allocated to one of eight groups: Group 1, general; Group 2, zinc supplemented; Group 3, zinc-supplemented diabetic; Group 4, swimming control; Group 5, zinc-supplemented swimming; Group 6, zinc-supplemented diabetic swimming; Group 7, diabetic swimming; and Group 8, diabetes. The rats were injected with 40 mg/kg/day subcutaneous streptozotocin (STZ) twice, with a 24-h interval between two injections. Zinc was supplemented at a dose of 6 mg/kg/day (ip) for 4 weeks. Blood samples were collected at the end of the 4-week study, and serum levels of lead, cobalt, molybdenum, chrome, sulfur, magnesium, manganese, sodium, potassium, phosphorus, copper, iron, calcium, zinc, and selenium (mg/L) were determined with atomic emission. The lowest molybdenum, chrome, copper, iron, potassium, magnesium, sodium, phosphorus, lead, selenium, and zinc values were obtained in Group 7 and 8. These same parameters were higher in the swimming exercise group (Group 4), relative to all other groups. The values in zinc-supplemented groups were found lower than the values in Group 4, but higher than those in Group 6 and 7. The results obtained from the study demonstrate that acute swimming exercise and diabetes affect the distribution of various elements in the serum, while zinc supplementation can prevent the negative conditions associated with both exercise and diabetes. PMID- 21607733 TI - Positive contrast with therapeutic iron nanoparticles at 4.7 T. AB - OBJECT: The purpose of the study was to show the feasibility of a positive contrast technique GRadient echo Acquisition for Superparamagnetic particles with Positive contrast (GRASP), for a specific type of magnetic particles, designed for tumor treatment under MRI monitoring. MATERIALS AND METHODS: A simulation study was performed to estimate field inhomogeneity intensities induced by increasing concentrations of particles at different static fields. The GRASP sequence was setup on a 4.7 T Bruker system during an in vitro study. Six mice, included in the in vivo study received particles in the left calf muscle and contrast enhancement values, were measured over three time points, for both negative and positive contrast images. RESULTS: Comparing values obtained by simulation at 1.5, 3, and 4.7 T, the strongest susceptibility effect was obtained at 4.7 T. Based on simulation and in vitro data, gradient settings were chosen for in vivo imaging. GRASP resulted in bright regions at and around the injection site, and higher enhancement values, compared to standard GRE imaging. Both contrasts were useful for longitudinal follow-up, with a faster decay over time for GRASP. CONCLUSION: The magnetic nanoparticles for drug delivery can be detected using positive contrast. Combining imaging sequences, i.e., negative contrast and susceptibility methods, increased imaging specificity of large magnetic particles and enabled their follow-up for theranostic applications. PMID- 21607734 TI - [Polyps of the colorectum: non-neoplastic and non-hamartomatous]. AB - Non-neoplastic and non-hamartomatous colorectal polyps or tumor-like lesions comprise a very heterogeneous group of changes in the colorectal mucosa or the colon wall. Mucosal prolapse-associated lesions and inflammatory polyps, which are predominantly associated with chronic inflammatory bowel disease, are the most prominent examples for polypoid lesions difficult to distinguish from neoplastic lesions such as adenomas, hyperplastic/serrated polyps/adenomas and invasive carcinomas. The considerably less frequent tumor-like lesions like heterotopias, endometriosis, amyloid tumors and pseudolipomatous changes are histologically often well defined and should be considered in the differential diagnosis of colorectal lesions. The etiology, endoscopic and histological appearance of these entities and their most important differential diagnoses are discussed. PMID- 21607736 TI - Minor or occult shoulder instability: an intra-articular pathology presenting with extra-articular subacromial impingement symptoms. AB - PURPOSE: Disruption in the balance of shoulder stability can produce a widely varied spectrum of clinical symptoms, ranging from minor shoulder instability to frank shoulder dislocation, followed by recurrent instability. In this study, a series of patients suffering from minor shoulder instability, all with clinical signs of preoperative subacromial impingement associated with instability, were treated. The shoulder instability alone was addressed, with the aim of eliminating the clinical symptoms of subacromial impingement and pain. MATERIAL: In this study, 20 patients with minor shoulder instability, presenting with subacromial impingement symptoms, underwent arthroscopic treatment to address capsule-labral pathology. All patients underwent a preoperative assessment by one independent physiotherapist, using Constant and WOSI scores, as well as the Castagna test, on both the affected and non-affected sides. The Hawkins test and subacromial pain in 90 degrees of abduction and internal rotation were also evaluated. All patients followed the same rehabilitation protocol by a second physiotherapist. All patients were followed up at 6, 12 and 24 months postoperatively by the same independent physiotherapist. RESULTS: We observed that 20/20 patients had a positive Hawkins sign at >20 degrees of internal rotation preoperatively, while 4/19 had a positive Hawkins sign--all with less pain--at the 24-month follow-up (P < 0.0001). Moreover, 20/20 had a positive Castagna test preoperatively, while 1/20 had a positive Castagna test at the 24 month follow-up. In terms of shoulder scores, at 24 months, the Constant score had improved from a median value of 70 (51-91) preoperatively to a median value of 91 (86-100). The median WOSI score was 48.3 (12.7-78.6) preoperatively and improved to 84.9 (39.5-98.5) at 24 months postoperatively. CONCLUSION: Minor shoulder instability is an intra-articular pathology presenting with extra articular subacromial impingement symptoms. By treating the intra-articular pathology, the extra-articular symptoms can be relieved in the vast majority of patients. PMID- 21607737 TI - Triple-bundle ACL grafts evaluated by second-look arthroscopy. AB - PURPOSE: The purpose of this study was to evaluate the morphology of transplanted triple-bundle anterior cruciate ligament (ACL) grafts by second-look arthroscopy. METHODS: The subjects were 41 patients with a mean age of 25.5 +/- 8.5 years who underwent second-look arthroscopy at between 6 and 22 months after the anatomical triple-bundle ACL reconstruction using semitendinosus tendon autograft. Lachman test was negative in 38 knees and mildly positive with a firm endpoint in 3 knees. Arthroscopic evaluation of grafts was performed for the anteromedial graft (AM), the intermediate graft (IM), and the posterolateral graft (PL), focusing on tension and graft damage. RESULTS: All grafts showed "fan-out" shape approaching the tibial attachment, which looked closer to the natural ACL compared to the double-bundle grafts. As to graft tension, 93% of AM, 90% of IM, and 88% of PL grafts were evaluated as taut, respectively. As to graft damage, there was no apparent rupture in the AM and IM grafts, while complete or substantial rupture was observed in 10% of PL grafts around the femoral tunnel aperture. The incidence of graft rupture in PL grafts was significantly greater than those in the AM and IM grafts. As to synovial coverage, 76% of AM, 78% of IM, and 59% of PL grafts were evaluated as "Good," while 41% of PL grafts were not fully covered with synovium. All of the synovial defects were observed around the femoral tunnel aperture. CONCLUSION: The morphology of the triple-bundle grafts resembled that of the natural ACL, while complete or substantial rupture was observed in 10% of the PL grafts. LEVEL OF EVIDENCE: Study of case series with no comparison group, Level IV. PMID- 21607738 TI - A clinical sign to detect root avulsions of the posterior horn of the medial meniscus. AB - PURPOSE: The goal of the present report was to describe a new clinical sign to make a clinical diagnosis of meniscal extrusion related to medial meniscal root avulsion. METHODS: Description of an easy clinical sign to detect extrusion of the medial meniscus at the anteromedial joint line. A varus stress test was applied in full extension before and after transosseous repair of an isolated traumatic avulsion of the posterior root of the medial meniscus in a 21-year-old patient. The clinical sign was verified by sectioning of the meniscotibial ligament during knee arthroplasty surgery in 3 patients. RESULTS: With a deficient posterior root, the clinical sign was positive, showing anteromedial extrusion under varus stress. After repair and at clinical follow-up, extrusion was normalized. CONCLUSION: Making the clinical diagnosis of medial meniscus extrusion after knee injury by applying a simple varus stress test to the knee and palpating the anteromedial meniscal extrusion might help physicians to suspect a medial meniscus root tear in the early stages after the injury as well as to evaluate its reduction after repair. A varus stress test in full extension should be performed systematically in patients where a root tear of the medial meniscus is suspected as well as after surgery to evaluate the success of the repair. PMID- 21607739 TI - Is there a correlation between posterior tibial slope and non-contact anterior cruciate ligament injuries? AB - PURPOSE: The purpose of this study was (1) to determine differences in posterior tibial slope (PTS) between subjects who underwent ACL reconstruction following a non-contact ACL injury and a matched control uninjured group and (2) to investigate gender differences between ACL-injured subjects and gender-matched controls. METHODS: A retrospective chart review was conducted of all 316 ACL deficient patients at a large regional academic teaching hospital. A control group was established searching the database of the same hospital for subjects who underwent knee radiographs for acute knee complaints with no ACL injury. Subjects (n = 272; males n = 199; females n = 73) were included if a non-contact mechanism could be established. Exclusion criteria included previous ipsilateral knee injury and/or knee previous surgery. PTS was measured on a digitalized lateral radiograph using the axis of the posterior tibial cortex as a reference. RESULTS: There was a significant difference (P = 0.008) within the ACL injury group between males and females. There was no significant difference in the PTS angle between those patients with an ACL injury (5.8 +/- 3.5 degrees) and the uninjured control group (5.6 +/- 3.2 degrees), or between the male ACL injury patients (5.5 +/- 3.4) and their control group (5.8 +/- 3.1). However, there was a significant difference between the female ACL injury patients (6.7 +/- 3.7) and their uninjured control group (5.0 +/- 3.4) (P = 0.004). CONCLUSION: The results of this study suggest that increased posterior tibial slope appears to contribute to non-contact ACL injuries in females, but not in males. PMID- 21607741 TI - Anterior labroligamentous periosteal sleeve avulsion lesion in arthroscopic capsulolabral repair for anterior shoulder instability. AB - PURPOSE: This study aims to compare the associated lesions, clinical results, and postoperative recurrence rates in patients with ALPSA lesions (ALPSA group) versus those with Bankart lesions or Perthes lesions (Bankart group) in arthroscopic capsulolabral repair for anterior shoulder instability. METHODS: Two hundred and twenty-two patients (227 shoulders) who had been followed for a minimum of 1 year were enrolled for this study. Mean age at the time of first dislocation was 19.5 +/- 4.8 years. Mean age at the time of operation was 23.3 +/ 4.6 years. One hundred and seventy-four shoulders were included in the Bankart group and fifty-three shoulders in the ALPSA group. RESULTS: The mean preoperative number of dislocations was significantly higher in the ALPSA group with 12.3 +/- 6.2 times than in the Bankart group with 6.9 +/- 5.7 times. No statistically significant differences were found in final clinical results except postoperative loss of external rotation (P < 0.01) between the two groups. The ALPSA group had significantly higher rates of the lesion extended to the superior part of the 2 o'clock position (P < 0.01), synovitis (P < 0.01), glenoid erosion (P < 0.01), large Hill-Sachs lesions (P < 0.01), and engaging Hill-Sachs lesions (P = 0.03). The recurrence rate was 15.1% in the ALPSA group, more than twice the rate in the Bankart group with 7.4% (P = n.s.). The size and engagement of Hill Sachs were significantly associated with redislocation (P < 0.01, P = 0.02). CONCLUSIONS: Compared with the Bankart group, the ALPSA group showed a significantly higher number of preoperative dislocations, an associated larger sized Hill-Sachs lesion, and a higher tendency to develop into an engaging Hill Sachs lesion. In addition, the ALPSA group presented a higher tendency to redislocate and significant postoperative loss of external rotation after capsulolabral repair. PMID- 21607740 TI - Patellar chondral defects: a review of a challenging entity. AB - PURPOSE: The aim of this study was to perform a review of the management of patellar cartilage defects, identify prognostic factors for better clinical outcomes, and propose a treatment algorithm of this challenging entity. METHODS: We conducted a review of multiple databases, evaluating the clinical outcomes after patellar cartilage lesion treatment. Because of the heterogeneity of data, a meta-analysis could not be performed. RESULTS: Twelve studies were identified for inclusion. Based on the clinical outcomes of these studies, a treatment algorithm was proposed. The clinical outcomes after patellar cartilage defects repair depend on the location and size of the articular defect, the age of the patient, the successful reconstruction of the patellar ridge, the repair of extensor mechanism malalignment, and the coexistence of chondromalacia. CONCLUSION: The optimal treatment for cartilaginous defects of the patella is still elusive. More prospective studies are needed, in order to identify which techniques are cost-effective especially on a long-term basis. PMID- 21607742 TI - Monoamine oxidase A regulates neural differentiation of murine embryonic stem cells. AB - Monoamine oxidase (MAO) A is the major metabolizing enzyme of serotonin (5 hydroxytryptamine, 5-HT) which regulates early brain development. In this study, wild-type (WT) and MAO A(neo) embryonic stem (ES) cell lines were established from the inner cell mass of murine blastocysts and their characteristics during ES and differentiating stages were studied. Our results show that the differentiation to neural cells in MAO A(neo) ES cells was reduced compared to WT, suggesting MAO A played a regulatory role in stem cells neural differentiation. PMID- 21607743 TI - Self-monitoring and its relationship to medical knowledge. AB - In the domain of self-assessment, researchers have begun to draw distinctions between summative self-assessment activities (i.e., making an overall judgment of one's ability in a particular domain) and self-monitoring processes (i.e., an "in the moment" awareness of whether one has the necessary knowledge or skills to address a specific problem with which one is faced). Indeed, previous research has shown that, when responding to both short answer and multiple choice questions, individuals are able to assess the likelihood of answering questions correctly on a moment-by-moment basis, even though they are not able to generate an accurate self-assessment of overall performance on the test. These studies, however, were conducted in the context of low-stakes tests of general "trivia". The purpose of the present study was to further this line of research by investigating the relationship between self-monitoring and performance in the context of a high stakes test assessing medical knowledge. Using a recent administration of the Medical Council of Canada Qualifying Examination Part I, we examined three measures intended to capture self-monitoring: (1) the time taken to respond to each question, (2) the number of questions a candidate flagged as needing to be considered further, and (3) the likelihood of changing one's initial answer. Differences in these measures as a function of the accuracy of the candidate's response were treated as indices of each candidate's ability to judge his or her likelihood of responding correctly. The three self-monitoring indices were compared for candidates at three different levels of overall performance on the exam. Relative to correct responses, when examinees initially responded incorrectly, they spent more time answering the question, were more likely to flag the question for future consideration, and were more likely to change their answer before committing to a final answer. These measures of self monitoring were modulated by candidate performance in that high performing examinees showed greater differences on these indices relative to poor performing examinees. Furthermore, reliability analyses suggest that these difference measures hold promise for reliably differentiating self-monitoring at the level of individuals, at least within a given content area. The results suggest that examinees were self-monitoring their knowledge and skills on a question by question basis and altering their behavior appropriately in the moment. High performing individuals showed stronger evidence of accurate self-monitoring than did low performing individuals and the reliability of these measures suggests that they have the potential to differentiate between individuals. How these findings relate to performance in actual clinical settings remains to be seen. PMID- 21607744 TI - Supervisor assessment of clinical and professional competence of medical trainees: a reliability study using workplace data and a focused analytical literature review. AB - Even though rater-based judgements of clinical competence are widely used, they are context sensitive and vary between individuals and institutions. To deal adequately with rater-judgement unreliability, evaluating the reliability of workplace rater-based assessments in the local context is essential. Using such an approach, the primary intention of this study was to identify the trainee score variation around supervisor ratings, identify sampling number needs of workplace assessments for certification of competence and position the findings within the known literature. This reliability study of workplace-based supervisors' assessments of trainees has a rater-nested-within-trainee design. Score variation attributable to the trainee for each competency item assessed (variance component) were estimated by the minimum-norm quadratic unbiased estimator. Score variance was used to estimate the number needed for a reliability value of 0.80. The trainee score variance for each of 14 competency items varied between 2.3% for emergency skills to 35.6% for communication skills, with an average for all competency items of 20.3%; the "Overall rating" competency item trainee variance was 28.8%. These variance components translated into 169, 7, 17 and 28 assessments needed for a reliability of 0.80, respectively. Most variation in assessment scores was due to measurement error, ranging from 97.7% for emergency skills to 63.4% for communication skills. Similar results have been demonstrated in previously published studies. In summary, overall supervisors' workplace based assessments have poor reliability and are not suitable for use in certification processes in their current form. The marked variation in the supervisors' reliability in assessing different competencies indicates that supervisors may be able to assess some with acceptable reproducibility; in this case communication and possibly overall competence. However, any continued use of this format for assessment of trainee competencies necessitates the identification of what supervisors in different institutions can reliably assess rather than continuing to impose false expectations from unreliable assessments. PMID- 21607745 TI - Interferential electric stimulation applied to the neck increases swallowing frequency. AB - Swallowing disorders are a common complaint among the elderly. Recently, surface electrical stimulation applied to the neck region has received increased attention as a new modality to treat pharyngeal dysphagia. Previous reports used pulsed current at a frequency range of 1-120 Hz. Kilohertz-frequency alternating currents (ACs) have not been tested for treating dysphagia. Therefore, we evaluated the effects of interferential currents (IFCs), the most popular modality of amplitude-modulated kilohertz-frequency ACs in clinical practice, on the swallowing reflex in healthy subjects. We found that IFC stimulation at the sensory threshold with 50-Hz modulation significantly increased the number of swallows without any discomfort, but pure AC stimulation at the carrier frequency did not have a significant effect. There was no statistically significant difference in the time course of the number of swallows among 1,000-, 2,000-, 4,000-, and 6,000-Hz carrier frequencies. The number of swallows remained increased during the 15-min IFC stimulation, suggesting that IFC stimulation facilitates the swallowing reflex without adaptation, at least during this stimulation period. We suggest that an IFC stimulation or a low-frequency, modulated kilohertz AC stimulation, which would be more comfortable than pulsed currents, is an alternative stimulation mode for treating pharyngeal dysphagia. PMID- 21607746 TI - Influence of TiO2 on prebiotic thermal synthesis of the Gly-Gln polymer. AB - The role of the titanium dioxide (rutile and anatase) with and without room light on the thermal synthesis of the glycine-L-glutamine (Gly-Gln) polymer is described. The efficiency in percentage of polymerization with room light was increased in 6% in the presence of rutile and in 23% in the presence of anatase. The thermal synthesis in the molten state was carried out in the absence and presence of both oxides. In all cases, the vibrational spectra showed characteristic group frequencies corresponding to a polypeptide structure. No spectral differences were observed by room light effect on the polymer on rutile. However, the polymer obtained in the presence of anatase and room light shows spectral changes associated with the formation of shorter new abundant and conformationally different species compared with the original polymer. The SEM EDX characterization of the solid phase involved in the thermal synthesis showed that the morphology of the polypeptide is different in the presence of rutile compared to anatase. The SDS-PAGE and GPC results suggest that smaller chains are formed in the presence of both oxides and the distribution of the size and weight of each polymer molecule is completely different when the condensation is performed in the presence of anatase or rutile. Nuclear magnetic resonance analyses confirmed the incorporation of both Gly and Gln residues in the polymers, with a prevalence of Gly. Both possible sequences N-GlyGln-C and N GlnGly-C were also detected. PMID- 21607747 TI - Fabrication of biodegradable poly(ester-amide)s based on tyrosine natural amino acid. AB - N,N'-Bis[2-(methyl-3-(4-hydroxyphenyl)propanoate)]isophthaldiamide (5), a novel diol monomer containing chiral group, was prepared by the reaction of S-tyrosine methyl ester (3) with isophthaloyl dichloride (4a). A new family of optically active and potentially biodegradable poly(ester-amide)s (PEAs) based on tyrosine amino acid were prepared by the polycondensation reaction of diol monomer 5 with several aromatic diacid chlorides. The resulting new polymers were obtained in good yields with inherent viscosities ranging between 0.25 and 0.42 dL/g and are soluble in polar aprotic solvents. They showed good thermal stability and high optical purity. The synthetic compounds were characterized and studied by FT-IR, 1H-NMR, specific rotation, elemental and thermogravimetric analysis (TGA) techniques and typical ones by 13C-NMR, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and field emission scanning electron microscopy (FE-SEM) analysis. Soil burial test of the diphenolic monomer 5, and obtained PEA6a, and soil enzymatic assay showed that the synthesized diol and its polymer are biologically active and probably biodegradable in soil environment. PMID- 21607748 TI - A mutation screen in patients with Kabuki syndrome. AB - Kabuki syndrome (KS) is one of the classical, clinically well-known multiple anomalies/mental retardation syndromes, mainly characterized by a very distinctive facial appearance in combination with additional clinical signs such as developmental delay, short stature, persistent fingerpads, and urogenital tract anomalies. In our study, we sequenced all 54 coding exons of the recently identified MLL2 gene in 34 patients with Kabuki syndrome. We identified 18 distinct mutations in 19 patients, 11 of 12 tested de novo. Mutations were located all over the gene and included three nonsense mutations, two splice-site mutations, six small deletions or insertions, and seven missense mutations. We compared frequencies of clinical symptoms in MLL2 mutation carriers versus non carriers. MLL2 mutation carriers significantly more often presented with short stature and renal anomalies (p = 0.026 and 0.031, respectively), and in addition, MLL2 carriers obviously showed more frequently a typical facial gestalt (17/19) compared with non-carriers (9/15), although this result was not statistically significant (p = 0.1). Mutation-negative patients were subsequently tested for mutations in ten functional candidate genes (e.g. MLL, ASC2, ASH2L, and WDR5), but no convincing causative mutations could be found. Our results indicate that MLL2 is the major gene for Kabuki syndrome with a wide spectrum of de novo mutations and strongly suggest further genetic heterogeneity. PMID- 21607749 TI - Lyme borreliosis--analysis of the trends in Slovakia, 1999-2008. AB - Lyme borreliosis (LB) presents as one of the most frequent tick-borne diseases in Europe with more than 85,000 reported cases every year. The transport of this disease on humans is by tick species of the genus Ixodes. In our work, we aimed to perform a retrospective analysis of the incidence and seasonality of Lyme borreliosis during the period 1999-2008 in Slovakia. For our analysis, we used all the relevant data about the patients with Lyme borreliosis reported in the Epidemiological Informative System of Communicable Diseases in Slovakia during the decade of 1999-2008. During the observed period, there were 7,349 reported cases of LB in Slovakia. Whereas the incidence of early localized infection did not change during the observed period, there was a significant increase in the incidence of early disseminated infection and late persistent infection of LB. Seventy per cent of all patients was infected by tick bite. LB was more frequently reported in females than in males (56.1% vs. 43.9%; p < 0.05), and the most involved age group was the productive age (15-64 years). The incidence of disseminated infection and persistent infection was rising with increasing age. Regarding the seasonality of LB, we found the highest incidence during the summer months. Comparing the situation of LB in 1999 and 2008, significant increase in the number of reported cases was in April and June and from September to November (p < 0.05). Our epidemiological analysis confirmed that Lyme borreliosis requires increased attention due to its increasing incidence. PMID- 21607750 TI - A minimally invasive stabilizing system for dorsal pelvic ring injuries. AB - BACKGROUND: Open reduction and stabilization of dorsal pelvic ring injuries is accompanied by a high rate of soft tissue complications. Minimally invasive techniques have the potential to decrease soft tissue trauma, but the risk of iatrogenic nerve and vessel damage through the reduced surgical exposure should be considered. We treated these injuries using a transiliac internal fixator (TIFI) in a minimally invasive technique characterized by implantation of a pedicle screw and rod system, bridging the sacroiliac joints and the sacral area. QUESTIONS/PURPOSES: We asked whether (1) we could achieve anatomic restoration with the device, (2) specific complications were associated with this minimally invasive approach (particularly enhanced intraoperative blood loss, soft tissue complications, and iatrogenic neurovascular damage), and (3) function 3 years after trauma was comparable to that of established methods. METHODS: We retrospectively reviewed 67 patients with dorsal pelvic injuries during a 7-year period. We evaluated the (1) reduction by grading the maximal displacement measured with three radiographic views, (2) the complications during the observation period, and (3) the function with a validated questionnaire (Pelvic Outcome Score) in all but five patients at least 3 years after trauma (mean, 37 months; range, 36-42 months). RESULTS: At last followup we observed a secondary fracture displacement greater than 5 mm in one patient. The intraoperative blood loss was less than 50 mL in all patients. No neurovascular lesions occurred owing to implantation. Four patients had wound infections, one had loosening of a single pedicle screw, and one had an iatrogenic screw malpositioning. Thirty-five of the 62 patients achieved Pelvic Outcome Scores of either a maximum score or 6 of 7 points. CONCLUSION: Our observations suggest TIFI is a reasonable alternative to other established fixation devices for injuries of the dorsal pelvic ring with minor risks of major blood loss or iatrogenic neurovascular damage. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21607751 TI - Cancer-immune equilibrium: questions unanswered. AB - Cancer-immune (CI) equilibrium constitutes an important component of the cancer immunoediting theory. It is defined as a period during which our immune system and cancer live in harmony in the body. The immune system, though not able to completely eliminate the cancer, doesn't allow it to progress or metastasize further. Mechanisms of this phase are poorly understood because this phase is difficult to identify even by the most modern detection methods. Till now, the work done on the equilibrium phase of cancer, suggests promising improvements in cancer therapy if the disease could be withheld in this phase. However, there are many queries which remain to be addressed about this interesting yet unresolved phase of cancer immunity. PMID- 21607752 TI - Microglial activation during acute cerebral infarction in the presence of diabetes mellitus. AB - The patients suffering from acute cerebral infarction in the presence of diabetes mellitus (DMCI) often have poor clinical outcomes when compared with those in the absence of diabetes mellitus (non-DMCI), but the corresponding differences in pathology still remain elusive. Here, we investigated the proliferation of microglia in DMCI and non-DMCI. Patients who came to autopsy involved four DMCI cases and four non-DMCI cases. The peri-infarct region and the equivalent non lesional region in the contralateral hemisphere were removed and analyzed. The hematoxylin-eosin staining and immunohistochemistry staining with anti-ferritin were used for evaluating the microglial activation. We found a more evident microglial proliferation in the peri-infarct region (P < 0.01) and in the non lesional hemisphere (P < 0.05) in DMCI than in non-DMCI patients. In addition, neuronophagia was observed in peri-infarct region of DMCI. Future studies are warranted to further clarify the influence of microglial activation in DMCI. PMID- 21607753 TI - Chronic fusiform aneurysm evolving into giant aneurysm in the basilar artery. AB - Fusiform basilar aneurysm is a rare condition with elevated mortality within a few days if untreated. On the basis of clinical course, the fusiform aneurysm can be distinguished in an acute type, such as dissecting aneurysm, which usually causes subarachnoid hemorrhage or cerebral ischemia and in a chronic type with a relatively slow growth, which may evolve into a giant aneurysm leading to serious complications. We report a case of an 80-year-old man with a surgically untreated fusiform aneurysm that evolved into a giant aneurysm of the basilar artery within 4 years. The patient presented recurrent ischemic events involving the posterior circulation without aneurysmal rupture or bleeding. PMID- 21607755 TI - Commentary on "Lombrosian prejudice in medicine". PMID- 21607754 TI - Slowly progressive aphemia: a neuropsychological, conventional, and functional MRI study. AB - Slowly progressive aphemia (SPA) is a rare focal degenerative disorder characterized by severe dysarthria, frequent orofacial apraxia, dysprosody, phonetic and phonemic errors without global cognitive deterioration for many years. This condition is caused by a degeneration of anterior frontal lobe regions, mainly of the left frontal operculum. We report a case of SPA with a course of 8 years, evaluated by repeated neuropsychological, conventional, and functional MRI examinations. In our case, neuropsychological examinations showed a progressive impairment of speech articulation including dysprosody, phonetic and phonemic errors, and slight writing errors. No global cognitive deterioration was detected and the patient is still completely autonomous. Morphological and functional investigations showed, respectively, a progressive atrophy and progressive impairment of the left frontal region, confirming the role of the opercular region in determining this rare syndrome. During verbal task generation as the cortical activation of this region gradually decreased, the language articulation worsened. PMID- 21607756 TI - fMRI of the sensorimotor cortex in patients with traumatic brain injury after intensive rehabilitation. AB - For evaluating the patterns of brain activation in sensorimotor areas following motor rehabilitation, seven male patients diagnosed with TBI underwent an fMRI study before and after being subjected to motor rehabilitation. Six patients showed a reduction in the BOLD signal of their motor cortical areas during the second fMRI evaluation. A decrease in cerebellum activation was also observed in two patients. Newly activated areas, were observed in four patients after treatment. In addition, an increase in the activation of the supplementary motor area (SMA) following rehabilitation was observed in only one test subject. The findings show that motor rehabilitation in TBI patients produces a decrease in the BOLD signal for the sensorimotor areas that were activated prior to treatment. In addition, we observed the recruitment of different brain areas to compensate for functional loss due to TBI in line with the cortical reorganisation mechanism. PMID- 21607757 TI - Local strain distribution in real three-dimensional alveolar geometries. AB - Mechanical ventilation is not only a life saving treatment but can also cause negative side effects. One of the main complications is inflammation caused by overstretching of the alveolar tissue. Previously, studies investigated either global strains or looked into which states lead to inflammatory reactions in cell cultures. However, the connection between the global deformation, of a tissue strip or the whole organ, and the strains reaching the single cells lining the alveolar walls is unknown and respective studies are still missing. The main reason for this is most likely the complex, sponge-like alveolar geometry, whose three-dimensional details have been unknown until recently. Utilizing synchrotron based X-ray tomographic microscopy, we were able to generate real and detailed three-dimensional alveolar geometries on which we have performed finite-element simulations. This allowed us to determine, for the first time, a three dimensional strain state within the alveolar wall. Briefly, precision-cut lung slices, prepared from isolated rat lungs, were scanned and segmented to provide a three-dimensional geometry. This was then discretized using newly developed tetrahedral elements. The main conclusions of this study are that the local strain in the alveolar wall can reach a multiple of the value of the global strain, for our simulations up to four times as high and that thin structures obviously cause hotspots that are especially at risk of overstretching. PMID- 21607758 TI - Hemodynamics of the hepatic venous three-vessel confluences using particle image velocimetry. AB - Despite rapid advancements in the patient-specific hemodynamic analysis of systemic arterial anatomies, limited attention has been given to the characterization of major venous flow components, such as the hepatic venous confluence. A detailed investigation of hepatic flow structures is essential to better understand the origin of characteristic abnormal venous flow patterns observed in patients with cardiovascular venous disease. The present study incorporates transparent rapid-prototype replicas of two pediatric hepatic venous confluence anatomies and two-component particle image velocimetry to investigate the primary flow structures influencing the inferior vena cava outflow. Novel jet flow regimes are reported at physiologically relevant mean venous conditions. The sensitivity of fluid unsteadiness and hydraulic resistance to multiple-inlet flow regimes is documented. Pressure drop measurements, jet flow characterization, and blood damage assessments are also performed. Results indicate that the orientation of the inlets significantly influences the major unsteady flow structures and power loss characteristics of this complex venous flow junction. Compared to out-of-plane arranged inlet vessel configuration, the internal flow field observed in planar inlet configurations was less sensitive to the venous inlet flow split. Under pathological flow conditions, the effective pressure drop increased as much as 77% compared to the healthy flow state. Experimental flow field results presented here can serve as a benchmark case for the surgical optimization of complex anatomical confluences including visceral hemodynamics as well as for the experimental validation of high-resolution computational fluid dynamics solvers applied to anatomical confluences with multiple inlets and outlets. PMID- 21607760 TI - Combined OXPHOS complex I and IV defect, due to mutated complex I assembly factor C20ORF7. AB - Defects of the mitochondrial oxidative phosphorylation (OXPHOS) system are frequent causes of neurological disorders in children. Linkage analysis and DNA sequencing identified a new founder p.G250V substitution in the C20ORF7 complex I chaperone in five Ashkenazi Jewish patients from two families with a combined OXPHOS complex I and IV defect presenting with Leigh's syndrome in infancy. Complementation with the wild type gene restored complex I, but only partially complex IV activity. Although the pathogenic mechanism remains elusive, a C20ORF7 defect should be considered not only in isolated complex I deficiency, but also in combination with decreased complex IV. Given the significant 1:290 carrier rate for the p.G250V mutation among Ashkenazi Jews, this mutation should be screened in all Ashkenazi patients with Leigh's syndrome prior to muscle biopsy. PMID- 21607759 TI - Aberrant expression of costimulatory molecules in splenocytes of the mevalonate kinase-deficient mouse model of human hyper-IgD syndrome (HIDS). AB - OBJECTIVE: We sought to determine the activation status and proliferative capacities of splenic lymphocyte populations from a mevalonate kinase-deficient mouse model of hyper-IgD syndrome (HIDS). We previously reported that murine mevalonate kinase gene ablation was embryonic lethal for homozygous mutants while heterozygotes (Mvk (+/-)) demonstrated several phenotypic features of human HIDS including increased serum levels of IgD, IgA, and TNFalpha, temperature dysregulation, hematological abnormalities, and splenomegaly. METHODS AND RESULTS: Flow cytometric analysis of cell surface activation markers on T and B lymphocytes, and macrophage populations, demonstrated aberrant expression of B7 glycoproteins in all splenic cell types studied. Differences in expression levels between Mvk (+/-) and Mvk (+/+) littermate controls were observed in both the basal state (unstimulated) and after Concanavalin A (Con-A) stimulation in vitro of whole splenocyte cultures. In Mvk (+/-) CD4 and CD8 T cells, alterations in expression of CD25, CD80, CD152, and CD28 were observed. Mvk (+/-) splenic macrophages expressed altered levels of CD80, CD86, CD40, and CD11c while Mvk (+/ ) B lymphocytes had differential expression of CD40, CD80, and CD86. Mvk (+/-) splenocyte subpopulations also exhibited altered proliferative capacities in response to in vitro stimulation. CONCLUSION: We postulate that imbalances in the expression of cell surface proteins necessary for activation, proliferation, and regulation of the intensity and duration of an immune response may result in defective T cell activation, proliferation, and effector functions in our model and potentially in human HIDS. PMID- 21607761 TI - Neutralization of Neisseria meningitidis outer membrane vesicles. AB - INTRODUCTION: We aimed to determine the neutralization of Neisseria meningitidis outer membrane vesicles (blebs) by humoral and cellular elements of whole blood. METHODS: The interaction of FITC-labeled blebs with monocytes was studied by spectrofluorometry. Blebs are able to induce an oxidative burst in neutrophils, and we evaluated the inhibitory effect of plasma on this process. RESULTS: Human plasma reduced the priming activity of blebs containing 1-3 ng/ml lipopolysaccharide (LPS) by 50-60% and bactericidal permeability increasing protein (BPI) reduced priming to background levels. A complete neutralization of LPS and blebs by plasma and BPI was measured using the limulus amebocyte lysate (LAL) assay. Furthermore, only 3% of blebs were cell-associated, while the remainder were in the supernatant. CONCLUSIONS: Plasma and BPI are able to neutralize blebs, with phagocytosis playing only a minor role. As such, we conclude that blebs do not behave like particles but more like free LPS. PMID- 21607762 TI - Finding cancer-associated miRNAs: methods and tools. AB - Changes in the structure and/or the expression of protein coding genes were thought to be the major cause of cancer for many decades. The recent discovery of non-coding RNA (ncRNA) transcripts (i.e., microRNAs) suggests that the molecular biology of cancer is far more complex. MicroRNAs (miRNAs) have been under investigation due to their involvement in carcinogenesis, often taking up roles of tumor suppressors or oncogenes. Due to the slow nature of experimental identification of miRNA genes, computational procedures have been applied as a valuable complement to cloning. Numerous computational tools, implemented to recognize the features of miRNA biogenesis, have resulted in the prediction of novel miRNA genes. Computational approaches provide clues as to which are the dominant features that characterize these regulatory units and furthermore act by narrowing down the search space making experimental verification faster and cheaper. In combination with large scale, high throughput methods, such as deep sequencing, computational methods have aided in the discovery of putative molecular signatures of miRNA deregulation in human tumors. This review focuses on existing computational methods for identifying miRNA genes, provides an overview of the methodology undertaken by these tools, and underlies their contribution towards unraveling the role of miRNAs in cancer. PMID- 21607763 TI - [Contrast-enhanced sonography for blunt force abdominal trauma]. AB - With the introduction of second generation ultrasound contrast agents, contrast enhanced ultrasound (CEUS) has become available as an adjunct to the conventional FAST (focused assessment with sonography in trauma) protocol and B-mode sonography of the abdomen after blunt force abdominal trauma. Results from several controlled studies indicate excellent diagnostic accuracy of CEUS for the exclusion of clinically relevant parenchymal injuries after blunt force abdominal trauma. Particularly in younger, hemodynamically stable patients this technique could contribute to a reliable exclusion of parenchymal injuries without the use of ionizing radiation. This report provides details on the technical performance of CEUS, shows examples of typical CEUS findings after blunt abdominal trauma and summarizes the current clinical evidence regarding the use of CEUS after blunt abdominal trauma. PMID- 21607764 TI - [Detection and characterization of liver metastases]. AB - Since the advent of second generation ultrasound (US) contrast agents, ultrasound has caught up with other imaging modalities for the detection and characterization of liver metastases and as a result of its high temporal and spatial resolution it can in some cases even be superior to computed tomography (CT) and magnetic resonance imaging (MRI). Many studies have demonstrated a sensitivity and specificity of over 90%. Due to its high temporal resolution contrast-enhanced US (CEUS) is capable of detecting even a very short duration of hyper-enhancement during the arterial phase. Radiation protection and lack of adverse effects on renal or thyroid function are additional arguments why CEUS should be recommended as the first imaging modality in the evaluation of hepatic metastases in cases of favorable scanning conditions. PMID- 21607765 TI - Administration of dexmedetomidine alone during diagnostic cardiac catheterization in adults with congenital heart disease: two case reports. AB - We report the clinical management of 2 adults with mental retardation because of trisomy 21 who were sedated with high-dose dexmedetomidine (DEX) alone during diagnostic cardiac catheterization (DCC). The first patient was a 25-year-old man with aortic regurgitation and ventricular septal defect. DEX increased his Ramsay sedation score; however, a high dose and bolus injection of DEX were required to perform an invasive procedure. Cardiovascular drugs were not administered and heart rate was maintained in the low 40s. The maximum predicted plasma concentration (pCp) of DEX was 2.3 ng/mL. The second patient was a 26-year-old woman who had developed hypoxia 20 years after palliative surgery for tetralogy of Fallot. High-dose DEX was administered to keep the bispectral index value below 70 and maintain an immobile state; her maximum pCp of DEX was 4.3 ng/mL. Percutaneous oxygen saturation was kept above 83%, because of the suspicion that DEX may increase the ratio of pulmonary artery flow to systemic artery flow. In both cases, no respiratory system complications occurred despite inspiration of room air, indicating the usefulness of DEX for DCC. However, because of DEX may affect DCC data, it is necessary to pay careful attention to the use of DEX during DCC. PMID- 21607766 TI - Preoperative carbohydrate-rich beverage reduces hypothermia during general anesthesia in rats. AB - PURPOSE: Intraoperative hypothermia is associated with several unfavorable events; therefore, it is important to prevent the development of hypothermia. Amino acid consumption and/or infusion have been reported to prevent hypothermia. We hypothesized that preoperative carbohydrate-rich beverage (Arginaid WaterTM) loading can reduce intraoperative hypothermia in rats under general anesthesia. METHODS: We divided 18 rats into 3 groups (group A, 8 mL/kg of saline; group B, 8 mL/kg of a carbohydrate-rich beverage; and group C, 21 mL/kg of the carbohydrate rich beverage). The rats were administered each beverage at the above mentioned doses via an oral gastric tube 30 min before the induction of anesthesia. During the 2-h general anesthesia, rectal temperature was measured at 20-min intervals. Serum ketone body concentration was measured at 0 and 120 min. RESULTS: The baseline temperature was not significantly different among the groups. At the end of the experiment, group A showed a significantly greater decrease in temperature from the baseline (5.4 +/- 0.8 degrees C) than group B (3.9 +/- 0.7 degrees C, P = 0.01) and group C (3.8 +/- 0.8 degrees C, P = 0.01). The temperatures in groups B and C were not significantly different. There was no significant change in the serum ketone body concentration from the baseline at the end of the experiment in group A. However, the serum ketone body concentrations in group B and group C were significantly decreased from the baseline. CONCLUSION: Preoperative carbohydrate loading reduces hypothermia in rats under general anesthesia. PMID- 21607768 TI - Rocuronium-sugammadex as an alternative to succinylcholine in electroconvulsive therapy. PMID- 21607767 TI - Dexmedetomidine and clonidine inhibit the function of Na(v)1.7 independent of alpha(2)-adrenoceptor in adrenal chromaffin cells. AB - PURPOSE: Besides being administered systemically for sedation and analgesia, alpha(2)-agonists such as dexmedetomidine and clonidine have been administered with intrathecal, epidural, or perineural injections, leading to an antinociceptive effect at the spinal cord or peripheral nerve level. However, the mechanism for this remains unclear. In the present study, we examined whether dexmedetomidine and clonidine could inhibit the function of tetrodotoxin sensitive Na(+) channels, which play important roles in the generation of pain. METHODS: Cultured bovine adrenal chromaffin cells expressing the tetrodotoxin sensitive Na(v)1.7 Na(+) channel isoform were incubated in KRP buffer containing 2 MUCi (22)NaCl for 5 min without or with dexmedetomidine or clonidine in the absence or presence of veratridine, alpha-scorpion venom, beta-scorpion venom, Ptychodiscus brevis toxin-3 or ouabain. Cells were then washed and counted radioactively. RESULTS: Dexmedetomidine and clonidine reduced veratridine-induced (22)Na(+) influx via Na(v)1.7 in a concentration-dependent manner (EC(50) = 50 MUM and 530 MUM), even in the presence of ouabain, an inhibitor of Na(+), K(+) ATPase. Dexmedetomidine and clonidine shifted the concentration-response curve of veratridine for (22)Na(+) influx downward without altering the EC(50) of veratridine. Atipamezole and yohimbine, alpha(2)-antagonists, did not prevent the inhibition of veratridine-induced (22)Na(+) influx by dexmedetomidine. Dexmedetomidine and clonidine combined with lidocaine induced more inhibition of veratridine-induced (22)Na(+) influx than each drug did individually. Atipamezole and yohimbine did not prevent the lidocaine-enhancing effect of dexmedetomidine and clonidine. CONCLUSION: Dexmedetomidine and clonidine inhibit the function of Na(v)1.7 independent of alpha(2)-adrenoceptor. These results may lead to a deeper understanding of the peripheral antinociceptive effects of alpha (2)-agonists. PMID- 21607769 TI - T-cell receptor gene rearrangement in Epstein-Barr virus infectious mononucleosis. AB - This report describes the case of a previously healthy young man who presented with fever, pharyngitis, cervical lymphadenopathy, lymphocytosis, and severe thrombocytopenia. Serological tests for Epstein-Barr virus were diagnostic of a primary Epstein-Barr virus infectious mononucleosis but severe thrombocytopenia aroused the suspicion of a lymphoproliferative disease. T-cell receptor gene analysis performed on peripheral and bone marrow blood revealed a T-cell receptor gamma-chain rearrangement without the evidence of malignancy using standard histologic and immunophenotype studies. Signs and symptoms of the infectious disease, blood count, and T-cell receptor gene rearrangement resolved with observation without the evidence of emergence of a lymphoproliferative disease. In the contest of a suspected lymphoproliferative disease, molecular results should be integrated with all available data for an appropriate diagnosis. PMID- 21607770 TI - Meat intake and risk of bladder cancer: a meta-analysis. AB - Meat consumption is inconsistently associated with the development of bladder cancer in several epidemiological studies. We performed a meta-analysis of evidence for relationships of meat consumption with risk of bladder cancer. Literature searches were conducted to identify peer-reviewed manuscripts published up to October 2010. Twenty publications from 10 cohort studies and 11 case-control studies were included in the analyses. We quantified associations with bladder cancer using meta-analysis of relative risk (RR) associated with the highest versus the lowest category of meat intake using random effect model. Pooled results indicate that overall meat intake was not related to the risk of bladder cancer (RR = 1.04, 95% CI = 0.80-1.27), while high red and processed meat consumer had a significantly increased 17 and 10% risk, respectively, when comparing the highest with the lowest category of meat intake. In subgroup analyses, studies conduced in Unites States/Canada exhibited a positive relationship between high meat intake and bladder cancer risk, and studies using self-administered questionnaires for exposure assessment also showed a significant increased relative risk for high meat consumers. However, because of borderline significance and small number of publications in individual analyses, more studies, particularly well-designed prospective studies, are needed to confirm these findings. PMID- 21607772 TI - Impact of KRAS and EGFR gene mutations on recurrence and survival in patients with surgically resected lung adenocarcinomas. AB - BACKGROUND: Oncogenic gene mutations observed in lung adenocarcinomas, such as epidermal growth factor receptor (EGFR) and KRAS, have some predictive value for chemotherapeutic drugs or EGFR-tyrosine kinase inhibitors. However, the influence of these gene alterations on patients' prognosis remains controversial. METHODS: We retrospectively analyzed the tumors of 180 patients with completely resected pathological stage I-III lung adenocarcinoma which harbored either KRAS codon 12 mutation or EGFR gene mutations within exons 18-21 to investigate the impact of these gene mutations on the patients' survival. Gene mutations were detected by established methods. RESULTS: Of 180 patients, 32 had KRAS codon 12 mutations (KRAS group), 148 had EGFR mutations within exon 18-21 (EGFR group). Pathological stage and operation mode were independent factors for disease-free survival. However, the EGFR group had better overall survival than the KRAS group (P = 0.0271). Cox proportional hazard model revealed pathological stage (P = 0.0001) and presence of EGFR gene mutations (P = 0.0408) were independent factors for overall survival. In survival after tumor recurrence, the EGFR group had a better median survival time (46.7 months) after recurrence than the KRAS group (26.0 months). CONCLUSIONS: In patients with completely resected lung adenocarcinomas, KRAS and EGFR gene mutation status of tumors was not associated with disease-free survival. However, the presence of an EGFR gene mutation boded well for the patient's overall survival, and thus patients with EGFR mutations have a better prognosis than those with KRAS mutations. PMID- 21607771 TI - Pioglitazone, etoricoxib, interferon-alpha, and metronomic capecitabine for metastatic renal cell carcinoma: final results of a prospective phase II trial. AB - We enrolled 45 patients with metastatic renal cell carcinoma (RCC) at a progressive disease between March 2003 and April 2008 to assess the impact of an anti-inflammatory treatment regime in combination with metronomic low-dose chemotherapy. 42% of the patients had been systemically pre-treated. Therapy consisted of etoricoxib 60 mg daily plus pioglitazone 60 mg daily, day 1+, low dose interferon-alpha 4.5 MU sc three times a week, week 1+ and low-dose capecitabine 1 g/m(2) twice daily orally for 14 days, every 3 weeks, day 1+, until disease progression. Objective response was observed in 35% of the patients (PR 27, CR 9%), which was paralleled by strong CRP decline for all patients with initially elevated CRP levels (n = 32). CRP values decreased from mean 42.3 mg/L (range 9.1-236), to 11.1 mg/L, (range 1.1-35.6), P = 0.006. Median overall survival and progression-free survival for the total cohort were 26.9 and 7.2 months for patients with elevated CRP 24.4 and 11.3 months (95% CI, 22.8-31.0/5.7 16.9) and 13.8-2.6 months (95% CI, 6.5-21.1/0.4-4.8) for the non-elevated CRP group, respectively (P = 0.082/0.017). Median observation time: 26.1 months; Overall survival at 5 years: 18%. Toxicity>WHO grade 3 was reported: Hand-foot syndrome in 16 patients (36%), diarrhea in 4, and pneumonia in 2 patients. Our data allow us to conclude that the control of tumor-associated inflammation is an important therapeutic principle in patients with metastatic RCC. PMID- 21607773 TI - Role of the hypoxia-related gene, JMJD1A, in hepatocellular carcinoma: clinical impact on recurrence after hepatic resection. AB - BACKGROUND AND AIMS: Intratumoral hypoxia affects every major aspect of cancer biology, but the relationship between hypoxia-induced genes and hepatocellular carcinoma has not been fully investigated. From a previously ranked microarray of hypoxia-inducible genes related to hepatocellular carcinoma, we focused on a histone H3 lysine 9 demethylase, known as Jumonji domain containing 1A. One function of this demethylase is to amplify hypoxia-inducible gene expression. We hypothesized that the demethylase would be a significant marker of hepatocellular carcinoma. METHODS: We examined Jumonji domain containing 1A expression in 110 hepatocellular carcinoma samples with quantitative real-time polymerase chain reaction and immunohistochemistry. We performed a small interfering RNA suppression analysis to determine the biological roles of the demethylase in proliferation, invasion, and the expression of epithelial-mesenchymal transition related genes. RESULTS: The level of Jumonji domain containing 1A in cancer tissues was higher than in normal tissues (P < 0.0001). Protein expression was significantly related to gene expression (P < 0.0001). Samples with high Jumonji domain containing 1A expression (n = 47) had higher recurrence rates (P = 0.0006) than those with low expression. Multivariate Cox regression analysis revealed that Jumonji domain containing 1A expression was an independent predictor of recurrence (P = 0.0016), but was not significantly associated with any clinicopathological characteristics. Moreover, suppression of Jumonji domain containing 1A expression in hepatocellular carcinoma cell lines under hypoxic conditions reduced cell growth inhibition, reduced invasion ability, and arrested epithelial-mesenchymal transitions. CONCLUSION: Jumonji domain containing 1A is a useful prognostic marker and may ameliorate malignant transformation in hepatocellular carcinoma. PMID- 21607774 TI - Avoiding mastectomy: accelerated partial breast irradiation for breast cancer patients with pacemakers or defibrillators. AB - INTRODUCTION: The objective of this study was to evaluate the safety, toxicity, and planning concerns involved in accelerated partial breast irradiation (APBI) for patients with breast cancer who have a pacemaker or an automatic implantable cardioverter-defibrillator (AICD) and who desire breast conservation. METHODS: We performed a review of prospectively obtained data for patients with early-stage breast cancer with a pacemaker or AICD treated between April 2007 and July 2010. Patients were treated with either 3D conformal external beam irradiation (3D-CRT) or high-dose rate balloon brachytherapy (HDRBB) as performed in the National Surgical Adjuvant Breast and Nowel Project (NSABP) B-39/Radiation Therapy Oncology Group (RTOG) 0413 protocol. Device interrogation was performed after the first and last radiation treatment, with comparative cardiac monitoring performed before and after the first three treatments. RESULTS: Eight patients were treated and have a mean follow-up of 6 months. Three patients received HDRBB delivering 34 Gy in 10 fractions. Mean planning target volume for evaluation (PTV_EVAL) coverage was 93.6%. The maximum radiation dose delivered to any device was 1.03 Gy, with a mean pacemaker distance to lumpectomy cavity (DLC) of 9.1 cm. Five patients received 3D-CRT consisting of 38.5 Gy in 10 fractions. The mean 90% PTV_EVAL coverage was 97.3%. Maximum dose delivered to any device was 1.68 Gy at a DLC of 9 cm. Local toxicity did not exceed grade 1, and no adverse device events were noted. CONCLUSIONS: APBI in patients with pacemakers or AICDs who desire breast preservation seems to be a technically safe and reasonable application of targeted radiation therapy. PMID- 21607775 TI - SPIO-enhanced magnetic resonance imaging for the detection of metastases in sentinel nodes localized by computed tomography lymphography in patients with breast cancer. AB - BACKGROUND: Superparamagnetic nanoparticle-enhanced magnetic resonance (MR) imaging has been reported to be a promising improvement for diagnostic imaging of lymph node metastases from various tumors. Moreover, sentinel nodes have been reported to be well identified using computed tomography (CT) lymphography (CT LG) in patients with breast cancer. The aim of this study was to evaluate MR imaging with superparamagnetic iron oxide (SPIO) enhancement for the detection of metastases in sentinel nodes localized by CT-LG in patients with breast cancer. METHODS: This study included 102 patients with breast cancer and clinically negative nodes. Sentinel nodes were identified by CT-LG, and SPIO-enhanced MR imaging of the axilla was performed to detect metastases in the sentinel nodes. A node was considered nonmetastatic if it showed a homogenous low signal intensity and metastatic if the entire node or a focal area did not show low signal intensity on MR imaging. Sentinel node biopsy was performed, and imaging results were correlated with histopathologic findings. RESULTS: The mean number of sentinel nodes identified by CT-LG was 1.1 (range, 1-3). The sensitivity, specificity, and accuracy of MR imaging for the diagnosis of sentinel node metastases were 84.0%, 90.9%, and 89.2%, respectively. In 4 of 10 patients with micrometastases, metastases were not detected, but all 15 patients with macrometastases were successfully identified. CONCLUSIONS: SPIO-enhanced MR imaging is a useful method of detecting metastases in sentinel nodes localized by CT-LG in patients with breast cancer and may avoid sentinel node biopsy when the sentinel node is diagnosed as disease-free. PMID- 21607776 TI - Finding promiscuous old drugs for new uses. AB - From research published in the last six years we have identified 34 studies that have screened libraries of FDA-approved drugs against various whole cell or target assays. These studies have each identified one or more compounds with a suggested new bioactivity that had not been described previously. We now show that 13 of these drugs were active against more than one additional disease, thereby suggesting a degree of promiscuity. We also show that following compilation of all the studies, 109 molecules were identified by screening in vitro. These molecules appear to be statistically more hydrophobic with a higher molecular weight and AlogP than orphan-designated products with at least one marketing approval for a common disease indication or one marketing approval for a rare disease from the FDA's rare disease research database. Capturing these in vitro data on old drugs for new uses will be important for potential reuse and analysis by others to repurpose or reposition these or other existing drugs. We have created databases which can be searched by the public and envisage that these can be updated as more studies are published. PMID- 21607777 TI - CLSM as quantitative method to determine the size of drug crystals in a solid dispersion. AB - PURPOSE: To test whether confocal laser scanning microscopy (CLSM) can be used as an analytical tool to determine the drug crystal size in a powder mixture or a crystalline solid dispersion. METHODS: Crystals of the autofluorescent drug dipyridamole were incorporated in a matrix of crystalline mannitol by physical mixing or freeze-drying. Laser diffraction analysis and dissolution testing were used to validate the particle size that was found by CLSM. RESULTS: The particle size of the pure drug as determined by laser diffraction and CLSM were similar (D(50) of approximately 22 MUm). CLSM showed that the dipyridamole crystals in the crystalline dispersion obtained by freeze-drying of less concentrated solutions were of sub-micron size (0.7 MUm), whereas the crystals obtained by freeze-drying of more concentrated solutions were larger (1.3 MUm). This trend in drug crystal size was in agreement with the dissolution behavior of the tablets prepared from these products. CONCLUSION: CLSM is a useful technique to determine the particle size in a powder mixture. Furthermore, CLSM can be used to determine the drug crystal size over a broad size distribution. A limitation of the method is that the drug should be autofluorescent. PMID- 21607778 TI - Compositional analysis of low quantities of phase separation in hot-melt-extruded solid dispersions: a combined atomic force microscopy, photothermal fourier transform infrared microspectroscopy, and localised thermal analysis approach. AB - PURPOSE: To characterise phase separations in aged hot-melt-extruded solid dispersions at a micron to submicron scale. METHODS: Hot-melt-extruded felodipine and Eudragit(r) E PO systems at a range of compositions were studied after a standard period of aging to allow phase separation to occur. The samples were characterised using combined nano-thermal analysis, photothermal FTIR microspectroscopy coupled with pulsed force mode AFM as a novel characterisation approach. RESULT: Crystalline felodipine presents in all formulations with drug loadings from 10-70% (w/w). In formulations with high drug loadings (50 and 70%), amorphous felodipine co-exists with crystalline forms, and higher drug concentration is observed in the centre compared to the outer surface of the extrudates. Drug crystal dimensions in extrudates with low drug loadings (10-30%) are small, in the micron to submicron range. We propose that uneven drug distribution is principally caused by processing-associated factors such as expansion of extrudates during extrusion. CONCLUSIONS: We have demonstrated that the novel combined approach allows site-specific characterisation of the extruded systems and that drug distribution may be uneven across the extrudates, with concomitant implications for understanding stability and drug release behaviour. PMID- 21607779 TI - Agarose surface coating influences intracellular accumulation and enhances payload stability of a nano-delivery system. AB - PURPOSE: Protein therapeutics often require repeated administrations of drug over a long period of time. Protein instability is a major obstacle to the development of systems for their controlled and sustained release. We describe a surface modification of nanoporous silicon particles (NSP) with an agarose hydrogel matrix that enhances their ability to load and release proteins, influencing intracellular delivery and preserving molecular stability. METHODS: We developed and characterized an agarose surface modification of NSP. Stability of the released protein after enzymatic treatment of loaded particles was evaluated with SDS-page and HPLC analysis. FITC-conjugated BSA was chosen as probe protein and intracellular delivery evaluated by fluorescence microscopy. RESULTS: We showed that agarose coating does not affect NSP protein release rate, while fewer digestion products were found in the released solution after all the enzymatic treatments. Confocal images show that the hydrogel coating improves intracellular delivery, specifically within the nucleus, without affecting the internalization process. CONCLUSIONS: This modification of porous silicon adds to its tunability, biocompatibility, and biodegradability the ability to preserve protein integrity during delivery without affecting release rates and internalization dynamics. Moreover, it may allow the silicon particles to function as protein carriers that enable control of cell function. PMID- 21607780 TI - [Tonsillotomy and adenotonsillectomy in childhood. Study on postoperative pain therapy]. AB - BACKGROUND: The primary aim of this study was to determine whether the combination of i.v. ketoprofen and i.v. paracetamol provides superior postoperative analgesia in children undergoing adenoidectomy or tonsillotomy compared to either drug alone. The secondary goal was to assess the time until rescue analgesia was needed, propofol requirements and the incidence of vomiting and time of discharge from the postanaesthesia recovery unit (PARU). METHODS: This double-blinded study included 120 children (aged 3-13 years) scheduled for elective tonsillectomy, adenoidectomy or adenotonsillectomy. The children were randomly assigned to one of 3 groups of 40 children each, using the sealed envelope method. The children received i.v. ketoprofen 2 mg/kgBW (group 1) or paracetamol 15 mg/kgBW (group 2) or the combination of these 2 drugs (group 3) after induction of anaesthesia. Standardized general anaesthesia consisted of sevoflurane and fentanyl at a dose of 2-3 MUg/kgBW. Pain was assessed using a 5 point scoring system based on the Smiley scale. The Smiley scale shows various faces from a laughing face which corresponds to the state of no pain to a very unhappy face which corresponds to the situation of worst pain (1: no pain, 2: mild pain, 3: moderate pain, 4: severe pain, 5: worst pain). Pain was assessed at 30 min, 1 h, 2 h, 3 h and 4 h after arriving in the PACU. If the pain score exceeded 2 an i.v. dose of 0.1 mg/kgBW morphine was administered as rescue analgesia. RESULTS: During the stay in the PACU the children in the combination group required significantly less supplementary rescue analgesia than children in the ketoprofen and paracetamol groups (17.5% versus 30.8% versus 45%, respectively, chi(2) analysis <0.05). Pain scoring was highest after paracetamol, however, this difference was only significant when compared to the group receiving the combination of paracetamol and ketoprofen (U-test p<0.05). Rescue analgesia was administered earliest in group 2 (paracetamol) reaching statistical significance, however, only when compared to group 3 (logrank test p<0.05). Propofol requirements and time to discharge from the PACU did not differ significantly between the 3 groups (chi(2) analysis; U-test; p>0.05). The overall incidence of vomiting was very low in this study with 6.4% (9/139). Significantly more children in the paracetamol group compared to ketoprofen group and combination group suffered from vomiting (17.5% versus 2.6% versus 2.5%; chi(2) analysis; p<0.05). The time to discharge from PACU did not differ significantly between the 3 groups (U-test: p>0.05). CONCLUSION: The combination of i.v. paracetamol and i.v. ketoprofen provides superior postoperative analgesia compared to the single use of paracetamol. PMID- 21607781 TI - Negative emotional processing induced by spoken scenarios modulates corticospinal excitability. AB - Emotion is assumed to facilitate the preparation of behavioral responses to environmental stimuli. In the present study, we examined whether emotional processing induced by spoken scenarios of positive and negative content, related to the self or to other people, modulates corticospinal excitability. Motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in 20 volunteers indicated that processing of negative emotional content increased MEP amplitude, regardless of the perspective taken in the scenario. By contrast, positive emotional processing did not reliably alter MEP amplitude. These results provide the first TMS evidence that the auditory processing of emotionally negative information triggers action preparation. PMID- 21607782 TI - Visuo-spatial path learning, stress, and cortisol secretion following military cadets' first parachute jump: the effect of increasing task complexity. AB - The present field experiment examined how multi-trial visuo-spatial learning and memory performance are impacted by excessive arousal, instigated by a potentially life-threatening event (i.e., a first parachute jump). Throughout a parachute training activity, subjective and neuroendocrine (i.e., cortisol) stress levels were assessed of 61 male military cadets who were randomly assigned to a control (n = 30) or a jump stress condition (n = 31). Post-stress learning and memory capacity was assessed with a 10-trial path-learning task that permitted emergence of learning curves. Pre-activity cortisol concentrations indicated a significant neuroendocrine anticipatory stress response in the stress group. Following parachuting, subjective stress levels and salivary cortisol reactivity differed significantly between groups. Visuo-spatial path-learning performance was impaired significantly after jump stress exposure, relative to the control group. Moreover, examination of the learning curves showed similar learning and memory performance at onset of the trials, with curves bifurcating as the task became more complex. These findings are in accordance with leading theories that acknowledge a moderating effect of task complexity. In sum, the present study extends knowledge concerning anticipatory stress effects, endogenously instigated cortisol reactivity, and the influence of extreme arousal on visuo-spatial path learning. PMID- 21607783 TI - Evaluating the perceptual and pathophysiological consequences of auditory deprivation in early postnatal life: a comparison of basic and clinical studies. AB - Decades of clinical and basic research in visual system development have shown that degraded or imbalanced visual inputs can induce a long-lasting visual impairment called amblyopia. In the auditory domain, it is well established that inducing a conductive hearing loss (CHL) in young laboratory animals is associated with a panoply of central auditory system irregularities, ranging from cellular morphology to behavior. Human auditory deprivation, in the form of otitis media (OM), is tremendously common in young children, yet the evidence linking a history of OM to long-lasting auditory processing impairments has been equivocal for decades. Here, we review the apparent discrepancies in the clinical and basic auditory literature and provide a meta-analysis to show that the evidence for human amblyaudia, the auditory analog of amblyopia, is considerably more compelling than is generally believed. We argue that a major cause for this discrepancy is the fact that most clinical studies attempt to link central auditory deficits to a history of middle ear pathology, when the primary risk factor for brain-based developmental impairments such as amblyopia and amblyaudia is whether the afferent sensory signal is degraded during critical periods of brain development. Accordingly, clinical studies that target the subset of children with a history of OM that is also accompanied by elevated hearing thresholds consistently identify perceptual and physiological deficits that can endure for years after peripheral hearing is audiometrically normal, in keeping with the animal studies on CHL. These studies suggest that infants with OM severe enough to cause degraded afferent signal transmission (e.g., CHL) are particularly at risk to develop lasting central auditory impairments. We propose some practical guidelines to identify at-risk infants and test for the positive expression of amblyaudia in older children. PMID- 21607784 TI - Environmental change challenges decision-making during post-market environmental monitoring of transgenic crops. AB - The ability to decide what kind of environmental changes observed during post market environmental monitoring of genetically modified (GM) crops represent environmental harm is an essential part of most legal frameworks regulating the commercial release of GM crops into the environment. Among others, such decisions are necessary to initiate remedial measures or to sustain claims of redress linked to environmental liability. Given that consensus on criteria to evaluate 'environmental harm' has not yet been found, there are a number of challenges for risk managers when interpreting GM crop monitoring data for environmental decision-making. In the present paper, we argue that the challenges in decision making have four main causes. The first three causes relate to scientific data collection and analysis, which have methodological limits. The forth cause concerns scientific data evaluation, which is controversial among the different stakeholders involved in the debate on potential impacts of GM crops on the environment. This results in controversy how the effects of GM crops should be valued and what constitutes environmental harm. This controversy may influence decision-making about triggering corrective actions by regulators. We analyse all four challenges and propose potential strategies for addressing them. We conclude that environmental monitoring has its limits in reducing uncertainties remaining from the environmental risk assessment prior to market approval. We argue that remaining uncertainties related to adverse environmental effects of GM crops would probably be assessed in a more efficient and rigorous way during pre-market risk assessment. Risk managers should acknowledge the limits of environmental monitoring programmes as a tool for decision-making. PMID- 21607785 TI - The oculocardiac reflex may mimic signs of intracranial hypertension in patients with combined cerebral and ocular trauma. AB - BACKGROUND: In the setting of head trauma, progressive bradycardia may raise suspicion for intracranial hypertension, especially when accompanied by pupillary abnormalities or systemic hypertension. METHODS: We describe the case of a patient with concomitant cerebral and ocular trauma who presented with a fixed and dilated pupil and progressive bradycardia due to an oculocardiac reflex. RESULTS: The oculocardiac reflex is an unusual cause of bradycardia due to stimulation of the ophthalmic division of the trigeminal nerve and has been described in a variety of clinical settings. CONCLUSIONS: Clinicians should be aware that the oculocardiac reflex might mimic signs of intracranial hypertension in patients with combined facial and cerebral trauma. PMID- 21607786 TI - Serial forced displacement in American cities, 1916-2010. AB - Serial forced displacement has been defined as the repetitive, coercive upheaval of groups. In this essay, we examine the history of serial forced displacement in American cities due to federal, state, and local government policies. We propose that serial forced displacement sets up a dynamic process that includes an increase in interpersonal and structural violence, an inability to react in a timely fashion to patterns of threat or opportunity, and a cycle of fragmentation as a result of the first two. We present the history of the policies as they affected one urban neighborhood, Pittsburgh's Hill District. We conclude by examining ways in which this problematic process might be addressed. PMID- 21607787 TI - "Weathering" HOPE VI: the importance of evaluating the population health impact of public housing demolition and displacement. AB - HOPE VI has funded the demolition of public housing developments across the United States and created in their place mixed-income communities that are often inaccessible to the majority of former tenants. This recent uprooting of low income, urban, and predominantly African American communities raises concern about the health impacts of the HOPE VI program for a population that already shoulders an enormous burden of excess morbidity and mortality. In this paper, we rely on existing literature about HOPE VI relocation to evaluate the program from the perspective of weathering-a biosocial process hypothesized by Geronimus to underlie early health deterioration and excess mortality observed among African Americans. Relying on the weathering framework, we consider the effects of HOPE VI relocation on the material context of urban poverty, autonomous institutions that are health protective, and on the broader discourse surrounding urban poverty. We conclude that relocated HOPE VI residents have experienced few improvements to the living conditions and economic realities that are likely sources of stress and illness among this population. Additionally, we find that relocated residents must contend with these material realities, without the health-protective, community-based social resources that they often rely on in public housing. Finally, we conclude that by disregarding the significance of health-protective autonomous institutions and by obscuring the structural context that gave rise to racially segregated public housing projects, the discourse surrounding HOPE VI is likely to reinforce health-demoting stereotypes of low income urban African American communities. Given the potential for urban and housing policies to negatively affect the health of an already vulnerable population, we argue that a health-equity perspective is a critical component of future policy conversations. PMID- 21607788 TI - [Intrathecal administration of methylene blue is obsolete]. PMID- 21607789 TI - [Current concepts in the treatment of mallet fractures of the distal phalanx]. AB - Articular fractures of the dorsal part of the distal phalanx may result in a painful dysfunction and a bothersome deformity of the distal interphalangeal joint. For this injury multiple treatment procedures exist. We performed a survey among German hand surgeons and a review of the literature in order to present current concepts of treatment and to verify the feasibility of a randomized trial. There is a tendency to prefer conservative treatment options. The indication for operative treatment depends on size and displacement of the articular fragment as well as on subluxation of the joint. Operative techniques vary widely and the comparability of their results is restricted. Complications more often occur after operative treatment. The type of injury and the individual demands of the patient are the most relevant factors for the choice of treatment. From the results of the survey and the review of the literature, a randomized trial of conservative and operative treatment has to be considered as a challenge. PMID- 21607790 TI - [One-stage defect closure of deperiosted bone and exposed tendons with MATRIDERM(r) and skin transplantation. Possibilities and limitations]. AB - BACKGROUND: Full-thickness skin defects over functional structures (tendons, vessels) or deperiosted bones of the extremities usually require extensive soft tissue reconstruction to cover the defect. A new option for coverage of the defect is the application of MATRIDERM(r), a bovine matrix consisting of collagen and elastin, as a neodermis underneath skin transplants. Can this combined one stage surgical intervention successfully cover deperiosted bone or tendon? PATIENTS AND METHODS: We performed this one-stage procedure in ten patients instead of soft tissue reconstruction. The success of wound coverage with the one stage method and in combination with skin transplantation for defects generally associated with considerable loss of transplants (deperiosted bones and tendons without paratenons) was determined. RESULTS: In nine of ten patients, complete defect coverage could be achieved. A one-stage wound closure in extensive defects with exposed tendons in four of five locations could be achieved. In deperiosted bone defects the one-stage coverage was only successful in two of six patients. However, complete wound closure could be achieved with a second skin transplantation in a patient with exposed tendon and bone in three of the four locations. CONCLUSION: As a one- or two-stage procedure, MATRIDERM(r) application with skin transplantation resulted in an effective defect closure without the need for a complex plastic reconstructive procedure. With regard to its functionality it cannot be considered as a substitute for skin flaps. In selected cases MATRIDERM(r) is an interesting and successful method in plastic reconstructive surgery. PMID- 21607791 TI - [A simple clavicle score. An effective and reliable classification for outcome assessments of midclavicular fractures]. AB - BACKGROUND: To compile an evaluation system (score) for post-treatment outcomes of midclavicular fractures, 172 patients were studied on average 15 months post injury. As a control group 45 healthy volunteers were examined. The most relevant elements were filtered out for use in a new classification system, the Clavicle Score (CS). METHODS: The CS is based on a system of three partnered objective/subjective items as well as radiographic assessment of fracture healing. For the partnered items, subjective responses with the most significant correlation to the specific objective parameters were selected. Total score cutoff values (very good, good, moderate, poor) were established to keep interpretation simple. To validate the system, linear regression analysis was performed comparing the CS to two established assessment systems (Constant Score and the DASH Score). ERGEBNISSE: The correlation coefficients R=0.756 (Constant) and R=0.687 indicated that the conclusions were comparable and therefore valid. The reliability coefficient Cronbach's alpha was calculated at 0.8241, indicating high reliability. CONCLUSION: The CS is a simple, valid and reliable instrument to assess outcomes post-midclavicular fracture. PMID- 21607793 TI - [Accidents, illness and injuries involved in road haulage : consequences for medical care and prevention]. AB - This article reviews basic characteristics of road traffic crashes of heavy vehicles and the current health status of truck drivers. It summarises previous findings from research with a focus on orthopaedic diseases and injuries. These findings comprise a risky health behaviour and high prevalence of associated diseases which can be attributed to both the occupational framework and personal risk-taking behavioural patterns. These are of major importance given the increasing number of drivers and the consequences for acute care and prevention. On the other hand there is a substantial lack of medical care for the drivers on the road. Therefore this article presents the"DocStop Initiative" for medical care on the road, an initiative that runs an international network of care providers (http://www.docstop-online.eu). PMID- 21607792 TI - [Arthroscopy after hip joint injury. Case studies and indications]. AB - Intra-articular injuries are common after dislocation and fracture of the hip joint and can be addressed using hip arthroscopy. The most common indications for this procedure are loose bodies, labral tears and chondral defects. In addition, preexisting femoroacetabular impingement can be addressed at the time of surgery. Arthroscopically guided fracture reduction and fixation has been described. We present two case reports of intra-articular lesions after traumatic hip dislocation. The first is a case of a man with an anterior labral tear and loose bodies after closed hip reduction. The second case is a man with a large anterior labral tear with preexisting femoroacetabular impingement. Both of them were treated by arthroscopic debridement of the unstable labrum. In addition loose bodies were removed in the first patient and a femoral osteoplasty was performed in the second patient. Hip arthroscopy has proven to be a safe and effective surgical technique for treating specific post-traumatic lesions and preexisting femoroacetabular impingement. The current case reports provide an overview of the indication for hip arthroscopy following traumatic injuries to the hip. PMID- 21607794 TI - Mosapride citrate improves postoperative ileus of patients with colectomy. AB - BACKGROUND AND AIMS: Postoperative ileus is a transient bowel dysmotility that occurs following many types of operations and is a common complication of gastrointestinal surgery. Mosapride citrate is an agonist of the 5 hydroxytryptamine 4 receptor and accelerates upper gut motility. No study has evaluated its effect on gastrointestinal motility after surgery. The aim of this study was to investigate whether mosapride citrate reduces the duration of postoperative ileus. METHODS: Thirty patients with colon cancer who underwent colectomy were divided into two groups: the mosapride group and the control group. The mosapride group received mosapride 15 mg by mouth with a minimal amount of water three times a day, starting on postoperative day 1. The control group received only a minimal amount of water on the same schedule. Patients were allowed to resume oral feeding on postoperative day 4. Postoperative time to first flatus and defecation were evaluated, and the amount of food intake was observed. Gastrointestinal motility was recorded on postoperative day 8. RESULTS: The appearance ratio of interdigestive migrating contractions and the motility index at the antrum and duodenum were significantly higher in the mosapride group than in the control group. The time to first flatus and defecation were significantly shorter in the mosapride group than in the control group. The amount of food intake on postoperative days 6 and 7 was significantly larger in the mosapride group than in the control group. CONCLUSION: Mosapride citrate reduces the duration of postoperative ileus and may improve outcomes after gastrointestinal surgery. PMID- 21607795 TI - Prognostic impact of preoperative the branched-chain amino acid to the tyrosine ratio in hepatocellular carcinoma patients after initial hepatectomy. AB - INTRODUCTION: The branched-chain amino acid/tyrosine ratio (BTR) reflects the amino acid balance and the severity of liver disease. The aim of the present study was to determine the relationship between BTR and liver function in patients with hepatocellular carcinoma (HCC). Furthermore, we evaluated the clinical usefulness of BTR as a prognostic indicator of disease-free and overall patient survival after initial hepatectomy. METHODS: Between January 2004 and December 2008, 105 consecutive HCC patients who underwent initial hepatectomy were enrolled in this study. The correlation between BTR and preoperative liver functional indicators was evaluated. The cutoff levels of BTR for 2-year survival prediction were evaluated using a dot blot diagram. The patients were divided into high BTR (4.5 or higher) and low BTR (4.4 or lower) groups and these were compared in terms of clinical variables such as liver functional indicators, operative variables, and tumor characteristics. RESULTS: The preoperative BTR level decreased according to the severity of liver disease. BTR was correlated with the albumin, bilirubin, and prealbumin levels, as well as the prothrombin time. Although the preoperative liver function was significantly different between the high BTR and low BTR groups, the operative variables and tumor related variables were not found to be significantly different. Postoperative complications in the high BTR group were significantly less frequent than in the low BTR group (p = 0.003). Disease-free and overall patient survival in the high BTR group were significantly longer than in the low BTR group (p < 0.001 and p = 0.021, respectively). CONCLUSIONS: BTR reflected the pathological liver background with a high correlation to the other liver functional indicators. BTR is thus considered to be a useful marker to predict postoperative complications, disease-free survival, and overall survival of HCC patients after initial hepatectomy. It is, therefore, a useful indicator of liver function and a predictor for the risk of cancer recurrence and overall survival in HCC patients. PMID- 21607796 TI - Perioperative care of the older patient. AB - Nearly 60% of the Dutch population undergoing surgery is aged 65 years and over. Older patients are at increased risk of developing perioperative complications (e.g., myocardial infarction, pneumonia, or delirium), which may lead to a prolonged hospital stay or death. Preoperative risk stratification calculates a patient's risk by evaluating the presence and extent of frailty, pathophysiological risk factors, type of surgery, and the results of (additional) testing. Type of anesthesia, fluid management, and pain management affect outcome of surgery. Recent developments focus on multimodal perioperative care of the older patient, using minimally invasive surgery, postoperative anesthesiology rounds, and early geriatric consultation. PMID- 21607798 TI - [Assessing the audiological results of tympanoplasty]. PMID- 21607797 TI - [Chronic inflammation and biomarkers. Is ageing an expression of chronic inflammation?]. AB - Ageing shows a high interindividual and intraindividual variability. Subclinical and clinical cardiovascular diseases accelerate the ageing process in part and in total. This leads to the idea that ageing is a result of a chronic inflammation process and to the term "inflammageing". A variety of biomarkers (e.g. C-reactive protein, interleukin-6, tumor necrosis factor alpha, fibrinogen, albumin and serum amyloid A) are described in this context. Furthermore there is a relationship to changes in the immune system across the lifespan (immunosenescence), viral infections, the occurrence of markers of oxidative stress and genetic changes. At this point in time the role for determining ageing and its use as a prognostic tool seems to be impossible. Whether inflammageing is a valid model for describing the ageing process or is the consequence of other mechanisms needs further discussion. PMID- 21607799 TI - [Efficacy of plant products against herpetic infections]. AB - Essential oils from various aromatic medicinal plants are highly active against some viral infections, e.g. labial herpes caused by herpes simplex virus type 1. Balm oil, tea tree oil and peppermint oil demonstrate in vitro a significant antiherpetic activity, mainly related to a direct drug-virus particle interaction, some essential oils also act directly virucidal. Interestingly, these essential oils are also highly active against acyclovir-resistant herpes simplex virus strains. In clinical studies, tea tree oil has been shown to possess antiherpetic, anti-inflammatory and pain-relieving properties, as well as to accelerate the healing process of herpes labialis. Applying diluted essential oils three to four times daily for the antiherpetic treatment of affected areas is recommended. Some companies have marketed plant products, e.g. from Melissa, for the treatment of recurrent herpetic infections. PMID- 21607800 TI - [Unilateral maxillary sinusitis: a cavernous haemangioma with bone destruction]. AB - Haemangioma originating in the paranasal sinuses are a rare entity. In the case of unilateral sinusitis the differential diagnosis should include tumors. The following case of a 30-year-old female patient with a therapy-resistant sinusitis showed bone destruction and a maxillary shadow on computed tomography. The histological exam resulted in a cavernous haemangioma. PMID- 21607801 TI - [Cystic lesion with a displaced tooth in the maxillary sinus]. AB - Ameloblastomas are epithelial odontogenic tumors in the mandibula or maxilla with potential local infiltrating growth; therefore, relapses can occur after incomplete resection. Among the different histological subtypes, the following are of clinical importance: The so-called unicystic ameloblastoma, radiologically presenting as a common dentigerous cyst, and the so-called extraosseous ameloblastoma. This case report describes the rare combination of a unicystic ameloblastoma with extraosseous localization in the maxillary sinus and association with a displaced tooth. This unusual constellation can cause major diagnostic problems. PMID- 21607802 TI - [Responsible dealing with sexuality. Recommendations in a clinical institution]. AB - Sexuality is excluded in house regulations, guidelines, instructions and regulations in German hospitals. The English literature does not show much more, but more often the wish for clear guidelines is formulated. Under the guidance of the clinical Ethics Committee a paper with recommendations was prepared, which comprises regulations for responsible handling of sexuality in the Pfalzklinikum. This includes sexuality of acute patients in psychiatry, nursing home inhabitants, forensic patients and above all patients in the department of child and youth psychiatry. The right of self-realization on the one hand, the staff's responsibility for patients with limitations in the determination of one's intent on the other hand and the rules for staff members define the range of the paper. PMID- 21607803 TI - Dickkopf-1 is frequently overexpressed in ovarian serous carcinoma and involved in tumor invasion. AB - Dickkopf-1 (DKK1) was known as a negative regulator of the Wnt signaling pathway, which played a crucial role in carcinogenesis. However, its function in human cancers remained elusive. In this study, we aimed to investigate the role of DKK1 in ovarian serous papillary adenocarcinoma (OSC) tumor progression and invasion. Quantitative real-time RT-PCR and Western blot analysis showed that the expression of DKK1 mRNA and protein in 32 OSC tissues were elevated as compared with those in 10 normal ovarian tissues (P = 0.005, P = 0.003, respectively). Immunohistochemical analysis in 178 clinical OSC samples showed that the expression of DKK1 was positively associated with FIGO stage (P = 0.016). Furthermore, the expression of DKK1 protein was positively associated with P-JNK1 protein expression in 178 OSC tissues. DKK1, P-JNK1 and the co-expression of DKK1 and P-JNK1 were all unfavorable prognosis factors for OSC patients (P < 0.0001). DKK1, alone or combined with P-JNK1, was an independent predictor for the 5 year survival (P = 0.015, P < 0.0001, respectively). DKK1 could promote OSC cells invasion and the growth of OSC nude mice xenograft. DKK1 in OSC cells could activate P-JNK1 expression and significantly promote formations of actin filaments and filopodia. Thus, DKK1, alone or combined with P-JNK1, was a novel prognostic predictor for OSC patients and contributed to the invasion of OSC. PMID- 21607804 TI - Workload capacity spaces: a unified methodology for response time measures of efficiency as workload is varied. AB - Increasing the number of available sources of information may impair or facilitate performance, depending on the capacity of the processing system. Tests performed on response time distributions are proving to be useful tools in determining the workload capacity (as well as other properties) of cognitive systems. In this article, we develop a framework and relevant mathematical formulae that represent different capacity assays (Miller's race model bound, Grice's bound, and Townsend's capacity coefficient) in the same space. The new space allows a direct comparison between the distinct bounds and the capacity coefficient values and helps explicate the relationships among the different measures. An analogous common space is proposed for the AND paradigm, relating the capacity index to the Colonius-Vorberg bounds. We illustrate the effectiveness of the unified spaces by presenting data from two simulated models (standard parallel, coactive) and a prototypical visual detection experiment. A conversion table for the unified spaces is provided. PMID- 21607806 TI - Breaking the fragility fracture cycle. PMID- 21607805 TI - Changes in bone mineral density and body composition during pregnancy and postpartum. A controlled cohort study. AB - In a controlled cohort study, bone mineral density (BMD) was measured in 153 women pre-pregnancy; during pregnancy; and 0.5, 4, 9, and 19 months postpartum. Seventy-five age-matched controls, without pregnancy plans, were followed in parallel. Pregnancy and breastfeeding cause a reversible bone loss, which, initially, is most pronounced at trabecular sites but also involves cortical sites during prolonged breastfeeding. INTRODUCTION: Conflicting results have been reported on effects of pregnancy and breastfeeding on BMD and body composition (BC). In a controlled cohort study, we elucidate changes in BMD and BC during and following a pregnancy. METHODS: We measured BMD and BC in 153 women planning pregnancy (n = 92 conceived), once in each trimester during pregnancy and 15, 129, and 280 days postpartum. Moreover, BMD was measured 19 months postpartum (n = 31). Seventy-five age-matched controls, without pregnancy plans, were followed in parallel. RESULTS: Compared with controls, BMD decreased significantly during pregnancy by 1.8 +/- 0.5% at the lumbar spine, 3.2 +/- 0.5% at the total hip, 2.4 +/- 0.3% at the whole body, and 4.2 +/- 0.7% at the ultra distal forearm. Postpartum, BMD decreased further with an effect of breastfeeding. At 9 months postpartum, women who had breastfed for <9 months had a BMD similar to that of the controls, whereas BMD at the lumbar spine and hip was decreased in women who were still breastfeeding. During prolonged breastfeeding, BMD at sites which consist of mostly trabecular bone started to be regained, whereas BMD at sites rich in cortical bone decreased further. At 19 months postpartum, BMD did not differ from baseline at any site. During pregnancy, fat- and lean-tissue mass increased by 19 +/- 22% and 5 +/- 6% (p < 0.001), respectively. Postpartum, changes in fat mass differed according to breastfeeding status with a slower decline in women who continued breastfeeding. Calcium and vitamin D intake was not associated with BMD changes. CONCLUSION: Pregnancy and breastfeeding cause a reversible bone loss. At 19 months postpartum, BMD has returned to pre-pregnancy level independently of breastfeeding length. Reversal of changes in fat mass depends on breastfeeding status. PMID- 21607807 TI - Coordinator-based systems for secondary prevention in fragility fracture patients. AB - The underlying causes of incident fractures--bone fragility and the tendency to fall--remain under-diagnosed and under-treated. This care gap in secondary prevention must be addressed to minimise both the debilitating consequences of subsequent fractures for patients and the associated economic burden to healthcare systems. Clinical systems aimed at ensuring appropriate management of patients following fracture have been developed around the world. A systematic review of the literature showed that 65% of systems reported include a dedicated coordinator who acts as the link between the orthopaedic team, the osteoporosis and falls services, the patient and the primary care physician. Coordinator-based systems facilitate bone mineral density testing, osteoporosis education and care in patients following a fragility fracture and have been shown to be cost-saving. Other success factors included a fracture registry and a database to monitor the care provided to the fracture patient. Implementation of such a system requires an audit of existing arrangements, creation of a network of healthcare professionals with clearly defined roles and the identification of a 'medical champion' to lead the project. A business case is needed to acquire the necessary funding. Incremental, achievable targets should be identified. Clinical pathways should be supported by evidence-based recommendations from national or regional guidelines. Endorsement of the proposed model within national healthcare policies and advocacy programmes can achieve alignment of the objectives of policy makers, professionals and patients. Successful transformation of care relies upon consensus amongst all participants in the multi-disciplinary team that cares for fragility fracture patients. PMID- 21607808 TI - Systematic review on interventions to improve osteoporosis investigation and treatment in fragility fracture patients. AB - This study aims to determine osteoporosis (OP) investigation and treatment within post-fracture initiatives conducted in fracture clinics and other orthopedic environments. A systematic review was conducted. Eligibility criteria were: hip fracture patients plus all other fracture patients presenting with a fragility fracture, orthopedic setting where orthopedic physicians/staff were involved, intervention to improve OP management, primary data on >=20 patients from randomized controlled trials (RCTs) and other study designs. We calculated outcome data within 6 months of screening from an intention-to-treat principle to derive an equated proportion (EP) across interventions. Outcomes were: (1) proportion of patients investigated with bone densitometry, (2) proportion of patients initiating OP medication, and (3) proportion of patients taking OP medication. We identified 2,259 citations, of which 57 articles that included 64 intervention groups were eligible. The median EP for patients investigated was 43% and the 75th percentile was 71%. The median EP for medication initiation was 22% and the 75th percentile was 34%. The median EP for medication taking was 27.5% and the 75th percentile was 43%. The EPs for all outcomes were higher for interventions with dedicated personnel to implement the intervention and those within which bone mineral density testing and/or treatment were included. In studies with an EP, up to 71% of patients were investigated for OP, but <35% initiated medication, and <45% were taking medication within 6 months of screening. Calculating an EP allowed us to compare outcomes across the studies, therefore capturing both RCTs and other study designs typical of real-world settings. PMID- 21607809 TI - Fracture liaison services for the evaluation and management of patients with osteoporotic fracture: a cost-effectiveness evaluation based on data collected over 8 years of service provision. AB - SUMMARY: The cost-effectiveness of Fracture Liaison Services (FLSs) for prevention of secondary fracture in osteoporosis patients in the United Kingdom (UK), and the cost associated with their widespread adoption, were evaluated. An estimated 18 fractures were prevented and L21,000 saved per 1,000 patients. Setup across the UK would cost an estimated L9.7 million. INTRODUCTION: Only 11% to 28% of patients with a fragility fracture receive osteoporosis treatment in the UK. FLSs provide an efficient means to identify patients and are endorsed by the Department of Health but have not been widely adopted. The objective of this study was to evaluate the cost-effectiveness of FLSs in the UK and the cost associated with their widespread adoption. METHODS: A cost-effectiveness and budget-impact model was developed, utilising detailed audit data collected by the West Glasgow FLS. RESULTS: For a hypothetical cohort of 1,000 fragility-fracture patients (740 requiring treatment), 686 received treatment in the FLS compared with 193 in usual care. Assessments and osteoporosis treatments cost an additional L83,598 and L206,544, respectively, in the FLS; 18 fractures (including 11 hip fractures) were prevented, giving an overall saving of L21,000. Setup costs for widespread adoption of FLSs across the UK were estimated at L9.7 million. CONCLUSIONS: FLSs are cost-effective for the prevention of further fractures in fragility-fracture patients. The cost of widespread adoption of FLS across the UK is small in comparison with other service provision and would be expected to result in important benefits in fractures avoided and reduced hospital bed occupancy. PMID- 21607810 TI - Hidalgo, I. J., Raub, T. J., and Borchardt, R. T.: Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability, Gastroenterology, 96, 736-749, 1989--the backstory. PMID- 21607811 TI - Hepatic metabolism and disposition of baicalein via the coupling of conjugation enzymes and transporters-in vitro and in vivo evidences. AB - Baicalein (Ba) was found to be subject to serious first-pass metabolism after oral administration. We previously revealed the important role of intestine in the low oral bioavailability of Ba. The present study aims to evaluate the hepatic metabolism and disposition of Ba. Ba was given to Sprague-Dawley rats through bolus or infusion via intravenous or intra-portal route of administrations. Both plasma and bile samples at different time intervals were obtained. Concentrations of Ba and potential metabolites in the collected samples were analyzed with HPLC/UV and identified by LC/MS/MS, respectively. Plasma concentration versus time profiles of Ba obtained from intravenous and intra portal administrations were compared to estimate the extent of hepatic metabolism. In addition, transport studies of baicalein-7-glucuronide (BG), one of the major metabolites of Ba, were carried out using transfected cell systems overexpressing various human organic anion-transporting polypeptide (OATP) isoforms to estimate the specific transporters involved in the hepatic disposition of Ba metabolites. The results showed that liver, in addition to intestine, also conferred extensive metabolism to Ba. Several mono- and di conjugates of Ba, which were mainly glucuronides, sulfates, and methylates, were found in bile. The transport study demonstrated that besides MRPs and BCRP, human OATP2B1 and OATP1B3 in liver might also mediate the secretion of BG to bile. In summary, liver plays an important role in the metabolism of Ba and transport of its conjugated metabolites. PMID- 21607812 TI - [Precision of a new device for biometric measurements in pseudophakic eyes]. AB - BACKGROUND: Biometric measurements and the knowledge of interrelationships of structures within the eye are especially mandatory for cataract and refractive surgery. As the number of pseudophakic patients steadily increases because cataract surgery becomes more easily available all over the world, exact biometry of eyes with crystalline lenses as well as pseudophakic eyes is gaining interest. In the present study we compared biometric measurements in pseudophakic eyes using a new optical low-coherence reflectometry (OLCR) device with results measured by the IOLMaster. PATIENTS AND METHODS: In this prospective study 140 pseudophakic eyes from 123 adult volunteers following uneventful cataract surgery and IOL implantation were examined at the International Vision Correction Research Centre (IVCRC) at the University of Heidelberg, Germany. The aim of this study was to evaluate a functional prototype of the new LENSTAR LS 900 (Haag Streit)/ALLEGRO BioGraph (Wavelight) biometer and the IOLMaster V.5 (Carl Zeiss Meditec) and to compare axial length (AL) and keratometry measurements with those obtained by the IOLMaster. Additionally we investigated whether the LENSTAR/BioGraph can detect anterior chamber depth (ACD) and the effective lens position (ELP) of IOLs by OLCR in pseudophakic eyes. Patients with corneal or intraocular pathology and patients who had undergone other surgery in the investigated eye or whose cataract surgery dated back less than 4 weeks were not included in the study. Measurements were repeated with both devices as recommended by the manufacturers. Results were compared using Bland-Altman plots, Passing Bablok regression analysis and Pearson correlation calculations (MedCalc version 7.3.0.1). RESULTS: Valid axial length measurements were available in 137 eyes. The mean values were 23.75 mm for both devices (SD+/-2.08 with the IOLMaster, +/-1.7 with the LENSTAR/BioGraph). The mean corneal radius (R) was 7.7+/-0.27 mm (IOLMaster) vs. 7.74+/-0.29 mm (LENSTAR/BioGraph). Valid ACD measurements with the LENSTAR/BioGraph were achieved in 30% of all cases. In 98.6% of the eyes in which ACD was analyzed manually a mean ACD of 4.73+/-0.53 mm was found. CONCLUSIONS: Both devices tested in this study showed a high correlation for AL and keratometry measurements. ACD measurements performed with the LENSTAR/BioGraph showed a measurable signal but the prototype calculated a value only in the minority (30%) of cases. This study showed that on the one hand the LENSTAR/BioGraph has the potential to be a reliable and useful machine for clinical everyday routine: This space and time-saving device includes several features which make it a patient and user friendly tool for diagnostics as well as screening. On the other hand we found that the software used in the prototype could be improved especially in order to identify IOLs and to measure reliable ACD values in pseudophakic patients. IOL surfaces did not generate sufficient interference signals in the LENSTAR/BioGraph and although the light reflected by the IOL surfaces was recognized by the device the software version used in this study did not generate numerical results for ACD. PMID- 21607813 TI - Nmp4/CIZ suppresses the response of bone to anabolic parathyroid hormone by regulating both osteoblasts and osteoclasts. AB - How parathyroid hormone (PTH) increases bone mass is unclear, but understanding this phenomenon is significant to the improvement of osteoporosis therapy. Nmp4/CIZ is a nucleocytoplasmic shuttling transcriptional repressor that suppresses PTH-induced osteoblast gene expression and hormone-stimulated gains in murine femoral trabecular bone. To further characterize Nmp4/CIZ suppression of hormone-mediated bone growth, we treated 10-week-old Nmp4-knockout (KO) and wild type (WT) mice with intermittent human PTH(1-34) at 30 MUg/kg daily or vehicle, 7 days/week, for 2, 3, or 7 weeks. Null mice treated with hormone (7 weeks) gained more vertebral and tibial cancellous bone than WT animals, paralleling the exaggerated response in the femur. Interestingly, Nmp4/CIZ suppression of this hormone-stimulated bone formation was not apparent during the first 2 weeks of treatment. Consistent with the null mice enhanced PTH-stimulated addition of trabecular bone, these animals exhibited an augmented hormone-induced increase in serum osteocalcin 3 weeks into treatment. Unexpectedly, the Nmp4-KO mice displayed an osteoclast phenotype. Serum C-terminal telopeptide, a marker for bone resorption, was elevated in the null mice, irrespective of treatment. Nmp4 KO bone marrow cultures produced more osteoclasts, which exhibited elevated resorbing activity, compared to WT cultures. The expression of several genes critical to the development of both osteoblasts and osteoclasts was elevated in Nmp4-KO mice at 2 weeks, but not 3 weeks, of hormone exposure. We propose that Nmp4/CIZ dampens PTH-induced improvement of trabecular bone throughout the skeleton by transiently suppressing hormone-stimulated increases in the expression of proteins key to the required enhanced activity and number of both osteoblasts and osteoclasts. PMID- 21607814 TI - Object-scene inconsistencies do not capture gaze: evidence from the flash-preview moving-window paradigm. AB - In the present study, we investigated the influence of object-scene relationships on eye movement control during scene viewing. We specifically tested whether an object that is inconsistent with its scene context is able to capture gaze from the visual periphery. In four experiments, we presented rendered images of naturalistic scenes and compared baseline consistent objects with semantically, syntactically, or both semantically and syntactically inconsistent objects within those scenes. To disentangle the effects of extrafoveal and foveal object-scene processing on eye movement control, we used the flash-preview moving-window paradigm: A short scene preview was followed by an object search or free viewing of the scene, during which visual input was available only via a small gaze contingent window. This method maximized extrafoveal processing during the preview but limited scene analysis to near-foveal regions during later stages of scene viewing. Across all experiments, there was no indication of an attraction of gaze toward object-scene inconsistencies. Rather than capturing gaze, the semantic inconsistency of an object weakened contextual guidance, resulting in impeded search performance and inefficient eye movement control. We conclude that inconsistent objects do not capture gaze from an initial glimpse of a scene. PMID- 21607815 TI - Dimension-specific attention directs learning and listening on auditory training tasks. AB - The relative contributions of bottom-up versus top-down sensory inputs to auditory learning are not well established. In our experiment, listeners were instructed to perform either a frequency discrimination (FD) task ("FD-train group") or an intensity discrimination (ID) task ("ID-train group") during training on a set of physically identical tones that were impossible to discriminate consistently above chance, allowing us to vary top-down attention whilst keeping bottom-up inputs fixed. A third, control group did not receive any training. Only the FD-train group improved on a FD probe following training, whereas all groups improved on ID following training. However, only the ID-train group also showed changes in performance accuracy as a function of interval with training on the ID task. These findings suggest that top-down, dimension-specific attention can direct auditory learning, even when this learning is not reflected in conventional performance measures of threshold change. PMID- 21607816 TI - Consolidation of statistical information of multiple objects in working memory. AB - The present study investigated working memory consolidation in focused and distributed attention tasks by examining the time course of the consolidation process (Experiment 1) and its dependence on capacity-limited central resources (Experiment 2) in both tasks. In a match-to-sample design using masks at various intervals to vary consolidation rates, the participants performed either an identification task (focused attention) or a mean estimation task (distributed attention) with (Experiment 1) or without (Experiment 2) prior knowledge of what task they were to perform. We found that consolidation in the distributed attention task was more efficient and was about twice as fast as in the focused attention task. In addition, both tasks suffered interference when they had to be performed together, indicating that both types of attention rely on a common set of control processes. These findings can be attributed to differences in the resolution of object representations and in the scope of attention associated with focused and distributed attention. PMID- 21607817 TI - Mercury bioremediation by mercury accumulating Enterobacter sp. cells and its alginate immobilized application. AB - The effective microbial remediation of the mercury necessitates the mercury to be trapped within the cells without being recycled back to the environment. The study describes a mercury bioaccumulating strain of Enterobacter sp., which remediated mercury from the medium simultaneous to its growth. The transmission electron micrographs and electron dispersive X-ray analysis revealed the accumulation of remediated mercury as nano-size particles in the cytoplasm as well as on the cell wall. The Enterobacter sp. in the present work was able to accumulate mercury, without being engineered in its native form. The possibility of recovering the accumulated mercury from the cells is also indicated. The applicability of the alginate immobilized cells in removing mercury from synthetic and complex industrial effluent in a batch mode was amply demonstrated. The initial load of 7.3 mg l(-1) mercury in the industrial effluent was completely removed in 72 h. The cells immobilized in calcium alginate were similarly effective in the complete removal of 5 mg l(-1) HgCl(2) of mercury from the synthetic effluent in less than 72 h. The immobilized cells could be reused for multiple cycles. PMID- 21607818 TI - Thoracoscopic simultaneous bilateral bullectomy through apicoposterior transmediastinal access for bilateral spontaneous pneumothorax: a challenging approach. AB - BACKGROUND: Video-assisted thoracoscopic surgery (VATS) through transmediastinal access (TMA) for contralateral thoracic cavity is an operative alternative for bilateral pulmonary lesions. Recently, we introduced a novel method of apicoposterior TMA to perform simultaneous VATS bilateral bullectomy (BB) for bilateral spontaneous pneumothorax (BPTX). We retrospectively analyzed ten patients on whom this procedure was performed and evaluated the effectiveness of this approach. METHODS: From April 2006 to May 2010, ten patients underwent simultaneous BB through this approach. Mean postoperative follow-up was 33.2 months. All patients were young males (age range = 15-20 years) and eight patients had BPTX that developed simultaneously. Apical blebs or bullae were carefully identified using multidirectional high-resonance computed tomography (HRCT). VATS right bullectomy was done first. The left thorax was reached by going through the apicoposterior mediastinum between the esophagus and vertebral bodies, and then left procedure was performed through this access. RESULTS: All ten patients successfully underwent VATS BB through TMA without intraoperative complications. One patient developed prolonged air leakage for 6 days on the right side. During the follow-up period, two patients developed left PTX recurrence; one was treated with a chest tube at 13 months, and another underwent a left VATS reoperation at 20 months postoperatively because of new bulla formation around the previous stapling line. CONCLUSIONS: A VATS apicoposterior transmediastinal approach is relatively safe and technically reliable for highly selective BPTX patients who have localized blebs or bullae on the left apical lung. Pleural reinforcement procedures may also be required for the prevention of postoperative recurrence. PMID- 21607819 TI - Local recurrence after intended curative excision of presacral lesions: causes and preventions. AB - OBJECTIVE: This study was designed to explore causes for local recurrence of presacral lesions after intended curative surgery and discuss prevention strategies. METHODS: Medical data of presacral lesions in our hospital from January 2001 to September 2009 were retrospectively studied, including preoperative examinations, intraoperative findings, and postoperative histopathologies. RESULTS: Of 39 patients (29 women and 10 men) with presacral lesions, who ranged in age from 14 to 71 (mean, 39.56) years, 7 patients were diagnosed with recurrent presacral lesions on admission. Preoperative pelvic MRI, pelvic CT, and endorectal ultrasonography (ERUS) were performed in 23, 22, and 8 cases, respectively. MRI/CT showed that five cases had two coexisting lesions and three cases had lobulated or dumbbell shaped lesions, all of which were confirmed by intraoperative findings. ERUS suspected involvement of the rectal wall in three cases: adhesion to the rectal wall in two cases, and tumor invasion in the remaining case. During the operation, 26, 8, and 2 cases were resected by the transsacral, transabdominal, and combined abdominosacral approach, respectively. Four patients underwent simultaneous coccygectomy, and three patients received simultaneous resection of the sacrum and coccyx. Simultaneous partial resection of the invaded sigmoid colon or rectum was performed in two patients, respectively. By postoperative pathological examination, three cases were found to have ruptured cystic lesions, three had previous cyst rupture history, and five had infected lesions. CONCLUSIONS: Presacral lesions are likely to be multiple, lobulated, infected, ruptured, and adhesive to the sacrococcyx and rectum, which contribute to the high local recurrence rate. Preoperative CT/MRI/ERUS and careful intraoperative exploration are required to direct surgical treatment and to reduce local recurrence. Optimal selection of surgical approach also is very important to reduce local recurrence. Presacral lesions attached to the sacrococcyx or rectum require simultaneous partial resection of the sacrococcyx or rectum to reduce local recurrence. PMID- 21607820 TI - Re: Is it possible to train surgeons for rural Africa? A report of a successful international program. PMID- 21607821 TI - Early postoperative and one year results of a randomized controlled trial comparing the impact of extralight titanized polypropylene mesh and traditional heavyweight polypropylene mesh on pain and seroma production in laparoscopic hernia repair (TAPP). AB - BACKGROUND: Today the main goals of inguinal hernia repair are maximum postoperative comfort and a minimal rate of chronic pain. This randomized trial compares these parameters after laparoscopic hernia repair (TAPP) using an extralight titanized polypropylene mesh (ELW group) TiMesh((r)) 16 g/m(2) without any fixation with those using a standard heavyweight mesh (HW) Prolene 90 g/m(2) fixed in a standardized way with two absorbable sutures. METHODS: Three hundred patients with an inguinal hernia and a defect diameter <=3 cm were included in the trial. Patients were assessed for pain, foreign body sensation, and physical activities preoperatively, early postoperatively, at 4 weeks, 6 months, and 1 year by questionnaire and were examined clinically. Postoperatively, seroma formation was measured by ultrasound. RESULTS: One year after TAPP, the frequency of chronic pain was not greater than 3%, with no difference between the two mesh groups; in no patient was intensity of pain higher than VAS 40. In the early postoperative period, 40% of the patients in the titanized ELW group needed pain medication compared with 52.7% in the HW group (P = 0.0378). Foreign body sensation was not different between the groups but there was significantly less impairment of physical activities (P = 0.0425) and seroma production (P = 0.0415) in the titanized ELW group compared to the HW group in the early postoperative period. CONCLUSION: Use of titanized ELW mesh for laparoscopic hernia repair did not affect the rate of chronic pain but it seems to improve early postoperative convalescence. Its use without any fixation can be recommended in TAPP for inguinal hernia patients with a defect size <=3 cm. PMID- 21607822 TI - Vascular relaxation induced by aqueous extract of Lespedeza cuneata via the NO cGMP pathway. AB - The aqueous extract of Lespedeza cuneata G. Don. (ALC) induced vasorelaxation of phenylephrine precontracted aorta in a dose-dependent manner. This effect disappeared in the absence of functional endothelium. Pretreatment of the aortic tissues with N(G)-nitro-L-arginine methyl ester (L-NAME), or 1H-[1,2,4] oxadiazole-[4,3-alpha]-quinoxalin-1-one (ODQ) blocked ALC-induced vascular relaxation. Incubation of endothelium-intact thoracic aortic rings with ALC increased cGMP production. ALC-induced cGMP production was blocked by pretreatment with L-NAME or ODQ. ALC-induced vascular relaxation was also markedly attenuated by addition of verapamil or diltiazem, but was not blocked by pretreatment with indomethacine, glibenclamide, tetraethylammonium, atropine, or propranolol. The results suggest that ALC dilates vascular smooth muscle via endothelium-dependent NO-cGMP signaling. PMID- 21607824 TI - Combined treatment of large hepatocellular carcinoma with transcatheter arterial chemoembolization and percutaneous ethanol injection with a multipronged needle: experimental and clinical investigation. AB - PURPOSE: This study was designed to evaluate the usefulness of percutaneous ethanol injection (PEI) with a multipronged needle for the treatment of large hepatocellular carcinoma (HCC). An experimental animal study and a clinical investigation were performed. METHODS: In the experimental study, 20 ml of 99.5% ethanol was injected into porcine liver in vivo with a multipronged needle (n = 5) or a straight needle (n = 5), and the volumes of coagulation necrosis were compared. In the clinical investigation, PEI was performed in 17 patients (10 men, 7 women; mean age 73.4 +/- 6.7 years) with single, large HCC (mean tumor diameter, 47.2 +/- 11.5 mm; range, 32-70 mm) by using a multipronged needle. Fifteen of 17 patients received transarterial chemoembolization (TACE) before PEI. RESULTS: The volume of coagulation in porcine liver in vivo was significantly increased with the multipronged needle compared with the straight needle (longest perpendicular diameters, 34.2 +/- 3.6 mm * 30.2 +/- 3.6 mm vs. 22.6 +/- 2.5 mm * 19 +/- 2.2 mm, respectively; P < 0.05). In the clinical trial, initial complete response (CR) of the tumor was achieved in 17 of 17 patients, 7 of whom required two PEI sessions. During the follow-up, local recurrence was detected in 4 of 17 patients at 3-19 months after the procedure, for a rate of sustained local CR of 76%. No major complication occurred. CONCLUSIONS: Use of a multipronged needle substantially increases the volume of coagulation in vivo with respect to the conventional PEI technique. Combined TACE and PEI with multipronged needles is a safe and effective option for percutaneous treatment of single, large HCC. PMID- 21607823 TI - Piriformis syndrome: long-term follow-up in patients treated with percutaneous injection of anesthetic and corticosteroid under CT guidance. AB - PURPOSE: This study was designed to evaluate the efficacy of CT-guided injection of anesthetic and corticosteroid for the treatment of pain in patients with piriformis syndrome unresponsive to conservative treatment. METHODS: We enrolled 23 patients with piriformis syndrome, proposing a percutaneous intramuscular injection of methylprednisone-lidocaine. Among them, 13 patients accepted and 10 refused to undergo the procedure; the second group was used as a control group. Clinical evaluation was performed with four maneuvers (Lasegue sign, FAIR test, Beatty and Freiberg maneuver) and a VAS questionnaire before the injection, after 5-7 days, and after 2 months. A telephonic follow-up was conducted to 3, 6, and 12 months. RESULTS: Procedural success was achieved in all patients who were treated without any complications. After 2 months, among 13 treated subjects, 2 of 13 patients showed positivity to FAIR test (hip flexion, adduction, and internal rotation), 2 of 13 were positive to Lasegue sign, and the Beatty maneuver was positive in 1 patient. Patients who underwent conservative treatment were positive respectively in 7 of 10 (p = 0.01), 6 of 10 (p = 0.03), and 6 of 10 (p = 0.01). The VAS score showed a difference between patients treated with percutaneous approach and those managed with conservative therapy at the baseline evaluation (p = 0.04), after 2 months (p = 0.02), and 12 months (p = 0.002). We observed a significant reduction in pain for patients treated percutaneously, who were evaluated with the VAS scale at 5-7 days, 2 months, 3, 6, and 12 months (p < 0.001). CONCLUSIONS: Our findings suggested potential benefit from the percutaneous injection of anesthetics and corticosteroids under CT guidance for the treatment of piriformis syndrome. PMID- 21607825 TI - Differentiation of Candida glabrata, C. nivariensis and C. bracarensis based on fragment length polymorphism of ITS1 and ITS2 and restriction fragment length polymorphism of ITS and D1/D2 regions in rDNA. AB - Different molecular methods for the discrimination of Candida glabrata, C. bracarensis and C. nivariensis were evaluated and the prevalence of these species among Danish blood isolates investigated. Control strains were used to determine fragment length polymorphism in the ITS1, ITS2, ITS1-5.8S-ITS2 regions and in the D1/D2 domain of 26S rDNA using primers designed for this study. A total of 133 blood isolates previously identified as C. glabrata were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the peptide nucleic acid-fluorescent in situ hybridization (PNA-FISH) method. The size of ITS1 allowed differentiation between C. glabrata (483), C. nivariensis (361) and C. bracarensis (385), whereas the ITS2 region was of similar size in C. nivariensis (417) and C. glabrata (418). Sequence analysis of the ITS region suggested that many restriction enzymes were suitable for RFLP differentiation of the species. Enzymatic digestion of the D1/D2 domain with TatI produced unique band sizes for each of the three species. PCR-RFLP and PNA-FISH were in agreement for all of the isolates tested. None of the 133 Danish blood isolates were C. nivariensis or C. bracarensis. Fragment size polymorphism of ITS1 and RFLP of the D1/D2 domain or the ITS region are useful methods for the differentiation of the species within the C. glabrata group. C. bracarensis and C. nivariensis are rare among Danish C. glabrata blood isolates. PMID- 21607826 TI - Exposure to violence and socioemotional adjustment in low-income youth: an examination of protective factors. AB - Using a sample of 391 low-income youth ages 13-17, this study investigated the potential moderating effects of school climate, participation in extracurricular activities, and positive parent-child relations on associations between exposure to violence (i.e., witnessing violence and violent victimization) and adolescent socioemotional adjustment (i.e., internalizing and externalizing problems). Exposure to violence was related to both internalizing and externalizing problems. High levels of participation in extracurricular activities and positive parent-child relations appeared to function as protective factors, weakening the positive association between exposure to violence and externalizing problems. Contrary to prediction, school climate did not moderate associations between exposure to violence and socioemotional adjustment. Further, none of the hypothesized protective factors moderated the association between exposure to violence and internalizing problems. PMID- 21607827 TI - Physiologic effects of simultaneous carbon dioxide insufflation by laparoscopy and colonoscopy: prospective evaluation. AB - BACKGROUND: The use of intraoperative carbon dioxide (CO(2)) colonoscopy during a laparoscopic colon operation is becoming more common. Simultaneous intracolonic and intraabdominal CO(2) insufflation may result in significant physiologic changes, but in-depth physiologic effects have not been studied to date. This study aimed to evaluate the physiologic changes and the overall safety of simultaneous CO(2) laparoscopy and colonoscopy. METHODS: A prospective pilot study was performed with 26 subjects (17 men and 9 women) undergoing laparoscopic surgical treatment for colorectal conditions adjunctively managed with CO(2) intraoperative colonoscopy. Surgery proceeded with CO(2) insufflation to a maximum pressure of 12 mmHg by laparoscopy and with a maximum CO(2) flow of 5 l/min via colonoscopy. Serial intra- and postoperative arterial blood gases, end tidal CO(2), and minute ventilation were recorded during predetermined periods: during initial laparoscopy, during simultaneous colonoscopy and laparoscopy, during laparoscopy after colonoscopy, and after desufflation. RESULTS: No significant morbidity resulted from simultaneous CO(2) insufflation. Three patients had a CO(2) partial pressure (PaCO(2)) greater than 50, and one patient with a body mass index (BMI) higher than 42 kg/m(2) had a PaCO(2) greater than 50 for more than 30 min and was compensated by increasing minute ventilation. The mean pH was 7.36 in the recovery room. Postoperatively, no patient had a pH lower than 7.3, prolonged intubation, or reintubation. CONCLUSION: Simultaneous CO(2) colonoscopy and laparoscopy lead only to transient alterations in respiratory parameters that can be compensated. Based on these findings, simultaneous insufflation of CO(2) into the peritoneal cavity and the large bowel lumen during complex endoscopic procedures may be considered safe for most patients. PMID- 21607828 TI - Lymph node metastasis mapping in extended lymphadenectomy to the level of the inferior mesenteric artery for bladder cancer. AB - BACKGROUND: The aim of this study was to evaluate the distribution of lymph node metastasis in extended lymphadenectomy for patients with bladder cancer. METHODS: We analyzed 31 patients who underwent extended lymphadenectomy at radical cystectomy for bladder cancer between April 2008 and February 2010. Specimens were evaluated as 14 separate packages from predesignated anatomical locations. The lymph node mapping was prospectively registered. RESULTS: The median lymph node count was 37 (range 19-68). Ten (32%) patients had lymph node metastasis. The positive rates at each lymph node site were 0% at the left internal iliac, 13% at the left obturator, 3.2% at the left external iliac, 6.5% at the right internal iliac, 10% at the right obturator, 16% at the right external iliac, 3.2% at the left common iliac, 3.2% at the right common iliac and 6.5% at the presacral node. No lymph node metastasis was detected in the Cloquet, paracaval, aortocaval or paraaortic nodes. One (3.2%) patient had a skip metastasis from the left obturator to the presacral node. CONCLUSIONS: Extended lymphadenectomy provides more accurate lymph node staging. We suggest that it is better to perform lymphadenectomy at least below the aortic bifurcation including the presacral node. PMID- 21607829 TI - Clinical practice and outcome of radiotherapy for esophageal cancer between 1999 and 2003: the Japanese Radiation Oncology Study Group (JROSG) Survey. AB - BACKGROUND: To determine the clinical results of radiotherapy (RT) for esophageal cancer in Japan. MATERIALS AND METHODS: A questionnaire-based survey was conducted for esophageal cancer treated by definitive RT between 1999 and 2003. Clinical results of definitive RT for patients were collected from 9 major institutions. Only patients with good performance status (PS 0-2) who received a total dose of 50 Gy or more were included. Patients were classified into three groups: (A) stage I, (B) resectable stages II-III, (C) unresectable stages III IVA. For group A, all patients treated by RT alone or chemo-radiotherapy (CRT) were included. For groups B and C, only those treated by CRT were included. RESULTS: In total, 167 patients were included in group A, 239 in group B, and 244 in group C. Approximately half of the patients in group A were treated by CRT. The median total RT dose ranged from 60 to 66 Gy. The median and range of the 5 year overall survival rates were 56% (48-83%) for group A, 29% (12-52%) for group B, and 19% (0-31%) for group C, respectively. A wide disparity in overall survival rates was noted among the institutions. A significant correlation between the number of patients treated per year and the 5-year overall survival rate was noted for groups B and C (both p < 0.05). CONCLUSION: Although the overall survival rates for stage I esophageal cancer were excellent, a significant disparity in survival rates was noted among the institutions for stage II-IVA tumors treated by CRT. PMID- 21607830 TI - Serum HER2 levels determined by two methods in patients with metastatic breast cancer. AB - BACKGROUND: The role and the optimal measurement method of serum HER2 levels are not defined in patients with metastatic breast cancer (MBC). We prospectively assessed the prognostic value of serum HER2 levels in MBC using two methods, enzyme immunoassay (EIA) and chemiluminescence immunoassay (CLIA). METHODS: We collected blood samples from patients with MBC at baseline and at subsequent 3- to 4-week intervals up to 12 weeks. Samples were divided, and serum HER2 levels were determined using EIA and CLIA. We also determined whether serum HER2 levels had decreased by >=20% at first follow-up. These results were evaluated against overall survival, progression-free survival, and tumor response. RESULTS: We obtained 196 samples from 52 patients. In 59 samples from patients who received trastuzumab, serum HER2 positivity rates were significantly lower for EIA (n = 22) than for CLIA (n = 33, P = 0.042); in 137 samples from patients who did not receive trastuzumab, there was no significant difference in rates of serum HER2 positivity for CLIA (n = 83) and EIA (n = 80). Serum HER2 level at baseline, the level at first follow-up, and a decrease of >=20% between baseline and first follow-up were not associated with overall survival, progression-free survival, and tumor response. CONCLUSIONS: Chemiluminescence immunoassay was a more sensitive method than EIA for measuring serum HER2 levels in patients who received trastuzumab. However, because serum HER2 levels did not correlate with patient outcome, we do not currently recommend measuring serum HER2 levels by either method for prognostic evaluation in patients with MBC. PMID- 21607831 TI - Time-course of changes in phosphorylated CREB in neuroblasts and BDNF in the mouse dentate gyrus at early postnatal stages. AB - Cyclic AMP (cAMP) response element-binding protein (CREB) is involved in memory, learning, and synaptic transmission. In this study, we observed changes of phosphorylated CREB (pCREB) immunoreactivity and its protein levels as well as brain-derived neurotrophic factor (BDNF) levels in the hippocampal dentate gyrus at postnatal (P) 1, 7, 14, and 21 in mice. In addition, we also investigated pCREB expression in doublecortin (DCX, a marker for neuronal progenitors) immunoreactive neuroblasts at P21. pCREB immunoreaction at P1 was detected in most of cells in the dentate gyrus, thereafter pCREB immunoreactivity was decreased in all the layers of the dentate gyrus with time, however, strong pCREB immunoreactivity was shown in cells confined to the subgranular zone of the dentate gyrus at P21. In this group, many pCREB immunoreactive cells were co localized with DCX immunoreactive neuroblasts. In addition, pCREB protein levels were decreased with age, showing that their levels were very low at P21, while BDNF protein levels were increased with age. These results suggest that pCREB may play important roles in functional maturity of granule cells in mice. PMID- 21607832 TI - Analysis of the cluster formation in two-component cylindrical bottle-brush polymers under poor solvent conditions: a simulation study. AB - Two-component bottle-brush polymers, where flexible side chains containing N = 20, 35 and 50 effective monomers are grafted alternatingly to a rigid backbone, are studied by Molecular Dynamics simulations, varying the grafting density [Formula: see text] and the solvent quality. Whereas for poor solvents and large enough [Formula: see text] the molecular brush is a cylindrical object with monomers of different type occupying locally the two different halves of the cylinder, for intermediate values of [Formula: see text] an axially inhomogeneous structure of "pearl-necklace" type is formed, where microphase separation between monomers of different type within a cluster takes place. These "pearls" have a strongly non-spherical ellipsoidal shape, due to the fact that several side chains cluster together in one "pearl". We discuss the resulting structures in detail and we present a comparison with the single-component bottle-brush case. PMID- 21607833 TI - Reversible sphere-to-lamellar wetting transition at the interface of a diblock copolymer system. AB - We use ellipsometry to investigate a transition in the morphology of a sphere forming diblock copolymer thin-film system. At an interface the diblock morphology may differ from the bulk when the interfacial tension favours wetting of the minority domain, thereby inducing a sphere-to-lamella transition. In a small, favourable window in energetics, one may observe this transition simply by adjusting the temperature. Ellipsometry is ideally suited to the study of the transition because the additional interface created by the wetting layer affects the polarisation of light reflected from the sample. Here we study thin films of poly(butadiene-ethylene oxide) (PB-PEO), which order to form PEO minority spheres in a PB matrix. As temperature is varied, the reversible transition from a partially wetting layer of PEO spheres to a full wetting layer at the substrate is investigated. PMID- 21607834 TI - Epithelial tissue statistics: eliminating bias reveals morphological and morphogenetic features. AB - Geometric order in quasi-two-dimensional epithelia has been extensively researched in order to identify and classify different tissues to help our understanding of how tissues form (morphogenesis) and how their formation may be influenced (tissue regeneration). However, the significance of published data such as the distribution of numbers of cell neighbors- has been debatable because of measurement bias. We shown that such bias can be detected and corrected without detailed knowledge of the original samples, using only the biased (measured) distributions. This is true for both of the most important sources of bias: the measurement of apparent four-fold vertices and the selective preference for measuring smaller cells introduced by selecting a finite sampling window. The resulting unbiased data allows for a meaningful comparison of all available data, from different sources, taken with different experimental resolution and methodology. Conclusive evidence is found that the apparent four-fold vertices are neither distributed randomly nor oriented randomly, revealing profound differences in topological correlation between proliferating and remodeling tissues. The method is applied to measurements of Drosophila wing tissue, where it successfully disentangles distributional moments, allowing for an assessment of their relative importance, independence, and significance in tissue identification and classification. PMID- 21607835 TI - High-resolution computed tomography of chest complications in patients treated with hematopoietic stem cell transplantation. AB - Hematopoietic stem cell transplantation (HSCT) has become a standard method for treating patients with hematological malignancies. Preconditioning chemotherapeutic drugs, total body irradiation (TBI), or chronic graft-versus host disease (GVHD) can cause several chest complications after HSCT. Because immunosuppression is marked after HSCT, it takes at least 1 year for the immune system to recover completely. Therefore, several infectious and noninfectious complications may occur within the year after HSCT. HSCT-specific complications occur in a characteristic temporal sequence associated with the period following HSCT. During the neutropenic phase, bacterial pneumonia, fungal infection, pulmonary edema, and diffuse alveolar hemorrhage may occur. During the early phase, pneumocystis pneumonia, cytomegalovirus pneumonia, engraftment syndrome, and idiopathic pneumonia syndrome are the common complications. During the late phase, constrictive bronchiolitis and organizing pneumonia may occur probably associated with chronic GVHD. Although high-resolution CT findings lack specificity, the frequency and likelihood of occurrence of certain complications in certain phases and sometimes characteristic features (such as a CT halo sign for fungal infection) facilitate early detection of a life-threatening complication. PMID- 21607836 TI - Clinical efficacy and value of redistributed subclavian arterial infusion chemotherapy for locally advanced breast cancer. AB - PURPOSE: The aim of this study was to evaluate the efficacy and safety of redistributed subclavian arterial infusion chemotherapy (RESAIC). We have focused on the local response, quality of life (QOL), and complications. We have also investigated factors that influence the local response of RESAIC. MATERIALS AND METHODS: The subjects were patients with locally advanced breast cancer whose tumors were resistant to standard systemic chemotherapy (at least more than two regimens), those who were physically unable to tolerate systemic chemotherapy, and patients with locally recurrent breast cancer. The registration period was between April 2006 and May 2009. RESULTS: A total of 24 cases in 22 patients (mean age 59.5 years, range 36-82 years) were entered in the study. The local response rate of RESAIC was 77.3% (17/22). The QOL score showed improvement on average. There were no serious complications during catheter port implantation, and there was hematological toxicity over grade 3 in 27.3% (6/22) of patients. A significant difference between responders and nonresponders was seen in patients with a replaced type tumor (on imaging, diffuse contrast enhancement was seen in whole quadrants) (P = 0.043), and the patients underwent radiotherapy (P = 0.043). CONCLUSION: RESAIC is an effective, safe treatment for locally advanced breast cancer. Because it was reviewed in only a few cases, however, large-scale studies are warranted. PMID- 21607837 TI - Oxygen-enhanced lung magnetic resonance imaging: influence of inversion pulse slice selectivity on inversion recovery half-Fourier single-shot turbo spin-echo signal. AB - PURPOSE: The purpose of this study was to evaluate in vivo the influence of inversion pulse slice selectivity on oxygen-enhanced magnetic resonance imaging (MRI). MATERIALS AND METHODS: Thirteen healthy volunteers were studied with a two dimensional cardiac- and respiratory-gated adiabatic inversion-recovery half Fourier single-shot turbo spin-echo (HASTE) sequence with either slice-selective or non-slice-selective inversion recovery (IR) pulse at inversion times increasing from 300 to 1400 ms. The signal-to-noise ratio (SNR) at every inversion time (TI), real signal difference (DeltaSI), and relative enhancement ratio of lung parenchyma at TI >= 800 ms were statistically compared for oxygen enhanced and non-oxygen-enhanced MR images with slice-selective or non-slice selective IR pulses. RESULTS: The SNRs of acquisitions with slice-selective IR pulses were significantly higher than those of non-slice-selective IR pulses (P < 0.05). At TI 800 ms, the DeltaSI of lung parenchyma on IR-HASTE images with slice selective inversion pulse type was significantly higher than on that with the non slice-selective type (P < 0.05). Relative enhancement ratios of the slice selective IR pulses were significantly lower than those of non-slice-selective IR pulses at TIs between 800 and 1400 ms (P < 0.05). CONCLUSION: Slice selectivity of inversion pulse type affects oxygen-enhanced MRI in vivo. PMID- 21607838 TI - Quantitative computed tomographic measurement of a cross-sectional area of a small pulmonary vessel in nonsmokers without airflow limitation. AB - PURPOSE: Pulmonary vascular alterations are not exclusive to pulmonary vascular disorders; they are also present in patients with mild chronic obstructive pulmonary disease (COPD) with normal pulmonary function. Moreover, vascular alteration is closely related to lung ventilation. We hypothesized that pulmonary vascular alterations might occur even in nonsmokers with subtle airflow limitation, and there could be a significant correlation between pulmonary vascular alterations and airflow impairment. The purpose of this study was to evaluate the correlation between the vascular alterations measured by cross sectional area (CSA) and airflow impairment in nonsmokers with normal pulmonary function. MATERIALS AND METHODS: Thirty patients (1 man, 29 women; mean age 55 +/ 14 years, range 33-81 years) underwent pulmonary function tests (PFTs) within 2 weeks of undergoing multidetector computed tomography (CT) scans. Total vessel CSA < 5 mm(2) was calculated by a threshold technique using imaging software. Forced expiratory volume in 1 s (FEV(1)), the ratio of FEV(1) to FVC (FEV(1)/FVC), and the mid-expiratory phase of the forced expiratory flow (FEF(25% 75%)) were obtained from PFTs. We calculated Spearman correlation coefficients between %CSA < 5 and the results of PFTs. RESULTS: %CSA < 5 had a significant positive correlation with FEV(1)/FVC (r = 0.651, P < 0.0001) and FEF(25%-75%) (r = 0.627, P = 0.0002), whereas CSA < 5% had no significant correlation with FEV(1) (r = 0.172, P = 0.362). CONCLUSION: There was a significant correlation between pulmonary small vascular alteration and airflow impairment even in nonsmokers without airway obstruction. PMID- 21607839 TI - Influence of the distribution of emphysema on diaphragmatic motion in patients with chronic obstructive pulmonary disease. AB - PURPOSE: We investigated whether the distribution of emphysema on computed tomography (CT) images can affect chest wall motion in patients with chronic obstructive lung disease (COPD). MATERIALS AND METHODS: The subjects were 35 male patients with COPD (age, 69.7 +/- 6.2 years). The RA-950 (the ratio of lung volume under -950 HU to total lung volume on CT) was measured separately for the upper and lower halves of the lung. We analyzed the flatness of the diaphragm (Kdome) and its motion (DeltaLappo) using dynamic magnetic resonance imaging. Paradoxical motion (Mpr) represented the ratio of the paradoxical diaphragmatic movement (downward or upward) when the lung area decreased or increased, respectively, to he total diaphragm movement (expressed as a percent). These parameters were analyzed in correlation with pulmonary function tests and St. George Respiratory Questionnaire (SGRQ) scores. RESULTS: The RA-950 of the lower lung zone correlated significantly with the Kdome (P = 0.033), DeltaLappo (P = 0.006), Mpr (%) (P = 0.001), forced expiratory volume at 1 s (% predicted; P < 0.001), and activity score of the SGRQ (p = 0.017). The RA-950 of the upper lung zone did not correlate with these parameters. CONCLUSION: In COPD patients, the distribution of emphysema on CT correlates with airflow obstruction and abnormal diaphragmatic motion. PMID- 21607840 TI - Pancreatic cancer screening employing noncontrast magnetic resonance imaging combined with ultrasonography. AB - PURPOSE: We have conducted an initial evaluation on the potential of combining noncontrast magnetic resonance imaging (MRI) and ultrasonography (US) to screen for pancreatic cancer. MATERIALS AND METHODS: An independent ethics committee approved this study. A total of 2511 patients who underwent US were enrolled. Among them, noncontrast MRI was performed in patients in whom the entire pancreas was difficult to depict or in those with US-suspected pancreatic lesions. In total, using 1.5-T MRI, T1- and T2-weighted imaging, magnetic resonance cholangiopancreatography, and diffusion-weighted imaging, we acquired a variety of images. The efficacy of US and MRI in screening for pancreatic lesions, including pancreatic cancer, was evaluated. RESULTS: Of 2511 patients, 184 underwent MRI, and the pancreas was demonstrated in all of them. Among the 2511, five pancreatic cancers were detected by MRI combined with US (detection rate 0.20%). Of the five pancreatic cancers, three were detected by US (detection rate 0.12%) and two by MRI. Four of the five pancreatic cancers were resectable. CONCLUSION: By combining noncontrast MRI with US, pancreatic cancer can be detected with high accuracy. Other pancreatic lesions that require follow-up, including intraductal papillary mucinous neoplasms, can also be detected. Thus, pancreatic cancer screening with a combination of US and MRI is suggested. PMID- 21607841 TI - Adenomyosis with extensive glandular proliferation simulating infiltrating malignancy on magnetic resonance imaging. AB - We report a case of multicystic adenomyosis, which is an exceedingly rare benign tumor. The patient complained of an irregular menstrual cycle and abnormal genital bleeding that gradually increased in amount and frequency. The patient finally became severely anemic, and a hysterectomy was therefore performed. T2 weighted magnetic resonance imaging (MRI) indicated hyperplasia of the endometrium, with a myometrial lesion, where a high signal intensity multicystic mass was observed. The preoperative diagnosis was complicated by confusing MRI results. Postoperative macroscopic examination revealed a villous endometrium and a myometrium thickened with multiple small cysts containing serous transparent fluid. The final diagnosis, based on the hysterectomy specimen, was adenomyosis coexisting with simple endometrial hyperplasia. The MRI and positron emission tomography images are presented. PMID- 21607842 TI - Incomplete left-hand and complete right-hand pisiform and hamate coalition: multidetector computed tomography findings. AB - Pisiform-hamate coalition is a rare form of carpal coalition. Only 14 cases of pisiform-hamate coalition have been reported in the English-language literature. We present a case of asymptomatic bilateral pisiform-hamate coalition in a 16 year-old boy. We also review the embryology, pathogenesis, and clinical features of pisiform and hamate coalition, along with the associated multidetector computed tomography findings. PMID- 21607843 TI - Pulmonary artery intimal sarcoma: the role of 18F-fluorodeoxyglucose positron emission tomography in monitoring response to treatment. AB - We report the case of 58-year-old man with pulmonary artery intimal sarcoma. He initially presented with cough, right-sided chest pain, and shortness of breath. Although the diagnosis of pulmonary embolism had been considered, chest radiograph and pulmonary perfusion scintigraphy showed a mass in the right hilum and no perfusion in the right lung. (18)F-fluorodeoxyglucose positron emission computed tomography (FDGPET) showed increased FDG uptake in the mass obstructing the right pulmonary artery. Fine-needle biopsy revealed a pathological diagnosis of pulmonary artery intimal sarcoma. The patient was successfully treated with radiotherapy and adjuvant chemotherapy. FDG-PET was used for monitoring the response to therapy. PMID- 21607844 TI - Idiopathic chondrolysis of hip. AB - An uncommon case of idiopathic chondrolysis of the hip in an 11-year-old girl is reported. It was characterized by clinical presentation, laboratory tests, and imaging techniques. A differential diagnosis is discussed highlighting the radiological features for quick diagnosis. PMID- 21607845 TI - Microcoil embolization during abdominal vascular interventions through microcatheters with a tip of 2 French or less. AB - PURPOSE: The aim of this study was to evaluate the technical aspects of embolization using microcoils through a microcatheter with a tip of 2F or smaller during abdominal vascular interventions. MATERIALS AND METHODS: Coil embolization through a microcatheter with a tip of 2F or smaller was attempted in 73 procedures. Two types of microcoil-Liquid Coil (Boston Scientific, Watertown, MA, USA) and Tornado Coil (Cook, Bloomington, IN, USA)-were deployed through four types of thinner microcatheter [2F tip (n = 49) and 1.8F tip (n = 24)]. Coil jams in the microcatheter and coil migration were evaluated. RESULTS: In total, 286 microcoils were placed (mean +/- SD, 3.9 +/- 4.3 coils per procedure, range 1-32 coils). In 19 procedures (26.9%), Liquid Coils were used alone. In 44 (60.3%), Tornado Coils were used alone. In 10 (13.7%), Liquid Coils and Tornado Coils were combined. There were no coil jams in the microcatheter in this series. One Tornado Coil (0.3%) delivered into the gastroduodenal artery migrated to the right hepatic artery. CONCLUSION: Liquid Coils and Tornado Coils can be placed through a thinner microcatheter without difficulty. However, there is a risk of coil migration in large vessels or at the proximal site because the catheter tip is not stabilized. PMID- 21607847 TI - Pentavalent organobismuth reagents in organic synthesis: alkylation, alcohol oxidation and cationic photopolymerization. AB - Organic transformations using organobismuth(V) reagents developed by my group are reviewed. The characteristic properties of bismuth, such as the inert pair effect, small bond dissociation energy, and polarized bonding are strongly related to the reactivity of pentavalent organobismuth compounds. The Bi(V) reagents discussed in this chapter include tetraorganylbismuthonium salts ([Ar(3)RBi(+)][X(-)]), triarylbismuth ylides (Ar(3)Bi=CHCOR), triarylbismuth imides (Ar(3)Bi=NCOR), triarylbismuth oxides (Ar(3)Bi=O), and triarylbismuth dichlorides (Ar(3)BiCl(2)). These organobismuth(V) compounds are readily accessible in a few steps from triarylbismuthanes (Ar(3)Bi). New and efficient carbon-carbon bond forming reactions, carbon-heteroatom bond forming reactions, alcohol oxidation, and photoinduced cationic polymerization have been investigated using these reagents. In all these reactions, the good leaving ability as well as the high nucleofugality of the triarylbismuthonio group plays a crucial role in bond-forming and bond-breaking steps. PMID- 21607846 TI - Response to low-dose oral capecitabine monotherapy in an elderly frail patient with metastatic breast carcinoma and impaired renal function: documentation by fluorodeoxyglucose positron emission tomography. PMID- 21607848 TI - Integrated microfluidic systems for DNA analysis. AB - The potential utility of genome-related research in terms of evolving basic discoveries in biology has generated widespread use of DNA diagnostics and DNA forensics and driven the accelerated development of fully integrated microfluidic systems for genome processing. To produce a microsystem with favorable performance characteristics for genetic-based analyses, several key operational elements must be strategically chosen, including device substrate material, temperature control, fluidic control, and reaction product readout. As a matter of definition, a microdevice is a chip that performs a single processing step, for example microchip electrophoresis. Several microdevices can be integrated to a single wafer, or combined on a control board as separate devices to form a microsystem. A microsystem is defined as a chip composed of at least two microdevices. Among the many documented analytical microdevices, those focused on the ability to perform the polymerase chain reaction (PCR) have been reported extensively due to the importance of this processing step in most genetic-based assays. Other microdevices that have been detailed in the literature include those for solid-phase extractions, microchip electrophoresis, and devices composed of DNA microarrays used for interrogating DNA primary structure. Great progress has also been made in the areas of chip fabrication, bonding and sealing to enclose fluidic networks, evaluation of different chip substrate materials, surface chemistries, and the architecture of reaction conduits for basic processing steps such as mixing. Other important elements that have been developed to realize functional systems include miniaturized readout formats comprising optical or electrochemical transduction and interconnect technologies. These discoveries have led to the development of fully autonomous and functional integrated systems for genome processing that can supply "sample in/answer out" capabilities. In this chapter, we focus on microfluidic systems that are composed of two or more microdevices directed toward DNA analyses. Our discussions will primarily be focused on the integration of various processing steps with microcapillary electrophoresis (MUCE) or microarrays. The advantages afforded by fully integrated microfluidic systems to enable challenging applications, such as single-copy DNA sequencing, single-cell gene expression analysis, pathogen detection, and forensic DNA analysis in formats that provide high throughput and point-of-analysis capabilities will be discussed as well. PMID- 21607849 TI - Inducible expression of G protein-coupled receptors in transfected cells. AB - Biochemical or pharmacological studies of G protein-coupled receptors (GPCRs) are widely conducted in transfected mammalian cells. A variety of commercially available systems allow the generation of stable cell-lines in which expression of the recombinant receptor can be induced on addition of a defined chemical to the culture medium, which operates as a control switch for the transcription of the cloned sequence. Such systems offer the possibility to induce graded levels of receptor expression in the experimental model, or to induce an abrupt downregulation of receptor expression during the maintenance of the cell-line. This chapter provides an overview of the different systems available and provides methods for the generation and validation of stably transfected cell-lines expressing the GPCR of choice. PMID- 21607850 TI - Using the Flp-InTM T-RexTM system to regulate GPCR expression. AB - The development of a cell-based system that allows the integration of a gene of interest (GOI), such as a G protein-coupled receptor (GPCR), into a specific site on the genome, has made the generation of mammalian cell lines able to express such proteins easy and efficient. Flp-InTM stable cell lines are isogenic and hence protein expression is constant across a population of cells. A useful addition to the Flp-InTM system (Flp-InTM T-RexTM) allows this expression to be controlled by the addition of a small molecule inducer to the cell culture medium. Stable cell lines generated as described here can be used to great advantage in the study of receptor pharmacology signalling and oligomerisation. PMID- 21607851 TI - Viral infection for GPCR expression in eukaryotic cells. AB - This chapter describes the protocol for the preparation of recombinant adenoviruses and infection of target cells to transiently express G protein coupled receptors (GPCRs) or other proteins of interest. Adenoviruses are non enveloped viruses containing a linear double-stranded DNA genome. Their life cycle does not normally involve integration into the host genome, rather they replicate as episomal -elements in the nucleus of the host cell, and consequently there is no risk of insertional mutagenesis. Up to 30 kb out of the 35 kb of the wild-type adenovirus genome can be replaced by foreign DNA. Adenoviral vectors are very efficient in transducing target cells in vitro and in vivo and can be produced at high titers (>1011/mL). The viral infection has a number of useful features: (1) the efficiency of gene transduction is very high (up to 100% in sensitive cells); (2) the infection is easy and does not physically alter the cell membrane for gene transduction; (3) it is possible to infect cells that are resistant to transfection with plasmids (including nondividing cells); and (4) the viral vectors can be used for infection in vivo (including gene therapy) and can potentially be targeted cell-specifically. PMID- 21607852 TI - Generation of epitope-tagged GPCRs. AB - The addition of one or more epitope tags to G-protein-coupled receptors (GPCRs) has facilitated a wide variety of studies on their structure and function. Epitope-tagging is achieved using relatively straightforward molecular techniques but requires careful consideration about the nature of the epitope tag and its location within the receptor. Here, we describe both the strategies and methodologies for the generation of epitope-tagged GPCRs. We highlight a range of possible techniques that depend upon the available starting material, the nature of the epitope to be incorporated, and suggest a strategy to ease the tagging of multiple receptor types. PMID- 21607853 TI - The use of site-directed mutagenesis to study GPCRs. AB - G protein coupled receptors (GPCRs) are highly flexible and dynamic proteins, which are able to interact with diverse ligands, effectors, and regulatory proteins. Site-directed mutagenesis (SDM) is a powerful tool for providing insight into how these proteins actually work, both in its own right and when used in conjunction with information provided by other techniques such as crystallography or molecular modelling. Mutagenesis has been used to identify and characterise a myriad of functionally important residues, motifs and domains within the GPCR architecture, and to identify aspects of similarity and differences between the major families of GPCRs. This chapter presents the necessary information for undertaking informative SDM of these proteins. Whilst this is relevant to protein structure/function studies in -general, specific pitfalls and protocols suited to investigating GPCRs in particular will be highlighted. PMID- 21607854 TI - Approaches to study GPCR regulation in native systems. AB - The ability to assess whether individual proteins are involved in the signalling or regulation of G -protein-coupled receptor signalling is highly dependent on the pharmacological tools available. In the absence of appropriate pharmacological agents, alternative molecular approaches have been developed to alter either protein function or expression. This has included the use of mutants, for example catalytically inactive (kinase-dead) enzymes, which when overexpressed function as dominant negatives to inhibit endogenous enzyme function, and more latterly small (21-23 bp) interfering RNA dsRNA oligos, whose antisense strand is designed complementary to the target protein mRNA and which can be used to deplete target protein expression. Critically, the success of these approaches depends on the transfection efficiency, and the chosen experimental assay in the cell type studied. Therefore, three transfection techniques and their merits and drawbacks are described. In addition, one method of examining G protein-coupled receptor (GPCR) regulation, combining siRNA mediated GRK depletion and imaging of fluorescent GPCR -signalling reporter biosensors in difficult-to-transfect cells is briefly described. PMID- 21607855 TI - Heterologous expression of GPCRs in fission yeast. AB - In this chapter, we describe methods to heterologously express G protein-coupled receptors (GPCRs) in the fission yeast Schizosaccharomyces (Sz.) pombe. GPCRs regulate a diverse range of biological processes in all eukaryotic cells, including plants, insects, humans, and yeast. The high degree of conservation between GPCRs from different organisms has facilitated the development of a large number of model systems to enable study of this pharmaceutically important family of cell-surface receptors. Of the many model systems available for investigating GPCRs, yeast have proven to be one of the more attractive. Yeasts' amenability to both genetic and biochemical manipulation, a reduced number of endogenous GPCRs and their relative low culturing costs has facilitated their use in many high throughput drug screens. Given the high number of detailed methods relating to the expression of GPCRs within budding yeast, we have focused our attention on the use of fission yeast as a model system. We describe the methods used and provide examples from our own experiences of expressing a number of human GPCRs in Sz. pombe cells. PMID- 21607856 TI - Radioligand binding methods for membrane preparations and intact cells. AB - The radioligand binding assay is a relatively simple but powerful tool for studying G protein-coupled receptors. There are three basic types of radioligand binding experiments: (1) saturation experiments from which the affinity of the radioligand for the receptor and the binding site density can be determined; (2) inhibition experiments from which the affinity of a competing, unlabeled compound for the receptor can be determined; and (3) kinetic experiments from which the forward and reverse rate constants for radioligand binding can be determined. Detailed methods for typical radioligand binding assays for G protein-coupled receptors in membranes and intact cells are presented for these types of experiments. Detailed procedures for analysis of the data obtained from these experiments are also given. PMID- 21607857 TI - Quantification of GPCR mRNA using real-time RT-PCR. AB - Characterisation of G-protein-coupled receptor (GPCR) mRNA expression under normal, different pharmacological and pathological conditions in experimental animal models and human tissue biopsies by quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) is a valuable approach to understand the regulation of GPCR expression. RT-qPCR is specific and sensitive with a broad dynamic range, which allows precise quantification of mRNA species of interest. In addition to measuring the relative levels of mRNA in a tissue or changes in expression levels between groups of genes of interest, RT-qPCR is also used to identify splice variants and single nucleotide polymorphisms (SNPs) of GPCRs. Even though RT-qPCR has become the standard method for quantification of gene expression, RT-qPCR is sensitive to RNA quality, assay design, normalisation approach and data analysis. This protocol is meant as a guide to RT-qPCR methodology with references to the best standard methods available at present. PMID- 21607858 TI - Determining allosteric modulator mechanism of action: integration of radioligand binding and functional assay data. AB - The drive to produce safer and more receptor subtype selective drugs has sparked a renewed interest in allosteric modulators of G protein-coupled receptors. The increasing use of functional assays has shown that allosteric ligands are capable of modulating both orthosteric agonist affinity and efficacy, as well as mediating receptor activation in their own right. Such a complex range of behaviours can be difficult to discern from single datasets; this chapter seeks to explain how to use radioligand binding and functional assay datasets in concert to elucidate allosteric modulator mechanism of action. PMID- 21607859 TI - Design and use of fluorescent ligands to study ligand-receptor interactions in single living cells. AB - The interaction of ligands with G protein-coupled receptors (GPCRs) has been traditionally studied using radiolabelled variants of receptor ligands. More recently, increased knowledge about the way in which GPCRs exist in a highly organised membrane environment has led to an interest in investigating receptor ligand interactions in single cells. In addition, substantial improvements in imaging technology and an increase in the expense of radioactive waste disposal have resulted in an expansion in the use of fluorescent technologies. One major requirement for these methods is a suitable fluorescent ligand for the receptor of interest. The design of fluorescent ligands for GPCRs is complex, and has to take into account their pharmacological, photophysical, and also physicochemical properties. Here, we describe some basic considerations in the design of fluorescent GPCR ligands, including choice of pharmacological template, linker, and fluorophore. In addition, we describe basic protocols for determining the photophysical properties of the ligand and determining the cellular localisation of their interaction with the target receptors. Finally, we provide a basic protocol for using fluorescent GPCR ligands to quantify the number and diffusion of receptor-ligand complexes in small areas of the cell membrane. PMID- 21607860 TI - Examining site-specific GPCR phosphorylation. AB - Phosphorylation of G protein-coupled receptors (GPCRs) is one of the most prominent post-translation modifications mediated by agonist stimulation. This process has been shown to result not only in receptor desensitisation but also, via the recruitment of arrestin adaptor proteins, to promote receptor coupling to numerous signalling pathways. Furthermore, there is now a growing body of evidence suggesting that GPCRs may employ phosphorylation as a mechanism to regulate their cell-type-specific signalling, hence generating tissue-specific functions. These advances have resulted partly from improved methods used in the determination of phospho-acceptor sites on GPCRs and improved analysis of the consequences of phosphorylation. This chapter aims to describe the methods used in our laboratory for the investigation of site-specific phosphorylation of the M3-muscarinic receptor. These methods could easily be applied in the study of other receptors. PMID- 21607861 TI - Ubiquitination of GPCRs. AB - In this chapter, we describe a method for detecting the ubiquitination status of G protein-coupled receptors (GPCRs). This involves co-expression of a GPCR with an epitope-tagged ubiquitin construct in a -heterologous mammalian expression system. Stimulus-dependent modification of the GPCR by -ubiquitin is detected by immunoprecipitation and subsequent immunoblotting to detect incorporation of the epitope-tagged ubiquitin. We describe here a well-established protocol to detect ubiquitination of the chemokine receptor CXCR4, which can be easily applied to detect the ubiquitination status of other GPCRs. PMID- 21607862 TI - [35S]GTPgammaS binding as an index of total G-protein and Galpha-subtype-specific activation by GPCRs. AB - On activation, G-protein-coupled receptors (GPCRs) exert many of their cellular actions through -promoting guanine nucleotide exchange on Galpha subunits of heterotrimeric G proteins to release Galpha-GTP and free betagamma-subunits. In membrane preparations, GTP can be substituted by 35S-labeled guanosine- 5'-O-(3 thio)triphosphate ([35S]GTPgammaS) and on agonist stimulation a quasi-stable [35S]GTPgammaS-Galpha -complex forms and accumulates. Separation of [35S]GTPgammaS-Galpha complexes from free [35S]GTPgammaS allows differences between basal and agonist-stimulated rates of [35S]GTPgammaS-Galpha complex formation- to be used to obtain pharmacological information on receptor-G-protein information transfer. Further, by releasing Galpha-subunits into solution following the [35S]GTPgammaS binding step, Galpha-subunit-specific antibodies can be used to investigate the Galpha-protein subpopulations activated by receptors by immunoprecipitation of [35S]GTPgammaS-Galpha complexes and quantification by scintillation counting. Here, we describe a total [35S]GTPgammaS binding assay and a modification of this method that incorporates a Galpha-specific immunoprecipitation step. PMID- 21607863 TI - Using calcium imaging as a readout of GPCR activation. AB - Monitoring cellular calcium concentration using fluorescent reporters can provide a rapid, proportional assay of G-protein-coupled receptor activation. Recording calcium changes in single cells, or cell populations, is relatively straightforward, but requires careful deliberation regarding the appropriate calcium reporter and experimental approach. Here, we describe strategies to ensure that calcium changes are recorded with good fidelity and minimal invasiveness. We highlight a range of issues that need to be considered within the design of an experiment to measure cellular calcium, and suggest strategies to avoid common pit-falls. PMID- 21607864 TI - Measuring spatiotemporal dynamics of cyclic AMP signaling in real-time using FRET based biosensors. AB - Cyclic AMP governs many fundamental signaling events in eukaryotic cells. Although cAMP signaling has been a major research focus for a long time, recent technological developments are revealing novel aspects of this paradigmatic pathway. In this chapter, we give an overview over current fluorescence resonance energy transfer (FRET)-based sensors for detection of cAMP dynamics, and their application in monitoring local, compartmentalized cAMP signals within living cells. A basic step-by-step protocol is given for conducting a FRET experiment in primary cells with a unimolecular cAMP sensor, which can easily be adapted to a user's specific requirements. PMID- 21607865 TI - Determining the activation of rho as an index of receptor coupling to G12/13 proteins. AB - Heterotrimeric G proteins are composed of alpha, beta, and gamma subunits. G proteins can be activated by a large number of cell-surface hepathelical receptors and can transduce signals from these receptors to various intracellular signaling molecules. When G protein-coupled receptors are bound by their cognate ligand, interaction with specific subtypes of G protein leads to dissociation of the alpha subunit of the heterotrimeric G protein from the betagamma dimer, and both Galpha-GTP and Gbetagamma are capable of initiating their own signal transduction pathways. G proteins are functionally divided into four groups based on the nature of alpha subunit into G(s), G(i), G(q), and G12 families. The members of the G12 subfamily are G12 and G13. Increasing evidence indicates that G12/13 proteins play critical roles in various physiological functions. G12 and G13 regulate the small GTPase Rho through modulation of guanine nucleotide exchange factor (RhoGEF) activity to regulate various cellular responses, such as cytoskeletal changes and cell growth. Therefore, Rho activity can often represent a sensitive marker of G12/13 activity. Here, we describe the Rho activation assay to monitor the activity of G12/13 proteins. PMID- 21607866 TI - The use of translocating fluorescent biosensors for real-time monitoring of GPCR mediated signaling events. AB - The ability to visualize the subcellular localization of proteins by labeling them with fluorescent proteins is a powerful tool in cell biology. In the G protein-coupled receptor signaling field, this technique has been utilized to examine the various aspects of receptor behavior, including activation, internalization and recycling, as well as alterations in the cellular levels of a variety of second messengers and signaling intermediates. Attaching variants of green fluorescent protein on to protein modules, which possess high affinity and selectivity for specific signaling molecules has allowed the visualization of key signaling pathway intermediates in real time, in living cells. This chapter outlines a protocol for the expression and visualization (by confocal microscopy) of such fluorescent "biosensors" and provides guidance on the analysis and interpretation of data obtained from such experiments. PMID- 21607867 TI - Study of GPCR-protein interactions using gel overlay assays and glutathione-S transferase-fusion protein pull-downs. AB - Numerous recent studies have suggested that the predicted cytosolic domains of G protein-coupled receptors represent a surface for association with proteins that may serve multiple roles in receptor localization, turnover, and signaling beyond the well-characterized interactions of these receptors with heterotrimeric G proteins. This Chapter describes two in vitro methods for ascertaining interactions between G protein-coupled receptors and various binding partners: gel overlay strategies and GST-fusion protein pull-downs. PMID- 21607868 TI - Study of GPCR-protein interactions by BRET. AB - Bioluminescence resonance energy transfer (BRET) has become an extremely valuable technology for the real-time study of protein-protein interactions in live cells. This technique is highly amenable to the monitoring of G protein-coupled receptor (GPCR)-protein interactions, especially involving scaffolding, regulatory and signaling proteins, such as beta-arrestins, which are now known to have significant roles in addition to receptor desensitization. The BRET procedure utilizes heterologous coexpression of fusion proteins linking one protein of interest (e.g. a GPCR) to a bioluminescent donor enzyme, a variant of Renilla luciferase, and a second protein of interest (e.g. beta-arrestin) to an acceptor fluorophore. If in close proximity, energy resulting from the rapid oxidation of a cell-permeable coelenterazine substrate by the donor will transfer to the acceptor, which in turn fluoresces at a longer characteristic wavelength. Therefore, the occurrence of such energy transfer implies that the proteins of interest fused to the donor and acceptor interact directly or as part of a complex. BRET detection can be carried out using scanning spectrometry or dual filter luminometry. The latest improvements in BRET methodology have enabled live cell drug screening as well as monitoring of previously undetectable protein protein complexes, including constitutive GPCR/beta-arrestin interactions. Therefore, BRET is likely to play an increasingly important role in GPCR research and drug discovery over the coming years. PMID- 21607869 TI - Time resolved FRET strategy with fluorescent ligands to analyze receptor interactions in native tissues: application to GPCR oligomerization. AB - G protein-coupled receptors (GPCRs) play a key role in the regulation of physiological functions. Deregulation of their activities often results in pathological disorders and therefore these receptors constitute major targets for drug development. The emergence of new concepts such as GPCR oligomerization has modified our understanding of these proteins, and identifying the role of receptor complexes is probably a major challenge for the next decade. Various experimental strategies have been developed to study GPCR oligomers and energy transfer experiments between partners within a complex constitute one of the most convenient approaches. These experimental strategies usually require receptor fusion to tags or fluorescent or luminescent proteins and therefore cannot be easily applied to native tissues. We developed a new experimental approach based on the labeling of receptors with high affinity fluorescent ligands compatible with time-resolved energy transfer measurements. Because of the very high signal to-noise ratio of the time-resolved fluorescent energy transfer (TR-FRET) signals, this approach constitutes a breakthrough since it allows the direct identification of wild-type GPCR oligomers in native tissues. PMID- 21607870 TI - Peptide affinity purification for the isolation and identification of GPCR associated protein complexes. AB - Protein networks and their dynamic regulation play a fundamental role in biological systems. Seven transmembrane-spanning G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors controlling the flow of information from the extracellular environment into cells by inducing intracellular signaling pathways. Several GPCR-associated protein complexes (GAPCs), particularly those binding to the intracellular carboxyl-terminus (C terminus), have been identified over the last 20 years. Recent optimizations in purification protocols and advances in mass spectrometry-based protein identification techniques have considerably accelerated the identification of GAPCs. We will concentrate here on a description of the latest version of the peptide affinity purification approach dedicated to the purification of GAPCs interacting with GPCR C-termini or any other soluble receptor subdomain. PMID- 21607871 TI - Tandem affinity purification and identification of GPCR-associated protein complexes. AB - The first tandem affinity purification (TAP) protocol was described in 1999. Originally designed for the purification of protein complexes in yeast RNA splicing, its application rapidly expanded towards whole proteome analysis in yeast and mammalian cells. More recently, TAP has been applied to the purification of G protein-coupled receptor (GPCR)-associated protein complexes (GAPCs). This approach is particularly attractive for GPCRs, as the native, seven transmembrane structure is used as bait to purify GAPCs from mammalian cells expressing receptors at physiological levels. Here, a detailed protocol of the TAP method applied to GPCRs is presented. PMID- 21607872 TI - Identification of GPCR localization in detergent resistant membranes. AB - Lipid domains of the plasma membrane were originally described as a cell matrix insoluble in cold -nonionic detergents and enriched in glycosphingolipids. Because of these biochemical properties, these membrane domains were termed detergent-resistant membranes (DRMs) or detergent-insoluble -glycolipid-enriched (DIG) membranes. Membrane rafts and caveolae are two types of lipid domains that share these properties, as well as structural/functional dependence on membrane cholesterol. Membrane rafts and caveolae are believed to act as signaling platforms for ligand-activated receptors, thereby contributing to the regulation of receptor function. Here we describe a simple method to assess the association of GPCRs with detergent resistant membranes in native brain tissue and cultured cells. PMID- 21607873 TI - Analysis of GPCR localization and trafficking. AB - Localization and trafficking of G protein-coupled receptors (GPCRs) is increasingly recognized to play a fundamental role in receptor-mediated signaling and its regulation. Individual receptors, including closely homologous subtypes with otherwise similar functional properties, can differ considerably in their membrane trafficking properties. In this chapter, we describe several approaches for experimentally assessing the subcellular localization and trafficking of selected GPCRs. Firstly, we describe a flexible method for receptor localization using fluorescence microscopy. We then describe two complementary approaches, using fluorescence flow cytometry and surface biotinylation, for examining receptor internalization and trafficking in the endocytic pathway. PMID- 21607874 TI - Statistical methods in research. AB - Statistical methods appropriate in research are described with examples. Topics covered include the choice of appropriate averages and measures of dispersion to summarize data sets, and the choice of tests of significance, including t-tests and a one- and a two-way ANOVA plus post-tests for normally distributed (Gaussian) data and their non-parametric equivalents. Techniques for transforming non-normally distributed data to more Gaussian distributions are discussed. Concepts of statistical power, errors and the use of these in determining the optimal size of experiments are considered. Statistical aspects of linear and non linear regression are discussed, including tests for goodness-of-fit to the chosen model and methods for comparing fitted lines and curves. PMID- 21607875 TI - Antimuscarinic drugs: review of the cognitive impact when used to treat overactive bladder in elderly patients. AB - The blockade of muscarinic receptors in the management of overactive bladder (OAB) symptoms provides beneficial as well as adverse effects. The cognitive changes observed are caused by the drugs' ability to cross the blood-brain barrier and bind to muscarinic receptors within the central nervous system (CNS). To date, while not specifically testing for CNS side effects, most of the controlled efficacy trials of multiple OAB medications have not shown significant adverse effects on cognitive function. However, elderly individuals, in whom OAB is more prevalent, often are excluded from these studies. The few trials that have performed cognitive testing in healthy elderly people taking antimuscarinics have clearly shown that oxybutynin can adversely affect cognition. Darifenacin, trospium, solifenacin, and tolterodine appear to have little to no risk of causing CNS side effects in this population. However, caution needs to be used in elderly patients with preexisting dementia. PMID- 21607876 TI - Beetle (Coleoptera: Scirtidae) facilitation of larval mosquito growth in tree hole habitats is linked to multitrophic microbial interactions. AB - Container-breeding mosquitoes, such as Aedes triseriatus, ingest biofilms and filter water column microorganisms directly to obtain the bulk of their nutrition. Scirtid beetles often co-occur with A. triseriatus and may facilitate the production of mosquito adults under low-resource conditions. Using molecular genetic techniques and quantitative assays, we observed changes in the dynamics and composition of bacterial and fungal communities present on leaf detritus and in the water column when scirtid beetles co-occur with A. triseriatus. Data from terminal restriction fragment polymorphism analysis indicated scirtid presence alters the structure of fungal communities in the water column but not leaf associated fungal communities. Similar changes in leaf and water bacterial communities occurred in response to mosquito presence. In addition, we observed increased processing of leaf detritus, higher leaf-associated enzyme activity, higher bacterial productivity, and higher leaf-associated fungal biomass when scirtid beetles were present. Such shifts suggest beetle feeding facilitates mosquito production indirectly through the microbial community rather than directly through an increase in available fine particulate organic matter. PMID- 21607877 TI - Effects of propofol on P2X7 receptors and the secretion of tumor necrosis factor alpha in cultured astrocytes. AB - Upon CNS injury, adenosine-5'-triphosphate is released and acts on P2X7 receptors, which might influence many cytokines secretion from glial cells and, in turn, affects the survival of neurons. Propofol, an intravenous anesthetic, has been shown to provide neuroprotective effect. However, the effect of propofol on astrocyte-associated processes remains to be clarified. In this study, we investigated the effects of propofol on P2X7 activity in astrocytes and tumor necrosis factor-alpha (TNF-alpha) secretion from these cells and thereby to infer the possible role(s) of glial P2X7 receptors in propofol neural protective effects. Whole-cell patch clamp results showed that in clinically relevant concentrations (3.3, 10 or 33 MUM), propofol increased the P2X7 current amplitudes significantly and propofol in 10 MUM extended the inactivation times of P2X7 receptors. Enzyme-linked immunosorbent assay showed that propofol increased the secretion of TNF-alpha from astrocytes in high concentration (300 MUM), while inhibited in clinically relevant concentration (10 MUM). Both of these effects were not influenced by Brilliant blue G. These results suggest that in clinically relevant concentrations, propofol increases the activity of P2X7 receptors in activated astrocytes, but this does not contribute to the downregulation of the secretion of TNF-alpha. PMID- 21607878 TI - Hyperoxaluria-induced tubular ischemia: the effects of verapamil and vitamin E on apoptotic changes with an emphasis on renal papilla in rat model. AB - An experimental study in rats was performed to evaluate the presence and the degree of both tubular apoptotic changes and crystallization at cortical, medullar and papillary regions of the kidney during hyperoxaluric phase and assess the possible protective effects of vitamin E and verapamil on these pathologic changes (particularly in papillary part of the affected kidneys). A total of 32 rats have been included into the study program. Hyperoxaluria was induced by continuous administration of ethylene glycol (0.75%). In addition to hyperoxaluria induction, animals in Groups 2 and 3 did receive a calcium channel blocking agent (verapamil) and vitamin E, respectively. Histologic alterations of the kidneys including crystal formation together with apoptotic changes were evaluated on days 1, 14 and 28, respectively. Both apoptotic changes and the presence and degree of crystallization were assessed separately in renal cortical region, medulla and particularly papillary parts of the removed kidneys. Although verapamil did well limit the degree of crystal formation and apoptosis and brought it to the same levels observed in control group animals in all parts of the kidneys during intermediate phase, addition of vitamin E was failed to show the same protective effect during both intermediate and late phase evaluations. As demonstrated in our study, the limitation of both crystal deposition and apoptotic changes might be instituted by calcium channel-blocking agents. Clinical application of such agents in the prophylaxis of stone disease might limit the formation of urinary calculi, especially in recurrent stone formers. PMID- 21607880 TI - "All You Need is Holt"-is the socio-cultural phenomenon a problem for a neorealist ecological psychology? AB - The aim of this paper is to discuss Charles's (2011) attempt to turn E.B. Holt's theoretical approach into the only possible bridge to connect Gibsonian ecological psychology with social psychology. Criticism of Charles's claims is carried out at four different conceptual levels: historiographical, logico epistemological, methodological, and theoretical. From this critical perspective, Charles's resort to Holt's ideas is viewed as an effort to legitimate Charles's own line of work. Moreover, far from being this the only possible approach to the subject, many other rich alternatives to the application of Gibsonian principles to the explanation of socio-cultural phenomena already exist. In fact, it is questionable whether Holt's behavioral neorealism allows dealing with many of the most complex socio-cultural issues, particularly those related to purposive behavior and intersubjective contexts. In order to address these questions from a Holtian point of view, Charles is forced to make a number of argumentative leaps and epistemological transgressions. In the last analysis, his insistence on keeping to the Holtian stance leads him to lose sight of the Gibsonian framework and to modify the very nature of his object of study, the social phenomenon which, along the lines of classic neorealist behaviorism, becomes reduced to a simple consideration of behavioral purposiveness. PMID- 21607879 TI - UCP4 overexpression improves fatty acid oxidation and insulin sensitivity in L6 myocytes. AB - Obesity, which is caused by energy uptake being greater than energy expenditure, is widely prevalent today. Currently, only a limited number of efficient interventional strategies are available for the prevention of obesity. Previous studies have shown that UCP4 transcription occurs at a considerable level in mouse skeletal muscle; however, the exact functions of UCP4 remain unclear. In this study, we investigated the effect of UCP4 on mitochondrial function and insulin sensitivity in mature L6 myocytes. UCP4 overexpression in L6 myocytes induced increased mitochondrial carnitine palmitoyltransferase 1A (CPT1A) and decreased citrate synthase (CS) mRNA in the basal condition (i.e., in the absence of insulin). UCP4 overexpression significantly improved insulin sensitivity, increased tyrosine phosphorylation of IRS-1 in the presence of insulin, and significantly reduced intracellular triglyceride (TG). Additionally, intracellular ATP content and mitochondrial membrane potential were downregulated. We also observed that intracellular ROS, mitochondrial morphology, and mitochondrial mtDNA copy number were maintained upon UCP4 expression, with no change in mitochondrial fusion and fission. In summary, our findings provide evidence to show that UCP4 overexpression reduced the insulin sensitivity and mitochondrial fatty acid oxidation of L6 myocytes. These findings support the notion that UCPs are ideal targets for treatment of insulin resistance. PMID- 21607881 TI - Cardiac repair with allogeneic mesenchymal stem cells after myocardial infarction. AB - Over the past decade, use of autologous bone marrow-derived mononuclear cells (BMCs) has proven to be safe in phase-I/II studies in patients with myocardial infarction (MI). Taken as a whole, results support a modest yet significant improvement in cardiac function in cell-treated patients. Skeletal myoblasts, adipose-derived stem cells, and bone marrow-derived mesenchymal stem cells (MSCs) have also been tested in clinical studies. MSCs expand rapidly in vitro and have a potential for multilineage differentiation. However, their regenerative capacity decreases with aging, limiting efficacy in old patients. Allogeneic MSCs offer several advantages over autologous BMCs; however, immune rejection of allogeneic cells remains a key issue. As human MSCs do not express the human leukocyte antigen (HLA) class II under normal conditions, and because they modulate T-cell-mediated responses, it has been proposed that allogeneic MSCs may escape immunosurveillance. However, recent data suggest that allogeneic MSCs may switch immune states in vivo to express HLA class II, present alloantigen and induce immune rejection. Allogeneic MSCs, unlike syngeneic ones, were eliminated from rat hearts by 5 weeks, with a loss of functional benefit. Allogeneic MSCs have also been tested in initial clinical studies in cardiology patients. Intravenous allogeneic MSC infusion has proven to be safe in a phase-I trial in patients with acute MI. Endoventricular allogeneic MSC injection has been associated with reduced adverse cardiac events in a phase-II trial in patients with chronic heart failure. The long-term safety and efficacy of allogeneic MSCs for cardiac repair remain to be established. Ongoing phase-II trials are addressing these issues. PMID- 21607882 TI - Novel diagnostic and therapeutic approaches to malignant glioma. AB - Glioblastomas (World Health Organisation (WHO) grade IV) and anaplastic gliomas (astrocytomas, oligoastrocytomas, oligodendrogliomas) (WHO grade III) are collectively referred to as malignant gliomas. The diagnosis of malignant glioma may be suspected based on clinical history and neuroimaging findings, but histological confirmation remains the diagnostic "gold standard". Molecular markers such as 1p/19q codeletion and isocitrate dehydrogenase (IDH) mutation provide important diagnostic and prognostic information. O methylguanylmethyltransferase (MGMT) promoter methylation is another favourable prognostic marker and predicts benefit from alkylating agent chemotherapy in glioblastoma. Additionally, the extent of neurosurgical resection is a prognostic factor. Radiotherapy of the involved brain region or chemotherapy using the alkylating agent, temozolomide, are common therapeutic options for patients with anaplastic glioma. In contrast, temozolomide plus radiotherapy is the standard of care for most patients with glioblastoma. The increasing population of elderly patients with glioblastoma represents a particular challenge, with surgery followed by radiotherapy as the standard of care. Contemporary clinical studies focus on the role of angiogenesis. Specifically, pivotal phase III studies exploring the antibody to vascular endothelial growth factor (VEGF), bevacizumab, and the alphavbeta3/5 antagonist, cilengitide, in the management of newly diagnosed glioblastoma have completed enrolment. Moreover, a broad spectrum of other experimental treatment approaches, including immunotherapy with vaccines against glioma-associated antigens, are currently being explored in phase I/II clinical trials. PMID- 21607883 TI - Disequilibrium in the mind, disharmony in the body. AB - Although it is generally acknowledged that experiences of frustration, confusion, and anxiety are embodied phenomena, very little is known about how these processes modulate presumably unconscious, but constantly present, subtle bodily movement. We addressed this problem by tracking the low-level dynamics of body movement, using 1/f noise, pink noise, or "fractal scaling", during naturalistic experiences of affect in two studies involving deep learning and effortful problem-solving. Our results indicate that body movement fluctuations of individuals experiencing cognitive equilibrium was characteristic of correlated pink noise, but there was a whitening of the signal when participants experienced states that are diagnostic of cognitive distress such as anxiety, confusion, and frustration. We orient our findings within theories that emphasise the embodied nature of cognition and affect and with perspectives that view affective and cognitive processes as emergent products of a self-organising dynamical system (the brain) that is inextricably coupled to the body. PMID- 21607884 TI - Is the Charcot and Bernard case (1883) of loss of visual imagery really based on neurological impairment? AB - INTRODUCTION. The Charcot and Bernard case of visual imagery, Monsieur X, is a classic case in the history of neuropsychology. Published in 1883, it has been considered the first case of visual imagery loss due to brain injury. Also in recent times a neurological valence has been given to it. However, the presence of analogous cases of loss of visual imagery in the psychiatric field have led us to hypothesise functional origins rather than organic. METHODS. In order to assess the validity of such an inference, we have compared the symptomatology of Monsieur X with that found in cases of loss of visual mental images, both psychiatric and neurological, presented in literature. RESULTS. The clinical findings show strong assonances of the Monsieur X case with the symptoms manifested over time by the patients with functionally based loss of visual imagery. CONCLUSION. Although Monsieur X's damage was initially interpreted as neurological, reports of similar symptoms in the psychiatric field lead us to postulate a functional cause for his impairment as well. PMID- 21607885 TI - Estimating joint kinematics from skin motion observation: modelling and validation. AB - Modelling of soft tissue motion is required in many areas, such as computer animation, surgical simulation, 3D motion analysis and gait analysis. In this paper, we will focus on the use of modelling of skin deformation during 3D motion analysis. The most frequently used method in 3D human motion analysis involves placing markers on the skin of the analysed segment which is composed of the rigid bone and the surrounding soft tissues. Skin and soft tissue deformations introduce a significant artefact which strongly influences the resulting bone position, orientation and joint kinematics. For this study, we used a statistical solid dynamics approach which is a combination of several previously reported tools: the point cluster technique (PCT) and a Kalman filter which was added to the PCT. The methods were tested and evaluated on controlled human-arm motions, using an optical motion capture system (Vicon(TM)). The addition of a Kalman filter to the PCT for rigid body motion estimation results in a smoother signal that better represents the joint motion. Calculations indicate less signal distortion than when using a digital low-pass filter. Furthermore, adding a Kalman filter to the PCT substantially reduces the dispersion of the maximal and minimal instantaneous frequencies. For controlled human movements, the result indicated that adding a Kalman filter to the PCT produced a more accurate signal. However, it could not be concluded that the proposed Kalman filter is better than a low-pass filter for estimation of the motion. We suggest that implementation of a Kalman filter with a better biomechanical motion model will be more likely to improve the results. PMID- 21607886 TI - Development of software for human muscle force estimation. AB - Muscle force estimation (MFE) has become more and more important in exploring principles of pathological movement, studying functions of artificial muscles, making surgery plan for artificial joint replacement, improving the biomechanical effects of treatments and so on. At present, existing software are complex for professionals, so we have developed a new software named as concise MFE (CMFE). CMFE which provides us a platform to analyse muscle force in various actions includes two MFE methods (static optimisation method and electromyographic-based method). Common features between these two methods have been found and used to improve CMFE. A case studying the major muscles of lower limb of a healthy subject walking at normal speed has been presented. The results are well explained from the effect of the motion produced by muscles during movement. The development of this software can improve the accuracy of the motion simulations and can provide a more extensive and deeper insight in to muscle study. PMID- 21607888 TI - Numerical simulation of cross-country skiing. AB - A program for numerical simulation of a whole ski race, from start to finish, is developed in MATLAB. The track is modelled by a set of cubical splines in two dimensions and can be used to simulate a track in a closed loop or with the start and finish at different locations. The forces considered in the simulations are gravitational force, normal force between snow and skis, drag force from the wind, frictional force between snow and ski and driving force from the skier. The differential equations of motion are solved from start to finish with the Runge Kutta method. Different wind situations during the race can be modelled, as well as different glide conditions on different parts of the track. It is also possible to vary the available power during the race. The simulation program's output is the total time of the race, together with the forces and speed during different parts of the race and intermediate times at selected points. Some preliminary simulations are also presented. PMID- 21607887 TI - Biomechanical effect after Coflex and Coflex rivet implantation for segmental instability at surgical and adjacent segments: a finite element analysis. AB - The Coflex device may provide stability to the surgical segment in extension but does not restore stability in other motion. Recently, a modified version called the Coflex rivet has been developed. The effects of Coflex and Coflex rivet implantation on the adjacent segments are still not clear; therefore, the purpose of this study was to investigate the biomechanical differences between Coflex and Coflex rivet implantation by using finite element analyses. The results show that the Coflex implantation can provide stability in extension, lateral bending, and axial rotation at the surgical segment, and it had no influence at adjacent segments except for extension. The Coflex rivet implantation can provide stability in all motions and reduce disc annulus stress at the surgical segment. Therefore, the higher range of motion and stress induced by the Coflex rivet at both adjacent discs may result in adjacent segment degeneration in flexion and extension. PMID- 21607890 TI - The non-linear response of a muscle in transverse compression: assessment of geometry influence using a finite element model. AB - Most recent finite element models that represent muscles are generic or subject specific models that use complex, constitutive laws. Identification of the parameters of such complex, constitutive laws could be an important limit for subject-specific approaches. The aim of this study was to assess the possibility of modelling muscle behaviour in compression with a parametric model and a simple, constitutive law. A quasi-static compression test was performed on the muscles of dogs. A parametric finite element model was designed using a linear, elastic, constitutive law. A multi-variate analysis was performed to assess the effects of geometry on muscle response. An inverse method was used to define Young's modulus. The non-linear response of the muscles was obtained using a subject-specific geometry and a linear elastic law. Thus, a simple muscle model can be used to have a bio-faithful, biomechanical response. PMID- 21607889 TI - Verification of accuracy and validity of gait phase detection system using motion sensors for applying walking assistive FES. AB - In this study, we have analysed heel strike (HS) and toe off (TO) of normal individuals and hemiplegic patients, taking advantage of output curves acquired from various sensors, and verified the validity of sensor detection methods and their effectiveness when they were used for hemiplegic gaits. Gait phase detections using three different motion sensors were valid, since they all had reliabilities more than 95%, when compared with foot velocity algorithm. Results showed that the tilt sensor and the gyrosensor could detect gait phase more accurately in normal individuals. Vertical acceleration could detect HS most accurately in hemiplegic patient group A. The gyrosensor could detect HS and TO most accurately in hemiplegic patient groups A and B. The detection of TO from all sensor signals was valid in both the patient groups A and B. However, the vertical acceleration detected HS validly in patient group A and the gyrosensor detected HS validly in patient group B. PMID- 21607891 TI - Identification of heterogeneous elastic properties in stenosed arteries: a numerical plane strain study. AB - Assessing the vulnerability of atherosclerotic plaques requires an accurate knowledge of the mechanical properties of the plaque constituents. It is possible to measure displacements in vivo inside a plaque using magnetic resonance imaging. An important issue is to solve the inverse problem that consists in estimating the elastic properties inside the plaque from measured displacements. This study focuses on the identifiability of elastic parameters, e.g. on the compromise between identification time and identification accuracy. An idealised plane strain finite element (FE) model is used. The effects of the FE mesh of the a priori assumptions about the constituents, of the measurement resolution and of the data noise are numerically investigated. PMID- 21607892 TI - Analysis of melamine migration from melamine food contact articles. AB - Migration of melamine has been determined for 41 types of retail melamine-ware products in Malaysia. This study was initiated by the Ministry of Health, Malaysia, in the midst of public anxiety on the possibility of melamine leaching into foods that come into contact with the melamine-ware. Thus, the objective of this study was to investigate the level of melamine migration in melamine utensils available on the market. Samples of melamine tableware, including cups and plates, forks and spoons, tumblers, bowls, etc., were collected from various retail outlets. Following the test guidelines for melamine migration set by the European Committee for Standardisation (CEN 2004) with some modifications, the samples were exposed to two types of food simulants (3% acetic acid and distilled water) at three test conditions (25 degrees C (room temperature), 70 and 100 degrees C) for 30 min. Melamine analysis was carried out using LC-MS/MS with a HILIC column and mobile phase consisting of ammonium acetate/formic acid (0.05%) in water and ammonium acetate/formic acid (0.05%) in acetonitrile (95 : 5, v/v). The limit of quantification (LOQ) was 5 ng/ml. Melamine migration was detected from all samples. For the articles tested with distilled water, melamine migration were [median (interquartile range)] 22.2 (32.6), 49.3 (50.9), 84.9 (89.9) ng/ml at room temperature (25 degrees C), 70 and 100 degrees C, respectively. In 3% acetic acid, melamine migration was 31.5 (35.7), 81.5 (76.2), 122.0 (126.7) ng/ml at room temperature (25 degrees C), 70 and 100 degrees C, respectively. This study suggests that excessive heat and acidity may directly affect melamine migration from melamine-ware products. However the results showed that melamine migration in the tested items were well below the specific migration limit (SML) of 30 mg/kg (30,000 ng/ml) set out in European Commission Directive 2002/72/EC. PMID- 21607893 TI - UN resolution on the prevention and control of non-communicable diseases: an opportunity for global action. AB - In May 2010, the United Nations (UN) General Assembly unanimously adopted a resolution on non-communicable diseases (NCDs) that called for high-level meetings to address the global burden of NCDs. This paper highlights the growing global burden of NCDs (cardiovascular diseases, cancer, chronic obstructive pulmonary diseases and diabetes), provides a brief historical background on the adoption of the UN NCDs resolution and argues that the resolution provides a remarkable new opportunity for improved international collaboration to address NCDs. Additionally, the paper argues that while the existing World Health Organisation programme on NCDs be continued and expanded, the UN can provide the expanded political leadership that is necessary for multi-sectoral collaboration and can serve as a respected forum for dealing with the issue across numerous key UN agencies. PMID- 21607894 TI - Structural investigations of anthranilimide derivatives by CoMFA and CoMSIA 3D QSAR studies reveal novel insight into their structures toward glycogen phosphorylase inhibition. AB - In the present work, three-dimensional quantitative structure-activity relationship (3-D QSAR) studies on a set of 70 anthranilimide compounds has been performed using docking-based as well as substructure-based molecular alignments. This resulted in the selection of more statistically relevant substructure-based alignment for further studies. Further, molecular models with good predictive power were derived using CoMFA (r2 = 0.997; Q2 = 0.578) and CoMSIA (r2 = 0.976; Q2 = 0.506), for predicting the biological activity of new compounds. The so developed contour plots identified several key features of the compounds explaining wide activity ranges. Based on the information derived from the CoMFA contour maps, novel leads were proposed which showed better predicted activity with respect to the already reported systems. Thus, the present study not only offers a highly significant predictive QSAR model for anthranilimide derivatives as glycogen phosphorylase (GP) inhibitors which can eventually assist and complement the rational drug-design attempts, but also proposes a highly predictive pharmacophore model as a guide for further development of selective and more potent GP inhibitors as anti-diabetic agents. PMID- 21607895 TI - Pulmonary hypertension in neonates with high-risk congenital diaphragmatic hernia does not affect mid-term outcome. AB - PURPOSE: Congenital diaphragmatic hernia (CDH) presents with a broad spectrum of severity, depending on the degree of pulmonary hypoplasia and persistent pulmonary hypertension (PPH). It is currently not clear whether pulmonary hypertension may affect late morbidity. Aim of the present study was to evaluate the influence of PPH on mid-term morbidity in high-risk CDH survivors. METHODS: All high-risk (prenatal diagnosis and/or respiratory symptoms within 6 h of life) CDH survivors, treated between 2004 and 2008 in our Department were followed up in a multidisciplinary outpatient clinic as part of a longitudinal prospective study. Auxological, gastroesophageal, pulmonary and orthopedic evaluations were done at specific time-points (at 6, 12, and 24 months of age). Patients were grouped depending on the presence/absence of pulmonary hypertension (defined by expert pediatric cardiologists after echocardiography). Paired t-test and Fisher's exact test were used as appropriate. P < 0.05 was considered significant. RESULTS: 70 survivors out of a total of 95 high-risk CDH infants treated in our Department attended our follow-up clinic and were prospectively evaluated. 17 patients were excluded from the present study because no clear data was available regarding the presence/absence of PPH during the perinatal period. Moreover, 9 infants were not enrolled because they did not reach at least 6 months of age. A total of 44 survivors were finally enrolled since they met the inclusion criteria. 26 infants did not present with PPH during the first hospital admission, while 18 had PPH. The 2 groups did not differ with regard to any of the outcomes considered at follow-up (p > 0.2). CONCLUSION: In our cohort of high risk CDH survivors, PPH was not found to affect late sequelae at mid-term follow up. This may indicate that postnatal pulmonary development is not (always) influenced by perinatal PPH. Nevertheless, a longer follow-up and more patients are needed to properly quantify possible late problems in high-risk CDH survivors with associated neonatal PPH. PMID- 21607896 TI - OK-432 is not suitable for abdominal lymphatic malformations. PMID- 21607898 TI - [Febuxostat]. PMID- 21607899 TI - A Comparison of DASH, PEM and Levine questionnaires in outcome measurement of carpal tunnel release. AB - The objective of this study was to compare the 3 commonly used questionnaires DASH, PEM and Levine to assess which is the best as an outcome measure after carpal tunnel release. 50 patients (43 women and 7 men) with an average age of 56 years underwent minimally invasive carpal tunnel release. Patients were examined before the operation, and at 1 and 6 months after, according to the same protocol. They completed the DASH, PEM and Levine questionnaires and undertook total grip, key-pinch strengths, and sensation by filament tests. The results showed higher responsiveness to change in the Levine and the PEM, compared to the DASH at the 1- and 6-month-assessments. The Levine showed the highest validity as it correlated strongly with all functional measures, although all 3 questionnaires, including Levine, showed a discordance with total grip and key pinch strength at the 1-month assessment. The instruments were characterized by various (excellent and poor) concurrent validity in the assumed periods of observation and all 3 showed high internal consistency. PMID- 21607900 TI - 1831. PMID- 21607901 TI - We don't know what we don't know: prehospital data in combat casualty care. PMID- 21607902 TI - A prehospital trauma registry for tactical combat casualty care. AB - Many combat-related deaths occur in the prehospital environment before the casualty reaches a medical treatment facility. The tenets of Tactical Combat Casualty Care (TCCC) were published in 1996 and integrated throughout the 75th Ranger Regiment in 1999. In order to validate and refine TCCC protocols and procedures, a prehospital trauma registry was developed and maintained. The application of TCCC, in conjunction with validation and refinement of TCCC through feedback from a prehospital trauma registry, has translated to an increase in survivability on the battlefield. PMID- 21607903 TI - Current concepts in fluid resuscitation for prehospital care of combat casualties. AB - Historically, hemorrhage accounts for the primary cause of death on the battlefield in conventional warfare. In addition, hemorrhage was associated with 85% of potentially survivable deaths in the current conflicts, approximately two thirds of which were from noncompressible injuries. Future combat casualty care strategies suggest the likelihood of long transport times or significant time delays in evacuation of casualties. In addition, there are logistical limitations to providing large volumes of resuscitation fluid far-forward, and current guidelines do not recommend infusing large volumes of fluid until bleeding is controlled. Since the medic has few options for treating noncompressible injuries short of infusing fluid to maintain a blood pressure, the concept of damage control resuscitation was developed to promote hemostatic resuscitation. Damage control resuscitation recommends limiting the amount of crystalloids or colloids infused and using plasma and other blood products in more optimal ratios for the treatment of severe hemorrhage to improve battlefield survival and to reduce or prevent early and late deleterious sequelae. Taken together, these efforts have important implications towards the development of optimal fluid resuscitation strategies for stabilization of the combat casualty. PMID- 21607904 TI - Evaluation of topical hemostatic agents for combat wound treatment. AB - Uncontrolled hemorrhage remains the leading cause of potentially preventable death in combat casualties. In the current conflict, nearly two-thirds of these deaths occurred as a result of torso injuries with noncompressible hemorrhage and one-third from extremity injuries with compressible bleeding. The natural ability of blood to clot rapidly and stop bleeding from large vessels is far less than needed in the face of severe injuries and may even be diminished as a result of a massive tissue trauma (acute coagulopathy). Therefore, the use of a pressure device (ie, tourniquet) or topical hemostatic dressing is essential to stop compressible hemorrhage and prevent possible shock or death of casualties at the point of injury. To provide combat medics with the best means of treating hemorrhages, it is essential to understand the mechanism of action, efficacy strength, and possible adverse effects of each available hemostatic agent. In this article, we review the risks and benefits of the agents/dressings that have been used on the battlefield, the process that led to the selection of the new agents, and the present deficiencies that must be addressed in the development of new products. PMID- 21607905 TI - New tourniquet device concepts for battlefield hemorrhage control. AB - BACKGROUND: Given the recent success of emergency tourniquets, limb exsanguination is no longer the most common cause of preventable death on the battlefield; hemorrhage amenable to truncal tourniquets now is. The purpose of the present study is to discuss the gaps today in battlefield hemorrhage control and candidate solutions in order to stimulate the advancement of prehospital combat casualty care. METHODS: A literature review, a market survey of candidate devices, a request for devices, and an analysis of the current situation regarding battlefield hemorrhage control were performed. RESULTS: Hemorrhage control for wounds in the junction between the trunk and the limbs and neck is a care gap in the current war, and, of these, the pelvic (including buttock and groin proximal to the inguinal ligament) area is the most common. Historical and recent reports give background information indicating that truncal tourniquets are plausible devices for controlling junctional hemorrhage on the battlefield. A request for candidate devices yielded few prototypes, only one of which was approved by the US Food and Drug Administration. CONCLUSIONS: In order to solve the now most common cause of preventable death on the battlefield, junctional hemorrhage from the pelvic area, the planned approach is a systematic review of research, device and model development, and the fielding of a good device with appropriate training and doctrine. PMID- 21607906 TI - The role of normoventilation in improving traumatic brain injury outcomes. PMID- 21607907 TI - Advances in prehospital burn resuscitation for the combat injured. PMID- 21607908 TI - Advanced technology development for remote triage applications in bleeding combat casualties. AB - Combat developers within the Army have envisioned development of a "wear-and forget" physiological status monitor (PSM) that will enhance far forward capabilities for assessment of Warrior readiness for battle, as well as for remote triage, diagnosis and decision-making once Soldiers are injured. This paper will review recent work testing remote triage system prototypes in both the laboratory and during field exercises. Current PSM prototypes measure the electrocardiogram and respiration, but we have shown that information derived from these measurements alone will not be suited for specific, accurate triage of combat injuries. Because of this, we have suggested that development of a capability to provide a metric of circulating blood volume status is required for remote triage. Recently, volume status has been successfully modeled using low level physiological signals obtained from wearable devices as input to machine learning algorithms; these algorithms are already able to discriminate between a state of physical activity (common in combat) and that of central hypovolemia, and thus show promise for use in wearable remote triage devices. PMID- 21607909 TI - Advanced monitoring and decision support for battlefield critical care environment. AB - Automation and decision support systems are vital for improving critical patient care in the battlefield environment. However, advances in data management, sensor fusion, and decision support algorithms must be developed and incorporated into existing patient monitoring systems for this technology to improve battlefield patient care. This paper examines issues related to research and development of advanced monitoring and decision support systems for use both on the battlefield and in the civilian trauma environment. PMID- 21607910 TI - Prehospital and emergency care research at the US Army Institute of Surgical Research: enabling the next great leap in combat casualty survival. AB - Minimizing preventable death continues to be a primary focus of the combat casualty care research community, and of the Army Medical Department as a whole. Toward that end, tremendous successes have been realized in resuscitative surgery, critical care, rehabilitation, preventive medicine, and in our collective ability to project effective medical care into the most austere locations throughout the globe. Innovation in the care rendered outside of theater hospitals or strategic air evacuation conveyances, however, has not kept the same pace. The US military experience in World War II, Korea, and Vietnam served as a prime source for the development of the tactics, techniques, and procedures which spawned modern civilian sector trauma care and emergency medical services. But this ascendance was driven by the dedicated medics, corpsmen, physicians, nurses, and allied health practitioners from those conflicts who left the military for the civilian sector, leaving their replacements, in many cases, to repeat the same mistakes, and to relearn hard lessons that otherwise might have been assimilated had they been effectively captured and integrated into doctrine and training. A prime example of this phenomenon is the recent acknowledgement of the "en route care gap" existing in tactical medical evacuation. The US Army Institute of Surgical Research (USAISR) and the Army emergency medicine community have made a significant commitment toward elucidating the requirements, capability gaps, and a way-forward in search of the development of an integrated prehospital combat casualty care system, nested within the Joint Theater Trauma System. This paper examines specific research programs, concept development, and collaborations with other Army, joint, and civilian center organizations which comprise the USAISR Prehospital and Emergency Care Research Program, including the Remote Damage Control Resuscitation initiative, Emergency Telemedical Direction of Role-I providers, Combat Medical Voice Documentation System, and establishment of the Remote Trauma Outcomes Research Network. PMID- 21607911 TI - Improving role I battlefield casualty care from point of injury to surgery. PMID- 21607912 TI - Sharpening the edge: paramedic training for flight medics. PMID- 21607913 TI - Age- and sex-tailored serum phosphate thresholds do not improve cardiovascular risk estimation in CKD. AB - BACKGROUND: Disordered metabolism of phosphorus is one of the hallmarks of chronic kidney disease (CKD), resulting in increased cardiovascular morbidity and mortality. Age and sex may affect the metabolism of phosphorus and subsequently its serum level. We evaluated if age- and sex-specific cutoffs for hyperphosphatemia may define cardiovascular risk better than the current guideline cutoffs. METHODS: We used data from 16,834 subjects participating in the 1999-2006 National Health and Nutrition Examination Survey (NHANES); the prevalence of self-reported cardiovascular disease (CVD) and mortality rates were analyzed in CKD patients for both the classic definitions (CH; i.e., NKF-KDOQI and K-DIGO) and a tailored definition (TH) of hyperphosphatemia by means of regression models adjusted for age, sex, race/ethnicity, smoking status and body mass index. The cutoffs for TH were represented by the 95th percentile of an age- and sex-matched non-CKD population. RESULTS: Serum phosphorus levels showed an inverse correlation with age (r = -0.12; p<0.001); females showed higher levels than males (3.78 +/- 0.54 mg/dL vs. 3.62 +/- 0.58 mg/dL; p<0.001). Even if the association between the TH definition and CVD was marginally better compared with the CH definition (odds ratio [OR] = 1.49, 95% confidence interval [95% CI], 1.04 2.13; p=0.030 vs. OR=1.55, 95% CI, 0.98-2.44; p = 0.059), the TH model was not superior in predicting CVD or mortality. CONCLUSIONS: Our data suggest that a tailored, age- and sex-specific definition of hyperphosphatemia is not superior to conventional definitions in predicting cardiovascular events in patients with CKD. PMID- 21607914 TI - Glycosylated hemoglobin levels are associated with cardiovascular events in nondiabetic peritoneal dialysis patients. AB - BACKGROUND: High glycosylated hemoglobin (HbA1c) levels are recognized as a risk factor for cardiovascular disease in the diabetic dialysis population. However, it is not known whether this also applies to nondiabetic dialysis patients. We prospectively investigated the association between HbA1c levels and new cardiovascular events in nondiabetic patients treated with peritoneal dialysis. METHODS: Eighty nondiabetic patients who had been on peritoneal dialysis treatment were prospectively followed for 5 years. HbA1c levels were measured at baseline and every 3 months. Fatal and nonfatal cardiovascular events were assessed during the follow-up. RESULTS: Mean age was 48.5 +/- 15.2 years; 51% were male. Baseline HbA1c level was 5.46% +/- 0.41% (range 4.6%-6.3%). Mean HbA1c was 5.44% +/- 0.31% (range 4.8%-6.3%) during the study, and positively correlated with age and high-sensitivity C-reactive protein. Twenty fatal and nonfatal cardiovascular events were observed during a mean 41.8 +/- 7.1 months of follow up. Event-free survival was better in patients with HbA1c levels <5.45%, compared with that for those with HbA1c levels =5.45% (p=0.01). In crude Cox regression analysis, an increase in HbA1c level of 0.1% was associated with a 1.22-fold increase in new cardiovascular events (p=0.007). In Cox analyses, HbA1c level was found as a significant predictor of cardiovascular events. CONCLUSION: HbA1c levels predict fatal and nonfatal cardiovascular events in nondiabetic peritoneal dialysis patients. PMID- 21607915 TI - Visceral leishmaniasis reactivation in transplant patients: a minireview with report of a new case. AB - An updated review of cases of reactivated visceral leishmaniasis (VL) in transplant patients is presented, with a new report of a kidney transplant patient who had VL caused by reactivation of a dormant infection contracted 21 years previously. Close to the time of disease reactivation, the patient had a primary varicella-zoster infection. PMID- 21607916 TI - Three-dimensional echocardiographic assessment of left ventricular remodeling in predialysis chronic kidney disease patients. AB - BACKGROUND: The aim of this study was to investigate the relations of left ventricular (LV) mass and geometry to LV function in patients with predialysis chronic kidney disease (CKD), by real-time 3-dimensional echocardiography (RT3 DE). METHODS: Echocardiography was performed on 76 consecutively enrolled patients (51 men) with different stages of CKD, including 26 patients with mild CKD (CKD stages 1-2) and 50 patients with moderate-to-severe CKD (CKD stages 3 5). LV mass and LV end-diastolic volume were measured by RT3-DE. RESULTS: Greater prevalence of LV diastolic dysfunction and higher mitral E/myocardial velocities in early diastole (Em) values were noted in patients with moderate-to-severe CKD. In the moderate-to-severe CKD group, patients with increased LV mass had lower myocardial velocities in peak systole (Sm) and longer isovolumic relaxation time (IVRT). In the mild CKD group, patients with increased LV mass to volume ratios had lower Em. Moderate-to-severe CKD was associated with lower Sm and Em and higher mitral rapid filling to Em (E/Em) ratios by LV mass quartile stratification. Using LV mass/volume quartile stratification, moderate-to-severe CKD was associated with longer IVRT, lower Sm and higher mitral E/Em. Multivariable logistic regression analysis showed that CKD severity was the most independent predictor of elevated LV filling pressure (odds ratio = 2.96, p=0.019). CONCLUSIONS: Increased LV mass impaired LV contraction and relaxation in patients with moderate-to-severe CKD. Concentric remodeling impaired LV diastolic function in patients with mild CKD. CKD severity was positively associated with elevated LV filling pressure. PMID- 21607917 TI - Validation of a prognostic function for renal transplant recipients in Hungary. AB - BACKGROUND: Renal transplantation (RTx) is the treatment of choice for end-stage renal failure, but these patients are increasingly older and have additional conditions leading to high mortality after RTx. The aim of our study was to validate a Spanish prognostic function that estimates survival in Hungarian renal transplant recipients. METHODS: We estimated the 5-year survival of 339 patients who received a cadaver kidney between 1 January 1991 and 15 September 2004 at the Center of Transplantation, Medical and Health Science Centre, University of Debrecen, and who were followed up until death or 15 September 2009. To assess the calibration, we used the Hosmer-Lemeshow test to compare the observed and expected numbers of deaths in the deciles of the predicted 5-year risk of death. Additionally, we applied a smoother to obtain a nonparametric estimate of the 5 year cumulative incidence of death by robust locally weighted regression. To describe the discriminative power of the function, we calculated the area under the receiver operating characteristic (ROC) curve. RESULTS: The range of the estimated 5-year risk of death was 7%-100%. In the high-risk groups, the function severely overestimated the risk of death. The area under the ROC curve was 0.65 (95% confidence interval, 0.60-0.70). CONCLUSIONS: The poor performance of the prognostic function studied limits its clinical applicability. PMID- 21607918 TI - Regional citrate anticoagulation in critically ill patients with liver and kidney failure. AB - BACKGROUND: Regional citrate anticoagulation (RCA) is being used increasingly in critically ill patients who require continuous renal replacement therapy (CRRT). RCA may be avoided in patients with liver disease because of perceived increased risk of metabolic complications. The study compares the circuit lifespan and metabolic complications using RCA for CRRT at varying levels of liver dysfunction. METHODS: Data was collected retrospectively including the number of days on CRRT, number of circuit (re)initiations within that time and serum ionized and total calcium, bicarbonate, and sodium, repeatedly during treatment. Model for end-stage liver disease (MELD) scores were calculated and patients were divided into 4 groups according to MELD score quartiles. RESULTS: A total of 697 patients were included in the present study. The median circuit survival time was not different between groups. The median minimum serum ionized calcium levels during treatment were significantly lower in groups 3 and 4 (p<0.001), but by the last day of treatment, mean serum ionized calcium levels were not different between groups. The median minimum bicarbonate levels were significantly lower in groups 3 and 4 compared with groups 1 and 2 (p<0.01), but this is not considered clinically significant. The median maximum and mean serum bicarbonate levels were not significant between groups. Total to ionized calcium ratio levels were similar in groups 1, 2 and 3, but significantly higher in group 4 compared with other groups. CONCLUSION: RCA is a reasonably safe form of anticoagulation for maintaining efficiency and patency of the dialyzer in critically ill patients with liver dysfunction. PMID- 21607919 TI - Plasma protein carbonylation in chronic uremia. AB - BACKGROUND: Carbonylation is an irreversible modification caused by the introduction into proteins of carbonyl derivatives (aldehydes and ketones), which can alter protein structure and function and lead to cellular dysfunction and tissue damage. Chronic uremia may be associated with an increased carbonyl overload ("carbonyl stress"), though carbonyl formation has been proposed so far for major plasma proteins only. In this study we looked for evidence and for the targets of plasma protein carbonylation in patients on hemodialysis. We also examined the effect of in vitro carbonylated albumin on mRNA levels of endothelial cell adhesion molecules involved in early atherogenesis. METHODS: Carbonylated proteins in uremic plasma were detected by a covalent hydrazine bait strategy and identified by combining electrophoretic separation with mass spectrometry analysis of tryptic digests. Some plasma samples were first depleted of albumin and immunoglobulins to improve detection of lower abundance proteins. The functional impact of carbonylation was assessed in human vein endothelial cells by studying models of modified human serum albumin. RESULTS: Post-dialysis plasma carbonylated protein levels were significantly increased compared to pre dialysis levels. Susceptibility to carbonyl formation was described on a open platform investigation for a number of plasma proteins, albumin being the main scavenger of carbonyl reactive species. Incubation of endothelial cells with low doses of carbonylated albumin caused a significant increase in intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 mRNA levels. CONCLUSIONS: Chronic uremia appears as a state of "carbonyl stress" targeting several different plasma proteins. Carbonylated albumin displayed biological effects that may be relevant to uremic atherosclerosis. PMID- 21607920 TI - Looking at appearance of urine before performing a renal biopsy in nephrotic syndrome. AB - Chyluria results from an abnormal connection between lymphatic bed and urinary tract, causing lymph leakage into the urine. The clinical picture often begins with the appearance of cloudy, milky urines accompanied by monolateral flank pain, malnutrition, weight loss and weakness. We report a case of chyluria that occurred in a young woman who was referred to our unit for nephrotic-range proteinuria. Before performing a renal biopsy, we found that urine analysis demonstrated a massive lipiduria. Therefore, we collected urine samples from each kidney with a selective ureteral catheterization, demonstrating a monolateral source of lipids and proteins. We suspended the renal biopsy and performed a lymphography that showed an inherited lymphangioma on the left lumbar lymphatic bed. Sclerosing solution instillation, renal pedicle lymphatic disconnection or laser therapy are invasive therapeutical options that may cause severe adverse effects. Instead of these procedures, a conservative therapy based on a low-fat diet supplemented with medium-chain triglycerides was chosen. This dietetic schedule was followed by complete resolution of proteinuria and lipiduria. The patient progressively gained body weight and improved quality of life. No relapses were observed after 3 years of follow-up. This case emphasizes the possible role of a noninvasive therapeutical option for patients with chyluria. PMID- 21607921 TI - Tert-Butylhydroquinone pretreatment protects kidney from ischemia-reperfusion injury. AB - BACKGROUND: It is generally accepted that an excessive production of reactive oxygen species plays an important role in acute renal failure secondary to ischemia and reperfusion. tert-Butylhydroquinone (tBHQ) is a well-known antioxidant. In this study, we evaluated whether tBHQ pretreatment prevented renal damage induced by ischemia and reperfusion (I/R). METHODS: Four groups of rats were studied: (a) control-sham (CT), (b) tBHQ-sham (tBHQ), (c) I/R and (d) tBHQ + I/R. Intraperitoneal (i.p.) injections of tBHQ (50 mg/kg) were given to the tBHQ and tBHQ + I/R groups and 3% ethanol/isotonic saline solution to the CT and I/R groups. Animals were killed 24 hours after I/R. RESULTS: tBHQ attenuated I/R-induced renal dysfunction, structural damage, oxidative/nitrosative stress, glutathione depletion and the decrease in several antioxidant enzymes. CONCLUSION: The renoprotective effect of tBHQ on I/R injury was associated with the attenuation in oxidative/nitrosative stress and the preservation of antioxidant enzymes. PMID- 21607922 TI - The brachiobasilic arteriovenous fistula: effect of patient variables. AB - PURPOSE: The hemodialysis population is constantly expanding as patients on dialysis have increased longevity and the number of kidneys available for transplantation remains static (1). After radiocephalic and brachiocephalic fistulas have been exhausted the use of the autologous brachiobasilic fistula (BBAVF) should be considered prior to use of a synthetic graft. We present our single center experience of 140 brachiobasilic fistulas in a five-year period and examine any factors that influence patency and long-term function. METHODS: Patients who had undergone formation of a BBAVF between January 2004 and January 2009 were identified; a review of all case notes and databases was undertaken. Details on demographics, cause of renal failure, co-morbidities (including diabetes, cardiac morbidity, hypertension, peripheral vascular disease), dialysis status at the time of fistula creation, hemoglobin, anti-coagulation regimens, and complications from surgery were recorded. RESULTS: Patency (defined as use of AVF for dialysis) was 83% at 3 months, 77% at 6 months, and 69% at 12 months. Length of patency ranged from 0 to 1918 days (at study cut-off) with a mean patency of 532 days. Factors found to significantly affect fistula patency included age over 60 (P=<0.001) and presence of peripheral vascular disease (P=0.048). CONCLUSIONS: Our brachiobasilic fistula patency rates are comparable with published literature and other fistulas. Within our population patient variables including age over 60 and the presence of peripheral vascular disease are associated with worse outcomes as would be expected. In spite of these factors we feel the brachiobasilic fistula is an excellent option for patients with more challenging access and should certainly be undertaken prior to the use of prosthetic grafts. PMID- 21607923 TI - Serum proteomic profiling reveals potential biomarkers for cutaneous malignant melanoma. AB - Cutaneous malignant melanoma (CMM) is the most serious type of skin cancer because of its tendency to metastasize. The prognosis and therapeutic management of patients are primarily based on clinical criteria (number of cancerous lymph nodes and/or the presence of distant metastases) and histopathological criteria (tumor depth, presence of ulceration and mitotic index). Although these factors are informative in advanced stages of the disease, they are less important in the early stages. In recent years, a number of attempts have been made to identify new serological prognostic biomarkers, especially for early forms of CMM. The recent development of proteomic techniques may offer new perspectives in this field. This article details the considerations of each of the proteomic techniques used today and describes the results of the most recent clinical studies conducted to identify new potential prognostic serum biomarkers for CMM. However, independent and large validation studies are needed before such markers can be used in everyday clinical practice. PMID- 21607924 TI - Lack of prognostic significance of connexin-43 labeling in a series of 46 gastrointestinal stromal tumors. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors with variable malignant potential. Connexin-43 (Cx43) is the commonest gap-junction protein and has been frequently investigated in oncology. Our aim was to establish the immunohistochemical expression of Cx43 in relation to GIST location, size, Ki67 index, tumor grade and follow-up.? MATERIALS AND METHODS: The study included postoperative samples of 46 patients treated for GIST in the 1999-2010 time frame. Complete clinical workup was available for 38 patients (82.6%); total surgical resection was carried out in 32 (84.2%) patients, while 13 (34.2%) patients underwent chemotherapy. Median follow-up was 40.7 months (range, 1-134). ? RESULTS: The calculated incidence of GIST in our setting was 11.5 per million. Cx43 was expressed in 43/46 (93.5%) GIST cases, with a significant difference between stomach- and small intestine-derived tumors (p=0.006). Ki67 was 10% on average (range, 1-22) and was not correlated with tumor location (p=0.194). Cx43 did not show significance with regard to tumor size (p=0.264) or higher tumor grade (p=0.658), as opposed to Ki67, which significantly correlated with both (p=0.0048 and p<0.001, respectively). Cx43 and Ki67 were not significantly correlated (p=0.708). Ki67 correlated with time to recurrence (p=0.022). Ki67 >11% was taken as the indication to start imatinib chemotherapy (sensitivity 61.5%, specificity 92.0%, p=0.022). Ten (66.7%) of 15 patients with long-term (>5 years) follow-up were in remission.? CONCLUSION: Cx43 was frequently expressed in GISTs regardless of tumor site. However, no significant relationships to histopathological parameters suggestive for prognosis were found. Further investigations might clarify the roles of Cx43 in GIST oncogenesis. PMID- 21607925 TI - Retinal detachment in morning glory syndrome with large hole in the excavated disc. AB - PURPOSE: To present a case of morning glory syndrome (MGS) associated with retinal detachment and to discuss the pathogenesis of retinal tear. METHODS: A 2 year-old-girl had a MGS with a large hole in the excavated disc and retinal detachment. The visual acuity was 4/200 in the affected eye. The excavated disc and retinal detachment were confirmed by echogram. Optical coherence tomography demonstrated that the large hole was connected to the subretinal space. The excavated lesion did not show contractions. The detachment area and the volume of subretinal fluid rose and fell between initial examinations, but ultimately increased. After 2 years of observations, surgery was performed as the retinal detachment had enlarged to include the macula. RESULTS: Surgery included triamcinolone-assisted vitrectomy, subretinal fluid drainage through the large hole in the excavated disc, retinal photocoagulation along the excavated disc, and long-acting gas tamponade. One month later, the retina was redetached due to incomplete closure of the hole. A second operation was performed using silicone oil tamponade. Ultimately, the retina was reattached after silicone oil-fluid exchange surgery. CONCLUSIONS: One possible reason for a large hole in an excavated disc is origination of the tear from a congenital defect, such as an optic pit. The retinal detachment in patients with MGS with a large hole in the disc can be treated with triamcinolone-assisted pars plana vitrectomy and retinal photocoagulation along the excavated disc. This case has shown that one critical component for a high success rate is the tamponade agent used in the vitreous. PMID- 21607927 TI - Short-wavelength automated perimetry in type I diabetic patients without retinal involvement: a test modification to decrease test duration. AB - PURPOSE: To compare short-wavelength automated perimetry (SWAP) between type I diabetic patients without clinical posterior segment involvement and nondiabetic control subjects. METHODS: Forty eyes of diabetic patients without obvious posterior segment involvement and 34 eyes of the nondiabetic control group were included in the study. A complete set of ophthalmic examination was followed by SWAP perimetry in all subjects. Short-wavelength automated perimetry results were compared between the 2 groups. In addition, as a modification to SWAP, the data of the central 16 points were omitted and the resulting data of the remaining 60 points (corrected data) were compared between the 2 groups. RESULTS: Mean deviation in the diabetic patients (group I) was -6.51 dB and in the control group (group II) -3.0 dB; the difference was statistically significant. Mean corrected sensitivity in group I was 19.79 dB and in group II 22.37 dB. Mean corrected total deviation in group I was -6.67 and in group II -3.22. Both differences were highly statistically significant. The mean corrected pattern deviation in group I was -3.29 and in group II -3.04, which was not a statistically significant difference. CONCLUSIONS: Short-wave automated perimetry abnormalities precede diabetic retinopathy in type I diabetic patients and omission of central 16 points does not compromise test results in this situation. PMID- 21607928 TI - Visual quality after AcrySof IQ ReSTOR intraocular lens implantation in eyes with high myopia. AB - PURPOSE: To evaluate the visual performance of patients with high myopia with diffractive multifocal intraocular lens (MIOL) as compared with aspheric monofocal intraocular lens (IOL). METHODS: A prospective nonrandomized controlled study was conducted. Consecutively, 36 patients with senile cataract (72 eyes) received phacoemulsification and IOL implantation: 12 patients (24 eyes) were implanted with AcrySof IQ ReSTOR SN6AD3 IOL, 12 patients (24 eyes) were implanted with AcrySof IQ ReSTOR SN6AD1 IOL, and another 12 patients (24 eyes) were implanted with AcrySof IQ SN60WF as control group. All patients were assessed at 6 months postoperatively in these aspects: uncorrected and best-corrected visual acuities for distance (5 mo), intermediate (60 cm), and near (30 cm), modulation transfer function, and defocus curve. Patient satisfaction (spectacle independence, glare or halo disturbance, and overall satisfaction) was assessed by a questionnaire. RESULTS: At 6 months postoperatively, both uncorrected and distance-corrected intermediate and near visual acuity were significantly better in multifocal groups than the control monofocal group (p<0.01). Intermediate visual acuity in the SN6AD1 group was a little higher than that in the SN6AD3 group (p<0.05); conversely, the near visual acuity in the SN6AD3 group was better than in the SN6AD1 group (p<0.05). Modulation transfer function with a 5.0-mm aperture was similar in the 3 groups and there was no statistically significant difference. Patients in both multifocal groups reported excellent overall spectacle independence and satisfaction with the IOLs. CONCLUSIONS: Compared with aspheric monofocal IOL, AcrySof ReSTOR IQ multifocal IOLs could provide a functional vision range from near to distance, resulting in high level of spectacle independence and satisfaction among patients with high myopia. PMID- 21607929 TI - Phialemonium curvatum infection after phacoemulsification: a case report. AB - PURPOSE: A case of Phialemonium curvatum wound corneal infection after phacoemulsification is reported. METHODS: Case report. RESULTS: The marked aggressiveness of this fungus is demonstrated by the absence of therapeutic response to both medical and surgical treatment. CONCLUSIONS: The poor outcome resulted in evisceration of the affected eye. PMID- 21607930 TI - Secondary or new compensatory head posture after Anderson-Kestenbaum surgery. AB - PURPOSE: To report clinical findings and surgical management of 4 patients with congenital nystagmus who presented with a new or reversal of their original horizontal compensatory head posture (CHP) after Anderson-Kestenbaum (A-K) surgery. METHOD: Retrospective chart review. RESULTS: All 4 patients demonstrated a 40 degrees -45 degrees horizontal face turn at the time of their initial surgery and 3 underwent 20% and one 30% augmented A-K surgery to correct the CHP. The new CHP or reversal of the original CHP was observed at a mean of 4 years (range 1-9 years) after the initial surgery. The reversed CHPs measured 20 degrees , 40 degrees , 20 degrees , and 20 degrees , respectively. These new or residual CHPs were surgically managed in 3 patients and an acceptable head position was achieved in all patients. CONCLUSIONS: This series of patients points out the occurrence of secondary null points and reversed CHP after surgical correction of initial CHP. PMID- 21607931 TI - Diagnostic value of clinical examination and radiographic imaging in identification of intraocular foreign bodies in open globe injury. AB - PURPOSE: To evaluate the diagnostic accuracy of clinical eye examination and radiographic imaging in the identification of intraocular foreign bodies (IOFBs) in open-globe traumatic injuries. METHODS: This was a retrospective chart review of open-globe traumatic injuries with IOFBs presenting to University Hospital (UH) at New Jersey Medical School between 1998 and 2008. RESULTS: A total of 527 patients with traumatic open globe injuries presented to UH, Newark, New Jersey, USA, between 1998 and 2008. Of these, 74 patients had surgically confirmed IOFBs. Mean age of patients with traumatic open globe injury and an IOFB was 33 years (range, 8-69 years); mean follow-up was 17.6 months (range, 1 day-90 months). Foreign bodies were identified as glass (13), metal (58), wood (1), plastic (0), and other (2). There were 24 anterior segment (AS) IOFBs, 45 posterior segment (PS) IOFBs, and 5 noted in both segments. Clinical eye examination at presentation identified an IOFB in 34 (45.6%) of 74 patients. B-scan echography revealed an IOFB in 14 (51.9%) of 27 cases. Computed tomography scan of the orbits identified IOFBs in 56 (94.9%) of 59 cases. Clinical eye examination was performed in all (100%) patients. B-scan was performed only when posterior segment pathology was suspected. Computed tomography scan was performed when an IOFB or orbital fracture was suspected. CONCLUSIONS: Computed tomography scan was the most reliable method for identifying IOFBs in patients presenting with open globe injuries in comparison to clinical eye examination and B-scan echography. This result was consistent regardless of IOFB location within the globe. PMID- 21607932 TI - Changes in objective vault and effect on vision outcomes after implantable Collamer lens implantation: 1-year follow-up. AB - PURPOSE: To investigate the changes in vault and the effect on visual outcomes 1 year after implantable Collamer lens (ICL) implantation. METHODS: In this retrospective study, 127 eyes of 66 patients undergoing ICL implantation were examined both before and up to 1 year after the surgery. The examination contents included white-to-white (WTW) diameter, central vault of the ICL (distance between posterior surface of ICL and anterior surface of crystalline lens), refractive error, and wavefront high-order aberration (HOA). All statistical analyses were performed using SPSS 13.0 software. RESULTS: A significant decrease in vault was noted up to 1 month, after which the value stabilized (p=0.001). The moderate vault decreased significantly after the first 3 months postsurgery (paired-samples t test, p<0.05). Low vault showed a tendency to increase and high vault showed a tendency to decrease, but not significantly, over time. There was no statistically significant correlation between the amount of vault and the refractive error (Pearson correlation coefficient R=0.111, p=0.473) and there was a statistically significant correlation between the vault and HOAs (R=0.304, p=0.024). CONCLUSIONS: Implantable Collamer lens vault over the crystalline lens had the tendency toward a slight decrease with time and did not significantly affect the vision outcome 1 year after surgery. PMID- 21607934 TI - The ceramic-on-metal coupling in total hip replacements for young patients: a review study. AB - In the last two decades the performance of total hip replacements (THR) has constantly improved, thanks largely to advances in the field of material science and technology. Although contemporary devices are clinically very reliable, some problems still need to be addressed: the wear of ultra high molecular weight polyethylene components, the release of metal ions from metal-on-metal joints, the toughness of the ceramic cups and the possibility of squeaking for ceramic-on ceramic couplings. All these drawbacks become particularly relevant in case of THR for young and active patients, when the life expectancy of the orthopedic device is very high and the possibility of mechanical shocks is not negligible.In the last few years an innovative ceramic-on-metal tribologic coupling has been introduced in clinical use. This novel configuration represents a very promising solution to all the aforementioned issues. Ceramic-on-metal offers both the strength points of ceramic and metal surfaces, and overcomes the limits of metal on-metal and ceramic-on-ceramic bearings. For this reason, the ceramic-on-metal coupling has become the object of investigation for several laboratory studies and has been tested in clinical trials. This review study compares the scientific outcomes of the research on ceramic-on-metal bearings, confirming that this innovative articulation has the potential to be a suitable and attractive solution for young and active patients. PMID- 21607935 TI - Coating of titanium implants with copolymer supports bone regeneration: a comparative in vivo study in rabbits. AB - PURPOSE: In modern orthopedics aseptic loosening caused by the formation of micro wear particles remains a problem for endoprosthetic joint replacements as revision surgery is necessary with corresponding costs and exertions by patients. This study is devoted to the question of how the osseous ingrowth of implants can be supported. It was investigated whether the developed copolymer, p-VBP-co-GMA, coated on the surface of the implants, supports bone healing. In addition, it was analyzed whether covalent linkage of Bone Morphogenetic Protein 2 (BMP-2) to the copolymer layer enhances bone formation. METHODS: Eight adult New Zealand White Rabbits were implanted with four different foils (control, copolymer, copolymer + BMP-2, control + BMP-2) each. The histomorphometric analysis of all samples was made 28 days after implantation. RESULTS: The copolymer had a positive effect on bone remodeling compared to the control group. We observed that the copolymer group had a significantly increased bone volume per tissue volume ratio and bone density to the control group. In contrast, this in-vivo study showed that the immobilization of BMP-2 onto the copolymer layer did not enhance bone healing. The bone volume per tissue volume ratio was decreased as well as the bone density compared to control + BMP-2 group. CONCLUSION: The analysis showed that the bone remodeling process in the copolymer + BMP-2-group is in an early phase comparable to the control group. These results suggest that the coating with the developed copolymer has major potential for medical use as it enhances bone mass around the implant. PMID- 21607936 TI - Evaluation of counter movement jump parameters in young male soccer players. AB - PURPOSE: The Counter Movement Jump (CMJ) is widely used as a field test to evaluate the muscular explosive power of lower limbs in various sports, including soccer. The aim of the present study was to verify the possibility to discriminate the effect of training level and age on young adult male soccer players, adopting the flight time, the peak force, or the peak power obtained from a countermovement jump. METHODS: One hundred and twenty three young male soccer players were enrolled in the study; the participants were split into groups according to Tanner's stages (pre- and post-pubertal) and training level (high and low activity). A piezoelectric force plate was used to acquire the ground reaction force used to calculate the flight time, the peak value of the vertical component of the ground reaction force, and the peak value of the developed power. RESULTS: As expected, the best performances were obtained by the post pubertal highly-trained soccer players. All performance parameters presented statistically significant differences between ages, while only the flight time exhibited statistically significant differences between training levels. After normalization of the experimental data to body height and weight, there were no statistical differences between ages; statistically significant differences were found only for the flight time and for peak power between training levels. CONCLUSIONS: The flight time was the parameter more sensitive to detect differences in the jump performance related to training and age. Adopting a normalization procedure it was possible to highlight that only the flight time and the peak power are sensitive to training effects on young adult male soccer players. PMID- 21607937 TI - Anodic oxidation of titanium: from technical aspects to biomedical applications. AB - Titanium biomaterials are widely employed to produce medical components, such as hip and knee-joint prostheses, bone plates and screws, dental implants, pacemaker cases, surgical equipment, etc. Their diffusion is ascribed to the broad spectrum of optimal mechanical and surface properties, such as the corrosion resistance and correlated low ionic release, the biocompatibility, and especially, the enhanced osseointegration that can be achieved by surface modifications, particularly by suitable anodizing treatments. This review is intended to provide a survey of the wide class of anodic oxidation treatments on titanium, focusing on the oxide structures, morphologies, and compositions that best apply to the variegated fields of titanium applications. PMID- 21607938 TI - Abdominal organ donation after death. PMID- 21607939 TI - Full access to medical records does not modify anxiety in cancer patients: results of a randomized study. AB - BACKGROUND: Information is crucial for increasing the patients' empowerment and autonomy in relevant decision-making processes, especially in malignant diseases. However, the extent to which information should be delivered is debated. The objective of this study was to assess the impact of providing systematic full access (SFA) to the medical record on anxiety, quality of life, and satisfaction. METHODS: Patients with newly diagnosed breast cancer, colon cancer, or lymphoma who had received adjuvant chemotherapy in an outpatient setting were included in a randomized controlled trial comparing those who requested access (RA) and those who provided SFA to the medical record. Anxiety was assessed using the Spielberger State-Trait Anxiety Inventory before, during, and at the end of treatment. Quality of life was evaluated using the European Organization for Research and Cancer quality-of-life questionnaire (EORTC QLQ-C30) before and at the end of treatment. Patients' satisfaction and perception of the organized medical record (OMR) were evaluated using a specifically designed questionnaire at the end of treatment. RESULTS: Most patients (98%) who had the opportunity to obtain the OMR chose to do so. Anxiety levels did not increase in the SFA arm, although they did not differ significantly compared with anxiety levels in the RA arm. The patients who had full access to their medical record were more satisfied with information (odds ratio, 1.68; 95% confidence interval, 0.98-2.9) and felt sufficiently informed more often (odds ratio, 1.86; 95% confidence interval, 1.08 3.19), but the differences were not statistically significant at the 5% level. CONCLUSIONS: Allowing full access to personal medical records increased satisfaction without increasing anxiety in patients with newly diagnosed cancer. PMID- 21607941 TI - Risk of mortality in patients with cancer who experience febrile neutropenia. PMID- 21607942 TI - An E3 ubiquitin ligase: c-Cbl: a new therapeutic target of lung cancer. AB - BACKGROUND: Casitas B-lineage lymphoma (Cbl) is an E3 ubiquitin ligase of many tyrosine kinase receptors. The authors previously detected c-Cbl mutation and low protein expression in non-small cell lung cancer (NSCLC). Therefore, it was hypothesized that overexpression of wild-type c-Cbl (c-Cbl WT) exhibits tumor growth inhibition. METHODS: Wound healing and transwell assays were conducted to examine cell motility after c-Cbl WT transfection in NSCLC cell lines. The cell cycle was investigated by flow cytometry. A549 and H1299-Luc c-Cbl WT-transfected xenografts and experimental metastasis models were performed to investigate tumor growth and metastasis inhibition in vivo. RESULTS: Wound healing and transwell assays demonstrated inhibition of migration in the A549 and H226br cells 4 to 24 hours after transfection. Ectopic c-Cbl WT expression was found to reduce cell proliferation at 48 hours in A549 cells. It is important to note that A549 and H1299-Luc cells with ectopic c-Cbl WT expression demonstrated inhibition of tumor growth in vivo. A549 cells overexpressing c-Cbl WT inhibited tumor metastasis in animal models. CONCLUSIONS: To the best of the authors' knowledge, the current study is the first to demonstrate that c-Cbl WT protein overexpression inhibits tumor metastasis and tumor growth in lung cancer xenograft models. These results provide evidence that ectopic expression of c-Cbl WT protein can be potentially applied as targeted therapy for the treatment of lung cancer. PMID- 21607943 TI - Regulators of macrophage activation. AB - Macrophages are ubiquitous phagocytes that can constitute up to 15% of the cellular content of tissues. These heterogeneous cells of the innate immune system perform important functions during health and disease. Equipped with receptors for the T helper cell cytokines INF-gamma and IL-4, macrophages undergo specific activation programs during Th1 or Th2 immune responses. These activation profiles, termed classical (M1) or alternative (M2) activation respectively, are further tuned by the presence and recognition of microbial-associated molecular patterns, other cytokines, lipids, and even adhesion to the substratum. The activation of macrophages also relies on the maturation background of the cells, elicitation of complicated intracellular signalling cascades, and the crosstalk between the different signalling elements. Of interest, not all genes participating in the activation-related signalling cascades are equally important for the elicitation of functional profiles and a regulator gene hierarchy is emerging for the different types of activation. In this issue of the European Journal of Immunology, two papers add to our understanding of how cellular kinases and phosphatases, related to the PI3K pathway, regulate M1 or M2 activation programmes in macrophages. PMID- 21607944 TI - The inflammatory milieu in the rheumatic joint reduces regulatory T-cell function. AB - Regulatory T cells (Tregs) are important for maintaining immune homeostasis, but many studies suggest that Tregs are functionally impaired in autoimmune and chronic inflammatory disorders. In addition, effector T cells may vary in sensitivity toward Treg suppression. Herein, we have studied the interplay between T effectors and Tregs in the rheumatic joint. Synovial Tregs demonstrated a high degree of FOXP3 demethylation and displayed only marginal IL-17 and virtually no IFN-gamma production following in vitro stimulation, altogether indicating suppressive capacity. Still, the frequency of FOXP3 expression could not predict the degree of suppression. Instead, the inflammatory milieu in the joint, i.e. proliferative capacity of effector T cells and in situ levels of pro inflammatory cytokines influenced Treg function. Indeed, blocking IL-6 or TNF increased the suppression by Tregs in co-cultures. Additionally, approximately 30% of the synovial FOXP3(+) T cells were Ki67(+) and hence actively dividing, but proliferation did not overlap with cytokine production, suggesting that these cells represent functional Tregs having met their cognate antigen and expanded in an attempt to alleviate joint inflammation. Overall, our data argue against a general functional deficit in joint-derived Tregs and instead emphasize the importance of the inflammatory milieu to set the threshold for immune regulation. PMID- 21607945 TI - Impaired tumor rejection by memory CD8 T cells in mice with NKG2D dysfunction. AB - Cytotoxic T cells are important effectors for robust antitumor immune responses. However, tumor-infiltrating CD8 T cells are often functionally impaired. Insufficient antitumor activity of CD8 T cells can be due to a lack of costimulatory signals. NKG2D is such a costimulatory receptor on CD8 T cells that facilitates immunorecognition of stressed and malignant cells, promotes tumor rejection by NK and CD8 T cells and contributes to immunosurveillance of spontaneous malignancies. Previous reports suggested an involvement of NKG2D in establishing CD8 T cell-mediated antitumor memory. However, the significance of NKG2D for the generation and effector phase of memory CD8 T cell responses is largely unknown. To address these issues, we made use of a transgenic mouse model (H2-K(b)-MICA mice) where the human NKG2D ligand MICA is ubiquitously and constitutively expressed resulting in a severe dysfunction of NKG2D. Both, ovalbumin (OVA)-specific (H2-K(b)/OVA(257-264)) memory CD8 T cells arisen from the endogenous T cell pool and adoptively transferred OVA-specific OT-I memory cells were unable to control growth of an OVA-expressing lymphoma in H2-K(b)-MICA mice. While expansion of memory T cells in these mice on antigen challenge was not different from controls, CD8 memory T cells of H2-K(b)-MICA mice did not effectively eliminate tumor cells in vivo. Altogether, our data suggest that NKG2D has no major role in the generation and expansion of memory CD8 T cells, but rather substantially enhances the cytolytic effector responses of reactivated memory T cells and thereby contributes to an efficacious tumor rejection. PMID- 21607946 TI - Progress in colorectal cancer survival in Europe from the late 1980s to the early 21st century: the EUROCARE study. AB - Colorectal cancer (CRC) is the second most common cause of death due to cancer causing death in Europe, accounting for more than 200,000 deaths per year. Prognosis strongly depends on stage at diagnosis, and the disease can be cured in most cases if diagnosed at an early stage. We aimed to assess trends and recent developments in 5-year relative survival in European countries, with a special focus on age, stage at diagnosis and anatomical cancer subsite. Data from 25 population-based cancer registries from 16 European countries collected in the context of the EUROCARE-4 project were analyzed. Using period analysis, age adjusted and age-specific 5-year relative survival was calculated by country, European region, stage and cancer subsite for time periods from 1988-1990 to 2000 2002. Survival substantially increased over time in all European regions. In general, increases were more pronounced in younger than in older patients, for earlier than for more advanced cancer stages and for rectum than for colon cancer. Substantial variation of CRC survival between European countries and between age groups persisted and even tentatively increased over time. There is a huge potential for reducing the burden of CRC in Europe by more widespread and equal delivery of existing options of effective early detection and curative treatment to the European population. PMID- 21607947 TI - Yogurt consumption and risk of colorectal cancer in the Italian European prospective investigation into cancer and nutrition cohort. AB - Fermented dairy products like yogurt have been suggested to protect against colorectal cancer (CRC). We conducted a prospective study on 45,241 (14,178 men; 31,063 women) volunteers of the EPIC-Italy cohort who completed a dietary questionnaire including specific questions on yogurt intake. During 12 years of follow-up, 289 volunteers were diagnosed with CRC. Hazard ratios (HRs) for the disease and 95% confidence intervals (CIs) were estimated by Cox proportional hazard models, stratified by dietary questionnaire and adjusted for energy intake and other potential confounders. Yogurt intake was inversely associated with CRC risk. For the energy-adjusted model, HR for CRC in the highest versus lowest tertile of yogurt intake was 0.62 (95% CI, 0.46-0.83). In the full model adjusted for energy, simple sugar, calcium, fiber, animal fat, alcohol and red meat intake, as well as body mass index, smoking, education and physical activity, HR was 0.65 (95% CI, 0.48-0.89) in the highest versus lowest tertile. The protective effect of yogurt was evident in the entire cohort, but was stronger in men, although there was no interaction of sex with the yogurt-CRC association (p(interaction) 0.20, fully adjusted model). In our prospective study, high yogurt intake was significantly associated with decreased CRC risk, suggesting that yogurt should be part of a diet to prevent the disease. Investigation of larger cohorts is necessary to reveal any residual confounding of the association of yogurt intake with CRC risk. PMID- 21607948 TI - Switch from cytology-based to human papillomavirus test-based cervical screening: implications for colposcopy. AB - Human papillomavirus (HPV) testing is more sensitive than cytology; some cervical cancer prevention programs will switch from cytology to carcinogenic HPV test based screening. The objective of our study is to evaluate the clinical implications of a switch to HPV test-based screening on performance and workload of colposcopy. Women in the population-based, 7-year Guanacaste cohort study were screened at enrollment using cytology. We also took another specimen for HPV DNA testing and collected magnified cervical photographic images (cervigrams). A final case diagnosis (>=cervical intraepithelial neoplasia [CIN] grade 3, CIN2, =CIN2 and >=CIN3. A program based on immediate colposcopic referral after positive HPV would immediately identify as high risk more of the cumulative >=CIN2 cases than conventional cytology, because of an increased number of referrals. However, the proportion of women that would have visible lesions at referral to colposcopy and the sensitivity versus specificity trade-off of the colposcopic impressions would be similar to programs using cytology (>= atypical squamous cells of unknown significance [ASCUS]) for referral. The major concern with switching from cytology to more sensitive HPV screening is management of the many HPV-positive women, including those with still nonvisible >=CIN2 lesions. Our data support the need for a nonvisual diagnostic method to guide management and treatment of HPV-positive women. PMID- 21607949 TI - Human papillomavirus status in young patients with head and neck squamous cell carcinoma. AB - The role of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) development has been recognized only in the last decade. Although younger patients develop HNSCC associated with HPV, the incidence in young patients has not been studied. Forty-five young HNSCC patients (<40 years) were tested for HPV and the expression of p16(ink4a) and p53 in tumor biopsies. The presence of HPV was correlated with the absence and presence of alcohol and tobacco exposure. Paraffin-embedded, archival biopsy materials from HNSCC of 45 patients younger than 40 years were analyzed. HPV subtypes were identified by PCR followed by genotyping. Expression of p16(ink4a) and p53 were determined by immunohistochemistry. Fourteen (31%) of the HNSCC specimens from 45 patients unequivocally exhibited HPV16 positivity. Sixty percentage of the oropharyngeal tumors and 5% of the oral cavity tumors were HPV16 positive. P16(ink4a) overexpression was detected in 93% of the HPV16-positive tumors. None of the HPV16 tumors showed p53 overexpression. There was no association of HPV positivity with (lack of) exposure to alcohol and smoking. HPV association was not exclusively detected in nonsmoking, nondrinking young HNSCC patients. The presence of p16(ink4a) accumulation and the absence of p53 overexpression are good surrogate markers for HPV-associated HNSCC. PMID- 21607951 TI - Dissolution and precipitation behavior of amorphous solid dispersions. AB - Amorphous solid dispersions (ASDs) are widely utilized in the pharmaceutical industry for bioavailability enhancement of low solubility drugs. The important factors governing the dissolution behavior of these systems are still far from adequately understood. As a consequence, it is of interest to investigate the behavior of these systems during the dissolution process. The purpose of this research was twofold. First, the degree of supersaturation generated upon dissolution as a function of drug-polymer composition was investigated. Second, an investigation was conducted to correlate physical behavior upon dissolution with polymer loading. Felodipine and indomethacin were selected as model drugs and hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were used to form the dispersions. Diffusion and nuclear magnetic resonance spectroscopy experiments revealed that the extent of bulk supersaturation generated on dissolution of the ASD did not depend on the drug-polymer ratio. Interestingly, the maximum supersaturation generated was similar to the predicted amorphous solubility advantage. However, dynamic light scattering measurements revealed that particles on the submicron scale were generated during dissolution of the solid dispersions containing 90% polymer, whereas solid dispersions at a 50% polymer loading did not yield these nanoparticles. The nanoparticles were found to result in anomalous concentration measurements when using in situ ultraviolet spectroscopy. The supersaturation generated upon dissolution of the solid dispersions was maintained for biologically relevant timeframes for the HPMC dispersions, whereas PVP appeared to be a less effective crystallization inhibitor. PMID- 21607952 TI - Effects of organic solvents on the barrier properties of human nail. AB - The effects of organic solvent systems on nail hydration and permeability have not been well studied. The objectives of the present study were to investigate the effects of binary aqueous organic solvent systems of ethanol (EtOH), propylene glycol (PPG), and polyethylene glycol 400 (PEG) on the barrier properties of nail plates. (3) H-water, (14) C-urea, and (14) C tetraethylammonium ions were the probes in the nail uptake and transport experiments to study the effect(s) of organic solvents on nail hydration and permeability. Gravimetric studies were also performed as a secondary method to study nail hydration and the reversibility of the nail after organic solvent treatments. Both ungual uptake and transport were directly related to the concentration of the organic solvent in the binary systems. Partitioning of the probes into and transport across the nail decreased with an increase in the organic solvent concentration. These changes corresponded to the changes in solution viscosity and the barrier properties of the nail. In general, the effects for PPG and PEG were more pronounced than those for EtOH. Practically, these results suggest that organic solvents in formulations can increase nail barrier resistivity. PMID- 21607953 TI - High-throughput screening of PLGA thin films utilizing hydrophobic fluorescent dyes for hydrophobic drug compounds. AB - Hydrophobic, antirestenotic drugs such as paclitaxel (PCTX) and rapamycin are often incorporated into thin film coatings for local delivery using implantable medical devices and polymers such as drug-eluting stents and balloons. Selecting the optimum coating formulation through screening the release profile of these drugs in thin films is time consuming and labor intensive. We describe here a high-throughput assay utilizing three model hydrophobic fluorescent compounds: fluorescein diacetate (FDAc), coumarin-6, and rhodamine 6G that were incorporated into poly(d,l-lactide-co-glycolide) (PLGA) and PLGA-polyethylene glycol films. Raman microscopy determined the hydrophobic fluorescent dye distribution within the PLGA thin films in comparison with that of PCTX. Their subsequent release was screened in a high-throughput assay and directly compared with HPLC quantification of PCTX release. It was observed that PCTX controlled-release kinetics could be mimicked by a hydrophobic dye that had similar octanol-water partition coefficient values and homogeneous dissolution in a PLGA matrix as the drug. In particular, FDAc was found to be the optimal hydrophobic dye at modeling the burst release as well as the total amount of PCTX released over a period of 30 days. PMID- 21607954 TI - Effect of milk on the pharmacokinetics of oseltamivir in healthy volunteers. AB - We previously showed that oseltamivir, a prodrug of the influenza virus neuraminidase inhibitor Ro 64-0802, is a substrate of proton-coupled oligopeptide transporter (PEPT1), and its intestinal absorption in rats is markedly inhibited by administration with milk. To investigate the importance of PEPT1 for oseltamivir absorption in humans, and the characteristics of the drug-milk interaction, a crossover clinical study was conducted in healthy volunteers, who received 75 mg of oseltamivir with 400 mL of water or milk. Milk significantly reduced the maximum plasma concentration (C(max) ) and the area under the plasma concentration-time curve from 0 to 2 h (AUC(0-2) ) of both oseltamivir and Ro 64 0802 (oseltamivir, 68.9% and 34.5%; Ro 64-0802, 69.5% and 14.2%, respectively, vs. water), but had no significant effect on the apparent terminal half-life (t(1/2) ) or AUC(0-infinity) . Urinary recovery of oseltamivir and Ro 64-0802 was significantly reduced to 77.5% of the control by milk. The early reduction of oseltamivir absorption might be through the PEPT1 inhibition by milk peptides. However, the extent of interaction in humans was limited as compared with that in rats, possibly because of species difference in the PEPT1 expression and its contribution. This might be the first report suggesting the clinical drug-food interaction via PEPT1. PMID- 21607955 TI - Development of a taste-masked generic ibuprofen suspension: top-down approach guided by electronic tongue measurements. AB - Electronic tongues are sensor array systems that are increasingly being used in the field of pharmaceutics to provide taste assessment data of formulations. The applicability of an electronic tongue in the development of a taste masked generic ibuprofen suspension, starting from a commercial taste masked product, was evaluated in this study. The initial screening study on 3 proprietary and 11 generic products showed that sensors of the taste sensing system TS-5000Z could clearly detect differences between the products. The variation of sensor responses were mainly caused by sodium salts, sweeteners, and preservatives, whereas pH and viscosity did not affect sensor response. In addition, the presence of the particles (20-100 um) did not damage the sensor membranes. Based on this screening, and the known qualitative composition of the proprietary formulations, the approximate quantitative composition of a proprietary formulation could be deduced and a taste masked generic formulation could be developed using the electronic tongue data. Differences in sensor responses between the proprietary and optimized generic formulation were smaller than 11 mV for each sensor. Based on these results a rational approach of implementing an electronic tongue to simplify the development of a taste masked generic formulation could be introduced. PMID- 21607956 TI - Interactions between organic anions on multiple transporters in Caco-2 cells. AB - In drug development, Caco-2 cells are often employed to study the influence of membrane transporters on drug permeability. The aim of the current study was to characterize permeability and kinetic parameters of selected organic anionic compounds in Caco-2 cells, and to investigate whether the Caco-2 cell line may be used as an overall model to predict interactions on multiple membrane transporters in the intestine. Taurocholic acid (TCA) and estrone-3-sulfate (E(1) S) were used as model substrates. Possible inhibitors studied were TCA, E(1) S, taurolithocholic acid, fluvastatin, and glipizide. The effects of these compounds on initial uptake, apparent permeability, and intracellular end-point accumulations of the probe substrates were studied. Both interactions on apical and basolateral influx transporters were observed. These interactions were proposed to be mediated mainly by the apical sodium-dependent bile acid transporter and the organic solute transporter alpha/beta, and to less extent by the organic anion transporting polypeptide 2B1. However, interactions on efflux transporters were not detected, although they were expected from the literature on the investigated compounds. Biosimulation methods may be the key to further distinguish between interactions on multiple transporters, including the involvement of efflux transporters, by taking into account the changes in dynamics that drug interactions may cause. PMID- 21607957 TI - Freeze drying of nanosuspensions, 2: the role of the critical formulation temperature on stability of drug nanosuspensions and its practical implication on process design. AB - The present study investigates whether controlling the product temperature below the critical formulation temperature (CFT) during primary drying in a freeze drying cycle is a prerequisite for the stabilization of drug nanoparticles. For that purpose, the CFT of four drug nanosuspensions stabilized with different types (amorphous and crystalline) and concentrations of steric stabilizers and either of the disaccharides, trehalose and sucrose, was determined by differential scanning calorimetry and freeze-dry microscopy. Freeze-drying experiments were performed such that product temperatures during primary drying remained either below or well above the CFT of individual mixtures. It was found that glass formation did not influence the stability of the nanoparticles, suggesting that an adequate type of steric stabilizer and lyoprotectant concentration is present. Freeze drying could also be performed above the eutectic temperature without compromising on the final product quality profile, such as nanoparticle size and structural preservation of the lyophilized cake. The high concentration of solid drug nanoparticles provided additional cake stability. The results of this study confirm for the first time that primary drying for drug nanosuspensions can be greatly shortened because induced viscous flow or even meltback is not a limitation for nanoparticle stability and cake elegancy. PMID- 21607962 TI - Review of the evolution of electrodiagnostic criteria for chronic inflammatory demyelinating polyradicoloneuropathy. AB - Chronic inflammatory demyelinating polyradicoloneuropathy (CIDP) is a treatable form of neuropathy. Efforts to devise sets of electrodiagnostic (nerve conduction) criteria to distinguish primary demyelination from primary axonal neuropathies have been elusive, and at least 16 criteria have been proposed. Modifications to criteria frequently represent minor changes based on applying a set to a small number of patients with the clinical diagnosis of CIDP, whereas others are based on physiological changes related to demyelination and other pathophysiological features. The various modifications continue to result in limited sensitivity, likely related to the wide range of nerve conduction abnormalities among CIDP patients. Although some sets are appropriate for formal clinical drug trials, their complexity makes them difficult to apply in the clinic or electromyography laboratory. This study considers the evolution of the criteria, discusses their limitations, and ends with a simplified set of guidelines that can be applied in the clinic or laboratory. PMID- 21607963 TI - Quantification of changes in muscle from individuals with and without mitochondrial disease. AB - INTRODUCTION: Muscle biopsy is used in the diagnosis of mitochondrial disorders. There are limited data on the normal ranges, so interpretation of findings can be difficult. METHODS: We evaluated the percentage of fibers showing mitochondrial abnormalities using Gomori trichrome staining, succinate dehydrogenase, and cytochrome oxidase histochemistry in autopsy samples taken from 45 individuals without evidence of muscle disease and biopsies from 17 patients with mitochondrial disorders. RESULTS: In controls, mitochondrial abnormalities were rare before the fifth decade, and most had <0.1% abnormal fibers. The proportion of abnormal fibers increased with age and was higher in deltoid than quadriceps. Most patients with mitochondrial disorders had >0.5% abnormal fibers. CONCLUSIONS: Although some patients with mitochondrial disease have very few muscle fibers that show mitochondrial abnormalities, a rate of abnormality of >0.5% fibers, in the absence of a primary muscle disease this should raise the possibility of a mitochondrial disorder. PMID- 21607964 TI - Analysis of continuous diaphragm electromyographic signal: results from a patient with amyotrophic lateral sclerosis. AB - INTRODUCTION: Analysis of continuous diaphragm electromyography (dEMG) has not been well studied. We describe a system of analyzing continuous dEMG using implanted electrodes. METHODS: dEMG signal was acquired via two pairs of electrodes near the diaphragm motor points. Raw bursts of dEMG signal were compared to externally captured electrocardiogram (ECG) using adaptive filtering in order to remove cardiac contamination. Differential energy levels were used to identify each dEMG burst, and average amplitude and area values from both hemidiaphragms were aggregated and averaged for the duration of the recording. RESULTS: A 64-year-old patient with amyotrophic lateral sclerosis underwent three serial dEMG studies every 6 months. An average of three tracings were collected per visit, and all had excellent intertest reliability (kappa > 0.8). Average dEMG area correlated with forced vital capacity and mean inspiratory pressure (r(2) > 0.9). CONCLUSIONS: The approach described represents a comprehensive method for capturing and analyzing continuous diaphragm EMG signal. PMID- 21607965 TI - Jaw muscle weakness: a differential indicator of neuromuscular weakness- preliminary observations. AB - INTRODUCTION: Flaccid quadriparesis is a common neurological problem. Guillain Barre syndrome Guillain-Barre syndrome (GBS), polymyositis/dermatomyositis (PM/DM), generalized myasthenia gravis (MG), and hypokalemic periodic paralysis (HPP) constitute the majority of cases of flaccid quadriparesis. Few patients from any of these disease groups lack the cardinal clinical features. We established clinical marker(s) that might have significant discriminating power for diagnosis. METHODS: Forty-six patients satisfied all of our criteria. Cases were evaluated clinically followed by laboratory and electrophysiological study, and, in selected cases, muscle histopathology. RESULTS: Twenty-four patients had GBS, 9 had MG, 7 had PM/DM, and 6 had HPP. Jaw-opening weakness was found in 71.4% of PM/DM, 83.3% of HPP, and 4.1% of GBS cases. Jaw-closing weakness was found in 88.8% of MG cases. CONCLUSIONS: Presence of jaw-closing weakness pointed toward MG, whereas presence of jaw-opening weakness suggested muscle disease (PM/DM and HPP). GBS patients very rarely had jaw muscle weakness. PMID- 21607966 TI - Electrodiagnostic consultation and identification of neuromuscular conditions in persons with diabetes. AB - INTRODUCTION: Although the American Association of Neuromuscular and Electrodiagnostic Medicine recommends that electrodiagnostic procedures should be performed by physicians with specialty training, these procedures are increasingly being performed by non-specialists. METHODS: We used a nationally representative sample of Medicare beneficiaries with diabetes who used electrodiagnostic services in 2006 to examine whether specialists and non specialists were different in the rates of identifying common neuromuscular conditions. RESULTS: Specialists (neurologists and physiatrists) performed 62% of electrodiagnostic consultations; non-specialist physicians and non-physicians performed 31% and 5%, respectively. After adjusting for age, race/ethnicity, diabetes severity, and comorbidities, specialists were 1.26-9 times more likely than non-physicians to diagnose polyneuropathy, lumbosacral radiculopathy, cervical radiculopathy, carpal tunnel syndrome, and ulnar neuropathy. Almost 80% of electrodiagnostic studies performed by specialists included electromyography testing; fewer than 13% by non-specialists did. CONCLUSIONS: Inadequate use of electromyography and fewer specific diagnoses suggest that many non-specialists perform insufficiently comprehensive electrodiagnostic studies. PMID- 21607967 TI - Exercise-induced muscle growth is muscle-specific and age-dependent. AB - INTRODUCTION: Sarcopenia, and the importance of satellite cells (SCs) in muscle growth led us to examine the effects of exercise and age on SC activation and gene expression. METHODS: Eight- and 18-month-old mice were either sedentary or underwent 3 weeks of exercise (N = 24). Body mass, distance traveled, and grip strength were recorded at weekly intervals. The extensor digitorum longus (EDL), tibialis anterior (TA), gastrocnemius (GAST), and quadriceps (QUAD) muscles were analyzed along with muscle fiber area, SC activation, neuronal nitric oxide synthase (NOS-I), MyoD, and myostatin protein content. RESULTS: Older mice demonstrated decreased body mass, grip strength, and fiber area, but these changes were not affected by exercise. The QUAD muscle from young mice demonstrated an exercise-induced increase in SC activation and NOS-I and downregulation of myostatin. CONCLUSIONS: Exercise-induced activation of SCs and regulation of gene expression are muscle-specific and age-dependent. Perturbed sensitivity to exercise in older mice provides insight into sarcopenia and potential treatments. PMID- 21607968 TI - Crossed spinal soleus muscle communication demonstrated by H-reflex conditioning. AB - INTRODUCTION: A conditioning volley to the ipsilateral tibial nerve (iTN) inhibits contralateral soleus (cSOL) electromyographic activity at latencies of 37-41 ms. This is evidence for spinal muscular communication in opposing limbs. The aim of our study was to determine whether the cSOL H-reflex would be inhibited in a similar manner. METHODS: Thirteen subjects participated in two experiments: (1) stimuli delivered to the iTN at 85% of the maximal peak-to-peak M-wave (85% M-max) with a pre-contracted cSOL; (2) 510 stimuli delivered at 85% M max to the iTN with a test volley delivered to the contralateral tibial nerve at interstimulus intervals of -6 to 100 ms. RESULTS: Significant inhibition was observed in the cSOL H-reflex when conditioning stimuli were delivered 3-33 ms before the test H-reflex. CONCLUSIONS: The activity of this spinal pathway can be quantified using H-reflex conditioning to provide a controlled model for further studies of this response. PMID- 21607969 TI - A novel mutation of gap junction protein beta 1 gene in X-linked Charcot-Marie Tooth disease. AB - INTRODUCTION: In this study we report a novel mutation in the gap junction protein beta 1 (GJB1) gene of a Chinese X-linked Charcot-Marie-Tooth disease (CMTX1) family, which has specific electrophysiological characteristics. METHODS: Twenty members in the family were studied by clinical neurological examination and GJB1 gene mutation analysis, and 3 patients were studied electrophysiologically. The proband and his mother also underwent sural nerve biopsy. RESULTS: All patients have the CMT phenotype, except for 2 asymptomatic carriers. Electrophysiological examinations showed non-uniform slowing of motor conduction velocities and partial motor conduction blocks and temporal dispersion. Sural nerve biopsy confirmed a predominantly demyelinating neuropathy, and an Asn2Lys mutation in the amino-terminal domain was found in 9 members of this family, but not in 25 normal controls in the family. CONCLUSIONS: This family represents a novel mutation in the GJB1 form of CMTX1. The mutation in the amino-terminus has an impact on the electrophysiological characteristics of the disease. PMID- 21607970 TI - Safety of influenza and H1N1 vaccinations in patients with myasthenia gravis, and patient compliance. AB - Myasthenia gravis (MG) exacerbations may be triggered by infections.In the winter of 2009/2010, the Israeli Ministry of Health recommended that each individual with a chronic condition be vaccinated against both the seasonal influenza and the H1N1 virus. We examined vaccination practices in 74 MG patients. Only 38 patients (51.4%) received the seasonal influenza vaccine, and 24 (32.4%) received the H1N1 vaccine. No exacerbation of MG was found, and therefore seasonal influenza and H1N1 vaccines seem to be safe in MG. PMID- 21607971 TI - Number of motor units in human abductor hallucis. AB - Motor unit number was estimated for the human abductor hallucis (AH) muscle in 11 subjects by counting the number of increments in surface electromyographic responses to progressive increases in current-pulse amplitude applied to the muscle-nerve. The average motor unit count for AH (43) was substantially smaller than that estimated for other human muscles. Consequently, motor unit activity should be readily recordable up to high forces in AH, making it well suited for studies of recruitment and rate coding. PMID- 21607972 TI - Electrical conduction block in large nerves: high-frequency current delivery in the nonhuman primate. AB - Recent studies have made significant progress toward the clinical implementation of high-frequency conduction block (HFB) of peripheral nerves. However, these studies were performed in small nerves, and questions remain regarding the nature of HFB in large-diameter nerves. This study in nonhuman primates shows reliable conduction block in large-diameter nerves (up to 4.1 mm) with relatively low threshold current amplitude and only moderate nerve discharge prior to the onset of block. PMID- 21607973 TI - A case of sensory ataxia as the presenting manifestation of neurosarcoidosis. AB - Sarcoidosis rarely selectively affects the cauda equina with characteristic motor and sensory impairments.Using imaging, we report a case of cauda equina polyradiculopathy presenting with progressive sensory ataxia without clinical or electrophysiological evidence of motor involvement. Neurosarcoidosis was diagnosed pathologically by proximal dorsal root biopsy after systemic investigations for inflammatory, infectious, and neoplastic etiologies were found to be negative. There was clinical and radiographic improvement with corticosteroids. In addition, we review previously reported cases of cauda equina sarcoidosis. PMID- 21607974 TI - Primary amyloidosis presenting as "dropped head syndrome". AB - A 77-year-old man, with a history of lymphoma, presented with isolated neck extensor weakness and a 2-year history of bilateral carpal tunnel syndrome (CTS). Needle electromyography showed myopathic changes, and biopsy of cervical paraspinal muscles showed amyloid deposition in blood vessels. Amyloidosis should be considered in the differential diagnosis of dropped head syndrome. PMID- 21607975 TI - Although olfactory ensheathing cells have remarkable potential to sustain nerve regeneration, they cannot be applied to a severe vagus nerve section/resection model. PMID- 21607976 TI - Methods of sudomotor innervation quantification. PMID- 21607978 TI - Distinct cytokine patterns associated with different forms of chronic dysimmune neuropathy. PMID- 21607982 TI - Axonal hyperpolarization in inclusion-body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD). AB - INTRODUCTION: Inclusion-body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder due to mutations in the valosin-containing protein (VCP) gene. Patients with this disorder may have neuropathic or myopathic features. METHODS: Peripheral nerve function and axonal excitability were studied in three members from two families with VCP mutations (p.Arg155Leu and p.Leu198Trp). RESULTS: Patients from the first family had neurogenic patterns on needle electromyography (EMG), whereas those in the second family had myopathic EMG changes. In threshold electrotonus for motor axons, the changes to depolarizing and hyperpolarizing conditioning currents were at or outside control limits in all three patients. Superexcitability was increased, and the relative refractory period was reduced. The strength-duration time constant was normal. In sensory axons of all three patients, there were similar changes in threshold electrotonus, but not in superexcitability. DISCUSSION: These features are best explained by axonal hyperpolarization. The findings provide insight into the pathophysiological mechanisms in these genotypes and, possibly, into all patients with IBMPFD. PMID- 21607983 TI - Fluoroquinolones influence the intracellular calcium handling in individuals susceptible to malignant hyperthermia. AB - INTRODUCTION: The mechanisms of fluoroquinolone-induced myotoxicity are unknown but an involvement of intracellular calcium handling is suspected. An in vitro contracture test used to investigate cellular processes in malignant hyperthermia (MH) can be applied to study the effects of fluoroquinolones. METHODS: With approval of the local ethics committee, muscle biopsies of 18 MH susceptible (MHS) and 12 MHS non-susceptible (MHN) pigs were performed. Individual bundles were mounted on an isometric force transducer, preloaded, and electrically stimulated. After equilibration they were exposed to ciprofloxacin or levofloxacin. The measured baseline tension was analyzed (Wilcoxon test: P < 0.05). RESULTS: There were no differences in weight, length, or predrug tension between the groups. Both levofloxacin an ciprofloxacin induced significant contractures in MHS muscle bundles but not in MHN. CONCLUSIONS: Fluoroquinolones appear to have a pathological influence on intracellular calcium handling. A pre existing impairment of the calcium homeostasis, however, seems to be necessary for this behavior. PMID- 21607984 TI - Succinylcholine in malignant hyperthermia: evaluation of a novel in vivo model. AB - INTRODUCTION: Malignant hyperthermia (MH) is a potentially lethal anesthetic complication characterized by muscle hypermetabolism and generalized rigor. The exact mechanism of succinylcholine as an MH trigger cannot be examined in existing in vitro models. Therefore, a novel in vivo model was used to examine the metabolic response to succinylcholine. METHODS: With institutional review board approval, 6 MH susceptible (MHS) and 6 MH non-susceptible (MHN) pigs were anesthetized with hemodynamic and systemic metabolic monitoring. Microdialysis catheters were placed intramuscularly. After equilibration, succinylcholine, halothane, and Ringer solution were injected. Lactate was measured in the dialysate and statistically analyzed by Mann-Whitney U-test (significance level P < 0.05). RESULTS: Hemodynamic and systemic metabolic parameters were not different between the groups throughout the experiment. In the MHS pigs, halothane induced a significant increase of lactate. In MHN pigs, no substance induced a reaction. CONCLUSIONS: Halothane, but not succinylcholine, induced a hypermetabolic reaction in this model. Therefore, the role of succinylcholine as an MH trigger remains questionable. PMID- 21607985 TI - Therapeutics development in myotonic dystrophy type 1. AB - Myotonic dystrophy (DM1), the most common adult muscular dystrophy, is a multisystem, autosomal dominant genetic disorder caused by an expanded CTG repeat that leads to nuclear retention of a mutant RNA and subsequent RNA toxicity. Significant insights into the molecular mechanisms of RNA toxicity have led to the previously unforeseen possibility that treating DM1 is a viable prospect. In this review, we briefly present the clinical picture in DM1, and describe how the research in understanding the pathogenesis of RNA toxicity in DM1 has led to targeted approaches to therapeutic development at various steps in the pathogenesis of the disease. We discuss the promise and current limitations of each with an emphasis on RNA-based therapeutics and small molecules. We conclude with a discussion of the unmet need for clinical tools and outcome measures that are essential prerequisites to proceed in evaluating these potential therapies in clinical trials. PMID- 21607986 TI - What does body mass index measure in amyotrophic lateral sclerosis and why should we care? PMID- 21607987 TI - Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. AB - INTRODUCTION: Recent studies have provided conflicting data regarding the role of dyslipidemia in amyotrophic lateral sclerosis (ALS). The aim of this study was to determine whether cholesterol level are an independent predictor of survival in ALS. METHODS: Cholesterol levels were measured in 427 ALS subjects from three clinical trial databases. RESULTS: The LDL/HDL ratio did not decrease over time, despite significant declines in body mass index (BMI), forced vital capacity (FVC), and ALSFRS-R. After adjusting for BMI, FVC, and age, the lipid ratio was not associated with survival. There was a "U"-shaped association between BMI and mortality, with the highest survival at 30-35 kg/m(2). The adjusted hazard ratio for the linear association between BMI and survival was 0.860 (95% CI 0.80-0.93, P = 0.0001). CONCLUSIONS: We found that dyslipidemia is not an independent predictor of survival in ALS. BMI is an independent prognostic factor for survival after adjusting for markers of disease severity. PMID- 21607989 TI - Biotin-modified glutathione as a functionalized coating for bioconjugation of CdTe-based quantum dots. AB - In this study, biotin-conjugated glutathione was synthesized using peptide bonding of the biotin carboxy group and amino group of the gamma-glutamic acid to prepare an alternative coating for CdTe quantum dots (QDs). This type of coating combines the functionality of the biotin with the fluorescent properties of the QDs to create a specific, high-affinity fluorescent probe able to react with avidin, streptavidin and/or neutravidin. Biotin-functionalized glutathione-coated CdTe QDs were prepared by a simple one-step method using Na2 TeO3 and CdCl2. Obtained QDs were separated from the excess of the biotin-conjugated glutathione by CE employing 300 mM borate buffer with pH 7.8 as a background electrolyte. The detection of sample components was performed by the photometric detection at 214 nm and LIF employing Ar+ ion laser (488 nm). PMID- 21607990 TI - Unmasking low-abundance peptides from human blood plasma and serum samples by a simple and robust two-step precipitation/immunoaffinity enrichment method. AB - Proteomic analysis of human plasma and serum for identifying and validating disease-specific marker proteins and peptides has one major drawback besides its unique advantage as a readily available sample source for diagnostic assays. This disadvantage is represented by the predominance of several high- and middle abundant proteins, which clearly hamper identification and quantification approaches of potential and validated protein and peptide biomarkers, which are often of very low abundance. During the last decades, a significant number of depletion and enrichment techniques evolved to address these two issues. We present here a cost-effective and easy-to-use strategy for protein depletion comprising a thermal precipitation protocol followed by a two-step liquid/liquid precipitation as well as using an immunoaffinity chromatography method for the specific enrichment and isolation of the low-abundance polypeptide N-terminal pro B-type natriuretic peptide and its precursor proBNP clinically used as biomarkers for the detection of severe human heart failure and related diseases. The applicability of this approach is shown by SDS -CGE, SDS-PAGE, electrochemiluminescence immunoassay and nano-LC ESI-MS/MS. Our thermal precipitation protocol followed by a two-step liquid/liquid precipitation could also serve as a potential depletion technique for the characterization of other low-abundance peptides and proteins. PMID- 21607991 TI - Avoiding the van der Waals endpoint problem using serial atomic insertion. AB - In the past analyses of the so-called van der Waals end point problem focused on thermodynamic integration. Here we investigate which of the recommendations, such as the need for soft-core potentials, are still valid when Bennett's acceptance ratio method is used. We show that in combination with Bennett's acceptance ratio method intermediate states characterized by the coupling parameter lambda can be replaced by intermediate states in which Lennard-Jones interactions are turned on or off on an "atom by atom" basis. By doing so, there is no necessity to use soft core potentials. In fact, one can compute free energy differences without dedicated code, making it possible to use any molecular dynamics program to compute alchemical free energy differences. Such an approach, which we illustrate by several examples, makes it possible to exploit the tremendous computational power of the graphics processing unit. PMID- 21607992 TI - Commercial naphthenic acids and the organic fraction of oil sands process water induce different effects on pro-inflammatory gene expression and macrophage phagocytosis in mice. AB - Naphthenic acids (NAs) are believed to be the major toxic component of oil sands process water (OSPW). Different OSPW preparations have distinct NA compositions, and additional organics, that differ from the commercial NAs (C-NAs) often used for toxicology studies. To evaluate whether C-NAs are an adequate model to study OSPW toxicity in complex organisms, we compared the effects of C-NAs and the extractable organic fraction of OSPW (OSPW-OF) on mice immune mechanisms. Mice were orally exposed to different C-NA doses, or OSPW-OF at the same NA dose, for up to 8 weeks, and the expression of pro-inflammatory genes in different organs was determined using quantitative PCR. C-NAs and OSPW-OF altered the expression of pro-inflammatory genes, inducing either expression down-regulation or up regulation, depending on the organ examined and time after exposure. The time at which gene expression alterations occurred, and the specific sets of genes whose expression was altered, were very different between animals exposed to C-NAs or to OSPW-OF. We evaluated the ability of mouse peritoneal macrophages to phagocytose yeast cell wall, as a measure of the ability of mice to mount a central function of the innate immune response. Phagocytosis was significantly reduced in animals exposed to C-NAs, but enhanced in mice exposed to OSPW-OF. Our results indicate that studies using C-NAs may not necessarily reflect the possible effects induced in animals by process water from tailing ponds. PMID- 21607993 TI - Aluminum phosphide poisoning: an unsolved riddle. AB - Aluminum phosphide (ALP), a widely used insecticide and rodenticide, is also infamous for the mortality and morbidity it causes in ALP-poisoned individuals. The toxicity of metal phosphides is due to phosphine liberated when ingested phosphides come into contact with gut fluids. ALP poisoning is lethal, having a mortality rate in excess of 70%. Circulatory failure and severe hypotension are common features of ALP poisoning and frequent cause of death. Severe poisoning also has the potential to induce multi-organ failure. The exact site or mechanism of its action has not been proved in humans. Rather than targeting a single organ to cause gross damage, ALP seems to work at the cellular level, resulting in widespread damage leading to multiorgan dysfunction (MOD) and death. There has been proof in vitro that phosphine inhibits cytochrome c oxidase. However, it is unlikely that this interaction is the primary cause of its toxicity. Mitochondria could be the possible site of maximum damage in ALP poisoning, resulting in low ATP production followed by metabolic shutdown and MOD; also, owing to impairment in electron flow, there could be free radical generation and damage, again producing MOD. Evidence of reactive oxygen species-induced toxicity owing to ALP has been observed in insects and rats. A similar mechanism could also play a role in humans and contribute to the missing link in the pathogenesis of ALP toxicity. There is no specific antidote for ALP poisoning and supportive measures are all that are currently available. PMID- 21607994 TI - Acute administration of toluene affects memory retention in novel object recognition test and memory function-related gene expression in mice. AB - The present study was designed to investigate the acute effect of a single administration of toluene (300 mg kg(-1), i.p.) on memory retention in the hippocampus-dependent novel object recognition test and N-methyl-D-aspartate (NMDA) receptor subunit expression in the hippocampus of C3H/HeN female mice using real-time RT-PCR. We performed a novel object recognition test including a habituation phase, training phase and test phase in each mouse. Twenty-four hours after the training phase, to determine the effect of acute toluene administration on memory retention, half of the mice (n=10) were injected with toluene 60 min before the test phase. Toluene-injected mice did not prefer novel objects and showed poor discrimination between novel and familiar objects and decreased expression of NMDA receptor subunit NR2B mRNA in the hippocampus. This is the first study to show that acute toluene injection impairs hippocampus-dependent nonspatial memory retention accompanied by selective modulation of NMDA receptor subunit expression. PMID- 21607996 TI - Towards cracking the epigenetic code using a combination of high-throughput epigenomics and quantitative mass spectrometry-based proteomics. AB - High-throughput genomic sequencing and quantitative mass spectrometry (MS)-based proteomics technology have recently emerged as powerful tools, increasing our understanding of chromatin structure and function. Both of these approaches require substantial investments and expertise in terms of instrumentation, experimental methodology, bioinformatics, and data interpretation and are, therefore, usually applied independently from each other by dedicated research groups. However, when applied reiteratively in the context of epigenetics research these approaches are strongly synergistic in nature. PMID- 21607995 TI - Retinal determination genes function along with cell-cell signals to regulate Drosophila eye development: examples of multi-layered regulation by master regulators. AB - It is thought that retinal determination (RD) gene products define the response made to cell-cell signals in the field of eye development by binding to enhancers of genes that are also regulated by cell-cell signaling pathways. In Drosophila, RD genes, including eyeless, teashirt, eyes absent, dachsous, and sine oculis, are required for normal eye development and can induce ectopic eyes when mis expressed. Characterization of the enhancers responsible for eye expression of the hedgehog, shaven, and atonal genes, as well as the dynamics of RD gene expression themselves, now suggest a multilayered network whereby transcriptional regulation by either RD genes or cell-cell signaling pathways can sometimes be indirect and mediated by other transcription factor intermediates. In this updated view of the interaction between extracellular information and cell intrinsic programs during development, regulation of individual genes might sometimes be several steps removed from either the RD genes or the cell-cell signaling pathways that nevertheless govern their expression. PMID- 21607997 TI - Determination of chlorfenapyr in leek grown under greenhouse conditions with GC MUECD and confirmation by mass spectrometry. AB - A simple analytical method was developed for the determination of chlorfenapyr residues in leeks grown under greenhouse conditions. Residues were extracted by salting out, analyzed by gas chromatography with microelectron-capture detection, and confirmed via gas chromatography-mass spectrometry. The calibration curves were found to be linear with correlation coefficients (r(2) ) in excess of 0.998. The limits of detection and quantification were 0.0015 and 0.005 mg kg(-1) , respectively. For validation purposes, recovery studies were carried out at low and high levels. Yield recovery rates were 87.27-89.64% with a relative standard deviation <6%. A maximum of 0.32 mg kg(-1) of chlorfenapyr residue was detected in leek sample sprayed three times at 7 day intervals until 7 days prior to harvest. The results of this study suggest that chlorfenapyr is acceptable for application in/on leeks under the recommended dosage regimen. PMID- 21607998 TI - Stem cells or macrophages: which contribute to bone marrow cell therapy for liver cirrhosis? PMID- 21607999 TI - Saffron: a potential candidate for a novel anticancer drug against hepatocellular carcinoma. AB - Saffron has been proposed as a promising candidate for cancer chemoprevention. The purpose of this investigation was to investigate the chemopreventive action and the possible mechanisms of saffron against diethylnitrosamine (DEN)-induced liver cancer in rats. Administration of saffron at doses of 75, 150, and 300 mg/kg/day was started 2 weeks prior to the DEN injection and was continued for 22 weeks. Saffron significantly reduced the DEN-induced increase in the number and the incidence of hepatic dyschromatic nodules. Saffron also decreased the number and the area of placental glutathione S-transferase-positive foci in livers of DEN-treated rats. Furthermore, saffron counteracted DEN-induced oxidative stress in rats as assessed by restoration of superoxide dismutase, catalase, and glutathione-S-transferase levels and diminishing of myeloperoxidase activity, malondialdehyde and protein carbonyl formation in liver. The results of immunohistochemical staining of rat liver showed that saffron inhibited the DEN mediated elevations in numbers of cells positive for Ki-67, cyclooxygenase 2, inducible nitric oxide synthase, nuclear factor-kappa B p-65, and phosphorylated tumor necrosis factor receptor. Saffron also blocked the depletion in the number of cells positive for TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) and M30 CytoDeath in liver tissues of DEN-treated rats. In vitro experiments carried out using HepG2 cells also confirmed these findings and showed inhibition of nuclear factor-kappa B activation, increased cleavage of caspase-3, as well as DNA damage and cell cycle arrest upon saffron treatment. CONCLUSION: This study provides evidence that saffron exerts a significant chemopreventive effect against liver cancer through inhibition of cell proliferation and induction of apoptosis. This report also shows some evidence that saffron protects rat liver from cancer via modulating oxidative damage and suppressing inflammatory response. PMID- 21608000 TI - Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes. AB - Our study aimed to investigate the short-term efficacy and long-term prognosis of liver failure patients caused by hepatitis B after a single transplantation with autologous marrow mesenchymal stem cells (MMSCs). A total of 527 inpatients with liver failure caused by hepatitis B were recruited and received the same medical treatments, among whom 53 patients underwent a single transplantation with autologous MMSCs. A total of 105 patients matched for age, sex, and biochemical indexes, including alanine aminotransferase (ALT), albumin, total bilirubin (TBIL), prothrombin time (PT), and Model for End-Stage Liver Disease (MELD), comprised the control group. A total of 120 mL of bone marrow was obtained from each patient and then diluted and separated. Then, the MMSC suspension was slowly transfused into the liver through the proper hepatic artery. The success rate of transplantation was 100%, without serious side effects or complications. Levels of ALB, TBIL, and PT and MELD score of patients in the transplantation group were markedly improved from 2-3 weeks after transplantation, compared with those in the control group. At 192 weeks of follow-up, there were no dramatic differences in incidence of hepatocellular carcinoma (HCC) or mortality between the two groups. Additionally, there were no significant differences in the incidence of HCC or mortality between patients with and without cirrhosis in the transplantation group. CONCLUSION: Autologous MMSC transplantation is safe for liver failure patients caused by chronic hepatitis B. Short-term efficacy was favorable, but long-term outcomes were not markedly improved. In respect to several parameters, this method is preferable for patients with liver cirrhosis and may have potential for reducing their incidence of HCC and mortality. PMID- 21608001 TI - Dr. Jekyll and Mr. Hyde: a paradoxical oncogenic and tumor suppressive role of signal transducer and activator of transcription 3 in liver cancer. PMID- 21608002 TI - Absence of occult hepatitis C virus infection in patients under immunosupressive therapy for oncohematological diseases. PMID- 21608003 TI - Metabolic syndrome and liver cancer: is excess iron the link? PMID- 21608005 TI - Raised sympathetic activity and blood ammonia could increase sensitivity to infections in patients with cirrhosis and refractory ascites who are using beta blockers. PMID- 21608006 TI - Association of the cannabinoid receptor 2 (CB2) Gln63Arg polymorphism with indices of liver damage in obese children: an alternative way to highlight the CB2 hepatoprotective properties. PMID- 21608007 TI - MicroRNAs-372/373 promote the expression of hepatitis B virus through the targeting of nuclear factor I/B. AB - MicroRNAs (miRNAs) play important roles in the posttranscriptional regulation of gene expression. Recent evidence has indicated the pathological relevance of miRNA dysregulation in hepatitis virus infection; however, the roles of microRNAs in the regulation of hepatitis B virus (HBV) expression are still largely unknown. In this study we identified that miR-373 was up-regulated in HBV infected liver tissues and that the members of the miRs-371-372-373 (miRs-371-3) gene cluster were also significantly co-up-regulated in HBV-producing HepG2.2.15 cells. A positive in vivo association was identified between hepatic HBV DNA levels and the copy number variation of the miRs-371-3 gene cluster. The enhanced expression of miRs-372/373 stimulated the production of HBV proteins and HBV core associated DNA in HepG2 cells transfected with 1.3*HBV. Further, nuclear factor I/B (NFIB) was identified to be a direct functional target of miRs-372/373 by in silico algorithms and this was subsequently confirmed by western blotting and luciferase reporter assays. Knockdown of NFIB by small interfering RNA (siRNA) promoted HBV expression, whereas rescue of NFIB attenuated the stimulation in the 1.3*HBV-transfected HepG2 cells. CONCLUSION: Our study revealed that miRNA (miRs 372/373) can promote HBV expression through a pathway involving the transcription factor (NFIB). This novel model provides new insights into the molecular basis in HBV and host interaction. PMID- 21608008 TI - How tufted capuchin monkeys (Cebus apella spp) and common chimpanzees (Pan troglodytes) align objects to surfaces: insights into spatial reasoning and implications for tool use. AB - This report addresses phylogenetic variation in a spatial skill that underlies tool use: aligning objects to a feature of a surface. Fragaszy and Cummins Sebree's [Behavioral and Cognitive Neuroscience Reviews 4:282-306, 2005] model of relational spatial reasoning and Skill Development and Perception-Action theories guided the design of the study. We examined how capuchins and chimpanzees place stick objects of varying shapes into matching grooves on a flat surface. Although most individuals aligned the long axis of the object with the matching groove more often than expected by chance, all typically did so with poor precision. Some individuals managed to align a second feature, and only one (a capuchin monkey) achieved above-chance success at aligning three features with matching grooves. Our findings suggest that capuchins and chimpanzees do not reliably align objects along even one axis, and that neither species can reliably or easily master object placement tasks that require managing two or more spatial relations concurrently. Moreover, they did not systematically vary their behavior in a manner that would aid discovery of the affordances of the stick-surface combination beyond sliding the stick along the surface (which may have provided haptic information about the location of the groove). These limitations have profound consequences for the forms of tool use we can expect these individuals to master. PMID- 21608009 TI - Parental disorders, childhood abuse, and binge eating in a large community sample. AB - OBJECTIVE: Genetic and nonshared environmental factors are implicated in the etiology of binge eating behaviors (BEB), with genetic risk expressed as parental psychopathology. Traumatic experiences including child abuse predict onset of BEB. It is not clear if each separately contribute to BEB, or whether parental pathology leads to abuse which in turn influences BEB. METHOD: Data were obtained from the National Comorbidity Survey-Replication (N = 2960). Through structural equation modeling, we estimated unique and combined effects of mother's and father's internalizing (INT) and externalizing (EXT) disorders, and child abuse on BEB. RESULTS: Parental INT and EXT psychopathology contributed to child abuse and BEB. Abuse predicted BEB and partially mediated associations between parental psychopathology and BEB. DISCUSSION: Results emphasize the value of models that incorporate nature and nurture to understand risk for psychopathology in offspring, with childhood abuse being one mediator of how parental psychopathology may reflect genetic risk and influence environmental risk. PMID- 21608010 TI - Homogeneity test of rate ratios in stratified matched-pair studies. AB - This paper investigates homogeneity test of rate ratios in stratified matched pair studies on the basis of asymptotic and bootstrap-resampling methods. Based on the efficient score approach, we develop a simple and computationally tractable score test statistic. Several other homogeneity test statistics are also proposed on the basis of the weighted least-squares estimate and logarithmic transformation. Sample size formulae are derived to guarantee a pre-specified power for the proposed tests at the pre-given significance level. Empirical results confirm that (i) the modified score statistic based on the bootstrap resampling method performs better in the sense that its empirical type I error rate is much closer to the pre-specified nominal level than those of other tests and its power is greater than those of other tests, and is hence recommended, whilst the statistics based on the weighted least-squares estimate and logarithmic transformation are slightly conservative under some of the considered settings; (ii) the derived sample size formulae are rather accurate in the sense that their empirical powers obtained from the estimated sample sizes are very close to the pre-specified nominal powers. A real example is used to illustrate the proposed methodologies. PMID- 21608011 TI - Deficiency of the mitochondrial transporter of aspartate/glutamate aralar/AGC1 causes hypomyelination and neuronal defects unrelated to myelin deficits in mouse brain. AB - The aralar/AGC1 knockout (KO) mouse shows a drastic decrease in brain aspartate and N-acetylaspartate levels and global hypomyelination, which are attributed to the lack of neuron-produced NAA used by oligodendrocytes as precursor of myelin lipid synthesis. In addition, these mice have a gradual drop in brain glutamine synthesis. We show here that hypomyelination is more pronounced in gray than in white matter regions. We find a lack of neurofilament-labelled processes in hypomyelinated fiber tracks from cerebral cortex but not from those of the cerebellar granule cell layer, which correspond to Purkinje neurons. Therefore, the impaired development or degeneration of neuronal processes in cerebral cortex is independent of hypomyelination. An increase in O4-labelled, immature oligodendrocytes is observed in gray and white matter regions of the aralar KO brain, suggesting a block in maturation compatible with the lack of NAA supplied by neurons. However, no defects in oligodendrocyte maturation were observed in in vitro-cultured mixed astroglial cultures. We conclude that the primary defect of pyramidal neurons in cerebral cortex is possibly associated with a progressive failure in glutamatergic neurotransmission and may be among the main causes of the pathology of aralar/AGC1 deficiency. PMID- 21608012 TI - Nicotinamide adenine dinucleotide phosphate/neuronal nitric oxide synthase positive neurons in the trigeminal subnucleus caudalis involved in tooth pulp nociception. AB - Sensory information on facial structures, including teeth pulp, periodontium, and gingiva, is relayed in the trigeminal complex. Tooth pulp inflammation constitutes a common clinical problem, and this peripheral injury can induce neuroplastic changes in trigeminal nociceptive neurons. There is considerable evidence that the trigeminal subnucleus caudalis (Vc) is the principal relay for trigeminal nociceptive information as well as modulation of the painful stimuli. Glutamatergic primary afferents innervating the tooth pulp project to the most superficial laminae of the Vc. N-methyl-D-aspartate receptor stimulation leads to the activation of the enzyme nitric oxide synthase (NOS), which synthesizes the free radical nitric oxide (NO). This enzyme is expressed mainly in lamina II interneurons, and in a small number of cells in lamina I as well as in deep laminae projection neurons of Vc. In the present study, we analyzed the temporal changes in neuronal NOS (nNOS) in Vc local circuitries after unilateral intermediate molar pulp injury. Our results demonstrate that a peripheral dental pulp injury leads to neuroplastic changes in the relative amount and activity of nNOS enzyme. Moreover, after a period of time, the nitrergic system shifts to the initial values, independently of the persistence of inflammation in the pulp tissues. PMID- 21608013 TI - Amino acid analog toxicity in primary rat neuronal and astrocyte cultures: implications for protein misfolding and TDP-43 regulation. AB - Amino acid analogs promote translational errors that result in aberrant protein synthesis and have been used to understand the effects of protein misfolding in a variety of physiological and pathological settings. TDP-43 is a protein that is linked to protein aggregation and toxicity in a variety of neurodegenerative diseases. This study exposed primary rat neurons and astrocyte cultures to established amino acid analogs (canavanine and azetidine-2-carboxylic acid) and showed that both cell types undergo a dose-dependent increase in toxicity, with neurons exhibiting a greater degree of toxicity compared with astrocytes. Neurons and astrocytes exhibited similar increases in ubiquitinated and oxidized protein following analog treatment. Analog treatment increased heat shock protein (Hsp) levels in both neurons and astrocytes. In neurons, and to a lesser extent astrocytes, the levels of TDP-43 increased in response to analog treatment. Taken together, these data indicate that neurons exhibit preferential toxicity and alterations in TDP-43 in response to increased protein misfolding compared with astrocytes. PMID- 21608015 TI - Regulatory and pathogenesis roles of Mycobacterium Lrp/AsnC family transcriptional factors. AB - Lrp/AsnC (leucine-responsive regulatory protein/asparagine synthase C products) family transcriptional regulators, widespread among bacteria and archaea, is also known as feast/famine regulatory protein (FFRPs). They regulate multiple cellular metabolisms globally (Lrp) or specifically (AsnC), such as amino acid metabolism, pili synthesis, DNA transactions during DNA repair and recombination, and also might be implicated in persistence. To better understanding of the pathogenesis of M. tuberculosis, based on our lab's work on this transcriptional factor family, these progresses are summarized, with special focus on that of Mycobacterium via comparative genomics. PMID- 21608014 TI - The bromodomain-containing gene BRD2 is regulated at transcription, splicing, and translation levels. AB - The human BRD2 gene has been linked and associated with a form of common epilepsy and electroencephalographic abnormalities. Disruption of Brd2 in the mouse revealed that it is essential for embryonic neural development and that viable Brd2(+/-) heterozygotes show both decreased GABAergic neuron counts and increased susceptibility to seizures. To understand the molecular mechanisms by which mis expression of BRD2 might contribute to epilepsy, we examined its regulation at multiple levels. We discovered that BRD2 expresses distinct tissue-specific transcripts that originate from different promoters and have strikingly different lengths of 5' untranslated regions (5'UTR). We also experimentally confirmed the presence of a highly conserved, alternatively spliced exon, inclusion of which would result in a premature termination of translation. Downstream of this alternative exon is a polymorphic microsatellite (GT-repeats). Manipulation of the number of the GT-repeats revealed that the length of the GT-repeats affects the ratio of the two alternative splicing products. In vitro translation and expression in cultured cells revealed that among the four different mRNAs (long and short 5'UTR combined with regular and alternative splicing), only the regularly spliced mRNA with the short 5'UTR yields full-length protein. In situ hybridization and immunohistochemical studies showed that although Brd2 mRNA is expressed in both the hippocampus and cerebellum, Brd2 protein only can be detected in the cerebellar Purkinje cells and not in hippocampal cells. These multiple levels of regulation would likely affect the production of functional BRD2 protein during neural development and hence, its role in the etiology of seizure susceptibility. PMID- 21608016 TI - Activation by 2-arachidonoylglycerol of platelet p38MAPK/cPLA2 pathway. AB - The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) is described as a platelet agonist able to induce aggregation and to increase intracellular calcium. In the present report we have confirmed these data and demonstrated that the inhibitor of p38MAPK SB203580 and the inhibitor of cPLA(2) metabolism ETYA affect both these parameters. Thus, we aimed to define the role of p38MAPK/cytosolic phospholipase A(2) (cPLA(2)) pathway in 2-AG-induced human platelet activation. p38MAPK activation was assayed by phosphorylation. cPLA(2) activation was assayed by phosphorylation and as arachidonic acid release and thromboxane B(2) formation. It was shown that 2-AG in a dose- and time-dependent manner activates p38MAPK peaking at 10 uM after 1 min of incubation. The 2-AG effect on p38MAPK was not impaired by apyrase, indomethacin or RGDS peptide but it was significantly reduced by SR141716, specific inhibitor of type-1 cannabinoid receptor and unaffected by the specific inhibitor of type-2 cannabinoid receptor SR144528. Moreover, the incubation of platelets with 2-AG led to the phosphorylation of cPLA(2) and its activation. Platelet pretreatment with SB203580, inhibitor of p38MAPK, abolished both cPLA(2) phosphorylation and activation. In addition SR141716 strongly impaired cPLA(2) phosphorylation, arachidonic acid release and thromboxane B(2) formation, whereas SR144528 did not change these parameters. Finally platelet stimulation with 2-AG led to an increase in free oxygen radical species. In conclusion, data provide insight into the mechanisms involved in platelet activation by 2-AG, indicating that p38MAPK/cPLA(2) pathway could play a relevant role in this complicated process. PMID- 21608017 TI - Anion exchanger 3 is required for sasanquasaponin to inhibit ischemia/reperfusion induced elevation of intracellular Cl- concentration and to elicit cardioprotection. AB - Recent studies have shown that the cardioprotection of sasanquasaponin (SQS) against ischemia/reperfusion injury is related to inhibiting ischemia/reperfusion induced elevation of intracellular Cl(-) concentration ([Cl(-) ](i)). However, the mechanism of inhibition remains unclear. Anion exchanger 3 (AE(3)) is an important regulatory protein for [Cl(-)](i). This study investigated whether AE(3) plays the critical role in the inhibitory effect of SQS on elevation of [Cl(-)](i) induced by ischemia/reperfusion and mediates the cardioprotection of SQS in H9c2 cells. Normal and AE(3) -knockdown H9c2 cells were incubated for 24 h with or without various concentrations of SQS (0.1, 1, or 10 uM) followed by simulated ischemia/reperfusion (sI/R). AE(3) expression was detected by Western blot. Flow cytometer analysis was employed to determine [Cl(-)](i,) [Ca(2+)](i) , reactive oxygen species (ROS) production, and cell apoptosis. The results showed that SQS pretreatment concentration-dependently attenuated sI/R-induced viability loss and lactate dehydrogenase leakage in normal H9c2 cells. Additionally, SQS concentration-dependently up-regulated AE(3) protein expression, and inhibited sI/R-induced the elevation of [Cl(-)](i) followed by the attenuation of Ca(2+) overload, ROS production, and cell apoptosis. However, the dose-dependent cardioprotection induced by SQS was abolished in AE(3) -knockdown H9c2 cells, and the inhibitory effects of SQS on [Cl(-)](i), Ca(2+) overload, ROS production, and cell apoptosis were also reversed. Our data indicate that AE(3) mediates the cardioprotective effect of SQS against sI/R injury. Importantly, AE(3) is required for SQS to inhibit sI/R-induced elevation of [Cl(-)](i), which subsequently inhibited sI/R-induced Ca(2+) overload, ROS production, and cell apoptosis. PMID- 21608018 TI - Role of glucose as a modulator of anabolic and catabolic gene expression in normal and osteoarthritic human chondrocytes. AB - Cartilage matrix homeostasis involves a dynamic balance between numerous signals that modulate chondrocyte functions. This study aimed at elucidating the role of the extracellular glucose concentration in modulating anabolic and catabolic gene expression in normal and osteoarthritic (OA) human chondrocytes and its ability to modify the gene expression responses induced by pro-anabolic stimuli, namely Transforming Growth Factor-beta (TGF). For this, we analyzed by real time RT-PCR the expression of articular cartilage matrix-specific and non-specific genes, namely collagen types II and I, respectively. The expression of the matrix metalloproteinases (MMPs)-1 and -13, which plays a major role in cartilage degradation in arthritic conditions, and of their tissue inhibitors (TIMP) was also measured. The results showed that exposure to high glucose (30 mM) increased the mRNA levels of both MMPs in OA chondrocytes, whereas in normal ones only MMP 1 increased. Collagen II mRNA was similarly increased in normal and OA chondrocytes, but the increase lasted longer in the later. Exposure to high glucose for 24 h prevented TGF-induced downregulation of MMP-13 gene expression in normal and OA chondrocytes, while the inhibitory effect of TGF on MMP-1 expression was only partially reduced. Other responses were not significantly modified. In conclusion, exposure of human chondrocytes to high glucose, as occurs in vivo in diabetes mellitus patients and in vitro for the production of engineered cartilage, favors the chondrocyte catabolic program. This may promote articular cartilage degradation, facilitating OA development and/or progression, as well as compromise the quality and consequent in vivo efficacy of tissue engineered cartilage. PMID- 21608019 TI - Sex, fiber-type, and age dependent in vitro proliferation of mouse muscle satellite cells. AB - During postnatal growth and after muscle injury, satellite cells proliferate and differentiate into myotubes to form and repair musculature. Comparison of studies on satellite cell proliferation and differentiation characteristics is confounded by the heterogeneity of the experimental conditions used. To examine the influence of sex, age, and fiber-type origin on in vitro properties of satellite cells derived from postnatal muscles, fast extensor digitorum longus (EDL) and slow soleus (SOL) muscles were extracted from male and female mice of 1 week to 3 months of age. Myoblast proliferation and myogenic regulatory factor (MRF) expression was measured from cultures of freshly isolated satellite cells. Higher proliferation rate and elevated Myod1 expression was found in male EDL and SOL derived cells compared with females at age of 40, 60, and 120 days, whereas inverse tendency for cell proliferation was apparent in EDL of juvenile (7-day old) pups. Myogenin and Mrf4 transcripts were generally elevated in males of 40 and 60 days of age and in female EDL of juveniles. However, these differentiation markers did not significantly correlate with proliferation rate at all ages. Pax7, whose overexpression can block myogenesis, was up-regulated especially in 40-day-old females where MRF expression was low. These results indicate that gender, postnatal age, and muscle fiber origin affect proliferation and muscle transcription factor expression in vitro. The results also support the view that satellite cells originating from slow and fast muscles are intrinsically different and warrant further studies on the effect of cell origin for therapeutic approaches. PMID- 21608020 TI - Arctigenin enhances chemosensitivity of cancer cells to cisplatin through inhibition of the STAT3 signaling pathway. AB - Arctigenin is a dibenzylbutyrolactone lignan isolated from Bardanae fructus, Arctium lappa L, Saussureamedusa, Torreya nucifera, and Ipomea cairica. It has been reported to exhibit anti-inflammatory activities, which is mainly mediated through its inhibitory effect on nuclear transcription factor-kappaB (NF-kappaB). But the role of arctigenin in JAK-STAT3 signaling pathways is still unclear. In present study, we investigated the effect of arctigenin on signal transducer and activator of transcription 3 (STAT3) pathway and evaluated whether suppression of STAT3 activity by arctigenin could sensitize cancer cells to a chemotherapeutic drug cisplatin. Our results show that arctigenin significantly suppressed both constitutively activated and IL-6-induced STAT3 phosphorylation and subsequent nuclear translocation in cancer cells. Inhibition of STAT3 tyrosine phosphorylation was found to be achieved through suppression of Src, JAK1, and JAK2, while suppression of STAT3 serine phosphorylation was mediated by inhibition of ERK activation. Pervanadate reversed the arctigenin-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, arctigenin can obviously induce the expression of the PTP SHP-2. Furthermore, the constitutive activation level of STAT3 was found to be correlated to the resistance of cancer cells to cisplatin-induced apoptosis. Arctigenin dramatically promoted cisplatin-induced cell death in cancer cells, indicating that arctigenin enhanced the sensitivity of cancer cells to cisplatin mainly via STAT3 suppression. These observations suggest a novel anticancer function of arctigenin and a potential therapeutic strategy of using arctigenin in combination with chemotherapeutic agents for cancer treatment. PMID- 21608021 TI - Normal bladder sensations in healthy volunteers: a focus group investigation. AB - AIMS: To describe the bladder sensations experienced during non-invasive rapid bladder filling in a controlled setting in healthy volunteers. METHODS: Three groups of healthy volunteers, total 11 subjects (4 men, 7 women), participated in three consecutive focus group sessions. Before each session a strict water loading protocol was given. The first two sessions focused on how participants described and experienced bladder sensations in daily life and during a physiological bladder filling with constant focus on their bladder. The third session focused on verifying the interpretation of the data gathered so far and describing the pattern of sensations. RESULTS: During the focus group sessions with constant focus on their bladder, all participants experienced their bladder sensation as a continuous progression. Healthy subjects describe their bladder sensation(s) as a "pressure" and a "tingling" sensation, but a terminology ranging from no sensations to an absolute need to void is used by all participants and better describes the pattern in which the need to void develops in healthy volunteers. CONCLUSIONS: By means of focus group research it is possible to describe the development of normal bladder sensation and to refine terminology used by healthy participants. The findings show that two types of bladder sensations are reported spontaneously by healthy uninitiated volunteers, pressure and a tingling sensation, of which the first develops in a continuous manner. The pattern in which the absolute need develops is described by the terms: no sensation, weak awareness, stronger awareness, weak need, stronger need and absolute need to void. PMID- 21608022 TI - Evaluation of demographic, clinical characteristics, and genetic polymorphism as risk factors for pelvic organ prolapse in Brazilian women. AB - OBJECTIVE: Verify the association between genital prolapse, other risk factors and a polymorphism in exon 31 of the collagen III-a1 gene (COL3A1). SETTING: The etiology of genital prolapse is multifactorial, and genetic defects have been proposed. Also, there is evidence that changes in collagen may be responsible for defects in pelvic floor support. The exon 31 polymorphism results in structural changes in the triple helical of the collagen and appears to lead to abnormal synthesis of type III collagen. DESIGN: Basic science study. POPULATION: The studied group consisted of 107 patients with stage III and IV genital prolapse (POP-Q). The control group included 209 women with stage 0 and I prolapse. METHODS: After extracting genomic DNA from the peripheral blood, the exon 31 COL3A1 polymorphism was typed by restriction fragment length polymorphism analysis. MAIN OUTCOME MEASURES: Association between genital prolapse and exon 31 COL3A1 polymorphism. RESULTS: No statistically significant differences in genotype and allele frequencies were found between cases and controls (P = 0.75 and 0.66, respectively). Multiple logistic regression analyses identified age (OR = 1.05; 95%CI = 1.01-1.10), BMI (OR = 1.09; 95%CI = 1.01-1.17), presence of at least one vaginal delivery (OR = 7.22; 95%CI = 1.84-28.27), positive family history of POP (OR = 2.27; 95%CI = 1.05-4.93) and a macrosomic foetus (OR = 2.91; 95%CI = 1.24-6.79) as independent risk factors for genital prolapse. In contrast, the number of caesarean deliveries was found to be an independent protective factor (OR = 0.43; 95%CI = 0.24-0.78). CONCLUSIONS: The type III collagen exon 31 polymorphism is not a risk factor for pelvic genital prolapse in this sample. PMID- 21608023 TI - Postoccupancy evaluations in zoological settings. AB - A postoccupancy evaluation (POE) is a systematic assessment performed to examine the effectiveness of the built environment after occupation. Although POEs have been mainly used to examine the effectiveness of built environments for human usage, they can and should be adapted for use in zoological settings. Zoological exhibits have evolved from when hygiene concerns ruled design to current trends that involve elaborate exhibits that often cost millions of dollars. Thus, it is imperative to conduct evaluations to ensure that these exhibits function to meet the complex needs of all users. It is crucial to perform a comprehensive POE that focuses on all three user groups; animals, visitors, and staff. However, work in this field is limited. Animal research has tended to remain very primate-focused with differing opinions as to what constitutes optimal outcomes. Zoo visitor studies often have limited scope and differing methodologies. Additionally, research on zoo staff opinions and feedback is almost nonexistent. A new exhibit opening at a zoo has huge potential for improving the welfare of the animals it will house, enhancing the zoo visitor experience, and improving the workplace for zoo personnel. Building the best possible exhibits requires not only the analysis of how the built environment affects all three groups, but also dissemination of those findings to guide future design. PMID- 21608024 TI - Area and shape changes of the carpal tunnel in response to tunnel pressure. AB - Carpal tunnel mechanics is relevant to our understanding of median nerve compression in the tunnel. The compliant characteristics of the tunnel strongly influence its mechanical environment. We investigated the distensibility of the carpal tunnel in response to tunnel pressure. A custom balloon device was designed to apply controlled pressure. Tunnel cross sections were obtained using magnetic resonance imaging to derive the relationship between carpal tunnel pressure and morphological parameters at the hook of hamate. The results showed that the cross-sectional area (CSA) at the level of the hook of hamate increased, on average, by 9.2% and 14.8% at 100 and 200 mmHg, respectively. The increased CSA was attained by a shape change of the cross section, displaying increased circularity. The increase in CSA was mainly attributable to the increase of area in the carpal arch region formed by the transverse carpal ligament. The narrowing of the carpal arch width was associated with an increase in the carpal arch. We concluded that the carpal tunnel is compliant to accommodate physiological variations of the carpal tunnel pressure, and that the increase in tunnel CSA is achieved by increasing the circularity of the cross section. PMID- 21608025 TI - Surprising evidence of pelvic growth (widening) after skeletal maturity. AB - Following an increase in length and width during childhood and adolescence, skeletal growth is generally assumed to stop. This study investigates the influence of aging on the dimensions of the pelvis and the L4 lumbar vertebra during adulthood. The dimensions of the pelvis, L4 vertebra, and femoral heads were calculated for 246 patients who had received pelvic and abdominal Computed Tomography scans from the UNC Health Care System. Linear regression analysis determined the significance of relationships between age and width of the pelvis. There was a strong correlation between increasing patient age and increasing width of the pelvis at the trochanters, (0.333 mm/year of age p<0.0001), at the iliac wings, (0.371 mm/year of age p < 0.0002), and between the femoral heads, indicating that the bony pelvis widens over 20 mm between the ages of 20 and 80. The pelvic inlet did not enlarge over time while the distance between the hips and the femoral head diameter did significantly increase. The height of L4 did not increase over time, but the L4 width did increase. These correlations were seen in both genders. Surprisingly, our results suggest that the pelvis and L4 vertebra increase in width after skeletal maturity and cessation of longitudinal growth. PMID- 21608026 TI - Characterization of paramagnetic effects of molecular oxygen on blood oxygenation level-dependent-modulated hyperoxic contrast studies of the human brain. AB - In hyperoxic contrast studies modulated by the blood oxygenation level-dependent effect, it is often assumed that hyperoxia is a purely intravascular, positive contrast agent in T 2*-weighted images, and the effects that are not due to blood oxygenation level-dependent contrast are small enough to be ignored. In this study, this assumption is re-evaluated and non-blood oxygenation level-dependent effects in T 2*-weighted hyperoxic contrast studies of the human brain were characterized. We observed significant negative signal changes in T 2*-weighted images in the frontal lobes; B(0) maps suggest that this effect was primarily due to increased intravoxel dephasing from increased static field inhomogeneity due to susceptibility changes from oxygen in and around the upper airway. These static field effects were shown to scale with magnetic field strength. Signal changes observed around the brain periphery and in the ventricles suggest the effect of image distortions from oxygen-induced bulk B(0) shifts, along with a possible contribution from decreased T 2* due to oxygen dissolved in the cerebrospinal fluid. Reducing the concentration of inhaled oxygen was shown to mitigate negative contrast of molecular oxygen due to these effects, while still maintaining sufficient blood oxygenation level-dependent contrast to produce accurate measurements of cerebral blood volume. PMID- 21608027 TI - B0 mapping with multi-channel RF coils at high field. AB - Mapping the static magnetic field via the phase evolution over gradient echo scans acquired at two or more echo times is an established method. A number of possibilities exist, however, for combining phase data from multi-channel coils, denoising and thresholding field maps for high field applications. Three methods for combining phase images when no body/volume coil is available are tested: (i) Hermitian product, (ii) phase-matching over channels, and (iii) a new approach based on calculating separate field maps for each channel. The separate channel method is shown to yield field maps with higher signal-to-noise ratio than the Hermitian product and phase-matching methods and fewer unwrapping errors at low signal-to-noise ratio. Separate channel combination also allows unreliable voxels to be identified via the standard deviation over channels, which is found to be the most effective means of denoising field maps. Tests were performed using multichannel coils with between 8 and 32 channels at 3 T, 4 T, and 7 T. For application in the correction of distortions in echo-planar images, a formulation is proposed for reducing the local gradient of field maps to eliminate signal pile-up or swapping artifacts. Field maps calculated using these techniques, implemented in a freely available MATLAB toolbox, provide the basis for an effective correction for echo-planar imaging distortions at high fields. PMID- 21608028 TI - Sparse-CAPR: highly accelerated 4D CE-MRA with parallel imaging and nonconvex compressive sensing. AB - Cartesian Acquisition with Projection-Reconstruction-like sampling is a SENSE type parallel 3DFT acquisition paradigm for 4D contrast-enhanced magnetic resonance angiography that has been demonstrated capable of providing high spatial and temporal resolution, diagnostic-quality images at very high acceleration rates. However, Cartesian Acquisition with Projection-Reconstruction like sampling images are typically reconstructed online using Tikhonov regularization and partial Fourier methods, which are prone to exhibit noise amplification and undersampling artifacts when operating at very high acceleration rates. In this work, a sparsity-driven offline reconstruction framework for Cartesian Acquisition with Projection-Reconstruction-like sampling is developed and demonstrated to consistently provide improvements over the currently-employed reconstruction strategy against these ill-effects. Moreover, the proposed reconstruction strategy requires no changes to the existing Cartesian Acquisition with Projection-Reconstruction-like sampling acquisition protocol, and an efficient numerical optimization and hardware system are described that allow for a 256 * 160 * 80 volume contrast-enhanced magnetic resonance angiography volume to be reconstructed from an eight-channel data set in less than 2 min. PMID- 21608029 TI - Amide proton transfer imaging with improved robustness to magnetic field inhomogeneity and magnetization transfer asymmetry using saturation with frequency alternating RF irradiation. AB - Amide proton transfer (APT) imaging has shown promise as an indicator of tissue pH and as a marker for brain tumors. Sources of error in APT measurements include direct water saturation, and magnetization transfer (MT) from membranes and macromolecules. These are typically suppressed by postprocessing asymmetry analysis. However, this approach is strongly dependent on B(0) homogeneity and can introduce additional errors due to intrinsic MT asymmetry, aliphatic proton features opposite the amide peak and radiation damping-induced asymmetry. Although several methods exist to correct for B(0) inhomogeneity, they tremendously increase scan times and do not address errors induced by asymmetry of the z-spectrum. In this article, a novel saturation scheme-saturation with frequency alternating RF irradiation (SAFARI)-is proposed in combination with a new magnetization transfer ratio (MTR) parameter designed to generate APT images insensitive to direct water saturation and MT, even in the presence of B(0) inhomogeneity. The feasibility of the SAFARI technique is demonstrated in phantoms and in the human brain. Experimental results show that SAFARI successfully removes direct water saturation and MT contamination from APT images. It is insensitive to B(0) offsets up to 180 Hz without using additional B(0) correction, thereby dramatically reducing scanning time. PMID- 21608030 TI - Quantitative magnetization transfer imaging in human brain at 3 T via selective inversion recovery. AB - Quantitative magnetization transfer imaging yields indices describing the interactions between free water protons and immobile, macromolecular protons including the macromolecular to free pool size ratio (PSR) and the rate of magnetization transfer between pools k(mf) . This study describes the first implementation of the selective inversion recovery quantitative magnetization transfer method on a clinical 3.0-T scanner in human brain in vivo. Selective inversion recovery data were acquired at 16 different inversion times in nine healthy subjects and two patients with relapsing remitting multiple sclerosis. Data were collected using a fast spin-echo readout and reduced repetition time, resulting in an acquisition time of 4 min for a single slice. In healthy subjects, excellent intersubject and intrasubject reproducibilities (assessed via repeated measures) were demonstrated. Furthermore, PSR values in white (mean +/- SD = 11.4 +/- 1.2%) and gray matter (7.5 +/- 0.7%) were consistent with previously reported values, while k(mf) values were approximately 2-fold slower in both white (11 +/- 2 s(-1) ) and gray matter (15 +/- 6 s(-1) ). In relapsing remitting multiple sclerosis patients, quantitative magnetization transfer indices were sensitive to pathological changes in lesions and in normal appearing white matter. PMID- 21608031 TI - T2 exchange agents: a new class of paramagnetic MRI contrast agent that shortens water T2 by chemical exchange rather than relaxation. AB - Exchange of water molecules between the frequency-shifted inner-sphere of a paramagnetic lanthanide ion and aqueous solvent can shorten the T(2) of bulk water protons. The magnitude of the line-broadening T(2) exchange (T(2exch)) is determined by the lanthanide concentration, the chemical shift of the exchanging water molecule, and the rate of water exchange between the two pools. A large T(2exch) contribution to the water linewidth was initially observed in experiments involving Eu(3+)-based paramagnetic chemical exchange saturation transfer agents in vivo at 9.4 T. Further in vitro and in vivo experiments using six different Eu(3+) complexes having water exchange rates ranging from zero (no exchange) to 5 * 10(6) s(-1) (fast exchange) were performed. The results showed that the exchange relaxivity (r(2exch)) is small for complexes having either very fast or very slow exchange, but reaches a well-defined maximum for complexes with intermediate water exchange rates. These experimental results were verified by Bloch simulations for two site exchange. This new class of T(2exch) agent could prove useful in the design of responsive MRI contrast agents for molecular imaging of biological processes. PMID- 21608032 TI - 2H2O incorporation into hepatic acetyl-CoA and de novo lipogenesis as measured by Krebs cycle-mediated 2H-enrichment of glutamate and glutamine. AB - Deuterated water is widely used for measuring de novo lipogenesis on the basis of quantifying lipid (2)H-enrichment relative to that of body water. However, incorporation of (2)H-enrichment from body water into newly synthesized lipid molecules is incomplete therefore the true lipid precursor enrichment differs from that of body water. We describe a novel measurement of de novo lipogenesis that is based on a true precursor-product analysis of hepatic acetyl-CoA and triglyceride methyl enrichments from deuterated water. After deuterated water administration to seven in situ and seven perfused livers, acetyl-CoA methyl enrichment was inferred from (2)H nuclear magnetic resonance analysis of hepatic glutamate/glutamine (Glx) enrichment and triglyceride methyl enrichment was directly determined by (2)H nuclear magnetic resonance of triglycerides. Acetyl CoA (2) H-enrichment was 71% +/- 1% that of body water for in situ livers and 53% +/- 2% of perfusate water for perfused livers. From the ratio of triglyceride methyl/acetyl-CoA enrichments, fractional de novo lipogenesis rates of 0.97% +/- 0.09%/2 hr and 7.92% +/- 1.47%/48 hr were obtained for perfused and in situ liver triglycerides, respectively. Our method reveals that acetyl-CoA enrichment is significantly less than body water both for in situ and perfused livers. Furthermore, the difference between acetyl-CoA and body water enrichments is sensitive to the experimental setting. PMID- 21608033 TI - Efficacy of serotonin inhibition in mouse models of bone loss. AB - In a proof-of-concept study it was shown that decreasing synthesis of gut serotonin through a small molecule inhibitor of Tph1 could prevent and treat ovariectomy-induced osteoporosis in young mice and rats. In this study, we define the minimal efficacy of this Tph1 inhibitor, demonstrate that its activity is improved with the duration of treatment, and show that its anabolic effect persists on interruption. Importantly, given the prevalence of osteoporosis in the aging population, we then show that Tph1 inhibition rescues ovariectomy induced bone loss in aged mice. It also cures the low bone mass of Lrp5-deficient mice through a sole anabolic effect. Lastly, we provide evidence that inhibition of gut serotonin synthesis can work in concert with an antiresorptive agent to increase bone mass in ovariectomized mice. This study provides a more comprehensive view of the anabolic efficacy of Tph1 inhibitors and further establishes the spectrum of their therapeutic potential in the treatment of bone loss disorders. PMID- 21608034 TI - Endogenous aspartoacylase expression is responsive to glutamatergic activity in vitro and in vivo. AB - Aspartoacylase (ASPA) is an enzyme that functions to catabolize the neuronal amino acid derivative N-acetyl-L-aspartic acid (NAA). Loss of this function results in the failure of developmental myelination. NAA synthesis and catabolism are tightly compartmentalized within neurons and oligodendrocytes, respectively, and there is evidence to suggest the developmental regulation of ASPA activity is transcriptional. NAA has no known direct physiological mode of action, and the identification of a transcriptional regulator of aspa would provide an opportunity to link NAA to relatively more characterized physiological contexts with a view to definitive functional classification. Using transcriptional and immunohistochemical endpoints, we define a window of postnatal development punctuated by increases in aspa within a pre-existing population of oligodendrocytes in the rat brain. Ontological mining of expression data generated in aspa-null rats during this developmental window identifies both neuronal and oligodendroglial transcriptional abnormalities that suggest an association between glutamatergic synaptic activity and ASPA. Glutamate, but not NAA, is shown to activate endogenous aspa expression in vitro, and endogenous aspa expression is upregulated in the brains of animals over expressing vesicular glutamate transporter type-I (vglut1). These results define a discrete period of postnatal development within which glutamate provides a means by which the tightly compartmentalized NAA metabolic cycle can function in sync with normal development and may be a factor in pathological models of dysregulated NAA metabolism. PMID- 21608035 TI - Posttraumatic stress disorder symptoms among adult survivors of the 2008 Sichuan earthquake in China. AB - This study examined the estimated prevalence rate of posttraumatic stress disorder (PTSD) symptoms and associated risk factors among Chinese adult survivors 7 to 8 months after the 2008 Sichuan earthquake. The sample was recruited from 2 areas close to the epicenter but of different distances. The estimated rate of PTSD symptoms was 55.6% and 26.4% respectively in the two areas. Loss of a child was a strong predictive factor for PTSD symptoms for the parents. Other predictive factors included female gender, loss of a parent, loss of friends or neighbors, residential house damage or collapse, and proximity to the epicenter. Effective and sustainable mental health services are needed and should be directed particularly to bereaved survivors. PMID- 21608037 TI - Materials research at the University of California, Santa Barbara. PMID- 21608039 TI - Correlated compositions, structures, and photoluminescence properties of gallium nitride nanoparticles. PMID- 21608040 TI - Structural order in bulk heterojunction films prepared with solvent additives. PMID- 21608041 TI - Effect of surface roughness and electrostatic surface potentials on forces between dissimilar surfaces in aqueous solution. PMID- 21608042 TI - Gate-tunable surface processes on a single-nanowire field-effect transistor. PMID- 21608043 TI - Design and in situ characterization of lipid containers with enhanced drug retention. PMID- 21608045 TI - A new femtosecond laser-based tomography technique for multiphase materials. PMID- 21608046 TI - p-i-n Homojunction in organic light-emitting transistors. PMID- 21608047 TI - Functionalized carbon nanotube networks with field-tunable bandgaps. PMID- 21608048 TI - Advances in tailoring resorcinol-formaldehyde organic and carbon gels. AB - An overview on the preparation and properties of resorcinol-formaldehyde (RF) organic and carbon gels reveals the fascinating and remarkably flexible properties of RF carbon and organic gels and how these properties are related to the synthesis and processing conditions. The structural properties can be easily tailored by rigidly controlling such conditions. However, slight variations in some conditions may cause drastic variations in the structural characteristics, and hence properties. Therefore, the effects of different conditions must be well understood before attempting to tailor organic or carbon gels to specific applications. The most important factors that affect the properties of an organic gel are the precursor concentrations, the catalyst type and concentration, the time and temperature of curing, and the drying method. In addition to these factors, characteristics of activated carbon gels also depend on the pyrolysis temperature and the activation method. These conditions impact the structural and performance characteristics significantly. PMID- 21608049 TI - Mussel-inspired polydopamine-treated polyethylene separators for high-power li ion batteries. PMID- 21608050 TI - Cascaded energy transfer for efficient broad-band pumping of high-quality, micro lasers. PMID- 21608051 TI - Anisotropic proton-conductive materials formed by the self-organization of phosphonium-type zwitterions. PMID- 21608052 TI - Fabrication and characterization of MIM diodes based on Nb/Nb2O5 via a rapid screening technique. PMID- 21608053 TI - Nanoscale structure and mechanism for enhanced electromechanical response of highly Strained BiFeO3 thin films. PMID- 21608054 TI - Morphology optimization for the fabrication of high mobility thin-film transistors. PMID- 21608055 TI - Direct fabrication of functional and biofunctional nanostructures through reactive imprinting. PMID- 21608056 TI - Modeling the gas-phase thermochemistry of organosulfur compounds. AB - Key to understanding the involvement of organosulfur compounds in a variety of radical chemistries, such as atmospheric chemistry, polymerization, pyrolysis, and so forth, is knowledge of their thermochemical properties. For organosulfur compounds and radicals, thermochemical data are, however, much less well documented than for hydrocarbons. The traditional recourse to the Benson group additivity method offers no solace since only a very limited number of group additivity values (GAVs) is available. In this work, CBS-QB3 calculations augmented with 1D hindered rotor corrections for 122 organosulfur compounds and 45 organosulfur radicals were used to derive 93 Benson group additivity values, 18 ring-strain corrections, 2 non-nearest-neighbor interactions, and 3 resonance corrections for standard enthalpies of formation, standard molar entropies, and heat capacities for organosulfur compounds and organosulfur radicals. The reported GAVs are consistent with previously reported GAVs for hydrocarbons and hydrocarbon radicals and include 77 contributions, among which 26 radical contributions, which, to the best of our knowledge, have not been reported before. The GAVs allow one to estimate the standard enthalpies of formation at 298 K, the standard entropies at 298 K, and standard heat capacities in the temperature range 300-1500 K for a large set of organosulfur compounds, that is, thiols, thioketons, polysulfides, alkylsulfides, thials, dithioates, and cyclic sulfur compounds. For a validation set of 26 organosulfur compounds, the mean absolute deviation between experimental and group additively modeled enthalpies of formation amounts to 1.9 kJ mol(-1). For an additional set of 14 organosulfur compounds, it was shown that the mean absolute deviations between calculated and group additively modeled standard entropies and heat capacities are restricted to 4 and 2 J mol(-1) K(-1), respectively. As an alternative to Benson GAVs, 26 new hydrogen-bond increments are reported, which can also be useful for the prediction of radical thermochemistry. PMID- 21608057 TI - Measurement of absolute arterial cerebral blood volume in human brain without using a contrast agent. AB - Arterial cerebral blood volume (CBV(a) ) is a vital indicator of tissue perfusion and vascular reactivity. We extended the recently developed inflow vascular-space occupancy (iVASO) MRI technique, which uses spatially selective inversion to suppress the signal from blood flowing into a slice, with a control scan to measure absolute CBV(a) using cerebrospinal fluid (CSF) for signal normalization. Images were acquired at multiple blood nulling times to account for the heterogeneity of arterial transit times across the brain, from which both CBV(a) and arterial transit times were quantified. Arteriolar CBV(a) was determined separately by incorporating velocity-dependent bipolar crusher gradients. Gray matter (GM) CBV(a) values (n=11) were 2.04 +/- 0.27 and 0.76 +/- 0.17 ml blood/100 ml tissue without and with crusher gradients (b=1.8 s/mm(2) ), respectively. Arterial transit times were 671 +/- 43 and 785 +/- 69 ms, respectively. The arterial origin of the signal was validated by measuring its T(2) , which was within the arterial range. The proposed approach does not require exogenous contrast agent administration, and provides a non-invasive alternative to existing blood volume techniques for mapping absolute CBV(a) in studies of brain physiology and neurovascular diseases. PMID- 21608058 TI - Could 13C MRI assist clinical decision-making for patients with heart disease? AB - Even at this early stage of development, it is clear that the imaging of hyperpolarized (13)C-enriched molecules and their metabolic products offers a new approach to the study of the physiology and disease of the heart. The technology is practical in humans and, for this reason, we consider whether a role in clinical decision-making should motivate further development. The range of interventions available to treat coronary and valvular heart disease is already extensive, and new options are imminent. Yet the appropriate management of patients with left ventricular dysfunction can be challenging because the mechanism of reduced function may be unclear and the ability of the ventricle to respond to therapy may be difficult to predict. Pyruvate is a promising early target for development as a diagnostic agent because it lies at a critical branch point in cardiac biochemistry. The rate of metabolism of hyperpolarized pyruvate to CO(2) relative to lactate may prove to be a useful indicator of preserved mitochondrial function, and therefore provide a specific signal of viable myocardium. Other species including physiological substrates and nonphysiological molecules may provide additional information. Once suitable technology becomes available, it is likely that clinical research will progress quickly. The ability to monitor directly specific metabolic pathways may lead to an improvement in the selection of patients who will benefit from interventions, pharmacologic or otherwise. PMID- 21608059 TI - Nuclear magnetic resonance structure of calcium-binding protein 1 in a Ca(2+) bound closed state: implications for target recognition. AB - Calcium-binding protein 1 (CaBP1), a neuron-specific member of the calmodulin (CaM) superfamily, regulates the Ca(2+) -dependent activity of inositol 1,4,5 triphosphate receptors (InsP3Rs) and various voltage-gated Ca(2+) channels. Here, we present the NMR structure of full-length CaBP1 with Ca(2+) bound at the first, third, and fourth EF-hands. A total of 1250 nuclear Overhauser effect distance measurements and 70 residual dipolar coupling restraints define the overall main chain structure with a root-mean-squared deviation of 0.54 A (N domain) and 0.48 A (C-domain). The first 18 residues from the N-terminus in CaBP1 (located upstream of the first EF-hand) are structurally disordered and solvent exposed. The Ca(2+) -saturated CaBP1 structure contains two independent domains separated by a flexible central linker similar to that in calmodulin and troponin C. The N-domain structure of CaBP1 contains two EF-hands (EF1 and EF2), both in a closed conformation [interhelical angles = 129 degrees (EF1) and 142 degrees (EF2)]. The C-domain contains EF3 and EF4 in the familiar Ca(2+) -bound open conformation [interhelical angles = 105 degrees (EF3) and 91 degrees (EF4)]. Surprisingly, the N-domain adopts the same closed conformation in the presence or absence of Ca(2+) bound at EF1. The Ca(2+) -bound closed conformation of EF1 is reminiscent of Ca(2+) -bound EF-hands in a closed conformation found in cardiac troponin C and calpain. We propose that the Ca(2+) -bound closed conformation of EF1 in CaBP1 might undergo an induced-fit opening only in the presence of a specific target protein, and thus may help explain the highly specialized target binding by CaBP1. PMID- 21608060 TI - Biochemical and structural studies on the high affinity of Hsp70 for ADP. AB - The molecular chaperone 70-kDa heat shock protein (Hsp70) is driven by ATP hydrolysis and ADP-ATP exchange. ADP dissociation from Hsp70 is reportedly slow in the presence of inorganic phosphate (P(i) ). In this study, we investigated the interaction of Hsp70 and its nucleotide-binding domain (NBD) with ADP in detail, by isothermal titration calorimetry measurements and found that Mg(2+) ion dramatically elevates the affinity of Hsp70 for ADP. On the other hand, P(i) increased the affinity in the presence of Mg(2+) ion, but not in its absence. Thus, P(i) enhances the effect of the Mg(2+) ion on the ADP binding. Next, we determined the crystal structures of the ADP-bound NBD with and without Mg(2+) ion. As compared with the Mg(2+) ion-free structure, the ADP- and Mg(2+) ion bound NBD contains one Mg(2+) ion, which is coordinated with the beta-phosphate group of ADP and associates with Asp10, Glu175, and Asp199, through four water molecules. The Mg(2+) ion is also coordinated with one P(i) molecule, which interacts with Lys71, Glu175, and Thr204. In fact, the mutations of Asp10 and Asp199 reduced the affinity of the NBD for ADP, in both the presence and the absence of P(i) . Therefore, the Mg(2+) ion-mediated network, including the P(i) and water molecules, increases the affinity of Hsp70 for ADP, and thus the dissociation of ADP is slow. In ADP-ATP exchange, the slow ADP dissociation might be rate-limiting. However, the nucleotide-exchange factors actually enhance ADP release by disrupting the Mg(2+) ion-mediated network. PMID- 21608061 TI - A study on fine motor skills of Iranian children with attention deficit/hyper activity disorder aged from 6 to 11 years. AB - The aim of this study was to compare the fine motor skills of two groups of Iranian children. Of the 55 male Tehranian children aged 6 to 10 years, 29 children were typically developing and 26 were identified as attention deficit hyperactivity disorder (ADHD) using the Diagnostic and Statistical Manual of Mental Disorder. All children were assessed using the Raven Intelligence Test and nine fine motor tasks. There were no significant differences between the groups based on intelligence. In eight of the fine motor tasks, there was a significant difference between the groups. These tasks were cutting, placing dots in a grid pattern without direction, threading beads, drawing a line within 1 and 2 minutes, finger movements and Purdue pegboard. Boys who have been identified as ADHD have poorer fine motor skills compared to typically developing boys of the same age. Children aged 6 to 10 years who have been identified as ADHD will require more attention to their fine motor skill performance to enable greater participation in daily living tasks in Tehran such as writing, fine arts and dressing which require fast and quick hand motor skills. There are still limitations in this area; therefore, research in fine motor skills and ADHD children are recommended for future research. PMID- 21608062 TI - Prevalence and incidence of acute and chronic comorbidity in patients with squamous cell carcinoma of the head and neck. AB - BACKGROUND: Limited data exist on the burden of comorbidity among patients with squamous cell head and neck cancer (SCCHN) before and during cancer treatment. METHODS: The precancer prevalence and incidence rates of 8 comorbid conditions were estimated among a population-based cohort of 1499 patients with SCCHN in the Netherlands. Patients with cancer, treatments, and comorbidities were identified in the PHARMO Record Linkage System (RLS) using hospital admissions and/or dispensing codes. Prevalence proportions and incidence rates were also compared against a matched cancer-free population. RESULTS: Cardiovascular (41%) and respiratory diseases (12%) were the most prevalent comorbidities. Incidence rates of most comorbidities were highest the first 6 months after cancer diagnosis and decreased over time. Patients receiving chemotherapy-based treatment had significantly higher incidence rates of anemia and other malignant diseases. CONCLUSIONS: High rates of acute and chronic comorbidity were observed; knowledge of comorbidity burden aids in establishing a benefit-risk profile for investigational SCCHN therapies. PMID- 21608063 TI - Prevalence of human papillomavirus, Epstein-Barr virus, p21, and p53 expression in sinonasal inverted papilloma, nasal polyp, and hypertrophied turbinate in Hong Kong patients. AB - BACKGROUND: The purpose of this study of human papillomavirus (HPV), Epstein-Barr virus (EBV), p21, and p53 in sinonasal inverted papilloma (IP) was to help elucidate its pathogenesis. METHODS: Seventy-three IPs, 48 nasal polyps, and 85 hypertrophied turbinates were subjected to HPV polymerase chain reaction (PCR) study. Seventy-three IPs, 30 nasal polyps, and 32 hypertrophied turbinates were subjected to EBV in situ hybridization (ISH), p21, and p53 immunohistochemical (IHC) studies. RESULTS: HPV was positive in 3 of 73 IPs (4.1%). All specimens were EBV negative. In all, 99% of IPs showed strong and diffuse p21 nuclear reactivity. Most nasal polyps and hypertrophied turbinates showed weak to moderate immunoreactivity of the basal and parabasal cells. Only focal p53 immunoreactivity of the basal and parabasal cells was found in 19% of IPs and 40% of nasal polyps. CONCLUSIONS: HPV prevalence of our IP is low. EBV is not present in IP. High p21 and low p53 expression in IP suggests a non-p53-dependent regulation pathway. PMID- 21608064 TI - Reproducibility analysis of diffusion tensor indices and fiber architecture of human calf muscles in vivo at 1.5 Tesla in neutral and plantarflexed ankle positions at rest. AB - PURPOSE: To investigate the reproducibility of diffusion tensor imaging (DTI) derived indices and fiber architecture of calf muscles at 1.5 Tesla (T), to establish an imaging based method to confirm ankle position, and to compare fiber architecture at different ankle positions. MATERIALS AND METHODS: Six subjects were imaged at 1.5T with the foot in neutral and plantarflexed positions. DTI indices were calculated in four muscle compartments (medial and lateral gastrocnemius [MG, LG], superficial and deep anterior tibialis [AT-S, AT-D]). Two subjects were scanned on 3 days to calculate the coefficient of variability (CV) and the repeatability coefficient (RC). RESULTS: DTI indices were close to the values obtained in earlier 3T and 1.5T studies. Fractional anisotropy decreased significantly in the MG and increased significantly in the AT-S and AT-D compartments while fiber orientation with respect to the magnet Z-axis increased significantly in the MG and decreased significantly in the AT-S compartment with plantarflexion. The CV and RC for the DTI indices and fiber orientations were comparable to 3T studies. Fiber lengths and orientation angles in the MG matched corresponding measures from ultrasound studies. CONCLUSION: DTI at 1.5T provides reproducible measures of diffusion indices and fiber architecture of calf muscle at different muscle lengths. PMID- 21608065 TI - Exercise training increases myocardial perfusion in residual viable myocardium within infarct zone. AB - PURPOSE: To study the effect of exercise training on the myocardial perfusion in the postinfarct myocardium. MATERIALS AND METHODS: Twenty-nine patients with stable chronic myocardial infarction were randomly assigned to either a training group (N = 17) or a control group (N = 12). The training group received a 3-month exercise program. Cardiovascular MR was first performed before the training to establish a baseline, and subsequently performed once again upon conclusion of the program. Late gadolinium enhancement was used both to define the infarct and remote zones and to quantify the ratio of the residual viable myocardium (VMR) within the infarct zone. The myocardium was divided into subendocardial and subepicardial layers with equal thickness. The interval change of myocardial perfusion reserve (MPR) was computed for each zone and layer. The association between the exercise-induced perfusion change and VMR was analyzed for layers of the infarct zone. RESULTS: In the training group, the remote zone showed significantly increased MPR. The infarct zone showed no perfusion change in the subendocardial layer, but it demonstrated significantly increased MPR in the subepicardial layer. In the infarct zone, the change in MPR was associated with VMR. CONCLUSION: In chronic myocardial infarction, the exercise-induced perfusion change in the infarct zone is proportional to the amount of residual viable myocardium. PMID- 21608066 TI - Portal hypertension correlates with splenic stiffness as measured with MR elastography. AB - PURPOSE: To investigate the correlation between MR elastography (MRE) assessed spleen stiffness and direct portal vein pressure gradient (D-HVPG) measurements in a large animal model of portal hypertension. MATERIALS AND METHODS: Cholestatic liver disease was established in adult canines by common bile duct ligation. A spin echo based echo planar imaging (EPI) MRE sequence was used to acquire three-dimensional/three axis (3D/3-axis) abdominal MRE data at baseline, 4 weeks, and 8 weeks. Liver biopsies, blood samples, and D-HVPG measurements were obtained simultaneously. RESULTS: Animals developed portal hypertension (D-HVPG: 11.0 +/- 5.1 mmHg) with only F1 fibrosis after 4 weeks. F3 fibrosis was confirmed after 8 weeks despite no further rise in portal hypertension (D-HVPG: 11.3 +/- 3.2 mmHg). Mean stiffnesses of the spleen increased over two-fold from baseline (1.72 +/- 0.33 kPa) to 4 weeks (3.54 +/- 0.31 kPa), and stabilized at 8 weeks (3.38 +/- 0.06 kPa) in a pattern consistent with changes in portal pressure. A positive correlation was observed between spleen stiffness and D-HVPG (r(2) = 0.86; P < 0.01). CONCLUSION: These findings indicate a temporal relationship between portal hypertension and the development of liver fibrosis in a large animal model of cholestatic liver disease. The observed direct correlation between spleen stiffness and D-HVPG suggest a noninvasive MRE approach to diagnose and screen for portal hypertension. PMID- 21608067 TI - Impact of magnetic resonance imaging on cardiac mortality in thalassemia major. AB - PURPOSE: To evaluate whether the introduction of magnetic resonance imaging (MRI) in the management of thalassemia major (TM) patients has affected the risk of cardiac death. MATERIALS AND METHODS: In all, 804 TM patients from two large reference units were included and the risk of dying of cardiac causes, before and after their first MRI, was assessed by a Cox proportional hazards model with time dependent covariates. RESULTS: Adding information from MRI reduced the risk of cardiac death from 6.0 deaths/1000 patient-years to 3.9 deaths/1000 patient-years (P = 0.22). The risk of cardiac death before having an MRI study was 82% higher compared to the risk observed after the first MRI. CONCLUSION: MRI has become a vital component of ongoing management and seems to have a beneficial effect on cardiac mortality in TM. PMID- 21608068 TI - Outcome of hypovascular hepatic nodules revealing no gadoxetic acid uptake in patients with chronic liver disease. AB - PURPOSE: To elucidate the natural history of hypovascular nodules that appear hypointense on hepatocyte-phase gadoxetic acid-enhanced MR images by focusing on hypervascularization over time. MATERIALS AND METHODS: In this study, 135 hypovascular nodules revealing no gadoxetic acid uptake in 53 patients were examined. All nodules were retrospectively examined using serial follow-up computed tomography (CT) and MRI examinations until hypervascularity was observed on arterial-phase dynamic CT or gadoxetic acid-enhanced MR images, or on CT during hepatic arteriography. Logistic regression analysis was used to investigate the association between hypervascularization and MR findings including a presence of fat assessed by a signal drop on opposed-phase T1 weighted images. RESULTS: Of the 135 nodules, 16 underwent hypervascularization. The size of the nodules and the presence of fat in the nodules were independent indicators of hypervascularization. The 1-year cumulative risk of hypervascularization was 15.6%. This risk was significantly increased in the case of nodules >10 mm (37.6%, P < 0.01) and fat-containing nodules (26.5%, P < 0.01). CONCLUSION: Hypovascular nodules that appear hypointense on hepatocyte-phase gadoxetic acid-enhanced MR images may progress to conventional hypervascular hepatocellular carcinoma. Nodules more than 10 mm in diameter and containing fat are at high risk for developing hypervascularization. PMID- 21608069 TI - Hepatic enhancement during the hepatobiliary phase after gadoxetate disodium administration in patients with chronic liver disease: the role of laboratory factors. AB - PURPOSE: To identify factors influencing hepatobiliary phase (HBP) hepatic enhancement on gadoxetate disodium-enhanced MRI in patients with chronic liver disease (CLD). MATERIALS AND METHODS: We retrospectively reviewed abdominal gadoxetate disodium-enhanced MRIs and medical records of patients with (n=97) and without (n=48) CLD. CLD subgroups were formed based on normal/abnormal components of liver function tests (LFTs). Hepatic enhancement coefficients (HEKs) were calculated on MRI, and compared with LFTs and Model for End-stage Liver Disease (MELD) scores. RESULTS: The mean HEK was significantly lower (P<0.0008) in the CLD than control group. The mean HEK was similar to controls in the subgroup with all normal LFTs (P=0.09) and subgroup with normal direct bilirubin (DB) (p=0.09), while it was significantly reduced (P<0.0001) in the subgroup with elevated DB. For all other LFT components, regardless of normal or abnormal values, there was a significant reduction in the mean HEKs versus controls (all P values<0.01). There was a highly negative correlation between the mean HEKs in CLD subgroups and number of abnormal LFTs (r=-0.93) and MELD scores (r=-0.89). CONCLUSION: HBP hepatic enhancement in CLD patients is similar to those with no CLD as long as direct bilirubin remains normal. Higher MELD scores and higher number of abnormal LFT components are associated with reduced hepatic enhancement. PMID- 21608070 TI - Validity of claims-based definitions of left ventricular systolic dysfunction in Medicare patients. AB - PURPOSE: Ejection fraction (EF) is crucial information when studying the use and effectiveness of therapies in patients with heart failure (HF) and myocardial infarction (MI). We aimed to assess the validity of claims data-based definitions of systolic dysfunction (SD). METHODS: We identified 1072 patients with EF recorded for an HF/MI hospitalization in Medicare linked with pharmacy data and national HF/MI registries in 1999-2006. Thirteen claims-based definitions for SD were developed using a single or combination of ICD-9 diagnosis codes and cardiovascular medications use. We calculated sensitivity, specificity, and positive predictive values (PPVs) using recorded EFs as the gold standard. RESULTS: Using an EF cutoff of 45%, the definitions based on digoxin use and no atrial fibrillation or flutter had the highest PPVs (76% to 84%) and specificity (>97%) but low sensitivity (6%-14%). As we varied the EF cutoff between 50% and 25%, the specificity decreased by 3%, but the PPVs decreased by 52%. We observed potential differences in the PPVs by patients' characteristics. In a hypothetical study assessing implantable defibrillator effectiveness, using our definition to identify patients with SD would underestimate the effectiveness by 3% to 24%. In another hypothetical study comparing two classes of angiotensin system blockers where SD was considered confounding, our definition introduced ~43% misclassification bias. CONCLUSIONS: Claims-based definitions for SD had excellent specificity and good PPV but low sensitivity. The definitions with good PPV could be used for cohort identification or confounding adjustment by restriction and would result in relatively small misclassification bias albeit limited generalizability. PMID- 21608071 TI - Comparing and decomposing differences in preventive and hospital care: USA versus Taiwan. AB - As the USA expands health insurance coverage, comparing utilization of healthcare services with countries like Taiwan that already have universal coverage can highlight problematic areas of each system. The universal coverage plan of Taiwan is the newest among developed countries, and it is known for readily providing access to care at low costs. However, Taiwan experiences problems on the supply side, such as inadequate compensation for providers, especially in the area of preventive care. We compare the use of preventive, hospital, and emergency care between the USA and Taiwan. The rate of preventive care use is much higher in the USA than in Taiwan, whereas the use of hospital and emergency care is about the same. Results of our decomposition analysis suggest that higher levels of education and income, along with inferior health status in the USA, are significant factors, each explaining between 7% and 15% of the gap in preventive care use. Our analysis suggests that, in addition to universal coverage, proper remuneration schemes, education levels, and cultural attitudes towards health care are important factors that influence the use of preventive care. PMID- 21608072 TI - Coping and its effect on psychological distress of parents of pediatric cancer patients: a longitudinal prospective study. AB - OBJECTIVE: This prospective 5-year longitudinal study examined the use of coping styles of fathers and mothers of pediatric cancer patients over time and the prospective effects of coping on distress. METHODS: Psychological distress (General Health Questionnaire) and the use of seven coping styles (Utrecht Coping List: active problem focussing, palliative and passive reaction patterns, avoidance, social support seeking, expression of emotions, and comforting cognition) were assessed in 115 parents shortly after diagnosis, 6 and 12 months, and 5 years later. RESULTS: At diagnosis, parents' use of coping styles did not differ from the norm population except more frequent use of support seeking. No significant change over time was found in a palliative reaction pattern. Support seeking declined and emotional expression increased linearly, whereas use of the remaining coping styles decreased, followed by an increase. At 5 years, parents' use differed from the norm population only in less use of expression of emotions and comforting cognitions. Initial coping use significantly predicted fathers' future distress at 6 and 12 months but not at 5 years. This was not found for mothers. Changes in coping were significantly associated with both parents' changes in distress only during the first year. Increased passive reaction pattern and social support seeking were the risk factors for mothers. Increased avoidance, a passive reaction pattern, expression of emotions, and decreased active problem focussing formed the risk factors for fathers. CONCLUSION: Findings illustrate that coping seems to be a situation-specific process and that coping predictors vary as a function of parents' gender. PMID- 21608073 TI - Survivor identity after colorectal cancer: antecedents, prevalence and outcomes. AB - OBJECTIVE: Cancer survivor identity has become a dominant paradigm in describing people with cancer and in driving the focus of programmes and research in supportive care. This study investigated antecedents of survivor identity adoption and population-based prevalence. METHODS: A prospective survey of a population-based sample of 1966 (57% response) patients with colorectal cancer assessed socio-demographic variables, health behaviours, optimism, benefit finding, cancer threat appraisal, psychological distress and satisfaction with life at 5 months post-diagnosis as predictors of survivor identity 5 years subsequently. Prevalence of survivor identity at 5 years post-diagnosis and psychological and lifestyle outcomes (n = 786) were later assessed. RESULTS: Fifty-five per cent of people identified as a cancer survivor, 39.4% as a person who had had (or has) cancer, 1.4% as a cancer patient and 1.2% as a cancer victim. People who were older and who reported higher personal growth after diagnosis were more likely to assume a survivor identity at 5 years. At 5 years, survivors had higher benefit finding and better satisfaction with life. Cancer survivors uniquely reported a significant decrease in somatization and acceptance, and increases in satisfaction with life and physical activity over time. CONCLUSIONS: For patients with colorectal cancer, the cancer survivor identity is common but not universal 5 years after diagnosis; and may evolve from looking for benefit after cancer through personal growth. People who adopt a cancer survivor identity report more positive adjustment outcomes after cancer and this has implications for the design of clinical and community support interventions. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21608074 TI - The impact of molar pregnancy on the male partner. AB - BACKGROUND: Molar pregnancy is a complication of 1 in 200-2000 pregnancies whereby abnormal placental tissue proliferates in the absence of a fetus and may lead to metastases. The disease origin lies in dispermy or dual fertilisation of the egg. The aim of this study was to explore the impact of molar pregnancy upon the male partner. METHODS: Institutional ethics committee approval and individual consent were obtained. All women listed on the state molar pregnancy database who were receiving active follow-up (n = 102) and a random sample of women who had been registered in the previous 30 years (n = 56) were sent a postal survey outlining the purpose of the study and an invitation for their partner to participate. Sixty-six women gave permission for their partner to participate in the study. Questionnaires included the Hospital Anxiety and Depression Scale, Satisfaction with Life Scale and Sexual History Form 12. Responding partners were also invited to make comments about any aspect of particular concern. A reminder mail out was issued after 6 weeks. RESULTS: The response rate was 62% (N = 41). The key findings were that 32.5% and 12.5% of men met the case criteria for anxiety and depressive disorder, respectively. These figures represent a doubling of usual community rates for anxiety disorder. However, overall quality of life and sexual functioning outcomes were consistent with community samples. The presence of children played a protective role and was associated with significantly better psychological function and quality of life in univariate and multivariate analysis. Qualitative results complemented the quantitative data, with anxiety as the dominant emotional theme. CONCLUSION: There are high persisting levels of anxiety in male partners of women with molar pregnancy. Partners may benefit from therapy where anxiety disorders are detected. PMID- 21608075 TI - Internet interventions for improving psychological well-being in psycho-oncology: review and recommendations. AB - OBJECTIVE: Too few cancer patients and survivors receive evidence-based interventions for mental health symptoms. This review examines the potential for Internet interventions to help fill treatment gaps in psychosocial oncology and presents evidence regarding the likely utility of Internet interventions for cancer patients. METHODS: The authors examined available literature regarding Internet interventions tailored to cancer patients' mental health needs and reviewed elements of Internet interventions for mental health relevant to advancing psycho-oncology Internet intervention research. RESULTS: Few rigorous studies focusing on mental health of cancer patients have been conducted online. A growing body of evidence supports the efficacy, accessibility, and acceptability of mental health Internet interventions for a variety of general and medical patient populations. The authors present recommendations and guidelines to assist researchers in developing, testing, and disseminating Internet interventions for cancer patients and survivors, to manage and improve their mental health. Issues unique to Internet interventions-including intervention structure, customization, provider interaction, and privacy and confidentiality issues-are discussed. These guidelines are offered as a step toward establishing a set of "best practices" for Internet interventions in psycho-oncology and to generate further discussion regarding the goals of such interventions and their place in cancer care. CONCLUSIONS: Internet interventions have the potential to fill an important gap in quality cancer care by augmenting limited available mental health services. These interventions should be developed in a manner consistent with best practices and must be empirically tested and validated. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21608076 TI - Role of paraxial mesoderm in limb/flank regionalization of the trunk lateral plate. AB - To understand the developmental mechanism that determines limb size and the consequent limb-to-trunk proportions in the tetrapod body, we investigated the role of the paraxial mesoderm in the specification of the limb and flank fields in the chick embryo. We found that the paraxial mesoderm subjacent to the limb field can affect the size of the limb bud along the anterior-posterior and proximal-distal axes. We also found that the paraxial mesoderm subjacent to the flank plays roles in suppressing the emergence and growth of the limb bud and in promoting flank-specific apoptosis in the lateral plate mesoderm. Our results suggest that signals from the paraxial mesoderm specify the limb and flank fields in the competent lateral plate mesoderm. PMID- 21608077 TI - Differential recruitment of methyl CpG-binding domain factors and DNA methyltransferases by the orphan receptor germ cell nuclear factor initiates the repression and silencing of Oct4. AB - The pluripotency gene Oct4 encodes a key transcription factor that maintains self renewal of embryonic stem cell (ESC) and is downregulated upon differentiation of ESCs and silenced in somatic cells. A combination of cis elements, transcription factors, and epigenetic modifications, such as DNA methylation, mediates Oct4 gene expression. Here, we show that the orphan nuclear receptor germ cell nuclear factor (GCNF) initiates Oct4 repression and DNA methylation by the differential recruitment of methyl-CpG binding domain (MBD) and DNA methyltransferases (Dnmts) to the Oct4 promoter. When compared with wild-type ESCs and gastrulating embryos, Oct4 repression is lost and its proximal promoter is significantly hypomethylated in retinoic acid (RA)-differentiated GCNF(-/-) ESCs and GCNF(-/-) embryos. Efforts to characterize mediators of GCNF's repressive function and DNA methylation of the Oct4 promoter identified MBD3, MBD2, and de novo Dnmts as GCNF interacting factors. Upon differentiation, endogenous GCNF binds to the Oct4 proximal promoter and differentially recruits MBD3 and MBD2 as well as Dnmt3A. In differentiated GCNF(-/-) ESCs, recruitment of MBD3 and MBD2 as well as Dnmt3A to Oct4 promoter is lost and subsequently Oct4 repression and DNA methylation failed to occur. Hypomethylation of the Oct4 promoter is also observed in RA differentiated MBD3(-/-) and Dnmt3A(-/-) ESCs, but not in MBD2(-/-) and Dnmt3B(-/ ) ESCs. Thus, recruitment of MBD3, MBD2, and Dnmt3A by GCNF links two events: gene-specific repression and DNA methylation, which occur differentially at the Oct4 promoter. GCNF initiates the repression and epigenetic modification of Oct4 gene during ESC differentiation. PMID- 21608078 TI - Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1alpha in an Alzheimer's disease mouse model. AB - Transplantation of bone marrow-derived stem cells (BMSCs) has been suggested as a potential therapeutic approach to prevent neurodegenerative diseases, but it remains problematic due to issues of engraftment, potential toxicities, and other factors. An alternative strategy is pharmacological-induced recruitment of endogenous BMSCs into an injured site by systemic administration of growth factors or chemokines. Therefore, the aim of this study was to examine the effects of therapy involving granulocyte colony stimulating factor (G CSF)/AMD3100 (CXCR4 antagonist) and stromal cell-derived factor-1alpha (SDF 1alpha) on endogenous BM-derived hematopoietic progenitor cell (BM-HPC) recruitment into the brain of an Alzheimer's disease (AD) mouse model. To mobilize BM-HPCs, G-CSF was injected intraperitoneally and boosted by AMD3100. Simultaneously, these mice received an intracerebral injection with SDF-1alpha to induce migration of mobilized BM-HPCs into brain. We found that the memory deficit in the AD mice was significantly improved by these treatments, but amyloid beta deposition was unchanged. Interestingly, microglial activation was increased with alternative activation of microglia to a neuroprotective phenotype. Furthermore, by generating an amyloid precursor protein/presenilin 1 green fluorescent protein (GFP) chimeric mouse, we ascertained that the GFP positive microglia identified in the brain were BM-derived. Additionally, increased hippocampal neurogenesis and improved memory was observed in mice receiving combined G-CSF/AMD3100 and SDF-1alpha, but not in controls or animals receiving each treatment alone. These results suggest that SDF-1alpha is an effective adjuvant in inducing migration into brain of the endogenous BM-HPCs, mobilized by G-CSF/AMD3100, and that the two can act synergistically to produce a therapeutic effect. This approach warrants further investigation as a potential therapeutic option for the treatment of AD patients in the future. PMID- 21608079 TI - p53 directly represses Id2 to inhibit the proliferation of neural progenitor cells. AB - Neural progenitor cells (NPCs) have the capacity to proliferate and give rise to all major central nervous system cell types and represent a possible cell of origin in gliomagenesis. Deletion of the tumor suppressor gene Tp53 (p53) results in increased proliferation and self-renewal of NPCs and is a common genetic mutation found in glioma. We have identified inhibitor of DNA binding 2 (Id2) as a novel target gene directly repressed by p53 to maintain normal NPC proliferation. p53((-/-)) NPCs express elevated levels of Id2 and suppression of Id2 expression is sufficient to inhibit the increased proliferation and self renewal which results from p53 loss. Elevated expression of Id2 in wild-type NPCs phenocopies the behavior of p53((-/-)) NPCs by enhancing NPC proliferation and self-renewal. Interestingly, p53 directly binds to a conserved site within the Id2 promoter to mediate these effects. Finally, we have identified elevated Id2 expression in glioma cell lines with mutated p53 and demonstrated that constitutive expression of Id2 plays a key role in the proliferation of glioma stem-like cells. These findings indicate that Id2 functions as a proproliferative gene that antagonizes p53-mediated cell cycle regulation in NPCs and may contribute to the malignant proliferation of glioma-derived tumor stem cells. PMID- 21608080 TI - Fibroblast growth factor 2 (Fgf2) inhibits differentiation of mesenchymal stem cells by inducing Twist2 and Spry4, blocking extracellular regulated kinase activation, and altering Fgf receptor expression levels. AB - Mesenchymal stem cells (MSCs) are known to differentiate into connective tissue lineages but intracellular signaling pathways that maintain cells in an undifferentiated state remain largely unexplored. Previously, we reported that fibroblast growth factor 2 (Fgf2) reversibly inhibited multilineage differentiation of primary mouse MSCs and now identify a unique compliment of signaling proteins that are dynamically regulated by this mitogen and whose expression levels are strongly correlated with inhibition of cell differentiation. Fgf2 selectively induced expression of Twist2 and Sprouty4 (Spry4) and repressed expression of soluble frizzled related receptor 2 (Sfrp2), runt-related transcription factor 2 (Runx2), and peroxisome proliferation activated receptor gamma (Pparg). In contrast, Wnt3a induced expression of Twist but not Twist2 or Spry4 and bone morphogenetic protein 2 (Bmp2) failed to alter expression of all three genes. Moreover, pretreatment of MSCs with Fgf2 delayed extracellular regulated kinase 1 (Erk1) and Erk2 phosphorylation and repressed bone-specific gene expression during an osteoinduction time course. Alternatively, pretreatment with Wnt3a had no effect, whereas Bmp2 pretreatment augmented Erk1/2 activation and bone-specific gene expression. Fgf2 also induced expression of Fgf receptor 1 (Fgfr1) and Fgfr4 and repressed Fgfr2 and Fgfr3 expression in MSCs, whereas Wnt3a and Bmp2 had the opposite effect. Finally, immunostaining revealed that Twist and Spry4 were coexpressed in MSCs and that Fgf2 treatment altered their subcellular distribution in a manner consistent with their mode of action. Collectively, these studies demonstrate that inhibition of mouse MSC differentiation by Fgf2 is strongly correlated with upregulation of Twist2 and Spry4 and suppression of Erk1/2 activation. PMID- 21608082 TI - Enhanced neural progenitor/stem cells self-renewal via the interaction of stress inducible protein 1 with the prion protein. AB - Prion protein (PrP(C) ), when associated with the secreted form of the stress inducible protein 1 (STI1), plays an important role in neural survival, neuritogenesis, and memory formation. However, the role of the PrP(C) -STI1 complex in the physiology of neural progenitor/stem cells is unknown. In this article, we observed that neurospheres cultured from fetal forebrain of wild-type (Prnp(+/+) ) and PrP(C) -null (Prnp(0/0) ) mice were maintained for several passages without the loss of self-renewal or multipotentiality, as assessed by their continued capacity to generate neurons, astrocytes, and oligodendrocytes. The homogeneous expression and colocalization of STI1 and PrP(C) suggest that they may associate and function as a complex in neurosphere-derived stem cells. The formation of neurospheres from Prnp(0/0) mice was reduced significantly when compared with their wild-type counterparts. In addition, blockade of secreted STI1, and its cell surface ligand, PrP(C) , with specific antibodies, impaired Prnp(+/+) neurosphere formation without further impairing the formation of Prnp(0/0) neurospheres. Alternatively, neurosphere formation was enhanced by recombinant STI1 application in cells expressing PrP(C) but not in cells from Prnp(0/0) mice. The STI1-PrP(C) interaction was able to stimulate cell proliferation in the neurosphere-forming assay, while no effect on cell survival or the expression of neural markers was observed. These data suggest that the STI1-PrP(C) complex may play a critical role in neural progenitor/stem cells self renewal via the modulation of cell proliferation, leading to the control of the stemness capacity of these cells during nervous system development. PMID- 21608081 TI - Development of histocompatible primate-induced pluripotent stem cells for neural transplantation. AB - Immune rejection and risk of tumor formation are perhaps the greatest hurdles in the field of stem cell transplantation. Here, we report the generation of several lines of induced pluripotent stem cells (iPSCs) from cynomolgus macaque (CM) skin fibroblasts carrying specific major histocompatibility complex (MHC) haplotypes. To develop a collection of MHC-matched iPSCs, we genotyped the MHC locus of 25 CMs by microsatellite polymerase chain reaction analysis. Using retroviral infection of dermal skin fibroblasts, we generated several CM-iPSC lines carrying different haplotypes. We characterized the immunological properties of CM-iPSCs and demonstrated that CM-iPSCs can be induced to differentiate in vitro along specific neuronal populations, such as midbrain dopaminergic (DA) neurons. Midbrain-like DA neurons generated from CM-iPSCs integrated into the striatum of a rodent model of Parkinson's disease and promoted behavioral recovery. Importantly, neither tumor formation nor inflammatory reactions were observed in the transplanted animals up to 6 months after transplantation. We believe that the generation and characterization of such histocompatible iPSCs will allow the preclinical validation of safety and efficacy of iPSCs for neurodegenerative diseases and several other human conditions in the field of regenerative medicine. PMID- 21608083 TI - Mesenchymal Stem Cell-mediated delivery of the sodium iodide symporter supports radionuclide imaging and treatment of breast cancer. AB - Mesenchymal Stem Cells (MSCs) migrate specifically to tumors in vivo, and coupled with their capacity to bypass immune surveillance, are attractive vehicles for tumor-targeted delivery of therapeutic agents. This study aimed to introduce MSC mediated expression of the sodium iodide symporter (NIS) for imaging and therapy of breast cancer. Tumor bearing animals received an intravenous or intratumoral injection of NIS expressing MSCs (MSC-NIS), followed by (99m) Technetium pertechnetate imaging 3-14 days later using a BazookaSPECT gamma-camera. Tissue was harvested for analysis of human NIS (hNIS) expression by relative quantitative-polymerase chain reaction. Therapy animals received an i.p. injection of (131) I or saline 14 days after injection of MSC-NIS, and tumor volume was monitored for 8 weeks. After injection of MSC-NIS, BazookaSPECT imaging revealed an image of animal intestines and chest area at day 3, along with a visible weak tumor image. By day 14, the tumor was visible with a significant reduction in radionuclide accumulation in nontarget tissue observed. hNIS gene expression was detected in the intestines, heart, lungs, and tumors at early time points but later depleted in nontarget tissues and persisted at the tumor site. Based on imaging/biodistribution data, animals received a therapeutic dose of (131) I 14 days after MSC-NIS injection. This resulted in a significant reduction in tumor growth (mean +/- SEM, 236 +/- 62 mm(3) vs. 665 +/- 204 mm(3) in controls). The ability to track MSC migration and transgene expression noninvasively in real time before therapy is a major advantage to this strategy. This promising data supports the feasibility of this approach as a novel therapy for breast cancer. PMID- 21608085 TI - Comparison of object and animal hoarding. AB - Recent research has highlighted the prevalence and harmful consequences of hoarding, and investigators have proposed inclusion of hoarding disorder in DSM 5. An unanswered question about the proposed disorder is whether people who hoard animals would meet diagnostic criteria for it. This article discusses the similarities and differences between object and animal hoarding. People who hoard animals appear to meet the basic diagnostic criteria for hoarding disorder. Their homes are cluttered, disorganized, and dysfunctional. They have great difficulty relinquishing animals to people who can more adequately care for them, and they form intense attachments (urges to save) that result in significant impairment. However, they differ from people who hoard objects in several ways. These differences are significant enough to warrant comment in the text description accompanying the diagnostic criteria and consideration as a subtype of hoarding disorder. More research is necessary to determine the exact relationship between object and animal hoarding. PMID- 21608084 TI - SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is a common and debilitating mental disorder that occurs following exposure to a traumatic event. However, most individuals do not develop PTSD following even a severe trauma, leading to a search for new variables, such as genetic and other molecular variation, associated with vulnerability and resilience in the face of trauma exposure. METHOD: We examined whether serotonin transporter (SLC6A4) promoter genotype and methylation status modified the association between number of traumatic events experienced and PTSD in a subset of 100 individuals from the Detroit Neighborhood Health Study. RESULTS: Number of traumatic events was strongly associated with risk of PTSD. Neither SLC6A4 genotype nor methylation status was associated with PTSD in main effects models. However, SLC6A4 methylation levels modified the effect of the number of traumatic events on PTSD after controlling for SLC6A4 genotype. Persons with more traumatic events were at increased risk for PTSD, but only at lower methylation levels. At higher methylation levels, individuals with more traumatic events were protected from this disorder. This interaction was observed whether the outcome was PTSD diagnosis, symptom severity, or number of symptoms. CONCLUSIONS: Gene-specific methylation patterns may offer potential molecular signatures of increased risk for and resilience to PTSD. PMID- 21608087 TI - Relative effects of CBT and pharmacotherapy in depression versus anxiety: is medication somewhat better for depression, and CBT somewhat better for anxiety? AB - BACKGROUND: Little is known about whether cognitive behavioral therapy (CBT) or pharmacotherapy is relatively more advantageous for depressive versus anxiety disorders. METHODS: We conducted a meta-analysis wherein we searched electronic databases and references to select randomized controlled studies comparing CBT and pharmacotherapy, with or without placebo, in adults with major depressive or anxiety disorders. The primary effect size was calculated from disorder-specific outcome measures as the difference between CBT and pharmacotherapy outcomes (i.e., positive effect size favors CBT; negative effect size favors pharmacotherapy). RESULTS: Twenty-one anxiety (N = 1,266) and twenty-one depression (N = 2,027) studies comparing medication to CBT were included. Including all anxiety disorders, the overall effect size was.25 (95% CI: -0.02, 0.55, P =.07). Effects for panic disorder significantly favored CBT over medications (.50, 95% CI: 0.02, 0.98). Obsessive-compulsive disorder showed similar effects-sizes, though not statistically significant (.49, 95% CI: -0.11, 1.09). Medications showed a nonsignificant advantage for social anxiety disorder (-.22, 95% CI: -0.50, 0.06). The overall effect size for depression studies was.05 (95% CI: -0.09, 0.19), with no advantage for medications or CBT. Pooling anxiety disorder and depression studies, the omnibus comparison of the relative difference between anxiety and depression in effectiveness for CBT versus pharmacotherapy pointed to a nonsignificant advantage for CBT in anxiety versus depression (B =.14, 95% CI: -0.14, 0.43). CONCLUSIONS: On balance, the evidence presented here indicates that there are at most very modest differences in effects of CBT versus pharmacotherapy in the treatment of anxiety versus depressive disorders. There seems to be larger differences between the anxiety disorders in terms of their relative responsiveness to pharmacotherapy versus CBT. PMID- 21608086 TI - Sleep disturbances in depressed and nondepressed pregnant women. AB - BACKGROUND: Sleep disturbances and symptoms of depression are common during pregnancy. Both are independent and interrelated risk factors for adverse outcomes. It is unclear the degree to which sleep differs between depressed and nondepressed pregnant women. We sought to (1) describe and compare sleep disturbances in depressed pregnant and nondepressed pregnant women, (2) determine the impact of selective serotonin reuptake inhibitors (SSRI) treatment on sleep, and (3) evaluate whether sleep at 20 weeks is associated with increased depressive symptoms and major depressive disorder (MDD) in later pregnancy. METHODS: Pregnant women (N = 240) were recruited in the second trimester (20 weeks gestation) and assigned to depressed (N = 59) and nondepressed (N = 181) groups based on a Structured Clinical Interview for DSM-IV diagnosis of major depressive disorder. The Structured Interview Guide for the Hamilton Rating Scale with Atypical Depression Supplement was administered at 20, 30, and 36 weeks gestation from which the sleep variables were obtained. RESULTS: Depressed women had more fragmented sleep at each assessment (P values<=.05). However, the frequency of insomnia symptoms was greater for depressed women only at 20 weeks gestation. SSRI use, regardless of MDD status, did significantly affect several sleep variables. Among the nondepressed women, those with short or longer sleep duration, symptoms of insomnia and long periods of nocturnal waketime had higher Structured Interview Guide for the Hamilton Rating Scale with Atypical Depression Supplement scores later in pregnancy (P values<=.05). CONCLUSIONS: At 20 and 30 weeks gestation sleep was more disturbed in depressed pregnant women compared to nondepressed pregnant women. At 36 weeks, sleep was disturbed regardless of depression status or SSRI use. Among the nondepressed women, disturbed sleep in conjunction with SSRI use was associated with higher depressive symptoms. PMID- 21608088 TI - Reproducibility of the physiological cost index among individuals with a lower limb amputation and healthy adults. AB - BACKGROUND AND PURPOSE: The physiological cost index (PCI) is a clinical measurement used to estimate the energy cost of walking. The reproducibility of the PCI has been questioned and no study has investigated the measurement error among individuals with a lower-limb amputation. The aim was to investigate the test-retest reproducibility of the PCI in individuals with a lower-limb amputation and healthy adults. METHODS: The study comprised 28 individuals (20 males, eight females, mean age 49 years) with a unilateral amputation due to reasons other than vascular disease and 31 healthy volunteers (20 males, 11 females, mean age 47 years). PCI values were obtained by registering heart rate at rest and during level indoor walking for 5 minutes at a comfortable speed. A within-day test-retest assessment was performed. Reproducibility analyses included intra-class correlation, analyses of systematic differences between measurements, calculation of the smallest detectable change (SDC) and coefficient of variation (CV), and the results were finally visualized using Bland-Altman plots. RESULTS: The reliability in terms of intra-class correlation was excellent for both groups (0.966 and 0.948). In the amputee group, the PCI revealed a mean difference of 0.026 (p = 0.016) between tests (PCI = 0.555, standard deviation [SD] = 0.214 and PCI = 0.581, SD = 0.236, respectively). In the healthy group, there was no systematic difference between tests (PCI = 0.329, SD = 0.114 and PCI = 0.331, SD = 0.110, respectively). The SDC was 0.116 in the amputee group and 0.070 in the healthy group, giving a CV of 20.4% and 21.0%,respectively. CONCLUSIONS: The within-day test-retest reproducibility of the PCI was excellent among individuals with lower-limb amputations and healthy adults in terms of intra-class correlation and acceptable in terms of agreement. The SDC, which was calculated for each group, should be considered when demonstrating an individual difference after an intervention. PMID- 21608089 TI - Multiple catalysis with two chiral units: an additional dimension for asymmetric synthesis. AB - This Minireview focuses on asymmetric reactions mediated by two distinct chiral catalysts (chiral multiple catalysis). Initially, this approach appears unconventional, but indeed it allows a fast multidimensional optimization and fine-tuning of the catalytic system required to perform a given transformation. Herein, this emerging concept is presented and its potential applications are highlighted. PMID- 21608090 TI - In vivo solid-phase microextraction in metabolomics: opportunities for the direct investigation of biological systems. AB - Sample preparation has a strong impact on the quality of metabolomics studies. The use of solid-phase microextraction (SPME), particularly its in vivo format, enables the capture of a more representative metabolome and presents opportunities to detect low-abundance, short-lived, and/or unstable species not easily captured by traditional methods. The technique is ideally suited for temporal, spatial, and longitudinal studies of the same living system, as well as multicompartmental studies of the same organism. SPME is useful for the investigation of biological systems ranging in complexity from cells to mammalian tissues. Selected examples are highlighted in this Minireview in order to place the technique within the context of conventional methods of sample preparation for metabolomics. PMID- 21608091 TI - Distillable acid-base conjugate ionic liquids for cellulose dissolution and processing. PMID- 21608092 TI - Interfacial self-assembly of cell-like filamentous microcapsules. PMID- 21608093 TI - Coupling of quinone monoacetals promoted by sandwiched Bronsted acids: synthesis of oxygenated biaryls. PMID- 21608094 TI - Genetic safeguard against mycotoxin cyclopiazonic acid production in Aspergillus oryzae. AB - Aspergillus oryzae is a fungus widely used in traditional Japanese fermentation industries. Its inability to produce mycotoxins, due to mutation or transcriptional repression of the genes responsible for their biosynthesis, is consistent with the hypothesis that A. oryzae is a domesticated species derived from A. flavus, a wild species that is a well-known producer of aflatoxin. In contrast, the cyclopiazonic acid (CPA) biosynthetic gene (cpa) cluster in A. oryzae contains genes that have been lost in A. flavus. Through targeted gene inactivation, isolation of the corresponding metabolite, and evaluation of biological activity of the metabolite, we demonstrated that an A. oryzae-specific gene-cpaH-mediates the conversion of CPA into the less toxic 2-oxocyclopiazonic acid, a new analogue of CPA. The detoxifying properties of cpaH, which have been lost in the A. flavus pathway, reflect the relationship of the two species. PMID- 21608095 TI - Site-specific labeling of proteins by using biotin protein ligase conjugated with fluorophores. AB - Biotin protein ligase (BPL) mediates the covalent attachment of biotin to a specific lysine residue of biotin carboxyl carrier protein (BCCP). This biotinylation in Sulfolobus tokodaii is unique in that BPL forms a tight complex with the product, biotinylated BCCP, and this property was exploited for fluorescent labeling of a membrane protein. Thus, the truncated form of BCCP (BCCPDelta100, 69 residues) was fused to either the N or C terminus of the bradykinin B2 receptor (B2R). The resulting fusion proteins, BCCPDelta100-B2R and B2R-BCCPDelta100, respectively, were separately expressed in mammalian HEK293 cells, and labeled with BPL conjugated with a fluorophore: either fluorescein, DyLight549 or green fluorescent protein. The fusion proteins were biotinylated and bound to BPL, thereby giving rise to strong fluorescence along the periphery of the cell. Some were capable of binding bradykinin and an antagonist. When stimulated with the former, the receptor translocated to the cytosol; this suggests that the labeled receptor retains its integrity in terms of ligand binding and translocation. PMID- 21608096 TI - Engineering biofilms for biocatalysis. PMID- 21608099 TI - Intermolecular clamping by hydrogen bonds: 2-pyridone?NH3. AB - A combined spectroscopic and ab initio theoretical study of the doubly hydrogen bonded complex of 2-pyridone (2PY) with NH(3) has been performed. The S(1)<-S(0) spectrum extends up to ~1200 cm(-1) above the 0(0) (0) band, close to twice the range observed for 2PY. The S(1) state nonradiative decay for vibrations above ~300 cm(-1) in the NH(3) complex is dramatically slowed down relative to bare 2PY. Also, the Deltav=2, 4,... overtone bands of the nu(1) ' and nu(2) ' out-of plane vibrations that dominate the low-energy spectral region of 2PY are much weaker or missing for 2PY?NH3, which implies that the bridging (2PY)NH???NH(3) and H(2) NH???O=C H-bonds clamp the 2PY at a planar geometry in the S(1) state. The mass-resolved UV vibronic spectra of jet-cooled 2PY?NH(3) and its H/D mixed isotopomers are measured using two-color resonant two-photon ionization spectroscopy. The S(0) and S(1) equilibrium structures and normal-mode frequencies are calculated by density functional (B3LYP) and correlated ab initio methods (MP2 and approximate second-order coupled-cluster, CC2). The S(1)<-S(0) vibronic assignments are based on configuration interaction singles (CIS) and CC2 calculations. A doubly H-bonded bridged structure of C(S) symmetry is predicted, in agreement with that of Held and Pratt [J. Am. Chem. Soc. 1993, 115, 9718]. While the B3LYP and MP2 calculated rotational constants are in very good agreement with experiment, the calculated H(2) NH???O=C H-bond distance is ~0.7 A shorter than that derived by Held and Pratt. On the other hand, this underlines their observation that ammonia can act as a strong H-bond donor when built into an H-bonded bridge. The CC2 calculations predict the H(2) NH???O distance to increase by 0.2 A upon S(1)<-S(0) electronic excitation, while the (2PY)NH???NH(3) H-bond remains nearly unchanged. Thus, the expansion of the doubly H-bonded bridge in the excited state is asymmetric and almost wholly due to the weakening of the interaction of ammonia with the keto acceptor group. PMID- 21608100 TI - Types of interaction of meso-tetraphenylporphyrin with alkali and alkaline-earth metal ions. AB - The cavity in a porphyrin can accommodate metal ions through electron donor acceptor (EDA) interaction in acetonitrile media without any specially designed fabrication with the porphyrin subunit. Alkali metal ion forms a complex with meso-tetraphenylporphyrin (TP) in 2:1 stoichiometry, while the bivalent Mg(2+) ion follows a 1:1 stoichiometry. A fluorescence interaction study indicated that TP can behave like a chemosensor for these ions present in the blood electrolytes. Specifically, for the alkali metal ions intensity-based sensing was observed, due to inhibition of photoinduced electron transfer (PET), entailing enhancement of fluorescence intensity, and for the alkaline-earth Mg(2+) a mixed quenching was observed. Na(+) and K(+) ions can be differentiated depending upon the extent of fluorescence enhancement. PMID- 21608101 TI - Gold nanoparticles-based fluorescence enhancement of the terbium-levofloxacin system and its application in pharmaceutical preparations. AB - A sensitive fluorescence (FL) technique is proposed for the determination of levofloxacin (LVX). The method is based on the fact that the weak FL signal of the Tb(III)-LVX system is strongly enhanced in the presence of gold nanoparticles. Gold nanoparticles were prepared by the citrate reduction of HAuCl(4) and characterized by transmission electron microscopy (TEM). Levofloxacin and Tb(III) ion form a fluorescence complex in aqueous solution, and its maximum emission wavelength was found at 545 nm. Optimal conditions for the formation of the levofloxacin-Tb(III) complexes were studied. Levofloxacin was detected by measuring the FL intensity, which increases linearly with the concentration of LVX in the range 6.2 * 10(-10)-2.6 * 10(-8) mol/L. Recovery of the target analytes was > 96% with good quality parameters: linearity (r(2) > 0.996), limit of detection (LOD) and limit of quantification (LOQ) values 2.1 * 10(-10) mol/L and 7.2 * 10(-10) mol/L, and run-to-run and day-to-day precisions with relative standard deviations (RSDs) around 3%. Thus, the proposed method can be successfully applied to the routine determination of levofloxacin in pharmaceutical preparations. PMID- 21608103 TI - Fluorescence modulation of 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5 dione by silver nanoparticles and its possible analytical application. AB - The effects of silver nanoparticles on the photophysical properties of 1,7-bis(4 hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, popularly known as curcumin, have been investigated using optical absorption and fluorescence techniques. Although absorption spectroscopy suggests a ground-state complex formation, fluorescence quenching data confirms a simultaneous static and dynamic quenching, inferring ground as well as excited-state complex formation. The recovery of fluorescence quenching of the curcumin-silver nanoparticle complex in the presence of ascorbic acid or uric acid emphasizes a strong interaction between the silver nanoparticles and ascorbic acid/uric acid, suggesting that fluorescence recovery after the quenching of curcumin-silver nanoparticle complexes has potential for ascorbic acid or uric acid assay development. PMID- 21608102 TI - Effect of amino acids on aggregation behaviour of sodium deoxycholate in solution: a fluorescence study. AB - The influence of three alkaline amino acids, L-lysine (L-Lys), L-arginine (L-Arg) and L-histidine (L-His), on the aggregation behaviour of sodium deoxycholate (NaDC) in phosphate buffer, pH 7.0, was studied at 25 degrees C. The fluorescence probe technique based on pyrene was employed to determine accurately the critical aggregation concentration (cac), polarity of the microenvironment and aggregation numbers for the NaDC aggregates. The added amino acids can effectively reduce the cac values and micropolarity of NaDC, indicating that it is easier for NaDC to aggregate in a compact manner in the presence of amino acids. The aggregation numbers of NaDC were increased, indicating that more NaDC molecules connect together to form stable aggregates. The performance of L-Arg is similar to that of L-His, and both have a smaller effect on the above parameters than L-Lys. In view of this, it may be inferred that both electrostatic and hydrophobic interaction are responsible for the interaction between NaDC and amino acids in aqueous solution. PMID- 21608104 TI - De novo deletion of chromosome 20q13.33 in a patient with tracheo-esophageal fistula, cardiac defects and genitourinary anomalies implicates GTPBP5 as a candidate gene. AB - BACKGROUND: Tracheo-esophageal fistula (TEF) with/or without esophageal atresia (EA) is a common congenital malformation that is often accompanied by other anomalies. The causes of this condition are thought to be heterogeneous but are overall not well understood. CASE REPORT: We identified a patient with a TEF/EA, as well as cardiac and genitourinary anomalies, who was found to have a 0.7 Mb de novo deletion of chromosome 20q13.33. One gene within the deleted interval, GTPBP5, is of particular interest as a candidate gene. CONCLUSIONS: GTPBP5 bears further study as a cause of TEF/EA accompanied by other malformations. PMID- 21608105 TI - Fukushima Daiichi: implications for carbon-free energy, nuclear nonproliferation, and community resilience. AB - Implications of the nuclear power plant accidents at Fukushima Daiichi are explored in this commentary. In addition to questions of nuclear reactor regulatory standards, broader implications on noncarbon-emitting energy production, nuclear nonproliferation objectives, and community resilience and emergency response against catastrophic events are explored. PMID- 21608106 TI - Social and ethical issues in environmental risk management. AB - The recognition of the social and ethical aspects of radiation risk management has been an important part of international projects following the Chernobyl accident of 1986. This study comments on the science and policy issues in environmental risk assessment, including the social and ethical dimensions of emergency preparedness and remediation experiences gained from the Chernobyl accident. While the unique situation of Fukushima, combined with an earthquake and tsunami, raises its own social and political challenges, it is hoped that some of the lessons learnt from Chernobyl will be relevant to long-term management of the Fukushima site. PMID- 21608107 TI - Environmental radiation: risk benchmarks or benchmarking risk assessment. AB - In the wake of the compound March 2011 nuclear disaster at the Fukushima I nuclear power plant in Japan, international public dialogue has repeatedly turned to questions of the accuracy of current risk assessment processes to assess nuclear risks and the adequacy of existing regulatory risk thresholds to protect us from nuclear harm. We confront these issues with an emphasis on learning from the incident in Japan for future US policy discussions. Without delving into a broader philosophical discussion of the general social acceptance of the risk, the relative adequacy of existing US Nuclear Regulatory Commission (NRC) risk thresholds is assessed in comparison with the risk thresholds of federal agencies not currently under heightened public scrutiny. Existing NRC thresholds are found to be among the most conservative in the comparison, suggesting that the agency's current regulatory framework is consistent with larger societal ideals. In turning to risk assessment methodologies, the disaster in Japan does indicate room for growth. Emerging lessons seem to indicate an opportunity to enhance resilience through systemic levels of risk aggregation. Specifically, we believe bringing systemic reasoning to the risk management process requires a framework that (i) is able to represent risk-based knowledge and information about a panoply of threats; (ii) provides a systemic understanding (and representation) of the natural and built environments of interest and their dependencies; and (iii) allows for the rational and coherent valuation of a range of outcome variables of interest, both tangible and intangible. Rather than revisiting the thresholds themselves, we see the goal of future nuclear risk management in adopting and implementing risk assessment techniques that systemically evaluate large-scale socio-technical systems with a view toward enhancing resilience and minimizing the potential for surprise. PMID- 21608108 TI - Lessons in risk- versus resilience-based design and management. AB - The implications of recent catastrophic disasters, including the Fukushima Daiichi nuclear power plant accident, reach well beyond the immediate, direct environmental and human health risks. In a complex coupled system, disruptions from natural disasters and man-made accidents can quickly propagate through a complex chain of networks to cause unpredictable failures in other economic or social networks and other parts of the world. Recent disasters have revealed the inadequacy of a classical risk management approach. This study calls for a new resilience-based design and management paradigm that draws upon the ecological analogues of diversity and adaptation in response to low-probability and high consequence disruptions. PMID- 21608109 TI - Environmental risk management for radiological accidents: integrating risk assessment and decision analysis for remediation at different spatial scales. AB - The consequences of the Tohuku earthquake and subsequent tsunami in March 2011 caused a loss of power at the Fukushima Daiichi nuclear power plant, in Japan, and led to the release of radioactive materials into the environment. Although the full extent of the contamination is not currently known, the highly complex nature of the environmental contamination (radionuclides in water, soil, and agricultural produce) typical of nuclear accidents requires a detailed geospatial analysis of information with the ability to extrapolate across different scales with applications to risk assessment models and decision making support. This article briefly summarizes the approach used to inform risk-based land management and remediation decision making after the Chernobyl, Soviet Ukraine, accident in 1986. PMID- 21608110 TI - Impact of nuclear accidents on marine biota. AB - The accident at the Fukushima Daiichi nuclear power plant, precipitated by the earthquake and subsequent tsunami that struck the northeastern coast of Japan in March 2011, has raised concerns about the potential impact to marine biota posed by the release of radioactive water and radionuclide particles into the environment. The Fukushima accident is the only major nuclear accident that has resulted in the direct discharge of radioactive materials into a coastal environment. This article briefly summarizes what is currently understood about the effects of radioactive wastewaters and radionuclides to marine life. PMID- 21608111 TI - Radionuclides released to the environment following nuclear events. AB - The accident at the Fukushima Daiichi nuclear power plant, precipitated by the devastating earthquake and subsequent tsunami that struck the northeastern coast of Japan in March 2011, has raised concerns about the fate of radioactive particles released into the environment. Radioactive particles with different composition, size, shape, structures, and colors have been identified throughout the world in different biotic and abiotic media. This article briefly summarizes what is currently understood about the fate of, and risks posed by, these materials in the environment. PMID- 21608112 TI - A Bayesian network model for integrative river rehabilitation planning and management. AB - As rehabilitation of previously channelized rivers becomes more common worldwide, flexible integrative modeling tools are needed to help predict the morphological, hydraulic, economic, and ecological consequences of the rehabilitation activities. Such predictions can provide the basis for planning and long-term management efforts that attempt to balance the diverse interests of river system stakeholders. We have previously reported on a variety of modeling methods and decision support concepts that can assist with various aspects of the river rehabilitation process. Here, we bring all of these tools together into a probability network model that links management actions, through morphological and hydraulic changes, to the ultimate ecological and economic consequences. Although our model uses a causal graph representation common to Bayesian networks, we do not limit ourselves to discrete-valued nodes or conditional Gaussian distributions as required by most Bayesian network implementations. This precludes us from carrying out easy probabilistic inference but gives us the advantages of functional and distributional flexibility and enhanced predictive accuracy, which we believe to be more important in most environmental management applications. We exemplify model application to a large, recently completed rehabilitation project in Switzerland. PMID- 21608113 TI - Agricultural land management options following large-scale environmental contamination. AB - The recent events at the Fukushima Daiichi nuclear power plant, in Japan, have raised questions about the accumulation of radionuclides in soils, the transfer in the food chain, and the possibility for restricted land use in the foreseeable future. This article summarizes what is generally understood about the application of agricultural countermeasures as a land management option to reduce the transfer of radionuclides in the food chain and to facilitate the return of potentially affected soils to agricultural practices in the vicinity of the Fukushima plant. PMID- 21608114 TI - An overview of the transfer of radionuclides to farm animals and potential countermeasures of relevance to Fukushima releases. AB - Initial information since the releases of radioactive materials from the Fukushima Daiichi nuclear power plant, in Japan, shows that some animal food products are contaminated with 131I (mostly milk) and, to a lesser extent with 134Cs and 137Cs. Current knowledge on the transfer of these radioisotopes to animal products and available relevant countermeasures and management options to reduce radiation doses to humans are summarized. Much of this knowledge was obtained during the years of global fallout from atmospheric nuclear weapons tests and the response to the Chernobyl accident, in Ukraine in 1986. PMID- 21608115 TI - The transfer of radiocesium from soil to plants: Mechanisms, data, and perspectives for potential countermeasures in Japan. AB - The recent events at the Fukushima Daiichi nuclear power plant, Japan, have raised questions about radiocesium (137Cs) transfer from soil to agricultural plants. This transfer has been studied extensively in Europe following the Chernobyl accident, in Soviet Ukraine in 1986. This article briefly discusses whether that transfer may be different in Japan in the aftermath of the Fukushima accident. PMID- 21608116 TI - Soil vulnerability for cesium transfer. AB - The recent events at the Fukushima Daiichi nuclear power plant in Japan have raised questions about the accumulation of radionuclides in soils and the possible impacts on agriculture surrounding nuclear power plants. This article summarizes the knowledge gained after the nuclear power plant accident in Chernobyl, Ukraine, on how soil parameters influence soil vulnerability for radiocesium bioavailability, discusses some potential agrochemical countermeasures, and presents some predictions of radiocesium crop concentrations for areas affected by the Fukushima accident. PMID- 21608117 TI - Effects of ionizing radiation on wildlife: what knowledge have we gained between the Chernobyl and Fukushima accidents? AB - The recent events at the Fukushima Daiichi nuclear power plant in Japan have raised questions over the effects of radiation in the environment. This article considers what we have learned about the radiological consequences for the environment from the Chernobyl accident, Ukraine, in April 1986. The literature offers mixed opinions of the long-term impacts on wildlife close to the Chernobyl plant, with some articles reporting significant effects at very low dose rates (below natural background dose rate levels in, for example, the United Kingdom). The lack of agreement highlights the need for further research to establish whether current radiological protection criteria for wildlife are adequate (and to determine if there are any implications for human radiological protection). PMID- 21608118 TI - Overview of exposure to and effects from radionuclides in terrestrial and marine environments. AB - The accident at the Fukushima Daiichi nuclear power plant, precipitated by the devastating earthquake and subsequent tsunami that struck the northeastern coast of Japan in March 2011, has raised concerns about potential impacts to terrestrial and marine environments from radionuclides released into the environment. A preliminary understanding of the potential ecological impacts from radionuclides can be ascertained from observations and data developed following previous environmental incidents elsewhere in the world. This article briefly summarizes how biota experience exposure to ionizing radiation, what effects may be produced, and how they may differ among taxa and habitats. PMID- 21608120 TI - Technology and the forces of nature: a lesson of humility calling for ecocentrism. AB - The incident at the Fukushima Daiichi nuclear power plant, resulting from the powerful earthquake and tsunami that struck the northeastern coast of Japan in March 2011, reminds humankind of the powerful natural forces that shape our world. This article calls for a new ecocentric approach to human interaction with the environment, with particular reference to the environmental consequences of radiation. PMID- 21608119 TI - The challenges posed by radiation and radionuclide releases to the environment. AB - The recent accident at the Fukushima I nuclear power plant in Japan (also known as Fukushima Daiichi) captured the world's attention and re-invigorated concerns about the safety of nuclear power technology. The Editors of Integrated Environmental Assessment and Management invited experts in the field to describe the primary issues associated with the control and release of radioactive materials to the environment, particularly those that are of importance to the health of the human populations and the ecological systems that populate our planet. This collection of invited short commentaries aims to inform on the safety of nuclear power plants damaged by natural disasters and provide a primer on the potential environmental impacts. The intent of these invited commentaries is not to fuel the excitement and fears about the Fukushima Daiichi incident; rather, it is to collect views and comments from some of the world's experts on the broad science and policy challenges raised by this event, and to provide high level views on the science issues that surround this situation in order to improve our collective ability to avoid or at least minimize the consequences of future events. PMID- 21608121 TI - Recommendations from the International Union of Radioecology to improve guidance on radiation protection. AB - This brief commentary summarizes the views of a working group assembled by the International Union of Radioecology to advance the approaches used to evaluate effects of radioactive materials in the environment. The key message in both the research needs and the recommendations for management of radioactive materials centers around the need to adopt an ecocentric approach that recognizes the interconnectedness of biota, including humans, and ecological processes. PMID- 21608122 TI - Highly-ordered, 3D petal-like array for surface-enhanced Raman scattering. AB - Despite the great potential of the application of surface-enhanced Raman scattering (SERS), the difficulty in fabricating suitable SERS substrates is still a problem. Based on the self-assembly of silica nanoparticles, a simple method is here proposed to fabricate a highly-ordered, 3D, petal-like arrayed structure (3D PLAS) that serves as a promising SERS substrate for both its high reproducibility and enormous SERS enhancement. Such a novel structure is easily achieved by anisotropically etching a self-assembly bilayer of silica nanoparticles, followed by metal deposition. The SERS performance of the 3D PLAS and its relationship with the main parameters, including the etching time, the diameter of silica nanoparticles, and the deposited metal film, are characterized using 632.8 nm incident light. With Rhodamine 6G as a probe molecule, the spatially averaged SERS enhancement factor is on the order of 5 * 10(7) and the local enhancement factor is much higher, both of which can be improved further by optimizing the parameters. PMID- 21608123 TI - Nanogap electrode fabrication for a nanoscale device by volume-expanding electrochemical synthesis. AB - A novel nanogap fabrication method using an electrochemical nanopatterning technique is presented. Electrochemical deposition of platinum ions reduces the microgap size to the sub-50-nm range due to the self-limited volume expansion of the electrodes. Additionally, the low crystallinity of platinum reduces the line edge roughness in the electrodes, whereas the high crystallinity of gold increases it. Current compliance, a buffered resistor, and a symmetric deposition strategy are used to achieve high reliability and practicality of nanogap electrodes. As a possible application, an organic thin-film transistor using the nanogap electrodes is also demonstrated. PMID- 21608124 TI - Preclinical evaluation of Raman nanoparticle biodistribution for their potential use in clinical endoscopy imaging. AB - Raman imaging offers unsurpassed sensitivity and multiplexing capabilities. However, its limited depth of light penetration makes direct clinical translation challenging. Therefore, a more suitable way to harness its attributes in a clinical setting would be to couple Raman spectroscopy with endoscopy. The use of an accessory Raman endoscope in conjunction with topically administered tumor targeting Raman nanoparticles during a routine colonoscopy could offer a new way to sensitively detect dysplastic lesions while circumventing Raman's limited depth of penetration and avoiding systemic toxicity. In this study, the natural biodistribution of gold surface-enhanced Raman scattering (SERS) nanoparticles is evaluated by radiolabeling them with (64) Cu and imaging their localization over time using micropositron emission tomography (PET). Mice are injected either intravenously (IV) or intrarectally (IR) with approximately 100 microcuries (MUCi) (3.7 megabecquerel (MBq)) of (64) Cu-SERS nanoparticles and imaged with microPET at various time points post injection. Quantitative biodistribution data are obtained as % injected dose per gram (%ID g(-1)) from each organ, and the results correlate well with the corresponding microPET images, revealing that IV injected mice have significantly higher uptake (p < 0.05) in the liver (5 h = 8.96% ID g(-1); 24 h = 8.27% ID g(-1)) than IR-injected mice (5 h = 0.09% ID g( 1); 24 h = 0.08% ID g(-1)). IR-injected mice show localized uptake in the large intestine (5 h = 10.37% ID g(-1); 24 h = 0.42% ID g(-1)) with minimal uptake in other organs. Raman imaging of excised tissues correlate well with biodistribution data. These results suggest that the topical application of SERS nanoparticles in the mouse colon appears to minimize their systemic distribution, thus avoiding potential toxicity and supporting the clinical translation of Raman spectroscopy as an endoscopic imaging tool. PMID- 21608125 TI - Antibody covalent immobilization on carbon nanotubes and assessment of antigen binding. AB - Controlling the covalent bonding of antibodies onto functionalized carbon nanotubes is a key step in the design and preparation of nanotube-based conjugates for targeting cancer cells. For this purpose, an anti-MUC1 antibody (Ab) is linked to both multi-walled (MWCNTs) and double-walled carbon nanotubes (DWCNTs) using different synthetic strategies. The presence of the Ab attached to the nanotubes is confirmed by gel electrophoresis and thermogravimetric analysis. Most importantly, molecular recognition of the antigen by surface plasmon resonance is able to determine similar Ab binding capacities for both Ab-DWCNTs and Ab-MWCNTs. These results are very relevant for the design of future receptor targeting strategies using chemically functionalized carbon nanotubes. PMID- 21608126 TI - Water transport and purification in nanochannels controlled by asymmetric wettability. AB - Biomimetic asymmetric nanochannels have recently attracted increasing attention from researchers, especially in the aspect of the asymmetric wettability (a hydrophilic-hydrophobic system), which can be utilized to control the wetting behavior of aqueous media and to offer a means for guiding water motion. By using molecular dynamics simulations, a design for a potentially efficient water filter is presented based on (n, n) single-walled carbon nanotubes, where n = 6, 8, 10 and 12, asymmetrically modified with hydrophilic groups (carboxyl, -COOH) at one tip and hydrophobic groups (trifluoromethyl, -CF(3) ) at the other. The reduced water density on the hydrophobic sides of the functionalized nanotubes are observed in both pure water and aqueous electrolyte solution, except for the functionalized (6, 6) tube, due to the change of dipole orientation of the single file water wire within it. The functionalized (8, 8) tube can significantly maintain the low water density on the hydrophobic side. Both (6, 6) and (8, 8) tubes have relatively high energy barriers at their tips for ion permeation, which can be obtained by calculating the potential of mean force. Such tip functionalization of a nanotube therefore suggests the great possibilities of water transport and filtration, dominated by asymmetric wettability. The functionalized (8, 8) tube could act as a nanofluidic channel for water purification, not only for ion exclusion but also as a stable water column structure. PMID- 21608127 TI - DNA origami-templated growth of arbitrarily shaped metal nanoparticles. PMID- 21608128 TI - Analysis of abuse drugs in urine using surfactant-assisted dispersive liquid liquid microextraction. AB - The process of surfactant-assisted dispersive liquid-liquid microextraction (SA DLLME) followed by high-performance liquid chromatography-UV detection was successfully applied for the extraction and determination of selected cannabinoids (cannabidiol, Delta(9)-tetrahydrocannabinol, and cannabinol) in urine samples. The effective parameters on the extraction efficiency were studied and optimized utilizing two different optimization methods: one variable at a time (OVAT) and face center design (FCD). Under the optimum conditions (extraction solvent and its volume, toluene, 85 MUL; disperser agent and its concentration, 1.0 mL of ultra-pure water containing 0.5 mmol/L tetradecyl tremethyl ammonium bromide (TTAB); sample pH, 2.0 and salt concentration, 11% w/v NaCl), the limits of detection of the method were in the range of 0.1-0.5 MUg/L and the repeatability and reproducibility of the proposed method, expressed as relative deviation, varied between 4.1 and 8.5% and 6.7 and 11.6%, respectively. Linearity was found to be in the range of 1.0-200 MUg/L and under the optimum conditions, the preconcentration factors (PFs) were between 190 and 292. This proposed method was successfully applied in the analysis of three male advocate urine samples and good recoveries were obtained. PMID- 21608129 TI - Applications of monolithic columns in liquid chromatography-based clinical chemistry assays. AB - Monolithic columns have slowly been applied to HPLC methods for clinical chemistry testing in the last 10 years. The application areas include therapeutic drug monitoring, drugs of abuse, vitamins, porphyrins, and steroids. In comparison with conventional particulate columns, the monolithic columns may offer shorter chromatography time, more robustness, and better resolution for certain analytes. The potential drawback of large mobile phase consumption may be improved with smaller id columns, which are currently on the market. Methods covered in this review are those searchable in PubMed up to December 2010. This review highlights the emergence of monolithic column technology in HPLC methods used for clinical chemistry testing. The goals of this review are threefold: (i) To identify the areas of clinical chemistry that analytical monolithic columns have been used in HPLC methods. (ii) To demonstrate the application of analytical monolithic columns in HPLC methods using different detection systems. (iii) To discuss the advantages and limitations of the monolithic columns compared with particulate columns in the clinical chemistry applications. PMID- 21608130 TI - Determination of parabens in cosmetic products by solid-phase microextraction of poly(ethylene glycol) diacrylate thin film on fibers and ultra high-speed liquid chromatography with diode array detector. AB - The fabrication of a solid-phase microextraction (SPME) fiber through UV-induced polymerization of poly(ethylene glycol) diacrylate (PEG-DA) for determination of parabens in cosmetic products is presented in this work. The PEG-DA polymer coating was covalently attached to the fiber by introducing a surface modification with 3-(trichlorosilyl)propyl methacrylate (TPM). The PEG-DA polymer thin film coated on the fiber was homogeneous and wrinkled, which led to an increase of the surface area and high extraction efficiency. The extraction performances of the prepared SPME fibers were assessed by preconcentration of parabens including methylparaben, ethylparaben, propylparaben and benzylparaben from cosmetic products. The analysis was performed on an ultra high-speed liquid chromatography with diode array detector. The prepared SPME fibers exhibited good repeatability (for one fiber) and reproducibility (fiber-to-fiber) with RSDs of 5.4 and 6.9%, respectively. The optimized SPME method supported a wide linear range of 0.50-160 MUg/mL and the detection limits for parabens were in the range of 0.12-0.15 MUg/mL (S/N=3). The developed method was successfully applied for determination of parabens in cosmetic products with different natures. PMID- 21608131 TI - Synthesis, structural characterization, and pro-apoptotic activity of 1-indanone thiosemicarbazone platinum(II) and palladium(II) complexes: potential as antileukemic agents. AB - In the search for alternative chemotherapeutic strategies against leukemia, various 1-indanone thiosemicarbazones, as well as eight novel platinum(II) and palladium(II) complexes, with the formula [MCl2(HL)] and [M(HL)(L)]Cl, derived from two 1-indanone thiosemicarbazones were synthesized and tested for antiproliferative activity against the human leukemia U937 cell line. The crystal structure of [Pt(HL1)(L1)]Cl.2MeOH, where L1=1-indanone thiosemicarbazone, was solved by X-ray diffraction. Free thiosemicarbazone ligands showed no antiproliferative effect, but the corresponding platinum(II) and palladium(II) complexes inhibited cell proliferation and induced apoptosis. Platinum(II) complexes also displayed selective apoptotic activity in U937 cells but not in peripheral blood monocytes or the human hepatocellular carcinoma HepG2 cell line used to screen for potential hepatotoxicity. Present findings show that, in U937 cells, 1-indanone thiosemicarbazones coordinated to palladium(II) were more cytotoxic than those complexed with platinum(II), although the latter were found to be more selective for leukemic cells suggesting that they are promising compounds with potential therapeutic application against hematological malignancies. PMID- 21608132 TI - Discovery of adamantyl heterocyclic ketones as potent 11beta-hydroxysteroid dehydrogenase type 1 inhibitors. AB - 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11beta-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11beta-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11beta-HSD1 and are selective with no activity against 11beta-HSD2 and 17beta-HSD1. Selected potent 11beta-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes. PMID- 21608135 TI - Conversion of mono- and disaccharides to ethyl levulinate and ethyl pyranoside with sulfonic acid-functionalized ionic liquids. PMID- 21608134 TI - Oxidative dissolution of silver nanoparticles by dioxygen: a kinetic and mechanistic study. AB - We have recently reported a kinetic and mechanistic study on oxidative dissolution of silver nanoparticles (AgNPs) by H(2)O(2). In the present study, the parameters that govern the dissolution of AgNPs by O(2) were revealed by using UV/Vis spectrophotometry. Under the same reaction conditions (Tris-HOAc, pH 8.5, I=0.1 M at 25 degrees C) the apparent dissolution rate (k(app)) of AgNPs (10+/-2.8 nm) by O(2) is about 100-fold slower than that of H(2)O(2). The reaction rate is first-order with respect to [Ag(0)], [O(2)], and [Tris](T), and inverse first-order with respect to [Ag(+)] (where [Ag(0)]=total concentration of Ag metal and [Tris](T)=total concentration of Tris). The rate constant is dependent on the size of AgNPs. No free superoxide (O(2)(-)) and hydroxyl radical (.OH) were detected by trapping experiments. On the basis of kinetic and trapping experiments, an amine-activated pathway for the oxidation of AgNPs by O(2) is proposed. PMID- 21608133 TI - Aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole and vorozole templates. AB - Concurrent inhibition of aromatase and steroid sulfatase (STS) may provide a more effective treatment for hormone-dependent breast cancer than monotherapy against individual enzymes, and several dual aromatase-sulfatase inhibitors (DASIs) have been reported. Three aromatase inhibitors with sub-nanomolar potency, better than the benchmark agent letrozole, were designed. To further explore the DASI concept, a new series of letrozole-derived sulfamates and a vorozole-based sulfamate were designed and biologically evaluated in JEG-3 cells to reveal structure-activity relationships. Amongst achiral and racemic compounds, 2-bromo 4-(2-(4-cyanophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl)phenyl sulfamate is the most potent DASI (aromatase: IC50 =0.87 nM; STS: IC50 =593 nM). The enantiomers of the phenolic precursor to this compound were separated by chiral HPLC and their absolute configuration determined by X-ray crystallography. Following conversion to their corresponding sulfamates, the S-(+)-enantiomer was found to inhibit aromatase and sulfatase most potently (aromatase: IC50 =0.52 nM; STS: IC50 =280 nM). The docking of each enantiomer and other ligands into the aromatase and sulfatase active sites was also investigated. PMID- 21608137 TI - Perceptual grouping abilities in individuals with autism spectrum disorder; exploring patterns of ability in relation to grouping type and levels of development. AB - This study further investigates findings of impairment in Gestalt, but not global processing in Autism Spectrum Disorder (ASD) [Brosnan, Scott, Fox, & Pye, 2004]. Nineteen males with ASD and nineteen typically developing (TD) males matched by nonverbal ability, took part in five Gestalt perceptual grouping tasks. Results showed that performance differed according to grouping type. The ASD group showed typical performance for grouping by proximity and by alignment, impairment on low difficulty trials for orientation and luminance similarity, and general impairment for grouping by shape similarity. Group differences were also observed developmentally; for the ASD group, with the exception of grouping by shape similarity, perceptual grouping performance was poorer at lower than higher levels of nonverbal ability. In contrast, no developmental progression was observed in the TD controls. PMID- 21608138 TI - Cell clarification and size separation using continuous countercurrent magnetophoresis. AB - Nonmagnetic microparticles (e.g., cells, polymer beads) immersed in a magnetic fluid (ferrofluid) under a nonuniform magnetic field experience a magnetophoretic force in the direction of decreasing magnetic field strength. This phenomenon was exploited in the development of a continuous magnetophoretic countercurrent separation for the removal and concentration of micron-sized particles from aqueous suspensions, and in particular as a viable approach for cell clarification of raw fermentation broth. A magnetic fluid is added to the cell suspension, the mixture is introduced to the magnetic separator, which consists of an open flow tube passing between pairs of magnets that move in a direction counter to the flow of the suspension. The cells are pushed ahead of the magnet pairs owing to the magnetophoretic forces acting on them, collected in a tube upstream of the feed injection point, and removed as a concentrated suspension for further treatment. PMID- 21608139 TI - Dual perfluorocarbon method to noninvasively monitor dissolved oxygen concentration in tissue engineered constructs in vitro and in vivo. AB - Noninvasive in vivo monitoring of tissue implants provides important correlations between construct function and the observed physiologic effects. As oxygen is a key parameter affecting cell and tissue function, we established a monitoring method that utilizes (19) F nuclear magnetic resonance (NMR) spectroscopy, with perfluorocarbons (PFCs) as oxygen concentration markers, to noninvasively monitor dissolved oxygen concentration (DO) in tissue engineered implants. Specifically, we developed a dual PFC method capable of simultaneously measuring DO within a tissue construct and its surrounding environment, as the latter varies among animals and with physiologic conditions. In vitro studies using an NMR-compatible bioreactor demonstrated the feasibility of this method to monitor the DO within alginate beads containing metabolically active murine insulinoma betaTC-tet cells, relative to the DO in the culture medium, under perfusion and static conditions. The DO profiles obtained under static conditions were supported by mathematical simulations of the system. In vivo, the dual PFC method was successful in tracking the oxygenation state of entrapped betaTC-tet cells and the surrounding peritoneal DO over 16 days in normal mice. DO measurements correlated well with the extent of cell growth and host cell attachment examined postexplantation. The peritoneal oxygen environment was found to be variable and hypoxic, and significantly lower in the presence of metabolically active cells. The significance of the dual PFC system in providing critical DO measurements for entrapped cells and other tissue constructs, in vitro and in vivo, is discussed. PMID- 21608140 TI - Microfibrous carriers for cell culture: a comparative study. AB - Small patches of polyethylene terephthalate (PET) nonwoven microfibrous matrices have excellent properties and can be used as carriers for culturing cells in agitated bioreactors. The microfibrous carriers are highly porous and can provide large surface areas and three-dimensional space for high-density cell growth. In this work, the microfibrous carriers and several commercial microcarriers were used to study cell attachment kinetics, growth, and monoclonal antibody production with Chinese hamster ovary cells. Compared with commercial solid and macroporous microcarriers, the microfibrous carriers showed better or similar performances. In addition, the microfibrous carriers provided a wider operable range for agitation rate than commercial microcarriers, effectively protecting cells from shear stress and carrier collisions. In addition, the microfibrous carriers are available at a much lower cost than commercial microcarriers, providing an attractive alternative to microcarrier-based large-scale cell cultures. PMID- 21608142 TI - High-pressure refolding of human vascular endothelial growth factor (VEGF) recombinantly expressed in bacterial inclusion bodies: refolding optimization, and feasibility assessment. AB - High-pressure has been established as an effective technique for refolding proteins at high concentrations. In this study, high hydrostatic pressure (1-3 kbar) was utilized to refold a homodimeric protein from inclusion bodies and the process was evaluated for large-scale manufacturing feasibility. This research focused on increasing protein concentration while maximizing yield and product quality. Refolding yields of 29-42% were achieved in the absence of urea at 2 kbar and at a protein concentration of 6 g/L. Optimization of the refolding buffer composition via multivariate design of experiments and other process parameters such as refolding pressure, gas sparging, and time under pressure are discussed. Although high-pressure refolding can be considered a viable technology for manufacturing if the gains are clearly identified, in this particular case, the benefits that the high-pressure technology offers do not compensate for the drawbacks of implementing new equipment in an existing facility, and unknown impact of scale-up for this molecule. PMID- 21608141 TI - Isolation and characterization of a subset of erythropoietin glycoforms with cytoprotective but minimal erythropoietic activity. AB - Although historically used for the treatment of anemia, erythropoietin (EPO) has emerged as a neurotrophic and neuroprotective agent in different conditions of neuronal damage (traumatic brain injury, ischemia, spinal cord compression, peripheral neuropathy, retinal damage, epilepsy, Parkinson's Disease, among others). Nonetheless, EPO's therapeutic application is limited due to its hematological side-effects. With the aim of obtaining EPO derivatives resembling the hormone isolated from cells and tissues of neural origin, a novel combination of less acidic EPO glycoforms -designated as neuroepoetin (rhNEPO)- was purified to homogeneity from the supernatant of a CHO-producing cell line by a four-step chromatographic procedure. This simple and single process allowed us to prepare two EPO derivatives with distinct therapeutic expectations: the hematopoietic version and a minimally hematopoietic, but mainly in vitro cytoprotective, alternative. Further biological characterization showed that the in vivo erythropoietic activity of rhNEPO was 25-times lower than that of rhEPO. Interestingly, using different in vitro cytoprotective assays we found that this molecule exerts cytoprotection equivalent to, or better than, that of rhEPO in cells of neural phenotype. Furthermore, despite its shorter plasma half-life, rhNEPO was rapidly absorbed and promptly detected in the cerebrospinal fluid after intravenous administration in rats (5 min postinjection, in comparison with 30 min for rhEPO). Therefore, our results support the study of neuroepoetin as a potential drug for the treatment of neurological diseases, combining high cytoprotective activity with reduced hematological side-effects. PMID- 21608143 TI - Protein adsorption and transport in cation exchangers with a rigid backbone matrix with and without polymeric surface extenders. AB - We compare the properties and protein adsorption characteristics of two polymeric cation exchangers: UNOsphere S, which has an open macroporous architecture, and Nuvia S, which is based on a very similar backbone matrix but contains sulfonated polymeric surface extenders. A monoclonal IgG and lysozyme were used as model adsorbates. The characteristic pore sizes, determined by inverse size exclusion chromatography, were about 140 nm for UNOsphere S, and only about 10 nm for Nuvia S, indicating that the polymeric extenders occupy a substantial portion of the base matrix pores. Greater exclusion limits were found for Nuvia S in 1 M NaCl and for a similar matrix containing uncharged surface extenders, suggesting that the polymeric extenders collapse partially at high ionic strength or when they are uncharged. Large equilibrium binding capacities were obtained for Nuvia S, approaching 320 +/- 10 mg/mL of particle volume for both proteins in comparison with the UNOsphere S values of 170 +/- 10 and 120 +/- 10 mg/mL for lysozyme and IgG, respectively. Much higher adsorption rates were also found for Nuvia S, and the rate was nearly independent of protein concentration in solution. Confocal laser scanning microscopy showed very sharp intraparticle protein concentration profiles for UNOsphere S, consistent with a pore diffusion mechanism but diffuse concentration profiles for Nuvia S, consistent with a solid diffusion mechanism. The improved capacity and transport afforded by the polymeric extenders provide substantial potential benefits for bioprocess applications without sacrificing the desirable flow properties of the backbone matrix. PMID- 21608144 TI - Assessment of the manufacturability of Escherichia coli high cell density fermentations. AB - The physical and biological conditions of the host cell obtained at the end of fermentation influences subsequent downstream processing unit operations. The ability to monitor these characteristics is central to the improvement of biopharmaceutical manufacture. In this study, we have used a combination of techniques such as adaptive focus acoustics (AFA) and ultra scale-down (USD) centrifugation that utilize milliliter quantities of sample to obtain an insight into the interaction between cells from the upstream process and initial downstream unit operations. This is achieved primarily through an assessment of cell strength and its impact on large-scale disc stack centrifugation performance, measuring critical attributes such as viscosity and particle size distribution. An Escherichia coli fed-batch fermentation expressing antibody fragments in the periplasm was used as a model system representative of current manufacturing challenges. The weakening of cell strength during cultivation time, detected through increased micronization and viscosity, resulted in a 2.6-fold increase in product release rates from the cell (as measured by AFA) and approximately fourfold decrease in clarification performance (as measured by USD centrifugation). The information obtained allows for informed harvest point decisions accounting for both product leakages during fermentation and potential losses during primary recovery. The clarification performance results were verified at pilot scale. The use of these technologies forms a route to the process understanding needed to tailor the host cell and upstream process to the product and downstream process, critical to the implementation of quality-by design principles. PMID- 21608145 TI - Are heart disease and kidney disease related? Does one cause the other? PMID- 21608146 TI - Is it possible for an adult to have ADHD (attention-deficit hyperactivity disorder) or is it largely a children's/adolescents' disorder? What are the signs and symptoms of ADHD? PMID- 21608147 TI - [Untrained specialty work. It is possible in private practice]. PMID- 21608148 TI - [Patient information - tumor after-care - palliative care. What cancer patients need from their family practitioner]. PMID- 21608149 TI - Gun control is not clinically relevant. PMID- 21608151 TI - Health professionals under threat in Bahrain. PMID- 21608150 TI - Mcl-1 ubiquitination and destruction. AB - Loss of the Fbw7 tumor suppressor is common in diverse human cancer types, including T-Cell Acute Lymphoblastic Leukemia (T-ALL), although the mechanistic basis of its anti-oncogenic activity remains largely unclear. We recently reported that SCFFbw7 regulates cellular apoptosis by controlling the ubiquitination and destruction of the pro-survival protein, Mcl-1, in a GSK3 phosphorylation-dependent manner. We found that human T-ALL cell lines displayed a close relationship between Fbw7 loss and Mcl-1 overexpression. More interestingly, T-ALL cell lines that are deficient in Fbw7 are particularly sensitive to sorafenib, a multi-kinase inhibitor that has been demonstrated to reduce Mcl-1 expression through an unknown mechanism. On the other hand, Fbw7 deficient T-ALL cell lines are much more resistant to the Bcl-2 antagonist, ABT 737. Furthermore, reconstitution of Fbw7 or depletion of Mcl-1 in Fbw7-deficient cells restores ABT-737 sensitivity, suggesting that elevated Mcl-1 expression is important for Fbw7-deficient cells to evade apoptosis. Therefore, our work provides a novel molecular mechanism for the tumor suppression function of Fbw7. Furthermore, it provides the rationale for targeted usage of Mcl-1 antagonists to treat Fbw7-deficient T-ALL patients. PMID- 21608152 TI - Growing up in Rio's favelas. PMID- 21608153 TI - Carlos Chagas: science, health, and national debate in Brazil. PMID- 21608154 TI - Findings of research misconduct. PMID- 21608155 TI - Findings of research misconduct. PMID- 21608156 TI - The effect of rising health care costs on U.S. tax rates. PMID- 21608157 TI - Mortality, health, and disability insurance around the world. PMID- 21608158 TI - First, do no harm. HHS' National Quality Strategy uses broad approach to communicate expectations to providers. AB - HHS laid out the framework for its quality-improvement priorities, and providers greeted it with praise. "This is very much in keeping with what we are trying to do for our community as an integrated health system. It helps us partner with patients so there is shared responsibility, and there is also a focus on wellness, which we know is critical to the future of healthcare and controlling costs," says Dr. Nick Turkal, left, of Aurora Health Care. PMID- 21608159 TI - New Medicaid headache. Separate penalties proposed for acquired conditions. PMID- 21608160 TI - Loss-ratio bandwagon. Iowa, N.D. also seek reprieve from requirement. PMID- 21608161 TI - Staying open. Open-source health IT gets boost from foundation. PMID- 21608162 TI - Katrina fallout. Tenet settles biggest suit from Memorial flooding. PMID- 21608163 TI - 'We've come to a precipice'. Reform's impact, physician integration are hot topics. PMID- 21608164 TI - Attention to detail. 100 top hospitals closely monitor their operations to improve performance. PMID- 21608165 TI - Largest behavioral health providers. Ranked by behavioral health net patient revenue. PMID- 21608166 TI - Trusts set 'unlikely' savings targets for 2011-12. Efficiency. PMID- 21608167 TI - Constitutional rights and wrongs. PMID- 21608168 TI - On governance. There's too much at stake on quality. The governance debate must be informed by hard evidence and sound principles. PMID- 21608169 TI - Competition should never be first choice, but it could be best. PMID- 21608170 TI - Dozens of hospitals at risk from PCT efficiencies. PMID- 21608171 TI - This is a massive opportunity. PMID- 21608173 TI - Regulation of managers is just a fig leaf over the issues they face. PMID- 21608172 TI - Why competition needs tactics. PMID- 21608174 TI - Commissioning funds siphoned off for basics. PMID- 21608175 TI - Right-touch regulation. PMID- 21608176 TI - Who knows if we're here or there? PMID- 21608177 TI - 'Sink estate' warning as leading GPs link up. PMID- 21608178 TI - Putting half truths and confusions to the sword. Interview by Dave West. PMID- 21608179 TI - Evolution not revolution? Lansley's reforms will challenge our GPs to make big changes. PMID- 21608180 TI - Patient pathway. Decongesting cardiology. PMID- 21608181 TI - Rewarding senior staff. Performance bonuses: a fair swap for public service pension reform? PMID- 21608182 TI - PCTs diverge on consortium handover. GP commissioning. PMID- 21608183 TI - The failure regime: phase 2. Wanted: one careful owner for failed hospital. PMID- 21608184 TI - Commissioning. Primary care trusts are dead. Long live the PCT cluster? PMID- 21608186 TI - NHS reform--irrelevant at best? PMID- 21608185 TI - Consortium boards are 'closed shop'. Commissioning. PMID- 21608187 TI - On elusive evidence. No more than a shot in the dark. Out of hospital interventions are the panacea for the NHS's financial ills... right? PMID- 21608188 TI - Consortium commissioning. The long view. PMID- 21608189 TI - Offering salvation. Ascension, equity firm forge deal they say could save Catholic hospitals. AB - As more Catholic hospitals have become acquisition targets by for-profit companies, the nation's largest Catholic system wants to keep more facilities in the fold. Ascension Health has teamed with a private-equity firm to do just that. But "can a for-profit enterprise that is owned by a private-equity firm pursue and live the ministry of Jesus in providing healthcare?" asks Seton Hall law professor Kathleen Boozang, left. PMID- 21608190 TI - Little agreement. Obama's 2012 budget proposal has Dems, GOP rehashing old arguments. PMID- 21608191 TI - Uphill climb at HHS. Policymakers struggle with how to meet recommendations for IT program. PMID- 21608192 TI - In the hot seat. Study questions FDA's fast-track process. PMID- 21608193 TI - A swift kick. That's what our ignorant, pandering politicians need. PMID- 21608194 TI - Congress can help. Rather than 'repeal and replace,' both parties should consider 'improve and innovate'. PMID- 21608196 TI - Largest U.S. military hospitals. Ranked by number of staffed total beds. PMID- 21608195 TI - About that quality chasm. 10 years after IOM report, authors see progress, but... PMID- 21608197 TI - Asymptomatic filariasis. PMID- 21608198 TI - Outbreak news. Measles outbreaks in Europe. PMID- 21608199 TI - Rotavirus surveillance worldwide - 2009. PMID- 21608200 TI - Second meeting of the GPEI Independent Monitoring Board. PMID- 21608201 TI - Progress towards meeting the 2012 hepatitis B control milestone: WHO Western Pacific Region, 2011. PMID- 21608202 TI - Dracunculiasis eradication - global surveillance summary, 2010. PMID- 21608203 TI - Progress towards interrupting wild poliovirus transmission worldwide: January 2010-March 2011. PMID- 21608204 TI - [The past and present therapeutic opinions of disease-syndrome combination]. PMID- 21608205 TI - [Transformation medicine and evidence-based medicine, and Chinese medicine therapeutic efficacy assessment]. PMID- 21608206 TI - [Thinking of difficulties and strategies in establishing Chinese medicine clinical therapeutic efficacy assessment system]. PMID- 21608207 TI - [Chinese medicine syndrome typing and complicated intervention measures are core problems for influencing Chinese medicine clinical therapeutic efficacy assessment]. PMID- 21608208 TI - [Thinking of Chinese medicine clinical therapeutic efficacy contents and research strategies]. PMID- 21608209 TI - [Thinking of basic problems for Chinese medicine clinical therapeutic efficacy assessment]. PMID- 21608210 TI - [Mechanism and Chinese medicine treatment of gout]. PMID- 21608211 TI - [The staging and typing syndrome differentiating treatment of gout]. PMID- 21608213 TI - [Treatment of gout by integrative medicine]. PMID- 21608212 TI - [Experience of treating gout and hyperuricemia from phlegm and stasis]. PMID- 21608214 TI - [The objectivity research on 322 rheumatoid arthritis patients of dampness-heat impeding and cold-dampness impeding Chinese medical syndrome types]. AB - OBJECTIVE: To analyze the Chinese medical syndrome typing laws in rheumatoid arthritis (RA) patients of the dampness-heat impeding syndrome and the cold dampness impeding syndrome. METHODS: Clinical data and serum of 322 inpatients and outpatients were collected to perform DAS28 score. Laboratory indices including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), albumin (ALB), globulin (GLB), and blood routines (white blood cell, red blood cell, and platelet) were tested by conventional methods, and the serum levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta were detected by ELISA. The difference of each index was analyzed between RA patients of the dampness heat impeding syndrome and the cold-dampness impeding syndrome. RESULTS: The levels of DAS28 scores, ESR, CRP, white blood cell count, and platelet of RA patients of the dampness-heat impeding syndrome were significantly higher than those of the cold-dampness impeding syndrome (P <0.01). The serum level of GLB of RA patients of the dampness-heat impeding syndrome was obviously higher than that of the cold-dampness impeding syndrome (P <0.01), while the serum ALB level of RA patients of the dampness-heat impeding syndrome was obviously lower than that of the cold-dampness impeding syndrome (P<0.01). Compared with the dampness-heat impeding syndrome, ROC curve results showed the area under the curve (AUC) were ranked from large to small as DAS28 score > ESR >CRP >GLB > PLT >WBC (P<0.01). Compared with the cold-dampness impeding syndrome, only ALB was of diagnostic value for cold-dampness impeding syndrome and the AUC was 0.636 (P = 0.000). CONCLUSION: DAS28 score, ESR, CRP, PLT, WBC, GLB, and ALB could be used as objective index in identifying the differences between the dampness-heat impeding syndrome and the cold-dampness impeding syndrome in RA patients. PMID- 21608215 TI - [Effect of bushen qiangdu recipe on osteoporosis and bone loss of patients with ankylosing spondylitis]. AB - OBJECTIVE: To observe the therapeutic effect of Bushen Qiangdu Recipe (BSQDR) on osteoporosis and bone loss in patients with ankylosing spondylitis (AS). METHODS: Patients with AS were randomly assigned to two groups. The 288 patients in the treatment group received BSQDR (consisting of cibotii rhizoma, antler, prepared rehmannia root, epimedium herb, rhizoma drynariae, teasel root, eucommia bark, pangolin scales, etc., one dose daily, taken in two portions, once in the morning and once in the evening). The 72 patients in the control group received SIDSM and sulfasalazine. The therapeutic course for both was six months. Clinical symptoms, pillow distance from the wall, hand distance from the ground, jaw distance from the handle, chest mobility, Schober test, spinal mobility and other signs of disease activity indices (ESR and CRP) were observed in patients before and after treatment. The bone mineral density (BMD) testing was performed in the lumbar spine, the femur, the forearm, and the heels, etc. Osteocalcin (BGP), calcitonin, parathyroid hormone (PTH), etc. bone metabolic indices were detected. RESULTS: BASFI, BASDAI, the overall assessment, the spinal pain, pillow distance from the wall, hand distance from the ground, jaw distance from the handle, chest mobility, Schober test, spinal mobility, and so on were all improved to some extent when compared with before treatment in the treatment group (P<0.05). The ESR and CRP decreased to various degrees, showing statistical significance when compared with before treatment (P <0.01). BGP increased and PTH decreased, showing statistical difference when compared with before treatment (P<0.05). The BMD in patients' lumbar spine, femoral neck, Ward's triangle, femoral trochanter increased to various degrees. The calcaneal intensity index, blood uric acid (BUA) and SOS values also increased more than before treatment, showing statistical significance (P<0.05). Long-term oral administration of BSQDR was safe, with no obvious adverse reaction. CONCLUSIONS: BSQDR showed significant effect in treatment of AS. It could regulate the bone metabolic level in patients, attenuate the immune inflammatory response, improve the spine and joint activities functions, increase bone formation, reduce bone resorption, thereby, enhancing the BMD, showing significant therapeutic effect on osteoporosis in AS patients. PMID- 21608216 TI - [Clinical study of total glucosides of paeony in patients with systemic lupus erythematosus]. AB - OBJECTIVE: To study the therapeutic efficacy and adverse reaction of total glucosides of paeony (TGP, extracted from Paeonia lactiflora Pall.) in patients with systemic lupus erythematosus (SLE). METHODS: Clinical data of patients with SLE were analyzed. Those who orally took TGP continuously for five years or more were taken as TGP1 group (29 cases). Those who orally took TGP continuously or intermittently for more than one year but less than five years were taken as TGP2 group (47 cases). Twenty patients matched with the TGP1 group and the TGP2 group in age, affected duration, urine protein, and SLE disease activity index (SLEDAI) were selected as the control group. The average daily dose of prednisone, total cyclophosphamide (CTX) dose, urine protein, SLEDAI score, recurrent case, and episodes of infection were compared among the three groups after five-year treatment. RESULTS: The average daily dose of prednisone, total CTX dose, and SLEDAI score were obviously lower in the TGP1 group than in the control group (P<0.01). The average daily dose of prednisone, total CTX dose, and SLEDAI score were obviously lower in the TGP1 group than in the TGP2 group, Significant difference was shown (P <0. 05). The average daily dose of prednisone and total CTX dose were lower in the TGP2 group than in the control group (P<0.05, P<0.01). There was no statistical difference in the urine protein among the three groups. As for the recurrence, one case occurred in the TGP1 group, nine in the TGP2 group, and seven in the control group. As for episodes of infection, there were three cases in the TGP1 group, seventeen in the TGP2 group, and eighteen in the control group during the five years. No adverse reaction correlated to TGP was found in the three groups. CONCLUSIONS: TGP had definite therapeutic efficacy in treatment of patients with SLE. It could reduce the average daily dose of prednisone and the total CTX dose, lower the recurrent cases and episodes of infection, especially for the medication of more than five years. PMID- 21608217 TI - [Study on the four-year retention rate and influencing factors for 2,353 AIDS patients by Chinese medicine]. AB - OBJECTIVE: To analyze the retention rate and its influencing factors of HIV/AIDS patients by Chinese medicine (CM) maintenance treatment in the first 5 provinces in China. METHODS: Kaplan-Meier method was used to analyze the retention rate of treatment in patients. Cox hazard regression model was used to assess factors that might influence the treatment time of Chinese medication. RESULTS: Totally 2,353 patients took part in this four-year study. Of them, 1,156 (49. 1%) were male, 2,344 (99. 6%) were Han nationality, 2,260 (96%) were married, 2,219 (94.3%) had junior middle-schooling or below, the average age was 41.52 +/- 8.98 years, 1,758 (74.7%) received paid blood donation, 478 (20.3%) received blood transfusion, 737 (31.3%) were absent of symptoms, 963 (40.9%) received combined treatment of CM and Western medicine. The median time within the four years was 44.84 months. The average retention rate for 1, 2, 3, 4 years of CM treatment were 86.6%, 78.4%, 72.2%, 65.6%, respectively. The results of Cox model indicated that the drop-out risk could be reduced in combined treatment of CM and Western medicine patients (HR=0. 805, P<0.01) and AIDS patients (HR=0. 769, P<0.01). The drop-out risk could be increased by the infection route of paid blood donation (HR =1. 373, P<0.01). CONCLUSIONS: The four-year retention rate of the 2 353 patients by CM treatment in the first 5 provinces in China was 65. 6%. Route of infection, whether or not in combination of Western medicine, and staging showed influence on CM maintenance treatment time. PMID- 21608218 TI - [Effect of electro-needling at acupoints of the yangming meridian on the expression of PAC-1 and lower limb functions in acute cerebral infarction patients]. AB - OBJECTIVE: To observe the effect of electro-needling at acupoints of the yangming meridian on the expression of platelet associated complement-1 (PAC-1) and lower limb functions in acute cerebral infarction (ACI) patients. METHODS: 58 ACI patients were randomly assigned to the treatment group and the control group. Conventional therapies were given to all patients. Additionally, the electro needling at acupoints of the yangming meridian was given to patients in the treatment group. Changes of PAC-1 were detected using flow cytometry. Effect of lower limbs functions of ACI patients before and after electro-needling was assessed using Fugl-Meyer Index. Meanwhile, 20 healthy subjects were selected for reference value. RESULTS: In the acute stage, the PAC-1 level in ACI patients were significantly higher than that in healthy subjects (P<0.05). The PAC-1 level in the electro-needling group was obviously lowered after treatment (P<0.01). There was no significant difference in the control group between before and after treatment. Significant difference was found in Fugl-Meyer index in the same group between before and after two-week treatment (P<0.05). It was higher in the electro-needling group than in the control group, showing significant difference (P<0.01). CONCLUSIONS: Platelet activation exists in the acute stage of ACI. Electro-needling at acupoints of the yangming meridian showed obvious inhibition on PAC-1 levels, could improve lower limbs functions of ACI patients. It was inferred that electro-needling at acupoints of the yangming meridian promoted the recovery of paralyzed lower limbs at the early stage mainly by regulating PAC-1 levels, thus postponing the progress of ACI. PMID- 21608219 TI - [Effect of tongxinluo capsule on platelet activities and vascular endothelial functions as well as prognosis in patients with acute coronary syndrome undergoing percutaneous coronary intervention]. AB - OBJECTIVE: To observe the effect of Tongxinluo Capsule on platelet activities and vascular endothelial functions as well as prognosis in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI) at different stages. METHODS: 160 patients with acute coronary syndrome were randomly assigned to Tongxinluo (TXL) group (80 patients) and the conventional treatment group (80 patients). And 50 healthy subjects were set up as the health control group. Patients' plasma platelet activating factors (CD62p, CD63), and glucose protein (GP) IIb/IIIa, and endothelium-1 (ET-1), von Willebrand factor (vWF), nitric oxide (NO) levels, and endothelium dependent flow-mediated dilatation (FMD) were detected respectively. Patients in the TXL group orally took TXLC for six months. The aforesaid indices were re-detected in all patients after two months and six months. Comparison between before and after treatment in the same group and inter-group comparison were performed in the two groups. RESULTS: Compared with the health control group, CD62p, CD63, GPIIb/IIIa, vWF, and ET-1 levels increased significantly in ACS patients after PCI (all P<0.01), NO and FMD significantly decreased (P<0.01). CD62p, CD63, GPIIb/IIIa and, vWF also increased, and FMD decreased after PCI (all P<0.05), but insignificant difference was found in ET-1 and NO (P>0.05). In the TXL group and the conventional treatment group, the levels of CD62p, CD63, GPIIb/IIIa, vWF and ET-1 decreased significantly (P<0.05, P<0.01), NO and FMD increased (P<0.05, P<0. 01) when compared with before treatment. Compared with the conventional treatment group, the decrement of CD62p, CD63, GPIIb/IIIa and vWF (P<0.05, P<0.01), and the increment of FMD and NO (both P<0.05) were more obvious in the TXL group. The aforesaid indices were more obviously different between 6-month treatment and 2 month treatment in the TXL group and the conventional treatment group (P<0.05, P<0.01). Seven patients suffered from angina, six from heart failure, three from ventricular tachycardiac (VT)/ventricular fibrillation (VF), and two died suddenly in the conventional treatment group after six months of treatment, while only one suffered from angina, one from heart failure, and none from VT/VF or died suddenly in the TXL treatment group after 6 months of treatment. CONCLUSION: TXL could be used in the prevention and treatment of coronary thrombosis, protect the vascular endothelial functions, as well as improve the prognosis of ACS patients after PCI. PMID- 21608220 TI - [Plasma metabonomics analysis of tumor patients of phlegm-stasis syndrome]. AB - OBJECTIVE: To study metabonomic changes in plasma of tumor patients of phlegm stasis syndrome by Chinese medicine and their in vivo metabolic mechanism. METHODS: 1H nuclear magnetic resonance (NMR) based metabonomic analysis was performed on plasma samples from 356 tumor patients of the phlegm-stasis syndrome and 104 tumor patients of the non-phlegm-stasis syndrome, and 50 healthy subjects. The spectrogram integral results were analyzed by orthogonal partial least-squares discriminant analysis (OPLS-DA). RESULTS: Compared with healthy subjects, various amino acids including leucine, alanine, citrulline, tyrosine, histidine, arginine, methionine, isoleucine, valine, acetylcysteine, etc. in the plasma of patients of the phlegm-stasis syndrome were significantly lowered (P <0.05). Glucose, glycoprotein, glutamine, myo-inositol, lactic acid, choline, creatine also significantly decreased (P<0.05). But the plasma formic acid, acetone, acetic acid, acetoacetate, pyruvate, beta-hydroxy butyrate, carnitine, malonic acid, and unsaturated fatty acid, very low density lipoprotein cholesterol (VLDL-C), low density lipoprotein cholesterol (LDL-C) increased in tumor patients of the phlegm-stasis syndrome. Compared with tumor patients of non phlegm-stasis syndrome, patients of the phlegm-stasis syndrome had obvious lower plasma contents of leucine, alanine, citrulline, tyrosine, histidine, soleucine, valine, glutamine, myo-inositol, scyllo-inositol, lactic acid, creatine (P <0. 05), higher plasma contents of acetone, acetoacetate, unsaturated fatty acid, VLDL-C, alpha-glucose, beta-glucose, glycoprotein, and so on (P <0. 05). CONCLUSIONS: Tumor patients of the phlegm-stasis syndrome had strengthened in vivo fat metabolism and lowered various amino acids. The decreased antioxidation capacities resulted in aggravated cell membrane injuries. The in vivo metabolic disorder was more severe in tumor patients of the phlegm-stasis syndrome than in tumor patients of the non-phlegm-stasis syndrome. PMID- 21608221 TI - [Effect of huazhuo jiedu recipe on gastric juice compositions and tumor markers in patients with chronic atrophic gastritic precancerosis]. AB - OBJECTIVE: To observe clinical efficacy of Huazhuo Jiedu Recipe (HJR) on chronic atrophic gastritic precancerosis (CAGP), and its effect on contents of lactic acid, total acid, free acid, and nitrite in the gastric juice, as well as tumor markers in gastric juice and blood. METHODS: Two hundred and twenty-nine patients with CAGP were randomly assigned to two groups, the 119 patients in the treated group orally took HJR and the 110 patients in the control group orally took Weifuchun Tablet. The therapeutic course for all was three months, two courses in total. The therapeutic efficacy, changes of gastric acid contents before and after treatment were observed, and the tumor markers in the gastric juice and blood were detected using electrochemical luminescence immunoassay. RESULTS: The pathological effective rate was 83.2% (99/119) in the treated group and 60.9% (67/110) in the control group, showing significant difference between the two groups (P <0.05). The total acids and free acids in the gastric juice were significantly improved, contents of lactic acid and nitrite were significantly lowered in the two groups. Both contents of carcinoembryonic antigen (CEA), carbohydrate antigen19-9 (CA19-9), carbohydrate antigen72-4 (CA72-4), and carbohydrate antigen125 (CA125) in the gastric juice and serum were significantly lowered after treatment in the treated group (P<0.05). Compared with the normal control group, the therapeutic effect was more obvious in the treated group (P<0.05). CONCLUSIONS: HJR could stimulate the gastric membranous secretion, enhance contents of total acids and free acids. It could prevent the further progress of CAGP by decreasing contents of lactic acid and nitrite in the gastric juice, and lowering contents of CEA, CA19-9, CA72-4, and CA125 in the gastric juice and serum. PMID- 21608222 TI - [Analysis of symptom compositions in sub-health insomnia patients of Yin deficiency fire hyperactivity syndrome and Xin-Pi deficiency syndrome]. AB - OBJECTIVE: To study Chinese medicine syndrome features in sub-health insomnia patients, and to make clear the symptom compositions of each syndrome, thus providing references for main and minor symptoms selection, and establishing a syndrome differentiation system in clinical testing. METHODS: Chinese medicine syndrome information was collected by multi-centered large-sample clinical data. The information was statistically managed to get common syndrome types, symptoms compositions, and the Pittsburgh Sleep Quality Index (PSQI) scores of sub-health insomnia patients. RESULTS: The most common symptoms of sub-health insomnia patients of yin deficiency fire hyperactivity syndrome and Xin-Pi deficiency syndrome cover difficulties in falling asleep, early awakening, dreaminess, sometimes sleeping sometimes awake, failing in falling into sleep when wake up, failing in sleep all night. There was insignificant difference between the two syndrome types (P>0.05). Some unique symptoms occurred in the two syndrome types as minor symptoms. Fatigue, abdominal distension after eating occurred in patients of Xin-Pi deficiency syndrome. Burning sensation of five centers, irritability, etc. occurred in patients of yin deficiency fire hyperactivity syndrome. Significant difference was shown in minor symptoms (except irritability, vexation, frequent urine) (P<0.05, P<0.01). No significant difference was shown in PSQI score between the two syndrome types (P>0.05). But significant difference was shown in sleep disturbance factors (P<0.05). Patients of yin deficiency fire hyperactivity syndrome had severe sleep disturbance factors. CONCLUSION: There was no significant difference in main symptoms between the two syndrome types. Some unique symptoms occurred in the two syndrome types as minor symptoms. There was difference in sleep quality compositions. PMID- 21608223 TI - [Effect of herbs in early intervention of children with Henoch-Schonlein purpura nephritis]. AB - OBJECTIVE: To observe the effect of blood activating and cooling, stasis removing herbs on the occurrence rate of Henoch-Schonlein purpura nephritis (HSPN). METHODS: The 141 HSP children patients with bleeding of the blood stasis syndrome and of the blood heat syndrome (having normal results of urine routines) were assigned to the blood activating and stasis removing group and the blood cooling and arresting group. They were treated with blood activating and stasis removing herbs and blood cooling and arresting herbs respectively for eight weeks. The occurrence rate and time of the renal injury, changes of transforming growth factor (TGF), D-dimer (D-D), immunoglobulin (Ig), urine micro-protein, and urease before and after treatment were observed. RESULTS: The occurrence of the renal injury in the blood activating and stasis removing group was 36.2%, obviously lower than that in the blood cooling and arresting group (69.4%). The occurrence time of the renal injury was 32.2 +/- 10.6 days, obviously later than that in the blood cooling and arresting group (20.0 +/- 9.0 days), showing statistical difference (P<0.05). The levels of TGF, D-D, IgA, microglobulin (MG), immunoglobulin G (IgG), albuminuria (ALB) of children patients in the blood activating and stasis removing group were lower after treatment than before treatment, showing significant difference (P<0.05). Significant difference was also shown when compared with those of the blood cooling and arresting group (P<0.05). CONCLUSION: The application of activating blood and removing stasis method could lower the probability of the renal injury in Henoch-Schonlein purpura (HSP). It played a role in preventing the occurrence of HSPN. PMID- 21608224 TI - [Experimental study on constitutions of NZB/W F1 lupus mice]. AB - OBJECTIVE: To classify NZB/W F1 lupus mice into three different constitutions, i. e. the cold, normal, and hot constitutions, and to prove the objective existence of the difference among them. METHODS: Using the Four Diagnosis Work Station for Mice (founded by Prof. FANG Zhao-qin, the Research Faculty of Experimental Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine), the body weight, the armpit temperature, the heart rate, the 35-s activities, and the color of their tails and claws (r value) were detected. The total weight was calculated according to the formula: The total weight sum = the correction value of claws x 1 + the correction value of tail x 0.2 + the correction value of the armpit temperature x 0.7 + the correction value of heart rate x0. 05 + the number of the quadrant crossing x 0.025. The NZB/W F1 lupus mice were classified into the three different constitutions according to the higher total weight sum, the hotter the constitution, the lower total weight sum, the colder the constitution. The hydroxyproline content, connective tissue growth factor (CTGF), and transforming growth factor-beta1, (TGF-beta1) gene expression difference in the renal tissue were detected and the immunofluorescence staining observed. RESULTS: Among the 158 NZB/W F1 lupus mice, 33 mice were classified into the hot constitution, 34 into the cold constitution, and 91 into the normal constitution. The renal hydroxyproline content in mice of normal and cold constitutions were higher than that of mice of the hot constitution (P<0.01). No statistical difference was shown between mice of the normal constitution and mice of the cold constitution. The CTGF gene expression level was significantly higher in mice of the cold constitution and mice of the hot constitution than in mice of the normal constitution (P<0.05). No significant difference was found between mice of the cold constitution and mice of the hot constitution. Lower level of TGF-beta1, expression existed in mice of the cold constitution than in mice of the normal constitution or mice of the hot constitution, showing insignificant difference. The immunofluorescence stain of the renal tissue among the three constitutions also showed some difference. CONCLUSION: Constitution difference did exist among NZB/W F1 lupus mice. PMID- 21608225 TI - [Effect of sihui mixture on the learning and memory ability, mRNA expressions of hippocampal NMDA subunit NR2A and NR2B, and EphB2 receptor in fatigue rats]. AB - OBJECTIVE: To study the learning and memory ability, expressions of hippocampal N methyl D-aspartate (NMDA) subunit NR2A and NR2B, and EphB2 receptor in fatigue rats, and to observe effects of Sini Powder, Shenghui Decoction, and Sihui Mixture on them. METHODS: The central nervous system fatigue model was duplicated by paradoxical sleep deprivation for 168 h using multiple platform method. Experimental rats were randomly divided into the normal control group, the model group, the Sini Powder group, and the Shenghui Decoction group, ten in each. Corresponding medicines and distilled water were given to them by gastrogavage at 6, 30, 54, 78, 102, 126, and 150 h after sleep deprivation. Changes of the learning and memory ability were observed using Y maze. mRNA expressions of NMDA subunit NR2A and NR2B, and EphB2 receptor in fatigue rats were quantitatively analyzed using Real-time PCR. RESULTS: Compared with the normal control group, the Y maze correct percentage in the model group obviously decreased (P<0.05), mRNA expressions of NR2B and EphB2 obviously decreased (P<0.901), with no obvious change in NR2A. Compared with the model group, Sihui Mixture could obviously improve Y maze results and mRNA expressions of NR2A and NR2B, and EphB2 (P<0 01). No statistical difference was found between the Sini Powder group and the Shenghui Decoction group. Compared with the Sini Powder group, mRNA expressions of EphB2 obviously increased in the Sihui Mixture group (P<0 01). mRNA expression of NR2A could be more obviously increased in the Shenghui Decoction group than in the model group (P <0 01). CONCLUSION: The central nervous system fatigue could result in decreased Y maze results and gene expressions of hippocampal NR2B and EphB2. Sihui Mixture could improve rats' learning and memory ability, which might be possibly achieved through up-regulating mRNA expressions of hippocampal EphB2 and NR2B. PMID- 21608226 TI - [Effect of multi-glycoside of Tripterygium wilfordii Hook. f. in intervening TGF beta1/Smad signaling pathway of adriamycin-induced nephropathy model rat]. AB - OBJECTIVE: To explore the potential molecular mechanisms of multi-glycoside of Tripterygium wilfordii Hook. f. (GTW) for ameliorating glomerulosclerosis (GS) by observing its intervention effect on transforming growth factor (TGF)-beta1/Smad signaling pathway in adriamycin-induced nephropathy (ADRN) model rat. METHODS: Fifteen female Sprague-Dawley (SD) rats were randomly divided into three groups, the sham-operation group (A), the untreated model group (B), and the GTW treated model group (C). Rats in Group B and C were made into ADRN model by right nephrectomy and intravenous injection of adriamycin (ADR, 0. 4 mL and 0. 2 mL respectively in 4 weeks). After the model was successfully established, rats in Group C were orally given GTW (50 mg/kg per day), while rats in Group B were intervened with distilled water. The intervention for two groups was 6 weeks. Rats' body weight were weighed and 24 h urinary protein excretion (Upro) detected by the end of the 2nd, 4th, 8th and 10th week. All rats were sacrificed at the end of 10th week after operation to withdraw blood and kidney tissue to examine serum biochemical parameters, glomerular morphological changes, alpha-smooth muscle actin (alpha-SMA), and collagen type I expression. Besides, the mRNA expressions of TGF-beta1, Smad3 and Smad7, as well as protein expressions of TGF beta1, and phosphorylated Smad2/3 (p-Smad2/3) in glomeruli were detected by RT PCR or Western blotting. RESULTS: As compared with Group B, in Group C, Upro and serum albumin were improved significantly, but no difference between groups was found in levels of blood urea nitrogen(BUN), serum creatinine(SCr), or hepatic cell injury. Mesangial cell proliferation, extracellular matrix (ECM) and collagen deposition were suppressed by GTW. Expressions of alpha-SMA and collagen type I decreased, and the characteristic changes of GS were attenuated. The mRNA expressions of TGF-P,31, Smad3 and protein expression of TGF-beta1, p-Smad2/3 in renal tissues were down-regulated, while the protein expression of Smad7 mRNA was up-regulated. CONCLUSION: GTW showed effect in ameliorating GS in vivo. It could reduce the ECM deposition and improve GS by way of intervening TGF-beta1/Smad signaling pathway in the kidney through regulating the mRNA or protein expressions of key signal molecules, such as Smad3 and p-Smad2/3. PMID- 21608227 TI - [Extract of Ginkgo biloba and alpha-lipoic acid attenuate advanced glycation end products accumulation and RAGE expression in diabetic nephropathy rats]. AB - OBJECTIVE: To investigate the accumulation of advanced glycation end products (AGEs) and expression of receptor for AGEs (RAGE) in streptozocin (STZ)-induced diabetic nephropathy in rats, and the role of antioxidants on the AGEs-RAGE signaling. METHODS: Diabetic rats were induced by once intraperitoneal injection of STZ at the dose of 60 mg/kg, and randomly divided into the DN group (n=12, treated with normal saline by intraperitoneal injection, once daily), the extract of Ginkgo biloba (EGb) group (n=14, treated with EGb 300 mg/kg by oral administration, once every other day), and the alpha-lipoic acid (ALA) group (n=12, treated with ALA at the dose of 35 mg/kg by intraperitoneal injection, once every other day). Rats of the normal control group (n=10) were given vehicle citrate buffer at the dose of 60 mg/kg. Rats were sacrificed at the 12th week and the 20th week of this study. The four groups were compared in terms of body weight, blood glucose, renal function, 24-h urine protein. Renal pathological changes were observed by PAS staining. Oxidative stress indices were detected using spectrophotometry. The concentrations of AGEs were measured using fluoro spectrophotometry, and the expressions of RAGE were detected by Real-time PCR and Western blot. RESULTS: Compared with the normal control group, the 24-h urine protein quantitation was higher and the glomerular filtration rate increased in rats at the 12th week and the 20th week. The pathological tissue staining showed dilated glomerular mesangium, proliferated glomerular matrix, vacuolar degeneration of the renal tubular epithelium. Malonaldehyde (MDA) levels and 8 hydroxide radical guanine deoxyriboside (8-OHdG) levels increased, and catalase (CAT) and reduced glutathione hormone (GSH) levels decreased. The AGEs contents in serum and renal tissue homogenate increased. The expressions of RAGE mRNA and protein increased in the DN group at the 12th and the 20th week. The 24-h urine protein quantitation was reduced in the EGb group and the ALA group, with alleviated pathological changes, lowered MDA and 8-OHdG levels, increased CAT and GSH levels, decreased AGEs contents, and down-regulated RAGE expressions. CONCLUSIONS: AGEs contents increased and RAGE expression up-regulated in the circulation and local renal tissues in DN rats. EGb and ALA could inhibit AGEs production and down-regulate RAGE expressions by reducing oxidative stress, thus further improving the renal tissue structure and renal functions of DN rats. It had better application prospect in treatment and prevention of DN. PMID- 21608228 TI - [Effects of xiaotan sanjie recipe on vasculogenic mimicry of human gastric cancer xenografts in nude mice]. AB - OBJECTIVE: To study the effect of Xiaotan Sanjie Recipe (XTSJD) and its mechanism on vasculogenic mimicry (VM) of human gastric cancer xenografts in nude mice. METHODS: The tumor-bearing mice model was established by subcutaneous inoculating with xenografts of human gastric cancer into the right armpit of 30 BALB/c nude mice. After modeling, the tumor-bearing mice were randomly divided into the normal saline group, the XTSJD group, and the doxycycline hyclate (DH) group, 10 in each. And the mice were administered with corresponding medicine by gastrogavage for 4 weeks. Then all mice were killed by cervical dislocation. The tumor mass were weighed and the tumor inhibition rate calculated. The amount of VM in tumor was counted. Expressions of matrix metalloproteinase (MMP) -2 and MMP 9 were tested using immunohistochemical method. RESULTS: Tumor weight in the XTSJD group and the OH group decreased significantly when compared with the NS group (P<0.01). The amount of VM in the XTSJD group (24.50+/-3.03) and the OH group (14.70+/-1.34) was significantly less than that in the NS group (33.10+/ 2.64) (P<0.01). The positive expressions of MMP-2 and MMP-9 in the XTSJD group and the OH group was significantly lower than that in the NS group (P <0.01). CONCLUSION: XTSJD could inhibit the formation of VM in xenografted tumor of nude mice. The mechanism might be correlated with the down-regulation of MMP-2 and MMP 9 expressions. PMID- 21608229 TI - [The expression and significance of Wnt/beta-catenin signal pathway protein in the effect of bushen huoxue granule containing serum on the osteoblast]. AB - OBJECTIVE: To investigate the effect of Wnt/beta-catenin signal pathway protein in the effect of Bushen Huoxue Granule (BHG) containing serum on the osteoblast, and to provide necessary experimental reliance for its action of mechanism in treatment of osteoporosis. METHODS: The osteoblast from cranial bones of neonates rat were isolated and cultured in vitro, which was divided into the blank control group and the BHG containing serum group. The alkaline phosphatase (ALP) activities of the osteoblast in each group were quantitatively detected and the ALP staining was performed six days later. The alizarin red staining was performed eighteen days later. At the same time, levels of Wnt/beta-catenin signal pathway protein--beta-catenin, low density lipoprotein correlated protein 5 (LRP 5), and T cell factor (TCF) of osteoblasts in each group were detected by ELISA. RESULTS: BHG containing serum could significantly increase the expression of ALP and promote the formation of mineralizing nodus in the osteoblasts. At the same time it also markedly up-regulated the expressions of p-catenin, LRP 5, and TCF in this process. CONCLUSION: BHG containing serum could markedly increase ossify activities and mineralization of osteoblast. This action was closely correlated with Wnt/p-catenin signal pathway. So it indicated that Wnt/beta catenin signal pathway played a very important role in the treatment of the osteoporosis by BHG. PMID- 21608230 TI - [Effect of tianoan zhuangyang powder on the stAR protein expression of Leydig cells in model rats with partial androgen deficiency of aging male]. AB - OBJECTIVE: To observe the effect of Tiancan Zhuangyang Powder (TCZYP) on the steroidogenic acute regulatory protein (stAR protein) expression of Leydig cells in model rats with partial androgen deficiency of aging male (PADAM). METHODS: PADAM rat model was prepared by cyclophosphamide induced reproductive system damage. Rats were randomly divided into four groups, i. e. the normal control group, the model group, the testosterone propionate group, and the TCZYP group. The general condition, body weight, tail suspension experiment and exhaustion swimming test, and the testicular index, etc. were observed to assess the state of rats. The serum total testosterone (TT), and free testosterone (FT) levels were detected by radioimmunoassay before and after treatment. The stAR protein expression level of Leydig cells were determined using immunohistochemical assay. Statistic analyses were performed. RESULTS: By modeling with cyclophosphamide, serum TT and FT levels decreased (P<0.01), behavior changes were basically similar to PADAM (by tail suspension test), indicating a successful modeling. After treatment serum rTT and FT levels in the testosterone propionate group and the TCZYP group significantly increased when compared with before treatment and with the model group after treatment (P<0.01). There was no statistical difference between the TCZYP group and the testosterone propionate group (P>0.05). The immobility time in the tail suspension test were significantly shortened in the testosterone propionate group and the TCZYP group (P<0.05). The exhausted swimming time was more significantly prolongated than that of the model group (P<0.05). The stAR protein gray value significantly decreased (P<0. 01). CONCLUSION: TCZYP could prevent serum TT and FT levels from decrease, improve stAR protein activities, and attenuate the depression state and muscular tension in PADAM rats. Its action was equivalent to that of testosterone propionate. PMID- 21608231 TI - [Effect of salvianolic acid B on CD14 expression in rats with liver fibrosis]. AB - OBJECTIVE: To observe the effect of salvianolic acid B (SAB), an extract from Radix Salviae miltiorrhizae, on expression of leucocyte differentiation antigen 14 (CD14) in the liver tissue of experimental rats with carbon tetrachloride (CCl4)-induced liver fibrosis. METHODS: Thirty SD rats were randomly divided into three groups, the model group, the treated group, and the control group. The pathological fibrosis changes in liver of rats were observed. Meantime, their liver function was detected by automatic biochemical analyzer. Serum content of endotoxin was assayed by matrix staining, and plasma content of tumor necrosis factor-alpha (TNF-alpha) was detected by radioimmunoassay. mRNA and protein expressions of CD14 in the liver tissue were measured using reverse transcriptional-polymerase chain reaction and immunohistochemistry respectively. RESULTS: All the laboratory parameters, including liver function, degree of liver fibrosis, serum endotoxin levels, plasma TNF-alpha contents, and CD14 mRNA and protein expressions in the model group were higher than those in the control group (all P<0.01). All the aforesaid indices were lowered more in the treated group than in the model group (all P<0.01). CONCLUSIONS: SAB could antagonize the CCl4, induced liver fibrosis in rats. Its mechanism of action was possibly correlated with its effects on down-regulating hepatic CD14 expression and blocking the endotoxin signal transduction pathway. PMID- 21608232 TI - [Effect of emodin combined gemcitabine on the growth and apoptosis of pancreatic cancer cell line BxPC-3 in vitro]. AB - OBJECTIVE: To explore the effect of emodin combined gemcitabine (E&G) on human pancreatic cancer cell line BxPC-3 in vitro. METHODS: BxPC-3 cells were treated with emodin alone in different concentrations (0, 10, 20, 40, 80, and 160 micromol/L, respectively) for 24, 48, and 72 h, and E&G (emodin 40 micromol/L + gemcitabine 20 micromol/L) for 72 h. The inhibition on BxPC-3 cell proliferation was detected by Cell Counting Kit-8 assay and the cell apoptosis of BxPC-3 was determined using flow cytometry. RESULTS: Emodin obviously suppressed the proliferation of BxPC-3 cells in a dose- and time-dependent manner. The survival rates of BxPC-3 cells by 40 micromol/L emodin for 24, 48, and 72 h were 79. 39%, 46. 35%, and 45. 44%, respectively, while the survival rate of BxPC-3 cells acted by 72-h E&G was only 26. 62%, showing significant difference from that by gemcitabine alone (42.78%) and the emodin alone (47.18%). The early apoptotic ratio of BxPC-3 cells induced by 24 h emodin (40 micromol/L) and gemcitabine (20 micromol/L) were 4.70% +/- 1.54% and 11.20% +/- 1.41% respectively, while early apoptotic ratio of BxPC-3 cells induced by E&G was 20.60% +/-3.23%, showing significant difference from that induced by emodin or gemcitabine alone (P<0.05). CONCLUSIONS: Emodin could significantly inhibit BxPC-3 cell growth. It could act synergistically with gemcitabine to inhibit the tumor proliferation of BxPC-3 cells. Its synergistic action was achieved mainly through inducing pancreatic cancer cell apoptosis. PMID- 21608233 TI - [Effect of Chinese materia medica on nerve repair and regeneration in diabetic peripheral neuropathy]. PMID- 21608234 TI - [Study of wilforlide on foot cells and renal tubular epithelial cells protection]. PMID- 21608235 TI - [Strengthening blood glucose lowering and individualized treatment strategies]. PMID- 21608236 TI - [Vegetation carbon storage in Larix gmelinii plantations in Great Xing' an Mountains]. AB - Through sampling site investigation, this paper studied the carbon storage of arbor, herb, and whole vegetation in 10-, 12-, 15-, 26-, and 61-year old Larix gmelinii plantations in Huzhong Forestry Bureau of Great Xing' an Mountains, Northeast China, and 'temporal for spatial' method was employed to approach the variations of the vegetation carbon storage during the growth of the plantations. The results revealed that the vegetation carbon storage in the plantations increased with stand age, and reached 105.69 t x hm(-2) at age of 61 years, representing a marked role as a carbon sink. The L. gmelinii plantations at the ages from 15 to 26 years had the strongest capability in carbon sequestration, in which, the carbon storage in trunk occupied 54.3% -73.9% of the total carbon storage of arbor, and, with the increase of stand age, the trunk's carbon storage to the total carbon storage of arbor as well as the trunk's carbon density increased. As for the other organs, the rate of their carbon storage to the total carbon storage of arbor decreased with stand age, while their carbon density increased first but eventually leveled off or had a slight decrease till at age of 61 years. Based on these results, the rotation age for the L. gmelinii plantations in Great Xing' an Mountains would properly be lengthened to at least 60 years. PMID- 21608237 TI - [Application of indicator species in predicting forest management effect on forest species diversity and community composition]. AB - By using indicator species analysis (ISA) method, this paper studied the feasibility of using indicator species to reflect the responses of species diversity and community composition of subtropical forests in Huitong of China to forest management. Ninety-four significant indicator species from 357 understory species were identified, and a new indicator species dataset (community level) was constructed to examine the association between indicator species dataset and original community dataset, and to evaluate the predictive potential of indicator species in reflecting forest management effect. There existed a strong association between the two datasets (Mantel r = 0.898). The indicator species dataset could well predict the management effect on species diversity (regression analysis, R2 > 0.74) and community composition (ANOVA, F >16.79). When the two datasets were applied to Nonmetric Multi-Dimensional Scaling (NMDS) ordination and K-mean cluster analysis, the indicator species dataset could well identify the forest types with different management treatments, as the original community dataset did. Also, the indicator species dataset nearly played the same role as the original community dataset in identifying the species diversity, community composition, and forest type. It was suggested that for saving costs in overall investigation of forest ecosystem, indicator species could be used as a surrogate of full community to predict forest management effect. PMID- 21608238 TI - [Forest biomass and its spatial pattern in Guizhou Province]. AB - Based on the forest inventory data of 5500 sampling plots from 1996 to 2000 in Guizhou Province and according to the biomass expansion factors (BEF) of various forest types, the forest biomass in the Province was estimated, with its spatial pattern and its differences between karst and non-karst regions analyzed. In the study period, the total biomass of trees and shrubs on forest and non-forest lands was 3.51 x 10(8) t, 18% and 82% of which came from karst and non-karst regions, respectively. Different forest types had different forest biomass. Forest stands had the highest forest biomass, accounting for 71.4% of the total, and the total forest biomass in karst region was obviously lower than that in non karst region. Among the dominant tree species and groups, Cunninghamia lanceolata had the highest total biomass (5.38 x 10(7) t), followed by sclerophyll broadleaved woods (4.99 x 10(7) t), Pinus massoniana, P. yunnanensis, and Quercus (2.87 x 10(7) -3.54 x 10(7) t), Cupress (1.52 x 10(7) t) and malacophyll broadleaved woods (1.43 x 10(7) t), and the others (< 1.00 x 10(7) t). Based on the administrative division, the total forest biomass (9.83 x 10(7)t) and forest stand biomass (5.88 x 10(7)t) in South Guizhou were 1-2 folds higher than those in Zunyi, Tongren and Qiannan Districts, and far higher than those in Qianxinan, Bijie, Guiyang, Anshun, and Liupanshui Districts (total forest biomass 0.53 x 10(7) -1.85 x 10(7) t and forest stand biomass 0.16 x 10(7) -0.86 x 10(7)t). High biomass (> 400 t x hm(-2)) and medium-high biomass density (100-400 t x hm(-2)) mainly occurred in the bamboo forest and other forest stands in Southeast, East, and Northwest Guizhou, while medium-low biomass (30-100 t x hm(-2)) occurred in the forest and non-forest areas of the Province. Low forest biomass (0-30 t x hm( 2)) mainly occurred in karst region. Overall, the forest biomass in the Province was relatively low, being closely related to the topography of plateau and mountains, the rocky-desertification in karst region, and the shallow soil layer and dry habitat under karst forests, as well as the strong disturbance of human activities. PMID- 21608239 TI - [Effects of tourism disturbance on plant diversity in Qingshan Lake scenic area of Zhejiang Province]. AB - From May 2007 to June 2008, an investigation was made on the changes of plant community in Qingshan Lake scenic area of Zhejiang Province under the effects of tourism disturbance. With the increase of tourism disturbance, the importance value of the plants was mainly fastened on a few species such as Pinus hwangshanensis, apt to decrease for tree and shrub species and to increase for herb species, and the individuals of the plants increased. The values of richness index (D) and diversity index (H) were in the order of medium disturbance > slight disturbance > severe disturbance, while the evenness index (J) value was in the order of medium disturbance > severe disturbance > slight disturbance. At the same vegetation layers, only a few species such as Cinnamomum camphora existed under different disturbances, and thereby, the similarity index values were smaller than 0.500. Slight disturbance affected coniferous forest most, with the average values of D, H, and J being the lowest (1.188, 1.056, and 0.697, respectively); severe disturbance affected broadleaf forest and shrub-herbage most, with the D value (2.013) of shrub-herbage and the H value (1.286) and J value (0.807) of broadleaf forest being the lowest; while medium disturbance was favorable to the increase of plant diversity and to the normal exertion of ecosystem function. The eco-safety of the structural elements of plant community in the scenic area was threatened to some extent, resulting in the reduction of indigenous species such as Sinocalycanthus chinensis and the incursion of exotic species as Setaria viridis. PMID- 21608240 TI - [ALOS PALSAR estimation of vegetation biomass in Daxing' anling region]. AB - Based on field survey data, the correlations between the ALOS PALSAR L-band HH (L HH) polarization data and the parameters of forest components in Daxing' anling region were systematically analyzed, and by adopting forest biomass estimation models, including simple linear model, exponential model, and model with terrain factors, optimal inversion was conducted. The results showed that backscattering coefficient had the greatest correlation with total forest biomass, and secondly, with trunk biomass, suggesting that the L-HH data could be used to estimate the total forest aboveground biomass. Among the three models adopted, the model with terrain factors could greatly reduce the biomass estimation error, with the accuracy reached 0.851, and the inversion result coincided best with the actual situation. It was forecasted that under the 41.5 degrees incidence angle L-HH polarization, the vegetation biomass saturation point within the Tahe and Amuer forest bureaus of Daxing' anling was at about 15.4 kg x m(-2). PMID- 21608241 TI - [Simulation of the effects of climate change on canopy transpiration over a broad leaved Korean pine forest in Changbai Mountains]. AB - To investigate the effects of climate change on canopy transpiration, a process based carbon and water coupling multi-layer model was verified, and used to simulate the canopy transpiration over a broad-leaved Korean pine forest in Changbai Mountains. This multi-layer model could well estimate canopy transpiration. The simulated values fitted well with the measured data based on eddy covariance method. The simulation of the responses of canopy transpiration to climate change indicated that the latent heat flux (LE) increased with increasing air temperature, and decreased with the decline of soil water content or the increase of air CO2 concentration. Under the climate scenarios in this study, the LE was most sensitive to the associated variation of 10% reduction of soil water content in 0-20 cm layer and 190 micromol x mol(-1) increase of CO2 concentration, but not sensitive to the synchronous variation of 10% reduce of soil water content and 3.6 degrees C increase of air temperature. PMID- 21608242 TI - [Correlation analysis on normalized difference vegetation index (NDVI) of different vegetations and climatic factors in Southwest China]. AB - Based on the 1982-2006 NDVI remote sensing data and meteorological data of Southwest China, and by using GIS technology, this paper interpolated and extracted the mean annual temperature, annual precipitation, and drought index in the region, and analyzed the correlations of the annual variation of NDVI in different vegetation types (marsh, shrub, bush, grassland, meadow, coniferous forest, broad-leaved forest, alpine vegetation, and cultural vegetation) with corresponding climatic factors. In 1982-2006, the NDVI, mean annual temperature, and annual precipitation had an overall increasing trend, and the drought index decreased. Particularly, the upward trend of mean annual temperature was statistically significant. Among the nine vegetation types, the NDVI of bush and mash decreased, and the downward trend was significant for bush. The NDVI of the other seven vegetation types increased, and the upward trend was significant for coniferous forest, meadow, and alpine vegetation, and extremely significant for shrub. The mean annual temperature in the areas with all the nine vegetation types increased significantly, while the annual precipitation had no significant change. The drought index in the areas with marsh, bush, and cultural vegetation presented an increasing trend, that in the areas with meadow and alpine vegetation decreased significantly, and this index in the areas with other four vegetation types had an unobvious decreasing trend. The NDVI of shrub and coniferous forest had a significantly positive correlation with mean annual temperature, and that of shrub and meadow had significantly negative correlation with drought index. Under the conditions of the other two climatic factors unchanged, the NDVI of coniferous forest, broad-leaved forest, and alpine vegetation showed the strongest correlation with mean annual temperature, that of grass showed the strongest correlation with annual precipitation, and the NDVI of mash, shrub, grass, meadow, and cultural vegetation showed the strongest correlation with drought index. There existed definite correlations among the climatic factors. If the correlations among the climatic factors were ignored, the significant level of the correlations between NDVI and climatic factors would be somewhat reduced. PMID- 21608243 TI - [Soil moisture content and fine root biomass of rubber tree (Hevea brasiliensis) plantations at different ages]. AB - By using soil core sampling method, this paper studied the soil moisture regime of rubber plantations and the fine root biomass of Hevea brasiliensis in immature period (5 a), early yielding period (9 a), and peak yielding period (16 a). With the increasing age of rubber trees, the soil moisture content of rubber plantations increased but the fine root biomass decreased. The soil moisture content at the depth of 0-60 cm in test rubber plantations increased with soil depth, and presented a double-peak pattern over the period of one year. The fine root biomass of rubber trees at different ages had the maximum value in the top 10 cm soil layers and decreased with soil depth, its seasonal variation also showed a double-peak pattern, but the peak values appeared at different time. Soil moisture content and soil depth were the main factors affecting the fine root biomass of H. brasiliensis. PMID- 21608244 TI - [Clonal plasticity of Iris japonica under different soil and canopy conditions in subtropocal evergreen broad-leaved forest]. AB - An investigation was made on the growth indices of Iris japonica growing on the yellow soil and Karst soil within a subtropical evergreen broad-leaved forest and in the forest gaps, aimed to approach the clonal plasticity of I. japonica in heterogeneous habitats. The results showed that the ramet height and diameter and the rhizome diameter of I. japonica were significantly higher in yellow soil habitat than in Karst soil habitat, while the individual density was in adverse. Light had significant effects on rhizome diameter, but soil condition had lesser effects under the same light environment. Within the forest of Karst soil habitat, the bud number and flower number of I. japonica were zero, possibly due to the double pressure from soil quality and light environment for the balance between resources uptake and energy assignment and for the sustaining of growth. In a certain extent, I. japonica in yellow soil habitat tended to K strategy via decreasing the individual number for improving competition to adapt environment, while I. japonica in Karst soil habitat tended to r strategy via increasing individual number for sustaining competition capability. PMID- 21608245 TI - [Effects of green space vegetation canopy pattern on the microclimate in residential quarters of Shenzhen City]. AB - Based on field survey and landscape pattern analysis, this paper studied the effects of green space vegetation canopy on the microclimate in three typical residential quarters in Shenzhen City. In each of the residential quarters, 22-26 points were chosen for meteorological observation; and around each of the observation points, a 20 m x 20 m quadrat was installed, with each quadrat divided into two different patches, one covered by vegetation canopy and the another no-covered. The patch density index (D(p)) and contagion index (CONTAG) in each quadrat were calculated to analyze the relationships between vegetation canopy pattern index and microclimate in each point. The results showed that the green space vegetation canopy pattern in Shenzhen had significant regulation effect on temperature and humidity. The cooling effect was mainly from the shading effect of vegetation, and also, correlated with vegetation quantity. The increase in the CONTAG of bare surface had obvious negative effects on the regulation effect of vegetation on microclimate. The regulation capability of green space vegetation on the temperature and humidity in residential quarters mainly came from tall arbor species. PMID- 21608246 TI - [Endogenous hormone contents and their habitat differentia of Reaumuria trigyna and R. soongorica in different salt habitats]. AB - By means of Enzyme Linked Immunosorbent Assay (ELISA), this paper analyzed the contents of endogenous hormones ABA, IAA, ZR, and GA3 in Reaumuria trigyna and its related congener R. soongorica from four different salt habitats. In the identical habitats, the contents of growth-promoting hormones IAA, ZR, and GA3 in R. trigyna were lower than those in R. soongorica, while the content of growth suppressing hormone ABA was in contrary, which could be one of the main reasons that R. trigyna had a weaker ecological adaptability than R. soongorica. The (IAA+ZR+GA3) /ABA in wild R. trigyna varied with habitats, being saline soil > non-salinized soil > heavy solonchack, which was consistent with the density and coverage of R. trigyna population being the largest on saline soil and followed by on non-salinized soil and heavy solonchack, and suggested that R. trigyna having lived in saline habitat for a long time developed a corresponding inherent adaptation mechanism, and that the integrative regulation of endogenous hormones under salt stress played a key role for the growth and development of R. trigyna. PMID- 21608247 TI - [Diurnal rhythm of Viburnum awabuki and Betula luminifera volatiles and electroantennogram response of Batocera horsfieldi]. AB - By the method of Tenax-TA absorbent adsorption combined with GC-MS, this paper analyzed the changes of the diurnal rhythm of the volatiles in the healthy branches and Batocera horsfieldi-damaged branches of Viburnum awabuki and Betula luminifera, and electroantennogram technique was used to perform a comparative analysis on the electroantennogram (EAG) responses of unmated male and female B. horsfieldi to the volatiles. After the feeding by B. horsfieldi, there was a decrease in the contents of limonene, nonanal, hexadecane, butyl acrylate, and 3 methyl-butanoic acid in damaged branches of V. awabuki and in the neohexane and hexadecane contents in damaged branches of B. luminifera. Simultaneously, new materials such as permethyl 99A, octyl alcohol, iodo, decanal, hexanal, and bioallethrin etc. were newly synthesized in the damaged branches. The EAG response values of unmated male and female B. horsfieldi adults to the volatiles in the damaged branches of B. luminifera were the highest, being 1.23 mV and 1.38 mV, while to the healthy branches of V. awabuki were the lowest, being 0.95 mV and 1.01 mV, respectively. As for the time period, the EAG response values of the adults to the volatiles were the lowest from 12:00 to 14:00, which accorded with the feeding behaviors of the adults, i. e., taking food in the field in early morning or at dusk. PMID- 21608248 TI - [Effects of irrigation amount and nitrogen fertilization rate on wheat yield and soil nitrate content]. AB - A field experiment was conducted to study the effects of irrigation amount and nitrogen fertilization rate on wheat yield and soil nitrate content. With the increase of irrigation amount, the soil nitrate content in 0-200 cm layer at the same nitrogen fertilization rates had a trend of decrease -increase-decrease. Under irrigation, the soil nitrate content was significantly lower in 0-80 cm layer while significantly higher in 80-200 cm layer, compared with the control. As the irrigation amount increased, the translocation of soil nitrate nitrogen to deeper layers accelerated dramatically, with the content decreased in 0-80 cm layer, increased in 120-200 cm layer, and peaked in 120-140 cm layer. When the nitrogen fertilization rate increased from 210 kg x hm(-2) to 300 kg x hm(-2) the soil nitrate content at the same irrigation amounts increased significantly through anthesis, filling, and maturity stages. With the increase of irrigation amount, the grain yield decreased after an initial increase, being the highest when the irrigation amount in whole growth period was 60 mm. The grain yield, grain protein content, and grain protein yield all increased significantly with increasing nitrogen fertilization rate. Under the conditions of the present experiment, the treatment with nitrogen fertilization rate 210 kg N x hm(-2) and irrigation amount 60 mm (split into two times) had the highest grain yield, grain protein content, grain protein yield, and harvest index but the least NO3(-)-N leaching, being the more available irrigation and nitrogen fertilization mode for wheat production in the study area. PMID- 21608249 TI - [Genotype difference in nitrogen utilization efficiency of wheat]. AB - A pot experiment with 130 wheat cultivars was conducted to study their genotype difference in biomass per plant, nitrogen accumulation, and nitrogen production efficiency under the same level of nitrogen supply, aimed to screen the high efficiency nitrogen-utilizing wheat genotypes. The results showed that the biomass per plant of the cultivars at jointing, heading, and maturing stages was within the ranges of 1.06-3.08 g, 1.88-9.05 g, and 2.64-13.75 g, respectively, and the yield per plant was 1.38-9.90 g. The nitrogen dry matter production efficiency was 25.62-65.41 g x g(-1) N (F = 5.099 * *) at jointing stage and 35.79 - 88.70 g x g(-1) N (F = 5.325 * *) at heading stage, and the nitrogen production efficiency of grain yield was 19.06-38.54 g x g(-1) N (F = 4.669 * *) at maturing stage. There were significant differences in nitrogen dry matter production efficiency (jointing stage, F = 637.941 * *; heading stage, F = 201.173 * *) and nitrogen grain yield production efficiency (maturing stage, F = 443.450 * *), and also, in biomass accumulation among the cultivars, but no significant differences in tiller number and effective tiller number. The wheat genotypes with high nitrogen utilization efficiency had the characteristics of less ineffective tiller, high nitrogen utilization before heading stage, and high effective nitrogen absorption and reuse capability at heading and maturing stage. The grain yields of high nitrogen efficiency genotypes Sheng CXK027-4 and Liangmai 4 were 2.44 times and 1.86 times higher than those of low nitrogen use efficiency genotype 694, and the nitrogen accumulation in grain yields was 2.06 times and 1.81 times higher than that of low nitrogen use efficiency genotype 694, respectively. PMID- 21608250 TI - [Defining of wheat growth management zones based on remote sensing and geostatistics]. AB - Taking the winter wheat planting areas in Rugao City and Haian County of Jiangsu Province as test objects, the clustering defining of wheat growth management zones was made, based on the spatial variability analysis and principal component extraction of the normalized difference vegetation index (NDVI) data calculated from the HJ-1A/B CCD images (30 m resolution) at different growth stages of winter wheat, and of the soil nutrient indices (total nitrogen, organic matter, available phosphorus, and available potassium). The results showed that the integration of the NDVI at heading stage with above-mentioned soil nutrient indices produced the best results of wheat growth management zone defining, with the variation coefficients of NDVI and soil nutrient indices in each defined zone ranged in 4.5% -6.1% and 3.3% -87.9%, respectively. However, the variation coefficients were much larger when the wheat growth management zones were defined individually by NDVI or by soil nutrient indices, suggesting that the newly developed defining method could reduce the variability within the defined management zones and improve the crop management precision, and thereby, contribute to the winter wheat growth management and process simulation at regional scale. PMID- 21608251 TI - [Effects of 5-aminolevulinic acid on winter wheat dry matter accumulation after anthesis and flag leaf senescence]. AB - Taking wheat cultivar Bainong AK58 as test material, a field experiment was conducted to study the effects of different concentration 5-aminolevulinic acid (ALA) (0,10, 30 and 50 mg x L(-1)) applied at initial heading stage on the post anthesis dry matter accumulation and flag leaf senescence of the cultivar. Applying 10-50 mg x L(-1) of ALA benefited the dry matter accumulation, with its total amount at maturing stage being significantly higher than that of the control (0 mg x L(-1) ALA). 10-50 mg x L(-1) of ALA had no significant effects on the distribution of accumulated dry matter in leaf, stem and sheath, and grain, but increased the contribution of the dry matter to grain yield. 10-50 mg x L(-1) of ALA increased the leaf area index at milky and dough stages, but had no effects on it at flowering stage. After treated with 10-50 mg x L(-1) ALA, the leaf SPAD value and net photosynthetic rate from anthesis to milky stage were significantly higher, and the MDA content and relative electric conductivity at later grain-filling stage were lower, compared with those of the control. Applying 10-50 mg x L(-1) of ALA increased the grain number per spike, 1000-grain mass, and grain yield significantly, with the best effect when applying 30 mg x L(-1) ALA. PMID- 21608252 TI - [Effects of different film mulch and ridge-furrow cropping patterns on yield formation and water translocation of rainfed potato]. AB - This paper studied the effects of different film mulch and ridge-furrow cropping patterns on the yield formation and water translocation of rainfed potato in the semi-arid area of west Loess Plateau. Comparing with those under traditional harrowed bedding without film mulch (T1), the potato yield under harrowed bedding with film mulching (T2), completely mulched alternating narrow and wide ridges with furrow planting (T3), completely mulched alternating narrow and wide ridges with ridge planting (T4), mulched raised bedding with furrow planting (T5), and mulched raised bedding with bedding planting (T6) was increased by 50.1%, 75.9%, 86.8%, 69.6%, and 60. 6%, and the water use efficiency (WUE) was increased by 47.0%, 82.7%, 84.0%, 75.2%, and 54.3% respectively, with the increments being the highest under T4 and T3. All the film much and ridge-furrow cropping patterns improved the yield component of potato, and T4 and T3 were most beneficial to the increase of mid and big tubers, tuber number per plant, and tuber yield per plant, and to the decrease of the proportions of green and blet tubers. It was concluded that completely mulched alternating narrow and wide ridges with ridge planting (T4) and completely mulched alternating narrow and wide ridges with furrow planting (T3) were the two better cropping patterns in water-saving and high yielding for potato cultivation in semiarid areas. PMID- 21608253 TI - [Effects of irrigation with treated wastewater on nutrient distribution in cucumber and tomato plants and their fruit quality]. AB - A field experiment was conducted to investigate the effects of irrigation with treated wastewater on the nutrient distribution in cucumber and tomato plants and their fruit quality. Irrigation with treated wastewater promoted tomato growth significantly, but had definite inhibition effect on cucumber growth. After the irrigation with treated wastewater, the nitrogen in plants had the characteristics of upward translocation, potassium was easily to be accumulated in cucumber leaf but not accumulated in tomato root, and sodium was mostly accumulated in root but less enriched in leaf, not giving damage to the plants. No significant effects were observed on the distribution of calcium, magnesium, and chlorine in plants. Under the irrigation with treated wastewater, the overall quality of cucumber and tomato fruits was less affected. The nitrate concentration in cucumber and tomato fruits was increased by 5.3% and 32.9%, respectively, but still lower than the state food safety standard of China. PMID- 21608254 TI - [Food security in 'Grain for Green Project' area of North Shaanxi based on households]. AB - This paper analyzed the food production by the households in the counties with high population (Mizhi County) and low population (Wuqi County) in North Shaanxi, and studied the food security and its affecting factors in the two counties by using minimum cropland area per capita and Cobb-Douglass production function methods. The results demonstrated that the food production in low population county could meet the basic standard of food security, while that in high population county could not. Cultivated area and investment in agricultural technology were the major factors affecting food security; labor force, labor quality, and grain subsidy also had positive effects on food production. The current technology and labor quality did not reach their potential for food production. This region needed to increase grain production area to reach the minimum standard of 0.14 bm2 per capita, put much stress on labor force training, and formulate appropriate following policies for 'Grain for Green' to realize the food security strategy. PMID- 21608255 TI - [Effects of land use and environmental factors on the variability of soil quality indicators in hilly Loess Plateau region of China]. AB - Classical statistics methods were adopted to analyze the soil quality variability, its affecting factors, and affecting degree at a regional scale (700 km2) in the central part of hilly Loess Plateau region of China. There existed great differences in the variability of test soil quality indicators. Soil pH, structural coefficient, silt content, specific gravity, bulk density, total porosity, capillary porosity, and catalase activity were the indicators with weak variability; soil nutrients (N, P, and K) contents, CaCO3 content, cation exchange capacity (CEC), clay content, micro-aggregate mean mass diameter, aggregate mean mass diameter, water-stable aggregates, respiration rate, microbial quotient, invertase and phosphatase activities, respiratory quotient, and microbial carbon and nitrogen showed medium variation; while soil labile organic carbon and phosphorus contents, erosion-resistance, permeability coefficient, and urease activity were the indicators with strong variability. The variability of soil CaCO3, total P and K, CEC, texture, and specific gravity, etc. was correlated with topography and other environmental factors, while the variability of dynamic soil quality indicators, including soil organic matter content, nitrogen content, water-stable aggregates, permeability, microbial biomass carbon and nitrogen, enzyme activities, and respiration rate, was mainly correlated with land use type. Overall, land use pattern explained 97% of the variability of soil quality indicators in the region. It was suggested that in the evaluation of soil quality in hilly Loess Plateau region, land use type and environmental factors should be fully considered. PMID- 21608256 TI - [Soil physical properties of different hedgerow systems in upper reaches of Yangtze River]. AB - Based on the investigation of present hedgerows in the upper reaches of Yangtze River, this paper analyzed the soil physical properties at different positions of three kinds of hedgerows (arbor, shrub, and grass). Comparing with those between the hedgerows, the soil physical properties within the hedgerows improved significantly. The average values of soil porosity, moisture content, saturated conductivity, water stable aggregates content, anti-erodibility index, anti scouribility index, and clay content within the arbor, grass, and shrub hedgerows increased by 18.8%, 30.1%, 12.9%, 139.3%, 108.3%, 95.9%, and 25.5%, and the soil bulk density and sand content averagely decreased by 17.3% and 9.6%, respectively. The soil properties within the three hedgerows differed significantly. The soil anti-scouribility index within arbor hedgerow was the highest; the soil porosity, moisture content, saturated conductivity, anti scouribility index, water-stable aggregates content, and clay content within the shrub hedgerow were higher than those within the tree and grass hedgerows; while the soil bulk density within the shrub hedgerows was lower than that within the tree and grass hedgerows. Because of the differences in the affecting degree of hedgerow on the soil physical properties at different positions of the three hedgerow systems, the related parameters presented definite horizontal variation at steep lands within, before, and behind the hedgerows, and between the hedgerows. The coefficient of variation (CV) of soil moisture content, anti erodibility index, saturated conductivity, and clay content of arbor hedgerows was bigger than that of shrub and grass hedgerows, while the CV of soil bulk density, porosity, water-stable aggregates content, and anti-scouribility index of shrub hedgerow was bigger than that of arbor and grass hedgerows. PMID- 21608257 TI - [Spatiotemporal variation of soil pH in Guangdong Province of China in past 30 years]. AB - Based on the 1980s' soil inventory data and the 2002-2007 soil pH data of Guangdong Province, the spatiotemporal variation of soil pH in the Province in past 30 years was studied. In the study period, the spatial distribution pattern of soil pH in the Province had less change (mainly acidic), except that in Pearl River Delta and parts of Qingyuan and Shaoguan (weak alkaline). The overall variation of soil pH was represented as acidification, with the average pH value changed from 5.70 to 5.44. Among the soil types in the Province, alluvial soil had an increased pH, lateritic red soil, paddy soil, and red soil had a large decrement of pH value, and lime soil was most obvious in the decrease of pH value and its area percentage. The soil acidification was mainly induced by soil characteristics, some natural factors such as acid rain, and human factors such as unreasonable fertilization and urbanization. In addition, industrialization and mining increased the soil pH in some areas. PMID- 21608258 TI - [Scale-dependency of spatial variability of soil available nutrients]. AB - With the support of GIS and by using classical statistics and geostatistics methods, the spatial variability of soil available P (AP) and available K (AK) in cultivated lands in Yucheng City of Shandong Province was approached at county and township scales. The results showed that both the soil AP and AK followed the logarithmic normal distribution, with the coefficient of variation (CV) at the two scales being 26.5% - 36.6% and presenting a moderate variation. With the decrease of the scale, the CV of the soil AP and AK increased. Both the soil AP and AK were spatially correlated with scale. At county scale, the soil AP and AK had a larger spatial correlation distance, being 9.0 km and 26.5 km, respectively; while at township scale, the soil AP and AK had a smaller spatial correlation distance, being 1.7 km and 2.8 km, respectively. The spatial distribution of the soil AP and AK at the two scales was obviously different, which was mainly affected by structural factors and random factors. PMID- 21608259 TI - [Effects of exogenous dimethylarsinic acid on Brassica campestris growth and soil arsenic bioavailability]. AB - A pot experiment was conducted to study the effects of exogenous dimethylarsinic acid (DMA) on the growth of Brassica campestris and the bioavailability of soil arsenic (As). With the increasing concentration of applied DMA, the emergence rate and biomass of B. campestris increased at low concentration DMA, but decreased at high concentration DMA. When the DMA concentration reached 90 mg x kg(-1), the emergence rate and biomass of B. campestris in the second cropping decreased by 9.5% and 57.0%, respectively, compared with those in the control, indicating that exogenous DMA had longer-term effects on the growth of B. campestris. The soil available As and the As uptake by B. campestris all increased with increasing concentration of exogenous DMA, and there existed significant correlations among them. After applied into soil, the exogenous DMA demethylated, with As(V) as the main product and lesser amount of As (III), and the concentrations of soil As(V) and As(III) increased with increasing application rate of exogenous DMA. PMID- 21608260 TI - [Changes of China agricultural climate resources under the background of climate change. II. Spatiotemporal change characteristics of agricultural climate resources in Southwest China]. AB - Based on the 1961-2007 ground observation data from 88 meteorological stations in Southwest China, and by using statistical methods and GIS software, this paper analyzed the spatiotemporal change characteristics of agricultural climate resources in this region in the whole year and during temperature-defined growth period. In 1961-2007, the annual mean temperature in the region showed an increasing trend, with the increment averaged 0.18 degrees C x (10 a)(-1). The > or = 10 degrees C and > or = 15 degrees C accumulated temperature during temperature-defined growth period also showed an increasing trend, with the increment averaged 55.3 degrees C x d x (10 a)(-1) and 37 degrees C x d x (10 a)( 1), respectively. The annual sunshine hours decreased gradually from west to east, and the decreasing trend was more significant in eastern than in western region. The sunshine hours during temperature-defined growth period showed an overall increasing trend, and the spatial difference was great. The precipitation resource had an overall decrease, with the decrement in whole year and during temperature-defined growth period averaged 10 mm x (10 a)(-1) and 8 mm x (10 a)( 1), respectively. The annual reference crop evapotranspiration generally decreased, but the decrement was less than that of annual precipitation. The reference crop evapotranspiration during temperature-defined growth period within about 53% meteorological stations decreased. PMID- 21608261 TI - [Variation pattern and its affecting factors of three-dimensional landscape in urban residential community of Shenyang]. AB - Based on the 1:10000 aerial photo in 1997 and the three QuickBird images in 2002, 2005, and 2008, and by using Barista software and GIS and RS techniques, the three-dimensional information of the residential community in Tiexi District of Shenyang was extracted, and the variation pattern of the three-dimensional landscape in the district during its reconstruction in 1997-2008 and related affecting factors were analyzed with the indices, ie. road density, greening rate, average building height, building height standard deviation, building coverage rate, floor area rate, building shape coefficient, population density, and per capita GDP. The results showed that in 1997-2008, the building area for industry decreased, that for commerce and other public affairs increased, and the area for residents, education, and medical cares basically remained stable. The building number, building coverage rate, and building shape coefficient decreased, while the floor area rate, average building height, height standard deviation, road density, and greening rate increased. Within the limited space of residential community, the containing capacity of population and economic activity increased, and the environment quality also improved to some extent. The variation degree of average building height increased, but the building energy consumption decreased. Population growth and economic development had positive correlations with floor area rate, road density, and greening rate, but negative correlation with building coverage rate. PMID- 21608262 TI - [Eco-efficiency change and its driving factors in Tongling City of Anhui Province]. AB - This paper first applied material flow analysis (MFA) to construct three levels of regional eco-efficiency indicators, i.e., regional direct eco-efficiency (RDE), regional total eco-efficiency (RTE), and holistic eco-efficiency (HE), and adopted the newly developed data envelopment analysis (DEA) to evaluate the eco efficiency of Tongling City during the period of 1990-2008. We also applied Malmquist productivity index (MPI) to explore the eco-efficiency change between two following years and its driving factors. The main results were summarized as 1) though the RDE of Tongling City in 1990-2008 kept an increasing trend, its mean eco-efficiency was not high (close to 0.8 in 80% of the years), being lower than that of the RTE and HE, and 2) the RDE change was closely relevant to the improvement in resource management and the technical input in environmental protection in recent years. In order to further improve the RDE of the City, it would be necessary to raise its eco-efficiency via expanding raw material input, reducing domestic extraction, promoting resources productivity, and taking more measures on environmental protection facilities construction. PMID- 21608263 TI - [Evolution process and related driving mechanisms of Yellow River Delta since the diversion of Yellow River]. AB - Based on the 23 sheets of remote sensing images from 1976 to 2009, in combining with the water and sediment data from Lijin station and the annual precipitation data of Yellow River Basin from 1976 to 2008, this paper quantitatively analyzed the features of water and sediment discharge from Yellow River, and the evolution process of Yellow River Delta and related driving mechanisms. In 1976-2008, the annual runoff and the annual sediment discharge into sea changed largely and frequently, but overall, presented a decreasing trend. Since the course of the Yellow River changed its direction to Qingshui channel in 1976, the Delta coastline and area were generally in a silting-up state. The evolution process of the Delta could be approximately divided into three stages, i.e., 1976-1985, 1986 1995, and 1996-2009, and the increasing rate of the Delta decreased with the stages. The coastline and area of the Delta were significantly exponentially correlated to the sediment accumulated at Lijin station, and the inter-annual variation of the precipitation of the Yellow River Basin had a strong correlation with that of the sediment at Lijin station, suggesting that the annual variation of the precipitation in Yellow River Basin was the main factor affecting the runoff and sediment discharge into sea. PMID- 21608264 TI - [Cadmium tolerance and enrichment characteristics of Eulaliopsis binata]. AB - A pot experiment was conducted to study the cadmium (Cd) tolerance and enrichment characteristics of Eulaliopsis binata. Applying low concentration Cd (5 mg x kg( 1)) could boost the growth and physiological vigor of E. binata, with the twelve indexes such as biomass and net photosynthetic rate, etc. increased by 1.0% 15.5%, compared with CK; while applying high concentration Cd (> 5 mg x kg(-1)) had negative effects on the growth of E. binata. Even though the E. binata still finished its physiological circle under the application of 100 mg Cd x kg(-1), the biomass and net photosynthetic rate were decreased by 27.0% and 25.6%, respectively, in comparison with CK. The Cd content in the organs of E. binata increased greatly with increasing concentration of applied Cd. The Cd content in roots was from 350 mg x kg(-1) to 500 mg x kg(-1), and that in stems and leaves was from 15 mg x kg(-1) to 35 mg x kg(-1). When the concentration of applied Cd was < 50 mg x kg(-1), the Cd uptake by E. binata increased with increasing concentration of applied Cd. The Cd content in stems and leaves amounted 15.7% - 38.4% of the total uptake, and the ratio of the Cd content in stems and leaves to that in roots was up to 0.62. All the results indicated that E. binata had stronger capability in tolerating, enriching, and transporting Cd, being a potential Cd hyperaccumulator. PMID- 21608265 TI - [Combined effects of copper and simulated acid rain on copper accumulation, growth, and antioxidant enzyme activities of Rumex acetosa]. AB - A pot experiment was conducted to study the combined effects of Cu (0-1500 mg x kg(-1)) and simulated acid rain (pH 2.5-5.6) on the copper accumulation, growth, and antioxidant enzyme activities of Rumex acetosa. With the increasing concentration of soil Cu, the Cu accumulation in R. acetosa increased, being higher in root than in stem and leaf. The exposure to low pH acid rain promoted the Cu uptake by R. acetosa. With the increase of soil Cu concentration and/or of acid rain acidity, the biomass of R. acetosa decreased, leaf and root MDA contents increased and had good correlation with soil Cu concentration, and the SOD and POD activities in leaf and root displayed a decreasing trend after an initial increase. This study showed that R. acetosa had a strong adaptive ability to Cu and acid rain stress, exhibiting a high application potential in the remediation of Cu-contaminated soil in acid rain areas. PMID- 21608266 TI - [Environmental impact assessment based on planning support system]. AB - How to assess environmental impact is one of the keys in land use planning. This article described in detail the concepts of activities, impact zones, functions, and sensitivities, as well as the development of STEPP (strategic tool for integrating environmental aspects in planning procedures) based on Avenue, the secondary developing language of ArcView GIS. The system makes it convenient for planning practitioners exchanging information, and can spatially, visually and quantitatively describe environmental impact and its change. In this study, the urban-rural combination area located between EDE and Veenendaal of The Netherlands was taken as case, and the results indicated that the environment was incorporated well in the planning procedure based on the concepts, and could also demonstrate the effects of planning measures on environment spatially, explicitly, and in real-time, facilitating the participation of planning practitioners and decision-making. Some proposals of how to promote STEEP application in China were suggested. PMID- 21608267 TI - [Marine environment of Nanri Archipelago, Fujian Province in summer: diagnosis and assessment]. AB - Based on the ecological investigation data in September and October 2007, the status of the marine ecological environment of Nanri Archipelago, Fujian Province in summer was diagnosed and assessed from the aspects of sea water quality, nutrient structure and levels, and biodiversity. The comprehensive quality index method was used for the assessment of the marine ecological environment, and the rationality of the assessment obtained from different indices was also discussed. The sea water pH, dissolved oxygen (DO), chemical oxygen demand (COD), and Pb, Cd, Hg, and As concentrations were all within the limit values of the Grade II standard of Sea Water Quality Standard (GB 3097-1997), while the phosphate concentration at 71% stations, inorganic nitrogen at 14% stations, and oil concentration at 7% stations were all above the Grade II standard of Sea Water Quality Standard. Overall, the seawater quality was of better grade, nutrient structure was characterized by N-limited, most of the sea water was at a state of eutrophication, and the diversity index of plankton was at mildly polluted or unpolluted level. The comprehensive quality index indicated that the seawater quality of the Nanri Archipelago was relatively fine. There existed definite differences in the assessment results by using different diagnosis methods, and hence, a relatively objective assessment about marine environmental quality and health status could only be made when the chemical and biological indicators were comprehensively used. PMID- 21608268 TI - [Community composition of phytoplankton in Fujian-Guangdong coastal upwelling region in summer and related affecting factors]. AB - Based on the investigation data of 133 samples from 30 grid stations in the Fujian-Guangdong coastal upwelling region (21.6 degrees - 24.3 degrees N,115.7 degrees -118.7 degrees E) in 11-16 June 2009, this paper studied the phytoplankton species composition and cell abundance in the region in three dimensions (vertical, horizontal, and sectional), and approached their relations with major environmental factors. A total of 159 taxa belonging to 85 genera of 4 phyla were identified, among which, diatom was predominant, followed by dinoflagellate. Cyanophyceae mainly composed of Trichodesmium also occupied a greater proportion, but Chrysophyceae was only checked out in the upper 10 m water layer at coastal stations. The dominant species were Rhizosolenia alata f. gracillma, Thalassionema nitzschioides, Pseudonitzschia pungens, Skeletonema costatum, Thalassionema frauenfeldii, Paralia sulcata, Guinadia striata, Trichodesmium thiebautii, Ceratium fusus, and Gyrodinium spirale. Most of the phytoplankton taxa were cosmopolitan species, followed by warm-water species, while tropic high-salinity or oceanic eurythermal species were lesser. The cell abundance of the phytoplankton was average of 67.59 x10(2) ind x L(-1). In vertical profile, the cell abundance of the phytoplankton was the highest in surface water, and decreased with water depth. In horizontal and sectional profiles, the cell abundance had no definite patterns, but the high abundance region was in Nanao Island water area, being anastomosed with the center of upwelling region, which indicated that the weak and small intensity of deep-sea water upwelling caused lesser phytoplankton cell abundance and superposition. The comparatively high phytoplankton cell abundance in the four sections (B, C, D, E) along Nanao-Zhangpu was resulted from the upwelling from Taiwan Bank. The phytoplankton cell abundance had a significant positive correlation with the PO4(3-) concentration in the upper 10 m water layer, but no correlation with the dissolved inorganic nitrogen (DIN) concentration. Thereby, to study the eco physiological responses of phytoplankton species to nutrient stress would be helpful to reveal the formation mechanism of algal bloom in upwelling region. PMID- 21608269 TI - [Construction of degradation diagnosis system for the ecosystems in Dongtan coastal zone of Chongming, Shanghai]. AB - Based on the "pressure-state-response (PSR)" concept model, a degradation evaluation index system was constructed for the cropland, wetland, and inshore ecosystems in Dongtan coastal zone of Chongming. By using multiplication synthesis, a combination of analytic hierarchy process and entropy weight method, the weights of each evaluation index were obtained, and, through geographical space index quantification and spatial clustering, the degradation degree of each ecological system was analyzed. The results showed that the degradation degree of Dongtan coastal ecosystems in 2005 could be spatially classified into four classes, i.e., class I, class II, class III and class IV, with the degradation degree aggravated increasingly. For the cropland, wetland, and inshore ecosystems, the weight of heavy metals was the largest, being 0.65, 0.20, and 0.26, respectively. Bird diversity index, land use degree, and Spartina alterniflora coverage also had greater effects on wetland ecosystem, and their weights were 0.26, 0.16, and 0.10, respectively. For cropland ecosystem, land use degree was also an important affecting factor, with the weight of 0.22. PMID- 21608270 TI - [Habitat selection attributes of giant panda]. AB - Based on the 1997-2009 inventory data of Wanglang Nature Reserve, the habitat selection attributes of giant panda were studied from the aspects of topography, forest community structure, and main feeding bamboo by the methods of frequency distribution and Bailey. The giant panda had obvious habitat preferences. Topographically, the preferred microhabitat was on the even or convex slopes at the ridge, top, or middle part of mountain body at an elevation 2500-3000 m, with southwest aspect, 6 degrees-30 degrees, and the distance to the nearest water source > 300 m. As for the forest community structure, the giant panda preferred the microhabitat with the bamboo succeeded from secondary forest or mixed conifer and broad-leaved forest, and with the average tree height being 20-29 m and the shrub coverage being 0-24%. The preferred main feeding bamboo by the giant panda was the growing well Fargesia denudate with an average height of 2-5 m and the coverage of > 50%. PMID- 21608271 TI - [Degradative mobile genetic elements (MGEs) and their potential use in MGE mediated biodegradation]. AB - The horizontal transfer of mobile genetic elements (MGEs) in environmental microbial communities plays an important role in the evolution of bacterial genomes and the adaption of microbial populations to specific environmental stress. Inoculation of the bacterial strains with MGEs with pollutant-degrading gene and the subsequent horizontal transfer of the MGEs to one or various well established and competitive indigenous bacterial populations in an ecosystem will allow the catabolic gene to be transferred and expressed in indigenous microbial populations, and hence, the survival of the introduced donor strains is no longer needed to be considered. The MGE-mediated bioremediation provides the feasibility for developing new bioremediation strategies. This paper summarized the diversity of MGEs with pollutant-degrading gene in the environment and the important roles of these MGEs in promoting pollutant degradation, introduced the methodological approaches for the isolation of the MGEs from environmental samples, and listed several studies that monitored the horizontal transfer of the MGEs in polluted soil, activated sludge, and other bioreactors. PMID- 21608272 TI - [Acidophilic methanogens and their applications in anaerobic digestion]. AB - Methanogens play an important role in global carbon cycle. There exists a range of unknown methanogenic archaea in acidic peat lands, among which, acidophilic methanogens have attracted increasing research interests because of their special metabolic characteristics. To introduce acidophilic methanogens in the anaerobic digestion process of high concentration organic wastes or waste water could essentially overcome the inhibition of acid accumulation on the methanogens and help reduce the operation cost, broadening the industrial application of anaerobic bio-treatment technology. In this paper, we reviewed the recent researches on acidophilic methanogens, with the focus on enrichment and isolation methods, physiological and biochemical characters, metabolic characteristics, and application of molecular biology. The potential applications of acidophilic methanogens in anaerobic digestion process were analyzed and proposed, and the directions for further researches were suggested. PMID- 21608273 TI - [Bioremediation of heavy metal pollution by edible fungi: a review]. AB - Bioremediation is the method of using organisms and their derivatives to absorb heavy metals from polluted environment, with the characteristics of low cost, broad sources, and no secondary pollution. Heavy metals enrichment by edible fungi is an important research focus of bioremediation, because it can decrease the eco-toxicity of heavy metals via the uptake by edible fungi, and thereby, take a definite role in heavy metal remediation. This paper reviewed the research progress on the enrichment of heavy metal copper, cadmium, lead, zinc, arsenic, and chromium by edible fungi and the possible enrichment mechanisms, and prospected the development and applications of heavy metal enrichment by edible fungi in the management of polluted environment. PMID- 21608274 TI - [Selected spinal anesthesia: diluted solutions and low dosages]. PMID- 21608275 TI - [Utility of preoperative chest radiography in smokers undergoing transurethral resection of urinary bladder tumors]. AB - OBJECTIVES: To assess the utility of preoperative chest radiographic findings for predicting cardiopulmonary complications in smokers undergoing transurethral resection of urinary bladder tumors under spinal anesthesia. To analyze perioperative changes in attitude in this setting. MATERIAL AND METHODS: Prospective study of 309 smokers with > or = 20 pack-years of cumulative smoking who were candidates for transurethral resection of urinary bladder tumors. The patients were classified in 2 groups according to radiographic findings. Between groups we compared the incidence of cardiopulmonary complications, perioperative changes in attitude to anesthesia and surgery, delays in completing the preanesthesia workup, and differences in the duration of surgery and hospital stay. RESULTS: Patients older than 65 years were 1.92 times more likely to have significant findings on the chest radiograph. Radiographic findings were associated with a higher incidence of perioperative complications (P=.02), need for further preoperative consultations (P<.01), longer delay in completing the preanesthesia study (P<.01), longer mean (SD) hospital stay (3.43 [3.17] days vs 2.50 [1.77] days, P<.001), and longer duration of surgery (P<.001). Attitudes did not change in relation to radiographic findings during or after surgery. Chest radiography correctly classified 3.54% of the patients with complications (predictive value). CONCLUSIONS: The predictive value of chest radiography for cardiopulmonary complications is low and findings do not influence intra- or postoperative attitudes. We therefore find no justification for performing chest x-rays in the population studied. PMID- 21608276 TI - [Perioperative anesthetic management of 300 morbidly obese patients undergoing laparoscopic bariatric surgery and a brief review of relevant pathophysiology]. AB - OBJECTIVES: Laparoscopic bariatric surgery is a challenge for anesthesiologists because morbidly obese patients are at high risk and laparoscopy may complicate respiratory and hemodynamic management. The aim of this study was to analyze the perioperative anesthetic management of morbidly obese patents undergoing laparoscopic bariatric surgery. MATERIAL AND METHODS: Prospective study of 300 consecutive patients diagnosed with morbid obesity and scheduled for laparoscopic bariatric surgery. Patients were positioned with a wedge cushion under the head and shoulders. A rapid sequence induction of anesthesia was carried out. A short handled, articulated-blade McCoy laryngoscope was used for intubation; an intubation laryngeal mask airway (Fastrach) was on hand as a rescue device. Propofol and remifentanil were used for maintenance of anesthesia and morphine was administered at the end of surgery. Incentive spirometry was initiated in the postanesthetic recovery unit. RESULTS: Eighty percent of the patients were women with a mean (SD) body mass index (kg/m2) of 46 (5). The first choice of direct laryngoscopic intubation was successful in 98.6% of cases. All patients were successfully intubated. Only 5 patients required intensive care. Postoperative complications (mainly respiratory problems, bleeding, and infections) were observed in 17%. No patient died. CONCLUSIONS: Perianesthetic management of morbidly obese patients who undergo laparoscopic surgery is safe. To minimize pulmonary complications, preoxygenation and rapid sequence induction should be performed correctly and incentive spirometry should be initiated in the immediate postoperative period. The McCoy laryngoscope ensures intubation in most cases. PMID- 21608277 TI - [Risk factors for postoperative complications in major head and neck surgery]. AB - BACKGROUND AND OBJECTIVE: Tumor extension is the factor that usually determines the choice of radiotherapy or surgery for head and neck cancers. The choice of surgery carries with it certain specific risks that must be assessed jointly by the maxillofacial surgeon and the anesthetist so that they can agree on the best course of action to choose. We aimed to identify risk factors for complications after major head and neck surgery. PATIENTS AND METHODS: Retrospective descriptive analysis of data for patients who underwent oncologic head and neck surgery with graft reconstruction. The main candidate predictors gathered from records were age, sex, ASA physical status classification, time under anesthesia, and intra- and postoperative events. The main dependent variables were records of early and delayed complications, time until extubation, and related mortality. RESULTS: We identified 61 interventions in 56 patients (mean duration of surgery, 9 hours). Early complications developed in 57.4% while they were in the critical care area. Age > or =60 years was associated with longer hospital stays. Short term mortality was higher in current smokers (P= .01). Survival was significantly higher in patients classified ASA 1 or 2 in comparison with those classified as ASA 3 or 4, in whom long-term mortality was higher (P < .05). CONCLUSIONS: The incidence of postoperative complications was associated with comorbidity and risk behaviors found in this type of patient. We feel that a multidisciplinary medical team should assess the surgical and postoperative care of these patients. PMID- 21608278 TI - [Teaching experience of the anesthesiology training unit at Hospital Universitario Nuestra Senora de Candelaria]. AB - BACKGROUND: Health care in Spain has improved progressively and professionals are now required to meet competency levels that safeguard the citizen's right to health protection. To achieve this, instructors in residency training programs and resident physicians themselves are calling for a common framework for training to ensure quality and consistency. Given the scarcity of articles related to training in our journal and following the First Meeting of Residency Program Instructors of the Sociedad Espanola de Anestesiologia y Reanimacion (SEDAR), there has arisen a need to explain how SEDAR's training unit is organized. METHODS: In order to facilitate the sharing of experiences of those involved in training anesthesiology medical residents, we undertook a descriptive analysis of our hospital's curriculum. RESULTS: The structure and operation of the department are described in this report. The results of anonymous surveys completed annually show the satisfaction of residents (9.4 out of 10) and physicians (8.7 out of 10). An audit by the Ministry of Health showed that the curriculum met 100% of the required criteria. PMID- 21608279 TI - [Protective measures against cerebral ischemia following subarachnoid hemorrhage: Part 1]. AB - BACKGROUND AND OBJECTIVES: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage contributes significantly to morbidity and mortality. Many studies on the various treatments aimed at preventing cerebral vasospasm have been carried out, but evidence of efficacy is limited. Our aim was to review the literature on the various therapies for which there is scientific evidence of protection against cerebral vasospasm following aneurysmal subarachnoid hemorrhage. METHODS: MEDLINE search (1950 to the october 2009) and review of articles found on the prevention of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. The search was restricted to articles in English, French, and Spanish. The keywords were cerebral vasospasm, subarachnoid hemorrhage, therapy, nimodipine, triple H, clazosentan, statins, and magnesium in addition to the word forms derived from them. We also searched manually for references cited in the selected articles. A title was included if it was a randomized controlled trial, meta analysis, nonrandomized clinical trial, descriptive study, observational study with statistical analysis, opinion article, or expert review. RESULTS: Part 1 analyzed treatment with calcium antagonists and triple-H therapy (hypertension, hemodilution, and hypervolemia). Part 2 analyzed new therapies such as clazosentan, magnesium, and statins. A total of 597 titles were located; 283 were initially selected. The 61 articles finally selected for review were of the following types: 2 opinion articles, 21 randomized controlled trials, 22 expert review articles, 3 meta-analyses, 4 nonrandomized clinical trials, 1 descriptive study, and 5 observational studies with statistical analysis. Three studies (2 meta-analyses and 1 randomized controlled trial) demonstrated that nimodipine use confers benefits (reduced morbidity and mortality) for patients with aneurysmatic subarachnoid hemorrhage. Statistically significant clinical benefits could not be demonstrated for the other drugs (clazosentan, statins, and magnesium). CONCLUSIONS: Insufficient evidence is available to support the use of the triple H therapy, clazosentan, statins, or magnesium sulfate for the prevention of cerebral vasospasm following subarachnoid hemorrhage. Nimodipine is the only preventative treatment that can be recommended. PMID- 21608280 TI - [Protective measures against cerebral ischemia following subarachnoid hemorrhage: Part 2]. PMID- 21608281 TI - [Clinical practice guidelines for the perioperative management of antiplatelet therapy in noncardiac surgery (Sociedad Espanola de Anestesiologia y Reanimacion)]. PMID- 21608283 TI - [Intraoperative use of transesophageal echocardiography and a laryngeal mask airway in anesthesia for repair of a patent foramen ovale]. PMID- 21608282 TI - [Postoperative management of postpneumonectomy pulmonary edema in a patient with ostium secundum atrial septal defect]. AB - We report the case of a 55-year-old woman who underwent right pneumonectomy for invasive squamous cell carcinoma. At 48 hours after surgery she developed severe dyspnea and hypoxemia that required reintubation and a progressively higher inspired oxygen fraction. A radiograph demonstrated pulmonary edema; echocardiography revealed an ostium secundum atrial septal defect with increased flow to the lung and severe pulmonary hypertension. Emergency percutaneous closure of this defect was carried out. This case report describes the management and treatment of postpneumonectomy pulmonary edema and atrial septal defect, as well as the circumstances that favor their development. We recommend that cardiac defects be investigated and possible treatment be considered prior to pneumonectomy. PMID- 21608284 TI - [Obstetric epidural analgesia, a safe choice in a patient with Charcot-Marie Tooth disease]. PMID- 21608286 TI - [Noninvasive ventilation through a nasal mask to sedate a man with amyotrophic lateral sclerosis during percutaneous endoscopic gastrostomy]. PMID- 21608285 TI - [Anesthetic considerations in Charcot-Marie-Tooth disease]. PMID- 21608287 TI - [General anesthesia in Dandy-Walker syndrome]. PMID- 21608288 TI - [Anesthetic considerations in Miller Fisher syndrome]. PMID- 21608289 TI - [Changes in the bispectral index during heart arrest and extracorporeal circulation]. PMID- 21608290 TI - [Intraoperative transesophageal echocardiography in a patient with persistent left superior vena cava syndrome]. PMID- 21608291 TI - [Chance finding of persistent left superior vena cava]. PMID- 21608292 TI - [Persistent left superior vena cava in a 2-month-old infant]. PMID- 21608293 TI - Puzzles in practice. Central pontine myelinolysis (osmotic demyelination syndrome). PMID- 21608295 TI - Journal of Invasive Cardiology. Editor's message. PMID- 21608294 TI - Coronary restenosis and contact allergy to stent material. PMID- 21608296 TI - Letter from the editor. PMID- 21608297 TI - Editorial retraction. PMID- 21608298 TI - [Combined interferon alpha2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial]. PMID- 21608299 TI - [Treatment of Adults. Orthodontics in the Fight against Aging. 83rd Scientific Meeting of the Societe Francaise d'Orthopedie Dento-Faciale. Lyons, 2-4 June 2011. Preface]. PMID- 21608300 TI - Meeting of the Strategic Advisory Group of Experts on immunization, April 2011 - conclusions and recommendations. PMID- 21608301 TI - [Treatment of adults. Orthodontics in the fight against aging. Introduction]. PMID- 21608302 TI - [Molecular mechanism of central nervous system control of eating]. PMID- 21608303 TI - [Professor Doctor Veaceslav Carasievici, October 8, 1921-April 5, 2008]. PMID- 21608304 TI - Some last thoughts about autonomy. PMID- 21608306 TI - Computer-generated prescriptions must be signed manually? PMID- 21608305 TI - Professional courtesy: it's not all about money. PMID- 21608307 TI - Health system reform: sharing risk & reward with ACOs. PMID- 21608308 TI - TMF broadens scope, continues work with impaired physicians. PMID- 21608309 TI - Legal challenges to federal health reform add to uncertainty. PMID- 21608310 TI - Tort reform: background and case studies. PMID- 21608311 TI - Diabetic ketoacidosis presenting with acute pancreatitis and visceral vein thrombosis. AB - Abdominal pain is a frequent manifestation in patients presenting with Diabetic Ketoacidosis (DKA). Usually it is attributed to severe metabolic acidosis but it can be due to underlying abdominal pathologies (i.e., pancreatitis, appendicitis). We report a case of a 19-year-old female who presented with DKA and severe abdominal pain and was found on further examination to have underlying pancreatitis and visceral vein thrombosis. The patient improved with treatment for the mentioned co-morbidities, including anticoagulation. PMID- 21608312 TI - Asymptomatic colonic histoplasmosis in a patient receiving methotrexate. AB - Disease due to infection with Histoplasma capsulatum usually manifests as a disseminated infection in patients with the Acquired Immunodeficiency Syndrome (AIDS). However, it may also present with focal disease in patients with or without AIDS. Unusual presentations or less well-recognized risk factors may make diagnosis of histoplasmosis more difficult. We describe the case of a patient who presented for screening colonoscopy and was found to have isolated asymptomatic colonic histoplasmosis. PMID- 21608313 TI - The allegory of politics. PMID- 21608314 TI - Difficult choices: forgoing life-sustaining treatment. PMID- 21608315 TI - Debate rages over antibiotic prophylaxis in patients with total joint replacements. PMID- 21608316 TI - Concept review: Managing complications associated with implant procedures. PMID- 21608317 TI - 'Spread' remains challenge in patient safety improvement. AB - Hospital quality professionals, staff must think more broadly. Map all the areas in your facility where patients would benefit from specific best practices. Recognize the potential danger in all medical procedures. PMID- 21608318 TI - Study: palliative care cuts hospitalization costs. AB - Patients spend less time in ICU and have lower in-hospital mortality rates. Identifying patient values and goals for their care is of primary importance. Palliative care improves quality of life. PMID- 21608319 TI - Tech helps facility slash HAIs by 22%. AB - Technology alone will not solve patient safety problems. Make sure staff knows you are seeking team success, not serving as a watchdog. Involve staff in new initiatives early on to ensure buy-in. PMID- 21608320 TI - Posted wait times an added advantage? PMID- 21608321 TI - Guidelines offer models for improving quality. PMID- 21608322 TI - Learn the key items in new guidelines. PMID- 21608323 TI - Patient safety and metrics: obtain good data. PMID- 21608324 TI - A flurry of updates from Keystone. Advances in understanding the arms race between HIV and its host, and efforts to capitalize on recent success in the HIV prevention field were among the highlights of this year's joint symposia. PMID- 21608325 TI - A PrEP rally. Key updates on pre-exposure prophylaxis and HIV-specific antibodies were among the main attractions at the annual Conference on Retroviruses and Opportunistic Infections. PMID- 21608326 TI - Giving HIV the zinc finger. PMID- 21608327 TI - Passive immunization with a broadly neutralizing antibody provides cross-clade protection. PMID- 21608328 TI - Phase I trial of novel HIV vaccine candidate prime-boost regimen starts in Africa. PMID- 21608329 TI - PrEP trial in women halted due to doubts that it could show efficacy. PMID- 21608330 TI - Study finds evidence of sieve effect in phase IIb STEP trial vaccinees. PMID- 21608331 TI - Community pediatrics in Israel: time for change? PMID- 21608332 TI - Screening for diabetic retinopathy with a mobile non-mydriatic digital fundus camera in southern Israel. AB - BACKGROUND: Diabetic retinopathy is a leading cause of adult blindness and accounts for about 10% of cases of legal blindness in Israel. Only about half of the patients with diabetes in Israel have regular eye examinations. OBJECTIVES: To evaluate, for the first time in southern Israel, a new service for diabetic retinopathy screening that uses a mobile non-mydriatic mobile fundus camera in primary care patients. METHODS: Diabetic members of the largest health fund in southern Israel and over 18 years old were invited for non-mydriatic fundus examination between January and October 2009. Screening was performed by a trained photographer using the Topcon TRC NW-6S non-mydriatic camera in nine primary care centers. RESULTS: A total of 4318 diabetic patients were screened, of whom 53% were classified as normal. The incidence of diabetic retinopathy was 15.8% (1.2% had proliferative retinopathy and 2.4% had suspected macular edema and were referred for laser treatment). Other possible sight-threatening conditions were detected in 9.3%. Fundus pictures were inadequate for assessment in 16% of cases. CONCLUSIONS: Diabetic retinopathy screening with a mobile non mydriatic fundus camera improved the quality of care for diabetic patients in southern Israel. This screening method identified patients requiring prompt referral to the ophthalmologist for further complete eye examination. Extending this screening program to other areas in the country should be considered. PMID- 21608333 TI - National survey of the ophthalmic use of anti-vascular endothelial growth factor drugs in Israel. AB - BACKGROUND: Intravitreal injections of the anti-vascular endothelial growth factor (VEGF) drugs bevacizumab (Avastin) and ranibizumab (Lucentis) became the mainstay of treatment for various retinal pathologies, but there is no consensus among ophthalmologists on the precise use of these drugs. OBJECTIVES: To describe the routine practices of retinal specialists in Israel regarding anti-VEGF drug treatment. METHODS: A questionnaire was sent via email to all 62 members of the Israeli Society of Retinal Specialists. The survey included 34 questions on various aspects of the use of anti-VEGF drugs: diagnosis, treatment, follow-up of different retinal pathologies, and the measures taken for ensuring sterile administration of the intravitreal injections. RESULTS: Fifty members (80%) completed the survey. Most of them (56%) offered both bevacizumab and ranibizumab to their patients for age-related macular degeneration, but 70% were influenced by the patient's socioeconomic status. Three consecutive monthly injections were usually recommended (58%) for the first 3 months, and treatment was extended as long as subretinal or intraretinal fluids persisted (57%). Over two-thirds (68%) switched the drugs after the 3-monthly series if the first one yielded no improvement in fluid status. The routine practice for intravitreal injection (> 80%) involved the wearing of sterile gloves, using an eyelid speculum, and administering povidone-iodine pretreatment and topical antibiotics after treatment. CONCLUSIONS: Intravitreal VEGF administration varies widely among Israeli retinal specialists. The current survey is intended to assist Israeli ophthalmologists in establishing their own treatment strategy for patients with retinal pathologies. PMID- 21608334 TI - Effects of adalimumab treatment on vascular disease associated with early rheumatoid arthritis. AB - BACKGROUND: Increased cardiovascular morbidity has become a leading cause of mortality in rheumatoid arthritis (RA). Tumor necrosis factor-alpha (TNFa) inhibitors may influence flow-mediated vasodilation (FMD) of the brachial artery, common carotid intima-media thickness (ccIMT) and arterial stiffness indicated by pulse-wave velocity (PWV) in RA. OBJECTIVES: To assess the effects of adalimumab treatment on FMD, ccIMT and PWV in early RA. METHODS: Eight RA patients with a disease duration < or =1 year received 40 mg adalimumab subcutaneously every 2 weeks. Ultrasound was used to assess brachial FMD and ccIMT. PWV was determined by arteriograph. These parameters were correlated with C-reactive protein, vonWillebrand factor (vWF), immunoglobulin M (IgM)-rheumatoid factor (RF), anti CCP levels and 28-joint disease activity score (DAS28). RESULTS: Adalimumab therapy successfully ameliorated arthritis as it decreased CRP levels (P = 0.04) and DAS28 (P < 0.0001). Endothelial function (FMD) improved in comparison to baseline (P < 0.05). ccIMT decreased after 24 weeks, indicating a mean 11.9% significant improvement (P = 0.002). Adalimumab relieved arterial stiffness (PWV) after 24 weeks. Although plasma vWF levels decreased only non-significantly after 12 weeks of treatment, an inverse correlation was found between FMD and vWF (R = 0.643, P = 0.007). FMD also inversely correlated with CRP (R = -0.596, P= 0.015). CRP and vWF also correlated with each other (R = 0.598, P = 0.014). PWV and ccIMT showed a positive correlation (R = 0.735, P = 0.038). CONCLUSIONS: Treatment with adalimumab exerted favorable effects on disease activity and endothelial dysfunction. It also ameliorated carotid atherosclerosis and arterial stiffness in patients with early RA. Early adalimumab therapy may have an important role in the prevention and management of vascular comorbidity in RA. PMID- 21608335 TI - Impact of dialysis type on outcome of acute renal failure in children: a single center experience. AB - BACKGROUND: Acute renal failure (ARF) is a common complication in critically ill children. It is known as an important predictor of morbidity and mortality in this population. Data on the factors affecting the choice of renal replacement therapy (RRT) modality and its impact on mortality of children with ARF are limited. OBJECTIVES: We retrospectively studied 115 children with ARF necessitating RRT during the period 1995-2005 to evaluate the effect of several prognostic factors as well as RRT type on their immediate outcome. METHODS: The data collected from charts included demographics, primary disease, accompanying medical conditions, use of vasopressor support, indications for dialysis, RRT modality, and complications of dialysis. Categorical variables were analyzed using chi-square or Fisher's exact tests. Variables associated with mortality (P < 0.1) at the univariable level were studied by a multivariable logistic regression model. RESULTS: The most common cause of ARF was congenital heart disease (n=75). RRT modalities included peritoneal dialysis (PD) (n=81), hemodialfiltration (HDF) (n=31) and intermittent hemodialysis (IHD) (n=18). Median RRT duration was 4 days (range 1-63 days). Overall mortality was 52.2%. IHD was associated with the best survival rate (P < 0.01 vs. PD and HDF), while children treated with HDF had the worse outcome. Hemodynamic instability and systemic infections were associated with greater mortality, but the rate of these complications did not differ between the study groups. CONCLUSIONS: Our results suggest that IHD when applied to the right patient in an appropriate setting may be a safe and efficient RRT modality in children with ARF. Randomized prospective trials are needed to further evaluate the impact of different RRT modalities on outcome in children with ARF. PMID- 21608336 TI - Outcome of untreated meningiomas. AB - BACKGROUND: Nowadays meningiomas are frequently detected incidentally. Their natural history has not yet been established because it is difficult to predict the growth pattern. Therefore, the management, after the radiological diagnosis, is still controversial. OBJECTIVES: To evaluate the clinical outcome and growth rate of conservatively treated meningiomas at our tertiary center, identify prognostic factors of tumor growth, and suggest guidelines based on the available data and our experience. METHODS: We reviewed the clinical records of 56 patients with 63 untreated meningiomas. Most were diagniosed incidentally. Clinical features and imaging findings at diagnosis and during follow-up were compared between growing and non-growing tumors. Potential patient- and tumor-related predictive factors for growth were analyzed. RESULTS: The study group included 46 women (52 meningiomas) and 10 men (11 meningiomas) aged 39-83 years. Mean tumor size was 18 +/- 11 mm (range 3-70 mm) at diagnosis and 22 +/- 11 mm (range 8-70 mm) at last follow-up; mean follow-up time was 65 +/- 34 months (range 15-152 months). During follow-up 24 tumors (38%) grew ata rate of 4 mm per year; none became symptomatic. Only two prognostic factors were statistically significantly associated with low growth rate: older age and tumor calcifications. CONCLUSIONS: Given our finding of a low growth incidence of meningiomas in the elderly, we support conservative management in patients aged 70 years or older. Calcifications into the meningioma are also indicative of slow growth, suggesting a conservative strategy. Surgery is recommended in younger patients in whom tumor growth occurs more often and a longer follow-up is necessary. PMID- 21608337 TI - Treatment of T cell lymphoblastic lymphoma in children and adolescents: Israel Society of Pediatric Hematology Oncology retrospective study. AB - BACKGROUND: Survival in T cell lymphoblastic lymphoma has improved over the past 30 years, largely due to treatment protocols derived from regimens designed for children with acute lymphoblastic leukemia. OBJECTIVES: To assess the outcome of the NHL-BFM-95 protocol in children and adolescents hospitalized during the period 1999-2006. METHODS: We conducted a retrospective multi-institutional, non randomized study of children and adolescents up to age 21 with T cell lymphoma admitted to pediatric departments in six hospitals in Israel, with regard to prevalence, clinical characteristics, pathological characteristics, prognostic factors, overall survival (OS) and event-free survival (EFS). All patients had a minimal follow-up of one year after diagnosis. The study was based on the NHL-BFM 95 protocol. RESULTS: At a median follow-up of 4 years (range 1-9 years), OS and EFS for all patients was 86.5% and 83.8%, respectively. OS was 86.7% and 83.3% for patients with stage III and stage IV, respectively, and EFS was 83.3% and 83.3%, respectively. EFS was 62.5% for Arab patients and 89.7% for Jewish patients (P = 0.014). Patients who did not express CD45 antigen showed superior survival (P = 0.028). Five patients (13.5%) relapsed, four of whom died of their disease. Death as a consequence of therapy toxicity was documented in one patient while on the re-induction protocol (protocol IIA). CONCLUSIONS: Our study shows that OS and EFS for all patients was 86.5% and 83.8%, respectively. PMID- 21608338 TI - Predictors and mechanisms of oncological failure following nephron-sparing surgery for renal cancer. AB - BACKGROUND: One of the major concerns in performing nephron-sparing surgery (NSS) for renal cell carcinoma (RCC) is the risk of tumor recurrence. OBJECTIVES: To assess the rate, predictors and mechanisms of oncological failure in patients after NSS for renal cancer. METHODS: Between 1993 and 2008 NSS was performed in 229 patients via flank incision. Only patients without metastases at diagnosis and minimal 12 months follow-up were included in the outcome analysis. RESULTS: During a mean follow-up of 45 +/- 34 months (range 6-168 months) tumor recurrence was observed in 13 patients (5.6%). Mean follow-up time for detection of oncological failure was 51 months (range 6-132 months). All patients with oncological failure were males, with a mean age of 61 years (median 58, range 51 74 years). The average size of the enucleated lesion was 5 cm (range 4-7 cm). Intraoperative frozen sections as well as postoperative final pathological examination of the surgical margins were negative in all recurrent cases. Mechanisms of recurrence were distant metastases (n=4), surgical scar implantation (n=2), perirenal fat recurrence (n=2), local renal recurrence at the surgical site (n=1), and new renal lesions (n=4). Predictors of oncological failure included warm ischemia time (P = 0.058), tumor size (P = 0.001), tumor location (central versus peripheral) (P = 0.015), and multifocality (P = 0.001). CONCLUSIONS: Distant dissemination, seeding during surgery, residual disease and new growth are the mechanisms responsible for cancer relapse. Large central lesions, long warm ischemia time and multifocality were significant predictors of oncological failure. PMID- 21608339 TI - Magnetic resonance enterography: 4 years experience in a tertiary medical center. AB - BACKGROUND: Assessment of small intestinal disease remains a challenge for both clinicians and radiologists. Modern magnetic resonance enterography (MRE) is a nonradiation modality that can demonstrate both intestinal wall pathologies and extraluminal lesions. OBJECTIVES: To analyze the results of 213 MRE scans performed since 2005. METHODS: Consecutive MRE scans performed in our academic medical center between December 2005 and November 2009 were reviewed for patients' demographic data, indications for the examination, and main imaging findings. The imaging signs recorded were mural changes, intraluminal filling defects as well as mesenteric and extraintestinal inflammatory findings. RESULTS: During the study period 213 MRE scans were performed; 70% of them for proven or suspected Crohn's disease (CD) of the small bowel. Another indication was small bowel neoplasm (6% of the scans). Bowel wall thickening and enhancement were seen in 60% and 53% of MRE scans, respectively. Mesenteric involvement was found in 52% of the patients. Incidental extraintestinal findings were detected in 17% of the scans. In 22% of the scans there was no pathological finding. CONCLUSIONS: In our 4-year clinical experience with MRE this non-invasive and non-radiating modality proved to be a reliable technique for the evaluation and long-term follow-up of small bowel pathologies. The most common clinical indication was the evaluation of Crohn's disease. With physicians' increased awareness, the use of MRE in the evaluation of other small bowel pathologies such as neoplasm and celiac disease will increase. curate assessment of small intestinal disease remains c a challenge for both clinicians and radiologists. Until a decade ago, the modality most used to examine the small bowel in its entirety was barium based techniques, such as neoplasm and celiac disease will increase. PMID- 21608340 TI - Addressing the needs of children and families in Israel: strengthening community pediatrics. PMID- 21608341 TI - Extensive epidermal necrosis due to terlipressin. PMID- 21608342 TI - Pathogenic role of aquaporin antibodies in the development of neuromyelitis optica in a woman with celiac disease. PMID- 21608343 TI - Bilateral, simultaneous rupture of the quadriceps tendon associated with simvastatin. PMID- 21608344 TI - Laparoscopic resection of gastric Dieulafoy lesion following preoperative tattooing. PMID- 21608345 TI - Severe weight loss in a young Parkinson's disease patient: a multidisciplinary approach to diagnosis and treatment. PMID- 21608346 TI - Fabry disease in an oligosymptomatic male. PMID- 21608347 TI - Security and psychiatry. PMID- 21608348 TI - Government financing of health in India. PMID- 21608349 TI - Hype, hope and myths of malaria control: are the mortality estimates correct? PMID- 21608351 TI - Prevalence and pattern of substance use among the higher secondary school students of Imphal, Manipur, India. AB - BACKGROUND: Substance use often begins in adolescence. We did a study to describe substance use and its associated factors among adolescent students in Imphal. METHODS: We defined substance use as the use of licit and illicit substance other than when medically indicated. Using a WHO self-administered questionnaire, we collected Information about substance use from 61 randomly selected students of 1 7 government/private higher secondary schools. We calculated the prevalence of substance use according to selected characteristics. RESULTS: We surveyed 1020 students, 551 of whom reported prior substance use (prevalence of ever use: 54%, 95% confidence interval [CI] 42%-67%). Prevalence of recent and current user was 35% (95% CI 28%-43%) and 22% (95% CI 17%-28%), respectively. Among ever users, tobacco (46%) was used most commonly, followed by alcohol (29%), cannabis (14%) and opiates (12%). On multivariate analysis, substance use was significantly higher among boys (adjusted odds ratio [AOR] 2.6, 95% CI [2.0-3.4]), whose father (AOR 2.0, 95% CI 1.6-2.7) or sibling (AOR 2.1, 95% CI 1.5-3.0) used substance. It was significantly lower among children of Hindu/Jain religion (AOR 0.5, 95% CI 0.4-0.7). CONCLUSION: Prevalence of tobacco and alcohol use was high among students. Familial use of substances was associated with the behaviour of adolescents. Friends were the key proximal determinant. We recommend Introducing a substance use prevention policy in schools to educate students about various adverse effects and to impart refusal skills. PMID- 21608350 TI - Under-nutrition among adolescents: a survey in five secondary schools in rural Goa. AB - BACKGROUND: This study was done in 2008-09 to assess the nutritional status among adolescents (10-19 years of age, Classes V-XII) in 5 schools in rural Goa to inform the content of a health promotion intervention in these schools. METHODS: Three methods were used. First, nutritional status was measured by assessing body mass index among 1015 students during a health camp in each school. Second, a diet analysis was done to measure energy and protein Intake of 76 randomly selected underweight students. Third, a self-report questionnaire survey measured the prevalence of hunger among 684 students. RESULTS: One-third of students (338; 37.8% boys and 27.5% girls) who attended the health camps were underweight and 59.2% of the 684 students who completed the survey reported experiencing hunger due to inadequate food consumption. More boys were underweight than girls (p<0.001) and under-nutrition was uniform across all the years of schooling. Energy intake of underweight students was significantly lower than the recommended daily allowance. The results were shared with the School Health Promotion Advisory Boards to generate information on the stakeholders' perception about the issue and ways to address it. CONCLUSION: There is an immediate need to address the high burden of hunger and under-nutrition in adolescents of both sexes in schools by instituting routine annual monitoring of nutritional status, extending the mid-day meal programme to all school-going adolescents, providing nutritional counselling for underweight adolescents and expanding research on the causes and impact of under-nutrition and evaluation of the impact of the enhanced mid-day meal programme. PMID- 21608352 TI - Prevalence of diabetes mellitus in a rural population of Goa, India. AB - BACKGROUND: We aimed to estimate the prevalence of diabetes mellitus and study the associated factors in a rural population in Goa, India. METHODS: A cross sectional study was done in the rural area of Mandur, Goa. Participants>20 years of age were selected by systematic random sampling. They were interviewed with the help of a structured, pretested questionnaire. This was followed by clinical examination, anthropometry and relevant laboratory investigations. Diabetes mellitus was defined as per the American Diabetes Association (ADA) criteria. Statistical analysis was done using the SPSS software package (version 14.0). RESULTS: The prevalence of diabetes mellitus in the study population was 10.3% (130/1266) with a prevalence of 8.4% among men and 12% among women. On bivariate analysis, the prevalence of diabetes mellitus was found to be significantly associated with age, occupation, family income, family history of diabetes, smoking, obesity, hypertension, and high serum cholesterol and triglycerides levels. Multiple logistic regression analysis identified age, family history, hypertension, smoking, total cholesterol and triglyceride as the Independently associated variables for diabetes mellitus. CONCLUSION: Innovative community outreach programmes are required to create awareness, and for screening and treatment of diabetes mellitus to curb the growing epidemic of diabetes in the population. PMID- 21608353 TI - Primary haemophagocytic syndrome in a young girl. AB - Haemophagocytic syndrome is a life-threatening systemic illness characterized by an uncontrolled inflammatory response. Patients present with fever, hepatosplenomegaly, jaundice and liver dysfunction, neurological manifestations and often pancytopenla. Bone marrow, lymph node, hepatic or splenic biopsy shows macrophages with Ingested blood cells or their precursors. Laboratory markers include elevated triglycerides and ferritin, low fibrinogen with normal or low erythrocyte sedimentation rate (ESR). Familial haemophagocytic lymphohistiocytosis (HLH) is an autosomal recessive disorder. Secondary haemophagocytic syndrome results from infections, malignancy and collagen vascular disorders. We describe a young girl with primary haemophagocytic syndrome. PMID- 21608355 TI - What is the best approach to treat invasive fungal infection in haematological malignancies? PMID- 21608354 TI - Intensive glycaemic control in type 2 diabetes mellitus: does it improve cardiovascular outcomes? AB - With growing urbanization and economic development, there is a rapid increase in the incidence of type 2 diabetes mellitus (T2DM) in India. T2DM is associated with 2-4 times higher risk for cardiovascular disease (CVD), including coronary artery disease, stroke and peripheral vascular disease. Several studies have shown the benefit of intensive glycaemic control in reducing the frequency of diabetic microvascular complications such as retinopathy and nephropathy. Results of long term follow up of patients with diabetes, who were enrolled in earlier trials, have shown that initial intensive glycaemic control led to a reduction in CVD outcomes when compared with standard therapy. However, it is unclear if intensive glycaemic control, aiming to reduce haemoglobin A1c to levels even lower than the current goal of <7%, will similarly lead to reduction in the rates of CVD. Recently, the results of 3 large, randomized controlled trials have been published, which suggest that in established T2DM with previous CVD or high risk of CVD, the benefits of intensive glycaemic control when compared with conventional good control, are minimal with regards to reduction of cardiovascular outcomes. Intensive therapy increases the risk of side-effects such as severe hypoglycaemia and weight gain. The implementation of such a therapy, with rigorous attention to frequent monitoring of blood glucose and visits to the physician, is not likely to be possible on a large scale, especially in a developing country such as India. The aim of management of patients with established T2DM should be to achieve the goal of good glycaemic control (haemoglobin A1c<7%), with avoidance of hypoglycaemia. It is equally, if not more important, to control other risk factors of CVD by paying greater attention to lifestyle measures (weight loss if overweight or obese, regular exercise, cessation of smoking), rigorous control of blood pressure (<130/80 mmHg) and low density lipoprotein (LDL) cholesterol (<100 mg/dl or <70 mg/dl if already diagnosed with CVD) and the prophylactic use of low dose aspirin as per current recommendations. A multifactorial approach targeting multiple cardiovascular risk factors is likely to be most effective in reducing CVD outcomes in T2DM. PMID- 21608356 TI - Hepatitis E: another effective vaccine, but will it make a difference? PMID- 21608357 TI - High body mass index and alcohol intake increase deaths due to liver disease. PMID- 21608359 TI - PG entrance for dummies. (Are you looking for a postgraduate seat?). PMID- 21608358 TI - Bachelor of rural health care: do we need another cadre of health practitioners for rural areas? PMID- 21608360 TI - Follow the dirty money. PMID- 21608361 TI - The ageing physician. PMID- 21608362 TI - Tough times ahead for the NHS in Scotland. PMID- 21608363 TI - The importance of 'evidence-based debate'. PMID- 21608364 TI - Heart failure in India: an area of darkness. PMID- 21608366 TI - Commerce helps public health: the Mother Dairy example. PMID- 21608365 TI - Do we need to do the calcium profile in the fasting state and without a tourniquet? PMID- 21608367 TI - Calf muscle injury due to dog bite leading to deep vein thrombosis: a rare case. PMID- 21608368 TI - Reforms in undergraduate medical education. PMID- 21608369 TI - Patient safety during CT brain perfusion scans. PMID- 21608370 TI - Taste disturbances during therapy with pegylated interferon-alpha 2b and ribavirin in patients with chronic hepatitis C. AB - INTRODUCTION: The effectiveness of current standard therapy of chronic hepatitis C with pegylated interferon-alpha and ribavirin is unsatisfactory and associated with a variety of side effects. In addition to common side effects, appetite disorders and weight loss are universal problems that lead to decreased quality of life. The causes of appetite disorders are not known. The aim of the present study was to evaluate the influence of pegylated interferon-alpha 2b and ribavirin therapy on taste sensitivity, hedonic perception of taste sensations, and food preferences. MATERIAL AND METHODS: Nineteen chronic hepatitis C patients infected with genotype 1 HCV participated in the study. All patients received combined therapy with pegylated interferon-alpha 2b and ribavirin in adequate doses. The study included gustatory tests (taste recognition threshold and taste intensity with hedonic perception) using a gustometric method and an evaluation of the pleasure derived from eating. All examinations were performed before therapy and during the thirteenth week of therapy. RESULTS: After 12 weeks of therapy, patient sensitivity to salty and sweet was significantly decreased (p < 0.05), and bitter was described as being more unpleasant than before the therapy (p < 0.05). Also, the therapy decreased appetite without significant changes in patients' food preferences. CONCLUSIONS: We found multidirectional taste disturbances during treatment with pegylated interferon and ribavirin. The results may be useful in determining the role of taste in the development of appetite disorders in chronic hepatitis C patients treated with pegylated interferon and ribavirin. PMID- 21608371 TI - Cereal pollen sensitisation in pollen allergic patients: to treat or not to treat? AB - Pollen allergens of the Poaceae family comprise one of the main causes of pollinosis worldwide. Although most of cereals are included in this family, certain pollination characteristics and aerobiological features differentiate them from common wild grass pollen. Cereal pollen grains cannot be easily characterised as potential sources of aero allergens, because of their pollination mode (most of them are autogamous plants), the consecutive low numbers of pollen they produce and their pollen's large volume and consequent high weight which further prevent dispersion and pollen transport. However, various epidemiologicalstudies concluded in comparable sensitisation patterns between common grass and cereal pollen. This fact can be attributed to the common epitopes shared between grass and cereal pollen allergens, which are responsible for the high cross reactivity observed not only in vitro but also in vivo. Therefore, the sensitisation patterns do not usually reflect a genuine, cereal specific IgE recognition. On the contrary, genuine cereal sensitisation and allergy are referred to only in rare cases of occupational exposure to high amounts of these pollen grains (farmers and field workers) or in patients staying in the vicinity of cereal fields. Thus, cautious considerations should be taken into account when diagnostically approaching patients in which cereal pollen allergy could be considered in the differential diagnosis. PMID- 21608372 TI - Cost-utility of add-on omalizumab in difficult-to-treat allergic asthma in Italy. AB - OBJECTIVE: Omalizumab (OM), an innovative biological treatment for difficult asthma with perennial sensitisations, is an humanized monoclonal anti-IgE antibody that binds free circulating IgE; inhibits mast cell and basophil activation by combining free IgE, leads to IgE receptor down-regulation, thus blocking the inflammatory cascade. AIM OF THE STUDY: To assess real-world cost utility ofadd-on OM in Italy. METHODS: changes in clinical and economical outcomes, and in quality of life (QoL) associated with add-on OM in adults (n=23) with severe dfficult asthma were compared with those recorded before OM in the same subjects. Variables were: lung function; IgE levels; health status; ACT score; QoL (SGRQ); n. GP and specialist visits; emergency visits; hospitalizations, and concomitant pharmacological treatments. Further indices were: changes in Health-related QoL; total health-care costs, and incremental cost/utility. Data were statistically compared (Student's T test), and p < 0.01 was accepted for statistical significance. RESULTS: asthma clinical outcomes and patients' health-related quality of life improved significantly by adding OM, and both costs for drugs and hospital care dropped significantly (p < 0.01). The net economic effect was a 350 Euro increase in overall monthly costs; when related to health benefits, it corresponded to an incremental cost/utility ratio ofabout 26,000 Euro/QALY, which represents a quite favourable figure in terms of willingness to pay for health benefits in industrialised countries. CONCLUSIONS: Omalizumab added to an optimised therapy significantly improves clinical outcomes in difficult-to-treat, persistent allergic asthma. Costs also increased, but proved justified by health benefits achieved. PMID- 21608373 TI - Analysis of the allergenic profile of patients hypersensitive to pollen pan allergens living in two distinct areas of northern Italy. AB - BACKGROUND: The allergenic profile of patients hypersensitive to pollen pan allergens, profilin and polcalcin, has received little attention so far. OBJECTIVE: To detect whether hypersensitivity to profilin and polcalcin follows sensitization to specific allergen sources or represents a primary phenomenon, and to examine the sensitization profiles of patients hypersensitive to pollen pan-allergens. METHODS: IgE reactivity to markers of primary sensitisation to different pollen species including grass, mugwort, ragweed, pellitory, birch, olive, and cypress was detected in sera from 106 pollen-allergic subjects, 86 sensitised to profilin and 29 to polcalcin living in two distinct areas of Northern Italy. RESULTS: In profilin hypersensitive patients the primary sensitizer was detected in 24/86 (28%) cases: grass (n=15), ragweed (n=7), and birch (n=2). In 62 (72%) cases the primary sensitizing pollen was not detectable. In the polcalcin group the primary sensitizing pollen was detected in 8/29 (28%) cases: grass (n=6), ragweed and pellitory (1 each). All ragweed-allergic subjects were from the Milan area. In the 9 patients hypersensitive to both panallergens the primary sensitizing source could be identified in 2 (23%) cases (grass in both cases). CONCLUSION: A putative primary sensitizer to pollen pan-allergens can be detected only in 1/4 of cases, as most patients show IgE specific for >1 pollen species. In these patients the prevalence of the primary sensitizer parallels the prevalence of clinical allergy to the different pollen sources in that specific geographic area. Most pollen sources are probably able to cause sensitization to cross-reacting pollen pan-allergens. PMID- 21608374 TI - Safety of ultrashort-term sit with pollen allergoids adjuvanted by monophosphoryl lipid A: a prospective Italian survey. AB - A 3-year prospective post marketing survey on the safety of the recently developed ultrashort pre-seasonal subcutaneous immunotherapy (uSCIT-MPL4) with pollen allergoids adjuvanted with monophosphoryl lipid A was performed. A total of 510 patients received uSCIT-MPL4, 61% for grass, 35.7% for birch, 13.2% for parietaria and 3% for other pollens (ragweed, mugwort, and olive). A total of 3308 injections were given and the mean duration of uSCIT-MPL-4 was 2.3 years. Overall, only 7 slight systemic reactions (SR) were observed in 510 patients (1.37%) and 2.11/1000 injections suggesting that this treatment is even safer than traditional depot injection SIT. PMID- 21608375 TI - Can food protein induced enterocolitis syndrome shift to immediate gastrointestinal hypersensitivity? A report of two cases. AB - Food protein induced enterocolitis syndrome (FPIES) is a food-related non-IgE mediated gastrointestinal hypersensitivity disorder. Atypical FPIES is characterized by the presence of specific IgE for the causative food. The guidelines suggested for diagnostic oral food challenge in pediatric patients affected by suspected FPIES are different from the ones for children with IgE mediated food allergy. We describe two cases of atypical FPIES that turned into IgE-mediated gastrointestinal anaphylaxis. Our experience suggests to adapt OFC according to the outcome of specific IgE for the causative food When causative food-related IgE werepositive, we suggest to follow the guidelines for IgE mediated food allergy. PMID- 21608376 TI - Is there a need for heroin substitution treatment in Vancouver's Downtown Eastside? AB - The North American Opiate Medication Initiative (NAOMI) was a randomized controlled trial conducted in Vancouver and Montreal comparing heroin substitution treatment (HST) to methadone treatment (MT) for heroin addicts. The HST group had a higher treatment retention rate and lower illicit heroin use than the MT group. Despite the rigour with which the study was designed, systematic flaws have affected the interpretation of the results. In the MT arm, the dose was titrated slowly, contributing to the high early dropout rate. The mean maintenance dose was suboptimal. The investigators did not calculate on-treatment retention rates; by the end of the trial, more subjects were on MT than HST. Life threatening events were more common in the HST than the MT group. Overall, the only clear advantage of HST over MT was its greater initial treatment attractiveness, resulting in more early drop-outs in the MT group. HST is intended for treatment-refractory addicts who have no other option but to use street heroin. Yet for most NAOMI subjects, the safest and most cost-effective approach is comprehensive MT or buprenorphine with optimal dosing, flexible program policies, and the provision of integrated primary care and social services. These proven strategies, currently lacking in Vancouver's Downtown Eastside, should be implemented before diverting already insufficient resources to HST, given its risks, cost and uncertain efficacy. PMID- 21608377 TI - Is there a need for heroin substitution treatment in Vancouver's Downtown Eastside? Yes there is, and in many other places too. AB - The prescription of medically-supervised diacetylmorphine, the active ingredient in heroin, to individuals with treatment-refractory opioid dependence is a controversial and often politically charged subject. Just as methadone maintenance was opposed in the 1960s by some treatment providers who preferred abstinence-based therapies, heroin-assisted therapy is now being opposed by some methadone treatment providers--this despite the fact that the effectiveness of heroin-assisted treatment has been demonstrated in no less than six randomized trials in Switzerland, the Netherlands, Spain, Germany, Canada and the UK. The North American Opiate Medication Initiative (NAOMI) trial in Canada clearly showed heroin-assisted therapy to be superior to methadone in individuals with chronic, treatment-refractory heroin addiction both in terms of retention in addiction treatment and clinical response. An international internal review panel, three Research Ethics Boards, the CIHR RCT review panel, the Therapeutic Products Directorate of Health Canada, and several journal peer-reviewers reviewed the NAOMI trial. Nevertheless, authors of a commentary in this issue of CJPH find fault with the trial in terms of methadone prescribing, use of intention-to-treat analysis, safety and cost. We take this opportunity to respond to the numerous misconceptions and errors in their commentary. PMID- 21608378 TI - All-cause and HIV-related mortality rates among HIV-infected patients after initiating highly active antiretroviral therapy: the impact of Aboriginal ethnicity and injection drug use. AB - BACKGROUND: Aboriginals are over-represented in Canada's HIV epidemic and are commonly infected with HIV via injection drug use (IDU); however, little is known about the impact of Aboriginal ethnicity on mortality after starting highly active antiretroviral therapy (HAART). Therefore, we compared mortality rates between Aboriginal and non-Aboriginal HIV patients and between IDU and non-IDU HIV patients after they initiated HAART. METHODS: We conducted a retrospective cohort study of antiretroviral-naive patients starting HAART January 1999-June 2005 (baseline), followed until December 2005. We constructed two Cox proportional hazards models, one to estimate all-cause and one to estimate HIV related mortality hazard ratios (HRs), considering sex, and baseline age, CD4 cell count, HIV RNA level, calendar year, and HAART regimen as potential confounders. RESULTS: The 548 study patients were followed for 1,889.8 person years; 194 (35%) were Aboriginal, 255 (46%) were IDUs. We observed 55 deaths; 47% were HIV-related. In multivariable models, Aboriginals experienced higher all cause (HR = 1.85, 95% CI = 1.05-3.26, p = 0.034) and HIV-related (HR = 3.47, 95% CI = 1.36-8.83, p = 0.009) mortality rates compared to non-Aboriginals; and, compared to patients with other exposures, IDUs experienced higher all-cause (HR = 2.45, 95% CI = 1.31-4.57, p = 0.005) but similar HIV-related (p = 0.27) mortality rates. CONCLUSIONS: Compared to non-Aboriginals, Aboriginal HIV patients suffer higher all-cause and HIV-related mortality rates after starting HAART. The strongest and most significant predictor of higher all-cause mortality was IDU. Future research should examine reasons for the observed poorer survival of Aboriginal and IDU HIV patients after initiating HAART to develop interventions to improve the prognosis for these vulnerable populations. PMID- 21608380 TI - Factors associated with different cigarette access behaviours among underage smoking youth who usually smoke contraband (native) cigarettes. AB - OBJECTIVES: Given that little is known about how youth access contraband cigarettes, the current study seeks to examine factors associated with how underage smoking youth report usually accessing contraband cigarettes. METHODS: This study used nationally representative data collected from 41,886 students (grades 9 to 12) as part of the 2006-07 Canadian Youth Smoking Survey (YSS). Using data from current smokers who report that their usual brand of cigarettes is contraband, three logistic regression models were used to examine factors associated with buying cigarettes from a store, getting cigarettes from a family member, or getting cigarettes from friends or strangers. RESULTS: In 2006, 7.9% (n = 1 3,300) of Canadian youth who were current smokers reported that their usual brand of cigarettes was contraband. Among these youth, the majority reported that they usually get their cigarettes from a friend or stranger (54.8%), whereas 26.4% report usually getting them from a family member and 18.8% usually buying their own from a store. Boys were more likely to buy contraband cigarettes from a store, whereas youth with a parent who smokes contraband cigarettes were substantially more likely to get contraband cigarettes from a family member and youth with friends who smoke contraband cigarettes were substantially more likely to get contraband cigarettes from a friend or stranger. CONCLUSION: Ongoing surveillance of contraband cigarette use among youth and how youth access contraband cigarettes is required for guiding future tobacco control policy and programming activities. PMID- 21608379 TI - Hepatitis C infection among pregnant women in British Columbia: reported prevalence and critical appraisal of current prenatal screening methods. AB - BACKGROUND: Despite the fact that hepatitis C virus (HCV) is a relatively common infection in Canada, particularly in British Columbia (BC), there is a paucity of information on actual HCV prevalence in pregnant women. At present, pregnant women are only screened if they fit risk criteria, which may result in under identification of HCV in this population. The purpose of this study was to determine the overall prevalence rate, age and geographic distribution of reported HCV infection among pregnant women in BC, and compare results to a previously conducted anonymous seroprevalence survey. METHODS: Reported HCV prevalence was determined through a confidential database linkage of all prenatal screening results at the Canadian Blood Services (CBS) with all HCV test results at the Provincial Laboratory, from May 2000 to Oct 2002. Data were stratified by age group and geographic location, and subsequently compared to an anonymous prenatal seroprevalence survey conducted in 1994. RESULTS: The overall HCV prevalence rate was 50.3/10,000 (95% CI 46.3-54.6), or 0.5% of the cohort. Prevalence was highest in the northern BC region (66.2/10,000, 95% CI 51.4-85.3) and lowest in the populous suburban region southwest of Vancouver (38.0/10,000, 95% CI 32.3-44.8). Of note, the rate of reported HCV among pregnant women was significantly lower than the anonymous seroprevalence rate: 50.3/10,000 vs. 91.3/10,000 (p < 0.0001). CONCLUSION: Rates of reported HCV among pregnant women were approximately 50% lower than the rates determined by the anonymous seroprevalence survey. Further research is needed to determine the relative merits of the current selective screening policy versus universal prenatal HCV screening in pregnancy. PMID- 21608381 TI - Trends in duration of hospitalization for patients with tuberculosis in Montreal, Canada from 1993 to 2007. AB - OBJECTIVE: To study the trend of hospital stays for patients diagnosed with pulmonary TB in Montreal from 1993 to 2007. METHODS: From the registry of hospital discharge summary information, we selected first hospitalizations for patients with a diagnosis of TB, and from the reportable diseases registry, patients with culture positive pulmonary TB. We linked the selected cases, using the first 3 characters of postal code of residence, sex and age. From the linked cases, we included those for whom date of patient's admission to hospital (from the former registry) was similar to the date of notification to the public health department (from the latter registry), while allowing for an appropriate variation. RESULTS: Among the 563 linked cases, the median duration of hospitalization was 17.0 days. Duration of hospitalization did not significantly decrease during the study period. Cases with positive sputum smear were more likely to stay in hospital > or = 14 days compared to those without one (OR = 1.90, 95% CI: 1.34-2.70). TB cases > or = 50 years of age remained in hospital longer than those between 18-49 years of age (OR = 1.66, 95% CI: 1.15-2.40). CONCLUSION: For 63.9% (360) of the cases studied, the duration of hospitalization was > or = 14 days, which is consistent with the minimum recommended hospital stay for patients with pulmonary TB in Canada. Further studies are necessary to examine the impact of discharging hospitalized TB patients before 14 days of hospital stay on the risk of TB transmission in the community. PMID- 21608382 TI - A holistic model for the selection of environmental assessment indicators to assess the impact of industrialization on indigenous health. AB - OBJECTIVES: Mainstream environmental assessment (EA) methodologies often inadequately address health, social and cultural impacts of concern for Canadian indigenous communities affected by industrialization. Our objective is to present a holistic, culturally-appropriate framework for the selection of indigenous health indicators for baseline health assessment, impact prediction, or monitoring of impacts over time. METHODS: We used a critical population health approach to explore the determinants of health and health inequities in indigenous communities and conceptualize the pathways by which industrialization affects these determinants. We integrated and extended key elements from three indigenous health frameworks into a new holistic model for the selection of indigenous EA indicators. RESULTS: The holistic model conceptualizes individual and community determinants of health within external social, economic and political contexts and thus provides a comprehensive framework for selecting indicators of indigenous health. Indigenous health is the product of interactions among multiple determinants of health and contexts. Potential applications are discussed using case study examples involving indigenous communities affected by industrialization. CONCLUSION: Industrialization can worsen indigenous health inequities by perpetuating the health, social and cultural impacts of historic environmental dispossession. To mitigate impacts, EA should explicitly recognize linkages between environmental dispossession and the determinants of health and health inequities and meaningfully involve indigenous communities in the process. PMID- 21608383 TI - Lead in school drinking water: Canada can and should address this important ongoing exposure source. AB - Reducing all preventable lead exposures in children should be a public health priority given that blood lead levels in children that were once considered "safe" have since been associated with important neuro-developmental deficits. Limited Canadian data indicate that school drinking water can be an important component of children's overall exposure to lead. Outside of Ontario, however, Canadian schools are not required to test for lead in water; in most of Canada, school testing is case by case, typically initiated by parental concerns. Provinces and territories are encouraged to follow Ontario's example by instituting a routine school water lead testing program in order to identify facilities where action can result in a decrease in students' exposure to lead. Testing and remediation frameworks developed by the US Environmental Protection Agency, Health Canada, and the province of Ontario provide direction to school boards and local and provincial/territorial health authorities. PMID- 21608384 TI - Perceived health status of Francophones and Anglophones in an officially bilingual Canadian province. AB - OBJECTIVE: It has been reported that being part of a minority group may be negatively associated with self-perceived health. The objective of this analysis was to determine whether there are differences in perceived health between the Francophone minority and Anglophone majority in New Brunswick, the only officially bilingual province in Canada. METHODS: Data from the first four primary cycles of the Canadian Community Health Survey (2001 to 2007) were obtained for 17,729 New Brunswick residents. Odds of reporting good health among Francophones and Anglophones were compared using multivariate logistic regressions accounting for age, health-related behaviours, socio-demographic variables, and medical conditions. RESULTS: In the final models, Francophone men and women were less likely than Anglophones to report their health as being good, although these differences were not statistically significant (Odds ratio, 95% confidence interval: 0.88, 0.61-1.26; 0.71, 0.49-1.04, in men and women, respectively). CONCLUSION: This study suggests that being part of the linguistic minority in New Brunswick is not associated with statistically significant differences in self-perceived health. PMID- 21608386 TI - Bicycle helmet use after the introduction of all ages helmet legislation in an urban community in Alberta, Canada. AB - BACKGROUND: Bicycle trauma is a common cause of recreational death and disability and helmets have been shown to reduce fatal and non-fatal head and face injuries. This study evaluated the effect of mandatory bicycle helmet legislation for all ages in St. Albert, Alberta. METHODS: We observed bicyclists from June to September of 2006 in St. Albert, a community subject to both provincial (< 18 years old) and municipal (all ages) helmet legislation, and compared our results with observations taken in 2000 when no legislation existed. Helmet wearing and rider characteristics were recorded by trained observers. Poisson regression analysis was used to obtain helmet prevalence (HP) and prevalence ratio (PR) estimates. RESULTS: HP increased from 45% to 92% (PR = 2.03; 95% CI: 1.72-2.39) post-legislation. Controlling for other covariates, children were 53% (PR = 1.53; 95% CI: 1.34-1.74) and adolescents greater than 6 times (PR =6.57; 95% CI: 1.39 31.0) more likely to wear helmets; however, adults (PR = 1.26; 95% CI: 0.96-1.66) did not show a statistically significant change post-legislation. Restricting the analysis to high socio-economic status areas, adult helmet prevalence increased in St. Albert from 58% to 73% post-legislation compared with a 52% to 57% change across the province; this effect was not statistically significant. CONCLUSIONS: Helmet legislation in St. Albert was associated with a significant increase in helmet use among child and adolescent cyclists. A larger increase in HP was observed for adults in St. Albert than in other areas of the province; however, this difference was not statistically significant, which may reflect the small sample size or insufficient time passage after bylaw enactment. PMID- 21608385 TI - Examining changes in reported work conditions in Quebec, Ontario and Saskatchewan between 1994 and 2003-05. AB - OBJECTIVES: To examine changes in work hours, work schedules, the psychosocial work environment and job satisfaction in three Canadian provinces between 1994 and 2003-05. METHODS: The study sample consisted of 46,998 respondents over four cross-sectional surveys: 1994, 2000 and 2003/05 in Quebec, Ontario and Saskatchewan. Using regression models, we examined trends in work conditions across survey cycles both unadjusted, and after adjustment for differences in age, education, gender, immigration, and method of interview. RESULTS: Crude models observed increases in rotating shifts, long work hours and job security between 1994 and 2003-05, and decreases in physical demands and job satisfaction. When models were adjusted for changes in labour market demographics and educational capacity, we further observed decreases in skill discretion, decision authority, co-worker support and in regular scheduled work across survey cycles. We also noted differences in trends for two outcomes (decision authority and co worker support) depending on interview method. CONCLUSIONS: Employees in Quebec, Ontario and Saskatchewan were more likely to be working longer hours, at non standard time during the week, and to be less satisfied with their jobs between 1994 and 2003/05. In addition, it appears the labour market in these provinces has not adjusted sufficiently to accommodate the increasing number of workers with high levels of education and increasing age, with declines observed in decision authority, skill discretion and co-worker support once these changes were taken into account. PMID- 21608387 TI - Sleep difficulties and obesity among preadolescents. AB - OBJECTIVE: To determine if sleep difficulties are associated with overweight/obesity status among preadolescents. METHODS: A total of 606 (288 males, 318 females) students, ages 11-13 years from southern Ontario, Canada, were included in this analysis. Overweight/obesity status was determined using age- and gender-specific criteria. Sleep difficulty status was determined if the parents reported children 'sometimes' or 'often' experiencing waking up at night, snoring or breathing loudly, and restlessness while sleeping. Logistic regression analysis was used to examine the association of childhood overweight status and sleep difficulties adjusting for age, gender, total physical activity score, total calories intake, maternal education level, and total hours of sleep. RESULTS: In this sample, 28% of children (76 boys and 95 girls) were identified as being overweight or obese. Relative to their normal-weight peers, overweight and obese individuals reported a higher prevalence of sleep difficulties (10.3% vs. 26.3%, p < 0.0001), reduced hours of sleep (9.4 vs. 9.2 hrs, p < 0.001), and a lower physical activity score (17.2 vs. 19.1, p < 0.01). Using a multiple logistic regression model, in comparison to children reporting none of the three sleep behaviour problems, the odds ratios (95% CI) of being overweight or obese for those having any one, two, or all three sleep behaviour problems were 1.04 (0.46-2.36), 1.35 (0.58-2.10), and 3.52 (1.42-8.74), respectively. CONCLUSIONS: The results suggest that the risk of overweight/obesity is associated with sleep difficulties among preadolescents. Further study is needed to determine the direction of this relationship. PMID- 21608388 TI - The cost of obesity and overweight in 2005: a case study of Alberta, Canada. AB - OBJECTIVE: The aim of this paper is to highlight the potential impact of costs associated with overweight and obesity for provincial policy and prevention initiatives. METHOD: Prevalence-based cost-of-illness methodology was used to estimate the direct costs (hospital care, drugs, physician care, institutional care, additional costs) and indirect costs (short- and long-term disability, premature mortality) associated with excess weight for 22 health conditions. Total costs for each health condition were estimated using the Public Health Agency of Canada's Economic Burden of Illness database. Population attributable fractions (PAF) were also estimated using 2004 and 2005 CCHS data and current literature reviews. RESULTS: In 2005, the cost of excess weight in Alberta totaled $1.27 billion. The direct cost of excess weight was $630.1M (49.5%), the indirect cost $643.8M (50.5%). Excluding costs associated with premature mortality and caregiving, obesity accounted for 69.5% ($500.8M) of costs and overweight the remaining 30.5% ($220.2M). Among the 22 health conditions, coronary heart disease had the highest costs attributable to excess weight ($307.1 M), followed by osteoarthritis ($167.7M) and type 2 diabetes ($161.5M). The total cost of excess weight equated to 5.6% of the province's annual health care expenditures for 2005. CONCLUSION: While obesity costing research often focuses on the direct health care costs, this study reveals that the indirect costs of excess weight are also significant and can account for over half of the total costs. Interventions to reduce excess weight among Canadians have the potential to improve the health of the population while reducing provincial and national health care costs. PMID- 21608389 TI - Grand Challenges Canada: inappropriate emphasis and missed opportunities in global health research? AB - In May 2010, Grand Challenges Canada (GCC) was launched with the mandate to identify global challenges in health that could be supported through the Government of Canada's Development Innovations Fund (DIF: $225 million over five years). The GCC offers a potentially excellent mechanism for taking Canada's participation in global health challenges "to a higher level". Recent GCC announcements raise new questions about the emphasis being placed on technological discovery or "catalytic" research. Missing so far are opportunities that the Fund could offer in order to support innovative research addressing i) health systems strengthening, ii) more effective delivery of existing interventions, and iii) policies and programs that address broader social determinants of health. The Canadian Grand Challenges announced to date risk pushing to the sidelines good translational and implementation science and early career-stage scientists addressing important social, environmental and political conditions that affect disease prevalence, progress and treatment; and the many unresolved challenges faced in bringing to scale proven interventions within resource-constrained health systems. We wish to register our concern at the apparent prioritization of biotechnical innovation research and the subordination of the social, environmental, economic and political context in which human health is either protected or eroded. PMID- 21608390 TI - Disability, displacement and public health: a vision for Haiti. AB - Refugees and internally displaced persons (IDPs) with disabilities are some of the most neglected and socially excluded groups within any population. Natural disasters are events that cause bodily harm resulting in disability and that result in the displacement of people. Many predict a continual increase of natural disasters in the future due to changing climates. People with disabilities constitute one of the most vulnerable social groups in the case of a natural disaster. In 2010, Haiti suffered a devastating earthquake leading to great social, health and economic hardship including the displacement of people with disabilities. Due to the very extent of the structural devastation Haiti experienced and the international focus on assisting Haitians who suffered injuries leading to disabilities, there is an opportunity for Haiti to become a model for future disaster management in terms of mainstreaming the needs of people with disabilities in the restoration, resettlement and reintegration process. PMID- 21608391 TI - Coming clean about nuclear power. Regulators and industry have one precious moment to recapture the public's trust. PMID- 21608392 TI - An epidemic of false claims. Competition and conflicts of interest distort too many medical findings. PMID- 21608393 TI - Hack my ride. Increasingly sophisticated onboard computers may put cars in danger of cyberattacks. PMID- 21608394 TI - The smallest hitchhikers. Marine microbes may hold the key to the ocean's disappearing plastic. PMID- 21608395 TI - Treating Tourette's. A gene mutation that causes low histamine levels may be behind some tic disorders. PMID- 21608396 TI - Spies inside. A new generation of electrodes is small and flexible enough to fit inside the heart or brain. PMID- 21608397 TI - No X-aggeration. How companies can gather information and still preserve privacy. PMID- 21608398 TI - How brains bounce back. After a traumatic injury, neurons that govern memory can regenerate. PMID- 21608399 TI - Shades of grief. PMID- 21608400 TI - Critical mass. PMID- 21608401 TI - Living in a quantum world. PMID- 21608402 TI - A test for consciousness. PMID- 21608403 TI - Planning for the black swan. PMID- 21608404 TI - A Nobel celebration. PMID- 21608405 TI - Inside the meat lab. PMID- 21608406 TI - The smartest bacteria on earth. PMID- 21608407 TI - The devil's cancer. PMID- 21608409 TI - "I stick to the the science". Interview by Michael D. Lemonick. PMID- 21608408 TI - Greater glory. PMID- 21608410 TI - The myth of the evil aliens. PMID- 21608411 TI - Use of tensorial description in tissue remodeling: examples of F-actin distributions in pulmonary arteries in hypoxic hypertension. AB - A molecular configuration tensor Pij was introduced to analyze the distribution of fibrous proteins in vascular cells for studying cells and tissues biomechanics. We have used this technique to study the biomechanics of vascular remodeling in response to the changes of blood pressure and flow. In this paper, the remodeling of the geometrical arrangement of F-actin fibers in the smooth muscle cells in rat's pulmonary arteries in hypoxic hypertension was studied. The rats were exposed to a hypoxia condition of 10% for 0, 2, 12, and 24 hr at sea level. Remodeling of blood vessels were studied at the in vivo state under normal perfusion, no-load state when small rings from blood vessels were excised, and zero-stress state after the rings were cut open radially to release the residual stress. Tissue remodeling in response to changes in blood pressure is reflected in the zero-stress state. The tensor components were determined by analyzing the configuration of phalloidin stained F-actin fibers in the media layer of pulmonary arteries. The values of P31, P32, P33 in the in-vivo state, the no-load state, and the zero-stress state are obtained. This study demonstrated the distributions of fibrous molecules in tissue remodeling can be described quantitatively using the molecular configuration tensor. PMID- 21608412 TI - A continuum model for pressure-flow relationship in human pulmonary circulation. AB - A continuum model was introduced to analyze the pressure-flow relationship for steady flow in human pulmonary circulation. The continuum approach was based on the principles of continuum mechanics in conjunction with detailed measurement of vascular geometry, vascular elasticity and blood rheology. The pulmonary arteries and veins were considered as elastic tubes and the "fifth-power law" was used to describe the pressure-flow relationship. For pulmonary capillaries, the "sheet flow" theory was employed and the pressure-flow relationship was represented by the "fourth-power law". In this paper, the pressure-flow relationship for the whole pulmonary circulation and the longitudinal pressure distribution along the streamlines were studied. Our computed data showed general agreement with the experimental data for the normal subjects and the patients with mitral stenosis and chronic bronchitis in the literature. In conclusion, our continuum model can be used to predict the changes of steady flow in human pulmonary circulation. PMID- 21608413 TI - Effect of meniscus replacement fixation technique on restoration of knee contact mechanics and stability. AB - The menisci are important biomechanical components of the knee. We developed and validated a finite element model of meniscal replacement to assess the effect of surgical fixation technique on contact behavior and knee stability. The geometry of femoral and tibial articular cartilage and menisci was segmented from magnetic resonance images of a normal cadaver knee using MIMICS (Materialise, Leuven, Belgium). A finite element mesh was generated using HyperWorks (Altair Inc, Santa Ana, CA). A finite element solver (Abaqus v6.9, Simulia, Providence, RI) was used to compute contact area and stresses under axial loading and to assess stability (reaction force generated during anteroposterior translation of the femur). The natural and surgical attachments of the meniscal horns and peripheral rim were simulated using springs. After total meniscectomy, femoral contact area decreased by 26% with a concomitant increase in average contact stresses (36%) and peak contact stresses (33%). Replacing the meniscus without suturing the horns did little to restore femoral contact area. Suturing the horns increased contact area and reduced peak contact stresses. Increasing suture stiffness correlated with increased meniscal contact stresses as a greater proportion of tibiofemoral load was transferred to the meniscus. A small incremental benefit was seen of simulated bone plug fixation over the suture construct with the highest stiffness (50 N/mm). Suturing the rim did little to change contact conditions. The nominal anteroposterior stiffness reduced by 3.1 N/mm after meniscectomy. In contrast to contact area and stress, stiffness of the horn fixation sutures had a smaller effect on anteroposterior stability. On the other hand suturing the rim of the meniscus affected anteroposterior stability to a much larger degree. This model emphasizes the importance of the meniscus in knee biomechanics. Appropriate meniscal replacement fixation techniques are likely to be critical to the clinical success of meniscal replacement. While contact conditions are mainly sensitive to meniscus horn fixation, the stability of the knee under anteroposterior shear loads appeared to be more sensitive to meniscal rim fixation. This model may also be useful in predicting the effect of biomaterial mechanical properties and meniscal replacement shape on knee contact conditions. PMID- 21608414 TI - A nonlinear viscoelastic finite element model of polyethylene. AB - A nonlinear viscoelastic finite element model of ultra-high molecular weight polyethylene (UHMWPE) was developed in this study. Eight cylindrical specimens were machined from ram extruded UHMWPE bar stock (GUR 1020) and tested under constant compression at 7% strain for 100 sec. The stress strain data during the initial ramp up to 7% strain was utilized to model the "instantaneous" stress strain response using a Mooney-Rivlin material model. The viscoelastic behavior was modeled using the time-dependent relaxation in stress seen after the initial maximum stress was achieved using a stored energy formulation. A cylindrical model of similar dimensions was created using a finite element analysis software program. The cylinder was made up of hexahedral elements, which were given the material properties utilizing the "instantaneous" stress-strain curve and the energy-relaxation curve obtained from the experimental data. The cylinder was compressed between two flat rigid bodies that simulated the fixtures of the testing machine. Experimental stress-relaxation, creep and dynamic testing data were then used to validate the model. The mean error for predicted versus experimental data for stress relaxation at different strain levels was 4.2%. The mean error for the creep test was 7% and for dynamic test was 5.4%. Finally, dynamic loading in a hip arthroplasty was modeled and validated experimentally with an error of 8%. This study establishes a working finite element material model of UHMWPE that can be utilized to simulate a variety of postoperative arthroplasty conditions. PMID- 21608415 TI - Tissue strains induced in airways due to mechanical ventilation. AB - Better understanding of the stress/strain environment in airway tissues is very important in order to avoid lung injuries for patients undergoing mechanical ventilation for treatment of respiratory problems. Airway tissue strains responsible for stressing the lung's fiber network and rupturing the lung due to compliant airways are very difficult to measure experimentally. A computational model that incorporates the heterogeneity of the airways was developed to study the effects of airway tissue material properties on strain distributions within each layer of the airway wall. The geometry and boundary conditions of the tissue strain analysis were obtained from the organ-level analysis model. Two sets of airway tissue properties (heterogeneous and homogeneous) were considered in order to estimate the strain levels induced within the tissue. The simulation results showed that the homogeneous model overestimated the maximum strain in the mucosa layer and underestimated the maximum strain in the smooth muscle and cartilage layers. The results of strain levels obtained from the tissue analysis are very important because these strains at the cellular-level can create inflammatory responses, thus damaging the airway tissues. PMID- 21608416 TI - Concentrations of air toxics in motor vehicle-dominated environments. AB - We at the Desert Research Institute (DRI*) measured volatile organic compounds (VOCs), including several mobile-source air toxics (MSATs), particulate matter with a mass mean aerodynamic diameter < or = 2.5 pm (PM2.5), black carbon (BC), nitrogen oxides (NOx), particulate matter (PM), and carbon monoxide (CO) on highways in Los Angeles County during summer and fall 2004, to characterize the diurnal and seasonal variations in measured concentrations related to volume and mix of traffic. Concentrations of on-road pollutants were then compared to corresponding measurements at fixed monitoring sites. The on-road concentrations of CO and MSATs were higher in the morning under stable atmospheric conditions and during periods of higher traffic volumes. In contrast, BC concentrations, measured as particulate light absorption, were higher on truck routes during the midday sampling periods despite more unstable atmospheric conditions. Compared to the measurements at the three near-road sites, the 1-hour averages of on-road BC concentrations were as much as an order of magnitude higher. The peak 1-minute average concentrations were two orders of magnitude higher for BC and were between two and six times higher for PM2.5 mass. The on-road concentrations of benzene, toluene, ethylbenzene, and xylenes (BTEX) during the summer were 3.5 +/- 0.7 and 1.2 +/- 0.6 times higher during morning and afternoon commuting periods, respectively, compared to annual average 24-hour concentrations measured at air toxic monitoring network sites. These ratios were higher during the fall, with smaller diurnal differences (4.8 +/- 0.7 and 3.9 +/- 0.6 for morning and afternoon commuting periods, respectively). Ratios similar to those for BTEX were obtained for 1,3-butadiene (BD) and styrene. On-road concentrations of formaldehyde and acetaldehyde were up to two times higher than at air toxics monitoring sites, with fall ratios slightly higher than summer ratios. Chemical mass balance (CMB) receptor model calculations attributed the sum of BTEX almost exclusively to gasoline engine exhaust for on-road samples and all but 5% to 10% of the BTEX at the three near-road sites. CMB analysis attributed 46% to 52% (+/- 7) of the ambient total particulate carbon (TC) at the three near-road sites to diesel exhaust and 10% to 17% (+/- 7) to gasoline exhaust; it attributed about 90% of the ambient elemental carbon (EC) concentrations (measured as refractory carbon using the thermal evolution method) to diesel exhaust. Diesel particulate carbon (DPC) concentrations were estimated by multiplying the mean ratio of TC to EC from the source-dominated ambient samples collected on road on Terminal Island (1.30 +/- 0.28), which is located between the Long Beach and Los Angeles ports, with the measured ambient EC concentrations at the three near-road sites. DPC estimates from EC measurements correlate well with the diesel source contributions calculated with the CMB model. The indication from these apportionments that BC or EC is a good surrogate for diesel exhaust is further supported by the positive correlation of on-road BC concentrations with volumes of truck traffic. Traffic counts have been used in past health assessment studies as surrogates for estimating near-road exposure concentrations with appropriate weighting for proximity to the road. However, the results of this study show that it is necessary to account for the proportion of diesel trucks to total vehicular traffic because of the disproportionate contribution of diesel exhaust to BC and to directly emitted PM. Alternatively, easily measured pollutants such as CO and BC can serve as reasonable surrogates for MSATs (e.g., BTEX and BD) and DPC, respectively. Measuring CO and BC is a reasonably cost-effective approach to quantifying hot-spot exposure concentrations of MSATs that is perhaps more accurate than what is possible using only data from regional air quality monitoring stations or air quality modeling results. PMID- 21608417 TI - Where there are (few) skilled birth attendants. AB - Recent efforts to reduce maternal mortality in developing countries have focused primarily on two long-term aims: training and deploying skilled birth attendants and upgrading emergency obstetric care facilities. Given the future population level benefits, strengthening of health systems makes excellent strategic sense but it does not address the immediate safe-delivery needs of the estimated 45 million women who are likely to deliver at home, without a skilled birth attendant. There are currently 28 countries from four major regions in which fewer than half of all births are attended by skilled birth attendants. Sixty nine percent of maternal deaths in these four regions can be attributed to these 28 countries, despite the fact that these countries only constitute 34% of the total population in these regions. Trends documenting the change in the proportion of births accompanied by a skilled attendant in these 28 countries over the last 15-20 years offer no indication that adequate change is imminent. To rapidly reduce maternal mortality in regions where births in the home without skilled birth attendants are common, governments and community-based organizations could implement a cost-effective, complementary strategy involving health workers who are likely to be present when births in the home take place. Training community-based birth attendants in primary and secondary prevention technologies (e.g. misoprostol, family planning, measurement of blood loss, and postpartum care) will increase the chance that women in the lowest economic quintiles will also benefit from global safe motherhood efforts. PMID- 21608418 TI - Achieving the millennium development goal for under-five mortality in Bangladesh: current status and lessons for issues and challenges for further improvements. AB - The study assessed the achievements in, critically reviewed the relevant issues of, and put forward recommendations for achieving the target of the Millennium Development Goal relating to mortality of children aged less than five years (under-five mortality) in Bangladesh within 2015. To materialize the study objectives, a thorough literature review was done. Mortality of under-five children and infants decreased respectively to 65 from 151 and to 52 from 94 per 1,000 livebirths during 1990-2006. The immunization coverage increased from 54% to 81.9% during the same period. The projection shows that Bangladesh will achieve targeted reduction in under-five mortality and infant mortality within the time limit, except immunization coverage. Neonatal mortality contributed to the majority of childhood deaths. Contribution of neonatal mortality to child mortality was the highest. There were remarkable differences in child mortality by sex, division, and residence. To progress further for achieving the target of MDG relating to child mortality, some issues, such as lower use of maternal healthcare services, hazardous environmental effects on childhood illness, high malnutrition among children, shorter duration of exclusive breastfeeding practices, various child injuries leading to death, low healthcare-use of children, probable future threat of financial shortage, and strategies lacking area-wise focus on child mortality, need to be considered. Without these, the achievement of MDG relating to child mortality may not be possible within 2015. PMID- 21608419 TI - Incidence and determinants of acute diarrhoea in Malaysia: a population-based study. AB - Acute diarrhoea is a major health problem in many parts of the world, contributing to about 1.8 million deaths globally. The objectives of the study were to assess the incidence, determinants, and severity of acute diarrhoea in the population. A nation-wide cross-sectional survey involving about 57,000 respondents was conducted via face-to-face interview among eligible respondents of all ages. An acute diarrhoeal episode was defined as having three or more episodes of loose stools in any 24-hour period within the past four weeks before the interview. The severity was measured by duration of acute diarrhoea and associated symptoms. The variables tested as determinants were age, sex, ethnicity, the highest educational level, total monthly household income, and locality. Univariate, bivariate and multivariate procedures meant for complex study design were used in the analyses. The four-week incidence of acute diarrhoea was 5% [95% confidence interval (CI) 4.8-5.2]. The incidence of acute diarrhoea among the estimated population was the highest among young adults aged 20-29 years, Other Bumiputras (the pre-dominant ethnic group in East Malaysia), those with tertiary-level of education, those earning a monthly household income of less than RM 400, and rural dwellers. Only age, ethnicity, the highest level of education attained, and locality were significantly associated with acute diarrhoea in bivariate analysis. In multivariate analysis, these four variables were found to be the determinants of acute diarrhoea. Sex and monthly household income were excluded from the model. The mean duration of acute diarrhoea was 2.0 days (standard deviation 1.3). Forty-six percent of the respondents reported stomach cramps as an associated symptom. The findings revealed that acute diarrhoea is still a major public-health concern in Malaysia and grossly under notified. There is a need for intensification of public-health intervention efforts to reduce the incidence of acute diarrhoea while improving surveillance and notification of the disease. PMID- 21608420 TI - Transactional sex among youths in post-conflict Liberia. AB - This paper presents findings on sexual risk behaviours of Liberian youths based on five focus-group discussions conducted with 6th and 7th graders (n = 36) attending an elementary/middle school in Monrovia, Liberia. The purpose of the focus-group discussions was to gain an understanding of the sexual behaviours of in-school Liberian adolescents. The focus-group discussions were part of a larger study to adapt an evidence-based HIV-prevention intervention-Making Proud Choices!-for in-school youths. Post-conflict conditions were discussed as a contributor to the emergence of high-risk sexual behaviours, including transactional sex, sexual violence, and lack of condom-use. Transactional sex was often described by the focus-group participants as occurring between young females and older, more financially-secure males to obtain cash, food, clothing, western commodities, and school-fees and was often encouraged by parents and promoted by peers. The findings also indicate that female adolescents make choices to engage in transactional sex to gain access to a continuum of material and consumer needs. These findings suggest that individual risk-taking behaviours are nested within complex sexual economies and that HIV-prevention interventions should be considered that leverage females' agency and control. PMID- 21608421 TI - Healthcare-use for major infectious disease syndromes in an informal settlement in Nairobi, Kenya. AB - A healthcare-use survey was conducted in the Kibera informal settlement in Nairobi, Kenya, in July 2005 to inform subsequent surveillance in the site for infectious diseases. Sets of standardized questionnaires were administered to 1,542 caretakers and heads of households with one or more child(ren) aged less than five years. The average household-size was 5.1 (range 1-15) persons. Most (90%) resided in a single room with monthly rents of US$ 4.50-7.00. Within the previous two weeks, 49% of children (n=1,378) aged less than five years (under five children) and 18% of persons (n = 1,139) aged > or = 5 years experienced febrile, diarrhoeal or respiratory illnesses. The large majority (> 75%) of illnesses were associated with healthcare-seeking. While licensed clinics were the most-frequently visited settings, kiosks, unlicensed care providers, and traditional healers were also frequently visited. Expense was cited most often (50%) as the reason for not seeking healthcare. Of those who sought healthcare, 34-44% of the first and/or the only visits were made with non-licensed care providers, potentially delaying opportunities for early optimal intervention. The proportions of patients accessing healthcare facilities were higher with diarrhoeal disease and fever (but not for respiratory diseases in under-five children) than those reported from a contemporaneous study conducted in a rural area in Kenya. The findings support community-based rather than facility-based surveillance in this setting to achieve objectives for comprehensive assessment of the burden of disease. PMID- 21608422 TI - A systematic review of effect of prenatal zinc supplementation on birthweight: meta-analysis of 17 randomized controlled trials. AB - The effect of prenatal zinc supplementation on birthweight is controversial as randomized controlled trials (RCTs) report conflicting conclusions. A systematic review which includes meta-analysis was done on 17 RCTs conducted worldwide since 1984 to assess the effect of prenatal zinc supplementation on birthweight. The studies were identified through web-based search. Heterogeneity among studies was assessed using Cochrane Q test statistic. Effect-size was measured based on standardized mean difference. Pooled effect-size was computed using a variant of random effect model. Thirteen of the 17 RCTs found no association, three reported positive association, and one reported negative association. Based on fixed and random effect models, the pooled effect-sizes were 0.0268 [95% confidence interval (CI) 0.0764, -0.0229) and 0.0712 (95% CI 0.1619, -0.0194) respectively. The effect-size estimate remains insignificant after stratification was made based on the dose of supplementation (optimal vs high dose), type of study (community vs institution-based), and type of source country (developed vs developing). The meta-analysis did not witness any association between birthweight and prenatal zinc supplementation. PMID- 21608423 TI - Improving nutrition and health through non-timber forest products in Ghana. AB - Nutrition and health are fundamental pillars of human development across the entire life-span. The potential role of non-timber forest products (NTFPs) in improving nutrition and health and reduction of poverty has been recognized in recent years. NTFPs continue to be an important source of household food security, nutrition, and health. Despite their significant contribution to food security, nutrition, and sustainable livelihoods, these tend to be overlooked by policy-makers. NTFPs have not been accorded adequate attention in development planning and in nutrition-improvement programmes in Ghana. Using exploratory and participatory research methods, this study identified the potentials of NTFPs in improving nutrition and food security in the country. Data collected from the survey were analyzed using the SPSS software (version 16.0). Pearson's correlation (p < 0.05) showed that a significant association exists between NTFPs and household food security, nutrition, and income among the populations of Bibiani-Bekwai and Sefwi Wiawso districts in the western region of Ghana. NTFPs contributed significantly to nutrition and health of the poor in the two districts, especially during the lean seasons. The results of the survey also indicated that 90% of the sampled population used plant medicine to cure various ailments, including malaria, typhoid, fever, diarrhoea, arthritis, rheumatism, and snake-bite. However, a number of factors, including policy vacuum, increased overharvesting of NTFPs, destruction of natural habitats, bushfires, poor farming practices, population growth, and market demand, are hindering the use and development of NTFPs in Ghana. The study also provides relevant information that policy-makers and development actors require for improving nutrition and health in Ghana. PMID- 21608424 TI - Prevalence of vitamin D deficiency among adult population of Isfahan City, Iran. AB - Determination of vitamin D status in different age-groups in a community and in different climates of a country is necessary and has important implications for general health. The study was conducted to determine the prevalence of vitamin D deficiency among the adult population of Isfahan, a centrally-located city in Iran. In this cross-sectional study, 1,111 healthy people-243 men and 868 women- aged 41.4 (mean 14 and range 20-80) years, who attended a single-consultation outpatient clinic, were selected. Serum 25-hydroxy vitamin D (25-OHD), parathyroid hormone (PTH), calcium and phosphorus concentrations were measured. Mild, moderate and severe vitamin D deficiencies were defined as 25-OHD values of 20-30 ng/mL, 10-20 ng/mL, and < 10 ng/mL respectively. The median (range) concentrations of 25-OHD were 21 (4.0-105.0) ng/mL in males and 18 (1.5-117) ng/mL in females (p = 0.05). The prevalence of mild, moderate and severe vitamin D deficiencies among the adult population was 19.6%, 23.9%, and 26.9% respectively. Vitamin D deficiency was more prevalent among women (p = 0.001) and younger age-group (p = 0.001). Medians of 25-OHD in spring-summer and autumn winter were 21 ng/mL and 18 ng/mL respectively (p = 0.005). The prevalence of severe vitamin D deficiency was higher in autumn-winter than in spring-summer (odds ratio = 1.6, 95% confidence interval 1.2-2.2, p = 0.001). The prevalence of vitamin D deficiency was high in a sunny city--Isfahan--especially among women and younger population. The high prevalence of vitamin D deficiency in this city emphasizes the necessity of vitamin D supplementation as more exposure to sun is limited due to the type of clothing required by current law. PMID- 21608425 TI - Maternal sociodemographic parameters: impact on trace element status and pregnancy outcomes in Nigerian women. AB - To determine the impact of socioeconomic status on plasma trace element status and pregnancy outcomes, 349 pregnant women, aged 15-40 years (mean 27.04 +/- 2.75 years), recruited at < or = 25 weeks (mean 21.76 +/- 3.12 weeks) gestational age, were followed up till delivery during which maternal and foetal outcomes were recorded. Plasma copper, iron, and zinc were determined using atomic absorption spectrophotometer while maternal sociodemographic data were obtained using a questionnaire. Except for copper, lower plasma iron and zinc were significantly (p < 0.05) higher in women from socioeconomically-disadvantaged groups. Both adverse maternal health and foetal outcomes also seemed to be more prevalent in socioeconomically-disadvantaged women, although without a definite trend. This study has shown that, in economically-disadvantaged setting of developing countries, maternal socioeconomic status impacts on maternal trace element (copper, iron, and zinc) status and health and foetal outcomes. PMID- 21608426 TI - Type, content, and source of social support perceived by women during pregnancy: evidence from Matlab, Bangladesh. AB - Specific and contextualized data on social support during distinct health events are needed to improve social support interventions. This study identified the type, content, and source of social support perceived by women during pregnancy. In-depth interviews with 25 women, aged 18-49 years, living in Matlab, Bangladesh, were conducted. The findings demonstrated that women perceived, the receipt of eight distinct types of support. The four most frequently-mentioned types included: practical help with routine activities, information/advice, emotional support and assurance, as well as the provision of resources and material goods. Sources varied by type of support and most frequently included mothers, mothers-in-law, sisters-in-law, and husbands. Examples depicting the content of each type of support revealed culturally-specific issues that can inform community-based social support interventions. PMID- 21608427 TI - Seroprevalence of hepatitis A among Thai population residing near Myanmar border. AB - hen compared with Thailand, the seroprevalence of hepatitis A virus (HAV) is extremely high among its neighbouring countries. To investigate the seroprevalence of HAV among the Thai people residing in the border area between Thailand and Myanmar, 308 residents in Umphang, Maesod district, Tak, were recruited. Sera were tested for HAV IgG antibodies by enzyme-linked immunosorbent assay. The overall seroprevalence among the Thai people residing in the border area of Thailand was significantly higher than that among the general Thai population (71% vs 27% respectively, p < 0.05). As asymptomatic or mild HAV infection typically occurs in children, the Thai people residing in the border area may receive little benefit from universal HAV vaccination. Lower protective antibodies against HAV, along with the exclusion of HAV vaccine from the Expanded Programme on Immunization, potentially increase the susceptibility to HAV among the general Thai population and may lead to more future outbreaks if HAV is introduced from the border areas. The findings suggest that HAV vaccines should be recommended to travellers before their journey to the border between Thailand and Myanmar where HAV is endemic. PMID- 21608428 TI - Biventricular thrombi associated with peripartum cardiomyopathy. AB - A 22-year old woman visited the LAMB Hospital, Parbatipur, Dinajpur, Bangladesh, in February 2010, with exertional dyspnea for three weeks. She had had a normal vaginal delivery four months ago; 2-dimensional echocardiogram showed severe left ventricular dysfunction and biventricular thrombi, which resolved without complications after anticoagulation. Biventricular thrombosis with peripartum cardiomyopathy is quite a rare finding, and its clinical course and proper management is not known. No such case has previously been reported in Bangladesh. PMID- 21608429 TI - Hypomagnesaemia as a mortality risk factor in protein-energy malnutrition. PMID- 21608430 TI - Adipose tissue-derived mesenchymal stem cells and hepatic differentiation: old concepts and future perspectives. AB - Mesenchymal stem cells (MSCs) are multipotent cells, able to differentiate into elements of the mesodermal lineage. Bone marrow and adipose tissue represent the main sources for MSC isolation. In the last decade, several studies have reported the plasticity of MSCs toward a hepatocyte-like phenotype. The use of MSCs to generate hepatocyte-like cells holds great promises to overcome the scarcity of available organs for transplantation. However, little is known about the molecular pathways involved in lineage cross-differentiation and several issues remain to be answered before MSC application in clinical settings. Aim of this review is to critically analyze the possible sources of MSCs suitable for liver repopulation and the molecular mechanisms underlying MSC hepatic differentiation. PMID- 21608431 TI - Extrapulmonary tuberculosis: tuberculous meningitis new developments. AB - Tuberculosis (TB) can involve any organ system in the body. Extrapulmonary involvement can occur in isolation or along with a pulmonary focus as in the case of patients with disseminated tuberculosis. Tuberculosis meningitis (TBM) is the most severe form of extrapulmonary tuberculosis. TBM a medical emergency, is still a major cause of serious illness in many parts of the world. TBM remains difficult to diagnose, and it is usually due to hematogenous dissemination of the tubercle bacillus. The exact incidence and prevalence are not known. The clinical spectrum is broad and may be non-specific making early diagnosis difficult. Improved outcome requires early recognition and treatment of these conditions. Clinical features included fever for more than 7 days, headache, or neck stiffness. While TBM is a disease of childhood, tuberculomas and spinal tuberculosis are invariably an adult manifestation. In HIV infection, TB is often atypical in presentation, frequently causing extrapulmonary disease, and patients have a high incidence of TBM. Clinical response to antituberculous therapy in all forms of neurotuberculosis is excellent if the diagnosis is made early before irreversible neurological deficit is established. Diagnosis is based on the characteristic clinical picture, neuroimaging abnormalities, cerebrospinal fluid changes and the response to anti-tuberculosis drugs. Diagnosis is best made with lumbar puncture and examination of the cerebrospinal fluid (CSF). Suspect TBM if there is a CSF leucocytosis (predominantly lymphocytes), the CSF protein is raised, and the CSF plasma glucose is <50%. Rapid techniques based on nucleic acid amplification such as PCR are more sensitive and specific as they attempt to detect specific DNA sequences of the organism. The hallmark pathological processes are meningeal inflammation, basal exudates, vasculitis and hydrocephalus. Treatment delay is strongly associated with death and empirical anti-tuberculosis therapy should be started promptly in all patients in whom the diagnosis of TBM is suspected. Corticosteroids reduce the number of deaths. Development of an effective vaccine against tuberculosis hinges on an improved understanding of the human immune response to Mycobacterium tuberculosis (Mtb). The emergence of drug resistant tuberculosis poses a serious threat to the control of this pathogen, and the development of drugs that are active against the resistant strains is vital. Further research into the epidemiology, immune mechanisms, diagnosis, treatment, and prevention of TBM is urgently needed. PMID- 21608432 TI - Effect of insulin in combination with selenium on blood glucose and PI3K-mediated GLUT4 expression in skeletal muscle of streptozotocin-induced diabetic rats. AB - OBJECTIVES: We evaluated the effect of low doses of insulin (1 U/kg/day) and selenium (180 microg/kg/day) in combination on general physiological parameters, and on PI3K and GLUT4 levels in skeletal muscle of streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Diabetic rats were treated with insulin, selenium, and insulin and selenium in combination for four weeks. The levels of blood glucose and hemoglobin A1c were estimated, and the levels of P13K and GLUT4 in skeletal muscle were examined by immunoblotting and immunohistochemistry. RESULTS: Insulin in combination with selenium could significantly lower blood glucose and HbAlc levels, and restore the disturbances in PI3K and GLUT4 levels in skeletal muscle. Treatment with insulin was only partially effective in the restoration of diabetic alterations. CONCLUSION: We conclude that there was cooperation between insulin and selenium, and that treatment of diabetic rats with combined doses of insulin and selenium was effective in the normalization of blood glucose and correction of altered PI3K and GLUT4 distribution in skeletal muscle of diabetic rats. PMID- 21608433 TI - Ultrasound in the selective screening of developmental dysplasia of the hip. AB - INTRODUCTION: Developmental dysplasia of the hip (DDH) can result in chronic pain, gait abnormalities and degenerative arthritis. Infants with a family history, Breech delivery or unstable/"clicking" of the hip on examination are at higher risk. The goal is to detect cases early enough for normal hip development and function by the end of adolescence, but clinical examination alone is ineffective. MATERIALS AND METHODS: All infants born at the West Middlesex University Hospital, Isle-worth, U.K., between 3/3/2005 and 21/10/2006 underwent prospective clinical screening to reveal risk factors of unstable hip on examination, family history of DDH and Breech delivery. Infants with risk factors underwent static and dynamic ultrasound of the hips (Harke's method with Terjesen measurements), performed by a consultant radiologist or sonographer. The infant was then examined by an Orthopaedic Surgeon who was blinded to the ultrasound findings until after creating a management plan. RESULTS: 5772 infants were born during the study period. 200 (3.5%) at-risk infants were identified, resulting in 400 hip ultrasounds. Following review of ultrasound findings, the majority of cases (163/200, 81.5%) lead to no change in management. Change in timing or type of clinical follow up occurred in 31 cases with normal ultrasounds and 20 cases with abnormal (immature hip) ultrasounds. Dysplasia was demonstrated in 6 infants (3%) on ultrasound, who were treated with Parvlik Harness. Of these, only 5 were detected on examination. Therefore, the ultrasound findings lead to 1 intervention with Parvlik Harness which would have otherwise gone undiagnosed from clinical examination. CONCLUSION: Whereas type and timing of follow up was adjusted in 18.5% of the at-risk infants, targeted screening of at-risk with ultrasound lead to only one intervention. This encourages discussion on the resource implication and viability of ultrasound screening, as only one from two hundred lead to an intervention. PMID- 21608434 TI - The abnormal pattern of thorax in the patients with spontaneous pneumothorax coexists with blebs of the lungs: a commonly observed finding. AB - BACKGROUND AND OBJECTIVES: Spontaneous pneumothorax is common between young, thin people, usually without previous history of any respiratory disease or symptom. Of note, there has been not observed any other characteristics or findings from thorax imaging (Rx and thorax computed tomography-CT) in these people, in exception of blebs or bullae in upper lobes of the lungs. MATERIALS AND METHODS: We studied 19 consecutive young patients (17-40 years old), admitted in the Department with spontaneous pneumothorax. An x-ray in the admission and a CT after complete lung re-expansion were performed in all patients. RESULTS: In a large percentage of our patients, 14 out of 19 (73.68%) was observed an abnormal pattern of the thoracic cage and the coexistence of blebs and/or bullae in the upper lobes. CONCLUSION: The abnormal and particular pattern of thorax in the patients with spontaneous pneumothorax coexists with blebs of the lungs. This is a commonly observed finding. PMID- 21608435 TI - Severe pneumonia caused by Nocardia farcinica and complicated by Staphylococcus haemoliticus superinfection. AB - It is reported the case of a subject 54 years old, painter, drinker and smoker who after an episode of cooling and the occurrence of widespread pain was taking its own initiative, cortisone and analgesics from approximately 30 days. The symptoms worsened and the patient was hospitalized. Chest X-ray and CT scan showed an extensive opacity in the left upper lobe with excavations in the context and also some nodular opacities excavated in the contralateral lung. In the first eight days after admission, the clinical picture despite empirical antibiotic therapy worsened towards adult respiratory distress syndrome (ARDS). On the ninth day after the admission, strains of Nocardia farcinica and Staphylococcus haemoliticus were isolated from the sputum. The targeted therapy (trimethoprim-sulfamethoxazole, amikacin, etc.) induced a rapid improvement of the clinical picture that was resolved in 6 months. Pneumonia caused by Nocardia farcinica is rare but its identification is necessary to set an appropriate therapy. PMID- 21608436 TI - In vitro antioxidant activity of flower, seed and leaves of Alcea hyrcana Grossh. AB - OBJECTIVES: Alcea hyrcana Grossh (A. hyrcana Grossh) (malvacea), is native to northern of Iran. Many of the plants belonging to the genus Alcea are known to possess ethnomedical and biological properties. In this study, antioxidant activities of methanolic extracts of flower, seed and leaves of Alcea hyrcana Grossh were evaluated by various antioxidant assays. MATERIAL AND METHODS: 1,1 diphenyl-2-picryl hydrazyl radical (DPPH), nitric oxide and hydrogen peroxide scavenging activities, Fe2+ chelating ability, reducing power and hemoglobin induced linoleic acid peroxidation test were used to evaluate antioxidant activities. The total amount of phenolic compounds was determined as gallic acid equivalents and total flavonoid contents were calculated as quercetin equivalents from a calibration curve. Total phenolic and flavonoid contents also have been determined. RESULTS: All extracts showed good antioxidant activities. The A. hyrcana Grossh leaves extract exhibited strong ferrous chelating activity with IC50 = 0.11 +/- 0.01 mg ml(-1), nitric oxide radical scavenging with IC50 = 0.45 +/- 0.01 mg ml(-1) and better reducing power activity than other extracts. The seeds extract showed high scavenging activity against free radicals, including both the hydrogen peroxide and DPPH radicals. Only leaves extract had good activity in linoleic acid model. Seeds extract had significant higher total phenol (68.9 +/- 3.7 mg gallic acid equivalent/g of extract powder) and leaves had higher flavonoids contents (28.3 +/- 2.6 mg quercetin equivalent/g of extract powder) than other parts. CONCLUSIONS: The leaves, seed and flower extracts of A. hyrcana Grossh exhibited good but different levels of antioxidant activity in all the models studied. The extracts had good iron chelation, H2O2 and nitric oxide scavenging activities. Antioxidant activities may be attributed, at least in part, to the presence of phenols and flavonoids. PMID- 21608437 TI - Therapeutic effects of olive leaves extract on rats treated with a sublethal concentration of carbendazim. AB - OBJECTIVES: The present study was carried out to establish the possible protective effects of administration of olive leaves extract on carbendazim induced physiological and histopathological alterations in male rats. MATERIALS AND METHODS: The experimental rats were divided randomly into five groups and kept at ten rats per group. The first group was untreated and served as a control. The second group was orally administered with carbendazim (200 mg/kg) for one month. The third group was supplemented with olive leaves extract and exposed to carbendazim at the same dose given to the second group. Rats of the fourth group were supplemented with olive leaves extract at the same dose given to the third group. Rats of the fifth group were supplemented with only corn oil. RESULTS: Carbendazim induced statistically declines in the values of red blood corpuscles (RBC) count, hemoglobin (Hb) concentration, hematocrit (Hct) and the level of plasma and liver total protein, while the value of white blood cells (WBC) count, the levels of plasma glucose, triglycerides, cholesterol, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and liver glycogen and total lipid were elevated. Moreover, after one month of carbendazim exposure, there were severe changes in the structures of liver, kidney and testis. Pretreatment of carbendazim-exposed rats with olive leaves extract showed marked improvement in both physiological and histopathological alterations. CONCLUSIONS: We conclude that olive leaves extract is a promising chemotherapeutic agent for reducing the toxicity of carbendazim and may be for other pesticides and toxicants. PMID- 21608438 TI - Protective role of Trigonella foenum graceum extract against oxidative stress in hyperglycemic rats. AB - BACKGROUND AND OBJECTIVES: "In all things of nature there is something of the marvelous". In the present study the anti-hyperglycemic and anti-oxidative potential of aqueous extract of Trigonella foenum graceum (TFG), a traditional medicinal herb was assessed in liver and WBC of alloxan induced diabetic rats. Free radicals can cause oxidative damage, which is balanced by the antioxidants. This has been implicated in aging, and diseases such as diabetes and other chronic conditions. MATERIAL AND METHODS: TFG extract was administered orally [500 (LM) and 1000 mg/kg body weight (HM)] for six weeks. The effect of TFG on blood glucose were studied and the levels of lipid peroxidation [MDA (Malondialdehyde)] and antioxidant enzymes [SOD (Superoxide dismutase), GPx (Reduced Glutathione peroxidase)] were estimated and compared with standard drugs glibenclamide and insulin. RESULTS: Treatment with TFG, insulin and glibenclamide resulted in significantly reduced blood glucose in LM (8.71%) and HM (3.87%) in comparison with normal controls. There was a significant decrease in lipid peroxidation in liver and white blood cells (WBC) in both low and high doses [liver LM (49%), HM (57.25%)], [WBC LM (54.28%), HM (62.5%)] and increase in antioxidant enzymes SOD [liver LM (33.59%), HM (58.7%)] [WBC LM (44.9%)] HM (58.7%) and GPx [Liver LM (58.55%), HM (40.20%)], [WBC LM (55.46%), HM (56.4%)] when compared to diabetic controls. DISCUSSION: Potency of TFG in restoring several parameters to normal values is comparable to glibenclamide, though not as efficient as insulin, an indication of its antihyperglycemic and antioxidant effect. PMID- 21608439 TI - Prevalence of anaemia in pregnant women during the last trimester: consequense for birth weight. AB - OBJECTIVES: Iron deficiency continues to be one of the most prevalent single nutrient deficiencies in the world. The current study aimed to estimate the prevalence of iron deficiency anemia (IDA) among pregnant women who attend Antenatal Care Centers in Sidi Bel Abbes, Algeria. The effect of anaemia on infant birth weight was also examined. MATERIALS AND METHODS: The study was conducted during the period March-Mai, 2010 and the sample consisted of 207 pregnant women (in the third trimesters) in the age group (17-41) years. The subjects were not taking iron, folate or vitamin B12 supplements at the time of the study. Blood samples were collected from each pregnant woman and a questionnaire was completed at the time of blood collection. A series of determinations was conducted to determine hemoglobin concentration (Hb); packed cell volume (PCV); corpuscular hemoglobin concentration (MCHC), corpuscular volume (MCV). The effect of anemia on the weight of new born babies was examined by calculating the correlation coefficient of birth weight and hematological indexes. RESULTS: The overall prevalence of anemia was found to be 46.86%. According to the severity anemia was 36.08% mild, 49.48% moderate and 14.43% severe anemia. The mean values (+/- SD) of haematological indexes were as follows: Hb 9.00 +/- 1.57 g/dl; PCV 27 +/- 5.37%; mean corpuscular haemoglobin concentration (MCHC) 33.75 +/- 2.69 g/dl and mean corpuscular volume (MCV) 75.7 +/- 10.4 fl. The results have shown that 46.39% of the subjects had MCV values less than standard value of 75 fl suggesting a microcytic anemia. The mean haemoglobin concentration was 9 +/- 1.57 g/dl while the mean birth weight was 3201.54 +/- 566.71 g. There was a not significant correlation between the Hb level and the birth weight of the infants (r = 0.28, p > 0.05). The prevalence of low birth weight was 9.2%. There was no statistically significant haemoglobin concentration /foetal birth weight difference among the various hemoglobin concentration (Chi square test = 0.34, p > 0.05). CONCLUSIONS: Anemia had no significant obstetric adverse effects in our pregnant population (Fischer test = 0.06, p > 0.05). There was no statistically significant difference in mean birth weight among the various haemoglobin groups suggesting that other parameters may play important roles in influencing the birth weight than the maternal haemoglobin concentration. PMID- 21608440 TI - Isolated fallopian tube torsion in early pregnancy presenting as resolving appendicular lump. AB - Isolated fallopian tube torsion (IFTT) is a rare clinical entity, especially in pregnancy. It is frequently misdiagnosed as acute appendicitis or ovarian torsion. We present an unusual case of IFTT occurring in early pregnancy, which was detected when patient presented for medical termination of pregnancy in family planning clinic. This case report highlights sub acute presentation of IFTT in early pregnancy which clinically presented as resolving appendicular lump. PMID- 21608441 TI - Hydronephrosis of pregnancy associated with torsion of the fallopian tube: a case report. AB - Isolated tubal torsion accompanying pregnancy is an extremely rare condition. Preoperative diagnosis is generally difficult; most of the cases can be diagnosed intraoperatively. Here, we reported a 36-week pregnant with a complaint of acute pain in right lower quadrant that emanating to right lomber region. Abdominal utrasonography showed grade 3 hydronephrosis in right kidney, other findings were normal. A cesarean section was carried out and a twisted right tube were diagnosed. Right ovary was normal in appearance. The torsioned tube compressed the right ureter and caused ureteral dilatation. Right salpingectomy was performed. Postoperative follow-up of the patient was uneventful. PMID- 21608442 TI - Myo-inositol rather than D-chiro-inositol is able to improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is the most common cause of infertility due to menstrual dysfunction, and the most promising treatments for this disease are insulin sensitising agents. Myo-inositol and D-chiro-inositol are insulin sensitizing agents used in PCOS treatment. In the present paper, we aimed to compare the effects myo-inositol and D-chiro-inositol on oocyte quality in euglycemic PCOS patients. MATERIALS AND METHODS: Eighty-four euglycemic PCOS patients, undergoing ovulation induction for ICSI, were recruited for this study. Forty-three participants received MyoInositol 2 g twice a day and forty-one patients received D-chiro inositol 0.6 g twice a day. RESULTS: The results of our study showed that the total number of oocytes retrieved did not differ in the two treatments groups. However, the number of mature oocytes was significantly increased in the myo-inositol group compared to D-chiro-inositol. Concurrently, the number of immature oocytes decreased in myo-inositol treated patients. Furthermore, the myo-inositol-treated group showed an increase in the mean number of top quality embryos and in the total number of pregnancies compared to the D chiro-inositol-treated group. CONCLUSIONS: Our data show that, in PCOS patients having a normal insulin response, myo-inositol treatment rather than D-chiro inositol is able to improve oocyte and embryo quality during ovarian stimulation protocols. PMID- 21608443 TI - A 12-month follow-up for neurological complication after subarachnoid anesthesia in a parturient affected by multiple sclerosis. AB - Multiple sclerosis is common among women of childbearing age. Neuraxial blocks have been administered to them with reluctance because of the hypothetical risk that local anesthetics might be more histotoxic to neural tissue already compromised by multiple sclerosis. In spite of the lack of uniform guidelines on disorders in pregnancy like multiple sclerosis, and of the published data that sometimes contrast each other, experience gained in recent years has indicated that regional anesthesia is safe even in these patients, but there aren't many published cases. We describe the case of a pregnant woman affected by multiple sclerosis in which we administered spinal anesthesia for a cesarean section, and we analyzed the aspects that literature defines as critical points in this group of patients. The results were favorable with regard to the level, intensity and duration of anesthesia. No neurological exacerbations were recognized during the hospital stay, nor during the follow-up that lasted 12 months. PMID- 21608444 TI - Incidental congenital transmesenteric hernia in an adult. AB - Transmesenteric hernia is a rare type of internal hernia. We report a case of a 45 year old lady who was found to have an incidental congenital transmesenteric hernia of ileum caused by a congenital mesenteric defect during radical cystectomy done for muscle invasive transitional cell carcinoma of urinary bladder. PMID- 21608445 TI - Acoustic Radiation Force Impulse (ARFI) imaging-based needle visualization. AB - Ultrasound-guided needle placement is widely used in the clinical setting, particularly for central venous catheter placement, tissue biopsy and regional anesthesia. Difficulties with ultrasound guidance in these areas often result from steep needle insertion angles and spatial offsets between the imaging plane and the needle. Acoustic Radiation Force Impulse (ARFI) imaging leads to improved needle visualization because it uses a standard diagnostic scanner to perform radiation force based elasticity imaging, creating a displacement map that displays tissue stiffness variations. The needle visualization in ARFI images is independent of needle-insertion angle and also extends needle visibility out of plane. Although ARFI images portray needles well, they often do not contain the usual B-mode landmarks. Therefore, a three-step segmentation algorithm has been developed to identify a needle in an ARFI image and overlay the needle prediction on a coregistered B-mode image. The steps are: (1) contrast enhancement by median filtration and Laplacian operator filtration, (2) noise suppression through displacement estimate correlation coefficient thresholding and (3) smoothing by removal of outliers and best-fit line prediction. The algorithm was applied to data sets from horizontal 18, 21 and 25 gauge needles between 0-4 mm offset in elevation from the transducer imaging plane and to 18G needles on the transducer axis (in plane) between 10 degrees and 35 degrees from the horizontal. Needle tips were visualized within 2 mm of their actual position for both horizontal needle orientations up to 1.5 mm offset in elevation from the transducer imaging plane and on-axis angled needles between 10 degrees-35 degrees above the horizontal orientation. We conclude that segmented ARFI images overlaid on matched B-mode images hold promise for improved needle visibility in many clinical applications. PMID- 21608446 TI - Ultrasonic multi-feature analysis procedure for computer-aided diagnosis of solid breast lesions. AB - We have developed quantitative descriptors to provide an objective means of noninvasive identification of cancerous breast lesions. These descriptors include quantitative acoustic features assessed using spectrum analysis of ultrasonic radiofrequency (rf) echo signals and morphometric properties related to lesion shape. Acoustic features include measures of echogenicity, heterogeneity and shadowing, computed by generating spectral-parameter images of the lesion and surrounding tissue. Spectral-parameter values are derived from rf echo signals at each pixel using a sliding-window Fourier analysis. We derive quantitative acoustic features from spectral-parameter maps of the lesion and adjacent areas. We quantify morphometric features by geometric and fractal analysis of traced lesion boundaries. Initial results on biopsy-proven cases show that although a single parameter cannot reliably discriminate cancerous from noncancerous breast lesions, multi-feature analysis provides excellent discrimination for this data set. We have processed data for 130 biopsy-proven patients, acquired during routine ultrasonic examinations at three clinical sites and produced an area under the receiver-operating-characteristics (ROC) curve of 0.947 +/- 0.045. Among the quantitative descriptors, lesion-margin definition, spiculation and border irregularity are the most useful; some additional morphometric features (such as border irregularity) also are particularly effective in lesion classification. Our findings are consistent with many of the BI-RADS (Breast Imaging Reporting and Data System) breast-lesion-classification criteria in use today. PMID- 21608447 TI - If nothing gets looked at...nothing changes. PMID- 21608448 TI - Control of obesity--a call for collective action. PMID- 21608449 TI - Question: Should gastric protection with a histamine2-receptor blocker or a proton pump inhibitor be ordered for stress ulcer prophylaxis on virtually every adult patient admitted to the hospital for something other than elective surgery? PMID- 21608450 TI - Colonoscopic fecal bacteriotherapy in the treatment of recurrent Clostridium difficile infection--results and follow-up. PMID- 21608451 TI - Linear accelerator based intracranial and extracranial stereotactic radiation therapy at the University of Oklahoma. AB - PURPOSE: Review our institutional outcomes with linear accelerator based stereotactic radiation therapy at the University of Oklahoma. METHODS: We retrospectively reviewed all patients treated in our department with linear accelerator based stereotactic radiation therapy since we implemented this modality in 2008. Thirty-seven patients have been treated with a mean follow-up of 8.3 months. Seventeen patients had tumors near critical structures; ten had treatment sites not suited for gamma knife therapy. Outcomes are reviewed for efficacy and toxicity. RESULTS: Acute and long term complications reported are minimal. Stabilization of treatment sites was achieved in 96% of patients on follow-up imaging. Thirteen patients (35%) have died, of which eleven died to systemic disease progression outside of the treatment site. No treatment related deaths occurred. CONCLUSIONS: Stereotactic radiation therapy is a successful treatment modality to achieve local disease control with minimal toxicity. We plan to expand its use and applications in the future. PMID- 21608452 TI - Cesarean section quality initiative. PMID- 21608453 TI - Fixing the poor performers requires tough decisions. PMID- 21608454 TI - Looking at reactions to the ACO rules. PMID- 21608455 TI - Applying the FHN trial results to practice. PMID- 21608456 TI - More hemodialysis is not bad for blood access. PMID- 21608457 TI - Paper calls for incentivizing AVF placement. PMID- 21608458 TI - The promise of symptom-targeted intervention to manage depression in dialysis patients. AB - Research with tens of thousands of dialysis patients has established a link between depression, health-related quality of life scores, survival, and hospitalizations. In fact, physical and mental functioning scores are as predictive of death and hospitalization as Kt/V and albumin. Some models for managing depression in the dialysis clinic have been developed. These models address barriers to accessing community mental health services. They also promote collaboration between the nephrology social worker and nephrologist to assurethat patients receive counseling and/or antidepressant medications when they need them. Part 1 of this article will introduce a promising new method designed for nephrology social workers to help patients manage depression. This method, known as symptom-targeted intervention (STI), can be used in brief intervals with patients while they are receiving dialysis treatments to help reduce depressive symptoms and improve quality of life. The second part of this article, which will appear in the June issue of Nephrology News & Issues, will report the outcomes of a 17-state pilot study in which more than 45 nephrology social workers used brief, focused STI methods with more than 75 patients in the dialysis clinic setting. The impact of STI on depression and quality of life in this sample will be explored as well as how those outcomes may impact hospitalizations, improve patient survival, and contain costs in a bundled reimbursement environment. PMID- 21608459 TI - Should we treat depression in the dialysis clinic? The impact of STI. PMID- 21608460 TI - Parasite competition hidden by correlated coinfection: using surveys and experiments to understand parasite interactions. AB - Within most free-living species exists a cryptic community of interacting parasites. By combining multiscale field data with manipulative experiments, we evaluated patterns of parasite coinfection in amphibian hosts and their underlying mechanisms. Surveys of 86 wetlands and 1273 hosts revealed positive correlations between two pathogenic trematodes (Ribeiroia ondatrae and Echinostoma trivolvis) both between wetlands and within individual hosts. In infection and coinfection experiments, Ribeiroia caused greater pathology than Echinostoma, including high host mortality (24%) and severe limb malformations (75%). No interactive effects were noted for host pathology, but both parasites decreased the per capita persistence of one another by 17-36%. Thus, in spite of consistently positive associations from field data, these parasites negatively affected the persistence of one another, likely via cross immunity (apparent competition). These findings underscore the danger of inferring parasite interactions from coinfection patterns and emphasize the potential disconnect between within-host processes (e.g., competition) and between-host processes (e.g., exposure and transmission). Here, correlated coinfections likely resulted from similarities in the parasites' host requirements and heterogeneity in host susceptibility or exposure. Understanding complex interactions among parasites depends critically on the scale under consideration, highlighting the importance of combining coinfection field studies with mechanistic experiments. PMID- 21608461 TI - Ecomorphology and disease: cryptic effects of parasitism on host habitat use, thermoregulation, and predator avoidance. AB - Parasites can cause dramatic changes in the phenotypes of their hosts, sometimes leading to a higher probability of predation and parasite transmission. Because an organism's morphology directly affects its locomotion, even subtle changes in key morphological traits may affect survival and behavior. However, despite the ubiquity of parasites in natural communities, few studies have incorporated parasites into ecomorphological research. Here, we evaluated the effects of parasite-induced changes in host phenotype on the habitat use, thermal biology, and simulated predator-escape ability of Pacific chorus frogs (Pseudacris regilla) in natural environments. Frogs with parasite-induced limb malformations were more likely to use ground microhabitats relative to vertical refugia and selected less-angled perches closer to the ground in comparison with normal frogs. Although both groups had similar levels of infection, malformed frogs used warmer microhabitats, which resulted in higher body temperatures. Likely as a result of their morphological abnormalities, malformed frogs allowed a simulated predator to approach closer before escaping and escaped shorter distances relative to normal frogs. These data indicate that parasite-induced morphological changes can significantly alter host behavior and habitat use, highlighting the importance of incorporating the ubiquitous, albeit cryptic, role of parasites into ecomorphological research. PMID- 21608462 TI - Predators, prey, and transient states in the assembly of spatially structured communities. AB - Ecological theory suggests that both dispersal limitation and resource limitation can exert strong effects on community assembly. However, empirical studies of community assembly have focused almost exclusively on communities with a single trophic level. Thus, little is known about the combined effects of dispersal and resource limitation on assembly of communities with multiple trophic levels. We performed a landscape-scale experiment using spatially arranged mesocosms to study effects of dispersal and resource limitation on the assembly dynamics of aquatic invertebrate communities with two trophic levels. We found that interplay between dispersal and resource limitation regulated the assembly of predator and prey trophic levels in these pond communities. Early in assembly, predators and prey were strongly dispersal limited, and resource (i.e., prey) availability did not influence predator colonization. Later in assembly, after predators colonized, resource limitation was the strongest driver of predator abundance, and dispersal limitation played a negligible role. Thus, habitat isolation affected predators directly by reducing predator colonization rate, and indirectly through the effect of distance on prey availability. Dispersal and resource limitation of predators resulted in a transient period in which predators were absent or rare in isolated habitats. This period may be important for understanding population dynamics of vulnerable prey species. Our findings demonstrate that dispersal and resource limitation can jointly regulate assembly dynamics in multi-trophic systems. They also highlight the need to develop a temporal picture of the assembly process in multi-trophic communities because the availability and spatial distribution of limiting resources (i.e., prey) and the distribution of predators can shift radically over time. PMID- 21608463 TI - A century of increasing pine density and associated shifts in understory plant strategies. AB - We analyzed one of the longest-term ecological data sets to evaluate how forest overstory structure is related to herbaceous understory plant strategies in a ponderosa pine forest. Eighty-two permanent 1-m2 chart quadrats that were established as early as 1912 were remeasured in 2007. We reconstructed historical forest structure using dendrochronological techniques. Ponderosa pine basal area increased from an average of 4 m2/ha in the early 1900s to 29 m2/ha in 2007. Understory plant foliar cover declined by 21%, species richness declined by two species per square meter, and functional diversity also declined. The relative cover of C4 graminoids decreased by 18% and C3 graminoids increased by 19%. Herbaceous plant species with low leaf and fine root nitrogen concentrations, low specific leaf area, high leaf dry matter content, large seed mass, low specific root length, short maximum height, and early flowering date increased in relative abundance in sites where pine basal area increased the most. Overall, we observed a long-term shift in composition toward more conservative shade- and stress tolerant herbaceous species. Our analysis of temporal changes in plant strategies provides a general framework for evaluating compositional and functional changes in terrestrial plant communities. PMID- 21608464 TI - Frailty in state-space models: application to actuarial senescence in the Dipper. AB - Senescence, a decrease in life history traits with age, is a within-individual process. The lack of suitable methods to deal with individual heterogeneity has long impeded progress in exploring senescence in wild populations. Analyses of survival senescence are additionally complicated by the often neglected issue of imperfect detectability. To deal with both these issues, we developed state-space models to analyze capture-mark-recapture data while accounting for individual heterogeneity by incorporating random effects. We illustrated our approach by applying it to 29 years of data on breeding females in a Dipper (Cinclus cinclus) population. We highlighted patterns of age-related variation in annual survival by statistical comparisons of piecewise linear, quadratic, Gompertz, and Weibull survival models. The Gompertz model was ranked first in our set. It provided strong evidence for actuarial senescence with an onset of senescence estimated at about 2.3 years. The probability for this model to involve a frailty was 0.15, and the probability to involve an individual latent effect in detection was about 0.4. The estimated mean age at first reproduction was 1.2 years. The general case model described here in detail should encourage the reanalysis of actuarial senescence in cases where imperfect detection or individual heterogeneity is suspected. PMID- 21608465 TI - Estimating behavioral parameters in animal movement models using a state augmented particle filter. AB - Data on fine-scale animal movement are being collected worldwide, with the number of species being tagged and the resolution of data rapidly increasing. In this study, a general methodology is proposed to understand the patterns in these high resolution movement time series that relate to marine animal behavior. The approach is illustrated with dive data from a northern fur seal (Callorhinus ursinus) tagged on the Pribilof Islands, Alaska, USA. We apply a state-space model composed of a movement model and corresponding high-resolution vertical movement data. The central goal is to estimate parameters of this movement model, particularly their variation on appropriate time scales, thereby providing a direct link to behavior. A particle filter with state augmentation is used to jointly estimate the movement parameters and the state. A multiple iterated filter using overlapping data segments is implemented to match the parameter time scale with the behavioral inference. The time variation in the auto-covariance function facilitates identification of a movement model, allows separation of observation and process noise, and provides for validation of results. The analysis yields fitted parameters that show distinct time-evolving changes in fur seal behavior over time, matching well what is observed in the original data set. PMID- 21608466 TI - Substrate size mediates thermal stress in the rocky intertidal. AB - Variation in physical factors, such as slope, orientation, and wind exposure, shapes thermal conditions. Variation in substrate size is common in many habitats, but its thermal consequences for organisms are not well characterized. Larger substrates should remain more thermally stable and act as thermal refuges for associated organisms during short, thermally stressful periods such as midday temperature peaks or tidal exposure. In observations and a transplant and thermal integration experiment, we found that larger rock substrates stayed cooler and facilitated greater survival of the barnacle Semibalanus balanoides in the high intertidal relative to small substrates during the hot summer months in southern New England, USA. However, in thermally benign northern New England, rock substrate size had no effect on barnacle distributions, indicating that the thermal effects of substrate size are mediated by regional climate. PMID- 21608467 TI - Generalized functional responses for species distributions. AB - Researchers employing resource selection functions (RSFs) and other related methods aim to detect correlates of space-use and mitigate against detrimental environmental change. However, an empirical model fit to data from one place or time is unlikely to capture species responses under different conditions because organisms respond nonlinearly to changes in habitat availability. This phenomenon, known as a functional response in resource selection, has been debated extensively in the RSF literature but continues to be ignored by practitioners for lack of a practical treatment. We therefore extend the RSF approach to enable it to estimate generalized functional responses (GFRs) from spatial data. GFRs employ data from several sampling instances characterized by diverse profiles of habitat availability. By modeling the regression coefficients of the underlying RSF as functions of availability, GFRs can account for environmental change and thus predict population distributions in new environments. We formulate the approach as a mixed-effects model so that it is estimable by readily available statistical software. We illustrate its application using (1) simulation and (2) wolf home-range telemetry. Our results indicate that GFRs can offer considerable improvements in estimation speed and predictive ability over existing mixed-effects approaches. PMID- 21608468 TI - Holocene forest development and maintenance on different substrates in the Klamath Mountains, northern California, USA. AB - The influence of substrate on long-term vegetation dynamics has received little attention, and yet nutrient-limited ecosystems have some of the highest levels of endemism in the world. The diverse geology of the Klamath Mountains of northern California (USA) allows examination of the long-term influence of edaphic constraints in subalpine forests through a comparison of vegetation histories between nutrient-limited ultramafic substrates and terrain that is more fertile. Pollen and charcoal records spanning up to 15000 years from ultramafic settings reveal a distinctly different vegetation history compared to other soil types. In non-ultramafic settings, the dominant trees and shrubs shifted in elevation in response to Holocene climate variations resulting in compositional and structural changes, whereas on ultramafic substrates changes were primarily structural, not compositional. Fire activity was similar through most of the Holocene with the exception of declines over the last 4000 years on ultramafic substrates, likely due to the reduction of understory fuels and cooler wetter conditions than in the middle Holocene. These results suggest that the tree and shrub distributions were more responsive to past climate changes on non-ultramafic substrates compared to those on ultramafic substrates. The combination of these dynamics may help explain high levels of plant diversity in the Klamath Mountains and provide insights for managing these complex ecosystems. PMID- 21608469 TI - Is plant community richness regulated over time? Contrasting results from experiments and long-term observations. AB - There is considerable debate among ecologists as to whether or not communities are saturated. In saturated communities, species richness should remain relatively constant over time, despite compositional turnover, because richness is negatively correlated with colonization and positively correlated with local extinction. Few studies have tested for saturation using temporal observational data as well as diversity-perturbation experiments. We analyzed 10 years of data for plant species richness at 71 sites on contrasting serpentine and non serpentine soils within Californian (USA) grasslands. We also manipulated local richness and measured its effects on immigration and extinction. Consistent with saturation, we observed that richness was positively correlated with extinction rates and negatively correlated with colonization rates, and randomization tests confirmed that diversity fluctuated less than expected by chance. However, experimental species additions and removals did not affect extinction or colonization, suggesting that richness is not regulated by local species interactions. Instead, we propose three reasons why richness may fluctuate within narrow limits causing the appearance of saturation in temporal observational data sets: negatively autocorrelated patterns of biotic response to yearly conditions, differential affinities of particular species for local conditions, or stochastic abundance-dependent colonization and extinction rates. We illustrate the latter using a metacommunity model. PMID- 21608470 TI - Root plasticity buffers competition among plants: theory meets experimental data. AB - Morphological plasticity is a striking characteristic of plants in natural communities. In the context of foraging behavior particularly, root plasticity has been documented for numerous species. Root plasticity is known to mitigate competitive interactions by reducing the overlap of the individuals' rhizospheres. But despite its obvious effect on resource acquisition, plasticity has been generally neglected in previous empirical and theoretical studies estimating interaction intensity among plants. In this study, we developed a semi mechanistic model that addresses this shortcoming by introducing the idea of compensatory growth into the classical-zone-of influence (ZOI) and field-of neighborhood (FON) approaches. The model parameters describing the belowground plastic sphere of influence (PSI) were parameterized using data from an accompanying field experiment. Measurements of the uptake of a stable nutrient analogue at distinct distances to the neighboring plants showed that the study species responded plastically to belowground competition by avoiding overlap of individuals' rhizospheres. An unexpected finding was that the sphere of influence of the study species Bromus hordeaceus could be best described by a unimodal function of distance to the plant's center and not with a continuously decreasing function as commonly assumed. We employed the parameterized model to investigate the interplay between plasticity and two other important factors determining the intensity of competitive interactions: overall plant density and the distribution of individuals in space. The simulation results confirm that the reduction of competition intensity due to morphological plasticity strongly depends on the spatial structure of the competitive environment. We advocate the use of semi mechanistic simulations that explicitly consider morphological plasticity to improve our mechanistic understanding of plant interactions. PMID- 21608471 TI - Changes in microbial community characteristics and soil organic matter with nitrogen additions in two tropical forests. AB - Microbial communities and their associated enzyme activities affect the amount and chemical quality of carbon (C) in soils. Increasing nitrogen (N) deposition, particularly in N-rich tropical forests, is likely to change the composition and behavior of microbial communities and feed back on ecosystem structure and function. This study presents a novel assessment of mechanistic links between microbial responses to N deposition and shifts in soil organic matter (SOM) quality and quantity. We used phospholipid fatty acid (PLFA) analysis and microbial enzyme assays in soils to assess microbial community responses to long term N additions in two distinct tropical rain forests. We used soil density fractionation and 13C nuclear magnetic resonance (NMR) spectroscopy to measure related changes in SOM pool sizes and chemical quality. Microbial biomass increased in response to N fertilization in both tropical forests and corresponded to declines in pools of low-density SOM. The chemical quality of this soil C pool reflected ecosystem-specific changes in microbial community composition. In the lower-elevation forest, there was an increase in gram negative bacteria PLFA biomass, and there were significant losses of labile C chemical groups (O-alkyls). In contrast, the upper-elevation tropical forest had an increase in fungal PLFAs with N additions and declines in C groups associated with increased soil C storage (alkyls). The dynamics of microbial enzymatic activities with N addition provided a functional link between changes in microbial community structure and SOM chemistry. Ecosystem-specific changes in microbial community composition are likely to have far-reaching effects on soil carbon storage and cycling. This study indicates that microbial communities in N rich tropical forests can be sensitive to added N, but we can expect significant variability in how ecosystem structure and function respond to N deposition among tropical forest types. PMID- 21608472 TI - Light-stress avoidance mechanisms in a Sphagnum-dominated wet coastal Arctic tundra ecosystem in Alaska. AB - The Arctic experiences a high-radiation environment in the summer with 24-hour daylight for more than two months. Damage to plants and ecosystem metabolism can be muted by overcast conditions common in much of the Arctic. However, with climate change, extreme dry years and clearer skies could lead to the risk of increased photoxidation and photoinhibition in Arctic primary producers. Mosses, which often exceed the NPP of vascular plants in Arctic areas, are often understudied. As a result, the effect of specific environmental factors, including light, on these growth forms is poorly understood. Here, we investigated net ecosystem exchange (NEE) at the ecosystem scale, net Sphagnum CO2 exchange (NSE), and photoinhibition to better understand the impact of light on carbon exchange from a moss-dominated coastal tundra ecosystem during the summer season 2006. Sphagnum photosynthesis showed photoinhibition early in the season coupled with low ecosystem NEE. However, later in the season, Sphagnum maintained a significant CO2 uptake, probably for the development of subsurface moss layers protected from strong radiation. We suggest that the compact canopy structure of Sphagnum reduces light penetration to the subsurface layers of the moss mat and thereby protects the active photosynthetic tissues from damage. This stress avoidance mechanism allowed Sphagnum to constitute a significant percentage (up to 60%) of the ecosystem net daytime CO2 uptake at the end of the growing season despite the high levels of radiation experienced. PMID- 21608473 TI - Long-term aboveground and belowground consequences of red wood ant exclusion in boreal forest. AB - Despite their ubiquity, the role of ants in driving ecosystem processes both aboveground and belowground has been seldom explored, except within the nest. During 1995 we established 16 ant exclusion plots of approximately 1.1 x 1.1 m, together with paired control plots, in the understory layer of a boreal forest ecosystem in northern Sweden that supports high densities of the mound-forming ant Formica aquilonia, a red wood ant species of the Formica rufa group. Aboveground and belowground measurements were then made on destructively sampled subplots in 2001 and 2008, i.e., 6 and 13 years after set-up. While ant exclusion had no effect on total understory plant biomass, it did greatly increase the relative contribution of herbaceous species, most likely through preventing ants from removing their seeds. This in turn led to higher quality resources entering the belowground subsystem, which in turn stimulated soil microbial biomass and activity and the rates of loss of mass and carbon (C) and nitrogen (N) from litter in litterbags placed in the plots. This was accompanied by losses of approximately 15% of N and C stored in the humus on a per area basis. Ant exclusion also had some effects on foliar stable isotope ratios for both C and N, most probably as a consequence of greater soil fertility. Further, exclusion of ants had multitrophic effects on a microbe-nematode soil food web with three consumer trophic levels and after six years promoted the bacterial-based relative to the fungal-based energy channel in this food web. Our results point to a major role of red wood ants in determining forest floor vegetation and thereby exerting wide-ranging effects on belowground properties and processes. Given that the boreal forest occupies 11% of the Earth's terrestrial surface and stores more C than any other forest biome, our results suggest that this role of ants could potentially be of widespread significance for biogeochemical nutrient cycling, soil nutrient capital, and sequestration of belowground carbon. PMID- 21608474 TI - The invasive grass Agropyron cristatum doubles belowground productivity but not soil carbon. AB - Root dynamics are among the largest knowledge gaps in determining how terrestrial carbon (C) cycles will respond to environmental change. Increases in productivity accompanying plant invasions and introductions could increase ecosystem C storage, but belowground changes are unknown, even though roots may account for 50-90% of production in temperate ecosystems. We examined whether the introduction of a widespread invasive grass with relatively high shoot production also increased belowground productivity and soil C storage, using a multiyear rhizotron study in 50-year-old stands dominated either by the invasive C3 grass Agropyron cristatum or by largely C4 native grasses. Relative to native vegetation, stands dominated by the invader had doubled root productivity. Soil carbon isotope values showed that the invader had made detectable contributions to soil C. Soil C content, however, was not significantly different between invader-dominated stands (0.42 mg C/g soil) and native vegetation (0.45 mg C/g soil). The discrepancy between enhanced production and lack of soil C changes was attributable to differences in root traits between invader-dominated stands and native vegetation. Relative to native vegetation, roots beneath the invader had 59% more young white tissue, with 80% higher mortality and 19% lower C:N ratios (all P < 0.05). Such patterns have previously been reported for aboveground tissues of invaders, and we show that they are also found belowground. If these root traits occur in other invasive species, then the global phenomenon of increased productivity following biological invasion may not increase soil C storage. PMID- 21608475 TI - Population regulation by enemies of the grass Brachypodium sylvaticum: demography in native and invaded ranges. AB - The enemy-release hypothesis (ERH) states that species become more successful in their introduced range than in their native range because they leave behind natural enemies in their native range and are thus "released" from enemy pressures in their introduced range. The ERH is popularly cited to explain the invasive properties of many species and is the underpinning of biological control. We tested the prediction that plant populations are more strongly regulated by natural enemies (herbivores and pathogens) in their native range than in their introduced range with enemy-removal experiments using pesticides. These experiments were replicated at multiple sites in both the native and invaded ranges of the grass Brachypodium sylvaticum. In support of the ERH, enemies consistently regulated populations in the native range. There were more tillers and more seeds produced in treated vs. untreated plots in the native range, and few seedlings survived in the native range. Contrary to the ERH, total measured leaf damage was similar in both ranges, though the enemies that caused it differed. There was more damage by generalist mollusks and pathogens in the native range, and more damage by generalist insect herbivores in the invaded range. Demographic analysis showed that population growth rates were lower in the native range than in the invaded range, and that sexually produced seedlings constituted a smaller fraction of the total in the native range. Our removal experiment showed that enemies regulate plant populations in their native range and suggest that generalist enemies, not just specialists, are important for population regulation. PMID- 21608476 TI - Seed arrival and ecological filters interact to assemble high-diversity plant communities. AB - Two prominent mechanisms proposed to structure biodiversity are niche-based ecological filtering and chance arrival of propagules from the species pool. Seed arrival is hypothesized to play a particularly strong role in high-diversity plant communities with large potential species pools and many rare species, but few studies have explored how seed arrival and local ecological filters interactively assemble species-rich communities in space and time. We experimentally manipulated seed arrival and multiple ecological filters in high diversity, herbaceous-dominated groundcover communities in longleaf pine savannas, which contain the highest small-scale species richness in North America (up to > 40 species/m2). We tested three hypotheses: (1) local communities constitute relatively open-membership assemblages, in which increased seed arrival from the species pool strongly increases species richness; (2) ecological filters imposed by local fire intensity and soil moisture influence recruitment and richness of immigrating species; and (3) ecological filters increase similarity in the composition of immigrating species. In a two-year factorial field experiment, we manipulated local fire intensity by increasing pre-fire fuel loads, soil moisture using rain shelters and irrigation, and seed arrival by adding seeds from the local species pool. Seed arrival increased species richness regardless of fire intensity and soil moisture but interacted with both ecological filters to influence community assembly. High-intensity fire decreased richness of resident species, suggesting an important abiotic filter. In contrast, high-intensity fire increased recruitment and richness of immigrating species, presumably by decreasing effects of other ecological filters (competition and resource limitation) in postfire environments. Drought decreased recruitment and richness of immigrating species, whereas wet soil conditions increased recruitment but decreased or had little effect on richness. Moreover, some ecological filters (wet soil conditions and, to a lesser extent, high intensity fire) increased similarity in the composition of immigrating species, illustrating conditions that influence deterministic community assembly in species-rich communities. Our experiment provides insights into how dispersal assembly mechanisms may interact with niche-assembly mechanisms in space (spatial variation in disturbance) and time (temporal variation in resource availability) to structure high-diversity communities and can help guide conservation of threatened longleaf pine ecosystems in the face of habitat fragmentation and environmental change. PMID- 21608477 TI - Daily temporal structure in African savanna flower visitation networks and consequences for network sampling. AB - Ecological interaction networks are a valuable approach to understanding plant pollinator interactions at the community level. Highly structured daily activity patterns are a feature of the biology of many flower visitors, particularly provisioning female bees, which often visit different floral sources at different times. Such temporal structure implies that presence/absence and relative abundance of specific flower-visitor interactions (links) in interaction networks may be highly sensitive to the daily timing of data collection. Further, relative timing of interactions is central to their possible role in competition or facilitation of seed set among coflowering plants sharing pollinators. To date, however, no study has examined the network impacts of daily temporal variation in visitor activity at a community scale. Here we use temporally structured sampling to examine the consequences of daily activity patterns upon network properties using fully quantified flower-visitor interaction data for a Kenyan savanna habitat. Interactions were sampled at four sequential three-hour time intervals between 06:00 and 18:00, across multiple seasonal time points for two sampling sites. In all data sets the richness and relative abundance of links depended critically on when during the day visitation was observed. Permutation-based null modeling revealed significant temporal structure across daily time intervals at three of the four seasonal time points, driven primarily by patterns in bee activity. This sensitivity of network structure shows the need to consider daily time in network sampling design, both to maximize the probability of sampling links relevant to plant reproductive success and to facilitate appropriate interpretation of interspecific relationships. Our data also suggest that daily structuring at a community level could reduce indirect competitive interactions when coflowering plants share pollinators, as is commonly observed during flowering in highly seasonal habitats. PMID- 21608478 TI - Leaf quality, predators, and stochastic processes in the assembly of a diverse herbivore community. AB - Ecological communities are structured by both deterministic, niche-based processes and stochastic processes such as dispersal. A pressing issue in ecology is to determine when and for which organisms each of these types of processes is important in community assembly. The roles of deterministic and stochastic processes have been studied for a variety of communities, but very few researchers have addressed their contribution to insect herbivore community structure. Insect herbivore niches are often described as largely shaped by the antagonistic pressures of predation and host plant defenses. However host plants are frequently discrete patches of habitat, and their spatial arrangement can affect herbivore dispersal patterns. We studied the roles of predation, host plant quality, and host spatial proximity for the assembly of a diverse insect herbivore community on Quercus alba (white oak) across two growing seasons. We examined abundances of feeding guilds to determine if ecologically similar species responded similarly to variation in niches. Most guilds responded similarly to leaf quality, preferring high-nitrogen, low-tannin host plants, particularly late in the growing season, while bird predation had little impact on herbivore abundance. The communities on the high-quality plants tended to be larger and, in some cases, have greater species richness. We analyzed community composition by correlating indices of community similarity with predator presence, leaf quality similarity, and host plant proximity. Birds did not affect community composition. Community similarity was significantly associated with distance between host plants and uncorrelated with leaf quality similarity. Thus although leaf quality significantly affected the total abundance of herbivores on a host plant, in some cases leading to increased species richness, dispersal limitation may weaken this relationship. The species composition of these communities may be driven by stochastic processes rather than variation in host plant characteristics or differential predation by insectivorous birds. PMID- 21608479 TI - Model selection analysis of temporal variation in benefit for an ant-tended treehopper. AB - Recent studies of mutualism have emphasized both that the net benefit to participants depends on the ecological context and that the density-dependent pattern of benefit is key to understanding the population dynamics of mutualism. Indeed, changes in the ecological context are likely to drive changes in both the magnitude of benefit and the density-dependent pattern of benefit. Despite the close linkage between these two areas of research, however, few studies have addressed the factors underlying variation in the density-dependent pattern of benefit. Here I use model selection to evaluate how variation in the benefits of a mutualism drives temporal variation in the density-dependent pattern of net benefit for the ant-tended treehopper Publilia concava. In the interaction between ants and treehoppers in the genus Publilia, ants collect the sugary excretions of treehoppers as a food resource, and treehoppers benefit both directly (e.g., by feeding facilitation) and indirectly (e.g., by predator protection). Results presented here show that temporal changes in the relative magnitude of direct and indirect benefit components of ant tending, especially the effectiveness of predator protection by ants, qualitatively change the overall pattern of density-dependent benefit between years with maximum benefit shifting from treehoppers in small to large aggregations. These results emphasize the need for empirical studies that evaluate the long-term dynamics of mutualism and theoretical studies that consider the population dynamics consequences of variation in the density-dependent pattern of benefit. PMID- 21608480 TI - Examining the coupling of carbon and nitrogen cycles in Appalachian streams: the role of dissolved organic nitrogen. AB - Although regional and global models of nitrogen (N) cycling typically focus on nitrate, dissolved organic nitrogen (DON) is the dominant form of nitrogen export from many watersheds and thus the dominant form of dissolved N in many streams. Our understanding of the processes controlling DON export from temperate forests is poor. In pristine systems, where biological N limitation is common, N contained in recalcitrant organic matter (OM) can dominate watershed N losses. This recalcitrant OM often has moderately constrained carbon:nitrogen (C:N) molar ratios (approximately 25-55) and therefore, greater DON losses should be observed in sites where there is greater total dissolved organic carbon (DOC) loss. In regions where anthropogenic N pollution is high, it has been suggested that increased inorganic N availability can reduce biological demand for organic N and therefore increase watershed DON losses. This would result in a positive correlation between inorganic and organic N concentrations across sites with varying N availability. In four repeated synoptic surveys of stream water chemistry from forested watersheds along an N loading gradient in the southern Appalachians, we found surprisingly little correlation between DON and DOC concentrations. Further, we found that DON concentrations were always significantly correlated with watershed N loading and stream water [NO3-] but that the direction of this relationship was negative in three of the four surveys. The C:N molar ratio of dissolved organic matter (DOM) in streams draining watersheds with high N deposition was very high relative to other freshwaters. This finding, together with results from bioavailability assays in which we directly manipulated C and N availabilities, suggests that heterotrophic demand for labile C can increase as a result of dissolved inorganic N (DIN) loading, and that heterotrophs can preferentially remove N-rich molecules from DOM. These results are inconsistent with the two prevailing hypotheses that dominate interpretations of watershed DON loss. Therefore, we propose a new hypothesis, the indirect carbon control hypothesis, which recognizes that heterotrophic demand for N-rich DOM can keep stream water DON concentrations low when N is not limiting and heterotrophic demand for labile C is high. PMID- 21608481 TI - Predicting richness effects on ecosystem function in natural communities: insights from high-elevation streams. AB - . Despite the increased complexity of experimental and theoretical studies on the biodiversity-ecosystem functioning (B-EF) relationship, a major challenge is to demonstrate whether the observed importance of biodiversity in controlled experimental systems also persists in nature. Due to their structural simplicity and their low levels of human impacts, extreme species-poor ecosystems may provide new insights into B-EF relationships in natural systems. We address this issue using shredder invertebrate communities and organic matter decomposition rates in 24 high-altitude (3200-3900 m) Neotropical streams as a study model. We first assessed the effects of stream characteristics and shredder diversity and abundance on organic matter decomposition rates in coarse- and fine-mesh bags. We found the interaction term shredder richness x shredder abundance had the most significant impact on decomposition rates in the field, although water discharge may also play a role locally. We also examined the relative contribution of the three most abundant shredders on decomposition rates by manipulating shredder richness and community composition in a field experiment. Transgressive overyielding was detected among the three shredder species, indicating complementary resource use and/or facilitation. By integrating survey and experimental data in surface response analyses we found that observed B-EF patterns fit those predicted by a linear model that described litter decomposition rates as a function of increasing shredder richness and the relative abundance of the most efficient shredders. Finally, the validity of our approach was tested in a broader context by using two independent but comparable data sets from 49 French and Swedish streams showing more complex shredder community structure. Results revealed that richness and identity effects on decomposition rates were lost with increasing shredder community complexity. Our approach of combining experimental and empirical data with modeling in species poor ecosystems may serve as an impetus for new B-EF studies. If theory can explain B-EF in low-diversity ecosystems, it may also have credibility in more complex ones. PMID- 21608482 TI - Prey morphology constrains the feeding ecology of an aquatic generalist predator. AB - Resource availability and accessibility are primary factors guiding the distribution and abundance of organisms. For generalists, prey availability reflects both prey abundance and differences in quality among prey taxa. Although some aspects of prey quality, such as nutritional composition, are well studied, our understanding of how prey morphology contributes to overall prey quality is limited. Because snakes cannot reduce prey size by mastication, many aspects of their feeding ecology (e.g., maximum prey size, feeding performance, and the degree of postprandial locomotor impairment) may be affected by prey shape. We conducted a uniquely comprehensive comparison of prey quality for a generalist species, the banded watersnake (Nerodia fasciata), using prey that were similar in mass and presumably similar in nutritional composition but different in shape and habitat association. Specifically, we compared nutritional composition and shape of paedomorphic salamanders (Ambystoma talpoideum) and sunfish (Lepomis MARGINATUS) and used a series of repeated-measures experiments to examine feeding performance (number of prey consumed, maximum prey size, and intra-oral transport time), digestive metabolism (specific dynamic action, SDA), and postprandial locomotor performance of snakes fed Ambystoma and Lepomis. Cost of digestion was similar between the prey types, likely reflecting their similar nutritional composition. However, snakes consumed larger Ambystoma than Lepomis and intra oral transport time was much shorter for Ambystoma. Snakes fed Lepomis also suffered greater reduction in crawling speed than those fed Ambystoma. These differences highlight the need for behaviorally integrated approaches to understanding prey quality and support field observations of the importance of amphibian prey for juvenile watersnakes. PMID- 21608483 TI - The stochastic demography of two coexisting male morphs. AB - Abstract. If genetically distinct morphs coexist under a range of natural conditions, they should have equal long-run fitnesses across a wide range of different stochastic environments. In other words, the sequence and frequency of good and bad environments should not substantially impact long-run growth rates. When different morphs have contrasting life histories that vary with environmental conditions, however, it seems improbable that growth rates can be equivalent across a range of stochastic environments without invoking a strong stabilizing mechanism to explain their persistence. As yet, there has been no research characterizing the long-run stochastic growth rate (lambdaS) of different morphs across a wide range of stochastic environments. Assuming density independence, we show that the two genetic male morphs in the bulb mite (Rhizoglyphus robini-fighters, which are able to kill other mites, and benign scramblers-have similar lambdas in different Markovian environments (different simulated random sequences of good and bad habitats). Elasticity analyses revealed that Xs was most sensitive to perturbation of adult survival rate. A slight (biologically and statistically realistic) increase in scrambler adult survival equalized scrambler and fighter X,. The fitness equivalence of the two morphs suggests that stabilizing mechanisms, such as density or frequency dependence, required to maintain their coexistence, are weak. We advocate that stochastic demography can offer a powerful approach to identify and understand the circumstances under which genetic polymorphisms can be maintained in stochastic environments. PMID- 21608484 TI - The influence of resource subsidies on cave invertebrates: results from an ecosystem-level manipulation experiment. AB - Spatial resource subsidies can greatly affect the composition and dynamics of recipient communities. Caves are especially tractable for studying spatial subsidies because primary productivity is absent. Here, we performed an ecosystem level manipulation experiment to test the direct influence of detrital subsidies on community structure in terrestrial cave ecosystems. After performing baseline censuses of invertebrates, we removed all organic material from 12 caves and constructed exclusion boxes to prevent natural resource inputs. Next, we stocked each cave with standardized quantities of two major natural subsidies to caves: leaves (leaf packs) and carcasses (commercially supplied rodents), and measured the invertebrate colonization and utilization of these resources for 23 months. Over the course of the experiment, 102 morphospecies were observed. Diplopods and collembolans were most abundant on leaf packs, and dipteran larvae and collembolans were most abundant on the rats. On average, caves receiving either treatment did not differ in species richness, but abundance was significantly higher in rat caves over both the duration of the experiment and the temporal "life" of the individual resources, which were restocked upon exhaustion. Post manipulation invertebrate communities differed predictably depending on the type of subsidy introduced. Over the course of the experiment, caves that received the same subsidy clustered together based on community composition. In addition, the invertebrate community utilizing the resource changed over the duration of the two-year experiment, and evidence of succession (i.e., directional change) was observed. Results from this study demonstrate how allochthonous resources can drive the community dynamics of terrestrial invertebrates in cave ecosystems and highlight the need for consideration of the surface environment when managing and protecting these unique habitats. PMID- 21608485 TI - How well do predators adjust to climate-mediated shifts in prey distribution? A study on Australian water pythons. AB - Climate change can move the spatial location of resources critical for population viability, and a species' resilience to such changes will depend upon its ability to flexibly shift its activities away from no-longer-suitable sites to exploit new opportunities. Intuition suggests that vagile predators should be able to track spatial shifts in prey availability, but our data on water pythons (Liasisfuscus) in tropical Australia suggest a less encouraging scenario. These pythons undergo regular long-range (to >10 kmin) seasonal migrations to follow flooding-induced migrations by their prey (native dusky rats, Rattus colletti). However, when an extreme flooding event virtually eliminated rats for a three year period, the local pythons did not disperse despite the presence of abundant rats only 8 km away; instead, many pythons starved to death. This inflexibility suggests that some vagile species that track seasonally migrating prey may do so by responding to habitat attributes that have consistently predicted prey availability over evolutionary time, rather than reacting to proximate cues that signal the presence of prey per se. A species' vulnerability to climate change will be increased by an inability to shift its activities away from historical sites toward newly favorable areas. PMID- 21608486 TI - Avian predators are less abundant during periodical cicada emergences, but why? AB - Despite a substantial resource pulse, numerous avian insectivores known to depredate periodical cicadas (Magicicada spp.) are detected less commonly during emergence years than in either the previous or following years. We used data on periodical cicada calls collected by volunteers conducting North American Breeding Bird Surveys within the range of cicada Brood X to test three hypotheses for this observation: lower detection rates could be caused by bird calls being obscured by cicada calls ("detectability" hypothesis), by birds avoiding areas with cicadas ("repel" hypothesis), or because bird abundances are generally lower during emergence years for some reason unrelated to the current emergence event ("true decline" hypothesis). We tested these hypotheses by comparing bird detections at stations coincident with calling cicadas vs. those without calling cicadas in the year prior to and during cicada emergences. At four distinct levels (stop, route, range, and season), parallel declines of birds in groups exposed and not exposed to cicada calls supported the true decline hypothesis. We discuss several potential mechanisms for this pattern, including the possibility that it is a consequence of the ecological and evolutionary interactions between predators of this extraordinary group of insects. PMID- 21608487 TI - Issues with ozone attainment methodology for Houston, TX. PMID- 21608488 TI - Greenhouse gas emissions from waste management--assessment of quantification methods. AB - Of the many sources of urban greenhouse gas (GHG) emissions, solid waste is the only one for which management decisions are undertaken primarily by municipal governments themselves and is hence often the largest component of cities' corporate inventories. It is essential that decision-makers select an appropriate quantification methodology and have an appreciation of methodological strengths and shortcomings. This work compares four different waste emissions quantification methods, including Intergovernmental Panel on Climate Change (IPCC) 1996 guidelines, IPCC 2006 guidelines, U.S. Environmental Protection Agency (EPA) Waste Reduction Model (WARM), and the Federation of Canadian Municipalities-Partners for Climate Protection (FCM-PCP) quantification tool. Waste disposal data for the greater Toronto area (GTA) in 2005 are used for all methodologies; treatment options (including landfill, incineration, compost, and anaerobic digestion) are examined where available in methodologies. Landfill was shown to be the greatest source of GHG emissions, contributing more than three quarters of total emissions associated with waste management. Results from the different landfill gas (LFG) quantification approaches ranged from an emissions source of 557 kt carbon dioxide equivalents (CO2e) (FCM-PCP) to a carbon sink of 53 kt CO2e (EPA WARM). Similar values were obtained between IPCC approaches. The IPCC 2006 method was found to be more appropriate for inventorying applications because it uses a waste-in-place (WIP) approach, rather than a methane commitment (MC) approach, despite perceived onerous data requirements for WIP. MC approaches were found to be useful from a planning standpoint; however, uncertainty associated with their projections of future parameter values limits their applicability for GHG inventorying. MC and WIP methods provided similar results in this case study; however, this is case specific because of similarity in assumptions of present and future landfill parameters and quantities of annual waste deposited in recent years being relatively consistent. PMID- 21608489 TI - Measuring in-cabin school bus tailpipe and crankcase PM2.5: a new dual tracer method. AB - Exposures of occupants in school buses to on-road vehicle emissions, including emissions from the bus itself, can be substantially greater than those in outdoor settings. A dual tracer method was developed and applied to two school buses in Seattle in 2005 to quantify in-cabin fine particulate matter (PM2.5) concentrations attributable to the buses' diesel engine tailpipe (DPMtp) and crankcase vent (PMck) emissions. The new method avoids the problem of differentiating bus emissions from chemically identical emissions of other vehicles by using a fuel-based organometallic iridium tracer for engine exhaust and by adding deuterated hexatriacontane to engine oil. Source testing results showed consistent PM:tracer ratios for the primary tracer for each type of emissions. Comparisons of the PM:tracer ratios indicated that there was a small amount of unburned lubricating oil emitted from the tailpipe; however, virtually no diesel fuel combustion products were found in the crankcase emissions. For the limited testing conducted here, although PMck emission rates (averages of 0.028 and 0.099 g/km for the two buses) were lower than those from the tailpipe (0.18 and 0.14 g/km), in-cabin PMck concentrations averaging 6.8 microg/m3 were higher than DPMtp (0.91 microg/m3 average). In-cabin DPMtp and PMck concentrations were significantly higher with bus windows closed (1.4 and 12 microg/m3, respectively) as compared with open (0.44 and 1.3 microg/m3, respectively). For comparison, average closed- and open-window in-cabin total PM2.5 concentrations were 26 and 12 microg/m3, respectively. Despite the relatively short in-cabin sampling times, very high sensitivities were achieved, with detection limits of 0.002 microg/m3 for DPMtp and 0.05 microg/m3 for PMck. PMID- 21608490 TI - In-use fuel economy of hybrid-electric school buses in Iowa. AB - Although it is much safer and more fuel-efficient to transport children to school in buses than in private vehicles, school buses in the United States still consume 822 million gal of diesel fuel annually, and school transportation costs can account for a significant portion of resource-constrained school district budgets. Additionally, children in diesel-powered school buses may be exposed to higher levels of particulates and other pollutants than children in cars. One solution to emission and fuel concerns is use of hybrid-electric school buses, which have the potential to reduce emissions and overall lifecycle costs compared with conventional diesel buses. Hybrid-electric technologies are available in the passenger vehicle market as well as the transit bus market and have a track record indicating fuel economy and emissions benefits. This paper summarizes the results of an in-use fuel economy evaluation for two plug-in hybrid school buses deployed in two different school districts in Iowa. Each school district selected a control bus with a route similar to that of the hybrid bus. Odometer readings, fuel consumption, and maintenance needs were recorded for each bus. The buses were deployed in 2008 and data were collected through May 2010. Fuel consumption was calculated for each school district. In Nevada, IA, the overall average fuel economy was 8.23 mpg for the hybrid and 6.35 mpg for the control bus. In Sigourney, IA, the overall average fuel economy was 8.94 mpg for the hybrid and 6.42 mpg for the control bus. The fuel consumption data were compared for the hybrid and control buses using a Wilcoxon signed rank test. Results indicate that fuel economy for the Nevada hybrid bus was 29.6% better than for the Nevada control bus, and fuel economy for the Sigourney hybrid bus was 39.2% higher than for the Sigourney control bus. Both differences were statistically significant. PMID- 21608491 TI - The reduction of dioxin emissions from the processes of heat and power generation. AB - The first reports that it is possible to emit dioxins from the heat and power generation sector are from the beginning of the 1980s. Detailed research proved that the emission of dioxins might occur during combustion of hard coal, brown coal, and furnace oil as well as coke-oven gas. The emission of dioxins occurs in wood incineration; wood that is clean and understood as biomass; or, in particular, wood waste (polluted). This paper thoroughly discusses the mechanism of dioxin formation in thermal processes, first and foremost in combustion processes. The parameters influencing the quantity of dioxins formed and the dependence of their quantity on the conditions of combustion are highlighted. Furthermore, the methods of reducing dioxin emissions from combustion processes (primary and secondary) are discussed. The most efficacious methods that may find application in the heat and power generation sector are proposed; this is relevant from the point of view of the implementation of the Stockholm Convention resolutions in Poland with regard to persistent organic pollutants. PMID- 21608492 TI - Removal of propylene and butylene as individual compounds with compost and wood chip biofilters. AB - Propylene and butylene are highly reactive volatile organic compounds (HRVOCs) in terms of ground-level ozone formation. This study examined the effectiveness of biofiltration in removing propylene and butylene as separate compounds. Specific objectives were (1) to measure maximum removal efficiencies for propylene and butylene and the corresponding microbial acclimation times, which will be useful in the design of future biofilters for removal of these compounds; (2) to compare removal efficiencies of propylene and butylene for different ratios of compost/hard wood-chip media; and (3) to identify the microorganisms responsible for propylene and butylene degradation. Two laboratory-scale polyvinyl chloride biofilter columns were filled with 28 in. of biofilter media (compost/wood-chip mixtures of 80:20 and 50:50 ratios). Close to 100% removal efficiency was obtained for propylene for inlet concentrations ranging from 2.9 x 10(4) to 6.3 x 10(4) parts per million (ppm) (232-602 g/m3-hr) and for butylene for inlet concentrations ranging from 91 to 643 ppm (1.7-13.6 g/m3-hr). The microbial acclimation period to attain 100% removal efficiency was 12-13 weeks for both compounds. The lack of similar microbial species in the fresh and used media likely accounts for the long acclimation time required. Both ratios of compost/wood chips (80:20 and 50:50) gave similar results. During the testing, media pH increased slightly from 7.1 to 7.5-7.7. None of the species in the used media that treated butylene were the same as those in the used media that treated propylene, indicating that different microbes are adept at degrading the two compounds. PMID- 21608493 TI - Study of the transference rules for bromine in waste printed circuit boards during microwave-induced pyrolysis. AB - The production of waste printed circuit boards (WPCBs) has drawn increasing global concern, especially because the high bromine (Br) content (5-15%) places obstacles in the way of simple disposal techniques. Microwave-induced pyrolysis of WPCBs provides a promising way to dispose of these hazardous and resource filled wastes. The transference rules for Br during microwave-induced pyrolysis have been investigated experimentally. It was found that the microwave energy could be used more efficiently to accelerate the heating rate and improve the final pyrolysis temperature by adding some activated carbon (AC) as microwave absorbents. The high temperature and rapid pyrolysis process promoted the yields of gaseous products and the decomposition of brominated compounds into hydrogen bromide and then benefited the capture of Br and the debromination of byproducts. The application of a calcium carbonate (CaCO3) layer overhead led to over 95% debromination of the liquid products and over 50% capture of the total Br. It can be concluded that the presented method is suitable for the control of Br transference in the recycling of WPCBs. This method can also be extended to the disposal of the electronic scraps. PMID- 21608494 TI - Preparation of activated carbons from raw and biotreated agricultural residues for removal of volatile organic compounds. AB - Activated carbons with diverse physical and chemical properties were produced from four agriculture residues, including raw barley husk, biotreated barley husk, rice husk, and pistachio shell. Results showed that with adequate steam activation (30-90 min, 50% H2O(g),/50% N2), activated carbons with surface areas between 360 and 950 m2 g(-1) were developed. Further increases in the activation time destroyed the pore structure of activated carbons, which resulted in a decrease in the surface area and pore volume. Biotreated agricultural residues were found to be suitable precursors for producing mesoporous activated carbons. The oxygen content of activated carbons increased with increasing activation time. Results from X-ray photoelectron spectroscopy examination further suggested that H2O molecules react with the carbon surface, enhancing the deconvoluted peak area of carbonyl and carboxyl groups. Equilibrium adsorption of toluene indicated that the adsorption capacities increased with an increase in the inlet toluene concentration and a decrease in temperature. The adsorption isotherms were successfully fitted with Freundlich, Langmuir, and Dubinin-Radushkevich equations. Activated carbons derived from agricultural residues appear to be more applicable to adsorb volatile organic compounds at a low concentration and high temperature environment. PMID- 21608495 TI - A study on the reaction characteristics of vanadium-impregnated natural manganese oxide in ammonia selective catalytic reduction. AB - This study investigated the effect of adding vanadium (V) to natural manganese oxide (NMO) in ammonia (NH3) selective catalytic reduction (SCR). The addition of V to NMO decreased the catalytic activity at low temperatures by blocking the active site. However, the enhancement of catalytic activity was achieved by controlling NH3 oxidation at high temperatures. From the NH3 temperature programmed desorption and oxygen on/off test, it was confirmed that the amount of Lewis acid site and active lattice oxygen of the catalyst affects the catalytic performance at low temperature. PMID- 21608496 TI - Photochemical modeling in California with two chemical mechanisms: model intercomparison and response to emission reductions. AB - An updated version of the Statewide Air Pollution Research Center (SAPRC) chemical mechanism (SAPRC07C) was implemented into the Community Multiscale Air Quality (CMAQ) version 4.6. CMAQ simulations using SAPRC07C and the previously released version, SAPRC99, were performed and compared for an episode during July August, 2000. Ozone (O3) predictions of the SAPRC07C simulation are generally lower than those of the SAPRC99 simulation in the key areas of central and southern California, especially in areas where modeled concentrations are greater than the federal 8-hr O3 standard of 75 parts per billion (ppb) and/or when the volatile organic compound (VOC)/nitrogen oxides (NOx) ratio is less than 13. The relative changes of ozone production efficiency (OPE) against the VOC/NOx ratio at 46 sites indicate that the OPE is reduced in SAPRC07C compared with SAPRC99 at most sites by as much as approximately 22%. The SAPRC99 and SAPRC07C mechanisms respond similarly to 20% reductions in anthropogenic VOC emissions. The response of the mechanisms to 20% NOx emissions reductions can be grouped into three cases. In case 1, in which both mechanisms show a decrease in daily maximum 8-hr O3 concentration with decreasing NOx emissions, the O3 decrease in SAPRC07C is smaller. In case 2, in which both mechanisms show an increase in O3 with decreasing NOx emissions, the O3 increase is larger in SAPRC07C. In case 3, SAPRC07C simulates an increase in O3 in response to reduced NOx emissions whereas SAPRC99 simulates a decrease in O3 for the same region. As a result, the areas where NOx controls would be disbeneficial are spatially expanded in SAPRC07C. Although the results presented here are valuable for understanding differences in predictions and model response for SAPRC99 and SAPRC07C, the study did not evaluate the impact of mechanism differences in the context of the U.S. Environmental Protection Agency's guidance for using numerical models in demonstrating air quality attainment. Therefore, additional study is required to evaluate the full regulatory implications of upgrading air quality models to SAPRC07. PMID- 21608497 TI - Temporal analysis of PM10 in Metropolitan Monterrey, Mexico. AB - The Monterrey Metropolitan Area (MMA) is the third largest city in Mexico. Few studies have been carried out regarding its air pollution. The aim of this study was to analyze the temporal behavior of PM10 (particulate matter < or =10 microm in aerodynamic diameter). Data reported by the "Sistema Integral de Monitoreo Ambiental" (Integrated Environmental Monitoring System) network from 2006 to 2008 were used. PM10 levels were compared among the stations by year, season, and day of week. A bootstrap technique was used to obtain subsamples to which Student's t test and ANOVA were applied. PM10 levels were high and exceeded the annual limit of 50 microg/m3 set up by the Mexican standard Norma Oficial Mexicana NOM-025 SSA1-1993. These levels could have serious health effects. The southwest zone of MMA had the highest levels of PM10 during the period studied. Winter was the most polluted season, and summer was the least polluted season. Thursday and Friday were the most polluted days, and Sunday was the least polluted day. The hours with the highest levels of PM10 were 8:00 to 10:00 a.m., whereas nighttime hours were the cleanest. PMID- 21608498 TI - University of Pretoria inaugurates new wing of the oral and dental hospital. PMID- 21608499 TI - Occlusal considerations in implantology: good occlusal practice in implantology. AB - This article is concerned with implants that are being used for fixed crown and bridgework rather than removable prostheses. The huge increase in the provision of implants over the past two decades is set to continue. Most of the research is related to avoiding failures in implants. This research, in the main, has concentrated on the essential interface between the artificial implant and living bone: osseointegration. The other interface, which is worthy of our full attention, is the one between the implant-supported crown and the antagonist tooth: the occlusion. PMID- 21608500 TI - The effect of in-office vital bleaching and patient perception of the shade change. AB - OBJECTIVES: This study aimed to evaluate the degree of colour change after an in office vital tooth bleaching procedure with a 35% hydrogen peroxide gel using a spectrophotometer. The study also determined the patients' perceptions of the colour change and assessed the post operative sensitivity during the first week of the intervention. METHODS: The maxillary teeth (from 15 to 25) of 22 patients comprising of 11 males and 11 females were bleached with a 35% hydrogen peroxide (HP) gel in a single visit treatment procedure (Yotuel Special, Biocosmetics Laboratories, Spain). Colour readings of the two maxillary central incisors were obtained using a spectrophotometer (CM-2600d Konica, Minolta) before and after the bleaching procedure. All the patients were requested to complete a form regarding post-operative tooth sensitivity and to record their perceptions toward the success of the bleaching treatment. RESULTS: The quantitative effect of the bleaching material on tooth colour showed an increase in the L* values and a decrease in the a* and b* values. The changes were significant (Wilcoxon Signed Rank Sum Test; p < 0.05) from baseline until one month, except for the b* values one month after the bleaching procedure which were only significant at p < or = 0.1. The median overall colour change (deltaE) between baseline and after the bleaching procedure was 3.56. The mean value of the patients' colour perception was found to be 2.14 immediately after bleaching on a 3 point visual analogue scale. A Spearman correlation test showed a positive relationship between the deltaE values immediately and one week after bleaching and a weak relationship one week and one month after the bleaching procedure. There was a significant consistency in the patients' colour perception data immediately and one week after the bleaching process and a weak relationship between the deltaE values and the patients' colour perception one month after bleaching. Ten out of the twenty two patients experienced tooth sensitivity on the first day, immediately after the bleaching procedure. However only five patients experienced sensitivity on the second day, four patients on the third day and only one patient experienced sensitivity on the fourth and the fifth days after bleaching which was described as mild. CONCLUSIONS: Yotuel Special 35% HP was able to bleach the patients' teeth with a perceptive colour change noticeable by the patients; however colour regression was evident quantitatively from the first week. Tooth sensitivity was a temporary side effect. The material cost is reasonable, it was easy to use and the procedure is not dependant on light activation. CLINICAL IMPLICATIONS: A single application of this product may not be sufficient to give patients the bright smile they desire. However it is important to monitor the rebound effect after this procedure. Patients may experience some tooth sensitivity after the use of this bleaching material but the sensitivity is of a transient nature. PMID- 21608501 TI - Oro-facial manifestations of Burkitt's lymphoma: an analysis of 680 cases from Malawi. AB - Burkitt's lymphoma (BL) is a highly aggressive, fast growing, mature B-cell non Hodgkin's Lymphoma (NHL) and has one of the highest proliferation rates of any human tumour. There are three forms of BL: endemic or the African form (eBL), sporadic or non-endemic form (sBL) and the immunodeficiency-associated form in HIV-AIDS. The survival rate of a child with BL is dependent upon rapid diagnosis and treatment. The aim of the present study was to determine the oro-facial manifestations in children with BL in Malawi. It was carried out in two parts: the first, a retrospective record-based study (2005-2007) consisting of 661 cases of BL and the second, a prospective study (June 2008 -October 2009) documenting 19 cases of suspected and confirmed cases of BL. In the retrospective study, two thirds presented with BL at various sites of which the abdomen was the most common site. The 5-9 year age group predominated with an average peak incidence of 7 years and accounted for 60.0% of all the cases. There was a male preponderance with a ratio of male to female of 1.6:1. The maxilla was the most common site for oro-facial BL (13.7%) followed by the mandible (7.2%), cheeks (5.7%), maxilla and mandible (4.5%) and cervical lymph nodes (4.1%). Of the 397 with BL, 41.4% were tested for HIV and 37.97% were HIV-negative while 5% were HIV positive. In the prospective study, females predominated with a male to female ratio of 1.1:1 and the mandible was the most common site accounting for 19.04%. The age group 5-9 years predominated with 68.4% relative frequency. Generally the trend of BL had decreased from 2005 to 2007 possibly due to better access to health services, increased use of bed-treated mosquito nets for malaria prevention and knowledgeable healthcare workers. All oral healthcare and other healthcare workers need to be educated on the oro-facial manifestations of BL for prompt referral and management. This would result in a better prognosis since BL is curable as it responds favourably to chemotherapy. Furthermore, communities need to be educated on the early signs and symptoms of BL and the importance of visiting a hospital as soon as possible. PMID- 21608502 TI - HPV-associated oral warts. AB - Human papillomavirus (HPV) is strictly epitheliotropic, infecting stratified squamous cutaneous and mucosal epithelial cells. Oral HPV infection may be subclinical or putatively associated with benign or malignant oral neoplasms. The benign HPV-associated oral lesions, focal epithelial hyperplasia (Heck disease), oral squamous cell papilloma, oral verruca vulgaris (common wart) and oral condyloma acuminatum, are collectively referred to as oral warts. Oral warts are usually asymptomatic, may be persistent or uncommonly, may regress spontaneously. HPV-associated oral warts have a prevalence of 0.5% in the general population, occur in up to 5% of HIV-seropositive subjects, and in up to 23% of HIV seropositive subjects on highly active antiretroviral therapy. This paper is a clinico-pathological review of HPV-associated oral warts. PMID- 21608503 TI - Complete dentures, the first visit. PMID- 21608504 TI - General practitioner's radiology case 90. Macrodontia. PMID- 21608505 TI - Reviewing your accounting systems. PMID- 21608506 TI - Dental ethics case 9. What to do when the patient cannot pay? PMID- 21608507 TI - Successful service integration depends on authentic partnerships. PMID- 21608508 TI - HIE plans draw bipartisan support. PMID- 21608509 TI - Redefining addiction treatment. PMID- 21608510 TI - A conversation with Andy Eckert. Interview by Dennis Grantham. PMID- 21608511 TI - Pames W West, MD Quality Improvement Awards. Patient satisfaction made simple. PMID- 21608512 TI - Opening doors to patient safety. PMID- 21608513 TI - 'Spice' users left high and dry? PMID- 21608514 TI - Medicaid amendments allow states to offer more services. PMID- 21608516 TI - Could a managed care contract be for you? PMID- 21608515 TI - No single path to integration. PMID- 21608517 TI - Mitigating risks in antipsychotic prescribing. PMID- 21608518 TI - Overcoming stigma. Education and advocacy can make a difference action on in mental health care and services practice issues. PMID- 21608519 TI - Advanced nursing education is better for patients. PMID- 21608520 TI - Taking stock of the consensus model. PMID- 21608521 TI - The dilemma of breastmilk feeding. PMID- 21608522 TI - Relax, you're soaking in it: sources of information about infant formula. AB - Although the advertising of infant and follow-on formula products in Australia is prohibited by the Marketing in Australia of Infant Formulas: Manufacturers and Importers Agreement (1992), toddler milk is advertised without restriction. Recent research suggests that Australian mothers perceive advertisements for toddler milk to also be advertisements for infant formula. Furthermore, they tend to accept the messages they encounter in these advertisements uncritically. This study used established qualitative market research strategies to investigate what mothers, and those who influence mothers, know about formula milk products. This included exploration of commonly used sources of information, how toddler milk advertisements are interpreted and how the claims made in these advertisements are evaluated. Eight interviews were conducted: two individual interviews (involving a General Practitioner and a Community Dietitian) and six discussion groups (two groups of two mothers, two groups of two grandmothers, one group of two child and family health nurses and one group of five Child and Family Health Nurses). The results suggest that mothers seek advice about formula milk products from health professionals, their friends and their own mothers. The responses also suggest that all of these groups understand toddler milk advertisements to be advertising formula milk products and tend to rely on the messages contained in them to inform their decisions or advice about infant feeding products. It may therefore be difficult for mothers to access independent information upon which to base their decisions about infant feeding products. Further research is needed on whether sufficient independent information about infant feeding products is available to health professionals and mothers. PMID- 21608523 TI - Tongue-tie and breastfeeding: a review of the literature. AB - In Australia, initial exclusive breastfeeding rates are 80%, reducing to 14% at 6 months. One factor that contributes to early breastfeeding cessation is infant tongue-tie, a congenital abnormality occurring in 2.8-10.7% of infants, in which a thickened, tightened or shortened frenulum is present. Tongue-tie is linked to breastfeeding difficulties, speech and dental problems. It may prevent the baby from taking enough breast tissue into its mouth to form a teat and the mother may experience painful, bleeding nipples and frequent feeding with poor infant weight gain; these problems may contribute to early breastfeeding cessation. This review of research literature analyses the evidence regarding tongue-tie to determine if appropriate intervention can reduce its impact on breastfeeding cessation, concluding that, for most infants, frenotomy offers the best chance of improved and continued breastfeeding. Furthermore, studies have demonstrated that the procedure does not lead to complications for the infant or mother. PMID- 21608524 TI - Strabismus in pediatric lens disorders. AB - PURPOSE: To evaluate the prevalence and types of strabismus in children with cataract and ectopia lentis. METHODS: The authors retrospectively evaluated 860 children treated in the ophthalmological department of Children's Hospital "Agia Sophia" during the past decade. Their medical files with reference to strabismus prevalence, correlation between the time of strabismus occurrence and lens extraction surgery, and type of strabismus were studied. RESULTS: Of the 822 children with cataract, 337 had congenital cataract and 485 had acquired cataract. Strabismus occurred in 199 (24.2%) patients; 113 (56.8%) patients had esotropia and 86 (43.2%) patients had exotropia. Of the 38 children with ectopia lentis, strabismus occurred in 5 (13.2%); 1 patient had esotropia and 4 patients had exotropia. There is no significant difference in the time of appearance of strabismus in relation to the cataract operation, whereas there is a significant difference in ectopia lentis, although this may be a result of the small sample size. The incidence of strabismus is higher in patients with unilateral cataracts (27.4%) than in those with bilateral cataracts (19.6%). Strabismus occurred more frequently in patients with congenital cataracts (30.3%) than in acquired cases (20%), with esotropia being more common in congenital cataracts (76.5%) and exotropia more common in acquired cataracts (63.9%). CONCLUSION: The authors believe it is imperative that great attention should be given to ocular alignment in addition to management of refractive error and intense amblyopia therapy during long-term follow-up. PMID- 21608525 TI - New (1)h NMR procedure for the characterization of native and modified food-grade starches. AB - A novel, fast, and straightforward procedure is presented for the characterization of starch (the largest energy component in food) and modified starches (such as octenyl succinic anhydride (OSA)-modified starches used as a dispersing agent in the food industry). The method uses (1)H NMR to measure the degree of branching and also, for modified starches, the degree of chemical substitution. The substrate is dissolved in dimethyl-d(6) sulfoxide; addition of a very low amount of deuterated trifluoroacetic acid (d(1)-TFA) to the medium gives rise to a shift to high frequency of the exchangeable protons of the starch hydroxyl groups, leading to a clear and well-defined (1)H NMR spectrum, which provides an improved way to determine the degrees of both branching and chemical substitution. Measurements of the size and molecular weight distributions by multiple-detector size exclusion chromatography show that degradation by TFA does not affect the accuracy of the method. PMID- 21608526 TI - Allelic diversity of a beer haze active protein gene in cultivated and Tibetan wild barley and development of allelic specific markers. AB - The formation of haze is a serious quality problem in beer production. It has been shown that the use of silica elute (SE)-ve malt (absence of molecular weight (MW) ~14000 Da) for brewing can improve haze stability in the resultant beer, and the protein was identified as a barley trypsin inhibitor of the chloroform/methanol type (BTI-CMe). The objectives of this study were to determine (1) the allelic diversity of the gene controlling BTI-CMe in cultivated and Tibetan wild barley and (2) allele-specific (AS) markers for screening SE protein type. A survey of 172 Tibetan annual wild barley accessions and 71 cultivated barley genotypes was conducted, and 104 wild accessions and 35 cultivated genotypes were identified as SE+ve and 68 wild accessions and 36 cultivated genotypes as SE-ve. The allelic diversity of the gene controlling BTI CMe was investigated by cloning, alignment, and association analysis. It was found that there were significant differences between the SE+ve and SE-ve types in single-nucleotide polymorphisms at 234 (SNP(234)), SNP(313), and SNP(385.) Furthermore, two sets of AS markers were developed to screen SE protein type based on SNP(313). AS-PCR had results very similar to those obtained by immunoblot method. Mapping analysis showed that the gene controlling the MW~14 kDa band was located on the short arm of chromosome 3H, at the position of marker BPB-0527 (33.302 cM) in the Franklin/Yerong DH population. PMID- 21608527 TI - Dendritic poly(ethylene glycol) bearing paclitaxel and alendronate for targeting bone neoplasms. AB - Poly(ethylene glycol) (PEG) is the most popular polymer for protein conjugation, but its potential as carrier of low molecular weight drugs has been limited by the intrinsic low loading, owing to its chemical structure. In fact, only the two end chain groups of PEG can be modified and exploited for drug coupling. We have demonstrated that by synthesizing a dendrimer structure at the polymer end chains, it is possible to increase the drug payload and overcome this limitation. Furthermore, this approach can be improved by using heterobifunctional PEG. These polymers allow the precise linking of two different drugs, or a drug and a targeting agent, on the same polymeric chain. Heterobifunctional PEG-dendrimers have been obtained with defined chemical structures leading to their attractive use as drug delivery systems. In fact, they offer a double benefit; first, the possibility to choose the best drug/targeting agent ratio, and second, the separation of the two functions, activity and targeting, which are coupled at the opposite polymer end chains. In this study, we investigated the role of a PEG dendrimer, H(2)N-PEG-dendrimer-(COOH)(4), as carrier for a combination of paclitaxel (PTX) and alendronate (ALN). PTX is a potent anticancer drug that is affected by severe side effects originating from both the drug itself and its solubilizing formulation, Cremophor EL. ALN is an aminobiphosphonate used for the treatment of osteoporosis and bone metastases as well as a bone-targeting moiety. The PTX-PEG-ALN conjugate was designed to exploit active targeting by the ALN molecule and passive targeting through the enhanced permeability and retention (EPR) effect. Our conjugate demonstrated a great binding affinity to the bone mineral hydroxyapatite in vitro and an IC(50) comparable to that of the free drugs combination in human adenocarcinoma of the prostate (PC3) cells. The PTX PEG-ALN conjugate exhibited an improved pharmacokinetic profile compared with the free drugs owed to the marked increase in their half-life. In addition, PTX-PEG ALN could be solubilized directly in physiological solutions without the need for Cremophor EL. The data presented in this manuscript encourage further investigations on the potential of PTX-PEG-ALN as treatment for cancer bone metastases. PMID- 21608529 TI - 2,5,8,11-Tetraboronic ester perylenediimides: a next generation building block for dye-stuff synthesis. AB - Via an unprecedentedly reported ruthenium catalyzed reaction, an efficient and straightforward method was developed for the synthesis of 2,5,8,11-tetraboronate perylenediimide derivatives. A possible reaction mechanism is proposed. The synthesis of 2,5,8,11-tetra-iodo and tetra-amino perylenediimides derivatives is also reported. PMID- 21608530 TI - Contribution of partially labile complexes to the DGT metal flux. AB - Penetration of complexes into the resin layer can dramatically increase the contribution of complexes to the metal flux measured with a DGT (diffusive gradients in thin films) sensor, but equations to describe this phenomenon were not available. Here, simple approximate analytical expressions for the metal flux, the lability degree and the concentration profiles in a DGT experiment are reported. Together with the thickness of the reaction layer in the gel domain, the effective penetration distance into the resin layer that would be necessary for full dissociation of the complex (lambda(ML)) plays a key role in determining the metal flux. An increase in the resin-layer thickness (r) effectively increases the metal flux and the lability degree until r ~ 3lambda(ML). For the usual DGT configuration, where the thickness of the gel layer exceeds that of the resin layer, the complex is labile if r > (D(ML)/k(d))1/2, where D(ML) is the diffusion coefficient of the metal complex and k(d) its dissociation rate constant. A general procedure for estimating the lability of any complex in a standard DGT configuration is provided. PMID- 21608528 TI - Discovery of a 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer. AB - c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2 b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties. PMID- 21608644 TI - Directly assembling ligand-free ZnO nanocrystals into three-dimensional mesoporous structures by oriented attachment. AB - Mesoporous materials have found a great number of important utilities due to their well-defined pore structure and high internal surface area, which are routinely synthesized with the assistance of block copolymers or templates. So far, a key challenge is how to assemble directly ligand-free inorganic nanocrystals into mesoporous structures, so that the high surface activity of ligand-free nanocrystals is not destroyed by further treatment to remove organic species or templates. In this paper, we report the direct assembly of highly uniform ZnO mesoporous ellipsoids from ligand-free ZnO nanocrystals of ~5 nm. The size of the synthesized uniform ZnO mesoporous ellipsoids can be efficiently tuned from 132 * 75 to 190 * 111 nm (length * width), by varying the size and concentration of primary ZnO nanocrystal building blocks and the composition of the designed assembling solvent. The BET detection indicates that these ZnO mesoporous ellipsoids have high specific surface areas reaching to 136.57 m(2)/g, while their average BJH pore diameters are located at 8.8 nm. Especially, the high-resolution TEM images and XRD analysis revealed the occurrence of an oriented attachment mechanism in the assembly of uniform ZnO mesoporous ellipsoids, which supplied an important proof for the possibility of constructing stable three-dimensional structures by oriented attachment. The benefits of these ZnO mesoporous ellipsoids were demonstrated by their excellent photocatalytic activity under weak UV irradiation. PMID- 21608776 TI - Adsorption of cationic gemini surfactants at solid surfaces studied by QCM-D and SPR: effect of the rigidity of the spacer. AB - Two small series of cationic gemini surfactants with dodecyl tails have been synthesized and evaluated with respect to self-assembly in bulk water and at different solid surfaces. The first series contained a flexible alkane spacer and is denoted 12-n-12, with n = 2, 4, and 6. The second series had a phenylene group connected to the quaternary nitrogens in either the meta or para position and the surfactants are referred to as 12-m-Phi-12 and 12-p-Phi-12, respectively. The phenylene group is a rigid linker unit. The critical micelle concentration (cmc) was determined both by tensiometry and by conductometry, and the packing density of the surfactants at the air-water interface was calculated from the Gibbs equation. The cmc values for the geminis with a rigid spacer, 12-m-Phi-12 and 12 p-Phi-12, were of the same order of magnitude as for 12-4-12, which is the flexible surfactant that most closely matches the phenylene-based surfactants with respect to hydrophobicity, measured as log P, and distance between the positively charged nitrogen atoms. The adsorption of flexible and rigid surfactants was investigated on gold, silicon dioxide (silica), gold made hydrophobic by the self-assembly of hexadecanethiol, and gold made hydrophilic by the self-assembly of 16-hydroxyhexadecanethiol. On all of the surfaces, there was a reverse relationship between the adsorbed amount at the cmc and the length of the spacer (i.e., 12-2-12 gave the highest and 12-6-12 gave the lowest amount of adsorbed material). The adsorption pattern was similar for all of the surfactants when recorded at 25 degrees C. Thus, one can conclude that a rigid spacer does not render the self-assembly of a gemini surfactant difficult, neither in bulk water nor at solid surfaces. However, on one of the surfaces-untreated gold-the adsorbed amount of the geminis with a rigid spacer at 40 degrees C was approximately twice the values obtained at 25 degrees C. This is interpreted as the formation of an interdigitated bilayer at 25 degrees C and a regular bilayer without interpenetration of the alkyl chains at 40 degrees C. PMID- 21608971 TI - Cell wall polysaccharides of near-isogenic lines of melon (Cucumis melo L.) and their inbred parentals which show differential flesh firmness or physiological behavior. AB - We characterized differences in cell wall material and polysaccharide structures, due to the quantitative trait loci associated with higher flesh firmness in a nonclimacteric near-isogenic line (NIL) SC7-2, and with the climacteric behavior of the NIL SC3-5-1, using their nonclimacteric inbred parentals, "Piel de Sapo" (PS) and PI 161375 (SC). PS was firmer and had a higher ripening index and greater hemicellulosic content than SC, with its lower wall material yield, and uronic acid, neutral sugar, cellulose and free sugar content and higher pectic content. SC3-5-1 showed lower uronic acid values, a higher soluble solid content, and similar flesh firmness to PS. SC3-5-1 yielded mainly high molecular weight polysaccharides in the imidazole-soluble fraction than PS. SC7-2 showed greater flesh firmness, a higher neutral sugar (especially galactose and mannose) and uronic acid content, together with a larger cellulose and alpha-cellulose residue than PS. SC7-2 also contained more polysaccharides of low molecular weight in the first pectic fraction and shifted toward higher molecular weights in the main peak of the 4 M potassium-soluble fraction compared with PS. PMID- 21608972 TI - Rapid self-assembly of uranyl polyhedra into crown clusters. AB - Clusters built from 32 uranyl peroxide polyhedra self-assemble and crystallize within 15 min after combining uranyl nitrate, ammonium hydroxide, and hydrogen peroxide in aqueous solution under ambient conditions. These novel crown-shaped clusters are remarkable in that they form so quickly, have extraordinarily low aqueous solubility, form with at least two distinct peroxide to hydroxyl ratios, and form in very high yield. The clusters, which have outer diameters of 23 A, topologically consist of eight pentagons and four hexagons. Their rapid formation and low solubility in aqueous systems may be useful properties at various stages in an advanced nuclear energy system. PMID- 21608973 TI - Solid-state thiotropolone: an extremely rapid intramolecular proton transfer. AB - Through variable-temperature solution-state NMR and molten- and solid-state CP/MAS (13)C NMR spectra, thiotropolone is found to exist as two rapidly equilibrated tautomeric structures, thione and enethiol, even in the solid state far below the melting point. The crystal structure shows an almost perpendicular packing, suggesting that the intramolecular hydrogen bond is dominant. PMID- 21608974 TI - Assembly of bioactive peptide-chitosan nanocomplexes. AB - The assembly of nanocomplexes from bioactive peptides, namely, caseinophosphopeptides (CPPs) and chitosan (CS), at physiological conditions and various CS/CPP mass ratios has been systematically studied using a combination of liquid chromatography-tandem mass spectrometry (LC-MS/MS), turbidimetric titration, dynamic light scattering (DLS), electrophoretic mobility (zeta potential) measurements, transmission electron microscopy (TEM), and fluorescence spectroscopy. Peptides incorporated with CS forming nanoparticles were prepared and identified using LC-MS/MS. They were characterized by different amounts of clusters of phosphorylated seryl residues. At low salt concentrations, an increase in CS/CPP mass ratio shifted the critical pH(phi1) value, which was designated as the formation of CS/CPP nanocomplexes, as well as pH(max), which represents the neutralization of positive and negative charges at higher pH values. The sizes, charges, morphologies, binding mechanisms, and binding constants of the bioactive peptide-chitosan nanocomplexes were analyzed, and our results suggest that three processes are involved in nanocomplex formation: First, negatively charged CPPs absorb to positively charged CS molecular chains to form intrapolymer nanocomplexes saturated with CPPs (CPPNPs). Subsequently, the negatively charged CPPNPs are bridged by the addition of positively charged CS, resulting in the formation of nearly neutral associative biopolymer complexes. Finally, further addition of excess chitosan breaks down the bridges of associative complexes and causes the formation of positively charged isolated spherical nanocomplexes. The binding between the peptides and CS is mainly driven by electrostatic interactions with a binding constant of K(cs) = 4.6 * 10(4) M( 1). Phosphorylated groups and other negatively charged amino acids, such as aspartic acid (Asp) and glutamic acid (Glu), in the CPPs might be the dominant sites for interaction with -NH(3)(+) groups on the CS molecular chains. PMID- 21608976 TI - Effect of O2 on the adsorption of SO2 on carbon-supported Pt electrocatalysts. AB - Adsorption of SO(2) in the presence of O(2) on Pt/C catalysts often used as electrocatalysts has been investigated by temperature programmed desorption (TPD) and X-ray photoelectron spectroscopy (XPS). The amounts of SO(2) adsorption on Pt/C in the presence of O(2) were much higher than those in the absence of O(2) (SO(2)-N(2)) and from the carbon support (Vulcan XC-72) alone. Adsorption is dependent on oxygen concentration over the range 0-20% but reaches saturation at 20% O(2). The spillover of SO(2) from Pt to the carbon support has been proposed for 10, 20, and 40% Pt loadings, characterized by desorption temperatures of approximately 150 and 260 degrees C for SO(2) adsorbed on Pt and carbon, respectively. Adsorbed Pt-S, C-S, C-SO(x), and Pt-SO(4) species were identified by XPS as S-containing species on both Pt and carbon. Both TPD and XPS indicate that the carbon support plays a major role in SO(2) adsorption, primarily as SO(x) (x = 3, 4). The bonding of S and SO(x) on the carbon support was strong enough that back diffusion to the Pt surface did not occur. PMID- 21608975 TI - Surface modification of droplet polymeric microfluidic devices for the stable and continuous generation of aqueous droplets. AB - Droplet microfluidics performed in poly(methyl methacrylate) (PMMA) microfluidic devices resulted in significant wall wetting by water droplets formed in a liquid liquid segmented flow when using a hydrophobic carrier fluid such as perfluorotripropylamine (FC-3283). This wall wetting led to water droplets with nonuniform sizes that were often trapped on the wall surfaces, leading to unstable and poorly controlled liquid-liquid segmented flow. To circumvent this problem, we developed a two-step procedure to hydrophobically modify the surfaces of PMMA and other thermoplastic materials commonly used to make microfluidic devices. The surface-modification route involved the introduction of hydroxyl groups by oxygen plasma treatment of the polymer surface followed by a solution phase reaction with heptadecafluoro-1,1,2,2-tetrahydrodecyl trichlorosilane dissolved in fluorocarbon solvent FC-3283. This procedure was found to be useful for the modification of PMMA and other thermoplastic surfaces, including polycyclic olefin copolymer (COC) and polycarbonate (PC). Angle-resolved X-ray photoelectron spectroscopy indicated that the fluorination of these polymers took place with high surface selectivity. This procedure was used to modify the surface of a PMMA droplet microfluidic device (DMFD) and was shown to be useful in reducing the wetting problem during the generation of aqueous droplets in a perfluorotripropylamine (FC-3283) carrier fluid and could generate stable segmented flows for hours of operation. In the case of PMMA DMFD, oxygen plasma treatment was carried out after the PMMA cover plate was thermally fusion bonded to the PMMA microfluidic chip. Because the appended chemistry to the channel wall created a hydrophobic surface, it will accommodate the use of other carrier fluids that are hydrophobic as well, such as hexadecane or mineral oils. PMID- 21608977 TI - Manipulating energy landscapes to tune ordering in biotemplated nanoparticle arrays. AB - Two-dimensional non-close-packed crystals of the protein streptavidin, grown on phospholipid membranes, can serve as nanoscale templates capable of directing the formation of ordered nanoparticle arrays through site-specific electrostatic adsorption. Here we examine the effects of both interparticle and nanoparticle/lipid membrane electrostatic interactions on the degree of structural order exhibited by the templated nanoparticle array. Interparticle electrostatic repulsion is shown to have only marginal influence on nanoparticle ordering. In contrast, the degree of order exhibited by the templated array can be tuned by controlling the charge on the lipid membrane. Analysis of the local and global structure of arrays generated with negatively charged gold nanoparticles (~6 nm) indicate improved long-range order when the lipid membrane supporting the protein crystal is derived from cationic lipid molecules as opposed to zwitterionic phospholipids. Furthermore, as nanoparticle size is reduced (~3 nm), the presence of a charged lipid membrane is found to be essential, as smaller particles do not adhere to streptavidin crystals grown on zwitterionic membranes. These findings demonstrate that the composition of the lipid support can influence the efficacy of directed-assembly processes which utilize protein templates and are important results toward enhancing control over bottom-up nanofabrication applications. PMID- 21608978 TI - Headgroup effects of template monolayers on the adsorption behavior and conformation of glucose oxidase adsorbed at air/liquid interfaces. AB - Stearic acid (SA) and octadecylamine (ODA) monolayers at the air/liquid interface were used as template layers to adsorb glucose oxidase (GOx) from aqueous solution. The effect of the template monolayers on the adsorption behavior of GOx was studied in terms of the variation of surface pressure, the evolution of surface morphology observed by BAM and AFM, and the conformation of adsorbed GOx. The results show that the presence of a template monolayer can enhance the adsorption rate of GOx; furthermore, ODA has a higher ability, compared to SA, to adsorb GOx, which is attributed to the electrostatic attractive interaction between ODA and GOx. For adsorption performed on a bare surface or on an SA monolayer, the surface pressure approaches an equilibrium value (ca. 8 mN/m) after 2 to 3 h of adsorption and remains nearly constant in the following adsorption process. For the adsorption on an ODA monolayer, the surface pressure will increase further 1 to 2 h after approaching the first equilibrium pressure, which is termed the second adsorption stage. The measurement of circular dichroism (CD) spectroscopy indicates that the Langmuir-Blodgett films of adsorbed GOx transferred at the first equilibrium state (pi = 8 mN/m) have mainly a beta-sheet conformation, which is independent of the type of template monolayers. However, the ODA/GOx LB film transferred at the second adsorption stage has mainly an alpha-helix conformation. It is concluded that the specific interaction between ODA and GOx not only leads to a higher adsorption rate and adsorbed amount of GOx but also induces a conformation change in adsorbed GOx from beta-sheet to alpha-helix. The present results indicate that is possible to control the conformation of adsorbed protein by selecting the appropriate template monolayer. PMID- 21608979 TI - Retention of regiochemistry and chirality in the ruthenium catalyzed allylic alkylation of disubstituted allylic esters. AB - The regiospecific nucleophilic substitution during the ruthenium catalyzed allylic alkylation of 1,3-unsymmetrical disubstituted allylic esters was demonstrated. The nucleophile was selectively introduced at the position originally substituted with leaving group in the 2-DPPBA or ip-pybox ligated [RuCl(2)(p-cymene)](2) catalyzed allylic alkylation of 1,3-unsymmetrical disubstituted allylic esters. The chirality of the optically active allylic esters was also transferred to the alkylated products. PMID- 21608980 TI - Redox-promoting protein motions in rubredoxin. AB - Proteins are dynamic objects, constantly undergoing conformational fluctuations, yet the linkage between internal protein motion and function is widely debated. This study reports on the characterization of temperature-activated collective and individual atomic motions of oxidized rubredoxin, a small 53 residue protein from thermophilic Pyrococcus furiosus (RdPf). Computational modeling allows detailed investigations of protein motions as a function of temperature, and neutron scattering experiments are used to compare to computational results. Just above the dynamical transition temperature which marks the onset of significant anharmonic motions of the protein, the computational simulations show both a significant reorientation of the average electrostatic force experienced by the coordinated Fe(3+) ion and a dramatic rise in its strength. At higher temperatures, additional anharmonic modes become activated and dominate the electrostatic fluctuations experienced by the ion. At 360 K, close to the optimal growth temperature of P. furiosus, simulations show that three anharmonic modes including motions of two conserved residues located at the protein active site (Ile7 and Ile40) give rise to the majority of the electrostatic fluctuations experienced by the Fe(3+) ion. The motions of these residues undergo displacements which may facilitate solvent access to the ion. PMID- 21608981 TI - Electronic and molecular structures of trans-dioxotechnetium(V) polypyridyl complexes in the solid state. AB - The structures of novel Tc(V) complexes trans-[TcO(2)(py)(4)]Cl.2H(2)O (1a), trans-[TcO(2)(pic)(4)]Cl.2H(2)O (2a), and trans-[TcO(2)(pic)(4)]BPh(4) (2b) were determined by X-ray crystallography, and their spectroscopic characteristics were investigated by emission spectroscopy and atomic scale calculations. The cations adopt a tetragonally distorted octahedral geometry, with a trans orientation of the apical oxo groups. trans-[TcO(2)(pic)(4)]BPh(4) has an inversion center located on technetium; however, for trans-[TcO(2)(py)(4)]Cl.2H(2)O and trans [TcO(2)(pic)(4)]Cl.2H(2)O, a strong H bond formed by only one of the oxo substituents introduces an asymmetry in the structure, resulting in inequivalent trans Tc-N and Tc?O distances. Upon 415 nm excitation at room temperature, the complexes exhibited broad, structureless luminescences with emission maxima at approximately 710 nm (1a) and 750 nm (2a, 2b). Like the Re(V) analogs, the Tc(V) complexes luminesce from a (3)E(g) excited state. Upon cooling the samples from 278 to 8 K, distinct vibronic features appear in the spectra of the complexes along with increases in emission intensities. The low temperature emission spectra display the characteristic progressions of the symmetric O?Tc?O and the Tc-L stretching modes. Lowest-energy, triplet excited-state distortions calculated using a time-dependent theoretical approach are in good agreement with the experimental spectra. The discovery of luminescence from the trans dioxotechnetium(V) complexes provides the first opportunity to directly compare fundamental luminescence properties of second- and third-row d(2) metal-oxo congeners. PMID- 21608982 TI - New types of multishell nanoclusters with a Frank-Kasper polyhedral core in intermetallics. AB - A comprehensive study of the occurrence of two-shell clusters with the first shell as a Frank-Kasper polyhedron Z12, Z14, Z15, or Z16 (Frank-Kasper nanoclusters) is performed for 22,951 crystal structures of intermetallics containing only metal atoms. It is shown that besides the familiar Bergman and Mackay clusters, two more types of high-symmetrical icosahedron-based nanoclusters are rather frequent; they both have a 50-atom second shell. Moreover, two types of high-symmetrical Frank-Kasper nanoclusters with a Friauf polyhedron (Z16) core are revealed; these nanoclusters have 44 and 58 atoms in the second shell. On the contrary, Z14 and Z15 Frank-Kasper polyhedra have been found to be rare and improper to form distinct nanoclusters in crystals. The second shells of Frank-Kasper nanoclusters have been revealed possessing their own stability: they can be realized in nanoclusters with different internal polyhedra and can shift around the core shell. The role of Frank-Kasper nanoclusters in assembling intermetallic crystal structures is illustrated by several examples. PMID- 21608983 TI - Free-energy landscapes of protein domain movements upon ligand binding. AB - The conformation and functions of proteins are closely linked, and many proteins undergo conformational changes upon ligand binding. The X-ray crystallographic studies have revealed conformational differences in proteins between the liganded and unliganded states. Currently, the conformational transitions that originate in the ligand binding are explained on the basis of two representative models, the induced-fit and preexisting equilibrium dynamics models. However, the actual dynamics of the proteins remain ambiguous. Though these two models are the extreme ones, it is important to understand the difference between these two, particularly in structural biology and medicinal chemistry studies. Here, we clarified the difference in the mechanisms responsible for the conformational changes induced in two proteins upon ligand binding by examining computationally determined free-energy profiles of the apo- and holoproteins. The lysine/arginine/ornithine-binding protein and maltose/maltodextrin-binding protein were chosen as the target proteins, and the energy profiles were generated by a molecular simulation approach. Our results revealed that fluctuations in the apo state and protein-ligand interactions both play important roles in conformational transition, and the mechanism is highly influenced by the fluctuations in the apo state, which are unique to a particular structure. PMID- 21608985 TI - Hydrogen-bonded cyclic tetramers based on ureidopyrimidinones attached to a 3,6 carbazolyl spacer. AB - Direct attachment of two 2-ureido-4-[1H]-pyrimidinone (UPy) subunits to a 3,6 carbazolyl core gives rise to a highly viscous, supramolecular polymer. However, insertion of a methylene spacer between the UPy's and the carbazole leads to a well-defined, cyclic tetramer, in a belt-shaped arrangement, as evidenced by MALDI-TOF, DOSY, and NOESY spectra. PMID- 21608984 TI - Fluorescent gold nanoclusters as a biocompatible marker for in vitro and in vivo tracking of endothelial cells. AB - We have been investigating the fluorescent property and biocompatibility of novel fluorescent gold nanoclusters (FANC) in human aortic endothelial cells (HAEC) and endothelial progenitor cells (EPC). FANC (50-1000 nmol/L) was delivered into cells via the liposome complex. The fluorescence lasted for at least 28 days with a half-life of 9 days in vitro. Examination of 12 transcripts regulating the essential function of endothelial cells after a 72 h delivery showed that only the vascular cell adhesion molecule 1 and the vascular endothelial cadherin were down-regulated at high concentration (500 nmol/L). In addition, no activation of caspase 3 or proliferating cell nuclear antigens was detected. 3-[4,5 Dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide (MTT) assay demonstrated that, unlike the markedly suppressed viability in cells treated with quantum dots, FANC had minimal effect on the viability, unless above 500 nmol/L, at which level a minor reduction of viability mainly caused by liposome was found. Tube formation assay showed no impaired angiogenesis in the EPC treated with FANC. In vivo study using hindlimb ischemic mice with an intramuscular injection of FANC labeled human EPC showed that the cells preserved an angiogenic potential and exhibited traceable signals after 21 days. These findings demonstrated that FANC is a promising biocompatible fluorescent probe. PMID- 21608986 TI - Anodic coupling of guaiacol derivatives on boron-doped diamond electrodes. AB - The anodic treatment of guaiacol derivatives on boron-doped diamond electrodes (BDD) provides a direct access to nonsymmetrical biphenols, which would require a multistep sequence by conventional methods. Despite the destructive nature of BDD anodes they can be exploited for chemical synthesis. PMID- 21608987 TI - Vicenin-2, a potential anti-inflammatory constituent of Urtica circularis. AB - Vicenin-2 (1), a flavonoid glycoside, was isolated and identified from an ethanol extract of the aerial parts of Urtica circularis. This crude extract was found to possess significant anti-inflammatory activity in a carrageenan-induced rat hind paw edema model (41.5% inhibition at a dose of 300 mg/kg; ip). The effects of 1 on several inflammatory mediators were investigated. In cultured murine macrophages, this compound modified LPS-induced total nitrite and TNF-alpha production, in addition to the LPS-induced translocation of the nuclear factor NF kappaB. PMID- 21608988 TI - Molecular-level mechanisms of vibrational frequency shifts in a polar liquid. AB - A molecular-level analysis of the origins of the vibrational frequency shifts of the CN stretching mode in neat liquid acetonitrile is presented. The frequency shifts and infrared spectrum are calculated using a perturbation theory approach within a molecular dynamics simulation and are in good agreement with measured values reported in the literature. The resulting instantaneous frequency of each nitrile group is decomposed into the contributions from each molecule in the liquid and by interaction type. This provides a detailed picture of the mechanisms of frequency shifts, including the number of surrounding molecules that contribute to the shift, the relationship between their position and relative contribution, and the roles of electrostatic and van der Waals interactions. These results provide insight into what information is contained in infrared (IR) and Raman spectra about the environment of the probed vibrational mode. PMID- 21608989 TI - Nonlinear optical response in single alkaline niobate nanowires. AB - We have synthesized and characterized three types of perovskite alkaline niobate nanowires: NaNbO(3), KNbO(3), and LiNbO(3) (XNbO(3)). All three types of nanowires exhibit strong nonlinear response. Confocal imaging has been employed to quantitatively compare the efficiency of synthesized nanowires to generate second harmonic signal and to show that LiNbO(3) nanowires exhibit the strongest nonlinear response. We also investigated the polarization response of the second harmonic generation (SHG) signal in all three types of alkaline nanowires for the two geometries tractable by our optical trapping setup. The SHG signal is highly influenced by the nanowire crystallinity and experimental geometry. We also demonstrate for the first time wave-guiding of SHG signal in all three types of alkaline niobate nanowires. By carefully examining nonlinear properties of (XNbO(3)) nanowires we suggest which type of wires are best suited for the given application. PMID- 21608990 TI - Highly-ordered supportless three-dimensional nanowire networks with tunable complexity and interwire connectivity for device integration. AB - The fabrication of three-dimensional assemblies consisting of large quantities of nanowires is of great technological importance for various applications including (electro-)catalysis, sensitive sensing, and improvement of electronic devices. Because the spatial distribution of the nanostructured material can strongly influence the properties, architectural design is required in order to use assembled nanowires to their full potential. In addition, special effort has to be dedicated to the development of efficient methods that allow precise control over structural parameters of the nanoscale building blocks as a means of tuning their characteristics. This paper reports the direct synthesis of highly ordered large-area nanowire networks by a method based on hard templates using electrodeposition within nanochannels of ion track-etched polymer membranes. Control over the complexity of the networks and the dimensions of the integrated nanostructures are achieved by a modified template fabrication. The networks possess high surface area and excellent transport properties, turning them into a promising electrocatalyst material as demonstrated by cyclic voltammetry studies on platinum nanowire networks catalyzing methanol oxidation. Our method opens up a new general route for interconnecting nanowires to stable macroscopic network structures of very high integration level that allow easy handling of nanowires while maintaining their connectivity. PMID- 21608991 TI - Longitudinal splitting of boron nitride nanotubes for the facile synthesis of high quality boron nitride nanoribbons. AB - Boron nitride nanoribbons (BNNRs), the boron nitride structural equivalent of graphene nanoribbons (GNRs), are predicted to possess unique electronic and magnetic properties. We report the synthesis of BNNRs through the potassium intercalation-induced longitudinal splitting of boron nitride nanotubes (BNNTs). This facile, scalable synthesis results in narrow (down to 20 nm), few sheet (typically 2-10), high crystallinity BNNRs with very uniform widths. The BNNRs are at least 1 MUm in length with minimal defects within the ribbon plane and along the ribbon edges. PMID- 21608992 TI - Cobalt-catalyzed coupling of alkyl Grignard reagent with benzamide and 2 phenylpyridine derivatives through directed C-H bond activation under air. AB - Aromatic carboxamides and 2-phenylpyridine derivatives can be ortho-alkylated with Grignard reagents in the presence of a cobalt catalyst and DMPU as a ligand. The reaction proceeds smoothly at room temperature, using air as the sole oxidant. The dialkylated product is selectively obtained when N-methylcarboxamide is employed as a substrate, whereas N-phenyl- or N-isopropylcarboxamide preferentially gives the monoalkylated product. PMID- 21608993 TI - Origin and activity of gold nanoparticles as aerobic oxidation catalysts in aqueous solution. AB - Whether gold is catalytically active on its own has been hotly debated since the discovery of gold-based catalysis in the 1980s. One of the central controversies is on the O(2) activation mechanism. This work, by investigating aerobic phenylethanol oxidation on gold nanoparticles in aqueous solution, demonstrates that gold nanoparticles are capable to activate O(2) at the solid-liquid interface. Extensive density functional theory (DFT) calculations combined with the periodic continuum solvation model have been utilized to provide a complete reaction network of aerobic alcohol oxidation. We show that the adsorption of O(2) is very sensitive to the environment: the presence of water can double the O(2) adsorption energy to ~0.4 eV at commonly available edge sites of nanoparticles (~4 nm) because of its strongly polarized nature in adsorption. In alcohol oxidation, the hydroxyl bond of alcohol can break only with the help of an external base at ambient conditions, while the consequent alpha-C-H bond breaking occurs on pure Au, both on edges and terraces, with a reaction barrier of 0.7 eV, which is the rate-determining step. The surface H from the alpha-C-H bond cleavage can be easily removed by O(2) and OOH via a H(2)O(2) pathway without involving atomic O. We find that Au particles become negatively charged at the steady state because of a facile proton-shift equilibrium on surface, OOH + OH <-> O(2) + H(2)O. The theoretical results are utilized to rationalize experimental findings and provide a firm basis for utilizing nanoparticle gold as aerobic oxidation catalysts in aqueous surroundings. PMID- 21608994 TI - Polymeric vesicles: from drug carriers to nanoreactors and artificial organelles. AB - One strategy in modern medicine is the development of new platforms that combine multifunctional compounds with stable, safe carriers in patient-oriented therapeutic strategies. The simultaneous detection and treatment of pathological events through interactions manipulated at the molecular level offer treatment strategies that can decrease side effects resulting from conventional therapeutic approaches. Several types of nanocarriers have been proposed for biomedical purposes, including inorganic nanoparticles, lipid aggregates, including liposomes, and synthetic polymeric systems, such as vesicles, micelles, or nanotubes. Polymeric vesicles--structures similar to lipid vesicles but created using synthetic block copolymers--represent an excellent candidate for new nanocarriers for medical applications. These structures are more stable than liposomes but retain their low immunogenicity. Significant efforts have been made to improve the size, membrane flexibility, and permeability of polymeric vesicles and to enhance their target specificity. The optimization of these properties will allow researchers to design smart compartments that can co-encapsulate sensitive molecules, such as RNA, enzymes, and proteins, and their membranes allow insertion of membrane proteins rather than simply serving as passive carriers. In this Account, we illustrate the advances that are shifting these molecular systems from simple polymeric carriers to smart-complex protein-polymer assemblies, such as nanoreactors or synthetic organelles. Polymeric vesicles generated by the self-assembly of amphiphilic copolymers (polymersomes) offer the advantage of simultaneous encapsulation of hydrophilic compounds in their aqueous cavities and the insertion of fragile, hydrophobic compounds in their membranes. This strategy has permitted us and others to design and develop new systems such as nanoreactors and artificial organelles in which active compounds are simultaneously protected and allowed to act in situ. In recent years, we have created a variety of multifunctional, proteinpolymersomes combinations for biomedical applications. The insertion of membrane proteins or biopores into the polymer membrane supported the activity of co-encapsulated enzymes that act in tandem inside the cavity or of combinations of drugs and imaging agents. Surface functionalization of these nanocarriers permitted specific targeting of the desired biological compartments. Polymeric vesicles alone are relatively easy to prepare and functionalize. Those features, along with their stability and multifunctionality, promote their use in the development of new theranostic strategies. The combination of polymer vesicles and biological entities will serve as tools to improve the observation and treatment of pathological events and the overall condition of the patient. PMID- 21608995 TI - Isobutrin from butea monosperma (flame of the forest): a promising new natural sensitizer belonging to chalcone class. AB - In this work, "isobutrin", an ecofriendly sensitizer that is extracted from Butea monosperma (commonly known as "Flame of the Forest") flowers, is introduced. It is a bright yellow pigment belonging to the chalcone class and is examined as a sensitizer for optoelectronic applications. It is observed that chelation of this dye with Ti ions results into a strong dye-TiO(2) charge transfer (DTCT) band in the visible region. This Ti-Isobutrin chelate is stable, irreversible and its formation is studied using Benesi-Hildebrand plot. The locations of HOMO-LUMO states of the Ti-isobutrin chelate and the corresponding band alignment with TiO(2) are obtained. Also, a thermal stability test revealed that isobutrin is stable above 100 degrees C. PMID- 21608996 TI - Poly(3-alkylthiophene) diblock copolymers with ordered microstructures and continuous semiconducting pathways. AB - Conjugated rod-coil diblock copolymers self-assemble due to a balance of liquid crystalline (rod-rod) and enthalpic (rod-coil) interactions. Previous work has shown that while classical block copolymers self-assemble into a wide variety of nanostructures, when rod-rod interactions dominate self-assembly in rod-coil block copolymers, lamellar structures are preferred. Here, it is demonstrated that other, potentially more useful, nanostructures can be formed when these two interactions are more closely balanced. In particular, hexagonally packed polylactide (PLA) cylinders embedded in a semiconducting poly(3-alkylthiophene) (P3AT) matrix can be formed. This microstructure has been long-sought as it provides an opportunity to incorporate additional functionalities into a majority phase nanostructured conjugated polymer, for example in organic photovoltaic applications. Previous efforts to generate this phase in polythiophene-based block copolymers have failed due to the high driving force for P3AT crystallization. Here, we demonstrate that careful design of the P3AT moiety allows for a balance between crystallization and microphase separation due to chemical dissimilarity between copolymer blocks. In addition to hexagonally packed cylinders, P3AT-PLA block copolymers form nanostructures with long-range order at all block copolymer compositions. Importantly, the conjugated moiety of the P3AT-PLA block copolymers retains the crystalline packing structure and characteristic high time-of-flight charge transport of the homopolymer polythiophene (MU(h) ~10(-4) cm(2) V(-1) s(-1)) in the confined geometry of the block copolymer domains. PMID- 21608997 TI - Tuning porosity of Ti-MCM-41: implication for shape selective catalysis. AB - This paper describes a method to regulate porosity of Ti-containing mesoporous molecular sieves (Ti-MCM-41) by employing swelling agents that are hydrophobic in nature, such as dodecylamine, n-heptane, and sym-trimethylbenzene (TMB). Physicochemical properties of the samples were investigated using XRD, FT-IR, IR spectra of pyridine absorption, UV-vis, TEM, and N(2) adsorption-desorption techniques. Addition of favorable swelling agents leads to an increase in pore size accompanied by retaining the mesostructure with a certain decrease of structure ordering. Swelling agents also have significant impact on the integration of Ti into the silica framework, which further affect the formation of Lewis acid sites. N-heptane is the most favorable agent for pore expansion of Ti-MCM-41. The material with n-heptane/CTAB ratio of 1 exhibits the largest pore size of 48.3 A, and mesopore volume of 1.266 cm(3)/g and narrow pore-size distribution. We also demonstrated that shape-selective transesterification catalytic activity of Ti-MCM-41 was greatly enhanced because of pore expansion. PMID- 21608998 TI - Reduction of benzylidene dibenzo[a,d]cycloheptenes: over-reduction of antiaromatic dianions to aromatic tetraanions. AB - The antiaromaticity of a series of dianions of p-substituted benzylidene dibenzo[a,d]cycloheptenes was examined through calculated measures of antiaromaticity. The nucleus-independent chemical shifts (NICS) and magnetic susceptibility exaltation both showed substantial antiaromatic character in the benzannulated tropylium anion. When the antiaromaticity was normalized for the area of the ring, these tropylium anions were shown to be among the most antiaromatic anions in the chemical literature. Attempts to make the dianion through reduction with lithium or potassium gave the tetraanion as the only species observable in the (1)H NMR spectrum. Quench of the reaction mixture with trimethylsilyl chloride or D(2)O confirmed the presence of the tetraanion, but only as a small portion of the reaction mixture, with the major product being unreacted starting material. The failure to observe starting material was attributed to similarities in the structures of the starting material and anion radical (first reduction), allowing rapid electron transfer between them. The inability to see the dianion (second reduction) could be the result of the very small HOMO-LUMO gap anticipated for highly antiaromatic species, which would allow access to diradical species. The magnitude of the HOMO-LUMO gap was determined by the difference between the HOMO and LUMO energies from geometry optimization and the lowest energy transition from TD-DFT calculations. The HOMO LUMO gap for the benzylidene dibenzocycloheptatriene dianions was shown to be much smaller than the HOMO-LUMO gap of species for which (1)H NMR spectra had been observed. PMID- 21608999 TI - Offspring metabolomic response to maternal protein restriction in a rat model of intrauterine growth restriction (IUGR). AB - Intrauterine growth restriction (IUGR), along with postnatal growth trajectory, is closely linked with metabolic diseases and obesity at adulthood. The present study reports the time-dependent metabolomic response of male offspring of rat dams exposed to maternal adequate protein diet during pregnancy and lactation (CC) or protein deprivation during pregnancy only (IUGR with rapid catch-up growth, RC) or through pregnancy and lactation (IUGR with slow postnatal growth, RR). Plasma LC-HRMS metabolomic fingerprints for 8 male rats per group, combined with multivariate statistical analysis (PLS-DA and HCA), were used to study the impact of IUGR and postnatal growth velocity on the offspring metabolism in early life (until weaning) and once they reached adulthood (8 months). Compared with CC rats, RR pups had clear-cut alterations in plasma metabolome during suckling, but none at adulthood; in contrast, in RC pups, alterations in metabolome were minimal in early life but more pronounced in the long run. In particular, our results pinpoint transient alterations in proline, arginine, and histidine in RR rats, compared to CC rats, and persistent differences in tyrosine and carnitine, compared to RC rats at adulthood. These findings suggest that the long-term deregulation in feeding behavior and fatty acid metabolism in IUGR rats depends on postnatal growth velocity. PMID- 21609001 TI - PeaksPTM: Mass spectrometry-based identification of peptides with unspecified modifications. AB - Tandem mass spectrometry (MS/MS) has been routinely used to identify peptides from a protein sequence database. To identify post-translationally modified peptides, most existing software requires the specification of a few possible modifications. However, such knowledge of possible modifications is not always available. In this paper, we describe a new algorithm for identifying modified peptides without requiring the user to specify the possible modifications; instead, all modifications from the Unimod database are considered. Meanwhile, several new techniques are employed to avoid the exponential growth of the search space, as well as to control the false discoveries due to this unrestricted search approach. Finally, a software tool, PeaksPTM, has been developed and already achieved a stronger performance than competitive tools for unrestricted identification of post-translational modifications. PMID- 21609000 TI - The metastasis-associated extracellular matrix protein osteopontin forms transient structure in ligand interaction sites. AB - Osteopontin (OPN) is an acidic hydrophilic glycophosphoprotein that was first identified as a major sialoprotein in bones. It functions as a cell attachment protein displaying a RGD cell adhesion sequence and as a cytokine that signals through integrin and CD44 cell adhesion molecules. OPN is also implicated in human tumor progression and cell invasion. OPN has intrinsic transforming activity, and elevated OPN levels promote metastasis. OPN gene expression is also strongly activated in avian fibroblasts simultaneously transformed by the v-myc and v-mil(raf) oncogenes. Here we have investigated the solution structure of a 220-amino acid recombinant OPN protein by an integrated structural biology approach employing bioinformatic sequence analysis, multidimensional nuclear magnetic resonance spectroscopy, synchrotron radiation circular dichroism spectroscopy, and small-angle X-ray scattering. These studies suggest that OPN is an intrinsically unstructured protein in solution. Although OPN does not fold into a single defined structure, its conformational flexibility significantly deviates from random coil-like behavior. OPN comprises distinct local secondary structure elements with reduced conformational flexibility and substantially populates a compact subspace displaying distinct tertiary contacts. These compacted regions of OPN encompass the binding sites for alpha(V)beta(III) integrin and heparin. The conformational flexibility combined with the modular architecture of OPN may represent an important structural prerequisite for its functional diversity. PMID- 21609002 TI - Hybrid Si microwire and planar solar cells: passivation and characterization. AB - We report an efficient hybrid Si microwire (radial junction) and planar solar cell with a maximum efficiency of 11.0% under AM 1.5G illumination. The maximum efficiency of the hybrid cell is improved from 7.2% to 11.0% by passivating the top surface and p-n junction with thin a-SiN:H and intrinsic poly-Si films, respectively, and is higher than that of planar cells of the identical layers due to increased light absorption and improved charge-carrier collections in both wires and planar components. PMID- 21609003 TI - Systematic evaluation of nanomaterial toxicity: utility of standardized materials and rapid assays. AB - The challenge of optimizing both performance and safety in nanomaterials hinges on our ability to resolve which structural features lead to desired properties. It has been difficult to draw meaningful conclusions about biological impacts from many studies of nanomaterials due to the lack of nanomaterial characterization, unknown purity, and/or alteration of the nanomaterials by the biological environment. To investigate the relative influence of core size, surface chemistry, and charge on nanomaterial toxicity, we tested the biological response of whole animals exposed to a matrix of nine structurally diverse, precision-engineered gold nanoparticles (AuNPs) of high purity and known composition. Members of the matrix include three core sizes and four unique surface coatings that include positively and negatively charged headgroups. Mortality, malformations, uptake, and elimination of AuNPs were all dependent on these parameters, showing the need for tightly controlled experimental design and nanomaterial characterization. Results presented herein illustrate the value of an integrated approach to identify design rules that minimize potential hazard. PMID- 21609004 TI - Highly organized two- and three-dimensional single-walled carbon nanotube-polymer hybrid architectures. AB - Single-walled carbon nanotube (SWCNT) network architectures combined with flexible mediums (especially polymers) are strong candidates for functional flexible devices and composite structures requiring the combination of unique electronic, optical, and/or mechanical properties of SWCNTs and polymer materials. However, to build functional flexible devices with SWCNTs, it is required to have abilities to assemble and incorporate SWCNTs in desired locations, orientations, and dimensions on/inside polymer substrates. Here, we present unique two- and three-dimensional SWCNT network-polymer hybrid architectures by combining unprecedented control over growth, assembly, and transfer processes of SWCNTs. Several SWCNT architectures have been built on polymer materials ranging from two-dimensional suspended SWCNT microlines on PDMS microchannels to three-dimensional "PDMS-vertically aligned SWCNTs-PDMS" sandwich structures. Also a combined lateral SWCNT microline and vertically aligned SWCNT flexible device was demonstrated with good electrical conductivity and low junction resistance. The results reported here open the pathway for the development of SWCNT-based functional systems in various flexible device applications. PMID- 21609005 TI - Polar charges induced electric hysteresis of ZnO nano/microwire for fast data storage. AB - We demonstrate an innovative memory device made of a single crystalline ZnO nanowire/microwire that works with a different mechanism from the p-n junction based memristor. A nonsymmetric, Schottky-Ohmic contacted ZnO nano/microwire can serve as a memristor if the channel length is short and the applied frequency is high. The observed phenomena could be explained based on a screening model of the polar charges at the two ends of the wire owing to the crystal structure of ZnO. The polar charges are usually fully screened by free electrons coming from the metal sides. But when the magnitude of the externally applied field exceeds a threshold value, the free electrons that screen the polar surfaces can be pulled away from the interface region, leading to a transient change in the effective height of the local Schottky barrier height owing to the electrical field formed by the polar surfaces of ZnO nanowires, which acts as a resistor with its magnitude depending on the total charges being transported. Such a phenomenon could be used for high density and fast writing/erasing data storage. PMID- 21609006 TI - Reversibly electroswitched quantum dot luminescence in aqueous solution. AB - In this study, we fabricated a novel hybrid film system, in which reversible electroswitching quantum dot (QD) luminescence was realized in aqueous solution for the first time. On the basis of an electrochromic material, poly(methylene blue) (PMB), QD luminescence could be switched effectively in a narrow potential range of -0.4 to 0 V via the corresponding luminescence quenching effect. The luminescence switching operation was reversible and reproducible, and no noticeable changes in both "on" and "off" luminescence intensities were observed in 20 cycles. This simple system not only effectively overcame the harsh operation environment that generally existed in previous reports but also provided an easy method for the design and fabrication of other novel QD electroswitchable hybrid components. PMID- 21609007 TI - Influence of 150 years of land use on anthropogenic and natural carbon stocks in Emilia-Romagna region (Italy). AB - Changes in land use/cover that are commonly associated with urbanization can dramatically influence the amount, chemical form, and spatial distribution of carbon (C) stocks. Measured values and relative literature for composition of natural and anthropogenic materials have been compiled. These data are used in conjunction with land cover statistics and expert assessment of building design to calculate C stocks associated with 150 years of land use change and development for an area of the Po River Valley, Northern Italy. Using 4 time periods (1853, 1954, 1976, and 2003), we demonstrate that the C stocks within this densely populated area have undergone considerable modification. A 52% increase in population density has been associated with an increase in the proportion of total C stored in anthropogenic stocks from 0.2% to 6%; this has been accompanied by a one order of magnitude increase in the carbon emission per capita per unit area. These changes have also been accompanied by a major shift in stocks from organic to inorganic forms of C. PMID- 21609008 TI - Microbial diversity and changes in the distribution of dehalogenase genes during dechlorination with different concentrations of cis-DCE. AB - A dechlorinating consortium (designated as TES-1 culture) able to convert trichloroethene (TCE) to ethene was established from TCE-contaminated groundwater. This culture had the ability of complete dechlorination of TCE within about one month. From the clone library analysis of 16S rRNA gene, this culture was mainly composed of fermentation bacteria, such as Clostridium spp., and Desulfitobacterium spp. known as facultative dechlorinator. PCR using specific primers for Dehalococcoides spp. and the dehalogenase genes confirmed that the culture contained the Dehalococcoides spp. 16S rRNA gene and three dehalogenase genes, tceA, vcrA and bvcA. Dechlorination experiments using cis dichloroethene (cis-DCE) at concentrations of 37-146 MUM, revealed that the gene copy numbers of tceA, vcrA, and bvcA increased up to 107 copy/mL, indicating that Dehalococcoides spp. containing these three dehalogenase genes were involved in cis-DCE dechlorination. However, in the culture to which 292 MUM of cis-DCE was added, only the tceA gene and the Dehalococcoides spp. 16S rRNA gene increased up to 107 copy/mL. The culture containing 292 MUM of cis-DCE also exhibited about one tenth slower ethene production rate compared to the other cultures. PMID- 21609009 TI - Preliminary estimates of nanoparticle number emissions from road vehicles in megacity Delhi and associated health impacts. AB - Rapid urbanisation in developing megacities like Delhi has resulted in an increased number of road vehicles and hence total particle number (ToN) emissions. For the first time, this study presents preliminary estimates of ToN emissions from road vehicles, roadside and ambient ToN concentrations, and exposure related excess deaths in Delhi in current and two future scenarios; business as usual (BAU) and best estimate scenario (BES). Annual ToN emissions are estimated as 1.37 * 10(25) for 2010 which are expected to increase by ~4 times in 2030-BAU, but to decrease by ~18 times in 2030-BES. Such reduction is anticipated due to a larger number of compressed natural gas driven vehicles and assumed retrofitting of diesel particulate filters to all diesel vehicles by 2020. Heavy duty vehicles emit the majority (~65%) of ToN for only ~4% of total vehicle kilometres traveled in 2010. Their contribution remains dominant under both scenarios in 2030, clearly requiring major mitigation efforts. Roadside and ambient ToN concentrations were up to a factor of 30 and 3 higher to those found in respective European environments. Exposure to ambient ToN concentrations resulted in ~508, 1888, and 31 deaths per million people in 2010, 2030-BAU and 2030-BES, respectively. PMID- 21609010 TI - Inorganic geochemistry and redox dynamics in bank filtration settings. AB - Bank filtration induces flow of surface water through a hydraulically connected aquifer by excess pumping from a production well in the aquifer. This review presents the four main geochemical processes relevant for inorganic geochemistry, with a focus on iron (Fe) and manganese (Mn), during bank filtration: reduction near the bank, oxidation near the production well, carbonate dissolution, and sorption to aquifer materials. Physical and transport processes affect these geochemical processes and influence the redox state of the infiltrate. The presence of Fe and Mn in bank infiltrate is directly related to its redox status and can necessitate drinking water treatment after extraction. Long-term, in situ sequestration of Fe and Mn requires precipitation of oxide or carbonate solids, since a sorption front can breakthrough at the production well. PMID- 21609011 TI - Microbial bioavailability of covalently bound polymer coatings on model engineered nanomaterials. AB - By controlling nanoparticle flocculation and deposition, polymer coatings strongly affect nanoparticle fate, transport, and subsequent biological impact in the environment. Biodegradation is a potential route to coating breakdown, but it is unknown whether surface-bound polymers are bioavailable. Here we demonstrate, for the first time, that polymer coatings covalently bound to nanomaterials are bioavailable. Model poly(ethylene oxide) (PEO) brush-coated nanoparticles (densely cross-linked bottle brush copolymers) with hydrophobic divinyl benzene cross-linked cores and hydrophilic PEO brush shells, having ~ 30 nm hydrodynamic radii, were synthesized to obtain a nanomaterial in which biodegradation was the only available coating breakdown mechanism. PEO-degrading enrichment cultures were supplied with either PEO homopolymer or PEO brush nanoparticles as the sole carbon source, and protein and CO2 production were monitored as a measure of biological conversion. Protein production after 90 h corresponded to 14% and 8% of the total carbon available in the PEO homopolymer and PEO brush nanoparticle cultures, respectively, and CO2 production corresponded to 37% and 3.8% of the carbon added to the respective system. These results indicate that the PEO in the brush is bioavailable. Brush biodegradation resulted in particle aggregation, pointing to the need to understand biologically mediated transformations of nanoparticle coatings in order to understand the fate and transport of nanoparticles in the environment. PMID- 21609012 TI - Spatial assignment of emissions using a new locomotive emissions model. AB - Estimates of fuel use and air pollutant emissions from freight rail currently rely highly on aggregate methods and largely obsolete data which offer little insight into contemporary air quality problems. Because the freight industry is for the most part privately held and data are closely guarded for competitive reasons, the challenge is to produce robust estimates using current reporting requirements, while accurately portraying the spatial nature of freight rail impacts. This research presents a new spatially resolved model for estimating air pollutant emissions (hydrocarbons, carbon monoxide, nitrogen oxides, particulate matter less than 10 MUm in diameter, sulfur dioxide, and carbon dioxide) from locomotives. Emission estimates are based on track segment level data including track grade, type of train traffic (bulk, intermodal, or manifest) and the local locomotive fleet (EPA tier certification level and fuel efficiency). We model the California Class I freight rail system and compare our results to regional estimates from the California Air Resources Board and to estimates following U.S. Environmental Protection Agency guidance. We find that our results vary considerably from the other methods depending on the region or corridor analyzed. We also find large differences in fuel and emission intensity for individual rail corridors. PMID- 21609013 TI - Effects of surface features on sulfur dioxide adsorption on calcined NiAl hydrotalcite-like compounds. AB - The hydrotalcite-based NiAl mixed oxides were synthesized by coprecipitation and urea hydrolysis approaches and employed for SO2 removal. The samples were well characterized by inductively coupled plasma (ICP) elemental analysis, X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and N2 adsorption/desorption isotherm analyses. The acid-base properties were characterized by pyridine chemisorption and CO2 temperature programmed desorption (TPD). The calcined NiAlO from the urea method showed excellent SO2 adsorption and its adsorption equilibrium showed a type I isotherm, which significantly improved the adsorption performance for low-concentration SO2. Both the physical structure and the acidic-basic sites were found to play important roles in the SO2 adsorption process. In situ Fourier transform infrared spectroscopy (FTIR) investigation revealed that adsorbed SO2 molecules formed surface bisulfite, sulfite, and bidentate binuclear sulfate. The mechanisms for SO2 adsorption and transformation are discussed in detail. PMID- 21609014 TI - Consensus models of activity landscapes with multiple chemical, conformer, and property representations. AB - We report consensus Structure-Activity Similarity (SAS) maps that address the dependence of activity landscapes on molecular representation. As a case study, we characterized the activity landscape of 54 compounds with activities against human cathepsin B (hCatB), human cathepsin L (hCatL), and Trypanosoma brucei cathepsin B (TbCatB). Starting from an initial set of 28 descriptors we selected ten representations that capture different aspects of the chemical structures. These included four 2D (MACCS keys, GpiDAPH3, pairwise, and radial fingerprints) and six 3D (4p and piDAPH4 fingerprints with each including three conformers) representations. Multiple conformers are used for the first time in consensus activity landscape modeling. The results emphasize the feasibility of identifying consensus data points that are consistently formed in different reference spaces generated with several fingerprint models, including multiple 3D conformers. Consensus data points are not meant to eliminate data, disregarding, for example, "true" activity cliffs that are not identified by some molecular representations. Instead, consensus models are designed to prioritize the SAR analysis of activity cliffs and other consistent regions in the activity landscape that are captured by several molecular representations. Systematic description of the SARs of two targets give rise to the identification of pairs of compounds located in the same region of the activity landscape of hCatL and TbCatB suggesting similar mechanisms of action for the pairs involved. We also explored the relationship between property similarity and activity similarity and found that property similarities are suitable to characterize SARs. We also introduce the concept of structure-property-activity (SPA) similarity in SAR studies. PMID- 21609015 TI - Promiscuity in alkaline phosphatase superfamily. Unraveling evolution through molecular simulations. AB - We here present a theoretical study of the alkaline hydrolysis of a phosphodiester (methyl p-nitrophenyl phosphate or MpNPP) in the active site of Escherichia coli alkaline phosphatase (AP), a monoesterase that also presents promiscuous activity as a diesterase. The analysis of our simulations, carried out by means of molecular dynamics (MD) simulations with hybrid quantum mechanics/molecular mechanics (QM/MM) potentials, shows that the reaction takes place through a D(N)A(N) or dissociative mechanism, the same mechanism employed by AP in the hydrolysis of monoesters. The promiscuous activity observed in this superfamily can be then explained on the basis of a conserved reaction mechanism. According to our simulations the specialization in the hydrolysis of phosphomonoesters or phosphodiesters, developed in different members of the superfamily, is a consequence of the interactions established between the protein and the oxygen atoms of the phosphate group and, in particular, with the oxygen atom that bears the additional alkyl group when the substrate is a diester. A water molecule, belonging to the coordination shell of the Mg(2+) ion, and residue Lys328 seem to play decisive roles stabilizing a phosphomonoester substrate, but the latter contributes to increase the energy barrier for the hydrolysis of phosphodiesters. Then, mutations affecting the nature or positioning of Lys328 lead to an increased diesterase activity in AP. Finally, the capacity of this enzymatic family to catalyze the reaction of phosphoesters having different leaving groups, or substrate promiscuity, is explained by the ability of the enzyme to stabilize different charge distributions in the leaving group using different interactions involving either one of the zinc centers or residues placed on the outer side of the catalytic site. PMID- 21609017 TI - Solution-deposited organic-inorganic hybrid multilayer gate dielectrics. Design, synthesis, microstructures, and electrical properties with thin-film transistors. AB - We report here on the rational synthesis, processing, and dielectric properties of novel layer-by-layer organic/inorganic hybrid multilayer dielectric films enabled by polarizable pi-electron phosphonic acid building blocks and ultrathin ZrO(2) layers. These new zirconia-based self-assembled nanodielectric (Zr-SAND) films (5-12 nm thick) are readily fabricated via solution processes under ambient atmosphere. Attractive Zr-SAND properties include amenability to accurate control of film thickness, large-area uniformity, well-defined nanostructure, exceptionally large electrical capacitance (up to 750 nF/cm(2)), excellent insulating properties (leakage current densities as low as 10(-7) A/cm(2)), and excellent thermal stability. Thin-film transistors (TFTs) fabricated with pentacene and PDIF-CN(2) as representative organic semiconductors and zinc-tin oxide (Zn-Sn-O) as a representative inorganic semiconductor function well at low voltages (<+/-4.0 V). Furthermore, the TFT performance parameters of representative organic semiconductors deposited on Zr-SAND films, functionalized on the surface with various alkylphosphonic acid self-assembled monolayers, are investigated and shown to correlate closely with the alkylphosphonic acid chain dimensions. PMID- 21609018 TI - Nitrile-functionalized pyridinium, pyrrolidinium, and piperidinium ionic liquids. AB - Two series of 1-alkylpyridinium and N-alkyl-N-methylpiperidinium ionic liquids functionalized with a nitrile group at the end of the alkyl chain have been synthesized. Structural modifications include a change of the alkyl spacer length between the nitrile group and the heterocycle of the cationic core, as well as adding methyl or ethyl substituents on different positions of the pyridinium ring. The anions are the bromide and the bis(trifluoromethylsulfonyl)imide ion. All the bis(trifluoromethylsulfonyl)imide salts as well as the bromide salts with a long alkyl spacer were obtained as viscous liquids at room temperature, but some turned out to be supercooled liquids. In addition, pyrrolidinium and piperidinium ionic liquids with two nitrile functions attached to the heterocyclic core have been prepared. The crystal structures of seven pyridinium bis(trifluoromethylsulfonyl)imide salts are reported. Quantum chemical calculations have been performed on model cations and ion pairs with the bis(trifluoromethylsulfonyl)imide anion. A continuum model has been used to take solvation effects into account. These calculations show that the natural partial charge on the nitrogen atom of the nitrile group becomes more negative when the length of the alkyl spacer between the nitrile functional group and the heterocyclic core of the cation is increased. Methyl or methoxy substituents on the pyridinium ring slightly increase the negative charge on the nitrile nitrogen atom due to their electron-donating abilities. The position of the substituent (ortho, meta, or para) has only a very minor effect on the charge of the nitrogen atom. The (15)N NMR spectra of the bis(trifluoromethylsulfonyl)imide ionic liquids were recorded with the nitrogen-15 nucleus at its natural abundance. The chemical shift of the (15)N nucleus of the nitrile nitrogen atom could be correlated with the calculated negative partial charge on the nitrogen atom. PMID- 21609016 TI - Design, synthesis, and validation of a beta-turn mimetic library targeting protein-protein and peptide-receptor interactions. AB - The design and synthesis of a beta-turn mimetic library as a key component of a small-molecule library targeting the major recognition motifs involved in protein protein interactions is described. Analysis of a geometric characterization of 10,245 beta-turns in the protein data bank (PDB) suggested that trans-pyrrolidine 3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a beta-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (K(i) = 390 and 23 nM, respectively) for the kappa-opioid receptor (KOR). Consistent with the screening capabilities of collaborators and following the design validation, the complete library was assembled as 210 mixtures of 20 compounds, providing a total of 4200 compounds designed to mimic all possible permutations of 3 of the 4 residues in a naturally occurring beta-turn. Unique to the design and because of the C(2) symmetry of the template, a typical 20 * 20 * 20-mix (8000 compounds prepared as 400 mixtures of 20 compounds) needed to represent 20 variations in the side chains of three amino acid residues reduces to a 210 * 20-mix, thereby simplifying the library synthesis and subsequent screening. The library was prepared using a solution-phase synthetic protocol with liquid-liquid or liquid-solid extractions for purification and conducted on a scale that insures its long-term availability for screening campaigns. Screening the library against the human opioid receptors (KOR, MOR, and DOR) identified not only the activity of library members expected to mimic the opioid receptor peptide ligands but also additional side-chain combinations that provided enhanced receptor binding selectivities (>100-fold) and affinities (as low as K(i) = 80 nM for KOR). A key insight to emerge from the studies is that the phenol of Tyr in endogenous ligands bearing the H-Tyr-Pro-Trp/Phe-Phe-NH(2) beta-turn is important for MOR binding but may not be important for KOR (accommodated, but not preferred) and that the resulting selectivity for KOR observed with its removal can be increased by replacing the phenol OH with a chlorine substituent, further enhancing KOR affinity. PMID- 21609019 TI - Synthesis of dibenzofurans via palladium-catalyzed phenol-directed C-H activation/C-O cyclization. AB - A practical, Pd(0)/Pd(II)-catalyzed reaction was developed for phenol-directed C H activation/C-O cyclization using air as an oxidant. The turnover-limiting step of the process was found to be C-O reductive elimination instead of C-H activation. This reaction can tolerate a variety of functional groups and is complementary to the previous methods for the synthesis of substituted dibenzofurans. PMID- 21609020 TI - Carbonyl oxides reactions from geraniol-trans-(3,7-dimethylocta-2,6-dien-1-ol), 6 methyl-5-hepten-2-one, and 6-hydroxy-4-methyl-4-hexenal ozonolysis: kinetics and mechanisms. AB - A density functional theory (DFT) study of the mechanisms of carbonyl oxide reactions from geraniol-trans, 6-methyl-5-hepten-2-one, and 6-hydroxy-4-methyl-4 hexenal ozonolysis is presented. The geometries, energies, and harmonic vibrational frequencies of each stationary point were determined by B3LYP/6 31(d,p) and BH&HLYP/cc-pVDZ methods. According to the calculations, the ozonolysis reactions are initiated by the formation of van der Waals (VDW) complexes to yield primary ozonides, which rapidly open to carbonyl oxide compounds. These carbonyl oxide compounds react to form dioxanes and hydroperoxides. The hydroperoxides react by isomerization to form stable products. Glyoxal and methyl-glyoxal have been identified as the final product from geraniol-trans, 6-methyl-5-hepten-2-one, and 6-hydroxy-4-methyl-4-hexenal ozonolysis. Our results are in good agreement with the experimental studies. PMID- 21609021 TI - Mass spectrometric determination of IgG subclass-specific glycosylation profiles in siblings discordant for myositis syndromes. AB - Many autoimmune conditions are believed to result from chronic inflammation as a consequence of the interaction of genetic and environmental factors in susceptible individuals. One common feature in some autoimmune diseases is the decrease in terminal galactosylation of the constant region N-glycan of the total plasma immunoglobulin. To determine whether a similar pattern is characteristic for the autoimmune disorder myositis, we analyzed the antibody subclass specific glycosylation in patients with myositis, their asymptomatic siblings, and healthy unrelated age- and sex-matched controls. The antibody subclass specific glycosylation was determined from the LC-MS analyses of the IgG glycopeptides generated by trypsin digestion of the antibody heavy chain. The glycosylation profiles of the IgG subclasses were determined relative to the total abundance of all glycoforms. We found elevated amounts of glycoforms lacking terminal galactose in myositis patients. Pairwise statistical analyses reveals that galactosylation is statistically different between the myositis patients and control groups. Furthermore, the trend analysis for glycosylation indicates a pattern of decreasing galactosylation in the order controls >= siblings >= myositis patients, suggesting the existence of a genetic, immune-related predisposition in the group of asymptomatic siblings that can be detected before the onset of clinical symptoms at the level of plasma proteins. PMID- 21609023 TI - Direct synthesis of lithium-intercalated graphene for electrochemical energy storage application. AB - A novel approach for bulk synthesis of lithium-intercalated graphene sheets through the reduction of exfoliated graphene oxide in liquid ammonia and lithium metal is reported. It is demonstrated here that as-synthesized lithiated graphite oxide sheets (Li-RGO) can be directly used as an electrode material in lithium batteries. The electrochemical studies on Li-RGO electrodes show a significant enhancement in the specific capacity of the lithium battery over commercially available graphite electrodes. Partial intercalation of lithium ions in between graphene layers makes this material a good candidate for electrochemical energy storage applications. PMID- 21609022 TI - Quantitative phospho-proteomic profiling of hepatocyte growth factor (HGF)-MET signaling in colorectal cancer. AB - Colorectal cancer (CRC) is the second leading cause of death from cancer. The MET receptor tyrosine kinase and/or its ligand HGF are frequently amplified or overexpressed in CRC. It is known that tyrosine phosphorylated proteins are involved in progression and metastasis of colorectal cancer; however, little is known about the MET phospho-proteome in CRC. High resolution mass spectrometry was used to characterize immunoaffinity-purified, phosphotyrosine (pY)-containing tryptic peptides of the MET-expressing CRC cell model, DLD1. A total of 266 unambiguously identified pY sites spanning 168 proteins were identified. Quantification of mass spectrometry ion currents identified 161 pY sites, including many not previously linked to MET signaling, that were modulated in abundance by HGF stimulation. Overlay of these data with protein-protein interaction data sets suggested that many of the identified HGF-modulated phospho proteins may be directly or indirectly associated with MET. Analysis of pY sequence motifs indicated a prevalence of Src family kinase consensus sequences, and reciprocal signaling between Src and MET was confirmed by using selective small molecule inhibitors of these kinases. Therefore, using quantitative phospho proteomics profiling, kinase modulation by ligand and inhibitors, and data integration, an outline of the MET signaling network was generated for the CRC model. PMID- 21609024 TI - Structural rearrangement of ethanol-denatured soy proteins by high hydrostatic pressure treatment. AB - The effects of high hydrostatic pressure (HHP) treatment (100-500 MPa) on solubility and structural properties of ethanol (EtOH)-denatured soy beta conglycinin and glycinin were investigated using differential scanning calorimetry, Fourier transform infrared and ultraviolet spectroscopy. HHP treatment above 200 MPa, especially at neutral and alkaline pH as well as low ionic strength, significantly improved the solubility of denatured soy proteins. Structural rearrangements of denatured beta-conglycinin subjected to high pressure were confirmed, as evidenced by the increase in enthalpy value (DeltaH) and the formation of the ordered supramolecular structure with stronger intramolecular hydrogen bond. HHP treatment (200-400 MPa) caused an increase in surface hydrophobicity (F(max)) of beta-conglycinin, partially attributable to the exposure of the Tyr and Phe residues, whereas higher pressure (500 MPa) induced the decrease in F(max) due to hydrophobic rearrangements. The Trp residues in beta-conglycinin gradually transferred into a hydrophobic environment, which might further support the finding of structural rearrangements. In contrast, increasing pressure induced the progressive unfolding of denatured glycinin, accompanied by the movement of the Tyr and Phe residues to the molecular surface of protein. These results suggested that EtOH denatured beta-conglycinin and glycinin were involved in different pathways of structural changes during HHP treatment. PMID- 21609025 TI - Electrically conductive gold-coated collagen nanofibers for placental-derived mesenchymal stem cells enhanced differentiation and proliferation. AB - Gold-coated collagen nanofibers (GCNFs) were produced by a single-step reduction process and used for the growth and differentiation of human adult stem cells. The nanomaterials were characterized by a number of analytical techniques including electron microscopy and spectroscopy. They were found to be biocompatible and to improve the myocardial and neuronal differentiation process of the mesenchymal stem cells isolated from the placental chorionic component. The expression of specific differentiation markers (atrium, natriuretic peptide, actin F and actin monomer, glial fibrilary acidic protein, and neurofilaments) was investigated by immunocytochemistry. PMID- 21609026 TI - A general strategy to fabricate simple polyoxometalate nanostructures: electrochemistry-assisted laser ablation in liquid. AB - Polyoxometalate nanostructures have attracted much attention because of significant technical demands in applications such as catalysts, sensors, and smart windows. Therefore, researchers have recently developed many methods for the synthesis of these nanomaterials. However, these techniques have many visible flaws such as high temperatures or high pressure environments, various templates or additives, demanding and complicated synthesis procedures as well as the presence of impurities in the final products. We therefore propose a general strategy for the fabrication of particular polyoxometalate nanostructures by electrochemically assisted laser ablation in liquid (ECLAL). These polyoxometalates are usually simple as they typically contain two metals and are not soluble in water. This approach is a green, simple, and catalyst-free approach under an ambient environment. Apart from these merits, this novel technique allows researchers to choose and design interesting solid targets and to use an electrochemical approach toward the fabrication of polyoxometalate nanostructures for the purpose of fundamental research and for potential applications. Using the synthesis of Cu(3)Mo(2)O(9) nanorods as an example, we substantiate the validity of the proposed strategy. For the fabrication of Cu(3)Mo(2)O(9) nanostructures, we chose molybdenum as a solid target for laser ablation in liquid copper electrodes for the electrochemical reaction and water as a solvent for the ECLAL synthesis. We successfully fabricated Cu(3)(OH)(2)(MoO(4))(2) nanorods with magnetic properties. Interestingly, we obtained well-defined Cu(3)Mo(2)O(9) nanorods by annealing the Cu(3)(OH)(2)(MoO(4))(2) nanostructures at 500 degrees C. Additionally, the basic physics and chemistry involved in the ECLAL fabrication of nanostructures are discussed. PMID- 21609027 TI - Specific cell targeting with nanobody conjugated branched gold nanoparticles for photothermal therapy. AB - Branched gold nanoparticles are potential photothermal therapy agents because of their large absorption cross section in the near-infrared window. Upon laser irradiation they produce enough heat to destroy tumor cells. In this work, branched gold nanoparticles are biofunctionalized with nanobodies, the smallest fully functional antigen-binding fragments evolved from the variable domain, the VHH, of a camel heavy chain-only antibody. These nanobodies bind to the HER2 antigen which is highly expressed on breast and ovarian cancer cells. Flow cytometric analysis and dark field images of HER2 positive SKOV3 cells incubated with anti-HER2 conjugated branched gold nanoparticles show specific cell targeting. Laser irradiation studies reveal that HER2 positive SKOV3 cells exposed to the anti-HER2 targeted branched gold nanoparticles are destroyed after five minutes of laser treatment at 38 W/cm(2) using a 690 nm continuous wave laser. Starting from a nanoparticle optical density of 4, cell death is observed, whereas the control samples, nanoparticles with anti-PSA nanobodies, nanoparticles only, and laser only, do not show any cell death. These results suggest that this new type of bioconjugated branched gold nanoparticles are effective antigen-targeted photothermal therapeutic agents for cancer treatment. PMID- 21609028 TI - Negotiation of intracellular membrane barriers by TAT-modified gold nanoparticles. AB - This paper contributes to the debate on how nanosized objects negotiate membrane barriers inside biological cells. The uptake of peptide-modified gold nanoparticles by HeLa cells has been quantified using atomic emission spectroscopy. The TAT peptide from the HIV virus was singled out as a particularly effective promoter of cellular uptake. The evolution of the intracellular distribution of TAT-modified gold nanoparticles with time has been studied in detail by TEM and systematic image analysis. An unusual trend of particles disappearing from the cytosol and the nucleus and accumulating massively in vesicular bodies was observed. Subsequent release of the particles, both by membrane rupture and by direct transfer across the membrane boundary, was frequently found. Ultimately, near total clearing of particles from the cells occurred. This work provides support for the hypothesis that cell-penetrating peptides can enable small objects to negotiate membrane barriers also in the absence of dedicated transport mechanisms. PMID- 21609029 TI - Millimeter-long carbon nanotubes: outstanding electron-emitting sources. AB - We are reporting the fabrication of a very efficient electron source using millimeter-long and highly crystalline carbon nanotubes. These devices start to emit electrons at fields as low as 0.17 V/MUm and reach threshold emission at 0.24 V/MUm. In addition, these electron sources are very stable and can achieve a peak current density of 750 mA cm(-2) at only 0.45 V/MUm. In order to demonstrate intense electron beam generation, these devices were used to produce visible light by cathodoluminescence. Finally, density functional theory calculations were used to rationalize the measured electronic field emission properties in open carbon nanotubes of different lengths. The modeling establishes a clear correlation between length and field enhancement factor. PMID- 21609030 TI - Preparation of polymer-coated, scintillating ion-exchange resins for monitoring of 99Tc in groundwater. AB - The present study was oriented to prepare new scintillating anion-exchange resins for measurement of (99)TcO(4)(-) in natural waters. The organic fluor 2-(1 naphthyl)-5-phenyloxazole was diffused into (chloromethyl)polystyrene resin. Thereafter, a thin layer of poly[[2-(methacryloyloxy)ethyl]trimethylammonium chloride] was grafted from the resin surface by surface-initiated atom transfer radical polymerization as an attempt to overcome potential problems related to the leaching of fluor molecules during usage. The residual chloromethyl groups of the polymer-coated resin were aminated by reaction with two different tertiary amines, triethylamine (TEA) and methyldioctylamine (MDOA). Off- and on-line quantification of (99)Tc was achieved with high detection efficiencies of 60.72 +/- 1.93% and 72.83 +/- 0.81% for resin with TEA and MDOA functional groups, respectively. The detection limit was determined to be less than the maximum contaminant level (33 Bq L(-1)) established under the Safe Drinking Water Act. The two functionalized resins were demonstrated to be selective for pertechnetate from synthetic groundwater containing up to 1000 ppm Cl(-), SO(4)(2-), and HCO(3)(-) and up to 1200 ppb Cr(2)O(7)(2-) in an acidic medium. PMID- 21609031 TI - Starch characteristics and their influences on in vitro and pig prececal starch digestion. AB - The main objective of this research was to study the characteristics of starch granules and their influences on in vitro and pig prececal starch digestion of corn, dehulled barley, wheat, and potato. Scanning electron microscopy was used to study the starch endosperm structure in the parent material as well as in vitro starch digestion. The results showed that corn starch granules were polyhedral, with a diameter ranging from 2 to 10 MUm, whereas those of dehulled barley and wheat were spherical, with a diameter ranging from 5 to 20 MUm. Potato had the largest starch granules among starch sources reported herein, with oval spheres of 10-50 MUm in diameter. In vitro starch hydrolysis showed that starch granules of corn degraded faster than the starch of dehulled barley and wheat, with the potato starch being degraded the slowest. The in vivo digestibility trial using ileal-cannulated pigs confirmed the starch degradation of grains. The in vitro (x, %) and in vivo (y, %) digestibility were highly correlated [y = 6.5304x - 538.48 (R(2) = 0.9924)]. On the basis of the results, in vitro starch hydrolysis might be useful in predicting in vivo prececal starch digestibility. The digestion kinetic characteristics of different starch sources might be employed to evaluate the starch digestive rate at the pig ileum. PMID- 21609127 TI - Size exclusion chromatography for semipreparative scale separation of Au38(SR)24 and Au40(SR)24 and larger clusters. AB - Size exclusion chromatography (SEC) on a semipreparative scale (10 mg and more) was used to size-select ultrasmall gold nanoclusters (<2 nm) from polydisperse mixtures. In particular, the ubiquitous byproducts of the etching process toward Au(38)(SR)(24) (SR, thiolate) clusters were separated and gained in high monodispersity (based on mass spectrometry). The isolated fractions were characterized by UV-vis spectroscopy, MALDI mass spectrometry, HPLC, and electron microscopy. Most notably, the separation of Au(38)(SR)(24) and Au(40)(SR)(24) clusters is demonstrated. PMID- 21609128 TI - Shift reagents for multidimensional ion mobility spectrometry-mass spectrometry analysis of complex peptide mixtures: evaluation of 18-crown-6 ether complexes. AB - 18-Crown-6 ether (18C6) is evaluated as a shift reagent for multidimensional ion mobility spectrometry-mass spectrometry (IMS-IMS-MS) analyses of tryptic protein digests. In this approach, 18C6 is spiked into the solution-phase mixture and noncovalent peptide-crown ion complexes are formed by electrospraying the mixture into the gas phase. After an initial mobility separation in the first IMS drift region, complexes of similar mobility are selected and dissociated via collisional activation prior to entering the second drift region. These dissociation products (including smaller complexes, naked peptide ions, charge transfer products, and fragment ions) differ in mobility from their precursor ion complexes and (in favorable cases) from one another, allowing the mixture to resolve further in the second IMS region. We estimate an IMS-IMS peak capacity of ~2400 when shift reagents are employed. The approach is illustrated by examining a tryptic digest of cytochrome c and by identifying a peptide out of a complex mixture obtained by digestion of human plasma proteins. Disadvantages arising from increased complexity of data sets as well as other advantages of this approach are considered. PMID- 21609129 TI - Photoinducible bioorthogonal chemistry: a spatiotemporally controllable tool to visualize and perturb proteins in live cells. AB - Visualization in biology has been greatly facilitated by the use of fluorescent proteins as in-cell probes. The genes coding for these wavelength-tunable proteins can be readily fused with the DNA coding for a protein of interest, which enables direct monitoring of natural proteins in real time inside living cells. Despite their success, however, fluorescent proteins have limitations that have only begun to be addressed in the past decade through the development of bioorthogonal chemistry. In this approach, a very small bioorthogonal tag is embedded within the basic building blocks of the cell, and then a variety of external molecules can be selectively conjugated to these pretagged biomolecules. The result is a veritable palette of biophysical probes for the researcher to choose from. In this Account, we review our progress in developing a photoinducible, bioorthogonal tetrazole-alkene cycloaddition reaction ("photoclick chemistry") and applying it to probe protein dynamics and function in live cells. The work described here summarizes the synthesis, structure, and reactivity studies of tetrazoles, including their optimization for applications in biology. Building on key insights from earlier reports, our initial studies of the reaction have revealed full water compatibility, high photoactivation quantum yield, tunable photoactivation wavelength, and broad substrate scope; an added benefit is the formation of fluorescent cycloadducts. Subsequent studies have shown fast reaction kinetics (up to 11.0 M(-1) s(-1)), with the rate depending on the HOMO energy of the nitrile imine dipole as well as the LUMO energy of the alkene dipolarophile. Moreover, through the use of photocrystallography, we have observed that the photogenerated nitrile imine adopts a bent geometry in the solid state. This observation has led to the synthesis of reactive, macrocyclic tetrazoles that contain a short "bridge" between two flanking phenyl rings. This photoclick chemistry has been used to label proteins rapidly (within ~1 min) both in vitro and in E. coli . To create an effective interface with biology, we have identified both a metabolically incorporable alkene amino acid, homoallylglycine, and a genetically encodable tetrazole amino acid, p-(2-tetrazole)phenylalanine. We demonstrate the utility of these two moieties, respectively, in spatiotemporally controlled imaging of newly synthesized proteins and in site specific labeling of proteins. Additionally, we demonstrate the use of the photoclick chemistry to perturb the localization of a fluorescent protein in mammalian cells. PMID- 21609130 TI - Magnesium and calcium organophyllosilicates: synthesis and in vitro cytotoxicity study. AB - Synthesis of multifunctional hybrid nanomaterials for biomedical applications has received great attention. Herein, we examine the potential toxicity of organophyllosilicates on cells from different organs such as A549 (lung epithelial cancer), HT-29 (colon epithelial cancer), MRC-5 (lung fibroblast) and CCD-986sk (skin fibroblast) cells. For this, aminopropyl functionalized magnesium phyllosilicate (AMP clay) and aminopropyl functionalized calcium phyllosilicate (ACP clay) were prepared using one-pot direct sol-gel method. Toxic effects of these organoclays on normal fibroblast and tumor cells were examined under varying concentrations and exposure times. MTT and LDH assays indicated that both organoclays had little cytotoxicity in all of the cells tested at concentrations as high as 500 MUg/mL. Even at high concentration (1000 MUg/mL), the toxicity of both organoclays on cell viability and membrane damage was not severe and appeared to be cell type specific. In addition, organoclays did not induce apoptosis at concentrations as high as 1000 MUg/mL. PMID- 21609131 TI - Pharmacological, structural, and drug delivery properties and applications of 1,3 beta-glucans. AB - 1,3-beta-Glucans are a class of natural polysaccharides with unique pharmacological properties and the ability to form single- and triple-helical structures that can be formed into resilient gels with the application of heat and humidity. The pharmacological capabilities of 1,3-beta-glucans include the impartation of tumor inhibition, resistance to infectious disease, and improvements in wound healing. Curdlan is a linear 1,3-beta-glucan that has been used extensively to study the nature of these helical structures and gels, and Curdlan sulfates have found ongoing application in the inhibition of HIV infection. 1,3-beta-Glucan gels have been used in food science as stabilizers and encapsulating agents, in nanoscience as scaffolds to build nanofibers and nanowires, and in drug delivery to form nanoparticles and create helical micelles encapsulating polynucleotides. 1,3-beta-Glucans are beginning to have enormous significance due to their dual nature as structure-forming agents and pharmacological substances, and research is especially focused on the application of these polymers in animal nutrition and drug delivery. PMID- 21609132 TI - Developing rural palliative care: validating a conceptual model. AB - INTRODUCTION: The purpose of this research was to validate a conceptual model for developing palliative care in rural communities. This model articulates how local rural healthcare providers develop palliative care services according to four sequential phases. The model has roots in concepts of community capacity development, evolves from collaborative, generalist rural practice, and utilizes existing health services infrastructure. It addresses how rural providers manage challenges, specifically those related to: lack of resources, minimal community understanding of palliative care, health professionals' resistance, the bureaucracy of the health system, and the obstacles of providing services in rural environments. METHODS: Seven semi-structured focus groups were conducted with interdisciplinary health providers in 7 rural communities in two Canadian provinces. Using a constant comparative analysis approach, focus group data were analyzed by examining participants' statements in relation to the model and comparing emerging themes in the development of rural palliative care to the elements of the model. RESULTS: The data validated the conceptual model as the model was able to theoretically predict and explain the experiences of the 7 rural communities that participated in the study. New emerging themes from the data elaborated existing elements in the model and informed the requirement for minor revisions. CONCLUSION: The model was validated and slightly revised, as suggested by the data. The model was confirmed as being a useful theoretical tool for conceptualizing the development of rural palliative care that is applicable in diverse rural communities. PMID- 21609133 TI - Student opinions on a rural placement program in New South Wales, Australia. AB - INTRODUCTION: Australia's dental workforce is largely metropolitan, with a corresponding lack of dentists in rural areas. Some evidence from the discipline of medicine suggests that providing a rural placement program for undergraduates may encourage them work in a rural area post-graduation. Therefore, the University of Sydney Faculty of Dentistry implemented a rural placement program for final year dental undergraduates with funding provided by the Australian Government Department of Health and Ageing. METHODS: In 2009, a one-month Rural Placement Program was introduced for 4th (final) year dental undergraduates. Of the 80 fourth year students, 40% volunteered to participate in the program. Their views on the program were collected in pre- and post-questionnaires which were self-completed. Framework analysis was used to identify common themes in the student responses. This article focuses on the placement experience of the participants with particular emphasis on the factors and barriers which influenced their intention to work in a rural location post-graduation. RESULTS: Participants' characteristics included a mean age of 27 years, 59% female and 77% had been raised in a city environment. All the participants completed the pre- and post-placement questionnaires. The most common pre-placement hopes were to increase their clinical skills and to experience a rural environment. Pre placement concerns related to missing lecture time at the university and having less time there to complete their clinical quota requirements. Over half of the students (57%) were considering employment in a rural location prior to the placement. Post-placement the students reported being pleased with the clinical experience provided, with increased time management skills and clinical confidence emphasised. The rural clinical supervisors and staff were highly rated by students for their support, helpfulness and teaching ability. After the placement the majority of students (97%) were considering working in a rural environment once qualified. Positive factors identified as influencing their decision were the broad clinical range of procedures available, good clinical mentors, reduced commuting and a quieter lifestyle. Barriers to working in a rural location were identified as missing friends, partners and the number of available job opportunities. All participants would recommend the placement to future students. CONCLUSIONS: In this successful undergraduate Rural Placement Program the students valued both personal and educational components. They became more aware of the potential advantages of working in a rural location and almost all would consider working in a rural area after graduation. PMID- 21609135 TI - Nano-TiO2--feasibility and challenges for human health risk assessment based on open literature. AB - This study aims at investigating feasibility and challenges associated with conducting a human health risk assessment for nano-titanium-dioxide (nano-TiO2) based on the open literature by following an approach similar to a classical regulatory risk assessment. Gaps in the available data set, both in relation to exposures and hazard, do not allow reaching any definite conclusions that could be used for regulatory decision-making. Results show that repeated inhalation in the workplace and possibly consumer inhalation may cause risks. Also short-term inhalation following spray applications may cause risks. Main future work should focus on generating occupational and consumer inhalation exposure data, as well as toxicity data on absorption following inhalation, repeated dermal contact, and contact with damaged skin. Also relevant seems further information on possible neurotoxicity and genotoxicity/carcinogenicity, as well as establishing a No Observed Adverse Effect Level (NOAEL) for acute inhalation of nano-TiO2. PMID- 21609134 TI - Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing alpha1-antitrypsin: interim results. AB - Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of alpha(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0*10(11), 1.9*10(12), and 6.0*10(12) vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-gamma enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8(+) subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT >20 MUg/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations. PMID- 21609136 TI - Dispersion stabilization of silver nanoparticles in synthetic lung fluid studied under in situ conditions. AB - The dispersion stabilization of silver nanoparticles (AgNPs) in synthetic lung fluid was studied to interrogate the effects on colloidal stability due to the principal constituents of the fluid. The colloidal stability of 20 nm citrate AgNPs dispersed in the presence of each constituent of the synthetic lung fluid (individually, the complete fluid, and without additives) was observed during titration of increasing sodium chloride concentration. A variety of complementary in situ measurement techniques were utilized, including dynamic light scattering, ultraviolet-visible absorption spectroscopy, atomic force microscopy, and small angle X-ray scattering, which provided a collective set of information that enabled far better understanding of the dispersion behavior in the fluid than any one technique alone. It was observed that AgNPs continued to adsorb bovine serum albumin (BSA) protein from the synthetic lung fluid solution as the sodium chloride concentration increased, until a maximum BSA coating was achieved prior to reaching the physiological sodium chloride concentration of 154 mmol L(-1). BSA was determined to be the constituent of the synthetic lung fluid that is required to provide colloidal stability at high salt loadings, though the phospholipid constituent exerts a subtle effect. Additionally, as AgNPs are a distinctly different class of nanoparticles apart from the carbon nanotubes and titanium dioxide nanoparticles initially reported to be dispersible using this fluid, this work also demonstrates the broad applicability of synthetic lung fluid in providing stable dispersions for engineered nanoparticles for use in biological assays. PMID- 21609137 TI - In vitro assessment of cellular responses to rod-shaped hydroxyapatite nanoparticles of varying lengths and surface areas. AB - Rod-shaped hydroxyapatite nanoparticles of varying dimensions (~ 60 +/- 10, 120 +/- 15, 240 +/- 30 nm in length, labeled respectively as nHA60, nHA120 and nHA240) with specific surface areas (47.02, 23.33, 46.12 nm(2), respectively), were synthesized and their effects on cell viability, reactive oxygen species generation and cellular interaction with BEAS-2B, RAW264.7 and HepG2 were investigated. In vitro exposure of these cell lines to rod shape nHA particles within a range of 10-300 MUg/ml for 24 h did not significantly alter cell viability studied by the WST-8 assay. A significant increase in reactive oxygen species (ROS) generation was however observed with the dihydrofluorescein diacetate (DFDA) assay after 4 h incubation with these nanoparticles. The lowest level of ROS generation was observed with nHA120 (with the smallest specific surface area); whereas nHA60 and nHA240 exhibited comparable ROS generation. Subsequently, the Alizarin Red-S (ARS) assay indicated a weaker association of calcium with cells compared to nHA60 and nHA240. The results thus suggest that high surface area may increase cell-particle interaction, which in turn influenced ROS generation. The combined results from all the cell lines thus indicated high biocompatibility of rod-shaped nHA. PMID- 21609138 TI - A theoretical framework for predicting the oxidative stress potential of oxide nanoparticles. AB - In this paper we propose a theoretical model that predicts the oxidative stress potential of oxide nanoparticles by looking at the ability of these materials to perturb the intracellular redox state. The model uses reactivity descriptors to build the energy band structure of oxide nanoparticles, assuming a particle diameter larger than 20-30 nm and no surface states in the band gap, and predicts their ability to induce an oxidative stress by comparing the redox potentials of relevant intracellular reactions with the oxides' energy structure. Nanoparticles displaying band energy values comparable with redox potentials of antioxidants or radical formation reactions have the ability to cause an oxidative stress and a cytotoxic response in vitro. We discuss the model's predictions for six relevant oxide nanoparticles (TiO(2), CuO, ZnO, FeO, Fe(2)O(3), Fe(3)O(4)) with literature in vitro studies and calculate the energy structure for 64 additional oxide nanomaterials. Such a framework would guide the development of more rational and efficient screening strategies avoiding random or exhaustive testing of new nanomaterials. PMID- 21609139 TI - Global issues in volatile substance misuse. AB - This special issue of Substance Use & Misuse addresses the public health issue of volatile substance misuse (VSM), the inhalation of gases or vapors for psychoactive effects, assessing the similarities and differences in the products misused, patterns, prevalence, etiologies, and impacts of VSM by examining it through sociocultural epidemiology, neuroscience, and interventions research. The Canadian, US, and Australian guest editors contend that, when compared with other drugs used at a similar prevalence, VSM has attracted relatively little research effort. The authors and editors call for further research to develop evidence based policies and comprehensive interventions that respect culture and context specific knowledge. PMID- 21609140 TI - Volatile substance misuse in the United States. AB - Volatile substance misuse (VSM) is prevalent in the United States and associated with manifold deleterious outcomes. This review summarizes research on: (1) the prevalence of VSM in the United States and its trends since 1975, (2) population subgroups at an elevated risk for VSM, (3) key correlates of VSM, (4) psychosocial consequences of VSM, including emerging public health threats, and (5) etiological and contextual considerations of VSM use. Implications for future research and practice with volatile substance misusers in the United States are identified. PMID- 21609141 TI - Volatile substance misuse among youth in Israel: results of a national school survey. AB - Volatile substance misuse (VSM) among Israeli youth has been identified as widespread and growing. Using data from the 2009 National School Survey of 12-18 year olds (N = 7,166), this study describes VSM prevalence among Jews and Arabs, examining relationships between past-month VSM and sociodemographic, behavioral, psychological, and interpersonal characteristics. Past-month VSM, reported by 7.5% of respondents, was significantly associated with other risky behaviors including past-month illicit drug use (Adjusted odds ratios (AOR) = 5.41, 95% CI: 3.5-8.1), Internet gambling (AOR = 2.12, 95% CI: 1.5-3.1), smoking, binge drinking, and truancy. National drug policy must address VSM and develop strategies to reduce demand and supply. Potential study limitations are noted. PMID- 21609142 TI - Volatile substance misuse among high school students in South America. AB - This article summarizes data from a 2004 study of over 300,000 high school students (aged 13-18 years) in nine South American countries. A probabilistic sample targeted urban secondary schools, utilizing a self-administered questionnaire on prevalence and frequency of substance use. Multivariate analysis showed that volatile substances were the first or second most commonly reported substances used after alcohol and cigarettes in all countries (lifetime prevalence range: 2.67% [Paraguay] to 16.55% [Brazil]). Previous studies have highlighted volatile substance misuse among street children, whereas this study demonstrates that it is common among South American high school students. PMID- 21609143 TI - Volatile substance misuse among street children in Upper Egypt. AB - This work assessed the extent, patterns, attitudes, motivations, and impacts of volatile substance misuse (VSM) among street children in Upper Egypt. In 2009, a 36-item questionnaire was administered to a randomly selected sample of 120 street children aged 10-18 years. Nearly 91% (n = 109) reported misusing products containing volatile substances because they are inexpensive, legal, and easy to acquire. Familial neglect and lack of supervision were the main social motivations reported by street youth for misusing volatile substances. One-third (34.2%, n = 41) reported inhaling "Kolla," a commercial glue; this study identifies its physicochemical, neuropharmacological, and toxicological properties. The study's limitations are noted. PMID- 21609144 TI - Volatile substance misuse in Mexico: correlates and trends. AB - This paper analyzes volatile substance misuse in Mexico since the 1980s. Data were collected from national household and school surveys, epidemiological surveillance systems, and studies among special populations. Volatile substance misuse begins at 12-14 years. Prevalence is approximately 1% in the general population, 7% among high school students, and higher for street children. Toluene is the main solvent used, but preferences vary within population groups. Volatile substance misuse has increased among youngsters that live in families and attend school. Marijuana and volatile substances are now the drugs of choice among Mexican female high school students. The study's limitations are noted. PMID- 21609145 TI - Volatile substance misuse among street children in India: a preliminary report. AB - Although substance misuse among children in India has been documented for over a decade, volatile substance misuse (VSM) is a comparatively recent phenomenon there. This paper reviews available Indian studies about VSM among street children and documents the extent of misuse, experienced benefits and harms, and risk factors. Reported perceived benefits include enhanced physical strength, decreased shyness, sleep induction, feeling good, and numbing physical and psychological pain. Identified risk factors include domestic violence, a dictatorial father, presence of stepparents, migrant status, and substance use in the family. Limitations of the current paper and the need for further research are discussed. PMID- 21609146 TI - The epidemiology of volatile substance misuse among school children in Bogota, Colombia. AB - Volatile substance misuse (VSM) is increasing among Colombian youth. Rates and correlates of VSM, exposure-opportunity (EO) to VSM, and positive VSM intentions were examined in 2006 among 2,279 students (mean age 14.8 years) in 23 schools in Bogota, Colombia. Sixteen percent experienced an EO, 3% reported past-year VSM, and 7-10% reported positive VSM intentions. Multilevel-logistic models revealed that VSM among friends was associated with past-year VSM (adjusted odds ratio (AOR) = 5.56, 95% confidence interval (CI) = 2.3-13.6) and VSM intention (AOR = 2.48, 95%CI = 1.6-3.9). Other correlates include male gender, a low perceived risk, and poor academic achievement. At-risk groups were identified, and targeted prevention strategies were suggested. The study's limitations are also noted. PMID- 21609147 TI - Chronic toluene misuse among Roma youth in Eastern Slovakia. AB - This report presents pilot data on toluene misuse among Roma (Gypsy) youth in eastern Slovakia. Twenty interviews were conducted with field social workers (FSWs) working in seven Roma settlements with a combined population of 17,050 people. An estimated 340 chronic toluene users, mostly males (90%, n = 306), were identified in the researched communities. FSWs reported that children younger than 10 years of age represented about 15% of users (n = 52) and that the majority of users (75%, n = 255) were between 10 and 25 years of age. Consequences of prolonged use on individuals and communities are discussed. The study's limitations are noted. PMID- 21609148 TI - The latest evidence in the neuroscience of solvent misuse: an article written for service providers. AB - This work reviews preclinical and clinical studies published during the past two decades on the cellular and behavioral effects of commonly misused solvents. In animals, acute solvent exposure produces motor impairment and antidepressant- and anxiolytic-like effects. Human intoxication from misusing solvents is similar to that of ethanol; however, hallucinations and sudden sniffing death may occur at high solvent concentrations. Among chronic misusers, there is evidence of impaired memory, increased prevalence of psychiatric disorders, and neurological damage. Solvents facilitate inhibitory neurotransmission and block excitatory mechanisms. Toluene, in particular, increases brain dopamine levels and its effects occur at concentrations that do not dissolve cell membranes; therefore, neuronal damage is not an immediate, unavoidable consequence of solvent misuse. PMID- 21609149 TI - Two serious and challenging medical complications associated with volatile substance misuse: sudden sniffing death and fetal solvent syndrome. AB - Volatile substance misuse is a prevalent and often overlooked behavior among adolescents, including reported use among young pregnant women. Several medical repercussions can arise from the improper use of volatile substances, yet they are often underappreciated among scientists and health professionals. This brief review reports on the recent advances made in the preclinical and clinical data about two serious medical complications surrounding volatile substance misuse: sudden sniffing death and fetal solvent syndrome. Suggestions for treatment interventions are discussed. The paper's limitations are noted. PMID- 21609150 TI - Recovery from central nervous system changes following volatile substance misuse. AB - This review examines cognitive, neurological, and neuroanatomical recovery associated with abstinence from volatile substance misuse (VSM). Articles describing functional or structural brain changes longitudinally or cross sectional reports comparing current and abstinent users were identified and reviewed. A significant lack of empirical studies investigating central nervous system recovery following VSM was noted. The few case reports and group studies identified indicated that cognitive and neurological impairments appear to follow a progression of decline and progression of recovery model, with the severity of impairment related to the duration and severity of misuse, blood lead levels among leaded petrol misusers, and the duration of abstinence for recovery. By contrast, severe neurological impairment known as lead encephalopathy from sniffing leaded petrol occurred as more catastrophic or abrupt damage to cerebellar processes that may never fully recover. Neuroanatomical damage may not recover even with prolonged abstinence. PMID- 21609151 TI - Misusing volatile substances for their hallucinatory effects: a qualitative pilot study with Mexican teenagers and a pharmacological discussion of their hallucinations. AB - This work describes the solvent-induced hallucinatory experiences of 10 male and seven female teenagers in Mexico City from 1998 to 2000. The youth were recruited from public schools through a combined snowball and convenience sampling procedure. Inclusion criteria were: 13-18 years of age, school attendance, living with family, and weekly toluene-based solvent misuse. Interested students were interviewed and transcripts were analyzed. Hallucinations and illusions were common, including changes in color perception, visual, somatic, auditory, and tactile hallucinations. Some users described their hallucinatory experience as being able to be shared by a group and modulated by their environment. The pharmacological linkages with hallucinations are discussed. The study's limitations are noted. PMID- 21609152 TI - Solvent-induced leukoencephalopathy: a disorder of adolescence? AB - Volatile substance misuse is common during early adolescence; however, limited work has been conducted investigating the neurobiological effects of such use on the developing brain. While both animal and human studies report cognitive and neurobiological harm associated with volatile substance misuse during adolescence (particularly involving white matter structures), the complex psychosocial characteristics of volatile substance misusers confound the specificity of reported volatile substance-related pathology in human subjects. In addition, few studies have examined whether cognitive and neurobiological recovery occurs with abstinence, although there is some literature indicating that neurological and cognitive improvement is possible, but relates to the frequency and duration of previous use. Longitudinal studies utilizing well-matched control samples are required to fully delineate the short- and long-term impact of volatile substance misuse on adolescent brain development. PMID- 21609153 TI - Petrol sniffing interventions among Australian indigenous communities through product substitution: from skunk juice to opal. AB - Inhalation of petrol (gasoline) fumes has been prevalent in some Australian Indigenous communities since World War II, and has led to a continuing quest for an effective method of preventing the practice either by modifying the substance or by substituting nonharmful alternatives. This article traces the results of this search, beginning with the addition of ethyl mercaptan, then describing the substitution of aviation fuel for conventional vehicle fuel, and concluding with the staged introduction of Opal--a vehicle fuel containing low levels of aromatic hydrocarbons--throughout many communities from 2005. The article assesses the benefits and limitations of supply reduction methods. PMID- 21609154 TI - Residential volatile substance misuse treatment for indigenous youth in Canada. AB - The Youth Solvent Addiction Program (YSAP) was established in 1996 in response to the misuse of volatile substances among First Nations and Inuit youth in Canada. This article outlines the role of Indigenous culture and its intersection with Western approaches to recovery in YSAP's operation of nine residential treatment centers for youth. Treatment practices and client outcome data are used to illustrate YSAP's approach. Limitations of the article are noted. PMID- 21609155 TI - The outstation model of rehabilitation as practiced in Central Australia: the case for its recognition and acceptance. AB - This paper describes and analyzes the model of care provided by the Ilpurla remote outstation rehabilitation program in Australia's Northern Territory. Reflections are offered about the cultural antecedents of the model, and how it addresses the needs of young Indigenous people. Data describing client numbers, length of stay, the underlying approach to rehabilitation, and the practices of the program are presented. The paper aims to promote an understanding of the outstation model of care, highlight difficulties between programs and their funding sources, and encourages recognition of its importance in the response to drug and alcohol use-related problems among Indigenous people. PMID- 21609156 TI - The lived experience of volatile substance misuse: how support contributes to recovery and sustained well-being. AB - This article examines the role of support in the lives, recovery, and sustained well-being of two long-term First Nations volatile substance misusers in Canada. Through the application of visual-arts-based and oral life history methodologies, support is conceptualized and analyzed from joint Indigenous and Western worldviews. With a culturally informed understanding of the types of connections that bring about support, insight is offered to those who are a part of the recovery and maintenance support systems of individuals who misuse volatile substances. PMID- 21609157 TI - Cognitive behavioral therapy-based brief intervention for volatile substance misusers during adolescence: a follow-up study. AB - Of 62 males admitted for treatment in Turkey in 2008 with a diagnosis of volatile substance misuse (VSM) dependency, half were randomly allocated to receive a cognitive behavioral therapy (CBT)-based brief intervention and an education program and half participated only in the education program. One year after treatment, 38.2% of the experimental group and 58.1% of the control group had continued VSM during the last three months. This statistically significant difference indicates that CBT-based brief intervention is associated with reducing VSM in adolescents. Factors associated with abstinence after treatment are identified and study limitations are noted. PMID- 21609158 TI - Meeting professionals' needs in the United Kingdom for effective VSM intervention. AB - An exploratory study examined what professionals needed to support their responses to volatile substance misuse (VSM). Many respondents saw VSM as a problem of unknown dimensions and were uncertain about how to tackle it. Resources for treatment and prevention were seen as outdated. Workers were concerned that VSM was becoming more common among adults, supporting an indication found in a study of VSM-related deaths. Evidence-informed treatment protocols, information on working with clients, assessments of local needs, and the evaluation of existing approaches to VSM would improve the response. A further phase of the research will be reported in 2012. PMID- 21609160 TI - External aortic diameter ratios: a reliable method to diagnose preductal aortic coarctation. AB - Aortic Coarctation (AC) is associated with sudden infantile death. Current pathological diagnosis depends on absolute vessel size which is prone to errors due to different rates of development. This study explores the use of ratios of the external diameter between the aortic isthmus (AI), ascending aorta (AA) and the descending aortas (DA). Our study found that while the vessel diameter increased with gestational age, the ratios remained constant and are therefore preferable than absolute size. This simple and highly reproducible method will allow more cases of AC that may be misdiagnosed to get a proper pathological diagnosis. PMID- 21609161 TI - Angiomyomatous hamartoma of the popliteal lymph nodes in a patient with Klippel Trenaunay syndrome: case report. AB - We present a case of angiomyomatous hamartoma (AMH) in the popliteal region of a patient with Klippel-Trenaunay syndrome. A 14-year-old boy with a right popliteal mass and recurrent edema of the right leg was admitted to a local hospital where a diagnosis of Klippel-Trenaunay syndrome was made. Three lymph nodes in the right popliteal fossa were removed. Histopathologic examination showed angiomyomatous hamartomas. Postoperatively, the patient was followed for 6 years. He had occasional mild edema of the right leg, but no signs of inflammation or recurrence of the angiomyomas. Our case is the first reported case of angiomyomatous hamartoma in a patient with Klippel-Trenaunay (KT) syndrome. PMID- 21609162 TI - Alpha-1-antitrypsin deficiency in early childhood. AB - Alpha-1-antitrypsin deficiency (AATD), which predisposes liver disease in children, is often undiagnosed. Isoelectric focusing in 161 infants with liver dysfunction revealed 14.7% severe and 12.2% moderate AATD. Positive PAS-D and immunohistochemical staining was found in 60% of severe AATD, but in moderate AATD, only immunohistochemistry was positive in 100%. Bilirubinostasis, hepatomegaly, splenomegaly, cholestasis, hepatomegaly associated with cholestasis, acholia, high transaminases, and low birthweight were significantly more frequent in severe than in moderate AATD. Both AATDs showed significant portal inflammation, hepatic fibrosis, and viral infection. Early screening in children with liver dysfunction can contribute to the successful detection of AATD. PMID- 21609163 TI - Association between TGFBR2 gene polymorphism (rs2228048, Asn389Asn) and intracerebral hemorrhage in Korean population. AB - Transforming growth factor, beta receptor II (TGFBR2) is mainly expressed by neurons in the central nervous system, and reduced neuronal TGFBR2 signaling results in accelerated age-dependent neurodegeneration. To investigate whether TGFBR2 polymorphisms are associated with ischemic stroke (IS) and intracerebral hemorrhage (ICH), two single nucleotide polymorphisms (SNPs) of TGFBR2 gene (rs764522, -1444C/G; rs2228048, Asn389Asn) were selected and genotyped by direct sequencing in 247 stroke patients (120 IS and 127 ICH) and 655 control subjects (260 for IS and 395 for ICH). SNPStats, SNPAnalyzer, Helixtree, and Haploview version 4.2 were used to analyze genetic data. Multiple logistic regression models (codominant, dominant, recessive, and log-additive) were performed to evaluate odds ratios (ORs), 95% confidence intervals (CIs), and p values. The synonymous SNP rs2228048 was significantly associated with ICH (p = 0.032 in codominant 2 model, p = 0.024 in dominant model, p = 0.020 in recessive model, and p = 0.005 in log-additive model) and Fisher's exact test (p = 0.009). Allele frequencies of rs2228048 were different between ICH and controls (p = 0.006). In Bonferroni correction, these correlations were also significant. These results suggest that the synonymous SNP rs2228048 of TGFBR2 gene may be associated with development of ICH in Korean population. PMID- 21609164 TI - The development of an instrument to assess clinical teaching with linkage to CanMEDS roles: A psychometric analysis. AB - BACKGROUND: Assessment of clinical teaching by learners is of value to teachers, department heads, and program directors, and must be comprehensive and feasible. AIMS: To review published evaluation instruments with psychometric evaluations and to develop and psychometrically evaluate an instrument for assessing clinical teaching with linkages to the CanMEDS roles. METHOD: We developed a 19-item questionnaire to reflect 10 domains relevant to teaching and the CanMEDS roles. A total of 317 medical learners assessed 170 instructors. Fourteen (4.4 %) clinical clerks, 229 (72.3%) residents, and 53 (16.7%) fellows assessed 170 instructors. Twenty-one (6.6%) did not specify their position. RESULTS: A mean number of eight raters assessed each instructor. The internal consistency reliability of the 19 item instrument was Cronbach's alpha = 0.95. The generalizability coefficient (Ep(2)) analysis indicated that the raters achieved Ep(2) of 0.95. The factor analysis showed three factors that accounted for 67.97% of the total variance. The three factors together, with the variance accounted for and their internal consistency reliability, are teaching skills (variance = 53.25s%; Cronbach's alpha = 0.92), Patient interaction (variance = 8.56%; Cronbach's alpha = 0.91), and professionalism (variance = 6.16%; Cronbach's alpha = 0.86). The three factors are intercorrelated (correlations = 0.48, 0.58, 0.46; p < 0.01). CONCLUSION: It is feasible to assess clinical teaching with the 19-item instrument that has demonstrated evidence of both validity and reliability. PMID- 21609165 TI - Transferable skills of incoming medical students and their development over the first academic year: The United Arab Emirates experience. AB - Increasingly, it is being recognised in higher and medical education that learners should be adequately prepared for the unpredictable nature of professional practice. Several generic or transferable skills or capabilities (e.g., communication, information handling) that will enable graduates to function in an ever-changing professional world have been identified. Using a validated inventory comprising six categories of transferable skills, three cohorts of incoming male and female medical students at a Gulf university documented their level of practice and confidence for 31 skills. The exercise was repeated a year later. New medical students identified computer and organisational skills and the ability to manage their learning as strengths, but scores for technical and numeracy, information handling and presentation and communication skills suggested that learners generally required guidance. A year later, despite considerable self-reported information handling and communication skills development, learners generally did not consider themselves self sufficient. A significant gender difference emerged, with incoming males reporting less experience and confidence in many skills. This gap was reduced but did not disappear over the first academic year. An audit such as this may be useful for identifying individual skills levels as well as providing insight into shortcomings in the academic programme in terms of opportunities for transferable skills development. PMID- 21609166 TI - Teaching evidence-based medicine: Impact on students' literature use and inpatient clinical documentation. AB - BACKGROUND: Effective teaching of evidence-based medicine (EBM) to medical students is important for lifelong self-directed learning. AIMS: We implemented a brief workshop designed to teach literature searching skills to third-year medical students. We assessed its impact on students' utilization of EBM resources during their clinical rotation and the quality of EBM integration in inpatient notes. METHODS: We developed a physician-led, hands-on workshop to introduce EBM resources to all internal medicine clerks. Pre- and post-workshop measures included student's attitudes to EBM, citations of EBM resources in their clinical notes, and quality of the EBM component of the discussion in the note. Computer log analysis recorded students' online search attempts. RESULTS: After the workshop, students reported improved comfort using EBM and increased utilization of EBM resources. EBM integration into the discussion component of the notes also showed significant improvement. Computer log analysis of students' searches demonstrated increased utilization of EBM resources following the workshop. CONCLUSIONS: We describe the successful implementation of a workshop designed to teach third-year medical students how to perform an efficient EBM literature search. We demonstrated improvements in students' confidence regarding EBM, increased utilization of EBM resources, and improved integration of EBM into inpatient notes. PMID- 21609167 TI - Effects of partial substitution of pre-clinical skills training by attachments to primary health care centers: An experimental study. AB - BACKGROUND: Recent studies indicate that students may encounter problems when they have to apply clinical skills learned in a skills laboratory to patients. To facilitate this transition, it has been advised to include patient contacts early in the pre-clinical curriculum. OBJECTIVE: To compare clinical skills performance and level of preparedness for entering the clerkships between students who were prepared exclusively in a skills laboratory and peers for whom part of their skills training program was substituted by training in a primary health care (PHC) center. METHODS: Pre-clinical students either trained clinical skills exclusively in a skills laboratory while their peers attended a mixed program of laboratory trainings and practice in PHC centers. Students' perception of preparedness for the clerkships was explored through the Preparation for Hospital Practice Questionnaire. Students' clinical skills were assessed by an Objective Structured Clinical Examination (OSCE) and by supervisors in PHC centers. RESULTS: Students following the mixed program felt better prepared for their clerkships than skills lab-trained peers. Students' perceptions were supported by assessments by their supervisors. However, mean OSCE scores of both groups did not differ significantly. CONCLUSION: PHC centers can be involved to better prepare pre-clinical students for their clerkships. PMID- 21609168 TI - Computer-supported collaborative learning in the medical workplace: Students' experiences on formative peer feedback of a critical appraisal of a topic paper. AB - BACKGROUND: Medical workplace learning consists largely of individual activities, since workplace settings do not lend themselves readily to group learning. An electronic Learning Management with System Computer-Supported Collaborative Learning (CSCL) could enable learners at different workplace locations to discuss personal clinical experiences at a distance to enhance learning. AIM: To explore whether CSCL-enabled structured asynchronous discussions on an authentic task has additional value for learning in the medical workplace. METHODS: Between January 2008 and June 2010, we conducted an exploratory evaluation study among senior medical students that were engaged in clinical electives. Students wrote a Critical Appraisal of a Topic paper about a clinical problem they had encountered and discussed it in discipline homogeneous subgroups on an asynchronous forum in a CSCL environment. A mixed method design was used to explore students' perceptions of the CSCL arrangement with respect to their preparation and participation, the design and knowledge gains. We analysed the messages recorded during the discussions to investigate which types of interactions occurred. RESULTS: Students perceived knowledge improvement of their papers. The discussions were mostly task-focused. The students considered an instruction session and a manual necessary to prepare for CSCL. A high amount of sent messages and a high activity in discussion seem to influence scores on perceptions: 'participation' and 'knowledge gain' positively. CONCLUSION: CSCL appears to offer a suitable environment for peers to provide formative feedback on a Critical Appraisal of a Topic paper during workplace learning. The CSCL environment enabled students to collaborate in asynchronous discussions, which positively influenced their learning. PMID- 21609169 TI - The impact of discussing a sexual history in role-play simulation teaching on pre clinical student attitudes towards people who submit for STI testing. AB - Sex, sexuality and sexual health beliefs are individual, impacting on physical and mental health. Sexual history taking is rarely taught in General Practice (GP). However, 'sex' is routinely relevant in this setting. Birmingham students practice discussing sexual history with a simulated-patient in GP. Simulated patient inclusion in teaching/assessment is well-documented, but no study evaluating the impact of role play on attitudes to people who need STI testing was identified. We aimed to identify whether facilitated simulations featuring a sexual history scenario effected change in students' attitudes towards people who need STI testing. A randomised-controlled-trial was used to compare attitudinal scores between students exposed to an STI role play and a control group who did not receive the role-play teaching until after data capture. There were no significant differences in attitude, either in negative or positive direction, observed between control and intervention groups. Ethnicity was a significant variable, with white-British students self-reporting more positive attitudes. Twenty five percent students admitted personal STI exposure. Again response varied significantly between ethnic groups (the white-British group reporting 4* the exposure). Females reported more positive attitudes than males, most marked in relation to 'willingness to date' someone who admitted to STI testing. PMID- 21609170 TI - Using a Delphi process to establish consensus on emergency medicine clerkship competencies. AB - BACKGROUND: Currently, there is no consensus on the core competencies required for emergency medicine (EM) clerkships in Canada. Existing EM curricula have been developed through informal consensus or local efforts. The Delphi process has been used extensively as a means for establishing consensus. AIM: The purpose of this project was to define core competencies for EM clerkships in Canada, to validate a Delphi process in the context of national curriculum development, and to demonstrate the adoption of the CanMEDS physician competency paradigm in the undergraduate medical education realm. METHODS: Using a modified Delphi process, we developed a consensus amongst a panel of expert emergency physicians from across Canada utilizing the CanMEDS 2005 Physician Competency Framework. RESULTS: Thirty experts from nine different medical schools across Canada participated on the panel. The initial list consisted of 152 competencies organized in the seven domains of the CanMEDS 2005 Physician Competency Framework. After the second round of the Delphi process, the list of competencies was reduced to 62 (59% reduction). CONCLUSION: This study demonstrated that a modified Delphi process can result in a strong consensus around a realistic number of core competencies for EM clerkships. We propose that such a method could be used by other medical specialties and health professions to develop rotation-specific core competencies. PMID- 21609171 TI - Chronic illness needs educated doctors: An innovative primary care training program for chronic illness education. AB - BACKGROUND: Medical educators need proven curriculum innovations that prepare trainees for the expanding number of patients with chronic illnesses. PURPOSE: We describe and evaluate the effectiveness of a chronic illness training program, Chronic Illness Needs Educated Doctors (CINED). METHOD: Forty-seven trainees completed four instructional components: (1) measurements of the health-related quality of life of patients with chronic illnesses; (2) didactic sessions in which they described chronically ill patients and their care; (3) written narratives describing the trainees' reactions for these patients; and (4) portfolios offering evidence of chronic illness learning. We measured the accuracy of the trainees' clinical skills at the end of CINED with an objective standardized clinical exercise (OSCE). RESULTS: Forty-seven trainees scored the perceptions of mental and physical health of 414 chronic illnesses patients. In 47 didactic sessions and 93 written narratives, the trainees explained the relationship between the scores and their clinical observations. Accurate differential diagnoses of and communications with chronically ill patients were observed in an OSCE by standardized patients. The trainers rated 13 of the trainees' chronic illness portfolios as excellent and the remainder satisfactory. CONCLUSION: Initial evaluations suggest that the CINED is an effective curriculum for promoting chronic illness learning among trainees. PMID- 21609172 TI - The ethics of student assessment. PMID- 21609173 TI - Medical education in Albania: Challenges and opportunities. AB - Albania is a small south-eastern European country still recovering from almost half a century of a fierce communist regime. While major reform and support have focused on healthcare and higher education (HE) in the past decade, there have not been major attempts to improve medical education. The time is now ready for medical education improvements created by increasing internal and external pressures as Albania aims to align its HE with the European Union standards and adapts the Bologna system. This article presents a summary of the current status of undergraduate, postgraduate and continuous medical education in Albania and suggests opportunities for development and partnerships that would help the country's medical education reform. PMID- 21609174 TI - Post-examination analysis of objective tests. AB - One of the key goals of assessment in medical education is the minimisation of all errors influencing a test in order to produce an observed score which approaches a learner's 'true' score, as reliably and validly as possible. In order to achieve this, assessors need to be aware of the potential biases that can influence all components of the assessment cycle from question creation to the interpretation of exam scores. This Guide describes and explains the processes whereby objective examination results can be analysed to improve the validity and reliability of assessments in medical education. We cover the interpretation of measures of central tendency, measures of variability and standard scores. We describe how to calculate the item-difficulty index and item discrimination index in examination tests using different statistical procedures. This is followed by an overview of reliability estimates. The post-examination analytical methods described in this guide enable medical educators to construct reliable and valid achievement tests. They also enable medical educators to develop question banks using the collection of appropriate questions from existing examination tests in order to use computerised adaptive testing. PMID- 21609175 TI - Does undergraduate curriculum design make a difference to readiness to practice as a junior doctor? AB - BACKGROUND: Undergraduate medicine curricula can be designed to enable smoother transition to work as a junior doctor. Evaluations should improve curriculum design. AIM: To compare a graduate cohort from one medical school with a cohort from other medical schools in the same Foundation Year 1 (FY1) programme in terms of retrospective perceptions of readiness for practice. METHOD: A Likert-scale questionnaire measured self-perception of readiness to practice, including general capabilities and specific clinical skills. RESULTS: Response rate was 74% (n = 146). The Peninsula Medical School cohort reported readiness for practice at a significantly higher level than the comparison cohort in 14 out of 58 items (24%), particularly for 'coping with uncertainty'. In only one item (2%) does the comparison cohort report at a significantly higher level. CONCLUSIONS: Significant differences between cohorts may be explained by undergraduate curriculum design, where the opportunity for early, structured work-based, experiential learning as students, with patient contact at the core of the experience, may promote smoother transition to work as a junior doctor. Evaluation informs continuous quality improvement of the curriculum. PMID- 21609177 TI - Programmatic assessment: From assessment of learning to assessment for learning. AB - In assessment a considerable shift in thinking has occurred from assessment of learning to assessment for learning. This has important implications for the conceptual framework from which to approach the issue of assessment, but also with respect to the research agenda. The main conceptual changes pertain to programmes of assessment. This has led to a broadened perspective on the types of construct assessment tries to capture, the way information from various sources is collected and collated, the role of human judgement and the variety of psychometric methods to determine the quality of the assessment. Research into the quality of assessment programmes, how assessment influences learning and teaching, new psychometric models and the role of human judgement is much needed. PMID- 21609176 TI - Assessment of clinical reasoning: A Script Concordance test designed for pre clinical medical students. AB - BACKGROUND: The Script Concordance test (SCT) measures clinical reasoning in the context of uncertainty by comparing the responses of examinees and expert clinicians. It uses the level of agreement with a panel of experts to assign credit for the examinee's answers. AIM: This study describes the development and validation of a SCT for pre-clinical medical students. METHODS: Faculty from two US medical schools developed SCT items in the domains of anatomy, biochemistry, physiology, and histology. Scoring procedures utilized data from a panel of 30 expert physicians. Validation focused on internal reliability and the ability of the SCT to distinguish between different cohorts. RESULTS: The SCT was administered to an aggregate of 411 second-year and 70 fourth-year students from both schools. Internal consistency for the 75 test items was satisfactory (Cronbach's alpha = 0.73). The SCT successfully differentiated second- from fourth-year students and both student groups from the expert panel in a one-way analysis of variance (F(2,508) = 120.4; p < 0.0001). Mean scores for students from the two schools were not significantly different (p = 0.20). CONCLUSION: This SCT successfully differentiated pre-clinical medical students from fourth year medical students and both cohorts of medical students from expert clinicians across different institutions and geographic areas. The SCT shows promise as an easy-to-administer measure of "problem-solving" performance in competency evaluation even in the beginning years of medical education. PMID- 21609178 TI - Sources of distress during medical training and clinical practice: Suggestions for reducing their impact. AB - BACKGROUND: Medical students and doctors experience several types of professional distress. Their causes ("stressors") are commonly classified as exogenous (adapting to medical school or clinical practice) and endogenous (due to personality traits). Attempts to reduce distress have consisted of providing students with support and counseling, and improving doctors' management of work time and workload. AIM: To review the common professional stressors, suggest additional ones, and propose ways to reduce their impact. METHOD: Narrative review of the literature. RESULTS AND CONCLUSION: We suggest adding two professional stressors to those already described in the literature. First, the incongruity between students' expectations and the realities of medical training and practice. Second, the inconsistencies between some aspects of medical education (e.g., its biomedical orientation) and clinical practice (e.g., high proportion of patients with psychosocial problems). The impact of these stressors may be reduced by two modifications in undergraduate medical programs. First, by identifying training-practice discrepancies, with a view of correcting them. Second, by informing medical students, both upon admission and throughout the curriculum, about the types and frequency of professional distress, with a view of creating realistic expectations, teaching students how to deal with stressors, and encouraging them to seek counseling when needed. PMID- 21609179 TI - Young Chinese medical students adapt well to problem-based learning. PMID- 21609180 TI - eMedical Teacher. PMID- 21609182 TI - Increased Muller cell de-differentiation after grafting of retinal stem cell in the sub-retinal space of Royal College of Surgeons rats. AB - In several vertebrate classes, the Muller glia are capable of de-differentiating, proliferating, and acquiring a progenitor-like state in response to acute retinal injury or in response to exogenous growth factors. Our previous study has shown that Muller cells can be activated and de-differentiated into retinal progenitors during Royal College of Surgeons (RCS) rats' degeneration, although the limited proliferation cannot maintain retinal function. We now report that rat retinal stem cells (rSCs) transplanted into RCS rats slowed the progression of retinal morphological degeneration and prevented the functional disruption. Further, we found that retinal progenitor cells labeled with Chx10 were increased significantly after rSCs transplantation, and most of them are mainly from activated Muller cells. rSCs transplantation also enhances neurogenic potential by producing more recoverin-positive photoreceptors, which was proved coming from Muller glia-derived cells. These results provide evidence that stem cell-based therapy may offer a novel therapeutic approach for the treatment of retinal degeneration, and that Muller glia in mammalian retina can be activated and de differentiated by rSC transplantation and may have therapeutic effects. PMID- 21609183 TI - Uniaxial cyclic strain drives assembly and differentiation of skeletal myocytes. AB - Ex vivo engineering of skeletal muscle represents an exciting new area of biotechnology. Although the ability of skeletal muscle cells to sense and respond to mechanical forces is well known, strategies based on the use of mechanical stimuli to optimize myogenesis in vitro remain limited. In this work, we describe a simple but powerful method based on uniaxial cyclic tensile strain (CTS) to induce assembly and differentiation of skeletal myocytes in vitro. Confluent mouse myoblastic precursors cultured on flexible-bottomed culture plates were subjected to either uniaxial or equibiaxial CTS. The uniaxial CTS protocol resulted in a highly aligned array of cross-striated fibers, with the major axis of most cells aligned perpendicularly to the axis of strain. In addition, a short period of myogenin activation and significant increase in the myotube/myoblast ratio and percentage of myosin-positive myotubes was found, indicating an enhanced cell differentiation. In contrast, cells under equibiaxial strain regimen had no clear orientation and displayed signs of membrane damage and impaired differentiation. These results, thus, demonstrate that the selection of a proper paradigm is a key element when discussing the relevance of mechanical stimulation for myogenesis in vitro. This study provides a rational framework to optimize engineering of functional skeletal muscle. PMID- 21609184 TI - The effect of pH levels on nonlatex vs latex interarch elastics. AB - OBJECTIVE: To evaluate the force decay characteristics of nonlatex vs latex interarch elastics within the normal range of salivary pH levels. MATERIALS AND METHODS: Two nonlatex groups and one latex quasi-control group were tested. Elastics were stretched to 15 mm and were held for 10 seconds (baseline), 4 hours, 8 hours, and 12 hours in artificial saliva solutions with pH levels of 5.0, 6.0, and 7.5. Force magnitudes were measured at 25 mm of activation. Each specimen was used once. Measurements were assessed using three-way analysis of variance (ANOVA). RESULTS: The three-way interaction between group, pH, and time was not significant (P = .13); the group-by-pH interaction also was not significant (P = .70). However, pH-by-time (P = .0179) and group-by-time (P = .0001) interactions were significant. American Orthodontics nonlatex generated significantly higher loads than Auradonics nonlatex. American Orthodontics nonlatex produced significantly higher forces than American Orthodontics latex at 4, 8, and 12 hours, but not at 10 seconds. American Orthodontics latex was significantly stronger than Auradonics nonlatex at 10 seconds, but not at 4, 8, and 12 hours. CONCLUSIONS: No clinically significant correlation between pH and force decay was observed. PMID- 21609185 TI - Autologous haemopoietic stem cell transplantation for autoimmune diseases. AB - INTRODUCTION: Autoimmune diseases are signified by complex errors of immune regulation, and the development of autoreactive T and B cells targeting self antigens, which eventually can lead to permanent organ damage. Despite novel therapeutic protocols, the disease course is chronic, debilitating and in some instances the outcome is lethal. Previously, stem cell transplantation has been reported to be beneficial in autoimmune animal models, as well as in autoimmune diseases related to hematological abnormalities, which opened potential new avenues in the treatment of human autoimmune diseases. AREAS COVERED: In this review, the authors describe the compound cellular regulatory effects of autologous hemopoietic stem cell transplantation (ASCT) and also clinical observations, related to the therapy in a variety of organ-specific and systemic autoimmune diseases. EXPERT OPINION: ASCT has a broad effect on the re-populated immune system, complex regulatory potentials and long term beneficial effect via down-regulating immune-reactivity, yet its widespread use in autoimmune diseases is limited, mostly due to the serious side-effects of the conditioning treatments. However, in certain autoimmune diseases with severe debilitating, or even life-threatening course, including systemic lupus erythematosus, systemic sclerosis or multiple sclerosis, ASCT can be a reasonable choice when conventional therapy has failed. PMID- 21609186 TI - New adjuvants in evolving vaccine strategies. AB - Adjuvants are becoming the key players of vaccine formulations to enhance the immunogenicity of subunit (peptides, proteins, virus-like particles (VLPs)) and DNA vaccines, as well as to reach the current new goals of preventing and/or treating chronic infectious diseases and cancers. Induction of humoral response, in particular neutralizing antibodies able to inhibit the binding of pathogens to their cellular receptors, remains a major goal of vaccines targeted to prevent acute lytic infections; induction/modulation of cellular immunity is, however, critical to fight latently/chronically infected cells as well as cancer cells. The new adjuvants, included in vaccine preparations, are currently able to modify the presentation of epitopes to the immune system with a specific T(H)1 versus T(H)2 polarization efficacy. A paradigm of the relevance of these new adjuvants is the immunological result obtained with the inclusion of monophosphoryl lipid A in the formulation of L1-based human papillomavirus (HPV)-naked VLPs. In the May issue of this journal, Garcon and colleagues describe the highly enhanced humoral and memory B cellular immunity of the AS04-adjuvanted HPV vaccine, which results in a long-lasting and broad spectrum immunity. PMID- 21609187 TI - Extended-release formulations of tramadol in the treatment of chronic pain. AB - INTRODUCTION: Tramadol is a centrally acting analgesic available throughout the world. Its dual opioid and non-opioid mechanisms of action, favorable efficacy and safety clinical profiles and non-controlled regulatory status in most markets contribute to its widespread use. A drawback of the immediate-release formulation of tramadol (four-times-a-day dosing) might be addressed by an extended-release formulation. Extended-release formulations also can offer advantages in the management of chronic pain: convenience, reduced pill burden (possibly leading to improved compliance) and the attenuation of peaks and troughs in serum concentration (possibly leading to reduced adverse effects). AREAS COVERED: The authors review tramadol's mechanisms of action and the clinical literature regarding the use of tramadol extended-release formulations for the management of conditions involving chronic pain, such as neuropathic pain syndromes, osteoarthritis and cancer pain. EXPERT OPINION: Based on the literature cited, extended-release formulations of tramadol seem to offer a rational and important addition to the analgesic armamentarium. As is true for all such options, the benefits and risks must be assessed for each patient. PMID- 21609188 TI - Quetiapine monotherapy for bipolar depression. AB - INTRODUCTION: Depression, in the context of bipolar disorder, is more prevalent than hypomania or mania and accounts for most of the disability. Furthermore, the treatment of bipolar depression is more complicated than the treatment of unipolar major depression. Finally, the evidence base for pharmacotherapy of bipolar depression is much smaller than for unipolar depression or hypomania/mania. AREAS COVERED: The article examines the mechanism of action and pharmacokinetics of quetiapine, its evidence base as a treatment for bipolar depression and related issues of safety and tolerability. EXPERT OPINION: In the context of bipolar disorder, quetiapine is the only monotherapy approved for the treatment of hypomania/mania, depression and as an adjunctive maintenance therapy. In addition to its antipsychotic properties, this broad mood stabilizing potential may uniquely benefit and simplify the management of some bipolar patients who can tolerate this agent. PMID- 21609189 TI - Fentanyl nasal spray for the treatment of cancer pain. AB - INTRODUCTION: Breakthrough pain, a transitory flare of pain in patients with otherwise controlled chronic pain, has been well characterized in cancer patients but despite medical awareness, sometimes remains underdiagnosed and therefore undertreated. AREAS COVERED: Oral transmucosal fentanyl citrate (OTFC) and fentanyl buccal tablets are the first medications developed specifically for the treatment of breakthrough pain in opioid-tolerant patients. Since oral administration of fentanyl is not an option for many cancer patients, the development of intranasal fentanyl spray (INFS) emerged as a more effective method of administration. Intranasal administration of fentanyl has several advantages over the oral/gastrointestinal route and clinical trials have shown that it is superior to OTFC while being well tolerated and more acceptable by the majority of patients. EXPERT OPINION: The aim of this review is to summarize the pharmacological characteristics and data obtained from clinical studies of INFS in the past few years, and present Fentanyl Pectin Nasal Spray (PecFent), which uses an innovative delivery system and is now approved in the EU. Finally, we discuss the impact that it may have in the future management of breakthrough pain in cancer patients, because an accurate diagnosis followed by the best treatment is crucial for effective pain alleviation. PMID- 21609190 TI - Bioactivation of herbal constituents: simple alerts in the complex system. AB - INTRODUCTION: The elucidation of the toxicological mechanisms of herbal medicines is becoming more and more important with the increasing application of herbal medicines, for treatment of various diseases and the promotion of health. Furthermore, it is widely recognized that as herbal components undergo bioactivation, there is a critical need for a greater understanding of herbal toxicity induction. AREAS COVERED: This article summarizes the current understanding of structural alerts present in herbal remedies as well as the herbs' and individuals' factors, complicating the interpretation of herbal toxicity via bioactivation. Medline (by means of PubMed up to July 2010) has been searched using proper relevant terms. The reader is provided with reported examples of herbal bioactivation based on toxicophores, which are summarized in an extended list. The article also discusses the factors which influence the herbal bioactivation study, including herbal complexity, competitive detoxification metabolism pathways as well as the individual and species difference of drug metabolizing enzymes and intestinal factors. EXPERT OPINION: The early evaluation of the bioactivation potential of herbal components is helpful for providing alerts of herbal toxicity. However, the potential toxic effects should be considered in the context of the complex systems of herbs and the individual patient. PMID- 21609192 TI - An in vitro model system to quantify stress generation, compaction, and retraction in engineered heart valve tissue. AB - Autologous heart valve tissue engineering relies on extracellular matrix production by cells seeded into a degrading scaffold material. The cells naturally exert traction forces to their surroundings, and due to an imbalance between scaffold, tissue, and these traction forces, stress is generated within the tissue. This stress results in compaction during culture and retraction of the leaflets at release of constraints, causing shape loss of the heart valve leaflets. In the present study, an in vitro model system has been developed to quantify stress generation, compaction, and retraction during culture and after release of constraints. Tissue-engineered (TE) constructs based on polyglycolic acid/poly-4-hydroxybutyrate scaffolds seeded with human vascular-derived cells were cultured for 4 weeks. Compaction in width was measured during culture, stress generation was measured during culture and after release of constraints at week 4, and contraction was measured after release of constraints at week 4. Both compaction and stress generation started after 2 weeks of culture and continued up to week 4. TE constructs compacted up to half of their original width and reached an internal stress of 6-8 kPa at week 4, which resulted in a retraction of 36%. The model system has provided a useful tool to unravel and optimize the balance between the different aspects of TE constructs to develop functional TE leaflets. PMID- 21609193 TI - Good news for beta-blockers in perioperative medicine. AB - Myocardial ischemia is a relatively frequent complication in patients undergoing non-cardiac surgery and beta-blockers may have a protective effect. beta-blockers reduce the oxygen supply:demand ratio, and exert anti-inflammatory and anti arrhythmic effects. However, randomized trials, specifically conducted to test this hypothesis, yielded conflicting results. The absolute risk for cardiac mortality and morbidity during and after non-cardiac surgery varies between patient groups defined by surgical risk categories, making it difficult to establish a risk:benefit ratio. We discuss the hypothesis that the protective effect of beta-blockers on cardiovascular outcome differs across the different risk classes of surgical procedures, thereby explaining the conflicting evidence across studies. In particular, we examine the results of a recent meta-analysis that suggests that beta-blockers may reduce mortality in patients under going high-risk non-cardiac surgery. PMID- 21609191 TI - Carboxylesterase inhibitors. AB - INTRODUCTION: Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis. AREAS COVERED: This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors. EXPERT OPINION: The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties and potential uses of such agents are discussed here. PMID- 21609194 TI - Retinol-binding protein 4 in adipose and placental tissue of women with gestational diabetes. AB - In the present study, we evaluated serum levels of retinol-binding protein 4 (RBP4) and the expression of RBP4, glucose transporter-4 (GLUT4) and peroxisome proliferator activated receptor gamma (PPARgamma) mRNA (using quantitative real time-PCR) in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and placental tissue obtained from patients with gestational diabetes (GDM) and healthy pregnant women. Serum RBP4 concentrations and its expression in SAT were higher in the women with GDM than in the controls (p = 0.03). No association between serum or tissue RBP4 and the indices of insulin resistance was noted. In the GDM group serum RBP4 correlated with its mRNA expression in SAT (r = 0.67, p = 0.007). Stepwise regression analysis revealed that RBP4 mRNA expression in SAT was independently predicted by GLUT4 mRNA expression (beta= 0.59, p = 0.003) and the presence of GDM (beta=0.46, p = 0.01), whereas RBP4 mRNA expression in VAT was related to PPARgamma mRNA expression (beta= 0.64, p = 0.0003) and the patient's age (beta= -0.38, p = 0.03). In conclusion, our results suggest that the elevated expression of RBP4 in SAT may contribute to the increase in circulating RBP4 in GDM subjects. PMID- 21609195 TI - Genetic screening in Italian infertile couples undergoing intrauterine insemination and in vitro fertilization techniques: a multicentric study. AB - AIM OF THE STUDY: To report the frequency of aberrant karyotype and mutated cystic fibrosis transmembrane conductance regulator (CFTR) gene, according to a careful application of Italian guidelines for genetic screening in infertile couple candidates for intrauterine insemination (IUI) and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). MATERIALS AND METHODS: Two thousand and sixteen consecutive infertile couple candidates for Assisted Reproduction Techniques (ART) were screened for karyotype and 616 couples for CFTR analysis. RESULTS: Regarding karyotype analysis, 59 chromosomal abnormalities were diagnosed in candidates for IVF/ICSI: 27 mutations in women corresponding to a frequency equal to 1.53% (27/1762; 95% confidence interval [CI], 0.96-2.1%) and 32 mutations in men corresponding to a frequency equal to 1.82% (32/1762; 95% CI, 1.2-2.44%) for men. The frequency differs according to the sperm count. In couple candidates for IUI techniques, no genetic abnormalities were found in male patients and only one aberration in a female patient with a frequency of 0.41% (1/245 CI 0.01-0.81%). Regarding CFTR analysis, excluding the 5T variant, we obtained 20 mutations in couples undergoing IVF/ICSI and 8 mutations in IUI group. CONCLUSION: Couples undergoing IVF/ICSI show a higher prevalence of aberrant karyotypes than general population, whereas the frequency of a mutation of the CFTR gene is similar. On the other hand, couples undergoing IUI do not differ from the general population either for karyotype or for CFTR mutations. PMID- 21609196 TI - Hashimoto's thyroiditis in a benign cystic teratoma of the ovary: case report and literature review. AB - Ectopic thyroid tissue in ovarian teratoma or in struma ovarii appears to be histologically identical to the thyroid gland tissue and may virtually exhibit all the pathological patterns found in the thyroid gland. However, the concurrent lymphocytic infiltration of the thyroid gland, as found in Hashimoto's thyroiditis, and of the ectopic thyroid tissue is extremely rare. We describe the case of an 18-years old patient, in which a right ovarian 4 cm cyst has been found during pelvic ultrasound exam. The cyst was resected and microscopic examination of the mass revealed a mature cystic teratoma in which epidermal-like lining with skin adnexa, admixed with respiratory type epithelium, and areas of mature fatty, chondroid and dentigerous tissues were found. In a peripheral area of 0.7 cm * 0.5 cm, a prominent lymphocytic infiltrate surrounding thyroid follicles was identifiable. Thyroid function evaluation at different time points after surgery, revealed the development of mild hypothyroidism. Anti-TPO and anti Tg autoantibodies were elevated, at fine needle aspiration biopsy a lymphocytic infiltrate, compatible with Hashimoto's thyroiditis, was present. We report here a rare case of Hashimoto's thyroiditis occurring both in the thyroid and in the ectopic thyroid tissue in the context of a benign cystic teratoma of the ovary. PMID- 21609197 TI - Diet composition and physical activity in overweight and obese premenopausal women with or without polycystic ovary syndrome. AB - The polycystic ovary syndrome (PCOS) is a complex polygenic disorder in which environmental factors play an important modifying role. We aimed to find differences in diet and life-style that might contribute to the development of PCOS among overweight or obese premenopausal women. We compared diet composition and self-reported physical activity among 22 patients with PCOS and 59 women without androgen excess recruited from a total of 113 consecutive premenopausal women reporting for management of weight excess. After correcting for a difference in age between women with PCOS and controls, there were no overall statistical significant differences between them in the total caloric intake, in the intake of macro- and micro-nutrients, caffeine, fiber and alcohol, in the proportion of women exercising regularly, or in the number of hours of exercise per week. The proportion of fat in the diets of the overweight and obese women irrespective of PCOS was well-above current recommendations, yet this excessive fat intake occurred at the expense of monounsaturated fatty acids mostly. In conclusion, diet composition and physical activity were apparently not decisive for the development of PCOS among overweight and obese premenopausal women. PMID- 21609198 TI - Aquaporin-7 expression during coronary artery bypass grafting with diazoxide. AB - OBJECTIVES: Aquaporin-7 is a water-channel protein that controls tissue glycerol supply after ischemia. A burden of experimental studies suggests that diazoxide, a mitochondrial K(ATP)-channel opener, may decrease myocardial edema during coronary artery bypass grafting (CABG). We evaluated whether diazoxide has an impact on atrial aquaporin-7 expression during CABG. DESIGN: Sixteen patients with a history of stable coronary artery disease were enrolled in the study. Eight patients were treated during cardiopulmonary bypass with diazoxide, while the rest eight patients remained as controls. Histopathology was evaluated from biopsies procured before and during CABG from the right atrium. From fresh atrial tissue biopsies, Aquaporin-7 was quantified by RT-PCR. RESULTS: Histological differences were apparent between individual patients already before operation at base line reflecting differences in severity of myocardial ischemia. As compared with fold change values before operation, Aquaporin-7 expression after operation was positive in all but one control, whereas aquaporin-7 expression was positive in only two patients receiving diazoxide. The relative aquaporin-7 expression was significantly lower in patients treated with diazoxide as compared with controls (p < 0.05). CONCLUSIONS: Diazoxide may have an impact on myocardial water balance and glycerol energy supply by decreasing relative aquaporin-7 expression during CABG. PMID- 21609199 TI - Differences in metabolic risk factors between normal weight and overweight children. AB - BACKGROUND: The effect of overweight on metabolic risk factors and the role of physical activity (PA) in pre-pubertal children is unclear. OBJECTIVE: To study differences in metabolic risk factors between groups of normal weight and overweight children and how these risk factors are associated with objectively measured PA and cardio-respiratory fitness (CRF). DESIGN: A cross-sectional study was conducted with 68 children aged 8?11 years. Children were categorized into normal weight (n = 39) and overweight/obese (n = 24/5). PA and CRF were measured objectively. An oral glucose tolerance test (OGTT) was performed and triglycerides (TG) and HDL-cholesterol (HDL-C) were measured. A metabolic risk score (MRS) was calculated from the standardized values of insulin, glucose, TG, inverted HDL-C and blood pressure. RESULTS: There was a significant (P < 0.05) difference between normal weight and overweight children in clustered metabolic risk, insulin (AUC), fasting insulin and systolic blood pressure. PA and CRF did not differ significantly between groups. In linear regression analysis combining the two groups, PA was negatively associated with insulin (AUC) (? = ?0.25, 95% CI = ?0.50, ?0.002) and CRF was negatively associated with fasting insulin (? = ?0.41, 95% CI = ?0.67, ?0.15). CONCLUSIONS: Metabolic risk factors are elevated in overweight pre-pubertal children compared with normal weight controls. This is not explained by lower PA or CRF in the overweight group although PA and CRF were associated with lower insulin levels in pooled analyses. This highlights the importance of preventing overweight in children from an early age in order to prevent the metabolic syndrome and its associated diseases. PMID- 21609200 TI - Adefovir induced hypophosphatemic osteomalacia. PMID- 21609201 TI - Defective placental adhesion in voluntary termination of second-trimester pregnancy and risk of recurrence in subsequent pregnancies. AB - OBJECTIVE: To evaluate the prevalence of defective placental adhesion (DPA) in voluntary termination of second-trimester pregnancy and the risk of DPA recurrence in subsequent pregnancies. METHODS: We retrospectively reviewed the records of all patients who underwent voluntary second-trimester pregnancy termination in the period between January 2000 and December 2009. In all cases, the fetus and the placenta were submitted to pathological examination accordingly to our clinical protocol. RESULTS: Four hundred twenty-seven cases of voluntary termination of second-trimester pregnancy were included in the study. Ten histologically confirmed cases of placenta accreta were observed (2.3%). Two patients with histological diagnosis of placenta accreta were lost at follow-up. Among the eight remaining patients, six had further pregnancies. Overall, nine pregnancies were recorded, and placenta accreta recurred in one patient. CONCLUSIONS: This study shows that DPA occurs in 2.3% of second-trimester voluntary termination of pregnancy; these patients should have an accurate ultrasound examination of the placenta in subsequent pregnancies. PMID- 21609202 TI - Fetal thigh and upper arm volumes by 3D-sonography: comparison between multiplanar and XI VOCAL methods. AB - OBJECTIVE: To compare fetal upper arm and thigh volume measurements acquired by three-dimensional (3D) ultrasound using the multiplanar and the eXtended Imaging Virtual Organ Computer-aided AnaLysis (XI VOCAL) methods with different number of sectional planes. METHODS: This study enrolled 40 healthy pregnant women between 20 and 40 weeks of gestation. The volume of fetal limbs was calculated using the multiplanar (with 5.0 mm intervals) and the XI VOCAL (with 5, 10, 15, and 20 slice planes) methods. Comparison between the techniques was made by analysis of variance and Bonferroni statistical tests. RESULTS: Mean fetal upper arm volume measured by the 15 sectional planes XI VOCAL method was lower than the same method using 5 and 10 planes instead (p = 0.025 and 0.039, respectively). Fetal thigh volume showed no statistically significant differences among all studied methods. CONCLUSION: The XI VOCAL using 15 sectional planes method underestimated the fetal upper arm volume by 5 and 10 planes XI VOCAL techniques. PMID- 21609203 TI - Altered maternal micronutrients (folic acid, vitamin B(12)) and omega 3 fatty acids through oxidative stress may reduce neurotrophic factors in preterm pregnancy. AB - Preterm pregnancies account for approximately 10% of the total pregnancies and are associated with low birth weight (LBW) babies. Recent studies have shown that LBW babies are at an increased risk of developing brain disorders such as cognitive dysfunction and psychiatric disorders. Maternal nutrition, particularly, micronutrients involved in one-carbon metabolism (folic acid, vitamin B(12), and docosahexaenoic acid (DHA)) have a major role during pregnancy for developing fetus and are important determinants of epigenesis. A series of our studies in pregnancy complications have well established the importance of omega 3 fatty acids especially DHA. DHA regulates levels of neurotrophins like brain-derived neurotrophic factor and nerve growth factor, which are required for normal neurological development. We have recently described that in one carbon metabolic pathway, membrane phospholipids are major methyl group acceptors and reduced DHA levels may result in diversion of methyl groups toward deoxyribonucleic acid (DNA) ultimately resulting in DNA methylation. In this review, we propose that altered maternal micronutrients (folic acid, vitamin B(12)), increased homocysteine, and oxidative stress levels that cause epigenetic modifications may be one of the mechanisms that contribute to preterm birth and poor fetal outcome, increasing risk for behavioural disorders in children. PMID- 21609204 TI - Histological chorioamnionitis - implication for bacterial colonization, laboratory markers of infection, and early onset sepsis in very-low-birth-weight neonates. AB - OBJECTIVE: The objective of this study was to evaluate the relationship between histological chorioamnionitis and laboratory markers of infection and congenital sepsis in very-low-birth-weight (VLBW) premature neonates. METHOD: This study is a retrospective review of laboratory results of VLBW neonates with birth weight less than 1500 g in our neonatal intensive care unit (NICU) in the last 5 years. RESULTS: Ninety-nine VLBW neonates had histological chorioamnionitis, and 50 of them further had funisitis. One hundred and sixty-two VLBW neonates did not have chorioamnionitis. The chorioamnionitis group was more likely than the 'no chorioamnionitis' group to have raised C-reactive proteins (23% versus 9.9%; p = 0.006) and neutrophilia (41% versus 4.3%; p < 0.001). White blood cells were more likely to be present in gastric lavage of the former group than the latter group (70% versus 50%; p = 0.002). Ear swab and gastric lavage were more likely to yield positive growth of micro-organisms from the former group than the latter group (34% versus 9.9% and 22% versus 2.7%; p < 0.001 and p < 0.001, respectively). Congenital sepsis proven by positive blood culture was also more likely to occur (3% versus 0%; p = 0.027). Presence of funisitis further increased the likelihood of the above abnormal laboratory results. CONCLUSIONS: Histological chorioamnionitis increases the likelihood of having markers of infection, bacterial colonization, and congenital sepsis. Only 3% of histological chorioamnionitis resulted in congenital sepsis confirmed by blood culture. PMID- 21609205 TI - Granulocyte-macrophage colony-stimulating factor increases the proportion of circulating dendritic cells after autologous but not after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND AIMS: Granulocyte-macrophage (GM) colony-stimulating factor (CSF) has been used as an adjuvant in cancer immunotherapy. We tested the hypothesis that GM-CSF (Leukine((r)); sargramostim) improves immune reconstitution after hematopoietic stem cell transplantation (HSCT) based on our prior in vitro work that demonstrated the pro-inflammatory effects of GM-CSF on dendritic cells (DC). METHODS: GM-CSF was administered to donors, along with standard granulocyte (G) CSF, during stem cell mobilization, and to recipients from the day prior to transplant until engraftment. Eighteen patients consented to the GM-CSF(+) protocol and were compared with 17 matched controls undergoing HSCT during the same time period (GM-CSF(-)). RESULTS: Numbers of white blood cells (WBC) and CD34(+) stem cells in the graft were comparable to controls. Surprisingly, contrary to our hypothesis, the allogeneic donor graft had significantly decreased numbers of CD3(+) T cells and their subsets (CD4(+), CD4(+) CD45RA(+), CD4(+) CD45RO(+), CD8(+) and CD8(+) CD45RO(+)), DC (both myeloid and plasmacytoid) and natural killer (NK) cells (CD16(+) CD56(+)). In the GM-CSF arm, following allogeneic transplantation, the levels of DC, T cells and NK cells did not increase with treatment. Conversely, autologous transplant patients receiving GM-CSF had a higher proportion of DC at the time of engraftment. CONCLUSIONS: These findings demonstrate that administration of GM-CSF improves DC reconstitution after autologous rather than allogeneic HSCT. PMID- 21609206 TI - Validity and test-retest reliability in assessing current body size with figure drawings in Chinese adolescents. AB - OBJECTIVE: The reliability and validity of Stunkard's Figure Rating Scale (FRS) as a measure of current body size (CBS) was established in Western adolescent girls but not in non-Western population. We examined the validity and test-retest reliability of Stunkard's FRS in assessing CBS among Chinese adolescents. Methods. In a school-based survey in Hong Kong, 5666 adolescents (boys: 45.1%; mean age 14.7 years) provided data on self-reported height and weight, CBS, perceived weight status, and health-related quality of life using the Medical Outcomes Study Short-Form version 2 (SF-12v2). Height and weight were also objectively measured. Spearman's correlation was used to assess construct validity, concurrent validity and test-retest reliability. RESULTS: Convergent and discriminant validity were good: CBS correlated strongly with weight and self reported/measured BMI, but only weakly with SF-12v2. CBS correlated strongly with perceived weight status, showing concurrent validity. Spearman's correlation (r) for CBS was 0.78 for girls and 0.72 for boys indicating good test-retest reliability. Validity and reliability results did not differ significantly between senior and junior grade adolescents. CONCLUSION: Our findings support the use of Stunkard's FRS to measure body size among Chinese adolescents. PMID- 21609207 TI - Thorough QT study of the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor, on cardiac repolarization and conduction in healthy volunteers. AB - OBJECTIVE: This randomized, double-blind study evaluated the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor for treating type 2 diabetes, on cardiac repolarization and conduction. METHODS: Healthy volunteers (n = 101) were randomized (1:1:1:1 ratio) to vildagliptin 100 or 400 mg, moxifloxacin 400 mg (active control), or placebo once daily for 5 days. Electrocardiograms were recorded at baseline and day 5 for 24 hours post-dose. Placebo-adjusted mean change from baseline in QT interval, heart-rate-corrected QT intervals by Fridericia's (QTcF) or Bazett's (QTcB) formula, and PR and QRS intervals were compared at each time-point (time-matched analysis) and for values averaged across the dosing period (time-averaged analysis). RESULTS: For time-matched analysis, mean changes in QTcF with vildagliptin were below predefined limits for QTc prolongation (mean increase <5 ms; upper 90% confidence interval [CI] < 10 ms), except for vildagliptin 100 mg at 1 and 8 hours post-dose (upper 90% CI > 10 ms). With moxifloxacin, significant QTcF prolongation occurred at most time points, demonstrating assay sensitivity. No vildagliptin- or placebo-treated volunteer had QTcF > 450 ms. Incidences of QTcF increases >=30 ms with vildagliptin (100 and 400 mg) and placebo were similar (4-8%) and were much lower than with moxifloxacin (39%). No QTcF increase >=60 ms was observed with vildagliptin or placebo (versus one with moxifloxacin). Time-averaged, time matched, and categorical analyses of QT/QTcF/QTcB showed similar results. Drug exposure analysis showed no correlation between vildagliptin plasma levels and QTc changes. Vildagliptin had no effect on PR or QRS intervals. Although this study, completed before publication of current ICH E14 guidelines, was underpowered for time-matched analysis, the results are consistent with lack of effect of vildagliptin on QTc. CONCLUSION: Vildagliptin did not prolong QT interval or affect cardiac conduction at the highest daily therapeutic dose or a fourfold higher dose. PMID- 21609208 TI - Movement skill mastery in a clinical sample of overweight and obese children. AB - This study describes the prevalence of fundamental movement skill (FMS) mastery and advanced skill proficiency among treatment-seeking 6-10-year old children with overweight/obesity. A total of 132 participants (8.4 +/- 1.0 years, BMI 24.2 +/- 3.1 kg/m(2), 55% female, 76.5% obese) were assessed on 12 FMS and compared with a normative sample. The prevalence of FMS mastery was significantly lower among children categorized as overweight/obese for all skills across all age groups (all p < 0.05). Excluding the leap for 6-7-year olds, differences between the two samples remained when the prevalence of advance skill proficiency was examined for children categorized as overweight/obese. Physical activity programs designed for children with overweight/obesity need to address deficiencies in FMS proficiency as part of an overall strategy to promote physical activity participation. PMID- 21609211 TI - Effects of the Nd:YAG 1320-nm laser on skin rejuvenation: clinical and histological correlations. AB - The neodymium:yttrium-aluminum-garnet (Nd:YAG) laser is a popular non-ablative treatment used for skin rejuvenation. The purpose of this prospective study was to evaluate the clinical effects, coupled with a quantitative assessment, of the histological changes in response to Nd:YAG 1320-nm laser treatment of periocular wrinkles. Six volunteers with Fitzpatrick skin types III and IV and Glogau class I-II wrinkles were subjected to 3 months of Nd:YAG 1320-nm treatment in the periocular area (six sessions at 2-week intervals). Volunteers were photographed, and skin biopsies were obtained at baseline as well as 3 and 6 months after the start of treatments. Quantitative evaluation of total elastin, newly synthesized tropoelastin, collagen types I, III and VII, and newly synthesized collagen was performed using a computerized morphometric analysis. A noticeable clinical and histological improvement was observed after Nd:YAG 1320-nm treatment. Collagen types I, III and VII, as well as newly synthesized collagen, together with tropoelastin showed a statistically significant increase in response to treatment, while the mean level of total elastin was significantly decreased after treatment. Our data suggest that Nd:YAG 1320 nm is an effective treatment for skin rejuvenation as it stimulates the repair processes, and reverses the clinical, as well as the histopathological, signs of skin aging. PMID- 21609212 TI - Efficacy and safety of a new hyaluronic acid dermal filler in the treatment of moderate nasolabial folds: 6-month interim results of a randomized, evaluator blinded, intra-individual comparison study. AB - BACKGROUND: Hyaluronic acid (HA) fillers such as Restylane((r)) are frequently used for the correction of facial soft tissue defects. OBJECTIVE: To compare the efficacy and safety of a novel HA filler, Emervel((r)) Classic, with those of Restylane in the treatment of moderate nasolabial folds. METHODS: This was a split-face, randomized and evaluator-blinded comparison study. Subjects were randomized to receive an injection of Emervel Classic or Restylane on their left or right side. Efficacy was evaluated based on the change in Wrinkle Severity Rating Score (WSRS) from baseline. Local tolerability was assessed based on subject diary, which recorded the severity of erythema, oedema/swelling, bruising, pain/tenderness and pruritus during the first 3 weeks after injection. RESULTS: The interim results 6 months after injection are reported. At week 24, the mean improvement in WSRS from baseline was 0.83 +/- 0.51 for Emervel Classic, similar to that for Restylane (0.90 +/- 0.57). A similar volume of both fillers was injected. Most local tolerability events were mild and transient. Erythema, oedema/swelling and pain/tenderness were significantly less severe and disappeared faster with Emervel Classic than with Restylane (at least p < 0.05). CONCLUSION: Emervel Classic provides similar efficacy and better overall local tolerability compared with Restylane 6 months after treatment of moderate nasolabial folds. PMID- 21609209 TI - Differentiation-independent fluctuation of pluripotency-related transcription factors and other epigenetic markers in embryonic stem cell colonies. AB - Embryonic stem cells (ESCs) maintain their pluripotency through high expression of pluripotency-related genes. Here, we show that differing levels of Oct4, Nanog, and c-myc proteins among the individual cells of mouse ESC (mESC) colonies and fluctuations in these levels do not disturb mESC pluripotency. Cells with strong expression of Oct4 had low levels of Nanog and c-myc proteins and vice versa. In addition, cells with high levels of Nanog tended to occupy interior regions of mESC colonies. In contrast, peripherally positioned cells within colonies had dense H3K27-trimethylation, especially at the nuclear periphery. We also observed distinct levels of endogenous and exogenous Oct4 in particular cell cycle phases. The highest levels of Oct4 occurred in G2 phase, which correlated with the pKi-67 nuclear pattern. Moreover, the Oct4 protein resided on mitotic chromosomes. We suggest that there must be an endogenous mechanism that prevents the induction of spontaneous differentiation, despite fluctuations in protein levels within an mESC colony. Based on the results presented here, it is likely that cells within a colony support each other in the maintenance of pluripotency. PMID- 21609213 TI - Reversing precancerous actinic damage by mixing wavelengths (1064 nm, 532 nm). AB - BACKGROUND: Premalignancies resulting from photodamage, such as actinic keratosis and carcinoma in situ, can be treated with various modalities. Most of these treatments may reverse or treat these conditions although they often involve considerable skin irritation over a long period of time, are very uncomfortable for the patients or they need many office visits and sometimes are very expensive, such as photodynamic therapy (PDT). OBJECTIVE: To study the effectiveness of a mixed session of Q-switched KTP 532 nm and Nd:YAG 1064 nm laser treatment on precancerous lesions resulting from solar damage. METHODS: Ten patients with long-standing actinic damage/keratosis or carcinoma in situ were subjected to only one session of mixed Q-switched KTP 532 nm and Nd:YAG 1064 nm laser treatment. Lesions were evenly and repeatedly scanned with both wavelengths until light pain or purpura presented. RESULTS: All patients responded extremely well within a period of 20 days, with just one session, with virtually no pain, minimum irritation, no down time at all and excellent cosmetic outcome. CONCLUSION: The use of a mixed Q-switched 532 nm and Nd:YAG 1064 nm laser session seems to be ideal for treating precancerous lesions resulting from photodamage since it can be a fast, painless and simple office procedure with no down time and minimum discomfort for the patient. This method proves to be much more selective than traditional intense pulse light (IPL) photorejuvenation. PMID- 21609214 TI - Treatment of pigmented keratosis pilaris in Asian patients with a novel Q switched Nd:YAG laser. AB - BACKGROUND: Treatment for most cases of keratosis pilaris requires simple reassurance and general skin care recommendations. Many Asian patients find lesions due to pigmented keratosis pilaris to be cosmetically unappealing. Treatment of post-inflammatory hyperpigmentation using a 1064-nm Q-switched Nd:YAG laser with low fluence is reported. OBJECTIVE: To investigate the efficacy of a novel Q-switched Nd:YAG laser for the treatment of pigmented keratosis pilaris in Asian patients. METHODS: Ten patients with pigmented keratosis pilaris underwent five weekly treatments using a Q-switched Nd:YAG laser (RevLite((r)); HOYA ConBio((r)), Freemont, CA, USA) at 1064 nm with a 6-mm spot size and a fluence of 5.9 J/cm(2). Photographic documentation was obtained at baseline and 2 months after the final treatment. RESULTS: Clinical improvement was achieved in all 10 patients with minimal adverse effects. CONCLUSION: For the treatment of keratosis pilaris, the use of a Q-switched Nd:YAG laser can be helpful for improving cosmetic appearance as it can improve pigmentation. PMID- 21609215 TI - Re: lift capabilities of hyaluronic acid fillers by Marcos Borrell, Dustin B. Leslie & Ahmet Tezel (J Cosmet Laser Ther. 2011;13:21-27). PMID- 21609216 TI - Monopolar radio-frequency treatment in Asian skin: a questionnaire-based study. PMID- 21609217 TI - Syringomas versus sebaceous gland prominence of the eyelids. PMID- 21609218 TI - Vision rehabilitation of persons with age related macular degeneration. AB - As the population of the United States ages, there is an increase in the number of persons with age related macular degeneration (ARMD). Even as new prevention and treatment techniques are developed, the vision loss associated with ARMD may lead to loss of independence and quality of life. Low vision is a rehabilitative process designed to improve visual function and restore independence. This paper is a review of the current research related to low vision in the areas of magnification, contrast and illumination, reading, training, driving and outcomes assessment. PMID- 21609219 TI - Bevacizumab and neovascular age related macular degeneration: pathogenesis and treatment. AB - The pathogenesis of neovascular age related macular degeneration (AMD) is multifactorial including inflammation and angiogenesis leading to choroidal neovascularization (CNV). Therapy against vascular endothelial growth factor (VEGF) has revolutionized the treatment of neovascular AMD. Intravitreal off label use of bevacizumab proved to be safe. This literature review was conducted to study improvement in visual acuity, change in central retinal thickness (CRT), safety, pharmacodynamics, and possible resistance to intravitreal bevacizumab over a one-year period in eyes with neovascular AMD. We reviewed articles between 1997 and January 2010 that included at least 30 patients with AMD who received intravitreal bevacizumab monotherapy for at least 1 year. The mean number of letters gained, decrease in CRT, and number of injections were 8 letters, 125.3 um, and 4.3 injections, respectively. Further, randomized prospective clinical trials are needed to determine the efficacy and safety of intravitreal bevacizumab in the treatment of neovascular AMD. PMID- 21609221 TI - Retinal pigment epithelial tears and the management of exudative age-related macular degeneration. AB - Tears of the retinal pigment epithelium (RPE) are a known and potentially catastrophic complication of exudative age-related macular degeneration (AMD). Eyes with vascularized retinal pigment epithelial detachments (PED) are especially at risk for the development of RPE tears. This long-recognized complication faces increased scrutiny in an era of improved anti-angiogenic treatments for AMD, particularly given that these newly developed therapeutics have been implicated as a potential factor in the formation of some RPE tears. PMID- 21609222 TI - Intravitreal injection technique. AB - As the intravitreal injection of therapeutic medication plays an increasingly large role in ophthalmology, its implementation continues to be modified and refined. Variations in injection technique are discussed, and the authors combine their clinical and research experience with a review of the literature to propose a recommended intravitreal injection protocol. PMID- 21609223 TI - Review of combination therapies for neovascular age-related macular degeneration. AB - While angiogenesis is one of the factors associated with the development of CNV due to age-related macular degeneration (AMD), inflammation and oxidative stress also appear to play a role. Treatment of CNV with intravitreal anti-vascular endothelial growth factor monotherapy is currently the standard of care. However, not all patients respond to monotherapy, and combination therapy may target the CNV through multiple mechanisms, thus reducing treatment frequency or improving visual outcome. Photodynamic therapy (with regular or reduced fluence), as well as intravitreal steroids are used in combination with anti-VEGF therapy. This paper reviews the many clinical trials that have been performed utilizing several combinations of double and triple therapy. While combination therapy is biologically justifiable, further study is required to determine correct combinations and dosage. PMID- 21609224 TI - Radiation treatment for age-related macular degeneration. AB - Age-related macular degeneration (AMD) remains a devastating cause of visual loss among elderly individuals. While considerable progress has been made towards combating the disease, most recently with intravitreal anti-VEGF agents, visual outcomes are still limited by continued retinal pigment epithelium (RPE) degeneration and subsequent neurosensory retinal atrophy. Among the promising new treatment options being explored, radiotherapy appears apt to address the multifactorial etiology of AMD. Current investigative studies underway will hopefully yield clinical efficacy to complement this theoretical suitability for arresting visual loss. PMID- 21609220 TI - Genetics of age-related macular degeneration: current concepts, future directions. AB - Age-related macular degeneration (AMD) is a progressive degenerative disease which leads to blindness, affecting the quality of life of millions of Americans. More than 1.75 million individuals in the United States are affected by the advanced form of AMD. The etiological pathway of AMD is not yet fully understood, but there is a clear genetic influence on disease risk. To date, the 1q32 (CFH) and 10q26 (PLEKHA1/ARMS2/HTRA1) loci are the most strongly associated with disease; however, the variation in these genomic regions alone is unable to predict disease development with high accuracy. Therefore, current genetic studies are aimed at identifying new genes associated with AMD and their modifiers, with the goal of discovering diagnostic or prognostic biomarkers. Moreover, these studies provide the foundation for further investigation into the pathophysiology of AMD by utilizing a systems-biology-based approach to elucidate underlying mechanistic pathways. PMID- 21609225 TI - Nutritional supplementation and age-related macular degeneration. AB - The prevalence of Age-related macular degeneration (AMD) is increasing as the population of elderly in the United States grows. Currently the pathogenesis is not fully understood, however oxidative injury is felt to play a significant role. The Age-Related Eye Disease Study (AREDS) established that a supplemental combination of dietary antioxidants of zinc, beta-carotene, vitamin C and vitamin E slowed progression of AMD. Recently lutein, zeaxanthin, B vitamins, and omega-3 fatty acids have also been reported to decrease AMD progression, while vitamin E and beta-carotene where found to increase the risk of late AMD. AREDS2 is currently underway, further examining the effects of omega-3 fatty acids, carotenoids, and the original AREDS formulation. While awaiting the results of AREDS2, it is important to understand the evidence currently available, so that physicians can safely advise patients today. This review examines the most current literature available exploring nutritional supplementation in age-related macular degeneration. PMID- 21609226 TI - Vitreomacular traction and age-related macular degeneration. AB - The interaction between the vitreous and the internal limiting membrane of the retina is important in the pathoetiology of numerous ocular disease processes. Recent studies have focused on the vitreo-retinal interface in the context of age related macular degeneration (AMD), linking vitreo-retinal adhesion to exudative AMD in particular. This review summarizes our knowledge of vitreous anatomy and recent investigations regarding vitreomacular adhesion and AMD. PMID- 21609227 TI - Endophthalmitis following intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration. AB - Endophthalmitis following intravitreal injections of therapeutic medications is a rare but potentially vision-threatening problem. Infectious agents associated with endophthalmitis following injection of vascular endothelial growth factor (VEGF) inhibitors are typically Gram positive organisms with a predominance of Streptococcal and Staphylococcal microbiologic isolates. Patients with infectious endophthalmitis generally present within the first 72 hours following an intravitreal anti-VEGF injection with complaints of pain, redness, and decreased vision. Prompt treatment with a conventional endophthalmitis management approach may mitigate irreversible vision loss; however, poorer outcomes have been reported with more virulent organisms such as those associated with Streptococcal species. As the number of intravitreal injections performed each year continues to increase, ophthalmologists must maintain a rigorous approach to their injection technique and remain vigilant for the signs and symptoms of endophthalmitis. PMID- 21609228 TI - Emerging therapies for the treatment of neovascular age related macular degeneration. AB - Numerous drugs that show promise in the treatment of neovascular age related macular degeneration are currently being evaluated in early clinical trials. Some of these drugs target the vascular endothelial growth factor pathway while others act on different targets along the angiogenesis cascade. The mechanism of action of these novel therapeutics and the results of early clinical trials will be discussed along with a review of angiogenesis. PMID- 21609229 TI - Imaging characteristics of dry age-related macular degeneration. AB - PURPOSE: To review the current literature regarding the imaging characteristics of dry age-related macular degeneration (AMD) lesions, with a special focus on drusen and geographic atrophy imaging. We also explore the role of novel approach of hyperspectral imaging in AMD. METHODS: Review of current literature as well as findings in a small group of patients imaged with hyperspectral imaging. RESULTS: The use of optical coherence tomography, and especially fourier-domain devices, has enhanced our ability to classify various lesions of dry AMD. The increasing role of autofluorescence in characterization and prognostication in geographic atrophy is reviewed. The advances made in automated detection and multimodal imaging are highlighted, with their potential to revolutionize this area of research. CONCLUSIONS: Recent advances in retinal imaging have improved our understanding of the characteristics and prognostication of dry AMD, with an increasing role for multimodal imaging and image correlations. The potential future role of hyperspectral imaging in dry AMD is also presented herein. PMID- 21609230 TI - Current Clinical Trials in Dry AMD and the Definition of Appropriate Clinical Outcome Measures. AB - Currently, there is no proven drug treatment for dry age-related macular degeneration (AMD). Several different treatment strategies are being investigated, including complement inhibition, neuroprotection, and visual cycle inhibitors, and novel clinical trial endpoints are being explored. Studies have identified genetic predispositions for dry AMD associated with complement dysfunction. Consequently, complement-based therapeutic treatment modalities are promising. PMID- 21609231 TI - Surgical treatment of age-related macular degeneration. AB - Choroidal neovascularization (CNV) and geographic atrophy (GA) are serious and potentially devastating complications of age-related macular degeneration (AMD), a leading cause of blindness in the developed world. While anti-vascular endothelial growth factor (VEGF) therapies have emerged as the current standard treatment of choice for choroidal neovascularization, the requirement for indefinite injections places a tremendous burden on physicians and patients, and may have disappointing outcomes in hemorrhagic neovascular AMD. No superior agents exist to treat large subretinal hemorrhage and geographic atrophy. Over the years, several vitreoretinal surgical approaches have been developed to treat macular degeneration, and these surgical options may still play a role in the management of specific complications of AMD. This review summarizes the principles, techniques, and results of surgical treatments for neovascular and non-neovascular age-related macular degeneration, with emphasis on submacular surgery for removal of CNV, full and limited macular translocation, retinal pigment epithelium, and choroid transplants as well as treatment of thick subretinal hemorrhage. PMID- 21609232 TI - Inflammation and age-related macular degeneration (AMD). AB - Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. The cause of AMD is complex and many risk factors have been implicated including age, family history (genetics), diet, smoking, and other environmental risk factors. Over the past decade, studies has found that inflammation play a large role in the pathogenesis of age-related macular degeneration (AMD). In fact, the main genetic changes (polymorphism) associated with AMD were found to be genes that regulate inflammation, most notably complement Factor H. This review ties together many studies done over the past decade to give us new insight into the role inflammation plays in the development of AMD. PMID- 21609233 TI - Retinal pigment epithelial detachments in age-related macular degeneration: classification and therapeutic options. AB - Retinal pigment epithelial detachment (PED) is an important predictor of vision loss in patients with age-related macular degeneration (AMD). Here we review the historical PEDs subtypes, include recent insights into PED pathogenesis provided by modern imaging modalities, and summarize the current options for treatment. PMID- 21609234 TI - Mimickers of age-related macular degeneration. AB - In the Western World, the leading cause of irreversible blindness is Age- Related Macular Degeneration (ARMD). It can have significant visual impairment, and it is important that the practicing ophthalmologist is knowledgeable in the diagnosis and treatment of ARMD. Equally important is knowledge in the diagnosis of other disease entities that may mimic ARMD, as this may change the prognosis, treatment and visual outcome of patients. This article discusses those diseases that mimic ARMD and their distinguishing features. PMID- 21609236 TI - Imaging in neovascular age-related macular degeneration. AB - Imaging plays an essential role in the diagnosis and treatment of age-related macular degeneration (AMD). This review describes the imaging modalities most commonly employed by ophthalmologists caring for patients with neovascular AMD. Imaging modalities discussed include fluorescein angiography, optical coherence tomography, indocyanine green angiography, and fundus autofluorescence. PMID- 21609237 TI - The need for a revised approach to epidemiological monitoring of the prevalence of visual impairment. PMID- 21609235 TI - Induced pluripotent stem cell therapies for geographic atrophy of age-related macular degeneration. AB - There is currently no FDA-approved therapy for treating patients with geographic atrophy (GA), a late stage of age-related macular degeneration (AMD). Cell transplantation has the potential to restore vision in these patients. This review discusses how recent advancement in induced pluripotent stem (iPS) cells provides a promising therapy for GA treatment. Recent advances in stem cell biology have demonstrated that it is possible to derive iPS cells from human somatic cells by introducing reprogramming factors. Human retinal pigment epithelium (RPE) cells and photoreceptors can be derived from iPS cells by defined factors. Studies show that transplanting these cells can stabilize or recover vision in animal models. However, cell derivation protocols and transplantation procedures still need to be optimized. Much validation has to be done before clinical-grade, patient-derived iPS can be applied for human therapy. For now, RPE cells and photoreceptors derived from patient-specific iPS cells can serve as a valuable tool in elucidating the mechanism of pathogenesis and drug discovery for GA. PMID- 21609238 TI - Results of a rapid assessment of avoidable blindness (RAAB) in Eritrea. AB - PURPOSE: To collect baseline data for planning of the National Blindness Prevention & Control Program and for monitoring future achievements. METHODS: Sixty six clusters of 50 people were selected from a sampling frame that included all 2,593 villages in Eritrea (population 3.56 million). Within each selected village, 50 eligible people aged 50+ years were selected. All eligible participants underwent visual acuity (VA) measurement followed by examination by an ophthalmologist if the presenting VA (PVA) was less than 6/18. RESULTS: Three thousand one hundred sixty three of the 3300 eligible persons were examined (coverage 95.9%). The adjusted prevalence of blindness (PVA < 3/60 in the better eye) in the survey population was 7.5% (95% confidence interval [CI]: 6.2-8.8%), bilateral severe visual impairment (PVA < 6/60 to >= 3/60 in the better eye) 3.0% (95% CI: 2.3-3.7%) and of bilateral moderate visual impairment (PVA < 6/18 to >= 6/60 in the better eye) 10.5% (95% CI: 9.1-11.9%). Of all bilateral blindness 55% was due to cataract. The adjusted cataract surgical coverage (percentage of people requiring cataract surgery that have had surgery) was 68% for blind people and 41% for blind eyes. Cataract surgery outcome was poor (PVA < 6/60) in 39% of all eyes operated in the past. CONCLUSIONS: The prevalence of blindness was high compared to recent surveys in Africa. Visual outcome after cataract surgery potentially could be improved by more detailed pre-operative examination, coaching of surgeons, and provision of adequate optical correction, including routine monitoring of visual outcome after cataract surgery. The development of intervention programs for refractive error and glaucoma should be considered. PMID- 21609239 TI - A global survey of low vision service provision. AB - PURPOSE: To conduct a global survey of low vision services to describe the needs, priorities, and barriers in provision and coverage. METHODS: Data were mainly derived from a survey and from some secondary sources. The survey was distributed to Vision 2020 contacts, government, and non-government organizations (NGOs) in 195 countries during 2006-2008. Themes in the survey were: epidemiology of low vision, policies on low vision, provision of services, human resources, barriers to service delivery, equipment availability, and monitoring and evaluation of service outcomes. Contradictory and/or incomplete data were returned for further clarification and verification. The Human Poverty Index was used to compare the findings from developed and developing countries. RESULTS: Service availability was established for 178/195 countries, with 115 having some low vision service. Approximately half the countries in the African and Western Pacific regions have no services. Few countries have >10 low vision health professionals per 10 million of population. In many of the countries NGOs were the main providers and funders. Funding and awareness were frequently cited as barriers to service access. Women, people with disabilities, and rural dwellers were less likely to access services. There were few reports of monitoring and evaluation into the quality and impact of services. CONCLUSION: This global survey provides the first consolidated baseline of low vision service provision. Where data are available, coverage of services is generally poor. Low vision health professional numbers are low. Services in over half of the world's countries are funded by NGOs, raising issues of sustainability. PMID- 21609240 TI - Prevalence and risk factors for anisometropia in the Tehran eye study, Iran. AB - PURPOSE: To determine the prevalence of anisometropia and its determinants in a population-based sample. METHODS: In a cross-sectional population-based study, stratified cluster sampling was carried out from the population of Tehran. Respondents were transferred to a clinic for an interview and ophthalmic examinations including tests for visual acuity with and without correction, cycloplegic refraction, the slit lamp examination, fundoscopy, and lensometry. Anisometropia was defined as unequal spherical equivalent cycloplegic refractions in the two eyes. RESULTS: Of 4565 participants, cycloplegic refraction was performed in both eyes of 3519 people. The mean age of the examinees was 31.5 +/- 18.0 (range, 5-86) years. The mean anisometropia was 0.34 diopter (D) (95% Confidence Interval (CI): 0.31-0.37). The prevalence rates of anisometropia more than 0.5, 1.0, 1.5 and 2.0 D were 18.5% (95% CI: 17.0-19.9), 6.7% (95% CI: 5.8 7.7), 3.8% (95% CI: 3.1-4.5) and 2.6% (95% CI: 2.1-3.1). The inter-gender difference in the prevalence of anisometropia >= 1.0D was not statistically significant (P = 0.952). The prevalence of anisometropia increased after the age of 45 years. Overall, 15.7% of the examinees had anisomyopia and 4.7% had anisohypermetropia equal to or more than 1.0D. Anisometropia was more prevalent among patients with cataracts, amblyopia, and pseudophakia. The prevalence rates of spherical and cylindrical anisometropia in the studied sample were 8.0% and 7.1%, respectively. CONCLUSIONS: The prevalence of anisometropia in the population of Tehran is beyond negligible. It showed a significant increase with age. Results also indicate that myopic patients are more likely to have anisometropia. PMID- 21609241 TI - The prevalence of age-related macular degeneration in Italy (PAMDI) study: report 1. AB - PURPOSE: The present study aimed to estimate prevalence and risk factors associated with age-related macular degeneration (ARMD) in an Italian population and to analyze differences between urban and rural communities. METHODS: We conducted a population-based cross-sectional study among elderly residents in Northeast Italy. Participants were divided into urban and rural groups based on whether they lived in the city of Padova or the villages of Teolo and Torreglia, respectively. Fundus photographs were graded according to the International Classification for Age-related Maculopathy. RESULTS: A total of 1162 randomly selected subjects aged 61 years or more were invited to participate in the study. We examined 885 subjects, and 845 were eligible for fundus photograph grading. ARMD was estimated to affect 62.7% of the whole population (drusen 63-124 MUm = 48.3%; drusen >=125 MUm = 10.4%; advanced ARMD = 4.1%). Age was confirmed as a risk factor for drusen >=125 MUm and advanced ARMD (Odds Ratio [OR] = 1.47, 95% Confidence Interval [CI] 1.28-1.69 and OR = 1.62, 95% CI 1.28-2.05, respectively, for a 5-year increase in age). The rural group appeared to be at a higher risk of developing large drusen compared to the urban sample (OR = 1.61, 95% CI 1.01 2.63) when adjusting for age and gender. CONCLUSIONS: The results confirmed that ARMD affects a high percentage of the elderly population in Italy. This study does not support the hypothesis that living in a rural environment or belonging to a population of the Mediterranean basin may be protective against the intermediate stages of the disease. PMID- 21609242 TI - Age-related macular degeneration-susceptibility single nucleotide polymorphisms in a han chinese control population. AB - PURPOSE: Our study aimed to detect the frequency of age-related macular degeneration (AMD)-susceptibility single nucleotide polymorphisms (SNPs) in control subjects of Han Chinese in a population-based study. METHODS: A total of 419 subjects of Han Chinese without AMD were recruited from our population-based Nantong Eye Study. Nine AMD-susceptibility SNPs were genotyped. The allele/genotype frequencies were compared with the data from the literature and NCBI Reference Assembly. RESULTS: The call rates of genotyping were > 98%. All tested SNPs except for HTRA1 rs11200638 were in Hardy-Weinberg Equilibrium (HWE). The allele distributions of some AMD-susceptibility SNPs were different from the records for the Chinese population in the National Center for Biotechnology Information (NCBI) Reference Assembly. Compared to those in a Caucasian population, the frequency of minor alleles of CFH rs800292 (48% vs. 19.2%) and HTRA1 rs11200638 were much higher (47% vs. 25%), while the frequency of minor alleles of CFH rs1061170 (9% vs. 35%), CX3CR1 rs3732379 (3% vs. 21%), CX3CR1 rs3732378 (3% vs. 11%) and SERPING1 rs2511989 (11% vs. 48%) were much lower in the Han Chinese population. Minor differences were observed in the frequency of minor alleles of CFB rs4151667, C2 rs547154 and TLR3 rs3775291. The allele/genotype frequencies of CFH rs1061170 and HTRA1 rs11200638, two well confirmed AMD-susceptible SNPs, were close to each other in the Han Chinese and Japanese population. CONCLUSION: The distribution of AMD-susceptibility SNPs shows ethnicity specificity. Substantial differences of the SNPs' distribution were noted from study to study, even within the same ethnic group. The genotype data will be used for longitudinal observation of AMD onset in the follow-up of the cohort. PMID- 21609243 TI - An early inflammatory gene profile in visceral adipose tissue in children. AB - The aim of this study was to characterize expression profiles of visceral and subcutaneous adipose tissue in children. Adipose tissue samples were collected from children having elective surgery (n = 71, [54 boys], 6.0 +/- 4.3 years). Affymetrix microarrays (n = 20) were performed to characterize the functional profile and identify genes of interest in adipose tissue. Visceral adipose tissue had an overrepresentation of Gene Ontology themes related to immune and inflammatory responses and subcutaneous adipose tissue had an overrepresentation of themes related to adipocyte growth and development. Likewise, qPCR performed in the whole cohort showed a 30-fold increase in haptoglobin (P = 0.005), 7-fold increase in IL-10 (P < 0.001), 8-fold decrease in VEGF (P = 0.01) and a 28-fold decrease in TBOX15 (P < 0.001) in visceral compared to subcutaneous adipose tissue. The inflammatory pattern in visceral adipose tissue may represent an early stage of the adverse effects of this depot, and combined with chronic obesity, may contribute to increased metabolic and cardiovascular risk. PMID- 21609244 TI - Metabolic abnormalities associated with obesity in children and adolescents in Jordan. AB - OBJECTIVE: To estimate the prevalence of overweight and obesity among Jordanian children and adolescents and to determine their association with metabolic abnormalities. METHODS: In a national population-based household survey, a systematic sample of households was selected. All members aged ?7 years in the selected households were invited to participate in the study. Of the respondents, 1,034 subjects were 18 years old or younger. Anthropometric and biochemical measurements were obtained. Overweight and obesity were defined according to age and sex specific cut-off points of BMI defined by the International Obesity Task Force criteria proposed by Cole et al. The metabolic abnormalities were defined for subjects, based on their age, according to the definition of Cook et al. and International Diabetes Federation (IDF) criteria. RESULTS: The overall prevalence of overweight and obesity among children were 6.0% and 5.5%, respectively. Among adolescents, the overall prevalence rates of overweight and obesity were 13.7% and 10.0%, respectively. After adjusting for gender and age, overweight was significantly associated with increased odds of having high triglycerides (Odds ratio [OR] = 1.7), low HDL-cholesterol (OR = 1.9), and at least one metabolic abnormality (OR = 2.2). Obesity was significantly associated with increased odds of individual metabolic abnormalities and their clustering. CONCLUSIONS: A relatively high proportion of Jordanian children and adolescents had overweight or obesity. Overweight and obesity in children and adolescents were associated with increased odds of metabolic abnormalities and their clustering. Programs addressing eating behavior and physical activity of children and adolescents to maintain a healthy weight are needed in Jordan. PMID- 21609245 TI - Effectiveness of a primary school-based intervention to reduce overweight. AB - OBJECTIVES: The purpose of this study was to evaluate the effect of a school based intervention program to reduce overweight and improve fitness in primary school children. METHODS: A cluster randomized controlled design was used over one school year with schools as unit of randomization. In total 20 schools and 2,622 children aged 6-12 years (grades 3-8) from multi-ethnic, low income inner city neighbourhoods in Rotterdam, Netherlands, participated. The intervention, named Lekker Fit! (Enjoy being fit!) was a multi-component intervention based on behavioural and ecological models. Main components of the intervention are the implementation of three physical education (PE) sessions a week by a professional PE teacher, additional sport and play activities outside school hours and an educational program. Main primary outcome measures were weight status, body mass index (BMI), waist circumference and fitness (20 m shuttle run). RESULTS: Significant positive intervention effects were found for percentage overweight children (OR 0.53; 95% CI 0.36-0.78), waist circumference (-1.29 cm; 95% CI -2.16 to -0.42 cm) and 20 m shuttle run (0.57 laps; 95% CI 0.13-1.01 laps) among pupils of grades 3-5 (6-9-year olds). The prevalence of overweight in grades 3-5 increased by 4.3% in the control group and by 1.3% in the intervention group. No significant effects were found for BMI or for grades 6-8 (9-12-year olds). CONCLUSIONS: Our results provide evidence for the effectiveness of the multi component intervention Lekker Fit! among pupils of grades 3-5 and adds to the growing body of evidence that school-based programs with a focus on PA are most effective in reducing childhood obesity. [ISRCTN84383524]. PMID- 21609247 TI - Validity of jitter measures in non-quasi-periodic voices. Part II: the effect of noise. AB - In this paper the effect of noise on both perceptual and automatic evaluation of the glottal cycle length in irregular voice signals (sustained vowels) is studied. The reliability of four tools for voice analysis (MDVP, Praat, AMPEX, and BioVoice) is compared to visual inspection made by trained clinicians using two measures of voice signal irregularity: the jitter (J) and the coefficient of variation of the fundamental frequency (F0CV). The purpose is also to test to what extent of irregularity trained raters are capable of determining visually the glottal cycle length as compared to dedicated software tools. For a perfect control of the amount of jitter and noise put in, data consist of synthesized sustained vowels corrupted by increasing jitter and noise. Both jitter and noise can be varied to the desired extent according to built-in functions. All the tools give almost reliable measurements up to 15% of jitter, for low or moderate noise, while only few of them are reliable for higher jitter and noise levels and would thus be suited for perturbation measures in strongly irregular voice signals. As shown in Part I of this work, for low noise levels the results obtained by visual inspection from expert raters are comparable or better than those obtained with the tools presented here, at the expense of a larger amount of time devoted to searching visually for the glottal cycle lengths in the signal waveform. In this paper it is shown that results rapidly deteriorate with increasing noise. Hence, the use of a robust tool for voice analysis can give valid support to clinicians in term of reliability, reproducibility of results, and time-saving. PMID- 21609248 TI - Monitoring of blood pressure in overweight and obese children in Shandong, China. AB - BACKGROUND: Obesity and hypertension are common health problems in children and adolescents. Several studies have reported that obesity is associated with elevated blood pressure (BP) in both adults and children. However, there are few data of population-wide blood pressure monitoring in overweight and obese children and adolescents. AIM: The present study examined the prevalence of overweight, obesity and relative high BP among children and adolescents and compared the level of blood pressure among children and adolescents with different weight status in Shandong, China. SUBJECTS AND METHODS: A total of 8,555 students (4,325 boys and 4,230 girls) aged 7-18 years participated in this study. Height, weight and BP of all subjects were measured, body mass index (BMI) of adolescents was calculated from their height and weight and prevalence of overweight and obesity were obtained according to the screening criteria for overweight and obesity in Chinese students using BMI. RESULTS: The overall prevalence of overweight, obesity and relatively high BP were 14.31%, 10.64% and 24.14% in boys and 8.75%, 5.70% and 22.39% in girls, respectively. An increasing trend was observed in systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) from the normal weight group, to the overweight and obese groups. CONCLUSION: There is a high prevalence of overweight, obesity and relatively high BP among children and adolescents in Shandong, China. The present findings emphasize the importance of prevention of overweight and obesity in order to prevent future related problems such as hypertension in children and adolescents. PMID- 21609249 TI - Somatic complaints and social competence predict success in childhood overweight treatment. AB - OBJECTIVE: To determine baseline predictors of treatment success in terms of Body Mass Index-Standard Deviation Scores (BMI-SDS) in a multidisciplinary family based behavioural lifestyle intervention for overweight and obese children. METHODS: Overweight and obese children (N = 248; age 8-14 years) and their caregivers participated in a prospective study and attended a lifestyle intervention. Baseline data assessment included anthropometrics, demographics, breakfast behaviour, competence and behavioural problems (Child Behaviour Checklist [CBCL]), family functioning (Family Adaptability and Cohesion Evaluation Scales [FACES] III), and personality (Dutch Personality Questionnaire Youth [NPV-J]). BMI-SDS was measured at start and after 3, 9, and 12 months of treatment. Mixed modelling was used for analysis. RESULTS: Greater BMI-SDS reductions over the course of one year were found in children with Caucasian parents, with lower baseline BMI-SDS, and higher CBCL-social competence scores. Furthermore, children with non-overweight parents, younger children, and children with lower CBCL-somatic scores were more successful in BMI-SDS reduction. No effects on treatment success were found for the number or position of siblings, having divorced parents or a working mother, educational level of the parents, breakfast behaviour, family functioning, and personality. CONCLUSIONS: These results suggest that screening for baseline characteristics in childhood obesity treatment could identify who will benefit most from a paediatric lifestyle intervention. Tailored programs should be developed and the treatment team should focus on children who are less successful in achieving weight reductions. Future research should study by which mechanisms somatic complaints and social competence influence treatment success. PMID- 21609250 TI - Comment on efficacy and safety of propranolol in the treatment of parotid hemangioma. AB - A brief comment on efficacy and safety of propranolol in the treatment of parotid hemangioma is presented, with illustration of a typical case. PMID- 21609251 TI - Redox pioneer: professor Roland Stocker. AB - Dr. Roland Stocker (Ph.D. 1985) is recognized here as a Redox Pioneer, because he has published one article on antioxidant/redox biology as first author that has been cited over 1000 times and has published another 32 articles, each cited over 100 times. Dr. Stocker received his undergraduate education at the Federal Institute of Technology Zurich, Switzerland (1975-1981), followed by postgraduate training at the Australian National University Canberra, Australia (1982-1985) and postdoctoral training at the University of California, Berkeley (1986-1987), and the University of Berne, Switzerland (1987-1988). Dr. Stocker's top scientific contributions are in the following areas: (i) molecular action and interaction of nonproteinaceous antioxidants, particularly bilirubin, alpha tocopherol, and ubiquinol-10; (ii) lipoprotein lipid oxidation and its inhibition, with a particular focus on how alpha-tocopherol affects these processes; (iii) the role of arterial lipoprotein lipid oxidation in atherosclerosis and related diseases; (iv) modes of antiatherosclerotic action of probucol and the involvement of heme oxygenase-1 in vascular protection; and (v) the regulation of indoleamine 2,3-dioxygenase and its contribution to vascular tone and blood pressure in inflammatory diseases. PMID- 21609252 TI - Clostridium difficile infection: a comprehensive review. AB - Clostridium difficile is one of the most important causes of healthcare acquired diarrhea. The disease spectrum caused by C. difficile infection ranges from mild, self-limited, illness to a severe, life-threatening colitis. The incidence of C. difficile associated disease has risen dramatically over the last decade, leading to increased research interest aiming at the discovery of new virulence factors and the development of new treatment and prevention regimens. This review summarizes the pathogenesis and changing epidemiology of C. difficile associated disease, the clinical spectrum and laboratory methods to diagnose C. difficile infection, and current treatment strategies. PMID- 21609253 TI - Reproductive toxicants have a threshold of adversity. AB - This paper surveys the scientific basis for the current threshold approach for reproductive hazard and risk assessment. In some regulatory areas it was recently suggested to consider reproductive toxicants under the stringent linear extrapolation risk assessment paradigm that was developed for genotoxic carcinogens. First, the current risk assessment paradigm for genotoxic carcinogens is addressed, followed by an overview of reproductive toxicology and its threshold dose approach for hazard and risk assessment, the testing procedures for assessing the reproductive toxicity of chemicals, and the derivation of conclusions on their risk assessment and Classification, Labelling and Packaging (CLP). Relevant details of testing methodologies are discussed, such as exposure time windows, parameters determined, and the coverage of the entire reproductive cycle. In addition, the dose-response relationship is considered, illustrated with several examples. It is concluded that the current risk assessment methodology for genotoxic carcinogens is a debatable worst-case scenario and that for risk assessment of reproductive toxicants the threshold dose approach remains valid. PMID- 21609254 TI - Clinical efficacy of 1% alendronate gel in adjunct to mechanotherapy in the treatment of aggressive periodontitis: a randomized controlled clinical trial. AB - BACKGROUND: Bisphosphonates represent a class of pharmacologic agents that have a potentially important role in the treatment of periodontitis and bone disorders. The present study aims to explore the clinical efficacy of 1% alendronate (ALN) gel as a local drug delivery system in adjunct to scaling and root planing for the treatment of patients with aggressive periodontitis (AgP) compared to placebo gel. METHODS: Fifty-two intrabony defects from 17 patients with AgP were treated either with 1% ALN gel or placebo gel. ALN gel was prepared by adding ALN to a polyacrylic acid-distilled water mixture. Clinical parameters (modified sulcus bleeding index, plaque index, probing depth [PD], and clinical attachment level [CAL]) were recorded at baseline, 2 months, and 6 months, and radiographic parameters were recorded at baseline and 6 months. Defect fill at baseline and at 6 months was calculated on standardized radiographs by using image analysis software. RESULTS: Mean PD reduction was greater in the ALN group (3.88 +/- 1.39 mm) compared to placebo (1.65 +/- 1.35 mm) at 6 months. Similarly, mean CAL gain was greater in the ALN group (3.27 +/- 1.11 mm) than the placebo group (1.42 +/- 1.70 mm) at 6 months. Furthermore, significantly greater mean percentage of bone fill was found in the ALN group (46.1% +/- 9.48%) compared to the placebo group (2% +/- 1.02%). CONCLUSIONS: The results of the present study show local delivery of 1% ALN stimulates a significant increase in PD reduction, CAL gain, and improved bone fill compared to placebo gel as an adjunct to scaling and root planing in patients with AgP. However, long-term, multicentered, randomized, controlled clinical trials are required to know the clinical, histologic, and radiographic effect on bone regeneration in patients with AgP. PMID- 21609255 TI - A population-based study of periodontal care among those with and without diabetes. AB - BACKGROUND: Our objectives were to describe the prevalence of periodontal care (a marker of periodontitis) among persons with and without diabetes and to examine the association between periodontal care and diabetes. METHODS: We conducted a cross-sectional analysis, using 5 years of electronic data from a population based cohort (N = 46,132), aged 40 to 70 years, with dental and medical insurance, and >= 1 dental and >= 1 medical visit. Periodontal care (yes/no) was defined by dental claims codes for procedures used to manage periodontitis. The association between periodontal care and diabetes was determined using logistic regression adjusted for and stratified by age, sex, insurance type, smoking status, body mass index (BMI) (in kilograms per square meter), and resource utilization band (RUB) (a measure of expected health care utilization attributable to comorbidity). RESULTS: Overall, 11.2% (5,153 of 46,132) met diabetes criteria. The age-adjusted prevalence of periodontal care among those with and without diabetes was 39.1% and 32.5%, respectively (P <0.0001). The association between diabetes and periodontal care decreased with increasing age (interaction, P <0.0001), adjusting for BMI and RUB. The aged-stratified, adjusted odds ratio (OR) for periodontal care associated with diabetes was highest among those aged 40 to 44 years [OR, 1.6; confidence interval (CI), 1.30 to 1.97] and lowest among those aged 60 to 64 years (OR, 0.97; CI, 0.81 to 1.15) and was significant only among those aged 40 to 54 years. CONCLUSION: We found that the prevalence of periodontal care was significantly higher among those with diabetes compared to those without diabetes and that the magnitude of this association decreased with increasing age. PMID- 21609256 TI - Single-flap approach for surgical debridement of deep intraosseous defects: a randomized controlled trial. AB - BACKGROUND: The single-flap approach (SFA) consists of the elevation of a limited mucoperiosteal flap to allow surgical access to periodontal defects from either the buccal or oral aspect only, leaving the interproximal supracrestal gingival tissues intact. The aim of the present randomized controlled trial is to assess the effectiveness of a buccal SFA used for the surgical debridement of deep intraosseous defects compared to the double-flap approach (DFA). METHODS: Fourteen patients were treated according to SFA principles and 14 patients received the DFA. In all patients, root surfaces and defects were thoroughly debrided, and conditions for the primary intention healing and blood clot stability were ensured by a proper flap design and suture technique. The clinical attachment level (CAL), probing depth (PD), and gingival recession (REC) were assessed immediately before surgery and at 6 months post-surgery. RESULTS: The results of the study indicate that: 1) the SFA and DFA resulted in significant CAL gains and PD reductions at 6 months post-surgery; and 2) the SFA was similarly effective compared to the DFA in terms of CAL gain and PD reduction. CONCLUSION: The surgical debridement of intraosseous periodontal defects resulted in comparable, substantial CAL gains and PD reductions as well as limited postoperative REC increases when defects were accessed with the SFA or DFA. PMID- 21609258 TI - Treatment of latent TB: first do no harm. PMID- 21609257 TI - Levels of serum immunoglobulin G specific to bacterial surface protein A of Tannerella forsythia are related to periodontal status. AB - BACKGROUND: Tannerella forsythia (Tf) is a Gram-negative anaerobe implicated in the development of periodontal disease. Bacterial surface protein A (BspA) is a surface-expressed and -secreted protein that is recognized as an important virulence factor of Tf. This study was undertaken to determine whether Tf BspA induces an antibody response in periodontal disease. We hypothesized that serum immunoglobulin (Ig)G antibody levels against BspA correlate with the disease of patients. METHODS: Sera were obtained from 100 patients with cardiac disorders and periodontal disease and 73 patients who experienced myocardial infarction but were periodontally healthy. Sera samples were assayed for anti-BspA antibody (total IgG and IgG subtypes) by enzyme-linked immunosorbent assay (ELISA). Antibody levels were measured in ELISA units by using an arbitrary patient as a standard. RESULTS: A negative correlation was found with BspA-specific total IgG antibody titers and the severity of disease measured as the clinical attachment level (CAL) when healthy and diseased groups were analyzed separately (healthy group: [-0.23, correlation value] Student's t value [73 degrees of freedom] = 1.99; P = 0.05; diseased group: [-0.21] t [100 degrees of freedom] = 2.12; P = 0.03]). However, there was a positive correlation ([0.18 correlation value] Student's t value [173 degrees of freedom] = 2.39; P = 0.017) when healthy and diseased groups were combined. A strong positive correlation ([0.338 correlation value] Student's t value [173 degrees of freedom] = 4.69; P <0.0001) between the BspA-specific IgG titers and periodontal probing depth was observed when healthy and disease groups were combined. CONCLUSIONS: Data demonstrated that antibodies to Tf BspA were elicited in patients with periodontal disease, and antibody levels were associated with the disease severity. Furthermore, data suggested that anti-BspA IgG might have a protective function in periodontal disease by minimizing the loss of tooth attachment tissue. PMID- 21609259 TI - MRSA guidelines: a matter of time. PMID- 21609260 TI - Flubendazole: a candidate macrofilaricide for lymphatic filariasis and onchocerciasis field programs. PMID- 21609262 TI - Toll-like receptor-4 antagonist eritoran tetrasodium for severe sepsis. AB - The human innate immune system initiates inflammation in response to bacterial molecules, particularly Gram-negative bacterial endotoxin. The steps by which endotoxin exposure leads to systemic inflammation include binding to Toll-like receptor-4 that specifically recognizes endotoxin and subsequently triggers cellular and molecular inflammatory responses. Severe sepsis is a systemic inflammatory response to infection that induces organ dysfunction and threatens a person's survival. Severe sepsis is frequently associated with increased blood levels of endotoxin. It is a significant medical problem that effects approximately 700,000 patients every year in the USA, resulting in 250,000 deaths. Eritoran tetrasodium is a nonpathogenic analog of bacterial endotoxin that antagonizes inflammatory signaling by the immune receptor Toll-like receptor 4. Eritoran is being evaluated for the treatment of patients with severe sepsis. PMID- 21609263 TI - Is screening for malaria necessary among asymptomatic refugees and immigrants coming from endemic countries? AB - Malaria is endemic throughout most of the tropics mainly due to Plasmodium falciparum. Outside the tropics, cases have been described among mobile population groups, such as travellers, immigrants and refugees. Malaria prevalence among refugees ranges from 3% to more than 60%, many of them being asymptomatic. This article assesses the findings of a recent study performed in Canada where malaria prevalence among recently arrived asymptomatic refugees was measured. A total of 324 refugees were screened for malaria, obtaining a global prevalence of 3.1% by PCR. Identifying imported, asymptomatic cases of malaria may have an important impact both for the individual concerned and for public health. PMID- 21609264 TI - Hepatitis C virus-associated insulin resistance: pathogenic mechanisms and clinical implications. AB - It is now widely recognized that chronic hepatitis C is a metabolic disease, strongly associated with Type 2 diabetic mellitus and insulin resistance (IR). Chronic hepatitis C virus (HCV) infection promotes IR mainly through interfering with the insulin signaling pathway in hepatocytes, increasing the inflammatory response with production of cytokines such as TNF-alpha and IL-6, and increasing oxidative stress. Accumulated evidence indicates that HCV-associated IR may lead to fibrosis progression, resistance to antiviral therapy, hepatocarcinogenesis and extrahepatic manifestations. Thus, HCV-associated IR is a therapeutic target at any stage of HCV infection. However, specific pharmaceutical treatments of IR are still being evaluated in clinical trials, but available data do not warrant their use in all chronic hepatitis C patients with IR. PMID- 21609265 TI - Antiviral therapy: why does it fail in HCV-related chronic hepatitis? AB - HCV infection is a very common cause of chronic viral hepatitis. It is a worldwide health problem with approximately 170 million persons infected and areas of high endemicity in which the percentage of the population infected reaches 30%. It is a progressive disease that can lead to complications such as severe liver fibrosis and cirrhosis, ascites, esophageal varices, gastrointestinal bleeding and, in 30-50% of patients with cirrhosis, hepatocellular carcinoma. Extrahepatic pathologies such as mixed cryoglobulinemia, non-Hodgkin lymphoma and membrano-proliferative glomerulonephritis have been associated with HCV infection. Effective treatment exists, and is based on IFN-alpha. Sustained disappearance of the virus (sustained virological response) radically changes the natural history of chronic hepatitis C, with reduced or no disease progression and complications. Interferon based treatment has improved over the years owing to the association with ribavirin and subsequently with 'pegylation' of interferon molecules. The present standard of care results in a response rate of up to 80% in some subpopulations. Nevertheless, some patients do not respond to this therapy. Several factors predicting nonresponse to interferon therapy have been investigated since it became available. These factors include the characteristics of the virus and of the subject infected, and the therapy used. The aim of this article is to provide an overview of these factors, and insights into the newly recognized causes of nonresponse to help clinicians select the most appropriate therapy for HCV viral hepatitis. PMID- 21609266 TI - Viral arthritides. AB - Viral infections may manifest as acute or chronic arthritis. Joint involvement arises from either direct infection of the joint, through an immunological response directed towards the virus or autoimmunity. Epidemiological clues to the diagnosis include geographic location and exposure to vector-borne, blood-borne or sexually transmitted viruses. Although not always possible, it is important to diagnose the pathogenic virus, usually by serology, nucleic acid tests or rarely, viral culture. In general, viral arthritides are self-limiting and treatment is targeted at symptomatic relief. This article focuses on the causes, clinical features, diagnosis and treatment of viral arthritides. PMID- 21609267 TI - Status report on carbapenemases: challenges and prospects. AB - Antimicrobial resistance in hospital and community-onset bacterial infections is a significant source of patient morbidity and mortality. In the past decade, we have witnessed the increasing recovery of carbapenem-resistant Gram-negative bacteria. For many isolates, carbapenem resistance is due to the production of carbapenemases, beta-lactamases that can inactivate carbapenems and frequently other beta-lactam antibiotics. Currently, these enzymes are mainly found in three different beta-lactamase classes (class A, B and D). Regardless of the molecular classification, there are few antimicrobials available to treat infections with these organisms and data regarding agents in development are limited to in vitro studies. This article focuses on the epidemiology of carbapenemase-producing Gram negative bacteria. We also review available agents and those in development with potential activity against this evolving threat. PMID- 21609268 TI - Antifungal prophylaxis in solid organ transplant recipients. AB - Solid organ transplantation is life saving for thousands of patients worldwide with end-stage organ failure, but post-transplantation invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality. To improve patient outcomes, investigators have explored various strategies of prevention, including the use of antifungal prophylaxis with both systemic and topical nonabsorbable agents. Often, the strategy is to identify those patients at highest risk for IFIs who would be expected to derive the most benefit from antifungal prophylaxis. Currently, data support the use of antifungal prophylaxis in liver, lung, small bowel and pancreas transplant recipients. By understanding the epidemiology of post-transplant IFIs and antifungal adverse effects, clinicians may target antifungal prophylaxis more optimally. Herein, we review antifungal prophylaxis with systemic agents among solid organ transplant recipients. PMID- 21609269 TI - Therapy of vector-borne protozoan infections in nonendemic settings. AB - Vector-borne protozoan infections are responsible for a wide variety of illnesses (mainly malaria, trypanosomiasis and leishmaniasis) affecting tropical and subtropical areas, but increasingly diagnosed in nonendemic settings. This article summarizes the therapeutic developments for these conditions during the past decade and focuses specifically on treatment recommendations for returning travelers and migrants. The treatment of malaria has known the most spectacular improvements. Progress in the management of leishmaniasis and trypanosomiasis has also been substantial and includes introduction of new drugs into clinical practice, combinations of existing drugs, or new laboratory tools for treatment monitoring as well as extension of treatment indications to new groups of patients. Serious gaps still exist in terms of effectiveness and tolerance. Since the research pipeline is very limited for the coming 5-10 years, optimized combinations of existing drugs need to be urgently explored. PMID- 21609270 TI - Current status of Chagas disease chemotherapy. AB - Chagas disease affects 7.7 million people and 28 million people are at risk of acquiring the disease in 15 endemic countries of Latin America. Benznidazole and nifurtimox are drugs that have been used to treat the disease. However, both drugs induce severe side effects. Treatment with benznidazole has been recommended for the acute phase (0-4 months after infection), recent chronic phase (children 0-14 years of age, treated 4 months after infection) and congenital infection. Average cure rates for Chagas disease patients obtained from clinical trials were 97.9% (congenital infection, treatment performed 0-6 months of age), 71.5% (acute phase), 57.6% (recent chronic phase, children 0-13 years of age) and 5.9% (late chronic phase, great majority of patients between 15 and 69 years of age). Clinical evidence about the capacity of antiparasitic treatment to avoid, stop or revert heart pathology in indeterminate and cardiac chronic patients is contradictory. The investigation of novel therapeutic strategies against Chagas disease remains a priority in the research of tropical diseases. Unfortunately, Chagas disease remains neglected in the formulation of strategies toward control of this disease. This article focuses on current therapeutic approaches to Chagas disease. PMID- 21609272 TI - The hemorheological mechanisms in normal tension glaucoma. AB - PURPOSE: To investigate the differences in hemorheological parameters between patients with normal tension glaucoma (NTG) and normal controls. METHODS: Twenty patients with NTG and 21 age-matched normal controls were included in the study. Hemorheological parameters of the venous blood samples, including blood viscosity at the shear rates of 500, 250, and 5 s(-1), and viscoelasticity were measured using a rotational rheometer; erythrocyte deformability and aggregation were measured using a ektacytometer; and erythrocyte rigidity and the oxygen transport efficiency of blood were calculated. RESULTS: Higher blood viscosities at the high (p < 0.01), medium (p < 0.01), and low (p < 0.01) shear rates were found in the NTG group than in the control group. Significantly higher erythrocyte aggregation index (p < 0.01); lower index of erythrocyte deformability at medium (p < 0.01) and high shear rates (p < 0.05); and lower oxygen transport efficiency of blood at low (p < 0.01), medium (p < 0.01), and high shear rates (p < 0.05) were obtained in the NTG group. CONCLUSIONS: The higher blood viscosity of the NTG patients at the high shear rate may be related to impaired erythrocyte deformability associated with a change in erythrocyte rigidity. Higher blood viscoelasticity and blood viscosity of NTG patients at the low shear rate was due to increased erythrocyte aggregability. Also, the impaired erythrocyte deformability of NTG patients is susceptible to developing abnormalities of the distal microcirculation. Furthermore, the increased blood viscosity and low oxygen transport efficiency of blood may result in hypoperfusion of optic nerve in NTG patients. PMID- 21609273 TI - Automating the packing heuristic design process with genetic programming. AB - The literature shows that one-, two-, and three-dimensional bin packing and knapsack packing are difficult problems in operational research. Many techniques, including exact, heuristic, and metaheuristic approaches, have been investigated to solve these problems and it is often not clear which method to use when presented with a new instance. This paper presents an approach which is motivated by the goal of building computer systems which can design heuristic methods. The overall aim is to explore the possibilities for automating the heuristic design process. We present a genetic programming system to automatically generate a good quality heuristic for each instance. It is not necessary to change the methodology depending on the problem type (one-, two-, or three-dimensional knapsack and bin packing problems), and it therefore has a level of generality unmatched by other systems in the literature. We carry out an extensive suite of experiments and compare with the best human designed heuristics in the literature. Note that our heuristic design methodology uses the same parameters for all the experiments. The contribution of this paper is to present a more general packing methodology than those currently available, and to show that, by using this methodology, it is possible for a computer system to design heuristics which are competitive with the human designed heuristics from the literature. This represents the first packing algorithm in the literature able to claim human competitive results in such a wide variety of packing domains. PMID- 21609274 TI - Ultrasound-guided percutaneous microwave ablation of splenic metastasis: report of four cases and literature review. AB - PURPOSE: To investigate the feasibility, safety and efficacy of ultrasound guided percutaneous microwave (MW) ablation for small splenic metastasis. MATERIALS AND METHODS: A total of four patients with five pathologically proven splenic metastases (from ovarian, pulmonary, gastric adenocarcinoma and hepatocellular carcinoma, respectively) 1.3 to 2.9 cm in diameter were treated with microwave ablation. A cooled-shaft needle antenna was percutaneously inserted into the tumour under ultrasound guidance. One thermocouple was placed about 0.5 cm away from the tumour to monitor temperature in real time during ablation. Microwaves were emitted at 60 W for 600 s routinely and prolonged as necessary to attain temperatures sufficient to ensure tumour killing. Treatment efficacy was assessed by contrast-enhanced imaging at 1, 3 and 6 months, and every 6 months thereafter. RESULTS: All tumours were completely ablated at a single session and no complications occurred. No local tumour progression was observed at a mean follow up of 22 +/- 17.1 months (range 4 to 43 months). The ablation zone was well defined on contrast-enhanced imaging and it gradually shrank with time. One new metastatic lesion was detected in the spleen at 11 months after the ablation and was successfully treated by another MW ablation. The post-ablation survival was mean 22 months. No other complications were observed except for fever and abdominal pain. CONCLUSIONS: Ultrasound-guided percutaneous MW ablation appears to be a safe and effective minimally invasive technique for management of small splenic metastasis in selected patients. PMID- 21609275 TI - beta-Cyclodextrin and permeability to water in the bladder of Bufo arenarum. AB - We measured the effect of beta-cyclodextrin (BCD, a cholesterol scavenger) on water flow across the isolated toad bladder exposed to an osmotic gradient (J(w)) by a gravimetric technique. BCD, when present in the solution bathing the apical side of the bladder, inhibited the increase in J(w) caused by nystatin, a polyene antibiotic that acts by directly binding apical membrane cholesterol. When present in the basolateral bath, BCD inhibited the increase in J(w) caused by basolateral exposure to oxytocin (which binds membrane receptors and stimulates the synthesis of cAMP), but did not alter the response to theophylline (which inhibits hydrolysis of cAMP by cyclic nucleotide phosphodiesterase). The present data are consistent with the notion that agents that increase J(w) by interacting with membrane receptors, which appear to be clustered in cholesterol-rich domains of the basolateral membrane, are altered by cholesterol depletion, whereas agents that do not interact with receptors or other basolateral membrane components are not affected by this treatment. In either case, cholesterol depletion of the apical membrane does not affect the increase in J(w) brought about by an increase in intracellular cAMP concentration. PMID- 21609276 TI - The effect of N-acetylcysteine on the antitumor activity of ifosfamide. AB - Ifosfamide-induced nephrotoxicity is a serious adverse effect in children undergoing chemotherapy. Our previous cell and rodent models have shown that the antioxidant N-acetylcysteine (NAC), used extensively as an antidote for acetaminophen poisoning, protects renal tubular cells from ifosfamide-induced nephrotoxicity at a clinically relevant concentration. For the use of NAC to be clinically relevant in preventing ifosfamide nephrotoxicity, we must ensure there is no effect of NAC on the antitumor activity of ifosfamide. Common pediatric tumors that are sensitive to ifosfamide, human neuroblastoma SK-N-BE(2) and rhabdomyosarcoma RD114-B cells, received either no pretreatment or pretreatment with 400 umol/L of NAC, followed by concurrent treatment with NAC and either ifosfamide or the active agent ifosfamide mustard. Ifosfamide mustard significantly decreased the growth of both cancer cell lines in a dose-dependent manner (p < 0.001). The different combined treatments of NAC alone, sodium 2 mercaptoethanesulfonate alone, or NAC plus sodium 2-mercaptoethanesulfonate did not significantly interfere with the tumor cytotoxic effect of ifosfamide mustard. These observations suggest that NAC may improve the risk/benefit ratio of ifosfamide by decreasing ifosfamide-induced nephrotoxicity without interfering with its antitumor effect in cancer cells clinically treated with ifosfamide. PMID- 21609278 TI - Effect of pasteurization on immune components of milk: implications for feeding preterm infants. AB - It has been unequivocally proven that human breast milk is the ideal source of nutrition for infants. However, mothers of preterm infants face a number of barriers to providing sufficient milk volume to their babies, who are at risk for developing necrotizing enterocolitis (NEC). Donated milk, distributed through milk banks, is becoming a desirable alternative to formula feeding, and is increasingly being considered for hospitalized, preterm infants in North America. Donor milk in North America is pasteurized (62.5 degrees C, 30 min) to remove possible infectious contaminants; a number of immune and bioactive components are either partially or entirely inactivated by this process. Identifying the impact of pasteurization on immune components of breast milk has been the focus of numerous research studies over the past several decades. The objective of this review is to summarize the literature on the feeding of pasteurized donor milk to preterm infants and the current understanding of the impact of pasteurization on immune components of breast milk, with particular reference to those implicated in the prevention of NEC. PMID- 21609279 TI - The reliability and validity of using clothing size as a proxy for waist circumference measurement in adults. AB - Waist circumference (WC) is a useful tool for predicting health risk, but its use at the population level remains uncertain. This study examined (i) the ability of participants to report their current WC without actual measurement, (ii) the accuracy of reporting WC using self-reported or self-measured WC, and (iii) the reliability and validity of using clothing size (CS) as a proxy to predict WC. Men and women (n = 293), aged 18-80 years, were randomized to either self-report WC or self-measure WC groups. Both completed 2 telephone surveys and their WC was professionally measured. Predictive equations were then developed to determine whether CS could be used as a proxy for WC. Only 66% of participants reported their current WC, although this was underreported (p < 0.05) compared with professionally measured WC. Professionally measured WC correlated strongly with CS for men (r = 0.8; p < 0.01) and women (r = 0.78; p < 0.05), respectively. While predicted WC demonstrated good agreement for men (kappa = 0.82) with respect to classifying individuals at increased health risk, this was attenuated in women (kappa = 0.6). Due to the fact that only 66% of participants know their current WC and that both self-report WC and self-measure WC groups underreport actual WC, a reliable and valid proxy for WC is needed. CS presents a reliable and feasible means of obtaining an estimate of WC at the population level in adults and predicting the percentage of the population at increased health risk. PMID- 21609280 TI - Improvement in insulin sensitivity by weight loss does not affect hyperinsulinemia-mediated reduction in total and high molecular weight adiponectin: a MONET study. AB - Acute hyperinsulinemia reduces total and high molecular weight (HMW) adiponectin levels in humans. Whether an increase in insulin sensitivity (IS) is accompanied by a greater suppressive effect of hyperinsulinemia on adiponectin levels is unknown, however. To clarify the inhibitory role of insulin on adiponectin, total and HMW adiponectin levels were measured during acute hyperinsulinemia before and after an improvement in insulin sensitivity in response to weight loss. Forty-six overweight and obese postmenopausal women were randomized to either 6-month caloric restriction (CR) alone (n = 22), or CR with resistance training (CR+RT, n = 24). IS (hyperinsulinemic-euglycemic clamp) was assessed before and after weight loss. Total and HMW adiponectin levels were measured by ELISA at baseline, 90, 160, and 180 min of each clamp. Relative mean body weight loss was -8.0% +/- 4.4% for both groups (CR: -7.7% +/- 3.8%; CR+RT: -8.2% +/- 5.0%). IS increased significantly, by 18.4% +/- 25.3% (CR: 19.3% +/- 29.7%; CR+RT: 17.7% +/- 21.0%). Before each intervention, total and HMW adiponectin levels in both groups significantly decreased in response to hyperinsulinemia (total: -8.4% +/- 19.4%; HMW: -3.2% +/- 13.2%). Despite the improvement in IS seen after each intervention, a similar pattern of reduction to that before weight loss was observed in total and HMW adiponectin levels during hyperinsulinemia. These results establish that total and HMW adiponectin levels decline during a hyperinsulinemic-euglycemic clamp. Also, the insulin-sensitizing effect of weight loss via caloric restriction alone or with resistance training does not amplify the reduction in adiponectin levels observed during hyperinsulinemia in healthy postmenopausal women. PMID- 21609281 TI - Antilithogenic influence of dietary capsaicin and curcumin during experimental induction of cholesterol gallstone in mice. AB - Spice bioactive compounds, capsaicin and curcumin, were both individually and in combination examined for antilithogenic potential during experimental induction of cholesterol gallstones in mice. Cholesterol gallstones were induced by feeding mice a high-cholesterol (0.5%) diet for 10 weeks. Groups of mice were maintained on a lithogenic diet that was supplemented with 0.015% capsaicin/0.2% curcumin/0.015% capsaicin + 0.2% curcumin. The lithogenic diet that contained capsaicin, curcumin, or their combination reduced the incidence of cholesterol gallstones by 50%, 66%, and 56%, respectively, compared with lithogenic control. This was accompanied by reduced biliary cholesterol and a marginal increase in phospholipid in these spice-fed groups. Increased cholesterol saturation index and cholesterol : phospholipid ratio in the bile caused by the lithogenic diet was countered by the dietary spice compounds. The antilithogenic influence of spice compounds was attributable to the cholesterol-lowering effect of these dietary spices in blood and liver, as well as a moderate increase in phospholipids. Decreased activities of hepatic glutathione reductase and glutathione-S-transferase caused by the lithogenic diet were countered by the combination of capsaicin and curcumin. The increased lipid peroxidation and the decreased concentration of ascorbic acid in the liver that was caused by the lithogenic diet was countered by the dietary spice compounds, individually or in combination. Thus, while the capsaicin and curcumin combination did not have an additive influence in reducing the incidence of cholesterol gallstones in mice, their combination nevertheless was more beneficial in enhancing the activity of hepatic antioxidant enzyme ? glutathione reductase in the lithogenic situation. The antioxidant effects of dietary spice compounds are consistent with the observed reduction in cholesterol gallstones formed under lithogenic condition. PMID- 21609282 TI - Short-term stability of resting heart rate variability: influence of position and gender. AB - Heart rate variability (HRV) is utilized within laboratory and clinical settings as a noninvasive indicator of cardiac autonomic modulation. Past research has utilized a wide variety of resting methodologies and, as such, it is difficult to draw conclusions on the nature of HRV from different studies. Therefore, the current study aimed to assess the short-term stability of resting HRV during a 40 min resting trial and the impact of body position and gender on this short-term stability. Resting HRV was determined from 40-min trials in 3 standard positions (supine, seated, and standing) for healthy males (n = 14) and females (n = 16). Time-domain, geometric, and frequency-domain measures of resting HRV were examined during consecutive 10-min segments using a 3-way ANOVA (time * position * gender) and Tukeys' post-hoc tests with reproducibility assessed by intraclass correlation coefficients (ICC) and coefficients of variation. During rest, most HRV measures fluctuated over time, were greater in the supine compared to the standing position, and were greater for males compared with females. Variables that reflected primarily vagal modulations of heart rate remained stable, whereas other HRV measures varied over time. The majority of HRV variables exhibited substantial to excellent short-term reproducibility (ICC > 0.6) with time-domain and geometric measures of HRV demonstrating greater values compared with frequency-domain parameters. Based on the current results, the recording and analysis of HRV at 0-10 min of rest was recommended as a standardized protocol for the assessment of resting HRV in any standard position for either gender during laboratory and (or) clinical settings. PMID- 21609283 TI - [Dynamics of oxygen uptake during a 100 m front crawl event, performed during competition ]. AB - The main purpose of this study is to estimate the dynamics of oxygen uptake (VO2) during a 100 m front crawl event, performed in competition conditions. Eleven trained swimmers participated in 2 separate sessions, in a 25 m swimming pool. Maximal oxygen uptake (VO2max) was determined during a 400 m maximal event. Swimmers also performed a 100 m front crawl in competition conditions, and then, 3 tests (25, 50, and 75 m) following the pacing strategy of the 100 m event. To be free of technical constraints, VO2 was not measured during the tests, but before and just at the end of each test with a 1 min breath-by-breath method. Each post-test VO2 measurement (after 25, 50, 75, and 100 m) allows us to reconstruct the VO2 kinetics of the 100 m performance. Our results differ from previous studies in that VO2 increases faster in the first half of the race (at 50 m, VO2 ~ 94% VO2max), reaches VO2max at the 75 m mark; then a decrease in VO2 corresponding to 7% of VO2max appears during the last 25 m. These differences are supposed to be mainly the consequences of the adoption of technical elements and a pacing strategy similar to competition conditions. In the future, these observations may lead to different considerations of the bioenergetic contributions. PMID- 21609284 TI - Associations of the SREBP-1c gene polymorphism with gender-specific changes in serum lipids induced by a high-carbohydrate diet in healthy Chinese youth. AB - We investigated the possible association between the sterol regulatory element binding protein-1c gene (SREBP-1c) rs2297508 polymorphism and the changes in lipid profiles in a high-carbohydrate and low-fat (high-CHO/LF) diet in a Chinese population well characterized by a lower incidence of coronary heart disease and a diet featuring higher carbohydrate and lower fat. Fifty-six healthy youth (aged 22.89 +/- 1.80 years) were given wash-out diets of 31% fat and 54% carbohydrate for 7 days, followed by the high-CHO/LF diet of 15% fat and 70% carbohydrate for 6 days, without total energy restriction. Fasting blood samples were collected. Serum variables of lipid and glucose metabolism after the wash-out and high CHO/LF diets, as well as the rs2297508 polymorphism, were analyzed. Compared with the male subjects on the wash-out diet, significantly elevated levels of high density lipoprotein cholesterol (HDL-C) and decreased levels of apolipoprotein B 100 were observed in the male carriers of the C allele after the high-CHO/LF diet. In the female subjects, significantly increased triacylglycerol levels, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were found in the GG genotype after the high-CHO/LF diet. These results suggest that the C allele of the rs2297508 polymorphism is associated with a retardation of the increases in serum triacylglycerol, serum insulin, and HOMA-IR in females and with the elevated serum HDL-C in males after the high-CHO/LF diet. PMID- 21609285 TI - Contractile activity-induced gene expression in fast- and slow-twitch muscle. AB - Many proteins that function as transcription factors regulate the transcriptional activity of nuclear genes encoding mitochondrial proteins. Several of these are rapidly inducible with contractile activity, followed by a recovery phase. The aim of the present study was to evaluate the expression of a number of rapidly responding gene products to an acute bout of contractile activity followed by a recovery period in both slow- and fast-twitch muscle. Using an in vitro isolated muscle preparation, extensor digitorum longus (EDL) and soleus muscles were stimulated for 15 min, followed by 30 min recovery. Following stimulation, ATP levels were decreased in both the EDL and soleus (25% and 32%, respectively). We found that phosphorylation of p38 MAP kinase was elevated in both muscle types, with a more dramatic 3.5-fold increase observed in the EDL muscle. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) mRNA expression was unchanged as a result of stimulation and recovery, while c-Fos transcript levels were decreased as a result of stimulation, but returned to resting values following recovery. Interestingly, nuclear respiratory factor 1 mRNA levels were unaffected by stimulation, but increased significantly (34%) during the recovery phase. These data suggest that the extent of the induction of transcription factor mRNA to acute exercise, which leads to subsequent muscle adaptations, is transcript specific and dependent on (i) the activation of upstream kinases, (ii) the muscle phenotype, and (iii) the duration of the recovery period. PMID- 21609286 TI - Leucine-protein supplemented recovery feeding enhances subsequent cycling performance in well-trained men. AB - The purpose of this study was to determine whether a practical leucine-protein, high-carbohydrate postexercise feeding regimen could improve recovery, as measured by subsequent cycling performance and mechanistic markers, relative to control feeding. In a crossover, 10 male cyclists performed 2- to 2.5-h interval training bouts on 3 consecutive evenings, ingesting either leucine-protein, high carbohydrate nutrition (0.1/0.4/1.2/0.2 g.kg(-1).h(-1); leucine, protein, carbohydrate, fat, respectively) or isocaloric control (0.06/1.6/0.2 g.kg(-1).h( 1); protein, carbohydrate, fat, respectively) nutrition for 1.5 h postexercise. Throughout the experimental period diet was controlled, energy and macronutrient intake balanced, and protein intake clamped at 1.6 g.kg(-1).day(-1). The alternate supplement was provided the next morning, thereby isolating the postexercise nutrition effect. Following 39 h of recovery, cyclists performed a repeat-sprint performance test. Postexercise leucine-protein ingestion improved mean sprint power by 2.5% (99% confidence limit, +/-2.6%; p = 0.013) and reduced perceived overall tiredness during the sprints by 13% (90% confidence limit, +/ 9.2%), but perceptions of leg tiredness and soreness were unaffected. Before exercise, creatine-kinase concentration was lowered by 19% (90% confidence limits, +/-18%), but lactate dehydrogenase and pressure-pain threshold were unaltered. There was a small reduction in anger (25% +/- 18%), but other moods were unchanged. Plasma leucine (3-fold) and essential amino acid (47%) concentrations were elevated postexercise. Net nitrogen balance trended mildly negative in both conditions (mean +/- SD: leucine-protein, -20 +/- 46 mg.kg(-1) per 24 h; control, -25 +/- 36 mg.kg(-1) per 24 h). The ingestion of a leucine protein supplement along with other high-carbohydrate food following intense training on consecutive days enhances subsequent high-intensity endurance performance and may attenuate muscle membrane disruption in well-trained male cyclists. PMID- 21609287 TI - Resistance exercise training does not affect postexercise hypotension and wave reflection in women with fibromyalgia. AB - The purpose of this study was to assess the effects of resistance exercise training (RET) on aortic wave reflection and hemodynamics during recovery from acute resistance exercise in women with fibromyalgia (FM) and healthy women (HW). Nine women with FM (aged 42 +/- 5 years; mean +/- SD) and 14 HW (aged 45 +/- 5 years) completed testing at baseline and after 12 weeks of whole-body RET that consisted of 3 sets of 5 exercises. Heart rate (HR), digital blood pressure (BP, plethysmography), aortic BP, and wave reflection (radial tonometry) were assessed before and 20 min after acute leg resistance exercise. Aortic and digital diastolic blood pressure (DBP) were significantly decreased (p < 0.05) and aortic and digital pulse pressures (PP) were significantly increased (p < 0.05) after acute exercise before RET. Acute resistance exercise had no effect on HR, wave reflection (augmentation index and reflection time), digital, or aortic systolic BP. RET improved muscle strength without affecting acute DBP and PP responses. Acute resistance exercise produces postexercise diastolic hypotension without affecting systolic blood pressure, HR, and wave reflection responses in women with and without FM. RET does not alter resting and postexercise hemodynamics and aortic wave reflection in premenopausal women. PMID- 21609288 TI - Serum 25OH vitamin D level, femur length, and risk of type 2 diabetes among adults. AB - The objective of this study was to examine the relationship between serum 25 hydroxyvitamin-D (25(OH)D) and femur length (FL) and their risk in association with diabetes in adults. A total of 3983 adults aged 20+ years from the National Health and Nutrition Examination Survey (2001-2002, 2003-2004) who had no missing measurements of FL or 25(OH)D were used in this analysis. Diabetes was defined as either being diagnosed with diabetes or an overnight fasting plasma glucose of (FPG) > 125 mg.dL(-1). Prediabetes was defined as having an FPG of 100 mg.dL(-1) < FPG < 126 mg.dL(-1). In addition, each individual was grouped into a sex specified quintile of FL (Q1-Q5). Overall, approximately 11% of males and 9% of females had diabetes and 33% of males and 20% of females had prediabetes. Although the Pearson correlation between 25(OH)D and FL was weak, since FL changed from Q1 to Q5, the adjusted means of 25(OH)D in both sexes increased, while the adjusted means of FPG, insulin, glycohemoglobin, and the adjusted prevalence of diabetes were all decreased (p for trends <0.05). Logistic regression results indicate that the levels of 25(OH)D and FL were independently and negatively associated with the prevalence of diabetes, unaffected by other known risk factors. Among those without diabetes we observed the same trends. An increase in the means of 25(OH)D and a decreased prevalence of prediabetes were observed with FL changing from Q1 to Q5. Both 25(OH)D and FL are independently associated with diabetes risk in adults. However, the novel hypothesis of this association needs further research. PMID- 21609289 TI - Effect of electrical stimulation on lipolysis of human white adipocytes. AB - The goal of the present study was to investigate the effect of 30 min of electrical stimulation on the activation of lipolysis in human white adipocytes. Two stimulation protocols (S1, S2) were conducted in vitro on isolated human white adipocytes. Subcutaneous adipose tissue was obtained from female subjects undergoing abdominal adipose tissue reduction. Adipose tissue of 10 female subjects (mean age, 38.7 +/- 9.1 years) and 6 female subjects (mean age, 37.2 +/- 11.3 years) was obtained for S1 and S2, respectively. All subjects fasted overnight before tissue removal. The control conditions were a basal and a beta adrenergic stimulation (isoproterenol (ISO), 10(-6) mol.L(-1)) of lipolysis. For S1, the 3 electrostimulation conditions consisted of a monopolar square-wave pulse current for 30 min at intensities of 4, 8, and 20 mA, respectively. In S2, the 2 electrostimulation conditions consisted of a bipolar square-wave alternating current for 30 min at intensities of 4 and 6 mA, respectively. Fat cell lipolysis was measured by quantifying the release of glycerol from adipocytes for 3 trials in each experimental condition. For S1, 4 mA significantly increased lipolysis 1.5 times over basal values (p <= 0.01), 8 mA and 20 mA did not increase lipolysis significantly, and no significant difference (p > 0.05) was found between ISO and 4 mA. For S2, 4 mA (p <= 0.05) and 6 mA (p <= 0.01) significantly increased lipolysis by 1.8 and 2.3 times above basal, respectively. Our results demonstrate that both monopolar (4 mA) and bipolar (4 and 6 mA) electrical stimulations significantly activated in vitro lipolysis. Our findings suggest the existence of a new lipolytic pathway that may involve K(v) channels shown to exist in human white adipocytes. PMID- 21609290 TI - Hybrid training of voluntary and electrical muscle contractions decreased fasting blood glucose and serum interleukin-6 levels in elderly people: a pilot study. AB - A new muscle-training method, "hybrid training", utilizing combined voluntary and electrical muscle contractions, is effective for increasing muscle mass and force on lower extremities in elderly people. Although skeletal muscle regulates glucose metabolism, partly by releasing interleukin (IL)-6, the effects of hybrid training on glucose metabolism remains unclear. The aim of this study was to investigate the effects of hybrid training on glucose metabolism and serum IL-6 levels in elderly people. Hybrid training was performed on 7 elderly subjects. Both quadriceps and hamstrings were contracted voluntarily or electrically at the same time for 19 min twice a week. The effects on glucose metabolism and serum IL 6 levels were evaluated after 12 weeks of hybrid training. All of the subjects completed the study, and no severe adverse events developed during the study period. There were no significant differences in body mass index, serum insulin levels, homeostasis model assessment for insulin resistance values, or hemoglobin A1c values after hybrid training. However, fasting blood glucose levels were significantly decreased after hybrid training (114 +/- 13 vs. 103 +/- 9 mg.dL( 1); p = 0.0340). In addition, all 7 subjects showed a decrease in serum IL-6 levels after hybrid training, and this decrease was statistically significant (44.0 +/- 35.6 vs. 14.6 +/- 10.5 pg.mL(-1); p = 0.0180). Furthermore, there was a significant correlation between changes in serum IL-6 levels and changes in fasting blood glucose levels (rho = 0.883; p = 0.0306). In this study, we showed the safety and good adherence of hybrid training for lower extremities in elderly people. Furthermore, hybrid training decreased fasting blood glucose and serum IL 6 levels in elderly people. PMID- 21609291 TI - Effect of eccentric exercise velocity on akt/mtor/p70(s6k) signaling in human skeletal muscle. AB - It has been suggested that muscle tension plays a major role in the activation of intracellular pathways for skeletal muscle hypertrophy via an increase in mechano growth factor (MGF) and other downstream targets. Eccentric exercise (EE) imposes a greater amount of tension on the active muscle. In particular, high-speed EE seems to exert an additional effect on muscle tension and, thus, on muscle hypertrophy. However, little is known about the effect of EE velocity on hypertrophy signaling. This study investigated the effect of acute EE-velocity manipulation on the Akt/mTORCI/p70(S6K) hypertrophy pathway. Twenty subjects were assigned to either a slow (20 degrees .s(-1); ES) or fast EE (210 degrees .s(-1); EF) group. Biopsies were taken from vastus lateralis at baseline (B), immediately after (T1), and 2 h after (T2) the completion of 5 sets of 8 repetitions of eccentric knee extensions. Akt, mTOR, and p70(S6K) total protein were similar between groups, and did not change postintervention. Further, Akt and p70(S6K) protein phosphorylation were higher at T2 than at B for ES and EF. MGF messenger RNA was similar between groups, and only significantly higher at T2 than at B in ES. The acute manipulation of EE velocity does not seem to differently influence intracellular hypertrophy signaling through the Akt/mTORCI/p70S6K pathway. PMID- 21609292 TI - Physical activity in Ontario preschoolers: prevalence and measurement issues. AB - Early childhood is a critical period for the development of active living behaviours; however, very little is known about the physical activity levels of preschoolers from Canada. The objectives of this study were to (i) examine physical activity in a sample of Ontario preschoolers by using high-frequency accelerometry to determine activity and step counts; (ii) assess the relationship between step counts and physical activity; (iii) examine the influence of epoch length or sampling interval on physical activity; and (iv) compare measured physical activity to existing recommendations. Thirty 3- to 5-year-old children wore accelerometers to monitor habitual physical activity in 3-s epochs over a 7 day period. Preschoolers engaged in an average of 220 min of daily physical activity, 75 min of which were spent in moderate-to-vigorous physical activity (MVPA), and they accumulated 7529 +/- 1539 steps.day(-1). Preschoolers who engaged in more MVPA also took more steps on a daily basis (r = 0.81, p < 0.001). Compared with a 3-s epoch, sampling intervals of 15, 30, and 60 s resulted in an average of 2.9, 9.0, and 16.7 missed minutes of MVPA per day, respectively. All 30 preschoolers met the National Association for Sport and Physical Education recommendation of at least 120 min of total physical activity per day for preschool-age children. Our data highlight important methodological considerations when measuring physical activity in preschoolers and the need for preschool-specific physical activity guidelines for Canadian children. PMID- 21609293 TI - Lower oxidation of a high molecular weight glucose polymer vs. glucose during cycling. AB - We previously reported no difference in the oxidation rate of a high molecular weight glucose polymer (GP) vs. maltodextrin (8 kDa) during exercise; however, the ingestion rate (1.8 g.min(-1)) was above the glucose absorption-oxidation maxima (~1.0 g.min(-1)), possibly masking either faster gastric emptying of the GP and delivery to the circulation observed at rest or physical properties of the GP that might slow intestinal absorption. Therefore, we asked whether GP oxidation could be differentially affected when ingested at a lower rate (0.8 g.min(-1)). Eight cyclists performed three 150-min rides at 50% peak power while ingesting solutions containing 8% GP (500-750 kDa, 21 mosm.kg(-1)), 8% glucose (469 mosm.kg(-1)), or water. The exogenous carbohydrate oxidation rate was determined using stable isotope methodology and indirect calorimetry. Glucose and GP were oxidized on average at 0.54 g.min(-1) (coefficient of variation (CV) 37%) and 0.41 g.min(-1) (CV 60%), respectively, which equated to a moderate (effect size) reduction of 24% (90% confidence limits: +/-22%) with GP. The endogenous carbohydrate oxidation rate with glucose (1.04 g.min(-1); CV 68%) was not clearly different from GP (15%; 90% confidence limits: +/-24%) and total carbohydrate oxidation rate was not affected. Plasma glucose concentration was 8.3% lower (+/ 7.0%, moderate) and nausea 0.4 units higher (+/-0.4 units, moderate) with GP vs. glucose. To conclude, the oxidation rate of GP when ingested below the glucose absorption-oxidation maxima is slower than glucose. Further work could determine the physical properties of the carbohydrate and (or) physiological mechanism determining this response. Meanwhile, utility of the glucose polymer over glucose or maltodextrin in energy beverages appears limited. PMID- 21609295 TI - CCR1 as a target for multiple myeloma. AB - INTRODUCTION: By directing cell trafficking, differentiation and growth, chemokines modulate the immune response and are involved in the pathogenesis of autoimmune diseases and cancers, including multiple myeloma (MM). MM, the second most common hematological malignancy in the US, is characterized by disordered plasma cell growth within the bone marrow microenvironment. CCL3 and its receptors, CCR1 in particular, play a central role in the pathogenesis of MM and MM-induced osteolytic bone disease. AREAS COVERED: This review describes the functional role of CCR1 in MM and the preclinical results observed with CCR1 antagonists. CCL3 and CCR1 stimulate tumor growth, both directly and indirectly, via upregulation of cell adhesion and cytokine secretion. In addition, they modulate the osteoclast/osteoblast balance, by inducing osteoclast differentiation and inhibiting osteoblast function. Targeting either ligand or receptor reverses these effects, leading to in vivo tumor burden control and prevention of osteolysis, as confirmed in both murine and humanized mouse models. EXPERT OPINION: These promising data set the stage for clinical trials to assess the effects of CCR1 inhibitors in MM. The success of these studies depends on the development of novel antagonists with improved chemical/physical properties and careful selection of the patient population who may benefit the most from these agents. PMID- 21609296 TI - Expressive vocabulary acquisition in children with intellectual disability: speech or manual signs? AB - BACKGROUND: The aim of this study was to examine the degree to which children with intellectual disability (ID) depend on manual signs during their expressive vocabulary acquisition, in relation to child and social-environmental characteristics. METHOD: Expressive vocabulary acquisition in speech and manual signs was monitored over a 2-year period in 23 children with ID using parent report. The children's cognitive, communicative, and vocabulary comprehension skills were measured at baseline. Speech-language pathologists' and parents' use of and attitudes towards manual signs were measured using self-report. RESULTS: Four distinct profiles of vocabulary acquisition were evident. Those children who initially demonstrated the most significant cognitive, communicative, and comprehension delays acquired the smallest expressive vocabularies during follow up, yet these variables were not related to the children's degree of dependence on manual signs. CONCLUSIONS: Specific cognitive, communicative, and comprehension skills relate to vocabulary acquisition. The same skills that allow for speech development seem to be fundamental to the acquisition of manual signs. PMID- 21609297 TI - Vulnerability and protection talk: systemic therapy process with people with intellectual disability. AB - BACKGROUND: Vulnerability and protection are key concepts within the literature relating to systemic therapy for people with an intellectual disability (ID). This paper explores the processes by which these concepts were discussed in systemic therapy sessions. METHOD: Four videotapes of systemic therapy sessions were evaluated using a qualitative design, incorporating thematic and conversation analysis. The videotapes were drawn from systemic therapy sessions with 3 families with an adult with ID. RESULTS: Vulnerability and protection themes were identified within the content of therapeutic conversations, including protection from the disability and its consequences; protection from peers, siblings, and the world at large; and protection from emotionally sensitive topics. Protective strategies were also used by all system members through the process of therapy. Key strategies were topic switch and reversals. CONCLUSIONS: Protection is a key issue. Clinical practice could be enhanced if therapists reflect on the strategies they employ in addressing protection effectively. PMID- 21609298 TI - Choice processes and satisfaction with care according to parents of children and young adults with intellectual disability in The Netherlands. AB - BACKGROUND: Despite the expressed desire for access to information on care providers and increased availability of this information, the use of available information falls short of expectations. We lack research on the decision-making processes and on how these processes are influenced. A study that employs "real life" decisions is necessary. METHODS: Our experimental study design established the effects of providing decision-support information only (services/quality indicators) and providing a combination of information and personal decision making support (counselling/peer meetings) on the choice process and satisfaction with care. RESULTS: These forms of support affected the choice process, but did not affect satisfaction with care. Decision-support information combined with personal decision-making support led to less frequent switching of care providers and to more satisfaction with choice information. Parents make limited use of online decision-support information, but did use decision counselling. CONCLUSION: This population is better supported with an intensified personal approach rather than through the current generic approach using websites. PMID- 21609299 TI - Comorbidity of intellectual disability and mental disorder in children and adolescents: a systematic review. AB - BACKGROUND: Mental disorder and intellectual disability each accounts for substantial burden of disease. However, the extent of this co-occurrence varies substantially between reports. We sought to determine whether studies in children and/or adolescents with acceptably rigorous methods can be distinguished from existing reports, and whether key risk factors could be ascertained. METHOD: Published studies investigating the prevalence of mental disorders in children and/or adolescents with intellectual disability were reviewed. RESULTS: Nine studies with acceptable methods were identified, 4 which compared the prevalence of mental disorder in populations of those with and without intellectual disability, and a further 5 studies that estimated the rates of mental disorder in those with intellectual disability were identified. Collectively, these studies demonstrate rates of comorbidity for children and adolescents between 30 and 50% with a relative risk of mental disorder associated with intellectual disability ranging from 2.8-4.5. The risks for this comorbidity associated with age, gender, severity of intellectual disability, and socioeconomic status remain uncertain. CONCLUSIONS: Appreciation of this comorbidity needs to be a fundamental component of both mental health and intellectual disability services. PMID- 21609300 TI - Trends in the proportion of students with a disability in Australian schools, 2000-2009. PMID- 21609302 TI - Pediatric pulmonary arterial hypertension: current and emerging therapeutic options. AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) is a rare disease in neonates, infants and children that is associated with significant morbidity and mortality. An adequate understanding of the controlling pathophysiologic mechanisms is lacking and although mortality has decreased as therapeutic options have increased over the past several decades, outcomes remain unacceptable. AREAS COVERED: This review summarizes the currently available therapies for neonates, infants and children with PAH and describes emerging therapies in the context of what is known about the underlying pathophysiology of the disease. EXPERT OPINION: All of the currently approved PAH therapies impact one of three endothelial-based pathways: nitric oxide-guanosine-3'-5'cyclic monophosphate, prostacyclin or endothelin-1. The beneficial effects of these agents may relate to their impact on pulmonary vascular tone, and/or their antiproliferative and antithrombotic properties. Fundamental advances in PAH therapy are likely to relate to: i) a better understanding of PAH subpopulations, allowing for therapies to be better tailored to individual patients and pathophysiologic processes; and ii) therapies that promote the regression of advanced structural remodeling. PMID- 21609303 TI - Anti-inflammatory properties from isolated compounds of Cyclolepis genistoides. AB - CONTEXT: Cyclolepis genistoides D. Don (Asteraceae) is an Argentinean endemic shrub, known by the vernacular name "palo azul" or "matorro negro". It is widely used in folk medicine as a diuretic, an antirheumatic, and an antispasmodic agent. OBJECTIVE: The aim of this work was to describe the activity of two isolated compounds of C. genistoides, oleanolic acid (1) and deacylcynaropicrin (2), using the carrageenan-induced paw edema method in mice. MATERIALS AND METHODS: Aerial parts of C. genistoides were dried, powdered, and extracted with petroleum ether, ethyl acetate, dichloromethane, and methanol for 48 h. The fractions obtained from the ethyl acetate extract yielded oleanolic acid, while deacylcynaropicrin was obtained according to Abdei-Mogib et al. Structures were elucidated by 1H-NMR and 13C-NMR. The products were administered intraperitoneally at doses of 40, 75, and 100 mg/kg. RESULTS AND DISCUSSION: Compound 1 exhibited significant activity during the first 7 h of the inflammatory phase (at 1, 3, 5, and 7 h), exercising its inhibitory action on inflammation mediated by histamine, prostaglandins, serotonin, and kinins, while compound 2 showed a significant inhibition at 3 and 5 h contributing to this effect, acting in the intermediate phase. CONCLUSIONS: According to the results of this work, the intraperitoneal administration of oleanolic acid and deacylcynaropicrin isolated from the aerial parts of C. genistoides produced a significant inhibition of carrageenan-induced inflammation at doses of 75 and 100 mg/kg. These results give support to the use of this plant as an anti inflammatory in traditional medicine. PMID- 21609304 TI - Formulation and comparative evaluation of poly herbal anti-acne face wash gels. AB - CONTEXT: Rauvolfia serpentina (L). Benth. ex Kurz. (Apocynaceae) possessing antibacterial properties are widely used in modern herbal medicines. Curcuma longa L. (Zingiberaceae), a readily available antiseptic, possess antioxidant, antibacterial, blood purifying and antiinflammatory properties and used in various skin creams. Azadirachta indica A. Juss. (Meliaceae) possess astringent, antiviral, discutient, stimulant and antibacterial properties and works excellently well against acne and keeps the skin healthy. OBJECTIVE: Acne is the common skin problem that 85% of the teenagers face today. In this study, poly herbal anti-acne face wash gels were prepared using two polymers Carbopol and hydroxy propyl methyl cellulose (HPMC) along with the extracts of plants Rawvolfia serpentina, Curcuma longa, and Azadiracta indica. MATERIALS AND METHODS: The gel formulations were prepared in four different concentrations of 50, 100, 200 mg/ml as Gel-CRB 100, Gel-HPMC 50, Gel-HPMC 100, Gel-HPMC 200, respectively. The formulations were tested for the anti-acne activity by turbidimetric method. RESULTS: RESULTS showed that the gels were non-irritant, stable and posses anti-acne activity. The efficacy when tested with a standard was almost same to that of Clindamycin gel. DISCUSSION AND CONCLUSION: From this study, Gel-HPMC 100 was proved to be stable and considered as an effective herbal formulation for acne treatment. PMID- 21609305 TI - Comparison of human bone marrow mononuclear cell isolation methods for creating tissue-engineered vascular grafts: novel filter system versus traditional density centrifugation method. AB - INTRODUCTION: We created the first tissue-engineered vascular graft (TEVG) to be successfully used in humans. The TEVG is made by seeding autologous bone marrow derived mononuclear cells (BM-MNCs) onto a biodegradable tubular scaffold fabricated from polyglycolic-acid mesh coated with a 50:50 copolymer of poly-L lactide and-E-caprolactone. In the initial clinical study, the BM-MNCs were isolated using a Ficoll density centrifugation method. Use of this cell isolation technique is problematic in that it is performed using an open system and therefore is susceptible to contamination. As a first step toward creating a closed system for assembling a TEVG, we evaluated the use of a filter-based method for isolating BM-MNCs and compared it to density centrifugation in Ficoll. METHODS: BM-MNCs were isolated from human BM using density centrifugation in Ficoll or a filter-based method. BM-MNCs were seeded onto biodegradable tubular scaffold and incubated for 24 h before implantation. The TEVG were implanted as inferior vena cava interposition grafts in SCID/bg mice (n=24) using microsurgical technique. Grafts were followed with ultrasonography and computed tomography-angiography. Ten weeks after implantation the TEVG were explanted and examined using histology and immunohistochemistry. RESULTS: Both methods isolated similar number of cells (Ficoll: 8.5+/-6.6*10(6)/mL, Filter: 6.6+/-3.5*10(6)/mL; p=0.686) with similar viability as assayed using fluorescence-activated cell sorting (FACS) (Ficoll: 97.0%+/-1.5%, Filter: 95.9%+/-3.0%; p=0.339). FACS analysis demonstrated that the fraction of lymphocytes and monocytes to total cells was lower in the filter group (CD4 in Ficoll: 8.9%+/-1.1%, CD4 in Filter: 3.5%+/-0.8%; p=0.002, CD8 in Ficoll: 9.4%+/-2.1%, CD8 in Filter: 3.9%+/-1.4%; p=0.021, Monocyte in Ficoll: 6.9%+/-1.0%, Monocyte in Filter: 2.7%+/-1.0%; p=0.008), consistent with granulocyte contamination (Ficoll: 46.6+/-2.7*10(6)/mL, Filter: 58.1+/-5.2*10(6)/mL; p<0.001). The ratio of stem cells to BM-MNCs was comparable between groups. There were no statistically significant differences with regard to TEVG patency and morphology between groups. Both methods of cell isolation produced neovessels with similar histology. CONCLUSION: Filter-based BM MNC isolation is comparable to BM-MNC isolation using density centrifugation in Ficoll for TEVG assembly. The filter-based cell isolation technique has the added advantage of the potential to create a closed disposable system. PMID- 21609306 TI - Asthma and major depressive episode in adolescents in France. AB - RATIONALE: The association between asthma and anxiety disorders in teenagers is well documented, but data about the association with mood disorders are scarce. METHODS: We analyzed data from a cross-sectional study conducted among ninth grade schoolchildren in France in 2003-2004. The teenagers were selected by two stage sampling and interviewed by school doctors/nurses using a standardized questionnaire including questions about asthma and asthma-like symptoms. They also completed a self-administered questionnaire in which the occurrence of major depressive episodes (MDEs) during the past 12 months was assessed by the Composite International Diagnostic Interview-Short Form. RESULTS: A total of 7000 teenagers (mean age 15.1 years) were included. The prevalence of wheezing in the past 12 months was 10.0% and that of current asthma (wheezing in the past 12 months in children who had already had asthma attacks, or treatment for wheezing or asthma in the past 12 months) was 8.5%. The prevalence of MDE during the past year was 14.2% in teenagers with current asthma versus 9.2% among the others. The association between current asthma and past-year MDE remained significant after adjustment for age, gender, family structure, and the father's employment status. Asthma was uncontrolled (at least four attacks of wheezing, one awakening per week due to wheezing, one severe wheezing, four unplanned medical visits, or one hospitalization for a wheezing attack in the past year) in more than half (58.3%) of asthmatic teenagers with an MDE in the past year versus 35.3% of those without an MDE. CONCLUSION: Asthma is associated with a higher prevalence of MDE. Among adolescents with asthma, MDE is associated with poorer asthma control. These findings highlight the need for a comprehensive care management of asthma in France that takes the psychological dimension into account. PMID- 21609308 TI - In vitro evaluation of chitosan coated- and uncoated-calcium alginate beads containing methyl salicylate-lactose physical mixture. AB - CONTEXT: Methyl salicylate-lactose physical mixture (1:1 and 1:1.5 ratios) was incorporated into calcium alginate beads by a coacervation method involving an ionotropic gelation/polyelectrolyte complexation approach. OBJECTIVES: This study aims to determine the influence of chitosan coating over the beads on drug entrapment efficiency (DEE) and release characteristics in artificial saliva compared to that of the uncoated beads. RESULTS AND DISCUSSION: Changes in formulation parameters (gelation time, concentrations of Ca(2+) and alginate) resulted in decrease in DEE of chitosan-uncoated beads (p < 0.05). This is due to the combined effects of drug leach-out from the physical mixture by Ca(2+) ions, alginate gel matrix cross-linking and free drug diffusion from chitosan-uncoated beads. However, an increment in the DEE was seen for chitosan-coated beads. A rapid drug release profile was noted for uncoated beads, but for chitosan-coated beads a sustained release profile was depicted depending upon the coating conditions. Chitosan-coated beads had reduced swelling and erosion properties and thus behaved as a physical barrier to drug release. Shifting from anomalous transport type to Fickian transport confirmed the formation of physical barrier onto chitosan-coated beads. CONCLUSION: Calcium alginate beads could be used as a controlled-release system for methyl salicylate-lactose physical mixture. PMID- 21609310 TI - Human dental pulp cells: a new source of cell therapy in a mouse model of compressive spinal cord injury. AB - Strategies aimed at improving spinal cord regeneration after trauma are still challenging neurologists and neuroscientists throughout the world. Many cell based therapies have been tested, with limited success in terms of functional outcome. In this study, we investigated the effects of human dental pulp cells (HDPCs) in a mouse model of compressive spinal cord injury (SCI). These cells present some advantages, such as the ease of the extraction process, and expression of trophic factors and embryonic markers from both ecto-mesenchymal and mesenchymal components. Young adult female C57/BL6 mice were subjected to laminectomy at T9 and compression of the spinal cord with a vascular clip for 1 min. The cells were transplanted 7 days or 28 days after the lesion, in order to compare the recovery when treatment is applied in a subacute or chronic phase. We performed quantitative analyses of white-matter preservation, trophic-factor expression and quantification, and ultrastructural and functional analysis. Our results for the HDPC-transplanted animals showed better white-matter preservation than the DMEM groups, higher levels of trophic-factor expression in the tissue, better tissue organization, and the presence of many axons being myelinated by either Schwann cells or oligodendrocytes, in addition to the presence of some healthy-appearing intact neurons with synapse contacts on their cell bodies. We also demonstrated that HDPCs were able to express some glial markers such as GFAP and S-100. The functional analysis also showed locomotor improvement in these animals. Based on these findings, we propose that HDPCs may be feasible candidates for therapeutic intervention after SCI and central nervous system disorders in humans. PMID- 21609311 TI - Topoisomerase I inhibitor SN-38 effectively attenuates growth of human non-small cell lung cancer cell lines in vitro and in vivo. AB - The effect of SN-38 was evaluated on multiple lung cancer cell lines. It inhibits anchorage-dependent and -independent growth as monitored by MTT and soft agar colony assay, respectively. SN-38 collapsed the mitochondrial membrane potential (MMP), arrested cells in S- and G2-phases of the cell cycle, and induced apoptosis via activation of caspase 3 and PARP. A single injection of 2 mg/kg body weight of SN-38 caused a significant reduction of lung cancer xenografts. These findings indicate that SN-38 induces apoptosis in the lung cancer cells effectively. Thus, SN-38 can potentially be an effective therapeutic agent against lung cancer. PMID- 21609312 TI - Effect of ukrain on cell survival and apoptosis in the androgen-independent prostate cancer cell line PC-3. AB - Prostate cancer is the most common malignancy and the second leading cause of cancer death in the male population in developing countries. Ukrain is a reaction product of different alkaloids from Chelidoniummajus L. (celandine) conjugated with thiophosphoric acid, which has cytotoxic effects on various malignant cells. In the present study, cell viability was assessed using the dimethyl thiazolyl tetrazolium bromide (MTT)method in PC-3 cells after treatment with Ukrain. The IC(50) value was observed in 10 MUg concentration of Ukrain. Bax, Bad, and FasL mRNA expression was analyzed by reverse transcriptase-polymerase chain reaction, and protein expressions of p-Akt, Bcl-2, and caspase 10 were determined by western-blot analysis. Nuclei were stained with 4',6-diamidino-2-phenylindole, dihydrochloride (DAPI). Ukrain significantly increased the pro-apoptotic mRNA expression of Bad, Bax, and FasL; decreased the cell survival protein p-Akt and the anti-apoptotic protein Bcl-2; and increased the protein levels of cleaved poly(ADP)-ribose polymerase (PARP) and caspase-10.The results of this study suggest that Ukrain decreases the cell survival of androgen-independent prostate cancer cells and induces their apoptosis, thus supporting its use as a therapeutic drug for the treatment of prostate cancer PMID- 21609313 TI - Oleanolic acid induces apoptosis by modulating p53, Bax, Bcl-2 and caspase-3 gene expression and regulates the activation of transcription factors and cytokine profile in B16F. AB - The objective of this study was to assess the effect of OA, a triterpene on inducing apoptosis in B16F-10 melanoma cells. Treatment of B16F-10 cells with nontoxic concentration of OA showed the presence of apoptotic bodies and induced DNA fragmentation in a dose-depended manner. Cell cycle analysis and TUNEL assay also confirmed the observation. The apoptotic genes p53, BAX, caspase-9, and caspase-3 were found upregulated in oleanolic acid-treated cells, whereas the antiapoptotic gene Bcl-2 was downregulated. OA treatment also showed a downregulation of Cyclin D1 expression and upregulated p21 and p27 gene expression in B16F-10 melanoma cells. OA inhibited the activation and nuclear translocation of transcription factors such asNF-kappaB, c-fos, ATF-2, and CREB 1, and also downregulated the production and expression of TNF-alpha, IL-1beta,IL 6, and GM-CS. These results suggest that OA induces apoptosis through activating the p53-induced caspase mediated proapoptotic pathway and suppression of the NF kappaB-nduced Bcl-2-ediated antiapoptotic pathway PMID- 21609314 TI - Andrographolide inhibits human umbilical vein endothelial cell invasion and migration by regulating MMP-2 and MMP-9 during angiogenesis. AB - Angiogenesis, the formation of new blood vessels from preexisting blood vessels, is essential for tumor progression and metastasis. Studies using human umbilical vein endothelial cells clearly demonstrated that administration of andrographolide significantly retarded endothelial cell proliferation, migration, and invasion and tube formation. Gelatin zymographic analysis showed the inhibitory effect of andrographolide on the activation of matrix metalloproteinases MMP-2 and MMP-9. The study reveals that andrographolide treatment could inhibit the activation and nuclear translocation of p65, p50, and c-Rel subunits of nuclear factor-kappaB, and other transcription factors such as c-fos, activated transcription factor-2, and cyclic adenosine monophosphate response element-binding protein in B16F-10 melanoma cells. All these results demonstrate that andrographolide inhibits in vitro angiogenesis by inhibiting MMP 2 and MMP-9, and also by regulating the nuclear translocation of transcription factors. PMID- 21609315 TI - Modulatory influence of Phyllanthus niruri on oxidative stress, antioxidant defense and chemically induced skin tumors. AB - The present study evaluates the modulatory potential of Phyllanthus niruri on chemically induced skin carcinogenesis, and its influence on oxidative stress and the antioxidant defense system. Oral administration of P. niruri extract (PNE), during peri- (Gr. III), post- (Gr. IV), or peri- and post- (Gr. V) initiational stages of 7,12-dimethylbenz(a) anthracene (DMBA)-croton oil-induced papillomagenesis considerably reduced tumor burden to 4.20, 4.00, and 3.33(positive control value 6.20); cumulative number of papillomas to 21, 16, and 10, respectively, (positive control value 62); and incidence of mice bearing papillomas to 50, 40, and 30%, respectively (positive control value 100%), but significantly increased the average latent period to 10.14, 10.62, and 11.60, and inhibition of tumor multiplicity to 66, 74,and 83%, respectively. Enzyme analysis of skin and liver showed a significant (p <= 0.05, <= 0.01, <= 0.001) elevation in antioxidant parameters such as superoxide dismutase, catalase, glutathione, and vitamin C in PNE-treated groups (Gr. III-V) when compared with the carcinogen treated control (Gr. II). The elevated level of lipid peroxidation in the carcinogen-treated positive control group was significantly (p <= 0.05, <= 0.01, <= 0.001) inhibited by PNE administration. These results indicate that P. niruri extract has potentiality to reduce skin papillomas by enhancing antioxidant defense system. PMID- 21609316 TI - Radioprotection of Swiss albino mice by Prunus avium with special reference to hematopoietic system. AB - Prunus avium (family Rosaceae) has been used ethnomedicinally for the treatment of many diseases,but its radioprotective efficacy has hardly been explored. Presence of high anthocyanin content and phenolic compound with good antioxidative capacity has been reported by researchers. Its radioprotective effect against 5, 7, 10, and 12 Gygamma radiation was evaluated by 30 day survival assay. Regression analysis yielded LD(50/30) 5.81 and 9.43Gy for irradiated only and (P. avium fruit extract) PAE + radiation groups, respectively. The dose reduction factor was computed as 1.62. For biochemical and hematological studies, Swiss albino mice were divided into four groups: (i) control (vehicle treated), (ii) PAE treated (450 mg kg/day for 15 consequetive days), (iii) irradiated (5 Gy), and (4) PAE + irradiated. The irradiation of animals resulted in a significant elevation of lipid peroxidation and depletion in glutathione and protein levels in blood serum and spleen, which could be significantly checked by administration of PAE. Radiation-induced deficit in blood sugar, cholesterol, and hematological constituents could also be modulated by supplementation of PAE before and after irradiation. The possible prophylactic and therapeutic action noted by P. avium against radiation induced metabolic disorders may be due to synergistic action of various antioxidants, minerals, vitamins, etc., present in the fruit. Further mechanistic studies aimed at identifying the role of major ingredients in the extract are needed. PMID- 21609317 TI - In utero and lactation exposure of mice to pan masala: effect on dams and pregnancy outcome. AB - Pan masala, a chewing mixture, is a popular alternate of areca nut/tobacco/betal quid in various parts of the world. In view of embryotoxic effects of areca nut and tobacco, it is hypothesized that in utero and lactational exposure to pan masala plain (PMP, containing areca nut as major ingredient), and pan masala with tobacco (PMT) can also have similar effects. To investigate this, pregnant female Swiss albino mice were treated with 3 and 6% of PMP and PMT from gestation day (GD) 0, 6, and 14 until lactation. They were weighed during pregnancy and lactation. At parturition, pups were counted, weighed, and measured. At weaning, dams were sacrificed for implantation count. Three percent and 6% PMT considerably reduced female fertility. Gestation length was lower in all the pan masala-treated mice, which was significant at 3 and 6% PMT treatment from GD 0. Pups born to pan masala-treated dams had significantly low birth weight at 3 and 6% PMT in GD 0 and GD 6, and 6% PMT in the GD 14 group. Sex ratio declined in the GD 0 pan masala-treated group. Neonatal death was observed in all the pan masala treated groups from GD 0 and 6% of both PMP- and PMT-treated groups from GD 14 with respect to control. Weaning index was considerably altered in GD 0 and 14 pan masala-treated groups. Postimplantation loss was considerably high in all the pan masala-treated groups. The data points toward the in utero and lactational fetotoxic effects of pan masala treatment, mainly PMT. PMID- 21609318 TI - Comparative evaluation of the cytotoxic and apoptotic potential of Poecilocerus pictus and Calotropis gigantea. AB - Calotropis gigantea, the giant milkweed, is traditionally used for the treatment of cancer and in Ayurvedic medicine as an anti-helminthic, anti-pyretic, and anti malarial agent. Poecilocerus pictus, an orthopteran insect, feeds on C. gigantea and both are known to possess cardiac glycosides. The increasing reports on the specific cytotoxicity of cardiac glycosides on human tumor cell lines led us to attempt characterization and comparative evaluation of cardenolides in both the insect and plant extracts for their anti-tumor and apoptotic potential.Chemical characterization using high-performance thin layer chromatography, ultraviolet and infrared spectra analysis confirmed the presence of cardiac glycosides, but differences in the components of the insect extract were indicative of biotransformation. The cytotoxicity studies revealed a more potent trend for the insect extract compared with the plant extract on A549 and COLO205 cells. There was a considerably lesser measure of toxicity on WI38 cells and peripheral blood lymphocytes, whereas B16F1 remained unaffected by both extracts. DNA ploidy analysis on COLO205 indicated that both extracts induced dose-dependent apoptosis. Therefore, both the insect and the plant extracts differentiate between human cancer cells and normal cells and exhibit species specificity. Further investigations are necessary to establish these extracts as promising lead candidates for anti-neoplastic activity. PMID- 21609319 TI - Multifunctional nanoparticles, nanocages and degradable polymers as a potential novel generation of non-invasive molecular and cellular imaging systems. AB - In recent years, polymeric scaffolds have been used in several biomedical applications for delivery of drugs or other biologically relevant molecules. Polymeric nanostructures display different (and in some cases more powerful) properties respect to bulk materials. This, lead academic researchers and industry to cooperate in developing pioneering nanostructured materials for industrial and biomedical applications. Moreover, the preparation and use of systems with multiple (multifunctional) properties (i.e., bioconjugation with superparamagnetic, fluorescent or targeting molecules) is positioned to become a viable and innovative tool for application in several clinical fields. Other nanostructured systems like nanocages and degradable nanoparticles, are emerging as potential innovative systems that could be exploited as multifunctional delivery vectors. This brief critical review is aimed at collecting and discussing some recent patents dealing with the preparation and use of multifunctional nanoparticles, nanocages and degradable nanoparticles in biomedicine and non-invasive bioimaging applications. Perspectives for a potential use of these multifunctional nanosystems in pediatries have been also discussed. PMID- 21609320 TI - GATA-4 transcription factor regulates hepatic hepcidin expression. AB - Hepcidin, a hormone mainly synthesized by hepatocytes and secreted in plasma, controls iron bioavailability. Thus, by inducing the internalization of the iron exporter ferroportin, it regulates iron release from macrophages, enterocytes and hepatocytes towards plasma. Abnormal levels of hepcidin expression alter plasma iron parameters and lead to iron metabolism disorders. Understanding the mechanisms controlling hepcidin (HAMP encodes hepcidin) gene expression is therefore an important goal. We identified a potential GATA-binding site within the human hepcidin promoter. Indeed, in hepatic HepG2 cells, luciferase experiments demonstrated that mutation of this GATA-binding site impaired the hepcidin promoter transcriptional activity in basal conditions. Gel-retardation experiments showed that GATA-4 could bind to this site. Co-transfection of a GATA 4 expression vector with a hepcidin promoter reporter construct enhanced hepcidin promoter transcriptional activity. Furthermore, modulation of GATA4 mRNA expression using specific siRNAs (small interfering RNAs) down-regulated endogenous hepcidin gene expression. Finally, we found that mutation of the GATA binding site impaired the interleukin-6 induction of hepcidin gene expression, but did not prevent the bone morphogenetic protein-6 response. In conclusion, the findings of the present study (i) indicate that GATA-4 may participate in the control of hepcidin expression, and (ii) suggest that alteration of its expression could contribute to the development of iron-related disorders. PMID- 21609321 TI - Function of MRP1/ABCC1 is not dependent on cholesterol or cholesterol-stabilized lipid rafts. AB - MRP1 (multidrug-resistance-related protein 1)/ABCC1 (ATP-binding cassette transporter C1) has been localized in cholesterol-enriched lipid rafts, which suggests a role for these lipid rafts and/or cholesterol in MRP1 function. In the present study, we have shown for the first time that nearly complete oxidation of free cholesterol in the plasma membrane of BHK-MRP1 (MRP1-expressing baby hamster kidney) cells did not affect MRP1 localization in lipid rafts or its efflux function, using 5-carboxyfluorescein diacetate as a substrate. Inhibition of cholesterol biosynthesis, using lovastatin in combination with RO 48-8071, an inhibitor of oxidosqualene cyclase, resulted in a shift of MRP1 out of lipid raft fractions, but did not affect MRP1-mediated efflux in Neuro-2a (neuroblastoma) cells. Short-term methyl-beta-cyclodextrin treatment was equally effective in removing free cholesterol from Neuro-2a and BHK-MRP1 cells, but affected MRP1 function only in the latter. The kinetics of loss of both MRP1 efflux function and lipid raft association during long-term methyl-beta-cyclodextrin treatment did not match the kinetics of free cholesterol removal in both cell lines. Moreover, MRP1 activity was measured in vesicles consisting of membranes isolated from BHK-MRP1 cells using the substrate cysteinyl leukotriene C4 and was not changed when the free cholesterol level of these membranes was either decreased or increased. In conclusion, MRP1 activity is not correlated with the level of free cholesterol or with localization in cholesterol-dependent lipid rafts. PMID- 21609322 TI - PPARalpha-LXR as a novel metabolostatic signalling axis in skeletal muscle that acts to optimize substrate selection in response to nutrient status. AB - LXR (liver X receptor) and PPARalpha (peroxisome-proliferator-activated receptor alpha) are nuclear receptors that control the expression of genes involved in glucose and lipid homoeostasis. Using wild-type and PPARalpha-null mice fed on an LXR-agonist-supplemented diet, the present study analysed the impact of pharmacological LXR activation on the expression of metabolically important genes in skeletal muscle, testing the hypothesis that LXR activation can modulate PPAR action in skeletal muscle in a manner dependent on nutritional status. In the fed state, LXR activation promoted a gene profile favouring lipid storage and glucose oxidation, increasing SCD1 (stearoyl-CoA desaturase 1) expression and down regulating PGC-1alpha (PPARgamma co-activator-1alpha) and PDK4 (pyruvate dehydrogenase kinase 4) expression. PPARalpha deficiency enhanced LXR stimulation of SCD1 expression, and facilitated elevated SREBP-1 (sterol-regulatory-element binding protein-1) expression. However, LXR-mediated down-regulation of PGC 1alpha and PDK4 was opposed and reversed by PPARalpha deficiency. During fasting, prior LXR activation augmented PPARalpha signalling to heighten FA (fatty acid) oxidation and decrease glucose oxidation by augmenting fasting-induced up regulation of PGC-1alpha and PDK4 expression, effects opposed by PPARalpha deficiency. Starvation-induced down-regulation of SCD1 expression was opposed by antecedent LXR activation in wild-type mice, an effect enhanced further by PPARalpha deficiency, which may elicit increased channelling of FA into triacylglycerol to limit lipotoxicity. Our results also identified potential regulatory links between the protein deacetylases SIRT1 (sirtuin 1) and SIRT3 and PDK4 expression in muscle from fasted mice, with a requirement for PPARalpha. In summary, we therefore propose that a LXR-PPARalpha signalling axis acts as a metabolostatic regulatory mechanism to optimize substrate selection and disposition in skeletal muscle according to metabolic requirement. PMID- 21609323 TI - Differential functions of phospholipid binding and palmitoylation of tumour suppressor EWI2/PGRL. AB - The tumour suppressor EWI2 associates with tetraspanins and regulates tumour cell movement and proliferation. The short cytoplasmic domain of EWI2 is positively charged; five out of the ten residues of this domain are basic. In the present study we demonstrated that the EWI2 cytoplasmic tail interacts specifically with negatively charged PIPs (phosphatidylinositol phosphates), but not with other membrane lipids. The PIPs that interact with EWI2 cytoplasmic tail include PtdIns5P, PtdIns4P, PtdIns3P, PtdIns(3,5)P(2) and PtdIns(3,4)P2. The binding affinity of PIPs to the EWI2 tail, however, is not solely based on charge because PtdIns5P, PtdIns4P and PtdIns3P have a higher affinity to EWI2 than PtdIns(3,5)P(2) and PtdIns(3,4)P(2) do. Mutation of either of two basic residue clusters in the EWI2 cytoplasmic tail abolishes PIP binding, and PIP binding is also determined by the position of basic residues in the EWI2 cytoplasmic tail. In addition, EWI2 is constitutively palmitoylated at the cytoplasmic cysteine residues located at the N-terminal of those basic residues. The PIP interaction is not required for, but appears to regulate, the palmitoylation, whereas palmitoylation is neither required for nor regulates the PIP interaction. Functionally, the PIP interaction regulates the stability of EWI2 proteins, whereas palmitoylation is needed for tetraspanin-EWI2 association and EWI2 dependent inhibition of cell migration and lamellipodia formation. For cell-cell adhesion and cell proliferation, the PIP interaction functions in opposition to the palmitoylation. In conclusion, the EWI2 cytoplasmic tail actively engages with the cell membrane via PIP binding and palmitoylation, which play differential roles in EWI2 functions. PMID- 21609324 TI - Metabolic effects and cost-effectiveness of aripiprazole versus olanzapine in schizophrenia and bipolar disorder. AB - OBJECTIVE: To assess the cost-effectiveness of aripiprazole versus olanzapine in the treatment of patients with schizophrenia or bipolar disorder in Sweden with focus on the metabolic impact of the treatments. METHOD: A Markov health-state transition model was developed. The risks of developing metabolic syndrome after one year of treatment with aripiprazole or olanzapine were derived from a pooled analysis of three randomised clinical trials. The subsequent risks of developing diabetes or coronary heart disease were based on previously published risk models. A societal perspective was applied, adopting a lifetime horizon. Univariate and probabilistic sensitivity analyses were conducted. RESULTS: Treatment with aripiprazole dominates over olanzapine in both schizophrenia and bipolar disorder. In schizophrenia, quality-adjusted life-years (QALYs) gained were 0.08 and cost savings Swedish kronor (SEK) 30,570 (USD 4000); in bipolar disorder, QALYs gained were 0.09 and cost savings SEK 28,450 (USD 3720). In probabilistic sensitivity analyses, aripiprazole resulted in a dominant outcome in 84% of cases in schizophrenia and in 77% of cases in bipolar syndrome. CONCLUSION: The significantly lower risk of developing metabolic syndrome observed with aripiprazole compared with olanzapine is associated with less risk of diabetes and cardiovascular morbidity and mortality that translates into lower overall treatment cost and improved quality of life over time. PMID- 21609325 TI - One vs two applications of chlorhexidine/ethanol for disinfecting the skin: implications for regional anaesthesia. AB - Chlorohexidine/ethanol is commonly used for skin disinfection before neuraxial procedures. Two applications of this solution have been advocated but no evidence exists to support this. Our aim was to ascertain whether two applications of chlorohexidine/ethanol solution are more effective than one for skin disinfection before neuraxial anaesthesia. A 4-cm diameter soya agar contact plate was applied to the skin of the lumbar region of 309 healthy volunteers, followed by a single spray application of chlorhexidine gluconate 0.5% w/v in 70% v/v denatured ethanol. This was allowed to dry and a second contact plate applied. The disinfectant was re-applied and after drying, a third contact plate applied. Agar plates were incubated at 37 degrees C for 24 h. No growth occurred in any plates after the first or second spray (p < 0.0001). We feel reassured that the current practice of using a single application of chlorhexidine/ethanol solution is sufficient to disinfect the skin before regional anaesthesia, particularly in the emergency situation when waiting for a second application to dry may add needless delay and risk translocation of excess chlorhexidine into the subarachnoid space. PMID- 21609327 TI - Designing payment for Collaborative Care for Depression in primary care. AB - OBJECTIVE: To design a bundled case rate for Collaborative Care for Depression (CCD) that aligns incentives with evidence-based depression care in primary care. DATA SOURCES: A clinical information system used by all care managers in a randomized controlled trial of CCD for older primary care patients. STUDY DESIGN: We conducted an empirical investigation of factors accounting for variation in CCD resource use over time and across patients. CCD resource use at the patient episode and patient-month levels was measured by number of care manager contacts and direct patient contact time and analyzed with count data (Poisson or negative binomial) models. PRINCIPAL FINDINGS: Episode-level resource use varies substantially with patient's time in the program. Monthly use declines sharply in the first 6 months regardless of treatment response or remission status, but it remains stable afterwards. An adjusted episode or monthly case rate design better matches payment with variation in resource use compared with a fixed design. CONCLUSIONS: Our findings lend support to an episode payment adjusted by number of months receiving CCD and a monthly payment adjusted by the ordinal month. Nonpayment tools including program certification and performance evaluation and reward systems are needed to fully align incentives. PMID- 21609328 TI - The impact of Medicare Part D on out-of-pocket costs for prescription drugs, medication utilization, health resource utilization, and preference-based health utility. AB - OBJECTIVES: To quantify the impact of Medicare Part D eligibility on medication utilization, emergency department use, hospitalization, and preference-based health utility among civilian noninstitutionalized Medicare beneficiaries. STUDY DESIGN: Difference-in-differences analyses were used to estimate the effects of Part D eligibility on health outcomes by comparing a 12-month period before and after Part D implementation using the Medical Expenditure Panel Survey. Models adjusted for sociodemographic characteristics and health status and compared Medicare beneficiaries aged 65 and older with near elderly aged 55-63 years old. PRINCIPAL FINDINGS: Five hundred and fifty-six elderly and 549 near elderly were included. After adjustment, Part D was associated with a U.S.$179.86 (p=.034) reduction in out-of-pocket costs and an increase of 2.05 prescriptions (p=.081) per patient year. The associations between Part D and emergency department use, hospitalizations, and preference-based health utility did not suggest cost offsets and were not statistically significant. CONCLUSIONS: Although there was a substantial reduction in out-of-pocket costs and a moderate increase in medication utilization among Medicare beneficiaries during the first year after Part D, there was no evidence of improvement in emergency department use, hospitalizations, or preference-based health utility for those eligible for Part D during its first year of implementation. PMID- 21609329 TI - Staffing ratios and quality: an analysis of minimum direct care staffing requirements for nursing homes. AB - OBJECTIVE: To study the impact of minimum direct care staffing (MDCS) requirements on nurse staffing levels, nurse skill mix, and quality. DATA SOURCES: U.S. nursing home facility data from the Online Survey Certification and Reporting (OSCAR) System merged with MDCS requirements. STUDY DESIGN; Facility level outcomes of nurse staffing levels, nurse skill mix, and quality measures are regressed on the level of nurse staffing required by MDCS requirements in the prior year and other controls using fixed effect panel regression. Quality measures are care practices, resident outcomes, and regulatory deficiencies. DATA EXTRACTION METHOD: Analysis used all OSCAR surveys from 1999 to 2004, resulting in 17,552 unique facilities with a total of 94,371 survey observations. PRINCIPLE FINDINGS: The effect of MDCS requirements varied with reliance of the nursing home on Medicaid. Higher MDCS requirements increase nurse staffing levels, while their effect on nurse skill mix depends on the reliance of the nursing home on Medicaid. MDCS have mixed effects on care practices but are generally associated with improved resident outcomes and meeting regulatory standards. CONCLUSIONS: MDCS requirements change staffing levels and skill mix, improve certain aspects of quality, but can also lead to use of care practices associated with lower quality. PMID- 21609330 TI - Modeling the impact of Medicare Advantage payment cuts on ambulatory care sensitive and elective hospitalizations. AB - OBJECTIVE: To assess relationships between changes in Medicare Advantage (MA) payment rates and Medicare beneficiary hospitalizations and to simulate the effects of scheduled payment cuts on ambulatory care sensitive (ACS) and elective hospitalization rates. DATA: State Inpatient Database discharge abstracts from Arizona, Florida, and New York merged with administrative Medicare enrollment and MA payment data. STUDY DESIGN: Retrospective, fixed effect regression analysis of the relationship between MA payment rates and rates of ACS and elective hospitalizations among Medicare beneficiaries in counties with at least 10,000 Medicare beneficiaries and 3 percent MA penetration from 1999 to 2005. PRINCIPAL FINDINGS: MA payment rates were negatively related to rates of ACS admissions. Simulations suggest that payment cuts could be associated with higher rates of ACS admissions. No relationship between MA payments and rates of elective hospitalizations was found. CONCLUSIONS: Reductions in MA payment rates may result in a small increase in ACS admissions. Trends in ACS admissions among chronically ill Medicare beneficiaries should be tracked following MA payment cuts. PMID- 21609331 TI - Medical spending and the health of the elderly. AB - OBJECTIVE: To estimate the relationship between variations in medical spending and health outcomes of the elderly. DATA SOURCES: 1992-2002 Medicare Current Beneficiary Surveys. STUDY DESIGN: We used instrumental variable (IV) estimation to identify the relationships between alternative measures of elderly Medicare beneficiaries' medical spending over a 3-year observation period and health status, measured by the Health and Activity Limitation Index (HALex) and survival status at the end of the 3 years. We used the Dartmouth Atlas End-of-Life Expenditure Index defined for hospital referral regions in 1996 as the exogenous identifying variable to construct the IVs for medical spending. DATA COLLECTION/EXTRACTION METHODS: The analysis sample includes 17,438 elderly (age >64) beneficiaries who entered the Medicare Current Beneficiary Survey in the fall of each year from 1991 to 1999, were not institutionalized at baseline, stayed in fee-for-service Medicare for the entire observation period, and survived for at least 2 years. Measures of baseline health were constructed from information obtained in the fall of the year the person entered the survey, and changes in health were from subsequent interviews over the entire observation period. Medicare and total medical spending were constructed from Medicare claims and self-reports of other spending over the entire observation period. PRINCIPAL FINDINGS: IV estimation results in a positive and statistically significant relationship between medical spending and better health: 10 percent greater medical spending over the prior 3 years (mean=U.S.$2,709) is associated with a 1.9 percent larger HALex value (p=.045; range 1.2-2.2 percent depending on medical spending measure) and a 1.5 percent greater survival probability (p=.039; range 1.2-1.7 percent). CONCLUSIONS: On average, greater medical spending is associated with better health status of Medicare beneficiaries, implying that across-the-board reductions in Medicare spending may result in poorer health for some beneficiaries. PMID- 21609332 TI - The molecular basis of quantitative variation in foliar secondary metabolites in Eucalyptus globulus. AB - Eucalyptus is characterized by high foliar concentrations of plant secondary metabolites with marked qualitative and quantitative variation within a single species. Secondary metabolites in eucalypts are important mediators of a diverse community of herbivores. We used a candidate gene approach to investigate genetic associations between 195 single nucleotide polymorphisms (SNPs) from 24 candidate genes and 33 traits related to secondary metabolites in the Tasmanian Blue Gum (Eucalyptus globulus). We discovered 37 significant associations (false discovery rate (FDR) Q < 0.05) across 11 candidate genes and 19 traits. The effects of SNPs on phenotypic variation were within the expected range (0.018 < r(2) < 0.061) for forest trees. Whereas most marker effects were nonadditive, two alleles from two consecutive genes in the methylerythritol phosphate pathway (MEP) showed additive effects. This study successfully links allelic variants to ecologically important phenotypes which can have a large impact on the entire community. It is one of very few studies to identify the genetic variants of a foundation tree that influences ecosystem function. PMID- 21609333 TI - On the multi-temporal correlation between photosynthesis and soil CO2 efflux: reconciling lags and observations. AB - Although there is increasing evidence of the temporal correlation between photosynthesis and soil CO(2) efflux, no study has so far tested its generality across the growing season at multiple study sites and across several time scales. Here, we used continuous (hourly) data and applied time series analysis (wavelet coherence analysis) to identify temporal correlations and time lags between photosynthesis and soil CO(2) efflux for three forests from different climates and a grassland. Results showed the existence of multi-temporal correlations at time periods that varied between 1 and 16 d during the growing seasons at all study sites. Temporal correlations were strongest at the 1 d time period, with longer time lags for forests relative to the grassland. The multi-temporal correlations were not continuous throughout the growing season, and were weakened when the effect of variations in soil temperature and CO(2) diffusivity on soil CO(2) efflux was taken into account. Multi-temporal correlations between photosynthesis and soil CO(2) efflux exist, and suggest that multiple biophysical drivers (i.e. photosynthesis, soil CO(2) diffusion, temperature) are likely to coexist for the regulation of allocation and transport speed of carbon during a growing season. Future studies should consider the multi-temporal influence of these biophysical drivers to investigate their effect on the transport of carbon through the soil-plant-atmosphere continuum. PMID- 21609334 TI - African trypanosomiasis. PMID- 21609335 TI - Intraperitoneal murine Echinococcus multilocularis infection induces differentiation of TGF-beta-expressing DCs that remain immature. AB - Intraperitoneal larval infection (alveolar echinococcosis, AE) with Echinococcus multilocularis in mice impairs host immunity. Metacestode metabolites may modulate immunity putatively via dendritic cells. During murine AE, a relative increase of peritoneal DCs (pe-DCs) in infected mice (AE-pe-DCs; 4% of total peritoneal cells) as compared to control mice (naive pe-DCs; 2%) became apparent in our study. The differentiation of AE-pe-DCs into TGF-beta-expressing cells and the higher level of IL-4 than IFN-gamma/IL-2 mRNA expression in AE-CD4+pe-T cells indicated a Th2 orientation. Analysis of major accessory molecule expression on pe-DCs from AE-infected mice revealed that CD80 and CD86 were down-regulated on AE-pe-DCs, while ICAM-1(CD54) remained practically unchanged. Moreover, AE-pe-DCs had a weaker surface expression of MHC class II (Ia) molecules as compared to naive pe-DCs. The gene expression level of molecules involved in MHC class II (Ia) synthesis and formation of MHC class II (Ia)-peptide complexes were down regulated. In addition, metacestodes excreted/secreted (E/S) or vesicle-fluid (V/F) antigens were found to alter MHC class II molecule expression on the surface of BMDCs. Finally, conversely to naive pe-DCs, an increasing number of AE pe-DCs down-regulated Con A-induced proliferation of naive CD4+pe-T cells. These findings altogether suggested that TGF-beta-expressing immature AE-pe-DCs might play a significant role in the generation of a regulatory immune response within the peritoneal cavity of AE-infected mice. PMID- 21609336 TI - A tomato stem cell extract, containing antioxidant compounds and metal chelating factors, protects skin cells from heavy metal-induced damages. AB - Heavy metals can cause several genotoxic effects on cells, including oxidative stress, DNA sequence breakage and protein modification. Among the body organs, skin is certainly the most exposed to heavy metal stress and thus the most damaged by the toxic effects that these chemicals cause. Moreover, heavy metals, in particular nickel, can induce the over-expression of collagenases (enzymes responsible for collagen degradation), leading to weakening of the skin extracellular matrix. Plants have evolved sophisticated mechanisms to protect their cells from heavy metal toxicity, including the synthesis of metal chelating proteins and peptides, such as metallothioneins and phytochelatins (PC), which capture the metals and prevent the damages on the cellular structures. To protect human skin cells from heavy metal toxicity, we developed a new cosmetic active ingredient from Lycopersicon esculentum (tomato) cultured stem cells. This product, besides its high content of antioxidant compounds, contained PC, effective in the protection of skin cells towards heavy metal toxicity. We have demonstrated that this new product preserves nuclear DNA integrity from heavy metal damages, by inducing genes responsible for DNA repair and protection, and neutralizes the effect of heavy metals on collagen degradation, by inhibiting collagenase expression and inducing the synthesis of new collagen. PMID- 21609337 TI - Noninvasive risk stratification techniques in pediatric patients with ventricular preexcitation. AB - BACKGROUND: Individuals with ventricular preexcitation (VP) are known to have an increased risk of sudden death. This risk has been associated with conduction properties of the accessory pathway. METHODS: Patients with VP underwent risk stratification through the use of exercise and transesophageal testing. All patients were initially screened with exercise testing and those with preexcitation throughout exercise went on to have transesophageal testing. Patients who demonstrated high-risk pathway characteristics by transesophageal testing or developed clinical indications for an electrophysiology (EP) study underwent ablation. This stepwise risk stratification technique was evaluated for the ability to avoid the need for intracardiac EP study. Patients stratified as low risk were contacted for follow-up. RESULTS: One hundred and twenty-nine exercise studies were performed in 127 patients. Thirty-five of 129 exercise studies demonstrated accessory pathway block during exercise. Twenty-seven of 35 underwent no additional testing. Sixty-six patients underwent transesophageal testing. Forty-nine of 66 patients demonstrated low-risk pathway characteristics and 40 of 49 underwent no further testing. In total, 68 of 129 (53%) patients avoided the need for intracardiac EP study and ablation. A noncardiac indication for the initial diagnostic electrocardiogram was associated with lower likelihood of intracardiac EP study. None of the patients stratified as low risk had additional invasive procedures or life-threatening arrhythmias upon follow-up. CONCLUSIONS: Successful risk stratification of pediatric patients with VP is possible through the use of exercise and transesophageal testing. In this patient population, half of the patients were able to avoid an intracardiac EP study. PMID- 21609338 TI - Entrance skin dose during radiofrequency catheter ablation for tachyarrhythmia: a multicenter study. AB - BACKGROUND: To assess the entrance skin dose (ESD) during radiofrequency catheter ablation procedures for tachyarrhythmia including atrial fibrillation (Af). METHODS: This study focused on 99 consecutive patients who underwent procedures for tachyarrhythmia (Af; n = 34, non-Af; n = 65) in three institutions. The non Af group included atrial flutter, atrial tachycardia, paroxysmal supraventricular tachycardia, ventricular tachycardia, ventricular premature contraction, atrial premature contraction, atrioventricular nodal reentry tachycardia, and Wolff Parkinson-White syndrome. In two of the three institutions, the procedures were performed for both Af and non-Af. The ESDs were measured using 100 radiosensitive indicators attached to the back of each patient's jacket at 5-cm intervals. For statistical analyses, multiple regression analysis (the dependent variable, Max ESD; and the independent variables, dose area product [DAP], total fluoroscopic time [TFT], body mass index, etc.), Pearson's correlation test, and the Mann Whitney test were employed. RESULTS: The overall averages for the TFTs, the DAPs, and the Max-ESDs were 49.9 +/- 28.2 minutes, 71.2 +/- 73.7 Gy cm(2) , and 0.57 +/ 0.51 Gy, respectively. DAP was positively related to the Max-ESD and was significant in stepwise multiple regression analysis (P < 0.0001). There was a significant association between TFT and Max-ESD in five of the six kinds of angiographic unit, and between DAP and Max-ESD in all three systems with available DAP measures. In one institution, TFT, DAP, and Max-ESD differed significantly between the Af and non-Af groups (P = 0.0002, P < 0.0001, and P < 0.0001). CONCLUSIONS: During the cardiac catheter ablation, ESDs of only a few patients exceeded the thresholds of radiation skin injuries, and the DAP proved useful to estimate each patient's Max-ESD. PMID- 21609339 TI - Effects of pacing rates on global and regional myocardial blood flow. AB - BACKGROUND: Information is scarce on the effects of right ventricular apical (RVA) pacing on regional and global myocardial blood flow (MBF). The purpose of this study was to assess the relationship between pacing rate and both regional and global MBF. METHODS: Four patients with exclusive atrial pacing and six patients with exclusive RVA pacing underwent three consecutive H(2) (15)O positron emission tomography scans at 60, 90, and 130 pulses per minute (ppm). For each pacing rate, regional and global MBF was determined. In all patients, the left ventricular (LV) function was normal. RESULTS: By varying the atrial pacing rate from 60 to 130 ppm, the mean global MBF increased from 0.94 to 1.40 mL/g/min, whereas the mean septal to lateral MBF ratio decreased from 1.09 to 0.83. In ventricular-paced patients at corresponding rates, the mean global MBF also increased from 1.07 to 1.52 mL/g/min but here the mean septal to lateral MBF ratio increased from 0.83 to 1.0. CONCLUSIONS: During both acute atrial and RVA pacing, regional and global MBF increases with higher pacing rates. However, the septal to lateral MBF ratio decreases with atrial pacing and increases with RVA pacing in patients with normal LV function. In RVA pacing, these different rate dependent effects on regional MBF can be considered as a favorable factor that helps to understand why in some long-term paced patients, LV function is preserved. PMID- 21609340 TI - Cardiac resynchronization therapy and obstructive sleep-related breathing disorder in patients with congestive heart failure. AB - OBJECTIVES: To assess the impact of cardiac resynchronization therapy (CRT) with or without atrial overdrive pacing, on sleep-related breathing disorder (SRBD). INTRODUCTION: CRT may have a positive influence on SRBD in patients who qualify for the therapy. Data are inconclusive in patients with obstructive SRBD. METHODS: Consenting patients eligible for CRT underwent a baseline polysomnography (PSG) 2 weeks after implantation during which pacing was withheld. Patients with an apnea hypopnea index (AHI) >=15 but <50 were enrolled and randomized to atrial overdrive pacing (DDD) versus atrial synchronous pacing (VDD) with biventricular pacing in both arms. Patients underwent two further PSGs 12 weeks apart. RESULTS: Nineteen men with New York Heart Association class III congestive heart failure participated in the study (age 67.2 +/- 7.5, Caucasian 78.9%, ischemic 73.7%). The score on Epworth Sleepiness Score was 7.3 +/- 4.0, Pittsburgh Sleep Quality Index 7.4 +/- 3.1, and Minnesota Living with Heart Failure Questionnaire 36.9 +/- 21.9. There were no differences between the groups. At baseline, patients exhibited poor sleep efficiency (65.3 +/- 16.6%) with nadir oxygen saturation of 83.5 +/- 5.3% and moderate to severe SRBD (AHI 21.5 +/- 15.3) that was mainly obstructive (central apnea index 3.3 +/- 6.7/hour). On both follow-up assessments, there was no improvement in indices of SRBD (sleep efficiency [68.3 +/- 17.9%], nadir oxygen saturation of 82.8 +/- 4.6%, and AHI 24.9 +/- 21.9). CONCLUSION: In a cohort of elderly male CHF patients receiving CRT, CRT had no impact on obstructive SRBD burden with or without atrial overdrive pacing. PMID- 21609341 TI - Supraventricular tachycardia inducible only with para-Hisian pacing--what is the mechanism? PMID- 21609342 TI - Trichoderma harzianum might impact phosphorus transport by arbuscular mycorrhizal fungi. AB - Trichoderma sp. is a biocontrol agent active against plant pathogens via mechanisms such as mycoparasitism. Recently, it was demonstrated that Trichoderma harzianum was able to parasitize the mycelium of an arbuscular mycorrhizal (AM) fungus, thus affecting its viability. Here, we question whether this mycoparasitism may reduce the capacity of Glomus sp. to transport phosphorus ((33)P) to its host plant in an in vitro culture system. (33)P was measured in the plant and in the fungal mycelium in the presence/absence of T. harzianum. The viability and metabolic activity of the extraradical mycelium was measured via succinate dehydrogenase and alkaline phosphatase staining. Our study demonstrated an increased uptake of (33)P by the AM fungus in the presence of T. harzianum, possibly related to a stress reaction caused by mycoparasitism. In addition, the disruption of AM extraradical hyphae in the presence of T. harzianum affected the (33)P translocation within the AM fungal mycelium and consequently the transfer of (33)P to the host plant. The effects of T. harzianum on Glomus sp. may thus impact the growth and function of AM fungi and also indirectly plant performance by influencing the source-sink relationship between the two partners of the symbiosis. PMID- 21609343 TI - A plant growth-promoting pseudomonad is closely related to the Pseudomonas syringae complex of plant pathogens. AB - Pseudomonas putida GR12-2 is well known as a plant growth-promoting rhizobacterium; however, phylogenetic analysis using the 16S rRNA gene and four housekeeping genes indicated that this strain forms a monophyletic group with the Pseudomonas syringae complex, which is composed of several species of plant pathogens. On the basis of these sequence analyses, we suggest that P. putida GR12-2 be redesignated as P. syringae GR12-2. To compare the ecological roles of P. syringae GR12-2 with its close relatives P. syringae pathovar (pv.) tomato DC3000 and P. syringae pv. syringae B728a, we investigated their ability to cause disease and promote plant growth. When introduced on tobacco or tomato leaves, P. syringae GR12-2 was unable to elicit a hypersensitive response or cause disease, which are characteristic responses of P. syringae DC3000 and B728a, nor were type III secretion system genes required for virulence detected in P. syringae GR12-2 by PCR or DNA hybridization. In contrast to P. syringae GR12-2, neither of the phytopathogens was able to promote root growth when inoculated onto canola seeds. Although commensals and nonpathogens have been reported among the strains of the P. syringae complex, P. syringae GR12-2 is a mutualist and a phytostimulator. PMID- 21609344 TI - Norfloxacin and ursolic acid: in vitro association and postantibiotic effect against Staphylococcus aureus. AB - AIMS: We investigated the effectiveness in vitro of the association between norfloxacin (NOR) and ursolic acid (UA) against Staphylococcus aureus. METHODS AND RESULTS: The minimal inhibitory concentrations (MICs), the minimal bactericidal concentrations, the bacterial killing and the postantibiotic effect (PAE) of NOR and UA were determined both singly and in combination. A synergistic interaction was observed against Staph. aureus ATCC 29213: the mean PAEs were 3 h for NOR, -1.2 h for UA (1 * MIC) and 2.0 h for UA (2 * MIC). Synergism was observed with longer PAEs and postantibiotic sub-MIC effects after NOR/UA exposure. UA was also active against clinical isolates and methicillin-resistant Staph. aureus. CONCLUSIONS: The application of antimicrobial combinations may address the rising resistance to established classes of both systemic and topical agents. SIGNIFICANCE AND IMPACT OF THE STUDY: In vitro interactions between NOR and UA may contribute to the development of novel topical agents for the treatment of skin infections as well as for topical formulations. PMID- 21609345 TI - Nisin F, intraperitoneally injected, may have a stabilizing effect on the bacterial population in the gastro-intestinal tract, as determined in a preliminary study with mice as model. AB - AIMS: To determine if nisin F has an effect on the bacterial population in the gastro-intestinal tract. METHODS AND RESULTS: Six male C57BL/6 mice were intraperitoneally injected with 200 MUl sterile saline and six with nisin F (200 MUl, equivalent to 640 arbitrary units). Fecal samples were collected before injection and 8, 24 and 48 h after injection, and the bacteria amplified by PCR DGGE using 16S rDNA primers. The composition of the bacterial population in the gastro-intestinal tract (GIT) of mice that were injected with saline changed during 48 h, whereas the bacterial population in the GIT remained relatively unchanged in animals injected with nisin F. CONCLUSIONS: These results suggest that nisin F inhibits the growth of specific bacteria in the GIT within the first 4 h. Furthermore, the species remained repressed for at least 44 h after one intraperitoneal injection with nisin F. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report suggesting that nisin F may have a stabilizing effect on the bacterial population in the gastro-intestinal tract. PMID- 21609346 TI - Initial experience of 3 Tesla versus conventional field strength magnetic resonance imaging of small functioning pituitary tumours. AB - BACKGROUND: Higher field strength magnetic resonance imaging (MRI) is becoming increasingly available and offers improved image quality; however, the clinical usefulness of this technique for the demonstration of surgically treatable functional pituitary adenomas has not been clearly established. OBJECTIVE: To determine whether 3 Tesla (3T) MRI improves the detection of ACTH- and GH secreting microadenomas over conventional imaging at field strengths of up to 1.5 Tesla (1.5T). DESIGN: Data sets from postgadolinium T1-weighted MRI at 1.5T and 3T were blinded, randomly ordered and assessed for the presence of pituitary tumour by two radiologists. Where possible, lesion signal difference to noise ratio (SDNR) was calculated for quantitative comparison. Imaging diagnoses were correlated with subsequent surgical and histological findings. PATIENTS: Twenty four patients (10 men, 14 women) with biochemical evidence of Cushing's disease (19) or acromegaly (5) were identified over a 5-year period. RESULTS: 1.5T MRI gave a clear diagnosis of 12 pituitary tumours, all confirmed at 3T. Four additional definite lesions and one suspicious case were correctly identified at 3T. Histological correlation in 21 cases showed sensitivity improving from 54% with 1.5T to 85% with 3T. Radiologists' subjective image preference favoured 3T in 92%. Quantitative difference between tumour and parenchymal signal was significantly greater at 3T (mean SDNR -7.9 [3T] and -2.8 [1.5T], paired t-test P < 0.05). CONCLUSIONS: 3T MRI appears to offer increased conspicuity and detection of GH- and ACTH-secreting pituitary microadenomas. It is potentially clinically useful when 1.5T imaging is negative or equivocal. PMID- 21609347 TI - Pyrosequencing cut-off value identifying BRAFV600E mutation in fine needle aspiration samples of thyroid nodules. AB - CONTEXT: Recently, tremendous efforts have been made towards the development of sensitive techniques to detect the BRAF(V600E) mutation in fine needle aspiration biopsy (FNAB) samples. However, newly developed quantitative and semi quantitative methods, such as dual-priming oligonucleotide (DPO)-based multiplex polymerase chain reaction (PCR), have the potential to generate false-positive (FP) results. OBJECTIVES: To eliminate the possibility of FP results, we generated a receiver operating characteristic (ROC) curve to investigate the diagnostic accuracy of pyrosequencing using quantitative data. DESIGN: Cytological diagnoses of 983 thyroid nodules were made according to the Bethesda System 2007. The BRAF(V600E) mutation was analysed by pyrosequencing, and statistical analyses were performed. RESULTS: Of the 983 nodules, 902 were adopted to evaluate the diagnostic value of pyrosequencing. The number of pathologically confirmed malignancies was 192, of which 182 were papillary thyroid cancer (PTC). By generating an ROC curve, we defined the optimal cut-off value of the mutant allele peak as 5.95% (area under the curve, 0.849; sensitivity, 0.55; 1-specificity, 0). When we applied this selective cut-off value, the number of PTCs positive for BRAF(V600E) was 99 (54.4% of the total number of PTCs). With cytology alone, the diagnostic sensitivity and specificity of detecting malignancy were 71.2% and 100%, respectively. Pyrosequencing improved the diagnostic sensitivity from 71.2% to 78.5% (McNemar's test, P < 0.001), without any change in the diagnostic specificity. When 'suspicious for malignancy' was considered a positive cytological outcome, pyrosequencing increased the diagnostic sensitivity of cytology from 95.8% to 96.9%; however, this improvement did not show statistical significance (McNemar's test, P > 0.05). CONCLUSIONS: Pyrosequencing is an effective method for detecting the BRAF(V600E) mutation in FNAB samples. By allowing the optimal cut-off value to be determined, pyrosequencing improves the diagnostic sensitivity while eliminating the possibility of FP results. PMID- 21609348 TI - Preterm birth and the endocrine regulation of growth in childhood and adolescence. AB - OBJECTIVE: Poor growth during childhood is a common problem associated with preterm birth, but few studies have examined the associations between linear growth, weight and body composition with the postnatal hormonal milieu in preterm children. We aimed to define the IGF-IGFBP axis in preterm children and its association with growth. DESIGN AND PATIENTS: A cohort of healthy 2- to 20-year old subjects who were born prematurely (<37 weeks gestation) and experienced normal neurological development were recruited. In total, 54 premature and 82 control subjects were included in this study. RESULTS: Preterm subjects were relatively shorter (P < 0.001) and leaner (P < 0.05) than their parents in contrast to the term cohort. Preterm children also appeared to fail to reach their genetic height potential (prepuberty: P < 0.01; puberty: P < 0.05). Only IGFBP-2 differed between preterm and term cohorts, with higher levels observed in prepubertal preterm subjects (P < 0.01). In the term group, height SDS was positively associated with IGF-I (P < 0.01) and IGFBP-3 (P < 0.001) concentrations, but no such associations were observed for preterm subjects. CONCLUSION: Preterm children are shorter and lighter than controls throughout childhood, remaining below their genetic height potential. Preterm birth appears to alter the endocrine regulation of postnatal growth in childhood and adolescence, so growth is no longer associated with its normal endocrine regulators. PMID- 21609349 TI - Quantifying the risk of hypoglycaemia in children undergoing the glucagon stimulation test. AB - OBJECTIVE: The low-dose (15-30 MUg/kg) glucagon stimulation test (GST) is assumed to be associated with fewer episodes of low blood glucose (BG). We aimed to quantify the risk of hypoglycaemia in children undergoing the low-dose GST to evaluate their growth hormone status. DESIGN AND PATIENTS: Blood glucose fluctuations during the GST in 80 children (median age 8.7 years, 45 boys, 66 prepubertal) who received a median 20.5 MUg/kg of intramuscular glucagon were reviewed. MEASUREMENTS: The rate of (i) hypoglycaemia (BG < 3.3 mm), (ii) falling BG trend at the end of the GST (lower BG at 180 min than at 120 min), (iii) hypoglycaemia and falling BG trend at the end of the GST, and (iv) at-risk patients (those with at least one of the three risks measures). RESULTS: Twenty seven of the 80 children had hypoglycaemia during the GST. Twenty-six children showed a falling BG trend at the end of the GST and were significantly younger than the other 54 children with a rising BG trend [5.1 (3.1-10.4) years vs 9.6 (5.4-11.8) years, P = 0.02]. Eight children had both a falling BG trend and hypoglycaemia at end of the test. Forty-four children were at-risk patients, and the odds ratio of being an at-risk patient in those <8 years old was 2.63 (95% CI 1.06-6.57, P = 0.04). CONCLUSIONS: Hypoglycaemia is not uncommon during the low dose GST. Young children, especially those <8 years old, are particularly at risk. BG monitoring should be considered essential from a safety perspective. PMID- 21609350 TI - Serum CXC ligand 5 is a new marker of subclinical atherosclerosis in type 2 diabetes. AB - OBJECTIVE: To assess the relationship between serum chemokine CXC ligand 5 (CXCL5) and intima-media thickness (IMT) of the common carotid artery, a marker of preclinical atherosclerosis. DESIGN, PATIENTS AND MEASUREMENTS: We measured the IMT (mean of three segments of both carotid arteries by ultrasonography), serum CXCL5, fasting plasma glucose, serum insulin, serum urea, serum uric acid, HbA1c, serum CRP, adiponectin and lipid profile of 730 Chinese type 2 diabetic participants older than 30 years in a cross-sectional community-based study performed in downtown Shanghai. RESULTS: Serum CXCL5 correlated with carotid IMT (r = 0.112, P = 0.019) after adjustment for age, gender, serum CRP and HbA1c. Multivariate linear regression analysis demonstrated that age (P = 2.30 * 10(-7) ), gender (P = 2.70 * 10(-2) ), systolic blood pressure (P = 9.26 * 10(-3) ), serum CRP (P = 2.12 * 10(-2) ), low-density lipoprotein cholesterol (P = 2.40 * 10(-2) ), CXCL5 (P = 5.27 * 10(-3) ) and high-density lipoprotein cholesterol (P = 3.80 * 10(-3) ) were independently associated with carotid IMT. CONCLUSIONS: Serum CXCL5 is an important determinant of carotid artery IMT in patients with type 2 diabetes. The correlation is independent of inflammation and glucose control. PMID- 21609351 TI - Steroid 21-hydroxylase gene mutational spectrum in 454 Argentinean patients: genotype-phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia. AB - OBJECTIVE: To report genotype-phenotype correlation in a large cohort of patients. CONTEXT: Study of the CYP21A2 gene in 866 unrelated chromosomes of 21 hydroxylase deficiency in Argentinean patients with classic and nonclassic (NC) forms of congenital adrenal hyperplasia (CAH). METHODS: Eleven most common mutations were analysed by allele-specific polymerase chain reaction, restriction fragment length polymorphism (RFLP) or southern blot analysis. Gene sequencing was performed when no mutation was detected in one allele or the genotype phenotype correlation was lacking. RESULTS: The 11-most-common-mutation screening allowed for the detection of 88.1% of affected alleles (80.3% in the NC and 95.2% in the classic forms). p.V281L, IVS2-13A/C>G (In2) and gene deletions and large gene conversions were the most prevalent mutations. In2 (35.2%) in salt wasting (SW), p.I172N (37.3%) in simple virilizing and p.V281L (54.1%) in NC CAH were the most prevalent mutations within the clinical forms. In 7/15 p.P30L mutation alleles, a chimeric CYP21A1P/CYP21A2 gene [PromCYP21A1P; p.P30L] was detected, while 6/15 represented a single-nucleotide substitution, and in 2/15 linkage with mutations, p.[P30L; V281L] and [p.P30L; IVS2-13A/C > G; p.Q318X] was found. In two SW patients, a novel nonsense mutation, p.Q41X, was observed. In three p.V281L mutation patients, the phenotype was more severe than predicted by genotype. Sequence analysis revealed an intronic alteration in the allele carrying the p.V281L mutation [IVS2 + 5G > A; p.V281L]. An aberrant splicing in this p.V281L mutated allele explains the clinical phenotype. CONCLUSIONS: A high percentage of CYP21A2 affected alleles is detected by the 11-mutation screening study. Genotype-phenotype correlation was high, but when the phenotype is more severe than predicted by genotype, presence of two alterations in one allele should be ruled out. PMID- 21609352 TI - Mortality and morbidity in Cushing's syndrome in New Zealand. AB - OBJECTIVE: Untreated Cushing's syndrome (CS) is associated with significant morbidity and mortality. However, recent operative series suggest low morbidity and mortality for CS, whereas population-based surveys report elevated mortality rates. We investigated the mortality and morbidity of CS in New Zealand. DESIGN: A nationwide retrospective survey of patients with CS between 1960 and 2005 managed at the four main endocrinology services. PATIENTS: A total of 253 patients with CS were identified, excluding adrenal carcinoma and malignant ectopic CS. MEASUREMENTS; The primary outcome was the standardized mortality ratio (SMR), comparing the observed number of deaths with the expected number for the population matched for age, sex and duration of follow-up. Secondary outcomes were the change in prevalence of co-morbidities at presentation and at final follow-up. RESULTS: The approximate prevalence and incidence of CS was 79/million and 1.8/million/y. The mean age at presentation was 39 year, and median duration of follow-up was 6.4 year (range 0-46). Overall, 89% achieved biochemical cure at last follow-up, with >90% achieving biochemical cure for CS from adrenal adenoma and pituitary causes. Thirty-six patients died during follow-up compared with 8.8 expected deaths (SMR 4.1, 95%CI 2.9-5.6). While hypertension, sexual dysfunction, myopathy and mild psychiatric illness were significantly reduced after treatment, hypertension, diabetes mellitus, moderate or major psychiatric illness, and osteoporosis were common at final follow-up. CONCLUSION: CS is associated with both high mortality and a high prevalence of co-morbidities, even when biochemical cure rates are between 80% and 90%. PMID- 21609353 TI - Overnight ACTH-cortisol dose responsiveness: comparison with 24-h data, metyrapone administration and insulin-tolerance test in healthy adults. AB - OBJECTIVE: To estimate the dose dependence of endogenous ACTH stimulation of adrenal cortisol secretion overnight. DESIGN: Ten-minute sampling for ACTH and cortisol over 8 and 24 h (n = 17), after metyrapone administration (n = 6), during an insulin-tolerance test (n = 7). SUBJECTS: Healthy adults. MEASUREMENTS: ACTH dose-responsive estimates. RESULTS: Twenty-four hour ACTH-cortisol concentration pairs yielded an estimated EC(50) (one-half maximally stimulatory ACTH concentration) of 5.1 (2.2-9.5) pmol/l [median (range)]. This did not differ from EC(50) s based on 8- or 6-h data [5.9 (3.5-11) and 7.5 (3.7-41) pmol/l] in the same individuals. ACTH efficacy (maximally stimulatable cortisol secretion rate) was 8.4 (3.1-20), 11 (5.9-24) and 15 (5.9-22) nmol/l/min, when calculated over 24, 8 and 6 h, respectively (P = NS). Adrenal sensitivity (slope term) was also consistent across sampling durations, viz. 14 (1.3-95), 18 (1.3-64) and 20 (1.3-64) slope units. Compared with placebo, metyrapone reduced ACTH efficacy from 11 (6.2-62) to 2.8 (1.5-4.5) nmol/l/min for cortisol (n = 9, P < 0.001), while increasing ACTH efficacy for 11-desoxycortisol from 2.3 (0.9-2.9) to 99 (70 218) nmol/l/min (n = 6, P < 0.01), thus affirming face validity. Combined ACTH and cortisol responses to hypoglycaemia allowed an estimate of ACTH efficacy of 28 (22-81) nmol/l/min, compared with the control value of 8.7 (5.6-26), suggesting enhanced adrenal responsiveness. CONCLUSIONS: The results suggest that endogenous ACTH-adrenal drive can be approximated from overnight 8-h sampling of paired ACTH and cortisol concentrations. This strategy may have merit in clinical research in childhood, pregnancy, anxiety states and frail elderly individuals, when ACTH injections are not desired. PMID- 21609354 TI - Category transfer in sequential causal learning: the unbroken mechanism hypothesis. AB - The goal of the present set of studies is to explore the boundary conditions of category transfer in causal learning. Previous research has shown that people are capable of inducing categories based on causal learning input, and they often transfer these categories to new causal learning tasks. However, occasionally learners abandon the learned categories and induce new ones. Whereas previously it has been argued that transfer is only observed with essentialist categories in which the hidden properties are causally relevant for the target effect in the transfer relation, we here propose an alternative explanation, the unbroken mechanism hypothesis. This hypothesis claims that categories are transferred from a previously learned causal relation to a new causal relation when learners assume a causal mechanism linking the two relations that is continuous and unbroken. The findings of two causal learning experiments support the unbroken mechanism hypothesis. PMID- 21609355 TI - Impulse processing: a dynamical systems model of incremental eye movements in the visual world paradigm. AB - The Visual World Paradigm (VWP) presents listeners with a challenging problem: They must integrate two disparate signals, the spoken language and the visual context, in support of action (e.g., complex movements of the eyes across a scene). We present Impulse Processing, a dynamical systems approach to incremental eye movements in the visual world that suggests a framework for integrating language, vision, and action generally. Our approach assumes that impulses driven by the language and the visual context impinge minutely on a dynamical landscape of attractors corresponding to the potential eye-movement behaviors of the system. We test three unique predictions of our approach in an empirical study in the VWP, and describe an implementation in an artificial neural network. We discuss the Impulse Processing framework in relation to other models of the VWP. PMID- 21609356 TI - Using variability to guide dimensional weighting: associative mechanisms in early word learning. AB - At 14 months, children appear to struggle to apply their fairly well-developed speech perception abilities to learning similar sounding words (e.g., bih/dih; Stager & Werker, 1997). However, variability in nonphonetic aspects of the training stimuli seems to aid word learning at this age. Extant theories of early word learning cannot account for this benefit of variability. We offer a simple explanation for this range of effects based on associative learning. Simulations suggest that if infants encode both noncontrastive information (e.g., cues to speaker voice) and meaningful linguistic cues (e.g., place of articulation or voicing), then associative learning mechanisms predict these variability effects in early word learning. Crucially, this means that despite the importance of task variables in predicting performance, this body of work shows that phonological categories are still developing at this age, and that the structure of noninformative cues has critical influences on word learning abilities. PMID- 21609357 TI - Bayesian intractability is not an ailment that approximation can cure. PMID- 21609358 TI - Anxiety in chronic illness: general salutogenic and specific pathological factors. PMID- 21609359 TI - Psychiatric problems associated with subthreshold ADHD and disruptive behaviour diagnoses in teenagers. AB - AIM: To study the coexistence of subthreshold diagnoses of both attention deficit hyperactivity disorder (ADHD) and disruptive behaviour disorders (DBD) with other symptoms of child and adolescent psychiatric disorders as well as risk behaviours associated with smoking, alcohol and drug use. METHODS: A population-based sample of twins including 177 girls and 135 boys was interviewed using the Swedish version of Kiddie-SADS Present and Lifetime Version (K-SADS-PL). Subthreshold diagnoses were compiled based on the ADHD and DBD criteria, where each criterion was assessed as 'possible' or 'certain' according to K-SADS-PL. The odds ratios (OR) between the subthreshold diagnoses and each of the screening questions in K SADS-PL were calculated. RESULTS: Subthreshold diagnoses of ADHD and DBD coexisted with the screening questions concerning depression, mania, panic attack, phobias, anorexia nervosa, motor tics and posttraumatic stress disorder (PTSD) in girls. In boys, these subthreshold diagnoses coexisted with symptoms of depression and PTSD. For both boys and girls, smoking and high alcohol consumption contributed to a high OR with regard to ADHD and DBD. CONCLUSION: Subthreshold diagnoses of ADHD and DBD were risk factors for several other psychiatric symptoms as well as smoking and high alcohol consumption. Thus, a broad clinical assessment is needed for adolescents with such preliminary diagnoses. PMID- 21609360 TI - Long-standing iron-containing intraocular foreign body without siderosis. PMID- 21609361 TI - Translocator protein (18 kDa) as a target for novel anxiolytics with a favourable side-effect profile. AB - Anxiety disorders are frequent and highly disabling diseases with considerable socio-economic impact. In the treatment of anxiety disorders, benzodiazepines (BZDs) as direct modulators of the GABA(A) receptor are used as emergency medication because of their rapid onset of action. However, BZDs act also as sedatives and rather quickly induce tolerance and abuse liability associated with withdrawal symptoms. Antidepressants with anxiolytic properties are also applied as first line long-term treatment of anxiety disorders. However, the onset of action of antidepressants takes several weeks. Obviously, novel pharmacological approaches are needed that combine a rapid anxiolytic efficacy with the lack of tolerance induction, abuse liability and withdrawal symptoms. Neurosteroids are potent allosteric modulators of GABA(A) receptor function. The translocator protein (18 kDa) (TSPO) plays an important role for the synthesis of neurosteroids by promoting the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Etifoxine not only exerts anxiolytic effects as a TSPO ligand by enhancing neurosteroidogenesis, but also acts as a weak direct GABA(A) receptor enhancer. The TSPO ligand XBD173 enhances GABAergic neurotransmission via the promotion of neurosteroidogenesis without direct effects at the GABA(A) receptor. XBD173 counteracts pharmacologically-induced panic in rodents in the absence of sedation and tolerance development. Also in humans, XBD173 displays antipanic activity and does not cause sedation and withdrawal symptoms after 7 days of treatment. XBD173 therefore appears to be a promising candidate for fast acting anxiolytic drugs with less severe side-effects than BZDs. In this review, we focus on the pathophysiology of anxiety disorders and TSPO ligands as a novel pharmacological approach in the treatment of these disorders. PMID- 21609362 TI - The Arabidopsis SOC1-like genes AGL42, AGL71 and AGL72 promote flowering in the shoot apical and axillary meristems. AB - The floral transition is the switch from vegetative development to flowering. Proper timing of the floral transition is regulated by different pathways and is critical for the reproductive success of plants. Some of the flowering pathways are controlled by environmental signals such as photoperiod and vernalization, others by autonomous signals such as the developmental state of the plant and hormones, particularly gibberellin. SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1) acts in Arabidopsis as an integrative centre of these pathways, promoting the floral transition. In this work, we show that AGAMOUS-LIKE 42 (AGL42), AGAMOUS LIKE 71 (AGL71) and AGAMOUS-LIKE 72 (AGL72), which encode MADS-box transcription factors phylogenetically closely related to SOC1, are also involved in the floral transition. They promote flowering at the shoot apical and axillary meristems and seem to act through a gibberellin-dependent pathway. Furthermore SOC1 directly controls the expression of AGL42, AGL71 and AGL72 to balance the expression level of these SOC1-like genes. Our data reveal roles for AGL42, AGL71 and AGL72 in the floral transition, demonstrate their genetic interactions with SOC1 and suggest that their roles differ in the apical and axillary meristems. PMID- 21609363 TI - Is vitamin B(6) deficiency an under-recognized risk in patients receiving haemodialysis? A systematic review: 2000-2010. AB - Vitamin B6 is a water-soluble vitamin, important for the normal functioning of multiple organ systems. In patients receiving haemodialysis, vitamin B6 deficiency has been reported. The impact of ongoing advances in renal medicine on vitamin B6 status has not been evaluated. The aims of this review were (i) to determine the current level of vitamin B(6) deficiency in the haemodialysis population; (ii) to determine the effect of current haemodialysis prescriptions on vitamin B(6) levels; and (iii) to consider the impact of recent medical advances in haemodialysis on vitamin B(6) levels. Electronic databases were used to locate studies with biochemical measures of vitamin B6 between the years 2000 and 2010. Inclusion exclusion criteria were applied by two independent reviewers. Of 316 articles identified, 53 were selected for detailed review. Appropriate vitamin B6 measures and information were extracted. Eleven final studies were included. Vitamin B6 deficiency was shown to be between 24% and 56%. Dialysis reduced plasma levels by 28-48% depending on the dialyser used. Advances in renal medicine including the use of erythropoietin stimulating agents and ion exchange phosphate binding resins were shown to negatively affect vitamin B6 status. Current recommendations for supplementation range from 10-50 mg. These figures are based on older studies often with small numbers of patients. Suboptimal vitamin B6 status is common in the haemodialysis population. Advances in renal medicine and engineering of dialysis membranes may contribute to increased levels of deficiency. PMID- 21609364 TI - Long-term outcomes of kidney allografts obtained by transplant tourism: observations from a single center in Korea. AB - AIM: Organ shortages lead end stage renal disease patients to seek overseas kidney transplantations (OTs), but the long-term outcomes of OTs have not been evaluated extensively. METHODS: Patients who received OT and were followed at Seoul National University Hospital (SNUH) from 2000 to 2009 (n = 87) were compared with patients who received kidneys from local donors (LTs) and were followed at SNUH (n = 577). Furthermore, we matched OT patients and LT patients via a propensity score using operation date, age, renal replacement therapy duration, and donor sources (n = 87 vs 87). RESULTS: The recipient age was older in the OT group (48 vs 41 years), and donor age was younger in the OT group (29 vs 39 years). The estimated glomerular filtration rates (eGFR) of functioning grafts between the groups were not different throughout the follow-up period. Biopsy-proven acute rejection, infectious disease, and hospitalization were more frequent in the OT group (27/87 vs 141/577, log-rank P < 0.001; 39/87 vs 28/577, log-rank P < 0.001; 66/87 vs 99/577, log-rank P < 0.001). The graft survival rate was lower in the OT group (82/87 vs 542/577, log-rank P = 0.003). Patient survival rate, however, was similar between the groups. After propensity score matching, the donor age was still younger in the OT group (29 vs 38 years). The risks of biopsy-proven acute rejection, infectious disease, and hospitalization were still higher in the OT group (27/87 vs 36/87, log-rank P = 0.04; 39/87 vs 3/87, log-rank P < 0.001; 66/87 vs 19/87, log-rank P < 0.001). CONCLUSION: Overseas kidney transplantation connotes risk factors that may negatively affect the long-term graft outcome. PMID- 21609365 TI - Lessons from eight cases of adult pulmonary toxocariasis: abridged republication. PMID- 21609366 TI - Small cell variant of mantle cell lymphoma is an indolent lymphoma characterized by bone marrow involvement, splenomegaly, and a low Ki-67 index. AB - Mantle cell lymphoma (MCL) is recognized as a well-defined B cell neoplasm characterized by overexpression of cyclin D1 (CCND1), with "classical" and "aggressive" variant subtypes. A small-cell variant of MCL (small-MCL), resembling small lymphocytic lymphoma/chronic lymphocytic lymphoma (CLL/SLL), has been added to the World Health Organization classification. However, to the best of our knowledge, there have been no studies focusing on this neoplasm. In the present study, we analyzed 15 cases of CCND1-positive small-MCL, including immunohistochemical analysis of Ki-67 and CCND1 expression, and compared our findings with those of 151 cases of classical MCL. Morphologically, most small MCL showed a diffuse growth pattern (76.9%), whereas others featured a very thin mantle zone pattern resembling a reactive follicle (23.1%). Bone marrow involvement and splenomegaly occurred significantly more frequently in small-MCL than in classical MCL (P < 0.05). Ki-67 expression in small-MCL was lower than in classical MCL (mean [+/- 2 SD] 12.5 +/- 17.3% and 25.2 +/- 25.5%, respectively; P < 0.001), but there was no significant difference in CCND1 expression (P = 0.2445). The 5-year survival rate in small-MCL was 83.3%. Although there was no significant difference in outcome between small-MCL and classical MCL (P = 0.287), only one small-MCL patient died of the disease. Thus, small-MCL constitutes a specific subset of indolent lymphoma with distinguishing features, possibly making a major contribution to the accuracy of therapeutic decisions. In addition, clinicians should be aware of the possible presence of small-MCL to avoid making a misdiagnosis of follicular hyperplasia or CLL/SLL. PMID- 21609367 TI - Infected pancreatic necrosis: drain first, but do it better. PMID- 21609368 TI - Clinical implications of DNA methylation in hepatocellular carcinoma. AB - BACKGROUND: Epigenetics is a rapidly evolving field of genetic study applicable to nearly every aspect of genome-related research. The importance of epigenetics has been recognised in human hepatocellular carcinoma (HCC). Changes in DNA methylation patterns, including global hypomethylation and promoter hypermethylation, are thought to be early events in hepatocarcinogenesis. OBJECTIVES: This review aimed to summarise the role of epigenetics in HCC, to describe the mechanisms of epigenetic changes in HCC and to examine the clinical relevance of epigenetics in HCC. METHODS: This review examines the role of CpG rich regions and DNA methylation, and describes an epigenetic model of cancer, tumour type-specific methylation, the relationships among methylation, cirrhosis and hepatocarcinogenesis, and the role of DNA methylation in HCC. The clinical implications of epigenetics in HCC are discussed. RESULTS: A multivariate predictor model based on traditional clinical factors and DNA methylation profile may have important applications in the early detection of neoplastic transformation in populations at high risk for HCC. CpG methylation may be valuable in HCC prognostics. DNA methylation profiles may enable clinical prediction in pre-therapy patient biopsies, paraffin-embedded samples or plasma DNA. CONCLUSIONS: Epigenetic changes and profiles may correlate to the biological behaviour of tumours and clinical outcome of HCC patients. The use of DNA methylation profiles as a surrogate biomarker remains an active area of clinical cancer research. PMID- 21609369 TI - History of pancreaticoduodenectomy: early misconceptions, initial milestones and the pioneers. AB - Pancreaticoduodenectomy is one of the most challenging surgical procedures which requires the highest level of surgical expertise. This procedure has constantly evolved over the years through the meticulous efforts of a number of surgeons before reaching its current state. This review navigates through some of the early limitations and misconceptions and highlights the initial milestones which laid the foundation of this procedure. The current review also provides a few excerpts from the lives and illuminates on some of the seminal contributions of the three great surgeons: William Stewart Halsted, Walther Carl Eduard Kausch and Allen Oldfather Whipple. These surgeons pioneered the nascent stages of this procedure and paved the way for the modern day pancreaticoduodenectomy. PMID- 21609370 TI - Differences in phosphatidylcholine and bile acids in bile from Egyptian and UK patients with and without cholangiocarcinoma. AB - BACKGROUND: Cholangiocarcinoma (CC) is a fatal malignancy, the incidence of which is increasing worldwide, with substantial regional variation. Current diagnostic techniques to distinguish benign from malignant biliary disease are unsatisfactory. Metabolic profiling of bile may help to differentiate benign from malignant disease. No previous studies have compared the metabolic profiles of bile from two geographically and racially distinct groups of CC patients. OBJECTIVES: This study aimed to compare metabolic profiles of bile, using in vitro proton magnetic resonance spectroscopy, from CC patients from Egypt and the UK, and from patients with CC and patients with non-malignant biliary disease. METHODS: A total of 29 bile samples, collected at cholangiography, were analysed using an 11.7-T system. Samples were from eight CC patients in either Egypt (n = 4) or the UK (n = 4) and 21 patients with benign biliary disease (choledocholithiasis [n = 8], sphincter of Oddi dysfunction [n = 8], primary sclerosing cholangitis [n = 5]). RESULTS: Bile phosphatidylcholine (PtC) was significantly reduced in CC patients. Egyptian CC patients had significantly lower biliary PtC levels compared with UK patients. Taurine- and glycine conjugated bile acids (H-26 and H-25 protons, respectively) were significantly elevated in bile from patients with CC compared with bile from patients with benign diseases (P = 0.013 and P < 0.01, respectively). CONCLUSIONS: Biliary PtC levels potentially differentiate CC from benign biliary disease. Reduced biliary PtC in Egyptian compared with UK patients may reflect underlying carcinogenic mechanisms. PMID- 21609371 TI - Biliary complications following orthotopic liver transplantation: a 10-year audit. AB - BACKGROUND: Biliary complications following liver transplantation result in major morbidity. We undertook a 10-year audit of the incidence, management and outcomes of post-transplant biliary complications at the New Zealand Liver Transplant Unit. METHODS: Prospectively collected data on 348 consecutive liver transplants performed between February 1998 and October 2008 were reviewed. The minimum follow-up was 6 months. RESULTS: A total of 309 adult and 39 paediatric transplants were performed over the study period. Of these, 296 (85%) were whole liver grafts and 52 (15%) were partial liver grafts (24 split-liver, eight reduced-size and 20 live-donor grafts). There were 80 biliary complications, which included 63 (18%) strictures and 17 (5%) bile leaks. Partial graft, a paediatric recipient and a Roux-en-Y biliary anastomosis were independent predictors of biliary strictures. Twenty-five (40%) strictures were successfully managed non-operatively and 38 (60%) required surgery (31 biliary reconstructions, three segmental resections and four retransplants). Seven (41%) bile leaks required surgical revision and 10 (59%) were managed non-operatively. There was no mortality related directly to biliary complications. CONCLUSIONS: Biliary complications affected one in five transplant recipients. Paediatric status, partial graft and Roux-en-Y anastomosis were independently associated with the occurrence of biliary strictures. Over half of the affected patients required surgical revision, but no mortality resulted from biliary complications. PMID- 21609372 TI - Colour doppler ultrasonography provides real-time microwave field visualisation in an ex vivo porcine model. AB - INTRODUCTION: Microwave ablation (MWA) uses non-ionising thermal energy to cause cell death by coagulative necrosis. Colour Doppler ultrasound (US) produces a spherical image during tissue ablation that appears to approximate the microwave near field (MNF) in shape and size. The aim of the present study was to determine whether colour Doppler US images observed during microwave ablation correlate with the actual thermocoagulation zone (TCZ) observed in liver tissue. METHODS: Twenty MWAs were performed in ex vivo bovine liver using a 915-MHz ablation antenna set to 45 W for 6 min concomitant with Doppler US imaging. The edges of spherical images observed with colour Doppler US were marked circumferentially in the tissue. The tissue was transected parallel to the angle of antenna insertion, and the distances between methylene blue markings and the TCZ were measured. RESULTS: The images observed using colour Doppler US were similar in size and shape to the actual TCZ observed in the tissue. The mean distance between the observed colour Doppler US field diameter and the measured TCZ was 2 +/- 1 mm. CONCLUSIONS: Using colour Doppler US, the visualised field during MWA correlates with the TCZ in an ex vivo bovine liver model. Real-time, dynamic feedback of the treatment area may increase the effectiveness of MWA for liver tumours in vivo. PMID- 21609373 TI - Preoperative computed tomography measurements of pancreatic steatosis and visceral fat: prognostic markers for dissemination and lethality of pancreatic adenocarcinoma. AB - BACKGROUND: Increased visceral fat and pancreatic steatosis promote lymphatic metastases and decreased survival in patients with pancreatic adenocarcinoma after pancreatoduodenectomy (PD). OBJECTIVES: We aim to determine the utility of preoperative computed tomography (CT) measurements of pancreatic steatosis and visceral fat as prognostic indicators in patients with pancreatic adenocarcinoma. METHODS: High-resolution CT scans of 42 patients undergoing PD for pancreatic adenocarcinoma were reviewed. Attenuation in CT of the pancreas, liver and spleen were measured in Hounsfield units and scored by two blinded investigators. Perirenal adipose tissue was measured in mm. RESULTS: Lymphatic metastases were present in 57% of patients. Age, gender, tumour size and margin status were similar in patients with and without nodal metastases. Node-positive patients had increased visceral but not subcutaneous fat pads compared with node-negative patients and decreased CT attenuation of the pancreatic body and tail and liver. Node-positive patients stratified by visceral adiposity (>=10 mm vs. <10 mm) demonstrated poorer survival (7 +/- 1 months vs. 16 +/- 2 months; P < 0.01). CONCLUSIONS: In resected pancreatic adenocarcinoma, increased pancreatic steatosis and increased visceral fat stores are associated with lymphatic metastases. Furthermore, increased visceral fat is associated with abbreviated survival in patients with lymphatic metastases. Hence, increased visceral fat may be a causative factor of abbreviated survival and serves a prognostic role in patients with pancreatic malignancies. PMID- 21609374 TI - Minimising cold ischaemic time is essential in cardiac death donor-associated liver transplantation. AB - BACKGROUND: An important issue in the transplantation of livers procured from cardiac death donors (CDDs) concerns why some centres report equivalent outcomes and others report inferior outcomes in transplantations using CDD organs compared with standard criteria donor (SCD) organs. Resolving this discrepancy may increase the number of usable organs. OBJECTIVES: This study aimed to test whether differences in cold ischaemic time (CIT) are critical during CDD organ transplantation and whether such differences might explain the disparate outcomes. METHODS: Results of CDD liver transplants in our own centre were compared retrospectively with results in a matched cohort of SCD liver recipients. Endpoints of primary non-function (PNF) and ischaemic cholangiopathy (IC) were used because these outcomes are clearly associated with CDD organ use. RESULTS: In 22 CDD organ transplants, CIT was a strong predictor of PNF or IC (P = 0.021). Minimising CIT in CDD organ transplants produced outcomes similar to those in a matched SCD organ transplant cohort at our centre and in SCD organ transplant results nationally (1- and 3-year graft and patient survival rates: 90.9% and 73.3% vs. 77.6% and 69.2% in CDD and SCD grafts, respectively. A review of the published literature demonstrated that centres with higher CITs tend to have higher rates of PNF or IC (correlation coefficient: 0.41). CONCLUSIONS: These findings suggest that a targeted effort to minimise CIT might improve outcomes and allow the safer use of CDD organs. PMID- 21609375 TI - Hepatic steatosis is not always a contraindication for cadaveric liver transplantation. AB - BACKGROUND: Macrovesicular steatosis is assumed to be an important risk factor for early allograft dysfunction (EAD) after orthotopic liver transplantation (OLT). AIM: To evaluate the impact of steatosis in combination with other risk factors on the outcome of OLT. METHODS: The degree of steatosis was analysed in 165 consecutive OLTs and was classified by histological examination as non (M0), mild (<30%, M1), moderate (30-60%, M2) or severe steatosis (>60%, M3). Recipients were analysed for EAD. RESULTS: EAD was observed in 28% of patients with M0, 26% with M1, 53% with M2 and 73% with M3 (P < 0.001). Patients with EAD had a significantly shorter graft survival after liver transplantation (P = 0.005) but did not correlate with survival. In multivariate regression analysis, the grade of steatosis, donating after cardiocirculatory death (DCD) grafts and duration of cold ischaemia time were significantly associated with EAD (P < 0.001, P = 0.01 and P = 0.001, respectively). CONCLUSION: Livers with severe (M3) steatosis from DCD donors, combined with a prolonged CIT have a high risk for developing EAD which is correlated with shorter graft survival. Therefore M3 livers should only be considered for OLT in selected recipients without the presence of additional risk factors. PMID- 21609376 TI - Bilirubin levels predict malignancy in patients with obstructive jaundice. AB - BACKGROUND: Differentiating between benign and malignant causes of obstructive jaundice can be challenging, even with the advanced imaging and endoscopic techniques currently available. In patients with obstructive jaundice, the predictive accuracy of bilirubin levels at presentation was examined in order to determine whether such data could be used to differentiate between malignant and benign disease. METHODS: A total of 1,026 patients with obstructive jaundice were identified. Patients were divided into benign and malignant groups. The benign patients were subgrouped into those with choledocholithiasis and those with inflammatory strictures of the biliary tree. Bilirubin levels at presentation and other demographic data were obtained from case records. RESULTS: Area under the curve (AUC) values for bilirubin as a predictor of malignancy were highly significant for all benign presentations and for those with benign biliary strictures (AUC: 0.8 for both groups; P < 0.001). A bilirubin level > 100 umol/l was determined to provide the optimum sensitivity and specificity for malignancy in all patients and in those without choledocholithiasis (71.9% and 86.9%, 71.9% and 88.0%, respectively). The application of a bilirubin level > 250 umol/l achieved specificities of 97.1% and 98.0% in each subgroup of patients, respectively. CONCLUSIONS: In patients with obstructive jaundice, bilirubin levels in isolation represent an important tool for discriminating between benign and malignant underlying causes. PMID- 21609379 TI - Should births be centralised in higher level hospitals? Experiences from regionalised health care in Finland. AB - OBJECTIVE: To describe: (i) trends in centralisation and unplanned out-of hospital births; (ii) perinatal mortality by place of birth; and (iii) health and birth outcomes in areas served by hospitals of different levels. DESIGN: Cross sectional analysis of medical birth register data. SETTING: Finland, from 1991 to 2008, and Uusimaa district from 2004 to 2008. POPULATION: All births. METHODS: In the hospital-based analysis, birthweight was adjusted by logistic regression. In the area-based analysis results were calculated according to where women lived, grouping them into areas served by different hospitals. The mother's background characteristics were adjusted for by logistic regression. MAIN OUTCOME MEASURES: Place of birth, unplanned out-of-hospital birth, perinatal mortality, newborn outcomes, and birth procedures. RESULTS: The number of birthing hospitals declined, the mean number of births per hospital increased, and more births, particularly high-risk births, occurred in university hospitals. Unplanned out-of hospital births were rare, and their numbers increased in the 2000s, but regional differences declined. Perinatal mortality was higher in the university hospitals than in other hospitals, but after adjusting for birthweight, it was lower. Among children weighing more than 2500 g, mortality was similar for all hospital levels. In out-of-hospital births, perinatal mortality was much higher than in other children. The area-based analysis did not systematically show better or worse results for the areas served by lower level hospitals: after adjusting for the background characteristics of the mothers, all differences were found to be small. CONCLUSIONS: The health and service data do not support the need to close down small hospitals in a regionalised system where there is a referral system that functions well. PMID- 21609377 TI - Modification of right hepatectomy results in improvement outcome: a retrospective comparative study. AB - OBJECTIVE: To evaluate any change in the operative and survival outcomes in patients undergoing a right hepatectomy after adoption of the no-clamp technique using a radiofrequency dissecting sealer (TissueLinkTM) in liver resection. METHODS: In all, 58 consecutive patients who underwent a right hepatectomy from July 2003 to December 2007 (Group 1) were compared with 66 consecutive patients who underwent a right hepatectomy from January 1999 to June 2003 (Group 2). In group 1, a liver transection was performed with a cavitron ultrasonic surgical aspirator (CUSA) and TissueLinkTM without hilar clamping whereas in group 2, a liver transection was performed with CUSA and diathermy with routine continuous hilar clamping. RESULTS: For the operative outcomes, there was significantly less blood loss (median 450 vs. 900 ml, P < 0.001) in group 1. The complication rate was also significantly lower in group 1 (22.4% vs. 47.0%, P = 0.004). In subgroup analysis for patients with hepatocellular carcinoma (HCC), the overall survival rate was significantly better in group 1; 1-, 3- and 5-year survival rates were 78%, 72% and 57% in group 1 vs. 72%, 44% and 39% in group 2, respectively (P = 0.048). CONCLUSIONS: When compared with the retrospective cohort, a right hepatectomy utilizing TissueLinkTM without hilar clamping was feasible with potential benefits in surgical outcomes. PMID- 21609380 TI - Acupuncture for premenstrual syndrome: a systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: Although acupuncture is widely applied in obstetrics and gynaecology, evidence for its efficacy in treating premenstrual syndrome (PMS) is equivocal. OBJECTIVE: To summarise and evaluate the current evidence for acupuncture as a treatment for PMS. SEARCH STRATEGY: Ten databases were searched electronically, and relevant reviews were searched by hand through June 2009. SELECTION CRITERIA: Our review included randomised controlled trials (RCTs) of women with PMS; these RCTs compared acupuncture with sham acupuncture, medication, or no treatment. DATA COLLECTION AND ANALYSIS: Study outcomes were presented as mean differences (for continuous data) or risk ratios (RRs) (for dichotomous data) with a 95% confidence interval (95% CI). The risk of bias was assessed using the assessment tool from the Cochrane Handbook. MAIN RESULTS: Ten RCTs were included in our review. The pooled results demonstrated that acupuncture is superior to all controls (eight trials, pooled RR 1.55, 95% CI 1.33-1.80, P < 0.00001). A meta analysis comparing the effects of acupuncture with different doses of progestin and/or anxiolytics supported the use of acupuncture (four trials, RR 1.49, 95% CI 1.27-1.74, P < 0.00001). In addition, acupuncture significantly improved symptoms when compared with sham acupuncture (two trials, RR 5.99, 95% CI 2.84-12.66, P < 0.00001). No evidence of harm resulting from acupuncture emerged. Most of the included studies demonstrated a high risk of bias in terms of random sequence generation, allocation concealment, and blinding. AUTHOR'S CONCLUSIONS: Although acupuncture seems promising for symptom improvement in women with PMS, important methodological flaws in the included studies weaken the evidence. Considering the potential of acupuncture, further rigorous studies are needed. PMID- 21609381 TI - Knowledge of adverse neonatal outcome alters clinicians' interpretation of the intrapartum cardiotocograph. AB - OBJECTIVE: To evaluate the impact of knowledge of neonatal outcome on clinicians' interpretation of the intrapartum cardiotocograph (CTG). DESIGN: Prospective evaluation of pre-recorded cases. SETTING: Five maternity hospitals. POPULATION: From a database of intrapartum CTGs acquired with a scalp electrode in singleton near-term fetuses, 20 tracings were sequentially selected from cases with newborn umbilical artery pH < 7.05 and 20 from cases with pH > 7.20. METHODS: Five experienced obstetricians practising in different maternity hospitals were asked to analyse the 40 tracings individually, according to the International Federation of Gynaecology and Obstetrics guidelines. In a first round, clinicians were given no information on neonatal outcome. In a second round, carried out 2 months later, clinicians were asked to analyse the same tracings, but the order was randomly altered and information on the newborn's arterial pH was provided. Clinicians were not informed of the purpose of the study or whether the tracings were the same. MAIN OUTCOME MEASURES: The incidence of individual fetal heart rate feature identification and tracing classification, before and after neonatal outcome was made available. RESULTS: In the group with pH < 7.05, repetitive decelerations and reduced variability were more common in the second round (P < 0.001 and P = 0.001, respectively), as was a pathological classification (P = 0.002); variable decelerations were less common (P = 0.008). In the group with normal pH, less tracings in the second round had prolonged decelerations (P = 0.013) and no accelerations (P = 0.013), but more had pronounced decelerations (P = 0.031) and reduced variability (P = 0.007); there was a reduction in pathological classifications, but this difference failed to reach statistical significance (P = 0.051). CONCLUSIONS: A knowledge of adverse neonatal outcome leads to a more severe classification of the intrapartum CTG, which derives mainly from the evaluation of decelerations and variability. PMID- 21609382 TI - Integrating plasma high-sensitivity C-reactive protein and myeloperoxidase for risk prediction in chronic systolic heart failure. AB - Various inflammatory biomarkers predict long-term outcomes in patients with acute and chronic heart failure (HF). Their relative contributions when measured in combination have not been evaluated. The authors measured both plasma levels of high-sensitivity C-reactive protein (hsCRP) and myeloperoxidase (MPO) in 136 patients with chronic systolic HF (left ventricular ejection fraction <= 40%), and performed echocardiography with prospective follow-up of adverse clinical events (death, cardiac transplant, and HF hospitalizations) over 34 +/- 17 months. A lack of significant correlation between log-transformed hsCRP and MPO (Spearman's r = 0.11, P = .185) was observed. Within the lower two hsCRP tertiles (<5.34 mg/L), patients with plasma MPO above median levels demonstrated a 2.9 fold increased risk in adverse clinical events (95% confidence interval [CI], 1.2 8.1; P < .05), whereas within lower plasma MPO levels (<303 pM), increase in hsCRP demonstrated a 1.9-fold increased risk (95% CI, 0.56-6.2; P = not significant). Combined analysis of hsCRP and MPO levels demonstrated a 6-fold increased risk (95% CI, 2.4-16.8; P < .01) when both markers were elevated. Stratifying patients according to hsCRP, MPO, and amino-terminal pro-B-type natriuretic peptide cutoff values provided a stepwise increment of risk prediction of adverse clinical events. Combining hsCRP and MPO measurements provided distinct and complementary prognostic value in a patient cohort of chronic systolic HF. PMID- 21609383 TI - The effect of physical training on systemic proinflammatory cytokine expression in heart failure patients: a systematic review. AB - Systemic inflammation is associated with cardiovascular disease, especially the end stages of heart failure (HF). The authors sought to determine by systematic review whether physical therapy reduces serum levels of pro-inflammatory cytokines in HF patients. Potential studies were identified from a systematic search of Medline (Ovid) (1950-October 2010), Embase.com (1974-current), Cochrane Central Register of Controlled Trials, CINAHL (1981-current), and Web of Science (2000-current). The search strategy included a mix of MeSH and free text terms for key concepts. A total of 11 studies were included, with 4 reporting a post training reduction in tumor necrosis factor alpha (TNF-alpha), of which 3 used traditional aerobic or resistance exercise and 1 used functional electrical stimulation. Reduced post-training serum levels of interleukin 6 were reported by one exercise study. The one study that employed combined resistance and aerobic training only showed soluble receptors TNF-alpha1 and TNF-alpha2 to be lower. The one study of respiratory muscle training and two studies that employed electrical stimulation had limited effect on cytokines and peak maximal oxygen uptake. With the exception of one study, those therapies that employed >= 5 sessions per week lowered serum TNF-alpha. Our review data suggest that physical therapies employing >= 5 sessions per week are most likely to reduce serum levels of TNF alpha in HF patients. No isolated study of resistance training has yet examined the relationship between muscle wasting, glycogen depletion, and the ability of exercise training to reverse both of these conditions in HF patients. PMID- 21609384 TI - Cardiopulmonary exercise testing is a core assessment for patients with heart failure. AB - Despite advances in the treatment of heart failure (HF), which have resulted in improved survival, overall prognosis continues to be poor. Given the high short term mortality rate, it remains important to utilize assessment techniques with established prognostic value in this patient population. Ideally, a given assessment should also be able to accurately reflect disease severity, a heterogeneous phenomenon in patients with HF, and accurately reflect the magnitude of physiologic/clinical improvement following the implementation or titration of an intervention. Cardiopulmonary exercise testing (CPX) satisfies all of the aforementioned desirable assessment attributes. Peak oxygen consumption and the minute ventilation/carbon dioxide production slope are key CPX variables in assessing prognosis and gauging disease severity. Given the high value of information obtained from this procedure, CPX should be considered a core assessment in the HF population. The current review will concisely define key CPX variables and summarize their clinical applications in patients with HF. PMID- 21609385 TI - Characteristics of a subset of patients with reversible systolic dysfunction in chronic kidney disease. AB - There exists a subgroup of uremic cardiomyopathy patients who experience resolution of heart failure symptoms with recovery of normal cardiac geometry following hemodialysis. The authors studied 52 patients with chronic kidney disease on hemodialysis over a period of 190 days. There were 29 patients with systolic dysfunction (left ventricular ejection fraction <40%). Twenty-three patients with preserved systolic function had diastolic dysfunction. Of the 29 patients with systolic dysfunction, 10 patients had significant improvement in New York Heart Association functional class and left ventricular internal diameter in diastole (LVIDd: 59.8 +/- 2.6-55.92 mm and left ventricular internal diameter in systole [LVIDs]: 51.8 +/- 1.8-34 +/- 1.2 mm; P < .001) with significant increases in left ventricular ejection fraction (30.55%-50.14%; P < .001). These patients had the highest baseline serum levels of troponin I (P = .024), which decreased significantly with recovery of cardiac function. When the entire study group was regrouped as those below and those above the median change of C-reactive protein (CRP), patients with CRP greater than the median change had significant improvements in LVIDs and ejection fraction. A subgroup of patients with uremic cardiomyopathy who demonstrated reversible left ventricular systolic dysfunction had high levels of serum troponin I levels at presentation, which regressed with recovery of ventricular function in parallel with CRP levels. PMID- 21609386 TI - Neurogenic stunned myocardium and takotsubo cardiomyopathy are the same syndrome: a pooled analysis. AB - Neurogenic stunned myocardium (NSM) and Takotsubo cardiomyopathy (TCM) are two syndromes that coexist in the medical literature. They share many common features. We hypothesized that they, in fact, represent the same syndrome. We collected and analyzed case reports of transient left ventricular (LV) dysfunction in neurologic conditions. Cases were compared based on the diagnosis and then based on the pattern of wall motion abnormality. Of 112 cases, 61 were diagnosed as TCM and 37 as NSM, and in 14 cases, the authors used both terms. Overall, the patients with NSM were younger, and the severity of LV systolic dysfunction and timing of recovery was similar, as well as the prevalence of cardiac enzyme elevation. Pulmonary edema on presentation was more prevalent in patients with NSM while chest pain and ST-segment elevation was more common in patients with TCM. While only regional, predominantly apical, wall motion abnormality was described in TCM, some patients in the NSM group had global LV dysfunction. NSM and TCM likely share the same mechanism and pathologic substrate. Their natural course is almost identical. They both likely represent the same syndrome of stress-induced cardiomyopathy. Current definition of stress induced cardiomyopathy includes only regional wall motion abnormalities. It should be expanded to include all varieties of wall motion abnormalities including global hypokinesis. PMID- 21609387 TI - Racial and sex differences in prevalence of hypothyroidism in patients with cardiomyopathies enrolled into a heart failure disease management program. AB - The authors evaluated the prevalence of hypothyroidism in patients with heart failure (HF) to determine whether there are racial and sex differences and to determine the number of new cases of hypothyroidism. The study included 194 patients in an HF disease management program (HFDMP) in South Florida. Patients were interviewed for a history of hypothyroidism and referred for measurement of thyrotropin. The prevalence of hypothyroidism was calculated by race and sex. The prevalence of hypothyroidism was 18% for all patients with HF and 23% among Hispanics; however, this trend was not statistically significant (P = .06). More men than women had hypothyroidism (P = .04). Patients with hypothyroidism had higher mean lipid profiles (P < .01) and lower mean heart rates (P = .03) than healthy patients. Hypothyroidism is prevalent among HF patients, especially men. Hispanics with HF may have a higher prevalence of hypothyroidism. The standardized protocol of the HFDMP helped identify new cases of hypothyroidism. PMID- 21609388 TI - Cellular evidence of reverse cardiac remodeling induced by cardiac resynchronization therapy. AB - Left ventricular assist devices (LVADs) induce reverse cardiac remodeling by reducing myocyte size and collagen deposition. On the other hand, cardiac resynchronization therapy (CRT) induces reverse cardiac remodeling by improving electromechanical synchronization. The clinical and structural changes produced by CRT in failing myocardium are known, but whether these changes are accompanied by reverse cellular remodeling is unknown. A total of 12 patients with chronic heart failure (CHF) who underwent CRT and 15 patients who had LVAD therapy as clinically indicated and 8 healthy controls were compared. Demographics, echocardiographic data, and histologic samples from myocardial biopsies were analyzed and compared among groups. The authors found significant increases in myocyte size, myocardial fibrosis, and inflammation in both CHF groups who underwent CRT or LVAD, compared with healthy controls. After CRT or LVAD therapy, a significant decrease in myocyte size and tumor necrosis factor alpha (TNF alpha) expression compared with healthy controls (P < .05) was found. In the CRT group, 6 of 8 patients demonstrated reduction in myocyte size and interstitial fibrosis. In addition, there was a decrease in myocyte size by 13%, total collagen by 27% and TNF-alpha by 49% in the CRT group vs 28%, 45%, and 45% in the LVAD group. CRT produces cellular reverse remodeling in failing human hearts that are comparable with those produced by LVAD therapy. PMID- 21609389 TI - Optimizing cardiac resynchronization therapy in advanced heart failure. AB - Up to 30% of cardiac resynchronization therapy (CRT) patients are considered to be "nonresponders." While the absolute number might increase because of the increased use of CRT, this proportion remains stable. As a result, there is a pressing need for guidelines for practicing clinicians to maximize the effectiveness of CRT. This clinician update describes easy-to-comprehend cases that might provide a practical insight for cardiologists, as well as for all professionals who take care of patients with heart failure who have undergone CRT. PMID- 21609390 TI - Prediction values of T wave alternans for sudden cardiac death in patients with chronic heart failure: a brief review. AB - More than 50% of patients with heart failure die from sudden cardiac death as a result of malignant arrhythmia. T wave alternans (TWA) is a convenient, noninvasive, and inexpensive testing modality, with a higher sensitivity and specificity for sudden cardiac death. Its prediction value for malignant arrhythmia may even exceed electrophysiologic study. Generally, the algorithms of TWA can be divided into frequency-domain and time-domain methods, and the latter has a stronger anti-interference ability. So far, a unified measuring formula and diagnostic criteria about TWA measurements have been created. Large clinical studies in recent years strongly suggest that TWA can predict sudden cardiac death, which can be used as a guide for the implanting of implantable cardioverter-defibrillator. This article reviews the current literature on recording techniques and clinical implications of TWA. PMID- 21609391 TI - Nitroprusside in refractory heart failure. PMID- 21609392 TI - Identification of telocytes in skeletal muscle interstitium: implication for muscle regeneration. AB - Skeletal muscle interstitium is crucial for regulation of blood flow, passage of substances from capillaries to myocytes and muscle regeneration. We show here, probably, for the first time, the presence of telocytes (TCs), a peculiar type of interstitial (stromal) cells, in rat, mouse and human skeletal muscle. TC features include (as already described in other tissues) a small cell body and very long and thin cell prolongations-telopodes (Tps) with moniliform appearance, dichotomous branching and 3D-network distribution. Transmission electron microscopy (TEM) revealed close vicinity of Tps with nerve endings, capillaries, satellite cells and myocytes, suggesting a TC role in intercellular signalling (via shed vesicles or exosomes). In situ immunolabelling showed that skeletal muscle TCs express c-kit, caveolin-1 and secrete VEGF. The same phenotypic profile was demonstrated in cell cultures. These markers and TEM data differentiate TCs from both satellite cells (e.g. TCs are Pax7 negative) and fibroblasts (which are c-kit negative). We also described non-satellite (resident) progenitor cell niche. In culture, TCs (but not satellite cells) emerge from muscle explants and form networks suggesting a key role in muscle regeneration and repair, at least after trauma. PMID- 21609395 TI - [Light protection in sport]. PMID- 21609393 TI - Early transcriptional pattern of angiogenesis induced by EGCG treatment in cervical tumour cells. AB - The major green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been shown to exhibit antitumour activities in several tumour models. One of the possible mechanisms by which EGCG can inhibit cancer progression is through the modulation of angiogenesis signalling cascade. The tumour cells' ability to tightly adhere to endothelium is a very important process in the metastatic process, because once disseminated into the bloodstream the tumour cells must re establish adhesive connections to endothelium in order to extravasate into the target tissues. In this study, we investigated the anti-angiogenic effects of EGCG treatment (10 MUM) on human cervical tumour cells (HeLa) by evaluating the changes in the expression pattern of 84 genes known to be involved in the angiogenesis process. Transcriptional analysis revealed 11 genes to be differentially expressed and was further validated by measuring the induced biological effects. Our results show that EGCG treatment not only leads to the down-regulation of genes involved in the stimulation of proliferation, adhesion and motility as well as invasion processes, but also to the up-regulation of several genes known to have antagonist effects. We observed reduced proliferation rates, adhesion and spreading ability as well as invasiveness of HeLa tumour cells upon treatment, which suggest that EGCG might be an important anti angiogenic therapeutic approach in cervical cancers. PMID- 21609401 TI - Clinical long-term studies: data collection and assessment. AB - Short-term randomized controlled clinical trials often provide the basis of regulatory approval for a new drug application, while long-term clinical studies are essential for monitoring the (long-term) effectiveness and safety of a drug. As the duration of a study increases and the number of patients continuing in the study declines, missing data become more of a problem, as they may bias the results. Therefore, standard analytical strategies used in short-term trials (intention-to-treat, per-protocol) may not always be appropriate for data generated in long-term studies. In this article, commonly used analytical approaches in the assessment of clinical trial data will be reviewed. Given their specific characteristics, regulatory authorities and expert guidelines suggest to use several of these approaches in parallel to correctly interpret the data of long-term clinical studies and to come to better informed decisions. PMID- 21609394 TI - mTOR-STAT3-notch signalling contributes to ALDH2-induced protection against cardiac contractile dysfunction and autophagy under alcoholism. AB - Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been shown to benefit myopathic changes following alcohol intake, although the precise mechanism is still unclear. This study was designed to evaluate the role of ALDH2 on chronic alcohol intake-induced myocardial geometric and functional damage with a focus on autophagic signalling. Wild-type friendly virus B (FVB) and transgenic mice overexpressing ALDH2 driven by chicken beta-actin promoter were fed a 4% alcohol liquid diet for 12 weeks. Cardiac geometry and function were assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate the essential autophagy markers, Akt and AMP-dependent protein kinase (AMPK) as well as their downstream signalling mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3). Alcohol intake altered cardiac geometry and function as demonstrated by lessened LV wall and septal thickness, enlarged end systolic and diastolic diameters, decreased fractional shortening and cell shortening, the effects of which were mitigated by ALDH2 transgene. Chronic alcohol intake triggered myocardial autophagy as shown by LC3B II isoform switch, as well as decreased phosphorylation of mTOR, the effects of which were ablated by ALDH2. Chronic alcohol intake suppressed phosphorylation of Akt and AMPK, which was reconciled by ALDH2. Levels of Notch1 and STAT3 phosphorylation were dampened by chronic alcohol intake in FVB but not ALDH2 myocardium. Moreover, the gamma-secretase Notch inhibitor N?xE2?x80?x90[N (3,5-difluorophenacetyl)-1-alany1]-S-phenyglycine t-butyl ester exacerbated ethanol-induced cardiomyocyte contractile dysfunction, apoptosis and autophagy. In summary, these findings suggested that ALDH2 elicits cardioprotection against chronic alcohol intake-induced cardiac geometric and functional anomalies by inhibition of autophagy possibly via restoring the Akt-mTOR-STAT3-Notch signalling cascade. PMID- 21609403 TI - [Ulcerating nodules on the right arm after hunting muskrats]. PMID- 21609405 TI - Comment on Riede F., Koenen W., Goerdt S., Ehmke H., Faulhaber J. "Medicinal leeches for the treatment of venous congestion and hematoma after plastic reconstructive surgery" in J Dtsch Dermatol Ges 2010; 11: 881-889. PMID- 21609408 TI - Pyrone-based inhibitors of metalloproteinase types 2 and 3 may work as conformation-selective inhibitors. AB - Matrix metalloproteinases are zinc-containing enzymes capable of degrading all components of the extracellular matrix. Owing to their role in human disease, matrix metalloproteinase have been the subject of extensive study. A bioinorganic approach was recently used to identify novel inhibitors based on a maltol zinc binding group, but accompanying molecular-docking studies failed to explain why one of these inhibitors, AM-6, had approximately 2500-fold selectivity for MMP-3 over MMP-2. A number of studies have suggested that the matrix-metalloproteinase active site is highly flexible, leading some to speculate that differences in active-site flexibility may explain inhibitor selectivity. To extend the bioinorganic approach in a way that accounts for MMP-2 and MMP-3 dynamics, we here investigate the predicted binding modes and energies of AM-6 docked into multiple structures extracted from matrix-metalloproteinase molecular dynamics simulations. Our findings suggest that accounting for protein dynamics is essential for the accurate prediction of binding affinity and selectivity. Additionally, AM-6 and other similar inhibitors likely select for and stabilize only a subpopulation of all matrix-metalloproteinase conformations sampled by the apo protein. Consequently, when attempting to predict ligand affinity and selectivity using an ensemble of protein structures, it may be wise to disregard protein conformations that cannot accommodate the ligand. PMID- 21609409 TI - Establishing a rodent stroke perfusion computed tomography model. AB - Brain computed tomography perfusion imaging in acute stroke may help guide therapy. However, the perfusion thresholds defining potentially salvageable (penumbra) and irreversibly injured (infarct core) tissue require further validation. The aim of this study was to validate infarct core and penumbra perfusion thresholds in a rodent stroke model by developing and optimising perfusion computed tomography imaging, performing serial scanning and correlating scans with final histology. Stroke was induced in male Wistar rats (n=17) using the middle cerebral artery thread-occlusion method. Perfusion computed tomography scans were obtained immediately pre- and postocclusion, and every 30 min for 2.5 h. Histological changes of infarction were assessed after 24 h. High-quality maps of cerebral blood flow and cerebral blood volume were generated at multiple coronal planes after optimisation of contrast injection and scanning parameters. The prestroke absolute cerebral blood flow and cerebral blood volume values (mean +/- SD) were 158.2 +/- 49.94 ml/min per 100 g and 5.6 +/- 1.13 ml per 100 g, respectively. Cerebral blood flow was significantly lower in the infarct region of interest than the contralateral hemisphere region of interest at all time points, except the 0.5 h postocclusion time point. However, cerebral blood volume was only significantly lower in the infarct region of interest than the contralateral hemisphere region of interest at the 1 h and the 1.5 h time points (postocclusion). This study has demonstrated for the first time the feasibility of performing perfusion computed tomography in the most commonly used animal model of stroke. The model will allow definitive studies to determine optimal thresholds and the reliability of perfusion computed tomography measures for infarct core and penumbra. PMID- 21609410 TI - The effect of transdermal glyceryl trinitrate on 24 h ambulatory blood pressure in acute/subacute stroke. AB - BACKGROUND: High blood pressure is a common complication in acute stroke and is associated with a poor outcome. Aims This study assesses the effects of transdermal glyceryl trinitrate on 24 h ambulatory blood pressure in patients with recent stroke. METHODS: One hundred and seven patients with acute ischaemic or haemorrhagic stroke were included. The patients had been enrolled in one of two trials of transdermal glyceryl trinitrate (5 mg daily) or placebo/control, and underwent 24 h ambulatory blood pressure monitoring (56 glyceryl trinitrate, 51 control). Ambulatory blood pressure data were analysed using area under the curve for the entire 24 h, and day and night periods. Nocturnal dipping was defined as a decline in systolic blood pressure >10%. Comparisons of blood pressure between groups were performed by analysis of covariance (ANCOVA) with adjustments for trial and baseline measure. RESULTS: In comparison with control, glyceryl trinitrate significantly lowered 24 h blood pressure (systolic blood pressure/diastolic blood pressure 9.4/4.8 mmHg, P < 0.001/0.001, n=104), daytime blood pressure (8.7/4.2, P < 0.001/ <0.001, n=103) and night-time blood pressure (6.9/1.7, P=0.008/0.458, n=86). Only 86 patients (glyceryl trinitrate 45, placebo/control 41) had sufficient night blood pressure measurements to assign dipping status; 28 were dippers (12 glyceryl trinitrate, 16 control) and 58 were nondippers (33 glyceryl trinitrate, 25 control); glyceryl trinitrate significantly lowered systolic but not diastolic blood pressure in both dippers and nondippers. Treatment with glyceryl trinitrate increased the daytime heart rate (4.8 beats/min) but not the night-time heart rate. Patients whose blood pressure did not dip at night had a worse functional outcome at three-months. CONCLUSIONS: Transdermal glyceryl trinitrate (5 mg) significantly lowered 24 h blood pressure by 9/5 mmHg (equivalent to a 6% reduction) in both dipping and nondipping patients with acute/subacute stroke. This reduction in blood pressure is clinically relevant and is unlikely to be excessive. PMID- 21609411 TI - Prognosis of ischaemic stroke is improving similarly in patients with type 2 diabetes as in nondiabetic patients in Finland. AB - BACKGROUND: Case fatality of first ischaemic stroke has improved markedly during the past two decades. Aims To investigate whether stroke patients with type 2 diabetes have shared this favourable development. METHODS: Nation-wide registers were used to identify all patients with type 2 diabetes in Finland during 1988 2002. All first ischaemic strokes among them and also among all nondiabetic persons were identified from the National Hospital Discharge Register and the Causes of Death Register. Trends over time were calculated, for age-standardised case fatality of first stroke events, separately for two time periods: 0-27 and 28-364 days after the onset of stroke. These trends were compared between patients with type 2 diabetes and nondiabetic patients. RESULTS: Altogether, 23,097 first-ever ischaemic strokes were recorded among 222,940 persons with type 2 diabetes. The 28 day case fatality was 1.1-1.3 times higher, and the one-year case fatality of 28 day survivors was 1.4-2.2 times higher in patients with type 2 diabetes compared with nondiabetic patients. A significant decline in case fatality trends was observed, but the trends did not differ between type 2 diabetes and nondiabetic patients. CONCLUSIONS: The study revealed a positive development in survival after the first stroke event in persons with type 2 diabetes, similar to the development in nondiabetic persons. However, the level of case fatality has remained higher in patients with type 2 diabetes. PMID- 21609412 TI - Quantomo: validation of a computer-assisted methodology for the volumetric analysis of intracerebral haemorrhage. AB - BACKGROUND: Volume measurements of intracerebral haemorrhage are prognostically important and are increasingly used in clinical trials to measure the effects of potential interventions. The purpose of this work is to establish the reliability of haematoma volume measurements obtained using a computer-assisted method called Quantomo (for quantitative tomography) and the ABC/2 method. Hypothesis Quantomo reliably detects smaller changes in intracerebral haemorrhage volume as compared with the ABC/2 method because computer-assisted volume measurements are tailored to measure the geometry of individual haematoma volumes whereas the ABC/2 method approximates all haematoma volumes as ellipsoids. METHODS: Thirty randomly selected computed tomography scans with intracerebral haemorrhage were measured by four raters a total of four times each (two sessions using Quantomo and two using the ABC/2 method). Interrater and intrarater reliability for both techniques were calculated simultaneously using a two-way random-effects analysis of variance model. The precision of intracerebral haemorrhage volume measurement was quantified as the minimum detectable difference with 95% confidence intervals. RESULTS: The median (first quartile and third quartile) intracerebral haemorrhage volume measurements of all rater and sessions for Quantomo were 32.7 ml (6.2 and 54.4 ml) and for ABC/2 40.7 ml (8.6 and 76.0 ml). Quantomo intracerebral haemorrhage volume measurements were more precise, having an inter- and intrarater minimum detectable difference of 8.1 and 5.3 ml, while the inter- and intrarater minimum detectable difference for ABC/2 were 37.0 and 15.7 ml. CONCLUSIONS: Quantomo is a computer-assisted methodology that is more reliable for quantifying intracerebral haemorrhage volume as compared with the ABC/2 method. PMID- 21609413 TI - Reading difficulty after stroke: ocular and non ocular causes. AB - BACKGROUND: Ocular causes of reading impairment following stroke include visual field loss, eye movement impairment and poor central vision. Non ocular causes may include cognitive errors or language impairment. AIM: The purpose of this study was to identify all patients referred with suspected visual impairment who had reported reading difficulty to establish the prevalence of ocular and non ocular causes. METHODS: Prospective, multicentre, observation study with standardised referral and assessment forms across 21 sites. Visual assessment included visual acuity measurement, visual field assessment, ocular alignment, and movement and visual inattention assessment. Multicentre ethical approval and informed patient consent were obtained. RESULTS: A total of 915 patients were recruited, with a mean age of 69.18 years (standard deviation 14.19). Reading difficulties were reported by 177 patients (19.3%), with reading difficulty as the only symptom in 39 patients. Fifteen patients had normal visual assessment but with a diagnosis of expressive or receptive aphasia. Eight patients had alexia. One hundred and nine patients had visual field loss, 85 with eye movement abnormality, 27 with low vision and 39 patients with visual perceptual impairment. Eighty-seven patients had multiple ocular diagnoses with combined visual field, eye movement, low vision or inattention problems. All patients with visual impairment were given targeted treatment and/or advice including prisms, occlusion, refraction, low vision aids and scanning exercises. CONCLUSIONS: Patients complaining of reading difficulty were mostly found to have visual impairment relating to low vision, eye movement or visual field loss. A small number were found to have non ocular causes of reading difficulty. Treatment or advice was possible for all patients with visual impairment. PMID- 21609414 TI - The China National Stroke Registry for patients with acute cerebrovascular events: design, rationale, and baseline patient characteristics. AB - BACKGROUND: As a leading cause of severe disability and death, stroke places an enormous burden on the health care system in China. There are limited data on the pattern of current medical practice and quality of care delivery for stroke patients at the national level. AIM: The nation-wide prospective registry, China National Stroke Registry, will be considered with regard to its design, progress, geographic coverage, and hospital and patient characteristics. METHODS: Between September 2007 and August 2008, the China National Stroke Registry recruited consecutive patients with diagnoses of acute cerebrovascular events from 132 hospitals that cover all 27 provinces and four municipalities (including Hong Kong region) in China. Clinical data were collected prospectively using paper based registry forms. Patients were followed for clinical and functional outcomes through phone interviews at three, six, 12, 18, and 24 months after disease onset. RESULTS: These patients (n=21,902) were 63.8 years of age on average, and 39% were females. Ischaemic stroke was predominant (66.4%), and the other subtypes were intracerebral haemorrhage (23.4%), subarachnoid haemorrhage (3.4%), and transient ischaemic attack (6.2%). CONCLUSIONS: The China National Stroke Registry is a large-scale nationwide registry in China. Rich data collected from this prospective registry may provide the opportunity to evaluate the quality of care for stroke patients in China. PMID- 21609415 TI - Avoiding in hospital delays and eliminating the three-hour effect in thrombolysis for stroke. AB - BACKGROUND: Intravenous thrombolysis for acute stroke is more efficient the earlier the treatment is initiated. In-hospital delays account for a significant proportion of avoidable time loss before treatment is initiated. Paradoxically, studies have reported longer door-to-needle times the earlier the patients arrive ('three-hour effect'). Hypothesis We hypothesized that a standardized thrombolysis procedure carried out in a specialized neurological emergency room can minimize in-hospital delays and erase the 'three-hour effect'. METHODS: Onset to-door and door-to-needle times of 246 consecutive thrombolysis patients were analyzed. A standardized protocol designed to minimize in-hospital delays was tested using a resident-based stroke team within a neurological emergency room. Correlation of onset-to-door and door-to-needle times was measured as well as differences in treatment times for daytime versus night hours and weekend vs. weekday. Outcome, rate of symptomatic intracranial hemorrhage and mortality were compared with the results of SITS-MOST. RESULTS: Median door-to-needle time was 25 min compared with a mean of 68 min in SITS-MOST. door-to-needle time did not correlate with onset-to-door time (Pearson's r = -0 . 097; P = 0 . 13) and patients arriving within 90 min from symptom onset showed comparable door-to needle times with patients arriving within 90-180 min. Neither treatment on weekends nor during night hours led to significant in-hospital treatment delays. Outcome and safety parameters were comparable with those observed in SITS-MOST. CONCLUSIONS: By applying a standardized and diligently monitored thrombolysis protocol, carried out by a specialized stroke team within a neurological emergency room, in-hospital delays can be minimized. This allows improvement of door-to-needle times irrespective of the time to arrival and treatment during off hours. PMID- 21609416 TI - Recent age- and gender-specific trends in mortality during stroke hospitalization in the United States. AB - BACKGROUND: Advancements in diagnosis and treatment have resulted in better clinical outcomes after stroke; however, the influence of age and gender on recent trends in death during stroke hospitalization has not been specifically investigated. We assessed the impact of age and gender on nationwide patterns of in-hospital mortality after stroke. METHODS: Data were obtained from all US states that contributed to the Nationwide Inpatient Sample. All patients admitted to hospitals between 1997 and 1998 (n=1 351 293) and 2005 and 2006 (n=1 202 449), with a discharge diagnosis of stroke (identified by the International Classification of Diseases, Ninth Revision procedure codes), were included. Time trends for in-hospital mortality after stroke were evaluated by gender and age group based on 10-year age increments (<55, 55-64, 65-74, 75-84, >84) using multivariable logistic regression. RESULTS: Between 1997 and 2006, in-hospital mortality rates decreased across time in all sub-groups (all P<0.01), except in men >84 years. In unadjusted analysis, men aged >84 years in 1997-1998 had poorer mortality outcomes than similarly aged women (odds ratio 0.93, 95% confidence interval=0.88-0.98). This disparity worsened by 2005-2006 (odds ratio 0.88, 95% confidence interval=0.84-0.93). After adjusting for confounders, compared with similarly aged women, the mortality outcomes among men aged >84 years were poorer in 1997-1998 (odds ratio 0.97, 95% confidence interval=0.92-1.02) and were poorer in 2005-2006 (odds ratio 0.92, 95% confidence interval=0.87-0.96), P=0.04, for gender * time trend. CONCLUSIONS: Over the last decade, in-hospital mortality rates after stroke in the United States have declined for every age/gender group, except men aged >84 years. Given the rapidly ageing US population, avenues for boosting in-hospital survival among very elderly men with stroke need to be explored. PMID- 21609417 TI - Long-term outcome following attendance at a transient ischemic attack clinic. AB - BACKGROUND AND PURPOSE: Many patients who attend transient ischemic attack clinics have a noncerebrovascular diagnosis. The long-term outcomes in this group are not well described. We evaluated these in a cohort referred to a transient ischemic attack clinic with a suspected transient ischemic attack. METHODS: Patients were clinically classified as having stroke or a transient ischemic attack or a noncerebrovascular diagnosis (nontransient ischemic attack). Follow up was via electronic record linkage. The primary endpoint was cardiovascular death or a major cardiovascular event. Secondary outcomes included incident neurological disease (excluding stroke or transient ischemic attack) and the need for permanent pacemaker insertion. Outcomes in the transient ischemic attack and nontransient ischemic attack cohorts were compared using Cox's proportional hazards models. Mortality outcomes were further compared with those in a contemporary control group of individuals with hypertension. RESULTS: Of the 3533 patients who attended the transient ischemic attack clinic, 53.5% had a transient ischemic attack. Of these, 769 (40.7%) suffered a cardiovascular endpoint, compared with 458 (27.9%) with a nontransient ischemic attack (hazard ratio 1.53, 95% confidence interval 1.36-1.72). The risk remained higher but was attenuated following adjustment (hazard ratio 1.21, 95% confidence interval 1.05-1.41). Cardiovascular mortality in both groups was higher than that in hypertensive controls. The risk of a subsequent nonstroke neurological event was higher in those without a transient ischemic attack. CONCLUSIONS: Patients without a transient ischemic attack referred to a transient ischemic attack clinic have a high risk of future vascular events that exceeds risk in a cohort with hypertension. All patients attending transient ischemic attack clinics should undergo assessment of their cardiovascular risk and the use of methods to reduce this risk should be explored. PMID- 21609418 TI - Actimeter-derived sleep and wake data and nocturnal ambulatory blood pressure estimation in subjects with stroke and transient ischaemic attack. AB - BACKGROUND/AIMS: Abnormalities in nocturnal blood pressure control identified using ambulatory blood pressure monitoring are associated with adverse cardiovascular outcomes. Sleep and wake episodes during such studies are usually identified by means of sleep diaries but these may be inaccurate in stroke patients. We performed a study to determine whether sleep-wake data obtained using wrist-mounted actimeters would significantly influence the results of routinely performed nocturnal ambulatory blood pressure monitoring when compared with diary-based sleep-wake recording and fixed time-period data. METHODS: Actimetry was performed using a wrist-mounted device during routine ambulatory blood pressure monitoring in subjects who had suffered a transient ischaemic attack or stroke. The mean nocturnal blood pressure readings were calculated using sleep data derived from actimetry and diaries and compared for a fixed time period from 11:00 pm to 8:00 am. RESULTS: Twenty subjects (mean age 68 years, and 13 female) were studied. Patients were found to have slept for a median of six hours (one- to eight-hours) by diary and five-hours (zero- to eight-hours) by actimeter data. Diary and actimeter data agreed in 69% of recordings. The mean sleeping systolic blood pressure was lower when calculated by actimeter data than by diary data (119.6 mmHg vs. 123.2 mmHg, P=0.049, paired t-test) but there was no significant difference in diastolic blood pressure. The mean nocturnal blood pressure calculated from 11:00 pm to 7:00 am was higher than sleeping blood pressure calculated from diary data. (mean systolic blood pressure: 127.6 mmHg vs. 123.6 mmHg, P=0.065; mean diastolic blood pressure 69.0 vs. 64.0, P=0.028). CONCLUSION: Calculation of nocturnal and sleeping blood pressure is lower in subjects with stroke and transient ischaemic attack when objective actimeter derived sleep/wake data are used. PMID- 21609419 TI - Should persons with autosomal dominant AD be included in clinical trials? PMID- 21609420 TI - GiSAO.db: a database for ageing research. AB - BACKGROUND: Age-related gene expression patterns of Homo sapiens as well as of model organisms such as Mus musculus, Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster are a basis for understanding the genetic mechanisms of ageing. For an effective analysis and interpretation of expression profiles it is necessary to store and manage huge amounts of data in an organized way, so that these data can be accessed and processed easily. DESCRIPTION: GiSAO.db (Genes involved in senescence, apoptosis and oxidative stress database) is a web-based database system for storing and retrieving ageing-related experimental data. Expression data of genes and miRNAs, annotation data like gene identifiers and GO terms, orthologs data and data of follow-up experiments are stored in the database. A user-friendly web application provides access to the stored data. KEGG pathways were incorporated and links to external databases augment the information in GiSAO.db. Search functions facilitate retrieval of data which can also be exported for further processing. CONCLUSIONS: We have developed a centralized database that is very well suited for the management of data for ageing research. The database can be accessed at https://gisao.genome.tugraz.at and all the stored data can be viewed with a guest account. PMID- 21609421 TI - Evaluation of the proliferation markers Ki-67/MIB-1, mitosin, survivin, pHH3, and DNA topoisomerase IIalpha in human anaplastic astrocytomas--an immunohistochemical study. AB - BACKGROUND: Histological malignancy grading of astrocytomas can be challenging despite criteria given by the World Health Organisation (WHO). Grading is fundamental for optimal prognostication and treatment, and additional biomarkers are needed to support the histopathological diagnosis. Estimation of proliferative activity has gained much enthusiasm, and the present study was designed to evaluate and compare novel immunohistochemical proliferative markers in human anaplastic astrocytomas. METHODS: Proliferative activity was determined in twenty-seven cases with antibodies reactive against the Ki-67 antigen, mitosin, survivin, pHH3, and DNA topoisomerase IIalpha, and they were mutually compared as well as related to mitotic activity. RESULTS: The markers correlated well with each other, but poorly with mitoses, probably because of small and squeezed tumour samples, in which identification of mitoses can be difficult. Positive association to overall survival was observed as well. CONCLUSIONS: Our data show that these markers may assist significantly in the evaluation of proliferative activity in anaplastic astrocytomas and even have prognostic value. PMID- 21609422 TI - Patient self-management and pharmacist-led patient self-management in Hong Kong: a focus group study from different healthcare professionals' perspectives. AB - BACKGROUND: Patient self-management is a key approach to manage non-communicable diseases. A pharmacist-led approach in patient self-management means collaborative care between pharmacists and patients. However, the development of both patient self-management and role of pharmacists is limited in Hong Kong. The objectives of this study are to understand the perspectives of physicians, pharmacists, traditional Chinese medicine (TCM) practitioners, and dispensers on self-management of patients with chronic conditions, in addition to exploring the possibilities of developing pharmacist-led patient self-management in Hong Kong. METHODS: Participants were invited through the University as well as professional networks. Fifty-one participants comprised of physicians, pharmacists, TCM practitioners and dispensers participated in homogenous focus group discussions. Perspectives in patient self-management and pharmacist-led patient self management were discussed. The discussions were audio recorded, transcribed and analysed accordingly. RESULTS: The majority of the participants were in support of patients with stable chronic diseases engaging in self-management. Medication compliance, monitoring of disease parameters and complications, lifestyle modification and identifying situations to seek help from health professionals were generally agreed to be covered in patient self-management. All pharmacists believed that they had extended roles in addition to drug management but the other three professionals believed that pharmacists were drug experts only and could only play an assisting role. Physicians, TCM practitioners, and dispensers were concerned that pharmacist-led patient self-management could be hindered, due to unfamiliarity with the pharmacy profession, the perception of insufficient training in disease management, and lack of trust of patients. CONCLUSIONS: An effective chronic disease management model should involve patients in stable condition to participate in self-management in order to prevent health deterioration and to save healthcare costs. The role of pharmacists should not be limited to drugs and should be extended in the primary healthcare system. Pharmacist-led patient self-management could be developed gradually with the support of government by enhancing pharmacists' responsibilities in health services and developing public-private partnership with community pharmacists. Developing facilitating measures to enhance the implementation of the pharmacist led approach should also be considered, such as allowing pharmacists to access electronic health records, as well as deregulation of more prescription-only medicines to pharmacy-only medicines. PMID- 21609423 TI - Development of a universal dual-bolus injection scheme for the quantitative assessment of myocardial perfusion cardiovascular magnetic resonance. AB - BACKGROUND: The dual-bolus protocol enables accurate quantification of myocardial blood flow (MBF) by first-pass perfusion cardiovascular magnetic resonance (CMR). However, despite the advantages and increasing demand for the dual-bolus method for accurate quantification of MBF, thus far, it has not been widely used in the field of quantitative perfusion CMR. The main reasons for this are that the setup for the dual-bolus method is complex and requires a state-of-the-art injector and there is also a lack of post processing software. As a solution to one of these problems, we have devised a universal dual-bolus injection scheme for use in a clinical setting. The purpose of this study is to show the setup and feasibility of the universal dual-bolus injection scheme. METHODS: The universal dual-bolus injection scheme was tested using multiple combinations of different contrast agents, contrast agent dose, power injectors, perfusion sequences, and CMR scanners. This included 3 different contrast agents (Gd-DO3A-butrol, Gd-DTPA and Gd-DOTA), 4 different doses (0.025 mmol/kg, 0.05 mmol/kg, 0.075 mmol/kg and 0.1 mmol/kg), 2 different types of injectors (with and without "pause" function), 5 different sequences (turbo field echo (TFE), balanced TFE, k-space and time (k-t) accelerated TFE, k-t accelerated balanced TFE, turbo fast low-angle shot) and 3 different CMR scanners from 2 different manufacturers. The relation between the time width of dilute contrast agent bolus curve and cardiac output was obtained to determine the optimal predefined pause duration between dilute and neat contrast agent injection. RESULTS: 161 dual-bolus perfusion scans were performed. Three non-injector-related technical errors were observed (1.9%). No injector related errors were observed. The dual-bolus scheme worked well in all the combinations of parameters if the optimal predefined pause was used. Linear regression analysis showed that the optimal duration for the predefined pause is 25s to separate the dilute and neat contrast agent bolus curves if 0.1 mmol/kg dose of Gd-DO3A-butrol is used. CONCLUSION: The universal dual-bolus injection scheme does not require sophisticated double-head power injector function and is a feasible technique to obtain reasonable arterial input function curves for absolute MBF quantification. PMID- 21609425 TI - Giant Merkel cell carcinoma of the eyelid: a case report and review of the literature. AB - Merkel cell carcinoma (MCC) is a rare cutaneous tumor and cases located in the eyelid have been described, but still its rarity may lead to difficulty in diagnosis and delay in treatment. A 51-year-old female patient that presented with large lesions in the eyelid underwent surgery after the diagnosis of acute chalazion. Following respiratory distress secondary to pulmonary metastasis, the patient's condition deteriorated and was not fit for complete excision treatment. Histopathological investigation of the biopsies, taken from the tumor, revealed that it was undifferentiated small cell carcinoma. Our aim with this paper is to point out that more cases should be reported for more effective diagnosis, histopathological study, clinical investigation, treatment and prognosis of this specific neoplasm. PMID- 21609424 TI - Mapping turnaround times (TAT) to a generic timeline: a systematic review of TAT definitions in clinical domains. AB - BACKGROUND: Assessing turnaround times can help to analyse workflows in hospital information systems. This paper presents a systematic review of literature concerning different turnaround time definitions. Our objectives were to collect relevant literature with respect to this kind of process times in hospitals and their respective domains. We then analysed the existing definitions and summarised them in an appropriate format. METHODS: Our search strategy was based on Pubmed queries and manual reviews of the bibliographies of retrieved articles. Studies were included if precise definitions of turnaround times were available. A generic timeline was designed through a consensus process to provide an overview of these definitions. RESULTS: More than 1000 articles were analysed and resulted in 122 papers. Of those, 162 turnaround time definitions in different clinical domains were identified. Starting and end points vary between these domains. To illustrate those turnaround time definitions, a generic timeline was constructed using preferred terms derived from the identified definitions. The consensus process resulted in the following 15 terms: admission, order, biopsy/examination, receipt of specimen in laboratory, procedure completion, interpretation, dictation, transcription, verification, report available, delivery, physician views report, treatment, discharge and discharge letter sent. Based on this analysis, several standard terms for turnaround time definitions are proposed. CONCLUSION: Using turnaround times to benchmark clinical workflows is still difficult, because even within the same clinical domain many different definitions exist. Mapping of turnaround time definitions to a generic timeline is feasible. PMID- 21609426 TI - A quantitative association study of SLC25A12 and restricted repetitive behavior traits in autism spectrum disorders. AB - BACKGROUND: SLC25A12 was previously identified by a linkage-directed association analysis in autism. In this study, we investigated the relationship between three SLC25A12 single nucleotide polymorphisms (SNPs) (rs2056202, rs908670 and rs2292813) and restricted repetitive behavior (RRB) traits in autism spectrum disorders (ASDs), based on a positive correlation between the G allele of rs2056202 and an RRB subdomain score on the Autism Diagnostic Interview-Revised (ADI-R). METHODS: We used the Repetitive Behavior Scale-Revised (RBS-R) as a quantitative RRB measure, and conducted linear regression analyses for individual SNPs and a previously identified haplotype (rs2056202-rs2292813). We examined associations in our University of Illinois at Chicago-University of Florida (UIC UF) sample (179 unrelated individuals with an ASD), and then attempted to replicate our findings in the Simons Simplex Collection (SSC) sample (720 ASD families). RESULTS: In the UIC-UF sample, three RBS-R scores (ritualistic, sameness, sum) had positive associations with the A allele of rs2292813 (p = 0.006-0.012) and with the rs2056202-rs2292813 haplotype (omnibus test, p = 0.025 0.040). The SSC sample had positive associations between the A allele of rs2056202 and four RBS-R scores (stereotyped, sameness, restricted, sum) (p = 0.006-0.010), between the A allele of rs908670 and three RBS-R scores (stereotyped, self-injurious, sum) (p = 0.003-0.015), and between the rs2056202 rs2292813 haplotype and six RBS-R scores (stereotyped, self-injurious, compulsive, sameness, restricted, sum)(omnibus test, p = 0.002-0.028). Taken together, the A alleles of rs2056202 and rs2292813 were consistently and positively associated with RRB traits in both the UIC-UF and SSC samples, but the most significant SNP with phenotype association varied in each dataset. CONCLUSIONS: This study confirmed an association between SLC25A12 and RRB traits in ASDs, but the direction of the association was different from that in the initial study. This could be due to the examined SLC25A12 SNPs being in linkage disequilibrium with another risk allele, and/or genetic/phenotypic heterogeneity of the ASD samples across studies. PMID- 21609427 TI - Alternative splicing of the human gene SYBL1 modulates protein domain architecture of Longin VAMP7/TI-VAMP, showing both non-SNARE and synaptobrevin like isoforms. AB - BACKGROUND: The control of intracellular vesicle trafficking is an ideal target to weigh the role of alternative splicing in shaping genomes to make cells. Alternative splicing has been reported for several Soluble N-ethylmaleimide sensitive factor Attachment protein REceptors of the vesicle (v-SNAREs) or of the target membrane (t-SNARES), which are crucial to intracellular membrane fusion and protein and lipid traffic in Eukaryotes. However, splicing has not yet been investigated in Longins, i.e. the most widespread v-SNAREs. Longins are essential in Eukaryotes and prototyped by VAMP7, Sec22b and Ykt6, sharing a conserved N terminal Longin domain which regulates membrane fusion and subcellular targeting. Human VAMP7/TI-VAMP, encoded by gene SYBL1, is involved in multiple cell pathways, including control of neurite outgrowth. RESULTS: Alternative splicing of SYBL1 by exon skipping events results in the production of a number of VAMP7 isoforms. In-frame or frameshift coding sequence modifications modulate domain architecture of VAMP7 isoforms, which can lack whole domains or domain fragments and show variant or extra domains. Intriguingly, two main types of VAMP7 isoforms either share the inhibitory Longin domain and lack the fusion-promoting SNARE motif, or vice versa. Expression analysis in different tissues and cell lines, quantitative real time RT-PCR and confocal microscopy analysis of fluorescent protein-tagged isoforms demonstrate that VAMP7 variants have different tissue specificities and subcellular localizations. Moreover, design and use of isoform specific antibodies provided preliminary evidence for the existence of splice variants at the protein level. CONCLUSIONS: Previous evidence on VAMP7 suggests inhibitory functions for the Longin domain and fusion/growth promoting activity for the Delta-longin molecule. Thus, non-SNARE isoforms with Longin domain and non-longin SNARE isoforms might have somehow opposite regulatory functions. When considering splice variants as "natural mutants", evidence on modulation of subcellular localization by variation in domain combination can shed further light on targeting determinants. Although further work will be needed to characterize identified variants, our data might open the route to unravel novel molecular partners and mechanisms, accounting for the multiplicity of functions carried out by the different members of the Longin proteins family. PMID- 21609428 TI - LiCl induces TNF-alpha and FasL production, thereby stimulating apoptosis in cancer cells. AB - BACKGROUND: The incidence of cancer in patients with neurological diseases, who have been treated with LiCl, is below average. LiCl is a well-established inhibitor of Glycogen synthase kinase-3, a kinase that controls several cellular processes, among which is the degradation of the tumour suppressor protein p53. We therefore wondered whether LiCl induces p53-dependent cell death in cancer cell lines and experimental tumours. RESULTS: Here we show that LiCl induces apoptosis of tumour cells both in vitro and in vivo. Cell death was accompanied by cleavage of PARP and Caspases-3, -8 and -10. LiCl-induced cell death was not dependent on p53, but was augmented by its presence. Treatment of tumour cells with LiCl strongly increased TNF-alpha and FasL expression. Inhibition of TNF alpha induction using siRNA or inhibition of FasL binding to its receptor by the Nok-1 antibody potently reduced LiCl-dependent cleavage of Caspase-3 and increased cell survival. Treatment of xenografted rats with LiCl strongly reduced tumour growth. CONCLUSIONS: Induction of cell death by LiCl supports the notion that GSK-3 may represent a promising target for cancer therapy. LiCl-induced cell death is largely independent of p53 and mediated by the release of TNF-alpha and FasL.Key words: LiCl, TNF-alpha, FasL, apoptosis, GSK-3, FasL. PMID- 21609429 TI - Fixed dystonia in complex regional pain syndrome: a descriptive and computational modeling approach. AB - BACKGROUND: Complex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. Involvement of dysfunctional GABAergic interneurons has been suggested, however the mechanisms that underpin fixed dystonia are still unknown. We hypothesized that dystonia could be the result of aberrant proprioceptive reflex strengths of position, velocity or force feedback. METHODS: We systematically characterized the pattern of dystonia in 85 CRPS-patients with dystonia according to the posture held at each joint of the affected limb. We compared the patterns with a neuromuscular computer model simulating aberrations of proprioceptive reflexes. The computer model consists of an antagonistic muscle pair with explicit contributions of the musculotendinous system and reflex pathways originating from muscle spindles and Golgi tendon organs, with time delays reflective of neural latencies. Three scenarios were simulated with the model: (i) increased reflex sensitivity (increased sensitivity of the agonistic and antagonistic reflex loops); (ii) imbalanced reflex sensitivity (increased sensitivity of the agonistic reflex loop); (iii) imbalanced reflex offset (an offset to the reflex output of the agonistic proprioceptors). RESULTS: For the arm, fixed postures were present in 123 arms of 77 patients. The dominant pattern involved flexion of the fingers (116/123), the wrists (41/123) and elbows (38/123). For the leg, fixed postures were present in 114 legs of 77 patients. The dominant pattern was plantar flexion of the toes (55/114 legs), plantar flexion and inversion of the ankle (73/114) and flexion of the knee (55/114).Only the computer simulations of imbalanced reflex sensitivity to muscle force from Golgi tendon organs caused patterns that closely resembled the observed patient characteristics. In parallel experiments using robot manipulators we have shown that patients with dystonia were less able to adapt their force feedback strength. CONCLUSIONS: Findings derived from a neuromuscular model suggest that aberrant force feedback regulation from Golgi tendon organs involving an inhibitory interneuron may underpin the typical fixed flexion postures in CRPS patients with dystonia. PMID- 21609430 TI - Sesamin ameliorates oxidative stress and mortality in kainic acid-induced status epilepticus by inhibition of MAPK and COX-2 activation. AB - BACKGROUND: Kainic acid (KA)-induced status epilepticus (SE) was involved with release of free radicals. Sesamin is a well-known antioxidant from sesame seeds and it scavenges free radicals in several brain injury models. However the neuroprotective mechanism of sesamin to KA-induced seizure has not been studied. METHODS: Rodents (male FVB mice and Sprague-Dawley rats) were fed with sesamin extract (90% of sesamin and 10% sesamolin), 15 mg/kg or 30 mg/kg, for 3 days before KA subcutaneous injection. The effect of sesamin on KA-induced cell injury was also investigated on several cellular pathways including neuronal plasticity (RhoA), neurodegeneration (Caspase-3), and inflammation (COX-2) in PC12 cells and microglial BV-2 cells. RESULTS: Treatment with sesamin extract (30 mg/kg) significantly increased plasma alpha-tocopherol level 50% and 55.8% from rats without and with KA treatment, respectively. It also decreased malondialdehyde (MDA) from 145% to 117% (p=0.017) and preserved superoxide dismutase from 55% of the vehicle control mice to 81% of sesamin-treated mice, respectively to the normal levels (p=0.013). The treatment significantly decreased the mortality from 22% to 0% in rats. Sesamin was effective to protect PC12 cells and BV-2 cells from KA-injury in a dose-dependent manner. It decreased the release of Ca2+, reactive oxygen species, and MDA from PC12 cells. Western blot analysis revealed that sesamin significantly reduced ERK1/2, p38 mitogen-activated protein kinases, Caspase-3, and COX-2 expression in both cells and RhoA expression in BV-2 cells. Furthermore, Sesamin was able to reduce PGE2 production from both cells under KA stimulation. CONCLUSIONS: Taken together, it suggests that sesamin could protect KA-induced brain injury through anti-inflammatory and partially antioxidative mechanisms. PMID- 21609431 TI - Infection by agnoprotein-negative mutants of polyomavirus JC and SV40 results in the release of virions that are mostly deficient in DNA content. AB - BACKGROUND: Human polyomavirus JC (JCV) is the etiologic agent of a brain disease, known as progressive multifocal leukoencephalopathy (PML). The JCV genome encodes a small multifunctional phospho-protein, agnoprotein, from the late coding region of the virus, whose regulatory functions in viral replication cycle remain elusive. In this work, the functional role of JCV and SV40 agnoproteins in virion release was investigated using a point mutant (Pt) of each virus, where the ATG codon of agnoprotein was mutated to abrogate its expression. RESULTS: Analysis of both viral protein expression and replication using Pt mutant of each virus revealed that both processes were substantially down regulated in the absence of agnoprotein compared to wild-type (WT) virus. Complementation studies in cells, which are constitutively expressing JCV agnoprotein and transfected with the JCV Pt mutant genome, showed an elevation in the level of viral DNA replication near to that observed for WT. Constitutive expression of large T antigen was found to be not sufficient to compensate the loss of agnoprotein for efficient replication of neither JCV nor SV40 in vivo. Examination of the viral release process for both JCV and SV40 Pt mutants showed that viral particles are efficiently released from the infected cells in the absence of agnoprotein but were found to be mostly deficient in viral DNA content. CONCLUSIONS: The results of this study provide evidence that agnoprotein plays an important role in the polyomavirus JC and SV40 life cycle. Infection by agnoprotein-negative mutants of both viruses results in the release of virions that are mostly deficient in DNA content. PMID- 21609432 TI - Clinical utility of tibial motor and sensory nerve conduction studies with motor recording from the flexor hallucis brevis: a methodological and reliability study. AB - BACKGROUND: Standard tibial motor nerve conduction measures are established with recording from the abductor hallucis. This technique is often technically challenging and clinicians have difficulty interpreting the information particularly in the short segment needed to assess focal tibial nerve entrapment at the medial ankle as occurs in posterior tarsal tunnel syndrome. The flexor hallucis brevis (FHB) has been described as an alternative site for recording tibial nerve function in those with posterior tarsal tunnel syndrome. Normative data has not been established for this technique. This pilot study describes the technique in detail. In addition we provide reference values for medial and lateral plantar orthodromic sensory measures and assessed intrarater reliability for all measures. METHODS: Eighty healthy female participants took part, and 39 returned for serial testing at 4 time points. Mean values +/- SD were recorded for nerve conduction measures, and coefficient of variation as well as intraclass correlation coefficients (ICC) were calculated. RESULTS: Motor latency, amplitude and velocity values for the FHB were 4.1 +/- 0.9 msec, 8.0 +/- 3.0 mV and 45.6 +/ 3.4 m/s, respectively. Sensory latencies, amplitudes, and velocities, respectively, were 2.8 +/- 0.3 msec, 26.7 +/- 10.1 MUV, and 41.4 +/- 3.5 m/s for the medial plantar nerve and 3.2 +/- 0.5 msec, 13.3 +/- 4.7 MUV, and 44.3 +/- 4.0 msec for the lateral plantar nerve. All values demonstrated significant ICC values (P <= 0.007). CONCLUSION: Motor recording from the FHB provides technically clear waveforms that allow for an improved ability to assess tibial nerve function in the short segments used to assess tarsal tunnel syndrome. The reported means will begin to establish normal values for this technique. PMID- 21609433 TI - Delayed endovascular treatment of descending aorta stent graft collapse in a patient treated for post- traumatic aortic rupture: a case report. AB - BACKGROUND: We report a case of delayed endovascular correction of graft collapse occurred after emergent Thoracic Endovascular Aortic Repair (TEVAR) for traumatic aortic isthmus rupture. CASE PRESENTATION: In 7th post-operative day after emergent TEVAR for traumatic aortic isthmus rupture (Gore TAG(r) 28-150), a partial collapse of the endoprosthesis at the descending tract occurred, with no signs of visceral ischemia. Considering patient's clinical conditions, the graft collapse wasn't treated at that time. When general conditions allowed reintervention, the patient refused any new treatment, so he was discharged.Four months later the patient complained of severe gluteal and sural claudication, erectile disfunction and abdominal angina; endovascular correction was performed. At 18 months the graft was still patent. DISCUSSION AND CONCLUSION: Graft collapse after TEVAR is a rare event, which should be detected and treated as soon as possible. Delayed correction of this complication can be lethal due to the risk of visceral ischemia and limbs loss. PMID- 21609434 TI - Acorn: a grid computing system for constraint based modeling and visualization of the genome scale metabolic reaction networks via a web interface. AB - BACKGROUND: Constraint-based approaches facilitate the prediction of cellular metabolic capabilities, based, in turn on predictions of the repertoire of enzymes encoded in the genome. Recently, genome annotations have been used to reconstruct genome scale metabolic reaction networks for numerous species, including Homo sapiens, which allow simulations that provide valuable insights into topics, including predictions of gene essentiality of pathogens, interpretation of genetic polymorphism in metabolic disease syndromes and suggestions for novel approaches to microbial metabolic engineering. These constraint-based simulations are being integrated with the functional genomics portals, an activity that requires efficient implementation of the constraint based simulations in the web-based environment. RESULTS: Here, we present Acorn, an open source (GNU GPL) grid computing system for constraint-based simulations of genome scale metabolic reaction networks within an interactive web environment. The grid-based architecture allows efficient execution of computationally intensive, iterative protocols such as Flux Variability Analysis, which can be readily scaled up as the numbers of models (and users) increase. The web interface uses AJAX, which facilitates efficient model browsing and other search functions, and intuitive implementation of appropriate simulation conditions. Research groups can install Acorn locally and create user accounts. Users can also import models in the familiar SBML format and link reaction formulas to major functional genomics portals of choice. Selected models and simulation results can be shared between different users and made publically available. Users can construct pathway map layouts and import them into the server using a desktop editor integrated within the system. Pathway maps are then used to visualise numerical results within the web environment. To illustrate these features we have deployed Acorn and created a web server allowing constraint based simulations of the genome scale metabolic reaction networks of E. coli, S. cerevisiae and M. tuberculosis. CONCLUSIONS: Acorn is a free software package, which can be installed by research groups to create a web based environment for computer simulations of genome scale metabolic reaction networks. It facilitates shared access to models and creation of publicly available constraint based modelling resources. PMID- 21609435 TI - Assessment of joystick control during the performance of powered wheelchair driving tasks. AB - BACKGROUND: Powered wheelchairs are essential for many individuals who have mobility impairments. Nevertheless, if operated improperly, the powered wheelchair poses dangers to both the user and to those in its vicinity. Thus, operating a powered wheelchair with some degree of proficiency is important for safety, and measuring driving skills becomes an important issue to address. The objective of this study was to explore the discriminate validity of outcome measures of driving skills based on joystick control strategies and performance recorded using a data logging system. METHODS: We compared joystick control strategies and performance during standardized driving tasks between a group of 10 expert and 13 novice powered wheelchair users. Driving tasks were drawn from the Wheelchair Skills Test (v. 4.1). Data from the joystick controller were collected on a data logging system. Joystick control strategies and performance outcome measures included the mean number of joystick movements, time required to complete tasks, as well as variability of joystick direction. RESULTS: In simpler tasks, the expert group's driving skills were comparable to those of the novice group. Yet, in more difficult and spatially confined tasks, the expert group required fewer joystick movements for task completion. In some cases, experts also completed tasks in approximately half the time with respect to the novice group. CONCLUSIONS: The analysis of joystick control made it possible to discriminate between novice and expert powered wheelchair users in a variety of driving tasks. These results imply that in spatially confined areas, a greater powered wheelchair driving skill level is required to complete tasks efficiently. Based on these findings, it would appear that the use of joystick signal analysis constitutes an objective tool for the measurement of powered wheelchair driving skills. This tool may be useful for the clinical assessment and training of powered wheelchair skills. PMID- 21609436 TI - Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. AB - BACKGROUND: A molecular linkage between the MAPK and the LKB1-AMPK energy sensor pathways suggests that combined MAPK oncogene inhibition and metabolic modulation of AMPK would be more effective than either manipulation alone in melanoma cell lines. MATERIALS AND METHODS: The combination of the BRAF inhibitor vemurafenib (formerly PLX4032) and metformin were tested against a panel of human melanoma cell lines with defined BRAF and NRAS mutations for effects on viability, cell cycle and apoptosis. Signaling molecules in the MAPK, PI3K-AKT and LKB1-AMPK pathways were studied by Western blot. RESULTS: Single agent metformin inhibited proliferation in 12 out of 19 cell lines irrespective of the BRAF mutation status, but in one NRASQ61K mutant cell line it powerfully stimulated cell growth. Synergistic anti-proliferative effects of the combination of metformin with vemurafenib were observed in 6 out of 11 BRAFV600E mutants, including highly synergistic effects in two BRAFV600E mutant melanoma cell lines. Antagonistic effects were noted in some cell lines, in particular in BRAFV600E mutant cell lines resistant to single agent vemurafenib. Seven out of 8 BRAF wild type cell lines showed marginally synergistic anti-proliferative effects with the combination, and one cell line had highly antagonistic effects with the combination. The differential effects were not dependent on the sensitivity to each drug alone, effects on cell cycle or signaling pathways. CONCLUSIONS: The combination of vemurafenib and metformin tended to have stronger anti proliferative effects on BRAFV600E mutant cell lines. However, determinants of vemurafenib and metformin synergism or antagonism need to be understood with greater detail before any potential clinical utility of this combination. PMID- 21609437 TI - Thermal stability of RNA phage virus-like particles displaying foreign peptides. AB - BACKGROUND: To be useful for genetic display of foreign peptides a viral coat protein must tolerate peptide insertions without major disruption of subunit folding and capsid assembly. The folding of the coat protein of RNA phage MS2 does not normally tolerate insertions in its AB-loop, but an engineered single chain dimer readily accepts them as long as they are restricted to one of its two halves. RESULTS: Here we characterize the effects of peptide insertions on the thermal stabilities of MS2 virus-like particles (VLPs) displaying a variety of different peptides in one AB-loop of the coat protein single-chain dimer. These particles typically denature at temperatures around 5-10 degrees C lower than unmodified VLPs. Even so, they are generally stable up to about 50 degrees C. VLPs of the related RNA phage PP7 are cross-linked with intersubunit disulfide bonds and are therefore significantly more stable. An AB-loop insertion also reduces the stability of PP7 VLPs, but they only begin to denature above about 70 degrees C. CONCLUSIONS: VLPs assembled from MS2 single-chain dimer coat proteins with peptide insertions in one of their AB-loops are somewhat less stable than the wild-type particle, but still resist heating up to about 50 degrees C. Because they possess disulfide cross-links, PP7-derived VLPs provide an alternate platform with even higher stability. PMID- 21609438 TI - No connection between the level of exposition to statins in the population and the incidence/mortality of acute myocardial infarction: an ecological study based on Sweden's municipalities. AB - BACKGROUND: Randomised controlled trials have shown an excellent preventive effect of statins on ischemic heart disease. Our objective was to investigate if a relation can be detected between acute myocardial infarction- (AMI) mortality or incidence and statin utilisation, for men and women in different age-groups on a population basis. RESULTS: The utilisation rate of statins increased almost three times for both men and women between 1998 and 2002. During 1998-2000 the incidence of AMI decreased clearly for men but only slightly for women. Mortality decreased from 1998 to 2002. The change in statin utilisation from 1998 to 2000 showed no correlation to the change in AMI mortality from 2000 to 2002. Statin utilisation and AMI- incidence or mortality showed no correlations when adjusting for socio-economic deprivation, antidiabetic drugs and geographic coordinates. CONCLUSIONS: Despite a widespread and increasing utilisation of statins, no correlation to the incidence or mortality of AMI could be detected. Other factors than increased statin treatment should be analysed especially when discussing the allocation of public resources. PMID- 21609440 TI - ParaHaplo 3.0: A program package for imputation and a haplotype-based whole genome association study using hybrid parallel computing. AB - BACKGROUND: Use of missing genotype imputations and haplotype reconstructions are valuable in genome-wide association studies (GWASs). By modeling the patterns of linkage disequilibrium in a reference panel, genotypes not directly measured in the study samples can be imputed and used for GWASs. Since millions of single nucleotide polymorphisms need to be imputed in a GWAS, faster methods for genotype imputation and haplotype reconstruction are required. RESULTS: We developed a program package for parallel computation of genotype imputation and haplotype reconstruction. Our program package, ParaHaplo 3.0, is intended for use in workstation clusters using the Intel Message Passing Interface. We compared the performance of ParaHaplo 3.0 on the Japanese in Tokyo, Japan and Han Chinese in Beijing, and Chinese in the HapMap dataset. A parallel version of ParaHaplo 3.0 can conduct genotype imputation 20 times faster than a non-parallel version of ParaHaplo. CONCLUSIONS: ParaHaplo 3.0 is an invaluable tool for conducting haplotype-based GWASs. The need for faster genotype imputation and haplotype reconstruction using parallel computing will become increasingly important as the data sizes of such projects continue to increase. ParaHaplo executable binaries and program sources are available at http://en.sourceforge.jp/projects/parallelgwas/releases/. PMID- 21609439 TI - A reduction of CETP activity, not an increase, is associated with modestly impaired postprandial lipemia and increased HDL-cholesterol in adult asymptomatic women. AB - BACKGROUND: The relationship between CETP and postprandial hyperlipemia is still unclear. We verified the effects of varying activities of plasma CETP on postprandial lipemia and precocious atherosclerosis in asymptomatic adult women. METHODS: Twenty-eight women, selected from a healthy population sample (n = 148) were classified according to three CETP levels, all statistically different: CETP deficiency (CETPd <= 4.5%, n = 8), high activity (CETPi >= 23.8, n = 6) and controls (CTL, CETP >= 4.6% and <= 23.7%, n = 14). After a 12 h fast they underwent an oral fat tolerance test (40 g of fat/m2 of body surface area) for 8 hours. TG, TG-rich-lipoproteins (TRL), cholesterol and TRL-TG measurements (AUC, AUIC, AR, RR and late peaks) and comparisons were performed on all time points. Lipases and phospholipids transfer protein (PLTP) were determined. Correlation between carotid atherosclerosis (c-IMT) and postprandial parameters was determined. CETP TaqIB and I405V and ApoE-epsilon3/epsilon2/epsilon4 polymorphisms were examined. To elucidate the regulation of increased lipemia in CETPd a multiple linear regression analysis was performed. RESULTS: In the CETPi and CTL groups, CETP activity was respectively 9 and 5.3 higher compared to the CETPd group. Concentrations of all HDL fractions and ApoA-I were higher in the CETPd group and clearance was delayed, as demonstrated by modified lipemia parameters (AUC, AUIC, RR, AR and late peaks and meal response patterns). LPL or HL deficiencies were not observed. No genetic determinants of CETP deficiency or of postprandial lipemia were found. Correlations with c-IMT in the CETPd group indicated postprandial pro-atherogenic associations. In CETPd the regression multivariate analysis (model A) showed that CETP was largely and negatively predicted by VLDL-C lipemia (R2 = 92%) and much less by TG, LDL-C, ApoAI, phospholipids and non-HDL-C. CETP (model B) influenced mainly the increment in ApoB-100 containing lipoproteins (R2 = 85% negatively) and phospholipids (R2 = 13%), at the 6(th)h point. CONCLUSION: The moderate CETP deficiency phenotype included a paradoxically high HDL-C and its sub fractions (as earlier described), positive associations with c-IMT, a postprandial VLDL-C increment predicting negatively CETP activity and CETP activity regulating inversely the increment in ApoB100-containing lipoproteins. We hypothesize that the enrichment of TG content in triglyceride-rich ApoB-containing lipoproteins and in TG rich remnants increases lipoproteins' competition to active lipolysis sites,reducing their catabolism and resulting on postprandial lipemia with atherogenic consequences. PMID- 21609441 TI - The impact of rainfall and school break time policies on physical activity in 9 10 year old British children: a repeated measures study. AB - BACKGROUND: The weather may be a driver of seasonal patterns in children's physical activity (PA). A better understanding of the relationships between weather and PA may help increase children's PA. This study aims to examine the association between PA and rainfall in 9-10 year old children, and how it may be modified by school policies. METHODS: 1794 participants in the SPEEDY study in Norfolk, UK recorded PA using ActiGraph accelerometers over up to six days in the summer term of 2007. Multilevel regression models were used to determine the day by-day association between rainfall and minutes spent sedentary, in moderate-to vigorous PA (MVPA), and average counts per minute (cpm) over the whole day (07:00 21:00) and the lunchtime period (12:00-14:00). School policies for break times in bad weather were fitted as interaction terms with rainfall. RESULTS: Relative to days with no rain, children spent 9.4 minutes (95%CI 7.0 to 11.9) fewer in MVPA, were sedentary for 13.6 minutes (8.8 to 18.4) more, and accumulated 85.9 cpm (66.2 to 105.5) fewer over the whole day on the wettest days. Children allowed to play outside in wet weather showed the lowest lunchtime PA levels on the wettest days, undertaking 9.8 minutes (6.2 to 13.5) fewer MVPA, 16.1 minutes (10.3 to 21.9) more sedentary, and accumulating 408.0 cpm (250.9 to 565.1) fewer than those allowed to be active indoors. CONCLUSIONS: Rainfall is negatively associated with PA in primary school children, but providing indoor physical activities in wet weather may help children maintain physical activity levels irrespective of rainfall. PMID- 21609442 TI - Group and individual stability of three parenting dimensions. AB - BACKGROUND: The Parental Bonding Instrument, present self-report version, (PBI PCh) includes three scales, Warmth, Protectiveness and Authoritarianism, which describe three dimensions of current parenting. The purposes of this study were to (1) evaluate the true and observed stability of these parenting dimensions related to older children, (2) explore the distribution of individual-level change across nine months and (3) test potential parental predictors of parenting instability. METHODS: Questionnaires were distributed to school-based samples of community parents of both genders (n = 150) twice, nine months apart. These questionnaires measured parenting, parental personality and emotional symptoms. RESULTS: Based on 1) stability correlations, 2) true stability estimates from structural equation modeling (SEM) and 3) distribution of individual-level change, Warmth appeared rather stable, although not as stable as personality traits. Protectiveness was moderately stable, whereas Authoritarianism was the least stable parenting dimension among community parents. The differences in stability between the three dimensions were consistent in both estimated true stability and observed stability. Most of the instability in Warmth originated from a minority of parents with personality, childhood care characteristics and lower current parenting warmth. For the Protectiveness dimension, instability was associated with higher Protectiveness scores. CONCLUSIONS: True instability with all three self-reported parenting dimensions can occur across nine months in a community sample related to older children (7-15), but it may occur with varying degrees among dimensions and subpopulations. The highest stability was found for the Warmth parenting dimension, but a subgroup of "unstably cold" parents could be identified. Stability needs to be taken into account when interpreting longitudinal research on parenting and when planning and evaluating parenting interventions in research and clinical practice. PMID- 21609443 TI - The zebrafish transcriptome during early development. AB - BACKGROUND: The transition from fertilized egg to embryo is accompanied by a multitude of changes in gene expression, and the transcriptional events that underlie these processes have not yet been fully characterized. In this study RNA Seq is used to compare the transcription profiles of four early developmental stages in zebrafish (Danio rerio) on a global scale. RESULTS: An average of 79 M total reads were detected from the different stages. Out of the total number of reads 65% - 73% reads were successfully mapped and 36% - 44% out of those were uniquely mapped. The total number of detected unique gene transcripts was 11187, of which 10096 were present at 1-cell stage. The largest number of common transcripts was observed between 1-cell stage and 16-cell stage. An enrichment of gene transcripts with molecular functions of DNA binding, protein folding and processing as well as metal ion binding was observed with progression of development. The sequence data (accession number ERP000635) is available at the European Nucleotide Archive. CONCLUSION: Clustering of expression profiles shows that a majority of the detected gene transcripts are present at steady levels, and thus a minority of the gene transcripts clusters as increasing or decreasing in expression over the four investigated developmental stages. The three earliest developmental stages were similar when comparing highly expressed genes, whereas the 50% epiboly stage differed from the other three stages in the identity of highly expressed genes, number of uniquely expressed genes and enrichment of GO molecular functions. Taken together, these observations indicate a major transition in gene regulation and transcriptional activity taking place between the 512-cell and 50% epiboly stages, in accordance with previous studies. PMID- 21609445 TI - Biotransformation of myrcene by Pseudomonas aeruginosa. AB - BACKGROUND: Dihydrolinalool and terpineol are sources of fragrances that provide a unique volatile terpenoid alcohol of low toxicity and thus are widely used in the perfumery industry, in folk medicine, and in aromatherapy. They are important chemical constituents of the essential oil of many plants. Previous studies have concerned the biotransformation of limonene by Pseudomonas putida. The objective of this research was to study biotransformation of myrcene by Pseudomonas aeruginosa. The culture preparation was done using such variables as different microbial methods and incubation periods to obtain maximum cells of P. aeruginosa for myrcene biotransformation. RESULTS: It was found that myrcene was converted to dihydrolinalool and 2,6-dimethyloctane in high percentages. The biotransformation products were identified by Fourier-transform infrared spectroscopy (FT-IR), ultraviolet (UV) analysis, gas chromatography (GC), and gas chromatography-mass spectroscopy (GC-MS). Comparison of the different incubation times showed that 3 days was more effective, the major products being 2,6 dimethyloctane (90.0%) and alpha-terpineol (7.7%) and comprising 97.7%. In contrast, the main compounds derived for an incubation time of 1.5 days were dihydrolinalool (79.5%) and 2,6-dimethyloctane (9.3%), with a total yield of 88.8%. PMID- 21609444 TI - Drug safety of rosiglitazone and pioglitazone in France: a study using the French PharmacoVigilance database. AB - BACKGROUND: Thiazolidinediones (TZDs), rosiglitazone (RGZ) and pioglitazone (PGZ) are widely used as hypoglycemic drugs in patients with type 2 diabetes mellitus. The aim of our study was to investigate the profile of adverse drug reactions (ADRs) related to TZDs and to investigate potential risk factors of these ADRs. METHODS: Type 2 diabetic patients were identified from the French Database of PharmacoVigilance (FPVD) between 2002 and 2006. We investigated ADR related to TZD, focusing on 4 ADR: edema, heart failure, myocardial infarction and hepatitis corresponding to specific WHO-ART terms. RESULTS: Among a total of 99,284 adult patients in the FPVD, 2295 reports concerned type 2 diabetic patients (2.3% of the whole database), with 161 (7%) exposed to TZDs. The frequency of edema and cardiac failure was significantly higher with TZDs than in other patients (18% and 7.4% versus 0.8% and 0.1% respectively, p < 0.001) whereas the frequency of hepatitis was similar (5.9% versus 4%, NS). A multiple logistic regression model taking into account potential confounding factors (age, gender, drug exposure and co-morbidities) found that TZD exposure remained associated with heart failure and edema, but not with hepatitis or myocardial infarction. CONCLUSIONS: Thiazolidinediones exposure is associated with an increased risk of edema and heart failure in patients with type 2 diabetes even when recommendations for use are respected. In contrast, the risk of hepatic reactions and myocardial infarction with this class of drugs seems to be similar to other hypoglycemic agents. PMID- 21609446 TI - Investigation of tension wood formation and 2,6-dichlorbenzonitrile application in short rotation coppice willow composition and enzymatic saccharification. AB - BACKGROUND: Short rotation coppice willow is a potential lignocellulosic feedstock in the United Kingdom and elsewhere; however, research on optimising willow specifically for bioethanol production has started developing only recently. We have used the feedstock Salix viminalis * Salix schwerinii cultivar 'Olof' in a three-month pot experiment with the aim of modifying cell wall composition and structure within the stem to the benefit of bioethanol production. Trees were treated for 26 or 43 days with tension wood induction and/or with an application of the cellulose synthesis inhibitor 2,6 dichlorobenzonitrile that is specific to secondary cell walls. Reaction wood (tension and opposite wood) was isolated from material that had received the 43 day tension wood induction treatment. RESULTS: Glucan content, lignin content and enzymatically released glucose were assayed. All measured parameters were altered without loss of total stem biomass yield, indicating that enzymatic saccharification yield can be enhanced by both alterations to cell wall structure and alterations to absolute contents of either glucan or lignin. CONCLUSIONS: Final glucose yields can be improved by the induction of tension wood without a detrimental impact on biomass yield. The increase in glucan accessibility to cell wall degrading enzymes could help contribute to reducing the energy and environmental impacts of the lignocellulosic bioethanol production process. PMID- 21609447 TI - Long-term benefits of omalizumab in a patient with severe non-allergic asthma. AB - INTRODUCTION: Currently, omalizumab is indicated for the treatment of patients with severe allergic uncontrolled asthma despite optimal therapy. CASE PRESENTATION: We studied a 52-year-old man who has been suffering from severe non allergic steroid-resistant asthma with increased levels of total IgE and a lot of comorbidity. After a 3 years long treatment with omalizumab, he presented a significant improvement in disease control in terms of hospitalizations, exacerbation, quality of life and lung function with good safety profile. CONCLUSION: Our case shows, after a long follow-up, how omalizumab can be effective in a severe form of non-atopic asthma. It is therefore hoped that further studies can identify indicators that are able to give to clinicians information about patients who can be responsive to monoclonal anti-IgE antibody even if non allergic. PMID- 21609448 TI - Ecological character displacement in the face of gene flow: evidence from two species of nightingales. AB - BACKGROUND: Ecological character displacement is a process of phenotypic differentiation of sympatric populations caused by interspecific competition. Such differentiation could facilitate speciation by enhancing reproductive isolation between incipient species, although empirical evidence for it at early stages of divergence when gene flow still occurs between the species is relatively scarce. Here we studied patterns of morphological variation in sympatric and allopatric populations of two hybridizing species of birds, the Common Nightingale (Luscinia megarhynchos) and the Thrush Nightingale (L. luscinia). RESULTS: We conducted principal component (PC) analysis of morphological traits and found that nightingale species converged in overall body size (PC1) and diverged in relative bill size (PC3) in sympatry. Closer analysis of morphological variation along geographical gradients revealed that the convergence in body size can be attributed largely to increasing body size with increasing latitude, a phenomenon known as Bergmann's rule. In contrast, interspecific interactions contributed significantly to the observed divergence in relative bill size, even after controlling for the effects of geographical gradients. We suggest that the divergence in bill size most likely reflects segregation of feeding niches between the species in sympatry. CONCLUSIONS: Our results suggest that interspecific competition for food resources can drive species divergence even in the face of ongoing hybridization. Such divergence may enhance reproductive isolation between the species and thus contribute to speciation. PMID- 21609449 TI - Monitoring trends in HIV prevalence among young people, aged 15 to 24 years, in Manicaland, Zimbabwe. AB - BACKGROUND: In June 2001, the United Nations General Assembly Special Session (UNGASS) set a target of reducing HIV prevalence among young women and men, aged 15 to 24 years, by 25% in the worst-affected countries by 2005, and by 25% globally by 2010. We assessed progress toward this target in Manicaland, Zimbabwe, using repeated household-based population serosurvey data. We also validated the representativeness of surveillance data from young pregnant women, aged 15 to 24 years, attending antenatal care (ANC) clinics, which UNAIDS recommends for monitoring population HIV prevalence trends in this age group. Changes in socio-demographic characteristics and reported sexual behaviour are investigated. METHODS: Progress towards the UNGASS target was measured by calculating the proportional change in HIV prevalence among youth and young ANC attendees over three survey periods (round 1: 1998-2000; round 2: 2001-2003; and round 3: 2003-2005). The Z-score test was used to compare differences in trends between the two data sources. Characteristics of participants and trends in sexual risk behaviour were analyzed using Student's and two-tailed Z-score tests. RESULTS: HIV prevalence among youth in the general population declined by 50.7% (from 12.2% to 6.0%) from round 1 to 3. Intermediary trends showed a large decline from round 1 to 2 of 60.9% (from 12.2% to 4.8%), offset by an increase from round 2 to 3 of 26.0% (from 4.8% to 6.0%). Among young ANC attendees, the proportional decline in prevalence of 43.5% (from 17.9% to 10.1%) was similar to that in the population (test for differences in trend: p value=0.488) although ANC data significantly underestimated the population prevalence decline from round 1 to 2 (test for difference in trend: p value=0.003) and underestimated the increase from round 2 to 3 (test for difference in trend: p value=0.012). Reductions in risk behaviour between rounds 1 and 2 may have been responsible for general population prevalence declines. CONCLUSIONS: In Manicaland, Zimbabwe, the 2005 UNGASS target to reduce HIV prevalence by 25% was achieved. However, most prevention gains occurred before 2003. ANC surveillance trends overall were an adequate indicator of trends in the population, although lags were observed. Behaviour data and socio-demographic characteristics of participants are needed to interpret ANC trends. PMID- 21609450 TI - Attenuated expression of HRH4 in colorectal carcinomas: a potential influence on tumor growth and progression. AB - BACKGROUND: Earlier studies have reported the production of histamine in colorectal cancers (CRCs). The effect of histamine is largely determined locally by the histamine receptor expression pattern. Recent evidence suggests that the expression level of histamine receptor H4 (HRH4) is abnormal in colorectal cancer tissues. However, the role of HRH4 in CRC progression and its clinical relevance is not well understood. The aim of this study is to evaluate the clinical and molecular phenotypes of colorectal tumors with abnormal HRH4 expression. METHODS: Immunoblotting, real-time PCR, immunofluorescence and immunohistochemistry assays were adopted to examine HRH4 expression in case-matched CRC samples (n = 107) and adjacent normal tissues (ANTs). To assess the functions of HRH4 in CRC cells, we established stable HRH4-transfected colorectal cells and examined cell proliferation, colony formation, cell cycle and apoptosis in these cells. RESULTS: The protein levels of HRH4 were reduced in most of the human CRC samples regardless of grade or Dukes classification. mRNA levels of HRH4 were also reduced in both early-stage and advanced CRC samples. In vitro studies showed that HRH4 over-expression caused growth arrest and induced expression of cell cycle proteins in CRC cells upon exposure to histamine through a cAMP -dependent pathway. Furthermore, HRH4 stimulation promoted the 5-Fu-induced cell apoptosis in HRH4-positive colorectal cells. CONCLUSION: The results from the current study supported previous findings of HRH4 abnormalities in CRCs. Expression levels of HRH4 could influence the histamine-mediated growth regulation in CRC cells. These findings suggested a potential role of abnormal HRH4 expression in the progression of CRCs and provided some new clues for the application of HRH4 specific agonist or antagonist in the molecular therapy of CRCs. PMID- 21609451 TI - Principal component approach in variance component estimation for international sire evaluation. AB - BACKGROUND: The dairy cattle breeding industry is a highly globalized business, which needs internationally comparable and reliable breeding values of sires. The international Bull Evaluation Service, Interbull, was established in 1983 to respond to this need. Currently, Interbull performs multiple-trait across country evaluations (MACE) for several traits and breeds in dairy cattle and provides international breeding values to its member countries. Estimating parameters for MACE is challenging since the structure of datasets and conventional use of multiple-trait models easily result in over-parameterized genetic covariance matrices. The number of parameters to be estimated can be reduced by taking into account only the leading principal components of the traits considered. For MACE, this is readily implemented in a random regression model. METHODS: This article compares two principal component approaches to estimate variance components for MACE using real datasets. The methods tested were a REML approach that directly estimates the genetic principal components (direct PC) and the so-called bottom up REML approach (bottom-up PC), in which traits are sequentially added to the analysis and the statistically significant genetic principal components are retained. Furthermore, this article evaluates the utility of the bottom-up PC approach to determine the appropriate rank of the (co)variance matrix. RESULTS: Our study demonstrates the usefulness of both approaches and shows that they can be applied to large multi-country models considering all concerned countries simultaneously. These strategies can thus replace the current practice of estimating the covariance components required through a series of analyses involving selected subsets of traits. Our results support the importance of using the appropriate rank in the genetic (co)variance matrix. Using too low a rank resulted in biased parameter estimates, whereas too high a rank did not result in bias, but increased standard errors of the estimates and notably the computing time. CONCLUSIONS: In terms of estimation's accuracy, both principal component approaches performed equally well and permitted the use of more parsimonious models through random regression MACE. The advantage of the bottom-up PC approach is that it does not need any previous knowledge on the rank. However, with a predetermined rank, the direct PC approach needs less computing time than the bottom-up PC. PMID- 21609452 TI - Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer. AB - BACKGROUND: Elucidating the exact relationship between gene copy number and expression would enable identification of regulatory mechanisms of abnormal gene expression and biological pathways of regulation. Most current approaches either depend on linear correlation or on nonparametric tests of association that are insensitive to the exact shape of the relationship. Based on knowledge of enzyme kinetics and gene regulation, we would expect the functional shape of the relationship to be gene dependent and to be related to the gene regulatory mechanisms involved. Here, we propose a statistical approach to investigate and distinguish between linear and nonlinear dependences between DNA copy number alteration and mRNA expression. RESULTS: We applied the proposed method to DNA copy numbers derived from Illumina 109 K SNP-CGH arrays (using the log R values) and expression data from Agilent 44 K mRNA arrays, focusing on commonly aberrated genomic loci in a collection of 102 breast tumors. Regression analysis was used to identify the type of relationship (linear or nonlinear), and subsequent pathway analysis revealed that genes displaying a linear relationship were overall associated with substantially different biological processes than genes displaying a nonlinear relationship. In the group of genes with a linear relationship, we found significant association to canonical pathways, including purine and pyrimidine metabolism (for both deletions and amplifications) as well as estrogen metabolism (linear amplification) and BRCA-related response to damage (linear deletion). In the group of genes displaying a nonlinear relationship, the top canonical pathways were specific pathways like PTEN and PI13K/AKT (nonlinear amplification) and Wnt(B) and IL-2 signalling (nonlinear deletion). Both amplifications and deletions pointed to the same affected pathways and identified cancer as the top significant disease and cell cycle, cell signaling and cellular development as significant networks. CONCLUSIONS: This paper presents a novel approach to assessing the validity of the dependence of expression data on copy number data, and this approach may help in identifying the drivers of carcinogenesis. PMID- 21609453 TI - Recurrence patterns of locally advanced head and neck squamous cell carcinoma after 3D conformal (chemo)-radiotherapy. AB - BACKGROUND: To establish recurrence patterns among locally advanced head and neck non-nasopharyngeal squamous cell carcinoma (HNSCC) patients treated with radical (chemo-) radiotherapy and to correlate the sites of loco-regional recurrence with radiotherapy doses and target volumes METHOD: 151 locally advanced HNSCC patients were treated between 2004-2005 using radical three-dimensional conformal radiotherapy. Patients with prior surgery to the primary tumour site were excluded. The sites of locoregional relapses were correlated with radiotherapy plans by the radiologist and a planning dosimetrist. RESULTS: Median age was 59 years (range:34-89). 35 patients had stage III disease, 116 patients had stage IV A/B. 36 patients were treated with radiotherapy alone, 42 with induction chemotherapy, 63 with induction and concomitant chemoradiotherapy and 10 concomitant chemoradiotherapy. Median follow-up was 38 months (range 3-62). 3 year cause specific survival was 66.8%. 125 of 151 (82.8%) achieved a complete response to treatment. Amongst these 125 there were 20 local-regional recurrence, comprising 8 local, 5 regional and 7 simultaneous local and regional; synchronous distant metastases occurred in 7 of the 20. 9 patients developed distant metastases in the absence of locoregional failure. For the 14 local recurrences with planning data available, 12 were in-field, 1 was marginal, and 1 was out-of field. Of the 11 regional failures with planning data available, 7 were in-field, 1 was marginal and 3 were out-of-field recurrences. CONCLUSION: The majority of failures following non-surgical treatment for locally advanced HNSCC were loco regional, within the radiotherapy target volume. Improving locoregional control remains a high priority. PMID- 21609454 TI - Transcriptomic assessment of resistance to effects of an aryl hydrocarbon receptor (AHR) agonist in embryos of Atlantic killifish (Fundulus heteroclitus) from a marine Superfund site. AB - BACKGROUND: Populations of Atlantic killifish (Fundulus heteroclitus) have evolved resistance to the embryotoxic effects of polychlorinated biphenyls (PCBs) and other halogenated and nonhalogenated aromatic hydrocarbons that act through an aryl hydrocarbon receptor (AHR)-dependent signaling pathway. The resistance is accompanied by reduced sensitivity to induction of cytochrome P450 1A (CYP1A), a widely used biomarker of aromatic hydrocarbon exposure and effect, but whether the reduced sensitivity is specific to CYP1A or reflects a genome-wide reduction in responsiveness to all AHR-mediated changes in gene expression is unknown. We compared gene expression profiles and the response to 3,3',4,4',5 pentachlorobiphenyl (PCB-126) exposure in embryos (5 and 10 dpf) and larvae (15 dpf) from F. heteroclitus populations inhabiting the New Bedford Harbor, Massachusetts (NBH) Superfund site (PCB-resistant) and a reference site, Scorton Creek, Massachusetts (SC; PCB-sensitive). RESULTS: Analysis using a 7,000-gene cDNA array revealed striking differences in responsiveness to PCB-126 between the populations; the differences occur at all three stages examined. There was a sizeable set of PCB-responsive genes in the sensitive SC population, a much smaller set of PCB-responsive genes in NBH fish, and few similarities in PCB responsive genes between the two populations. Most of the array results were confirmed, and additional PCB-regulated genes identified, by RNA-Seq (deep pyrosequencing). CONCLUSIONS: The results suggest that NBH fish possess a gene regulatory defect that is not specific to one target gene such as CYP1A but rather lies in a regulatory pathway that controls the transcriptional response of multiple genes to PCB exposure. The results are consistent with genome-wide disruption of AHR-dependent signaling in NBH fish. PMID- 21609455 TI - Assessment and comparative analysis of a rapid diagnostic test (Tubex(r)) for the diagnosis of typhoid fever among hospitalized children in rural Tanzania. AB - BACKGROUND: Typhoid fever remains a significant health problem in many developing countries. A rapid test with a performance comparable to that of blood culture would be highly useful. A rapid diagnostic test for typhoid fever, Tubex(r), is commercially available that uses particle separation to detect immunoglobulin M directed towards Salmonella Typhi O9 lipopolysaccharide in sera. METHODS: We assessed the sensitivity and specificity of the Tubex test among Tanzanian children hospitalized with febrile illness using blood culture as gold standard. Evaluation was done considering blood culture confirmed S. Typhi with non-typhi salmonella (NTS) and non - salmonella isolates as controls as well as with non salmonella isolates only. RESULTS: Of 139 samples tested with Tubex, 33 were positive for S. Typhi in blood culture, 49 were culture-confirmed NTS infections, and 57 were other non-salmonella infections. Thirteen hemolyzed samples were excluded. Using all non - S. Typhi isolates as controls, we showed a sensitivity of 79% and a specificity of 89%. When the analysis was repeated excluding NTS from the pool of controls we showed a sensitivity of 79% and a specificity of 97%. There was no significant difference in the test performance using the two different control groups (p > 0.05). CONCLUSION: This first evaluation of the Tubex test in an African setting showed a similar performance to those seen in some Asian settings. Comparison with the earlier results of a Widal test using the same samples showed no significant difference (p > 0.05) for any of the performance indicators, irrespective of the applied control group. PMID- 21609456 TI - Associations between ozone and morbidity using the Spatial Synoptic Classification system. AB - BACKGROUND: Synoptic circulation patterns (large-scale tropospheric motion systems) affect air pollution and, potentially, air-pollution-morbidity associations. We evaluated the effect of synoptic circulation patterns (air masses) on the association between ozone and hospital admissions for asthma and myocardial infarction (MI) among adults in North Carolina. METHODS: Daily surface meteorology data (including precipitation, wind speed, and dew point) for five selected cities in North Carolina were obtained from the U.S. EPA Air Quality System (AQS), which were in turn based on data from the National Climatic Data Center of the National Oceanic and Atmospheric Administration. We used the Spatial Synoptic Classification system to classify each day of the 9-year period from 1996 through 2004 into one of seven different air mass types: dry polar, dry moderate, dry tropical, moist polar, moist moderate, moist tropical, or transitional. Daily 24-hour maximum 1-hour ambient concentrations of ozone were obtained from the AQS. Asthma and MI hospital admissions data for the 9-year period were obtained from the North Carolina Department of Health and Human Services. Generalized linear models were used to assess the association of the hospitalizations with ozone concentrations and specific air mass types, using pollutant lags of 0 to 5 days. We examined the effect across cities on days with the same air mass type. In all models we adjusted for dew point and day-of-the week effects related to hospital admissions. RESULTS: Ozone was associated with asthma under dry tropical (1- to 5-day lags), transitional (3- and 4-day lags), and extreme moist tropical (0-day lag) air masses. Ozone was associated with MI only under the extreme moist tropical (5-day lag) air masses. CONCLUSIONS: Elevated ozone levels are associated with dry tropical, dry moderate, and moist tropical air masses, with the highest ozone levels being associated with the dry tropical air mass. Certain synoptic circulation patterns/air masses in conjunction with ambient ozone levels were associated with increased asthma and MI hospitalizations. PMID- 21609457 TI - Effect of recombinant IL-10 on cultured fetal rat alveolar type II cells exposed to 65%-hyperoxia. AB - BACKGROUND: Hyperoxia plays an important role in the genesis of lung injury in preterm infants. Although alveolar type II cells are the main target of hyperoxic lung injury, the exact mechanisms whereby hyperoxia on fetal alveolar type II cells contributes to the genesis of lung injury are not fully defined, and there have been no specific measures for protection of fetal alveolar type II cells. OBJECTIVE: The aim of this study was to investigate (a) cell death response and inflammatory response in fetal alveolar type II cells in the transitional period from canalicular to saccular stages during 65%-hyperoxia and (b) whether the injurious stimulus is promoted by creating an imbalance between pro- and anti inflammatory cytokines and (c) whether treatment with an anti-inflammatory cytokine may be effective for protection of fetal alveolar type II cells from injury secondary to 65%-hyperoxia. METHODS: Fetal alveolar type II cells were isolated on embryonic day 19 and exposed to 65%-oxygen for 24 h and 36 h. Cells in room air were used as controls. Cellular necrosis was assessed by lactate dehydrogenase-release and flow cytometry, and apoptosis was analyzed by TUNEL assay and flow cytometry, and cell proliferation was studied by BrdU incorporation. Release of cytokines including VEGF was analyzed by ELISA, and their gene expressions were investigated by qRT-PCR. RESULTS: 65%-hyperoxia increased cellular necrosis, whereas it decreased cell proliferation in a time dependent manner compared to controls. 65%-hyperoxia stimulated IL-8-release in a time-dependent fashion, whereas the anti-inflammatory cytokine, IL-10, showed an opposite response. 65%-hyperoxia induced a significant decrease of VEGF-release compared to controls, and similar findings were observed on IL-8/IL-10/VEGF genes expression. Preincubation of recombinant IL-10 prior to 65%-hyperoxia decreased cellular necrosis and IL-8-release, and increased VEGF-release and cell proliferation significantly compared to hyperoxic cells without IL-10. CONCLUSIONS: The present study provides an experimental evidence that IL-10 may play a potential role in protection of fetal alveolar type II cells from injury induced by 65%-hyperoxia. PMID- 21609458 TI - The Regulation of Leptin, Leptin Receptor and Pro-opiomelanocortin Expression by N-3 PUFAs in Diet-Induced Obese Mice Is Not Related to the Methylation of Their Promoters. AB - BACKGROUND: The expression of leptin is increased in obesity and inhibited by n-3 polyunsaturated fatty acids (n-3 PUFAs), but the underlying molecular mechanisms have not been firmly established. METHODS: In this study, we investigated the effects of dietary n-3 PUFAs on the methylation of CpG islands in the promoter regions of the leptin, leptin-R and POMC genes, as well as the effects of n-3 PUFA status in early life on the modification of the promoters of these three genes. Male C57 BL/6J mice were fed a high-fat diet with one of four different fat types: sunflower oil (n-3 PUFA deficient), soy oil, fish oil, or a mixture of soy and fish oil (soy:fish oil = 1:1). Two low-fat diets with sunflower oil or soy oil served as controls. Female mice were fed two breeding diets, sunflower oil or a mixture of soy and fish oil (soy:fish oil = 1:1), during pregnancy and lactation to breed new pups. RESULTS: Compared to mice fed the control diets, the expression of leptin in fat tissue and leptin-R and POMC in the hypothalamus was higher in the diet-induced obesity (DIO) mice, and the n-3 PUFAs in the diets reversed these elevated expression levels. The mean methylation levels of CpG sites in the promoter regions of the leptin and POMC genes showed no difference between the DIO and the control diet groups nor between the n-3 PUFA-containing and -deficient diet groups. For the CpG sites in the promoter regions of leptin R, no methylation was found in any of the DIO or control groups. Feeding mice with the n-3 PUFA diet during pregnancy and lactation did not affect CpG methylation in the leptin or POMC promoters. CONCLUSIONS: Our findings indicate that promoter DNA methylation may not be related to the expression of leptin, leptin-R or its related hypothalamic satiety regulator POMC. PMID- 21609459 TI - Seizure classification in EEG signals utilizing Hilbert-Huang transform. AB - BACKGROUND: Classification method capable of recognizing abnormal activities of the brain functionality are either brain imaging or brain signal analysis. The abnormal activity of interest in this study is characterized by a disturbance caused by changes in neuronal electrochemical activity that results in abnormal synchronous discharges. The method aims at helping physicians discriminate between healthy and seizure electroencephalographic (EEG) signals. METHOD: Discrimination in this work is achieved by analyzing EEG signals obtained from freely accessible databases. MATLAB has been used to implement and test the proposed classification algorithm. The analysis in question presents a classification of normal and ictal activities using a feature relied on Hilbert Huang Transform. Through this method, information related to the intrinsic functions contained in the EEG signal has been extracted to track the local amplitude and the frequency of the signal. Based on this local information, weighted frequencies are calculated and a comparison between ictal and seizure free determinant intrinsic functions is then performed. Methods of comparison used are the t-test and the Euclidean clustering. RESULTS: The t-test results in a P-value < 0.02 and the clustering leads to accurate (94%) and specific (96%) results. The proposed method is also contrasted against the Multivariate Empirical Mode Decomposition that reaches 80% accuracy. Comparison results strengthen the contribution of this paper not only from the accuracy point of view but also with respect to its fast response and ease to use. CONCLUSION: An original tool for EEG signal processing giving physicians the possibility to diagnose brain functionality abnormalities is presented in this paper. The proposed system bears the potential of providing several credible benefits such as fast diagnosis, high accuracy, good sensitivity and specificity, time saving and user friendly. Furthermore, the classification of mode mixing can be achieved using the extracted instantaneous information of every IMF, but it would be most likely a hard task if only the average value is used. Extra benefits of this proposed system include low cost, and ease of interface. All of that indicate the usefulness of the tool and its use as an efficient diagnostic tool. PMID- 21609460 TI - Impact of today's media on university student's body image in Pakistan: a conservative, developing country's perspective. AB - BACKGROUND: Living in a world greatly controlled by mass media makes it impossible to escape its pervading influence. As media in Pakistan has been free in the true sense of the word for only a few years, its impact on individuals is yet to be assessed. Our study aims to be the first to look at the effect media has on the body image of university students in a conservative, developing country like Pakistan. Also, we introduced the novel concept of body image dissatisfaction as being both negative and positive. METHODS: A cross-sectional study was conducted among 7 private universities over a period of two weeks in the city of Karachi, Pakistan's largest and most populous city. Convenience sampling was used to select both male and female undergraduate students aged between 18 and 25 and a sample size of 783 was calculated. RESULTS: Of the 784 final respondents, 376 (48%) were males and 408 (52%) females. The mean age of males was 20.77 (+/- 1.85) years and females was 20.38 (+/- 1.63) years. Out of these, 358 (45.6%) respondents had a positive BID (body image dissatisfaction) score while 426 (54.4%) had a negative BID score. Of the respondents who had positive BID scores, 93 (24.7%) were male and 265 (65.0%) were female. Of the respondents with a negative BID score, 283 (75.3%) were male and 143 (35.0%) were female. The results for BID vs. media exposure were similar in both high and low peer pressure groups. Low media exposure meant positive BID scores and vice versa in both groups (p < 0.0001) showing a statistically significant association between high media exposure and negative body image dissatisfaction. Finally, we looked at the association between gender and image dissatisfaction. Again a statistically significant association was found between positive body image dissatisfaction and female gender and negative body image dissatisfaction and male gender (p < 0.0001). CONCLUSIONS: Our study confirmed the tendency of the media to have an overall negative effect on individuals' body image. A striking feature of our study, however, was the finding that negative body image dissatisfaction was found to be more prevalent in males as compared to females. Likewise, positive BID scores were more prevalent amongst females. PMID- 21609461 TI - Complementary and alternative medicine use in oncology: a questionnaire survey of patients and health care professionals. AB - BACKGROUND: We aimed to investigate the prevalence and predictors of Complementary and Alternative Medicine (CAM) use among cancer patients and non cancer volunteers, and to assess the knowledge of and attitudes toward CAM use in oncology among health care professionals. METHODS: This is a cross-sectional questionnaire survey conducted in a single institution in Ireland. Survey was performed in outpatient and inpatient settings involving cancer patients and non cancer volunteers. Clinicians and allied health care professionals were asked to complete a different questionnaire. RESULTS: In 676 participants including 219 cancer patients; 301 non-cancer volunteers and 156 health care professionals, the overall prevalence of CAM use was 32.5% (29.1%, 30.9% and 39.7% respectively in the three study cohorts). Female gender (p < 0.001), younger age (p = 0.004), higher educational background (p < 0.001), higher annual household income (p = 0.001), private health insurance (p = 0.001) and non-Christian (p < 0.001) were factors associated with more likely CAM use. Multivariate analysis identified female gender (p < 0.001), non-Christian (p = 0.001) and private health insurance (p = 0.015) as independent predictors of CAM use. Most health care professionals thought they did not have adequate knowledge (58.8%) nor were up to date with the best evidence (79.2%) on CAM use in oncology. Health care professionals who used CAM were more likely to recommend it to patients (p < 0.001). CONCLUSIONS: This study demonstrates a similarly high prevalence of CAM use among oncology health care professionals, cancer and non cancer patients. Patients are more likely to disclose CAM usage if they are specifically asked. Health care professionals are interested to learn more about various CAM therapies and have poor evidence-based knowledge on specific oncology treatments. There is a need for further training to meet to the escalation of CAM use among patients and to raise awareness of potential benefits and risks associated with these therapies. PMID- 21609462 TI - Using spatial analysis to demonstrate the heterogeneity of the cardiovascular drug-prescribing pattern in Taiwan. AB - BACKGROUND: Geographic Information Systems (GIS) combined with spatial analytical methods could be helpful in examining patterns of drug use. Little attention has been paid to geographic variation of cardiovascular prescription use in Taiwan. The main objective was to use local spatial association statistics to test whether or not the cardiovascular medication-prescribing pattern is homogenous across 352 townships in Taiwan. METHODS: The statistical methods used were the global measures of Moran's I and Local Indicators of Spatial Association (LISA). While Moran's I provides information on the overall spatial distribution of the data, LISA provides information on types of spatial association at the local level. LISA statistics can also be used to identify influential locations in spatial association analysis. The major classes of prescription cardiovascular drugs were taken from Taiwan's National Health Insurance Research Database (NHIRD), which has a coverage rate of over 97%. The dosage of each prescription was converted into defined daily doses to measure the consumption of each class of drugs. Data were analyzed with ArcGIS and GeoDa at the township level. RESULTS: The LISA statistics showed an unusual use of cardiovascular medications in the southern townships with high local variation. Patterns of drug use also showed more low-low spatial clusters (cold spots) than high-high spatial clusters (hot spots), and those low-low associations were clustered in the rural areas. CONCLUSIONS: The cardiovascular drug prescribing patterns were heterogeneous across Taiwan. In particular, a clear pattern of north-south disparity exists. Such spatial clustering helps prioritize the target areas that require better education concerning drug use. PMID- 21609463 TI - HMM-FRAME: accurate protein domain classification for metagenomic sequences containing frameshift errors. AB - BACKGROUND: Protein domain classification is an important step in metagenomic annotation. The state-of-the-art method for protein domain classification is profile HMM-based alignment. However, the relatively high rates of insertions and deletions in homopolymer regions of pyrosequencing reads create frameshifts, causing conventional profile HMM alignment tools to generate alignments with marginal scores. This makes error-containing gene fragments unclassifiable with conventional tools. Thus, there is a need for an accurate domain classification tool that can detect and correct sequencing errors. RESULTS: We introduce HMM FRAME, a protein domain classification tool based on an augmented Viterbi algorithm that can incorporate error models from different sequencing platforms. HMM-FRAME corrects sequencing errors and classifies putative gene fragments into domain families. It achieved high error detection sensitivity and specificity in a data set with annotated errors. We applied HMM-FRAME in Targeted Metagenomics and a published metagenomic data set. The results showed that our tool can correct frameshifts in error-containing sequences, generate much longer alignments with significantly smaller E-values, and classify more sequences into their native families. CONCLUSIONS: HMM-FRAME provides a complementary protein domain classification tool to conventional profile HMM-based methods for data sets containing frameshifts. Its current implementation is best used for small scale metagenomic data sets. The source code of HMM-FRAME can be downloaded at http://www.cse.msu.edu/~zhangy72/hmmframe/ and at https://sourceforge.net/projects/hmm-frame/. PMID- 21609464 TI - Clusterin confers gemcitabine resistance in pancreatic cancer. AB - OBJECTIVE: To measure clusterin expression in pancreatic cancer tissues and cell lines and to evaluate whether clusterin confers resistance to gmcitabine in pancreatic cancer cells. METHODS: Immunohistochemistry for clusterin was performed on 50 primary pancreatic cancer tissues and 25 matched backgrounds, and clusterin expression in 5 pancreatic cancer cell lines was quantified by Western blot and PT-PCR. The correlation between clusterin expression level and gmcitabine IC50 in pancreatic cancer cell lines was evaluated. The effect of an antisense oligonucleotide (ASO) against clusterin (ASO-CLU) [corrected] on gmcitabine resistance was evaluated by MTT assays. Xenograft model was used to demonstrate tumor growth. RESULTS: Pancreatic cancer tissues expressed significantly higher levels of clusterin than did normal pancreatic tissues (P < 0.01). Clusterin expression levels were correlated with gmcitabine resistance in pancreatic cancer cell lines, and ASO-CLU [corrected] significantly decreased BxPc-3 cells resistance to gmcitabine (P < 0.01). In vivo systemic administration of AS clusterin and gmcitabine significantly decreased the s.c. BxPC-3 tumor volume compared with mismatch control ODN plus gmcitabine. CONCLUSION: Our finding that clusterin expression was significantly higher in pancreatic cancer than in normal pancreatic tissues suggests that clusterin may confer gmcitabine resistance in pancreatic cancer cells. PMID- 21609465 TI - Endothelial progenitor cell biology in disease and tissue regeneration. AB - Endothelial progenitor cells are increasingly being studied in various diseases ranging from ischemia, diabetic retinopathy, and in cancer. The discovery that these cells can be mobilized from their bone marrow niche to sites of inflammation and tumor to induce neovasculogenesis has afforded a novel opportunity to understand the tissue microenvironment and specific cell-cell interactive pathways. This review provides a comprehensive up-to-date understanding of the physiological function and therapeutic utility of these cells. The emphasis is on the systemic factors that modulate their differentiation/mobilization and survival and presents the challenges of its potential therapeutic clinical utility as a diagnostic and prognostic reagent. PMID- 21609466 TI - The HPV-16 E7 oncoprotein induces centriole multiplication through deregulation of Polo-like kinase 4 expression. AB - BACKGROUND: Infection with high-risk human papillomaviruses (HPVs) such as HPV-16 is intimately associated with squamous cell carcinomas (SCCs) of the anogenital tract and a subset of oropharyngeal carcinomas. Such lesions, including pre invasive precursors, frequently show multipolar mitoses and aneuploidy. The high risk HPV-16-encoded E7 oncoprotein has been shown to rapidly induce centrosome abnormalities thereby causing the formation of supernumerary mitotic spindle poles and increasing the risk for chromosome missegregation. HPV-16 E7 has been found to rapidly induce centriole overduplication, in part, through the simultaneous formation of more than one daughter centriole at single maternal centrioles (centriole multiplication). The precise molecular mechanism that underlies HPV-16 E7-induced centriole multiplication, however, remains poorly understood. FINDINGS: Here, we show that human keratinocytes engineered to stably express the HPV-16 E7 oncoprotein exhibit aberrant Polo-like kinase 4 (PLK4) protein expression at maternal centrioles. Real-time quantitative reverse transcriptase (qRT-PCR) analysis of these cells revealed an increase of PLK4 mRNA levels compared to control cells. Importantly, the ability of the HPV-16 E7 oncoprotein to induce centriole multiplication was found to correlate with its ability to activate the PLK4 promoter and to up-regulate PLK4 mRNA. CONCLUSIONS: These results highlight the critical role of PLK4 transcriptional deregulation in centriole multiplication in HPV-16 E7-expressing cells. Our findings encourage further experiments to test transcriptional inhibitors or small molecules targeting PLK4 to prevent centriole abnormalities, mitotic infidelity and malignant progression in HPV-associated neoplasms and other tumors in which PLK4 regulation is disrupted. PMID- 21609467 TI - The effects of disruption of phosphoglucose isomerase gene on carbon utilisation and cellulase production in Trichoderma reesei Rut-C30. AB - BACKGROUND: Cellulase and hemicellulase genes in the fungus Trichoderma reesei are repressed by glucose and induced by lactose. Regulation of the cellulase genes is mediated by the repressor CRE1 and the activator XYR1. T. reesei strain Rut-C30 is a hypercellulolytic mutant, obtained from the natural strain QM6a, that has a truncated version of the catabolite repressor gene, cre1. It has been previously shown that bacterial mutants lacking phosphoglucose isomerase (PGI) produce more nucleotide precursors and amino acids. PGI catalyzes the second step of glycolysis, the formation of fructose-6-P from glucose-6-P. RESULTS: We deleted the gene pgi1, encoding PGI, in the T. reesei strain Rut-C30 and we introduced the cre1 gene in a Deltapgi1 mutant. Both Deltapgi1 and cre1+Deltapgi1 mutants showed a pellet-like and growth as well as morphological alterations compared with Rut-C30. None of the mutants grew in media with fructose, galactose, xylose, glycerol or lactose but they grew in media with glucose, with fructose and glucose, with galactose and fructose or with lactose and fructose. No growth was observed in media with xylose and glucose. On glucose, Deltapgi1 and cre1+Deltapgi1 mutants showed higher cellulase activity than Rut-C30 and QM6a, respectively. But in media with lactose, none of the mutants improved the production of the reference strains. The increase in the activity did not correlate with the expression of mRNA of the xylanase regulator gene, xyr1. Deltapgi1 mutants were also affected in the extracellular beta-galactosidase activity. Levels of mRNA of the glucose 6-phosphate dehydrogenase did not increase in Deltapgi1 during growth on glucose. CONCLUSIONS: The ability to grow in media with glucose as the sole carbon source indicated that Trichoderma Deltapgi1 mutants were able to use the pentose phosphate pathway. But, they did not increase the expression of gpdh. Morphological characteristics were the result of the pgi1 deletion. Deletion of pgi1 in Rut-C30 increased cellulase production, but only under repressing conditions. This increase resulted partly from the deletion itself and partly from a genetic interaction with the cre1-1 mutation. The lower cellulase activity of these mutants in media with lactose could be attributed to a reduced ability to hydrolyse this sugar but not to an effect on the expression of xyr1. PMID- 21609468 TI - Oral ingestion of hexavalent chromium through drinking water and cancer mortality in an industrial area of Greece--an ecological study. AB - BACKGROUND: Hexavalent chromium is a known carcinogen when inhaled, but its carcinogenic potential when orally ingested remains controversial. Water contaminated with hexavalent chromium is a worldwide problem, making this a question of significant public health importance. METHODS: We conducted an ecological mortality study within the Oinofita region of Greece, where water has been contaminated with hexavalent chromium. We calculated gender, age, and period standardized mortality ratios (SMRs) for all deaths, cancer deaths, and specific cancer types of Oinofita residents over an 11-year period (1999 - 2009), using the greater prefecture of Voiotia as the standard population. RESULTS: A total of 474 deaths were observed. The SMR for all cause mortality was 98 (95% CI 89-107) and for all cancer mortality 114 (95% CI 94-136). The SMR for primary liver cancer was 1104 (95% CI 405-2403, p-value < 0.001). Furthermore, statistically significantly higher SMRs were identified for lung cancer (SMR = 145, 95% CI 100 203, p-value = 0.047) and cancer of the kidney and other genitourinary organs among women (SMR = 368, 95% CI 119-858, p-value = 0.025). Elevated SMRs for several other cancers were also noted (lip, oral cavity and pharynx 344, stomach 121, female breast 134, prostate 128, and leukaemias 168), but these did not reach statistical significance. CONCLUSIONS: Elevated cancer mortality in the Oinofita area of Greece supports the hypothesis of hexavalent chromium carcinogenicity via the oral ingestion pathway of exposure. Further studies are needed to determine whether this association is causal, and to establish preventive guidelines and public health recommendations. PMID- 21609469 TI - Altered postural sway in patients suffering from non-specific neck pain and whiplash associated disorder - A systematic review of the literature. AB - STUDY DESIGN: Systematic literature review. OBJECTIVES: To assess differences in center of pressure (COP) measures in patients suffering from non-specific neck pain (NSNP) or whiplash-associated disorder (WAD) compared to healthy controls and any relationship between changes in postural sway and the presence of pain, its intensity, previous pain duration and the perceived level of disability. SUMMARY OF BACKGROUND DATA: Over the past 20 years, the center of pressure (COP) has been commonly used as an index of postural stability in standing. While several studies investigated COP excursions in neck pain and WAD patients and compared these to healthy individuals, no comprehensive analysis of the reported differences in postural sway pattern exists. SEARCH METHODS: Six online databases were systematically searched followed by a manual search of the retrieved papers. SELECTION CRITERIA: Papers comparing COP measures derived from bipedal static task conditions on a force plate of people with NSNP and WAD to those of healthy controls. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened titles and abstracts for relevance. Screening for final inclusion, data extraction and quality assessment were carried out with a third reviewer to reconcile differences. RESULTS: Ten papers met the inclusion criteria. Heterogeneity in study designs prevented pooling of the data and no direct comparison of data across the studies was possible. Instead, a qualitative data analysis was conducted. There was broad consensus that patients with either type of neck pain have increased COP excursions compared to healthy individuals, a difference that was more pronounced in people with WAD. An increased sway in antero-posterior direction was observed in both groups. CONCLUSIONS: Patients with neck pain (due to either NSNP or WAD) exhibit greater postural instability than healthy controls, signified by greater COP excursions irrespective of the COP parameter chosen. Further, the decreased postural stability in people with neck pain appears to be associated with the presence of pain and correlates with the extent of proprioceptive impairment, but appears unrelated to pain duration. PMID- 21609470 TI - Biogenic amines and their metabolites are differentially affected in the Mecp2 deficient mouse brain. AB - BACKGROUND: Rett syndrome (RTT, MIM #312750) is a severe neurological disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Female patients are affected with an incidence of 1/15000 live births and develop normally from birth to 6-18 months of age before the onset of deficits in autonomic, cognitive, motor functions (stereotypic hand movements, impaired locomotion) and autistic features. Studies on Mecp2 mouse models, and specifically null mice, revealed morphological and functional alterations of neurons. Several functions that are regulated by bioaminergic nuclei or peripheral ganglia are impaired in the absence of Mecp2. RESULTS: Using high performance liquid chromatography, combined with electrochemical detection (HPLC/EC) we found that Mecp2(-/y) mice exhibit an alteration of DA metabolism in the ponto-bulbar region at 5 weeks followed by a more global alteration of monoamines when the disease progresses (8 weeks). Hypothalamic measurements suggest biphasic disturbances of norepinephrine and serotonin at pathology onset (5 weeks) that were found stabilized later on (8 weeks). Interestingly, the postnatal nigrostriatal dopaminergic deficit identified previously does not parallel the reduction of the other neurotransmitters investigated. Finally, dosage in cortical samples do not suggest modification in the monoaminergic content respectively at 5 and 8 weeks of age. CONCLUSIONS: We have identified that the level of catecholamines and serotonin is differentially affected in Mecp2(-/y) brain areas in a time-dependent fashion. PMID- 21609471 TI - Not sold here: limited access to legally available syringes at pharmacies in Tijuana, Mexico. AB - BACKGROUND: Sterile syringe access is a critical component of HIV prevention programs. Although retail pharmacies provide convenient outlets for syringe access, injection drug users (IDUs) may encounter barriers to syringe purchase even where purchase without a prescription is legal. We sought to obtain an objective measure of syringe access in Tijuana, Mexico, where IDUs report being denied or overcharged for syringes at pharmacies. METHODS: Trained "mystery shoppers" attempted to buy a 1 cc insulin syringe according to a predetermined script at all retail pharmacies in three Tijuana neighborhoods. The same pharmacies were surveyed by telephone regarding their syringe sales policies. Data on purchase attempts were analyzed using basic statistics to obtain an objective measure of syringe access and compared with data on stated sales policies to ascertain consistency. RESULTS: Only 46 (28.4%) of 162 syringe purchase attempts were successful. Leading reasons for unsuccessful attempts were being told that the pharmacy didn't sell syringes (35.3%), there were no syringes in stock (31.0%), or a prescription was required (20.7%). Of 136 pharmacies also surveyed by telephone, a majority (88.2%) reported selling syringes but only one third (32.5%) had a successful mystery shopper purchase; the majority of unsuccessful purchases were attributed to being told the pharmacy didn't sell syringes. There was similar discordance regarding prescription policies: 74 pharmacies said in the telephone survey that they did not require a prescription for syringes, yet 10 of these pharmacies asked the mystery shopper for a prescription. CONCLUSIONS: IDUs in Tijuana have limited access to syringes through retail pharmacies and policies and practices regarding syringe sales are inconsistent. Reasons for these restrictive and inconsistent practices must be identified and addressed to expand syringe access, reduce syringe sharing and prevent HIV transmission. PMID- 21609473 TI - Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. AB - Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance. PMID- 21609472 TI - Evolution of endogenous retroviruses in the Suidae: evidence for different viral subpopulations in African and Eurasian host species. AB - BACKGROUND: Porcine endogenous retroviruses (PERVs) represent remnants of an exogenous form that have become integrated in the domestic pig (Sus scrofa) genome. Although they are usually inactive, the capacity of gamma1 ERVs to infect human cells in vitro has raised concerns about xenotransplantation because the viruses could cross the species barrier to humans. Here we have analyzed the evolution of gamma1 ERVs in ten species of Suidae (suids, pigs and hogs) from Eurasia and Africa using DNA sequences for their coding domains (gag, pro/pol and env genes). For comparison with gamma1 PERVs, we have also analysed gamma2 ERVs which in domestic pigs are known to be inactive and do not pose a risk to xenotransplantation. RESULTS: Phylogenetic analysis using Bayesian inference showed that gamma1 and gamma2 ERVs have distinctive evolutionary histories. Firstly, two different viral lineages of gamma1 ERVs were found and a coevolutionary analysis demonstrated that they correspond broadly to their host phylogeny, one of Eurasian and another of African species, and show no evidence of horizontal transmission. gamma2 ERVs, however, show a bush-like evolution, suggesting a rapid viral radiation from a single common ancestor with no correspondence between host and viral evolutionary trees. Furthermore, though gamma1 ERV env genes do not possess frequent stop codons, gamma2 env genes do. To understand whether gamma1 suid ERVs may be still replicating, we have also evaluated their likely mechanism of proliferation by statistically testing internal to terminal branches using nonsynonymous versus synonymous substitution ratios. Our results suggest that gamma1 ERVs are increasing in copy number by reinfection, which requires the translocation of the virus from one cell to another. CONCLUSIONS: Evidence of at least two viral subpopulations was observed in gamma1 ERVs from Eurasian and African host species. These results should be taken into account in xenotransplantation since gamma1 ERVs appear to be codiverging with their host and maintaining ongoing capacity to infect somatic and germ cells. PMID- 21609474 TI - Characterization of the duck enteritis virus UL55 protein. AB - BACKGROUND: Characteration of the newly identified duck enteritis virus UL55 gene product has not been reported yet. Knowledge of the protein UL55 can provide useful insights about its function. RESULTS: The newly identified duck enteritis virus UL55 gene was about 561 bp, it was amplified and digested for construction of a recombinant plasmid pET32a(+)/UL55 for expression in Escherichia coli. SDS PAGE analysis revealed the recombinant protein UL55(pUL55) was overexpressed in Escherichia coli BL21 host cells after induction by 0.2 mM IPTG at 37 degrees C for 4 h and aggregated as inclusion bodies. The denatured protein about 40 KDa named pUL55 was purified by washing five times, and used to immune rabbits for preparation of polyclonal antibody. The prepared polyclonal antibody against pUL55 was detected and determined by Agar immundiffusion and Neutralization test. The results of Wstern blotting assay and intracellular analysis revealed that pUL55 was expressed most abundantly during the late phase of replication and mainly distributed in cytoplasm in duck enteritis virus infected cells. CONCLUSIONS: In this study, the duck enteritis virus UL55 protein was successfully expressed in prokaryotic expression system. Besides, we have prepared the polyclonal antibody against recombinant prtein UL55, and characterized some properties of the duck enteritis virus UL55 protein for the first time. The research will be useful for further functional analysis of this gene. PMID- 21609475 TI - Copy number polymorphisms and anticancer pharmacogenomics. AB - BACKGROUND: Recent studies have investigated the contribution of copy number variants (CNVs) to disease susceptibility in a multitude of complex disorders, including systemic lupus erythematosus, Crohn's disease, and various neurodevelopmental disorders. Relatively few CNV studies, however, have been conducted on pharmacologic phenotypes even though these structural variants are likely to play an important role. We developed a genome-wide method to identify CNVs that contribute to heterogeneity in drug response, focusing on drugs that are widely used in anticancer treatment regimens. RESULTS: We conducted a comprehensive genome-wide study of CNVs from population-scale array-based and sequencing-based surveys by analyzing their effect on cellular sensitivity to platinating agents and topoisomerase II inhibitors. We identified extensive CNV regions associated with cellular sensitivity to functionally diverse chemotherapeutics, supporting the hypothesis that variation in copy number contributes to variation in drug response. Interestingly, although single nucleotide polymorphisms (SNPs) tag some of the CNVs associated with drug sensitivity, several of the most significant CNV-drug associations are independent of SNPs; consequently, they represent genetic variations that have not been previously interrogated by SNP studies of pharmacologic phenotypes. CONCLUSIONS: Our findings demonstrate that pharmacogenomic studies may greatly benefit from the study of CNVs as expression quantitative trait loci, thus contributing broadly to our understanding of the complex traits genetics of CNVs. We also extend our PACdb resource, a database that makes available to the scientific community relationships between genetic variation, gene expression, and sensitivity to various drugs in cell-based models. PMID- 21609477 TI - Developing a matrix to identify and prioritise research recommendations in HIV prevention. AB - BACKGROUND: HIV prevention continues to be problematic in the UK, as it does globally. The UK Department of Health has a strategic direction with greater focus on prevention as part of its World Class Commissioning Programme. There is a need for targeted evidence-based prevention initiatives. This is an exploratory study to develop an evidence mapping tool in the form of a matrix: this will be used to identify important gaps in contemporary HIV prevention evidence relevant to the UK. It has the potential to aid prioritisation in future research. METHODS: Categories for prevention and risk groups were developed for HIV prevention in consultation with external experts. These were used as axes on a matrix tool to map evidence. Systematic searches for publications on HIV prevention were undertaken using electronic databases for primary and secondary research undertaken mainly in UK, USA, Canada, Australia and New Zealand, 2006-9. Each publication was screened for inclusion then coded. The risk groups and prevention areas in each paper were counted: several publications addressed multiple risk groups. The counts were exported to the matrix and clearly illustrate the concentrations and gaps of literature in HIV prevention. RESULTS: 716 systematic reviews, randomised control trials and other primary research met the inclusion criteria for HIV prevention. The matrix identified several under researched areas in HIV prevention. CONCLUSIONS: This is the first categorisation system for HIV prevention and the matrix is a novel tool for evidence mapping. Some important yet under-researched areas have been identified in HIV prevention evidence: identifying the undiagnosed population; international adaptation; education; intervention combinations; transgender; sex-workers; heterosexuals and older age groups. PMID- 21609476 TI - Microarray analysis and scale-free gene networks identify candidate regulators in drought-stressed roots of loblolly pine (P. taeda L.). AB - BACKGROUND: Global transcriptional analysis of loblolly pine (Pinus taeda L.) is challenging due to limited molecular tools. PtGen2, a 26,496 feature cDNA microarray, was fabricated and used to assess drought-induced gene expression in loblolly pine propagule roots. Statistical analysis of differential expression and weighted gene correlation network analysis were used to identify drought responsive genes and further characterize the molecular basis of drought tolerance in loblolly pine. RESULTS: Microarrays were used to interrogate root cDNA populations obtained from 12 genotype * treatment combinations (four genotypes, three watering regimes). Comparison of drought-stressed roots with roots from the control treatment identified 2445 genes displaying at least a 1.5 fold expression difference (false discovery rate = 0.01). Genes commonly associated with drought response in pine and other plant species, as well as a number of abiotic and biotic stress-related genes, were up-regulated in drought stressed roots. Only 76 genes were identified as differentially expressed in drought-recovered roots, indicating that the transcript population can return to the pre-drought state within 48 hours. Gene correlation analysis predicts a scale free network topology and identifies eleven co-expression modules that ranged in size from 34 to 938 members. Network topological parameters identified a number of central nodes (hubs) including those with significant homology (E-values <= 2 * 10-30) to 9-cis-epoxycarotenoid dioxygenase, zeatin O-glucosyltransferase, and ABA-responsive protein. Identified hubs also include genes that have been associated previously with osmotic stress, phytohormones, enzymes that detoxify reactive oxygen species, and several genes of unknown function. CONCLUSION: PtGen2 was used to evaluate transcriptome responses in loblolly pine and was leveraged to identify 2445 differentially expressed genes responding to severe drought stress in roots. Many of the genes identified are known to be up regulated in response to osmotic stress in pine and other plant species and encode proteins involved in both signal transduction and stress tolerance. Gene expression levels returned to control values within a 48-hour recovery period in all but 76 transcripts. Correlation network analysis indicates a scale-free network topology for the pine root transcriptome and identifies central nodes that may serve as drivers of drought-responsive transcriptome dynamics in the roots of loblolly pine. PMID- 21609478 TI - Decreased expression of BRCA1 in SK-BR-3 cells is the result of aberrant activation of the GABP Beta promoter by an NRF-1-containing complex. AB - BACKGROUND: BRCA1 has recently been identified as a potential regulator of mammary stem/progenitor cell differentiation, and this function may explain the high prevalence of breast cancer in BRCA1 mutation carriers, as well as the downregulation of BRCA1 in a large proportion of sporadic breast cancers. That is, loss of BRCA1 function results in blocked differentiation with expansion of the mammary stem/progenitor cells. Because BRCA1 also maintains genomic integrity, its loss could produce a pool of genetically unstable stem/progenitor cells that are prime targets for further transforming events. Thus, elucidating the regulatory mechanisms of BRCA1 expression is important to our understanding of normal and malignant breast differentiation. RESULTS: Loss of BRCA1 expression in the ErbB2-amplified SK-BR-3 cell line was found to be the result of loss of activity of the ets transcription factor GABP, a previously characterized regulator of BRCA1 transcription. The expression of the non-DNA binding GABPbeta subunit was shown to be deficient, while the DNA binding subunit, GABPalpha was rendered unstable by the absence of GABPbeta. Deletion analysis of the GABPbeta proximal promoter identified a potential NRF-1 binding site as being critical for expression. Supershift analysis, the binding of recombinant protein and chromatin immunoprecipitation confirmed the role of NRF-1 in regulating the expression of GABPbeta. The siRNA knockdown of NRF-1 resulted in decreased GABPbeta and BRCA1 expression in MCF-7 cells indicating that they form a transcriptional network. NRF-1 levels and activity did not differ between SK-BR-3 and MCF-7 cells, however the NRF-1 containing complex on the GABPbeta promoter differed between the two lines and appears to be the result of altered coactivator binding. CONCLUSIONS: Both NRF-1 and GABP have been linked to the regulation of nuclear-encoded mitochondrial proteins, and the results of this study suggest their expression is coordinated by NRF-1's activation of the GABPbeta promoter. Their linkage to BRCA1, a potential breast stem cell regulator, implies a connection between the induction of mitochondrial metabolism and breast differentiation. PMID- 21609479 TI - Comparative study on sound production in different Holocentridae species. AB - BACKGROUND: Holocentrids (squirrelfish and soldierfish) are vocal reef fishes whose calls and sound-producing mechanisms have been studied in some species only. The present study aims to compare sound-producing mechanisms in different Holocentridae genera (Holocentrus, Myripristis, Neoniphon, Sargocentron) from separate regions and, in some cases, at different developmental stages. An accurate comparison was made by recording six species while being hand-held, by observing TEM) the sonic muscles and by dissections of the sound-producing mechanism. RESULTS: In all these species, calls presented harmonics, their dominant frequency was between 80 and 130 Hz and they were composed of trains of 4 to 11 pulses with gradual increasing periods towards the end of the call. In each case, the calls did not provide reliable information on fish size. The sounds were produced by homologous fast-contracting sonic muscles that insert on articulated ribs whose proximal heads are integrated into the swimbladder: each pulse is the result of the back and forth movements of the ribs. Small differences in the shape of the oscillograms of the different species could be related to the number of ribs that are involved in the sound-producing mechanism. These fish species are able to make sounds as soon as they settle on the reef, when they are 40 days old. Comparison between Neoniphon from Madagascar and from Rangiroa in French Polynesia showed a new, unexpected kind of dialect involving differences at the level of pulse distribution. Neoniphon calls were characterised by a single pulse that was isolated at the beginning of the remaining train in Madagascar whereas they did not show any isolated single pulses at the beginning of the call in Rangiroa. CONCLUSION: This family cannot use the acoustic fundamental frequencies (or pulse periods) of grunts to infer the size of partners. Pulse duration and number of pulses are statistically related to fish size. However, these characteristics are poorly informative because the correlation slope values are weak. It remains other features (sound amplitude, resistance to muscle fatigue, calling frequency) could be used to assess the body size. Characteristics of the sound producing mechanisms are conservative. All species possess fast-contracting muscles and have the same kind of sound producing mechanism. They do show some change between clades but these differences are not important enough to deeply modify the waveforms of the calls. In this case, our description of the grunt could be considered as the signature for the holocentrid family and can be used in passive acoustic monitoring. PMID- 21609480 TI - NGOs and government partnership for health systems strengthening: a qualitative study presenting viewpoints of government, NGOs and donors in Pakistan. AB - BACKGROUND: Health systems are expected to serve the population needs in an effective, efficient and equitable manner. Therefore, the importance of strengthening of public, private and community health systems has been emphasized time and again. In most of the developing countries, certain weaknesses and gaps in the government health systems have been hampering the achievement of improved health outcomes. Public sector in Pakistan has been deficient in the capacity to deliver equitable and quality health services and thus has been grossly underutilized. METHODS: A qualitative study comprising in-depth interviews was conducted capturing the perceptions of the government functionaries, NGO representatives and donor community about the role and position of NGOs in health systems strengthening in Pakistan's context. Analysis of the data was done manually to generate nodes, sub-nodes and themes. RESULTS: Since many years, international and local non-governmental organizations (NGOs) have endeavored to fill the gaps in health service delivery, research and advocacy. NGOs have relatively performed better and achieved the results because of the flexible planning and the ability to design population based projects on health education, health promotion, social marketing, community development and advocacy. This paper captures the need and the opportunity of public private partnership in Pakistan and presents a framework for a meaningful engagement of the government and the private and nonprofit NGOs. CONCLUSION: Involving the NGOs for health system strengthening may eventually contribute to create a healthcare system reflecting an increased efficiency, more equity and good governance in the wake of the Millennium Development Goals. Nevertheless, few questions need to be answered and pre-requisites have to be fulfilled before moving on. PMID- 21609481 TI - Cross-cultural validation of the Educational Needs Assessment Tool in RA in 7 European countries. AB - BACKGROUND: The Educational Needs Assessment Tool (the ENAT) is a 39-item patient questionnaire originally developed in the UK to assess educational needs of patients with rheumatoid arthritis (RA). The objective of this study was to assess the cross-cultural validity of the ENAT in 7 European countries. METHODS: The ENAT was translated into Dutch, Finnish, Norwegian, Portuguese, Spanish and Swedish versions by using Beaton's cross-cultural adaptation process, and was completed by a convenience sample of patients with RA in each country. The generated country-specific data were assessed for construct validity and were then pooled and assessed for cross-cultural invariance using Rasch analysis. RESULTS: Individual country-specific analysis showed adequate fit to the Rasch model after adjustment for local dependency within domains. When data from the different countries were pooled, the 39 items deviated significantly from Rasch model's expectations (X(2)=977.055, DF=351, p=0.000, PSI=0.976). Again, most items within domains were found to be locally dependent, significantly affecting the fit. Consequently each domain was treated as a unit (i.e. testlet) and the ENAT was re-analysed as a seven-testlet scale resulting into a good fit to the Rasch model (X(2)=71.909; DF=63; p=0.207, PSI=0.951). A test of strict unidimensionality confirmed that all domains contributed to measuring a single construct. Cross-cultural non-invariance was discounted by splitting domains for DIF maintaining an excellent fit to the Rasch model. This allowed calibration of the ENAT into an interval scale. CONCLUSION: The ENAT is a simple tool, which is a valid measure of educational needs of people with RA. Adjustment for cross cultural non-invariance is available if data from the 7 European countries are to be pooled or compared. PMID- 21609482 TI - CNVassoc: Association analysis of CNV data using R. AB - BACKGROUND: Copy number variants (CNV) are a potentially important component of the genetic contribution to risk of common complex diseases. Analysis of the association between CNVs and disease requires that uncertainty in CNV copy-number calls, which can be substantial, be taken into account; failure to consider this uncertainty can lead to biased results. Therefore, there is a need to develop and use appropriate statistical tools. To address this issue, we have developed CNVassoc, an R package for carrying out association analysis of common copy number variants in population-based studies. This package includes functions for testing for association with different classes of response variables (e.g. class status, censored data, counts) under a series of study designs (case-control, cohort, etc) and inheritance models, adjusting for covariates. The package includes functions for inferring copy number (CNV genotype calling), but can also accept copy number data generated by other algorithms (e.g. CANARY, CGHcall, IMPUTE). RESULTS: Here we present a new R package, CNVassoc, that can deal with different types of CNV arising from different platforms such as MLPA o aCGH. Through a real data example we illustrate that our method is able to incorporate uncertainty in the association process. We also show how our package can also be useful when analyzing imputed data when analyzing imputed SNPs. Through a simulation study we show that CNVassoc outperforms CNVtools in terms of computing time as well as in convergence failure rate. CONCLUSIONS: We provide a package that outperforms the existing ones in terms of modelling flexibility, power, convergence rate, ease of covariate adjustment, and requirements for sample size and signal quality. Therefore, we offer CNVassoc as a method for routine use in CNV association studies. PMID- 21609483 TI - Homeobox gene Rhox5 is regulated by epigenetic mechanisms in cancer and stem cells and promotes cancer growth. AB - BACKGROUND: Homeobox genes murine Rhox5 and human RHOXF1 are expressed in early embryonic stages and then mostly restricted to germline tissues in normal adult, yet they are aberrantly expressed in cancer cells in vitro and in vivo . Here we study the epigenetic regulation and potential functions of Rhox5 gene. FINDINGS: In Rhox5-silenced or extremely low expresser cells, we observed low levels of active histone epigenetic marks (H3ac, H4ac and H3K4me2) and high levels of repressive mark H3K9me2 along with DNA hypermethylation in the promoter. In Rhox5 low expresser cells, we typically observed modest levels of both active and repressive histone marks along with moderate DNA methylation. In Rhox5 highly expressed CT26 cancer cells, we observed DNA hypomethylation along with high levels of both active and repressive histone marks. Epigenetic drugs (retinoic acid and MS-275) induced F9 cell differentiation with enhanced Rhox5 expression and dynamic changes of epigenetic marks. Finally, Rhox5 knockdown by small hairpin RNA (shRNA) in CT26 colon cancer decreased cell proliferation and migration in vitro and tumor growth in vivo . CONCLUSIONS: Both DNA methylation and histone methylation/acetylation play key roles in modulating Rhox5 expression in various cell types. The stem cell-like "bivalent domain", an epigenetic feature originally identified in key differentiation genes within stem cells, exists in the Rhox5 gene promoter in not only embryonic stem cells but also cancer cells, cancer stem cells, and differentiated Sertoli cells. As Ras signaling-dependent Rhox5 expression promotes tumor growth, Rhox5 may be an ideal target for therapeutic intervention in cancer. PMID- 21609484 TI - Patient discomfort associated with the use of intra-arterial iodinated contrast media: a meta-analysis of comparative randomized controlled trials. AB - BACKGROUND: Discomfort characterized by pain and warmth are common adverse effects associated with the use of intra-arterial iodinated contrast media (CM). The objective of this review was to pool patient-reported outcomes available from head-to-head randomized controlled trials (RCTs) and to compare the discomfort rates associated with iso-osmolar contrast media (IOCM; i.e., iodixanol) to those reported with various low-osmolar contrast media (LOCM). METHODS: A review of the literature published between 1990 and 2009 available through Medline, Medline Preprints, Embase, Biological Abstracts, BioBase, Cab Abstracts, International Pharmaceutical Abstracts, Life Sciences Collection, Inside Conferences, Energy Database, Engineering Index and Technology Collection was performed to compare rates of discomfort associated with the use of the IOCM (iodixanol) vs. various LOCM agents in head-to-head RCTs. All trials with a Jadad score >=2 that reported patient discomfort data following intra-arterial administration of CM were reviewed, coded, and extracted. RESULTS: A total of 22 RCTs (n = 8087) were included. Overall discomfort (regardless of severity) was significantly different between patients receiving IOCM and various LOCMs (risk difference [RD] -0.049; 95% confidence interval [CI]: -0.076, -0.021; p = 0.001). IOCM was favored over all LOCMs combined with a summary RD value of -0.188 (95% CI: -0.265, -0.112; p < 0.001) for incidence of pain, regardless of severity. A greater reduction in the magnitude of pain was observed with IOCM (iodixanol), particularly with selective limb and carotid/intracerebral procedures. Similarly, the meta-analysis of warmth sensation, regardless of severity, favored IOCM over LOCMs with an RD of -0.043 (95% CI: -0.074, -0.011; p = 0.008). A positive linear relationship was observed between the discomfort effect size and age and a negative relationship with increasing proportion of women. The opposite trends were observed with warmth sensation. CONCLUSIONS: IOCM was associated with less frequent and severe patient discomfort during intra-arterial administration. These data support differences in osmolality as a possible determinant of CM discomfort. PMID- 21609485 TI - Hyperbaric oxygen therapy for painful bladder syndrome/interstitial cystitis resistant to conventional treatments: long-term results of a case series in Japan. AB - BACKGROUND: There is no confirmed strategy for treating painful bladder syndrome/interstitial cystitis (PBS/IC) with unclear etiology. Therefore, a pilot study was carried out to evaluate the efficacy and safety of hyperbaric oxygen (HBO) therapy in treatment-resistant PBS/IC patients. METHODS: HBO treatment (2.0 ATA for 60 minutes/day * 5 days/week for 2 or 4 weeks) was performed on 11 patients with severe symptoms that had not been improved by previous therapy regimens between December 2004 and July 2009. RESULTS: Seven of the 11 patients demonstrated persistent improvement in symptoms during the 12 months after HBO treatment. These responders demonstrated a decrease in the pelvic pain scale and urgency scale from 7.7 +/- 1.0 and, 6.6 +/- 0.9 to 3.4 +/- 2.5 and 4.3 +/- 2.4 after 12 months, respectively (p < 0.05). The total score of the interstitial cystitis symptom index and 24-hour urinary frequency demonstrated a significant sustained decrease from the baseline. Two responders, who received an additional course of HBO 12 and 13 months after initial treatment, respectively, did not suffer impairment for more than two years. There was one case of transient eustachian tube dysfunction and three cases of reversible exudative otitis media as a consequence of HBO treatment. CONCLUSIONS: HBO is a potent treatment for PBS/IC patients resistant to conventional therapy. It was well tolerated and provided maintained amelioration of pain, urgency and urinary frequency for at least 12 months. PMID- 21609486 TI - Modification of an OSCE format to enhance patient continuity in a high-stakes assessment of clinical performance. AB - BACKGROUND: Traditional Objective Structured Clinical Examinations (OSCEs) are psychometrically sound but have the limitation of fragmenting complex clinical cases into brief stations. We describe a pilot study of a modified OSCE that attempts to balance a typical OSCE format with a semblance of a continuous, complex, patient case. METHODS: Two OSCE scenarios were developed. Each scenario involved a single standardized patient and was subdivided into three sequential 10 minute sections that assessed separate content areas and competencies. Twenty Canadian PGY-4 internal medicine trainees were assessed by trained examiner pairs during each OSCE scenario. Paired examiners rated participant performance independent of each other, on each section of each scenario using a validated global rating scale. Inter-rater reliabilities and Pearson correlations between ratings of the 3 sections of each scenario were calculated. A generalizability study was conducted. Participant and examiner satisfaction was surveyed. RESULTS: There was no main effect of section or scenario. Inter-rater reliability was acceptable. The g-coefficient was 0.68; four scenarios would achieve 0.80. Moderate correlations between sections of a scenario suggest a possible halo effect. The majority of examiners and participants felt that the modified OSCE provided a sense of patient continuity. CONCLUSIONS: The modified OSCE provides another approach to the assessment of clinical performance. It attempts to balance the advantages of a traditional OSCE with a sense of patient continuity. PMID- 21609487 TI - CD10 and osteopontin expression in dentigerous cyst and ameloblastoma. AB - AIMS AND OBJECTIVES: To investigate the expression of CD10 and osteopontin in dentigerous cyst and ameloblastoma and to correlate their expression with neoplastic potentiality of dentigerous cyst and local invasion and risk of local recurrence in ameloblastoma. METHODS: CD10 and osteopontin expression was studied by means of immunohistochemistry in 9 cases of dentigerous cysts (DC) and 17 cases of ameloblastoma. There were 7 unicystic ameloblastoma (UCA) and 10 multicystic ameloblastoma (MCA). Positive cases were included in the statistical analysis, carried on the tabulated data using the Open Office Spreadsheet 3.2.1 under Linux operating system. Analysis of variance and correlation studies were performed using "R" under Linux operating system (R Development Core Team (2010). Tukey post-hoc test was also performed as a pair-wise test. The significant level was set at 0.05. RESULTS: High CD10 and osteopontin expression was observed in UCA and MCA, and low CD10 and osteopontin expression was observed in DC. Significant correlation was seen between CD10 and osteopontin expression and neoplastic potentiality of DC and local invasion and risk of recurrences in ameloblastoma. CONCLUSIONS: In DC, high CD10 and osteopontin expression may indicate the neoplastic potentiality of certain areas. In UCA & MCA, high CD10 and osteopontin expression may identify areas with locally invasive behavior and high risk of recurrence. PMID- 21609488 TI - Back and neck pain are related to mental health problems in adolescence. AB - BACKGROUND: There is a high prevalence of mental health problems amongst adolescents. In addition there is a high prevalence of spinal pain in this population. Evidence suggests that these conditions are related. This study sought to extend earlier findings by examining the relationship between mental health problems as measured by the Child Behaviour Check List (CBCL) and the experience of back and neck pain in adolescents. METHODS: One thousand five hundred and eighty participants (mean age 14.1 years) from the Western Australian Pregnancy (Raine) Study provided cross-sectional spinal pain and CBCL data. RESULTS: As predicted, there was a high prevalence of back and neck pain in this cohort. On the whole, females reported more mental health difficulties than males. There were strong relationships between the majority of symptom scales of the CBCL and back and neck pain. Scores on the CBCL were associated with higher odds of comorbid back and neck pain. CONCLUSIONS: These findings strongly support the need to consider both psychological and pain symptoms when providing assessments and treatment for adolescents. Further research is required to inform causal models. PMID- 21609489 TI - Transcriptome sequencing of lentil based on second-generation technology permits large-scale unigene assembly and SSR marker discovery. AB - BACKGROUND: Lentil (Lens culinaris Medik.) is a cool-season grain legume which provides a rich source of protein for human consumption. In terms of genomic resources, lentil is relatively underdeveloped, in comparison to other Fabaceae species, with limited available data. There is hence a significant need to enhance such resources in order to identify novel genes and alleles for molecular breeding to increase crop productivity and quality. RESULTS: Tissue-specific cDNA samples from six distinct lentil genotypes were sequenced using Roche 454 GS-FLX Titanium technology, generating c. 1.38 * 106 expressed sequence tags (ESTs). De novo assembly generated a total of 15,354 contigs and 68,715 singletons. The complete unigene set was sequence-analysed against genome drafts of the model legume species Medicago truncatula and Arabidopsis thaliana to identify 12,639, and 7,476 unique matches, respectively. When compared to the genome of Glycine max, a total of 20,419 unique hits were observed corresponding to c. 31% of the known gene space. A total of 25,592 lentil unigenes were subsequently annoated from GenBank. Simple sequence repeat (SSR)-containing ESTs were identified from consensus sequences and a total of 2,393 primer pairs were designed. A subset of 192 EST-SSR markers was screened for validation across a panel 12 cultivated lentil genotypes and one wild relative species. A total of 166 primer pairs obtained successful amplification, of which 47.5% detected genetic polymorphism. CONCLUSIONS: A substantial collection of ESTs has been developed from sequence analysis of lentil genotypes using second-generation technology, permitting unigene definition across a broad range of functional categories. As well as providing resources for functional genomics studies, the unigene set has permitted significant enhancement of the number of publicly-available molecular genetic markers as tools for improvement of this species. PMID- 21609490 TI - Herpes simplex virus induces the marked up-regulation of the zinc finger transcriptional factor INSM1, which modulates the expression and localization of the immediate early protein ICP0. AB - BACKGROUND: Herpes simplex viruses (HSVs) rapidly shut off macromolecular synthesis in host cells. In contrast, global microarray analyses have shown that HSV infection markedly up-regulates a number of host cell genes that may play important roles in HSV-host cell interactions. To understand the regulatory mechanisms involved, we initiated studies focusing on the zinc finger transcription factor insulinoma-associated 1 (INSM1), a host cell protein markedly up-regulated by HSV infection. RESULTS: INSM1 gene expression in HSV-1 infected normal human epidermal keratinocytes increased at least 400-fold 9 h after infection; INSM1 promoter activity was also markedly stimulated. Expression and subcellular localization of the immediate early HSV protein ICP0 was affected by INSM1 expression, and chromatin immunoprecipitation (ChIP) assays revealed binding of INSM1 to the ICP0 promoter. Moreover, the role of INSM1 in HSV-1 infection was further clarified by inhibition of HSV-1 replication by INSM1 specific siRNA. CONCLUSIONS: The results suggest that INSM1 up-regulation plays a positive role in HSV-1 replication, probably by binding to the ICP0 promoter. PMID- 21609491 TI - Exploring the metabolic network of the epidemic pathogen Burkholderia cenocepacia J2315 via genome-scale reconstruction. AB - BACKGROUND: Burkholderia cenocepacia is a threatening nosocomial epidemic pathogen in patients with cystic fibrosis (CF) or a compromised immune system. Its high level of antibiotic resistance is an increasing concern in treatments against its infection. Strain B. cenocepacia J2315 is the most infectious isolate from CF patients. There is a strong demand to reconstruct a genome-scale metabolic network of B. cenocepacia J2315 to systematically analyze its metabolic capabilities and its virulence traits, and to search for potential clinical therapy targets. RESULTS: We reconstructed the genome-scale metabolic network of B. cenocepacia J2315. An iterative reconstruction process led to the establishment of a robust model, iKF1028, which accounts for 1,028 genes, 859 internal reactions, and 834 metabolites. The model iKF1028 captures important metabolic capabilities of B. cenocepacia J2315 with a particular focus on the biosyntheses of key metabolic virulence factors to assist in understanding the mechanism of disease infection and identifying potential drug targets. The model was tested through BIOLOG assays. Based on the model, the genome annotation of B. cenocepacia J2315 was refined and 24 genes were properly re-annotated. Gene and enzyme essentiality were analyzed to provide further insights into the genome function and architecture. A total of 45 essential enzymes were identified as potential therapeutic targets. CONCLUSIONS: As the first genome-scale metabolic network of B. cenocepacia J2315, iKF1028 allows a systematic study of the metabolic properties of B. cenocepacia and its key metabolic virulence factors affecting the CF community. The model can be used as a discovery tool to design novel drugs against diseases caused by this notorious pathogen. PMID- 21609492 TI - A genome scan for quantitative trait loci affecting cyanogenic potential of cassava root in an outbred population. AB - BACKGROUND: Cassava (Manihot esculenta Crantz) can produce cyanide, a toxic compound, without self-injury. That ability was called the cyanogenic potential (CN). This project aimed to identify quantitative trait loci (QTL) associated with the CN in an outbred population derived from 'Hanatee' * 'Huay Bong 60', two contrasting cultivars. CN was evaluated in 2008 and in 2009 at Rayong province, and in 2009 at Lop Buri province, Thailand. CN was measured using a picrate paper kit. QTL analysis affecting CN was performed with 303 SSR markers. RESULTS: The phenotypic values showed continuous variation with transgressive segregation events with more (115 ppm) and less CN (15 ppm) than either parent ('Hanatee' had 33 ppm and 'Huay Bong 60' had 95 ppm). The linkage map consisted of 303 SSR markers, on 27 linkage groups with a map that encompassed 1,328 cM. The average marker interval was 5.8 cM. Five QTL underlying CN were detected. CN08R1from 2008 at Rayong, CN09R1and CN09R2 from 2009 at Rayong, and CN09L1 and CN09L2 from 2009 at Lop Buri were mapped on linkage group 2, 5, 10 and 11, respectively. Among all the identified QTL, CN09R1 was the most significantly associated with the CN trait with LOD score 5.75 and explained the greatest percentage of phenotypic variation (%Expl.) of 26%. CONCLUSIONS: Five new QTL affecting CN were successfully identified from 4 linkage groups. Discovery of these QTL can provide useful markers to assist in cassava breeding and studying genes affecting the trait. PMID- 21609493 TI - Retest reliability of measuring hip extensor muscle strength in different testing positions in young people with cerebral palsy. AB - BACKGROUND: In young people with spastic diplegic cerebral palsy weakness of the hip extensor muscles are associated with limitations in activity. It is important that clinicians can reliably measure hip extensor muscle strength to monitor changes over time and the effects of any interventions. Previous research has demonstrated high reliability for measuring strength of all muscles of the lower limb, with the exception of the hip extensors. Therefore the aim of this study was to examine the retest reliability of measuring hip extensor strength in young people with cerebral palsy. METHODS: Using a test-retest reliability research design, 19 participants with spastic diplegic cerebral palsy (Gross Motor Function Classification System Levels II and III) (mean 19 y 2 mo [S D 2 y 5 mo]) attended two testing sessions held 12 weeks apart. Three trials with a hand-held dynamometer were taken at each testing session in supine, prone and standing. Retest reliability was calculated with Intraclass Correlation Coefficients (ICC(2,1)) and with units of measurement (kilograms) converted to a percentage strength change. RESULTS: ICC values ranged from .74 to .78 in supine, .75 to .80 in prone, and .73 to .75 in standing. To be 95% confident that real change had occurred, an individual's strength would need to increase 55 to 60% in supine, 86 to 102% in prone, and 102 to 105% in standing. To be 95% confident that real change had occurred across groups, strength would need to increase 4 to 8% in supine, 22 to 31% in prone, and 32% to 34% in standing. Higher ICC values were observed when three trials were used for testing. CONCLUSIONS: The supine testing position was more reliable than the prone or standing testing positions. It is possible to measure hip extensor strength with sufficient reliability to be able monitor change within groups using the supine position provided three trials are used during testing. However, there is insufficient reliability to monitor changes in hip extensor strength in individuals with cerebral palsy unless they exhibit very large strength increases. PMID- 21609494 TI - Time-dependent cytotoxic drugs selectively cooperate with IL-18 for cancer chemo immunotherapy. AB - BACKGROUND: Time-dependent chemotherapeutic agents can selectively target tumor cells in susceptible phases of the cell cycle however a fraction of tumor cells in non-vulnerable cell cycle phases remain drug-resistant. Immunotherapy represents a promising approach to overcome the limitation of phase-specific drugs and improve their clinical efficacy. Here, we investigated the potential use of anticancer chemotherapeutic drugs in combination with IL-18, a cytokine with strong immunostimulatory properties. METHODS: Four chemotherapeutic drugs commonly used in ovarian cancer were first tested for the ability to increase the immunogenicity and killing of the murine ovarian cancer cell line ID8 in vitro. Chemotherapeutric agents with measured time-dependent immune-enhancing effects were then tested for antitumor effectiveness in vivo in combination with IL-18 immunotherapy using the ID8-Vegf ovarian cancer model. RESULTS: Paclitaxel or topotecan exposure alone mediated incomplete, time-dependent killing against the murine ovarian cancer cell line ID8 in vitro, whereas carboplatin or gemcitabine mediated comprehensive, dose-dependent killing. In the plateau phase of the time dependent killing by topotecan or paclitaxel, drug-resistant ID8 cells were more immunogenic with elevated expression of MHC-I and Fas, and increased sensitivity to CTL and Fas agonistic antibody in vitro. Moreover, the antitumor effectiveness of time-dependent agents in vivo was significantly improved with the addition of IL-18 through a T cell-dependent mechanism, while the effectiveness of drugs without significant phase specificity were not. CONCLUSIONS: Tumor immunotherapy with IL-18 can significantly augment the killing fraction of phase-specific chemotherapeutic drugs and provide survival benefit. The safety profile of IL-18 and its positive interactions with select anticancer chemotherapeutic agents strongly supports the clinical investigation of this combinatorial approach. PMID- 21609495 TI - Response to combination therapy of HCV 3a infected Pakistani patients and the role of NS5A protein. AB - BACKGROUND: Hepatitis C virus (HCV) genotype 3a is known to show comparatively better response to combination therapy than genotype 1 and 4. Mutations within NS5A gene of HCV have earlier been implicated with response to interferon (IFN) therapies in chronic HCV patients among various populations. As response to therapy are available in different populations because of the ethnic and viral factors and there was no study available on the phenomenon of resistivity to IFN. RESULTS: Chronic HCV 3a infected Pakistani patients were kept on IFN-alpha and ribavirin therapy for six months. NS5A gene of HCV was amplified and sequenced in the case of all the patients prior to therapy and the sequences were analysed for mutations. Out of the total 27 patients, 20 (74.07%) were observed with sustained virological response (SVR), 4 (14.81%) patients were non responder (NR) while 3 (11.11%) patients exhibited in end of treatment response (ETR). Three (3/20) (15%) SVR patients and two (2/3) ETR patients had mutations (ranging from I-V amino acids) within the NS5A ISDR regions. While the rest of the SVR patients (85%) and the NR had no mutations at ISDR region when compared with HCV K3a ISDR. CONCLUSIONS: Mutations within the NS5A gene of HCV 3a genotype may not influence the outcome of combination therapy in Pakistani populations. PMID- 21609497 TI - "Predictability of body mass index for diabetes: affected by the presence of metabolic syndrome?". AB - BACKGROUND: Metabolic syndrome (MetS) and body mass index (BMI, kg.m(-2)) are established independent risk factors in the development of diabetes; we prospectively examined their relative contributions and joint relationship with incident diabetes in a Middle Eastern cohort. METHOD: participants of the ongoing Tehran lipid and glucose study are followed on a triennial basis. Among non diabetic participants aged>= 20 years at baseline (8,121) those with at least one follow-up examination (5,250) were included for the current study. Multivariate logistic regression models were used to estimate sex-specific adjusted odd ratios (ORs) and 95% confidence intervals (CIs) of baseline BMI-MetS categories (normal weight without MetS as reference group) for incident diabetes among 2186 men and 3064 women, aged >= 20 years, free of diabetes at baseline. RESULT: During follow up (median 6.5 years); there were 369 incident diabetes (147 in men). In women without MetS, the multivariate adjusted ORs (95% CIs) for overweight (BMI 25-30 kg/m(2)) and obese (BMI>=30) participants were 2.3 (1.2-4.3) and 2.2 (1.0-4.7), respectively. The corresponding ORs for men without MetS were 1.6 (0.9-2.9) and 3.6 (1.5-8.4) respectively. As compared to the normal-weight/without MetS, normal weight women and men with MetS, had a multivariate-adjusted ORs for incident diabetes of 8.8 (3.7-21.2) and 3.1 (1.3-7.0), respectively. The corresponding ORs for overweight and obese women with MetS reached to 7.7 (4.0-14.9) and 12.6 (6.9 23.2) and for men reached to 3.4(2.0-5.8) and 5.7(3.9-9.9), respectively. CONCLUSION: This study highlights the importance of screening for MetS in normal weight individuals. Obesity increases diabetes risk in the absence of MetS, underscores the need for more stringent criteria to define healthy metabolic state among obese individuals. Weight reduction measures, thus, should be encouraged in conjunction with achieving metabolic targets not addressed by current definition of MetS, both in every day encounter and public health setting. PMID- 21609496 TI - Assessment of left ventricular regional function in affected and carrier dogs with Duchenne muscular dystrophy using speckle tracking echocardiography. AB - BACKGROUND: Two-dimensional speckle tracking echocardiography (STE) is a relatively new method to detect regional myocardial dysfunction. To assess left ventricular (LV) regional myocardial dysfunction using STE in Duchenne muscular dystrophy model dogs (CXMD(J)) without overt clinical signs of heart failure. METHODS: Six affected dogs, 8 carrier dogs with CXMD(J), and 8 control dogs were used. Conventional echocardiography, systolic and diastolic function by Doppler echocardiography, tissue Doppler imaging (TDI), and strain indices using STE, were assessed and compared among the 3 groups. RESULTS: Significant differences were seen in body weight, transmitral E wave and E' wave derived from TDI among the 3 groups. Although no significant difference was observed in any global strain indices, in segmental analysis, the peak radial strain rate during early diastole in posterior segment at chordae the tendineae level showed significant differences among the 3 groups. CONCLUSIONS: The myocardial strain rate by STE served to detect the impaired cardiac diastolic function in CXMD(J) without any obvious LV dilation or clinical signs. The radial strain rate may be a useful parameter to detect early myocardial impairment in CXMD(J). PMID- 21609498 TI - Re-surgery and chest wall re-irradiation for recurrent breast cancer: a second curative approach. AB - BACKGROUND: Repeat radiation is a rarely used treatment strategy that must be performed with caution. The efficacy and toxicity of a second curative radiotherapy series was investigated in cases of recurrent breast cancer. METHODS: Forty-two patients treated from 1993 to 2003 with resection (n = 30) and postoperative re-irradiation or definitive re-irradiation (n = 12) for recurrent breast cancer were enrolled in the study. Concurrent hyperthermia was performed in 29 patients. The median age was 57 years. The median pre-radiation exposure was 54Gy. Re-irradiation was conventionally fractionated to a median total dose of 60Gy. RESULTS: After a median follow-up of 41 months (range 3-92 months) higher graded late toxicity > G3 according to CTC 3.0 and LENT-SOMA was not observed. The estimated 5-year local control rate reached 62%. The estimated 5 year overall survival rate was 59%. Significantly inferior survival was associated with recurrence within two years (40 vs. 71%, p < ([0-9]).01) and presence of macroscopic tumour load (24 vs. 75%, p = 0.03). CONCLUSIONS: Repeat radiotherapy for recurrent breast cancer with total radiation doses of 60 Gy and the addition of hyperthermia in the majority of patients was feasible, with acceptable late morbidity and improved prognosis, particularly in patients with previous resection of recurrent tumours. PMID- 21609499 TI - Use of AUDIT, and measures of drinking frequency and patterns to detect associations between alcohol and sexual behaviour in male sex workers in Kenya. AB - BACKGROUND: Previous research has linked alcohol use with an increased number of sexual partners, inconsistent condom use and a raised incidence of sexually transmitted infections (STIs). However, alcohol measures have been poorly standardised, with many ill-suited to eliciting, with adequate precision, the relationship between alcohol use and sexual risk behaviour. This study investigates which alcohol indicator--single-item measures of frequency and patterns of drinking ( > = 6 drinks on 1 occasion), or the Alcohol Use Disorders Identification Test (AUDIT)--can detect associations between alcohol use and unsafe sexual behaviour among male sex workers. METHODS: A cross-sectional survey in 2008 recruited male sex workers who sell sex to men from 65 venues in Mombasa district, Kenya, similar to a 2006 survey. Information was collected on socio demographics, substance use, sexual behaviour, violence and STI symptoms. Multivariate models examined associations between the three measures of alcohol use and condom use, sexual violence, and penile or anal discharge. RESULTS: The 442 participants reported a median 2 clients/week (IQR = 1-3), with half using condoms consistently in the last 30 days. Of the approximately 70% of men who drink alcohol, half (50.5%) drink two or more times a week. Binge drinking was common (38.9%). As defined by AUDIT, 35% of participants who drink had hazardous drinking, 15% harmful drinking and 21% alcohol dependence. Compared with abstinence, alcohol dependence was associated with inconsistent condom use (AOR = 2.5, 95%CI = 1.3-4.6), penile or anal discharge (AOR = 1.9, 95%CI = 1.0-3.8), and two-fold higher odds of sexual violence (AOR = 2.0, 95%CI = 0.9-4.9). Frequent drinking was associated with inconsistent condom use (AOR = 1.8, 95%CI = 1.1-3.0) and partner number, while binge drinking was only linked with inconsistent condom use (AOR = 1.6, 95%CI = 1.0-2.5). CONCLUSIONS: Male sex workers have high levels of hazardous and harmful drinking, and require alcohol-reduction interventions. Compared with indicators of drinking frequency or pattern, the AUDIT measure has stronger associations with inconsistent condom use, STI symptoms and sexual violence. Increased use of the AUDIT tool in future studies may assist in delineating with greater precision the explanatory mechanisms which link alcohol use, drinking contexts, sexual behaviours and HIV transmission. PMID- 21609501 TI - MimoPro: a more efficient Web-based tool for epitope prediction using phage display libraries. AB - BACKGROUND: A B-cell epitope is a group of residues on the surface of an antigen which stimulates humoral responses. Locating these epitopes on antigens is important for the purpose of effective vaccine design. In recent years, mapping affinity-selected peptides screened from a random phage display library to the native epitope has become popular in epitope prediction. These peptides, also known as mimotopes, share the similar structure and function with the corresponding native epitopes. Great effort has been made in using this similarity between such mimotopes and native epitopes in prediction, which has resulted in better outcomes than statistics-based methods can. However, it cannot maintain a high degree of satisfaction in various circumstances. RESULTS: In this study, we propose a new method that maps a group of mimotopes back to a source antigen so as to locate the interacting epitope on the antigen. The core of this method is a searching algorithm that is incorporated with both dynamic programming (DP) and branch and bound (BB) optimization and operated on a series of overlapping patches on the surface of a protein. These patches are then transformed to a number of graphs using an adaptable distance threshold (ADT) regulated by an appropriate compactness factor (CF), a novel parameter proposed in this study. Compared with both Pep-3D-Search and PepSurf, two leading graph based search tools, on average from the results of 18 test cases, MimoPro, the Web-based implementation of our proposed method, performed better in sensitivity, precision, and Matthews correlation coefficient (MCC) than both did in epitope prediction. In addition, MimoPro is significantly faster than both Pep-3D-Search and PepSurf in processing. CONCLUSIONS: Our search algorithm designed for processing well constructed graphs using an ADT regulated by CF is more sensitive and significantly faster than other graph-based approaches in epitope prediction. MimoPro is a viable alternative to both PepSurf and Pep-3D-Search for epitope prediction in the same kind, and freely accessible through the MimoPro server located at http://informatics.nenu.edu.cn/MimoPro. PMID- 21609500 TI - The Lactobacillus flora in vagina and rectum of fertile and postmenopausal healthy Swedish women. AB - BACKGROUND: Lactobacillus species are the most often found inhabitants of vaginal ecosystem of fertile women. In postmenopausal women with low oestrogen levels, Lactobacillus flora is diminishing or absent. However, no studies have been performed to investigate the correlation between oestrogen levels and the lactobacilli in the gut. The aim of the present study was to investigate the relation in healthy women between vaginal and rectal microbial flora as well as possible variations with hormone levels. METHODS: Vaginal and rectal smears were taken from 20 healthy fertile women, average 40 years (range 28-49 years), in two different phases of the menstrual cycle, and from 20 postmenopausal women, average 60 years (range 52-85 years). Serum sex hormone levels were analyzed. Bacteria from the smears isolated on Rogosa Agar were grouped by Randomly Amplified Polymorphic DNA and identified by multiplex PCR and partial 16S rRNA gene sequencing. RESULTS: Lactobacillus crispatus was more often found in the vaginal flora of fertile women than in that of postmenopausal (p = 0.036). Fifteen of 20 fertile women had lactobacilli in their rectal smears compared to 10 postmenopausal women (p = 0.071). There was no correlation between the number of bacteria in vagina and rectum, or between the number of bacteria and hormonal levels. Neither could any association between the presence of rectal lactobacilli and hormonal levels be found. CONCLUSION: Lactobacillus crispatus was more prevalent in the vaginal flora of fertile women, whereas the Lactobacillus flora of rectum did not correlate to the vaginal flora nor to hormonal levels. PMID- 21609502 TI - Family origin and mortality: prospective Finnish cohort study. AB - BACKGROUND: Death rates are notably higher in eastern Finland than in western Finland, and life expectancy of Finnish speakers shorter than that of Swedish speakers. The mortality differences correspond to recent genetic mappings of the population and are prominent for causes of death that are known to be associated with genetic risk factors. METHODS: Using intergenerational data, we studied the impact of parental birth area on all-cause mortality risks of middle-aged men in Finland 1985-2003, assuming that geographic family origin reflects genetic predisposition to complex disorders. Relative death risks at ages 30-49 years were estimated by parental birth region and ethnicity, according to Cox regressions standardised for own education, family type at childhood, and year of birth. RESULTS: The death risk of Finnish speakers born in eastern Finland was 1.13 (95% confidence interval 1.01 to 1.26) that of Finnish speakers born in western Finland, whereas that of Swedish speakers was only 0.60 (0.52 to 0.71). In Finnish speakers, the effects of own birth area and area of residence disappeared when parental birth area was accounted for. The death risk of persons with at least one parent born in eastern Finland was 1.23 (1.09 to 1.39) that of people with both parents born in western Finland. CONCLUSIONS: Parental birth area is the driving force behind the regional mortality difference in Finland. The findings highlight and give further support for the potentially important role of genetic risk factors in mortality. Close monitoring of persons' geographic and ethnic ancestry may promote public health and avoid many early deaths. PMID- 21609503 TI - Enhancer of zeste homolog 2 (EZH2) in pediatric soft tissue sarcomas: first implications. AB - Soft tissue sarcomas of childhood are a group of heterogeneous tumors thought to be derived from mesenchymal stem cells. Surgical resection is effective only in about 50% of cases and resistance to conventional chemotherapy is often responsible for treatment failure. Therefore, investigations on novel therapeutic targets are of fundamental importance. Deregulation of epigenetic mechanisms underlying chromatin modifications during stem cell differentiation has been suggested to contribute to soft tissue sarcoma pathogenesis. One of the main elements in this scenario is enhancer of zeste homolog 2 (EZH2), a methyltransferase belonging to the Polycomb group proteins. EZH2 catalyzes histone H3 methylation on gene promoters, thus repressing genes that induce stem cell differentiation to maintain an embryonic stem cell signature. EZH2 deregulated expression/function in soft tissue sarcomas has been recently reported. In this review, an overview of the recently reported functions of EZH2 in soft tissue sarcomas is given and the hypothesis that its expression might be involved in soft tissue sarcomagenesis is discussed. Finally, the therapeutic potential of epigenetic therapies modulating EZH2-mediated gene repression is considered. PMID- 21609504 TI - The effect of using assessment instruments on substance-abuse outpatients' adherence to treatment: a multi-centre randomised controlled trial. AB - BACKGROUND: Drop-out is an important problem in the treatment of substance use disorder. The focus of this study was to investigate the effectiveness of within treatment assessment with feedback directly to patients with multiple substance use disorder on outpatient individual treatment adherence. Feedback consisted of personal resources' and readiness to change status and progress that facilitate or hinder change, thereby using graphical representation. METHODS: Informed consent was obtained from both the control and experimental groups to be involved in research and follow-up. Following Zelen's single consent design, baseline participants (n = 280) were randomised (sample-size-estimation: 80%power, p=.05, 2-sided) and treatment consent was obtained from those allocated to the experiment (n = 142). In both groups, equal numbers of patients did not attend sessions after allocation. So, 227 persons were analyzed according to intention to-treat analysis (ITT: experiment n = 116;control n = 111). Excluding refusals 211 participants remained for per-protocol analysis (PP: experiment n = 100; control n = 111), The study was conducted in five outpatient treatment-centres of a large network (De Sleutel) in Belgium. Participants were people with multiple substance use disorder -abuse and dependence- who had asked for treatment and who had been advised to start individual treatment after a standardised admission assessment with the European Addiction Severity Index.The experimental condition consisted of informing the patient about the intervention and of subsequent assessments plus feedback following a protocol within the first seven sessions. Assessments were made with the Readiness to Change Questionnaire and the Personal Resources Diagnostic System. The control group received the usual treatment without within treatment assessment with feedback. The most important outcome measure in this analysis of the study was the level of adherence to treatment at and beyond eight sessions. RESULTS: Individual treatment that included assessment with feedback increased adherence to treatment at and beyond eight sessions (RR = 1.6,95%CI:1.2-2.2). Benefit was also found at and beyond twelve sessions, which was the number of sessions required to complete 90% of the assessments with feedback in practice (RR = 1.6,95%CI:1.2-2.5). CONCLUSIONS: Assessment with feedback in routine practice improved adherence to treatment. More research is needed to evaluate progress in social functioning and motivation to change in outpatient treatment of substance use disorder, thereby using objective measures. PMID- 21609505 TI - Understanding client satisfaction with a health insurance scheme in Nigeria: factors and enrollees experiences. AB - BACKGROUND: Health insurance schemes have been widely introduced during this last decade in many African countries, which have strived for improvements in health service provision and the promotion of health care utilization. Client satisfaction with health service provision during the implementation of health insurance schemes has often been neglected since numerous activities take place concurrently. The satisfaction of enrollees and its influencing factors have been providing evidence which have assisted in policy and decision making. Our objective is to determine the enrollee's satisfaction with health service provision under a health insurance scheme and the factors which influence the satisfaction. METHODS: This retrospective, cross-sectional survey took place between May and September 2008. Two hundred and eighty (280) enrollees insured for more than one year in Zaria-Nigeria were recruited using two stage sampling. Enrollee's satisfaction was categorized into more satisfied and less satisfied based on positive responses obtained. Satisfaction, general knowledge and awareness of contribution were each aggregated and assessed as composite measure. Logistic regression analysis was used to analyze factors that influenced the satisfaction of enrollees. RESULTS: A high satisfaction rate with the health insurance scheme was observed (42.1%). Marital status (p < .05), general knowledge (p < .001) and awareness of contributions (p < .05) positively influenced clients' satisfaction. Length of employment, salary income, hospital visits and duration of enrolment slightly influenced satisfaction. CONCLUSIONS: This study highlighted the potential effects of general health insurance knowledge and awareness of contributions by end-users (beneficiaries) of such new program on client satisfaction which have significant importance. The findings provided evidence which have assisted the amendment and re-prioritization of the medium term strategic plan of operations for the scheme. Future planning efforts could consider the client satisfaction and the factors which influenced it regularly. PMID- 21609506 TI - A unique cause of hemoperitoneum: spontaneous rupture of a splenic hemangiopericytoma. AB - Non-traumatic hemoperitoneum may be catastrophic if it is not promptly diagnosed and treated. It is critical to identify this clinical picture and treat any active bleeding. We report the first case in the literature (to our knowledge) of spontaneous hemoperitoneum caused by a cystic splenic hemangiopericytoma. Hemangiopericytomas represent a small subset of soft tissue sarcomas. They rarely originate in the spleen as a primary tumor, with only ten cases having been previously described. The difficulty of predicting the prognosis and clinical behavior of these lesions has been repeatedly stressed. The literature concerning this rare and unusual neoplasm is reviewed. PMID- 21609507 TI - Impact of additional module training on the level of basic life support knowledge of first year students at the University of Maribor. AB - AIM: The aim of this study was to investigate the impact of additional (two versus one session) basic life support (BLS) training of university students on knowledge and attitude concerning the performance of cardiopulmonary resuscitation. METHODS: A total of 439 students in three separate groups were tested: those with no prior BLS training; BLS training in high school (part of the driver's education course); and BLS training in high school (in the driver's education course) and additional BLS training at the university. RESULTS: Our study showed the best results of BLS education in a group of university students who took an additional BLS module approximately half a year after the driver's education BLS course. In our study we observed equal levels of knowledge between the group with BLS training in high school and the group without any formal BLS education. The questionnaire revealed a disappointing level of knowledge about BLS in both groups. CONCLUSION: Additional basic life support training (two BLS training sessions: high school and university) improves retention of knowledge and attitudes concerning performing CPR in first year university students. PMID- 21609508 TI - Acute severe non-traumatic muscle injury following reperfusion surgery for acute aortic occlusion: case report. AB - Acute aortic occlusion is a rare but catastrophic disease with a high mortality rate. Severe perioperative complications could result from revascularization of infarcted muscles. Muscle cell ischaemia and massive volume cell death lead to the release of myoglobin, potassium, and lactic acid, which could be fatal if not recognised or treated early. We highlight the life-threatening adverse effects resulting from bulk tissue infarction from non-traumatic causes such as aortic occlusion followed by the metabolic sequelae of reperfusion. This is similar to the pathophysiology of traumatic crush injuries and rhabdomyolysis. The case highlights the vigorous pre-emptive treatment of acidosis and hyperkalaemia required during surgical revascularisation to potentially avert adverse surgical outcomes in acute aortic obstruction. PMID- 21609509 TI - Renal failure (chronic). AB - INTRODUCTION: Continued progression of renal failure will lead to renal function too low to sustain healthy life. In developed countries, such people will be offered renal replacement therapy in the form of dialysis or renal transplantation. Requirement for dialysis or transplantation is termed end-stage renal disease (ESRD). METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments used to reduce progression rate of chronic renal failure? What are the effects of lifestyle changes used to reduce progression rate of chronic renal failure? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 44 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: angiotensin II receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors (with or without angiotensin II receptor antagonists), exercise, erythropoiesis-stimulating agents, fibrates, lowering blood pressure below usual targets, nicotinates, psychoeducational intervention, smoking cessation, sodium (dietary), statins, structured programmes to achieve therapeutic goals, and targeted lowering of albuminuria/proteinuria. PMID- 21609510 TI - Depression in adults: drug and physical treatments. AB - INTRODUCTION: Depression may affect up to 10% of the population, with half of affected people having recurrence of their symptoms. In mild to moderate depression, there is no reliable evidence that any one treatment is superior in improving symptoms of depression, but the strength of evidence supporting different treatments varies. In severe depression, only prescription antidepressants and electroconvulsive therapy are known to improve symptoms. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in mild to moderate and severe depression, and in treatment-resistant depression? Which interventions reduce relapse rates? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 88 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antidepressant drugs (tricyclic antidepressants [including low-dose tricyclic antidepressants], selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, or venlafaxine), continuing prescription antidepressant drugs, electroconvulsive therapy, exercise, lithium augmentation, pindolol augmentation, and St John's wort. PMID- 21609511 TI - Diabetic retinopathy (treatment). AB - INTRODUCTION: Diabetic retinopathy is the most common cause of blindness in the UK, with older people and those with worse diabetes control, hypertension, and hyperlipidaemia being most at risk. Diabetic retinopathy can cause microaneurysms, haemorrhages, exudates, changes to blood vessels, and retinal thickening. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with diabetic retinopathy? What are the effects of treatments for vitreous haemorrhage? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 58 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: peripheral retinal laser photocoagulation, focal and grid laser photocoagulation for maculopathy, corticosteroids for macular oedema, vascular endothelial growth factor inhibitors, and vitrectomy for vitreous haemorrhage. PMID- 21609515 TI - Royal College white papers: assessment of training. PMID- 21609512 TI - Eczema. AB - INTRODUCTION: Eczema, as defined by the World Allergy Organization (WAO) revised nomenclature in 2003, affects 15% to 20% of school children and 2% to 5% of adults worldwide. About 50% of people with eczema demonstrate atopy, with specific immunoglobulin E responses to allergens. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of topical medical treatments, and dietary interventions in adults and children with established eczema? What are the effects of breastfeeding, reducing allergens, or dietary interventions for primary prevention of eczema in predisposed infants? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 54 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: breastfeeding, controlling house dust mites, corticosteroids, dietary exclusion of eggs or cow's milk, elementary diets, emollients, essential fatty oils, few foods diet, multivitamins, pimecrolimus, probiotics, pyridoxine, reducing maternal dietary allergens, tacrolimus, vitamin E, and zinc supplements. PMID- 21609516 TI - Comparison of public and private bariatric surgery services in Canada. AB - BACKGROUND: Surgical treatment of obesity is cost-effective and improves life expectancy. Roux-en-Y gastric bypass (RYGB) and adjustable gastric banding (AGB) are dominant surgical techniques, but RYGB is the only publicly insured procedure in all Canadian provinces. Private clinics currently offer AGB with minimal wait times. We sought to compare RYGB in public facilities with AGB in private clinics in terms of cost, wait times and certain aspects of patient care. METHODS: We conducted telephone interviews of all bariatric surgery providers across Canada (100% response rate). We asked about various aspects of care, such as wait time, cost, pre- and postoperative care and surgeon experience. RESULTS: The median out of-pocket cost for AGB at private facilities is $16,000 (range $13,160-$18,375). Private clinics have much shorter wait times for AGB than public facilities do for RYGB (1 v. 21 mo, p < 0.001). Private clinics provide significantly fewer preoperative visits with multidisciplinary health professionals (2.7 v. 4.3, p = 0.045), and 5 of 12 (42%) private clinics conduct AGB surgeries without on-site critical care for high-risk (based on the respondents' definitions) patients. CONCLUSION: Private clinics performing AGB offer short wait times, but the cost is high. We found a great deal of variation between pre- and postoperative care among bariatric surgery facilities, and in some cases patient care appears to be less comprehensive. Our findings suggest that further research on obesity treatment is needed to inform policy so that all Canadians can have equitable and timely access to proven, evidence-based care. PMID- 21609517 TI - Average 10.1-year follow-up of cementless total knee arthroplasty in patients with rheumatoid arthritis. AB - BACKGROUND: Total knee arthroplasty (TKA) using a cemented technique has been recommended in patients with rheumatoid arthritis owing to the initial stability of the fixation and long-term durability of the components; however, similar long term follow-up results have been reported in patients who have undergone cementless TKA. The purpose of this study was to evaluate the radiologic and clinical outcomes of cementless TKA in patients with rheumatoid arthritis. METHODS: We enrolled patients undergoing cementless TKA from March 1990 to February 2000. Clinical and radiologic evaluations were performed using the Knee Society clinical rating system and radiographic evaluation and scoring system. RESULTS: We included the cases of 112 patients who underwent 179 cementless TKA procedures in our analysis. Their mean age was 62.3 years, and the mean follow-up period was 10.1 years. The final survival rate was 0.968 at the 15.5-year follow up. Regarding radiologic results after surgery, the mean total valgus angle was 6.7 degrees , the mean femoral flexion angle was 97.5 degrees and the mean tibial angle was 89.2 degrees on the anteroposterior radiographs. On the lateral films, the mean femoral flexion angle was 1.6 degrees and the mean tibial angle was 89.2 degrees . At the last follow-up, the mean total valgus angle was 6.5 degrees , the mean femoral flexion angle was 97.4 degrees and the mean tibial angle was 89.1 degrees , as seen on the anteroposterior view. On the lateral views, the mean femoral flexion angle was 1.4 degrees and the mean tibial angle was 89.0 degrees . Regarding the clinical outcome, the mean knee score and function score on the Knee Society clinical rating system were also enhanced from 47.5 and 43.6, respectively, before the operation to 91.2 and 82.3, respectively, at the last follow-up. CONCLUSION: On radiologic and clinical follow-up of cementless TKA for patients with rheumatoid arthritis, there were no serious complications, and the results of the operation were satisfactory with improvement in range of motion and clinical symptoms. PMID- 21609518 TI - Radiographic assessment of uncemented total hip arthroplasty: reliability of the Engh Grading Scale. AB - BACKGROUND: Radiographic evaluation has a prominent place in the follow-up of long-term results of uncemented total hip arthroplasty (THA). The most prominent scale reported in studies is the Engh Grading Scale, but there is a lack of literature on the reliability of the scale. METHODS: We evaluated intra- and interrater reliability of the Engh Grading System for uncemented THA using 26 follow-up radiographs of patients who had primary uncemented THAs. Four evaluators with different skill levels and specialties participated: 2 arthroplasty surgeons, an orthopedic resident and a radiologist. Reliability was measured using a weighted kappa coefficient for paired comparisons among the evaluators. RESULTS: Intrarater reliability was dependent on the skill and specialty of the evaluator, with the highest values achieved for the arthroplasty surgeons (kappa = 0.52 and kappa = 0.68) and the lowest values for the radiologist (kappa = 0.14). Interrater reliability was comparable among participants, regardless of skill or specialty, and rated a moderate level of reliability (kappa = 0.29-0.41) for all pairings. CONCLUSION: The Engh Grading Scale appears to be reliable when used by a single, experienced arthroplasty surgeon. Caution must be exercised when multiple raters are used, regardless of experience, as the interrater reliability achieved lower ratings. PMID- 21609521 TI - [How to improve the safety of percutaneous transluminal septal myocardial ablation]. PMID- 21609519 TI - CAGS and ACS evidence based reviews in surgery. Is there a role for prophylactic antibiotics in the prevention of urinary tract infections following Foley catheter removal in patients having abdominal surgery? PMID- 21609522 TI - [Evaluation on the neointimal coverage post drug-eluting stent implantation by optical coherence tomography]. AB - OBJECTIVE: To assess the neointimal coverage after the implantation of various drug eluting stents (DES) by optical coherence tomography (OCT). METHODS: The study comprised of 62 patients implanted DES for (15.3 +/- 5.7) months. Patients were divided into three groups according to the type of implanted stent: Cypher group (patient = 26, stent = 57), Endeavor group (patient = 17, stent = 23) and Firebird group (patient = 19, stent = 32). OCT images of the stent were analyzed by software equipped by Light Lab system. Intimal thickness of 64 um, 168 um and 366 um represents 10%, 25% and 50% lumen area loss, respectively. Neointimal coverage was thin with intimal thickness <= 64 um, satisfactory with intimal thickness between 65 um and 366 um and hyperplasia and restenosis with intimal thickness > 366 um. RESULTS: The percent of complete neointimal coverage was similar among groups (P > 0.05). The thickness of neointimal coverage in Cypher and Endeavor and Firebird group was (178.7 +/- 11.9) um, (228.7 +/- 17.1) um and (170.3 +/- 13.3) um, respectively (all P < 0.05). The symmetry of Cypher stent was better than Firebird stent, and the symmetry of Firebird stent was better than Endeavor stent. CONCLUSION: There was significant difference on neointimal coverage after various types of DES implantation, and OCT can be used to evaluate the symmetry of neointimal coverage post implantation of various DES. PMID- 21609523 TI - [The in-hospital outcome and predictors of major adverse cardiac events after transradial intervention in patients with coronary artery disease]. AB - OBJECTIVE: The purpose of this study is to evaluate the in-hospital clinical outcome of patients with coronary artery disease who underwent transradial intervention (TRI) and analyze the predictors of clinical outcome. METHODS: From May 2004 to May 2009, there were 16 281 patients who underwent transradial intervention, as well as 5388 patients who underwent transfemoral intervention (TFI) at our institution. The clinical characteristics, procedural characteristics, and in-hospital clinical adverse events were compared between TRI and TFI groups. Multivariable logistic regression analysis was performed to determine predictors of in-hospital major adverse cardiac events (composite of death, myocardial infarction, or target lesion revascularization) of TRI. RESULTS: The annulations time was significantly longer for TRI than TFI (P < 0.01), fluoroscopy time, amount of contrast agent and procedural success rate (95.5% for TRI and 96.2% for TFI) were similar between the two groups. However, the rates of vascular complications (0.1% for TRI group and 1.3% for TFI group, P < 0.01), incidence of in-hospital major adverse cardiac events (1.6% vs. 3.8%, P < 0.01) and in-hospital death (0.2% vs. 0.4%, P < 0.01) were all significantly lower in TRI group compared with TFI group. The following characteristics were identified as independent multivariate predictors of in-hospital major adverse cardiac events of TRI: age >= 65 (OR: 1.98, 95%CI: 1.50 - 2.61, P < 0.01), prior myocardial infarction (OR: 2.14, 95%CI: 1.63 - 2.82, P < 0.01), use of drug eluting stent (DES) (OR: 0.68, 95%CI: 0.47 - 0.98, P = 0.04), dissection during procedure (OR: 4.08, 95%CI: 2.28 - 7.33, P < 0.01), left main lesion (OR: 2.12, 95%CI: 1.09 - 4.13, P = 0.03), number of implanted stents (OR: 1.25, 95%CI: 1.09 1.43, P < 0.01), and total stented length (OR: 1.01, 95%CI: 1.00 - 1.02, P = 0.03). CONCLUSIONS: In this large single-centre patient cohort, the transradial intervention is superior to transfemoral intervention in terms of in-hospital safety and efficacy. Age >= 65, prior myocardial infarction, use of DES, dissection during procedure, left main lesion, number of implanted stents and total stented length were identified as independent multivariate predictors of in hospital major adverse cardiac events of TRI. PMID- 21609524 TI - [Relationship between post-stenting coronary thrombolysis in myocardial infarction flow and plasma von Willebrand factor and ADAMTS-13 levels in patients with ST segment elevation myocardial infarction]. AB - OBJECTIVE: To investigate the relationship between post-stenting coronary thrombolysis in myocardial infarction (TIMI) flow and plasma von Willebrand factor (vWF) and its cleaving protease (ADAMTS-13) levels in patients with ST segment elevation myocardial infarction (STEMI). METHODS: STEMI patients who underwent primary percutaneous coronary intervention (PCI) and stenting between September, 2007 and December, 2009 were enrolled. According to the post-stenting TIMI flow, patients were divided to TIMI <= 2 group (n = 43) and TIMI 3 group (n = 43). Patients with chest pain or dyspnea and normal coronary angiographic results served as control group (n = 43). The levels of vWF and ADAMTS-13 were measured by ELISA at three time points: immediately after admission, beginning of PCI and 1 week after PCI. RESULTS: Levels of vWF in STEMI patients at all 3 time points were significantly higher than in control patients, and the level of vWF was significantly higher in TIMI <= 2 group than in TIMI 3 group [at admission: (6721.83 +/- 1380.58) U/L vs. (4786.12 +/- 2362.01) U/L, P < 0.05; at the beginning of PCI: (5744.65 +/- 1240.71) U/L vs. (3011.33 +/- 2270.40) U/L, P < 0.05 and at 1 week after PCI: (2001.48 +/- 931.70) U/L vs. (1365.17 +/- 724.12) U/L, P < 0.05]. ADAMTS-13 levels were similar among groups at admission and at beginning of PCI, however, the level of ADAMTS-13 at 1 week after PCI was significantly higher in TIMI <= 2 group than that in TIMI 3 group [(406.93 +/- 101.44) mg/L vs. (270.34 +/- 115.12) mg/L, P < 0.001]. Logistic regression analysis showed that both vWF at admission (OR = 1.917, P < 0.01) and vWF at the beginning of PCI (OR = 2.016, P < 0.01) were risk factors of TIMI <= 2. CONCLUSION: Increased vWF during peri-PCI periods was associated with post stenting coronary TIMI <= 2 after primary PCI in STEMI patients, and the imbalance between vWF and ADAMTS-13 may thus play an important role in the development of slow flow post PCI. PMID- 21609525 TI - [Transcatheter closure of paraprosthetic valve leaks post surgical valve replacements]. AB - OBJECTIVE: To evaluate the feasibility and efficacy of transcatheter closure of paravalvular leak (PVL) with Chinese-made occluder. METHODS: Five PVL patients were involved in this study, 2 out of the 5 patients underwent aortic mechanical valve replacements, 2 underwent mitral bioprosthetic valve replacements, and the remaining 1 underwent double mechanical valve replacement.Left ventricular end diastolic diameter, left atrial diameter and the systolic pulmonary artery pressure were assessed by echocardiography before and post the procedure. RESULTS: Complete occlusion without residual regurgitation was achieved in 2 patients with aortic PVL, for the 3 patients with mitral PVL, there was only tiny or mild mitral paraprosthetic leak remained post closure procedure. Cardiac perforation and pericardium tamponade occurred in 1 patient with aortic PVL during interventional closure and the patient recovered post emergent pericardiocentesis. Transient severe hemolysis and hemoglobinuria occurred in 3 patients with mitral PVL post closure procedure and they recovered after 1 to 3 weeks conservative therapy. During 3 months follow up, left ventricular end diastolic diameter [(52.2 +/- 6.8) mm vs. (61.1 +/- 7.2) mm, P < 0.05], the systolic pulmonary artery pressure [(40.0 +/- 5.4) mm Hg (1 mm Hg = 0.133 kPa) vs. (57.0 +/- 3.6) mm Hg, P < 0.05] and left atrial diameter of mitral PVL patient [(49.0 +/- 4.3) mm vs. (56.0 +/- 6.3) mm, P < 0.05] were significantly reduced compared to before closure procedure. CONCLUSION: Percutaneous or transapical left ventricular access closure of PVL is feasible, effective and relative safe in selected patients. PMID- 21609526 TI - [Genetic variations of bone morphogenetic protein 7 gene are associated with hypertriglyceridemia of Uygur Chinese in Xinjiang]. AB - OBJECTIVE: To analyze the association between the genetic variations of functional region in bone morphogenetic protein (BMP7) gene and dyslipidemia in Chinese Uygur individuals. METHODS: The case-control study was conducted in 1514 Uygur Chinese based on epidemiological investigation. The all exons, segmental introns and the promoter regions of BMP7 gene were sequenced in 48 out of 1514 Uygur Chinese. Representative variations were then selected according to the minor allele frequency (MAF) and linkage disequilibrium, and genotyped using the TaqMan polymerase chain reaction method in 1514 Uygur Chinese, a relatively isolated general population in a relatively homogeneous environment, to observe the association between genetic variations of BMP7 gene and dyslipidemia. RESULTS: Five novel and eight known variations in the BMP7 gene were identified. All genotype distributions were tested for deviations from Hardy-Weinberg equilibrium. There were significant differences of genotype distribution of rs6025422 between hypertriglyceridemia group and control group (P = 0.001). The levels of triglyceride (TG) showed a decreasing tendency in individuals with AA, AG and GG genotypes of rs6025422. Odd ratio (OR) value adjusted for age, gender, body mass index, smoking and alcohol drinking habits was 0.562 by logistic regression analysis (95%CI: 0.393 - 0.802, P = 0.002). CONCLUSION: The present study shows rs6025422 polymorphism in the BMP7 gene is linked with hypertriglyceridemia phenotype in Uygur Chinese population. PMID- 21609527 TI - [Comparison of clinical characteristics of Chinese patients with apical hypertrophic cardiomyopathy and typical hypertrophic cardiomyopathy]. AB - OBJECTIVE: To evaluate the clinical features in Chinese patients with apical hypertrophic cardiomyopathy (AHCM) and typical hypertrophic cardiomyopathy (HCM). METHODS: This retrospective analysis included 160 patients hospitalized in Fuwai hospital. Patients were divided into three groups: apical hypertrophic cardiomyopathy (AHCM, n = 41) group, non-obstructive typical hypertrophic cardiomyopathy group [NOHCM, LVOT < 30 mm Hg (1 mm Hg = 0.133 kPa) at rest, n = 52] and obstructive typical hypertrophic cardiomyopathy (OHCM, LVOT >= 30 mm Hg at rest, n = 67). Clinical features, diagnosis, therapy, and plasma levels of biomarkers of these three groups were analyzed. RESULTS: (1) The age at disease onset was older in AHCM group than in OHCM group [(49.9 +/- 13.6) years vs. (41.4 +/- 14.6) years, P < 0.01]. Exertional dyspnea appeared more often in HCM patients than in AHCM patients, NT-proBNP level was significantly lower in AHCM patients than in OHCM patients (P = 0.001). Plasma CK-MB, LDH, TnI and MYO levels were similar among the three groups. (2) Thirty-three AHCM patients were first hospitalized for suspected coronary heart disease (CHD) and CHD was excluded in 18 cases (43.9%). (3) The frequency of giant negative T waves (depth >= 10 mm) on ECG was 43.9%, 13.5% and 4.4% (P < 0.01) in AHCM, NOHCM and OHCM respectively. Half of AHCM patients showed left ventricular high voltage on ECG. (4) Cardiac magnetic resonance imaging is superior to echocardiography on correctly diagnosing AHCM. CONCLUSION: AHCM patients differ from typical OHCM patients in clinical characteristics. There were significant differences on echocardiography and electrocardiography features among three groups. Cardiac magnetic resonance imaging and giant negative T waves on ECG are helpful for the diagnosis of AHCM. PMID- 21609528 TI - [Value of combined CT coronary angiography and adenosine stress myocardial perfusion scintigraphy for diagnosis of coronary artery disease]. AB - OBJECTIVE: To assess the accuracy and feasibility of combination of CT coronary angiography (CTCA) and adenosine stress myocardial perfusion scintigraphy (MPS) for diagnosis of coronary artery disease (CAD). METHODS: CTCA, MPS were performed in 105 patients with suspected or diagnosed CAD within 4 weeks before coronary angiography (CAG) examination. RESULTS: The sensibility, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were 97.1%, 75.0%, 88.2%, 93.1% and 89.5%, respectively, for CTCA; 79.7%, 63.9%, 80.9%, 62.2% and 74.3%, respectively, for MPS and 97.2%, 98.5%, 98.5%, 89.7% and 95.2%, respectively, for CTCA + MPS. CONCLUSION: Combination of CTCA and adenosine stress MPS, which provided both anatomical and functional information of coronary vessels, could significantly increase the specificity and PPV of diagnosing CAD with CTCA. PMID- 21609529 TI - [Readthrough of nonsense mutation W822X in the SCN5A gene can effectively restore expression of cardiac Na+ channels W822X]. AB - OBJECTIVE: In this study we investigated the functional restoration of nonsense mutations in the SCN5A gene. METHODS: The readthrough-enhancing reagents were introduced to HEK293 cells to suppress one nonsense mutation W822X in the SCN5A gene. Patch-clamp was used to record the whole-cell current and dynamics. Western blot and immunofluorescence staining were used to certify the expression and the location of the sodium channel. RESULTS: In transfected HEK293 cells, the nonsense mutation in SCN5A inhibited the expression level of full-length protein, and the sodium currents from the mutant channels were less than 3% of the wild type level. Readthrough enhancement by decreasing translation termination efficiency with a siRNA targeting eukaryotic release factor eRF3a (a GTPase that binds eRF1), the sodium current from the mutant cDNAs was restored to as much as 30% of the wild-type. After the treatment by the readthrough-enhancing reagents, the channels from cDNA carrying W822X remained the features of wild-type phenotype, and Western blot and immunochemical staining also showed the expression of full-length channel proteins. CONCLUSION: Readthrough-enhancing reagents could effectively suppress nonsense mutations in SCN5A and partially restore the function of sodium channel and the expression of full-length channels. PMID- 21609530 TI - [Effects of mixed-tocopherols and eicosapentaenoic acid on oxidized LDL-induced oxidative damage and inflammatory cytokine secretion in human umbilical vein endothelial cells]. AB - OBJECTIVE: To observe the influence of either alone or combined mixed-tocopherols combined with eicosapentaenoic acid (EPA) and alpha-Tocopherol use on oxidized LDL (oxLDL) induced 8-hydroxy-2'-deoxyguanosine (8-OHDG) and interleukin-6 (IL-6) secretion by human umbilical vein endothelial cells (HUVECs) and to explore the potential mechanism. METHOD: Cultured HUVECs in vitro were incubated with oxLDL, oxLDL + alpha-tocopherol, oxLDL + mixed-tocopherols, oxLDL + EPA, oxLDL + alpha tocopherol + EPA, oxLDL + mixed-tocopherols + EPA for 24 hours, respectively. Secretion of 8-OHDG and IL-6 were detected by cell enzyme linked immunosorbent assay (ELISA). The expressions of superoxide dismutase (SOD), protein kinase C delta (PKC-delta), phosphorylated PKC-delta (p-PKC-delta) were analyzed by Western blot. RESULTS: 8-OHDG and IL-6 secretion of HUVECs was significantly increased significantly after incubated with oxLDL for 24 hours which could be significantly attenuated in the presence of tocopherols and EPA (alone or in combination, all P < 0.05) while the strongest inhibition effects were seen with combined use of mixed-tocopherols and EPA. Moreover, combination of mixed tocopherols and EPA could also significantly increase SOD activity and decrease PKC activity (all P < 0.05). However, the protein expression of SOD and PKC-was similar among groups. CONCLUSION: Combined mixed-tocopherols + EPA use enhanced the inhibiting effects on the secretion of 8-OHDG and IL-6 in oxLDL stimulated HUVECs which might be linked with increased SOD activity and reduced p-PKC activity. PMID- 21609531 TI - [Effects of rosuvastatin on monocrotaline-induced pulmonary artery hypertension in rats]. AB - OBJECTIVE: To investigate the effects of rosuvastatin on monocrotaline (MCT) induced pulmonary artery hypertension in rats. METHODS: Pulmonary arterial hypertension was induced by a single subcutaneous injection of monocrotaline (50 mg/kg) in rats. In the prevention protocol, 32 male Sprague-Dawley rats were randomly divided into four groups (n = 8 each): low-dose rosuvastatin prevention group (2 mg*kg(-1)*d(-1)), high-dose rosuvastatin prevention group (10 mg*kg( 1)*d(-1)), pulmonary arterial hypertension group, normal control group. Beginning on the MCT injection day, rats were treated with rosuvastatin by daily gavage for 4 weeks. Normal control group and pulmonary arterial hypertension group received vehicle by gavage. In the treatment protocol, 52 male Sprague-Dawley rats were randomly divided into four groups (n = 13 each): low-dose rosuvastatin treatment group (2 mg*kg(-1)*d(-1)), high-dose rosuvastatin treatment group (10 mg*kg( 1)*d(-1)), pulmonary arterial hypertension group, normal control group. Four weeks after MCT injection, rats were treated with rosuvastatin by daily gavage for 4 weeks. Normal control group and pulmonary arterial hypertension group received vehicle by gavage. At the end of study, survival rates, mean pulmonary arterial pressure (mPAP), wall thickness of small pulmonary artery and right ventricular hypertrophy among groups were compared. The expression levels of proliferating cell nuclear antigen (PCNA) and endothelial nitricoxide synthase (eNOS) protein in small pulmonary artery, the expression levels of Rho kinase 1(ROCK-1) and eNOS mRNA in lung tissue were also detected. RESULTS: All rats in the prevention protocol survived. Rosuvastatin treatment improved survival in the treatment protocol (58%, 75% vs.30%, P < 0.05). Rosuvastatin therapy in both preventive or treatment protocols significantly lowered mPAP [prevention protocol: (27.53 +/- 3.43), (25.72 +/- 1.76) vs. (36.05 +/- 2.45) mm Hg (1 mm Hg = 0.133 kPa), P < 0.01; treatment protocol: (30.39 +/- 3.17), (27.59 +/- 1.99) vs. (40.68 +/- 1.39) mm Hg, P < 0.01], reduced thickening of small pulmonary artery wall (P < 0.01) and right ventricular hypertrophy (P < 0.01). Rosuvastatin also inhibited PCNA expression of SMC (P < 0.01), restored eNOS expression of EC (P < 0.05) and inhibited ROCK-1 mRNA expressions in lung tissue (P < 0.05). CONCLUSIONS: Rosuvastatin therapy reduced mPAP in monocrotaline-induced pulmonary arterial hypertension rat model and this effect is linked with inhibition of ROCK 1 expression, inhibition of smooth muscle cell proliferation and restoration of endothelial cell functions. PMID- 21609532 TI - [Hypertension and cardiovascular risk evaluation of Chinese cardiovascular physicians]. AB - OBJECTIVE: To observe the prevalence, awareness, treatment and control rate of hypertension and to evaluate the 10-year absolute risk of coronary heart disease(CHD) and ischemic cardiovascular disease(ICVD) in Chinese cardiovascular physicians. METHODS: A total of 4032 cardiovascular physicians (28 to 79 years old) from 386 hospitals in 31 provinces, autonomous regions and municipalities were randomly selected and received an epidemiologic survey of prevalence, awareness, and control of hypertension and evaluations of CHD and ICVD risk. RESULTS: The prevalence of hypertension in Chinese cardiovascular physicians was 13.1%. The awareness rate of hypertension in Chinese cardiovascular physicians was 81.7%. Hypertension treatment rate was 69.6% and blood pressure control rate was 44.6%. The prevalence of hypertension was higher in male physicians than in female physicians before the age of 55 years old. Ten-year absolute risk of CHD and ICVD was 0.08 and 0.03 in hypertensive physicians compared to 0.03 and 0.01 in non-hypertensive physicians. CONCLUSIONS: The results show suboptimal awareness, treatment and control rate in Chinese cardiovascular physicians for their own hypertension status.Physicians suffering from hypertension face higher risk for cardiovascular disease. It is therefore necessary to improve the self monitoring of blood pressure in Chinese cardiovascular physicians. PMID- 21609533 TI - [Low ankle brachial index and risk of death: a meta-analysis]. AB - OBJECTIVE: To evaluate the association between low ankle brachial index and risk of death. METHODS: Related cohort studies in the past 12 years were collected. Heterogeneity was analyzed with chi(2) and I(2). Pooled hazard ratio (HR) as the effect indicator and 95% confidence interval (CI) were used to estimate the association of low ankle brachial index and risk of death by fixed effect model (inverse variance method). RESULTS: A total of 8 studies were included with sum sample size of 30 029. In heterogeneity analysis, chi(2) was 5.46, I(2) was 0.0%, and P was 0.604. Meta-analysis resulted in pooled HR of 1.69 (95%CI: 1.55 - 1.84). CONCLUSION: Low ankle brachial index is associated with increased risk of death. PMID- 21609534 TI - [A meta-analysis on efficacy of anti-platelet agents and anticoagulants for preventing stroke in patients with nonvalvular atrial fibrillation]. AB - OBJECTIVE: To evaluate the efficacy and security of anti-platelet and anticoagulant therapy on prevention of ischemic stroke in patients with nonvalvular atrial fibrillation (NAF). METHODS: We searched PubMed, EMbase, CENTREN and its affiliated clinical trial registration data center, CBMdisc, VIP, and CNKI databases from establishment to Dec 2009 to identify randomized controlled trials (RCTs) covering the use of anti-platelet agents and anticoagulants for patients with NAF. Meta-analysis was performed by using RevMan 5.0 software after the strict evaluation of the methodological quality of the included RCTs. RESULTS: Fourteen RCTs involving 15 880 patients were include. Compared with placebo or no use of anti-platelet drugs, antiplatelet therapy didn't reduce ischemic stroke (RR = 0.83, 95%CI 0.68 to 1.00, P = 0.05), systemic emboli (RR = 0.71, 95%CI 0.34 to 1.51, P = 0.38) and all-cause mortality (RR = 0.88, 95%CI 0.73 to 1.07, P = 0.21) while significantly increased the major bleeding (RR = 2.88, 95%CI 1.21 to 6.86, P = 0.02) in patients with NAF, intracranial hemorrhage was not affected by antiplatelet therapy in patients with atrial fibrillation (RR = 3.25, 95%CI 0.84 to 12.62, P = 0.09). Compared with anti-platelet therapy, anticoagulant therapy significantly reduced the incidence of ischemic stroke (RR = 1.84, 95%CI 1.48 to 2.28, P < 0.01) and systemic emboli (RR = 1.94, 95%CI 1.24 to 3.03, P = 0.004) but significantly increased the incidence of intracranial hemorrhage (RR = 0.49, 95%CI 0.31 to 0.78, P = 0.003), did not affect all-cause mortality (RR = 1.06, 95%CI 0.90 to 1.23, P = 0.50) and the incidence of major bleeding (RR = 0.95, 95%CI 0.76 to 1.19, P = 0.66) in NAF patients. CONCLUSIONS: Compared with the placebo and no use of anti-platelet drugs, anti-platelet therapy didn't reduce ischemic stroke and systemic emboli but increased the risk of major bleeding in NAF patients. Compared with anti platelet therapy, anticoagulant therapy significantly reduced the ischemic stroke and systemic emboli without increasing the risk of major bleeding, but significantly increased the incidence of intracranial hemorrhage in NAF patients. Since the study included RCTs with limited and less uniform outcome endpoints, the conclusions should be verified with RCTs with more uniform endpoints and longer follow-up time. PMID- 21609535 TI - [Successful thrombolysis of occluded superior mesenteric artery in a dilated cardiomyopathy patient with sinus rhythm]. PMID- 21609536 TI - [A case report of myocardial infarctions in patient with diffuse coronary artery ectasia]. PMID- 21609537 TI - [One case of angina pectoris and bradycardia caused by mechanical aortic prosthesis dysfunction due to tissue ingrowth]. PMID- 21609538 TI - [Advance on clinical applications of platelet glycoprotein IIb/IIIa receptor inhibitors]. PMID- 21609539 TI - [Update on late-acquired stent malapposition after stent implantation]. PMID- 21609540 TI - [Association between particulate matter air pollution and atherosclerosis]. PMID- 21609541 TI - [Reflections on how to increase success rates of percutaneous Coronary Interventions in Chronic Total Occlusions]. PMID- 21609542 TI - [Chinese guidelines for diagnosis and management of cognitive impairment and dementia (V): dementia therapy]. PMID- 21609543 TI - [Comparison of postprandial insulin and fasting insulin on the evaluation of cardiovascular risk factors]. AB - OBJECTIVE: To study the feasibility of using postprandial insulin (2hINS) and fasting insulin (FINS) on evaluation of insulin resistance, comparison was conducted between 2hINS and FINS on evaluation of cardiovascular risk factors. METHODS: A survey were conducted among individuals in the community in May 2008 and data of routine clinical examination were collected. All subjects were investigated and received 75 g oral glucose tolerance test (OGTT), and fasting and OGTT2 h blood glucose as well as insulin concentrations were determined. Hyperinsulinemia was defined as a FINS or 2hINS concentration at or above the 95th percentile of the distribution among normal glucose tolerance individuals. RESULTS: 1148 individuals were investigated and insulin concentration in male was similar to female. Prevalence of 2hHINS (40.8%) in individuals with abnormal glucose metabolism was higher than FHINS (18.4%, P < 0.01). The number of metabolic risk factors in subjects with 2hHINS was similar to subjects with FHINS. After adjustment by sex, age, BMI and waist circumference, partial correlation analysis showed that the correlation between 2hINS and 2hPG (r = 0.370) was higher than that of FINS and FPG (r = 0.104); FINS was higher correlated with TG and HDL- cholesterol than 2hINS, however, 2hINS was higher correlated with diastolic blood pressure, total cholesterol and LDL-cholesterol than FINS. Logistic regression analysis showed that FHINS and 2hHINS were both the independent risk factor of metabolic syndrome, the OR (95%CI) were 5.11 (2.953 - 8.842) and 3.46 (2.109 - 5.687). CONCLUSION: 2hINS and FINS were both closely associated with cardiovascular risk factors. The correlation was inconsistent when 2hINS and FINS were related to different risk factors. The combination of 2hINS and FINS might be more helpful on evaluation of insulin resistance. PMID- 21609544 TI - [Experience of the treatment following downstaging of larger hepatocellular carcinomas by transcathetheter hepatic arterial chemoembolization in 58 patients]. AB - OBJECTIVE: To evaluate the feasibility of sequential liver resection or liver transplantation following downstaging of larger hepatocellular carcinoma (HCC) by transcatheter arterial chemoembolization (TACE). METHODS: A retrospective study was conducted. And a total of 58 patients with unresectable larger HCC (diameter > 5 cm) from June 2006 to March 2010 underwent TACE. According the outcomes of TACE, they received liver transplantation (LT, n = 36) and liver resection (LR, n = 22) respectively. The overall survival (OS) and recurrence-free survival (RFS) rates were calculated by the Kaplan-Meier method. The multivariate analyses for the influencing factors were evaluated by the Cox proportional hazard model. RESULTS: The median follow-up period of 58 cases was 22 months and the median survival time 23.57 +/- 1.54 months. The 1-, 2-, 3-year OS and RFS rates after LT was 94%, 84% & 73% and 88%, 75% & 64% respectively. The median recurrence time was 12.3 +/- 6.4 months (range: 3 - 23). Twenty-eight patients had adequate downstaging to qualify for LT under the Milan criteria. The 1-, 2-, 3-year OS and RFS of the downstaging group was better than those of the non-downstaging group (OS: 96%, 88%, 75% vs 92%, 48%, 48% P = 0.067; RFS: 95%, 95%, 79% vs 76%, 40%, 40% P = 0.002). The 1-, 2-, 3-years OS and RFS after LR was 100%, 64% & 52% and 72%, 49% & 49% respectively. The median recurrence time was 9.3 +/- 4.5 months (range: 3 - 23). The long-term results of LT group following TACE were better than those of LR group (OS, P = 0.178; RFS, P = 0.139). The multivariate analyses showed that only pathologic total tumor diameter > 7 cm (P = 0.002, RR = 6.578), microvascular invasion (P = 0.001, RR = 5.737) and poor differentiation (P = 0.048, RR = 4.335) were significantly correlated with tumor recurrence. CONCLUSION: Sequential liver resection and liver transplantation after downstaging by TACE are feasible for some larger HCCs. And the long-term prognosis is satisfactory. PMID- 21609545 TI - [Eosinophilic infiltration of lung cancer tissue and its correlation with the expression of interleukin-5]. AB - OBJECTIVE: To study the correlation of the eosinophilic infiltration with the expression of Interleukin-5 (IL-5) in tissue specimens from the patients with lung cancer. METHODS: Eosinophilic infiltration was detected by chromotrope-2R histochemical staining. And the level of IL-5 was detected by immunohistochemistry in 45 lung cancer tissues and 36 corresponding normal lung tissues. RESULTS: High-level tissue eosinophilic infiltration was found in 17 of 45 (37.8%) cases of lung cancer. In cases with high-level tissue eosinophilic infiltration, the count of eosinophil in tumor tissues was significantly higher than that in corresponding normal lung tissue (P < 0.05). In non-small cell lung cancer (NSCLC), the rate of high-level tissue eosinophilic infiltration cases was significantly higher than that of small cell lung cancer (SCLC) (P < 0.05). IL-5 was expressed at a high level in all 45 cases of lung cancer and at a low level in corresponding normal lung tissues. Eosinophilic infiltration was not correlated with the expression of IL-5 in lung cancer tissues (r = 0.026, P > 0.05). CONCLUSION: High-level eosinophilic infiltration of tumor tissues is found in some cases of lung cancer. Compared with SCLC, the rate of high-level tissue eosinophilic infiltration cases of NSCLC is significantly elevated. There is no correlation between the eosinophilic infiltration and the expression of IL-5 in lung cancer tissues. PMID- 21609546 TI - [Reconstructive approaches of alimentary canal for subtotal gastrectomy]. AB - OBJECTIVE: To explore the optimal technique of digestive tract reconstruction for radical proximal gastrectomy. METHODS: The clinical data for 120 cases of proximal gastric cancer undergoing radical proximal gastrectomy at our hospital from 2000 to 2009 were analyzed retrospectively. They included three approaches of digestive tract reconstruction. The patients were divided into esophagogastric anterior wall anastomosis group (n = 50), jejunal interposition group (n = 26) and gastric tube group (n = 44). The quality of life was evaluated and compared among 3 groups. RESULTS: The rates of anastomotic fistula, anastomotic obstruction and the scores of heart burn and reflux esophagitis were higher in gastric tube group. And the increments of hemoglobin and body weight were less in gastric tube group than those in other groups (P < 0.05). The rates of gastric emptying in gastric tube group had no obvious differences with esophagogastric anterior wall anastomosis group at 120 min and 180 min (P > 0.05). And they were higher than those in jejunal interposition group (P < 0.05). There was no statistical difference in any parameter between esophagogastric anterior wall anastomosis and jejunal interposition groups (P > 0.05). CONCLUSION: The anastomosis of esophagogastric anterior wall is an ideal approach of digestive reconstruction for radical proximal gastrectomy. And it may improve the quality of life for surgical patients with proximal gastric cancer. PMID- 21609547 TI - [Reconstruction of proximal humerus tumors with massive osteoarticular allograft transplantation]. AB - OBJECTIVE: To analyze the functional efficacies and complications for the reconstruction of defects in proximal humerus tumors with massive osteoarticular allograft transplantation and evaluate the feasibility of this method. METHODS: A retrospective review was performed for proximal humerus tumors surgically treated and followed up from November 2001 to November 2008. There were 6 males and 1 female with an average age of 38.4 years old (range: 21 - 65). The tumor characteristics were as follows: giant cell tumor (n = 5), osteosarcoma (n = 1) and malignant fibrous tissue tumor (n = 1). According to the Enneking classification system, there were IA (n = 5), IIA (n = 1) and IIB (n = 1). All patients were reconstructed with massive osteoarticular allograft transplantation and immobilized with interlocking nail. The average length of massive allograft was 15.2 cm (range: 11 - 19). RESULTS: All patients were followed up for an average of 5.5 years (range: 2 - 8). In a long-term follow-up, atrophy and adsorption of allograft were found in all cases without clinical symptoms. This phenomenon started to appear after 1.5 years. And bone graft disappeared completely in around 6 years postoperatively. The atrophy of bone graft usually originated from greater tubercles and extended gradually to metaphysic. According to the Musculoskeletal Tumor Society (MSTS) functional classification system, the average score of osteoarticular allografts was 17.6 (range: 15 - 19). According to the MSTS radiological evaluation system, the long-term perfect/fair rate was 0. CONCLUSION: Massive osteoarticular allograft transplantation is one of feasible options for the reconstruction of structural bone defects due to bone tumor resection. PMID- 21609548 TI - [Screening of mitochondrial deoxyribonucleic acid 3271T > C, 8356T > C, 9176T > C/G and 13513G > A mutations in mitochondrial encephalomyopathies]. AB - OBJECTIVE: To investigate the spectrum of mitochondrial DNA (deoxyribonucleic acid) 3271T > C, 8356T > C, 9176T > C/G and 13513G > A mutations in Chinese patients with mitochondrial encephalomyopathies. METHODS: Peripheral blood samples were collected from 500 mitochondrial encephalomyopathies patients clinically diagnosed as mitochondrial encephalomyopathy lactic acidosis & stroke like episodes (MELAS), myoclonus epilepsy & ragged-red fibers (MERRF) or Leigh's syndrome from October 2005 to October 2009. The methods of PCR- polymerase chain reaction-restriction fragment length polymorphism (RFLP) and PCR-sequencing were performed to identify the mutations. RESULTS: No patients with the 3271T > C, 8356T > C, 9176T > C/G or 13513G > A mutations were identified. CONCLUSION: The mutations of 3271T > C, 8356T > C, 9176T > C/G and 13513G > A are rare causes of mitochondrial encephalomyopathies in Chinese patients. PMID- 21609549 TI - [Correlation of breast tumor pathogenesis and somatic mutations on the basis of mitochondrial DNA whole genome]. AB - OBJECTIVE: To investigate the correlation of somatic mutations in whole genome of mitochondrial DNA (mtDNA) in patients with breast tumor. METHODS: The DNA of tumor tissue and peripheral blood in 4 benign breast tumor patients from August 2009 to December 2009 in our hospital were extracted. The mtDNA whole genomes were amplified by polymerase chain reaction (PCR) and the mutations of products screened by sequencing to compare the difference of mutation distribution between tumor tissue and peripheral blood. The likelihood of somatic mutations in tumor tissue was determined. RESULTS: The mutation spectrum of mtDNA genomes was obtained by PCR and sequencing. Then a phylogenetic tree was constructed to identify their haplogroups (D4i, G1, R9b, N9a). Their private mutations in peripheral blood were detected and the somatic mutation at 16292 position was found in one patient (haplogroups: R9b). CONCLUSION: Based on the extensively study on the mtDNA genomes from the tumor issues of 4 patients, our current report observed only a single somatic variation from the control region, no any further mutations with potential function from the coding region were observed. PMID- 21609550 TI - [Cohort study of remifentanil-induced hyperalgesia in postoperative patients]. AB - OBJECTIVE: To investigate the incidence of remifentanil-induced hyperalgesia and screen for the relevant influencing factors in the post-operative patients. METHODS: A total of 1620 patients from June 2008 to December 2008 in our hospital undergoing general anesthesia with remifentanil and whose length of operative incision was less than 4 cm were enrolled. The incidence of postoperative hyperalgesia was investigated and recorded at the timepoints of staying at post anesthesia care unit (PACU), 4 h and 24 h postoperation respectively. The unconditional statistical analysis of Logistic regression was used to explore such possible influencing factors as age, gender, methods of general anesthesia, operative duration, operative sites and remifentanil dose. RESULTS: The incidence of postoperative remifentanil-induced hyperalgesia was 16.1% (n = 261). The incidence of postoperative hyperalgesia was significantly increased in patients < 16 yrs (25.9%) vs >= 16 yrs (15.6%) (P < 0.05), males vs females (20.8% vs 13.0%, P < 0.01), operative duration > 2 h (32.7%) vs <= 2 h (9.9%) (P < 0.01) and remifentanil dose > 30 ug/kg (41.8%) vs <= 30 ug/kg (4.8%) (P < 0.01). And the incidence of limb protective action, touch and cold-induced allodynia were the two highest indicators (39.0%, 34.5%). Analysis of Logistic regression showed that ages under 16 years old, operative duration > 2 h and remifentanil dose > 30 ug/kg were relevant with hyperalgesia (all P < 0.05). CONCLUSION: Ages under 16 years old, operative duration and remifentanil dose are the risk factors for postoperative remifentanil-induced hyperalgesia. Neither methods of general anesthesia nor operative sites has any effect on the occurrence of hyperalgesia. PMID- 21609551 TI - [Establishment of normal reference values for thromboelastography on Chinese population in Beijing]. AB - OBJECTIVE: To determine the normal values for thromboelastography (TEG) in Chinese healthy adult volunteers residing in Beijing for over three years and compare them with those of the manufacturer's. METHODS: A total of 137 healthy adult volunteers were enrolled from June 2010 to August 2010. The technique was standardized with citrated blood and kaolin activator. And a Haemoscope 5000 device was employed. The TEG parameters analyzed were R, K, alpha, maximal amplitude (MA), LY30 and coagulation index (CI). All volunteers underwent the tests of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and plasma fibrinogen level with the same blood sample. RESULTS: The reference ranges of 95% for 137 volunteers were R: 3.8 - 8.4 min, K: 0.8 - 3.3 min, alpha-Angle: 46.2 - 76.2 degrees , MA: 50.0 - 70.8 mm, LY30: -3.3% - 4.0% and CI: -3.8 - 2.9. Overall, 24.1% (33/137) of the volunteers had at least one abnormal parameter while 7.3% (10/137) would have been considered coagulopathy had the manufacturer's reference values been used, resulting in a test specificity of 76.0%. As compared with the western ethnicity (the manufacturer's reference values), Chinese healthy volunteers were associated with lower fibrinogen functions. There were significantly different in R, K, alpha Angle, MA and CI between men and women groups (all P < 0.01). CONCLUSION: This study supports the manufacturer's recommendation that each institute should determine its own normal reference values. PMID- 21609552 TI - [Correlation of endogenous androgen and androgen receptor level with coronary artery diseases in elderly males]. AB - OBJECTIVE: To investigate the correlation of endogenous androgen and androgen receptor (AR) level with coronary artery diseases (CAD) in elderly males and elucidate the potential mechanism of gender difference in the prevalence of CAD. METHODS: A total of 296 male patients from different centers were divided into the CAD group (n = 237) and the control group (n = 59) according to the results of coronary angiography. Their mean ages were 68.6 +/- 6.8 and 66.2 +/- 6.5 years old respectively. The serum levels of FT (free testosterone), TT (total testosterone), E2 (estradiol), LH (luteinizing hormone), FSH (follicle stimulating hormone), SHBG (sex hormone-binding globulin) and DHEA (dehydroepiandrosterone) were measured in all participants. And the androgen receptors of peripheral lymphocytes were assessed by flow cytometry. RESULTS: The serum level of FT was lower in the CAD group than that in the control group [(24.1 +/- 22.2) * 10(-9) mmol/L vs (34.1 +/- 31.8) * 10(-9) mmol/L, P = 0.06]. But two groups showed no statistic differences in the levels of TT, E(2), LH, FSH, SHBG, DHEA and lymphocyte AR (56.3% +/- 24.00 vs 57.1% +/- 20.8%). As demonstrated by the logistic regression analysis, the level of FT was negatively correlated with the CAD risk (OR = 0.98, P = 0.0049) and positively correlated with the peripheral lymphocyte AR level. However age was negatively correlated with the levels of FT and AR. CONCLUSION: The deficiency of endogenous androgen contributes to a high prevalence of CAD in elderly males. The age-related decreases of FT and AR impair the physiological functions of androgen so as to accelerate the progression of coronary atherosclerosis. PMID- 21609553 TI - [Upgrading to resynchronization therapy in patients with heart failure after chronic right ventricular apical pacing]. AB - OBJECTIVE: To investigate the clinical efficacy of cardiac resynchronization therapy (CRT) through biventricular pacing in chronically right ventricular apical paced patients with heart failure. METHODS: Ten chronically right ventricular apical paced patients with left ventricular ejection fraction (EF) <= 35% underwent CRT upgrading. And the follow-up period was over 12 months. Seven of them reported a significant improvement in their symptoms. Two patients died and one patient had no response. As compared with pre-CRT, CRT significantly improved NYHA classification, decreased left atrium diameter [(43 +/- 5) mm vs (46 +/- 7) mm], pulmonary arterial pressure [(42 +/- 6) mm Hg vs (54 +/- 13) mm Hg] and BNP [(184 +/- 73) ng/L vs (545 +/- 286) ng/L] (P < 0.05), improved left ventricular EF [(35 +/- 5)% vs (32 +/- 4)%]. Tissue Doppler imaging revealed the maximal difference of time to peak myocardial systolic contraction of 12 left ventricular segment shortened [(136 +/- 28) ms vs (97 +/- 18) ms], interventricular mechanical delay shortened [(52 +/- 5) ms vs (31 +/- 6) ms)] after upgrading. CONCLUSION: CRT upgrading from right ventricular apical pacing may improve left ventricular function in patients with heart failure. PMID- 21609554 TI - [Correction of penile curvature by various tunica albuginea plasty]. AB - OBJECTIVE: To explore various tunica albuginea plasty for penile curvature and their efficacies. METHODS: From July 2005 to July 2008, there were a total of 8 patients with a mean age of 34 +/- 9 years old (range: 23 - 47) undergoing corrective surgery for various types of penile curvature. Among them, 4 patients (3 with ventral curvature, 1 with lateral curvature) were treated by 16-dot plication technique, 2 patients of lateral curvature with tightening ring in tunica albuginea corrected by V-Y plasty and 2 patients (one caused by Peyronie's disease while the other by tunica scar contracture) repaired by venous graft patch. The pre-and post-operative levels of sexual satisfaction were evaluated by the International Index of Erectile Function (IIEF-5) scoring system. RESULTS: All cases were followed up at 3, 6 & 9 months postoperatively. Their mean curvature at maximal erection was (58.2 +/- 9.7) degrees . And a postoperative office assessment revealed a functional straight in all patients [mean degree (11 +/- 4) degrees ]. One patient (12.5%) reported penile shortening without dissatisfaction about it. No patients complained of anesthesia or other sensory abnormality on their penile skin. An improvement of IIEF-5 scores was noted (21 +/- 3 vs 15 +/- 5, P < 0.05) and all patients were satisfied with their outcomes. No complications, such as hematoma, infection or erectile dysfunction, occurred. CONCLUSION: To achieve a better penile morphology and functional outcomes with fewer complications, various arthroplasty should be adopted according to the cause, degree and direction of penile curvature. PMID- 21609555 TI - [Endoscopic surgery by infraclavicular approach for larger benign thyroid tumors]. AB - OBJECTIVE: To investigate the endoscopic surgical efficacy of larger benign thyroid tumors and to evaluate its feasibility and safety. METHODS: Forty-two patients with benign thyroid tumors underwent endoscopic surgery by infraclavicular approach (a 4 - 6 cm incision on larger side of the tumor >= 3 cm off midline) at our hospital between April 2005 and January 2010. Fifty-four patients were enrolled as controls by conventional approach. Two groups were compared with regards to tumor size, surgical approach, complications, operative duration, hospital stay and incision cosmetic outcomes. RESULTS: Two groups were matched by age, sex and tumor size. No statistical significance was found in surgical approach. Pathology examinations proved benign in both groups. The cosmetic results in endoscopic group were obviously favorable than those in conventional group (1.6 +/- 0.9 vs 5.8 +/- 1.2, Z = 8.418, P = 0.000). All patients were followed up for a period of 6 months to 4 years. Endoscopic group: no permanent glottic paralysis; one patient appeared hypocalcemic and recovered in 1 week; two patients presented with skin tension and alleviated in 3 months; two patients occurred temporary glottic paralysis and recovered in 1 month. Conventional group: no permanent glottic paralysis; three patients appeared temporarily hypocalcemic; no dyspnea from airway collapse; no recurrence. There was no significant distinction between two groups (chi(2) = 1.247, P = 0.459). CONCLUSION: Endoscopic surgery by infraclavicular approach is suitable for patients with >= 4 cm thyroid tumors. PMID- 21609556 TI - [Effects of baicalin on pulmonary functions of acute respiratory distress syndrome induced by oleic acid in rats]. AB - OBJECTIVE: To investigate the effect of baicalin on pulmonary functions and its mechanism during the development of acute respiratory distress syndrome (ARDS) induced by oleic acid (OA) in rats. METHODS: Rats were randomized into 5 groups: control, ARDS (OA induction, 0.12 mg/kg), baicalin-treated group (150 mg/kg), baicalin-treated group (300 mg/kg) and baicalin-treated group (450 mg/kg). The blood samples and lung tissue were collected at 10 min, 1, 2 and 6 h after OA injection. The lung concentration of myeloperoxidase (MPO) was detected by an ELISA (enzyme-linked immunosorbent assay) kit. Meanwhile, blood gas analysis and pulmonary pathological examination were also performed. RESULTS: The level of arterial oxygen partial pressure and oxygenation index decreased (P < 0.01 vs. control) and oxygenation index (190 mm Hg, 1 mm Hg = 0.133 kPa) reached the diagnostic standard of ARDS at 2 h in ARDS group. In baicalin-treated group (150 mg/kg and 300 mg/kg), the level of arterial oxygen partial pressure and oxygenation index increased versus the ARDS group. In baicalin-treated group (450 mg/kg), the level of arterial oxygen partial pressure was undifferentiated at 1, 2 and 6 h (P > 0.05) and decreased at 10 min (46.8 mm Hg, P < 0.05) versus the ARDS group. The level of MPO increased in baicalin-treated (300 mg/kg) and ARDS groups. Compared with the ARDS group, the level of MPO decreased significantly in baicalin-treated group (300 mg/kg) at 10 min, 1 and 2 h. Meanwhile, the pulmonary pathological damage improved in baicalin-treated group (300 mg/kg). CONCLUSION: An appropriate dose of baicalin may improve hypoxemia of ARDS induced by OA in rats. It may be due to the inhibition of MPO activity. PMID- 21609558 TI - [Comprehensive therapy of gastric carcinoma]. PMID- 21609557 TI - [Effect of skin autograft with different thickness on the transdifferentiation of fibroblasts after deep partial thickness burn in rats]. AB - OBJECTIVE: To investigate the effect of thin split-thickness skin, inter-mediate thickness skin and full-thickness skin autograft on the differentiation of fibroblasts into myofibroblasts in rats after deep partial thickness burn. METHODS: A total of 40 SD rats were divided randomly into two groups (Group A & Group B, n = 20 each). In Group A, tissue samples were collected at Day 2 after skin-grafting while Day 7 in Group B. In each group, every rat was scalded to cause deep partial thickness wound with an area of 10% of total body surface. The wounds received eschar shaving instantly coupled with skin-autograft, covering with thin split-thickness skin, inter-mediate thickness skin and full-thickness skin respectively. Meanwhile the control wound on the same rat was scalded only. Then the expression of alpha-SMA was detected by immunohistochemistry in each wound. And the numbers of myofibroblasts (alpha-SMA positive cells) and fibroblasts (negative cells) were counted to calculate the conversion ratio of myofibroblasts. RESULTS: In Group A, the conversion ratios of myofibroblasts of control, thin split-thickness skin autograft, inter-mediate thickness skin and full-thickness skin groups were (76.3 +/- 3.3)%, (69.8 +/- 1.6)%, (57.5 +/- 1.6)% and (44.7 +/- 1.7)% respectively. In Group B, the ratios were (72.9 +/- 6.1)%, (63.6 +/- 4.7)%, (50.2 +/- 1.6)% and (32.3 +/- 1.2)% respectively. The ratio was higher in control group than that in any other one (P < 0.01). There was statistic difference between thin split-thickness skin, inter-mediate thickness skin and full-thickness skin autograft groups (P < 0.05). CONCLUSION: A direct association may exist between the conversion ratio of myofibroblasts and the application of skin-grafting in rats after deep partial thickness scalding. It is probably related with varying degrees of scar contracture in the long-term. PMID- 21609559 TI - [Physiological study on the treatment of acute pancreatitis]. PMID- 21609560 TI - [Effect of laparoscopy assisted vs. open radical gastrectomy on lymph node dissection in patients with gastric cancer]. AB - OBJECTIVE: To explore the feasibility and efficacy of laparoscopy assisted radical gastrectomy on lymph node (LN) dissection for gastric cancer and to compare it with open gastrectomy. METHODS: The clinical data of 934 patients with gastric cancer underwent radical resection from January 2007 to May 2010 were analyzed retrospectively. Among the patients, 506 cases received laparoscopy assisted gastrectomy (LAG group) and 428 cases received open gastrectomy (OG group). The number of retrieved LNs and the survival curve between the two groups was compared. Then, the relations between the number of dissected LNs and postoperative morbidity were analyzed. RESULTS: For all patients, the mean number of dissected LNs was 29 +/- 10, there was no significantly differences between LAG group and OG group (P < 0.05). While the number of the retrieved No.7, 8 LNs in LAG group were significantly more than those in OG group. No significant differences was found in the number of dissected LNs for the pT1-2 stages tumors between the two groups, but significantly greater number of LNs was harvested by LAG group in pT3 stage (P < 0.05). No significant differences were found in the number of dissected LNs in different gastrectomy types or extents of LN dissection between the two groups. In the first 50 cases, there were less dissected LNs in LAG group than that in OG group, while 51 cases later, there was no significantly differences in number of dissected LNS between the two groups (P > 0.05). The postoperative morbidity of LAG group and OG group was 11.1% and 20.1%, respectively (P < 0.05), but there was no significant correlations between the number of dissected LNs and postoperative morbidity in both groups. CONCLUSIONS: With the improvement in surgical skills, laparoscopy-assisted radical gastrectomy with lymph node dissection is a safe and feasible procedure, and it is oncologically compatible with open gastrectomy. Suitable increment of dissected LN count would not increase the postoperative complication rate. PMID- 21609561 TI - [A retrospective analysis of clinicopathological characteristics and prognostic factors of gastric stump cancer]. AB - OBJECTIVE: To explore the clinicopathological characteristics and prognostic factors of gastric stump cancer(GSC). METHODS: The clinical data of 138 patients with GSC treated from January 1992 to July 2008 were reviewed and analyzed. The patients included 122 males and 16 females with a mean age of 61.5 years, and the mean interval between the initial operation and second diagnosis was 21.9 years. RESULTS: The endoscopy and pathological examination showed Borrmann III/IV in 127 (92.7%) patients and undifferentiated carcinoma in 115 (83.3%) patients. The resectability and radical resectability rate were 72.4% and 59.4%. The 1-, 3- and 5-year survival rates was 59.2%, 30.1% and 14.2%, respectively. The median overall survival time was 19.4 months. Univariate Log-rank test indicated that Borrmann type, histological type, tumor diameter, TNM stage, depth of invasion, number of metastatic lymph node, distant metastasis and option of treatment were significant prognostic factors for GSC. While TNM stage, depth of invasion, distant metastasis and option of treatment were prognostic factors on multivariable analysis. The median survival time of patients underwent radical resection was significantly longer (36 months) than that of patients received palliative resection (8 months, P < 0.05) and chemotherapy only (5 months, P < 0.05). Among patients with a tumor of T4 stage, the median survival time was statistically prolonged by combined evisceration (18.6 months) when compared with the patients received palliative surgery. CONCLUSIONS: TNM stage, depth of invasion, distant metastasis and option of treatment are independent prognostic factors for GSC. Early diagnosis and radical resection may play an important role in improving the prognosis of GSC. PMID- 21609562 TI - [Subintimal arterial flossing with antegrade-retrograde intervention technique to treat long-segment occlusion of peripheral artery]. AB - OBJECTIVE: To discuss the technique details of subintimal arterial flossing with antegrade-retrograde intervention (SAFARI) to improve technical success in the treatment of chronic total occlusions (CTO) diseases in lower extremity when there is failure to reenter the distal true lumen. METHODS: Between May 2009 and Aug 2010, 15 patients underwent endovascular recanalization with SAFARI technique. There were 8 male and 7 female patients with a mean age of 74.9 years. There were 3 patients with severe claudication (Rutherford category 3) and 12 patients with critical limb ischemia (Rutherford category 4 to 6). The clinical and follow-up data of these patients were analyzed retrospectively. RESULTS: Fourteen patients were treated with SAFARI technique successfully. The technique success rates were 93.3%. The mean ankle brachial index increased from 0.39 to 0.83.Symptoms were relieved in 86.6% patients, Ulcer were healed in 93.3%patients. CONCLUSIONS: SAFARI technique is a safe and effective method in treating CTO diseases, when it is failure to renter the distal true lumen with subintimal angioplasty technique. PMID- 21609563 TI - [The application of biopsy and kyphoplasty in the diagnosis and treatment of osteoporotic thoracolumbar vertebral compression fracture nonunion]. AB - OBJECTIVES: To investigate the clinical efficacy and safety of biopsy and Kyphoplasty in the diagnosis and treatment of osteoporotic thoracolumbar vertebral fracture nonunion, and to explore the clinical characteristics of the disease. METHODS: From July 2005 to May 2010, the clinical data of 8 patients with nonunion of osteoporotic thoracolumbar vertebral fractures were studied. There were 3 males and 5 females, with the mean age of 73.5 years (range, 65 - 86 years). The fracture vertebrae were 3 cases in T(12), 4 in L(1), and 1 in L(2). All cases received radiography, CT and MRI examination. All patients were treated by using Kyphoplasty. Five patients were performed bone biopsy successfully, 3 patients were failed. The curative effect was evaluated by visual analogue scale (VAS), anterior vertebral height restoration at preoperative, postoperative and followed-up time. RESULTS: All patients tolerated the procedure well with immediate relief of back pain after Kyphoplasty. No severe complications were found in all patients. Three cases had the pathologic appearance of sequestrum, 2 cases were sparse cancellous bone, 3 cases were abortive to biopsy. All the patients were followed up of 22.6 months (range, 3 - 37 months), the VAS was 9.5 before operation, 2.1 at the third day postoperatively, there were significant difference between the two phase (P < 0.05), and 2.3 at last follow-up, there were no difference between postoperation and follow-up phase (P > 0.05). And the height of compressed body recovered markedly. The vertebral height had a recovery rate of 67.2% postoperatively, 64.1% and at last follow-up, there were no difference between the two phase (P > 0.05). CONCLUSIONS: Kyphoplasty is an effective and safe method in the treatment of osteoporotic throacolumbar vertebral fracture nonunion. Bone biopsy can play a further role of differential diagnosis. PMID- 21609564 TI - [The preliminary study of the efficiency of using cervical vertebral maturation of growth level of female adolescent idiopathic scoliosis]. AB - OBJECTIVES: To investigate the reliability of cervical vertebral maturation (CVM) and to verify the possibility in the growth evaluation of female adolescent idiopathic scoliosis patients as a helpful supplementary to the Risser sign. METHODS: Coronal and lateral full-length spine X-ray film and left hand-wrist radiographs of 77 female adolescent patients with idiopathic scoliosis were selected from January 2010 to October 2010. The interval period between lateral length of the spine and left hand-wrist radiographs did not exceed 3 months. The CVM was assessed by a method developed by Baccetti and co-workers, whereas hand wrist maturation was assessed by Fishman's method. The results were analyzed by Spearman correlation with patients Risser sign, chronological age, and menarche period. RESULTS: There were strong correlations between CVM and SMI or Risser sign (r = 0.862 and 0.762, P < 0.01). While in 26 patients whose Risser sign were 0-I, the correlation between CVM and SMI was more pronounced (r = 0.761, P < 0.01), compared with the correlation between Risser sign and SMI (r = 0.641, P < 0.01). CONCLUSIONS: CVM is a valid indicator of skeletal growth evaluation and can be used as a helpful supplementary to Risser sign. PMID- 21609565 TI - [Management of postoperative pain after total knee arthroplasty]. AB - OBJECTIVE: To evaluate causes and clinical management of postoperative pain after total knee arthroplasty (TKA). METHODS: From January 2004 to June 2009, 41 patients (44 knees) with knee pain post TKA were treated. There were 9 male and 32 female patients aging from 51 to 84 years with a mean of 63.5 years. The diagnosis followed to Brown diagnostic system. One case of extraarticular pain was complex regional pain syndrome type 1 (CRPS-1) and underwent conservative treatment, the remaining 5 cases were treated by surgery. Three cases of joint instability, 1 case of patellar baja, 2 cases of soft tissue impingement caused by overhang of the prosthesis, 1 case of popliteal tendon impact underwent conservative treatment, the other 27 cases underwent surgical intervention. The patients were followed up and the Knee Society Score (KSS) knee score, pain visual analog scale (VAS) score were recorded. RESULTS: Forty-one cases were followed up for 1 to 6 years. At the last time of follow-up, the 5 cases received surgical treatment to extra-articular pain showed VAS score as 2.5 +/- 0.2, KSS clinical and functional score as 92.8 +/- 2.6 and 89.0 +/- 3.4. There was significantly difference compared with preoperative (P < 0.05). One case of CRPS 1 performed conservative treatment, the therapy was effective. In the infected 12 cases of intra-articular pain, 1 case received amputation, 3 cases received antibiotic bone cement insert, 8 cases received two stage revision. All infections were cured, and VAS score was 3.8 +/- 0.2, KSS clinical score was 88.3 +/- 4.6, function score was 85.0 +/- 4.6 postoperatively, with significantly difference compared with preoperative (P < 0.05). In the 8 cases received conservative treatment in non-infected group, at the last time of follow-up, VAS score was 4.5 +/- 0.4, KSS clinical and functional score was 85.4 +/- 4.2 and 84.2 +/- 2.3, with significantly difference compared with preoperative (P < 0.05). Fifteen cases underwent surgical treatment, at the last time of follow-up, VAS score was 3.4 +/- 0.1, KSS clinical and functional score was 86.6 +/- 5.4 and 87.1 +/- 2.4, with significantly difference compared with preoperative (P < 0.05). CONCLUSIONS: Patients with knee pain post TKA need systematic assessment to identify the causes. Appropriate treatment due to the positive diagnosis generally lead to satisfactory results, surgical intervention with indefinite causes is strictly prohibited. PMID- 21609566 TI - [Treatment strategies for pediatric patients with primary cardiac tumors]. AB - OBJECTIVE: To analyze the experience of treatment strategies for pediatric patients with primary cardiac tumors. METHODS: The clinical data of 27 patients with primary cardiac tumors which detected by echocardiography from May 1999 to May 2009 was analyzed retrospectively. There were 20 male and 7 female patients, aged from 24 d to 12.6 years. There were 59.2% less than 1 year old at the time of diagnosis. A single tumor were present in 22 cases and multiple in 5 cases. Surgery was performed for 22 patients due to the varied significant symptoms such as arrhythmia, pericardial effusion, swoon and congestive heart failure with dyspnoea. Five patients were discharged hospital without surgical treatment. The surgical approaches were adopted according to tumor location. Complete surgical resection was performed in 14 patients and partial resection in 8 patients. Seven patients were underwent valve reconstruction, 5 involving the mitral valve and 2 involving the tricuspid valve. RESULTS: Histologic examination of the surgically resected tumors showed rhabdomyomas in 8 cases, fibromas in 5 cases, hemangiomas 3 cases, myxomas in 4 cases, fibrosarcoma in 1 case and yolk sac sarcoma in 1 case. Sixteen cases revealed stable haemodynamic status postoperative. Two cases occurred apparent symptoms of low cardiac output and significant arrhythmias, finally recovery after comprehensive treatment of restoration the heart function. There was a total of 4 patients in-hospital death following surgery due to multiorgan system failure. Of the 18 patients who survived after the surgery were followed up from 1 to 10 years, echocardiography showed the residual mass of the tumor with partial resection, rhabdomyoma diminishing in 2 patients and almost vanishing in 1 patient. The residual mass of one fibrosarcoma patient and one hemangioma patient were not increased. Patients with myxomas had no recur or systemic embolisation after the initial surgery. Five nonsurgical patients were followed up from 1 to 3 years, 2 patients without haemodynamic alterations, 1 patients with giant tumor of left ventricular free wall was died of arrhythmia, the other one was alive; the patient of multiple cardiac tumor with low cardiac output was died of heart failure. CONCLUSIONS: Despite the benign histology of most paediatric primary cardiac tumours, there may be significant associated with morbidity and occasional mortality. Therapy strategies should be individualised: surgery is indicated in cases with significant clinical symptoms and close follow up is necessary for asymptomatic patients. Total resection is not the only therapeutic aim. Most important is the restoration of the normal haemodynamic heart function. PMID- 21609567 TI - [Strategy of dealing with left subclavian artery in total arch replacement combined with stented elephant trunk implantation for Stanford type A aortic dissection]. AB - OBJECTIVE: To summarize the experiences of ligating left subclavian artery (LSA) in total arch replacement and stented elephant trunk implantation for Stanford type A aortic dissection patients with difficulty in exposing the LSA. METHODS: Total arch replacement and stented elephant trunk implantation were performed on 79 consecutive patients from January 2008 to June 2010. Twenty-nine cases of the cohort undertook LSA ligation due to bad exposure. There were 21 males and 8 females patients, aged from 19 to 55 years with a mean of (44 +/- 12) years. There were 12 acute dissections, 4 sub-acute dissections and 13 chronic dissections. Based on thoroughly evaluation of the Willis' circle and bilateral vertebral arteries through pre-operative imaging and intra-operative circulative parameters, if the collateral circulation was considered sufficient, LSA was ligated directly and only the innominate artery and carotid artery were reconstructed; if considered insufficient, an additional bypass from ascending aorta to left axillary artery was performed. RESULTS: All the 29 operations were completed successfully. There was one patient died from pulmonary infection and the others recovered well.Blood pressure of left arms were lower than right postoperatively [(78 +/- 17) mmHg vs. (126 +/- 24) mmHg, 1 mmHg = 0.133 kPa, P < 0.01], but oxygen saturation, skin temperature and strength of the left hand were normal compared to the right. All the survived patients have been followed 1 - 27 months and none of them presented with any symptoms of left subclavian artery steal syndrome and ischemia of left arms. CONCLUSIONS: Ligation of LSA under strict evaluation of collateral circulation could be safe in Type A dissection patients with bad exposure due to big ascending aortic aneurysm and will simplify the procedure significantly. PMID- 21609568 TI - [The clinical study of modified total aortic arch replacement and stent elephant trunk technique treatment for patients with DeBakey I thoracic aortic dissection]. AB - OBJECTIVE: To summarize the clinical study of modified total aortic arch replacement and stent elephant trunk technique treatment to patients with DeBakey I thoracic aortic dissection. METHODS: From January 2006 to October 2010, 101 cases of DeBakey I aortic dissection were treated by modified total arch replacement and stent elephant trunk technique, in which emergency surgery for 73 cases. There were 76 male and 25 female patients, aged from 21 to 77 years with a mean of (49 +/- 8) years. Intraoperative ascending aortic replacement in 31 cases, Bentall procedure in 29 cases, Wheat procedure in 7 cases, David procedure in 34 cases. At the same time stent elephant trunk in the left subclavian artery corresponding position was windowed to rebuild the blood supply. Deep hypothermic circulatory arrest cerebral protection was completed by bilateral antegrade cerebral perfusion. RESULTS: The mean cardiopulmonary bypass time was (212 +/- 40) min, mean myocardial occlusion time was (95 +/- 16) min, mean circulatory arrest time was (42 +/- 8) min. Operative mortality was 1 case and hospital mortality was 5 case, which died of septicemia, acute renal failure and hemiplegia complicated with multiple organ failure. Compared with selective cerebral perfusion, the incidence of postoperative cerebral vascular accident and transient neurological dysfunction decreased. Seventy-six cases received aorta CTA before discharged, the closure rate of descending thoracic aortic dissection false lumen was 78.9%. Seventy-one patients were followed up for 5 to 49 months, 50 cases was reviewed by CTA, of which closure rate of descending thoracic aortic dissection false lumen was 88.0%, no late death and re-surgery. CONCLUSIONS: The modified total aortic arch replacement and stent elephant trunk technique treatment for patients with DeBakey I thoracic aortic dissection was safe and effective, with less postoperative complications. PMID- 21609569 TI - [Facial nerve preservation following microsurgical removal of large and huge acoustic neuroma]. AB - OBJECTIVES: To evaluate the long-term facial nerve function of patients following microsurgical removal of large and huge acoustic neuroma, and to identify the factors that influence these outcomes. METHODS: A retrospective review was performed which included 176 consecutive patients with a large acoustic neuroma (>= 30 mm) underwent a retrosigmoid craniotomy for tumor resection between January 2002 to November 2009. House-Brackmann (HB) Scale was used preoperatively and in a long-term follow-up after surgery. Test for linear trend was applied for statistic analysis. RESULTS: Complete resection was achieved in 168 (95.5%) of these 176 patients with a mortality of 1.7%. Anatomic preservation of the facial nerve was attained in 96.0% of the patients. In the series of 96 patients who had at least 1-year follow-up (mean 3.0 years) the facial nerve function preservation (HB grade 1 - 2) was totally attained in 79 patients (82.3%), and 40 of 55 patients (72.7%) who presented huge tumors (diameter > 40 mm) among the 96 patients had facial nerve function preserved. Analysis showed that facial nerve function correlated linearly with tumor sizes (chi(2) = 14.114, nu = 1, P < 0.05). CONCLUSIONS: Complete removal of large and giant acoustic neuroma may be obtained via retrosigmoid approach with facial nerve preservation. Excellent long term facial function can be expected in the majority of patients who undergo microsurgical removal of vestibular schwannoma via the suboccipital retrosigmoid approach. Tumor size is a significant prognostic parameter for facial nerve function following vestibular schwannoma surgery. PMID- 21609570 TI - [Suboccipital transtentorial approach to pineal region meningiomas by 3D-CTA assistance: surgical considerations]. AB - OBJECTIVE: To evaluate the three-dimensional CT angiography (3D-CTA) assisted suboccipital transtentorial approach (Poppen's approach) in the treatment of pineal region meningioma. METHODS: During the period of January 2005 to January 2010, 8 patients with pineal region meningioma were successfully treated using Poppen's approach through cerebral falx and tentorium. There were three male patients and five female patients were aged at a range of 41 - 64 years, average age was (54 +/- 10) years. According to the Karnofsky performance scale (KPS), 5 patients' KPS scores were more than or equal to 80 and 3 were less than 80. MRI was used for the diagnosis of meningioma. 3D-CTA was applied to detect meningioma staining and blood supply. For preoperative concurrent hydrocephalus, follow-up observations were given. If hydrocephalus didn't get better or even became worse, ventriculoperitoneal shunt should be considered. RESULTS: All the surgery were successfully performed, and venous complexes (VC) were well protected according to the CTA images. Out of the eight cases whose meningiomas were removed, one patient had got postoperative intracranial infection and recovered after given antibiotics. All patients were followed up for a period of 6 - 24 months. Preoperative concurrent hydrocephalus in 7 patients were improved. However, there was an aggravation of the hydrocephalus in one patient who was treated with ventriculoperitoneal shunt. The MRIs which were performed at the end of follow-up period, showed no recurrence of meningiomas, and preoperative symptoms were improved to varying degrees, 7 patients' KPS scores were more than or equal to 80 and 1 was less than 80. A chi(2) test was used to analyze and to make comparisons between preoperative and postoperative KPS. The significance was indicated (chi(2) = 1.33, P < 0.05). CONCLUSIONS: For meningiomas in the pineal region, 3D CTA is of great clinical value to distinguish the anatomic relationship among the meningioma, blood supply and VC. This case study has strongly supported using Poppen's approach assisted by 3D-CTA to proceed with the operation. PMID- 21609571 TI - [Expression of ephrin-A7 and metadherin and its clinicopathological significances in the benign and malignant lesions of gallbladder]. AB - OBJECTIVE: To study the expression of ephrin-A7 (EphA7) and metadherin (MTDH) and their clinicopathological significances in the benign and malignant lesions of gallbladder. METHODS: EnVisiom immunohistochemical methods was used for determining the expressions of EphA7 and MTDH in routinely paraffin-embedded sections of surgically-resected specimens from 108 cases with gallbladder adenocarcinoma, 15 cases with adenomatous polyp and 35 cases with chronic cholecystitis treated from June 1996 to June 2006. And 46 cases of peritumoral tissues were also harvested as controls (n = 35). RESULTS: The positive expression rates of EphA7 and MTDH were significantly higher in gallbladder adenocarcinoma than those in peritumoral tissues (chi(2)(EphA7) = 12.65, chi(2)(MTDH) = 13.00; P < 0.01), adenomatous polyp (chi(2)(EphA7) = 8.21, chi(2)(MTDH) = 9.39; P < 0.01) and chronic cholecystitis (chi(2)(EphA7) = 21.21, chi(2)(MTDH) = 23.68; P < 0.01); Moderately-or severely-atypical hyperplasia of gallbladder epithelium was found in the benign lesions with positive expression of EphA7 and/or MTDH. The positive rates of EphA7 and MTDH were significantly lower in the cases of well-differentiated adenocarcinoma, maximal diameter of tumor < 2 cm, no-metastasis of lymph node, and tumor with no-invasiveness of regional tissues than those in the poorly-differentiated adenocarcinoma (chi(2)(EphA7) = 12.34, chi(2)(MTDH) = 12.80; P < 0.01), maximal diameter of tumor >= 2 cm (chi(2)(EphA7) = 5.22, chi(2)(MTDH) = 5.00; P < 0.05), cases with metastasis of lymph node (chi(2)(EphA7) = 5.15, chi(2)(MTDH) = 5.86; P < 0.05) and cases with invasiveness of regional tissues (chi(2)(EphA7) = 7.06, P < 0.01; chi(2)(MTDH) = 4.13; P < 0.05) in gallbladder adenocarcinoma (P < 0.05). The high consistency was found between the expressive levels of EphA7 and MTDH in gallbladder adenocarcinoma (chi(2) = 13.11, P < 0.01). The univariate Kaplan Meier analysis showed that the increased expression of EphA7 (P = 0.023) and MTDH (P = 0.034) was negatively associated with the overall survival. The multivariate Cox regression analysis showed that increased expression of EphA7 and/or MTDH (P(EphA2) = 0.023, P(MTDH) = 0.034) was an independent poor-prognostic predictor for gallbladder adenocarcinoma. CONCLUSIONS: The expression of EphA7 and/or MTDH might be closely related to the carcinogenesis, progression, clinical biological behaviors and prognosis of gallbladder adenocarcinoma. The positive expression of EphA7 and/or MTDH may predict bad-prognosis in gallbladder adenocarcinoma. PMID- 21609572 TI - [The sheltering effects of omega-3 polyunsaturated fatty acids and lymphatic drainage on distant organs after intestinal ischemia reperfusion injury in rats]. AB - OBJECTIVE: To investigate the sheltering effects of omega-3 polyunsaturated fatty acid (omega-3PUFA) and lymphatic drainage on distant organs in intestinal ischemia-reperfusion injury in rats. METHODS: Forty-eight healthy Sprague-Dawley (SD) male rats (SPF grade) were randomly divided into 3 groups (16 rats in each group): normal diet group (N), enteral nutrition group (EN), enteral nutrition and omega-3PUFA group(PUFA group). Each group was divided into lymphatic drainage (I/R + D) group and no-drainage (I/R) group (n = 8). Each rats received gastrostomy. After given different nutrition for five days, the rats subjected to 60 min ischemia and 120 min reperfusion injury of the superior mesenteric artery. When the rats subjected to ischemia-reperfusion injury, drained intestinal lymph for 180 min in the I/R + D group. The serum level of alanine aminotransferase (ALT) and level of myeloperoxidase (MPO), nitric oxide (NO), total of nitric oxide synthase (tNOS), inducible nitric oxide synthase (iNOS) of lung were detected. The organ injury of lung and liver and the expression of high mobility group box 1(HMGB1, the endogenous ligand of TLR4) in these organs were investigated too. RESULTS: The serum level of ALT in PUFA I/R + D and I/R group and EN I/R + D group were significantly lower than that in normal diet I/R group: (46 +/- 20), (53 +/- 15), (46 +/- 21) and (100 +/- 60) U/L (P < 0.05), respectively. The level of MPO, NO, tNOS, iNOS in lung in the I/R + D group were significantly lower than those in I/R group (P < 0.05): MPO (0.73 +/- 0.15):(0.85 +/- 0.10) unit/grams wet slice; NO (0.72 +/- 0.51):(1.79 +/- 1.32) umol/gprot; tNOS (0.46 +/- 0.15):(0.78 +/- 0.27) U/mgprot; iNOS (0.06 +/- 0.04):(0.11 +/- 0.07) U/mgprot, respectively. The level of tNOS in PUFA I/R group was significantly lower than that in normal diet I/R group: (0.56 +/- 0.13):(0.78 +/- 0.27) U/mgprot (P < 0.05). MPO, NO, INOS levels in PUFA group were reduced compared with those in EN and normal diet group. HE stained sections and HMGB1 immunohistochemistry results showed that the organ injury in I/R group was severer than that in I/R + D group. The expression of HMGB1 increased in I/R group. The organ injury and the expression of HMGB1 in PUFA group were less than that in the other two main groups. CONCLUSIONS: Lymphatic drainage can alleviate injury of distant organs after intestinal ischemia-reperfusion in rats. omega-3 polyunsaturated fatty acids can increase body resistance to injury and promote recovery. PMID- 21609573 TI - [Expression of connective tissue growth factor and pathological remodeling in ascending thoracic aortic aneurysm]. AB - OBJECTIVE: To study the expression of connective tissue growth factor (CTGF) and its significance in sporadic ascending thoracic aortic aneurysm (AAA), and initially to investigate the mechanisms of pathological remodeling in AAA. METHODS: AAA specimens were taken from 18 patients during elective surgical intervention, and 18 control specimens of ascending aorta were obtained from patients undergoing coronary artery bypass surgery. Specimens were stained with HE and Masson to evaluate the arrangement and aggregation of cells and collagen types I and III; immunohistochemistry staining was performed using antibodies directed against markers of CTGF; real-time PCR analysis was performed to quantify the expression level of CTGF and collagen types I and III. RESULTS: Pathological results show degradation of elastin and hyperplasia of collagen fibers as well as disordered arrangement of smooth muscle cells in AAA. When compared with controls, protein levels of CTGF were significantly increased [(44 +/- 4)% vs. (33 +/- 5)%, P < 0.01]. Similar patterns were shown in mRNA levels of CTGF (P < 0.01). Using real-time PCR method, elevated levels (relative expression ratio of mRNA: 10.54/3.8 and 1.79/1.19, respectively; P < 0.01, both) of collagen types I and III were observed. CTGF expression had a correlation with both collagen fibers and aortic aneurysm diameter (r = 0.784, P < 0.01; r = 0.793, P < 0.01). CONCLUSIONS: These results indicate increased expression of aortic collagen types I and III as well as CTGF in AAA specimens, which is likely to be responsible for the aortic wall pathological remodeling. The expression of CTGF was positively correlated with the aortic diameter. As a cytokines factor can stimulate collagen synthesis, CTGF may be involved in the pathogenesis and progression of AAA. PMID- 21609574 TI - [Anatomy and drawing of obsterics and gynecology]. PMID- 21609575 TI - [Analysis of maternal deaths in Shanghai from 2000 to 2009]. AB - OBJECTIVES: To find problems in the systematic management of maternal health and to provide evidence for developing effective interventions to reduce maternal mortality in Shanghai. METHODS: Every maternal death from 2000 to 2009 was audited by experts and relevant informations were collected and analyzed retrospectively. RESULTS: (1) Number of live births. The number of live births in Shanghai rised from 84 898 in 2000 to 187 335 in 2009, which increased by 120.7%. Notably, the number of live births of migrating people increased 4.6 times. In 2000, it took up 25.5% and in 2009, it rose to 54.8%. (2) Maternal mortality ratio (MMR) and its composition. The total live births from 2000 to 2009 was 1 279 010, among which there were 262 maternal deaths, with average maternal mortality of 20.48 per 100,000 live birth (262/1,279,010). For Shanghai residents, the MMR was 8.09 per 100,000 live births (55/680,005), while the MMR of migrating people was 34.56 per 100,000 live births (207/599,005). (3) Trends of MMR. The MMR declined from 21.2 per 100,000 live births in 2000 to 9.61 per 100,000 live births in 2009. The MMR of Shanghai residents maintained below 10 per 100,000 live births with exception of year 2003 and 2004. The MMR of migrating people declined sharply. In 2002 it was 77.42 per 100,000 live births, and in 2009 it decreased to 11.69 per 100,000 live births. (4) The composition of causes of maternal deaths and rank order. The top 5 causes of deaths were obstetric hemorrhage (69 cases, 26.3% of the total deaths), pregnancy induced hypertension (27 cases, 10.3% of the total deaths), heart diseases (24 cases, 9.2% of the total deaths), liver diseases (17 cases, 6.5% of the total deaths), amniotic fluid embolism and ectopic pregnancy (15 cases respectively, 5.7% of the total deaths). (5) The changes of causes between the first 5 years and the latter 5 years. The MMR of ectopic pregnancy, heart diseases and pregnancy induced hypertension changed significantly in Shanghai residents. The MMR of ectopic pregnancy decreased from 1.36 per 100,000 live births in the first 5 years to 0.26 per 100,000 live births in the latter 5 years. The MMR of heart diseases decreased from 1.36 per 100,000 live births to 0.52 per 100,000 live births. While the MMR of pregnancy induced hypertension increased from 0 to 0.78 per 100,000 live births. For migrating population, the MMR of obstetric hemorrhage, ectopic pregnancy and pregnancy induced pregnancy deceased significantly. As the primary cause, the MMR of obstetric hemorrhage deceased from 21.85 per 100,000 live births in the first 5 years to 5.47 per 100,000 live births in the second 5 years. The MMR of ectopic pregnancy decreased from 4.37 per 100,000 live births to 0.68 per 100,000 live births. And the MMR of pregnancy induced hypertension decreased from 6.87 per 100,000 live births to 2.96 per 100,000 live births. (6) Direct obstetric causes and indirect obstetric causes of maternal deaths. Among the 262 deaths, 141 cases (53.8%) were due to Direct obstetric causes and 121 (46.2%) were due to indirect obstetric causes. (7) The trend of MMR of obstetric hemorrhage. The MMR of obstetric hemorrhage declined from 10.6 per 100,000 live births in 2000 to 1.7 per 100,000 live births in 2009. (8) The results of maternal death audit. The results of maternal death audit were classified into 3 categories: 41 cases (15.6%) belonged to the first category, i.e, avoidable deaths; 66 cases (25.2%) belonged to the second category, i.e, avoidable when creating some conditions; and 155 cases (59.2%) belonged to the third category, which means not avoidable. Among 55 deaths of Shanghai residents, 17 cases (30.9%) belonged to the first category, 14 cases (25.5%) belonged to the second, and 24 cases (43.6%) belonged to the third category. Among 207 deaths of migrating population, 24 cases (11.6%) belonged to the first category, 52 cases (25.1%) belonged to the second, and 131 cases (63.3%) belonged to the third category. (9) WHO twelve-grid classification of maternal deaths. The factors, including attitude, knowledge and skills, resources and management of the dead people and their families, the medical institutes and social supportive departments were integrated and analyzed. It showed that the main reason of maternal deaths of Shanghai residents was poor knowledge and skills of medical staffs, accounting for 80.0% of the deaths. While the main reasons of maternal deaths of migrating people were poor knowledge and skills, inappropriate attitude of the dead people and their families, which took up 54.1% and 40.1% respectively. CONCLUSIONS: The MMR in Shanghai declined continuously from 2000 to 2009, especially for migrating population which reflected the interventions of maternal management in Shanghai were effective. Though obstetric hemorrhage was the first top cause of maternal death during past 10 years, it declined Sharply. 30% to 40% maternal deaths were avoidable if some conditions were created. However, in order to adapt the changes of main causes of maternal deaths and accomplish increasing service requirements, it is necessary to develop new service and management mode. PMID- 21609576 TI - [Evaluation of levonorgestrel-releasing intrauterine system in treatment of recurrent endometriosis after conservative surgery]. AB - OBJECTIVE: To evaluate the efficiency of levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of recurrent endometriosis after conservative surgery or conservative surgery combined with medical treatment. METHODS: Twenty three patients with recurrent endometriosis after conservative surgery or conservative surgery combined with medical treatment were treated by LNG-IUS. All patients rejected further operation and had no desire of fertility. The visual analogue scale (VAS) scores of pain, menstrual model, weight and serum CA125 level and the volume of ovarian endometriotic cysts before and after 3, 6, 12, 24 and 36 months of treatment were recorded and compared. RESULTS: (1) VAS score:after 12 months of using LNG-IUS, dysmenorrheal, chronic pelvic pain or dyspareunia were relieved significantly. VAS score were dropped from 5.9+/-2.3, 4.3+/-2.0 to 1.0+/-0.7, 1.4+/-1.1 (P<0.01). (2) Volum of cysts:after 6 months of using LNG-IUS, the volume of recurrent ovarian endometriotic cysts in 11 patients were reduced from (11.4+/-6.1) cm3 to (5.5+/-3.4) cm3 significantly (P<0.01). At 12 months of follow-up, it suggested that 2 patients' ovarian endometriotic cysts disappeared. At 24 months follow-up, 9 patients ovarian endometriotic cysts disappeared (3) CA125: serum CA125 decreased from (65.5+/-19.6) kU/L to (42.1+/ 13.6) kU/L at 6 months after treatment remarkably (P<0.01). Continued to decrease after 12 months and then become steady. Irregular bleeding and spotting was the main side effects, weight gain was also observed in few patients. CONCLUSIONS: LNG-IUS could be used in treatment of recurrent endometriosis after conservative surgery or conservative surgery combined with medical treatment effectively. It could relieve pain, reduce the level of CA125 and decrease the size of ovarian endometriotic cysts. LNG-IUS seems to be an effective, safe, and long term treatment for endometriosis with fewer side effects and better compliance. PMID- 21609577 TI - [Clinical analysis of 100 preimplantation genetic diagnosis cycles]. AB - OBJECTIVE: To investigate influence of chromosomal translocations on early embryo development and to evaluate the efficacy and feasibility of preimplantation genetic diagnosis (PGD) techniques through clinical analysis on PGD cycles. METHODS: Embryo development, efficacy of PGD and clinical outcome of 100 cycles were studied retrospectively, including 23 cycles with Robertsonian translocations, 19 cycles with reciprocal translocations, and 58 cycles for alpha Thalassaemia. RESULTS: Among 354 embryos biopsied by PGD for translocations, 321 (90.7%) presented fluorescence in situ hybridization (FISH) results. The rate of normal/balanced embryos in the Robertsonian translocation was 38.3% (64/167), which was significantly higher than 20.8% (32/154) in the reciprocal translocation group. Amplification was achieved in 443 blastomeres from 537 embryos in Thalassaemia group, which given to an amplification efficiency rate of 82.5% (443/537). Totally, 140 normal homozygous, 112 heterozygotes and 155 affected homozygous embryos were identified, while 36 embryos had uncertain result. The successful diagnostic rate was 75.8% (407/537). After 3 days in the translocation groups, the rate of normal and/or balanced translocations in biopsed embryos with >=7 cells was 34.4% (77/224), which was significantly higher than 19.6% (19/97) of biopsed embryos with <7 cells. After 4 days, the compaction rate in normal/balanced embryos was 59.4% (57/96), which was significantly higher than 34.2% (77/225) in imbalanced embryos significantly. Seventy-five embryos transferred in 37 cycles with translocations group led to clinical pregnancy rate of 27.0% (10/37), and 170 embryos transferred in 58 cycles with Thalassaemia got a clinical pregnancy rate of 43.1% (25/58). CONCLUSIONS: PGD can provide management efficiently for both chromosome translocations and Thalassaemia. Translocations might have slightly negative impact on embryo development before implantation. PMID- 21609578 TI - [Relationship between nitric oxide in cervical microenvironment and different HPV types and effect on cervical cancer cells]. AB - OBJECTIVE: To study the relationship between nitric oxide within cervical microenvironment and different HPV types as well as the effect of sodium nitroprusside (SNP), a nitric oxide donor, on the proliferation and apoptosis of cervical cancer cell lines. METHODS: HPV typing test was assessed from 115 women by using high-risk HPV (HR-HPV) 21 typing test and the release of cervical nitric oxide (NO) was assessed as nitrate, nitrite in cervical fluid. Cervical NO was then compared between women showing different HPV types. Proliferation of Caski and HeLa cervical cells was determined by methyl thiazolyl tetrazolium (MTT) assay, cell apoptosis was detected by flow cytometry after 24 hours treated by different final concentration of SNP (0.125, 0.25, 0.5, 1.0 and 2.0 mmol/L, respectively). The expressions of HPV E6, E7 gene mRNA and p53 protein were detected by SYBR Green I quantitative real-time PCR and western blot. RESULTS: (1) The cervical NO release of women with HR-HPV was higher compared to that in HPV negative women [(47.6+/-1.4) umol/L vs (22.8+/-0.3) umol/L; P<0.05]; but there was no statistical difference between low-risk HPV (LR-HPV) group [(24.1+/ 1.2) umol/L] and control group (P>0.05). (2) After 24 hours treated by different final concentration of SNP, the results shown that SNP could inhibited the proliferation and increased apoptosis rate in Caski and HeLa cells, in which the concentration of SNP>=1.0 mmol/L, there were significantly different (P<0.05), while when SNP>=2.0 mmol/L, the proliferation of cells inhibited seriously. Treated by SNP (1.0 mmol/L) 24 hours, the expressions of HPV18 E6, E7 mRNA in HeLa cells were reduced from 27.362+/-0.191, 22.962+/-0.053 to 19.181+/-0.360, 17.571+/-0.010 and the protein expression of p53 increased from 1.17+/-0.03 to 0.23+/-0.05, there were statistically significant differences between adding SNP group and the control group (P<0.05); but there were no statistically significant differences in HPV16 E6, E7 mRNA and that of p53 in Caski cells (P>0.05). CONCLUSIONS: The presence of HR-HPV is associated with an increased release of NO in the human uterine cervix; NO could inhibit the growth and proliferation and enhance the apoptosis of cervical cancer cells, inhibit the expression of HPV18 E6, E7 mRNA in HeLa cells and activate the expression of p53 protein, the mechanism may be due to higher sensitivity of HeLa cells (cervical adenocarcinoma cell) to SNP. The increasing release of NO may play a role in regulating the elimination of HPV in cervical microenvironment, which is a part of mucous membrane immunity. PMID- 21609579 TI - [Diagnosis and treatment of ureter endometriosis]. AB - OBJECTIVE: To investigate strategies of diagnosis and treatment of ureter endometriosis. METHODS: From 1983 to 2010, the cases registered in Peking Union Medical College Hospital and confirmed as ureter endometriosis by surgery were enrolled in this study. Clinical manifestations, pre-operative examinations, surgical categories and routes, surgical and pathological findings, post operative medical treatment, relapse and relating factors were collected and studied. RESULTS: Totally 46 patients with ureter endometriosis underwent one or two surgeries. Forty-eight per cent (22/46) of patients were not be diagnosed with ureter endometriosis pre-operatively, and 46% (21/46) only presented dysmenorrhea or even no symptoms. Ureterolysis (72%, 33/46) and laparotomy (63%, 29/46) were the most common surgical category and surgical approach. There were 64% (25/39) of patients had left ureter involved and 80% (37/46) had extrinsic ureter endometriosis. Fifteen per cent (7/46) of patients had relapsed disease with median recurrent time of 24 months (13-49 months), and they all received second surgeries. Logistic regression analysis showed that only gonadotropin releasing hormone analogue agents were related with recurrence when compared with those patients without medical treatment post-operatively significantly (OR=23.2, 95%CI: 2.4-221.7, P=0.002). CONCLUSIONS: Ureter endometriosis was related with reproductive tract endometriosis. It has insidious process resulting in difficulty for early diagnosis. It's important to treat pelvic deep infiltrating endometriosis and ovarian endometrioma to prevent ureter from further involvement. Post-operative treatment of pelvic endometriosis is the key point of preventing relapse of ureter endometriosis. PMID- 21609580 TI - [Effects of human leukocyte antigen-G on p38 mitogen-activated protein kinase signaling pathway in HTR-8/SVneo cell line]. AB - OBJECTIVE: To investigate the role of human leukocyte antigen-G (HLA-G) on the invasion and the molecular mechanism involved in this cellular progress in HTR 8/SVneo cell line. METHODS: There were three groups: groups of transfection, negative control and blank control, which corresponding to treatment by HLA-G specific siRNA, negative siRNA and only lipofectamine 2000 using lipofection technology in HTR-8/SVneo cell line. The efficiency of down-regulated of HLA-G was detected by reverse transcription-polymerase chain reaction and western blot analysis in mRNA and protein level, respectively. Changes of p38 mitogen activated protein kinases (p-p38MAPK)/p38MAPK protein levels and the cell invasion were respectively detected by western blot analysis and transwell test. RESULTS: (1) The mRNA levels of HLA-G transfection group, negative control group and blank control group were 0.26+/-0.08, 0.71+/-0.11, 0.79+/-0.07, respectively. There was significant difference between transfection group and negative control group (P<0.01), while there was no significant difference between negative control group and blank control group (P>0.05). The efficiencies of down regulated of HLA-G were (69.8+/-6.3)%, (14.9+/-2.2)%, 0 in transfection group, negative control group and blank control group respectively in mRNA level. (2) In protein levels, HLA-G were 0.20+/-0.15, 0.75+/-0.12, 0.76+/-0.21 in transfection group, negative control group and blank control group, respectively. There was significant difference between transfection group and negative control group (P<0.01), whereas there was no significant difference between negative control group and blank control group (P>0.05). The efficiencies of down-regulated of HLA G were (81.1+/-14.4)%, (18.0+/-7.7)%, 0 in transfection group, negative control group and blank control group respectively. (3) The invasive number of transfection group, negative control group and blank control group were 57+/-38, 364+/-79 and 260+/-84, respectively, with a significant difference between transfection group and negative control group (P<0.01). There was no significant difference between negative control group and blank control group (P>0.05). (4) The p-p38MAPK/p38MAPK values of the HLA-G transfection group, negative control group and blank control group were 0.74+/-0.04, 0.47+/-0.09 and 0.36+/-0.21, respectively. HLA-G transfection group was significantly different compared with the other two groups (P<0.01). (5) Without or with SB203580, the p p38MAPK/p38MAPK values of the HLA-G transfection group were 0.89+/-0.09 and 0.16+/-0.04, the values of negative control group and blank control group were 0.76+/-0.08, 0.14+/-0.03 and 0.51+/-0.05, 0.03+/-0.01, respectively. There was significant difference between without SB203580 and with SB203580 (P<0.01). (6) Without or with SB203580, the invasive number of transfection group were 51+/-13 and 90+/-21, respectively, which was significantly different (P<0.01). The invasive number of negative control group and blank control group were 290+/-52, 298+/-33 and 290+/-73, 264+/-64, respectively, which was no significant difference between without SB203580 and with SB203580 (P>0.05). CONCLUSIONS: HLA G gene may regulate invasion of trophoblast-derived cell line HTR-8/SVneo via p38MAPK signaling pathway. The lower expression of HLA-G in trophoblast cells may lead to the occurrence of pathologic pregnancy. PMID- 21609581 TI - [Genes involved in folate metabolim and neural tube defects]. PMID- 21609582 TI - [Role of microRNA in the occurrence and development of endometriosis]. PMID- 21609583 TI - [Progress on surgical treatment and prevention of recurrence in endometrial polyps]. PMID- 21609584 TI - [Progress on calcitonin and endometrial receptivity]. PMID- 21609585 TI - [Hormone replacement therapy and urinary incontinence in post-menopausal women]. PMID- 21609586 TI - [Chinese guidelines for diagnosis and management of cognitive impairment and dementia (VII): care and ethical consultation]. PMID- 21609587 TI - [Percentages and functions of natural killer cell subsets in peripheral blood of patients with severe aplastic anemia]. AB - OBJECTIVE: To analyze the percentage and functional changes of natural killer (NK) cell subsets in peripheral blood of severe aplastic anemia (SAA) patients before and after immunosuppressive therapy (IST) so as to evaluate the relationships between these changes and hematopoietic functions and explore the role of NK cells in the pathogenesis of SAA. METHODS: By flow cytometry, the percentages of NK cells (CD3(-)CD56(+)CD16(+)) and its subsets [CD3( )CD56(bright)CD16(-)(CD56(bright)), CD3(-)CD56(dim) CD16(+)(CD56(dim)), CD3( )CD56(-)CD16(+)] in peripheral blood lymphocytes were detected in 12 untreated patients, 30 recovered patients and 13 normal controls respectively from April 2010 to December 2010 in our hospital. NK cells activating receptors (NKG2D and NKp46), perforin and granzyme-beta of patients and normal controls were also detected. The correlation between these changes and hematopoietic functions, including the percentages of neutrophil granulocyte (ANC%), lymphocyte and reticulocyte absolute value in peripheral blood, and hyperplasia degree, percentage of granulocytes, erythrocytes, lymphocytes and megakaryocytes absolute value in bone marrow were evaluated. RESULTS: (1) The percentages of NK cells (10.30% +/- 6.08%) and CD56 bright cells (0.11%) in untreated patients were significantly lower than those of recovered patients (16.47% +/- 8.29%, 0.68%, both P < 0.05) or normal controls (19.45% +/- 6.88%, 0.53%, both P < 0.05). The percentage of CD56(dim) cells in untreated patients was significantly lower than that of normal controls (9.62% +/- 6.04% vs 18.21% +/- 7.16%, P < 0.05). The percentage of CD3(-)CD56(-)CD16(+) cells was significantly higher in recovered patients than that of untreated patients or normal controls (0.79% vs 0.37%, 0.41%, both P < 0.05). (2) The expression of NKp46 and perforin of NK cells in untreated (88.23%, 64.97% +/- 21.61%) and recovered patients (82.97%, 66.14% +/- 20.73%) were significantly higher than those of healthy controls (40.99%, 42.11% +/- 27.25%, all P < 0.05). (3) The percentage of NK CD56(bright) and CD3(-)CD56( )CD16(+) cells of patients was positively correlated with ANC% (r = 0.423, 0.609, 0.468 respectively, all P < 0.05) and the percentage of granulocytes in bone marrow (r = 0.357, 0.517, 0.434 respectively, all P < 0.05). The percentages of NK, CD56(bright), CD56(dim) and CD3(-)CD56(-)CD16(+) cells were positively correlated with the hyperplasic degree of bone marrow (r = 0.455, 0.412, 0.404, 0.451 respectively, all P < 0.05), but they were negatively correlated with the percentage of lymphocytes in bone marrow (r = -0.522, -0.435, -0.411, -0.547 respectively, all P < 0.05). The expression of NKG2D, NKp46, perforin and granzyme-beta of NK cells had no correlation with hematopoiesis (all P > 0.05). CONCLUSION: The lowered percentage of NK CD56(bright), CD56(dim) cells and a higher expression of perforin may cause the over-function of T lymphocytes and thus lead to hematopoietic failure in SAA. PMID- 21609588 TI - [Relationship of glucose metabolic rate and plasma levels of adiponectin and leptin in patients with metabolic syndrome]. AB - OBJECTIVE: To investigate the relationship of glucose metabolic rate (GMR) and plasma levels of adiponectin and leptin in patients with metabolic syndrome (MS). METHODS: A total of 30 MS subjects aged 36-60 years old were selected as MS group. And 20 normal adults were selected as control group. The GMR was evaluated by the technique of hyperinsulinemic euglycemia clamp. The plasma concentrations of adiponectin and leptin were detected by enzyme-linked immunosorbent assay (ELISA). Blood pressure, waist circumference (WC), body weight and body height were measured. RESULTS: (1) During the steady state (last 30 min), the GMR was significantly lower in MS group than that in control Group [(4.13 +/- 1.34) mg*kg(-1)*min(-1) vs (8.33 +/- 1.59) mg.kg(-1)*min(-1), P < 0.01]. (2) The plasma level of adiponectin was significantly lower in MS group than that in control group [(5.15 +/- 2.54) ug/ml vs (10.28 +/- 5.50) ug/ml, P < 0.01]. The plasma level of leptin were significantly higher in MS group than that in control group [(189.37 +/- 90.48) ng/ml vs (126.55 +/- 72.70) ng/ml, P < 0.01]. (3) In MS group, glucose metabolic rate was associated with WC, BMI, TG, HDL-C FINS, leptin, and adiponectin, (all P < 0.05). CONCLUSION: The technique of hyperinsulinemic euglycemic clamp shows that the BMR of MS patients significantly decreases. It may be associated with their lowered plasma levels of adiponectin and leptin. PMID- 21609589 TI - [Evaluation of the role of serum vascular endothelial growth factor and urinary basic fibroblast growth factor in differential diagnosis of vascular anomalies]. AB - OBJECTIVE: To evaluate the role of serum vascular endothelial growth factor (VEGF) and urine basic fibroblast growth factor (bFGF) in the differential diagnosis of vascular anomalies by receiver operating characteristic curve. METHODS: Using the method of enzyme linked immunosorbent assay (ELISA), 364 cases of various vascular anomalies (proliferating hemangiomas, n = 146; hemangiomas, n = 106; vascular malformations, n = 112) and 440 cases of various vascular anomalies (proliferating hemangiomas, n = 154; involuting hemangiomas, n = 148; vascular malformations, n = 138) subjects were examined for the serum levels of VEGF and the urine bFGF respectively. Nonparametric statistical tests were used for data analysis. The VEGF levels of proliferating hemangioma, involuting hemangioma, vascular malformation and control groups were analyzed by the Kruskal Wallis test. When there was significance (P < 0.05), a subgroup analysis was performed by the Mann-Whitney U test. A receiver operator characteristic (ROC) curve was constructed for both the serum levels of VEGF and urine bFGF to determine the optimal diagnostic cut-off to differentiate proliferating hemangioma from involuting hemangioma, vascular malformation and controls. RESULTS: The serum level of VEGF and the urine bFGF in proliferating hemangiomas were significantly higher than those in involuting hemangiomas, vascular malformations and negative controls (P < 0.01). And the differences among the latter three groups were not statistically significant (P > 0.05). The optimal diagnostic cut-off point of serum VEGF and urine bFGF to differentiate proliferating hemangioma from involuting hemangioma, vascular malformation and controls was 99.6 pg/mg and 0.16 ng/mmol respectively. The area under ROC curve, the sensitivity and specificity were 99.7%, 99.3%, 99.7% and 91.9%, 98.7%, 71.1% respectively. The differences of the area under ROC curve of serum VEGF and urine bFGF showed no statistical significance (P > 0.05). CONCLUSION: Serum VEGF and urine bFGF are helpful for differentiating proliferating hemangioma from involuting hemangioma, vascular malformation and controls. Both parameters have higher values of clinical application. PMID- 21609590 TI - [ST segment deviation in acute myocardial infarction with isolated disease of left anterior descending artery]. AB - OBJECTIVE: To analyze the characteristics of the electrocardiogram (ECG) of left anterior descending coronary artery (LAD) occlusion in patients with acute ST elevation myocardial infarction (STEMI). METHODS: Patients included were those diagnosed with STEMI in Peking Union Medical College Hospital from January 1996 to March 2009, and underwent coronary angiography (CAG). The infarction related artery (IRA) was LAD, and there were no significant stenosis in left circumflex artery and right coronary artery. A total of 170 cases were consecutively enrolled. They were divided into 2 groups according to occlusive sites of the LAD: LAD proximal (n = 77), LAD medius distal group (n = 93). Standard 18 leads ECG within 12 hours from the onset of STEMI were recorded and ST segment deviation was analyzed quantitatively. RESULTS: Proximal LAD occlusion as IRA was diagnosed with aVL >= 0.1 mV, ST aVL > aVR, sum of II, III and aVF STsegment depression >= 0.1 mV, in which sensitivity was 39.0%, 37.7% and 50.6%, specificity was 78.5%, 77.4% and 74.2% respectively. Statisticully significance (P < 0.05). Medius-distal LAD occlusion as IRA was diagnosed with no II ST depression, aVF ST depression and sum of II, III and aVF ST segment depression > 0.1 mV, In which sensitivity were 86.0%, 81.7% and 74.2% and the were 31.2%, 48.1% and 50.6% respectively. Statisticully significance (P < 0.05). CONCLUSION: In STEMI patients with isolated LAD occlusion, ECG can be useful to predict the occlusion site. PMID- 21609591 TI - [Qianlie Beixi Capsules for unliquefiable semen: a multi-center clinical study]. AB - OBJECTIVE: To investigate the efficacy and possible action mechanism of Qianlie Beixi Capsules in the treatment of unliquefiable semen. METHODS: A total of 190 patients with unliquefiable semen were treated with Qianlie Beixi Capsules for 1 or 2 courses (3 weeks per a course). The seminal changes were observed and recorded. RESULTS: Of the 190 patients in the 1-course treatment arm, 99 were cured and 91 failed to respond after the first course. And the effectiveness rate was 52.1%. Of the 122 patients in the 2-course treatment arm, 81 were cured and 41 failed to respond after the second course. And the effectiveness rate was 66.4%. The efficacy of 2-course regimen was obviously better than that of 1 course regiment. In the meantime, sperm density improved in the 2-course treatment arm. Sperm motility improved slightly in the effective subjects of 1 course treatment arm. All the above results had statistically significant differences (P < 0.05). CONCLUSION: Qianlie Beixi Capsules is both safe and effective for unliquefiable semen and may shorten the time of seminal liquefaction. PMID- 21609592 TI - [Infectious keratitis in China during the past two decades: a bibliometric analysis]. AB - OBJECTIVE: To gain insights into the construction and content of literature on infectious keratitis in China during the past two decades. METHODS: Through VIP VMIS, SinoMed and PubMed databases for the period of 1989 to 2008, the literature regarding infectious keratitis published in domestic and foreign journals by China authors was retrieved. Numbers, types, time, journal distribution of documents published and provincial distribution of authors were recorded. Meanwhile the subject content was roughly analyzed. RESULTS: There were 1982 Chinese articles on infectious keratitis during the past two decades, of which 629 were pertaining to traditional Chinese medicine. In the remaining 1353 of Western medicine articles, 704 were published in kernel journals, 78 in serial journals of Chinese Medical Association and 443 as original research articles (including 160 basic research papers). Moreover, 30 articles regarding epidemiology and etiology of infectious keratitis were retrieved from VIP-VMIS. And 31 papers published in foreign journals were retrieved from PubMed database. CONCLUSIONS: During the past two decades, the China oculists have made great progress in research works on infectious keratitis. However more attention should be devoted to the basic researches, epidemiologic survey and etiologic analysis. PMID- 21609593 TI - [Prognostic effects on percutaneous coronary intervention of different time windows in patients with acute myocardial infarction]. AB - OBJECTIVE: To compare the prognostic effects of different time windows on initiating PCI (percutaneous coronary intervention) in AMI (acute myocardial infarction) patients. METHODS: Ninety-five AMI patients undergoing PCI were enrolled continuously from January 2007 to September 2008. According to the timing of direct PCI, the patients were divided into 3 groups: after AMI, < 6 h (Group A, n = 45), 6 - 12 h (Group B, n = 45) and 12 - 24 h (Group C, n = 35). Comparisons were made among these 3 groups in terms of the post-PCI incidence of heart failure and mortality. The left ventricular ejection fraction (LVEF) and left ventricular end-diastolic inside diameter (LVEDV) were measured by echocardiogram at Month 6. RESULTS: During the hospitalization and follow-up, Group A had a lower incidence of heart failure and mortality than Groups B and C. And Group B had a lower rate than Group C. The difference was significant (P < 0.05). Compared with LVEF(%) (52.25 +/- 4.27) in Group B and LVEF (%) (47.75 +/- 6.86) in Group C, LVEF(%) (57.51 +/- 6.9) in Group A were significantly improved on ECG at Month 6 months. LVEDV (mm) (45.89 +/- 4.23) in Group A were significantly lower than LVEDV (mm) (49.0 +/- 3.1) in Group B and LVEDV (mm) (52.46 +/- 4.9) in Group C. The differences were both statistically significant (P < 0.05). CONCLUSION: An early time windows of initiating PCI in AMI patients can significantly improve the left ventricular functions and reduce the incidence of heart failure, left ventricular remodeling and the mortality rate. All these measures could improve left ventricular functions and prognosis. PMID- 21609594 TI - [A multiplicity of morbidity and prognostic factors in patients with septic and acute kidney injury]. AB - OBJECTIVE: To investigate the risk factors of morbidity and prognosis in patients with acute kidney injury (AKI) due to sepsis. METHODS: A case-control retrospective study was carried out in AKI patients with/without sepsis from February 2000.to March 2010. APACHE III and ATN-ISI were calculated. Multivariate logistic regression analysis was used to explore the clinical data and the risk factors of morbidity and prognosis in patients with septic AKI. RESULTS: (1) The overall mortality rate was 23.3% and the mortality rate of septic AKI patients 44.6%. (2) With no correlation with the level of D-dimer (r = 0.356, P = 0.019), the number of failed organs was positively correlated with the mortality rate in septic AKI patients (r = 0.545, P < 0.01). (3) As demonstrated by multivariate analysis, D-dimer (> 2.2 mg/L), supports of vasoactive agents, APTT (activated partial thromboplastin time) (> 50 s) were the pathogenetic risk factors for septic AKI patients; APACHE III score (> 60), the number of failed organs, supports of mechanical ventilation were the prognostic risk factors for septic AKI patients. CONCLUSIONS: The pathogenetic risk factors of septic AKI patients are D-dimer (> 2.2 mg/L), supports of vasoactive agents and APTT (> 50 s); APACHE III score (> 60), the number of failed organs and supports of mechanical ventilation are the prognostic risk factors for septic AKI patients. D-dimer may predict the morbidity of septic AKI patients, but it can not predict their prognoses. PMID- 21609595 TI - [Treatment of pyonephrosis with upper urinary tract calculi]. AB - OBJECTIVE: To improve the treatment of pyonephrosis with upper urinary tract calculi (UTC). METHODS: A total of 49 UTC patients with pyonephrosis were selected at our hospital during May 2004 to February 2010. Among them, 22 cases were treated with transurethral ureteroscope lithotripsy followed by tube internal drainage while another 27 cases underwent percutaneous nephrolithotomy. RESULTS: No such complications as septicemia and septic shock occurred during the first stage of external and internal drainage. The bacteremic symptoms of chill or fever occurred in 3 cases during the second stage of percutaneous nephrolithotomy and pyelolithotomy/ureterolithotomy (11.1%). There were 3 cases of nephrectomy. A follow-up period of 3 months to 5.5 years showed that all 33 cases had a varying degree of recovered renal functions. And there was no nephrectomy. CONCLUSION: The keys to a successful surgical treatment of pyonephrosis with upper urinary tract calculi are early diagnosis, timely drainage and relief of obstruction. Ureteroscopic lithotripsy, double-J placement and percutaneous nephrostomy drainage are excellent for relieving obstruction. As a safe procedure with minor complications, it creates proper conditions for a second stage operation. PMID- 21609596 TI - [Diagnosis and surgical treatment of Castleman's disease]. AB - OBJECTIVE: To explore the clinical features and surgical treatment of tumors associated with Castleman's disease (CD). METHODS: The clinical profiles of 19 patients with neck giant lymph node hyperplasia were analyzed retrospectively. There were 8 males and 11 females with a median age of 40 years old (range: 7 - 74). The tumor locations were neck (n = 12), neck & mediastinal cavity (n = 2), axillary fossa (n = 2), retroperitoneal area (n = 2) and abdominal cavity (n = 1). RESULTS: Eighteen of them underwent surgical resection of tumor or lymph nodes. All were diagnosed as CD by pathological examinations. There were 16 localized CD (LCD) including hyaline vascular type (HV type, n = 11), mixed type (mix type, n = 4) and plasma cell type-Hodgkin's disease (n = 1). Among 3 multicentric CD (MCD), there were 2 case of plasma cell type (PC type) and 1 case of mixed type (mix type). Long-term survival was achieved in 19 cases among which 1 case of plasma cell type MCD survived for 5 years and underwent a second operation and postoperative chemotherapy of CVP (cyclophosphamide, vincristine & prednisone) regimen for 3 cycles due to recurrence in 2 years and 1 case of plasma cell type LCD-Hodgkin's disease survived for 15 months and underwent a second operation and postoperative chemotherapy of ABVD (adriamycin, bleomycin, vinblastine & dacarbazine)regimen for 6 cycles due to recurrence in 6 months. One case of plasma cell type MCD in abdominal cavity on chemotherapy of CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine & prednisone) regimen for 6 cycles was discharged after a successful management of intestinal obstruction. CONCLUSIONS: The major clinical symptom of CD is a gradually enlarging painless mass. Surgical resection of tumor remains the first-line treatment for localized CD and the prognosis is excellent. Multicentric and plasma cell type CDs are prone to recurrence and transformation to lymphoma. And their first-line therapeutic should encompass multi-modality regimens of surgery and adjuvant chemotherapy. However, the clinical prognosis is still poor. PMID- 21609597 TI - [Genetic analysis in the clinical diagnosis of Ehlers-Danlos syndrome type IV]. AB - OBJECTIVE: To ascertain the diagnosis of such a rare disease as Ehlers-Danlos syndrome type IV by the technique of DNA(deoxyribonucleic acid)analysis. METHODS: The primer sequences of Col3A1 gene were designed. Genomic DNA was isolated from the peripheral blood samples. The amplification of polymerase chain reaction (PCR) was performed and direct sequencing used to screen the mutations. A definite diagnosis was made in conjunctions with clinical features. RESULTS: Two nucleotide mutations for Col3A1 were found. One was in intron 15 while another in exon 30. The latter was an important mutation of a G to A transition (c.2209G > A) resulting in alanine to threonine substitution at position (p.Ala698Thr). The mutations were inherited from proband of pedigree. CONCLUSION: Genetic testing of Col3A1 mutation can facilitate an accurate diagnosis of Ehlers-Danlos syndrome. PMID- 21609598 TI - [Production of connective tissue growth factor by angiotensin II in human embryonic lung fibroblast via RhoA-ROCK pathway]. AB - OBJECTIVE: To explore the production of connective tissue growth factor (CTGF) by Angiotensin II (AngII) in human embryonic lung fibroblast via the RhoA-ROCK pathway. METHODS: Human embryonic lung fibroblast (HFL-1) was divided into 4 groups: (1) control group: no stimulation; (2) AngII group: stimulation of AngII (10(-7) mol/L) ; (3) Irbesartan plus AngII group: stimulation by AngII (10(-7) mol/L) with AT-1 receptor antagonist irbesartan (10(-6) mol/L) pre-treatment; (4) Irbesartan plus AngII group: stimulation by AngII (10(-7) mol/L) with ROCK inhibitor Y27632 (10(-6) mol/L) pre-treatment. Then the products of protein and RNA were collected. Western blot and QuantiGene were used to detect the activation of RhoA-Rock pathway and CTGF. RESULTS: Exploring the affect of irbesartan on AngII through the Western blot analysis of CTGF and RhoA protein expression: the CTGF level was up-regulated by AngII (0.89 +/- 0.05 vs control 0.48 +/- 0.10, P < 0.01). Such an effect was markedly blocked by a pretreatment of irbesartan (0.72 +/- 0.05, P < 0.05). After the use of AngII, the expression of RhoA protein was significantly enhanced (3.40 +/- 0.46 vs control 1.77 +/- 0.37, P < 0.01) and blunted by a pretreatment of irbesartan (2.27 +/- 0.45, P < 0.05). The Western blot analysis of CTGF protein expression showed that AngII caused a robust increase in CTGF (0.62 +/- 0.15 vs control 0.16 +/- 0.05, P < 0.01). Such an effect was markedly blocked by a pretreatment of Y27632 (0.17 +/- 0.04, P < 0.01). The result was similar at the gene level. AngII significantly increased the expression of CTGF mRNA (1.16 +/- 0.06 vs control 1.00 +/- 0.01, P < 0.01). And it was markedly blocked by a pretreatment of irbesartan (0.99 +/- 0.07, P < 0.01) or Y27632 (1.04 +/- 0.08, P < 0.05). AngII significantly increased the expression of RhoA mRNA (1.21 +/- 0.07 vs control 1.00 +/- 0.06, P < 0.01). And it was markedly blocked by a pretreatment of irbesartan (1.00 +/- 0.12, P < 0.05) but not Y27632 (1.10 +/- 0.05, P > 0.05). CONCLUSION: Ang II activates HFL-1 to produce CTGF through the AT-1 receptor. And the RhoA-Rock pathway is involved. PMID- 21609599 TI - [Preventive effects of ischemic postconditioning and penehyclidine hydrochloride on gastric against ischemia-reperfusion injury in rats]. AB - OBJECTIVE: To investigate the protective effects of ischemic postconditioning and penehyclidine hydrochloride on gastric injury induced by ischemia-reperfusion of lower limb in rats. METHODS: The model of limb ischemia reperfusion injury was used to perform this experiment. One hundred and forty four male Wistar rats weighing 220 - 250 g were randomly divided into 4 groups: group I Control (C), group II Ischemic Reperfusion (IR), group III Ischemic postconditioning (IPO) and group IV penehyclidine hydrochloride (IPHC); C, IR, IPO and IPHC groups has been followed for 0(T(0)), 1(T(1)), 3(T(3)), 6(T(6)), 12(T(12)), or 24(T(24)) perfusion, all the groups were secondary separated into six subgroups as time point and each subgroup contained six rats, respectively. Blood samples from the inferior vena cava were taken for determination of LDH, CK activities and TNF alpha, IL-10 content at every time point of reperfusion;the animals were killed at every time point respectively and the gastric were removed for determination of SOD, MPO, XOD and LDH activities, MDA content, and histological examination and the expression of HIF-1alpha was analyzed. RESULTS: Compared with group C, IR, IPO and IPHC, in serum LDH and CK activities were increased, TNF-alpha and IL 10 content were increased (P < 0.05 or P < 0.01); and in gastric tissue MPO, XOD and LDH activities were increased and MDA content increased, while SOD activity decreased in group IR, IPO and IPHC (P < 0.05 or P < 0.01); and gastric tissue resulted in significant injury as evidenced by infiltrated of few neutrophils or eosinophils and rare neutrophils between the gastric mucosa or muscularis mucosa and the glands, interstitial vascular dilation hyperemia and small quantity hemorrhage from deep layers of mucosa or interstitial vascular dilation hyperemia, and the expression of HIF-1alpha was significantly increased (P < 0.01). Compared with group IR, IPO and IPHC in serum LDH and CK activities, TNF alpha content decreased while IL-10 content were increased (P < 0.01); and in gastric tissue MDA content, MPO, XOD and LDH activities were decreased, and SOD activity increased in group IPO and IPHC (P < 0.05 or P < 0.01); and the histological injury were milder and the expression of HIF-1alpha was significantly decreased (P < 0.01). Compared with group IPO, IPHC, in serum LDH activities were makable decreased, CK activities were first increased and then declined, TNF-alpha content makable declined while IL-10 content were increased (P < 0.05 or P < 0.01), and the histological injury were milder and the expression of HIF-1alpha was makable decreased (P < 0.01) and in gastric tissue SOD activity were makable increased, MPO activities significantly decreased, MDA content increased at T(3), XOD activities increased after T(12), LDH activities increased at T(3) and declined after T(12) in group IPHC (P < 0.05 or P < 0.01). CONCLUSION: The combination of ischemia postconditioning and postconditioning with penehyclidine hydrochloride can protect the gastric from ischemia reperfusion injury induced by ischemia reperfusion of the lower limbs in rats, the main mechanism may be reducing post-ischemic oxidative damage, inflammatory reaction, amelio-rating microcirculatory and cellular energy metabolism et al. Additionally, this study found that the protective effects of penehyclidine hydrochloride on gastric injury induced by ischemia reperfusion of the lower limbs, were better than ischemic postconditioning, and the mechanism might be related to its anti-inflammatory effect, antioxidant action and prevention of cell injury et al. PMID- 21609600 TI - [Effects of milk and coenzyme Q10 on the interference of acrylonitrile on vascular endothelial functions]. AB - OBJECTIVE: To explore the influences of milk or coenzyme Q(10) pretreatment to acrylonitrile on vascular endothelial functions in rats. METHODS: A total of 80 rats were randomly divided into 4 groups: control group (Con), acrylonitrile exposure group (ACN), milk pretreatment group (M + ACN) and coenzyme Q(10) pretreatment group (Q(10) + ACN). The experiment was conducted by the method of gavage exposure in rats. Control group was exposed to corn oil; acrylonitrile was administered to other three groups at the doses of 25 mg/kg. The M + ACN and Q(10) + ACN groups were pretreated by milk or coenzyme Q(10) at 30 minutes before acrylonitrile exposure. After a 12-week exposure, the activities of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) were measured in serum and aortal tissues. RESULTS: As compared with Con group [(21.9 +/- 1.6) U/ml], the activity of blood serum iNOS was higher in ACN, M + ACN and Q(10) + ACN groups [(42.9 +/- 2.5) U/ml, (26.5 +/- 4.4) U/ml, (26.7 +/- 3.3) U/ml, P < 0.05]. As compared with Con group [(0.540 +/- 0.028) U/mg protein], the activity of aortal iNOS was higher in ACN, M + ACN and Q(10) + ACN groups [(0.812 +/- 0.008), (0.773 +/- 0.019), (0.622 +/- 0.013) U/mg protein, (P < 0.05)]. Furthermore the activity of aortal eNOS in Q(10) + ACN group [(0.471 +/- 0.011) U/mg protein] was higher than Con, ACN or M + ACN group [(0.371 +/- 0.029), (0.380 +/- 0.016), (0.425 +/- 0.020) U/mg protein, P < 0.05]. CONCLUSION: Chronic administration of ACN by gavages results in vascular endothelial dysfunctions. Milk and coenzyme Q(10) pretreatment reduce this effect in rats. PMID- 21609602 TI - [Expectorant therapy revisited in chronic obstructive pulmonary disease]. PMID- 21609601 TI - [Comparison and evaluation of testing results for two different coagulation analyzers]. AB - OBJECTIVE: To evaluate the performance of a newly installed fully automatic coagulation analyzer and compare the consistency of its testing results with the confirmed clinical automatic coagulation analyzer at our department. METHODS: Precision, linearity, carryover and accuracy of the newly installed coagulation analyzer were evaluated according to the national required standards. Then the testing results were analyzed between the newly installed and confirmed coagulation analyzers according to the EP-5 and EP-9 documents of national committee for clinical laboratory standards (NCCLS). RESULTS: For the newly installed coagulation analyzer, the low, median and high values of relative intra precision were: 0.93%, 1.32% and 1.27% for prothrombin time (PT); 1.42%, 0.84% and 1.17% for activated partial thromboplastin time (APTT); 1.82%, 3.13% and 3.19% for fibrinogen (FIB); 1.78%, 1.76% and 1.38% for thrombin time (TT) respectively. The linear regression equation of FIB actual and theoretical values was y = 1.012x + 0.0219 (P > 0.05). There was no significant statistical difference between the intercept and 0 (t = 0.2287, P > 0.05) and between linear slope and 1 (t = 0.3221, P > 0.05). The carryover was -2.33%. The testing results of defined acceptable bias of PT and FIB in CLIA'88 for two analyzers were within the acceptable 95% confidence interval of bias. CONCLUSION: The precision, linearity, carryover and accuracy of the newly installed coagulation analyzer meet the requirements of instrument user manual. The performance and the testing results of the same sample from two coagulation analyzers are consistent. PMID- 21609603 TI - [New concepts in chronic obstructive pulmonary disease and cor pulmonale]. PMID- 21609604 TI - [The understanding for pulmonary vascular changes of chronic obstructive pulmonary disease]. PMID- 21609605 TI - [Skeletal muscle dysfunction and chronic obstructive pulmonary disease]. PMID- 21609606 TI - [The impact of the treatment of anticholinergic medicine in chronic obstructive pulmonary disease]. PMID- 21609607 TI - [Evaluation of clinical significance of chronic obstructive pulmonary disease assessment test]. AB - OBJECTIVE: To determine the reliability and validity of the COPD assessment test (CAT) Chinese version in patients with chronic obstructive pulmonary disease (COPD), and to study its value in evaluating quality of life in Chinese patients. METHODS: One hundred and thirty-five patients with COPD in stable condition from Peking Union Medical College Hospital were assessed by interview with CAT Chinese version, and underwent pulmonary function test on the same day. The validity was documented by performing correlation analysis, and Pearson's correlation coefficients were calculated. The stages of COPD determined by CAT score and lung function were compared to observe the value of CAT in determining disease severity. RESULTS: Cronbach's alpha of CAT Chinese version was 0.805. CAT score increased with the severity of the disease, and was negatively correlated to FEV(1)% of predicted (r = -0.567, P < 0.01). CAT score varied significantly in patients (10 +/- 5, 16 +/- 6, 21 +/- 7 and 23 +/- 6), with different severity of COPD (chi(2) = 48.437, P < 0.01). There was a high degree of consistency between the stages of COPD determined by CAT score and lung function. CONCLUSIONS: The Chinese version of the CAT had good internal consistency reliability and validity, and can be used to assess the quality of life for Chinese COPD patients. It provided a simple, valid and standardized measurement of COPD health status. PMID- 21609608 TI - [Effect of interleukin-17-producing CD4+ T helper lymphocytes on cigarette smoke induced lung inflammation and emphysema in mice]. AB - OBJECTIVE: To evaluate the expression and the role of Th17 in cigarette smoke induced lung inflammation and emphysema in mice. METHODS: Forty male BALB/c mice were randomly divided into 4 groups, including a control group C12, a control group C24, a smoke-exposure 12 week group (S12) and a smoke-exposure 24 week group S24 (n = 10 each). Morphological changes were evaluated by mean linear intercepts and destructive index (DI). The proportion of CD(4)(+)IL-17(+)Th17, CD(4)(+)IFN-gamma(+)Th1, CD(4)(+)IL-17(+)IFN-gamma(+)T(Th17/Th1), CD(8)(+)IFN gamma(+)Tc1, CD(8)(+)IL-21R(+) and CD(4)(+)IL-17(+)IL-21(+) T cells in lungs of mice was determined by flow cytometry. The mRNA expressions of RORgammat and IL 17 were evaluated by real-time PCR. RESULTS: Mean linear intercepts and DI were significantly higher in S12 and S24 groups [(39 +/- 4) um, (47 +/- 7) um], (39.1 +/- 1.6, 45.2 +/- 3.1) as compared to C12 [(32 +/- 4) um, 28.2 +/- 1.6] and C24 groups [(33 +/- 3) um, 28.9 +/- 2.1], all P < 0.05. The percentage of Th17 of S12 and S24 groups [(3.3 +/- 1.1)%, (7.2 +/- 2.2)%] was significantly increased as compared with that of C12 and C24 groups [(1.8 +/- 0.8)%, (2.0 +/- 0.6)%], all P < 0.05. The mRNA levels of RORgammat [(25 +/- 4), (35 +/- 3)] and IL-17 [(26 +/- 3), (36 +/- 3)] in S12 and S24 groups were higher than in C12 [(10 +/- 5), (13 +/ 5)] and C24 groups [(11 +/- 7), (8 +/- 6)], all P < 0.05. The percentage of Th1, Th17/Th1 and Tc1 cells of S12 and S24 groups [(10.0 +/- 3.7)%, (26.2 +/- 6.0)%], [(0.61 +/- 0.30)%, (1.82 +/- 0.52)%], [(17.0 +/- 4.5)%, (26.8 +/- 8.5)%] was significantly increased as compared with that of C12 [(3.8 +/- 1.7)%, (0.27 +/- 0.17)%, (4.8 +/- 1.9)%] and C24 groups [(4.2 +/- 1.3)%, (0.28 +/- 0.11)%, (5.2 +/ 1.0)%], all P < 0.05. Moreover, the frequency of Th17 cells had a positive correlation with Th1, Tc1 cells and emphysematous lesions (r = 0.519 - 0.797, all P < 0.01). In addition, a positive correlation between Th17/Th1 cells and emphysematous lesions was also found (r = 0.742, 0.802, all P < 0.01). The percentage of CD(4)(+)IL-17(+)IL-21(+) T cells was significantly increased in S12 and S24 groups [(0.19 +/- 0.04)%, (0.55 +/- 0.24)%] compared to controls [(0.07 +/- 0.03)%, (0.08 +/- 0.03)%], all P < 0.05. Meanwhile, as compared with that of the controls [(1.22 +/- 0.31), (1.34 +/- 0.18)], the percentage of CD(8)(+)IL 21R(+) T cells was also increased in S12 and S24 groups [(2.94 +/- 1.26), (4.12 +/- 2.26)], but there were no differences among smoke-exposure groups (P > 0.05). The frequency of CD(4)(+)IL-17(+)IL-21(+) T cells had a positive correlation with Th1, Tc1 cells and emphysematous lesions (r = 0.694 - 0.754, all P < 0.05). And the frequency of CD(8)(+)IL-21R(+) T cells also had a positive correlation with emphysematous lesions (r = 0.516, 0.725, all P < 0.05). CONCLUSIONS: Cigarette smoke increased the expression and the activity of Th17 in mice. Th17 may play a potential (active) role in the development of lung inflammation through IL-21/IL 21R pathway. PMID- 21609609 TI - [The effect of the regimen containing cefoxitin on highly drug-resistant rapidly growing nontuberculous mycobacterial pulmonary disease]. AB - OBJECTIVE: To evaluate the therapeutic effect and safety of the regimen containing cefoxitin on highly drug-resistant rapidly growing nontuberculous mycobacterial (RGM) pulmonary disease. METHODS: From January to December 2007, 16 patients with RGM pulmonary disease, who had been treated for 6-48 months, average (15 +/- 11) months but still sputum positive, were included in the study and treated with a new regimen containing cefoxitin, fluoroquinolone, macrolide, and SMZco. Cefoxitin was used in the first 3 months and the total duration of therapy was 18 months. Sputum conversion rate, radiology change and side effects were observed before and after the therapy. RESULTS: Underlying chronic diseases including COPD (n = 2), tuberculosis (n = 3), bone-marrow transplantation due to chronic leukemia (n = 1) and bronchiectasis (n = 5), were present in 11 patients. Main symptoms before therapy were cough and expectoration. There were multi-focal patchy, small nodular shadows with cavities on CT scans. The 16 clinical strains were highly resistant to anti-tuberculous drugs: 15/16 to streptomycin, 16/16 to isoniazid, 14/16 to rifampin, 13/16 to ethambutol, 14/15 to amikacin, 15/15 to capreomycin and 14/15 to ofloxacin. After treatment, the clinical symptoms improved in all patients. Eight of the 16 patients became sputum negative by 6 months which lasted to the end of the therapy, while another 8 patients remained sputum positive. Six patients showed radiological improvement. No one experienced side effects induced by cefoxitin. The total cure rate was 8/16. CONCLUSION: The regimen containing cefoxitin has certain effect on highly drug-resistant nontuberculous mycobacterial pulmonary disease, especially for RGM. PMID- 21609610 TI - [The effect of various antigen compounds of tuberculosis composite antigen vaccine on the immune function in mice]. AB - OBJECTIVE: To study the immune function of mice immunized by different combinations of antigen 85b (Ag85b), fusion protein culture filtered protein 10 (CFP-10), early secreted antigenic target 6 kDa protein (ESAT-6) and heat shock protein X (Hsp X) with combined adjuvants of Bacille Calmette-Guerin (BCG) CpG and aluminum. METHODS: According to antigen combinations, 48 BALB/c mice were divided into 8 groups: (1) group A: Ag85b + CFP-10/ESAT-6 + HspX + adjuvant; (2) group B: CFP-10/ESAT-6 + HspX + adjuvant; (3) group C: Ag85b + HspX + adjuvant; (4) group D: Ag85b + CFP-10/ESAT-6 + adjuvant; (5) group E: Ag85b + adjuvant; (6) group F: CFP-10/ESAT-6 + adjuvant; (7) group G: HspX + adjuvants; (8) control group: saline (6 mice per group). The mice were subcutaneously immunized 3 times. One week after the third subcutaneous immunization, spleens were collected for enzyme-linked immunospot (ELISPOT) assay to detect IFN-gamma and IL-4 secretion, and for the lymphocyte proliferation assay to observe antigen-specific lymphocyte proliferation. Serum samples were separated for enzyme-linked immunosorbent assay (ELISA) to detect the titers of antigen-specific IgG, IgG(1) and IgG(2a) antibodies. RESULTS: The amount of IFN-gamma spots in Group E [median(quartile), 122.8 (78.4 - 184.4)] was significantly more than that in group C [14.3 (6.5 - 14.6)] and the control group [0.5 (0.5 - 1.3)] (u = 0.0, P < 0.01). The amount of IL-4 spots in Group D stimulated with Ag85b and CFP-10/ESAT-6 [173.5 (78.8 - 233.4), 132.8 (50.3 - 159.4)] were significantly more than those in the control group [0.5 (0.5 - 1.3), 5.3 (2.9 - 6.5)] (u = 0.0, P < 0.01). The level of stimulation index of lymphocyte proliferation in Group A, C, D, E (2.42 +/- 0.50, 2.18 +/- 0.37, 2.86 +/- 0.51, 2.70 +/- 0.15) was significantly higher than that of the control group (1.11 +/- 0.13) (F = 20.96, P < 0.01). The level of antigen specific IgG, IgG(1), IgG(2a) antibody titers induced by Hsp X [lg(antibody dilution degree), 3.90 - 5.21] was significantly higher than those induced by Ag85b (3.30 - 4.51) and CFP-10/ESAT-6 (3.10 - 4.05) (F = 63.8 - 70.4, P < 0.01). CONCLUSIONS: With the use of adjuvants, different antigen combinations showed different influences on the immune function in mice. A combination of 3 antigens did not elicit the best immune effect, suggesting that the interaction among antigens may affect their immunity. PMID- 21609611 TI - [Comparative study of protein markers in serum and bronchoalveolar lavage fluid from patients with lung cancer by surface-enhanced laser desorption ionization time of flight mass spectrometry]. AB - OBJECTIVE: To detect the protein markers in serum and bronchoalveolar lavage fluid (BALF) of the patients with lung cancer by surface-enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF-MS) technology, and to explore if they can be used as markers for the diagnosis of lung cancer. METHODS: SELDI-TOF-MS technology and protein chips weak cation exchange (WCX-2 chip) were used to detect the protein mass spectrum in serum and BALF of 35 patients with lung cancer and 18 cases of benign pulmonary diseases. The different protein markers were analyzed by Biomarker Pattern Software and the initial diagnosis models were set up. The diagnosis models were verified further by blind screen to confirm the efficacy of diagnosis. RESULTS: Five protein peaks in the sera of the patients with lung cancer were significantly higher (P < 0.05). The protein peak with a mass/charge ratio (M/Z) of 5639 was selected to establish the classification tree model. The sensitivity of diagnosis was 80% (28/35) and the specificity was 78% (14/18). The results verified by blind screen showed a sensitivity of 85% (17/20), a specificity of 90% (9/10), a crude accuracy (CA) of 87% (26/30) and Youden's index (gamma) of 0.7. Eight protein peaks in the BALF of the patients with lung cancer were significantly higher (P < 0.05). The different protein peaks with M/Z of 7976 and 11 809 respectively were selected to establish the classification tree model. The sensitivity of diagnosis was 86% (30/35) and the specificity was 72% (13/18). The results verified by blind screen showed a sensitivity of 90% (18/20), a specificity of 90% (9/10), a CA of 90% (27/30) and gamma of 0.8. There was a complementary role in combination of differential proteins in serum and BALF and the sensitivity, specificity and accuracy of diagnosis for lung cancer were 100% by parallel test. CONCLUSIONS: The SELDI-TOF-MS technology can screen out the differential protein markers in serum and BALF of the patients with lung cancer, which show high sensitivity and specificity as tumor markers. The differential proteins in the BALF may be more promising for clinical application. PMID- 21609612 TI - [Related factor analysis of brachial-ankle pulse wave velocity in patients with obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To explore the related factors for the measurement of arterial stiffness by brachial-ankle pulse wave velocity (baPWV) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: The blood pressure and baPWV in 76 patients with OSAHS confirmed by polysomnography (PSG) were measured. Clinical data were collected, and the carotid and extremity arteries were examined by ultrasound. Arterial intima thickening, atherosclerotic plaque formation and calcification, and the morphological changes of the arterial wall were evaluated. The related factors for baPWV in patients with OSAHS were analyzed. RESULTS: The baPWV was significantly higher in the severe OSAHS group as compared to the low-moderate group (P < 0.01), as classified according to the apnea hypopnea index and the lowest oxygen saturation. Multiple regression analysis showed that the baPWV of patients with OSAHS was related to age, oxygen desaturation index and systolic blood pressure (F = 1.726 - 5.574, P < 0.05). CONCLUSIONS: Our study showed that with OSAHS exacerbations, the baPWV value increased. The baPWV of patients with OSAHS was related to age, oxygen desaturation index and systolic blood pressure. The abnormal changes of baPWV were present earlier than the morphological changes of atherosclerosis for OSAHS patients. PMID- 21609613 TI - [An experimental study on the safety of intratracheal drug administration]. AB - OBJECTIVE: To explore whether injury and repair occur in the trachea and the lung after intra-tracheal administration of different drugs. METHODS: Wistar rats were randomly divided into 5 groups, a normal group, a blank control (BC) group, a normal saline (NS) group, a lidocaine (LD) group and an amikacin (AK) group. For the latter 3 groups, normal saline, lidocaine and amikacin were injected into trachea by needle puncture. Scanning electron microscope was used to observe the ultra-structural changes of the epithelium, and the percentage of the area of damage (PAD) in tracheal mucosa was calculated. Moreover, pathological changes of the mucous membrane of bronchioles and alveolar epithelial cells were also examined, and the degree of lung pathology was semi-quantified. RESULTS: Two hours after the injection of the 3 drugs, derangement and edema of the cilia were evident by scanning electron microscopy. The PAD of the NS group, the LD group and the AK group were (94.2 +/- 3.2)%, (93.1 +/- 3.0)% and (95.5 +/- 1.8)%, respectively; all being significantly higher than that of the BC group (1.3 +/- 0.3)%. For the NS group and the LD group, the PAD decreased significantly after 24 h, which were (73.7 +/- 7.8)% and (81.0 +/- 4.6)% respectively, and returned to normal at 48 h and 96 h. While for the AK group, the damage began to improve at 72 h [PAD (62.1 +/- 5.2)%], and recovered at 96 h. Airway epithelial derangement and cell edema in the alveoli and the bronchioles also occurred 2 h after drug injection, and inflammatory cell infiltration became evident at 24 h. At this time, the score of pathology was 1.80 +/- 0.84, 2.60 +/- 0.55 and 2.80 +/ 0.45 for the NS group, the LD group and the AK group, respectively; all being higher than that of the BC group (0). These pathological changes recovered totally after 72 h for the NS and the LD groups, and 96 h for the AK group. CONCLUSIONS: Intra-tracheal administration of normal saline, lidocaine and amikacin in rats led to reversible airway mucosal and lung tissue damages. PMID- 21609614 TI - [Effects of neurally adjusted ventilatory assist on prevention of ventilator induced diaphragmatic dysfunction in acute respiratory distress syndrome rabbits]. AB - OBJECTIVE: To evaluate the effect of neurally adjusted ventilatory assist (NAVA) on prevention of ventilator-induced diaphragmatic dysfunction (VIDD) in ARDS rabbits. METHODS: Twenty New Zealand white rabbits were randomly divided into 4 groups: (1) control group (n = 5); (2) Volume control (VC) group (n = 5); (3) Pressure support (PSV) group (n = 5); (4) NAVA group (n = 5). In VC, PSV and NAVA groups, the rabbits were killed and the diaphragm was removed after 4 hours of ventilation. Animals in the control group were not mechanically ventilated, and the diaphragm was also removed immediately after anesthetizing. In all rabbits, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) of diaphragm were measured. Structure of diaphragm was observed by light microscope, electron microscope, constituent ratio and mean cross-sectional area (CSA) of diaphragm fiber. RESULTS: (1) MDA: Compared with the control [(0.15 +/- 0.06) nmol/mg], PSV group [(0.30 +/- 0.11) nmol/mg], there was no significant difference in MDA of diaphragm in NAVA group [(0.28 +/- 0.19) nmol/mg] (F = 2.730, P > 0.05). MDA in VC group [(0.40 +/- 0.16) nmol/mg] was significantly higher than the control group (P < 0.05). (2) SOD: Compared with control [(111 +/ 12) U/mg], PSV group [(93 +/- 4) U/mg], there was no significant difference in SOD of diaphragm in NAVA group [(94 +/- 9) U/mg] (F = 4.422, P > 0.05). SOD in VC group [(80 +/- 21) U/mg] was significantly lower than the control group (P < 0.05). (3) GSH: Compared with control [(5.3 +/- 1.0) mg/g] and PSV group [(4.5 +/ 1.2) mg/g], there was no significant difference in GSH of diaphragm in NAVA group [(5.6 +/- 1.0) mg/g] (F = 3.001, P > 0.05). GSH in VC group [(3.3 +/- 1.7) mg/g] is significantly lower than control and NAVA groups (P < 0.05). (4) Light microscope: In VC group, many changes were observed in the muscle, such as myelofibrosis, necrosis, and some of muscle fibers became atrophy, but these were no obvious changes of pathological structure in control, PSV or NAVA groups. (5) Electron microscope: In control, PSV and NAVA groups, the ultrastructure of diaphragm was normal. Different from the above 3 groups, some abnormal ultrastructure was observed in VC group, including disrupted myofibrils, swollen mitochondria. (6) CSA of diaphragm fiber: Compared with control and PSV group, there was no significant difference in CSA of diaphragm fiber in NAVA group (P > 0.05); The CSA of type II fibers in VC group was markedly lower than control group (P < 0.05). CONCLUSIONS: Compared with volume control ventilation, NAVA may mitigate diaphragmatic oxidative stress, atrophy and injury, and prevent VIDD better than VC. PMID- 21609615 TI - [Recent advances in chronic obstructive pulmonary disease 2010]. PMID- 21609616 TI - [The effect of statins in chronic obstructive pulmonary disease]. PMID- 21609617 TI - [The research advancement on asthmatic predisposing gene orosomucoid 1-like protein 3]. PMID- 21609618 TI - [Translational medicine is advocated on the ophthalmic research in China]. AB - OBJECTIVE: In recent years, a lot of achievements on the basic research of ocular disease have been made in our country, however, among these basic research works, few were finally become a agent or device to be applied in the clinic. The concept of "translational medicine", i.e. "from bench to bedside" research should be strongly advocated to catalyze the medical applications of basic research on ocular disease. For doing better this way, we suggest to do more research work of originality, to persevere the a meaningful research work and to cooperate well with biomedical enterprise. Meanwhile, we emphasize the importance of the reverse translational way, i.e., "from bedside to bench" not only because of the limited resources including financial resources and research facility, but also for improving the efficiency of the basic research of ocular diseases in China. PMID- 21609619 TI - [The effect of rAAV2-PEDF on proliferation of human retinal capillary endothelium cells]. AB - OBJECTIVE: To culture human retinal capillary endothelium cells (HRCECs) in vitro and explore the effect of rAAV2-PEDF on proliferation of HRCEs. METHODS: Retinas were digested by 2.5% trypsin and 0.1% collagenase I in order. The isolated cells were cultured on fibronectin-coated dishes in media of human endothelial-sFM basal growth medium (HE-SFM BGM) with 10% fetal bovine serum, insulin-transferrin selenium (ITS) and endothelial cell growth factor (ECGF). The cultured cells were identified by anti-factor VIII related antigen though immunohistochemistry stain. The effect of hypoxia induced by CoCl2 on proliferation of HRCECs was assessed by MTT assay. After rAAV2-PEDF were transfected into HRCECs, the EGPF positive cells were observed by laser confocal scanning microscopy, the protein expression of PEDF were detected by Western blot, and the proliferation of HRCECs were checked by MTT assay. Flow cytometry was used to analyze the apoptosis of HRCECs. RESULTS: Cultured HRCECs attached in the bottom of dishes in 48 h - 72 h and grew to confluence in 2 weeks after seeding. HRCECs were with a positive brown staining for factor VIII. EGPF positive cells were seen under laser confocal scanning microscopy after 48 h of rAAV2-EGFP transfection. The expression level of PEDF protein was higher in experimental group than in control group. The results of MTT assay showed the numeric value OA was 0.085 +/- 0.021 in normal group and 0.166 +/- 0.024 in hypoxia group (t = 3.938, P < 0.05). In normal oxygen condition, the numeric value OA was 0.171 +/- 0.011 in normal control group, 0.178 +/- 0.016 in rAAV2-EGFP treated group, and 0.169 +/- 0.017 in rAAV2 PEDF treated group (F = 0.01, P > 0.05). In hypoxia condition, the numeric value OA was 0.166 +/- 0.013 in CoCl(2) treated group, 0.155 +/- 0.012 in CoCl(2) + rAAV2-EGFP treated group, and 0.116 +/- 0.015 in CoCl(2) + rAAV2-PEDF treated group. In normal oxygen condition, the ratio of apoptosis was 2.3% in normal control group, and 3.3% in rAAV2-EGFP treated group, and 1.7% in rAAV2-PEDF treated group. In hypoxia condition, the ratio of apoptosis was 3.6% in CoCl(2) treated group, 6.7% in CoCl(2) + rAAV2-EGFP treated group, and 36.4% in CoCl(2) + rAAV2-PEDF treated group. CONCLUSIONS: PEDF gene can stably express in HRCECs after rAAV2-PEDF transfection and can obviously inhibit proliferation of HRCECs in hypoxia. PMID- 21609620 TI - [Experimental study of (Pro)renin receptor siRNA inhibiting retinal neovascularization]. AB - OBJECTIVE: To observe the inhibit effect of (pro)renin receptor siRNA on mice retinal neovascularization, and investigate its possible mechanism. METHODS: Experimental study. 72 new born C57BL/6J mouse were randomly divided into six groups: group A to group E were exposed to hyperoxia, and then returned to normoxia to induce retinal neovascularization. Group A were treated with PRR siRNA plasmid, group B with control plasmid, group C with PRR siRNA and Losartan, and group D with Losartan. Group E were not treated. Group F was control group. Mouse were sacrificed at postnatal day 17, retinal perfusion stretched preparation and HE dyeing method were used to observe the status of retinal neovascularization. PRR expression and the activation of extracellular regulated protein kinases 1/2 (ERK1/2) were detected by Western Blot. And Real Time PCR was used to detect the expression of transforming growth factor-beta1 (TGF-beta1) in group A, B, E and F. Analysis of one way variance (LSD) was used and statistical difference was considered significant at a P value less than 0.05. RESULTS: The mouse treated with PRR siRNA, Losartan and combined therapy could significantly reduce retina neovascularization and vessel leakage compared with oxygen-induced retinopathy group and control plasmid group. Average counts of vascular endothelial cells which break through the inner limiting membrane performed at postnatal day 17 in PRR siRNA group (4.47 +/- 1.96), Losartan group (5.94 +/- 2.54) and combined therapy group (4.49 +/- 2.53) were significantly lower than oxygen-induced retinopathy group (32.73 +/- 6.38) (P < 0.05) and control plasmid group (21.04 +/- 5.39). Western Blot showed that PRR protein express in hyperoxia induced group was significantly higher than normal (P = 0.007). After treated with PRR siRNA or combined therapy, the expression of PRR protein was significantly lower than hyperoxia induced group (P < 0.05). There are no significantly differences between control plasmid group, Losartan group and hyperoxia induced group (P > 0.05). The activated ERK1/2 lever in hyperoxia group was significantly higher than normal (P = 0.003). After treated with PRRsiRNA, Losartan or combined therapy, activated ERK1/2 lever was significantly lower than hyperoxia induced group (P < 0.05). And the effect of PRR siRNA group and combined therapy group seems more obviously, compared with Losartan group, the difference was significantly (P < 0.05). Real Time PCR showed that the lever of TGF-beta1 in hyperoxia group was significantly higher than normal (P = 0.001). After treated with PRR siRNA, the TGF-beta1 was significantly reduced (P = 0.004), and there was no significantly difference between control plasma group and hyperoxia induced group (P = 0.222). CONCLUSIONS: PRR combined with prorenin or renin could activate ERK1/2 signal transduction passageway, and promote cell proliferation, differentiation and migration, thus promote retinal neovascularization. PRR siRNA could obviously reduce PRR expression, inhibit ERK1/2 signal transduction passageway activation, and diminish retinal neovascularization. PMID- 21609621 TI - [The modification of electrophysiology affected by ectopic synapse in ON-retinal bipolar cells of RCS rats]. AB - OBJECTIVE: To study the influence of the ectopic synapse for electrophysiological characteristics modification in ON retinal bipolar cells (ON-RBCs) of RCS rat. METHODS: Immunofluorescence of the retinal frozen section was taken in P60 d, P90 d of RCS rat (RCS) and control rat (CTR) with the anti-mGluR6 and anti Synaptophysin, Lucifer Yellow staining solo ON-RBCs was taken in all the group. The whole cell recording was performed in the retinal slice of P60 d, P90 d in RCS and CTR. The modification of the passive membrane properties and the outward currents properties in RCS-ON-RBCs, CTR-ON-RBCs and CTR-OFF-RBCs were observed. RESULTS: RCS-ON-RBCs stretched out the ectopic neurite in different direction and the activity of synapse could be detected around the ectopic neurite. From Pn60d, passive membrane properties of RCS-ON-RBCs kept immature, The RMP in RCS-ON-RBCs and CTR-ON-RBCs were (-61.8 +/- 3.07), (-50.44 +/- 1.36) mV and (-63.1 +/- 2.59), (-48.37 +/- 3.69) mV when P60 d and P90 d, there ware significantly higher than CTR group (t = 2.191, 2.435, 5.817, 6.912;P < 0.05). The IR in RCS-ON-RBCs and CTR-ON-RBCs were (323.3 +/- 42.6), (337.6 +/- 71.3) MOmega and (321.2 +/- 58.6), (340.3 +/- 62.8) MOmega when P60 d and P90 d, there ware significantly higher than CTR group (t = 3.561, 1.987, 5.211, 4.034; P < 0.05). Outward currents were recorded when giving hyper- and depolarized voltage steps. In retinal degeneration, the amplitude of outward currents in RCS-ON-RBCs is significantly different with CTR-ON-RBCs (t = 5.561, 6.341; P < 0.05) or CTR-OFF-RBCs (t = 5.357, 6.997; P < 0.05). CONCLUSION: The ectopic neurite from RCS-ON-RBCs has the possibility for translating the signal. In retinitis pigmentosa, the modification of electrophysiology characteristics in RCS-ON-RBCs was significantly different with CTR-ON-RBCs and CTR-OFF-RBCs. Influence with the ectopic neurite is the possible cause. PMID- 21609622 TI - [Experimental study of Twist siRNA to inhibit the formation of retinal neovascularization in mice]. AB - OBJECTIVE: The purpose of this research is to find the law of neovascular endothelial cell migration and transition through repressing the expression of Twist in mouse's retinal neovascularization with RNAi, and get a new target of inhibit retinal neovascularization. METHODS: Oxygen-induced retinopathy (OIR) was produced in new born C57BL/6J mice by exposing postnatal day 7 (P7) pups to 75% oxygen for 5 days. P12 pups were injected 1 ul pTwist. siRNA plasmid solution or 1 ul negative siRNA plasmid solution into vitreous cavity. Eyeballs were enucleated for Evans blue angiography, histopathologic examination, neovascular endothelial cell counting, immunohistochemistry and Real-Time PCR. RESULTS: Observed by light microscopy retinal neovascularization, the number of vascular endothelial cells per eye were 0.34 +/- 0.11, 32.73 +/- 6.38, 4.56 +/- 2.02 and 20.17 +/- 6.49 in the normal control group, hyperoxia group, Twist plasmid group and the control plasmid group. Mouse retinal Evans blue perfusion and HE staining of paraffin sections showed that retinal vascular leakage, tortuous and angiogenesis significantly reduced in Twist plasmid group compared with hyperoxia group. Endothelial cell count was significantly decrease in Twist plasmid group. Both immunohistochemistry and real time PCR proved that Twist and vimentin expression in hyperoxia group were significantly higher than that of Twist plasmid group (F = 27.214, 31.211;P < 0.05). CONCLUSION: As mice retinal neovascular growth, Twist may play important roles as a cell transition regulatory factor. Repressing Twist with RNAi, we can repress cell transition and inhibit retinal neovascular. PMID- 21609623 TI - [Changes of asphericity of posterior corneal surface after corneal refractive surgery]. AB - OBJECTIVE: To investigate the changes of the asphericity (Q-value) of the posterior corneal surface with different corneal diameters after corneal refractive surgery. METHODS: One hundred and fifteen myopic eyes of 115 subjects undertaken corneal refractive surgery (59 LASIK and 56 EPI-LASIK) were enrolled in this prospective study. The Q-value of the posterior corneal surface for patients with different corneal diameters (6, 7, 8 and 9 mm) was measured with Pentacin pre- and post-operatively. The correlations between Q-value, Q change (DeltaQ), and the mean preoperative spherical equivalent refraction (SE), central corneal thickness (CCT), central ablation depth (AD) and AD/CCT were investigated. RESULTS: The mean Q-value of the posterior corneal surface in 115 preoperative eyes with corneal diameters at 6, 7, 8 and 9 mm was 0.08 +/- 0.16, 0.05 +/- 0.13, -0.15 +/- 0.12 and -0.26 +/- 0.11, respectively. The Q-value had a statistically significant positive shift 1 month after surgery in eyes with 6, 7 and 8 mm corneal diameters (LASIK: t(6mm) = -2.076, P = 0.042; t(7mm) = -2.873, P = 0.006; t(8mm) = -2.180, P = 0.033; EPI-LASIK: t(6mm) = -2.859, P = 0.006; t(7mm) = -3.901, P = 0.000; t(8mm) = -3.510, P = 0.001). The mean Q-value diminished significantly 6 months compared to 1 month after surgery, and had an obvious tendency back to its preoperative level. No statistically significant correlation between Q and SE or CCT was found in the preoperative eyes. Also, no correlation between DeltaQ and SE, CCT, AD and AD/CCT was found after surgery. CONCLUSIONS: The shape of the posterior corneal surface in myopic eyes was more prolate as corneal diameter increased, which was similar to the anterior corneal surface. The posterior corneal surface showed central flattening and peripheral steepening (oblate shift) at early stage either post-LASIK or post-EPI-LASIK, and then returned to its original state over time. PMID- 21609624 TI - [Clinical features and carotid artery color Doppler imaging in patients with ocular ischemic syndrome]. AB - OBJECTIVE: To report the clinical manifestations and results of carotid artery color Doppler imaging (CDI) of ocular ischemic syndrome (OIS). METHODS: It was a retrospective case series study. Consecutive patients suspected with OIS were retrospectively studied from 1995 to 2009. We evaluated all patients with medical history, visual acuity, slit lamp, direct and indirect funduscopy, Fundus fluorescence angiography. CDI for internal carotid artery (ICA), Diagnostic Cerebral Angiography and magnetic resonance imaging were also performed. RESULTS: 17 patients (20 eyes) with OIS were studied, 13 males and 4 females. The age range of patients was 46 to 83 years old (median 70). 13 right eyes and 7 left eyes (3 bilateral) were involved. (1) SYMPTOMS: 70.6% (12/17) of the patients complained of visual decrease. 17.6% (3/17) had history of repeated amaurosis fugax (transient monocular visual loss); 11.8% (2/17) patients presented with floaters. The course before the first presentation was 2 days to 6 years (median 3 months). (2) Visual Acuity (VA): among the 20 involved eyes, the best corrected VA < 0.05 in 3 eyes (15.0%); 0.05 to < 0.3 in 7 eyes (35.0%); 0.3 to < 0.7 in 7 eyes (35.0%); >= 0.7 in 3 eyes (15.0%). (3) Fundus manifestations: 15.0% (3/20) eyes had cotton-wool spots; 25.0% (5/20) had retinal hemorrhages; retinal arterioles and vein became narrow; venous beading could be seen in severe cases. 30.0% (6/20) had microaneurysms in mid-peripheral area. The pressure of central retinal artery decreased; 25.0% (5/20) had optic disc or retinal neovascularization; 10.0% (2/20) had iris neovascularization. 5.0% (1/20) had neovascular glaucoma; 5.0% (1/20) had optic atrophy. (4) Fundus fluorescence angiography: arm-retinal circulation time prolonged to 14.5 to 39.9 seconds, (median 20.9 seconds). The retinal and choroidal circulation time was also prolonged. The wall of artery and venous could be staining. Hyperfluorescence dots indicating microaneurysms could be seen in the mid-peripheral area. Arterio venous shunts, non-perfusion area and the leakage of new vessels were observed in some cases. (5) Internal carotid artery CDI examination: The ipsilateral ICA of the 19 involved eyes (another patient with pulseless disease had abnormal subclavian arterial flow) showed completely occluded in 5 cases (26.4%), > 80.0% to 95.0% stenosis in 7 cases (36.8%), 52.0% to 80.0% stenosis in 7 cases (36.8%). Among the 14 contralateral eyes of the same group of patients, CDI showed stenosis of 80.0%, 70.0%, 60.0%, 50.0% and 40.0% in 5 eyes, whereas no fundus abnormal was found. Peak of systolic velocity (PSV): Among the 20 involved eyes of the 17 patients, PSV of the ipsilateral ICA was undetectable in 8 cases which occluded completely or stenosis severely. Among the ipsilateral ICA of the other 12 eyes, 11 cases showed abnormal PSV; PSV increased to 92 to 524 cm/s in 9 cases and decreased to 41 cm/s in 1 case. The blood flow of subclavian artery reduced to 20 cm/s in one patient with pulseless disease. The blood flow of subclavian artery reduced to 20 cm/s in one patient with pulseless disease. CONCLUSIONS: The patients with OIS are usually older than 60 years of age. It is a chronic disease with unnoticed symptoms. The clinical manifestations may include: amaurosis fugax (transient monocular visual loss), hypoperfusion retinopathy and ischemic optic neuropathy. Internal carotid artery severe stenosis or occlusion are the most frequent cause of this disease. CDI is the best safe, reliable and non-invaded method for carotid artery examination. PMID- 21609625 TI - [The morphology and thickness of cornea in patients with Marfan syndrome]. AB - OBJECTIVE: To search for the characteristics of MFS in corneal morphology and thickness. METHODS: Twenty-four patients (48 eyes) with MFS and 24 healthy age- and gender-matched volunteers (48 eyes) were recruited in this clinical prospective, and comparative series study. Firstly, biomicroscopic examination and Type-A ultrasonometry was conducted to search for ectopia lentis and axis length. Secondly, the corneal morphologic parameter [including the height of anterior and posterior surface, the centre corneal curvature, the mean astigmatism in the 3.0-mm central zone (Mean A), the mean simulated astigmatism (Sim A), the mean keratometry in the 3.0-mm central zone (Mean K), the mean simulated keratometry (Sim K), the 3.0-mm zone irregularity (3.0ZI), the 5.0-mm zone irregularity (5.0ZI), corneal thickness index (CTI)] and thickness (at the central location and at eight midperipheral locations) were obtained by the the autorefractometer and the Orbscan II Z corneal topography. Last, the statistics method including Crosstabs, One-way ANOVA, student-t test and discriminant analysis were applied and the correlations were established. RESULTS: There is no statistically significance between MFS group and control group in ages (38 +/- 7) and (37 +/- 8) years, gender (8/16) and (9/15), and axis length (23.12 +/- 1.06) mm and (24.26 +/- 2.96) mm (age chi(2) = 0.091, P = 0.763;gender t = 0.324, axis length t = 1.976, P > 0.05). Flat cornea ratio (66.7% and 12.5%) and topography of the oval (25.0% and 16.7%), irregular bow-shaped (41.7% and 37.5%) and irregular-shaped (12.5% and 8.3%) were increased significantly in patients with MFS. The corneal topography (MFS/control) showed that there are statistically significance in the thinnest thickness of cornea (489.8 +/- 42.9)um and (544.8 +/ 25.7)um, Mean K (40.60 +/- 1.30) D and (42.80 +/- 1.40) D, Sim K (40.50 +/- 1.30) D and (42.80 +/- 1.20) D, Sim A (1.08 +/- 0.86)D and (0.91 +/- 0.46) D, CTI 1.57 +/- 0.24 and 1.21 +/- 0.14, 3.0ZI (1.76 +/- 0.96) D and (1.54 +/- 0.82) D, and 5.0ZI (1.91 +/- 1.26) D and (0.92 +/- 0.68) D (thinnest thickness t = 6.996, Mean K t = 2.554, Sim K t = 3.326, Sim A t = 2.324, CTI t = 3.116, 3.0ZI t = 2.686, 5.0ZI t = 3.768, P < 0.05), while no statistically significance in the Mean A between the MFS (1.11 +/- 0.89) D and control group (0.99 +/- 0.49) D (Mean A t = 1.898, P = 0.08); except for temple inferior, the significant decrease of pachymetry (including the center and the seven midperipheral locations) appeared in the MFS group compared with the control group. CONCLUSION: The characteristic of MFS in corneal topography is that corneal axial refractive power descends and corneal thickness decreases. PMID- 21609626 TI - [Clinical observation of extraocular extension of choroidal melanoma]. AB - OBJECTIVE: To evaluate the clinical features, diagnostic methods and treatment of extraocular extension of choroidal melanoma. METHODS: It was a retrospective case series study. The records of 12 consecutive cases with extraocular extension of choroidal melanoma confirmed by pathologic examination were analyzed with special attention to the case histories, clinical manifestations, imaging findings, treatment and follow up results. RESULTS: Four patients were misdiagnosed as glaucoma. Another 4 patients were confirmed the diagnosis of melanoma and 3 of them received the operations of transscleral local resection. The common clinical manifestations included: impaired vision, exophthalmos, blepharoptosis, limited ocular motility, conjunctival hyperemia, and increased ocular or orbital pressure, etc. Characteristic sign was raised mass on the surface of sclera. All cases underwent orbital MRI preoperatively, 6 underwent ocular B-scan echography, and 6 underwent orbital CT scanning to evaluate for extraocular extension of tumor. Typical ultrasonography revealed the discontinued ocular wall and an intraocular mass with a continuous hypoechoic extraocular mass. In some cases the extraocular mass showed hypoechoic with medium echo area. CT scan showed a well defined homogeneous intraconal mass connecting with intraocular lesion in 6 cases, which could infiltrate eye or optic nerve. The MR signal features of intraocular tumors with extraocular extension showed 4 patterns in all patients. The typical pattern was the tumor showed hyperintensity on T(1) and hypointensity on T(2)-weighted image. The maximum diameter of extraocular tumor was measured over 4 mm in 9 cases. MRI was useful for demonstrating multiple extraocular lesions, remote metastatic lesion or micro extraocular tumor, of which minimal diameter was 3 mm in our cases. Orbital exenteration was performed in 11 cases and ocular enucleation with excision of extraocular tumor was in 1 cases. Microscopic examination showed the epithelioid-cell-type tumors were the most common. The tumor extended out of the eye by three types of way in our cases. Follow-up ranged from 1 to 5 years in 8 cases, who underwent chemotherapy, radiotherapy or interferon. Six cases had no recurrences and general health. Death and metastasis was respectively recorded in one case. CONCLUSIONS: Delayed treatment could induce the growth of choroidal melanoma to the stage of extraocular extension, which has few specific clinical manifestations. The combination of multiple imaging examinations was helpful for the correct diagnosis. Surgical operation with adjunctive therapies could partly reduce recurrence and metastasis of melanoma. PMID- 21609627 TI - [Preliminary study on the establishment of the animal model and biological activity of human being meibomian gland carcinoma]. AB - OBJECTIVE: To explore the methods to establish a xenografted model of meibomian gland carcinoma in nude mice, then find the best method to establish the animal model. The last purpose of this study was to establish a suitable animal model for clinic therapy and basic research of meibomian gland carcinoma. METHODS: Small pieces of meibomian gland carcinoma tissue from four patients were transplanted subcutaneously in the flanks of eight nude mice through a skin incision. Nature of transplantation tumor including formation, growth and size were observed. The transplanted tumors were stained with hematoxylin-eosin, Sudan III and Immunohistochemistry. RESULTS: The human meibomian gland carcinoma tissue can survived in nude mice. The pathologic examination revealed that the transplanted tumor was arranged in mass. The tumor cells were round or multisided. The proportion of the nuclei and cytoplasm was imbalance. Nuclear division could be easily observed. The test of Sudan III was positive. Immunohistochemical observation: the results showed that both CK and EMA were positive. CONCLUSIONS: The subcutaneously xenotransplanted tumor model of human meibomian gland carcinoma with tissue explant in nude mice was successfully established. The transplanted tumor maintained the properties of human meibomian gland carcinoma. PMID- 21609628 TI - [The effects of hyperosmotic stress on rabbit ocular surface and mucin 5AC expression]. AB - OBJECTIVE: To investigate the effects of hyperosmotic stress on rabbit ocular surface and mucin 5AC (MUC5AC) expression. METHODS: Experimental study. Eighteen New Zealand white rabbits were randomly divided into three groups with equal number as hyperosmolar saline solution (HOSS, 500 mmol/L) group, normal saline (NS, 308 mmol/L) group and blank control group respectively. In HOSS and NS groups, the HOSS and NS eye drops were instilled on bilateral eyes six times every day for 14 days. On day 0, 7 and 14, Schirmer I test and tear break-up time (BUT) were measured and conjunctival impression cytology specimens were collected. On day 7 and 14, cornea and conjunctiva were harvested for Hematoxylin and Eosin (HE) staining, scanning and transmission electron microscopy observation and conjunctival TUNEL examination. On day 14, the conjunctiva were also harvested for immunology histological staining and western blot to evaluate the expression of MUC5AC. RESULTS: In HOSS group, the BUT on day 7 and 14 was (7.6 +/- 2.5) and (7.0 +/- 2.3) s respectively which was significantly shorter than the (10.3 +/- 2.5) s on day 0(t = 5.800, 4.950; P < 0.01), and also significantly shorter than the BUT in NS and control groups (F = 8.030, P < 0.01). But the Schirmer I test value did not change obviously in and between all those three groups. The mean conjunctival goblet cell (GC) density in HOSS group on day 7 and 14 was (19.5 +/- 16.6) and (32.3 +/- 18.2) cells/mm(2) respectively which was also significantly lower than the (75.7 +/- 43.4) cells/mm(2) on day 0 (t = 5.319, 2.970; P < 0.05). However the GC density did not change obviously in other two groups with time. After instillation of HOSS for 14 days, subepithelial inflammatory cell infiltration was showed on conjunctival tissue specimens and decreased epithelial layers and evident desquamation were found in the cornea specimens by the HE staining. Under the electron microscope, decreased microvilli and loosened intercellular junction in the superficial epithelium and increased autophagic vesicles in basal epithelium were observed in the cornea in HOSS group; and decreased microvilli and mucous granules were found in the conjunctiva in HOSS group. Obvious TUNEL positive staining was showed in the conjunctiva in the HOSS group. Also the MUC5AC immunology histological staining and western blot indicated decreased MUC5AC protein expression in HOSS group. CONCLUSION: Hyperosmotic stress destroyed the structure of ocular surface epithelium, induced the decrease of conjunctival goblet cell density and MUC5AC expression, and led to the decreased tear film stability. PMID- 21609629 TI - [Effects of diabetes mellitus on the occurrence of age-related macular degeneration]. AB - Diabetes mellitus causing long term disturbed glucose metabolism could result in tissue injury and multiple complications. According to recent studies, diabetes mellitus might be regarded as one of the risk factors of age related macular degeneration (AMD). Diabetes mellitus affects the incidence and progression of AMD through altering hemodynamics, increasing oxidative stress, accumulating advanced glycation end products, etc. By studying epidemiological investigation and basic research on this subject comprehensively, it is required to review the correlation between diabetes mellitus and AMD. PMID- 21609630 TI - [The changes of bioactive substances in the aqueous humor of Pseudoexfoliation syndrome]. AB - Pseudoexfoliation syndrome, which represents the most commonly identified specific cause of open-angle glaucoma, is a kind of clinically systemic disease. Why there are so much exfoliative material deposited in the anterior chamber? Where did exfoliative material come from? The pathogenesis is never be confirmed exactly, though there are so many theories described by investigators. In recent years, in order to survey and evaluate the changes of the materials of the aqueous humor of patients with the Pseudoexfoliation syndrome, many investigators had done more works. This review will give a summarization of these findings. PMID- 21609631 TI - [Characteristics of corneal endothelium during allograft rejection after corneal transplantation]. AB - Allograft corneal transplantation is currently the most effective and optimum method to treat corneal disease, however it is the immune rejection that the main reason for graft edema caused by vascularization and inflammation of the cornea and surgical failure after transplantation. Corneal endothelial cells occupy a crucial position as immune privilege and the primary barriers for maintaining normal physiological function of eye. In this paper, the various stages (recognition, response and reaction of immune system) of corneal endothelial changes in the morphological and biological characteristics had been presented after allograft corneal transplantation. PMID- 21609632 TI - [New insights into the treatment of vascular cognitive impairment based on the mechanisms of chronic cerebral hypoperfusion]. PMID- 21609633 TI - [Chinese guidelines for diagnosis and management of cognitive impairment and dementia (VI): dementia nursing]. PMID- 21609634 TI - [Early, middle and long-term clinical outcomes of coronary artery bypass grafting for left main coronary stenosis]. AB - OBJECTIVE: To evaluate the early, middle and long-term clinical outcomes of coronary artery bypass grafting (CABG) for a special subset of left main coronary stenosis (LMS). METHODS: A total of 626 LMS patients, recruited at our hospital between January 1998 and March 2008, were classified them into the statin therapy group (Group A, n = 322) or the non-statin therapy group (Group B, n = 304) according to whether or not taking statins pre-operatively. Then their clinical data were retrospectively analyzed. RESULTS: The inhospital mortality was 4.31% (n = 27). And the mortality was 1.90% (n = 6) for Group A and 6.91% for Group B (n = 21) (chi2 test, chi2 = 9.642, P = 0.002). Preoperative statin therapy could lower the all-cause mortality rate (1.90% vs 6.91%, P = 0.002), the prevalence of new atrial fibrillation or flutter (14.69% vs 19.61%, P = 0.016, chi 2= 5.780) and disabling stroke (2.50% vs 4.58%, P = 0.047, chi(2) = 3.94). Among 599 CABG survivors, 565 cases (94.3%) were actually followed up with a mean duration of 55.5 +/- 26.1 months (range: 2 - 98). During the follow-up period, there were 29 (4.63%) cardiac events, including 12 deaths and 17 myocardial infarctions. There were 43 (7.18%) cases with relapsing angina pectoris. The univariate analysis showed that emergency procedure, abnormal C-reactive protein (CRP), abnormal troponin I(TnI), complicated LMS pathology, preoperative IABP (intra-aortic balloon pump) support, preoperative cardiac arrest, preoperative history of myocardium infarction and no preoperative statin therapy were the risk factors for perioperative death while complicated LMS pathology, preoperative IABP support, preoperative cardiac arrest, preoperative myocardium infarction and no preoperative statin therapy were the risk factor for late cardiac events. The multivariate binary logistic regression showed that emergency procedure, preoperative IABP support, no preoperative statin therapy and preoperative IABP support were independent predictors for peri-operative death. And preoperative IABP support, preoperative cardiac arrest, no preoperative statin therapy and complicated LMS pathology were independent predictors for late cardiac events. There was no statistical significance in inhospital mortality between on pump CABG and OPCAB (off pump coronary artery bypass). CONCLUSION: The CABG procedure for LMS carries a relative high mortality. However preoperative statin therapy may offer such protective effects as lowering the all-cause mortality rate and reducing the prevalence of new atrial fibrillation or flutter and disabling stroke. PMID- 21609635 TI - [Radiological progression and life quality analysis in ankylosing spondylitis patients using etanercept/methotrexate combination therapy]. AB - OBJECTIVE: To analyze the relationship between the radiological progression and quality of life in ankylosing spondylitis (AS) patients using etanercept/methotrexate (MTX) combination therapy. METHODS: A total of 153 AS cases fulfilling the 1984 modified New York diagnostic criteria were reviewed. All patients received radiological evolution at baseline and during a follow-up period. Radiological progression, clinical remission and life quality were recorded and analyzed for their relations. RESULTS: The radiological assessments of mSASSS (modified Stoke ankylosing spondylitis spine score) were recorded at baseline, 3, 6 & 12 months after treatment. Life quality assessments were recorded with SF (short-form)-36 simultaneously. No significant radiological improvement was observed at the end points. However, most patients reported a significant improvement of life quality after a combination therapy of etanercept/MTX. BASDAI (Bath ankylosing spondylitis disease activity index), C reactive protein and erythrocyte sedimentation rate demonstrated similar trends. With no relevance with mSASSS, life quality was significantly correlated with disease activity and pain control. CONCLUSION: The combination therapy of etanercept/MTX greatly improves life quality in AS patients. Yet clinical remission and pain control offer no hint of a suspension of radiological progression. Routine radiological assessment is required throughout the follow-up period of AS even if life quality index reaches a high level. PMID- 21609636 TI - [Management of femoral neck fracture post total knee arthroplasty]. AB - OBJECTIVE: To investigate the risk factors, management and prognosis of femoral neck fracture post total knee arthroplasty (TKA). METHODS: From January 2003 to August 2009, 45 cases of femoral neck fracture post TKA were treated. There were 8 males and 37 females with an age range of 56 - 81 years old. Among them, there were ipsilateral (n = 36) and contralateral (n = 9) femoral neck fractures. Due to the fracture site and type, the treatment plans were formulated. And a follow up was conducted to record the Harris hip score and complications. RESULTS: The incidence of femoral neck fracture following TKA and osteoporosis had a linear correlation. And the fracture rate increased with the aggravation of osteoporosis. The stability of ipsilateral fracture group was lower than those of contralateral fracture and no fracture groups. Except for 4 mortality cases, 41 patients were followed up for 2 to 7 years with an average period of 3.6 years. There were 12 patients in the cannulated screw fixation group. The outcomes were fracture healing (n = 5) and femoral head necrosis (n = 7). Twenty-five cases underwent femoral head replacement. And 3 died and second fracture occurred in 3 cases. Eight cases underwent total hip arthroplasty. And 1 died and there was 1 case of second fracture. The Harris scores of the cannulated screw fixation group was significantly lower than the hip replacement groups (q test, P < 0.05). COMPLICATIONS: After internal fixation, 7 cases suffered femoral head necrosis and underwent femoral head replacement. And secondary fractures after hip replacement occurred in 4 cases and they were treated by plate and cable or LISS (less invasive stabilization system) system. CONCLUSION: Femoral neck fracture following TKA is usually caused by a low-energy injury. Osteoporosis is one of its high-risk factors. Knee instability is associated with ipsilateral femoral neck fracture. Clinically it can be treated by internal fixation or hip arthroplasty. And internal fixation of femoral neck fracture frequently induces femoral head necrosis. And femoral head replacement is applicable. PMID- 21609637 TI - [Effect of siRNA-Cox-2 on the growth inhibition and apoptosis of cartilage endplate chondrocytes]. AB - OBJECTIVE: To investigate the influence of siRNA-COX-2 gene upon the growth inhibition and apoptosis of cartilage endplate chondrocytes and provide new methods and evidence for siRNA in gene therapy of cartilage endplate chondrocytes. METHODS: According to the sequence of COX-2 mRNA, COX-2 siRNA was designed, synthesized, cloned into the GFP reporter pcDNA6.2GW/EmGFPmiR vector and transfected into Hep cell line. The integrity of inset fragment was detected by colony PCR (polymerase chain reaction) and sequencing analysis. The cultured cartilage endplate chondrocytes were divided into 4 groups: control group (untreated), negative siRNA group (treatment with 30 nmol/L negative control siRNA), siRNA1 group (treatment with 15 nmol/L COX-2 siRNA) and siRNA2 group (treatment with 30 nmol/L COX-2 siRNA). The biological activity of recombinants was identified with the interference efficiency of COX-2 siRNA recombinant by real-time PCR and Western blot. And the effects of COX-2 inhibitor on the growth of chondrocytes were detected by WST-8 and the mRNA expressions of survivin, bcl 2 and bax genes measured by real-time PCR. RESULTS: The sequences of inset fragment in 4 siRNA expressing recombinants were correct. After COX-2 transfection, the expression of COX-2 mRNA in chondrocytes was 51.3% +/- 7.2% in the siRNA1 group and 35.4% +/- 3.6% in the siRNA2 group. Western blot showed that the expression of COX-2 protein decreased, especially in siRNA2 group (P < 0.05). And the cell survival rate was 100.0% +/- 8.3% in the control group, 84.9% +/- 4.2% in the negative control siRNA group, 52.5% +/- 6.7% in the siRNA1 group and 48.9% +/- 5.4% in the siRNA2 group (P < 0.05). Meanwhile, the expressions of mRNA of survivin and bcl-2 decreased while the expression of bax mRNA increased in degenerative cartilage endplate chondrocytes transfected with COX-2 siRNA (P < 0.05). CONCLUSION: COX-2-targeting siRNA inhibits the expression of COX-2, suppresses the proliferation of chondrocytes and induces the cell apoptosis. These effects may be attributable to the up-regulation of survivin and bcl-2 and the down-regulation of bax. PMID- 21609638 TI - [Disassembly of tubulin cytoskeleton disrupts the homeostasis of articular cartilage chondrocytes]. AB - OBJECTIVE: To investigate the influence of tubulin disassembly on the in vitro metabolism of articular chondrocytes. METHODS: Eight New Zealand rabbits aged 2 months were sacrificed by air embolism. The full-thickness cartilages were harvested from both knees under sterile conditions. Then 0.4% pronase and 0.025% II collagenase were used to digest for primary chondrocytes. The cells were cultured for 3 days after attachment and then divided into the control and experimental groups. The control group continued culturing with primary medium and the experimental group with colchicine, a tubulin destructive agent, at a final concentration of 0.1 umol/L. At Days 1 & 2, the early apoptosis of two cell groups was assayed with phosphatidylserine (Annexin V). At Day 6, the morphological changes of cells were observed by hematoxylin and eosin staining. At Days 3, 6 & 9, the expression levels of type II collagen, proteoglycan and MMP (matrix metalloproteinase)-13 mRNA were measured by real time quantitative fluorescent reverse transcription-polymerase chain reaction (real time RT-PCR). Meanwhile at Days 3, 6 & 9, the cultured supernatant of each group was obtained to detect the contents of type II collagen and proteoglycan by the methods of ELISA (enzyme-linked immunosorbent assay) and Alcian blue. RESULTS: At Day 2, the early cell apoptosis rate of the experimental group was higher than that of the control group (P < 0.05). At Day 6 post-dosing, the experimental cell morphology was found to be irregular and polygonal. Hyperchromatic nucleus and division phase increased while matrix cell decreased. At Days 3, 6 & 9, the expressions of collagen and proteoglycan mRNA in the experimental group decreased versus those in the control group (P < 0.05). The level of MMP-13 mRNA showed no significant changes in the control group at Day 3. And it significantly increased at Days 6 & 9 (P < 0.01). Meanwhile, type II collagen and glycosaminoglycan were significantly lower in the experimental group at Days 3, 6 & 9 than those in the control group (P < 0.05). CONCLUSION: A disassembly of tubulin can induce early apoptosis of chondrocytes. The synthesis and secretion of type II collagen and proteoglycan decrease while there is an elevated expression of MMP-13. The degeneration of cartilage cells and their disrupted synthesis and catabolism result in a serious decline in biological functions. PMID- 21609639 TI - [Experimental study of percutaneous vertebroplasty with a novel bone void filling container system]. AB - OBJECTIVE: To investigate vertebral augmentation with a novel reticulate bone filling container system by polymethyl methacrylate (PMMA) injection in cadaveric simulated vertebral compressive fracture and explore the effect of reticulate bone filling container on cement distribution controlling within vertebral body and the restoration of biomechanical properties after augmentation. METHODS: A total of 28 freshly frozen human vertebrae specimens were randomly divided into 4 groups. After the measurements of bone mineral density (BMD) and vertebral height, each vertebra received an axle load by a MTS (material testing system) machine to test the initial strength and stiffness. Subsequently a simultaneous compressive fracture model was created to measure the stiffness and height of fractured vertebrae. Then the augmentation procedure was performed. Afterward the biomechanical properties and the vertebral height were similarly measured as pre operatively. The expansion of bone filling container and the distribution of cement within vertebral body were morphologically observed by crossing the specimens in sagittal midline and also integrated with the radiographic results. RESULTS: Stiffness was significantly restored comparing with that of fractured level (P < 0.05). And the bipedicular groups had better restoration results than the unipedicular groups. The strength and height of specimens significantly increased after the augmentation procedure but without difference among groups. In axial radiographic view, the distribution of cement in vertebral body was oval or long oval-shaped in double-layer bone filling container groups while it was irregular in single-layer groups. After crossing, the double-layer version expanded well in vertebral body and could enwrap most of injected cement. There was only a little leakage near the vessel layer. But the single-layer version had a poor expansion and a large amount of cement leakage. CONCLUSION: This novel reticulate bone void filling container system with different layers may restore both the biomechanical properties and the height of fractured vertebrae. But, with the benefit of reducing cement leakage, a double-layer design can enwrap most of injected PMMA and has a brighter prospect of clinical application. PMID- 21609640 TI - [Levonorgestrel-releasing intrauterine system and combined oral contraceptives as conservative treatments for recurrent ovarian endometriosis: a comparative clinical study]. AB - OBJECTIVE: To evaluate and compare the efficiency and safety of levonorgestrel releasing intrauterine system (LNG-IUS) and combined oral contraceptives (COC) in the treatment of recurrent ovarian endometriosis after conservative surgery or conservative surgery plus medical therapy. METHODS: A total of 48 patients with recurrent ovarian endometriosis underwent randomization. The regimens of LNG-IUS (n = 24) and COC (n = 24) were offered. The volume of ovarian endometriotic cysts was recorded before treatment and at 6, 12, 18 and 24 months. The volume of ovarian endometriotic cysts, pain score of visual analogue scale (VAS), menstrual pattern, body weight, serum CA125 and serum lipids were compared to the pretreatment level within each treatment group, as well as between two treatment groups during the same period. RESULTS: (1) At 18 months after LNG-IUS, the cysts in 2 subjects entirely disappeared. At 24 months, 18 patients had a disappearance of cysts. The overall size reduction was statistically significant (9.2 +/- 3.0) vs (0.9 +/- 1.5) cm(3) (P < 0.01). In the COC group, 12 subjects had a complete resolution of cysts at 24 months. The overall size reduction was statistically significant (9.4 +/- 2.2) vs (2.9 +/- 3.1) cm(3) (P < 0.01). At 18 & 24 months, the cyst size reduction was significantly larger in the LNG-INS group than the COC group (2.4 +/- 1.5) vs (4.7 +/- 2.6) cm(3) (P < 0.01) and (0.9 +/- 1.5) vs (2.9 +/- 3.1) cm(3) (P < 0.05); (2) There was a significant improvement of dysmenorrhea, chronic pelvic pain and dyspareunia at 6- & 12-month follow-up in both groups; (3) serum CA125 decreased at 6 & 12 months in both groups with statistical significance. It decreased more sharply in the LNG-IUS group and remained at low levels beyond 12 months; (4) within 6 months of LNS-IUS, irregular bleeding and spotting were the major side effects. Beyond that period the symptoms were significantly relieved. Weight gain and dyslipidemia were the major side effects of COC. CONCLUSION: For patients with recurrent ovarian endometriosis after conservative surgery or conservative surgery plus medical therapy, LNG-IUS and COC may be used to control and reduce endometriotic cysts, relieve pain and reduce the level of CA125. LNG-IUS has the advantages of a greater convenience and minor systemic side effects. PMID- 21609641 TI - [Related factors of early post-operative prognosis of meningiomas: an analysis of 953 surgical cases]. AB - OBJECTIVE: To study the related factors of early post-operative prognosis of meningiomas. METHODS: The clinical data of 953 patients with meningiomas were recorded and statistically analyzed with chi(2) test of single factor and logistic regression model of multivariate factors. Patient age; tumor size; tumor location; pre-operative complication of patients such as hypertension, diabetes, heart disease and cerebral infarction; the extent of tumor resection; hemorrhagic shock; blood loss or hemorrhagic shock and brain swelling intra-operatively were taken as variables. The prognosis was evaluated by postoperative Karnofsky performance scale. RESULTS: The prognosis was significantly correlated with the patient age, tumor size, tumor location, preoperative cerebral infarction, the extent of tumor resection, blood loss and hemorrhagic shock intra-operatively (P < 0.05). Such factors as tumor size, preoperative cerebral infarction, the extent of tumor resection (Simpson's scale) and intra-operative hemorrhagic shock were independent risk factors of prognosis for meningiomas. Other factors, such as hypertension, diabetes and heart disease, were unrelated with the prognosis of meningiomas (P > 0.05). CONCLUSION: Patient age, tumor location and pre-operative complications of patients maybe affect the early postoperative prognosis of meningiomas. But such factors as tumor size, preoperative cerebral infarction, the extent of tumor resection and intra-operative hemorrhagic shock are independent risk factors for the post-operative prognosis of meningiomas. PMID- 21609642 TI - [Clinical analysis of 57 patients with Takayasu's arteritis]. AB - OBJECTIVE: To analyze the characteristics of vascular involvement in Takayasu's arteritis (TA) patients and explore the differences between the involvements of whole range versus origin of vessels and those whose origin of vessels were involved. METHODS: A total of 57 TA patients were divided into the origin and whole range groups according to their CTA (computed tomography angiography) examination reports. Then a retrospective analysis was performed on their clinical data. RESULTS: (1) TA had a female dominance of 1:10.4. The TA-extensive type was the most common type. And carotid and subclavian arteries were the most common sites of involvement. (2) The ratio of whole range and origin groups was 1.28:1. The delay of whole range group from the onset to a correct diagnosis was longer than that of origin group (P < 0.05). The rate of aortic arch type in whole range group was less than that in origin group (P < 0.05). (3) More patients in whole range group had the initial symptom of headache than those in origin group, as well as the subsequent symptoms of claudication, weight loss and urination problems (P < 0.05). (4) 37.5% of patients in whole range group and 64% in origin group had an elevated level of C-reactive protein (CRP) (P < 0.05). CONCLUSION: Patients with whole range of arteries involved in TA are common. With atypical clinical manifestations and a low positive rate of CRP, a diagnostic delay is an important issue. Thus due attention should be paid to its clinical diagnosis and treatment. PMID- 21609643 TI - [Relationship of serum levels of adiponectin, leptin, tumor necrosis factor-alpha and c-reactive protein with insulin resistance during first trimester pregnancy]. AB - OBJECTIVE: To explore the relationships between serum levels of adiponectin, leptin, TNF-alpha and CRP (c-reactive protein) versus insulin resistance in early pregnancy. METHODS: A total of 342 pregnant women delivering at our hospital were recruited from October 2007 to July 2008. Their clinical data were collected and analyzed. According to the 50-g 1-hour oral glucose screening test, they were divided into 3 groups: gestational diabetes, gestational impaired glucose tolerance and normal pregnancy. The serum levels of adiponectin, leptin, TNF alpha and CRP were determined by ELISA (enzyme-linked immunosorbent assay) and multivariate correlation analysis was used to analyze their relationships with the indices of insulin resistance. RESULTS: Among them, there were gestational diabetes (n = 13) and gestational impaired glucose tolerance (n = 19). Thirty five normal pregnant women were selected as the control group. The result of analysis of variance indicted that adiponectin, leptin and TNF-alpha had significant statistical differences among three groups. Through the multivariate correlation analysis, adiponectin had a adverse correlation with the indices of insulin resistance. Leptin, CRP, TNF-alpha and BMI (body mass index) had positive correlations with the indices of insulin resistance. CONCLUSION: Adiponectin, leptin, TNF-alpha and CRP are correlated with the indices of insulin resistance. And TNF-alpha may become an important predictor of gestational diabetes in early pregnancy. PMID- 21609644 TI - [Interventional therapy of hepatic artery-portal vein fistula with gelatin sponge and lipiodol]. AB - OBJECTIVE: To observe and compare the revasculation rate after embolization of hepatic artery-portal vein fistula (APVF) by gelatin sponge versus gelatin sponge with lipiodol. METHODS: The clinical data of 51 patients were retrospectively analyzed. They were divided into Groups A and B. APVF was embolized by gelatin sponge alone in Group A and gelatin sponge with lipiodol in Group B. Then the investigators observed and compared the revasculation rate of hepatic artery portal vein fistula at Days 30 - 40 and 60 - 70 post-embolization respectively. RESULTS: There was no statistical difference in age, gender, pathological types and hepatic functions before intervention between Groups A and B. One of 28 APVF sites was embolized unsuccessfully in Group A while all APVF cases were embolized successfully in Group B. The revasculation rate of hepatic APVF were 70.37% and 46.15% at Days 30 - 40 post-embolization in Groups A and B respectively (chi(2) = 4.25, P = 0.039, chi-square test); the revasculation rates of APVF were 92.59% and 88.46% respectively at Days 60 - 70 post-embolization (P = 0.67). CONCLUSION: Interventional therapy of hepatic APVF by gelatin sponge and lipiodol is a safe method of reducing the short-term revasculation rate. It may be employed in clinical practices to save precious time for controlling hepatic malignant tumors. PMID- 21609645 TI - [Clinical observation of 16 patients with synchronous esophageal cancer and lung cancer treated with simultaneous esophagus and lung resection]. AB - OBJECTIVE: To study the pathogenesis, clinical features, curative effect and prognosis of esophageal cancer associated with lung cancer. METHODS: We reviewed 16 cases of esophageal cancer associated with lung cancer managed at our hospital between January 2003 and July 2009 and analyzed their clinical data. RESULTS: There were 16 cases of esophageal cancer associated with lung cancer. There were 12 males and 4 females with a male to female ratio of 3:1. The average age at the onset of the disease was 67 years old (range: 51 - 76). The resection rate of esophageal cancers was 100%. There was 1 case of non-radical resection. And the resection rate of lung cancer was 100%. There were radical resection (n = 7) and wedge resection (n = 9). The 1-year overall survival rate was 87.5%. CONCLUSION: Lung lesions of esophageal cancer patients may be discovered by computed tomography screening of chest. More male patients than female patients are diagnosed with esophageal cancer associated with lung cancer. The operative risks and complication rates are generally acceptable. PMID- 21609646 TI - [Investigation on prevalence rate of essential tremor in population aged 55 years old and above in Kashkar, between 2008 and 2009]. AB - OBJECTIVE: To investigate the prevalence and clinical feature of essential tremor (ET) in a community cohort of the elderly in Kashkar. METHODS: By using a door-to door, two-phase screening approach, some 2834 residents of Hans ethnicity were investigated form 2008 to 2009. RESULTS: In this study, 184 ET patients were found. The prevalence rate of ET was 6.49%. The prevalence rate was increased with age and higher in men (8.45%) than in women (4.59%), especially in people aged above 75 years old. The prevalence rate of ET was 7.26% in illiterate people, followed by 7.27%, 5.81%, 5.58% and 9.37% in those having received primary, junior, senior high school and college. The ratio of windowed people in ET patients was 15.21%, higher to the ratio of windowed people in total number. CONCLUSIONS: The prevalence rate of ET increased with age, but not influenced by education. PMID- 21609647 TI - [TLR9 mRNA expression and tumor necrosis factor-alpha/interleukin-6 secretion in murine microglia by hepatitis C virus stimulation]. AB - OBJECTIVE: To analyze the expression of toll-like receptor 9 mRNA, TNF (tumor necrosis factor)-alpha and IL (interleukin)-6 after the stimulation of murine microglia (BV2) by hepatitis C virus (HCV) so as to elucidate the immune pathogenesis of HCV in the injury of central nervous system (CNS). METHODS: BV2 cells were cultured in vitro and divided into 3 groups: HCV-positive serum group, normal serum group (negative control) and blank control group. Each group had 20 samples. The cells and supernatant were collected at 4, 12, 20, 36 h. And TLR9 mRNA was detected by RT-PCR (reverse transcription-polymerase chain reaction) and the levels of TNF-alpha and IL-6 were detected by ELISA (enzyme-linked immunosorbent assay). Comparison analyses were performed by SPSS13.0 statistical package. RESULTS: (1) RT-PCR showed that there was the expression of TLR9 mRNA in BV2 cells. And the level of TLR9 mRNA in HCV-positive serum group (0.85 +/- 0.11, 0.55 +/- 0.08, 0.58 +/- 0.09, 0.61 +/- 0.07) was higher than that in the other groups. The difference had statistical significance (F = 17.258, P < 0.05). It was the highest at 4 h (0.85 +/- 0.11). And the difference had statistical significance (F = 7.427, P < 0.05); but there were no statistical significance between normal serum group and control group (P > 0.05); no significant difference existed among 12, 20 and 36 h (P > 0.05). (2) The levels of TNF-alpha [(926 +/- 133), (327 +/- 59), (367 +/- 69), (354 +/- 71) pg/ml] and IL-6 [(125 +/ 34), (84 +/- 20), (82 +/- 24), (87 +/- 18) pg/ml] in the HCV-positive serum group were higher than those in the other groups (F = 18.263 - 27.469, P < 0.05); in HCV-positive serum group, the levels of TLR9 mRNA and TNF-alpha (r = 0.425, P < 0.01)/IL-6 (r = 0.489, P < 0.01) were positively correlated. CONCLUSION: The expression of TLR9 mRNA is elevated after the stimulation of BV2 cells by HCV positive serum. It peak comes at 4 h. And it may induce the secretions of TNF alpha and IL-6. Thus TLR9 may increase the secretions of Th1 and Th2 cytokines so as to participate in the early inherent immune response during the infection of CNS by HCV. PMID- 21609648 TI - Bevacizumab in combination with a taxane for the first-line treatment of HER2 negative metastatic breast cancer. AB - This paper presents a summary of the evidence review group (ERG) report into the use of bevacizumab (Avastin(r), Roche) in combination with a taxane for the treatment of untreated metastatic breast cancer (mBC). The main clinical effectiveness data were derived from a single, open-label randomised controlled trial (RCT) (E2100) that evaluated the addition of bevacizumab to weekly (q.w.) paclitaxel in patients with human epidermal growth factor receptor 2-negative mBC who had not previously received chemotherapy for advanced disease. This trial reported statistically significant increases in median progression-free survival (PFS) for the addition of bevacizumab (5.8-11.3 months). Median overall survival was not significantly different between the two groups; whether this is a true null finding or due to crossover between treatment arms cannot be established, as relevant data were not collected. The manufacturer reported that the addition of bevacizumab to paclitaxel q.w. therapy was associated with a significant improvement in quality of life, as measured by FACT-B (functional assessment of cancer therapy for breast cancer) scores. However, the ERG noted that these results were based on extreme imputed values, the removal of which led to non significant differences in quality of life. The manufacturer conducted an indirect comparison. However, owing to methodological limitations and concerns about the validity and exchangeability of the included trials, the ERG did not consider the findings to be reliable. One additional relevant RCT [AVADO (Avastin and Docetaxel); BO17708] evaluating the addition of bevacizumab to docetaxel was excluded from the manufacturer's submission. This was summarised by the ERG. In terms of response rate and PFS, AVADO reported a markedly smaller benefit of adding bevacizumab to docetaxel than that reported for adding bevacizumab to q.w. paclitaxel in E2100. AVADO also reported no statistically significant effect of combination therapy versus docetaxel in terms of overall survival. The manufacturer developed a de novo economic model that considered patients with the same baseline characteristics as women in the E2100 trial. The model assessed BEV + PAC - bevacizumab 10 mg/kg every 2 weeks in combination with paclitaxel 90 mg/m2 weekly for 3 weeks followed by 1 week of rest; PAC q.w. - paclitaxel (monotherapy) 90 mg/m2 weekly for 3 weeks followed by 1 week of rest; DOC - docetaxel (monotherapy) 75 mg/m2 on day 1 every 21 days (considered current UK NHS clinical practice in the submission); and GEM + PAC - gemcitabine 1250 mg/m2 on days 1 and 8 plus paclitaxel 175 mg/m2 on day 1 every 21 days. Pairwise comparisons were made between BEV + PAC and PAC (using the E2100 trial), BEV + PAC and DOC, and BEV + PAC and GEM + PAC. Based on NHS list prices, the manufacturer's model estimated incremental cost-effectiveness ratios (ICERs) for BEV + PAC of L 117,803, L 115,059 and L 105,777 per QALY gained, relative to PAC, DOC and GEM + PAC regimens, respectively. If the NHS Purchasing and Supply Agency prices for PAC with a 10-g cap on the cost per patient of BEV were used instead, the ICERs for BEV + PAC were estimated at L 77,314, L 57,753 and L 60,101 per QALY, respectively. The submission suggested that the regimen of BEV + DOC is not cost-effective because it is considered less effective and more costly than BEV + PAC. Analysis by the ERG suggested that alternative assumptions can increase the ICERs further and, based on current prices, no plausible changes to the model assumptions will bring the ICERs for BEV + PAC lower. PMID- 21609649 TI - Omalizumab for the treatment of severe persistent allergic asthma in children aged 6-11 years. AB - This paper presents a summary of the evidence review group report into the clinical effectiveness and cost-effectiveness of omalizumab for the treatment of severe persistent asthma in children aged 6-11 years, based upon the evidence submission from Novartis Pharmaceutical UK Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The manufacturer's submission was generally considered to be of good quality. The submission was based primarily on a preplanned subgroup IA-05 EUP (European Union Population) from the IA-05 trial, with outcomes including the number of clinically significant (CS) and clinically significant severe (CSS) exacerbations. Omalizumab therapy was associated with a statistically significant reduction in the rate of CS exacerbations, but the reduction in the rate of CSS exacerbations was not statistically significant. The benefit in terms of CS exacerbations was achieved mainly in patients with more than three exacerbations per year at baseline. The manufacturer found no previous published cost effectiveness studies of omalizumab in children aged 6-11 years, so their de novo economic evaluation formed the basis of the submitted economic evidence. The economic model was considered appropriate for the decision problem. The results from the model indicated that omalizumab in addition to standard therapy compared with standard therapy alone did not appear cost-effective in either the overall population or a subgroup of patients hospitalised in the year prior to enrollment, with incremental cost-effectiveness ratios of L 91,169 and L 65,911 per quality-adjusted life-year, respectively. These findings were found to be robust across a wide range of alternative assumptions through one-way sensitivity analyses. The guidance issued by NICE states that omalizumab is not recommended for the treatment of severe persistent allergic asthma in children aged 6-11 years. PMID- 21609650 TI - Eltrombopag for the treatment of chronic idiopathic (immune) thrombocytopenic purpura (ITP). AB - This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of eltrombopag for the treatment of adults with chronic idiopathic (immune) thrombocytopenic purpura (ITP), based on a review of the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. ITP is an autoimmune disorder by which antibodies are formed against platelets with annual incidence rates in the UK/USA ranging from 1.13 to 6.62 cases per 100,000 adults. Eltrombopag increases the production of platelets at a rate that outpaces their destruction by the immune system, and has a UK marketing authorisation both for the treatment of adult ITP in splenectomised patients who are refractory to other treatments and as a second-line treatment for adult non splenectomised patients for whom surgery is contraindicated. Both splenectomised and non-splenectomised patient groups were considered in the analysis. Two economic models were presented, one for a watch-and-rescue treatment scenario and the second for the long-term treatment of patients with more severe ITP. The submission's evidence was sourced from the relatively high-quality RAISE [RAndomized placebo-controlled Idiopathic thrombocytopenic purpura (ITP) Study with Eltrombopag] randomised controlled trial. The study indicated a statistically significant difference in favour of eltrombopag compared with placebo in the odds of achieving the primary outcome of a platelet count of between 50 and 400 * 109/l during the 6-month treatment period (odds ratio 8.2, 99% confidence interval 3.6 to 18.7). In the eltrombopag group, 50/83 (60%) non splenectomised patients and 18/49 (37%) splenectomised patients achieved this outcome. Median duration of response for all patients was 10.9 weeks (splenectomised patients 6 weeks and non-splenectomised patients 13.4 weeks). Patients treated with eltrombopag required less rescue medication and had lower odds of bleeding events than placebo-treated subjects in both patient groups. In the watch-and-rescue economic model, the ERG found that substantial reductions in the cost of eltrombopag are needed for the incremental cost-effectiveness ratio (ICER) to fall below L 30,000. Further analyses found that the ICER varied from L33,561 to L 103,500 per quality-adjusted life-year (QALY) (splenectomised) and from L 39,657 to L 150,245 per QALY (non-splenectomised). Other than bleeding, no adverse events were modelled. In relation to the long-term treatment model, the ERG found that using non-randomised non-comparative data may result in biased estimates of unknown magnitude and direction. None of the treatment sequences resulted in an ICER approaching the recommended threshold of L 30,000. The base case results, using a 2-year time horizon and prescribing eltrombopag as second line treatment post rituximab, were found to be favourable towards eltrombopag. In conclusion, based on the MS and additional ERG work, eltrombopag appears to be a safe treatment for ITP (although long-term follow-up studies are awaited) and has short-term efficacy. However, there is no robust evidence on long-term efficacy or cost-effectiveness of eltrombopag, and there is a lack of robust direct evidence on the effectiveness and cost-effectiveness of eltrombopag compared with other relevant comparators. NICE did not recommend eltrombopag for the treatment of chronic ITP within its marketing authorisation for splenectomised or non-splenectomised patients. PMID- 21609651 TI - Trastuzumab for the treatment of HER2-positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. AB - This paper presents a summary of the evidence review group (ERG) report into trastuzumab for the treatment of human epidermal growth factor receptor 2 (HER2) positive metastatic adenocarcinoma of the stomach (mGC) or gastro-oesophageal junction. HER2 positivity is defined by immunohistochemistry (IHC)3+ or IHC2+/fluorescence in situ hybridisation (FISH)+. The decision problem addressed was the testing of the whole mGC population with IHC and, for IHC2+ patients, also with FISH, followed by treatment of HER2-positive patients with trastuzumab combined with cisplatin and either capecitabine or 5-fluorouracil (5-FU) [HCX (trastuzumab, cisplatin, capecitabine)/fluorouracil (F)] compared with current standard NHS therapy. The manufacturer's submission contained direct evidence from the ToGA trial, a well-conducted, multinational, phase III randomised controlled trial (RCT) that compared HCX/F with cisplatin and a fluoropyrimidine alone [cisplatin, capecitabine (CX)/F]. HCX/F showed statistically significantly better overall survival in the European Medicines Agency-licensed population subgroup (74%) (hazard ratio 0.65, 95% confidence interval 0.51 to 0.83), corresponding to median survival of 16 months versus 11.8 months. No other evidence exists for the efficacy of any therapy in a known HER2-positive mGC population; other comparisons extrapolate from trials in mixed HER2 status populations. The ERG accepted the manufacturer's view that a meaningful network meta-analysis to establish a comparison for HCX/F compared with current standard NHS therapy [epirubicin, cisplatin, capecitabine (ECX)/epirubicin, oxaliplatin, capecitabine (EOX)/epirubicin, cisplatin, 5-FU (ECF)] was not possible, but was unconvinced by arguments advanced in the alternative narrative synthesis. These involved disregarding evidence from a meta-analysis and interpreting non significant results of small RCTs comparing epirubicin-containing triplets with cisplatin, 5-FU (CF)/capecitabine (X) doublets as evidence of no difference between triplet and doublet regimens. The high CX/F dose in the ToGA trial was an additional basis for the contention of equivalence. An appropriate de novo economic evaluation, including an economic model that separately compared HCX or trastuzumab, cisplatin, 5-FU (HCF) with the triplet regimens ECX, EOX and ECF, based on a simple, three-state cohort model (progression-free, disease, progression and death), was submitted. Utility weights were applied to estimate quality-adjusted life-years (QALYs). Costs were assessed from an NHS perspective, and incorporated the acquisition and monitoring costs of the alternative regimens, HER2 testing, adverse events and other supportive care costs. An 8-year time horizon was used to represent a lifetime analysis. Results from the ToGA trial were combined with a series of assumptions on relative treatment effects and testing strategies. The manufacturer's results produced an incremental cost effectiveness ratio (ICER) of L 53,010 per QALY for HCX versus ECX. Although the manufacturer undertook a detailed set of sensitivity analyses, several alternative model assumptions were not evaluated. The ERG undertook a series of alternative base-case analyses. As a result of these analyses, EOX replaced ECX as the appropriate comparator, and the ICER for the comparison of HCX vs EOX increased to between L 66,982 and L 71,636 per QALY. The impact of implementation of alternative testing strategies remained unclear. There is also considerable uncertainty surrounding the true estimate of effectiveness for the comparison between triplet regimens containing epirubicin (ECX/ECF/EOX) and doublet CX/F regimens. Consequently, the view of the ERG was that there is insufficient evidence on the efficacy of HCX/F compared with current NHS standard therapy for an ICER to be determined with any degree of certainty. PMID- 21609652 TI - Prucalopride for the treatment of women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief. AB - This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of prucalopride for the treatment of women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief. The ERG report is based on the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence as part of the single technology appraisal process. In the submission, quality-of life data [Patient Assessment of Constipation Quality of Life (PAC-QOL) and Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaires] from trials of prucalopride were extrapolated to EQ-5D (European Quality of Life-5 Dimensions) data and used to inform effectiveness in an economic model. Response rates to prucalopride were derived from observed response rates in trials, defined as the proportion of patients achieving an average of three or more spontaneous complete bowel movements over the 4- or 12-week trial periods. Adult (18-64 years) and elderly (>= 65 years) patients were considered separately in the model. Cost-effectiveness was determined from estimated improvements in EQ-5D and anticipated response rates, adjusted for baseline severity of chronic constipation. The ERG considered that the patients participating in these trials were not representative of those in the licensed indication. They were not all refractory to laxatives, and baseline EQ-5D scores showed a large spread in quality of life, with many patients experiencing little baseline dissatisfaction. The mapping of quality-of-life data from trials (PAC-QOL and PAC-SYM data) to EQ 5D was unclear and invalidated. The assumption of the long-term effectiveness and safety of prucalopride to 1 year was considered unjustified. There was no justification or sources given for coefficients used to predict effectiveness in the economic model, and no costs other than the cost of prucalopride were incorporated into the model. Owing to the many areas of uncertainty, particularly the effectiveness of prucalopride in the licensed patient group and its long-term effectiveness and safety, it was considered that the MS provided no evidence for whether prucalopride is effective or not in women with laxative-refractory chronic constipation. Further subgroup analysis of the actual patient group of interest may have better guided decision-making. However, long-term efficacy data, with validated estimates of quality of life incorporated in a well-founded model, would be important for an evidence-based judgement to be made. PMID- 21609653 TI - Denosumab for the prevention of osteoporotic fractures in postmenopausal women. AB - This paper presents a summary of the evidence review group (ERG) report into denosumab for the prevention of osteoporotic fractures in postmenopausal women. Denosumab has been shown in a large randomised trial to reduce the frequency of osteoporotic fractures when given subcutaneously at 6-monthly intervals. Compared with placebo, the relative risks of clinical vertebral and hip fractures were 0.32 and 0.60, respectively. Clinical vertebral fractures occurred in 0.8% of women taking denosumab and 2.6% of control subjects. Hip fractures occurred in 1.2% of women on placebo and 0.7% on denosumab. The expected use is in women who cannot tolerate oral bisphosphonates. Other options in that situation include strontium ranelate and zoledronate, which, compared with placebo, also reduced the risk of clinical vertebral fractures [relative risk (RR) 0.65 and 0.23, respectively]. Zoledronate also significantly reduced the risk of hip fractures (RR 0.59). The ERG concluded that zoledronate was the main comparator. The relative cost-effectiveness of denosumab and zoledronate depends mainly on assumptions about costs of administration. PMID- 21609654 TI - Ofatumumab for the treatment of chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab: a critique of the submission from GSK. AB - This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of ofatumumab for the treatment of refractory chronic lymphocytic leukaemia (CLL), based upon the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included one study: a non-randomised, single-arm study. Two other studies were identified but both were non-comparative and provided evidence for therapies other than ofatumumab. For this reason these studies were not discussed in full in the main body of the submission. In the Hx-CD20-406 study, the overall response rate was 58% (99% confidence interval 40% to 74%, p < 0.001). Complete resolution of constitutional symptoms and improved performance status occurred in 57% of patients. Median progression-free survival (PFS) and overall survival (OS) times were 5.7 and 13.7 months, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. The MS concluded that ofatumumab provides a new, effective and well-tolerated therapy for patients with CLL who are refractory to both fludarabine and alemtuzumab [double refractory (DR)]. The ERG undertook a critical appraisal of the submission. The ERG had a number of concerns regarding the manufacturer's estimates of effectiveness based on evidence from a single arm, non-randomised study. An 'area-under-the-curve' or 'partitioned-survival' model was used to project expected clinical and economic outcomes for patients with DR CLL who were assumed to receive ofatumumab or best supportive care (BSC). The model had a three-state structure: 'alive pre-progression', 'alive post progression' and 'dead'. Overall, the modelling approach is reasonable given the limited evidence available for the drug in the patient population under review. However, a number of uncertainties were identified in the economic evaluation; for example, the BSC arm used data from patients in the Hx-CD20-406 study who did not respond to ofatumumab treatment - 'non-responders' - and the ofatumumab arm used data from all of those treated in the Hx-CD20-406 study. Further uncertainty arose regarding the choice of utilities, the omission of 17p and 11q chromosomal deletions as factors in the Cox proportional hazards models for PFS and OS, and the omission of the costs of drugs in progressive disease. It was felt that these factors biased cost-effectiveness in favour of ofatumumab. When revisions were made to the assumptions in the model based on the ERG's review of the published and submitted evidence, the revised base-case incremental cost-effectiveness ratio for ofatumumab increased to L 81,500 per quality-adjusted life-year. The final appraisal determination was issued by NICE in September 2010 (www.nice.org.uk/nicemedia/live/12264/50758/50758.pdf). PMID- 21609655 TI - Trabectedin for the treatment of relapsed ovarian cancer. AB - The paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of trabectedin for the treatment of relapsed platinum-sensitive ovarian cancer, based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submission addressed only part of the decision problem and did not provide evidence to compare trabectedin (Yondelis(r), PharmaMar) and pegylated liposomal doxorubicin hydrochloride (PLDH) (Caelyx(r), Schering-Plough) with key comparators. The submission's direct comparison evidence came from one reasonable quality randomised controlled trial (RCT) of trabectedin and PLDH versus PLDH alone (ET743-OVA-301). The results of the RCT were subdivided into the entire platinum-sensitive population (> 6-month relapse after initial platinum-based chemotherapy) and partially platinum-sensitive (>= 6- to 12-month relapse) and fully platinum-sensitive (> 12-month relapse) populations. The outcomes included were overall survival, progression-free survival measured by three types of assessor, response rates, adverse effects of treatment, health-related quality of life and cost per quality-adjusted-life-year (QALY) gained. A mixed treatment comparison (MTC) meta-analysis comparing trabectedin and PLDH with single-agent PLDH within the entire platinum-sensitive population, with paclitaxel or with topotecan also formed part of the submission. The RCT data showed that trabectedin plus PLDH compared with PLDH monotherapy had a significant effect on overall survival only within the partially platinum-sensitive subgroup. PFS results reported by the independent radiologists showed significant effects in favour of the trabectedin and PLDH arm for the entire and partially platinum sensitive populations only. Rates of grade 3 and 4 adverse events were mostly higher in the trabectedin and PLDH arm than in the PLDH alone arm. There were several issues regarding the undertaking of the MTC, and thus the data were not considered robust. Furthermore, the ERG did not believe the MTC to be necessary to answer the decision problem. The manufacturer submitted a de novo cost effectiveness model. The main analysis compared trabectedin in combination with PLDH versus paclitaxel, topotecan and PLDH (each as monotherapy) in the entire platinum-sensitive population, using results estimated from the MTC. Additional analyses were presented comparing trabectedin in combination with PLDH versus PLDH monotherapy using direct evidence from the OVA-301 trial for the fully, partially and entire platinum-sensitive populations. The cost per QALY gained for trabectedin in combination with PLDH versus PLDH monotherapy was estimated to be L 70,076 in the main analysis. In the additional analyses, the cost per QALY gained for trabectedin in combination with PLDH versus PLDH monotherapy was L 94,832, L 43,996 and L 31,092 for the entire, partially and fully platinum sensitive populations, respectively. Additional work was undertaken by the ERG using patient-level data and amending some assumptions to provide a better statistical fit to the Kaplan-Meier data than the exponential distribution assumed by the manufacturer. The ERG base-case estimate of the cost per QALY of trabectedin in combination with PLDH ranged from L46,503 to L54,607 in the partially platinum-sensitive population. At the time of writing, trabectedin in combination with PLDH for the treatment of women with relapsed platinum-sensitive ovarian cancer is not recommended by NICE in the final appraisal determination. PMID- 21609656 TI - Liraglutide for the treatment of type 2 diabetes. AB - This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of liraglutide in the treatment of type 2 diabetes mellitus, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The manufacturer proposed the use of liraglutide as a second or third drug in patients with type 2 diabetes whose glycaemic control was unsatisfactory with metformin, with or without a second oral glucose-lowering drug. The submission included six manufacturer-sponsored trials that compared the efficacy of liraglutide against other glucose-lowering agents. Not all of the trials were relevant to the decision problem. The most relevant were Liraglutide Effects and Actions in Diabetes 5 (LEAD-5) (liraglutide used as part of triple therapy and compared against insulin glargine) and LEAD-6 [liraglutide in triple therapy compared against another glucagon-like peptide-1 agonist, exenatide]. Five of the six trials were published in full and one was then unpublished. Two doses of liraglutide, 1.2 and 1.8 mg, were used in some trials, but in the two comparisons in triple therapy, against glargine and exenatide, only the 1.8-mg dose was used. Liraglutide in both doses was found to be clinically effective in lowering blood glucose concentration [glycated haemoglobin (HbA1c)], reducing weight (unlike other glucose-lowering agents, such as sulphonylureas, glitazones and insulins, which cause weight gain) and also reducing systolic blood pressure (SBP). Hypoglycaemia was uncommon. The ERG carried out meta-analyses comparing the 1.2- and 1.8-mg doses of liraglutide, which suggested that there was no difference in control of diabetes, and only a slight difference in weight loss, insufficient to justify the extra cost. The cost-effectiveness analysis was carried out using the Center for Outcomes Research model. The health benefit was reported as quality-adjusted life-years (QALYs). The manufacturer estimated the cost-effectiveness to be L 15,130 per QALY for liraglutide 1.8 mg compared with glargine, L 10,054 per QALY for liraglutide 1.8 mg compared with exenatide, L 10,465 per QALY for liraglutide 1.8 mg compared with sitagliptin, and L 9851 per QALY for liraglutide 1.2 mg compared with sitagliptin. The ERG conducted additional sensitivity analyses and concluded that the factors that carried most weight were: in the comparison with glargine, the direct utility effects of body mass index (BMI) changes and SBP, with some additional contribution from HbA1c, in the comparison with exenatide, HbA1c, with some additional effects from cholesterol and triglycerides in the comparison with sitagliptin, HbA1c and direct utility effects of BMI changes. The European Medicines Agency has approved liraglutide in dual therapy with other oral glucose lowering agents. NICE guidance recommends the use of liraglutide 1.2 mg in triple therapy when glycaemic control remains or becomes inadequate with a combination of two oral glucose-lowering drugs. The use of liraglutide 1.2 mg in a dual therapy is indicated only in patients who are intolerant of, or have contraindications to, three oral glucose-lowering drugs. The use of liraglutide 1.8 mg was not approved by NICE. The ERG recommends research into the (currently unlicensed) use of liraglutide in combination with long-acting insulin. PMID- 21609657 TI - Golimumab for the treatment of psoriatic arthritis. AB - This paper presents a summary of the evidence review group (ERG) report into the use of golimumab for the treatment of psoriatic arthritis (PsA). The main clinical effectiveness data were derived from a single phase III randomised controlled trial (RCT: GO-REVEAL) that compared golimumab with placebo for treating patients with active and progressive PsA who were symptomatic despite the use of previous disease-modifying antirheumatic drugs or non-steroidal anti inflammatory drugs. The 14-week data showed that, compared with placebo, golimumab 50 mg significantly improved joint disease response as measured by American College of Rheumatology (ACR) 20 [relative risk (RR) 5.73, 95% confidence interval (CI) 3.24 to 10.56] and Psoriatic Arthritis Response Criteria (PsARC) (RR 3.45, 95% CI 2.49 to 4.87), and skin disease response as measured by the Psoriasis Area and Severity Index (PASI) 75 (RR 15.95, 95% CI 4.62 to 59.11). The 24-week absolute data showed that these treatment benefits were maintained. There was a significant improvement in patients' functional status as measured by the Health Assessment Questionnaire (HAQ) change from baseline at 24 weeks ( 0.33, p < 0.001). The open-label extension data showed that these beneficial effects were also maintained at 52 and 104 weeks. However, PASI 50 and PASI 90 at 14 weeks, and all of the PASI outcomes at 24 weeks, were not performed on the basis of intention-to-treat analysis. Furthermore, analyses of the 24-week data were less robust, failing to adjust for treatment contamination due to patient crossover at week 16. The manufacturer conducted a mixed treatment comparison (MTC) analysis. The ERG considered the assumption of exchangeability between the trials for the purpose of the MTC analysis to be acceptable, and the statistical approach in the MTC analysis to be reliable. Regarding the safety evaluation of golimumab, the manufacturer failed to provide longer-term data or to consider adverse event data of golimumab from controlled studies in other conditions, such as rheumatoid arthritis and ankylosing spondylitis. Although the adverse effect profile of golimumab appears similar to other anti-tumour necrosis factor (TNF) agents, the longer-term safety profile of golimumab remains uncertain. The manufacturer's submission presented a decision model to compare etanercept, infliximab, golimumab and adalimumab versus palliative care for patients with PsA. In the base-case model, 73% of the cohort of patients were assumed to have significant psoriasis (> 3% of body surface area). Estimates of the effectiveness of anti-TNF agents in terms of PsARC, HAQ change and PASI change were obtained from an MTC analysis of RCT data. The manufacturer failed to calculate incremental cost-effectiveness ratios (ICERs) correctly by comparing golimumab with palliative care instead of the most cost-effective alternative (etanercept). Despite the manufacturer's claim that golimumab is a cost-effective treatment option, the manufacturer's own model showed that golimumab is not cost-effective compared with other biologics when the ICERs are correctly calculated. None of the sensitivity analyses carried out by the manufacturer or the ERG regarding uncertainty in the estimates of clinical effectiveness, the acquisition and administration cost of drugs, the cost of treating psoriasis and the utility functions estimated to generate health outcomes changed this conclusion. However, a key area in determining the cost-effectiveness of anti-TNF agents is whether they should be treated as a class. If all anti-TNF agents are considered equally effective then etanercept, adalimumab and golimumab have very nearly equal costs and equal quality-adjusted life-years (QALYs), and all have an ICER of about L 15,000 per QALY versus palliative care, whereas infliximab with a higher acquisition cost is dominated by the other biologics. PMID- 21609658 TI - [When the father's environment influences gene expression in the child]. PMID- 21609659 TI - [Novel amygdala neuronal circuits controlling fear behavior]. PMID- 21609660 TI - [The myotubularin-desmin complex regulates mitochondria dynamics]. PMID- 21609661 TI - [Arginine and innate immune response]. PMID- 21609662 TI - [Microtubule polyglutamylation and neurodegeneration]. PMID- 21609663 TI - [Xeroderma pigmentosum: a useful model to study the relation between genomic mutations and cell transformation]. PMID- 21609664 TI - [Could we cure type 1 diabetes by stimulating T(reg)?]. PMID- 21609665 TI - [Thalassemia: therapeutic hopes carried by hepcidin]. PMID- 21609666 TI - [Epigenetic reprogramming: the importance of X inactivation]. PMID- 21609667 TI - [Hippo-YAP signaling pathway in the liver: more than a size gatekeeper!]. PMID- 21609668 TI - [A new type of non genetic eukaryotic circadian clock]. PMID- 21609669 TI - [DNA methylation, a key player in pluripotency]. PMID- 21609670 TI - [New oral anticoagulant drugs: dabigatran, rivaroxaban and apixaban. Present and future]. AB - For years, prevention and treatment of thromboembolic events have been restricted to the use of heparins and vitamin K antagonists. These treatments, in spite of their unquestioned efficacy, present numerous limits (hemorrhagic risk, need for regular laboratory controls). These limits call for the development of new antithrombotic drugs. This review briefly reports on three new molecules, in very advanced phases of clinical research: dabigatran (Pradaxa(r)), rivaroxaban (Xarelto(r)) and apixaban. These molecules represent new oral anticoagulants, which directly inhibit a coagulation factor (thrombin for dabigatran, factor Xa for rivaroxaban and apixaban) and do not need regular anticoagulant monitoring or dose adjustment. The approval is still restricted in France to the prophylaxis of venous thromboembolism in orthopaedics. Dabigratran will be soon available in the prevention of stroke in atrial fibrillation. With the forthcoming phase III studies to prevent and treat venous thromboembolism, anticoagulant therapy management will be most probably improved in the coming years. PMID- 21609671 TI - [Activated protein C, a protein at the crossroads between coagulation and inflammation]. AB - Sepsis is defined as a systemic response to infection, characterized by an intense inflammatory response linked to coagulation activation and fibrinolysis inhibition, two processes which are intimately associated. In a field where mortality remains very high, administration of activated protein C, a physiological coagulation inhibitor with cytoprotective properties, has demonstrated its effectiveness and was able to reduce mortality. Protein C belongs to a system that involves plasma proteins and endothelial cell receptors. In addition to well documented effects on coagulation and fibrinolysis, activated protein C exhibits anti-inflammatory, anti-apoptotic but also anti-histone activities. Indeed, a recent study focusing on the cytoprotective effects of activated protein C showed that extracellular histones are released during severe sepsis and may participate in the pathophysiology of severe sepsis. These histones appear to be new targets of activated protein C. PMID- 21609672 TI - [Emerging key role of cell cycle regulators in cell metabolism]. AB - The role of cell cycle regulators in the control of cell proliferation has been extensively studied, but independently of these functions in cell proliferation, it now appears that these proteins are also key to the adapted metabolic response of the cells. This has some logic since cell cycle is linked to metabolic control. This review focusses on the involvment of cyclins, cyclin dependent kinases or E2F factor in the control of adipogenesis, glucidic homeostasis, and energy consumption. Murine models in which genes encoding these regulators have been invalidated have been key to unravel these novel functions of cell cycle regulators in cell metabolism. Furthermore, these findings may also have some relevance for metabolic disorders such as obesity or diabetes. PMID- 21609673 TI - [Signaling and metabolic predispositions linked to the colorectal cancer]. AB - The setting up and the progression of the colorectal cancer (CCR) follow a sequence of events that are spatio-temporally rigorously orchestrated. The failures that specifically target the signaling pathways responsible for the cancerization of the colorectal mucosa have been well described and among these it seems that a dysregulation of the Wnt/beta-catenin pathway is involved in the triggering of near 90 % of the cases. It has been also described that several risk factors linked to metabolic disorders (feeding, insulin resistance, metabolic syndrome, etc.) predispose individuals to CCR but no rational explanations were given. We propose that, since it is implicated in the control of the insulin pathway among other actions, the nutritional sensor O GlcNAcylation may be the element linking these metabolic disorders to CCR. PMID- 21609674 TI - [Notch pathway: from development to regeneration of skeletal muscle]. AB - In vertebrates, skeletal muscle is derived from mesodermal structures called somites. Myogenic progenitor cells that form skeletal muscles of the trunk and limbs are derived from the dermomyotome, the dorsal region of the somite. These cells enter the myogenic program by activating a set of four myogenic regulatory factors. During embryonic and fetal growth, muscle progenitor cells provide the source for muscle growth. Around birth, the muscle progenitor enters quiescence, and adopts a satellite cell position on muscle fibers, providing a pool of adult muscle stem cells. They are essential for the growth and regeneration of muscles. Among the mechanisms that control the maintenance of satellite cells properties, the Notch pathway plays a crucial role. In facts, this pathway is implicated from the early steps of somitogenesis and the development of skeletal muscles in the embryo. Furthermore, during ageing, Notch activity decreases which results in decreased muscle regeneration. Thus, the Notch pathway is a key regulator of muscle plasticity. PMID- 21609675 TI - [Potential of cell penetrating peptides for cell drug delivery]. AB - The interest of the scientific community for cell penetrating peptides (CPP) has been growing exponentially for these last years, and the list of novel CPP is increasing. These peptides are powerful tools for the delivery of cargoes to their site of action. Indeed, several drugs that cannot translocate through the cell plasma membrane have been successfully delivered into cells when grafted to a CPP. Various cargoes have been linked to CPP, such as oligonucleotides, pharmacologically active drugs, contrast agents for imaging, or nanoparticles as platforms for multigrafting purposes... This review illustrates the fabulous potential of CPP and the diversity of their use, but their most interesting application appears their future clinical use for the treatment of various pathological conditions. PMID- 21609676 TI - [The neural impact of cognitive training]. AB - Tracing the connections from brain functions to education is a major goal of modern neuroscience. By providing insights into the abilities and constraints of the learning brain, neuroscience can help to explain why some learning environments work while others fail. The results presented here provide the first insights into neuropedagogy of reasoning. PMID- 21609677 TI - [Greatness and tribulations of Zeiss and Leitz, two famous German optic companies III. Zeiss Ikon and elimination of Emanuel Goldberg]. AB - Gathering archival documents to trace the history of the Zeiss company presents no difficulty : they are abundant... except for a period from 1932 to 1945, systematically ignored, and that corresponds to the Nazi period. On the website Zeiss Historica, among the outstanding personalities of the Zeiss company, we note that, for Professor Emanuel Goldberg, the web page " is still under development but an early picture of the professor is available. ". But fortunately, Mickael Buckland, a Professor at the UC Berkeley School of Information brought the life and the work of Emanuel Goldberg to light. Thanks to him, his works and innovations, who had disappeared from our cultural and scientific heritage, return to light after being erased during fifty years. Goldberg had published dozens of articles, obtained patents, developed cameras, microdots, movie cameras, and he designed what he called a "Statistical Machine ", the first electronic document retrieval machine. In France, if this rediscovery was made known to the world of information science, it has not had the impact it deserved in the scientific world. Therefore it is time to reconstruct his career and his work, and to analyse the reasons why some attempted to erase definitively his name and memory. PMID- 21609678 TI - [Imaging of single molecules in live cells]. AB - Progress in optical microscopy, combined to the emergence of new fluorescent probes and advanced instrumentation, now permits the imaging of single molecules in fixed and live cells. This extreme detection sensitivity has opened new modalities in cellular imaging. On the one hand, optical images with an unprecedented resolution in the 10-50 nm range, well below the diffraction limit of light, can be recorded. These super-resolution images give new insights into the properties of cellular structures. On the other hand, proteins, either in the membrane or intracellular, can be tracked in live cells and in physiological conditions. Their individual trajectories provide invaluable information on the molecular interactions that control their dynamics and their spatial organization. Single molecule imaging is rapidly becoming a unique tool to understand the biochemical and biophysical processes that determine the properties of molecular assemblies in a cellular context. PMID- 21609679 TI - [The real " personal genome " ?]. PMID- 21609681 TI - The SLAS inaugural strategic plan: a guide to strengthening and sustaining organizational achievement. PMID- 21609682 TI - A LEAN approach toward automated analysis and data processing of polymers using proton NMR spectroscopy. AB - To maximize utilization of expensive laboratory instruments and to make most effective use of skilled human resources, the entire chain of data processing, calculation, and reporting that is needed to transform raw NMR data into meaningful results was automated. The LEAN process improvement tools were used to identify non-value-added steps in the existing process. These steps were eliminated using an in-house developed software package, which allowed us to meet the key requirement of improving quality and reliability compared with the existing process while freeing up valuable human resources and increasing productivity. Reliability and quality were improved by the consistent data treatment as performed by the software and the uniform administration of results. Automating a single NMR spectrophotometer led to a reduction in operator time of 35%, doubling of the annual sample throughput from 1400 to 2800, and reducing the turn around time from 6 days to less than 2. PMID- 21609683 TI - Production of Candida antarctica lipase B gene open reading frame using automated PCR gene assembly protocol on robotic workcell and expression in an ethanologenic yeast for use as resin-bound biocatalyst in biodiesel production. AB - A synthetic Candida antarctica lipase B (CALB) gene open reading frame (ORF) for expression in yeast was constructed, and the lycotoxin-1 (Lyt-1) C3 variant gene ORF, potentially to improve the availability of the active enzyme at the surface of the yeast cell, was added in frame with the CALB ORF using an automated PCR assembly and DNA purification protocol on an integrated robotic workcell. Saccharomyces cerevisiae strains expressing CALB protein or CALB Lyt-1 fusion protein were first grown on 2% (w/v) glucose, producing 9.3 g/L ethanol during fermentation. The carbon source was switched to galactose for GAL1-driven expression, and the CALB and CALB Lyt-1 enzymes expressed were tested for fatty acid ethyl ester (biodiesel) production. The synthetic enzymes catalyzed the formation of fatty acid ethyl esters from ethanol and either corn or soybean oil. It was further demonstrated that a one-step-charging resin, specifically selected for binding to lipase, was capable of covalent attachment of the CALB Lyt-1 enzyme, and that the resin-bound enzyme catalyzed the production of biodiesel. High-level expression of lipase in an ethanologenic yeast strain has the potential to increase the profitability of an integrated biorefinery by combining bioethanol production with coproduction of a low-cost biocatalyst that converts corn oil to biodiesel. PMID- 21609684 TI - Automation and miniaturization of the bioluminescent UGT-Glo assay for screening of UDP-glucuronosyltransferase inhibition by various compounds. AB - The uridine 5'-diphospho-glucuronosyltransferase (UGT) family of enzymes is involved in the metabolism of various compounds. These enzymes transfer a hydrophilic glucuronic acid moiety to their substrates, rendering them more water soluble and amenable to excretion. The UGTs act on various endogenous substrates, such as bilirubin, 17beta-estradiol, and testosterone, and drugs and other xenobiotics. The function of these enzymes is essential for the clearance of drugs and toxicants, and alteration of UGT activity is a potential cause of adverse drug-drug interactions in vivo. This has stimulated an increased interest in the study of UGT function and inhibition, and the desire to profile new drug entities against UGT enzymes, similar to CYP450 profiling. However, certain factors have hindered the development of a robust method for UGT profiling. Current methods for assessing UGT enzyme activity are laborious and involve protein precipitation and/or chromatographic separation steps, which are not amenable to rapid screening applications for UGT inhibitors or substrates. The approach presented here is a bioluminescent assay for measuring UGT enzyme activity and inhibition in vitro. Using flexible, robust instrumentation in a 384 well microplate format, this study highlights the quick and easy assay implementation for estimation of inhibition kinetics with a variety of known and suspected UGT substrates and inhibitors. PMID- 21609685 TI - Automated luminescence-based cytochrome P450 profiling using a simple, elegant robotic platform. AB - The determination of inhibitory effects that lead compounds have on cytochrome P450 (CYP) enzymes is an important part of today's drug discovery process. Assays can be performed early in the discovery process to predict adverse drug-drug interactions caused by CYP inhibition and to minimize the costs associated with terminating candidates in late stage development or worse, removing a drug from the market after launch. For early discovery work, testing substantial numbers of compounds is desirable, thus automated "mix and read" assays are beneficial. Here, we demonstrate the automation of the CYP profiling process using a simple, yet robust robotic platform. Compound titration, as well as transfer of compounds and assay components was performed by the same automated pipetting system. IC(50)s of small molecule drugs were determined using recombinant CYP enzymes, CYP3A4, -2C9, and -2D6 and luminogenic substrates specific to each. Compounds were profiled against all three enzymes on the same 384-well assay plate. PMID- 21609686 TI - Development and validation of a higher-throughput equilibrium dialysis assay for plasma protein binding. AB - We describe the practical aspects of developing a semiautomated, higher throughput plasma protein binding (PPB) assay. The assay has a capacity of 32 PPB measurements per screen using triplicate incubations per measurement, and it is flexible with respect to the number of compounds and the number of plasma types used. The described method is based on the 48-well format rapid equilibrium dialysis (RED) device in combination with a robotic liquid handling platform and quantitative bioanalysis. The RED device method was optimized with respect to equilibration time. Method validation was performed by comparison of results from the semiautomated RED PPB assay with both of those obtained using an alternative, manual equilibrium dialysis method and with literature values. Propranolol and warfarin were used as control compounds. We have modeled the effect of dialysis membrane leakage on the measured unbound fraction and implemented a test for measuring protein content in the buffer compartment to confirm the integrity of each insert of the RED device. With the described method, it is possible to screen a relatively large number of compounds for PPB in a drug discovery environment. PMID- 21609687 TI - A microdevice for the mixing of a highly viscous biosample with water/membrane protein solution using microchannel and centrifugation. AB - A mechanism for controlling the mixing of highly viscous biosamples at the microliter scale is presented. Existing methods for mixing biosamples using microstirrers or shaking microwells are only effective for non-highly viscous materials. The proposed mechanism mixes monoolein, a highly viscous biosample, with water/membrane protein solution in a microdevice called microcapsule using a microchannel and centrifugation. To achieve effective mixing, the design of the microcapsule along with the microchannel is presented and so is the hydrodynamic model describing the flow of viscous materials in the microchannel. The mixing process is analyzed according to the Reynolds number of the biosamples using computer simulation, which is observed during the experiment using digital images for further analysis. Finally, the new approach is verified by X-ray diffraction experiments with water and the Rh membrane protein solution, which are used to evaluate the effectiveness of mixing. Experimental results not only validate the proposed method but also determine the flow oscillation time in the microchannel to achieve effective and efficient mixing. PMID- 21609688 TI - LINA: a laboratory inventory system for oligonucleotides, microbial strains, and cell lines. AB - In this article, we present the Laboratory Inventory Network Application (LINA), a software system that assists research laboratories in keeping track of their collections of biologically relevant materials. This open source application uses relational Microsoft Access database technology as a back end and a Microsoft .NET application as a front end. Preconstructed table templates are provided that contain standardized and customizable data fields. As new samples are added to the inventory, each is provided with a unique laboratory identifier, which is assigned automatically and sequentially, allowing rapid retrieval when a given reagent is required. The LINA contains a number of useful search tools including a general search, which allows database searches using up to four user-defined criteria. The LINA represents an easily implemented and useful organizational tool for biological laboratories with large numbers of strains, clones, or other reagents. PMID- 21609689 TI - A review of electronic laboratory notebooks available in the market today. AB - Electronic laboratory notebooks are becoming an increasingly popular tool for research and routine laboratories as part of a way to optimize workflow and minimize cost while realizing time-saving benefits. The number and variety of available solutions are quickly increasing; making selection of the right notebook a cumbersome process. To allay some of the strain associated with an exhaustive search through notebook technologies, this paper details some key features from a pool of 35 electronic notebooks available today. This review effectively classifies these notebooks into five categories based on market audience as follows: notebooks suited for a Quality environment can be found within the Quality Assurance/Quality Control pool. Notebooks suited for specialized tasks in Biology or Chemistry can be found within the Biology or Chemistry pools, respectively. Notebooks that are suitable for general science functionalities can be found under either the Research and Development or the Multidiscipline pools. Lastly, notebooks that are designed and developed for the spectrum of stringent Quality laboratories to free-form research laboratories can be found within the Multidiscipline pool. The guidelines put forth in this paper eliminate the need to perform an exhaustive search for a suitable notebook. PMID- 21609691 TI - Image-based fluidic sorting system for automated Zebrafish egg sorting into multiwell plates. AB - The global demand for the reduction of animal testing has led to the emergence of Zebrafish eggs/larvae as model organisms to replace current adult animal testing in, for example, toxicity testing. Because of the egg size (diameter 1.6mm) and the relatively easy maintenance of Zebrafish farms the eggs also offer high throughput screening (HTS). However, the current bottleneck for HTS is the cost efficient placing of individual organisms into single wells of a multiwell plate (MWP). The system presented here is capable of storing, sorting, and placing individual organisms in a highly reproducible manner. In about 11 min a complete 96-MWP is filled, which corresponds to about 8 sec per egg. The survival rate of fertilized transgenic and wild-type eggs was comparable to the one of the control (control 6.7%, system 7.6%). Furthermore, it was also possible to place dechorionated eggs into individual wells. The results demonstrate that the cost efficient system works gentle and reliable enough to disburden scientists from the exhausting and monotonous job of placing single eggs into single wells, such that they can concentrate on the scientific aspects of their experiments and create results with a higher statistical relevance. PMID- 21609692 TI - Automated scanning probe lithography with n-alkanethiol self-assembled monolayers on Au(111): application for teaching undergraduate laboratories. AB - Controllers for scanning probe instruments can be programmed for automated lithography to generate desired surface arrangements of nanopatterns of organic thin films, such as n-alkanethiol self-assembled monolayers (SAMs). In this report, atomic force microscopy (AFM) methods of lithography known as nanoshaving and nanografting are used to write nanopatterns within organic thin films. Commercial instruments provide software to control the length, direction, speed, and applied force of the scanning motion of the tip. For nanoshaving, higher forces are applied to an AFM tip to selectively remove regions of the matrix monolayer, exposing bare areas of the gold substrate. Nanografting is accomplished by force-induced displacement of molecules of a matrix SAM, followed immediately by the surface self-assembly of n-alkanethiol molecules from solution. Advancements in AFM automation enable rapid protocols for nanolithography, which can be accomplished within the tight time restraints of undergraduate laboratories. Example experiments with scanning probe lithography will be described in this report that were accomplished by undergraduate students during laboratory course activities and research internships in the chemistry department of Louisiana State University. Students were introduced to principles of surface analysis and gained "hands-on" experience with nanoscale chemistry. PMID- 21609693 TI - NanoProbeArrays for the analysis of ultra-low-volume protein samples using piezoelectric liquid dispensing technology. AB - Antibody microarrays are gaining popularity as a high-throughput technology to investigate the proteome. However, protein extracts from most body fluid or biopsy samples are available in very small volumes and are often unsuitable for large-scale antibody microarray studies. To demonstrate the potential for protein analysis with as little as a few nanoliters of sample, we have developed a new technology called NanoProbeArrays based on piezoelectric liquid dispensing for non-contact printing and probing of antibody arrays. Instead of flooding the protein sample on the antibody microarray surface, as in conventional microarray screening, a piezoelectric inkjet printer is used to dispense nanoliters of fluorescently labeled proteins over the antibody spots on the array. The ability of NanoProbeArrays to precisely identify and reliably distinguish between test proteins from different sources, without any loss of sensitivity and specificity as compared with conventional antibody microarrays, is illustrated here. The utility of NanoProbeArrays for biomarker identification in a complex biological sample was tested by detecting the cytokine interleukin-4 in serum. The significant reduction in volume of sample during NanoProbeArray analysis, as compared with conventional antibody microarrays, offers new opportunities for basic and applied proteomic research. PMID- 21609694 TI - Automated extraction of DNA from blood and PCR setup using a Tecan Freedom EVO liquid handler for forensic genetic STR typing of reference samples. AB - We have implemented and validated automated protocols for DNA extraction and PCR setup using a Tecan Freedom EVO liquid handler mounted with the Te-MagS magnetic separation device (Tecan, Mannedorf, Switzerland). The protocols were validated for accredited forensic genetic work according to ISO 17025 using the Qiagen MagAttract DNA Mini M48 kit (Qiagen GmbH, Hilden, Germany) from fresh whole blood and blood from deceased individuals. The workflow was simplified by returning the DNA extracts to the original tubes minimizing the risk of misplacing samples. The tubes that originally contained the samples were washed with MilliQ water before the return of the DNA extracts. The PCR was setup in 96-well microtiter plates. The methods were validated for the kits: AmpFlSTR Identifiler, SGM Plus and Yfiler (Applied Biosystems, Foster City, CA), GenePrint FFFL and PowerPlex Y (Promega, Madison, WI). The automated protocols allowed for extraction and addition of PCR master mix of 96 samples within 3.5h. In conclusion, we demonstrated that (1) DNA extraction with magnetic beads and (2) PCR setup for accredited, forensic genetic short tandem repeat typing can be implemented on a simple automated liquid handler leading to the reduction of manual work, and increased quality and throughput. PMID- 21609695 TI - Development of an automated platform for high-throughput P1-phage transduction of Escherichia coli. AB - Synthetic biology depends on the ability to rapidly produce strains with improved phenotypes but is limited by the ability to rapidly produce strain collections with directed mutations. Here, we present a system capable of overcoming this limitation through automated P1-phage transductions of Escherichia coli. By combining the Keio collection of single-gene deletion E. coli mutants with P1 phage, it is possible to generate an engineered host-strain collection consisting of every possible gene deletion mutant. This strategy was tested by transducing 355 genetic markers from the Keio collection into five different host strains, and it achieved a 98% success rate. This method offers an improved mechanism for rapidly engineering collections of microbes and provides one method for rapidly deploying a broader synthetic biology effort. PMID- 21609696 TI - Using well-plate microfluidic devices to conduct shear-based thrombosis assays. AB - Shear stress plays a critical role in regulating platelet adhesion and thrombus formation at the site of vascular injury. As such, platelets are often examined in vitro under controlled shear flow conditions for their hemostatic and thrombotic functions. Common shear-based platelet analyses include the evaluation of genetic mutants, inhibitory or experimental compounds, matrix substrates, and the effects of different physiological and pathological shear forces. There are several laboratory instruments widely used for studying shear flow, including cone and plate viscometers and parallel plate perfusion chambers. These technologies vary widely in the types of samples, substrates, blood volumes, and throughput that are involved. Here, we describe a microfluidic system for platelet analysis under shear flow. We used the devices to study thrombus formation on collagen I and von Willebrand factor. The system was also used to investigate dose response to the antiplatelet compound, Abciximab, under shear flow conditions with an emphasis on maximizing the number of data points per single patient sample. The presented method confers multiple advantages over conventional approaches. These include the ability to assess up to 24 conditions simultaneously in real time, maintain identical physical conditions across experiments, and use extremely low donor volumes. PMID- 21609697 TI - Evaluation of a sugar-based edible adhesive using a tensile strength tester. AB - A method to evaluate adhesives has been developed and used to reformulate a recently patented adhesive which is based on sugar and citric acid. Factors affecting adhesive performance were uncovered, such as an optimal curing temperature of 60 degrees C. The addition of maltodextrin and soy protein at optimized levels was shown to nearly double the bonding strength of the adhesive, from 0.46 +/- 0.076 to 0.74 +/- 0.26 kN, under our test conditions. Also discussed is the potential for this method to be automated using commercially available equipment. PMID- 21609698 TI - Automated immunomagnetic processing and separation of Legionella pneumophila with manual detection by sandwich ELISA and PCR amplification of the ompS gene. AB - The culture-independent and automated detection of bacteria in the environment is a scientific and technological challenge. For detection alone, a number of sensitive methods are known (e.g., PCR, enzyme-linked immunosorbent assay [ELISA], fluorescent in situ hybridization) but a major problem remaining is the enrichment and separation of the bacteria that usually occur at low concentrations. Here, we present an automated capturing and separation system, which can easily be combined with one of the sensitive detection techniques. We have developed a method for enrichment and detection of Legionella pneumophila in liquid media. Concentrated microorganisms were either detected by PCR or by sandwich ELISA. The limit of detection with the immunological assay was about 750 bacteria. Using PCR, the equivalent of about 2000 genomes could be detected. The assays were then transferred to a laboratory prototype for automated processing. It was possible to automatically enrich L. pneumophila by immunomagnetic separation (IMS), and again, the bacteria were detected by sandwich ELISA and PCR amplification of the ompS gene. As a novel aspect, ompS gene was used for the first time as a target for the detection of L. pneumophila on magnetic beads. The aim of this work was to develop an automated procedure and a device for IMS of bacteria. With Legionella as a model organism, we could show that such a novel fully automated system can be an alternative to time-consuming conventional cultivation methods for detecting bacteria or other microorganisms. PMID- 21609701 TI - Fully automated microinjection system for Xenopus laevis oocytes with integrated sorting and collection. AB - Microinjection is the most flexible transfection method in terms of choice of reagents to inject into cells. But this method lacks the high throughput to compete with less flexible methods like chemical- or viral-based approaches. Various approaches have been pursued to increase the throughput by automating the microinjection process. However, these approaches focused solely on the microinjection itself and disregarded the tasks before and after the injection, which also belong to the critical time path of the whole process, that is, sorting out viable cells from a cell suspension, placing the cell for injection, and collecting the cell after the injection. In the approach with our XenoFactor, we demonstrate a system capable of running the whole process automatically. By optimizing the XenoFactor for Xenopus laevis oocytes, we could demonstrate the successful automated injection. Starting from a suspension with a mixture of defolliculated oocytes at different stages and quality levels, the manual approach requires 1 day in total for the preparation of 400 microinjected oocytes. The XenoFactor takes only 4h for the same amount and delivers injected oocytes of reproducible quality and without the fatigue symptoms experienced during the manual approach. PMID- 21609700 TI - Automation of three-dimensional cell culture in arrayed microfluidic devices. AB - The increasing interest in studying the interactions between cells and the extracellular matrix (ECM) has created a need for high throughput low-cost three dimensional (3D) culture systems. The recent development of tubeless microfluidics via passive pumping provides a high throughput microchannel culture platform compatible with existing high throughput infrastructures (e.g., automated liquid handlers). Here, we build on a previously reported high throughput two-dimensional system to create a robust automated system for 3D culture. Operational controls including temperature and sample handling have been characterized and automated. Human mammary fibroblasts (HMFs) suspended in type I collagen are loaded and cultured in microchannel arrays and used to optimize the system operational parameters. A Peltier cooler maintains the collagen as a liquid at 4 degrees C during cell seeding, followed by polymerization at 37 degrees C. Optimization of this platform is discussed (e.g., controlling collagen contraction, increasing cell viability, preventing the removal of microchannel contents), and 3D distribution of HMFs is examined by fluorescent microscopy. Finally, we validate the platform by automating a previously developed 3D breast carcinoma coculture assay. The platform allows more efficient 3D culture experiments and lays the foundation for high throughput studies of cell-ECM interactions. PMID- 21609702 TI - Monitoring of HTS compound library quality via a high-resolution image acquisition and processing instrument. AB - This report presents the high-resolution image acquisition and processing instrument for compound management applications (HIAPI-CM). The HIAPI-CM combines imaging spectroscopy and machine-vision analysis to perform rapid assessment of high-throughput screening (HTS) compound library quality. It has been customized to detect and classify typical artifacts found in HTS compound library microtiter plates (MTPs). These artifacts include (1) insufficient volume of liquid compound sample, (2) compound precipitation, and (3) colored compounds that interfere with HTS assay detection format readout. The HIAPI-CM is also configured to automatically query and compare its analysis results to data stored in a LIMS or corporate database, aiding in the detection of compound registration errors. To demonstrate its capabilities, several compound plates (n=5760 wells total) containing different artifacts were measured via automated HIAPI-CM analysis, and results compared with those obtained by manual (visual) inspection. In all cases, the instrument demonstrated high fidelity (99.8% empty wells; 100.1% filled wells; 94.4% for partially filled wells; 94.0% for wells containing colored compounds), and in the case of precipitate detection, the HIAPI-CM results significantly exceeded the fidelity of visual observations (220.0%). As described, the HIAPI-CM allows for noninvasive, nondestructive MTP assessment with a diagnostic throughput of about 1min per plate, reducing analytical expenses and improving the quality and stewardship of HTS compound libraries. PMID- 21609703 TI - Development of a novel automated cell isolation, expansion, and characterization platform. AB - Implementation of regenerative medicine in the clinical setting requires not only biological inventions, but also the development of reproducible and safe method for cell isolation and expansion. As the currently used manual techniques do not fulfill these requirements, there is a clear need to develop an adequate robotic platform for automated, large-scale production of cells or cell-based products. Here, we demonstrate an automated liquid-handling cell-culture platform that can be used to isolate, expand, and characterize human primary cells (e.g., from intervertebral disc tissue) with results that are comparable to the manual procedure. Specifically, no differences could be observed for cell yield, viability, aggregation rate, growth rate, and phenotype. Importantly, all steps from the enzymatic isolation of cells through the biopsy to the final quality control-can be performed completely by the automated system because of novel tools that were incorporated into the platform. This automated cell-culture platform can therefore replace entirely manual processes in areas that require high throughput while maintaining stability and safety, such as clinical or industrial settings. PMID- 21609704 TI - The 104-well microplate. AB - The 96-well microplate is a ubiquitous tool in the laboratory; its use is so extensive that in a limited number of situations it can be restrictive. Consider the situation where 96 samples need analysis or a downstream process in which the 96-well format leaves no space for additional standards or controls in the upstream 96-well processing. Consequently, plates are split or sample number reduced thereby incurring additional cost for plates, reagents, standards, controls, sample tracking, data files, and time to analyze the entire plate. A simple solution is proposed with the development of a companion 8 * 13-array microplate. The 104-well microplate was developed within the American National Standards Institute/Society for Biomolecular Science standards as to plate geometry and dimension, including well spacing (9 mm) with the exception that the columns have been shifted 4.5mm to the left to accommodate the 13th column. The extra column allows for additional standards/controls without modifying chemistry, incorporating additional plates or changing to a 384-well plate. We show negligible difference (-0.0003 optical density) when comparing mean absorbance readings in 96- and 104-well format. We demonstrate use of the 104 well plate in a 96-well environment by incorporating it in an enzyme-linked immunosorbent assay on a standard liquid handler. Results from the assay show no difference between formats (y=1.039x-0.004, r=0.997). Although the 104 plate was not created to supplant the 96-well standard, we conclude that the 104 plate can be incorporated into the 96-well environment without significant change in existing systems. PMID- 21609705 TI - Adding precise nanoliter volume capabilities to liquid-handling automation for compound screening experimentation. AB - Miniaturizing experimental sample volumes to the nanoliter volume range is one of the most economical ways to perform mid- and high-throughput compound screening experiments. Existing automation platforms for nanoliter fluid handling can be bulky, expensive, and require periodic calibration to provide consistent liquid dispensing. In addition, even with frequent calibration, significant instrument to-instrument variation in low-volume dispensing can occur between different instrument platforms. Many of these issues can be addressed by the use of PocketTips. PocketTips are tips with a defined internal pocket designed to hold specific nanoliter volumes of compound dissolved in dimethylsulfoxide. Although the overall liquid-handling process with PocketTips uses the aspirate/dispense features of the specific liquid-handling device being used, the dispensed nanoliter volume is solely based on the dimensions of the pocket of the PocketTip and thus, the liquid-handling device itself need not have nanoliter dispensing capabilities. In this report, we demonstrate the performance of PocketTips on different automation platforms. In addition, we used a cell-based beta-lactamase reporter assay system to demonstrate that compound delivery by PocketTips compares favorably with a standard compound addition technique. PMID- 21609706 TI - Expanding the application of the tablet processing workstation to support the sample preparation of oral suspensions. AB - Sample preparation is the most time-consuming part of the analytical method for powder for oral suspension (POS) assay, purity, and preservative analysis, as this involves multiple dilution and filtration steps. The Tablet Processing Workstation (TPW) was used to automate the sample preparation of a POS formulation. Although the TPW is typically used to automate the preparation of solid oral dosage forms and powders, it contains all of the necessary components to perform POS sample preparation. The TPW exhibited acceptable repeatability in testing 3 lots using 10 replicate preparations per lot. Acceptable linearity of the drug and preservative in the presence of excipients was demonstrated over the range corresponding to 50-150% of intent. Accuracy showed suitable recoveries for all points evaluated. TPW results were shown to correlate to results obtained with the manual method. The TPW method was used to prepare samples in support of manufacturing scale-up efforts. With the efficiencies gained using the TPW, it was possible to analyze a large number of samples generated during process development activities for the POS formulation with minimal human intervention. The extensive data enabled trending of the manufacturing development runs and helped to identify optimization strategies for the process. PMID- 21609707 TI - An inline QC method for determining serial dilution performance of DMSO-based systems. AB - Serial dilution of compounds solubilized in dimethylsulfoxide (DMSO) for dose response curves is a common method for efficacy analysis of potential drug candidates. In general, serial dilution methods are particularly prone to error propagation because each dilution is dependent on the previous concentration. Moreover, assumptions about quality control parameters (i.e., dye linearity) can lead to an erroneous process. Here, an inline performance measurement is sought to improve the precision and accuracy of dilution plates. Sulforhodamine 101 (S101) dye is introduced as the quantitative fluorometric method of choice for DMSO-based systems. Although S101 in DMSO behaves in a nonlinear fashion over its detectable range, we account for this with a direct calibration method that includes every point of the dilution template. This report contains dye selection rationale for the S101 dye and its use in quantifying the performance of 96- and 384-well dilution protocols as tested on five identical instruments. PMID- 21609708 TI - Evaluation of a new preparative supercritical fluid chromatography system for compound library purification: the TharSFC SFC-MS Prep-100 system. AB - Preparative HPLC-MS is often the method of choice for purification of small amounts (<100mg) of diverse new molecules, such as compound libraries for drug discovery. The method is robust, well proven, and widely applicable. In contrast, preparative supercritical fluid chromatography coupled with mass spectrometry (SFC-MS) has seen only slow acceptance for the same application--despite some potential scientific and economic advantages. One of the reasons for slow adoption of SFC-MS is the lack of well-proven, robust, and commercially available instrumentation. In early 2009, TharSFC (a Waters Company, Pittsburgh, PA) introduced a new fully integrated system for preparative SFC-MS: The SFC-MS Prep 100. We report herein an objective evaluation of the SFC-MS Prep-100, including tests for pump and autosampler performance, sample recovery, sample carryover, fraction triggering, detector/fraction collector synchronization, and overall robustness. Our results suggest that the SFC-MS Prep-100 represents a significant advance over previous generation instrumentation. PMID- 21609709 TI - IgG subclass antibodies to three variants of Plasmodium falciparum merozoite surface protein-1 (PfMSP-1(19)) in an area with unstable malaria transmission in Iran. AB - Plasmodium falciparum remains globally an important cause of mortality and morbidity and despite decades of research, no effective vaccine is available against this deadly parasite. The 19-kDa C-terminal fragment of P. falciparum merozoite surface protein 1 (PfMSP-1(19)) is a target for protective immunity against malaria and the major concern in development of vaccine based on this antigen is the presence of polymorphisms. This investigation was designed to evaluate naturally acquired antibodies and antigen-binding avidity of IgG antibodies to three variant forms of PfMSP-1(19) antigen (E/TSG/L, E/KNG/F and Q/KNG/L) in malaria individuals who are living in hypoendemic areas in Iran (n=92, 4-75 years old). The three variant forms of PfMSP-1(19) were expressed in Escherichia coli and IgG isotype composition and avidity of naturally acquired antibodies to the 19-kDa antigen were measured by ELISA assay. Results showed that almost 72% of the studied individuals had positive antibody responses to three PfMSP-1(19) variants and the prevalence of responders did not differ significantly (P>0.05). High-avidity IgG (62.7%, 65.7% and 47.76%) and IgG1 (64.2%, 50.75%, and 50.75%) were found in positive sera for E/TSG/L, E/KNG/F and Q/KNG/L variants, respectively. Moreover, the prevalence and titers of IgG1 antibody responses to the three variants increased with age (P<0.05). In summary, individuals in low transmission areas in Iran can develop and maintain equal immune responses with high avidity to the PfMSP-1(19) variants (E/TSG/L, E/KNG/F and Q/KNG/L); however, the precise role of the total IgG and its isotypes in protection requires further investigation. These results could support the design of a universal PfMSP-1(19)-based vaccine. PMID- 21609710 TI - Ultra sensitive quantitation of endogenous oxytocin in rat and human plasma using a two-dimensional liquid chromatography-tandem mass spectrometry assay. AB - Oxytocin (OT) is a neuropeptide with an extremely low endogenous level (low pg/ml) in human plasma. It is very challenging to develop a highly sensitive assay to measure endogenous OT, including radioimmunoassay (RIA) and enzyme linked immunosorbent assay (ELISA). Electrospray ionization (ESI) liquid chromatography-tandem mass spectrometry (LC-MS/MS) can provide high-throughput and selective methods for quantification of peptides in biological samples. A novel and highly sensitive two-dimensional LC-MS/MS (2D-LC-MS/MS) assay combining solid-phase extraction (SPE) has been developed and validated for the determination of endogenous OT in both human and rat plasma. The lower limit of quantification (LLOQ) was 1.00 pg/ml for human and 50.0 pg/ml for rat. Human plasma diluted with water (1:6, v/v) was successfully optimized as a surrogate matrix for human to prepare standard curves without endogenous interference. The extraction efficiency and absolute recovery were above 65.8% using the HLB SPE procedure, and matrix effects were lower than 12%. The method was validated in the range of 1.00-250 pg/ml for human plasma and 50.0-10,000 pg/ml for rat plasma with precision less than 12.7% and accuracy less than 7%. PMID- 21609711 TI - Monitoring triplex DNA formation with fluorescence resonance energy transfer between a fluorophore-labeled probe and intercalating dyes. AB - Triplex-forming oligonucleotides (TFOs) are sequence-dependent DNA binders that may be useful for DNA targeting and detection. A sensitive and convenient method to monitor triplex formation by a TFO and its target DNA duplex is required for the application of TFO probes. Here we describe a novel design by which triplex formation can be monitored homogeneously without prelabeling the target duplex. The design uses a TFO probe tagged with a fluorophore that undergoes fluorescence resonance energy transfer with fluorescent dyes that intercalate into the target duplex. Through color compensation analysis, the specific emission of the TFO probe reveals the status of the triple helices. We used this method to show that triple helix formation with TFOs is magnesium dependent. We also demonstrated that the TFO probe can be used for detection of sequence variation in melting analysis and for DNA quantitation in real-time polymerase chain reaction. PMID- 21609712 TI - Time-resolved single-turnover of caa(3) oxidase from Thermus thermophilus. Fifth electron of the fully reduced enzyme converts O(H) into E(H) state. AB - The oxidative part of the catalytic cycle of the caa(3)-type cytochrome c oxidase from Thermus thermophilus was followed by time-resolved optical spectroscopy. Rate constants, chemical nature and the spectral properties of the catalytic cycle intermediates (Compounds A, P, F) reproduce generally the features typical for the aa(3)-type oxidases with some distinctive peculiarities caused by the presence of an additional 5-th redox-center-a heme center of the covalently bound cytochrome c. Compound A was formed with significantly smaller yield compared to aa(3) oxidases in general and to ba(3) oxidase from the same organism. Two electrons, equilibrated between three input redox-centers: heme a, Cu(A) and heme c are transferred in a single transition to the binuclear center during reduction of the compound F, converting the binuclear center through the highly reactive O(H) state into the final product of the reaction-E(H) (one-electron reduced) state of the catalytic site. In contrast to previous works on the caa(3)-type enzymes, we concluded that the finally produced E(H) state of caa(3) oxidase is characterized by the localization of the fifth electron in the binuclear center, similar to the O(H)->E(H) transition of the aa(3)-type oxidases. So, the fully reduced caa(3) oxidase is competent in rapid electron transfer from the input redox-centers into the catalytic heme-copper site. PMID- 21609713 TI - Quantum dots-based double-color imaging of HER2 positive breast cancer invasion. AB - It has been well recognized that human epidermal growth factor receptor 2 (HER2) level in breast cancer (BC) is closely related to the malignant biologic behaviors of the tumor, including invasion and metastasis. Yet, there has been a lack of directly observable evidence to support such notion. Here we report a quantum dots (QDs)-based double-color imaging technique to simultaneously show the HER2 level on BC cells and the type IV collagen in the tumor matrix. In benign breast tumor, the type IV collagen was intact. With the increasing of HER2 expression level, there has been a progressive decrease in type IV collagen around the cancer nest. At HER2 (3+) expression level, there has virtually been a total destruction of type IV collagen. Moreover, HER2 (3+) BC cells also show direct invasion into the blood vessels. This novel imaging method provides direct observable evidence to support the theory that the HER2 expression level is directly related to BC invasion. PMID- 21609714 TI - Solution structure of a human minimembrane protein Ost4, a subunit of the oligosaccharyltransferase complex. AB - Oligosaccharyltransferase (OST) is a membrane associated enzyme complex that mediates transfer of an oligosaccharide onto asparagine residue of a protein. Human Ost4 is a small membrane protein and belongs to one of the seven subunits of human OST. This study determined the solution structure of human Ost4 in solvent system using NMR spectroscopy. Ost4 was demonstrated that the residues 5 30 adopt an alpha-helical structure. A kink structure was observed in the transmembrane domain, which may be important for its function. PMID- 21609715 TI - Characterizing functional alpha6beta2 nicotinic acetylcholine receptors in vitro: mutant beta2 subunits improve membrane expression, and fluorescent proteins reveal responsive cells. AB - alpha6* nicotinic acetylcholine receptors (nAChRs) are highly expressed in mesostriatal and nigrostriatal dopaminergic systems, and participate in motor control, reward, and learning and memory. In vitro functional expression of alpha6* nAChRs is essential for full pharmacological characterization of these receptors and for drug screening, but has been challenging. We expressed eGFP tagged-alpha6 and beta2 nAChR subunits in Neuro-2a cells, leading to functional channels. Inward currents were elicited with 300 MUM ACh in 26% (5/19) of cells with evenly expressed alpha6-eGFP in cytoplasm and periphery. We dramatically increased chances of detecting functional alpha6-eGFPbeta2 nAChRs by (i) introducing two endoplasmic reticulum (ER) export-enhancing mutations into beta2 subunits, and (ii) choosing cells with abundant Sec24D-mCherry-labeled ER exit sites. Both manipulations also modestly increased alpha6-eGFPbeta2 nAChR current amplitude. alpha6-eGFPbeta2 nAChRs were also activated by nicotine and by TC 2403. The alpha6-eGFPbeta2 currents were desensitized by 1MUM nicotine, blocked by alpha-conotoxin MII, partially inhibited by dihydro-beta-erythroidine, and potentiated by extracellular Ca(2+). Single-channel recordings showed that alpha6 eGFPbeta2 nAChRs had similar single-channel conductance to, but longer open time than, alpha4-eGFPbeta2 nAChRs. These methods provide avenues for developing cell lines expressing subtypes of alpha6* nAChRs for both pharmacological study and drug screening. PMID- 21609717 TI - MicroRNA-98 negatively regulates IL-10 production and endotoxin tolerance in macrophages after LPS stimulation. AB - Interleukin 10 (IL-10) is a potent anti-inflammatory cytokine that is crucial for dampening the inflammatory response after pathogen invasion, and was found to be produced by macrophages after exposure to lipopolysaccharide (LPS). It remains unclear whether microRNA-mediated regulatory mechanism is involved in LPS-induced IL-10 production. Here we reported that miR-98 expression in macrophages significantly decreased following LPS stimulation. We also found that miR-98 targets the 3'untranslated region of IL-10 transcript. Overexpression of miR-98 inhibited TLR4-triggered IL-10 production and promoted COX-2 expression. We further demonstrated that miR-98 significantly mitigated the induction of endotoxin tolerance, suggesting that miR-98-mediated posttranscriptional control could potentially be involved in fine tuning the critical level of IL-10 production in endotoxin tolerance. PMID- 21609716 TI - Intracellular colocalization of HAP1/STBs with steroid hormone receptors and its enhancement by a proteasome inhibitor. AB - The stigmoid body (STB) is a cytoplasmic inclusion containing huntingtin associated protein 1 (HAP1), and HAP1/STB formation is induced by transfection of the HAP1 gene into cultured cells. In the present study, we examined the intracellular colocalization of HAP1/STBs with steroid hormone receptors (SHRs), including the androgen receptor (AR), estrogen receptor, glucocorticoid receptor (GR), and mineralocorticoid receptor, in COS-7 cells cotransfected with HAP1 and each receptor. We found that C-terminal ligand-binding domains of all SHRs had potential for colocalization with HAP1/STBs, whereas only AR and GR were clearly colocalized with HAP1/STBs when each full-length SHR was coexpressed with HAP1. In addition, it appeared that HAP1/STBs did not disrupt GR and AR functions because the receptors on HAP1/STBs maintained nuclear translocation activity in response to their specific ligands. When the cells were treated with a proteasome inhibitor, GR and AR localized outside HAP1/STBs translocated into the nucleus, whereas the receptors colocalized with HAP1/STBs persisted in their colocalization even after treatment with their ligands. Therefore, HAP1/STBs may be involved in cytoplasmic modifications of the nuclear translocation of GR and AR in a ubiquitin-proteasome system. PMID- 21609718 TI - Double mutant MBP refolds at same rate in free solution as inside the GroEL/GroES chaperonin chamber when aggregation in free solution is prevented. AB - Under "permissive" conditions at 25 degrees C, the chaperonin substrate protein DM-MBP refolds 5-10 times more rapidly in the GroEL/GroES folding chamber than in free solution. This has been suggested to indicate that the chaperonin accelerates polypeptide folding by entropic effects of close confinement. Here, using native-purified DM-MBP, we show that the different rates of refolding are due to reversible aggregation of DM-MBP while folding free in solution, slowing its kinetics of renaturation: the protein exhibited concentration-dependent refolding in solution, with aggregation directly observed by dynamic light scattering. When refolded in chloride-free buffer, however, dynamic light scattering was eliminated, refolding became concentration-independent, and the rate of refolding became the same as that in GroEL/GroES. The GroEL/GroES chamber thus appears to function passively toward DM-MBP. PMID- 21609719 TI - p90 ribosomal S6 kinase regulates activity of the renin-angiotensin system: a pathogenic mechanism for ischemia-reperfusion injury. AB - Increasing evidence suggests that local renin-angiotensin system (RAS) plays an important role in cardiac diseases. Elevated p90 ribosomal S6 kinase (RSK) activity has been observed in diabetic animal, as well as in human failing hearts. We hypothesize that RSK mediates cardiac dysfunction by up regulating local RAS signaling. In the present study, we show that the prorenin mRNA level was significantly increased (~5.6-fold) in transgenic mouse hearts with cardiac specific expression of RSK (RSK-Tg). The RSK-Tg mice were more vulnerable to ischemia/reperfusion (I/R) injury than non-transgenic littermate controls (NLC). To further understand the direct contribution of cardiac renin to I/R injury, we used a Langendorff system to evaluate the effect of renin inhibition by aliskiren in RSK-Tg mouse hearts. In the vehicle-perfused group, I/R significantly decreased left ventricular developed pressure (LVDP) in RSK-Tg hearts compared to NLC (7% versus 60% of the baseline). However, aliskiren perfusion significantly increased LVDP in RSK-Tg (7% to 61%, p<0.01) but not in NLC hearts (60% to 62%, n.s.). The protective effect of aliskiren in RSK-Tg hearts was further demonstrated with positive (contraction) dp/dt (6.5% to 63%, p<0.01) and rate pressure product (RPP) (5% to 51%, p<0.01). Moreover, aliskiren significantly decreased I/R induced infarction in RSK-Tg (60% to 32%, p<0.01), compared to NLC hearts (37% to 32%, n.s.). These results suggest that RSK plays a crucial role in regulating local cardiac renin, which contributes to I/R induced cardiac injury and dysfunction. Thus, renin inhibition may provide an alternative therapeutic strategy under conditions of increased RAS. PMID- 21609720 TI - Differential reduction of HCN channel activity by various types of lipopolysaccharide. AB - Recently it was shown that lipopolysaccharide (LPS) impairs the pacemaker current in human atrial myocytes. It was speculated that reduced heart rate variability (HRV), typical of patients with severe sepsis, may partially be explained by this impairment. We evaluated the effect of various types of LPS on the activity of human hyperpolarization-activated cyclic nucleotide-gated channel 2 (hHCN2) expressed in HEK293 cells, and on pacemaker channels in native murine sino-atrial node (SAN) cells, in order to determine the structure of LPS necessary to modulate pacemaker channel function. Application of LPS caused a robust inhibition of hHCN2-mediated current (I(hHCN2)) owing to a negative shift of the voltage dependence of current activation and to a reduced maximal conductance. In addition, kinetics of channel gating were modulated by LPS. Pro-inflammatory LPS types lacking the O-chain did not reduce I(hHCN2), whereas pro-inflammatory LPS types containing the O-chain reduced I(hHCN2). On the other hand, a detoxified LPS without inflammatory activity, but containing the O-chain reduced I(hHCN2). Similar observations were made in HEK293 cells expressing hHCN4 and in murine SAN cells. This mechanistic analysis showed the novel finding that the O-chain of LPS is required for reduction of HCN channel activity. In the clinical situation the observed modulation of HCN channels may slow down diastolic depolarization of pacemaker cells and, hence, influence heart rate variability and heart rate. PMID- 21609721 TI - Elastic instability model of rapid beak closure in hummingbirds. AB - The hummingbird beak, specialized for feeding on floral nectars, is also uniquely adapted to eating flying insects. During insect capture the beak often appears to close at a rate that cannot be explained by direct muscular action alone. Here we show that the lower jaw of hummingbirds has a shape and compliance that allows for a controlled elastic snap. Furthermore, hummingbirds have the musculature needed to independently bend and twist the sides of the lower jaw. According to both our simple physical model and our elastic instability calculation, the jaw can be smoothly opened and then snapped closed through an appropriate sequence of bending and twisting actions by the muscles of the lower jaw. PMID- 21609722 TI - A new biophysical decompression model for estimating the risk of articular bends during and after decompression. AB - The biophysical models that intend to predict the risk of decompression sickness after a change of pressure are not numerous. Few approaches focus in particular on joints as target tissues, with the aim to describe properly the mechanisms inducing pain. Nevertheless, for this type of decompression incidents, called articular bends, no model proved to fit the empirical results for a broad range of exposures and decompression procedures. We present here an original biophysical decompression model for describing the occurrence of articular bends. A target joint is broken down into two parts that exchange inert gases with the blood by perfusion and with each other by diffusion over distances of a few millimetres. This diffusion pathway allows the slow amplification of microbubbles growing during and after decompression, consistent with the possible delayed occurrence of bends. The diffusion coefficients introduced into this model are larger than those introduced into most modern decompression models. Their value remains physical (#10(-9)m(2)/s). Inert gas exchanges and the formation, amplification and resorption of microbubbles during and after decompression were simulated. We used a critical gas volume criterion for predicting the occurrence of bends. A risk database extracted from COMEX experience and other published studies were used for the correlation of model parameters not known a priori. We considered a large range of exposure, and the commonly used inert gases nitrogen and helium. This correlation phase identified the worst biophysical conformations most likely to lead to the formation, in tissues such as tendons, of a large number of microbubbles recruited from pre-existing gas nuclei during decompression. The risk of bends occurrence was found to be linked to the total separated gas volume generated during and after decompression. A clamping phenomenon occurs soon after the start of decompression, greatly slowing the gas exchanges controlled especially by the oxygen window. This model, which reproduces many empirical findings, may be considered both descriptive and predictive. PMID- 21609723 TI - Modeling bidirectional transport of quantum dot nanoparticles in membrane nanotubes. AB - This paper develops a model of transport of quantum dot (QD) nanoparticles in membrane nanotubes (MNTs). It is assumed that QDs are transported inside intracellular organelles (called here nanoparticle-loaded vesicles, NLVs) that are propelled by either kinesin or dynein molecular motors while moving on microtubules (MTs). A vesicle may have both types of motors attached to it, but the motors are assumed to work in a cooperative fashion, meaning that at a given time the vesicle is moved by either kinesin or dynein motors. The motors are assumed not to work against each other, when one type of motors is pulling the vesicle, the other type is inactive. From time to time the motors may switch their roles: passive motors can become active motors and vice versa, resulting in the change of the vesicle's direction of motion. It is further assumed that QDs can escape NLVs and become free QDs, which are then transported by diffusion. Free QDs can be internalized by NLVs. The effects of two possible types of MT orientation in MNTs are investigated: when all MTs have a uniform polarity orientation, with their plus-ends directed toward one of the cells connected by an MNT, and when MTs have a mixed polarity orientation, with half of MTs having their plus-ends directed toward one of the cells and the other half having their plus-ends directed toward the other cell. Computational results are presented for three cases. The first case is when organelles are as likely to be transported by kinesin motors as by dynein motors. The second case is when organelles are more likely to be transported by kinesin motors than by dynein motors, and the third case is when NLVs do not associate with dynein motors at all. PMID- 21609724 TI - Environmental chemicals and microRNAs. AB - MicroRNAs (miRNAs) are short single-stranded non-coding molecules that function as negative regulators to silence or suppress gene expression. Aberrant miRNA expression has been implicated in a several cellular processes and pathogenic pathways of a number of diseases. Evidence is rapidly growing that miRNA regulation of gene expression may be affected by environmental chemicals. These environmental exposures include those that have frequently been associated with chronic diseases, such as heavy metals, air pollution, bisphenol A, and cigarette smoking. In this article, we review the published data on miRNAs in relation to the exposure to several environmental chemicals, and discuss the potential mechanisms that may link environmental chemicals to miRNA alterations. We further discuss the challenges in environmental-miRNA research and possible future directions. The accumulating evidence linking miRNAs to environmental chemicals, coupled with the unique regulatory role of miRNAs in gene expression, makes miRNAs potential biomarkers for better understanding the mechanisms of environmental diseases. PMID- 21609725 TI - Conjunctive Continuous Performance Task (CCPT)--a pure measure of sustained attention. AB - Among the large variety of attentional tasks that have been used to study sustained attention, the Continuous Performance Task (CPT) is perhaps the most widely used. Despite substantial differences in task characteristics and demands, all CPT paradigms have been referred to as measures of sustained attention. In the present study we introduce a new variant of CPT, which minimizes perceptual and memory components while maximizing the sustained attention components of the task. In addition, we tested the contention that the ability to sustain attention should not be overly dependent on the specific stimuli and task-modality. To this end, we used a new visual Conjunctive CPT (CCPT) developed by Tsal, Shalev, & Mevorach (2005) and its auditory analogue. Using a Multi-Trait-Multi-Method (MTMM) analysis investigating reliability coefficients, convergent validity coefficients and divergent (discriminant) validity coefficients, we established that the new CCPT is a valid measure of sustained attention. In particular, high correlations were obtained between mean RT and SD-RT within each sensory modality. High correlations were also found between performance across sensory modalities (mean convergent validity: .71). Finally, low correlations (mean correlation of .18) were found between performance in the CCPT tasks and performance in two additional visuospatial attention tasks, which do not rely on sustained attention. These findings suggest that independent of sensory modality, the two CCPT tasks used here tap the same stable construct, namely, sustained attention. We conclude that when a measure of sustained attention is required, researchers should be aware of the caveats of standard CPT's and should be careful in selecting a proper task. Moreover, clinicians should appreciate that some CPT measures may reflect a combination of different cognitive operations rather than pure sustained attention. PMID- 21609726 TI - Modulation of a fronto-parietal network in event-based prospective memory: an rTMS study. AB - Event-based prospective memory (PM) is a multi-component process that requires remembering the delayed execution of an intended action in response to a pre specified PM cue, while being actively engaged in an ongoing task. Some neuroimaging studies have suggested that both prefrontal and parietal areas are involved in the maintenance and realization of delayed intentions. In the present study, transcranial magnetic stimulation (TMS) was used to investigate the causal involvement of frontal and parietal areas in different stages of the PM process (in particular, target checking and intention retrieval), and to determine the specific contribution of these regions to PM performance. Our results demonstrate that repetitive TMS (rTMS) interferes with prospective memory performance when applied at 150-350 ms to the right dorsolateral prefrontal cortex (DLPFC), and at 400-600 ms when applied to the left posterior parietal cortex (PPC). The present study provides clear evidence that the right DLPFC plays a crucial role in early components of the PM process (target checking), while the left PPC seems to be mainly involved in later processes, such as the retrieval of the intended action. PMID- 21609727 TI - A unifying framework for assessing changes in life expectancy associated with changes in mortality: the case of violent deaths. AB - For over forty years, demographers have worked intensely to develop methods that assess a gain in life expectancy from a reduction in mortality, either hypothetical or observed. This considerable body of research was motivated by assessing the gains in life expectancy when mortality declined in a particular manner and determining the contribution of a cause of death in observed changes in life expectancy over time. As yet, there has been no framework unifying this important demographic work. In this paper, we provide a unifying framework for assessing the change in life expectancy given a change in age- and cause-specific mortality. We consider both conceptualizations of mortality change-counterfactual assessment of a hypothetical change and a retrospective assessment of an observed change. We apply our methodology to violent deaths, the leading cause of death among young adults, and show that realistic targeted reductions could have important impacts on life expectancy. PMID- 21609728 TI - A review of potential neurotoxic mechanisms among three chlorinated organic solvents. AB - The potential for central nervous system depressant effects from three widely used chlorinated solvents, trichloroethylene (TCE), perchloroethylene (PERC), and dichloromethane (DCM), has been shown in human and animal studies. Commonalities of neurobehavioral and neurophysiological changes for the chlorinated solvents in in vivo studies suggest that there is a common mechanism(s) of action in producing resultant neurotoxicological consequences. The purpose of this review is to examine the mechanistic studies conducted with these chlorinated solvents and to propose potential mechanisms of action for the different neurological effects observed. Mechanistic studies indicate that this solvent class has several molecular targets in the brain. Additionally, there are several pieces of evidence from animal studies indicating this solvent class alters neurochemical functions in the brain. Although earlier evidence indicated that these three chlorinated solvents perturb the lipid bilayer, more recent data suggest an interaction between several specific neuronal receptors produces the resultant neurobehavioral effects. Collectively, TCE, PERC, and DCM have been reported to interact directly with several different classes of neuronal receptors by generally inhibiting excitatory receptors/channels and potentiating the function of inhibitory receptors/channels. Given this mechanistic information and available studies for TCE, DCM, and PERC, we provide hypotheses on primary targets (e.g. ion channel targets) that appear to be most influential in producing the resultant neurological effects. PMID- 21609729 TI - Depth of focus and visual acuity with primary and secondary spherical aberration. AB - It is known that the depth of focus (DOF) of the human eye can be affected by the higher order aberrations. We estimated the optimal combinations of primary and secondary Zernike spherical aberration to expand the DOF and evaluated their efficiency in real eyes using an adaptive optics system. The ratio between increased DOF and loss of visual acuity was used as the performance indicator. The results indicate that primary or secondary spherical aberration alone shows similar effectiveness in extending the DOF. However, combinations of primary and secondary spherical aberration with different signs provide better efficiency for expanding the DOF. This finding suggests that the optimal combinations of primary and secondary spherical aberration may be useful in the design of optical presbyopic corrections. PMID- 21609730 TI - The influence of the built environment, social environment and health behaviors on body mass index. results from RESIDE. AB - OBJECTIVE: To examine the individual, behavioral, social and built environment correlates of body mass index (BMI) in an Australian adult population. METHOD: Using data from 2003 to 2005 on 1151 participants in the RESIDential Environments project (RESIDE), Perth, Western Australia, linear regression was used to construct multivariate models to examine the variance in BMI explained by significant socio-demographic, environmental and health behavior variables. Both self-report and GIS-derived measures of the built environment were examined. RESULTS: Age, gender, hours of work, total physical activity, sedentary leisure time and dietary fat were all associated with BMI (p<=0.05). BMI was not associated with any objective measures of the built environment or social capital, social cohesion or dog ownership but was independently associated with one perceived environment measure (perceived safety from crime). Overall, 3.3% of the variance in BMI was explained by socio-demographic factors, a further 2.7% by health behaviors and a further 1.5% by perceived environment factors. CONCLUSION: Whilst evidence mounts of built environment correlates to physical activity, the demonstrated translation of these effects on BMI remain more elusive. Nevertheless, built environment factors that constrain physical activity warrant further exploration. PMID- 21609732 TI - Prevalence of psychiatric disorders in patients with chronic solvent induced encephalopathy (CSE). AB - INTRODUCTION: Long term occupational exposure to organic solvents may induce chronic solvent-induced encephalopathy (CSE), characterized by mild to severe cognitive impairment, generally seen as the key diagnostic feature. Psychiatric disorders are often diagnosed in subjects with CSE, but were never studied in more detail. This study was designed to establish the prevalence rates of DSM IV mood, anxiety, and alcohol and substance related disorders in patients with CSE. MATERIALS AND METHODS: In CSE, n=203 (consecutively recruited between 2002 and 2005), defined according to the criteria of the World Health Organisation (WHO), one month prevalence rates of DSM IV mood, anxiety, and life time alcohol/substance related disorders were assessed using the Structured Clinical Interview for DSM IV disorders (SCID). These prevalences were compared with those from an age and gender matched community sample (n=3212) while controlling for insufficient neuropsychological test effort. RESULTS: In CSE, prevalence rates for major depressive disorder (n=36, relative risk (RR)=7.4), dysthymia (n=15, RR=6.0), panic disorders (n=18, RR=7.1), agoraphobia (n=7, RR=5.5) and generalized anxiety disorder (n=19, RR=15.8) were increased. Reduced prevalence rates were found for alcohol related disorders (n=21, RR=0.3). Insufficient neuropsychological test effort was not associated with increased prevalence rates of DSM IV disorders in subjects suspected of CSE. DISCUSSION AND CONCLUSIONS: In conclusion, in this first large scale study in patients with CSE, prevalence rates of DSM IV mood and anxiety disorders were elevated as compared with those in the general community, while the prevalence rates of alcohol related disorders were reduced. Further study must determine whether CSE, and mood and anxiety disorders, share a same, solvent induced, neurobiological pathway, supporting the use of a more inclusive diagnostic approach. Additionally, randomised controlled trials are needed for the urgent issue of how to treat mood and anxiety disorders in CSE patients effectively. PMID- 21609733 TI - Retraction. Neurological assessments after treatment with the antimalarial beta arteether in neonatal and adult rats. PMID- 21609731 TI - From elementary synaptic circuits to information processing in primary auditory cortex. AB - A key for understanding how information is processed in the cortex is to unravel the dauntingly complex cortical neural circuitry. Recent technical innovations, in particular the in vivo whole-cell voltage-clamp recording techniques, make it possible to directly dissect the excitatory and inhibitory inputs underlying an individual cortical neuron's processing function. This method provides an essential complement to conventional approaches, with which the transfer functions of the neural system are derived by correlating neuronal spike outputs to sensory inputs. Here, we intend to introduce a potentially systematic strategy for resolving the structure of functional synaptic circuits. As complex circuits can be built upon elementary modules, the primary focus of this strategy is to identify elementary synaptic circuits and determine how these circuit units contribute to specific processing functions. This review will summarize recent studies on functional synaptic circuits in the primary auditory cortex, comment on existing experimental techniques for in vivo circuitry studies, and provide a perspective on immediate future directions. PMID- 21609734 TI - Development of a three-dimensional, all-human in vitro model of the blood-brain barrier using mono-, co-, and tri-cultivation Transwell models. AB - In vitro models of the blood-brain barrier (B-BB) generally utilise murine or porcine brain endothelium and rat astrocytes which are commonly grown in foetal calf serum supplemented conditions which modulate cell growth rates. Consequently, results gained from these experimental models can be difficult to extrapolate to the human in vivo situation since they are not of human origin. The proposed in vitro Transwell model of the B-BB is a multi-culture human cell system. It requires reconstruction of the human derived B-BB components in vitro (cerebral microvascular endothelial cells, astrocytes, and brain vascular pericytes) in a three-dimensional (3D) configuration based on Transwell filters. Different cell permutations (mono-, co-, and tri-cultivation) were investigated to find the most effective model in terms of tight junction resistance of the human cerebral microvascular endothelial cells. The B-BB model permutations comprised of human astrocytes (CC-2565 and SC-1810), human brain vascular pericytes (HBVP), and human cerebral microvascular endothelial cells (hCMEC/D3), under human serum supplementation. The models were assessed by trans-endothelial electrical resistance (TEER) measurements using an epithelial voltohmmeter, to validate the tight junction formation between hCMEC/D3 cells. Mono-, co-, and tri cultivation Transwell models constructed with human brain-derived cells under human serum supplementation demonstrated that co-cultivation of astrocytes with endothelial cells produced the most successful model, as determined by TEER. Pericytes on the other hand improved tight junction formation when co-cultured with endothelial cells but did not improve the model to such an extent when grown in tri-cultivation with astrocytes. PMID- 21609735 TI - Leptin-derived peptides that stimulate food intake and increase body weight following peripheral administration. AB - We previously showed that peptides containing leptin sequences 1-33 or 61-90 are taken up by the rat brain. We now report the effects of these peptides on food intake and body weight in mature rats. Peptides were infused intravenously for 4weeks, using Alzet minipumps. Dosages were 20MUg/kg/day in experiment I, and 60MUg/kg/day in experiment 2. In experiment 1, female rats receiving peptides 1 33 and 61-90 each underwent an approximate doubling of the weight gain of control rats. These peptides also increased food intake in female rats. Peptide 15-32, which has a lesser degree of brain uptake, gave a smaller weight gain. Peptide 83 108, which is not taken up by the brain, had no effect on weight gain or food intake. Similar results were obtained in experiment 2. In male rats, however, none of the peptides caused significant changes in food intake or body weight. This was at least partly due to the fact that all male rats underwent vigorous weight increases. We conclude that peptides 1-33 and 61-90 acted as leptin antagonists, stimulating food intake and body weight increases, at least in female rats. These peptides may lead to clinical applications in conditions such as anorexia and cachexia. PMID- 21609736 TI - Expression of inflammation-related genes in mouse spleen under tuftsin analog Selank. AB - Previous studies have shown that synthetic tuftsin analogue Selank causes a transcriptomic response in the rat hippocampus and in spleen cells and may participate in the regulation of inflammatory processes in the body. In this work we studied the effect of Selank and two of its fragments on the expression of genes involved in processes of inflammation. We analyzed the expression of 84 genes involved in processes of inflammation (e.g., chemokines, cytokines, and its receptors) in mouse spleen 6 and 24 h after Selank single intraperitoneal injection (100 MUg/kg) using real-time PCR method. We found significant changes in the expression of 34 genes involved in inflammation processes. The detailed analysis of quantitative data showed that the Bcl6 gene, which plays a main role in the formation and development of the immune system, exhibited significant changes in its expression levels in response to injection of each of the peptides. Also, we observed expression changes for Bcl6 target and corepressor genes under the influence of Selank and its fragments. Our results showed that Selank and its fragments caused a number of alterations in the expression of genes involved in inflammation. The data obtained confirmed the participation of Selank in the processes of regulation of inflammation in the body. The complex biological effect of Selank may be partially determined by the systematic effect of this peptide on genomic expression. PMID- 21609737 TI - Temporally distinct expression of vesicular glutamate transporters 1 and 2 during embryonic development of the rat olfactory system. AB - To study the development of glutamatergic neurons during the main olfactory bulb morphogenesis in rats, we examined the expression of vesicular glutamate transporters 1 (VGLUT1) and 2 (VGLUT2). On VGLUT1, expressions of mRNA and immunoreactivity were first detected in the mitral cell layer on embryonic day (E) 17.5 and E18.5, respectively, and persisted in the E20.5 olfactory bulb. Much earlier (on E12.5) than VGLUT1, expressions of VGLUT2 mRNA and/or immunoreactivity were found in the olfactory epithelium, migratory cells and telencephalon. On E14.5, the mRNA expression was also observed in the prospective bulbar region and vomeronasal organ, while immunoreactivity existed in migratory cells and growing fibers. Some fibers were observed in the deep telencephalic wall. From E16.5 onward, mRNA expression became gradually detectable in cells of the mitral cell layer with development. On E17.5, immunoreactivity was first found in fibers of the developing olfactory bulb and in some immature mitral cells from E18.5 to E20.5. The present study clarifies the expression of VGLUT2 precedent to VGLUT1 during olfactory bulb morphogenesis, suggesting differential contribution of the two VGLUT subtypes to glutamate-mediated embryonic events. PMID- 21609738 TI - Molecular characterization of the AMPA-receptor potentiator S70340 in rat primary cortical culture: whole-genome expression profiling. AB - To improve our understanding of the molecular events underlying the effects of positive allosteric modulators of the alpha-amino-3-hydroxy-5-methyl-4 isoxazoleproprionic acid (S)-AMPA-type glutamate receptors, gene expression profiles of primary cortical culture were measured by Agilent-Microarray technique under (S)-AMPA (1MUM) stimulation for 0.5, 6, 24 and 48h in the presence or absence of S70340 (30MUM), an allosteric potentiator of AMPA receptors. (S)-AMPA and S70340 treatment alone have little effect on gene expression whereas as early as 6h, their combination induced a large number of genes known to decrease apoptosis and mediate cell survival. Pathway analyses of (S)-AMPA+S70340 treatment-mediated gene expression from 6 to 48h further suggested the activation of cellular functions including neuron differentiation and neurite outgrowth. A proportion of genes implicated in these functions encode proteins involved in environmental cues and are expressed in growth cones, such as extracellular matrix component proteins and filopodia microfilament-associated proteins. Time course analysis of mRNA expression combined with in silico promoter analysis revealed an enrichment in the cAMP response element (CRE) among co-regulated genes. This study demonstrated that S70340-mediated AMPA potentialisation activated genes and functional processes involved in neuroprotective and cognitive effects and describes putative new functional biomarkers. PMID- 21609739 TI - Integrating molecular dynamics and co-evolutionary analysis for reliable target prediction and deregulation of the allosteric inhibition of aspartokinase for amino acid production. AB - Deregulation of allosteric inhibition of enzymes is a challenge for strain engineering and has been achieved so far primarily by random mutation and trial and-error. In this work, we used aspartokinase, an important allosteric enzyme for industrial amino acids production, to demonstrate a predictive approach that combines protein dynamics and evolution for a rational reengineering of enzyme allostery. Molecular dynamic simulation of aspartokinase III (AK3) from Escherichia coli and statistical coupling analysis of protein sequences of the aspartokinase family allowed to identify a cluster of residues which are correlated during protein motion and coupled during the evolution. This cluster of residues forms an interconnected network mediating the allosteric regulation, including most of the previously reported positions mutated in feedback insensitive AK3 mutants. Beyond these mutation positions, we have successfully constructed another twelve targeted mutations of AK3 desensitized toward lysine inhibition. Six threonine-insensitive mutants of aspartokinase I-homoserine dehydrogenase I (AK1-HD1) were also created based on the predictions. The proposed approach can be widely applied for the deregulation of other allosteric enzymes. PMID- 21609740 TI - Real-time on-line flow cytometry for bioprocess monitoring. AB - As the understanding of variation is the key to a good process and product quality one should pay attention to dynamics on the single-cell level. The basic idea of this approach was to qualify and quantify variations on the single-cell level during bioreactor cultivations by monitoring the expression of an eGFP tagged target protein (human membrane protein) using fully automated real-time, flow injection flow cytometry (FI-FCM). The FI-FCM system consists of a sampling- and defoaming- as well as of a dilution-section. It allows a very short monitoring interval (5 min) and is able to dilute the reactor sample by a factor ranging up to more than 10,000. In bioreactor cultivations of recombinant Pichia pastoris expressing the eGFP tagged target protein, high correlations (R(2)>= 0.97) between the FI-FCM fluorescent signal and other, however, population averaged fluorescence signals (off-line fluorescence, in situ fluorescence probe) were obtained. FI-FCM is the only method able to distinguish between few cells with high fluorescence and many cells with low fluorescence intensity and proved that cells differ significantly from each other within the population during bioreactor cultivations. Single-cell fluorescence was distributed over a broad range within the cell population. These distributions strongly suggest that (a) the AOX-I promoter is leaky and (b) a fraction of the population is able to express more protein of interest within shorter time and (c) a fraction of the population does not express the fusion protein at all. These findings can help in the selection of high producing, stable strains. To show the platform independency of the system, it has successfully been tested during bioreactor cultivations of three different strains (P. pastoris, Saccharomyces cerevisiae, Escherichia coli). Along with its applications in PAT, the FI-FCM could be used as a platform-independent (prokaryotes and eukaryotes) method in various other applications; for example in the closed-loop-control of bioprocesses using different kinds of fluorescent reporters, (waste- and drinking-) water analysis, clone selection in combination with FACS or even for surgery applications. PMID- 21609741 TI - TRAIL and doxorubicin combination enhances anti-glioblastoma effect based on passive tumor targeting of liposomes. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel anticancer agent for glioblastoma multiforme (GBM). Some GBM cell lines, however, are relatively resistant to TRAIL. Doxorubicin (DOX) can sensitize GBM cells to TRAIL-induced apoptosis, indicating that the combination of DOX and TRAIL may be an effective strategy to kill TRAIL-resistant GBM cells. However, the therapeutic effect is limited by the short serum half-life of TRAIL, chronic cardiac toxicity of DOX, multidrug resistance (MDR) property of GBM cells and poor drug delivery across the blood-brain barrier (BBB). To solve such problems, combination treatment of TRAIL liposomes (TRAIL-LP) and DOX liposomes (DOX-LP) were developed for the first time. The in vitro cytotoxicity study indicated that DOX-LP sensitized GBM cell line U87MG but not normal bovine caruncular epithelial cells (BCECs) to TRAIL-LP-induced apoptosis, demonstrating the safety of the combination treatment. This sensitization was accompanied by up-regulation of death receptor 5 (DR5) expression and caspase activation. Furthermore, the combination therapy of TRAIL-LP and DOX-LP displayed stronger anti-GBM effect than free drugs or liposomal drugs alone in vivo. In summary, the combination treatment reported here showed improved therapeutic effect on GBM. Therefore, it has good potential to become a new therapeutic approach for patients with GBM. PMID- 21609742 TI - Target cell movement in cardiovascular and malignant diseases. PMID- 21609743 TI - The joint moderating effect of health consciousness and healthy lifestyle on consumers' willingness to use functional foods in Taiwan. AB - Functional foods marketed as promoting health or reducing the risk of disease open a promising avenue for consumers to pursue a healthier life. Despite the stable growth in functional foods in Taiwan, at present little is known about whether or not consumers with varying degrees of health consciousness and different healthy lifestyles will have dissimilar attitudes toward functional foods and will vary in their willingness to use them. Regression analysis of this empirical study verifies that consumers' attitudes toward functional foods do have an impact on their willingness to use such foods. Moreover, moderated regression analysis (MRA) reveals that the joint moderator of health consciousness and healthy lifestyle indeed exerts an impact on consumers' willingness to consume functional foods. Finally, one-way ANOVA tests show that there are some differences between the consumers of the "Healthy Life Attentive" group and those of the "Healthy Life Inattentive" one both in attitudes toward and in willingness to consume functional foods. The empirical results and findings from this study would be valuable for the marketers in the functional food industry to formulate marketing communication strategies and facilitate this industry's development. PMID- 21609744 TI - Barriers to implementation of the new targeted BCG vaccination in France: a cross sectional study. AB - The aim of the study was to assess factors influencing BCG vaccination among targeted children after the end of universal and mandatory BCG vaccination in France. A cross-sectional study was conducted in 2009 among general practitioners (GPs) of the French Sentinel Network. With the participation of 358 physician investigators, 920 children were included. Of the 261 children (31%) identified to be at risk of tuberculosis, only 113 (44%) were vaccinated. The median number of French criteria for BCG vaccination correctly cited by the GPs was 3 of the existing 6. Of the 10 proposed, a median number of 5 regions in the world according to their level of tuberculosis risk were correctly classified by GPs. After adjustment using an alternating logistic model, 7 variables were found to be associated with the immunisation status of the target population. Six of these increased the probability of being vaccinated: children older than 6 months (OR=3.4 (CI 95% [1.4-8.6])), residents in central Paris or its suburbs (OR=14.7 [4.4-49.5]), children expected to travel to highly endemic regions (OR=3.5 [1.4 8.6]), those living in unfavourable conditions (OR=19.9 [6.2-63.9]), the GP's good knowledge of vaccination guidelines (OR=1.4 [1.1-1.9]) and the GP's perception of tuberculosis as a common disease (OR=2.2 [1.1-4.5]). Surprisingly, GPs with university training on infectious diseases tended to be more reluctant to follow vaccination guidelines (OR=0.14 [0.1-0.4]). Actions targeted at these factors could contribute to improving BCG immunisation coverage. PMID- 21609745 TI - Induction of protection against vaginal shedding and infertility by a recombinant Chlamydia vaccine. AB - A vaccine formulated with the Chlamydia muridarum recombinant major outer membrane protein, plus the adjuvants CpG and Montanide, was tested for its ability to protect BALB/c mice against a vaginal challenge. Mice were immunized by mucosal [intravaginal (i.vag.) plus colonic (col.), or intranasal (i.n.) plus sublingual (s.l.)], or systemic [intramuscular (i.m.) plus subcutaneous (s.c.)] routes, and a combination of mucosal priming and systemic boosting routes. A negative control group was vaccinated with the Neisseria gonorrhoeae porin B (Ng rPorB) and a positive control group was inoculated in the nares with live Chlamydia. The strongest Chlamydia-specific humoral and cell-mediated immune responses were observed in the groups immunized by a combination of mucosal and systemic routes. Following the vaginal challenge, groups immunized using mucosal priming followed by systemic immunization had a significant decrease in the number of mice with positive vaginal cultures. For example, of the mice immunized i.n./s.l.+i.m./s.c., 24% had positive cultures during the six weeks of the experiment versus 69% for the negative control group immunized with Ng-rPorB (P<0.05). Similarly, the groups of mice primed by the mucosal routes and boosted by the systemic routes had significantly less IFU in the vaginal cultures when compared to the Ng-rPorB animals (P<0.05). These combination groups were also protected against infertility. The two groups had fertility rates of 100% (i.n./s.l.+i.m./s.c.) and 81% (i.vag./col.+i.m./s.c.) equivalent to the positive control group immunized with live Chlamydia (100% fertility; P>0.05). These results show the importance of the schedule and routes of vaccination and represent the first study to show protection against infertility by a Chlamydia recombinant subunit vaccine. PMID- 21609746 TI - A cell-to-cell HIV transfer assay identifies humoral responses with broad neutralization activity. AB - BACKGROUND: Cell-to-cell HIV spread through virological synapses proceeds in two steps, first HIV particles are rapidly transferred to target cells in a CD4 dependent manner and then coreceptor-dependent events allow for infection or death of single target cells and cell-to-cell fusion. METHODS: 293T or MOLT cells producing HIV particles were cocultured with primary CD4 T-cells or reporter cell lines. The extent of HIV transfer, cell fusion and target cell death was assessed. Inhibition by sera from 19 HIV-infected patients was evaluated and compared with cell-free HIV neutralization using different envelopes from clades A, B, C and E. RESULTS: Sera showed different abilities to protect CD4 T-cells from cell-to-cell transfer, fusion or death when cocultured with HIV producing 293T cells. Some sera were able to block all parameters (a property of IgGb12), while other showed lower activity against HIV transfer despite being able to block fusion and death (a property of antibodies blocking post-CD4 binding steps). Neutralization of cell-to-cell HIV transfer strongly correlated with IgG binding to native Env. Interestingly, sera that efficiently blocked HIV transfer showed broader neutralizing response, as they neutralized a higher percentage of the viruses tested compared with sera showing low CD4 binding site responses (P=0.01). Similar results were observed in a model of T cell-T cell HIV transmission, although this experimental model showed lower capacity to discriminate broadly neutralizing responses. CONCLUSION: Cell-to-cell HIV transfer assays identify sera with broadly neutralizing capacity and may help to characterize anti-HIV humoral responses. PMID- 21609747 TI - Archaeosomes with encapsulated antigens for oral vaccine delivery. AB - Traditional phosphodiester lipid vesicles (liposomes) are not stable and could be easily degraded in the gastrointestinal (GI) tract. We prepared a novel lipid based oral delivery system: archaeosomes, made of the polar lipid fraction E (PLFE) extracted from Sulfolobus acidocaldarius, and tested their immunogenic potentials as oral vaccine delivery vehicles. Our study showed that the archaeosomes had significant superior stability in simulated gastric and intestinal fluids, and would help fluorescent labeled antigens to reside longer time in the GI tract after oral administration. The resulted immune responses against model antigen ovalbumin (OVA) were greatly improved, eliciting substantial IgG response systemically as well as IgA response mucosally. In addition, the archaeosomes also facilitated antigen specific CD8(+) T cell proliferation. These data indicate that archaeosomes may be a potential vaccine carrier and adjuvant for effective oral immunization. PMID- 21609748 TI - Strategies to vaccinate against cancer of the cervix: feasibility of a school based HPV vaccination program in Peru. AB - Operational research using a mixed method, cross-sectional, case-study approach assessed the feasibility and health system impact of large-scale implementation of human papillomavirus (HPV) vaccination into routine vaccine delivery by the Ministry of Health in Peru. The strategy was school-based vaccination of fifth grade girls in 527 primary schools in Piura region. Our evaluation showed that school-based HPV vaccination is feasible without major changes in existing health systems. This was reflected in the opinions of health personnel, the lack of impact on other vaccine coverage, and the high HPV vaccine coverage documented in routine records and by an independent community-based survey. PMID- 21609750 TI - A twenty-volunteer study using deuterium labelling to determine the kinetics and fractional excretion of primary and secondary urinary metabolites of di-2 ethylhexylphthalate and di-iso-nonylphthalate. AB - This study has obtained estimates of the kinetics and fractional excretion factors of metabolism of DEHP and DINP to their main primary and secondary metabolites. Samples were obtained from an open-label, fixed sequence, single oral dose study in 10 male and 10 female subjects. The dosed substances were deuterated di-2-ethylhexylphthalate (D(4)-DEHP) and di-isononylphthalate (D(4) DINP) at two dose levels. Urine samples were collected at intervals up to 48 h post-dose. LC-MS/MS was used to measure metabolite concentrations. Excreted amounts were then calculated using urine volumes. Metabolite half-lives were estimated to be 4-8h with more than 90% of metabolites in the first 24h of urine collections and the remainder in the 24-48 h period. The four metabolites of DEHP amounted to 47.1 +/- 8.5% fractional excretion on a molar basis. For DINP the identified metabolites totalled 32.9 +/- 6.4%. For both DEHP and DINP the metabolites were in the abundance order -monoester<-oxo<-carboxy<-hydroxy. These robust fractional excretion values for the main primary and secondary phthalate metabolites along with estimates of their uncertainty can be used in future surveys of human exposure to DEHP and DINP. PMID- 21609749 TI - Role of functional dopaminergic gene polymorphisms in the etiology of idiopathic intellectual disability. AB - Intellectual disability (ID) is of major concern throughout the world, though in ~40% of cases etiology remains unknown (idiopathic ID or IID). Cognitive impairment and behavioral problems are of common occurrence in these subjects and dopamine is known to play an important role in regulating these traits. In the present study the role of functional polymorphisms in three dopaminergic genes, dopamine receptor D4 (DRD4: exon3 VNTR and rs1800955), dopamine transporter (DAT1: 3'UTR VNTR and intron8 VNTR) and catechol-O-methyl transferase (COMT: rs4680 and rs165599), was explored in IID. Probands (n=225), parents (n=298) and ethnically matched controls (n=175) were recruited following DSM-IV. Genotype data obtained was used for population- and family-based statistical analyses. Population-based analysis showed significant association of DRD4 exon3 VNTR 6R allele (P=0.01), DAT1 3'UTR VNTR lower repeat (6R and 7R) alleles (P<0.02) and intron8 VNTR 5R allele (P=0.0012) with IID. Stratified analysis revealed significant association of these alleles (P<0.05) with IID individuals exhibiting severe behavioral problems. On the other hand, preferential transmission of COMT rs4680 A allele and A-A haplotype (P<0.05) was observed specifically in male IID probands without any behavioral problem. Markers failed to show any significant epistatic interaction by MDR analysis. Alleles showing positive association were all reported to confer suboptimal activity to the transcribed proteins. Therefore, an alteration in dopaminergic neurotransmission could be predicted that may lead to impairments in cognition and behavioral problems. PMID- 21609751 TI - High doses of olive leaf extract induce liver changes in mice. AB - Virtually ever since it was first commercialized in 1995, there have been several studies focusing on the use of olive leaf extract (OLE) as a natural therapy and its medical properties. The aim of this study was to investigate the effects of three different concentrations of OLE on the function of mice livers over the course of 14 weeks. Female ICR mice were divided into four groups, depending on OLE concentration used: 0%, 0.25%, 0.5%, and 0.75%. Alanine aminotransferase, alkaline phosphatase, total bilirubin and albumin serum concentrations were all measured. Histopathological changes of the liver were observed after haematoxylin and eosin, reticulin, and Masson's trichrome staining was carried out while liver mitochondrial bioenergetics were also evaluated. Alanine aminotransferase and alkaline phosphatase serum enzyme activities increased significantly in the groups in which 0.5% and 0.75% OLE concentrations were used. Histologically, all the groups exposed to OLE exhibited hyperplasia of the bile ducts, cholestasis, hepatocyte necrosis and inflammatory infiltrated. Hepatic fibrosis was observed in the groups featuring 0.5% and 0.75% OLE concentrations. The mitochondrial membrane potential, respiratory control ratio and ADP/O of samples from animals fed the higher OLE concentration was significantly decreased when compared to the control group. PMID- 21609752 TI - Bidirectional interactions between bone metabolism and hematopoiesis. AB - Interactions between hematopoiesis and bone metabolism have been described in various developmental and pathological situations. Here we review this evidence from the literature with a focus on microenvironmental regulation of hematopoiesis and bone metabolism. Our hypothesis is that this process occurs by bidirectional signaling between hematopoietic and mesenchymal cells through cell adhesion molecules, membrane-bound growth factors, and secreted matrix proteins. Examples of steady-state hematopoiesis and pathologies are presented and support our view that hematopoietic and mesenchymal cell functions are modulated by specific microenvironments in the bone marrow. PMID- 21609753 TI - Apelin-transgenic mice exhibit a resistance against diet-induced obesity by increasing vascular mass and mitochondrial biogenesis in skeletal muscle. AB - BACKGROUND: Apelin is an endogenous ligand for the G-protein-coupled 7 transmembrane receptor, APJ. The administration of apelin-13, a truncated 13 amino acid apelin peptide, in diet-induced obese mice is reported to result in a decrease in adiposity due to the increase of energy expenditure with an increase in the expression of uncoupling proteins. METHODS: We systematically compared the phenotype of human apelin-transgenic (apelin-Tg) mice fed standard or high-fat diets (HFD) with that of non-Tg control mice to clarify the effect of apelin on obesity. The beneficial effects of apelin were evaluated by multiple assay methods including indirect calorimetrical measurements, gene expression analysis, and immunohistochemical staining. RESULTS: Apelin-Tg mice inhibited HFD-induced obesity without altering food intake and exhibited increased oxygen consumption and body temperature compared to non-Tg controls. Interestingly, the mRNA expressions of angiopoietin-1 (Ang1), a key molecule for vascular maturation, and its receptor, endothelium-specific receptor tyrosine kinase 2 (Tie2), were significantly upregulated in the skeletal muscle of HFD-fed apelin-Tg mice, and the areas of anti-CD31 antibody-positive endothelial cells also increased. Furthermore, both the aerobic type-I muscle fibre ratio and the DNA copy number of mitochondrial NADH dehydrogenase subunit 1 increased 2.0- and 1.4-fold in skeletal muscle, respectively. CONCLUSIONS: These findings suggest that apelin stimulates energy expenditure via increase vascular mass and mitochondrial biogenesis in skeletal muscle. GENERAL SIGNIFICANCE: Apelin is a prerequisite factor for anti-obesity by stimulating energy expenditure via regulating homeostatic energy balance. PMID- 21609754 TI - A method to assess the migration properties of cell-derived microparticles within a living tissue. AB - BACKGROUND: Cells undergoing activation or apoptosis exhibit plasma membrane changes, leading to the formation of shed vesicles (microparticles, MP). Although their effects on recipient cells in vitro, and their ability to support inflammatory or thrombotic events in the circulation have been studied, the spreading of such vesicles in tissues is still elusive. Our aim was to set up a method to examine the behavior of these vesicles in vivo. METHODS: We examined the persistence of green-fluorescent microparticles (fMP), prepared after Ca2+ ionophore activation (iono-fMP) or apoptogenic treatment (eto-fMP) of human Jurkat T lymphoblastic or non-hematopoietic embryonic kidney (HEK) cell lines, following injection in zebrafish embryos 2h after egg fertilization. RESULTS: One hour post-injection, iono-fMP issued from both cell types formed a fluorescent dispersal in the intercellular space of embryos. In contrast, eto-fMP or MP deprived of sialic acid at their membrane, gathered together at the site of injection. CONCLUSIONS: We propose a method characterizing the abilities of MP to spread in the intercellular space. We showed that MP produced by apoptosis of T cells and those deprived of sialic acid at their membrane do not diffuse within the living cells. On the contrary, MP shed upon calcium induced activation of T and HEK cells, diffuse at a distance and spread in the intercellular space. GENERAL SIGNIFICANCE: The fate of injected MP relies on the type of induction rather than the cell species and results provide a model to test the ability of vesicles to interact locally or to spread outside of the site of production. PMID- 21609755 TI - 2-Naphthol levels and genotoxicity in rubber workers. AB - Urinary bladder cancer is a historical disease of rubber workers often been associated with exposure to aromatic amines such as 2-naphthylamine. While exposure to these compounds has decreased markedly over time, the bladder cancer risk has not decreased in direct proportion. Polycyclic aromatic compounds (PAC) are candidates for urinary bladder cancer causation. We determined pre- and post exposure urinary levels of 2-napthol (2NAP), the major metabolite of a model volatile PAC, in a group of non-smoking rubber workers. Pre- and post-exposure urine samples were collected from 43 non-smoking workers. Overall mean post-shift 2-naphthol levels were increased (13.95 +/- 28.4 MUg/l), but non-significantly compared to samples collected pre-exposure (7.97 +/- 22.1 MUg/l; p=0.29). The greatest difference was observed in the curing department where post-exposure samples were 4.5 fold higher, post shift samples were significantly higher in production workers as compared to non-production workers (p=0.02). Levels of 2NAP were not correlated with levels of carcinogen-DNA adducts in exfoliated urothelial cells nor with other estimates of exposure or effect. These data suggest that post-shift urinary 2NAP levels are increased, particularly in the curing department. However, the differences were not significantly different overall and urinary 2NAP levels did not predict the level of carcinogen DNA adducts in exfoliated urothelial cells. PMID- 21609756 TI - Doxorubicin and paclitaxel loaded microbubbles for ultrasound triggered drug delivery. AB - A polymer ultrasound contrast agent (UCA) developed in our lab has been shown to greatly reduce in size when exposed to ultrasound, resulting in nanoparticles less than 400 nm in diameter capable of escaping the leaky vasculature of a tumor to provide a sustained release of drug. Previous studies with the hydrophilic drug doxorubicin (DOX) demonstrated enhanced drug delivery to tumors when triggered with ultrasound. However the therapeutic potential has been limited due to the relatively low payload of DOX. This study compares the effects of loading the hydrophobic drug paclitaxel (PTX) on the agent's acoustic properties, drug payload, tumoricidal activity, and the ability to deliver drugs through 400 nm pores. A maximum payload of 129.46 +/- 1.80 MUg PTX/mg UCA (encapsulation efficiency 71.92 +/- 0.99%) was achieved, 20 times greater than the maximum payload of DOX (6.2 MUg/mg), while maintaining the acoustic properties. In vitro, the tumoricidal activity of paclitaxel loaded UCA exposed to ultrasound was significantly greater than controls not exposed to ultrasound (p<0.0016). This study has shown that PTX loaded UCA triggered with focused ultrasound have the potential to provide a targeted and sustained delivery of drug to tumors. PMID- 21609757 TI - Age-related changes in auditory temporal processing in the rat. AB - Presbycusis, as the deterioration of hearing ability occurring with aging, can be manifested not only in a shift of hearing thresholds, but also in a deterioration of the temporal processing of acoustical signals, which may in elderly people result in degraded speech comprehension. In this study we assessed the age related changes in the temporal processing of acoustical signals in the auditory system of pigmented rats (Long Evans strain). The temporal resolution was investigated in young adult (3-4 months) and old (30-34 months) rats by behavioral and electrophysiological methods: the rats' ability to detect and discriminate gaps in a continuous noise was examined behaviorally, and the amplitude-rate function was assessed for the middle latency response (MLR) to clicks. A worsening of the temporal resolution with aging was observed in the results of all tests. The values of the gap detection threshold (GDT) and the gap duration difference limen (GDDL) in old rats increased about two-fold in comparison with young adult rats. The MLR to a click train in old rats exhibited a significantly faster reduction in amplitude with an increasing stimulation rate in comparison with young adult rats. None of the age-related changes in the parameters characterizing temporal resolution (GDT, GDDL and MLR to a click train) correlated with the degree of the age-related hearing loss. However, the age-related changes in MLR amplitude-rate function correlated with the age related changes in GDDL, but not with the changes in GDT. The behavioral and electrophysiological data clearly show that aging in rats is accompanied with a pronounced deficit in the temporal processing of acoustical signals that is associated with the deteriorated function of the central auditory system. PMID- 21609758 TI - Manufactured RBC--rivers of blood, or an oasis in the desert? AB - Red blood cell (RBC) transfusion is an essential practice in modern medicine, one that is entirely dependent on the availability of donor blood. Constraints in donor supply have led to proposals that transfusible RBC could be manufactured from stem cells. While it is possible to generate small amounts of RBC in vitro, very large numbers of cells are required to be of clinical significance. We explore the challenges facing large scale manufacture of RBC and technological developments required for such a scenario to be realised. PMID- 21609759 TI - Thymoquinone from Nigella sativa was more potent than cisplatin in eliminating of SiHa cells via apoptosis with down-regulation of Bcl-2 protein. AB - Thymoquinone (TQ), the active constituent of Nigella sativa or black cumin exhibited cytotoxic effects in several cancer cell lines. In this study, the cytotoxicity of TQ in human cervical squamous carcinoma cells (SiHa) was investigated. TQ was cytotoxic towards SiHa cells with IC50 values of 10.67 +/- 0.12 and 9.33 +/- 0.19 MUg/mL as determined by MTT assay and trypan blue dye exclusion test, respectively, after 72 h of incubation. TQ was more cytotoxic towards SiHa cells compared to cisplatin. Interestingly, TQ was less cytotoxic towards the normal cells (3T3-L1 and Vero). Cell cycle analysis performed by flowcytometer showed a significant increase in the accumulation of TQ-treated cells at sub-G1 phase, indicating induction of apoptosis by the compound. Apoptosis induction by TQ was further confirmed by Annexin V/PI and AO/PI staining. Significant elevation of p53 and down-regulation of the anti-apoptotic Bcl-2 protein was found in the treated cells, without any changes in the expression of the pro-apoptotic Bax protein. In conclusion, thymoquinone from N. sativa was more potent than cisplatin in elimination of SiHa cells via apoptosis with down-regulation of Bcl-2 protein. PMID- 21609760 TI - Myoglobin-H2O2 catalyzes the oxidation of beta-ketoacids to alpha-dicarbonyls: mechanism and implications in ketosis. AB - Acetoacetate (AA) and 2-methylacetoacetate (MAA) are accumulated in metabolic disorders such as diabetes and isoleucinemia. Here we examine the mechanism of AA and MAA aerobic oxidation initiated by myoglobin (Mb)/H(2)O(2). We propose a chemiluminescent route involving a dioxetanone intermediate whose thermolysis yields triplet alpha-dicarbonyl species (methylglyoxal and diacetyl). The observed ultraweak chemiluminescence increased linearly on raising the concentration of either Mb (10-500 MUM) or AA (10-100 mM). Oxygen uptake studies revealed that MAA is almost a 100-fold more reactive than AA. EPR spin-trapping studies with MNP/MAA revealed the intermediacy of an alpha-carbon-centered radical and acetyl radical. The latter radical, probably derived from triplet diacetyl, is totally suppressed by sorbate, a well-known quencher of triplet carbonyls. Furthermore, an EPR signal assignable to MNP-AA(*) adduct was observed and confirmed by isotope effects. Oxygen consumption and alpha-dicarbonyl yield were shown to be dependent on AA or MAA concentrations (1-50 mM) and on H(2)O(2) or tert-butOOH added to the Mb-containing reaction mixtures. That ferrylMb is involved in a peroxidase cycle acting on the substrates is suggested by the reaction pH profiles and immunospin-trapping experiments. The generation of radicals and triplet dicarbonyl products by Mb/H(2)O(2)/beta-ketoacids may contribute to the adverse health effects of ketogenic unbalance. PMID- 21609761 TI - Inhibitory effect of lithium on nucleotide hydrolysis and acetylcholinesterase activity in zebrafish (Danio rerio) brain. AB - Lithium has been used as an effective antimanic drug in humans and it is well known for its effects on neuropsychiatric disorders and neuronal communication. ATP and adenosine are important signaling molecules, and most nerves release ATP as a fast co-transmitter together with classical neurotransmitters such as acetylcholine. In this study, we evaluated the in vitro and in vivo effects of lithium on acetylcholinesterase and ectonucleotidase activities in zebrafish brain. There was a significant inhibition of ADP hydrolysis after in vivo exposure to lithium at 5 and 10 mg/l (27.6% and 29% inhibition, respectively), whereas an inhibitory effect was observed for AMP hydrolysis only at 10 mg/l (30%). Lithium treatment in vivo also significantly decreased the acetylcholinesterase activity at 10 mg/l (21.9%). The mRNA transcript levels of the genes encoding for these enzymes were unchanged after exposure to 5 and 10 mg/l lithium chloride. In order to directly evaluate the action of lithium on enzyme activities, we tested the in vitro effect of lithium at concentrations ranging from 1 to 1000 MUM. There were no significant changes in zebrafish brain ectonucleotidase and acetylcholinesterase activities at all concentrations tested in vitro. Our findings show that lithium treatment can alter ectonucleotidase and acetylcholinesterase activities, which may regulate extracellular nucleotide, nucleoside, and acetylcholine levels. These data suggest that cholinergic and purinergic signaling may be targets of the pharmacological effects induced by this compound. PMID- 21609762 TI - Myostatin: a novel insight into its role in metabolism, signal pathways, and expression regulation. AB - Myostatin, a member of the transforming growth factor-beta (TGF-beta) superfamily, is a critical autocrine/paracrine inhibitor of skeletal muscle growth. Since the first observed double-muscling phenotype was reported in myostatin-null animals, a functional role of myostatin has been demonstrated in the control of skeletal muscle development. However, beyond the confines of its traditional role in muscle growth inhibition, myostatin has recently been shown to play an important role in metabolism. During the past several years, it has been well established that Smads are canonical mediators of signals for myostatin from the receptors to the nucleus. However, growing evidence supports the notion that Non-Smad signal pathways also participate in myostatin signaling. Myostatin expression is increased in muscle atrophy and metabolic disorders, suggesting that changes in endogenous expression of myostatin may provide therapeutic benefit for these diseases. MicroRNAs (miRNAs) are a class of non-coding RNAs that negatively regulate gene expression and recent evidence has accumulated supporting a role for miRNAs in the regulation of myostatin expression. This review highlights some of these areas in myostatin research: a novel role in metabolism, signal pathways, and miRNA-mediated expression regulation. PMID- 21609763 TI - Sequence variants within the 3'-UTR of the COL5A1 gene alters mRNA stability: implications for musculoskeletal soft tissue injuries. AB - COL5A1 encodes the alpha1 chain of type V collagen, a quantitatively minor fibrillar collagen that regulates fibrillogenesis. A variant within the 3'-UTR of COL5A1 is associated with chronic Achilles tendinopathy (AT) and other exercise related phenotypes but the functional significance of this is unknown. The aim of this study was therefore to identify functional differences between the COL5A1 3' UTR from patients with AT and asymptomatic controls. To this end we have used a reporter assay in which the COL5A1 3'-UTR from AT patients and controls were cloned downstream of the firefly luciferase gene and luciferase activity measured as an indication of mRNA stability. When the cloned COL5A13'-UTRs were sequenced, two major forms named C- and T-alleles were predominantly identified in the controls and the AT subjects respectively. The luciferase activity of the C alleles was significantly lower than that of the T-alleles (69.0+/-22.0% (N=24) vs. 90.6+/-13.7% (N=30), p<0.001) which suggests an overall increase in mRNA stability for the T-allele. Furthermore, we identified a functional miRNA site for Hsa-miR-608 within the COL5A1 3'-UTR and using deletion constructs we have identified additional elements which regulate COL5A1 mRNA stability. These results have important implications for our understanding of the molecular basis of musculoskeletal soft tissue injuries and other exercise-related phenotypes. PMID- 21609765 TI - Molecular cloning and functional analysis of an orange-spotted grouper (Epinephelus coioides) secreted protein acidic and rich in cysteine (SPARC) and characterization of its expression response to nodavirus. AB - Mammalian secreted protein acidic and rich in cysteine (SPARC) is the primary regulator of cell shape and cell adhesion to fibronectin. We, for the first time, report the complete sequencing of SPARC cDNA from orange-spotted grouper. Despite the difference in the lengths of the SPARC transcripts, all of the SPARC molecules encoded a signal peptide, follistain-like copper binding sequence (KGHK) domain, and extracellular domain. The grouper SPARC gene was differentially expressed in vivo and contributed differently to high-level expression of SPARC in muscle. Immunohistochemical staining demonstrated a decreased level of SPARC in nodavirus-infected grouper compared with healthy grouper. Comparative real-time polymerase chain reaction analyses of eye tissues of viral nervous necrosis grouper and healthy grouper were performed. Recombinant SPARC produced changes in grouper cell shape 24 h after treatment. The results provide new insight into the pathogenesis of nodavirus, and demonstrate an experimental rationale for SPARC characterization in nodavirus-infected grouper. PMID- 21609764 TI - A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320, shows significant therapeutic effects in a mouse model of muscular dystrophy. AB - A resolutive therapy for muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration and in the severe forms to death, is still lacking. Since inflammation and defects in nitric oxide generation are recognized key pathogenic events in muscular dystrophy, we have analysed the effects of a derivative of ibuprofen, NCX 320, belonging to the class of cyclooxygenase inhibiting nitric oxide donator (CINOD), in the alpha-sarcoglycan null mice, a severe mouse model of dystrophy. NCX 320 was administered daily in the diet for 8months starting 1month from weaning. Muscle functional recovery was evaluated by free wheel and treadmill tests at 8months. Serum creatine kinase activity, as well as the number of diaphragm inflammatory infiltrates and necrotic fibres, was measured as indexes of skeletal muscle damage. Muscle regeneration was evaluated in diaphragm and tibialis anterior muscles, measuring the numbers of centronucleated fibres and of myogenic precursor cells. NCX 320 mitigated muscle damage, reducing significantly serum creatine kinase activity, the number of necrotic fibres and inflammatory infiltrates. Moreover, NCX 320 stimulated muscle regeneration increasing significantly the number of myogenic precursor cells and regenerating fibres. All these effects concurred in inducing a significant improvement of muscle function, as assessed by both free wheel and treadmill tests. These results describe the properties of a new compound incorporating nitric oxide donation together with anti-inflammatory properties, showing that it is effective in slowing muscle dystrophy progression long term. Of importance, this new compound deserves specific attention for its potential in the therapy of muscular dystrophy given that ibuprofen is well tolerated in paediatric patients and with a profile of safety that makes it suitable for chronic treatment such as the one required in muscular dystrophies. PMID- 21609766 TI - Proteome reference map of the skin mucus of Atlantic cod (Gadus morhua) revealing immune competent molecules. AB - The skin mucosal proteome of Atlantic cod (Gadus morhua) was mapped using a 2D PAGE, LC-MS/MS coupled approach. Mucosal proteins from naive fish were identified primarily by similarity searches across various cod EST databases. The identified proteins were clustered into 8 groups based on gene ontology classification for biological process. Most of the proteins identified from the gel are hitherto unreported for cod. Galectin-1, mannan binding lectin (MBL), serpins, cystatin B, cyclophilin A, FK-506 binding protein, proteasome subunits (alpha-3 and -7), ubiquitin, and g-type lysozyme are considered immune competent molecules. Five of the aforementioned proteins were cloned and their tissue distribution was analysed by RT-PCR. PMID- 21609767 TI - Word frequency effects in the left IFG in dyslexic and normally reading children during picture naming and reading. AB - Word frequency effects have been reported in numerous neuroimaging studies with typically reading adults, emphasising the role of the left inferior frontal gyrus (LIFG). Within LIFG, different cytoarchitectonic modules (areas 44 and 45) have been related to phonological vs. lexico-semantic processing, respectively. This fMRI study investigated the differential impact of word frequency on LIFG activation in reading and picture naming in primary school children with and without developmental dyslexia. All children showed the typical LIFG frequency effect in both tasks. The effect was comparable in a fronto-orbital region anterior-inferior adjacent to area 45. During reading but not picture naming, a second effect was observed in area 44. Here, the fMRI effect for lexical frequency was stronger for the dyslexic than the normal readers. These findings demonstrate the neural underpinnings of a selective deficit in dyslexic children in the graphemic input lexicon, whereas abstract lexical representations appear to be processed equally well in dyslexic and normally reading children. To conclude, the present fMRI study demonstrated differential impact of word frequency on LIFG activation in primary school children during reading but not picture naming. Apart from extending previous knowledge from studies with adults to childhood, the study sheds further light on a potential neural mechanism for deficient grapheme-to-phoneme conversion in dyslexic children. PMID- 21609768 TI - Diffusion based abnormality markers of pathology: toward learned diagnostic prediction of ASD. AB - This paper presents a paradigm for generating a quantifiable marker of pathology that supports diagnosis and provides a potential biomarker of neuropsychiatric disorders, such as autism spectrum disorder (ASD). This is achieved by creating high-dimensional nonlinear pattern classifiers using support vector machines (SVM), that learn the underlying pattern of pathology using numerous atlas-based regional features extracted from diffusion tensor imaging (DTI) data. These classifiers, in addition to providing insight into the group separation between patients and controls, are applicable on a single subject basis and have the potential to aid in diagnosis by assigning a probabilistic abnormality score to each subject that quantifies the degree of pathology and can be used in combination with other clinical scores to aid in diagnostic decision. They also produce a ranking of regions that contribute most to the group classification and separation, thereby providing a neurobiological insight into the pathology. As an illustrative application of the general framework for creating diffusion based abnormality classifiers we create classifiers for a dataset consisting of 45 children with ASD (mean age 10.5 +/- 2.5 yr) as compared to 30 typically developing (TD) controls (mean age 10.3 +/- 2.5 yr). Based on the abnormality scores, a distinction between the ASD population and TD controls was achieved with 80% leave one out (LOO) cross-validation accuracy with high significance of p<0.001, ~84% specificity and ~74% sensitivity. Regions that contributed to this abnormality score involved fractional anisotropy (FA) differences mainly in right occipital regions as well as in left superior longitudinal fasciculus, external and internal capsule while mean diffusivity (MD) discriminates were observed primarily in right occipital gyrus and right temporal white matter. PMID- 21609769 TI - Functional connectivity hubs in the human brain. AB - Brain networks appear to have few and well localized regions with high functional connectivity density (hubs) for fast integration of neural processing, and their dysfunction could contribute to neuropsychiatric diseases. However the variability in the distribution of these brain hubs is unknown due in part to the overwhelming computational demands associated to their localization. Recently we developed a fast algorithm to map the local functional connectivity density (lFCD). Here we extend our method to map the global density (gFDC) taking advantage of parallel computing. We mapped the gFCD in the brain of 1031 subjects from the 1000 Functional Connectomes project and show that the strongest hubs are located in regions of the default mode network (DMN) and in sensory cortices, whereas subcortical regions exhibited the weakest hubs. The strongest hubs were consistently located in ventral precuneus/cingulate gyrus (previously identified by other analytical methods including lFCD) and in primary visual cortex (BA 17/18), which highlights their centrality to resting connectivity networks. In contrast and after rescaling, hubs in prefrontal regions had lower gFCD than lFCD, which suggests that their local functional connectivity (as opposed to long range connectivity) prevails in the resting state. The power scaling of the probability distribution of gFCD hubs (as for lFCD) was consistent across research centers further corroborating the "scale-free" topology of brain networks. Within and between-subject variability for gFCD were twice than that for lFCD (20% vs. 12% and 84% vs. 34%, respectively) suggesting that gFCD is more sensitive to individual differences in functional connectivity. PMID- 21609770 TI - Co-activation patterns distinguish cortical modules, their connectivity and functional differentiation. AB - The organization of the cerebral cortex into distinct modules may be described along several dimensions, most importantly, structure, connectivity and function. Identification of cortical modules by differences in whole-brain connectivity profiles derived from diffusion tensor imaging or resting state correlations has already been shown. These approaches, however, carry no task-related information. Hence, inference on the functional relevance of the ensuing parcellation remains tentative. Here, we demonstrate, that Meta-Analytic Connectivity Modeling (MACM) allows the delineation of cortical modules based on their whole-brain co activation pattern across databased neuroimaging results. Using a model free approach, two regions of the medial pre-motor cortex, SMA and pre-SMA were differentiated solely based on their functional connectivity. Assessing the behavioral domain and paradigm class meta-data of the experiments associated with the clusters derived from the co-activation based parcellation moreover allows the identification of their functional characteristics. The ensuing hypotheses about functional differentiation and distinct functional connectivity between pre SMA and SMA were then explicitly tested and confirmed in independent datasets using functional and resting state fMRI. Co-activation based parcellation thus provides a new perspective for identifying modules of functional connectivity and linking them to functional properties, hereby generating new and subsequently testable hypotheses about the organization of cortical modules. PMID- 21609771 TI - Dynamic decoding of ongoing perception. AB - Decoding of perceptual and mental states using multivariate analysis methods has received much recent attention. It relies on selective responses to experimental conditions in single trials, aggregated across voxels. In this study, we show that decoding is also possible when the state of interest changes continuously over time. It is shown that both orientation and rotation direction of a continuously rotating grating can be decoded with high accuracy using linear dynamical systems and hidden Markov models. These findings extend the decoding results for static gratings and are of importance in the decoding of ongoing changes in mental state. PMID- 21609772 TI - How is our self related to midline regions and the default-mode network? AB - The problem of the self has been of increasing interest in recent neuroscience. Brain imaging studies have raised the question of whether neural activity in cortical midline regions is self-specific and whether self-specific activity is related to resting state activity (RSA). A quantitative meta-analysis that included 87 studies, representing 1433 participants, was conducted to discuss these questions. First, the specificity of the self (e.g. hearing one's own name, seeing one's own face) was tested and compared across familiar (using stimuli from personally known people) and other (non-self-non-familiar, i.e. strangers and widely-known figures) conditions. Second, the relationship between the self and resting state activity, as reflected by the default-mode network (DMN), was tested. The results indicated that the perigenual anterior cingulate cortex (PACC) is specifically involved in self-processing when compared to familiarity, other, and task/stimulus effects. On the contrary, other midline regions, i.e., medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC) were functionally unspecific as they were recruited during the processing of both self specific and familiar stimuli. Finally, the PACC was recruited during self specific stimuli and this activity overlapped with DMN activity during resting state, thus distinguishing the self-related processing from both that of the familiar and other conditions. Taken together, our data suggest that our sense of self may result from a specific kind of interaction between resting state activity and stimulus-induced activity, i.e., rest-stimulus interaction, within the midline regions. PMID- 21609773 TI - Simultaneous in vivo measurements of receptor density and affinity using [11C]flumazenil and positron emission tomography: comparison of full saturation and steady state methods. AB - The binding of PET radiotracer [(11)C]flumazenil to the GABA(A) receptors is described by the receptor density (B(max)) and binding affinity (K(D)). The estimation of B(max) and K(D) is usually based on Scatchard analysis including at least two PET scans at steady state of various specific activities. Recently, a novel full saturation method to estimate both B(max) and K(D) was proposed, in which a saturating dose of flumazenil is given to cover a wide range of different receptor occupancies within a single scan. The aim of the present study was a direct comparison of steady state and full saturation methods for determining B(max) and K(D) of [(11)C]flumazenil in the same group of male Sprague-Dawley rats. Fourteen rats underwent 3 consecutive [(11)C]flumazenil scans of 30 min duration each. A tracer dose was injected at the start of the first scan. Prior to the second scan the tracer was mixed with 5, 20, 100 or 500 MUg unlabelled (cold) flumazenil to cover a wide range of receptor occupancies during the scan. The third scan was performed during a constant intravenous infusion of unlabelled flumazenil, resulting in ~50% GABA(A) receptor occupancy. The first and third scans were part of the steady state method, whilst the second scan was performed according to the full saturation method. For both methods, B(max) and K(D) were then derived by compartmental modelling. Both methods yielded similar B(max) and K(D) estimates. The full saturation method yielded B(max) values of 37 +/- 5.8 ng . mL(-1) and K(D) values of 7.6 +/- 2.0 ng . mL(-1), whilst the steady state method yielded B(max) values of 33 +/- 5.4 ng . mL(-1) and K(D) values of 7.1 +/- 0.8 ng . mL(-1). The main advantage of the full saturation method is that B(max) and K(D) can be obtained from a single PET scan. PMID- 21609774 TI - Parallel evolution in eight-barbel loaches of the genus Lefua (Balitoridae, Cypriniformes) revealed by mitochondrial and nuclear DNA phylogenies. AB - The evolutionary history of eight-barbel loaches of the genus Lefua contains important phylogenetic information that will aid in resolution of the faunal formations and evolutionary histories of Japanese and East Asian freshwater fishes. Our sequencing of the mitochondrial D-loop region in a large number of samples allowed construction of the most comprehensive phylogeny of these loaches to date; we demonstrated monophyly of five Lefua species and identified populations of Lufua. sp. and Lefua echigonia. Loaches inhabiting the Tokai region in Japan were morphologically and ecologically indistinguishable from Lefua sp. However, they were included in the L. echigonia lineage. We determined a novel phylogeny by sequencing the nuclear ribosomal S7 subunit and showed that nuclear DNA phylogeny essentially matched the mitochondrial DNA phylogeny. Loaches from the Tokai region were part of the L. echigonia lineage, indicating parallel evolution between Tokai loaches and Lefua sp. in western Japan. We presented the most robust phylogeny to date using concatenated mitochondrial and nuclear sequences. The wealth of molecular information allowed us to speculate on evolutionary processes in the genus Lefua. PMID- 21609775 TI - Drosophila melanogaster larvae fed by glucose and fructose demonstrate difference in oxidative stress markers and antioxidant enzymes of adult flies. AB - Activities of antioxidant and associated enzymes, and oxidative stress markers were assessed in newly enclosed adult fruit flies Drosophila melanogaster developed on diets with 4 and 10% glucose or fructose. In fly males, 10% fructose promoted higher content of protein carbonyls and catalase activity, but lower superoxide dismutase (SOD) activity than 4%, while in females-lower levels of high molecular mass thiols (H-SH). Females at all diets had virtually the same level of lipid peroxides, low-molecular-mass thiols, catalase, and superoxide dismutase activities. Fed with 4% fructose and glucose males demonstrated 24 and 26% lower H-SH level than females, respectively. On diets with 4% glucose, 10% glucose and fructose females had 32, 26 and 27% lower catalase activity than respective males, and 1.3-1.5-fold lower glucose-6-phosphate dehydrogenase activity on glucose-containing diets. Strong positive correlations between H-SH level and G6PD activity, as well as between catalase and G6PDH activity were found. These results suggest that type and concentration of dietary carbohydrate affect antioxidant defense in fruit flies. It also substantially depends on fly sex, comprising presumably levels of protein carbonyls and lipid peroxides, as well as catalase and SOD activities in males and G6PDH activity in females. PMID- 21609776 TI - Induction of pro-inflammatory mediators in Plasmodium berghei infected BALB/c mice breaks blood-brain-barrier and leads to cerebral malaria in an IL-12 dependent manner. AB - A severe complication of Plasmodium infection is cerebral malaria, a condition mainly attributed to overwhelming inflammatory immune reactions of the host. Murine models differing in susceptibility to experimental cerebral malaria (ECM) allow detailed studies of the host response. We show that ECM- resistant BALB/c mice were driven into interferon gamma- and IL-12-dependent ECM and subsequent death if they received CpG-oligonucleotides after Plasmodium berghei ANKA (PbA) infection. CpG application triggered production of pro-inflammatory cytokines systemically as well in spleen and brain and induced neuropathological symptoms, leading to increased mortality. Experiments with genetically deficient mice confirmed the role of IFN-gamma and IL-12 during CpG-triggered immunopathology. Furthermore, the application of CpG and downstream production of pro-inflammatory cytokines contributed to the break down of the blood brain barrier visualized by Evan's Blue, comparable to PbA-infected C57BL/6 mice. Taken together, resistance of BALB/c mice towards ECM development could be altered through induction of pro inflammatory cytokines by CpG. Therefore, approaches discussed earlier to induce pro-inflammatory immune reactions for malaria protection should be considered with caution. PMID- 21609777 TI - Bordetella avium causes induction of apoptosis and nitric oxide synthase in turkey tracheal explant cultures. AB - Bordetellosis is an upper respiratory disease of turkeys caused by Bordetella avium in which the bacteria attach specifically to ciliated respiratory epithelial cells. Little is known about the mechanisms of pathogenesis of this disease, which has a negative impact in the commercial turkey industry. In this study, we produced a novel explant organ culture system that was able to successfully reproduce pathogenesis of B. avium in vitro, using tracheal tissue derived from 26 day-old turkey embryos. Treatment of the explants with whole cells of B. avium virulent strain 197N and culture supernatant, but not lipopolysaccharide (LPS) or tracheal cytotoxin (TCT), specifically induced apoptosis in ciliated cells, as shown by annexin V and TUNEL staining. LPS and TCT are known virulence factors of Bordetella pertussis, the causative agent of whooping cough. Treatment with whole cells of B. avium and LPS specifically induced NO response in ciliated cells, shown by uNOS staining and diaphorase activity. The explant system is being used as a model to elucidate specific molecules responsible for the symptoms of bordetellosis. PMID- 21609778 TI - Evidence of involvement of the receptor for advanced glycation end-products (RAGE) in the adhesion of Helicobacter pylori to gastric epithelial cells. AB - The adherence of Helicobacter pylori to gastric epithelial cells is required for prolonged persistence in the stomach and for induction of injury. Here, we first reported a new role of the receptor for advanced glycation end-products (RAGE) on the adherence of H. pylori to gastric epithelial cells, assessed by different methods and binding to immobilized RAGE. RAGE-targeted knock-down in MKN74 cell line markedly reduced not only the adhesion of H. pylori, but also the levels of IL-8 transcripts and protein released in response to infection. These data suggest that RAGE may represent a new factor on the pathogenesis of H. pylori infection. PMID- 21609779 TI - Association of TNF-alpha and IL-10 polymorphisms with tuberculosis in Tunisian populations. AB - Cytokine Th1/Th2 balance is known to play a key role in controlling Mycobacterium tuberculosis infection. Based upon the functional role of the TNF-alpha [-308 G(low) -> A(high) (rs1800629)] and IL-10 [-1082 A(low) -> G(high) (rs1800870), 819 T(low) -> C(high) (rs1800871) and -592 A(low) -> C(high) (rs1800872)] single nucleotide polymorphisms (SNPs) on production levels, we genotyped 76 patients with pulmonary tuberculosis (TB) (pTB), 55 patients with extrapulmonary TB (epTB) and 95 healthy blood donors by polymerase chain reaction fragment length polymorphism (PCR-RFLP). We observed that -308 A allele was associated with increased risk susceptibility to epTB (OR = 1.96; 95% CI, 1.04-3.71; P = 0.024). The -1082 AG genotype was significantly associated with increased risk development of epTB (odds ratio [OR] = 3.69; 95% confidence intervals [CI], 1.73 7.92; P corrected for the number of genotypes [Pc] = 0.0003). By contrast, -1082 AA genotype appeared to be associated with resistance to pTB (OR = 0.38; 95% CI, 0.19-0.74; Pc = 0.006) and epTB (OR = 0.22; 95% CI, 0.1-0.48; Pc = 0.00006). High producer IL-10 GCC haplotype seemed to be associated with 2.11-fold (95% CI, 1.28 3.46; Pc = 0.003) and 2.57-fold (95% CI, 1.5-4.4; Pc = 0.0006) increased susceptibility to pTB and epTB, respectively. Combination of TNF-alpha/IL-10 high producer genotypes was associated with increased 3.13-fold (95% CI, 1.23-8.05; Pc = 0.028) susceptibility to epTB. However, combined TNF-alpha/IL-10 low producer genotypes appeared to have protect effect to pTB (OR = 0.44, 95% CI, 0.21-0.89; Pc = 0.04) and epTB (OR = 0.26, 95% CI, 0.1-0.62; Pc = 0.0028). Collectively, our results showed that analysed SNPs in the TNF-alpha and IL-10 gene polymorphisms play key role in susceptibility to or protection against TB development in Tunisian populations. PMID- 21609780 TI - Yersiniabactin iron uptake: mechanisms and role in Yersinia pestis pathogenesis. AB - Yersiniabactin (Ybt) is a siderophore-dependent iron uptake system encoded on a pathogenicity island that is widespread among pathogenic bacteria including the Yersiniae. While biosynthesis of the siderophore has been elucidated, the secretion mechanism and a few components of the uptake/utilization pathway are unidentified. ybt genes are transcriptionally repressed by Fur but activated by YbtA, likely in combination with the siderophore itself. The Ybt system is essential for the ability of Yersinia pestis to cause bubonic plague and important in pneumonic plague as well. However, the ability to cause fatal septicemic plague is independent of Ybt. PMID- 21609781 TI - Activation of DNA damage response signaling in lung adenocarcinoma A549 cells following oxygen beam irradiation. AB - Oxygen beams are high linear energy transfer (LET) radiation characterized by higher relative biological effectiveness than low LET radiation. The aim of the current study was to determine the signaling differences between gamma- and oxygen ion-irradiation. Activation of various signaling molecules was looked in A549 lung adenocarcinoma cells irradiated with 2Gy oxygen, 2Gy or 6Gy gamma radiation. Oxygen beam was found to be three times more cytotoxic than gamma radiation. By 4h there was efficient repair of DNA in A549 cells exposed to 2Gy or 6Gy gamma radiation but not in cells exposed to 2Gy oxygen beam as determined by gamma-H2AX counting. Number of ATM foci was found to be significantly higher in cells exposed to 2Gy oxygen beam. Percentage of cells showing ATR foci were more with gamma however number of foci per cell were more in case of oxygen beam. Oxygen beam irradiated cells showed phosphorylation of Chk1, Chk2 and p53. Many apoptotic nuclei were seen by DAPI staining in cells exposed to oxygen beam. The noteworthy finding of this study is the activation of the sensor proteins, ATM and ATR by oxygen irradiation and the significant activation of Chk1, Chk2 and p53 only in the oxygen beam irradiated cells. PMID- 21609782 TI - A novel liquid-phase piezoelectric immunosensor for detecting Schistosoma japonicum circulating antigen. AB - AIMS: A new liquid-phase piezoelectric immunosensor (LP-PEIS), which can detect Schistosoma japonicum (Sj) circulating antigens (SjCAg) quantificationally, was developed. METHODS: The IgG antibodies were purified from the sera of rabbits which had been infected or immunized by Sj and were immobilized on the surface of piezoelectric quartz crystal in LP-PEIS by staphylococcal protein A (SPA). It was used to detect SjCAg in sera of rabbits which had been infected by Sj in order to acquire some optimum conditions for detecting SjCAg. Finally, the LP-PEIS with optimum conditions was used to detect SjCAg in sera of patients who had been infected by Sj, and was compared with sandwich ELISA. RESULTS: A lot of optimum conditions of LP-PEIS for detecting SjCAg had been acquired. In the detection of patients' sera with acute Schistosomiasis, LP-PEIS has higher positive rate (100%) and lower false positive rate (3.0%) than sandwich ELISA (92.8%, 6.0%). However, there were no significant difference between LP-PEIS and sandwich ELISA. CONCLUSIONS: LP-PEIS can quantificationally detect SjCAg in patients' sera as well as sandwich ELISA. PMID- 21609783 TI - Multiple reassortment and interspecies transmission events contribute to the diversity of feline, canine and feline/canine-like human group A rotavirus strains. AB - RNA-RNA hybridization assays and complete genome sequence analyses have shown that feline rotavirus (FRV) and canine rotavirus (CRV) strains display at least two distinct genotype constellations (genogroups), represented by the FRV strain RVA/Cat-tc/AUS/Cat97/1984/G3P[3] and the human rotavirus (HRV) strain RVA/Human tc/JPN/AU-1/1982/G3P3[9], respectively. G3P[3] and G3P[9] strains have been detected sporadically in humans. The complete genomes of two CRV strains (RVA/Dog tc/ITA/RV198-95/1995/G3P[3] and RVA/Dog-tc/ITA/RV52-96/1996/G3P[3]) and an unusual HRV strain (RVA/Human-tc/ITA/PA260-97/1997/G3P[3]) were determined to further elucidate the complex relationships among FRV, CRV and HRV strains. The CRV strains RV198-95 and RV52-96 were shown to possess a Cat97-like genotype constellation. However, 3 and 5 genes of RV198-95 and RV52-96, respectively, were found in distinct subclusters of the same genotypes, suggesting the occurrence of reassortment events among strains belonging to this FRV/CRV/HRV genogroup. Detailed phylogenetic analyses of the HRV strain PA260-97 showed that (i) 8 genome segments (VP3, VP4, VP6, VP7 and NSP2-5) clustered closely with RV198-95 and/or RV52-96; (ii) 2 genome segments (VP1 and VP2) were more closely related to HRV AU-1; and (iii) 1 genome segment (NSP1) was distantly related to any other established NSP1 genotypes and was ratified as a new NSP1 genotype, A15. These findings suggest that the human strain PA260-97 has a history of zoonotic transmission and is likely a reassortant among FRV/CRV strains from the Cat97 and AU-1-like genogroups. In addition, a potential third BA222-05-like genogroup of FRV and HRV strains should be recognized, consisting of rotavirus strains with a stable genetic genotype constellation of genes also partially related to bovine rotavirus (BRV) and bovine-like rotaviruses. The detailed phylogenetic analysis indicated that three major genotype constellations exist among FRV, CRV and feline/canine-like HRV strains, and that reassortment and interspecies transmission events contribute significantly to their wide genetic diversity. PMID- 21609784 TI - Fluorescence analysis detects gp60 subtype diversity in Cryptosporidium infections. AB - Ninety percent of human cryptosporidiosis infections are attributed to two species; the anthroponotic Cryptosporidium hominis and the zoonotic Cryptosporidium parvum. Sequence analysis of the hypervariable gp60 gene, which is used to classify Cryptosporidium to the subtype level, has highlighted extensive intra-species diversity within both C. hominis and C. parvum. The gp60 has also facilitated contamination source tracking and increased understanding of the epidemiology of cryptosporidiosis. Two surface glycoproteins, the gp40 and gp15 are encoded in the gp60 gene; both are exposed to the hosts' immune system and play a pivotal role in the disease initiation process. The extent of genetic diversity observed within the gp60 would support the hypotheses of significant selection pressure placed on the gp40 and gp15. This study used a dual fluorescent terminal-restriction fragment length polymorphism (T-RFLP) analysis to investigate the genetic diversity of Cryptosporidium subtype populations in a single host infection. Terminal-RFLP showed subtype variation within one human Cryptosporidium sample and mouse samples from seven consecutive passages with C. parvum. Furthermore, this was the first study to show that differences in the ratio of subtype populations occur between infections. T-RFLP has provided a novel platform to study infection populations and to begin to investigate the impact of the hosts' immune system on the gp60 gene. PMID- 21609785 TI - Non-ionic surfactant vesicles mediated transcutaneous immunization against hepatitis B. AB - Transcutaneous immunization (TI) has many practical merits compared to parenteral routes of administration. In the present study, non ionic surfactant vesicular carrier, i.e. niosomes, was evaluated for topical delivery of vaccines using hepatitis B surface protein as an antigen and cholera toxin B as an adjuvant. Niosomes were characterized for size, shape, entrapment efficiency and in process antigen stability. In vitro permeation and skin deposition studies of antigen were performed using human cadaver skin. Skin penetration efficiency of niosomes was assessed by confocal laser scanning microscopy. The immune stimulating activity of these vesicles was studied by measuring the serum IgG titer, isotype ratio IgG2a/IgG1 and mucosal immune responses following transcutaneous immunization in Balb/c mice and results were compared with the alum adsorbed HBsAg given intramuscularly and topically administered plain HBsAg solution. The result shows that optimal niosomal formulation could entrap 58.11 +/- 0.71 of antigen with vesicle size range of 2.83 +/- 0.29 MUm. Serum IgG titers after three consecutive topical administrations were significantly better than single administration of hepatitis antigen with niosomal system, suggesting an effective stimulation of serum immune response; higher IgG1/IgG2a ratio revealed CTB mixed niosomes elicit both Th1 and Th2 responses. This study suggests that topical immunization with cholera toxin B is potential adjuvant for cutaneous immune responses when coadministered with the HBsAg encapsulated niosomes. Results also suggest that the investigated niosomes systems can be effective as topical delivery of vaccines. PMID- 21609786 TI - Protective effect of Artin M from extract of Artocarpus integrifolia seeds by Th1 and Th17 immune response on the course of infection by Candida albicans. AB - The immunoregulatory effect of Artin M and jacalin from extract of Artocarpus integrifolia seeds (jack extract) against infection with Candida albicans was investigated. Swiss mice received jack extract containing 500 MUg protein/ml PBS intraperitoneally (i.p.) or PBS alone and after 72 h were infected i.p. with C. albicans CR15 (10(7)) and sacrificed after 30 min, 2, 6, 24, and 72 h. ELISA analysis revealed that in jack extract-treated mice IFN-gamma was predominantly produced versus IL-10 in control mice. These results suggest that jack extract induced a protective immune response, since C. albicans clearance was complete at 72 h postinfection. Jack extract presents two lectins (Artin M and jacalin) with distinct biological properties. Artin M was able to induce IL-12 production by macrophages. Also, Artin M in different concentrations, associated with jacalin or in jack extract induced both IFN-gamma and IL-17 production. As a consequence, phagocytic and candidacidal activity increased significantly. Alanine aminotransferase activity (ALT) was used as parameter for damage of the liver. The activity of ALT correlated with inoculum size that increased significantly in control group, however, mice pretreated with jack extract 3 days before infection presented normal ALT. Mice pretreated with jack extract that received a lethal inoculum of Candida presented 90% survival versus 20% among controls or mice pretreated with jacalin. Thus, the results suggest that Artin M by itself, associated with jacalin or present in jack extract is able to induce protective Th1 and Th17 immune responses against Candida albicans infection. PMID- 21609787 TI - Compartmental chest wall volume changes during volitional normocapnic hyperpnoea. AB - During increased ventilation, inspiratory rib cage muscles have been suggested to take over part of diaphragmatic work after the diaphragm fatigues. We investigated the extent to which this proposed change in muscle recruitment is associated with changes in the relative contribution of chest wall compartments to tidal volume (V(T)). Thirteen healthy subjects performed 1 h of fatiguing normocapnic hyperpnoea. Chest wall volumes were assessed by optoelectronic plethysmography. While breathing frequency increased (43+/-3 to 56+/-5 breaths min(-1), p=0.006) and V(T) decreased during normocapnic hyperpnoea (2.6+/-0.2 to 1.9+/-0.1l, p<0.001), the relative contribution of chest wall compartments to V(T) remained unchanged (pulmonary rib cage: 48+/-9 versus 51+/-14%; abdominal rib cage: 24+/-4 versus 23+/-9%; abdomen: 28+/-8 versus 26+/-9%; all p>0.05). In conclusion, fatiguing respiratory work is not associated with a change in compartmental contribution to V(T), even in the presence of a change in breathing pattern. PMID- 21609788 TI - Alteration of carotid body chemoreflexes after neonatal intermittent hypoxia and caffeine treatment in rat pups. AB - In human neonates, caffeine therapy for apnoea of prematurity, especially when associated with hypoxemia, is maintained for several weeks after birth. In the present study, we used newborn rats and whole-body plethysmography to test whether chronic exposure to neonatal caffeine treatment (NCT), alone or combined with neonatal intermittent hypoxia (n-IH) alters: (1) baseline ventilation and response to hypoxia (12% O(2), 20 min); and (2) response to acute i.p. injection of caffeine citrate (20 mg/kg) or domperidone, a peripheral dopamine D2 receptor antagonist (1 mg/kg). Four groups of rats were studied as follows: raised under normal conditions with daily gavage with water (NWT) or NCT, or exposed to n-IH (n-IH+NWT and n-IH+NCT) from postnatal days 3 to 12. In n-IH+NCT rats, baseline ventilation was higher than in the other groups. Caffeine or domperidone enhanced baseline ventilation only in NWT and n-IH+NWT rats, but neither caffeine nor domperidone affected the hypoxic ventilatory response in these groups. In n IH+NWT rats, the response during the early phase of hypoxia (<10 min) was higher than in other groups. During the late response phase to hypoxia (20 min), ventilation was lower in n-IH+NWT and n-IH+NCT rats compared to NWT or NCT, and were not affected by caffeine or domperidone injection. NCT or caffeine injection decreased baseline apnoea frequency in all groups. These data suggest that chronic exposure to NCT alters both carotid body dopaminergic and adenosinergic systems and central regulation of breathing under baseline conditions and in response to hypoxia. PMID- 21609790 TI - Identification of the phosphorylation sites in the survival motor neuron protein by protein kinase A. AB - The survival motor neuron (SMN) protein plays an essential role in the assembly of uridine-rich small nuclear ribonuclear protein complexes. Phosphorylation of SMN can regulate its function, stability, and sub-cellular localization. This study shows that protein kinase A (PKA) phosphorylates SMN both in vitro and in vivo. Bioinformatic analysis predicts 12 potential PKA phosphorylation sites in human SMN. Mass spectrometric analysis of a tryptic digest of SMN after PKA phosphorylation identified five distinct phosphorylation sites in SMN (serines 4, 5, 8, 187 and threonine 85). Mutagenesis of this subset of PKA-phosphorylated sites in SMN affects association of SMN with Gemin2 and Gemin8. This result indicates that phosphorylation of SMN by PKA may play a role in regulation of the in vivo function of SMN. PMID- 21609789 TI - Airway inflammation and central respiratory control: results from in vivo and in vitro neonatal rat. AB - In infants, respiratory infection elicits tachypnea. To begin to evaluate the role of brainstem cytokine expression in modulation of breathing pattern changes, we compared the pattern generated after endotracheal instillation of lipopolysaccharide (LPS) in in vivo rat pups to local pro-inflammatory cytokine injection in the nucleus tractus solitarius (nTS) in an in vitro en bloc brainstem spinal cord preparation. We hypothesized that both challenges would elicit similar changes in patterning of respiration. In anesthetized, spontaneously breathing rat pups, lipopolysaccharide (LPS) or saline was instilled in the airway of urethane-anesthetized rats (postnatal days 10-11). We recorded diaphragm EMG over the subsequent 2h and saw a 20-30% decrease in interburst interval (Te) at 20-80min post-injection in LPS-instilled animals with no significant change in Ti. In contrast, IL-1beta injections into the nTS of en bloc in vitro brainstem-spinal cord preparations from 0 to 5 day-old pups maintained Ti and caused an increase in Te as early as 20min later, decreasing frequency for 80-120min after injection. Our results suggest that the neonatal respiratory response to the cytokine IL-1beta mediated inflammatory response depends on the site of the inflammatory stimulus and that the direct effect of IL 1beta in the nTS is to slow rather than increase rate. PMID- 21609792 TI - SPIRE: Systematic protein investigative research environment. AB - The SPIRE (Systematic Protein Investigative Research Environment) provides web based experiment-specific mass spectrometry (MS) proteomics analysis (https://www.proteinspire.org). Its emphasis is on usability and integration of the best analytic tools. SPIRE provides an easy to use web-interface and generates results in both interactive and simple data formats. In contrast to run based approaches, SPIRE conducts the analysis based on the experimental design. It employs novel methods to generate false discovery rates and local false discovery rates (FDR, LFDR) and integrates the best and complementary open-source search and data analysis methods. The SPIRE approach of integrating X!Tandem, OMSSA and SpectraST can produce an increase in protein IDs (52-88%) over current combinations of scoring and single search engines while also providing accurate multi-faceted error estimation. One of SPIRE's primary assets is combining the results with data on protein function, pathways and protein expression from model organisms. We demonstrate some of SPIRE's capabilities by analyzing mitochondrial proteins from the wild type and 3 mutants of C. elegans. SPIRE also connects results to publically available proteomics data through its Model Organism Protein Expression Database (MOPED). SPIRE can also provide analysis and annotation for user supplied protein ID and expression data. PMID- 21609793 TI - Implant stability is affected by local bone microstructural quality. AB - It is known that low bone quality, caused for instance by osteoporosis, not only increases the risk of fractures, but also decreases the performance of fracture implants; yet the specific mechanisms behind this phenomenon are still largely unknown. We hypothesized that especially peri-implant bone microstructure affects implant stability in trabecular bone, to a greater degree than more distant bone. To test this hypothesis we performed a computational study on implant stability in trabecular bone. Twelve humeral heads were measured using micro-computed tomography. Screws were inserted digitally into these heads at 25 positions. In addition, at each screw location, a virtual biopsy was taken. Bone structural quality was quantified by morphometric parameters. The stiffness of the 300 screw bone constructs was quantified as a measure of implant stability. Global bone density correlated moderately with screw-bone stiffness (r2=0.52), whereas local bone density was a very good predictor (r2=0.91). The best correlation with screw bone stiffness was found for local bone apparent Young's modulus (r2=0.97), revealing that not only bone mass but also its arrangement in the trabecular microarchitecture are important for implant stability. In conclusion, we confirmed our hypothesis that implant stability is affected by the microstructural bone quality of the trabecular bone in the direct vicinity of the implant. Local bone density was the best single morphometric predictor of implant stability. The best predictability was provided by the mechanical competence of the peri-implant bone. A clinical implication of this work is that apparently good bone stock, such as assessed by DXA, does not guarantee good local bone quality, and hence does not guarantee good implant stability. New tools that could quantify the structural or mechanical quality of the peri-implant bone may help improve the surgical intervention in reaching better clinical outcomes for screw fixation. PMID- 21609794 TI - Invited commentary: outcome of carotid artery interventions among female patients, 2004 to 2005. PMID- 21609791 TI - Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications. AB - Aldehyde dehydrogenases (ALDHs) represent large family members of NAD(P)+ dependent dehydrogenases responsible for the irreversible metabolism of many endogenous and exogenous aldehydes to the corresponding acids. Among 19 ALDH isozymes, mitochondrial ALDH2 is a low Km enzyme responsible for the metabolism of acetaldehyde and lipid peroxides such as malondialdehyde and 4-hydroxynonenal, both of which are highly reactive and toxic. Consequently, inhibition of ALDH2 would lead to elevated levels of acetaldehyde and other reactive lipid peroxides following ethanol intake and/or exposure to toxic chemicals. In addition, many East Asian people with a dominant negative mutation in ALDH2 gene possess a decreased ALDH2 activity with increased risks for various types of cancer, myocardial infarct, alcoholic liver disease, and other pathological conditions. The aim of this review is to briefly describe the multiple post-translational modifications of mitochondrial ALDH2, as an example, after exposure to toxic chemicals or under different disease states and their pathophysiological roles in promoting alcohol/drug-mediated tissue damage. We also briefly mention exciting preclinical translational research opportunities to identify small molecule activators of ALDH2 and its isozymes as potentially therapeutic/preventive agents against various disease states where the expression or activity of ALDH enzymes is altered or inactivated. PMID- 21609796 TI - Reinterventions during midterm follow-up after endovascular treatment of thoracic aortic disease. AB - OBJECTIVES: To report incidence, indication, and timing of reinterventions after thoracic endovascular aortic repair (TEVAR) and identify subgroups most prone to reinterventions. METHODS: Between January 1997 and March 2010, a total of 264 patients received TEVAR in our institution. During follow-up, 58 patients (39 men, median age 63 years, range 28-87 years) required a total of 68 reinterventions, which represent the study population of this retrospective, single center analysis. The mean follow-up of all 264 patients was 31.2 months (range 0-141 months). RESULTS: The overall reintervention rate was 22%: 1-, 3-, and 5-year free reintervention rates were 82% +/- 3%, 74% +/- 3%, and 70% +/- 4%, respectively. Indications for reintervention were predominately endoleaks (41%) and progression of the underlying aortic disease (29%). Reinterventions were performed by endovascular means in 44%, by open repair in 35% (including 11 conversions), and by hybrid procedures in 21%. Multiple logistic regression analysis revealed patients with chronic expanding aortic dissections (odds ratio [OR]: 2.35), hybrid aortic procedures (OR: 2.11), and connective tissue diseases (OR: 7.54) at an increased risk for reintervention. The necessity for reintervention did not influence survival in this cohort (log-rank test P = .1706). CONCLUSIONS: TEVAR is associated with a relevant reintervention rate, predominately caused by endoleaks and progression of the aortic pathology. Patients with chronic expanding aortic dissections, hybrid aortic procedures, and connective tissue diseases are at an increased risk for reintervention and should therefore undergo close follow-up. PMID- 21609795 TI - National trends and regional variation of open and endovascular repair of thoracic and thoracoabdominal aneurysms in contemporary practice. AB - OBJECTIVES: Successful surgical management of thoracic aortic aneurysms (TAA) and thoracoabdominal aortic aneurysms (TAAA) has historically relied upon open surgical repair (OSR). More recently, the advent and application of thoracic endovascular stent graft aneurysm repair (TEVAR) permutations have become increasingly performed in contemporary practice. To better determine the effect of TEVAR techniques on OSR, we examined national and regional trends in treatment use. METHODS: All Medicare patients from 1998 through 2007 undergoing isolated TAA and TAAA repair were analyzed using a clinically validated algorithm using diagnostic International Classification of Disease 9th revision (ICD-9; 441.1, 441.2, 441.6, 441.7, 441.9) codes and procedural (ICD-9 OSR: 38.35, 38.45 and TEVAR: 39.73, 39.79) codes. Differential rates of OSR and TEVAR were compared across census tract regions during the study interval. RESULTS: Total complex aortic repairs increased by 60%, from 10.8 to 17.8/100,000, between 1998 and 2007 (P < .001). A dramatic increase occurred in TEVAR (not performed in 1998, 5.8/100,000 in 2007) during the study period, but OSR rates remained stable during the same interval (10.7 to 12.0/100,000 in 2007, P = NS). There was substantial regional variation for both OSR and TEVAR. This regional variation was greater in OSR (range, 8.8-16.7/100,000) than in TEVAR (range, 4.5 6.9/100,000). CONCLUSIONS: Degenerative TAA and TAAA aneurysms are being repaired in the United States at an increasing rate. This reflects the rapid acceptance of TEVAR, which apparently supplements rather than supplants OSR. There appears to be greater regional variation in OSR compared with TEVAR. These data may have significant implications for those interested in the effect of new technologies on health care and cost containment. PMID- 21609797 TI - A prospective, randomized comparison of bovine carotid artery and expanded polytetrafluoroethylene for permanent hemodialysis vascular access. AB - BACKGROUND: Many patients on hemodialysis do not have adequate anatomy for native arteriovenous fistulas. In these patients, synthetic conduits remain an alternative option for permanent hemodialysis access. We sought to compare the standard cuffed expanded polytetrafluoroethylene (ePTFE) graft with the bovine carotid artery (BCA) graft. METHODS: This was a prospective, randomized controlled trial that was set in an academic medical center. We enrolled 26 patients in the BCA group and 27 patients in the ePTFE group. Primary, assisted primary, and secondary patency were calculated using the Kaplan-Meier method. Complications were monitored and are reported. RESULTS: Although there was no significant difference in secondary patency rates, primary and assisted primary patency rates were significantly higher in BCA than in the ePTFE grafts (60.5% vs 10.1% and 60.5% vs 20.8% at 1 year, respectively). The BCA graft survival advantage was most profound in the upper arm grafts with significantly higher primary and assisted patency rates (P < .0001 and .0005, respectively). The total number of interventions (upper arm grafts) and total number of angioplasties (overall and upper arm) required to maintain patency were significantly fewer in the BCA group. The most common complication was graft thrombosis which occurred 0.34 +/- 0.09 times per patient year in the BCA group compared to 0.77 +/- 0.16 times per patient year in the ePTFE group, P = .01. CONCLUSION: The BCA graft is an excellent option for patients on hemodialysis that are not suitable for native arteriovenous fistulas, as these grafts required fewer interventions than the ePTFE grafts to maintain patency. PMID- 21609798 TI - Skin erythrodiapedesis during chronic venous disorders. AB - BACKGROUND: Extravasation of erythrocytes (erythrodiapedesis [ED]) is currently included among causes of skin damage in legs with chronic venous disorders (CVD) and ascribed to venular hypertension. ED is followed by erythrocyte disruption, degradation of hemoglobin, and storing of ferric iron into hemosiderin. The aim of this study was to evaluate the occurrence of ED in the skin of legs with different clinical stages of CVD. METHODS: One hundred eighteen skin biopsies from legs with CVD underwent histologic evaluation for ED and hemosiderin deposition (HD). RESULTS: ED was found in only 21/118 specimens. In particular, it was found in ulcer samples, in tissues surrounding varicophlebitis and, finally, in acute eczematous skin. ED was found in only 15/30 samples showing HD. CONCLUSION: Our findings confirm the occurrence of ED during CVD. However, it was found only in concomitance of severe dermal inflammation. Hemosiderin deposition in the absence of actual ED could be explained with previous healed episodes of skin inflammation. However, ED is not likely the only cause of skin iron overload, which could also occur by a molecular mechanism. Further studies are needed to define the mechanism of iron deposition in the skin of legs afflicted with CVD. PMID- 21609799 TI - Effect of hyperglycemia and neuropeptides on interleukin-8 expression and angiogenesis in dermal microvascular endothelial cells. AB - BACKGROUND: Impaired wound healing is a major complication associated with diabetes, involving a dysregulation and impairments in the inflammatory and angiogenic phases of wound healing. Here, we examine the effects of the neuropeptides substance P (SP) and neuropeptide Y (NPY) on dermal microvascular endothelial cell (DMVEC) angiogenesis and interleukin-8 (IL-8) expression, a known effector of the neuropeptide pathways in normal and hyperglycemic conditions in vitro. METHODS: DMVECs are treated with one of four glucose concentrations: 1) 5 mM glucose; 2) 10 mM glucose; 3) 30 mM glucose; or 4) 30 mM mannitol and cotreated with 100 nM NPY, 100 nM SP, or 10 ng/mL IL-8. Angiogenesis is assessed with proliferation and tube formation assays. IL-8 mRNA and protein expression are evaluated at days 1 and 7. RESULTS: As compared with noromoglycemia (5 mM glucose), hyperglycemia (30 mM glucose) decreases DMVEC proliferation and tube formation by 39% and 42%, respectively. SP cotreatment restores DMVEC proliferation (211%) and tube formation (152%), and decreases IL-8 expression (34%) in DMVECs exposed to hyperglycemic conditions. These effects are not observed with NPY. However, IL-8 treatment by itself does not affect proliferation or tube formation, suggesting that the effect of SP on DMVEC angiogenesis is unlikely through changes in IL-8 expression. CONCLUSION: Hyperglycemic conditions impair DMVEC proliferation and tube formation. SP mitigates the effect of hyperglycemia on DMVECs by increasing DMVEC proliferation and tube formation. These findings are not likely to be related to a dysregulation of IL-8 due to the lack of effects of hyperglycemia on IL-8 expression and the lack of effect of IL-8 on DMVEC proliferation and tube formation. The effect of SP on DMVECs makes SP a promising potential target for therapy in impaired wound healing in diabetes, but the exact mechanism remains unknown. PMID- 21609800 TI - Reporting standards for carotid interventions from the Society for Vascular Surgery. PMID- 21609801 TI - Rapid recurrence of cystic adventitial disease in femoral artery and an etiologic consideration for the cyst. AB - A 53-year-old man, complaining of left calf and hip claudication, was treated with surgery of the occluded common femoral artery. After incision in the artery, gelatinous material came out from the intramural cavity. All the contained material was evacuated, and definitive diagnosis of cystic adventitial disease was confirmed postoperatively. Twenty days later, he complained of identical claudication again. Follow-up study suggested the recurrence. Therefore, the artery replacement with polytetrafluoroethylene graft was performed. Pathologic examinations showed that the adventitial cyst lining cells expressed macrophage markers (CD68 and CD14), while fibroblast-like cells were not found on the lining. Cystic adventitial disease was not derived from synovium in this case. PMID- 21609803 TI - Masson's vegetant intravascular hemangioendothelioma in an external jugular vein aneurysm with recurrent thrombosis. AB - A 50-year-old male patient was admitted for a symptomatic aneurysm of the external jugular vein. Thrombosis of the aneurysm was treated by oral anticoagulant but recurrence of neck swelling and thrombosis occurred 1 year after oral anticoagulant was discontinued. No other vascular anomalies were detected, and blood tests were normal. Surgical resection was done "en bloc" with the muscular fibers in contact. Pathologic examination was compatible with a Masson's vegetant intravascular hemangioendothelioma. To our knowledge, this is the first case of symptomatic Masson's vegetant intravascular hemangioendothelioma diagnosed in a patient with thrombosed aneurysm of a cervical vein. PMID- 21609802 TI - Mechanical and pharmacologic catheter-directed thrombolysis treatment of severe, symptomatic, bilateral deep vein thrombosis with congenital absence of the inferior vena cava. AB - We report the use of mechanical and pharmacologic catheter-directed thrombolysis in treating deep vein thrombosis with congenital absence of the inferior vena cava The patient presented with disabling bilateral lower extremity swelling and pain and was found to have extensive bilateral iliofemoral deep vein thromboses. Genetic testing revealed a factor V Leiden mutation. The patient underwent thrombolysis using a Possis (MEDRAD Inc, Warrendale, Pa) catheter and overnight infusion of tissue plasminogen activator. The patient tolerated the procedure well, with prompt return to daily activities. He remains free of symptoms at 3 years on oral anticoagulation, with a patent venous architecture. PMID- 21609804 TI - Early and late outcomes of percutaneous treatment of TransAtlantic Inter-Society Consensus class C and D aorto-iliac lesions. AB - OBJECTIVES: The aim of this study was to analyze the technical success and long term patency of the endovascular treatment of TransAtlantic Inter-Society Consensus (TASC) C and D aorto-iliac arterial lesions. METHODS: All studies reporting original series of patients published in English between 2000 and 2010 were enrolled into meta-analysis. Separate meta-analyses were performed for groups with immediate technical success, 12-month patency, and long-term outcomes. Subgroup analyses were performed to determine if there were differences in outcomes between patients with varying types of lesions (TASC C or D lesions) or between different stenting strategies, including primary or selective stenting. RESULTS: Sixteen articles consisting of 958 patients were enrolled in this meta-analysis. The pooled estimate for technical success was 92.8% (95% confidence interval [CI], 89.8%-95.0%, 749 cases). Primary patency at 12 months was 88.7% (95% CI, 85.9%-91.0%, 787 cases). Subgroup analyses demonstrated a technical success rate of 93.7% (95% CI, 88.9%-96.5%) and a 12-month primary patency rate of 89.6% (95% CI, 84.8%-93.0%) for TASC C lesions. For TASC D lesions, these rates were 90.1% (95% CI, 76.6%-96.2%) and 87.3% (95% CI, 82.5% 90.9%), respectively. The technical success and 12-month primary patency rates for primary stenting were 94.2% (95% CI, 91.8%-95.9%) and 92.1% (95% CI, 89.0% 94.3%), respectively; for selective stenting, these rates were 88.0% (95% CI, 67.9%-96.2%) and 82.9% (95% CI, 72.2%-90.0%), respectively. The long-term, primary patency rates for patients receiving primary stenting were significantly better than those receiving selective stenting. Publication bias was not significant for these analyses. CONCLUSIONS: This study demonstrates that early and midterm outcomes of endovascular treatment for TASC C and D aorto-iliac lesions were acceptable, with a better patency for primary stenting than selective stenting. PMID- 21609805 TI - Creation of the Adams-DeWeese inferior vena cava clip. PMID- 21609807 TI - Regarding "congenital anomaly of the external iliac artery: a case report". PMID- 21609808 TI - Regarding "pilot testing of a decision support tool for patients with abdominal aortic aneurysms". PMID- 21609811 TI - Securing the future of our field. PMID- 21609809 TI - Regarding "late outcomes following open and endovascular repair of blunt thoracic aortic injury". PMID- 21609812 TI - A report from Japanese Society of Echocardiography. PMID- 21609814 TI - Focus on laboratory organization and productivity. PMID- 21609815 TI - Global challenges in stem cell research and the many roads ahead. AB - The field of stem cell research has grown to include a vibrant international community of scientists and clinicians who come from both academia and industry and who strive to shed light on the biology of these remarkable cells and find applications in drug discovery, disease modeling, and regenerative medicine. PMID- 21609816 TI - Responsibility rewarded: ethics, engagement, and scientific autonomy in the labyrinth of the minotaur. AB - Dramatic changes in the stem cell ethical and research ecosystem in the last 10 years depended on active engagement among scientists, ethicists, government, and public. Tracing that story demonstrates the value of such engagement, and forecasts a successful method for meeting future challenges. PMID- 21609817 TI - Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. AB - While adult-born neurons in the olfactory bulb (OB) and the dentate gyrus (DG) subregion of the hippocampus have fundamentally different properties, they may have more in common than meets the eye. Here, we propose that new granule cells in the OB and DG may function as modulators of principal neurons to influence pattern separation and that adult neurogenesis constitutes an adaptive mechanism to optimally encode contextual or olfactory information. See the related Perspective from Aimone, Deng, and Gage, "Resolving New Memories: A Critical Look at the Dentate Gyrus, Adult Neurogenesis, and Pattern Separation," in this issue of Neuron. PMID- 21609818 TI - Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. AB - Recently, investigation of new neurons in memory formation has focused on a specific function-pattern separation. However, it has been difficult to reconcile the form of separation tested in behavioral tasks with how it is conceptualized according to computational and electrophysiology perspectives. Here, we propose a memory resolution hypothesis that considers the unique information contributions of broadly tuned young neurons and highly specific mature neurons and describe how the fidelity of memories can relate to spatial and contextual discrimination. See the related Perspective from Sahay, Wilson, and Hen, "Pattern Separation: A Common Function for New Neurons in Hippocampus and Olfactory Bulb," in this issue of Neuron. PMID- 21609819 TI - Translating stem cell studies to the clinic for CNS repair: current state of the art and the need for a Rosetta stone. AB - Since their discovery twenty years ago and prospective isolation a decade later, neural stem cells (NSCs), their progenitors, and differentiated cell derivatives along with other stem-cell based strategies have advanced steadily toward clinical trials, spurred by the immense need to find reparative therapeutics for central nervous system (CNS) diseases and injury. Current phase I/II trials using stem cells in the CNS are the vanguard for the widely anticipated next generation of regenerative therapies and as such are pioneering the stem cell therapy process. While translation has typically been the purview of industry, academic researchers are increasingly driven to bring their findings toward treatments and face challenges in knowledge gap and resource access that are accentuated by the unique financial, manufacturing, scientific, and regulatory aspects of cell therapy. Solutions are envisioned that both address the significant unmet medical need and lead to increased funding for basic and translational research. PMID- 21609821 TI - Constructing and deconstructing stem cell models of neurological disease. AB - Among the disciplines of medicine, the study of neurological disorders is particularly challenging. The fundamental inaccessibility of the human neural types affected by disease prevents their isolation for in vitro studies of degenerative mechanisms or for drug screening efforts. However, the ability to reprogram readily accessible tissue from patients into pluripotent stem (iPS) cells may now provide a general solution to this shortage of human neurons. Gradually improving methods for directing the differentiation of patient-specific stem cells has enabled the production of several neural cell types affected by disease. Furthermore, initial studies with stem cell lines derived from individuals with pediatric, monogenic disorders have validated the stem cell approach to disease modeling, allowing relevant neural phenotypes to be observed and studied. Whether iPS cell-derived neurons will always faithfully recapitulate the same degenerative processes observed in patients and serve as platforms for drug discovery relevant to common late-onset diseases remains to be determined. PMID- 21609820 TI - Neural stem cells: historical perspective and future prospects. AB - How a single fertilized cell generates diverse neuronal populations has been a fundamental biological problem since the 19(th) century. Classical histological methods revealed that postmitotic neurons are produced in a precise temporal and spatial order from germinal cells lining the cerebral ventricles. In the 20(th) century, DNA labeling and histo- and immunohistochemistry helped to distinguish the subtypes of dividing cells and delineate their locations in the ventricular and subventricular zones. Recently, genetic and cell biological methods have provided insights into sequential gene expression and molecular and cellular interactions that generate heterogeneous populations of NSCs leading to specific neuronal classes. This precisely regulated developmental process does not tolerate significant in vivo deviation, making replacement of adult neurons by NSCs during pathology a colossal challenge. In contrast, utilizing the trophic factors emanating from the NSC or their derivatives to slow down deterioration or prevent death of degenerating neurons may be a more feasible strategy. PMID- 21609822 TI - Deriving excitatory neurons of the neocortex from pluripotent stem cells. AB - The human cerebral cortex is an immensely complex structure that subserves critical functions that can be disrupted in developmental and degenerative disorders. Recent innovations in cellular reprogramming and differentiation techniques have provided new ways to study the cellular components of the cerebral cortex. Here, we discuss approaches to generate specific subtypes of excitatory cortical neurons from pluripotent stem cells. We review spatial and temporal aspects of cortical neuron specification that can guide efforts to produce excitatory neuron subtypes with increased resolution. Finally, we discuss distinguishing features of human cortical development and their translational ramifications for cortical stem cell technologies. PMID- 21609823 TI - NG2-glia as multipotent neural stem cells: fact or fantasy? AB - Cycling glial precursors-"NG2-glia"-are abundant in the developing and mature central nervous system (CNS). During development, they generate oligodendrocytes. In culture, they can revert to a multipotent state, suggesting that they might have latent stem cell potential that could be harnessed to treat neurodegenerative disease. This hope has been subdued recently by a series of fate-mapping studies that cast NG2-glia as dedicated oligodendrocyte precursors in the healthy adult CNS-though rare, neuron production in the piriform cortex remains a possibility. Following CNS damage, the repertoire of NG2-glia expands to include Schwann cells and possibly astrocytes-but so far not neurons. This reaffirms the central role of NG2-glia in myelin repair. The realization that oligodendrocyte generation continues throughout normal adulthood has seeded the idea that myelin genesis might also be involved in neural plasticity. We review these developments, highlighting areas of current interest, contention, and speculation. PMID- 21609824 TI - Lake-front property: a unique germinal niche by the lateral ventricles of the adult brain. AB - New neurons and glial cells are generated in an extensive germinal niche adjacent to the walls of the lateral ventricles in the adult brain. The primary progenitors (B1 cells) have astroglial characteristics but retain important neuroepithelial properties. Recent work shows how B1 cells contact all major compartments of this niche. They share the "shoreline" on the ventricles with ependymal cells, forming a unique adult ventricular zone (VZ). In the subventricular zone (SVZ), B1 cells contact transit amplifying (type C) cells, chains of young neurons (A cells), and blood vessels. How signals from these compartments influence the behavior of B1 or C cells remains largely unknown, but recent work highlights growth factors, neurotransmitters, morphogens, and the extracellular matrix as key regulators of this niche. The integration of emerging molecular and anatomical clues forecasts an exciting new understanding of how the germ of youth is actively maintained in the adult brain. PMID- 21609827 TI - Neural stem cell biology in vertebrates and invertebrates: more alike than different? AB - Many of the regulatory mechanisms controlling neural stem cell behavior are proving to be conserved between organisms as diverse as worms and man. Common principles are emerging with respect to the regulation of neural stem cell division and the specification of distinct stem and progenitor cell types. Great progress has been made in recent years in identifying the cellular mechanisms underpinning these processes, thanks in large part to the cross-fertilization of research on different model systems. We review here recent findings that highlight hitherto unappreciated similarities in the cell and molecular biology of neural stem cell self-renewal and differentiation between invertebrates and vertebrates. As well as underscoring the possible conservation of stem cell mechanisms across phyla, these similarities are proving to be practically useful in studying neural stem cell biology in health and disease. PMID- 21609825 TI - Adult neurogenesis in the mammalian brain: significant answers and significant questions. AB - Adult neurogenesis, a process of generating functional neurons from adult neural precursors, occurs throughout life in restricted brain regions in mammals. The past decade has witnessed tremendous progress in addressing questions related to almost every aspect of adult neurogenesis in the mammalian brain. Here we review major advances in our understanding of adult mammalian neurogenesis in the dentate gyrus of the hippocampus and from the subventricular zone of the lateral ventricle, the rostral migratory stream to the olfactory bulb. We highlight emerging principles that have significant implications for stem cell biology, developmental neurobiology, neural plasticity, and disease mechanisms. We also discuss remaining questions related to adult neural stem cells and their niches, underlying regulatory mechanisms, and potential functions of newborn neurons in the adult brain. Building upon the recent progress and aided by new technologies, the adult neurogenesis field is poised to leap forward in the next decade. PMID- 21609828 TI - Distributed coding of actual and hypothetical outcomes in the orbital and dorsolateral prefrontal cortex. AB - Knowledge about hypothetical outcomes from unchosen actions is beneficial only when such outcomes can be correctly attributed to specific actions. Here we show that during a simulated rock-paper-scissors game, rhesus monkeys can adjust their choice behaviors according to both actual and hypothetical outcomes from their chosen and unchosen actions, respectively. In addition, neurons in both dorsolateral prefrontal cortex and orbitofrontal cortex encoded the signals related to actual and hypothetical outcomes immediately after they were revealed to the animal. Moreover, compared to the neurons in the orbitofrontal cortex, those in the dorsolateral prefrontal cortex were more likely to change their activity according to the hypothetical outcomes from specific actions. Conjunctive and parallel coding of multiple actions and their outcomes in the prefrontal cortex might enhance the efficiency of reinforcement learning and also contribute to their context-dependent memory. PMID- 21609826 TI - Integrating physiological regulation with stem cell and tissue homeostasis. AB - Stem cells are uniquely able to self-renew, to undergo multilineage differentiation, and to persist throughout life in a number of tissues. Stem cells are regulated by a combination of shared and tissue-specific mechanisms and are distinguished from restricted progenitors by differences in transcriptional and epigenetic regulation. Emerging evidence suggests that other aspects of cellular physiology, including mitosis, signal transduction, and metabolic regulation, also differ between stem cells and their progeny. These differences may allow stem cells to be regulated independently of differentiated cells in response to circadian rhythms, changes in metabolism, diet, exercise, mating, aging, infection, and disease. This allows stem cells to sustain homeostasis or to remodel relevant tissues in response to physiological change. Stem cells are therefore not only regulated by short-range signals that maintain homeostasis within their tissue of origin, but also by long-range signals that integrate stem cell function with systemic physiology. PMID- 21609829 TI - CYY-1/cyclin Y and CDK-5 differentially regulate synapse elimination and formation for rewiring neural circuits. AB - The assembly and maturation of neural circuits require a delicate balance between synapse formation and elimination. The cellular and molecular mechanisms that coordinate synaptogenesis and synapse elimination are poorly understood. In C. elegans, DD motoneurons respecify their synaptic connectivity during development by completely eliminating existing synapses and forming new synapses without changing cell morphology. Using loss- and gain-of-function genetic approaches, we demonstrate that CYY-1, a cyclin box-containing protein, drives synapse removal in this process. In addition, cyclin-dependent kinase-5 (CDK-5) facilitates new synapse formation by regulating the transport of synaptic vesicles to the sites of synaptogenesis. Furthermore, we show that coordinated activation of UNC 104/Kinesin3 and Dynein is required for patterning newly formed synapses. During the remodeling process, presynaptic components from eliminated synapses are recycled to new synapses, suggesting that signaling mechanisms and molecular motors link the deconstruction of existing synapses and the assembly of new synapses during structural synaptic plasticity. PMID- 21609830 TI - Nonapoptotic function of BAD and BAX in long-term depression of synaptic transmission. AB - It has recently been found that caspases not only function in apoptosis, but are also crucial for nonapoptotic processes such as NMDA receptor-dependent long-term depression (LTD) of synaptic transmission. It remains unknown, however, how caspases are activated and how neurons escape death in LTD. Here we show that caspase-3 is activated by the BAD-BAX cascade for LTD induction. This cascade is required specifically for NMDA receptor-dependent LTD but not for mGluR-LTD, and its activation is sufficient to induce synaptic depression. In contrast to apoptosis, however, BAD is activated only moderately and transiently and BAX is not translocated to mitochondria, resulting in only modest caspase-3 activation. We further demonstrate that the intensity and duration of caspase-3 activation determine whether it leads to cell death or LTD, thus fine-tuning of caspase-3 activation is critical in distinguishing between these two pathways. PMID- 21609831 TI - Microcircuits of functionally identified neurons in the rat medial entorhinal cortex. AB - VIDEO ABSTRACT: Extracellular recordings have elucidated spatial neural representations without identifying underlying microcircuits. We labeled neurons juxtacellularly in medial entorhinal cortex of freely moving rats with a friction based, pipette-stabilization system. In a linear maze novel to the animals, spatial firing of superficial layer neurons was reminiscent of grid cell activity. Layer 2 stellate cells showed stronger theta modulation than layer 3 neurons, and both fired during the ascending phase of field potential theta. Deep layer neurons showed little or no activity. Layer 2 stellate cells resided in hundreds of small patches. At the dorsomedial entorhinal border, we identified larger (putative parasubicular) patches, which contained polarized head-direction selective neurons firing during the descending theta phase. Three axon systems interconnected patches: centrifugal axons from superficial cells to single large patches, centripetal axons from large-patch cells to single small patches, and circumcurrent axons interconnecting large patches. Our microcircuit analysis during behavior reveals modularity of entorhinal processing. PMID- 21609833 TI - Mixed signals: cannabinoid system offers new therapeutic possibilities as well as challenges. PMID- 21609832 TI - Rethinking motor learning and savings in adaptation paradigms: model-free memory for successful actions combines with internal models. AB - Although motor learning is likely to involve multiple processes, phenomena observed in error-based motor learning paradigms tend to be conceptualized in terms of only a single process: adaptation, which occurs through updating an internal model. Here we argue that fundamental phenomena like movement direction biases, savings (faster relearning), and interference do not relate to adaptation but instead are attributable to two additional learning processes that can be characterized as model-free: use-dependent plasticity and operant reinforcement. Although usually "hidden" behind adaptation, we demonstrate, with modified visuomotor rotation paradigms, that these distinct model-based and model-free processes combine to learn an error-based motor task. (1) Adaptation of an internal model channels movements toward successful error reduction in visual space. (2) Repetition of the newly adapted movement induces directional biases toward the repeated movement. (3) Operant reinforcement through association of the adapted movement with successful error reduction is responsible for savings. PMID- 21609834 TI - Chemical inhibitors: the challenge of finding the right target. AB - A paper in this issue of Chemistry & Biology shows that the diaryl oxazole compound UA62784 that targets pancreatic cancer cells interacts with tubulin near the colchicine binding site (Tcherniuk et al., 2011). These findings differ from previous observations, highlighting the challenges of identifying the biological target for chemical inhibitors. PMID- 21609835 TI - Activity-based profiling of 2-oxoglutarate oxygenases. AB - 2-Oxoglutarate oxygenases (2-OGs) are a large enzyme family involved in numerous processes in health and disease. Rotili et al. (2011) describe in this issue of Chemistry & Biology an activity-based protein profiling-based strategy with which the activity of individual members of the 2-OG family can be addressed in the context of complex biological systems. PMID- 21609836 TI - Methylations: a radical mechanism. AB - On the basis of labeling experiments, Grove et al. (2011) have shown how an electrophilic carbon (from an RNA adenosine) can be methylated by S adenosylmethionine-dependent methyltransferases though an original radical mechanism. PMID- 21609837 TI - NIR-mbc94, a fluorescent ligand that binds to endogenous CB(2) receptors and is amenable to high-throughput screening. AB - High-throughput screening (HTS) of chemical libraries is often used for the unbiased identification of compounds interacting with G protein-coupled receptors (GPCRs), the largest family of therapeutic targets. However, current HTS methods require removing GPCRs from their native environment, which modifies their pharmacodynamic properties and biases the screen toward false positive hits. Here, we developed and validated a molecular imaging (MI) agent, NIR-mbc94, which emits near infrared (NIR) light and selectively binds to endogenously expressed cannabinoid CB(2) receptors, a recognized target for treating autoimmune diseases, chronic pain and cancer. The precision and ease of this assay allows for the HTS of compounds interacting with CB(2) receptors expressed in their native environment. PMID- 21609838 TI - Analyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor. AB - Acidic mammalian chitinase (AMCase) is produced in the lung during allergic inflammation and asthma, and inhibition of enzymatic activity has been considered as a therapeutic strategy. However, most chitinase inhibitors are nonselective, additionally inhibiting chitotriosidase activity. Here, we describe bisdionin F, a competitive AMCase inhibitor with 20-fold selectivity for AMCase over chitotriosidase, designed by utilizing the AMCase crystal structure and dicaffeine scaffold. In a murine model of allergic inflammation, bisdionin F treatment attenuated chitinase activity and alleviated the primary features of allergic inflammation including eosinophilia. However, selective AMCase inhibition by bisdionin F also caused dramatic and unexpected neutrophilia in the lungs. This class of inhibitor will be a powerful tool to dissect the functions of mammalian chitinases in disease and represents a synthetically accessible scaffold to optimize inhibitory properties in terms of airway inflammation. PMID- 21609839 TI - A possible oligosaccharide-conjugate vaccine candidate for Clostridium difficile is antigenic and immunogenic. AB - Nosocomial infections with the Gram-positive pathogen Clostridium difficile pose a major risk for hospitalized patients and result in significant costs to health care systems. Here, we present the chemical synthesis of a PS-II hapten of a cell wall polysaccharide of hypervirulent ribotype 027 of C. difficile. Mice were immunized with a conjugate consisting of the synthetic hexasaccharide and the diphtheria toxoid variant CRM(197). The immunogenicity of the glycan repeating unit was demonstrated by the presence of specific IgG antibodies in the serum of immunized mice. Murine monoclonal antibodies interact with the synthetic hexasaccharide, as determined by microarray analysis. Finally, we found that specific IgA antibodies in the stool of hospital patients infected with C. difficile recognize the synthetic PS-II hexasaccharide hapten. PMID- 21609840 TI - Differential effects of thiopeptide and orthosomycin antibiotics on translational GTPases. AB - The ribosome is a major target in the bacterial cell for antibiotics. Here, we dissect the effects that the thiopeptide antibiotics thiostrepton (ThS) and micrococcin (MiC) as well as the orthosomycin antibiotic evernimicin (Evn) have on translational GTPases. We demonstrate that, like ThS, MiC is a translocation inhibitor, and that the activation by MiC of the ribosome-dependent GTPase activity of EF-G is dependent on the presence of the ribosomal proteins L7/L12 as well as the G' subdomain of EF-G. In contrast, Evn does not inhibit translocation but is a potent inhibitor of back-translocation as well as IF2-dependent 70S initiation complex formation. Collectively, these results shed insight not only into fundamental aspects of translation but also into the unappreciated specificities of these classes of translational inhibitors. PMID- 21609841 TI - Directed evolution of the nonribosomal peptide synthetase AdmK generates new andrimid derivatives in vivo. AB - Many lead compounds in the search for new drugs derive from peptides and polyketides whose similar biosynthetic enzymes have been difficult to engineer for production of new derivatives. Problems with generating multiple analogs in a single experiment along with lack of high-throughput methods for structure-based screening have slowed progress in this area. Here, we use directed evolution and a multiplexed assay to screen a library of >14,000 members to generate three derivatives of the antibacterial compound, andrimid. Another limiting factor in reengineering these mega-enzymes of secondary metabolism has been that commonly used hosts such as Escherichia coli often give lower product titers, so our reengineering was performed in the native producer, Pantoea agglomerans. This integrated in vivo approach can be extended to larger enzymes to create analogs of natural products for bioactivity testing. PMID- 21609842 TI - Specific cell-permeable inhibitor of proteasome trypsin-like sites selectively sensitizes myeloma cells to bortezomib and carfilzomib. AB - Proteasomes degrade the majority of proteins in mammalian cells, are involved in the regulation of multiple physiological functions, and are established targets of anticancer drugs. The proteasome has three types of active sites. Chymotrypsin like sites are the most important for protein breakdown and have long been considered the only suitable targets for antineoplastic drugs; however, our recent work demonstrated that inhibitors of caspase-like sites sensitize malignant cells to inhibitors of the chymotrypsin-like sites. Here, we describe the development of specific cell-permeable inhibitors and an activity-based probe of the trypsin-like sites. These compounds selectively sensitize multiple myeloma cells to inhibitors of the chymotrypsin-like sites, including antimyeloma agents bortezomib and carfilzomib. Thus, trypsin-like sites are cotargets for anticancers drugs. Together with inhibitors of chymotrypsin- and caspase-like sites developed earlier, we provide the scientific community with a complete set of tools to separately modulate proteasome active sites in living cells. PMID- 21609843 TI - Directed evolution of a small-molecule-triggered intein with improved splicing properties in mammalian cells. AB - Laboratory-created small-molecule-dependent inteins enable protein structure and function to be controlled posttranslationally in living cells. Previously we evolved inteins that splice efficiently in Saccharomyces cerevisiae only in the presence of the cell-permeable small molecule 4-hydroxytamoxifen (4-HT). In mammalian cells, however, these inteins exhibited lower splicing efficiencies and slower splicing in the presence of 4-HT, as well as higher background splicing in the absence of 4-HT. Here we further evolved ligand-dependent inteins in yeast at 30 degrees C and 37 degrees C. The resulting second-generation evolved inteins exhibit substantially improved splicing yields and kinetics. The improvements carried over to mammalian cells, in which the newly evolved inteins spliced with substantially greater (~2- to 8-fold) efficiency while maintaining low background splicing levels. These second-generation inteins augment the promise of ligand dependent protein splicing for probing protein function in mammalian cells. PMID- 21609844 TI - UA62784 Is a cytotoxic inhibitor of microtubules, not CENP-E. AB - A recent screen for compounds that selectively targeted pancreatic cancer cells isolated UA62784. We found that UA62784 inhibits microtubule polymerization in vitro. UA62784 interacts with tubulin dimers ten times more potently than colchicine, vinblastine, or nocodazole. Competition experiments revealed that UA62784 interacts with tubulin at or near the colchicine-binding site. Nanomolar doses of UA62784 promote the accumulation of mammalian cells in mitosis, due to aberrant mitotic spindles, as shown by immunofluorescence and live cell imaging. Treatment of cancerous cell lines with UA62784 is lethal, following activation of apoptosis signaling. By monitoring mitotic spindle perturbations and apoptosis, we found that the effects of UA62784 and of some known microtubule-depolymerizing drugs are additive. Finally, high content screening of H2B-GFP HeLa cells revealed that low doses of UA62784 and vinblastine potentiate each other to inhibit proliferation. PMID- 21609845 TI - A photoreactive small-molecule probe for 2-oxoglutarate oxygenases. AB - 2-oxoglutarate (2-OG)-dependent oxygenases have diverse roles in human biology. The inhibition of several 2-OG oxygenases is being targeted for therapeutic intervention, including for cancer, anemia, and ischemic diseases. We report a small-molecule probe for 2-OG oxygenases that employs a hydroxyquinoline template coupled to a photoactivable crosslinking group and an affinity-purification tag. Following studies with recombinant proteins, the probe was shown to crosslink to 2-OG oxygenases in human crude cell extracts, including to proteins at endogenous levels. This approach is useful for inhibitor profiling, as demonstrated by crosslinking to the histone demethylase FBXL11 (KDM2A) in HEK293T nuclear extracts. The results also suggest that small-molecule probes may be suitable for substrate identification studies. PMID- 21609846 TI - Identification and characterization of the lysobactin biosynthetic gene cluster reveals mechanistic insights into an unusual termination module architecture. AB - Lysobactin (katanosin B) is a macrocyclic depsipeptide, displaying high antibacterial activity against human pathogens. In this work, we have identified and characterized the entire biosynthetic gene cluster responsible for lysobactin assembly. Sequential analysis of the Lysobacter sp. ATCC 53042 genome revealed the lysobactin gene cluster to encode two multimodular nonribosomal peptide synthetases. As the number of modules found within the synthetases LybA and LybB directly correlates with the primary sequence of lysobactin, a linear logic of lysobactin biosynthesis is proposed. Investigation of adenylation domain specificities in vitro confirmed the direct association between the synthetases and lysobactin biosynthesis. Furthermore, an unusual tandem thioesterase architecture of the LybB termination module was identified. Biochemical characterization of the individual thioesterases in vitro provides evidence that solely penultimate thioesterase domain mediates the cyclization and simultaneous release of lysobactin. PMID- 21609847 TI - Enacyloxins are products of an unusual hybrid modular polyketide synthase encoded by a cryptic Burkholderia ambifaria Genomic Island. AB - Gram-negative Burkholderia cepacia complex (Bcc) isolates were screened for antimicrobial activity against cystic fibrosis microbial pathogens, and the ability of B. ambifaria to inhibit B. multivorans was identified. The activity was mapped to a cluster of cryptic, quorum-sensing-regulated modular polyketide synthase (PKS) genes. Enacyloxin IIa and its stereoisomer designated iso enacyloxin IIa were identified as metabolic products of the gene cluster, which encoded an unusual hybrid modular PKS consisting of multiple proteins with sequence similarity to cis-acyltransferase (cis-AT) PKSs and a single protein with sequence similarity to trans-AT PKSs. The discovery of the potent activity of enacyloxins against drug-resistant bacteria and the gene cluster that directs their production provides an opportunity for engineered biosynthesis of innovative enacyloxin derivatives and highlights the potential of Bcc bacteria as an underexploited resource for antibiotic discovery. PMID- 21609848 TI - Composition and antifungal activity of the essential oil from the rhizome and roots of Ferula hermonis. AB - The analysis of the essential oil from rhizome and roots of Ferula hermonis Boiss. (Apiaceae) by GC-FID, GC-MS and 13C NMR allowed the identification of 79 constituents, more than 90% of the oil, the major one being alpha-pinene (43.3%), followed by alpha-bisabolol (11.1%) and the unusual acetylenic compound 3,5 nonadiyne (4.4%). The antifungal activity of the essential oil before and after fractionation was assayed against several yeasts and filamentous fungi. Purification of the active fractions afforded 3,5-nonadiyne, alpha-bisabolol, jaeschkeanadiol angelate, alpha-bisabolol oxide B and trans-verbenol, as well as two purified fractions, one of them (JB73) with 73% of jaeschkeanadiol benzoate and the other with 50% of spathulenol. Determination of MIC and MFC values of all these products evidenced strong antifungal activities for JB73 and 3,5-nonadiyne. Particularly, against the dermatophyte Tricophyton mentagrophytes, MIC and MFC values were 0.25 MUg/ml for JB73, and 8 MUg/ml for 3,5-nonadiyne, the former being more active than amphotericin B and nystatin. PMID- 21609849 TI - Rheological and fractal characteristics of unconditioned and conditioned water treatment residuals. AB - The rheological and fractal characteristics of raw (unconditioned) and conditioned water treatment residuals (WTRs) were investigated in this study. Variations in morphology, size, and image fractal dimensions of the flocs/aggregates in these WTR systems with increasing polymer doses were analyzed. The results showed that when the raw WTRs were conditioned with the polymer CZ8688, the optimum polymer dosage was observed at 24 kg/ton dry sludge. The average diameter of irregularly shaped flocs/aggregates in the WTR suspensions increased from 42.54 MUm to several hundred micrometers with increasing polymer doses. Furthermore, the aggregates in the conditioned WTR system displayed boundary/surface and mass fractals. At the optimum polymer dosage, the aggregates formed had a volumetric average diameter of about 820.7 MUm, with a one-dimensional fractal dimension of 1.01 and a mass fractal dimension of 2.74 on the basis of the image analysis. Rheological tests indicated that the conditioned WTRs at the optimum polymer dosage showed higher levels of shear-thinning behavior than the raw WTRs. Variations in the limiting viscosity (eta(infinity)) of conditioned WTRs with sludge content could be described by a linear equation, which were different from the often-observed empirical exponential relationship for most municipal sludge. With increasing temperature, the eta(infinity) of the raw WTRs decreased more rapidly than that of the raw WTRs. Good fitting results for the relationships between lgeta(infinity)~T using the Arrhenius equation indicate that the WTRs had a much higher activation energy for viscosity of about 17.86-26.91 J/mol compared with that of anaerobic granular sludge (2.51 J/mol) (Mu and Yu, 2006). In addition, the Bingham plastic model adequately described the rheological behavior of the conditioned WTRs, whereas the rheology of the raw WTRs fit the Herschel-Bulkley model well at only certain sludge contents. Considering the good power-law relationships between the limiting viscosity and sludge content of the conditioned WTRs, their mass fractal dimensions were calculated through the models proposed by Shih et al. (1990), which were 2.48 for these conditioned WTR aggregates. The results demonstrate that conditioned WTRs behave like weak-link flocs/aggregates. PMID- 21609851 TI - Suicidal overdoses of psychotropic drugs by elderly in New York City: comparison with younger adults. AB - We compared New York City suicide victims aged 18-59 with those 60+ according to rates by which psychotropic/analgesic drugs and ethanol contributed to death. Barbiturates were more frequent in the elderly, while antidepressants were more frequent in younger adults. Addressing the potential for overdose with barbiturates may aid suicide prevention in the elderly. PMID- 21609850 TI - The fate of ultrafast degrading polymeric implants in the brain. AB - We have recently reported on an ultrafast degrading tyrosine-derived terpolymer that degrades and resorbs within hours, and is suitable for use in cortical neural prosthetic applications. Here we further characterize this polymer, and describe a new tyrosine-derived fast degrading terpolymer in which the poly(ethylene glycol) (PEG) is replaced by poly(trimethylene carbonate) (PTMC). This PTMC containing terpolymer showed similar degradation characteristics but its resorption was negligible in the same period. Thus, changes in the polymer chemistry allowed for the development of two ultrafast degrading polymers with distinct difference in resorption properties. The in vivo tissue response to both polymers used as intraparenchymal cortical devices was compared to poly(lactic-co glycolic acid) (PLGA). Slow resorbing, indwelling implant resulted in continuous glial activation and loss of neural tissue. In contrast, the fast degrading tyrosine-derived terpolymer that is also fast resorbing, significantly reduced both the glial response in the implantation site and the neuronal exclusion zone. Such polymers allow for brain tissue recovery, thus render them suitable for neural interfacing applications. PMID- 21609852 TI - Development of novel naphthalimide derivatives and their evaluation as potential melanoma therapeutics. AB - Synthesis and anti-melanoma activity of various naphthalimide analogs, rationally modified by introducing isothiocyanate (ITC) and thiourea (TU) functionalities, found in well-known anti-cancer agents, is described. The structure-activity relationship comparison of the novel agents in inhibiting cancer cell growth was evaluated in various melanoma cell lines. Both ITC and TU analogs effectively inhibited cell viability and induced apoptosis in various human melanoma cells. Nitro substitution and increase in alkyl chain length, in general, enhanced the apoptotic activity of ITC derivatives. All the new compounds were well tolerated when injected intraperitoneal (i.p.) in mice at effective doses at which both the ITC and TU derivatives inhibited melanoma tumor growth in mice following i.p. xenograft. The nitro substituted naphthalimide-ITC derivative 3d was found to be the most effective in inducing apoptosis, and in inhibiting melanoma cell and tumor growth. PMID- 21609853 TI - 'Tackling health inequalities' and its pros, cons and contradictions: a commentary on Blackman, Wistow and Byrne. PMID- 21609854 TI - Management of non metastatic phyllodes tumors of the breast: review of the literature. AB - Phyllodes tumors of the breast are rare tumors, accounting for less than 0.5% of all breast tumors. These tumors are comprised of both stromal and epithelial elements; and traditionally they are graded by the use of a set of histologic features into benign, borderline, and malignant subtypes. Unfortunately, the histologic classification of phyllodes tumors does not reliably predict clinical behavior. The mainstay of treatment of non metastatic phyllodes tumors of the breast is complete surgical resection with wide resection margins. Lumpectomy or partial mastectomy is the preferred surgical therapy. However, despite the complete surgical resection, local failure rate may be high; and 22% of malignant tumors may give rise to haematogenous metastases. The most frequent site of distant metastases is the lungs. Several predictive factors of recurrence and metastases have been described in the literature, such as positive surgical margins, increased stromal cellularity, stromal overgrowth, stromal atypia and increased mitotic activity. Nevertheless, the role of adjuvant therapies (radiotherapy and chemotherapy) is presently undefined and should be tested in multicenter, prospective, randomized trials. PMID- 21609855 TI - Using NMR-detected backbone amide 1H exchange to assess macromolecular crowding effects on globular-protein stability. AB - The biophysical properties of proteins in the crowded intracellular environment are expected to differ from those for proteins in dilute solution. Crowding can be studied in vitro through addition of polymers at high concentrations. NMR detected amide (1)H exchange is the only technique that provides equilibrium stability data for proteins on a per-residue basis under crowded conditions. We describe the theory behind amide (1)H exchange and provide a detailed description of the experiments used to quantify globular protein stability at the residue level under crowded conditions. We also discuss the detection of weak interactions between the test protein and the crowding molecules. PMID- 21609856 TI - Fluorescence spectroscopy in thermodynamic and kinetic analysis of pH-dependent membrane protein insertion. AB - Experimental determination of the free energy stabilizing the structure of membrane proteins in their native lipid environment is undermined by a lack of appropriate methods and suitable model systems. Here, we demonstrate how fluorescence correlation spectroscopy can be used to characterize thermodynamics of pH-triggered bilayer insertion of nonconstitutive membrane proteins (e.g., bacterial toxins, colicins). The experimental design is guided by the appropriate thermodynamic scheme which considers two independent processes: pH-dependent formation of a membrane-competent form and its insertion into the lipid bilayer. Measurements of a model protein annexin B12 under conditions of lipid saturation demonstrate that protonation leading to the formation of the membrane-competent state occurs near membrane interface. Lipid titration experiments demonstrate that the free energy of transfer to the intermediate interfacial state is especially favorable, while the free energy of final insertion is modulated by interplay of hydrophobic and electrostatic interactions on the bilayer interface. The general principles of kinetic measurements along the insertion pathway containing interfacial intermediate are discussed and practical examples emphasizing appropriate fitting and normalization procedures are presented. PMID- 21609857 TI - Evaluating the energy-dependent "binding" in the early stage of protein import into chloroplasts. AB - During protein import into chloroplasts, precursor proteins are synthesized in the cytosol with an amino-terminal extension signal and irreversibly bind to chloroplasts under stringent energy conditions, such as low levels of GTP/ATP and low temperature, to form the early translocation intermediates. Whether the states of the early-intermediates that are formed under different energy conditions are similar has not been well studied. To evaluate the early intermediate states, we analyzed how precursor proteins within the early intermediates behave by employing two different approaches, limited proteolysis and site-specific cross-linking. Our results indicate that three different combinations of three different early intermediate stages are present and that the extent of precursor translocation differs between these stages based upon temperature as well as hydrolysis of GTP and ATP. Furthermore, the transition from the second to the third stage was only observed by increasing the temperature. This transition is also accompanied by the hydrolysis of ATP and the movement of the transit peptide. These results suggest the presence of temperature-sensitive and temperature-insensitive ATP-hydrolyzing steps during the early stages of protein import. PMID- 21609858 TI - Use of DNA length variation to detect periodicities in positively cooperative, nonspecific binding. AB - The experiments described here demonstrate ways in which DNA length can be used as an experimental variable for the characterization of positively cooperative, sequence nonspecific DNA binding. Examples are drawn from recent studies of the interactions of O(6)-alkylguanine DNA alkyltransferase (AGT) with duplex DNAs (Melikishvili et al. (2008). Interactions of human O(6)-alkylguanine-DNA alkyltransferase (AGT) with short double-stranded DNAs. Biochemistry 47, 13754 13763). Oscillations in binding density and apparent binding site size (S(app)) are predicted by models in which a single cooperative assembly forms on each DNA molecule and in which enzyme molecules bind full-length binding sites, but not partial ones. These oscillations provide an accurate, DNA-length independent measure of the occluded binding site size (the length of DNA that one protein molecule occupies to the exclusion of others). In addition, length-dependent oscillations in association constant (K) and cooperativity (omega) reveal the degree to which substrate length can influence these parameters. PMID- 21609860 TI - Conformational stability of cytochrome C probed by optical spectroscopy. AB - Over the last 50 years cytochrome c has been used as a model system for studying electron transfer and protein folding processes. Recently, convincing evidence has been provided that this protein is also involved in other biological processes such as the apoptosis and alpha-synuclein aggregation. Numerous lines of evidence suggest that the diversity of the functional properties of cytochrome c is linked to its conformational plasticity. This chapter introduces circular dichroism and absorption spectroscopy, as an ideal tool to explore this protein's conformational in solution. Besides assisting in distinguishing different conformations and in obtaining the equilibrium thermodynamics of the transitions between them, the two spectroscopies can also be used to explore details of heme protein interaction, for example, the influence of the external electric field on the prosthetic heme group. PMID- 21609859 TI - The impact of ions on allosteric functions in human liver pyruvate kinase. AB - Experimental designs used to monitor the magnitude of an allosteric response can greatly influence observed values. We report here the impact of buffer, monovalent cation, divalent cation, and anion on the magnitude of the allosteric regulation of the affinity of human liver pyruvate kinase (hL-PYK) for substrate, phosphoenolpyruvate (PEP). The magnitudes of the allosteric activation by fructose-1,6-bisphosphate (Fru-1,6-BP) and the allosteric inhibition by alanine are independent of most, but not all buffers tested. However, these magnitudes are dependent on whether Mg(2+) or Mn(2+) is included as the divalent cation. In the presence of Mn(2+), any change in K(app-PEP) caused by Fru-1,6-BP is minimal. hL-PYK activity does not appear to require monovalent cation. Monovalent cation binding in the active site impacts PEP affinity with minimum influence on the magnitude of allosteric coupling. However, Na(+) and Li(+) reduce the magnitude of the allosteric response to Fru-1,6-BP, likely due to mechanisms outside of the active site. Which anion is used to maintain a constant monovalent cation concentration also influences the magnitude of the allosteric response. The value of determining the impact of ions on allosteric function can be appreciated by considering that representative structures used in comparative studies have often been determined using protein crystals grown in diverse buffer and salt conditions. PMID- 21609861 TI - Examining ion channel properties using free-energy methods. AB - Recent advances in structural biology have revealed the architecture of a number of transmembrane channels, allowing for these complex biological systems to be understood in atomistic detail. Computational simulations are a powerful tool by which the dynamic and energetic properties, and thereby the function of these protein architectures, can be investigated. The experimentally observable properties of a system are often determined more by energetic than dynamics, and therefore understanding the underlying free energy (FE) of biophysical processes is of crucial importance. Critical to the accurate evaluation of FE values are the problems of obtaining accurate sampling of complex biological energy landscapes, and of obtaining accurate representations of the potential energy of a system, this latter problem having been addressed through the development of molecular force fields. While these challenges are common to all FE methods, depending on the system under study, and the questions being asked of it, one technique for FE calculation may be preferable to another, the choice of method and simulation protocol being crucial to achieve efficiency. Applied in a correct manner, FE calculations represent a predictive and affordable computational tool with which to make relevant contact with experiments. This chapter, therefore, aims to give an overview of the most widely implemented computational methods used to calculate the FE associated with particular biochemical or biophysical events, and to highlight their recent applications to ion channels. PMID- 21609862 TI - Examining cooperative gating phenomena in voltage-dependent potassium channels: taking the energetic approach. AB - Allosteric regulation of protein function is often achieved by changes in protein conformation induced by changes in chemical or electrical potential. In multisubunit proteins, such conformational changes may give rise to cooperativity in ligand binding. Conformational changes between open and closed states are central to the function of voltage-activated potassium (Kv) channel proteins, homotetrameric pore-forming membrane proteins involved in generating and shaping action potentials in excitable cells. Accessible to extremely high signal-to noise ratio in functional measurements, combined with the availability of high resolution structural data for different conformations of the protein, the Kv channel represents an excellent allosteric model system to further understand the aspects of synergism and cooperative effects in protein function. In this chapter, we demonstrate how the use of the simple law of mass action combined with thermodynamic mutant cycle energetic coupling analysis of Kv channel gating can be used to provide valuable information regarding (1) how cooperativity in Kv channel pore opening can be assessed; (2) how one can directly discriminate whether conformational transitions during Kv channel pore opening occur in a concerted or sequential manner; and (3) how mechanistically, the coupling between distant activation gate and selectivity filter functional elements of the prototypical Shaker Kv channel protein might be achieved. In addition to providing valuable insight into the function of this important protein, the conclusions reached at using high-order thermodynamic energetic coupling analysis applied to the Kv channel allosteric model system reveal much about the function of allosteric proteins, in general. PMID- 21609864 TI - Electrostatic contributions to the stabilities of native proteins and amyloid complexes. AB - The ability to predict electrostatic contributions to protein stability from structure has been a long-standing goal of experimentalists and theorists. With recent advances in NMR spectroscopy, it is possible to determine pK(a) values of all ionizable residues for at least small proteins, and to use the pK(a) shift between the folded and unfolded states to calculate the thermodynamic contribution from a change in charge to the change in free energy of unfolding. Results for globular proteins and for alpha-helical coiled coils show that electrostatic contributions to stability are typically small on an individual basis, particularly for surface-exposed residues. We discuss why NMR often suggests smaller electrostatic contributions to stability than X-ray crystallography or site-directed mutagenesis, and discuss the type of information needed to improve structure-based modeling of electrostatic forces. Large pK(a) shifts from random coil values are observed for proteins bound to negatively charged sodium dodecyl sulfate micelles. The results suggest that electrostatic interactions between proteins and charges on the surfaces of membrane lipid bilayers could be a major driving force in stabilizing the structures of peripheral membrane proteins. Finally, we discuss how changes in ionization states affect amyloid-beta fibril formation and suggest that electrostatic repulsion may be a common destabilizing force in amyloid fibrils. PMID- 21609863 TI - Thermal stability of collagen triple helix. AB - Chief among the challenges of characterizing the thermal stability of the collagen triple helix are the lack of the reversibility of the thermal transition and the presence of multiple folding-unfolding steps during the thermal transition which rarely follows the simple two-state, all-or-none mechanism. Despite of the difficulties inherited in the quantitative depiction of the thermal transition of collagen, biophysical studies combined with proteolysis and mutagenesis approaches using full-chain collagens, short synthetic peptides, and recombinant collagen fragments have revealed molecular features of the thermal unfolding of the subdomains of collagen and led to a better understanding of the diverse biological functions of this versatile protein. The subdomain of collagen generally refers to a segment of the long, rope-like triple helical molecule that can unfold cooperatively as an independent unit whose properties (their size, location, and thermal stability) are considered essential for the molecular recognition during the self-assembly of collagen and during the interactions of collagen with other macromolecules. While the unfolding of segments of the triple helix at temperatures below the apparent melting temperature of the molecule has been used to interpret much of the features of the thermal unfolding of full chain collagens, the thermal studies of short, synthetic peptides have firmly established the molecular basis of the subdomains by clearly demonstrating the close dependence of the thermal stability of a triple helix on the constituent amino acid residues at the X and the Y positions of the characteristic Gly-X-Y repeating sequence patterns of the triple helix. Studies using recombinant collagen fragments further revealed that in the context of the long, linear molecule, the stability of a segment of the triple helix is also modulated by long-range impact of the local interactions such as the interchain salt bridges. Together, the combined approaches represent a unique example on delineating molecular properties of a protein under suboptimal conditions. The related knowledge is likely not to be limited to the applications of collagen studies, but contributes to the understanding of the molecular properties and functions of protein in general. PMID- 21609865 TI - Kinetics of allosteric activation. AB - Although enzyme inhibition results in most cases from the competing effect of a ligand with substrate, the ability of ligands to enhance enzyme function requires binding to a site distinct from the active site. This is the basis of allosteric activation of enzyme activity, documented most conspicuously in the vast family of enzymes activated by monovalent cations. In this chapter, we review the basic kinetic aspects of allosteric activation by taking into consideration the biologically relevant case of an enzyme E possessing a single site for substrate S and a single site for the allosteric effector L. PMID- 21609866 TI - Thermodynamics of the protein translocation. AB - Many proteins synthesized in bacteria are secreted from the cytoplasm into the periplasm to function in the cell envelope or in the extracellular medium. The Sec translocase is a primary and evolutionary conserved secretion pathway in bacteria. It catalyzes the translocation of unfolded proteins across the cytoplasmic membrane via the pore-forming SecYEG complex. This process is driven by the proton motive force and ATP hydrolysis facilitated by the SecA motor protein. Current insights in the mechanism of protein translocation are largely based on elaborate multidisciplinary studies performed during the last three decades. To understand the process dynamics, the thermodynamic principles of translocation and the subunit interactions need to be addressed. Isothermal titration calorimetry has been widely applied to study thermodynamics of biological interactions, their stability, and driving forces. Here, we describe the examples that exploit this method to investigate key interactions among components of the Sec translocase and suggest further potential applications of calorimetry. PMID- 21609867 TI - Equilibrium and kinetic approaches for studying oligomeric protein folding. AB - This chapter describes the approaches and considerations necessary for extension of current protein folding methods to the equilibrium and kinetic reactions of oligomeric proteins, using dimers as the primary example. Spectroscopic and transport methods to monitor folding and unfolding transitions are summarized. The data collection and analyses to determine protein stability and kinetic folding mechanisms are discussed in the context of the additional dimension of complexity that arises in higher order folding processes, compared to first order monomeric proteins. As a case study to illustrate the data analysis process, equilibrium, and kinetic data are presented for SmtB, a homodimeric DNA-binding protein from Synechococcus PCC7942. PMID- 21609869 TI - Thermodynamic and kinetic analysis of bromodomain-histone interactions. AB - Multiple factors are involved when selecting a technique and designing experiments to investigate emerging questions in biochemistry. Success depends on a conceptual understanding of a given spectroscopic approach and the ability to design a system to optimize the quality of the acquired data. In this chapter, we discuss fluorescence anisotropy and its application in characterizing the factors that drive the acetylation-dependent interactions between histone and bromodomain proteins. The steady-state and pre-steady-state binding events associated with biomolecular assemblies can be quantified with this technique, so long as the proper assays and binding models are developed. To accomplish this, the continuum of experimental considerations from instrumental setup and choice of fluorophore, to experimental procedures, and data analysis is described. The methodology is discussed in sufficient detail such that this chapter is a complete guide to setting up and performing fluorescence anisotropy measurements to study biomolecular interactions. A thermodynamic and kinetic analysis is performed to determine the factors that drive molecular recognition and binding affinity, resulting in the identification of an induced-folding mechanism. PMID- 21609868 TI - Methods for quantifying T cell receptor binding affinities and thermodynamics. AB - alphabeta T cell receptors (TCRs) recognize peptide antigens bound and presented by class I or class II major histocompatibility complex (MHC) proteins. Recognition of a peptide/MHC complex is required for initiation and propagation of a cellular immune response, as well as the development and maintenance of the T cell repertoire. Here, we discuss methods to quantify the affinities and thermodynamics of interactions between soluble ectodomains of TCRs and their peptide/MHC ligands, focusing on titration calorimetry, surface plasmon resonance, and fluorescence anisotropy. As TCRs typically bind ligand with weak to-moderate affinities, we focus the discussion on means to enhance the accuracy and precision of low-affinity measurements. In addition to further elucidating the biology of the T cell mediated immune response, more reliable low-affinity measurements will aid with more probing studies with mutants or altered peptides that can help illuminate the physical underpinnings of how TCRs achieve their remarkable recognition properties. PMID- 21609870 TI - Thermodynamics of 2-Cys peroxiredoxin assembly determined by isothermal titration calorimetry. AB - Oligomerization is a frequently encountered physical characteristic of biological molecules that occurs for a wide number of transcription factors, ion channels, oxygen-carrying macromolecules such as hemocyanin and enzymes. On the other hand, unwanted protein oligomerization can lead to the formation of pathogenic structures related with Alzheimer and other diseases. Self-assembly is also a well-described phenomenon within peroxiredoxins, a family of thiol peroxidases. Peroxiredoxin hyperaggregate formation is the key mechanism that triggers the switch between Prx activity as peroxidase and chaperone. The oligomerization process is fundamental for understanding the multiple peroxiredoxin function. The chapter gives a detailed description of typical 2-Cys Peroxiredoxin oligomerization using isothermal titration calorimetry (ITC) and provides a recipe for studying the thermodynamic parameters of peroxiredoxin assembly, that is, association and dissociation constant, enthalpy, entropy, and the Gibbs free energy of the process. PMID- 21609871 TI - Protein-lipid interactions role of membrane plasticity and lipid specificity on peripheral protein interactions. AB - Lipid mixtures are inherently nonrandom as each lipid species differs slightly in its chemical structure. A protein associates not with a lipid but with a membrane comprised of lipids where the chemical activities of each lipid is determined by the composition of the mixture. There can be selectivity in this association because a protein can enhance the underlying tendency of lipids to be heterogeneously distributed. This is dependent on the protein having a preferential association of sufficient magnitude with some of the lipids within the membrane. To measure and model protein-lipid interactions, an understanding of the underlying lipid behavior is necessary to interpret their association constants. Methods to measure protein-lipid interactions are discussed within the context of using these techniques in modeling and a general framework is presented for the use of a signal arising from these interactions. The use of binding partition functions is presented as this allows the modeling of cooperative or independent (noncooperative) interactions of protein with lipids and of proteins with additional ligands as well as lipids. A model is also provided using the binding partition function formalism where protein dimerization, and by extension, oligomerization is enhanced at the membrane compared to in solution. PMID- 21609872 TI - Predicting pKa values with continuous constant pH molecular dynamics. AB - Knowledge of pK(a) values is important for understanding structure and function relationships in proteins. Over the past two decades, theoretical methods for pK(a) calculations have been mainly based on macroscopic models, in which the protein is considered as a low-dielectric cavity embedded in a high-dielectric continuum. In recent years, constant pH molecular dynamics methods have been developed based on a microscopic description of the protein. We describe here the methodology of continuous constant pH molecular dynamics (CPHMD), which has emerged as one of the most robust and accurate tools for predicting protein pK(a)s and for the study of pH-modulated conformational dynamics. We illustrate the utility of CPHMD by the calculation of pK(a)s for surface residues in ribonuclease A, buried residues in staphylococcal nuclease, and titratable groups in the intrinsically flexible protein alpha-lactalbumin. We will compare the CPHMD results with experimental data as well as calculations from PB-based and empirical methods. These examples demonstrate the accuracy and robustness of the CPHMD method and its ability to capture the correlation between ionization equilibria and conformational dynamics as well as the local dielectric response to structural rearrangement. Finally, we discuss future improvement of the CPHMD method. PMID- 21609873 TI - Unfolding thermodynamics of DNA intramolecular complexes involving joined triple- and double-helical motifs. AB - Our laboratory is interested in predicting the thermal stability and melting behavior of nucleic acids from knowledge of their sequence. One focus is to understand how sequence, duplex and triplex stabilities, and solution conditions affect the melting behavior of complex DNA structures, such as intramolecular DNA complexes containing triplex and duplex motifs. For these reasons, in this chapter, we used a combination of UV and circular dichroism (CD) spectroscopies and differential scanning calorimetry (DSC) techniques to obtain a full thermodynamic description of the melting behavior of six intramolecular DNA complexes with joined triplex and duplex motifs. The CD spectra at low temperatures indicated that these complexes maintained the "B" conformation. UV and DSC melting curves of each complex show biphasic or triphasic transitions. However, their corresponding transition temperatures (T(m)s) remained constant with increasing strand concentration, confirming their intramolecular formation. Deconvolution of the DSC thermograms allowed us to determine standard thermodynamic profiles for the transitions of each complex. For each transition, the favorable free energy terms result from the characteristic compensation of a favorable enthalpy and unfavorable entropy contributions. The magnitude of these thermodynamic parameters (and associated T(m)s) indicate that the overall folding of each complex depends on several factors: (a) the extent of the favorable heat contributions (formation of base-pair and base-triplet stacks) that are compensated with both the ordering of the oligonucleotide and the putative uptake of protons and ions; (b) inclusion of the more stable C(+)GC base triplets; (c) stabilizing the duplex stem of the complex; and (d) solution conditions, such as pH and salt concentration. Overall, the temperature-induced unfolding of each complex corresponds to the initial disruption of the triplex motif (removal of the third strand) followed by the partial or full unfolding of the duplex stem. PMID- 21609874 TI - Thermodynamics and conformational change governing domain-domain interactions of calmodulin. AB - Calmodulin (CaM) is a small (148 amino acid), ubiquitously expressed eukaryotic protein essential for Ca(2+) regulation and signaling. This highly acidic polypeptide (pI<4) has two homologous domains (N and C), each consisting of two EF-hand Ca(2+)-binding sites. Despite significant homology, the domains have intrinsic differences in their Ca(2+)-binding properties and separable roles in regulating physiological targets such as kinases and ion channels. In mammalian full-length CaM, sites III and IV in the C-domain bind Ca(2+) cooperatively with ~10-fold higher affinity than sites I and II in the N-domain. However, the difference is only twofold when CaM is severed at residue 75, indicating that anticooperative interactions occur in full-length CaM. The Ca(2+)-binding properties of sites I and II are regulated by several factors including the interplay of interdomain linker residues far from the binding sites. Our prior thermodynamic studies showed that these residues inhibit thermal denaturation and decrease calcium affinity. Based on high-resolution structures and NMR spectra, there appear to be interactions between charged residues in the sequence 75-80 and those near the amino terminus of CaM. To explore electrostatic contributions to interdomain interactions in CaM, KCl was used to perturb the Ca(2+)-binding affinity, thermal stability, and hydrodynamic size of a nested set of recombinant mammalian CaM (rCaM) fragments terminating at residues 75, 80, 85, or 90. Potassium chloride is known to decrease Ca(2+)-binding affinity of full-length CaM. It may act directly by competition with acidic side chains that chelate Ca(2+) in the binding sites, and indirectly elsewhere in the molecule by changing tertiary constraints and conformation. In all proteins studied, KCl decreased Ca(2+)-affinity, decreased Stokes radius, and increased thermal stability, but not monotonically. Crystallographic structures of Ca(2+)-saturated rCaM(1-75) (3B32.pdb) and rCaM(1-90) (3IFK.pdb) were determined, offering cautionary notes about the effect of packing interactions on flexible linkers. This chapter describes an array of methods for characterizing system-specific thermodynamic properties that in concert govern structure and function. PMID- 21609875 TI - Use of pressure perturbation calorimetry to characterize the volumetric properties of proteins. AB - Pressure perturbation calorimetry (PPC) is a new technique that makes possible to study the volumetric changes that occur upon protein unfolding. Here, we summarize the thermodynamic foundation of the method and introduce a two-state model for the analysis of the unfolding data monitored by PPC. Several examples of data analysis illustrating potential pitfalls and solutions are discussed. PMID- 21609876 TI - Solvent denaturation of proteins and interpretations of the m value. AB - The stability of globular proteins is important in medicine, proteomics, and basic research. The conformational stability of the folded state can be determined experimentally by analyzing urea, guanidinium chloride, and thermal denaturation curves. Solvent denaturation curves in particular may give useful information about a protein such as the existence of domains or the presence of stable folding intermediates. The linear extrapolation method (LEM) for analyzing solvent denaturation curves gives the parameter m, which is a measure of the dependence of DeltaG on denaturant concentration. There is much recent interest in the m value as it relates to the change in accessible surface area of a protein when it unfolds and what it may reveal about the denatured states of proteins. PMID- 21609877 TI - Measuring cotranslational folding of nascent polypeptide chains on ribosomes. AB - Protein folding has been studied extensively in vitro, but much less is known about how folding proceeds in vivo. A particular distinction of folding in vivo is that folding begins while the nascent polypeptide chain is still undergoing synthesis by the ribosome. Studies of cotranslational protein folding are inherently much more complex than classical in vitro protein folding studies, and historically there have been few methods available to produce the quantities of pure material required for biophysical studies of the nascent chain, or assays to specifically interrogate its conformation. However, the past few years have produced dramatic methodological advances, which now place cotranslational folding studies within reach of more biochemists, enabling a detailed comparison of the earliest stages of protein folding on the ribosome to the wealth of information available for the refolding of full-length polypeptide chains in vitro. PMID- 21609878 TI - A reproducing kernel hilbert space approach for q-ball imaging. AB - Diffusion magnetic resonance (MR) imaging has enabled us to reveal the white matter geometry in the living human brain. The Q-ball technique is widely used nowadays to recover the orientational heterogeneity of the intra-voxel fiber architecture. This article proposes to employ the Funk-Radon transform in a Hilbert space with a reproducing kernel derived from the spherical Laplace Beltrami operator, thus generalizing previous approaches that assume a bandlimited diffusion signal. The function estimation problem is solved within a Tikhonov regularization framework, while a Gaussian process model allows for the selection of the smoothing parameter and the specification of confidence bands. Shortcomings of Q-ball imaging are discussed. PMID- 21609879 TI - An anatomically oriented breast coordinate system for mammogram analysis. AB - We have developed a breast coordinate system that is based on breast anatomy to register female breasts into a common coordinate frame in 2-D mediolateral (ML) or mediolateral oblique (MLO) view mammograms. The breasts are registered according to the location of the pectoral muscle and the nipple and the shape of the breast boundary because these are the most robust features independent of the breast size and shape. On the basis of these landmarks, we have constructed a nonlinear mapping between the parameter frame and the breast region in the mammogram. This mapping makes it possible to identify the corresponding positions and orientations among all of the ML or MLO mammograms, which facilitates an implicit use of the registration, i.e., no explicit image warping is needed. We additionally show how the coordinate transform can be used to extract Gaussian derivative features so that the feature positions and orientations are registered and extracted without nonlinearly deforming the images. We use the proposed breast coordinate transform in a cross-sectional breast cancer risk assessment study of 490 women, in which we attempt to learn breast cancer risk factors from mammograms that were taken prior to when the breast cancer became visible to a radiologist. The coordinate system provides both the relative position and orientation information on the breast region from which the features are derived. In addition, the coordinate system can be used in temporal studies to pinpoint anatomically equivalent locations between the mammograms of each woman and among the mammograms of all of the women in the study. The results of the cross sectional study show that the classification into cancer and control groups can be improved by using the new coordinate system, compared to other systems evaluated. Comparisons were performed using the area-under-the-receiver-operating characteristic-curve score. In general, the new coordinate system makes an accurate anatomical registration of breasts possible, which suggests its wide applicability wherever 2-D mammogram registration is required. PMID- 21609880 TI - Selectable and unselectable sets of neurons in recurrent neural networks with saturated piecewise linear transfer function. AB - The concepts of selectable and unselectable sets are proposed to describe some interesting dynamical properties of a class of recurrent neural networks (RNNs) with saturated piecewise linear transfer function. A set of neurons is said to be selectable if it can be co-unsaturated at a stable equilibrium point by some external input. A set of neurons is said to be unselectable if it is not selectable, i.e., such set of neurons can never be co-unsaturated at any stable equilibrium point regardless of what the input is. The importance of such concepts is that they enable a new perspective of the memory in RNNs. Necessary and sufficient conditions for the existence of selectable and unselectable sets of neurons are obtained. As an application, the problem of group selection is discussed by using such concepts. It shows that, under some conditions, each group is a selectable set, and each selectable set is contained in some group. Thus, groups are indicated by selectable sets of the RNNs and can be selected by external inputs. Simulations are carried out to further illustrate the theory. PMID- 21609881 TI - LMI-based approach for global asymptotic stability analysis of recurrent neural networks with various delays and structures. AB - Global asymptotic stability problem is studied for a class of recurrent neural networks with distributed delays satisfying Lebesgue-Stieljies measures on the basis of linear matrix inequality. The concerned network model includes many neural network models with various delays and structures as its special cases, such as the delays covering the discrete delays and distributed delays, and the network structures containing the neutral-type networks and high-order networks. Therefore, many new stability criteria for the above neural network models have also been derived from the present stability analysis method. All the obtained stability results have similar matrix inequality structures and can be easily checked. Three numerical examples are used to show the effectiveness of the obtained results. PMID- 21609882 TI - Image authentication using distributed source coding. AB - We present a novel approach using distributed source coding for image authentication. The key idea is to provide a Slepian-Wolf encoded quantized image projection as authentication data. This version can be correctly decoded with the help of an authentic image as side information. Distributed source coding provides the desired robustness against legitimate variations while detecting illegitimate modification. The decoder incorporating expectation maximization algorithms can authenticate images which have undergone contrast, brightness, and affine warping adjustments. Our authentication system also offers tampering localization by using the sum-product algorithm. PMID- 21609883 TI - Probabilistic exposure fusion. AB - The luminance of a natural scene is often of high dynamic range (HDR). In this paper, we propose a new scheme to handle HDR scenes by integrating locally adaptive scene detail capture and suppressing gradient reversals introduced by the local adaptation. The proposed scheme is novel for capturing an HDR scene by using a standard dynamic range (SDR) device and synthesizing an image suitable for SDR displays. In particular, we use an SDR capture device to record scene details (i.e., the visible contrasts and the scene gradients) in a series of SDR images with different exposure levels. Each SDR image responds to a fraction of the HDR and partially records scene details. With the captured SDR image series, we first calculate the image luminance levels, which maximize the visible contrasts, and then the scene gradients embedded in these images. Next, we synthesize an SDR image by using a probabilistic model that preserves the calculated image luminance levels and suppresses reversals in the image luminance gradients. The synthesized SDR image contains much more scene details than any of the captured SDR image. Moreover, the proposed scheme also functions as the tone mapping of an HDR image to the SDR image, and it is superior to both global and local tone mapping operators. This is because global operators fail to preserve visual details when the contrast ratio of a scene is large, whereas local operators often produce halos in the synthesized SDR image. The proposed scheme does not require any human interaction or parameter tuning for different scenes. Subjective evaluations have shown that it is preferred over a number of existing approaches. PMID- 21609884 TI - Contextual and variational contrast enhancement. AB - This paper proposes an algorithm that enhances the contrast of an input image using interpixel contextual information. The algorithm uses a 2-D histogram of the input image constructed using a mutual relationship between each pixel and its neighboring pixels. A smooth 2-D target histogram is obtained by minimizing the sum of Frobenius norms of the differences from the input histogram and the uniformly distributed histogram. The enhancement is achieved by mapping the diagonal elements of the input histogram to the diagonal elements of the target histogram. Experimental results show that the algorithm produces better or comparable enhanced images than four state-of-the-art algorithms. PMID- 21609885 TI - Automatic image segmentation by dynamic region merging. AB - This paper addresses the automatic image segmentation problem in a region merging style. With an initially oversegmented image, in which many regions (or superpixels) with homogeneous color are detected, an image segmentation is performed by iteratively merging the regions according to a statistical test. There are two essential issues in a region-merging algorithm: order of merging and the stopping criterion. In the proposed algorithm, these two issues are solved by a novel predicate, which is defined by the sequential probability ratio test and the minimal cost criterion. Starting from an oversegmented image, neighboring regions are progressively merged if there is an evidence for merging according to this predicate. We show that the merging order follows the principle of dynamic programming. This formulates the image segmentation as an inference problem, where the final segmentation is established based on the observed image. We also prove that the produced segmentation satisfies certain global properties. In addition, a faster algorithm is developed to accelerate the region-merging process, which maintains a nearest neighbor graph in each iteration. Experiments on real natural images are conducted to demonstrate the performance of the proposed dynamic region-merging algorithm. PMID- 21609886 TI - Analysis of the noise reduction property of type-2 fuzzy logic systems using a novel type-2 membership function. AB - In this paper, the noise reduction property of type-2 fuzzy logic (FL) systems (FLSs) (T2FLSs) that use a novel type-2 fuzzy membership function is studied. The proposed type-2 membership function has certain values on both ends of the support and the kernel and some uncertain values for the other values of the support. The parameter tuning rules of a T2FLS that uses such a membership function are derived using the gradient descend learning algorithm. There exist a number of papers in the literature that claim that the performance of T2FLSs is better than type-1 FLSs under noisy conditions, and the claim is tried to be justified by simulation studies only for some specific systems. In this paper, a simpler T2FLS is considered with the novel membership function proposed in which the effect of input noise in the rule base is shown numerically in a general way. The proposed type-2 fuzzy neuro structure is tested on different input-output data sets, and it is shown that the T2FLS with the proposed novel membership function has better noise reduction property when compared to the type-1 counterparts. PMID- 21609887 TI - Recurring two-stage evolutionary programming: a novel approach for numeric optimization. AB - In the application of evolutionary algorithms (EAs) to complex problem solving, it is essential to maintain proper balance between global exploration and local exploitation to achieve a good near-optimum solution to the problem. This paper presents a recurring two-stage evolutionary programming (RTEP) to balance the explorative and exploitative features of the conventional EAs. Unlike most previous works, RTEP is based on repeated and alternated execution of two different stages, namely, the exploration and exploitation stages, each with its own mutation operator, selection strategy, and explorative/exploitative objective. Both analytical and empirical studies have been carried out to understand the necessity of repeated and alternated exploration and exploitation operations in EAs. A suite of 48 benchmark numerical optimization problems has been used in the empirical studies. The experimental results show the remarkable effectiveness of the repeated exploration and exploitation operations employed by RTEP. PMID- 21609888 TI - A new particle swarm algorithm and its globally convergent modifications. AB - Particle swarm optimization (PSO) is a population-based optimization technique that can be applied to a wide range of problems. Here, we first investigate the behavior of particles in the PSO using a Monte Carlo method. The results reveal the essence of the trajectory of particles during iterations and the reasons why the PSO lacks a global search ability in the last stage of iterations. Then, we report a novel PSO with a moderate-random-search strategy (MRPSO), which enhances the ability of particles to explore the solution spaces more effectively and increases their convergence rates. Furthermore, a new mutation strategy is used, which makes it easier for particles in hybrid MRPSO (HMRPSO) to find the global optimum and which also seeks a balance between the exploration of new regions and the exploitation of the already sampled regions in the solution spaces. Thirteen benchmark functions are employed to test the performance of the HMRPSO. The results show that the new PSO algorithm performs much better than other PSO algorithms for each multimodal and unimodal function. Furthermore, compared with recent evolutionary algorithms, experimental results empirically demonstrate that the proposed framework yields promising search performance. PMID- 21609889 TI - Design of a gaze-sensitive virtual social interactive system for children with autism. AB - Impairments in social communication skills are thought to be core deficits in children with autism spectrum disorder (ASD). In recent years, several assistive technologies, particularly Virtual Reality (VR), have been investigated to promote social interactions in this population. It is well known that children with ASD demonstrate atypical viewing patterns during social interactions and thus monitoring eye-gaze can be valuable to design intervention strategies. While several studies have used eye-tracking technology to monitor eye-gaze for offline analysis, there exists no real-time system that can monitor eye-gaze dynamically and provide individualized feedback. Given the promise of VR-based social interaction and the usefulness of monitoring eye-gaze in real-time, a novel VR based dynamic eye-tracking system is developed in this work. This system, called Virtual Interactive system with Gaze-sensitive Adaptive Response Technology (VIGART), is capable of delivering individualized feedback based on a child's dynamic gaze patterns during VR-based interaction. Results from a usability study with six adolescents with ASD are presented that examines the acceptability and usefulness of VIGART. The results in terms of improvement in behavioral viewing and changes in relevant eye physiological indexes of participants while interacting with VIGART indicate the potential of this novel technology. PMID- 21609890 TI - [Radio iodized metaiodobenzylguanidine (MIBG) in the treatment of neuroblastoma: modalities and indications]. AB - Neuroblastoma is the most common pediatric extracranial solid cancer. Patients with metastatic disease at initial diagnosis who are greater than 18 months of age and patients with MycN amplified locoregional tumors are treated with intensive multimodal therapy. While this intensive approach has been shown to improve outcome, patients with high-risk disease frequently relapse and fewer than 50% of these patients will be long-term survivors necessitating new approaches for therapy. Derived from the sympathetic nervous system, this tumor typically expresses the norepinephrine transporter. This transporter mediates active intracellular uptake of metaiodobenzylguanidine (MIBG) an analogue of norepinephrine in approximately 90% of patients allowing the use of radiolabeled (metaiodobenzylguanidine) MIBG, for targeted radiotherapy. This article will review the clinical experience of using MIBG as targeted radiotherapy in neuroblastoma. The administration guidelines, toxicity, response and survival are discussed. Recent studies have evaluated combinations of (131)I-MIBG with myeloablative regimens such as chemotherapy agents with radiation sensitizing properties, or with biologic agents. Most of them report a response rate of 30 40% with (131)I-MIBG in patients with relapsed or refractory neuroblastoma. Due to this high response rates and low non-hematologic toxicity, (131)I-MIBG seems to be an interesting agent for incorporation into the upfront management of newly diagnosed patients with high-risk neuroblastoma. PMID- 21609891 TI - [Genetic alterations in neuroblastoma and their usefulness for clinical management]. AB - Neuroblastoma, the most frequent solid extracranial tumor of childhood, is characterized by a wide variability of its clinical course. The most important clinical prognostic markers are stage and age at diagnosis, but these markers are insufficient to predict outcome reliably and to determine treatment intensity. Recent evidence indicates that neuroblastoma can be considered as a "genetic disease", firstly by the recent observation that certain alleles of specific genes significantly increase the relative risk to develop neuroblastoma, and the discovery of mutations in genes such as ALK or PHOX2B in rare familial cases. On the other hand, a large number of recurrent genetic somatic alterations have been described in neuroblastoma. Recent technological advances, such as array-CGH (comparative genomic hybridisation), now enable the analysis of these markers in a single step and allow the definition of genomic profiles associated with typical clinical features. Numerical chromosome alterations are observed more frequently in tumors of younger children with localised disease and a good prognosis, whereas segmental chromosome alterations are found more frequently in tumors of older children with advanced stages of disease and a poorer outcome. Future therapeutic stratification schemes can make use of the tumor genomic profile by proposing less intense treatment for infants with a neuroblastoma harboring a favorable tumor genomic profile, while intensifying treatment in case of a defavorable tumor genomic profile. Such approaches require standardisation of the molecular techniques and the interpretation of results for application in international trials. PMID- 21609892 TI - Hypoxic mitochondria: accomplices in resistance. AB - Mitochondria originated from a distant ancestor: the alpha-proteobacteria. They evolved over millions of years in a symbiotic relationship in eukaryotic cells by favoring consumption of oxygen by the electron transport chain with production of ATP. Contemporary mitochondria still play a crucial role in providing energy but also in apoptosis. Because of this symbiotic relationship and their pivotal function, mitochondria undoubtedly participate in tumorigenesis. Genetic defects in mitochondrial DNA, blockade of oxidative phosphorylation and mitophagy in tumor cells modify the production of damaging reactive oxygen species and restrain apoptosis. As the environment of tumor cells becomes more and more hypoxic, the hypoxia-inducible factor (HIF) is stabilized and participates in the reprogramming of cell metabolism. Recently, we became interested in asking whether HIF and hypoxia affect mitochondrial function. In this review, we show that hypoxia induces enlargement of mitochondria, due to abnormal fusion, which results in resistance to apoptosis and thus in survival. The role of hypoxia induced BNIP3 and BNIP3L, proteins recently described as pro-survival proteins, in survival is also discussed. PMID- 21609893 TI - [Fertility preservation in prepubertal children]. AB - Gonadotoxic therapies during childhood may impair future fertility in adult life and fertility preservation techniques should be discussed before starting gonadotoxic therapies. In both sexes, fertility preservation often means immature gametes cryopreservation. For girls, ovarian tissue cryopreservation is the only existing option to preserve fertility in prepubertal girls at risk of premature ovarian failure. This promising approach involves the storage of a large number of follicles, which could subsequently be transplanted or cultured to obtain mature oocytes. The results of ovarian tissue cryopreservation in adults are encouraging. At least nine children have been born after orthotopic reimplantation of frozen-thawed ovarian cortex. None of these pregnancies were obtained by reimplantation of ovarian tissue harvested before puberty; however, the probability of restoring fertility should be higher for younger girls, as their ovarian cortex clearly contains a large number of follicules. In vitro growth of primordial follicles to mature oocytes could be an option but this goal has not yet reached in humans. This option may be reach in the future, when young patients are in their twenties or thirties. For boys, spermatogonial stem cells can be cryopreserved and uni or bilateral testicular pieces can be stored for future use. Animal data reveals that healthy offspring were reported after grafting of frozen testicular cell suspensions or tissue pieces in different species. Although recent data show promising results, restoring fertility by using frozen testicular cells after transplantation or in vitro culture is not shown yet. Then, immature testicular tissue cryopreservation for prepubertal boys is still an experimental procedure. However, as their use for restoring fertility should not be requested before 10-30 years, a long time is given for advances in medical research. PMID- 21609894 TI - [Personality disorders in oncology: characteristic and management]. AB - Confronted with a patient with a personality disorder, the oncologist must recognize it and adapt his treatment accordingly. Some pathological character types require interpersonal adjustments to ensure a good understanding of the cancer disease and also to obtain the best compliance with supportive care. Given the fact that specific pharmacological treatment does not exist, collaboration between oncologists and the psycho-oncology team is paramount. The interaction between the somatic disease and the psychiatric disorder demand collaboration among caregivers sharing explanations and recommendations. Clinical examples will illustrate each personality disorder and will focus on the several problems raised by the psychiatric disorder. Treatment principles will be addressed in a second section. PMID- 21609895 TI - Interleukin-15 is a major regulator of the cell-microenvironment interactions in human renal cancer. AB - Primary human epithelial renal cells of normal (HRE), paratumoral (pTEC) and tumoral (RCC) origin display important differences, concerning the expression and biological effects of the IL-15/IL-15R system that deeply influences the evolution of the tumour microenvironment. A major distinguishing feature is represented in RCC and pTEC by the loss of the gammac chain leading to the assembly of a IL-15Ralphabeta heterodimer that in response to physiologic concentrations of IL-15 initiates the process of their epithelial-mesenchymal transition (EMT). In contrast, this treatment in HRE cells, which display the IL 15Ralphabetagammac heterotrimer, causes opposite effects inhibiting their drift towards EMT. Thus, IL-15 at physiologic concentrations displays novel functions acting as a major regulator of renal epithelial homeostasis. As second distinguishing feature, RCC and pTEC but not HRE cells express a trans-membrane bound IL-15 (tmb-IL-15) able to deliver a reverse signal in response to the soluble IL-15Ralpha chain inducing their EMT. In conclusion, comparison of primary normal (HRE) to primary pathological cells (pTEC and RCC) highlights two major issues: (1) IL-15 is a major regulator of epithelial homeostasis; (2) "apparently normal" pTEC cells, could contribute to organize a generalized "pre neoplastic" environment committed to favour tumour progression. PMID- 21609896 TI - [Brachytherapy in paediatric sarcoma]. AB - Publications on brachytherapy in paediatric malignancies are scarce, limited to expert institutions. Techniques, brachytherapy modalities (low dose-rate, high dose-rate, pulsed dose-rate), doses and indications vary according to centres. The most frequent tumor sites treated with brachytherapy are gynaecological rhabdomyosarcomas, prostate/bladder rhabdomyosarcomas and soft-tissue sarcomas. Brachytherapy advantages are in relation with ballistic properties, allowing a very high dose to the target with normal tissue sparing. This review analyzes brachytherapy techniques and indications according to tumor sites, brachytherapy results and perspectives. This technique requires a muldisciplinary approach. PMID- 21609897 TI - Unexpected healing of radiation-induced scalp lesions with OTR4120, a heparan sulfate mimetic. PMID- 21609898 TI - Pathways to inflammation: acne pathophysiology. AB - Acne vulgaris affects as much as 80% of the adolescent population and persists in approximately 3% of middle-aged adults. Only a percentage of these persons seek medical help, however, acne can cause levels of anxiety and depression akin to a chronic illness. A recurring question from patients who seek help from various healthcare professionals - their pharmacist, family doctor or dermatologist, is "why?" They also ask questions about a possible familial link, the impact of their diet and the association with their hormones. The following review aims to link these factors with the end result - inflammation. PMID- 21609899 TI - Dermoscopy of pyogenic granuloma on the lip: the differing appearances of vascular structures with and without pressure. PMID- 21609900 TI - Restrictions in oral functions caused by oral manifestations of epidermolysis bullosa. AB - Several forms of epidermolysis bullosa (EB) present oral manifestations. Blistering of the (peri)oral mucosa affects the opening of the mouth, the mobility of the tongue and lips, thereby restricting oral functions. We describe the prevalence and characteristics of oral manifestations of EB in relation to loss of oral functions in a cross-sectional study of different types of EB patients using standardized measurement techniques. Twenty-two patients were included. The mobility of the mandible, lips and tongue was measured, the mandibular function impairment questionnaire (MFIQ) was filled out and additional questions regarding hindrance of EB during oral hygiene and intelligibility of speech (being understood) were asked in structured interviews. The median age was 11.8 yrs. Mobility of the mandible, tongue and lip was restricted, oral hygiene procedures were hindered in most patients. A data comparison was made between the recessive dystrophic EB (RDEB) and junctional EB (JEB) groups. Mandibular function was impaired in both groups but more severely in the RDEB-population. Intelligibility in both groups was almost unaffected. Restrictions in mobility of the mouth, tongue and lips are frequently present in EB patients. These are most severe in the RDEB group and support the clinical relevance of optimizing symptomatic treatment. PMID- 21609901 TI - Panfolliculoma, an unusual cutaneous adnexal neoplasm. PMID- 21609902 TI - Biological evaluation of a new C-xylopyranoside derivative (C-Xyloside) and its role in glycosaminoglycan biosynthesis. AB - The mechanical properties of skin are determined primarily by the extracellular matrix of the dermis. These mechanical and biological properties change significantly as a function of age. Key components of the extracellular matrix are proteoglycans, which are molecules composed of a core protein and covalently attached glycosaminoglycans. Proteoglycans and their constituent glycosaminoglycans are involved in many biological processes which are important for dermal function, such as proper formation of the collagen network. A recently developed compound, C-xylopyranoside derivative (C-Xyloside), was designed to mimic beta-xylosides, which are known initiators of glycosaminoglycan biosynthesis. C-Xyloside was found, by several criteria, to act like beta xylosides, such as in the eliciting of an increase in glycosaminoglycan synthesis by human dermal fibroblasts in culture. This increase may lead to the preservation of matrix integrity and thereby contribute to the firmness of skin. Thus, C-Xyloside may be useful in improving the quality of skin. PMID- 21609903 TI - Severe hypomagnesemia and low-grade inflammation in metabolic syndrome. AB - To evaluate the association between severe hypomagnesemia and the low-grade inflammatory response in subjects with metabolic syndrome (MetS), ninety-eight individuals with new diagnosis of MetS were enrolled in a cross-sectional study. Pregnancy, smoking, alcohol intake, renal damage, hepatic disorders, infectious or chronic inflammatory diseases, malignancy, use of diuretics, statins, calcium antagonist, antioxidants, vitamins, anti-inflammatory drugs, or previous oral magnesium supplementation were exclusion criteria. According serum magnesium levels, participants were assigned to the following groups: 1) severe hypomagnesemia (<=1.2 mg/dL); 2) hypomagnesemia (>1.2<=1.8 mg/dL); 3) Normal serum magnesium levels (>1.8 mg/dL). The low-grade inflammatory response was defined by elevation of serum levels of (hsCRP >1.0 <=10.0 mg/L) or TNF-alpha (TNF-alpha >=3.5 pg/mL). Severe hypomagnesemia, hypomagnesemia, and normomagnesemia were identified in 21 (21.4%), 38 (38.8%), and 39 (39.8%) individuals. The ORs, adjusted by WC, showed that severe hypomagnesemia (OR: 8.1; CI 95%: 3.6-19.4 and OR: 3.7; CI 95%: 1.1-12.1), but not hypomagnesemia (OR: 1.8; CI 95%: 0.9-15.5 and OR: 1.6; CI 95%: 0.7-3.6), was strongly associated with elevated hsCRP and TNF-alpha levels, and that normomagnesemia exhibited a protective role (OR: 0.32; CI 95%: 0.1-0.7 and OR: 0.28; CI 95%: 0.1-0.6) for elevation of CRP and TNF-alpha. Results of this study show that, in subjects with MetS, severe hypomagnesemia, but not hypomagnesemia, is associated with elevated concentrations of CRP and TNF-alpha. PMID- 21609904 TI - Magnesium supplement promotes sciatic nerve regeneration and down-regulates inflammatory response. AB - Magnesium (Mg) supplements have been shown to significantly improve functional recovery in various neurological disorders. The essential benefits of Mg supplementation in peripheral nerve disorders have not been elucidated yet. The effect and mechanism of Mg supplementation on a sciatic nerve crush injury model was investigated. Sciatic nerve injury was induced in mice by crushing the left sciatic nerve. Mice were randomly divided into three groups with low-, basal- or high-Mg diets (corresponding to 10, 100 or 200% Mg of the basal diet). Neurobehavioral, electrophysiological and regeneration marker studies were conducted to explore nerve regeneration. First, a high Mg diet significantly increased plasma and nerve tissue Mg concentrations. In addition, Mg supplementation improved neurobehavioral, electrophysiological functions, enhanced regeneration marker, and reduced deposits of inflammatory cells as well as expression of inflammatory cytokines. Furthermore, reduced Schwann cell apoptosis was in line with the significant expression of bcl-2, bcl-X(L) and down regulated expression of active caspase-3 and cytochrome C. In summary, improved neurological function recovery and enhanced nerve regeneration were found in mice with a sciatic nerve injury that were fed a high- Mg diet, and Schwann cells may have been rescued from apoptosis by the suppression of inflammatory responses. PMID- 21609907 TI - Vestibulo-ocular reflex as predictor of cerebral death in comatose patients. AB - OBJECTIVE: Our goal was to establish the role of VOR - vestibular ocular reflex - in predicting cerebral death in comatose patients. PATIENTS AND METHODS: Prognosis study based on three concurrent cohorts of comatose patients of known etiology followed until the ultimate outcomes: recovery, vegetative state or death. Sixty comatose patients (Glasgow scale 8 or less) with known causes were studied: 49 males and 11 females; 7 to 83 years old. The cold water vestibular stimulation was performed at the bedside by irrigation with 0o Celsius saline in the external auditory canal during one minute. The reflex was considered present when both eyes deviated toward the stimulated side (19 patients group 1); present but abnormal for irregular unconjugated eye movements (11 patients group 2) or absent (30 patients, group 3). RESULTS: Group 1 had total recovery in 42%, partial recovery in 37% and cerebral death in 21%. These results were 9%, 18% and 73% for group 2, respectively and group 3 had 100% cerebral death. The difference was statistically significant between groups 1 and 2, 3 (p<0,05 Fischer exact test and X2 test). CONCLUSION: Absence of VOR predicted 100% of cerebral death and VOR present normal predicted 21% of cerebral death in the comatose patients we studied. PMID- 21609909 TI - The possible contribution of angiitis to the onset of benign paroxysmal positional vertigo (BPPV). AB - OBJECTIVE: The aim was to evaluate the oxidative stress and the angiitis in patients with BPPV. METHOD: Patients with benign paroxysmal positional vertigo (BPPV) within 14 days of onset were analyzed. The level of diacron reactive oxygen metabolites (d-ROM) and circulating soluble vascular cell adhesion molecule 1 (VCAM-1), were evaluated. As a treatment the patients were taught to perform the Brandt-Daroff exercise at home by themselves. The prognosis of BPPV, which is measured as the time until the disappearance of positional nystagmus by a physician during the outpatient visit each week, the relation among the level of oxygen metabolites, vascular molecule and the duration until remission were analyzed. RESULTS: The patients who required longer time for the disappearance of positional nystagmus showed high d-ROM and VCAM levels, whereas those who required shorter time for remission showed lower d-ROM and VCAM levels. CONCLUSION: There is an increased expression of VCAM-1 and d-ROM confirming the existence of an angiitis and supporting the vascular involvement in BPPV. The identification of the high levels of d-ROM and VCAM-1 can open the way to selective pharmacological treatments able to correct the oxidative stress and activation of endothelial cells. PMID- 21609910 TI - Two cases of intractable auditory hallucination successfully treated with sound therapy. AB - We report two cases of patients with schizoaffective disorder with treatment refractory auditory verbal hallucinations (AVHs) who were successfully treated with sound therapy, which is effective to treat tinnitus. AVHs in both patients were alleviated within about one month, and no recurrence was reported for 31 and 17 months after the sound therapy together with medication. Further studies may confirm the therapeutic value of sound therapy in patients with intractable AVHs. PMID- 21609911 TI - Effect of treatment with betahistine dihydrochloride on the postural stability in patients with different duration of benign paroxysmal positional vertigo. AB - The effect of betahistine dihydrochloride on the postural stability after repositioning Epley's maneuver (EM) in patients with BPPV was evaluated by static posturography in open and closed eyes conditions. Ninety patients were divided into four groups by duration (less and above 60 days of BPPV) and by treatment (with and without treatment with betahistine). The investigation was made one hour after the positive Dix-Hallpike test, 10 and 20 days after the treatment with EM. "Sway velocity" (SV) was calculated to evaluate postural stability. The results show dependence between efficacy of treatment with betahistine applied after EM and duration of BPPV. Betahistine normalized postural stability of patients with duration of BPPV less than 60 days after 10 days of treatment and had less effect on patients with duration of BPPV above 60 days. We assume that after removing the otoconia betahistine plays an important role for improving blood flow in the inner ear. The short presence of otoconia didn't damage sensory receptor, and restoring the normal function of motion-sensitive hairs cells and stabilizing the posture was observed. PMID- 21609912 TI - Tinnitus treatment with sound stimulation during sleep. AB - A new strategy for idiopathic subjective tinnitus treatment - sound stimulation during sleep - has been applied. It was based on the acknowledgement that the auditory system also works during sleep, processing the incoming information. Eleven patients were stimulated every night during 6 months. The stimulus was a sound that mimetized the tinnitus and was fixed at the same tinnitus intensity, applied through an iPod. All patients decreased their tinnitus intensity in the first month of treatment (statistically significant), most of them in the first week. Tinnitus intensity continued decreasing in the following weeks; three patients presented periods of total silence. PMID- 21609913 TI - Posturography measures and efficacy of different physical treatments in somatic tinnitus. AB - Somatic modulation in tinnitus has been demonstrated by several studies although few investigations have been published on the efficacy of physical treatments in tinnitus subjects. In the present study the prevalence of somatic components to tinnitus were evaluated and the efficacy of two different physical treatments were compared: InterX(r) transcutaneous dynamic electrical stimulation and manual osteopathic therapy. Furthermore, posturographic measurements were analysed to verify the postural control in tinnitus subjects. 40 consecutive tinnitus patients, aged 18-65, were randomly selected for treatment (once a week for 2 months): 20 tinnitus subjects were treated with osteopathic manipulations, 20 with InterX(r). They were evaluated pre and post therapy with audiogram up to 16 kHz, tinnitus pitch and loudness match, MML, THI questionnaire, posturography, structured interview with special attention on postural and movement influence on tinnitus, physical evaluation and osteopathic evaluation. 40 controls with no tinnitus, underwent audiological tests, postural and osteopathic evaluation for comparison. In our population, tinnitus sufferers presented more frequently musculoscheletal strains assessed with osteopathic visit and postural problems assessed with posturography measures in comparison with controls. Posturographic test, showed an average oscillating areas significantly greater in tinnitus participants (p <= 0.05), compared with control subjects. On the average in the treated groups, the enveloped areas were not significantly affected by either of the treatments. Tinnitus improved subjectively in most patients: loudness decreased, % time of awareness, % time of annoyance and quality of life was overall perceived as improved. This was mostly evident in subjects with muscular strain and tensions. This study indicates the benefit of physical, manipulation therapy for those patients with somatic modulation of their tinnitus, further studies are needed to establish the diagnostic or prognostic role of posturographic measurements. PMID- 21609914 TI - Middle ear myoclonus: a new technique for suppression of spontaneous clicking tinnitus. AB - Middle ear myoclonus is one of the causes of clicking tinnitus and can be psychologically distressing. Current management of intractable clicking includes medication or tenotomy. Two cases with spontaneous intrusive irregular clicking are presented where relief and a sense of control were obtained using non invasive self - administered zygomatic pressure. This technique may be useful in selected patients before resorting to medication or tenotomy. PMID- 21609915 TI - Tinnitus Retraining Therapy (TRT): outcomes after one-year treatment. AB - The aim of the study is to present our results regarding the efficacy of TRT for tinnitus relief in patients with clinically significant tinnitus compared to a group treated with vasoactive agents. In a nonrandomized prospective study, 63 patients with disabling tinnitus were recruited. Greek translation of the Tinnitus Handicap Inventory (THI) and visual analogue scale (VAS) for annoyance caused by tinnitus when conducting four major activities of everyday life (work, sleep, relaxation and concentration) were examined in a 12-month period. The THI score was significantly improved in the TRT group, as well as mean VAS scores, in all measures. Comparison of the mean improvement of THI and VAS scores after treatment showed significant differences between the two groups, favoring TRT treatment. Our data suggest that TRT is an effective treatment. It reduces the level of annoyance induced by tinnitus and improves the ability of patients to work, sleep, relax or be concentrated. PMID- 21609916 TI - Clinical benefits to vestibular rehabilitation in multiple sclerosis. Report of 4 cases. AB - BACKGROUND: Balance difficulties are common among multiple sclerosis patients. OBJECTIVE: To evaluate the effectiveness of the Cawthorne and Cooksey protocol of vestibular rehabilitation (VR) exercises in reducing the physical, functional and emotional impact of multiple sclerosis among individuals who complained of vertigo. METHODS: Four patients with remittent-recurrent multiple sclerosis underwent an interview, otorhinolaryngological and vestibular evaluation, VR exercises and the Dizziness Handicap Inventory pre- and post-intervention. RESULTS: There was significant improvement in the physical, functional and emotional aspects of the DHI after the completion of the VR. CONCLUSION: The VR exercises appeared useful in reducing subjective complaints of the study participants. PMID- 21609917 TI - A cognitive model of tinnitus and hyperacusis; a clinical tool for patient information, appeasement and assessment. AB - Tinnitus and hyperacusis are both aggravating audiological symptoms. Their underlying mechanisms are not fully understood, but the pathophysiology involves a central mechanism rather than a peripheral one. There is no curative treatment. A review of the available research on tinnitus and auditory processing was conducted to connect insights gained from different approaches to the subject; this resulted in the development of a holistic view of both conditions. In this view, the chronic course of the symptoms is pathological and attributed to a stress-related lack of habituation. This article adds to the literature on tinnitus and hyperacusis by presenting a schematic model of the cognitive mechanisms which can be used clinically in patient information sessions which are geared towards provide reassurance and encouraging the development of coping skills. In cooperation with the patient, the model can also help in the identification of underlying pathology. Future aims of study are suggested, elaborating on the role of tinnitus and hyperacusis in normal auditory processing and on the value of insight. Finally, parallels are drawn between tinnitus and positive symptom syndromes in neuropsychiatry and some of its modern visions on their treatment. PMID- 21609918 TI - Principles of tinnitology: tinnitus diagnosis and treatment a tinnitus-targeted therapy. AB - OBJECTIVE: To provide to the tinnitus professional a rationale for establishing accuracy in tinnitus diagnosis and the selection of modalities of therapy (i.e., medication, instrumentation, and surgery) for attempting tinnitus relief for patients with tinnitus diagnosed by completion of a medical-audiological tinnitus protocol (MATPP) and clinical course and found to be subjective idiopathic tinnitus of the severe disabling type (SIT). BACKGROUND: The completion of a MATPP has been recommended since 1977 for each tinnitus patient in an attempt to establish an accurate diagnosis. A tinnitus-targeted therapy (TTT), a combined treatment of medication and instrumentation focusing on pharmacotherapy, has evolved from our ongoing clinical experience since 1977 (now in excess of 10,000 SIT patients) [1-4]. Principles for SIT treatment have evolved from the TTT experience that provides a rationale for attempting tinnitus relief. In this report, the term tinnitus refers to SIT. METHOD: The strategies of TTT are based on the clinical translation for SIT diagnosis and treatment of (1) fundamentals of neuro-otological diagnosis; (2) fundamentals of sensory physiology; (3) extrapolation for treatment of known underlying neurochemistries from nuclear medicine imaging results e.g. single-photon emission computed tomography and positron emission tomography; (4) hypothesis of mechanism of tinnitus production , Tinnitus Dysynchrony Synchrony Theory (TDST) [5] , and hypothesis of the transformation-transition of the sensation of an aberrant auditory sensation tinnitus (i.e., sensory component)-to one of affect (i.e., the emotional behavioral component), Final Common Pathway of Tinnitus (FCP)[8]; and (5) innovative application of drug therapies designed for indications other than tinnitus [2,3]. RESULTS AND CONCLUSION: The ongoing clinical application of a rationale based on principles of diagnosis and treatment for SIT, which has evolved from our TTT clinical experience in SIT patients, continues to result in long-term tinnitus relief: in excess of 1 year in approximately 75% to 85% with medication and in 10% to 15% with instrumentation. SIT patients resistant to therapy persist at 10% to 15%. PMID- 21609919 TI - [Intensive care is in need of conceptual reorganization in Hungary]. PMID- 21609920 TI - [Parameters of bed occupancy of intensive care units in Hungary]. AB - According to the Semmelweis Plan for Saving Health Care, "the capacity of the national network of intensive care units in Hungary is one but not the only bottleneck of emergency care at present". Author shows on the basis of data reported to the health insurance that not on a single calendar day more than 75% of beds in intensive care units were occupied. There were about 15 to 20 thousand sick days which could be considered unnecessary because patients occupying these beds were discharged to their homes directly from the intensive care unit. The data indicate that on the whole bed capacity is not low, only in some institutions insufficient. Thus, in order to improve emergency care in Hungary, the rearrangement of existing beds, rather than an increase of bed capacity is needed. PMID- 21609908 TI - Effects of betahistine on patient-reported outcomes in routine practice in patients with vestibular vertigo and appraisal of tolerability: experience in the OSVaLD study. AB - This was a 3-month multicentre, open-label post-marketing surveillance study of betahistine (24 mg b.i.d. or 16 mg t.i.d.) in patients with vertigo of peripheral vestibular origin. Study endpoints comprised on-treatment changes in the Dizziness Handicap Index (DHI), Hospital Anxiety and Depression Score (HADS) and the Short-Form (SF)-36v2. Total DHI score improved 37.2 points (of a 100-point scale) following betahistine treatment. Corresponding improvements occurred in all three DHI scale domains (all p < 0.001 vs baseline). Betahistine therapy was also accompanied by progressive, significant improvements in both HADS-A and HADS D scores (p < 0.001), and improvements in the distribution profiles of anxiety and depression scores. Significant improvements in the Physical Component Summary and Mental Component Summary scores of the SF-36v2 were recorded during betahistine treatment. Betahistine was generally well tolerated. A total of 76 adverse drug reactions (ADRs) were recorded in 49 patients (2.4%), of which 75 were classified as mild or moderate and 54 were possibly related to betahistine. ADRs led to study drug discontinuation in 17 patients. These data illustrate that treatment with betahistine 48 mg/day in patients with recurrent peripheral vestibular vertigo is associated with improvements in objective measures of health-related quality of life and satisfactory tolerability. PMID- 21609921 TI - [Frequency and possible reasons for the loss of response to biological therapy in Crohn's disease after a one-year treatment period]. AB - Secondary loss of response (initial good response followed by loss of response and flare up) is a frequent event occurring during biological therapy. The aim of this study was to assess loss of efficacy in patients with Crohn's disease treated with infliximab or adalimumab for a year. Secondary goals were to identify clinical or laboratory predictors of loss of response and to evaluate whether the frequency of dose escalation differs in patients receiving infliximab or adalimumab. Data were provided by a computerized database. PATIENTS AND METHODS: Sixty-one patients with Crohn's disease achieved remission after induction therapy and received regular maintenance treatment. 35 of them were on infliximab, and 26 on adalimumab therapy. None of the patients treated with infliximab received previous biological therapy, while 10 of the adalimumab treated patients were naive to biological therapy. Authors compared the data of patients who relapsed with those who remained in remission and also the characteristics of infliximab-treated patients with adalimumab-naive patients. Data were analyzed using Chi-square test. Kaplan Meier curve was used to show the time of loss of efficacy. RESULTS: Remission was achieved in 70.5%, and response was achieved in 29.5% of the patients after induction. Loss of response occurred in 22 of the 61 patients after a year of therapy. The proportion of remission after induction was significantly lower in patients who lost response vs. those who remained in remission. More patients with sustained remission received immunosuppressive therapy before and during the biological therapy vs. those with loss of response. Loss of response was significantly more frequent and occurred earlier in adalimumab-naive patients vs. infliximab-treated patients. CONCLUSION: The need for dose escalation should be calculated in the budget in the majority of patients, especially in adalimumab-treated patients. PMID- 21609922 TI - [Practical considerations and questions in the treatment of chronic lymphocytic leukemia]. AB - Understanding the pathogenesis and refine the treatment of chronic lymphocytic leukemia have been tremendously improved in the past decade. Treatment outcome and estimated prognosis have become more accurate due to the advanced molecular biological techniques and the classical prognostic markers. Incorporation of fludarabine and rituximab into the standard protocols fundamentally improved treatment outcome in chronic lymphocytic leukemia. Chemoimmunotherapy has improved not only the remission rates but had a significant impact on overall survival, as well. Eliminating residual leukemia and achieving complete hematological remissions at such high rates establish potential background for cure. Still, a great deal of dispute has been emerged regarding everyday clinical practice. Authors present their institutional experiences and review the literature. PMID- 21609923 TI - [Occurrence of struma ovarii among women operated for ovarian teratoma]. AB - Ovarian monodermal teratoma containing thyroid tissue is a rare tumor. Authors reviewed the records of 94 patients operated for ovarian teratoma in their department between 1986 and 2002, of which 3 patients proved to have struma ovarii. They found that the 3 patients had highly variable clinical symptoms and morphological characteristics including tumor size, pain as main symptom, and the presence or absence of ascites and hormonal activity. It is concluded that struma ovarii appears to be poorly diagnosed, but an extensive histological examination may increase the diagnostic efficacy. PMID- 21609924 TI - [Dr. Arpad Eisert (1911-1974), the pioneer of Hungarian heart surgery, was born 100 years ago ]. PMID- 21609925 TI - [Janos Wagner was born 200 years ago]. PMID- 21609927 TI - Vascular and metabolic response to bevacizumab-containing regimens in two patients with colorectal liver metastases measured by dynamic contrast-enhanced MRI and dynamic 18F-FDG-PET. AB - Early monitoring of response to treatment is one of the cornerstones of personalized treatment. As new and often expensive targeted therapies, which are tumoristatic rather than tumoricidal, become available, new demands are posed on response assessment. Bevacizumab, an antiangiogenic agent causing normalization of the tumor microvasculature, potentiates the effect of cytotoxic agents on colorectal liver metastases. It is known that assessment of glucose metabolism by (dynamic) positron emission tomography using [(18)F]-2-fluoro-2-deoxy-D-glucose ((18)F-FDG PET) can be used as an early surrogate endpoint to determine treatment efficacy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to quantify functional tumor vasculature (permeability, vascular surface area). Here, we describe the response of colorectal liver metastases to cytotoxic regimens including bevacizumab using both (18)F-FDG PET and DCE-MRI in 2 cases. In both cases, a large reduction in glucose metabolic rate and functional tumor vasculature are observed after 3 treatment cycles. PMID- 21609928 TI - Safe use of FOLFOX in two patients with metastatic colorectal carcinoma and severe hepatic dysfunction. AB - BACKGROUND: Chemotherapeutic options for patients with metastasised colorectal cancer and impaired liver function are limited. Although oxaliplatin and 5-FU are well tolerated as single therapeutic agents, data supporting their use as combination chemotherapy in the setting of severe hepatic dysfunction are insufficient. PATIENTS AND METHODS: Here, we report on 2 patients with colorectal cancer and severe liver dysfunction secondary to hepatic metastases. On admission both patients displayed a bilirubin of > 22 mg/dL and an alkaline phosphatase (AP) of > 350 U/L as signs of extensive hepatic tumor spread. We initiated a 5 FU/oxaliplatin-based combination chemotherapy in both patients. RESULTS: Liver function and clinical performance improved dramatically within the first cycles of therapy in both patients. On radiologic evaluation, we observed 1 partial response and one long-term (10 months) disease stabilization. The toxicity was acceptable in both patients. CONCLUSION: We concluded that oxaliplatin-based combination chemotherapies (eg FOLFOX4) may achieve good tumor response without significant side effects in patients with metastatic colorectal cancer and hepatic dysfunction. PMID- 21609931 TI - Molecular tests for colorectal cancer screening. AB - Detecting and removing high-risk adenomas and early colorectal cancer (CRC) can reduce mortality of this disease. The noninvasive fecal occult blood test (FOBT; guaiac-based or immunochemical) is widely used in screening programs and although effective, it leaves room for improvement in terms of test accuracy. Molecular tests are expected to be more sensitive, specific and informative than current detection tests, and are promising future tools for CRC screening. This review provides an overview of the performances of DNA, RNA, and protein markers for CRC detection in stool and blood. Most emphasis currently is on DNA and protein markers. Among DNA markers there is trend to move away from mutation markers in favor of methylation markers. The recent boost in proteomics research leads to many new candidate protein markers. Usually in small series, some markers show better performance than the present FOBT. Evaluation in large well-controlled randomized trials is the next step needed to take molecular markers for CRC screening to the next level and warrant implementation in a screening setting. PMID- 21609932 TI - Prognostic value of reduced SMAD4 expression in patients with metastatic colorectal cancer under oxaliplatin-containing chemotherapy: a translational study of the AIO colorectal study group. AB - BACKGROUND: SMAD4 is a polypeptide with tumor suppressor function being investigated as a prognostic biomarker in Union Internationale Contre le Cancer stages II and III in previous studies, but its role as a prognostic marker in stage IV colorectal cancer (CRC) is still undefined. We investigated the prognostic value of reduced SMAD4 expression in patients with metastatic (mCRC) under first-line oxaliplatin-containing combination chemotherapy. PATIENTS AND METHODS: Tumor samples were obtained from patients who took part in a prospective randomized phase III chemotherapy trial of the Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society colorectal study group, comparing the use of capecitabine plus oxaliplatin with infusional 5-fluorouracil (5-FU) plus oxaliplatin as first-line therapy in mCRC. SMAD4 expression was determined by immunohistochemistry. RESULTS: Tumor tissues from 230 patients were obtained. Reduced SMAD4 expression was identified in 34% of samples. Patients with reduced nuclear SMAD4 expression in tumor tissue showed a shorter progression-free survival (PFS; 7.0 months vs. 8.9 months; P = .024) and overall survival (OS; 13.9 months vs. 17.8 months; P = .044) compared with patients retaining SMAD4 expression. The effect of SMAD4 expression on PFS and OS could be demonstrated in univariate and multivariate analyses. CONCLUSION: Our data demonstrate the importance of reduced SMAD4 expression in patients with mCRC receiving chemotherapy with oxaliplatin and 5-FU. PMID- 21609933 TI - Upregulation of glycogen synthase kinase 3beta in human colorectal adenocarcinomas correlates with accumulation of CTNNB1. AB - INTRODUCTION: Mutations of the adenomatous polyposis coli (APC) tumor suppressor gene or the CTNNB1 protooncogene have been implicated in the initiation of most human colorectal epithelial neoplasms. Glycogen synthase kinase 3beta (GSK3B) serves a critical role in regulating their functions by phosphorylating both APC and CTNNB1 to facilitate CTNNB1 degradation. The current studies were performed to investigate whether GSK3B itself is regulated during the process of colorectal tumorigenesis. PATIENTS AND METHODS: We examined the expression of GSK3B and CTNNB1 in tissue samples from 24 human colorectal adenocarcinomas by Western immunoblotting analysis, kinase activity assays and immunohistochemistry. Normal colonic mucosa from the same colectomy specimens were used as a reference for comparison. RESULTS: We demonstrated that GSK3B expression levels and kinase activities were markedly and significantly increased in colorectal adenocarcinomas in all 24 cases compared with paired adjacent normal-appearing colonic mucosa. These increases correlated with significantly increased expression of CTNNB1 in the same tumors. Similar results were obtained in several cultured human colon cancer cell lines, demonstrating GSK3B levels correlated with CTNNB1 expression. CONCLUSION: Though APC and CTNNB1 regulation by GSK3B are frequently disrupted by mutations in colon cancers, our observations suggest that increased functional GSK3B might drive other growth-promoting signals in colorectal tumorigenesis. PMID- 21609934 TI - Long-term outcome of early-stage rectal cancer undergoing standard resection and local excision. AB - OBJECTIVES: To explore the long-term outcome and prognostic factors for early stage rectal cancer patients undergoing standard resection (SR) or local excision (LE). PATIENTS AND METHODS: This study included 350 patients with stage I rectal cancer, in which 283 cases (80.9%) received SR, and 67 cases (19.1%) received LE. Survival analyses were performed to compare outcomes of different surgeries. RESULTS: The 5-year local recurrence (LR) rate was 14.1% in LE group versus 3.3% in SR group (P= .0004), and the 10-year overall survival (OS) rate was not significantly different between the 2 groups. Multivariate analysis suggested that LE was an independent risk factor for 5-year LR rate and 10-year OS rate. Tumor grade was found related to 5-year LR, and T stage was found related to 10 year OS. Tumor size of 2.5 cm is found as a possible cut-off for predicting 5 year LR rate in LE group, with a sensitivity of 77.8% and a specificity of 75.9%. In patients with LE, the 5-year LR rate for tumors >= 2.5 cm was 40%, compared with 4.3% for tumors < 2.5 cm (P = .001). CONCLUSION: Local excision in early stage rectal cancer may result in high local recurrence rate. The procedure is only recommended in highly selective groups of patients. A tumor size of 2.5 cm is a useful criterion for choosing LE rather than SR. PMID- 21609935 TI - Efficacy and tolerability of biweekly bevacizumab, irinotecan, folinic acid and fluorouracil intravenous bolus (BIFF Regimen) in patients with metastatic colorectal cancer: the southern Italy cooperative oncology group experience. AB - BACKGROUND: We have extensively assessed a biweekly regimen of irinotecan plus folinic acid and fluorouracil bolus (IRIFAFU) in metastatic colorectal cancer (MCRC). Here, we report on the safety and activity of BIFF (bevacizumab plus IRIFAFU) regimen in 94 mCRC patients. PATIENTS AND METHODS: Bevacizumab 5 mg/kg (1 hour), and irinotecan 180 mg/m(2) (1 hour) were given intravenously on day 1, 6S-folinic acid 250 mg/m(2) (2 hours), and fluorouracil 850 mg/m(2) (bolus) were given intravenously on day 2 every 2 weeks for a median of 9 cycles per patient (range, 1-12), and maintenance bevacizumab alone was delivered in 16 cases. RESULTS: Grade >= 3 hematologic toxicities were neutropenia (50%) and febrile neutropenia (5%). Most common grade 3 nonhematologic side effects were diarrhea (20%), vomiting (7%), nausea (4%), and stomatitis (4%). Severe hypertension (1%) and epistaxis (1%) rarely occurred. Six complete responses and 44 partial responses were registered, giving a response rate of 53% (95% CI, 43%-64%). Median progression-free survival was 11.5 months (95% CI, 9.0-14.0 months). Forty three (46%) patients eventually died, and the median overall survival was 24.0 months (95% CI, 20.2-27.8 months). CONCLUSION: Bevacizumab appeared to increase the activity of the IRIFAFU regimen without worsening its tolerability. Efficacy of BIFF was comparable with that reported with other bevacizumab plus irinotecan based combinations. PMID- 21609936 TI - Correlation of overall survival with gene expression profiles in a prospective study of resectable esophageal cancer. AB - PURPOSE: Preoperative chemotherapy has demonstrated a survival benefit for patients with potentially resectable esophageal cancer; however, currently it is not possible to predict the benefit of this treatment for an individual patient. This prospective study was designed to correlate gene expression profiles with clinical outcome in this setting. PATIENTS AND METHODS: Eligible patients were deemed to have resectable disease after staging by computed tomography, endoscopic ultrasound, and laparoscopy as indicated and following discussion at the multidisciplinary team meeting. All patients received neoadjuvant platinum and fluoropyrimidine-based chemotherapy; and clinical data were entered prospectively onto a study-specific database. Total RNA was isolated from pretreatment tumor biopsies obtained at baseline endoscopy and analyzed using a cDNA array consisting of 22,000 cDNA clones. RESULTS: Of the patients with adequate follow-up accrued between 2002 and 2005, 35 satisfied the quality control measures for the microarray profiling. Median follow-up was 938 days. Supervised hierarchical clustering of normalized data revealed 165 significantly differentially expressed genes based on overall survival (OS; P < .01) with 2 distinct clusters: a poor outcome group: N = 17 (1 year OS 46.2%) and a good outcome group: N = 18 (1 year OS 100%). Genes identified included those previously associated with esophageal cancer and, interestingly, a group of genes encoding proteins involved in the regulation of the TOLL receptor-signaling pathway. CONCLUSION: This initial study has highlighted groups of tumors with distinct gene expression profiles based on survival and warrants further validation in a larger cohort. This approach may further our understanding of individual tumor biology and thus facilitate the development of tailored treatment. PMID- 21609937 TI - A phase I study of capecitabine, oxaliplatin, and lapatinib in metastatic or advanced solid tumors. AB - BACKGROUND: Metastatic colorectal cancer (mCRC) is a leading cause of cancer related mortality in the United States, and new treatment options are needed. This phase I study investigated a novel regimen combining 2 chemotherapy drugs with proven efficacy in mCRC (capecitabine and oxaliplatin) with a tyrosine kinase inhibitor (lapatinib). Lapatinib has already been approved by the US Food and Drug Administration for treatment of selected cases of breast cancer. PATIENTS AND METHODS: Patients with solid tumors responsive to fluoropyrimidines or oxaliplatin were eligible for enrollment. Treatment was given over a 21-day cycle with a fixed dosing of intravenous oxaliplatin of 130 mg/m(2) on day 1. Capecitabine and lapatinib were given orally at escalating doses, starting at capecitabine 1500 mg/m(2)/day on days 1-14 and lapatinib 1000 mg daily on days 1 21. RESULTS: Ten patients received treatment per study protocol. All had received previous systemic treatment. Diarrhea was one of the most common side effects and accounted for nearly all grade 3/4 toxicity. The starting dose level was determined to be the maximum tolerated dose. One patient with pancreatic cancer had evidence of a partial response. Three other patients demonstrated stable disease. There were no complete responses. CONCLUSION: Results of this study suggest the regimen of capecitabine, oxaliplatin, and lapatinib has some efficacy in types of advanced or metastatic solid malignancies with known responsiveness to fluoropyrimidines or oxaliplatin. Further research may help determine whether this regimen can improve on the response rates seen with current standard regimens for mCRC. PMID- 21609938 TI - Effect of KRAS mutational status in advanced colorectal cancer on the outcomes of anti-epidermal growth factor receptor monoclonal antibody therapy: a systematic review and meta-analysis. AB - BACKGROUND: Emerging data suggest that somatic KRAS mutation in advanced colorectal cancer is a strong predictor of non-response to anti-epidermal growth factor receptor antibody (anti-EGFR) therapy. PATIENTS AND METHODS: A comprehensive search through March 2010 identified randomized controlled trials in metastatic colorectal cancer that evaluated chemotherapy regimens or best supportive care, with and without anti-EGFR therapy. Outcomes included progression-free survival (PFS), median overall survival (OS), and predictive test performance. RESULTS: In pooled data from 8 trials with 5325 patients, the addition of anti-EGFR to standard chemotherapy resulted in improved PFS (HR 0.66 [95% CI, 0.53-0.82]) in patients with wild-type KRAS in the tumor tissue, but not in patients with KRAS mutation (HR 1.07 [95% CI, 0.91-1.27]). Anti-EGFR treatment in the wild-type group did not significantly improve median OS. As a predictive biomarker, KRAS mutation had a positive likelihood ratio of 2.0 (95% CI, 1.45 2.76) in predicting nonresponse to anti-EGFR treatment. CONCLUSION: In patients with advanced colorectal cancer, the addition of anti-EGFR treatment to standard chemotherapy improves PFS for those with wild-type, but not mutant KRAS status. KRAS gene mutation testing provides a fair biomarker in predicting non-response to anti-EGFR treatment. PMID- 21609939 TI - Brief commentary: largest randomized trial of biliary tract cancer treatment with cisplatin plus gemcitabine versus gemcitabine alone: an excellent opportunity to evaluate the prognostic value of tumor marker CA 19-9. PMID- 21609940 TI - Crew resource management and VTE prophylaxis in surgery: a quality improvement initiative. AB - Despite the availability of safe and effective prophylaxis, appropriate use of venous thromboembolism (VTE) prophylaxis in surgical patients remains suboptimal. Multifaceted quality improvement (QI) activities are needed for sustained improvement at the individual institution level. This work describes a QI initiative for VTE prophylaxis in surgery that combined clinical education with Crew Resource Management (CRM)--a set of principles and techniques for communication, teamwork, and error avoidance used in the aviation industry. Surveys of clinicians participating in the initiative demonstrated immediate and retained confidence and increased knowledge in identifying process-related factors leading to errors, applying CRM to patient care, and identifying VTE prophylaxis candidates and guideline-recommended prophylaxis regimens. Reviews of patient charts preinitiative and postinitiative demonstrated performance improvement in meeting guideline recommendations for the timing, inpatient duration, and use of VTE prophylaxis beyond discharge. This new model joins continuing medical education with CRM to improve the appropriate use of VTE prophylaxis in surgery. PMID- 21609941 TI - The implications of using adjusted versus unadjusted methods to measure health care disparities at the practice level. AB - Reducing disparities in care requires that health care providers identify populations at risk for suboptimal quality of care. Stratified analyses are often used to examine disparities (eg, by race or sex). However, stratified analyses can be misleading if the variables are confounded. The authors examined disparities in quality within a large ambulatory care practice using both unadjusted and adjusted methods for 18 measures. In unadjusted analyses, differences in quality were identified for 9 measures by race. However, in analyses adjusted simultaneously for race, sex, age, socioeconomic status, and chronic medical conditions, racial differences were apparent for only 4 measures. Women received lower quality care for 4 measures in both unadjusted and adjusted analyses. The pattern of observed disparities can differ significantly based on whether unadjusted or adjusted methods are applied. Health care organizations should consider the routine use of adjusted methods to measure disparities in order to better inform disparity reduction initiatives. PMID- 21609942 TI - Spontaneous theory of mind and its absence in autism spectrum disorders. AB - Theory of mind, the cognitive capacity to infer others' mental states, is crucial for the development of social communication. The impairment of theory of mind may relate to autism spectrum disorder (ASD), which is characterized by profound difficulties in social interaction and communication. In the current article, I summarize recent updates in theory of mind research utilizing the spontaneous false belief test, which assesses participants' spontaneous tendency to attribute belief status to others. These studies reveal that young infants pass the spontaneous false belief test well before they can pass the same task when explicitly asked to answer. By contrast, high-functioning adults with ASD, who can easily pass the false belief task when explicitly asked to, do not show spontaneous false belief attribution. These findings suggest that the capacity for theory of mind develops much earlier than was previously thought, and the absence of spontaneous theory of mind may relate to impairment in social interaction and communication found in ASD. PMID- 21609943 TI - Central role of GABA in neuron-glia interactions. AB - The major types of glial cells-astrocytes, microglia, and cells of the oligodendroglial lineage-are known to express functional metabotropic and ionotropic GABA receptors. Neuronal signaling mechanisms allowing for the activation of these receptors in glia are probably as complex as those described among neurons and involve synaptic and extrasynaptic transmission modes. In addition, astrocytes can signal back to neurons by releasing GABA, probably through unconventional nonvesicular mechanisms. The decryption of the roles played by GABAergic signaling in neuron-glia interactions is only beginning, but it has been suggested that activation of glial cells by GABA influences important functions of the brain such as neuronal activity, differentiation, myelination, and neuroprotection. This review discusses the cellular mechanisms allowing the major types of glial cells to sense and transmit GABAergic signals and gives an overview of potential roles of this signaling pathway in developing and mature brains. PMID- 21609944 TI - Medical problems presenting to paediatric emergency departments: 10 years on. AB - OBJECTIVE: To describe the common medical presenting problems of children attending a paediatric emergency department (ED) compared with 10 years previously. DESIGN: A retrospective review of electronic patient record and comparison with previous cohort. SETTING: A UK university hospital ED. PATIENTS: A cohort of children and young people aged 0-15 years who attended the ED between 7 February 2007 and 6 February 2008 (n=39 394) compared with a historical cohort from 10 years earlier. MAIN OUTCOME MEASURES AND RESULTS: Information on presenting problem, demographic data and source of referral were collected. Presenting problems were ranked and comparisons made with previous data using the difference between proportions analysis and the significance test for a difference in two proportions. A total of 39 394 children (57% boys) were seen with 14 724 medical attendances compared with 10 369 attendances from the 1997 cohort, an increase of 42%. Most (85%) ED attendances can be accounted for by the 10 most common presenting problems, including breathing difficulty (2494, 20.1%), febrile illness (1752, 14.1%), diarrhoea with or without vomiting (1731, 14.0%), rash (1066, 8.6%) and cough (835, 6.7%). Similar proportions are described to a decade earlier; however, there were fewer patients attending with breathing difficulty (-10.9%, p<0.001). CONCLUSIONS: Over a 10-year period, there has been a rise in the number of people attending the ED with medical conditions. The 10 most common presenting problems account for 85% of medical attendees. These results suggest the increasing utilisation of ED services for children with common medical presenting problems and should inform further research exploring the pathways for attendance and the thresholds in seeking medical advice in order to inform the commissioning of paediatric emergency and urgent care services. PMID- 21609945 TI - Hospital facilities for head injured children: UK national survey. AB - AIM: To assess how child emergency department (ED) attendances are distributed between hospitals across England, Wales and Northern Ireland and how care is organised for children with a head injury. METHODS: A cross-sectional survey was performed of the 245 hospitals in England Wales, Northern Ireland and the Crown Dependencies (Channel Islands and Isle of Man) which were eligible to participate in the enquiry from September 2009 to April 2010. The survey covered hospital details, departments and procedures, ED activity, imaging, admission and discharge procedures, referral and transfer, documentation, training and audit, information and advice, and non-accidental head injuries. RESULTS: 64% of hospitals have an established pathway for management of head injured children. Not infrequently hospitals asserting designation as specialist trauma or specialist neurosurgical centres do not offer an intensive care service for children. 82% of child ED attendances are to hospitals that would not care for a critically ill child on-site. Hospitals that do offer such care are much more likely to have children's trained staff available in the ED. They are also more likely to have access to surgical support beyond neurosurgery. CONCLUSION: Given the extent of variation between hospitals in the facilities available for head injured children, further comparative studies into the standards of care delivered and outcomes (including a confidential enquiry) are indicated. PMID- 21609946 TI - Patterns of receptive and creative cultural activities and their association with perceived health, anxiety, depression and satisfaction with life among adults: the HUNT study, Norway. AB - BACKGROUND: Cultural participation has been used both in governmental health policies and as medical therapy, based on the assumption that cultural activities will improve health. Previous population studies and a human intervention study have shown that religious, social and cultural activities predict increased survival rate. The aim of this study was to analyse the association between cultural activity and perceived health, anxiety, depression and satisfaction with life in both genders. METHODS: The study is based on the third population-based Nord-Trondelag Health Study (2006-2008), including 50,797 adult participants from Nord-Trondelag County, Norway. Data on cultural activities, both receptive and creative, perceived health, anxiety, depression and satisfaction with life were collected by comprehensive questionnaires. RESULTS: The logistic regression models, adjusted for relevant cofactors, show that participation in receptive and creative cultural activities was significantly associated with good health, good satisfaction with life, low anxiety and depression scores in both genders. Especially in men, attending receptive, rather than creative, cultural activities was more strongly associated with all health-related outcomes. Statistically significant associations between several single receptive, creative cultural activities and the health-related outcome variables were revealed. CONCLUSION: This population-based study suggests gender-dependent associations between cultural participation and perceived health, anxiety, depression and satisfaction with life. The results support hypotheses on the effect of cultural activities in health promotion and healthcare, but further longitudinal and experimental studies are warranted to establish a reliable cause-effect relationship. PMID- 21609947 TI - Mutations of TSEN and CASK genes are prevalent in pontocerebellar hypoplasias type 2 and 4. PMID- 21609948 TI - PredUs: a web server for predicting protein interfaces using structural neighbors. AB - We describe PredUs, an interactive web server for the prediction of protein protein interfaces. Potential interfacial residues for a query protein are identified by 'mapping' contacts from known interfaces of the query protein's structural neighbors to surface residues of the query. We calculate a score for each residue to be interfacial with a support vector machine. Results can be visualized in a molecular viewer and a number of interactive features allow users to tailor a prediction to a particular hypothesis. The PredUs server is available at: http://wiki.c2b2.columbia.edu/honiglab_public/index.php/Software:PredUs. PMID- 21609949 TI - BioProfiling.de: analytical web portal for high-throughput cell biology. AB - BioProfiling.de provides a comprehensive analytical toolkit for the interpretation gene/protein lists. As input, BioProfiling.de accepts a gene/protein list. As output, in one submission, the gene list is analyzed by a collection of tools which employs advanced enrichment or network-based statistical frameworks. The gene list is profiled with respect to the most information available regarding gene function, protein interactions, pathway relationships, in silico predicted microRNA to gene associations, as well as, information collected by text mining. BioProfiling.de provides a user friendly dialog-driven web interface for several model organisms and supports most available gene identifiers. The web portal is freely available at http://www.BioProfiling.de/gene_list. PMID- 21609950 TI - R.E.D. Server: a web service for deriving RESP and ESP charges and building force field libraries for new molecules and molecular fragments. AB - R.E.D. Server is a unique, open web service, designed to derive non-polarizable RESP and ESP charges and to build force field libraries for new molecules/molecular fragments. It provides to computational biologists the means to derive rigorously molecular electrostatic potential-based charges embedded in force field libraries that are ready to be used in force field development, charge validation and molecular dynamics simulations. R.E.D. Server interfaces quantum mechanics programs, the RESP program and the latest version of the R.E.D. tools. A two step approach has been developed. The first one consists of preparing P2N file(s) to rigorously define key elements such as atom names, topology and chemical equivalencing needed when building a force field library. Then, P2N files are used to derive RESP or ESP charges embedded in force field libraries in the Tripos mol2 format. In complex cases an entire set of force field libraries or force field topology database is generated. Other features developed in R.E.D. Server include help services, a demonstration, tutorials, frequently asked questions, Jmol-based tools useful to construct PDB input files and parse R.E.D. Server outputs as well as a graphical queuing system allowing any user to check the status of R.E.D. Server jobs. PMID- 21609951 TI - Genome-wide analysis of mobile genetic element insertion sites. AB - Mobile genetic elements (MGEs) account for a significant fraction of eukaryotic genomes and are implicated in altered gene expression and disease. We present an efficient computational protocol for MGE insertion site analysis. ELAN, the suite of tools described here uses standard techniques to identify different MGEs and their distribution on the genome. One component, DNASCANNER analyses known insertion sites of MGEs for the presence of signals that are based on a combination of local physical and chemical properties. ISF (insertion site finder) is a machine-learning tool that incorporates information derived from DNASCANNER. ISF permits classification of a given DNA sequence as a potential insertion site or not, using a support vector machine. We have studied the genomes of Homo sapiens, Mus musculus, Drosophila melanogaster and Entamoeba histolytica via a protocol whereby DNASCANNER is used to identify a common set of statistically important signals flanking the insertion sites in the various genomes. These are used in ISF for insertion site prediction, and the current accuracy of the tool is over 65%. We find similar signals at gene boundaries and splice sites. Together, these data are suggestive of a common insertion mechanism that operates in a variety of eukaryotes. PMID- 21609952 TI - Direct and indirect effects in the regulation of overlapping promoters. AB - Optimal response to environmental stimuli often requires activation of certain genes and repression of others. Dual function regulatory proteins play a key role in the differential regulation of gene expression. While repression can be achieved by any DNA binding protein through steric occlusion of RNA polymerase in the promoter region, activation often requires a surface on the regulatory protein to contact RNAP and thus facilitate transcription initiation. RNAP itself is also a DNA binding protein, therefore it can function as a transcriptional repressor. Searching the Escherichia coli promoter database we found that ~14% of the identified 'forward' promoters overlap with a promoter oriented in the opposite direction. In this article we combine a mathematical model with experimental analysis of synthetic regulatory regions to investigate interference of overlapping promoters. We find that promoter interference depends on the characteristics of overlapping promoters. The model predicts that promoter strength and interference can be regulated separately, which provides unique opportunities for regulation. Our experimental data suggest that in principle any DNA binding protein can be used for both activation and repression of promoter transcription, depending on the context. These findings can be exploited in the construction of synthetic networks. PMID- 21609953 TI - Modified bases enable high-efficiency oligonucleotide-mediated allelic replacement via mismatch repair evasion. AB - Genome engineering using single-stranded oligonucleotides is an efficient method for generating small chromosomal and episomal modifications in a variety of host organisms. The efficiency of this allelic replacement strategy is highly dependent on avoidance of the endogenous mismatch repair (MMR) machinery. However, global MMR inactivation generally results in significant accumulation of undesired background mutations. Here, we present a novel strategy using oligos containing chemically modified bases (2'-Fluoro-Uridine, 5-Methyl-deoxyCytidine, 2,6-Diaminopurine or Iso-deoxyGuanosine) in place of the standard T, C, A or G to avoid mismatch detection and repair, which we tested in Escherichia coli. This strategy increases transient allelic-replacement efficiencies by up to 20-fold, while maintaining a 100-fold lower background mutation level. We further show that the mismatched bases between the full length oligo and the chromosome are often not incorporated at the target site, probably due to nuclease activity at the 5' and 3' termini of the oligo. These results further elucidate the mechanism of oligo-mediated allelic replacement (OMAR) and enable improved methodologies for efficient, large-scale engineering of genomes. PMID- 21609954 TI - Genie: literature-based gene prioritization at multi genomic scale. AB - Biomedical literature is traditionally used as a way to inform scientists of the relevance of genes in relation to a research topic. However many genes, especially from poorly studied organisms, are not discussed in the literature. Moreover, a manual and comprehensive summarization of the literature attached to the genes of an organism is in general impossible due to the high number of genes and abstracts involved. We introduce the novel Genie algorithm that overcomes these problems by evaluating the literature attached to all genes in a genome and to their orthologs according to a selected topic. Genie showed high precision (up to 100%) and the best performance in comparison to other algorithms in most of the benchmarks, especially when high sensitivity was required. Moreover, the prioritization of zebrafish genes involved in heart development, using human and mouse orthologs, showed high enrichment in differentially expressed genes from microarray experiments. The Genie web server supports hundreds of species, millions of genes and offers novel functionalities. Common run times below a minute, even when analyzing the human genome with hundreds of thousands of literature records, allows the use of Genie in routine lab work. AVAILABILITY: http://cbdm.mdc-berlin.de/tools/genie/. PMID- 21609955 TI - GCView: the genomic context viewer for protein homology searches. AB - Genomic neighborhood can provide important insights into evolution and function of a protein or gene. When looking at operons, changes in operon structure and composition can only be revealed by looking at the operon as a whole. To facilitate the analysis of the genomic context of a query in multiple organisms we have developed Genomic Context Viewer (GCView). GCView accepts results from one or multiple protein homology searches such as BLASTp as input. For each hit, the neighboring protein-coding genes are extracted, the regions of homology are labeled for each input and the results are presented as a clear, interactive graphical output. It is also possible to add more searches to iteratively refine the output. GCView groups outputs by the hits for different proteins. This allows for easy comparison of different operon compositions and structures. The tool is embedded in the framework of the Bioinformatics Toolkit of the Max-Planck Institute for Developmental Biology (MPI Toolkit). Job results from the homology search tools inside the MPI Toolkit can be forwarded to GCView and results can be subsequently analyzed by sequence analysis tools. Results are stored online, allowing for later reinspection. GCView is freely available at http://toolkit.tuebingen.mpg.de/gcview. PMID- 21609956 TI - Compensatory signals associated with the activation of human GC 5' splice sites. AB - GC 5' splice sites (5'ss) are present in ~1% of human introns, but factors promoting their efficient selection are poorly understood. Here, we describe a case of X-linked agammaglobulinemia resulting from a GC 5'ss activated by a mutation in BTK intron 3. This GC 5'ss was intrinsically weak, yet it was selected in >90% primary transcripts in the presence of a strong and intact natural GT counterpart. We show that efficient selection of this GC 5'ss required a high density of GAA/CAA-containing splicing enhancers in the exonized segment and was promoted by SR proteins 9G8, Tra2beta and SC35. The GC 5'ss was efficiently inhibited by splice-switching oligonucleotides targeting either the GC 5'ss itself or the enhancer. Comprehensive analysis of natural GC-AG introns and previously reported pathogenic GC 5'ss showed that their efficient activation was facilitated by higher densities of splicing enhancers and lower densities of silencers than their GT 5'ss equivalents. Removal of the GC-AG introns was promoted to a minor extent by the splice-site strength of adjacent exons and inhibited by flanking Alu repeats, with the first downstream Alus located on average at a longer distance from the GC 5'ss than other transposable elements. These results provide new insights into the splicing code that governs selection of noncanonical splice sites. PMID- 21609957 TI - Depurination of Brome mosaic virus RNA3 inhibits its packaging into virus particles. AB - Packaging of the segmented RNA genome of Brome mosaic virus (BMV) into discrete particles is an essential step in the virus life cycle; however, questions remain regarding the mechanism of RNA packaging and the degree to which the viral coat protein controls the process. In this study, we used a plant-derived glycosidase, Pokeweed antiviral protein, to remove 14 specific bases from BMV RNA3 to examine the effect of depurination on virus assembly. Depurination of A771 within ORF3 and A1006 in the intergenic region inhibited coat protein binding and prevented RNA3 incorporation into particles. The disruption of interaction was not based on sequence identity, as mutation of these two purines to pyrimidines did not decrease coat protein-binding affinity. Rather, we suggest that base removal results in decreased thermodynamic stability of local RNA structures required for packaging, and that this instability is detected by coat protein. These results describe a new level of discrimination by coat protein, whereby it recognizes damage to specific viral RNA elements in the form of base removal and selects against incorporating the RNA into particles. PMID- 21609958 TI - Avoiding cytotoxicity of transposases by dose-controlled mRNA delivery. AB - The Sleeping Beauty (SB) transposase and its newly developed hyperactive variant, SB100X, are of increasing interest for genome modification in experimental models and gene therapy. The potential cytotoxicity of transposases requires careful assessment, considering that residual integration events of transposase expression vectors delivered by physicochemical transfection or episomal retroviral vectors may lead to permanent transposase expression and resulting uncontrollable transposition. Comparing retrovirus-based approaches for delivery of mRNA, episomal DNA or integrating DNA, we found that conventional SB transposase, SB100X and a newly developed codon-optimized SB100Xo may trigger premitotic arrest and apoptosis. Cell stress induced by continued SB overexpression was self-limiting due to the induction of cell death, which occurred even in the absence of a co-transfected transposable element. The cytotoxic effects of SB transposase were strictly dose dependent and heralded by induction of p53 and c-Jun. Inactivating mutations in SB's catalytic domain could not abrogate cytotoxicity, suggesting a mechanism independent of DNA cleavage activity. An improved approach of retrovirus particle-mediated mRNA transfer allowed transient and dose-controlled expression of SB100X, supported efficient transposition and prevented cytotoxicity. Transposase-mediated gene transfer can thus be tuned to maintain high efficiency in the absence of overt cell damage. PMID- 21609959 TI - Update of PROFEAT: a web server for computing structural and physicochemical features of proteins and peptides from amino acid sequence. AB - Sequence-derived structural and physicochemical features have been extensively used for analyzing and predicting structural, functional, expression and interaction profiles of proteins and peptides. PROFEAT has been developed as a web server for computing commonly used features of proteins and peptides from amino acid sequence. To facilitate more extensive studies of protein and peptides, numerous improvements and updates have been made to PROFEAT. We added new functions for computing descriptors of protein-protein and protein-small molecule interactions, segment descriptors for local properties of protein sequences, topological descriptors for peptide sequences and small molecule structures. We also added new feature groups for proteins and peptides (pseudo amino acid composition, amphiphilic pseudo-amino acid composition, total amino acid properties and atomic-level topological descriptors) as well as for small molecules (atomic-level topological descriptors). Overall, PROFEAT computes 11 feature groups of descriptors for proteins and peptides, and a feature group of more than 400 descriptors for small molecules plus the derived features for protein-protein and protein-small molecule interactions. Our computational algorithms have been extensively tested and used in a number of published works for predicting proteins of specific structural or functional classes, protein protein interactions, peptides of specific functions and quantitative structure activity relationships of small molecules. PROFEAT is accessible free of charge at http://bidd.cz3.nus.edu.sg/cgi-bin/prof/protein/profnew.cgi. PMID- 21609960 TI - The PETfold and PETcofold web servers for intra- and intermolecular structures of multiple RNA sequences. AB - The function of non-coding RNA genes largely depends on their secondary structure and the interaction with other molecules. Thus, an accurate prediction of secondary structure and RNA-RNA interaction is essential for the understanding of biological roles and pathways associated with a specific RNA gene. We present web servers to analyze multiple RNA sequences for common RNA structure and for RNA interaction sites. The web servers are based on the recent PET (Probabilistic Evolutionary and Thermodynamic) models PETfold and PETcofold, but add user friendly features ranging from a graphical layer to interactive usage of the predictors. Additionally, the web servers provide direct access to annotated RNA alignments, such as the Rfam 10.0 database and multiple alignments of 16 vertebrate genomes with human. The web servers are freely available at: http://rth.dk/resources/petfold/ PMID- 21609961 TI - The role of Holliday junction resolvases in the repair of spontaneous and induced DNA damage. AB - DNA double-strand breaks (DSBs) and other lesions occur frequently during cell growth and in meiosis. These are often repaired by homologous recombination (HR). HR may result in the formation of DNA structures called Holliday junctions (HJs), which need to be resolved to allow chromosome segregation. Whereas HJs are present in most HR events in meiosis, it has been proposed that in vegetative cells most HR events occur through intermediates lacking HJs. A recent screen in yeast has shown HJ resolution activity for a protein called Yen1, in addition to the previously known Mus81/Mms4 complex. Yeast strains deleted for both YEN1 and MMS4 show a reduction in growth rate, and are very sensitive to DNA-damaging agents. In addition, we investigate the genetic interaction of yen1 and mms4 with mutants defective in different repair pathways. We find that in the absence of Yen1 and Mms4 deletion of RAD1 or RAD52 have no further effect, whereas additional sensitivity is seen if RAD51 is deleted. Finally, we show that yeast cells are unable to carry out meiosis in the absence of both resolvases. Our results show that both Yen1 and Mms4/Mus81 play important (although not identical) roles during vegetative growth and in meiosis. PMID- 21609962 TI - PRI-CAT: a web-tool for the analysis, storage and visualization of plant ChIP-seq experiments. AB - Although several tools for the analysis of ChIP-seq data have been published recently, there is a growing demand, in particular in the plant research community, for computational resources with which such data can be processed, analyzed, stored, visualized and integrated within a single, user-friendly environment. To accommodate this demand, we have developed PRI-CAT (Plant Research International ChIP-seq analysis tool), a web-based workflow tool for the management and analysis of ChIP-seq experiments. PRI-CAT is currently focused on Arabidopsis, but will be extended with other plant species in the near future. Users can directly submit their sequencing data to PRI-CAT for automated analysis. A QuickLoad server compatible with genome browsers is implemented for the storage and visualization of DNA-binding maps. Submitted datasets and results can be made publicly available through PRI-CAT, a feature that will enable community-based integrative analysis and visualization of ChIP-seq experiments. Secondary analysis of data can be performed with the aid of GALAXY, an external framework for tool and data integration. PRI-CAT is freely available at http://www.ab.wur.nl/pricat. No login is required. PMID- 21609963 TI - The distinctive roles of erythroid specific activator GATA-1 and NF-E2 in transcription of the human fetal gamma-globin genes. AB - GATA-1 and NF-E2 are erythroid specific activators that bind to the beta-globin locus. To explore the roles of these activators in transcription of the human fetal stage specific gamma-globin genes, we reduced GATA-1 and p45/NF-E2 using shRNA in erythroid K562 cells. GATA-1 or p45/NF-E2 knockdown inhibited the transcription of the gamma-globin genes, hypersensitive site (HS) formation in the LCR and chromatin loop formation of the beta-globin locus, but histone acetylation across the locus was decreased only in the case of GATA-1 knockdown. In p45/NF-E2 knockdown cells, GATA-1 binding was maintained at the LCR HSs and gamma-globin promoter, but NF-E2 binding at the LCR HSs was reduced by GATA-1 knockdown regardless of the amount of p45/NF-E2 in K562 cells. These results indicate that histone acetylation is dependent on GATA-1 binding, but the binding of GATA-1 is not sufficient for the gamma-globin transcription, HS formation and chromatin loop formation and NF-E2 is required. This idea is supported by the distinctive binding pattern of CBP and Brg1 in the beta-globin locus. Furthermore GATA-1-dependent loop formation between HS5 and 3'HS1 suggests correlation between histone modifications and chromatin looping. PMID- 21609964 TI - Characterization of extracellular circulating microRNA. AB - MicroRNAs (miRNAs), a class of post-transcriptional gene expression regulators, have recently been detected in human body fluids, including peripheral blood plasma as extracellular nuclease resistant entities. However, the origin and function of extracellular circulating miRNA remain essentially unknown. Here, we confirmed that circulating mature miRNA in contrast to mRNA or snRNA is strikingly stable in blood plasma and cell culture media. Furthermore, we found that most miRNA in plasma and cell culture media completely passed through 0.22 um filters but remained in the supernatant after ultracentrifugation at 110 000g indicating the non-vesicular origin of the extracellular miRNA. Furthermore, western blot immunoassay revealed that extracellular miRNA ultrafiltrated together with the 96 kDa Ago2 protein, a part of RNA-induced silencing complex. Moreover, miRNAs in both blood plasma and cell culture media co-immunoprecipited with anti-Ago2 antibody in a detergent free environment. This is the first study to show that extracellular miRNAs are predominantly exosomes/microvesicles free and are associated with Ago proteins. We hypothesize that extracellular miRNAs are in the most part by-products of dead cells that remain in extracellular space due to the high stability of the Ago2 protein and Ago2-miRNA complex. Nevertheless, our data does not reject the possibility that some miRNAs can be associated with exosomes. PMID- 21609965 TI - Analysis and visualization of Arabidopsis thaliana GWAS using web 2.0 technologies. AB - With large-scale genomic data becoming the norm in biological studies, the storing, integrating, viewing and searching of such data have become a major challenge. In this article, we describe the development of an Arabidopsis thaliana database that hosts the geographic information and genetic polymorphism data for over 6000 accessions and genome-wide association study (GWAS) results for 107 phenotypes representing the largest collection of Arabidopsis polymorphism data and GWAS results to date. Taking advantage of a series of the latest web 2.0 technologies, such as Ajax (Asynchronous JavaScript and XML), GWT (Google-Web-Toolkit), MVC (Model-View-Controller) web framework and Object Relationship Mapper, we have created a web-based application (web app) for the database, that offers an integrated and dynamic view of geographic information, genetic polymorphism and GWAS results. Essential search functionalities are incorporated into the web app to aid reverse genetics research. The database and its web app have proven to be a valuable resource to the Arabidopsis community. The whole framework serves as an example of how biological data, especially GWAS, can be presented and accessed through the web. In the end, we illustrate the potential to gain new insights through the web app by two examples, showcasing how it can be used to facilitate forward and reverse genetics research. Database URL: http://arabidopsis.usc.edu/ PMID- 21609966 TI - Data mining using the Catalogue of Somatic Mutations in Cancer BioMart. AB - Catalogue of Somatic Mutations in Cancer (COSMIC) (http://www.sanger.ac.uk/cosmic) is a publicly available resource providing information on somatic mutations implicated in human cancer. Release v51 (January 2011) includes data from just over 19,000 genes, 161,787 coding mutations and 5573 gene fusions, described in more than 577,000 tumour samples. COSMICMart (COSMIC BioMart) provides a flexible way to mine these data and combine somatic mutations with other biological relevant data sets. This article describes the data available in COSMIC along with examples of how to successfully mine and integrate data sets using COSMICMart. DATABASE URL: http://www.sanger.ac.uk/genetics/CGP/cosmic/biomart/martview/. PMID- 21609967 TI - The on-line processing of socio-emotional information in prototypical scenarios: inferences from brain potentials. AB - Little is known about the time course of the mechanisms involved in the on-line processing of socio-emotional information. We used event-related brain potentials (ERPs) to investigate this issue using vignettes that described prototypical, social scenarios. An initial sentence established the social context and the following target sentence ended with a critical word that informed the reader of the character's socio-emotional response to the situation. Critical words that mismatched rather than matched with a character's expected feelings elicited a larger ERP negativity (N400) ~200-500 ms after word onset, followed by a larger frontal positivity. Dipole source modeling results indicated that an anterior temporal lobe source accounted for the N400-like effect, which we attribute to the increased demands of integrating general knowledge about social situations (e.g. scripts) with personal- and context-specific information. An additional mediofrontal source contributed to the later ERP effect and presumably reflects high-level mindreading functions. Together, these findings indicate that readers rapidly infer and evaluate on-line a character's likely socio-emotional response based on the prototypical information provided by the text. PMID- 21609968 TI - Gender differences in reward-related decision processing under stress. AB - Recent research indicates gender differences in the impact of stress on decision behavior, but little is known about the brain mechanisms involved in these gender specific stress effects. The current study used functional magnetic resonance imaging (fMRI) to determine whether induced stress resulted in gender-specific patterns of brain activation during a decision task involving monetary reward. Specifically, we manipulated physiological stress levels using a cold pressor task, prior to a risky decision making task. Healthy men (n = 24, 12 stressed) and women (n = 23, 11 stressed) completed the decision task after either cold pressor stress or a control task during the period of cortisol response to the cold pressor. Gender differences in behavior were present in stressed participants but not controls, such that stress led to greater reward collection and faster decision speed in males but less reward collection and slower decision speed in females. A gender-by-stress interaction was observed for the dorsal striatum and anterior insula. With cold stress, activation in these regions was increased in males but decreased in females. The findings of this study indicate that the impact of stress on reward-related decision processing differs depending on gender. PMID- 21609969 TI - Individual differences in neural responses to social rejection: the joint effect of self-esteem and attentional control. AB - Individuals with low self-esteem have been found to react more negatively to signs of interpersonal rejection than those with high self-esteem. However, previous research has found that individual differences in attentional control can attenuate negative reactions to social rejection among vulnerable, low self esteem individuals. The current fMRI study sought to elucidate the neurobiological substrate of this buffering effect. We hypothesized and found that while looking at scenes of social rejection (vs negative scenes) low self esteem high attentional control individuals engaged the rostral anterior cingulate cortex (rACC), an area of the brain associated with emotional control, more than their low self-esteem low attentional control peers. Furthermore, we found that low self-esteem high attentional control individuals evaluated social rejection as less arousing and less rejecting in a separate behavioral task. Importantly, activation in the rACC fully mediated the relationship between the interaction of self-esteem and attentional control and emotional evaluations, suggesting that the rACC activation underlies the buffering effects of attentional control. Results are discussed in terms of individual differences in emotional vulnerability and protection and by highlighting the role of rACC in emotion regulation. PMID- 21609971 TI - Lessons from two decades of health reform in Central Asia. AB - Since becoming independent at the break-up of the Soviet Union in 1991, the countries of Central Asia have made profound changes to their health systems, affecting organization and governance, financing and delivery of care. The changes took place in a context of adversity, with major political transition, economic recession, and, in the case of Tajikistan, civil war, and with varying degrees of success. In this paper we review these experiences in this rarely studied part of the world to identify what has worked. This includes effective governance, the co-ordination of donor activities, linkage of health care restructuring to new economic instruments, and the importance of pilot projects as precursors to national implementation, as well as gathering support among both health workers and the public. PMID- 21609970 TI - Functional mechanisms involved in the internal inhibition of taboo words. AB - The present study used functional magnetic resonance imaging to investigate brain processes associated with the inhibition of socially undesirable speech. It is tested whether the inhibition of undesirable speech is solely related to brain areas associated with classical stop signal tasks or rather also involves brain areas involved in endogenous self-control. During the experiment, subjects had to do a SLIP task, which was designed to elicit taboo or neutral spoonerisms. Here we show that the internal inhibition of taboo words activates the right inferior frontal gyrus, an area that has previously been associated with externally triggered inhibition. This finding strongly suggests that external social rules become internalized and act as a stop-signal. PMID- 21609972 TI - Right heart complications of ventriculoatrial shunt. PMID- 21609973 TI - Safety of clopidogrel being continued until the time of coronary artery bypass grafting in patients with acute coronary syndrome: a meta-analysis of 34 studies. AB - AIMS Guidelines suggest that patients should discontinue clopidogrel for 5 days prior to coronary artery bypass grafting (CABG) where possible. Those with acute coronary syndrome (ACS) are at elevated risk of further myocardial infarction (MI) and death without clopidogrel. This meta-analysis aims to determine the risk of CABG in ACS patients while continuing clopidogrel. METHOD AND RESULTS Thirty four studies with 22 584 patients undergoing CABG were assessed. Patients with recent clopidogrel exposure (CL) were compared with those without recent clopidogrel (NC). Although mortality is increased in CL vs. NC [odds ratio (OR) 1.6, 95% CI 1.30-1.96, P < 0.00001], it is influenced by the ACS status and case urgency in these mainly non-randomized studies. In ACS patients, there is no significant difference in mortality (OR 1.44, 95% CI 0.97-2.1, P= 0.07) or in postoperative MI (OR 0.57, 95% CI 0.31-1.07, P = 0.08) and stroke rates (OR 1.23, 95% CI 0.66-2.29, P = 0.52). Combined major adverse cardiovascular event (stroke, MI, and death) was not different in the two groups (OR 1.10, 95% CI 0.87-1.41, P= 0.43). Reoperation rates are elevated on clopidogrel but have reduced over time, and were specifically not different in ACS patients (OR 1.5, 95% CI 0.88-2.54, P= 0.13). CONCLUSION Previous studies focused on surrogate endpoints and compared higher risk ACS patients with elective cases. However, many patients have safely undergone CABG on clopidogrel and surgical expertise is growing. Multinational trials are required to fully determine the balance of ischaemia and bleeding. While results are awaited we suggest ACS patients requiring urgent CABG proceed with surgery without delay for a clopidogrel-free period. PMID- 21609974 TI - Relationship between improvement in left ventricular dyssynchrony and contractile function and clinical outcome with cardiac resynchronization therapy: the MADIT CRT trial. AB - AIMS: To assess long-term effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) dyssynchrony and contractile function, by two-dimensional speckle-tracking echocardiography, compared with implantable cardioverter defibrillator (ICD) only in MADIT-CRT. METHODS AND RESULTS: We studied 761 patients in New York Heart Association I/II, ejection fraction <=30%, and QRS >=130 ms [n = 434, CRT-defibrillator (CRT-D), n = 327, ICD] with echocardiographic studies available at baseline and 12 months. Dyssynchrony was determined as the standard deviation of time to peak transverse strain between 12 segments of apical four- and two-chamber views, and contractile function as global longitudinal strain (GLS) by averaging longitudinal strain over these 12 segments. We compared changes in LV dyssynchrony and contractile function between treatment groups and assessed relationships between these changes over the first year and subsequent outcomes (median post 1-year follow-up = 14.9 months). Mean changes in LV dyssynchrony and contractile function measured by GLS in the overall population were, respectively, -29 +/- 83 ms and -1 +/- 2.9%. However, both LV dyssynchrony (CRT-D: -47 +/- 83 ms vs. ICD: -6 +/- 76 ms, P < 0.001) and contractile function (CRT-D: -1.4 +/- 3.1% vs. ICD: -0.4 +/- 2.5%, P < 0.001) improved to a greater extent in the CRT-D group compared with the ICD-only group. A greater improvement in dyssynchrony and contractile function at 1 year was associated with lower rates of the subsequent primary outcome of death or heart failure, adjusting for baseline dyssynchrony and contractile function, treatment arm, ischaemic status, and change in LV end-systolic volume. Each 20 ms decrease in LV dyssynchrony was associated with a 7% reduction in the primary outcome (P = 0.047); each 1% improvement in GLS over the 12-month period was associated with a 24% reduction in the primary outcome (P < 0.001). CONCLUSION: Cardiac resynchronization therapy resulted in a significant improvement in both LV dyssynchrony and contractile function measured by GLS compared with ICD only and these improvements were associated with better subsequent outcomes. PMID- 21609975 TI - Postsystolic shortening is a strong predictor of recovery of systolic function in patients with non-ST-elevation myocardial infarction. AB - AIMS: Differentiation between necrotic and viable myocardium is difficult in the setting of acute myocardial infarction (MI). Post-systolic shortening (PSS) has been proposed as a marker of recovery after revascularization, but has not previously been assessed in patients with NSTEMI prior to revascularization. In this study, we aimed to examine the relation between PSS and improvement of contractile function after successful revascularization. METHODS AND RESULTS: Thirty-five patients with non-segment elevation MI and regional systolic dysfunction were examined immediately prior to revascularization, and at follow up 9 +/- 3 months after successful revascularization. Regional systolic function was assessed by speckle tracking echocardiography as regional strain, expressed as mean peak negative longitudinal strain in segments supplied by the culprit artery. Recovery of systolic function was assessed as the difference between regional strain at follow-up and baseline (DeltaStrain). Post-systolic shortening was defined as shortening in diastole beyond minimum systolic length. By multivariate regression analysis, several other variables that may affect viability were also assessed. Post-systolic shortening was observed in 32 patients (91%), mean -1.9 +/- 1.4%. Mean DeltaStrain was -3.3 +/- 2.9%. After adjustment for baseline systolic function, PSS (beta = 0.77, P= 0.022), and angiographic severity were independent predictors of viability by multiple regression analysis. Interestingly, troponin T was not a significant predictor. CONCLUSIONS: Post-systolic shortening is associated with improved myocardial function after revascularization in patients with acute MI. It predicts long-term systolic function, and provides information on the potential benefit of the procedure. PMID- 21609976 TI - Adding a low-dose antihypertensive regimen would substantially improve the control of hypertension and reduce cardiovascular morbidity among uncomplicated hypertensive patients. AB - AIMS: To assess the utilization of antihypertensive drugs among uncomplicated hypertensive patients in Finland between 2000 and 2006 and to calculate the achievable reduction in cardiovascular morbidity, with intensified antihypertensive treatment. METHODS: From the databases of the Social Insurance Institution of Finland, 428,986 treated hypertensives without diabetes or cardiac disease (further named uncomplicated hypertensives) in 2000 and 591,206 in 2006, respectively, were identified. In addition, from the Health 2000 survey representing the whole Finnish adult population, 729 uncomplicated hypertensives were determined to assess their characteristics and control of hypertension. Applying Law's meta-analyses we calculated the reduction of blood pressure (BP) by intensifying the treatment with low-dose antihypertensive regimens for those with a BP >=140/90 mmHg. RESULTS: The nationwide data suggests a relative overuse of beta-blockers. Combination antihypertensive treatment increased relatively 8%, while at least three drug combinations increased from 19.8% to 21.6% between 2000 and 2006. However, calculated prevalence of controlled BP (<140/90 mmHg) increased only from 30.3% to 33.9%. Addition of one half standard dose or one to two half standard doses for the treatment of the patients with a BP >=140/90 mmHg would improve the control of hypertension from 33.9% to 47.8% and 67.3%, respectively. The intensified treatment would reduce strokes by 18% and 28%, and ischaemic heart disease events by 13% and 21%, respectively. CONCLUSIONS: Underutilization of preferred drugs and poor control of BP continues. Surprisingly small addition of the number of low-dose antihypertensive regimen is needed in order to substantially improve the control of hypertension and to decrease cardiovascular morbidity among uncomplicated hypertensive patients. PMID- 21609977 TI - Modelling the cumulative risk of a false-positive screening test. PMID- 21609980 TI - Gentamicin and acute kidney injury requiring renal replacement therapy in the context of a restrictive antibiotic policy. PMID- 21609979 TI - Antimicrobial activity of a chlorhexidine intravascular catheter site gel dressing. AB - OBJECTIVES: The antimicrobial efficacy of a chlorhexidine gluconate (CHG) intravascular catheter gel dressing was evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and an extended-spectrum beta-lactamase (ESBL) producing Escherichia coli. Chlorhexidine deposition on the skin surface and release from the gel were determined. METHODS: The antimicrobial efficacy was evaluated in in vitro studies following microbial inoculation of the dressing and application of the dressing on the inoculated surface of a silicone membrane and donor skin [with and without a catheter segment and/or 10% (v/v) serum] on diffusion cells. Antimicrobial activity was evaluated for up to 7 days. Chlorhexidine skin surface deposition and release were also determined. RESULTS: MRSA and E. coli were not detectable within 5 min following direct inoculation onto the CHG gel dressing. On the silicone membrane, 3 log and 6 log inocula of MRSA were eradicated within 5 min and 1 h, respectively. Time to kill was prolonged in the presence of serum and a catheter segment. Following inoculation of donor skin with 6 log cfu of MRSA, none was detected after 24 h. Chlorhexidine was released from the gel after a lag time of 30 min and increasing amounts were detected on the donor skin surface over the 48 h test period. The CHG gel dressing retained its antimicrobial activity on the artificial skin for 7 days. CONCLUSIONS: The CHG intravascular catheter site gel dressing had detectable antimicrobial activity for up to 7 days, which should suppress bacterial growth on the skin at the catheter insertion site, thereby reducing the risk of infection. PMID- 21609981 TI - Staphylococcal nasal carriage in calves: multiresistant Staphylococcus sciuri and immune evasion cluster (IEC) genes in methicillin-resistant Staphylococcus aureus ST398. PMID- 21609982 TI - Emergence of beta-lactamases OXA-10, VEB-1 and CMY in Providencia spp. from Nigeria. PMID- 21609984 TI - The characteristics of people with mental illness who are under treatment in traditional healer centres in Sudan. AB - AIMS: To determine the general characteristics of people with mental disorders in traditional healers centres in Sudan in terms of sociodemographic profile, common clinical presentations and diagnostic features, and to look at the treatment methods and intervention procedures used in these centres for treating people with mental illness. METHODS: This is a descriptive cross-sectional study using both quantitative and qualitative research methods. All inpatients with mental illness (405) from 10 selected traditional healers centres in Sudan who gave consent were interviewed, using a specially designed questionnaire and the Mini International Neuropsychiatric Interview (MINI). RESULTS: Most of the visitors to the centres were from central Sudan with a mean age of 31 years, illiterate or with only a primary basic education, male and jobless. The average mean duration of stay in the traditional healer centre was five months and the mean duration of untreated illness before coming to the centre was 13 months. Only 17% reported a history of alcohol abuse and only 11% of drug abuse. The most common prevalent diagnosis was psychotic disorder. CONCLUSION: This study improves the understanding about what types of people with mental illness are treated at these traditional healer centres and gives recommendations that can help in improving the quality of services in these centres. It can probably be used in building bridges of collaboration between these centres and the available mental health and psychiatric services in Sudan, especially at primary healthcare level. PMID- 21609983 TI - Study of parasite kinetics with antileishmanial drugs using real-time quantitative PCR in Indian visceral leishmaniasis. AB - OBJECTIVES: This study describes parasite kinetics in the blood of visceral leishmaniasis patients treated with liposomal amphotericin B (L-AmB) or a preformed fat emulsion of amphotericin B (ApL) using real-time quantitative PCR (qPCR). METHODS: Forty-six patients were treated with a single dose (15 mg/kg of body weight) of either L-AmB (n = 13) or ApL (n = 33). qPCR was used to estimate parasite kinetics by detection of Leishmania donovani DNA using kinetoplast DNA specific primers in peripheral blood samples using an absolute quantification method. RESULTS: The mean parasite load decreased from baseline (day 0) values of 894.07 and 980.48 to 71.72 and 211.52 parasite genomes/mL at day 7 in L-AmB and ApL groups, respectively, and at day 30 these further declined to 8.30 and 133.98 parasite genomes/mL, respectively. At day 30 post-treatment evaluation, the decline in parasite load was significantly greater (P = 0.024) with L-AmB compared with ApL. Four of 33 patients in the ApL group failed treatment (1 primary failure and 3 relapses) with the presence of parasites, whereas all patients in the L-AmB group were cured at 6 month follow-up. CONCLUSIONS: qPCR can be a tool to measure parasite dynamics accurately and provide a marker to measure the efficacy of various drugs. It can be used as a test of cure, allowing us to do away with invasive and risky methods such as splenic or bone marrow aspiration. PMID- 21609985 TI - More placebo use promoted in Germany. PMID- 21609986 TI - Ontario introduces "hospital secrecy clause". PMID- 21609987 TI - Cullen and Grey Turner signs in idiopathic perirenal hemorrhage. PMID- 21609988 TI - Demystifying radiation disaster preparedness. PMID- 21609989 TI - Dialysis and transplantation among Aboriginal children with kidney failure. AB - BACKGROUND: Relatively little is known about the management and outcomes of Aboriginal children with renal failure in Canada. We evaluated differences in dialysis modality, time spent on dialysis, rates of kidney transplantation, and patient and allograft survival between Aboriginal children and non-Aboriginal children. METHODS: For this population-based cohort study, we used data from a national pediatric end-stage renal disease database. Patients less than 18 years old who started renal replacement treatment (dialysis or kidney transplantation) in nine Canadian provinces (Quebec data were not available) and all three territories between 1992 and 2007 were followed until death, loss to follow-up or end of the study period. We compared initial modality of dialysis and time to first kidney transplant between Aboriginal children, white children and children of other ethnicity. We examined the association between ethnicity and likelihood of kidney transplantation using adjusted Cox proportional hazard models for Aboriginal and white children (data for the children of other ethnicity did not meet the assumptions of proportional hazards). RESULTS: Among 843 pediatric patients included in the study, 104 (12.3%) were Aboriginal, 521 (61.8%) were white, and 218 (25.9%) were from other ethnic minorities. Hemodialysis was the initial modality of dialysis for 48.0% of the Aboriginal patients, 42.7% of the white patients and 62.6% of those of other ethnicity (p < 0.001). The time from start of dialysis to first kidney transplant was longer among the Aboriginal children (median 1.75 years, interquartile range 0.69-2.81) than among the children in the other two groups (p < 0.001). After adjustment for confounders, Aboriginal children were less likely than white children to receive a transplant from a living donor (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.21 0.61) or a transplant from any donor (HR 0.54, 95% CI 0.40-0.74) during the study period. INTERPRETATION: The time from start of dialysis to first kidney transplant was longer among Aboriginal children than among white children. Further evaluation is needed to determine barriers to transplantation among Aboriginal children. PMID- 21609990 TI - Left atrial size and risk for all-cause mortality and ischemic stroke. AB - BACKGROUND: Limited data are available on the relation between left atrial size and outcome among patients referred for clinically indicated echocardiograms. Our aim was to assess the association of left atrial size with all-cause mortality and ischemic stroke in a large cohort of patients referred for echocardiography. METHODS: Left atrial diameter was measured in 52 639 patients aged 18 years or older (mean age 61.8 [standard deviation (SD) 16.3] years; 52.9% men) who underwent a first transthoracic echocardiogram for clinical reasons at our institution between April 1990 and March 2008. The outcomes were all-cause mortality and nonfatal ischemic stroke. RESULTS: Based on the criteria of the American Society of Echocardiography, 50.4% of the patients had no left atrial enlargement, whereas 24.5% had mild, 13.3% had moderate and 11.7% had severe left atrial enlargement. Over a mean follow-up period of 5.5 (SD 4.1) years, 12 527 patients died, and 2314 patients had a nonfatal ischemic stroke. Cumulative 10 year survival was 73.7% among patients with normal left atrial size, 62.5% among those with mild enlargement, 54.8% among those with moderate enlargement and 45% among those with severe enlargement (p < 0.001). After adjustment in multivariable Cox proportional hazard analysis, left atrial diameter remained a predictor of all-cause mortality in both sexes (hazard ratio [HR] per 1-cm increment in left atrial size 1.17, 95% confidence interval [CI] 1.12-1.22, p < 0.001 in women, and HR 1.09, 95% CI 1.05-1.13, p < 0.001 in men) and of ischemic stroke in women (HR 1.25, 95% CI 1.14-1.37, p < 0.001). INTERPRETATION: Left atrial diameter has a graded and independent association with all-cause mortality in both sexes and with ischemic stroke in women. PMID- 21609991 TI - SaskPharm: a proposal for provincial drug production. PMID- 21609992 TI - Working while sleep-deprived: not just a problem for residents. PMID- 21609993 TI - Combating community resistance to care facilities. PMID- 21609994 TI - Left atrial enlargement: a cause of stroke? PMID- 21609995 TI - Tinnitus: identifying the ominous causes. PMID- 21609997 TI - The potential for misusing "genetic predisposition" in Canadian courts and tribunals. PMID- 21609998 TI - Verdict still out on family health teams. PMID- 21609999 TI - Limitations in physical functioning among older people as a predictor of subsequent disability in instrumental activities of daily living. AB - BACKGROUND: physical functioning describes the underlying abilities that make activities necessary for independent living in the community possible. OBJECTIVE: to test self-reported and objective measures of physical functioning in predicting subsequent disability in cooking, shopping and housework. DESIGN: we used data from the first and second waves of the Survey of Health, Ageing and Retirement in Europe. The respondents were asked about physical functioning (climbing, pulling/pushing, stooping/crouching/kneeling, lifting/carrying and reaching/extending were comparable) and they had their grip strength and walking speed measured. PARTICIPANTS: men and women aged 65 years or over who reported no disability in cooking, shopping and housework at baseline were included in the analysis. There were 6,841 individuals for whom data on disability status at follow-up were available. METHODS: Poisson regression was used to calculate relative risks for the associations between self-reported and objective measures of physical functioning with disability at 2 years, adjusting for age, gender, educational level, cognitive function and chronic conditions. RESULTS: those with limitations in physical functioning at baseline more frequently reported subsequent disability. Walking ability was most strongly associated with disability; climbing, pulling/pushing, lifting/carrying and reaching/extending were comparable (picking was non-significant). Similar results were obtained with grip strength and walking speed. CONCLUSIONS: both self-reports and objective measures capture information on the functional ability of older people that can be used to predict disability onset. Objective measures offer little to the development of intervention strategies, whereas self-reports provide some insight into the demands of the environment, being more amenable to interventions. PMID- 21610000 TI - Outbreak of pandemic influenza (H1N1) 2009 in pigs in Korea. PMID- 21610001 TI - Mycobacterium avium subspecies paratuberculosis in bioaerosols after depopulation and cleaning of two cattle barns. AB - Settled dust samples were collected on a commercial dairy farm in the Netherlands with a high prevalence of Mycobacterium avium subspecies paratuberculosis (MAP) (barn A) and on a Dutch experimental cattle farm (barn B) stocked with cattle confirmed to be MAP shedders. Barns were sampled while animals were present, after both barns were destocked and cleaned by cold high-pressure cleaning, and after being kept empty for two weeks (barn A) or after additional disinfection (barn B). MAP DNA was detected by IS900 real-time PCR and viable MAP were detected by liquid culture. MAP DNA was detected in 78 per cent of samples from barn A and 86 per cent of samples from barn B collected while animals were still present. Viable MAP was detected in six of nine samples from barn A and in three of seven samples from barn B. After cold high-pressure cleaning, viable MAP could be detected in only two samples from each barn. After leaving barn A empty for two weeks, and following additional disinfection of barn B, no viable MAP could be detected in any settled dust sample. PMID- 21610002 TI - Mycoplasma ovipneumoniae associated with severe respiratory disease in goats. PMID- 21610003 TI - Estimates of the seroprevalence of production-limiting diseases in wild pigs. PMID- 21610004 TI - The superiority of the time-to-event continual reassessment method to the rolling six design in pediatric oncology Phase I trials. AB - BACKGROUND: The rolling six design (RSD) is currently being used by the Children's Oncology Group (COG) as their standard design for Phase I trials. Because the COG has large multi-center trials with fast accrual, the motivation for adopting the RSD is to hasten accrual and shorten the duration of their trials. However, trial suspension due to completion of follow-up still cannot be entirely avoided by the RSD. Therefore, a design that allows continuous enrollment of patients throughout the entire trial is needed. PURPOSE: To demonstrate the superior performance of the Time-to-Event Continual Reassessment Method (TITE-CRM) with continuous patient recruitment relative to the RSD, in terms of identifying the maximum tolerated dose (MTD) and reducing exposure of patients to toxic doses. METHODS: Using scenarios that were based on an actual pediatric Phase I trial at the University of Michigan, Monte Carlo simulations were used to investigate the operational characteristics of RSD and TITE-CRM. RESULTS: The TITE-CRM treated all available patients, identified the MTD more accurately than the RSD and did not increase the probability of exposing patients to toxic doses. LIMITATIONS: Both the TITE-CRM and RSD assume that the probability of dose limiting toxicity increases with higher dose level. CONCLUSIONS: The TITE-CRM, which allows for continual enrollment of patients, provides a safe design for pediatric oncology Phase I trials with better accuracy than the RSD. PMID- 21610005 TI - Confounding due to changing background risk in adaptively randomized trials. AB - BACKGROUND: While adaptive trials tend to improve efficiency, they are also subject to some unique biases. PURPOSE: We address a bias that arises from adaptive randomization in the setting of a time trend in disease incidence. METHODS: We use a potential-outcome model and directed acyclic graphs to illustrate the bias that arises from a changing subject allocation ratio with a concurrent change in background risk. RESULTS: In a trial that uses adaptive randomization, time trends in risk can bias the crude effect estimate obtained by naively combining the data from the different stages of the trial. We illustrate how the bias arises from an interplay of departures from exchangeability among groups and the changing randomization proportions. LIMITATIONS: We focus on risk ratio and risk-difference analysis. CONCLUSIONS: Analysis of trials using adaptive randomization should involve attention to or adjustment for possible trends in background risk. Numerous modeling strategies are available for that purpose, including stratification, trend modeling, inverse-probability-of treatment weighting, and hierarchical regression. PMID- 21610006 TI - Association studies in thyroid cancer susceptibility: are we on the right track? AB - It is widely accepted that thyroid cancer is strongly determined by the individual genetic background. In this regard, it is expected that sporadic thyroid cancer is the result of multiple low- to moderate-penetrance genes interacting with each other and with the environment, thus modulating individual susceptibility. In the last years, an important number of association studies on thyroid cancer have been published, trying to determine this genetic contribution. The aim of this review is to provide a comprehensive and critical evaluation of the associations reported so far in thyroid cancer susceptibility in case-control studies performed in both non-medullary (papillary and follicular) and medullary thyroid cancers, including their potential strengths and pitfalls. We summarize the genetic variants reported to date, and stress the importance of validating the results in independent series and assessing the functional role of the associated loci. PMID- 21610007 TI - Dietary restriction of mice on a high-fat diet induces substrate efficiency and improves metabolic health. AB - High energy intake and, specifically, high dietary fat intake challenge the mammalian metabolism and correlate with many metabolic disorders such as obesity and diabetes. However, dietary restriction (DR) is known to prevent the development of metabolic disorders. The current western diets are highly enriched in fat, and it is as yet unclear whether DR on a certain high-fat (HF) diet elicits similar beneficial effects on health. In this research, we report that HF DR improves metabolic health of mice compared with mice receiving the same diet on an ad libitum basis (HF-AL). Already after five weeks of restriction, the serum levels of cholesterol and leptin were significantly decreased in HF-DR mice, whereas their glucose sensitivity and serum adiponectin levels were increased. The body weight and measured serum parameters remained stable in the following 7 weeks of restriction, implying metabolic adaptation. To understand the molecular events associated with this adaptation, we analyzed gene expression in white adipose tissue (WAT) with whole genome microarrays. HF-DR strongly influenced gene expression in WAT; in total, 8643 genes were differentially expressed between both groups of mice, with a major role for genes involved in lipid metabolism and mitochondrial functioning. This was confirmed by quantitative real-time reverse transcription-PCR and substantiated by increase in mitochondrial density in WAT of HF-DR mice. These results provide new insights in the metabolic flexibility of dietary restricted animals and suggest the development of substrate efficiency. PMID- 21610008 TI - Substance use by adolescents of the USA National Longitudinal Lesbian Family Study. AB - Although studies show that adolescents with same-sex parents experience homophobic discrimination, little is known about associations between stigmatization and substance use in this population. The 17-year-old offspring of lesbian parents from the largest, longest-running, longitudinal study of same-sex parented families were surveyed about substance use, experiences of homophobic stigmatization, and overall life satisfaction. Compared to matched adolescents from a national probability sample, adolescents with same-sex parents were more likely to report occasional substance use but not more likely to report heavy use. No associations were found between substance use and homophobic stigmatization or life satisfaction. PMID- 21610009 TI - Self-determination and exercise stages of change: results from the Diabetes Aerobic and Resistance Exercise trial. AB - Little longitudinal research exists on the relationship between exercise self determination and stage of change. This study investigated how self-determined motivation changes in patients with type 2 diabetes (N = 175) as they moved through the stages of change over a six-month exercise trial. Hierarchical linear modelling revealed that patients who progressed through the stages of exercise change had an overall increase in self-determined motivation, while non progressors experienced a reduction in self-determined motivation from three to six months. These results indicate that individuals engaging in regular exercise at six months maintain initial increases in self-determined motivation. Findings are discussed in light of self-determination theory. PMID- 21610010 TI - 'Cos girls aren't supposed to eat like pigs are they?' Young women negotiating gendered discursive constructions of food and eating. AB - While psycho-medical understandings of 'eating disorders' draw distinctions between those who 'have'/'do not have' eating disorders, feminist poststructuralist researchers argue that these detract from political/socio cultural conditions that invoke problematic eating and embodied subjectivities. Using poststructuralist discourse analysis, we examine young women's talk around food and eating, in particular, the negotiation of tensions arising from derogating aspects of hetero-normative femininities, while accounting for own 'feminine' practices (e.g. 'dieting') and subjectivities. Analysis suggested that eating/dieting was accounted for by drawing upon neo-liberalist discourses around individual choice; however, these may obscure gendered, classed and racialized power relations operating in local and wider contexts. PMID- 21610011 TI - Conditional indirect relations of cardiac patients' subjective health to optimism through illness representations: a self-regulation circuit. AB - The aim of this study was to examine whether chronic patients' subjective health can prospectively predict optimism through illness representations, as well as whether this relation depends on health levels. A sample of 97 cardiac patients participated in the two phases of the study. Subjective health predicted optimism with several illness representations serving as mediators. These relations were, however, conditional on the values of subjective health. Such findings suggest that the interplay between patients' subjective health, illness representations, and optimism seems to function rather as a complex circuit system, than as a process of simple cyclical feedbacks. PMID- 21610012 TI - Analysis of social inequalities in health through an integrated measure of perceived and experienced health in Spanish and Portuguese adolescents. AB - This article compares the self reported health of a sample of 9854 Spanish and Portuguese adolescents aged 11-15 years using an integrated measure of health, which takes account of positive and negative factors that affect overall feelings of health and wellbeing. This improved measure supports the emergence of health agendas that aim to make wellbeing improvements in populations through a combination of both the promotion of positive protective factors and the need to deal with those risk factors that inhibit individuals, communities and populations to attain good health. PMID- 21610013 TI - B-type natriuretic peptide predicts long-term survival after major non-cardiac surgery. AB - BACKGROUND: The prediction of long-term survival after surgery is complex. Natriuretic peptides can predict short-term postoperative cardiac morbidity and mortality. This study aims to determine the long-term prognostic significance of preoperative B-type natriuretic peptide (BNP) concentration after major non cardiac surgery. METHODS: We conducted a prospective single-centre observational cohort study in a West of Scotland teaching hospital. Three hundred and forty five patients undergoing major non-cardiac surgery were included. The primary endpoint was long-term all-cause mortality. RESULTS: Overall survival was 67.8% (234/345), with 27 postoperative deaths (within 42 days) and 84 deaths at subsequent follow-up (median follow-up 953 days). A BNP concentration of >87.5 pg ml(-1) best predicted mortality, and the mean survival of patients with an elevated BNP (>87.5 pg ml(-1)) was 731.9 (95% CI 613.6-850.2) days compared with 1284.6 days [(95% CI 1219.3-1350.0), P<0.001] in patients with a BNP<87.5 pg ml( 1). BNP was an independent predictor of survival. CONCLUSIONS: BNP is an independent predictor of long-term survival after major non-cardiac surgery. A simple preoperative blood test can provide predictive information on future risk of death, and potentially has a role in preoperative risk assessment. PMID- 21610014 TI - Persistent postoperative pain: where are we now? AB - There has been considerable interest and controversy around persistent postoperative pain for several years. Most of the available data arise from studies with methodological problems (especially its definition in terms of duration, severity, and effect on quality of life and function); however, more recent investigations have begun to address these issues. Although the quoted incidence varies considerably, analysis of the most conservative data shows that there is no doubt that persistent postoperative pain is a significant clinical problem and a burden to those who suffer from it. There is a wealth of literature describing factors associated with increased likelihood of persistent postoperative pain. Although it is difficult to be precise, it is clear that psychosocial factors probably play a role in some situations and that significant preoperative pain, severe immediate postoperative pain, and nerve damage are often good predictors. There are some data indicating that the incidence and severity of persistent postoperative pain can be reduced by special perioperative interventions; however, as yet, the evidence is not compelling and consistent. A reliable prevention strategy is not yet emerging from the published literature and considerably more work is required to deliver this. PMID- 21610015 TI - Diabetes mellitus: new drugs for a new epidemic. AB - The prevalence of diabetes mellitus (DM) is increasing rapidly in the 21st century as a result of obesity, an ageing population, lack of exercise, and increased migration of susceptible patients. This costly and chronic disease has been likened recently to the 'Black Death' of the 14th century. Type 2 DM is the more common form and the primary aim of management is to delay the micro- and macrovascular complications by achieving good glycaemic control. This involves changes in lifestyle, such as weight loss and exercise, and drug therapy. Increased knowledge of the pathophysiology of diabetes has contributed to the development of novel treatments: glucagon-like peptide-1 (GLP-1) mimetics, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), and insulin analogues. GLP-1 agonists mimic the effect of this incretin, whereas DPP-4 inhibitors prevent the inactivation of the endogenously released hormone. Both agents offer an effective alternative to the currently available hypoglycaemic drugs but further evaluation is needed to confirm their safety and clinical role. The past decade has seen the rise and fall in the use of the TZDs (glitazones), such that the only glitazone recommended is pioglitazone as a third-line treatment. The association between the use of rosiglitazone and adverse cardiac outcomes is still disputed by some authorities. The advent of new insulin analogues, fast-acting, and basal release formulations, has enabled the adoption of a basal-bolus regimen for the management of blood glucose. This regimen aims to provide a continuous, low basal insulin release between meals with bolus fast acting insulin to limit hyperglycaemia after meals. Insulin therapy is increasingly used in type 2 DM to enhance glycaemic control. Recently, it has been suggested that the use of the basal-release insulins, particularly insulin glargine may be associated with an increased risk of cancer. Although attention is focused increasingly on newer agents in the treatment of diabetes, metformin and the sulphonylureas are still used in many patients. Metformin, in particular, remains of great value and may have novel anti-cancer properties. PMID- 21610016 TI - Preoperative cardiac management of the patient for non-cardiac surgery: an individualized and evidence-based approach. AB - Preoperative cardiovascular management is an essential component of overall perioperative cardiovascular care. It involves preoperative detection and management of cardiovascular disease and prediction of both short- and long-term cardiovascular risk. It thereby not only affects anaesthetic perioperative management (e.g. choice of anaesthetic drug and method, type of monitoring, and postoperative care) but also surgical decision-making (e.g. postponement, modification, and cancellation of surgical procedure). The ultimate goal of preoperative cardiovascular management is to improve overall patient outcome. This requires individualized management. Although preoperative cardiac management has improved during the past decades, we are not yet in the situation where we can accurately predict individual perioperative risk. The individual stress response and the individual interactions between pharmacological intervention and intra- and postoperative risk factors are highly variable. More importantly, preoperative cardiac management is only one aspect of overall perioperative care. There are numerous intra- and postoperative factors which have been shown to affect overall outcome. However, not all of them can reliably be predicted or modified in a way to positively affect overall outcome. Recognition of such factors and aggressive attempts at appropriate intervention may reduce overall risk more than preoperative management in isolation. Without defining and subsequently targeting intra- and postoperative risk factors, the benefit of preoperative cardiac management will be limited. PMID- 21610017 TI - A conservative pattern of water use, rather than deep or profuse rooting, is critical for the terminal drought tolerance of chickpea. AB - Chickpea is mostly grown on stored soil moisture, and deep/profuse rooting has been hypothesized for almost three decades to be critical for improving chickpea tolerance to terminal drought. However, temporal patterns of water use that leave water available for reproduction and grain filling could be equally critical. Therefore, variation in water use pattern and root depth/density were measured, and their relationships to yield tested under fully irrigated and terminal drought stress, using lysimeters that provided soil volumes equivalent to field conditions. Twenty chickpea genotypes having similar plant phenology but contrasting for a field-derived terminal drought-tolerance index based on yield were used. The pattern of water extraction clearly discriminated tolerant and sensitive genotypes. Tolerant genotypes had a lower water uptake and a lower index of stomatal conductance at the vegetative stage than sensitive ones, while tolerant genotypes extracted more water than sensitive genotypes after flowering. The magnitude of the variation in root growth components (depth, length density, RLD, dry weight, RDW) did not distinguish tolerant from sensitive genotypes. The seed yield was not significantly correlated with the root length density (RLD) in any soil layers, whereas seed yield was both negatively related to water uptake between 23-38 DAS, and positively related to water uptake between 48-61 DAS. Under these conditions of terminal drought, the most critical component of tolerance in chickpea was the conservative use of water early in the cropping cycle, explained partly by a lower canopy conductance, which resulted in more water available in the soil profile during reproduction leading to higher reproductive success. PMID- 21610018 TI - HYL1 regulates the balance between adaxial and abaxial identity for leaf flattening via miRNA-mediated pathways. AB - HYPONASTIC LEAVES1 (HYL1) is an important regulator of microRNA (miRNA) biogenesis. Incurvature of rosette leaves in loss-of-function mutants of HYL1 implicates the regulation of leaf flatness by HYL1 via miRNA pathways. Recent studies have identified jba-1D, jaw-1D, and oe-160c, the dominant mutants of MIR166g, MIR319a, and MIR160c genes, respectively, which display three types of leaf curvature. However, it remains unclear whether or how HYL1 controls leaf flatness through the pathways mediated by these miRNAs. To define which miRNAs and target genes are relevant to the hyl1 phenotype in terms of leaf incurvature, the effects of three mutated MIRNA genes and their targets on the direction and extent of leaf curvature in hyl1 mutants were examined. The genetic analysis shows that the hyl1 phenotype is strongly rescued by jba-1D, but not by jaw-1D or oe-160c, whereas the mutant phenotypes of jba-1D, jaw-1D, or oe-160c leaves are compromised by the hyl1 allele. Expression analysis indicates that reduced accumulation of miR166, rather than of miR319a or miR160, causes incurvature of hyl1 leaves, and that miR319a-targeted TCP3 positively regulates the adaxial identity gene PHABULOSA while miR160-targeted ARF16 negatively regulates the abaxial identity gene FILAMENTOUS FLOWER. In these cases, the direction and extent of leaf incurvature are associated with the expression ratio of adaxial to abaxial genes (adaxial to abaxial ratio). HYL1 regulates the balance between adaxial and abaxial identity and modulates leaf flatness by preventing leaf incurvature, wavy margins, and downward curvature. It is concluded that HYL1 monitors the roles of miR165/166, miR319a, and miR160 in leaf flattening through the relative activities of adaxial and abaxial identity genes, thus playing an essential role in leaf development. PMID- 21610020 TI - Comparative cost-efficiency across the European G5 countries of various regimens of filgrastim, biosimilar filgrastim, and pegfilgrastim to reduce the incidence of chemotherapy-induced febrile neutropenia. AB - OBJECTIVES: This cost-efficiency analysis of the granulocyte colony-stimulating factors (G-CSF) filgrastim (originator Neupogen(r) and biosimilar Zarzio(r)) and pegfilgrastim (Neulasta(r)) examined against a time horizon of 1-14 days of treatment and across the European Union G5 countries (a) when, cost-wise, using Neulasta(r) 6 mg versus Neupogen(r) or Zarzio(r) 300 ug may be cost-saving in reducing the incidence of chemotherapy-induced febrile neutropenia; and (b) if cost-wise, treatment with Zarzio(r) 300 ug yields a savings advantage over Neupogen(r) 300 ug. METHODS: Cost-efficiency analysis of the direct costs a buyer or payer would incur when purchasing or covering any of these agents for managing one patient during one cycle of chemotherapy under regimens of 1-14 days of standard filgrastim using the population-weighted average unit dose cost of each agent per their public pack cost across the European G5 countries. RESULTS: The cost of Neupogen(r) treatment ranged from ?128.16 (1 day) to ?1794.30 (14 days), compared to ?95.46 and ?1336.46 for Zarzio(r), thus yielding potential cost savings from ?32.70 to ?457.84 for the latter. Neulasta(r) turns cost-saving at day 12 of Neupogen(r) treatment. At no point over a 14-day treatment period did Neulasta(r) yield a savings advantage over Zarzio(r). CONCLUSION: Prophylaxis or treatment of febrile neutropenia with Zarzio(r) is cost-efficient under all possible treatment scenarios relative to Neupogen(r) and to Neulasta(r). In the absence of convincing evidence that pegfilgrastim is pharmacotherapeutically superior to standard filgrastim, there is no cost-efficiency rationale to treat with Neulasta(r) over Zarzio(r), though there may be a small window of approximately 3 days where Neulasta(r) is cost-efficient over Neupogen(r). Regardless, our analysis shows Zarzio(r) to be the most cost-efficient approach to reducing the incidence of febrile neutropenia in chemotherapy-treated patients. PMID- 21610019 TI - Two mitogen-activated protein kinase kinases, MKK1 and MEK2, are involved in wounding- and specialist lepidopteran herbivore Manduca sexta-induced responses in Nicotiana attenuata. AB - In a wild tobacco plant, Nicotiana attenuata, two mitogen-activated protein kinases (MAPKs), salicylic acid-induced protein kinase (SIPK) and wound-induced protein kinase (WIPK), play central roles in modulating herbivory-induced phytohormone and anti-herbivore secondary metabolites. However, the identities of their upstream MAPK kinases (MAPKKs) were elusive. Ectopic overexpression studies in N. benthamiana and N. tabacum suggested that two MAPKKs, MKK1 and MEK2, may activate SIPK and WIPK. The homologues of MKK1 and MEK2 were cloned in N. attenuata (NaMKK1 and NaMEK2) and a virus-induced gene silencing approach was used to knock-down the transcript levels of these MAPKK genes. Plants silenced in NaMKK1 and NaMEK2 were treated with wounding or simulated herbivory by applying the oral secretions of the specialist herbivore Manduca sexta to wounds. MAPK activity assay indicated that after wounding or simulated herbivory NaMKK1 is not required for the phosphorylation of NaSIPK and NaWIPK; in contrast, NaMEK2 and other unknown MAPKKs are important for simulated herbivory-elicited activation of NaSIPK and NaWIPK, and after wounding NaMEK2 probably does not activate NaWIPK but plays a minor role in activating NaSIPK. Consistently, NaMEK2 and certain other MAPKKs, but not NaMKK1, are needed for wounding- and simulated herbivory elicited accumulation of jasmonic acid (JA), JA-isoleucine, and ethylene. Furthermore, both NaMEK2 and NaMKK1 regulate the levels of trypsin proteinase inhibitors. The findings underscore the complexity of MAPK signalling pathways and highlight the importance of MAPKKs in regulating wounding- and herbivory induced responses. PMID- 21610021 TI - An interview with Elisabeth Knust: President of the German Society for Developmental Biology. Interview by Eva Amsen. PMID- 21610022 TI - An eye on the head: the development and evolution of craniofacial muscles. AB - Skeletal muscles exert diverse functions, enabling both crushing with great force and movement with exquisite precision. A remarkably distinct repertoire of genes and ontological features characterise this tissue, and recent evidence has shown that skeletal muscles of the head, the craniofacial muscles, are evolutionarily, morphologically and molecularly distinct from those of the trunk. Here, we review the molecular basis of craniofacial muscle development and discuss how this process is different to trunk and limb muscle development. Through evolutionary comparisons of primitive chordates (such as amphioxus) and jawless vertebrates (such as lampreys) with jawed vertebrates, we also provide some clues as to how this dichotomy arose. PMID- 21610023 TI - ERK signaling controls blastema cell differentiation during planarian regeneration. AB - The robust regenerative ability of planarians depends on a population of somatic stem cells called neoblasts, which are the only mitotic cells in adults and are responsible for blastema formation after amputation. The molecular mechanism underlying neoblast differentiation associated with blastema formation remains unknown. Here, using the planarian Dugesia japonica we found that DjmkpA, a planarian mitogen-activated protein kinase (MAPK) phosphatase-related gene, was specifically expressed in blastema cells in response to increased extracellular signal-related kinase (ERK) activity. Pharmacological and genetic [RNA interference (RNAi)] approaches provided evidence that ERK activity was required for blastema cells to exit the proliferative state and undergo differentiation. By contrast, DjmkpA RNAi induced an increased level of ERK activity and rescued the differentiation defect of blastema cells caused by pharmacological reduction of ERK activity. These observations suggest that ERK signaling plays an instructive role in the cell fate decisions of blastema cells regarding whether to differentiate or not, by inducing DjmkpA as a negative regulator of ERK signaling during planarian regeneration. PMID- 21610024 TI - Induced stem cell neoplasia in a cnidarian by ectopic expression of a POU domain transcription factor. AB - The evolutionary origin of stem cell pluripotency is an unresolved question. In mammals, pluripotency is limited to early embryos and is induced and maintained by a small number of key transcription factors, of which the POU domain protein Oct4 is considered central. Clonal invertebrates, by contrast, possess pluripotent stem cells throughout their life, but the molecular mechanisms that control their pluripotency are poorly defined. To address this problem, we analyzed the expression pattern and function of Polynem (Pln), a POU domain gene from the marine cnidarian Hydractinia echinata. We show that Pln is expressed in the embryo and adult stem cells of the animal and that ectopic expression in epithelial cells induces stem cell neoplasms and loss of epithelial tissue. Neoplasm cells downregulated the transgene but expressed the endogenous Pln gene and also Nanos, Vasa, Piwi and Myc, which are all known cnidarian stem cell markers. Retinoic acid treatment caused downregulation of Pln and the differentiation of neoplasm cells to neurosensory and epithelial cells. Pln downregulation by RNAi led to differentiation. Collectively, our results suggest an ancient role of POU proteins as key regulators of animal stem cells. PMID- 21610025 TI - Sequential changes at differentiation gene promoters as they become active in a stem cell lineage. AB - Transcriptional silencing of terminal differentiation genes by the Polycomb group (PcG) machinery is emerging as a key feature of precursor cells in stem cell lineages. How, then, is this epigenetic silencing reversed for proper cellular differentiation? Here, we investigate how the developmental program reverses local PcG action to allow expression of terminal differentiation genes in the Drosophila male germline stem cell (GSC) lineage. We find that the silenced state, set up in precursor cells, is relieved through developmentally regulated sequential events at promoters once cells commit to spermatocyte differentiation. The programmed events include global downregulation of Polycomb repressive complex 2 (PRC2) components, recruitment of hypophosphorylated RNA polymerase II (Pol II) to promoters, as well as the expression and action of testis-specific homologs of TATA-binding protein-associated factors (tTAFs). In addition, action of the testis-specific meiotic arrest complex (tMAC), a tissue-specific version of the MIP/dREAM complex, is required both for recruitment of tTAFs to target differentiation genes and for proper cell type-specific localization of PRC1 components and tTAFs within the spermatocyte nucleolus. Together, the action of the tMAC and tTAF cell type-specific chromatin and transcription machinery leads to loss of Polycomb and release of stalled Pol II from the terminal differentiation gene promoters, allowing robust transcription. PMID- 21610026 TI - LEUNIG and SEUSS co-repressors regulate miR172 expression in Arabidopsis flowers. AB - Central to the ABCE model of flower development is the antagonistic interaction between class A and class C genes. The molecular mechanisms underlying the A-C antagonism are not completely understood. In Arabidopsis thaliana, miR172 is expressed in the inner floral whorls where it downregulates the class A gene APETALA 2 (AP2). However, what controls this predominantly inner whorl-specific expression of miR172 is not known. We show that the LEUNIG (LUG) and SEUSS (SEU) co-repressors repress miR172 expression in the outer whorls of A. thaliana flowers. The recruitment of LUG/SEU to the miR172 promoters is dependent on AP2, suggesting that AP2 represses the expression of its cognate microRNA. Our study provides new insights into the molecular mechanisms underlying the A-C antagonism and shed light on the transcriptional regulation of miR172 during flower development. PMID- 21610027 TI - Topoisomerase IIbeta is required for lamina-specific targeting of retinal ganglion cell axons and dendrites. AB - The specific partnering of synaptically connected neurons is central to nervous system function. Proper wiring requires the interchange of signals between a postmitotic neuron and its environment, a distinct pattern of transcription in the nucleus, and deployment of guidance and adhesion cues to the cell surface. To identify genes involved in neurite targeting by retinal ganglion cells (GCs), their presynaptic partners in the retina, and their postsynaptic targets in the optic tectum, we undertook a forward genetic screen for mutations disrupting visual responses in zebrafish. This rapid primary screen was subsequently refined by immunohistochemical labeling of retinal and tectal neurites to detect patterning errors. From this unbiased screen, the notorious (noto) mutant exhibited the most specific phenotypes: intact retinal and tectal differentiation but multiple neurite targeting defects in the retinal inner plexiform layer (IPL) and tectal neuropil. Positional cloning and morpholino phenocopy revealed that the mutation disrupts Topoisomerase IIbeta (Top2b), a broadly distributed nuclear protein involved in chromatin modifications during postmitotic differentiation. Top2b-DNA interactions are known to regulate transcription of developmentally important genes, including axon guidance factors and cell adhesion molecules, but a specific role in local synaptic targeting has not been previously described. The neurite targeting defects among GC axons are largely restricted to crossovers between sublaminae of a specific layer, SFGS, and were shown by mosaic analysis to be autonomous to the GC axons. The noto mutant provides the first example of the importance of an epigenetic regulator, Top2b, in the intricate series of events that lead to a properly wired visual system. PMID- 21610028 TI - Restoring eye size in Astyanax mexicanus blind cavefish embryos through modulation of the Shh and Fgf8 forebrain organising centres. AB - The cavefish morph of the Mexican tetra (Astyanax mexicanus) is blind at adult stage, although an eye that includes a retina and a lens develops during embryogenesis. There are, however, two major defects in cavefish eye development. One is lens apoptosis, a phenomenon that is indirectly linked to the expansion of ventral midline sonic hedgehog (Shh) expression during gastrulation and that induces eye degeneration. The other is the lack of the ventral quadrant of the retina. Here, we show that such ventralisation is not extended to the entire forebrain because fibroblast growth factor 8 (Fgf8), which is expressed in the forebrain rostral signalling centre, is activated 2 hours earlier in cavefish embryos than in their surface fish counterparts, in response to stronger Shh signalling in cavefish. We also show that neural plate patterning and morphogenesis are modified in cavefish, as assessed by Lhx2 and Lhx9 expression. Inhibition of Fgf receptor signalling in cavefish with SU5402 during gastrulation/early neurulation mimics the typical surface fish phenotype for both Shh and Lhx2/9 gene expression. Fate-mapping experiments show that posterior medial cells of the anterior neural plate, which lack Lhx2 expression in cavefish, contribute to the ventral quadrant of the retina in surface fish, whereas they contribute to the hypothalamus in cavefish. Furthermore, when Lhx2 expression is rescued in cavefish after SU5402 treatment, the ventral quadrant of the retina is also rescued. We propose that increased Shh signalling in cavefish causes earlier Fgf8 expression, a crucial heterochrony that is responsible for Lhx2 expression and retina morphogenesis defect. PMID- 21610029 TI - Drosophila Mon2 couples Oskar-induced endocytosis with actin remodeling for cortical anchorage of the germ plasm. AB - Drosophila pole (germ) plasm contains germline and abdominal determinants. Its assembly begins with the localization and translation of oskar (osk) RNA at the oocyte posterior, to which the pole plasm must be restricted for proper embryonic development. Osk stimulates endocytosis, which in turn promotes actin remodeling to form long F-actin projections at the oocyte posterior pole. Although the endocytosis-coupled actin remodeling appears to be crucial for the pole plasm anchoring, the mechanism linking Osk-induced endocytic activity and actin remodeling is unknown. Here, we report that a Golgi-endosomal protein, Mon2, acts downstream of Osk to remodel cortical actin and to anchor the pole plasm. Mon2 interacts with two actin nucleators known to be involved in osk RNA localization in the oocyte, Cappuccino (Capu) and Spire (Spir), and promotes the accumulation of the small GTPase Rho1 at the oocyte posterior. We also found that these actin regulators are required for Osk-dependent formation of long F-actin projections and cortical anchoring of pole plasm components. We propose that, in response to the Osk-mediated endocytic activation, vesicle-localized Mon2 acts as a scaffold that instructs the actin-remodeling complex to form long F-actin projections. This Mon2-mediated coupling event is crucial to restrict the pole plasm to the oocyte posterior cortex. PMID- 21610030 TI - Regulation of mammalian Gli proteins by Costal 2 and PKA in Drosophila reveals Hedgehog pathway conservation. AB - Hedgehog (Hh) signaling activates full-length Ci/Gli family transcription factors and prevents Ci/Gli proteolytic processing to repressor forms. In the absence of Hh, Ci/Gli processing is initiated by direct Pka phosphorylation. Despite those fundamental similarities between Drosophila and mammalian Hh pathways, the differential reliance on cilia and some key signal transduction components had suggested a major divergence in the mechanisms that regulate Ci/Gli protein activities, including the role of the kinesin-family protein Costal 2 (Cos2), which directs Ci processing in Drosophila. Here, we show that Cos2 binds to three regions of Gli1, just as for Ci, and that Cos2 functions to silence mammalian Gli1 in Drosophila in a Hh-regulated manner. Cos2 and the mammalian kinesin Kif7 can also direct Gli3 and Ci processing in fly, underscoring a fundamental conserved role for Cos2 family proteins in Hh signaling. We also show that direct PKA phosphorylation regulates the activity, rather than the proteolysis of Gli in Drosophilia, and we provide evidence for an analogous action of PKA on Ci. PMID- 21610031 TI - Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling. AB - The decision of a neural precursor to stop dividing and begin its terminal differentiation at the correct place, and at the right time, is a crucial step in the generation of cell diversity in the nervous system. Here, we show that the Down's syndrome candidate gene (Mnb/Dyrk1a) is transiently expressed in prospective neurons of vertebrate CNS neuroepithelia. The gain of function (GoF) of Mnb/Dyrk1a induced proliferation arrest. Conversely, its loss of function (LoF) caused over proliferation and cell death. We found that MNB/DYRK1A is both necessary and sufficient to upregulate, at transcriptional level, the expression of the cyclin-dependent kinase inhibitor p27(KIP1) in the embryonic chick spinal cord and mouse telencephalon, supporting a regulatory role for MNB/DYRK1A in cell cycle exit of vertebrate CNS neurons. All these actions required the kinase activity of MNB/DYRK1A. We also observed that MNB/DYRK1A is co-expressed with the NOTCH ligand Delta1 in single neuronal precursors. Furthermore, we found that MNB/DYRK1A suppressed NOTCH signaling, counteracted the pro-proliferative action of the NOTCH intracellular domain (NICD), stimulated Delta1 expression and was required for the neuronal differentiation induced by the decrease in NOTCH signaling. Nevertheless, although Mnb/Dyrk1a GoF led to extensive withdrawal of neuronal precursors from the cell cycle, it was insufficient to elicit their differentiation. Remarkably, a transient (ON/OFF) Mnb/Dyrk1a GoF efficiently induced neuronal differentiation. We propose that the transient expression of MNB/DYRK1A in neuronal precursors acts as a binary switch, coupling the end of proliferation and the initiation of neuronal differentiation by upregulating p27KIP1 expression and suppressing NOTCH signaling. PMID- 21610033 TI - Notch destabilises maternal beta-catenin and restricts dorsal-anterior development in Xenopus. AB - The blastula chordin- and noggin-expressing centre (BCNE) is the predecessor of the Spemann-Mangold's organiser and also contains the precursors of the brain. This signalling centre comprises animal-dorsal and marginal-dorsal cells and appears as a consequence of the nuclear accumulation of beta-catenin on the dorsal side. Here, we propose a role for Notch that was not previously explored during early development in vertebrates. Notch initially destabilises beta catenin in a process that does not depend on its phosphorylation by GSK3. This is important to restrict the BCNE to its normal extent and to control the size of the brain. PMID- 21610032 TI - The MADS box transcription factor MEF2C regulates melanocyte development and is a direct transcriptional target and partner of SOX10. AB - Waardenburg syndromes are characterized by pigmentation and autosensory hearing defects, and mutations in genes encoding transcription factors that control neural crest specification and differentiation are often associated with Waardenburg and related disorders. For example, mutations in SOX10 result in a severe form of Waardenburg syndrome, Type IV, also known as Waardenburg Hirschsprung disease, characterized by pigmentation and other neural crest defects, including defective innervation of the gut. SOX10 controls neural crest development through interactions with other transcription factors. The MADS box transcription factor MEF2C is an important regulator of brain, skeleton, lymphocyte and cardiovascular development and is required in the neural crest for craniofacial development. Here, we establish a novel role for MEF2C in melanocyte development. Inactivation of Mef2c in the neural crest of mice results in reduced expression of melanocyte genes during development and a significant loss of pigmentation at birth due to defective differentiation and reduced abundance of melanocytes. We identify a transcriptional enhancer of Mef2c that directs expression to the neural crest and its derivatives, including melanocytes, in transgenic mouse embryos. This novel Mef2c neural crest enhancer contains three functional SOX binding sites and a single essential MEF2 site. We demonstrate that Mef2c is a direct transcriptional target of SOX10 and MEF2 via this evolutionarily conserved enhancer. Furthermore, we show that SOX10 and MEF2C physically interact and function cooperatively to activate the Mef2c gene in a feed-forward transcriptional circuit, suggesting that MEF2C might serve as a potentiator of the transcriptional pathways affected in Waardenburg syndromes. PMID- 21610034 TI - Regulative deployment of the skeletogenic gene regulatory network during sea urchin development. AB - The well-known regulative properties of the sea urchin embryo, coupled with the recent elucidation of gene regulatory networks (GRNs) that underlie cell specification, make this a valuable experimental model for analyzing developmental plasticity. In the sea urchin, the primary mesenchyme cell (PMC) GRN controls the development of the embryonic skeleton. Remarkably, experimental manipulations reveal that this GRN can be activated in almost any cell of the embryo. Here, we focus on the activation of the PMC GRN during gastrulation by non-skeletogenic mesoderm (NSM) cells and by endoderm cells. We show that most transfating NSM cells are prospective blastocoelar cells, not prospective pigment cells, as was previously believed. Earlier work showed that the regulative deployment of the GRN, unlike its deployment in the micromere-PMC lineage, is independent of the transcriptional repressor Pmar1. In this work, we identify several additional differences in the upstream regulation of the GRN during normal and regulative development. We provide evidence that, despite these changes in the upstream regulation of the network, downstream regulatory genes and key morphoregulatory genes are deployed in transfating NSM cells in a fashion that recapitulates the normal deployment of the GRN, and which can account for the striking changes in migratory behavior that accompany NSM transfating. Finally, we report that mitotic cell division is not required for genomic reprogramming in this system, either within a germ layer (NSM transfating) or across a germ layer boundary (endoderm transfating). PMID- 21610035 TI - The transcription factor FoxB mediates temporal loss of cellular competence for notochord induction in ascidian embryos. AB - In embryos of the ascidian Halocynthia roretzi, the competence of isolated presumptive notochord blastomeres to respond to fibroblast growth factor (FGF) for induction of the primary notochord decays by 1 hour after cleavage from the 32- to 64-cell stage. This study analyzes the molecular mechanisms responsible for this loss of competence and provides evidence for a novel mechanism. A forkhead family transcription factor, FoxB, plays a role in competence decay by preventing the induction of notochord-specific Brachyury (Bra) gene expression by the FGF/MAPK signaling pathway. Unlike the mechanisms reported previously in other animals, no component in the FGF signal transduction cascade appeared to be lost or inactivated at the time of competence loss. Knockdown of FoxB functions allowed the isolated cells to retain their competence for a longer period, and to respond to FGF with expression of Bra beyond the stage at which competence was normally lost. FoxB acts as a transcription repressor by directly binding to the cis-regulatory element of the Bra gene. Our results suggest that FoxB prevents ectopic induction of the notochord fate within the cells that assume a default nerve cord fate, after the stage when notochord induction has been completed. The merit of this system is that embryos can use the same FGF signaling cascade again for another purpose in the same cell lineage at later stages by keeping the signaling cascade itself available. Temporally and spatially regulated FoxB expression in nerve cord cells was promoted by the ZicN transcription factor and absence of FGF/MAPK signaling. PMID- 21610036 TI - BMP and non-canonical Wnt signaling are required for inhibition of secondary tail formation in zebrafish. AB - The role of bone morphogenetic protein (BMP) signaling in specifying cell fate in the zebrafish tailbud has been well established. In addition to a loss of ventral tissues, such as ventral tailfin and cloaca, some embryos with compromised BMP signaling produce an additional phenotype: a ventrally located secondary tail containing both somitic muscle and notochord. This phenotype has been proposed to reflect a fate-patterning defect due to a change in a hypothesized BMP activity gradient. Here, we show that a defect in morphogenetic movements, not fate patterning, underlies the formation of secondary tails in BMP-inhibited embryos. Our data indicate that BMP signaling is activated in the ventroposterior tailbud to promote cell migration during tailbud protrusion, and that defective migration of these cells in BMP mutants ultimately leads to bifurcation of the caudal notochord. Additionally, we show that non-canonical Wnt signaling is also required for proper tail morphogenesis, possibly by maintaining cohesion of notochord progenitors by regulation of cadherin localization. We propose a model in which BMP and the non-canonical Wnt pathway regulate tail morphogenesis by controlling cell migration and cell adhesion within the tailbud. PMID- 21610037 TI - FGF-dependent midline-derived progenitor cells in hypothalamic infundibular development. AB - The infundibulum links the nervous and endocrine systems, serving as a crucial integrating centre for body homeostasis. Here we describe that the chick infundibulum derives from two subsets of anterior ventral midline cells. One set remains at the ventral midline and forms the posterior-ventral infundibulum. A second set migrates laterally, forming a collar around the midline. We show that collar cells are composed of Fgf3(+) SOX3(+) proliferating progenitors, the induction of which is SHH dependent, but the maintenance of which requires FGF signalling. Collar cells proliferate late into embryogenesis, can generate neurospheres that passage extensively, and differentiate to distinct fates, including hypothalamic neuronal fates and Fgf10(+) anterior-dorsal infundibular cells. Together, our study shows that a subset of anterior floor plate-like cells gives rise to Fgf3(+) SOX3(+) progenitor cells, demonstrates a dual origin of infundibular cells and reveals a crucial role for FGF signalling in governing extended infundibular growth. PMID- 21610038 TI - A versatile strategy for gene trapping and trap conversion in emerging model organisms. AB - Genetic model organisms such as Drosophila, C. elegans and the mouse provide formidable tools for studying mechanisms of development, physiology and behaviour. Established models alone, however, allow us to survey only a tiny fraction of the morphological and functional diversity present in the animal kingdom. Here, we present iTRAC, a versatile gene-trapping approach that combines the implementation of unbiased genetic screens with the generation of sophisticated genetic tools both in established and emerging model organisms. The approach utilises an exon-trapping transposon vector that carries an integrase docking site, allowing the targeted integration of new constructs into trapped loci. We provide proof of principle for iTRAC in the emerging model crustacean Parhyale hawaiensis: we generate traps that allow specific developmental and physiological processes to be visualised in unparalleled detail, we show that trapped genes can be easily cloned from an unsequenced genome, and we demonstrate targeting of new constructs into a trapped locus. Using this approach, gene traps can serve as platforms for generating diverse reporters, drivers for tissue specific expression, gene knockdown and other genetic tools not yet imagined. PMID- 21610039 TI - Duration of anticoagulation for venous thromboembolism. PMID- 21610041 TI - Cardiovascular risk during androgen deprivation therapy for prostate cancer. PMID- 21610045 TI - Rise in attacks on health personnel and facilities is "not acceptable," WHO assembly hears. PMID- 21610040 TI - Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials. AB - OBJECTIVE: To determine how length of anticoagulation and clinical presentation of venous thromboembolism influence the risk of recurrence after anticoagulant treatment is stopped and to identify the shortest length of anticoagulation that reduces the risk of recurrence to its lowest level. DESIGN: Pooled analysis of individual participants' data from seven randomised trials. SETTING: Outpatient anticoagulant clinics in academic centres. POPULATION: 2925 men or women with a first venous thromboembolism who did not have cancer and received different durations of anticoagulant treatment. MAIN OUTCOME MEASURE: First recurrent venous thromboembolism after stopping anticoagulant treatment during up to 24 months of follow-up. RESULTS: Recurrence was lower after isolated distal deep vein thrombosis than after proximal deep vein thrombosis (hazard ratio 0.49, 95% confidence interval 0.34 to 0.71), similar after pulmonary embolism and proximal deep vein thrombosis (1.19, 0.87 to 1.63), and lower after thrombosis provoked by a temporary risk factor than after unprovoked thrombosis (0.55, 0.41 to 0.74). Recurrence was higher if anticoagulation was stopped at 1.0 or 1.5 months compared with at 3 months or later (hazard ratio 1.52, 1.14 to 2.02) and similar if treatment was stopped at 3 months compared with at 6 months or later (1.19, 0.86 to 1.65). High rates of recurrence associated with shorter durations of anticoagulation were confined to the first 6 months after stopping treatment. CONCLUSION: Three months of treatment achieves a similar risk of recurrent venous thromboembolism after stopping anticoagulation to a longer course of treatment. Unprovoked proximal deep vein thrombosis and pulmonary embolism have a high risk of recurrence whenever treatment is stopped. PMID- 21610046 TI - Impact of genetic insights into calpain biology. AB - Calpain has long been an enigmatic enzyme, although it is involved in a variety of biological phenomena. Recent progress in calpain genetics has highlighted numerous physiological contexts in which the functions of calpain are of great significance. This review focuses on recent findings in the field of calpain genetics and the importance of calpain function. Calpain is an intracellular Ca(2+)-dependent cysteine protease (EC 3.4.22.17; Clan CA, family C02) found in almost all eukaryotes. It is also present in a few bacteria, but not in archaebacteria. Calpain has limited proteolytic activity; rather, it transforms or modulates the structure and/or activity of its substrates. It is, therefore, referred to as a 'modulator protease'. Within the human genome, 15 genes (CAPN1 3, CAPN5-16) encode a calpain-like protease (CysPc) domain along with several different functional domains. Thus, calpains can be regarded as a distinct family of versatile enzymes that fulfil numerous tasks in vivo. Genetic studies show that a variety of defects in many different organisms, including lethality, muscular dystrophies and gastropathy, actually stem from calpain deficiencies. The cause-effect relationships identified by these studies form the basis for ongoing and future studies regarding the physiological role of calpains. PMID- 21610047 TI - Ectodomain shedding and remnant peptide signalling of EGFRs and their ligands. AB - Both receptor tyrosine kinases epidermal growth factor receptors (EGFRs) and their ligands are transmembrane proteins. It has been known that ligand binding activates cytoplasmic tyrosine kinase domains of EGFRs, resulting in the transduction of signals for cell proliferation, migration, differentiation or survival. In an EGFRs-ligands system, however, signal transduction occurs not only unidirectionally but also bidirectionally, which is regulated by cell-cell contact and proteolytic cleavage. Recent studies of proteolytic cleavage 'ectodomain shedding' of EGFRs and their ligands mediated by membrane-type metalloproteinases, a disintegrin and metalloproteinases have been unveiling novel functions and molecular mechanism of their remnant peptides. In addition, the study of the remnant peptide signalling would be essential for understanding the physiological and pathological relevance of anti-shedding therapeutic strategies for diseases such as cancer. PMID- 21610049 TI - Identification and care pathways for common mental health disorders: summary of NICE guidance. PMID- 21610048 TI - Dietary calcium intake and risk of fracture and osteoporosis: prospective longitudinal cohort study. AB - OBJECTIVE: To investigate associations between long term dietary intake of calcium and risk of fracture of any type, hip fractures, and osteoporosis. DESIGN: A longitudinal and prospective cohort study, based on the Swedish Mammography Cohort, including a subcohort, the Swedish Mammography Cohort Clinical. SETTING: A population based cohort in Sweden established in 1987. PARTICIPANTS: 61,433 women (born between 1914 and 1948) were followed up for 19 years. 5022 of these women participated in the subcohort. MAIN OUTCOME MEASURES: Primary outcome measures were incident fractures of any type and hip fractures, which were identified from registry data. Secondary outcome was osteoporosis diagnosed by dual energy x ray absorptiometry in the subcohort. Diet was assessed by repeated food frequency questionnaires. RESULTS: During follow-up, 14,738 women (24%) experienced a first fracture of any type and among them 3871 (6%) a first hip fracture. Of the 5022 women in the subcohort, 1012 (20%) were measured as osteoporotic. The risk patterns with dietary calcium were non-linear. The crude rate of a first fracture of any type was 17.2/1000 person years at risk in the lowest quintile of calcium intake, and 14.0/1000 person years at risk in the third quintile, corresponding to a multivariable adjusted hazard ratio of 1.18 (95% confidence interval 1.12 to 1.25). The hazard ratio for a first hip fracture was 1.29 (1.17 to 1.43) and the odds ratio for osteoporosis was 1.47 (1.09 to 2.00). With a low vitamin D intake, the rate of fracture in the first calcium quintile was more pronounced. The highest quintile of calcium intake did not further reduce the risk of fractures of any type, or of osteoporosis, but was associated with a higher rate of hip fracture, hazard ratio 1.19 (1.06 to 1.32). CONCLUSION: Gradual increases in dietary calcium intake above the first quintile in our female population were not associated with further reductions in fracture risk or osteoporosis. PMID- 21610050 TI - What's happening to NHS spending across the UK? PMID- 21610051 TI - Intraoperative fluid management guided by oesophageal Doppler monitoring. AB - PROBLEM: Fluid management during major surgery poses a challenge to the surgical team as postoperative complications are often related to giving the wrong amount of intravenous fluid. Postoperative morbidity can be reduced by using the oesophageal Doppler cardiac output monitor to individualise fluid administration, but this technology has not been widely adopted. DESIGN: A campaign for adopting this technology in major surgical specialties explored clinical and managerial barriers throughout the procurement and implementation process. We compared patient outcomes 12 months before implementation and after implementation. SETTING: Three large hospitals in England with different size, geographical location, and case mix. STRATEGIES FOR CHANGE: Project leads at each site included a consultant anaesthetist, a divisional manager, and an audit facilitator. A business case was prepared by each team with support from NHS Technology Adoption Centre, allowing senior management to overcome the unequal spread of costs versus benefits. A survey of anaesthetists revealed concerns about familiarity with the device, which we dealt with by clinicians volunteering to "champion" the technique, supported by standard training provided by the manufacturer. We encouraged appropriate use of the technology by collecting intraoperative patient related data and postoperative patient outcomes and by giving regular, timely feedback. KEY MEASURES FOR IMPROVEMENT: The key outcome measure was length of hospital stay. In-hospital mortality, readmission, and reoperation rates were also recorded. Process measures were use of monitors and change in stroke volume during surgery. EFFECTS OF THE CHANGE: We compared 649 patients after implementation across all sites with 658 matched cases before implementation. Use of Doppler increased from 11% to 65% of eligible operations, with a 3.7 day reduction in total length of stay. Length of stay was reduced at each site, and in most specialties. Concurrent improvements in patient care could have contributed to these findings. The only sign of harm from the intervention was one episode of pulmonary oedema. Mortality, readmission, and reoperation rates all fell non-significantly. LESSONS LEARNT: Managerial barriers consisted of silo budgeting, difficulties with preparing a business case, and fears about uncontrolled implementation. By collecting outcome data, we convinced senior managers to support and sustain investment. Clinical barriers consisted mainly of scepticism regarding clinical effectiveness and worries about training. Clinicians "championing" the technology took on responsibility for data collection, education, advocacy, and spanning boundaries. When barriers to adoption of oesophageal Doppler monitoring are overcome, outcome improvements suggested by research can be replicated in the real world. The project generated a web based guide (www.howtowhyto.nhs.uk) to provide tools and resources to support implementation. PMID- 21610052 TI - Paracetamol poisoning. Paracetamol concentrations should be in mg/L in UK. PMID- 21610053 TI - Private alcohol detox clinics. Please tell us about them. PMID- 21610054 TI - Bipolar II disorder. Bad medicine or bad mouthing? PMID- 21610055 TI - Law on assisted dying. Better framework needed. PMID- 21610056 TI - Law on assisted dying. Anti-euthanasia cards. PMID- 21610057 TI - Bipolar II disorder. Trivialisation of suffering. PMID- 21610058 TI - Law on assisted dying. European-wide debate needed. PMID- 21610059 TI - NHS reforms. Issues MPs and the media have missed in Lansley's bill. PMID- 21610060 TI - Bipolar II disorder. Constructionism. PMID- 21610061 TI - Surgical intervention after medical abortion. PMID- 21610062 TI - Cost of preventive drugs. Dare to tell? PMID- 21610063 TI - Atrial fibrillation guidelines. Don't forget HASBLED score. PMID- 21610064 TI - GP accused of "pushing religion" on patient opts for full GMC hearing. PMID- 21610067 TI - GMC drops case of alleged research misconduct against orthopaedic surgeons. PMID- 21610068 TI - RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase, mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation. AB - Inositol 1,4,5-trisphosphate (IP(3)) receptors are endoplasmic reticulum membrane calcium channels that, upon activation, are degraded via the ubiquitin-proteasome pathway. While searching for novel mediators of IP(3) receptor processing, we discovered that RNF170, an uncharacterized RING domain-containing protein, associates rapidly with activated IP(3) receptors. RNF170 is predicted to have three membrane-spanning helices, is localized to the ER membrane, and possesses ubiquitin ligase activity. Depletion of endogenous RNF170 by RNA interference inhibited stimulus-induced IP(3) receptor ubiquitination, and degradation and overexpression of a catalytically inactive RNF170 mutant suppressed stimulus induced IP(3) receptor processing. A substantial proportion of RNF170 is constitutively associated with the erlin1/2 (SPFH1/2) complex, which has been shown previously to bind to IP(3) receptors immediately after their activation. Depletion of RNF170 did not affect the binding of the erlin1/2 complex to stimulated IP(3) receptors, whereas erlin1/2 complex depletion inhibited RNF170 binding. These results suggest a model in which the erlin1/2 complex recruits RNF170 to activated IP(3) receptors where it mediates IP(3) receptor ubiquitination. Thus, RNF170 plays an essential role in IP(3) receptor processing via the ubiquitin-proteasome pathway. PMID- 21610069 TI - Luminal lipid regulates CD36 levels and downstream signaling to stimulate chylomicron synthesis. AB - The membrane glycoprotein CD36 binds nanomolar concentrations of long chain fatty acids (LCFA) and is highly expressed on the luminal surface of enterocytes. CD36 deficiency reduces chylomicron production through unknown mechanisms. In this report, we provide novel insights into some of the underlying mechanisms. Our in vivo data demonstrate that CD36 gene deletion in mice does not affect LCFA uptake and subsequent esterification into triglycerides by the intestinal mucosa exposed to the micellar LCFA concentrations prevailing in the intestine. In rodents, the CD36 protein disappears early from the luminal side of intestinal villi during the postprandial period, but only when the diet contains lipids. This drop is significant 1 h after a lipid supply and associates with ubiquitination of CD36. Using CHO cells expressing CD36, it is shown that the digestion products LCFA and diglycerides trigger CD36 ubiquitination. In vivo treatment with the proteasome inhibitor MG132 prevents the lipid-mediated degradation of CD36. In vivo and ex vivo, CD36 is shown to be required for lipid activation of ERK1/2, which associates with an increase of the key chylomicron synthesis proteins, apolipoprotein B48 and microsomal triglyceride transfer protein. Therefore, intestinal CD36, possibly through ERK1/2-mediated signaling, is involved in the adaptation of enterocyte metabolism to the postprandial lipid challenge by promoting the production of large triglyceride-rich lipoproteins that are rapidly cleared in the blood. This suggests that CD36 may be a therapeutic target for reducing the postprandial hypertriglyceridemia and associated cardiovascular risks. PMID- 21610070 TI - Structural basis of Rnd1 binding to plexin Rho GTPase binding domains (RBDs). AB - Plexin receptors regulate cell adhesion, migration, and guidance. The Rho GTPase binding domain (RBD) of plexin-A1 and -B1 can bind GTPases, including Rnd1. By contrast, plexin-C1 and -D1 reportedly bind Rnd2 but associate with Rnd1 only weakly. The structural basis of this differential Rnd1 GTPase binding to plexin RBDs remains unclear. Here, we solved the structure of the plexin-A2 RBD in complex with Rnd1 and the structures of the plexin-C1 and plexin-D1 RBDs alone, also compared with the previously determined plexin-B1 RBD.Rnd1 complex structure. The plexin-A2 RBD.Rnd1 complex is a heterodimer, whereas plexin-B1 and -A2 RBDs homodimerize at high concentration in solution, consistent with a proposed model for plexin activation. Plexin-C1 and -D1 RBDs are monomeric, consistent with major residue changes in the homodimerization loop. In plexin-A2 and -B1, the RBD beta3-beta4 loop adjusts its conformation to allow Rnd1 binding, whereas minimal structural changes occur in Rnd1. The plexin-C1 and -D1 RBDs lack several key non-polar residues at the corresponding GTPase binding surface and do not significantly interact with Rnd1. Isothermal titration calorimetry measurements on plexin-C1 and -D1 mutants reveal that the introduction of non polar residues in this loop generates affinity for Rnd1. Structure and sequence comparisons suggest a similar mode of Rnd1 binding to the RBDs, whereas mutagenesis suggests that the interface with the highly homologous Rnd2 GTPase is different in detail. Our results confirm, from a structural perspective, that Rnd1 does not play a role in the activation of plexin-C1 and -D1. Plexin functions appear to be regulated by subfamily-specific mechanisms, some of which involve different Rho family GTPases. PMID- 21610071 TI - Desensitization of alpha7 nicotinic receptor is governed by coupling strength relative to gate tightness. AB - Binding of a neurotransmitter to its membrane receptor opens an integral ion conducting pore. However, prolonged exposure to the neurotransmitter drives the receptor to a refractory state termed desensitization, which plays an important role in shaping synaptic transmission. Despite intensive research in the past, the structural mechanism of desensitization is still elusive. Using mutagenesis and voltage clamp in an oocyte expression system, we provide several lines of evidence supporting a novel hypothesis that uncoupling between binding and gating machinery is the underlying mechanism for alpha7 nicotinic receptor (nAChR) desensitization. First, the decrease in gate tightness was highly correlated to the reduced desensitization. Second, nonfunctional mutants in three important coupling loops (loop 2, loop 7, and the M2-M3 linker) could be rescued by a gating mutant. Furthermore, the decrease in coupling strength in these rescued coupling loop mutants reversed the gating effect on desensitization. Finally, coupling between M1 and hinge region of the M2-M3 linker also influenced the receptor desensitization. Thus, the uncoupling between N-terminal domain and transmembrane domain, governed by the balance of coupling strength and gate tightness, underlies the mechanism of desensitization for the alpha7 nAChR. PMID- 21610072 TI - Signal integration and coincidence detection in the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) cascade: concomitant activation of receptor tyrosine kinases and of LRP-1 leads to sustained ERK phosphorylation via down-regulation of dual specificity phosphatases (DUSP1 and 6). AB - Diverse stimuli can feed into the MAPK/ERK cascade; this includes receptor tyrosine kinases, G protein-coupled receptors, integrins, and scavenger receptors (LDL receptor-related protein (LRP)). Here, we investigated the consequence of concomitant occupancy of the receptor tyrosine kinases (by EGF, basic FGF, VEGF, etc.) and of LRP family members (by LDL or lactoferrin). The simultaneous stimulation of a receptor tyrosine kinase by its cognate ligand and of LRP-1 (by lactoferrin or LDL) resulted in sustained activation of ERK, which was redirected to the cytoplasm. Accordingly, elevated levels of active cytosolic ERK were translated into accelerated adhesion to vitronectin. The sustained ERK response was seen in several cell types, but it was absent in cells deficient in LRP-1 (but not in cells lacking the LDL receptor). This response was also contingent on the presence of urokinase (uPA) and its receptor (uPAR), because it was absent in uPA(-/-) and uPAR(-/-) fibroblasts. Combined stimulation of the EGF receptor and of LRP-1 delayed nuclear accumulation of phosphorylated ERK. This shift in favor of cytosolic accumulation of phospho-ERK was accounted for by enhanced proteasomal degradation of dual specificity phosphatases DUSP1 and DUSP6, which precluded dephosphorylation of cytosolic ERK. These observations demonstrate that the ERK cascade can act as a coincidence detector to decode the simultaneous engagement of a receptor tyrosine kinase and of LRP-1 and as a signal integrator that encodes this information in a spatially and temporally distinct biological signal. In addition, the findings provide an explanation of why chronic elevation of LRP-1 ligands (e.g. PAI-1) can predispose to cancer. PMID- 21610073 TI - Evidence for the assembly of a bacterial tripartite multidrug pump with a stoichiometry of 3:6:3. AB - The multiple transferable resistance (mTR) pump from Neisseria gonorrhoeae MtrCDE multidrug pump is assembled from the inner and outer membrane proteins MtrD and MtrE and the periplasmic membrane fusion protein MtrC. Previously we established that while there is a weak interaction of MtrD and MtrE, MtrC binds with relatively high affinity to both MtrD and MtrE. MtrD conferred antibiotic resistance only when it was expressed with MtrE and MtrC, suggesting that these proteins form a functional tripartite complex in which MtrC bridges MtrD and MtrE. Furthermore, we demonstrated that MtrC interacts with an intraprotomer groove on the surface of MtrE, inducing channel opening. However, a second groove is apparent at the interface of the MtrE subunits, which might also be capable of engaging MtrC. We have now established that MtrC can be cross-linked to cysteines placed in this interprotomer groove and that mutation of residues in the groove impair the ability of the pump to confer antibiotic resistance by locking MtrE in the closed channel conformation. Moreover, MtrE K390C forms an intermolecular disulfide bond with MtrC E149C locking MtrE in the open channel conformation, suggesting that a functional salt bridge forms between these residues during the transition from closed to open channel conformations. MtrC forms dimers that assemble into hexamers, and electron microscopy studies of single particles revealed that these hexamers are arranged into ring-like structures with an internal aperture sufficiently large to accommodate the MtrE trimer. Cross linking of single cysteine mutants of MtrC to stabilize the dimer interface in the presence of MtrE, trapped an MtrC-MtrE complex with a molecular mass consistent with a stoichiometry of 3:6 (MtrE(3)MtrC(6)), suggesting that dimers of MtrC interact with MtrE, presumably by binding to the two grooves. As both MtrE and MtrD are trimeric, our studies suggest that the functional pump is assembled with a stoichiometry of 3:6:3. PMID- 21610074 TI - Synaptotagmin 1 modulates lipid acyl chain order in lipid bilayers by demixing phosphatidylserine. AB - Synaptotagmin 1 (syt1) functions as the Ca(2+) sensor in neuronal exocytosis, and it has been proposed to act by modulating lipid bilayer curvature. Here we examine the effect of the two C2 domains (C2A and C2B) of syt1 on membrane lipid order and lateral organization. In mixtures of phosphatidylcholine and phosphatidylserine (PS), attenuated total internal reflection Fourier transform infrared spectroscopy indicates that a fragment containing both domains (C2AB) or C2B alone disorders the lipid acyl chains, whereas the C2A domain has little effect upon chain order. Two observations suggest that these changes reflect a demixing of PS. First, the changes in acyl chain order are reversed at higher protein concentration; second, selective lipid deuteration demonstrates that the changes in lipid order are associated only with the PS component of the bilayer. Independent evidence for lipid demixing is obtained from fluorescence self quenching of labeled lipid and from natural abundance (13)C NMR, where heteronuclear single quantum correlation spectra reveal Ca(2+)-dependent chemical shift changes for PS, but not for phosphatidylcholine, in the presence of the syt1 C2 domains. The ability of syt1 to demix PS is observed in a range of lipid mixtures that includes cholesterol, phosphatidylethanolamine, and varied PS content. These data suggest that syt1 might facilitate SNARE (soluble N ethylmaleimide-sensitive factor attachment protein receptors)-mediated membrane fusion by phase separating PS, a process that is expected to locally buckle bilayers and disorder lipids due to the curvature tendencies of PS. PMID- 21610075 TI - An interaction between the Walker A and D-loop motifs is critical to ATP hydrolysis and cooperativity in bacteriophage T4 Rad50. AB - The ATP binding cassette (ABC) proteins make up a large superfamily with members coming from all kingdoms. The functional form of the ABC protein nucleotide binding domain (NBD) is dimeric with ATP binding sites shared between subunits. The NBD is defined by six motifs: the Walker A, Q-loop, Signature, Walker-B, D loop, and H-loop. The D-loop contains a conserved aspartate whose function is not clear but has been proposed to be involved in cross-talk between ATP binding sites. Structures of various ABC proteins suggest an interaction between the D loop aspartate and an asparagine residue located in Walker A loop of the opposing subunit. Here, we evaluate the functional role of the D-loop using a bacteriophage T4 ABC protein, Rad50 (gp46). Mutation of either the D-loop aspartate or the Walker A asparagine results in dramatic reductions in ATP affinity, hydrolysis rate, and cooperativity. The mutant proteins bind Mre11 (gp47) and DNA normally, but no longer support the ATP-dependent nuclease activities of Mre11. We propose that the D-loop aspartate functions to stabilize the Walker A asparagine in a position favorable for catalysis. We find that the asparagine is crucially important to the mechanism of ATP hydrolysis by increasing the affinity for ATP and positioning the gamma-phosphate of ATP for catalysis. Additionally, we propose that the asparagine acts as a gamma-phosphate sensor and, through its interaction with the conserved D-loop aspartate, transmits conformational changes across the dimer interface to the second ATP binding site. PMID- 21610076 TI - Nicotinic acid adenine dinucleotide phosphate (NAADP) regulates autophagy in cultured astrocytes. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca(2+) mobilizing messenger that in many cells releases Ca(2+) from the endolysosomal system. Recent studies have shown that NAADP-induced Ca(2+) mobilization is mediated by the two-pore channels (TPCs). Whether NAADP acts as a messenger in astrocytes is unclear, and downstream functional consequences have yet to be defined. Here, we show that intracellular delivery of NAADP evokes Ca(2+) signals from acidic organelles in rat astrocytes and that these signals are potentiated upon overexpression of TPCs. We also show that NAADP increases acidic vesicular organelle formation and levels of the autophagic markers, LC3II and beclin-1. NAADP-mediated increases in LC3II levels were reduced in cells expressing a dominant-negative TPC2 construct. Our data provide evidence that NAADP-evoked Ca(2+) signals mediated by TPCs regulate autophagy. PMID- 21610077 TI - Tissue-specific distribution and dynamic changes of 5-hydroxymethylcytosine in mammalian genomes. AB - Cytosine residues in the vertebrate genome are enzymatically modified to 5 methylcytosine, which participates in transcriptional repression of genes during development and disease progression. 5-Methylcytosine can be further enzymatically modified to 5-hydroxymethylcytosine by the TET family of methylcytosine dioxygenases. Analysis of 5-methylcytosine and 5 hydroxymethylcytosine is confounded, as these modifications are indistinguishable by traditional sequencing methods even when supplemented by bisulfite conversion. Here we demonstrate a simple enzymatic approach that involves cloning, identification, and quantification of 5-hydroxymethylcytosine in various CCGG loci within murine and human genomes. 5-Hydroxymethylcytosine was prevalent in human and murine brain and heart genomic DNAs at several regions. The cultured cell lines NIH3T3 and HeLa both displayed very low or undetectable amounts of 5 hydroxymethylcytosine at the examined loci. Interestingly, 5 hydroxymethylcytosine levels in mouse embryonic stem cell DNA first increased then slowly decreased upon differentiation to embryoid bodies, whereas 5 methylcytosine levels increased gradually over time. Finally, using a quantitative PCR approach, we established that a portion of VANGL1 and EGFR gene body methylation in human tissue DNA samples is indeed hydroxymethylation. PMID- 21610078 TI - Regulation of F0F1-ATPase from Synechocystis sp. PCC 6803 by gamma and epsilon subunits is significant for light/dark adaptation. AB - The gamma and epsilon subunits of F(0)F(1)-ATP synthase from photosynthetic organisms display unique properties not found in other organisms. Although the gamma subunit of both chloroplast and cyanobacterial F(0)F(1) contains an extra amino acid segment whose deletion results in a high ATP hydrolysis activity (Sunamura, E., Konno, H., Imashimizu-Kobayashi, M., Sugano, Y., and Hisabori, T. (2010) Plant Cell Physiol. 51, 855-865), its epsilon subunit strongly inhibits ATP hydrolysis activity. To understand the physiological significance of these phenomena, we studied mutant strains with (i) a C-terminally truncated epsilon (epsilon(DeltaC)), (ii) gamma lacking the inserted sequence (gamma(Delta198 222)), and (iii) a double mutation of (i) and (ii) in Synechocystis sp. PCC 6803. Although thylakoid membranes from the epsilon(DeltaC) strain showed higher ATP hydrolysis and lower ATP synthesis activities than those of the wild type, no significant difference was observed in growth rate and in intracellular ATP level both under light conditions and during light-dark cycles. However, both the epsilon(DeltaC) and gamma(Delta198-222) and the double mutant strains showed a lower intracellular ATP level and lower cell viability under prolonged dark incubation compared with the wild type. These data suggest that internal inhibition of ATP hydrolysis activity is very important for cyanobacteria that are exposed to prolonged dark adaptation and, in general, for the survival of photosynthetic organisms in an ever-changing environment. PMID- 21610079 TI - Transcription factors KLF1 and KLF2 positively regulate embryonic and fetal beta globin genes through direct promoter binding. AB - Kruppel-like factors (KLFs) control cell differentiation and embryonic development. KLF1 (erythroid Kruppel-like factor) plays essential roles in embryonic and adult erythropoiesis. KLF2 is a positive regulator of the mouse and human embryonic beta-globin genes. KLF1 and KLF2 have highly homologous zinc finger DNA-binding domains. They have overlapping roles in embryonic erythropoiesis, as demonstrated using single and double KO mouse models. Ablation of the KLF1 or KLF2 gene causes embryonic lethality, but double KO embryos are more anemic and die sooner than either single KO. In this work, a dual human beta globin locus transgenic and KLF knockout mouse model was used. The results demonstrate that the human epsilon- (embryonic) and gamma-globin (fetal) genes are positively regulated by KLF1 and KLF2 in embryos. Conditional KO mouse experiments indicate that the effect of KLF2 on embryonic globin gene regulation is at least partly erythroid cell-autonomous. KLF1 and KLF2 bind directly to the promoters of the human epsilon- and gamma-globin genes, the mouse embryonic Ey- and betah1-globin genes, and also to the beta-globin locus control region, as demonstrated by ChIP assays with mouse embryonic blood cells. H3K9Ac and H3K4me3 marks indicate open chromatin and active transcription, respectively. These marks are diminished at the Ey-, betah1-, epsilon- and gamma-globin genes and locus control region in KLF1(-/-) embryos, correlating with reduced gene expression. Therefore, KLF1 and KLF2 positively regulate the embryonic and fetal beta-globin genes through direct promoter binding. KLF1 is required for normal histone modifications in the beta-globin locus in mouse embryos. PMID- 21610080 TI - Characterization of a central Ca2+/calmodulin-dependent protein kinase IIalpha/beta binding domain in densin that selectively modulates glutamate receptor subunit phosphorylation. AB - The densin C-terminal domain can target Ca(2+)/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) in cells. Although the C-terminal domain selectively binds CaMKIIalpha in vitro, full-length densin associates with CaMKIIalpha or CaMKIIbeta in brain extracts and in transfected HEK293 cells. This interaction requires a second central CaMKII binding site, the densin-IN domain, and an "open" activated CaMKII conformation caused by Ca(2+)/calmodulin binding, autophosphorylation at Thr-286/287, or mutation of Thr-286/287 to Asp. Mutations in the densin-IN domain (L815E) or in the CaMKIIalpha/beta catalytic domain (I205/206K) disrupt the interaction. The amino acid sequence of the densin-IN domain is similar to the CaMKII inhibitor protein, CaMKIIN, and a CaMKIIN peptide competitively blocks CaMKII binding to densin. CaMKII is inhibited by both CaMKIIN and the densin-IN domain, but the inhibition by densin is substrate selective. Phosphorylation of a model peptide substrate, syntide-2, or of Ser-831 in AMPA receptor GluA1 subunits is fully inhibited by densin. However, CaMKII phosphorylation of Ser-1303 in NMDA receptor GluN2B subunits is not effectively inhibited by densin in vitro or in intact cells. Thus, densin can target multiple CaMKII isoforms to differentially modulate phosphorylation of physiologically relevant downstream targets. PMID- 21610082 TI - Confidence limits for lognormal percentiles and for lognormal mean based on samples with multiple detection limits. AB - The problem of assessing occupational exposure using the mean or an upper percentile of a lognormal distribution is addressed. Inferential methods for constructing an upper confidence limit for an upper percentile of a lognormal distribution and for finding confidence intervals for a lognormal mean based on samples with multiple detection limits are proposed. The proposed methods are based on the maximum likelihood estimates. They perform well with respect to coverage probabilities as well as power and are applicable to small sample sizes. The proposed approaches are also applicable for finding confidence limits for the percentiles of a gamma distribution. Computational details and a source for the computer programs are given. An advantage of the proposed approach is the ease of computation and implementation. Illustrative examples with real data sets and a simulated data set are given. PMID- 21610081 TI - A survey of antiprion compounds reveals the prevalence of non-PrP molecular targets. AB - Prion diseases are fatal neurodegenerative diseases caused by the accumulation of the misfolded isoform (PrP(Sc)) of the prion protein (PrP(C)). Cell-based screens have identified several compounds that induce a reduction in PrP(Sc) levels in infected cultured cells. However, the molecular targets of most antiprion compounds remain unknown. We undertook a large-scale, unbiased, cell-based screen for antiprion compounds and then investigated whether a representative subset of the active molecules had measurable affinity for PrP, increased the susceptibility of PrP(Sc) to proteolysis, or altered the cellular localization or expression level of PrP(C). None of the antiprion compounds showed in vitro affinity for PrP or had the ability to disaggregate PrP(Sc) in infected brain homogenates. These observations suggest that most antiprion compounds identified in cell-based screens deploy their activity via non-PrP targets in the cell. Our findings indicate that in comparison to PrP conformers themselves, proteins that play auxiliary roles in prion propagation may be more effective targets for future drug discovery efforts. PMID- 21610084 TI - The acute effect of ethanol on adrenal cortex in female rats--possible role of nitric oxide. AB - AIMS: The present study was designed to investigate a possible role of endogenous nitric oxide (NO) in the adrenal response to an acute alcohol administration in female rats. To this end, N(omega)-nitro-L-arginine-methyl ester (L-NAME), a competitive inhibitor of all isoforms of NO synthase, was used. METHODS: Adult female Wistar rats showing diestrus Day 1 were treated with: (a) ethanol (2 or 4 g/kg, intraperitoneally); (b) L-NAME (30 or 50 mg/kg, subcutaneously) followed by either ethanol or saline 3 h later. Untreated and saline-injected rats were used as controls. The animals were killed 30 min after last injection. Adrenal cortex was analyzed morphometrically, and plasma levels of adrenocorticotropic hormone (ACTH) and serum concentrations of corticosterone were determined. RESULTS: Acute ethanol treatment enhanced the levels of ACTH and corticosterone in a dose dependent manner. Stereological analysis revealed that acute alcohol administration induced a significant increase in absolute volume of the cortex and the zona fasciculata (ZF). In addition, ethanol at a dose of 4 g/kg increased volume density and length of the capillaries in the ZF. However, other stereological parameters were unaffected by alcohol exposure. Pretreatment with both doses of L-NAME had no effect on ethanol-induced changes. CONCLUSION: Obtained findings indicate that acute ethanol treatment stimulates the activity of the adrenal cortex and that this effect is not mediated by endogenous NO in female rats under these experimental conditions. PMID- 21610083 TI - Airline pilot cosmic radiation and circadian disruption exposure assessment from logbooks and company records. AB - OBJECTIVES: US commercial airline pilots, like all flight crew, are at increased risk for specific cancers, but the relation of these outcomes to specific air cabin exposures is unclear. Flight time or block (airborne plus taxi) time often substitutes for assessment of exposure to cosmic radiation. Our objectives were to develop methods to estimate exposures to cosmic radiation and circadian disruption for a study of chromosome aberrations in pilots and to describe workplace exposures for these pilots. METHODS: Exposures were estimated for cosmic ionizing radiation and circadian disruption between August 1963 and March 2003 for 83 male pilots from a major US airline. Estimates were based on 523 387 individual flight segments in company records and pilot logbooks as well as summary records of hours flown from other sources. Exposure was estimated by calculation or imputation for all but 0.02% of the individual flight segments' block time. Exposures were estimated from questionnaire data for a comparison group of 51 male university faculty. RESULTS: Pilots flew a median of 7126 flight segments and 14 959 block hours for 27.8 years. In the final study year, a hypothetical pilot incurred an estimated median effective dose of 1.92 mSv (absorbed dose, 0.85 mGy) from cosmic radiation and crossed 362 time zones. This study pilot was possibly exposed to a moderate or large solar particle event a median of 6 times or once every 3.7 years of work. Work at the study airline and military flying were the two highest sources of pilot exposure for all metrics. An index of work during the standard sleep interval (SSI travel) also suggested potential chronic sleep disturbance in some pilots. For study airline flights, median segment radiation doses, time zones crossed, and SSI travel increased markedly from the 1990s to 2003 (P(trend) < 0.0001). Dose metrics were moderately correlated with records-based duration metrics (Spearman's r = 0.61-0.69). CONCLUSIONS: The methods developed provided an exposure profile of this group of US airline pilots, many of whom have been exposed to increasing cosmic radiation and circadian disruption from the 1990s through 2003. This assessment is likely to decrease exposure misclassification in health studies. PMID- 21610085 TI - Global image properties do not guide visual search. AB - While basic visual features such as color, motion, and orientation can guide attention, it is likely that additional features guide search for objects in real world scenes. Recent work has shown that human observers efficiently extract global scene properties such as mean depth or navigability from a brief glance at a single scene (M. R. Greene & A. Oliva, 2009a, 2009b). Can human observers also efficiently search for an image possessing a particular global scene property among other images lacking that property? Observers searched for scene image targets defined by global properties of naturalness, transience, navigability, and mean depth. All produced inefficient search. Search efficiency for a property was not correlated with its classification threshold time from M. R. Greene and A. Oliva (2009b). Differences in search efficiency between properties can be partially explained by low-level visual features that are correlated with the global property. Overall, while global scene properties can be rapidly classified from a single image, it does not appear to be possible to use those properties to guide attention to one of several images. PMID- 21610086 TI - Increased proinflammatory and oxidant gene expression in circulating mononuclear cells in older adults: amelioration by habitual exercise. AB - We tested the hypothesis that peripheral blood mononuclear cells (PBMC) of older adults demonstrate a proinflammatory/-oxidative gene expression profile that can be improved by regular aerobic exercise. PBMC were isolated from young (n = 25, 18-33 yr) and middle-aged/older (n = 40, 50-76 yr) healthy adults. The older adults had greater mRNA expression (real-time RT-PCR) of the proinflammatory/ oxidant transcription factor nuclear factor-kappaB (1.58-fold, P < 0.05) and receptor for advanced glycation end products (1.12-fold, P < 0.05), the proinflammatory cytokines tumor necrosis factor-alpha (1.90-fold, P < 0.05) and monocyte chemoattractant protein-1 (1.47-fold, P < 0.05), and the oxidant producing enzymes nicotinamide adenine dinucleotide phosphate-oxidase (0.91-fold, P < 0.05) and inducible nitric oxide synthase (2.60-fold, P < 0.05). In 11 subjects (58-70 yr), maximal oxygen consumption (+11%) and exercise time (+19%) were increased (both P < 0.001), and expression of the above proinflammatory/ oxidative genes was or tended to be decreased in PBMC after vs. before 2 mo of aerobic exercise (brisk walking ~6 days/wk, 50 min/day, 70% of maximal heart rate). Expression of interleukin-6 was not different with age or exercise intervention. Age group- and exercise intervention-related differences in gene expression were independent of other factors. PBMC of healthy older adults demonstrate increased expression of several genes associated with inflammation and oxidative stress, which is largely ameliorated by habitual aerobic exercise. This proinflammatory/-oxidative gene signature may represent a therapeutic target for lifestyle and pharmacological prevention and treatment strategies. PMID- 21610087 TI - Endometrial expression of progesterone-induced blocking factor and galectins-1, 3, -9, and -3 binding protein in the luteal phase and early pregnancy in cattle. AB - Progesterone-induced blocking factor (PIBF) and galectins modulate the maternal immune response during pregnancy. We hypothesized that the relative transcript abundance of the above genes would be different during the luteal phase/early pregnancy and would be affected by progesterone supplementation. To further test this, hypothesis protein expression analyses were carried out to evaluate the abundance and localization of LGALS9 and PIBF. Following estrus synchronization, heifers were inseminated (n = 140) or not (n = 70). Half the heifers in each status (cyclic or potentially pregnant) were randomly assigned to receive a progesterone-releasing intravaginal device (PRID) on day 3 after estrus, which elevated progesterone concentrations from day 3.5 to 8 (P < 0.05), resulting in four treatment groups: cyclic and pregnant heifers, each with normal and high progesterone. After confirmation of pregnancy status in inseminated animals, uterine tissue was collected on days 5, 7, 13, or 16 of the luteal phase of the cycle/pregnancy. Gene and protein expression was determined using Q-RT-PCR and IHC, respectively, on 5 heifers per treatment per time point (i.e., 80 in total). Progesterone concentrations did not affect expression of any of the genes (P > 0.05). LGALS9 and LGALS3BP were expressed at low levels in both cyclic and pregnant endometria until day 13. On day 16, expression increased only in the pregnant heifers (P < 0.0001). LGALS1 and LGALS3 decreased on day 7 (P < 0.0001) and remained low until day 16. Pregnancy had no effect on the expression of LGALS1, LGALS3, and PIBF. Additionally, LGALS9 and PIBF proteins were expressed in distinct uterine cell types. These results indicate that the galectins may be involved in uterine receptivity and/or implantation in heifers. PMID- 21610088 TI - Cadherins at cell-autonomous membrane contacts control macropinocytosis. AB - Cadherins aggregate and stabilize cell-cell junctions through interactions with adjacent cells. In addition, N-cadherin and E-cadherin concentrate at free edges or at the lamellipodia of migrating cells and are found within large vesicles called macropinosomes, which develop from membrane ruffles. The binding properties of cadherins have not previously been associated with the localization of cadherins at membrane ruffles; however, we report that the dorsal, ventral and lateral membrane contacts that occur as a result of the overlap of membrane ruffles aggregate N-cadherin, and that both N-cadherin and E-cadherin promote macropinosome closure and fluid-phase uptake in macropinosomes. These data reveal a previously unsuspected function for cadherin-mediated cell-cell adhesion molecules in the closure of cell-autonomous membrane contacts at membrane ruffles, resulting in macropinocytosis. PMID- 21610090 TI - Samp1 is functionally associated with the LINC complex and A-type lamina networks. AB - The transmembrane inner nuclear membrane (INM) protein Samp1 is required for anchoring centrosomes near the nuclei. Using high-resolution fluorescence microscopy we show that Samp1 is distributed in a distinct and characteristic pattern in the nuclear envelope (NE), where it partially colocalizes with the LINC complex protein Sun1. By studying the localization of Samp1 deletion mutants and fusion proteins, we conclude that the cysteine-rich N-terminal half of Samp1 is nucleoplasmically exposed and is responsible for targeting to the INM. It contains four conserved CxxC motifs with the potential to form zinc fingers. The distribution of cysteine-to-alanine substitution mutants, designed to prevent zinc finger formation, showed that NE localization of Samp1 depends on intact CxxC motifs. Overexpression of Samp1 zinc finger mutants produced an abnormal dominant phenotype characterized by disrupted organization of a selective subset NE proteins, including emerin, Sun1, endogenous Samp1 and, in some cases, lamin A/C, but not lamin B, Sun2 or nucleoporins. Silencing of Samp1 expression showed that emerin depends on Samp1 for its correct localization in the NE. Our results demonstrate that Samp1 is functionally associated with the LINC complex protein Sun1 and proteins of the A-type lamina network. PMID- 21610089 TI - Dynamic interaction of Y RNAs with chromatin and initiation proteins during human DNA replication. AB - Non-coding Y RNAs are required for the initiation of chromosomal DNA replication in mammalian cells. It is unknown how they perform this function or if they associate with a nuclear structure during DNA replication. Here, we investigate the association of Y RNAs with chromatin and their interaction with replication proteins during DNA replication in a human cell-free system. Our results show that fluorescently labelled Y RNAs associate with unreplicated euchromatin in late G1 phase cell nuclei before the initiation of DNA replication. Following initiation, Y RNAs are displaced locally from nascent and replicated DNA present in replication foci. In intact human cells, a substantial fraction of endogenous Y RNAs are associated with G1 phase nuclei, but not with G2 phase nuclei. Y RNAs interact and colocalise with the origin recognition complex (ORC), the pre replication complex (pre-RC) protein Cdt1, and other proteins implicated in the initiation of DNA replication. These data support a molecular 'catch and release' mechanism for Y RNA function during the initiation of chromosomal DNA replication, which is consistent with Y RNAs acting as replication licensing factors. PMID- 21610091 TI - Actin behavior in bulk cytoplasm is cell cycle regulated in early vertebrate embryos. AB - The mechanical properties of cells change as they proceed through the cell cycle, primarily owing to regulation of actin and myosin II. Most models for cell mechanics focus on actomyosin in the cortex and ignore possible roles in bulk cytoplasm. We explored cell cycle regulation of bulk cytoplasmic actomyosin in Xenopus egg extracts, which is almost undiluted cytoplasm from unfertilized eggs. We observed dramatic gelation-contraction of actomyosin in mitotic (M phase) extract where Cdk1 activity is high, but not in interphase (I-phase) extract. In spread droplets, M-phase extract exhibited regular, periodic pulses of gelation contraction a few minutes apart that continued for many minutes. Comparing actin nucleation, disassembly and myosin II activity between M-phase and I-phase extracts, we conclude that regulation of nucleation is likely to be the most important for cell cycle regulation. We then imaged F-actin in early zebrafish blastomeres using a GFP-Utrophin probe. Polymerization in bulk cytoplasm around vesicles increased dramatically during mitosis, consistent with enhanced nucleation. We conclude that F-actin polymerization in bulk cytoplasm is cell cycle regulated in early vertebrate embryos and discuss possible biological functions of this regulation. PMID- 21610092 TI - Loss of keratins 8 and 18 leads to alterations in alpha6beta4-integrin-mediated signalling and decreased neoplastic progression in an oral-tumour-derived cell line. AB - Keratins 8 and 18 (K8 and K18) are predominantly expressed in simple epithelial tissues and perform both mechanical and regulatory functions. Aberrant expression of K8 and K18 is associated with neoplastic progression and invasion in squamous cell carcinomas (SCCs). To understand the molecular basis by which K8 promotes neoplastic progression in oral SCC (OSCC), K8 expression was inhibited in AW13516 cells. The K8-knockdown clones showed a significant reduction in tumorigenic potential, which was accompanied by a reduction in cell motility, cell invasion, decreased fascin levels, alterations in the organization of the actin cytoskeleton and changes in cell shape. Furthermore, K8 knockdown led to a decrease in alpha6beta4 integrin levels and alpha6beta4-integrin-dependent signalling events, which have been reported to play an important role in neoplastic progression in epithelial tissues. Therefore, modulation of alpha6beta4 integrin signalling might be one of the mechanisms by which K8 and K18 promote malignant transformation and/or progression in OSCCs. PMID- 21610094 TI - Essential role of PACSIN2/syndapin-II in caveolae membrane sculpting. AB - Caveolae are flask-shaped invaginations of the plasma membrane that are associated with tumor formation, pathogen entry and muscular dystrophy, through the regulation of lipids, signal transduction and endocytosis. Caveolae are generated by the fusion of caveolin-1-containing vesicles with the plasma membrane, which then participate in endocytosis via dynamin. Proteins containing membrane-sculpting F-BAR (or EFC) domains organize the membrane in clathrin mediated endocytosis. Here, we show that the F-BAR protein PACSIN2 sculpts the plasma membrane of the caveola. The PACSIN2 F-BAR domain interacts directly with caveolin-1 by unmasking autoinhibition of PACSIN2. Furthermore, the membrane invaginations induced by the PACSIN2 F-BAR domain contained caveolin-1. Knockdown of PACSIN2 resulted in abnormal morphology of caveolin-1-associated plasma membranes, presumably as a result of decreased recruitment of dynamin-2 to caveolin-1. These results indicate that PACSIN2 mediates membrane sculpting by caveolin-1 in caveola morphology and recruits dynamin-2 for caveola fission. PMID- 21610093 TI - PLD1 rather than PLD2 regulates phorbol-ester-, adhesion-dependent and Fc{gamma} receptor-stimulated ROS production in neutrophils. AB - The signalling lipid phosphatidic acid (PA) is generated by the hydrolysis of phosphatidylcholine (PC), which is catalysed by phospholipase D (PLD) enzymes. Neutrophils, important cells of the innate immune system, maintain the body's defence against infection. Previous studies have implicated PLD-generated PA in neutrophil function; these have relied heavily on the use of primary alcohols to act as inhibitors of PA production. The recent development of isoform-selective small molecule inhibitors and the generation of a knockout mouse model provide us with accurate tools to study the role of PLDs in neutrophil responses. We show that PLD1 is a regulator of phorbol-ester-, chemoattractant, adhesion-dependent and Fcgamma-receptor-stimulated production of reactive oxygen species (ROS) in neutrophils. Significantly we found that this role of PLD is isoform specific: the absence of PLD2 does not negatively affect these processes. Contrary to expectation, other functions required for an efficient immune response operate effectively in Pld2-deficient neutrophils or when both isoforms are inhibited pharmacologically. We conclude that although PLD1 does have important regulatory roles in neutrophils, the field has been confused by the use of primary alcohols; now that gold standard Pld-knockout mouse models are available, previous work might need to be reassessed. PMID- 21610095 TI - Phosphorylation of CSF-1R Y721 mediates its association with PI3K to regulate macrophage motility and enhancement of tumor cell invasion. AB - Colony stimulating factor-1 (CSF-1) regulates macrophage morphology and motility, as well as mononuclear phagocytic cell proliferation and differentiation. The CSF 1 receptor (CSF-1R) transduces these pleiotropic signals through autophosphorylation of eight intracellular tyrosine residues. We have used a novel bone-marrow-derived macrophage cell line system to examine specific signaling pathways activated by tyrosine-phosphorylated CSF-1R in macrophages. Screening of macrophages expressing a single species of CSF-1R with individual tyrosine-to-phenylalanine residue mutations revealed striking morphological alterations upon mutation of Y721. M-/-.Y721F cells were apolar and ruffled poorly in response to CSF-1. Y721-P-mediated CSF-1R signaling regulated adhesion and actin polymerization to control macrophage spreading and motility. Moreover, the reduced motility of M-/-.Y721F macrophages was associated with their reduced capacity to enhance carcinoma cell invasion. Y721 phosphorylation mediated the direct association of the p85 subunit of phosphoinositide 3-kinase (PI3K) with the CSF-1R, but not that of phospholipase C (PLC) gamma2, and induced polarized PtdIns(3,4,5)P3 production at the putative leading edge, implicating PI3K as a major regulator of CSF-1-induced macrophage motility. The Y721-P-motif-based motility signaling was at least partially independent of both Akt and increased Rac and Cdc42 activation but mediated the rapid and transient association of an unidentified ~170 kDa phosphorylated protein with either Rac-GTP or Cdc42-GTP. These studies identify CSF-1R-Y721-P-PI3K signaling as a major pathway in CSF-1 regulated macrophage motility and provide a starting point for the discovery of the immediate downstream signaling events. PMID- 21610096 TI - Stargazin-related protein gamma7 is associated with signalling endosomes in superior cervical ganglion neurons and modulates neurite outgrowth. AB - The role(s) of the newly discovered stargazin-like gamma-subunit proteins remains unclear; although they are now widely accepted to be transmembrane AMPA receptor regulatory proteins (TARPs), rather than Ca2+ channel subunits, it is possible that they have more general roles in trafficking within neurons. We previously found that gamma7 subunit is associated with vesicles when it is expressed in neurons and other cells. Here, we show that gamma7 is present mainly in retrogradely transported organelles in sympathetic neurons, where it colocalises with TrkA-YFP, and with the early endosome marker EEA1, suggesting that gamma7 localises to signalling endosomes. It was not found to colocalise with markers of the endoplasmic reticulum, mitochondria, lysosomes or late endosomes. Furthermore, knockdown of endogenous gamma7 by short hairpin RNA transfection into sympathetic neurons reduced neurite outgrowth. The same was true in the PC12 neuronal cell line, where neurite outgrowth was restored by overexpression of human gamma7. These findings open the possibility that gamma7 has an essential trafficking role in relation to neurite outgrowth as a component of endosomes involved in neurite extension and growth cone remodelling. PMID- 21610097 TI - Interplay between N-WASP and CK2 optimizes clathrin-mediated endocytosis of EGFR. AB - Clathrin-mediated endocytosis (CME) involves spatially and temporally restricted molecular dynamics, to which protein kinases and actin contribute. However, whether and how these two elements merge to properly execute CME remains unknown. Here, we show that neural Wiskott-Aldrich syndrome protein (N-WASP) and casein kinase 2 (CK2) form a complex and localize to clathrin-coated vesicles. N-WASP binds to and is phosphorylated by CK2, thereby reducing the kinase activity of CK2. By contrast, N-WASP-promoted actin polymerization is decreased upon both phosphorylation and binding of CK2. Knockdown of CK2 and N-WASP, either alone or in combination, causes a similar inhibition in the initial rate of CME of epidermal growth factor receptor (EGFR) and its accumulation at the plasma membrane. Increased levels of EGFR at the cell surface can only be efficiently rescued by reconstituting the N-WASP-CK2 complex with either wild-type or phosphorylation-mimicking N-WASP and wild-type CK2. Notably, perturbation of N WASP-CK2 complex function showed that N-WASP controls the presence of F-actin at clathrin-coated structures. In summary, the N-WASP-CK2 complex integrates in a single circuit different activities contributing to CME. PMID- 21610098 TI - HMGB-1 promotes fibrinolysis and reduces neurotoxicity mediated by tissue plasminogen activator. AB - Owing to its ability to generate the clot-dissolving protease plasmin, tissue plasminogen activator (tPA) is the only approved drug for the acute treatment of ischemic stroke. However, tPA also promotes hemorrhagic transformation and excitotoxic events. High mobility group box-1 protein (HMGB-1) is a non-histone transcription factor and a pro-inflammatory cytokine, which has also been shown to bind to both tPA and plasminogen. We thus investigated the cellular and molecular effects through which HMGB-1 could influence the vascular and parenchymal effects of tPA during ischemia. We demonstrate that HMGB-1 not only increases clot lysis by tPA, but also reduces the passage of vascular tPA across the blood-brain barrier, as well as tPA-driven leakage of the blood-brain barrier. In addition, HMGB-1 prevents the pro-neurotoxic effect of tPA, by blocking its interaction with N-methyl-D-aspartate (NMDA) receptors and the attendant potentiation of NMDA-induced neuronal Ca2+ influx. In conclusion, we show in vitro that HMGB-1 can promote the beneficial effects of tPA while counteracting its deleterious properties. We suggest that derivatives of HMGB-1, devoid of pro-inflammatory properties, could be used as adjunctive therapies to improve the overall benefit of tPA-mediated thrombolysis following stroke. PMID- 21610099 TI - A novel chemically directed route for the generation of definitive endoderm from human embryonic stem cells based on inhibition of GSK-3. AB - The use of small molecules to 'chemically direct' differentiation represents a powerful approach to promote specification of embryonic stem cells (ESCs) towards particular functional cell types for use in regenerative medicine and pharmaceutical applications. Here, we demonstrate a novel route for chemically directed differentiation of human ESCs (hESCs) into definitive endoderm (DE) exploiting a selective small-molecule inhibitor of glycogen synthase kinase 3 (GSK-3). This GSK-3 inhibitor, termed 1m, when used as the only supplement to a chemically defined feeder-free culture system, effectively promoted differentiation of ESC lines towards primitive streak (PS), mesoderm and DE. This contrasts with the role of GSK-3 in murine ESCs, where GSK-3 inhibition promotes pluripotency. Interestingly, 1m-mediated induction of differentiation involved transient NODAL expression and Nodal signalling. Prolonged treatment of hESCs with 1m resulted in the generation of a population of cells displaying hepatoblast characteristics, that is expressing alpha-fetoprotein and HNF4alpha. Furthermore, 1m-induced DE had the capacity to mature and generate hepatocyte like cells capable of producing albumin. These findings describe, for the first time, the utility of GSK-3 inhibition, in a chemically directed approach, to a method of DE generation that is robust, potentially scalable and applicable to different hESC lines. PMID- 21610100 TI - Alterations in glycopeptides associated with herceptin treatment of human breast carcinoma mcf-7 and T-lymphoblastoid cells. AB - The therapeutic humanized monoclonal antibody IgG1 known as Herceptin(r) has shown remarkable antitumor effects. Although this type of therapy has increased the cancer-free survival of patients, not all tumors respond to this treatment and cancers often develop resistance to the antibody. Despite the fact that Herceptin function has been extensively studied, the precise mechanism underlying its antitumor activity still remains incompletely defined. We previously demonstrated on human breast MCF-7 carcinoma and T-lymphoblastoid CEM cells that monoclonal antibody in combination with Lipoplex consisting of Lipofectamine mixed with plasmid DNA showed a more profound effect on cancer cell viability than antibody alone. The analyses of N-glycans isolated from cancer cells showed dramatic differences in profiles when cells were exposed to Herceptin. Moreover, the investigation of glycosylated peptides from the same cancer cell models after treatment revealed further alterations in the post-translational modifications. Tandem mass spectra obtained from the samples treated confirmed the presence of a series of glycopeptides bearing characteristic oligosaccharides as described in IgG1. However some of them differed by mass differences that corresponded to peptide backbones not described previously and more of them were detected from Herceptin treated samples than from cells transfected with Heceptin/Lipoplex. The results indicate that the presence of Lipoplex prevents antibody transformation and elongates its proper function. The better understanding of the multipart changes described in the glycoconjugates could provide new insights into the mechanism by which antibody induces regression in cancers. PMID- 21610101 TI - A membrane cell for on-line hydrogen/deuterium exchange to study protein folding and protein-protein interactions by mass spectrometry. AB - A membrane cell for hydrogen and deuterium exchange on-line with mass spectrometry has been developed to monitor protein-protein interactions and protein conformations. It consists of two channels separated by a semipermeable membrane, where one channel carries the protein sample and the other deuterium oxide. The membrane allows transfer of deuterium oxide into the sample flow. The labeling time is controlled via the flow rate in the sample channel. This cell was validated against three models commonly used in hydrogen-deuterium exchange mass spectrometry: monitoring of folded and unfolded states in a protein, mapping the protein secondary structure at the peptide level, and detection of protein and antibody interactions. The system avoids the conventionally used sample dilution and handling, allowing for potential automation. PMID- 21610102 TI - Comparative protein expression in different strains of the bloom-forming cyanobacterium Microcystis aeruginosa. AB - Toxin production in algal blooms presents a significant problem for the water industry. Of particular concern is microcystin, a potent hepatotoxin produced by the unicellular freshwater species Microcystis aeruginosa. In this study, the proteomes of six toxic and nontoxic strains of M. aeruginosa were analyzed to gain further knowledge in elucidating the role of microcystin production in this microorganism. This represents the first comparative proteomic study in a cyanobacterial species. A large diversity in the protein expression profiles of each strain was observed, with a significant proportion of the identified proteins appearing to be strain-specific. In total, 475 proteins were identified reproducibly and of these, 82 comprised the core proteome of M. aeruginosa. The expression of several hypothetical and unknown proteins, including four possible operons was confirmed. Surprisingly, no proteins were found to be produced only by toxic or nontoxic strains. Quantitative proteome analysis using the label-free normalized spectrum abundance factor approach revealed nine proteins that were differentially expressed between toxic and nontoxic strains. These proteins participate in carbon-nitrogen metabolism and redox balance maintenance and point to an involvement of the global nitrogen regulator NtcA in toxicity. In addition, the switching of a previously inactive toxin-producing strain to microcystin synthesis is reported. PMID- 21610103 TI - Trypanosoma brucei mitochondrial respiratome: composition and organization in procyclic form. AB - The mitochondrial respiratory chain is comprised of four different protein complexes (I-IV), which are responsible for electron transport and generation of proton gradient in the mitochondrial intermembrane space. This proton gradient is then used by F0F1-ATP synthase (complex V) to produce ATP by oxidative phosphorylation. In this study, the respiratory complexes I, II, and III were affinity purified from Trypanosoma brucei procyclic form cells and their composition was determined by mass spectrometry. The results along with those that we previously reported for complexes IV and V showed that the respiratome of Trypanosoma is divergent because many of its proteins are unique to this group of organisms. The studies also identified two mitochondrial subunit proteins of respiratory complex IV that are encoded by edited RNAs. Proteomics data from analyses of complexes purified using numerous tagged component proteins in each of the five complexes were used to generate the first predicted protein-protein interaction network of the Trypanosoma brucei respiratory chain. These results provide the first comprehensive insight into the unique composition of the respiratory complexes in Trypanosoma brucei, an early diverged eukaryotic pathogen. PMID- 21610104 TI - Quantitative shotgun proteomics using a uniform 15N-labeled standard to monitor proteome dynamics in time course experiments reveals new insights into the heat stress response of Chlamydomonas reinhardtii. AB - Crop-plant-yield safety is jeopardized by temperature stress caused by the global climate change. To take countermeasures by breeding and/or transgenic approaches it is essential to understand the mechanisms underlying plant acclimation to heat stress. To this end proteomics approaches are most promising, as acclimation is largely mediated by proteins. Accordingly, several proteomics studies, mainly based on two-dimensional gel-tandem MS approaches, were conducted in the past. However, results often were inconsistent, presumably attributable to artifacts inherent to the display of complex proteomes via two-dimensional-gels. We describe here a new approach to monitor proteome dynamics in time course experiments. This approach involves full 15N metabolic labeling and mass spectrometry based quantitative shotgun proteomics using a uniform 15N standard over all time points. It comprises a software framework, IOMIQS, that features batch job mediated automated peptide identification by four parallelized search engines, peptide quantification and data assembly for the processing of large numbers of samples. We have applied this approach to monitor proteome dynamics in a heat stress time course using the unicellular green alga Chlamydomonas reinhardtii as model system. We were able to identify 3433 Chlamydomonas proteins, of which 1116 were quantified in at least three of five time points of the time course. Statistical analyses revealed that levels of 38 proteins significantly increased, whereas levels of 206 proteins significantly decreased during heat stress. The increasing proteins comprise 25 (co-)chaperones and 13 proteins involved in chromatin remodeling, signal transduction, apoptosis, photosynthetic light reactions, and yet unknown functions. Proteins decreasing during heat stress were significantly enriched in functional categories that mediate carbon flux from CO2 and external acetate into protein biosynthesis, which also correlated with a rapid, but fully reversible cell cycle arrest after onset of stress. Our approach opens up new perspectives for plant systems biology and provides novel insights into plant stress acclimation. PMID- 21610105 TI - Unusual N-glycan structures required for trafficking Toxoplasma gondii GAP50 to the inner membrane complex regulate host cell entry through parasite motility. AB - Toxoplasma gondii motility, which is essential for host cell entry, migration through host tissues, and invasion, is a unique form of actin-dependent gliding. It is powered by a motor complex mainly composed of myosin heavy chain A, myosin light chain 1, gliding associated proteins GAP45, and GAP50, the only integral membrane anchor so far described. In the present study, we have combined glycomic and proteomic approaches to demonstrate that all three potential N-glycosylated sites of GAP50 are occupied by unusual N-glycan structures that are rarely found on mature mammalian glycoproteins. Using site-directed mutagenesis, we show that N-glycosylation is a prerequisite for GAP50 transport from the endoplasmic reticulum to the Golgi apparatus and for its subsequent delivery into the inner complex membrane. Assembly of key partners into the gliding complex, and parasite motility are severely impaired in the unglycosylated GAP50 mutants. Furthermore, comparative affinity purification using N-glycosylated and unglycosylated GAP50 as bait identified three novel hypothetical proteins including the recently described gliding associated protein GAP40, and we demonstrate that N-glycans are required for efficient binding to gliding partners. Collectively, these results provide the first detailed analyses of T. gondii N-glycosylation functions that are vital for parasite motility and host cell entry. PMID- 21610106 TI - Podoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progression. AB - During the metastatic process, cancer cells interact with vascular adventitial fibroblasts (VAF), which are the main components of the outermost connective tissue layer of blood vessels. This activity suggests the presence of a specific tumor microenvironment in the perivascular area. The s.c. coinjection of human lung adenocarcinoma cell lines (A549, PC-14, and CRL-5807) and human VAF (hVAF) resulted in a high rate of tumor formation, compared with the coinjection of these cell lines and human lung tissue-derived fibroblasts (hLF). A cDNA microarray analysis revealed a higher expression level of podoplanin in hVAFs than in hLFs (4.7-fold). Flow cytometry analysis also showed a higher expression level of podoplanin in hVAFs (43% +/- 17.5%) than in hLFs (16% +/- 10.3%). Sorted podoplanin-positive hVAFs displayed enhanced tumor formation, lymph node metastasis, and lung metastasis of A549 compared to sorted podoplanin-negative hVAFs. Knockdown of podoplanin in hVAFs decreased the augmenting effect of tumor formation and in vitro colony formation. The overexpression of podoplanin in hVAFs hastened the tumor formation of A549, compared with control hVAFs. Furthermore, the analysis of small-sized human lung adenocarcinoma (n = 112) revealed that patients with podoplanin-positive cancer-associated fibroblasts had a significantly higher rate of lymph node metastasis and a high risk of recurrence. These results indicate a promotive effect of hVAFs mediated by podoplanin on cancer progression and suggest that the perivascular environment may constitute a specific niche for tumor progression. PMID- 21610107 TI - Roles of sildenafil in enhancing drug sensitivity in cancer. AB - The phenomenon of multidrug resistance (MDR) has decreased the hope for successful cancer chemotherapy. The ATP-binding cassette (ABC) transporter superfamily is the largest transmembrane family. The overexpression of ABC transporters is a major determinant of MDR in cancer cells both in vitro and in vivo. Unfortunately, until recently, most of the strategies used to surmount ABC transporter-mediated MDR have had limited success. An ideal modulator of MDR would be one that has a low liability to induce toxicity and alter the pharmacokinetic profile of antineoplastic drugs. Sildenafil, an inhibitor of cGMP specific phosphodiesterase type 5, was found to significantly reverse ABC transporter-mediated MDR. Our results indicate that sildenafil has differential inhibitory effects on ABC transporters: It significantly decreases the efflux activity of ABCB1 and ABCG2, but has no significant effects on ABCC1. Emerging evidence indicates that sildenafil and other phosphodiesterase type 5 inhibitors may enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs. PMID- 21610108 TI - A multistage association study identifies a breast cancer genetic locus at NCOA7. AB - Estrogen metabolism and growth factor signaling pathway genes play key roles in breast cancer development. We evaluated associations between breast cancer and tagging single-nucleotide polymorphisms (SNP) of 107 candidate genes of these pathways using single allele- and haplotype-based tests. We first sought concordance of associations between two study populations: the Nashville Breast Cohort (NBC; 510 cases, 988 controls), and the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer study (1,145 cases, 1,142 controls). Findings across the two study populations were concordant at tagging SNPs of six genes, and at previously published SNPs of FGFR2. We sought further replication of results for EGFR, NCOA7, and FGFR2 in the independent Collaborative Breast Cancer Study (CBCS; 1,552 cases, 1,185 controls). Associations at NCOA7 and FGFR2 replicated across all three studies. The association at NCOA7 on 6q22.32, detected by a haplotype spanning the initial protein-coding exon (5'-rs9375411, rs11967627, rs549438, rs529858, rs490361, rs17708107-3'), has not been previously reported. The haplotype had a significant inverse association with breast cancer in each study [OR(Het): 0.69 (NBC), 0.76 (CGEMS), 0.79 (CBCS)], and a meta analysis OR(Het) of 0.75 (95% CI, 0.65-0.87, P = 1.4 * 10(-4)) in the combined study populations. The haplotype frequency was 0.07 among cases, and 0.09 among controls; homozygotes were infrequent and each OR(Hom) was not significant. NCOA7 encodes a nuclear receptor coactivator that interacts with estrogen receptor alpha to modulate its activity. These observations provide consistent evidence that genetic variants at the NCOA7 locus may confer a reduced risk of breast cancer. PMID- 21610109 TI - Evolved tumor suppression: why are we so good at not getting cancer? AB - The law of natural selection can be used to understand cancer development at the level of species as well as at the level of cells and tissues. Through this perspective, I seek to explain: (i) Why the lack of sufficient selective pressure to prevent cancers in old age helps explain the exponential increase in cancer incidence in the elderly. (ii) Why the evolution of long-lived animals necessitated the acquisition of potent tumor suppressive mechanisms. (iii) How the requirement to prevent inappropriate somatic cell expansion and cancer has constrained developmental and tissue architectural modalities. (iv) How the evolution of well-adapted stem cells with complex niche requirements has conferred resistance to oncogenic mutations, as phenotype-altering genetic change is almost always disadvantageous within a well-adapted cell population. (v) How the impairment of stem cell fitness, as occurs in old age, can promote selection for adaptive mutations and cancer initiation. (vi) Why differential maintenance of stem cell fitness may explain how different vertebrate species with enormous differences in life span and body size similarly avoid cancer through reproductive years. PMID- 21610110 TI - Physical activity after diagnosis and risk of prostate cancer progression: data from the cancer of the prostate strategic urologic research endeavor. AB - Vigorous activity after diagnosis was recently reported to be inversely associated with prostate cancer-specific mortality. However, men with metastatic disease may decrease their activity due to their disease; thus, a causal interpretation is uncertain. We therefore prospectively examined vigorous activity and brisk walking after diagnosis in relation to risk of prostate cancer progression, an outcome less susceptible to reverse causation, among 1,455 men diagnosed with clinically localized prostate cancer. Cox proportional hazards regression was used to examine vigorous activity, nonvigorous activity, walking duration, and walking pace after diagnosis and risk of prostate cancer progression. We observed 117 events (45 biochemical recurrences, 66 secondary treatments, 3 bone metastases, 3 prostate cancer deaths) during 2,750 person years. Walking accounted for nearly half of all activity. Men who walked briskly for 3 h/wk or more had a 57% lower rate of progression than men who walked at an easy pace for less than 3 h/wk (HR = 0.43; 95% CI: 0.21-0.91; P = 0.03). Walking pace was associated with decreased risk of progression independent of duration (HR brisk vs. easy pace = 0.52; 95% CI: 0.29-0.91; P(trend) = 0.01). Few men engaged in vigorous activity, but there was a suggestive inverse association (HR >=3 h/wk vs. none = 0.63; 95% CI: 0.32-1.23; P(trend) = 0.17). Walking duration and total nonvigorous activity were not associated with risk of progression independent of pace or vigorous activity, respectively. Brisk walking after diagnosis may inhibit or delay prostate cancer progression among men diagnosed with clinically localized prostate cancer. PMID- 21610111 TI - Epithelial cell organization suppresses Myc function by attenuating Myc expression. AB - c-Myc is an oncogene transcription factor that causes cancer in many settings, including solid tumors that arise in the context of organized tissue structures. Given that disruption of tissue architecture frequently occurs in cancer, there is considerable interest in how cell organization impacts oncogene function. A previous report found that organization of mammary epithelial cells into defined 3-dimensional structures renders them insensitive to the effects of retrovirus mediated overexpression of Myc, leading to the notion that organization tempers the sensitivity of individual cells to Myc activity. In this article, we report that epithelial cell organization does not profoundly alter Myc activity but, instead, suppresses Myc by modulating its expression. We show that the morphogenesis of mammary epithelial cells into organized acinar structures in vitro is accompanied by widespread changes in gene expression patterns, including a substantial decrease in the expression of Myc. Concomitant with the decrease in endogenous Myc expression, we observe a decrease in transcription from retroviral vectors during morphogenesis and find that Myc transgene expression in acini is much lower than in unorganized cells. This decrease in Myc transgene activity is responsible for the apparent recalcitrance of organized cells to ectopic Myc, as adenovirus-mediated expression of Myc in organized structures potently induces apoptosis. These observations reveal that organization does not alter the inherent response of epithelial cells to Myc and suggest that other tumor suppression mechanisms, apart from structure, antagonize Myc in the development of solid tumors. PMID- 21610112 TI - 6-Bromoindirubin-3'-oxime inhibits JAK/STAT3 signaling and induces apoptosis of human melanoma cells. AB - STAT3 is persistently activated and contributes to malignant progression in various cancers. Janus activated kinases (JAK) phosphorylate STAT3 in response to stimulation by cytokines or growth factors. The STAT3 signaling pathway has been validated as a promising target for development of anticancer therapeutics. Small molecule inhibitors of JAK/STAT3 signaling represent potential molecular-targeted cancer therapeutic agents. In this study, we investigated the role of JAK/STAT3 signaling in 6-bromoindirubin-3'-oxime (6BIO)-mediated growth inhibition of human melanoma cells and assessed 6BIO as a potential anticancer drug candidate. We found that 6BIO is a pan-JAK inhibitor that induces apoptosis of human melanoma cells. 6BIO directly inhibited JAK-family kinase activity, both in vitro and in cancer cells. Apoptosis of human melanoma cells induced by 6BIO was associated with reduced phosphorylation of JAKs and STAT3 in both dose- and time-dependent manners. Consistent with inhibition of STAT3 signaling, expression of the antiapoptotic protein Mcl-1 was downregulated. In contrast to the decreased levels of phosphorylation of JAKs and STAT3, phosphorylation levels of the Akt and mitogen-activated protein kinase (MAPK) signaling proteins were not inhibited in cells treated with 6BIO. Importantly, 6BIO suppressed tumor growth in vivo with low toxicity in a mouse xenograft model of melanoma. Taken together, these results show that 6BIO is a novel pan-JAK inhibitor that can selectively inhibit STAT3 signaling and induces tumor cell apoptosis. Our findings support further development of 6BIO as a potential anticancer therapeutic agent that targets JAK/STAT3 signaling in tumor cells. PMID- 21610113 TI - Using the 'surprise question' can identify people with advanced heart failure and COPD who would benefit from a palliative care approach. PMID- 21610114 TI - Radbruch L and Nauck F. How should I know? Researching attitudes and practices around hastening death. Palliat Med 2010; 24: 751-752. PMID- 21610115 TI - Shotgun lipidomics on high resolution mass spectrometers. AB - Despite their compositional complexity, lipidomes comprise a large number of isobaric species that cannot be distinguished by conventional low resolution mass spectrometry and therefore in-depth MS/MS analysis was required for their accurate quantification. Here we argue that the progress in high resolution mass spectrometry is changing the concept of lipidome characterization. Because exact masses of isobaric species belonging to different lipid classes are not necessarily identical, they can now be distinguished and directly quantified in total lipid extracts. By streamlining and simplifying the molecular characterization of lipidomes, high resolution mass spectrometry has developed into a generic tool for cell biology and molecular medicine. PMID- 21610116 TI - Model answers to lipid membrane questions. AB - Ever since it was discovered that biological membranes have a core of a bimolecular sheet of lipid molecules, lipid bilayers have been a model laboratory for investigating physicochemical and functional properties of biological membranes. Experimental and theoretical models help the experimental scientist to plan experiments and interpret data. Theoretical models are the theoretical scientist's preferred toys to make contact between membrane theory and experiments. Most importantly, models serve to shape our intuition about which membrane questions are the more fundamental and relevant ones to pursue. Here we review some membrane models for lipid self-assembly, monolayers, bilayers, liposomes, and lipid-protein interactions and illustrate how such models can help answering questions in modern lipid cell biology. PMID- 21610117 TI - Location of gliomas in relation to mobile telephone use: a case-case and case specular analysis. AB - The energy absorbed from the radio-frequency fields of mobile telephones depends strongly on distance from the source. The authors' objective in this study was to evaluate whether gliomas occur preferentially in the areas of the brain having the highest radio-frequency exposure. The authors used 2 approaches: In a case case analysis, tumor locations were compared with varying exposure levels; in a case-specular analysis, a hypothetical reference location was assigned for each glioma, and the distances from the actual and specular locations to the handset were compared. The study included 888 gliomas from 7 European countries (2000 2004), with tumor midpoints defined on a 3-dimensional grid based on radiologic images. The case-case analyses were carried out using unconditional logistic regression, whereas in the case-specular analysis, conditional logistic regression was used. In the case-case analyses, tumors were located closest to the source of exposure among never-regular and contralateral users, but not statistically significantly. In the case-specular analysis, the mean distances between exposure source and location were similar for cases and speculars. These results do not suggest that gliomas in mobile phone users are preferentially located in the parts of the brain with the highest radio-frequency fields from mobile phones. PMID- 21610119 TI - Diversion of the immune response to Neisseria gonorrhoeae from Th17 to Th1/Th2 by treatment with anti-transforming growth factor beta antibody generates immunological memory and protective immunity. AB - The immune response to Neisseria gonorrhoeae is poorly understood, but its extensive antigenic variability and resistance to complement are thought to allow it to evade destruction by the host's immune defenses. We propose that N. gonorrhoeae also avoids inducing protective immune responses in the first place. We previously found that N. gonorrhoeae induces interleukin-17 (IL-17)-dependent innate responses in mice and suppresses Th1/Th2-dependent adaptive responses in murine cells in vitro through the induction of transforming growth factor beta (TGF-beta). In this study using a murine model of vaginal gonococcal infection, mice treated with anti-TGF-beta antibody during primary infection showed accelerated clearance of N. gonorrhoeae, with incipient development of Th1 and Th2 responses and diminished Th17 responses in genital tract tissue. Upon secondary reinfection, mice that had been treated with anti-TGF-beta during primary infection showed anamnestic recall of both Th1 and Th2 responses, with the development of antigonococcal antibodies in sera and secretions, and enhanced resistance to reinfection. In mouse knockout strains defective in Th1 or Th2 responses, accelerated clearance of primary infection due to anti-TGF-beta treatment was dependent on Th1 activity but not Th2 activity, whereas resistance to secondary infection resulting from anti-TGF-beta treatment during primary infection was due to both Th1- and Th2-dependent memory responses. We propose that N. gonorrhoeae proactively elicits Th17-driven innate responses that it can resist and concomitantly suppresses Th1/Th2-driven specific adaptive immunity that would protect the host. Blockade of TGF-beta reverses this pattern of host immune responsiveness and facilitates the emergence of protective antigonococcal immunity. IMPORTANCE: Pathogen-host interactions during infectious disease are conventionally thought of as two-way reactions, that of the host against the pathogen and vice versa, with the outcome dependent on which one ultimately prevails. We propose that Neisseria gonorrhoeae, a pathogen that has become extremely well adapted to its exclusive human host, proactively directs the manner in which the host responds in ways that are beneficial to its own survival but detrimental to the host. Gonorrhea is a widely prevalent sexually transmitted infection, and naturally occurring gonococcal strains are becoming resistant to most available antibiotics, yet no effective vaccine has been developed. These new insights into the immune response to N. gonorrhoeae should lead to novel therapeutic strategies and facilitate new approaches to vaccine development. PMID- 21610120 TI - Streptococcus pneumoniae is desiccation tolerant and infectious upon rehydration. AB - Streptococcus pneumoniae (pneumococcus) is a frequent colonizer of the nasopharynx and one of the leading causative agents of otitis media, pneumonia, and meningitis. The current literature asserts that S. pneumoniae is transmitted person to person via respiratory droplets; however, environmental surfaces (fomites) have been linked to the spread of other respiratory pathogens. Desiccation tolerance has been to shown to be essential for long-term survival on dry surfaces. This study investigated the survival and infectivity of S. pneumoniae following desiccation under ambient conditions. We recovered viable bacteria after all desiccation periods tested, ranging from 1 h to 4 weeks. Experiments conducted under nutrient limitation indicate that desiccation is a condition separate from starvation. Desiccation of an acapsular mutant and 15 different clinical isolates shows that S. pneumoniae desiccation tolerance is independent of the polysaccharide capsule and is a species-wide phenomenon, respectively. Experiments demonstrating that nondesiccated and desiccated S. pneumoniae strains colonize the nasopharynx at comparable levels, combined with their ability to survive long-term desiccation, suggest that fomites may serve as alternate sources of pneumococcal infection. IMPORTANCE: Even with the advent of multivalent capsular polysaccharide conjugate vaccines, S. pneumoniae continues to be a major cause of morbidity and mortality worldwide. Every year, there are approximately 7 million cases of pneumococcus-based otitis media in the United States alone, while pneumococcal invasive diseases are responsible for more than 1 million deaths globally. It is believed that the human upper respiratory tract is the sole niche of S. pneumoniae and, thus, that spread occurs via close contact with an infected individual. In this study, we characterized the desiccation tolerance of S. pneumoniae and found that it can survive for many weeks postdehydration and retain infectivity. Our results suggest that desiccation tolerance is an inherent trait of this genetically variable species and that fomites may be a source of transmission. PMID- 21610121 TI - Transient suppression of Shigella flexneri type 3 secretion by a protective O antigen-specific monoclonal IgA. AB - Mucosal immunity to the enteric pathogen Shigella flexneri is mediated by secretory IgA (S-IgA) antibodies directed against the O-antigen (O-Ag) side chain of lipopolysaccharide. While secretory antibodies against the O-Ag are known to prevent bacterial invasion of the intestinal epithelium, the mechanisms by which this occurs are not fully understood. In this study, we report that the binding of a murine monoclonal IgA (IgAC5) to the O-Ag of S. flexneri serotype 5a suppresses activity of the type 3 secretion (T3S) system, which is necessary for S. flexneri to gain entry into intestinal epithelial cells. IgAC5's effects on the T3S were rapid (5 to 15 min) and were coincident with a partial reduction in the bacterial membrane potential and a decrease in intracellular ATP levels. Activity of the T3S system returned to normal levels 45 to 90 min following antibody treatment, demonstrating that IgAC5's effects were transient. Nonetheless, these data suggest a model in which the association of IgA with the O-Ag of S. flexneri partially de-energizes the T3S system and temporarily renders the bacterium incapable of invading intestinal epithelial cells. IMPORTANCE: Secretory IgA (S-IgA) serves as the first line of defense against enteric infections. However, despite its well-recognized role in mucosal immunity, relatively little is known at the molecular level about how this class of antibody functions to prevent pathogenic bacteria from penetrating the epithelial barrier. It is generally assumed that S-IgA functions primarily by "immune exclusion," a phenomenon in which the antibody binds to microbial surface antigens and thereby promotes bacterial agglutination, entrapment in mucus, and physical clearance from the gastrointestinal tract via peristalsis. The results of the present study suggest that in addition to serving as a physical barrier, S IgA may have a direct impact on the ability of microbial pathogens to secrete virulence factors required for invasion of intestinal epithelial cells. PMID- 21610122 TI - HIV-1 Vpu blocks recycling and biosynthetic transport of the intrinsic immunity factor CD317/tetherin to overcome the virion release restriction. AB - The intrinsic immunity factor CD317 (BST-2/HM1.24/tetherin) imposes a barrier to HIV-1 release at the cell surface that can be overcome by the viral protein Vpu. Expression of Vpu results in a reduction of CD317 surface levels; however, the mechanism of this Vpu activity and its contribution to the virological antagonism are incompletely understood. Here, we characterized the influence of Vpu on major CD317 trafficking pathways using quantitative antibody-based endocytosis and recycling assays as well as a microinjection/microscopy-based kinetic de novo expression approach. We report that HIV-1 Vpu inhibited both the anterograde transport of newly synthesized CD317 and the recycling of CD317 to the cell surface, while the kinetics of CD317 endocytosis remained unaffected. Vpu trapped trafficking CD317 molecules at the trans-Golgi network, where the two molecules colocalized. The subversion of both CD317 transport pathways was dependent on the highly conserved diserine S52/S56 motif of Vpu; however, it did not require recruitment of the diserine motif interactor and substrate adaptor of the SCF-E3 ubiquitin ligase complex, beta-TrCP. Treatment of cells with the malaria drug primaquine resulted in a CD317 trafficking defect that mirrored that induced by Vpu. Importantly, primaquine could functionally replace Vpu as a CD317 antagonist and rescue HIV-1 particle release. IMPORTANCE: HIV efficiently replicates in the human host and induces the life-threatening immunodeficiency AIDS. Mammalian genomes encode proteins such as CD317 that can inhibit viral replication at the cellular level. As a countermeasure, HIV has evolved genes like vpu that can antagonize these intrinsic immunity factors. Investigating the mechanism by which Vpu overcomes the virion release restriction imposed by CD317, we find that Vpu subverts recycling and anterograde trafficking pathways of CD317, resulting in surface levels of the restriction factor insufficient to block HIV-1 spread. This describes a novel mechanism of immune evasion by HIV. PMID- 21610123 TI - Effect of diacerein on insulin secretion and metabolic control in drug-naive patients with type 2 diabetes: a randomized clinical trial. AB - OBJECTIVE: To assess the effect of diacerein on insulin secretion and metabolic control in drug-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled clinical trial was carried out in 40 drug-naive adult patients with type 2 diabetes. A metabolic profile including interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6, and fasting insulin levels was carried out before the intervention and 2 months afterward. A hyperglycemic-hyperinsulinemic clamp technique was performed to assess the phases of insulin secretion and insulin sensitivity. After randomization, 20 patients received diacerein (50 mg once daily) for the first 15 days and twice daily for 45 additional days. The remaining patients received placebo. Intra- and intergroup differences were calculated by Wilcoxon signed rank and Mann-Whitney U tests. RESULTS: There were significant increases in first (102+/-63 vs. 130+/-75 pmol/L; P<0.01), late (219+/-111 vs. 280+/-135 pmol/L; P<0.01), and total insulin (178+/-91 vs. 216+/-99 pmol/L; P<0.01) secretions without changes in insulin sensitivity after diacerein administration. There were significant decreases in fasting glucose (7.9+/-1.4 vs. 6.8+/-1.0 mmol/L; P<0.01) and in A1C levels (8.3+/ 1.0 vs. 7.0+/-0.8%; P<0.001) after diacerein administration. There were no significant changes after placebo administration in the above-mentioned evaluations. CONCLUSIONS: Insulin secretion increased and metabolic control improved after diacerein administration in drug-naive patients with type 2 diabetes. PMID- 21610125 TI - Evaluation and optimization of therapeutic footwear for neuropathic diabetic foot patients using in-shoe plantar pressure analysis. AB - OBJECTIVE: Therapeutic footwear for diabetic foot patients aims to reduce the risk of ulceration by relieving mechanical pressure on the foot. However, footwear efficacy is generally not assessed in clinical practice. The purpose of this study was to assess the value of in-shoe plantar pressure analysis to evaluate and optimize the pressure-reducing effects of diabetic therapeutic footwear. RESEARCH DESIGN AND METHODS: Dynamic in-shoe plantar pressure distribution was measured in 23 neuropathic diabetic foot patients wearing fully customized footwear. Regions of interest (with peak pressure>200 kPa) were selected and targeted for pressure optimization by modifying the shoe or insole. After each of a maximum of three rounds of modifications, the effect on in-shoe plantar pressure was measured. Successful optimization was achieved with a peak pressure reduction of >25% (criterion A) or below an absolute level of 200 kPa (criterion B). RESULTS: In 35 defined regions, mean peak pressure was significantly reduced from 303 (SD 77) to 208 (46) kPa after an average 1.6 rounds of footwear modifications (P<0.001). This result constitutes a 30.2% pressure relief (range 18-50% across regions). All regions were successfully optimized: 16 according to criterion A, 7 to criterion B, and 12 to criterion A and B. Footwear optimization lasted on average 53 min. CONCLUSIONS: These findings suggest that in-shoe plantar pressure analysis is an effective and efficient tool to evaluate and guide footwear modifications that significantly reduce pressure in the neuropathic diabetic foot. This result provides an objective approach to instantly improve footwear quality, which should reduce the risk for pressure-related plantar foot ulcers. PMID- 21610124 TI - Long-term outcome of individuals treated with oral insulin: diabetes prevention trial-type 1 (DPT-1) oral insulin trial. AB - OBJECTIVE: To evaluate the long-term intervention effects of oral insulin on the development of type 1 diabetes and to assess the rate of progression to type 1 diabetes before and after oral insulin treatment was stopped in the Diabetes Prevention Trial-Type 1 (DPT-1). RESEARCH DESIGN AND METHODS: The follow-up included subjects who participated in the early intervention of oral insulin (1994-2003) to prevent or delay type 1 diabetes. A telephone survey was conducted in 2009 to determine whether diabetes had been diagnosed and, if not, an oral glucose tolerance test (OGTT), hemoglobin A1c (HbA1c), and autoantibody levels were obtained on all subjects who agreed to participate. RESULTS: Of 372 subjects randomized, 97 developed type 1 diabetes before follow-up; 75% of the remaining 275 subjects were contacted. In the interim, 77 subjects had been diagnosed with type 1 diabetes and 54 of the remainder have had an OGTT; 10 of these were diagnosed with type 1 diabetes, subsequently. Among individuals meeting the original criteria for insulin autoantibodies (IAAs) (>=80 nU/mL), the overall benefit of oral insulin remained significant (P=0.05). However, the hazard rate in this group increased (from 6.4% [95% CI 4.5-9.1] to 10.0% [7.1-14.1]) after cessation of therapy, which approximated the rate of individuals treated with placebo (10.2% [7.1-14.6]). CONCLUSIONS: Overall, the oral insulin treatment effect in individuals with confirmed IAA>=80 nU/mL appeared to be maintained with additional follow-up; however, once therapy stopped, the rate of developing diabetes in the oral insulin group increased to a rate similar to that in the placebo group. PMID- 21610126 TI - Impact of glycemic and blood pressure variability on surrogate measures of cardiovascular outcomes in type 2 diabetic patients. AB - OBJECTIVE: The effect of glycemic variability (GV) on cardiovascular risk has not been fully clarified in type 2 diabetes. We evaluated the effect of GV, blood pressure (BP), and oxidative stress on intima-media thickness (IMT), left ventricular mass index (LVMI), flow-mediated dilation (FMD), and sympathovagal balance (low frequency [LF]/high frequency [HF] ratio) in 26 type 2 diabetic patients (diabetes duration 4.41+/-4.81 years; HbA1c 6.70+/-1.25%) receiving diet and/or metformin treatment, with no hypotensive treatment or complications. RESEARCH DESIGN AND METHODS: Continuous glucose monitoring (CGM) data were used to calculate mean amplitude of glycemic excursion (MAGE), continuous overall net glycemic action (CONGA)-2, mean blood glucose (MBG), mean postprandial glucose excursion (MPPGE), and incremental area under the curve (IAUC). Blood pressure (BP), circadian rhythm, and urinary 15-F2t-isoprostane (8-iso-prostaglandin F2alpha [PGF2alpha]) were also evaluated. Subjects were divided into dipper (D) and nondipper (ND) groups according to DeltaBP. RESULTS: IMT and LVMI were increased in ND versus D (0.77+/-0.08 vs. 0.68+/-0.13 [P=0.04] and 67+/-14 vs. 55+/-11 [P=0.03], respectively). MBG, MAGE, and IAUC were significantly associated with LF/HF ratio at night (r=0.50, P=0.01; r=0.40, P=0.04; r=0.41, P=0.04, respectively), MPPGE was negatively associated with FMD (r=-0.45, P=0.02), and CONGA-2 was positively associated with LVMI (r=0.55, P=0.006). The Deltasystolic BP was negatively associated with IMT (r=-0.43, P=0.03) and with LVMI (r=-0.52, P=0.01). Urinary 8-iso-PGF2alpha was positively associated with LVMI (r=0.68 P<0.001). CONCLUSIONS: An impaired GV and BP variability is associated with endothelial and cardiovascular damage in short-term diabetic patients with optimal metabolic control. Oxidative stress is the only independent predictor of increased LV mass and correlates with glucose and BP variability. PMID- 21610127 TI - Application of the fluorescent probe 1-anilinonaphthalene-8-sulfonate to the measurement of the nonspecific binding of drugs to human liver microsomes. AB - The fluorescence of 1-anilinonaphthalene-8-sulfonate (ANS) in the presence of human liver microsomes (HLMs) is altered by drugs that bind nonspecifically to the lipid bilayer. The present study characterized the relationship between the nonspecific binding (NSB) of drugs to HLMs as measured by equilibrium dialysis and the magnitude of the change in baseline ANS fluorescence. Fraction unbound in incubations of HLMs (f(u(mic))) was determined for 16 drugs (12 bases, 3 acids, and 1 neutral) with log P values in the range 0.1 to 6.7 at three concentrations (100, 200, and 500 MUM). Changes in ANS fluorescence induced by each of the drugs in the presence of HLMs were measured by spectrofluorometry. Values of f(u(mic)) determined by equilibrium dialysis ranged from 0.08 to 1.0. Although NSB of the basic drugs tended to increase with increasing log P, exceptions occurred. Basic drugs generally caused an increase in ANS fluorescence, whereas the acidic and neutral drugs resulted in a decrease in ANS fluorescence. There were highly significant (p < 0.001) linear relationships between the modulus (absolute value) of the increment/decrement in ANS fluorescence and both f(u(mic)) (r = 0.90 to 0.96) and log(1 - f(u(mic))/f(u(mic))) (r = 0.85 to 0.92) at the three drug concentrations. Agreement between measured f(u(mic)) and that predicted by ANS fluorescence was very good (<10% variance) for a validation set of six compounds. The ANS fluorescence method provides an accurate measure of the NSB of drugs to HLMs. Physicochemical determinants other than log P and charge type influence the NSB of drugs to HLMs. PMID- 21610128 TI - Monoclonal antibodies with identical Fc sequences can bind to FcRn differentially with pharmacokinetic consequences. AB - The neonatal Fc receptor (FcRn) is a key determinant of IgG homeostasis. It binds to the Fc domain of IgG in a strictly pH-dependent manner and protects IgG from lysosomal degradation. The impact of FcRn salvage pathway on IgG monoclonal antibody (mAb) pharmacokinetics (PK) has been well established. In this report, a set of mAbs with wild-type human Fc sequences but different Fab domains were used to examine the potential impact of Fab domain on in vitro FcRn binding and in vivo PK. We were surprised to find that mAbs with the same wild-type human Fc sequences but different Fab domains were shown to bind FcRn with considerable differences in both the binding at acidic pH and the dissociation at neutral pH, suggesting that the Fab domain may also have an impact on FcRn interaction. For these mAbs, no relationship between the FcRn binding affinity at acidic pH and in vivo PK was found. Instead, an apparent correlation between the in vitro FcRn dissociation at neutral pH and the in vivo PK in human FcRn mice, nonhuman primates and humans was observed. Our results suggested that the Fab domain of mAbs can affect their interaction with FcRn and thus their pharmacokinetic properties and that in vitro FcRn binding/dissociation assays can be a useful screening tool for pharmacokinetic assessment of mAbs with wild-type Fc sequences. PMID- 21610129 TI - Cars, carbon and change. PMID- 21610130 TI - Are cars the new tobacco? AB - BACKGROUND: Public health must continually respond to new threats reflecting wider societal changes. Ecological public health recognizes the links between human health and global sustainability. We argue that these links are typified by the harms caused by dependence on private cars. METHODS: We present routine data and literature on the health impacts of private car use; the activities of the 'car lobby' and factors underpinning car dependence. We compare these with experience of tobacco. RESULTS: Private cars cause significant health harm. The impacts include physical inactivity, obesity, death and injury from crashes, cardio-respiratory disease from air pollution, noise, community severance and climate change. The car lobby resists measures that would restrict car use, using tactics similar to the tobacco industry. Decisions about location and design of neighbourhoods have created environments that reinforce and reflect car dependence. Car ownership and use has greatly increased in recent decades and there is little public support for measures that would reduce this. CONCLUSIONS: Car dependence is a potent example of an issue that ecological public health should address. The public health community should advocate strongly for effective policies that reduce car use and increase active travel. PMID- 21610131 TI - Why petrol tanks and stomachs are competing to be filled. PMID- 21610132 TI - Healthy lives, healthy transport. PMID- 21610133 TI - Cars: beating a new addiction. PMID- 21610134 TI - Reviewing interventions delivered to whole communities: learnings and recommendations for application to policy, practice and evidence development. PMID- 21610135 TI - NICE public health guidance update. PMID- 21610137 TI - Expression of concern. PMID- 21610138 TI - Central excitability contributes to supramaximal volitional contractions in human incomplete spinal cord injury. AB - Despite greater muscle fatigue in individuals with spinal cord injury (SCI) when compared to neurologically intact subjects using neuromuscular electrical stimulation (NMES)protocols, few studies have investigated the extent of volitional fatigue in motor incomplete SCI. Using an established protocol of 20 repeated, intermittent, maximal volitional effort (MVE) contractions, we previously demonstrated that subjects with incomplete SCI unexpectedly demonstrated a 15% increase in peak knee extensor torques within the first five MVEs with minimal evidence of fatigue after 20 contraction. In the present study, we investigated potential segmental mechanisms underlying this supramaximal torque generation. Changes in twitch properties and maximum compound muscle action potentials (M-waves) were assessed prior to and following one, three and five MVEs, revealing a significant 17% increase only in maximum twitch torques after a single MVE. Despite this post-activation potentiation of the muscle, use of conventional NMES protocols to elicit repeated muscular contractions resulted in a significant decrease in evoked torque generation, suggesting limited the muscular contributions to the observed phenomenon. To evaluate potential central mechanisms underlying the augmented torques, non-linear responses to wide-pulse width (1 ms), low-intensity, variable-frequency (25-100 Hz) NMES were also tested prior to and following repeated MVEs.When variable-frequency NMES was applied following the repeated MVEs, augmented and prolonged torques were observed and accompanied by sustained quadriceps electromyographic activity often lasting > 2s after stimulus termination. Such data suggest a potential contribution of elevated spinal excitability to the reserve in volitional force generation in incomplete SCI. PMID- 21610140 TI - Therapeutic effect of nicotine in a mouse model of intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) resulting from the leakage of blood into the brain parenchyma triggers severe tissue damage involving neurodegeneration and inflammation. Increasing lines of evidence indicate that the stimulation of central nicotinic acetylcholine receptors affords neuroprotection against various insults and also suppresses the proinflammatory activation of microglia. Therefore, the present study aimed to determine whether the administration of nicotine modifies the pathological consequences of ICH, using a mouse model of ICH induced by intrastriatal injection of collagenase. Daily intraperitoneal administration of nicotine (2 mg/kg), starting from 3 h after the induction of ICH, inhibited apoptosis and decreased the number of remaining striatal neurons at 3 days after the insult. We also found that nicotine administration increased the relative expression level of the antiapoptotic protein B cell lymphoma-2 versus that of the proapoptotic protein Bax in the brain. In addition, nicotine administration attenuated the activation of microglia/macrophages, infiltration of neutrophils, and increases in oxidative stress associated with ICH, without affecting hematoma expansion and brain edema. It is noteworthy that mice treated with nicotine exhibited improved sensorimotor performance and a marked increase in survival rate after ICH. These results indicate that nicotinic acetylcholine receptors may serve as a novel target for emergency therapy for ICH. PMID- 21610139 TI - Central efferent pathways for cold-defensive and febrile shivering. AB - Shivering is a remarkable somatomotor thermogenic response that is controlled by brain mechanisms. We recorded EMGs in anaesthetized rats to elucidate the central neural circuitry for shivering and identified several brain regions whose thermoregulatory neurons comprise the efferent pathway driving shivering responses to skin cooling and pyrogenic stimulation. We simultaneously monitored parameters from sympathetic effectors: brown adipose tissue (BAT) temperature for non-shivering thermogenesis and arterial pressure and heart rate for cardiovascular responses. Acute skin cooling consistently increased EMG, BAT temperature and heart rate and these responses were eliminated by inhibition of neurons in the median preoptic nucleus (MnPO) with nanoinjection of muscimol. Stimulation of the MnPO evoked shivering, BAT thermogenesis and tachycardia, which were all reversed by antagonizing GABA(A) receptors in the medial preoptic area (MPO). Inhibition of neurons in the dorsomedial hypothalamus (DMH) or rostral raphe pallidus nucleus (rRPa) with muscimol or activation of 5-HT1A receptors in the rRPa with 8-OH-DPAT eliminated the shivering, BAT thermogenic, tachycardic and pressor responses evoked by skin cooling or by nanoinjection of prostaglandin (PG) E2, a pyrogenic mediator, into the MPO. These data are summarized with a schematic model in which the shivering as well as the sympathetic responses for cold defence and fever are driven by descending excitatory signalling through the DMH and the rRPa, which is under a tonic inhibitory control from a local circuit in the preoptic area. These results provide the interesting notion that, under the demand for increasing levels of heat production, parallel central efferent pathways control the somatic and sympathetic motor systems to drive thermogenesis. PMID- 21610141 TI - Synergistic effects of p38 mitogen-activated protein kinase inhibition with a corticosteroid in alveolar macrophages from patients with chronic obstructive pulmonary disease. AB - Corticosteroids partially suppress cytokine production by chronic obstructive pulmonary disease (COPD) alveolar macrophages. p38 mitogen-activated protein kinase (MAPK) inhibitors are a novel class of anti-inflammatory drug. We have studied the effects of combined treatment with a corticosteroid and a p38 MAPK inhibitor on cytokine production by COPD alveolar macrophages, with the aim of investigating dose-sparing and efficacy-enhancing effects. Alveolar macrophages from 10 patients with COPD, six smokers, and six nonsmokers were stimulated with lipopolysaccharide (LPS) after preincubation with five concentrations of dexamethasone alone, five concentrations of the p38 MAPK inhibitor 1-(5-tert butyl-2-p-tolyl-2H-pyrazol-3-yl)-3(4-(2-morpholin-4-yl-ethoxy)naphthalen-1 yl)urea (BIRB-796) alone, and all combinations of these concentrations. After 24 h, the supernatants were analyzed for interleukin (IL)-8, IL-6, tumor necrosis factor alpha (TNFalpha), granulocyte macrophage-colony-stimulating factor (GM CSF), IL-1alpha, IL-1beta, IL-1ra, IL-10, monocyte chemoattractant protein 3, macrophage-derived chemokine (MDC), and regulated on activation normal T cell expressed and secreted (RANTES). The effect of dexamethasone on p38 MAPK activation was analyzed by Western blotting. Dexamethasone and BIRB-796 both reduced LPS-induced cytokine production in a dose-dependent manner in all subject groups, with no differences between groups. Increasing the concentration of BIRB 796 in combination with dexamethasone produced progressively greater inhibition of cytokine production than dexamethasone alone. There were significant efficacy enhancing benefits and synergistic dose-sparing effects (p < 0.05) for the combination treatment for IL-8, IL-6, TNFalpha, GM-CSF, IL-1ra, IL-10, MDC, and RANTES in one or more subject groups. Dexamethasone had no effect on LPS-induced p38 MAPK activation. We conclude that p38 MAPK activation in alveolar macrophages is corticosteroid-insensitive. Combining a p38 MAPK inhibitor with a corticosteroid synergistically enhances the anti-inflammatory effects on LPS mediated cytokine production by alveolar macrophages from patients with COPD and controls. PMID- 21610142 TI - BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. AB - PURPOSE: Recent studies have revealed that the majority of pediatric low-grade astrocytomas (PLGA) harbor the BRAF-KIAA1549 (B-K) fusion gene resulting in constitutive activation of the RAS/MAPK pathway. However, the clinical significance of this genetic alteration is yet to be determined. We aimed to test the prognostic role of the B-K fusion in progression of incompletely resected PLGA. EXPERIMENTAL DESIGN: We retrospectively identified 70 consecutive patients with incompletely resected "clinically relevant" PLGA. We added 76 tumors diagnosed at our institution between 1985 and 2010 as controls. We examined BRAF alterations by reverse transcriptase PCR, FISH, and single-nucleotide polymorphism array analysis and correlated that with progression-free survival (PFS). RESULTS: Overall, 60% of tumors were B-K fusion positive. All patients with B-K fused PLGA are still alive. Five-year PFS was 61% +/- 8% and 18% +/- 8% for fusion positive and negative patients, respectively (P = 0.0004). B-K fusion resulted in similarly significant favorable PFS for patients who received chemotherapy. Multivariate analysis revealed that B-K fusion was the most significant favorable prognostic factor in incompletely resected PLGA and was independent of location, pathology, and age. In vitro, BRAF overexpression resulted in growth arrest associated with DNA damage (gammaH2AX expression). Five year PFS was 68% +/- 15% and 0% for patients with B-K fused and gammaH2AX expressing PLGA versus negative tumors (P = 0.001). CONCLUSION: These data suggest that B-K fusion confers a less aggressive clinical phenotype on PLGA and may explain their tendency to growth arrest. Combined analysis of B-K fusion and gammaH2AX expression can determine prognosis and may be a powerful tool to tailor therapy for these patients. PMID- 21610143 TI - MicroRNA-146a downregulates NFkappaB activity via targeting TRAF6 and functions as a tumor suppressor having strong prognostic implications in NK/T cell lymphoma. AB - PURPOSE: We investigated prognostic implications of microRNAs in extranodal NK/T cell lymphoma (NKTL). EXPERIMENTAL DESIGN: We measured miRNA expression in NKTL tissues and cell lines, using real-time PCR, and analyzed its role in NKTL, using cell lines. RESULTS: Multivariate analysis showed low miR-146a expression (P < 0.001; HR = 13.110), primary non-upper aerodigestive tract lesion (non-UAT; P = 0.008; HR = 5.376) and high International Prognostic Index (IPI; >=3; P = 0.013; HR = 3.584) to be independent poor prognostic factors. miR-146a expression could subdivide UAT-NKTL into 2 prognostic groups, resulting in the following prognostic groups: (i) UAT(Low-146a), (ii) UAT(High-146a), and (iii) non-UAT. Compared with UAT(High-146a), UAT(Low-146a) showed distinctively poor prognosis (P < 0.001; HR = 15.620), similar to the non-UAT group. In vitro, miR-146a overexpression in NKTL cell lines, SNK6 and YT, inhibited nuclear factor kappaB (NFkappaB) activity, suppressed cell proliferation, induced apoptosis, and enhanced chemosensitivity. TNF receptor-associated factor 6, a target of miR-146a and a known NFkappaB activator, was downregulated by miR-146a in SNK6 and YT cells. Promoter methylation of miR-146a gene was observed in SNK6 and YT cells, as well as in NKTL tissues with low miR-146a expression, and miR-146a expression was induced by the conversion of methylation status with a demethylating agent in SNK6 and YT cells. CONCLUSIONS: These results suggest that miR-146a might function as a potent tumor suppressor in NKTL and be useful for patient assessment and therapeutic targeting. PMID- 21610144 TI - Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma. AB - PURPOSE: The goal of this study was to comprehensively identify CpG island methylation alterations between pancreatic cancers and normal pancreata and their associated gene expression alterations. EXPERIMENTAL DESIGN: We employed methylated CpG island amplification followed by CpG island microarray, a method previously validated for its accuracy and reproducibility, to analyze the methylation profile of 27,800 CpG islands covering 21 MB of the human genome in nine pairs of pancreatic cancer versus normal pancreatic epithelial tissues and in three matched pairs of pancreatic cancer versus lymphoid tissues from the same individual. RESULTS: This analysis identified 1,658 known loci that were commonly differentially methylated in pancreatic cancer compared with normal pancreas. By integrating the pancreatic DNA methylation status with the gene expression profiles of the same samples before and after treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine, and the histone deacetylase inhibitor, trichostatin A, we identified dozens of aberrantly methylated and differentially expressed genes in pancreatic cancers including a more comprehensive list of hypermethylated and silenced genes that have not been previously described as targets for aberrant methylation in cancer. CONCLUSION: We expected that the identification of aberrantly hypermethylated and silenced genes will have diagnostic, prognostic, and therapeutic applications. PMID- 21610145 TI - Effect of eIF3a on response of lung cancer patients to platinum-based chemotherapy by regulating DNA repair. AB - PURPOSE: The purpose of this study is to test the hypothesis that eIF3a may regulate the expression of DNA repair proteins which, in turn, affects response of lung cancer patients to treatments by DNA-damaging anticancer drugs. EXPERIMENTAL DESIGN: Immunohistochemistry was used to determine the expression of eIF3a in 211 human lung cancer tissues followed by association analysis of eIF3a expression with patient's response to platinum-based chemotherapy. Ectopic overexpression and RNA interference knockdown of eIF3a were carried out in NIH3T3 and H1299 cell lines, respectively, to determine the effect of altered eIF3a expression on cellular response to cisplatin, doxorubicine, etoposide (VP-16), vincristine, and vinblastine by using MTT assay. The DNA repair capacity of these cells was evaluated by using host-cell reactivation assay. Real-time reverse transcriptase PCR and Western Blot analyses were carried out to determine the effect of eIF3a on the DNA repair genes by using cells with altered eIF3a expression. RESULTS: eIF3a expression associates with response of lung cancer patients to platinum-based chemotherapy. eIF3a knockdown or overexpression, respectively, increased and decreased the cellular resistance to cisplatin and anthrocycline anticancer drugs, DNA repair activity, and expression of DNA repair proteins. CONCLUSIONS: eIF3a plays an important role in regulating the expression of DNA repair proteins which, in turn, contributes to cellular response to DNA damaging anticancer drugs and patients' response to platinum-based chemotherapy. PMID- 21610146 TI - Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. AB - PURPOSE: Adoptive T-cell immunotherapy with tumor infiltrating lymphocytes or genetically-modified T cells has yielded dramatic results in some cancers. However, T cells need to traffic properly into tumors to adequately exert therapeutic effects. EXPERIMENTAL DESIGN: The chemokine CCL2 was highly secreted by malignant pleural mesotheliomas (MPM; a planned tumor target), but the corresponding chemokine receptor (CCR2) was minimally expressed on activated human T cells transduced with a chimeric antibody receptor (CAR) directed to the MPM tumor antigen mesothelin (mesoCAR T cells). The chemokine receptor CCR2b was thus transduced into mesoCAR T cells using a lentiviral vector, and the modified T cells were used to treat established mesothelin-expressing tumors. RESULTS: CCR2b transduction led to CCL2-induced calcium flux and increased transmigration, as well as augmentation of in vitro T-cell killing ability. A single intravenous injection of 20 million mesoCAR + CCR2b T cells into immunodeficient mice bearing large, established tumors (without any adjunct therapy) resulted in a 12.5-fold increase in T-cell tumor infiltration by day 5 compared with mesoCAR T cells. This was associated with significantly increased antitumor activity. CONCLUSIONS: CAR T cells bearing a functional chemokine receptor can overcome the inadequate tumor localization that limits conventional CAR targeting strategies and can significantly improve antitumor efficacy in vivo. PMID- 21610147 TI - An epigenetic marker panel for detection of lung cancer using cell-free serum DNA. AB - PURPOSE: We investigated the feasibility of detecting aberrant DNA methylation of some novel and known genes in the serum of lung cancer patients. EXPERIMENTAL DESIGN: To determine the analytic sensitivity, we examined the tumor and the matched serum DNA for aberrant methylation of 15 gene promoters from 10 patients with primary lung tumors by using quantitative methylation-specific PCR. We then tested this 15-gene set to identify the more useful DNA methylation changes in the serum of a limited number of lung cancer patients and controls. In an independent set, we tested the six most promising genes (APC, CDH1, MGMT, DCC, RASSF1A, and AIM1) for further elucidation of the diagnostic application of this panel of markers. RESULTS: Promoter hypermethylation of at least one of the genes studied was detected in all 10 lung primary tumors. In majority of cases, aberrant methylation in serum DNA was accompanied by methylation in the matched tumor samples. In the independent set, using a single gene that had 100% specificity (DCC), 35.5% (95% CI: 25-47) of the 76 lung cancer patients were correctly identified. For patients without methylated DCC, addition of a logistic regression score that was based on the five remaining genes improved sensitivity from 35.5% to 75% (95% CI: 64-84) but decreased the specificity from 100% to 73% (95% CI: 54-88). CONCLUSION: This approach needs to be evaluated in a larger test set to determine the role of this gene set in early detection and surveillance of lung cancer. PMID- 21610148 TI - Pharmacokinetic-pharmacodynamic analysis of vismodegib in preclinical models of mutational and ligand-dependent Hedgehog pathway activation. AB - PURPOSE: Vismodegib (GDC-0449) is a potent and selective inhibitor of the Hedgehog (Hh) pathway that shows antitumor activity in preclinical models driven by mutational or ligand-dependent activation of the Hh pathway. We wished to characterize the pharmacokinetic-pharmacodynamic (PK/PD) relationship of vismodegib in both model systems to guide optimal dose and schedule for vismodegib in the clinic. EXPERIMENTAL DESIGN: Preclinical efficacy and PK/PD studies were carried out with vismodegib in a Ptch(+/-) allograft model of medulloblastoma exhibiting mutational activation of the Hh pathway and patient derived colorectal cancer (CRC) xenograft models exhibiting ligand-dependent pathway activation. Inhibition of the hedgehog pathway was related to vismodegib levels in plasma and to antitumor efficacy using an integrated population-based PK/PD model. RESULTS: Oral dosing of vismodegib caused tumor regressions in the Ptch(+/-) allograft model of medulloblastoma at doses >=25 mg/kg and tumor growth inhibition at doses up to 92 mg/kg dosed twice daily in two ligand-dependent CRC models, D5123, and 1040830. Analysis of Hh pathway activity and PK/PD modeling reveals that vismodegib inhibits Gli1 with a similar IC(50) in both the medulloblastoma and D5123 models (0.165 MUmol/L +/-11.5% and 0.267 MUmol/L +/ 4.83%, respectively). Pathway modulation was linked to efficacy using an integrated PK/PD model revealing a steep relationship where > 50% of the activity of vismodegib is associated with >80% repression of the Hh pathway. CONCLUSIONS: These results suggest that even small reductions in vismodegib exposure can lead to large changes in antitumor activity and will help guide proper dose selection for vismodegib in the clinic. PMID- 21610149 TI - PLK1 Is transcriptionally activated by NF-kappaB during cell detachment and enhances anoikis resistance through inhibiting beta-catenin degradation in esophageal squamous cell carcinoma. AB - PURPOSE: To investigate the molecular mechanisms through which polo-like kinase-1 (PLK1) takes part in anoikis resistance of esophageal squamous cell carcinoma (ESCC) cells. EXPERIMENTAL DESIGN: The role of PLK1 in cell anoikis resistance was examined by ectopic gene expression and siRNA-mediated knockdown. Glutathione S-transferase pull-down and co-immunoprecipitation assays were utilized to investigate PLK1-interacting proteins. Electrophoretic mobility shift assay, chromatin immunoprecipitation, and reporter gene assays were carried out to identify the transcription factors responsible for PLK1 expression during anoikis resistance. RESULTS: We found that detachment of ESCC cells triggers the upregulation of PLK1. Elevated PLK1 expression contributes to protection against anoikis in cancer cells through the regulation of beta-catenin expression. Moreover, we showed that, through direct binding to the PLK1 promoter, the NF kappaB subunit RelA transcriptionally activates PLK1, which inhibits the ubiquitination and degradation of beta-catenin. Inhibition of the NF-kappaB pathway restores the sensitivity of cancer cells to anoikis by downregulating PLK1/beta-catenin expression. In addition, RelA gene amplification and protein overexpression was significantly correlated with PLK1 expression in ESCC tissues. CONCLUSIONS: Our findings suggest that upregulation of PLK1 triggered by cell detachment is regulated by RelA at the transcriptional level. PLK1 protects esophageal carcinoma cells from anoikis through modulation of beta-catenin protein levels by inhibiting their degradation. Taken together, this study reveals critical mechanisms involved in the role of RelA/PLK1/beta-catenin in anoikis resistance of ESCC cells. PMID- 21610150 TI - NEMO-binding domain peptide inhibits constitutive NF-kappaB activity and reduces tumor burden in a canine model of relapsed, refractory diffuse large B-cell lymphoma. AB - PURPOSE: Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive, poorly chemoresponsive lymphoid malignancy characterized by constitutive canonical NF-kappaB activity that promotes lymphomagenesis and chemotherapy resistance via overexpression of antiapoptotic NF-kappaB target genes. Inhibition of the canonical NF-kappaB pathway may therefore have therapeutic relevance in ABC-DLBCL. Here, we set out to determine whether dogs with spontaneous DLBCL have comparative aberrant constitutive NF-kappaB activity and to determine the therapeutic relevance of NF-kappaB inhibition in dogs with relapsed, resistant DLBCL. EXPERIMENTAL DESIGN: Canonical NF-kappaB activity was evaluated by electrophoretic mobility shift assays and immunoblot analyses, and NF-kappaB target gene expression was measured by quantitative real time PCR. Primary malignant canine B lymphocytes were treated with the selective IKK complex inhibitor NF-kappaB essential modulator-binding domain (NBD) peptide and evaluated for NF-kappaB activity and apoptosis. NBD peptide was administered intranodally to dogs with relapsed B-cell lymphoma and NF-kappaB target gene expression and tumor burden were evaluated pre- and post-treatment. RESULTS: Constitutive canonical NF-kappaB activity and increased NF-kappaB target gene expression were detected in primary DLBCL tissue. NBD peptide inhibited this activity and induced apoptosis of primary malignant B cells in vitro. Intratumoral injections of NBD peptide to dogs with relapsed DLBCL inhibited NF kappaB target gene expression and reduced tumor burden. CONCLUSIONS: This work shows that dogs with spontaneous DLBCL represent a clinically relevant, spontaneous, large animal model for human ABC-DLBCL and shows the therapeutic relevance of NF-kappaB inhibition in the treatment of ABC-DLBCL. These results have important translational relevance for ABC-DLBCL treatment in human patients. PMID- 21610152 TI - Distinct apoptotic signaling characteristics of the anti-CD40 monoclonal antibody dacetuzumab and rituximab produce enhanced antitumor activity in non-Hodgkin lymphoma. AB - PURPOSE: Individually targeting B-cell antigens with monoclonal antibody therapeutics has improved the treatment of non-Hodgkin lymphoma (NHL). We examined if the antitumor activity of rituximab, CD20-specific antibody, could be improved by simultaneously targeting CD40 with the humanized monoclonal antibody dacetuzumab (SGN-40). EXPERIMENTAL DESIGN: Dacetuzumab was dosed with rituximab to determine the in vivo activity of this combination in a subcutaneous Ramos xenograft model of non-Hodgkin lymphoma (NHL). The effect of dacetuzumab on rituximab antibody-dependent cell mediated-cytotoxicity (ADCC), antiproliferative, and apoptotic activities were evaluated in vitro using NHL cell lines. Western blotting and flow cytometry were used to contrast the signaling pathways activated by dacetuzumab and rituximab in NHL cells. RESULTS: The dacetuzumab-rituximab combination had significantly improved antitumor activity over the equivalent dose of rituximab in the Ramos xenograft model (P = 0.0021). Dacetuzumab did not augment rituximab-mediated ADCC activity; however, these antibodies were additive to synergistic in cell-proliferation assays and produced increased apoptosis in combination. Rituximab signaling downregulated BCL-6 oncoprotein in a cell line-specific manner, whereas dacetuzumab strongly downregulated BCL-6 in each cell line. Dacetuzumab induced expression of the proapoptotic proteins TAp63 and Fas, whereas rituximab did not affect basal expression of either protein. Finally, rituximab partially blocked dacetuzumab mediated upregulation of the prosurvival protein BCL-x(L). CONCLUSIONS: Targeting CD40 with dacetuzumab enhanced the antitumor activity of rituximab in cell line and xenograft NHL models. The distinct but complementary apoptotic signal transduction profiles of dacetuzumab and rituximab are an important mechanism behind the improved activity of this combination. PMID- 21610151 TI - Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. AB - PURPOSE: Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA. EXPERIMENTAL DESIGN: We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600E-mutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes. RESULTS: Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic beta-galactosidase activity, low KI-67 index, and induction of p16(INK4a) but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes [CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7] was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16(INK4a) in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16(INK4a) pathway induction following aberrant MAPK activation. CONCLUSIONS: OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas, and the high overall survival of affected patients. PMID- 21610153 TI - Inhibiting the mTOR pathway synergistically enhances cytotoxicity in ovarian cancer cells induced by etoposide through upregulation of c-Jun. AB - PURPOSE: The mTOR pathway is thought to be a central regulator of proliferation and survival of cells. Rapamycin and its analogs are undergoing clinical trials in patients with epithelial ovarian cancer. This study aimed to assess the potential to use rapamycin and anticancer agents in combination for first- and second-line chemotherapy to treat ovarian cancer. EXPERIMENTAL DESIGN: We used six ovarian serous adenocarcinoma cell lines (KF, KOC-2S, SHIN-3, SK-OV-3, TU-OS 3, and TU-OS-4) in this study. We treated the cells with rapamycin and anticancer agents, then assessed cell viability, apoptosis, and the expression of protein in apoptotic pathways and molecules downstream of the mTOR signaling pathways. We also investigated the effect of these drug combinations on survival in nude mouse xenograft models. RESULTS: Synergistic effects were observed in five cell lines from the combination of etoposide and rapamycin. However, we observed antagonistic effects when rapamycin was combined with gemcitabine, cisplatin, or paclitaxel on more than two cell lines. Rapamycin dramatically enhanced apoptosis induced by etoposide and the expression of cleaved caspase 9. This effect was associated with upregulation of phosphorylated c-Jun and downregulation of Bcl xL. The synergistic interaction of rapamycin and etoposide was lower when the c Jun pathway was suppressed by a c-Jun N-terminal kinase inhibitor (SP600125). Finally, treating nude mice with rapamycin and etoposide significantly prolonged survival in the model mice with ovarian cancer xenografts. CONCLUSIONS: Chemotherapy with rapamycin and etoposide combined is worth exploring as a treatment modality for women with epithelial ovarian cancer. PMID- 21610154 TI - Survival benefit with erlotinib maintenance therapy in patients with advanced non small-cell lung cancer (NSCLC) according to response to first-line chemotherapy. AB - BACKGROUND: In the placebo-controlled phase III SATURN study, maintenance erlotinib after first-line chemotherapy demonstrated significantly prolonged progression-free survival (PFS) and overall survival (OS) in the overall study population of patients with advanced non-small-cell lung cancer (NSCLC). METHODS: After four cycles of platinum-based doublet chemotherapy, patients without progressive disease (PD) were randomised to erlotinib (150 mg/day) or placebo until PD or unacceptable toxicity. In this pre-planned analysis, data are assessed according to response to first-line chemotherapy (complete/partial response [CR/PR] or stable disease [SD]). RESULTS: Following first-line chemotherapy, 889 non-PD patients were included in the intention-to-treat population (55% SD; 44% CR/PR; <1% unknown response). Erlotinib maintenance therapy significantly prolonged PFS in both the SD (hazard ratio [HR] = 0.68; P < 0.0001) and CR/PR (HR = 0.74; P = 0.0059) groups, while OS was significantly prolonged in the SD group only (HR = 0.72; P = 0.0019). The erlotinib-related OS benefit in the SD group remained significant across subgroups, irrespective of tumour histology and/or EGFR mutation status. The incidence of adverse events was similar in the SD group and the overall population, and erlotinib treatment did not negatively impact quality of life. CONCLUSIONS: Patients with advanced NSCLC and SD following first-line platinum-based doublet chemotherapy derive a significant OS benefit from maintenance erlotinib therapy. PMID- 21610155 TI - Locoregional recurrence risk after lipofilling in breast cancer patients. AB - BACKGROUND: Lipofilling has been indicated for postmastectomy and postlumpectomy breast reconstruction. The clinical literatures underline its technical efficacy but experimental studies raise important questions about the potential detrimental effect of adipocytes on the stimulation of cancer growth and reappearance. DESIGN: We collected 321 consecutive patients operated for a primary breast cancer between 1997 and 2008 who subsequently underwent lipofilling for reconstructive purpose. For each patient, we selected two matched patients with similar characteristics who did not undergo a lipofilling. RESULTS: Eighty-nine percent of the tumors were invasive. Median follow-up was 56 months from the primary surgery and 26 months from the lipofilling. Eight and 19 patients had a local event in the lipofilling and control group, respectively, leading to comparable cumulative incidence curves [P = 0.792; Hazard Ratio(Lipo vs No lipo) = 1.11 (95% confidence interval 0.47-2.64)]. These results were confirmed when patients undergoing quadrantectomy and mastectomy were analyzed separately and when the analysis was limited to invasive tumors. Based on 37 cases, the lipofilling group resulted at higher risk of local events when the analysis was limited to intraepithelial neoplasia. CONCLUSIONS: Lipofilling seems to be a safe procedure in breast cancer patients. Longer follow-up and further experiences from oncological series are urgently required to confirm these findings. PMID- 21610157 TI - Minireview: The stem cell next door: skeletal and hematopoietic stem cell "niches" in bone. AB - Long known to be home to hematopoietic stem cells (HSC), the bone/bone marrow organ and its cellular components are directly implicated in regulating hematopoiesis and HSC function. Over the past few years, advances on the identity of HSC "niche" cells have brought into focus the role of cells of osteogenic lineage and of marrow microvessels. At the same time, the identity of self renewing multipotent skeletal progenitors (skeletal stem cells, also known as mesenchymal stem cells) has also been more precisely defined, along with the recognition of their own microvascular niche. The two sets of evidence converge in delineating a picture in which two kinds of stem cells share an identical microanatomical location in the bone/bone marrow organ. This opens a new view on the manner in which the skeleton and hematopoiesis can cross-regulate via interacting stem cells but also a novel view of our general concept of stem cell niches. PMID- 21610156 TI - Steroidogenic factor-1 (SF-1)-driven differentiation of murine embryonic stem (ES) cells into a gonadal lineage. AB - Steroidogenic factor 1 (SF-1) is essential for the development and function of steroidogenic tissues. Stable incorporation of SF-1 into embryonic stem cells (SF 1-ES cells) has been shown to prime the cells for steroidogenesis. When provided with exogenous cholesterol substrate, and after treatment with retinoic acid and cAMP, SF-1-ES cells produce progesterone but do not produce other steroids such as cortisol, estradiol, or testosterone. In this study, we explored culture conditions that optimize SF-1-mediated differentiation of ES cells into defined steroidogenic lineages. When embryoid body formation was used to facilitate cell lineage differentiation, SF-1-ES cells were found to be restricted in their differentiation, with fewer cells entering neuronal pathways and a larger fraction entering the steroidogenic lineage. Among the differentiation protocols tested, leukemia inhibitory factor (LIF) removal, followed by prolonged cAMP treatment was most efficacious for inducing steroidogenesis in SF-1-ES cells. In this protocol, a subset of SF-1-ES cells survives after LIF withdrawal, undergoes morphologic differentiation, and recovers proliferative capacity. These cells are characterized by induction of steroidogenic enzyme genes, use of de novo cholesterol, and production of multiple steroids including estradiol and testosterone. Microarray studies identified additional pathways associated with SF-1 mediated differentiation. Using biotinylated SF-1 in chromatin immunoprecipitation assays, SF-1 was shown to bind directly to multiple target genes, with induction of binding to some targets after steroidogenic treatment. These studies indicate that SF-1 expression, followed by LIF removal and treatment with cAMP drives ES cells into a steroidogenic pathway characteristic of gonadal steroid-producing cells. PMID- 21610159 TI - Endoplasmic reticulum stress response in P104L mutant caveolin-3 transgenic mice. AB - Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C). However, the precise molecular pathogenesis of caveolin-3 related muscular dystrophy remains uncertain. Here, we demonstrate the effect of gene dosage on the severity of the myopathic phenotype in P104L mutant caveolin-3 (mCav3(P104L)) transgenic mice, a model of LGMD1C. We analyzed the endoplasmic reticulum (ER) stress response in the transgenic mice and found upregulated transcription of the molecular chaperone, glucose-regulated protein (GRP78). Moreover, signaling downstream of GRP78 in the myofibers was activated toward apoptosis. However, terminal transferase dUTP nick end labeling assays detected a few apoptotic nuclei in transgenic mouse skeletal muscle, probably due to the transcriptional activation of Dad1, an anti-apoptotic factor in the ER. These findings suggest that the ER stress response caused by mCav3(P104L) plays a role in the pathogenesis of LGMD1C as a toxic gain of function effect. PMID- 21610158 TI - Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28. AB - Congenital and progressive hearing impairment is a common distressing disease. The progressive dominant hearing loss DFNA28 in human is associated with a frameshift mutation of Grainyhead-like 2 (GRHL2) but its etiology and mechanism remain unknown. Here we report a zebrafish grhl2b(T086) mutant line in which grhl2b expression is interrupted by an insertion of a Tol2 transposon element. The mutants exhibit enlarged otocysts, smaller or eliminated otoliths, malformed semicircular canals, insensitiveness to sound stimulation and imbalanced swimming motion. Since grainyhead-like family members can regulate epithelial adhesion, we examined the expression of some genes encoding junction proteins in mutants. We show that the expression of claudin b (cldnb) and epcam is abolished or dramatically reduced and apical junctional complexes are abnormal in otic epithelial cells of mutant embryos. Co-injection of cldnb and epcam mRNA could largely rescue the mutant phenotype. Injection of human wild-type GRHL2 mRNA but not the mutant GRHL2 mRNA derived from DFNA28 patients into grhl2b(T086) mutant embryos could rescue the inner-ear defects. Furthermore, we demonstrate that Grhl2b directly binds to the enhancers and promotes the expression of cldnb and epcam. Thus, this work reveals an evolutionarily conserved function of Grhl2 in otic development and provides a fish model for further studying mechanisms of Grhl2-related hearing loss. PMID- 21610160 TI - Ataxin-2 repeat-length variation and neurodegeneration. AB - Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31-33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy. PMID- 21610161 TI - Building interdisciplinary frameworks: The importance of institutions, scale, and politics. PMID- 21610162 TI - A biophysical protein folding model accounts for most mutational fitness effects in viruses. AB - Fitness effects of mutations fall on a continuum ranging from lethal to deleterious to beneficial. The distribution of fitness effects (DFE) among random mutations is an essential component of every evolutionary model and a mathematical portrait of robustness. Recent experiments on five viral species all revealed a characteristic bimodal-shaped DFE featuring peaks at neutrality and lethality. However, the phenotypic causes underlying observed fitness effects are still unknown and presumably, are thought to vary unpredictably from one mutation to another. By combining population genetics simulations with a simple biophysical protein folding model, we show that protein thermodynamic stability accounts for a large fraction of observed mutational effects. We assume that moderately destabilizing mutations inflict a fitness penalty proportional to the reduction in folded protein, which depends continuously on folding free energy (DeltaG). Most mutations in our model affect fitness by altering DeltaG, whereas based on simple estimates, ~10% abolish activity and are unconditionally lethal. Mutations pushing DeltaG > 0 are also considered lethal. Contrary to neutral network theory, we find that, in mutation/selection/drift steady state, high mutation rates (m) lead to less stable proteins and a more dispersed DFE (i.e., less mutational robustness). Small population size (N) also decreases stability and robustness. In our model, a continuum of nonlethal mutations reduces fitness by ~2% on average, whereas ~10-35% of mutations are lethal depending on N and m. Compensatory mutations are common in small populations with high mutation rates. More broadly, we conclude that interplay between biophysical and population genetic forces shapes the DFE. PMID- 21610163 TI - Surface tension helps a tongue grab liquid. PMID- 21610164 TI - Cross-linking, ligation, and sequencing of hybrids reveals RNA-RNA interactions in yeast. AB - Many protein-protein and protein-nucleic acid interactions have been experimentally characterized, whereas RNA-RNA interactions have generally only been predicted computationally. Here, we describe a high-throughput method to identify intramolecular and intermolecular RNA-RNA interactions experimentally by cross-linking, ligation, and sequencing of hybrids (CLASH). As validation, we identified 39 known target sites for box C/D modification-guide small nucleolar RNAs (snoRNAs) on the yeast pre-rRNA. Novel snoRNA-rRNA hybrids were recovered between snR4-5S and U14-25S. These are supported by native electrophoresis and consistent with previously unexplained data. The U3 snoRNA was found to be associated with sequences close to the 3' side of the central pseudoknot in 18S rRNA, supporting a role in formation of this structure. Applying CLASH to the yeast U2 spliceosomal snRNA led to a revised predicted secondary structure, featuring alternative folding of the 3' domain and long-range contacts between the 3' and 5' domains. CLASH should allow transcriptome-wide analyses of RNA-RNA interactions in many organisms. PMID- 21610166 TI - Museum collections: Mining the past to manage the future. PMID- 21610165 TI - Characterization of a canine homolog of hepatitis C virus. AB - An estimated 3% of the world's population is chronically infected with hepatitis C virus (HCV). Although HCV was discovered more than 20 y ago, its origin remains obscure largely because no closely related animal virus homolog has been identified; furthermore, efforts to understand HCV pathogenesis have been hampered by the absence of animal models other than chimpanzees for human disease. Here we report the identification in domestic dogs of a nonprimate hepacivirus. Comparative phylogenetic analysis of the canine hepacivirus (CHV) confirmed it to be the most genetically similar animal virus homolog of HCV. Bayesian Markov chains Monte Carlo and associated time to most recent common ancestor analyses suggest a mean recent divergence time of CHV and HCV clades within the past 500-1,000 y, well after the domestication of canines. The discovery of CHV may provide new insights into the origin and evolution of HCV and a tractable model system with which to probe the pathogenesis, prevention, and treatment of diseases caused by hepacivirus infection. PMID- 21610167 TI - Mechanisms of oocyte development in European sea bass (Dicentrarchus labrax L.): investigations via application of unilateral ovariectomy. AB - Unilateral ovariectomy (ULO) was performed in European sea bass (Dicentrarchus labrax L.) during late pre-vitellogenesis/early vitellogenesis. Plasma steroid levels and the expression of a suite of potential oogenesis-relevant genes in the ovary, brain, and pituitary were evaluated with the aim of understanding their involvement in the compensatory oocyte development occurring within the remaining ovarian lobe. After 69 days of surgery the remaining ovarian lobe in ULO fish was gravimetrically equivalent to an intact-paired ovary of sham operated, control fish. This compensatory ovarian growth was based on an increased number of early perinucleolar oocytes and mid-late stage vitellogenic follicles without an apparent recruitment of primary oocytes into the secondary growth phase. Plasma steroid levels were similar in ULO and control females at all time points analyzed, suggesting an increased steroid production of the remaining ovarian lobe in hemi-castrated females. Results of the gene expression survey conducted indicate that the signaling pathways mediated by Fsh and Gnrh1 constitute the central axes orchestrating the observed ovarian compensatory growth. In addition, steroid receptors, Star protein, Igfs, and members of the transforming growth factor beta superfamily including anti-Mullerian hormone and bone morphogenetic protein 4 were identified as potentially relevant players within this process, although their specific actions and interactions remain to be established. Our results demonstrate that ULO provides an excellent in vivo model for elucidating the interconnected endocrine and molecular mechanisms controlling oocyte development in European sea bass. PMID- 21610168 TI - Gene expression in mouse ovarian follicle development in vivo versus an ex vivo alginate culture system. AB - Ovarian follicle maturation results from a complex interplay of endocrine, paracrine, and direct cell-cell interactions. This study compared the dynamic expression of key developmental genes during folliculogenesis in vivo and during in vitro culture in a 3D alginate hydrogel system. Candidate gene expression profiles were measured within mouse two-layered secondary follicles, multi layered secondary follicles, and cumulus-oocyte complexes (COCs). The expression of 20 genes involved in endocrine communication, growth signaling, and oocyte development was investigated by real-time PCR. Gene product levels were compared between i) follicles of similar stage and ii) COCs derived either in vivo or by in vitro culture. For follicles cultured for 4 days, the expression pattern and the expression level of 12 genes were the same in vivo and in vitro. Some endocrine (cytochrome P450, family 19, subfamily A, polypeptide 1 (Cyp19a1) and inhibin betaA subunit (Inhba)) and growth-related genes (bone morphogenetic protein 15 (Bmp15), kit ligand (Kitl), and transforming growth factor beta receptor 2 (Tgfbr2)) were downregulated relative to in vivo follicles. For COCs obtained from cultured follicles, endocrine-related genes (inhibin alpha-subunit (Inha) and Inhba) had increased expression relative to in vivo counterparts, whereas growth-related genes (Bmp15, growth differentiation factor 9, and kit oncogene (Kit)) and zona pellucida genes were decreased. However, most of the oocyte-specific genes (e.g. factor in the germline alpha (Figla), jagged 1 (Jag1), and Nlrp5 (Mater)) were expressed in vitro at the same level and with the same pattern as in vivo-derived follicles. These studies establish the similarities and differences between in vivo and in vitro cultured follicles, guiding the creation of environments that maximize follicle development and oocyte quality. PMID- 21610169 TI - Pre-treatment of sperm reduces success of ICSI in the pig. AB - In pigs, although ICSI is a feasible fertilization technique, its efficiency is low. In general, injected pig sperm are insufficient to induce oocyte activation and embryonic development. Pretreatments for disrupting sperm membranes have been applied to improve the fertility of ICSI oocytes; however, we hypothesize that such pretreatment(s) may reduce the ability of the sperm to induce oocyte activation. We first evaluated the effects of sperm pretreatments (sonication (SO) to isolate the sperm heads from the tails, Triton X-100 (TX), and three cycles of repeated freezing/thawing (3*-FT) for disrupting sperm membranes) on the rate of pronucleus (PN) formation after ICSI. We found that oocytes injected with control (whole) sperm had higher rates of PN formation than those obtained after subjecting the sperm to SO, TX, and 3*-FT. The amounts of phospholipase Czeta (PLCzeta), which is thought to be the oocyte-activating factor in mammalian sperm, in sperm treated by each method was significantly lower than that in whole untreated sperm. Furthermore, using immunofluorescence, it was found that in pig sperm, PLCzeta was localized to both the post-acrosomal region and the tail area. Thus we demonstrated for the first time that sperm pretreatment leads to a reduction of oocyte-activating capacity. Our data also show that in addition to its expected localization to the sperm head, PLCzeta is also localized in the tail of pig sperm, thus raising the possibility that injection of whole sperm may be required to attain successful activation in pigs. PMID- 21610171 TI - Quality improvement specific for child neurology. PMID- 21610172 TI - Abnormal brain structure and function in newborns with complex congenital heart defects before open heart surgery: a review of the evidence. AB - Newborns with complex congenital heart defects are at high risk for developing neurological abnormalities. It is important to understand the timing, progression, and extent of these abnormalities to better elucidate their potential impact on neurodevelopment, and their implications for early screening and intervention. This review synthesizes the recent literature describing neurological and neurobehavioral abnormalities observed in fetuses and newborns before cardiac surgery. A considerable proportion of newborns with complex congenital heart defects exhibit neurobehavioral and electrophysiological abnormalities preoperatively. Likewise, conventional neuroimaging studies reported that a high percentage of this population experienced brain injury. Advanced neuroimaging modalities indicated that fetuses showed delayed third trimester brain growth, and newborns showed impaired white matter maturation, reduced N-acetylaspartate, and increased lactate. These findings suggest a fetal or early postnatal onset of impaired brain growth and development. Consequently, reliable methods for early screening and subsequent developmental intervention must be implemented. PMID- 21610170 TI - Dual targeting of tumor angiogenesis and chemotherapy by endostatin-cytosine deaminase-uracil phosphoribosyltransferase. AB - Several antiangiogenic drugs targeting VEGF/VEGF receptor (VEGFR) that were approved by the Food and Drug Administration for many cancer types, including colorectal and lung cancer, can effectively reduce tumor growth. However, targeting the VEGF signaling pathway will probably influence the normal function of endothelial cells in maintaining homeostasis and can cause unwanted adverse effects. Indeed, emerging experimental evidence suggests that VEGF-targeting therapy induced less tumor cell-specific cytotoxicity, allowing residual cells to become more resistant and eventually develop a more malignant phenotype. We report an antitumor therapeutic EndoCD fusion protein developed by linking endostatin (Endo) to cytosine deaminase and uracil phosphoribosyltransferase (CD). Specifically, Endo possesses tumor antiangiogenesis activity that targets tumor endothelial cells, followed by CD, which converts the nontoxic prodrug 5 fluorocytosine (5-FC) to the cytotoxic antitumor drug 5-fluorouracil (5-FU) in the local tumor area. Moreover, selective targeting of tumor sites allows an increasing local intratumoral concentration of 5-FU, thus providing high levels of cytotoxic activity. We showed that treatment with EndoCD plus 5-FC, compared with bevacizumab plus 5-FU treatment, significantly increased the 5-FU concentration around tumor sites and suppressed tumor growth and metastasis in human breast and colorectal orthotropic animal models. In addition, in contrast to treatment with bevacizumab/5-FU, EndoCD/5-FC did not induce cardiotoxicity leading to heart failure in mice after long-term treatment. Our results showed that, compared with currently used antiangiogenic drugs, EndoCD possesses potent anticancer activity with virtually no toxic effects and does not increase tumor invasion or metastasis. Together, these findings suggest that EndoCD/5-FC could become an alternative option for future antiangiogenesis therapy. PMID- 21610173 TI - Cerebellum enlargement and corpus callosum agenesis: a longitudinal case report. AB - Macrocerebellum, a neuroradiological and clinical entity of unknown etiology characterized by an isolated, disproportionately large cerebellum, has to date been reported in only a few cases. It has been suggested that the condition could represent a marker for disturbed cerebral development, however, longitudinal reports are lacking. We describe a 19-month-old patient with agenesis of the corpus callosum, who developed enlargement of the cerebellum without clinical signs of cerebellar impairment, a picture that has not been previously described. PMID- 21610174 TI - Central pontine and extrapontine myelinosis in a child with traumatic brain injury. PMID- 21610179 TI - Staff assist: a resource to improve nursing home quality and staffing. AB - PURPOSE: This study describes the creation and use of a web-based resource, designed to help nursing homes implement quality improvements through changes in staffing characteristics. DESIGN AND METHODS: Information on staffing characteristics (i.e., staffing levels, turnover, stability, and use of agency staff), facility characteristics (e.g., ownership, size), and quality (i.e., quality measures [QMs]) coming from 2,946 nursing homes were utilized in a simulation analysis. The simulation was used to predict changes in each of 11 QMs, based on changes in staffing characteristics for individual nursing homes using the web-tool. RESULTS: The website was visited 2,347 times in the first 6 months after it became operational. Evidence would suggest that it was useful in informing nursing home management of the importance of staffing and facilitating staffing changes; moreover, active users of the website showed improvements in quality, with an average of 5 of the 11 QMs improving by more than 1%. IMPLICATIONS: The web-based resource may be a feasible low-cost model that can be replicated, to provide further information for other areas of quality improvement in nursing homes. PMID- 21610180 TI - Root phenes for enhanced soil exploration and phosphorus acquisition: tools for future crops. PMID- 21610181 TI - K+ transport by the OsHKT2;4 transporter from rice with atypical Na+ transport properties and competition in permeation of K+ over Mg2+ and Ca2+ ions. AB - Members of class II of the HKT transporters, which have thus far only been isolated from grasses, were found to mediate Na(+)-K(+) cotransport and at high Na(+) concentrations preferred Na(+)-selective transport, depending on the ionic conditions. But the physiological functions of this K(+)-transporting class II of HKT transporters remain unknown in plants, with the exception of the unique class II Na(+) transporter OsHKT2;1. The genetically tractable rice (Oryza sativa; background Nipponbare) possesses two predicted K(+)-transporting class II HKT transporter genes, OsHKT2;3 and OsHKT2;4. In this study, we have characterized the ion selectivity of the class II rice HKT transporter OsHKT2;4 in yeast and Xenopus laevis oocytes. OsHKT2;4 rescued the growth defect of a K(+) uptake deficient yeast mutant. Green fluorescent protein-OsHKT2;4 is targeted to the plasma membrane in transgenic plant cells. OsHKT2;4-expressing oocytes exhibited strong K(+) permeability. Interestingly, however, K(+) influx in OsHKT2;4 expressing oocytes did not require stimulation by extracellular Na(+), in contrast to other class II HKT transporters. Furthermore, OsHKT2;4-mediated currents exhibited permeabilities to both Mg(2+) and Ca(2+) in the absence of competing K(+) ions. Comparative analyses of Ca(2+) and Mg(2+) permeabilities in several HKT transporters, including Arabidopsis thaliana HKT1;1 (AtHKT1;1), Triticum aestivum HKT2;1 (TaHKT2;1), OsHKT2;1, OsHKT2;2, and OsHKT2;4, revealed that only OsHKT2;4 and to a lesser degree TaHKT2;1 mediate Mg(2+) transport. Interestingly, cation competition analyses demonstrate that the selectivity of both of these class II HKT transporters for K(+) is dominant over divalent cations, suggesting that Mg(2+) and Ca(2+) transport via OsHKT2;4 may be small and would depend on competing K(+) concentrations in plants. PMID- 21610182 TI - Effects of combined balanced colloid and crystalloid on rotational thromboelastometry in vitro. AB - Our objective was to investigate the in vitro effects of a totally balanced fluid concept on whole blood coagulation. Venous blood from 12 healthy volunteers was diluted by 20% and 40% with a combination of an equal amount of colloid (balanced or unbalanced 6% HES 130/0.4, or 4% gelatin) and crystalloid (balanced or unbalanced Ringer's acetate). Blood samples were analyzed with rotational thromboelastometry (ROTEM(r)). The initiation of coagulation was delayed in all dilutions except for the 20 vol% gelatin-dilution. In the extrinsic activation test, maximum clot firmness was decreased and clot formation time prolonged after 40 vol% hemodilution with a balanced Ringer's/unbalanced HES combination, more than in the corresponding gelatin hemodilution. In the fibrin-based test, after both 20- and 40 vol% hemodilution with unbalanced Ringer's/gelatin solution, maximum clot firmness was significantly stronger than in the Ringer's/HES combinations. The combination of balanced colloid and crystalloid has similar coagulation effects in vitro as their respective combination of unbalanced solutions. PMID- 21610184 TI - Motor skills of toddlers with autism spectrum disorders. AB - With increased interest in the early diagnosis and treatment of children with autism spectrum disorders (ASD), more attention has been called to the motor skills of very young children with ASD. This study describes the gross and fine motor skills of a cross-sectional group of 162 children with ASD between the ages of 12 and 36 months, as well as a subset of 58 children followed longitudinally. Gross motor and fine motor age equivalent scores were obtained for all children. A 'motor difference' variable was calculated for each child's gross and fine motor skills by taking the absolute difference of the children's age equivalent motor score and their respective chronological age. In Study 1 (the cross sectional analysis), ANCOVA (co-varied for nonverbal problem solving) revealed significant group differences in the gross motor and fine motor age difference variables. Post-hoc analysis revealed that gross motor and fine motor differences became significantly greater with each 6-month period of chronological age. In Study 2, 58 children were measured twice, an average of 12 months apart. Results indicate that the gross motor and fine motor difference scores significantly increased between the first and second measurements. The importance of addressing motor development in early intervention treatments is discussed. PMID- 21610183 TI - The plant cuticle is required for osmotic stress regulation of abscisic acid biosynthesis and osmotic stress tolerance in Arabidopsis. AB - Osmotic stress activates the biosynthesis of abscisic acid (ABA). One major step in ABA biosynthesis is the carotenoid cleavage catalyzed by a 9-cis epoxycarotenoid dioxygenase (NCED). To understand the mechanism for osmotic stress activation of ABA biosynthesis, we screened for Arabidopsis thaliana mutants that failed to induce the NCED3 gene expression in response to osmotic stress treatments. The ced1 (for 9-cis epoxycarotenoid dioxygenase defective 1) mutant isolated in this study showed markedly reduced expression of NCED3 in response to osmotic stress (polyethylene glycol) treatments compared with the wild type. Other ABA biosynthesis genes are also greatly reduced in ced1 under osmotic stress. ced1 mutant plants are very sensitive to even mild osmotic stress. Map-based cloning revealed unexpectedly that CED1 encodes a putative alpha/beta hydrolase domain-containing protein and is allelic to the BODYGUARD gene that was recently shown to be essential for cuticle biogenesis. Further studies discovered that other cutin biosynthesis mutants are also impaired in osmotic stress induction of ABA biosynthesis genes and are sensitive to osmotic stress. Our work demonstrates that the cuticle functions not merely as a physical barrier to minimize water loss but also mediates osmotic stress signaling and tolerance by regulating ABA biosynthesis and signaling. PMID- 21610185 TI - Perception of mirror symmetry in autism spectrum disorders. AB - Gestalt grouping in autism spectrum disorders (ASD) is selectively impaired for certain organization principles but for not others. Symmetry is a fundamental Gestalt principle characterizing many biological shapes. Sensitivity to symmetry was tested using the Picture Symmetry Test, which requires finding symmetry lines on pictures. Individuals with ASD showed decreased sensitivity to symmetry and a correlation of test performance with performance IQ. Decreased sensitivity for symmetry in ASD is discussed in relation to reduced visual experience of faces in early development. PMID- 21610186 TI - Minor physical anomalies in children with autism spectrum disorders. AB - OBJECTIVE: There is clinical heterogeneity among the autism spectrum disorders (ASD). The presence of dysmorphology (minor physical anomalies; MPAs) is one possible tool for defining a clinically relevant subset in ASD. This study employs an adaptation of Miles and Hillman's (2000) classifications by using photographs to identify a subgroup with significant dysmorphology among children with ASD, typical development (TYP), and developmental delay (DD). METHOD: Children with ASD, DD, and TYP between 2 and 5 years old were part of the CHARGE Study. Pediatric specialists blinded to diagnostic group classified photographs based on the number of MPAs present: 'dysmorphic' if >3 and 'nondysmorphic' if <3 MPAs. RESULTS: Photographs for 324 children were included. Significantly more children with ASD were classified as dysmorphic compared to TYP children (p = .007). In children with ASD, seizures were more prevalent in those rated dysmorphic (p = .005). Frequencies were similar between ASD versus DD (p = .19) after removing those with known syndromes. CONCLUSION: Photographic assessment can be used to detect generalized dysmorphology in children who are often difficult to examine. This has clinical relevance, as children with multiple MPAs can be identified through the use of photographs and prioritized for investigation of brain abnormalities and underlying genetic disorders. PMID- 21610187 TI - Evaluation of the revised algorithm of Autism Diagnostic Observation Schedule (ADOS) in the diagnostic investigation of high-functioning children and adolescents with autism spectrum disorders. AB - The Autism Diagnostic Observation Schedule (ADOS) is a semi-structured, standardized assessment designed for use in diagnostic evaluation of individuals with suspected autism spectrum disorder (ASD). The ADOS has been effective in categorizing children who definitely have autism or not, but has lower specificity and sometimes sensitivity for distinguishing children with milder ASDs. Revised ADOS algorithms have been recently developed. The goals of this study were to analyze the predictive validity of different ADOS algorithms for module 3, in particular for high-functioning autism spectrum disorder. The participants were 252 children and adolescents aged between four and 16 years, with a full-scale IQ above 70 (126 with a diagnosis of ASD, 126 with a heterogeneous non-spectrum diagnosis). As a main finding, sensitivity was substantially higher for the newly developed 'revised algorithm', both for autism versus non-spectrum, as well as for the broader ASD versus non-spectrum, using the higher cut-off. The strength of the original algorithm lies in its positive predictive power, while the revised algorithm shows weaknesses in specificity for non-autism ASD. As the ADOS is valid and reliable even for higher functioning ASD, the findings of the present study have been used to make recommendations regarding the best use of ADOS algorithms in a high-functioning sample. PMID- 21610188 TI - 'I just don't fit anywhere': support experiences and future support needs of individuals with Asperger syndrome in middle adulthood. AB - The experiences of individuals in middle adulthood with Asperger syndrome have been the subject of little previous research, especially in terms of their experience of support services. In the present research, 11 adults with Asperger syndrome were interviewed. Interpretative phenomenological analysis (IPA) was used to interpret the interviews. Four themes emerged from the analysis: living with Asperger syndrome; employment issues; experiences with mainstream support; and future steps towards supporting adults with Asperger syndrome. The findings highlighted the anxiety, depression, and communication difficulties that people with Asperger syndrome may experience. Much of the available support is perceived as unsuitable for individuals with Asperger syndrome. All participants wanted to remain as independent as possible, and believed an individualized approach to support would be greatly beneficial. Recommendations are made for future practice to help support adults with Asperger syndrome. PMID- 21610189 TI - Do sheltered workshops enhance employment outcomes for adults with autism spectrum disorder? AB - This study investigated whether sheltered workshops help prepare individuals with autism spectrum disorder (ASD) for competitive employment within the community. Two groups of individuals were compared: (a) 215 supported employees who were in sheltered workshops prior to entering supported employment and (b) 215 supported employees who were not in sheltered workshops. Individuals from both groups were matched based on their primary diagnosis, secondary diagnosis (if present), and gender. Results showed that there were no differences in rates of employment between these two groups. However, individuals who participated in sheltered workshops earned significantly less (US$129.36 versus US$191.42 per week), and cost significantly more to serve (US$6,065.08 versus US$2,440.60), than their non sheltered workshop peers. Results presented here suggest that individuals with ASD achieve better vocational outcomes if they do not participate in sheltered workshops prior to enrolling in supported employment. PMID- 21610190 TI - A national study of the prevalence of autism among five-year-old children in Iran. AB - In Iran, more than 1.3 million five-year olds have been screened for autism over three academic years, with the Social Communication Questionnaire (SCQ). The Autism Diagnostic Interview-Revised (ADI-R) is used to confirm a diagnosis of typical autism. The resulting prevalence of 6.26 per 10,000 for typical autism is in line with rates for certain countries but is lower than those reported recently for some Western nations. This may be due to the younger age range assessed but the suitability of the tools and aspects of Iranian culture could be other reasons for the lower prevalence. International comparisons of prevalence rates is fraught with difficulties, but it is a valuable endeavour as it can identify issues around cultural and societal perceptions of children's development. PMID- 21610192 TI - NHS reform. PMID- 21610191 TI - College students on the autism spectrum: prevalence and associated problems. AB - As more young people are identified with autism spectrum diagnoses without co occurring intellectual disability (i.e. high-functioning autism spectrum disorder; HFASD), it is imperative that we begin to study the needs of this population. We sought to gain a preliminary estimate of the scope of the problem and to examine psychiatric risks associated HFASD symptoms in university students. In a large sample (n = 667), we examined prevalence of ASD in students at a single university both diagnostically and dimensionally, and surveyed students on other behavioral and psychiatric problems. Dependent upon the ascertainment method, between .7 per cent and 1.9 per cent of college students could meet criteria for HFASD. Of special interest, none of the students who were found to meet diagnostic criteria (n = 5) formally for HFASD in this study had been previously diagnosed. From a dimensional perspective, those students scoring above the clinical threshold for symptoms of autism (n = 13) self-reported more problems with social anxiety than a matched comparison group of students with lower autism severity scores. In addition, symptoms of HFASD were significantly correlated with symptoms of social anxiety, as well as depression and aggression. Findings demonstrate the importance of screening for autism-related impairment among university students. PMID- 21610193 TI - Dynamic aspects of antibody:oligosaccharide complexes characterized by molecular dynamics simulations and saturation transfer difference nuclear magnetic resonance. AB - Carbohydrates are likely to maintain significant conformational flexibility in antibody (Ab):carbohydrate complexes. As demonstrated herein for the protective monoclonal Ab (mAb) F22-4 recognizing the Shigella flexneri 2a O-antigen (O-Ag) and numerous synthetic oligosaccharide fragments thereof, the combination of molecular dynamics simulations and nuclear magnetic resonance saturation transfer difference experiments, supported by physicochemical analysis, allows us to determine the binding epitope and its various contributions to affinity without using any modified oligosaccharides. Moreover, the methods used provide insights into ligand flexibility in the complex, thus enabling a better understanding of the Ab affinities observed for a representative set of synthetic O-Ag fragments. Additionally, these complementary pieces of information give evidence to the ability of the studied mAb to recognize internal as well as terminal epitopes of its cognate polysaccharide antigen. Hence, we show that an appropriate combination of computational and experimental methods provides a basis to explore carbohydrate functional mimicry and receptor binding. The strategy may facilitate the design of either ligands or carbohydrate recognition domains, according to needed improvements of the natural carbohydrate:receptor properties. PMID- 21610194 TI - Binding of Clostridium difficile toxins to human milk oligosaccharides. AB - The binding of recombinant fragments of the C-terminal cell-binding domains of the two large exotoxins, toxin A (TcdA) and toxin B (TcdB), expressed by Clostridium difficile and a library consisting of the most abundant neutral and acidic human milk oligosaccharides (HMOs) was examined quantitatively at 25 degrees C and pH 7 using the direct electrospray ionization mass spectrometry (ES MS) assay. The results of the ES-MS measurements indicate that both toxin fragments investigated, TcdB-B1 and TcdA-A2, which possess one and two carbohydrate binding sites, respectively, bind specifically to HMOs ranging in size from tri- to heptasaccharides. Notably, five of the HMOs tested bind to both toxins: Fuc(alpha1-2)Gal(beta1-4)Glc, Gal(beta1-3)GlcNAc(beta1-3)Gal(beta1-4)Glc, Fuc(alpha1-2)Gal(beta1-3)GlcNAc(beta1-3)Gal(beta1-4)Glc, Gal(beta1-3)[Fuc(alpha1 4)]GlcNAc(beta1-3)Gal(beta1-4)Glc and Gal(beta1-4)[Fuc(alpha1-3)]GlcNAc(beta1 3)Gal(beta1-4)Glc. However, the binding of the HMOs is uniformly weak, with apparent affinities <=10(3 )M(-1). The results of molecular docking simulations, taken together with the experimental binding data, suggest that a disaccharide moiety (lactose or lactosamine) represents the core HMO recognition element for both toxin fragments. The results of a Verocytotoxicity neutralization assay reveal that HMOs do not significantly inhibit the cytotoxic effects of TcdA or TcdB. The absence of protection is attributed to the very weak intrinsic affinities that the toxins exhibit towards the HMOs. PMID- 21610195 TI - Comamonas testosteronan synthase, a bifunctional glycosyltransferase that produces a unique heparosan polysaccharide analog. AB - Glycosaminoglycans (GAGs) are linear hexosamine-containing polysaccharides. These polysaccharides are synthesized by some pathogenic bacteria to form an extracellular coating or capsule. This strategy forms the basis of molecular camouflage since vertebrates possess naturally occurring GAGs that are essential for life. A recent sequence database search identified a putative protein from the opportunistic pathogen Comamonas testosteroni that exhibits similarity with the Pasteurella multocida GAG synthase PmHS1, which is responsible for the synthesis of a heparosan polysaccharide capsule. Initial supportive evidence included glucuronic acid (GlcUA)-containing polysaccharides extracted from C. testosteroni KF-1. We describe here the cloning and analysis of a novel Comamonas GAG synthase, CtTS. The GAG produced by CtTS in vitro consists of the sugars d GlcUA and N-acetyl-D-glucosamine, but is insensitive to digestion by GAG digesting enzymes, thus has distinct glycosidic linkages from vertebrate GAGs. The backbone structure of the polysaccharide product [-4-D-GlcUA-alpha1,4-D GlcNAc-alpha1-](n) was confirmed by nuclear magnetic resonance. Therefore, this novel GAG, testosteronan, consists of the same sugars as the biomedically relevant GAGs heparosan (N-acetyl-heparosan) and hyaluronan but may have distinct properties useful for future medical applications. PMID- 21610196 TI - Quantifying ligand bias at seven-transmembrane receptors. AB - Seven transmembrane receptors (7TMRs), commonly referred to as G protein-coupled receptors, form a large part of the "druggable" genome. 7TMRs can signal through parallel pathways simultaneously, such as through heterotrimeric G proteins from different families, or, as more recently appreciated, through the multifunctional adapters, beta-arrestins. Biased agonists, which signal with different efficacies to a receptor's multiple downstream pathways, are useful tools for deconvoluting this signaling complexity. These compounds may also be of therapeutic use because they have distinct functional and therapeutic profiles from "balanced agonists." Although some methods have been proposed to identify biased ligands, no comparison of these methods applied to the same set of data has been performed. Therefore, at this time, there are no generally accepted methods to quantify the relative bias of different ligands, making studies of biased signaling difficult. Here, we use complementary computational approaches for the quantification of ligand bias and demonstrate their application to two well known drug targets, the beta2 adrenergic and angiotensin II type 1A receptors. The strategy outlined here allows a quantification of ligand bias and the identification of weakly biased compounds. This general method should aid in deciphering complex signaling pathways and may be useful for the development of novel biased therapeutic ligands as drugs. PMID- 21610197 TI - Miltefosine induces apoptosis-like cell death in yeast via Cox9p in cytochrome c oxidase. AB - Miltefosine has antifungal properties and potential for development as a therapeutic for invasive fungal infections. However, its mode of action in fungi is poorly understood. We demonstrate that miltefosine is rapidly incorporated into yeast, where it penetrates the mitochondrial inner membrane, disrupting mitochondrial membrane potential and leading to an apoptosis-like cell death. COX9, which encodes subunit VIIa of the cytochrome c oxidase (COX) complex in the electron transport chain of the mitochondrial membrane, was identified as a potential target of miltefosine from a genomic library screen of the model yeast Saccharomyces cerevisiae. When overexpressed in S. cerevisiae, COX9, but not COX7 or COX8, led to a miltefosine-resistant phenotype. The effect of miltefosine on COX activity was assessed in cells expressing different levels of COX9. Miltefosine inhibited COX activity in a dose-dependent manner in Cox9p-positive cells. This inhibition most likely contributed to the miltefosine-induced apoptosis-like cell death. PMID- 21610198 TI - Endotoxin-induced uveitis is primarily dependent on radiation-resistant cells and on MyD88 but not TRIF. AB - TLR4 activation by LPS (endotoxin) is mediated by the MyD88 and TRIF intracellular signaling pathways. We determined the relative activation of these pathways in murine ocular tissue after LPS exposure. Additionally, we explored whether BM-derived or non-BM-derived cells were the major contributors to EIU. Mice deficient in TRIF or MyD88 and their congenic (WT) controls received 250 ng ultrapure LPS ivt at 0 h. Ocular inflammation was assessed by histological analysis at 4, 6, and 24 h, and additionally, in MyD88(-/-) mice, intravital microscopy was performed at 4 h and 6 h to assess adherent, rolling, and infiltrating cells in the iris vasculature and tissue. Cytokines associated with the MyD88 and TRIF intracellular signaling pathways were analyzed in ocular tissue at 4 h. BM chimeric mice (WT->WT, TLR4(-/-)->WT, WT->TLR4(-/-)) received 250 ng LPS by ivt injection, and ocular tissues were examined by histology at 6 h. Lack of MyD88 resulted in a markedly diminished cellular response and reduced production of MyD88-related cytokines 4 h post-LPS treatment. In contrast, lack of TRIF led to reduced production of TRIF-related cytokines and no change in the cellular response to LPS. Therefore, the MyD88 pathway appears to be the dominant TLR4 pathway in EIU. Only WT -> TLR4(-/-) chimeric mice were resistant to EIU, and this suggests, surprisingly, that non-BM-derived (radiation-resistant) cells in the eye play a greater role than BM-derived cells. PMID- 21610200 TI - Mood and trust in intuition interactively orchestrate correspondence between implicit and explicit attitudes. AB - The goal of the current research was to subject the prediction that affect and trust in intuition would interactively shape implicit and explicit attitude correspondence to empirical assessment. In four experiments, either trust versus distrust in intuition was measured or manipulated and positive or negative moods were induced. The outcome of interest was correspondence between implicit and explicit academic attitudes (Experiments 1-2) and self-attitudes (Experiments 3 4). As predicted, affect served as information about chronically or temporarily accessible tendencies to trust or distrust their intuitions, with positive affect validating and negative affect invalidating such tendencies, which in turn shaped correspondence between implicit and explicit attitudes. By drawing together these two seemingly unrelated lines of research, these experiments provide important insights into the sometimes mysterious circumstances in which implicit attitudes are translated into explicit attitude reports. PMID- 21610201 TI - Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of the GPR40 agonist TAK-875: results from a double-blind, placebo-controlled single oral dose rising study in healthy volunteers. AB - TAK-875 is a selective G-protein-coupled receptor 40 agonist in development for the treatment of type 2 diabetes mellitus. This randomized, double-blind, placebo controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-875 following administration of a single oral dose of TAK 875 (25-800 mg) in 60 healthy volunteers. TAK-875 was eliminated slowly with a mean terminal elimination t(1/2) of approximately 28.1 to 36.6 hours. Systemic exposure of TAK-875 did not exhibit dose-proportional increases across the dose range evaluated due to a greater than proportional increase in exposure at doses greater than 200 mg. A preliminary food effect assessment indicated that coadministration of TAK-875 with a high-fat meal decreased C(max) of TAK-875 by 40% and AUC by 17%. Clinical adverse experiences were generally mild and transient. No dose-dependent pattern was observed. In healthy volunteers, no glucose-lowering effect and no increase in insulin or c-peptide secretion were evident following administration of TAK-875; the frequency of plasma glucose concentrations <70 mg/dL was similar in the TAK-875 and pooled placebo groups. TAK-875 was well tolerated in the study and has pharmacokinetic characteristics suitable for a once-daily regimen. The pharmacodynamic data support the notion that TAK-875, if effective in diabetic patients, may bear a low risk of hypoglycemia. PMID- 21610202 TI - Renal profiles of anticoagulants. AB - Anticoagulants are widely used to prevent and treat venous thromboembolism, prevent stroke in atrial fibrillation, and manage acute coronary syndrome. These drugs are often used in elderly patients, who commonly have renal impairment, comorbidities, and polypharmacy. Renal impairment is a risk factor for bleeding and thrombosis during anticoagulant therapy and can influence the balance between the safety and efficacy of such agents. Some of the more established anticoagulants, such as the low-molecular-weight heparins, warfarin, and fondaparinux, are contraindicated for use in patients with severe renal impairment. Of the new oral anticoagulants, dabigatran etexilate, rivaroxaban, and apixaban are at the most advanced stages of development. Dabigatran requires dose adjustment in patients with moderate renal impairment and is contraindicated in patients with severe renal impairment. Rivaroxaban can be administered as a fixed dose for the prevention of venous thromboembolism in patients with moderate renal impairment and should be used with caution in patients with severe renal impairment. Apixaban excretion is also partly dependent on renal function, although the impact of renal insufficiency has not been determined. Additional data on the safety of chronic dosing of the newer oral anticoagulants in renal impairment are awaited. PMID- 21610199 TI - Epigenetics, bioenergetics, and microRNA coordinate gene-specific reprogramming during acute systemic inflammation. AB - Acute systemic inflammation from infectious and noninfectious etiologies has stereotypic features that progress through an initiation (proinflammatory) phase, an adaptive (anti-inflammatory) phase, and a resolution (restoration of homeostasis) phase. These phase-shifts are accompanied by profound and predictable changes in gene expression and metabolism. Here, we review the emerging concept that the temporal phases of acute systemic inflammation are controlled by an integrated bioenergy and epigenetic bridge that guides the timing of transcriptional and post-transcriptional processes of specific gene sets. This unifying connection depends, at least in part, on redox sensor NAD(+) dependent deacetylase, Sirt1, and a NF-kappaB-dependent p65 and RelB feed-forward and gene-specific pathway that generates silent facultative heterochromatin and active euchromatin. An additional level of regulation for gene-specific reprogramming is generated by differential expression of miRNA that directly and indirectly disrupts translation of inflammatory genes. These molecular reprogramming circuits generate a dynamic chromatin landscape that temporally defines the course of acute inflammation. PMID- 21610203 TI - Pharmacokinetics of intranasal crushed OxyContin and intravenous oxycodone in nondependent prescription opioid abusers. PMID- 21610204 TI - Low-density lipoprotein cholesterol and high-sensitivity C-reactive protein lowering with atorvastatin in patients of South Asian compared with European origin: insights from the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study. AB - The aim of this study was to determine the effects of atorvastatin in patients of South Asian versus European origin who participated in the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study. ACTFAST was a 12-week prospective, open-label study in patients at high risk for atherosclerosis (European origin, n = 1978; South Asian origin, n = 64). Compared with patients of European origin, patients of South Asian origin were younger, were less likely to smoke, and had lower body mass index, systolic blood pressure, low-density lipoprotein cholesterol (LDL-C) and triglycerides. Because significant differences were observed in baseline characteristics between patient groups, case control propensity scores were used. In the unmatched analysis, South Asians had greater LDL-C response to atorvastatin than patients of European origin. However, after propensity matching, atorvastatin lowered LDL-C and high sensitivity C-reactive protein (hs-CRP) to a similar degree in both groups, with no differences in safety profile. The authors observed no correlation between change in hs-CRP and LDL-C concentrations in either population. In conclusion, atorvastatin lowered both LDL-C and hs-CRP to a similar degree in patients of South Asian or European origin, suggesting usual starting doses of atorvastatin (with appropriate monitoring), rather than lower starting doses as has been advocated by some, may be used in patients of South Asian origin. PMID- 21610205 TI - Pharmacokinetics of levodopa/carbidopa delivered from gastric-retentive extended release formulations in patients with Parkinson's disease. AB - The investigators conducted a single-dose pharmacokinetic (PK) study of levodopa/carbidopa delivered from novel gastric-retentive extended-release (ER) tablets versus a comparator ER tablet (M-ER) in patients with Parkinson's disease. Two levodopa/carbidopa (200 mg/50 mg) gastric-retentive ER formulations (4 hours and 6 hours) and M-ER were administered orally with food. Blood samples were collected for up to 24 hours post dose to determine levodopa and carbidopa concentrations. Tolerability was assessed by monitoring adverse events and measuring vital signs. PK modeling was conducted to estimate the release characteristics for future gastric-retentive ER formulations to achieve a less fluctuating plasma concentration profiles. Compared with M-ER, both gastric retentive ER formulations exhibited a longer time to reach a lower maximal plasma concentration for levodopa and carbidopa. The 4-hour formulation demonstrated a similar area under the concentration-time curve compared with M-ER, whereas the 6 hour formulation demonstrated a lower area under the concentration-time curve. All formulations were well tolerated. Modeling suggests that a gastric-retentive ER formulation with a longer release duration administered twice daily may achieve a less fluctuating levodopa concentration profile than M-ER administered 3 times daily. This study demonstrates that gastric-retentive ER dosage forms may reduce dose frequency while minimizing the plasma peak-to-trough fluctuation and consequently reduce motor fluctuation in patients with Parkinson's disease. PMID- 21610206 TI - Pharmacokinetics of oral tonapofylline and its acyl-glucuronide metabolite in patients with mild and moderate hepatic impairment. AB - The objective of the study was to evaluate the effect of hepatic impairment on the pharmacokinetics of tonapofylline. Patients with mild or moderate hepatic impairment were enrolled in parallel with demographically matched healthy subjects. All study participants received a single 75-mg oral tonapofylline capsule. The pharmacokinetic parameters for both tonapofylline and its active metabolite, acyl-glucuronide (tonapofylline-AG), were affected by hepatic impairment significantly (P < .1) except for time to peak plasma concentration (t(max)), terminal half-life (t(1/2)), and apparent volume of distribution based on the terminal phase (Vdz/F). In the mild group, peak plasma concentration (C(max)), area under the time-concentration curve from time 0 to 48 hours postdose (AUC(48 h)), and from time 0 to infinity (AU(Cinf)) of tonapofylline modestly increased as compared with the control healthy subjects (GMR 1.62, 1.57, and 1.53, respectively). The extent of increase of these parameters for tonapofylline-AG was more profound than tonapofylline with geometric mean ratio (GMR) ranging from 2.02 to 2.08. Moderate hepatic impairment was also associated with modest increases of C(max), AUC(48 h), and AUC(inf) of tonapofylline (GMR 1.41, 1.98, and 2.08, respectively). Similar to the mild group, the increase of these parameters were higher for tonapofylline-AG with GMR ranging from 2.80 to 3.86. Single oral 75-mg tonapofylline was safe and well tolerated in patients with mild or moderate hepatic impairment. PMID- 21610207 TI - Opioid receptor modulation of hedonic taste preference and food intake: a single dose safety, pharmacokinetic, and pharmacodynamic investigation with GSK1521498, a novel MU-opioid receptor inverse agonist. AB - Endogenous opioids and u-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a u-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption. PMID- 21610208 TI - Nutrition therapy in a pediatric intensive care unit: indications, monitoring, and complications. AB - BACKGROUND: Nutrition therapy (NT) is essential for the care of critically ill children. Inadequate feeding leads to malnutrition and may increase the patient's risk of morbidity and mortality. The aim of this study was to describe the NT used in a tertiary pediatric intensive care unit (PICU). METHODS: The authors evaluated NT administered to 90 consecutive patients who were hospitalized for 7 days in the PICU of Instituto da Crianca, Hospital das Clinicas, Universidade de Sao Paulo, Brazil. NT was established according to the protocol provided by the institution's NT team. NT provided a balance of fluids and nutrients and was monitored with a weekly anthropometric nutrition assessment and an evaluation of complications. RESULTS: NT was initiated, on average, within 72 hours of hospitalization. Most children (80%) received enteral nutrition (EN) therapy; of these, 35% were fed orally and the rest via nasogastric or postpyloric tube. There were gastrointestinal complications in patients (5%) who needed a postpyloric tube. Parenteral nutrition (PN) was used in only 10% of the cases, and the remaining 10% received mixed NT (EN + PN). The average calorie and protein intake was 82 kcal/kg and 2.7 g/kg per day. Arm circumference and triceps skinfold thickness decreased. CONCLUSIONS: The use of EN was prevalent in the tertiary PICU, and few clinical complications occurred. There was no statistically significant change in most anthropometric indicators evaluated during hospitalization, which suggests that NT probably helped patients maintain their nutrition status. PMID- 21610209 TI - Phylogeny, evolutionary trends and classification of the Spathelia-Ptaeroxylon clade: morphological and molecular insights. AB - BACKGROUND AND AIMS: The Spathelia-Ptaeroxylon clade is a group of morphologically diverse plants that have been classified together as a result of molecular phylogenetic studies. The clade is currently included in Rutaceae and recognized at a subfamilial level (Spathelioideae) despite the fact that most of its genera have traditionally been associated with other families and that there are no obvious morphological synapomorphies for the clade. The aim of the present study is to construct phylogenetic trees for the Spathelia-Ptaeroxylon clade and to investigate anatomical characters in order to decide whether it should be kept in Rutaceae or recognized at the familial level. Anatomical characters were plotted on a cladogram to help explain character evolution within the group. Moreover, phylogenetic relationships and generic limits within the clade are also addressed. METHODS: A species-level phylogenetic analysis of the Spathelia Ptaeroxylon clade based on five plastid DNA regions (rbcL, atpB, trnL-trnF, rps16 and psbA-trnH) was conducted using Bayesian, maximum parsimony and maximum likelihood methods. Leaf and seed anatomical characters of all genera were (re)investigated by light and scanning electron microscopy. KEY RESULTS: With the exception of Spathelia, all genera of the Spathelila-Ptaeroxylon clade are monophyletic. The typical leaf and seed anatomical characters of Rutaceae were found. Further, the presence of oil cells in the leaves provides a possible synapomorphy for the clade. CONCLUSIONS: The Spathelia-Ptaeroxylon clade is well placed in Rutaceae and it is reasonable to unite the genera into one subfamily (Spathelioideae). We propose a new tribal classification of Spathelioideae. A narrow circumscription of Spathelia is established to make the genus monophyletic, and Sohnreyia is resurrected to accommodate the South American species of Spathelia. The most recent common ancestor of Spathelioideae probably had leaves with secretory cavities and oil cells, haplostemonous flowers with appendaged staminal filaments, and a tracheidal tegmen. PMID- 21610210 TI - Pterandra pyroidea: a case of pollination shift within neotropical Malpighiaceae. AB - BACKGROUND AND AIMS: Most Neotropical species of Malpighiaceae produce floral fatty oils in calyx glands to attract pollinating oil-collecting bees, which depend on this resource for reproduction. This specialized type of pollination system tends to be lost in members of the family that occur outside the geographic distribution (e.g. Africa) of Neotropical oil-collecting bees. This study focused on the pollination ecology, chemical ecology and reproductive biology of an oil flower species, Pterandra pyroidea (Malpighiaceae) from the Brazilian Cerrado. Populations of this species consist of plants with oil secreting (glandular) flowers, plants with non-oil-secreting flowers (eglandular) or a mix of both plant types. This study specifically aims to clarify the role of eglandular morphs in this species. METHODS: Data on pollinators were recorded by in situ observations. Breeding system experiments were conducted by isolating inflorescences and by enzymatic reactions. Floral resources, pollen and floral oils offered by this species were analysed by staining and a combination of various spectroscopic methods. KEY RESULTS: Eglandular flowers of P. pyroidea do not act as mimics of their oil-producing conspecifics to attract pollinators. Instead, both oil-producing and oil-free flowers depend on pollen-collecting bees for reproduction, and their main pollinators are bumble-bees. Floral oils produced by glandular flowers are less complex than those described in closely related genera. CONCLUSIONS: Eglandular flowers represent a shift in the pollination system in which oil is being lost and pollen is becoming the main reward of P. pyroidea flowers. Pollination shifts of this kind have hitherto not been demonstrated empirically within Neotropical Malpighiaceae and this species exhibits an unusual transition from a specialized towards a generalized pollination system in an area considered the hotspot of oil-collecting bee diversity in the Neotropics. Transitions of this type provide an opportunity to study ongoing evolutionary mechanisms that promote the persistence of species previously involved in specialized mutualistic relationships. PMID- 21610211 TI - The rocks and shallows of deep RNA sequencing: Examples in the Vibrio cholerae RNome. AB - New deep RNA sequencing methodologies in transcriptome analyses identified a wealth of novel nonprotein-coding RNAs (npcRNAs). Recently, deep sequencing was used to delineate the small npcRNA transcriptome of the human pathogen Vibrio cholerae and 627 novel npcRNA candidates were identified. Here, we report the detection of 223 npcRNA candidates in V. cholerae by different cDNA library construction and conventional sequencing methods. Remarkably, only 39 of the candidates were common to both surveys. We therefore examined possible biasing influences in the transcriptome analyses. Key steps, including tailing and adapter ligations for generating cDNA, contribute qualitatively and quantitatively to the discrepancies between data sets. In addition, the state of 5'-end phosphorylation influences the efficiency of adapter ligation and C tailing at the 3'-end of the RNA. Finally, our data indicate that the inclusion of sample-specific molecular identifier sequences during ligation steps also leads to biases in cDNA representation. In summary, even deep sequencing is unlikely to identify all RNA species, and caution should be used for meta analyses among alternatively generated data sets. PMID- 21610212 TI - Sharing and archiving nucleic acid structure mapping data. AB - Nucleic acids are particularly amenable to structural characterization using chemical and enzymatic probes. Each individual structure mapping experiment reveals specific information about the structure and/or dynamics of the nucleic acid. Currently, there is no simple approach for making these data publically available in a standardized format. We therefore developed a standard for reporting the results of single nucleotide resolution nucleic acid structure mapping experiments, or SNRNASMs. We propose a schema for sharing nucleic acid chemical probing data that uses generic public servers for storing, retrieving, and searching the data. We have also developed a consistent nomenclature (ontology) within the Ontology of Biomedical Investigations (OBI), which provides unique identifiers (termed persistent URLs, or PURLs) for classifying the data. Links to standardized data sets shared using our proposed format along with a tutorial and links to templates can be found at http://snrnasm.bio.unc.edu. PMID- 21610213 TI - Substrate specificity and mutational analysis of Kluyveromyces lactis gamma toxin, a eukaryal tRNA anticodon nuclease. AB - tRNA anticodon damage inflicted by the Kluyveromyces lactis gamma-toxin underlies an RNA-based innate immune system that distinguishes self from nonself species. gamma-toxin arrests the growth of Saccharomyces cerevisiae by incising a single phosphodiester 3' of the wobble base of tRNA(Glu(UUC)) to generate a break with 2',3'-cyclic phosphate and 5'-OH ends. Recombinant gamma-toxin cleaves oligonucleotide substrates in vitro that mimic the anticodon stem-loop of tRNA(Glu). A single 2'-deoxy sugar substitution at the wobble nucleoside abolishes anticodon nuclease activity. To gain further insights to gamma-toxin's substrate specificity, we tested deoxynucleoside effects at positions other than the site of transesterification. The results attest to a stringent requirement for a ribonucleoside at the uridine 5' of the wobble base. In contrast, every other nonwobble ribonucleoside in the anticodon loop can be replaced by a deoxy without significantly affecting gamma-toxin's cleavage activity. Whereas either the 5' half or the 3' half of the anticodon stem can be replaced en bloc with DNA without a major effect, simultaneously replacing both strands with DNA interfered strongly, signifying that gamma-toxin requires an A-form helical conformation of the anticodon stem. We purified gamma-toxin mutants identified previously as nontoxic in vivo and gauged their anticodon nuclease activities in vitro. The results highlight Glu9 and Arg151 as candidate catalytic residues, along with His209 implicated previously. By analogy to other endoribonucleases, we speculate that gamma-toxin drives transesterification by general acid-base catalysis (via His209 and Glu9) and transition-state stabilization (via Arg151). PMID- 21610215 TI - Sperm chemotaxis and regulation of flagellar movement by Ca2+. AB - The chemotaxis of sperm towards eggs is a widespread phenomenon that occurs in most forms of life from lower plants to mammals and plays important roles in ensuring fertilization. In spermatozoa, the attractants act as beacons, indicating the path leading to the eggs from the same species. The existence of species-specific sperm chemotaxis has been demonstrated in marine invertebrates; thus, sperm chemotaxis may be involved in preventing crossbreeding, especially in marine invertebrates with external fertilization. However, the mechanisms of sperm chemotaxis in mammalian species differ from those of marine invertebrates. In mammals, the attractant source is not the egg, but follicular fluids or cumulus cells and chemotactic behaviour is shown only in small populations of sperm. Nevertheless, the fundamental mechanisms underlying sperm chemotaxis are likely to be common among all species. Among these mechanisms, intracellular Ca(2+) concentration ([Ca(2+)](i)) is an important factor for the regulation of chemotactic behaviour in spermatozoa. Sperm attractants induce the entry of extracellular Ca(2+), resulting in [Ca(2+)](i) increase in the sperm cells. Furthermore, [Ca(2+)](i) modulates sperm flagellar movement. However, the relationship between [Ca(2+)](i) and the chemotactic response of a sperm flagellum is not well known. Investigation of the dynamic responses of sperm cells to their attractants is important for our understanding of the regulation of fertilization. Here, we reviewed sperm chemotaxis focusing on the mechanisms that regulate sperm flagellar beating during the chemotactic response. PMID- 21610214 TI - Structural and functional analysis of Nro1/Ett1: a protein involved in translation termination in S. cerevisiae and in O2-mediated gene control in S. pombe. AB - In Saccharomyces cerevisiae, the putative 2-OG-Fe(II) dioxygenase Tpa1 and its partner Ett1 have been shown to impact mRNA decay and translation. Hence, inactivation of these factors was shown to influence stop codon read-though. In addition, Tpa1 represses, by an unknown mechanism, genes regulated by Hap1, a transcription factor involved in the response to levels of heme and O(2). The Schizosaccharomyces pombe orthologs of Tpa1 and Ett1, Ofd1, and its partner Nro1, respectively, have been shown to regulate the stability of the Sre1 transcription factor in response to oxygen levels. To gain insight into the function of Nro1/Ett1, we have solved the crystal structure of the S. pombe Nro1 protein deleted of its 54 N-terminal residues. Nro1 unexpectedly adopts a Tetratrico Peptide Repeat (TPR) fold, a motif often responsible for protein or peptide binding. Two ligands, a sulfate ion and an unknown molecule, interact with a cluster of highly conserved amino acids on the protein surface. Mutation of these residues demonstrates that these ligand binding sites are essential for Ett1 function in S. cerevisiae, as investigated by assaying for efficient translation termination. PMID- 21610216 TI - Patient safety and clinical effectiveness as imperatives for achieving harmonization inside and outside the clinical laboratory. PMID- 21610217 TI - Between-method differences in prostate-specific antigen assays affect prostate cancer risk prediction by nomograms. AB - BACKGROUND: To date, no published nomogram for prostate cancer (PCa) risk prediction has considered the between-method differences associated with estimating concentrations of prostate-specific antigen (PSA). METHODS: Total PSA (tPSA) and free PSA were measured in 780 biopsy-referred men with 5 different assays. These data, together with other clinical parameters, were applied to 5 published nomograms that are used for PCa detection. Discrimination and calibration criteria were used to characterize the accuracy of the nomogram models under these conditions. RESULTS: PCa was found in 455 men (58.3%), and 325 men had no evidence of malignancy. Median tPSA concentrations ranged from 5.5 MUg/L to 7.04 MUg/L, whereas the median percentage of free PSA ranged from 10.6% to 16.4%. Both the calibration and discrimination of the nomograms varied significantly across different types of PSA assays. Median PCa probabilities, which indicate PCa risk, ranged from 0.59 to 0.76 when different PSA assays were used within the same nomogram. On the other hand, various nomograms produced different PCa probabilities when the same PSA assay was used. Although the ROC curves had comparable areas under the ROC curve, considerable differences were observed among the 5 assays when the sensitivities and specificities at various PCa probability cutoffs were analyzed. CONCLUSIONS: The accuracy of the PCa probabilities predicted according to different nomograms is limited by the lack of agreement between the different PSA assays. This difference between methods may lead to unacceptable variation in PCa risk prediction. A more cautious application of nomograms is recommended. PMID- 21610219 TI - Does exposure to asbestos cause ovarian cancer? A systematic literature review and meta-analysis. AB - INTRODUCTION: The asbestos and ovarian cancer relationship is not well understood because of small numbers of women exposed to asbestos, small numbers of cases, and misclassification of peritoneal mesothelioma as ovarian cancer on death certificates. The aim of this study was to conduct a meta-analysis to quantify the evidence that exposure to asbestos causes ovarian cancer. METHODS: Fourteen cohort and two case-control studies were identified in Medline searches from 1950 to 2008. RESULTS: Statistically significant excess mortality was reported in four of the cohort studies, all of which determined their outcomes from the death certificate. Peritoneal mesotheliomas were reported in these studies, two of which reexamined pathology specimens and reported disease misclassification. Exposure-response relationships were inconsistent. When all studies were included in a meta-analysis, the effect size was 1.75 (95% CI, 1.45-2.10) attenuating to 1.29 (95% CI, 0.97-1.73) in studies with confirmed ovarian cancers. CONCLUSION: Taken without further analysis, women thought to have ovarian cancer had an increased rate in the meta-analysis if reporting having been exposed to asbestos, compared with reference populations. This result may have occurred because of disease misclassification. PMID- 21610220 TI - Volume of mammographic density and risk of breast cancer. AB - BACKGROUND: Assessing the volume of mammographic density might more accurately reflect the amount of breast volume at risk of malignant transformation and provide a stronger indication of risk of breast cancer than methods based on qualitative scores or dense breast area. METHODS: We prospectively collected mammograms for women undergoing screening mammography. We determined the diagnosis of subsequent invasive or ductal carcinoma in situ for 275 cases, selected 825 controls matched for age, ethnicity, and mammography system, and assessed three measures of breast density: percent dense area, fibroglandular volume, and percent fibroglandular volume. RESULTS: After adjustment for familial breast cancer history, body mass index, history of breast biopsy, and age at first live birth, the ORs for breast cancer risk in the highest versus lowest measurement quintiles were 2.5 (95% CI: 1.5-4.3) for percent dense area, 2.9 (95% CI: 1.7-4.9) for fibroglandular volume, and 4.1 (95% CI: 2.3-7.2) for percent fibroglandular volume. Net reclassification indexes for density measures plus risk factors versus risk factors alone were 9.6% (P = 0.07) for percent dense area, 21.1% (P = 0.0001) for fibroglandular volume, and 14.8% (P = 0.004) for percent fibroglandular volume. Fibroglandular volume improved the categorical risk classification of 1 in 5 women for both women with and without breast cancer. CONCLUSION: Volumetric measures of breast density are more accurate predictors of breast cancer risk than risk factors alone and than percent dense area. IMPACT: Risk models including dense fibroglandular volume may more accurately predict breast cancer risk than current risk models. PMID- 21610218 TI - Estrogen metabolism and exposure in a genotypic-phenotypic model for breast cancer risk prediction. AB - BACKGROUND: Current models of breast cancer risk prediction do not directly reflect mammary estrogen metabolism or genetic variability in exposure to carcinogenic estrogen metabolites. METHODS: We developed a model that simulates the kinetic effect of genetic variants of the enzymes CYP1A1, CYP1B1, and COMT on the production of the main carcinogenic estrogen metabolite, 4-hydroxyestradiol (4-OHE(2)), expressed as area under the curve metric (4-OHE(2)-AUC). The model also incorporates phenotypic factors (age, body mass index, hormone replacement therapy, oral contraceptives, and family history), which plausibly influence estrogen metabolism and the production of 4-OHE(2). We applied the model to two independent, population-based breast cancer case-control groups, the German GENICA study (967 cases, 971 controls) and the Nashville Breast Cohort (NBC; 465 cases, 885 controls). RESULTS: In the GENICA study, premenopausal women at the 90th percentile of 4-OHE(2)-AUC among control subjects had a risk of breast cancer that was 2.30 times that of women at the 10th control 4-OHE(2)-AUC percentile (95% CI: 1.7-3.2, P = 2.9 * 10(-7)). This relative risk was 1.89 (95% CI: 1.5-2.4, P = 2.2 * 10(-8)) in postmenopausal women. In the NBC, this relative risk in postmenopausal women was 1.81 (95% CI: 1.3-2.6, P = 7.6 * 10(-4)), which increased to 1.83 (95% CI: 1.4-2.3, P = 9.5 * 10(-7)) when a history of proliferative breast disease was included in the model. CONCLUSIONS: The model combines genotypic and phenotypic factors involved in carcinogenic estrogen metabolite production and cumulative estrogen exposure to predict breast cancer risk. IMPACT: The estrogen carcinogenesis-based model has the potential to provide personalized risk estimates. PMID- 21610221 TI - Chemokine RANTES promoter dimorphisms and hepatocellular carcinoma occurrence in patients with alcoholic or hepatitis C virus-related cirrhosis. AB - BACKGROUND: This study explores the influence of two functional genetic polymorphisms in the regulated on activation in normal T-cell expressed and secreted(RANTES) promoter on the risk of hepatocellular carcinoma (HCC) occurrence in patients with alcoholic or Hepatitis C Virus (HCV)-related cirrhosis. METHODS: RANTES C-28G and G-403A promoter dimorphisms and RANTES serum levels were assessed in 243 HCV-infected patients and 253 alcoholic patients, included at the time of diagnosis of cirrhosis and prospectively followed-up. RESULTS: During a mean follow-up time of 76 months, 137 (27.6%) patients developed HCC and 170 (34.2%) died or were transplanted. During follow-up, patients with alcoholic cirrhosis and bearing two copies of the RANTES G-403 variant (2G-403 genotype, n = 156/253) had a higher rate of HCC occurrence compared with patients carrying at least one RANTES A-403 allele (26.3% vs. 8.2%, P = 0.0004). The RANTES 2G-403 genotype was a risk factor for HCC occurrence [HR = 3.0 (1.3-5.8); first quartile time to HCC occurrence: 60 vs. 120 months; LogRank = 0.007] and death [HR = 1.4 (1.0-2.0); median time to death: 55 vs. 79 months; LogRank = 0.01] in this subgroup. Carriage of the RANTES 2G-403 genotype was not associated with HCC development or death in patients with HCV-related cirrhosis. The RANTES C-28G dimorphism did not influence the occurrence of death or HCC in either cohort of patients. CONCLUSION: This study suggests an influence of the chemokine RANTES G-403A dimorphism on the occurrence of HCC in patients with alcoholic cirrhosis. IMPACT: Our findings provide clues for future studies on RANTES gene in relation to HCC susceptibility. PMID- 21610222 TI - Variation in TP63 is associated with lung adenocarcinoma in the UK population. AB - BACKGROUND: Variation at TP63 has recently been shown to be associated with lung adenocarcinoma in the Asian population. METHODS: To investigate how this finding translates to the European population we compared the genotypes of SNPs annotating the TP63 locus at 3q28 in 4,462 lung cancer patients, including 911 with adenocarcinoma, and 8,235 controls from the United Kingdom. RESULTS: A statistically significant association between adenocarcinoma risk and SNP genotype was shown: rs10937405, OR = 1.21, P = 1.82 * 10(-4); rs17429138, OR = 1.23, P = 7.49 * 10(-5); and rs4396880, OR = 1.21, P = 2.03 * 10(-4). Haplotype analysis was consistent with a single TP63 risk locus defined by SNPs rs10937405, rs17429138, and rs4396880. While no association between SNPs and small cell lung cancer was shown, the rs10937405 and rs439680 associations were significant for squamous cancer (respective P-values, 0.0022 and 0.02). CONCLUSIONS: These findings show TP63 variation is a risk factor for the development of lung adenocarcinoma in the UK population. Furthermore, they provide additional insight into the subtype-specificity of the 3q28 lung cancer association. IMPACT: Our data confirm the association of 3q28 with lung adenocarcinoma and that this association is not confined to the Asian population. Elucidating the functional basis of this association will be contingent on future fine mapping of the TP63 loci. PMID- 21610223 TI - Age-period-cohort models in cancer surveillance research: ready for prime time? AB - Standard descriptive methods for the analysis of cancer surveillance data include canonical plots based on the lexis diagram, directly age-standardized rates (ASR), estimated annual percentage change (EAPC), and joinpoint regression. The age-period-cohort (APC) model has been used less often. Here, we argue that it merits much broader use. First, we describe close connections between estimable functions of the model parameters and standard quantities such as the ASR, EAPC, and joinpoints. Estimable functions have the added value of being fully adjusted for period and cohort effects, and generally more precise. Second, the APC model provides the descriptive epidemiologist with powerful new tools, including rigorous statistical methods for comparative analyses, and the ability to project the future burden of cancer. We illustrate these principles by using invasive female breast cancer incidence in the United States, but these concepts apply equally well to other cancer sites for incidence or mortality. PMID- 21610224 TI - Smoking and passive smoking in cervical cancer risk: pooled analysis of couples from the IARC multicentric case-control studies. AB - BACKGROUND: The independent role of tobacco smoking in invasive cervical cancer (ICC) has been established. We evaluated the potential impact of passive smoking (PS). METHODS: A pooled analysis of 1,919 couples enrolled in one of seven case control studies involving cervical carcinoma in situ (CIS) or ICC was investigated. Information on smoking and sexual behavior was collected from interviews. Specimens were taken from the cervix and penis for human papillomavirus (HPV) DNA testing. Three PS risk models were constructed with all couples, couples with monogamous women, and couples with lifetime nonsmoking monogamous women. For the third model, the analysis considered potential misclassification of smoking status and was restricted to the risk period for which the woman was exposed to both HPV, a necessary cause of ICC, and PS. Multivariable unconditional logistic regression was used to estimate associations between CIS or ICC and PS. RESULTS: An increased risk was found among couples with both ever smoking men and women (OR = 2.26; 95% CI: 1.40-3.64). No statistically increased risk of CIS was found with PS in the models analyzed. Similar significant increased risks of ICC with PS was found among all couples (OR = 1.57; 95% CI: 1.15-2.15) and couples with monogamous women (OR = 1.55; 95% CI: 1.07-2.23) but not among lifetime nonsmoking monogamous women married to ever smoking men. CONCLUSION: PS could not be detected as an independent risk factor of ICC in the absence of active smoking. IMPACT: The combined effects of exposure to active and PS suggest its potential adverse role in cervical carcinogenesis. PMID- 21610225 TI - Difference of tissue characteristics between early and very late restenosis lesions after bare-metal stent implantation: an optical coherence tomography study. AB - BACKGROUND: Although in-stent restenosis (ISR) after bare-metal stent (BMS) implantation peaks in the early phase, very late (VL) ISR occasionally is observed beyond a few years after BMS implantation. To date, this mechanism has not been fully clarified. METHODS AND RESULTS: We compared the morphological characteristics of VL-ISR (>5 years, without restenosis within the first year) (n=43) to those of early (E) ISR (within the first year) (n=39) using optical coherence tomography (OCT). Qualitative restenotic tissue analysis included assessment of tissue structure (homogeneous or heterogeneous), presence of microvessels, disrupted intima with cavity, and intraluminal material and was performed at every 1-mm slice of the entire stent. The proportions of cross sections with heterogeneous intima in the entire stent was significantly higher in the VL-ISR group compared to the E-ISR group (60.5+/-28.5% versus 5.8+/-11.5%, P<0.0001), with heterogeneous intima being more frequently observed at the minimum lumen area site in the VL-ISR group (90.7% versus 17.9%, P<0.0001). Disrupted intima with cavity and intraluminal material also were observed more frequently in the VL-ISR group for the entire stent (18.6% versus 0%, 20.9% versus 2.6%, P<0.03) as well as at the minimum lumen area site (13.9% versus 0%,16.2% versus 0%, P<0.03). CONCLUSIONS: The morphological characteristics of restenotic tissue in VL-ISR were different from those in E-ISR and similar to atherosclerotic plaque. In BMS, progression of the atherosclerotic process within neointima after stent implantation may be associated with VL-ISR. PMID- 21610228 TI - The cover. Portrait of Dorothy (Dorothy Williamson). PMID- 21610226 TI - Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. AB - Insulin, at physiological concentrations, regulates the volume of microvasculature perfused within skeletal and cardiac muscle. It can also, by relaxing the larger resistance vessels, increase total muscle blood flow. Both of these effects require endothelial cell nitric oxide generation and smooth muscle cell relaxation, and each could increase delivery of insulin and nutrients to muscle. The capillary microvasculature possesses the greatest endothelial surface area of the body. Yet, whether insulin acts on the capillary endothelial cell is not known. Here, we review insulin's actions at each of three levels of the arterial vasculature as well as recent data suggesting that insulin can regulate a vesicular transport system within the endothelial cell. This latter action, if it occurs at the capillary level, could enhance insulin delivery to muscle interstitium and thereby complement insulin's actions on arteriolar endothelium to increase insulin delivery. We also review work that suggests that this action of insulin on vesicle transport depends on endothelial cell nitric oxide generation and that insulin's ability to regulate this vesicular transport system is impaired by inflammatory cytokines that provoke insulin resistance. PMID- 21610227 TI - Characterization of the diurnal rhythm of peptide YY and its association with energy balance parameters in normal-weight premenopausal women. AB - PYY may play a role in modulating satiety and energy expenditure; increasing PYY postprandially has been studied largely in single-meal responses. The diurnal rhythm of PYY and its role in energy balance have not been fully characterized. The purpose of our study was to characterize features of the diurnal rhythm of PYY and determine its role in regulating energy balance. This study was a cross sectional analysis of 11 subjects in whom 24-h repeated blood sampling was conducted at baseline of a larger prospective study. Breakfast (B), lunch (L), dinner (D), and a snack (S) occurred between 0900 and 1900. Total PYY was assayed every hour from 0800 to 1000, every 20 min from 1000 to 2000, and every hour from 2000 to 0800. PYY variables included total AUC, postprandial peaks, and 24-h mean. Energy balance variables included energy intake, RMR, RQ, and NEAT. PYY postprandial peaks were significantly higher than fasting (P < 0.05). Twenty-four hour peak PYY occurred after L and was significantly higher than all other peaks (P < 0.05). A cubic curve function accounted for most of the variance in PYY (r(2) = 69.9%, P < 0.01). Fasting PYY (0800) correlated with postprandial peaks at B (r = 0.77, P = 0.01), L (r = 0.71, P = 0.01), and D (r = 0.65, P = 0.03). The only significant association between PYY and energy expenditure was that RMR (kcal/24 h) correlated with 24-h mean PYY (r = 0.71, P = 0.013) and total AUC (r = 0.69, P = 0.019). We conclude that PYY displays a meal-driven diurnal rhythm and is correlated to RMR, a major contributor to energy expenditure. Thus, PYY varies in accordance with energy content and RMR, supporting a role for PYY in energy balance modulation. PMID- 21610229 TI - A piece of my mind. Dear provider. PMID- 21610230 TI - Researchers praise drug-eluting stents but appropriate use is still debated. PMID- 21610231 TI - Cancer drug offers effective, cheaper option for AMD. PMID- 21610232 TI - Albany prize honors stem cell scientists. PMID- 21610233 TI - Cell phone activation and brain glucose metabolism. PMID- 21610234 TI - Cell phone activation and brain glucose metabolism. PMID- 21610235 TI - Cell phone activation and brain glucose metabolism. PMID- 21610236 TI - Bisphosphonate use and femoral fractures in older women. PMID- 21610237 TI - Bisphosphonate use and femoral fractures in older women. PMID- 21610238 TI - Safety of genetically modified mosquitoes. PMID- 21610239 TI - Oral vs intratympanic corticosteroid therapy for idiopathic sudden sensorineural hearing loss: a randomized trial. AB - CONTEXT: Idiopathic sudden sensorineural hearing loss has been treated with oral corticosteroids for more than 30 years. Recently, many patients' symptoms have been managed with intratympanic steroid therapy. No satisfactory comparative effectiveness study to support this practice exists. OBJECTIVE: To compare the effectiveness of oral vs intratympanic steroid to treat sudden sensorineural hearing loss. DESIGN, SETTING, AND PATIENTS: Prospective, randomized, noninferiority trial involving 250 patients with unilateral sensorineural hearing loss presenting within 14 days of onset of 50 dB or higher of pure tone average (PTA) hearing threshold. The study was conducted from December 2004 through October 2009 at 16 academic community-based otology practices. Participants were followed up for 6 months. INTERVENTION: One hundred twenty-one patients received either 60 mg/d of oral prednisone for 14 days with a 5-day taper and 129 patients received 4 doses over 14 days of 40 mg/mL of methylprednisolone injected into the middle ear. MAIN OUTCOME MEASURES: Primary end point was change in hearing at 2 months after treatment. Noninferiority was defined as less than a 10-dB difference in hearing outcome between treatments. RESULTS: In the oral prednisone group, PTA improved by 30.7 dB compared with a 28.7-dB improvement in the intratympanic treatment group. Mean pure tone average at 2 months was 56.0 for the oral steroid treatment group and 57.6 dB for the intratympanic treatment group. Recovery of hearing on oral treatment at 2 months by intention-to-treat analysis was 2.0 dB greater than intratympanic treatment (95.21% upper confidence interval, 6.6 dB). Per-protocol analysis confirmed the intention-to-treat result. Thus, the hypothesis of inferiority of intratympanic methylprednisolone to oral prednisone for primary treatment of sudden sensorineural hearing loss was rejected. CONCLUSION: Among patients with idiopathic sudden sensorineural hearing loss, hearing level 2 months after treatment showed that intratympanic treatment was not inferior to oral prednisone treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00097448. PMID- 21610240 TI - Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation. AB - CONTEXT: The risks associated with new-onset atrial fibrillation (AF) among middle-aged women and populations with a low comorbidity burden are poorly defined. OBJECTIVES: To examine the association between incident AF and mortality in initially healthy women and to evaluate the influence of associated cardiovascular comorbidities on risk. DESIGN, SETTING, AND PARTICIPANTS: Between 1993 and March 16, 2010, 34,722 women participating in the Women's Health Study underwent prospective follow-up. Participants were 95% white, older than 45 years (median, 53 [interquartile range {IQR}, 49-59] years), and free of AF and cardiovascular disease at baseline. Cox proportional hazards models with time varying covariates were used to determine the risk of events among women with incident AF. Secondary analyses were performed among women with paroxysmal AF. MAIN OUTCOME MEASURES: Primary outcomes included all-cause, cardiovascular, and noncardiovascular mortality. Secondary outcomes included stroke, congestive heart failure, and myocardial infarction. RESULTS: During a median follow-up of 15.4 (IQR, 14.7-15.8) years, 1011 women developed AF. Incidence rates per 1000 person years among women with and without AF were 10.8 (95% confidence interval [CI], 8.1-13.5) and 3.1 (95% CI, 2.9-3.2) for all-cause mortality, 4.3 (95% CI, 2.6 6.0) and 0.57 (95% CI, 0.5-0.6) for cardiovascular mortality, and 6.5 (95% CI, 4.4-8.6) and 2.5 (95% CI, 2.4-2.6) for noncardiovascular mortality, respectively. In multivariable models, hazard ratios (HRs) of new-onset AF for all-cause, cardiovascular, and noncardiovascular mortality were 2.14 (95% CI, 1.64-2.77), 4.18 (95% CI, 2.69-6.51), and 1.66 (95% CI, 1.19-2.30), respectively. Adjustment for nonfatal cardiovascular events potentially on the causal pathway to death attenuated these risks, but incident AF remained associated with all mortality components (all-cause: HR, 1.70 [95% CI, 1.30-2.22]; cardiovascular: HR, 2.57 [95% CI, 1.63-4.07]; and noncardiovascular: HR, 1.42 [95% CI, 1.02-1.98]). Among women with paroxysmal AF (n = 656), the increase in mortality risk was limited to cardiovascular causes (HR, 2.94; 95% CI, 1.55-5.59). CONCLUSION: Among a group of healthy women, new-onset AF was independently associated with all-cause, cardiovascular, and noncardiovascular mortality, with some of the risk potentially explained by nonfatal cardiovascular events. PMID- 21610241 TI - Association of copeptin and N-terminal proBNP concentrations with risk of cardiovascular death in older patients with symptoms of heart failure. AB - CONTEXT: Measurement of plasma concentrations of the biomarker copeptin may help identify patients with heart failure at high and low risk of mortality, although the value of copeptin measurement in elderly patients is not fully known. OBJECTIVE: To evaluate the association between plasma concentrations of copeptin, a surrogate marker of vasopressin, combined with concentrations of the N-terminal fragment of the precursor to B-type natriuretic peptide (NT-proBNP), and mortality in a cohort of elderly patients with symptoms of heart failure. DESIGN, SETTING, AND PARTICIPANTS: Primary health care population in Sweden enrolling 470 elderly patients with heart failure symptoms between January and December 1996. Clinical examination, echocardiography, and measurement of peptide concentrations were performed, with follow-up through December 2009. MAIN OUTCOME MEASURES: All cause mortality and cardiovascular mortality. RESULTS: After a median follow-up of 13 years, there were 226 deaths from all causes, including 146 deaths from cardiovascular causes. Increased concentration of copeptin was associated with increased risk of all-cause mortality (fourth quartile vs first quartile: 69.5% vs 38.5%, respectively; hazard ratio [HR], 2.04 [95% confidence interval {CI}, 1.38-3.02]) and cardiovascular mortality (fourth quartile vs first quartile: 46.6% vs 26.5%; HR, 1.94 [95% CI, 1.20-3.13]). The combination of elevated NT proBNP concentrations and elevated copeptin concentrations also was associated with increased risk of all-cause mortality (copeptin fourth quartile: HR, 1.63 [95% CI, 1.08-2.47]; P = .01; NT-proBNP fourth quartile: HR, 3.17 [95% CI, 2.02 4.98]; P < .001). Using the 2 biomarkers simultaneously in the evaluation of cardiovascular mortality, there was a significant association for copeptin in the presence of NT-proBNP (log likelihood trend test, P = .048) and a significant association for NT-proBNP (fourth quartile: HR, 4.68 [95% CI 2.63-8.34]; P < .001). CONCLUSION: Among elderly patients with symptoms of heart failure, elevated concentrations of copeptin and the combination of elevated concentrations of copeptin and NT-proBNP were associated with increased risk of all-cause mortality. PMID- 21610242 TI - Primary care physician workforce and Medicare beneficiaries' health outcomes. AB - CONTEXT: Despite a widespread interest in increasing the numbers of primary care physicians to improve care and to moderate costs, the relationship of the primary care physician workforce to patient-level outcomes remains poorly understood. OBJECTIVE: To measure the association between the adult primary care physician workforce and individual patient outcomes. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional analysis of the outcomes of a 2007 20% sample of fee-for-service Medicare beneficiaries aged 65 years or older (N = 5,132,936), which used 2 measures of adult primary care physicians (general internists and family physicians) across Primary Care Service Areas (N = 6542): (1) American Medical Association (AMA) Masterfile nonfederal, office-based physicians per total population and (2) office-based primary care clinical full-time equivalents (FTEs) per Medicare beneficiary derived from Medicare claims. MAIN OUTCOME MEASURES: Annual individual-level outcomes (mortality, ambulatory care sensitive condition [ACSC] hospitalizations, and Medicare program spending), adjusted for individual patient characteristics and geographic area variables. RESULTS: Marked variation was observed in the primary care physician workforce across areas, but low correlation was observed between the 2 primary care workforce measures (Spearman r = 0.056; P < .001). Compared with areas with the lowest quintile of primary care physician measure using AMA Masterfile counts, beneficiaries in the highest quintile had fewer ACSC hospitalizations (74.90 vs 79.61 per 1000 beneficiaries; relative rate [RR], 0.94; 95% confidence interval [CI], 0.93 0.95), lower mortality (5.38 vs 5.47 per 100 beneficiaries; RR, 0.98; 95% CI, 0.97-0.997), and no significant difference in total Medicare spending ($8722 vs $8765 per beneficiary; RR, 1.00; 95% CI, 0.99-1.00). Beneficiaries residing in areas with the highest quintile of primary care clinician FTEs compared with those in the lowest quintile had lower mortality (5.19 vs 5.49 per 100 beneficiaries; RR, 0.95; 95% CI, 0.93-0.96), fewer ACSC hospitalizations (72.53 vs 79.48 per 1000 beneficiaries; RR, 0.91; 95% CI, 0.90-0.92), and higher overall Medicare spending ($8857 vs $8769 per beneficiary; RR, 1.01; 95% CI, 1.004-1.02). CONCLUSION: A higher level of primary care physician workforce, particularly with an FTE measure that may more accurately reflect ambulatory primary care, was generally associated with favorable patient outcomes. PMID- 21610243 TI - Dangerous people or dangerous weapons: access to firearms for persons with mental illness. PMID- 21610244 TI - An opportunity map for societal investment in health. PMID- 21610245 TI - Are patients knights, knaves, or pawns? PMID- 21610246 TI - Steroids for idiopathic sudden sensorineural hearing loss: some questions answered, others remain. PMID- 21610247 TI - Mortality risk among middle-aged women with first atrial fibrillation. PMID- 21610248 TI - JAMA patient page. Abdominal hernia. PMID- 21610249 TI - Fish intake and the risk of incident heart failure: the Women's Health Initiative. AB - BACKGROUND: Whether fish or the fatty acids they contain are independently associated with risk for incident heart failure (HF) among postmenopausal women is unclear. METHODS AND RESULTS: The baseline Women's Health Initiative Observational Study cohort consisted of 93 676 women ages 50 to 79 years of diverse ethnicity and background, of which 84 493 were eligible for analyses. Intakes of baked/broiled fish, fried fish, and omega-3 fatty acid (eicosapentaenoic acid+docosahexaenoic acid, alpha-linolenic acid), and trans fatty acid were determined from the Women's Health Initiative food frequency questionnaire. Baked/broiled fish consumption was divided into 5 frequency categories: <1/mo (referent), 1 to 3/mo, 1 to 2/wk, 3 to 4/wk, >=5/wk. Fried fish intake was grouped into 3 frequency categories: <1/mo (referent), 1-3/mo, and >=1/wk. Associations between fish or fatty acid intake and incident HF were determined using Cox models adjusting for HF risk factors and dietary factors. Baked/broiled fish consumption (>=5 servings/wk at baseline) was associated with a hazard ratio of 0.70 (95% confidence interval, 0.51 to 0.95) for incident HF. In contrast, fried fish consumption (>=1 serving/wk at baseline) was associated with a hazard ratio of 1.48 (95% confidence interval, 1.19 to 1.84) for incident HF. No significant associations were found between eicosapentaenoic acid+docosahexaenoic acid, alpha-linolenic acid, or trans-fatty acid intake and incident HF. CONCLUSIONS: Increased baked/broiled fish intake may lower HF risk, whereas increased fried fish intake may increase HF risk in postmenopausal women. PMID- 21610250 TI - Progress in the function and regulation of ADP-Ribosylation. AB - Adenosine 5'-diphosphate (ADP)-ribosylation is a protein posttranslational modification that is catalyzed by ADP-ribosyltransferases (ARTs), using nicotinamide adenine dinucleotide (NAD(+)) as a substrate. Mono-ribosylation can be extended into polymers of ADP-ribose (PAR). Poly(ADP-ribosyl)polymerase (PARP) 1, the best-characterized cellular enzyme catalyzing this process, is the prototypical member of a family of mono- and poly(ADP-ribosyl)transferases. The physiological consequences of ADP-ribosylation are inadequately understood. PARP2010, the 18th International Conference on ADP-Ribosylation, attracted scientists from all over the world to Zurich, Switzerland. Highlights from this meeting include promising clinical trials with PARP inhibitors and new insights into cell, structural, and developmental biology of ARTs and the (glyco)hydrolase proteins that catalyze de-ADP-ribosylation of mono- or poly-ADP-ribosylated proteins. Moreover, potential links to the NAD-dependent sirtuin family were explored on the basis of a shared dependence on cellular NAD(+) concentrations and the relationship of ADP-ribosylation with intermediary metabolism and cellular energetics. PMID- 21610251 TI - alpha-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1. AB - The Hippo pathway regulates contact inhibition of cell proliferation and, ultimately, organ size in diverse multicellular organisms. Inactivation of the Hippo pathway promotes nuclear localization of the transcriptional coactivator Yap1, a Hippo pathway effector, and can cause cancer. Here, we show that deletion of alphaE (alpha epithelial) catenin in the hair follicle stem cell compartment resulted in the development of skin squamous cell carcinoma in mice. Tumor formation was accelerated by simultaneous deletion of alphaE-catenin and the tumor suppressor-encoding gene p53. A small interfering RNA screen revealed a functional connection between alphaE-catenin and Yap1. By interacting with Yap1, alphaE-catenin promoted its cytoplasmic localization, and Yap1 showed constitutive nuclear localization in alphaE-catenin-null cells. We also found an inverse correlation between alphaE-catenin abundance and Yap1 activation in human squamous cell carcinoma tumors. These findings identify alphaE-catenin as a tumor suppressor that inhibits Yap1 activity and sequesters it in the cytoplasm. PMID- 21610253 TI - Thematic reviews. PMID- 21610254 TI - Deiodinases: keeping the thyroid hormone supply in balance. PMID- 21610252 TI - p38alpha Signaling Induces Anoikis and Lumen Formation During Mammary Morphogenesis. AB - The stress-activated protein kinase (SAPK) p38 can induce apoptosis, and its inhibition facilitates mammary tumorigenesis. We found that during mammary acinar morphogenesis in MCF-10A cells grown in three-dimensional culture, detachment of luminal cells from the basement membrane stimulated mitogen-activated protein kinase (MAPK) kinases 3 and 6 (MKK3/6) and p38alpha signaling to promote anoikis. p38alpha signaling increased transcription of the death-promoting protein BimEL by phosphorylating the activating transcription factor 2 (ATF-2) and increasing c Jun protein abundance, leading to cell death by anoikis and acinar lumen formation. Inhibition of p38alpha or ATF-2 caused luminal filling reminiscent of that observed in ductal carcinoma in situ (DCIS). The mammary glands of MKK3/6 knockout mice (MKK3(-/-)/MKK6(+/- )) showed accelerated branching morphogenesis relative to those of wild-type mice, as well as ductal lumen occlusion due to reduced anoikis. This phenotype was recapitulated by systemic pharmacological inhibition of p38alpha and beta (p38alpha/beta) in wild-type mice. Moreover, the development of DCIS-like lesions showing marked ductal occlusion was accelerated in MMTV-Neu transgenic mice treated with inhibitors of p38alpha and p38beta. We conclude that p38alpha is crucial for the development of hollow ducts during mammary gland development, a function that may be crucial to its ability to suppress breast cancer. PMID- 21610255 TI - Sow litter size is increased in the subsequent parity when lactating sows are fed diets containing n-3 fatty acids from fish oil. AB - Supplementing diets with n-3 fatty acids from fish oil has been shown to improve reproductive performance in dairy cattle and sheep, but there is little published literature on its effects in sows. The aim of this study was to evaluate the reproductive performance of sows fed fish oil as a source of n-3 PUFA prefarrowing and during lactation. From d 107.7 +/- 0.1 of pregnancy, 328 sows ranging in parity from 0 to 7 (parity 1.95 +/- 0.09, mean +/- SE) were fed either a diet containing tallow (control) or an isocaloric diet containing 3 g of fish oil/kg of diet (n-3). Diets were formulated to contain the same amount of DE (13.9 MJ/kg), crude fat (54 g/kg), and CP (174 g/kg). Sows were fed their treatment diet at 3 kg daily for 8 d before farrowing and continued on treatment diets ad libitum until weaning at 18.7 +/- 0.1 d of lactation. After weaning, all sows were fed a gestation diet without fish oil until their subsequent farrowing. There was no effect (P > 0.310) of feeding n-3 diets prefarrowing on piglet birth weight, preweaning growth rate, piglet weaning weight, or sow feed intake. However, n-3 sows had a larger subsequent litter size (10.7 +/- 0.3 vs. 9.7 +/- 0.3 total born; 10.2 +/- 0.3 vs. 9.3 +/- 0.3 born live; P < 0.05). In conclusion, this is the first study to demonstrate that feeding sows a diet containing n-3 PUFA from fish oil fed before farrowing and during lactation increased litter size in the subsequent parity independent of energy intake. PMID- 21610256 TI - Statistical methods for cost-effectiveness analyses that use data from cluster randomized trials: a systematic review and checklist for critical appraisal. AB - INTRODUCTION: The best data for cost-effectiveness analyses (CEAs) of group-level interventions often come from cluster randomized trials (CRTs), where randomization is by cluster (e.g., the hospital attended), not by individual. METHODS: for these CEAs need to recognize both the correlation between costs and outcomes and that these data may be dependent on the cluster. General checklists and methodological guidance for critically appraising CEA ignore these issues. This article develops a new checklist and applies it in a systematic review of CEAs that use CRTs. METHODS: The authors developed a checklist for CEAs that use CRTs, informed by a conceptual review of statistical methods. This checklist included criteria such as whether the analysis allowed for both clustering and the correlation between individuals' costs and outcomes. The authors undertook a systematic literature review of full economic evaluations that used CRTs. The quality of studies was assessed with the new checklist and by the "Drummond checklist." RESULTS: The authors identified 62 papers that met the inclusion criteria. On average, studies satisfied 9 of the 10 criteria for the checklist but only 20% of criteria for the new checklist. More than 40% of studies adopted statistical methods that completely ignored clustering, and 75% disregarded any correlation between costs and outcomes. Only 4 studies employed appropriate statistical methods that allowed for both clustering and correlation. CONCLUSIONS: Most economic evaluations that use data from CRTs ignored clustering or correlation. Statistical methods that address these issues are available, and their use should be encouraged. The new checklist can supplement generic CEA guidelines and highlight where research practice can be improved. PMID- 21610259 TI - Deceiving and informing: the risky business of risk perception. PMID- 21610260 TI - Prevalence of antibodies associated with herd immunity: a comment. PMID- 21610262 TI - Long-term survivorship of rotator cuff repairs using ultrasound and magnetic resonance imaging analysis. AB - BACKGROUND: Important differences in clinical outcomes likely exist between patients with healed and nonhealed rotator cuff repairs. The survival probability of rotator cuff repairs has not been published in a time-dependent manner up to now. HYPOTHESES: Recurrent tears occur more frequently in the early postoperative period. Early failures of the repair are a prognostic factor for the long-term outcome. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A series of 107 consecutive patients undergoing arthroscopically assisted mini-open repair of the rotator cuff between 1998 and 2002 were evaluated in a prospective study. Of these, 95 patients finished the study after a maximum follow-up of 11 years. The evaluation included 1 postoperative magnetic resonance imaging scan as well as multiple ultrasonographies and determinations of the American Shoulder and Elbow Surgeons (ASES) and Constant scores at 3 months, 6 months, 1 year, and then yearly with a median follow-up of 96 months. RESULTS: The overall failure rate was 33% (35 of 107). The survivorship analysis revealed that 74% of all failures occurred atraumatically in the first 3 months and 11% occurred between the third and the sixth month after the repair. The remaining reruptures (14%) happened 2 to 5 years postoperatively and were related to sports activities or direct trauma. The overall clinical results did not deteriorate over time. The parameters healed tendon, rerupture of less than 2 cm(2), and rerupture of more than 2 cm(2) at 6 months were predictors of the gender- and age-adjusted (normalized) Constant score at 84 months (P < .0001). CONCLUSION: The majority of recurrent tears occurred in the first 3 months after surgical repair. The parameters "recurrent tear" as well as "healed tendon" evaluated at 6 months postoperatively appear to be predictors for the clinical outcomes at 7 years. Efforts to improve healing during the initial 3 months have long-term implications for maintenance of cuff integrity and clinical outcomes. PMID- 21610263 TI - Double-bundle versus single-bundle anterior cruciate ligament reconstruction: randomized clinical and magnetic resonance imaging study with 2-year follow-up. AB - BACKGROUND: One aspect of the debate over the reconstruction of the anterior cruciate ligament is whether it should be carried out with the single-bundle or double-bundle technique. HYPOTHESIS: The double-bundle technique results in fewer graft failures than the single-bundle technique in anterior cruciate ligament reconstruction. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 153 patients were prospectively randomized into 2 groups of anterior cruciate ligament reconstruction with hamstring autografts using aperture interference screw fixation: single-bundle technique (SB group, n = 78) and double-bundle technique (DB group, n = 75). The evaluation methods were clinical examination, KT-1000 arthrometric measurement, the International Knee Documentation Committee (IKDC) and the Lysholm knee scores, and magnetic resonance imaging (MRI) evaluation. All of the operations were performed by 1 experienced orthopaedic surgeon, and all clinical assessments were made by 2 blinded and independent examiners. A musculoskeletal radiologist blinded to the clinical data made the MRI interpretation. RESULTS: There were no differences between the study groups preoperatively. Ninety percent of patients (n = 138) were available at a minimum 2-year follow-up (range, 24-37 months). Eight patients (7 in the SB group and 1 in the DB group) had graft failure during the follow-up and had anterior cruciate ligament revision surgery (P = .04). In addition, 7 patients (5 in the SB group and 2 in the DB group) had an invisible graft on the MRI assessment at the 2-year follow-up. Also, the anteromedial bundle was partially invisible in 2 patients and the posterolateral bundle in 9 patients. Together, the total number of failures and invisible grafts were significantly higher in the SB group (12 patients, 15%) than the DB group (3 patients, 4%) (P = .024). No significant group differences were found in the knee scores or stability evaluations at the follow-up. CONCLUSION: This 2-year randomized trial showed that the revision rate of the anterior cruciate ligament reconstruction was significantly lower with the double-bundle technique than that with the single-bundle technique. However, additional years of follow-up are needed to reveal the long-term results. PMID- 21610264 TI - Validation of a short version of the glaucoma medication self-efficacy questionnaire. AB - AIMS: The aims of this study were: (1) to examine whether the original glaucoma medication adherence and eye drop technique self-efficacy scales could be shortened for easier use in practice settings; and (2) to validate these scales against objective medication adherence measures. METHODS: Prospective study conducted at a single private practice site. We measured subjects' adherence to glaucoma medications through Medication Event Monitoring System (MEMS) devices and assessed eye drop instillation technique by video-recording. Principal components factor analysis and logistic and linear regression were used to analyse the data. RESULTS: Our results yielded a 10-item Glaucoma Medication Adherence Self-Efficacy Scale that was strongly associated with subject adherence measured using MEMS (beta coefficient 8.52, 95% CI 1.94 to 15.1). In addition, the six-item Eye Drop Technique Self-Efficacy Scale was strongly associated with video-recorded subject eye drop installation technique (OR 10.47, 95% CI 1.78 to 61.63). CONCLUSIONS: Eye care providers and researchers could use these shorter scales to identify subjects with either poor glaucoma medication adherence and/or eye drop instillation technique. This could help to identify those who may benefit most from education and training on both adherence and eye drop instillation. PMID- 21610265 TI - Associations between cigarette smoking, obesity, sociodemographic characteristics and remote-sensing-derived estimates of ambient PM2.5: results from a Canadian population-based survey. AB - OBJECTIVES: Long-term exposure to ambient fine particles (PM2.)) has been shown to increase mortality. Variables measured on the same spatial scales of air pollution may confound associations, and so the authors' objectives were to evaluate the associations between PM2.5 and individual-level measures of smoking, obesity and sociodemographic status. The authors present an approach to evaluate the impact that uncontrolled confounding from smoking may have on associations between PM2.5 and mortality. METHODS: Individual-level behavioural and sociodemographic data were obtained from a 2003 national survey of 122,548 Canadians. Estimates of ground-level PM2.5 at a resolution of 10*10 km between 2001 and 2006 were derived from satellite remote sensing. Exposures were assigned to the residence of the participants at the time of the survey. Differences in the prevalence of smoking across concentrations of PM2.5 and RRs drawn from the literature were used to model the bias on rate ratios. RESULTS: Participants in areas with higher concentrations of PM2.5 had a higher income and educational attainment, smoked less and were more likely immigrants. Smoking had a negative confounding effect on the associations between PM2.5) and mortality. To compensate for this bias, for a 10 MUg/m3 increase in PM2.5, mortality from lung cancer and heart disease in the referent exposure group needed to be increased by 6.9% and 3.2%, respectively. CONCLUSIONS: Associations were found between sociodemographic and lifestyle characteristics and PM2.5 at a resolution of 10*10 km. The authors present a model to adjust for uncontrolled confounding of smoking that can be readily adapted to exposures measured at different spatial resolutions. PMID- 21610266 TI - Teamwork and team performance in multidisciplinary cancer teams: development and evaluation of an observational assessment tool. AB - AIM: Team performance is important in multidisciplinary teams (MDTs), but no tools exist for assessment. Our objective was to construct a robust tool for scientific assessment of MDT performance. MATERIALS AND METHODS: An observational tool was developed to assess performance in MDTs. Behaviours were scored on Likert scales, with objective anchors. Five MDT meetings (112 cases) were observed by a surgeon and a psychologist. The presentation of case history, radiological and pathological information, chair's effectiveness, and contributions to decision-making of surgeons, oncologists, radiologists, pathologists and clinical nurse specialists (CNSs) are analysed via descriptive statistics, a comparison of average scores (Mann-Whitney U) to test interobserver agreement and intraclass correlation coefficients (ICCs) to further assess interobserver agreement and learning curves. RESULTS: Contributions of surgeons, chair's effectiveness, presentation of case history and radiological information were rated above average (p <= 0.001). Contributions of histopathologists and CNS were rated below average (p <= 0.001), and others average. The interobserver agreement was high (ICC = 0.70+) for presentation of radiological information, and contribution of oncologists, radiologists, pathologists and CNSs; adequate for case history presentation (ICC = 0.68) and contribution of surgeons (ICC = 0.69); moderate for chairperson (ICC = 0.52); and poor for pathological information (ICC = 0.31). Average differences were found only for case-history presentation (p <= 0.001). ICCs improved significantly in assessment of case history, and Oncologists, and ICCs were consistently high for CNS, Radiologists, and Histopathologists. CONCLUSIONS: Scientific observational metrics can be reliably used by medical and non-medical observers in cancer MDTs. Such robust assessment tools provide part of a toolkit for team evaluation and enhancement. PMID- 21610268 TI - A comparison between quick-release nicotine lozenges and Swedish-style snus for the acute management of craving. PMID- 21610267 TI - A framework for classifying patient safety practices: results from an expert consensus process. AB - OBJECTIVE: Development of a coherent literature evaluating patient safety practices has been hampered by the lack of an underlying conceptual framework. The authors describe issues and choices in describing and classifying diverse patient safety practices (PSPs). METHODS: The authors developed a framework to classify PSPs by identifying and synthesising existing conceptual frameworks, evaluating the draft framework by asking a group of experts to use it to classify a diverse set of PSPs and revising the framework through an expert-panel consensus process. RESULTS: The 11 classification dimensions in the framework include: regulatory versus voluntary; setting; feasibility; individual activity versus organisational change; temporal (one-time vs repeated/long-term); pervasive versus targeted; common versus rare events; PSP maturity; degree of controversy/conflicting evidence; degree of behavioural change required for implementation; and sensitivity to context. CONCLUSION: This framework offers a way to classify and compare PSPs, and thereby to interpret the patient-safety literature. Further research is needed to develop understanding of these dimensions, how they evolve as the patient safety field matures, and their relative utilities in describing, evaluating and implementing PSPs. PMID- 21610269 TI - Courteous but not curious: how doctors' politeness masks their existential neglect. A qualitative study of video-recorded patient consultations. AB - OBJECTIVE: To study how doctors care for their patients, both medically and as fellow humans, through observing their conduct in patient-doctor encounters. DESIGN: Qualitative study in which 101 videotaped consultations were observed and analysed using a Grounded Theory approach, generating explanatory categories through a hermeneutical analysis of the taped consultations. SETTING: A 500-bed general teaching hospital in Norway. PARTICIPANTS: 71 doctors working in clinical non-psychiatric departments and their patients. RESULTS: The doctors were concerned about their patients' health and how their medical knowledge could be of service. This medical focus often over-rode other important aspects of the consultations, especially existential elements. The doctors actively directed the focus away from their patients' existential concerns onto medical facts and rarely addressed the personal aspects of a patient's condition, treating them in a biomechanical manner. At the same time, however, the doctors attended to their patients with courteousness, displaying a polite and friendly attitude and emphasising the relationship between them. CONCLUSIONS: The study suggests that the main failing of patient-doctor encounters is not a lack of courteous manners, but the moral offence patients experience when existential concerns are ignored. Improving doctors' social and communication skills cannot resolve this moral problem, which appears to be intrinsically bound to modern medical practice. Acknowledging this moral offence would, however, be the first step towards minimising the effects thereof. PMID- 21610271 TI - Virulence factors or ancestral origin of Helicobacter pylori: which is a better predictor of gastric cancer risk? PMID- 21610270 TI - Effect of rimonabant on carotid intima-media thickness (CIMT) progression in patients with abdominal obesity and metabolic syndrome: the AUDITOR Trial. AB - OBJECTIVE: The aim of this trial was to determine whether obese patients benefit from treatment with rimonabant in terms of progression of carotid atherosclerosis. Rimonabant, a selective cannabinoid-1 receptor blocker, reduces body weight and improves cardiometabolic risk factors in patients who are obese. DESIGN, SETTING, PATIENTS, INTERVENTIONS AND RESULTS: A prospective, double blind, placebo-controlled trial (Atherosclerosis Underlying Development assessed by Intima-media Thickness in patients On Rimonabant (AUDITOR)) randomised 661 patients with abdominal obesity and metabolic syndrome to rimonabant or placebo for 30 months of treatment. The absolute change in the average value for six segments of far wall carotid intima-media thickness from baseline to month 30 was 0.010 +/- 0.095 mm in the rimonabant group and 0.012 +/- 0.091 mm in the placebo group (p=0.67). The annualised change was an increase of 0.005 +/- 0.042 mm for the rimonabant-treated group and 0.007 +/- 0.043 mm for the placebo-treated group (p=0.45). CONCLUSIONS: There was no difference in atherosclerosis progression between patients receiving rimonabant for 30 months and those receiving placebo for the primary efficacy measure (absolute change in carotid intima-media thickness). These findings are consistent with a similar study using coronary intravascular ultrasound and another study evaluating the occurrence of cardiovascular events. Our findings suggest that a 5% loss of body weight over a 30-month period with rimonabant is insufficient to modify atherosclerosis progression in the carotid artery in obese patients with metabolic syndrome. Clinical trial registration information clinicaltrials.gov Identifier: NCT00228176. PMID- 21610272 TI - Altered brain microstructure assessed by diffusion tensor imaging in patients with chronic pancreatitis. AB - OBJECTIVE: In patients with painful chronic pancreatitis (CP) there is increasing evidence of abnormal pain processing in the central nervous system. Using magnetic resonance (MR) diffusion tensor imaging, brain microstructure in areas involved in processing of visceral pain was characterised and these findings were correlated to clinical pain scores. METHODS: 23 patients with CP pain and 14 controls were studied in a 3T MR scanner. Apparent diffusion coefficient (ADC) (ie, diffusivity of water) and fractional anisotropy (FA) (ie, organisation of fibres) values were assessed in the amygdala, cingulate cortex, insula, prefrontal cortex and secondary sensory cortex. Daily pain scores and the Brief Pain Inventory Short Form were collected 1 week before the investigation. RESULTS: In grey matter, patients had increased ADC values in amygdala, cingulate cortex, insula and prefrontal cortex, as well as decreased FA values in cingulate cortex and secondary sensory cortex. In white matter, patients had increased ADC values in insula and prefrontal cortex, and decreased FA values in insula and prefrontal cortex (all p values <0.05). An effect modification from the pain pattern (attacks vs continuous pain) was seen in the insula and secondary sensory cortex (p values <0.05), but no effect modifications from diabetes, alcoholic aetiology and opioid treatment were seen (all p values >0.05). Microstructural changes in cingulate and prefrontal cortices were correlated to patients' clinical pain scores. CONCLUSION: The findings suggest that microstructural changes of the brain accompany pain in CP. The changes are likely to be a consequence of ongoing pain and structural reorganisation of the neuromatrix as also seen in other diseases characterised by chronic pain. PMID- 21610273 TI - Surgery for adult Crohn's disease: what is the actual risk? PMID- 21610275 TI - [Increase of genitourinary system susceptibility/targeting for second primary neoplasias: a proposal for screening strategies modification]. PMID- 21610276 TI - [Robot assisted laparoscopic partial nephrectomy: techniques and outcomes]. AB - Nephron-sparing surgery is currently considered the gold standard treatment for T1 renal tumors. As laparoscopic partial nephrectomy (LPN) represents a technically challenging procedure, robotic surgery has been increasingly used during the last few years in the field of nephron-sparing surgery. The aim of this review is to analyze the techniques and outcomes of robotic partial nephrectomy (RPN). Currently available evidence shows that RPN is a feasible and safe procedure for small localized renal tumors and also for selected complex renal tumors. Early comparative studies have demonstrated similar perioperative outcomes between RPN and LPN, with a trend towards a shorter ischemia time for RPN. However, oncological follow-up remains limited and further prospective trials are awaited to confirm the benefits of robotic approach for partial nephrectomy. PMID- 21610277 TI - [Robot assisted laparoscopic partial nephrectomy: techniques and outcomes]. PMID- 21610278 TI - Suburethral single incision slings in the treatment of female stress urinary incontinence: what is the evidence for using them in 2010? AB - OBJECTIVES: To review the present evidence supporting the use of single-incision slings for treatment of female stress urinary incontinence. METHODS: A Pubmed search was performed using words as stress urinary incontinence, slings, single incision slings, mini-sling, TVT-Secur(TM), MiniArc(TM), TFS, Arcusto-Arcus(TM) and Ajust(TM). This search was complemented by a review of the references from the papers found in the initial search. Only papers written in English, with a minimum of 30 cases and 6 months follow up were analyzed. RESULTS: Sixteen papers were found with the defined characteristics, 4 of them being comparative studies. Most studies include a low number of patients with follow-up not exceeding 12 months. Techniques are easy and seem to require a short learning curve, exception being TVT-Secur(TM). Operating time is short and complications are few and mild. Generally, results at 12 months are close to those reported after conventional slings. In two comparative studies Mini-Arc(TM) was as effective as a transobturator comparator. However in two additional comparisons, single incision slings had worse outcomes than the conventional comparator. CONCLUSION: Some single-incision slings look promising in most series and even as effective as conventional sub-urethral slings at short term evaluation. However, no experience reported by independent authors can be found. Therefore, at this moment a clear statement in favor of the widespread use of single-incision slings cannot be made. More studies must define the efficacy of these techniques against conventional sub-urethral slings. In addition, comparisons among available single incision slings should define one ideal model. PMID- 21610279 TI - [Suburethral single incision slings in the treatment of female stress urinary incontinence:what is the evidence for using them in 2010?]. PMID- 21610280 TI - Penile cancer: are there currently indications for radiotherapy?. AB - Penile cancer is a radiocurable disease. The different types of radiotherapy (RT) brachytherapy, plesiotherapy, external beam radiation therapy-have proven valid in the treatment of the primary tumor allowing preservation of the penis and sexual function. RT is even an option in candidates for surgery who reject surgery for clinical or personal reasons. A high nodal recurrence rate has been observed after inguinal lymphadenectomy, specially in patients at high risk of relapse. Technological advances in the field of RT, new imaging techniques, and more modern equipment enable RT to enhance local control and improve survival in patients with this condition. Palliative RT can exercise a decompressive effect that makes possible tumor size reduction in cases of inguinal-pelvic recurrence in patients with lymphedema and thus improve quality of life. In this article, we review the current role of RT in the treatment of penile cancer. We also present two cases that illustrate the main indications. PMID- 21610281 TI - Impact of renal retransplantation on graft and recipient survival. AB - OBJECTIVES: The aim of this study was to evaluate the influence of retransplantation in graft and recipient survival. METHODS: We carried out a retrospective study in 419 renal transplants and studied the influence of retransplantation in graft and patient survival. A homogeneity study was performed between the two groups with a Student's T and a chi-square tests. Graft survival analysis was performed with Kaplan-Meyer and log rank tests. RESULTS: Of 419 transplants, 370 (88.3%) were first transplantations, 45 (10.7%) second transplantations and 4(1%) third ones. Mean follow-up of the whole group was 72.5 months (+/-54.1 SD). There were no differences in follow-up between groups (Mean Follow-up 73.1 months +/-54.4 SD in first transplantations vs. 61.6 months +/ 51.2 SD in repeat transplantation. p >0.05). The actuarial graft survival showed no differences between patients with first transplantation and those with a repeat one. [3 and 5 year SV of 89% (95% CI: 87-91%) and 84%(95% CI: 82-86%) Vs 88% (95% CI; 83-93%) and 85% (95% CI:i; 80-90%) respectively]. After adjusting for all the heterogeneity variables we still did not find differences on graft survival. The actuarial recipient survival showed no differences between patients with first transplantation and those with a repeat one. [3 and 5 year SV of 98% and 96% Vs.97%]. CONCLUSIONS: There are no differences of graft and recipient survival between patients with a first transplantation and those with a repeat one. PMID- 21610282 TI - Localized primary ureteral amyloidosis. AB - OBJECTIVE: To analyze a new case of primary localized amyloidosis of the ureter, describing the differential diagnosis with ureteral tumors and its pathogenic mechanism. METHOD: Description of the case of a male patient who presented clinical symptoms of renoureteral pain and hematuria and an image suspected of ureteral tumour undergoing laparoscopic nephroureterectomy. The pathological study confirmed amyloidosis of the ureter, AL by immunohistochemistry. RESULTS: This report further extends the slightly more than 50 published cases of primary localized amyloidosis of the ureter the clinical signs of which, pain and haematuria, are similar, showing stenosis and enlargement in an area of the ureteral wall on imaging techniques. In the majority of cases the diagnosis was obtained postoperatively, being necessary to exclude generalized and secondary affectation. CONCLUSIONS: Emphasis must be placed on the differential diagnosis of tumors of the ureter, especially in single-kidney patients, by using ureteroscopy and biopsy or preferably a careful cytological study. In our case a local inflammatory phenomenon could have been the basis of its pathogenesis. PMID- 21610283 TI - Retroperitoneal cystic mature teratoma as the presenting clinical scenario of testicular carcinoma. AB - OBJECTIVE: To describe a case of retroperitoneal mature teratoma presenting as metastasis of a testicular mixed germ cell tumor in a thirty year old man who had lumbar and abdominal pain and mass sensation in the left hemiabdomen. METHODS: Abdominal ultrasound and thoracic-abdominal-pelvic CT multidetector scan were performed, and then after a Doppler ultrasound study of the testicles. Surgical treatment was performed: orchiectomy and retroperitoneal lesion resection. RESULTS: Imaging studies showed a big cystic lesion in the left retroperitoneal space, 13 * 12 * 11 cm, well defined, with thin septa, displacing the kidney; and a solid-cystic 4 cm left testicular tumor, with multiple septa, solid poles and arterial flows with low resistances. Thoracic extension study did not show any finding. The histopathologic results of the orchiectomy and retroperitoneal resection pieces were, respectively, testicular mixed germ cell tumor (seminoma, with intratubular seminoma foci and teratoma) and mature cystic teratoma. CONCLUSIONS: Germ cell tumors derive from multipotencial cells with a large capacity of differentiation, and the nodal paraaortic chains are a natural way of dissemination of these neoplasms. Because of that, in the presence of a retroperitoneal lesion in a young patient we have to rule out testicular tumor metastasis. The retroperitoneal mature cystic teratoma must be considered as a lesion with malignant potential. PMID- 21610284 TI - Vaginal metastasis of a clear renal cell carcinoma. AB - OBJECTIVE: Remember that kidney cancer is a disease whose incidence is increasing due to increased use of additional imaging tests, which is changing the way of diagnosis, making the classic clinical syndrome synonymous with advanced illness. METHODS: We report the case of a patient with a right renal tumor with renal vein involvement that in the natural course of the disease showed a vaginal metastasis of clear renal cell carcinoma, which was treated with surgical excision. RESULTS: This case is a clear example of how unpredictable is the clinical evolution of this disease and how little we know about the way of dissemination. CONCLUSIONS: Local excision, with or without radiotherapy, or radiotherapy alone are recommended in cases of unique metastasis after nephrectomy. PMID- 21610285 TI - Giant bladder lithiasis: case report and bibliographic review. AB - OBJECTIVE: Urinary lithiasis is a very frequent urological disease but bladder lithiasis is very uncommon.Patients usually refer voiding symptoms and hematuria. The diagnosis is made after imaging tests. We report a clinical case describing a giant bladder stone and perform a bibliographic review. METHODS: A 43 year old man with the diagnosis of giant bladder stone (more than 10 cm diameter). We searched Medline using the terms: giant bladder stone, giant bladder lithiasis, bladder lithiasis, giant bladder lithiasis. RESULTS: We made the diagnosis of giant bladder stone after a simple kidney, ureter and bladder (KUB) X Ray. The treatment for this patient was a cystolithotomy. We found more than 230 reports at Medline and chose the most referred ones and the last 10 years reports. CONCLUSIONS: Giant bladder lithiasis is a very rare pathology. The gold standard for diagnosis is cystoscopy but sometimes with a KUB Xray or an ultrasound is enough. Because of its size, cistolitotomy is the correct treatment for giant bladder stone. PMID- 21610289 TI - Non invasive biomedical analysis. Breath networking session at PittCon 2011, Atlanta, Georgia. PMID- 21610290 TI - 'Dicty dynamics': Dictyostelium motility as persistent random motion. AB - We model the motility of Dictyostelium cells in a systematic data-driven manner. We deduce a minimal dynamical model that reproduces the statistical features of experimental trajectories. These are trajectories of the centroid of the cell perimeter, which is more sensitive to pseudopod activity than the usual tracking by centroid or nucleus. Our data account for cell individuality and dictate a model that extends the cell-type specific models recently derived for mammalian cells. Two generalized Langevin equations model stochastic periodic pseudopod motion parallel and orthogonal to the amoeba's direction of motion. This motion propels the amoeba with a random periodic left-right waddle in a direction that has a long persistence time. The model fully accounts for the statistics of the experimental trajectories, including velocity power spectra and auto correlations, non-Gaussian velocity distributions, and multiplicative noise. Thus, we find neither need nor place in our data for an interpretation in terms of anomalous diffusion. The model faithfully captures cell individuality as different parameter values in the model, and serves as a basis for integrating the local mechanics of cell motion with our observed long-term behavior. PMID- 21610291 TI - Effective count rates for PET scanners with reduced and extended axial field of view. AB - We investigated the relationship between noise equivalent count (NEC) and axial field of view (AFOV) for PET scanners with AFOVs ranging from one-half to twice those of current clinical scanners. PET scanners with longer or shorter AFOVs could fulfill different clinical needs depending on exam volumes and site economics. Using previously validated Monte Carlo simulations, we modeled true, scattered and random coincidence counting rates for a PET ring diameter of 88 cm with 2, 4, 6, and 8 rings of detector blocks (AFOV 7.8, 15.5, 23.3, and 31.0 cm). Fully 3D acquisition mode was compared to full collimation (2D) and partial collimation (2.5D) modes. Counting rates were estimated for a 200 cm long version of the 20 cm diameter NEMA count-rate phantom and for an anthropomorphic object based on a patient scan. We estimated the live-time characteristics of the scanner from measured count-rate data and applied that estimate to the simulated results to obtain NEC as a function of object activity. We found NEC increased as a quadratic function of AFOV for 3D mode, and linearly in 2D mode. Partial collimation provided the highest overall NEC on the 2-block system and fully 3D mode provided the highest NEC on the 8-block system for clinically relevant activities. On the 4-, and 6-block systems 3D mode NEC was highest up to ~300 MBq in the anthropomorphic phantom, above which 3D NEC dropped rapidly, and 2.5D NEC was highest. Projected total scan time to achieve NEC-density that matches current clinical practice in a typical oncology exam averaged 9, 15, 24, and 61 min for the 8-, 6-, 4-, and 2-block ring systems, when using optimal collimation. Increasing the AFOV should provide a greater than proportional increase in NEC, potentially benefiting patient throughput-to-cost ratio. Conversely, by using appropriate collimation, a two-ring (7.8 cm AFOV) system could acquire whole-body scans achieving NEC-density levels comparable to current standards within long, but feasible, scan times. PMID- 21610292 TI - Investigation of a clinical PET detector module design that employs large-area avalanche photodetectors. AB - We investigated the feasibility of designing an Anger-logic PET detector module using large-area high-gain avalanche photodiodes (APDs) for a brain-dedicated PET/MRI system. Using Monte Carlo simulations, we systematically optimized the detector design with regard to the scintillation crystal, optical diffuser, surface treatment, layout of large-area APDs, and signal-to-noise ratio (SNR, defined as the 511 keV photopeak position divided by the standard deviation of noise floor in an energy spectrum) of the APD devices. A detector prototype was built comprising an 8 * 8 array of 2.75 * 3.00 * 20.0 mm3 LYSO (lutetium-yttrium oxyorthosilicate) crystals and a 22.0 * 24.0 * 9.0 mm3 optical diffuser. From the four designs of the optical diffuser tested, two designs employing a slotted diffuser are able to resolve all 64 crystals within the block with good uniformity and peak-to-valley ratio. Good agreement was found between the simulation and experimental results. For the detector employing a slotted optical diffuser, the energy resolution of the global energy spectrum after normalization is 13.4 +/- 0.4%. The energy resolution of individual crystals varies between 11.3 +/- 0.3% and 17.3 +/- 0.4%. The time resolution varies between 4.85 +/- 0.04 (center crystal), 5.17 +/- 0.06 (edge crystal), and 5.18 +/- 0.07 ns (corner crystal). The generalized framework proposed in this work helps to guide the design of detector modules for selected PET system configurations, including scaling the design down to a preclinical PET system, scaling up to a whole-body clinical scanner, as well as replacing APDs with other novel photodetectors that have higher gain or SNR such as silicon photomultipliers. PMID- 21610293 TI - Validation of an online replanning technique for prostate adaptive radiotherapy. AB - We have previously developed an online adaptive replanning technique to rapidly adapt the original plan according to daily CT. This paper reports the quality assurance (QA) developments in its clinical implementation for prostate cancer patients. A series of pre-clinical validation tests were carried out to verify the overall accuracy and consistency of the online replanning procedure. These tests include (a) phantom measurements of 22 individual patient adaptive plans to verify their accuracy and deliverability and (b) efficiency and applicability of the online replanning process. A four-step QA procedure was established to ensure the safe and accurate delivery of an adaptive plan, including (1) offline phantom measurement of the original plan, (2) online independent monitor unit (MU) calculation for a redundancy check, (3) online verification of plan-data transfer using an in-house software and (4) offline validation of actually delivered beam parameters. The pre-clinical validations demonstrate that the newly implemented online replanning technique is dosimetrically accurate and practically efficient. The four-step QA procedure is capable of identifying possible errors in the process of online adaptive radiotherapy and to ensure the safe and accurate delivery of the adaptive plans. Based on the success of this work, the online replanning technique has been used in the clinic to correct for interfractional changes during the prostate radiation therapy. PMID- 21610294 TI - Comparative analysis of Pareto surfaces in multi-criteria IMRT planning. AB - In the multi-criteria optimization approach to IMRT planning, a given dose distribution is evaluated by a number of convex objective functions that measure tumor coverage and sparing of the different organs at risk. Within this context optimizing the intensity profiles for any fixed set of beams yields a convex Pareto set in the objective space. However, if the number of beam directions and irradiation angles are included as free parameters in the formulation of the optimization problem, the resulting Pareto set becomes more intricate. In this work, a method is presented that allows for the comparison of two convex Pareto sets emerging from two distinct beam configuration choices. For the two competing beam settings, the non-dominated and the dominated points of the corresponding Pareto sets are identified and the distance between the two sets in the objective space is calculated and subsequently plotted. The obtained information enables the planner to decide if, for a given compromise, the current beam setup is optimal. He may then re-adjust his choice accordingly during navigation. The method is applied to an artificial case and two clinical head neck cases. In all cases no configuration is dominating its competitor over the whole Pareto set. For example, in one of the head neck cases a seven-beam configuration turns out to be superior to a nine-beam configuration if the highest priority is the sparing of the spinal cord. The presented method of comparing Pareto sets is not restricted to comparing different beam angle configurations, but will allow for more comprehensive comparisons of competing treatment techniques (e.g., photons versus protons) than with the classical method of comparing single treatment plans. PMID- 21610295 TI - Development and characterization of an in vitro alpha radiation exposure system. AB - A simple in vitro alpha radiation exposure system (ARES) was designed to study the biological effects of alpha particle radiation. The ARES consists of six (241)Am electroplated stainless steel discs with activities averaging 66 kBq and Mylar-based culture dishes to allow the transmission of alpha particles. The dosimetry of the exposure system was calculated using the GEANT4 Monte Carlo simulation toolkit with the source code adapted from the open-source Microbeam example. The average dose rate and linear energy transfer of the system was simulated to be 0.98 +/- 0.01 (statistical)(+0.18)( - 0.00) (systematic) Gy h(-1) and 127.4 +/- 0.4 (statistical)(+23)( - 0) (systematic) keV um(-1), respectively. The system was characterized by a comparison of the survival curves of gamma and alpha irradiated cell lines which showed a relative biological effectiveness of 6.3. This is in good agreement with values obtained using other published alpha particle exposure systems. Results show that the ARES provides a simple, cost effective exposure platform for research into the biological effects of alpha particle radiation using in vitro modelling of cell cultures. PMID- 21610296 TI - Pure random search for ambient sensor distribution optimisation in a smart home environment. AB - Smart homes are living spaces facilitated with technology to allow individuals to remain in their own homes for longer, rather than be institutionalised. Sensors are the fundamental physical layer with any smart home, as the data they generate is used to inform decision support systems, facilitating appropriate actuator actions. Positioning of sensors is therefore a fundamental characteristic of a smart home. Contemporary smart home sensor distribution is aligned to either a) a total coverage approach; b) a human assessment approach. These methods for sensor arrangement are not data driven strategies, are unempirical and frequently irrational. This Study hypothesised that sensor deployment directed by an optimisation method that utilises inhabitants' spatial frequency data as the search space, would produce more optimal sensor distributions vs. the current method of sensor deployment by engineers. Seven human engineers were tasked to create sensor distributions based on perceived utility for 9 deployment scenarios. A Pure Random Search (PRS) algorithm was then tasked to create matched sensor distributions. The PRS method produced superior distributions in 98.4% of test cases (n=64) against human engineer instructed deployments when the engineers had no access to the spatial frequency data, and in 92.0% of test cases (n=64) when engineers had full access to these data. These results thus confirmed the hypothesis. PMID- 21610297 TI - Intraoperative reduction of distal tibiofibular joint aided by three-dimensional fluoroscopy. AB - OBJECTIVE: The aim of the study was to demonstrate the surgical work-flow of the intraoperative 3D fluoroscopy (Acadis)-aided reduction for distal tibiofibular joint. MATERIAL AND METHOD: Ten ankle fracture patients with dislocated syndesmosis were treated. The surgical work-flow of intraoperative 3D (Acadis) fluoroscopy-aided reduction was described. Axial imaging was measured for quality of syndesmotic reduction by measuring the distance between the fibular and the posterior and anterior facet of tibial incisura along a line perpendicular to joint space. RESULT: Acadis 3D scan was successfully accomplished. The syndesmosis of the healthy side was symmetrical. The asymmetry of syndesmosis prior to transsyndesmotic fixation (D) was 3.7 mm on average (2.2-8.2 mm). The asymmetry of syndesmosis after transsyndesmotic fixation (E) was 1.7 mm on average (1.2-4.2 mm). CONCLUSION: Intraoperative 3D-fluoroscopy was able to detect subtle malreduction of the syndesmosis in the operative treaetment of ankle fractures. The intraoperative 3D-fluoroscopy-aided reduction for the distal tibiofibular syndesmosis is effective. PMID- 21610298 TI - Two-stage revision of infected total knee arthroplasty using a distraction spacer. AB - BACKGROUND: The infection of a total knee arthroplasty (TKA) has remained as one of the most devastating potential complications. In this context we developed a new technique that keeps the spacer in distraction during the cementation process to achieve better weight-bearing stability. METHODS: We present a case of a 75 year-old male patient, who was treated in our hospital with an infected total knee replacement (TKR) using the distraction spacer. The operative technique includes the removal of the infected prosthesis after radical debridement. Then two carbon rods were inserted overlapping 2-3 cm in the medulla of the tibia and femur. Afterwards an external fixateur with distraction module is attached with two Schanz screws into the distal femur and the proximal tibia. The cementation process was performed under distraction. After hardening of the cement the external fixateur and the Schanz screws are then removed. RESULTS: Postoperatively the patient was mobilized with full weight-bearing using an extension splint. The antibiotic therapy was continued for five weeks. After sterile puncture, the reimplantation was performed using a Zimmer-Rotating-Hinge Knee without any complications. CONCLUSIONS: This method allows cement hardening without micromovements and early mobilization with partial full weight bearing and prevents the contraction of the capsule and the ligaments during the prosthesis-free period, preparing the knee for a secondary TKA or an intramedullary arthrodesis with a titanium stem. PMID- 21610299 TI - Telemetric in vivo measurement of compressive forces during consolidation in a rabbit model. AB - A quantitative device to gain information about bone healing after fracture or distraction osteogenesis would lower the risk of refracture, malunion and pseudarthrosis. To this date, different biomechanical methods have been proposed for this task with limited application. Furthermore, none of these devices allows monitoring of physiological motion. The aim of this study was to develop a telemetric method for in vivo measurement of compressive forces during physiological motion. An innovative method was developed that can be integrated in an external fixator and that transfers the data to the computer via Bluetooth. After ex vivo validation it was applied to rabbit tibia for assessment of consolidation after tibial osteotomy. After development of the innovative method, the technique was validated ex- and in-vivo in a rabbit model. The presented method enables a telemetric measurement of compressive forces during consolidation. It proved that during consolidation the forces decreased over time from 27.6 to 15.7 Newton. This study presents a new technique to quantify bone healing of fracture or distraction osteogenesis by determination of compressive forces. The innovative of this technique compared to existing methods is the fact that it allows monitoring forces during physiological motion. PMID- 21610300 TI - Clinical outcome and complication rate after posterior arthrodesis of the lumbar spine: are there age-related differences? A comparative study. AB - OBJECTIVES: Lumbar arthrodesis is a frequently performed intervention to treat several spinal disorders like degenerative or instable conditions. According to the demographic trend, more and more elderly patients are expected to become candidates for any kind of surgical procedures including operations of the spine. In case of more complex operations like fusion a higher risk potential in older persons could be assumed. The goal of our study was to analyze the clinical results after lumbar fusion and to find out, if there are differences in the outcome and complication rate in patients divided in two age groups. METHODS: 100 patients who consecutively had lumbar arthrodesis because of degenerative or instable conditions were retrospectively studied after a minimum of 12 months with regard to their clinical outcome and the complication rate. Statistical analysis was performed to find out any significant differences in patients younger and older than 65 years. RESULTS: In both patient groups we found neither any statistically significant difference in all clinical outcome scores except for two items of the SF-36 nor in the complication rate. CONCLUSION: Older age should not be the only criterion for exclusion for more extensive surgical procedures of the lumbar spine like arthrodesis. PMID- 21610302 TI - Biofluid mechanics and the circulatory system. AB - A fluid is a medium which deforms, or undergoes motion, continuously under the action of a shearing stress and includes liquids and gases. Applying biofluid mechanics to the cardiovascular system requires knowledge of anatomy and geometry, pressure data and blood flow, volume and velocity measurements. A good example is the assessment of the haemodynamics of biological and mechanical heart valves. PMID- 21610303 TI - Biomechanics of implants. AB - For simple constructions a mechanical analysis to determine internal stresses and deformation is possible using theoretical formulas. However, for complex constructions, like joint prostheses, this is not possible. Numerical simulation of internal stresses and deformations offers a solution for these constructions. The so-called Finite Element Analysis divides the complex structure in simple ones (elements), applies the mechanical formulas and adds the effect on each element to predict the behaviour of the complex contruction. PMID- 21610304 TI - Replication of the rotational center of the humeral head with second-generation stemmed prostheses. AB - OBJECTIVES: Reconstruction of the anatomy of the proximal humerus is an indispensible prerequisite to achieve good clinical results and long-term prosthesis stability. Modern, adjustable prostheses have greater flexibility of inclination, retrotorsion, as well as medial and dorsal offset, in comparison to older prostheses. Such improvements are expected to allow for more accurate reconstruction of the anatomical condition, such as targeted reconstruction of the primary and the secondary rotational centers. METHODS: The reconstruction of the humeral rotational center was assessed in 48 second-generation prostheses. All reconstructions were compared by radiographic parameters with the preoperative state and the operated opposite side. RESULTS: The positions of the new rotational centers after arthroplasty were not close to those of pre operative and healthy opposite side's radiographs. No characteristic change in the position of the humeral head, or of its rotational center was detected. CONCLUSION: Second-generation prostheses can only provide a limited reconstruction of the original anatomy in shoulder hemiarthroplasty. In contrast, the modern third- and fourth-generation modular prostheses with variable inclination are more potent in replicating the original shoulder anatomy with its primary and secondary rotational centers. PMID- 21610305 TI - The relationship of muscle strength and pain in subacromial impingement syndrome. AB - OBJECTIVES: We evaluated the relationship between muscle strength and pain in subacromial impingement syndrome (SIS). METHODS: 18 female, 2 male twenty patients (mean age 48.15+/-5.9 years; range 32 to 60 years) with Stage I and II SIS were enrolled in the study. Upper, middle and lower trapezius, serratus anterior, supraspinatus and anterior deltoid muscle strengths were assessed bilaterally by a handheld dynamometer. Each muscle was assessed 3 times and the mean value of strength was calculated. Pain and functional results were assessed with visual analog scale (VAS), and Constant scores. Modified Constant score was calculated, with the exclusion of pain parameters. RESULTS: Middle trapezius, serratus anterior, supraspinatus and anterior deltoid muscle strengths of the shoulder with positive impingement signs were significantly lower than healthy opposite side (p=0.01, p=0.04, p=0.01, p=0.003). The mean Constant score was 57.46 and the mean VAS 6.85, in shoulders with SIS. There was a significant correlation between VAS and Constant score, without pain assessment (p=0.016, rs= -0.44) CONCLUSION: In this study we found a relationship between the middle trapezius, serratus anterior, supraspinatus and anterior deltoid muscle weaknesses and pain in SIS. This result indicates that these muscles should be evaluated and strengthened in required cases during the rehabilitation. PMID- 21610306 TI - A new technique in the treatment of distal radius fractures: the Micronail(r). AB - OBJECTIVES: In 2006, an intramedullar titanium osteosynthesis for the stabilization of distal radius fractures was introduced in The Netherlands: the Micronail(r). The Micronail(r) can be used in approximately 30% of distal radius fracture treatments. This article presents the introduction of this new treatment, and first clinical results. METHODS: In the first year after introduction of the Micronail(r) in our clinic, 10 patients have been treated with 11 Micronails(r) (eight 23-A2 radius fractures and three distal 22-A3 forearm fractures). Our patients were mainly woman (n=9) and had a mean age of 81 years (range 69-88 years). After re-alignment of the fracture, the Micronail(r) was placed into the medulla through a small incision over the styloid process of the radius. By using a guidance system, three locking buttress screws were placed in the distal radial fragment and two locking bolts were placed in the proximal radius. Postoperative treatment consisted of a splint for 5 days, after which full loadcarrying exercises can be started. RESULTS: After 6 weeks, six patients had a full range of motion. Two patients were still in a cast because of secondary dislocation and CTS, respectively. One patient had a cast because of newly sustained trauma, which resulted in a peri-osteosynthetic fracture. Pain was not recorded in these patients. All fractures healed without major loss of alignment. Patients experienced good to excellent results on an analog scale showing the wrist function. At 4 months, all patients had a good range of motion in the operated wrist; the difference between the two wrists was a maximum of 10 degrees . CONCLUSION: The first results of Micronail(r) are promising. It has the advantages of other operative techniques (minimally invasive, stable, intramedullar) without their known disadvantages. Short immobilization is sufficient, after which full load-carrying exercises are indicated. PMID- 21610307 TI - The relation between the arthroscopic findings and functional outcomes in patients with septic arthritis of the knee joint, treated with arthroscopic debridement and irrigation. AB - OBJECTIVES: The aim of this study was to evaluate the relation between arthroscopic findings and functional outcomes in patients with septic arthritis of the knee joint, treated with arthroscopic debridement and irrigation. METHODS: Twenty patients (17 male, 3 female; mean age: 31 years [5-63 years]) with knee septic arthritis treated with arthroscopic debridement and irrigation in our clinic between 2004-2007 were included in the study. The decision for arthroscopic debridement was made based on the clinical findings, erythrocyte sedimentation rate, C-reactive protein level and the aspiration of the affected knee. During the arthroscopic debridement, the joint was staged according to Gachter criteria. Continuous irrigation system was set up for all cases following surgery. After the surgery, the Bussiere functional scale was used for clinical evaluation. The mean follow-up periodwas 29+/-11months (range 13-54 months). The McNemar test was used in comparing the results. The Spearman correlation coefficient was used in the correlation analysis. The level of significance was set at 0.05. RESULTS: The culture was positive in 3 cases, and negative in 8 cases who exhibited gram (+) cocci in gram stains. In nine cases, cultures were negative and no microorganisms were detected in gram stains. According to the arthroscopic Gachter classification, 4 cases (20%) were Stage 1, 10 cases (50%) were Stage 2, 5 cases (25%) Stage 3 and 1 case (5%) was Stage 4. There was a statistically significant difference between the mean functional score of the knees with differing Gachter stages (McNemar test, p=0.003). There was a statistically significant and strong correlation between Gachter score and functional results (correlation coefficient: 0.780; p<0.001). CONCLUSION: Advanced arthroscopic findings are associated with poor functional results in patients with septic arthritis of the knee joint. In addition, the time between the initial symptoms and the surgery directly affects the functional results. PMID- 21610308 TI - Lower extremity soft tissue reconstruction with free flap based on subscapular artery. AB - OBJECTIVES: The purpose of our study was to evaluate the results of the reconstruction of the lower extremity defects with free flaps based on the subscapular artery. METHODS: Between January, 1998 and December, 2008, 51 patients (mean age 26 years; 16 female and 35 male) presenting with a lower extremity defect underwent a reconstructive surgery with flaps based on the subscapular vascular system. Thirty-seven percent of the defects were located in the crus, 19% in the sole, 16% in the heel, and 14% in the dorsum of the foot. Eighty and a half percent of the patients had traffic-accident-related and 13.5% had burn-related tissue defects. RESULTS: Fifty-three percent of the patients presenting with lower extremity defects underwent reconstruction with latissimus dorsi muscle flaps, 21% with free serratus muscle and/or fascia flaps, 14% with free parascapular fasciocutaneous flaps, and 12% with free combined latissimus muscle and serratus muscle and/or fascia flaps. Anastomoses of 80% of the patients were performed on their posterior tibial artery and accompanying veins and/or foot dorsal veins. End-to-end anastomosis was performed on 14 patients, while 35 patients received end-to-side anastomosis. Six patients were treated with cross free flaps, of which 4 received cross latissimus, 1 cross serratus, and 1 cross combined serratus and latissimus flaps. End-to-side anastomoses were performed on these patients on the cross-leg tibialis posterior artery. The cross leg anastomosis was freed 4 weeks later. In the early period, venous occlusion was observed in 4 patients and arterial and venous occlusion was present in 1 patient. New anastomoses were performed in these patients. Partial necrosis was observed in 2 patients. The average follow-up period was 61 months. Pressure related late ulcerative lesions developed in 4 patients. The lesions of these patients were repaired by debridement and primary suturing or partial thickness skin grafts. CONCLUSION: The subscapular vascular system based flaps have an optimal vascularity once they are prepared with adequate pedicles, causing minimal donor site morbidity. These flaps are a safe and effective alternative in lower extremity reconstruction. On the other hand, in the absence of appropriate recipient vessels, single or combined cross-leg free flaps may provide successful repair. PMID- 21610309 TI - Biomechanical assessment of brachioradialis pronatorplasty. AB - OBJECTIVES: Transfer of the brachioradialis muscle, proposed by Ozkan et al. can be applied to cases, in which, the biceps rerouting technique is not appropriate for the correction of forearm supination contracture and restoration of active pronation. We have aimed to assess the biomechanical effects of the brachioradialis transfer. METHODS: Pronation strength was acquired in nine fresh frozen cadaver forearms by applying rerouting of the brachioradialis muscle through interosseous membrane (Group 1) or transferring the same muscle to the distal insertion of extensor carpi ulnaris (ECU) (Group 2). Then, a force of 5 to 35 N was applied to the muscle and the range of forearm rotation and rotation strength were measured. The normalities of the data were analyzed by Shapiro-Wilk test. Comparisons between the groups were made with independent-sample t-test and comparison of the data, obtained from the same group, was carried out with paired sample t-test and Bonferroni correction. RESULTS: A maximum of 74 degrees (with a mean of 61 degrees ) gain of pronation with rerouting and a maximum of 72 degrees (with a mean of 65 degrees ) gain with ECU transfer of brachioradialis muscle were observed. A significant regression was also found in the first group. Regression constant was - 9.59 (p = 0.001, 95%: -13.20; -6.00) for the applied force of 2.06 N (p = 0.001, 95%: 1.90; 2.22). Furthermore, a significant regression was found in the second group. Regression constant was - 9.73 (p = 0.001, 95%: -13.13; -6.34) for the applied force of 1.91 N (p = 0.001, 95%: 1.76; 2.06). CONCLUSION: The brachioradialis muscle works as a pronator in full forearm supination. However, when the forearm comes close to the neutral rotation, due to the lateral location of the proximal insertion, the brachioradialis muscle loses this pronator effect. The additional release or lengthening of contracted soft tissues increases the range of pronation. PMID- 21610310 TI - Is plating of mid-shaft clavicular fractures possible with a conventional straight 3.5 millimeter locking compression plate? AB - OBJECTIVES: Current literature describes improved clinical outcomes and a minor rate of pseudoarthrosis following operatively treated clavicular fractures. We investigated the feasibility of using a standard 3.5 mm AO locking compression plate (LCP) of adequate length for the stabilisation of mid-shaft fractures of the clavicle. METHODS: The length and acromial and diaphyseal curvature depths were measured in 49 cadaveric clavicles. We then assessed how well the 6, 7, 8 and 9-hole plates fit on the clavicles. RESULTS: The mean clavicular length was 155+/-12 mm, with a mean acromial curvature of 18.1+/-3.7 mm and a mean diaphyseal curvature of 12 mm+/-4 mm. The optimum plate for the clavicle was a 7 hole LCP, providing adequate fixation in 48 of the 49 clavicles. CONCLUSION: The described technique for plate osteosynthesis of the clavicle with AO locking compression plate is feasible and results in a biomechanically strong construct for mid-shaft fractures. With the use of a locking plate, comminuted fractures may be bridged without a reduction in the strength of the construct. PMID- 21610311 TI - Bifocal pyomyositis in a 3-year-old child with eczema: a case report. AB - Pyomyositis is an infection of the skeletal muscles, resulting in a pus-filled abscess. Immunodeficiency of the patient is considered to play an important role in pathogenesis. We report a case of a 3-year-old child, who presented with multifocal pyomyositis in the gastrocnemius muscle, extending to the posterior muscles of the thigh. Even though there was no evidence of immunodeficiency, the presence of atopic eczema in the big toe of the affected limb could interfere with the immune system response, and therefore, could be associated with pyomyositis. The increasing incidence of pyomyositis in non-tropical areas and its severe complications requires an acute clinical awareness. PMID- 21610312 TI - Normophosphatemic type tumoral calcinosis associated with chronic recurrent multifocal osteomyelitis: a case report. AB - Chronic recurrent multifocal osteomyelitis (CRMO) and tumoral calcinosis are two distinct musculoskeletal diseases with unclear etiopathogenesis. Previously, two CRMO cases with associated tumoral calcinosis were reported. We report a patient who developed tumoral calcinosis after the surgical treatment of CRMO. To our knowledge it is the third patient in whom tumoral calcinosis developed sporadically during follow-up for CRMO. PMID- 21610313 TI - Extraskeletal juxtaarticular chondroma of the knee. AB - Extraskeletal chondromas are atypical lesions and their recognition is important to avoid invasive treatment methods like marginal excision. The diagnosis must be confirmed with correlating clinical, radiological and histopathological examination. We report a 40-year-old woman with an extraskeletal chondroma around the knee joint. The radiological and histopathological aspects of the patient are presented along with a review of the literature. PMID- 21610314 TI - Hypoxia induces tumor and endothelial cell migration in a semaphorin 3F- and VEGF dependent manner via transcriptional repression of their common receptor neuropilin 2. AB - Neuropilin-2 (NRP2) is a receptor expressed by tumor cells and endothelial cells (EC) that binds both semaphorin 3F (SEMA3F), a potent inhibitor of tumor angiogenesis and metastasis, and vascular endothelial growth factor (VEGF), a potent stimulator of tumor angiogenesis. It was found that glioblastoma and melanoma cells repressed NRP2 expression when maintained under hypoxic conditions and after treatment with the hypoxia-mimetic agent desferrioxamine (DFO), at both the mRNA and protein levels. Silencing of HIF1-alpha, the hypoxia-induced subunit of the hypoxia inducible factor (HIF), abrogated DFO-induced NRP2 repression. Conversely, ectopic expression of HIF1-alpha directly repressed NRP2 promoter activity and expression. NRP2 is the sole receptor for SEMA3F. Loss of NRP2 expression in tumor cells inhibited SEMA3F-dependent activities, such as inactivation of RhoA, depolymerization of F-actin, and inhibition of tumor cell migration. On the other hand, loss of NRP2 expression in tumor cells increased VEGF protein levels in conditioned media, with no effects on VEGF mRNA levels. This increase in VEGF protein levels promoted paracrine activation of EC, including VEGF receptor-2 phosphorylation, and activation of downstream signaling proteins such as p44/42 MAPK and p38 MAPK. In addition, the elevated VEGF levels induced EC migration and sprouting, two key steps of tumor angiogenesis in vivo. It was concluded that hypoxia regulates VEGF and SEMA3F activities through transcriptional repression of their common receptor NRP2, providing a novel mechanism by which hypoxia induces tumor angiogenesis, growth and metastasis. PMID- 21610315 TI - Cleaving Beclin 1 to suppress autophagy in chemotherapy-induced apoptosis. AB - Autophagy is often found in apoptosis-defective cancer cells and contributes to chemotherapy resistance. However, it is far from clear how the coordination of apoptosis and autophagy determines sensitivity of cancer cells to chemotherapy. Our recent study showed that Beclin 1, a key regulator of autophagy, is cleaved by caspase 8 at the execution stage of chemotherapy-induced and mitochondria mediated apoptosis. Perturbation of Beclin 1 cleavage, by knock-in of a mutation, phenocopies the autophagy observed in apoptosis-defective cancer cells, and renders chemotherapy resistance in vitro and in vivo. These results demonstrate an important role of caspases in suppressing autophagy by cleaving autophagic machinery. PMID- 21610316 TI - A monitoring method for Atg4 activation in living cells using peptide-conjugated polymeric nanoparticles. AB - To date, several principal methods are presently used to monitor the autophagic process, but they have some potential experimental pitfalls or limitations that make them not applicable to living cells. In order to improve on the currently developed detection methods for autophagy, we report here fluorescent peptide conjugated polymeric nanoparticles loaded with a lysosome staining dye in their core. The fluorescent peptide is designed to be specifically cleaved by the Atg4 cysteine protease, which plays a crucial role in autophagy activation. In this study, we demonstrate that peptide-conjugated polymeric nanoparticles can be used to visualize Atg4 activity in both cell-free and cell culture systems. The fluorescence imaging of cells incubated with nanoparticles demonstrates that Atg4 activity is activated in the autophagy-induced conditions, but suppressed in the autophagy-inhibited conditions. These results indicate that Atg4 activity is correlated with autophagic flux through its own regulatory pathway. Therefore, our strategy provides an alternative detection method that can clearly distinguish between an "autophagy active" and "autophagy inactive" state in cultured cells. As our nanoparticles are highly cell-permeable and biocompatible, this detection system has general applicability to living cells and can be extended to cell-based screening to evaluate newly developed compounds. PMID- 21610317 TI - Brca2 deficiency and Trp53 deregulation in pancreatic cancer: implications for therapeutic targeting. PMID- 21610318 TI - Size and positional effects of promoter RNA segments on virus-induced RNA directed DNA methylation and transcriptional gene silencing. AB - DNA methylation at a gene promoter can be triggered by double-stranded RNAs (dsRNAs) through the RNA-directed DNA methylation (RdDM) pathway and induces transcriptional gene silencing (TGS). Although genes involved in the RdDM pathway have been identified, whether dsRNAs of different promoter regions have different extent of effects on RdDM and/or TGS is unknown. Here, we addressed this question by targeting the CaMV 35S promoter in the plant genome using a recombinant Cucumber mosaic virus that contained various portions of the promoter. The efficiency of the induction of TGS depended on the length of the promoter segment triggering the RdDM; the lower size limit for TGS induction was 81-91 nt. TGS was induced when 70-nt fragments were connected in tandem, none of which solely induced TGS. TGS induction did not simply depend on the production of small interfering RNAs corresponding to the promoter. Along with the induction of RdDM, spreading of DNA methylation from the originally targeted site toward the adjacent regions was detected. The maintenance of TGS in the progeny that lacks an RNA trigger depended on the promoter segments triggering the RdDM in the former generation and was correlated with the number of cytosines at symmetrical sites in the targeted region. These results indicate that both the length of dsRNA above the threshold and the frequency of cytosines at symmetric sites in the region targeted by dsRNA are the major factors that allow induction of heritable TGS via RdDM. PMID- 21610319 TI - Autophagic activity measured in whole rat hepatocytes as the accumulation of a novel BHMT fragment (p10), generated in amphisomes by the asparaginyl proteinase, legumain. AB - To investigate the stepwise autophagic-lysosomal processing of hepatocellular proteins, the abundant cytosolic enzyme, betaine:homocysteine methyltransferase (BHMT) was used as a probe. Full-length (45 kDa) endogenous BHMT was found to be cleaved in an autophagy-dependent (3-methyladenine-sensitive) manner in isolated rat hepatocytes to generate a novel N-terminal 10-kDa fragment (p10) identified and characterized by mass spectrometry. The cleavage site was consistent with cleavage by the asparaginyl proteinase, legumain and indeed a specific inhibitor of this enzyme (AJN-230) was able to completely suppress p10 formation in intact cells, causing instead accumulation of a 42-kDa intermediate. To prevent further degradation of p10 or p42 by the cysteine proteinases present in autophagic vacuoles, the proteinase inhibitor leupeptin had to be present. Asparagine, an inhibitor of amphisome-lysosome fusion, did not detectably impede either p42 or p10 formation, indicating that BHMT processing primarily takes place in amphisomes rather than in lysosomes. Lactate dehydrogenase (LDH) was similarly degraded primarily in amphisomes by leupeptin-sensitive proteolysis, but some additional leupeptin-resistant LDH degradation in lysosomes was also indicated. The autophagic sequestration of BHMT appeared to be nonselective, as the accumulation of p10 (in the presence of leupeptin) or of its precursors (in the additional presence of AJN-230) proceeded at approximately the same rate as the model autophagic cargo, LDH. The complete lack of a cytosolic background makes p10 suitable for use in a "fragment assay" of autophagic activity in whole cells. Incubation of hepatocytes with ammonium chloride, which neutralizes amphisomes as well as lysosomes, caused rapid, irreversible inhibition of legumain activity and stopped all p10 formation. The availability of several methods for selective targeting of legumain in intact cells may facilitate functional studies of this enigmatic enzyme, and perhaps suggest novel ways to reduce its contribution to cancer cell metastasis or autoimmune disease. PMID- 21610321 TI - Autophagy switches to apoptosis in prostate cancer cells infected with melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). AB - MDA-7/IL-24 has noteworthy potential as an anticancer therapeutic because of its diversity of antitumor properties, its lack of toxicity toward normal cells and tissues, and its safety and efficacy as evidenced in a phase I clinical trial. In a recent study, we document that Ad.mda-7-induced ER stress and ceramide production leads to early autophagy that subsequently switches to apoptosis in human prostate cancer cells. During the apoptotic phase, the MDA-7/IL-24 protein physically interacts with Beclin 1 and this interaction might inhibit Beclin 1 function culminating in apoptosis. Conversely, Ad.mda-7 infection leads to calpain-mediated cleavage of the Atg5 protein that might also facilitate a biochemical switch from autophagy to apoptosis. Our recent paper reveals novel aspects of the interplay between autophagy and apoptosis that underlie the cytotoxic action of MDA-7/IL-24 in prostate cancer cells. These new insights into MDA-7/IL-24 action provide intriguing leads for developing innovative combinatorial approaches for prostate cancer therapy. PMID- 21610320 TI - Quercetin induces protective autophagy in gastric cancer cells: involvement of Akt-mTOR- and hypoxia-induced factor 1alpha-mediated signaling. AB - Quercetin, a dietary antioxidant present in fruits and vegetables, is a promising cancer chemopreventive agent that inhibits tumor promotion by inducing cell cycle arrest and promoting apoptotic cell death. In this study, we examined the biological activities of quercetin against gastric cancer. Our studies demonstrated that exposure of gastric cancer cells AGS and MKN28 to quercetin resulted in pronounced pro-apoptotic effect through activating the mitochondria pathway. Meanwhile, treatment with quercetin induced appearance of autophagic vacuoles, formation of acidic vesicular organelles (AVOs), conversion of LC3-I to LC3-II, recruitment of LC3-II to the autophagosomes as well as activation of autophagy genes, suggesting that quercetin initiates the autophagic progression in gastric cancer cells. Furthermore, either administration of autophagic inhibitor chloroquine or selective ablation of atg5 or beclin 1 using small interfering RNA (siRNA) could augment quercetin-induced apoptotic cell death, suggesting that autophagy plays a protective role against quercetin-induced apoptosis. Moreover, functional studies revealed that quercetin activated autophagy by modulation of Akt-mTOR signaling and hypoxia-induced factor 1alpha (HIF-1alpha) signaling. Finally, a xenograft model provided additional evidence for occurrence of quercetin-induced apoptosis and autophagy in vivo. Together, our studies provided new insights regarding the biological and anti-proliferative activities of quercetin against gastric cancer, and may contribute to rational utility and pharmacological study of quercetin in future anti-cancer research. PMID- 21610322 TI - Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer. AB - The KEAP1/Nrf2 pathway is a master regulator of several redox-sensitive genes implicated in resistance of tumor cells against chemotherapeutic drugs. Recent data suggest that epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression. We performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 47 non-small cell lung cancer tissues and normal specimens. Promoter methylation analysis was performed using a quantitative methylation specific PCR assay in real time. Methylation at the KEAP1 promoter region was detected in 22 out of the 47 NSCLCs (47%) and in none of the normal tissues analyzed. Somatic mutations were detected in 7 out of the 47 tumors (15%) and loss of heterozygosity (LOH) in 10 out of the 47 (21%) of the cases. Overall, we found at least one molecular alteration in 57% of the cases. Approximately one third of the tumors had two alterations and this feature was associated with higher risk of disease progression in univariate COX regression analysis (HR = 3.62; 95% CI 1.24-10.65, p = 0.02). This result was confirmed by Kaplan-Meier analysis, which demonstrated an association between worst outcome and KEAP1 double alterations (p = 0.01, Log rank test). Our results further suggest that deregulation of the NRF2/KEAP1 system could play a pivotal role in the cancerogenesis of NSCLC. In addition identifying patients with KEAP1 genetic and epigenetic abnormalities may contribute to disease progression prediction and response to therapy in lung cancer patients. PMID- 21610323 TI - Polycomb group genes are targets of aberrant DNA methylation in renal cell carcinoma. AB - The combined effects of genetic and epigenetic aberrations are well recognized as causal in tumorigenesis. Here, we defined profiles of DNA methylation in primary renal cell carcinomas (RCC) and assessed the association of these profiles with the expression of genes required for the establishment and maintenance of epigenetic marks. A bead-based methylation array platform was used to measure methylation of 1,413 CpG loci in ~800 cancer-associated genes and three methylation classes were derived by unsupervised clustering of tumors using recursively partitioned mixture modeling (RPMM). Quantitative RT-PCR was performed on all tumor samples to determine the expression of DNMT1, DNMT3B, VEZF1 and EZH2. Additionally, methylation at LINE-1 and AluYb8 repetitive elements was measured using bisulfite pyrosequencing. Associations between methylation class and tumor stage (p = 0.05), LINE-1 (p < 0.0001) and AluYb8 (p < 0.0001) methylation, as well as EZH2 expression (p < 0.0001) were noted following univariate analyses. A multinomial logistic regression model controlling for potential confounders revealed that AluYb8 (p < 0.003) methylation and EZH2 expression (p < 0.008) were significantly associated with methylation class membership. Because EZH2 is a member of the Polycomb repressive complex 2 (PRC2), we next analyzed the distribution of Polycomb group (PcG) targets among methylation classes derived by clustering the 1,413 array CpG loci using RPMM. PcG target genes were significantly enriched (p < 0.0001) in methylation classes with greater differential methylation between RCC and non-diseased kidney tissue. This work contributes to our understanding of how repressive marks on DNA and chromatin are dysregulated in carcinogenesis, knowledge that might aid the development of therapies or preventive strategies for human malignancies. PMID- 21610325 TI - Loss of either hypoxia inducible factor 1 or 2 promotes lung cancer cell colonization. PMID- 21610324 TI - Environmental epigenetics in metal exposure. AB - Although it is widely accepted that chronic exposure to arsenite, nickel, chromium and cadmium increases cancer incidence in individuals, the molecular mechanisms underlying their ability to transform cells remain largely unknown. Carcinogenic metals are typically weak mutagens, suggesting that genetic-based mechanisms may not be primarily responsible for metal-induced carcinogenesis. Growing evidence shows that environmental metal exposure involves changes in epigenetic marks, which may lead to a possible link between heritable changes in gene expression and disease susceptibility and development. Here, we review recent advances in the understanding of metal exposure affecting epigenetic marks and discuss establishment of heritable gene expression in metal-induced carcinogenesis. PMID- 21610326 TI - Unleashing Chk1 in cancer therapy. AB - The checkpoint kinase 1 (Chk1) is one of the major players in the signal transduction pathway set in motion in response to DNA damage which activates different cell cycle checkpoints including the G 1/S, the intra-S, G 2-M and the mitotic spindle checkpoint, contributing to the maintenance of genomic stability. Chk1 is considered a good molecular target to inhibit, in combination with other anticancer agents, to increase the sensitivity of treatment, especially in tumors with a defective G 1 checkpoint. Experimental evidence highlights the essential role of Chk1 in normal and cancer cells even under unstressed conditions, especially in controlling DNA replication and cell division. This review looks at the main functions of Chk1 and the data on Chk1 inhibitors at their preclinical and clinical development are reported. This information may suggest novel approaches for new treatments with Chk1 inhibitors in combination with anticancer agents or as single agents. The emergent synthetic lethality approach may help define the genetic background features where Chk1 inhibitors alone could be very effective. PMID- 21610327 TI - Genistein, an epigenome modifier during cancer prevention. AB - Dietary compounds have been observed to have a great potential to regulate the epigenome, which is disrupted and reprogrammed during carcinogenesis. Because of their close association with cancer development, DNA methylation patterns have been used as a crucial marker for the study of cancer-related epigenetics. There is immense evidence indicating that dietary components play a critical role in cancer development. Genistein, one of the soy-derived bioactive isoflavones, affects tumorigenesis through epigenetic regulations. By modulating chromatin configuration and DNA methylation, genistein activates tumor suppressor genes and affects cancer cell survival. Here, we summarize and discuss both in vitro and in vivo studies in the field that investigate the effect of genistein on histone modifications and DNA methylation. The promising role of genistein in cancer prevention and therapeutic applications will be discussed from an epigenetic point of view. PMID- 21610329 TI - Direct-to-consumer genetic testing. PMID- 21610330 TI - Growing spectrum and relevance of pediatric neuro-immunology. PMID- 21610331 TI - Diagnosing central nervous system vasculitis in children. AB - PURPOSE OF REVIEW: To review the current literature of childhood central nervous system vasculitis, and to discuss a tailored approach to diagnosis and treatment based on recent evidence. RECENT FINDINGS: Primary angiitis of the central nervous system in children (cPACNS) is an increasingly recognized inflammatory brain disease with potentially devastating neurological consequences. The diagnostic approach should be tailored to the clinical presentation of the child with suspected cPACNS and should address the expanding spectrum of inflammatory and noninflammatory brain diseases with overlapping clinical features. New evidence has confirmed that elective brain biopsies in children have a higher diagnostic yield than in adults and improve our ability to diagnose angiography negative cPACNS. Finally, observational studies have shown that early diagnosis and aggressive treatment lead to improved neurological outcomes and lower mortality rates in patients with cPACNS. SUMMARY: This review summarizes the recent data on diagnosis, classification, treatment, and outcomes in cPACNS. Our improved understanding of cPACNS facilitates a tailored diagnostic approach that results in earlier diagnosis and initiation of therapy for this potentially reversible condition. PMID- 21610332 TI - The interplay of infection and genetics in acute necrotizing encephalopathy. AB - PURPOSE OF REVIEW: Acute necrotizing encephalopathy (ANE) presents with fulminant encephalopathy and characteristic brain lesions following viral infection. The rarity and unpredictability of the disorder have significantly impaired its study. Growing recognition of ANE and the discovery of causative missense mutations in the nuclear pore gene RANBP2 give promising steps toward unraveling this disease. This review summarizes recent advances of clinical and scientific understanding of ANE. RECENT FINDINGS: Inflammatory factors participate in the pathogenesis of ANE, but the lack of difference between influenza and noninfluenza ANE focuses attention on the abnormal host response as causative. Early treatment with steroids provides the best outcome for patients who do not have brainstem lesions. Missense mutations in RANBP2 cause the majority of familial and recurrent ANE cases, but other single-gene causes of ANE are possible for familial, recurrent, and sporadic cases. SUMMARY: Early recognition and systematic evaluation of ANE are necessary. Modeling ANE as a genetic disorder may provide the most immediate gains in the understanding and treatment of ANE and related disorders. PMID- 21610333 TI - Bibliography. Genetics. Current world literature. PMID- 21610334 TI - Reduction of inferior orbital wall fractures using a Foley catheter and an Endoloop. AB - BACKGROUND: Various surgical approaches have been used to treat orbital blowout fractures. Among them, the transnasal endoscopic approach avoids external scars and allows clear observation of the fracture site. We conducted a retrospective study of blowout fractures reduced using a Foley catheter and an Endoloop. METHODS: Patients (n=24) who underwent endoscopic reduction of inferior orbital wall fractures were analyzed. They were diagnosed using 3-mm facial computed tomography, and the surgical treatment consisted of fracture reduction using Foley catheter and Endoloop. Postoperatively, they were followed up for at least 3 months. RESULTS: There was no significant intraoperative or postoperative complication. The symptoms in all but two patients resolved completely after surgery. CONCLUSION: The technique using Foley catheter and Endoloop to reduce inferior orbital wall fractures endoscopically is safe and efficacious. PMID- 21610335 TI - Lower extremity injuries in snowboarding. AB - BACKGROUND: In snowboarding, the upper extremity is known as the most common injury site and little information is available for lower extremity injuries. Here, we aim to discuss lower extremity injuries during snowboarding. METHODS: We retrospectively analyzed the epidemiologic factors, injury types, and injury mechanisms for injured snowboarders (7,793 cases) between 2004-2005 and 2008-2009 seasons; information was gathered via questionnaires. Individuals were classified into a lower extremity injury group (961 cases) and a control group with other injuries (6,832 cases). RESULTS: The incidence of lower extremity injuries in snowboarding was 0.16 per 1,000 participant days, accounting for 12.3% of all snowboarding injuries. The mean age of the lower extremity injury group and injured control group was 26.1 years +/- 5.9 years and 25.1 years +/- 5.6 years, respectively. Approximately 90% of snowboarders in both the groups were equipped with soft-shelled boots. Skilled snowboarders tended to sustain lower extremity injuries (p<0.0001). In lower extremity injuries, the most common injury type was lacerations/contusions (22.4%), resulting from collision with other snow sports participants. The most common fracture site was the ankle. Overall, in lower extremity injuries, the leading side was the most commonly injured (53.8%). CONCLUSIONS: A typical lower extremity injury in snowboarding is lacerations/contusions caused by collision with other snow sport participants. Lower extremity injuries in snowboarding differ considerably from well-known upper extremity injuries in terms of injury types and mechanisms. The incidence of lower extremity injuries is high and deserves further attention. PMID- 21610336 TI - Steel bar impalement--the great fortune of misfortune. PMID- 21610337 TI - Varicocele secondary to giant posttraumatic hepatic cyst. PMID- 21610338 TI - Radiologic signs of barotrauma. PMID- 21610339 TI - Impact of socioethnic factors on outcomes following traumatic brain injury. AB - BACKGROUND: Ethnic minorities and low income families tend to be in poorer health and have worse outcomes for a spectrum of diseases. Health care provider bias has been reported to potentially affect the distribution of care away from poorer communities, minorities, and patients with a history of substance abuse. Trauma is perceived as a disease of the poor and medically underserved. Minorities are overrepresented in low income populations and are also less likely to possess health insurance leading to a potential overlapping effect. Traumatic brain injury (TBI) is a predominant cause of mortality and long-term morbidity, which imposes a considerable social and financial burden. We therefore sought to determine the independent effect on outcome after TBI from race, insurance status, intoxication on presentation, and median income. METHODS: A 5-year retrospective chart review of admitted trauma patients aged 18 years and older to a Level I trauma center. Zip code of residency was a surrogate marker for socioeconomic status, because median income for each zip code is available from the US Census. Charts review included race, insurance status, mechanisms of trauma, and injuries sustained. Outcomes were placement of tracheostomy, hospital length of stay (HLOS), leaving Against Medical Advice (AMA), and discharge to home versus rehabilitation and mortality. RESULTS: A total of 3,101 TBI patients were included in the analyses. Multivariable logistic and proportional hazard regression analyses were undertaken adjusting for age, gender, Injury Severity Score, and mechanism. Rates of tracheostomy placement were unaffected by race, median income, or insurance status. Race and median income did not affect HLOS, but private insurance was associated with shorter HLOS and intoxication was associated with longer HLOS. Neither race nor intoxication affected rates of AMA, but higher income and private insurance was associated with lower rates of AMA. Non-Caucasian race and lack of insurance had significantly lower likelihood of placement in a rehabilitation center. Mortality was unaffected by race, increased in intoxicated patients, was variably affected by median income, and was lowest in patients with private insurance. CONCLUSIONS: An extremely complex interplay exists between socioethnic factors and outcomes after TBI. Few physicians would claim overt discrimination. Tracheostomy, the factor most directed by the surgeon, was unbiased by race, income, or insurance status. The likelihood of placement in a rehabilitation center was significantly impacted by both race and insurance status. Future prospective studies are needed to better address causation. PMID- 21610340 TI - Reduced brain tissue oxygen in traumatic brain injury: are most commonly used interventions successful? AB - BACKGROUND: Brain tissue oxygenation (PbtO2)-guided management facilitates treatment of reduced PbtO2 episodes potentially conferring survival and outcome advantages in severe traumatic brain injury (TBI). To date, the nature and effectiveness of commonly used interventions in correcting compromised PbtO2 in TBI remains unclear. We sought to identify the most common interventions used in episodes of compromised PbtO2 and to analyze which were effective. METHODS: A retrospective 7-year review of consecutive severe TBI patients with a PbtO2 monitor was conducted in a Level I trauma center's intensive care unit or neurosurgical registry. Episodes of compromised PbtO2 (defined as <20 mm Hg for 0.25-4 hours) were identified, and clinical interventions conducted during these episodes were analyzed. Response to treatment was gauged on how rapidly (DeltaT) PbtO2 normalized (>20 mm Hg) and how great the PbtO2 increase was (DeltaPbtO2). Intracranial pressure (DeltaICP) and cerebral perfusion pressure (DeltaCPP) also were examined for these episodes. RESULTS: Six hundred twenty-five episodes of reduced PbtO2 were identified in 92 patients. Patient characteristics were: age 41.2 years, 77.2% men, and Injury Severity Score and head or neck Abbreviated Injury Scale score of 34.0 +/- 9.2 and 4.9 +/- 0.4, respectively. Five interventions: narcotics or sedation, pressors, repositioning, FIO2/PEEP increases, and combined sedation or narcotics + pressors were the most commonly used strategies. Increasing the number of interventions resulted in worsening the time to PbtO2 correction. Triple combinations resulted in the lowest DeltaICP and dual combinations in the highest DeltaCPP (p < 0.05). CONCLUSION: Clinicians use a limited number of interventions when correcting compromised PbtO2. Using strategies employing many interventions administered closely together may be less effective in correcting PbO2, ICP, and CPP deficits. Some PbtO2 deficits may be self-limited. PMID- 21610341 TI - Dynamic three-dimensional scoring of cerebral perfusion pressure and intracranial pressure provides a brain trauma index that predicts outcome in patients with severe traumatic brain injury. AB - BACKGROUND: Data on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) guide therapy in severe traumatic brain injury (TBI), but current linear analytic methods are insufficiently sensitive and specific for prognosis in dynamic situations over time. METHODS: We have developed algorithms incorporating continuous, automated, digital ICP and CPP monitoring data into a pressure times time "dose" function. In this study, we calculated cumulative doses using thresholds of ICP >20 mm Hg and CPP <60 mm Hg and graphed these as a Brain Trauma Index (BTI or CPP/ICP). Using receiver operator characteristics analysis, we examined BTI <3 and BTI <2 and various threshold levels of pressure times time doses of ICP and CPP as predictors of 30-day mortality and Extended Glasgow Outcome Scale (GOSE) <5 at 6 months and 12 months. Using the data processing and analysis tools underlying this work, we are also piloting a real-time bedside and telemetric display system as a means of indentifying and monitoring critical changes in physiologic metrics, including BTI, CPP, and ICP. RESULTS: Sixty subjects yielded 8678.1 hours of data (5,206,860 data points). BTI <2 was better than CPP <60 mm Hg in predicting unfavorable Extended Glasgow Outcome Scale at 6 months (p <0.05). An example of linear and graphically processed BTI, CPP, and ICP data from a representative TBI patient is provided. CONCLUSION: Calculation of a BTI from continuous digital data predicts outcome in severe TBI and has potential for the design of real-time bedside early warning systems. PMID- 21610342 TI - Diagnosing mild traumatic brain injury: where are we now? AB - BACKGROUND: The brain acoustic monitor (BAM), an indicator of cerebral autoregulation, has previously shown high sensitivity but low specificity for computed tomographic (CT) abnormality in patients following the clinical diagnosis of traumatic brain injury. We assessed the utility of the BAM in diagnosing mild TBI (mTBI) in patients with and without normal findings of CT scan, a population for which there are a few objective markers of disease. METHODS: We prospectively studied 369 patients with mechanism of injury consistent with TBI. The diagnosis was evaluated by five methods: (a) study enrollment (i.e., mechanism of injury), (b) signs of head trauma, (c) expert physician assessment, (d) presence of initial symptoms (loss of consciousness [LOC]; amnesia), and (e) BAM. All patients had a head CT scan. We compared the BAM screen results with the diagnosis of mTBI and BAM data from 50 normal volunteers and 49 trauma control patients not thought to have TBI. RESULTS: None of the diagnostic methods correlated well with the others. Correlation between the methods ranged from 21% to 71%. BAM discriminated between patients with mTBI versus without TBI (p<0.01) and patients with mTBI versus normal subjects (p<0.001). There were 14 patients with new abnormal findings of CT scans. A history of LOC and physical signs of head injury were associated with a new abnormality on head CT (p<0.05 and p<0.01, respectively), whereas an abnormal BAM signal was suggestive (p=0.08). The sensitivity of BAM abnormality for head CT abnormality was 100%, with a specificity of 30.14%. CONCLUSION: There is no gold standard for the diagnosis of mTBI. BAM screening is a useful diagnostic adjunct in patients with mTBI and may facilitate decision making. An abnormal BAM reading adds significance to LOC as a predictor of a new abnormality on head CT. In our study, opting not to CT scan patients with a normal BAM signal would have missed no new CT findings and no patients who required medical intervention for TBI, at a cost savings of $202,950. PMID- 21610343 TI - Resource commitment to improve outcomes and increase value at a level I trauma center. AB - BACKGROUND: Optimal care of trauma patients requires cost-effective organization and commitment of trauma center resources. We examined the impact of creating a dedicated trauma care unit (TCU) and adding advanced practice nurses on the quality and cost of care at an adult Level I trauma center. METHODS: Patient demographic and injury data, length of stay, complications, outcomes, and total direct cost of care were evaluated for four 1-year intervals in the recent history of our trauma center: Year A, a trauma team of in-house trauma surgeons and resident physicians; Year B, the addition of nurse practitioners to the trauma team 5 days/week; Year C, the creation of a dedicated TCU for all non intensive care unit trauma patients; and Year D, the addition of a permanent clinical nurse specialist and an increase in nurse practitioner coverage to 7 days/week. For each year, value was determined by calculating the median cost of a survivor and the median cost of a survivor with no complications. Significance was attributed to p<0.05. RESULTS: Patient volume increased from 1,927 in year A to 2,546 by year D. Over the period of study, there was an increase in blunt trauma (87.1-89.9%; p<0.05), median Injury Severity Score (5-6; p<0.05), and patients aged >=65 years (11.4-19.8%; p<0.05). However, risk-adjusted mortality was unchanged. There was a decrease in patients with a complication (20.8-14.9%; p < 0.05), median intensive care unit length of stay (39.5-23.4 hours; p < 0.05), and median cost of care ($4,306-$3,698; p<0.05). Value increased: both the median costs of a survivor and of a survivor with no complications decreased from $4,259 to $3,658 (p<0.05) and from $3,898 to $3,317 (p<0.05), respectively. The median cost of a survivor with severe injury (Injury Severity Score >=15) decreased from $17,651 to $12,285 (p<0.05). CONCLUSION: The addition of a dedicated TCU and advanced practice nurses improved the quality and reduced the cost of care, resulting in increased value at an adult Level I trauma center. PMID- 21610344 TI - Long-lasting performance improvement after formalization of a dedicated trauma service. AB - BACKGROUND: Few studies have evaluated intrainstitutional improvement of trauma care. We hypothesized that the formalization of a dedicated multidisciplinary trauma service in a major Scandinavian trauma center in 2005 would result in improved outcome. METHODS: Institutional trauma registry data for 7,243 consecutive patients from the years 2002-2008 were retrospectively evaluated using variable life-adjusted display (VLAD) as one of several performance indicators. VLAD is a refinement of the cumulative sum method that adjusts death and survival by each patient's risk status (probability of survival) and provides a graphical display of performance over time. Probability of survival was calculated according to Trauma and Injury Severity Score (TRISS) methodology with National Trauma Data Bank 2005 coefficients. RESULTS: VLAD demonstrated a sharp increase in cumulative survival starting at the beginning of 2005 and continuing linearly throughout the study period, amounting to 68 additional saved lives. The increase was mainly caused by improved survival among the critically injured (injury severity score 25-75). A cutoff point t0 for analysis of differences between time periods was set at January 1, 2005, coinciding with the formalization of a dedicated trauma service. Mortality in the whole trauma population showed a 33% decrease after t0. W-statistics confirmed the increased survival to be significant. There were no significant changes in age, gender, or injury mechanism. Injury severity score decreased, but differences in case mix were adjusted for in the survival prediction model. CONCLUSION: We have shown that the start of the long-lasting performance improvement coincided with formalization of a dedicated trauma service, providing increased multidisciplinary focus on all aspects of trauma care. PMID- 21610345 TI - Prevention of complications and successful rescue of patients with serious complications: characteristics of high-performing trauma centers. AB - BACKGROUND: "Failure to rescue" patients with complications is a factor contributing to high mortality rates after elective surgery. In trauma, where early deaths are the primary contributors to a trauma center's mortality rate, the rescue of patients with complications might not be related to overall trauma center mortality. We assessed the extent to which trauma center mortality was reflected by the center's ability to rescue patients with major complications. METHODS: Data were derived from the National Trauma Databank, and limited to adults with an Injury Severity Score >=9 and to centers with adequate complication reporting. Regression models were used to produce center-level adjusted rates for mortality and complications. Centers were ranked on their adjusted mortality rate and divided into quintiles. RESULTS: Of 76,048 patients, 9.6% had a major complication and 7.9% died. The mean complication rate in the quintile of centers with the highest mortality rates was 11.1%, compared with 7.7% in the quintile of centers with the lowest mortality rates (p=0.03). In addition, mortality among patients with complications differed significantly across quintiles. The mean mortality among patients with complications was 20.3% in the quintile of centers with the highest overall mortality rates, compared with 11.1% in the quintile of centers with the lowest overall mortality rates (p<0.001). CONCLUSIONS: Unlike reports from elective surgery, complication rates after severe injury differ across centers and parallel mortality rates. Centers with low overall mortality are more successful at rescuing patients who experience complications. A lower risk of complications and better care of those with complications are both at play in high-performing trauma centers. PMID- 21610346 TI - Global surgical package reimbursement and the acute care surgeon: a threat to optimal care. AB - BACKGROUND: Emergency surgery patients risk greater mortality and morbidity than elective patients undergoing the same procedure. However, the differential effort required for the care of emergency surgical patients is poorly defined. This study sought to characterize costs and outcomes of elective versus emergent right hemicolectomy. METHODS: 2006 Nationwide Inpatient Sample data were used to compare mortality, total charges, and length of stay (LOS) in patients undergoing emergency versus elective right hemicolectomy (International Classification of Diseases-9th procedure code 45.73). Mann-Whitney tests examined total costs and LOS; multivariable regression modeled inhospital mortality controlling for age, gender, insurance status, and comorbidities. RESULTS: Among 8,074,825 inpatient admissions, 7,767 emergent and 10,399 elective right hemicolectomies were identified. Emergent patients were similar in age (66.9 years vs. 67.6 years; p=0.129), more likely women (43.7% vs. 42.3%; p=0.048) and had greater comorbidity (Charlson score 3.37 vs. 3.01; p<0.001) compared with elective patients. Emergent patient LOS was approximately double that of elective patients (13 days vs. 7 days; p<0.001). Mean total charges were $78,118 for emergent versus $39,265 elective patients (p<0.001). Emergent patients had greater odds of inhospital mortality (odds ratio, 5.86; 95% confidence intervals, 4.80-7.14). CONCLUSIONS: Emergent right hemicolectomy patients have greater comorbidity, experience longer stays, accrue twice the charges, and have higher mortality risk. This reflects a heightened effort required to care for emergent patients unrecognized by Global Surgical Package reimbursement. The concentration of emergency surgical patients in acute care surgery services necessitates accounting for the additional effort associated with these predictable risks to ensure optimal care. PMID- 21610347 TI - An acute care surgery rotation contributes significant general surgical operative volume to residency training compared with other rotations. AB - BACKGROUND: Surgical resident rotations on trauma services are criticized for little operative experience and heavy workloads. This has resulted in diminished interest in trauma surgery among surgical residents. Acute care surgery (ACS) combines trauma and emergency/elective general surgery, enhancing operative volume and balancing operative and nonoperative effort. We hypothesize that a mature ACS service provides significant operative experience. METHODS: A retrospective review was performed of ACGME case logs of 14 graduates from a major, academic, Level I trauma center program during a 3-year period. Residency Review Committee index case volumes during the fourth and fifth years of postgraduate training (PGY-4 and PGY-5) ACS rotations were compared with other service rotations: in total and per resident week on service. RESULTS: Ten thousand six hundred fifty-four cases were analyzed for 14 graduates. Mean cases per resident was 432 +/- 57 in PGY-4, 330 +/- 40 in PGY-5, and 761 +/- 67 for both years combined. Mean case volume on ACS for both years was 273 +/- 44, which represented 35.8% (273 of 761) of the total experience and exceeded all other services. Residents averaged 8.9 cases per week on the ACS service, which exceeded all other services except private general surgery, gastrointestinal/minimally invasive surgery, and pediatric surgery rotations. Disproportionately more head/neck, small and large intestine, gastric, spleen, laparotomy, and hernia cases occurred on ACS than on other services. CONCLUSIONS: Residents gain a large operative experience on ACS. An ACS model is viable in training, provides valuable operative experience, and should not be considered a drain on resident effort. Valuable ACS rotation experiences as a resident may encourage graduates to pursue ACS as a career. PMID- 21610348 TI - Colon anastomosis after damage control laparotomy: recommendations from 174 trauma colectomies. AB - BACKGROUND: Primary colonic anastomosis in trauma patients has been demonstrated to be safe. However, few studies have investigated this in the setting of damage control laparotomy. We hypothesized that colonic anastomosis for trauma patients requiring an open abdomen (OA) would have a higher anastomotic leak (AL) rate when compared with patients having an immediate abdominal closure following trauma laparotomy. METHODS: We performed a cohort comparison study of all trauma patients who underwent colectomy, between the years 2004 and 2009. Exclusion criteria were mortality within 24 hours of admission or colectomy for indications unrelated to injury. Data collected included age, gender, injury severity score, mechanism, length of stay, and mortality. Multivariable logistic regression was performed to assess the relationship of OA to our primary outcome measure, AL. RESULTS: Totally, 174 patients met study criteria. Fecal diversion was performed in 58 patients, and colonic anastomosis was performed in the remaining 116 patients. Patients with OA had a clinically significant increase in AL rate compared with immediate abdominal closure (6% vs. 27%, p=0.002). Logistic regression demonstrated that OA was independently associated with AL, with OA patients having more than a sixfold increase in odds of AL compared with those who were closed (odds ratio=6.37, p=0.002, area under the receiver operator curve=0.72). Transfusion requirement and left-sided anastomosis were risk factors for leak. CONCLUSIONS: Patients with a colonic anastomosis and an OA have an unacceptably high leak rate compared with those who undergo reconstruction with immediate closure. Given the significant risk of AL, colonic anastomosis should not be routinely performed in patients with OA. PMID- 21610349 TI - Crystalloids after primary colon resection and anastomosis at initial trauma laparotomy: excessive volumes are associated with anastomotic leakage. AB - BACKGROUND: Recognition of preventable risk factors for suture line failure after colon anastomosis is important for optimizing anastomotic healing. The purpose of this study was to investigate the impact of crystalloids on the occurrence of anastomotic leakage after traumatic colonic injuries. METHODS: Retrospective review from January 2005 to August 2009 of severely injured patients who underwent primary colocolonic anastomosis and intensive care unit (ICU) admission for >=72 hours. Demographics on hospital and ICU admission, amount of crystalloids, and blood component transfusions within the first 72 hours were assessed by multivariate analysis to explore independent associations with anastomotic leakage. RESULTS: Of a total of 123 patients with primary colocolonic anastomosis, 7 died within 72 hour and 24 were discharged before 72 hour from the ICU. The remaining 92 patients required ICU admission for >=72 hour. Their mean Injury Severity Score was 20.8 +/- 10.7, and they were 29.9 years +/- 13.0 years old. Twelve patients (13.0%) developed an anastomotic leak. Demographics on hospital and ICU admission, intraoperative blood loss, and the volume of intraoperative fluids given did not differ statistically between patients with or without anastomotic leakage. However, the cumulative amount of crystalloids given over the first 72 hours significantly predicted anastomotic leakage (area under the receiver operating characteristic curve: 0.758 [95% confidence interval 0.592 0.924], p=0.009). By multivariate analysis, >=10.5 L of crystalloids given over the first 72 hours was independently associated with anastomotic breakdown (odds ratio [95% confidence interval]: 5.26 [1.14-24.39], p=0.033). In addition, increasing age, hemorrhagic shock on admission, and a concomitant stomach injury were independent risk factors for an anastomotic leak (R=0.396). CONCLUSION: Increased use of crystalloids after primary colocolonic anastomosis at initial trauma laparotomy is associated with anastomotic leakage. A threshold of 10.5 L of crystalloid fluid infused over the first 72 hours is associated with a 5-fold increased risk for colocolonic suture line failure. The impact of crystalloid restriction on anastomotic failure in trauma patients warrants prospective investigation. PMID- 21610350 TI - Increase in early mechanical ventilation of burn patients: an effect of current emergency trauma management? AB - BACKGROUND: Data relating to patients admitted with extensive burn injuries in the Netherlands have revealed a marked increase in patients whose initial care included mechanical ventilation (MV). The increase was abrupt, dating from 1997, and has been sustained since. The aim of this study is to quantify this observation and to discuss possible causes. METHODS: The study included 258 consecutive patients with burns >30% total body surface area admitted to the Beverwijk burns center. Patients were divided into two groups based on admission date: group 1 from 1987 to 1996 (n=135) and group 2 from 1997 to 2006 (n=123). Data were analyzed using chi or analysis of variance. RESULTS: There were no differences between groups in demographics, facial burns, inhalation injury, and % total body surface area. However, the number of patients subjected to MV at admission increased from 38% to 76% (group 1 vs. 2; p<0.001). In 57% of patients who were intubated based on the suspicion of inhalation injury, this condition could not be confirmed (p<0.05 vs. 9% [1987-1996]). CONCLUSIONS: This study has confirmed that a higher proportion of patients were treated with MV since 1997, whereas the severity of burn injury remained unchanged throughout the study period. In the absence of a clinical explanation, we surmise that there has been a change within Dutch casualty departments in the initial management of major burn injury. The change coincides with the implementation of the Advanced Life Trauma Support training course as the accepted standard of trauma care in Dutch hospitals. PMID- 21610351 TI - Outcomes of damage control laparotomy with open abdomen management in the octogenarian population. AB - BACKGROUND: Controversy surrounds the role of abbreviated laparotomy and open abdomen (OA) in the octogenarian population in the acute care surgery model based on concern that the initial insult, combined with its sequelae, is beyond the physiologic reserve of these patients. As the population ages further, this dilemma will arise more frequently, requiring the analysis of futility or utility of OA in this demographic. METHODS: The institutional review board approval was obtained to analyze retrospectively patients aged 80 years or older with OA from 1997 to 2009. Univariate, multivariate, and Kaplan-Meier analyses were used to evaluate the effects that demographics, comorbidities, and clinical factors had on in-hospital mortality and overall survival. RESULTS: Sixty-seven patients (32 men and 35 women) were identified. Acute general surgery (including vascular procedures) was the most common indication for laparotomy (94%) with trauma a distant second (6%). Early definitive closure was obtained in 52% of patients with a 34% planned ventral hernia rate. Overall complication rate was 62% and overall in-hospital mortality was 37%. Multivariate analysis revealed congestive heart failure (odds ratio, 11.4; 95% confidence interval, 1.01-128.03) and acute renal failure (odds ratio, 11.8; 95% confidence interval, 2.00-69.12) correlated with in-hospital mortality. Of those surviving to hospital dismissal, 2-year survival was 66% with a 17-month median follow-up (range, 1-125 months). CONCLUSION: There is utility in octogenarians undergoing aggressive surgical management that requires OA. These patients have high mortality rates, but long term survival can be better than their peers with other chronic diseases if they survive the surgical insult. Patient selection should be based on preexisting comorbidities such as congestive heart failure and the development of acute renal failure. Despite the adequate long-term survival, most patients will leave the hospital with a hernia. PMID- 21610352 TI - Use of the rectus abdominis muscle flap for repair of enterocutaneous fistulae: a case series. PMID- 21610353 TI - Observation for nonoperative management of blunt liver injuries: how long is long enough? AB - BACKGROUND: Nonoperative management (NOM) of blunt liver injury is the standard of care in hemodynamically stable patients. However, there are no data regarding the optimum length of inpatient observation. The purpose of this study is to review NOM guidelines for patient safety and optimal length of stay (LOS). METHODS: A retrospective review of the trauma registry at a Level I trauma center was performed to identify all patients admitted with blunt liver injuries. Guidelines for length of observation were developed, such that patients were discharged with normal physical examination and stable hemoglobin, regardless of grade of injury. Data collected include injury severity score, grade of liver injury, LOS, success rate of NOM, time to failure of NOM, and reason for failure of NOM. RESULTS: From August 2002 to March 2009, 591 patients were admitted for NOM of blunt liver injuries. Of these, 35 patients (6%) failed NOM; 19 failed secondary to hemorrhage, mostly from associated injuries. Average LOS for patients with isolated liver injuries was 2.2 days. Only one patient failed NOM as an outpatient. There were no adverse outcomes from these NOM guidelines. CONCLUSIONS: The length of observation should be based solely on clinical criteria. Patients with liver injuries may be safely discharged home in the presence of a normal abdominal examination and stable hemoglobin, regardless of the grade of injury. This guideline is safe and reduces LOS without increasing morbidity or mortality. PMID- 21610354 TI - Hemostatic and pharmacologic resuscitation: results of a long-term survival study in a swine polytrauma model. AB - BACKGROUND: We have previously demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, and spray-dried plasma (SDP) improve early survival after lethal hemorrhage and polytrauma, but their effect on long-term survival and organ function remains untested. METHODS: Yorkshire swine (n=27; 6-8/group) underwent a protocol simulating different phases of trauma care: (1) prehospital rib fracture, soft-tissue injury, hemorrhage (50% blood volume), 30 minutes of shock, and infusion of 0.9% saline (3* shed blood); (2) early hospital/treatment grade IV liver (partial amputation of the median lobe) and grade V splenic (transection of spleen into three pieces) injuries to simulate rupture of contained hematomas, followed by 30 minutes of uncontrolled hemorrhage. Animals were treated with (a) Hextend (6% hetastarch), (b) fresh whole blood (FWB), (c) SDP, and (d) VPA (300 mg/kg) plus Hextend. VPA was given during the prehospital phase, and the volumes of Hextend, FWB and SDP (reconstituted in water) matched shed blood; (3) repair/resuscitation-liver injury was controlled by suture control of the transected edge, and splenic injury was treated by partial splenectomy; 1 hour after repair of injuries, surviving animals were fully resuscitated with packed red blood cells; and (4) monitoring-survival was monitored for 7 days (primary endpoint), and blood samples were drawn serially to measure organ function. RESULTS: Only 25% of the Hextend-treated animals survived. Addition of VPA improved survival to only 50% (p=0.28), whereas treatment with SDP and FWB increased survival significantly to 83% and 100%, respectively (p<0.05). Surviving animals showed no long-term organ dysfunction, postoperative hemorrhage, and delayed complications. CONCLUSIONS: In a clinically relevant lethal polytrauma model, administration of SDP significantly improves survival without any long-term organ dysfunction or complications. PMID- 21610355 TI - Blood volume analysis can distinguish true anemia from hemodilution in critically ill patients. AB - BACKGROUND: Peripheral hematocrit (pHct) is traditionally used as a marker for blood loss. In critically ill patients who are fluid resuscitated, pHct may not adequately represent red blood cell volume (RBCV). We hypothesize that the use of pHct alone may overestimate anemia, potentially leading to unnecessary interventions. METHODS: Patients admitted to the intensive care unit underwent blood volume analysis. Serial blood samples were collected after injection of I albumin. Samples were then processed by the Blood Volume Analyzer-100. RBCV and total blood volume (TBV) were calculated using the directly measured plasma volume (PV) and pHct. A computed normalized hematocrit (nHct) adjusts pHct to the patient's ideal blood volume. RESULTS: Thirty-six patients (21 men), aged 49.8 years +/- 18.4 years, Acute Physiology And Chronic Health Evaluation II score 14.9 +/- 8.1, and injury severity score 29.4 +/- 12.4 had 84 blood volume analyses performed on 3 consecutive days. Using ratios of TBV compared with ideal TBV, patients were stratified into three separate groups: hypovolemic (16 of 84), normovolemic (23 of 84), and hypervolemic (45 of 84). Mean differences between pHct and nHct in each group were 4.5% +/- 3.1% (p<=0.01), 0.0% +/- 1.2% (p=0.85), and -6.5% +/- 4.1% (p<=0.01), respectively. pHct, when compared with nHct, diagnosed anemia (Hct <30) nearly equal within the hypovolemic and normovolemic groups. However, pHct overdiagnosed anemia in 46.7% of hypervolemic patients. CONCLUSION: Use of blood volume analysis in critically ill patients may help to distinguish true anemia from hemodilution, potentially preventing unnecessary interventions. PMID- 21610356 TI - Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial. AB - BACKGROUND: Trauma is a leading cause of death worldwide and is thus a major public health concern. Previous studies have shown that limiting the amount of fluids given by following a strategy of permissive hypotension during the initial resuscitation period may improve trauma outcomes. This study examines the clinical outcomes from the first 90 patients enrolled in a prospective, randomized controlled trial of hypotensive resuscitation, with the primary aim of assessing the effects of a limited transfusion and intravenous (IV) fluid strategy on 30-day morbidity and mortality. METHODS: Patients in hemorrhagic shock who required emergent surgery were randomized to one of the two arms of the study for intraoperative resuscitation. Those in the experimental (low mean arterial pressure [LMAP]) arm were managed with a hypotensive resuscitation strategy in which the target mean arterial pressure (MAP) was 50 mm Hg. Those in the control (high MAP [HMAP]) arm were managed with standard fluid resuscitation to a target MAP of 65 mm Hg. Patients were followed up for 30 days. Intraoperative fluid requirements, mortality, postoperative complications, and other clinical data were prospectively gathered and analyzed. RESULTS: Patients in the LMAP group received a significantly less blood products and total i.v. fluids during intraoperative resuscitation than those in the HMAP group. They had significantly lower mortality in the early postoperative period and a nonsignificant trend for lower mortality at 30 days. Patients in the LMAP group were significantly less likely to develop immediate postoperative coagulopathy and less likely to die from postoperatively bleeding associated with coagulopathy. Among those who developed coagulopathy in both groups, patients in the LMAP group had significantly lower international normalized ratio than those in the HMAP group, indicating a less severe coagulopathy. CONCLUSIONS: Hypotensive resuscitation is a safe strategy for use in the trauma population and results in a significant reduction in blood product transfusions and overall IV fluid administration. Specifically, resuscitating patients with the intent of maintaining a target minimum MAP of 50 mm Hg, rather than 65 mm Hg, significantly decreases postoperative coagulopathy and lowers the risk of early postoperative death and coagulopathy. These preliminary results provide convincing evidence that support the continued investigation and use of hypotensive resuscitation in the trauma setting. PMID- 21610357 TI - Development and testing of low-volume hyperoncotic, hyperosmotic spray-dried plasma for the treatment of trauma-associated coagulopathy. AB - BACKGROUND: Trauma-associated coagulopathy carries an extremely high mortality. Fresh-frozen plasma (FFP) is the mainstay of treatment; however, its availability in the battlefield is limited. We have already shown that lyophilized, freeze dried plasma (FDP) reconstituted in its original volume can reverse trauma associated coagulopathy. To enhance the logistical advantage (lower volume and weight), we developed and tested a hyperoncotic, hyperosmotic spray-dried plasma (SDP) product in a multiple injuries/hemorrhagic shock swine model. METHODS: Plasma separated from fresh porcine blood was stored as FFP or preserved as FDP and SDP. In in vitro testing, SDP was reconstituted in distilled water that was either equal (1 * SDP) or one-third (3 * SDP) the original volume of FFP. Analysis included measurements of prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen levels, and activity of selected clotting factors. In in vivo testing, swine were subjected to multiple injuries (femur fracture and grade V liver injury) and hemorrhagic shock (60% arterial hemorrhage, with the "lethal triad" of acidosis, coagulopathy, and hypothermia) and were treated with FFP, FDP, or 3 * SDP (n=4-5/group). Coagulation profiles (PT, PTT, and thromboelastography) were measured at baseline, post-shock, post-crystalloid, treatment (M0), and during 4 hours of monitoring (M1-4). RESULTS: In vitro testing revealed that clotting factors were preserved after spray drying. The coagulation profiles of FFP and 1 * SDP were similar, with 3 * SDP showing a prolonged PT/PTT. Multiple injuries/hemorrhagic shock produced significant coagulopathy, and 3 * SDP infusion was as effective as FFP and FDP in reversing it. CONCLUSION: Plasma can be spray dried and reconstituted to one-third of its original volume without compromising the coagulation properties in vivo. This shelf-stable, low-volume, hyperoncotic, hyperosmotic plasma is a logistically attractive option for the treatment of trauma-associated coagulopathy in austere environments, such as a battlefield. PMID- 21610358 TI - The epidemiology of sepsis in general surgery patients. AB - BACKGROUND: Sepsis is increasing in hospitalized patients. Our purpose is to describe its current epidemiology in a general surgery (GS) intensive care unit (ICU) where patients are routinely screened and aggressively treated for sepsis by an established protocol. METHODS: Our prospective, Institutional Review Board approved sepsis research database was queried for demographics, biomarkers reflecting organ dysfunction, and mortality. Patients were grouped as sepsis, severe sepsis, or septic shock using refined consensus criteria. Data are compared by analysis of variance, Student's t test, and chi test (p<0.05 significant). RESULTS: During 24 months ending September 2009, 231 patients (aged 59 years +/- 3 years; 43% men) were treated for sepsis. The abdomen was the source of infection in 69% of patients. Several baseline biomarkers of organ dysfunction (BOD) correlated with sepsis severity including lactate, creatinine, international normalized ratio, platelet count, and d-dimer. Direct correlation with mortality was noted with particular baseline BODs including beta natriuretic peptide, international normalized ratio, platelet count, aspartate transaminase, alanine aminotransferase, and total bilirubin. Most patients present with severe sepsis (56%) or septic shock (26%) each with increasing multiple BODs. Septic shock has prohibitive mortality rate (36%), and those who survive septic shock have prolonged ICU stays. CONCLUSION: In general surgery ICU patients, sepsis is predominantly caused by intra-abdominal infection. Multiple BODs are present in severe sepsis and septic shock but are notably advanced in septic shock. Despite aggressive sepsis screening and treatment, septic shock remains a morbid condition. PMID- 21610359 TI - Th17 (IFNgamma- IL17+) CD4+ T cells generated after burn injury may be a novel cellular mechanism for postburn immunosuppression. AB - BACKGROUND: The mechanism responsible for initiating and controlling the immunosuppressive response after burn injury remains unknown. Interleukin-17 (IL 17) secreting Th17 (interferon [IFN]gamma IL17) cells are a novel subset of CD4 T cells associated with a weak, proinflammatory response that antagonizes the proinflammatory Th1 (IFNgamma IL17) response. Given that transforming growth factor-beta and IL6 mediate Th17 cell development, we hypothesized that burn injury may generate Th17 cells that could mediate postburn immunosuppression. METHODS: After a 20% total body surface area burn in female C57BL/6 mice, wound draining lymph nodes were harvested 3 days, 7 days, or 14 days after injury. CD4 T cells were enriched by magnetic selection, and flow cytometry was used to identify intracellular IL17 and IFNgamma in CD3CD4 T cells. Additional purified CD3CD4 T cells were cultured with Th17 polarizing IL6 and transforming growth factor-beta for 4 days, and flow cytometry was again used to identify intracellular IL17 and IFNgamma in CD4 T cells. RESULTS: The number and percentage of preformed Th17 cells was significantly greater in burn mice compared with sham at all time points. In addition, the ratio of Th17 cells to Th1 cells was always significantly higher in burn mice compared with sham. These differences were eliminated in Th17 polarizing conditions in vitro. CD4 T cells never generated both IL17 and IFNgamma. CONCLUSION: These results demonstrate for the first time that Th17 cells (IFNgamma IL17) are spontaneously generated after burn injury. Given that Th17 cells (IFNgamma IL17) are antagonistic to Th1 (IFNgamma IL17) cells, these results suggest a novel mechanism for initiating and controlling postburn immunosuppression that deserves further investigation. PMID- 21610360 TI - Disparate effects of bacteria and Toll-like receptor-dependant bacterial ligand stimulation on immunoglobulin A transcytosis. AB - BACKGROUND: Recent studies have indicated that epithelial cells of the gut and other mucosal surfaces play an important role in orchestrating host responses to luminal microbes. Intestinal epithelial cells also play an important role in the transport of dimeric secretory immunoglobulin A (IgA) through the polyimmunoglobulin receptor (pIgR). The end product is secretory IgA, which contains a cleaved portion of the pIgR called secretory component. Transcytosis of dIgA may be responsive to various stimuli. We studied the effect of gram negative (G-) or gram-positive (G+) and Toll-like receptor (TLR) bacterial ligand pathways on IgA transcytosis in vitro. METHODS: Polarized HT-29 cells, a human intestinal epithelial cell line, were grown to confluence ion a two-chamber cell culture system. Rat dIgA was added to the basal chamber of HT-29 cell monolayers and cells and then stimulated with heat-killed Escherichia coli (DeltaE. coli), LPS (TLR-4 pathway ligand), heat-killed Staphylococcus aureus (DeltaS. aureus), or peptidoglycan (TLR-2 pathway ligand). IgA transcytosis was determined by ELISA. The pIgR expression was quantitated by flow cytometry and Western blot. HT 29 cell monolayer integrity was monitored by serial measurement of transepithelial electrical resistance. RESULTS: Transcytosis was stimulated by either DeltaE. coli or LPS. This was in part due to upregulation of pIgR expression and augmented intracellular trafficking of dIgA-pIgR complexes. CONCLUSION: The disparate effects between different bacteria and TLR-4 versus TLR 2 pathways may have implications in host responses at mucosal surfaces. PMID- 21610361 TI - Long-term functional and echocardiographic assessment after penetrating cardiac injury: 5-year follow-up results. AB - BACKGROUND: There is almost no data describing the long-term functional outcome of patients after penetrating cardiac injury. METHODS: A retrospective study at a Level I trauma center from 2000 to 2009. RESULTS: Sixty-three patients had penetrating cardiac injuries from 28 stabbings and 35 gunshots. Men comprised 89% (56) of the patients. Overall, there were 21 survivors (33%) and 42 died in the emergency room or perioperative period. The mean age did not significantly differ between survivors (36 years +/- 12 years) compared with those who died (30 years +/- 11 years; p=0.07). There was an increased chance of survival after being stabbed compared with being shot (17 patients vs. 4 patients; odds ratio=12; p=0.002). Thirteen (62%) had injuries to the right ventricle only. Three patients died during follow-up: one from lung cancer and two other patients died from myocardial infarctions, one 9 years later at the age of 45 years and the other 8 years later at the age of 55 years. The survivors had functional follow-up evaluations from 2 months to 114 months (median, 71; interquartile range, 34-92 months) and echocardiographic follow-up from 2 months to 107 months (median, 64; interquartile range, 31-84 months) after their injuries. Functionally, all patients were in NYHA class 1 status, except one patient in class II who was 54 years old and had a mild exertional limitation. The previously injured area could only be identified by echocardiogram in one patient who had a patch repair of a ventricular septal defect (VSD). The mean ejection fraction improved over time from a mean of 51% +/- 8% in the immediate postoperative period to 60% +/- 9% after a mean follow-up of 59 months (p=0.01). After surgery, 43% of patients had a mild to moderate pericardial effusion; however, the long-term follow-up studies showed that all these had resolved. Wall motion abnormalities occurred in 33% of patients in the immediate postoperative period and, again, all these resolved during long-term follow-up. CONCLUSIONS: Patients who survive penetrating cardiac injuries, without coronary arterial or valvular disruption, have an excellent long-term functional outcome with minimal subsequent cardiac morbidity related to the injury. Full physiologic recovery and normal cardiac function can be expected if the patient survives. PMID- 21610362 TI - Does temporary chest wall closure with or without chest packing improve survival for trauma patients in shock after emergent thoracotomy? AB - BACKGROUND: Many surgeons avoid the damage-control techniques of intrathoracic packing and temporary chest wall closure after thoracotomy for trauma because of concerns about packing's effects on intrathoracic pressure and infectious risks. We hypothesized that temporary chest closure with or without intrathoracic packing (TCC-P) as a method of thoracic damage control would yield higher than expected survival rates for trauma thoracotomy patients with metabolic exhaustion, whereas traditional definitive chest closure (DEF) would exhibit predicted survival rates. METHODS: This was a retrospective cohort study by two urban Level I trauma centers on patients who (1) underwent emergent thoracotomy for trauma, (2) received >=10 units (U) packed red blood cells and/or sustained a cardiac arrest before starting chest closure, and (3) survived to intensive care unit arrival. Demographic/physiologic data, chest closure method, and thoracic complications were gathered. Trauma injury severity scores (TRISS) were used to calculate survival probability for TCC-P and DEF. Nonparametric statistics were used for all comparisons. All values are expressed as medians and interquartile ranges (IQR). RESULTS: Sixty-one patients met inclusion criteria. Both TCC-P (n = 17) and DEF (n = 44) were severely injured (ISS=35 [IQR, 25-42] vs. 29 [IQR 19 45] and packed red blood cells = 16.5 U [IQR, 12.3-25.5 U] vs. 15 U [IQR, 11-23 U], respectively; p=ns). Patient demographics were similar except for the findings that the TCC-P cohort had higher rates of cardiac arrest before starting chest closure (TCC-P 82% vs. DEF 48%, p=0.04), significantly more severe abdominal injuries, and less severe head injuries than the DEF group. No significant differences were observed in survival of the overall samples (TCC P=47% vs. DEF=57%), nor for observed:expected (O:E) survival ratio in 13 patients with TCC-P and 30 with DEF meeting criteria for TRISS calculation (TCC-P O:E, 46%:39%; DEF O:E, 53%:57%). No significant differences were found for TCC-P and DEF thoracic infectious (24% vs. 25%) or hemorrhagic (18% vs. 14%) complications. Surprisingly, peak inspiratory pressures on intensive care unit arrival were markedly better after TCC-P (20 cm H2O [IQR, 18-31 cm H2O]) than after DEF (32.5 cm H2O [IQR, 28-37.5 cm H2O], p=0.003). CONCLUSION: Concerns about TCC-P are not borne out as thoracic infection rates are unaffected and peak pressures are actually lower, possibly due to greater pleural volume from an open chest wall and skin-only closure. However, no significant survival benefit was seen with TCC P. PMID- 21610363 TI - Long-term outcome of high-energy open Lisfranc injuries: a retrospective study. AB - BACKGROUND: The outcome of open Lisfranc injuries has been reported infrequently. Should these injuries be managed as closed injuries and is their outcome different? METHODS: We undertook a retrospective study of high-energy, open Lisfranc injuries treated between 1999 and 2005. The types of dislocation, the associated injuries to the same foot, the radiologic and functional outcome, and the complications were studied. There were 22 patients. Five patients died. One had amputation. Of the remaining 16 patients, 13 men were followed up at a mean of 56 months (range, 29-88 months). The average age was 36 years (range, 7-55 years). RESULTS: According to the modified Hardcastle classification, type B2 injury was the commonest. Ten patients had additional forefoot or midfoot injury. All patients were treated with debridement, open reduction, and multiple Kirschner (K) wire fixation. All injuries were Gustilo Anderson type IIIa or IIIb. Nine patients had split skin graft for soft tissue cover. Mean time taken for wound healing was 16 days (range, 10-30 days). Ten patients (77%) had fracture comminution. Eight patients had anatomic reduction, whereas five had nonanatomic reduction. Ten of 13 (77%) patients had at least one spontaneous tarsometatarsal joint fusion. The mean American Orthopaedic Foot and Ankle Society score was 82 (range, 59-100). Nonanatomic reduction, osteomyelitis, deformity of toes, planus foot, and mild discomfort on prolonged walking were the unfavorable outcomes present. CONCLUSION: In open Lisfranc injuries, multiple K wire fixation should be considered especially in the presence of comminution and soft tissue loss. Although anatomic reduction is always not obtained, the treatment principles should include adequate debridement, maintaining alignment with multiple K wires, and obtaining early soft tissue cover. There is a high incidence of fusion across tarsometatarsal joints. PMID- 21610365 TI - Pediatric radiation exposure during the initial evaluation for blunt trauma. AB - BACKGROUND: Increased utilization of computed tomography (CT) scans for evaluation of blunt trauma patients has resulted in increased doses of radiation to patients. Radiation dose is relatively amplified in children secondary to body size, and children are more susceptible to long-term carcinogenic effects of radiation. Our aim was to measure radiation dose received in pediatric blunt trauma patients during initial CT evaluation and to determine whether doses exceed doses historically correlated with an increased risk of thyroid cancer. METHODS: A prospective cohort study of patients aged 0 years to 17 years was conducted over 6 months. Dosimeters were placed on the neck, chest, and groin before CT scanning to measure surface radiation. Patient measurements and scanning parameters were collected prospectively along with diagnostic findings on CT imaging. Cumulative effective whole body dose and organ doses were calculated. RESULTS: The mean number of scans per patient was 3.1 +/- 1.3. Mean whole body effective dose was 17.43 mSv. Mean organ doses were thyroid 32.18 mGy, breast 10.89 mGy, and gonads 13.15 mGy. Patients with selective CT scanning defined as <=2 scans had a statistically significant decrease in radiation dose compared with patients with >2 scans. CONCLUSIONS: Thyroid doses in 71% of study patients fell within the dose range historically correlated with an increased risk of thyroid cancer and whole body effective doses fell within the range of historical doses correlated with an increased risk of all solid cancers and leukemia. Selective scanning of body areas as compared with whole body scanning results in a statistically significant decrease in all doses. PMID- 21610364 TI - The role of preconditioning and N-acetylcysteine on oxidative stress resulting from tourniquet-induced ischemia-reperfusion in arthroscopic knee surgery. AB - BACKGROUND: The aim of this study was to investigate the effects of ischemic preconditioning (IPC) and N-acetylcysteine (NAC) on oxidative stress resulting from tourniquet-induced ischemia-reperfusion (IR) period in arthroscopic knee surgery. METHODS: Forty-five patients who had arthroscopic knee surgery for meniscal and chondral lesions and for pathologic medial plica were included in this study. They were assigned to the following treatment groups: control (group C; n=15), IPC (group P; n=15), and NAC (group N; n=15). Subjects in the control group underwent routine surgical procedures. Subjects in the preconditioning group were subjected to temporary ischemia, with tourniquet performed by three compression cycles of 5 minutes followed by 5 minutes of reperfusion just before the application of tourniquet inflation. Subjects in the NAC group received 10 mg/kg NAC dissolved in 100 mL 0.9% normal saline intravenously 30 minutes before tourniquet inflation. An hour before the tourniquet was applied (preischemia) and 2 hours after tourniquet was removed (reperfusion), blood samples (to test for metabolites) were obtained. Levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (TAC), and total oxidant status (TOS) were measured in all serum samples. Results were compared between preischemia and reperfusion in three groups. RESULTS: MDA in the control group was found to be increased significantly compared with preischemia, whereas MDA in IPC and NAC groups did not change insignificantly. SOD and GSH activities in the control group were found to be increased significantly, whereas SOD and GSH activities in IPC and NAC groups did not change significantly after reperfusion. TAC in the control group was found to be decreased and TOS was found to be increased significantly, but TAC and TOS in IPC and NAC groups were not significantly different after reperfusion. Mean serum MDA, TOS, SOD, and GSH-Px levels were lower in group P than group C at reperfusion period (p<0.05). Mean serum SOD levels were lower in group P than group N at reperfusion period (p<0.05). CONCLUSIONS: Tourniquet-induced IR period in routine arthroscopic knee surgery resulted in oxidative stress by increasing MDA, SOD, GSH-Px, TOS and decreasing TAC. NAC and IPC had protective effect on occurrence of oxidative stress resulting from IR period by preventing MDA, SOD, GSH-Px, TAC, and TOS changes in routine arthroscopic knee surgery. PMID- 21610367 TI - The medial sural artery perforator flap: a versatile donor site for hand reconstruction. AB - BACKGROUND: The challenge of modern hand reconstruction goes beyond simple coverage. Thanks to the advances of microsurgery, there are ever-improving standards of functional and esthetic outcomes in hand reconstruction. The versatile donor site of the medial sural artery perforator flap can fulfill this purpose. MATERIALS: Between June 2006 and October 2008, we used free medial sural artery perforator flaps for hand reconstruction in 14 cases. The sites of reconstruction included digits (n=7), dorsal hand (n=3), palmar hand (n=2), and wrist (n=2). Associated tendon and nerve defects were found in five patients. The plantaris tendon (n=4), split Achilles tendon (n=1), saphenous nerve (n=1), and sural nerve (n=1) were harvested for reconstructive purpose from the same donor site in this series. RESULTS: The proximal perforator of the medial sural artery emerged 8 cm to 13 cm from the midpoint of the popliteal crease, correlating with the axis of the medial sural artery. Twelve flaps were raised with a single perforator. One flap failed because of perioperative vasospasm. The donor defect could be closed without skin grafts when the flap width was <6 cm. CONCLUSION: The free medial sural artery perforator flap transfer is appropriate for small- to medium-sized hand defect reconstruction. The donor site not only supplies a thin fasciocutaneous flap but also provides the option to harvest a segment of tendon or nerve graft through the same incision for composite tissue reconstruction in a single stage. PMID- 21610366 TI - Effectiveness of the P.A.R.T.Y. (Prevent Alcohol and Risk-related Trauma in Youth) program in preventing traumatic injuries: a 10-year analysis. AB - BACKGROUND: The P.A.R.T.Y. (Prevent Alcohol and Risk-Related Trauma in Youth) program is a 1-day injury awareness and prevention program for youth aged 15 years and older. The goal is to teach adolescents to recognize their injury risks and make informed decisions to reduce them. This study assessed the effectiveness of the P.A.R.T.Y. Program in preventing traumatic injuries during a period of 10 years (1992-2004). METHODS: P.A.R.T.Y. participants (STUDY) were matched with subjects having the same age, gender, residential area, and initial year in database, who did not attend the P.A.R.T.Y. Program (CONTROL). Data from hospital discharge database, and provincial health claims, were searched to determine the incidence of traumatic injuries in both groups. Statistical comparisons were made for the two groups, gender, calendar year, and before and after the graduating driver licensing system was implemented, using the chi and conditional logistic regression analysis with a p<0.05 considered significant. RESULTS: Of 3,905 P.A.R.T.Y. participants, 1,281 were successfully randomly matched on the above 4 variables with 1,281 controls. The most frequent injury was injury by other or homicide 373 of 2,562 (14.8%). There were fewer traumatic injuries in the STUDY group than in the CONTROL group (43.3% vs. 47.4%; p=0.02; OR, 1.22; 95% CI, 1.03 1.45). This difference was stronger in females (44.4% vs. 49.0%; p=0.04) and before the graduating driver licensing system implementation (60.1% vs. 67.2%; p=0.04). CONCLUSIONS: The P.A.R.T.Y. Program effectively reduced the incidence of traumatic injuries among its participants. This effectiveness was stronger among females and before the driver licensing system was implemented. PMID- 21610368 TI - What is the social cost of injured people in traffic collisions? An assessment for Catalonia. AB - BACKGROUND: Traffic collisions are an important public health problem worldwide, in terms of mortality, morbidity, and economic burden. The goal of this study is to estimate the social cost of injured people in traffic collisions in Catalonia in the year 2007. METHODS: We performed a cost-of-illness analysis, under the perspective of the healthcare system, the public sector, and the society, using a 1-year time horizon. In Catalonia, during 2007, there were a total of 26,063 collisions with victims, which translates into 34,565 non-mortal victims and 521 deaths. As direct costs, all healthcare costs (primary care, acute hospital care, emergency care, ambulances and transport, long-term care, and specialized care); costs of adaptation to disability, disability benefits, material costs, and administrative costs; and costs of police, fire-fighters, and road assistance have been included. As indirect costs, productivity losses as a result of hospital and long-term institutionalization as well as productivity losses from work sick leave and productivity losses of carers have been taken into account. RESULTS: From the perspective of the healthcare system, the cost of the injured people in traffic collisions was 31,803,024.03? in 2007; from the perspective of the public sector, it was 134,047,059.27? (up to 1,463,645,407.13? in the sensitivity analysis) and 144,043,238.88? (up to 1,558,926,995.12? in the sensitivity analysis) from the perspective of the society. The cost per injured person ranged from 3,855.38? from the perspective of the healthcare system to 17,461.90? from the perspective of the society (up to 188,983.76? in the sensitivity analysis). CONCLUSIONS: The importance of the costs of injured people in traffic collisions is an argument more-besides the epidemiologic and social impact-to start off preventive policies. PMID- 21610369 TI - East Practice Management Guidelines Work Group: update to practice management guidelines for prophylactic antibiotic use in open fractures. PMID- 21610370 TI - A novel technique to remove bent intramedullary nail. AB - Removing a bent femoral intramedullary nail is challenging and usually requires special equipment to weaken or transect the nail. We have developed a novel technique with simple devices including one dynamic compression plate and two bone-holding forceps to straighten a bent nail. The results showed that one can use this method for bent nail removal effectively and easily. PMID- 21610371 TI - The dynamic sonographic air bronchogram: a simple and immediate bedside diagnosis of alveolar consolidation in severe respiratory failure. PMID- 21610372 TI - Re-expansion pulmonary edema after insertion of chest tube for pneumothorax. PMID- 21610373 TI - Where is the civilian leadership for guideline-based treatment of severe head injury? PMID- 21610374 TI - Transcatheter arterial embolization for treatment of maxillofacial trauma. PMID- 21610375 TI - Predictors of intracranial hemorrhage in patients taking anticoagulant and antiplatelet medication. PMID- 21610377 TI - Early coagulopathy resulted from brain injury rather than hypoperfusion. PMID- 21610378 TI - Highly sensitive cardiac troponin in blunt chest trauma: after the gathering comes the scattering? PMID- 21610379 TI - Delay in diagnosis and treatment of blunt intestinal perforation does not adversely affect prognosis in the pediatric trauma patient: retraction. PMID- 21610380 TI - Letter of apology for duplicate publication. PMID- 21610382 TI - Air in temporomandibular joint: an indirect, specific CT sign of temporal bone fracture in the setting of head trauma. PMID- 21610383 TI - Aneurysm bone cyst presented as a zygomatic mass after facial trauma. PMID- 21610384 TI - Temporary abdominal closure: long-term outcomes. AB - BACKGROUND: Temporary abdominal closure (TAC) is an invaluable tool in the armamentarium of surgeons caring for critically ill and injured patients. The objective of this study was to determine the incidence of abdominal wall hernias and intestinal obstructions in patients who underwent TAC. METHODS: A retrospective review of the medical records of patients who underwent TAC from September 2000 to December 2007 was completed. Patients were stratified by technique and indication for TAC. Statistical analysis included analysis of variance, chi(2), Fisher's exact test, Wilcoxon rank sum test, Kruskal-Wallis test, and Kaplan-Meier analysis. RESULTS: One hundred seventeen patients underwent TAC during the study period. Nine patients were excluded from the analysis. For the remaining 108 patients, 30-day mortality was 17%. Definitive fascial closure was accomplished in 91% of patients. Median time to closure was 3 days. Seventy-six (70%) patients survived >=6 months after definitive fascial or skin-only closure. Median follow-up was 34.5 months. Intestinal obstructions developed in 11% of patients. Abdominal wall hernias developed in 30% of patients with definitive fascial closure. No differences were observed for rates of abdominal wall hernias or intestinal obstructions based on preoperative body mass index, TAC indication, or TAC technique (temporary skin, bridge, or vacuum assisted device closure). CONCLUSION: Successful definitive fascial closure was achieved in 91% of patients after TAC. Abdominal wall hernias and intestinal obstructions were associated with longer median time to closure and increased ventilator days. No associations with indications for TAC, temporary closure techniques, or definitive closure methods were demonstrated. PMID- 21610385 TI - A modified model of the abdominal compartment syndrome. AB - BACKGROUND: To develop an animal model in rats and to investigate whether an intra-abdominal pressure (IAP) of 20 mm Hg will lead to a condition comparable with the abdominal compartment syndrome in humans. METHODS: Forty Sprague-Dawley rats were used. In the study group, IAP was increased to 20 mm Hg using a nitrogen gas pneumoperitoneum for 4 hours. We also observed the next reperfusion period for another 4 hours. In the controls, IAP remained unchanged. Hemodynamic readings, peak inspiratory pressure, renal function parameters, and blood gas were obtained. Additionally, histopathologic examinations were performed. RESULTS: In the presence of intra-abdominal hypertension (IAH), mean arterial pressure was reduced, whereas central venous pressure was increased significantly. Peak inspiratory pressure remained >35 mbar in the 4 hours of IAH and recovered after decompression. Arterial Po(2) decreased substantially while Pco(2) increased soon after IAH. IAH caused a metabolic acidosis, which was further complicated by the respiratory acidosis. Decompression resulted in normocapnia but the metabolic acidosis persisted. Renal blood flow and urine output decreased obviously, whereas little change was found in blood urea nitrogen and creatinine. The histopathologic study revealed parenchymal injury in lung and intestine. CONCLUSIONS: This animal model was simple and easily reproducible. An IAP of 20 mm Hg can lead to a condition comparable with the abdominal compartment syndrome in humans. PMID- 21610386 TI - Prehospital serum lactate as a predictor of outcomes in trauma patients: a retrospective observational study. AB - BACKGROUND: Lactate is associated with morbidity and mortality; however, the value of prehospital lactate (pLA) is unknown. Our objective was to determine whether pLA improves identification of mortality and morbidity independent of vital signs. METHODS: We measured pLA in 1,168 patients transported by rotorcraft to a Level I trauma center over 18 months. The primary outcome was in-hospital mortality; secondary outcomes were emergent surgery and multiple organ dysfunction syndrome (MODS). Covariates include age, sex, prehospital vital signs, and mental status. We created multivariable logistic regression models and tested them for interaction terms and goodness of fit. Cutoff values were established for reporting operating characteristics using shock (defined as shock index >0.8, heart rate >110, and systolic blood pressure <100), tachypnea (RR >=30), and altered sensorium (Glasgow Coma Scale score <15). RESULTS: In-hospital mortality was 5.6%, 7.4% required surgery and 5.7% developed MODS. Median lactate was 2.4 mmol/L. Lactate was associated with mortality (odds ratio [OR], 1.23; p < 0.0001), surgery (OR, 1.13; p < 0.001), and MODS (OR, 1.14; p < 0.0001). Inclusion of pLA into a logistic model significantly improved the area under the receiver operator curves from 0.85 to 0.89 for death (p < 0.001), 0.68 to 0.71 for surgery (p = 0.02), and 0.78 to 0.81 for MODS (p = 0.002). When a threshold lactate value of >2 mmol/L was added to a predictive model of shock, respiratory distress, or altered sensorium, it improved sensitivity from 88% to 97% for death, 64% to 86% for surgery, and 94% to 99% for MODS. CONCLUSION: The pLA measurements improve prediction of mortality, surgery, and MODS. Lactate may improve the identification of patients who require monitoring, resources, and resuscitation. PMID- 21610387 TI - All massive transfusion criteria are not created equal: defining the predictive value of individual transfusion triggers to better determine who benefits from blood. AB - BACKGROUND: As familiarity with military massive transfusion (MT) triggers has increased, there is a growing interest in applying these in the civilian population to initiate MT protocols (MTP) earlier. We hypothesize that these triggers do not have equal predictability for MT and understanding the contribution of each would improve our ability to initiate the MTP earlier. METHODS: All patients presenting to a Level I trauma center from October 2007 to September 2008 requiring immediate operation were included in this study. Emergency department records, operative logs, and blood transfusion data from arrival to procedure end were analyzed using multivariate regression techniques. Triggers included systolic blood pressure (SBP) <90 mm Hg, hemoglobin <11 g/dL, temperature <35.5 degrees C, International normalized ratio (INR) >1.5, and base deficit >=6. RESULTS: One hundred seventy patients required immediate operation with an overall survival of 91%. Transfusion of packed red blood cells was noted in 45% (77 of 170) with the mean number of transfused units highest in those meeting SBP (12.9 Units) or INR (12.3 Units) triggers. The triggers do not contribute equal predictive value for the need for transfusion with INR being the most predictive (odds ratio, 16.7; 95% confidence interval, 2-137) for any transfusion and highly predictive for the need for MT (odds ratio, 11.3; 95% confidence interval, 3-47). In fact, if patients met either INR or SBP triggers alone, they were likely to receive MT (p = 0.018 and 0.003, respectively). CONCLUSION: Triggers have differential predictive values for need for transfusion. Defining the individual utility of each criterion will help to identify those most likely to benefit from an early initiation of the MTP. PMID- 21610388 TI - Prospective evaluation of multidetector computed tomography for extremity vascular trauma. AB - BACKGROUND: Multidetector computed tomographic angiography (MDCTA) is increasingly being used for the assessment of extremity vascular injury. However, to date, there are only retrospective series and a single small prospective study evaluating its efficacy. Therefore, the objective of this study was to prospectively evaluate the ability of MDCTA to detect arterial injury in the injured upper and lower extremities. METHODS: After institutional review board approval, all trauma patients aged 16 years or older admitted to a Level I trauma center who sustained extremity trauma and underwent initial evaluation with a 64 channel MDCTA from March 2009 to June 2010 were prospectively enrolled. The sensitivity and specificity of MDCTA were tested against an aggregate gold standard of operative intervention, conventional angiography, and clinical follow up. RESULTS: During the 20-month study period, 635 patients with extremity trauma underwent a structured clinical examination. Hard signs of vascular injury was observed in 5.5% of patients with a 97.1% incidence of clinically significant injury requiring operative intervention. Eighty-three percent of patients had no signs of vascular injury with no missed injuries detected during follow-up. Eighty-nine MDCTAs were performed in the remaining 73 patients (11.5%) with soft signs. The mechanism of injury was penetrating in 69.9% (42 gunshot wound, 5 stab wound, and 4 shotgun). There were 24 positive studies, 23 of which were confirmed at operation (5 brachial artery injuries, 2 radial, 1 ulnar, 1 external iliac, 2 common femoral, 5 proximal superficial femoral, 2 distal superficial femoral, 4 popliteal, and 1 posterior tibial artery injury). A left posterior tibial artery occlusion was managed nonoperatively. There were 58 negative studies with clinical follow-up available in 100%, for a mean of 10.6 days +/- 11.7 days (median, 6 days; range, 1-41 days). MDCTA was nondiagnostic in seven patients (9.6%), five secondary to artifact from retained missile fragments (3 shotgun and 2 gunshot wound), and two secondary to technical errors in reformatting. In the absence of artifact, MDCTA achieved 100% sensitivity and 100% specificity in detecting all clinically significant arterial injuries. CONCLUSIONS: Physical examination is critical in the decision-making process for the injured extremity and can accurately reduce unnecessary imaging. If imaging is required, MDCTA is a sensitive and a specific noninvasive modality for arterial evaluation and may replace conventional angiography as the diagnostic modality of choice for the evaluation of the acutely injured extremity. PMID- 21610389 TI - Treatment of traumatic internal carotid artery pseudoaneurysms with the Willis covered stent: a prospective study. AB - PURPOSE: To evaluate the efficacy of the Willis covered stent in the treatment of traumatic pseudoaneurysms of the internal carotid artery (ICA). MATERIALS: Thirty eight patients with traumatic head and neck injury underwent angiography. We evaluated 14 delayed pseudoaneurysms in 13 patients who underwent angiography after treatment with the Willis covered stent. Prospective data on the technical success, initial and final angiographic results, mortality, morbidity, and final clinical outcome were analyzed immediately after the procedure, at the time of discharge from the hospital, at 3 months, 6 months, and 12 months after the procedures, and yearly thereafter. RESULTS: The Willis covered stent placement was successful in all 14 pseudoaneurysms. The initial angiographic results showed complete exclusion in 9 patients with 10 aneurysms (71.4% [95% confidence interval {CI}: 44-98%]) and incomplete exclusion in 4 patients. The angiographic follow-up (mean, 15 months [95% CI: 9-20 months]; range, 3-36 months) findings exhibited a complete exclusion in 12 patients with 13 aneurysms (92.9% [95% CI: 77-108%]) and an incomplete exclusion in 1 patient and maintained patency of the ICA in all patients. The clinical follow-up (mean, 20 months [95% CI: 14-27 months]) findings demonstrated full recovery (11 patients), symptom improvement (1 patient), or no change in the symptoms (1 patient). No procedure-related complications or deaths occurred during follow-up. CONCLUSION: Treatment with the Willis covered stent provides a viable approach for patients with traumatic pseudoaneurysms of the ICA, maintaining patency of the ICA and thus leading to excellent clinical results. An expanded clinical experiences and a larger sample are needed. PMID- 21610390 TI - Pediatric vascular injuries: acute management and early outcomes. AB - BACKGROUND: Although uncommon in children, traumatic vascular injuries have the potential for lifelong disability. We reviewed these injuries, their acute management, and early outcomes at a Level I trauma center. METHODS: Retrospective review of patients identified through trauma registry was query of all noniatrogenic vascular injuries in a pediatric population during a 13-year period. Demographics, injury type and management, concomitant injuries, and inpatient outcomes were analyzed. RESULTS: From 1995 to 2008, 8,247 children with traumatic injuries were admitted. Of which 116 (1.4%) sustained 138 significant vascular injuries; 111 arterial and 27 venous. Mean age was 12.7 years +/- 4.1 years. Penetrating mechanism was more frequent (57.8%; 67 of 116) than blunt (42.2%; 49 of 116). The overall mean injury severity score was 17.3, of which 12.3 +/- 11.7 was for penetrating trauma and 24.1 +/- 19.3 for blunt trauma. Thirteen of the 36 patients with torso injuries and one with carotid/jugular injury died. The surviving 102 patients sustained 118 vascular injuries (102 arterial and 16 venous). Of this group, 15 (14.6%) had multiple vascular injuries. There were 23 (22.5%) with torso injuries, 72 (70.6%) with extremity injuries, and 7 (6.9%) with cerebrovascular injuries. Primary repair was the most common arterial repair technique for survivors (25.5%, 26 of 102) and was used more frequently in penetrating trauma (35.0%, 21 of 60) than blunt trauma (12.0%, 5 of 42). Limb salvage was 97.4% (113 of 116). CONCLUSIONS: Pediatric vascular trauma is uncommon. Penetrating mechanism is more common than blunt. Injuries to the torso carry a high mortality. Limb salvage is almost universal. PMID- 21610391 TI - National Emergency X-Radiography Utilization Study criteria is inadequate to rule out fracture after significant blunt trauma compared with computed tomography. AB - BACKGROUND: EAST guidelines now recommend computed tomography (CT) to evaluate cervical spine (c-spine) fractures after blunt trauma in patients who do not meet National Emergency X-Radiography Utilization Study criteria (NC), yet no imaging is required in those patients who do meet these criteria. NC are based on patients with both minor and severe (trauma team activation [TTA]) trauma. The purpose of this study was to evaluate the NC using CT as the gold standard in TTA patients. METHODS: We prospectively evaluated 2,606 blunt TTA patients at our Level I trauma center. NC defined as alertness (Glasgow Coma Scale [GCS] score = 15), evidence of intoxication, clinically distracting injury, midline c-spine tenderness, or neurologic deficits were documented. CT was used to determine the accuracy of these criteria. RESULTS: There were 157 patients with c-spine fractures and 2,449 patients without c-spine fractures. The fracture group was older (age, 43.4 years +/- 19.3 years fracture group vs. 37.7 years +/- 17.5 years no fracture group, p = 0.0003) with a lower GCS score (fracture group 13.7 +/- 4.5 vs. no fracture group 14.4 +/- 3.6, p = 0.0001) and initial systolic blood pressure (132.5 mm Hg +/- 23.4 mm Hg vs. 139.9 mm Hg vs. 23.5 mm Hg, p = 0.0009). The sensitivity and specificity of clinical examination for all patients were 82.8% (130 of 157) and 45.7% (1,118 of 2,449), respectively. The positive predictive value (PPV) and negative predictive value (NPV) were 8.9% (130 of 1,461) and 97.6% (1,118 of 1,145), respectively. Patients with a GCS score of 15 had a sensitivity of 77%, specificity of 52.3%, PPV of 8.5%, and NPV of 97.5% for clinical examination. In those patients with the GCS score of 15, no intoxication or distracting injury, clinical examination had a sensitivity of 59.4%, specificity of 79.5%, PPV of 12.5%, and NPV of 97.5%. Of 26 patients with missed injuries based on NC, 19 (73.1%) required further intervention (16 collars, 2 OR, 1 Halo). CONCLUSION: As in our previous trial, NC is inaccurate compared with CT to diagnose c-spine fractures in TTA patients. CT should be used in all blunt TTA patients regardless of whether they meet NC. PMID- 21610392 TI - Low-intensity pulsed ultrasound enhances healing of laminectomy chip bone grafts on spinal fusion: a model of posterolateral intertransverse fusion in rabbits. AB - BACKGROUND: Laminectomy-derived chip bone graft was usually used in spinal fusion; however, the result of this kind of local bone used in lumbar posterolateral fusion is uncertain. This study tested the hypotheses that low intensity pulsed ultrasound (LIPU) can accelerate the healing process of laminectomy bone chips in a spinal fusion and enhance the union rate. METHODS: Forty-eight rabbits were randomly divided into three groups for the spinal unilateral uninstrumented posterolateral fusion of L5-L6: autologous iliac bone graft (AIBG), laminectomy chip bone graft (LCBG), LCBG plus LIPU (LCBG + LIPU). Each group was subdivided into 6-week and 12-week subgroups. All rabbits were subjected to radiographic examination and manual testing. All successful spinal fusion specimens received biomechanical testing and a histologic examination. RESULTS: The LCBG + LIPU group had the highest successful fusion rate at 6-week and 12-week examination (75% and 100%, respectively). At 6 weeks, the average maximum toque at failure values of the fusion masses for the LCBG + LIPU group was significantly higher than that for the LCBG group (p = 0.034). The average maximum torque of the 12-week LCBG + LIPU group was significantly higher than those of the 12-week AIBG and 12-week LCBG groups (p = 0.040 and p = 0.026, respectively). CONCLUSIONS: This study suggested that LIPU can enhance bone healing. With augmentation by LIPU, laminectomy chip bone used in lumbar posterolateral fusion can achieve a similar fusion rate and stronger fusion mass than those of an AIBG. PMID- 21610393 TI - Trauma association of Canada Pediatric Subcommittee National Pediatric Cervical Spine Evaluation Pathway: consensus guidelines. AB - BACKGROUND: The Institute of Medicine calls for the use of clinical guidelines and practice parameters to promote "best practices" and improve patient outcomes. In 2006, The Trauma Association of Canada Pediatric Committee set out to create an evidence-based, national pediatric cervical spine (c-spine) clearance guideline based on the literature, existing algorithms from each pediatric trauma center and from expert opinion from across Canada. METHODS: A review of the literature took place in September 2006 using the PubMed database. Search criteria were "cervical spine," "c-spine," "clearance," and "trauma." Limits that were applied were "Languages: English," "Humans," "Type of Article: Meta Analysis, Practice Guidelines, Randomized Control Trial, Review," and "Ages: all child 0-18 years." These search criteria were repeated in December 2007, April 2009, and October 2009. A total of 248 articles were identified. Existing guidelines were identified and their practices examined as models of care. Two draft guidelines were created for discussion: one for the pediatric patient with a reliable clinical examination and the other for the pediatric patient with an unreliable clinical examination. Via email, telephone, and two national videoconferences, the content of the guidelines was reviewed, discussed, and amended. The final article was prepared and circulated for author input until consensus was reached. RESULTS: A consensus was reached on two pathways to evaluate the pediatric cervical spine: a patient with a reliable clinical examination and a patient with an unreliable examination. CONCLUSION: Presented herein are the consensus Trauma Association of Canada, National Pediatric Cervical Spine Evaluation Pathways for the patient with a reliable clinical examination, and the patient with and unreliable clinical examination. PMID- 21610394 TI - Development of a computed tomography-based scoring system for necrotizing soft tissue infections. AB - BACKGROUND: Necrotizing soft-tissue infections (NSTIs) are associated with significant morbidity and mortality, but a definitive nonsurgical diagnostic test remains elusive. Despite the widespread use of computed tomography (CT) as a diagnostic adjunct, there is little data that definitively correlate CT findings with the presence of NSTI. Our goal was the development of a CT-based scoring system to discriminate non-NSTI from NSTI. METHODS: Patients older than 17 years undergoing CT for evaluation of soft-tissue infection at a tertiary care medical center over a 10-year period (2000-2009) were included. Abstracted data included comorbidities and social history, physical examination, laboratory findings, and operative and pathologic findings. NSTI was defined as soft-tissue necrosis in the dictated operative note or the accompanying pathology report. CT scans were reviewed by a radiologist blinded to clinical and laboratory data. A scoring system was developed and the area under the receiver operating characteristic curve was calculated. RESULTS: During the study period, 305 patients underwent CT scanning (57% men; mean age, 47.4 years). Forty-four patients (14.4%) evaluated had an NSTI. A scoring system was retrospectively developed (table). A score >6 points was 86.3% sensitive and 91.5% specific for the diagnosis of NSTI (positive predictive value, 63.3%; negative predictive value, 85.5%). The area under the receiver operating characteristic curve was 0.928 (95% confidence interval, 0.893 0.964). The mean score of the non-NSTI group was 2.74. CONCLUSIONS: We have developed a CT scoring system that is both sensitive and specific for the diagnosis of NSTIs. This system may allow clinicians to more accurately diagnose NSTIs. Prospective validation of this scoring system is planned. PMID- 21610395 TI - Minor head injury in warfarinized patients: indicators of risk for intracranial hemorrhage. AB - BACKGROUND: Head injury represents one of the most important and frequent traumatic pathology in the emergency department. Among the different risk factors, preinjury use of warfarin has received considerable attention in trauma literature. The aim of this study was to identify further risk indicators of intracranial hemorrhage (ICH) to improve risk stratification of warfarinized patients with minor head injuries. METHODS: Medical records of 1,554 adult patients with minor head injuries evaluated by the Emergency Department of Azienda Ospedaliera, Universitaria Careggi from January 2007 to February 2008 were analyzed retrospectively. All the patients included in the study were subjected to blood tests. The international normalized ratio (INR) measured on admission was correlated with the results of head computed tomography scan. RESULTS: Of the 1,410 patients included in the study, 75 (5.2%) were warfarin anticoagulated at the time of trauma. The INR measured on admission was 2.37 +/- 1.04 (mean +/- standard deviation), and this value was significantly associated with occurrence of ICH after head trauma (r = 0.37; p < 0.005). For 12 (of 75) patients of this group, the findings of the computed tomography scans were positive. The receiver operating characteristic curve show that the most effective INR cutoff value was 2.43, with a sensitivity of 92%, a specificity of 66%, and positive and negative predictive values of 33% and 97%, respectively. CONCLUSIONS: This study highlights the strong relationship between INR values and the probability of ICH, as shown in previous studies. The high negative predictive value of the identified cutoff, if confirmed, could be used to exclude ICH. PMID- 21610396 TI - Does hypoxia affect intensive care unit delirium or long-term cognitive impairment after multiple trauma without intracranial hemorrhage? AB - BACKGROUND: Within the traumatic brain injury population, outcomes are affected by hypoxic events in the early injury period. Previous work shows a high prevalence of cognitive deficits in patients with multiple injuries who do not have intracranial hemorrhage identified on admission head computed tomography scan. We hypothesize that intensive care unit (ICU) delirium and long-term cognitive impairment (LTCI) are more likely in patients who have a hypoxic event within the first 48 hours of ICU admission. METHODS: A total of 173 patients with multiple injuries (Injury Severity Score [ISS] >15) who presented to a Level I trauma center from July 2006 to July 2007 were enrolled in a study on long-term cognitive deficit. Ninety-seven patients required ICU management and all had continuous oxygen saturation data collected. The Confusion Assessment Method for the ICU was collected twice a day on all patients in ICU. Of the total enrolled population, 108 (62%) were evaluated 12 months after discharge by neuropsychological tests. Cognitive impairment was defined as having 2 neuropsychological test scores, 1.5 standard deviations below the mean or 1 neuropsychological test score, and 2 standard deviations below the mean. Demographic data, ISS, initial 24-hour blood requirements, presence of hypoxia (SpO(2) <90% and <85%) or hypotension (systolic blood pressure <90 mm Hg), emergency department (ED) pulse, Glasgow Coma Scale score, ventilator and ICU days were recorded. Significant univariate identification of clinical variables was used for multivariate analysis. RESULTS: Fifty-five of 97 ICU patients (57%) were Confusion Assessment Method-ICU positive for delirium and 59 of 108 (55%) demonstrated cognitive impairment at 12-month follow-up. There was no significant association between hypoxia and ICU delirium (74.5% vs. 74%; p = 0.9) or LTCI (89% vs. 83%; p = 0.5). Ventilator days (8.7 +/- 8.9 vs. 2.9 +/- 4.6; p < 0.0001), ED pulse (109 +/- 28.5 vs. 94 +/- 22.8; p = 0.01), and blood transfusions (10 U +/- 10.8 U vs. 5 U +/- 5.3 U; p = 0.015) were significant independent predictors of delirium. Ventilator days (odds ratio, 1.16; 95% confidence interval, 1.05-1.29; p = 0.004) and ED pulse (odds ratio, 1.02; 95% confidence interval, 1.00-1.04; p = 0.03) remained significant predictors of ICU delirium after adjusting for ISS, hypoxic state, blood transfusions, and ED blood pressure. Among ED Glasgow Coma Scale score (10.5 +/- 5.1 vs. 11.4 +/-5.5; p = 0.7), ISS (33.3 +/- 10.1 vs. 32.2 +/- 9.0; p = 0.5), ventilator days (6.5 +/- 7.5 vs. 6.2 +/- 8.8; p = 0.4), blood transfusions (8.1 +/- 6.8 vs. 9.4 +/- 8.1; p = 0.4), and delirium (62% vs. 62.5%; p = 0.9), there were no significant univariate associations with LTCI. CONCLUSIONS: Hypoxic events in the ICU do not have a direct correlation with ICU delirium or LTCI in the patients with multiple injuries without evidence of intracranial hemorrhage. PMID- 21610397 TI - Postinjury depression is a serious complication in adolescents after major trauma: injury severity and injury-event factors predict depression and long-term quality of life deficits. AB - BACKGROUND: Little is known about the impact of postinjury depression after major trauma in adolescents. A prospective epidemiologic study was conducted to examine depression in injured adolescents. Specific objectives of this report are to identify risk factors for depression onset and the impact of depression on quality of life (QoL) outcomes. METHODS: Four hundred one trauma patients were enrolled in this study (age, 12-19 years; injury severity score [ISS] >=4). Depression diagnosis was based on the Children's Depression Inventory. QoL outcomes were measured using the Quality of Well-being Scale at 3-, 6-, 12-, 18-, and 24-month follow-up. RESULTS: Depression at discharge was diagnosed in 41% of 399 adolescent trauma survivors with complete Children's Depression Inventory data. Multivariate logistic regression identified ISS, >3 body regions injured, low socioeconomic status, family members injured at the scene, and suicidal ideology or attempted suicide before injury as strong and independent predictors of depression risk. ISS and three or more body regions injured predicted depression risk. Patients with severe injury (ISS >=17) were twice more likely to have depressive symptoms than patients with moderate injury (ISS <17; odds ratio [OR] = 2.0; p < 0.01). Patients with three or more body regions injured were more likely to have depressive symptoms than patients with less than three body regions injured (OR = 2.1; p < 0.01). Adolescents from low socioeconomic status families were more likely to be depressed (OR = 2.2; p < 0.05). Adolescent patients who witnessed family injured at the trauma event were also more likely to be depressed (OR = 2.4; p < 0.01). Patients who experienced suicidal ideology or attempted suicide preinjury were more likely to be depressed than adolescent patients who did not (OR = 2.87; p < 0.05). Quality of well-being scores were significantly and markedly lesser for patients with depression across the 24 month follow-up (3-18 months follow-up, p < 0.0001; 24 months: with depression = 0.738 vs. without depression = 0.784, p < 0.0001). Patients with depression were also significantly more likely to develop acute stress disorder and long-term posttraumatic stress disorder (OR = 1.8, p < 0.001). CONCLUSIONS: Postinjury depression is a major and an important complication in seriously injured adolescents. Adolescent trauma survivors have high rates of predischarge depression. Depression severely impacts QoL outcomes and is associated with injury severity, injury event-related factors, social factors, acute stress disorder, and posttraumatic stress disorder. Early recognition and treatment of DEPR in seriously injured adolescents will improve acute trauma care and long term QoL outcomes. PMID- 21610398 TI - Alcohol-related brief interventions as a criterion for American College of Surgeons Level I Trauma Center verification: how best to train the interventionists? AB - BACKGROUND: The American College of Surgeons Committee on Trauma recently required that Level I trauma centers have the capability to perform counseling in the form of brief interventions (BIs) for injured patients identified as problem drinkers. However, it is not yet known what type of training is optimal for trauma center personnel who will conduct these BIs. METHODS: We conducted a prospective cohort study at the University of California, Davis Medical Center, a Level I trauma center. We compared two methods of training trauma nurse practitioners (NPs) without prior counseling expertise to conduct BIs: formal workshop training versus "on-the-job" (OTJ) training. We also evaluated whether a further "booster" training session would improve BI skills. We assessed BI skills in blinded fashion during interviews with a standardized patient actor using a 21 point checklist of BI counseling tasks ("FLO" score). RESULTS: Nine workshop- and five OTJ-trained NPs participated. FLO scores did not markedly differ between the two groups after initial training (total FLO score, 9.6 +/- 2.4 and 7.8 +/- 0.4, workshop vs. OTJ, respectively; 95% confidence interval of difference, -4.1 to 0.6). FLO scores did however improve in both groups after booster training (9.1 +/- 2.0 and 16.0 +/- 2.2, time 1 vs. time 2, respectively; 95% confidence interval of difference, 4.7-9.1). The magnitude of improvement in FLO scores after the booster session did not differ between the workshop and OTJ groups. CONCLUSIONS: In preparing NPs to conduct BIs, OTJ training by an experienced peer does not seem to differ markedly from workshop training by expert counselors. Interventionist knowledge and performance can be improved in the short term by follow-up training. This indicates that NP's taught by either method should undergo periodic continuing education to maintain the necessary skill set for performing BIs. PMID- 21610399 TI - Do trauma safety-net hospitals deliver truly safe trauma care? A multilevel analysis of the national trauma data bank. AB - BACKGROUND: Patients treated at "safety-net hospitals," facilities that care for a high percentage of uninsured patients, are known to have worse outcomes. This study seeks to analyze whether care at "trauma safety-net hospitals" (TSNH) accounts for the known mortality disparity between uninsured and insured trauma patients. METHODS: A retrospective analysis of trauma patients (age, 18-64 years) in the National Trauma Data Bank (6.2; 2001-2005) with moderate to severe injury (Injury Severity Score >=9) was performed. TSNH were defined as facilities treating >=47% uninsured trauma patients. The main outcome measure was adjusted mortality of patients treated at TSNH versus non-TSNH. A multilevel analysis using multiple logistic regression and generalized estimating equations was performed to control for both hospital and patient-level characteristics (age, gender, insurance, injury severity, shock, and type and mechanism of injury). Subset analyses by hospital trauma level designation and patient injury severity and type were also performed. RESULTS: Collectively 343,053 trauma patients were treated at 46 TSNH and 413 non-TSNH. TSNH patients (n = 36,774) were more likely to be minorities (55% vs. 27%; p < 0.05) compared with non-TSNH patients (n = 306,279). Unadjusted mortality was greater in TSNH versus non-TSNH patients (6.8% vs. 4.6%; *p < 0.05). After controlling for patient- and hospital-level factors, patients at TSNH and non-TSNH facilities had equivalent odds ratio of death = 0.93 (95% confidence interval = 0.65-1.32). Similar results were obtained in all subset analyses. CONCLUSION: Patients treated at TSNH have equivalent mortality compared with those treated at non-TSNH. Disparate trauma outcomes due to insurance status are not explained by differences between trauma treating institutions. PMID- 21610400 TI - Cost-driven injury prevention: creating an innovative plan to save lives with limited resources. AB - BACKGROUND: Pedestrian injury costs >$20 billion annually. Countermeasures such as blinking crosswalks can be expensive but expectedly vital to injury prevention efforts. We aimed to create a new framework of cost-driven surveillance. The purpose of our study was to carry out a detailed analysis of the hospital cost and its relationship to location of pedestrian injury. Targeting identified "high cost areas" with effective countermeasures could save lives and be most cost effective. Our hypothesis is that pedestrian injury creates a tremendous public funding burden and that hotspot sites can be mapped based on corresponding hospital costs. METHODS: We conducted a retrospective analysis of billing records of 694 auto versus pedestrian victims treated at Level I trauma center in our city in the sample year 2004. Total cost was computed using cost to charge ratios for hospital and ambulance fees and actual cost of professional fees. City district "price tags" were assigned per detailed patient cost data to corresponding spatial analysis of intersections. chi(2) analyses were conducted on demographic variables. Multiple regression analysis determined predictors of total cost. RESULTS: The total cost of injury was $9.8 million, whereas the total charge was $20.8 million. Ninety percent of victims resided in our City. Thirty one percent were admitted and cost of their care accounted for 76% of the total. Admitted patients were older than nonadmitted patients (47 years vs. 38 years; t = 5.45; p = 0.00). Spatial analysis determined that of 11 city districts, three districts accounted for almost 50% of the total cost. Seventy-six percent of the total cost was publicly funded. The strongest predictors of cost were length of stay (a = 0.77; t(220) = 30.42; p = 0.000) and ventilator days (a = 0.51; t(220) = 6.69; p = 0.000). CONCLUSIONS: These findings provide a roadmap to target costly hot spots for city planning of preventive countermeasures. In a climate of limited resources, this kind of roadmap outlines the three regions that could most benefit from countermeasures from both an injury prevention and cost containment standpoint. Cost-driven surveillance is useful in city strategic planning for cost-effective and life-saving pedestrian injury prevention. PMID- 21610401 TI - Trauma in the Russian Federation: then and now. AB - BACKGROUND: Russia has made substantial, largely unrecognized contributions to the field of trauma. These include the early development of triage, improvement of blood transfusions and blood bank networks, and Mobile Emergency Medical Services. Despite these advances, injury fatality rates in Russia are alarmingly high (~50% higher than other Eastern European countries). They fluctuated dramatically during 1980 to 2006, a period that included the dissolution of Union of Soviet Socialist Republics. Suggested causes, including inaccurate data, alcohol use, and economic hardship, are investigated in this article. METHODS: Injury mortality rates for homicide, suicide, accidental poisoning, and total injuries (source: World Health Organization), alcohol consumption (source: World Health Organization), and economic data (source: United Nations Economic Commission for Europe) for the Russian Federation from 1980 to 2006 were examined and compared with the Baltic States, Central Asian Republics, other Eastern European nations, and the United States. RESULTS: Injury mortality rates declined in Russia from 1980 to 1987. The total injury mortality rate more than doubled between 1987 and 1994, followed by a 40% decline from 1994 to 1998. The 1984 to 1994 mortality rates generally parallel alcohol consumption trends. The 1991 to 1994 climb coincides with the dissolution of the Union of Soviet Socialist Republics. A smaller rise in fatality rates occurred in the early 2000s. CONCLUSIONS: Deaths caused by injuries in the Russian Federation are related to multiple factors. Some authors conclude that the data accurately reflect injury mortality. Financial concerns during these times may have led to riskier behaviors resulting in more deaths from injuries. Heavy alcohol consumption also likely contributes to high injury mortality rates. Excessive injury mortality calls for action by Russian policy makers. PMID- 21610402 TI - American Association for the Surgery of Trauma Prevention Committee topical updates: getting started, fall prevention, domestic violence, and suicide. PMID- 21610403 TI - Temporary femoral-radial arterial shunting for arm replantation. PMID- 21610404 TI - Blunt abdominal trauma resulting in gallbladder injury: a review with emphasis on pediatrics. AB - BACKGROUND: Gallbladder injury in blunt abdominal trauma is a rare and difficult diagnosis. Gallbladder injury is reported to be between 1.9% and 2.1% of all abdominal traumas. It has vague symptoms usually with inconclusive investigation results; hence, it is often diagnosed at laparotomy. The patient typically has vague abdominal pain and occasionally a period of remission depending on the type of gallbladder injury. In pediatrics, blunt abdominal trauma presents additional challenges of difficult historians and compensating physiology. Any delay in diagnosis and definitive management will worsen the prognosis. Making the diagnosis requires astute clinical acumen and radiologic interpretation. The classification system of Losanoff has merit in guiding treatment. While cholecystectomy is the preferred treatment, there are occasions when the gallbladder may be left in situ and these are discussed. METHODS: Literature searches were performed using Pubmed and Medline with keywords "abdominal trauma," "gallbladder injury," and "gallbladder perforation." DISCUSSION: The authors highlight the incidence of associated visceral injuries in gallbladder trauma (>90%). Gallbladder perforation is more likely in cases when the gallbladder is distended and thin-walled at the time of injury. Therefore, we recommend that gallbladder perforation is suspected in those patients who have drunk alcohol or eaten recently. Despite the developments in modern computed tomography, identifying gallbladder perforation is difficult because of the subtlety and rarity of the condition. We draw attention to the proposed anatomic classification systems because they are of some use in guiding treatment. In the absence of a diagnosis after blunt abdominal trauma and with intra-abdominal free fluid, the clinician faces the difficult decision of whether surgery is indicated for a potential visceral injury. After discussing the available evidence, the authors advocate a low index of suspicion for performing diagnostic laparoscopy. PMID- 21610405 TI - Fallen lung sign (on chest radiograph). PMID- 21610406 TI - Singular distribution of smoke inhalation injury. PMID- 21610407 TI - Central venous-arterial carbon dioxide tension gradient: another marker to define fluid responsiveness. PMID- 21610408 TI - Cranioplasty after postinjury decompressive craniectomy. PMID- 21610411 TI - Raising arms; at any cost? PMID- 21610412 TI - Helmet use in Australia versus helmet use in Austria. PMID- 21610414 TI - Beaded mycotic aneurysm of the abdominal aorta. PMID- 21610415 TI - Biomechanical comparison of conventional technique versus oblique screw placement in plate fixation. AB - BACKGROUND: The aim of this study was to evaluate whether plate fixation with screws in an oblique fashion would change the strength of the fixation to bending forces and whether any relationship existed between deformity and increased strength of fixation. METHODS: Rear leg tibias from 2-year to 3-year-old sheep were affixed with the help of a custom-made guide to a six-hole dynamic compression plate and divided into three groups. In group 1, fixation was performed using screws perpendicular to the plate axis in two planes. In group 2, screws were placed at a 20-degree angle to the axis of the shaft and perpendicular to the transverse plane. In group 3, the screws were placed at a 20 degree angle to the shaft axis and 7 degrees on the transverse plane. Gap-close bending and side-bending tests were performed in a three-point bending fashion. The maximum moment of force and deformation at the time of the failure was analyzed. RESULTS: In gap-close bending tests, mean maximum moment of forces for groups 1, 2, and 3 was 51.90 Nm, 67.47 Nm, 82.05 Nm, respectively (p<0.05 for group 1 vs. groups 2 and 3; p=0.053 for group 2 vs. group 3). In side-bending tests, the mean maximum moment of force was 34.63 Nm, 49.91 Nm, and 49.29 Nm, respectively (p<0.05 for group 1 vs. groups 2 and 3; no significant difference was observed between groups 2 and 3). When the two bending tests were evaluated together, only the mean moment of forces of groups 1 and 3 were statistically different (p=0.006). There was no difference between any groups in terms of the deformity at the time of the maximum moment of force. CONCLUSION: Oblique screw placement in two planes increases the strength of the plate-screw fixation under bending forces; however, there is no relationship between deformity and increased strength of fixation. PMID- 21610416 TI - Modified tension band fixation for unstable distal clavicle fractures. AB - BACKGROUND: Optimal surgical treatment of unstable distal clavicle fractures is controversial, and various fixation options are available. The objective of this study was to evaluate a new modified tension band fixation technique for unstable distal clavicle fractures. METHODS: Forty-two patients with acute unstable distal clavicle fractures were managed with open reduction and internal fixation using modified tension band fixation. All patients had radiographic and clinical follow ups at a minimum of 12 months (range, 12-39 months). Bony union and coracoclavicular interval distance were evaluated radiographically. Clinical outcomes were measured with the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form. RESULTS: All fractures united solidly within 3 months. All patients had a good functional result, with a mean American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form score of 92 points and a coracoclavicular interval distance of 8.7 mm (range, 5-14 mm; 1.24 times of normal shoulder) at the final follow-up. CONCLUSION: Surgical treatment for unstable distal clavicle fractures using modified tension band fixation is effective. This technique allows simple, cost-effective, and minimally invasive fixation with universally available implants and good fracture healing. PMID- 21610417 TI - Sulfuric acid ingestion. PMID- 21610418 TI - Bilateral spontaneous tension pneumothorax secondary to lymphangioleiomyomatosis. PMID- 21610419 TI - Blunt traumatic occult pneumothorax: is observation safe?--results of a prospective, AAST multicenter study. AB - BACKGROUND: An occult pneumothorax (OPTX) is found incidentally in 2% to 10% of all blunt trauma patients. Indications for intervention remain controversial. We sought to determine which factors predicted failed observation in blunt trauma patients. METHODS: A prospective, observational, multicenter study was undertaken to identify patients with OPTX. Successfully observed patients and patients who failed observation were compared. Multivariate logistic regression was used to identify predictors of failure of observation. OPTX size was calculated by measuring the largest air collection along a line perpendicular from the chest wall to the lung or mediastinum. RESULTS: Sixteen trauma centers identified 588 OPTXs in 569 blunt trauma patients. One hundred twenty-one patients (21%) underwent immediate tube thoracostomy and 448 (79%) were observed. Twenty-seven patients (6%) failed observation and required tube thoracostomy for OPTX progression, respiratory distress, or subsequent hemothorax. Fourteen percent (10 of 73) failed observation during positive pressure ventilation. Hospital and intensive care unit lengths of stay, and ventilator days were longer in the failed observation group. OPTX progression and respiratory distress were significant predictors of failed observation. Most patient deaths were from traumatic brain injury. Fifteen percentage of patients in the failed observation group developed complications. No patient who failed observation developed a tension PTX, or experienced adverse events by delaying tube thoracostomy. CONCLUSION: Most blunt trauma patients with OPTX can be carefully monitored without tube thoracostomy; however, OPTX progression and respiratory distress are independently associated with observation failure. PMID- 21610420 TI - A survey of American Association for the Surgery of Trauma member practices in the management of blunt splenic injury. AB - OBJECTIVE: Conflicting data exist regarding pseudoaneurysm screening (PSA-S), initial angioembolization (IE), deep venous thrombosis prophylaxis (DVT-P), and activity limitation after hemodynamically stable blunt splenic injury (BSI). To determine whether there was consensus regarding BSI management, the multi institutional trial committee of the American Association for the Surgery of Trauma (AAST) approved a survey of member practice patterns regarding BSI management. METHODS: Over 2 months, AAST members were invited to participate in an online survey. Practice patterns and attitudes surrounding PSA-S, IE, DVT-P, and activity limitation after BSI were determined. RESULTS: The response rate was 37.5%. Practice patterns varied by injury grade. Observation only was thought appropriate for grades I (94.4%) and II (84.6%) injuries. For grades III to V injuries, fewer and fewer respondents felt observation only was appropriate. PSA S was the most commonly used strategy for grades IV and V injuries (32.7% and 28.2%), and IE was thought to be appropriate by 23.5% of respondents for grade IV injuries and 25.5% of respondents with grade V injuries. Thirty percent of respondents felt that no DVT-P was indicated for adult patients with BSI. Recommendations regarding return to full activity varied by perceived risk to the patient and by injury grade. CONCLUSIONS: There is considerable variation in the opinions of AAST members regarding BSI management, particularly for high-grade injuries. These results will aid in the design of prospective observational and random trials to determine optimal BSI management. PMID- 21610421 TI - Hepatic arterial embolization in the management of blunt hepatic trauma: indications and complications. AB - BACKGROUND: The objective was to clarify the role of hepatic arterial embolization (AE) in the management of blunt hepatic trauma. METHODS: Retrospective observational study of 183 patients with blunt hepatic trauma admitted to a trauma referral center over a 9-year period. The charts of 29 patients (16%) who underwent hepatic angiography were reviewed for demographics, injury specific data, management strategy, angiographic indication, efficacy and complications of embolization, and outcome. RESULTS: AE was performed in 23 (79%) of the patients requiring angiography. Thirteen patients managed conservatively underwent emergency embolization after preliminary computed tomography scan. Six had postoperative embolization after damage control laparotomy and four had delayed embolization. Arterial bleeding was controlled in all the cases. Sixteen patients (70%) had one or more liver-related complications; temporary biliary leak (n=11), intra-abdominal hypertension (n=14), inflammatory peritonitis (n=3), hepatic necrosis (n=3), gallbladder infarction (n=2), and compressive subcapsular hematoma (n=1). Unrecognized hepatic necrosis could have contributed to the late posttraumatic death of one patient. CONCLUSION: AE is a key element in modern management of high-grade liver injuries. Two principal indications exist in the acute postinjury phase: primary hemostatic control in hemodynamically stable or stabilized patients with radiologic computed tomography evidence of active arterial bleeding and adjunctive hemostatic control in patients with uncontrolled suspected arterial bleeding despite emergency laparotomy. Successful management of injuries of grade III upward often entails a combined angiographic and surgical approach. Awareness of the ischemic complications due to angioembolization is important. PMID- 21610423 TI - Screening for blunt cerebrovascular injuries is cost-effective. AB - BACKGROUND: Screening for blunt carotid and vertebral injury (BCVI) is increasing without a clear understanding of whether the chosen screening approach is cost effective. We hypothesized that screening for BCVI using computed tomography angiography (CTA) was cost-effective in populations at high risk for BCVI. METHODS: A decision analysis was performed modeling current BCVI screening approaches: no screening, duplex ultrasound, magnetic resonance angiography, angiography, and CTA. Treatment options included antiplatelet therapy, anticoagulation, stents for pseudoaneurysm, and no treatment. Probability estimates for incidence of injury and stroke, sensitivity and specificity of the screening modality, and type of treatment were taken from published data. Average wholesale price and medicare reimbursement costs were used. Two populations were analyzed; high-risk and overall blunt trauma populations. Two perspectives were taken; societal (including lifetime stroke costs) and institutional (ignoring lifetime stroke costs). RESULTS: In the high-risk population, from a societal perspective, CTA has the lowest cost and stroke rate; $3,727 per patient screened with a 1% stroke rate. No treatment has the highest cost and stroke rate. From an institutional perspective, no screening is the least costly option but has an 11% stroke rate. Duplex ultrasound is the most cost-effective screening modality; $8,940 per stroke prevented. CONCLUSION: From the societal perspective, CTA is the most cost-effective screening strategy for patients at high risk for BCVI. From an institutional perspective, CTA prevents the most strokes at a reasonable cost. PMID- 21610422 TI - Does beta blockade postinjury prevent bone marrow suppression? AB - BACKGROUND: Trauma-induced hypercatecholaminemia negatively impacts bone marrow (BM) function by suppressing BM hematopoietic progenitor cell (HPC) growth and increasing HPC egress to injured tissue. Beta blockade (BB) given before tissue injury alone has been shown to reduce both HPC mobilization and restore HPC colony growth within the BM. In a clinically relevant model, this study examines the effect of BB given after both tissue injury and hemorrhagic shock (HS). METHODS: Male Sprague-Dawley rats underwent lung contusion (LC) with a blast wave percussion. HS was achieved after LC by maintaining the mean arterial blood pressure 30 mm Hg to 35 mm Hg for 45 minutes. Propranolol (10 mg/kg) was given once the mean arterial blood pressure>80 mm Hg and subsequent doses were given daily (LC/HS/BB). One-day and 7-day postinjury, analysis of BM and lung tissue for the growth of HPCs, hematologic parameters, and histology of lung injury were performed. RESULTS: LC/HS significantly worsens BM CFU-E growth suppression (15+/ 8 vs. 35+/-2) and increases CFU-E growth in injured tissue when compared with LC at 1 day and 7 days (33+/-5 vs. 22+/-9). The use of BB after LC/HS ameliorated BM suppression, the degree of anemia and HPC growth in the injured lung at 1 day and 7 days postinjury. Lung injury score shows that there was no worsening of lung healing with BB (LC/HS/BB 3.2+/-2 vs. LC/HS 3.8+/-0.8). CONCLUSION: In an injury and shock model, administration of propranolol immediately after resuscitation significantly reduced BM suppression, and the protective effect is maintained at 7 days with daily BB. Although BB appears to improve BM function by decreasing HPC mobilization to injured tissue, there was no worsening of lung healing. Therefore, the use of propranolol after trauma and resuscitation may minimize long-term BM suppression after injury with no adverse impact on healing. PMID- 21610424 TI - Improving the screening criteria for blunt cerebrovascular injury: the appropriate role for computed tomography angiography. AB - BACKGROUND: Screening criteria and diagnostic methods for blunt cerebrovascular injury (BCVI) are evolving. Using current screening guidelines, up to 20% of injuries are not recognized until symptoms occur, and thus missing the therapeutic window. All patients who meet screening criteria at our institution undergo angiography due to conflicting sensitivity data reported for computed tomographic angiography (CTA). We sought to refine screening criteria for BCVI to optimize patient care. METHODS: All trauma admissions screened for BCVI over a 29 month period ending May 2009 were analyzed. Thirty-two channel CTA was obtained during initial radiologic evaluation. Patients underwent angiography for conventional screening criteria or abnormal CTA. Demographics, criteria for BCVI screening, fracture patterns, associated injuries, and results of CTA and angiography were analyzed. RESULTS: A total of 748 patients were screened, 143 injuries (78 carotid and 65 vertebral) were diagnosed in 117 patients (16%). Nineteen of the 117 patients (16%) with BCVI had no conventional criteria and were only screened for CTA abnormalities. One patient developed neurologic symptoms subsequent to initial evaluation with no conventional screening criteria or CTA findings. CONCLUSIONS: The conventional screening criteria identify most patients with BCVI (84%). CTA as a screening criterion captures nearly all remaining patients before symptoms developing. This allows for detection and treatment of injuries in patients that otherwise would be missed until symptomatic. CTA should be part of the radiologic evaluation for potential head, neck, and facial injuries. Unfortunately, CTA is not sensitive enough to reliably detect injuries, but should be added as a screening criterion. Angiography remains the gold standard for BCVI diagnosis. PMID- 21610425 TI - Unwarranted national variation in the use of prophylactic inferior vena cava filters after trauma: an analysis of the National Trauma Databank. AB - BACKGROUND: The proportion of patients undergoing placement of prophylactic inferior vena cava (IVC) filters after trauma has increased dramatically in the past decade. Guidelines for prophylactic IVC filters vary from never recommended (American College of Chest Physicians/CHEST) to the more liberal Eastern Association for the Surgery of Trauma guidelines that recommend prophylactic IVC filters for patients who have both contraindications to anticoagulation and high risk injury patterns. We hypothesized that U.S. trauma centers would practice according to Eastern Association for the Surgery of Trauma guidelines and that any variation in practice patterns would be due to variations in the number of high-risk patients treated. METHODS: The National Trauma Databank (2002-2007) was used to determine center rates of prophylactic IVC filter placement per high-risk patient. Centers were excluded if they did not submit procedure and comorbidity or diagnoses codes. Patients were excluded if they had diagnoses of deep vein thrombosis or pulmonary embolism, were younger than 16 years, or died within 24 hours of presentation. RESULTS: A total of 1,630,385 patients and 22,808 prophylactic IVC filters from 680 centers were eligible for analysis. We identified center rates of 0 to 13 prophylactic IVC filters per 100 patient admissions and 0 to 206 filters per high-risk patient. Center characteristics could not completely explain this variation, although filters were most commonly placed in the Northeast and least frequently placed in the West (p<0.001). CONCLUSION: U.S. trauma centers demonstrate considerable variation in the use of prophylactic IVC filter placement after trauma, which could not be entirely explained by either patient or center characteristics. PMID- 21610426 TI - Relationship of serum and cerebrospinal fluid biomarkers with intracranial hypertension and cerebral hypoperfusion after severe traumatic brain injury. AB - BACKGROUND: There is little that can be done to treat or reverse the primary injury that occurs at the time of a traumatic brain injury (TBI). Initial management of the patient with severe TBI focuses on prevention of subsequent secondary insults, namely, intracranial hypertension (ICH) and cerebral hypoperfusion (CH). Currently, there is no reliable way to predict which patients will develop ICH and CH other than clinical acumen; therefore, indicators of impending secondary intracranial insults may be useful in predicting these events and allowing for prevention and early intervention. This study was undertaken to investigate the relationship of cytokine levels with intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in patients with severe TBI. METHODS: Patients at the R Adams Cowley Shock Trauma Center were prospectively enrolled for a 6-month period. Inclusion criteria were older than 17 years, admission within the first 6 hours after injury, Glasgow Coma Scale<9 on admission, and placement of a clinically indicated ICP monitor. Serum and cerebrospinal fluid, when available, were collected on admission and twice daily for 7 days. Cytokine levels of interleukin (IL)-1beta, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha were analyzed by multiplex bead array assays. Hourly values for ICP and CPP were recorded, and means, minimum (for CPP) or maximum (for ICP) values, percentage time ICP>20 mm Hg (%ICP20) and CPP<60 mm Hg (%CPP60), and cumulative Pressure Times Time Dose (PTD; mm Hg.h) for ICP>20 mm Hg (PTD ICP20) and CPP<60 mm Hg (PTD CPP60) were compared with the serum and cerebrospinal fluid levels that were drawn before 12-hour time periods (PRE) and after 12-hour time periods (POST) of monitoring. RESULTS: Twenty-four patients were enrolled. In-hospital mortality was 12.5%, and good functional outcome was noted in 58%. Two hundred and seventy-five serum samples were taken and analyzed. IL-6 levels in the serum were found in the highest concentration of the cytokines measured. PTD ICP20 and PTD CPP60 were moderately correlated with increased PRE IL-8 levels (r=0.34, p<0.001; r=0.53, p<0.001). PTD ICP20 was also correlated with PRE TNF-alpha levels (r=0.27, p<0.001) as was PTD CPP60 (r=0.25, p<0.001). POST IL-8 levels were found to be correlated with PTD ICP20 (r=0.46, p<0.001) and PTD CPP60 (r=0.54, p<0.001). POST TNF-alpha was associated with PTD ICP20 (r=0.45, p<0.001). PTD CPP60 was also moderately correlated with POST TNF-alpha levels (r=0.26, p<0.001). When comparing patients with good versus poor outcome, median daily serum IL-8 levels were associated with poor outcome. CONCLUSIONS: IL-8 and, to a lesser extent, TNF-alpha demonstrated the most promise in this study to be candidate serum markers of impending ICH and CH. The clinical relevance of this is the suggestion that we may be able to predict impending secondary insults after TBI before the clinical manifestation of these events. Given the known morbidity of ICH and CH, early intervention and prevention may have a significant impact on outcome. This becomes even more important when decisions must be made about timing of interventions. Increased levels of IL-8 and TNF-alpha in the serum during episodes of ICH and CH imply there are significant systemic effects of these events. These serum biomarkers are promising as diagnostic targets. In addition, further study of the precise role of these molecules may have significant implications for inflammatory system manipulation in the management of severe TBI. PMID- 21610427 TI - Major traumatic brain injury: time to tertiary care and the impact of a clinical guideline. AB - BACKGROUND: To achieve timely access to neurosurgical care for adult brain injured patients, a Head Injury Guideline was implemented to standardize the emergency department evaluation and management of these patients. The goals of this study were to document times to neurosurgical care for patients with major traumatic brain injury presenting to a Provincial emergency room and to evaluate the impact of the Guideline on timely access to definitive care. METHODS: Data collected prospectively and stored in the Nova Scotia Trauma Registry and the Emergency Health Services Communications and Dispatch Centre database were analyzed for patients with head abbreviated injury scale score (AIS)>=3. Several time intervals from admission to a referring hospital to access to tertiary care were determined and compared for the periods before Guideline implementation, the implementation phase, and after implementation. RESULTS: The time elapsed before calling the provincial Trauma Hotline was not statistically different after Guideline implementation for polytrauma patients with head AIS score>=3 (n=388) during the preimplementation (2:34+/-1:30; median time in hours:minutes+/ standard deviation), implementation (1:57+/-2:33) and postimplementation (2:31+/ 4:06) periods. Subset group analysis of patients with isolated head injuries AIS score>=3 (n=99) also showed no statistical difference in preimplementation (1:51+/-1:42), implementation (2:49+/-2:57), and postimplementation (3:10+/-4:58) times. Examination of overall time to tertiary care revealed prolonged transfer times and that the Guideline had no influence on either the polytrauma patient group (preimplementation, 4:20+/-1:41; implementation, 5:01+/-2:55; and postimplementation 4:46+/-4:22) or those with isolated head injuries (preimplementation, 3:39+/-1:47; implementation, 6:06+/-4:00; and postimplementation, 5:13+/-4:59). CONCLUSIONS: Times to tertiary care are lengthy and have not been reduced by Guideline implementation. System changes beyond Guideline implementation are required to provide timely access to tertiary care for patients with major head injury. PMID- 21610428 TI - Diabetic patients with traumatic brain injury: insulin deficiency is associated with increased mortality. AB - BACKGROUND: Hyperglycemia after traumatic brain injury (TBI) is an independent predictor of mortality. Insulin deficiency, as opposed to elevated blood glucose, might be the reason for increased mortality. TBI patients with diabetes mellitus (DM) were analyzed to determine how insulin deficiency affects mortality after TBI. METHODS: NTDB version 7 was queried for patients with isolated moderate to severe TBI (head abbreviated injury score [AIS]>=3 with AIS<=3 for other body regions). Demographics and outcomes were compared between TBI patients with insulin-dependent DM (IDDM), noninsulin-dependent DM (NIDDM), and those without DM. Logistic regression analysis was used to investigate the relationship between mortality and DM. RESULTS: Overall, 51,585 patients with isolated moderate to severe TBI were analyzed. Mortality was 14.4% and 8.2% in patients with and without DM, respectively (p<0.0001). Although head AIS scores were similar, patients with DM had a statistically higher Glasgow coma scale (GCS) at presentation compared with patients without DM (GCS score 12.4 vs. GCS score 10.9; p<0.0001). After multivariable logistic regression analysis, DM was an independent predictor for mortality (odds ratio 1.5, confidence interval 1.29 1.74, p<0.0001). When comparing TBI patients with IDDM to NIDDM, mortality was 17.1% for IDDM and 13.0% for NIDDM (p=0.025). CONCLUSION: DM is a significant predictor for mortality after moderate to severe TBI. Insulin deficiency is a likely contributor to increased mortality after TBI as IDDM patients have higher mortality than NIDDM patients who have higher mortality than no-DM patients. PMID- 21610429 TI - Mortality and regional oxygen saturation index in septic shock patients: a pilot study. AB - BACKGROUND: Peripheral muscle tissue oxygenation determined noninvasively using near-infrared spectroscopy may help to identify tissue hypoperfusion in septic patients. The aim of this study was to investigate regional oxygen saturation index (rSO2) in the brachioradialis (forearm) muscle by comparing measurements in healthy subjects and in intensive care unit (ICU) septic shock patients, and determine whether brachioradialis muscle rSO2 is associated with poor outcome in ICU septic shock patients. METHODS: We conducted a prospective observational study in healthy volunteers (n = 50) and ICU septic shock patients (n=19). Brachioradialis (forearm) rSO2 measurements in healthy volunteers at rest and in ICU septic shock patients were compared. Pulmonary artery catheter monitoring was used in ICU patients. RESULTS: Significant differences in rSO2 were observed between healthy volunteers and ICU septic shock patients at ICU admission (68.7+/ 4.9 vs. 55.0+/-13.0; p<0.001). When comparing septic shock survivors and nonsurvivors, significant differences were observed in rSO2 at baseline (64.5+/ 8.9 vs. 47.5+/-10.7; p<0.01), 12 hours (67.3+/-9.6 vs. 45.0+/-14.9; p<0.01), and 24 hours (65.7+/-7.0 vs. 50.1+/-10.3; p<0.01). Lactate concentration was lower in survivors than nonsurvivors at 24 hours (12.0+/-7.5 mmol/L vs. 23.2+/-12.5 mmol/L; p<0.04). Cardiac index was greater in nonsurvivors than survivors at baseline (4.6+1.9 L/min/m vs. 3.0+0.9 L/min/m; p<0.05) and 12 h (3.9+0.5 L/min/m vs. 3.1+0.3 L/min/m; p<0.05). CONCLUSIONS: We observed that septic shock patients with forearm skeletal muscle rSO2<=60% throughout first 24 hours after ICU admission had significantly greater mortality rate than patients with forearm skeletal muscle rSO2>60% throughout this critical time. PMID- 21610430 TI - Computer protocol facilitates evidence-based care of sepsis in the surgical intensive care unit. AB - BACKGROUND: Care of sepsis has been the focus of intense research and guideline development for more than two decades. With ongoing success of computer protocol (CP) technology and with publication of Surviving Sepsis Campaign (SSC) guidelines, we undertook protocol development for management of sepsis of surgical intensive care unit patients in mid-2006. METHODS: A sepsis protocol was developed and implemented in The Methodist Hospital (TMH) (Houston, TX) surgical intensive care unit (27 beds) together with a sepsis research database. We compare paper-protocol (PP) (2008) and CP (2009) performance and results of the SSC guideline performance improvement initiative (2005-2008). TMH surgical intensive care unit sepsis protocol was developed to implement best evidence and to standardize decision making among surgical intensivists, nurse practitioners, and resident physicians. RESULTS: The 2008 and 2009 sepsis protocol cohorts had very similar number of patients, age, % male gender, Acute Physiology and Chronic Health Evaluation scoring system II, and Sequential Organ Failure Assessment scores. The 2008 PP patients had greater baseline lactate concentration consistent with greater mortality rate. Antibiotic agents were administered to 2009 CP cohort patients sooner than 2008 PP cohort patients. Both cohorts received similar volume of intravenous fluid boluses. Comparing 6-hour resuscitation bundle compliance, the 2009 CP cohort was substantially greater than SSC eighth quarter and 2008 PP cohorts (79% vs. 31% vs. 29%), and mortality rate was much less when using the CP (14% vs. 31% vs. 24%). CONCLUSIONS: Our comprehensive sepsis protocol has enabled rapid and consistent implementation of evidence-based care, and, implemented as a bedside CP, contributed to decreased mortality rate for management of surgical sepsis. PMID- 21610431 TI - Postinjury vagal nerve stimulation protects against intestinal epithelial barrier breakdown. AB - BACKGROUND: Vagal nerve stimulation (VNS) can have a marked anti-inflammatory effect. We have previously shown that preinjury VNS prevented intestinal barrier breakdown and preserved epithelial tight junction protein expression. However, a pretreatment model has little clinical relevance for the care of the trauma patient. Therefore, we postulated that VNS conducted postinjury would also have a similar protective effect on maintaining gut epithelial barrier integrity. METHODS: Male balb/c mice were subjected to a 30% total body surface area, full thickness steam burn followed by right cervical VNS at 15, 30, 60, 90, 120, and 150 minutes postinjury. Intestinal barrier dysfunction was quantified by permeability to 4 kDa fluorescein isothiocyanate-Dextran, histologic evaluation, gut tumor necrosis factor-alpha (TNF-alpha) enzyme-linked immunosorbent assay, and expression of tight junction proteins (myosin light chain kinase, occludin, and ZO-1) using immunoblot and immunoflourescence. RESULTS: Histologic examination documented intestinal villi appearance similar to sham if cervical VNS was performed within 90 minutes of burn insult. VNS done after injury decreased intestinal permeability to fluorescein isothiocyanate-Dextran when VNS was <=90 minutes after injury. Burn injury caused a marked increase in intestinal TNF-alpha levels. VNS-treated animals had TNF-alpha levels similar to sham when VNS was performed within 90 minutes of injury. Tight junction protein expression was maintained at near sham values if VNS was performed within 90 minutes of burn, whereas expression was significantly altered in burn. CONCLUSION: Postinjury VNS prevents gut epithelial breakdown when performed within 90 minutes of thermal injury. This could represent a therapeutic window and clinically relevant strategy to prevent systemic inflammatory response distant organ injury after trauma. PMID- 21610432 TI - Magnesium sulfate mitigates acute lung injury in endotoxemia rats. AB - BACKGROUND: Magnesium sulfate (MgSO4) possesses potent anti-inflammation capacity. We sought to elucidate the effects of MgSO4 on mitigating acute lung injury induced by endotoxemia. MgSO4 is an antagonist of the L-type calcium channels and the N-methyl-D-aspartate (NMDA) receptor. The roles of the L-type calcium channels and NMDA receptor in this regard were also elucidated. METHODS: Ninety-six adult male rats were randomized to receive normal saline, MgSO4 (100 mg/kg), lipopolysaccharide (LPS), LPS plus MgSO4 (10, 50, or 100 mg/kg), LPS plus MgSO4 (100 mg/kg) plus the L-type calcium channel activator BAY-K8644, or LPS plus MgSO4 (100 mg/kg) plus exogenous NMDA (n=12 in each group). Between-group differences in lung injury were evaluated. RESULTS: Histologic findings, in concert with assays of leukocyte infiltration (polymorphonuclear leukocytes/alveoli ratio and myeloperoxidase activity) and lung water content (wet/dry weight ratio), confirmed that LPS induced acute lung injury. LPS also caused significant inflammatory response (increases in chemokine, cytokine, and prostaglandin E2 concentrations) and imposed significant oxidative stress (increases in nitric oxide and malondialdehyde concentrations) in rat lungs. MgSO4 at the dosages of 50 mg/kg and 100 mg/kg, but not at 10 mg/kg, significantly mitigated the acute lung injury, lung inflammatory response, and oxidative stress caused by endotoxemia. Moreover, the protective effects of MgSO4 were counteracted by BAY-K8644 and exogenous NMDA. CONCLUSIONS: MgSO4 mitigates lung inflammatory response, oxidative stress, and acute lung injury in endotoxemia rats in a dose-dependent manner. The mechanisms may involve antagonizing the L-type calcium channels and the NMDA receptor. PMID- 21610433 TI - Poloxamer-188 reduces muscular edema after tourniquet-induced ischemia reperfusion injury in rats. AB - BACKGROUND: Skeletal muscle injury can result in significant edema, which can in turn lead to the development of acute extremity compartment syndrome (CS). Poloxamer-188 (P-188), a multiblock copolymer surfactant, has been shown to decrease edema by sealing damaged membranes in a number of tissues after a variety of injury modalities. The objective is to determine whether the administration of P-188 significantly reduces skeletal muscle edema associated with ischemia/reperfusion injury (I-R). METHODS: Male Sprague-Dawley rats underwent 180 minutes of tourniquet-induced ischemia. Five minutes before tourniquet release, rats received either a bolus of (1) P-188 (150 mg/kg; P-188 group) or (2) vehicle (Vehicle group) via a jugular catheter (n=10 per group). After 240 minutes reperfusion, both groups received a second bolus of either P 188 (P-188) or vehicle (Vehicle) via a tail vein catheter. Sixteen hours later, rats were killed; muscle weights were determined, infarct size (2,3,5 triphenyltetrazolium chloride method), and blinded histologic analysis (hematoxylin and eosin) were performed on the gastrocnemius and tibialis anterior muscles, as well as indices of antioxidant status. RESULTS: P-188 resulted in significantly less edema (wet weight) and reduced an index of lipid peroxidation compared with Vehicle (p<0.05). Wet:dry weight ratios were less in the P-188 group (indicating less edema). Muscle viability as indicated by 2,3,5 triphenyltetrazolium chloride staining or routine histology did not reveal statistically significant differences between groups. CONCLUSION: P-188 significantly reduced ischemia-reperfusion-related muscle edema and lipid peroxidation but did not impact muscle viability. Excess edema can lead to acute extremity CS, which is associated with significant morbidity and mortality. P-188 may provide a potential adjunctive treatment for the reduction of CS. PMID- 21610434 TI - Angiographic embolization of nonvariceal upper gastrointestinal bleeding: predictors of clinical failure. AB - BACKGROUND: Angiographic embolization (AE) has emerged as an important therapy for patients with nonvariceal upper gastrointestinal bleeding (UGIB). We hypothesized that discrete factors predictive of AE failure could be identified. METHODS: A retrospective review was performed for patients with nonvariceal UGIB who underwent AE from 1999 to 2009 at Penn State Milton S. Hershey Medical Center. AE clinical failure was defined as requirement for another intervention (surgery, endoscopic therapy, or another AE) for nonvariceal UGIB and/or death from bleeding after AE. Statistical analysis was performed using Fisher's exact test and Student's t test to explore the risk of AE failure. RESULTS: Of 48 total AE cases, 17 patients (35.4%) had clinically failed AE. Mortality rate was significantly higher in patients with AE clinical failure than in patients with AE clinical success (64.7% vs. 12.9%, p=0.001). Factors associated with AE clinical failure include anticoagulant use before admission (p=0.001), use of corticosteroids before admission (p=0.045), pre-AE vasopressor use (p=0.038), and embolization using either coils alone (p=0.05) or using coils with or without additional embolic materials (p=0.018). CONCLUSIONS: AE clinical failure portends poor prognosis. Caution should be exercised when considering AE, particularly AE using coils, in patients with a history of anticoagulant, corticosteroid, or vasopressor use. PMID- 21610435 TI - Crush syndrome and acute kidney injury in the Wenchuan Earthquake. AB - BACKGROUND: The Wenchuan Earthquake resulted in calamitous destruction and massive death. We report the characteristics of crush syndrome (CS) and acute kidney injury (AKI) brought by the earthquake, which took place in a mountainous area. METHODS: We conducted a cross-section survey of total 2,316 consecutive admissions because of seismic trauma, of which 1,827 had complete data available after we excluded those victims with mild injuries. The characteristics of CS and AKI in the mountainous earthquake were analyzed. RESULTS: A total of 149 patients (8.2%) were diagnosed with CS. They had various complications, including different kinds of infection or sepsis, AKI, hematological abnormality, adult respiratory distress syndrome, congestive heart failure, multiple organs dysfunction syndrome, etc. The incidence of hyperkalemia was 15.9% in patients with CS. The hyperkalemia relapsed in five patients after hemodialysis in the first 3 days. AKI occurred in 62 patients (41.6% of CS patients) with CS and 33 of them received renal replacement therapy. In our hospital, 5 of them died. The overall mortality rate was 1.0% and mortality of patients with CS was 6.7%. Twelve patients (50%) died in the first 3 days. CONCLUSIONS: Although the mountains hampered rescue actions, causing more loss of life, CS and AKI were still common and life-threatening events in the Wenchuan Earthquake. Most patients with CS and/or AKI had severe complications, especially hyperkalemia. PMID- 21610436 TI - What are the specific computed tomography scan criteria that can predict or exclude the need for renal angioembolization after high-grade renal trauma in a conservative management strategy? AB - BACKGROUND: The indications of renal angioembolization for patients with high grade renal trauma (HGRT) are based on angiographic criteria to reduce the failure rate of conservative management (CM). There is no consensus to predict or exclude an indication of renal angioembolization with a computed tomography (CT) scan. The aim of this study was to evaluate CT-specific criteria to predict or exclude the need for renal embolization. METHODS: All traumatized patients admitted with renal injury were considered between 2005 and 2009. We included all patients who had an HGRT (classified by American Association for the Surgery of Trauma Organ Injury Scale grade>=3) treated by CM. We collected the demographic, CT, angiographic, management, and outcome data for these patients. CT criteria were retrospectively studied to define their predictive values for renal embolization. RESULTS: Among 101 patients with renal injury, 58 were HGRT, and 53 of them were treated by CM. Ten patients (19%) received renal embolization because of an ongoing renal hemorrhage. There was no significant difference for urologic interventions (2 [20%] vs. 7 [16%]), CM failure rate (1 [10%] vs. 2 [5%]), and during hospital stay between these patients and those who did not received embolization. None of the CT criteria had a negative predictive value for renal embolization to 100%, only the absence of intravascular contrast extravasation associated with a perirenal hematoma rim distance<25 mm excludes an indication for embolization. CONCLUSIONS: In patients with HGRT who had bleeding, a strategy of targeted angiography can be realized safely in using specific CT scan criteria that can predict with high accuracy and exclude the need for embolization, without reducing the success rate of CM. PMID- 21610437 TI - Routine follow-up imaging of kidney injuries may not be justified. AB - BACKGROUND: The purpose of this investigation was to determine the yield of repeat follow-up imaging in patients sustaining renal trauma. METHODS: The Los Angeles County+University of Southern California Medical Center trauma registry was reviewed to identify all patients with a diagnosis of kidney injury from 2005 to 2008. All final attending radiologist interpretations and the dates of the initial and follow-up computerized tomography (CT) scans were also reviewed. Grades I, II, and III were grouped as low-grade injuries and grades IV and V as high-grade injuries. RESULTS: During the 4-year study period, 120 (1.2% of all trauma admissions) patients had a total of 121 kidney injuries: 85.8% were male, and the mean age+/-SD was 31.1 years+/-14.5 years. Overall, 22.6% of blunt and 35.6% of penetrating kidney injuries were high grade (IV-V; p=0.148). These high grade injuries were managed operatively in 35.7% and 76.2% of blunt and penetrating injuries, respectively, (p=0.022). Overall, 31.7% underwent at least one follow-up CT; 24.2% of patients with blunt and 39.7% of patients with penetrating kidney injury, respectively. None of the patients with a low-grade injury managed nonoperatively developed a complication, independent of the injury mechanism. High-grade blunt and penetrating kidney injuries managed nonoperatively were associated with 11.1% and 20.0% complication rate identified on follow-up CT, respectively. For patients who underwent surgical interventions for penetrating kidney injuries, the diagnosis of the complication was made at 9.8 days+/-7.0 days (range, 1-24 days), with 83.3% of them diagnosed within 8 days postoperatively. The most frequent complication identified was an abscess in the renal fossa (50.0% of all complications). Other complications included urinoma, ureteral stricture, and pseudoaneurysm. All patients who developed complications were symptomatic, prompting the imaging that led to the diagnosis. All patients who developed a complication after a penetrating injury required intervention for the management of the complication. CONCLUSION: Selective reimaging of renal injuries based on clinical and laboratory criteria seems to be safe regardless of injury mechanism or management. High-grade penetrating injuries undergoing operative intervention should carry the highest degree of vigilance and lowest threshold for repeat imaging. PMID- 21610438 TI - Combat versus civilian open tibia fractures: the effect of blast mechanism on limb salvage. AB - BACKGROUND: This study compares open tibia fractures in US Navy and US Marine Corps casualties from the current conflicts with those from a civilian Level I trauma center to analyze the effect of blast mechanism on limb-salvage rates. METHODS: Data from the 28,646 records in the University of California San Diego Trauma Registry from 1985 to 2006 was compared with 2,282 records from the US Navy and US Marine Corps Combat Trauma Registry Expeditionary Medical Encounter Database for the period of March 2004 to August 2007. Injuries were categorized by Gustilo-Anderson (G-A) open fracture classification. Independent variables included age, gender, mechanism of injury including blast mechanisms, shock, blood loss, prehospital time, procedures, Injury Severity Score, length of stay, and Mangled Extremity Severity Score (MESS). Dependent variables included early or late amputation and mortality. RESULTS: The civilian group had 850 open tibia fractures with 45 amputations; the military group had 21 amputation patients (3 bilateral) in 115 open tibia fractures. Military group patients were more severely injured, more likely have hypotension, and had a higher amputation rate for G-A IIIB and IIIC fractures then civilian group patients. Blast mechanism was seen in the majority of military group patients and was rare in the civilian group. MESS scores had poor sensitivity (0.46, 95% confidence interval: 0.29 0.64) in predicting the need for amputation in the civilian group; in the military group sensitivity was better (0.67, 95% confidence interval: 0.43-0.85), but successful limb salvage was still possible in most cases with an MESS score of >=7 when attempted. CONCLUSION: Despite current therapy, limb salvage for G-A IIIB and IIIC grades are significantly worse for open tibia fractures as a result of blast injury when compared with typical civilian mechanisms. MESS scores do not adequately predict likelihood of limb salvage in combat or civilian open tibia fractures. PMID- 21610439 TI - Progressive displacement of clavicular fractures in the early postinjury period. AB - BACKGROUND: Historically, minimally to moderately displaced clavicular fractures have been managed nonoperatively. However, there is no clear evidence on whether clavicular fractures can progressively displace following injury and whether such displacement might influence decisions for surgery. METHODS: We retrospectively reviewed data on 56 patients who received operative treatment for clavicular fractures at our institution from February 2002 to February 2007 and identified those patients who were initially managed nonoperatively based on radiographic evaluation (<2 cm displacement) and then subsequently went on to meet operative indications (>=2 cm displacement) as a result of progressive displacement. Standardized radiographic measurements for horizontal shortening (medial-lateral displacement) and vertical translation (cephalad-caudad displacement) were developed and used. RESULTS: Fifteen patients with clavicle fractures initially displaced less than 2 cm and treated nonoperatively underwent later surgery because of progressive displacement (14 diaphyseal and 1 lateral). Radiographs performed during the injury workup and at a mean of 14.8 days postinjury demonstrated that progressive deformity had taken place. Ten of 15 patients (67%) displayed progressive horizontal shortening. Average change in horizontal shortening between that of the injury radiographs and the repeat radiographs in this group was 14.3 mm (5.9-29 mm). Thirteen of 15 patients (87%) displayed progressive vertical translation. Eight of 15 patients (53%) displayed both progressive horizontal shortening and vertical translation. CONCLUSION: We have demonstrated that a significant proportion of clavicle fractures (27% of our operative cases over a 5-year period) are minimally displaced at presentation, but are unstable and demonstrate progressive deformity during the first few weeks after injury. Because of this experience, we recommend close monitoring of nonoperatively managed clavicular fractures in the early postinjury period. A prudent policy is to obtain serial radiographic evaluation for 3 weeks, even for initially, minimally displaced clavicle fractures. PMID- 21610440 TI - Complications and hardware removal after open reduction and internal fixation of humeral fractures. AB - BACKGROUND: The purpose of this study was to review internal fixation of humerus fractures using a large national database and assess the incidence of implant removal procedures based on patient characteristics. METHODS: The 2007 Nationwide Inpatient Sample was used to identify two different sets of patients: (1) all patients who received an open internal fixation procedure for a fracture of the upper end, shaft, or lower end of the humerus; and (2) all patients with a removal of implanted devices from the humerus. Patient variables included age, gender, race/ethnicity, median household income, patient geographic region, metropolitan location, and primary expected payor. The differences of characteristics between both groups were determined using chi, Fisher's exact, or unpaired t tests. RESULTS: Open reduction with internal fixation was reported in 7,391 patients. Hardware removals were reported in 751 patients who were determined to have an associated diagnosed complication. From these numbers, the "failure" removal rate as a percentage of the total number of procedures for the year was 10.2%. Nonunion (17.5%) and Mechanical Complication of the Implant (16.2%) were the most common complications. Both payor (p=0.0023) and age (p<0.0001) were found to have significantly different distributions among the open reduction with internal fixation and removal groups. CONCLUSION: These results suggest that the age of the patient and the patient's ability to pay may influence the likelihood of an implant removal procedure. The results will help identify patients who are at high risk for revision and who may benefit from preventative care. PMID- 21610441 TI - Removing a patient from the spine board: is the lift and slide safer than the log roll? AB - BACKGROUND: After spine board immobilization of the trauma victim and transport to the hospital, the patient is removed from the spine board as soon as practical. Current Advanced Trauma Life Support's recommendations are to log roll the patient 90 degrees, remove the spine board, inspect and palpate the back, and then log roll back to supine position. There are several publications showing unacceptable motion in an unstable spine when log rolling. METHODS: Cervical spine motion was evaluated during spine board removal. A C5 to C6 instability was surgically created in cadavers. A three-dimensional electromagnetic tracking system was used to assess motion between C5 and C6. The log roll was compared with a lift-and-slide technique. Throughout the log roll procedure, manual inline cervical stabilization was provided by a trained individual in a series of trials. In other trials, the lift-and-slide technique was used. In the final stage, the amount of motion generated was assessed when the spine board removal techniques were completed by experienced and novice persons in maintaining inline stabilization of the head and neck. RESULTS: Motion between C5 and C6 was reduced during the lift-and-slide technique in five of six parameters. The reduction was statistically significant in four parameters. When performing the log roll, motion was not reduced with increased head holder experience. CONCLUSIONS: Spine boards can be removed using a lift-and-slide maneuver with less motion and potentially less risk to the patient's long-term neurologic function than expected using the log roll. PMID- 21610442 TI - Treatment of segmental bone and soft-tissue defects of the forearm with the free osteocutaneous lateral arm flap. AB - BACKGROUND: Complex defects of the forearm often require microvascular reconstruction with osteocutaneous free flaps to salvage the limb. In this review, we report our experience with the use of the free osteocutaneous lateral arm flap to reconstruct such defects in four patients. METHODS: Three male patients with osseous defects of the ulna and one defect of the radius with associated soft-tissue defects were treated with a free osteocutaneous lateral arm flap between 2004 and 2007. The indications for the procedure included posttraumatic osteitis (3) and bone with soft-tissue defects after trauma (1). We evaluated the patients with respect to postoperative results by evaluating the range of motion, pain, strength, and score on the disabilities of the arm, shoulder, and hand questionnaire. Donor-site morbidity was also documented. RESULTS: The average length of segmental bone defects was 5.75 cm. The average dimension of the skin paddle was 99.5 cm. The average duration of follow-up was 43.3 months. All bone flaps healed without nonunion; the fasciocutaneous flaps healed without complications. No problems related to microanastomoses were found. Functional results were very satisfactory; disabilities of the arm, shoulder, and hand questionnaire scores showed a median of 5.8 (0-10.8). All patients had returned to their preinjury occupations. CONCLUSION: This analysis demonstrates that the free osteocutaneous lateral arm flap is an effective treatment for combined segmental osseous and soft-tissue defects of the forearm that are caused by osteitis and trauma. PMID- 21610443 TI - Vascular trauma at a crossroads. PMID- 21610444 TI - Treatment of sternoclavicular joint dislocations: a systematic review of 251 dislocations in 24 case series. PMID- 21610445 TI - The ultimate in genitourinary damage control: minimally invasive management of synchronous grade 4 and 5 bilateral penetrating renal injuries. PMID- 21610446 TI - Endovascular repair of a traumatic renal artery injury. PMID- 21610448 TI - Does mobile medical team involvement influence on-scene times and outcome in trauma patients? PMID- 21610449 TI - Is thromboelastography useful to achieve an fresh frozen plasma: packed red blood cell transfusion ratio more than or equal to 1:1.5? PMID- 21610450 TI - What is the optimal criteria for intensive care unit admission? PMID- 21610451 TI - Trauma surgeon or emergency medicine physician: who is the best for the patient? PMID- 21610452 TI - Trauma surgeon or emergency medicine specialist is the wrong question. PMID- 21610455 TI - Director of residency training, do your job! PMID- 21610456 TI - Potentially useful markers for desmoplastic melanoma: an analysis of KBA.62, p AKT, and ezrin. AB - Desmoplastic melanoma (DM) represents only a small portion of newly diagnosed melanoma cases but can be a significant diagnostic challenge for dermatopathologists. Immunohistochemical stains are often useful to confirm the diagnosis; however, DM is notorious for not expressing most of the melanocytic markers other than S100. Recent studies have suggested several new markers, which may be promising in the diagnosis of DM. KBA.62 is a relatively new antimelanoma monoclonal antibody, which has not been well characterized in DM. Ezrin and p-Akt are additional markers, which have been shown to be involved in cell survival and proliferation. We collected 12 cases of DM and 18 cases of other lesions that could be included in the differential diagnosis. The H&E sections were reviewed, and immunohistochemical stains for KBA.62, p-AKT, and Ezrin were performed. Seventy-five percent of the DM cases (9 of 12) demonstrated positive staining (>5% of tumor cells staining) with KBA.62, with an average of 39% of cells staining. One hundred percent of the DM cases (12 of 12) demonstrated positive staining with Ezrin, with an average of 49% of tumor cells staining. Seventy-five percent of the DM cases (9 of 12) demonstrated positive staining with p-Akt, with an average of 49% of cells staining. KBA.62 and Ezrin demonstrated statistically significant increased staining of DM cases compared with the other lesions (P = 0.05 and P = 0.007, respectively), although it was not useful in distinguishing DM versus malignant peripheral nerve sheath tumor, whereas p-Akt showed no significant differences in staining between DM and the other cases. These findings suggest that KBA.62 may be a useful marker in confirming the diagnosis of DM. PMID- 21610457 TI - Immunohistochemical double stains against Ki67/MART1 and HMB45/MITF: promising diagnostic tools in melanocytic lesions. AB - Distinction between benign and malignant melanocytic lesions may be difficult by today's methods, even for highly skilled dermatopathologists, emphasizing the need for improved diagnostic tools. We have studied the discriminative abilities of immunohistochemical (IHC) double stains using the IHC markers Ki67 combined with MART1, and HMB45 combined with MITF. Paraffin-embedded tissue sections from 50 melanomas and 78 benign nevi were stained using a simple simultaneous IHC double staining technique. Both simple semiquantitative estimates of the immunopositivity in the deepest third of the lesions and full-scale quantitative measurements of the Ki67 and HMB45 indices were performed, and scores for melanomas and nevi were compared. The differences between melanomas and nevi were significant (P < 0.0001) using either analysis or stain. The misclassification rates for melanomas and nevi were generally lower for Ki67/MART1 stains than for HMB45/MITF stains. In the simple semiquantitative Ki67/MART1 analysis, the misclassification rates were 6% (2%-17%) for melanomas and 12% (6%-21%) for nevi. In full-scale quantitative analysis the corresponding rates were 4% (1%-14%) and 8% (4%-16%), and by combining Ki67 and HMB45 indices, the misclassification rates were 0% (0%-7%) for melanomas and 13% (7%-22%) for nevi. We conclude that both semiscale and fullscale quantitative analyses of Ki67/MART1 stains are valuable diagnostic tools to distinguish melanomas and nevi with a large degree of certainty. The HMB45/MITF stains may serve as adjuncts to predict malignancy and the diagnostic potential of combining the HMB45 and Ki67 indices are promising. The IHC double stains may potentially reduce misinterpretations of melanomas in histopathology. PMID- 21610460 TI - Sir Humphry Davy, Bart., from Lady Davy. PMID- 21610461 TI - The "reckless" Humphry Davy of J. A. Paris. PMID- 21610462 TI - Davy's ease discovering elements and difficulty naming alumi(n)(i)um. PMID- 21610463 TI - The Davy safety lamp and "miner's lung". PMID- 21610464 TI - Inappropriate conclusion from meta-analysis of randomized controlled trials. PMID- 21610466 TI - Introduction for the advances in radiation therapy delivery: from the guest editors. PMID- 21610467 TI - Advances in imaging: target delineation. AB - Modern radiation oncology relies heavily on emerging technology. In this article, we review recent advances in target delineation as it applies to radiation treatment planning. We focus on the evidence to support methionine positron emission tomography use for target delineation in primary brain tumors, 2-deoxy-2 [(18)F] fluoro-D-glucose positron emission tomography use for target delineation for lung cancer and head and neck cancer, and the use of magnetic resonance imaging sequences for target delineation in prostate cancer. PMID- 21610468 TI - Image-guided positioning and tracking. AB - Radiation therapy aims at maximizing tumor control while minimizing normal tissue complication. The introduction of stereotactic treatment explores the volume effect and achieves dose escalation to tumor target with small margins. The use of ablative irradiation dose and sharp dose gradients requires accurate tumor definition and alignment between patient and treatment geometry. Patient geometry variation during treatment may significantly compromise the conformality of delivered dose and must be managed properly. Setup error and interfraction/intrafraction motion are incorporated in the target definition process by expanding the clinical target volume to planning target volume, whereas the alignment between patient and treatment geometry is obtained with an adaptive control process, by taking immediate actions in response to closely monitored patient geometry. This article focuses on the monitoring and adaptive response aspect of the problem. The term "image" in "image guidance" will be used in a most general sense, to be inclusive of some important point-based monitoring systems that can be considered as degenerate cases of imaging. Image-guided motion adaptive control, as a comprehensive system, involves a hierarchy of decisions, each of which balances simplicity versus flexibility and accuracy versus robustness. Patient specifics and machine specifics at the treatment facility also need to be incorporated into the decision-making process. Identifying operation bottlenecks from a system perspective and making informed compromises are crucial in the proper selection of image-guidance modality, the motion management mechanism, and the respective operation modes. Not intended as an exhaustive exposition, this article focuses on discussing the major issues and development principles for image-guided motion management systems. We hope these information and methodologies will facilitate conscientious practitioners to adopt image-guided motion management systems accounting for patient and institute specifics and to embrace advances in knowledge and new technologies subsequent to the publication of this article. PMID- 21610469 TI - Head and neck cancer as a model for advances in imaging prognosis, early assessment, and posttherapy evaluation. AB - Novel noninvasive functional imaging methods are necessary to predict therapeutic outcome and thereby improve the ability to properly select patients for treatment with both conventional and targeted therapies, to better evaluate therapeutic effectiveness during the early phases of treatment, and to enhance a priori risk assessment for treatment induced toxicity. Functional metabolic imaging typically involves pretreatment baseline magnetic resonance imaging (MRI) and/or positron emission tomographic (PET) scans and performance of subsequent scans during and/or after treatment. Imaging parameter changes are routinely attributed to the intervening therapy and clinical outcomes subsequently correlated with these changes. The physiologic parameter(s) that best correlate with clinical outcome and the relative utility of MRI versus PET are unknown, however. Furthermore, tumor vascular physiology and metabolic parameters are heterogeneous and dynamic processes. Large daily fluctuations often occur in the absence of treatment. The magnitude of this temporal variability is not established for MRI or for PET. Routine and meaningful clinical application of functional imaging requires understanding and quantification of the intrinsic variability of the underlying biologic processes and a demonstration that treatment-induced changes exceed intrinsic temporal variation. PMID- 21610470 TI - Advances in treatment techniques: arc-based and other intensity modulated therapies. AB - Treatment planning and radiation delivery techniques have advanced significantly during the past 2 decades. The development of the multileaf collimator has changed the scope of radiotherapy. The dynamic conformal arc technique emerged from traditional cone-based conformal arc therapies, which aim to improve target dose uniformity and reduce normal tissue doses. With dynamic conformal arc, the multileaf collimator aperture is shaped dynamically to conform to the target. With the advent of intensity-modulated radiotherapy (IMRT), the concept of arc therapy in combination with IMRT has enabled better-quality dose distributions and more efficient delivery. Helical tomotherapy has been developed to treat targets sequentially by modulating the beam intensity in each "slice" of the patient. Helical tomotherapy offers improved dose distributions for complicated treatments, such as whole-body radiation. Intensity-modulated arc therapy has been studied to modulate fluences in a cone beam rather than fan beam geometry to improve delivery efficiency. This article reviews arc-based IMRT, intensity modulated arc therapy, and helical tomotherapy techniques. We compare the dosimetric results reported in the literature for each technique in various treatment sites. We also review the application of these techniques in specialized clinical procedures including total marrow irradiation, simultaneous treatment of multiple brain metastases, dose painting, simultaneous integrated boost, and stereotactic radiosurgery. PMID- 21610471 TI - Advances in treatment techniques: stereotactic body radiation therapy and the spread of hypofractionation. AB - Radiation therapy (RT) is an essential component of the management of many cancers. Traditionally, a course of external bream RT often involved daily treatments for a duration of 6 weeks or longer in some instances. Now, however, emerging clinical evidence indicates that, for some common cancers, the total length of treatment can be substantially shortened, offering convenience to patients and opportunities for resource utilization efficiencies. This trend toward so-called hypofractionated RT has been supported by hypothesis-driven clinical research guided by a combination of radiobiological and clinical insights and technological enhancements. The present review presents the rationale behind and current status of hypofractionation for prostate, breast, and medically inoperable early stage lung cancer. PMID- 21610472 TI - Adaptive radiation therapy: technical components and clinical applications. AB - In current standard radiation therapy process, patient anatomy is represented by the snapshot of computed tomographic images at the simulation for treatment planning. However, patient anatomy during the treatment course is not static, and the changes can be in the order of centimeters. The goal of the adaptive radiation therapy (ART) is to measure and account these variations in the treatment process, so that the optimal planned dose distribution is the same as the final delivered dose distribution. The field of the ART is rapidly evolving. The implementation of the ART principle is built on technical components in 3 main areas: image guidance, dose verification, and plan adaptation. The purpose of this review was to present different ART methods currently developed and used by different investigators. PMID- 21610473 TI - A glimpse of the future: where will new combinations of diagnostics and therapies take us? AB - The field of radiation oncology has evolved, especially in the past 20 years. Advances in technology, particularly in computing power, software, and imaging, have fueled contributions to cancer care. It is currently fashionable to say that many of these advances have only served to increase costs of care without clear evidence of benefit, and certainly, efforts to evaluate the value of radiation oncology treatments are needed. However, it is undeniable that the future of radiation oncology depends on discovering such advances and to demonstrate that these increase the therapeutic index of treatment. Across the global radiation oncology community, investigations are proceeding in which innovative means are being used to achieve this goal. We review some of these novel methods to improve the therapeutic index of radiation therapy. PMID- 21610475 TI - Should LPNs be educated in hospitals? AB - Dr Welton's essay on the use of hospital clinical sites for the education of licensed practical nurse students is followed by Dr Hill's commentary. PMID- 21610476 TI - Should LPNs be educated in hospitals? Commentary from the editor of JONA, Dr Karen Hill. PMID- 21610477 TI - Physical activity and diet-focused worksite health promotion for direct care workers. PMID- 21610478 TI - Transformational leadership skills of successful nurse managers. PMID- 21610479 TI - Developing and testing a clinical information system evaluation tool: prioritizing modifications through end-user input. AB - OBJECTIVE: The objectives were to develop and validate the Information System Evaluation Tool (ISET), use feedback to modify the institution's clinical information system (CIS), and determine the modifications' success. BACKGROUND: The ability of a CIS to increase patient safety and care quality is dependent on its systems and processes. A survey was needed to provide the specificity necessary to make meaningful system improvements. METHODS: The ISET was pilot tested and revised before being administered before implementation of the CIS. It was administered at 2 times after implementation. The ISET was revised after analysis of the results, and comparisons were made between the times. RESULTS: The ISET is a valid and reliable instrument. Perceptions of the CIS initially decreased, but had significantly improved by 16 months after implementation. CONCLUSIONS: End-users must be convinced that the CIS supports their practice and improves care for adoption to be successful. The ISET measures these perceptions and highlights areas for improvement. PMID- 21610480 TI - Development of a professional nursing framework: the journey toward nursing excellence. AB - To achieve Magnet recognition designation, an organization must demonstrate a framework for nursing practice. However, successfully incorporating and sustaining frameworks and theories into practice are not easy undertakings. The authors describe how leaders and staff in a healthcare system created and implemented a conceptual framework for nursing practice to guide nursing practice for the system. PMID- 21610481 TI - Closing the RN engagement gap: which drivers of engagement matter? AB - OBJECTIVE: This study focused on the relationship between RNs' perceptions of drivers of engagement and their workplace engagement. BACKGROUND: In multiple studies, mostly not in healthcare, researchers found that employees engaged in their work are in the minority. This phenomenon is referred to as the engagement gap. METHODS: Drivers of engagement and levels of nurse engagement were measured among 510 RNs from a large urban academic university center. RESULTS: The greatest difference between engaged and not-engaged nurses was in the manager action index; the smallest difference was in the salary and benefits index. The passion-for-nursing index was the only significant driver related to RN levels of engagement when controlling for all the other drivers. CONCLUSION: Nurse managers play a critical role in promoting employee engagement. The nurses' passion for nursing is an important dimension of engagement. Salary and benefits were not primary drivers in employee engagement. PMID- 21610482 TI - Same-handed and mirrored unit configurations: is there a difference in patient and nurse outcomes? AB - OBJECTIVE: Despite growing awareness that hospital design can impact meaningful outcomes, the same-handed medical-surgical inpatient unit configuration has not been empirically investigated. This study measured differences in patient and nurse outcomes between the same-handed and mirrored unit configurations. BACKGROUND: It has been hypothesized that the same-handed unit configuration may contribute to operational efficiencies, fewer adverse events, and reduced noise levels. METHODS: A natural experiment of 8 medical-surgical inpatient units used 2 questionnaires developed for the study. The first questionnaire was available to registered nurses. The second was available to the nurses' patients. RESULTS: Compared with participants on the mirrored unit configuration, participants on the same-handed unit configuration reported lower noise levels, better sleep quality, more frequent approaches to patients' right side, and improved satisfaction with organization of the workspace at patients' bedsides. The increased right-side approach was related to fewer instances of patients catching themselves from falling. CONCLUSION: The same-handed unit configuration benefits patient experience, patient safety, and operational outcomes. Before renovation or new construction of units, nurse executives should consider the advantages of a same-handed unit configuration. PMID- 21610483 TI - Promoting clinical inquiry and evidence-based practice: the sacred cow contest strategy. AB - Achieving and sustaining evidence-based practice (EBP) in an organization's practice culture can be challenging for administrators and educators. Brown's Sacred Cow Contest provides a creative strategy to promote clinical inquiry and generate interest in EBP. The author discusses how replication of the strategy in a large healthcare system successfully inspired nurses to question traditional nursing practices, yielding 118 contest entries. Teams of nurses are currently applying EBP process steps to confirm or change the reported practices. PMID- 21610484 TI - Implementing relationship-based care. AB - OBJECTIVE: The authors describe verbal and nonverbal caring behaviors of nurses before and after implementation of a model of Relationship-Based Care (RBC). Nurse turnover and patient satisfaction were evaluated to support the organizational commitment to RBC. BACKGROUND: To become foundational for all interactions, caring behaviors must be enculturated among nurses, colleagues (professionals and nonprofessionals), and organizational leaders. METHODS: An observational design describing verbal and nonverbal caring behaviors prior to implementation of RBC and at 3 and 12 months after implementation. RESULTS: Findings suggest that verbal and nonverbal caring behaviors increased. Behaviors were sustained at 1 year. Nurse turnover rates decreased from 9.4% to 1.9%. CONCLUSION: Observable caring behaviors and nurse turnover rates improved with the implementation of RBC. PMID- 21610485 TI - Cost and health outcomes associated with mandatory MRSA screening in a special care nursery. AB - PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) rates continue to rise and pose a threat to patient health and limited hospital resources. In 2007, Illinois passed a legislative mandate requiring active surveillance cultures to screen for MRSA in all patients in hospital intensive care units. However, professional guidelines do not support mandated universal surveillance cultures, and funding to cover screening costs was not included. The purpose of the study was to examine the costs (personnel, screening test, and supply) associated with the mandated universal MRSA screening and to examine the infant health-related outcomes and costs associated with implementing MRSA screening in a special care nursery. SUBJECTS: Personnel-54 observations of staff members in a community based hospital in a large midwestern city. Infants-445 infants admitted from January 2008 through January 2009. METHODS: Time and motion (related to screening activities by registered nurses) based on observations of staff during MRSA screenings, and abstraction of health and cost data from the infant log, infant medical records, and financial reports. MAIN OUTCOME MEASURES: Costs (laboratory tests, personnel, and supplies) and infant health outcomes. DESIGN: A prospective descriptive study. RESULTS: Mandatory screening leads to increased costs, problems related to false-positives, and unintended consequences (eg, decision whether to treat non-MRSA organisms identified on screening cultures, possibility of legal implications, adverse family psychosocial affects, and questionable validity of the polymerase chain reaction test). The average total costs of laboratory, supply, and personnel were $15,270.12 ($34.31 per infant or $19.58 per screen). CONCLUSIONS: A screening test for MRSA with a high positive predictive value, low cost, and quick turnaround (<24 hours) is greatly needed for neonates. Our findings indicate that mandatory universal MRSA screening is not warranted when the incidence of MRSA is low. Just as health care providers require evidence when determining best practices, legislators should require adequate evidence before passing policy. PMID- 21610486 TI - Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants, children, and adolescents. AB - OBJECTIVE: To describe the pharmacokinetics of atazanavir (ATV) and ritonavir boosted ATV (ATV/r) in children aged 91 days to 21 years. DESIGN: A phase I/II, open-label, multicenter study of once-daily ATV and ATV/r as part of combination antiretroviral treatment in HIV-infected treatment-experienced and treatment naive children. SETTING: Sites in the United States and South Africa. PARTICIPANTS: One hundred and ninety-five children enrolled; 172 had evaluable ATV pharmacokinetics on day 7. INTERVENTION: Children were entered in age, dose, and formulation (powder or capsule) cohorts. Intensive pharmacokinetic sampling occurred 7 days after starting ATV. ATV doses were increased or decreased if the 24-h area under the concentration time curves (AUC0-24hr) were less than 30 or more than 90 MUg * h/ml, respectively. MAIN OUTCOMES: Cohorts satisfied protocol defined pharmacokinetic criteria if the median ATV AUC0-24hr was 60 MUg * h/ml or less, and AUC0-24hr and ATV concentrations 24-h postdose (C24) were more than 30 MUg * h/ml and at least 60 ng/ml, respectively, in at least 80% of the children, with no individual AUC0-24hr less than 15 MUg * h/ml. RESULTS: Unboosted ATV capsules satisfied pharmacokinetic criteria at a dose of 520 mg/m for those aged more than 2 to 13 years or less and 620 mg/m for those aged more than 13 to 21 years or less. ATV/r capsules satisfied criteria at a dose of 205 mg/m for those aged more than 2 to 21 years or less. ATV/r powder satisfied criteria at a dose of 310 mg/m for those aged more than 2 to 13 years or less, but pharmacokinetics in those aged 2 years or less were highly variable. CONCLUSION: Body surface area determined doses of ATV capsules and of ATV/r powder and capsules provide ATV exposures in children of more than 2 years that approximate concentrations in adults receiving ATV/r. PMID- 21610487 TI - The forgotten half of the equation: randomized controlled trial of a male invitation to attend couple voluntary counselling and testing. AB - OBJECTIVE: Increased male participation in antenatal care and uptake of couple voluntary counselling and testing (VCT) for HIV could reduce horizontal and vertical HIV transmission in sub-Saharan Africa. METHODS: Randomized controlled trial to compare pregnant women's acceptance of written invitations for VCT and pregnancy information sessions (PISs) - the control group - for their male sexual partners (MSPs) and uptake of VCT among these pregnancy partners in Khayelitsha, South Africa. RESULTS: All women in the study accepted the invitation letters and agreed to invite their pregnancy partners to attend for VCT or PIS as requested. Thirty-five percent (175 of 500) pregnant women given VCT invitations for their partners brought their MSPs for antenatal clinic visit compared with 26% (129 of 500) given PIS invitations [relative risk (RR) 1.36, 95% confidence interval (CI) 1.12-1.64, P = 0.002]. Thirty-two percent (161 of 500) MSPs in the VCT arm underwent HIV testing compared with 11% (57/500) in the PIS arm (RR 2.82, 95% CI 2.14-3.72, P < 0.001). The proportions of women and men reporting unprotected sex during the pregnancy were lower in the MSP VCT arm than in the MSP PIS arm - 25 versus 81% (RR 0.30, 95% CI 0.22-0.42, P < 0.001) and 26 versus 76% (RR 0.34, 95% CI 0.25-0.47, P < 0.001), respectively. No differences were seen in intimate partner violence. CONCLUSION: Providing pregnant women with a written invitation for their partners increased male participation in antenatal care and uptake of couple VCT in a township in Cape Town, South Africa where community sensitization was conducted and antiretroviral therapy was available. PMID- 21610488 TI - TLR2-induced cytokine responses may characterize HIV-infected patients experiencing mycobacterial immune restoration disease. AB - OBJECTIVES: Most HIV patients who experience Mycobacterium tuberculosis associated immune restoration disease (TB IRD) display elevated interferon-gamma (IFNgamma) responses against mycobacterial antigens, but these can occur without an IRD. Recognition of mycobacteria-associated molecular patterns through toll like receptors (TLRs) on dendritic cells and monocytes induces cytokine production. Here, we investigate TLR-induced responses in IRD. DESIGN: Peripheral blood mononuclear cells (PBMCs) were collected at approximately weeks 0, 6, 12, 24 and 48 after antiretroviral therapy from five patients experiencing TB IRD, nine matched non-IRD patients and 15 healthy controls. METHODS: IFNgamma production by PBMC stimulated with protein purified derivative (PPD) was assessed by ELISpot. TLR2 expression on myeloid dendritic cells (mDCs) and monocytes was assessed by flow cytometry. TNFalpha, IL-12p40 and IL-10 were measured by ELISA in 24-h cultures of PBMC with lipomannan (mycobacteria-derived TLR2 agonist). RESULTS: TLR2 expression on mDC and monocytes was higher in patients than controls at baseline (P < 0.005). TLR2 expression decreased to normal levels on mDC by week 12, but remained higher on monocytes at week 24 (P = 0.02). At week 24, IRD patients showed higher IFNgamma responses to PPD (P = 0.02), TLR2 expression on monocytes (P = 0.006) and lipomannan-induced TNFalpha production (P = 0.016) than non-IRD patients. Lipomannan-induced TNFalpha and IL-12p40 responses paralleled TB IRD in the patients with high TLR2 expression. IL-10 levels did not associate with IRD. CONCLUSION: TLR2-induced pro-inflammatory cytokines by dendritic cells or monocytes may contribute to the pathogenesis of mycobacterial IRD. PMID- 21610491 TI - Educational interventions by pharmacists to patients with chronic pain: systematic review and meta-analysis. AB - OBJECTIVE: We hypothesized that educational interventions delivered by pharmacists to patients with chronic pain might improve pain-related outcomes and sought to establish "proof of concept" for this hypothesis. METHODS: We searched electronic databases and published literature for randomized studies that examined an educational intervention in relation to the management of chronic pain that was delivered by a pharmacist to an adult patient. Four studies were included that randomized 400 patients with chronic pain and which followed up patients between 1 and 16 weeks. RESULTS: Patients receiving these interventions experienced statistically significant benefits in the following outcomes compared with controls: a reduction in average pain intensity of 0.5 on a 0 to 10 rating scale, a reduction in adverse effects by more than 50%, and an improvement in satisfaction with treatment equivalent to approximately 1 point on a 0 to 10 rating scale. The interventions neither had effect on reducing interference from pain on daily life, nor on improving self-efficacy. DISCUSSION: Pharmacist delivered educational interventions seem to reduce adverse events and improve satisfaction, but their clinical benefit on pain intensity is debatable. Our analysis suggests that the role of pharmacists may be important but a deeper understanding and evaluation of the active components of these interventions is needed within clinical trials before wider implementation into clinical practice can be recommended. PMID- 21610490 TI - CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain. AB - In light of the adverse side-effects of opioids, cannabinoid receptor agonists may provide an effective alternative for the treatment of cancer pain. This study examined the potency and efficacy of synthetic CB1 and CB2 receptor agonists in a murine model of tumor pain. Intraplantar injection of the CB1 receptor agonist arachidonylcyclopropylamide (ED(50) of 18.4 MUg) reduced tumor-related mechanical hyperalgesia by activation of peripheral CB1 but not CB2 receptors. Similar injection of the CB2 receptor agonist AM1241 (ED50 of 19.5 MUg) reduced mechanical hyperalgesia by activation of peripheral CB2 but not CB1 receptors. Both agonists had an efficacy comparable with that of morphine (intraplantar), but their analgesic effects were independent of opioid receptors. Isobolographic analysis of the coinjection of arachidonylcyclopropylamide and AM1241 determined that the CB1 and CB2 receptor agonists interacted synergistically to reduce mechanical hyperalgesia in the tumor-bearing paw. These data extend our previous findings that the peripheral cannabinoid receptors are a promising target for the management of cancer pain and mixed cannabinoid receptor agonists may have a therapeutic advantage over selective agonists. PMID- 21610489 TI - Tuberculosis among HIV-positive patients across Europe: changes over time and risk factors. AB - OBJECTIVE: To describe temporal changes in the incidence rate of tuberculosis (TB) (pulmonary or extrapulmonary) among HIV-positive patients in western Europe and risk factors of TB across Europe. METHODS: Poisson regression models were used to determine temporal changes in incidence rate of TB among 11,952 patients from western Europe (1994-2010), and to assess risk factors for TB among 12,673 patients from across Europe with follow-up after 2001. RESULTS: Two hundred and seventy-seven TB events occurred during 84,221 person-years of follow-up (PYFU) in western Europe. The incidence rate declined from 1.91 [95% confidence interval (CI) 1.51-2.37)] in 1994-1995 to 0.12 (0.07-0.21)/100 PYFU in 2002-2003, and remained stable thereafter. After January 2001, 159 TB events were diagnosed; 65 cases in western Europe and 94 cases in eastern Europe; resulting in incidence rates of 0.12 (0.09-0.14) and 0.65 (0.52-0.79)/100 PYFU, respectively. In multivariable analysis, incidence rate of TB was approximately four-fold higher in eastern Europe compared with western Europe [incidence rate ratio (IRR) 4.25 (2.78-6.49), P < 0.001]. There were no significant temporal changes after 2001 and risk factors did not differ significantly between eastern Europe and western Europe. Lower CD4 cell counts, higher HIV-RNA levels, male sex, intravenous drug usage and African origin were all associated with higher risk of TB. CONCLUSION: Incidence rates of TB in western Europe remained at a very low and stable level since 2001. After 2001, patients in eastern Europe were at substantially higher risk of TB than in western Europe. TB is of great concern in HIV-positive patients, especially in areas with high TB prevalence, high levels of immigration from TB-endemic regions, and with suboptimal access to combination antiretroviral therapy. PMID- 21610492 TI - Role of vitamin D levels and vitamin D receptor polymorphisms in relation to coronary artery disease: the Indian atherosclerosis research study. AB - OBJECTIVE: Assessment of association between plasma vitamin D levels, vitamin D receptor (VDR) gene polymorphisms, and coronary artery disease (CAD) in a predisposed Asian Indian cohort. MATERIALS AND METHODS: Patients with angiographically proven CAD having age at onset less than 60 years for men and less than 65 years for women were recruited in the Indian Atherosclerosis Research Study and treated as cases (N=287), whereas asymptomatic healthy matched individuals were enrolled from the population, who showed normal electrocardiogram and acted as controls (N=241). Plasma [vitamin D (25-hydroxy vitamin D)] levels were measured by enzyme-linked immunosorbent assay, and five haplotype-tagging single nucleotide polymorphisms were genotyped by ABI Taqman assays. RESULTS: Mean vitamin D levels were significantly lower in patients with CAD (10.59 ng/ml) than in controls (11.82 ng/ml) (P=0.036). Vitamin D showed protective association against CAD (odds ratio: 0.54, 95% confidence interval: 0.34-0.84, P=0.007) after adjusting for conventional risk factors. Patients in the first vitamin D quartile showed 2.54 times greater risk for CAD than those in the fourth quartile. There was no significant association of VDR single nucleotide polymorphisms/haplotypes with either vitamin D or CAD. Vitamin D levels were significantly lower in vegetarians than in nonvegetarians (P=0.048) and showed inverse association with body weight (P=0.054), triglyceride (P=0.031), and body mass index (P=0.020). CONCLUSION: Low vitamin D level was associated with an enhanced risk for incident CAD. VDR genotypes did not show any association with either vitamin D levels or CAD. PMID- 21610493 TI - Novel mechanisms for NaCl reabsorption in the collecting duct. AB - PURPOSE OF REVIEW: There is consensus that the abnormal retention of sodium by the kidney is the most important pathophysiological event in hypertension. The present review summarizes our current understanding of sodium reabsorption in the distal nephron. RECENT FINDINGS: The antihypertensive effect of thiazides is thought to be mediated by inhibiting Na+ uptake via the NaCl cotransporter NCC in the distal convoluted tubule. Although it was known that thiazide-sensitive Na+ reabsorption in isolated cortical collecting ducts can occur independently of the epithelial Na+ channel ENaC, its molecular correlate was unresolved. It was absent in isolated cortical collecting ducts of mice with a targeted disruption of the Na+-driven chloride/bicarbonate exchanger NDCBE suggesting that this pathway involves apical Na+ uptake into intercalated cells via the Na+-driven anion-exchanger NDCBE (SLC4A8). SUMMARY: The finding that SLC4A8-dependent thiazide-sensitive Na+ reabsorption occurs in the cortical collecting duct challenges our current model of how thiazides mediate their antihypertensive action and identifies a potentially new target for antihypertensive strategies. PMID- 21610494 TI - Role of SPAK and OSR1 signalling in the regulation of NaCl cotransporters. AB - PURPOSE OF REVIEW: Sodium and chloride transport play a fundamental role in many physiological processes. In the kidney, sodium secretion and reabsorption are essential to maintain the extracellular volume and, thus, blood pressure (BP). In vascular smooth muscle, it is important for contractility and in the nervous system for the functioning of GABAergic neurons. Hence, the emergence of a WNK/SPAK/OSR1 kinase cascade that activates NaCl cotransporters has widespread physiological implications. This review gives an overview of the actions of SPAK and OSR1 kinases on NaCl cotransporters and highlights their possible therapeutic potential. RECENT FINDINGS: Evidence has emerged from in-vitro phosphorylation assays that WNK kinases can activate SPAK and OSR1 kinases by phosphorylation of a key Thr residue in their catalytic domains. Once activated, SPAK and OSR1 in turn activate members of the SCL12A family of solute carriers by phosphorylation of conserved Ser/Thr residues in the N-terminal domain of these carrier proteins. The importance of this pathway has recently emerged from studies on mice that lack a catalytically active SPAK enzyme. These models are strikingly hypotensive with marked reduction in the phosphorylation of Na+/Cl- cotransporter (NCC) in the kidney, and reduced Na+/K+/2Cl- cotransporter (NKCC1) phosphorylation in the vessel wall. SUMMARY: SPAK and OSR1 kinases regulate SCL12A transporters with important physiological effects for sodium homeostasis by the kidney, aortic contractility and neuronal excitability. In vivo, SPAK plays a major role in the regulation of blood pressure and represents a potential target for the development of novel diuretics. PMID- 21610495 TI - Mouse models to study kidney development, function and disease. AB - PURPOSE OF REVIEW: The mouse is the most widely used model organism to study gene function in the kidney in vivo. Here we review recent advances in technologies to manipulate the mouse genome and gene function to study renal biology. We discuss strengths and weaknesses of the approaches and provide examples in which they have been used to address renal questions. In addition, we provide a summary of the available resources of mouse tools and gene-targeting consortia. RECENT FINDINGS: Although conventional gene-targeting and spontaneous genetic mutations in mice have provided great insights into kidney function over several decades, the addition of powerful renal-specific gene-targeting tools and the advent of RNA technologies to manipulate gene function in vivo allow investigators to address research questions more precisely in the laboratory. Together with the establishment of multiple international consortia to target all the genes in the mouse genome and the development of gene trap and N-ethyl-N-nitrosourea resources, genetic manipulation in mice has become more efficient. SUMMARY: The availability of newer technologies and tremendous resources for mouse strains and reagents ensures that the mouse will remain a key model organism to study renal function. PMID- 21610496 TI - The Drosophila nephrocyte. AB - PURPOSE OF REVIEW: The functioning kidney requires proper organization in multiple cell types that mediate filtration and removal of wastes. Interest has increasingly focused on the podocyte as an important mediator of kidney function; defects in podocyte function likely mediate a broad palate of kidney dysfunctions. Here I explore recent work that establishes the Drosophila nephrocyte as a useful model for podocyte function and dysfunction. RECENT FINDINGS: Although described many decades in the past, recent evidence has emphasized important similarities in the molecules that construct the 'nephrocyte diaphragm' and its vertebrate cousin the 'podocyte diaphragm'. For example, loss of Nephrin and its associated proteins lead to collapse of these structures and loss of proper filtration. SUMMARY: These data emphasize both differences between the podocyte and nephrocyte and also useful similarities. These similarities provide the promise of bringing Drosophila genetics--strongly successful in other disciplines--to the complex problem of how podocyte dysfunction leads to disease. To further explore this point I discuss work on Nephrin in a better understood tissue, the Drosophila eye, in which the role of Nephrin and its connection to actin dynamics is under intense study. PMID- 21610497 TI - CYP24A1 and kidney disease. AB - PURPOSE OF REVIEW: Patients with chronic renal disease have elevated serum phosphate levels, elevated fibroblast-like growth factor 23 (FGF-23), and declining vitamin D status. These changes are related and may be responsible for elevated 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) and dysfunctional vitamin D metabolism. This review focuses on the biochemistry and pathophysiology of CYP24A1 and the utility of blocking this enzyme with CYP24A1 inhibitors in chronic kidney disease (CKD) patients. RECENT FINDINGS: CYP24A1 is the cytochrome P450 enzyme that catalyzes the conversion of 25-hydroxyvitamin D3 (25-OHD3) and its hormonal form, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], into 24-hydroxylated products targeted for excretion. The CYP24A1-null phenotype is consistent with the catabolic role of CYP24A1. A number of polymorphisms of CYP24A1 have recently been identified. New data from the uremic rat and humans suggest that dysfunctional vitamin D metabolism is due to changes in CYP24A1 expression caused by phosphate and FGF-23 elevations. SUMMARY: Changes in serum phosphate and FGF 23 levels in the CKD patient increase CYP24A1 expression resulting in decreased vitamin D status. Vitamin D deficiency may exacerbate defective calcium and phosphate homeostasis causing renal osteodystrophy and contribute to the other complications of renal disease. These findings argue for increased focus on correcting vitamin D deficiency in CKD patients by blocking CYP24A1 activity. PMID- 21610498 TI - Intensity coding in electric hearing: effects of electrode configurations and stimulation waveforms. AB - OBJECTIVES: Current cochlear implants typically stimulate the auditory nerve with biphasic pulses and monopolar electrode configurations. Tripolar stimulation can increase spatial selectivity and potentially improve place pitch related perception but requires higher current levels to elicit the same loudness as monopolar stimulation. The present study combined delayed pseudomonophonasic pulses, which produce lower thresholds, with tripolar stimulation in an attempt to solve the power-performance tradeoff problem. DESIGN: The present study systematically measured thresholds, dynamic range, loudness growth, and intensity discrimination using either biphasic or delayed pseudomonophonasic pulses under both monopolar and tripolar stimulation. Participants were five Clarion cochlear implant users. For each subject, data from apical, middle, and basal electrode positions were collected when possible. RESULTS: Compared with biphasic pulses, delayed pseudomonophonasic pulses increased the dynamic range by lowering thresholds while maintaining comparable maximum allowable levels under both electrode configurations. However, delayed pseudomonophonasic pulses did not change the shape of loudness growth function and actually increased intensity discrimination limens, especially at lower current levels. CONCLUSIONS: The present results indicate that delayed pseudomonophonasic pulses coupled with tripolar stimulation cannot provide significant power savings nor can it increase the functional dynamic range. Whether this combined stimulation could improve functional spectral resolution remains to be seen. PMID- 21610499 TI - Diabetes prevalence in populations of South Asian Indian and African origins: a comparison of England and the Netherlands. AB - BACKGROUND: We determined whether the overall lower prevalence of type II diabetes in England versus the Netherlands is observed in South-Asian-Indian and African-Caribbean populations. Additionally, we assessed the contribution of health behavior, body size, and socioeconomic position to observed differences between countries. METHODS: Secondary analyses of population-based standardized individual-level data of 3386 participants were conducted. RESULTS: Indian and African-Caribbean populations had higher prevalence rates of diabetes than whites in both countries. In cross-country comparisons (and similar to whites), Indians residing in England had a lower prevalence of diabetes than those residing in the Netherlands; the prevalence ratio (PR) was 0.35 (95% confidence interval = 0.22 to 0.55) in women and 0.74 (0.50 to 1.10) in men after adjustment for other covariates. Among people of African descent as well, diabetes prevalence was lower in England than in the Netherlands; for women, PR = 0.43 (0.20 to 0.89) and for men, 0.57 (0.21 to 1.49). CONCLUSIONS: : The increasing prevalence of diabetes after migration may be modified by the context in which ethnic minority groups live. PMID- 21610500 TI - Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. AB - BACKGROUND: Causes of autism are unknown. Associations with maternal nutritional factors and their interactions with gene variants have not been reported. METHODS: Northern California families were enrolled from 2003 to 2009 in the CHARGE (CHildhood Autism Risks from Genetics and Environment) population-based case-control study. Children aged 24-60 months were evaluated and confirmed to have autism (n = 288), autism spectrum disorder (n = 141), or typical development (n = 278) at the University of California-Davis Medical Investigation of Neurodevelopmental Disorders Institute using standardized clinical assessments. We calculated adjusted odds ratios (ORs) for associations between autism and retrospectively collected data on maternal vitamin intake before and during pregnancy. We explored interaction effects with functional genetic variants involved in one-carbon metabolism (MTHFR, COMT, MTRR, BHMT, FOLR2, CBS, and TCN2) as carried by the mother or child. RESULTS: Mothers of children with autism were less likely than those of typically developing children to report having taken prenatal vitamins during the 3 months before pregnancy or the first month of pregnancy (OR = 0.62 [95% confidence interval = 0.42-0.93]). Significant interaction effects were observed for maternal MTHFR 677 TT, CBS rs234715 GT + TT, and child COMT 472 AA genotypes, with greater risk for autism when mothers did not report taking prenatal vitamins periconceptionally (4.5 [1.4-14.6]; 2.6 [1.2-5.4]; and 7.2 [2.3-22.4], respectively). Greater risk was also observed for children whose mothers had other one-carbon metabolism pathway gene variants and reported no prenatal vitamin intake. CONCLUSIONS: Periconceptional use of prenatal vitamins may reduce the risk of having children with autism, especially for genetically susceptible mothers and children. Replication and mechanistic investigations are warranted. PMID- 21610502 TI - Short thyromental distance is a surrogate for inadequate head extension, rather than small submandibular space, when indicating possible difficult direct laryngoscopy. AB - CONTEXT: Airway research in anaesthesia shows that the thyromental distance (TMD) as a predictor of difficult intubation is subject to variable sensitivity and specificity. Recently, its value in this regard has been questioned with calls for a redefinition of its role. OBJECTIVE(S): To define the role of TMD as a predictor of possible difficult laryngoscopy. DESIGN: A prospective observational study. SETTING: A tertiary university teaching hospital. PATIENTS OR OTHER PARTICIPANTS: Two hundred and thirty-five consecutive patients (137 men), planned for endotracheal intubation anaesthesia, were enrolled in the study. Those who were edentulous, or had facial asymmetry, teeth protrusion, limited mouth opening, history of head and/or neck radiation therapy or any disorder, were excluded. Nobody was excluded once enrolled. INTERVENTION(S): Preoperative straight-line morphometric measurements of the mandible and submandibular space (SMS) were taken by a measuring device and used to form a three-dimensional model of SMS. Sagittal dimensions of the SMS that determine the TMD were derived using trigonometric laws. MAIN OUTCOME MEASURES: Direct laryngoscopic view, assessed by a senior anaesthetist and classified according to Cormack/Lehane classification. RESULTS: Thirty-two patients were reported to have 'limited laryngoscopic view'. The TMD had a sensitivity of 19% and a specificity of 97% as a predictor of laryngoscopic view. Among the factors that determine the magnitude of TMD, only the degree of head extension was significantly different between the two laryngoscopy groups. The other two factors (sagittal angulomental distance, representing mandibular growth, and sagittal angulothyroid distance, representing laryngeal descent in the neck) did not differ between the two groups. Also, the SMS volume did not differ between the two laryngoscopy groups. CONCLUSION: The role of the TMD in prediction of difficult laryngoscopy should be redefined from a variable representing the SMS volume to one acting as a surrogate for inadequate head extension. PMID- 21610501 TI - Discordance in national estimates of hypertension among young adults. AB - BACKGROUND: In the United States, where coronary heart disease (CHD) is the leading cause of mortality, CHD risk assessment is a priority and accurate blood pressure (BP) measurement is essential. METHODS: Hypertension estimates in the National Longitudinal Study of Adolescent Health (Add Health), Wave IV (2008)-a nationally representative field study of 15,701 participants aged 24-32-was referenced against NHANES (2007-2008) participants of the same age. We examined discordances in hypertension, and estimated the accuracy and reliability of blood pressure in the Add Health study. RESULTS: Hypertension rates (BP: >= 140/90 mm Hg) were higher in Add Health compared with NHANES (19% vs. 4%), but self reported history was similar (11% vs. 9%) among adults aged 24-32. Survey weights and adjustments for differences in participant characteristics, examination time, use of antihypertensive medications, and consumption of food/caffeine/cigarettes before blood pressure measurement had little effect on between-study differences in hypertension estimates. Among Add Health participants interviewed and examined twice (full and abbreviated interviews), blood pressure was similar, as was blood pressure at the in-home and in-clinic examinations conducted by NHANES III (1988 1994). In Add Health, there was minimal digit preference in blood pressure measurements; mean bias never exceeded 2 mm Hg; and reliability (estimated as intraclass correlation coefficients) was 0.81 and 0.68 for systolic and diastolic BPs, respectively. CONCLUSIONS: The proportion of young adults in NHANES reporting a history of hypertension was twice that with measured hypertension, whereas the reverse was found in Add Health. Between-survey differences were not explained by digit preference, low validity, or reliability of Add Health blood pressure data, or by salient differences in participant selection, measurement context, or interview content. The prevalence of hypertension among Add Health Wave IV participants suggests an unexpectedly high risk of cardiovascular disease among US young adults and warrants further scrutiny. PMID- 21610503 TI - Depression and essential health risk factors in surgical patients in the preoperative anaesthesiological assessment clinic. AB - BACKGROUND AND OBJECTIVE: Depression is common in patients with medical illness. However, little is known about frequency and clinical relevance of preoperative depression in surgical patients. The objective of this study was to investigate the frequency of depression, essential health risk factors and hospital length of stay (LOS) of patients in preoperative anaesthesiological assessment. METHODS: Patients were consecutively screened in the preoperative anaesthesiological assessment clinics. In total, 5429 patients gave written informed consent to perform a computerised self-assessment of lifestyle factors, including alcohol use, tobacco smoking, weight, physical status, physical exercise, sleeping disturbance, subjective health and sense of coherence (SOC). Depression was defined by a WHO-5 well-being score of 13 or less. LOS was obtained from the electronic patient management system. RESULTS: A clinically relevant depressive state was found in 29.7% of the patients. Patients with depression had a median LOS of 6.0 days as compared to patients with positive well-being who had a LOS of 4.8 days (P < 0.001). Worse subjective health, less physical exercise and experience of SOC, as well as more severe sleeping disturbances were independently and significantly associated with depression (P < 0.001). CONCLUSION: Clinically significant depressive states are frequent conditions in surgical patients of preoperative anaesthesiological assessment and are associated with an increased LOS. Different clinical pathways delivering adequate preoperative information according to the needs, considering subjective health and SOC of the patient as well as avoiding immobilisation and sleep disturbances during hospital stay should be considered. Long-term treatment programmes including brief intervention in the hospital and an outpatient concept should be offered. PMID- 21610504 TI - Quantitative analysis of the diffusion-weighted steady-state free precession signal in vertebral bone marrow lesions. AB - OBJECTIVES: : Diffusion-weighted steady-state free precession (DW-SSFP) sequences have shown great potential for the differential diagnosis of benign osteoporotic and malignant neoplastic vertebral compression fractures, which appear hypo- to isointense or hyperintense in DW-SSFP magnetic resonance imaging, respectively. In contrast to other diffusion weighting sequences, the DW-SSFP signal depends not only on the apparent diffusion coefficient (ADC), but also on the tissue relaxation times and sequence parameters. The purpose of the present study was to provide a detailed analysis of the DW-SSFP signal in benign and malignant vertebral lesions (VLs) and in vertebral bone marrow (VBM) to understand the observed signal alterations and their dependence on tissue and sequence parameters. MATERIALS AND METHODS: : Magnetic resonance imaging was performed in 40 patients with benign (n = 20) or malignant (n = 20) VLs to determine the fat fraction and tissue parameters (ADC, T1, T2, T2*) for both the water and fat signal. With these values, the DW-SSFP signal was simulated and compared with the measured signals for different diffusion gradients by determining the signal intensity ratio between the SSFP signals of the lesions and of normal-appearing VBM for both malignant and benign VLs. RESULTS: : The simulated DW-SSFP contrast agreed well with the measured contrast and provided a very good differentiation between benign osteoporotic and malignant VLs. ADCs were significantly different in both lesion types (malignant 1.36 vs. osteoporotic 1.77 * 10 mm/s); however, the observed contrast differences were caused predominantly by an opposed-phase readout in combination with significantly different T2* values (malignant 22 vs. osteoporotic 14 ms) and fat fractions (malignant 3.9% vs. osteoporotic 12%) in the lesions as well as significantly different fat fractions in normal-appearing VBM (malignant 42% vs. osteoporotic 52%) of both patient groups. CONCLUSIONS: : Although the ADCs of the evaluated malignant and benign VLs showed highly significant differences, the influence of diffusion on the DW-SSFP signal contrast is relatively low compared with other tissue parameters due to the very complex signal mechanism of the SSFP sequence. Thus, the observed DW-SSFP signal contrast of different VLs (hypo-/isointense vs. hyperintense signal) is rather fat- and T2*-weighted than diffusion-weighted. The intermediate diffusion weighting of the applied SSFP sequence, however, helps to shift the different contrasts into a signal range that is easily visually accessible. PMID- 21610505 TI - Tracer kinetic model selection for dynamic contrast-enhanced computed tomography imaging of prostate cancer. AB - OBJECTIVES: To investigate the conditions under which the Tofts, extended Tofts, and adiabatic approximation to the tissue homogeneity (AATH) model are the optimal tracer kinetic models (TKMs) for the quantification of dynamic contrast enhanced (DCE) computed tomography (CT) examinations in prostate cancer. MATERIALS AND METHODS: This prospective study was approved by the local research ethics committee, and all patients gave written informed consent. A total of 29 patients (mean age, 69.1 years; range, 56-80 years) with biopsy-proven prostate cancer underwent a DCE-CT examination prior to radiation therapy. TKM parameter maps were calculated for each patient with the Tofts, extended Tofts, and AATH models. For each voxel, corrected Akaike information criterion values were calculated, taking into account both the goodness-of-fit and the number of model parameters. We consider the optimal model as the model with the lowest corrected Akaike information criterion. RESULTS: All 3 TKMs are the optimal models in part of the prostate. For individual patients, the AATH model was the optimal model in 25.0% to 88.9%, the Tofts in 2.7% to 71.8%, and the extended Tofts model in 0.7% to 68.7% of the prostate voxels. The Tofts model was optimal in low flow regions (<0.1 min-1), the extended Tofts model in regions with high flow (>0.4 min-1) and low transit time (<12 seconds), and the AATH model in the intermediate flow range (0.1-0.4 min-1). However, differences between the 3 models were small and TKM parameter estimates gave consistent results between the 3 models. CONCLUSIONS: All the 3 models gave reasonable fits of DCE-CT data from the prostate. In view of the small parameter range in which the Tofts and extended Tofts models outperform the AATH model, the latter seems the optimal model for quantification of DCE-CT data of the prostate. PMID- 21610506 TI - Porcine ex vivo liver phantom for dynamic contrast-enhanced computed tomography: development and initial results. AB - OBJECTIVES: : To demonstrate the feasibility of developing a fixed, dual-input, biologic liver phantom for dynamic contrast-enhanced computed tomography (CT) imaging and to report initial results of use of the phantom for quantitative CT perfusion imaging. MATERIALS AND METHODS: : Porcine livers were obtained from completed surgical studies and perfused with saline and fixative. The phantom was placed in a body-shaped, CT-compatible acrylic container and connected to a perfusion circuit fitted with a contrast injection port. Flow-controlled contrast enhanced imaging experiments were performed using 128-slice and 64-slice dual source multidetector CT scanners. CT angiography protocols were used to obtain portal venous and hepatic arterial vascular enhancement, reproduced over a period of 4 to 6 months. CT perfusion protocols were used at different input flow rates to correlate input flow with calculated tissue perfusion, to test reproducibility, and to determine the feasibility of simultaneous dual-input liver perfusion. Histologic analysis of the liver phantom was also performed. RESULTS: : CT angiogram 3-dimensional reconstructions demonstrated homogenous tertiary and quaternary branching of the portal venous system to the periphery of all lobes of the liver as well as enhancement of the hepatic arterial system to all lobes of the liver and gallbladder throughout the study period. For perfusion CT, the correlation between the calculated mean tissue perfusion in a volume of interest and input pump flow rate was excellent (R = 0.996) and color blood flow maps demonstrated variations in regional perfusion in a narrow range. Repeat perfusion CT experiments demonstrated reproducible time-attenuation curves, and dual-input perfusion CT experiments demonstrated that simultaneous dual input liver perfusion is feasible. Histologic analysis demonstrated that the hepatic microvasculature and architecture appeared intact and well preserved at the completion of 4 to 6 months of laboratory experiments and contrast-enhanced imaging. CONCLUSIONS: : We have demonstrated successful development of a porcine liver phantom using a flow-controlled extracorporeal perfusion circuit. This phantom exhibited reproducible dynamic contrast-enhanced CT of the hepatic arterial and portal venous system over a 4- to 6-month period. PMID- 21610508 TI - Ethical issues on defibrillator deactivation in end-of-life patients. PMID- 21610507 TI - Coronary multidetector computed tomographic angiography to evaluate coronary artery disease in liver transplant candidates: methods, feasibility and initial experience. AB - AIMS: In patients undergoing orthotopic liver transplantation (OLT), coronary artery disease (CAD), obstructive and nonobstructive, is associated with high morbidity and mortality. In OLT candidates, stress testing for detecting ischemia is often inaccurate, and this patient population often has relative contraindications for cardiac catheterization. The objective of this study was to describe the methods, assess the feasibility and determine the extent and severity of CAD in OLT candidates without a prior history of CAD using coronary multidetector computer tomographic angiography (MDCTA). METHODS: Sixty-five OLT candidates without known CAD underwent coronary MDCTA with dual source cardiac computed tomography (Siemens Definition). Coronary arteries were divided into 17 segments based on American Heart Association guidelines and evaluated independently by two blinded reviewers. Image quality of coronary MDCTA was assessed on a four-point Likert scale (0 = poor, 1 = fair, 2 = good, and 3 = excellent). Atherosclerotic lesions were evaluated for severity [mild (0-50%), moderate (51-70%), and severe (71-100%)], morphology, extent, location and consistency. RESULTS: Image quality was graded as good or excellent in 73.8%. In this cohort of OLT candidates without known CAD, 9% had normal coronary arteries, 58% had mild CAD and 34% had moderate to severe CAD. Plaque severity and burden scores were high. CONCLUSION: The prevalence of asymptomatic CAD is high in OLT candidates. Coronary MDCTA is feasible in OLT candidates and appears to be a useful technique to diagnose occult CAD in this patient population. PMID- 21610509 TI - A worrisome 'normal' ECG: implementation of multislice coronary CT scan in an integrated approach to ST-elevation suspected as not associated with acute coronary syndrome. PMID- 21610510 TI - Comprehensive assessment of a chronic total occlusion by dual-energy cardiac CT angiography with adenosine stress prior to retrograde percutaneous recanalization. PMID- 21610511 TI - Distinct role of electrocardiographic criteria in echocardiographic diagnosis of left ventricular hypertrophy according to age, in the general population: the Ikaria Study. AB - OBJECTIVE: The age-dependent performance of electrocardiographic (ECG) criteria was examined for left ventricular hypertrophy (LVH) prediction. METHODS: During 2009, 570 middle-aged (54 +/- 7 years, 45% men) and 507 elderly (75 +/- 6 years, 45% men) inhabitants of the Ikaria Island were studied. Seven ECG criteria were calculated (Sokolow-Lyon voltage and product, sex-specific Cornell voltage and product, Gubner-Ungerleider voltage, Lewis voltage and Framingham), whereas LVH was defined as left ventricular mass indexed for body surface area (BSA) at least 125 g/m in men and at least 110 g/m in women or left ventricular mass indexed for height 49 g/m or more in men and 45 g/m or more in women. RESULTS: The Framingham criteria had in hierarchical order the highest, although insignificant, sensitivity among the elderly individuals, either when LVH was indexed for BSA or for height (18.4 and 16.7%, respectively). Cornell voltage and product criteria had hierarchically the highest sensitivity among middle-aged participants, either when LVH was indexed for BSA (19.0 and 23.8%, respectively) or for height (17.2 and 20.3%, respectively). In the multiadjusted analysis applied in elderly participants, Cornell voltage, its product and Framingham criteria were associated with echocardiographic detection of LVH (indexed for BSA); however, when LVH was indexed for height, the Sokolow-Lyon and Framingham criteria were associated with LVH detection. In contrast, among middle-aged individuals, the Cornell product was the only ECG criterion that was associated with LVH detection (irrespective of indexation). CONCLUSION: Age should be taken into consideration in selection of appropriate ECG criteria for LVH detection. Indexation of left ventricular mass differentiates the diagnostic ability of ECG criteria, especially in older patients. PMID- 21610512 TI - Effect of the plasminogen-plasmin system on hypertensive renal and cardiac damage. AB - BACKGROUND: The plasminogen-plasmin system affects tissue fibrosis, presumably by interacting with metalloproteinases (MMPs) and macrophage recruitment. This study tests the influence of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPa) on angiotensin II-mediated hypertensive kidney and heart injury. METHOD: Hypertension was induced by continuous angiotensin II (Ang II) infusion via osmotic mini-pumps over 4 weeks. The effects of Ang II infusion were determined in mice lacking PAI-1 (PAI-1), mice lacking tPa (tPa), and wild type mice. Normotensive mice of the respective genotype served as controls. Blood pressure was recorded by continuous radiotelemetric intra-arterial measurements. RESULTS: Ang II infusion significantly enhanced arterial blood pressure in all groups. However, the increase in blood pressure was more pronounced in the tPa group. Albuminuria was highest in hypertensive wild-type compared to the other Ang II-infused groups. Hypertensive PAI-1 mice exhibited less glomerulosclerosis, higher nephrin immunostaining, and lower renal interstitial collagen I deposition. Gelatin zymography revealed higher activity of MMP-2 in hypertensive PAI-1, whereas no differences were observed in macrophage infiltration. tPa deficiency did not alter kidney fibrosis, although hypertensive tPa revealed less renal expression of fibrotic genes, less macrophage infiltration, and reduced MMP 2 activity. On the other hand, hypertension-induced fibrosis as well as macrophage infiltration in the heart was profoundly enhanced in PAI-1 mice. Fibrin staining revealed perivascular exudations in the myocardium of hypertensive PAI-1 suggesting vascular leakage. CONCLUSION: These findings underscore the unexpectedly complex role of plasminogen activation for hypertensive target organ damage. PMID- 21610515 TI - Optic atrophy in thalassemia intermedia. AB - A 21-year-old man with thalassemia intermedia presented with progressive decrease in vision and was found to have severe bilateral optic atrophy. Orbital and brain neuroimaging revealed massive diffuse expansion of the diploe of the craniofacial bones, narrowing of the optic canals, and expansion of hematopoietic tissue in the sellar region with compression of the optic chiasm. Although increased bone marrow is a well-known consequence of thalassemia, optic atrophy due to and such marked extramedullary expansion of hematopoietic tissue is a very rare phenomenon. Decompression of extramedullary hematopoietic tumors from thalassemia may be achieved with blood transfusions alone without the need for radiation or surgery. These findings suggest careful periodic ophthalmic examination of thalassemic patients. PMID- 21610516 TI - Effect of equated continuous and interval running programs on endurance performance and jump capacity. AB - We evaluated the effect of 2 different interval and continuous training programs on the maximal aerobic speed (MAS), time limit at MAS (T(lim)), and on the countermovement jump (CMJ). Twenty-two physically active men were randomly distributed in an interval training group (ITG), continuous training group (CTG), and control group. The CTG and ITG performed 2 different training programs (65-70 and 90-100% of the MAS for CTG and ITG, respectively) that consisted of 3 sessions per week during a period of 8 weeks with an identical external workload (% MAS * duration in minutes). The MAS, the T(lim) and the CMJ were recorded before and after the running training programs. The data analysis showed a significant and similar improvement (p < 0.01) of the MAS for both the ITG (5.8%) and CTG (8.3%). The T(lim) and CMJ did not change significantly for either group after the training period. Our results indicate that 8 weeks of continuous or interval running programs with externally equated load led to similar improvements in the MAS without changing T(lim) and CMJ performance in moderately trained nonrunners. PMID- 21610517 TI - The effects of static stretching on running economy and endurance performance in female distance runners during treadmill running. AB - Stretching can lead to decreased muscle stiffness and has been associated with decreased force and power production. The purpose of this study was to investigate the acute effects of static stretching (SS) on running economy and endurance performance in trained female distance runners. Twelve long distance female (30 +/- 9 years) runners were assessed for height (159.4 +/- 7.4 cm), weight (54.8 +/- 7.2 kg), % body fat (19.7 +/- 2.8%), and maximal oxygen consumption (VO2max: 48.4 +/- 5.1 ml.kg(-1).min(-1)). Participants performed 2 sessions of 60-minute treadmill runs following a randomly assigned SS protocol or quiet sitting (QS). During the first 30 minutes (running economy), expired gases, heart rate (HR), and rating of perceived exertion (RPE) were recorded while the participant ran at 65% VO2max. During the final 30 minutes (endurance performance), distance covered, speed, HR, and RPE were recorded while the participant attempted to cover as much distance as possible. Repeated measures analyses of variance were performed on the data. Significance was accepted at p < 0.05. The SS measured by sit-and-reach increased flexibility (SS: 29.8 +/- 8.3 vs. QS: 33.1 +/- 8.1 cm) but had no effect on running economy (VO2: 33.7 +/- 3.2 vs. 33.8 +/- 2.3 ml.kg(-1).min(-1)), calorie expenditure (270 +/- 41 vs. 270 +/- 41 kcal), HR (157 +/- 10 vs. 160 +/- 12 b.min(-1)), or endurance performance (5.5 +/- 0.6 vs. 5.5 +/- 0.7 km). These findings indicated that stretching did not have an adverse effect on endurance performance in trained women. This suggests that the performance decrements previously associated with stretching may not occur in trained women. PMID- 21610514 TI - Effects of perindopril-indapamide on left ventricular diastolic function and mass in patients with type 2 diabetes: the ADVANCE Echocardiography Substudy. AB - BACKGROUND: The Action in Diabetes and Vascular Disease (ADVANCE) Study demonstrated that a fixed combination of perindopril and indapamide reduced the risk of major vascular events and mortality in patients with type 2 diabetes. This Echocardiographic Substudy was designed to determine the effects of this treatment on left ventricular diastolic function and left ventricular mass. METHODS: Five hundred and fifty-five patients entering ADVANCE underwent quantitative echocardiography prior to randomization and after 6 months and 4 years of treatment with perindopril-indapamide or placebo. Main end points were left ventricular diastolic function (ratio of mitral E velocity/early medial mitral annular tissue Doppler velocity, E/Em, and left atrial volume index) and left ventricular mass index. RESULTS: Overall, blood pressure was reduced in the perindopril-indapamide group compared with placebo. E/Em and left atrial volume index both increased over the 4 years. There was no effect of perindopril indapamide on E/Em, although there was a small attenuation of the increase in left atrial volume index with active treatment. Left ventricular mass index was reduced by 2.7 g/m with active treatment (95% confidence interval -5.0 to -0.1, P = 0.04). CONCLUSION: Compared with placebo, the perindopril-indapamide combination reduced blood pressure and left ventricular mass in patients with diabetes, but did not improve left ventricular diastolic function. Left ventricular diastolic function worsened in both groups over 4 years, despite blood pressure reduction and reduction in left ventricular mass. Improving left ventricular diastolic function remains a challenge in patients with diabetes. PMID- 21610518 TI - Repeated high-intensity exercise in a professional rugby league. AB - The primary aim of this study was to identify and describe the frequency and duration of repeated high-intensity exercise (RHIE) bouts in Australian professional rugby league (National Rugby League) and whether these occurred at critical times during a game. Time motion analysis was used during 5 competition matches; 1 player from 3 positional groups (hit-up forward, adjustable, and outside back) was analyzed in each match. The ranges of RHIE bouts for the 3 positional groups were hit-up forwards 9-17, adjustables 2-8, and outside backs 3 7. Hit-up forwards were involved in a significantly greater number of RHIE bouts (p < 0.05) and had the shortest average recovery (376 +/- 205 seconds) between RHIE bouts. The single overall maximum durations of RHIE bouts for the hit-up forwards, the adjustables, and the outside backs were 64, 64, and 49 seconds. For all groups, 70% of the total RHIE bouts occurred within 5 minutes prior of a try being scored. The present data show that the nature of RHIE bouts was specific to playing position and occurred frequently at critical times during the game. These results can be used to develop training programs that mimic the 'worst case scenarios' that elite rugby league players are likely to encounter. PMID- 21610519 TI - Resection of primary mediastinal non-seminomatous germ cell tumors: a 28-year experience at memorial sloan-kettering cancer center. AB - INTRODUCTION: Surgical resection of residual tumor mass in responders to platinum based chemotherapy has evolved as the preferred treatment of primary mediastinal nonseminomatous germ cell tumors (PMNGCTs). We reviewed a single institution's operative experience with these rare tumors. METHODS: We reviewed charts of patients resected for PMNGCT at Memorial Sloan-Kettering Cancer Center between July 1980 and April 2008. Analyses included Kaplan-Meier survival with univariate log-rank comparisons and Cox multivariate regression. RESULTS: Fifty-seven patients were identified and followed up for a median of 5.3 years. Fifty-four of them received platinum-based preoperative chemotherapy, and 28 (49%) had limited stage I/II disease. Preoperative tumor markers normalized or decreased in 79% of patients. The most common surgical approach was anterolateral thoracotomy with partial sternotomy ("hemiclamshell," 38.6%). An R0 resection was achieved in 91% of the patients with a major morbidity of 17.5% and no postoperative deaths. The median overall survival was 31.5 months. Factors correlating with better survival on univariate analyses were necrosis or teratoma versus residual cancer on final pathology (p = 0.001), R0 resection (p = 0.03), normalized or decreased postchemotherapy/preoperative tumor markers (p < 0.001), normalized postoperative tumor markers (p = 0.004), stage I/II disease (p = 0.03), and surgery after 2000 versus 1980-1999 (p = 0.01). An exploratory multivariate analysis suggests that normalized or decreased postchemotherapy/preoperative tumor markers is the strongest independent predictor of improved survival. CONCLUSIONS: In a cohort of PMNGCT patients in which 91% of the patients underwent complete posttherapy resection, response to chemotherapy, measured by normalized or decreased preoperative tumor markers, was the strongest predictor of improved survival. PMID- 21610520 TI - Phase I and pharmacokinetic study of IV vinflunine in combination with gemcitabine for treatment of advanced non-small cell lung cancer in Chemonaive patients. AB - INTRODUCTION: Vinflunine (Javlor) has shown significant antitumour activity in advanced non-small cell lung cancer (NSCLC). We propose to define the recommended dose of vinflunine in combination with gemcitabine for treatment of advanced NSCLC in chemonaive patients. METHODS: A phase I and pharmacokinetic study was conducted to determine the maximum tolerated dose and to establish the recommended dose of vinflunine (VFL) administered on day 1 every 21 days combined with gemcitabine given on days 1 and 8 every 3 weeks. RESULTS: Nineteen patients were included in this study. Three patients experienced a dose limiting toxicity, with constipation in one patient, hypertension in one patient, and constipation and febrile neutropenia in one patient. The combination of VFL 320 mg/m2 and gemcitabine 1250 mg/m2 was defined as the maximum tolerated dose. The recommended dose was established at the dose of VFL 320 mg/m2 combined with gemcitabine 1000 mg/m2. Neither VFL nor gemcitabine seemed to be influencing the pharmacokinetics of each other. All patients were evaluable for tumor response. Seven presented a partial response and eight experienced a stable disease. CONCLUSIONS: The combination of VFL 320 mg/m2 administered on day 1 combined with gemcitabine 1000 mg/m2 given on days 1 and 8 every 3 weeks is established as the RD and was shown to be active in these chemonaive NSCLC patients. PMID- 21610521 TI - Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade. AB - BACKGROUND: The Japan Lung Cancer Society, the Japanese Association for Chest Surgery, and the Japanese Respiratory Society jointly established the Japanese Joint Committee for Lung Cancer Registration, which has regularly conducted lung cancer registries for surgical cases in 5-year periods. We analyzed data obtained in these registries to reveal the most recent surgical outcomes and trends related to lung cancer surgery in Japan. METHODS: Using data from the registry in 2010 for cases of surgery performed in 2004, demographics, surgical results, and stage-specific prognoses were analyzed. In addition, trends for those parameters over 10 years were assessed. RESULTS: The 5-year survival rate for all cases (n = 11,663, 7369 males, mean age 66.7 years) was 69.6%. The 5-year survival rates by c-stage and p-stage were as follow: IA, 82.0% (n = 6295) and 86.8% (n = 4978); IB, 66.8% (n = 2339) and 73.9% (n = 2552); IIA, 54.5% (n = 819) and 61.6% (n = 941); IIB, 46.4% (n = 648) and 49.8% (n = 848); IIIA, 42.8% (n = 1216) and 40.9% (n = 1804); IIIB, 40.3% (n = 90) and 27.8% (n = 106); and IV, 31.4% (n = 256) and 27.9% (n = 434), respectively. The percentages of female patients, cases with adenocarcinoma, stage I or II disease, and tumors sized less than 2 cm were increased, while those of operative and hospital deaths were decreased. Furthermore, the prognoses of all cases and cases in each stage improved over the decade. CONCLUSION: In Japanese cases of lung cancer surgery, demographics, surgical results, and stage-specific prognoses changed over the 10-year study period, while the 5-year survival rate for surgical cases improved to 69.6% in 2004. PMID- 21610522 TI - Detection of epithelial growth factor receptor mutations in cerebrospinal fluid from patients with lung adenocarcinoma suspected of neoplastic meningitis. AB - BACKGROUND: Neoplastic meningitis (NM) is a devastating neurological complication of cancer that needs to be diagnosed in the early stages of disease. Polymerase chain reaction detection of epithelial growth factor receptor (EGFR) mutations in cerebrospinal fluid (CSF), which are predictive markers for EGFR tyrosine kinase inhibitor therapy in lung cancer, might be important to diagnose and to treat NM in patients with lung cancer. In this study, we attempted to detect EGFR mutations in CSF and to compare EGFR status between CSF and primary or metastatic lesions in patients with lung adenocarcinoma suspected of NM. METHODS: Twenty nine patients with lung adenocarcinoma suspected of having NM underwent lumbar puncture. EGFR status of CSF was analyzed by direct DNA sequencing. EGFR mutations of primary or metastatic lesions (lymph nodes and bones) were analyzed in 20 cases. RESULTS: EGFR mutations were detected in CSF of 13 (45%) of 29 patients. In 5 (31%) of 16 patients with negative CSF cytology, EGFR mutations were detected. In four patients, EGFR mutations were shown in CSF, but not in primary or metastatic lesions. Conversely, in two patients, EGFR mutations were shown in primary or metastatic lesions, but not in CSF despite positive CSF cytology. CONCLUSIONS: EGFR mutations, suggesting the existence of malignant cells, were detected in CSF, even in patients with non-small cell lung cancer with negative cytological results. EGFR mutations in CSF do not always reflect the same status as in primary or metastatic lesions. PMID- 21610523 TI - Quantitative computed tomography analysis, airflow obstruction, and lung cancer in the pittsburgh lung screening study. AB - BACKGROUND: To study the relationship between emphysema, airflow obstruction, and lung cancer in a high-risk population, we performed quantitative analysis of screening computed tomography (CT) scans. METHODS: Subjects completed questionnaires, spirometry, and low-dose helical chest CT. Analyses compared cases and controls according to automated quantitative analysis of lung parenchyma and airways measures. RESULTS: Our case-control study of 117 matched pairs of lung cancer cases and controls did not reveal any airway or lung parenchymal findings on quantitative analysis of screening CT scans that were associated with increased lung cancer risk. Airway measures including wall area %, lumen perimeter, lumen area and average wall Hounsfield unit, and parenchymal measures including lung fraction less than -910 Hounsfield units were not statistically different between cases and controls. CONCLUSIONS: The relationship between visual assessment of emphysema and increased lung cancer risk could not be verified by quantitative analysis of low-dose screening CT scans in a high risk tobacco exposed population. PMID- 21610524 TI - Phase II study of sunitinib in patients with non-small cell lung cancer and irradiated brain metastases. AB - INTRODUCTION: Brain metastases frequently cause significant morbidity in patients with non-small cell lung cancer (NSCLC). Sunitinib is a multitargeted inhibitor of tyrosine kinase receptors, including vascular endothelial growth factor receptors and platelet-derived growth factor receptors, which has single-agent antitumor activity in refractory NSCLC. This phase II study evaluated the antitumor activity and safety of sunitinib in patients with pretreated NSCLC and irradiated brain metastases. METHODS: Patients received sunitinib 37.5 mg on a continuous daily dosing schedule. The primary end point was progression-free survival. Secondary end points included overall survival, patient-reported outcomes, and safety, including risk of intracranial hemorrhage (ICH) associated with focal neurological deficit. RESULTS: Sixty-four patients received sunitinib (median age 61 years), most (83%) had received prior systemic therapy, 63% had adenocarcinoma, and 19% had squamous cell carcinoma; most (55%) were never smokers. Median progression-free survival was 9.4 weeks (90% confidence interval [CI]: 7.5-13.1), and median overall survival was 25.1 weeks (95% CI: 13.4-35.5). The most common treatment-emergent (all-causality) nonhematologic toxicities (any grade) were fatigue (38%) and decreased appetite and constipation (both 25%). The most common grade 3/4 nonhematologic toxicities were dyspnea (9%) and fatigue (8%). Lymphopenia (20%) and neutropenia (13%) were the most common grade 3/4 hematologic abnormalities. Serious neurologic adverse events occurred in six patients (9%), and none were treatment-related. No cases of ICH were reported. CONCLUSIONS: Sunitinib administration on a continuous daily dosing schedule in patients with NSCLC and brain metastases was safe and manageable, with no increased risk of ICH. PMID- 21610526 TI - Treatment delays in non-small cell lung cancer and their prognostic implications. AB - INTRODUCTION: The impact of treatment delays on survival of patients with non small cell lung cancer (NSCLC) is uncertain. Although later treatment could negatively affect psychological well-being, the maximum acceptable waiting time has not been determined. METHODS: We analyzed consecutive patients with NSCLC between January 2005 and May 2007 in our center. Treatment delay was calculated from the first abnormal radiographic study. Cox proportional hazards analysis was used to identify predictive factors and log-rank tests to compare survival. RESULTS: Four hundred ninety-five cases were identified; shorter treatment delays were associated with a poor prognosis. Conversely, for every week that the treatment could be delayed, the hazard ratio was improved at 0.97 (p = 0.05). Standard treatment was given to 319 of these patients who were separated in localized, regional, and advanced stages. The median treatment delay was 73 days and distributed as follows: 85, 94, and 50 days for localized, regional, and advanced stages, respectively (p < 0.01). For localized or regional stages, the association between treatment delay and survival was inconclusive. In the advanced group, each week of treatment delay had a hazard ratio of 0.93 (p = 0.009). Survival of advanced patients who began treatment earlier versus later than the group median was 6.8 versus 11.6 months (p = 0.027). CONCLUSIONS: For patients with advanced NSCLC receiving equivalent chemotherapy regimens, shorter treatment delays were associated with shorter survival. We hypothesize that urgent treatment carried a negative prognostic meaning, as this was preferentially offered to patients presenting with a higher symptom burden, which conferred them a worse outcome. PMID- 21610525 TI - Assessment of objective responses using volumetric evaluation in advanced thymic malignancies and metastatic non-small cell lung cancer. AB - INTRODUCTION: Measurement of tumor response by standard response criteria is challenging in thymic malignancies, especially when the pleura is involved, as it often is in stage IV disease. In this study, we aimed to determine the effectiveness of volumetric response evaluation criteria in solid tumors (volumetrics) for evaluating response in patients with thymic malignancies treated on a phase II study of belinostat. METHODS: We evaluated the tumor responses of 25 patients with thymic cancer using computed tomography-based RECIST, World Health Organization (WHO), modified RECIST, and volumetrics. As a control, we assessed 37 patients with non-small cell lung cancer (NSCLC) with RECIST and volumetrics. RESULTS: Agreement analyses in 23 patients with thymic cancer at the time of RECIST-determined progressive disease (PD) compared volumetrics with RECIST, modified RECIST, and WHO criteria. Use of volumetrics was associated with 22% discordance compared with RECIST, 15% versus modified RECIST, and 22% versus WHO criteria. Volumetrics revealed PD 72 days earlier than RECIST (p = 0.016). In another cohort of 35 patients with NSCLC, there was 9% discordance between volumetrics and RECIST at the time of PD. Volumetrics demonstrated PD 32 days earlier than RECIST in NSCLC (p = 0.0078). CONCLUSIONS: Our study suggests that volumetrics might improve detection of PD. Prospective evaluation of this technique in a larger series of patients with thymic malignancies will be required. PMID- 21610527 TI - The use of home location to proxy injury location and implications for regionalized trauma system planning. AB - BACKGROUND: Trauma system planners use patient home address as a proxy for injury location, although this proxy has not been validated. We sought to determine the precision of this proxy by evaluating the relationship between the location of injury death and the location of residence. METHODS: This national descriptive analysis used the Multiple Cause of Death data files from 1999 to 2006 to determine the proportion of subjects in which county of residence (RC) matched county of death for all US injury deaths. Subgroup analyses were completed by age and injury intentionality using two sample tests of proportions. chi(2) tests were used to evaluate differences in concordance over time and by size of the RC. RESULTS: Analysis included 3,141 US counties and 1,255,881 subjects. A total of 73.4% of subjects died in the RC and 87.7% died in the RC or a contiguous county. Intentional injury deaths were more likely than unintentional to happen within a decedent's RC (85.1% vs. 68.1%, p < 0.001) and within the RC or contiguous county (93.4% vs. 85.2%, p < 0.001). Adult injury deaths were more likely than pediatric to happen within a decedent's RC (73.6% vs. 68.4%, p < 0.001) and within the RC or contiguous county (87.9% vs. 84.2%, p < 0.001). Subjects from larger counties were more likely to die within the RC or a contiguous county (same p < 0.001, same or adjacent p < 0.001). CONCLUSION: The preponderance of fatal injury deaths occur close to home. This supports the practice of trauma system's planning using home location available in administrative data to proxy injury location. PMID- 21610528 TI - Contralateral subdural effusion after decompressive craniectomy in patients with severe traumatic brain injury: clinical features and outcome. AB - BACKGROUND: Contralateral subdural effusion (SDE) is usually considered as an uncommon complication after decompressive craniectomy (DC) for head trauma. This complication may need more aggressive treatment because of its tendency to cause midline shift and neurologic deterioration. In this article, we present our experience with this group of patients and discuss the diagnosis and management of this entity. METHODS: This study included 13 patients with severe traumatic brain injury who developed contralateral SDE after DC. Clinical and radiographic information was obtained through a retrospective review of the medical records and the radiographs. RESULTS: The average time from the procedure of DC to the diagnosis of contralateral SDE was 13 days. Deterioration of clinical condition or appearance of new symptoms/signs related to the contralateral SDE was noted in four patients. In the remaining nine patients without apparent clinical deterioration, the contralateral SDE was discovered on routine computed tomography scan. Six patients were treated conservatively and the contralateral SDE resolved gradually. In six patients who underwent burr hole craniectomy to evacuate the SDE, the operation had successfully drained the SDE in four patients. Two patients received subsequent subduroperitoneal shunt to manage the reaccumulation of SDE. In one patient, subduroperitoneal shunt and cranioplasty were performed simultaneously to treat the SDE. Subsequently, six patients (46.2%) developed hydrocephalus and underwent ventriculoperitoneal shunt operation. CONCLUSIONS: Contralateral SDE may not be a rare complication after DC. Its diagnosis may be delayed or missed when it is asymptomatic or the clinical condition of the patient masks its clinical manifestations. It may be reasonable to repeat a computed tomography scan to detect contralateral SDE 2 weeks to 3 weeks after DC, irrespective of the clinical condition. In addition, posttraumatic hydrocephalus is a common late consequence in these patients. Close surveillance in these patients is indicated to prompt appropriate management. PMID- 21610529 TI - Recombinant activated factor VII safety in trauma patients: results from the CONTROL trial. AB - BACKGROUND: Safety data on recombinant activated factor VII (rFVIIa, NovoSeven; Novo Nordisk A/S, Bagsvaerd, Denmark) in actively hemorrhaging trauma patients are limited. We present detailed safety data from a large multicenter, randomized, placebo-controlled phase III study (the CONTROL trial). METHODS: Data from 560 patients were analyzed. Subjects were monitored for adverse events (AEs) after rFVIIa or placebo administration. Incidences, timing, and presence of risk factors were reported by site investigators, supported by external study monitors and overseen by an independent Data Monitoring Committee. RESULTS: There were no differences in overall mortality, organ system failure, or AEs, serious AEs, or medical events of special interest. Arterial and venous thromboembolic (TE) events and their risk factors were similar in both groups. The greatest risk factor for TE events was a chest injury requiring mechanical ventilation >3 days (86%). There were four site investigator-reported myocardial infarctions in the rFVIIa group of which only one met diagnostic criteria preestablished by the Data Monitoring Committee. There were no reported myocardial infarctions in the placebo group. Troponins were increased in 30% of all patients. The rate of acute respiratory distress syndrome was lower in the rFVIIa (3.0%) than in the placebo (7.2%) group (p = 0.022). CONCLUSIONS: This represents the largest placebo controlled dataset of rFVIIa use in trauma patients to date. In this prospective study of critically bleeding trauma patients, rFVIIa use was associated with an imbalance of investigator-reported Acute myocardial infarction/non-ST segment elevation myocardial infarction (AMI/NSTEMI), but was not associated with an increased risk for other AEs, including TE complications. PMID- 21610531 TI - Comparison of hospital mortality rates after burn injury in New York State: a risk-adjusted population-based observational study. AB - BACKGROUND: Severity-adjusted mortality is an unequivocal measure of burn care success. Hospitals can be compared on this metric using administrative data because information required for calculating statistically adjusted risk of mortality is routinely collected on hospital admission. METHODS: The New York State Department of Health provided information on all 13,113 thermally injured patients hospitalized at 1 of 194 hospitals between 2004 and 2008. We compared hospital survival rates using a random effects logistic model of mortality that incorporated age and several predictors that were present on admission and captured as International Classification of Diseases-9 codes: burn surface area, inhalation injury, three measures of physiologic compromise, and four medical comorbidities. Hospitals were compared on the adjusted odds of death and the number of excess deaths. RESULTS: Overall mortality was 3.2%. Nine high-volume hospitals (>100 patients/year) cared for 83% of patients with burn injuries. Overall variability of the odds of mortality among these high-volume centers was modest (median odds ratio=1.2) and we found little evidence for differences in the adjusted odds of mortality. A secondary analysis of the 185 low-volume hospitals that cared for 2,235 patients disclosed only 24 deaths. When examined in aggregate, these hospitals had better than predicted risk-adjusted mortality; a logical explanation is judicious case selection. CONCLUSIONS: Administrative hospital discharge data are extensive and comparably enough collected to allow comparison of the performance of burn centers. Risk-adjusted models show that patients have statistically indistinguishable risk-adjusted odds of mortality regardless of which hospital in New York State cared for them. PMID- 21610533 TI - The outcome of surgically treated femur fractures associated with long-term bisphosphonate use. AB - INTRODUCTION: Bisphosphonates (BPs) evolved as the mainstay for the treatment of osteoporosis, reducing the incidence of fractures. Recently several publications described the occurrence of low-energy subtrochanteric and femoral shaft fractures associated with long-term BP use. The aim of this study was to describe the outcome of surgically treated femur fractures associated with prolonged BP use. PATIENTS: Fifteen patients suffering from 17 atypical femoral fragility fractures associated with long-term (>3 years) BP use were located. Data included fracture type, time of BP use, last bone mineral density DEXA scores for the femoral neck and spine, type of surgery, and the need for revision. RESULTS: Fourteen female patients and one male patient were identified. The median age was 73 years (range, 51-80 years). The mean BP use was 7.8 years (range, 4-13 years). Fourteen patients had low-energy traumatic femoral shaft (proximal and distal) or low subtrochanteric fractures. The mean lumbar spine (for 13 patients) bone mineral density T-score was -3.0, whereas mean femoral neck T-score was -1.8 with only three patients in the osteoporotic range.Fracture healing after the first procedure for patients treated with nails was 54%, with 46% of patients requiring revision surgery. These included nail dynamization, exchange nailing, and one revision to a blade plate. All of these eventually healed. CONCLUSIONS: BP related fractures are a recently described phenomenon. Despite initial osteoporosis, the DEXA scan may appear outside the osteoporotic range for the femoral neck in these patients. In addition, a much higher failure rate with intramedullary nailing requiring revision surgery may occur with these patients. PMID- 21610534 TI - Discharge against medical advice after traumatic brain injury: is intentional injury a predictor? AB - BACKGROUND: Discharge against medical advice (DAMA) have consistently been reported as causing adverse outcomes for both patients and service providers. However, little is known about the DAMA of patients with traumatic brain injury (TBI). The objectives of this study were to develop a risk profile of DAMA patients in the TBI population, to examine factors associated with DAMA occurrence, and to examine specifically whether injury intention (unintentional vs. intentional) is a significant predictor of DAMA. METHODS: A retrospective cohort study was conducted using hospital discharge data obtained from the Minimal Data Set (MDS) of the Ontario Trauma Registry for the years 1993/1994 and 2000/2001 on TBI patients aged 15 to 64 years. RESULTS: The MDS review yielded 15,684 cases of TBI with an average length of stay of 2.7 days. Of these, 446 (2.84%) had recorded DAMA events. When compared with patients with unintentional TBI, DAMA was significantly associated with intentional injuries in those with self-inflicted TBI (adjusted odds ratio [aOR] = 1.97; 95% confidence interval [CI], 1.36-2.84) and other-inflicted TBI (aOR = 2.00; CI, 1.53-2.62). DAMA was also associated with younger age and a history of alcohol/drug abuse (aOR = 3.50; CI, 2.85-4.30). CONCLUSION: TBI patients who leave hospital against medical advice are a high-risk population. Early identification of these patients could allow implementation of better prevention and management strategies, thus improving health outcomes and enhancing healthcare delivery. PMID- 21610535 TI - Effect of hemodilution on coagulation and recombinant factor VIIa efficacy in human blood in vitro. AB - BACKGROUND: This study evaluates the effect of hemodilution by various common resuscitation fluids, and the efficacy of activated recombinant factor VII (rFVIIa) on coagulation parameters in human blood in vitro. METHODS: Samples from normal healthy volunteers (n = 9) were hemodiluted from 0% to 90% with normal saline, or 0%, 40%, 60%, and 80% with 5% albumin, Hespan, Hextend, normal saline, or lactated Ringer's, and incubated at 37 degrees C +/- 1 degrees C for 30 minutes with and without rFVIIa (1.26 MUg/mL). RESULTS: There was a strong correlation between the dilution of hemoglobin (Hb), platelets, or fibrinogen and coagulation parameters. Hemodilution 0% to 90% changed coagulation parameters (prothrombin time [PT], activated partial thromboplastin time [aPTT], and thromboelastography) in an exponential fashion; the greatest changes occurred after hemodilution lowered Hb <6 mg/dL, platelet count < 100,000/mm(3), and fibrinogen concentration <200 mg/dL. PT and aPTT were significantly prolonged after 60% and 80% dilution for all fluids. Hemodilution of 60% and 80% significantly decreased clot strength (maximum amplitude) and the kinetics of clot development (alpha angle) and increased the clot formation time (K). Hemodilution with Hextend and Hespan decreased maximum amplitude and alpha angle >5% albumin, lactated Ringer's, or normal saline. rFVIIa significantly improved PT at 60% and 80% dilutions, and aPTT at 80% dilution. There was a significant effect of dilution, but not fluid type, on the efficacy of rFVIIa to change PT and aPTT, and the onset of clotting (R). CONCLUSIONS: We have strong in vitro evidence that Hb <6 mg/dL, platelet count <100,000/mm(3), and fibrinogen concentration <200 mg/dL can be used as indexes of hemodilution-induced coagulopathy. This study also shows that Hextend and Hespan tend to decrease the clotting ability >5% albumin or the crystalloids. rFVIIa significantly decreased PT at all dilutions and aPTT at the highest dilution. The effectiveness of rFVIIa on PT and aPTT was significantly affected by the degree of dilution, but not by the type of fluid. PMID- 21610536 TI - Effects of intra-abdominal hypertension on the endocrine functions of the pancreas in rats. AB - BACKGROUND: Intra-abdominal hypertension (IAH) has negative effects on the functions of intra- and extra-abdominal organs and systems. Intra- and extraperitoneal hemorrhage, diffuse intestinal and retroperitoneal edema, intestinal ileus or obstruction, necrotizing pancreatitis, intra-abdominal packing, intra-abdominal sepsis, and pneumoperitoneum can all cause IAH. No studies were found in the literature relating to the effects of IAH on the endocrine functions of the pancreas. Therefore, the objective of this study was to investigate the effects of IAH on the endocrine functions of the pancreas. METHODS: Forty male rats were divided into four groups: control, sham control, and two study groups, each containing 10 rats. In one of the study groups, animals were subjected to IAH of up to 20 mm Hg and in the other study group to 25 mm Hg, for 3 hours. At the end of the study, blood samples were collected for biochemical analysis and pancreatic tissue samples for histopathologic examination. RESULTS: The results showed that glucagon levels were increased in the study groups (p<0.001) and insulin levels were decreased (p<0.001). There were no differences between the control and sham control groups. Histopathologic examination showed inflammatory cell infiltration in exocrine pancreatic tissue and vascular congestion in the islets of Langerhans. CONCLUSION: IAH causes an increase in glucagon levels and a decrease in insulin levels. These changes may be due to both the direct effects of IAH and the indirect effects of other organs that are affected by IAH. PMID- 21610537 TI - Retroperitoneal pelvic packing in the management of hemodynamically unstable pelvic fractures: a level I trauma center experience. AB - BACKGROUND: Our objective is to evaluate the mortality and outcomes of hemodynamically unstable patients with pelvic fractures treated with a protocol that directs the patient to either early pelvic angiography or early retroperitoneal pelvic packing. METHOD: This is a retrospective review of prospectively collected database at a local trauma center. Hemodynamically unstable pelvic fracture patients received treatment according to our hospital protocol during two different time periods. Before June 2008, these patients underwent early angiography (ANGIO group, n=13), and from June 2008 onward, these patients underwent early pelvic packing and subsequent angiography if there was continued hemorrhage from the pelvis (PACKING group, n=11). The mechanism of injury, physiologic parameters, blood transfusion requirements, time to intervention, trauma scores, and mortality were recorded. RESULTS: Mean time to intervention in the ANGIO group was longer than that in the PACKING group, although this was not statistically significant (139.5 minutes vs. 78.8 minutes, respectively, p=0.248). Mortality in the ANGIO group was higher than that in the PACKING group; however, this was also not significant (69.2% vs. 36.3%, p=0.107). After univariate analysis, factors associated with mortality included systolic blood pressure, Glasgow Coma Score, Injury Severity Score, Revised Trauma Score, Trauma and Injury Severity Score, pH, and base excess. In the PACKING group, one patient died of uncontrolled hemorrhage from a liver laceration. In the ANGIO group, three patients died of uncontrolled hemorrhage from the pelvic fracture. CONCLUSION: Early experience in our institution suggests that early pelvic packing with subsequent angiography if needed is as good as angiography with embolization in treating patients with hemodynamically unstable pelvic fractures. PMID- 21610538 TI - Anatomic reconstruction of unstable lateral clavicular fractures. AB - BACKGROUND: Fractures of the lateral clavicle result in a high rate of nonunion compared with midshaft fractures. Many operative treatment methods of unstable lateral clavicle fractures have been described, but no single method has become generally accepted. This study reports our experience treating unstable lateral clavicle fractures with coracoclavicular ligament rupture. METHODS: Within 7 years, 19 patients with acute unstable lateral clavicle fractures were treated using a 2.4-mm T-plate and a coracoclavicular polydioxanone cord. The follow-up averaged 5.3 years (range, 2.0-8.8). Shoulder function was assessed using the Constant score and Disabilities of the Arm, Shoulder and Hand score. General health of the patients was evaluated according to the Short Form 36 questionnaire. RESULTS: Eighteen of the 19 patients treated with our method achieved union at 8.8 weeks (range, 6-14), a Constant Murley score of 91.5 (range, 72-100) on the injured side versus 93.5 (range, 80-100) on the contralateral side, a Disabilities of the Arm, Shoulder and Hand score of 1.4 (range, 0-9.2), and a Short Form 36 Health Score of 85 (range, 89-100). One patient showed breakage of the plate and a delayed union at the radiologic follow up 4 months after surgery. CONCLUSION: This study shows that treatment of unstable lateral clavicular fractures with an angular stable locking plate together with a polydioxanone cord ligament augmentation leads to excellent results with a 95% union rate. Additional coracoclavicular augmentation next to plate fixation of the clavicle may partially solve the problem of uncertain plate fixation if the lateral fragment is small and multifragmented, as often observed. PMID- 21610539 TI - Biomechanical analysis of the less invasive stabilization system for mechanically unstable fractures of the distal femur: comparison of titanium versus stainless steel and bicortical versus unicortical fixation. AB - BACKGROUND: The purpose of this study was to test the effect of (1) titanium versus stainless steel metal and (2) locked unicortical versus bicortical shaft fixation on stiffness of Less Invasive Stabilization System (LISS) constructs in a mechanically unstable nonosteoporotic distal femur fracture model. METHODS: An AO/OTA 33-A3 fracture was created in 24 sawbone femur specimens that simulated normal bone quality. Testing was performed on three groups: titanium unicortical LISS fixation, stainless steel unicortical LISS fixation, and bicortical stainless steel LISS fixation. Specimens were tested in axial, torsional, and cyclic axial loading in a materials testing machine. The outcome measurement was stiffness in axial and torsional loading, total deformation, and irreversible (plastic) deformation in cyclical axial loading. RESULTS: No difference was found in stiffness in axial loading or plastic and total deformation between all three groups. There was a small decrease in stiffness in torsional loading in the titanium group compared with the stainless steel groups (p < 0.0001) and a small increase in stiffness in torsional loading with bicortical versus unicortical proximal fixation (p = 0.04). CONCLUSIONS: Unstable distal femur fracture constructs, created in sawbone specimens, fixed with stainless steel and titanium LISS implants, with or without bicortical locking screws proximally, show similar biomechanical properties under loading. Although there are numerous considerations when selecting implants for these fractures, our results indicate that stiffness is not a significant factor in choosing between the constructs tested. PMID- 21610540 TI - Computer-assisted surgery and intraoperative three-dimensional imaging for screw placement in different pelvic regions. AB - BACKGROUND: The purpose of this study was to assess the feasibility and accuracy of computer-assisted surgery (CAS) for screw placement in different pelvic regions using intraoperative three-dimensional (3D) imaging and to evaluate the influence of surgeons' experience with such a system on procedure time, radiation time, radiation dose, and misplacement rate. METHODS: Experimental study in a human cadaveric model (n=5) for percutaneous screw placement in the anterior column of the acetabulum, the posterior pelvic ring (S1, S2), and the superior pubic ramus via 3D fluoroscopic navigated procedure. Accuracy of screw placement was assessed by 3D image intensifier, including the reconstruction of multiplanar images and by computer tomography (CT) scan. Influence of surgeons' experience was assessed by direct comparison of a low- and high-volume surgeon using the same technical setting. RESULTS: In 100% of all procedures, intraoperative Iso C3D image analysis was sufficient to confirm a correct screw placement. The postoperative CT scan revealed no further screw misplacement. However, for a correct supraacetabular screw placement, the intraoperative 3D scan was essential. In this group, the 3D scan showed screw misplacement in three cases. Procedure time for all indications and screw failure rate were significantly lower for the higher experienced surgeon. CONCLUSION: The 3D fluoroscopic navigated procedure in pelvic surgery seems to be a useful tool for all surgeons and especially for less experienced ones. Furthermore, the intraoperative reconstruction of multiplanar 3D images allows a secure control of implant positioning. PMID- 21610541 TI - Comparison of nonoperative management with renorrhaphy and nephrectomy in penetrating renal injuries. AB - BACKGROUND: We reviewed our experience with penetrating renal injuries to compare nonoperative management of penetrating renal injuries with renorrhaphy and nephrectomy in light of concerns for unnecessary explorations and increased nephrectomy rates. METHODS: In this retrospective study, we reviewed the records of 98 penetrating renal injuries from 2003 to 2008. Renal injuries were classified according to the American Association for the Surgery of Trauma and analyzed based on nephrectomy, renorrhaphy, and nonoperative management. Patient characteristics and outcomes measured were compared between management types. Continuous variables were summarized by means and compared using t test. Categorical variables were compared using chi2 test. RESULTS: Nonoperative management was performed in 40% of renal injuries, followed by renorrhaphy (38%) and nephrectomy (22%). Of renal gunshot wounds (n = 79), 26%, 42%, and 32% required nephrectomy, renorrhaphy, and were managed nonoperatively, respectively. No renal stab wound (n = 16) resulted in a nephrectomy and 81% were managed conservatively. Renal injuries managed nonoperatively had a lower incidence of transfusion (34 vs. 95%, p < 0.001), shorter mean intensive care unit (ICU) (3.0 vs. 9.0 days, p = 0.028) and mean hospital length of stay (7.9 vs. 18.1 days, p = 0.006), and lower mortality rate (0 vs. 20%, p = 0.005) compared with nephrectomy but similar to renorrhaphy (transfusion: 34 vs. 36%, p = 0.864; mean ICU: 3.0 vs. 2.8 days, p = 0.931; mean hospital length of stay: 7.9 vs. 11.2 days, p = 0.197; mortality: 0 vs. 6%, p = 0.141). The complication rate of nonoperative management was favorable compared with operative management. CONCLUSIONS: Selective nonoperative management of penetrating renal injuries resulted in a lower mortality rate, lower incidence of blood transfusion, and shorter mean ICU and hospital stay compared with patients managed by nephrectomy but similar to renorrhaphy. Complication rates were low and similar to operative management. PMID- 21610542 TI - Determinants of the cost of health services used by veterans with HIV. AB - BACKGROUND: The effect of adherence, treatment failure, and comorbidities on the cost of HIV care is not well understood. OBJECTIVE: To characterize the cost of HIV care including combination antiretroviral treatment (ART). RESEARCH DESIGN: Observational study of administrative data. SUBJECTS: Total 1896 randomly selected HIV-infected patients and 288 trial participants with multidrug resistant HIV seen at the US Veterans Health Administration (VHA). MEASURES: Comorbidities, cost, pharmacy, and laboratory data. RESULTS: Many HIV-infected patients (24.5%) of the random sample did not receive ART. Outpatient pharmacy accounted for 62.8% of the costs of patients highly adherent with ART, 32.2% of the cost of those with lower adherence, and 6.2% of the cost of those not receiving ART. Compared with patients not receiving ART, high adherence was associated with lower hospital cost, but no greater total cost. Individuals with a low CD4 count (<50 cells/mm) incurred 1.9 times the cost of patients with counts >500. Most patients had medical, psychiatric, or substance abuse comorbidities. These conditions were associated with greater cost. Trial participants were less likely to have psychiatric and substance abuse comorbidities than the random sample of VHA patients with HIV. CONCLUSIONS: Patients receiving combination ART had higher medication costs but lower acute hospital cost. Poor control of HIV was associated with higher cost. The cost of psychiatric, substance abuse, rehabilitation, and long-term care and medications other than ART, often overlooked in HIV studies, was substantial. PMID- 21610543 TI - How can health care organizations be reliably compared?: Lessons from a national survey of patient experience. AB - BACKGROUND: Patient experience is increasingly used to assess organizational performance, for example in public reporting or pay-for-performance schemes. Conventional approaches using 95% confidence intervals are commonly used to determine required survey samples or to report performance but these may result in unreliable organizational comparisons. METHODS: We analyzed data from 2.2 million patients who responded to the English 2009 General Practice Patient Survey, which included 45 patient experience questions nested within 6 different care domains (access, continuity of care, communication, anticipatory care planning, out-of-hours care, and overall care satisfaction). For each question, unadjusted and case-mix adjusted (for age, sex, and ethnicity) organization-level reliability, and intraclass correlation coefficients were calculated. RESULTS: Mean responses per organization ranged from 23 to 256 for questions evaluating primary care practices, and from 1454 to 2758 for questions evaluating out-of hours care organizations. Adjusted and unadjusted reliability values were similar. Twenty-six questions had excellent reliability (>=0.90). Seven nurse communication questions had very good reliability (>=0.85), but 3 anticipatory care planning questions had lower reliability (<0.70). Reliability was typically <0.70 for questions with <100 mean responses per practice, usually indicating questions which only a subset of patients were eligible to answer. Nine questions had both excellent reliability and high intraclass correlation coefficients (>=0.10) indicating both reliable measurement and substantial performance variability. CONCLUSIONS: High reliability is a necessary property of indicators used to compare health care organizations. Using the English General Practice Patient Survey as a case study, we show how reliability and intraclass correlation coefficients can be used to select measures to support robust organizational comparisons, and to design surveys that will both provide high quality measurement and optimize survey costs. PMID- 21610513 TI - Prevention of cardiovascular events with calcium channel blocker-based combination therapies in patients with hypertension: a randomized controlled trial. AB - OBJECTIVES: Current guidelines recommend the use of multiple medications for hypertension. The present study was aimed at determining which combination was optimal to prevent cardiovascular events. METHODS: We conducted a prospective, randomized, open-label, blinded-endpoint trial. Hypertensive outpatients aged between 40 and 85 years who did not achieve target blood pressure (BP<140/90 mmHg) with calcium channel blocker (CCB) benidipine 4 mg/day were randomly assigned to receive angiotensin receptor blocker (ARB), beta-blocker, or thiazide diuretic in addition to benidipine. RESULTS: Among a total of 3501 patients (1167, benidipine-ARB; 1166, benidipine-beta-blocker; and 1168, benidipine thiazide), 3293 patients (1110, 1089, and 1094, respectively) who received each combination treatment were included in the analysis. Median follow-up was 3.61 years. At the end of the treatment, 64.1, 66.9, and 66.0% of patients in the benidipine-ARB, benidipine-beta-blocker, and benidipine-thiazide groups achieved target BP, respectively. The cardiovascular composite endpoint occurred in 41 (3.7%), 48 (4.4%), and 32 (2.9%) patients, respectively: the hazard ratio was 1.26 in the benidipine-ARB (P = 0.3505) and 1.54 in the benidipine-beta-blocker (P = 0.0567) groups compared with the benidipine-thiazide group. The secondary analyses revealed that benidipine and thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes (P = 0.0109) and benidipine and ARB significantly reduced new-onset diabetes (P = 0.0240) compared with benidipine and beta-blocker. All trial treatments were safe and well tolerated. CONCLUSION: CCB combined with ARB, beta-blocker, or thiazide diuretic was similarly effective for the prevention of cardiovascular events and the achievement of target BP. PMID- 21610544 TI - Event-related potential correlates of inhibition in bipolar disorder. AB - Lack of inhibitory control is a commonly reported impairment in patients with bipolar disorder, however, there has been little research regarding the time course of inhibitory processes. Twenty-six participants (13 bipolar and 13 controls) completed an emotional go/no-go inhibition task while event-related potentials were recorded. Go minus no-go difference waves were computed to index response inhibition. Across groups, there was greater activity in parietal and occipital compared with frontal and central electrodes. Longer latencies were found in bipolar disorder compared with controls. In conclusion, cortical regions recruited during response inhibition may be stimulus-dependent and not restricted to frontal areas. Impairments in bipolar disorder may relate to the speed at which inhibitory activity is executed, consistent with white matter deficits identified previously. PMID- 21610548 TI - Radiation-associated sarcoma? PMID- 21610545 TI - Phoneme discrimination and mismatch negativity in English and Japanese speakers. AB - Neural templates for phonemes in one's native language are formed early in life; these can be modified but are difficult to form de novo. These can be examined with mismatch negativity (MMN). Three phonemic contrasts were presented to adult native English compared with Japanese speakers who acquired English later in life: vowels native to both languages (/i//iy/), consonant-vowel contrasts (/da//wa/) phonemic in both languages, and consonant-vowel contrasts phonemic in English but not in Japanese (/ra//la/). For vowels, no MMN differences were found. For /da//wa/, MMN amplitude was significantly reduced in Japanese speakers. For /ra//la/, only 50% of the Japanese group showed an identifiable MMN. This suggests that phonemic templates are formed early in life, and non native consonant contrasts are difficult to learn later. PMID- 21610550 TI - Long-term surgical outcome of intraspinal ependymomas. PMID- 21610553 TI - Naming the soft tissue layers of the temporoparietal region: unifying anatomic terminology across surgical disciplines. PMID- 21610554 TI - Effect of heparin following cervical spinal cord injuries in rats. AB - BACKGROUND: Risks of neurological deterioration after heparin administration following cervical spinal cord injury (SCI) in humans are unknown. OBJECTIVE: To elucidate the safety of heparin following cervical SCI and investigate its potential neuroprotectant role. METHODS: Sixty-two Sprague Dawley adult rats were subjected to mild (0.6 mm), moderate (0.9 mm), or severe (1.2 mm) C7-SCI. At each injury severity, intravenous heparin or saline was administered for 72 hours following SCI. Behavioral tests (Basso, Beattie, Bresnahan scores, Hargreave's) were performed before killing the rats at week 7. Half of the rats were killed at day 3, and the remainder at week 7 after SCI. Immunohistochemistry, Western blot analysis, and axonal retrograde tracing were conducted at both times. RESULTS: Subpial hemorrhage was greater in heparin-treated animals compared with controls at all severities of SCI day 3 after injury. Counterintuitively, intraparencyhmal hemorrhage was minimal in the lesion epicenter following mild SCI in the heparin treated animals compared with controls. India ink perfusion revealed greater preservation of microcirculation in heparin-treated animals compared with a reduction in control animals. A decrease in spinal cord perfusion correlated directly with an increase in hypoxia-inducible factor-1alpha expression. There was significant gray matter sparing, but no change in white matter volume after heparin treatment at week 7 in the mild SCI group. Beneficial effects on hemorrhagic volume, axon sparing, and functional recovery following heparin treatment were not observed in the moderate or severe SCI group. CONCLUSION: Heparin treatment following SCI is safe at all degrees of injury. Heparin decreases platelet aggregation and microvascular occlusion, providing a potential neuroprotective effect following mild SCI. PMID- 21610555 TI - A Chinese pedigree with an individual homozygous for CAG repeats of Huntington's disease. PMID- 21610556 TI - Associations of MAOA-VNTR or 5HTT-LPR alleles with attention-deficit hyperactivity disorder symptoms are moderated by platelet monoamine oxidase B activity. AB - The monoamine systems have been suggested to play a role in the biological basis of attention-deficit hyperactivity disorder (ADHD) symptoms. Thus, polymorphisms, for example, in the monoamine oxidase A (MAOA) and the serotonin transporter (5HTT) genes have been associated with ADHD-like phenotypes. Furthermore, platelet monoamine oxidase B (MAOB) activity has frequently been linked to impulsiveness-related traits. In this study, we have studied ADHD symptoms with regard to the combination of platelet MAOB activity and MAOA-variable number of tandem repeats (VNTR) or 5HTT-LPR genotype. The study group consisted of 156 adolescent twin pairs, that is, 312 individuals, who participated in a previous study. ADHD symptoms were scored with a structured clinical interview of both the twins and a parent using Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. The presence of a short 5HTT-LPR or short MAOA-VNTR allele, in combination with high levels of platelet MAOB enzyme activity was associated with higher scores of ADHD-like problems (P<0.001 and 0.01, respectively). This re-examination of ADHD scores in a nonclinical sample suggests that effects of MAOA-VNTR and 5HTT-LPR are moderated by platelet MAOB activity. PMID- 21610557 TI - Low-volume ultrasound-guided nerve block provides inferior postoperative analgesia compared to a higher-volume landmark technique. AB - BACKGROUND AND OBJECTIVES: Ultrasound guidance reduces the required local anesthetic volume for successful peripheral nerve blockade, but it is unclear whether this impacts postoperative analgesia. This prospective, randomized, observer-blinded study tested the hypothesis that a low-volume ultrasound-guided ankle block would provide similar analgesia after foot surgery compared with a conventional-volume surface landmark technique. METHODS: A total of 72 patients presenting for elective foot surgery under general anesthesia were randomized to receive a low-volume ultrasound-guided ankle block (n = 37; ropivacaine 0.5% adjacent the anterior/posterior tibial arteries and short saphenous vein; subcutaneous infiltration around the saphenous and superficial peroneal nerves) or conventional-volume surface landmark guided technique (n = 35; 30 mL of ropivacaine 0.5%). Patients received regular postoperative acetaminophen, diclofenac, and rescue tramadol. Assessment was in the recovery room and at 24 hours for pain and tramadol consumption. RESULTS: Mean (SD) total local anesthetic volume for the low-volume ultrasound group was 16 (2.1) mL. Block success in the recovery room was similar between groups (low-volume ultrasound 89% versus conventional-volume landmark 80%, P = 0.34; however, during the first 24 hours, numerically rated (0-10) "average pain" (median [10-90th percentiles] = 1 [0-4] versus 0 [0-2], P = 0.01), worst pain at rest (1 [0-6] versus 0 [0-2], P = 0.03), and the proportion of patients requiring rescue tramadol (% [95% confidence interval]: 50 [34-46] versus 20 [10-36], P = 0.01) were higher in the low-volume ultrasound group. Numerically rated numbness, weakness, satisfaction, and procedural time were similar between groups. CONCLUSIONS: Low-volume ultrasound-guided ankle block is associated with a high block success rate after foot surgery; however, compared with a conventional volume (surface landmark) technique, the reduced local anesthetic volume marginally compromises postoperative analgesia during the first 24 hours. PMID- 21610558 TI - Interventional pain physicians' experiences of and attitudes toward surgical privileging. AB - BACKGROUND AND OBJECTIVES: No consensus guidelines exist on surgical privilege credentialing for nonsurgeons. We queried a group of academic interventional pain physicians about their experiences acquiring such credentials after training, how this process reflected their training, and their current attitudes toward both processes. METHODS: We designed an interactive, computer-based questionnaire and sent this electronically to the directors of all 93 accredited pain medicine subspecialty fellowship programs in the United States. The questionnaire included 17 items regarding interventional pain medicine training, procedures done, experience of credentialing for surgical privileges, and attitudes toward these processes, with 1 additional space for comments. RESULTS: Of the 93 program directors, 46 (49.5%) responded to our questionnaire. Forty-one (89%) of the respondents were anesthesiologists, and 43 (93%) included some form of implantation procedure in their current practice. Most (83%) of the respondents did fewer than 25 implants per year. Experience doing implant procedures during training varied widely among respondents: 43% did fewer than 5 implant procedures during fellowship; 33.3% did at least 15. Most respondents did their own wound closures and did not feel that immediate surgical backup should be required for interventional pain procedures. Most respondents (78%) felt that pertinent surgical training should be mandatory before credentialing, but fewer than 20% reported having been required to have even a proctoring experience before credentialing. CONCLUSIONS: Experience doing implantation procedures during fellowship training and subsequent experience with hospital surgical credentialing seems to vary widely, even among interventional pain physicians associated with academic training programs. PMID- 21610559 TI - Intraoperative local infiltration analgesia for early analgesia after total hip arthroplasty: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND AND OBJECTIVES: High-volume local infiltration analgesia (LIA) is widely applied as part of a multimodal pain management strategy in total hip arthroplasty (THA). However, methodological problems hinder the exact interpretation of previous trials, and the evidence for LIA in THA remains to be clarified. Therefore, we evaluated whether intraoperative high-volume LIA, in addition to a multimodal oral analgesic regimen, would further reduce acute postoperative pain after THA. METHODS: Patients scheduled for unilateral, primary THA under spinal anesthesia were included in this randomized, double-blind, placebo-controlled trial receiving high-volume (150 mL) wound infiltration with ropivacaine 0.2% with epinephrine (10 MUg/mL) or saline 0.9%. A multimodal oral analgesic regimen consisting of slow-release acetaminophen 2 g, celecoxib 400 mg, and gabapentin 600 mg was instituted preoperatively. Rescue analgesic consisted of oral oxycodone. Pain was assessed repeatedly the first 8 hrs after surgery using the 100-mm visual analog scale. The primary end point was pain during walking (5 m) 8 hrs after surgery. Secondary end points were pain at rest, pain on 45 degrees of passive flexion of the hip with the leg straight, and cumulative consumption of oxycodone. RESULTS: A total of 120 patients were included. Pain during walking (median [interquartile range] [95% confidence interval]) was low in the ropivacaine versus the placebo group (20 [14-38] [0-93] vs 22 [10-40] [0 83]) and did not differ significantly (P = 0.71). Consumption of rescue oxycodone (5 mg [0-10 mg] [0-24 mg] vs 10 mg [0-15 mg] [0-29 mg]) did not differ (P = 0.45). CONCLUSIONS: Intraoperative high-volume LIA with ropivacaine 0.2% provided no additional reduction in acute pain after THA when combined with a multimodal oral analgesic regimen consisting of acetaminophen, celecoxib, and gabapentin and is therefore not recommended. PMID- 21610560 TI - Clinical trial methodology of pain treatment studies: selection and measurement of self-report primary outcomes for efficacy. AB - The past century has seen immense progress in the advancement of methodology to evaluate efficacy of treatment interventions for acute and chronic pain. Continuing challenges revolve around how to best select and measure primary efficacy outcomes for a given analgesic trial. Recognizing the complex, multidimensional, sensory and emotional nature of pain and applying psychometric techniques have facilitated the development of several valid and reliable self report measures that evaluate pain intensity, pain relief, and other important outcome domains relevant to pain treatment. In the setting of emerging new pain treatment strategies, careful consideration must be given to match current or novel outcome measures to the specific goals of a proposed trial. Future research is needed to directly compare current methods with newer measurement approaches for the critical goal of maximizing validity, reliability, and utility of different outcome measures in clinical trials of pain treatment. PMID- 21610561 TI - Course of intraocular pressure after vitreoretinal surgery: is early postoperative intraocular pressure elevation predictable? AB - PURPOSE: Assessment of intraocular pressure (IOP) after vitreoretinal surgery is important to ensure functionality of the eye. Incidences and risk factors for early postoperative IOP elevation were evaluated. METHODS: In a prospective case series of 210 vitreoretinal cases, IOP-lowering treatment was performed at IOP values of >=30 mmHg. Differences in IOP elevation in relation to surgical procedures and tamponades were evaluated. RESULTS: Sixty-two patients required treatment (29.5%). Encircling bands were associated with a high risk for IOP elevation when combined with pars plana vitrectomy and gas tamponade (37.9%) or oil tamponade (50.0%). Panretinal laser photocoagulation in conjunction with oil tamponade for proliferative diabetic retinopathy traction retinal detachment (RD) resulted in the highest risk for IOP increases (83.3%). Intraocular pressure elevation in proliferative diabetic retinopathy traction RD often evolved 4 hours after vitreoretinal surgery compared with 8 hours to 12 hours after vitreoretinal surgery in rhegmatogenous RD. Silicone oil removals (7.1%) and external buckling procedures (0.0%) carried low risks for IOP increases. CONCLUSION: Patients treated for proliferative diabetic retinopathy traction RD and for primary rhegmatogenous RD were at high risk for prolonged IOP elevation. These groups also required medical retreatment most often and should therefore be closely monitored. Care must be taken not to overlook delayed IOP elevations. PMID- 21610562 TI - Incidence of iatrogenic peripheral retinal breaks in 23-gauge vitrectomy for macular diseases. AB - PURPOSE: To assess the incidence of iatrogenic peripheral retinal breaks in 23 gauge vitrectomy for macular diseases and to compare it with 20-gauge vitrectomy. METHODS: Retrospective, comparative, interventional case series. We compared the incidence of iatrogenic peripheral retinal breaks in 176 eyes undergoing 23-gauge vitrectomy between January 2007 and November 2009 (23-gauge group) and 153 eyes undergoing 20-gauge vitrectomy between January 2004 and June 2006 (20-gauge group) for either idiopathic macular holes or idiopathic epiretinal membranes. All surgeries were performed by one surgeon at a single hospital. Main outcome measure was the incidence rate of iatrogenic peripheral retinal breaks discovered intraoperatively and postoperatively. RESULTS: Iatrogenic peripheral retinal breaks occurred in 1 eye in the 23-gauge group and in 11 eyes in the 20-gauge group during surgery. Additional iatrogenic retinal breaks were found in 1 eye in the 23-gauge group and in 2 eyes in the 20-gauge group within 1 month after surgery. The overall incidence of iatrogenic peripheral retinal breaks was 1.1% (2 of 176) in the 23-gauge group and 8.5% (13 of 153) in the 20-gauge group. The difference was statistically significant (P = 0.0023). CONCLUSION: The incidence of iatrogenic peripheral retinal breaks during vitrectomy for macular diseases is significantly lower in 23-gauge vitrectomy than in 20-gauge vitrectomy. PMID- 21610563 TI - Intravitreal bevacizumab for treatment of proliferative and nonproliferative type 2 idiopathic macular telangiectasia. AB - PURPOSE: To determine the effect of treatment with intravitreal bevacizumab on retinal thickness and visual acuity in the nonproliferative and proliferative forms of Type 2 idiopathic macular telangiectasia. METHODS: Retrospective chart review of clinic patients treated with bevacizumab for macular telangiectasia Type 2. Treatment was performed until no further changes were seen after repeated bevacizumab injections. All patients had Snellen visual acuity testing, fundus fluorescein angiography, and measurement of central macular thickness by optical coherence tomography at baseline. Visual acuity and central macular thickness were recorded at follow-up visits. RESULTS: Fourteen eyes of 10 patients were included. In 5 eyes with nonproliferative macular telangiectasia Type 2, average follow-up was 17 months (+/- 7 months), and no eye demonstrated improvement in visual acuity or decrease in central macular thickness at final follow-up compared with baseline. In 9 eyes with proliferative disease, follow-up averaged 17 months (+/- 9 months). At 6 weeks, central macular thickness decreased 63 MUm (+/- 58 MUm), and acuity improved 1.7 lines (+/- 2 lines). At final follow-up, central macular thickness decreased 48 MUm (+/- 89 MUm) and acuity improved 1.1 lines (+/- 3 lines). Subretinal neovascularization resolved in eight of nine eyes with proliferative disease after treatment. CONCLUSION: Bevacizumab did not improve acuity or reduce retinal thickness in nonproliferative macular telangiectasia Type 2 at final follow-up. In proliferative macular telangiectasia Type 2, bevacizumab caused involution of neovascularization and improved visual acuity. PMID- 21610565 TI - Diagnostic and therapeutic challenges. PMID- 21610564 TI - Functional and morphologic benefits in early detection of neovascular age-related macular degeneration using the preferential hyperacuity perimeter. AB - PURPOSE: To estimate the usefulness of preferential hyperacuity perimetry (PHP) in detecting conversion of early to late age-related macular degeneration in the Carotenoids and co-antioxidants in patients with Age-Related Maculopathy, a multicenter randomized controlled clinical trial. METHODS: This was a nested case control study within the Carotenoids and co-antioxidants in patients with Age Related Maculopathy (CARMA) clinical trial and included all participants enrolled in a single center (n = 200). Data are from participants who progressed to neovascular age-related macular degeneration (nvAMD) during time on study, Group 1 (n = 10) before the use of PHP and Group 2 (n = 10) during use of PHP. We also randomly selected 21 other participants (Group 3) who did not progress to nvAMD during time on study as a control group. Change in best-corrected visual acuity and contrast sensitivity and size of neovascular lesion at detection of conversion to nvAMD in Groups 1 and 2. RESULTS: At detection of nvAMD, mean best corrected visual acuity in Group 1 was 57.5 letters versus 67.4 in Group 2. In Group 1, the change in best-corrected visual acuity from baseline to detection of nvAMD was twice that of Group 2 (21.6 +/- 9.0 versus 11.9 +/- 10.7) with a mean difference of 9.7 letters (95% confidence interval, 0.41 to 19.0, P = 0.04, independent-samples t-test). The size of the neovascular lesion at detection was 3.06 mm in Group 1 versus 0.89 mm in Group 2 (P = 0.02). Two thirds of the participants in Group 2 were asymptomatic at detection of nvAMD compared with one fifth in Group 1. Preferential hyperacuity perimetry distortion maps were abnormal in 9 of 10 eyes in Group 2, which were confirmed by optical coherence tomography. Of the 21 eyes in Group 3, PHP maps were normal in 18 and abnormal in 3. CONCLUSION: Preferential hyperacuity perimetry detected abnormalities in central visual function with high reliability. Eyes with nvAMD lesions detected by PHP had smaller lesions and better function when compared with the group before the introduction of PHP. The false-negative rate was <10% on PHP. The PHP distortion map was helpful in alerting clinicians to the presence of subclinical nvAMD. PMID- 21610566 TI - Intravitreal ranibizumab with or without photodynamic therapy for the treatment of symptomatic polypoidal choroidal vasculopathy. AB - PURPOSE: To evaluate the efficacy of intravitreal ranibizumab with or without verteporfin photodynamic therapy (PDT) in the treatment of symptomatic polypoidal choroidal vasculopathy. METHODS: Twenty-three eyes of 23 patients received 3 monthly intravitreal ranibizumab injections with or without indocyanine green angiography-guided PDT at baseline. All patients had follow-up of >=12 months. Visual and anatomical outcomes were compared between the two groups and a PDT monotherapy group. RESULTS: Seven eyes had ranibizumab monotherapy, 16 had combined ranibizumab injections and verteporfin PDT, and 12 had PDT monotherapy. At 3 months, the mean logarithm of minimal angle of resolution best-corrected visual acuity improved from 0.92 to 0.74 in the ranibizumab group (P = 0.18), from 0.70 to 0.59 in the combined group (P = 0.037), and from 0.74 to 0.57 in the PDT monotherapy group (P = 0.014). Complete regression of polypoidal lesions in indocyanine green angiography was found in 1 (14.3%) eye in the ranibizumab group, compared with 15 (93.8%) eyes in the combined group (P = 0.001). Additional PDT and ranibizumab injections in eyes with persistent polyps and fluorescein leakage resulted in regression of polyps in all eyes. At 12 months, no significant difference in logarithm of minimal angle of resolution best corrected visual acuity and visual change was found between eyes initially treated with ranibizumab monotherapy, combined ranibizumab and PDT, or PDT monotherapy (P = 1.00 and P = 0.11, respectively). CONCLUSION: Intravitreal ranibizumab appeared to result in stabilization of vision in patients with symptomatic polypoidal choroidal vasculopathy. However, combined ranibizumab and PDT appeared to be more effective in causing complete regression of the polypoidal lesions in indocyanine green angiography compared with ranibizumab monotherapy. PMID- 21610567 TI - Increases of vitreous monocyte chemotactic protein 1 and interleukin 8 levels in patients with concurrent hypertension and diabetic retinopathy. AB - PURPOSE: To investigate whether concurrent hypertension affects vitreous cytokine levels in diabetic retinopathy. METHODS: Vitreous samples from 41 patients with diabetic retinopathy with or without concurrent hypertension, who underwent vitrectomy, were collected. Vitreous cytokine concentrations were simultaneously measured using flow cytometry. Patients were stratified according to hypertension or other clinical conditions, and the differences in vitreous levels of monocyte chemotactic protein 1, interleukin 8, vascular endothelial growth factor, interferon-inducible protein 10, and monokine induced by interferon gamma were examined. RESULTS: Vitreous levels of monocyte chemotactic protein 1 and interleukin 8 were significantly (P < 0.05) higher in hypertensive patients than in nonhypertensive patients and were significantly (P < 0.05) higher in active diabetic retinopathy than in inactive diabetic retinopathy. Vitreous levels of vascular endothelial growth factor, interferon-inducible protein 10, and monokine induced by interferon gamma were not affected by the coexistence of hypertension. In multivariate models, active diabetic retinopathy (P = 0.004 and P = 0.007), systolic blood pressure (P = 0.039 and P = 0.041), and hypertension (P = 0.032 and P = 0.035) were significant and independent predictors for increased vitreous monocyte chemotactic protein 1 and interleukin 8 levels. CONCLUSION: Both monocyte chemotactic protein 1 and interleukin 8 levels were elevated in the vitreous of patients with diabetic retinopathy and concurrent hypertension. These findings may help to explain the epidemiologic and clinical evidence that systemic hypertension exacerbates diabetic retinopathy. PMID- 21610568 TI - Calcineurin mediates the protective effect of postconditioning on skeletal muscle. AB - We aimed to investigate whether ischemic postconditioning (I-postC) protects skeletal muscle against ischemia-reperfusion (I/R) injury through the calcineurin (CaN) pathway. Male Wistar rats underwent 4 h of right-hind-limb ischemia induced by clamping the femoral artery, then reperfusion for 2 h (I/R-2 h), 12 h (I/R-12 h), or 24 h (I/R-24 h) with or without I-postC. Ischemic postconditioning was induced by three cycles of 1-min reperfusion and 1-min ischemia at the onset of reperfusion after prolonged ischemia. The I-postC-24 h group was treated with or without cyclosporine A (a CaN inhibitor) 10 mg/kg per day for 3 days before artery occlusion. Cultured skeletal muscle cells (SMCs) from neonatal rats were exposed to 2-h hypoxia then 24-h reoxygenation (H/R), then postconditioned with two cycles of 10-min reoxygenation and 10-min hypoxia after prolonged hypoxia (hypoxia postconditioning [H-postC]) in the presence or absence of cyclosporine A. We observed the effects of activated CaN overexpression on apoptosis and viability of SMCs under H-postC. Ischemic postconditioning attenuated the increase in the level of malondialdehyde in skeletal muscle induced by I/R-2 h and I/R-24 h (P < 0.05) and lactate dehydrogenase in plasma induced by I/R-12 h and I/R-24 h (P < 0.05). Cyclosporine A abolished the protective role of I-postC in malondialdehyde level and lactate dehydrogenase leakage (P < 0.05, vs. I-postC group). Hypoxia postconditioning suppressed SMC apoptosis induced by H/R (P < 0.05, vs. H/R), which was accompanied by increased CaN expression. Cyclosporine A abolished the antiapoptotic effect of H-postC on SMCs (P < 0.05, vs. H-postC group). Overexpression of activated CaN strengthened the cytoprotection of H postC (P < 0.05, vs. H-postC group). Ischemic postconditioning may protect skeletal muscle against I/R injury through the CaN pathway. PMID- 21610569 TI - Trauma-activated polymorphonucleated leukocytes damage endothelial progenitor cells: probable role of CD11b/CD18-CD54 interaction and release of reactive oxygen species. AB - Endothelial progenitor cells (EPCs) and polymorphonucleated leukocytes (PMNLs) migrate to and accumulate at the site of tissue injury where they express complementary sets of surface receptors (CD11b/CD18, CD54), suggesting a possible cellular interaction. Trauma-activated PMNLs release inflammatory mediators and reactive oxygen species (ROS) produced by the NADPH oxidase, which may negatively impact EPCs. To characterize the interactions between PMNLs and EPCs, we identified common surface receptors and measured the role played by NADPH oxidase and neutrophil elastase. Polymorphonucleated leukocytes were obtained from either healthy volunteers or multiple-trauma patients. After stimulation with either n formyl-l-methionyl-l-leucyl-l-phenylalanine or phorbol 12-myristate 13-acetate, the PMNLs were incubated with DiL-prestained EPCs in a ratio of 20:1 for 3 h. Early EPCs were isolated from buffy coat. Endothelial progenitor cell killing was measured by flow cytometry, and necrotic EPCs were identified by measuring the uptake of 7-aminoactinomycin. We found that blocking CD11b, CD18, or CD54 on the EPC surface with monoclonal antibodies or blocking the intracellular production of ROS by neutralizing neutrophil's NADPH oxidase with a diphenyliodonium chloride pretreatment protected EPCs, enhancing its survival, whereas inhibiting neutrophil elastase had no effect on survival. Furthermore, we observed that native PMNLs obtained from multiple-trauma patients damaged EPCs, whereas native PMNLs from healthy volunteers did not. Our results demonstrate that EPCs and PMNLs do interact via complementary receptors and that this interaction results in PMNL-derived ROS-induced EPC damage. The effect of neutrophil-derived elastase was found to be negligible. These findings suggest that EPC damage by activated PMNLs may contribute to impaired wound healing observed after severe trauma. PMID- 21610570 TI - TNF-alpha-decreased thrombomodulin expression in monocytes is inhibited by propofol through regulation of tristetraprolin and human antigen R activities. AB - Thrombomodulin (TM) is expressed on the surface of monocytes and is a key regulator of actual immune capacity. Propofol is an anesthetic agent that exerts anti-inflammatory effects. The objective of this study was to determine whether propofol could modulate TM in TNF-alpha-stimulated monocytes. THP-1 cells and male New Zealand rabbits were used in this study. The results showed that TNF alpha decreases the TM expression by mediating posttranscriptional modification, and this inhibition may be repressed by treatment with propofol. Immunofluorescence, immunoprecipitation, and pull-down assays were used to demonstrate that Rac1-dependent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, Cdc42, and p38 mitogen-activated protein kinase activation, as well as tristetraprolin (TTP) expression, all contributed to the downregulation of TM in TNF-alpha-treated cells. Propofol reversed the effects of TNF-alpha on TM downregulation. Propofol mediated the expression of intracellular TTP and the distribution of cytosolic human antigen R (HuR) and changed their interactions with the 3'-untranslated region of TM mRNA regulating by Cdc42 and Rac1. In addition, the animal study showed that propofol regulates TM, TTP, and HuR expression on monocytes in TNF-alpha-treated rabbits. In conclusion, the inhibition of TM expression in TNF-alpha-treated monocytes was mediated by the activation of NADPH oxidase and the expression of TTP. Propofol may inhibit the downregulation of TM by mediating NADPH oxidase and TTP inactivation and through the activation of HuR in vitro and in vivo. Utilizing TTP and HuR to control TM expression may be a promising approach for controlling systemic inflammation, and propofol may possess potential implications for the clinical immunity of monocytes after anesthesia or surgery. PMID- 21610571 TI - Society of Critical Care Medicine presidential address-40th annual congress, January 2011, San Diego, CA. PMID- 21610572 TI - Quality, patient safety, and culture: 'We have met the enemy and he is us'--Pogo (Walt Kelly, 1971). PMID- 21610573 TI - Beta-blockers: essential heart failure therapy. PMID- 21610574 TI - From the bedside to the bench: how to improve the care of critically ill pregnant patients with influenza. PMID- 21610575 TI - Putting intensive care unit data into the public domain--and using it effectively. PMID- 21610576 TI - Passing the bug--translocation, bacteremia, and sepsis in the intensive care unit patient: is intestinal decontamination the answer? PMID- 21610577 TI - Palliative care makes intensive care units intensive care and intensive caring units. PMID- 21610578 TI - Biomarkers in fever and neutropenia: a solution in search of a problem? PMID- 21610579 TI - The family experience with intensive care unit care: more than mere satisfaction. PMID- 21610580 TI - Making progress with the egress. PMID- 21610581 TI - Mortality prediction in adult respiratory distress syndrome: get real. PMID- 21610582 TI - Surviving fulminant myocarditis: is the head the heart of the matter? PMID- 21610583 TI - Do-not-resuscitate orders in evolution: matching medical interventions with patient goals. PMID- 21610584 TI - "Sepsis--it ain't so much what you don't know that gets you into trouble, it's what you know for sure that just ain't so."--with apologies to Mark Twain. PMID- 21610585 TI - Has extracorporeal membrane oxygenation finally arrived for resuscitation and stabilization of critically ill patients? PMID- 21610586 TI - Page the critical care epidemiologist, STAT! PMID- 21610587 TI - Opening the lungs: do it slowly, please. PMID- 21610588 TI - Stemming electrical outage in myocardial infarction. PMID- 21610589 TI - The brain boggles the mind. PMID- 21610590 TI - From mice to men: treating sepsis with heparin. PMID- 21610591 TI - Targeted temperature management: the jury returns with a verdict. PMID- 21610592 TI - Visualizing the cortical microcirculation in patients with stroke. PMID- 21610593 TI - Experimental studies on ischemic neuroprotection: criteria for translational significance. PMID- 21610594 TI - Ten years later, still "gene in a haystack?". PMID- 21610595 TI - Yes, SIRS--I think we have come full circle. PMID- 21610596 TI - Pulmonary morbidity of catheter-related pediatric venous thromboembolism: old problem, new worry. PMID- 21610597 TI - Providing a good death. PMID- 21610599 TI - Out-of-hospital pediatric cardiac arrest: some clarifications needed. PMID- 21610600 TI - Fluid balance and central venous pressure in sepsis: small pieces in an enormous puzzle. PMID- 21610601 TI - Hydroxyethyl starch-induced bleeding after cardiac surgery. PMID- 21610604 TI - Epistemology of delirium in the critically ill: preemptive or therapeutic approach? PMID- 21610606 TI - Daptomycin pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy. PMID- 21610608 TI - Cuff damage during emergency intubation with the Airtraq optical laryngoscope in the prehospital setting. PMID- 21610610 TI - Therapeutic hypercapnia enhances the inflammatory response to endotoxin in the lung of spontaneously breathing rats. AB - OBJECTIVE: To test the hypothesis that therapeutic hypercapnia enhances the proinflammatory responses to endotoxemia in the lung and spleen of rats. DESIGN: Prospective randomized study. SETTINGS: Hospital research institute. SUBJECTS: Forty-eight adult male rats. INTERVENTIONS: Rats were randomly assigned for a 24 hr period to four breathing groups (n = 11/group), including air (controls), normoxic air with 5% CO2 (therapeutic hypercapnia), air and endotoxemia (5 mg/kg endotoxin), and therapeutic hypercapnia with endotoxemia. After euthanasia, the lung and spleen were removed for pro- and anti-inflammatory cytokine analyses and pulmonary histology evaluation. Four additional rats were used to examine changes in gas exchange and acid-base balance during exposure to therapeutic hypercapnia with and without endotoxemia before and at 4, 12, and 24 hrs into the study, using a permanently catheterized femoral artery. MEASUREMENTS AND MAIN RESULTS: The ratios of proinflammatory cytokines (interleukin-1beta [IL-1beta] and IL-6) and an anti-inflammatory cytokine (IL-10) in the lungs and spleen were used as indices of inflammatory status. The wet-weight to dry-weight ratios, histologic changes in lung interstitial inflammation, and alveolar structures were used as indices of endotoxin-induced acute lung injury. IL-1beta and IL-6 expression was significantly high in the lung of therapeutic hypercapnia-treated endotoxemic rats compared to the lung of rats subjected to only endotoxemia (p < .05 and p < .001, respectively). In the spleen, therapeutic hypercapnia-treated endotoxemic rats had low expression of IL-1beta and IL-6 compared to rats subjected to only endotoxemia (p > .05 and p < .001). Therapeutic hypercapnia following endotoxemic challenge was associated with a proinflammatory response in the lung and an anti inflammatory response in spleen, as assessed by the ratios of IL-1beta and IL-6 to IL-10. The wet-weight to dry-weight ratio and the interstitial space were significantly increased only in therapeutic hypercapnia-treated endotoxemic rats (p < .05). The alveolar-septal thickness was significantly increased by 21% in endotoxemic rats (p < .001) and by 33% in therapeutic hypercapnia-treated endotoxemic rats (p < .001). CONCLUSIONS: A 24-hr exposure to therapeutic hypercapnia in endotoxin-stimulated, spontaneously breathing rats is associated with a proinflammatory immune response in the lung and anti-inflammatory response in the spleen as well as an increase in certain histologic indices of endotoxin induced lung injury. PMID- 21610611 TI - Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest. AB - OBJECTIVE: Post-cardiac-arrest therapeutic hypothermia improves outcomes in comatose cardiac arrest survivors. This study tests the hypothesis that the efficacy of post-cardiac-arrest therapeutic hypothermia is dependent on the onset and duration of therapy. DESIGN: Prospective randomized laboratory investigation. SETTING: University research laboratory. SUBJECTS: A total of 268 male Long Evans rats. INTERVENTIONS: Post-cardiac-arrest therapeutic hypothermia. MEASUREMENTS AND MAIN RESULTS: Adult male Long Evans rats that achieved return of spontaneous circulation after a 10-min asphyxial cardiac arrest were block randomized to normothermia (37 degrees C +/- 1 degrees C) or therapeutic hypothermia (33 degrees C +/- 1 degrees C) initiated 0, 1, 4, or 8 hrs after return of spontaneous circulation and maintained for 24 or 48 hrs. Therapeutic hypothermia initiated 0, 1, 4, and 8 hrs after return of spontaneous circulation resulted in 7-day survival rates of 45%*, 36%*, 36%*, and 14%, respectively, compared to 17% for normothermic controls and survival with good neurologic function rates of 24%*, 24%*, 19%*, and 0%, respectively, compared to 2% for normothermic controls (*p < .05 vs. normothermia). These outcomes were not different when therapeutic hypothermia was maintained for 24 vs. 48 hrs. In contrast, hippocampal CA1 pyramidal neuron counts were 53% +/- 27%*, 53% +/- 19%*, 51% +/- 24%*, and 65% +/ 16%* of normal, respectively, when therapeutic hypothermia was initiated 0, 1, 4, or 8 hrs after return of spontaneous circulation compared to 9% in normothermic controls (*p < .01 vs. normothermia). Furthermore, surviving neuron counts were greater when therapeutic hypothermia was maintained for 48 hrs compared to 24 hrs (68% +/- 15%* vs. 42% +/- 22%, *p < .0001). CONCLUSIONS: In this study, post-cardiac-arrest therapeutic hypothermia resulted in comparable improvement of survival and survival with good neurologic function when initiated within 4 hrs after return of spontaneous circulation. However, histologic assessment of neuronal survival revealed a potentially broader therapeutic window and greater neuroprotection when therapeutic hypothermia was maintained for 48 vs. 24 hrs. PMID- 21610612 TI - Distinguishing chemical pneumonitis from bacterial aspiration: still a clinical determination. PMID- 21610613 TI - Is the time right for 24-hr/7-day coverage? PMID- 21610614 TI - Glutamine: the struggle for proof? PMID- 21610615 TI - The patient is in cardiac arrest! Let's be snappy: prepare a bolus of sodium nitroprusside, while I compress the chest. It's not a joke! PMID- 21610616 TI - Let the treatment fit the disease. PMID- 21610617 TI - Intestinal glucose absorption and glycemic response in the critically ill: the sweet Odyssey continues. PMID- 21610618 TI - Cytochrome c oxidase predicts the toll of sepsis. PMID- 21610619 TI - Bone loss during critical illness: a skeleton in the closet for the intensive care unit survivor? PMID- 21610620 TI - Should we still need to systematically perform catheter culture in the intensive care unit? PMID- 21610621 TI - Dollars and sense in sepsis. PMID- 21610622 TI - Trial designs for old problems in a new era. PMID- 21610623 TI - Refractory hypoxemia: How to treat it in the real world. PMID- 21610624 TI - Renal protection during liver transplantation: an ounce of prevention is worth a pound of cure. PMID- 21610625 TI - Colloids and renal dysfunction: another brick in the wall of safety concerns. PMID- 21610626 TI - Statins and sepsis: a magic bullet or just shooting blanks? PMID- 21610627 TI - Arginine and sepsis: a question of the right balance? PMID- 21610628 TI - Therapeutic hypothermia: is there an unintended surcharge? PMID- 21610629 TI - Does it help us to know what questions our patients' families might want to ask? PMID- 21610630 TI - Arterial catheters: "they don't get no respect". PMID- 21610631 TI - Time to fire the sim educators? Not quite yet. PMID- 21610632 TI - Do we really have other tools for respiratory failure besides mechanical ventilation? PMID- 21610633 TI - Conflicting roles of FcgammaRIIa H131R polymorphism in pneumonia. PMID- 21610634 TI - Systemic arterial pressure and fluid responsiveness: not only a swing story. PMID- 21610635 TI - Hypercapnia in acute illness: sometimes good, sometimes not. PMID- 21610636 TI - Blockade of interleukin-6 in murine sepsis revisited: is there an indication for a new therapy in human patients? PMID- 21610637 TI - Human serum albumin as a resuscitation fluid: less SAFE than presumed? PMID- 21610638 TI - Therapeutic hypothermia after cardiac arrest: it's about time. PMID- 21610639 TI - The n-3 polyunsaturated fatty acids: another option in the management of persistent pulmonary hypertension of the newborn? PMID- 21610640 TI - From xenon to argon: a more clinically accessible neuroprotectant? PMID- 21610641 TI - "C" is for sepsis? PMID- 21610642 TI - Dilate, dilute, constrict, or else in treating hemorrhage? PMID- 21610643 TI - New uses for my old friend. PMID- 21610644 TI - Mind over matter! PMID- 21610645 TI - Choosing brain over lungs: who wins? PMID- 21610646 TI - Kidney injury in kids following bypass surgery: more to know. PMID- 21610647 TI - Traumatic shock resuscitation with a 1:1 plasma to packed red blood cell ratio: is it to please ourselves or the injured? PMID- 21610648 TI - Benefits of statins in the critically ill: promising but not proven. PMID- 21610649 TI - Toxic epidermal necrolysis and Stevens-Johnson syndrome: things we should know! PMID- 21610650 TI - 'Reversible brain death'--is it true, confounded, or 'not proven'? PMID- 21610652 TI - A potential selection bias in the study of early combination antibiotic therapy versus monotherapy in septic shock. PMID- 21610653 TI - Informed consent for organ-donor management research: antemortem or postmortem human research. PMID- 21610656 TI - Mangiferin, an anti-HIV-1 agent targeting protease and effective against resistant strains. AB - The anti-HIV-1 activity of mangiferin was evaluated. Mangiferin can inhibit HIV 1(III)(B) induced syncytium formation at non-cytotoxic concentrations, with a 50% effective concentration (EC50) at 16.90 MUM and a therapeutic index (TI) above 140. Mangiferin also showed good activities in other laboratory-derived strains, clinically isolated strains and resistant HIV-1 strains. Mechanism studies revealed that mangiferin might inhibit the HIV-1 protease, but is still effective against HIV peptidic protease inhibitor resistant strains. A combination of docking and pharmacophore methods clarified possible binding modes of mangiferin in the HIV-1 protease. The pharmacophore model of mangiferin consists of two hydrogen bond donors and two hydrogen bond acceptors. Compared to pharmacophore features found in commercially available drugs, three pharmacophoric elements matched well and one novel pharmacophore element was observed. Moreover, molecular docking analysis demonstrated that the pharmacophoric elements play important roles in binding HIV-1 protease. Mangiferin is a novel nonpeptidic protease inhibitor with an original structure that represents an effective drug development strategy for combating drug resistance. PMID- 21610657 TI - A screening of a library of T7 phage-displayed peptide identifies E2F-4 as an etoposide-binding protein. AB - Etoposide (VP-16) is an anti-tumor compound that targets topoisomerase II (top II). In this study, we have identified an alternative binding protein of etoposide by screening a library of T7 phage-displayed peptides. After four rounds of selection using a biotinylated etoposide derivative immobilized on a streptavidin-coated plate, T7 phage particles that display a 16-mer peptide NSSASSRGNSSSNSVY (ETBP16) or a 10-mer NSLRKYSKLK (ETBP10) were enriched with the ratio of 40 or 11 out of the 69 clones, respectively. Binding of etoposide to these peptides was confirmed by surface plasmon resonance (SPR) analysis, which showed ETBP16 and ETBP10 to have a kinetic constant of 4.85 * 10-5 M or 6.45 * 10 5 M, respectively. ETBP16 displays similarity with the ser-rich domain in E2F-4, a transcription factor in cell cycle-regulated genes, suggesting that etoposide might interact with E2F-4 via this domain. SPR analysis confirmed the specific binding of etoposide to recombinant E2F-4 is in the order of 10-5 M. Furthermore, etoposide was shown to inhibit luciferase reporter gene expression mediated by the heterodimeric E2F-4/DP complex. Taken together, our results suggest that etoposide directly binds to E2F-4 and inhibits subsequent gene transcription mediated by heterodimeric E2F-4/DP complexes in the nucleus. PMID- 21610658 TI - Transformation of geniposide into genipin by immobilized beta-glucosidase in a two-phase aqueous-organic system. AB - Genipin is the bioactive compound of geniposide and a natural cross-linking agent. In order to improve the preparation process of genipin, the hydrolysis of geniposide to genipin by immobilized beta-glucosidase in an aqueous-organic two phase system was studied. beta-glucosidase was immobilized by the crosslinking embedding method using sodium alginate as the carrier. The optimum reaction temperature, pH value and time were 55 degrees C, 4.5 and 2.5 h, respectively. To reduce genipin hydrolysis and byproduct production the reaction was carried out in an aqueous-organic two-phase system comprising ethyl acetate and sodium acetate buffer. The product was analyzed by HPLC, UV, IR, and NMR. The yield of genipin was 47.81% and its purity was over 98% (HPLC). PMID- 21610659 TI - Synthesis, and antitumor activity of some N1-(coumarin-7-yl) amidrazones and related congeners. AB - A series of new N1-(coumarin-7-yl)amidrazones incorporating N-piperazines and related congeners were synthesized by reacting the hydrazonoyl chloride derived from 7-amino-4-methylcoumarin with the appropriate piperazines. The chemical structures of the newly prepared compounds were supported by elemental analyses, 1H-NMR, 13C-NMR, and ESI-HRMS spectral data. The antitumor activity of the newly synthesized compounds was evaluated. Among all the compounds tested, 7-{2-[1-(4 (1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-1-yl)-2 oxopropylidene]hydrazinyl}-4-methyl-2H-chromen-2-one (3n) was the most potent against MCF-7 and K562 cells, with IC50 values of 20.2 and 9.3 MUM, respectively. PMID- 21610660 TI - Chemical composition, and antioxidant and antimicrobial activities of essential Oil of Phyllostachys heterocycla cv. Pubescens varieties from China. AB - The essential oils of Phyllostachys heterocycla cv. Pubescens, Phyllostachys heterocycla cv. Gracilis, Phyllostachys heterocycla cv. Heterocycla and Phyllostachys kwangsiensis leaves were obtained by steam distillation. Their chemical components were separated and identified by gas chromatography/mass spectrometry (GC/MS). Meanwhile, the effect of scavenging free radicals of essential oil was assayed by using the DPPH.method with Trolox(r) as control to evaluate their antioxidant capacities. Gram-positive (Staphyloccocus aureus) and Gram-negative (Escherichia coli) were selected as the indicator microorganisms to evaluate the antimicrobial activity. Antimicrobial properties were estimated by the agar diffusion method. The results show that 63 components were separated and identified by GC/MS from these varieties of bamboo leaves. cis-3-Hexenol, whose content in cv. Pubescens, Gracilis, Heterocycla and Ph. kwangsiensis was 27.11%, 24.62%, 30.51% and 34.65%, respectively, was the main constituent. The relative content of alcohol compounds in these varieties of essential oils ranged from 39.8% to 46.64%. All of the bamboo leaf essential oils possessed certain antioxidant capacity; the corresponding IC50 values were 3.1622, 4.9353, 4.2473, and 5.4746 MUL/mL, respectively. Essential oils of all tested bamboo spp. were active against Staphylococcus epidermidis and E. coli, showing a positive correlation with the essential oil concentration of 50.42-300 MUL/mL. The results indicated there were no significant differences among three varieties and the related species with respect to their antioxidant and antimicrobial activities. This paper provides evidence for studying the essential composition from different varieties of bamboo leaves. PMID- 21610661 TI - Randomized Olmesartan And Diabetes Microalbuminuria Prevention Study (ROADMAP). PMID- 21610662 TI - The application of FRAX(r) to determine intervention thresholds in osteoporosis treatment in Poland. AB - INTRODUCTION: FRAX(r), an assessment algorithm for estimating fracture probability, has been widely used for the evaluation of osteoporosis since 2008. Its clinical use requires that osteoporotic fracture probability is established at which treatment can be recommended. OBJECTIVES: The aim of the present study was to explore possible treatment thresholds for Poland. PATIENTS AND METHODS: The FRAX-based probabilities were calculated in 1608 unselected postmenopausal women from Bialystok using the British model (version 3.1). Intervention thresholds were set at fracture probability equal to women with a bone mass density (BMD) T-score of -2.5 standard deviation (criterion A), equal to women with a prior fracture using a fixed threshold irrespective of age (criterion B), or an age-dependent threshold (criterion C). Additionally, we assumed that all women with a prior fracture would be eligible for treatment plus those with a fracture probability equal to women with a prior fracture using a fixed threshold (criterion D). RESULTS: Mean 10-year probability of a major osteoporotic fracture was 10.9% when BMD was not included in the FRAX calculation and 11.6% with BMD included. In women with a prior fragility fracture, the respective probabilities were 18.0% and 17.4%. For criterion A, 39% women aged 50 years or more would be eligible for treatment, for criterion D--35%, and for criteria B and C--16%. For criteria B and C, women with higher risk would be eligible for treatment compared with criteria A and D. Assuming a relative fracture risk reduction of 30%, the number needed to treat (NNT) to prevent a major fracture was lower for criteria B and C (NNT = 13 and 14, respectively) than for criteria A and D (NNT = 18). CONCLUSIONS: The use of intervention thresholds based on the probabilities equal to women with a prior fracture is most efficient. The use of an age-specific threshold may be more clinically appropriate than a fixed probability threshold for all ages. PMID- 21610663 TI - Incidence of diabetes in the Polish population: results of the Multicenter Polish Population Health Status Study--WOBASZ. AB - INTRODUCTION: Incidence of diabetes is increasing at an alarming rate worldwide. It has been estimated that 2.2 to 2.5 million of Poles will be affected by this disease by 2030. OBJECTIVES: The aim of the study was to conduct an epidemiological analysis of the incidence of diabetes and impaired fasting glucose (IFG) in the Polish population. PATIENTS AND METHODS: A sample of 21,600 individuals (men and women) aged 20-74 years was randomly selected from the general Polish population. A total of 14,769 individuals took part in the study (6977 men and 7792 women). Diabetes was identified in individuals with fasting glucose equal to or exceeding 7 mmol/l and in those with previously diagnosed diabetes. IFG was identified in nontreated individuals with fasting glucose between 5.6 and 6.9 mmol/l. RESULTS: Diabetes was diagnosed in 1000 individuals (6.8%), including 518 men (7.4%) and 482 women (6.2%). IFG was detected in 1401 individuals (9.5%), including 864 men (12.4%) and 537 women (6.9%). Incidence of diabetes increases with age: in men from 0.7% in those aged 20-29 years to 16.3% in those aged >60 years; in women from 0.5% in the youngest age group to 17.8% in the oldest group. Incidence of diabetes in Poland varies between the provinces- from 5.3% to 9% among men and from 4.2% to 7.5% among women. There was no significant correlation between the incidence of diabetes and the size of a particular local district (commune; gmina). Similar territorial differences were observed for IFG, i.e., from 5.8% to 20.8% among men and from 2.8% to 11.7% among women. As with diabetes, the incidence of IFG was not associated with the size of a commune. CONCLUSIONS: Incidence of diabetes and IFG in the study population varies depending on age, sex, and region. Incidence of diabetes in Poland is comparable to the average values observed worldwide. PMID- 21610664 TI - Lipid-lowering drugs and control of hypercholesterolemia in Poland: recent evidence. AB - The role of hypercholesterolemia as a risk factor for cardiovascular disease has been well-documented. Hypercholesterolemia is the most prevalent modifiable risk factor in Poland. Despite the fact that the benefits of cholesterol lowering have been known for a long time, the therapeutic goals recommended by guidelines are still often not attained in clinical practice. Only 3% of Poles with hypercholesterolemia achieve recommended cholesterol levels, and the rate of reaching recommended goals among patients receiving lipid-lowering drugs is low, approximately 30%. Control of hypercholesterolemia is not satisfactory also in patients with ischemic heart disease. The introduction of new statins, use of higher statin doses, and the evidence pointing to the effectiveness of combination therapy have provided us with effective tools whose broad application in everyday practice may lead to a significant improvement in the control of hypercholesterolemia in Poland. PMID- 21610665 TI - A new difficult airway management algorithm based upon the El Ganzouri Risk Index and GlideScope(r) videolaryngoscope. A new look for intubation? AB - BACKGROUND: An El Ganzouri risk index test (EGRI) score of seven and the ability to achieve difficult laryngeal exposure with the GlideScope(r) may represent a highly predictive decisional threshold. Hence, we hypothesized that a new difficult airways algorithm that is EGRI- and GlideScope(r)-based may enable tracheal intubation in every patient. METHODS: Thirteen staff practitioners trained in videolaryngoscopic intubation followed the algorithm from 2008 through 2010. Elective and emergency neurosurgical patients assessed as having an EGRI score of seven and higher underwent flexible fiberoptic bronchoscopy (FFB) intubation while conscious. Those with a score of six and lower were intubated with the GlideScope(r), excluding patients with morbid obesity or pharyngo laryngeal or neck tumors. A decision to perform alternative procedures, difficult laryngeal exposure [Cormack and Lehane (CL) grades III-IV], difficult ventilation and failure to intubate were recorded. RESULTS: The decisional rule was applied in 6,276 patients and resulted in six FFB intubations in conscious patients. The overall incidence of CL grade III-IV views was 0.2%. Difficult videolaryngoscopy was found in 14 patients (0.14%) with a score of 6 and lower. Post-hoc examinations of FFB intubations revealed five difficult laryngeal exposures. The positive predictive value was 85.7%, while the negative predictive value was 99.9%. The incidence of difficult ventilation and difficult laryngeal exposure was 0.03%. Two patients with neck tumors were assigned to alternative procedures. CONCLUSION: Adherence to the decisional process of the algorithm and to GlideScope(r) videolaryngoscopy achieved successful tracheal intubation in our cohort of patients. PMID- 21610667 TI - Genomic MRI--a public resource for studying sequence patterns within genomic DNA. AB - Non-coding genomic regions in complex eukaryotes, including intergenic areas, introns, and untranslated segments of exons, are profoundly non-random in their nucleotide composition and consist of a complex mosaic of sequence patterns. These patterns include so-called Mid-Range Inhomogeneity (MRI) regions--sequences 30-10000 nucleotides in length that are enriched by a particular base or combination of bases (e.g. (G+T)-rich, purine-rich, etc.). MRI regions are associated with unusual (non-B-form) DNA structures that are often involved in regulation of gene expression, recombination, and other genetic processes (Fedorova & Fedorov 2010). The existence of a strong fixation bias within MRI regions against mutations that tend to reduce their sequence inhomogeneity additionally supports the functionality and importance of these genomic sequences (Prakash et al. 2009). Here we demonstrate a freely available Internet resource- the Genomic MRI program package--designed for computational analysis of genomic sequences in order to find and characterize various MRI patterns within them (Bechtel et al. 2008). This package also allows generation of randomized sequences with various properties and level of correspondence to the natural input DNA sequences. The main goal of this resource is to facilitate examination of vast regions of non-coding DNA that are still scarcely investigated and await thorough exploration and recognition. PMID- 21610668 TI - Ex vivo culture of primary human fallopian tube epithelial cells. AB - Epithelial ovarian cancer is a leading cause of female cancer mortality in the United States. In contrast to other women-specific cancers, like breast and uterine carcinomas, where death rates have fallen in recent years, ovarian cancer cure rates have remained relatively unchanged over the past two decades (1). This is largely due to the lack of appropriate screening tools for detection of early stage disease where surgery and chemotherapy are most effective (2, 3). As a result, most patients present with advanced stage disease and diffuse abdominal involvement. This is further complicated by the fact that ovarian cancer is a heterogeneous disease with multiple histologic subtypes (4, 5). Serous ovarian carcinoma (SOC) is the most common and aggressive subtype and the form most often associated with mutations in the BRCA genes. Current experimental models in this field involve the use of cancer cell lines and mouse models to better understand the initiating genetic events and pathogenesis of disease (6, 7). Recently, the fallopian tube has emerged as a novel site for the origin of SOC, with the fallopian tube (FT) secretory epithelial cell (FTSEC) as the proposed cell of origin (8, 9). There are currently no cell lines or culture systems available to study the FT epithelium or the FTSEC. Here we describe a novel ex vivo culture system where primary human FT epithelial cells are cultured in a manner that preserves their architecture, polarity, immunophenotype, and response to physiologic and genotoxic stressors. This ex vivo model provides a useful tool for the study of SOC, allowing a better understanding of how tumors can arise from this tissue, and the mechanisms involved in tumor initiation and progression. PMID- 21610669 TI - Use of fluorescent immuno-chemistry for the detection of Edwardsiella ictaluri in channel catfish (I. punctatus) samples. AB - While Edwardsiella ictaluri is a major pathogen of channel catfish Ictalurus punctatus and has been discovered nearly three decades ago (1,2), so far, to the best of these authors' knowledge, no method has been developed to allow for the in situ visualization of the bacteria in histological sections. While bacterial localization has been determined in vivo in previous studies using plate counts (3), radiometric labeled (4), or bioluminescent bacteria (5), most of these studies have only been performed at the gross organ level, with one exception (6). This limitation is of particular concern because E. ictaluri has a complex infection cycle (1,7), and it has a variety of virulence factors (8,9). The complex interaction of E. ictaluri with its host is similar in many respects to Salmonella typhi (10), which is in the same taxonomic family. Here we describe a technique allowing for the detection of bacteria using indirect immuno histochemistry using the monoclonal Ed9 antibody described by Ainsworth et al.(11). Briefly, a blocking serum is applied to paraffin embedded histological sections to prevent non-specific biding. Then, the sections are incubated with the primary antibody: E. ictaluri specific monoclonal antibody Ed9. Excess antibodies are rinsed away and the FitC labeled secondary antibodies are added. After rinsing, the sections are mounted with a fluorescent specific mounting medium. This allowed for the detection of E. ictaluri in situ in histological sections of channel catfish tissues. PMID- 21610670 TI - Seven steps to stellate cells. AB - Hepatic stellate cells are liver-resident cells of star-like morphology and are located in the space of Disse between liver sinusoidal endothelial cells and hepatocytes(1,2). Stellate cells are derived from bone marrow precursors and store up to 80% of the total body vitamin A(1, 2). Upon activation, stellate cells differentiate into myofibroblasts to produce extracellular matrix, thus contributing to liver fibrosis(3). Based on their ability to contract, myofibroblastic stellate cells can regulate the vascular tone associated with portal hypertension(4). Recently, we demonstrated that hepatic stellate cells are potent antigen presenting cells and can activate NKT cells as well as conventional T lymphocytes(5). Here we present a method for the efficient preparation of hepatic stellate cells from mouse liver. Due to their perisinusoidal localization, the isolation of hepatic stellate cells is a multi step process. In order to render stellate cells accessible to isolation from the space of Disse, mouse livers are perfused in situ with the digestive enzymes Pronase E and Collagenase P. Following perfusion, the liver tissue is subjected to additional enzymatic treatment with Pronase E and Collagenase P in vitro. Subsequently, the method takes advantage of the massive amount of vitamin A storing lipid droplets in hepatic stellate cells. This feature allows the separation of stellate cells from other hepatic cell types by centrifugation on an 8% Nycodenz gradient. The protocol described here yields a highly pure and homogenous population of stellate cells. Purity of preparations can be assessed by staining for the marker molecule glial fibrillary acidic protein (GFAP), prior to analysis by fluorescence microscopy or flow cytometry. Further, light microscopy reveals the unique appearance of star-shaped hepatic stellate cells that harbor high amounts of lipid droplets. Taken together, we present a detailed protocol for the efficient isolation of hepatic stellate cells, including representative images of their morphological appearance and GFAP expression that help to define the stellate cell entity. PMID- 21610671 TI - An in vivo rodent model of contraction-induced injury and non-invasive monitoring of recovery. AB - Muscle strains are one of the most common complaints treated by physicians. A muscle injury is typically diagnosed from the patient history and physical exam alone, however the clinical presentation can vary greatly depending on the extent of injury, the patient's pain tolerance, etc. In patients with muscle injury or muscle disease, assessment of muscle damage is typically limited to clinical signs, such as tenderness, strength, range of motion, and more recently, imaging studies. Biological markers, such as serum creatine kinase levels, are typically elevated with muscle injury, but their levels do not always correlate with the loss of force production. This is even true of histological findings from animals, which provide a "direct measure" of damage, but do not account for all the loss of function. Some have argued that the most comprehensive measure of the overall health of the muscle in contractile force. Because muscle injury is a random event that occurs under a variety of biomechanical conditions, it is difficult to study. Here, we describe an in vivo animal model to measure torque and to produce a reliable muscle injury. We also describe our model for measurement of force from an isolated muscle in situ. Furthermore, we describe our small animal MRI procedure. PMID- 21610672 TI - Microsurgical venous pouch arterial-bifurcation aneurysms in the rabbit model: technical aspects. AB - For ruptured human cerebral aneurysms endovascular embolization has become an equivalent alternative to aneurysm clipping.(1) However, large clinical trials have shown disappointing long-term results with unacceptable high rates of aneurysm recanalization and delayed aneurysm rupture.(2) To overcome these problems, animal experimental studies are crucial for the development of better endovascular devices.(3-5) Several animal models in rats, rabbits, canines and swine are available.(6-8) Comparisons of the different animal models showed the superiority of the rabbit model with regard to hemodynamics and comparability of the coagulation system and cost-effectiveness.(9-11) The venous pouch arterial bifurcation model in rabbits is formed by a venous pouch sutured into an artificially created true bifurcation of both common carotid arteries (CCA). The main advantage of this model are true bifurcational hemodynamics.(12) The major drawbacks are the sofar high microsurgical technical demands and high morbidity and mortality rates of up to 50%.(13) These limitations have resulted in less frequent use of this aneurysm model in the recent years. These shortcomings could be overcome with improved surgical procedures and modified peri- and postoperative analgetic management and anticoagulation.(14-16) Our techniques reported in this paper demonstrate this optimized technique for microsurgical creation of arterial bifurcation aneurysms. PMID- 21610673 TI - Optic nerve transection: a model of adult neuron apoptosis in the central nervous system. AB - Retinal ganglion cells (RGCs) are CNS neurons that output visual information from the retina to the brain, via the optic nerve. The optic nerve can be accessed within the orbit of the eye and completely transected (axotomized), cutting the axons of the entire RGC population. Optic nerve transection is a reproducible model of apoptotic neuronal cell death in the adult CNS (1-4). This model is particularly attractive because the vitreous chamber of the eye acts as a capsule for drug delivery to the retina, permitting experimental manipulations via intraocular injections. The diffusion of chemicals through the vitreous fluid ensures that they act upon the entire RGC population. Moreover, RGCs can be selectively transfected by applying short interfering RNAs (siRNAs), plasmids, or viral vectors to the cut end of the optic nerve (5-7) or injecting vectors into their target, the superior colliculus (8). This allows researchers to study apoptotic mechanisms in the desired neuronal population without confounding effects on other bystander neurons or surrounding glia. An additional benefit is the ease and accuracy with which cell survival can be quantified after injury. The retina is a flat, layered tissue and RGCs are localized in the innermost layer, the ganglion cell layer. The survival of RGCs can be tracked over time by applying a fluorescent tracer (3% Fluorogold) to the cut end of the optic nerve at the time of axotomy, or by injecting the tracer into the superior colliculus (RGC target) one week prior to axotomy. The tracer is retrogradely transported, labeling the entire RGC population. Because the ganglion cell layer is a monolayer (one cell thick), RGC densities can be quantified in flat-mounted tissue, without the need for stereology. Optic nerve transection leads to the apoptotic death of 90% of injured RGCs within 14 days postaxotomy (9-11). RGC apoptosis has a characteristic time-course whereby cell death is delayed 3-4 days postaxotomy, after which the cells rapidly degenerate. This provides a time window for experimental manipulations directed against pathways involved in apoptosis. PMID- 21610674 TI - Methods for experimental manipulations after optic nerve transection in the Mammalian CNS. AB - Retinal ganglion cells (RGCs) are CNS neurons that output visual information from the retina to the brain, via the optic nerve. The optic nerve can be accessed within the orbit of the eye and completely transected (axotomized), cutting the axons of the entire RGC population. Optic nerve transection is a reproducible model of apoptotic neuronal cell death in the adult CNS (1-4). This model is particularly attractive because the vitreous chamber of the eye acts as a capsule for drug delivery to the retina, permitting experimental manipulations via intraocular injections. The diffusion of chemicals through the vitreous fluid ensures that they act upon the entire RGC population. Viral vectors, plasmids or short interfering RNAs (siRNAs) can also be delivered to the vitreous chamber in order to infect or transfect retinal cells (5-12). The high tropism of Adeno Associated Virus (AAV) vectors is beneficial to target RGCs, with an infection rate approaching 90% of cells near the injection site (6, 7, 13-15). Moreover, RGCs can be selectively transfected by applying siRNAs, plasmids, or viral vectors to the cut end of the optic nerve (16-19) or injecting vectors into their target the superior colliculus (10). This allows researchers to study apoptotic mechanisms in the injured neuronal population without confounding effects on other bystander neurons or surrounding glia. RGC apoptosis has a characteristic time-course whereby cell death is delayed 3-4 days postaxotomy, after which the cells rapidly degenerate. This provides a window for experimental manipulations directed against pathways involved in apoptosis. Manipulations that directly target RGCs from the transected optic nerve stump are performed at the time of axotomy, immediately after cutting the nerve. In contrast, when substances are delivered via an intraocular route, they can be injected prior to surgery or within the first 3 days after surgery, preceding the initiation of apoptosis in axotomized RGCs. In the present article, we demonstrate several methods for experimental manipulations after optic nerve transection. PMID- 21610675 TI - Dissection and staining of Drosophila larval ovaries. AB - Many organs depend on stem cells for their development during embryogenesis and for maintenance or repair during adult life. Understanding how stem cells form, and how they interact with their environment is therefore crucial for understanding development, homeostasis and disease. The ovary of the fruit fly Drosophila melanogaster has served as an influential model for the interaction of germ line stem cells (GSCs) with their somatic support cells (niche) (1, 2). The known location of the niche and the GSCs, coupled to the ability to genetically manipulate them, has allowed researchers to elucidate a variety of interactions between stem cells and their niches (3-12). Despite the wealth of information about mechanisms controlling GSC maintenance and differentiation, relatively little is known about how GSCs and their somatic niches form during development. About 18 somatic niches, whose cellular components include terminal filament and cap cells (Figure 1), form during the third larval instar (13-17). GSCs originate from primordial germ cells (PGCs). PGCs proliferate at early larval stages, but following the formation of the niche a subgroup of PGCs becomes GSCs (7, 16, 18, 19). Together, the somatic niche cells and the GSCs make a functional unit that produces eggs throughout the lifetime of the organism. Many questions regarding the formation of the GSC unit remain unanswered. Processes such as coordination between precursor cells for niches and stem cell precursors, or the generation of asymmetry within PGCs as they become GSCs, can best be studied in the larva. However, a methodical study of larval ovary development is physically challenging. First, larval ovaries are small. Even at late larval stages they are only 100MUm across. In addition, the ovaries are transparent and are embedded in a white fat body. Here we describe a step-by-step protocol for isolating ovaries from late third instar (LL3) Drosophila larvae, followed by staining with fluorescent antibodies. We offer some technical solutions to problems such as locating the ovaries, staining and washing tissues that do not sink, and making sure that antibodies penetrate into the tissue. This protocol can be applied to earlier larval stages and to larval testes as well. PMID- 21610676 TI - Isolation of Drosophila melanogaster testes. AB - The testes of Drosophila melanogaster provide an important model for the study of stem cell maintenance and differentiation, meiosis, and soma-germline interactions. Testes are typically isolated from adult males 0-3 days after eclosion from the pupal case. The testes of wild-type flies are easily distinguished from other tissues because they are yellow, but the testes of white mutant flies, a common genetic background for laboratory experiments are similar in both shape and color to the fly gut. Performing dissection on a glass microscope slide with a black background makes identifying the testes considerably easier. Testes are removed from the flies using dissecting needles. Compared to protocols that use forceps for testes dissection, our method is far quicker, allowing a well-practiced individual to dissect testes from 200-300 wild type flies per hour, yielding 400-600 testes. Testes from white flies or from mutants that reduce testes size are harder to dissect and typically yield 200-400 testes per hour. PMID- 21610677 TI - Cannulation of the mouse submandibular salivary gland via the Wharton's duct. AB - Severe salivary gland hypofunction is frequently found in patients with Sjogren's syndrome and those who receiving therapeutic irradiation in their head and neck regions for cancer treatment. Both groups of patients experience symptoms such as xerostomia (dry mouth), dysphagia (impaired chewing and swallowing), severe dental caries, altered taste, oro-pharyngeal infections (candidiasis), mucositis, pain and discomfort. One innovative approach of regenerative medicine for the treatment of salivary gland hypo-function is speculated in RS Redman, E Mezey et al. 2009: stem cells can be directly deposited by cannulation into the gland as a potent method in reviving the functions of the impaired organ. Presumably, the migrated foreign stem cells will differentiate into glandular cells to function as part of the host salivary gland. Also, this cannulation technique is an expedient and effective delivery method for clinical gene transfer application. Here we illustrate the steps involved in performing the cannulation procedure on the mouse submandibular salivary gland via the Wharton's duct (Fig 1). C3H mice (Charles River, Montreal, QC, Canada) are used for this experiment, which have been kept under clean conventional conditions at the McGill University animal resource center. All experiments have been approved by the University Animal Care Committee and were in accordance with the guidelines of the Canadian Council on Animal Care. For this experiment, a trypan blue solution is infused into the gland through the opening of the Wharton's duct using a insulin syringe with a 29 gauge needle encased inside a polyethylene tube. Subsequently, the mouse is dissected to show that the infusions migrated into the gland successfully. PMID- 21610678 TI - Pediatrics: Extracellular volume in children with chronic kidney disease. PMID- 21610679 TI - Diabetes: ROADMAP: the road to renoprotection? PMID- 21610680 TI - BK polyomavirus infection and nephropathy: the virus-immune system interplay. AB - Reactivation of latent BK polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients. PMID- 21610681 TI - Chronic kidney disease: Association between ESA use and stroke in patients with CKD. PMID- 21610683 TI - Robotic surgery shows promise for the treatment of PTMC. PMID- 21610682 TI - New short interfering RNA-based therapies for glomerulonephritis. AB - Current treatments for glomerulonephritis are not satisfactory, and the development of new therapies would be indispensable. Short interfering RNAs (siRNAs) are promising candidates for molecular therapy because of their strong and specific gene-silencing effects. Despite rapid progress in research into the therapeutic uses of siRNAs, however, many hurdles must be overcome before siRNA based therapies can be brought to the clinic. Most in vivo studies of siRNA-based therapy have been limited to local administration or delivery to specific target organs, including the liver. Therapies based on siRNAs for patients with glomerulonephritis show promise, although tissue-specific protocols using siRNAs have not yet been established for this indication. This Review aims to provide an overview of the current challenges in siRNA-based therapy, primarily with respect to glomerular targeting. In addition, novel delivery approaches for glomerulus targeted, siRNA-based therapies are described. PMID- 21610685 TI - BMD and fracture risk in T2DM-clarifying a paradox. PMID- 21610684 TI - Reproductive tract function and dysfunction in women. AB - An appropriately developed and functional reproductive tract is essential for the natural production of offspring. However, abnormal development or disease, either within or external to the reproductive tract, can cause considerable morbidity and mortality. This Review describes the normal function of each section of the female reproductive tract. Some of the major conditions and diseases that cause reproductive tract dysfunction in women of reproductive age are reviewed, with a focus on endocrine-related dysfunction. As the female reproductive tract is vital for the continuation of the human species, it is crucial to have an improved understanding of how the cells and tissues of this system interact under normal conditions and to define how hormonal and genetic abnormalities cause pathophysiologic derangement of reproduction. PMID- 21610686 TI - Update on bone-modifying agents in metastatic breast cancer. PMID- 21610688 TI - Puberty induction in Turner syndrome. PMID- 21610687 TI - A comprehensive review of the clinical aspects of primary aldosteronism. AB - Primary aldosteronism is much more common than previously thought. The high prevalence of primary aldosteronism, the damage this condition does to the heart, blood vessels and kidneys (which causes a high rate of cardiovascular events), along with the notion that a timely diagnosis followed by an appropriate therapy can correct the arterial hypertension and hypokalemia, justify efforts to search for primary aldosteronism in many patients with hypertension. Most centers can use a cost-effective strategy to screen for patients with primary aldosteronism. By contrast, the identification of primary aldosteronism subtypes, which involves adrenal-vein sampling, should only be undertaken at tertiary referral centers that have experience in performing and interpreting this test. The identification of a curable form of primary aldosteronism can be beneficial for the patient. In some subgroups of patients with hypertension who are at high risk of primary aldosteronism or can benefit most from an accurate diagnosis, an aggressive diagnostic approach is necessary. PMID- 21610690 TI - The ethics of informed consent in Alzheimer disease research. AB - Clinical research on Alzheimer disease (AD) is much needed but requires the participation of patients with substantial cognitive impairment who have difficulty providing informed consent. Despite decades of debate, policies regulating such research are not well-defined. Although numerous studies have underscored the difficulties of obtaining informed consent for clinical research from patients compromised by AD, there is also increasing evidence that such individuals and their surrogates can make decisions about research participation that are consistent with the patients' values. Policy discussions and future research should consider how the ethical reservations about enrolling incapacitated patients in research could be mitigated by developing ways to promote the congruence between surrogates' decisions and patients' values. PMID- 21610691 TI - Potential of vitamin C in the prevention and treatment of gout. PMID- 21610692 TI - Connective tissue diseases: a molecular link between vascular disease, platelet activation and tissue fibrosis in SSc. PMID- 21610689 TI - AGE restriction in diabetes mellitus: a paradigm shift. AB - Persistently elevated oxidative stress and inflammation precede or occur during the development of type 1 or type 2 diabetes mellitus and precipitate devastating complications. Given the rapidly increasing incidence of diabetes mellitus and obesity in the space of a few decades, new genetic mutations are unlikely to be the cause, instead pointing to environmental initiators. A hallmark of contemporary culture is a preference for thermally processed foods, replete with pro-oxidant advanced glycation endproducts (AGEs). These molecules are appetite increasing and, thus, efficient enhancers of overnutrition (which promotes obesity) and oxidant overload (which promotes inflammation). Studies of genetic and nongenetic animal models of diabetes mellitus suggest that suppression of host defenses, under sustained pressure from food-derived AGEs, may potentially shift homeostasis towards a higher basal level of oxidative stress, inflammation and injury of both insulin-producing and insulin-responsive cells. This sequence promotes both types of diabetes mellitus. Reducing basal oxidative stress by AGE restriction in mice, without energy or nutrient change, reinstates host defenses, alleviates inflammation, prevents diabetes mellitus, vascular and renal complications and extends normal lifespan. Studies in healthy humans and in those with diabetes mellitus show that consumption of high amounts of food-related AGEs is a determinant of insulin resistance and inflammation and that AGE restriction improves both. This Review focuses on AGEs as novel initiators of oxidative stress that precedes, rather than results from, diabetes mellitus. Therapeutic gains from AGE restriction constitute a paradigm shift. PMID- 21610693 TI - Snail1, Snail2, and E47 promote mammary epithelial branching morphogenesis. AB - Several E-box-binding transcription factors regulate individual and collective cell migration and enhance the motility of epithelial cells by promoting epithelial-mesenchymal transition (EMT). Here, we characterized the role of a subset of these transcription factors and the EMT proteome in branching morphogenesis of mammary epithelial tissues using a three-dimensional organotypic culture model of the mammary duct. We found that the transcription factors Snail1, Snail2, and E47 were transiently upregulated at branch sites; decreasing the expression of these transcription factors inhibited branching. Conversely, ectopic expression of Snail1, Snail2, and E47 induced branching in the absence of exogenous stimuli. These changes correlated with the expression of mesenchymal markers and repression of E-cadherin, which was essential for branching. Snail1 and Snail2 also promoted cell survival at branch sites, but this was not sufficient to induce branching. These findings indicate that Snail1, Snail2, and E47 can promote collective migration during branching morphogenesis of mammary epithelial tissues through key regulators of EMT. PMID- 21610694 TI - Presequence-dependent folding ensures MrpL32 processing by the m-AAA protease in mitochondria. AB - m-AAA proteases exert dual functions in the mitochondrial inner membrane: they mediate the processing of specific regulatory proteins and ensure protein quality control degrading misfolded polypeptides to peptides. Loss of these activities leads to neuronal cell death in several neurodegenerative disorders. However, it is unclear how the m-AAA protease chooses between specific processing and complete degradation. A central and conserved function of the m-AAA protease is the processing of the ribosomal subunit MrpL32, which regulates ribosome biogenesis and the formation of respiratory complexes. Here, we demonstrate that the formation of a tightly folded domain harbouring a conserved CxxC-X(9)-CxxC sequence motif halts degradation initiated from the N-terminus and triggers the release of mature MrpL32. Oxidative stress impairs folding of MrpL32, resulting in its degradation by the m-AAA protease and decreased mitochondrial translation. Surprisingly, MrpL32 folding depends on its mitochondrial targeting sequence. Presequence-assisted folding of MrpL32 requires the complete import of the MrpL32 precursor before maturation occurs and therefore explains the need for post translocational processing by the m-AAA protease rather than co-translocational cleavage by the general mitochondrial processing peptidase. PMID- 21610695 TI - Spontaneous physical activity protects against fat mass gain. AB - OBJECTIVE: It is unclear whether elevated spontaneous physical activity (SPA, very low-intensity physical activity) positively influences body composition long term. We determined whether SPA and caloric intake were differentially related to the growth curve trajectories of body weight, fat mass (FM) and fat-free mass (FFM) between obesity resistant and Sprague-Dawley rats at specific age intervals. DESIGN AND SUBJECTS: Body composition, SPA and caloric intake were measured in selectively-bred obesity-resistant and out-bred Sprague-Dawley rats from 1 to 18 months. Data from development throughout maturation were analyzed by longitudinal growth curve modeling to determine the rate and acceleration of body weight, FM- and FFM-gain. RESULTS: Obesity-resistant rats had a lower rate of FM gain overall, a lower acceleration in body weight early in life, significantly greater SPA and lower cumulative caloric intake. Greater SPA in obesity-resistant rats was significantly associated with a lower rate of FM gain overall and lower acceleration in body weight early in life. Obesity resistant rats lost less FFM compared with Sprague-Dawley rats despite that obesity-resistant rats had a lower acceleration in FFM gain early in life. Obesity-resistant rats gained less FM and more FFM per gram body weight and were less energy efficient than Sprague-Dawley rats. Caloric intake was significantly and positively related to body weight, FM and FFM gain in both groups. Circadian patterns of caloric intake were group and age-dependent. Our data demonstrate that elevated and sustained SPA during development and over the lifespan are related to the reduced the rate of FM gain and may preserve FFM. CONCLUSION: These data support the idea that SPA level is a reproducible marker that reliably predicts propensity for obesity in rats, and that elevated levels of SPA maintained during the lifespan promote a lean phenotype. PMID- 21610696 TI - The effects of weight loss due to gastric banding and lifestyle modification on red blood cell aggregation and deformability in severe obese subjects. AB - OBJECTIVE: To investigate the changes in the aggregation index (AI) and the elongation index (EI), in severe obese subjects (MbObS) undergoing laparoscopic adjustable gastric banding (LAGB). AI and EI are measured by Laser assisted Optical Rotational Red Cell Analyzer (LORCA) and are markers of erythrocyte aggregation and deformability, respectively. DESIGN AND SUBJECTS: Before, 3 and 6 months after LAGB plus lifestyle changes (Mediterranean diet plus daily moderate exercise), we evaluated AI, EI, body mass index (BMI), total (ToT) cholesterol (Chol), high-density lipoprotein (HDL)-Chol, low-density lipoprotein (LDL)-Chol, triglycerides and fasting glucose and insulin levels in 20 MbObS. The Student's t test was used for comparisons between independent groups and the analysis of variance to assess differences in AI and EI at the 3 time points. Pearson's correlation coefficient was used to assess correlation among continuous variables and multiple linear regression analysis to assess predictive factors for AI and EI changes. RESULTS: BMI and all blood parameters showed a statistically significant decline 3 and 6 months after LAGB as compared with basal, except for EI and HDL-Chol that significantly increased. Stepwise selection of predictors shows that at 3 and 6 months, EI values depended on HDL-Chol values at the same time point. In the EI model, blood glucose was also statistically significant at 6 months. CONCLUSION: Our data show a significant improvement in EI after LAGB induced weight loss, which correlates with an improved lipid pattern and support the idea that the rapid weight loss induced by LAGB plus lifestyle changes might reduce the thromboembolic risk and the high mortality risk found in MbObS. PMID- 21610697 TI - Type I iodothyronine 5'-deiodinase mRNA and activity is increased in adipose tissue of obese subjects. AB - Differentiation and metabolism of adipose tissue are modulated by thyroid hormones (THs), but relatively little is known about the metabolism of THs in this tissue. Expression of the genes for type I iodothyronine 5'-deiodinase (D1), leptin (LEP) and stearoyl-CoA desaturase 1 (SCD-1) was evaluated in omental (OM) and subcutaneous (SC) fat using a cohort of 70 humans. Activities of iodothyronine deiodinases (D1, D2 and D3) were assessed in a randomly selected subpopulation of 19 subjects. D1 expression was upregulated in both OM (P=0.011) and SC (P=0.003) fat of obese subjects. Concomitantly, OM (P=0.002) and SC (P=0.028) LEP expression were increased in obesity, associated with both D1 mRNA (r=0.315, P=0.014) and activity (r=0.647, P=0.023) and inversely related to SCD-1 (r=-0.266, P=0.034) expression in SC fat. Also D1 (but not D2 and D3) activity was increased in OM (~fourfold, P=0.010) and SC (~eightfold, P=0.004) fat of obese when compared with non-obese subjects and correlated in both OM (r=0.528, P=0.036) and SC (r=0.749, P=0.005) fat with body mass index. Our results document increased D1 gene expression and activity in adipose tissue of obese humans and suggest a role of 3,5,3'-triiodo-L-thyronine formed by D1 in response to leptin in the modulation of adipose tissue metabolism. PMID- 21610698 TI - LiGluR restores visual responses in rodent models of inherited blindness. AB - Inherited retinal degeneration results from many different mutations in either photoreceptor-specific or nonphotoreceptor-specific genes. However, nearly all mutations lead to a common blinding phenotype that initiates with rod cell death, followed by loss of cones. In most retinal degenerations, other retinal neuron cell types survive for long periods after blindness from photoreceptor loss. One strategy to restore light responsiveness to a retina rendered blind by photoreceptor degeneration is to express light-regulated ion channels or transporters in surviving retinal neurons. Recent experiments in rodents have restored light-sensitivity by expressing melanopsin or microbial opsins either broadly throughout the retina or selectively in the inner segments of surviving cones or in bipolar cells. Here, we present an approach whereby a genetically and chemically engineered light-gated ionotropic glutamate receptor (LiGluR) is expressed selectively in retinal ganglion cells (RGCs), the longest-surviving cells in retinal blinding diseases. When expressed in the RGCs of a well established model of retinal degeneration, the rd1 mouse, LiGluR restores light sensitivity to the RGCs, reinstates light responsiveness to the primary visual cortex, and restores both the pupillary reflex and a natural light-avoidance behavior. PMID- 21610699 TI - Several rAAV vectors efficiently cross the blood-brain barrier and transduce neurons and astrocytes in the neonatal mouse central nervous system. AB - Noninvasive systemic gene delivery to the central nervous system (CNS) has largely been impeded by the blood-brain barrier (BBB). Recent studies documented widespread CNS gene transfer after intravascular delivery of recombinant adeno associated virus 9 (rAAV9). To investigate alternative and possibly more potent rAAV vectors for systemic gene delivery across the BBB, we systematically evaluated the CNS gene transfer properties of nine different rAAVEGFP vectors after intravascular infusion in neonatal mice. Several rAAVs efficiently transduce neurons, motor neurons, astrocytes, and Purkinje cells; among them, rAAVrh.10 is at least as efficient as rAAV9 in many of the regions examined. Importantly, intravenously delivered rAAVs did not cause abnormal microgliosis in the CNS. The rAAVs that achieve stable widespread gene transfer in the CNS are exceptionally useful platforms for the development of therapeutic approaches for neurological disorders affecting large regions of the CNS as well as convenient biological tools for neuroscience research. PMID- 21610700 TI - Tumor-specific expression of microRNA-26a suppresses human hepatocellular carcinoma growth via cyclin-dependent and -independent pathways. AB - MicroRNA-26a (miR-26a) is a tumor suppressor that is reduced in hepatocellular carcinoma (HCC). Increasing evidence indicates that the liver is a hormone responsive organ like the breast. The purpose of this study was to investigate whether miR-26a, regulated by a human alpha-fetoprotein (hAFP) and human telomerase reverse transcriptase (hTERT) dual promoter, could be specifically expressed in liver tumor cells to suppress their growth and to clarify whether estrogen receptor-alpha (ERalpha) is regulated by miR-26a and involved in the HCC process. Our data show that miR-26a expression driven by a hAFP-TERT dual promoter was tumor-specific and decreased the viability of tumor cells by regulating ERalpha, progesterone receptor (PR) and P53 except for cyclin D2 or cyclin E2 in vitro and in vivo. Our data also show that estradiol (E2) promotes the growth of liver cancer cells similar to breast cancer cells partly via the E2 ERalpha pathway and that miR-26a significantly down regulates ERalpha and prevents the stimulation of hepatoma cell growth by E2. These data suggest that ERalpha, which is regulated by miR-26a, is important for liver tumor cell growth. Moreover, hAFP-TERT dual promoter-mediated miR-26a expression could specifically exert potential antitumor activity and provide a novel targeting approach for cancer therapy. PMID- 21610701 TI - Envelope-chimeric entry-targeted measles virus escapes neutralization and achieves oncolysis. AB - Measles virus (MV) is a promising vector for cancer therapy and multivalent vaccination, but high prevalence of pre-existing neutralizing antibodies may reduce therapeutic efficacy, particularly following systemic administration. MV has only one serotype, but here we show that its envelope glycoproteins can be exchanged with those of the closely related canine distemper virus (CDV), generating a chimeric virus capable of escaping neutralization. To target its entry, we displayed on the CDV attachment protein a single-chain antibody specific for a designated receptor. To enhance oncolytic efficacy we armed the virus with a prodrug convertase gene capable of locally activating chemotherapeutic prodrugs. The new virus achieved high titers, was genetically stable, and was resistant to neutralization by sera from both MV-immunized mice and MV-immune humans. The new virus targeted syngeneic murine tumor cells expressing the designated receptor implanted in immunocompetent mice, and synergized with a chemotherapeutic prodrug in a model of oncolysis. Importantly, the chimeric MV remained oncolytic when administered systemically even in the presence of anti-MV antibodies capable of abrogating the therapeutic efficacy of the parental, nonshielded MV. This work shows that targeting, arming, and shielding can be combined to generate a tumor-specific, neutralization-resistant virus that can synergize with chemotherapeutics. PMID- 21610702 TI - Implementation of neuro-oncology service reconfiguration in accordance with NICE guidance provides enhanced clinical care for patients with glioblastoma multiforme. AB - BACKGROUND: Brain tumours account for <2% of all primary neoplasms but are responsible for 7% of the years of life lost from cancer before age 70 years. The latest survival trends for patients with CNS malignancies have remained largely static. The objective of this study was to evaluate the change in practice as a result of implementing the Improving Outcomes Guidance from the UK National Institute for Health and Clinical Excellence (NICE). METHODS: Patients were identified from the local cancer registry and hospital databases. We compared time from diagnosis to treatment, proportion of patients discussed at multidisciplinary team (MDT) meetings, treatment received, length of inpatient stay and survival. Inpatient and imaging costs were also estimated. RESULTS: Service reconfiguration and implementation of NICE guidance resulted in significantly more patients being discussed by the MDT--increased from 66 to 87%, reduced emergency admission in favour of elective surgery, reduced median hospital stay from 8 to 4.5 days, increased use of post-operative MRI from 17 to 91% facilitating early discharge and treatment planning, and reduced cost of inpatient stay from L2096 in 2006 to L1316 in 2009. Patients treated with optimal surgery followed by radiotherapy with concomitant and adjuvant temozolomide achieved outcomes comparable to those reported in clinical trials: median overall survival 18 months (2-year survival 35%). CONCLUSIONS: Advancing the management of neuro-oncology patients by moving from an emergency-based system of patient referral and management to a more planned elective outpatient-based pattern of care improves patient experience and has the potential to deliver better outcomes and research opportunities. PMID- 21610703 TI - Thiothymidine combined with UVA as a potential novel therapy for bladder cancer. AB - BACKGROUND: Thiothymidine (S(4)TdR) can be incorporated into DNA and sensitise cells to DNA damage and cell death following exposure to UVA light. Studies were performed to determine if the combination of S(4)TdR and UVA could be an effective treatment for bladder cancer. METHODS: Uptake and incorporation of S(4)TdR was determined in rat and human bladder tumour cell lines. Measures of DNA crosslinking and apoptosis were also performed. In vivo activity of the combination of S(4)TdR and UVA was investigated in an orthotopic model of bladder cancer in rats. RESULTS: Thiothymidine (200 MUM) replaced up to 0.63% of thymidine in rat and tumour bladder cancer cells. The combination of S(4)TdR (10 200 MUM) and UVA (1-5 kJ m(-2)) caused apoptosis and cell death at doses that were not toxic alone. Addition of raltitrexed (Astra Zeneca, Alderley Edge, Cheshire, UK) increased the incorporation of S(4)TdR into DNA (up to 20-fold at IC(5)) and further sensitised cells to UVA. Cytotoxic effect was associated with crosslinking of DNA, at least partially to protein. Intravenous administration of S(4)TdR, in combination with UVA delivered directly to the bladder, resulted in an antitumour effect in three of five animals treated. CONCLUSION: These data indicate that the combination of S(4)TdR and UVA has potential as a treatment for bladder cancer, and give some insight into the mechanism of action. Further work is necessary to optimise the delivery of the two components. PMID- 21610704 TI - A Q-TWiST analysis comparing panitumumab plus best supportive care (BSC) with BSC alone in patients with wild-type KRAS metastatic colorectal cancer. AB - BACKGROUND: Panitumumab+best supportive care (BSC) significantly improved progression-free survival (PFS) vs BSC alone in patients with chemo-refractory wild-type KRAS metastatic colorectal cancer (mCRC). We applied the quality adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis to provide an integrated measure of clinical benefit, with the objective of comparing quality-adjusted survival between the two arms. As the trial design allowed patients on BSC alone to receive panitumumab after disease progression, which confounded overall survival (OS), the focus of this analysis was on PFS. METHODS: For each treatment group, the time spent in the toxicity (grade 3 or 4 adverse events; TOX), time without symptoms of disease or toxicity (TWiST), and relapse (after disease progression; REL) states were estimated by the product limit method, and adjusted using utility weights derived from patient-reported EuroQoL 5-dimensions measures. Sensitivity analyses were performed in which utility weights (varying from 0 to 1) were applied to time in the TOX and REL health states. RESULTS: There was a significant difference between groups favouring panitumumab+BSC in quality-adjusted PFS (12.3 weeks vs 5.8 weeks, respectively, P<0.0001) and quality-adjusted OS (P=0.0303). CONCLUSION: In patients with chemo-refractory wild-type KRAS mCRC, panitumumab+BSC significantly improved quality-adjusted survival compared with BSC alone. PMID- 21610705 TI - Recurrence and survival after pathologic complete response to preoperative therapy followed by surgery for gastric or gastrooesophageal adenocarcinoma. AB - BACKGROUND: To characterise recurrence patterns and survival following pathologic complete response (pCR) in patients who received preoperative therapy for localised gastric or gastrooesophageal junction (GEJ) adenocarcinoma. METHODS: A retrospective review of a prospective database identified patients with pCR after preoperative chemotherapy for gastric or preoperative chemoradiation for GEJ (Siewert II/III) adenocarcinoma. Recurrence patterns, overall survival, recurrence-free survival, and disease-specific survival were analysed. RESULTS: From 1985 to 2009, 714 patients received preoperative therapy for localised gastric/GEJ adenocarcinoma, and 609 (85%) underwent a subsequent R0 resection. There were 60 patients (8.4%) with a pCR. Median follow-up was 46 months. Recurrence at 5 years was significantly lower for pCR vs non-pCR patients (27% and 51%, respectively, P=0.01). The probability of recurrence for patients with pCR was similar to non-pCR patients with pathologic stage I or II disease. Although the overall pattern of local/regional (LR) vs distant recurrence was comparable (43% LR vs 57% distant) between pCR and non-pCR groups, there was a significantly higher incidence of central nervous system (CNS) first recurrences in pCR patients (36 vs 4%, P=0.01). CONCLUSION: Patients with gastric or GEJ adenocarcinoma who achieve a pCR following preoperative therapy still have a significant risk of recurrence and cancer-specific death following resection. One third of the recurrences in the pCR group were symptomatic CNS recurrences. Increased awareness of the risk of CNS metastases and selective brain imaging in patients who achieve a pCR following preoperative therapy for gastric/GEJ adenocarcinoma is warranted. PMID- 21610706 TI - Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). AB - BACKGROUND: This phase I, open-label, first-in-human study determined dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo. METHODS: A total of 33 patients with retinoblastoma protein-positive advanced solid tumours or non-Hodgkin's lymphoma refractory to standard therapy or for which no therapy was available received PD 0332991 once daily (QD) for 14 days followed by 7 days off treatment (21-day cycles; Schedule 2/1). RESULTS: Six patients had DLTs (18%; four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild-moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (>=10 cycles in three cases). PD 0332991 was slowly absorbed (mean T(max) 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure. CONCLUSION: PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study. PMID- 21610707 TI - Predicting the outcome of grade II glioma treated with temozolomide using proton magnetic resonance spectroscopy. AB - BACKGROUND: This study was designed to evaluate proton magnetic resonance spectroscopy ((1)H-MRS) for monitoring the WHO grade II glioma (low-grade glioma (LGG)) treated with temozolomide (TMZ). METHODS: This prospective study included adult patients with progressive LGG that was confirmed by magnetic resonance imaging (MRI). Temozolomide was administered at every 28 days. Response to TMZ was evaluated by monthly MRI examinations that included MRI with volumetric calculations and (1)H-MRS for assessing Cho/Cr and Cho/NAA ratios. Univariate, multivariate and receiver-operating characteristic statistical analyses were performed on the results. RESULTS: A total of 21 LGGs from 31 patients were included in the study, and followed for at least n=14 months during treatment. A total of 18 (86%) patients experienced a decrease in tumour volume with a greater decrease of metabolic ratios. Subsequently, five (28%) of these tumours resumed growth despite the continuation of TMZ administration with an earlier increase of metabolic ratios of 2 months. Three (14%) patients did not show any volume or metabolic change. The evolutions of the metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated over time (Spearman rho=+0.95) and followed a logarithmic regression (P>0.001). The evolutions over time of metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated with the evolution of the mean relative decrease of tumour volume, mean(DeltaV(n)/V(o)), according to a linear regression (P<0.001) in the 'response/no relapse' patient group, and with the evolution of the mean tumour volume (meanV(n)), according to an exponential regression (P<0.001) in the 'response/relapse' patient group. The mean relative decrease of metabolic ratio, mean(Delta(Cho/Cr)(n)/(Cho/Cr)(o)), at n=3 months was predictive of tumour response over the 14 months of follow-up. The mean relative change between metabolic ratios, mean((Cho/NAA)(n)-(Cho/Cr)(n))/(Cho/NAA)(n), at n=4 months was predictive of tumour relapse with a significant cutoff of 0.046, a sensitivity of 60% and a specificity of 100% (P=0.004). CONCLUSIONS: The (1)H-MRS profile changes more widely and rapidly than tumour volume during the response and relapse phases, and represents an early predictive factor of outcome over 14 months of follow-up. Thus, (1)H-MRS may be a promising, non-invasive tool for predicting and monitoring the clinical response to TMZ. PMID- 21610708 TI - High CIP2A immunoreactivity is an independent prognostic indicator in early-stage tongue cancer. AB - BACKGROUND: No reliable prognostic markers exist for squamous cell carcinoma of the tongue, and its prognosis can even in early stages be unpredictable and survival poor despite treatment. A potential marker is oncoprotein cancerous inhibitor of PP2A (CIP2A), which acts as a prognostic marker in gastric and non small cell lung cancers. METHODS: We collected specimens of 73 stage T1N0M0 and T2N0M0 oral squamous cell carcinomas of the tongue, as well as samples from normal oral mucosa, dysplastic lesions, and invasive carcinomas (n=39). All samples were stained for CIP2A by immunohistochemistry. Survival curves were constructed according to the Kaplan-Meier method. The Cox proportional hazard model served for univariate and multivariate survival analysis. RESULTS: High CIP2A immunoreactivity predicted poor survival in tongue cancer patients (P=0.027, logrank test). In multivariate survival analysis, CIP2A was an independent prognostic factor (HR 2.02, 95% confidence interval 1.07-3.82, P=0.030). Cytoplasmic CIP2A expression was higher in severe dysplasia than in mild dysplasia. CONCLUSION: Our results suggest that high CIP2A expression characterises aggressive disease. Acting as a prognostic marker it might be of help when choosing patients for adjuvant treatment in tongue cancer patients. PMID- 21610709 TI - Delays in treating endometrial cancer in the South West of England. AB - BACKGROUND: Poor cancer survival rates in the United Kingdom are often blamed on delayed medical care. A local audit of endometrial cancer revealed a variety of preventable delays. We surveyed practice in the South West of England to see if this was an isolated or widespread problem. METHODS: All 15 hospitals in the South West of England collected information prospectively from all women with endometrial cancer over 3 months in the spring of 2009. RESULTS: There were delays in all stages of the uterine cancer pathway. Excluding extraneous cases, 52% of women waited more than a month and 12% waited more than 6 months to see their GP from the onset of symptoms. Almost half the cases said they were unaware that abnormal bleeding was a symptom of cancer. Only a quarter of women had treatment within 31 days from the outpatient visit to first definitive treatment and 18% waited more than the target of 62 days for their treatment. CONCLUSIONS: Significant treatment delays occur because women do not report bleeding. If this is replicated throughout Britain, approximately 1000 women per year will delay presentation for at least 3 months and 600 will wait for more than 6 months. PMID- 21610710 TI - Increased risk of hepatocellular carcinoma after cholecystectomy. AB - BACKGROUND: The association between gall bladder removal (cholecystectomy) and hepatocellular carcinoma warrants investigation. An increased intrahepatic bile duct pressure following cholecystectomy might cause chronic inflammation in the surrounding liver tissue, which might induce cancer development. METHODS: A nationwide Swedish population-based cohort study in 1965-2008 included 345,251 patients undergoing cholecystectomy because of gallstone. The number of observed hepatocellular carcinoma cases was divided by the expected number, calculated from the corresponding background Swedish population, thus providing standardised incidence ratios (SIRs) with 95% confidence intervals (CIs). RESULTS: During follow-up of 4,854,969 person-years, 333 new cases of hepatocellular carcinoma were identified, rendering an overall increased risk (SIR 1.24, 95% CI: 1.11 1.38). The risk increased with longer follow-up (P for trend=0.003). Among patients who underwent cholecystectomy 30-43 years earlier, SIR was 2.00 (95% CI: 1.32-2.87). The results were similar after exclusion of 15,634 patients with any recorded risk factor, that is, diabetes, obesity, hepatitis, liver cirrhosis, alcoholism, or blood transfusion. CONCLUSION: Cholecystectomy might be associated with a long-term increased risk of hepatocellular carcinoma. PMID- 21610712 TI - Design and syntheses of gramicidin S analogs, cyclo(-X-Leu-X-D-Phe-Pro-)2 (X=His, Lys, Orn, Dab and Dap). PMID- 21610711 TI - Central nervous system failure in melanoma patients: results of a randomised, multicentre phase 3 study of temozolomide- and dacarbazine- based regimens. AB - BACKGROUND: This study compared the central nervous system (CNS) metastasis incidence between a temozolomide- and a dacarbazine-based regimen in untreated stage IV melanoma patients. METHODS: A total of 150 patients were randomly assigned to receive either oral temozolomide (200 mg m(-2) per day; days 1-5) or intravenous dacarbazine (800 mg m(-2); day 1), in combination with intravenous cisplatin (75 mg m(-2); day 1) and subcutaneous interleukin-2 (3 MU twice daily; days 9-18), every 28 days (CTI and CDI). RESULTS: A total of 149 patients were eligible for an intention-to-treat analysis (CTI: n=74, CDI: n=75). The 1-year cumulative CNS incidence failure was 20.6% for CTI and 31.1% for CDI (P=0.22). In all 24 patients in CTI (32%) and 34 (45%) in CDI developed CNS metastases; 31 patients died of early systemic progression, before CNS evaluation. Median survival time was 8.4 months in the CTI and 8.7 in the CDI arm; in patients with CNS metastases the median survival time was 13.5 months in the CTI and 11.5 in the CDI arm. No difference in toxicity was observed between the two arms. CONCLUSION: The incidence of CNS failures in metastatic melanoma was not significantly reduced and the clinical course was not modified substituting a dacarbazine-based regimen with a temozolomide-based regimen. Patients who developed CNS metastases did not have a worse prognosis than patients progressing in other sites and should not be excluded from new investigational studies. PMID- 21610713 TI - Furaquinocins I and J: novel polyketide isoprenoid hybrid compounds from Streptomyces reveromyceticus SN-593. AB - Two novel furaquinocin (FQ) analogues, I (1) and J (2), were isolated from Streptomyces reveromyceticus SN-593 strain NRM2. Their structures were elucidated by MS and NMR analyses. Similar to the previously described FQ D (3), both 1 and 2 possessed a dihydrofuran ring fused to a polyketide naphthoquinone skeleton. The main difference between 1, 2 and 3 was the type of residue attached to C-13; these were a carboxyl, a carboxamide and a methyl residue, respectively. PMID- 21610715 TI - Taxonomic and ecological studies of actinomycetes from Vietnam: isolation and genus-level diversity. AB - Actinomycetes were isolated from 109 soil and 93 leaf-litter samples collected at five sites in Vietnam between 2005 and 2008 using the rehydration-centrifugation (RC) method, sodium dodecyl sulfate-yeast extract dilution method, dry-heating method and oil-separation method in conjunction with humic acid-vitamin agar as an isolation medium. A total of 1882 strains were identified as Vietnamese (VN) actinomycetes including 1080 (57%) streptomycetes (the genus Streptomyces isolates) and 802 (43%) non-streptomycetes. The 16S ribosomal RNA gene sequences of the VN-actinomycetes were analyzed using BLAST searches. The results showed that these isolates belonged to 53 genera distributed among 21 families. Approximately 90% of these strains were members of three families: Streptomycetaceae (1087 strains, 58%); Micromonosporaceae (516 strains, 27%); and Streptosporangiaceae (89 strains, 5%). Motile actinomycetes of the genera Actinoplanes, Kineosporia and Cryptosporangium, which have quite common morphological characteristics, were frequently isolated from leaf-litter samples using the RC method. It is possible that these three genera acquired common properties during a process of convergent evolution. By contrast, strains belonging to the suborder Streptosporangineae were exclusively isolated from soils. A comparison of the sampling sites revealed no significant difference in taxonomic diversity between these sites. Among the non-streptomycetes, 156 strains (19%) were considered as new taxa distributed into 21 genera belonging to 12 families. Interestingly, the isolation of actinomycetes from leaf-litter samples using the RC method proved to be the most efficient way to isolate new actinomycetes in Vietnam, especially the Micromonosporaceae species. PMID- 21610714 TI - Investigation of the biosynthesis of the pipecolate moiety of neuroprotective polyketide meridamycin. AB - Biogenesis of the pipecolate moiety of neuroprotective agent meridamycin in Streptomyces sp. NRRL30748 was investigated in feeding studies using lysine specifically labeled with (15)N at the alpha-amino or the epsilon-amino nitrogen position. Fourier transform mass spectrometry analysis with ultra-high mass resolving power and accurate mass measurement capability was employed to resolve the (15)N peak of labeled meridamycin from the (13)C peak of unlabeled meridamycin, allowing the precise calculation of labeling contents under each condition. The relative enrichment of (15)N-labeled meridamycin was ~43% with L [alpha-(15)N]-lysine feeding and ~14% with L-[alpha-(15)N]-lysine feeding, suggesting two distinguishable pathways, with concomitant loss of either the epsilon-amino group or the alpha-amino group of lysine, were involved in the generation of the pipecolate moiety of meridamycin in this bacterium. PCR cloning using degenerate primers identified a proC gene encoding a putative pyrroline-5 carboxylate reductase, which was expected to catalyze the conversion of piperideine-6-carboxylate to pipecolate. However, inactivation of this locus did not significantly affect the incorporation of alpha-(15)N- or epsilon-(15)N labeled lysine into meridamycin, indicating the existence of an alternative route for the last step of the lysine epsilon-transamination pathway. This work revealed the diversity and complexity of the biosynthetic pathways for pipecolate synthesis in the meridamycin producing bacterium Streptomyces sp. NRRL30748. PMID- 21610716 TI - Production of monapinones by fermentation of the dinapinone-producing fungus Penicillium pinophilum FKI-3864 in a seawater-containing medium. AB - Five new monapinones, including a dinapinone monomer, were isolated from the culture broth of the dinapinone-producing Penicillium pinophilum FKI-3864 in a medium modified to contain seawater. The structures of these monapinones were elucidated by various NMR experiments. Monapinones possessed the same dihydronaphthopyranone skeleton as the dinapinones, with different hydroxyalkyl chains: monapinone A was identified as the monomeric portion of the atropisomer dinapinones A1 and A2, and monapinones A and B showed weak inhibition of triacylglycerol (TG) synthesis in intact mammalian cells, whereas the others showed almost no effect on TG synthesis. PMID- 21610722 TI - Isolated human and rat cerebral arteries constrict to increases in flow: role of 20-HETE and TP receptors. AB - Elevation of intraluminal pressure increases vasomotor tone, which thought to have a substantial role in regulation of cerebral blood flow (CBF). Interestingly, responses of cerebral vessels to increases in flow varied and have not been studied in human cerebral arteries. We hypothesized that increases in flow elicit constrictions of isolated human and rat cerebral arteries and aimed to elucidate the underlying mechanisms. Human cerebral arteries and rat middle cerebral arteries constricted to increases in flow (P<0.05). Simultaneous increase in intraluminal flow+pressure further reduced the diameter compared with pressure-induced changes (P<0.05), leading to constant estimated CBF. Flow induced constrictions were abolished by HET0016 (inhibitor of synthesis of 20 hydroxyeicosatetraenoic acid (20-HETE) or inhibition of COXs or blocking TP (thromboxane A(2)/prostaglandin H(2), receptors and attenuated by scavenging reactive oxygen species (ROS). Flow-enhanced ROS formation was significantly reduced by HET0016. In conclusion, in human and rat cerebral arteries (1) increases in flow elicit constrictions, (2) signaling mechanism of flow-induced constriction of cerebral arteries involves enhanced production of ROS, COX activity, and mediated by 20-HETE via TP receptors, and (3) we propose that simultaneous operation of pressure- and flow-induced constrictions is necessary to provide an effective autoregulation of CBF. PMID- 21610723 TI - Quantitative MRI reveals the elderly ischemic brain is susceptible to increased early blood-brain barrier permeability following tissue plasminogen activator related to claudin 5 and occludin disassembly. AB - Great uncertainty exists as to whether aging enhances the detrimental effects of tissue plasminogen activator (tPA) on vascular integrity of the ischemic brain. We hypothesized that tPA treatment would augment ischemic injury by causing increased blood-brain barrier (BBB) breakdown as determined by quantitative serial T(1) and T(2) magnetic resonance imaging (MRI), and the transfer constant for gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) from blood to brain in aged (18 to 20 months) compared with young (3 to 4 months) Wistar rats after middle cerebral artery occlusion, mediated through the acute disassembly of claudin 5 and occludin. Increased T(2) values over the first hour of postreperfusion were independently augmented following treatment with tPA (P<0.001) and aging (P<0.01), supporting a synergistic effect of tPA on the aged ischemic brain. Blood-brain barrier permeability for Gd-DTPA (K(Gd)) was substantial following reperfusion in all animal groups and was exacerbated by tPA treatment in the elderly rat (P<0.001). The frequency of hematoma formation was proportionately increased in the elderly ischemic brain (P<0.05). Both tPA and age independently increased claudin 5 and occludin phosphorylation during ischemia. Early BBB permeability detected by quantitative MRI following ischemic stroke is enhanced by increased age and tPA and is related to claudin 5 and occludin phosphorylation. PMID- 21610725 TI - The rice mitochondrial iron transporter is essential for plant growth. AB - In plants, iron (Fe) is essential for mitochondrial electron transport, heme, and Fe-Sulphur (Fe-S) cluster synthesis; however, plant mitochondrial Fe transporters have not been identified. Here we show, identify and characterize the rice mitochondrial Fe transporter (MIT). Based on a transfer DNA library screen, we identified a rice line showing symptoms of Fe deficiency while accumulating high shoot levels of Fe. Homozygous knockout of MIT in this line resulted in a lethal phenotype. MIT localized to the mitochondria and complemented the growth of Deltamrs3Deltamrs4 yeast defective in mitochondrial Fe transport. The growth of MIT-knockdown (mit-2) plants was also significantly impaired despite abundant Fe accumulation. Further, the decrease in the activity of the mitochondrial and cytosolic Fe-S enzyme, aconitase, indicated that Fe-S cluster synthesis is affected in mit-2 plants. These results indicate that MIT is a mitochondrial Fe transporter essential for rice growth and development. PMID- 21610724 TI - A novel methodology for large-scale phylogeny partition. AB - Understanding the determinants of virus transmission is a fundamental step for effective design of screening and intervention strategies to control viral epidemics. Phylogenetic analysis can be a valid approach for the identification of transmission chains, and very-large data sets can be analysed through parallel computation. Here we propose and validate a new methodology for the partition of large-scale phylogenies and the inference of transmission clusters. This approach, on the basis of a depth-first search algorithm, conjugates the evaluation of node reliability, tree topology and patristic distance analysis. The method has been applied to identify transmission clusters of a phylogeny of 11,541 human immunodeficiency virus-1 subtype B pol gene sequences from a large Italian cohort. Molecular transmission chains were characterized by means of different clinical/demographic factors, such as the interaction between male homosexuals and male heterosexuals. Our method takes an advantage of a flexible notion of transmission cluster and can become a general framework to analyse other epidemics. PMID- 21610726 TI - Intron retention in the Drosophila melanogaster Rieske Iron Sulphur Protein gene generated a new protein. AB - Genomes can encode a variety of proteins with unrelated architectures and activities. It is known that protein-coding genes of de novo origin have significantly contributed to this diversity. However, the molecular mechanisms and evolutionary processes behind these originations are still poorly understood. Here we show that the last 102 codons of a novel gene, Noble, assembled directly from non-coding DNA following an intronic deletion that induced alternative intron retention at the Drosophila melanogaster Rieske Iron Sulphur Protein (RFeSP) locus. A systematic analysis of the evolutionary processes behind the origin of Noble showed that its emergence was strongly biased by natural selection on and around the RFeSP locus. Noble mRNA is shown to encode a bona fide protein that lacks an iron sulphur domain and localizes to mitochondria. Together, these results demonstrate the generation of a novel protein at a naturally selected site. PMID- 21610728 TI - Stabilizing lithium-sulphur cathodes using polysulphide reservoirs. AB - The possibility of achieving high-energy, long-life storage batteries has tremendous scientific and technological significance. An example is the Li-S cell, which can offer a 3-5-fold increase in energy density compared with conventional Li-ion cells, at lower cost. Despite significant advances, there are challenges to its wide-scale implementation, which include dissolution of intermediate polysulphide reaction species into the electrolyte. Here we report a new concept to mitigate the problem, which relies on the design principles of drug delivery. Our strategy employs absorption of the intermediate polysulphides by a porous silica embedded within the carbon-sulphur composite that not only absorbs the polysulphides by means of weak binding, but also permits reversible desorption and release. It functions as an internal polysulphide reservoir during the reversible electrochemical process to give rise to long-term stabilization and improved coulombic efficiency. The reservoir mechanism is general and applicable to Li/S cathodes of any nature. PMID- 21610727 TI - Unexpected layers of cryptic diversity in wood white Leptidea butterflies. AB - Uncovering cryptic biodiversity is essential for understanding evolutionary processes and patterns of ecosystem functioning, as well as for nature conservation. As European butterflies are arguably the best-studied group of invertebrates in the world, the discovery of a cryptic species, twenty years ago, within the common wood white Leptidea sinapis was a significant event, and these butterflies have become a model to study speciation. Here we show that the so called 'sibling' Leptidea actually consist of three species. The new species can be discriminated on the basis of either DNA or karyological data. Such an unexpected discovery challenges our current knowledge on biodiversity, exemplifying how a widespread species can remain unnoticed even within an intensely studied natural model system for speciation. PMID- 21610729 TI - A bacterial platform for fermentative production of plant alkaloids. AB - The secondary metabolites of higher plants include diverse chemicals, such as alkaloids, isoprenoids and phenolic compounds (phenylpropanoids and flavonoids). Although these compounds are widely used in human health and nutrition, at present they are mainly obtained by extraction from plants and extraction yields are low because most of these metabolites accumulate at low levels in plant cells. Recent advances in synthetic biology and metabolic engineering have enabled tailored production of plant secondary metabolites in microorganisms, but these methods often require the addition of expensive substrates. Here we develop an Escherichia coli fermentation system that yields plant alkaloids from simple carbon sources, using selected enzymes to construct a tailor-made biosynthetic pathway. In this system, engineered cells cultured in growth medium without additional substrates produce the plant benzylisoquinoline alkaloid, (S) reticuline (yield, 46.0 mg l(-1) culture medium). The fermentation platform described here offers opportunities for low-cost production of many diverse alkaloids. PMID- 21610731 TI - Memory: the foundations of accurate recall. PMID- 21610732 TI - Spatial coding: oscillations maintain grid position. PMID- 21610730 TI - Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus. AB - Synchronous oscillations of thousands of cellular clocks in the suprachiasmatic nucleus (SCN), the circadian centre, are coordinated by precisely timed cell-cell communication, the principle of which is largely unknown. Here we show that the amount of RGS16 (regulator of G protein signalling 16), a protein known to inactivate Galphai, increases at a selective circadian time to allow time dependent activation of intracellular cyclic AMP signalling in the SCN. Gene ablation of Rgs16 leads to the loss of circadian production of cAMP and as a result lengthens circadian period of behavioural rhythm. The temporally precise regulation of the cAMP signal by clock-controlled RGS16 is needed for the dorsomedial SCN to maintain a normal phase-relationship to the ventrolateral SCN. Thus, RGS16-dependent temporal regulation of intracellular G protein signalling coordinates the intercellular synchrony of SCN pacemaker neurons and thereby defines the 24 h rhythm in behaviour. PMID- 21610733 TI - Monocytes: nudged out of the niche. PMID- 21610734 TI - Innate immunity: Linking lipids and inflammasomes. PMID- 21610735 TI - T cell responses: CD4s work the doors. PMID- 21610736 TI - Phagocytosis: a synapse for snaps. PMID- 21610737 TI - Innate immunity: GBPs coordinate vesicular trafficking for host defence. PMID- 21610738 TI - Antiviral immunity: TRIM5 moonlights as a pattern recognition receptor. PMID- 21610742 TI - Evaluation of lean tissue density for use in air displacement plethysmography in obese children and adolescents. AB - BACKGROUND/OBJECTIVES: Body composition techniques are required for monitoring response to treatment in individual obese children, and assessing the efficacy of weight loss programmes. Densitometry is readily undertaken, using air displacement plethysmography (ADP), but requires appropriate information on the density of lean tissue (D(LT)). The aims of this study were to develop predictive equations for D(LT) in obese children and adolescents, and to test the accuracy of ADP when using such predicted D(LT) values in an independent longitudinal sample using the four-component model as the reference method. SUBJECTS/METHODS: Equations for the prediction of D(LT) from age, gender and body mass index standard deviation score were developed in 105 children (39 boys). Accuracy of ADP, when incorporating predicted D(LT) values, was tested for baseline body composition and its change over time in a separate sample of 51 children (20 boys). RESULTS: The predictive equation explained 33% of the variance in D(LT). Fat mass obtained from ADP using such predicted values had a mean (s.d.) bias of 0.32 (1.39) kg, nonsignificant, whereas change in fat mass had an error of -0.25 (1.38) kg, nonsignificant. Hydration was strongly correlated with D(LT). CONCLUSIONS: Use of ADP with predicted D(LT) values was associated with nonsignificant bias when estimating fat mass and its change over time. This study aids the application of ADP in childhood obesity research and clinical practise. The limits of agreement (+/-2.8 kg) relative to four-component values are moderately better than those for X-ray absorptiometry (+/-3.2 kg). Further improvement to accuracy would require assessment of lean tissue hydration by bioelectrical impedance. PMID- 21610741 TI - Diversity and dialogue in immunity to helminths. AB - The vertebrate immune system has evolved in concert with a broad range of infectious agents, including ubiquitous helminth (worm) parasites. The constant pressure of helminth infections has been a powerful force in shaping not only how immunity is initiated and maintained, but also how the body self-regulates and controls untoward immune responses to minimize overall harm. In this Review, we discuss recent advances in defining the immune cell types and molecules that are mobilized in response to helminth infection. Finally, we more broadly consider how these immunological players are blended and regulated in order to accommodate persistent infection or to mount a vigorous protective response and achieve sterile immunity. PMID- 21610743 TI - A comparison of dietary patterns derived by cluster and principal components analysis in a UK cohort of children. AB - BACKGROUND/OBJECTIVES: The objective of this study was to identify dietary patterns in a cohort of 7-year-old children through cluster analysis, compare with patterns derived by principal components analysis (PCA), and investigate associations with sociodemographic variables. SUBJECTS/METHODS: The main caregivers in the Avon Longitudinal Study of Parents and Children (ALSPAC) recorded dietary intakes of their children (8279 subjects) using a 94-item food frequency questionnaire. Items were then collapsed into 57 food groups. Dietary patterns were identified using k-means cluster analysis and associations with sociodemographic variables examined using multinomial logistic regression. Clusters were compared with patterns previously derived using PCA. RESULTS: Three distinct clusters were derived: Processed (4177 subjects), associated with higher consumption of processed foods and white bread, Plant-based (2065 subjects), characterized by higher consumption of fruit, vegetables and non-white bread, and Traditional British (2037 subjects), associated with higher consumption of meat, vegetables and full-fat milk. Membership of the Processed cluster was positively associated with girls, younger mothers, snacking and older siblings. Membership of the Plant-based cluster was associated with higher educated mothers and vegetarians. The Traditional British cluster was associated with council housing and younger siblings. The three clusters were similar to the three dietary patterns obtained through PCA; each principal component score being higher on average in the corresponding cluster. CONCLUSIONS: Both cluster analysis and PCA identified three dietary patterns very similar both in the foods associated with them and sociodemographic characteristics. Both methods are useful for deriving meaningful dietary patterns. PMID- 21610744 TI - Epigenetically silenced miR-34b/c as a novel faecal-based screening marker for colorectal cancer. AB - BACKGROUND: MicroRNAs are tiny non-coding small endogenous RNAs that regulate gene expression by translational repression, mRNA cleavage and mRNA inhibition. The aim of this study was to investigate the hypermethylation of miR-34b/c and miR-148a in colorectal cancer, and correlate this data to clinicopathological features. We also aimed to evaluate the hypermethylation of miR-34b/c in faeces specimens as a novel non-invasive faecal-DNA-based screening marker. METHODS: The 5-aza-2'-deoxycytidine treatment and methylation-specific PCR were carried out to detect the hypermethylation of miR-34b/c and miR-148a. RESULTS: The miR-34b/c hypermethylation was found in 97.5% (79 out of 82) of primary colorectal tumours, P=0.0110. In 75% (21 out of 28) of faecal specimens we found a hypermethylation of miR-34b/c while only in 16% (2 out of 12) of high-grade dysplasia. In addition, miR-148a was found to be hypermethylated in 65% (51 out of 78) of colorectal tumour tissues with no significant correlation to clinicopathological features. However, a trend with female gender and advanced age was found, P=0.083. We also observed a trend to lower survival rate in patients with miR 148a hypermethylation with 10-year survival probability: 48 vs 65%, P=0.561. CONCLUSIONS: These findings show that aberrant hypermethylation of miR-34b/c could be an ideal class of early screening marker, whereas miR-148a could serve as a disease progression follow-up marker. PMID- 21610746 TI - Alterations in KLRB1 gene expression and a Scandinavian multiple sclerosis association study of the KLRB1 SNP rs4763655. AB - Multiple sclerosis (MS) is a complex autoimmune disease affecting genetically susceptible individuals. A genome-wide association study performed by the International MS Genetics Consortium identified several putative susceptibility genes; among these, the KLRB1 gene is represented by the single-nucleotide polymorphism rs4763655. We could confirm a marginally significant association between rs4763655 and MS (P=0.046, odds ratio=1.06 (1.00-1.13)) in a large Scandinavian case-control study of 5367 MS patients and 4485 controls. The expression of KLRB1 in blood from MS patients was higher compared with healthy controls (P<0.001), and the KLRB1 expression decreased significantly (P<0.001) after interferon (IFN)-beta treatment. KLRB1 was expressed in T and natural killer (NK) cells, and expression mainly decreased in NK cells in patients treated with IFN-beta. Collectively, our results indicate that KLRB1 gene expression is altered in MS and likely to be involved in the pathogenesis of the disease, whereas rs4763655 in KLRB1 seems to have a minimal role in MS susceptibility. PMID- 21610747 TI - A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites. AB - Spinal muscular atrophy (SMA) is an autosomal recessive (AR) neuromuscular disease that is one of the most common lethal genetic disorders in children, with carrier frequencies as high as ~1 in 35 in US Whites. As part of our genetic studies in the Hutterites from South Dakota, we identified a large 22 Mb run of homozygosity, spanning the SMA locus in an affected child, of which 10 Mb was also homozygous in three affected Hutterites from Montana, supporting a single founder origin for the mutation. We developed a haplotype-based method for identifying carriers of the SMN1 deletion that leveraged existing genome-wide SNP genotype data for ~1400 Hutterites. In combination with two direct PCR-based assays, we identified 176 carriers of the SMN1 deletion, one asymptomatic homozygous adult and three carriers of a de novo deletion. This corresponds to a carrier frequency of one in eight (12.5%) in the South Dakota Hutterites, representing the highest carrier frequency reported to date for SMA and for an AR disease in the Hutterite population. Lastly, we show that 26 SNPs can be used to predict SMA carrier status in the Hutterites, with 99.86% specificity and 99.71% sensitivity. PMID- 21610748 TI - GWAS Integrator: a bioinformatics tool to explore human genetic associations reported in published genome-wide association studies. AB - Genome-wide association studies (GWAS) have successfully identified numerous genetic loci that are associated with phenotypic traits and diseases. GWAS Integrator is a bioinformatics tool that integrates information on these associations from the National Human Genome Research institute (NHGRI) Catalog, SNAP (SNP Annotation and Proxy Search), and the Human Genome Epidemiology (HuGE) Navigator literature database. This tool includes robust search and data mining functionalities that can be used to quickly identify relevant associations from GWAS, as well as proxy single-nucleotide polymorphisms (SNPs) and potential candidate genes. Query-based University of California Santa Cruz (UCSC) Genome Browser custom tracks are generated dynamically on the basis of users' selected GWAS hits or candidate genes from HuGE Navigator literature database (http://www.hugenavigator.net/HuGENavigator/gWAHitStartPage.do). The GWAS Integrator may help enhance inference on potential genetic associations identified from GWAS studies. PMID- 21610750 TI - Clinical utility gene card for: dyskeratosis congenita. PMID- 21610749 TI - Finding disease genes: a fast and flexible approach for analyzing high-throughput data. AB - Linkage disequilibrium (LD) is the non-random distribution of alleles across the genome, and it can create serious problems for modern linkage studies. In particular, computational feasibility is often obtained at the expense of power, precision, and/or accuracy. In our new approach, we combine linkage results over multiple marker subsets to provide fast, efficient, and robust analyses, without compromising power, precision, or accuracy. Allele frequencies and LD in the densely spaced markers are used to construct subsamples that are highly informative for linkage. We have tested our approach extensively, and implemented it in the software package EAGLET (Efficient Analysis of Genetic Linkage: Estimation and Testing). Relative to several commonly used methods we show that EAGLET has increased power to detect disease genes across a range of trait models, LD patterns, and family structures using both simulated and real data. In particular, when the underlying LD pattern is derived from real data, we find that EAGLET outperforms several commonly used linkage methods. In-depth analysis of family data, simulated with linkage and under the real-data derived LD pattern, showed that EAGLET had 78.1% power to detect a dominant disease with incomplete penetrance, whereas the method that uses one marker per cM had 69.7% power, and the cluster-based approach implemented in MERLIN had 76.7% power. In this same setting, EAGLET was three times faster than MERLIN, and it narrowed the MERLIN-based confidence interval for trait location by 29%. Overall, EAGLET gives researchers a fast, accurate, and powerful new tool for analyzing high-throughput linkage data, and large extended families are easily accommodated. PMID- 21610751 TI - Clinical presentation and mutations in Danish patients with Wilson disease. AB - This study describes the clinical presentation and diagnosis in all Danish patients (49, 41 unrelated) with Wilson disease (WND). On the basis of the number of diagnosed patients from 1990-2008, the prevalence was estimated to be 1:49 500. Among routinely used diagnostic tests, none were consistently indicative of WND, with the exception of the 24-h urine-Cu test, which is always outside the normal range. Mutations were identified in 100% of the screened ATP7B alleles (70 unrelated), including five novel mutations: p.1021K; p.G1158V; p.L1304F; IVS20 2A>G; Ex5_6del. In all, 70% of mutations were found in exons 8, 14, 17, 18, and 20. The most frequent mutation, p.H1069Q, comprised 18%. We propose a new and simple model that correlates genotype and age of onset. By assuming that the milder of two mutations is 'functionally dominant' and determines the age of onset, we classified 25/27 mutations as either severe (age of onset <20 years) or moderate (age of onset >20 years), and correctly predicted the age of onset in 37/39 patients. This method should be tested in other Wilson populations. PMID- 21610752 TI - Treatment of spinal muscular atrophy cells with drugs that upregulate SMN expression reveals inter- and intra-patient variability. AB - Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by mutations in the SMN1 gene. The homologous copy (SMN2) is always present in SMA patients. SMN1 gene transcripts are usually full-length (FL), but exon 7 is spliced out in a high proportion of SMN2 transcripts (delta7) (Delta7). Advances in drug therapy for SMA have shown that an increase in SMN mRNA and protein levels can be achieved in vitro. We performed a systematic analysis of SMN expression in primary fibroblasts and EBV-transformed lymphoblasts from seven SMA patients with varying clinical severity and different SMN1 genotypes to determine expression differences in two accessible tissues (skin and blood). The basal expression of SMN mRNA FL and Delta7 in fibroblasts and lymphoblasts was analyzed by quantitative real-time PCR. The FL-SMN and FL/Delta7 SMN ratios were higher in control cells than in patients. Furthermore, we investigated the response of these cell lines to hydroxyurea, valproate and phenylbutyrate, drugs previously reported to upregulate SMN2. The response to treatments with these compounds was heterogeneous. We found both intra-patient and inter-patient variability even within haploidentical siblings, suggesting that tissue and individual factors may affect the response to these compounds. To optimize the stratification of patients in clinical trials, in vitro studies should be performed before enrolment so as to define each patient as a responder or non-responder to the compound under investigation. PMID- 21610755 TI - The Pathogenesis of Narcolepsy, with a Consideration of Sleep-Paralysis and Localized Sleep. PMID- 21610753 TI - Assessing the pathological relevance of SPINK1 promoter variants. AB - The SPINK1 gene, encoding the human pancreatic secretory trypsin inhibitor, is one of the major genes involved in predisposition to chronic pancreatitis (CP). In this study we have assessed the potential functional impact of 11 SPINK1 promoter variants by means of both luciferase reporter gene assay and electrophoretic mobility shift assay (EMSA), using human pancreatic COLO-357 cells as an expression system. The 11 promoter variants were found to be separable into three distinct categories on the basis of the reporter gene assay results viz loss-of-function, gain-of-function and functionally neutral. These findings, which were validated by EMSA, concurred with data from previous deletion studies and DNase I footprinting assays. Further, binding sites for two transcription factors, HNF1 and PTF1, were newly identified within the SPINK1 promoter by virtue of their being affected by specific variants. Combining the functional data with epidemiological data (derived by resequencing the SPINK1 promoter region in French, German and Indian CP patients and controls), then allowed us to make meaningful inferences as to each variant's likely contribution to CP. We conclude that only the three promoter variants associated with a loss of-function (ie, -53C>T, -142T>C and -147A>G) are likely to be disease predisposing alterations. PMID- 21610756 TI - Recurrent Polyneuritis in Pregnancy and the Puerperium affecting Three Members of a Family. PMID- 21610754 TI - Plasma concentrations of parabens in postmenopausal women and self-reported use of personal care products: the NOWAC postgenome study. AB - Parabens are used extensively in personal care products; however, their estrogenic properties have raised concern over risks to human health. High levels of total parabens, mainly as conjugates, have been reported in human plasma/serum, with limited data on native parabens. Our objective was to assess and link plasma concentrations of native common parabens to self-reported use of personal care products in women from the general population. The information was obtained from an extensive questionnaire on diet and lifestyle previously answered by the women in the NOWAC study. Plasma samples from 332 individuals were extracted and cleaned up by automated solid phase extraction and analyzed by ultra high performance liquid chromatography time-of-flight mass spectrometry. Native methyl paraben dominated and was detected in 63% of the samples, with a median level of 9.4 ng/ml. Ethyl paraben (median < 3 ng/ml) and propyl paraben (median < 2 ng/ml) were detected in 22 and 29%, respectively. Butyl and benzyl parabens were not detected. For the first time, elevated levels of native parabens are reported in women from the general population. The concentrations were significantly associated with the use of skin lotions, indicating that frequent (daily or more) use maintain elevated concentrations despite the parabens short half-lives. These findings clearly emphasize the need to study potential health effects in the general population. PMID- 21610758 TI - The Extracortical Manifestations of Cerebromacular Degeneration. PMID- 21610757 TI - Familial Presenile Dementia with Spastic Paralysis. PMID- 21610759 TI - Cataplexy. PMID- 21610760 TI - Paresis of Upper Motor Neurone Type following Herpes Zoster. PMID- 21610761 TI - Short Notes and Clinical Cases: Complete Degeneration of the Posterior Columns of the Spinal Cord with Chronic Polyneuritis in a Case of Widespread Carcinomatous Disease elsewhere. PMID- 21610762 TI - Micrencephaly. PMID- 21610763 TI - Neurological Abnormalities: Their Occurrence and Significance as illustrated by an Examination of 500 Mental Defectives. PMID- 21610764 TI - Papilloma Choroideum with Diffuse Central Nervous System Metastases. PMID- 21610765 TI - The Propriety of Diagnostic Lumbar Puncture in Intracranial Hypertension. PMID- 21610766 TI - Military Aspects of Narcolepsy, with Remarks on the Pathogenesis of Narcolepsy and on Fatigue. PMID- 21610767 TI - Some Relationships between Personality and Body Chemistry. PMID- 21610768 TI - Editorial: Heredity in Psychiatry. PMID- 21610769 TI - Megalencephaly. PMID- 21610770 TI - The Brain of the Mental Defective: A Study of Morphology in its Relation to Intelligence: PART II.-THE CORPUS CALLOSUM IN ITS RELATION TO INTELLIGENCE. PMID- 21610771 TI - Disseminated Demyelinization of the Central Nervous System in Monkeys and Allied Disorders in Man. PMID- 21610772 TI - A Comparison of Some New Flocculation Tests for the Cerebrospinal Fluid with the Wassermann Reaction (M.B.R.II., Modified Citochol and Modified Kiss Reactions). PMID- 21610774 TI - A Case Of Subdural Haematomata. PMID- 21610773 TI - Sleep and Its Relationship to Schizophrenia. PMID- 21610775 TI - Editorial: The Study of Mental Deficiency in Relation to Neurology and Psychology. PMID- 21610777 TI - Cerebral Structure and Mental Function as illustrated by a Study of Four Defectives' Brains. PMID- 21610776 TI - Occasional Notes: REPORT OF THE CONFERENCE OF THE PROGRAMME-EXECUTIVE COMMITTEE OF THE SECOND INTERNATIONAL NEUROLOGICAL CONGRESS, LONDON, 1935. PMID- 21610778 TI - The Depth and Rate of Respiration in Normal and Psychotic Subjects. PMID- 21610780 TI - 'Crowding' of Inhibition and of Excitation. PMID- 21610779 TI - Cephalic Dysostosis. PMID- 21610782 TI - Editorial: Meningeal Haemorrhage. PMID- 21610781 TI - A Note on Cutaneous and Meningeal Haemangiectatic Naevi associated with Contralateral Epilepsy and/or Hemiplegia (Syndrome Neuro-Cutane). PMID- 21610783 TI - Acromegaly in One of Uniovular Twins. PMID- 21610785 TI - Traumatic Encephalopathy ('Punch Drunk') of Professional Pugilists. PMID- 21610784 TI - Psychoses associated with Pernicious Anaemia: With a Report of Two Cases. PMID- 21610786 TI - Calcium in Epilepsy. PMID- 21610787 TI - Cholesterol Tumour (Craniopharyngioma) of the Pituitary Body. PMID- 21610788 TI - The pH and Lactic Acid Content of the Cerebrospinal Fluid. PMID- 21610789 TI - Colloid Cyst of the Third Ventricle associated with Congenital Cystic Kidneys. PMID- 21610790 TI - Narcolepsy and the Machine Age; The Recent Increase in the Incidence of Narcolepsy. PMID- 21610791 TI - SUPPLEMENTARY NOTE. PMID- 21610792 TI - Changing Conceptions of Epilepsy. PMID- 21610793 TI - Observations on Records of Local Epileptic Convulsions. PMID- 21610794 TI - Apraxia in Corpus Callosum Lesions: Report of Three Cases. PMID- 21610795 TI - Congenital Syphilis in Mental Defective Adults. PMID- 21610797 TI - Clinical Research in Psychiatry. PMID- 21610796 TI - An Unusual Type of Cortical Gliosis. PMID- 21610798 TI - The Chemistry of the Brain in the Mental Defective. PMID- 21610799 TI - Symptomatic Epilepsy in One of Identical Twins: A Study of the Epileptic Character. PMID- 21610800 TI - A Case of Juvenile Amaurotic Family Idiocy. PMID- 21610801 TI - Dinitrophenol in Dementia PraeCox. PMID- 21610802 TI - The Role of the Cerebral Cortex in Narcolepsy; the Classification of Narcolepsy and Allied Disorders. PMID- 21610803 TI - Brain Fever. PMID- 21610804 TI - Occasional Notes: SECOND INTERNATIONAL NEUROLOGICAL CONGRESS, LONDON, 1935: July 29th to August 2nd. PMID- 21610805 TI - The 'Dreamy State' as an Epileptic Aura, with Remarks on the Occurrence of Elaborate Mental States at the Beginning of Epileptic Fits. PMID- 21610806 TI - The 'Frog' Child: A Congenital Lesion of the Corpus Striatum? PMID- 21610807 TI - Bloodvessel Tumours of the Brain with Particular Reference to the Lindau Syndrome. PMID- 21610808 TI - A Case of Acute Toxic Chorea. PMID- 21610809 TI - Unusual Size of Intraventricular Spongioblastoma in a Case of Tuberous Sclerosis. PMID- 21610810 TI - Laurence-Moon-Biedl Syndrome: A Report of Two Cases. PMID- 21610812 TI - Observations on the Motor Phenomena of Hysteria. PMID- 21610811 TI - Prophylactic Mental Hygiene. PMID- 21610813 TI - The Brain of the Mental Defective: Part 3. The Width of the Convolutions in the Normal and Defective Person. PMID- 21610814 TI - The Respiratory Rhythm in Normal and Psychotic Subjects. PMID- 21610815 TI - Some of the Structural Abnormalities presented by the Brains of Thirty-one Certified Mental Defectives. PMID- 21610816 TI - I. Barrier Permeability to Bromide and Protein Content of the Cerebrospinal Fluid. PMID- 21610817 TI - II. Barrier Permeability to Bromide and Sodium Chloride Content of the Cerebrospinal Fluid. PMID- 21610818 TI - Editorial: The Future of Psychopathology. PMID- 21610819 TI - Neurological Complications of the Third Molar Tooth. PMID- 21610820 TI - Crystal-Formations in the Spinal Fluid and their Diagnostic Significance. PMID- 21610821 TI - Meningeal Lipomas in the Foramen Magnum. PMID- 21610822 TI - A Case of Recurrent Attacks of Prolonged Sleep. PMID- 21610823 TI - The Pathogenesis of Cataplexy on Anger. PMID- 21610824 TI - Regarding the 'Stuff' of which Dreams are Made-The Psychophysiological Basis of Dreams. PMID- 21610825 TI - The Pathogenesis and Treatment of Acute Anterior Poliomyelitis. PMID- 21610826 TI - Mescalin and Depersonalization: Therapeutic Experiments. PMID- 21610827 TI - The Effective Use of Small Non-dehydrating Doses of Epsom Salt in Epilepsy: A Study of One Hundred and Nine Cases. PMID- 21610828 TI - Non-Alcoholic Polyneuritis associated with Korsakow Syndrome. PMID- 21610830 TI - Recent Advances in Therapeutic (Induced) Malaria. PMID- 21610831 TI - 'Crowding' of Excitation as the Immediate Cause of Some Epileptic Fits: A Consideration of the Pathogenesis of Epileptic Fits precipitated by Anger and of those occurring in Situations of Danger. PMID- 21610829 TI - A Survey of the Patients in a Large Mental Hospital. PMID- 21610832 TI - The Nomenclature of Intracranial Tumours. PMID- 21610833 TI - Multiple Metastatic Tumours in the Brain arising from Primary Bronchial Carcinoma. PMID- 21610834 TI - Heat Regulation in Dementia Praecox Reactions of Patients with Dementia Praecox to Cold. PMID- 21610835 TI - etat Marbre. PMID- 21610836 TI - Some Observations on Masked Epilepsy and the Simulation of Traumatic Epilepsy by Cerebral Tumour, with Special Reference to Head Injuries without Fracture. PMID- 21610837 TI - The Body Type of the General Paralytic. PMID- 21610839 TI - Neurological Therapeutics. PMID- 21610838 TI - Tonic Pupils with Absent Tendon Reflexes in Mother and Daughter. PMID- 21610840 TI - Spinal Symptoms with Lymphadenoma. PMID- 21610841 TI - On Some Constitutional Aspects of Chorea and on Its Sequelae. PMID- 21610842 TI - The Significance of the Frontal Lobes for Mental Performances. PMID- 21610843 TI - Speech Perseveration And Astasia-Abasia following Carbon Monoxide Intoxication. PMID- 21610845 TI - Traumatic Aphasia and Alexia. PMID- 21610844 TI - A Cyclops and a Synotus. PMID- 21610846 TI - Avitaminosis and the Nervous System. PMID- 21610847 TI - The Cerebrospinal Fluid in 'Essential' Epilepsy. PMID- 21610848 TI - The Sensation of Vibration, with Special Reference to its Clinical Significance. PMID- 21610849 TI - Bilateral Atrophic Lobar Sclerosis following Thrombosis of the Superior Longitudinal Sinus. PMID- 21610850 TI - Degrees of Automatic Action: Some Psychiatric Applications of Hughlings Jackson's Concept of 'Reduction to a More Automatic Condition'. PMID- 21610851 TI - Needed Reforms in Psychiatry and Neurology. PMID- 21610852 TI - Variation in vector competence for dengue viruses does not depend on mosquito midgut binding affinity. AB - BACKGROUND: Dengue virus genotypes of Southeast Asian origin have been associated with higher virulence and transmission compared to other genotypes of serotype 2 (DEN-2). We tested the hypothesis that genetic differences in dengue viruses may result in differential binding to the midgut of the primary vector, Aedes aegypti, resulting in increased transmission or vectorial capacity. METHODOLOGY/PRINCIPAL FINDING: Two strains of each of the four DEN-2 genotypes (Southeast Asian, American, Indian, and West African) were tested to determine their binding affinity for mosquito midguts from two distinct populations (Tapachula, Chiapas, Mexico and McAllen, Texas, USA). Our previous studies demonstrated that Southeast Asian viruses disseminated up to 65-fold more rapidly in Ae. aegypti from Texas and were therefore more likely to be transmitted to humans. Results shown here demonstrate that viruses from all four genotypes bind to midguts at the same rate, in a titer-dependent manner. In addition, we show population differences when comparing binding affinity for DEN-2 between the Tapachula and McAllen mosquito colonies. CONCLUSIONS: If midgut binding potential is the same for all DEN-2 viruses, then viral replication differences in these tissues and throughout the mosquito can thus probably explain the significant differences in dissemination and vector competence. These conclusions differ from the established paradigms to explain mosquito barriers to infection, dissemination, and transmission. PMID- 21610853 TI - Orientia tsutsugamushi stimulates an original gene expression program in monocytes: relationship with gene expression in patients with scrub typhus. AB - Orientia tsutsugamushi is the causal agent of scrub typhus, a public health problem in the Asia-Pacific region and a life-threatening disease. O. tsutsugamushi is an obligate intracellular bacterium that mainly infects endothelial cells. We demonstrated here that O. tsutsugamushi also replicated in monocytes isolated from healthy donors. In addition, O. tsutsugamushi altered the expression of more than 4,500 genes, as demonstrated by microarray analysis. The expression of type I interferon, interferon-stimulated genes and genes associated with the M1 polarization of macrophages was significantly upregulated. O. tsutsugamushi also induced the expression of apoptosis-related genes and promoted cell death in a small percentage of monocytes. Live organisms were indispensable to the type I interferon response and apoptosis and enhanced the expression of M1 associated cytokines. These data were related to the transcriptional changes detected in mononuclear cells isolated from patients with scrub typhus. Here, the microarray analyses revealed the upregulation of 613 genes, which included interferon-related genes, and some features of M1 polarization were observed in these patients, similar to what was observed in O. tsutsugamushi-stimulated monocytes in vitro. This is the first report demonstrating that monocytes are clearly polarized in vitro and ex vivo following exposure to O. tsutsugamushi. These results would improve our understanding of the pathogenesis of scrub typhus, during which interferon-mediated activation of monocytes and their subsequent polarization into an M1 phenotype appear critical. This study may give us a clue of new tools for the diagnosis of patients with scrub typhus. PMID- 21610854 TI - Preclinical evaluation of caprylic acid-fractionated IgG antivenom for the treatment of Taipan (Oxyuranus scutellatus) envenoming in Papua New Guinea. AB - BACKGROUND: Snake bite is a common medical emergency in Papua New Guinea (PNG). The taipan, Oxyuranus scutellatus, inflicts a large number of bites that, in the absence of antivenom therapy, result in high mortality. Parenteral administration of antivenoms manufactured in Australia is the current treatment of choice for these envenomings. However, the price of these products is high and has increased over the last 25 years; consequently the country can no longer afford all the antivenom it needs. This situation prompted an international collaborative project aimed at generating a new, low-cost antivenom against O. scutellatus for PNG. METHODOLOGY/PRINCIPAL FINDINGS: A new monospecific equine whole IgG antivenom, obtained by caprylic acid fractionation of plasma, was prepared by immunising horses with the venom of O. scutellatus from PNG. This antivenom was compared with the currently used F(ab')(2) monospecific taipan antivenom manufactured by CSL Limited, Australia. The comparison included physicochemical properties and the preclinical assessment of the neutralisation of lethal neurotoxicity and the myotoxic, coagulant and phospholipase A(2) activities of the venom of O. scutellatus from PNG. The F(ab')(2) antivenom had a higher protein concentration than whole IgG antivenom. Both antivenoms effectively neutralised, and had similar potency, against the lethal neurotoxic effect (both by intraperitoneal and intravenous routes of injection), myotoxicity, and phospholipase A(2) activity of O. scutellatus venom. However, the whole IgG antivenom showed a higher potency than the F(ab')(2) antivenom in the neutralisation of the coagulant activity of O. scutellatus venom from PNG. CONCLUSIONS/SIGNIFICANCE: The new whole IgG taipan antivenom described in this study compares favourably with the currently used F(ab')(2) antivenom, both in terms of physicochemical characteristics and neutralising potency. Therefore, it should be considered as a promising low-cost candidate for the treatment of envenomings by O. scutellatus in PNG, and is ready to be tested in clinical trials. PMID- 21610855 TI - Schistosoma haematobium treatment in 1-5 year old children: safety and efficacy of the antihelminthic drug praziquantel. AB - BACKGROUND: Morbidity due to schistosomiasis is currently controlled by treatment of schistosome infected people with the antihelminthic drug praziquantel (PZQ). Children aged up to 5 years are currently excluded from schistosome control programmes largely due to the lack of PZQ safety data in this age group. This study investigated the safety and efficacy of PZQ treatment in such children. METHODS: Zimbabwean children aged 1-5 years (n = 104) were treated with PZQ tablets and side effects were assessed by questionnaire administered to their caregivers within 24 hours of taking PZQ. Treatment efficacy was determined 6 weeks after PZQ administration through schistosome egg counts in urine. The change in infection levels in the children 1-5 years old (n = 100) was compared to that in 6-10 year old children (n = 435). PRINCIPAL FINDINGS: Pre-treatment S. haematobium infection intensity in 1-5 year olds was 14.6 eggs/10 ml urine and prevalence was 21%. Of the 104 children, 3.8% reported side effects within 24 hours of taking PZQ treatment. These were stomach ache, loss of appetite, lethargy and inflammation of the face and body. PZQ treatment significantly reduced schistosome infection levels in 1-5 year olds with an egg reduction rate (ERR) of 99% and cure rate (CR) of 92%. This was comparable to the efficacy of praziquantel in 6-10 year olds where ERR was 96% and CR was 67%. INTERPRETATION/SIGNIFICANCE: PZQ treatment is as safe and efficacious in children aged 1-5 years as it is in older children aged 6-10 years in whom PZQ is the drug of choice for control of schistosome infections. PMID- 21610857 TI - A Rosetta Stone for brain waves. PMID- 21610856 TI - Cracking the code of oscillatory activity. AB - Neural oscillations are ubiquitous measurements of cognitive processes and dynamic routing and gating of information. The fundamental and so far unresolved problem for neuroscience remains to understand how oscillatory activity in the brain codes information for human cognition. In a biologically relevant cognitive task, we instructed six human observers to categorize facial expressions of emotion while we measured the observers' EEG. We combined state-of-the-art stimulus control with statistical information theory analysis to quantify how the three parameters of oscillations (i.e., power, phase, and frequency) code the visual information relevant for behavior in a cognitive task. We make three points: First, we demonstrate that phase codes considerably more information (2.4 times) relating to the cognitive task than power. Second, we show that the conjunction of power and phase coding reflects detailed visual features relevant for behavioral response--that is, features of facial expressions predicted by behavior. Third, we demonstrate, in analogy to communication technology, that oscillatory frequencies in the brain multiplex the coding of visual features, increasing coding capacity. Together, our findings about the fundamental coding properties of neural oscillations will redirect the research agenda in neuroscience by establishing the differential role of frequency, phase, and amplitude in coding behaviorally relevant information in the brain. PMID- 21610858 TI - Chemotaxis: a feedback-based computational model robustly predicts multiple aspects of real cell behaviour. AB - The mechanism of eukaryotic chemotaxis remains unclear despite intensive study. The most frequently described mechanism acts through attractants causing actin polymerization, in turn leading to pseudopod formation and cell movement. We recently proposed an alternative mechanism, supported by several lines of data, in which pseudopods are made by a self-generated cycle. If chemoattractants are present, they modulate the cycle rather than directly causing actin polymerization. The aim of this work is to test the explanatory and predictive powers of such pseudopod-based models to predict the complex behaviour of cells in chemotaxis. We have now tested the effectiveness of this mechanism using a computational model of cell movement and chemotaxis based on pseudopod autocatalysis. The model reproduces a surprisingly wide range of existing data about cell movement and chemotaxis. It simulates cell polarization and persistence without stimuli and selection of accurate pseudopods when chemoattractant gradients are present. It predicts both bias of pseudopod position in low chemoattractant gradients and--unexpectedly--lateral pseudopod initiation in high gradients. To test the predictive ability of the model, we looked for untested and novel predictions. One prediction from the model is that the angle between successive pseudopods at the front of the cell will increase in proportion to the difference between the cell's direction and the direction of the gradient. We measured the angles between pseudopods in chemotaxing Dictyostelium cells under different conditions and found the results agreed with the model extremely well. Our model and data together suggest that in rapidly moving cells like Dictyostelium and neutrophils an intrinsic pseudopod cycle lies at the heart of cell motility. This implies that the mechanism behind chemotaxis relies on modification of intrinsic pseudopod behaviour, more than generation of new pseudopods or actin polymerization by chemoattractants. PMID- 21610859 TI - Advancing cervical cancer prevention initiatives in resource-constrained settings: insights from the Cervical Cancer Prevention Program in Zambia. AB - Groesbeck Parham and colleagues describe their Cervical Cancer Prevention Program in Zambia, which has provided services to over 58,000 women over the past five years, and share lessons learned from the program's implementation and integration with existing HIV/AIDS programs. PMID- 21610860 TI - Primary prevention of gestational diabetes mellitus and large-for-gestational-age newborns by lifestyle counseling: a cluster-randomized controlled trial. AB - BACKGROUND: Our objective was to examine whether gestational diabetes mellitus (GDM) or newborns' high birthweight can be prevented by lifestyle counseling in pregnant women at high risk of GDM. METHOD AND FINDINGS: We conducted a cluster randomized trial, the NELLI study, in 14 municipalities in Finland, where 2,271 women were screened by oral glucose tolerance test (OGTT) at 8-12 wk gestation. Euglycemic (n = 399) women with at least one GDM risk factor (body mass index [BMI] >= 25 kg/m(2), glucose intolerance or newborn's macrosomia (>= 4,500 g) in any earlier pregnancy, family history of diabetes, age >= 40 y) were included. The intervention included individual intensified counseling on physical activity and diet and weight gain at five antenatal visits. Primary outcomes were incidence of GDM as assessed by OGTT (maternal outcome) and newborns' birthweight adjusted for gestational age (neonatal outcome). Secondary outcomes were maternal weight gain and the need for insulin treatment during pregnancy. Adherence to the intervention was evaluated on the basis of changes in physical activity (weekly metabolic equivalent task (MET) minutes) and diet (intake of total fat, saturated and polyunsaturated fatty acids, saccharose, and fiber). Multilevel analyses took into account cluster, maternity clinic, and nurse level influences in addition to age, education, parity, and prepregnancy BMI. 15.8% (34/216) of women in the intervention group and 12.4% (22/179) in the usual care group developed GDM (absolute effect size 1.36, 95% confidence interval [CI] 0.71-2.62, p = 0.36). Neonatal birthweight was lower in the intervention than in the usual care group (absolute effect size -133 g, 95% CI -231 to -35, p = 0.008) as was proportion of large-for-gestational-age (LGA) newborns (26/216, 12.1% versus 34/179, 19.7%, p = 0.042). Women in the intervention group increased their intake of dietary fiber (adjusted coefficient 1.83, 95% CI 0.30-3.25, p = 0.023) and polyunsaturated fatty acids (adjusted coefficient 0.37, 95% CI 0.16-0.57, p < 0.001), decreased their intake of saturated fatty acids (adjusted coefficient -0.63, 95% CI -1.12 to -0.15, p = 0.01) and intake of saccharose (adjusted coefficient -0.83, 95% CI 1.55 to -0.11, p = 0.023), and had a tendency to a smaller decrease in MET minutes/week for at least moderate intensity activity (adjusted coefficient 91, 95% CI -37 to 219, p = 0.17) than women in the usual care group. In subgroup analysis, adherent women in the intervention group (n = 55/229) had decreased risk of GDM (27.3% versus 33.0%, p = 0.43) and LGA newborns (7.3% versus 19.5%, p = 0.03) compared to women in the usual care group. CONCLUSIONS: The intervention was effective in controlling birthweight of the newborns, but failed to have an effect on maternal GDM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33885819. Please see later in the article for the Editors' Summary. PMID- 21610861 TI - Ziehl-Neelsen staining technique can diagnose paragonimiasis. AB - BACKGROUND: We evaluated the Ziehl-Neelsen staining (ZNS) technique for the diagnosis of paragonimiasis in Laos and compared different modifications of the ZNS techniques. METHODOLOGY: WE APPLIED THE FOLLOWING APPROACH: We (1) examined a paragonimiasis index case's sputum with wet film direct examination (WF) and ZNS; (2) re-examined stored ZNS slides from two provinces; (3) compared prospectively WF, ZNS, and formalin-ether concentration technique (FECT) for sputum examination of patients with chronic cough; and (4) compared different ZNS procedures. Finally, we assessed excess direct costs associated with the use of different diagnostic techniques. PRINCIPAL FINDINGS: Paragonimus eggs were clearly visible in WF and ZNS sputum samples of the index case. They appeared brownish-reddish in ZNS and were detected in 6 of 263 archived ZNS slides corresponding to 5 patients. One hundred sputum samples from 43 patients were examined with three techniques, which revealed that 6 patients had paragonimiasis (13 positive samples). Sensitivity per slide of the FECT, ZNS and the WF technique was 84.6 (p = 0.48), 76.9 (p = 0.25) and 61.5% (p = 0.07), respectively. Percentage of fragmented eggs was below 19% and did not differ between techniques (p = 0.13). Additional operational costs per slide were 0 (ZNS), 0.10 US$ (WF), and 0.79 US$ (FECT). ZNS heated for five minutes contained less eggs than briefly heated slides (29 eggs per slide [eps] vs. 42 eps, p = 0.01). Bloodstained sputum portions contained more eggs than unstained parts (3.3 eps vs. 0.7 eps, p = 0.016). CONCLUSIONS/SIGNIFICANCE: Paragonimus eggs can easily be detected in today's widely used ZNS of sputum slides. The ZNS technique appears superior to the standard WF sputum examination for paragonimiasis and eliminates the risk of tuberculosis transmission. Our findings suggest that ZNS sputum slides should also be examined routinely for Paragonimus eggs. ZNS technique has potential in epidemiological research on paragonimiasis. PMID- 21610862 TI - Evaluation of spatially targeted strategies to control non-domiciliated Triatoma dimidiata vector of Chagas disease. AB - BACKGROUND: Chagas disease is a major neglected tropical disease with deep socio economical effects throughout Central and South America. Vector control programs have consistently reduced domestic populations of triatomine vectors, but non domiciliated vectors still have to be controlled efficiently. Designing control strategies targeting these vectors is challenging, as it requires a quantitative description of the spatio-temporal dynamics of village infestation, which can only be gained from combinations of extensive field studies and spatial population dynamic modelling. METHODOLOGY/PRINCIPAL FINDINGS: A spatially explicit population dynamic model was combined with a two-year field study of T. dimidiata infestation dynamics in the village of Teya, Mexico. The parameterized model fitted and predicted accurately both intra-annual variation and the spatial gradient in vector abundance. Five different control strategies were then applied in concentric rings to mimic spatial design targeting the periphery of the village, where vectors were most abundant. Indoor insecticide spraying and insect screens reduced vector abundance by up to 80% (when applied to the whole village), and half of this effect was obtained when control was applied only to the 33% of households closest to the village periphery. Peri-domicile cleaning was able to eliminate up to 60% of the vectors, but at the periphery of the village it has a low effect, as it is ineffective against sylvatic insects. The use of lethal traps and the management of house attractiveness provided similar levels of control. However this required either house attractiveness to be null, or >= 5 lethal traps, at least as attractive as houses, to be installed in each household. CONCLUSION/SIGNIFICANCE: Insecticide and insect screens used in houses at the periphery of the village can contribute to reduce house infestation in more central untreated zones. However, this beneficial effect remains insufficient to allow for a unique spatially targeted strategy to offer protection to all households. Most efficiently, control should combine the use of insect screens in outer zones to reduce infestation by both sylvatic and peri domiciliated vectors, and cleaning of peri-domicile in the centre of the village where sylvatic vectors are absent. The design of such spatially mixed strategies of control offers a promising avenue to reduce the economic cost associated with the control of non-domiciliated vectors. PMID- 21610863 TI - Estimates of outcomes up to ten years after stroke: analysis from the prospective South London Stroke Register. AB - BACKGROUND: Although stroke is acknowledged as a long-term condition, population estimates of outcomes longer term are lacking. Such estimates would be useful for planning health services and developing research that might ultimately improve outcomes. This burden of disease study provides population-based estimates of outcomes with a focus on disability, cognition, and psychological outcomes up to 10 y after initial stroke event in a multi-ethnic European population. METHODS AND FINDINGS: Data were collected from the population-based South London Stroke Register, a prospective population-based register documenting all first in a lifetime strokes since 1 January 1995 in a multi-ethnic inner city population. The outcomes assessed are reported as estimates of need and included disability (Barthel Index <15), inactivity (Frenchay Activities Index <15), cognitive impairment (Abbreviated Mental Test < 8 or Mini-Mental State Exam <24), anxiety and depression (Hospital Anxiety and Depression Scale >10), and mental and physical domain scores of the Medical Outcomes Study 12-item short form (SF-12) health survey. Estimates were stratified by age, gender, and ethnicity, and age adjusted using the standard European population. Plots of outcome estimates over time were constructed to examine temporal trends and sociodemographic differences. Between 1995 and 2006, 3,373 first-ever strokes were registered: 20% 30% of survivors had a poor outcome over 10 y of follow-up. The highest rate of disability was observed 7 d after stroke and remained at around 110 per 1,000 stroke survivors from 3 mo to 10 y. Rates of inactivity and cognitive impairment both declined up to 1 y (280/1,000 and 180/1,000 survivors, respectively); thereafter rates of inactivity remained stable till year eight, then increased, whereas rates of cognitive impairment fluctuated till year eight, then increased. Anxiety and depression showed some fluctuation over time, with a rate of 350 and 310 per 1,000 stroke survivors, respectively. SF-12 scores showed little variation from 3 mo to 10 y after stroke. Inactivity was higher in males at all time points, and in white compared to black stroke survivors, although black survivors reported better outcomes in the SF-12 physical domain. No other major differences were observed by gender or ethnicity. Increased age was associated with higher rates of disability, inactivity, and cognitive impairment. CONCLUSIONS: Between 20% and 30% of stroke survivors have a poor range of outcomes up to 10 y after stroke. Such epidemiological data demonstrate the sociodemographic groups that are most affected longer term and should be used to develop longer term management strategies that reduce the significant poor outcomes of this group, for whom effective interventions are currently elusive. Please see later in the article for the Editors' Summary. PMID- 21610865 TI - ELECTRO-ENCEPHALOGRAPHY IN CASES OF SUB-CORTICAL TUMOUR. PMID- 21610866 TI - THE WERNICKE SYNDROME: With Special Reference to Manic Syndromes Associated with Hypothalamic Lesions. PMID- 21610864 TI - Species diversity and phylogeographical affinities of the Branchiopoda (Crustacea) of Churchill, Manitoba, Canada. AB - The region of Churchill, Manitoba, contains a wide variety of habitats representative of both the boreal forest and arctic tundra and has been used as a model site for biodiversity studies for nearly seven decades within Canada. Much previous work has been done in Churchill to study the Daphnia pulex species complex in particular, but no study has completed a wide-scale survey on the crustacean species that inhabit Churchill's aquatic ecosystems using molecular markers. We have employed DNA barcoding to study the diversity of the Branchiopoda (Crustacea) in a wide variety of freshwater habitats and to determine the likely origins of the Churchill fauna following the last glaciation. The standard animal barcode marker (COI) was sequenced for 327 specimens, and a 3% divergence threshold was used to delineate potential species. We found 42 provisional and valid branchiopod species from this survey alone, including several cryptic lineages, in comparison with the 25 previously recorded from previous ecological works. Using published sequence data, we explored the phylogeographic affinities of Churchill's branchiopods, finding that the Churchill fauna apparently originated from all directions from multiple glacial refugia (including southern, Beringian, and high arctic regions). Overall, these microcrustaceans are very diverse in Churchill and contain multiple species complexes. The present study introduces among the first sequences for some understudied genera, for which further work is required to delineate species boundaries and develop a more complete understanding of branchiopod diversity over a larger spatial scale. PMID- 21610867 TI - THE EFFECT OF PERCUSSION OF NERVE. PMID- 21610868 TI - THE ELECTRO-ENCEPHALOGRAPHIC LOCALIZATION OF INTRA-CRANIAL NEOPLASMS. PMID- 21610869 TI - THE ELECTROENCEPHALOGRAM IN TRAUMATIC EPILEPSY. PMID- 21610870 TI - THE RELATION BETWEEN THE EFFECTS OF THE BLOOD SUGAR LEVELS AND HYPERVENTILATION ON THE ELECTROENCEPHALOGRAM. PMID- 21610871 TI - THE SCOPE AND LIMITATIONS OF VISUAL AND AUTOMATIC ANALYSIS OF THE ELECTROENCEPHALOGRAM. PMID- 21610872 TI - METABOLIC FACTORS AFFECTING FIBRILLATION IN DENERVATED MUSCLE. PMID- 21610873 TI - NEUROSIS AND SEXUALITY. PMID- 21610875 TI - CYCLIC OCULOMOTOR PALSY. PMID- 21610874 TI - AN EXPLORATORY STUDY OF MENTAL ORGANIZATION IN SENILITY. PMID- 21610876 TI - SOME OBSERVATIONS ON THE EFFECT OF CENTRIFUGAL FORCE IN MAN. PMID- 21610877 TI - NIGHT VISUAL CAPACITY OF NEUROTIC SOLDIERS. PMID- 21610878 TI - LESIONS OF THE CENTRAL NERVOUS SYSTEM IN HERPES ZOSTER. PMID- 21610879 TI - ANGIOMATOSE ENCEPHALO-TRIGEMINEE (STURGE-WEBER) SANS CALCIFICATIONS RADIOLOGIQUEMENT DECELABLES: (OBSERVATION ANATOMO-CLINIQUE). PMID- 21610880 TI - ELECTRICAL AIDS IN PROGNOSIS OF NERVE INJURIES. PMID- 21610881 TI - DIVERTICULUM OF THE LATERAL VENTRICLE EXTENDING INTO THE POSTERIOR CRANIAL FOSSA: REPORT OF A CASE SUCCESSFULLY RELIEVED BY OPERATION. PMID- 21610882 TI - A CASE OF MUSICOGENIC EPILEPSY. PMID- 21610884 TI - CEREBRAL RESPONSES TO ELECTRICAL STIMULATION OF PERIPHERAL NERVE IN MAN. PMID- 21610883 TI - ELECTROMYOGRAMS IN MUSCULAR DISORDERS. PMID- 21610885 TI - INTERNATIONAL FEDERATION OF E.E.G. SOCIETIES. PMID- 21610886 TI - PERCEPTUAL PATTERNS DURING RECOVERY FROM GENERAL ANAESTHESIA. PMID- 21610888 TI - Foundations' Fund for Research in Psychiatry. PMID- 21610887 TI - CESSATION OF DREAMING AFTER BRAIN INJURY. PMID- 21610889 TI - THE USE OF AN OBJECT SORTING TEST IN ELUCIDATING THE HEREDITARY FACTOR IN SCHIZOPHRENIA. PMID- 21610890 TI - A CEREBROSPINAL FLUID BANK. PMID- 21610891 TI - STUDIES ON INTERMEDIATE CARBOHYDRATE METABOLISM IN MULTIPLE SCLEROSIS. PMID- 21610892 TI - ADAPTATION TO POSTURAL CHANGE IN PSYCHIATRIC PATIENTS. PMID- 21610893 TI - NERVE FIBRE DEGENERATION IN THE BRAIN IN AMYOTROPHIC LATERAL SCLEROSIS. PMID- 21610894 TI - THE EFFECT OF HAEMODIALYSIS IN MYASTHENIA GRAVIS. PMID- 21610895 TI - A MYOPATHY PRESENTING IN ADULT LIFE WITH FEATURES SUGGESTIVE OF GLYCOGEN STORAGE DISEASE. PMID- 21610896 TI - THE EFFECT OF FOCAL LESIONS OF THE BRAIN UPON AUDITORY AND VISUAL RECENT MEMORY IN MAN. PMID- 21610897 TI - INTRATHECAL TUBERCULIN IN DISSEMINATED SCLEROSIS: THE IMMUNOLOGICAL ASPECTS. PMID- 21610898 TI - THE FICTION OF THE "GERSTMANN SYNDROME". PMID- 21610899 TI - INFANTILE METACHROMATIC LEUCODYSTROPHY. PMID- 21610900 TI - THE EFFECTS OF HEMISPHERECTOMY ON INTELLECTUAL FUNCTIONING IN CASES OF INFANTILE HEMIPLEGIA. PMID- 21610901 TI - THE RECORDING OF LATERAL POPLITEAL NERVE ACTION POTENTIALS IN MAN. PMID- 21610902 TI - A SYNDROME OF CONTINUOUS MUSCLE-FIBRE ACTIVITY. PMID- 21610903 TI - INTELLECTUAL IMPAIRMENT IN CHILDREN WITH LOCALIZED POST-INFANTILE CEREBRAL LESIONS. PMID- 21610904 TI - EXTRADURAL HAEMATOMA AT THE VERTEX. PMID- 21610905 TI - TENTORIAL MENINGIOMAS. PMID- 21610906 TI - II Experimental production of naming disorders in normal people. PMID- 21610907 TI - Myoclonic encephalopathy of infants. PMID- 21610908 TI - Editorial. PMID- 21610909 TI - The changes in nerve conduction in acute idiopathic polyneuritis. PMID- 21610910 TI - Scolloping of the vertebral bodies in von Recklinghausen's disease of the nervous system (neurofibromatosis). PMID- 21610911 TI - Clinical and pathological findings in a case of hepatolenticular degeneration treated with penicillamine. PMID- 21610912 TI - Studies on induced exacerbation of Parkinsonian rigidity: The effect of contralateral voluntary activity. PMID- 21610913 TI - A follow-up study of surgery in temporal lobe epilepsy. PMID- 21610914 TI - The influence of various stimuli upon Parkinsonian tremor and rigidity. PMID- 21610915 TI - THE LAURENCE - MOON - BIEDL SYNDROME: A PATHOLOGICAL REPORT. PMID- 21610916 TI - AN EXAMPLE OF STATUS MARMORATUS OF THE CEREBRAL CORTEX. PMID- 21610917 TI - EPENDYMAL STREAKS AND ACCESSORY CAVITIES IN THE HUMAN OCCIPITAL LOBE. PMID- 21610918 TI - CRITICAL REVIEW: THE PATHOLOGY OF APOPLEXY. PMID- 21610919 TI - THE EFFECT OF PITRESSIN AND WATER INTAKE ON THE CEREBROSPINAL FLUID. PMID- 21610920 TI - PSEUDOHERMAPHRODITISM, ADIPOSITY, POLYURIA, AND HYPERGLYCAEMIA. AN INFUNDIBULOTUBERIAN SYNDROME. PMID- 21610921 TI - A CLINICAL STUDY OF STATES OF "ECSTASY" OCCURRING IN AFFECTIVE DISORDERS. PMID- 21610922 TI - CEREBELLAR SYNDROME IN AN ADULT WITH MALFORMATION OF THE CEREBELLUM AND BRAIN STEM (ARNOLD-CHIARI DEFORMITY), WITH A NOTE ON THE OCCURRENCE OF "TORPEDOES" IN THE CEREBELLUM. PMID- 21610923 TI - MENTAL DISORDER IN CUSHING'S SYNDROME. PMID- 21610924 TI - A CRITICAL REVIEW: PRIMARY DISEASES OF VOLUNTARY MUSCLES. PMID- 21610925 TI - FURTHER OBSERVATIONS ON NEUROLOGICAL ABNORMALITIES IN MENTAL DEFECTIVES. PMID- 21610926 TI - THE ELECTRO-ENCEPHALOGRAM IN CONVULSIONS INDUCED BY CARDIAZOL. PMID- 21610927 TI - THE RELATIONSHIP BETWEEN THE BLOOD PRESSURE AND THE TONIC REGULATION OF THE PIAL ARTERIES. PMID- 21610928 TI - SOME OBSERVATIONS ON THE DEPTH AND NERVECELL CONTENT OF THE SUPRAGRANULAR CORTEX IN NORMAL AND MENTALLY DEFECTIVE PERSONS. PMID- 21610929 TI - THE RELATIONSHIP IN MAN OF CEREBRAL ACTIVITY TO BLOOD FLOW AND TO BLOOD CONSTITUENTS. PMID- 21610930 TI - OBSERVATIONS ON THE CEREBROSPINAL FLUID PRESSURE ON SIMULTANEOUS VENTRICULAR AND LUMBAR PUNCTURES. PMID- 21610931 TI - A CRITICAL REVIEW: TWIN RESEARCH IN PSYCHIATRY. PMID- 21610932 TI - BROWN-SEQUARD SYNDROME: A Case of Unusual AEtiology. PMID- 21610934 TI - A CASE OF APHASIA, WITH SPECIAL REFERENCE TO THE PROBLEMS OF REPETITION AND WORD FINDING. PMID- 21610933 TI - RECENT STUDIES OF THE MORPHOLOGY OF THE NEURONE IN HEALTH AND DISEASE. PMID- 21610935 TI - THALAMIC HYPERTROPHY OR GLIOMATOSIS OF THE OPTIC THALAMUS. PMID- 21610936 TI - CRITICAL REVIEW: THE TECHNIQUE AND APPLICATION OF ELECTRO-ENCEPHALOGRAPHY. PMID- 21610937 TI - COMPULSIVE FEATURES IN A PATIENT WITH LEBER'S DISEASE. PMID- 21610938 TI - THE ARM REFLEXES. PMID- 21610939 TI - PERSISTENT MIRROR-MOVEMENTS AS A HEREDO-FAMILIAL DISORDER. PMID- 21610940 TI - SHORT-DISTANCE PROGNOSIS OF SCHIZOPHRENIA. PMID- 21610941 TI - THE CORTICAL PROJECTION OF THE MEDIAL GENICULATE BODY. PMID- 21610942 TI - A CRITICAL REVIEW: NARCOSIS THERAPY. PMID- 21610943 TI - VASOMOTOR REACTIONS IN THE HYPNOTIC STATE. PMID- 21610944 TI - BRAIN POTENTIAL CHANGES IN MAN INDUCED BY METRAZOL. PMID- 21610945 TI - THE EFFECT OF CARDIAZOL CONVULSIONS ON THE SO-CALLED "BULBOCAPNINE CATATONIA" IN THE MONKEY. PMID- 21610946 TI - A CLINICAL STUDY OF THE EFFECTS OF SHORT PERIODS OF SEVERE ANOXIA WITH SPECIAL REFERENCE TO THE MECHANISM OF ACTION OF CARDIAZOL "SHOCK". PMID- 21610947 TI - THE BLOOD SUPPLY OF THE HUMAN SPINAL CORD. PMID- 21610948 TI - AN UNUSUAL CASE OF THE GRASP REFLEX, WITH SOME OBSERVATIONS ON THE VOLITIONAL AND REFLEX COMPONENTS. PMID- 21610950 TI - HEREDO-FAMILIAL TENDINOUS AREFLEXIA WITHOUT PUPILLARY CHANGES. PMID- 21610949 TI - A CRITICAL REVIEW: SOME ASPECTS OF THE STRUCTURE OF THE HYPOTHALAMUS. PMID- 21610951 TI - THE EFFECT OF FRUCTOSE INGESTION ON BLOOD FRUCTOSE IN PSYCHOTIC PATIENTS. PMID- 21610952 TI - A STUDY OF THE EFFECT OF RIGHT FRONTAL LOBECTOMY ON INTELLIGENCE AND TEMPERAMENT. PMID- 21610953 TI - THE REACTION OF THE PIAL ARTERIES TO SOME CHOLIN-LIKE AND ADRENALIN-LIKE SUBSTANCES. PMID- 21610954 TI - INCREASED SPONTANEOUS ACTIVITY AND FOOD INTAKE PRODUCED IN RATS BY REMOVAL OF THE FRONTAL POLES OF THE BRAIN. PMID- 21610955 TI - A CRITICAL REVIEW: SOMATIC RESEARCH IN PERIODIC CATATONIA. PMID- 21610956 TI - FACTORS IN FUNCTIONAL RECOVERY FOLLOWING SECTION OF THE OCULOMOTOR NERVE IN MONKEYS. PMID- 21610957 TI - FAMILIAL PRESENILE DEMENTIA: REPORT OF CASE WITH CLINICAL AND PATHOLOGICAL FEATURES OF ALZHEIMER'S DISEASE. PMID- 21610958 TI - ARHINENCEPHALY. PMID- 21610959 TI - THE FUNCTIONAL RESPONSES OF THE SYMPATHETIC NERVOUS SYSTEM OF MAN FOLLOWING HEMIDECORTICATION. PMID- 21610960 TI - SWAYBACK: A DEMYELINATING DISEASE OF LAMBS WITH AFFINITIES TO SCHILDER'S ENCEPHALITIS AND ITS PREVENTION BY COPPER. PMID- 21610961 TI - A CRITICAL REVIEW: VITAMIN B DEFICIENCY AND NERVOUS DISEASE. PMID- 21610962 TI - THE EMOTIONAL AND SOMATIC RESPONSE OF SCHIZOPHRENIC PATIENTS AND NORMAL CONTROLS TO ADRENALIN AND DORYL. PMID- 21610963 TI - THE DISTRIBUTION OF COMMISSURAL FIBRES IN THE CORPUS CALLOSUM IN THE MACAQUE MONKEY. PMID- 21610965 TI - HYPOGLYCAEMIC SHOCK AND THE GRASP-REFLEX: THE EFFECT OF INSULIN SHOCK ON BULBOCAPNINE CATALEPSY IN MONKEYS. PMID- 21610964 TI - BEHAVIOUR AND MOOD CYCLES APPARENTLY RELATED TO PARATHYROID DEFICIENCY. PMID- 21610966 TI - DEGENERATION OF THE PAPILLO-MACULAR BUNDLE IN APES AND ITS SIGNIFICANCE IN HUMAN NEURO-PATHOLOGY. PMID- 21610967 TI - A CRITICAL REVIEW: THE TREATMENT OF MENTAL DISORDERS BY INDUCED CONVULSIONS. PMID- 21610968 TI - PSYCHIATRIC COMPARISON OF ARTIFICIAL MENOPAUSE AND THE EFFECTS OF HYSTERECTOMY. PMID- 21610969 TI - ANTIBODIES TO BRAIN AND THEIR RELATION TO DEMYELINIZATION. PMID- 21610970 TI - THE ROLE OF POTASSIUM IN MYASTHENIA GRAVIS. PMID- 21610972 TI - ACOUSTIC TUMOURS. PMID- 21610971 TI - ATROPHY OF THE THALAMUS IN A CASE OF ACQUIRED HEMIPLEGIA ASSOCIATED WITH DIFFUSE PORENCEPHALY AND SCLEROSIS OF THE LEFT CEREBRAL HEMISPHERE. PMID- 21610973 TI - A CRITICAL REVIEW: THE PATHOLOGY OF CEREBRAL GLIOMAS. PMID- 21610974 TI - TOPOGRAPHIC STUDIES OF DISTURBANCES OF SWEAT SECRETION AFTER COMPLETE LESIONS OF PERIPHERAL NERVES. PMID- 21610975 TI - ALZHEIMER'S DISEASE: A REPORT OF SIX CASES. PMID- 21610976 TI - BASILAR IMPRESSION OF THE SKULL. PMID- 21610977 TI - A STUDY ON PURE WORD-DEAFNESS. PMID- 21610978 TI - NEURONAL DIFFERENTIATION IN IMPLANTED FOETAL CORTICAL TISSUE. PMID- 21610979 TI - SCIENCE AND THE BRITISH MEDICAL ASSOCIATION. PMID- 21610981 TI - THE METABOLISM OF THE BRAIN. PMID- 21610980 TI - THE EFFECT OF RAISED INTRACRANIAL PRESSURE ON THE CEREBRAL BLOOD FLOW. PMID- 21610982 TI - CEREBELLAR ATROPHY ASSOCIATED WITH ETAT MARBRE OF THE BASAL GANGLIA. PMID- 21610984 TI - JUVENILE PARESIS IN ONE TWIN. PMID- 21610983 TI - THE NEUROHISTOLOGICAL BASIS FOR THE SENSATION OF PAIN PROVOKED FROM DEEP FASCIA, TENDON, AND PERIOSTEUM. PMID- 21610985 TI - THE ELECTROENCEPHALOGRAM IN ELECTRICALLY INDUCED CONVULSIONS IN RABBITS. PMID- 21610986 TI - Reduction en-masse of inguinal hernia with strangulated obstruction. AB - "Reduction en masse of inguinal hernia" means reduction/migration of a hernial sac into the properitoneal space. We report the CT findings in a case of reduction en masse with strangulated obstruction. CT scan demonstrated a hernial sac with fibrous constriction band at the neck, situated in the properitoneal space superior to the inguinal region, causing closed-loop obstruction. The hernial sac contained thickened bowel loop with wall enhancement and fluid suggestive of incarceration/strangulation. We propose to call this, 'The properitoneal hernial sac sign', defined as "Presence of a hernial sac in the properitoneal space (and not in the inguinal/femoral canal) containing an obstructed/incarcerated bowel loop and causing small bowel obstruction" to identify "reduction en masse of inguinal hernia". PMID- 21610987 TI - Use of new radiochromic devices for peripheral dose measurement: potential in vivo dosimetry application. AB - The authors have studied the feasibility of using three new high-sensitivity radiochromic devices in measuring the doses to peripheral points outside the primary megavoltage photon beams. The three devices were GAFCHROMIC(r) EBT film, prototype Low Dose (LD) Film, and prototype LD Card. The authors performed point dosimetry using these three devices in water-equivalent solid phantoms at x = 3,5,8,10, and 15 cm from the edge of 6 MV and 15 MV photon beams of 10x10 cm(2), and at depths of 0, 0.5 cm, and depth of maximum dose. A full sheet of EBT film was exposed with 5000 MU. The prototype LD film pieces were 1.5x2 cm(2) in size. Some LD films were provided in the form of a card in 1.8x5 cm(2) holding an active film in 1.8x2 cm(2). These are referred to as "LD dosimeter cards". The small LD films and cards were exposed with 500 MU. For each scanned film, a 6 mm circular area centered at the measurement point was sampled and the mean pixel value was obtained. The calibration curves were established from the calibration data for each combination of film/cards and densitometer/scanner. The doses at the peripheral points determined from the films were compared with those obtained using ion chamber at respective locations in a water phantom and general agreements were found. It is feasible to accurately measure peripheral doses of megavoltage photon beams using the new high-sensitivity radiochromic devices. This near real-time and inexpensive method can be applied in a clinical setting for dose measurements to critical organs and sensitive patient implant devices. PMID- 21610988 TI - Diffuse panbronchiolitis: not just an Asian disease: Australian case series and review of the literature. AB - Diffuse panbronchiolitis is a disease of obscure aetiology that is traditionally associated with Asian ethnicity. We propose that this disease also occurs in Caucasians and the incidence in this population is greater than currently recognised. We further propose that high resolution computed tomography (HRCT) and response to macrolide therapy should be relied upon to make this diagnosis without verification by lung biopsy. In most circumstances, obtaining a biopsy for histopathology is not practical, and the disease may then be mistaken for other more common airway diseases. Accuracy of diagnosis is important as untreated disease is associated with a poor prognosis, and effective treatment is available. We report four out of a series of cases as evidence that DPB is in fact more common in the Western population than is currently understood. PMID- 21610989 TI - 3D vs. 2D cephalometric analysis comparisons with repeated measurements from 20 Thai males and 20 Thai females. AB - This paper presented 3D cephalometric analysis on DICOM data from I-CAT CT cone beam machine consisted of averages and standard deviations from 20 Thai males from 19 to 70 year (average 33.53 +/- 14.08 year) and 20 Thai females from 16 to 70 year (average 32.60 +/- 15.37 year). The angular measurements consisted of 49 lateral angular measurements and 9 frontal angular measurements while linear measurements consisted of 29 lateral linear measurements, 3 frontal linear measurements, and 8 perpendicular measurements. Results in 3D were compared with the corresponding 2D results showing that most midline-to-midline linear measurements and some midline-to-midline angular measurements were not different, while other types of measurements were significantly different. The 3D results will be used in the clinical Ceph3D services as requested by those with interests on cephalometric analysis and anthropology with focus on Thai subjects while the 2D results will be used for comparison with cephalometric analyses from other orthodontists.ts reserved. PMID- 21610990 TI - CT virtual endoscopy and 3D stereoscopic visualisation in the evaluation of coronary stenting. AB - The aim of this case report is to present the additional value provided by CT virtual endoscopy and 3D stereoscopic visualisation when compared with 2D visualisations in the assessment of coronary stenting. A 64-year old patient was treated with left coronary stenting 8 years ago and recently followed up with multidetector row CT angiography. An in-stent restenosis of the left coronary artery was suspected based on 2D axial and multiplanar reformatted images. 3D virtual endoscopy was generated to demonstrate the smooth intraluminal surface of coronary artery wall, and there was no evidence of restenosis or intraluminal irregularity. Virtual fly-through of the coronary artery was produced to examine the entire length of the coronary artery with the aim of demonstrating the intraluminal changes following placement of the coronary stent. In addition, stereoscopic views were generated to show the relationship between coronary artery branches and the coronary stent. In comparison with traditional 2D visualisations, virtual endoscopy was useful for assessment of the intraluminal appearance of the coronary artery wall following coronary stent implantation, while stereoscopic visualisation improved observers' understanding of the complex cardiac structures. Thus, both methods could be used as a complementary tool in cardiac imaging. PMID- 21610991 TI - Politics of a director of radiology. PMID- 21610992 TI - Reversible splenial lesion syndrome in neuroleptic malignant syndrome. AB - BACKGROUND: Reversible focal lesions in the splenium of the corpus callosum (SCC) or reversible splenial lesion syndrome are rare and little is known about their pathophysiology. CASE SUMMARY: The authors describe a case of a 65-year-old female who presented with fever, abnormal behaviour and mild hypernatremia. She was on neuropsychiatric treatment for bipolar disorder but denied any history of seizure. After an extensive workout to exclude infection, a clinical diagnosis of neuroleptic malignant syndrome (NMS) was made. Initial magnetic resonance imaging (MRI) of the brain showed a lesion in the SCC characterized by high-signal intensity on T2-weighted and FLAIR sequences with reduced signal intensity on T1 weighted sequence. Diffuse weighted imaging (DWI) showed restricted diffusion. There was no enhancement following Gadolinium administration. The follow-up MRI 8 weeks later showed complete resolution of the SCC lesion. CONCLUSION: While the pathophysiology of reversible SCC lesions is still unclear, this case highlights the need to consider NMS in the differential diagnosis of reversible splenial lesion of the corpus callosum. PMID- 21610993 TI - South East Asian Society of Interventional Radiology (SEASIR): state and future of radiology in interventional radiology. PMID- 21610994 TI - Medullary carcinoma of the breast: Role of contrast-enhanced MRI in the diagnosis of multiple breast lesions. AB - Medullary carcinoma is a rare breast carcinoma with a syncytial growth pattern and high-grade cytology. It can be difficult to diagnose and may be missed on conventional imaging as the findings may overlap with benign lesions i.e. fibroadenomas. The authors report a case of a 25-year-old female who presented with multifocal breast lumps diagnosed with medullary carcinoma and fibroadenomas. Imaging and pathological correlation with contrast-enhanced MRI are presented in the diagnosis of these lesions. PMID- 21610995 TI - Improvement in diagnosis of breast tumour using ultrasound elastography and echography: A phantom based analysis. AB - Due to the isoechoic nature of lesions and their poor contrast with neighbouring tissue, a lesion may remain undetected in ultrasound B mode imaging for cancerous tissue. Imaging of the elastic properties of tissue provides new information which is collateral to tissue pathology. This study provides quantitative analysis of improvements in tumour diagnosis when the ultrasound B mode imaging is combined with elastography. Quantification was based on the textural parameters measured from the ultrasound B mode image and strain measured from the elastogram. The ability of a parameter to discriminate between diseased cases and normal cases was evaluated using receiver operating characteristic (ROC) analysis. Polyacrylamide gel based tissue mimicking phantoms with embedded inclusions of varying stiffness were used for the analysis. PMID- 21610996 TI - Generational challenges to radiology education and practice. PMID- 21610997 TI - State and future of interventional radiology in Malaysia. PMID- 21610998 TI - State and future of radiology and nuclear medicine in Vietnam. PMID- 21610999 TI - Unproven medical devices and cancer therapy: big claims but no evidence. PMID- 21611000 TI - Frontiers of cancer care in Asia-Pacific region: cancer care in Australia. AB - Cancer has a significant impact on the Australian community. One in three men and one in four women will develop cancer by the age of 75. The estimated annual health expenditure due to cancer in 2000-1 in Australia was $2.7 billion, representing 5.5% of the country's total healthcare expenditure. An historical overview of the national cancer control strategies in Australia is provided. In males, the five most common cancers in order of decreasing incidence are: prostate cancer, colorectal cancer, lung cancer, melanoma and lymphoma, while for Australian women, breast cancer is the most common cancer. Key epidemiologic information about these common cancers, current management issues and comprehensive national clinical practice guidelines (where available) are highlighted. Aspects of skin cancer, a particularly common cancer in the Australian environment - with a focus on melanoma - are also included.Cancer outcomes in Australia, measured by selected outcomes, are among the best in the world. However, there is still evidence of health inequalities, especially among patients residing in regional and remote areas, the indigenous population and people from lower socio-economic classes. Limitations of current cancer care practices in Australia, including provision of oncology services, resources and other access issues, as well as suggested improvements for future cancer care, are summarised. Ongoing implementation of national and state cancer control plans and evaluation of their effectiveness will be needed to pursue the goal of optimal cancer care in Australia. PMID- 21611001 TI - Medical physics aspects of cancer care in the Asia Pacific region. AB - Medical physics plays an essential role in modern medicine. This is particularly evident in cancer care where medical physicists are involved in radiotherapy treatment planning and quality assurance as well as in imaging and radiation protection. Due to the large variety of tasks and interests, medical physics is often subdivided into specialties such as radiology, nuclear medicine and radiation oncology medical physics. However, even within their specialty, the role of radiation oncology medical physicists (ROMPs) is diverse and varies between different societies. Therefore, a questionnaire was sent to leading medical physicists in most countries/areas in the Asia/Pacific region to determine the education, role and status of medical physicists.Answers were received from 17 countries/areas representing nearly 2800 radiation oncology medical physicists. There was general agreement that medical physicists should have both academic (typically at MSc level) and clinical (typically at least 2 years) training. ROMPs spent most of their time working in radiotherapy treatment planning (average 17 hours per week); however radiation protection and engineering tasks were also common. Typically, only physicists in large centres are involved in research and teaching. Most respondents thought that the workload of physicists was high, with more than 500 patients per year per physicist, less than one ROMP per two oncologists being the norm, and on average, one megavoltage treatment unit per medical physicist.There was also a clear indication of increased complexity of technology in the region with many countries/areas reporting to have installed helical tomotherapy, IMRT (Intensity Modulated Radiation Therapy), IGRT (Image Guided Radiation Therapy), Gamma-knife and Cyber knife units. This and the continued workload from brachytherapy will require growing expertise and numbers in the medical physics workforce. Addressing these needs will be an important challenge for the future. PMID- 21611002 TI - Expanding the role of the oncology nurse. AB - Oncology nursing continues to evolve in response to advances in cancer treatment, information and biotechnology. As new scientific and technological discoveries are integrated into cancer care, oncology nurses need to play a key role in the management of this patient population. The role of the oncology nurse has expanded significantly and can differ greatly across cultures. Sophisticated treatments and the growth of targeted therapies will create the challenge of ensuring that all nurses working in this arena are well-educated, independent thinkers. Thus the future success of oncology nurses will focus on enhancement of nursing practice through advanced education. The increased globalisation of healthcare offers exciting opportunities to accomplish this goal by allowing for collaborative relationships among oncology nurses across the globe. PMID- 21611003 TI - An informatics strategy for cancer care. AB - Whether transitioning from paper to electronic records or attempting to leverage data from existing systems for outcome studies, oncology practices face many challenges in defining and executing an informatics strategy. With the increasing costs of oncology treatments and expected changes in reimbursement rules, including requirements for evidence that supports physician decisions, it will become essential to collect data on treatment decisions and treatment efficacy to run a successful program. This study evaluates the current state of informatics systems available for use in oncology programs and focuses on developing an informatics strategy to meet the challenges introduced by expected changes in reimbursement rules and in medical and information technologies. PMID- 21611004 TI - Cancer care in Singapore. AB - Singapore is a small country, but it is ideally and centrally located to conveniently serve not only its population but also patients from the surrounding regions. It's economy is sufficiently strong to maintain highly sophisticated and expensive equipment to manage a high level of healthcare, including oncology services.Cancer incidences in Singapore are on an upward trend based on the report of the Singapore Cancer Registry for the period of 2001-2005. Cancer is the number one cause of death in Singapore. The three most common cancers for males in Singapore, in decreasing occurrences, are colorectal, lung, and prostate. For females, the three most common cancers are breast, colorectal, lung cancers. Technological advances and advances in anti-cancer drugs have transformed cancer management leading to improved outcomes worldwide and in Singapore as well. The epidemiology and management of these common cancers in Singapore are presented. While Singapore presently has five radiotherapy centres (3 public, 2 private) to service its population of 4.5 million and regional needs, the government has plans to expand its radiotherapy services to accommodate the aging population and the rising expectations of increasingly affluent cancer patients seeking advanced cancer care. The current and future initiatives spearheaded by Singapore to achieve excellence in this aspect are discussed. PMID- 21611005 TI - Cancer care in China: A general review. AB - This article is to provide a general overview of cancer in China including the statistics, most common cancers, their epidemiological characteristics and the treatments. PMID- 21611007 TI - History and growth of radiation oncology in Indonesia. AB - In order to assess its progress, and to obtain a snapshot of the current situation, the Indonesian Radiation Oncology Society has routinely conducted annual surveys since 2004 to assess the current condition of resources for equipment and staffing in all radiation oncology centres in the country. Based on these routine surveys, the society has made recommendations to the government about providing cancer patients with better and more affordable access to radiotherapy services.Questionnaires in hard and soft copy forms were distributed annually to Indonesian Radiation Oncology Society members, and all 22 centres (19 in 2004) responded by sending back the completed questionnaires. The obtained data was compared with results of the first survey in 2004.In 2008, there were 22 radiotherapy centres in Indonesia, 18 Linear Accelerators and 17 cobalt units. There were 270 radiation oncology professionals, including 41 radiation oncologists, 38 medical physicists, 6 dosimetrists, 125 radiation therapy technologists, and 60 nurses. In addition, there were 17 residents and trainees participating in the Radiation Oncology training program.A lot of progress had been made in the four-year period from 2004 to 2008. Indonesia has seen the establishment of 4 new centres, which indicates a 50% increase in the number of available treatment units, and a 29% increase in the number of human resources. These achievements were possible because more attention has been placed on cancer care issues in Indonesia, a great success due to the advocacy efforts of the Society. However, numerous issues still need urgent attention from all the stakeholders. PMID- 21611006 TI - Innovations in chemotherapy and radiation therapy: Implications and opportunities for the Asia-Pacific Rim. AB - New cases of invasive cancer in the United States occur among nearly 1.5 million people annually. In 2007, more than 1,500 people died per day with this diagnosis. Cancer is responsible for nearly one in every four deaths reported in the country. Enormous amounts of money and research have been, and are being spent, in an attempt to improve these numbers. While prevention and early detection remain the key to long-term success, treatment in the neo-adjuvant, adjuvant and metastatic settings still centre around two main treatment modalities - radiation therapy and chemotherapy. This article will review the advances that have been made in both areas that are making these treatments more precise and convenient, as well as less toxic, for the patient. In the field of radiation therapy this involves the development of new therapy planning and delivery systems, such as intensity-modulated radiation therapy (IMRT), and positron emission and computed tomography, PET-CT. Chemotherapy has also evolved with the development of targeted chemotherapy for the treatment of specific malignancies as well as improved supportive care agents which allow for the administration of dose-dense chemotherapy when appropriate. PMID- 21611008 TI - Frontiers of cancer care in Asia-Pacific Region. PMID- 21611009 TI - Cancers in northern Thailand. AB - A retrospective study was undertaken to assess cancers in northern Thailand using the Chiang Mai Cancer registry and Maharaj Nakorn Chiang Mai Hospital records from January 2001 to December 2005. Maharaj Nakorn Chiang Mai Hospital is the university hospital for the Faculty of Medicine, Chiang Mai University. There were 4,108 new cancer cases being treated at the institution. The distribution of patients were (a) 32% from Chiang Mai, (b) 42% from nearby provinces of Lampoon, Phayao, and Chiang Rai, (c) 20.4% from other northern provinces, and (d) 1.2% from other parts of Thailand. Based on the data, the most common cancers by relative frequency are cancers of the lung, cervix, liver, breast, and non Hodgkin's lymphoma. The current treatment options used to manage these most common cancers are described in this article. PMID- 21611011 TI - Technical aspects of quality assurance in radiation oncology. AB - The technical aspects of quality assurance (QA) in radiation oncology as practice in the United States will be reviewed and updated in the spirit of offering the experience to the radiation oncology communities in the Asia-Pacific region. The word "technical" is used to express the organisational components or processes and not the materials within the QA program. A comprehensive QA program in radiation oncology will have an official statement declaring the quality plan for effective patient care services it provides in a document. The QA program will include all aspects of patient care: physical, clinical, and medical aspects of the services. The document will describe the organisational structure, responsibilities, checks and procedures, and resources allocated to ensure the successful implementation of the quality of patient management. Regulatory guidelines and guidelines from accreditation agencies should be incorporated in the QA program to ensure compliance. The organisational structure will have a multidisciplinary QA committee that has the authority to evaluate continuously the effectiveness of the QA program to provide prompt corrective recommendations and to request feedback as needed to monitor the response. The continuous monitoring aspects require meetings to be held at regular intervals with the minutes of the meetings officially recorded and documented. To ensure that a QA program is effective, the program itself should be audited for quality at regular intervals at least annually. It has been recognised that the current QA program has not kept abreast with the rapid implementation of new and advanced radiation therapy technologies with the most recent in image-based radiation therapy technology. The societal bodies (ASTRO and AAPM) and federal agency (NCI) acknowledge this inadequacy and have held workshops to address this issue. The challenges for the societal bodies and federal agency are numerous that include (a) the prescriptive methodology used may not be appropriate for currently implemented new technologies, (b) resources are becoming scarce, (c) advanced radiation therapy technologies have been introduced too rapidly, (d) advances in radiation therapy technologies have become too sophisticated and specialised with each therapy modality having its own separate set of equipment, for example its own dose planning software, computer system and dose delivery systems requiring individualised QA procedures. At the present time, industrial engineers are being recruited to assist in devising a methodology that is broad-based and more process-oriented risk-based formulation of QA in radiation oncology. PMID- 21611010 TI - Found in translation: Integrating laboratory and clinical oncology research. AB - Translational research in medicine aims to inform the clinic and the laboratory with the results of each other's work, and to bring promising and validated new therapies into clinical application. While laudable in intent, this is complicated in practice and the current state of translational research in cancer shows both striking success stories and examples of the numerous potential obstacles as well as opportunities for delays and errors in translation. This paper reviews the premises, promises, and problems of translational research with a focus on radiation oncology and suggests opportunities for improvements in future research design. PMID- 21611012 TI - Do we really need standards in digital image management? AB - Convention dictates that standards are a necessity rather than a luxury. Standards are supposed to improve the exchange of health and image data information resulting in improved quality and efficiency of patient care. True standardisation is some time away yet, as barriers exist with evolving equipment, storage formats and even the standards themselves. The explosive growth in the size and complexity of images such as those generated by multislice computed tomography have driven the need for digital image management, created problems of storage space and costs, and created a challenge for increasing or getting an adequate speed for transmitting, accessing and retrieving the image data. The search for a suitable and practical format for storing the data without loss of information and medico-legal implications has become a necessity and a matter of 'urgency'. Existing standards are either open or proprietary and must comply with local, regional or national laws. Currently there are the Picture Archiving and Communications System (PACS); Digital Imaging and Communications in Medicine (DICOM); Health Level 7 (HL7) and Integrating the Healthcare Enterprise (IHE). Issues in digital image management can be categorised as operational, procedural, technical and administrative. Standards must stay focussed on the ultimate goal - that is, improved patient care worldwide. PMID- 21611013 TI - Air in the kidney: between emphysematous pyelitis and pyelonephritis. AB - Presence of air in the kidney can be problematic as the location of the air in different parts of the kidney greatly affects the subsequent management and outcome of the patient. We present here a case of a patient who had emphysematous pyelitis, in which CT scan was able to display presence of air only in the collecting system, thus differentiating this condition from the more fulminant emphysematous pyelonephritis. This leads to a more favourable prognosis and outcome to the patient. PMID- 21611014 TI - Digital image management in a globalised world: opportunities and challenges. PMID- 21611015 TI - The diagnostic MRCP examination: overcoming technical challenges to ensure clinical success. AB - The magnetic resonance cholangiopancreatography (MRCP) examination has all but replaced the diagnostic endoscopic retrograde cholangiopancreatography (ERCP) examination for imaging the biliary tree and pancreatic ducts in many practical aspects of the clinical setting. Despite this increase in popularity, many magnetic resonance imaging (MRI) radiographers still find aspects of the MRCP examination quite challenging. The aim of this tutorial paper is to provide useful technical advice on how to overcome such perceived challenges and thus produce a successful diagnostic MRCP examination. This paper will be of interest to novice MRI radiographers who are at the beginning of their learning curve in MRCP examination. Other MRI radiographers who are interested in practical tips for protocol variations may also find the paper useful. PMID- 21611016 TI - Digital versus screen film mammography: a clinical comparison. PMID- 21611017 TI - Budgeting for PACS. AB - There are a number of models for the acquisition of digital image management systems. The specific details for development of a budget for a PACS/RIS acquisition will depend upon the acquisition model - although there are similarities in the overarching principles and general information, particularly concerning the radiology service requirements that will drive budget considerations.While budgeting for PACS/RIS should follow the same principles as budgeting for any new technology, it is important to understand how far the implementation of digital image management systems can reach in a healthcare setting. Accurate identification of those elements of the healthcare service that will be affected by a PACS/RIS implementation is a critical component of successful budget formation and of the success of any business case and subsequent project that relies on those budget estimates.A budget for a PACS/RIS capital acquisition project should contain capital and recurrent elements. The capital is associated with the acquisition of the system in a purchase model and capital budget may also be required for upgrade - depending upon a facility's financial management processes.The recurrent (or operational) cost component for the PACS/RIS is associated with maintaining the system(s) in a sustainable operational state.It is also important to consider the service efficiencies, cost savings and service quality improvements that PACS/RIS can generate and include these factors into the economic analysis of any proposal for a PACS/RIS project. PMID- 21611018 TI - Change is just more of the same. PMID- 21611019 TI - Hepatocellular carcinoma with extension to the diaphragm, falciform ligament, rectus abdominis and paraumbilical vein. AB - Hepatocellular carcinoma is the most common primary tumour of the liver. The most common extrahepatic metastatic sites are the lung, lymph nodes, bones and adrenal glands. All forms of HCC demonstrate a tendency for vascular invasion, producing extensive intrahepatic metastases and, occasionally, portal vein or inferior vena cava extension with spread into the right atrium in extreme cases. Tumour spread of abdominal diseases via hepatic ligaments has also been previously reported. We report a rare case of hepatocellular carcinoma with extension into the falciform ligament, overlying rectus sheath and adjacent diaphragm with concomitant infiltration into the recanalised paraumbilical vein. PMID- 21611021 TI - College of Radiology, Academy of Medicine of Malaysia position on whole body screening CT scans in healthy asymptomatic individuals (2008). AB - To date, the College of Radiology (CoR) does not see any clear benefit in performing whole body screening computed tomography (CT) examinations in healthy asymptomatic individuals. There are radiation risk issues in CT and principles of screening should be adhered to. There may be a role for targeted cardiac screening CT that derives calcium score, especially for asymptomatic medium-risk individuals and CT colonography when used as part of a strategic programme for colorectal cancer screening in those 50 years and older. However, population based screening CT examinations may become appropriate when evidence emerges regarding a clear benefit for the patient outweighing the associated radiation risks. PMID- 21611020 TI - The Malaysian consensus statement on utilisation of cardiac CT. PMID- 21611022 TI - Riding on the crest of electronic publishing wave. PMID- 21611023 TI - Does doctor know best? The recent trend in medical negligence. PMID- 21611024 TI - Role of ultrasonography in diagnosis of scrotal disorders: a review of 110 cases. AB - OBJECTIVE: To determine the role of ultrasonography in diagnosis of scrotal disorders. MATERIALS AND METHODS: This study was carried out after institutional review board approval was granted, and informed consent was waived. Between January 2005 and January 2007, 144 patients aged 12 years and older with scrotal symptoms, who underwent scrotal ultrasonography (US), were retrospectively reviewed. The clinical presentation, outcome, and US results were analysed. The presentation symptoms were divided into three groups including scrotal pain, painless scrotal mass or swelling, and others. Surgery was performed in 32 patients. RESULTS: Of 144 patients, 110 had clinical follow-up and constituted the material of this study. The patients ranged in age from 13 to 82 years (mean 38.6 years). Of 110 patients, 84 (76.4%) presented with scrotal pain, 21 (19%) had painless scrotal mass or swelling and 5 (4.5%) had other symptoms. Of the 84 patients with scrotal pain, 52 had infection, 4 had testicular torsion, 7 had testicular trauma, 10 had varicocele, 4 had hydrocele, 1 had epididymal cyst, 1 had scrotal sac and groin metastases, and 5 had unremarkable results. Of the 21 patients who presented with painless scrotal mass or swelling, 18 had extratesticular lesions and 3 had intratesticular lesions. All the extratesticular lesions were benign. Of the 3 intratesticular lesions, one was due to tuberculous epididymo-orchitis, one was non-Hodgkin's lymphoma, and one was metastasis from liposarcoma. Of the 5 patients who presented with other symptoms, 4 had undescended testes, and 1 had gynaecomastia. US gave incorrect diagnosis in only one patient with scrotal pain. CONCLUSION: The most common cause of scrotal pain was infection. The most common cause of scrotal mass or swelling was extratesticular lesion. US plays an important role in the diagnosis of scrotal disorders and in planning for proper management. PMID- 21611025 TI - The current status of the case report: Terminal or viable? AB - The case report, which has a long history in medicine, has seen its fortune wax and wane with time. We discuss the challenges facing the continued survival of the case report, including the inability of journals to cope with the increased load and increased cost of publication, ethical issues, the impact factor and the rise of evidence-based medicine. We highlight the important role that the case report will continue to play in medical research and education, as a means of sharing information and detecting novelty through observations. Most importantly, the case report serves as a stepping stone for young physicians and practitioners into the world of medical writing. PMID- 21611026 TI - Use of permeability surface area-product to differentiate intracranial tumours from abscess. AB - BACKGROUND AND PURPOSE: Clinical and radiological findings of intracranial abscesses may mimic the findings of brain tumours and vice versa. However, the discrimination is of great clinical importance in planning treatment and in following prognosis and response to therapy. This study evaluates the Computed Tomography (CT) perfusion parameters, especially the permeability index, with the aim of evaluating the usefulness of dynamic CT perfusion imaging as an alternative tool to differentiate necrotic brain tumours and intracerebral abscesses. MATERIALS AND METHODS: A total of 21 patients underwent perfusion CT study and were divided into 2 groups: Group 1, patients with necrotic brain tumours (n=13); and Group 2, patients with cerebral abscesses (n=8). The mean perfusion parameters were obtained from the enhancing part of the lesion. The relative ratios were then calculated by using the results from mirrored regions within the contralateral hemisphere as reference. RESULTS: The results of this study showed that there was significant difference in the relative permeability surface values between necrotic brain tumours and cerebral abscesses (p=0.005). By applying the ROC curve, a value of 25.1 for rPS was found to be the best estimate to distinguish necrotic brain tumours from cerebral abscesses with a specificity of 88 % and sensitivity of 70 %. CONCLUSION: CT perfusion, especially permeability surface, may allow for better differentiation of cerebral abscesses from brain tumours, making it a strong additional imaging modality in the early diagnosis of these two entities. PMID- 21611027 TI - The sonographer's role in RFA therapy of liver lesions. AB - Interventional techniques using ultrasound guidance, such as Radio Frequency Ablation (RFA) of liver lesions, are the domain of the radiologist. However, real time ultrasound imaging as performed by the sonographer, is critical in monitoring the successful insertion and placement of the RFA needle. RFA is used to create a localised and controlled application of heat in order to induce necrosis of cells within the liver lesions.The role of the sonographer is to assist in establishing the criteria for RFA therapy. This includes assessing the liver to establish how easily the lesion can be identified; the size of the lesion; its proximity to large blood vessels and adjacent vital organs and the access route to the lesion itself. In essence, in this discussion, the focus will be on the sonographic techniques in the assessment of the liver prior to RFA and the RFA procedure itself. A brief review of the clinical role that can be provided by Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) is also included. PMID- 21611028 TI - A statement of the rights of scientists and engineers. AB - As the Editors of the Biomedical Imaging and Intervention Journal, we are pleased to introduce "The Bill of Rights" written by Dr William Hendee, Chair of the Publication Committee of the International Organization of Medical Physics (IOMP). This document covers the fundamental rights and responsibilities of a scientist - not just medical physicists but the entire biomedical imaging community, including the clinicians and researchers. The simultaneous publication of this document in worldwide leading medical physics and allied journals aims to disseminate these standards to the whole scientific world. We, as part of the wider biomedical imaging science community and as the editors of the biij, are fully committed to ensuring these rights are not infringed by anyone, anywhere.BJJ Abdullah and KH NgEditors, Biomedical Imaging and Intervention Journal. PMID- 21611029 TI - Helical CT angiography of fenestrated stent grafting of abdominal aortic aneurysms. AB - Fenestrated stent grafts have been developed to treat patients with abdominal aortic aneurysms (AAA) associated with complicated aneurysm necks, such as short necks, severe angulated or poor quality necks (presence of calcification or thrombus). The technique is performed by creating an opening in the graft material so that the stent graft can be placed above the renal and other visceral branches without compromising blood perfusion to these vessels. In most situations, a supporting stent is inserted into the fenestrated vessel to provide fixation of the fenestrated vessel against stent grafts, as well as to preserve patency of the vessel. Helical CT angiography (CTA) is the preferred imaging modality in both pre-operative planning and post-procedural follow-up of fenestrated repair of AAA. The main concerns of fenestrated stent grafting lie in the following two aspects: patency of the fenestrated vessels and position of the fenestrated stents in relation to the artery branches. In this article, the author presents the clinical applications of 2D and 3D visualizations in the follow-up of patients with AAA treated with fenestrated stent grafts, with the aim of providing useful information to readers and increasing their knowledge of an increasingly used technique, fenestrated stent grafting in the treatment of AAA. PMID- 21611030 TI - Dural plasmacytoma mimicking meningioma in a young patient with multiple myeloma. AB - Intracranial involvement in multiple myeloma (MM) is rarely found, especially with dural involvement. There are only a few cases found concerning MM with intracranial involvement. MM usually involves an older group of patients. Cases involving young patients are very rare. The differential diagnosis of a dural plasmacytoma includes meningioma, metastasis, lymphoma and sarcoma of the dura mater. We present a young patient, 33 years old, with MM presenting an intracerebral mass mimicking meningioma on MRI. MM was diagnosed the previous year. The patient presented with headache, balance disturbance and back pain. MRI revealed an occipital extra-axial mass with a dural tail. Histopathological examination after excision showed MM. Published literatures on intracranial involvement of MM are also discussed. Plasmacytoma should be considered in the differential diagnosis of a solitary dural mass, particularly in a patient with MM. PMID- 21611031 TI - Avid F-FDG uptake of pectoralis major muscle: an equivocal sequela of strenuous physical exercise. AB - Avid functional (18)F-FDG uptake of skeletal muscle is a known false positive finding of PET-CT study especially after involuntary muscle exercise just prior to the study. We describe the case of a 50-year-old man in whom the finding of avid (18)F-FDG uptake of pectoralis major muscle was encountered during investigation of metastatic melanoma. PMID- 21611032 TI - Cervical brachalgia: Assessment by cervical CT epidurography post transforaminal injection. AB - Adjunct cervical CT epidurography (CCTE) can be used to image impingement in patients with cervical brachalgia undergoing fluoroscopic-guided cervical transforaminal injection (TFI) of steroid/local anaesthetic where magnetic resonance imaging (MRI) is contraindicated. CCTE images of the 9 patients on whom the authors performed CCTE post TFI over 6 years from 1998 to 2003 were retrospectively reviewed. CCTE is able to provide good images of the cervical spinal canal and its contents. CCTE may be an alternative imaging method for impingement in patients with cervical brachalgia contraindicated for MRI. PMID- 21611033 TI - Left main renal artery entrapment by diaphragmatic crura: spiral CT angiography. AB - Entrapment of renal artery by the diaphragmatic crus is a rare cause of renal artery stenosis. Spiral computed tomography angiography provides a definitive diagnosis and shows the precise relationship of the artery to the diaphragmatic crus. The authors present a case of hypertension developing in a young 20-year old female due to entrapment of the left renal artery by the diaphragmatic crus. This condition should be considered in young hypertensive patients with renal artery stenosis without cardiovascular risk factors. PMID- 21611034 TI - Development and use of iron oxide nanoparticles (Part 1): Synthesis of iron oxide nanoparticles for MRI. AB - Contrast agents, such as iron oxide, enhance MR images by altering the relaxation times of tissues in which the agent is present. They can also be used to label targeted molecular imaging probes. Unfortunately, no molecular imaging probe is currently available on the clinical MRI market. A promising platform for MRI contrast agent development is nanotechnology, where superparamagnetic iron oxide nanoparticles (SPIONS) are tailored for MR contrast enhancement, and/or for molecular imaging. SPIONs can be produced using a range of methods and the choice of method will be influenced by the characteristics most important for a particular application. In addition, the ability to attach molecular markers to SPIONS heralds their application in molecular imaging.There are many reviews on SPION synthesis for MRI; however, these tend to be targeted to a chemistry audience. The development of MRI contrast agents attracts experienced researchers from many fields including some researchers with little knowledge of medical imaging or MRI. This situation presents medical radiation practitioners with opportunities for involvement, collaboration or leadership in research depending on their level of commitment and their ability to learn. Medical radiation practitioners already possess a large portion of the understanding, knowledge and skills necessary for involvement in MRI development and molecular imaging. Their expertise in imaging technology, patient care and radiation safety provides them with skills that are directly applicable to research on the development and application of SPIONs and MRI.In this paper we argue that MRI SPIONs, currently limited to major research centres, will have widespread clinical use in the future. We believe that knowledge about this growing area of research provides an opportunity for medical radiation practitioners to enhance their specialised expertise to ensure best practice in a truly multi-disciplinary environment. This review outlines how and why SPIONs can be synthesised and examines their characteristics and limitations in the context of MR imaging. PMID- 21611035 TI - Business of medicine. PMID- 21611036 TI - Magnetic resonance-guided focused ultrasound surgery (MRgFUS) treatment for uterine fibroids. AB - Magnetic Resonance-guided focused Ultrasound Surgery (MRgFUS) is gaining popularity as an alternative to medical and surgical interventions in the management of symptomatic uterine fibroids. Studies have shown that it is an effective non-invasive treatment with minimal associated risks as compared to myomectomy and hysterectomy. MRgFUS can be offered to a majority of patients suffering from symptomatic uterine fibroids. It has been suggested that the use of broader inclusion criteria as well as the mitigation techniques makes it possible to offer MRgFUS to a much larger subset of patients than previously believed. This paper will describe how MRgFUS treatment for uterine fibroids is performed at the University of Malaya Medical Centre, Kuala Lumpur, Malaysia. PMID- 21611037 TI - Musculoskeletal MRI protocol. AB - The authors propose a musculoskeletal (MSK) magnetic resonance imaging (MRI) protocol using selected sequences for common orthopaedic indications. Selected sequences allow optimal visualisation of the indicated pathology while screening for other common conditions. The authors emphasise the need for standard positioning of the patient and standard orientation of scan planes to facilitate comparison with follow-up scans. PMID- 21611038 TI - Monoplane 3D reconstruction of mapping ablation catheters: a feasibility study. AB - PURPOSE: Radiofrequency (RF) catheter ablation has transformed treatment for arrhythmias and has become first-line therapy for some tachycardias. The precise localization of the arrhythmogenic site and the positioning of the RF catheter over that site are problematic: they can impair the efficiency of the procedure and are time consuming (several hours). This study evaluates the feasibility of using only single plane C-arm images in order to estimate the 3D coordinates of RF catheter electrodes in a cardiac phase. MATERIALS AND METHODS: The method makes use of a priori 3D model of the RF mapping catheter assuming rigid body motion equations in order to estimate the 3D locations of the catheter tip electrodes in single view C-arm fluoroscopy images. Validation is performed on both synthetic and clinical data using computer simulation models. The authors' monoplane reconstruction algorithm is applied to a 3D helix mimicking the shape of a catheter and undergoing solely rigid motion. Similarly, the authors test the feasibility of recovering nonrigid motion by applying their method on true 3D coordinates of 13 ventricular markers from a sheep's ventricle. RESULTS: The results of this study showed that the proposed monoplane algorithm recovers rigid motion adequately when using the spatial positions of a catheter in six consecutive C-arm image frames yielding maximum 3D root mean squares errors of 4.3 mm. On the other hand, the suggested algorithm did not recover nonrigid motion precisely as suggested by a maximum 3D root mean square value of 8 mm. CONCLUSION: Since RF catheter electrodes are rigid structures, the authors conclude that there is promise in recovering the 3D coordinates of the electrodes when making use of only single view images. Future work will involve adding nonrigid motion equations to their algorithm, which will then be applied to actual clinical data. PMID- 21611039 TI - Dual time point imaging of FDG PET/CT in a tuberculous spondylodiscitis. AB - Dual Time Point Imaging (DTPI) technique is a specialised protocol adopted in (18)F-Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) imaging. This technique is claimed to be useful in differentiating malignant and infective lesions. The authors adopted this technique in a patient diagnosed with tuberculous spondylodiscitis and psoas abscess which demonstrated higher Maximum Standardized Uptake Value (SUVmax) during initial scans as compared with those obtained on delayed scans. The SUVmax changes between the two time points are believed to be a valuable finding for chronic granulomatous infective lesions such as tuberculosis. PMID- 21611040 TI - Dose verification of helical tomotherapy intensity modulated radiation therapy planning using 2D-array ion chambers. AB - PURPOSE: To investigate the clinical usage of dose verification of Helical Tomotherapy plans by using 2D-array ion chambers, and to develop an efficient way to validate the dose delivered for the patients during treatments. MATERIALS AND METHODS: A pixel-segmented ionisation chamber device, IMRT MatriXXTM and MulticubeTM phantom from IBA were used on ten selected Tomotherapy IMRT/IGRT head and neck plans in this study. The combined phantom was set up to measure the dose distribution from coronal and sagittal planes. The setup of phantom was guided for verifying the correction position by pre-treatment Tomotherapy MVCT images. After the irradiation, the measured dose distributions of coronal and sagittal planes were compared with those from calculation by the planning system for cross verification. The results were evaluated by the absolute and relative doses as well as Gamma (gamma) function. The feasibility of the different measuring methods was studied for this rotational treatment technique. RESULTS: The dose distributions measured by the MatriXX 2D array were in good agreements with plans calculated by Tomotherapy planning system. The discrepancy between the measured dose and predicted dose in the selected points was within +/-3%. In the comparison of the pixel-segmented ionisation chamber versus treatment planning system using the 3 mm/3% gamma-function criteria, the mean passing rates of 2 mm dose grid with gamma-parameter <=1 were 97.37% and 96.91%, in two orthogonal planes (coronal and sagittal directions), respectively. CONCLUSION: MatriXX with Multicube is a new system created for rotational delivery quality assurance (QA) and found to be reliable to measure both absolute dose and relative dose distributions, simultaneously. It achieves the goal of an efficient and accurate dosimetry validation method of the helical delivery pattern for the Helical Tomotherapy IMRT planning. PMID- 21611041 TI - Uncomplicated term vaginal delivery following magnetic resonance-guided focused ultrasound surgery for uterine fibroids. AB - A 35 year-old para 1+0 underwent MRgFUS per study protocol for multiple uterine fibroids, the largest of which measured 5 cm. She conceived 10 months following the procedure. The patient was induced at 41+6 weeks and underwent a normal vaginal delivery. PMID- 21611042 TI - Induction chemotherapy with paclitaxel, ifosfamide, and cisplatin followed by concurrent chemoradiotherapy for unresectable locally advanced head and neck cancer. AB - OBJECTIVE: Induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT) for locally advanced head and neck cancer has been studied in many clinical trials. This study was conducted to determine the response rate of IC with paclitaxel, ifosfamide, and cisplatin followed by CCRT with cisplatin for this group of patients, and the effect of the entire treatment on survival and time to disease progression. METHODS: Thirty patients with advanced and unresectable head and neck cancer were treated with 2 cycles of induction paclitaxel/ ifosfamide/ cisplatin. If the primary tumor had a complete or partial response, patients were treated with 2 more cycles of IC followed by radiotherapy 70 Gy plus 3 cycles of cisplatin. For those with less than partial response or disease progression were treated according to the discretion of the physicians. RESULTS: Ninety percent of patients had stage IV disease and 40% of them had primary tumor at maxillary sinus and nasal cavity. One patient (3%) achieved complete response (CR) and 18 patients had partial responses (PR) to IC. CCRT enhanced the response rate, resulting in a total of 3 CR (10%) and 16 PR (53%) to treatment. The median time to progression was 11.5 months. The median overall survival was 27 months. The most severe hematologic toxicity occurred during IC was grade3-4 neutropenia (40%). Grade 3-4 mucositis occurred in 68% of patients during CCRT. CONCLUSION: This novel combined-modality treatment program, is toxic but feasible, and can be administered for selected patients with advanced and unresectable head and neck cancer. (c) 2010 Biomedical Imaging and Intervention Journal. All rights reserved. PMID- 21611043 TI - Awareness and attitudes amongst basic surgical trainees regarding radiation in orthopaedic trauma surgery. AB - This study investigated the awareness and attitudes of basic surgical trainees. Trainees were asked to answer questions from a pre-set questionnaire. Fifty basic surgical trainees from England and Wales were involved in the study. The areas covered were basic knowledge of radiation hazards, use of protective wear, pregnancy test in female trauma victims of reproductive age, and principles of safe radiation. All the questions were asked in the context of orthopaedic trauma surgery. All questions were evidence based.It was unfortunate to notice that basic surgical trainees are lacking in the essential knowledge of ionising radiation. Most of the trainees are not adhering to radiation safety principle, and are not practising safely. The authors strongly recommend that surgical trainees should have more robust training and information available in this context. And they suggest that it should be provided on local, regional and national basis. (c) 2010 Biomedical Imaging and Intervention Journal. All rights reserved. PMID- 21611044 TI - F-FDG PET/CT as a potential valuable adjunct to MRI in characterising the Brodie's abscess. AB - Chronic osteomyelitis (Brodie's abscess) is essentially a problem of diagnosis, and there may be considerable difficulty in distinguishing it from other benign and malignant bone lesions. Early diagnosis of Brodie's abscess is deemed important as the disease has a good curative potential following an appropriate antibiotic treatment. Of late, PET/CT using (18)F-FDG is taking a centre stage in the imaging of bone infection though documentation on its role in characterising the feature of Brodie's abscess is exceedingly scarce. On the other hand, it is well known that MRI imaging plays a very important role in distinguishing abscess loculation from malignancy. The authors present the case of a 13-year-old boy with pain in the right heel for few months. Radiograph of the right foot revealed a lucent focus with sclerotic margin in the right calcaneum. MRI T1-weighted images were inconclusive of penumbra sign to characterise abscess cavity due to the small volume lesion. Whole-body (18)F-FDG PET/CT scan showed multiple small avid lesions at the margin of the sclerotic rim in the right calcaneum. Final diagnosis of Brodie's abscess with Klebsiella culture was confirmed via bone debridement. PMID- 21611045 TI - Uterine artery embolisation for symptomatic fibroids: the University of Malaya Medical Centre experience. AB - BACKGROUND: Transcatheter uterine artery embolisation (UAE) for the treatment of symptomatic fibroids has been performed in several centres in the United States, Western Europe and Asia with promising results. This study reports the authors' experience with UAE at the University Malaya Medical Centre. METHOD: Fifty women with symptomatic uterine fibroids who declined surgery were treated by transcatheter UAE. The uterine arteries were selectively catheterised and embolised with polyvinyl alcohol particles. Post-procedure analgesia was administered via patient-controlled analgesic pump. The patients were followed up at an interval of 6/12 clinically and with MRI. RESULTS: Transcatheter UAE was performed on all 50 patients with no major complications. 49 patients had both uterine arteries embolised while 1 patient had only the right uterine artery embolised on account of hypoplasia of the left uterine artery due to previous myomectomy. The mean hospital stay was 3.5 days (range, 2 to 7). At a mean follow up of 24/52, all patients reported improvements in their presenting symptoms. Objective improvement in terms of reduction of uterine and fibroid sizes was determined on MRI. One patient, who initially responded with a decrease in uterine and dominant fibroid size, became symptomatic (menorrhagia) after 6 months and subsequent endometrial sampling revealed cystic glandular hyperplasia for which total abdominal hysterectomy was performed. Two other patients had no change in symptoms and after hysterectomy, the pathology revealed concurrent adenomyosis. Another 2 patients with cervical fibroids were treated with hysterectomy as there was no gross reduction in the size of fibroid following UAE. Overall, 90% of the patients had dramatic improvement of anaemia and symptoms at 1 year follow-up. CONCLUSION: Out of the 50 patients, 17 patients had total disappearance of their fibroids and 28 patients had more than 50% reduction in the size of fibroids after 1 year. 5 patients ended up with total abdominal hysterectomy. These results suggest that UAE is an appealing alternative to hysterectomy or myomectomy for many women with symptomatic fibroids. PMID- 21611046 TI - Evaluation of dose coverage to target volume and normal tissue sparing in the adjuvant radiotherapy of gastric cancers: 3D-CRT compared with dynamic IMRT. AB - PURPOSE: To assess the potential advantage of intensity-modulated radiotherapy (IMRT) over 3D-conformal radiotherapy (3D-CRT) planning in postoperative adjuvant radiotherapy for patients with gastric carcinoma. METHODS AND MATERIALS: In a retrospective study, for plan comparison, dose distribution was recalculated in 15 patients treated with 3D-CRT on the contoured structures of same CT images using an IMRT technique. 3D-conformal plans with three fields and four-fields were compared with seven-field dynamic IMRT plans. The different plans were compared by analyzing the dose coverage of planning target volume using TV(95), D(mean), uniformity index, conformity index and homogeneity index parameters. To assess critical organ sparing, D(mean), D(max), dose to one-third and two-third volumes of the OARs and percentage of volumes receiving more than their tolerance doses were compared. RESULTS: The average dose coverage values of PTV with 3F-CRT and 4F-CRT plans were comparable, where as IMRT plans achieved better target coverage(p<0.001) with higher conformity index value of 0.81+/-0.07 compared to both the 3D-CRT plans. The doses to the liver and bowel reduced significantly (p<0.001) with IMRT plans compared to other 3D-CRT plans. For all OARs the percentage of volumes receiving more than their tolerance doses were reduced with the IMRT plans. CONCLUSION: This study showed that a better target coverage and significant dose reduction to OARs could be achieved with the IMRT plans. The IMRT can be preferred with caution for organ motion. The authors are currently studying organ motion in the upper abdomen to use IMRT for patient treatment. PMID- 21611047 TI - Optimal slice thickness for cone-beam CT with on-board imager. AB - PURPOSE: To find the optimal slice thickness (Deltatau) setting for patient registration with kilovoltage cone-beam CT (kVCBCT) on the Varian On Board Imager (OBI) system by investigating the relationship of slice thickness to automatic registration accuracy and contrast-to-noise ratio. MATERIALS AND METHOD: Automatic registration was performed on kVCBCT studies of the head and pelvis of a RANDO anthropomorphic phantom. Images were reconstructed with 1.0 <= Deltatau (mm) <= 5.0 at 1.0 mm increments. The phantoms were offset by a known amount, and the suggested shifts were compared to the known shifts by calculating the residual error. A uniform cylindrical phantom with cylindrical inserts of various known CT numbers was scanned with kVCBCT at 1.0 <= Deltatau (mm) <= 5.0 at increments of 0.5 mm. The contrast-to-noise ratios for the inserts were measured at each Deltatau. RESULTS: For the planning CT slice thickness used in this study, there was no significant difference in residual error below a threshold equal to the planning CT slice thickness. For Deltatau > 3.0 mm, residual error increased for both the head and pelvis phantom studies. The contrast-to-noise ratio is proportional to slice thickness until Deltatau = 2.5 mm. Beyond this point, the contrast-to-noise ratio was not affected by Deltatau. CONCLUSION: Automatic registration accuracy is greatest when 1.0 <= Deltatau (mm) <= 3.0 is used. Contrast-to-noise ratio is optimal for the 2.5 <= Deltatau (mm) <= 5.0 range. Therefore 2.5 <= Deltatau (mm) <= 3.0 is recommended for kVCBCT patient registration where the planning CT is 3.0 mm. PMID- 21611048 TI - Image analysis in medical imaging: recent advances in selected examples. AB - Medical imaging has developed into one of the most important fields within scientific imaging due to the rapid and continuing progress in computerised medical image visualisation and advances in analysis methods and computer-aided diagnosis. Several research applications are selected to illustrate the advances in image analysis algorithms and visualisation. Recent results, including previously unpublished data, are presented to illustrate the challenges and ongoing developments. PMID- 21611049 TI - Overuse, overdose, overdiagnosis... overreaction? AB - When x-rays were first discovered, the harmful effects of radiation had to be manifest in the early users before they were known. Today, radiation protection and safety have been established and the effects of radiation, as well as its risks, are known. Even so, medical radiation, in particular the growth in the use of computed tomography (CT), has resulted in soaring radiation doses received by the population in general. Inappropriate use has resulted in overuse, overdose and, perhaps, overdiagnosis, especially when used in screening. In the quest to control and curb the use of procedures involving radiation, however, we must be careful not to provoke a pandemic of irrational fear of radiation. Overreaction to the overuse and overdose of radiation might deter patients from life-saving procedures. PMID- 21611050 TI - Can radiographic plain film be used to determine the depth of the tumour bed in the absence of surgical clips for breast boost planning. AB - PURPOSE: A number of studies have demonstrated the importance of using surgical clips to define the tumour bed in breast boost radiotherapy. In the absence of such clips, other techniques suggested to improve boost location have included CT and ultrasound (US). Determination of the depth of the tumour bed is important in the selection of electron energy. This study was conducted to prospectively compare the depth of the lumpectomy cavity as defined by ultrasound to radiographic plain film evaluation of the anterior border of the pectoralis muscle. MATERIALS AND METHODS: Forty-one breast-cancer patients treated at the Division of Therapeutic Radiology and Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University between December 2004 and December 2006 were prospectively identified as having no surgical clips within the lumpectomy cavity. All patients underwent both US evaluation of the depth of tumour bed (D1) and radiographic evaluation of the depth of the anterior border of the pectoralis muscle (D2). These depth dimensions (D1 and D2) were compared using a paired t test. The correlation of both methods was analyzed by Pearson correlation test. RESULTS: Depth dimensions by US were shorter than the radiographic film method in 85% of patients. The absolute mean difference of the depth (radiographic films minus US) was 0.129 cm. A paired t-test demonstrated that the difference between these two methods to be not statistically significant (p= 0.27). The absolute difference of depth between the two methods ranged from 0 to 0.5 cm. A significant correlation was found between US and radiographic film measurements (p<0.01). CONCLUSION: Plane radiographic film evaluation of the anterior border of the pectoralis muscle can be used to define the depth of the tumour bed in patients who have no surgical clips. However, the plane radiographic film method determines only the depth, not the transverse and longitudinal dimensions of the tumour bed. Additional information from US is needed to delineate the target volume for the tumour bed boost. In the absence of surgical clips, the authors recommend integration of both methods in breast boost planning process. PMID- 21611051 TI - A comparison between low-dose and standard-dose non-contrasted multidetector CT scanning of the paranasal sinuses. AB - PURPOSE: To compare the image quality of the low-dose to the standard-dose protocol of MDCT scanning of the paranasal sinuses, based on subjective assessment and determine the radiation doses to the eyes and thyroid gland and dose reduction between these two protocols. MATERIALS AND METHODS: 31 adult patients were scanned. Prior to scanning, thermoluminescent dosimeters (TLDs) were placed at 4 sites: outer canthus of right eye, outer canthus of left eye, inner canthus and anterior neck (thyroid gland). Every patient was scanned twice using the standard-dose protocol (100mAs) followed by the low-dose protocol (40mAs). The images were reviewed by 3 radiologists. Wilcoxon test was used as the test of significance for the image quality assessments. The paired sample t test was used as the test of significance for the analysis of the radiation doses measured by the TLDs. RESULTS: Of the 30 patients selected for analysis, this study showed no significant difference in the scores for the diagnostic image quality and the anatomical structures assessments between the two protocols. The average calculated mean entrance surface doses and standard deviation for the standard-dose and low-dose protocols were 12.40+/-1.39 mGy and 5.53+/-0.82 mGy respectively to the lens and 1.03+/-0.55 mGy and 0.63+/-0.53 mGy respectively to the thyroid gland. CONCLUSION: The reduction of mAs from 100 to 40 resulted in a significant reduction of the radiation doses to the lens and thyroid gland by 55.4% and 38.8% respectively without causing any significant effect to the diagnostic image quality and assessment of the anatomical structures. PMID- 21611052 TI - Automatic polyp detection and measurement with computed tomographic colonography: A phantom study. AB - PURPOSE: The purpose of this study is to assess the performance of computer-aided detection (CAD) software in detecting and measuring polyps for CT Colonography, based on an in vitro phantom study. MATERIAL AND METHODS: A colon phantom was constructed with a PVC pipe of 3.8 cm diameter. Nine simulated polyps of various sizes (3.2mm-25.4mm) were affixed inside the phantom that was placed in a water bath. The phantom was scanned on a 64-slice CT scanner with tube voltage of 120 kV and current of 205 mAs. Two separate scans were performed, with different slice thickness and reconstruction interval. The first scan (thin) had a slice thickness of 1mm and reconstruction interval 0.5mm. The second scan (thick) had a slice thickness of 2mm and reconstruction interval of 1mm. Images from both scans were processed using CT Colonography software that automatically segments the colon phantom and applies CAD that automatically highlights and provides the size (maximum and minimum diameters, volume) of each polyp. Two readers independently measured each polyp (two orthogonal diameters) using both 2D and 3D views. Readers' manual measurements (diameters) and automatic measurements from CAD (diameters and volume) were compared to actual polyp sizes as measured by mechanical calipers. RESULTS: All polyps except the smallest (3.2mm) were detected by CAD. CAD achieved 100% sensitivity in detecting polyps >=6mm. Mean errors in CAD automated volume measurements for thin and thick slice scans were 8.7% and 6.8%, respectively. Almost all CAD and manual readers' 3D measurements overestimated the size of polyps to variable extent. Both over- and underestimation of polyp sizes were observed in the readers' manual 2D measurements. Overall, Reader 1 (expert) had smaller mean error than Reader 2 (non-expert). CONCLUSION: CAD provided accurate size measurements for all polyps, and results were comparable to the two readers' manual measurements. PMID- 21611053 TI - Identification of masses in digital mammogram using gray level co-occurrence matrices. AB - Digital mammogram has become the most effective technique for early breast cancer detection modality. Digital mammogram takes an electronic image of the breast and stores it directly in a computer. The aim of this study is to develop an automated system for assisting the analysis of digital mammograms. Computer image processing techniques will be applied to enhance images and this is followed by segmentation of the region of interest (ROI). Subsequently, the textural features will be extracted from the ROI. The texture features will be used to classify the ROIs as either masses or non-masses. In this study normal breast images and breast image with masses used as the standard input to the proposed system are taken from Mammographic Image Analysis Society (MIAS) digital mammogram database. In MIAS database, masses are grouped into either spiculated, circumscribed or ill defined. Additional information includes location of masses centres and radius of masses. The extraction of the textural features of ROIs is done by using gray level co-occurrence matrices (GLCM) which is constructed at four different directions for each ROI. The results show that the GLCM at 0o, 45o, 90o and 135o with a block size of 8X8 give significant texture information to identify between masses and non-masses tissues. Analysis of GLCM properties i.e. contrast, energy and homogeneity resulted in receiver operating characteristics (ROC) curve area of Az = 0.84 for Otsu's method, 0.82 for thresholding method and Az = 0.7 for K mean clustering. ROC curve area of 0.8-0.9 is rated as good results. The authors' proposed method contains no complicated algorithm. The detection is based on a decision tree with five criterions to be analysed. This simplicity leads to less computational time. Thus, this approach is suitable for automated real-time breast cancer diagnosis system. PMID- 21611054 TI - Mesenteroaxial volvulus in an adult: time is of the essence in acute presentation. AB - Acute gastric volvulus is an uncommon condition with severe repercussions if untreated in the acute presentation. We describe such a case. We assert that computed tomography (CT) should be the first line of investigation. PMID- 21611055 TI - Intra-hepatic arterial pseudoaneurysm causing life-threatening upper gastrointestinal bleed after removal of biliary drainage catheter. AB - Hepatic artery pseudoaneurysms are an uncommon complication of percutaneous biliary drainage catheter insertion. The authors report a case of a hepatic artery pseudoaneurysm following percutaneous internal-external biliary drain insertion. This led to massive haemobilia when the catheter was removed and presented clinically as life-threatening upper gastrointestinal bleed. The clinical and imaging manifestations are discussed along with the management of the patient. PMID- 21611056 TI - Third party EPID with IGRT capability retrofitted onto an existing medical linear accelerator. AB - Radiation therapy requires precision to avoid unintended irradiation of normal organs. Electronic Portal Imaging Devices (EPIDs), can help with precise patient positioning for accurate treatment. EPIDs are now bundled with new linear accelerators, or they can be purchased from the Linac manufacturer for retrofit. Retrofitting a third party EPID to a linear accelerator can pose challenges. The authors describe a relatively inexpensive third party CCD camera-based EPID manufactured by TheraView (Cablon Medical B.V.), installed onto a Siemens Primus linear accelerator, and integrated with a Lantis record and verify system, an Oldelft simulator with Digital Therapy Imaging (DTI) unit, and a Philips ADAC Pinnacle treatment planning system (TPS). This system integrates well with existing equipment and its software can process DICOM images from other sources. The system provides a complete imaging system that eliminates the need for separate software for portal image viewing, interpretation, analysis, archiving, image guided radiation therapy and other image management applications. It can also be accessed remotely via safe VPN tunnels. TheraView EPID retrofit therefore presents an example of a less expensive alternative to linear accelerator manufacturers' proprietary EPIDs suitable for implementation in third world countries radiation therapy departments which are often faced with limited financial resources. PMID- 21611057 TI - A simple image processing approach for electronic cleansing in computed tomographic colonography. AB - The prevalence of colon cancer has seen strong demand in screening for colorectal neoplasia, and this has drawn considerable attention to the technological advances in Computed Tomographic Colonography (CTC). With the assistance of an oral contrast agent, an imaging technique known as Electronic Cleansing (EC), can affect virtual cleaning of the computed tomography (CT) images, to remove fecal material that is tagged by the agent. Technical problems can arise with electronic cleansing however, when the air lumen causes distortions to the tagged regions which result in partial volume effects.Combining the simple image arithmetic of an electronic cleansing algorithm, with a vertical motion filter at the fluid level of the bowel, artifacts such as those caused by an air lumen are eliminated. Essentially, the filter becomes a vector for that carries the measurement of vertical motion to neutralise the artifact that is causing partial volume effects. Results demonstrate that despite its simplicity, this technique offers accuracy and is able to successfully maintain the normal intra-colonic structure, while supporting digital leaning of tagged residual material appearing on the colon wall. PMID- 21611058 TI - Diagnostic image quality of hysterosalpingography: ionic versus non ionic water soluble iodinated contrast media. AB - OBJECTIVE: To compare the diagnostic image quality between three different water soluble iodinated contrast media in hysterosalpingography (HSG). MATERIAL AND METHOD: In a prospective randomised study of 204 patients, the diagnostic quality of images obtained after hysterosalpingography were evaluated using Iopramide (106 patients) and Ioxaglate (98 patients). 114 patients who had undergone HSG examination using Iodamide were analysed retrospectively. Image quality was assessed by three radiologists independently based on an objective set of criteria. The obtained results were statistically analysed using Kruskal-Wallis and Mann-Whitney U test. RESULTS: Visualisation of fimbrial rugae was significantly better with Iopramide and Ioxaglate than Iodamide. All contrast media provided acceptable diagnostic image quality with regard to uterine, fallopian tubes outline and peritoneal spill. Uterine opacification was noted to be too dense in all three contrast media and not optimal for the assessment of intrauterine pathology. Higher incidence of contrast intravasation was noted in the Iodamide group. Similarly, the numbers of patients diagnosed with bilateral blocked fallopian tubes were also higher in the Iodamide group. CONCLUSION: HSG using low osmolar contrast media (Iopramide and Ioxaglate) demonstrated diagnostic image qualities similar to HSG using conventional high osmolar contrast media (Iodamide). However, all three contrast media were found to be too dense for the detection of intrauterine pathology. Better visualisation of the fimbrial outline using Ioxaglate and Iopramide were attributed to their low contrast viscosity. The increased incidence of contrast media intravasation and bilateral tubal blockage using Iodamide are probably related to the high viscosity. PMID- 21611059 TI - From ultrasound images to block based region motion estimation. AB - By applying a hexagon-diamond search (HDS) method to an ultrasound image, the path of an object is able to be monitored by extracting images into macro-blocks, thereby achieving image redundancy is reduced from one frame to another, and also ascertaining the motion vector within the parameters searched. The HDS algorithm uses six search points to form the six sides of the hexagon pattern, a centre point, and a further four search points to create diamond pattern within the hexagon that clarifies the focus of the subject area. PMID- 21611060 TI - A survey of radiation dose to patients and operators during radiofrequency ablation using computed tomography. AB - Computed tomography (CT) fluoroscopy is able to give real time images to a physician undertaking minimally invasive procedures such as biopsies, percutaneous drainage, and radio frequency ablation (RFA). Both operators executing the procedure and patients too, are thus at risk of radiation exposure during a CT fluoroscopy.This study focuses on the radiation exposure present during a series of radio frequency ablation (RFA) procedures, and used Gafchromic film (Type XR-QA; International Specialty Products, USA) and thermoluminescent dosimeters (TLD-100H; Bicron, USA) to measure the radiation received by patients undergoing treatment, and also operators subject to scatter radiation.The voltage was held constant at 120 kVp and the current 70mA, with 5mm thickness. The duration of irradiation was between 150-638 seconds.Ultimately, from a sample of 30 liver that have undergone RFA, the study revealed that the operator received the highest dose at the hands, which was followed by the eyes and thyroid, while secondary staff dosage was moderately uniform across all parts of the body that were measured. PMID- 21611061 TI - BIIJ embracing social media. PMID- 21611062 TI - Multislice CT angiography of the plantar arch. AB - The aim of this case report is to present a multislice computed tomography angiography (CTA) procedure for viewing the plantar arch. A CTA was requested to determine the vascular sufficiency of the plantar arch of a 64-year-old patient with necrotic and gangrenous toes. The patient had recently undergone a proximal wedge osteotomy procedure for correction of a hallux valgus deformity. A 16 detector row CT scanner with 1.25 mm slice thickness and 0.625 mm reconstruction interval was used to reconstruct multiplanar reformats, maximum intensity projections and three-dimensional volume rendered images of the foot in question in both arterial and venous phases to determine if pathology of the plantar arch was present. The 3D reconstructed images of CTA demonstrated a loss of continuity of the plantar arch between the first and third metatarsals. This case report shows the diagnostic value of multislice CTA, especially 3D visualisation in the assessment of peripheral vascular branches. PMID- 21611063 TI - A new method for experimental characterisation of scattered radiation in 64-slice CT scanner. AB - PURPOSE: The consummate 64-slice CT scanner that spawns a new generation of non invasive diagnostic tool, however revolutionary, brings with it the incidental by product that is scattered radiation. The extended detector aperture capability in the 64-slcie CT scanner allows the effects of scattered radiation to be more pronounced and therefore demands that the magnitude and spatial distribution of scatter component be addressed during the imaging process. To this end, corrective algorithms need to be formulated on a basis of a precise understanding of scatter distribution. Relative to a 64-slice CT scanner, here now a unique solution is based upon dedicated blockers operative within various detector rows, calculating scatter profiles and scatter to primary ratios (SPR). MATERIALS AND METHODS: A single dimension blocker array was installed beneath the collimator, and the extrapolated shadow area on the detectors revealed the scatter radiation after exposure. The experiment was conducted using a 64-slice CT scanner manufactured by GE Healthcare Technologies. RESULTS: Variables such as tube voltage, phantom size and phantom-off centring on the scatter profile and the SPR was measured using the dedicated blocker method introduced above. When tube voltage is increased from 80kVp to 140kVp in a 21.5 cm water phantom, the SPR is found to reduce from 219.9 to 39.9 respectively. CONCLUSION: The method developed within this study is applicable to any measurement and is direct with minimal complexity. PMID- 21611064 TI - Multislice CT angiography in cardiac imaging: prospective ECG-gating or retrospective ECG-gating? AB - With the advent of multislice CT more than a decade ago, multislice CT angiography has demonstrated a huge potential in the less invasive imaging of cardiovascular disease, especially in the diagnosis of coronary artery disease. The diagnostic accuracy of multislice CT angiography has been significantly augmented with the rapid technical developments ranging from the initial 4-slice, to the current 64-slice and 256 and 320-slice CT scanners. This is mainly demonstrated by the improved spatial and temporal resolution when compared to the earlier type of CT scanners. Traditionally, multislice CT angiography is acquired with retrospective ECG-gating with acquisition of volume data at the expense of increased radiation dose, since data is acquired at the entire cardiac cycle, although not all of them are used for postprocessing or reconstructions. Recently, there is an increasing trend of utilising prospective ECG-gating in cardiac imaging with latest multislice CT scanners (64 or more slices) with significant reduction of radiation dose when compared to retrospective ECG-gating method. However, there is some debate as to the diagnostic value of prospective ECG-gating in the diagnosis of coronary artery disease, despite its attractive ability to reduce radiation dose. This article will review the performance of retrospective ECG-gating in the diagnostic value of coronary artery disease, highlight the potential applications of prospective ECG-gating, and explore the future directions of multislice CT angiography in cardiac imaging. PMID- 21611065 TI - A survey of digital radiography practice in four South African teaching hospitals: an illuminative study. AB - PURPOSE: The purpose of this study was to assess radiographer familiarity and preferences with digital radiography in four teaching hospitals and thereafter make recommendations in line with the migration from screen film to digital radiography. MATERIALS AND METHODS: A questionnaire was designed to collect data from either qualified or student radiographers from four teaching hospitals. From the four teaching hospitals, there were a total of 205 potential respondents. Among other things, responses regarding experiences and preferences with digital radiography, quality control procedures, patient dose, advantages and disadvantages of digital radiography were sought. The information collected was based on self-reporting by the participants. The study is exploratory in nature and descriptive statistics were generated from the collected data using Microsoft Excel 2007 and StatsDirect software. RESULTS: Sixty-three out of 205 (31%) radiographers from all the four radiology centers responded to the circulated questionnaire. Only 15% (8) of the qualified radiographers had 4 or more years of experience with digital radiography compared to 68% (36) for the same amount of experience with screen-film radiography. Sixty-one percent (38) of the participants had been exposed to digital radiography during their lectures while at university. A small proportion, 16% (10) of the respondents underwent formal training in quality control procedures on the digital X-ray units they were using. Slightly more than half (55%) of the participants felt it was easier for them to retake an image in digital radiography than in screen film radiography. CONCLUSION: The results of this survey showed that the participants are familiar with digital radiography and have embraced this relatively new technology as shown by the fact that they can identify both its advantages and disadvantages as applied to clinical practice. However, there are minimal quality control procedures specific to digital radiography being undertaken as such there is need for formal education, continuing education and manufacturer training with respect to quality control as institutions make the transition from conventional screen film radiology to digital radiology. PMID- 21611066 TI - Leigh syndrome: MRI findings in two children. AB - Leigh syndrome is a progressive neurodegenerative disorder of childhood. The symmetrical necrotic lesions in the basal ganglia and/or brainstem which appear as hyperintense lesions on T2-weighted MRI is characteristic and one of the essential diagnostic criteria. Recognising this MR imaging pattern in a child with neurological problems should prompt the clinician to investigate for Leigh syndrome. We present here two cases of Leigh syndrome due to different biochemical/genetic defects, and discuss the subtle differences in their MR neuroimaging features. PMID- 21611067 TI - Transarterial embolisation of hepatocellular carcinoma with doxorubicin-eluting beads: single centre early experience. AB - PURPOSE: This is a retrospective study to evaluate the results of our early experience of using doxorubicin eluting beads (DEB) to treat patients with early and intermediate hepatocellular carcinoma (HCC). MATERIAL AND METHODS: A cohort of 19 patients (84.2% male; 15.8% female; mean age 59.2 years +/- 11.0; range, 32 80 years) with documented HCC of size 1.8-10cm (mean, 4.0cm +/- 1.8 ) undergoing DEB transarterial chembolisation (TACE) was reviewed. All patients had at least one image examination (multiphase computed tomography or magnetic resonance imaging) after embolisation. RESULTS: A total of 32 procedures were performed. The objective response according to the European Association for the Study of the Liver criteria was 57.9% at 1-month, 42.8% at 6-month and 50.0% at 1-year follow up. There were 4 (21.1%) treatment-related complications (1 liver abscess, 2 pancreatitis and 1 tumour rupture) which resulted in 2 deaths. One death occurred 3 weeks after second embolisation, due to ruptured pancreatic pseudocyst, giving a 5.3% 30-day mortality rate. Another patient died 2 months after embolisation caused by tumour rupture. Eight patients received radiofrequency ablation after embolisation for residual or recurrent tumours. The 1-year survival rate in the DEB TACE only group was 80% while the 1- and 2-year survival rate in the group that received radiofrequency after DEB TACE was 85.7% and 100% respectively. CONCLUSION: DEB TACE is safe and effective in select group of patients. Survival may be improved when combined with other treatment modality. PMID- 21611068 TI - A visual tutorial on the synthesis of gold nanoparticles. AB - Many papers have been written on the synthesis of gold nanoparticles but very few included pictures of the process, and none of them used video to show the whole process of synthesis. This paper records the process of synthesis of gold nanoparticles using video clips. Every process from cleaning of glassware, an important step in the synthesis of metallic nanoparticles, to the dialysis process is shown. It also includes the preparation of aqua regia and the actual synthesis of gold nanoparticles. In some papers, the dialysis process was omitted, but in this paper, it is included to complete the whole process as it is being used for purification. PMID- 21611069 TI - Critical limb ischaemia in a diabetic population from an Asian Centre: angiographic pattern of disease and 3-year limb salvage rate with percutaneous angioplasty as first line of treatment. AB - PURPOSE: Lower extremity amputation prevention (LEAP) is an ongoing program in our institution aimed at salvaging limbs in patients with critical limb ischemia (CLI). Patients in the LEAP program with reconstructible anatomy on initial Doppler imaging received either bypass surgery or percutaneous transluminal balloon angioplasty (PTA). We present the 3 year limb salvage rate and angiographic disease patterns in 42 consecutive diabetic patients with CLI who received PTA in 2005. METHODS AND MATERIAL: 26 women and 16 men with diabetes between the ages of 45 and 91 years old (mean age, 70.8 years) received PTA in 2005. Presenting symptoms were rest pain (n = 22), pre-existing gangrene (n = 17), non-healing ulcer (n = 16) and cellulitis (n = 2). The aim of the PTA was to achieve straight-line flow from the abdominal aorta down to the patent dorsalis pedis or plantar arch, with limb salvage as the ultimate outcome. Failure of treatment was defined as any amputation above the level of a Syme's amputation or the need for further surgical bypass. Technical success was achieved in 90% (38 out of 42 patients). RESULTS: Limb salvage rates were 93% at 1 month, 87% at 3 months, 82% at 6 months, 78% at 1 year, 69% at 2 years and 66% at 3 years. Mortality was 17% (n = 7) at 3 years. Of the 13 patients with failed therapy, 3 underwent bypass, 9 had amputations and 1 had bypass followed by amputation. Four of the cases required further intervention due to worsening gangrene and infection, while the remaining was due to persistent rest pain. The rest of the 32 patients had no lower limb related issues at the end of 3 years, with improvement of the presenting symptoms. Patterns of treated segments were aortoiliac occlusions (n = 3), pure infrapopliteal disease (n = 3), femoropopliteal with at least 1 good infrapopliteal run-off vessel (n = 14) and combined femoropopliteal and infrapopliteal disease (n = 25). CONCLUSION: Involvement of infrapopliteal vessels that needs to be treated is common in Asian diabetics. While early limb salvage rates up to 1 year are similar, the 3 year limb salvage rates in Asian diabetics are lower than the western population. PMID- 21611070 TI - Significance of subcentimetre F-FDG PET/CT pulmonary abnormality in patients with known extrapulmonary malignancy. AB - The significance of a subcentimetre (18)F-FDG PET/CT pulmonary abnormality in a patient with known extrapulmonary primary malignancy can have a major impact on the clinical management of the patient. The clinician's reliance on the semi quantitative and qualitative PET/CT analysis of the abnormality has, at times, led to untoward diagnostic problems, given the limited spatial resolution of PET for a small volume lesion performed as part of the standard PET/CT study. This paper highlights a case each of an FDG-positive and an FDG-negative focal pulmonary abnormality in a combined PET/CT study of patients with known extrapulmonary malignancy. (c) 2010 Biomedical Imaging and Intervention Journal. All rights reserved. PMID- 21611071 TI - Chest imaging features of patients afflicted with Influenza A (H1N1) in a Malaysian tertiary referral centre. AB - This is a retrospective descriptive study of the chest imaging findings of 118 patients with confirmed A(H1N1) in a tertiary referral centre. About 42% of the patients had positive initial chest radiographic (CXR) findings. The common findings were bi-basal air-space opacities and perihilar reticular and alveolar infiltrates. In select cases, high-resolution computed tomography (CT) imaging showed ground-glass change with some widespread reticular changes and atelectasis. PMID- 21611072 TI - The boiling frog syndrome: A radiologist's perspective. PMID- 21611073 TI - An intense F-FDG pulmonary microfocus on PET without detectable abnormality on CT: A manifestation of an iatrogenic FDG pulmonary embolus. AB - An incidental finding of an intense focus of (18)F-Fluorodeoxyglucose (FDG) pulmonary uptake on positron emission tomography (PET) without detectable lesions on computed tomography (CT) is highly suggestive of FDG microembolus. Its microscopic nature means it is undetectable on CT. It is an artefact attributable to (18)F-FDG-tracer contamination at the injection site. This paper reports a case of a 61 year-old lady with a past history of breast carcinoma, in whom follow-up PET/CT images demonstrated an incidental intense FDG pulmonary abnormality. A follow-up PET/CT seven months later demonstrated complete resolution of the abnormality. PMID- 21611074 TI - Ultrasound diagnosis of cephalopagus conjoined twin pregnancy at 29 weeks. AB - The authors report a case of a cephalopagus conjoined twin that was diagnosed at 29 weeks of gestation despite the mother having had two ultrasounds done previously. The fetus had one head and face, fused thoraces, common umbilicus but had two pelvises and two sets of genitalia. The fetus had four normally formed legs and arms.Antenatal ultrasound images are supplemented by post natal photographs. A review of literature, clues to ultrasound diagnosis and possible causes of missing this significant abnormality until the 3rd trimester are discussed. PMID- 21611075 TI - Carcinoma of stomach detected by routine transabdominal ultrasound. AB - Assessment of the stomach is not commonly included in routine scanning protocol of upper abdominal ultrasound (USG). However, assessment of the stomach in patients presenting with epigastric pain can yield invaluable results. This paper presents, as an illustration, a case of carcinoma of stomach detected by transabdominal ultrasound. The diagnosis is confirmed by subsequent CT, upper endoscopy and operation. PMID- 21611076 TI - Chronic kidney disease - an exemplar for collaboration between the clinic and the laboratory. PMID- 21611078 TI - Estimating glomerular filtration rate in diabetes using serum cystatin C. AB - Chronic kidney disease (CKD) is a major public health problem, especially for people with diabetes. Not only is it a risk factor for end-stage renal disease (ESRD) but it is also a major cardiovascular disease (CVD) risk factor. Methods that accurately and simply estimate glomerular filtration rate (GFR) are therefore needed to optimise the detection and management of CKD in people with diabetes. One of the main failures of commonly used creatinine-based methods for estimating renal function is that they lack applicability across the full range of GFR values and underestimate GFR levels >60 mL/min/1.73m(2). Methods for accurately estimating an early pathological decline in GFR (i.e. DeltaGFR >3.3 mL/min/year before reaching a GFR <60 mL/min/1.73m(2)) are especially needed as appropriate interventions have been shown to retard progression to ESRD and reduce CVD risk in people with diabetes. In contrast, recent studies have suggested that estimates of GFR based on serum cystatin C concentration might provide a simple and accurate method for detecting and monitoring an early decline in renal function. PMID- 21611077 TI - Controversies in chronic kidney disease staging. AB - In 2002, a new chronic kidney disease staging system was developed by the US National Kidney Foundation. The classification system represented a new conceptual framework for the diagnosis of chronic kidney disease (moving to a schema based on disease severity defined by the glomerular filtration rate). While the introduction of the staging system stimulated significant clinical and research interest in kidney disease, there has been vigorous debate on its merits. This mini-review aims to summarise the recent controversies that have been raised since the introduction of the new classification. PMID- 21611079 TI - Drug dosing in renal disease. AB - Renal disease alters the effects of many drugs, particularly when active drug moieties are renally cleared. Drug doses should usually be reduced in renal disease in proportion to the predicted reduction in clearance of the active drug moiety. Patient factors to consider in adjusting drug doses include the degree of renal impairment and patient size. Drug factors to consider in adjusting doses include the fraction of the drug excreted unchanged in urine and the drug's therapeutic index. Estimates of renal function are useful to guide dosing of renally cleared drugs with medium therapeutic indices, but are not precise enough to guide dosing of drugs with narrow therapeutic indices. This article discusses principles of drug dose adjustment in renal disease. PMID- 21611080 TI - Methods of Estimating GFR - Different Equations Including CKD-EPI. AB - The initiative for estimating glomerular filtration rate (GFR) derives from the limitations of interpreting plasma creatinine alone, the cost and complexities of determining a gold standard GFR with either inulin or radionuclides, and the inaccuracies inherent in measuring a 24 h urine creatinine clearance. In August 2005, the Australasian Creatinine Consensus Working Group recommended that an eGFR based on the abbreviated MDRD (Modification of Diet in Renal Disease) formula shall be automatically calculated for every request for creatinine in people over 18 years. Uptake was almost universal, though with appropriate caveats in place regarding potential limitations. Updated recommendations in 2007 recognised uniform standardisation of the plasma creatinine assay. A recent development is the CKD-Epidemiology Collaboration (CKD-EPI) equation which confers less underestimation of GFR in subjects with normal renal function. Cystatin C and its derivative equations may have advantages in some situations. PMID- 21611081 TI - Estimating renal function for drug dosing decisions. AB - In order to adjust the dose of renally excreted drugs in response to reduced renal function, it is necessary to make a quantitative estimate of the glomerular filtration rate (GFR) of the patient. Traditionally this has been done with the use of the Cockcroft and Gault equation or a measured creatinine clearance. More recently the MDRD (Modification of Diet in Renal Disease) formula has become available, providing an estimate of GFR readily available on routine pathology reports. The presence of these different methods of assessing renal function has created some confusion for healthcare workers as to the best approach. In this paper the two methods are compared, together with a newer formula CKD-EPI (named after the Chronic Kidney Disease Epidemiology Collaborative), and a proposal is made for future practice. PMID- 21611082 TI - Global proteinuria guidelines: are we nearly there yet? AB - Assessment of albumin and/or protein excretion in the urine is a key step in the early detection and appropriate management of chronic kidney disease. The approach to testing for albuminuria/proteinuria in the community is variable and often suboptimal. It is hampered by: variation in laboratory measurement; lack of standard reference materials and testing procedures; variable definitions and units of reporting; conflicting recommendations and practices regarding who to test; and uncertainty over when and how testing is most appropriately done. This review discusses the current status of proteinuria guidelines around the world and the key clinical issues that need to be addressed before a unifying global guideline can be developed. PMID- 21611083 TI - Laboratory measurement of urine albumin and urine total protein in screening for proteinuria in chronic kidney disease. AB - Laboratory measurement of urine total protein has been important for the diagnosis and monitoring of renal disease for decades, and since the late 1990s, urine albumin has been measured to determine whether a diabetic patient has incipient nephropathy. Evolving understanding of chronic kidney disease (CKD) and, in particular, the cardiovascular risks that CKD confers, demands more sensitive detection of protein in urine. As well, evidence is now emerging that cardiovascular and all-cause mortality risks are increased at levels within the current 'normal' range for urine albumin. Standardisation is essential to permit valid application of universal decision points, and a National Kidney Disease Education Program/International Federation of Clinical Chemistry and Laboratory Medicine (NKDEP/IFCC) Working Party is making progress towards a reference system for urine albumin. In the meantime, available data suggest that Australasian laboratory performance is adequate in terms of precision and accuracy above current decision limits for urine albumin. In contrast, the complexity of proteins in urine makes standardisation of urine total protein measurement impossible. As well, urine total protein measurement is insufficiently sensitive to detect clinically important concentrations of urine albumin. An Australasian Expert Group, the Proteinuria Albuminuria Working Group (PAWG) has proposed that urine albumin/creatinine ratio is measured in a fresh, first morning, spot sample to screen for proteinuria in CKD. Both NKDEP/IFCC and PAWG emphasise the need for standardisation of sample collection and handling. PMID- 21611084 TI - Laboratory reporting of urine protein and albumin. AB - Communication between pathology laboratories and clients involves more than just a result. There may be advice on recommended specimen type as well as the units and reference intervals used to report results. Between-laboratory variability in these factors has the potential to cause unnecessary confusion and even to lead to variation in interpretation for samples sent to different laboratories. A survey of Australian and New Zealand laboratories covering sample recommendations, specimens received, units and reference intervals for urine albumin and urine protein was conducted through the Royal College of Pathologists of Australasia Quality Assurance Program (RCPA QAP). The results confirm earlier findings of wide between-laboratory variability in all these factors. It is proposed that only recommendations developed by relevant professional societies and adopted by all laboratories can lead to reduction in this variability. PMID- 21611085 TI - Point-of-Care Testing and Creatinine Measurement. AB - This paper reviews the current status of point-of-care testing (PoCT) devices that are available for measuring whole blood or serum/plasma creatinine globally and within Australasia. Information on non-analytical specifications and analytical performance is provided using data sourced from recently published literature, external quality assurance programs and evaluative work by the author's unit. The limitations of current devices are summarised. PMID- 21611086 TI - Biomarkers and cardiac disease in patients with end-stage renal disease on dialysis. AB - Very soon after troponin was introduced to routine clinical use in the mid-1990s, it was observed that troponin T was often increased in the blood of asymptomatic patients undergoing chronic dialysis for end-stage renal disease. Observation of these patients showed that the presence of troponin T in blood was predictive of a worse outcome for these patients.Cardiac disease is the major cause of death in dialysis patients. This review considers the heterogeneous cardiac disease that is found in these patients and reviews the role of cardiac biomarkers in identifying patients at risk of an adverse outcome. PMID- 21611087 TI - New markers of acute kidney injury: giant leaps and baby steps. AB - Treatment of acute kidney injury has been hampered by the inability of a creatinine-based diagnosis to allow clinicians to intervene with timely treatments aimed at preventing further development of the disease to the point where renal replacement therapy is necessary or death occurs. Novel biomarkers of injury have been touted as the tool by which early detection can occur and, on that basis, novel treatments can be developed and delivered early in the disease process. Sufficient new biomarkers have been discovered and evaluated to expect that not one biomarker but a panel of biomarkers applied according to phase of injury, baseline renal function and comorbidities will be necessary for the early diagnosis of acute kidney injury. Issues of validation of these biomarkers remain, particularly in heterogeneous populations of critically ill patients. Nevertheless, we are rapidly moving towards an era where the diagnosis of acute kidney injury will be proactive rather than by the traditional diagnosis of exclusion. PMID- 21611089 TI - Anaplastic thyroid carcinoma: A comprehensive review of current and future therapeutic options. AB - Anaplastic thyroid carcinoma (ATC) is the rarest, but deadliest histologic type among thyroid malignancies, with a dismal median survival of 3-9 mo. Even though ATC accounts for less than 2% of all thyroid tumors, it is responsible for 14% 39% of thyroid carcinoma-related deaths. ATC clinically presents as a rapidly growing mass in the neck, associated with dyspnoea, dysphagia and vocal cord paralysis. It is usually locally advanced and often metastatic at initial presentation. For operable diseases, the combination of radical surgery with adjuvant radiotherapy or chemotherapy, using agents such as doxorubicin and cisplatin, is the best treatment strategy. Cytotoxic drugs for advanced/metastatic ATC are poorly effective. On the other hand, targeted agents might represent a viable therapeutic option. Axitinib, combretastatin A4, sorafenib and imatinib have been tested in small clinical trials of ATC, with a promising disease control rate ranging from 33% to 75%. Other clinical trials of targeted therapy for thyroid carcinoma are currently ongoing. Biological agents that are under investigation include pazopanib, gefitinib and everolimus. With the very limited therapeutic armamentarium available at the present time, targeted therapy constitutes an exciting new horizon for ATC. In future, biological agents will probably represent the standard of care for this aggressive malignancy, in the same fashion as it has recently occurred for other chemo-refractory tumors, such as kidney and hepatic cancer. PMID- 21611088 TI - Targeting metastatic upper gastrointestinal adenocarcinomas. AB - Upper gastrointestinal (GI) tumors, including adenocarcinoma of the esophagus, stomach, pancreas, and biliary tree, have traditionally been difficult to treat with cytotoxic chemotherapeutic agents. There has been little drug development success in treating these cancers over the last 20 years, perhaps a reflection of a combination of the aggressive biology of these tumors, the void in effective and specific drug development for these varied tumors, and the lack of properly designed, biologically-based clinical trials. Recently, so called "targeted agents" have risen to the forefront in the care of cancer patients and have made strong impacts in many areas of oncology, particularly gastrointestinal stromal tumors (GIST), colon, breast, and lung cancers. Unfortunately, slow progress has been made using such agents in upper GI tumors. However, more recently, trials in some tumor types have demonstrated gains in progression free survival and overall survival. In this review, we discuss the drugs and pathways that have been most successful in the treatment of upper GI tumors and present the relevant data supporting their use for each tumor site. Additionally, we will explore a few novel pathways that may prove effective in the treatment of upper GI malignancies in the near future. PMID- 21611090 TI - Recent progress and limitations of chemotherapy for pancreatic and biliary tract cancers. AB - Gemcitabine chemotherapy has been the standard for advanced pancreatic cancer for more than a decade. New oral fluoropyrimidines such as S-1 and capecitabine are other key drugs. Gemcitabine plus erlotinib was the only combination therapy that significantly prolonged survival, although the effect was minimal. Little or no improvement in survival with recent molecular-targeted drugs might be attributed to the very high incidence of K-ras gene mutation in pancreatic cancer. Recently, the non-gemcitabine-based-regimen of FOLFIRINOX showed significantly greater overall survival compared with gemcitabine for the first time. For biliary tract cancer, gemcitabine plus cisplatin combination chemotherapy has been proved to significantly prolong survival and will become the standard therapy. Further improvement in survival is expected by the addition of cetuximab. PMID- 21611091 TI - Survivin and pancreatic cancer. AB - Pancreatic cancer is estimated to be the fourth most common cancer in men and fifth in women in the world and has poor prognosis. In recent years, more and more effort has been put on the relationship between pancreatic cancer and apoptosis. As a newly discovered inhibitor of apoptosis, survivin has drawn more attention. Strong evidence has shown that survivin is expressed in pancreatic cancer cells on frozen sections. Survivin increases in the development of pancreatic ductal adenocarcinoma and its expression can be a marker in evaluating the prognosis of pancreatic cancer patients. Survivin itself may be a new target in the treatment of pancreatic cancer and a survivin DNA vaccine could generate specific antitumor effects in pancreatic carcinoma models. PMID- 21611092 TI - Imaging as a diagnostic and therapeutic tool in clinical oncology. AB - According to the WHO report published in 2010, about 13% of all deaths are due to cancer. Of these, lung, liver, stomach, colon and breast cancer are the most prevalent. It was also reported that about 30% of the deaths due to cancer can be avoided, if diagnosed and treated early. Hence, there is an urgent need to diagnose these cancers efficiently. Various imaging and therapeutic methods have been proposed and used to accurately detect cancer. In this special two issues, there are eight papers covering different aspects of oncology using various imaging or therapeutic methods. PMID- 21611093 TI - Breast imaging: A survey. AB - Breast cancer is the second leading cause of death in women. It occurs when cells in the breast start to grow out of proportion and invade neighboring tissues or spread throughout the body. Mammography is one of the most effective and popular modalities presently used for breast cancer screening and detection. Efforts have been made to improve the accuracy of breast cancer diagnosis using different imaging modalities. Ultrasound and magnetic resonance imaging have been used to detect breast cancers in high risk patients. Recently, electrical impedance imaging and nuclear medicine techniques are also being widely used for breast cancer screening and diagnosis. In this paper, we discuss the capabilities of various breast imaging modalities. PMID- 21611094 TI - Online volume rendering of incrementally accumulated LSCEM images for superficial oral cancer detection. AB - Laser scanning confocal endomicroscope (LSCEM) has emerged as an imaging modality which provides non-invasive, in vivo imaging of biological tissue on a microscopic scale. Scientific visualizations for LSCEM datasets captured by current imaging systems require these datasets to be fully acquired and brought to a separate rendering machine. To extend the features and capabilities of this modality, we propose a system which is capable of performing realtime visualization of LSCEM datasets. Using field-programmable gate arrays, our system performs three tasks in parallel: (1) automated control of dataset acquisition; (2) imaging-rendering system synchronization; and (3) realtime volume rendering of dynamic datasets. Through fusion of LSCEM imaging and volume rendering processes, acquired datasets can be visualized in realtime to provide an immediate perception of the image quality and biological conditions of the subject, further assisting in realtime cancer diagnosis. Subsequently, the imaging procedure can be improved for more accurate diagnosis and reduce the need for repeating the process due to unsatisfactory datasets. PMID- 21611095 TI - Automation of immunohistochemical evaluation in breast cancer using image analysis. AB - AIM: To automate breast cancer diagnosis and to study the inter-observer and intra-observer variations in the manual evaluations. METHODS: Breast tissue specimens from sixty cases were stained separately for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER 2/neu). All cases were assessed by manual grading as well as image analysis. The manual grading was performed by an experienced expert pathologist. To study inter observer and intra-observer variations, we obtained readings from another pathologist as the second observer from a different laboratory who has a little less experience than the first observer. We also took a second reading from the second observer to study intra-observer variations. Image analysis was carried out using in-house developed software (TissueQuant). A comparison of the results from image analysis and manual scoring of ER, PR and HER-2/neu was also carried out. RESULTS: The performance of the automated analysis in the case of ER, PR and HER-2/neu expressions was compared with the manual evaluations. The performance of the automated system was found to correlate well with the manual evaluations. The inter-observer variations were measured using Spearman correlation coefficient r and 95% confidence interval. In the case of ER expression, Spearman correlation r = 0.53, in the case of PR expression, r = 0.63, and in the case of HER-2/neu expression, r = 0.68. Similarly, intra-observer variations were also measured. In the case of ER, PR and HER-2/neu expressions, r = 0.46, 0.66 and 0.70, respectively. CONCLUSION: The automation of breast cancer diagnosis from immunohistochemically stained specimens is very useful for providing objective and repeatable evaluations. PMID- 21611096 TI - Genetically-engineered mouse models for pancreatic cancer: Advances and current limitations. AB - Recently, there has been significant progress in the development of genetically engineered mouse (GEM) models. By introducing genetic alterations and/or signaling alterations of human pancreatic cancer into the mouse pancreas, animal models can recapitulate human disease. Pancreas epithelium-specific endogenous Kras activation develops murine pancreatic intraepithelial neoplasia (mPanIN). Additional inactivation of p16, p53, or transforming growth factor-beta signaling, in the context of Kras activation, dramatically accelerates mPanIN progression to invasive pancreatic ductal adenocarcinoma (PDAC) with abundant stromal expansion and marked fibrosis (desmoplasia). The autochthonous cancer models retain tumor progression processes from pre-cancer to cancer as well as the intact tumor microenvironment, which is superior to xenograft models, although there are some limitations and differences from human PDAC. By fully studying GEM models, we can understand the mechanisms of PDAC formation and progression more precisely, which will lead us to a breakthrough in novel diagnostic and therapeutic methods as well as identification of the origin of PDAC. PMID- 21611098 TI - Clinical oncology for pancreatic and biliary cancers: Advances and current limitations. AB - In the early 2000s, the main stream of endoscopic ultrasonography (EUS) changed from a mechanical scanning method to electronic radial or linear scanning methods. Subsequently, useful applications in trans-abdominal ultrasonography came within reach of EUS. In particular, contrast-enhanced EUS (CE-EUS) and EUS elastography became cutting-edge diagnostic modalities for pancreatic disorders. Each type of pancreatic disorder has characteristic hemodynamics. CE-EUS uses color Doppler flow imaging and harmonic imaging to classify pancreatic lesions. EUS-elastography can assess tissue hardness by measuring its elasticity. This parameter appears to correlate with the malignant potential of the lesions. Tissue elasticity studies can provide information on both its pattern and distribution. The former is the conventional method of morphological diagnosis, but it is restricted to observations made in a region of interest (ROI). The latter is an unbiased analysis that can be performed by image analysis software and is theoretically constant, regardless of the ROI. Though EUS-fine needle aspiration (FNA) is also a very useful diagnostic tool, there are several limitations. Diagnostic EUS-FNA of pancreatic cystic lesions has marginal utility mainly due to low sensitivity. Therefore, in particular, endoscopists should keep this limitation in mind. PMID- 21611099 TI - Recent advances and limitations of surgical treatment for pancreatic cancer. AB - Recent advances in surgical treatment for pancreatic cancer have been remarkable. Pancreatoduodenectomy is a standard surgical procedure for cancer of the pancreatic head, and is now indicated even for elderly patients over 80 years of age. Pancreatoduodenectomy with combined resection of the peripancreatic vessels has improved survival, but extended resection including lymph nodes is considered to have no extra survival benefit. Furthermore, laparoscopic resection procedures including pancreatoduodenectomy, distal pancreatectomy, enucleation and central pancreatectomy can now be performed safely. Neoadjuvant or adjuvant chemotherapy using gemcitabine may further improve the surgical outcome. An understanding of the oncological aspects of pancreatic cancer and the development of surgical techniques and chemotherapy may further contribute to improving the outcome of surgery for pancreatic cancer. PMID- 21611097 TI - Endoscopic diagnosis of extrahepatic bile duct carcinoma: Advances and current limitations. AB - The accurate diagnosis of extrahepatic bile duct carcinoma is difficult, even now. When ultrasonography (US) shows dilatation of the bile duct, magnetic resonance cholangiopancreatography followed by endoscopic US (EUS) is the next step. When US or EUS shows localized bile duct wall thickening, endoscopic retrograde cholangiopancreatography should be conducted with intraductal US (IDUS) and forceps biopsy. Fluorescence in situ hybridization increases the sensitivity of brush cytology with similar specificity. In patients with papillary type bile duct carcinoma, three biopsies are sufficient. In patients with nodular or infiltrating-type bile duct carcinoma, multiple biopsies are warranted, and IDUS can compensate for the limitations of biopsies. In preoperative staging, the combination of dynamic multi-detector low computed tomography (MDCT) and IDUS is useful for evaluating vascular invasion and cancer depth infiltration. However, assessment of lymph nodes metastases is difficult. In resectable cases, assessment of longitudinal cancer spread is important. The combination of IDUS and MDCT is useful for revealing submucosal cancer extension, which is common in hilar cholangiocarcinoma. To estimate the mucosal extension, which is common in extrahepatic bile duct carcinoma, the combination of IDUS and cholangioscopy is required. The utility of current peroral cholangioscopy is limited by the maneuverability of the "baby scope". A new baby scope (10 Fr), called "SpyGlass" has potential, if the image quality can be improved. Since extrahepatic bile duct carcinoma is common in the Far East, many researchers in Japan and Korea contributed these studies, especially, in the evaluation of longitudinal cancer extension. PMID- 21611100 TI - FDG-PET for hepatobiliary and pancreatic cancer: Advances and current limitations. AB - In Japan, the use of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for some malignant tumors came to be covered by the National Health Insurance in 2002. In 2010, the health insurance coverage was expanded to all types of malignant tumors. However, since PET examination requires a large amount of capital investment, facilities at which PET is available are still limited. On the other hand, PET equipment has rapidly been introduced in large hospitals and in the diagnostic imaging centers of major cities during the past few years. Although numerous middle-sized and small hospitals cannot afford to perform PET, physicians can refer their patients to facilities where PET is available. Therefore, it is essential for general physicians to gain accurate knowledge on PET, including the appropriate indications for PET, in order to select patients for referral to PET facilities. PET is not always a useful tool, especially for lesions of the pancreas and hepatobiliary system, which is the main topic of this review. The indications of PET for lesions in these organs vary depending on the purpose of the examination. In this article, we review the indications for PET (or PET/computed tomography [CT]) using FDG of the liver, biliary tract, and pancreas. PMID- 21611101 TI - Case Report of Suspected Rhabdomyolysis during Treatment with Trabectedin in a Patient with Metastatic Leiomyosarcoma. AB - Trabectedin has been reported to occasionally induce rhabdomyolysis. In the present case, continuation of trabectedin was maintained despite suspected rhabdomyolysis related to trabectedin. Creatinine kinase levels dropped to normal levels. We suggest that continuation of trabectedin despite suspected rhabdomyolysis was safe in this specific patient. PMID- 21611102 TI - Cetuximab concomitant with second-line radiation therapy in patients with locally advanced recurrent squamous cell head and neck cancer. AB - We presented 9 recurrent head and neck carcinoma patients. Priorly all of them had received radiochemotherapy. We used cetuximab and irradiation concomitantly. Overall survival analysis of the patients was performed using the Kaplan-Meier method on SPSS version 15.0. Based on this calculation, mean follow-up duration is 12.8 months. Mean survival time is 19.8 months and annual mean survival rate is 59.3%. PMID- 21611103 TI - Dual-Positive (CD4+/CD8+) Acute Adult T-Cell Leukemia/Lymphoma Associated with Complex Karyotype and Refractory Hypercalcemia: Case Report and Literature Review. AB - We describe a rare case of adult T-cell leukemia characterized by an expansion of CD4+ CD8+ double-positive lymphocytes associated with human T-lymphotropic virus type 1 (HTLV-1) and a complex karyotype in a 43-year-old Caribbean male who was initially admitted to our hospital with significant lethargy, visual disturbances, dysphagia, right facial palsy and numbness in both feet for 3 days. He was found to have severe hypercalcemia (15.6 mg/dl). Peripheral blood smear showed multilobulated clover-shaped nuclei. Bone marrow and CSF flow cytometries revealed abnormal monoclonal expansion of T cells positive for CD4, CD5, CD8 and CD25 but negative for CD7, CD20, CD56, CD68 and terminal deoxynucleotidyl transferase. The polymerase chain reaction analysis showed a distinct band of the T-cell receptor gamma gene, revealing T-cell clonal integration of the proviral DNA of HTLV-1, thus confirming the diagnosis of acute adult T-cell leukemia/lymphoma. Cytogenetic study revealed a male karyotype with monosomy 12, unbalanced translocation 5q and 13q and additional material on 5q, 7q, 14q and 17q. The patient underwent prednisone (EPOCH) chemotherapy followed by autologous transplantation with BEAM regimen. Although patients with a rare mixed CD4+ CD8+ immunophenotype usually present with an aggressive clinical course and have a poor prognosis, our patient was able to survive for 2.5 years. PMID- 21611104 TI - Cutaneous metastasis at a surgical drain site after gastric cancer resection. AB - Cutaneous metastasis from intra-abdominal malignant solid tumours such as gastric adenocarcinoma is very rare. Here, we report the case of a 76-year-old male patient with a T4N2M0, poorly differentiated, signet-ring cell gastric carcinoma, who underwent potentially curative resection of the tumour and developed cutaneous metastasis at the site of the surgical drain 4 months after the operation while he was on chemotherapy. The lesion involved the skin and the subcutaneous fat only. A CT scan revealed local recurrence at the resection bed but no distant metastases. The patient died 1 month later. It is concluded that the development of cutaneous metastasis after gastric carcinoma resection indicates tumour recurrence or disseminated disease and is associated with poor prognosis. PMID- 21611105 TI - Gemcitabine and s-1 combination chemotherapy in patients with advanced biliary tract cancer: a retrospective study. AB - BACKGROUND: The aim of this study was to investigate the efficacy and safety of gemcitabine and S-1 combination chemotherapy in patients with advanced biliary tract cancer. PATIENTS AND METHODS: A retrospective study was performed on 15 consecutive patients. Gemcitabine was administered intravenously at 1,000 mg/m(2) on days 8 and 15. Oral S-1 (60 mg/m(2) in 2 divided doses) was given daily for the first 2 weeks, followed by 1 week of rest. This 3-week course of treatment was repeated. The primary endpoint was response rate, and the secondary endpoints were overall survival, progression-free survival, and safety. RESULTS: The overall response rate was 26.7%, and the disease control rate was 73.4%. The overall survival was 12.0 months (95% CI, 9.5-14.5 months), and the progression free survival was 8.0 months (95% CI, 4.3-11.7 months). Adverse events of grade 3 or 4 occurred in 33.3%, and the major grade 3/4 toxicities were anemia (20.0%), leukopenia (13.3%), and anorexia (13.3%). CONCLUSION: Gemcitabine and S-1 combination chemotherapy is effective and safe in patients with advanced biliary tract cancer. PMID- 21611106 TI - Acute hepatitis A induction of precursor B-cell acute lymphoblastic leukemia: a causal relationship? AB - BACKGROUND: Precursor B-cell acute lymphoblastic leukemia accounts for 2% of all lymphoid neoplasms in the United States and occurs most frequently in childhood, but can also occur in adults with a median age of 39 years. It is more commonly seen in males and in Caucasians. CASE REPORT: We present a case of a 51-year-old Caucasian female with the development of precursor B-cell acute lymphoblastic leukemia after suffering acute hepatitis A 4 weeks prior to her diagnosis. She presented with malaise for a month without spontaneous bruising/bleeding, infections, or B-symptoms, such as fevers, night sweats, or unintentional weight loss. CONCLUSION: Nonspecific viral transformation of bone marrow has been discussed in the literature, but we specifically describe hepatitis A-induced adult-onset precursor B-cell acute lymphoblastic leukemia, which is the first reported case in the literature. PMID- 21611107 TI - Utilization of I-domain of LFA-1 to Target Drug and Marker Molecules to Leukocytes. AB - The long-term objective of this project is to utilize the I-domain protein for the alpha-subunit of LFA-1 to target drugs to lymphocytes by binding to ICAM receptors on the cell surface. The short-term goal is to provide proof-of-concept that I-domain conjugated to small molecules can still bind to and uptake by ICAM 1 on the surface of lymphocytes (i.e., Raji cells). To accomplish this goal, the I-domain protein was labeled with FITC at several lysine residues to produce the FITC-I-domain and CD spectroscopy showed that the FITC-I-domain has a secondary structure similar to that of the parent I-domain. The FITC-I-domain was taken up by Raji cells via receptor-mediated endocytosis and its uptake can be blocked by anti-I-domain mAb but not by its isotype control. Antibodies to ICAM-1 enhance the binding of I-domain to ICAM-1, suggesting it binds to ICAM-1 at different sites than the antibodies. The results indicate that fluorophore modification does not alter the binding and uptake properties of the I-domain protein. Thus, I domain could be useful as a carrier of drug to target ICAM-1-expressing lymphocytes. PMID- 21611108 TI - Differential genetic expression in large versus small clear cell renal cell carcinoma: results from microarray analysis. AB - PURPOSE: Tumor growth and progression requires multiple steps and genetic alterations. The molecular events that occur as tumors increase in size are unknown. Patients with von Hippel-Lindau (VHL) provide a unique opportunity to study molecular alterations during tumor growth as these patients develop multiple bilateral renal tumors. To better characterize biologic events associated with tumor growth, we evaluated the alterations in gene expression in large versus small renal tumors removed from the same kidney of the same individuals. EXPERIMENTAL DESIGN: We reviewed pathology reports from patients who underwent partial nephrectomies at the National Cancer Institute for multiple tumors. We identified 11 patients who fulfilled the following inclusion criteria: 1) The patient must have had a surgical resection of more than one solid tumor from the same kidney during the same operation; 2) Among the solid tumors at least one must have been greater than 3 cm in the largest dimension and at least one less than 2 cm; 3) the nuclear Furhman grade for both larger and smaller solid tumors was identical; 4) a portion of each tumor was procured and snap frozen after surgical removal; 5) Hematoxylin and eosin staining of the frozen sample confirmed clear cell carcinoma to be present in at least 80% of the section.Affymetrix platform and protocol for gene expression arrays were used. RNA from the frozen large and small tumor samples was extracted using Trizol Chlorophorm method. The RNA was then reverse transcribed, labeled, fragmented, and hybridized on to an Affymetrix U133 Plus 2.0 array that contains 54,000 probe sets representing 24,568 genes. Analysis included unsupervised clustering and chromosomal analysis. The paired t-test was performed to compare gene expression levels in small and large tumors. P<0.01 was considered statistically significant. RESULTS: Gene expression profiles were assessed for 22 tumors (11 patients). Upon unsupervised clustering the pairs with larger tumor volume difference clustered separately from pairs with smaller volume difference. Chromosomal analysis revealed few consistent changes other than reduced expression of chromosome 3p25 among all tumors. Paired t-test showed 860 differentially expressed genes in the T1b vs T1a group, a number far greater than expected due to chance alone. When analyzed by gene function, most differences were observed in genes involved in DNA replication and in cytokine signaling. CONCLUSIONS: This study demonstrates that as tumors increase in size there is an increasing difference in gene expression. Unsupervised clustering analysis confirms that as the volume difference increases there are a distinct set of genes that are regulated either as a response to a tumor's growth or as an early event that causes the tumor to grow. While we did not observe chromosomal instability, we did note differences in expression of individual transcripts as tumors grew larger. PMID- 21611109 TI - HN125: A Novel Immunoadhesin Targeting MUC16 with Potential for Cancer Therapy. AB - BACKGROUND: The mucin MUC16 expresses the repeating peptide epitope CA125 that has been known for decades to be a well-validated cancer marker that is overexpressed on the cell surface of ovarian cancers and other malignant tumors. In spite of recent efforts to make mouse monoclonal antibodies to MUC16 to treat ovarian cancer, a human monoclonal antibody against this mucin has not been described. MUC16 interacts with mesothelin, a protein that mediates heterotypic cancer cell adhesion, indicating that MUC16 and mesothelin play an important role in the peritoneal implantation and metastasis of ovarian tumors. Therefore, a suitable candidate for therapeutic targeting of MUC16 would functionally block the interaction of MUC16 and mesothelin. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the generation of a novel immunoadhesin, HN125, against MUC16 that consists of a functional MUC16 binding domain of mesothelin (IAB) and the Fc portion of a human antibody IgG1. The yield for purified HN125 proteins is over 100 ug/mL of HEK-293 culture supernatant. We show that HN125 has high and specific affinity for MUC16-expressing cancer cells by flow cytometry and immunohistochemistry. HN125 has the ability to disrupt the heterotypic cancer cell adhesion mediated by the MUC16-mesothelin interaction. Moreover, it elicits strong antibody-dependent cell mediated cytotoxicity against MUC16-positive cancer cells in vitro. CONCLUSION/SIGNIFICANCE: This report describes a novel human immunotherapeutic agent highly specific for MUC16 with potential for treating ovarian cancer and other MUC16-expressing tumors. Because of its lower immunogenicity in patients, a fully human protein is the most desirable format for clinical applications. We believe that the methods developed here may apply to the generation of other tumor-targeting immunoadhesins when it is difficult to obtain a human monoclonal antibody to a given antigen for clinical applications. The resultant immunoadhesins can have advantages usually found in monoclonal antibodies such as ease of purification, high binding affinity and effector functions. PMID- 21611111 TI - Soluble endothelial selectin in acute lung injury complicated by severe pneumonia. AB - BACKGROUND: Pneumonia is still one of the most frequent causes of death in the elderly. Complication of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) by pneumonia makes patients very ill due to severe respiratory failure. Biomarkers that can discriminate the presence of complicating ALI/ARDS are required for early detection. The aim of this research was to investigate whether soluble endothelial selectin (sES) could be a biomarker for ALI. METHODS: Serum sES levels were measured in 27 pneumonia patients, who were enrolled between April 2006 and September 2007. Among these patients, six had ALI or a condition that was clinically comparable to ALI (cALI). All patients who were enrolled were successfully treated and survived. RESULTS: Circulating sES levels were elevated in pneumonia patients with ALI/cALI, and sES levels decreased following treatment of their pneumonia. Univariate and multivariate logistic regression analyses showed that sES was the only significant factor for identifying complicating ALI/cALI, independently of C-reactive protein (CRP) and lactate dehydrogenase (LDH). By receiver operating characteristic (ROC) curve analysis, the cut-off value for sES was 40.1 ng/mL, with a sensitivity of 0.8 and a specificity of 0.8. CONCLUSION: sES may be a useful biomarker for discriminating complicating ALI/cALI in patients with severe pneumonia. PMID- 21611110 TI - Disruption of learning processes by chemotherapeutic agents in childhood survivors of acute lymphoblastic leukemia and preclinical models. AB - OBJECTIVE: With the survival rate of acute lymphoblastic leukemia (ALL) surpassing 90 percent within this decade, new research is emerging in the field of late effects. A review of the research investigating the relationship of treatment regimens for ALL to specific late effect deficits, underlying mechanisms, and possible remediation is warranted to support continued studies. METHODS: The clinical literature was briefly surveyed to describe the occurrence and topography of late effects, specifically neurocognitive deficits. Additionally, the preclinical literature was reviewed to uncover potential underlying mechanisms of these deficits. The advantages of using rodent models to answer these questions are outlined, as is an assessment of the limited number of rodent models of childhood cancer treatment. RESULTS: The literature supports that childhood survivors of ALL exhibit academic difficulties and are more likely to be placed in a special education program. Behavioral evidence has highlighted impairments in the areas of attention, working memory, and processing speed, leading to a decrease in full scale IQ. Neurophysiological and preclinical evidence for these deficits has implicated white matter abnormalities and acquired brain damage resulting from specific chemotherapeutic agents commonly used during treatment. CONCLUSIONS: The exact role of chemotherapeutic agents in learning deficits remains mostly unknown. Recommendations for an improved rodent model of learning deficits in childhood cancer survivors are proposed, along with suggestions for future directions in this area of research, in hopes that forthcoming treatment regimens will reduce or eliminate these types of impairments. PMID- 21611112 TI - Monoclonal antibodies against nucleophosmin mutants: potentials for the detection of acute myeloid leukemia. AB - Nucleophosmin (NPM1) gene mutations resulting in cytoplasmic delocalization of Nucleophosmin (NPMc+) are the most common genetic alteration in acute myeloid leukemia (AML). Here, we attempted to prepare monoclonal antibodies (mAbs) against NPM1 mutation A (NPM-mA) and investigated the mAbs' clinical utility in immunohistochemical detection of NPMc+AML. The pET-32a-NPM-mA vector with the whole open reading frame of the NPM-mA gene was constructed. E.coli BL21 transformed with the vector were induced to express the NPM-mA recombinant protein. BALB/c mice were immunized with the recombinant NPM-mA. Positive clones were selected by indirect ELISA and the mAbs were obtained. Immunohistochemistry was performed to detect the NPMc+ in bone marrow smears from 10 AML patients with NPM-mA. The results showed that the pET-32a-NPM-mA vector was successfully constructed and the NPM-mA recombinant protein was used to immunize the mice. Two positive clones (2G3 and 3F9) were selected. The mAbs against NPM-mA were raised, but did cross-react with wild type NPM1. The mAbs can be used to detect the cytoplasmic dislocation of NPM1 in all AMLs carrying NPM-mA. Our results show that anti-NPM-mA mAbs were produced. Though they would cross-react with wild type NPM1, the mAbs may still have potential in the detection of NPMc+AMLs. PMID- 21611113 TI - Can occult cystobiliary fistulas in hepatic hydatid disease be predicted before surgery? AB - BACKGROUND: Biliary fistulas because of the cystobiliary communication is the most frequent and undesirable postoperative complication of hepatic hydatid surgery. We aimed to identify the predicting factors of the occult cystobiliary communication in this study. METHODS: The patients who underwent surgical treatment for hepatic hydatid disease between 2003 and 2008 were reviewed retrospectively. The patients who had jaundice history, preoperative high total bilirubin and direct bilirubin levels, dilated bile duct in preoperative radiologic imagings were not included the study. Patients were divided into two groups: group A; without postoperative biliary fistula, group B; with biliary fistula. The two groups were compared according to preoperative descriptive findings, cystic specialties, and laboratory findings. RESULTS: There were 53 patients and 15 patients in groupA and groupB, respectively. The 20 (37.7%) of 53 patients were male in group A and the 10 (66.7%) patients were male in group B (p<0.05). The age, number of cysts, Garbi scores of cysts, the rate of recurrent cysts, the level of preoperative bilirubin, alkalene phosphatase, and transaminases were similar in both groups (p>0.05). GGT was significantly different between two groups (p<0.05). The cystotomy + drainage, cystotomy + omentopexy, and intracystic biliary suture rates were similar in both groups. Postoperative non biliary complications were determined in 4 (7.5%) patients in group A and 7 patients (46.7%) in group B (p<0.05). Hospital stay was longer in group B significantly (p<0.05). CONCLUSIONS: In conclusion, GGT as a laboratory [corrected] test for predicting occult CBC preoperatively have been shown to be useful in the clinical practice. However, larger prospective studies are needed on this subject. Occult cysto-biliary fistulas can only be exposed during surgery when suspected by a surgeon. If occult CBC is found, the opening in the biliary system should be sutured with absorbable material, with or without cystic duct drainage. If no biliary opening is found, cystic duct drainage may be performed if preoperative factors predict the presence of CBC. As the development of external biliary fistulas increases the morbidity and the hospitalization period, novel surgical methods to prevent the development of bile fistulas are required in such patients. PMID- 21611114 TI - Seroprevalence and risk factors for hepatitis B infection in an adult population in Northeast China. AB - BACKGROUND AND AIM: The prevalence of the hepatitis B virus (HBV) is higher in adults than in children. We determined the seroepidemiology of HBV infection in an adult population in JiLin, China, to guide effective preventive measures. METHODS: A cross-sectional serosurvey was conducted throughout JiLin, China. A total of 3833 people was selected and demographic and behavioral information gathered. Serum samples were tested for HBV markers and liver enzymes. RESULTS: The prevalence of the hepatitis B surface antigen (HBsAg), the antibody to the hepatitis B surface antigen (anti-HBs), the hepatitis B e antigen (HBeAg), the antibody to HBeAg (anti-HBe), and the antibody to the hepatitis B core antigen (anti-HBc) were 4.38%, 35.66%, 1.38%, 6.65%, and 40.88%, respectively. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly higher among HBsAg (+) than HBsAg (-) subjects. By multivariate logistic regression analysis, independent predictors for chronic HBV infection were smoking, poor sleep quality; occupation as private small-businessmen, laborers, or peasants; male gender; family history of HBV; personal history of vaccination; and older age. Independent predictors for exposure to HBV were large family size, occupation as a private small-businessman, male gender, family history of HBV, personal history of vaccination, and older age. Independent predictors for immunity by vaccination were occupation as a private small businessman, high income, personal history of vaccination, and young age. Independent predictors for immunity by exposure were drinking, male gender, personal history of vaccination, and older age. CONCLUSIONS: The prevalence rate of HBV infection (4.38%) was lower than the previous rate of general HBV vaccination. However, 44.59% of the population remained susceptible to HBV. The prevalence of HBV infection was high in young adults, private small-businessmen, peasants, those with a family history of HBV, and males. Therefore, immunization of the non-immune population is reasonable to reduce hepatitis B transmission between adults. PMID- 21611115 TI - Platinum agent-induced hypersensitivity reactions: data mining of the public version of the FDA adverse event reporting system, AERS. AB - OBJECTIVE: Adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) were reviewed to confirm the platinum agent-associated mild, severe, and lethal hypersensitivity reactions. METHODS: Authorized pharmacovigilance tools were used for quantitative signal detection, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Excess2, given by the multi-item gamma Poisson Shrinker algorithm, was used to evaluate the effects of dexamethasone and diphenhydramine on oxaliplatin-induced hypersensitivity reactions. RESULTS: Based on 1,644,220 AERs from 2004 to 2009, carboplatin and oxaliplatin proved to cause mild, severe, and lethal hypersensitivity reactions, whereas cisplatin did not. Dexamethasone affected oxaliplatin-induced mild hypersensitivity reactions, but had lesser effects on severe and lethal reactions. The effects of diphenhydramine were not confirmed. CONCLUSION: The FDA's adverse event reporting system, AERS, with optimized data mining tools is useful to authorize potential associations between platinum agents and hypersensitivity reactions. PMID- 21611116 TI - Establishment of a transgenic mouse model specifically expressing human serum amyloid A in adipose tissue. AB - Obesity and obesity co-morbidities are associated with a low grade inflammation and elevated serum levels of acute phase proteins, including serum amyloid A (SAA). In the non-acute phase in humans, adipocytes are major producers of SAA but the function of adipocyte-derived SAA is unknown. To clarify the role of adipocyte-derived SAA, a transgenic mouse model expressing human SAA1 (hSAA) in adipocytes was established. hSAA expression was analysed using real-time PCR analysis. Male animals were challenged with a high fat (HF) diet. Plasma samples were subjected to fast protein liquid chromatography (FPLC) separation. hSAA, cholesterol and triglyceride content were measured in plasma and in FPLC fractions. Real-time PCR analysis confirmed an adipose tissue-specific hSAA gene expression. Moreover, the hSAA gene expression was not influenced by HF diet. However, hSAA plasma levels in HF fed animals (37.7+/-4.0 ug/mL, n = 7) were increased compared to those in normal chow fed animals (4.8+/-0.5 ug/mL, n = 10; p<0.001), and plasma levels in the two groups were in the same ranges as in obese and lean human subjects, respectively. In FPLC separated plasma samples, the concentration of hSAA peaked in high-density lipoprotein (HDL) containing fractions. In addition, cholesterol distribution over the different lipoprotein subfractions as assessed by FPLC analysis was similar within the two experimental groups. The established transgenic mouse model demonstrates that adipose tissue produced hSAA enters the circulation, resulting in elevated plasma levels of hSAA. This new model will enable further studies of metabolic effects of adipose tissue-derived SAA. PMID- 21611117 TI - Incidence and risk factors of serious adverse events during antituberculous treatment in Rwanda: a prospective cohort study. AB - BACKGROUND: Tuberculosis (TB) and TB-human immunodeficiency virus infection (HIV) coinfection is a major public health concern in resource-limited settings. Although TB treatment is challenging in HIV-infected patients because of treatment interactions, immunopathological reactions, and concurrent infections, few prospective studies have addressed this in sub-Saharan Africa. In this study we aimed to determine incidence, causes of, and risk factors for serious adverse events among patients on first-line antituberculous treatment, as well as its impact on antituberculous treatment outcome. METHODS AND FINDINGS: Prospective observational cohort study of adults treated for TB at the Internal Medicine department of the Kigali University Hospital from May 2008 through August 2009. Of 263 patients enrolled, 253 were retained for analysis: median age 35 (Interquartile range, IQR 28-40), 55% male, 66% HIV-positive with a median CD4 count 104 cells/mm(3) (IQR 44-248 cells/mm(3)). Forty percent had pulmonary TB, 43% extrapulmonary TB and 17% a mixed form. Sixty-four (26%) developed a serious adverse event; 58/167 (35%) HIV-infected vs. 6/86 (7%) HIV-uninfected individuals. Commonest events were concurrent infection (n = 32), drug-induced hepatitis (n = 24) and paradoxical reactions/TB-IRIS (n = 23). HIV-infection (adjusted Hazard Ratio, aHR 3.4, 95% Confidence Interval, CI 1.4-8.7) and extrapulmonary TB (aHR 2, 95%CI 1.1-3.7) were associated with an increased risk of serious adverse events. For TB/HIV co-infected patients, extrapulmonary TB (aHR 2.0, 95%CI 1.1-3.9) and CD4 count <100 cells/mm3 at TB diagnosis (aHR 1.7, 95%CI 1.0-2.9) were independent predictors. Adverse events were associated with an almost two-fold higher risk of unsuccessful treatment outcome at 6 months (HR 1.89, 95%CI 1.3-3.0). CONCLUSION: Adverse events frequently complicate the course of antituberculous treatment and worsen treatment outcome, particularly in patients with extrapulmonary TB and advanced immunodeficiency. Concurrent infection accounts for most events. Our data suggest that deterioration in a patient already receiving antituberculous treatment should prompt an aggressive search for additional infections. PMID- 21611118 TI - Differential regulation and recovery of intracellular Ca2+ in cerebral and small mesenteric arterial smooth muscle cells of simulated microgravity rat. AB - BACKGROUND: The differential adaptations of cerebrovasculature and small mesenteric arteries could be one of critical factors in postspaceflight orthostatic intolerance, but the cellular mechanisms remain unknown. We hypothesize that there is a differential regulation of intracellular Ca(2+) determined by the alterations in the functions of plasma membrane Ca(L) channels and ryanodine-sensitive Ca(2+) releases from sarcoplasmic reticulum (SR) in cerebral and small mesenteric vascular smooth muscle cells (VSMCs) of simulated microgravity rats, respectively. METHODOLOGY/PRINCIPAL FINDINGS: Sprague-Dawley rats were subjected to 28-day hindlimb unweighting to simulate microgravity. In addition, tail-suspended rats were submitted to a recovery period of 3 or 7 days after removal of suspension. The function of Ca(L) channels was evaluated by patch clamp and Western blotting. The function of ryanodine-sensitive Ca(2+) releases in response to caffeine were assessed by a laser confocal microscope. Our results indicated that simulated microgravity increased the functions of Ca(L) channels and ryanodine-sensitive Ca(2+) releases in cerebral VSMCs, whereas, simulated microgravity decreased the functions of Ca(L) channels and ryanodine-sensitive Ca(2+) releases in small mesenteric VSMCs. In addition, 3- or 7-day recovery after removal of suspension could restore the functions of Ca(L) channels and ryanodine-sensitive Ca(2+) releases to their control levels in cerebral and small mesenteric VSMCs, respectively. CONCLUSIONS: The differential regulation of Ca(L) channels and ryanodine-sensitive Ca(2+) releases in cerebral and small mesenteric VSMCs may be responsible for the differential regulation of intracellular Ca(2+), which leads to the altered autoregulation of cerebral vasculature and the inability to adequately elevate peripheral vascular resistance in postspaceflight orthostatic intolerance. PMID- 21611119 TI - Identification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase. AB - Yersinia pestis is a gram negative zoonotic pathogen responsible for causing bubonic and pneumonic plague in humans. The pathogen uses a type III secretion system (T3SS) to deliver virulence factors directly from bacterium into host mammalian cells. The system contains a single ATPase, YscN, necessary for delivery of virulence factors. In this work, we show that deletion of the catalytic domain of the yscN gene in Y. pestis CO92 attenuated the strain over three million-fold in the Swiss-Webster mouse model of bubonic plague. The result validates the YscN protein as a therapeutic target for plague. The catalytic domain of the YscN protein was made using recombinant methods and its ATPase activity was characterized in vitro. To identify candidate therapeutics, we tested computationally selected small molecules for inhibition of YscN ATPase activity. The best inhibitors had measured IC(50) values below 20 uM in an in vitro ATPase assay and were also found to inhibit the homologous BsaS protein from Burkholderia mallei animal-like T3SS at similar concentrations. Moreover, the compounds fully inhibited YopE secretion by attenuated Y. pestis in a bacterial cell culture and mammalian cells at uM concentrations. The data demonstrate the feasibility of targeting and inhibiting a critical protein transport ATPase of a bacterial virulence system. It is likely the same strategy could be applied to many other common human pathogens using type III secretion system, including enteropathogenic E. coli, Shigella flexneri, Salmonella typhimurium, and Burkholderia mallei/pseudomallei species. PMID- 21611120 TI - Pregnancy and the risk of autoimmune disease. AB - Autoimmune diseases (AID) predominantly affect women of reproductive age. While basic molecular studies have implicated persisting fetal cells in the mother in some AID, supportive epidemiological evidence is limited. We investigated the effect of vaginal delivery, caesarean section (CS) and induced abortion on the risk of subsequent maternal AID. Using the Danish Civil Registration System (CRS) we identified women who were born between 1960 and 1992. We performed data linkage between the CRS other Danish national registers to identify women who had a pregnancy and those who developed AID. Women were categorised into 4 groups; nulligravida (control group), women who had 1st child by vaginal delivery, whose 1st delivery was by CS and who had abortions. Log-linear Poisson regression with person-years was used for data analysis adjusting for several potential confounders. There were 1,035,639 women aged >14 years and 25,570 developed AID: 43.4% nulligravida, 44.3% had their first pregnancy delivered vaginally, 7.6% CS and 4.1% abortions. The risk of AID was significantly higher in the 1st year after vaginal delivery (RR = 1.1[1.0, 1.2]) and CS (RR = 1.3[1.1, 1.5]) but significantly lower in the 1st year following abortion (RR = 0.7[0.6, 0.9]). These results suggest an association between pregnancy and the risk of subsequent maternal AID. Increased risks of AID after CS may be explained by amplified fetal cell traffic at delivery, while decreased risks after abortion may be due to the transfer of more primitive fetal stem cells. The increased risk of AID in the first year after delivery may also be related to greater testing during pregnancy. PMID- 21611121 TI - Novel AroA from Pseudomonas putida confers tobacco plant with high tolerance to glyphosate. AB - Glyphosate is a non-selective broad-spectrum herbicide that inhibits 5 enolpyruvylshikimate-3-phosphate synthase (EPSPS, also designated as AroA), a key enzyme in the aromatic amino acid biosynthesis pathway in microorganisms and plants. Previously, we reported that a novel AroA (PpAroA1) from Pseudomonas putida had high tolerance to glyphosate, with little homology to class I or class II glyphosate-tolerant AroA. In this study, the coding sequence of PpAroA1 was optimized for tobacco. For maturation of the enzyme in chloroplast, a chloroplast transit peptide coding sequence was fused in frame with the optimized aroA gene (PparoA1(optimized)) at the 5' end. The PparoA1(optimized) gene was introduced into the tobacco (Nicotiana tabacum L. cv. W38) genome via Agrobacterium-mediated transformation. The transformed explants were first screened in shoot induction medium containing kanamycin. Then glyphosate tolerance was assayed in putative transgenic plants and its T(1) progeny. Our results show that the PpAroA1 from Pseudomonas putida can efficiently confer tobacco plants with high glyphosate tolerance. Transgenic tobacco overexpressing the PparoA1(optimized) gene exhibit high tolerance to glyphosate, which suggest that the novel PpAroA1 is a new and good candidate applied in transgenic crops with glyphosate tolerance in future. PMID- 21611122 TI - Impaired representation of geometric relationships in humans with damage to the hippocampal formation. AB - The pivotal role of the hippocampus for spatial memory is well-established. However, while neurophysiological and imaging studies suggest a specialization of the hippocampus for viewpoint-independent or allocentric memory, results from human lesion studies have been less conclusive. It is currently unclear whether disproportionate impairment in allocentric memory tasks reflects impairment of cognitive functions that are not sufficiently supported by regions outside the medial temporal lobe or whether the deficits observed in some studies are due to experimental factors. Here, we have investigated whether hippocampal contributions to spatial memory depend on the spatial references that are available in a certain behavioral context. Patients with medial temporal lobe lesions affecting systematically the right hippocampal formation performed a series of three oculomotor tasks that required memory of a spatial cue either in retinal coordinates or relative to a single environmental reference across a delay of 5000 ms. Stimulus displays varied the availability of spatial references and contained no complex visuo-spatial associations. Patients showed a selective impairment in a condition that critically depended on memory of the geometric relationship between spatial cue and environmental reference. We infer that regions of the medial temporal lobe, most likely the hippocampal formation, contribute to behavior in conditions that exceed the potential of viewpoint dependent or egocentric representations. Apparently, this already applies to short-term memory of simple geometric relationships and does not necessarily depend on task difficulty or integration of landmarks into more complex representations. Deficient memory of basic geometric relationships may represent a core deficit that contributes to impaired performance in allocentric spatial memory tasks. PMID- 21611123 TI - Life expectancy at birth for people with serious mental illness and other major disorders from a secondary mental health care case register in London. AB - OBJECTIVE: Despite improving healthcare, the gap in mortality between people with serious mental illness (SMI) and general population persists, especially for younger age groups. The electronic database from a large and comprehensive secondary mental healthcare provider in London was utilized to assess the impact of SMI diagnoses on life expectancy at birth. METHOD: People who were diagnosed with SMI (schizophrenia, schizoaffective disorder, bipolar disorder), substance use disorder, and depressive episode/disorder before the end of 2009 and under active review by the South London and Maudsley NHS Foundation Trust (SLAM) in southeast London during 2007-09 comprised the sample, retrieved by the SLAM Case Register Interactive Search (CRIS) system. We estimated life expectancy at birth for people with SMI and each diagnosis, from national mortality returns between 2007-09, using a life table method. RESULTS: A total of 31,719 eligible people, aged 15 years or older, with SMI were analyzed. Among them, 1,370 died during 2007-09. Compared to national figures, all disorders were associated with substantially lower life expectancy: 8.0 to 14.6 life years lost for men and 9.8 to 17.5 life years lost for women. Highest reductions were found for men with schizophrenia (14.6 years lost) and women with schizoaffective disorders (17.5 years lost). CONCLUSION: The impact of serious mental illness on life expectancy is marked and generally higher than similarly calculated impacts of well recognised adverse exposures such as smoking, diabetes and obesity. Strategies to identify and prevent causes of premature death are urgently required. PMID- 21611124 TI - Vaginally administered PEGylated LIF antagonist blocked embryo implantation and eliminated non-target effects on bone in mice. AB - Female-controlled contraception/HIV prevention is critical to address health issues associated with gender inequality. Therefore, a contraceptive which can be administered in tandem with a microbicide to inhibit sexually transmitted infections, is desirable. Uterine leukemia inhibitory factor (LIF) is obligatory for blastocyst implantation in mice and associated with infertility in women. We aimed to determine whether a PEGylated LIF inhibitor (PEGLA) was an effective contraceptive following vaginal delivery and to identify non-uterine targets of PEGLA in mice.Vaginally-applied (125)I-PEGLA accumulated in blood more slowly (30 min vs 10 min) and showed reduced tissue and blood retention (24 h vs 96 h) compared to intraperitoneal injection in mice. Vaginally-applied PEGLA blocked implantation. PEGLA administered by intraperitoneal injection inhibited bone remodelling whereas vaginally-applied PEGLA had no effect on bone. Further, PEGLA had no effect in an animal model of multiple sclerosis, experimental auto-immune encephalomyelitis, suggesting PEGLA cannot target the central nervous system.Vaginally-administered PEGLA is a promising non-hormonal contraceptive, one which could be delivered alone, or in tandem with a microbicide. Vaginal application reduced the total dose of PEGLA required to block implantation and eliminated the systemic effect on bone, showing the vagina is a promising site of administration for larger drugs which target organs within the reproductive tract. PMID- 21611125 TI - Insight into the interaction of metal ions with TroA from Streptococcus suis. AB - BACKGROUND: The scavenging ability of sufficient divalent metal ions is pivotal for pathogenic bacteria to survive in the host. ATP-binding cassette (ABC)-type metal transporters provide a considerable amount of different transition metals for bacterial growth. TroA is a substrate binding protein for uptake of multiple metal ions. However, the function and structure of the TroA homologue from the epidemic Streptococcus suis isolates (SsTroA) have not been characterized. METHODOLOGY/PRINCIPAL FINDINGS: Here we determined the crystal structure of SsTroA from a highly pathogenic streptococcal toxic shock syndrome (STSS)-causing Streptococcus suis in complex with zinc. Inductively coupled plasma mass spectrometry (ICP-MS) analysis revealed that apo-SsTroA binds Zn(2+) and Mn(2+). Both metals bind to SsTroA with nanomolar affinity and stabilize the protein against thermal unfolding. Zn(2+) and Mn(2+) induce distinct conformational changes in SsTroA compared with the apo form as confirmed by both circular dichroism (CD) and nuclear magnetic resonance (NMR) spectra. NMR data also revealed that Zn(2+)/Mn(2+) bind to SsTroA in either the same site or an adjacent region. Finally, we found that the folding of the metal-bound protein is more compact than the corresponding apoprotein. CONCLUSIONS/SIGNIFICANCE: Our findings reveal a mechanism for uptake of metal ions in S. suis and this mechanism provides a reasonable explanation as to how SsTroA operates in metal transport. PMID- 21611126 TI - Postural control in bipolar disorder: increased sway area and decreased dynamical complexity. AB - Structural, neurochemical, and functional abnormalities have been identified in the brains of individuals with bipolar disorder, including in key brain structures implicated in postural control, i.e. the cerebellum, brainstem, and basal ganglia. Given these findings, we tested the hypothesis that postural control deficits are present in individuals with bipolar disorder. Sixteen participants with bipolar disorder (BD) and 16 age-matched non-psychiatric healthy controls were asked to stand as still as possible on a force platform for 2 minutes under 4 conditions: (1) eyes open-open base; (2) eyes closed-open base; (3) eyes open-closed base; and (4) eyes closed-closed base. Postural sway data were submitted to conventional quantitative analyses of the magnitude of sway area using the center of pressure measurement. In addition, data were submitted to detrended fluctuation analysis, a nonlinear dynamical systems analytic technique that measures complexity of a time-series, on both the anterior posterior and medio-lateral directions. The bipolar disorder group had increased sway area, indicative of reduced postural control. Decreased complexity in the medio-lateral direction was also observed for the bipolar disorder group, suggesting both a reduction in dynamic range available to them for postural control, and that their postural corrections were primarily dominated by longer time-scales. On both of these measures, significant interactions between diagnostic group and visual condition were also observed, suggesting that the BD participants were impaired in their ability to make corrections to their sway pattern when no visual information was available. Greater sway magnitude and reduced complexity suggest that individuals with bipolar disorder have deficits in sensorimotor integration and a reduced range of timescales available on which to make postural corrections. PMID- 21611127 TI - Evaluation of early and late effects into the acute spinal cord injury of an injectable functionalized self-assembling scaffold. AB - The complex physiopathological events occurring after spinal cord injury (SCI) make this devastating trauma still incurable. Self-assembling peptides (SAPs) are nanomaterials displaying some appealing properties for application in regenerative medicine because they mimic the structure of the extra-cellular matrix (ECM), are reabsorbable, allow biofunctionalizations and can be injected directly into the lesion. In this study we evaluated the putative neurorigenerative properties of RADA16-4G-BMHP1 SAP, proved to enhance in vitro neural stem cells survival and differentiation. This SAP (RADA16-I) has been functionalized with a bone marrow homing motif (BMHP1) and optimized via the insertion of a 4-glycine-spacer that ameliorates scaffold stability and exposure of the biomotifs. We injected the scaffold immediately after contusion in the rat spinal cord, then we evaluated the early effects by semi-quantitative RT-PCR and the late effects by histological analysis. Locomotor recovery over 8 weeks was assessed using Basso, Beattie, Bresnahan (BBB) test. Gene expression analysis showed that at 7 days after lesion the functionalized SAP induced a general upregulation of GAP-43, trophic factors and ECM remodelling proteins, whereas 3 days after SCI no remarkable changes were observed. Hystological analysis revealed that 8 weeks after SCI our scaffold increased cellular infiltration, basement membrane deposition and axon regeneration/sprouting within the cyst. Moreover the functionalized SAP showed to be compatible with the surrounding nervous tissue and to at least partially fill the cavities. Finally SAP injection resulted in a statistically significant improvement of both hindlimbs' motor performance and forelimbs-hindlimbs coordination. Altogether, these results indicate that RADA16-4G-BMHP1 induced favourable reparative processes, such as matrix remodelling, and provided a physical and trophic support to nervous tissue ingrowth. Thus this biomaterial, eventually combined with cells and growth factors, may constitute a promising biomimetic scaffold for regenerative applications in the injured central nervous system. PMID- 21611128 TI - Mitochondrial changes in ageing Caenorhabditis elegans--what do we learn from superoxide dismutase knockouts? AB - One of the most popular damage accumulation theories of ageing is the mitochondrial free radical theory of ageing (mFRTA). The mFRTA proposes that ageing is due to the accumulation of unrepaired oxidative damage, in particular damage to mitochondrial DNA (mtDNA). Within the mFRTA, the "vicious cycle" theory further proposes that reactive oxygen species (ROS) promote mtDNA mutations, which then lead to a further increase in ROS production. Recently, data have been published on Caenorhabditis elegans mutants deficient in one or both forms of mitochondrial superoxide dismutase (SOD). Surprisingly, even double mutants, lacking both mitochondrial forms of SOD, show no reduction in lifespan. This has been interpreted as evidence against the mFRTA because it is assumed that these mutants suffer from significantly elevated oxidative damage to their mitochondria. Here, using a novel mtDNA damage assay in conjunction with related, well established damage and metabolic markers, we first investigate the age dependent mitochondrial decline in a cohort of ageing wild-type nematodes, in particular testing the plausibility of the "vicious cycle" theory. We then apply the methods and insights gained from this investigation to a mutant strain for C. elegans that lacks both forms of mitochondrial SOD. While we show a clear age dependent, linear increase in oxidative damage in WT nematodes, we find no evidence for autocatalytic damage amplification as proposed by the "vicious cycle" theory. Comparing the SOD mutants with wild-type animals, we further show that oxidative damage levels in the mtDNA of SOD mutants are not significantly different from those in wild-type animals, i.e. even the total loss of mitochondrial SOD did not significantly increase oxidative damage to mtDNA. Possible reasons for this unexpected result and some implications for the mFRTA are discussed. PMID- 21611129 TI - Phylodynamics of hepatitis C virus subtype 2c in the province of Cordoba, Argentina. AB - The Hepatitis C Virus Genotype 2 subtype 2c (HCV-2c) is detected as a low prevalence subtype in many countries, except in Southern Europe and Western Africa. The current epidemiology of HCV in Argentina, a low-prevalence country, shows the expected low prevalence for this subtype. However, this subtype is the most prevalent in the central province of Cordoba. Cruz del Eje (CdE), a small rural city of this province, shows a prevalence for HCV infections of 5%, being 90% of the samples classified as HCV-2c. In other locations of Cordoba Province (OLC) with lower prevalence for HCV, HCV-2c was recorded in about 50% of the samples. The phylogenetic analysis of samples from Cordoba Province consistently conformed a monophyletic group with HCV-2c sequences from all the countries where HCV-2c has been sequenced. The phylogeographic analysis showed an overall association between geographical traits and phylogeny, being these associations significant (alpha = 0.05) for Italy, France, Argentina (places other than Cordoba), Martinique, CdE and OLC. The coalescence analysis for samples from CdE, OLC and France yielded a Time for the Most Common Recent Ancestor of about 140 years, whereas its demographic reconstruction showed a "lag" phase in the viral population until 1880 and then an exponential growth until 1940. These results were also obtained when each geographical area was analyzed separately, suggesting that HCV-2c came into Cordoba province during the migration process, mainly from Europe, which is compatible with the history of Argentina of the early 20th century. This also suggests that the spread of HCV-2c occurred in Europe and South America almost simultaneously, possibly as a result of the advances in medicine technology of the first half of the 20th century. PMID- 21611130 TI - Extracellular matrix formation enhances the ability of Streptococcus pneumoniae to cause invasive disease. AB - During infection, pneumococci exist mainly in sessile biofilms rather than in planktonic form, except during sepsis. However, relatively little is known about how biofilms contribute to pneumococcal pathogenesis. Here, we carried out a biofilm assay on opaque and transparent variants of a clinical serotype 19F strain WCH159. After 4 days incubation, scanning electron microscopy revealed that opaque biofilm bacteria produced an extracellular matrix, whereas the transparent variant did not. The opaque biofilm-derived bacteria translocated from the nasopharynx to the lungs and brain of mice, and showed 100-fold greater in vitro adherence to A549 cells than transparent bacteria. Microarray analysis of planktonic and sessile bacteria from transparent and opaque variants showed differential gene expression in two operons: the lic operon, which is involved in choline uptake, and in the two-component system, ciaRH. Mutants of these genes did not form an extracellular matrix, could not translocate from the nasopharynx to the lungs or the brain, and adhered poorly to A549 cells. We conclude that only the opaque phenotype is able to form extracellular matrix, and that the lic operon and ciaRH contribute to this process. We propose that during infection, extracellular matrix formation enhances the ability of pneumococci to cause invasive disease. PMID- 21611131 TI - Comparative genomic analysis of chitinase and chitinase-like genes in the African malaria mosquito (Anopheles gambiae). AB - Chitinase is an important enzyme responsible for chitin metabolism in a wide range of organisms including bacteria, yeasts and other fungi, nematodes and arthropods. However, current knowledge on chitinolytic enzymes, especially their structures, functions and regulation is very limited. In this study we have identified 20 chitinase and chitinase-like genes in the African malaria mosquito, Anopheles gambiae, through genome-wide searching and transcript profiling. We assigned these genes into eight different chitinase groupings (groups I-VIII). Domain analysis of their predicted proteins showed that all contained at least one catalytic domain. However, only seven (AgCht4, AgCht5-1, AgCht6, AgCht7, AgCht8, AgCht10 and AgCht23) displayed one or more chitin-binding domains. Analyses of stage- and tissue-specific gene expression revealed that most of these genes were expressed in larval stages. However, AgCht8 was mainly expressed in the pupal and adult stages. AgCht2 and AgCht12 were specifically expressed in the foregut, whereas AgCht13 was only expressed in the midgut. The high diversity and complexity of An. gambiae chitinase and chitinase-like genes suggest their diverse functions during different developmental stages and in different tissues of the insect. A comparative genomic analysis of these genes along with those present in Drosophila melanogaster, Tribolium castaneum and several other insect species led to a uniform classification and nomenclature of these genes. Our investigation also provided important information for conducting future studies on the functions of chitinase and chitinase-like genes in this important malaria vector and other species of arthropods. PMID- 21611133 TI - The acuity of echolocation: Spatial resolution in the sighted compared to expert performance. AB - Compared with the echolocation performance of a blind expert, sighted novices rapidly learned size and position discrimination with surprising precision. We use a novel task to characterize the population distribution of echolocation skill in the sighted and report the highest known human echolocation acuity in our expert subject. PMID- 21611132 TI - The inflammatory response to double stranded DNA in endothelial cells is mediated by NFkappaB and TNFalpha. AB - Endothelial cells represent an important barrier between the intravascular compartment and extravascular tissues, and therefore serve as key sensors, communicators, and amplifiers of danger signals in innate immunity and inflammation. Double stranded DNA (dsDNA) released from damaged host cells during injury or introduced by pathogens during infection, has emerged as a potent danger signal. While the dsDNA-mediated immune response has been extensively studied in immune cells, little is known about the direct and indirect effects of dsDNA on the vascular endothelium. In this study we show that direct dsDNA stimulation of endothelial cells induces a potent proinflammatory response as demonstrated by increased expression of ICAM1, E-selectin and VCAM1, and enhanced leukocyte adhesion. This response was dependent on the stress kinases JNK and p38 MAPK, required the activation of proinflammatory transcription factors NFkappaB and IRF3, and triggered the robust secretion of TNFalpha for sustained secondary activation of the endothelium. DNA-induced TNFalpha secretion proved to be essential in vivo, as mice deficient in the TNF receptor were unable to mount an acute inflammatory response to dsDNA. Our findings suggest that the endothelium plays an active role in mediating dsDNA-induced inflammatory responses, and implicate its importance in establishing an acute inflammatory response to sterile injury or systemic infection, where host or pathogen derived dsDNA may serve as a danger signal. PMID- 21611134 TI - Does Children's Academic Achievement Improve when Single Mothers Marry? AB - Promoting marriage, especially among low-income single mothers with children, is increasingly viewed as a promising public policy strategy for improving developmental outcomes for disadvantaged children. Previous research suggests, however, that children's academic achievement either does not improve or declines when single mothers marry. In this paper, we argue that previous research may understate the benefits of mothers' marriages to children from single-parent families because (1) the short-term and long-term developmental consequences of marriage are not adequately distinguished and (2) child and family contexts in which marriage is likely to confer developmental advantages are not differentiated from those that do not. Using multiple waves of data from the ECLS K, we find that single mothers' marriages are associated with modest but statistically significant improvements in their children's academic achievement trajectories. However, only children from more advantaged single-parent families benefit from their mothers' marriage. PMID- 21611135 TI - Spatial backward planar projection in absorbing media possessing an arbitrary dispersion relation. AB - Planar projection methods have been shown to rapidly relate fields between two planes. Such an approach is particularly useful for characterizing transducers, since only a single plane needs to be measured in order to characterize an entire field. The present work considers the same approach in the presence of an arbitrary dispersion relation. Unlike traditional methods that use Fourier solutions of the time-domain wave equation, the approach starts from a frequency domain Helmholtz equation for waves in a dispersive medium. It is shown that a transfer function similar to that derived from time domain equations can be utilized. Both the forward- and backward-projection behaviors are examined and it is demonstrated that the approach is invariant to propagation direction. PMID- 21611136 TI - Parametric non-mixture cure models for schedule finding of therapeutic agents. AB - We propose a phase I clinical trial design that seeks to determine the cumulative safety of a series of administrations of a fixed dose of an investigational agent. In contrast with traditional phase I trials that are designed solely to find the maximum tolerated dose of the agent, our design instead identifies a maximum tolerated schedule that includes a maximum tolerated dose as well as a vector of recommended administration times. Our model is based on a non-mixture cure model that constrains the probability of dose limiting toxicity for all patients to increase monotonically with both dose and the number of administrations received. We assume a specific parametric hazard function for each administration and compute the total hazard of dose limiting toxicity for a schedule as a sum of individual administration hazards. Throughout a variety of settings motivated by an actual study in allogeneic bone marrow transplant recipients, we demonstrate that our approach has excellent operating characteristics and performs as well as the only other currently published design for schedule finding studies. We also present arguments for the preference of our non-mixture cure model over the existing model. PMID- 21611137 TI - A scalable architecture for incremental specification and maintenance of procedural and declarative clinical decision-support knowledge. AB - Clinical guidelines have been shown to improve the quality of medical care and to reduce its costs. However, most guidelines exist in a free-text representation and, without automation, are not sufficiently accessible to clinicians at the point of care. A prerequisite for automated guideline application is a machine comprehensible representation of the guidelines. In this study, we designed and implemented a scalable architecture to support medical experts and knowledge engineers in specifying and maintaining the procedural and declarative aspects of clinical guideline knowledge, resulting in a machine comprehensible representation. The new framework significantly extends our previous work on the Digital electronic Guidelines Library (DeGeL) The current study designed and implemented a graphical framework for specification of declarative and procedural clinical knowledge, Gesher. We performed three different experiments to evaluate the functionality and usability of the major aspects of the new framework: Specification of procedural clinical knowledge, specification of declarative clinical knowledge, and exploration of a given clinical guideline. The subjects included clinicians and knowledge engineers (overall, 27 participants). The evaluations indicated high levels of completeness and correctness of the guideline specification process by both the clinicians and the knowledge engineers, although the best results, in the case of declarative-knowledge specification, were achieved by teams including a clinician and a knowledge engineer. The usability scores were high as well, although the clinicians' assessment was significantly lower than the assessment of the knowledge engineers. PMID- 21611138 TI - Cyclic Force Applied to FAs Induces Actin Recruitment Depending on the Dynamic Loading Pattern. AB - Mechanical forces acting on focal adhesions (FAs) are believed to be an important determinant for cytoskeletal reorganization. However, the effect of the temporal pattern of forces on cellular responses has not been elucidated. In the present study, we examined the responses of FAs to locally-applied cyclic forces. Magnetic micro beads coated with fibronectin were attached to the apical surface of endothelial cells and continuous or cyclic forces at frequencies of 0.1-10 Hz with duty cycles of 0-100% were applied to the beads using a newly developed electromagnetic tweezer. A significant increase in actin recruitment around the beads was observed when cyclic forces at 1-2 Hz and 25-50% duty cycles were applied. This tendency disappeared upon modification of myosin activity. These results indicate that the sensitivity to temporal patterns of forces is detemined by the viscoelastic properes of FAs and depends on myosin activity. PMID- 21611139 TI - Preliminary characterization of erythrocytes deformability on the entropy complexity plane. AB - We present an application of wavelet-based Information Theory quantifiers (Normalized Total Shannon Entropy, MPR-Statistical Complexity and Entropy Complexity plane) on red blood cells membrane viscoelasticity characterization. These quantifiers exhibit important localization advantages provided by the Wavelet Theory. The present approach produces a clear characterization of this dynamical system, finding out an evident manifestation of a random process on the red cell samples of healthy individuals, and its sharp reduction of randomness on analyzing a human haematological disease, such as beta-thalassaemia minor. PMID- 21611140 TI - Invasive electrical impedance tomography for blood vessel detection. AB - We present a novel method for localization of large blood vessels using a bioimpedance based needle positioning system on an array of ten monopolar needle electrodes. The purpose of the study is to develop a portable, low cost tool for rapid vascular access for cooling and controlled reperfusion of cardiac arrest patients. Preliminary results show that localization of blood vessels is feasible with this method, but larger studies are necessary to improve the technology. PMID- 21611141 TI - Initial experience of laparoendoscopic single-site radical prostatectomy requiring well-equipped appliances and a skilled technique. AB - We report an initial experience in laparoendoscopic single-site radical prostatectomy (LESSRP) using a homemade single-port device for prostate cancer. A 63-year-old man was diagnosed with prostate cancer. The patient underwent LESSRP using an Alexis(r) wound retractor, which was inserted through an umbilical incision. A homemade single-port device was made by fixing a 6 1/2 surgical glove to the retractor's outer ring and securing the glove finger to the end of 4 trocars with a tie. Using the flexible laparoscopic and rigid instruments, LESSRP was performed using a procedure similar to conventional laparoscopic radical prostatectomy (LRP). In the current case, we could not perform complete LESSRP, so we report our initial experience and consider the reason why laparoendoscopic single-site surgery was converted to conventional LRP. PMID- 21611142 TI - Primary signet ring cell mucinous ovarian carcinoma: a case report and literature review. AB - A 24-year-old female patient presented with an extremely rare primary signet cell carcinoma of the right ovary 1 year after surgery for a mucinous borderline tumour of the left ovary. Relaparotomy was carried out with right adnexectomy, appendectomy and partial omentectomy. Surgery was followed by 6 courses of paclitaxel/carboplatinum chemotherapy. After an initial response, the patient again developed increasing ascites. The patient was transferred to our hospital and a re-relaparotomy was carried out, completing the operation. After 3 courses of pegylated doxorubicin/trabectedin, the clinical course showed a positive response and a decline of the tumour marker CEA in peripheral blood. After 5 months, ascites developed in the retroperitoneum so that the chemotherapy had to be changed. In spite of a positive response with the new chemotherapy, the patient died of a very rare pulmonary complication after 1 month within 2 days. PMID- 21611143 TI - Neuroblastoma in a 55-year-old patient: a case report. AB - BACKGROUND: Neuroblastomas account for 97% of all neuroblastic tumors and for approximately 15% of all pediatric cancer fatalities. However, in adults neuroblastoma is a very rare finding. CASE REPORT: Here, we present the case of a 55-year-old patient who was diagnosed with neuroblastoma stage IV one year after the false diagnosis of a non-secretory multiple myeloma. RESULTS: The patient received six cycles of a chemotherapy protocol with cisplatin, etoposide and vindesine alternating with vincristine, dacarbazine, ifosfamide and doxorubicin, but the response to treatment was insufficient (stable disease). CONCLUSION: The standard chemotherapy protocols used for children are not sufficient for adult patients. Different treatment approaches are needed to improve the prognosis of adult patients with neuroblastoma. PMID- 21611144 TI - A case report of a patient with hereditary hemorrhagic telangiectasia treated successively with thalidomide and bevacizumab. AB - Hereditary hemorrhagic telangiectasia is characterized by mucocutaneous and visceral telangiectasia and involves several organs with vascular malformations. It is an autosomal dominant disease and is distinguished into three types, which are due to mutations in different genes. The common symptom is anemia, causing a continous need of blood transfusion. Depending on the severity and disease manifestation, there are various forms of therapy ranging from local therapy activities to operations or drug therapy. Here we describe a dramatic improvement of a patient with a high transfusion frequency due to severe recurrent anemia successively treated with thalidomide and bevacizumab. PMID- 21611145 TI - Endometrial cancer diagnosed by the presence of bone metastasis and treated with zoledronic Acid: a case report and review of the literature. AB - Bone metastasis from endometrial cancer is rare. We report a case of endometrial cancer which was diagnosed by the presence of bone metastasis and treated with zoledronic acid. A 57-year-old woman complaining of progressive right hip pain consulted an orthopedist. She had no gynecologic complaints. X-rays revealed an osteolytic lesion of the right ischium. Bone scintigraphy was subsequently carried out and showed isotope accumulation in the right ischium. Computed tomography revealed an enlarged uterus; the patient consequently consulted a gynecologist. Histological sections of an endometrial biopsy showed endometrioid adenocarcinoma. Hysterectomy and bilateral salpingo-oophorectomy, as well as bone biopsy of the right ischium, were therefore carried out. A moderately differentiated endometrioid adenocarcinoma was expressed in the corpus. Histopathological examination of the bone biopsy also revealed adenocarcinoma. The final diagnosis was stage IVB endometrial cancer with bone and lung metastasis. Good pain relief was achieved due to chemotherapy. However, 2 months after completion of the chemotherapy, the patient was administered zoledronic acid because her hip pain had gradually increased. Following zoledronic acid administration, the hip pain reduced. Radiotherapy was then given for the right ischial metastasis after the ninth course of zoledronic acid therapy because the metastasis site had increased and the possibility of a pathological fracture had risen. However, the patient died 21 months after the initial treatment because of disease progression. PMID- 21611146 TI - The P2 receptor antagonist PPADS supports recovery from experimental stroke in vivo. AB - BACKGROUND: After ischemia of the CNS, extracellular adenosine 5'-triphosphate (ATP) can reach high concentrations due to cell damage and subsequent increase of membrane permeability. ATP may cause cellular degeneration and death, mediated by P2X and P2Y receptors. METHODOLOGY/PRINCIPAL FINDINGS: The effects of inhibition of P2 receptors by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on electrophysiological, functional and morphological alterations in an ischemia model with permanent middle cerebral artery occlusion (MCAO) were investigated up to day 28. Spontaneously hypertensive rats received PPADS or vehicle intracerebroventricularly 15 minutes prior MCAO for up to 7 days. The functional recovery monitored by qEEG was improved by PPADS indicated by an accelerated recovery of ischemia-induced qEEG changes in the delta and alpha frequency bands along with a faster and sustained recovery of motor impairments. Whereas the functional improvements by PPADS were persistent at day 28, the infarct volume measured by magnetic resonance imaging and the amount of TUNEL-positive cells were significantly reduced by PPADS only until day 7. Further, by immunohistochemistry and confocal laser scanning microscopy, we identified both neurons and astrocytes as TUNEL-positive after MCAO. CONCLUSION: The persistent beneficial effect of PPADS on the functional parameters without differences in the late (day 28) infarct size and apoptosis suggests that the early inhibition of P2 receptors might be favourable for the maintenance or early reconstruction of neuronal connectivity in the periinfarct area after ischemic incidents. PMID- 21611148 TI - Relative impacts of adult movement, larval dispersal and harvester movement on the effectiveness of reserve networks. AB - Movement of individuals is a critical factor determining the effectiveness of reserve networks. Marine reserves have historically been used for the management of species that are sedentary as adults, and, therefore, larval dispersal has been a major focus of marine-reserve research. The push to use marine reserves for managing pelagic and demersal species poses significant questions regarding their utility for highly-mobile species. Here, a simple conceptual metapopulation model is developed to provide a rigorous comparison of the functioning of reserve networks for populations with different admixtures of larval dispersal and adult movement in a home range. We find that adult movement produces significantly lower persistence than larval dispersal, all other factors being equal. Furthermore, redistribution of harvest effort previously in reserves to remaining fished areas ('fishery squeeze') and fishing along reserve borders ('fishing-the line') considerably reduce persistence and harvests for populations mobile as adults, while they only marginally changes results for populations with dispersing larvae. Our results also indicate that adult home-range movement and larval dispersal are not simply additive processes, but rather that populations possessing both modes of movement have lower persistence than equivalent populations having the same amount of 'total movement' (sum of larval and adult movement spatial scales) in either larval dispersal or adult movement alone. PMID- 21611147 TI - beta2-Agonist induced cAMP is decreased in asthmatic airway smooth muscle due to increased PDE4D. AB - BACKGROUND AND OBJECTIVE: Asthma is associated with airway narrowing in response to bronchoconstricting stimuli and increased airway smooth muscle (ASM) mass. In addition, some studies have suggested impaired beta-agonist induced ASM relaxation in asthmatics, but the mechanism is not known. OBJECTIVE: To characterize the potential defect in beta-agonist induced cAMP in ASM derived from asthmatic in comparison to non-asthmatic subjects and to investigate its mechanism. METHODS: We examined beta(2)-adrenergic (beta(2)AR) receptor expression and basal beta-agonist and forskolin (direct activator of adenylyl cyclase) stimulated cAMP production in asthmatic cultured ASM (n = 15) and non asthmatic ASM (n = 22). Based on these results, PDE activity, PDE4D expression and cell proliferation were determined. RESULTS: In the presence of IBMX, a pan PDE inhibitor, asthmatic ASM had ~50% lower cAMP production in response to isoproterenol, albuterol, formoterol, and forskolin compared to non-asthmatic ASM. However when PDE4 was specifically inhibited, cAMP production by the agonists and forskolin was normalized in asthmatic ASM. We then measured the amount and activity of PDE4, and found ~2-fold greater expression and activity in asthmatic ASM compared to non-asthmatic ASM. Furthermore, inhibition of PDE4 reduced asthmatic ASM proliferation but not that of non-asthmatic ASM. CONCLUSION: Decreased beta-agonist induced cAMP in ASM from asthmatics results from enhanced degradation due to increased PDE4D expression. Clinical manifestations of this dysregulation would be suboptimal beta-agonist-mediated bronchodilation and possibly reduced control over increasing ASM mass. These phenotypes appear to be "hard-wired" into ASM from asthmatics, as they do not require an inflammatory environment in culture to be observed. PMID- 21611149 TI - A novel splice variant in the N-propeptide of COL5A1 causes an EDS phenotype with severe kyphoscoliosis and eye involvement. AB - BACKGROUND: The Ehlers-Danlos Syndrome (EDS) is a heritable connective tissue disorder characterized by hyperextensible skin, joint hypermobility and soft tissue fragility. The classic subtype of EDS is caused by mutations in one of the type V collagen genes (COL5A1 and COL5A2). Most mutations affect the type V collagen helical domain and lead to a diminished or structurally abnormal type V collagen protein. Remarkably, only two mutations were reported to affect the extended, highly conserved N-propeptide domain, which plays an important role in the regulation of the heterotypic collagen fibril diameter. We identified a novel COL5A1 N-propeptide mutation, resulting in an unusual but severe classic EDS phenotype and a remarkable splicing outcome. METHODOLOGY/PRINCIPAL FINDINGS: We identified a novel COL5A1 N-propeptide acceptor-splice site mutation (IVS6-2A>G, NM_000093.3_c.925-2A>G) in a patient with cutaneous features of EDS, severe progressive scoliosis and eye involvement. Two mutant transcripts were identified, one with an exon 7 skip and one in which exon 7 and the upstream exon 6 are deleted. Both transcripts are expressed and secreted into the extracellular matrix, where they can participate in and perturb collagen fibrillogenesis, as illustrated by the presence of dermal collagen cauliflowers. Determination of the order of intron removal and computational analysis showed that simultaneous skipping of exons 6 and 7 is due to the combined effect of delayed splicing of intron 7, altered pre-mRNA secondary structure, low splice site strength and possibly disturbed binding of splicing factors. CONCLUSIONS/SIGNIFICANCE: We report a novel COL5A1 N-propeptide acceptor-splice site mutation in intron 6, which not only affects splicing of the adjacent exon 7, but also causes a splicing error of the upstream exon 6. Our findings add further insights into the COL5A1 splicing order and show for the first time that a single COL5A1 acceptor splice site mutation can perturb splicing of the upstream exon. PMID- 21611150 TI - Meningothelial cells react to elevated pressure and oxidative stress. AB - BACKGROUND: Meningothelial cells (MECs) are the cellular components of the meninges enveloping the brain. Although MECs are not fully understood, several functions of these cells have been described. The presence of desmosomes and tight junctions between MECs hints towards a barrier function protecting the brain. In addition, MECs perform endocytosis and, by the secretion of cytokines, are involved in immunological processes in the brain. However, little is known about the influence of pathological conditions on MEC function; e.g., during diseases associated with elevated intracranial pressure, hypoxia or increased oxidative stress. METHODS: We studied the effect of elevated pressure, hypoxia, and oxidative stress on immortalized human as well as primary porcine MECs. We used MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium) bioreduction assays to assess the proliferation of MECs in response to treatment and compared to untreated control cells. To assess endocytotic activity, the uptake of fluorescently labeled latex beads was analyzed by fluorescence microscopy. RESULTS: We found that exposure of MECs to elevated pressure caused significant cellular proliferation and a dramatic decrease in endocytotic activity. In addition, mild oxidative stress severely inhibited endocytosis. CONCLUSION: Elevated pressure and oxidative stress impact MEC physiology and might therefore influence the microenvironment of the subarachnoid space and thus the cerebrospinal fluid within this compartment with potential negative impact on neuronal function. PMID- 21611151 TI - Characterization of the metabolic phenotype of rapamycin-treated CD8+ T cells with augmented ability to generate long-lasting memory cells. AB - BACKGROUND: Cellular metabolism plays a critical role in regulating T cell responses and the development of memory T cells with long-term protections. However, the metabolic phenotype of antigen-activated T cells that are responsible for the generation of long-lived memory cells has not been characterized. DESIGN AND METHODS: Using lymphocytic choriomeningitis virus (LCMV) peptide gp33-specific CD8(+) T cells derived from T cell receptor transgenic mice, we characterized the metabolic phenotype of proliferating T cells that were activated and expanded in vitro in the presence or absence of rapamycin, and determined the capability of these rapamycin-treated T cells to generate long-lived memory cells in vivo. RESULTS: Antigen-activated CD8(+) T cells treated with rapamycin gave rise to 5-fold more long-lived memory T cells in vivo than untreated control T cells. In contrast to that control T cells only increased glycolysis, rapamycin-treated T cells upregulated both glycolysis and oxidative phosphorylation (OXPHOS). These rapamycin-treated T cells had greater ability than control T cells to survive withdrawal of either glucose or growth factors. Inhibition of OXPHOS by oligomycin significantly reduced the ability of rapamycin-treated T cells to survive growth factor withdrawal. This effect of OXPHOS inhibition was accompanied with mitochondrial hyperpolarization and elevation of reactive oxygen species that are known to be toxic to cells. CONCLUSIONS: Our findings indicate that these rapamycin-treated T cells may represent a unique cell model for identifying nutrients and signals critical to regulating metabolism in both effector and memory T cells, and for the development of new methods to improve the efficacy of adoptive T cell cancer therapy. PMID- 21611152 TI - Rotavirus rearranged genomic RNA segments are preferentially packaged into viruses despite not conferring selective growth advantage to viruses. AB - The rotavirus (RV) genome consists of 11 double-stranded RNA segments. Sometimes, partial sequence duplication of an RNA segment leads to a rearranged RNA segment. To specify the impact of rearrangement, the replication efficiencies of human RV with rearranged segments 7, 11 or both were compared to these of the homologous human wild-type RV (wt-RV) and of the bovine wt-RV strain RF. As judged by viral growth curves, rotaviruses with a rearranged genome (r-RV) had no selective growth advantage over the homologous wt-RV. In contrast, r-RV were selected over wt-RV during competitive experiments (i.e mixed infections between r-RV and wt-RV followed by serial passages in cell culture). Moreover, when competitive experiments were performed between a human r-RV and the bovine wt-RV strain RF, which had a clear growth advantage, rearranged segments 7, 11 or both always segregated in viral progenies even when performing mixed infections at an MOI ratio of 1 r-RV to 100 wt-RV. Lastly, bovine reassortant viruses that had inherited a rearranged segment 7 from human r-RV were generated. Although substitution of wt by rearranged segment 7 did not result in any growth advantage, the rearranged segment was selected in the viral progenies resulting from mixed infections by bovine reassortant r-RV and wt-RV, even for an MOI ratio of 1 r-RV to 10(7) wt-RV. Lack of selective growth advantage of r-RV over wt-RV in cell culture suggests a mechanism of preferential packaging of the rearranged segments over their standard counterparts in the viral progeny. PMID- 21611153 TI - Harnessing expression data to identify novel candidate genes in polycystic ovary syndrome. AB - Novel pathways in polycystic ovary syndrome (PCOS) are being identified in gene expression studies in PCOS tissues; such pathways may contain key genes in disease etiology. Previous expression studies identified both dickkopf homolog 1 (DKK1) and DnaJ (Hsp40) homolog, subfamily B, member 1 (DNAJB1) as differentially expressed in PCOS tissue, implicating them as candidates for PCOS susceptibility. To test this, we genotyped a discovery cohort of 335 PCOS cases and 198 healthy controls for three DKK1 single nucleotide polymorphisms (SNPs) and four DNAJB1 SNPs and a replication cohort of 396 PCOS cases and 306 healthy controls for 1 DKK1 SNP and 1 DNAJB1 SNP. SNPs and haplotypes were determined and tested for association with PCOS and component phenotypes. We found that no single nucleotide polymorphisms were associated with PCOS risk; however, the major allele of rs1569198 from DKK1 was associated with increased total testosterone (discovery cohort P = 0.0035) and dehydroepiandrosterone sulfate (replication cohort P = 0.05). Minor allele carriers at rs3962158 from DNAJB1 had increased fasting insulin (discovery cohort P = 0.003), increased HOMA-IR (discovery cohort P = 0.006; replication cohort P = 0.036), and increased HOMA-%B (discovery cohort P = 0.004). Carriers of haplotype 2 at DNAJB1 also had increased fasting insulin, HOMA-IR, and HOMA-%B. These findings suggest that genetic variation in DKK1 and DNAJB1 may have a role in the hyperandrogenic and metabolic dysfunction of PCOS, respectively. Our results also demonstrate the utility of gene expression data as a source of novel candidate genes in PCOS, a complex and still incompletely defined disease, for which alternative methods of gene identification are needed. PMID- 21611154 TI - Guidelines on chemotherapy in advanced stage gynecological malignancies: an evaluation of 224 professional societies and organizations. AB - BACKGROUND: Clinical practice guidelines are important for guiding practice, but it is unclear if they are commensurate with the available evidence. METHODS: We examined guidelines produced by cancer and gynecological societies and organizations and evaluated their coverage of and stance towards chemotherapy for advanced stage disease among 4 gynecological malignancies (breast, ovarian, cervical, endometrial cancer) where the evidence for the use of chemotherapy is very different (substantial and conclusive for breast and ovarian cancer, limited and suggesting no major benefit for cervical and endometrial cancer). Eligible societies and organizations were identified through systematic internet searches (last update June 2009). Pertinent websites were scrutinized for presence of clinical practice guidelines, and relative guidelines were analyzed. RESULTS: Among 224 identified eligible societies and organizations, 69 (31%) provided any sort of guidelines, while recommendations for chemotherapy on advanced stage gynecological malignancies were available in 20 of them. Only 14 had developed their own guideline, and only 5 had developed guidelines for all 4 malignancies. Use of levels of evidence and grades of recommendations, and aspects of the production, implementation, and timeliness of the guidelines did not differ significantly across malignancies. Guidelines on breast and ovarian cancer utilized significantly more randomized trials and meta-analyses. Guidelines differed across malignancies on their coverage of disease-free survival (p = 0.033), response rates (p = 0.024), symptoms relief (p = 0.005), quality of life (p = 0.001) and toxicity (p = 0.039), with breast and ovarian cancer guidelines typically covering more frequently these outcomes. All guidelines explicitly or implicitly endorsed the use of chemotherapy. CONCLUSIONS: Clinical practice guidelines are provided by the minority of professional societies and organizations. Available guidelines tend to recommend chemotherapy even for diseases where the effect of chemotherapy is controversial and recommendations are based on scant evidence. PMID- 21611155 TI - Frontal-to-parietal top-down causal streams along the dorsal attention network exclusively mediate voluntary orienting of attention. AB - Previous effective connectivity analyses of functional magnetic resonance imaging (fMRI) have revealed dynamic causal streams along the dorsal attention network (DAN) during voluntary attentional control in the human brain. During resting state, however, fMRI has shown that the DAN is also intrinsically configured by functional connectivity, even in the absence of explicit task demands, and that may conflict with effective connectivity studies. To resolve this contradiction, we performed an effective connectivity analysis based on partial Granger causality (pGC) on event-related fMRI data during Posner's cueing paradigm while optimizing experimental and imaging parameters for pGC analysis. Analysis by pGC can factor out exogenous or latent influences due to unmeasured variables. Typical regions along the DAN with greater activation during orienting than withholding of attention were selected as regions of interest (ROIs). pGC analysis on fMRI data from the ROIs showed that frontal-to-parietal top-down causal streams along the DAN appeared during (voluntary) orienting, but not during other, less-attentive and/or resting-like conditions. These results demonstrate that these causal streams along the DAN exclusively mediate voluntary covert orienting. These findings suggest that neural representations of attention in frontal regions are at the top of the hierarchy of the DAN for embodying voluntary attentional control. PMID- 21611156 TI - Determining the sub-cellular localization of proteins within Caenorhabditis elegans body wall muscle. AB - Determining the sub-cellular localization of a protein within a cell is often an essential step towards understanding its function. In Caenorhabditis elegans, the relatively large size of the body wall muscle cells and the exquisite organization of their sarcomeres offer an opportunity to identify the precise position of proteins within cell substructures. Our goal in this study is to generate a comprehensive "localizome" for C. elegans body wall muscle by GFP tagging proteins expressed in muscle and determining their location within the cell. For this project, we focused on proteins that we know are expressed in muscle and are orthologs or at least homologs of human proteins. To date we have analyzed the expression of about 227 GFP-tagged proteins that show localized expression in the body wall muscle of this nematode (e.g. dense bodies, M-lines, myofilaments, mitochondria, cell membrane, nucleus or nucleolus). For most proteins analyzed in this study no prior data on sub-cellular localization was available. In addition to discrete sub-cellular localization we observe overlapping patterns of localization including the presence of a protein in the dense body and the nucleus, or the dense body and the M-lines. In total we discern more than 14 sub-cellular localization patterns within nematode body wall muscle. The localization of this large set of proteins within a muscle cell will serve as an invaluable resource in our investigation of muscle sarcomere assembly and function. PMID- 21611157 TI - Phylogenetic distribution of intron positions in alpha-amylase genes of bilateria suggests numerous gains and losses. AB - Most eukaryotes have at least some genes interrupted by introns. While it is well accepted that introns were already present at moderate density in the last eukaryote common ancestor, the conspicuous diversity of intron density among genomes suggests a complex evolutionary history, with marked differences between phyla. The question of the rates of intron gains and loss in the course of evolution and factors influencing them remains controversial. We have investigated a single gene family, alpha-amylase, in 55 species covering a variety of animal phyla. Comparison of intron positions across phyla suggests a complex history, with a likely ancestral intronless gene undergoing frequent intron loss and gain, leading to extant intron/exon structures that are highly variable, even among species from the same phylum. Because introns are known to play no regulatory role in this gene and there is no alternative splicing, the structural differences may be interpreted more easily: intron positions, sizes, losses or gains may be more likely related to factors linked to splicing mechanisms and requirements, and to recognition of introns and exons, or to more extrinsic factors, such as life cycle and population size. We have shown that intron losses outnumbered gains in recent periods, but that "resets" of intron positions occurred at the origin of several phyla, including vertebrates. Rates of gain and loss appear to be positively correlated. No phase preference was found. We also found evidence for parallel gains and for intron sliding. Presence of introns at given positions was correlated to a strong protosplice consensus sequence AG/G, which was much weaker in the absence of intron. In contrast, recent intron insertions were not associated with a specific sequence. In animal Amy genes, population size and generation time seem to have played only minor roles in shaping gene structures. PMID- 21611159 TI - Out of their depth? Isolated deep populations of the cosmopolitan coral Desmophyllum dianthus may be highly vulnerable to environmental change. AB - Deep sea scleractinian corals will be particularly vulnerable to the effects of climate change, facing loss of up to 70% of their habitat as the Aragonite Saturation Horizon (below which corals are unable to form calcium carbonate skeletons) rises. Persistence of deep sea scleractinian corals will therefore rely on the ability of larvae to disperse to, and colonise, suitable shallow water habitat. We used DNA sequence data of the internal transcribed spacer (ITS), the mitochondrial ribosomal subunit (16S) and mitochondrial control region (MtC) to determine levels of gene flow both within and among populations of the deep sea coral Desmophyllum dianthus in SE Australia, New Zealand and Chile to assess the ability of corals to disperse into different regions and habitats. We found significant genetic subdivision among the three widely separated geographic regions consistent with isolation and limited contemporary gene flow. Furthermore, corals from different depth strata (shallow <600 m, mid 1000-1500 m, deep >1500 m) even on the same or nearby seamounts were strongly differentiated, indicating limited vertical larval dispersal. Genetic differentiation with depth is consistent with the stratification of the Subantarctic Mode Water, Antarctic Intermediate Water, the Circumpolar Deep and North Pacific Deep Waters in the Southern Ocean, and we propose that coral larvae will be retained within, and rarely migrate among, these water masses. The apparent absence of vertical larval dispersal suggests deep populations of D. dianthus are unlikely to colonise shallow water as the aragonite saturation horizon rises and deep waters become uninhabitable. Similarly, assumptions that deep populations will act as refuges for shallow populations that are impacted by activities such as fishing or mining are also unlikely to hold true. Clearly future environmental management strategies must consider both regional and depth-related isolation of deep-sea coral populations. PMID- 21611158 TI - Identification of prognostic molecular features in the reactive stroma of human breast and prostate cancer. AB - Primary tumor growth induces host tissue responses that are believed to support and promote tumor progression. Identification of the molecular characteristics of the tumor microenvironment and elucidation of its crosstalk with tumor cells may therefore be crucial for improving our understanding of the processes implicated in cancer progression, identifying potential therapeutic targets, and uncovering stromal gene expression signatures that may predict clinical outcome. A key issue to resolve, therefore, is whether the stromal response to tumor growth is largely a generic phenomenon, irrespective of the tumor type or whether the response reflects tumor-specific properties. To address similarity or distinction of stromal gene expression changes during cancer progression, oligonucleotide-based Affymetrix microarray technology was used to compare the transcriptomes of laser microdissected stromal cells derived from invasive human breast and prostate carcinoma. Invasive breast and prostate cancer-associated stroma was observed to display distinct transcriptomes, with a limited number of shared genes. Interestingly, both breast and prostate tumor-specific dysregulated stromal genes were observed to cluster breast and prostate cancer patients, respectively, into two distinct groups with statistically different clinical outcomes. By contrast, a gene signature that was common to the reactive stroma of both tumor types did not have survival predictive value. Univariate Cox analysis identified genes whose expression level was most strongly associated with patient survival. Taken together, these observations suggest that the tumor microenvironment displays distinct features according to the tumor type that provides survival-predictive value. PMID- 21611160 TI - Evaluation of PRNP expression based on genotypes and alleles of two indel loci in the medulla oblongata of Japanese Black and Japanese Brown cattle. AB - BACKGROUND: Prion protein (PrP) level plays the central role in bovine spongiform encephalopathy (BSE) susceptibility. Increasing the level of PrP decreases incubation period for this disease. Therefore, studying the expression of the cellular PrP or at least the messenger RNA might be used in selection for preventing the propagation of BSE and other prion diseases. Two insertion/deletion (indel) variations have been tentatively associated with susceptibility/resistance of cattle to classical BSE. METHODOLOGY/PRINCIPAL FINDINGS: We studied the expression of each genotype at the two indel sites in Japanese Black (JB) and Japanese Brown (JBr) cattle breeds by a standard curve method of real-time PCR. Five diplotypes subdivided into two categories were selected from each breed. The two cattle breeds were considered differently. Expression of PRNP was significantly (p<0.0001) greater in the homozygous deletion genotype at the 23-bp locus in JB breed. Compared to the homozygous genotypes, the expression of PRNP was significantly greater in the heterozygous genotype at the 12-bp locus in JB (p<0.0001) and in JBr (p = 0.0394) breeds. In addition, there was a statistical significance in the PRNP levels between the insertion and the deletion alleles of the 23-bp locus in JB (p = 0.0003) as well as in JBr (p = 0.0032). There was no significance in relation to sex, age, geographical location or due to their interactions (p>0.05). CONCLUSION: Our results suggest that the del/del genotype or at least its del allele may modulate the expression of PRNP at the 23-bp locus in the medulla oblongata of these cattle breeds. PMID- 21611161 TI - Phytophagous arthropods and a pathogen sharing a host plant: evidence for indirect plant-mediated interactions. AB - In ecological systems, indirect interactions between plant pathogens and phytophagous arthropods can arise when infestation by a first attacker alters the common host plant so that although a second attacker could be spatially or temporally separated from the first one, the former could be affected. The induction of plant defense reactions leading to the production of secondary metabolites is thought to have an important role since it involves antagonistic and/or synergistic cross-talks that may determine the outcome of such interactions. We carried out experiments under controlled conditions on young rose plants in order to assess the impact of these indirect interactions on life history traits of three pests: the necrotrophic fungus Botrytis cinerea Pers.: Fr. (Helotiales: Sclerotiniaceae), the aphid Rhodobium porosum Sanderson (Hemiptera: Aphididae) and the thrips Frankliniella occidentalis Pergande (Thysanoptera: Thripidae). Our results indicated (i) a bi-directional negative interaction between B. cinerea and R. porosum, which is conveyed by decreased aphid growth rate and reduced fungal lesion area, as well as (ii) an indirect negative effect of B. cinerea on insect behavior. No indirect effect was observed between thrips and aphids. This research highlights several complex interactions that may be involved in structuring herbivore and plant pathogen communities within natural and managed ecosystems. PMID- 21611162 TI - Altering the Ad5 packaging domain affects the maturation of the Ad particles. AB - We have previously described a new family of mutant adenoviruses carrying different combinations of attB/attP sequences from bacteriophage PhiC31 flanking the Ad5 packaging domain. These novel helper viruses have a significantly delayed viral life cycle and a severe packaging impairment, regardless of the presence of PhiC31 recombinase. Their infectious viral titers are significantly lower (100 1000 fold) than those of control adenovirus at 36 hours post-infection, but allow for efficient packaging of helper-dependent adenovirus. In the present work, we have analyzed which steps of the adenovirus life cycle are altered in attB-helper adenoviruses and investigated whether these viruses can provide the necessary viral proteins in trans. The entry of attB-adenoviral genomes into the cell nucleus early at early timepoints post-infection was not impaired and viral protein expression levels were found to be similar to those of control adenovirus. However, electron microscopy and capsid protein composition analyses revealed that attB-adenoviruses remain at an intermediate state of maturation 36 hours post-infection in comparison to control adenovirus which were fully mature and infective at this time point. Therefore, an additional 20-24 hours were found to be required for the appearance of mature attB-adenovirus. Interestingly, attB adenovirus assembly and infectivity was restored by inserting a second packaging signal close to the right-end ITR, thus discarding the possibility that the attB adenovirus genome was retained in a nuclear compartment deleterious for virus assembly. The present study may have substantive implications for helper dependent adenovirus technology since helper attB-adenovirus allows for preferential packaging of helper-dependent adenovirus genomes. PMID- 21611163 TI - ACE I/D gene polymorphism can't predict the steroid responsiveness in Asian children with idiopathic nephrotic syndrome: a meta-analysis. AB - BACKGROUND: The results from the published studies on the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and the treatment response to steroid in Asian children with idiopathic nephrotic syndrome (INS) is still conflicting. This meta-analysis was performed to evaluate the relation between ACE I/D gene polymorphism and treatment response to steroid in Asian children and to explore whether ACE D allele or DD genotype could become a predictive marker for steroid responsiveness. METHODOLOGY/PRINCIPAL FINDINGS: Association studies were identified from the databases of PubMed, Embase, Cochrane Library and CBM-disc (China Biological Medicine Database) as of September 1, 2010, and eligible investigations were synthesized using meta analysis method. Five investigations were identified for the analysis of association between ACE I/D gene polymorphism and steroid-resistant nephrotic syndrome (SRNS) risk in Asian children and seven studies were included to explore the relationship between ACE I/D gene polymorphism and steroid-sensitive nephrotic syndrome (SSNS) susceptibility. Five investigations were recruited to explore the difference of ACE I/D gene distribution between SRNS and SSNS. There was no a markedly association between D allele or DD genotype and SRNS susceptibility or SSNS risk, and the gene distribution differences of ACE between SRNS and SSNS were not statistically significant. II genotype might play a positive role against SRNS onset but not for SSNS (OR = 0.51, P = 0.02; OR = 0.95, P = 0.85; respectively), however, the result for the association of II genotype with SRNS risk was not stable. CONCLUSIONS/SIGNIFICANCE: Our results indicate that D allele or DD homozygous can't become a significant genetic molecular marker to predict the treatment response to steroid in Asian children with INS. PMID- 21611164 TI - Why um helps auditory word recognition: the temporal delay hypothesis. AB - Several studies suggest that speech understanding can sometimes benefit from the presence of filled pauses (uh, um, and the like), and that words following such filled pauses are recognised more quickly. Three experiments examined whether this is because filled pauses serve to delay the onset of upcoming words and these delays facilitate auditory word recognition, or whether the fillers themselves serve to signal upcoming delays in a way which informs listeners' reactions. Participants viewed pairs of images on a computer screen, and followed recorded instructions to press buttons corresponding to either an easy (unmanipulated, with a high-frequency name) or a difficult (visually blurred, low frequency) image. In all three experiments, participants were faster to respond to easy images. In 50% of trials in each experiment, the name of the image was directly preceded by a delay; in the remaining trials an equivalent delay was included earlier in the instruction. Participants were quicker to respond when a name was directly preceded by a delay, regardless of whether this delay was filled with a spoken um, was silent, or contained an artificial tone. This effect did not interact with the effect of image difficulty, nor did it change over the course of each experiment. Taken together, our consistent finding that delays of any kind help word recognition indicates that natural delays such as fillers need not be seen as 'signals' to explain the benefits they have to listeners' ability to recognise and respond to the words which follow them. PMID- 21611165 TI - Evaluation of jackknife and bootstrap for defining confidence intervals for pairwise agreement measures. AB - Several research fields frequently deal with the analysis of diverse classification results of the same entities. This should imply an objective detection of overlaps and divergences between the formed clusters. The congruence between classifications can be quantified by clustering agreement measures, including pairwise agreement measures. Several measures have been proposed and the importance of obtaining confidence intervals for the point estimate in the comparison of these measures has been highlighted. A broad range of methods can be used for the estimation of confidence intervals. However, evidence is lacking about what are the appropriate methods for the calculation of confidence intervals for most clustering agreement measures. Here we evaluate the resampling techniques of bootstrap and jackknife for the calculation of the confidence intervals for clustering agreement measures. Contrary to what has been shown for some statistics, simulations showed that the jackknife performs better than the bootstrap at accurately estimating confidence intervals for pairwise agreement measures, especially when the agreement between partitions is low. The coverage of the jackknife confidence interval is robust to changes in cluster number and cluster size distribution. PMID- 21611167 TI - The advantage of standing up to fight and the evolution of habitual bipedalism in hominins. AB - BACKGROUND: Many quadrupedal species stand bipedally on their hindlimbs to fight. This posture may provide a performance advantage by allowing the forelimbs to strike an opponent with the range of motion that is intrinsic to high-speed running, jumping, rapid braking and turning; the range of motion over which peak force and power can be produced. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that bipedal (i.e., orthograde) posture provides a performance advantage when striking with the forelimbs, I measured the force and energy produced when human subjects struck from "quadrupedal" (i.e., pronograde) and bipedal postures. Downward and upward directed striking energy was measured with a custom designed pendulum transducer. Side and forward strikes were measured with a punching bag instrumented with an accelerometer. When subjects struck downward from a bipedal posture the work was 43.70+/-12.59% (mean +/- S.E.) greater than when they struck from a quadrupedal posture. Similarly, 47.49+/ 17.95% more work was produced when subjects struck upward from a bipedal stance compared to a quadrupedal stance. Importantly, subjects did 229.69+/-44.19% more work in downward than upward directed strikes. During side and forward strikes the force impulses were 30.12+/-3.68 and 43.04+/-9.00% greater from a bipedal posture than a quadrupedal posture, respectively. CONCLUSIONS/SIGNIFICANCE: These results indicate that bipedal posture does provide a performance advantage for striking with the forelimbs. The mating systems of great apes are characterized by intense male-male competition in which conflict is resolved through force or the threat of force. Great apes often fight from bipedal posture, striking with both the fore- and hindlimbs. These observations, plus the findings of this study, suggest that sexual selection contributed to the evolution of habitual bipedalism in hominins. PMID- 21611166 TI - In silico survey of the mitochondrial protein uptake and maturation systems in the brown alga Ectocarpus siliculosus. AB - The acquisition of mitochondria was a key event in eukaryote evolution. The aim of this study was to identify homologues of the components of the mitochondrial protein import machinery in the brown alga Ectocarpus and to use this information to investigate the evolutionary history of this fundamental cellular process. Detailed searches were carried out both for components of the protein import system and for related peptidases. Comparative and phylogenetic analyses were used to investigate the evolution of mitochondrial proteins during eukaryote diversification. Key observations include phylogenetic evidence for very ancient origins for many protein import components (Tim21, Tim50, for example) and indications of differences between the outer membrane receptors that recognize the mitochondrial targeting signals, suggesting replacement, rearrangement and/or emergence of new components across the major eukaryotic lineages. Overall, the mitochondrial protein import components analysed in this study confirmed a high level of conservation during evolution, indicating that most are derived from very ancient, ancestral proteins. Several of the protein import components identified in Ectocarpus, such as Tim21, Tim50 and metaxin, have also been found in other stramenopiles and this study suggests an early origin during the evolution of the eukaryotes. PMID- 21611168 TI - Exploring or avoiding novel food resources? The novelty conflict in an invasive bird. AB - For an animal invading a novel region, the ability to develop new behaviors should facilitate the use of novel food resources and hence increase its survival in the new environment. However, the need to explore new resources may entail costs such as exposing the animal to unfamiliar predators. These two opposing forces result in an exploration-avoidance conflict, which can be expected to interfere with the acquisition of new resources. However, its consequences should be less dramatic in highly urbanized environments where new food opportunities are common and predation risk is low. We tested this hypothesis experimentally by presenting three foraging tasks to introduced common mynas (Acridotheres tristis) from environments with low and high urbanization levels from Australia. Individuals from the highly urbanized environments, where mynas are both more opportunistic when foraging and less fearful to predators, resolved a technical task faster than those from less urbanized environments. These differences did not reflect innovative 'personalities' and were not confounded by sex, morphology or motivational state. Rather, the principal factors underlying differences in mynas' problem-solving ability were neophobic-neophilic responses, which varied across habitats. Thus, mynas seem to modulate their problem-solving ability according to the benefits and costs of innovating in their particular habitat, which may help us understand the great success of the species in highly urbanized environments. PMID- 21611169 TI - alpha-Synuclein expression selectively affects tumorigenesis in mice modeling Parkinson's disease. AB - Alpha Synuclein (alpha-Syn) is a protein implicated in mechanisms of neuronal degeneration in Parkinson's disease (PD). alpha-Syn is primarily a neuronal protein, however, its expression is found in various tumors including ovarian, colorectal and melanoma tumors. It has been hypothesized that neurodegeneration may share common mechanisms with oncogenesis. We tested whether alpha-Syn expression affects tumorigenesis of three types of tumors. Specifically, B16 melanoma, E0771 mammary gland adenocarcinoma and D122 Lewis lung carcinoma. For this aim, we utilized transgenic mice expression the human A53T alpha-Syn form. We found that the in vivo growth of B16 and E0771 but not D122 was enhanced in the A53T alpha-Syn mice. The effect on tumorigenesis was not detected in age matched APP/PS1 mice, modeling Alzheimer's disease (AD), suggesting a specific effect for alpha-Syn-dependent neurodegeneration. Importantly, transgenic alpha Syn expression was detected within the three tumor types. We further show uptake of exogenously added, purified alpha-Syn, by the cultured tumor cells. In accord, with the affected tumorigenesis in the young A53T alpha-Syn mice, over-expression of alpha-Syn in cultured B16 and E0771 cells enhanced proliferation, however, had no effect on the proliferation of D122 cells. Based on these results, we suggest that certain forms of alpha-Syn may selectively accelerate cellular mechanisms leading to cancer. PMID- 21611170 TI - Re-structuring of marine communities exposed to environmental change: a global study on the interactive effects of species and functional richness. AB - Species richness is the most commonly used but controversial biodiversity metric in studies on aspects of community stability such as structural composition or productivity. The apparent ambiguity of theoretical and experimental findings may in part be due to experimental shortcomings and/or heterogeneity of scales and methods in earlier studies. This has led to an urgent call for improved and more realistic experiments. In a series of experiments replicated at a global scale we translocated several hundred marine hard bottom communities to new environments simulating a rapid but moderate environmental change. Subsequently, we measured their rate of compositional change (re-structuring) which in the great majority of cases represented a compositional convergence towards local communities. Re structuring is driven by mortality of community components (original species) and establishment of new species in the changed environmental context. The rate of this re-structuring was then related to various system properties. We show that availability of free substratum relates negatively while taxon richness relates positively to structural persistence (i.e., no or slow re-structuring). Thus, when faced with environmental change, taxon-rich communities retain their original composition longer than taxon-poor communities. The effect of taxon richness, however, interacts with another aspect of diversity, functional richness. Indeed, taxon richness relates positively to persistence in functionally depauperate communities, but not in functionally diverse communities. The interaction between taxonomic and functional diversity with regard to the behaviour of communities exposed to environmental stress may help understand some of the seemingly contrasting findings of past research. PMID- 21611171 TI - Decreased functional diversity and biological pest control in conventional compared to organic crop fields. AB - Organic farming is one of the most successful agri-environmental schemes, as humans benefit from high quality food, farmers from higher prices for their products and it often successfully protects biodiversity. However there is little knowledge if organic farming also increases ecosystem services like pest control. We assessed 30 triticale fields (15 organic vs. 15 conventional) and recorded vascular plants, pollinators, aphids and their predators. Further, five conventional fields which were treated with insecticides were compared with 10 non-treated conventional fields. Organic fields had five times higher plant species richness and about twenty times higher pollinator species richness compared to conventional fields. Abundance of pollinators was even more than one hundred times higher on organic fields. In contrast, the abundance of cereal aphids was five times lower in organic fields, while predator abundances were three times higher and predator-prey ratios twenty times higher in organic fields, indicating a significantly higher potential for biological pest control in organic fields. Insecticide treatment in conventional fields had only a short term effect on aphid densities while later in the season aphid abundances were even higher and predator abundances lower in treated compared to untreated conventional fields. Our data indicate that insecticide treatment kept aphid predators at low abundances throughout the season, thereby significantly reducing top-down control of aphid populations. Plant and pollinator species richness as well as predator abundances and predator-prey ratios were higher at field edges compared to field centres, highlighting the importance of field edges for ecosystem services. In conclusion organic farming increases biodiversity, including important functional groups like plants, pollinators and predators which enhance natural pest control. Preventative insecticide application in conventional fields has only short-term effects on aphid densities but long-term negative effects on biological pest control. Therefore conventional farmers should restrict insecticide applications to situations where thresholds for pest densities are reached. PMID- 21611172 TI - The population growth consequences of variation in individual heterozygosity. AB - Heterozygosity has been associated with components of fitness in numerous studies across a wide range of taxa. Because heterozygosity is associated with individual performance it is also expected to be associated with population dynamics. However, investigations into the association between heterozygosity and population dynamics have been rare because of difficulties in linking evolutionary and ecological processes. The choice of heterozygosity measure is a further issue confounding such studies as it can be biased by individual differences in the frequencies of the alleles studied, the number of alleles at each locus as well as the total number of loci typed. In this study, we first examine the differences between the principal metrics used to calculate heterozygosity using long-term data from a marked population of Soay sheep (Ovis aries). Next, by means of statistical transformation of the homozygosity weighted by loci index, we determine how heterozygosity contributes to population growth in Soay sheep by modelling individual contributions to population growth (p(t(i))) as a function of several covariates, including sex, weight and faecal egg count--a surrogate of parasitic nematode burden in the gut. We demonstrate that although heterozygosity is associated with some components of fitness, most notably adult male reproductive success, in general it is only weakly associated with population growth. PMID- 21611173 TI - Predicting impaired extinction of traumatic memory and elevated startle. AB - BACKGROUND: Emotionally traumatic experiences can lead to debilitating anxiety disorders, such as phobias and Post-Traumatic Stress Disorder (PTSD). Exposure to such experiences, however, is not sufficient to induce pathology, as only up to one quarter of people exposed to such events develop PTSD. These statistics, combined with findings that smaller hippocampal size prior to the trauma is associated with higher risk of developing PTSD, suggest that there are pre disposing factors for such pathology. Because prospective studies in humans are limited and costly, investigating such pre-dispositions, and thus advancing understanding of the genesis of such pathologies, requires the use of animal models where predispositions are identified before the emotional trauma. Most existing animal models are retrospective: they classify subjects as those with or without a PTSD-like phenotype long after experiencing a traumatic event. Attempts to create prospective animal models have been largely unsuccessful. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that individual predispositions to a PTSD-like phenotype, consisting of impaired rate and magnitude of extinction of an emotionally traumatic event coupled with long-lasting elevation of acoustic startle responses, can be revealed following exposure to a mild stressor, but before experiencing emotional trauma. We compare, in rats, the utility of several classification criteria and report that a combination of criteria based on acoustic startle responses and behavior in an anxiogenic environment is a reliable predictor of a PTSD-like phenotype. CONCLUSIONS/SIGNIFICANCE: There are individual predispositions to developing impaired extinction and elevated acoustic startle that can be identified after exposure to a mildly stressful event, which by itself does not induce such a behavioral phenotype. The model presented here is a valuable tool for studying the etiology and pathophysiology of anxiety disorders and provides a platform for testing behavioral and pharmacological interventions that can reduce the probability of developing pathologic behaviors associated with such disorders. PMID- 21611174 TI - Wnt3a induces myofibroblast differentiation by upregulating TGF-beta signaling through SMAD2 in a beta-catenin-dependent manner. AB - Growing evidence suggests the Wnt family of secreted glycoproteins and their associated signaling pathways, linked to development, are recapitulated during wound repair and regeneration events. However, the role of the Wnt pathway in such settings remains unclear. In the current study, we treated mouse fibroblasts with 250 ng/mL of recombinant Wnt3a for 72 hours and examined its affect on cell morphology and function. Wnt3a induced a spindle-like morphology in fibroblasts characterized by the increased formation of stress fibres. Wnt3a decreased the proliferation of fibroblasts, but significantly increased cell migration as well as fibroblast-mediated contraction of a collagen lattice. Wnt3a significantly increased the expression of TGF-beta and its associated signaling through SMAD2. Consistent with this, we observed significantly increased smooth muscle alpha actin expression and incorporation of this contractile protein into stress fibres following Wnt3a treatment. Knockdown of beta-catenin using siRNA reversed the Wnt3a-induced smooth muscle alpha-actin expression, suggesting these changes were dependent on canonical Wnt signaling through beta-catenin. Neutralization of TGF beta with a blocking antibody significantly inhibited the Wnt3a-induced smooth muscle alpha-actin expression, indicating these changes were dependent on the increased TGF-beta signaling. Collectively, this data strongly suggests Wnt3a promotes the formation of a myofibroblast-like phenotype in cultured fibroblasts, in part, by upregulating TGF-beta signaling through SMAD2 in a beta-catenin dependent mechanism. As myofibroblasts are critical regulators of wound healing responses, these findings may have important implications for our understanding of normal and aberrant injury and repair events. PMID- 21611175 TI - Paracoccidioides brasilinsis-induced migration of dendritic cells and subsequent T-cell activation in the lung-draining lymph nodes. AB - Paracoccidioidomycosis is a mycotic disease caused by a dimorphic fungus, Paracoccidioides brasiliensis (Pb), that starts with inhalation of the fungus; thus, lung cells such as DC are part of the first line of defense against this microorganism. Migration of DC to the lymph nodes is the first step in initiating T cell responses. The mechanisms involved in resistance to Pb infection are poorly understood, but it is likely that DC play a pivotal role in the induction of effector T cells that control Pb infection. In this study, we showed that after Pb Infection, an important modification of lung DC receptor expression occurred. We observed an increased expression of CCR7 and CD103 on lung DC after infection, as well as MHC-II. After Pb infection, bone marrow-derived DC as well lung DC, migrate to lymph nodes. Migration of lung DC could represent an important mechanism of pathogenesis during PCM infection. In resume our data showed that Pb induced DC migration. Furthermore, we demonstrated that bone marrow-derived DC stimulated by Pb migrate to the lymph nodes and activate a T helper (Th) response. To the best of our knowledge, this is the first reported data showing that Pb induces migration of DC and activate a T helper (Th) response. PMID- 21611176 TI - Validation of a cost-efficient multi-purpose SNP panel for disease based research. AB - BACKGROUND: Here we present convergent methodologies using theoretical calculations, empirical assessment on in-house and publicly available datasets as well as in silico simulations, that validate a panel of SNPs for a variety of necessary tasks in human genetics disease research before resources are committed to larger-scale genotyping studies on those samples. While large-scale well funded human genetic studies routinely have up to a million SNP genotypes, samples in a human genetics laboratory that are not yet part of such studies may be productively utilized in pilot projects or as part of targeted follow-up work though such smaller scale applications require at least some genome-wide genotype data for quality control purposes such as DNA "barcoding" to detect swaps or contamination issues, determining familial relationships between samples and correcting biases due to population effects such as population stratification in pilot studies. PRINCIPAL FINDINGS: Empirical performance in classification of relative types for any two given DNA samples (e.g., full siblings, parental, etc) indicated that for outbred populations the panel performs sufficiently to classify relationship in extended families and therefore also for smaller structures such as trios and for twin zygosity testing. Additionally, familial relationships do not significantly diminish the (mean match) probability of sharing SNP genotypes in pedigrees, further indicating the uniqueness of the "barcode." Simulation using these SNPs for an African American case-control disease association study demonstrated that population stratification, even in complex admixed samples, can be adequately corrected under a range of disease models using the SNP panel. CONCLUSION: The panel has been validated for use in a variety of human disease genetics research tasks including sample barcoding, relationship verification, population substructure detection and statistical correction. Given the ease of genotyping our specific assay contained herein, this panel represents a useful and economical panel for human geneticists. PMID- 21611177 TI - Structural correlates of taste and smell loss in encephalitis disseminata. AB - BACKGROUND: Olfactory dysfunction in MS patients is reported in the literature. MRI of the olfactory bulb (OB) is discussed as a promising new testing method for measuring olfactory function (OF). Aim of this study was to explore reasons for and optimize the detection of olfactory dysfunction in MS patients with MRI. MATERIALS AND METHODS: OB and olfactory brain volume was assessed within 34 MS patients by manual segmentation. Olfactory function was tested using the Threshold-Discrimination-Identification-Test (TDI), gustatory function was tested using Taste Strips (TST). RESULTS: 41% of the MS patients displayed olfactory dysfunction (8% of the control group), 16% displayed gustatory dysfunction (5% of the control group). There was a correlation between the OB volume and the number and volume of MS lesions in the olfactory brain. Olfactory brain volume correlated with the volume of lesions in the olfactory brain and the EDSS score. The TST score correlated with the number and volume of lesions in the olfactory brain. CONCLUSION: The correlation between a higher number and volume of MS lesions with a decreased OB and olfactory brain volume could help to explain olfactory dysfunction. PMID- 21611178 TI - Toward a DNA taxonomy of Alpine Rhithrogena (Ephemeroptera: Heptageniidae) using a mixed Yule-coalescent analysis of mitochondrial and nuclear DNA. AB - Aquatic larvae of many Rhithrogena mayflies (Ephemeroptera) inhabit sensitive Alpine environments. A number of species are on the IUCN Red List and many recognized species have restricted distributions and are of conservation interest. Despite their ecological and conservation importance, ambiguous morphological differences among closely related species suggest that the current taxonomy may not accurately reflect the evolutionary diversity of the group. Here we examined the species status of nearly 50% of European Rhithrogena diversity using a widespread sampling scheme of Alpine species that included 22 type localities, general mixed Yule-coalescent (GMYC) model analysis of one standard mtDNA marker and one newly developed nDNA marker, and morphological identification where possible. Using sequences from 533 individuals from 144 sampling localities, we observed significant clustering of the mitochondrial (cox1) marker into 31 GMYC species. Twenty-one of these could be identified based on the presence of topotypes (expertly identified specimens from the species' type locality) or unambiguous morphology. These results strongly suggest the presence of both cryptic diversity and taxonomic oversplitting in Rhithrogena. Significant clustering was not detected with protein-coding nuclear PEPCK, although nine GMYC species were congruent with well supported terminal clusters of nDNA. Lack of greater congruence in the two data sets may be the result of incomplete sorting of ancestral polymorphism. Bayesian phylogenetic analyses of both gene regions recovered four of the six recognized Rhithrogena species groups in our samples as monophyletic. Future development of more nuclear markers would facilitate multi-locus analysis of unresolved, closely related species pairs. The DNA taxonomy developed here lays the groundwork for a future revision of the important but cryptic Rhithrogena genus in Europe. PMID- 21611180 TI - An experimental test of the information model for negotiation of biparental care. AB - BACKGROUND: Theoretical modelling of biparental care suggests that it can be a stable strategy if parents partially compensate for changes in behaviour by their partners. In empirical studies, however, parents occasionally match rather than compensate for the actions of their partners. The recently proposed "information model" adds to the earlier theory by factoring in information on brood value and/or need into parental decision-making. This leads to a variety of predicted parental responses following a change in partner work-rate depending on the information available to parents. METHODOLOGY/PRINCIPAL FINDINGS: We experimentally test predictions of the information model using a population of long-tailed tits. We show that parental information on brood need varies systematically through the nestling period and use this variation to predict parental responses to an experimental increase in partner work-rate via playback of extra chick begging calls. When parental information is relatively high, partial compensation is predicted, whereas when parental information is low, a matching response is predicted. CONCLUSIONS/SIGNIFICANCE: We find that although some responses are consistent with predictions, parents match a change in their partner's work-rate more often than expected and we discuss possible explanations for our findings. PMID- 21611179 TI - Plasma and liver lipidomics response to an intervention of rimonabant in ApoE*3Leiden.CETP transgenic mice. AB - BACKGROUND: Lipids are known to play crucial roles in the development of life style related risk factors such as obesity, dyslipoproteinemia, hypertension and diabetes. The first selective cannabinoid-1 receptor blocker rimonabant, an anorectic anti-obesity drug, was frequently used in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m(2) with associated risk factors such as type II diabetes and dyslipidaemia in the past. Less is known about the impact of this drug on the regulation of lipid metabolism in plasma and liver in the early stage of obesity. METHODOLOGY/PRINCIPAL FINDINGS: We designed a four-week parallel controlled intervention on apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) transgenic mice with mild overweight and hypercholesterolemia. A liquid chromatography-linear ion trap-Fourier transform ion cyclotron resonance-mass spectrometric approach was employed to investigate plasma and liver lipid responses to the rimonabant intervention. Rimonabant was found to induce a significant body weight loss (9.4%, p<0.05) and a significant plasma total cholesterol reduction (24%, p<0.05). Six plasma and three liver lipids in ApoE*3Leiden.CETP transgenic mice were detected to most significantly respond to rimonabant treatment. Distinct lipid patterns between the mice were observed for both plasma and liver samples in rimonabant treatment vs. non-treated controls. This study successfully applied, for the first time, systems biology based lipidomics approaches to evaluate treatment effects of rimonabant in the early stage of obesity. CONCLUSION: The effects of rimonabant on lipid metabolism and body weight reduction in the early stage obesity were shown to be moderate in ApoE*3Leiden.CETP mice on high-fat diet. PMID- 21611181 TI - A nonparametric mean-variance smoothing method to assess Arabidopsis cold stress transcriptional regulator CBF2 overexpression microarray data. AB - Microarray is a powerful tool for genome-wide gene expression analysis. In microarray expression data, often mean and variance have certain relationships. We present a non-parametric mean-variance smoothing method (NPMVS) to analyze differentially expressed genes. In this method, a nonlinear smoothing curve is fitted to estimate the relationship between mean and variance. Inference is then made upon shrinkage estimation of posterior means assuming variances are known. Different methods have been applied to simulated datasets, in which a variety of mean and variance relationships were imposed. The simulation study showed that NPMVS outperformed the other two popular shrinkage estimation methods in some mean-variance relationships; and NPMVS was competitive with the two methods in other relationships. A real biological dataset, in which a cold stress transcription factor gene, CBF2, was overexpressed, has also been analyzed with the three methods. Gene ontology and cis-element analysis showed that NPMVS identified more cold and stress responsive genes than the other two methods did. The good performance of NPMVS is mainly due to its shrinkage estimation for both means and variances. In addition, NPMVS exploits a non-parametric regression between mean and variance, instead of assuming a specific parametric relationship between mean and variance. The source code written in R is available from the authors on request. PMID- 21611182 TI - miR-132 mediates the integration of newborn neurons into the adult dentate gyrus. AB - Neuronal activity enhances the elaboration of newborn neurons as they integrate into the synaptic circuitry of the adult brain. The role microRNAs play in the transduction of neuronal activity into growth and synapse formation is largely unknown. MicroRNAs can influence the expression of hundreds of genes and thus could regulate gene assemblies during processes like activity-dependent integration. Here, we developed viral-based methods for the in vivo detection and manipulation of the activity-dependent microRNA, miR-132, in the mouse hippocampus. We find, using lentiviral and retroviral reporters of miR-132 activity, that miR-132 is expressed at the right place and right time to influence the integration of newborn neurons. Retroviral knockdown of miR-132 using a specific 'sponge' containing multiple target sequences impaired the integration of newborn neurons into the excitatory synaptic circuitry of the adult brain. To assess potential miR-132 targets, we used a whole-genome microarray in PC12 cells, which have been used as a model of neuronal differentiation. miR-132 knockdown in PC12 cells resulted in the increased expression of hundreds of genes. Functional grouping indicated that genes involved in inflammatory/immune signaling were the most enriched class of genes induced by miR-132 knockdown. The correlation of miR-132 knockdown to increased proinflammatory molecular expression may indicate a mechanistic link whereby miR 132 functions as an endogenous mediator of activity-dependent integration in vivo. PMID- 21611183 TI - Glycyrrhizin exerts antioxidative effects in H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory gene expression. AB - Glycyrrhizin is known to exert antiviral and anti-inflammatory effects. Here, the effects of an approved parenteral glycyrrhizin preparation (Stronger Neo Minophafen C) were investigated on highly pathogenic influenza A H5N1 virus replication, H5N1-induced apoptosis, and H5N1-induced pro-inflammatory responses in lung epithelial (A549) cells. Therapeutic glycyrrhizin concentrations substantially inhibited H5N1-induced expression of the pro-inflammatory molecules CXCL10, interleukin 6, CCL2, and CCL5 (effective glycyrrhizin concentrations 25 to 50 ug/ml) but interfered with H5N1 replication and H5N1-induced apoptosis to a lesser extent (effective glycyrrhizin concentrations 100 ug/ml or higher). Glycyrrhizin also diminished monocyte migration towards supernatants of H5N1 infected A549 cells. The mechanism by which glycyrrhizin interferes with H5N1 replication and H5N1-induced pro-inflammatory gene expression includes inhibition of H5N1-induced formation of reactive oxygen species and (in turn) reduced activation of NFkappaB, JNK, and p38, redox-sensitive signalling events known to be relevant for influenza A virus replication. Therefore, glycyrrhizin may complement the arsenal of potential drugs for the treatment of H5N1 disease. PMID- 21611184 TI - The appearance and modulation of osteocyte marker expression during calcification of vascular smooth muscle cells. AB - BACKGROUND: Vascular calcification is an indicator of elevated cardiovascular risk. Vascular smooth muscle cells (VSMCs), the predominant cell type involved in medial vascular calcification, can undergo phenotypic transition to both osteoblastic and chondrocytic cells within a calcifying environment. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, using in vitro VSMC calcification studies in conjunction with ex vivo analyses of a mouse model of medial calcification, we show that vascular calcification is also associated with the expression of osteocyte phenotype markers. As controls, the terminal differentiation of murine calvarial osteoblasts into osteocytes was induced in vitro in the presence of calcifying medium (containing beta-glycerophosphate and ascorbic acid), as determined by increased expression of the osteocyte markers DMP-1, E11 and sclerostin. Culture of murine aortic VSMCs under identical conditions confirmed that the calcification of these cells can also be induced in similar calcifying medium. Calcified VSMCs had increased alkaline phosphatase activity and PiT-1 expression, which are recognized markers of vascular calcification. Expression of DMP-1, E11 and sclerostin was up-regulated during VSMC calcification in vitro. Increased protein expression of E11, an early osteocyte marker, and sclerostin, expressed by more mature osteocytes was also observed in the calcified media of Enpp1(-/-) mouse aortic tissue. CONCLUSIONS/SIGNIFICANCE: This study has demonstrated the up-regulation of key osteocytic molecules during the vascular calcification process. A fuller understanding of the functional role of osteocyte formation and specifically sclerostin and E11 expression in the vascular calcification process may identify novel potential therapeutic strategies for clinical intervention. PMID- 21611185 TI - Comparison of sequence reads obtained from three next-generation sequencing platforms. AB - Next-generation sequencing technologies enable the rapid cost-effective production of sequence data. To evaluate the performance of these sequencing technologies, investigation of the quality of sequence reads obtained from these methods is important. In this study, we analyzed the quality of sequence reads and SNP detection performance using three commercially available next-generation sequencers, i.e., Roche Genome Sequencer FLX System (FLX), Illumina Genome Analyzer (GA), and Applied Biosystems SOLiD system (SOLiD). A common genomic DNA sample obtained from Escherichia coli strain DH1 was applied to these sequencers. The obtained sequence reads were aligned to the complete genome sequence of E. coli DH1, to evaluate the accuracy and sequence bias of these sequence methods. We found that the fraction of "junk" data, which could not be aligned to the reference genome, was largest in the data set of SOLiD, in which about half of reads could not be aligned. Among data sets after alignment to the reference, sequence accuracy was poorest in GA data sets, suggesting relatively low fidelity of the elongation reaction in the GA method. Furthermore, by aligning the sequence reads to the E. coli strain W3110, we screened sequence differences between two E. coli strains using data sets of three different next-generation platforms. The results revealed that the detected sequence differences were similar among these three methods, while the sequence coverage required for the detection was significantly small in the FLX data set. These results provided valuable information on the quality of short sequence reads and the performance of SNP detection in three next-generation sequencing platforms. PMID- 21611186 TI - AAV2-mediated subretinal gene transfer of hIFN-alpha attenuates experimental autoimmune uveoretinitis in mice. AB - BACKGROUND: Recent reports show that gene therapy may provide a long-term, safe and effective intervention for human diseases. In this study, we investigated the effectiveness of adeno-associated virus 2 (AAV2) based human interferon-alpha (hIFN-alpha) gene therapy in experimental autoimmune uveoretinitis (EAU), a classic model for human uveitis. METHODOLOGY/PRINCIPAL FINDINGS: An AAV2 vector harboring the hIFN-alpha gene (AAV2.hIFN-alpha) was subretinally injected into B10RIII mice at two doses (1.5*10(6) vg, 1.5*10(8) vg). AAV2 vector encoding green fluorescent protein (AAV2.GFP) was used as a control (5*10(8) vg). The expression of hIFN-alpha in homogenized eyes and serum was detected by ELISA three weeks after injection. The biodistribution of vector DNA in the injected eyes, contralateral eyes and distant organs was determined by PCR. EAU was induced by immunization with IRBP(161-180) three weeks following vector injections, and evaluated clinically and pathologically. IRBP-specific proliferation and IL-17 expression of lymphocytes from the spleen and lymph nodes were assayed to test the influence of the subretinal delivery of AAV2.hIFN-alpha on the systemic immune response. hIFN-alpha was effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2.hIFN alpha vector. DNA of AAV2.GFP was observed only in the injected eyes, but not in the distant organs or contralateral eyes. Subretinal injection of both doses significantly attenuated EAU activity clinically and histologically. For the lower dose, there was no difference concerning lymphocyte proliferation and IL-17 production among the AAV2.hIFN-alpha, AAV2.GFP and PBS injected mice. However, the higher dose of AAV2.hIFN-alpha significantly suppressed lymphocyte proliferation and IL-17 production. CONCLUSIONS/SIGNIFICANCE: Subretinal delivery of AAV2.hIFN-alpha lead to an effective expression within the eye for at least three months and significantly attenuated EAU activity. AAV2.hIFN-alpha was shown to inhibit the systemic IRBP-specific immune response. PMID- 21611187 TI - Genomic characterization of Haemophilus parasuis SH0165, a highly virulent strain of serovar 5 prevalent in China. AB - Haemophilus parasuis can be either a commensal bacterium of the porcine respiratory tract or an opportunistic pathogen causing Glasser's disease, a severe systemic disease that has led to significant economical losses in the pig industry worldwide. We determined the complete genomic sequence of H. parasuis SH0165, a highly virulent strain of serovar 5, which was isolated from a hog pen in North China. The single circular chromosome was 2,269,156 base pairs in length and contained 2,031 protein-coding genes. Together with the full spectrum of genes detected by the analysis of metabolic pathways, we confirmed that H. parasuis generates ATP via both fermentation and respiration, and possesses an intact TCA cycle for anabolism. In addition to possessing the complete pathway essential for the biosynthesis of heme, this pathogen was also found to be well equipped with different iron acquisition systems, such as the TonB system and ABC type transport complexes, to overcome iron limitation during infection and persistence. We identified a number of genes encoding potential virulence factors, such as type IV fimbriae and surface polysaccharides. Analysis of the genome confirmed that H. parasuis is naturally competent, as genes related to DNA uptake are present. A nine-mer DNA uptake signal sequence (ACAAGCGGT), identical to that found in Actinobacillus pleuropneumoniae and Mannheimia haemolytica, followed by similar downstream motifs, was identified in the SH0165 genome. Genomic and phylogenetic comparisons with other Pasteurellaceae species further indicated that H. parasuis was closely related to another swine pathogenic bacteria A. pleuropneumoniae. The comprehensive genetic analysis presented here provides a foundation for future research on the metabolism, natural competence and virulence of H. parasuis. PMID- 21611188 TI - Transcranial magnetic stimulation reveals attentional feedback to area V1 during serial visual search. AB - Visual search tasks have been used to understand how, where and when attention influences visual processing. Current theories suggest the involvement of a high level "saliency map" that selects a candidate location to focus attentional resources. For a parallel (or "pop-out") task, the first chosen location is systematically the target, but for a serial (or "difficult") task, the system may cycle on a few distractors before finally focusing on the target. This implies that attentional effects upon early visual areas, involving feedback from higher areas, should be visible at longer latencies during serial search. A previous study from Juan & Walsh (2003) had used Transcranial Magnetic Stimulation (TMS) to support this conclusion; however, only a few post-stimulus delays were compared, and no control TMS location was used. Here we applied TMS double-pulses (sub-threshold) to induce a transient inhibition of area V1 at every post stimulus delay between 100 ms and 500 ms (50 ms steps). The search array was presented either at the location affected by the TMS pulses (previously identified by applying several pulses at supra-threshold intensity to induce phosphene perception), or in the opposite hemifield, which served as a retinotopically-defined control location. Two search tasks were used: a parallel (+ among Ls) and a serial one (T among Ls). TMS specifically impaired the serial, but not the parallel search. We highlight an involvement of V1 in serial search 300 ms after the onset; conversely, V1 did not contribute to parallel search at delays beyond 100 ms. This study supports the idea that serial search differs from parallel search by the presence of additional cycles of a select-and-focus iterative loop between V1 and higher-level areas. PMID- 21611189 TI - Alcohol use disorders (AUD) among tuberculosis patients: a study from Chennai, South India. AB - BACKGROUND: Alcohol Use Disorders (AUDs) among tuberculosis (TB) patients are associated with nonadherence and poor treatment outcomes. Studies from Tuberculosis Research Centre (TRC), Chennai have reported that alcoholism has been one of the major reasons for default and mortality in under the DOTS programme in South India. Hence, it is planned to conduct a study to estimate prevalence of alcohol use and AUDs among TB patients attending the corporation health centres in Chennai, India. METHODOLOGY: This is a cross-sectional cohort study covering 10 corporation zones at Chennai and it included situational assessment followed by screening of TB patients by a WHO developed Alcohol Use Disorders Identification Test AUDIT scale. Four zones were randomly selected and all TB patients treated during July to September 2009 were screened with AUDIT scale for alcohol consumption. RESULTS: Out of 490 patients, 66% were males, 66% were 35 years and above, 57% were married, 58% were from the low monthly income group of 8. Age (>35 years), education (less educated), income (90%) with long-lived and functional human T and B cells. Unlike previous humanized mouse models reported in the literature and our control mice, the HLA DR4 expressing mice reconstituted serum levels (natural antibodies) of human IgM, IgG (all four subclasses), IgA, and IgE comparable to humans, and elicited high titers of specific human IgG antibodies upon tetanus toxoid vaccination. CONCLUSIONS: Our study demonstrates the critical role of HLA class II molecules for development of functional human T cells able to support immunoglobulin class switching and efficiently respond to vaccination. PMID- 21611198 TI - High resolution spectral domain optical coherence tomography (SD-OCT) in multiple sclerosis: the first follow up study over two years. AB - BACKGROUND: "Non-invasive, faster and less expensive than MRI" and "the eye is a window to the brain" are recent slogans promoting optical coherence tomography (OCT) as a new surrogate marker in multiple sclerosis (MS). Indeed, OCT allows for the first time a non-invasive visualization of axons of the central nervous system (CNS). Reduction of retina nerve fibre layer (RNFL) thickness was suggested to correlate with disease activity and duration. However, several issues are unclear: Do a few million axons, which build up both optic nerves, really resemble billions of CNS neurons? Does global CNS damage really result in global RNFL reduction? And if so, does global RNFL reduction really exist in all MS patients, and follow a slowly but steadily ongoing pattern? How can these (hypothesized) subtle global RNFL changes be reliably measured and separated from the rather gross RNFL changes caused by optic neuritis? Before generally being accepted, this interpretation needs further critical and objective validation. METHODOLOGY: We prospectively studied 37 MS patients with relapsing remitting (n = 27) and secondary progressive (n = 10) course on two occasions with a median interval of 22.4+/-0.5 months [range 19-27]. We used the high resolution spectral domain (SD-)OCT with the Spectralis 3.5 mm circle scan protocol with locked reference images and eye tracking mode. Patients with an attack of optic neuritis within 12 months prior to the onset of the study were excluded. PRINCIPAL FINDINGS: Although the disease was highly active over the observation period in more than half of the included relapsing remitting MS patients (19 patients/32 relapses) and the initial RNFL pattern showed a broad range, from normal to markedly reduced thickness, no significant changes between baseline and follow-up examinations could be detected. CONCLUSIONS: These results show that caution is required when using OCT for monitoring disease activity and global axonal injury in MS. PMID- 21611199 TI - Elevational patterns of species richness, range and body size for spiny frogs. AB - Quantifying spatial patterns of species richness is a core problem in biodiversity theory. Spiny frogs of the subfamily Painae (Anura: Dicroglossidae) are widespread, but endemic to Asia. Using spiny frog distribution and body size data, and a digital elevation model data set we explored altitudinal patterns of spiny frog richness and quantified the effect of area on the richness pattern over a large altitudinal gradient from 0-5000 m a.s.l. We also tested two hypotheses: (i) the Rapoport's altitudinal effect is valid for the Painae, and (ii) Bergmann's clines are present in spiny frogs. The species richness of Painae across four different altitudinal band widths (100 m, 200 m, 300 m and 400 m) all showed hump-shaped patterns along altitudinal gradient. The altitudinal changes in species richness of the Paini and Quasipaini tribes further confirmed this finding, while the peak of Quasipaini species richness occurred at lower elevations than the maxima of Paini. The area did not explain a significant amount of variation in total, nor Paini species richness, but it did explain variation in Quasipaini. Five distinct groups across altitudinal gradient were found. Species altitudinal ranges did not expand with an increase in the midpoints of altitudinal ranges. A significant negative correlation between body size and elevation was exhibited. Our findings demonstrate that Rapoport's altitudinal rule is not a compulsory attribute of spiny frogs and also suggest that Bergmann's rule is not generally applicable to amphibians. The study highlights a need to explore the underlying mechanisms of species richness patterns, particularly for amphibians in macroecology. PMID- 21611200 TI - Identification of autoantibodies against TRPM1 in patients with paraneoplastic retinopathy associated with ON bipolar cell dysfunction. AB - BACKGROUND: Paraneoplastic retinopathy (PR), including cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), is a progressive retinal disease caused by antibodies generated against neoplasms not associated with the eye. While several autoantibodies against retinal antigens have been identified, there has been no known autoantibody reacting specifically against bipolar cell antigens in the sera of patients with PR. We previously reported that the transient receptor potential cation channel, subfamily M, member 1 (TRPM1) is specifically expressed in retinal ON bipolar cells and functions as a component of ON bipolar cell transduction channels. In addition, this and other groups have reported that human TRPM1 mutations are associated with the complete form of congenital stationary night blindness. The purpose of the current study is to investigate whether there are autoantibodies against TRPM1 in the sera of PR patients exhibiting ON bipolar cell dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: We performed Western blot analysis to identify an autoantibody against TRPM1 in the serum of a patient with lung CAR. The electroretinograms of this patient showed a severely reduced ON response with normal OFF response, indicating that the defect is in the signal transmission between photoreceptors and ON bipolar cells. We also investigated the sera of 26 patients with MAR for autoantibodies against TRPM1 because MAR patients are known to exhibit retinal ON bipolar cell dysfunction. Two of the patients were found to have autoantibodies against TRPM1 in their sera. CONCLUSION/SIGNIFICANCE: Our study reveals TRPM1 to be one of the autoantigens targeted by autoantibodies in at least some patients with CAR or MAR associated with retinal ON bipolar cell dysfunction. PMID- 21611201 TI - An shRNA-based screen of splicing regulators identifies SFRS3 as a negative regulator of IL-1beta secretion. AB - The generation of diversity and plasticity of transcriptional programs are key components of effective vertebrate immune responses. The role of Alternative Splicing has been recognized, but it is underappreciated and poorly understood as a critical mechanism for the regulation and fine-tuning of physiological immune responses. Here we report the generation of loss-of-function phenotypes for a large collection of genes known or predicted to be involved in the splicing reaction and the identification of 19 novel regulators of IL-1beta secretion in response to E. coli challenge of THP-1 cells. Twelve of these genes are required for IL-1beta secretion, while seven are negative regulators of this process. Silencing of SFRS3 increased IL-1beta secretion due to elevation of IL-1beta and caspase-1 mRNA in addition to active caspase-1 levels. This study points to the relevance of splicing in the regulation of auto-inflammatory diseases. PMID- 21611202 TI - Plasma circulating nucleic acids levels increase according to the morbidity of Plasmodium vivax malaria. AB - BACKGROUND: Given the increasing evidence of Plasmodium vivax infections associated with severe and fatal disease, the identification of sensitive and reliable markers for vivax severity is crucial to improve patient care. Circulating nucleic acids (CNAs) have been increasingly recognized as powerful diagnostic and prognostic tools for various inflammatory diseases and tumors as their plasma concentrations increase according to malignancy. Given the marked inflammatory status of P. vivax infection, we investigated here the usefulness of CNAs as biomarkers for malaria morbidity. METHODS AND FINDINGS: CNAs levels in plasma from twenty-one acute P. vivax malaria patients from the Brazilian Amazon and 14 malaria non-exposed healthy donors were quantified by two different methodologies: amplification of the human telomerase reverse transcriptase (hTERT) genomic sequence by quantitative real time PCR (qPCR), and the fluorometric dsDNA quantification by Pico Green. CNAs levels were significantly increased in plasma from P. vivax patients as compared to healthy donors (p<0.0001). Importantly, plasma CNAs levels were strongly associated with vivax morbidity (p<0.0001), including a drop in platelet counts (p = 0.0021). These findings were further sustained when we assessed CNAS levels in plasma samples from 14 additional P. vivax patients of a different endemic area in Brazil, in which CNAS levels strongly correlated with thrombocytopenia (p = 0.0072). We further show that plasma CNAs levels decrease and reach physiological levels after antimalarial treatment. Although we found both host and parasite specific genomic sequences circulating in plasma, only host CNAs clearly reflected the clinical spectrum of P. vivax malaria. CONCLUSIONS: Here, we provide the first evidence of increased plasma CNAs levels in malaria patients and reveal their potential as sensitive biomarkers for vivax malaria morbidity. PMID- 21611203 TI - IGF1R signaling in Ewing sarcoma is shaped by clathrin-/caveolin-dependent endocytosis. AB - Receptor endocytosis is critical for cell signaling. IGF1R mediates an autocrine loop that is de-regulated in Ewing Sarcoma (ES) cells. Here we study the impact of IGF1R internalization, mediated by clathrin and caveolin-1 (CAV1), in ES signaling. We used clathrin and CAV1-siRNA to interfere in clathrin- and caveolin dependent endocytosis. Chlorpromazine (CPMZ) and methyl-beta-cyclo-dextrin (MCD) were also used in order to inhibit clathrin- and caveolin-dependent endocytosis, respectively. We analyzed IGF1R internalization and co-localization with clathrin and CAV1 upon ligand binding, as well as the status of the IGF1R pathway, cellular proliferation, and the apoptosis of interfered and inhibited ES cells. We performed a high-throughput tyrosine kinase phosphorylation assay to analyze the effects of combining the IGF1R tyrosine kinase inhibitor AEW541 (AEW) with CPMZ or MCD on the intracellular phospho-proteome. We observed that IGF1R is internalized upon ligand binding in ES cells and that this process is dependent on clathrin or CAV1. The blockage of receptor internalization inhibited AKT and MAPK phosphorylation, reducing the proliferative rate of ES cells and increasing the levels of apoptosis. Combination of AEW with CPMZ or MCD largely enhanced these effects. CAV1 and clathrin endocytosis controls IGF1R internalization and signaling and has a profound impact on ES IGF1R-promoted survival signaling. We propose the combination of tyrosine-kinase inhibitors with endocytosis inhibitors as a new therapeutic approach to achieve a stronger degree of receptor inhibition in this, or other neoplasms dependent on IGF1R signaling. PMID- 21611204 TI - Targeted skipping of human dystrophin exons in transgenic mouse model systemically for antisense drug development. AB - Antisense therapy has recently been demonstrated with great potential for targeted exon skipping and restoration of dystrophin production in cultured muscle cells and in muscles of Duchenne Muscular Dystrophy (DMD) patients. Therapeutic values of exon skipping critically depend on efficacy of the drugs, antisense oligomers (AOs). However, no animal model has been established to test AO targeting human dystrophin exon in vivo systemically. In this study, we applied Vivo-Morpholino to the hDMD mouse, a transgenic model carrying the full length human dystrophin gene, and achieved for the first time more than 70% efficiency of targeted human dystrophin exon skipping in vivo systemically. We also established a GFP-reporter myoblast culture to screen AOs targeting human dystrophin exon 50. Antisense efficiency for most AOs is consistent between the reporter cells, human myoblasts and in the hDMD mice in vivo. However, variation in efficiency was also clearly observed. A combination of in vitro cell culture and a Vivo-Morpholino based evaluation in vivo systemically in the hDMD mice therefore may represent a prudent approach for selecting AO drug and to meet the regulatory requirement. PMID- 21611206 TI - Original Papers.: DIABETES INSIPIDUS AS A SEQUEL TO EPIDEMIC ENCEPHALITIS: A STUDY OF THE WATER AND CHLORIDE BALANCE IN TWO CASES. PMID- 21611208 TI - Short Notes and Clinical Cases.:DISPLACEMENT OF THE PINEAL GLAND IN HEAD INJURY: REPORT OF A CASE. PMID- 21611205 TI - Adenoma formation following limited ablation of p120-catenin in the mouse intestine. AB - p120 loss destabilizes E-cadherin and could therefore result in tumor and/or metastasis-promoting activities similar to those caused by E-cadherin downregulation. Previously, we reported that p120 is essential in the intestine for barrier function, epithelial homeostasis and survival. Conditional p120 ablation in the mouse intestine induced severe inflammatory bowel disease, but long-term cancer-related studies were impossible because none of the animals survived longer than 21 days. Here, we used a tamoxifen-inducible mouse model (Vil-Cre-ER(T2);p120(fl/fl)) to limit the extent of p120 ablation and thereby enable long-term studies. Reducing p120 KO to ~10% of the intestinal epithelium produced long-lived animals outwardly indistinguishable from controls. Effects of prolonged p120 absence were then evaluated at intervals spanning 2 to 18 months. At all time points, immunostaining revealed microdomains of p120-null epithelium interspersed with normal epithelium. Thus, stochastic p120 ablation is compatible with crypt progenitor cell function and permitted lifelong renewal of the p120 null cells. Consistent with previous observations, a barrier defect and frequent infiltration of neutrophils was observed, suggesting that focal p120 loss generates a microenvironment disposed to chronic inflammation. We report that 45% of these animals developed tumors within 18 months of tamoxifen induction. Interestingly, beta-catenin was upregulated in the majority, but none of the tumors were p120 null. Although further work is required to directly establish mechanism, we conclude that limited p120 ablation can promote tumorigenesis by an indirect non-cell autonomous mechanism. Given that byproducts of inflammation are known to be highly mutagenic, we suggest that tumorigenesis in this model is ultimately driven by the lifelong inability to heal chronic wounds and the substantially increased rates of stochastic gene mutation in tissue microenvironments subjected to chronic inflammation. Indeed, although technical issues precluded direct identification of mutations, beta-catenin upregulation in human colon cancer almost invariably reflects mutations in APC and/or beta catenin. PMID- 21611207 TI - THE CLINICAL FEATURES OF SCORBUTIC NEURITIS. PMID- 21611209 TI - Editorial: UNCERTAIN KNOWLEDGE. PMID- 21611211 TI - GLIOMA IN THE FOURTH VENTRICLE, WITH INVOLVEMENT OF THE TRIANGULAR VESTIBULAR NUCLEUS: REPORT OF A CASE WITH SYMPTOMS OF DYSTONIA, DYSMETRIA, TREMOR AND TONIC FITS. PMID- 21611210 TI - Original Papers.: A THEORY OF DECUSSATION: NOTE ON A POSSIBLE ADAPTIVE SIGNIFICANCE OF THE TRANSLATERATION OF THE UPPER MOTOR AND SENSORY NEURONES. PMID- 21611212 TI - THE LAEVULOSE TOLERANCE TEST IN PARALYSIS AGITANS. PMID- 21611213 TI - Short Notes and Clinical Cases: A CASE OF HERPES ZOSTER, APPARENTLY DUE TO INVASION OF THE GANGLIA BY ROUND-CELL SARCOMA. PMID- 21611214 TI - Editorial: THE BORDERLAND PATIENT. PMID- 21611215 TI - Original Papers: THE AFFECTIVE SYMPTOMATOLOGY OF DISSEMINATED SCLEROSIS.: A STUDY OF 100 CASES. PMID- 21611216 TI - THE PSYCHOLOGY OF CHARACTER-I. PMID- 21611217 TI - SPONTANEOUS SUBARACHNOID HAEMORRHAGE WITH RECOVERY. PMID- 21611219 TI - PERSPECTIVE IN PSYCHIATRY. PMID- 21611218 TI - AN ANALYTICAL FRAGMENT. PMID- 21611220 TI - FATIGUE: A CLINICAL STUDY. PMID- 21611221 TI - A CASE OF CHRONIC INTERNAL HYDROCEPHALUS DUE TO EPENDYMITIS GRANULARIS. PMID- 21611222 TI - THE PSYCHOLOGY OF CHARACTER.-II. PMID- 21611223 TI - FACIAL PARESIS AS A MANIFESTATION OF TUMOURS OF THE UPPER HALF OF THE CERVICAL SPINAL CORD. PMID- 21611224 TI - Short Notes and Clinical Cases: A NOTE ON THREE CASES OF DISSEMINATED SCLEROSIS ASSOCIATED WITH EPILEPSY. PMID- 21611225 TI - THE METHODS OF NEUROLOGICAL RESEARCH. PMID- 21611227 TI - SOME RESULTS OF A SECOND INDUCTION OF MALARIA IN GENERAL PARALYSIS OF THE INSANE. PMID- 21611226 TI - OBSERVATIONS ON EPILEPSY. PMID- 21611228 TI - A CASE OF ASTASIA-ABASIA AND SPEECH PERSEVERATION, FOLLOWING CARBON MONOXIDE POISONING. PMID- 21611229 TI - THE ACETIC ANHYDRIDE TEST IN CEREBROSPINAL FLUID. PMID- 21611230 TI - THE MANNER OF INVASION AND DESTRUCTION OF BRAIN TISSUE BY SPONGIOBLASTOMA. PMID- 21611231 TI - Short Notes and Clinical Cases: A CASE OF MENINGISMUS OF OBSCURE ORIGIN FOLLOWING STRETCHING OF THE ADDUCTORS OF THE HIPS. PMID- 21611233 TI - PROGNOSIS IN THE PSYCHOSES. PMID- 21611232 TI - CIRCUMCISION AND THE ABREACTION OF FEAR. PMID- 21611234 TI - THE SURGICAL TREATMENT OF CERTAIN CONVULSIVE AND PSYCHICAL DISORDERS. PMID- 21611235 TI - PROGRESSION AND REGRESSION IN TWO HOMOSEXUALS. PMID- 21611236 TI - AURAL DISEASE IN THE INSANE. PMID- 21611237 TI - Short Notes and Clinical Cases: A NOTE ON THE PRESENCE OF ENDARTERITIS OBLITERANS IN THE BRAIN OF A MONGOLIAN IMBECILE. AB - THE hypothesis that mongolism is a special form of congenital syphilis appears to be gaining ground, particularly in France, but it must be admitted that the pathological evidence for such a view remains extremely scanty. Indeed, with the solitary exception of a report by Babonneix(1) syphilitic lesions in the brain of the mongol do not appear to have been recorded. In the case of Babonneix, in addition to vascular and meningeal changes, a small tumour having the histological features of a gumma was found in the sulcus separating the right prefrontal and postfrontal gyri. To this case I am now able to add a second in which the outstanding feature was a syphilitic affection of the cerebral vessels. PMID- 21611239 TI - THE AFFECTIVE NATURE OF ILLUSION AND HALLUCINATION. PMID- 21611238 TI - VEGETATIVE NEUROLOGY. PMID- 21611240 TI - A CLINICAL ANALYSIS OF AN EXTRAPYRAMIDAL SYNDROME; PARALYSIS AGITANS AND POSTENCEPHALITIC PARKINSONISM. PMID- 21611241 TI - VENOUS ANGIOMA OF THE CEREBRUM: REPORT OF A CASE WITH NECROPSY. PMID- 21611242 TI - ON PALILALIA. PMID- 21611244 TI - MENTAL DISSOCIATION. PMID- 21611243 TI - Short Notes and Clinical Cases: A CASE OF CATAPLEXY. PMID- 21611245 TI - THE TICS AND ALLIED CONDITIONS: OPENING PAPERS. PMID- 21611247 TI - SHYNESS. PMID- 21611246 TI - OBSERVATIONS AND RESULTS FROM INTRACRANIAL SECTION OF THE GLOSSOPHARYNGEUS AND VAGUS NERVES IN MAN. PMID- 21611248 TI - THE PATHOLOGY OF POSTENCEPHALITIC OCULAR DISTURBANCES IN THE LIGHT OF RECENT ANATOMICAL AND PHYSIOLOGICAL RESEARCH. AB - The relative identity of the forced movements and forced positions seen in the lower quadrupeds after lesions of the supravestibular structures with the paralysis of lateral and upward movements seen in man after similar lesions. PMID- 21611250 TI - THE END-RESULTS OF THE TREATMENT OF "SHELL-SHOCK.". PMID- 21611249 TI - Short Notes and Clinical Cases: A CASE OF MIMIC FACIAL PARALYSIS. PMID- 21611251 TI - THE PROGNOSIS AND THE LATE RESULTS OF POSTENCEPHALITIC RESPIRATORY DISORDERS. PMID- 21611252 TI - A REMARKABLE CASE OF PACHYMENINGITIS HYPERTROPHICA PRESENTING SPINAL BLOCK AND FROIN'S SYNDROME. PMID- 21611253 TI - EPILEPTIC VARIANTS. PMID- 21611254 TI - Short Notes and Clinical Cases: A CASE OF EPILEPSY ILLUSTRATING THE LOSS OF CORTICAL CONTROL OVER LOWER FUNCTIONS. PMID- 21611255 TI - A SUGGESTED ANALOGY BETWEEN PSYCHOLOGY AND NEUROLOGY. PMID- 21611256 TI - The Characteristics of a Psychogenic History. PMID- 21611257 TI - A Study of Muscle in Contracture: The Permanent Shortening of Muscles caused by Tenotomy and Tetanus Toxin. PMID- 21611258 TI - Localised Cranial Hyperostosis in the Insane. PMID- 21611259 TI - Inhibitory Epilepsy. PMID- 21611260 TI - Report of a Case of Post Encephalitic Respiratory Disorder associated with Conduct Changes: Apparent Complete Recovery. PMID- 21611262 TI - THE PROBLEM OF JUVENILE BEHAVIOUR DISORDERS IN CHRONIC EPIDEMIC ENCEPHALITIS. PMID- 21611261 TI - On Treatment. PMID- 21611263 TI - A CRITICAL REVIEW OF THE CEREBROSPINAL FLUID SUGAR. PMID- 21611265 TI - SOME TENTATIVE CONCLUSIONS ON THE BOLTZ TEST IN GENERAL PARALYSIS OF THE INSANE. PMID- 21611264 TI - THE QUANTITATIVE ESTIMATION OF SUDORIFEROUS ACTIVITY AND ITS RELATION TO TEMPERAMENT. PMID- 21611266 TI - THE OCCURRENCE OF AMYOTROPHIC LATERAL SCLEROSIS IN CHILDREN. PMID- 21611268 TI - THE TEACHING OF PSYCHOLOGICAL MEDICINE. PMID- 21611267 TI - Short Notes and Clinical Cases: NEUROSES IN THE TROPICS. PMID- 21611269 TI - Occasional Notes: A REPORT ON THE THIRD GERMAN MEDICAL CONGRESS FOR PSYCHOTHERAPY, BADEN-BADEN, 1928. PMID- 21611270 TI - INFLUENZA IN RELATION TO THE ONSET OF ACUTE PSYCHOSES. PMID- 21611271 TI - MAJOR HYSTERIA WITH ATTACKS OF IMPAIRED CIRCULATION OF THE LEFT UPPER LIMB. PMID- 21611272 TI - LEBER'S OPTIC ATROPHY AND ITS RELATIONSHIP WITH THE HEREDO-FAMILIAL ATAXIAS. PMID- 21611273 TI - UNUSUAL SENSORY PHENOMENA FOLLOWING REMOVAL OF A TUMOUR OF THE SENSORY CORTEX. PMID- 21611274 TI - SOME MEDICOPSYCHOLOGICAL PROBLEMS IN INDUSTRY. PMID- 21611275 TI - Short Notes and Clinical Cases: A CASE OF GLIOMA IN THE LUMBOSACRAL REGION. PMID- 21611276 TI - PAST AND PRESENT. PMID- 21611277 TI - CONGENITAL AUDITORY IMPERCEPTION (CONGENITAL WORD-DEAFNESS): WITH REPORT OF A CASE. PMID- 21611278 TI - MICROGLIA: AN EXPERIMENTAL STUDY IN RABBITS AFTER INTRACEREBRAL INJECTION OF BLOOD. PMID- 21611279 TI - THE NERVOUS SYSTEM IN CLEIDOCRANIAL DYSOSTOSIS: REPORT OF A CASE. PMID- 21611280 TI - SLEEP AND EPIDEMIC ENCEPHALITIS. PMID- 21611282 TI - A SURVEY OF PSYCHOTHERAPY. PMID- 21611281 TI - Short Notes and Clinical Cases: THE OCULO-AURAL MOVEMENT. PMID- 21611283 TI - CONGENITAL AUDITORY IMPERCEPTION (CONGENITAL WORD-DEAFNESS): INVESTIGATION OF A CASE BY HEAD'S METHOD. PMID- 21611285 TI - Critical Review: POSTENCEPHALITIC PARKINSONISM AS A CHRONIC INFECTION. PMID- 21611284 TI - GROUP PERSONALITY IN NEUROTICS. PMID- 21611286 TI - Editorial: INTRACRANIAL HYPERTENSION. PMID- 21611287 TI - TUMOUR OF THE BRAIN, ASSOCIATED WITH DIFFUSE SOFTENING AND TURBID CEREBROSPINAL FLUID: REPORT OF A CASE. PMID- 21611288 TI - PERSONALITY AND PSYCHOSIS: A STUDY IN SCHIZOPHRENIA. PMID- 21611289 TI - DEMENTIA PARALYTICA: THERAPEUTIC MEASURES AND RESULTS. PMID- 21611290 TI - Short Notes and Clinical Cases: POST-MENINGITIC BLINDNESS, DEAFNESS, HYPOGENITALISM AND HYPOPITUITARISM. PMID- 21611291 TI - Critical Review: ENCEPHALITIS AND SPECIFIC FEVERS. PMID- 21611292 TI - Editorial: PSYCHOTHERAPY: MAGIC OR EDUCATION? PMID- 21611293 TI - CEREBROSPINAL FLUID EXAMINED BY ULTRA-VIOLET LIGHT. PMID- 21611294 TI - THE PHYSIOLOGICAL BASIS OF REPRESSION AND DISSOCIATION. PMID- 21611295 TI - A NEUROLOGICAL TEST FOR STUTTERERS. PMID- 21611296 TI - Critical Review: THE NATURE AND SIGNIFICANCE OF SENILE PLAQUES. PMID- 21611297 TI - Editorial: NEUROSYPHILITIC UNCERTAINTIES. PMID- 21611298 TI - Occasional Notes: INTERNATIONAL NEUROLOGICAL CONGRESS, BERNE, 1931. PMID- 21611299 TI - CONGENITAL AUDITORY IMPERCEPTION (CONGENITAL WORD-DEAFNESS): AND ITS RELATION TO IDIOGLOSSIA AND OTHER SPEECH DEFECTS. PMID- 21611300 TI - THE SCHIZOPHRENIC MALADJUSTMENT. PMID- 21611302 TI - Editorial: THE PSYCHIATRY OF CHILDHOOD. PMID- 21611301 TI - Short Notes and Clinical Cases: A CONTRIBUTION TO THE PATHOLOGY OF THE LATER MANIFESTATIONS OF ENCEPHALITIS LETHARGICA: INVESTIGATION OF A CASE. PMID- 21611303 TI - LATE FORMS OF FAMILIAL PROGRESSIVE MYOPATHY. PMID- 21611304 TI - A CASE OF DECEREBRATE RIGIDITY WITH AUTOPSY. PMID- 21611305 TI - HUNTINGTON'S CHOREA WITHOUT CHOREIFORM MOVEMENTS. PMID- 21611306 TI - THE ROLE OF PSYCHICAL FACTORS IN THE PRODUCTION OF ORGANIC NERVOUS DISEASE. PMID- 21611307 TI - CONGENITAL FACIAL DIPLEGIA. PMID- 21611308 TI - Short Notes and Clinical Cases: A STUDY OF A HUMAN MIDBRAIN PREPARATION. PMID- 21611309 TI - Editorial: THE UNDERGRADUATE TRAINING IN NEUROLOGY. PMID- 21611310 TI - Landry's Paralysis: A Clinical and Pathological Study. PMID- 21611311 TI - Psychosis associated with Myxoedema. PMID- 21611312 TI - Congenital Word-Deafness, with some Observations on the accompanying Idioglossia. PMID- 21611313 TI - Biological and Serological Methods of Diagnosis in Epilepsy. PMID- 21611315 TI - The Dementia Praecox Problem. PMID- 21611314 TI - A Clinical and Pathological Study of Three Cases of Epidemic Encephalitis. PMID- 21611316 TI - Occasional Notes: INTERNATIONAL NEUROLOGICAL CONGRESS, BERNE, 1931. PMID- 21611317 TI - Further Experimental Work on Bacterially-Produced Nervous Tissue Lesions. PMID- 21611318 TI - Tumours Involving the Cauda Equina: A Review of their Clinical Features and Differential Diagnosis. PMID- 21611319 TI - Further Notes on Examination of Cerebrospinal Fluid by Ultra-Violet Light. PMID- 21611321 TI - Editorial: The Neuroses. PMID- 21611320 TI - Studies in Speech Neurology-I. PMID- 21611322 TI - The Approach to the Study of Hysteria. PMID- 21611323 TI - The Pathology of Chronic Epidemic Encephalitis: A Histological Study of Four Cases with Widespread Cerebral Lesions. PMID- 21611324 TI - The Problem of Social Adjustment. PMID- 21611326 TI - Psychology and Medicine. PMID- 21611325 TI - The Value of Routine Examination of the Cerebrospinal Fluid: Report on the Examination of 3,200 Fluids. PMID- 21611327 TI - Angioma Arteriale Racemosum in an Acallosal Brain: A Clinical and Pathological Report. PMID- 21611329 TI - Observations on Vibration Sense with Special Reference to Postencephalitic Parkinsonism. PMID- 21611328 TI - Auditory Imperception, Illustrated by Description of Three Clinical Cases. PMID- 21611330 TI - Short Notes and Clinical Cases: A Case of Adiposo-Genital Dystrophy Occurring in a Mongol. PMID- 21611332 TI - Editorial: The Brain and Mental Illness. PMID- 21611331 TI - The Cerebral Cortex During Unconsciousness: A critical review of the theory of conditioned reflexes, with reference to the symptoms of epilepsy and narcolepsy. PMID- 21611333 TI - Occasional Notes. PMID- 21611334 TI - THE AFFECTIVE NATURE OF ILLUSION AND HALLUCINATION. PART II: EIDETIC IMAGERY. PMID- 21611335 TI - HYPERVENTILATION EXPERIMENTS DURING CO(2) AND O(2) INHALATION IN PATIENTS WITH CONVULSIONS. PMID- 21611337 TI - A STUDY OF PHOBIAS. PMID- 21611336 TI - THE DISSOCIATION OF VOLUNTARY AND EMOTIONAL MOVEMENTS OF THE FACE WITH SPECIAL REFERENCE TO EMOTIONAL PARESIS AS A PHYSICAL SIGN. PMID- 21611338 TI - Short Notes and Clinical Cases: A CASE OF INFANTILE HEMIPLEGIA ASSOCIATED WITH FACIAL NAEVUS AND MENTAL DEFECT. PMID- 21611339 TI - THE LAWRENCE-BIEDL SYNDROME. PMID- 21611340 TI - THE NERVOUS SYSTEM IN REACTIONS OF THE HIGHER ANIMALS: A critical review of recent work on the physiology of the nervous system. PMID- 21611341 TI - Editorial: INTERNATIONAL NEUROLOGICAL CONGRESS, BERNE. PMID- 21611342 TI - THE BIOLOGICAL SIGNIFICANCE OF EXTRAPYRAMIDAL SYNDROMES, APROPOS A CASE OF WILSON'S DISEASE IN THE ADULT: Second contribution to the biology of extrapyramidal affections. PMID- 21611343 TI - PROGRESSIVE HYPERTROPHIC POLYNEURITIS. PMID- 21611345 TI - Editorial: EXTRAPYRAMIDAL CENTRAL MECHANISMS. PMID- 21611344 TI - THE 'PATH' THEORY OF CORTICAL FUNCTION. PMID- 21611346 TI - TORSION-SPASM (DYSTONIA LENTICULARIS): WITH CASE REPORT. PMID- 21611347 TI - THE SIGNIFICANCE AND VALUE OF THE LANGE GOLDSOL REACTION IN DISSEMINATED SCLEROSIS. PMID- 21611348 TI - THE DIRECT STIMULATION OF THE RED NUCLEUS IN CATS. PMID- 21611349 TI - HAEMANGIOMA OF VERTEBRA: A CAUSE OF COMPRESSION OF THE CORD. PMID- 21611351 TI - Editorial: SURGERY AND THE AUTONOMIC NERVOUS SYSTEM. PMID- 21611350 TI - A FLOCCULATION TEST FOR CEREBROSPINAL FLUID. PMID- 21611352 TI - FAMILIAL BILATERAL ACOUSTIC TUMOURS. PMID- 21611353 TI - THREE FATAL CASES OF THE BULBAR TYPE OF POLIOMYELITIS. PMID- 21611354 TI - PSEUDOSCLEROSIS OF STRUMPELL-WESTPHAL IN FIVE MEMBERS OF A FAMILY. PMID- 21611355 TI - A NOTE ON THE ACTION OF BULBOCAPNINE. PMID- 21611357 TI - THE MENOPAUSE AND MENTAL DISORDER. PMID- 21611356 TI - A CASE OF RECURRENT OCULAR PARALYSIS. PMID- 21611358 TI - HAEMORRHAGIC AFFECTION OF CORTICO-NEOSTRIATAL SITE REVEALED CLINICALLY BY ACUTE AND FATAL CHOREA. PMID- 21611360 TI - A PEDIGREE SHOWING AN ATYPICAL FORM OF HEREDITARY OPTIC ATROPHY EXHIBITING APPARENT POLYMORPHISM. PMID- 21611359 TI - OBSERVATIONS ON THE DIAGNOSIS OF SPINAL BLOCK BY MEANS OF LIPIODOL. PMID- 21611361 TI - OCCULT LUMBOSACRAL MENINGOCELE. PMID- 21611362 TI - Short Notes and Clinical Cases: THE QUESTION OF SILVER CELLS AS PROOF OF THE SPIROCHAETAL THEORY OF DISSEMINATED SCLEROSIS. PMID- 21611363 TI - Critical Review: THEORETICAL DEDUCTIONS FROM THE PHYSIOLOGY OF THE CEREBRAL CORTEX. PMID- 21611364 TI - Editorial: SOME PROBLEMS OF GENERAL PARALYSIS. PMID- 21611365 TI - BRAIN STRUCTURE IN RELATION TO THE MIND: Illustrated by new and original models. PMID- 21611366 TI - TUMOURS OF THE BRAIN ASSOCIATED WITH MARKED PLEOCYTOSIS IN THE CEREBROSPINAL FLUID. PMID- 21611367 TI - MENTAL CHANGES ASSOCIATED WITH PERNICIOUS ANAEMIA. PMID- 21611369 TI - THE LESIONS PRODUCED IN THE BRAIN OF RABBITS BY THE INJECTION OF INDIAN INK AND OF ARGYROL. PMID- 21611368 TI - A CASE OF PARTIAL DEAFNESS SIMULATING CONGENITAL AUDITORY IMPERCEPTION. PMID- 21611371 TI - THE SOCALLED LAW OF ANTICIPATION IN MENTAL DISEASE. PMID- 21611370 TI - Editorial: A DISCUSSION OF NORMALITY. PMID- 21611372 TI - CEREBROMACULAR DEGENERATION: WITH CLINICAL AND PATHOLOGICAL NOTES OF A CASE. PMID- 21611374 TI - PROBLEMS OF DISSEMINATED SCLEROSIS. PMID- 21611373 TI - THE CEREBROSPINAL FLUID IN 230 CASES OF GENERAL PARALYSIS AFTER MALARIAL TREATMENT. PMID- 21611375 TI - A FORM OF PROGRESSIVE CEREBRAL SCLEROSIS IN INFANTS ASSOCIATED WITH PRIMARY DEGENERATION OF THE INTERFASCICULAR GLIA. PMID- 21611376 TI - SIZE IN MENTAL DEFICIENCY. PMID- 21611377 TI - THE MENTAL SYMPTOMS ASSOCIATED WITH 58 CASES OF CEREBRAL TUMOUR. PMID- 21611378 TI - Short Notes and Clinical Cases: CONGENITAL DEFICIENCY OF CONSCIOUS AUDITORY PERCEPTION OF WORDS (WORD-DEAFNESS): WITH REMARKS ON OTHER DEFICIENCIES OF CONSCIOUS PERCEPTION. PMID- 21611379 TI - Critical Review: THE MYOTONIC PUPIL: A CONTRIBUTION AND A CRITICAL REVIEW. PMID- 21611380 TI - Editorial: THE CLINICAL METHOD IN NEUROLOGY AND PSYCHIATRY. PMID- 21611381 TI - CEREBRAL VASCULAR LESIONS AND THE TENTORIAL PRESSURE CONE. PMID- 21611382 TI - THE MECHANISM OF CONTRE-COUP INJURY. PMID- 21611383 TI - HEAD INJURIES AND MENINGITIS. PMID- 21611384 TI - THE EFFECT OF CHOLIN-LIKE SUBSTANCES ON THE CEREBRAL ELECTRICAL DISCHARGES IN EPILEPSY. PMID- 21611385 TI - A CRITICAL REVIEW: DEMENTIA IN MIDDLE AGE. PMID- 21611387 TI - THE ELECTRO-ENCEPHALOGRAM IN ACUTE HEAD INJURIES. PMID- 21611388 TI - THE ELECTRO-ENCEPHALOGRAM IN CHRONIC POST-TRAUMATIC STATES. PMID- 21611386 TI - ALZHEIMER'S DISEASE WITH PREDOMINATING CROSSED CEREBRO-CEREBELLAR HEMIATROPHY. PMID- 21611389 TI - SULPHANILAMIDE AND SULPHAPYRIDINE IN EXPERIMENTAL CEREBRAL WOUNDS. PMID- 21611390 TI - A CONGENITAL FORM OF AMAUROTIC FAMILY IDIOCY. PMID- 21611391 TI - IMPERCEPTION FOR THE POSITION OF THE EYELIDS ON ONE SIDE. PMID- 21611392 TI - THE LOCAL EXTENSION OF NERVE FIBRES INTO DENERVATED AREAS OF SKIN. PMID- 21611394 TI - THE EFFECT OF PROSTIGMIN ON THE URINARY EXCRETION OF POTASSIUM IN THE NORMAL SUBJECT. PMID- 21611393 TI - POTASSIUM AND MUSCULAR DISORDERS. PMID- 21611395 TI - TRAUMATIC SUBDURAL EFFUSIONS. PMID- 21611397 TI - THE TREATMENT OF BRAIN ABSCESS. PMID- 21611396 TI - THE SIGNIFICANCE OF AN ABNORMAL ELECTROENCEPHALOGRAM. PMID- 21611398 TI - AN EXPERIMENTAL APPROACH TO THE DETERMINATION OF COMPARATIVE EFFICIENCY OF INSULIN AND CONVULSION THERAPY. PMID- 21611399 TI - THE ACTION OF ADRENALIN IN NEUROTICS. PMID- 21611401 TI - ACUTE PULMONARY OEDEMA WITH HYPOGLYCAEMIC COMA: AN EXAMPLE OF ACUTE PULMONARY OEDEMA OF NERVOUS ORIGIN. PMID- 21611400 TI - LISSAUER'S DEMENTIA PARALYTICA: CONTRIBUTION TO THE STUDY OF ITS DIAGNOSIS AND PATHOGENESIS. PMID- 21611402 TI - CHEMICAL CHANGES IN THE BLOOD AND THE OCCURRENCE OF URAEMIA FOLLOWING HEAD INJURY. PMID- 21611403 TI - ELECTRO-ENCEPHALOGRAPHIC STUDIES OF PSYCHOPATHIC PERSONALITIES. PMID- 21611404 TI - FACTORS AFFECTING RECOVERY OF MOTOR FUNCTION AFTER NERVE LESIONS. PMID- 21611405 TI - CEREBELLAR EXTRADURAL HAEMATOMA. PMID- 21611406 TI - PROCAINE NERVE BLOCK IN THE INVESTIGATION OF PERIPHERAL NERVE INJURIES. PMID- 21611407 TI - FACTORS AFFECTING RECOVERY OF SENSORY FUNCTION AFTER NERVE LESIONS. PMID- 21611408 TI - THE CHEMICAL INHIBITION OF FIBRE REGENERATION AND NEUROMA FORMATION IN PERIPHERAL NERVES. PMID- 21611409 TI - FATAL INTRACRANIAL VENOUS HAEMATOMA FOLLOWING VENTRICULAR DRAINAGE. PMID- 21611410 TI - LYMPHO-EPITHELIOMA OF THE THYMUS: NERVOUS AND OTHER CLINICAL SYMPTOMS IN THE ADULT. PMID- 21611411 TI - THE NEUROTIC CONSTITUTION: A Statistical Study of Two Thousand Neurotic Soldiers. PMID- 21611412 TI - THE PSYCHO-SOMATIC SYNDROME OF SPURIOUS PREGNANCY AFTER THE MENOPAUSE. PMID- 21611413 TI - SUGGESTIBILITY AND HYSTERIA. PMID- 21611414 TI - A CASE OF ATYPICAL LINDAU'S DISEASE. PMID- 21611416 TI - EROSION OF THE ALA NASI FOLLOWING TRIGEMINAL DENERVATION. PMID- 21611415 TI - SPONTANEOUS VENTRICULAR RUPTURE IN HYDROCEPHALUS, WITH SUBTENTORIAL CYST FORMATION. PMID- 21611417 TI - VENTRICULAR CHANGES AFTER CLOSED HEAD INJURY. PMID- 21611418 TI - APPERCEPTIVE BLINDNESS IN LISSAUER'S DEMENTIA PARALYTICA. PMID- 21611420 TI - SIDEROSIS OF THE GLOBUS PALLIDUS IN A MONKEY. PMID- 21611419 TI - SOME OBSERVATIONS ON THE CEREBROSPINAL FLUID IN CLOSED HEAD INJURIES. PMID- 21611421 TI - STUDIES IN DENERVATION: A.-METHODS. PMID- 21611423 TI - STUDIES IN DENERVATION: C.-INFLAMMATION AND TROPHIC ULCERS IN DENERVATED AREAS. PMID- 21611422 TI - STUDIES IN DENERVATION: B.-THE CIRCULATION IN DENERVATED DIGITS. PMID- 21611424 TI - STUDIES IN DENERVATION: D.-THE MECHANISM OF AXONAL VASODILATATION. PMID- 21611425 TI - STUDIES IN DENERVATION: E.-OBSERVATIONS CONCERNING ADRENALINE. PMID- 21611427 TI - STUDIES IN DENERVATION: G.-SEBACEOUS SECRETION. PMID- 21611426 TI - STUDIES IN DENERVATION: F.-THE CIRCULATION IN THE SKIN OF THE PROXIMAL PARTS OF THE LIMBS. PMID- 21611428 TI - STUDIES IN DENERVATION: H.-THE EFFECT OF ELECTRICAL STIMULATION ON THE CIRCULATION AND RECOVERY OF DENERVATED MUSCLE. PMID- 21611429 TI - STUDIES IN DENERVATION: I.-THE CONTRACTILITY AND EXCITABILITY OF DENERVATED MUSCLE. PMID- 21611430 TI - A PEDIGREE OF MENTAL DEFECT SHOWING SEX-LINKAGE. PMID- 21611431 TI - SOCIETY OF BRITISH NEUROLOGICAL SURGEONS. PMID- 21611432 TI - Original Papers: A NOTE ON SUGGESTION. PMID- 21611433 TI - THE TREATMENT OF CEREBROSPINAL FEVER. PMID- 21611434 TI - THOUGHTS ABOUT THINKING AND DREAMING, AND THE FREUDIAN EXPLANATION OF DREAMS. PMID- 21611436 TI - Short Notes and Clinical Cases: A CLINICAL NOTE ON THE OCCURRENCE OF HYPOTONIA IN DEMENTIA PARALYTICA. PMID- 21611435 TI - A CASE OF ENCEPHALITIS LETHARGICA INVOLVING CHIEFLY THE CEREBRAL CORTEX. PMID- 21611437 TI - CEREBELLAR FITS OF THE HUGHLINGS JACKSON TYPE. PMID- 21611438 TI - A CASE OF CONCUSSION OF THE SPINAL CORD, RESULTANT ON A GRAZE BY A LIVE SHELL: WITH ESPECIAL REFERENCE TO THE PHENOMENON OF 'HETERAESTHESIA'. PMID- 21611439 TI - Critical Review: VAGOTONIA. PMID- 21611441 TI - Editorial: THE PRESENT POSITION OF PSYCHOPATHOLOGY. PMID- 21611440 TI - Editorial: THE REALM OF NEUROLOGY. PMID- 21611442 TI - Original Papers: A CONTRIBUTION TO THE HISTOPATHOLOGY OF CARBON-MONOXIDE POISONING. PMID- 21611443 TI - SOME FACTORS IN PSYCHOTHERAPY. PMID- 21611444 TI - ATAXIA, ASAPHIA, AND APRAXIA IN SPEECH. PMID- 21611446 TI - THE NATURE OF INSOMNIA IN THE PSYCHONEUROSES. PMID- 21611445 TI - THE ACUTE CONFUSIONAL STATES IN THE PSYCHONEUROSES. PMID- 21611447 TI - Short Notes and Clinical Cases: A CASE OF TORSION-DYSTONIA, OR TORSION-SPASM. PMID- 21611448 TI - Critical Review: EPILEPSY. PMID- 21611449 TI - Editorial: CONDITIONALISM AND CAUSALISM. PMID- 21611450 TI - Original Papers: PSYCHOLOGY AND THE MEDICAL CURRICULUM. PMID- 21611452 TI - EDUCATION AND ITS ROLE IN THE PREVENTION OF NEUROSES. PMID- 21611451 TI - EPIDEMIC ENCEPHALITIS: CLINICAL PAPERS BY VARIOUS AUTHORS: I.-INTRODUCTION. PMID- 21611454 TI - Critical Review: THE NEUROPATHIC INDIVIDUAL AS A SOCIAL UNIT. PMID- 21611453 TI - FAMILIAL TABES DORSALIS. PMID- 21611455 TI - Editorial: THE LOCALIZATION OF PSYCHIC FUNCTION IN THE BRAIN. PMID- 21611457 TI - NOTES ON THE ANALYSIS OF A CASE OF MELANCHOLIA. PMID- 21611456 TI - Original Papers: HYDROCEPHALUS COMPLICATING CEREBROSPINAL FEVER, AND ITS TREATMENT. PMID- 21611458 TI - Short Notes and Clinical Cases: A NOTE ON INTELLIGENCE TESTS. PMID- 21611460 TI - Editorial: PHILOSOPHY AND MEDICINE. PMID- 21611459 TI - Critical Review: THE LOCALIZATION OF FUNCTION IN THE CENTRAL NERVOUS SYSTEM: A REVIEW OF SOME RECENT STUDIES OF ANIMAL BEHAVIOUR. PMID- 21611462 TI - SOME ANALYTICAL INTERPRETATIONS. PMID- 21611463 TI - Critical Review: THE WISH AND THE AUTONOMIC SYSTEM. PMID- 21611461 TI - Original Papers: SOME PROBLEMS IN NEUROLOGY. PMID- 21611464 TI - Editorial: THE ORGANIC ASPECT OF SHELL SHOCK. PMID- 21611465 TI - Original Papers: ON FROIN'S SYNDROME, AND ITS RELATION TO ALLIED CONDITIONS IN THE CEREBROSPINAL FLUID. PMID- 21611466 TI - A CASE OF BILATERAL EIGHTH-NERVE TUMOURS ASSOCIATED WITH MULTIPLE NEUROFIBROMATA AND MULTIPLE ENDOTHELIOMATA OF THE MENINGES. PMID- 21611468 TI - RECURRENT HYPERTROPHIC NEURITIS. PMID- 21611467 TI - Short Notes and Clinical Cases: A CASE OF CATATONIA. PMID- 21611469 TI - Editorial: THE UNCONSCIOUS MOTIVE IN THE PSYCHONEUROSES OF WAR. PMID- 21611470 TI - Original Papers: THE RELATION OF PSYCHONEUROSES TO MENTAL DEFICIENCY. PMID- 21611471 TI - THE INCIDENCE OF SCLEROSIS OF THE CORNU AMMONIS AND CONVULSIONS IN GENERAL PARESIS. PMID- 21611472 TI - AN EXPIATION PROCESS IN A CASE OF SCHIZOPHRENIA. PMID- 21611473 TI - Short Notes and Clinical Cases: REPORT OF A CASE OF INSOMNIA FOLLOWING ENCEPHALITIS LETHARGICA. PMID- 21611474 TI - NOTE ON A CASE OF PREMATURE SENILITY (PROGERIA). PMID- 21611475 TI - Critical Review: THE PATHOGENESIS OF TABES DORSALIS. PMID- 21611476 TI - Editorial: FAMILIAL AND HEREDITARY NERVOUS DISEASE. PMID- 21611477 TI - Original Papers: THE NATURE OF MENTAL DEFICIENCY. PMID- 21611479 TI - THE PHYLOGENETIC SIGNIFICANCE OF THE PLANTAR RESPONSE IN MAN. PMID- 21611478 TI - A COMPARATIVE STUDY OF THREE COLLOIDAL REACTIONS ON THE CEREBROSPINAL FLUID. PMID- 21611480 TI - IRIDOCYCLITIS - PAROTITIS - POLYNEURITIS: A NEW CLINICAL SYNDROME. PMID- 21611481 TI - Editorial: THE PSYCHOLOGICAL FACTOR OF ALCOHOL. PMID- 21611482 TI - Original Papers: ON CAUSALGIA AND ALLIED PAINFUL CONDITIONS DUE TO LESIONS OF PERIPHERAL NERVES. PMID- 21611483 TI - INHIBITION AND EXCITATION IN THE CENTRAL NERVOUS SYSTEM: A PRELIMINARY NOTE: I. INEQUALITY OF INHIBITION AND EXCITATION GIVEN BY THE SAME REFLEX STIMULUS. PMID- 21611484 TI - PSYCHOPATHOLOGY AND THE THEORY OF PSYCHOPATHIC (GERMINAL) INHERITANCE. PMID- 21611485 TI - SOME CONSIDERATIONS ON THE TREATMENT OF SPASTIC PARALYSIS. PMID- 21611487 TI - Critical Review: SUGGESTION, AUTOSUGGESTION, AND MENTAL ANALYSIS. PMID- 21611486 TI - Short Notes and Clinical Cases: ERYTHROMELALGIA, CAUSALGIA, AND ALLIED CONDITIONS. PMID- 21611488 TI - Editorial: DIFFICULTIES OF PSYCHOLOGY. PMID- 21611489 TI - Original Papers: THE NOMENCLATURE OF MINOR MENTAL DISORDERS. PMID- 21611490 TI - THE PHYSIOLOGY OF STEPPING: I.-THE PRODUCTION OF RHYTHM. PMID- 21611492 TI - THE PHOBIA AS THE FUNDAMENTAL FACTOR IN THE PSYCHONEUROSIS. PMID- 21611491 TI - STUDIES FROM THE PATHOLOGICAL LABORATORY, BETHLEM ROYAL HOSPITAL: BRIEF EXPLANATORY NOTE. PMID- 21611493 TI - RIGHT-SIDED HEMI-HYPOTROPHY RESULTING FROM RIGHT-SIDED CONGENITAL SPASTIC HEMIPLEGIA, WITH A MORBID CONDITION OF THE LEFT SIDE OF THE BRAIN, REVEALED BY RADIOGRAMS. PMID- 21611494 TI - Short Notes and Clinical Cases: CASE OF MESENCEPHALIC TUMOUR WITH DOUBLE ARGYLL ROBERTSON PUPIL. PMID- 21611495 TI - Critical Review: THE CEREBROSPINAL FLUID: ITS SOURCE, DISTRIBUTION, AND CIRCULATION. PMID- 21611496 TI - Editorial: THE SCOPE OF NEUROLOGY IN HOSPITAL PRACTICE. PMID- 21611498 TI - AN EXAMINATION OF THE FREUDIAN THEORY OF SEX. PMID- 21611497 TI - Original Papers: ON THE PRODUCTION OF NEUROMUSCULAR PATTERNS BY RELEASE OF SPINAL INTEGRATIONS AFTER DECEREBRATION. PMID- 21611499 TI - THE TREATMENT OF RESIDUAL EPIDEMIC ENCEPHALITIS. PMID- 21611501 TI - FOLIE A DEUX: DUAL ORGAN INFERIORITY, RELIGIOUS CONVERSION, AND EVANGELISM: CONFLICT, PSYCHOSIS, AND ADJUSTMENT. PMID- 21611500 TI - Short Notes and Clinical Cases: THREE CASES OF MANGANESE POISONING. PMID- 21611502 TI - Editorial: THE NATURE OF DESIRE. PMID- 21611503 TI - Original Papers: EPILEPSY AND GUNSHOT WOUNDS OF THE HEAD. PMID- 21611504 TI - THE PHENOMENON OF ABREACTION. PMID- 21611505 TI - PONTO-BULBAR CRISES ASSOCIATED WITH SIALORRHOEA IN SYPHILIS OF THE NERVOUS SYSTEM. PMID- 21611506 TI - THE NATURE OF DESIRE. PMID- 21611507 TI - Short Notes and Clinical Cases: CASE OF INFLUENZAL MENINGITIS: RECOVERY AFTER REPEATED LUMBAR PUNCTURE. PMID- 21611509 TI - Editorial: THE LOCALIZATION OF INTRACRANIAL TUMOURS. PMID- 21611508 TI - SPIROCHAETOSIS OF THE CEREBROSPINAL FLUID. PMID- 21611510 TI - Original Papers: THE PATHOLOGICAL ANATOMY OF THE DUCTLESS GLANDS IN A SERIES OF DEMENTIA PRAECOX CASES. PMID- 21611511 TI - OSTEOGENETIC DURAL ENDOTHELIOMA: THE TRUE NATURE OF HEMICRANIOSIS. PMID- 21611512 TI - SOCIETY AND THE CRIMINAL. PMID- 21611513 TI - Short Notes and Clinical Cases: ORGANIC NERVOUS DISEASES SUPERVENING IN THE SUBJECTS OF OLD INFANTILE PARALYSIS OR OLD INFANTILE HEMIPLEGIA. PMID- 21611514 TI - A CASE OF OCCLUSION OF THE RIGHT POSTERIOR INFERIOR CEREBELLAR ARTERY. PMID- 21611515 TI - Editorial: MENTAL HYGIENE. PMID- 21611516 TI - Original Papers: VISCERO-CUTANEOUS ANAEMIC ZONES AND THEIR SIGNIFICANCE. PMID- 21611517 TI - THE NERVOUS CHILD. PMID- 21611518 TI - THE ROLE OF TRAUMA IN THE ETIOLOGY OF ORGANIC AND FUNCTIONAL NERVOUS DISEASE. PMID- 21611519 TI - A CASE OF UNILATERAL BULBAR LESION, PROBABLY SYRINGOBULBIA, WITH SPECIAL REFERENCE TO THE SENSORY PATHWAYS WITHIN THE MEDULLA. PMID- 21611520 TI - Short Notes and Clinical Cases: A CASE ILLUSTRATING THE ETIOLOGY OF THE ARGYLL ROBERTSON PUPIL. PMID- 21611521 TI - Editorial: NEUROLOGICAL THERAPEUTICS. PMID- 21611522 TI - Original Papers: MALIGNANT SPHENO-OCCIPITAL CHORDOMA. PMID- 21611523 TI - ECCHORDOSIS PHYSALIPHORA SPHENO-OCCIPITALIS. PMID- 21611525 TI - INTRACRANIAL PRESSURE CHANGES DURING EXPERIMENTAL CONVULSIONS. PMID- 21611524 TI - SYPHILIS AS AN ETIOLOGICAL FACTOR IN MONGOLIAN IDIOCY. PMID- 21611526 TI - THE AFTER-HISTORY OF SOME CASES OF EPIDEMIC ENCEPHALITIS, WITH ESPECIAL REFERENCE TO CHANGES IN CONDUCT. PMID- 21611528 TI - Editorial: SUICIDE. PMID- 21611527 TI - Short Notes and Clinical Cases: UVEO-PAROTITIC PARALYSIS. PMID- 21611529 TI - Original Papers: SOME PROBLEMS IN NEUROLOGY. PMID- 21611530 TI - THE DEVELOPMENT OF PSYCHOPATHOLOGY AS A BRANCH OF SCIENCE. PMID- 21611531 TI - Short Notes and Clinical Cases: A CASE OF MYASTHENIA GRAVIS. PMID- 21611532 TI - Editorial: CORTICAL FUNCTION IN RELATION TO THE NEUROSES. PMID- 21611533 TI - Original Papers: CRITIQUE OF THE THEORY OF MENTAL RECAPITULATION. PMID- 21611534 TI - THE TREATMENT OF GENERAL PARALYSIS OF THE INSANE BY MALARIA. PMID- 21611536 TI - MESENCEPHALITIS SYPHILITICA. PMID- 21611535 TI - A CASE OF WESTPHAL-STRUMPELL PSEUDOSCLEROSIS FOLLOWING ERYSIPELAS, WITH A DISCUSSION OF ALLIED CONDITIONS. PMID- 21611537 TI - Critical Review: METAPSYCHOLOGY AND BIOLOGY: Some criticisms of Freud's "Beyond the Pleasure Principle.". PMID- 21611538 TI - Editorial: THE VALUE OF HUMAN EVIDENCE. PMID- 21611539 TI - Original Papers: THE PRESENT-DAY PHYSIOLOGICAL BASIS OF THE CLINICAL STUDY OF FATIGUE. PMID- 21611540 TI - POSTINFECTIOUS AND ISOLATED PARALYSIS OF THE SERRATUS MAGNUS. PMID- 21611541 TI - FACIAL ASSOCIATED MOVEMENTS. PMID- 21611542 TI - THE DEVELOPMENT AND EVOLUTION OF MIND: BIOLOGICAL v. PSYCHOSOCIAL INTERPRETATIONS OF THE ONTOPHYLOGENETIC PARALLELISM. PMID- 21611543 TI - A CONTRIBUTION TO THE PSYCHOPATHOLOGY OF RESIDUAL ENCEPHALITIS LETHARGICA. PMID- 21611544 TI - Editorial: THEORIES OF SENSORY FUNCTION. PMID- 21611545 TI - Original Papers: ON THE OCCURRENCE OF ABNORMAL DEPOSITS OF IRON IN THE BRAIN IN PARKINSONISM WITH SPECIAL REFERENCE TO ITS LOCALISATION. PMID- 21611546 TI - PRIMARY TUMOURS OF THE OPTIC NERVE AND OF THE CHIASMA; WITH A REPORT OF A CASE. PMID- 21611548 TI - ON THE OCCURRENCE OF FITS IN SYRINGOMYELIA. PMID- 21611547 TI - BENIGN EXTRAVERTEBRAL TUMOURS PRODUCING SYMPTOMS OF THE SPINAL CORD: REPORT OF THREE CASES. PMID- 21611549 TI - Editorial: PSYCHOPATHIC PERSONALITIES. PMID- 21611550 TI - Original Papers: ON A CASE OF ORGANIC SPINAL HEMIANAESTHESIA SHOWING THE PERSISTENCE OF A PECULIAR FORM OF SENSATION AND THE OCCURRENCE OF PHENOMENA OF ALLOAESTHESIA AND HETERAESTHESIA. PMID- 21611551 TI - THE OPERATIVE TREATMENT OF GASTRIC CRISES: A CRITICAL SURVEY. PMID- 21611552 TI - THE TREATMENT OF PSYCHOTIC PATIENTS IN INSTITUTIONS IN THE LIGHT OF PSYCHOANALYSIS. PMID- 21611553 TI - MYOTONIA ATROPHICA (DYSTROPHIA MYOTONICA). PMID- 21611554 TI - Short Notes and Clinical Cases: THE BIOLOGICAL ORIGIN OF WEEPING. PMID- 21611555 TI - CEREBRAL LOCALIZATIONS OF FUNCTION. PMID- 21611556 TI - Original Papers: EXPERIMENTAL ANATOMICAL INVESTIGATIONS CONCERNING THE PROJECTION OF THE RETINA ON THE PRIMARY OPTIC CENTRES IN APES. PMID- 21611557 TI - DOES AUTONOMOUS MENINGOCOCCAL MENINGITIS EXIST AND CAN IT BE INFLUENCED BY SERUM ACTING LOCALLY? PMID- 21611558 TI - THE PSYCHOPATHOLOGY OF LYING. PMID- 21611559 TI - THE COLLOIDAL BENZOIN CURVE IN THE CEREBROSPINAL FLUID. PMID- 21611560 TI - FURTHER POINTS IN THE PHYSIOLOGY OF BRAIN SURGERY. PMID- 21611562 TI - Editorial: SOCIAL WORK AND PSYCHIATRY. PMID- 21611561 TI - Short Notes and Clinical Cases: A CASE OF BILATERAL CORTICAL BLINDNESS. PMID- 21611563 TI - Original Papers: EPILEPSY AS A SYMPTOM OF DISSEMINATED SCLEROSIS. PMID- 21611564 TI - A CASE OF MULTIPLE NEUROFIBROMATA ASSOCIATED WITH A TRUE ANGIONEUROFIBROMA OF THE ACOUSTIC NERVE, JACKSONIAN EPILEPSY AND OSTEOPOROSIS. PMID- 21611565 TI - SYRINGOMYELIA IN ASSOCIATION WITH ACROMEGALY. PMID- 21611566 TI - Short Notes and Clinical Cases: A PSYCHOANALYTICAL METHOD OF GETTING TO SLEEP. PMID- 21611568 TI - Editorial: SUBJECTIVITY AND OBJECTIVITY. PMID- 21611567 TI - A NOTE ON THE SIGNIFICANCE OF THE VEGETATIVE NERVOUS SYSTEM IN TABES DORSALIS. PMID- 21611569 TI - Managing Pleural Disease in Acute Medicine ( II ) : Spontaneous Pneumothorax. AB - Spontaneous pneumothoraces occur in individuals who have not experienced antecedent thoracic trauma. Primary spontaneous pneumothorax occurs in otherwise healthy individuals with no clinically apparent lung disease, whereas secondary pneumothorax is a consequence of an underlying lung disease. This review focuses on their management in the acute medical setting. The specific issues of simple aspiration versus intercostal tube drainage, who can be discharged home safely, and when to refer to a respiratory physician are addressed. In addition, recent developments in the management of pneumothorax are presented. PMID- 21611570 TI - Acquired haemophilia - A diagnosis not to be missed. AB - Acquired haemophilia is a rare , life threatening bleeding disorder characterised by the development of auto-antibodies to coagulation factor VIII. Diagnosis is based upon the clinical history of mucocutaneous haemorrhages combined with a selective prolongation of the APTT. The condition is associated with a wide range of conditions, such as autoimmune diseases , solid and haematological malignancies. Treatment involves controlling the bleeding manifestations and eliminating the inhibitor antibodies. Three cases from our recent practice are used to highlight the variable severity of this condition. PMID- 21611571 TI - Inclusion body myositis a clinical review with illustrative case report. AB - Every acute physician has come across elderly patients presenting with muscle weakness and falls. Distinction between normal age related muscle wasting and pathological muscle atrophy can be difficult. It is important for acute physicians to be aware of the differential diagnosis of such a presentation. Inclusion body myositis(IBM) is the most common type of acquired myopathy above the age of 50.1 This article aims to highlight the diagnosis and management of this chronic illness. It is frequently misdiagnosed as polymyositis and wrongly treated with steroids.3 The typical symptoms and signs are illustrated by a recent case which presented to our department (see box 1). PMID- 21611572 TI - An unusual case of 'exacerbation of COPD'. AB - A 66 year old man who had been diagnosed with COPD 18 months earlier was readmitted with breathlessness unresponsive to bronchodilators and steroids. His symptoms were noticeably improved by lying on his left side. CTPA showed no evidence of pulmonary embolism but raised the possibility of tracheomalacia, which was later confirmed with bronchoscopy and lung function testing. The classification and treatment options for tracheomalacia are discussed. PMID- 21611573 TI - An unusual cause of 'pleuritic' chest pain. AB - A 77 year old man presented to A&E with sudden onset left sided chest pain. This chest pain was severe enough to wake him up from sleep in the early hours of the morning. The pain was pleuritic in nature and severe enough to require administration of intravenous morphine. He had a past medical history of ischaemic heart disease (1997), pulmonary embolism (1997), and left sided pnuemothorax (1998). Drug history consisted of lansoprazole 30mg od, isosorbide mononitrate 60mg od, nicorandil 10mg bd, aspirin 75mg od, beclomethasone 100 inhaler 1 puff bd, salbutamol 100 inhaler prn and combivent nebuliser qds. He was a retired miner, having worked for 40 years underground. There was also a 20 pack year smoking history although he had stopped for 20 years. He was independent and had a 100 to 200 yard exercise tolerance on the flat. Observations showed respiratory rate of 18, temperature of 36.5 degrees Celsius, BP 133/69, oxygen saturation of 98% on air and a regular pulse of 70 beats per minute. Clinical examination did not reveal any abnormality, with no abdominal or chest wall tenderness. PMID- 21611574 TI - 'Outfoxed' - out of season. AB - A 65 year old woman presented to the Emergency Department of our district general hospital three hours following ingestion of a blended mixture of apples and foxglove leaves, mistaking them for spinach leaves. She complained of nausea, vomiting, abdominal cramps, dizziness and blurred vision. PMID- 21611575 TI - Unrecognised late post-partum eclampsia presenting as posterior reversible encephalopathy syndrome. AB - We present a lady in whom late post-partum eclampsia (LPE) was overlooked. The diagnosis was delayed and only made when MRI brain demonstrated posterior reversible encephalopathy syndrome (PRES(. There is a need for greater awareness of both LPE and PRES. We summarise the recent literature and emphasise the importance of recognising the conditions on clinical grounds so that treatment can be started without delay. PMID- 21611576 TI - An unusual cause of spinal cord compression. AB - Spinal subdural haematoma (SSDH) is a rare, but potentially reversible, cause of spinal cord compression. We describe the case of an 85-year-old lady on long-term low-dose aspirin who presented with features of spinal cord compression. Magnetic resonance imaging (MRI) confirmed a large anterior thoracic SSDH. The aetiology, pathophysiology, clinical features and treatment options are discussed. PMID- 21611577 TI - Bedside ultrasound in the Acute Medical setting - Practiced by the Acute Physician or Ultrasonographer? AB - Ultrasound is widely used by physicians in the emergency medical setting in the USA, Australia and Europe. The objective in bringing ultrasound to the bedside is to bring immediacy to diagnostic decisions and improve safety for interventional procedures. Additionally within the NHS there are increasing pressures to limit bed usage and manage more conditions in an ambulatory setting. Shortening the time to scan and decisions based on the results would be of benefit to the individual patient and the organisation. PMID- 21611578 TI - Basic ultrasound skills should be a core component of training in the acute medicine curriculum. AB - 6.30 pm Friday, and you are doing the afternoon intake round. A 33-year-old African woman presents with 2 months malaise, cough and dyspnoea. Her CXR shows an enlarged globular heart. HIV and TB are your first thoughts, but do you need to call in the cardiologist? 11 am Saturday on the Acute Medical Unit (AMU). A 35 year old man has been seen earlier this morning following a collapse, after being assaulted 2 days previously; the diagnosis is unclear. You spot him looking pale and tachycardic. Further examination shows bruising in the flanks. Is he bleeding internally? PMID- 21611579 TI - A position statement: echocardiography in the critically ill. AB - Numerous studies have demonstrated the value of echocardiography in the assessment of critically ill patients in the Intensive Care Unit (ICU) and Emergency Room (ER). We seek to encourage expansion of echocardiography in these areas. However it is important to establish training programmes, standards of knowledge and skills, assessment methods and quality assurance if echocardiography is to be offered with confidence in these clinical areas. We have undertaken discussion with the many groups with a relevant interest in critical echocardiography and developed a consensus on proposals for the appropriate provision of training in echocardiography for the ICU, ER, and increasingly the medical high dependency and admissions wards. PMID- 21611580 TI - Developing occupational therapy best practice guidelines for acute medical services. AB - Occupational Therapists began exploring their role in Acute Medicine in the late 1990's.1 A decade later the presence of Occupational Therapists in accident & emergency departments and acute medical units is seen as routine. The literature and evidence base to support this, however, has not progressed as rapidly. With few guidelines to support practice the authors produced a document locally to promote standardisation of good practice and equity of treatment within all relevant NHS Lothian and NHS Borders sites. A table illustrates the specialist skills necessary for Occupational Therapy in Acute Medicine and appendices outline components of various assessments. It is hoped that as therapists progress through the flow chart they can utilise further sections of the guidelines related to specific assessments. This article will introduce the reader to the occupational therapy process in acute medicine and describe the guidelines that are currently in use. PMID- 21611581 TI - The ACUMEN project. AB - E-learning for healthcare (e-LfH) is a collaborative programme between the Department of Health, the NHS and various professional bodies. It provides high quality, interactive education for healthcare workers, and has been described as 'The most positive development in medical education in 20 years' by the Chief Medical Officer, Sir Liam Donaldson. Indeed e-LfH have recently been awarded the elearning age 2007 Gold award for 'Excellence in the production of e-learning content'. PMID- 21611582 TI - Initial treatment of pulmonary embolism. AB - Acute pulmonary embolism (PE) is a common presentation on the acute medical take. In our previous article in Vol 6 issue 1 we discussed the diagnostic approach to this condition. This article concentrates on the treatment of PE, including guidance for treatment of PE in pregnancy and cancer. This article also discusses the role of alternative anticoagulants, thrombolysis, surgery and inferior vena caval filters. PMID- 21611583 TI - Haematological emergencies on the acute medical take. AB - As haematological emergencies are uncommon in daily clinical practice, enhanced awareness and high index of suspicion is required to ensure that the potentially lifesaving measures are offered. This article discusses some of the haematological conditions which may present on the acute medical take. PMID- 21611584 TI - Asymptomatic hyponatraemia on the acute medical unit. AB - Hyponatraemia is defined as a serum sodium concentration of 135 mmol/L or less. It is the most common electrolyte abnormality, and can be associated with significant morbidity and mortality.1 There are numerous causes and a systematic approach to the initial investigation and management is required. Clinical assessment should start with evaluation of the patient's degree of hydration, with the measurements of serum and urine osmolality and urinary sodium concentration being the key biochemical investigations. A recent article in this journal highlighted the challenges associated with acute symptomatic hyponatraemia; this article concentrates on the more common scenario of the patient with asymptomatic hyponatraemia. PMID- 21611585 TI - Managing pleural disease in acute medicine (I): pleural effusion. AB - A pleural effusion is the accumulation of fluid in the pleural space. It is a relatively common finding in clinical practice. The diagnostic approach to the patient presenting with a pleural effusion is aimed at defining the effusion as a transudate or an exudate. This review summarises the initial assessment and investigation of pleural effusions diagnosed during the acute medical take, and who should be referred for specialist advice. In addition, recent developments, including the measurement of NT-proBNP levels and diagnostic markers for mesothelioma, are presented. PMID- 21611586 TI - The admission of older patients to a dedicated short stay medical unit: learning from experience. AB - The admission of older patients with acute medical problems to short stay medical units (SSMUs) is controversial in light of their longer expected length of in patient stay (LoS), coupled with the greater resources required by such a department. We undertook a prospective study of 120 consecutive SSMU patients aged 60 years or over, to find out whether information gained during the admissions process could predict which candidates would subsequently have a successful SSMU outcome, as well as to assess the overall suitability of the SSMU to older patients. Our redesigned acute medicine services at Addenbrooker's Hospital (Cambridge, UK) have taken account of our results, and we continue to admit older patients to our new Medical Short Stay Emergency Unit. PMID- 21611587 TI - Fatal intra-hepatic haemorrhage presenting with cardiac-type chest pain and anaemia. AB - A 79-year-old woman presented to the accident and emergency department with a short history of central chest pain radiating to the arm and epigastrum, associated with vomiting. There was no history of haematemesis and no recent change of bowel habit or melaena. She had a myocardial infarction 4 months previously and had a metal prosthetic mitral valve replacement for which she was anticoagulated with warfarin, maintaining an INR between 2.5- 3.5. On examination she appeared pale, but there were no other abnormal findings; the liver was not enlarged or tender. PMID- 21611588 TI - A case of orthodeoxia platypnoea in a patient with adult polycystic kidney and liver disease with a patent foramen ovale. AB - We describe a case of a patient with polycystic kidney and liver disease presenting with a 4 year history of shortness of breath. This was caused by a liver cyst pressing on the inferior vena cava, right atrium and ventricle, leading to a right to left shunt across a patent foramen ovale. This is consistent with the condition Orthodeoxia Platypnoea, which occurs when desaturation and dyspnoea occur in the upright position in association with an intra atrial shunt. PMID- 21611589 TI - Recurrent 'Lactic' Acidosis-a Cautionary Tale. AB - Lactic acidosis can be caused by a variety of pathological conditions. We present a case of recurrent 'lactic' acidosis, which was eventually diagnosed to be secondary to ethylene glycol poisoning. Though there are a handful of cases reported in the literature, it is not widely known that glycolic acid (a metabolite of ethylene glycol) is measured spuriously as lactic acid by some point of care analysers. Literature review would indicate that this is a rare but potentially confounding factor in diagnosis. Given the nature of the pathology, we would suggest that greater awareness of the problem is important. PMID- 21611590 TI - A Response to the Viewpoint Paper in Vol 6 issue 2. AB - We read with interest the "viewpoint" by Sarbjit Clare and colleagues recommending that specialist registrars in acute medicine should receive patients in the resuscitation room.1 We agree that this is a valuable training experience, but question some of the assumptions made. PMID- 21611591 TI - Picture Quiz: A case of mediastinal shift. AB - An 86 year old woman with a background of hypertension and arthritis presented to our medical assessment unit with 3 weeks history of mild dyspnoea and central chest discomfort. She did not have any past history of respiratory problems. She denied any cough, hemoptysis or weight loss. There was no significant family history. She was a life long non smoker and used to drink alcohol occasionally. She was taking enalapril 5 mg and amlodipine 5 mg daily. She was living alone and was independent and self caring. PMID- 21611592 TI - Cerebral venous sinus thrombosis. AB - Cerebral (or dural) venous sinus thrombosis (CVST) is a condition distinct from other cerebrovascular disease, which presents its own particular diagnostic difficulties and treatment controversies. The clinical presentation is variable and may mimic a wide range of other neurological disorders that include subarachnoid haemorrhage, encephalitis, eclampsia, idiopathic intracranial hypertension and arterial stroke. PMID- 21611593 TI - Acute symptomatic hyponatraemia - a practical approach. AB - Hyponatraemia is the commonest electrolyte abnormality yet is poorly understood. Symptoms are dependent on the rate of onset and severity. The presence of features suggestive of neurological dysfunction should be regarded as a medical emergency and treated actively. The risk of not treating outweighs that of over aggressive management. This article concentrates on the immediate management of the patient presenting acutely with severe symptomatic hyponatraemia, and is illustrated by a case recently presenting to our department. The patient who is incidentally found to be hyponatraemic in the context of another presenting illness, or presenting with more minor, non-specific symptoms presents different challenges to the admitting clinician, which will be dealt with in a future edition of the journal. PMID- 21611594 TI - Boerhaave's Syndrome: A Review of the Initial Management with Illustrative Case History. AB - Boerhaave's syndrome is a rare condition on the acute medical 'take' but has a high mortality and significant morbidity if not diagnosed early. This article reviews the approach to management at the 'front door', summarising the initial investigations and treatment. A recent case presenting to our unit is included at the end of the review to illustrate some of the issues raised. PMID- 21611595 TI - Management of acute atrial fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia; despite many available guidelines the optimal management strategy remains elusive. The most common presentations of acute AF are palpitations, breathlessness, syncope, dizziness, chest pain, transient ischaemic attack (TIA) and stroke. Patients may need urgent electrical cardioversion (ECV) or pharmacological cardioversion (PCV) and long term anticoagulation therapy. This review aims to discuss some issues surrounding the early management of acute AF in the Acute Medical Unit. PMID- 21611596 TI - Caffeine overdose with rhabdomyolysis and hypokalaemia. AB - Caffeine, a normal content of various beverages and over the counter medications, taken in higher doses can cause serious toxicity. Complications like rhabdomyolysis and acute renal failure, which are life threatening, are reversible if diagnosed early and treated appropriately. Caffeine toxicity can also cause serious hypokalaemia, which needs prompt correction. Here we present a patient with caffeine toxicity complicated by rhabdomyolysis and acute renal failure who made a complete recovery. PMID- 21611597 TI - Tuberulous Meningitis masked by Temazepam Overdose. AB - A 47 year old Chinese businessman was found unconscious at home following an overdose of 280 mg temazepam. He was found by his sister who had visited because he had not returned her telephone calls for several weeks. He had been resident in England for 8 years but returned to Hong Kong frequently. Since his last visit to Hong Kong, 4 months previously, his mood had been low and he had developed anorexia, weight loss and insomnia. Physical examination and routine investigations were unremarkable and a diagnosis of depression was made. Citalopram 10 mg daily and temazepam 10 mg daily had been prescribed one day prior to admission. PMID- 21611598 TI - Occult bilateral hip fracture secondary to seizure: a case report and literature review. AB - Seizures are a common presenting complaint in acute medicine and post-ictal patients can pose a diagnostic challenge. Approximately 1% of patients presenting after a seizure will have sustained a fracture. Delayed diagnosis is common and can lead to worse functional outcomes. A case of occult bilateral neck of femur fracture secondary to seizure is presented together with a review of the literature. PMID- 21611599 TI - An unusual cause of pancytopaenia. AB - A 76-year-old man was admitted to the acute medical take with a long history of tiredness. He described slowed thinking, constipation, aching thighs, dry skin, a hoarse voice, hair loss and 10 kilograms of unintentional weight loss. He had lived in Spain for 7 years and his daughter had persuaded him to return to the UK for a medical check-up. PMID- 21611600 TI - Improving local practice of venous thromboembolism prevention in medical patients. AB - Venous thromboembolism has long been recognised as a potentially avoidable cause of significant morbidity and mortality in hospitalised patients. With national recommendations awaited there have been clear instructions from the department of health that steps need to be made at a local level to increase awareness and address the problem prior to the expected completion of the NICE guidelines in 2007. We demonstrated an improvement in the prescription of thromboprophylaxis following implementation of simple and inexpensive changes in our department. PMID- 21611601 TI - Specialist registrars in acute medicine receiving patients in the resuscitation room: a key component in the training curriculum. AB - A key component of training in Acute Medicine is the assessment and initial resuscitation of severely ill medical patients. The curriculum for General Internal Medicine (Acute Medicine) states that all specialists in Acute Medicine should attain Level 3 competencies in all emergency presentations.1 Different training programmes have variable exposure to the emergency department, to which the majority of these patients present. One module, currently being developed at City Hospital, Birmingham, is for the Acute Medicine Specialist Registrars (SpRs) to attend all medical alerts in Accident and Emergency (A&E) Department. This means that the SpR works as part of the receiving team, seeing patients first hand, rather than taking secondary referrals. At our hospital over 80% of alerts brought in the resuscitation room are medical emergencies. PMID- 21611602 TI - The President's Piece: A Final Word. AB - Well that's it from me! At the close of our 1st International meeting in Glasgow I handed the reins of Presidency to the safe hands of Rhid Dowdle. PMID- 21611603 TI - 'Setting new standards for acute care' the society for acute medicine international conference, 1-2 october 2007. AB - The Scottish Exhibition and Conference Centre provided the venue for the first truly International meeting of the Society for Acute Medicine in early October. Almost 600 delegates were treated to some unseasonal Glasgow sunshine and traditional Scottish hospitality, as they enjoyed the varied programme put together by Mike Jones, Derek Bell and Liz Myers. The long distance that the Society has travelled in the past 7 years to reach this size was emphasised repeatedly over the two days; in his inaugural address to the society as incoming President, Dr Rhid Dowdle told us that SAM is now playing in a much bigger league than ever before, but cautioned that the speciality still has a way to go to reach the 'top division'. Some of the highlights of the meeting are summarised below, but for those delegates who did not make it to the event most of the presentations are now available on the SAM website (www.acutemedicine.org.uk). PMID- 21611604 TI - Poster prize winners. PMID- 21611605 TI - Trainees update. AB - It has certainly been a huge year of change for all of us in training posts, and in acute medicine particularly. There are now trainees in Acute Care Common Stem (ACCS) and Core Medical Training (CMT) programmes as well as new posts at ST3 level and above. Across the UK we have doubled the number of specialty trainees in Acute Medicine, and the specialty is in a very strong position. PMID- 21611606 TI - The management of diabetic ketoacidosis. AB - This article reviews the management of diabetic ketoacidosis (DKA) in adults with a focus on the three basic principles of treatment: intravenous fluid therapy, intravenous insulin administration and potassium replacement. The recommendations are modelled on the national guidance for the management of DKA in children. We highlight the importance of being alert to signs of life-threatening complications of the condition such as cerebral oedema and adult respiratory distress syndrome (ARDS). We also discuss the use of near-patient testing of capillary beta-hydroxybutyrate (b-OHB) using a ketone meter as an aid to managing and preventing DKA. PMID- 21611607 TI - Management of Suspected Avian (H5N1) Influenza in a Non-pandemic Setting. AB - Avian (H5N1) influenza has been responsible for millions of wild bird and poultry deaths throughout the world. Sporadic human cases with a high mortality have occurred, almost exclusively in association with very close contact with sick, dying or dead birds. Appropriate management of suspected cases requires their prompt recognition via attention to travel and bird-exposure history. The early isolation, diagnosis and treatment of suspected cases as well as prompt involvement of the health protection unit should enable patients to be optimally managed with minimum risk to health care staff. PMID- 21611608 TI - A review of the evaluation and management of syncope in the acute medical unit. AB - Syncope is a common acute presentation and frequently results in hospitalisation. Cardiac syncope is potentially life threatening. The diagnosis and management of syncope demands a careful history, witness account wherever possible, and a comprehensive assessment. This, in combination with routine investigations, will provide an answer in a significant percentage of patients. PMID- 21611610 TI - Picture quiz: a case of sudden severe chest pain. AB - An 18-year-old male with no previous medical history presented to hospital with sudden onset of acute epigastric pain radiating to the anterior chest wall and both shoulders. There was no history of recent trauma and he had not been vomiting. PMID- 21611609 TI - The diagnostic assessment of suspected pulmonary embolism on the acute medical take: an evidence based guide. AB - Pulmonary Embolism is a common cardiopulmonary illness with an age and sex adjusted incidence of around 117 cases per 100 000 person years. The clinical presentation is extremely heterogeneous and non specific. Risk factors for venous thromboembolism are well established. When combined with presenting features and investigations. A multimodality algorithm has led to significant changes in the diagnostic approach of suspected PE. While the best combination of tests for any individual patient remains the subject of controversy this article aims to rationalise the acute physician's approach to diagnosis and use of available investigations. PMID- 21611611 TI - Jaundice, renal failure and pulmonary haemorrhage in a canal boat owner. AB - Leptospirosis is a rare notifiable disease with three major clinical manifestations: subclinical disease, a self limiting illness (90% cases) and Weil's disease, a fulminant, life-threatening condition with renal and hepatic failure, haemorrhagic pneumonitis and cardiovascular collapse. Diagnosis is by the detection of IgM antibodies to leptospira produced 7 to 14 days after the onset of illness. It is important for acute physicians to consider this condition in their initial differential diagnosis since early treatment reduces the severity and duration of symptoms and hospital stay. A history of environmental or occupational exposure to animals or potentially infected water should raise suspicions of leptospirosis. This article aims to remind clinicians of the diagnosis and management of this condition. The typical symptoms and signs are illustrated by a recent case which presented to our department. PMID- 21611612 TI - Severe thyrotoxicosis (thyroid storm) with liver failure. AB - Thyroid storm is a severe form of thyrotoxicosis. It is an uncommon condition but can be life-threatening. Most often it is seen in patients with a background history of thyroid disease and most cases are complicated with multi-organ involvement, mainly respiratory, cardiovascular, hepatic and renal. The association of severe thyrotoxicosis with severe hepatic dysfunction has been rarely reported. This case describes a 34-year-old male without a known prior history of thyroid disease who presented with severe liver failure. PMID- 21611613 TI - Alcohol Related Non-traumatic Rhabdomyolysis and Compartment Syndrome. AB - Rhabdomyolysis is a serious and life-threatening condition in which skeletal muscle is damaged, commonly resulting in acute renal failure. The causes of this clinical entity can be traumatic and non-traumatic. In the latter group, alcohol is the commonest cause. This report describes the case of a 25 year old man who presented with rhabdomyolysis leading to acute renal failure after an alcohol binge. He presented with painful legs and lower extremity compartment syndrome. The patient recovered with surgical fasciotomy and renal support. This case illustrates the importance of early recognition and treatment of alcohol related non-traumatic rhabdomyolysis and compartment syndrome. PMID- 21611615 TI - Abstracts from the society for acute medicine spring meeting. AB - Surviving Sepsis Campaign (SSC) recommendations highlight the importance of a 6 hour resuscitation care bundle, to be commenced in the initial assessment area. The aim of this survey was to collate information from Acute Medical Units nationally in order to assess their ability to implement the 6 hour resuscitation bundle. PMID- 21611614 TI - Picture quiz: a case of sudden severe chest pain: answers. AB - Pneumomediastinum is a condition in which air presents in the mediastinum. It was first described by Laennec in 1819 as a consequence of trauma. Spontaneous pneumomediastinum (SPM) was reported in 1939 by Hamman. PMID- 21611616 TI - Summary of breakout sessions. AB - During a lively and wide ranging discussion, two questions were considered: PMID- 21611618 TI - International conference Scottish exhibition and conference centre, glasgow. PMID- 21611617 TI - Halifax: A Trainee's perspective. AB - I have never been compelled to summarize my thoughts on a society meeting before, except in a social context... but the Spring meeting piqued my interest on a number of levels, and that's got to be a first for me. PMID- 21611619 TI - How to assess patients admitted with 'falls'. AB - Many Medical Admission Units admit patients who have suffered a fall. Falls are incredibly common, yet often assessed and managed suboptimally in hospitals. Falls may be due to an acute illness, or due to a combination of factors which can be identified and managed in order to reduce the risk of falling in the future. A true 'mechanical fall' in an older person is rare. PMID- 21611620 TI - The role of invasive ventilation in exacerbations of chronic obstructive pulmonary disease causing respiratory failure. AB - Acute hypercapnic respiratory failure in chronic obstructive pulmonary disease can usually be managed initially with medical treatment and non- invasive ventilation. In circumstances where non- invasive ventilation cannot be used or has failed, intubation and invasive ventilation may be lifesaving. The outcome of patients with an exacerbation of COPD requiring invasive ventilation is better than often thought, with a hospital survival of 70-89%. Decisions regarding invasive ventilation made by physicians and patients with COPD are unpredictable and vary with the individual. This article reviews the role of invasive ventilation in exacerbations of COPD to assist decision making. PMID- 21611621 TI - An unusual case of endocarditis. AB - A 74 year gentleman was admitted with a 6 month history of dizzy spells, malaise, generalised weakness and weight loss of over a stone. He attributed his weight loss to poor appetite due to persistent nausea. He had no significant past medical history apart from moderate mitral regurgitation and recent cholecystectomy. He felt some of these symptoms began after laparoscopic cholecystectomy 12 months before. The procedure had been complicated by a self limiting biliary leak. He had been recently evaluated by chest physicians and gastroenterologists for clubbing and weight loss. Computerised tomography (CT) of the chest showed right basal fibrosis, CT of the abdomen and pelvis was normal, and upper endoscopy revealed a non-obstructive mild pyloric stenosis. Routine blood tests were unremarkable. PMID- 21611622 TI - Ecstasy: an important cause of acute liver failure. AB - A twenty year old female was referred to hospital by her GP, after he received the results of blood tests taken earlier in the day. She had presented to him complaining of malaise, nausea and anorexia over a 3 day period. On the day of referral she had also become jaundiced with dark urine, but normal stool colour. There was no abdominal pain. She had no significant past medical history with no history of jaundice, liver disease or autoimmune conditions, and no apparent risk factors for blood-borne hepatitis infection. There was no relevant family history. She was taking no prescribed medication, had not taken any over the counter medication or herbal remedies. She denied excessive alcohol use or use of intravenous drugs in the past, although she was not specifically questioned on the use of other recreational drugs. She was a single mother and admitted to being under considerable stress recently. On examination she appeared well, apart from marked jaundice. There were no signs of hepatic encephalopathy or chronic liver disease. Abdominal examination revealed mild left upper quadrant tenderness, but no significant hepatomegaly. Liver function tests (LFTs) taken by her GP are shown in Table 1, revealing marked elevation of the Alanine Transaminase (ALT) (Table 1), with a relatively preserved albumin. Unfortunately her International Normalised Ratio (INR) had not been measured. An Ultrasound of the abdomen demonstrated a normal size liver with normal contour and texture with no other abnormality. PMID- 21611623 TI - Intra-pericardial rupture of bacterial hepatic abscess: an unusual cause of 'cardiac' chest pain. AB - We report a rare case of bacterial pericarditis secondary to rupture of liver abscess into the pericardium. The patient presented with cardiac-sounding chest pain and with normal ECG, CXR and Troponin-I assay. The initial echocardiogram showed minimal pericardial fluid but, when he later developed overt clinical signs of cardiac tamponade, a CT scan of chest and abdomen revealed a pronounced pericardial effusion. It also revealed an abscess located in the left lobe of liver and this had apparently ruptured into the pericardial sac. Culture of the purulent pericardial aspirate grew Proteus and Enterococcus; these organisms have been reported only rarely as responsible for causing purulent pericarditis. The patient was treated initially by emergency ultrasound-guided pericardiocentesis; later he required thoracotomy and pericardiectomy in order to manage persistent re-accumulation of pus in the pericardium. PMID- 21611624 TI - Metformin associated lactic acidosis not as rare as we think:. AB - Metformin Associated Lactic Acidoisis (MALA) has been reported to be a very rare but serious side effect of metformin treatment with a fatality rate of 50%. However, with the number of patients on metformin increasing the incidence of MALA is likely to increase. We aim to raise the awareness of MALA and prompt acute physicians to consider this diagnosis in the acutely unwell diabetic patient on metformin. We present 3 cases that presented with MALA in the course of 6 months, all of whom survived. We discuss metformin, its effects and lactic acidosis. We encourage effective prompt resuscitation of these individuals to increase survival. PMID- 21611625 TI - Addison's Disease Presenting with Abdominal Pain. AB - Primary Adrenal Insufficiency is due to bilateral destruction of the adrenal cortex and has a prevalence of approximately 40-60 per million adults.1 The commonest cause is autoimmune.1 Prompt treatment not only restores quality of life but also a normal life expectancy.2 Here we present an unusual case of primary adrenal insufficiency, which illustrates how such an important disease often provides a diagnostic conundrum. PMID- 21611626 TI - Hospital readmissions: patient, carer and clinician views. AB - AIM: To explore patients, carers, and clinician views and identify factors, which affect the likelihood of hospital readmission. Methods A cross sectional retrospective study of adult medical patients readmitted to hospital within 28 days of discharge. Medical and nursing records were reviewed and patients and their carers were interviewed regarding their views about their discharge and readmission. Data were collected regarding demographic, social and medical profiles. Results Seventy-seven patients were readmitted over a five-week period out of 1289 patients discharged during the previous five weeks, representing a 6% readmission rate. Mean (SD) age of readmitted patients was 71.3 (14.6) years. Forty patients (51.9%) were aged =75 and 39 (50.6%) were males. Mean (SD) number of comorbidities was 3.68 (1.82). Mean (SD) number of medications was 7.79 (4.14). Most common reasons for readmission were exacerbation of chronic obstructive pulmonary disease and acute coronary syndrome. Mean (SD) time to readmission was 11.6 (8.2) days. Fifty (64.9%) patients were readmitted within 14 days of discharge. Forty eight (62.3%) patients were readmitted with the same medical condition as their previous discharge. Fifty (64.9%) patients and 45 (66.2%) carers felt that discharge was appropriate. Forty five (58.0%) patients and 44 (57.0%) carers thought that readmission was unavoidable. Clinicians considered 56 (72.7%) discharges appropriate and 55 (71.5%) readmissions unavoidable. A trend towards higher readmission rate among patients = 75 years was noted (7.2% vs 5.1%, p=0.1). Conclusion Although the majority of discharges are appropriate, up to a third of readmissions may be avoidable in the views of carers, patients and clinicians. Patients and carers should be consulted regarding readiness for discharge before leaving hospital. PMID- 21611627 TI - Does a Post-take Ward Round Proforma Lead to Sustainable Improvements in Quality of Documentation for Patients Admitted to the Medical Assessment Unit? AB - This study assessed the quality of post-take ward round (PTWR) documentation, specifically looking at twelve criteria, in the medical assessment unit (MAU) prior to, 3- months and 2-years after introducing a PTWR proforma. 216 case records were analysed; 40 prior to, 40 three-months and 146 two-years after introducing the PTWR proforma. There was a significant improvement in eight criteria threemonths after introducing the PTWR proforma. These improvements were sustained two-years later and significant improvements made in a further 3 criteria (1 at p < 0.05 and 2 at p ) 0.01). PMID- 21611628 TI - Recognition and management of the patient with shock. AB - The term shock probably originates from an inappropriate English translation of the word choc, which was used by the French army surgeon Henri Francois Le Dran to describe the collapse of vital functions culminating in death that he observed in soldiers who had been struck by missiles. In the 1800's John Collins Warren described shock as a 'momentary pause in the act of death', a description which remains accurate to this day if the diagnosis is missed or delayed. Shock can be considered as the final pathway through which a variety of pathological processes lead to cardiovascular failure and death. Given the enormous spectrum of disease that can lead to shock it is not surprising that it is an extremely common cause of admission to the intensive care unit. PMID- 21611629 TI - Management of transient ischaemic attacks. AB - Symptoms compatible with a transient ischaemic attack (TIA) are a common reason to seek medical attention. Most TIAs resolve within an hour and leave no residual symptoms or signs. This can make the diagnosis problematic, but perhaps more importantly, can lead both patient and doctor to underestimate the importance of the event, and the urgency with which it should be addressed. The risk of a subsequent stroke is high: around 8% after seven days and 17-18% after three months.1,2 This review aims to discuss some of the issues surrounding the investigation and management of TIAs, including the potential role of Acute Medicine in the provision of timely and appropriate management for these patients. PMID- 21611630 TI - The management of acute endocarditis. AB - Infective endocarditis (IE) is an infection, usually of bacterial aetiology, which can affect any part of the endovascular surface of the heart or large intrathoracic vessels but most commonly affects cardiac valves. Without treatment this condition is invariably fatal and even with treatment is associated with a high incidence of morbidity and mortality. This article looks at the difficulties in diagnosing IE and the investigations used to confirm the diagnosis. It also lists the major causes of IE and its management. PMID- 21611631 TI - Fever in the returning traveller. AB - Travel-related infections are becoming more common as travel abroad becomes easier. Whilst most imported infections will have recognisable features some of the more obscure will be less familiar to the clinician. A detailed travel history including all stopovers is vital as is a thorough examination. Falciparum malaria is a medical emergency and prompt treatment is essential. Emerging infections such as SARS and avian influenza provide new challenges in diagnosis for the admitting team. PMID- 21611632 TI - Fatal Venlafaxine poisoning: Case Report. AB - Venlafaxine is a selective serotonin and noradrenaline re-uptake inhibitor (SNRI), used in the treatment of depressive illness and anxiety disorder. Overdose may result in cardiac and neurotoxicity, but there are very few case reports of fatal isolated Venlafaxine overdose.1 The following case highlights the potentially serious consequences of overdose of this drug. PMID- 21611633 TI - Surviving Sepsis and the acute medicine - critical care interface. AB - Critical care is now a well established specialty in the UK. The rapid development of acute medicine across the country has many similarities to the development of critical care in the 1960's. How these two specialties interface will be an important issue in the way acute hospitals deliver care over the next few years. The Surviving Sepsis Campaign resuscitation care bundle is a useful tool to help develop this interface. PMID- 21611634 TI - The society for acute medicine: trainees' news. AB - Acute Medicine remains high on the agenda at all levels of organisation and planning in Healthcare provision and training in the UK. In March 2006, an RCP report to the Health Committee Inquiry on Workforce Needs and Planning for the Health Service said, "The specialty of acute medicine is a new initiative and is likely to deliver improvements in delivery of this critical and expanding area of care in the NHS. To drive development we believe the number of SpRs and consultants in the field need rapid expansion to gain critical mass to deliver acute medicine efficiently." PMID- 21611635 TI - Acute Medicine and Academic Medicine - a unique opportunity to improve health care. AB - Acute medicine was recognised as a subspeciality of General (Internal) Medicine by the Specialist Training Authority in July 2003. In practice it had been growing as a clinical entity for over a decade and several reports have been published.1, 2, 3 The most recent Royal College of Physicians report on Acute medicine: making it work for patients4 states "Acute medicine in the UK requires the development of an academic and research base in order to support teaching and training at medical undergraduate and postgraduate level, to support basic and clinical research, to develop clinical standards, and to provide audit tools for the assessment of clinical performance." PMID- 21611636 TI - An unusual cause of fitting in a 20 year old girl. AB - Native renal artery stenosis resulting in hypertensive encephalopathy is exceptionally rare, with only 3 previous case reports in adults. We report such a case in a previously well 20 year old female. PMID- 21611637 TI - Hybrid lipid oligonucleotide conjugates: synthesis, self-assemblies and biomedical applications. AB - Hybrid lipid oligonucleotide conjugates are finding more and more biotechnological applications. This short critical review highlights their synthesis, supramolecular organization as well as their applications in the field of biotechnology (111 references). PMID- 21611638 TI - Sensitive detection of glucose based on gold nanoparticles assisted silver mirror reaction. AB - We developed a simple, non-enzymatic approach for the colorimetric detection of glucose based on a gold nanoparticles (Au NPs) assisted silver mirror reaction (AuSMR). The linear range of the concentration of glucose is from 0.04 mM to 1 mM, and the lowest concentration that can be distinguished by the naked eye is 10 nM. This approach has been successfully used for detecting glucose in serum. PMID- 21611639 TI - Hydrogen plasma interaction with (100) diamond surfaces. AB - Polycrystalline diamond films exhibiting (100) oriented surfaces have been subject to a low pressure hydrogen plasma for durations up to 20 h. The topography of spatially defined 20 * 20 MUm areas of the samples were imaged by atomic force microscopy at intervals during the plasma exposure. The mean surface roughness of individual (100) crystallites decreased from ca. 2.4 nm to <1 nm over the period and was independent of the twist and tilt angles of the crystallite. Whilst small hillock growth features were etched completely by the plasma treatment, there was no evidence for etch pits evident in similar experiments carried out with (100) natural diamond. Very low lateral etch rates of the (100) crystallites of 28 +/- 4 nm/h were measured for crystallites bounded by (111) planes. High resolution XPS analysis of the C(1s) and O(1s) transitions of the same samples showed that the surface graphitic phase, present in the as prepared samples, was removed to below detectable limits. The surface oxygen content was reduced from around 9-10% to ca. 3% after prolonged plasma exposure. The C(1s) and O(1s) band contours revealed the presence of oxygen in the form of ether and carbonyl functional groups. The ether:carbonyl: areal density ratio on (100) crystallites decreased only slightly from 83:17 to 64:37 after 20 h of plasma treatment based on fitting of the O(1s) band envelope. Etching products arising from the plasma interaction with the diamond surface were not detected by either optical emission spectroscopy or mass spectrometry. PMID- 21611640 TI - Hydrogen-induced passivation of boron acceptors in monocrystalline and polycrystalline diamond. AB - This paper presents a review of the properties induced by the presence of hydrogen in monocrystalline boron-doped diamond (BDD) and proposes a comparison with results obtained on polycrystalline materials. Hydrogen diffusion, luminescence and electrical properties show the passivation of boron acceptors in diamond by the formation of (B,H) complexes, in both monocrystalline and polycrystalline forms, but at a different level. This behaviour raises open questions concerning the role of structural defects in the passivation of boron impurities by hydrogenation. Based on the assessment of the high thermal stability of (B,H) complexes, this approach leads to a route to provide patterned diamond conductive structures for micro as well as for nanotechnology applications. PMID- 21611641 TI - Fluctuations of the Stokes and anti-Stokes surface-enhanced resonance Raman scattering intensities in an electrochemical environment. AB - Stokes and anti-Stokes SERRS intensity fluctuations were observed from a roughened silver electrode immersed in diluted solutions of Brilliant Green (BG), a behaviour linked to single-molecule events. The distributions of the anti Stokes to Stokes ratios were obtained and their shape showed a strong dependence on the applied potential. PMID- 21611642 TI - Limitations of the CLEA model when assessing human health risks from dioxins and furans in soil at an allotments site in Rochdale, NW England. AB - Many allotments in the UK today are situated on urban brownfield areas which creates a potential human health risk from soil borne contamination. This paper looks specifically at the risks to allotment users at a site in Rochdale, UK, from polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-furans (PCDD and PCDF). A contaminated land investigation was undertaken involving the collection and analysis of 24 soil samples from the top 0.0-0.3 m of the soil profile. Homogenised egg samples were also collected and analysed from plots where poultry were kept. The concentration of PCDD and PCDF in soil at the site varied from 0.69 to 13.62 MUg kg(-1); two plots out of a total of eight exceeded the soil guideline value (SGV) of 8 MUg kg(-1), however all plots fell below the site specific assessment criteria (SSAC) of 15.9 MUg kg(-1). Human health risks were assessed using the Environment Agency's contaminated land exposure assessment (CLEA) model. The assessment using CLEA alone did not provide enough evidence to indicate significant possibility of significant harm (SPOSH) across the entire allotment site. However, when the likely exposure from the soil was combined with potential exposure from consumption of site laid eggs, the results indicated that the potential risks could constitute SPOSH. This paper gives evidence to support the bioconcentration of PCDD and PCDF in eggs and highlights the importance of considering pollutant linkages outside the generic CLEA model. PMID- 21611643 TI - Comparative toxicity of nano-ZnO and bulk ZnO suspensions to zebrafish and the effects of sedimentation, OH production and particle dissolution in distilled water. AB - With the common application of nanoscale zinc oxide (nZnO) and significant potential for its release directly into aquatic environments, it is urgent to carry out research on ecotoxicological impact of nZnO. The characterization of nZnO, the amount of OH in suspensions in the presence of light and the acute toxicity of nZnO and its bulk counterpart suspensions, as well as the acute toxicity of Zn(2+) solution to zebrafish (Danio rerio) at 96 h were studied. It was found that nZnO aggregated into irregular shapes in suspensions, and showed a relationship between its size distribution and concentration. In the presence of light, nZnO suspensions could generate OH, the concentration of which increased with time. Although it was generally thought that OH played a role in the biotoxicity to zebrafish, similar toxicity was observed for the nZnO and bulk ZnO suspensions (96 h LC(50) 3.969 mg L(-1), 2.525 mg L(-1), respectively). Furthermore, the sedimentation of nZnO and bulk ZnO in suspensions, and the accumulation of Zn in zebrafish were studied. The results showed that dissolved Zn(2+), from nZnO and bulk ZnO in suspensions, were toxic to zebrafish, while the aggregation and sedimentation of nZnO suspensions reduced the toxicity of nZnO. However, Zn(2+) may not be the main source of acute toxicity of nZnO and bulk ZnO to zebrafish. The experimental results highlight the importance of a systematic assessment of toxicity mechanisms of metal oxide nanoparticles (NPs) to determine definitively whether their toxicity is caused by nano-effects. PMID- 21611644 TI - Influencing uptake and localization of aminoglycoside-functionalized peptoids. AB - The development of small-molecule therapeutics that target RNA remains a promising field but one hampered with considerable challenges that include programming high affinity, specificity, cell permeability, and favorable pharmacokinetic profiles. Previously, we employed the use of peptoids to modularly display RNA-binding modules to enhance binding affinity and specificity by altering valency and the distance between ligand modules. Herein, factors that affect uptake, localization, and toxicity of peptoids that display a kanamycin derivative into a variety of mammalian cells lines are reported. A series of peptoids that display various spacing modules was synthesized to determine if the spacing module affects permeability and localization. The spacing module does affect cellular permeability into C2C12, A549, HeLa, and MCF7 cell lines but not into Jurkat cells. Moreover, the modularly assembled peptoids carrying the kanamycin cargo localize in the cytoplasm and perinuclear region of C2C12 and A549 cells and throughout HeLa cells, including the nucleus. These studies could contribute to the development of general strategies to afford cell permeable, modularly assembled small molecules that specifically target RNAs present in a variety of cell types. PMID- 21611645 TI - Formation of monolayer and few-layer hexagonal boron nitride nanosheets via surface segregation. AB - We report that few-layer hexagonal boron nitride (h-BN) nanosheets can be produced by using a surface segregation method. The formation of h-BN sheets is via an intermediate boron-nitrogen buffer layer. Our results suggest that surface segregation of boron and nitrogen from a solid source is an alternative approach to tailoring synthesis of h-BN sheets for potential applications such as in graphene electronics. PMID- 21611646 TI - Determination of Ochratoxin A in apples contaminated with Aspergillus ochraceus by using a microfluidic competitive immunosensor with magnetic nanoparticles. AB - Ochratoxin A (OTA) is a mycotoxin produced by filamentous fungi of the genus Aspergillus and Penicillium that presents carcinogenic, teratogenic and nephrotoxic properties. In this work, we have developed, characterized and applied an immunoassay methodology comprised of magnetic nanoparticles (MNPs) as platform for immobilizing bioactive materials incorporated into a microfluidic system for rapid and sensitive quantification of Ochratoxin A (OTA) in apples (Red Delicious) contaminated with Aspergillus ochraceus. The sensor has the potential for automation and the detection of OTA was carried out using a competitive indirect immunoassay method based on the use of anti-OTA monoclonal antibodies immobilized on 3-aminopropyl-modified MNPs. The total assay time into the microfluidic competitive immunosensor was 16 min, and the calculated detection limit was 0.05 ug kg(-1). Moreover, the intra- and inter-assay coefficients of variation were below 6.5%. The proposed method can be a very promising analytical tool for the determination of OTA in apparently healthy fruits post-harvest and for its application in the agricultural industry. PMID- 21611647 TI - Infrared spectral changes identified during different stages of herpes viruses infection in vitro. AB - Microscopic Fourier transform infrared spectroscopy (FTIR) which is based on the characteristic molecular vibrational spectra of cells was previously applied for the identification of various biological samples. In the present study, FTIR spectroscopy was used for the characterization of different stages during the development of herpes viruses infection. Vero cells in culture were infected with high and low doses of different herpes viruses [herpes simplex virus types 1 and 2 (HSV-1, -2) or varicella-zoster virus (VZV)], and cellular changes were observed by optical and electron microscopy and analyzed by FTIR microscopy at different periods of time post-infection. Specific different spectral changes were observed at various stages of the viral infection development. The spectral intensity in the 1220-1260 cm(-1) region (mainly attributed to phosphate levels) was considerably increased in all infected cells compared to normal uninfected cells during the early stages of the viral infection development. However, at the late stages of the viral infection development (when all the cells in the infected culture lost their spindle shape and became circular) the spectral intensities in this region significantly decreased in the infected compared to the control cells. In addition, the peak at 1023 cm(-1), attributed to carbohydrates, almost fully disappeared at early stages of the viral infection development, whereas at late stages of the infection it raised to an equivalent or higher level than that of the uninfected control cells. These results support the potential of developing FTIR microspectroscopy as a simple, reagent free method for the early detection and accurate differentiation of different stages during the development of herpes virus infection. PMID- 21611649 TI - On the "yl" bond weakening in uranyl(VI) coordination complexes. AB - The U-O(yl) triple bonds in the UO(2)(2+) aquo ion are known to be weakened by replacing the first shell water with organic or inorganic ligands. Weakening of the U-O(yl) bond may enhance the reactivity of "yl" oxygens and uranyl(VI) cation cation interactions. Density functional theory calculations as well as previously published vibrational spectroscopic data have been used to study the origin of the U-O(yl) bond weakening in uranyl(VI) coordination complexes. Natural population analyses (NPA) revealed that the electron localization on the O(yl) 2p orbital is a direct measure of the U-O(yl) bond weakening, indicating that the bond weakening is correlated to the weakening of the U-O(yl) covalent bond and not that of the ionic bond. The Mulliken analysis gives poor results for uranium to ligand electron partitioning and is thus unreliable. Further analyses of molecular orbitals near the highest occupied molecular orbital (HOMO) show that both the sigma and pi donating abilities of the ligands may account for the U O(yl) bond weakening. The mechanism of the bond weakening varies with coordinating ligand so that each case needs to be examined independently. PMID- 21611648 TI - (E,E)-1,5-Cyclooctadiene: a small and fast click-chemistry multitalent. AB - Two in one--We show here that the highly strained trans,trans-diolefin (E,E)-1,5 cyclooctadiene can perform efficiently two different click reactions at fast reaction rates. It is capable of first undergoing [3+2] cycloadditions with 1,3 dipoles at a reaction rate comparable to that of strained cyclooctynes. The resulting cycloadduct can then perform a much faster inverse-electron-demand Diels-Alder reaction with tetrazines, effectively linking an azide to a tetrazine. Thus, (E,E)-1,5-cyclooctadiene could have many applications in chemical biology and polymer chemistry. PMID- 21611650 TI - A one-step colorimetric method of analysis detection of Hg2+ based on an in situ formation of Au@HgS core-shell structures. AB - A new approach for the detection of Hg(2+) is reported based on color changes from which gold nanoparticles (Au NPs) are surrounded by a layer of HgS quantum dots to form in situ Au@HgS core-shell nanostructures. The surface plasmon resonance (SPR) absorption of the gold core was changed due to a shell layer of HgS formed on the surface of the Au NPs, which brings the colour change of the aqueous solution. Therefore, Hg(2+) can be recognized by visualizing the colour change of the Au@HgS core-shell nanostructures, and can be detected quantitatively by measurement of the UV-vis spectra. Some effects on the detection of Hg(2+) were investigated in detail. This method was used to detect Hg(2+) with excellent selectivity and high sensitivity. In our method, the lowest detected concentrations for mercury ions were 5.0 * 10(-6) M observed by the naked eye and 0.486 nM as measured by UV-vis spectra. At the range from 8.0 * 10( 5) to 1.0 * 10(-8) M of Hg(2+), this method was shown to have a good linear relationship. PMID- 21611651 TI - Review on the progress in synthesis and application of magnetic carbon nanocomposites. AB - This review focuses on the synthesis and application of nanostructured composites containing magnetic nanostructures and carbon-based materials. Great progress in fabrication of magnetic carbon nanocomposites has been made by developing methods including filling process, template-based synthesis, chemical vapor deposition, hydrothermal/solvothermal method, pyrolysis procedure, sol-gel process, detonation induced reaction, self-assembly method, etc. The applications of magnetic carbon nanocomposites expanded to a wide range of fields such as environmental treatment, microwave absorption, magnetic recording media, electrochemical sensor, catalysis, separation/recognization of biomolecules and drug delivery are discussed. Finally, some future trends and perspectives in this research area are outlined. PMID- 21611652 TI - Dynamic behaviour attributed to chiral carbohydrate substituents of N heterocyclic carbene ligands in square planar nickel complexes. AB - Nickel complexes having acetylated glucopyranosyl group incorporated N heterocyclic carbene (NHC) ligands with methyl or benzyl groups as an N substituent exhibit two kinds of dynamic behaviours in solution (1)H NMR spectroscopy. One of the dynamic behaviours is attributed to the anti- and syn rotamers, which occur by the rotation of the unsymmetrical NHC ligands around the axes of the Ni-C bonds. The other is attributed to the diastereomers of the syn rotamers, which occur by opposite rotation of the imidazolylidene rings and the chiral carbohydrate group incorporated into the NHC ligands. Crystallographic analysis of the nickel complex having the NHC ligand with acetylated glucopyranosyl and benzyl groups as N-substituents showed CH-pi interaction between the glucopyranosyl unit of each NHC ligand and the phenyl ring of the other NHC ligand in the complex in the solid state. PMID- 21611653 TI - Assessment of regional metal levels in ambient air by statistical regression models. AB - The assessment of the particulate matter (PM) levels and its constituents presented in the atmosphere is an important requirement of the air quality management and air pollution abatement. The heavy metal levels in PM10 are commonly evaluated by experimental measurements; nevertheless, the EC Directives also allow the Regional Governments to estimate the regulated metal levels (Pb in Directive 2008/50/EC and As, Ni and Cd in Directive 2004/107/EC) by objective estimation and modelling techniques. These techniques are proper alternatives to the experimental determination because the required analysis and/or the number of required sampling sites are reduced. The present work aims to estimate the annual levels of regulated heavy metals by means of multivariate linear regression (MLR) and principal component regression (PCR) at four sites in the Cantabria region (Northern Spain). Since the objective estimation techniques may only be applied when the regulated metal concentrations are below to the lower assessment threshold, a previous evaluation of the determined annual levels of heavy metals is conducted to test the fulfilment of the EC Directives requirements. At the four studied sites, the results show that the objective estimations are allowed alternatives to the experimental determination. The annual average metal concentrations are well estimated by the MLR technique in all the studied sites; furthermore, the EC quality requirements for the objective estimations are fulfilled by the developed statistical MLR models. Hence these estimations may be used by Regional Governments as a proper alternative to the experimental measurements for the regulated metal levels assessment. PMID- 21611654 TI - Synthesis, characterization and coordination properties of bis(alkyl)selenosalen ligands. AB - New bis (alkyl) selenosalen podand ligands having Se2N2 donor sites have been synthesized by the condensation of unsymmetrical o-formylphenyl alkyl selenide (1 3) with ethylenediamine. The reaction of bis(alkyl)selenosalen podands with Pd(II) and Pt(II) afforded selenoether-selenolate coordination complexes 7-10via cleavage of one of the two Se-C(alkyl) bonds of bis(alkyl)selenosalen podands upon complexation. DFT calculations revealed that the cleavage of Se-C(alkyl) bonds occurred possibly via S(N)2 mechanism instead of a sequence of oxidative addition and reductive elimination reactions. The spectral data and elemental analyses confirmed the formation of selenoether-selenolate complexes. The structures of the podands N,N'-bis[(2-methylseleno)phenylmethylene]-1,2 ethanediamine (4), N,N'-bis[(2-decylseleno)phenylmethylene]-1,2-ethanediamine (5) and the selenoether-selenolate complex 8 have been determined by single crystal X ray diffraction analysis. The crystal structure of 5 showed SeH interaction with a ladder like 3D supramolecular arrangement via interdigitation of long alkyl chains. Comparison of crystal packing of podands 4 and 5 indicates that the alkyl chain length has significant impact on the crystal packing. The platinum selenolate complex 8 shows a square planar arrangement around the Pt centre, where the Se atoms in the selenolate and the selenoether have nearly equal Pt-Se bond length. PMID- 21611657 TI - 10th anniversary issue: The Netherlands. PMID- 21611655 TI - Facile oxidative addition of water at iridium: reactivity of trans-[Ir(4 C5NF4)(H)(OH)(PiPr3)2] towards CO2 and NH3. AB - A reaction of trans-[Ir(4-C(5)NF(4))(eta(2)-C(2)H(4))(PiPr(3))(2)] (1) with an excess of water in THF at room temperature affords the hydrido hydroxo complex trans-[Ir(4-C(5)NF(4))(H)(OH)(PiPr(3))(2)] (2). Treatment of 2 with CO furnishes trans-[Ir(4-C(5)NF(4))(H)(OH)(CO)(PiPr(3))(2)] (3). Reductive elimination of water from 3 leads to the formation of the iridium(I) carbonyl complex trans [Ir(4-C(5)NF(4))(CO)(PiPr(3))(2)] (4). The insertion of CO(2) into the Ir-O bond of 2 forms the hydrido hydrogencarbonato complex trans-[Ir(4 C(5)NF(4))(H)(kappa(2)-(O,O)-O(2)COH)(PiPr(3))(2)] (5). Treatment of 2 with NH(3) in C(6)D(6) yields trans-[Ir(4-C(5)NF(4))(H)(OH)(NH(3))(PiPr(3))(2)] (6). Storage of the reaction mixture at room temperature reveals the formation of the N-H activation product [Ir(4-C(5)NF(4))(H)(MU-NH(2))(NH(3))(PiPr(3))](2) (7). PMID- 21611658 TI - Silver and gold nanoparticles in plants: sites for the reduction to metal. AB - Induced formation of metal nanoparticles in living plants is poorly understood. The sites for the reduction of Ag(+) and Au(3+) to Ag(0) and Au(0) metal nanoparticles in vivo in plants were investigated in order to better understand the mechanism of the reduction processes. Brassica juncea was grown hydroponically, followed by growth in solutions of AgNO(3), [Ag(NH(3))(2)]NO(3) or HAuCl(4). Harvested plants were sectioned and studied by transmission electron microscopy. Total metal content was analysed by atomic absorption spectroscopy. The chemical state of the metals was determined by X-ray absorption spectroscopy. Nanoparticles of Ag(0) and Au(0) were found in leaves, stem, roots and cell walls of the plants at a concentration of 0.40% Ag and 0.44% Au in the leaves. Particles which were approximately spherical were formed with sizes of 2-100 nm. The sites of the most abundant reduction of metal salts to nanoparticles were the chloroplasts, regions of high reducing sugar (glucose and fructose) content. We propose that these sugars are responsible for the reduction of these metals and other metal salts with reduction potentials over +0.16 V and that the amount of reducing sugar present or produced determines the quantity of metal nanoparticles that may be formed. PMID- 21611659 TI - Structural modification of nanocrystalline ceria by ion beams. AB - Exceptional size-dependent electronic-ionic conductivity of nanostructured ceria can significantly alter materials properties in chemical, physical, electronic and optical applications. Using energetic ions, we have demonstrated effective modification of interface volume and grain size in nanocrystalline ceria from a few nm up to ~25 nm, which is the critical region for controlling size-dependent material property. The grain size increases and follows an exponential law as a function of ion fluence that increases with temperature, while the cubic phase is stable under the irradiation. The unique self-healing response of radiation damage at grain boundaries is utilized to control the grain size at the nanoscale. Structural modification by energetic ions is proposed to achieve desirable electronic-ionic conductivity. PMID- 21611660 TI - Interplay between structure, stoichiometry and properties of technetium nitrides. AB - We report first-principles calculations of the structures and properties of technetium nitride phases within the framework of gradient-corrected density functional theory. Specifically, we have investigated the possible existence of hexagonal Tc(3)N and Tc(2)N subnitrides, following the recent discovery of Re nitrides analogues synthesized directly from the elements. These novel Tc subnitride phases, which are predicted to be stable, are also compared with bulk Tc and Tc mononitride in order to shed light on the intrinsic relationships between the structure, Tc/N stoichiometry, and properties in the Tc-N system. PMID- 21611661 TI - Selectivity in DNA replication. Interplay of steric shape, hydrogen bonds, pi stacking and solvent effects. AB - Our dispersion-corrected DFT computations reveal key factors behind the intrinsic affinity of a DNA template-primer complex to select the correct nucleotide. PMID- 21611662 TI - Relationship between the c(4*2) and the (?3*?3)R30 degrees phases in alkanethiol self-assembled monolayers on Au(111). AB - Transformation between the two well-known phases of alkanethiol monolayers on Au(111), c(4*2) and (?3*?3)R30 degrees , has been studied using scanning tunneling microscopy in ultra-high vacuum. Among the many versions of the c(4*2) phases observed, one particular structure where a lateral shift of adsorbate by as much as 0.17 nm within the unit cell is found. This lateral shift along the [112[combining macron]] direction corresponds to the movement of one adsorbed unit, towards its nearest neighbour from one hollow site to another (fcc to hcp, or hcp to fcc). PMID- 21611663 TI - Hydrogen interactions with diamond. PMID- 21611664 TI - Feedback control system simulator for the control of biological cells in microfluidic cross slots and integrated microfluidic systems. AB - Control systems for lab on chip devices require careful characterisation and design for optimal performance. Traditionally, this involves either extremely computationally expensive simulations or lengthy iteration of laboratory experiments, prototype design, and manufacture. In this paper, an efficient control simulation technique, valid for typical microchannels, Computed Interpolated Flow Hydrodynamics (CIFH), is described that is over 500 times faster than conventional time integration techniques. CIFH is a hybrid approach, utilising a combination of pre-computed flows and hydrodynamic equations and allows the efficient simulation of dynamic control systems for the transport of cells through micro-fluidic devices. The speed-ups achieved by using pre-computed CFD solutions mapped to an n-dimensional control parameter space, significantly accelerate the evaluation and improvement of control strategies and chip design. Here, control strategies for a naturally unstable device geometry, the microfluidic cross-slot, have been simulated and optimal parameters have been found for proposed devices capable of trapping and sorting cells. PMID- 21611665 TI - The regulation of the secondary metabolism of Streptomyces: new links and experimental advances. AB - Streptomycetes and other actinobacteria are renowned as a rich source of natural products of clinical, agricultural and biotechnological value. They are being mined with renewed vigour, supported by genome sequencing efforts, which have revealed a coding capacity for secondary metabolites in vast excess of expectations that were based on the detection of antibiotic activities under standard laboratory conditions. Here we review what is known about the control of production of so-called secondary metabolites in streptomycetes, with an emphasis on examples where details of the underlying regulatory mechanisms are known. Intriguing links between nutritional regulators, primary and secondary metabolism and morphological development are discussed, and new data are included on the carbon control of development and antibiotic production, and on aspects of the regulation of the biosynthesis of microbial hormones. Given the tide of antibiotic resistance emerging in pathogens, this review is peppered with approaches that may expand the screening of streptomycetes for new antibiotics by awakening expression of cryptic antibiotic biosynthetic genes. New technologies are also described that have potential to greatly further our understanding of gene regulation in what is an area fertile for discovery and exploitation PMID- 21611666 TI - Mild and selective labeling of malondialdehyde with 2-aminoacridone: assessment of urinary malondialdehyde levels. AB - Malondialdehyde (MDA) has become a well-established biomarker for oxidative stress. The most commonly used way to determine urinary MDA levels is the thiobarbituric acid (TBA) assay, which suffers from several drawbacks. In this manuscript, we describe a novel derivatization strategy for the highly sensitive and selective fluorescence-based determination of MDA in urinary samples. The methodology is based on the mild labeling of MDA with 2-aminoacridone, which can be carried out in aqueous citrate buffer at 40 degrees C, yielding a highly fluorescent substance. No further sample preparation than mixing with the necessary chemicals is necessary. The formed MDA derivative can conveniently be separated from the label itself and matrix constituents by gradient LC in less than 5 minutes on a cyano-based reversed-phase material. The method was validated with respect to matrix effects, linearity, selectivity and sensitivity (values as low as 1.8 nM for the LOD and 5.8 nM for the LOQ could be achieved). Standard addition quantitation was applied for the determination of MDA in human urine samples. Additionally, the protocol was applied to the measurement of a stability indicating analysis of MDA in urine at different storage conditions. PMID- 21611667 TI - Fluorescence quantum yield and photochemistry of bacteriophytochrome constructs. AB - Bacteriophytochromes (Bphs) are red-light photoreceptor proteins with a photosensory core that consists of three distinct domains, PAS, GAF and PHY, and covalently binds biliverdin (BV) to a conserved cysteine in the PAS domain. In a recent development, PAS-GAF variants were engineered for use as a near-infrared fluorescent marker in mammalian tissues (Tsien and co-workers, Science, 2009, 324, 804-807). Here, we report the fluorescence quantum yield and photochemistry of two highly-related Bphs from Rps. palustris, RpBphP2 (P2) and RpBphP3 (P3) with distinct photoconversion and fluorescence properties. We applied ultrafast spectroscopy to wild type P3 and P2 PAS-GAF proteins and their P3 D216A, Y272F and P2 D202A PAS-GAF-PHY mutant proteins. In these mutants hydrogen-bond interactions between a conserved aspartate (Asp) which connects the BV chromophore with the PHY domains are disrupted. The excited-state lifetime of the truncated P3 and P2 PAS-GAF proteins was significantly longer than in their PAS GAF-PHY counterparts that constitute the full photosensory core. Mutation of the conserved Asp to Ala in the PAS-GAF-PHY protein had a similar but larger effect. The fluorescence quantum yields of the P3 D216A and Y272F mutants were 0.066, higher than that of wild type P3 (0.043) and similar to the engineered Bph of Tsien and co-workers. We conclude that elimination of a key hydrogen-bond interaction between Asp and a conserved Arg in the PHY domain is responsible for the excited-state lifetime increase in all Bph variants studied here. H/D exchange resulted in a 1.4-1.7 fold increase of excited-state lifetime. The results support a reaction model in which deactivation of the BV chromophore proceeds via excited-state proton transfer from the BV pyrrole nitrogens to the backbone of the conserved Asp or to a bound water. This work may aid in rational structure- and mechanism-based conversion of constructs based on P3 and other BPhs into efficient near-IR, deep tissue, fluorescent markers. PMID- 21611669 TI - Effect of ZnO#ZnS QDs heterojunctures on the stilbenes-plasma proteins interactions. AB - Zero-dimensional nanostructures such as ZnO#ZnS QDs heterojunctures (QDHJs) are green nanoparticles and have gained a tremendous amount of attention. However, very little information is available on the effects of these heterojunctures on the transportation of drugs in blood. Herein, stilbenes were studied for their affinities for common bovine plasma proteins (CBPP) in the presence and absence of QDHJs with different diameters. The affinities of QDHJs for CBPP improved with increasing QDHJs size. QDHJs improved the affinities of resveratrol and polydatin for CBPP by 14.74% to 22.36% and 12.56% to 21.34% depending on the size of QDHJs. The number of binding sites (n) between resveratrol and polydatin for CBPP in the presence of QDHJs were 1.04 +/- 0.03 and 1.06 +/- 0.04, which were obviously higher than those in the absence of QDHJs (n = 0.89 and 0.92). QDHJs in blood will decrease the free concentration of stilbenes and weaken their pharmacological effects. PMID- 21611668 TI - Nano-structured nickel oxide based DNA biosensor for detection of visceral leishmaniasis (Kala-azar). AB - Sol-gel synthesized nickel oxide (NiO) film deposited onto indium tin oxide (ITO) coated glass plate has been utilized for the development of sensitive and stable DNA biosensor and demonstrated for diagnosis of visceral leishmaniasis also known as Kala-azar. Leishmania specific sensor is developed by immobilizing 23mer DNA sequence (oligonucleotide) identified from 18S rRNA gene sequences from Leishmania donovani. Characterization studies like X-Ray Diffraction and Scanning Electron Microscopy revealed the formation of nano-structured NiO, while immobilization of single strand (ss)-DNA of Leishmania was supported by UV visible, Fourier Transform Infrared Spectroscopy and Scanning Electron Microscopy techniques. Response studies of ss-DNA/NiO/ITO bioelectrode are carried out using differential pulsed voltammetry in presence of methylene blue redox dye as a redox mediator. A linear response is obtained in the wide concentration range of 2 pg ml(-1) to 2 MUg ml(-1) of complementary target genomic DNA (disease DNA) within the variation of 10% for 5 sets of studies. The observed results hold promise not only for diagnosis of Kala-azar patients but also hold enormous potential of the nano-NiO based probe for development of stable and sensitive biosensors. PMID- 21611670 TI - Autocatalytic formation of fluorinated ferrocenophanes from 1,1' bis(trifluorovinyl)ferrocene. AB - 1,1'-Bis(trifluorovinyl)ferrocene is obtained in excellent yields from a Negishi type coupling reaction. Under certain redox conditions and in the presence of a suitable nucleophile, the highly reactive compound undergoes a transformation to fluorinated ferrocenophanes. Intra and intermolecular [2+2]-cycloaddition products are formed upon heating. PMID- 21611671 TI - Synthetic protocol for diarylethenes through Suzuki-Miyaura coupling. AB - The synthesis of a variety of diarylethenes through the Suzuki-Miyaura coupling reaction of 1,2-dichlorohexafluorocyclopentene with arylboronic acids and esters has been developed. Thiophenes with various substituents such as cyano and ester functionalities can be incorporated. PMID- 21611672 TI - Synthesis and structure of tridentate bis(phosphinic amide)-phosphine oxide complexes of yttrium nitrate. Applications of 31P,89Y NMR methods in structural elucidation in solution. AB - The synthesis and characterisation of a tridentate ligand containing two diphenylphosphinic amide side-arms connected through the ortho position to a phenylphosphine oxide moiety and the 1:1 and 2:1 complexes formed with yttrium nitrate are reported for the first time. The free ligand (R(P1)*,S(P3)*)-11 is obtained diastereoselectively by reaction of ortho-lithiated N,N-diisopropyl-P,P diphenylphosphinic amide with phenylphosphonic dichloride. Complexes [Y((R(P1)*,S(P3)*)-11)(NO(3))(3)] and [Y((R(P1)*,S(P3)*)-11)(2)(NO(3))](NO(3))(2) were isolated by mixing ligand 11 with Y(NO(3))(3).6H(2)O in acetonitrile at room temperature in a ligand to metal molar ratio of 1:1 and 2:1, respectively. The 1:1 derivative is the product of thermodynamic control when a molar ratio of ligand to yttrium salt of 1:1 is used. The new compounds have been characterised both as the solid (X-ray diffraction) and in solution (multinuclear magnetic resonance). In both yttrium complexes the ligand acts as a tridentate chelate. The arrangement of the two ligands in the 2:1 complex affords a pseudo-meso structure. Tridentate chelation of yttrium(III) in both complexes is retained in solution as evidenced by (89)Y NMR data obtained via(31)P,(89)Y-HMQC, and (89)Y,(31)P-DEPT experiments. The investigation of the solution behaviour of the Y(III) complexes through PGSE NMR diffusion measurements showed that average structures in agreement with the 1:1 and 1:2 stoichiometries are retained in acetonitrile. PMID- 21611673 TI - Surface chemistry: a non-negligible parameter in determining optical properties of small colloidal metal nanoparticles. AB - Surface chemistry can become pronounced in determining the optical properties of colloidal metal nanoparticles as the nanoparticles become so small (diameters <20 nm) that the surface atoms, which can undergo chemical interactions with the environment, represent a significant fraction of the total number of atoms although this effect is often ignored. For instance, formation of chemical bonds between surface atoms of small metal nanoparticles and capping molecules that help stabilize the nanoparticles can reduce the density of conduction band electrons in the surface layer of metal atoms. This reduced electron density consequently influences the frequency-dependent dielectric constant of the metal atoms in the surface layer and, for sufficiently high surface to volume ratios, the overall surface plasmon resonance (SPR) absorption spectrum. The important role of surface chemistry is highlighted here by carefully analyzing the classical Mie theory and a multi-layer model is presented to produce more accurate predictions by considering the chemically reduced density of conduction band electrons in the outer shell of metal atoms in nanoparticles. Calculated absorption spectra of small Ag nanoparticles quantitatively agree with the experimental results for our monodispersed Ag nanoparticles synthesized via a well-defined chemical reduction process, revealing an exceptional size-dependence of absorption peak positions: the peaks first blue-shift followed by a turnover and a dramatic red-shift as the particle size decreases. A comprehensive understanding of the relationship between surface chemistry and optical properties is beneficial to exploit new applications of small colloidal metal nanoparticles, such as colorimetric sensing, electrochromic devices, and surface enhanced spectroscopies. PMID- 21611674 TI - Dehydrogenation of cyclic thioethers bound to a [Rh(diphosphine)]+ fragment. AB - The metal-promoted dehydrogenation of cyclic thioethers S(C(5)H(9))(R) (R = C(5)H(9), Ph) to give the corresponding cycloalkenes, S(C(5)H(7))(R), using the [Rh{Ph(2)P(CH(2))(3)PPh(2)}](+) fragment is reported. PMID- 21611676 TI - The CH/pi hydrogen bond in chemistry. Conformation, supramolecules, optical resolution and interactions involving carbohydrates. AB - The CH/pi hydrogen bond is an attractive molecular force occurring between a soft acid and a soft base. Contribution from the dispersion energy is important in typical cases where aliphatic or aromatic CH groups are involved. Coulombic energy is of minor importance as compared to the other weak hydrogen bonds. The hydrogen bond nature of this force, however, has been confirmed by AIM analyses. The dual characteristic of the CH/pi hydrogen bond is the basis for ubiquitous existence of this force in various fields of chemistry. A salient feature is that the CH/pi hydrogen bond works cooperatively. Another significant point is that it works in nonpolar as well as polar, protic solvents such as water. The interaction energy depends on the nature of the molecular fragments, CH as well as pi-groups: the stronger the proton donating ability of the CH group, the larger the stabilizing effect. This Perspective focuses on the consequence of this molecular force in the conformation of organic compounds and supramolecular chemistry. Implication of the CH/pi hydrogen bond extends to the specificity of molecular recognition or selectivity in organic reactions, polymer science, surface phenomena and interactions involving proteins. Many problems, unsettled to date, will become clearer in the light of the CH/pi paradigm. PMID- 21611675 TI - Facile solvothermal synthesis of cube-like Ag@AgCl: a highly efficient visible light photocatalyst. AB - In this paper, a stable and highly efficient plasmonic photocatalyst, Ag@AgCl, with cube-like morphology, has been successfully prepared via a simple hydrothermal method. Using methylene dichloride as chlorine source in the synthesis can efficiently control the morphology of Ag@AgCl, due to the low release rate of chloride ions. Scanning electron microscopy (SEM), X-ray powder diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and UV-vis diffuse reflectance spectra were used to characterize the obtained product. The photocatalytic activity of the obtained product was evaluated by the photodegradation of methyl orange (MO) under visible light irradiation, and it was found, interestingly, that Ag@AgCl exhibits high visible light photocatalytic activity and good stability. PMID- 21611677 TI - Follow-up of FDG-PET/CT findings in retroperitoneal fibrosis associated with abdominal aortic aneurysm. PMID- 21611678 TI - Acitretin revisited. AB - Acitretin over the last 20 years has proven useful in a number of dermatologic diseases. Evidence of efficacy, side-effect profile, and approach to its use will be reviewed. PMID- 21611679 TI - Overview of treatment of vulvovaginal disease. AB - Vulvovaginal diseases commonly are inadequately diagnosed and treated. Most are dermatologic, but can be atypical in presentation in the warm, moist genital area. There is limited training or education for medical caregivers for these conditions. The first step is correct diagnosis, which requires time and knowledge of the normal anatomy, and careful examination. Dermatologists are invaluable for management as they recognize skin problems and can correct barrier function, control inflammation, and address itching and pain. PMID- 21611680 TI - Allergic contact dermatitis to preservatives and fragrances in cosmetics. AB - Cosmetics are an important cause of allergic contact dermatitis (ACD). Fragrances and preservatives are the two most clinically relevant allergens found in cosmetic products. Patch testing remains the gold standard for identification of causative allergens. Common cosmetic allergens are reviewed. Practical methods of allergen avoidance are also discussed. PMID- 21611681 TI - Alcohol and skin disorders: with a focus on psoriasis. AB - Alcohol is a serious cause of morbidity and mortality in our society and is implicated in multiple health conditions, including hepatic failure, neurological damage, hematological disorders, and nutritional deficiencies, to name a few. Although alcohol induced cutaneous abnormalities can also cause significant morbidity, they tend to be overshadowed by the other disease states associated with alcohol use. In addition to the cutaneous stigmata linked to chronic alcoholic liver disease, alcohol can directly cause or exacerbate several skin conditions. In particular, alcohol misuse is implicated in the development of psoriasis and discoid eczema, as well as confers increased susceptibility to skin and systemic infections. Alcohol misuse might also exacerbate rosacea, porphyria cutanea tarda, and post adolescent acne. Herein, we review the evidence concerning the influences of alcohol in skin conditions with a focus on psoriasis. PMID- 21611682 TI - Stress as an influencing factor in psoriasis. AB - Emotional stress may influence the development and exacerbation of psoriasis. The proportion of psoriasis patients who believe stress affects their skin condition (i.e., "stress responders") is considerably high, ranging from 37% to 78%. Stress may worsen psoriasis severity and may even lengthen the time to disease clearance. Although a pathogenic association appears likely, additional well controlled studies are necessary to confirm such a causal relationship. Dysregulation of the hypothalamus-pituitary-adrenal and sympathetic adrenomedullary systems has been proposed as one possible underlying cause of stress-induced flares of psoriasis. While stress may be an exacerbating factor, psoriasis itself may contribute to significant adverse psychological sequelae. Breaking this stress cycle may be an important part of any therapeutic approach. Thus, stress reduction through psychotherapy and pharmacotherapy may be useful in treating psoriatic patients who are stress responders. PMID- 21611683 TI - Propylene glycol: an often unrecognized cause of allergic contact dermatitis in patients using topical corticosteroids. AB - Propylene glycol (PG) is considered to be a ubiquitous formulary ingredient used in many personal care products and pharmaceutical preparations. It is an organic compound commonly found in topical corticosteroids (CS). Cutaneous reactions to PG are mostly irritant, but allergic contact dermatitis to PG is well-documented. Cosensitization to PG and topical CS can occur, making it challenging to choose the appropriate topical CS in a PG-allergic patient. This review is aimed at guiding clinicians in the selection of a suitable topical corticosteroid when presented with patients allergic to PG. PMID- 21611684 TI - Predictors of pain associated with photodynamic therapy: a retrospective study of 658 treatments. AB - Pain is the most common side-effect of photodynamic therapy (PDT). Our main objective was to identify pain predictors in PDT. In total, we performed 658 treatments on 377 patients at our department during 2004. Larger sized treatment areas were the strongest pain predictor, and actinic keratoses were more painful to treat than basal cell carcinomas and Bowen's disease. The most sensitive areas to treat were the face and scalp. Gender and age did not influence pain. Although treatment outcome was not our primary objective, 62% of 95 superficial basal cell carcinomas that were followed for 3 years showed complete clearance. Also, perforation of nodular basal cell carcinomas did not lead to better clinical results. In conclusion, the size of the treatment area, the diagnosis and the lesion location influence pain during PDT. Nevertheless, there is a large variance in visual analogue scale assessment within each group, thereby limiting the ability to predict pain. PMID- 21611685 TI - Acne as seen by adolescents: results of questionnaire study in 852 French individuals. AB - Acne can have an important psychological impact. We surveyed 852 adolescents aged 12-25 years about their knowledge of acne and its treatment in a non-medical context. The study involved a questionnaire administered to callers to a youth telephone helpline in France. Callers were categorized into those who currently had acne, those who had had acne previously, and those who had never had acne. Most respondents (66.2%) had experienced acne symptoms, which were mild in 50.2% of cases and severe in 16% of cases. Often, acne had been long-lasting (>12 months in 49.6% of cases). Many thought that gender, excess weight, eating dairy products, and physical activity did not influence acne, and that frequent washing could improve acne. Eating chocolate and snacks, smoking cigarettes, sweating, not washing, touching/squeezing spots, eating fatty foods, using make-up, pollution, and menstruation were thought to worsen acne. The majority (80.8%) did not believe acne to be a disease, but rather a normal phase of adolescence, yet 69.3% agreed it should be treated. There was a preference for topical vs. systemic treatment. Many (38.6%) of the respondents with acne had not consulted a physician. Almost two-thirds of respondents wanted more information about acne. Providing more information about acne might increase the likelihood of them consulting a physician and getting better treatment for the condition. PMID- 21611686 TI - Validation of a specific health-related quality of life instrument in a large cohort of patients with psoriasis: the QualiPso Questionnaire. AB - The aim of this study was to develop and validate a standardized tool designed to assess health-related quality of life (HRQoL) in a large cohort of French patients with psoriasis, the QualiPso Questionnaire. A draft questionnaire was developed based on a literature review, followed by one-to-one interviews of 50 patients with psoriasis conducted by trained psychologists. The interview transcripts were analysed, after which 56 items were retained and validated in a cohort of 569 patients. Four QualiPso subscales were derived from factor analysis. The first factor encompasses disturbances of social life, a key factor in HRQoL among psoriasis patients (Cronbach's alpha coefficient: alpha=0.948). The second factor assesses the impact of psoriasis on mental health (alpha=0.932). The third factor reflects concerns related to treatment outcomes (alpha=0.873), and the fourth factor is related to skin symptoms (alpha=0.772). The subscales are related but distinct, accounting for 60% of the common variance. In conclusion, the QualiPso questionnaire provides a reliable and valid measure of a patient's psychosocial well-being in relation to psoriasis. It also measures the impact of concerns related to treatment outcomes and skin symptoms, which have not been addressed previously by HRQoL research on psoriasis. PMID- 21611687 TI - Effects of continuous thermophilic composting (CTC) on bacterial community in the active composting process. AB - The method of continuous thermophilic composting (CTC) remarkably shortened the active composting cycle and enhanced the compost stability. Effects of CTC on the quantities of bacteria, with a comparison to the traditional composting (TC) method, were explored by plate count with incubation at 30, 40 and 50 degrees C, respectively, and by quantitative PCR targeting the universal bacterial 16S rRNA genes and the Bacillus 16S rRNA genes. The comparison of cultivatable or uncultivatable bacterial numbers indicated that CTC might have increased the biomass of bacteria, especially Bacillus spp., during the composting. Denaturing gradient gel electrophoresis (DGGE) analysis was employed to investigate the effects of CTC on bacterial diversity, and a community dominated by fewer species was detected in a typical CTC run. The analysis of sequence and phylogeny based on DGGE indicated that the continuously high temperature had changed the structure of bacterial community and strengthened the mainstay role of the thermophilic and spore-forming Bacillus spp. in CTC run. PMID- 21611688 TI - Extracellular hydrolytic enzyme activities of the heterotrophic microbial communities of the Rouge River: an approach to evaluate ecosystem response to urbanization. AB - The potential effects of urbanization on the bioavailability of dissolved organic carbon (DOC) were tested by determining the extracellular enzyme activities of the heterotrophic microbial communities of the Rouge River. The activities of 19 enzymes were monitored across two water samples (river water and groundwater) at different spatial and temporal scales. High phosphatase, esterase, and aminopeptidase activities was observed in site 9 (site most exposed to anthropogenic sources) showed higher concentrations of DOC compared to sites 1 and 8 (sites exposed to less anthropogenic sources), where moderate activities of diverse range of enzymes were observed. High relative contributions of phosphatase, esterase, and aminopeptidase activities to the overall enzyme activity as observed in site 9 stressed the increased importance of peptides as C source for heterotrophic communities and high in-stream carbon processing, which account for high nonspecific extracellular enzyme activities. In contrast, high contribution of glycosyl hydrolases occurred consistently across all sites, which highlights the significance of microbial detrital and plant biomass as carbon sources. Majority of the enzymes showed evidence of activity at various extents during spring and summer. However, higher activities of leucine aminopeptidase, valine aminopeptidase, beta-glucosidase, and alpha-mannosidase were observed in the summer; and alkaline phosphatase and alpha-glucosidase in the spring. The results presented here suggest a shift in organic carbon bioavailability across all sites of contrasting urbanization, despite similarities in DOC concentrations. Hence, API ZYM technique can be used as an effective indicator of river water and groundwater system health across an urban gradient. PMID- 21611689 TI - Coxiella symbionts in the Cayenne tick Amblyomma cajennense. AB - Members of the Coxiella genus are intracellular bacteria that can infect a variety of animals including humans. A symbiotic Coxiella was recently described in Amblyomma americanum ticks in the Northern Hemisphere with no further investigations of other Amblyomma species in other geographic regions. These ixodid ticks represent a group of important vectors for human infectious agents. In the present work, we have demonstrated that symbiotic Coxiella (SCox) are widespread, occurring in South America and infecting 100% of all life stages and eggs of the Cayenne ticks Amblyomma cajennense from Brazil and the USA. Using light microscopy, in situ hybridization, and PCR, we demonstrated SCox in salivary glands, ovaries, and the intestines of A. cajennense. These symbionts are vertically and transtadially transmitted in laboratory reared A. cajennense, and quantitative PCR analyses indicate that SCox are more abundant in adult female ticks, reaching values corresponding to an 11*, 38*, and 200* increase in SCox 16S rRNA gene copy number in unfed females, compared to unfed nymphs, larvae, and eggs, respectively. Phylogenetic analyses showed distinct SCox subpopulations in the USA and Brazil and demonstrated that SCox bacteria do not group with pathogenic Coxiella burnetii. PMID- 21611690 TI - Participation of cell-surface hydrophobins for hemin binding in Helicobacter pylori. AB - Treatment of Helicobacter pylori cells with several chaotropic agents resulted in different degrees of inhibition in the binding of the bacteria to hemin and Congo red dye. Polyanions also yielded a >50% inhibitory effect. Furthermore, hydrophobic interaction chromatography was used to determine the relative surface hydrophobicity of cell-associated proteins extracted with 3 mol/L urea, revealing proteins with a significant hydrophobic profile. PMID- 21611691 TI - allB, allantoin utilisation and Salmonella enterica serovar Enteritidis and Typhimurium colonisation of poultry and mice. AB - Natural variation in the presence or the absence of STM0517-0529 genes allowing allantoin utilisation has been described in field isolates of the multidrug resistant Salmonella enterica serovar Typhimurium belonging to the phage type DT104. Interestingly, S. enterica subspecies enterica serovar Typhimurium DT104 is quite frequent in pigs and cattle, but rarely present in egg-laying hens. Taking into account the different mode of allantoin metabolism in birds and mammals, we were interested in whether the absence of STM0517-0529 genes may disable this clone in poultry colonisation. We have therefore constructed the allB (also designated as STM0523) mutants in S. enterica subspecies enterica serovar Typhimurium and S. enterica subspecies enterica serovar Enteritidis, and with these, we infected mice, newly hatched chickens and adult egg-laying hens to show that the defect in allantoin utilisation does not influence S. enterica virulence for mice or adult hens, but slightly decreases virulence of S. enterica for chickens. The decrease in virulence of the allB mutant was relatively minor as it could be observed only after a mixed infection model, consistent with a lower prevalence, but not a total absence of such clones in poultry flocks. PMID- 21611712 TI - Scope for rotavirus vaccination in India: revisiting the scientific evidence. AB - Rotavirus vaccines have been developed to prevent deaths resulting from severe diarrhea of rotavirus origin. The use of vaccines as an intervention at scale to prevent and control the burden of rotavirus diarrhea is supported by the argument that prevailing public health measures such as hygiene and sanitation, breast feeding and use of ORS have failed to prevent severe dehydration resulting from diarrhea. The article reviews the existing evidence on the rationale of using rotavirus vaccine as against the feasibility of scaling it up in developing countries like India. The vaccines currently available may not cover the strains circulating in Indian population. The diversity of Rotavirus infection in the country is tremendous and since the safety, immunogenicity and efficacy data has not been collected for India, there is first a need to conduct studies to measure the extent of protection and cross-protection provided by the available vaccines for local strains, before venturing into Rotavirus vaccination program. The potential benefits of immunization have to be first vetted against the risks involved by the policymakers and other stakeholders. PMID- 21611713 TI - Calcinosis cutis in a newborn with transient pseudohypoparathyroidism. AB - Pseudohypoparathyroidism (PHP) is a heterogenous group of disorders characterized by hypocalcemia with hyperphosphatemia, increased serum concentration of parathyroid hormone (PTH), and insensitivity to the biological activity of PTH. Calcinosis cutis, the cutaneous deposition of calcium salts in the dermis, is a rare clinical symptom in infancy. The deposition of calcium in the skin may be classified as dystrophic, metastatic, idiopathic, and iatrogenic. Although a few infants with PHP and calcinosis cutis have been reported, to the authors' knowledge, the combination of neonatal transient PHP and calcinosis cutis associated with calcium treatment has not been previously reported. The authors report a newborn boy with transient PHP presenting with early hypocalcemia, hyperphosphatemia, increased PTH levels, and calcinosis cutis after intravenous treatment of calcium gluconate. PMID- 21611714 TI - Adolescent health care in India: progressive, regressive or at the cross-roads? AB - India has a sizeable adolescent population. Adolescents constitute a vulnerable population for both mental and physical illnesses, and yet their health-care needs and delivery systems are neither well defined nor developed. Many of the mental, reproductive and nutritional health needs of this population are required to be addressed and can be addressed in the primary-care pediatric setting itself if the current system of health-care can be re-organized. This restructuring will be more effective for this population if adolescent friendly approaches, public private partnership and policy as well as sectoral linkage between the NRHM and other national programs are achieved. The health program for this age group should have promotive and preventive as well as remedial and curative components. Also, improving the availability of trained personnel in these areas of health, culturally sensitive evidence based approaches and capacity building in the primary-care approach is essential to ensure the viability of adolescent health care in this country. PMID- 21611715 TI - Pediatric cardiopulmonary resuscitation and stabilization. AB - Cardiopulmonary arrest refers to cessation of clinically detectable cardiac activity. In children, it usually results from progression of shock, respiratory failure or cardiac dysrhythmia. Early recognition and timely interventions in above group of patients is the key to prevent progression to cardiac arrest. The goal of resuscitation is to urgently re-establish oxygenation of vital organs by attention to Airway, Breathing and Circulation. Measures to restore airway patency include positioning, suctioning, continuous positive airway pressure, relieving a foreign-body airway obstruction and, endotracheal intubation, tracheotomy or laryngeal mask airway. Breathing is supported with O(2) and if needed, bag-mask ventilation, or endotracheal intubation and ventilation. Patients with absent or feeble central pulse are given cardiac compressions (CPR) at a rate of 100/ min synchronized with ventilation. In sudden witnessed collapse, immediate defibrillation is warranted, followed by CPR and administration of drugs. In unwitnessed collapse, CPR is performed for five cycles or 2 min before defibrillation. In patients with shock, a venous or an intraosseous access is rapidly established to administer 20 ml/kg saline bolus. Supraventricular tachycardia is treated with vagal maneuvers and adenosine, if the patient is stable and with synchronized cardioversion, if unstable. Ventricular tachycardia is treated with amiodarone or lidocaine, if stable, and cardioversion if unstable or if drugs fail. Ventricular fibrillation needs defibrillation. Aggressive supportive care is needed during the post resuscitation phase. There is no definite marker to determine futility of CPR. Short duration of arrest, early initiation of CPR, hypothermia as the cause of arrest, and in-hospital arrest have better prognosis. PMID- 21611716 TI - Cultural implications of differing rates of medically indicated and elective cesarean deliveries for foreign-born versus native-born taiwanese mothers. AB - The study aimed to assess the number of medically indicated and elective cesarean deliveries among foreign-born and native-born mothers in Taiwan. National Health Insurance (NHI) inpatient datasets in Taiwan between 2001 and 2003 showed 673,830 singleton deliveries, of which 66,687 were to foreign-born mothers and 607,143 were to Taiwan-born mothers. Univariate and multivariate logistic regression models were used to estimate the likelihood of using inpatient services for medically indicated and elective cesarean delivery. During the study period, foreign-born mothers were significantly less likely to undergo medically indicated (odds ratio [OR], 0.82; 95% confidence interval (95% CI), 0.79-0.85) and elective (OR, 0.50; 95% CI, 0.47-0.53) cesarean delivery than Taiwan-born mothers after adjusting for clinical and nonclinical factors. Foreign-born mothers aged 18-50 years are less likely to undergo medically indicated and elective cesarean delivery under Taiwan's NHI coverage. As the birth rate for immigrant women increases, cross-cultural maternity care during pregnancy and childbirth for immigrant mothers needs to be addressed. PMID- 21611717 TI - Urban teens and young adults describe drama, disrespect, dating violence and help seeking preferences. AB - Adolescent dating violence is increasingly recognized as a public health problem. Our qualitative investigation sought input from urban, African-American adolescents at risk for dating violence concerning (Tjaden and Thoennes in Full report of the prevelance, incidence, and consequences of violence against women: findings from the national violence against women survey. US Department of Justice, Washington, DC, 2000) dating violence descriptions, (WHO multi-country study on women's health and domestic violence against women: Summary report of initial results on prevalence, health outcomes and women's responses. World Health Organization, Geneva, 2005) preferences for help-seeking for dating violence, and (Intimate partner violence in the United States. Bureau of Justice Statistics, US Department of Justice, Office of Justice Programs, Washington, DC, 2007) recommendations for a teen dating violence resource center. Four focus groups were conducted with urban, African American adolescents (n = 32) aged 13 24 recruited from an urban adolescent clinic's community outreach partners. Qualitative analysis was conducted. Participants assigned a wide range of meanings for the term "relationship drama", and used dating violence using language not typically heard among adults, e.g., "disrespect". Participants described preferences for turning to family or friends before seeking formal services for dating violence, but reported barriers to their ability to rely on these informal sources. When asked to consider formal services, they described their preferred resource center as confidential and safe, with empathetic, non judgmental staff. Teens also gave insight into preferred ways to outreach and publicize dating violence resources. Findings inform recommendations for youth specific tailoring of violence screening and intervention efforts. Current evidence that slang terms, i.e., "drama", lack specificity suggests that they should not be integrated within screening protocols. These data highlight the value of formative research in understanding terminology and help-seeking priorities so as to develop and refine dating violence prevention and intervention efforts for those most affected. PMID- 21611718 TI - Possible shift in macaque trophic level following a century of biodiversity loss in Singapore. AB - Biodiversity loss in tropical forests is a major problem in conservation biology, and nowhere is this more dire than in Southeast Asia. Deforestation and the associated loss of species may trigger shifts in habitat and feeding preferences of persisting species. In this study, I compared the habitat use and diet of long tailed macaque (Macaca fascicularis) populations in Singapore from two time periods: museum specimens originally collected between 1893 and 1944, and living macaques sampled in 2009. I collected hair and used stable carbon and nitrogen isotope analysis to identify temporal changes in dietary source and trophic position, respectively. delta(13)C ratios were virtually identical, suggesting that macaques foraged in similar habitats during both time periods. However, delta(15)N ratios decreased considerably over time, suggesting that macaques today feed at a lower trophic level than previously. This decline in trophic level may be because of the disappearance or decline of other species that compete with macaques for fruit. This study highlights the effect of biodiversity loss on persisting species in degraded habitats of Southeast Asia, and improves our understanding of how species will adapt to further human-driven changes in tropical forest habitats. PMID- 21611719 TI - Chronic treatment of paroxysmal nocturnal hemoglobinuria patients with eculizumab: safety, efficacy, and unexpected laboratory phenomena. AB - The terminal complement inhibitor eculizumab has become the standard of treatment in patients with symptomatic paroxysmal nocturnal hemoglobinuria (PNH). In this retrospective study, 19 PNH patients received chronic therapy with eculizumab with a median duration of 16 months (range 6-46 months). Parameters of hemolysis, transfusion requirements, and serum iron parameters were analyzed. Lactate dehydrogenase levels were significantly decreased by 85% from a median of 1897 U/l (range 293-3360) to 283 U/l (range 143-667), with an 86% reduction of transfusion requirements, whereas other parameters of hemolysis remained abnormal. Six patients (31.6%) became completely transfusion independent. A significant increase in ferritin levels from a median of 104 MUg/l before to a median of 528 MUg/l (p = 0.011) during treatment with eculizumab was observed. This was more pronounced in patients with low reticulocyte production index and/or requiring blood transfusions. Monospecific direct Coombs test was positive in most PNH patients, indicating a shift to extravascular hemolysis. Positive immunofixation for IgG kappa was observed, due to the presence of eculizumab in the serum. Eculizumab was safe and well tolerated long term in our study population. Iron should not be routinely supplemented in PNH patients treated with eculizumab without close monitoring of iron parameters, and iron depletion therapy should be considered in the case of overload. PMID- 21611720 TI - Water soaking and exogenous enzyme treatment of plant-based diets: effect on growth performance, whole-body composition, and digestive enzyme activities of rohu, Labeo rohita (Hamilton), fingerlings. AB - A 2 * 2 * 2 factorial experiment was conducted to delineate the main effect of water soaking of plant ingredients, phytase, cellulase, and their interactions on the growth and digestive enzyme activities of Labeo rohita fingerlings. Two basal diets were prepared using water-soaked (S) or unsoaked (US) plant-based ingredients. Feed of US ingredients was supplemented with phytase (U kg(-1)) and cellulase (%) at the level of 0, 0 (C(us)); 500, 0 (T(1)); 0, 0.2 (T(2)); 500, 0.2 (T(3)), and feed of S ingredients at 0, 0 (C(s)); 500, 0 (T(4)); 0, 0.2 (T(5)), and 500, 0.2 (T(6)), respectively. Three hundred and sixty fingerlings were randomly distributed into eight treatments, each with three replicates. Soaking of the ingredients for 24 h significantly reduced the tannin content. However, feeding of S diets did not improve the fish growth. Highest performance was recorded in the T(3) group. A significant interaction between dietary phytase and cellulase was observed for apparent net protein utilization. Tissue crude protein, ether extract, and ash content of the fingerlings were observed highest in the T(3) group. Activities of amylase, protease, and lipase were recorded highest in the T(3) group. Results suggested that soaking of plant-based ingredients reduces tannin content; however, growth and digestive enzyme activities of group fed soaked diet were not improved, possibly due to leaching of soluble nutrients. Probably, a shorter duration soaking may be effective in reducing tannin content and avoiding nutrients leaching. PMID- 21611721 TI - Fish under exercise. AB - Improved knowledge on the swimming physiology of fish and its application to fisheries science and aquaculture (i.e., farming a fitter fish) is currently needed in the face of global environmental changes, high fishing pressures, increased aquaculture production as well as increased concern on fish well-being. Here, we review existing data on teleost fish that indicate that sustained exercise at optimal speeds enhances muscle growth and has consequences for flesh quality. Potential added benefits of sustained exercise may be delay of ovarian development and stimulation of immune status. Exercise could represent a natural, noninvasive, and economical approach to improve growth, flesh quality as well as welfare of aquacultured fish: a FitFish for a healthy consumer. All these issues are important for setting directions for policy decisions and future studies in this area. For this purpose, the FitFish workshop on the Swimming Physiology of Fish ( http://www.ub.edu/fitfish2010 ) was organized to bring together a multidisciplinary group of scientists using exercise models, industrial partners, and policy makers. Sixteen international experts from Europe, North America, and Japan were invited to present their work and view on migration of fishes in their natural environment, beneficial effects of exercise, and applications for sustainable aquaculture. Eighty-eight participants from 19 different countries contributed through a poster session and round table discussion. Eight papers from invited speakers at the workshop have been contributed to this special issue on The Swimming Physiology of Fish. PMID- 21611722 TI - Role of computerized tomographic cisternography in idiopathic normal pressure hydrocephalus. AB - BACKGROUND: We prospectively evaluate the role of computerized tomographic cisternography (CTC) in idiopathic normal pressure hydrocephalus (iNPH). METHODS: The cerebrospinal fluid kinetics of 70 patients who passed the entry criteria for the Study of iNPH on Neurological Improvement (SINPHONI) and underwent insertion of a shunt were studied. RESULTS: Stasis of the contrast medium at the lateral ventricles over 24 h (positive ventricular stasis) was observed in 60 patients and at the Sylvian fissure or parietal sulci over 48 h (positive surface stasis) in 59 patients. Sixty patients showed a good response to shunt insertion. The sensitivities of CTC findings at the lateral ventricles and brain surface for shunt effectiveness were 81.7 and 86.7%, respectively; however, the specificities were 20 and 0%. Among the 60 patients who showed a good response to the shunt, 49 had positive surface stasis. Positive ventricular stasis was observed in 52 of the 60 patients, and both findings were observed in 44 patients. Three patients who responded to the shunt had negative stasis in both sites. The 11 patients who had negative surface stasis had significantly lower (p < 0.05) preoperative iNPH grading scale-R scores than the 49 patients with positive surface stasis; these patients were considered to be in an early stage of iNPH. CONCLUSIONS: CTC did not provide additional diagnostic value for predicting the shunt response among patients selected using SINPHONI criteria. We suggest that factors other than disturbances in CSF circulation may be related to the pathogenesis of iNPH. PMID- 21611723 TI - Sensation recovery of auricle following chronic ear surgery by retroauricular incision. AB - The aim of this prospective analysis was to objectify and quantify the sensory loss in the auricular area that occurs following surgery for chronic otitis media or cholesteatoma, and to assess the exact recovery time of the auricular sensation. Till now, no study has yet been conducted on the sensory loss that is developed after retroauricular incision is performed for chronic ear surgery. Forty-eight patients underwent surgery via retroauricular incision for chronic otitis media or for chronic otitis media or cholesteatoma between March 2009 and January 2010. The skin around the auricle was divided into six areas. The sensation of each area was assessed before the surgery and 3 days, 7 days, 1 month, 3 months, and 6 months after the surgery, using the Semmes-Weinstein monofilaments. The patients were also asked to record the sensation that they felt using the visual analog scale (VAS). In the objective sensory assessment, only area 5, which corresponds to the retroauricular area, showed significant sensory loss. Three months after the surgery, the sensation was recovered to a level comparable to that before the surgery in most of the patients. The mean subjective VAS score was 10 prior to the surgery, 8.56 (+/- 1.08) 3 months after the surgery, and 9.32 (+/- 0.74) 6 months after the surgery, respectively. In conclusion, following chronic ear surgery, the sensation of the auricle was recovered to the previous level within 3 months. Therefore, patients who are to undergo retroauricular incision should be informed that they will experience temporary sensory loss for approximately 3 months after the surgery. PMID- 21611725 TI - Is two better than one? Combining antiresorptive and anabolic osteoporosis medications. PMID- 21611724 TI - Human cognitive flexibility depends on dopamine D2 receptor signaling. AB - RATIONALE: Accumulating evidence indicates that the cognitive effects of dopamine depend on the subtype of dopamine receptor that is activated. In particular, recent work with animals as well as current theorizing has suggested that cognitive flexibility depends on dopamine D2 receptor signaling. However, there is no evidence for similar mechanisms in humans. OBJECTIVES: We aim to demonstrate that optimal dopamine D2 receptor signaling is critical for human cognitive flexibility. METHODS: To this end, a pharmacological pretreatment design was employed. This enabled us to investigate whether effects of the dopamine receptor agonist bromocriptine on task-set switching were abolished by pretreatment with the D2 receptor antagonist sulpiride. To account for individual (genetic) differences in baseline levels of dopamine, we made use of a common variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the dopamine transporter gene, DAT1. RESULTS: Bromocriptine improved cognitive flexibility relative to placebo, but only in subjects with genetically determined low levels of dopamine (n = 27). This beneficial effect of bromocriptine on cognitive flexibility was blocked by pretreatment with the selective dopamine D2 receptor antagonist sulpiride (n = 14). CONCLUSIONS: These results provide strong evidence in favor of the hypothesis that human cognitive flexibility implicates dopamine D2 receptor signaling. PMID- 21611726 TI - Diffuse vascular injury: convergent-type hemorrhage in the supratentorial white matter on susceptibility-weighted image in cases of severe traumatic brain damage. AB - INTRODUCTION: Susceptibility-weighted image (SWI) is one of the most sensitive methods for detect microbleeding and useful for evaluation of traumatic brain damage. The purpose of this study is to delineate the characteristics and importance of supratentorial deep white matter hemorrhages detected by SWI in cases of traumatic brain damage. METHODS: Twenty-one consecutive cases with severe traumatic head injury were included in the current study. MRI examinations were made within 1 month after injury. We evaluated the degree and distribution of the supratentorial hemorrhages on SWI retrospectively. We classified the degree of bleeding into four grades: "small hemorrhage," "single bead-like hemorrhage," "convergent-type hemorrhage," and "massive hemorrhage." We then correlated the degree and distribution of the hemorrhage to clinical outcomes. We also evaluated the apparent diffusion coefficient (ADC) image of lobes with "convergent-type hemorrhage." RESULTS: Existence of "massive hemorrhage" correlated with a poor outcome, that is, worse than "severely disabled" on the Glasgow Outcome Scale. The number of lobes affected by "convergent-type hemorrhage" also correlated with poor outcome. There were 45 lobes with "convergent-type hemorrhage" and 27 of them showed increased diffusivity on ADC images. CONCLUSION: Supratentorial massive hemorrhages and supratentorial convergent-type multiple hemorrhages were associated with poor prognosis after traumatic brain injury. The increased diffusivity in lobes with convergent-type hemorrhages may indicate that congestion of the proximal medullary vein may play some role for these hemorrhages. PMID- 21611727 TI - Complete washout of a colloid cyst on MRI after partial removal by endoscopic approach. PMID- 21611728 TI - Clinical success rates for polyether crown impressions when mixed dynamically and statically. AB - The purpose of this study is to compare success rates of dual-viscosity impressions for two types of mixing techniques of the polyether elastomeric impression material. Additionally, influencing parameters on the success rates should be evaluated. The expectation was that there would be no difference between the success rates for the two mixing techniques. Two centres enrolled 290 subjects (727 teeth) into the trial. Patients were randomized for the two types of mixing techniques. One step, dual-viscosity impressions were made with either statically mixed Impregum Soft tray material (SAM) or dynamically mixed Impregum Penta H DuoSoft (DMM). Low viscosity Impregum Garant L DuoSoft was used for both groups. Gingival displacement involved the use of two braided cords. Full-arch trays were used exclusively. Both critical defects and operator errors were assessed for the first impression taken by trained dentists. The primary outcome was impression success. For comparison of the two mixing techniques, the odds ratio for success and the corresponding one-sided 95% confidence interval was calculated by a logistic regression model. To account for the dependence between several teeth within one patient, the method of general estimating equations was used. The overall impression success rate was 35.4%. Both mixing techniques showed equal success rates indicated by an OR of 1.0 and a lower limit of the one sided 95% confidence interval of 0.71. Using this result to develop the corresponding interval for the difference, it could be shown that the success rate using SAM was at most 8.2% lower than that when using DMM with a probability of 95%. Multivariate logistic regression analysis of other potential influencing factors showed position of finish line (p = 0.008, supra compared to mixed), blood coagulation disorder (p = 0.021) and the level of training of the clinician (student vs dentist, p=0.008) to have an independent influence on the success rate. Dynamic mechanical mixing and the new static mixing of polyether tray material showed nearly equal success rates in the study even though success rates were comparatively low (DMM, 35.3%; SAM, 35.4%). PMID- 21611729 TI - Somatic symptoms, severe mood dysregulation, and aggressiveness in preschool children. AB - Many researchers have studied somatic symptoms in children. However, its association with severe mood dysregulation (SMD) is poorly known. The aim of this study is to detect the presence of SMD in preschool children and to know the prevalence of somatic symptoms and associations with psychopathology, SMD, and aggressiveness. The study population consists of children between 3 to 6 years of age enrolled in Barcelona's kindergarten schools (n = 319). Their parents completed questionnaires about the presence of somatic symptoms in children, absences from school and pediatric visits, child psychiatric symptoms, presence of symptoms of SMD, and aggressiveness. Teachers were also informed about SMD and aggressiveness. Children who complained frequent somatic symptoms (three or more in the last 2 weeks) were compared with those who did not. Two hundred five children (64.3%) reported at least one physical complaint in the 2 weeks preceding the study. One hundred participants (31.3%) reported frequent somatic complaints. Positive associations were found with anxiety symptomatology, separation anxiety, social phobia, pediatric visits, and school absences, but not with aggressiveness or SMD symptoms. Somatic symptoms are common in a sample of preschool children but do not show a positive association with the symptoms of SMD. PMID- 21611730 TI - Exercise training induces similar elevations in the activity of oxoglutarate dehydrogenase and peak oxygen uptake in the human quadriceps muscle. AB - During exercise involving a small muscle mass, peak oxygen uptake is thought to be limited by peripheral factors, such as the degree of oxygen extraction from the blood and/or mitochondrial oxidative capacity. Previously, the maximal activity of the Krebs cycle enzyme oxoglutarate dehydrogenase has been shown to provide a quantitative measure of maximal oxidative metabolism, but it is not known whether the increase in this activity after a period of training reflects the elevation in peak oxygen consumption. Fourteen subjects performed one-legged knee extension exercise for 5-7 weeks, while the other leg remained untrained. Thereafter, the peak oxygen uptake by the quadriceps muscle was determined for both legs, and muscle biopsies were taken for assays of maximal enzyme activities (at 25 degrees C). The peak oxygen uptake was 26% higher in the trained than in the untrained muscle (395 vs. 315 ml min(-1) kg(-1), respectively; P<0.01). The maximal activities of the Krebs cycle enzymes in the trained and untrained muscle were as follows: citrate synthase, 22.4 vs. 18.2 MUmol min(-1) g(-1) (23%, P<0.05); oxoglutarate dehydrogenase, 1.88 vs. 1.54 MUmol min(-1) g(-1) (22%, P<0.05); and succinate dehydrogenase, 3.88 vs. 3.28 MUmol min(-1) g(-1) (18%, P<0.05). The difference between the trained and untrained muscles with respect to peak oxygen uptake (80 ml min(-1) kg(-1)) corresponded to a flux through the Krebs cycle of 1.05 MUmol min(-1) g(-1), and the corresponding difference in oxoglutarate dehydrogenase activity (at 38 degrees C) was 0.83 MUmol min(-1) g( 1). These parallel increases suggest that there is no excess mitochondrial capacity during maximal exercise with a small muscle mass. PMID- 21611731 TI - Two sets of amino acids of the domain I of Cav2.3 Ca(2+) channels contribute to their high sensitivity to extracellular protons. AB - Extracellular acidification decreases Ca(2+) current amplitude and produces a depolarizing shift in the activation potential (Va) of voltage-gated Ca(2+) channels (VGCC). These effects are common to all VGCC, but differences exist between Ca(2+) channel types and the underlying molecular mechanisms remain largely unknown. We report here that the changes in current amplitude induced by extracellular acidification or alkalinisation are more important for Cav2.3 R type than for Cav2.1 P/Q-type Ca(2+) channels. This difference results from a higher shift of Va combined with a modification of channel conductance. Although involved in the sensitivity of channel conductance to extracellular protons, neither the EEEE locus nor the divalent cation selectivity locus could explain the specificity of the pH effects. We show that this specificity involves two separate sets of amino acids within domain I of the Cavalpha subunit. Residues of the voltage sensor domain and residues in the pore domain mediate the effects of extracellular protons on Va and on channel conductance, respectively. These new insights are important for elucidating the molecular mechanisms that control VGCC gating and conductance and for understanding the role of extracellular protons in other channels or membrane-tethered enzymes with similar pore and/or voltage sensor domains. PMID- 21611732 TI - Association of ADAM10 and CAMK2A polymorphisms with conduct disorder: evidence from family-based studies. AB - Twin and family studies have shown that genetic factors play a role in the development of conduct disorder (CD). The purpose of this study was to identify genetic variants associated with CD using a family-based association study. We used 4,720 single nucleotide polymorphisms (SNPs) from the Illumina Panel and 11,120 SNPs from the Affymetrix 10K GeneChips genotyped in 155 Caucasian nuclear families from Genetic Analysis Workshop (GAW) 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). 20 SNPs had suggestive associations with CD (p<10(-3)), nine of which were located in known genes, including ADAM10 (rs383902, p=0.00036) and CAMK2A (rs2053053, p=0.00098). Our results were verified using the International Multi-Center ADHD Genetics Project (IMAGE) dataset. In conclusion, we identified several loci associated with CD. Especially, the two genes (ADAM10 and CAMK2A) have been reported to be associated with Alzheimer's disease, bipolar disorder and depression. These findings may serve as a resource for replication in other populations. PMID- 21611733 TI - Modifying threat-related interpretive bias in adolescents. AB - Socially anxious feelings sharply increase during adolescence and such feelings have been associated with interpretive biases. Studies in adults have shown that interpretive biases can be modified using Cognitive Bias Modification procedures (CBM-I) and subsequent effects on anxiety have been observed. The current study was designed to examine whether the CBM-I procedure has similar effects in adolescents. Unselected adolescents were randomly allocated to either a positive interpretation training (n = 88) or a placebo-control condition (n = 82). Results revealed that the training was successful in modifying interpretations and effects generalized to a new task. The interpretive bias effects were most pronounced in individuals with a threat-related interpretive bias at pre-test. No effects on state anxiety were observed. The current findings are promising with regard to applying bias modification procedures to adolescents, while further research is warranted regarding emotional effects. PMID- 21611735 TI - Optical waveguides for the evanescent wave-induced cleavage of photolabile linker compounds. AB - Functional surfaces and especially the control of surface properties depending on external parameters such as light illumination have gained increasing importance in the last few years. We present the characterization of polymers from the cycloolefin (co)polymer class (COC/COP) functionalized with an aminosilane as a basis for the further immobilization of compounds. In a first step, an assay using AlexaFluor(r)647 fluorescent dye was used to assess surface homogeneity and reproducibility. A coefficient of variation of less than 15% for dot-to-dot and less than 25% for chip-to-chip could be achieved. The same amino-functionalized surfaces were then used to immobilize a biotinylated photolabile linker compound, binding AlexaFluor(r)647-labeled streptavidin. The linker was photocleaved with high efficiency at lambda = 365 nm and P = 0.15 mW/cm(2). Fluorescence measurements show that polymers of the COC/COP class can be used as versatile surfaces for the photoinduced release of compounds immobilized via photolabile linkers. PMID- 21611734 TI - Phase I results from a two-part Phase I/II study of cediranib in combination with mFOLFOX6 in Japanese patients with metastatic colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is the second most common malignancy in Japan. Inhibition of vascular endothelial growth factor (VEGF) signaling is a clinically validated therapeutic strategy in patients with metastatic CRC. Cediranib is an oral, highly potent VEGF signaling inhibitor of all three VEGF receptors. METHODS: This Phase I study investigated the safety, tolerability and pharmacokinetics of cediranib (20 or 30 mg) in combination with mFOLFOX6 in Japanese patients with previously untreated metastatic CRC. If the safety of the 20 mg dose was confirmed, a second cohort of patients was to be recruited to receive cediranib 30 mg + mFOLFOX6. RESULTS: Six patients received cediranib 20 mg + mFOLFOX6 and seven received cediranib 30 mg + mFOLFOX6. One patient in the initial cediranib 20 mg cohort experienced a dose-limiting toxicity (DLT; grade 3 bilirubin increase); no DLTs were observed in the 30 mg cohort. The most commonly reported adverse events were diarrhea, decreased appetite, peripheral neuropathy, hypertension and fatigue. Two patients in the 20 mg cohort and three in the 30 mg cohort experienced serious adverse events during all treatment courses. Cediranib was generally well tolerated in this patient population with no evidence to suggest any significant pharmacokinetic interactions between cediranib and fluorouracil or oxaliplatin. A preliminary evaluation showed that five of nine evaluable patients achieved a best response of partial response. CONCLUSION: Cediranib (20 or 30 mg) in combination with mFOLFOX6 was considered tolerable according to the protocol-defined criteria, providing justification for the Phase II part of this study. PMID- 21611736 TI - Fast quantitation of 5-hydroxymethylfurfural in honey using planar chromatography. AB - An approach for rapid quantitation of 5-hydroxymethylfurfural (HMF) in honey using planar chromatography is suggested for the first time. In high-performance thin-layer chromatography (HPTLC) the migration time is approximately 5 min. Detection is performed by absorbance measurement at 290 nm. Polynomial calibration in the matrix over a range of 1:80 showed correlation coefficients, r, of >= 0.9997 for peak areas and >= 0.9996 for peak heights. Repeatability in the matrix confirmed the suitability of HPTLC-UV for quantitation of HMF in honey. The relative standard deviation (RSD, %, n = 6) of HMF at 10 ng/band was 2.9% (peak height) and 5.2% (peak area); it was 0.6% and 1.0%, respectively, at 100 ng/band. Other possible detection modes, for example fluorescence measurement after post-chromatographic derivatization and mass spectrometric detection, were also evaluated and can coupling can be used as an additional tool when it is necessary to confirm the results of prior quantitation by HPTLC-UV. The confirmation is provided by monitoring the HMF sodium adduct [M + Na](+) at m/z 149 followed by quantitation in TIC or SIM mode. Detection limits for HPTLC-UV, HPTLC-MS (TIC), and HPTLC-MS (SIM) were 0.8 ng/band, 4 ng/band, and 0.9 ng/band, respectively. If 12 MUL honey solution was applied to an HPTLC plate, the respective detection limits for HMF in honey corresponded to 0.6 mg kg(-1). Thus, the developed method was highly suitable for quantitation of HMF in honey at the strictest regulated level of 15 mg kg(-1). Comparison of HPTLC-UV detection with HPTLC-MS showed findings were comparable, with a mean deviation of 5.1 mg kg(-1) for quantitation in SIM mode and 6.1 mg kg(-1) for quantitation in TIC mode. The mean deviation of the HPTLC method compared with the HPLC method was 0.9 mg kg( 1) HMF in honey. Re-evaluation of the same HPTLC plate after one month showed a deviation of 0.5 mg kg(-1) HMF in honey. It was demonstrated that the proposed HPTLC method is an effective method for HMF quantitation in honey. Figure Fast quantitation of 5-hydroxymethylfurfural in honey. PMID- 21611738 TI - Distribution of heavy metal residues in fish from the River Nile tributaries in Egypt. AB - The distribution patterns of some metals (zinc, iron, copper, cadmium and lead) in fish samples collected from El Menofiya Governorate, Egypt were studied. The samples were collected from El Menofiya, canal water supplies (El Sarsawia, El Bagoria and Bahr Shebin), in addition to El Embaby, El Menofi and Miet Rabiha drainage canals each 2 month during periods of 16 month, June 2007-Septemper 2008. In the present investigation, the high concentrations of metals were found in fish samples collected from the drainage canal. The highest mean concentration of lead (1.864 MUg/g), copper (1.495 MUg/g) and cadmium (1.840 MUg/g) were found in fish samples collected from El-Embaby drain. While the highest mean concentration of iron (108.26 MUg/g) and zinc (24.35 MUg/g) were present in fish samples collected from Miet-Rabiha drain. Lead and cadmium were found in higher concentration than those recommended by FAO for fish. PMID- 21611739 TI - Aflatoxins and ochratoxinin A in bean from Iran. AB - A study was undertaken to determine levels of aflatoxins and ochratoxin A in bean, using a technique preceded by an immunoaffinity clean-up step. For this purpose, a total of 30 bean samples were analyzed. 16.67% and 10% of examined bean samples contained Aflatoxin B(1) and ochratoxin A more than 0.2 ng g(-1). Recoveries were found to be 91.1% and 98.5% for Aflatoxin B(1) and ochratoxin A, respectively, while the detection limit was 0.2 ng g(-1) for both mycotoxins. PMID- 21611737 TI - A critical evaluation of biochemical activities reported for the nucleoside diphosphate kinase/Nm23/Awd family proteins: opportunities and missteps in understanding their biological functions. PMID- 21611741 TI - A fluorescent reporter protein containing AtRMR1 domains is targeted to the storage and central vacuoles in Arabidopsis thaliana and tobacco leaf cells. AB - To develop a new strategy to target recombinant proteins to the vacuolar storage system in transgenic plants, the ability of the transmembrane and cytosolic domains of Arabidopsis receptor homology-transmembrane-RING H2-1 (AtRMR1) was evaluated. A secreted version of RFP (secRFP) and a fusion of it to the transmembrane and cytosolic domains of AtRMR1 (RFP-TMCT) were produced and studied both in transient and stable expression assays. Transient expression in leaves of Nicotiana tabacum showed that secRFP is secreted to the apoplast while its fusion to TMCT of AtRMR1 is sufficient to prevent secretion of the reporter. In tobacco leaves, RFP-TMCT reporter showed an endoplasmic reticulum pattern in early expression stages while in late expression stages, it was found in the vacuolar lumen. For the first time, the role of TM and CT domains of AtRMR1 in stable expression in Arabidopsis thaliana is presented; the fusion of TMCT to secRFP is sufficient to sort RFP to the lumen of the central vacuoles in leaves and roots and to the lumen of PSV in cotyledons of mature embryos. In addition, biochemical studies performed in extract from transgenic plants showed that RFP TMCT is an integral membrane protein. Full-length RFP-TMCT was also found in the vacuolar lumen, suggesting internalization into destination vacuole. Not colocalization of RFP-TMCT with tonoplast and plasma membrane markers were observed. This membrane vacuolar determinant sorting signal could be used for future application in molecular pharming as an alternative means to sort proteins of interest to vacuoles. PMID- 21611742 TI - In vivo real-time two-photon microscopic imaging of platelet aggregation induced by selective laser irradiation to the endothelium created in the beta-actin-green fluorescent protein transgenic mice. AB - Although thrombus formation in vivo has recently been reported, all previous laser induced thrombus models have been associated with vessel wall disruption. This study aimed to evaluate in vivo real-time platelet aggregation after selective endothelial injury, and to visualize thrombus formation without disruption and swelling of the arterial intima induced by two-photon laser irradiation. Cecal arteriole thrombi were created in beta-actin-green fluorescent protein transgenic mice by selective endothelial injury using two-photon laser scanning microscopy (TPLSM). The in vivo real-time process of thrombus formation was assessed. Anticoagulant drug efficiency for thrombi was also analyzed in detail. TPLSM allowed visualization of microvessel components from the arterial smooth muscle to the intimal layer. Immediately after selective laser irradiation of the intimal layer, platelet adhesion and aggregation were seen only at the area of injury of the intimal layer after forming linear adhesions downstream of the injured area. When shear stress was overcome, thrombus formation began at the downstream edge of the injured area. Thrombus volume plateaued approximately 60 min after laser irradiation. The thrombolytic effects of anticoagulant drugs were precisely assessed; therefore, our model appears the most advanced model in point of real-time imaging of pathophysiological processes in vivo currently reported. In vivo real-time imaging of thrombus formation can be achieved using TPLSM in combination with an organ stabilizing system. The high magnification and resolution of TPLSM allows investigation of the mechanisms of thrombus formation along with assessment of antithrombotic drug efficacy with little interexperimental variation. PMID- 21611744 TI - Biodegradation of asphalt by Garciaella petrolearia TERIG02 for viscosity reduction of heavy oil. AB - Petroleum hydrocarbon is an important energy resource, but it is difficult to exploit due to the presence of dominated heavy constituents such as asphaltenes. In this study, viscosity reduction of Jodhpur heavy oil (2,637 cP at 50 degrees C) has been carried out by the biodegradation of asphalt using a bacterial strain TERIG02. TERIG02 was isolated from sea buried oil pipeline known as Mumbai Uran trunk line (MUT) located on western coast of India and identified as Garciaella petrolearia by 16S rRNA full gene sequencing. TERIG02 showed 42% viscosity reduction when asphalt along with molasses was used as a sole carbon source compared to only asphalt (37%). The viscosity reduction by asphaltene degradation has been structurally characterized by Fourier transform infrared spectroscopy (FTIR). This strain also shows an additional preference to degrade toxic asphalt and aromatics compounds first unlike the other known strains. All these characteristics makes TERIG02 a potential candidate for enhanced oil recovery and a solution to degrading toxic aromatic compounds. PMID- 21611743 TI - Microbial degradation of microcystin in Florida's freshwaters. AB - Presence of microcystin (MC), a predominant freshwater algal toxin and a suspected liver carcinogen, in Florida's freshwaters poses serious health threat to humans and aquatic species. Being recalcitrant to conventional physical and chemical water treatment methods, biological methods of MC removal is widely researched. Water samples collected from five sites of Lake Okeechobee (LO) frequently exposed to toxic Microcystis blooms were used as inoculum for enrichment with microcystin LR (MC-LR) supplied as sole C and N source. After 20 days incubation, MC levels were analyzed using high performance liquid chromatography (HPLC). A bacterial consortium consisting of two isolates DC7 and DC8 from the Indian Prairie Canal sample showed over 74% toxin degradation at the end of day 20. Optimal temperature requirement for biodegradation was identified and phosphorus levels did not affect the MC biodegradation. Based on 16S rRNA sequence similarity the isolate DC8 was found to have a match with Microbacterium sp. and the DC7 isolate with Rhizobium gallicum (AY972457). PMID- 21611745 TI - Ti:sapphire femtosecond laser ablation of dental enamel, dentine, and cementum. AB - This paper reports an investigation into the characteristics of femtosecond laser (800-nm central wavelength) in the ablation of human dental enamel, dentine, and cementum at various laser fluences from 0.2 to 3.68 J/cm(2) with single and multiple pulses. The femtosecond laser interaction with cementum is reported for the first time. Ablation thresholds were determined to be 0.58, 0.44, and 0.51 J/cm(2) for enamel, dentine, and cementum, respectively. Under the average laser fluences of 1.13 to 3.68 J/cm(2), clean ablated surfaces without debris and microcracks were obtained. Laser fluence was found to influence the ablated diameter and depth, whereas under a certain fluence, pulse number only affects the depth, without affecting the diameter. The ablation mechanism is found to be based on multi-photon absorption, not previously known for femtosecond laser ablation of dental materials. The low thermal loads of 0.708, 1.44, and 0.404 J/cm(3) required for ablating enamel, dentine, and cementum, determined for the first time, are beneficial for minimizing the heat-affected zones and micro damage. The Raman spectroscopic analysis of phosphate shows that the chemical components of the tooth remain intact before and after the fs-laser ablation. It also shows that different dental tissues respond differently to the laser irradiation. PMID- 21611746 TI - The application of gene co-expression network reconstruction based on CNVs and gene expression microarray data in breast cancer. AB - Copy number variations (CNVs) are one type of the human genetic variations and are pervasive in the human genome. It has been confirmed that they can play a causal role in complex diseases. Previous studies of CNVs focused more on identifying the disease-specific CNV regions or candidate genes on these CNV regions, but less on the synergistic actions between genes on CNV regions and other genes. Our research combined the CNVs with related gene co-expression to reconstruct gene co-expression network by using single nucleotide polymorphism microarray datasets and gene microarray datasets of breast cancer, and then extracted the modules which connected densely inside and analyzed the functions of modules. Interestingly, all of these modules' functions were related to breast cancer according to our enrichment analysis, and most of the genes in these modules have been reported to be involved in breast cancer. Our findings suggested that integrating CNVs and gene co-expressed relations was an available way to analyze the roles of CNV genes and their synergistic genes in breast cancer, and provided a novel insight into the pathological mechanism of breast cancer. PMID- 21611747 TI - Characterization of the porcine FBX07 gene: the first step towards generation of a pig model for Parkinsonian pyramidal syndrome. AB - Parkinsonian pyramidal syndrome, also named pallido-pyramidal syndrome (PKPS), is the combination of early-onset progressive Parkinsonism with pyramidal tract signs. FBXO7, an F-box protein, is a component of modular E3 ubiquitin protein ligases called SCFs (SKP1, cullin, F-box proteins), which functions in phosphorylation-dependent ubiquitination. FBXO7 mutations cause autosomal recessive, early-onset PKPS. Here we report the molecular cloning and characterization of two isoforms of FBXO7 cDNA from pigs. The encoded FBXO7 protein displays a very high homology to human FBXO7 with an amino acid identity of 90%. Phylogenetic analysis demonstrated that porcine FBXO7 is closely related to other mammalian FBXO7 proteins. Furthermore, the genomic structure of the porcine FBXO7 gene was determined. The intron-exon structure is similar to that of the human FBXO7 gene. The promoter sequence for the porcine FBXO7 gene was also identified. A recognition site for miR-301a was found in the 3'UTR region of porcine FBXO7. Investigating the genetic variation in the porcine FBXO7 gene revealed a missense A/G SNP in exon 5. The A/G SNP results in a substitution of an asparagine to a serine residue (N269S). Using a radiation hybrid map the FBXO7 gene was mapped to pig chromosome 5. Real-time quantitative RT-PCR analysis revealed that FBXO7 mRNA is differentially expressed in many tissues and organs, and that FBXO7 transcript can be detected early in embryo development. PMID- 21611748 TI - Survivin promoter -31G/C (rs9904341) polymorphism and cancer susceptibility: a meta-analysis. AB - This study aimed to perform a meta-analysis to assess the association of survivin -31 G/C promoter polymorphism and cancer risk. Thirteen case-control studies identified through PubMed and published between 2007 and 2011 with a total of 3329 cancer cases and 3979 controls were included in this meta-analysis. Odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Overall, the pooled analysis showed that survivin 31C allele was associated with 1.27 fold increased risk of cancer compared with the -31G allele (95% CI = 1.091-1.479; random model). Subgroup analyses based on type of cancer and ethnicity were also performed, and results indicated that survivin -31G/C polymorphism was not associated with risk of gastric cancer [OR = 2.879; 95% CI = 0.553-15.004) for CC vs.GG] and esophageal cancer [OR = 1.352; 95% CI = 0.494-3.699) for CC vs.GG]. Stratification on the basis of ethnicity showed that the risk due to -31C allele was significant only in Asian population [OR = 1.894; 95% CI = 1.206-2.974 for CC vs.GG]. The present meta-analysis suggests an important role of survivin -31 G/C polymorphism with cancer risk especially in Asian population. However, further studies with larger sample size are required to draw more comprehensive conclusions and provide more precise evidence in individual cancers. PMID- 21611749 TI - XPA A23G polymorphism and lung cancer risk: a meta-analysis. AB - Case-control studies on the association between XPA A23G and lung cancer have provided either controversial or inconclusive results. To clarify the effect of XPA A23G on the risk of lung cancer, a meta-analysis of all case-control observational studies was performed. Pooled odds ratios (ORs) for various polymorphisms were estimated using random and fixed effects models. The Q statistic was used to evaluate the homogeneity, and Egger and Begg tests were used to assess publication bias. For the homozygote GG and G allele carriers (GA + GG), the pooled ORs were 1.24 (95% CI 1.05-1.46; P = 0.27 for heterogeneity) and 1.30 (95% CI 1.13-1.51; P = 0.45 for heterogeneity) compared to the homozygous genotype (AA). In the stratified analysis by ethnicity, the ORs of the G allele carriers and the homozygote GG were 1.28 (95% CI 1.10-1.49; P = 0.07 for heterogeneity) and 1.42 (95% CI 1.04-1.93; P = 0.39 for heterogeneity) among non Caucasians. No significant associations were found in the Caucasian population in any of the genetic models. When studies that were not in Hardy-Weinberg equilibrium (HWE) were corrected, the pattern of the results remained the same. Our results indicated a significantly decreased risk of lung cancer in non Caucasians with the G allele. PMID- 21611751 TI - Interleukin-18 promoter polymorphism and asthma risk: a meta-analysis. AB - Some studies have shown that IL-18 was associated with aetiology and progression of asthma. However, the association between single-nucleotide polymorphisms 607C/A (rs1946518) and -137G/C (rs187238) located in the IL-18 gene promoter and asthma risk was still controversial and ambiguous. To derive a more precise effect on the association between these polymorphisms and asthma risk, we performed a meta-analysis based on the currently available evidence of the literature. A total of 5 studies with 1411 cases and 1525 controls for -607C/A polymorphism and 5 studies with 1883 cases and 6645 controls for -137G/C polymorphism were identified to perform a meta-analysis, up to October 2010. Summary ORs and corresponding 95% CIs for IL-18 polymorphisms and asthma were estimated using fixed- and random-effects models when appropriate. Heterogeneity and publication bias were evaluated. We found that individuals carrying AC/CC genotype of -607C/A polymorphism were associated with an increased asthma risk in recessive model (OR = 1.278; 95% CI, 1.073-1.522). However, no significant association was observed between -137G/C polymorphism and asthma risk under different contrast models. There was no evidence of publication bias. The present meta-analysis suggested that IL-18 -607C/A polymorphism in promoter region was associated with asthma risk. PMID- 21611750 TI - Association of SERPINE2 gene with the risk of chronic obstructive pulmonary disease and spirometric phenotypes in northern Han Chinese population. AB - Chronic obstructive pulmonary disease (COPD) is a complex human disease influenced by multiple genes and environmental factors. The SERPINE2 gene has recently been demonstrated to be associated with COPD onset in a non-East Asian population. In this study, we genotyped 20 single nucleotide polymorphisms (SNPs) in SERPINE2 from 310 cases and 203 controls, all of which belong to the Han from North China. Genotype frequencies were compared between the cases and the controls and analyzed for statistical significance. Two SNPs (rs729631 and rs975278), which are in strong linkage disequilibrium (LD) and locate in block 1 on the LD map of our samples, showed significant association both with the risk of COPD and decline in baseline lung function after Bonferroni correction (P < 0.05). This study provides further evidences for SERPINE2 gene as a COPD susceptible gene, and block 1 of SERPINE2 appears to be the genetic variant region that affects the Han Chinese. PMID- 21611752 TI - Genomic organization and recombination analysis of human norovirus identified from China. AB - Noroviruses (NoVs) are one of the major causal agents of acute gastroenteritis in both industrial and developing countries including China. Recent studies have revealed that NoV genome is highly prone to mutation and recombination which may lead to emergence of new strains. In the present study, three full-length genomes of human NoV from China were determined and the genomic organization and recombination were analyzed. They had similar genome organization and contained three predicted ORFs, though the 5'UTR of those three strains were 2, 4 and 8 nucleotides, respectively. Phylogenetic analysis showed that the HU/GII/SHANGHAI/SH312/2008/CHN strain may be a recombinant of GII-3 capsid and GII-4 polymerase. To confirm the finding and detect the breakpoints where the recombination event occurred, we performed recombination analysis based on the genomic sequences of HU/GII/SHANGHAI/SH312/2008/CHN as the query sequence, and AB220921/NOV/JP/GII-4 and AB365435/NOV/US/GII-3 as the background sequences, using RPD software. Results indicated that the two parental strains were AB220921/NOV/JP/GII-4 and AB365435/NOV/US/GII-3. The breakpoint for this recombination event located at position 5,107 nt of the genome (in the ORF1 and ORF2 overlap). PMID- 21611753 TI - Retinoic acid promotes neural conversion of mouse embryonic stem cells in adherent monoculture. AB - Retinoic acid (RA) plays multiple roles in the nervous system, including induction of neural differentiation, axon outgrowth and neural patterning. Previously, RA for neural differentiation of embryonic stem (ES) cells always relies on embryoid bodies (EBs) formation. Here we report an in vitro adherent monoculture system to induce mouse ES cells into neural cells accompanied with RA. RA (1 MUM) treatment, during initial 2 days of differentiation, can enhance the expression of neural markers, such as Nestin, Tuj1 and MAP2, and result in an earlier neural differentiation of ES cells. Furthermore, RA promotes a significant increase in neurite elongation of ES-derived neurons. Our study also implies that RA induced to express Wnt antagonist Dickkopf-1 (Dkk-1) for neural differentiation. However, the mechanisms of RA triggering neural induction remain to be determined. Our simple and efficient strategy is proposed to provide a basis for studying RA signaling pathways in neural differentiation in vitro. PMID- 21611754 TI - The variation of CD4+CD25+ regulatory T cells in the periphery blood and tumor microenvironment of non-small cell lung cancer patients and the downregulation effects induced by CpG ODN. AB - The aim of the study was to observe the variation of CD4(+)CD25(+) regulatory T cells in periphery blood and tumor microenvironment of non-small cell lung cancer (NSCLC) patients and the effects of CpG ODN. The proportion of CD4(+)CD25(+) regulatory T cells, Foxp3 gene expression, levels of tumor growth factor-beta (TGF-beta) and immunoreactive fibronectin-gamma (IFN-gamma) in the periphery blood of 30 NSCLC patients and 30 healthy volunteers were compared. These indicators were compared before and after CpG ODN treatment. Foxp3 gene expression in the tumor microenvironment of NSCLC patients was also observed. The results showed CD4(+)CD25(+) regulatory T cell proportion, Foxp3 expression and TGF-beta levels in the periphery blood of NSCLC patients were higher than those of healthy volunteers (p < 0.05), and these indicators of patients were significantly decreased after CpG ODN 2006 treatment (p < 0.05). Foxp3 expression in the metastatic lymph nodes was higher than that in the non-metastatic ones of NSCLC patients (p = 0.000). In conclusion, a rise in the proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells was demonstrated in the periphery blood and tumor microenvironments of NSCLC patients. CpG ODN 2006 downregulated the CD4(+)CD25(+)Foxp3(+) regulatory T cells proportion and TGF-beta levels in the periphery blood of these patients. PMID- 21611755 TI - Rituximab and minimal change nephrotic syndrome: a therapeutic option. AB - Minimal change nephrotic syndrome (MCNS) usually responds to steroids but frequently relapses, requiring additional treatment with immunosuppressive agents. Rituximab is a chimeric murine/human monoclonal immunoglobulin G1 antibody that targets CD20, a B-cell differentiation marker. B-cell recovery begins at approximately 6 months following the completion of treatment. Rituximab has a beneficial effect, with the sustained remission or reduction of proteinuria in patients with steroid-dependent MCNS. Relapses are thought to be associated with an increase in CD19 cells. The mean serum half-life of rituximab was reported to be 10-15 days in patients with steroid-dependent nephrotic syndrome. Only infusion reactions, such as rash and chills, occurred after single-dose rituximab infusion and can be managed by pre-medication or infusion rate adjustments. Even though severe adverse effects of rituximab are not expected, physicians must be aware of potentially life-threatening adverse effects. Controlled randomized trials that include adult patients with steroid-dependent or steroid-resistant MCNS are required to prove the efficacy and safety of rituximab and to evaluate the cost-effectiveness of rituximab treatment. PMID- 21611756 TI - Roles of organic anion/cation transporters at the blood-brain and blood cerebrospinal fluid barriers involving uremic toxins. AB - The blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) play key roles in the influx and efflux transport of endogenous substrates in the brain and cerebrospinal fluid. The organic anion transporter (OAT) 3 and organic cation transporter (OCT) 3, which belong to the solute carrier (SLC) 22A family, are expressed at the BBB and BCSFB, and regulate the excretion of endogenous and exogenous organic anions and cations. Our recent research provides novel molecular and functional evidence that indoxyl sulfate, an anionic uremic toxin, undergoes efflux transport at the BBB via OAT3 and creatinine, a uremic guanidino compound, undergoes efflux transport at the BCSFB via OCT3. Renal impairment is associated with the accumulation of uremic toxins in blood and uremic encephalopathy. It is conceivable that uremic encephalopathy is related to inhibition or dysfunction of efflux transport systems for uremic toxins in the brain. Here, we review the function of OAT3 and OCT3 at the BBB and BCSFB in the context of their roles in the progression of renal failure. PMID- 21611757 TI - A case of MPO-ANCA-positive polyarteritis nodosa complicated by exudative otitis media, mononeuritis multiplex, and acute renal failure. AB - In December 2008, a 69-year-old Japanese woman was admitted to the Department of Otorhinolaryngology because of hearing impairment due to bilateral exudative otitis media, and was discharged without complete recovery despite conventional treatment. Two weeks later, she was readmitted for worsened deafness, numbness, gait disturbance, and general fatigue. She was referred to our department for general investigation. On admission, laboratory examination revealed severe inflammatory signs and active nephritic urinary sediments. Cranial computed tomography (CT) revealed progressive exudative otitis media and sinusitis. Initially, Wegener's granulomatosis was suspected. Nasal cavity biopsy, however, showed no granuloma formation or vasculitis. Serology revealed high titer of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA), suggestive of microscopic polyangitis (MPA). However, contrast CT identified stenosis of a celiac artery, and renal biopsy showed tubulointerstitial changes with minor glomerular abnormalities. Therefore, polyarteritis nodosa (PAN) was suspected and treatment with intravenous methylprednisolone was initiated. However, a lacunar infarct developed followed by cerebral hemorrhage, and the patient died 19 days after readmission. Autopsy revealed fibrinoid necrosis, neutrophilic infiltration, and giant cell reaction in small to medium-sized arteries in multiple organs. These findings led to diagnosis of systemic vasculitis anatomically compatible with PAN. This was a rare case of a patient with MPO-ANCA positive PAN who may have developed bilateral exudative otitis media and hearing loss as the initial manifestation of PAN. PMID- 21611758 TI - Coronary CT angiography: image quality, diagnostic accuracy, and potential for radiation dose reduction using a novel iterative image reconstruction technique comparison with traditional filtered back projection. AB - OBJECTIVES: To compare image noise, image quality and diagnostic accuracy of coronary CT angiography (cCTA) using a novel iterative reconstruction algorithm versus traditional filtered back projection (FBP) and to estimate the potential for radiation dose savings. METHODS: Sixty five consecutive patients (48 men; 59.3 +/- 7.7 years) prospectively underwent cCTA and coronary catheter angiography (CCA). Full radiation dose data, using all projections, were reconstructed with FBP. To simulate image acquisition at half the radiation dose, 50% of the projections were discarded from the raw data. The resulting half-dose data were reconstructed with sinogram-affirmed iterative reconstruction (SAFIRE). Full-dose FBP and half-dose iterative reconstructions were compared with regard to image noise and image quality, and their respective accuracy for stenosis detection was compared against CCA. RESULTS: Compared with full-dose FBP, half dose iterative reconstructions showed significantly (p = 0.001 - p = 0.025) lower image noise and slightly higher image quality. Iterative reconstruction improved the accuracy of stenosis detection compared with FBP (per-patient: accuracy 96.9% vs. 93.8%, sensitivity 100% vs. 100%, specificity 94.6% vs. 89.2%, NPV 100% vs. 100%, PPV 93.3% vs. 87.5%). CONCLUSIONS: Iterative reconstruction significantly reduces image noise without loss of diagnostic information and holds the potential for substantial radiation dose reduction from cCTA. PMID- 21611759 TI - A novel tract imaging technique of the brainstem using phase difference enhanced imaging: normal anatomy and initial experience in multiple system atrophy. AB - OBJECTIVES: To develop a new tract imaging technique for visualising small fibre tracts of the brainstem and for detecting the abnormalities in multiple system atrophy of the cerebellar type (MSA-C) using a phase difference enhanced (PADRE) imaging technique, in which the phase difference between the target and surrounding tissue is selectively enhanced. METHODS: Two neuroradiologists compared the high-spatial-resolution PADRE imaging, which was acquired from six healthy volunteers, three patients with MSA-C, and 7 patients with other types of neurodegenerative diseases involving the brainstem or cerebellum. RESULTS: Various fine fibre tracts in the brainstem, the superior and inferior cerebellar peduncles, medial lemniscus, spinothalamic tract, medial longitudinal fasciculus, central tegmental tract, corticospinal tract and transverse pontine fibres, were identified on PADRE imaging. PADRE imaging from MSA-C demonstrated the disappearance of transverse pontine fibres and significant atrophy of the inferior cerebellar peduncles, while the superior cerebellar peduncles were intact. PADRE imaging also demonstrated that the transverse pontine fibres and inferior cerebellar peduncle were not involved in the other neurodegenerative diseases. CONCLUSION: PADRE imaging can offer a new form of tract imaging of the brainstem and may have the potential to reinforce the clinical utility of MRI in differentiating MSA from other conditions. PMID- 21611760 TI - Comparisons of four approximation algorithms for large-scale linkage map construction. AB - Efficient construction of large-scale linkage maps is highly desired in current gene mapping projects. To evaluate the performance of available approaches in the literature, four published methods, the insertion (IN), seriation (SER), neighbor mapping (NM), and unidirectional growth (UG) were compared on the basis of simulated F(2) data with various population sizes, interferences, missing genotype rates, and mis-genotyping rates. Simulation results showed that the IN method outperformed, or at least was comparable to, the other three methods. These algorithms were also applied to a real data set and results showed that the linkage order obtained by the IN algorithm was superior to the other methods. Thus, this study suggests that the IN method should be used when constructing large-scale linkage maps. PMID- 21611761 TI - High-throughput SNP discovery and genotyping in durum wheat (Triticum durum Desf.). AB - We describe the application of complexity reduction of polymorphic sequences (CRoPS((r))) technology for the discovery of SNP markers in tetraploid durum wheat (Triticum durum Desf.). A next-generation sequencing experiment was carried out on reduced representation libraries obtained from four durum cultivars. SNP validation and minor allele frequency (MAF) estimate were carried out on a panel of 12 cultivars, and the feasibility of genotyping these SNPs in segregating populations was tested using the Illumina Golden Gate (GG) technology. A total of 2,659 SNPs were identified on 1,206 consensus sequences. Among the 768 SNPs that were chosen irrespective of their genomic repetitiveness level and assayed on the Illumina BeadExpress genotyping system, 275 (35.8%) SNPs matched the expected genotypes observed in the SNP discovery phase. MAF data indicated that the overall SNP informativeness was high: a total of 196 (71.3%) SNPs had MAF >0.2, of which 76 (27.6%) showed MAF >0.4. Of these SNPs, 157 were mapped in one of two mapping populations (Meridiano * Claudio and Colosseo * Lloyd) and integrated into a common genetic map. Despite the relatively low genotyping efficiency of the GG assay, the validated CRoPS-derived SNPs showed valuable features for genomics and breeding applications such as a uniform distribution across the wheat genome, a prevailing single-locus codominant nature and a high polymorphism. Here, we report a new set of 275 highly robust genome-wide Triticum SNPs that are readily available for breeding purposes. PMID- 21611762 TI - Remodelling of collagen fibre transition stretch and angular distribution in soft biological tissues and cell-seeded hydrogels. AB - The extracellular matrix in many biological tissues is adapted to its mechanical environment. In this study, a phenomenological model for collagen remodelling is introduced that incorporates angular remodelling (fibre reorientation) and the adaptation of the so-called transition stretch. This is achieved by introducing a local stress-free configuration for the collagen network by a multiplicative decomposition of the deformation gradient and the appropriate definition of the anisotropic free Helmholtz energy potentials and structure tensors. The collagen network is either treated using discrete fibre directions or a continuous angular distribution. The first part of the study illustrates the influence of force- and displacement-controlled loading on either stress- or deformation-driven remodelling processes in tissues with various degrees of fibre reinforcement. The model is then applied to recent experimental studies of collagen remodelling, specifically periosteum adaptation (Foolen et al. in J Biomech 43(16):3168-3176, 2010), collagen gel (Thomopoulos et al. in J Biomech Eng 127(5):742-750, 2005) and fibrin cruciform (Sander et al. in Ann Biomed Eng 1-16, 2010) compaction. The model is able to capture the basic effects of an adapting transition stretch over time in the periosteal simulations, as well as the compaction and the development of structural anisotropy in the collagen and fibrin gels. The model can potentially be applied to elucidate structure-function relationships, better interpret in vitro experiments involving collagen remodelling, and help investigate aspects of certain pathologies, such as connective tissue contracture. PMID- 21611763 TI - Anterior interosseous nerve syndrome: retrospective analysis of 14 patients. AB - INTRODUCTION: The anterior interosseous nerve (AIN) is a only motor nerve innervating the deep muscles of the forearm. Its compression is rare. We present a retrospective analysis of 14 patients with an AIN syndrome with a variety of clinical manifestations who underwent operative and conservative treatment. PATIENTS AND METHODS: Fourteen patients (six female, eight male, mean age 48 +/- 9 years) were included. In six patients, the right limb was affected, and in eight patients the left limb. Conservative treatment was started for every patient. If no signs of recovery appeared within 3 months, operative exploration was performed. Final assessment was performed between 2 and 9 years after the onset of paralysis (mean duration of follow-up 46 +/- 11 months). Patients were examined clinically for return of power, range of motion, pinch and grip strengths. Also the disability of the arm, shoulder, and hand (DASH) score was calculated. RESULTS: Seven of our 14 patients had incomplete AIN palsy with isolated total loss of function of flexor pollicis longus (FPL), five of FPL and flexor digitorum profundus (FDP)1 simultaneously, and two of FDP1. Weakness of FDP2 could be seen in four patients. Pronator teres was paralysed in two patients. Pain in the forearm was present in nine patients. Four patients had predisposing factors. Eight patients treated conservatively exhibited spontaneous recovery from their paralysis during 3-12 months after the onset. In six patients, the AIN was explored 12 weeks after the initial symptoms and released from compressing structures. Thirteen patients showed good limb function. In one patient with poor result a tendon transfer was necessary. The DASH score of patients treated conservatively and operatively presented no significant difference. CONCLUSION: AIN syndrome can have different clinical manifestations. If no signs of spontaneous recovery appear within 12 weeks, operative treatment should be performed. PMID- 21611764 TI - Microvascular modifications in diabetic retinopathy. AB - Patients struggling with diabetes are at elevated risks for several sight threatening diseases, including proliferative diabetic retinopathy (DR). DR manifests in two stages: first, the retinal microvasculature is compromised and capillary degeneration occurs; subsequently, an over-compensatory angiogenic response is initiated. Early changes in the retinal microcirculation include disruptions in blood flow, thickening of basement membrane, eventual loss of mural cells, and the genesis of acellular capillaries. Endothelial apoptosis and capillary dropout lead to a hypoxic inner retina, alterations in growth factors, and upregulation of inflammatory mediators. With disease progression, pathologic angiogenesis generates abnormal preretinal microvessels. Current therapies, which include panretinal photocoagulation and vitrectomy, have remained unaltered for several decades. With several exciting preclinical advances, emergent technologies and innovative cellular targets may offer newfound hope for developing "next-generation" interventional or preventive clinical approaches that will significantly advance current standards of care and clinical outcomes. PMID- 21611765 TI - Painful diabetic neuropathy is more than pain alone: examining the role of anxiety and depression as mediators and complicators. AB - A wealth of information exists regarding the plight of patients suffering with diabetic peripheral neuropathic pain (DPNP). Although physical pain is certainly a primary challenge in the management of this condition, disorders associated with emotional pain-especially depression and anxiety-also greatly complicate the clinician's efforts to attain optimal outcomes for DPNP patients. This article reviews the high rate of comorbidity between DPNP and depression/anxiety with a focus on why this pattern of comorbidity exists and what can be done about it. To accomplish this, the many physiologic similarities between neuropathic pain and depression/anxiety are reviewed as a basis for better understanding how, and why, optimal treatment strategies use behavioral and pharmacologic modalities known to improve both physical pain and symptoms of depression and anxiety. We conclude by highlighting that screening, diagnosing, and optimally treating comorbid depression/anxiety not only improves quality of life, these but also positively impacts DPNP pain. PMID- 21611766 TI - Cell-based therapies for diabetic retinopathy. AB - Autologous endothelial progenitor cell (EPC) populations represent a novel treatment for therapeutic revascularization and vascular repair for diabetic patients with complications including diabetic retinopathy. Current therapies are applicable to late-stage disease and carry significant side effects, whereas cell based therapy may provide an alternative by repairing areas of vasodegeneration and reversing ischemia. However, EPCs from diabetic patients with vascular complications are dysfunctional. Moreover, the diabetic environment poses its own challenges and complicates the use of autologous EPCs. Before EPCs become the ideal "cell therapy," the optimal EPC must be determined, any functional dysfunction must be corrected prior to use, and the diabetic milieu will require modification to accept the EPCs. This review describes the rationale for harnessing the vascular reparative properties of EPCs with emphasis on the molecular and phenotypic nature of healthy EPCs, how diabetes alters them, and novel strategies to improve dysfunctional EPCs. PMID- 21611767 TI - Mutually exclusive distribution of the sap and eag S-layer genes and the lytB/lytA cell wall hydrolase genes in Bacillus thuringiensis. AB - Recently, two Bacillus thuringiensis strains were reported to synthesize parasporal inclusion bodies made not of the expected crystal (Cry) proteins but rather of the surface layer proteins (SLP) Sap (encoded by sap) and EA1 (encoded by eag), respectively. Whether the presence of the sap and eag genes is restricted to these two B. thuringiensis strains or ubiquitous in B. thuringiensis is unknown. We report here the distribution of the sap and eag genes in B. thuringiensis. Strains in the Bacillus cereus group were added for comparison purposes. We show that sap and eag are either present in tandem in 35% of the B. thuringiensis strains analysed and absent in 65% of the strains. When absent, a different tandem, the lytB/lytA cell wall hydrolase genes, is present. The distribution of the sap and eag S-layer and the lytB/lytA cell wall hydrolase genes is not species-specific in B. thuringiensis, B. cereus and Bacillus weihenstephanensis. Bacillus anthracis and Bacillus mycoides harbor sap and eag but not lytB/lytA. The sap, eag and lytB/lytA genes were absent in Bacillus pseudomycoides. Clearly, the distribution of the sap and eag S-layer and the lytB/lytA cell wall hydrolase genes in B. thuringiensis and in the Bacillus cereus group is mutually exclusive. We also showed that two genes involved in cell wall metabolism, csaA and csaB, are present not only upstream of the sap and eag S-layer genes, but also upstream of the lytB/lytA tandem in strains where sap and eag are absent. Bootstrapped neighbor-joining trees were inferred from the translated amino acid sequences of sap, eag and the tandem lytB/lytA, respectively. PMID- 21611768 TI - Microkeratome-assisted lamellar keratoplasty using frozen tissue for management of a post-LASIK corneal stromal scar. PMID- 21611770 TI - Grain and tortilla quality in landraces and improved maize grown in the highlands of Mexico. AB - The maize produced in the highlands of Mexico (>2,400 masl) is generally not accepted by the flour and masa and tortilla industry. The objective of this work was to evaluate the grain quality and tortilla properties of maize landraces commonly grown in the highlands of Mexico and compare them with improved germplasm (hybrids). Germplasm analysis included 11 landraces, 32 white hybrids, and six yellow hybrids. Grain quality was analyzed for a range of physical and chemical factors, as well as for alkaline cooking quality. Landrace grains tended to be heterogeneous in terms of size, hardness and color. All landraces had soft intermediate grains with an average flotation index (FI) of 61%. In contrast, hybrid grains were homogenous in size and color, and harder than landrace grains, with a FI of 38%. Protein, free sugars, oil and phenolic content in landraces were higher than in the hybrids. Significant correlations were found between phenolic content and tortilla color (r= -0.60; p<0.001). Three landraces were identified as appropriate for the masa and tortilla industry, while all the hybrids evaluated fulfilled the requirements of this industry. PMID- 21611769 TI - Lipid-soluble ginseng extract induces apoptosis and G0/G1 cell cycle arrest in NCI-H460 human lung cancer cells. AB - This study was performed to elucidate the anticancer mechanism of a lipid-soluble ginseng extract (LSGE) by analyzing induction of apoptosis and arrest of cell cycle progression using the NCI-H460 human lung cancer cell line. Proliferation of NCI-H460 cells was potently inhibited by LSGE in a dose-dependent manner. The cell cycle arrest at the G0/G1 phase in NCI-H460 cells was induced by LSGE. The percentage of G0/G1 phase cells significantly increased, while that of S phase cells decreased after treatment with LSGE. The expression levels of cyclin dependent kinase2 (CDK2), CDK4, CDK6, cyclin D3 and cyclin E related to G0/G1 cells progression were also altered by LSGE. In addition, LSGE-induced cell death occurred through apoptosis, which was accompanied by increasing the activity of caspases including caspase-8, caspase-9 and caspase-3. Consistent with enhancement of caspase activity, LSGE increased protein levels of cleaved caspase 3, caspase-8, caspase-9, and poly-ADP-ribose polymerase (PARP). These apoptotic effects of LSGE were inhibited by the pan-caspase inhibitor Z-VAD-fmk. These findings indicate that LSGE inhibits NCI-H460 human lung cancer cell growth by cell cycle arrest at the G0/G1 phase and induction of caspase-mediated apoptosis. PMID- 21611771 TI - Bietti crystalline retinal dystrophy with subfoveal neurosensory detachment and congenital tortuosity of retinal vessels: case report. AB - A 34-year-old man presented with reduction and distortion of vision in both the eyes. The best-corrected vision was 20/20 parts, N6 in either eye. The external and slit lamp examination of both the eyes was unremarkable. The fundus examination showed multiple intraretinal crystalline deposits at the posterior pole, extending up to midperiphery, tortuous retinal blood vessels with S-shaped deflections, and absent foveal reflex in both the eyes. There were no corneal crystals, and the color vision was defective in both the eyes. Fundus autofluorescence and fundus fluorescein angiogram (FFA) were suggestive of geographic areas of retinal pigment epithelium (RPE) and choriocapillary (CC) loss. OCT revealed subfoveal neurosensory detachment. Flash ERG and EOG were normal except for a slight decrease in amplitude and delay in latency of pattern ERG waveforms. The Humphrey's visual field showed paracentral scotoma with reduction in the amplitude of waveforms from the corresponding area in the multifocal ERG in both the eyes. Systemic evaluation for crystalline retinopathy was unremarkable. He was diagnosed to be a case of Bietti crystalline retinopathy (local/regional variant). The subfoveal neurosensory detachment could represent early RPE dysfunction caused by these crystals and could account for the mild visual disturbance in both the eyes. Retinal vascular tortuosity and neurosensory detachment seen in this case is the first time to be reported in literature. PMID- 21611772 TI - Cortisol affects tight junction morphology between pavement cells of rainbow trout gills in single-seeded insert culture. AB - A primary culture system of rainbow trout gill pavement cells grown on permeable support (single-seeded insert, SSI) was used to examine histological and physiological changes induced by the addition of the corticosteroid hormone cortisol. Pavement cell epithelia were cultured under symmetrical conditions (L15 apical/L15 basolateral) and developed a high transepithelial resistance (TER, 6.84 +/- 1.99 kOmega cm(2), mean +/- SEM) with a low phenol red diffusion rate (PRD, 0.15 +/- 0.03 MUmol l(-1)/day). Addition of cortisol to the basolateral compartment increased TER twofold and reduced PRD threefold over a 5-day period. A similar increase in TER could be seen after 24 h apical freshwater (FW) in control cultures. In cortisol-treated cultures FW exposure did not change TER, but PRD increased significantly. Histochemical staining of the cytoskeleton of cells in SSI culture revealed a morphological partitioning into a single mucosal layer of polarized, polygonal cells featuring cortical F-actin rings which were comparable to F-actin rings of epithelial cells on the lamellar and filamental surface, and several unorganized serosal layers of cells with F-actin stress fibers. Addition of cortisol increased cell density by 18% and in the mucosal layer it led to smaller, less polygonal cells with increased height and increased cell contact area. In transmission electron microscopic images two pairs of cytoplasmatic electron-dense structures confining the zonula occludens apically and basally toward the zonula adhaerens were found. Addition of cortisol increased the distance between those paired structures, hence led to deeper tight junctions. The cortisol-induced increase in barrier properties, therefore, involves a structural fortification of the tight junctions which was not generally modified by a short 24-h apical freshwater stress. These results identify cortisol as a regulator of tight junction morphology between pavement cells of euryhaline fish such as the trout. PMID- 21611773 TI - Factors affecting survival of Listeria monocytogenes and Listeria innocua in soil samples. AB - We investigated the ability of several strains of L. monocytogenes and Listeria innocua strains to survive in local soil samples in vitro. Survival of three L. monocytogenes strains, EGDe, CD83, and CD1038, and three L. innocua strains, CLIP, FH2117, FH2152, was monitored in soil samples by direct enumeration of colony-forming units on selective agar. The study did not demonstrate any species specific difference in soil survival, and all Listeria strains exhibited a marked decline in numbers over time. Bioluminescence imaging approaches to detect lux tagged strains in soil proved largely ineffective, most likely due to the reduced metabolic activity of strains in this environment. We investigated the influence of specific factors including the presence of a background microbiota, growth temperature, moisture and strain motility upon persistence in this environment. A sequenced L. monocytogenes strain, EGDe, was capable of active growth in sterile soil yet exhibited a decline in the presence of the normal soil microbiota. Furthermore, greater survival was seen at lower incubation temperatures in normal soil. Finally, we demonstrated a direct correlation between motility and survival of L. monocytogenes in soil with highly motile L. monocytogenes strains exhibiting greater soil survival than non-motile mutants. PMID- 21611774 TI - Association of interleukin-6 in women with persistence of DNA-HPV: a nested case control study. AB - OBJECTIVE: To identify the role of Interleukin-6, IL-10 and their epidemiological association in women with persistence of DNA-HPV. DESIGN AND METHODS: A nested case-control study within a longitudinal cohort study. Cervical specimens and blood samples were collected at enrolment from asymptomatic women who looked for a service of public health in a district of Porto Alegre, Brazil. A logistic regression analysis was performed with 95% confidence intervals. The outcome was the persistence of DNA-HPV infection. RESULTS: The analysis showed that the age of the first intercourse below 20 years old (OR = 19.65, IC 95% 2.43-68.85), four or more sexual partners during lifetime (OR = 5.67, IC 95% 1.28-24.99), women with a previous altered Pap smear (OR = 10.17, IC 95% 1.80-57.33), marital status (OR = 12.94, IC 95% 2.43-68.85) and IL6 <= 3.106 pg/ml were associated with persistence of HPV infection. IL-10 were not associated with the HPV persistence. CONCLUSION: The present study suggests that IL-6 levels may be a marker of HPV DNA persistence, although further investigation is necessary. PMID- 21611775 TI - Diagnosis and management of an unilateral giant fibroadenoma of the breast in pregnancy. AB - BACKGROUND: Fibroadenomas represent the vast majority of breast pathologies in young women. 2-4% of the fibroadenomas exceed 5 cm in size or 500 g in weight and are called "giant fibroadenomas". Due to their excessive growth they are usually enucleated to clarify a malignant origin, to differentiate from phyllodes tumor and to prevent persisting deformities of the breast. CASE: We present a case of a 17-year-old female who was pregnant in the 24th week and suffered from a giant fibroadenoma in the right breast. Besides the massive swelling no other illnesses were found. The patient was clinically asymptomatic and had noticed the tumor just 8 weeks ago. On clinical examination we found a tumor of more than 10 cm in size which fulfilled the criteria of a benign process. A prior performed biopsy and an ultrasound investigation could not definitely differentiate the mass from phyllodes tumor. Because of the rapid growth and the progressive deformation of the breast a lumpectomy was indicated and performed without complications in consideration of the gestational stage. CONCLUSION: We present a rare case of giant fibroadenoma in pregnant young women. Because of the progressive structural damage of the breast immediate surgical enucleation was indicated. Safety of the fetus was provided by perioperative monitoring. The pre-operative differentiation from phyllodes tumor is still challenging. PMID- 21611776 TI - On the Thermus thermophilus HB8 potential pathogenicity triggered from rhamnolipids secretion: morphological alterations and cytotoxicity induced on fibroblastic cell line. AB - A limited number of bacterial strains usually grown under nutrient limitation secrete rhamnolipids (RLs), which are recorded as virulence factors that are implicated in the pathogenicity of a microorganism. The non-pathogenic T. thermophilus HB8 produces extracellular rhamnolipids (TthRLs) under defined cultivation conditions using sunflower seed oil and sodium gluconate as carbon sources. In particular, the secreted TthRLs have been isolated, purified and identified with ATR-FTIR. Their effects on the cells' viability were examined when they were supplemented in a culture of human skin fibroblasts. Purified TthRLs triggered a sequence of rapid and pronounced morphological alterations characterized by transformation of fibroblast shape from polygonal to fusiform; retraction with cytoplasm condensation, rounding up, distortion of nuclei and loss of lamellar processes, and finally disruption of membrane. The addition of TthRLs in the cultured fibroblasts caused cytotoxicity, in contrast to that of rhamnose that stimulated viability, as it was assessed by MTT test. These results revealed that among the constituents of RLs that are implicated in the cytotoxicity, it has to be attributed to the lipidic chain variation and not to the carbohydrate part. TthRLs cytotoxicity on fibroblasts is comparable, and provoked similar effects, to that caused by saponin white, a known surfactant. TthRLs secretion might be a crucial point for the transformation of a non pathogenic bacterium to a pathogenic one under certain environmental conditions favoring their secretion. RLs secretion in the microorganism's world might be a general route for the passage in the pathogenicity to ensure their survival under nutrient limitation conditions. PMID- 21611777 TI - Efficient fitting of conductance-based model neurons from somatic current clamp. AB - Estimating biologically realistic model neurons from electrophysiological data is a key issue in neuroscience that is central to understanding neuronal function and network behavior. However, directly fitting detailed Hodgkin-Huxley type model neurons to somatic membrane potential data is a notoriously difficult optimization problem that can require hours/days of supercomputing time. Here we extend an efficient technique that indirectly matches neuronal currents derived from somatic membrane potential data to two-compartment model neurons with passive dendrites. In consequence, this approach can fit semi-realistic detailed model neurons in a few minutes. For validation, fits are obtained to model derived data for various thalamo-cortical neuron types, including fast/regular spiking and bursting neurons. A key aspect of the validation is sensitivity testing to perturbations arising in experimental data, including sampling rates, inadequately estimated membrane dynamics/channel kinetics and intrinsic noise. We find that maximal conductance estimates and the resulting membrane potential fits diverge smoothly and monotonically from near-perfect matches when unperturbed. Curiously, some perturbations have little effect on the error because they are compensated by the fitted maximal conductances. Therefore, the extended current based technique applies well under moderately inaccurate model assumptions, as required for application to experimental data. Furthermore, the accompanying perturbation analysis gives insights into neuronal homeostasis, whereby tuning intrinsic neuronal properties can compensate changes from development or neurodegeneration. PMID- 21611778 TI - Characterization of Rubus fruticosus mitochondria and salicylic acid inhibition of reactive oxygen species generation at Complex III/Q cycle: potential implications for hypersensitive response in plants. AB - In addition to adenosine triphosphate (ATP) production, mitochondria have been implicated in the regulation of several physiological responses in plants, such as programmed cell death (PCD) activation. Salicylic acid (SA) and reactive oxygen species (ROS) are essential signaling molecules involved in such physiological responses; however, the mechanisms by which they act remain unknown. In non-photosynthesizing tissues, mitochondria appear to serve as the main source of ROS generation. Evidence suggests that SA and ROS could regulate plant PCD through a synergistic mechanism that involves mitochondria. Herein, we isolate and characterize the mitochondria from non-photosynthesizing cell suspension cultures of Rubus fruticosus. Furthermore, we assess the primary site of ROS generation and the effects of SA on isolated organelles. Mitochondrial Complex III was found to be the major source of ROS generation in this model. In addition, we discovered that SA inhibits the electron transport chain by inactivating the semiquinone radical during the Q cycle. Computational analyses confirmed the experimental data, and a mechanism for this action is proposed. PMID- 21611779 TI - Prevalence of renal artery stenosis in patients undergoing cardiac catheterization. AB - To investigate the prevalence of significant renal artery stenosis (RAS >=50%), and to identify clinical predictors for significant RAS in patients with an elevated cardiovascular risk, such as those affected by ischemic heart disease. In patients with an elevated cardio-vascular risk, both atherosclerotic renovascular disease and coronary artery disease (CAD) are likely to occur. Prospectively from April 2007 to March 2008, all consecutive patients with ischemic heart disease undergoing non-emergent cardiac catheterization were also evaluated for atherosclerotic RAS by renal arteriography. A RAS >=50% was considered as significant. A total of 1,298 patients underwent cardiac and renal angiography. Significant RAS was found in 70 out of 1,298 patients (5.4%). The presence of peripheral vascular disease, eGFR <67 ml/min/1.73 m(2), age >66 years, dyslipidemia, CAD severity and pulse pressure >52 mmHg were independent clinical predictors of significant RAS, and jointly produced a ROC AUC of 0.79 (95% CI 0.73-0.85, P < 0.001). Based on these data, a prediction rule for significant RAS was developed, and it showed an adequate predictive performance with 64% sensitivity and 82% specificity. In a large cohort of patients undergoing coronary angiography, significant RAS is a relatively rare comorbidity (5.4%). A model based on simple clinical variables may be useful for the clinical identification of high CV risk patients who may be suitable for renal arteriography at the time of cardiac catheterization. PMID- 21611780 TI - Prevalence, predictors and prognostic significance of microalbuminuria in acute cardiac patients: a single center experience. AB - The objective of this study was to prospectively assess the prevalence, predictors and prognostic significance of microalbuminuria in a large cohort of consecutive acute cardiac patients, admitted to an intensive cardiac care unit from 1 January 2008 to 30 June 2009. In 815 acute cardiac patients, microalbuminuria is detectable in 39.3%. Microalbuminuria shows a significant negative correlation with left ventricular ejection fraction (Spearman's rho = 0.228; p < 0.001), while it is positively correlated with C-reactive protein (Spearman's rho = 0.239; p < 0.001), NT-pro-BNP (Spearman's rho = 0.306; p < 0.001) and glycemia (Spearman's rho = 0.191; p < 0.001). Microalbuminuria is an independent predictor for in-hospital mortality (1 MUg/min step) (OR 1.015; 95% CI 1.008-1.023; p < 0.001). In the acute phase of cardiac patients, microalbuminuria is a common finding, and it represents an independent predictor for early mortality. It is strictly linked to the inflammatory activation (as indicated by C-reactive protein) and to acute glucose values, thus suggesting that it may be part of the acute response to stress. PMID- 21611781 TI - Kinematic analysis of the flexion axis for correct femoral component placement. AB - PURPOSE: This study evaluates a new method for intraoperative determination of femoral component rotation by a navigation system (flexion axis, FA) driven by joint stability over the range of motion. METHODS: Seventy-five patients were treated with a navigated total knee replacement. Intraoperatively, the posterior condylar axis (PCA), the Whiteside's line (WL), and the surgical epicondylar axis (EA) were palpated, the flexion gap (FG) was determined, and the FA was calculated. The anatomical landmarks, lines, and angles were determined based on a postoperative computed tomography in all knees. The femoral rotation was intraoperatively determined by the surgeon based on the knowledge of the EA, the PCA, and the FG but not the FA. RESULTS: The deviation of the palpated EA was 3.5 degrees [0 degrees -13.8 degrees ], of the PCA externally rotated by 3 degrees was 2.2 degrees [0 degrees -9.6 degrees ], of the WL was 3.8 degrees [0.1 degrees -10.0 degrees ], of the FG was 2.5 degrees [0.2 degrees -8.8 degrees ], and of the FA was 2.5 degrees [0 degrees -10.0 degrees ]. CONCLUSIONS: The FA is a new functionally acquired axis for the determination of optimal femoral component alignment. Whether the FA leads to clinically superior results must be clarified by subsequent studies. PMID- 21611782 TI - Angiographic findings in patients with postoperative soft tissue defects following total knee arthroplasty. AB - PURPOSE: A postoperative defect of the surrounding soft tissue is one main risk factor for implant exposure and infection following total knee arthroplasty (TKR). The main factors that promote infection, tissue ischemia, and hypoxia are strongly associated with arterial insufficiency and the prevalence of impaired peripheral perfusion. We hypothesized that vascular malperfusion is the predisposing reason for soft tissue complications following TKR necessitating plastic reconstructive surgery. METHODS: A retrospective chart review was made among patients (n = 12) with soft tissue defects due to wound infection following a total knee arthroplasty referred to plastic reconstructive surgery. All patients presented with an exposed implant, and angiographic imaging was performed prior to reconstructive procedures. RESULTS: Eight out of twelve patients (67%) had a pathological vascular status. In three of these patients, interventional procedures were performed to ameliorate perfusion. In ten patients (83%), the defect was covered with a plastic reconstructive regional or free tissue transfer. Four patients received a free latissimus dorsi flap and six patients a pedicled a gastrocnemius muscle flap. In one patient, a secondary wound closure was needed after knee arthrodesis and an amputation was performed in another patient due to a multiresistant staphylococcus aureus infection and massive tissue destruction at the time of admission. CONCLUSIONS: We suggest to rule out peripheral occlusive disease among patients undergoing TKR at best prior to orthopedic surgery using pulses and, if in doubt ankle-brachial index and doppler sonography Consequently, if vascular occlusions are then confirmed by angiography, dilatation and stenting or revascularization should be performed, to ameliorate perfusion. PMID- 21611783 TI - Communities of color? Client-to-client racial concordance in the selection of mental health programs for Caucasians and African Americans. AB - A discrete-choice logit model was applied to study the determinants of mental health provider choice using data from a large urban county in the Northeast US. The study subjects were 9,544 adult Medicaid recipients who received outpatient treatment from the 20 Community Mental Health Center (CMHC) programs in 2001. In addition to a conventional set of variables representing client and provider characteristics, the regression model included several interaction terms to examine whether racial concordance level among patients influences the choice of an outpatient program. The results revealed that racial concordance among the clients seems to be a factor in choosing a program. In particular, Caucasian clients are much more likely to select a program with a higher percentage of Caucasian clients, even though they have to travel further. More generally, our results suggest that program choice may be driven more by the racial composition of the clients served than by spatial proximity to the program. PMID- 21611784 TI - Use of a short gambling screen with an arrestee population: a feasibility study. AB - Problem gamblers have been disproportionally found among prisoners. This study sought to (1) demonstrate if a short screening instrument (Lie/Bet Questionnaire) can expeditiously identify problem gamblers during the initial Criminal Justice System stage, and (2) examine the relationships between problem gambling and criminality among arrestees. Surveys were conducted with 959 inmates (from 1,445 approached) at a Central Booking Facility in Tampa, Florida. Among those surveyed, 81% were male with average age of 32.9. Ethnic distribution of those surveyed was Blacks (35.8%), Whites (43.3%), Hispanics (19.3%), Others (2.4%). Sixty-eight percent had completed trade school or less, 20% had some college and 12% were college graduates. Among those reporting gambling the year prior, 32.7% were problem gamblers according to the Lie/Bet. If including those who declined, the percent drops to a considerable 17.4% of the entire sample. Problem gamblers were significantly more likely to be charged with a drug or status crime, as well as being charged with a felony. Feasibility of screening inmates in an intake facility using the Lie/Bet Questionnaire was found. Furthermore, we found a need for gambling screening. Gambling courts should be considered. PMID- 21611785 TI - p53 regulates Ki-67 promoter activity through p53- and Sp1-dependent manner in HeLa cells. AB - The expression of the human Ki-67 protein, which is strictly associated with cell proliferation, is regulated by a variety of cellular mediators. In this study, we studied the effects of p53 on Ki-67 promoter in HeLa cells using luciferase reporter assay. The results showed that: (1) p53 inhibited Ki-67 promoter activity in a dose-dependent manner, (2) the p53-binding motifs mediated part of the transcriptional repression of Ki-67 promoter through a sequence-specific interaction with p53, (3) p53 was able to repress the Sp1-stimulated Ki-67 promoter activity, and (4) the Sp1-binding sites were responsible for the p53 mediated transcriptional repression of Ki-67 promoter. In conclusion, p53 inhibited Ki-67 promoter activity via p53- and Sp1-dependent pathways, and the interaction between p53 and Sp1 might be involved in the transcriptional regulatory mechanisms. PMID- 21611786 TI - Increased plasma proteasome chymotrypsin-like activity in patients with advanced solid tumors. AB - The chymotrypsin-like (ChT-L) activity is one of the key regulators of intracellular protein degradation. Elevated proteasome ChT-L activity has recently been reported in plasma of patients with leukemia and myelodysplastic syndrome and suggested to have a prognostic significance. The aim of the present study was to evaluate plasma proteasome ChT-L activity in patients with newly diagnosed solid tumors at early and advanced stages of the disease. The activity was assayed using the fluorogenic peptide substrate, Suc-Leu-Leu-Val-Tyr-AMC, in a cohort of 155 patients with early/advanced rectal (n=43/29), gastric (n=6/13), and breast (n=37/27) cancer and compared with that in normal individuals (n=55). The median plasma proteasome ChT-L activity was elevated by 20-32% in patients with advanced stage of rectal, gastric, and breast cancer compared with healthy donors. The difference turned out to be statistically significant (P<0.001). By contrast, values in patients with early stage of malignancies were not significantly different from those observed in normal individuals. We also found that plasma proteasome activity correlated with serum carcinoembryonic antigen levels in the group of patients with rectal cancer (r=0.433, P<0.05). Elevated plasma proteasome ChT-L activity is indicative of advanced stage of rectal, gastric, and breast cancer. However, the activity does not seem to be a parameter with clinically relevant potential in terms of early detection of cancer in this subset of patients. PMID- 21611787 TI - Application of attribute weighting method based on clustering centers to discrimination of linearly non-separable medical datasets. AB - In this paper, attribute weighting method based on the cluster centers with aim of increasing the discrimination between classes has been proposed and applied to nonlinear separable datasets including two medical datasets (mammographic mass dataset and bupa liver disorders dataset) and 2-D spiral dataset. The goals of this method are to gather the data points near to cluster center all together to transform from nonlinear separable datasets to linear separable dataset. As clustering algorithm, k-means clustering, fuzzy c-means clustering, and subtractive clustering have been used. The proposed attribute weighting methods are k-means clustering based attribute weighting (KMCBAW), fuzzy c-means clustering based attribute weighting (FCMCBAW), and subtractive clustering based attribute weighting (SCBAW) and used prior to classifier algorithms including C4.5 decision tree and adaptive neuro-fuzzy inference system (ANFIS). To evaluate the proposed method, the recall, precision value, true negative rate (TNR), G mean1, G-mean2, f-measure, and classification accuracy have been used. The results have shown that the best attribute weighting method was the subtractive clustering based attribute weighting with respect to classification performance in the classification of three used datasets. PMID- 21611788 TI - A remote patient monitoring system for congestive heart failure. AB - Congestive heart failure (CHF) is a leading cause of death in the United States affecting approximately 670,000 individuals. Due to the prevalence of CHF related issues, it is prudent to seek out methodologies that would facilitate the prevention, monitoring, and treatment of heart disease on a daily basis. This paper describes WANDA (Weight and Activity with Blood Pressure Monitoring System); a study that leverages sensor technologies and wireless communications to monitor the health related measurements of patients with CHF. The WANDA system is a three-tier architecture consisting of sensors, web servers, and back-end databases. The system was developed in conjunction with the UCLA School of Nursing and the UCLA Wireless Health Institute to enable early detection of key clinical symptoms indicative of CHF-related decompensation. This study shows that CHF patients monitored by WANDA are less likely to have readings fall outside a healthy range. In addition, WANDA provides a useful feedback system for regulating readings of CHF patients. PMID- 21611789 TI - The carriage of risk variants of CDKAL1 impairs beta-cell function in both diabetic and non-diabetic patients and reduces response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel. AB - On chromosome 6q22.3, a cluster of single-nucleotide polymorphisms located in intron 5 of the cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 (CDKAL1) gene were shown to confer susceptibility to type 2 diabetes in multiple ethnic groups. The diabetogenic role of CDKAL1 variants is suggested to consist in lower insulin secretion probably due to the insufficient inhibition of the CDK5 activity. In this study, we assessed the association of several SNPs of CDKAL1 with T2D in 772 Russian affected patients and 773 normoglycemic controls using a Taqman-based allelic discrimination assay. We showed association of the minor allele C of rs10946398 (Odds Ratio (OR) = 1.21, 95% CI = 1.04-1.4, P = 0.016), allele C of rs7754840 (OR = 1.18, 95% CI = 1.01 1.37, P = 0.038), and allele G of rs7756992 (OR = 1.21, 95% CI = 1.04-1.42, P = 0.017) with higher diabetes risk thereby replicating the predisposing role of CDKAL1 in etiology of T2D. These alleles contribute to three haplotypes (CCA, CGG, and CCG) related to higher diabetes risk (OR = 1.48, 2.12, and 1.95). Combinations of these haplotypes between each other form the group of high-risk haplogenotypes whose carriers had decreased HOMA-beta compared to other CDKAL1 variants in both diabetic (38.6 +/- 19.3 vs. 48.2 +/- 21.2, P(adjusted) = 0.019 0.044) and non-diabetic (91.8 +/- 42.1 vs. 108 +/- 47.2, P(adjusted) = 0.0054 0.01) patients. The carriage of the risk haplogenotypes of CDKAL1 was associated with reduced response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel. These data suggest that CDKAL1 is involved in the pathogenesis of T2D through impaired beta-cell function. PMID- 21611790 TI - Hands on or hands off the perineum: a survey of care of the perineum in labour (HOOPS). AB - INTRODUCTION AND HYPOTHESIS: There seems to be a temporal association between increasing use of "hands off" the perineum in labour and reduced use of episiotomy with an increasing rate of anal sphincter injuries. We aimed to determine how common the practice of "hands off" the perineum is. METHODS: An observational postal questionnaire study of 1,000 midwives in England in which the main objective was to obtain an estimate of the number of midwives practising either "hands on" or "hands off" was conducted. RESULTS: Six hundred and seven questionnaires were returned; 299 (49.3%, 95% CI 45.2-53.3%) midwives prefer the "hands-off" method. Less-experienced midwives were more likely to prefer the "hands off" (72% vs. 41.4%, p < 0.001). A higher proportion of midwives in the "hands-off" group would never do an episiotomy (37.1% vs. 24.4%, p = 0.001) for indications other than fetal distress. CONCLUSIONS: The "hands off" the perineum technique is prevalent in the management of labour. We hypothesise that a possible consequence might be an increased incidence of obstetric anal sphincter injury. PMID- 21611791 TI - Chinese validation of Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire. AB - INTRODUCTION AND HYPOTHESIS: The purpose of this study was to investigate the reliability and validity of the Chinese version of Pelvic Floor Distress Inventory (PFDI) and Pelvic Floor Impact Questionnaire (PFIQ). METHODS: Women who presented for pelvic floor disorders completed the Chinese version of PFDI and PFIQ, SF-36, a 3-day urinary and fecal diary. POP-Q assessment, urodynamic study, anal manometry, and ultrasound were performed where appropriate. RESULTS: Five hundred and ninety-seven women completed the study. The Cronbach's alpha and test retest reliability of PFDI and PFIQ was 0.92 and 0.98, and 0.77 and 0.79, respectively. Convergent validity was demonstrated with negative correlation of PFDI and PFIQ with SF-36; positive correlation of staging of prolapse, urinary or fecal incontinent episodes with the respective subscales of PFDI and PFIQ. CONCLUSIONS: The Chinese version of PFDI and PFIQ are reliable and valid condition-specific health-related quality of life questionnaires for women with pelvic floor disorders. PMID- 21611792 TI - The effect of surface treatments on the adhesion of electrochemically deposited hydroxyapatite coating to titanium and on its interaction with cells and bacteria. AB - The effect of different mechanical and chemical pre-treatments on the adhesion strength of hydroxyapatite (HAp) coating on a commercially pure titanium (CP-Ti) substrate was studied by means of a standard tensile test followed by microscopic and chemical analysis to determine the locus of fracture. In addition, the effects of either these pre-treatments or post-treatment by low-energy electron irradiation, which allowed tuning the wettability of the surface, on both osteoblast progenitor attachment and S. aureus bacteria attachment were investigated. A dedicated program was developed for unambiguous identification and count of stained cells. A single-phase HAp coating was formed by electrodeposition. A series of surface pre-treatments consisted of grinding down to P1000, etching in HNO3/HF solution, grit blast, soaking in NaOH and subsequent heat treatment provided the highest adhesion strength to the HAp coating. Osteoblast progenitors derived from rats may be attached preferentially to a hydrophilic surface (post-treatment to theta = 30 degrees ), while the bacteria seemed to be less attached to hydrophobic surfaces (post-treatment to theta = 105 degrees ). However, the results were not statistically different. The bacteria seemed to be less attached to the smoother, uncoated surfaces. PMID- 21611793 TI - Influence of nanometer scale particulate fillers on some properties of microfilled composite resin. AB - The aim of this study was to evaluate the effect of different weight fractions of nanometer sized particulate filler on properties of microfilled composite resin. Composite resin was prepared by mixing 33 wt% of resin matrix to the 67 wt% of silane treated microfine silica particulate fillers with various fractions of nanometer sized fillers (0, 10, 15, 20, 30 wt%) using a high speed mixing machine. Test specimens made of the composites were tested with a three-point bending test with a speed of 1.0 mm/min until fracture. Surface microhardess (Vicker's microhardness) was also determined. The volumetric shrinkage in percent was calculated as a buoyancy change in distilled water by means of the Archimedes principle. The degree of monomer conversion (DC%) of the experimental composites containing different nanofiller fractions was measured using FTIR spectroscopy. Surface roughness (Ra) was determined using a surface profilometer. Nanowear measurements were carried out using a nanoindentation device. The water uptake of specimens was also measured. Parameters were statistically analysed by ANOVA (P < 0.05). The group without nanofillers showed the highest flexural strength and modulus, DC% and Ra value. The group with 30% nanofillers had the highest water uptake and volumetric shrinkage. No significant difference was found in Vicker's microhardness and the nanowear of the composites. The plain microfilled composite demonstrated superior properties compared to the composites loaded with nanofillers with the exception of surface roughness. PMID- 21611794 TI - Treatment of periodontal defects in dogs using an injectable composite hydrogel/biphasic calcium phosphate. AB - An injectable composite silanized hydroxypropyl methyl cellulose/biphasic calcium phosphate (Si-HPMC/BCP) has been investigated in humans with promising results. The aim of this study was to evaluate his efficacy for treating periodontal defects (canine fenestration and premolar furcation) in dog models. At 3 months, we observed that bone formation around BCP particles in furcation model is more discernible but not statistically significant in defects filled with Si-HPMC/BCP compared to healing in control. We suggest that BCP particles sustain the bone healing process by osteoconduction, while the Si-HPMC hydrogel enhances intergranular cohesion and acts as an exclusion barrier. Furthermore, bone ingrowth is not so distinctive in superficial defects where the biomaterial appears unstable. These results with Si-HPMC/BCP are encouraging. In addition, this biomaterial is easy to use and simplifies the process of filling periodontal lesions. However, more researches are needed to improve the viscosity and hardness to adjust the material to the specificities of periodontal defects. PMID- 21611795 TI - Acetylsalicylic acid does not prevent digital subtraction angiography-related high signal intensity lesions in diffusion-weighted imaging in cerebrovascular patients. A retrospective analysis. AB - PURPOSE: Assuming thromboembolic events to be the origin of silent strokes during cerebral digital subtraction angiography (DSA), antiplatelet therapy with acetylsalicylic acid (ASA) should significantly reduce the risk for DSA-related silent stroke. The aim of this retrospective analysis was to assess whether ASA does prevent DSA-related silent stroke in terms of high signal intensity lesions in diffusion-weighted magnetic resonance imaging (DW-MRI). METHODS: All patients underwent a baseline DW-MRI 24 h before DSA and a follow-up DW-MRI 3-24 h after DSA. Patients were considered to have an acute (silent) infarction caused by DSA if there was at least one hyperintense lesion of at least 1 mm in diameter and no neurological deficits. RESULTS: Out of 52 patients in the ASA group 11 (21.2%) had high signal lesions on DW-MRI and 20 out of 123 (16.3%) in the non-ASA group. No significant relationship between the ASA and non-ASA group and the post angiographic appearance of high signal intensity lesions in DW-MRI could be found (Wilcoxon 2-sample test: p-value 0.9). CONCLUSIONS: The use of oral antiplatelet therapy by ASA (100 mg/day) in cerebrovascular patients did not prevent DSA related high signal intensity lesions in DW-MRI in this study. Despite a potential bias of this retrospective analysis the findings challenge the current theory of thromboembolisms being the predominant origin of silent stroke. The findings therefore support alternative hypotheseses of the etiology of silent strokes, such as air embolism and mobilized embolic material by the catheter at the vessel wall. PMID- 21611796 TI - Intronic microRNA suppresses endothelial nitric oxide synthase expression and endothelial cell proliferation via inhibition of STAT3 signaling. AB - Intronic microRNA (miRNAs) suppressed the expression of endothelial nitric oxide synthase (eNOS) gene in endothelial cells (ECs). This study was to investigate the role of signal transducer and activator of transcription 3 (STAT3) in the regulation of eNOS expression and vascular EC proliferation by the intronic 27 nucleotide (nt) miRNA derived from the 27-base pair repeats in intron 4 of eNOS gene. A detectable level of the 27-nt miRNA was present in the control ECs. Overexpression of the 27-nt miRNA dramatically suppressed the expression of eNOS and STAT3 at both transcription and translation levels in ECs in association with significant inhibition of EC proliferation. Mutation of the 27-nt miRNA at the 3' terminal region resulted in substantial reduction of the inhibitory effect of miRNA on eNOS and STAT3 expression, and EC proliferation. Overexpression of active STAT3 significantly reversed the inhibitory effect of the 27-nt miRNA on eNOS expression and EC proliferation. In summary, we demonstrated that the 27-nt intronic miRNA functioned as a negative regulator for the expression of its host gene eNOS and cell proliferation in ECs. The sequence in 3'-terminal region played a key role in the function of the 27-nt miRNA. The regulatory effect of the intronic miRNA on eNOS gene expression was associated with miRNA polymorphisms, and mediated through inhibition of STAT3 signaling in ECs. PMID- 21611797 TI - Dynamic microbial response of sulfidogenic wastewater biofilm to nitrate. AB - Nitrate is one of the chemicals often added to wastewater to control hydrogen sulfide production by sulfate-reducing bacteria (SRB). While the effect of nitrate in various SRB pure cultures is well documented, the effect observed in mixed microbial communities is not consistent. This study investigates the response of mixed SRB communities to nitrate, by examining the changes in activity and community composition of sulfidogenic wastewater biofilm over a 10 day period with 10 mmol L(-1) nitrate exposure. Biofilms were enriched in SRB belonging to the Desulfobacter, Desulfobulbus, Desulfomicrobium, and Desulfovibrio genera. Nitrate exposure decreased dsrB transcription within 4 h, and sulfate consumption within 10 days, but it did not fully eliminate sulfide production in the biofilms. The effect of nitrate on SRB was genus specific; Desulfobacter and Desulfobulbus disappeared while Desulfovibrio and Desulfomicrobium persisted in the biofilms. Nitrate exposure also led to the rapid proliferation of nitrate-reducing bacteria within the biofilms, and increased the biofilm thickness. Nitrate consumption began within 2 h of nitrate exposure and gradually increased in rate over time. Transcription of the nitrate reductase napA, and the diversity of nitrate reductase genes narG and napA also increased concurrently. Our results demonstrate that some SRB, presumably those able to tolerate or detoxify nitrite, will persist in sulfidogenic wastewater biofilms despite continuous exposure to high levels of nitrate. Nitrate is therefore unlikely to provide lasting hydrogen sulfide suppression in wastewater biofilms harboring Desulfovibrio or Desulfomicrobium populations. PMID- 21611798 TI - A method to generate recombinant Salmonella typhi Ty21a strains expressing multiple heterologous genes using an improved recombineering strategy. AB - Live attenuated Salmonella enterica serovar Typhi Ty21a (Ty21a) is an important vaccine strain used in clinical studies for typhoid fever and as a vaccine vector for the expression of heterologous antigens. To facilitate the use of Ty21a in such studies, it is desirable to develop improved strategies that enable the stable chromosomal integration and expression of multiple heterologous antigens. The phage lambda Red homologous recombination system has previously been used in various gram-negative bacteria species to mediate the accurate replacement of regions of chromosomal DNA with PCR-generated 'targeting cassettes' that contain flanking regions of shared homologous DNA sequence. However, the efficiency of lambda Red-mediated recombineering in Ty21a is far lower than in Escherichia coli and other Salmonella typhimurium strains. Here, we describe an improved strategy for recombineering-based methods in Ty21a. Our reliable and efficient method involves the use of linear DNA-targeting cassettes that contain relatively long flanking 'arms' of sequence (ca. 1,000 bp) homologous to the chromosomal target. This enables multiple gene-targeting procedures to be performed on a single Ty21a chromosome in a straightforward, sequential manner. Using this strategy, we inserted three different influenza antigen expression cassettes as well as a green fluorescent protein gene reporter into four different loci on the Ty21a chromosome, with high efficiency and accuracy. Fluorescent microscopy and Western blotting analysis confirmed that strong inducible expression of all four heterologous genes could be achieved. In summary, we have developed an efficient, robust, and versatile method that may be used to construct recombinant Ty21a antigen-expressing strains. PMID- 21611799 TI - Comprehensive analysis of Salmonella sequence polymorphisms and development of a LDR-UA assay for the detection and characterization of selected serotypes. AB - Salmonella is a major cause of food-borne disease, and Salmonella enterica subspecies I includes the most clinically relevant serotypes. Salmonella serotype determination is important for the disease etiology assessment and contamination source tracking. This task will be facilitated by the disclosure of Salmonella serotype sequence polymorphisms, here annotated in seven genes (sefA, safA, safC, bigA, invA, fimA, and phsB) from 139 S. enterica strains, of which 109 belonging to 44 serotypes of subsp. I. One hundred nineteen polymorphic sites were scored and associated to single serotypes or to serotype groups belonging to S. enterica subsp. I. A diagnostic tool was constructed based on the Ligation Detection Reaction-Universal Array (LDR-UA) for the detection of polymorphic sites uniquely associated to serotypes of primary interest (Salmonella Hadar, Salmonella Infantis, Salmonella Enteritidis, Salmonella Typhimurium, Salmonella Gallinarum, Salmonella Virchow, and Salmonella Paratyphi B). The implementation of promiscuous probes allowed the diagnosis of ten further serotypes that could be associated to a unique hybridization pattern. Finally, the sensitivity and applicability of the tool was tested on target DNA dilutions and with controlled meat contamination, allowing the detection of one Salmonella CFU in 25 g of meat. PMID- 21611800 TI - The effects of radiofrequency hyperthermia on pain and function in patients with knee osteoarthritis: a preliminary report. AB - BACKGROUND: The clinical evidence of the efficacy of hyperthermia on osteoarthritis (OA) has not yet been clearly established. In addition, the application of a modality that can control the temperature inside the joints has not been reported. The purpose of this study was to investigate the effect of percutaneous radiofrequency hyperthermia, which could safely raise the temperature of the body core, in patients with OA knees. METHODS: Temperature changes inside the knee joint without OA were measured during exposure to radiofrequency. Radiofrequency hyperthermia was performed on 12 OA knees by exposure to 8 MHz and 200 W for 20 min, 3 times, at 1-week intervals. The clinical outcome was evaluated by use of the Lequesne index (LI) and the Japan Orthopaedic Association (JOA) scale. The osteoarthritis research society international (OARSI) responder criteria were also analyzed. RESULTS: Radiofrequency hyperthermia of 8 MHz and 200 W for 20 min increased the temperature inside the joint from 34.4 to 39.4 degrees C. The LI decreased by 3.55 points from baseline during the 3 weeks. The JOA scale improved significantly during the period, reaching 86.25 points at the final examination from baseline of 67.5 points. 67% of patients had a response to the therapy according to OARSI criteria. No side effects were observed. CONCLUSIONS: Radiofrequency hyperthermia can safely increase the temperature inside the knee joint. Radiofrequency hyperthermia on OA knees provides a remarkable pain relief effect and can improve the patients' daily life. In the future, clinical studies should be performed with a protocol containing more cases, with appropriate control groups. PMID- 21611801 TI - Promotion of rabbit ligament healing by local delivery of hepatocyte growth factor. AB - BACKGROUND: Extracapsular ligament injuries of the knee and ankle are common injuries. Ligaments heal slowly, usually over months or longer by scar formation rather than by tissue regeneration. This study was performed to evaluate the therapeutic effect of locally delivered recombinant hepatocyte growth factor (HGF) on the early healing of ligaments in a rabbit model. METHODS: Japanese white rabbits were subjected to a standardized gap injury in the medial collateral ligaments (MCLs) of both knees. Each rabbit underwent bilateral transection of the midsubstance of the MCL, which was not repaired. During postoperative days 0-6, the rabbits were injected with 10 MUg human recombinant HGF into the right MCL, while the left MCL was injected with saline alone. One, 3, 6, and 12 weeks after surgery, experimental rabbits were sacrificed. The structural properties of the femur-MCL-tibia complex were then assessed and the tissue was subjected to histological evaluation. To see the distribution of cells that express c-Met receptor, the tissue was subjected to immunohistochemistry. RESULTS: Immunohistochemical evaluation revealed that c-Met expression was observed particularly at opposing ligament ends in the HGF-treated limbs 1 week after surgery. Histological evaluation revealed earlier neovascularization and more aligned collagen fibers in the MCLs of the HGF-treated group than the control group. In mechanical evaluations, similar ligament failure modes were noted in the two groups. After 3 weeks, HGF-treated limbs had significantly improved structural properties than the paired control limbs. CONCLUSIONS: Our findings indicate local administration of recombinant HGF promotes early steps in ligament healing and the repair of structural properties in a rabbit model. Local administration of HGF may represent a new therapeutic approach to accelerating healing and rehabilitation after ligament injury. PMID- 21611802 TI - Bone and/or joint attachment is a risk factor for local recurrence of myxofibrosarcoma. AB - BACKGROUND: Myxofibrosarcoma is characterized by a high local recurrence rate despite optimal surgical treatment. The definition of prognostic factors for recurrence offers high-risk patients a closer follow-up and a multidisciplinary therapeutic approach. METHODS: A cohort of 23 patients treated for primary myxofibrosarcoma was retrospectively analyzed. The patients (sex and age), tumors (size, stage, tumor location, bone and/or joint attachment), radiological findings (abnormal signal extension in MRI), histological findings (FNCLCC grade and microscopic extension along the muscle fascia), and treatment (surgical margin) characteristics were included in univariate prognostic factor analysis. RESULTS: After a median follow-up of 63.3 months (range 15-191), the overall recurrence rate was 34.7%. Median time between initial surgery and recurrence was 24.8 months (range 8-52). Inadequate surgical margins (p = 0.026) and bone and/or joint attachment (p = 0.001) were associated with an increased recurrence rate. CONCLUSION: For the further improvement of local recurrence-free survival of patients with myxofibrosarcoma, accurate diagnosis of the tumor extension and adequate planning for the surgical margin should be focused on in cases with bone and/or joint attachment. PMID- 21611804 TI - How much do physicians in Latin America know about behavioral variant frontotemporal dementia? AB - Diagnosis of behavioral variant frontotemporal dementia (bvFTD) can be especially challenging during the early stages for several reasons, including the fact that (a) behavioral disturbances in bvFTD can mimic the symptomatic profile of psychiatric disorders; (b) neuropsychological performance may be relatively spared; and (c) changes in structural neuroimaging may go undetected. Most frequently, bvFTD is not included as part of medical or residency training outside the field of cognitive neurology. The present study aimed at examining bvFTD-related practices concerning academic and professional training, diagnosis, and treatment across Latin America. We surveyed the academic and professional aspects of clinical practice related to bvFTD of 596 physicians from different fields throughout the continent. We discuss several aspects concerning Latin American physicians' training on dementia and bvFTD, the way in which they approach the differential diagnosis of bvFTD, and their most frequent strategies for the treatment of this condition. We conclude that information about bvFTD deserves more attention in both undergraduate and postgraduate medical education in Latin America, and that understanding clinical practices related to FTD can help design more efficient training programs for physicians in this and other world regions. PMID- 21611803 TI - Tendon-derived stem cells (TDSCs): from basic science to potential roles in tendon pathology and tissue engineering applications. AB - Traditionally, tendons are considered to only contain tenocytes that are responsible for the maintenance, repair and remodeling of tendons. Stem cells, which are termed tendon-derived stem cells (TDSCs), have recently been identified in tendons. This review aims to summarize the current information about the in vitro characteristics of TDSCs, including issues related to TDSC isolation and culture, their cell morphology, immunophenotypes, proliferation and differentiation characteristics and senescence during in vitro passaging. The challenges in studying the functions of these cells are also discussed. The niche where TDSCs resided essentially provides signals that are conducive to the maintenance of definitive stem cell properties of TDSCs. Yet the niche may also induce pathologies by imposing an aberrant function on TDSCs or other targets. The possible niche factors of TDSCs are herein discussed. We presented current evidences supporting the potential pathogenic role of TDSCs in the development of tendinopathy with reference to the recent findings on the altered biological responses of these cells in response to their potential niche factors. The use of resident stem cells may promote engraftment and differentiation of transplanted cells in tendon and tendon-bone junction repair because the tendon milieu is an ideal and familiar environment to the transplanted cells. Evidences are presented to show the potential advantages and results of using TDSCs as a new cell source for tendon and tendon-bone junction repair. Issues pertaining to the use of TDSCs for tissue repair are also discussed. PMID- 21611806 TI - To what extent can preventive treatments prevent damage from systemic lupus erythematosus? AB - Managing lupus patients traditionally involves treating manifestations of active disease with the most effective and least toxic therapies so that "damage" from ongoing disease or treatments can be minimized. Damage in clinical epidemiologic studies is usually defined by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, a validated, organ specific assessment tool. This review summarizes recent developments regarding organ-specific manifestations and lupus-related damage and their prevention. PMID- 21611807 TI - Developmental iodine deficiency and hypothyroidism impair neural development, upregulate caveolin-1, and downregulate synaptotagmin-1 in the rat cerebellum. AB - Adequate thyroid hormone is critical for cerebellar development. Developmental hypothyroidism induced by iodine deficiency during gestation and postnatal period results in permanent impairments of cerebellar development with an unclear mechanism. In the present study, we implicate cerebellar caveolin-1 and synaptotagmin-1, the two important molecules involved in neuronal development, in developmental iodine deficiency, and in developmental hypothyroidism. Two developmental rat models were created by administrating dam rats with either iodine-deficient diet or propylthiouracil (PTU, 5 or 15 ppm)-added drinking water from gestational day 6 till postnatal day (PN) 28. Nissl staining and the levels of caveolin-1 and synaptotagmin-1 in cerebella were assessed on PN28 and PN42. The results show that the numbers of Purkinje cells were reduced in the iodine deficient and PTU-treated rats. The upregulation of caveolin-1 and the downregulation of synaptotagmin-1 were observed in both iodine-deficient and PTU treated rats. These findings may implicate decreases in the number of Purkinje cells and the alterations in the levels of caveolin-1 and synaptotagmin-1 in the impairments of cerebellar development induced by developmental iodine deficiency and hypothyroidism. PMID- 21611805 TI - Cellular effects of progranulin in health and disease. AB - Progranulin is a fascinating multifunctional protein, which has been implicated in cell growth, wound repair, tumorigenesis, inflammation, neurodevelopment, and more recently in neurodegeneration. The mechanism of action of this protein is still largely unknown, but the knowledge about the cellular effects on various cell types is expanding. In the current review, we will summarize what is known about the cell biology of progranulin. A better understanding of the biology of progranulin will impact diverse areas of research. PMID- 21611808 TI - Pulsed radiofrequency of the second cervical ganglion (C2) for the treatment of cervicogenic headache. AB - In this case series report, two patients with cervicogenic headache were selected. After initial positive response to the greater occipital nerve block, pulse radiofrequency (PRF) was performed on the position of the second cervical ganglion (C2). Two patients reported 100% pain relief lasting for 6 months. The lateral puncture is safer and more comfortable than the posterior site. This case study demonstrates the effectiveness of PRF to treat cervicogenic headache originating from the C2 nerve. However, we need to further evaluate the results using more samples. PMID- 21611809 TI - Elevated carbon dioxide and/or ozone concentrations induce hormonal changes in Pinus tabulaeformis. AB - We investigated endogenous plant hormones and needle growth in Pinus tabulaeformis plants grown in open-top chambers and exposed to ambient or elevated concentrations of carbon dioxide (CO(2)) and/or ozone (O(3)). Exposure to elevated CO(2) for 100 days significantly increased the change in fresh needle weight, indole-3-acetic acid (IAA), isopentenyl-adenosine (iPA), and dihydrozeatin riboside (DHZR) content. Abscisic acid (ABA) content decreased, and no effect was observed on zeatin riboside (ZR) content or changes in needle dry weight. The ratios of IAA/ABA and total cytokinins (CKs)/ABA [Formula: see text] were increased. Elevated O(3) significantly decreased IAA and ZR, and decreased the ratios of IAA/ABA and CKs/ABA. Ozone treatment increased ABA content but did not change iPA or DHZR content or change fresh or dry needle weights. The combination treatment significantly increased ABA content and the IAA/ABA ratio but decreased the total CKs/ABA ratio and had no effect on CKs or IAA content or change in fresh and dry needle weights. The results indicate that elevated CO(2) ameliorated the effects of elevated O(3) on tree growth. PMID- 21611810 TI - Silver nanoparticles induce apoptosis and G2/M arrest via PKCzeta-dependent signaling in A549 lung cells. AB - The use of silver nanoparticles is one of the fastest growing product categories in the nanotechnology industry, with a focus on antimicrobial activity. However, thus far, toxicity data for silver nanoparticles are limited. In this study, we investigated the cytotoxic effects of silver nanoparticles (Ag NPs) and the pathway by which they affect A549 lung epithelial cells. The effects of Ag NPs on cell survival, cell cycle progression, and mRNA and protein alterations of selected cell cycle- and apoptosis-related genes were studied using formazan dye and LDH release assays, flow cytometric analysis, semi-quantitative RT-PCR, and Western blot analysis. Ag NPs reduced cell viability, increased LDH release, and modulated cell cycle distribution through the accumulation of cells at G2/M and sub-G1 phases (cell death), with a concurrent decrease in cells at G1. Ag NP treatment increased Bax and Bid mRNA levels and downregulated Bcl-2 and Bcl-w mRNAs in a dose-dependent manner. Furthermore, Ag NPs altered the mRNA levels of protein kinase C (PKC) family members. In particular, ectopic overexpression of PKCzeta led to the enhancement of cellular proliferation and reduced sensitivity to Ag NPs in A549 cells. Together, these results suggest that Ag NPs induce strong toxicity and G2/M cell cycle arrest by a mechanism involving PKCzeta downregulation in A549 cells. PMID- 21611811 TI - IL-12- and IL-18-mediated, nitric oxide-induced apoptosis in TNF-alpha-mediated osteoclastogenesis of bone marrow cells. AB - TNF-alpha has been recognized as an important factor for osteoclastogenesis and plays an important role in bone resorption under pathological conditions. IL-12 and IL-18, which are T-cell mediators, are also important inflammatory cytokines. We have reported that IL-12 and IL-18 induce apoptosis in bone marrow cells treated with TNF-alpha in vitro and that osteoclastogenesis is inhibited by the interaction of TNF-alpha-induced Fas and the IL-12-induced Fas ligand (FasL). However, the anti-FasL antibody could not completely inhibit apoptosis. Therefore, it is possible that IL-12 and IL-18 may also trigger some other apoptotic mechanisms. Nitric oxide (NO) may act as a mediator of the apoptotic effect. In this study, we examined whether NO causes the IL-12- and IL-18-induced apoptosis of bone marrow cells in TNF-alpha-mediated osteoclast formation. We found that NO production was induced in bone marrow cells cultured with IL-12 and IL-18 in the presence of TNF-alpha. When bone marrow cells were cultured with TNF alpha, osteoclasts were formed. In contrast, when bone marrow cells were cultured with both TNF-alpha and IL-12 or IL-18, the adherent cells were induced to undergo apoptosis. Apoptosis was partially inhibited when bone marrow cells were treated with NO synthase inhibitors. Furthermore, IL-12 and IL-18 synergistically induced cell death and upregulated NO production in the presence of TNF-alpha. These results indicate that the simultaneous effects of TNF-alpha and IL-12 or IL 18 on bone marrow cells induce apoptosis and that apoptosis is induced by the production of NO. PMID- 21611812 TI - Effects of an extended drought period on physiological properties of grassland species in the field. AB - A very high percentage (around 70%) of the agronomic area in Switzerland is covered by grasslands at various altitudes where environmental conditions, management, community structure and productivity vary widely. As heat waves and drought are predicted to increase in future climate, survival of plant species in grasslands is a major issue of concern in Central Europe. The effect of summer drought on representative grasslands in Switzerland was studied through drought experiments (using rain-out shelters avoiding natural precipitation) to understand the response of predominant species to changed climatic conditions. The physiological performance (gas exchange, leaf water potential) of selected species was investigated at three locations in Switzerland. The pre-dawn leaf water potential of all species was lower (more negative) under the dryer conditions at the three sites. Net photosynthesis and stomatal conductance of forb and legume species did not show major changes under drought, while grass species showed large decreases at the lowland site. These differences between forb-legume and grass species were not observed at the pre-alpine and alpine site. The apparent drought tolerance of the forb-legume species seems to be due at least partially-to increased water use efficiency under drought conditions. PMID- 21611813 TI - Re: totally tubeless percutaneous nephrolithotomy: a prospective randomized controlled study. AB - The study is unique in terms of defining the safety of totally tubeless percutaneous nephrolithotomy (PNL). Furthermore, the authors state that the tubeless group has an advantage of less pain. However, we interpreted the results of pain-related comparisons different than that the authors had. In our opinion, the results gained show that there is no difference in terms of pain in both groups. The authors state that they have inserted a double J catheter to patients that were included in the tubeless group in addition to the nephrostomy as a conventional procedure. However, routine Double-J placement in addition to nephrostomy is not a common procedure. Additionally, the large-bore nephrostomy tube preferred is certain to cause pain, as stated in the previous studies. It has been shown that small-bore tubes cause less pain. It may have been more appropriate to compare the groups in such a manner. Even though we have stated our comments with respect to pain issues, it is evident that the study is unique in terms of defining the safety of a totally tubeless procedure. PMID- 21611814 TI - Flexible ureteroscopy and holmium laser lithotripsy for treatment of upper urinary tract calculi in patients with autosomal dominant polycystic kidney disease. AB - The objective of the study was to investigate the safety and efficacy of flexible ureteroscopy and holmium laser lithotripsy for the management of patients with autosomal dominant polycystic kidney disease (ADPKD) and associated nephrolithiasis. Between 2005 and 2010, flexible ureteroscopic stone treatment was attempted in 13 patients with ADPKD. Two patients had bilateral renal stones. Most of the stones were located in the renal pelvis and/or calices with a stone size 1.7 cm in the largest diameter. The success rate and morbidity and complications were recorded. A total of 45 intrarenal calculi with a mean stone size of 5.6 mm (range 3-17) were identified. The mean number of stones per patients was 3.2 (range 2-5). The mean number of primary procedures was 1.2 (range 1-2). The overall stone-free rates after one and two procedures were 84.5 and 92.3%, respectively. Complications occurred in three procedures and consisted of low-grade fever in one procedure, flank pain in another procedure and stent pain in another procedure. No patient died. Flexible ureteroscopy with holmium laser lithotripsy is a safe and effective method for the treatment of patients with ADPKD and associated nephrolithiasis. PMID- 21611815 TI - Critical appraisal of the International Study Group of Pancreatic Surgery (ISGPS) consensus definition of postoperative hemorrhage after pancreatoduodenectomy. AB - PURPOSE: Postpancreatectomy hemorrhage (PPH) is one of the most serious complications after pancreatoduodenectomy (PD). This study analyzed and validated the International Study Group of Pancreatic Surgery (ISGPS) definition of PPH and aimed to identify risk factors for early (<24 h) and late PPH. METHODS: Patients who underwent PD for pancreatic head tumors between 2001 and 2008 were included and complications were prospectively recorded. Factors associated with PPH were assessed by uni- and multivariate analysis. RESULTS: Complete datasets were available for 796 patients. Classic and pylorus-preserving PD was performed in 13.8% and 86.2% of the patients, respectively. According to the ISGPS definition, PPH occurred in 29.1% of the cases (232 of 796 patients): 4.8% grade A, 15.2% grade B, and 9.2% grade C. The definition is based largely on surrogate markers (e.g., transfusion requirement) that are affected by other critical illnesses and more than 97% of patients with mild PPH had no clinical signs of bleeding. The need for postoperative intensive care as well as the incidence of pancreatic fistula, relaparotomy, and mortality rates significantly increased from grades A to C. Thirty-seven patients (4.6%) required interventional (endoscopy or angiography) and/or relaparotomy for PPH. Relaparotomy for PPH was performed in 3.1% of all patients. Independent risk factors for early PPH were preoperative anemia (hemoglobin, <11 mg/dl) and multivisceral resection while advanced age, chronic renal insufficiency, increased blood loss, and long operation time were associated with late PPH. CONCLUSIONS: The ISGPS definition of PPH is feasible and applicable but produces a high rate of false positive mild PPH cases. The different grades still significantly correlate with relevant outcome variables, thus the definition discriminates postoperative courses, but a minor modification of the definition of mild PPH is suggested. The new results further demonstrate the need to optimize preoperative anemia and chronic renal insufficiency. PMID- 21611817 TI - The Endurant Stent Graft System: 15-month follow-up report in patients with challenging abdominal aortic anatomies. AB - OBJECTIVE: The objective of this study is to report a 15-month follow-up with the Endurant Stent Graft System in patients with challenging aortic anatomies. METHODS: At three German clinics, a consecutive series of 50 patients underwent endovascular abdominal aortic repair (EVAR) for challenging abdominal aortic aneurysm with the Endurant stent graft between November 2008 and May 2009. EVAR was elective in 48 cases and emergent in two. Patients had short (<=15 mm) aortic necks, severe suprarenal/infrarenal angulation, and/or small (<8 mm), calcified, severely angulated, or tortuous iliac or femoral access vessels. Additionally, a cohort of 40 patients without challenging anatomies were retrospectively analysed to clarify differences concerning technical success, mortality, and morbidity between these groups. RESULTS: The primary technical success rate was 92% (46/50). The 30-day mortality rate was 2% (1/50), the death due to multiorgan failure. Intraoperative angiograms revealed three type I endoleaks (2 proximal and 1 distal), and one of those was persisting at 30 days (30-day rate, 2%). Postoperative imaging discovered no further type I or type III endoleaks. The 30 day rate of the type II endoleak was 6% (3/50). There were two cases of graft limb occlusion, both requiring reintervention within 30 days. Follow-up was available in all of the 50 patients (100%) over a median of 15 months (1-25). During this time, seven patients died (overall mortality, 16%; 8/50), besides the above-described patient, all of them unrelated to the procedure. Compared to the 30-day results with the Endurant stent graft in non-challenging anatomies (no type I endoleak; no graft limb occlusion; all-cause mortality, 0%), procedure related complications in challenging anatomies are increasing. CONCLUSION: Early and 15-month results with the Endurant stent graft in patients with challenging aortic anatomies are encouraging. PMID- 21611818 TI - [Transthoracic sonography as diagnostic option in case of suspected pulmonary embolism?]. PMID- 21611816 TI - Gastric carcinogenesis. AB - INTRODUCTION: In most patients, gastric cancer is diagnosed in advanced stage. Curative treatment options are limited and the mortality is high. The process of gastric carcinogenesis is triggered by Helicobacter pylori-driven gastritis and is further characterized by its complexity of interaction with other risk factors. Health care systems are challenged for the improvement of prevention, early diagnosis, and effective treatments. METHODS: An extensive literature research has been performed to elucidate the interplay between etiological factors involved in gastric carcinogenesis. RESULTS: H. pylori is the most important carcinogen for gastric adenocarcinoma. Evidence is provided by experiments including animal studies as well as clinical observational and interventional studies in humans. Eradication has the potential to prevent gastric cancer and offers the greatest benefit if performed before premalignant changes of the gastric mucosa have occurred. Bacterial virulence factors are essential players in modulating the immune response involved in the initiation of the carcinogenesis in the stomach. Host genetic factors contribute to the regulation of the inflammatory response and in the aggravation of mucosal damage. The harmful role of environmental factors is restricted to salt intake and smoking of tobacco. The ingestion of fruit and vegetables has some protective effect. CONCLUSION: Infection with H. pylori is the major risk factor for gastric cancer development, and thus, eradication of the Helicobacter offers a promising best option for prevention of the disease. Bacterial virulence, host genetic factors, and environmental influences are interacting in the multifactorial process of gastric carcinogenesis. PMID- 21611819 TI - [Complications of liver cirrhosis]. AB - The occurrence of complications increases the mortality in patients with cirrhosis of the liver. Therefore, early detection and treatment of complications of cirrhosis is of major importance. Following diagnosis of cirrhosis, a screening gastroscopy detects esophageal varices. Primary prevention of variceal bleeding can be initiated with beta-receptor antagonists or variceal band ligation. With the first episode of ascites or the manifestation of other complications of cirrhosis such as hepatic encephalopathy and hepatorenal syndrome, a paracentesis excludes spontaneous bacterial peritonitis. Hepatorenal syndrome can be treated with a combination of vasopressors and albumine. Furthermore, occurrence of complications in patients with cirrhosis of the liver should prompt the evaluation of an indication for liver transplantation. PMID- 21611820 TI - The risks of absolute medical confidentiality. AB - Some ethicists argue that patient confidentiality is absolute and thus should never be broken. I examine these arguments that when critically scrutinised, become porous. I will explore the concept of patient confidentiality and argue that although, this is a very important medical and bioethical issue, this needs to be wisely delivered to reduce third party harm or even detriment to the patient. The argument for absolute confidentiality is particularly weak when it comes to genetic information and inherited disease. PMID- 21611821 TI - Overview: underserved areas of education in the responsible conduct of research: authorship. AB - In February of 2007, the Responsible Conduct of Research Education Committee of the Association for Practical and Professional Ethics convened a mini-conference at the Association's annual meeting. The purpose of the mini-conference was to examine underserved areas of education in research ethics. The mini-conference consisted of panel discussions for two topics: authorship and social responsibility. Representatives from diverse academic disciplines were invited to participate in each of the two panels. This Special Section of Science and Engineering Ethics consists of the papers based on presentations in the authorship panel. The papers illustrate similarities and differences in authorship and publication practices in various disciplines including engineering, the life sciences, and the social sciences. PMID- 21611822 TI - [Congenital left ventricular aneurysm in a 17-year-old competitive athlete]. AB - We present the case of a 17-year-old competitive athlete with an asymptomatic left ventricular aneurysm (LVA). Echocardiography demonstrated hypoplasia of the septum and a large apical LVA. Magnetic resonance imaging (MRI) detected a very thin and fibrotic wall of the LVA. Due to the potential risk of rupture the LVA was surgically resected and the apex of the left ventricle was covered with a patch plasty. The patient had an event-free postoperative course. Because of the potential risk of arrhythmia, the patient was recommended not to participate further in competitive sport. PMID- 21611823 TI - Reduced postoperative pain in total hip arthroplasty after minimal-invasive anterior approach. AB - PURPOSE: The development of minimal-incision techniques for total hip replacement with preservation of soft tissue is generally associated with faster rehabilitation, reduction of postoperative pain and increased patient comfort. The aim of this study was to compare a minimal-incision anterior approach with a transgluteal lateral technique for hip replacement surgery with respect to postoperative pain, consumption of rescue medication, length of hospital stay and time to reach a defined range of motion. METHODS: In this retrospective cohort study we investigated 100 patients with a minimal-incision anterior approach (group I) and 100 patients with a transgluteal lateral approach (group II) retrospectively undergoing unilateral hip replacement. The study variables were pain at rest and during physiotherapy, amount of rescue medication, the time to reach a defined flexion and time in hospital. RESULTS: The patients of group I consumed less rescue medication (19.6 +/- 6.9 mg vs. 23.6 +/- 11.3 mg; p = 0.005) and experienced less pain on the day of surgery (1.3 +/- 1 vs. 2.3 +/- 1.3, p = 0.0001) and the first postoperative day (0.41 +/- 0.8 vs. 0.66 +/- 1.1, p = 0.036). The time to reach the defined range of motion (6.4 +/- 2 days vs. 7.4 +/- 2.1 days; p = 0.001) and the length of hospital stay were shorter (10.2 +/- 1.9 days vs. 13.4 +/- 1.6 days; p = 0.0001) for group I. However, pain during physiotherapy was higher on the third and sixth through ninth days after surgery in comparison to group II (p = 0.001-0.013). CONCLUSION: The implantation of a hip prosthesis through a minimal-incision anterior approach is successful in reducing postoperative pain and consumption of pain medication. Time to recovery and length of hospital stay are also influenced positively. Pain increases during physiotherapy, and may be mitigated by adopting limited weight bearing during the early postoperative period. PMID- 21611824 TI - Comparisons of local and systemic aerobic fitness parameters between finswimmers with different athlete grade levels. AB - To study the relationship between the local and systemic aerobic fitness parameters, and between the muscle oxygenation and aerobic performance, 16 female finswimmers were recruited and divided into high-level (HL) group and low-level group. Cardiorespiratory function, blood lactate concentration and near infrared spectroscopy muscle oxygenation in the vastus lateralis (VL) were monitored simultaneously during a maximal incremental exercise. We found that the break point (Bp) of the oxygenation index (OI) in the VL (BpVL) had significant correlations with lactate threshold (LT) and gas exchange threshold (GET), and the appearance sequence of the three thresholds was BpVL ~ LT <= GET. When considering different levels, the [Formula: see text] at BpVL, LT and GET were higher in the HL group. During intensive exercise, there were significantly faster [Formula: see text] increase and evidently slower OI decrease in the HL group, suggesting that faster [Formula: see text] increase in the HL group slowed down the muscle deoxygenation and facilitated subjects to cycle to higher workloads. In conclusion, multi-modality approaches combining local and systemic physiological monitoring technologies might provide better explanations of the relationship between local and systemic aerobic fitness parameters, and might be a novel way to analyze the difference between groups of different levels. PMID- 21611825 TI - Muscle damage protection by low-intensity eccentric contractions remains for 2 weeks but not 3 weeks. AB - This study investigated the hypothesis that the protective effect conferred by a low-intensity eccentric exercise against maximal eccentric exercise would not last more than a week. Untrained men (21.3 +/- 1.6 years) were allocated into either a control or one of four repeated bout groups (n = 13 per group). The repeated bout groups performed 30 low-intensity eccentric contractions (ECC) of the elbow flexors with a dumbbell set at 10% of maximal isometric strength (10% ECC) either 2 days, 7 days (1 week), 14 days (2 weeks) or 21 days (3 weeks) before 30 maximal eccentric contractions (Max-ECC). The control group performed Max-ECC only. Changes in maximal voluntary contraction strength, optimum angle, range of motion, upper arm circumference, muscle soreness, plasma creatine kinase activity and myoglobin concentration, and ultrasound echo-intensity following 10% ECC were analysed by a one-way repeated measures ANOVA. Changes in the variables following Max-ECC were compared among the groups by a two-way repeated measures ANOVA. The 10%-ECC did not change any variables, showing no indication of muscle damage. The changes in all variables following Max-ECC were smaller (P < 0.05) for 2-day, 1- and 2-week groups than control group, without significant differences between 2-day and 1-week groups. The 2-week group showed greater (P < 0.05) changes in all variables compared with 2-day and 1-week groups. Changes in the variables were similar between 3-week and control groups, except for muscle soreness showing smaller (P < 0.05) changes for 3-week group. These results suggest that non-damaging eccentric exercise confers a protective effect against Max-Ecc, but the effect is attenuated between 1 and 2 weeks. PMID- 21611826 TI - 'Benign' ovarian teratoma and N-methyl-D-aspartate receptor (NMDAR) encephalitis in a child. AB - N-methyl-D-aspartate receptor (NMDAR) encephalitis is a life-threatening paraneoplastic neuropsychiatric encephalitis that predominantly affects young women and has a strong association with ovarian teratomas. Removal of the ovarian teratomas improves the prognosis and decreases the risk of recurrence. We present an 11-year-old girl with NMDAR encephalitis with small bilateral teratomas not initially appreciated on abdominal CT or pelvic MRI. A 12-mm teratoma was identified in the right ovary and a 7-mm teratoma was identified in the left ovary on US follow-up at 5 months. Intraoperative sonography was used to localize the teratomas for excision. In NMDAR encephalitis, the ovarian teratomas can be very small, particularly in children, and easily missed on cross-sectional imaging. Awareness of the association of NMDAR encephalitis and ovarian teratomas will improve the diagnostic accuracy and imaging interpretation. Periodic sonography and MRI might be warranted in children if the initial study is negative. PMID- 21611827 TI - Racial pride and religiosity among African American boys: implications for academic motivation and achievement. AB - The persistent underachievement among African American boys has led to increased empirical inquiry, yet little research considers within-group variation in achievement nor positive youth characteristics that help explain positive achievement outcomes. This study conceptualized culturally-based factors (racial pride and religiosity) as adolescent assets that would promote African American boys' achievement and also enhance positive effects of other youth assets (positive educational utility beliefs) on achievement. Our sample included 158 adolescent boys (M = 17.08) from a large, socioeconomically diverse suburban community context. Accounting for demographic background variables, educational utility beliefs were positively associated with academic grade performance. A significant educational utility beliefs and racial pride interaction indicated a stronger, positive association of educational utility beliefs with grade performance among boys with higher racial pride relative to those with lower racial pride. Also, there was a stronger positive association between educational utility beliefs and grades for boys reporting lower religious importance, but boys endorsing both lower educational utility beliefs and religious importance were at highest risk for low grade performance. Overall results suggest the importance of considering culturally-based factors in studying achievement motivation processes among ethnic minority adolescents. PMID- 21611828 TI - A crystallographic approach to structural transitions in icosahedral viruses. AB - Viruses with icosahedral capsids, which form the largest class of all viruses and contain a number of important human pathogens, can be modelled via suitable icosahedrally invariant finite subsets of icosahedral 3D quasicrystals. We combine concepts from the theory of 3D quasicrystals, and from the theory of structural phase transformations in crystalline solids, to give a framework for the study of the structural transitions occurring in icosahedral viral capsids during maturation or infection. As 3D quasicrystals are in a one-to-one correspondence with suitable subsets of 6D icosahedral Bravais lattices, we study systematically the 6D-analogs of the classical Bain deformations in 3D, characterized by minimal symmetry loss at intermediate configurations, and use this information to infer putative viral-capsid transition paths in 3D via the cut-and-project method used for the construction of quasicrystals. We apply our approach to the Cowpea Chlorotic Mottle virus (CCMV) and show that the putative transition path between the experimentally observed initial and final CCMV structures is most likely to preserve one threefold axis. Our procedure suggests a general method for the investigation and prediction of symmetry constraints on the capsids of icosahedral viruses during structural transitions, and thus provides insights into the mechanisms underlying structural transitions of these pathogens. PMID- 21611829 TI - Chitosan membranes as sorbents for trace elements determination in surface waters: chitosan membranes as sorbents for trace elements. AB - PURPOSE: Chitosan membranes (non-crosslinked, crosslinked, and modified with L cysteine) were evaluated as sorbents prior to electrothermal atomic absorption spectrometry (ETAAS) determination of total dissolved metal content in surface water samples. METHODS: Different types of chitosan membranes were prepared in the presence or absence of L-cysteine. Chemical parameters for quantitative sorption/desorption of trace analytes have been optimized. RESULTS: The optimal pH for Cd(II), Cu(II), Ni(II), and Pb(II) sorption using L-cysteine-modified membrane is between 7 and 8.5 and coincides with typical surface water pH, allowing in situ preconcentration of analytes without any additional water sample pretreatments. Non-crosslinked chitosan membrane could be used for simultaneous sampling, transportation, and laboratory determination of Hg(II). Determination limits (calculated as 10sigma) achieved for total dissolved metal contents are: Cd 0.001 MUg/L, Cu 0.02 MUg/L, Ni and Pb 0.05 MUg/L, and relative standard deviations were 10-15% for all elements at concentration level of 0.05-2 MUg/L. The determination limit achieved for Hg(II) was 0.012 MUg/L and relative standard deviations at concentration levels 0.015-2 MUg/L were within 9% and 15%. CONCLUSIONS: Non-crosslinked chitosan membrane was proposed as an efficient sorbent for Hg(II) preconcentration and determination in river and lake waters; L: -cysteine modified chitosan membrane was recommended for solid phase extraction of Cd(II), Cu(II), Ni(II), and Pb(II) from surface (lake, river, and sea) waters. The application of chitosan membranes as adsorbents for in situ field preconcentration of the analytes and their subsequent determination by CVAAS and ETAAS in water samples has been demonstrated. PMID- 21611830 TI - Heavy metal contamination and risk assessment in water, paddy soil, and rice around an electroplating plant. AB - PURPOSE: The objective of this paper is to assess the impact of long-term electroplating industrial activities on heavy metal contamination in agricultural soils and potential health risks for local residents. METHODS: Water, soil, and rice samples were collected from sites upstream (control) and downstream of the electroplating wastewater outlet. The concentrations of heavy metals were determined by an atomic absorption spectrophotometer. Fractionation and risk assessment code (RAC) were used to evaluate the environmental risks of heavy metals in soils. The health risk index (HRI) and hazard index (HI) were calculated to assess potential health risks to local populations through rice consumption. RESULTS: Hazardous levels of Cu, Cr, and Ni were observed in water and paddy soils at sites near the plant. According to the RAC analysis, the soils showed a high risk for Ni and a medium risk for Cu and Cr at certain sites. The rice samples were primarily contaminated with Ni, followed by Cr and Cu. HRI values >1 were not found for any heavy metal. However, HI values for adults and children were 2.075 and 1.808, respectively. CONCLUSION: Water, paddy soil, and rice from the studied area have been contaminated by Cu, Cr, and Ni. The contamination of these elements is related to the electroplating wastewater. Although no single metal poses health risks for local residents through rice consumption, the combination of several metals may threaten the health of local residents. Cu and Ni are the key components contributing to the potential health risks. PMID- 21611831 TI - Optimum conditions for serum clearance of iodixanol, applicable to the estimation of glomerular filtration rate in horses. AB - To estimate the glomerular filtration rate (GFR) in horses, an optimum dose of the nonionic contrast medium iodixanol as a tracer was assessed with blood-sample times. Iodixanol was administered intravenously at 10-40 mg I/kg to geldings and mares, and blood was collected 30, 60, 90, 120, 150, and 180 min later. Serum iodixanol concentration was determined by high-performance liquid chromatography (HPLC), and serum urea nitrogen (UN) and creatinine concentrations were also measured. The combination of 20 mg I/kg iodixanol and sampling times of 60, 90, and 120 min after injection was considered to be appropriate for practical use. In clinically healthy horses, the reference values were determined to be 1.90 +/- 0.03 ml/min/kg (150.8 +/- 2.94 ml/min/m2), consistent with historical data using different tracers. The result suggests that serum clearance of iodixanol is a ready-to-use tool for a screening of alterations in the equine GFR, although it is necessary to perform a more longitudinal study using horses with a variety of renal functions. PMID- 21611832 TI - A reduction of licensed origins reveals strain-specific replication dynamics in mice. AB - Replication origin licensing builds a fundamental basis for DNA replication in all eukaryotes. This occurs during the late M to early G1 phases in which chromatin is licensed by loading of the MCM2-7 complex, an essential component of the replicative helicase. In the following S phase, only a minor fraction of chromatin-bound MCM2-7 complexes are activated to unwind the DNA. Therefore, it is proposed that the vast majority of MCM2-7 complexes license dormant origins that can be used as backups. Consistent with this idea, it has been repeatedly demonstrated that a reduction (~60%) in chromatin-bound MCM2-7 complexes has little effect on the density of active origins. In this study, however, we describe the first exception to this observation. A reduction of licensed origins due to Mcm4 ( chaos3 ) homozygosity reduces active origin density in primary embryonic fibroblasts (MEFs) in a C57BL/6J (B6) background. We found that this is associated with an intrinsically lower level of active origins in this background compared to others. B6 Mcm4 ( chaos3/chaos3 ) cells proliferate slowly due to p53 dependent upregulation of p21. In fact, the development of B6 Mcm4 ( chaos3/chaos3 ) mice is impaired and a significant fraction of them die at birth. While inactivation of p53 restores proliferation in B6 Mcm4 ( chaos3/chaos3 ) MEFs, it paradoxically does not rescue animal lethality. These findings indicate that a reduction of licensed origins may cause a more profound effect on cell types with lower densities of active origins. Moreover, p53 is required for the development of mice that suffer from intrinsic replication stress. PMID- 21611833 TI - The role of substance P in the marginal division of the neostriatum in learning and memory is mediated through the neurokinin 1 receptor in rats. AB - Substance P (SP) is a neuropeptide that plays an important role in inflammation, respiration, pain, aggression, anxiety, and learning and memory mainly through its high affinity neurokinin 1 receptor (NK1R). The marginal division (MrD) is a pan-shaped subdivision in the caudomedial margin of the neostriatum in the mammalian brain and is known to be involved in learning and memory. We studied the expression of SP, NK1R and NK1R mRNA in the rat striatum by immunohistochemistry, immunofluorescence and in situ hybridization, and found that the levels of SP, NK1R protein and NK1R mRNA were high in the cell bodies, fibers and terminals of neurons in the neostriatum, especially in the MrD. Knocking down NK1R activity in the MrD by using an antisense oligonucleotide against NK1R mRNA inhibited learning and memory in a Y-maze behavioral test. Our results show that NK1R mediates the role of SP in the MrD in learning and memory. PMID- 21611834 TI - Low dose estrogen prevents neuronal degeneration and microglial reactivity in an acute model of spinal cord injury: effect of dosing, route of administration, and therapy delay. AB - Spinal cord injury (SCI), depending on the severity of injury, leads to neurological dysfunction and paralysis. Methylprednisolone, the only currently available therapy renders limited protection in SCI. Therefore, other therapeutic agents must be tested to maximize neuroprotection and functional recovery. Previous data from our laboratory indicate that estrogen (17beta-estradiol) at a high dose may attenuate multiple damaging pathways involved in SCI and improve locomotor outcome. Since use of high dose estrogen may have detrimental side effects and therefore may never be used in the clinic, the current study investigated the efficacy of this steroid hormone at very low doses in SCI. In particular, we tested the impact of dosing (1-10 MUg/kg), mode of delivery (intravenous vs. osmotic pump), and delay in estrogen application (15 min-4 h post-SCI) on microgliosis and neuronal death in acute SCI in rats. Treatment with 17beta-estradiol (1-10 MUg/kg) significantly reduced microglial activation and also attenuated apoptosis of neurons compared to untreated SCI animals. The attenuation of cell death and inflammation by estrogen was observed regardless of mode and time of delivery following injury. These findings suggest estrogen as a potential agent for the treatment of individuals with SCI. PMID- 21611836 TI - Intracranial stent placement in a patient with moyamoya disease. PMID- 21611835 TI - Prenatal amphetamine exposure effects on dopaminergic receptors and transporter in postnatal rats. AB - We investigated the influence of prenatal amphetamine exposure (PAE) on dopamine (DA) receptors, and dopamine transporter (DAT) in various striatal and limbic subregions and locomotor activity induced by novel environmental conditions and amphetamine at two postnatal ages, 35 days old (prepubertal) and 60 days old (postpubertal). Experiments were carried out on pregnant female Sprague-Dawley rats, which were daily injected with either d-amphetamine sulfate (1 mg/kg) or saline solution (0.9%) for 11 days, from gestation day 11-21. In PAE rats compared to control we found the following: at pre-pubertal age, an enhancement of DA D1 in the dorsolateral area of the caudate-putamen (CPu), CPu-ventral and shell of the nucleus accumbens (NAcc) with a decrement of the DA D3 receptors in NAcc, olfactory tubercle (OT), and the islands of Calleja (IoC); whereas at postpubertal age, an increase in the levels of DAT in the NAcc and fundus of the CPu, and OT along with a decrease in the expression of DA D2 receptors only in the NAcc shell were found in PAE rats compared to control. In addition, amphetamine induces a marked decrease in locomotor activity at postpubertal age in rats with PAE. These results suggest a differential effect of amphetamines on the DAT mechanism of the nervous system during embryonic development of animals with implications in behavior and drug addictions at adulthood age. PMID- 21611837 TI - Fluorescence in situ hybridization analysis of chromosome aberrations in 60 Chinese patients with multiple myeloma. AB - Conventional cytogenetic analysis is often hampered owing to the low mitotic index of multiple myeloma (MM) cells in bone marrow samples of MM. Interphase fluorescence in situ hybridization (I-FISH) analysis combined with magnetic activated cell sorting (MACS) has substantially enhanced the sensitivity of cytogenetic analysis. Here, we used I-FISH to explore the incidence of chromosomal abnormalities in 60 Chinese patients with newly diagnosed MM. Five different specific probes for the regions containing 13q14.3 (D13S319), 14q32 (IGHC/IGHV), 1q21, 1p12, and 17p13 were used to detect chromosomal aberrations, and LSI IGH/CCND1, LSI IGH/FGFR3, and LSI IGH/MAF probes were further applied to detect t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23) in patients with 14q32 rearrangement. Fifty of the patients (83.3%) had at least one type of abnormalities regarding the regions analyzed. Nine patients (15%) had one abnormality; 10 patients (16.7%) had two abnormalities; 31 patients (51.7%) had three or more abnormalities. The most frequent abnormality in the patients was illegitimate IgH rearrangement (70%), followed by 13q14 deletion (63.3%), 1q21 amplification (61.7%), 1p12 deletion (33.3%), and 17p13 deletion (13.3%). These aberrations are not randomly distributed, but strongly interconnected. Patients with 17p13 deletion or t(4;14)(p16;q32) had significant higher beta2 microglobulin level (P < 0.05). However, all these abnormalities had no correlation with age, gender, disease stage, and Ig isotype; yet, it was showed that the frequencies of the individual chromosomal abnormalities were very high. Taken together, MACS in combination with I-FISH may be a promising tool to detect the molecular cytogenetic abnormalities of MM. PMID- 21611838 TI - Prognostic value of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase 9 (MMP-9) and aminopeptidase N/CD13 in breast cancer patients. AB - The aim of this study was to analyse the expression of matrix metalloproteinase 2(MMP-2), matrix metalloproteinase-9 (MMP-9) and aminopeptidase APN/CD13 in breast carcinoma samples, and their possible prognostic value in breast cancer patients. The expression of MMP-2, MMP-9 and APN/CD13 in tumor cells was analysed in 138 breast carcinomas by immunohistochemical staining of tumor cells using the semiquantitative method for the detection of cytoplasmic and membrane reaction in tumor cells as well as stromal cells positivity. MMP-2 was positive in tumor cells of 52.9% patients and in stromal cells of 74.6% patients, while MMP-9 positive tumor and stromal cells were found in 84.8 and 63.8% patients, respectively. Tumor cell APN/CD13 expression was found in 36.2% patients. Stromal cell MMP-2 expression correlated significantly with tumor size and neoangiogenesis. A positive correlation was also observed between tumor cell MMP 9 expression and hormone receptor status. Stromal cell coexpression of MMP-2/MMP 9 correlated significantly with tumor size. APN/CD13 expression in tumor cells significantly correlated with tumor type and neoangiogenesis. Overall survival was significantly shorter in patients with MMP-2, MMP-2/MMP-9 positive tumor cells, and tended to be shorter in patients with APN/CD13 positive tumor cells. Coexpression of MMP-2/MMP-9 in tumor cells was an independent risk factor for patient survival (OD = 13.9). Our results suggest that MMP-2, MMP-9, APN/CD13 expression and MMP-2/MMP-9 coexpression in combination with other standard prognostic factors can serve as a poor prognostic factor in the evaluation of breast cancer prognosis. PMID- 21611839 TI - UHRF1 is associated with tumor recurrence in non-muscle-invasive bladder cancer. AB - Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) is a novel anti apoptotic gene, and overexpression of UHRF1 is involved in tumorigenicity. Here, immunohistochemistry was used to detect UHRF1 expression in non-muscle-invasive bladder cancer (NMIBC), and these data were examined for correlation with clinicopathological parameters and prognosis. The UHRF1 expression rate was 49.2% in a total of 118 bladder cancer tissues, which was significantly higher than in normal tissues, and UHRF1 expression has a significantly positive correlation with tumor grade (P = 0.027) and recurrence (P = 0.013). Survival analysis showed that UHRF1 high expression patients' mean survival time (42.59 months) was significantly shorter than that (71.36 months) of UHRF1 low expression patients (P = 0.0002). Multivariate analysis showed that UHRF1 overexpression was an independent prognostic factor for tumor recurrence (P < 0.0001). So UHRF1 may be a molecular marker to predict the recurrence of NMIBC. PMID- 21611840 TI - (31)P NMR correlation maps of (18)O/ (16)O chemical shift isotopic effects for phosphometabolite labeling studies. AB - Intramolecular correlations among the (18)O-labels of metabolic oligophosphates, mapped by J-decoupled (31)P NMR 2D chemical shift correlation spectroscopy, impart stringent constraints to the (18)O-isotope distributions over the whole oligophosphate moiety. The multiple deduced correlations of isotopic labels enable determination of site-specific fractional isotope enrichments and unravel the isotopologue statistics. This approach ensures accurate determination of (18)O-labeling rates of phosphometabolites, critical in biochemical energy conversion and metabolic flux transmission. The biological usefulness of the J decoupled (31)P NMR 2D chemical shift correlation maps was validated on adenosine tri-phosphate fractionally (18)O labeled in perfused mammalian hearts. PMID- 21611841 TI - MRI findings, patterns of disease distribution, and muscle fat fraction calculation in five patients with Charcot-Marie-Tooth type 2 F disease. AB - PURPOSE: To describe the magnetic resonance imaging (MRI) pattern of muscle involvement and disease progression in five patients with late-onset Charcot Marie-Tooth (CMT) disease type 2 F, due to a previously unknown mutation. MATERIALS AND METHODS: Five patients (three males, two females) underwent MRI of the lower limbs to define the pattern of muscle involvement and evaluate the muscle fat fraction (MFF) of residual thigh muscle with gradient-echo (GRE) dual echo dual-flip angle technique. Evaluation of fatty infiltration both by visual inspection and MFF calculation was performed. RESULTS: A proximal-to-distal gradient of muscle involvement was depicted in male patients with extensive muscle wasting of lower legs, less severe impairment of distal thigh muscles, and sparing of proximal thigh muscles. A peculiar phenotype finding was that no or only slight muscle abnormalities could be found in the two female patients. CONCLUSION: We described the pattern of muscle involvement and disease progression in a family with CMT disease type 2 F. GRE dual-echo dual-flip angle MRI technique is a valuable technique to obtain a rapid quantification of MFF. PMID- 21611842 TI - A limp in a pregnant woman as a first presentation of celiac disease. AB - A 25-year-old Arab woman, reported to our endocrinology clinic one month post partum presenting with back pain and a limp that started during the seventh month of pregnancy. Upon examination, she was found to have a full range of motion and no tenderness in the hip joint or lower back. The pain was aggravated by walking. She had a limping gait with a lean to her right side. She had low calcium, low hemoglobin, high parathyroid hormone and high alkaline phosphatase levels. X-rays of her hip and lumbosacral areas were normal. Her spinal magnetic resonance imaging findings were also normal. A bone mineral density (BMD) study revealed severe osteoporosis with a lumbar spine T-score of -4.6 and femoral neck T-scores of -4.1 (left) and -3.9 (right). A celiac disease work-up included tests for anti endomysial antibodies and anti-tissue transglutaminase antibodies, which were positive, and the results of an endoscopy and biopsy confirmed the diagnosis of celiac disease. Gluten-free diet with calcium and vitamin D supplementation resulted in the complete resolution of her symptoms and a normal gait. The patient returned to normal calcium and parathyroid hormone levels and experienced a significant improvement in her BMD to normal. Celiac disease may initially presents during pregnancy result in severe osteoporosis that causes significant pain and disability. PMID- 21611843 TI - Prevalence of non-fracture short vertebral height is similar in premenopausal and postmenopausal women: the osteoporosis and ultrasound study. AB - We observed similar prevalence of short vertebral height without endplate depression (SVH) in young women aged 20-39 years and older women aged 55-79 years. There was no association between SVH and low bone density. In older women, therefore, SVH may be largely long standing and not indicative of osteoporotic fracture. INTRODUCTION: Algorithm-based qualitative (ABQ) definition of osteoporotic vertebral fracture (VF) requires evidence of endplate fracture, and there is no minimum threshold for apparent 'reduction' in vertebral height. In older women, SVH without endplate fracture identified on baseline assessment may be long standing and unrelated to VF. If this is so, we would expect to see a similar prevalence of SVH in younger women. We aimed to compare the prevalence of pre- and postmenopausal women with SVH and the characteristics of women with and without SVH. METHODS: We used the ABQ method to classify baseline vertebral images (DXA-based imaging) from 257 premenopausal and 1,361 postmenopausal women participating in the population-based Osteoporosis and Ultrasound Study. Images were classified as follows: normal (no VF, no SVH), SVH (no VF) or VF (with/without SVH in unfractured vertebrae). We compared proportions of women with SVH (chi-squared test) and compared age, height, weight and bone mineral density (BMD) by ABQ classification (two-sample t test/analysis of variance). RESULTS: The prevalence of pre- and postmenopausal women with SVH was 37% and 33%, respectively (P>0.05). Compared to women without SVH, premenopausal women with SVH were older (P<0.001) and heavier (P=0.05), and postmenopausal women with SVH were taller (P<0.05), with higher spine BMD (P<0.01). Postmenopausal women with VF were older (P<0.001) and shorter (P<0.01) with lower BMD (P<0.001) than women without VF. CONCLUSIONS: Short vertebral height without endplate fracture is equally prevalent in pre- and postmenopausal women and not associated with low bone density. PMID- 21611844 TI - Assessment of hydrogeochemical characteristics of groundwater in parts of Hindon Yamuna interfluve region, Baghpat District, western Uttar Pradesh. AB - The present study has been carried out to assess groundwater quality in parts of Hindon-Yamuna interfluve region of western Uttar Pradesh. Fifty-five groundwater samples were collected from hand pumps in post-monsoon 2005 and pre-monsoon 2006 period, respectively, covering an area of about 1,345 km(2). Physical and chemical parameters of groundwater such as electrical conductivity, pH, total dissolved solid, Na, K, Ca, Mg, HCO(3), Cl, and SO(4) were determined. Concentration of the chemical constituents in groundwater of the study area varies spatially and temporarily. Interpretation of analytical data of major ion chemistry helps to identify three chemical types of groundwater i.e. 'mixed', 'mixed bicarbonate' and 'alkali bicarbonate' types. The species likely to occur in groundwater of the study area are Ca-HCO(3), Mg-HCO(3), Ca-SO(4), Na-Cl, Na SO(4), Na-HCO(3), K-Cl, and some other possible species of K, depending on its abundance. The groundwater of the study area comes under the category of moderately hard to very hard, mildly acidic to slightly alkaline in nature. There is anomalously high concentration of major ions, particularly, Na, K, SO(4), and Cl. High SO(4) and K values may be related to anthropogenic influences, rather than through some natural process. Sodium along with Cl may be added to the system through sewage pollution and leachate percolation. PMID- 21611845 TI - An approach for determining bioassessment performance and comparability. AB - Many organizations in the USA collect aquatic bioassessment data using different sampling and analysis methods, most of which have unknown performance in terms of data quality produced. Thus, the comparability of bioassessments produced by different organizations is often unknown, ultimately affecting our ability to make comprehensive assessments on large spatial scales. We evaluated a pilot approach for determining bioassessment performance using macroinvertebrate data obtained from several states in the Southeastern USA. Performance measures evaluated included precision, sensitivity, and responsiveness to a human disturbance gradient, defined in terms of a land disturbance index value for each site, combined with a value for specific conductance, and instream habitat quality. A key finding of this study is the need to harmonize ecoregional reference conditions among states so as to yield more comparable and consistent bioassessment results. Our approach was also capable of identifying potential areas for refinement such as reevaluation of less precise, sensitive, or responsive metrics that may result in suboptimal index performance. Higher performing bioassessments can yield information beyond "impaired" versus "unimpaired" condition. Acknowledging the limitations of this pilot study, we would recommend that performance evaluations use at least 50 sites, 10 of which are ecoregional reference sites. Efforts should be made to obtain data from the entire human disturbance gradient in an ecoregion to improve statistical confidence in performance measures. Having too few sites will result in an under representation of certain parts of the disturbance gradient (e.g., too few poor quality sites), which may bias sensitivity and responsiveness estimates. PMID- 21611847 TI - Ground level volume mixing ratio of methane in a tropical coastal city. AB - Urban regions are hotspots of greenhouse gas emissions which include CO(2), CH(4), N(2)O, etc. Methane is a strong greenhouse gas which is produced from a number of sources including fossil fuel combustion, municipal waste, and sewage processing, etc. Ground level mixing ratio of methane in the tropical coastal city of Thiruvananthapuram in South India, during calm early morning period was measured. Measurements were done during both winter and summer seasons. Concentrations were significantly higher than global average value. Intra-city variation in ground level mixing ratio was also significant. Ground level methane concentration at Thiruvananthapuram urban area showed maximum value of 3.16 ppmV. Under stable atmospheric conditions in early morning, ground level mixing ratio of methane was 2.79 ppmV in winter and 2.54 ppmV during summer. The spatial distribution of methane concentration shows correlation with urban heat island. PMID- 21611846 TI - Use of metallothioneins as biomarkers for environmental quality assessment in the Gulf of Gabes (Tunisia). AB - Detection and assessment of the impact of pollution on biological resources imply increasing research on early-warning markers such as metallothioneins (MTs) in metal exposure. In this paper, we have collated published information on the use of metallothioneins and metallothionein-like proteins (MTLPs) as biomarkers for environmental quality assessment in the Gulf of Gabes. In this area, some species of fish and bivalve were used as bioindicators of pollution. In these species, an induction of MTs/MTLPs by the essential metals such as Cu and Zn and the non essential metals such as Cd was observed by different authors who suggest the potential use of these proteins as biomarkers. However, MT concentrations can be influenced by many biotic (sex, maturity stages, and tissues) and abiotic factors (temperature, salinity, and pH). This is essentially the case in field studies where many parameters can randomly affect MT levels, so the endogeneous regulation of MTs must be considered before using MTs as an indicator of heavy metal exposure. Moreover, the use of biomarker cannot be examined independently of the evaluation of techniques that enable its quantification. Therefore, the approach to the use of MTs/MTLP as biomarkers of exposure for an assessment of the physiological status of aquatic organisms is discussed in this paper. PMID- 21611848 TI - Airborne fungi and bacteria in indoor and outdoor environment of the Pediatric Unit of Edirne Government Hospital. AB - This study was performed between January 2004 and December 2004 in 13 stations in the Pediatric Unit of Edirne Government Hospital in order to determine the outdoor and indoor airborne microfungal and bacterial contents. The results of air samplings revealed that 1,376 microfungal and 2,429 bacterial colonies in total were isolated. The isolated microfungal specimens were identified and 65 species from 16 genera were determined. Among these, the most frequent genus was Cladosporium with 462 colonies (33.58%) followed by Alternaria with 310 (22.53%) and Penicillium with 280 (20.35%) colonies. The isolated bacterial samples were grouped based on their Gram-staining properties. The most frequent ones were Gram (+) cocci with 1,527 colonies (62.87%) followed by Gram (+) bacilli with 828 colonies (34.09%) and Gram (-) bacilli with 74 colonies (3.05%). Staphylococcus, Bacillus, Corynebacterium, and Microccus appeared to be the common genera isolated for all months. Statistical analyses were performed in order to see if there existed a relationship between meteorological conditions and the microfungal and bacterial species and their concentrations. PMID- 21611849 TI - Precordial R-wave reappearance predicting infarct size and myocardial recovery after acute STEMI. PMID- 21611850 TI - Dietary guar gum reduces lymph flow and diminishes lipid transport in thoracic duct-cannulated rats. AB - Guar gum has a well-recognized hypolipidemic effect. This effect is thought to be due to the physicochemical properties of guar gum, which may cause changes in adsorption of lipids or the viscosity of the intestinal contents. Guar gum is a non-specific absorption inhibitor of any type of lipid-soluble compound. Permanent lymph duct cannulation was performed on rats to investigate the effects of dietary guar gum on lymph flow and lipid transport. Rats fed a 5% guar gum diet were compared with those fed a 5% cellulose diet, and lymph was collected after feeding. The water-holding capacity (WHC), settling volume in water (SV), and viscosity of guar gum were compared with those of cellulose. Rats fed with the guar gum diet had significantly lower lymph flow and lymphatic lipid transport than did rats fed with the cellulose diet. The WHC, SV, and viscosity of guar gum were significantly higher than those of cellulose. We propose that dietary guar gum reduces lymph flow and thereby diminishes lipid transport by means of its physicochemical properties related to water behavior in the intestine. PMID- 21611851 TI - Vertebral fracture and cause-specific mortality: a prospective population study of 3,210 men and 3,730 women with 30 years of follow-up. AB - INTRODUCTION: Vertebral fractures predict mortality, but little is known about their associations with the causes of death. We studied vertebral fractures for prediction of cause-specific mortality. MATERIAL AND METHODS: A nationally representative sample of 3,210 men and 3,730 women participated Mini-Finland health survey in 1978-1980. Vertebral fractures at the Th1-Th12 levels were identified from chest radiographs at baseline. Cox's proportional hazard model was used to estimate the strength of association between vertebral fracture and mortality. RESULTS: The relative risk (95% confidence interval) of death from natural causes was 1.49 (0.89-2.48) in men and 0.89 (0.60-1.31) in women with vertebral fractures (adjusted for age, body mass index, serum 25-hydroxyvitamin D, educational level, smoking, alcohol intake, physical activity and self-rated general health). Among women the adjusted relative risk of an injury death was 8.51 (3.48-20.77), whereas none of the men with vertebral fracture died due to an injury. CONCLUSION: The patterns of mortality predicted by fracture in the thoracic spine differ between men and women. PMID- 21611852 TI - CT-guided percutaneous translaminar approach for blood patching: case report and technical note. AB - In this article the authors describe a novel technique for performing epidural blood patch (EBP) by percutaneous CT-guided translaminar approach in challenging cases where interlaminar approach is not possible. A 24-year-old woman with medical history of multiple spinal surgeries and instrumentations for the treatment of scoliosis, presented 3 months post-operatively with acute and severe orthostatic headaches that began 1 week after surgery. Neurological examination was normal. Brain magnetic resonance imaging (MRI) showed mild thickening and contrast enhancing in the bilateral dura. Computed tomography (CT) myelography revealed CSF leakage in the level of T3 vertebra. EBP was attempted using fluoroscopic and then CT guidance; however, despite multiple attempts, the epidural space could not be accessed through the interlaminar route due to extensive instrumentation of the spine and profound structural bony abnormalities. EBP was performed successfully via a CT-guided translaminar approach using an Ostycut trephine needle (Angiomed((r))/Bard, Karlsruhe), without complications. PMID- 21611853 TI - Protective role of taurine against morphine-induced neurotoxicity in C6 cells via inhibition of oxidative stress. AB - This study was carried out to investigate the protective role of taurine (2 aminoethanesulphonicacid) against morphine-induced neurotoxicity in C6 cells. It was found that taurine significantly increased the viability of C6 cells treated by morphine, showing the neuroprotective role against morphine-induced neurotoxicity. However, such neuroprotective effect of taurine could not be blocked by bicuculline, an antagonist of gamma-amino butyrate (GABA) receptor. To determine the oxidative damage induced by morphine, the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were measured in C6 cells. The decreased activities of SOD, CAT, and GPx in C6 cells were observed after morphine treatment for 48 h. However, taurine administration effectively ameliorated morphine-induced oxidative insult. To estimate anti-apoptosis effect of taurine, flow cytometry analysis as well as detection for caspase-3 and Bcl-2 expressions was performed after morphine exposure for 48 h. It was found that Bcl 2 expression was down regulated by morphine, whereas taurine could reverse morphine-induced decrease in Bcl-2 expression. Taurine showed no effect on caspase-3 expression. Collectively, the results show that taurine possesses the capability to ameliorate morphine-induced oxidative insult and apoptosis in C6 cells, probably due to its antioxidant activity rather than activation of GABA receptors. PMID- 21611854 TI - Equilibrium unfolding of A. niger RNase: pH dependence of chemical and thermal denaturation. AB - Equilibrium unfolding of A. niger RNase with chemical denaturants, for example GuHCl and urea, and thermal unfolding have been studied as a function of pH using fluorescence, far-UV, near-UV, and absorbance spectroscopy. Because of their ability to affect electrostatic interactions, pH and chemical denaturants have a marked effect on the stability, structure, and function of many globular proteins. ANS binding studies have been conducted to enable understanding of the folding mechanism of the protein in the presence of the denaturants. Spectroscopic studies by absorbance, fluorescence, and circular dichroism and use of K2D software revealed that the enzyme has alpha + beta type secondary structure with approximately 29% alpha-helix, 24% beta-sheet, and 47% random coil. Under neutral conditions the enzyme is stable in urea whereas GuHCl-induced equilibrium unfolding was cooperative. A. niger RNase has little ANS binding even under neutral conditions. Multiple intermediates were populated during the pH induced unfolding of A. niger RNase. Urea and temperature-induced unfolding of A. niger RNase into the molten globule-like state is non-cooperative, in contrast to the cooperativity seen with the native protein, suggesting the presence of two parts/domains, in the molecular structure of A. niger RNase, with different stability that unfolds in steps. Interestingly, the GuHCl-induced unfolding of the A state (molten globule state) of A. niger RNase is unique, because a low concentration of denaturant not only induces structural change but also facilitates transition from one molten globule like state (A(MG1)) into another (I(MG2)). PMID- 21611855 TI - Role of CCL19/21 and its possible signaling through CXCR3 in development of metallophilic macrophages in the mouse thymus. AB - We have already shown that metallophilic macrophages, which represent an important component in the thymus physiology, are lacking in lymphotoxin-beta receptor-deficient mice. However, further molecular requirements for the development and correct tissue positioning of these cells are unknown. To this end, we studied a panel of mice deficient in different chemokine ligand or receptor genes. In contrast to normal mice, which have these cells localized in the thymic cortico-medullary zone (CMZ) as a distinct row positioned between the cortex and medulla, in plt/plt (paucity of lymph node T cells) mice lacking the functional CCL19/CCL21 chemokines, metallophilic macrophages are not present in the thymic tissue. Interestingly, in contrast to the CCL19/21-deficient thymus, metallophilic macrophages are present in the CCR7-deficient thymus. However, these cells are not appropriately located in the CMZ, but are mostly crowded in central parts of thymic medulla. The double staining revealed that these metallophilic macrophages are CCR7-negative and CXCR3-positive. In the CXCL13 deficient thymus the number, morphology and localization of metallophilic macrophages are normal. Thus, our study shows that CCL19/21 and its possible signaling through CXCR3 are required for the development of thymic metallophilic macrophages, whereas the CXCL13-CXCR5 signaling is not necessary. PMID- 21611856 TI - Visual perceptual load induces inattentional deafness. AB - In this article, we establish a new phenomenon of "inattentional deafness" and highlight the level of load on visual attention as a critical determinant of this phenomenon. In three experiments, we modified an inattentional blindness paradigm to assess inattentional deafness. Participants made either a low- or high-load visual discrimination concerning a cross shape (respectively, a discrimination of line color or of line length with a subtle length difference). A brief pure tone was presented simultaneously with the visual task display on a final trial. Failures to notice the presence of this tone (i.e., inattentional deafness) reached a rate of 79% in the high-visual-load condition, significantly more than in the low-load condition. These findings establish the phenomenon of inattentional deafness under visual load, thereby extending the load theory of attention (e.g., Lavie, Journal of Experimental Psychology. Human Perception and Performance, 25, 596-616, 1995) to address the cross-modal effects of visual perceptual load. PMID- 21611857 TI - Outcome after therapeutic lymph node dissection in patients with unknown primary melanoma site. AB - PURPOSE: The aim of this study was to evaluate the incidence and outcome of melanoma of unknown primary site (MUP) after therapeutic lymph node dissection (TLND) of palpable nodal melanoma metastases. Disease-free (DFS) and overall survival (OS) time of MUP patients were analyzed and compared to patients undergoing a TLND for known primary melanomas (MKP). METHODS: This single institution retrospective study analyzed 342 consecutive patients who were treated with 415 TLNDs for palpable nodal disease from 1982 to 2009. Univariate and multivariate analyses included: MUP versus MKP, gender, Breslow thickness, ulceration of primary tumor, site of primary tumor, site of dissection, extracapsular extension, number of collected nodes, number of positive nodes and the node positive ratio. RESULTS: A total of 47 MUP were identified in 342 patients (13.7%). In univariate analysis, a trend was seen toward better survival for MUP patients compared to MKP patients having 5-year OS rates of 40% and 27%, respectively (P = 0.06). Multivariate analysis for OS showed two highly significant factors associated with worse prognosis: extracapsular extension and N3 status (both P < 0.001). Two factors were associated with a significant better prognosis: MUP (P = 0.03) and a neck dissection (P = 0.04). CONCLUSIONS: Patients with MUP showed a statistically significant better OS compared to patients with melanoma metastases from known primary tumors. Presence of extracapsular extension and an increased number of positive nodes are statistically significantly negative prognostic factors for OS. The absence of a primary melanoma in stage III melanoma patients does not preclude surgery. PMID- 21611858 TI - Oncologic impact of the curettage of grade 2 central chondrosarcoma of the extremity. AB - BACKGROUND: Wide excision is considered the standard treatment for high-grade chondrosarcoma, but little is known regarding the effect of curettage on patient outcome in grade 2 chondrosarcoma. METHODS: The records of 32 patients with nonmetastatic grade 2 central chondrosarcoma of the appendicular skeleton were analyzed. The clinical characteristics and outcomes of 15 patients who underwent curettage (the case group) followed by subsequent treatment and 17 patients who underwent standard treatment were compared. The mean follow-up period for all 32 patients was 110 months (range, 31-230 months). RESULTS: Cases had a smaller tumor volume at presentation (P = .02), a lower Enneking's stage IIA (P < .01), a lower rate of biopsy (P < .01), and a lower incidence of chondroid calcification by plain radiography (P < .01) than controls. Of the 32 study subjects, 2 (1 in the each group) developed local recurrence. The 10-year overall and metastasis free survival rates for all 32 chondrosarcomas were 84.6% +/- 14.5% and 70.3% +/- 16.5%, respectively. Event-free survivals were similar for cases and controls (P = .16). CONCLUSIONS: Intracompartmental grade 2 chondrosarcoma with nonaggressive radiologic pattern have a chance of curettage. However, proper subsequent management achieves outcomes comparable with those of primary wide excision. PMID- 21611860 TI - Co-responsibility: a new horizon for today's health care? AB - In this article, we focus at a key concept of today's healthcare, namely responsibility. Personal responsibility is so important today because it is obvious that the way society is organized, many people are facing a lot of difficulties to live their lives in a responsible way. We explicitly obtain an analysis of responsibility from a view which avoids the binary thinking which is so remarkably present in today's health care discourse. The aim of this pilot study is therefore to open up the horizon of the use of responsibility in today's healthcare. We develop the notion of 'co-responsibility' to understand how individuals, despite the fact they are responsible for their own agency, are always also affected by an ought which contaminates their efforts to fulfill their duties and obligations. We discuss co-responsibility not as conclusion or a magic formula to all problems, but as a new starting point of which we have to explore the opportunities for current and future health care dilemmas. PMID- 21611861 TI - Advancing the research mission of ASNC. PMID- 21611862 TI - Possible link between cyclooxygenase-inhibiting and antitumor properties of propofol. AB - The intravenous anesthetic propofol has a number of well-known nonanesthetic effects, including anti-oxidation and anti-emesis. Another interesting nonanesthetic effect of propofol may be its cyclooxygenase (COX)-inhibiting activity. This activity may have important clinical implications, as propofol could have antitumor properties through COX inhibition. Propofol could counteract the activity of COX, which elicits, via its major product prostaglandin E(2), (1) tumor growth stimulation, (2) increased tumor survival, (3) enhanced tumor invasiveness, (4) stimulation of new vessel formation, and (5) tumor evasion of host immune surveillance through suppression of immune cell functions. Indeed, accumulated evidence indicates that propofol suppresses the proliferation, motility, and invasiveness of tumors in vitro and in vivo. Therefore, propofol could be a particularly suitable anesthetic for use during the perioperative period for cancer surgery. However, whether the COX-inhibiting activity of propofol is related to the reported antitumor properties of propofol is not known. Definitive evidence remains to be provided. PMID- 21611863 TI - Characteristics of unilateral spinal anesthesia at different speeds of intrathecal injection. AB - PURPOSE: Unilateral spinal anesthesia is performed to provide restriction of sympathetic and motor block. The purpose of this study is to compare the effect of different speeds of intrathecal injection on unilateral spinal anesthesia. METHODS: The patient cohort comprised 66 patients who were placed in the lateral position with the side to be operated on dependent. After dural puncture, the needle aperture was turned towards the dependent side, and hyperbaric 0.5% bupivacaine was injected at a rate of 1 ml/min in Group Slow patients (Group S, n = 33) or 0.5 ml/min in Group Extra Slow patients (Group ES, n = 33). The lateral position was maintained for 15 min. Skin temperature, loss of pinprick sensation, and degree of motor block were recorded. RESULTS: There were significant differences in the characteristics of the non-operative side between the groups when on the block. Sensorial block was unilateral in 25 (75.8%) patients in Group S and in 29 patients in Group ES (87.9%) 15 min post-injection. At the end of the operation (approximately 50 min after spinal anesthesia), strictly unilateral anesthesia was present in 31 patients in Group ES (93.9%) and in 22 patients in Group S (66.6%) (p < 0.05). Unilateral sensory and motor block were observed in both groups, and the incidence of strict unilateral block was significantly higher in group ES patients. CONCLUSIONS: The result of the study show that the extra-slow injection of hyperbaric bupivacaine provided strictly unilateral sensorial and sympathetic block in 93.9 and 87.9% of the patients, respectively, and that a slow injection of low doses of hyperbaric 0.5% bupivacaine 1 ml was sufficient to provide unilateral spinal anesthesia. PMID- 21611864 TI - Role recognition and changes to self-identity in family caregivers of people with advanced cancer: a qualitative study. AB - PURPOSE: Family caregivers of people with advanced cancer can provide extensive support to the patient. However, the role is not well defined and their experiences are poorly understood. This study aimed to explore how caregivers view their role and the impact of their caregiving. METHODS: A symbolic interactionist framework guided the in-depth individual interviews and grounded theory methodology was used to analyse the data. A total of 17 interviews were conducted: 13 with active caregivers and 4 with bereaved caregivers. RESULTS: Three dominant codes are presented. Caregivers lacked role recognition, as they struggled to recognise their role existed, even though they took on extensive and challenging tasks. Caregivers reported substantial loss or changes to their self identity: with some caregivers reporting not being able to stop thinking about caregiving and others having difficulty answering questions about themselves. Caregivers also demonstrated difficulty in taking a break: active caregivers did not consider taking a break, whereas bereaved caregivers retrospectively admitted needing a break but reported an inability to take one. CONCLUSIONS: Caregiving is complex and extensive. People who care for those with advanced cancer are in need of intervention to provide support and assistance to them in their role. However, this needs to be structured with consideration for how caregivers view their role. PMID- 21611866 TI - Standardization of hyphal growth inhibition rate as a means of evaluating Microsporum spp. in vitro susceptibility to terbinafine, griseofulvin, and ciclopiroxolamine. AB - Reference methods for antifungal susceptibility tests recommend the use of conidia as inoculum. However, some isolates produce few conidia, while the invasive form of filamentous fungi in general is hyphae making susceptibility tests infeaseble. These facts suggest that other than conidia broth dilution method is required for susceptibility tests. The aim of this study was to clarify if the hyphal growth inhibition rate could be used as a method of determining the antifungal susceptibility of genus Microsporum. For this reason, a method which traces hyphal tips automatically and measures their growth rate was standardized for Microsporum spp. Control growth curves and test growth curves obtained by real-time observation of the hyphae groups responses to different concentrations of terbinafine, griseofulvin, and ciclopiroxolamine were used to compare with minimum inhibitory concentrations (MICs) obtained by conidia broth microdilution method. A visible reduction in the growth inhibition rate was observed when hyphal activity was evaluated using the third or fourth serial two-fold dilution below the MIC determined by broth microdilution for terbinafine and ciclopiroxolamine. For griseofulvin, this reduction occurred after the fifth dilution below the MIC. This study highlights the importance of the inoculum type used to determine the in vitro susceptibility of Microsporum strains. We conclude that measurement of hyphal growth inhibition, despite being time consuming, could be a suitable method for evaluating antifungal susceptibility, particularly for fungi as Microsporum spp. that produce a small (or not at all) number of conidia. PMID- 21611865 TI - Identifying determinants of quality of life of children with cancer and childhood cancer survivors: a systematic review. AB - PURPOSE: This paper describes a systematic review conducted to identify factors that have been investigated as explanations of variability in the quality of life of children with cancer and childhood cancer survivors. Our purpose was to build an evidence base that could be used to guide and direct future research. METHODS: MEDLINE, CINAHL, EMBASE, PsycINFO, Cancerlit, and Sociological Abstracts were searched from the inception of each database to June 15, 2009 using the following search terms: "quality of life," "health-related quality of life," "quality adjusted life years," "health status," "functional status," "well-being," or "patient-reported outcome." Sample characteristics and information about the relationship between a quality of life domain or total scale score and at least one factor (e.g., child gender or age, coping skills, family income) were extracted from eligible studies. RESULTS: Nine cancer-specific and nine generic QOL questionnaires were used in 58 publications described 239 factors (50 unique factors). The large number of cancer, treatment, child, and family variables considered indicates that extensive research activity has occurred. However, most of the variables identified were examined in only a few studies and most represent medical and treatment variables with less research attention paid to child and family variables. CONCLUSIONS: Our study has compiled evidence about determinants of QOL for children with cancer and childhood cancer survivors from the existing literature. Future research can build on this evidence base to expand the range of factors studied as most research to date has focused on medical and treatment factors. PMID- 21611867 TI - Perceived health in lung cancer patients: the role of positive and negative affect. AB - PURPOSE: To examine the association of affective experience and health-related quality of life in lung cancer patients, we hypothesized that negative affect would be positively, and positive affect would be negatively, associated with perceived health. METHODS: A sample of 133 English-speaking lung cancer patients (33% female; mean age = 63.68 years old, SD = 9.37) completed a battery of self report surveys. RESULTS: Results of our secondary analysis indicate that trait negative affect was significantly associated with poor physical and social functioning, greater role limitations due to emotional problems, greater bodily pain, and poor general health. Positive affect was significantly associated with adaptive social functioning, fewer emotion-based role limitations, and less severe bodily pain. In a full model, positive affect was significantly associated with greater levels of social functioning and general health, over and above the effects of negative affect. CONCLUSIONS: Reduction of negative affect is an important therapeutic goal, but the ability to maintain positive affect may result in greater perceived health. Indeed, engagement in behaviors that result in greater state positive affect may, over time, result in dispositional changes and enhancement of quality of life. PMID- 21611868 TI - The WHO quality of life (WHOQOL) questionnaire: Spanish development and validation studies. AB - BACKGROUND: In the 1990s, the World Health Organization (WHO) undertook a project to develop an instrument (the WHOQOL) for measuring quality of life (QoL). The WHOQOL was developed in the framework of a collaborative project involving numerous centers in different cultural settings. This paper describes the psychometric properties of the Spanish WHOQOL during its development. METHODS: One thousand and eighty-two patients with physical health conditions, persons without any health condition, patients with schizophrenia, and family caregivers of patients with schizophrenia participated on the WHOQOL-100 and WHOQOL-BREF field trials. QoL self-assessment was completed, together with sociodemographic and health status questions. Analysis was performed using classical psychometric methods. RESULTS: Both versions of the WHOQOL showed satisfactory psychometric properties as follows: acceptability, internal consistency, and evidence of convergent and discriminant validity. CONCLUSIONS: The WHOQOL-100 and WHOQOL-BREF are suitable to use in patients with different health conditions, including schizophrenia, and in different populations, including caregivers. Spanish field trials are the first to report on use of the WHOQOL in persons with schizophrenia and caregivers. These results indicate that both versions are useful tools in assessing these groups, as the WHOQOL includes important dimensions commonly omitted from other generic QoL measures. PMID- 21611869 TI - Therapeutic drug monitoring of posaconazole in hematology adults under posaconazole prophylaxis: influence of food intake. AB - Posaconazole (PCZ) is given at 200 mg three times daily as a fungal prophylaxis in neutropenic hematologic malignancy patients. A relationship between exposure, plasma concentration, and efficacy is suggested. The objectives of this prospective study were to analyze the PCZ plasma concentration in hematology adults at high risk of developing invasive fungal infections (IFIs), and factors that could have an impact on the PCZ plasma concentration. PCZ plasma concentrations were measured after 2, 7, 10, 14, and 21 days of PCZ prophylaxis. Factors such as gender, age, body weight, posology, treatment duration, mucositis, proton pump inhibitor (PPI) use, and food intake were studied. Sixty three patients were included, with a median age of 52 years (range 17-70) and a median weight of 75 kg (range 47-150). The median PCZ plasma concentration of the 63 patients ranged from 0.42 to 0.48 mg/L. At day 2, 30% of PCZ plasma concentration were under 0.35 mg/L, and at day 7, 74% were <0.70 mg/L. PCZ plasma concentrations were not affected by gender, age, body weight, or treatment duration. We found that food intake had a high influence on PCZ plasma concentrations (p = 0.0049). PCZ was well tolerated. One patient has developed a probable IFI, probably related to a low exposure to PCZ. PCZ therapeutic drug monitoring (TDM) is essential in order to early detect patients with low concentrations, to assess the etiology of such results, and to decide on the treatment strategy to apply. PMID- 21611870 TI - Evidence of circulation of an epidemic strain of Francisella tularensis in France by multispacer typing. AB - Multispacer typing (MST) was used to type ten Francisella tularensis strains detected in French patients. Incorporating 79 Swedish F. tularensis strains, phylogenetic analysis demonstrated that although tularemia appears as a sporadic disease in France, it is caused by an epidemic cluster of strains. PMID- 21611871 TI - A decade-long surveillance of nasopharyngeal colonisation with Streptococcus pneumoniae among children attending day-care centres in south-eastern France: 1999-2008. AB - The antimicrobial resistance and serotype distribution of Streptococcus pneumoniae (SP) among children attending day-care centres in south-eastern France were monitored from 1999 to 2008, before and after interventions promoting prudent antibiotic use initiated in 2000 and the availability of pneumococcal conjugate vaccine in 2003. Antibiotic susceptibility and serotypes of SP isolates were determined on nasopharyngeal samples of children aged 3-40 months attending day-care centres, from January to March 1999, 2002, 2004, 2006 and 2008. SP carriage fell from 54% to 45%, and SP with diminished susceptibility to penicillin (PDSP) fell from 34% to 19%. Antibiotic prescriptions dropped from 63% to 38% of children, but third-generation cephalosporins were increasingly prescribed. The overall antibiotic susceptibility increased. Over 90% of the children had received at least one vaccine dose in 2008. Vaccine serotypes 6B, 9V, 19F and 23F (76%) in 1999 were replaced by non-vaccine types (95%) in 2008, among which were 15 (20%), 19A (15%), 23A/B (10%) and 6A (9%). Serotypes 6A, 19A and 15 accounted for over 50% of PDSP strains in 2008 versus 6% in 1999. Children now mostly harbour non-vaccine types; however, PDSP isolates are mainly recruited among these. Vaccine-related benefits may be threatened by combined vaccine- and antibiotic-driven selective pressure. PMID- 21611873 TI - Identification of a LNCaP-specific binding peptide using phage display. AB - PURPOSE: To identify a LNCaP-specific peptide using a phage display library and evaluate its potential applications in targeted drug delivery. METHODS: Binding abilities of selected phages were evaluated by cell phage ELISA. The KYL peptide encoded by the most specific phage clone was synthesized, labeled with fluorescein, and assayed in various cell lines. A fusion peptide composed of the KYL peptide and a proapoptotic peptide ( D )(KLAKLAK)(2) was synthesized, and the cell death effect was evaluated on different cells. Moreover, the KYL peptide was conjugated to a cationic protein, protamine, to explore its potential application in siRNA delivery. RESULTS: One phage clone with a high binding affinity to LNCaP cells was identified. Cell phage ELISA and immunostaining demonstrated high specificity of this phage to LNCaP cells. The fluorescein-labeled KYL peptide exhibited higher binding to LNCaP cells in comparison to other cells. The fusion peptide composed of the KYL peptide and the proapoptotic peptide induced cell death in LNCaP cells, but not in PC-3 cells. The KYL peptide-protamine conjugate also efficiently delivered a fluorescein-labeled siRNA into LNCaP cells. CONCLUSION: We identified a LNCaP-specific peptide and demonstrated its potential applications in targeted drug delivery to LNCaP cells. PMID- 21611872 TI - Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. AB - Drug repositioning refers to the utilization of a known compound in a novel indication underscoring a new mode of action that predicts innovative therapeutic options. Since 1959, alkylating agents, such as the lead compound cyclophosphamide (CTX), have always been conceived, at high dosages, as potent cytotoxic and lymphoablative drugs, indispensable for dose intensity and immunosuppressive regimen in the oncological and internal medicine armamentarium. However, more recent work highlighted the immunostimulatory and/or antiangiogenic effects of low dosing CTX (also called "metronomic CTX") opening up novel indications in the field of cancer immunotherapy. CTX markedly influences dendritic cell homeostasis and promotes IFN type I secretion, contributing to the induction of antitumor cytotoxic T lymphocytes and/or the proliferation of adoptively transferred T cells, to the polarization of CD4(+) T cells into TH1 and/or TH17 lymphocytes eventually affecting the Treg/Teffector ratio in favor of tumor regression. Moreover, CTX has intrinsic "pro-immunogenic" activities on tumor cells, inducing the hallmarks of immunogenic cell death on a variety of tumor types. Fifty years after its Food and Drug Administration approval, CTX remains a safe and affordable compound endowed with multifaceted properties and plethora of clinical indications. Here we review its immunomodulatory effects and advocate why low dosing CTX could be successfully combined to new-generation cancer vaccines. PMID- 21611874 TI - Multivalent and flexible PEG-nitrilotriacetic acid derivatives for non-covalent protein pegylation. AB - PURPOSE: A new approach for non-covalent protein PEGylation is translated from immobilized metal ion affinity chromatography, and based on metal coordination bonds between a chelating agent linked to PEG, nitrilotriacetic acid (NTA), and the ring nitrogen of histidines in a protein. METHODS: PEG-NTA conjugates were synthesized differing in the number of NTA units and in the polymer structure. Three derivatives were investigated in association experiments with five model proteins. The most promising complex, PEG8-(NTA)(8)-Cu(2+)-G-CSF (granulocyte colony stimulating factor), was thoroughly characterized and the pharmacokinetic profile was evaluated in rats. RESULTS: The experiments demonstrated that only PEG8-(NTA)(8), bearing eight NTA molecules on flexible PEG arms, associated strongly with those proteins having several histidines. The protein secondary structure was not affected in the complex. PEG8-(NTA)(8)-Cu(2+)-G-CSF showed a K (D) of 4.7 nM, as determined by surface plasmon resonance, but the association was not stable in vivo. CONCLUSIONS: PEG8-(NTA)(8) is the first derivative able to associate with native proteins and form soluble complexes with a nanomolar K (D). The study highlights the need of a multivalent and flexible coordination and encourages further investigations to increase the stability of PEG8-(NTA)(8) complexes in vivo either through the use of protein mutants or His-tag proteins. PMID- 21611875 TI - Laparoscopic sleeve gastrectomy is a novel and effective treatment for obesity in patients with chronic kidney disease. AB - Obesity increases the risk of progression of chronic kidney disease (CKD) towards kidney failure and may preclude access to kidney transplantation. Weight loss surgery remains relatively novel in obese patients with CKD, with several studies reporting results using Roux-en-Y bypass and adjustable gastric banding. However, in obese patients with CKD, kidney failure after bypass surgery and gastric band erosion after kidney transplantation have been reported. We present the first report of laparoscopic sleeve gastrectomy (LSG) performed for the treatment of obesity in patients with CKD. Weight loss, blood pressure and lipids, estimated kidney function, surgical complications and adverse events were studied. Nine obese patients with CKD (five of whom were undergoing haemodialysis treatment) underwent LSG, with median body mass index decrease of 8.4 kg/m(2) and excess weight loss of 43.0% after 6 months. Four of the five patients on haemodialysis were added to the kidney transplantation waiting list as a result of weight loss achieved with LSG. Adverse events occurred in three patients: myocardial infarction (one patient), acute kidney injury secondary to dehydration (one patient) and compromised dialysis access (one patient). There was one complication-a gastric leak, detected 7 months after LSG, requiring further surgical intervention and nasojejunal feeding, and no mortality. Our preliminary evidence suggests that LSG is an effective treatment for obesity in patients with CKD. However, there may be additional risk associated with the procedure in patients with CKD, requiring further study. PMID- 21611876 TI - Role of thrombolestagrophy in monitoring perioperative coagulation status and effect of thromboprophylaxis in bariatric surgery. AB - BACKGROUND: Thromboelastography is a technique that surveys the properties of viscoelastic blood clot. The purpose of this paper was to evaluate the hypercoagulability state and the effect of antithrombotic prophylaxis on thromboelastogram (TEG) results in bariatric surgery. METHODS: Twenty-five patients enrolled received 0.8 ml of nodraparin starting on the day before surgery and continuing postoperatively. TEG profile was collected before induction of anesthesia, on the first and third postoperative days. Each sample was run also in a cup added with heparinase to eliminate the interference of antithrombotic prophylaxis. RESULTS: TEG analysis with heparinase showed a tendency to reduce the r-time (rate of initial fibrin formation) and k-time (time to clot firmness) and increase the alpha angle (rate of clot growth), while an increase of maximal amplitude (MA, a measure of maximal stiffness of the clot; p = 0.01) and GI or shear elastic modules strength (p = 0.03)was observed from basal to postoperative day 3 (POD3). TEG without heparinase evidenced and increase of r-time (p = 0.02) and k-time (p = 0.05), a reduction of the alpha angle (p = 0.03), and an increase of MA (p = 0.01) and GI (p = 0.03) from basal to POD3. The comparison of TEG techniques showed that normal TEGs had lower values of r-time and k-time and higher values of alpha angles and MA than TEG with heparinase. No differences were evident for basal and POD1 samples and the G values comparing the two TEG technique. No correlation was observed between the variation of normal TEG parameters and dosage of anticoagulant used in each patient. CONCLUSIONS: Our patients presented a tendency to hypercoagulability determined most by MA and GI. Comparison between TEGs indicates that low molecular-weight heparin not titrated on weight is able to determine a reduction of hypercoabulable tendency in the early postoperative period with few effects on increasing MA and GI. PMID- 21611877 TI - Long-term plasma ghrelin and leptin modulation after sleeve gastrectomy in Wistar rats in comparison with gastric tissue ghrelin expression. AB - BACKGROUND: Sleeve gastrectomy (SG) is a gaining ground operation amongst the ones applied for treatment of morbid obesity. Though SG is a food limiting operation, the removal of the gastric fundus where ghrelin is mainly produced may indicate a hormonal impact of the procedure. The purpose of this experiment is to study how SG affects the levels of ghrelin and leptin. METHODS: Twenty-four male, adult, diet induced obese Wistar rats were divided randomly into groups, one submitted to SG and the other to a sham operation. Fasting blood samples were taken before the operation and 14 weeks after the operation (leptin and acylated and des-acyl ghrelin levels were measured). Tissue samples from the gastric fundus were taken during the operation and at the end of the experiment, and ghrelin expression was measured with RT-PCR. RESULTS: Statistically significant weight loss was achieved comparing the weight progress of the SG group and the sham operation group. Serum leptin levels were significantly reduced in the SG group (p < 0.05) but not in the sham operation group. Serum acylated ghrelin was not significantly affected in both groups, but a significant decrease was documented in serum des-acyl ghrelin in the SG group (p < 0.05). RT-PCR analysis of the gastric fundus documented a significant decrease (p < 0.0001) in the expression of ghrelin in the SG group. CONCLUSIONS: SG may lead in significant long-term weight loss. SG affects the serum levels of leptin and des-acyl ghrelin but not the levels of acylated ghrelin in this animal model. PMID- 21611878 TI - Correlations between the modelled potato crop yield and the general atmospheric circulation. AB - Biology-related indicators do not usually depend on just one meteorological element but on a combination of several weather indicators. One way to establish such integral indicators is to classify the general atmospheric circulation into a small number of circulation types. The aim of present study is to analyse connections between general atmospheric circulation and potato crop yield in Estonia. Meteorologically possible yield (MPY), calculated by the model POMOD, is used to characterise potato crop yield. Data of three meteorological stations and the biological parameters of two potato sorts were applied to the model, and 73 different classifications of atmospheric circulation from catalogue 1.2 of COST 733, domain 05 are used to qualify circulation conditions. Correlation analysis showed that there is at least one circulation type in each of the classifications with at least one statistically significant (99%) correlation with potato crop yield, whether in Kuressaare, Tallinn or Tartu. However, no classifications with circulation types correlating with MPY in all three stations at the same time were revealed. Circulation types inducing a decrease in the potato crop yield are more clearly represented. Clear differences occurred between the observed geographical locations as well as between the seasons: derived from the number of significant circulation types, summer and Kuressaare stand out. Of potato varieties, late 'Anti' is more influenced by circulation. Analysis of MSLP maps of circulation types revealed that the seaside stations (Tallinn, Kuressaare) suffer from negative effects of anti-cyclonic conditions (drought), while Tartu suffers from the cyclonic activity (excessive water). PMID- 21611879 TI - Sustained ocular hypertension following intravitreal injections of 0.5 mg/0.05 ml ranibizumab. AB - To report three cases with sustained ocular hypertension following intravitreal injections of 0.5 mg/0.05 ml ranibizumab and to underline the importance of monitoring intraocular pressure (IOP) following intravitreal injections of ranibizumab (Lucentis). Three patients were found to have high IOP after intravitreal injections of 0.5 mg/0.05 ml ranibizumab. IOP was elevated after the second ranibizumab injection in patients 1 and 2, and after the third injection in patient 3. The increase in IOP was sustained, requiring treatment with anti glaucoma eye drops in all patients, the addition of systemic carbonic anhydrase inhibitor in one patient, and the application of selective laser trabeculoplasty (SLT) in another patient. None of the patients had a previous history of glaucoma or ocular hypertension. Sustained ocular hypertension may occur after intravitreal injections of 0.5 mg/0.05 ml ranibizumab. Although the precise mechanism of the pressure rise is unknown, three eyes in our series were controlled with topical or oral medication and one with SLT. The necessity of IOP monitoring is strongly emphasized after intravitreal injections of 0.5 mg/0.05 ml ranibizumab. PMID- 21611880 TI - Necrotic cell death in atherosclerosis. AB - Necrosis is a type of cell death characterized by a gain in cell volume, swelling of organelles, rupture of the plasma membrane and subsequent loss of intracellular contents. For a long time, the process has been considered as a merely accidental and uncontrolled form of cell death, but accumulating evidence suggests that it can also occur in a regulated fashion. Morphological studies using transmission electron microscopy indicate that the vast majority of dying cells in advanced human atherosclerotic plaques undergo necrosis. Various stimuli in the plaque including high levels of oxidative stress, depletion of cellular ATP, impaired clearance of apoptotic cells and increased intracellular calcium may cause necrotic death. Although the role of necrosis in atherosclerosis remains ill-defined, a growing body of evidence suggests that necrotic death stimulates atherogenesis through induction of inflammation and enlargement of the necrotic core. In addition, necrosis contributes to plaque instability by releasing tissue factor, matrix degrading proteases and pro-angiogenic compounds. Therapeutic agents against necrosis are limited, but efforts have recently been made to inhibit the necrotic pathway or its pro-inflammatory effects. PMID- 21611881 TI - Construction of Japanese BAC library Yamato-2 (JY2): a set of 330K clone resources of damage-minimized DNA taken from a genetically established Japanese individual. AB - A bacterial artificial chromosome (BAC) library referred to as Yamato-2 (JY2), was constructed from a Japanese individual and contained 330,000 clones. Library construction was based on 2 concepts: Japanese pedigree and non-immortalization. Genomic DNA was extracted from white blood cells from umbilical cord blood of a Japanese male individual. Four traits of the sample, (1) amelogenin DNA, (2) short tandem repeat (STR), (3) mitochondrial DNA (mtDNA), and (4) HLA-allele typing, were investigated to verify attribution of the donor. One of the samples with quite good Japanese characteristics was named JY2 and used as a resource for construction of a BAC library. Amelogenin DNA indicated male. STR indicated Mongoloid. MtDNA suggested haplogroup B, which is different from any other diploid whose sequence has been reported. The HLA gene was classified into east Asian specific haplotype. These results revealed that JY2 was obtained from a Japanese male. We sequenced both ends of 185,012 BAC clones. By using the BLAST search, BAC end sequences (BESs) were mapped on the human reference sequence provided by NCBI. Inserts of individual BAC clones were mapped with both ends properly placed. As a result, 103,647 BAC clones were successfully mapped. The average insert size of BAC calculated from the mapping information was 130 kb. Coverage and redundancy of the reference sequence by successfully mapped BAC clones were 96.4% and 3.9-fold, respectively. This library will be especially suitable as a Japanese standard genome resource. The availability of an accurate library is indispensable for diagnostics or drug-design based on genome information, and JY2 will provide an accurate sequence of the Japanese genome as an important addition to the human genome. PMID- 21611882 TI - Estimates of obesity trends in Brazil, 2006-2009. AB - OBJECTIVE: This study investigates the prevalence and trends of obesity among Brazilian adults, from 2006 to 2009, according to socio-demographic variables. METHODS: Data from the Surveillance System of Risk and Protective Factors for Chronic Non-Communicable Diseases through Telephone Interviews (VIGITEL) from a sample of adults living in all state capitals were used. Approximately, 41,500 individuals were interviewed each year. Obesity prevalence and recent trends were estimated in the total population and according to socio-demographic variables. RESULTS: In 2006, the obesity level reached 10.8% of adults, increasing to 13.5% in 2009. The increase in obesity was higher among women than men. For women, low levels of education and unemployment are also important factors. For men, higher obesity rate is seen among those who are young, resident of southeast region, higher educated and employed individuals. CONCLUSION: Despite obesity rates in Brazil not being among the highest in the world, the rapid increase in these rates, greater in women than men, demand immediate care. These findings will help to formulate strategies needed to reduce and prevent obesity. PMID- 21611884 TI - Gametophytic development of Brassica napus pollen in vitroenables examination of cytoskeleton and nuclear movements. AB - Isolated microspores and pollen suspension of Brassica napus "Topas" cultured in NLN-13 medium at 18 degrees C follow gametophytic pathway and develop into pollen grains closely resembling pollen formed in planta. This culture system complemented with whole-mount immunocytochemical technology and novel confocal laser scanning optical technique enables detailed studies of male gametophyte including asymmetric division, cytoskeleton, and nuclear movements. Microtubular cytoskeleton configurationally changed in successive stages of pollen development. The most prominent role of microtubules (MTs) was observed just before and during nuclear migration at the early and mid-bi-cellular stage. At the early bi-cellular stage, parallel arrangement of cortical and endoplasmic MTs to the long axis of the generative cell (GC) as well as MTs within GC under the plasmalemma bordering vegetative cell (VC) were responsible for GC lens shape. At the beginning of the GC migration, endoplasmic microtubules (EMTs) of the VC radiated from the nuclear envelope. Most cortical and EMTs of the VC were found near the sporoderm. At the same time, pattern of MTs observed in GC was considerably different. Multiple EMTs of the GC, previously parallel aligned, reorganized, and start to surround GC, forming a basket-like structure. These results suggest that EMTs of GC provoke changes in GC shape, its detachment from the sporoderm, and play an important role in GC migration to the vegetative nucleus (VN). During the process of migration of the GC to the VC, multiple and thick bundles of MTs, radiating from the cytoplasm near GC plasma membrane, arranged perpendicular to the narrow end of the GC and organized into a "comet tail" form. These GC "tail" MTs became shortened and the generative nucleus (GN) took a ball shape. The dynamic changes of MTs accompanied polarized distribution pattern of mitochondria and endoplasmic reticulum. In order to confirm the role of MTs in pollen development, a "whole-mount" immunodetection technique and confocal laser-scanning microscopy was essential. PMID- 21611883 TI - Universal rules for division plane selection in plants. AB - Coordinated cell divisions and cell expansion are the key processes that command growth in all organisms. The orientation of cell divisions and the direction of cell expansion are critical for normal development. Symmetric divisions contribute to proliferation and growth, while asymmetric divisions initiate pattern formation and differentiation. In plants these processes are of particular importance since their cells are encased in cellulosic walls that determine their shape and lock their position within tissues and organs. Several recent studies have analyzed the relationship between cell shape and patterns of symmetric cell division in diverse organisms and employed biophysical and mathematical considerations to develop computer simulations that have allowed accurate prediction of cell division patterns. From these studies, a picture emerges that diverse biological systems follow simple universal rules of geometry to select their division planes and that the microtubule cytoskeleton takes a major part in sensing the geometric information and translates this information into a specific division outcome. In plant cells, the division plane is selected before mitosis, and spatial information of the division plane is preserved throughout division by the presence of reference molecules at a distinct region of the plasma membrane, the cortical division zone. The recruitment of these division zone markers occurs multiple times by several mechanisms, suggesting that the cortical division zone is a highly dynamic region. PMID- 21611885 TI - Nephrotic syndrome in infancy can spontaneously resolve. AB - Nephrotic syndrome in the first year of life (NSFL) is a heterogeneous group of disorders, the management of which is supportive, as most patients do not respond to immunosuppression. Prognosis is guarded, as the syndrome tends to lead to end stage renal failure. We describe four cases, all of which went into spontaneous remission. These patients had severe nephrosis that began postnatally at ages 15 days to 7 months and had preceding symptoms of viral infections. One infant had proven pertussis and required ventilation for respiratory failure. Renal biopsies showed varying degrees of mesangial expansion and increased cellularity. Two biopsies showed mild mesangial sclerosis and the other two only scattered globally sclerosed glomeruli. Supportive treatment was started with 20% albumin infusions, diuretics, penicillin, and thyroxine. Angiotensin-converting enzyme (ACE) inhibitors were used to reduce proteinuria in all infants, and one was also treated with indomethacin. The nephrosis gradually resolved, and protein-lowering medications were successfully weaned completely 5-30 months after presentation. The patients were protein free with normal renal function at last follow-up. Investigations including viral studies and autoimmune profiles were negative. Genetic studies for NPHS1, NPHS2, WT1, and LAM-beta were negative. We therefore describe a subgroup of NSFL with good prognosis associated with infectious prodromes. This is also the first-described case of pertussis causing nephrotic syndrome. PMID- 21611886 TI - A mathematical model of Rift Valley Fever with human host. AB - Rift Valley Fever is a vector-borne disease mainly transmitted by mosquito. To gain some quantitative insights into its dynamics, a deterministic model with mosquito, livestock, and human host is formulated as a system of nonlinear ordinary differential equations and analyzed. The disease threshold [Formula: see text] is computed and used to investigate the local stability of the equilibria. A sensitivity analysis is performed and the most sensitive model parameters to the measure of initial disease transmission [Formula: see text] and the endemic equilibrium are determined. Both [Formula: see text] and the disease prevalence in mosquitoes are more sensitive to the natural mosquito death rate, d(m). The disease prevalence in livestock and humans are more sensitive to livestock and human recruitment rates, [Formula: see text] and [Formula: see text], respectively, suggesting isolation of livestock from humans is a viable preventive strategy during an outbreak. Numerical simulations support the analytical results in further exploring theoretically the long-term dynamics of the disease at the population level. PMID- 21611887 TI - The relation between ambulance transports stratified by heat stroke and air temperature in all 47 prefectures of Japan in August, 2009: ecological study. AB - OBJECTIVE: Our aim was to investigate the link between ambulance transports stratified by heat stroke and air temperature in August 2009 in Japan. METHODS: Monthly observations for ambulance transports stratified by heat stroke in August 2009, in all 47 prefectures of Japan were obtained from the Ministry of Internal Affairs and Communications. Daily air temperature data from the Japan Meteorological Agency in August 2009 for all 47 prefectures in Japan were also used. The effect of high air temperatures on ambulance transports stratified by heat stroke was analyzed in an ecological study. RESULTS: Various air temperature parameters , i.e., the mean of the mean air temperature, mean of the highest air temperature, mean of the lowest air temperature, the highest air temperature, and the lowest air temperature in August 2009 were significantly and positively correlated with ambulance transports stratified by heat stroke (per total number of ambulance transports and per 10,000 persons) in the 47 prefectures of Japan. The correlation coefficient between the mean of the highest air temperature in August 2009 and ambulance transports stratified by heat stroke (per 10 000 persons) was the highest among the examined parameters (r = 0.799, p < 0.0001). CONCLUSION: Higher air temperatures were closely associated with higher numbers of ambulance transports stratified by heat stroke in August 2009 in Japan. PMID- 21611888 TI - The relationship between social capital and self-rated health in a Japanese population: a multilevel analysis. AB - OBJECTIVE: The aim of this study was to use a multilevel analysis to examine whether cognitive and structural dimensions of regional social capital were associated with individual health outcomes after adjusting for compositional factors. METHODS: Data from the Japanese General Social Surveys project, a nationwide study with a two-stage stratified random sampling method conducted in 2000, 2001, 2002, 2005, and 2006, were aggregated and used for the multilevel analysis (n = 11,702). We examined whether both cognitive and structural aspects of social capital (social trust, neighborhood safety, and social participation) were associated with the self-rated health (SRH) of residents from 118 regions after adjustment for compositional factors. RESULTS: Social trust and existing neighborhood safety were negatively associated with poor SRH, whereas the effect of social participation was not significant. Social trust was still negatively associated with poor SRH after adjusting for individual demographic factors and socioeconomic status (p = 0.001). In contrast, neighborhood safety and social participation did not reach significance after adjusting for compositional factors. CONCLUSION: Based on the results of this study, social trust was associated with health outcomes. Further study is needed to clarify the path linking regional trust in others to individual health outcomes in the Japanese population. PMID- 21611889 TI - Recombinant human angiotensin-converting enzyme 2 as a new renin-angiotensin system peptidase for heart failure therapy. AB - Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes several peptides, including the degradation of angiotensin (Ang) II, a peptide with vasoconstrictive/proliferative effects, to generate Ang 1-7, which exerts vasodilatory/antiproliferative actions by acting through its receptor Mas. ACE2 is a multifunctional enzyme, and its actions on other vasoactive peptides, including the apelin-13 and apelin-17 peptides, also can contribute to its cardiovascular effects. The classical pathway of the renin-angiotensin system involving the ACE-Ang II-Ang II type-1 receptor axis is antagonized by the second arm constituted by the ACE2/Ang 1-7/Mas receptor axis. Loss of ACE2 enhances the adverse pathological remodeling susceptibility to pressure overload and myocardial infarction. Human recombinant ACE2 also is a negative regulator of Ang II-induced myocardial hypertrophy, fibrosis, and diastolic dysfunction and suppresses pressure overload-induced heart failure. Due to its characteristics, the ACE2/Ang 1-7/Mas axis may represent new possibilities for developing novel therapeutic strategies for the treatment of hypertension and heart failure. This review summarizes the beneficial effects of ACE2 in heart disease and the potential use of human recombinant ACE2 as a novel therapy for heart failure. PMID- 21611890 TI - Anticyclic citrullinated peptide autoantibodies in systemic lupus erythematosus. AB - Systemic lupus erythematosus is an autoimmune disease with protean manifestation. Arthritis is one of the most common manifestations seen in SLE. Anti-CCP Ab is a recently described autoantibody that has been claimed as a most sensitive and specific marker for the diagnosis of RA. Study was performed to see whether anti CCP2 Ab is positive in lupus arthritis or not. Anti-CCP Ab, ANA, ds DNA, and APLA were estimated by ELISA. Anti-CCP2 Ab was positive in 22 cases (37.93%) of SLE. Mean value of anti-CCP (18.08+/-16.95 U/ml) was statistically significant (P<0.001) when compared to control (5.07+/-U/ml). A total of 44 (75.86%) patients with SLE had arthritis. In 29 (50.00%) cases, arthritis resembled RA along with classical features of SLE, while 15 cases (25.86%) had nonspecific lupus arthritis. In 13 cases (44.82%) of RA type lupus arthritis, anti-CCP2 Ab was positive, while only three (20%) nonspecific lupus arthritis cases had elevated anti-CCP. In 14 (24.13) patients with SLE, there was no arthritis, but in this group also (6/14) 42.85% cases had elevated anti-CCP. A total of 11 (50%) patients with duration less than 1 year had more anti-CCP 2 positivity when compared to disease duration between 1 and 3 years (27.27%) and disease duration more than 3 years (22.72%), but specifically, it was not significant. Our study concludes that anti-CCP2 is not a specific antibody for RA, but it is present in autoimmune diseases. PMID- 21611892 TI - Fighting against acquired immunodeficiency syndrome with Chinese medicine: a perspective from China. AB - Continuing expansion of the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic has been recognized as an exceptional challenge to global health. Taking highly active antiretroviral treatment (HAART), a confirmed effective treatment, has its limitations. While a much cheaper and potential treatment-the Chinese medicine (CM) has not been paid enough attention from the worldwide. We explained the CM viewpoints about pathology and etiology to answer some questions about whether and how CM can treat AIDS. Some herbal formulae and their targeted patterns and common symptoms were also introduced. Chinese government has realized the important role of CM as an independent therapy for early management, bolstering immune-system functions depressed by HIV, and has funded large randomized double-blind controlled clinical trials to more accurately assess the benefits, and valued the fundamental research to establish a quantitative standardization of pattern diagnosis. Researchers of CM are looking for cooperation with all the world's top experts in the areas of AIDS and immunity to strive for victories in the fight against AIDS. PMID- 21611893 TI - Improving acquired immunodeficiency syndrome related cancer outcomes through international collaboration. PMID- 21611894 TI - Immune reconstitution--the footing of Chinese medicine treatment for acquired immunodeficiency syndrome. PMID- 21611891 TI - Regulation of flowering time: all roads lead to Rome. AB - Plants undergo a major physiological change as they transition from vegetative growth to reproductive development. This transition is a result of responses to various endogenous and exogenous signals that later integrate to result in flowering. Five genetically defined pathways have been identified that control flowering. The vernalization pathway refers to the acceleration of flowering on exposure to a long period of cold. The photoperiod pathway refers to regulation of flowering in response to day length and quality of light perceived. The gibberellin pathway refers to the requirement of gibberellic acid for normal flowering patterns. The autonomous pathway refers to endogenous regulators that are independent of the photoperiod and gibberellin pathways. Most recently, an endogenous pathway that adds plant age to the control of flowering time has been described. The molecular mechanisms of these pathways have been studied extensively in Arabidopsis thaliana and several other flowering plants. PMID- 21611895 TI - Study on the tongue manifestations for the blood-stasis and toxin syndrome in the stable patients of coronary heart disease. AB - OBJECTIVE: To explore the tongue manifestations for the blood-stasis and toxin syndrome in the stable patients of coronary heart disease (CHD) according to the acute cardiovascular events (ACEs) in one-year follow-up which based on the pathogenesis hypothesis of "blood-stasis and toxin causing catastrophe". METHODS: Totally 254 stable CHD cases were enrolled after diagnosed by coronary angiography, their tongue appearances were recorded by the digital camera of uniform type, 29 cases with ACEs during one-year follow-up were assigned in ACEs group. The non-ACEs were matched in proportion of 2:1 according to the gender, age (+/-2.5 years), diabetes mellitus history and previous acute coronary syndrome hospitalization history in the non-ACEs group, and 54 cases were eligibly included. The differences of tongue appearance between the ACEs and non ACEs group were compared. RESULTS: Fifteen cases manifested with bluish tongue (including bluish-grounding or bluish purple tongue), among which 11 cases (37.9%) in the ACEs group and four cases (7.4%) in the non-ACEs group, and there was significant difference (P<0.002). Twenty six cases showed yellow tongue coating in the non-ACEs group, which was significantly higher than that in the ACEs group (48.1 vs. 10.3%, P=0.001). The tongue of sticky greasy coating was more frequently occurred in the non-ACEs group than that in the ACEs group (66.7% vs. 41.4%, P=0.026). The proportion of purplish-red sublingual vessel was higher in the ACEs group than that in the non-ACEs group (41.4% vs. 20.4%, P=0.041). Odd ratio (OR) analysis showed that the patients with bluish tongue, purplish-red sublingual vessel, dry-greasy or dirty greasy coating were more likely to experience ACEs during one-year follow-up (OR: 11.67, 95%CI: 3.34 year 3.34 40.81, P<0.001; OR: 2.76, 95%CI: 1.02 1.02-7.44, P<0.05; OR: 3.12, 95%, CI: 0.89 0.89-10.92, P=0.066). CONCLUSIONS: The bluish tongue (including bluish-grounding or bluish purple tongue) and purplish-red sublingual vessel were potential tongue manifestations of blood-stasis and toxin. The tongue coating changing from sticky greasy to dry greasy or dirty greasy was also probably a tongue manifestation of "transforming toxin", which need demonstration by further study. PMID- 21611896 TI - A randomized, controlled, double-blinded and double-dummy trial of the effect of tongjiang granule on the nonerosive reflux disease of and Gan-Wei incoordination syndrome. AB - OBJECTIVE: To assess the effectiveness of tongjiang granule (TJG) on the patients with nonerosive reflux disease (NERD) of Gan-Wei incoordination syndrome, its impact on their quality of life, and its safety. METHOD: A randomized, controlled, double-blinded, and double-dummy method was adopted in the trial. There were 120 NERD patients enrolled in the study and randomly divided into the experiment and control groups, each with 60 patients; drugs were distributed according to the drug number by patients' inclusion sequences. In the experiment group, patients were given TJG 10 g and mosapride citrate dummy 5 mg three times a day, and in the control group, patients were given mosapride citrate 5 mg and TJG dummy 10 g three times a day. The treatment courses of both groups were 4 weeks. RESULTS: Among 120 included patients, 112 were screened for full analysis set (FAS), and 105 were screened per-protocol set (PPS). The results were as follows: (1) the improvement of total scores of symptom in the experiment group (0-4 week) were 15.93+/-7.88 scores by FAS and 16.22 +/-7.75 scores by PPS, and they were 10.43+/-10.16 scores and 10.79+/-10.27 scores in the control group, respectively. The 95% CI of net scores improvement between the two groups were 2.10-8.90 scores and 1.92-8.94 scores in FAS and PPS; it was significantly better in the experiment group than that in the control group (P<0.05). (2) The improvement of scores of major symptom in the experiment group (0-4 week) were 10.68+/-5.35 by FAS and 10.89+/-5.29 by PPS and 7.40+/-7.41 and 7.60+/-7.46 in the control group, respectively. The 95% CI of net scores improvement in the two groups were 0.85-5.71 and 0.71-5.69 in FAS and PPS separately, and the improvement in the experiment group was significantly better than that in the control group (P<0.05). (3) The total effective rates were 86.0% and 61.8% in the experiment and the control group separately, and the Ridit analysis results showed that it was better in the experiment group (P<0.05). (4) The improvement quality of life in the domain of physical functioning and general health in the experiment group was better than that in the control group (P<0.05). (5) One case of experiment group caught a cold and recovered in six days without drug suspension. No adverse event was found in the other cases. There was no meaningful safety examination indices change in pretreatment and posttreatment periods in both groups. CONCLUSION: TJG showed a definite effect on the treatment of NERD with Gan-Wei incoordination syndrome, and it could improve the quality of life of NERD patient without obvious toxic and side effects. PMID- 21611897 TI - Study on canceration law of gastric mucosal dysplasia based on syndromes of Chinese medicine. AB - OBJECTIVE: To study the syndrome evolution law of Chinese medicine (CM) in the patients with gastric mucosal dysplasia. METHODS: Three hundred and twenty four gastric mucosal dysplasia patients with deficiency and excess correlation syndromes were enrolled by a multi-center collaboration for two years' clinical follow-up to detect the levels of tumor supplied group of factors (TSGF) and carcino-embryonic antigen (CEA). RESULTS: Among the 324 cases, 29 cases turned cancer in the two years, and the canceration rate was 9.0%. The three syndromes with higher canceration rate were the damp-heat accumulating Wei syndrome concurring or combining with asthenia-cold in Pi and Wei syndrome for 16.7%; stagnation in Wei collaterals syndrome concurring or combining with asthenia of both qi and yin syndrome for 13.2%; stagnation of Gan and Wei qi syndrome concurring or combining with asthenia-cold in Pi and Wei syndrome for 8.0%, respectively. Among the three syndromes, the highest level of TSGF occurred in the former two syndromes. In the half year before carcinogenesis, the syndromes of the patients took on deficiency and excess concurrent syndromes, and the deficiency syndromes involving the qi and blood deficiency syndrome and the Shen deficiency syndrome accounting for 48.0%. CONCLUSIONS: Gastric mucosal dyspalsia canceration syndromes took on the polymorphism of excess and deficiency concurrent syndromes and had the characteristics of deficiency syndromes involving qi and blood deficiency syndrome and Shen-yin-yang deficiency syndrome. PMID- 21611898 TI - Rule of Chinese medicine syndrome differentiation in the patients with thoracic diseases at perioperation stage. AB - OBJECTIVE: To study the rule of syndrome differentiation in the patients with thoracic diseases at perioperation stage. METHODS: A standard was created referring to the related literature, and it was applied to differentiate the Chinese medicine syndrome in 150 patients before and three days after thoracic operation. RESULTS: Before operation, Chinese medicine syndromes were as differentiated as phlegm type in 45.3%, blood stasis type in 17.3%, and qi stagnancy type in 16.0%. The patients with asthenia syndrome markedly increased after operation, accounting for 34.0% (51 patients, including qi-, yin-, and blood-deficiency syndromes). The most frequently seen intermixed syndromes were qi-deficiency with phlegm-stasis syndrome and Pi ()-deficiency with phlegm dampness syndrome. The intermixed syndromes revealed in 37.5% and 42.0% of the patients before and after operation, respectively. CONCLUSIONS: The syndrome in the patients with thoracic disease before operation was mostly the excessive syndrome, mainly the phlegm syndrome type; at postoperation stage, Chinese medicine syndrome in patients become asthenia in essence with excessive superficiality, which is mostly revealed as Pi-deficiency with phlegm-dampness. PMID- 21611899 TI - Correlation between Fc gamma R III a and aortic atherosclerotic plaque destabilization in ApoE knockout mice and intervention effects of effective components of chuanxiong rhizome and red peony root. AB - OBJECTIVE: To explore the correlation between Fc gamma RIII A (CD16A) and aortic atherosclerotic plaque destabilization in apoE knockout (apoE KO) mice and the intervention effects of effective components of chuanxiong rhizome and red peony root. METHODS: Eight 8-week-old male C57BL/6J mice were selected as the control group. Forty 8-week-old male apoE KO mice were randomly divided into the model group, apoE KO + intraperitoneal injection immunoglobulin group (IVIG), apoE KO + simvastatin group (Sm), apoE KO + high dosage of xiongshao capsule (XSC) group (XSCH), and apoE KO + low dosage of XSC group (XSCL), 8 mice in each group. Mice in the control group were put on a normal diet, and others were fed with a high fat diet. After 10-week different interventions, monocyte CD16 expression was detected by flow cytometry, aortic matrix metalloproteinase-9 (MMP-9) mRNA expression was detected using reverse transcription polymerase chain reaction, and serum tumor necrosis factor (TNF)-alpha level was detected using enzyme linked immunosorbent assay. RESULTS: Compared with the control group, monocyte CD16 expression, aortic MMP-9 mRNA expression, and serum TNF-alpha level in the model group increased obviously (P<0.01). Injections of apoE KO mice with intraperitoneal immunoglobulin during a 5-day period significantly reduced the monocyte CD16 expression, aortic MMP-9 mRNA expression, and serum TNF-alpha level (P<0.01 or 0.05) over a 10-week period of high-fat diet. Indices above in the Sm group, XSCH group, and XSCL group decreased in a different degree. Of them, the aortic MMP-9 mRNA expression in XSCH group was lower than that in Sm group (P<0.05) and the monocyte CD16 expression and serum TNF-alpha level showed no significant difference between XSCH group and Sm group (P>0.05). Correlation analyses suggested positive correlation between monocyte CD16 expression and aortic MMP-9 mRNA expression or serum TNF-alpha level in IVIG group, XSCH group, and XSCL group. CONCLUSIONS: FcgammaR III A mediates systemic inflammation in the progression of coronary heart disease with blood stasis syndrome. XSC could stabilize atherosclerotic plaque by suppressing inflammation and its target was relative with FcgammaRIII A. PMID- 21611900 TI - Structural shifts of gut flora in rat acute alcoholic liver injury and jianpi huoxue decoction's effect displayed by ERIC-PCR fingerprint. AB - OBJECTIVE: To study the structural shifts of gut flora in rats with acute alcoholic liver injury (AALI), and the effect of jianpi huoxue decoction (JPHXD) on the gut flora. METHODS: Thirty-six Sprague-Dawley rats were randomly allocated to the control, AALI and JPHXD groups equally. The rats in the control group were given water and those in AALI and JPHXD groups were given ethanol by intragastric gavage for 5 days, while rats in the JPHXD group were administered JPHXD simultaneously. The blood and liver tissue were collected at the end of the experiment. The activities of serum alkaline aminotransferase (ALT), aspartate aminotransferase (AST), hepatic gamma-glutamyltranspetidase (gamma-GT) and hepatic triglyceride (TG) levels were determined. Plasma endotoxin level in the portal vein was measured. Pathological changes of liver tissues were determined by hematoxylin and eosin (HE) staining and oil red O staining. The total DNA of gut flora were extracted from fecal samples by Bead-beating method and determined by ERIC-PCR fingerprint method. The similarity cluster analysis and principal component analysis were performed to analyze the ERIC-PCR fingerprint respectively. RESULTS: In the AALI group, the ratio of liver/body weight, activities of ALT, AST and hepatic gamma-GT, amount of hepatic TG were elevated significantly compared with those in the control group (all P<0.01). JPHXD decreased the ratio, activities of ALT, AST, gamma-GT and TG significantly compared with those in the AALI group (P<0.05 or P<0.01). HE and oil red O staining showed that fat deposited markedly in liver tissue, while JPHXD alleviated pathological changes markedly. Plasma LPS level in rat portal vein in the AALI group increased significantly (P<0.01), but it was decreased significantly in the JPHXD group (P<0.01). The cluster analysis and principal component analysis of ERIC-PCR fingerprint showed that gut flora in the AALI group changed markedly, and JPHXD could recover gut flora to some extent. CONCLUSIONS: The structure of gut flora shifted markedly during acute alcoholic liver injury, JPHXD had prevention effect through the modification of gut flora. PMID- 21611901 TI - Evaluation study on urine metabolomics in yinhuang rat model induced by triplet factors of rhubarb, ethanol, and alpha-nephthylisothiolyanate. AB - OBJECTIVE: To ascertain the biomarkers capable to characterize the animal composite model of Chinese medicine (CM) yinhuang syndrome induced by triplet factors of rhubarb, ethanol, and alpha-nephthylisothiolyanate (abbreviated as R, E, and A below) through metabolomic study and to evaluate the established model by means of studying the sources of markers based on the changes of metabolites produced from various combinations of the three modeling drugs. METHODS: Eighty Wistar rats allocated equally in eight groups (A-H) were treated with saline, R+E+A, R, E, A, R+E, R+A, and E+A, respectively. Rats' 12 h urine in the 14 successive experimental days were collected separately using metabolic cages and analyzed by ultra performance liquid chromatograph/time of flight mass spectrometer (UPLC/TOF-MS) to create the metabolic contour graph of urine in different groups for identifying the differences between them. The similarities and differences of metabolic network among various groups were represented from microcosmic viewpoint by pattern recognition method (principal component analysis). RESULTS: Controlled by group A, the landing points in principal component map of various groups were apparently assorted, especially obvious on the 14th day; 19 biomarkers, which capable to represent the genesis and development process of the yinhuang syndrome in the triplet factors-induced rat model, were identified. CONCLUSION: Metabolomic method is successfully used in evaluating the animal model of CM syndrome. Furthermore, according to the holistic view and substance changes in vivo, the influences of disease on organism were comprehensively analyzed, and the pathogenic mechanism of CM yinhuang syndrome was explored at the level of metabolomics in vivo as well. PMID- 21611902 TI - Effects of yiqi huoxue recipe and Coxsackie virus B type 3 on the expression of ribosomal protein S20 in rat cardiac myocytes. AB - OBJECTIVE: To study the effects of yiqi huoxue recipe and Coxsackie B virus type 3 (CVB3) on the expression of ribosomal protein S20 in rat cardiac myocytes, to explore the pathogenesis of myocarditis induced by CVB3 and the mechanism of yiqi huoxue recipe on gene level, and to further investigate whether yiqi huoxue recipe is an effective prescription for CVB3 myocarditis. METHODS: A modified suppression subtractive hybridization (SSH) was used to isolate differentially expressed genes between the CVB3 infection group and the treatment group with yiqi huoxue recipe. The results were further verified by fluorescence RT-PCR. RESULTS: The results of SSH showed that the gene expression of ribosomal protein S20 in the treatment group was higher than that in the CVB3 infection group (P<0.05), which agreed with the results of fluorescent RT-PCR. CONCLUSION: Down regulation of ribosomal protein S20 mRNA expression might be one of the mechanisms in CVB3 myocarditis, and yiqi huoxue recipe could achieve the treatment of viral myocarditis by regulating the expression of ribosomal protein S20. PMID- 21611903 TI - Summary of integrative medicine for severe acute pancreatitis: 26-year clinical experiences and a report of 1 561 cases. AB - OBJECTIVE: To investigate the changing trends of clinical management for severe acute pancreatitis (SAP) with integrative medicine. METHODS: Clinical data of 1 561 patients with SAP from 1980 to 2005 was retrospectively analyzed. The mortality and morbidity of complications were compared. RESULTS: Of the 1 561 patients, 400 patients accepted surgical operation, while the rest were treated conservatively with integrative medicine. There was a change toward conservative management together with Chinese purgative herbal medication use after 1990 (22.4% from 1980-1990 compared with 45.5% from 1991-1993) because of high postoperative mortality. From 1994-2005, the treatment integrating Western medicine with Chinese herbal medications came to be preferred over the classic Western operation-based method. This change was associated with decreased morbidity (35.4% in 1980-1990 compared with 24.7% in 1991-1993 and 11.0% in 1994 2005, P<0.05) and lower mortality (40.52% of 1980-1990 compared with 17.17% of 1991-1993 and <10.25% of 1994-2005, P<0.05). CONCLUSION: The combination of conservative management with Chinese herbal medicines is preferable to classic Western medicine treatment to reduce morbidity and mortality of SAP, while surgery becomes a supplemental option. PMID- 21611905 TI - Reproductive experience may positively adjust the trajectory of senescence. AB - Although aging is inexorable, aging well is not. From the perspective of research in rats and complementary models, reproductive experience has significant effects; indeed, benefits, which include better-than-average cognitive skills, a slowing of the slope of decline, and a healthier brain and/or nervous system well later into life. Work from our lab and others has suggested that the events of pregnancy and parturition, collectively referred to as reproductive experience-an amalgam of hormone exposure, sensory stimulation, and offspring behavioral experience and interaction-may summate to flatten the degree of decline normally associated with aging. Mimicking the effects of an enriched environment, reproductive experience has been shown to: enhance/protect cognition and decrease anxiety well out to two-plus years; result in fewer hippocampal deposits of the Alzheimer's disease herald, amyloid precursor protein (APP); and, in general, lead to a healthier biology. Based on a suite of recent work in organisms as diverse as nematodes, flies, and mammals, the ubiquitous hormone insulin and its large family of related substances and receptors may play a major role in mediating some of the effects of RE on the parameters of aging studied thus far. We will discuss the current set of data that suggest mechanisms for successful biological and neurobiological aging, and the implications for understanding aging and senescence in their broadest terms. PMID- 21611904 TI - Acupuncture for infertility: is it an effective therapy? AB - Acupuncture has been used to treat infertility extensively, including ovulatory dysfunction, in vitro fertilization and embryo transfer (IVF-ET), and male infertility. This review summarizes the recent studies which investigated the role of acupuncture in infertility. In conclusion, most of the existing studies suggest a positive effect of acupuncture in infertility treatment. Firstly, acupuncture may improve ovulation by modulating the central and peripheral nervous systems, the neuroendocrine and endocrine systems, the ovarian blood flow, and metabolism. Secondly, acupuncture can improve the outcome of IVF-ET, and the mechanisms may be related to the increased uterine blood flow, inhibited uterine motility, and the anesis of depression, anxiety and stress. Its effect on modulating immune function also suggests helpfulness in improving the outcome of IVF-ET. Finally, the studies suggest that acupuncture plays a positive role in male infertility, the mechanism of which is not yet clear. Even though a positive effect of acupuncture in infertility has been found, well-designed multi-center, prospective randomized controlled studies are still needed to provide more reliable and valid scientific evidence. Furthermore, it is urgent and necessary to clarify the mechanism of acupuncture for infertility. PMID- 21611906 TI - The birth of intensive care medicine: Bjorn Ibsen's records. AB - The birth of intensive care medicine was a process that took place in Copenhagen, Denmark, during and after the poliomyelitis epidemic in 1952/1953. The events that led to the creation of the first intensive care unit in the world in December 1953 are well described. It is generally agreed upon that the start of the process was the fact that an anaesthesiologist (Bjorn Ibsen) was brought out of the operating theatre and asked to use his skills on a 12-year-old girl suffering from polio. The medical record of the girl contains a minute-by-minute description of the historical event. A translation of this part of the record is published as an Online Resource to the article. The role played by the epidemiologist Mogens Bjorneboe is further analysed. He was the catalyst of the process, being the one with the idea that the skills of an anaesthesiologist could be used for other purposes than surgery. When first Ibsen realised what could be done with his skills, he proved to be one of the most progressive and inventive doctors seen in modern medicine. An interview with Prof. Ibsen in 2006 is published as an Online Resource to the article. PMID- 21611907 TI - Seroprevalence study in forestry workers of a non-endemic region in eastern Germany reveals infections by Tula and Dobrava-Belgrade hantaviruses. AB - Highly endemic and outbreak regions for human hantavirus infections are located in the southern, southeastern, and western parts of Germany. The dominant hantavirus is the bank vole transmitted Puumala virus (PUUV). In the eastern part of Germany, previous investigations revealed Tula virus (TULV) and Dobrava Belgrade virus (DOBV) infections in the respective rodent reservoirs. Here, we describe a seroprevalence study in forestry workers from Brandenburg, eastern Germany, using IgG ELISA and immunoblot tests based on recombinant TULV, DOBV, and PUUV antigens. Out of the 563 sera tested, 499 from male and 64 from female workers, we found 41 out of the 499 (8.2%) sera from men (mean age 47 years) and 10 out of 64 (15.6%) from the women (mean age 48 years) anti-hantavirus-positive. The majority of the 51 seropositive samples reacted exclusively in the TULV (n=22) and DOBV tests (n=17). Focus reduction neutralization assay investigations on selected sera confirmed the presence of TULV- and DOBV-specific antibodies in the forestry workers. These investigations demonstrated a potential health threat for forestry workers and also the average population in non-endemic geographical regions where TULV and DOBV are circulating in the corresponding reservoir hosts. The infections in this region might be frequently overlooked due to their unspecific and mild symptoms. PMID- 21611911 TI - [Therapeutic climbing--barely explored but widely used]. AB - BACKGROUND: Therapeutic climbing had been used successfully as an intervention in orthopedic-traumatologic, neurologic, psychomotoric and congenital or chronic diseases. The aim of this abstract is to give an overview of the existing literature on this new form of therapy. This could also aid in assessing the methodology and work out future research directions. MATERIAL AND METHODS: National and international databases within the medical field (Evidence Based Medicine Reviews, PubMed ...) have been searched for German and English articles that dealt with climbing in a therapeutic context. RESULTS: Only a limited amount of scientific investigations regarding the effects of therapeutic climbing were found. Evidence for the effectiveness of this form of climbing was only found in the field of orthopedics. Other published results were field reports or individual case studies which did not make any reliable statements/conclusions. CONCLUSION: Based on the current review, therapeutic climbing cannot be wholly recommended as an interventional method. However, this should not be interpreted as a refusal to use therapeutic climbing as an intervention. The use of systematic analysis in studying the general effects of climbing movements as well as comparisons to classical interventional methods is necessary. Further approaches to this research study will be given. PMID- 21611910 TI - Development of defined microbial population standards using fluorescence activated cell sorting for the absolute quantification of S. aureus using real time PCR. AB - In this article, four types of standards were assessed in a SYBR Green-based real time PCR procedure for the quantification of Staphylococcus aureus (S. aureus) in DNA samples. The standards were purified S. aureus genomic DNA (type A), circular plasmid DNA containing a thermonuclease (nuc) gene fragment (type B), DNA extracted from defined populations of S. aureus cells generated by Fluorescence Activated Cell Sorting (FACS) technology with (type C) or without purification of DNA by boiling (type D). The optimal efficiency of 2.016 was obtained on Roche LightCycler((r)) 4.1. software for type C standards, whereas the lowest efficiency (1.682) corresponded to type D standards. Type C standards appeared to be more suitable for quantitative real-time PCR because of the use of defined populations for construction of standard curves. Overall, Fieller Confidence Interval algorithm may be improved for replicates having a low standard deviation in Cycle Threshold values such as found for type B and C standards. Stabilities of diluted PCR standards stored at -20 degrees C were compared after 0, 7, 14 and 30 days and were lower for type A or C standards compared with type B standards. However, FACS generated standards may be useful for bacterial quantification in real-time PCR assays once optimal storage and temperature conditions are defined. PMID- 21611909 TI - Neuroprotective effect of ginkgolide K against acute ischemic stroke on middle cerebral ischemia occlusion in rats. AB - Ginkgolide K, a natural platelet-activating factor receptor antagonist, was isolated from the leaves of Ginkgo biloba. However, little is known about its neuroprotective effect in ischemia-reperfusion (I/R)-induced cerebral injury. Hence, the present study was carried out to investigate the effect of ginkgolide K on neuroprotection and the potential mechanisms in the rat I/R model induced by middle cerebral artery occlusion (MCAO). The rats were pretreated with ginkgolide K 2, 4 and 8 mg/kg (i.v.) once a day for 5 days before MCAO. Neurological deficit score (NDS), brain water content, 2,3,5-triphenyltetrazolium chloride (TTC) staining and pathology of brain tissue, as well as indexes of oxidative stress [superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and nitric oxide synthase (NOS)] were measured at 24 h after ischemia. The results indicated that pretreatment with ginkgolide K significantly diminished the volume of infarction and brain water content, and improved NDS. Moreover, ginkgolide K markedly reversed the level of MDA, NO, NOS and SOD to their normal state in serum or cerebral ischemic section. In addition, hematoxylin and eosin staining showed the neuronal injury was significantly improved after being pretreated with ginkgolide K. These findings demonstrate that ginkgolide K exhibits neuroprotective properties through its antioxidative action in MCAO rats. PMID- 21611912 TI - [Spine injuries due to horse riding accidents - an analysis of 30 cases]. AB - INTRODUCTION: Horseback riding entails several risk factors that predispose the participant to injury. Especially craniocerebral as well as spinal trauma were common reasons for severe injuries. Hence, it is important to use effective protective gear during riding activities. However, the protective effect of actual safety vests and helmets in case of accident is still unknown. In the present study reasons, mechanisms and patterns of equine-related spine injuries were analyzed. Based on these data the effectiveness of used protective gear during accident was assessed. MATERIAL AND METHODS: 30 equestrians took part in a questionnaire survey. Based on these answered questionnaires reasons, mechanisms and patterns of equine-related injuries as well as used protective gear during accident were evaluated and analyzed. RESULTS: 24 patients (80 %) were female and 6 (20 %) were male. The median age at the time of injury was 36 years (range 14 - 72 years). The causalities suffered from 18 fractures (60 %) and 11 discoligamentous injuries (37 %), in one case a bone-bruise-injury (3 %) was found. 7 equestrians (23 %) wore a safety vest at time of injury. DISCUSSION: Despite wearing a safety vest, the spine can get damaged when accident occurred. It is not possible to create vests for equestrians capable of protecting against all spine injuries in all accidents. If the energy impact is too high, serious injuries can result, even though protective body gear is worn. But the development of improved safety vests is necessary to reduce the number of severe spine injury in the future. PMID- 21611913 TI - [Refixation of distal biceps tendon rupture using 2 anchor sutures - sports ability after 1 year follow-up and operative technique]. AB - BACKGROUND: Rupture of distal biceps tendon often occurs in physical active male persons between 30 and 50 years. The standard treatment consists of operative refixation of the ruptured tendon stump. In literature there are various methods described. Due to the high expectations of this group of patients, we examined the sports ability after 1 year follow-up and describe our employed operative fixation technique. MATERIAL: Between 2004 and 2008 we treated 20 male persons in a prospective study with distal biceps tendon rupture. Applying the score of Rattanen and Orawa we evaluated the M. biceps force in flexion and supination and changes in the patients' sports activity. Furthermore we documented complications and the anchor localization via x-ray. RESULTS: The score results varied between excellent in 14 patients and good and fair in 3 cases respectively. Using only 1 suture anchor (3 patients), either a knot or a wire failure appeared within 5 days. Anchor malpositions were discovered in 2 patients. The force measurement showed threetimes minor but in 3 patients major force deficits. Lack of extension or supination movement could be stated in 3 cases. Changes in their sports ability reported 8 persons. Of the remaining 12 patients, the original sports level was reached after 9 months. CONCLUSION: Two anchors proved to guarantee a stable fixation of the distal biceps tendon stump. On the contrary we see the danger of fixation failure in using only 1 anchor. The best results achieved patients with a primer stable and correct located anchoring, therefore we recommend two anchors placed under radiological control. Regarding the score results, fixation of the distal biceps tendon is a demanding procedure, that should be performed by experienced surgeon. PMID- 21611914 TI - [The "wheel gymnast's elbow" - first description of a common overuse syndrome]. AB - BACKGROUND: Overuse syndromes of the elbow due to wheel gymnastics are unknown in medical literature. This study describes a common overuse syndrome of the elbow in wheel gymnastics. METHODS: We conducted internet research and interviewed 260 wheel gymnasts, who trained the "hip roll" element. RESULTS: 60.4 % of the gymnasts reported changes of the elbow region. The intensity of pain during training was 1.51 out of 10 points. Lacerations were reported in 33.1 %, hematomas were reported in 68.7 %, and a loss of hair at the elbow region was reported in 11.7 %. 11.5 % of the gymnasts described a bump and 5.8 % described a depression of the proximal ulnar region that was not found before wheel gymnastics. Gymnasts using protective gear reported significantly higher levels of pain compared to gymnasts without protective gear. DISCUSSION: The "wheel gymnast's elbow" is a common overuse syndrome of the proximal ulnar due to direct contact and friction of the proximal ulnar to the giant wheel bars. The "wheel gymnast's elbow" describes a combination of lacerations, hematoma, hair loss, bumps, and depression of the proximal ulnar region with only slight pain. CONCLUSION: An early preventive use of protective gear during "hip roll" training can possibly reduce the "wheel gymnast's elbow" syndrome. PMID- 21611915 TI - [No clinical evidence for an enhanced bleeding tendency due to perioperative treatment with bromelain]. AB - BACKGROUND: Systemic enzyme therapy with bromelain resembles a sensible alternative to nonsteroidal antiinflammatory drugs for the treatment of sports injuries, with particular consideration of therapeutic benefits and possible risks. Beyond aftertreatment of sports injuries, bromelain is used postoperatively as well. Besides the desired effects remission of oedema and pain relief, however, the postoperative use of bromelain raises uncertainty in some patients and physicians since an enhanced bleeding tendency in case of concomitant therapy with anticoagulants was described as a possible interaction. Therefore, the goal of this study was to investigate the clinical relevance of this interaction. PATIENTS/METHODS: In two non-interventional studies, altogether 260 patients were peri- or postoperatively (cruciate ligament- or coxarthrosis surgery) treated with bromelain (n = 129, 1000 - 3000 F. I. P. units/day) or diclofenac (n = 131; 150 mg/day) under concomitant thrombosis prophylaxis with low molecular weight heparin. Parameters tested were prothrombin time, thrombin time, activated partial thromboplastin time, fibrinogen and tolerability of the medication. RESULTS AND CONCLUSION: Only marginal changes and a low variability of coagulation parameters were observed in both treatment groups (bromelain vs. diclofenac) in both studies. Elevated laboratory parameters were observed in both treatment groups for thrombin time which is very likely attributable to the therapy with low molecular weight heparin, due to the substantially parallel course of this parameter in both treatment groups. Therapy with bromelain was superior to the treatment with diclofenac concerning the number and the severity of undesirable effects, as was expected. The presented studies therefore support the previous clinical evidence that a perioperative treatment with bromelain is well tolerated and does not lead to an increased risk of haemorrhage when used concomitantly with low molecular weight heparin. PMID- 21611916 TI - [Treatment of locked chronic posterior dislocation of the shoulder]. AB - INTRODUCTION: The posterior locked shoulder dislocation is a rare injury that is often associated with an impression fracture of the anteromedial aspect of the humeral head. The majority of posterior shoulder dislocations are missed on the initial examination. METHODS: We demonstrate the case of an athlete, who presented with a posterior shoulder dislocation after a trauma two months ago. RESULTS: The patient was treated with a M. subscapularis transfer in the reverse hill-sachs-lesion. DISCUSSION: The diagnosis of the posterior shoulder dislocation remains a problem in the clinical setting. Treatment is based on the size defect of the anteromedial humeral head. Different treatment options are still controversially discussed. CONCLUSION: To diagnose a posterior shoulder dislocation correctly a standard clinical and radiological assessment is necessary. PMID- 21611917 TI - [Humeral fracture due to arm wrestling - an indirect fracture in a doped athlete]. AB - BACKGROUND: Humeral shaft fractures due to recreational arm wrestling are reported from time to time. CASE REPORT: We report the case of a 19 year old, anabolic steroids up taking, recreational arm wrestler who sustained a spiral fracture of the right humeral bone and secondary radial nerve palsy. We discuss the surgical treatment and the biomechanics of this rare injury mechanism. CONCLUSION: Every professional or recreational arm wrestler has to be aware of dangerous sports injuries. PMID- 21611918 TI - [Clinical research and science-based medical education]. PMID- 21611919 TI - [New oral anticoagulants for treatment of venous thromboembolism]. AB - In the current treatment of venous thromboembolism most patients are treated with vitamin K antagonists (VKA). VKA have many disadvantages including slow onset of action, multiple food and drug interactions and a large inter-individual variability in their efficacy. Recently several alternative oral anticoagulants have been developed, which have several advantages in comparison to VKA. So far two large randomized studies comparing new oral anticoagulants with VKA in patients with venous thromboembolism have been published: the RECOVER study with the oral direct thrombin antagonist dabigatran and the EINSTEIN-DVT study with the oral direct factor Xa-antagonist rivaroxaban. With regard to recurrent venous thromboembolism and bleeding complications, both drugs were comparable with VKA. In addition, two other studies are ongoing with the oral direct factor Xa antagonists apixaban and edoxaban for this indication. The final role of the new oral anticoagulants in the future treatment of venous thromboembolism has to be determined. However the first results from randomized trails are encouraging. PMID- 21611920 TI - [New therapeutic options for advanced thyroid cancer]. PMID- 21611921 TI - [Iatrogenesis]. PMID- 21611922 TI - [Immune thrombocytopenia]. PMID- 21611923 TI - [Tick-borne infections]. PMID- 21611924 TI - [Nutrition in intensive care]. AB - Nutrition is a supportive therapy in critically ill patients. The caloric need of a patient is not static and may change during the clinical course. Early enteral nutrition helps preventing an energy deficit of the patient leading to an increased rate of secondary infections and prolonged length of stay. By using protocols early enteral nutrition may be improved with benefit for the critically ill. Patients should not receive hypercaloric nutrition. Supplemental parenteral nutrition should be used to minimize the gap between energy needs and enteral supplied calories. Nutrition should be supplied according to metabolic and enteral tolerance. A strict glucose control is not recommended to all patients any more. Hyperglycemia may be part of the adaptive response to stress, infection, and trauma. It is important to avoid hypoglycaemia and increased variability in glucose concentrations. To this end, structured local protocols with instructions for sampling density, glucose and insulin administration, avoidance and treatment of hypoglycaemia should be installed. There are contradictory data on the use of probiotics in critically ill patients. Among patients with severe acute pancreatitis, more patients died after having received probiotics. The use of probiotics should be evaluated in controlled trials. Adherence to guidelines may be improved, and their appliance should be followed by constant training and evaluation processes. PMID- 21611925 TI - [Diagnosis and treatment of right ventricular dysfunction]. PMID- 21611926 TI - [Primary and secondary (renovascular) arterial hypertension]. PMID- 21611927 TI - [Interstitial lung disease]. AB - This concise article summarizes recent advances in the field of interstitial lung disease (ILD) with particular focus on clinically relevant findings. As a novel treatment option for idiopathic pulmonary fibrosis (IPF), pirfenidone has been granted marketing authorization in the European Union for the treatment of mild to moderate IPF. In contrast, the FDA refused to approve pirfenidone for the US market. Promising study results for the treatment of IPF were published for the triple tyrosine kinase inhibitor intedanib, other drugs such as the endothelin receptor antagonist (ERA) macitentan are currently investigated in clinical trials. Further studies that investigated the ERA bosentan, the phosphodiesterase 5 inhibitor sildenafil, or the tyrosine kinase inhibitor imatinib in IPF failed to show a benefit for the pertinent primary endpoint. Additionally, an evidence based guideline for the diagnosis and management of IPF has very recently been published. The European Respiratory Society established a guideline for the management of lymphangioleiomyomatosis (LAM), while another study showed the cost effectiveness of HRCT screening for LAM in selected female patients suffering from spontaneous pneumothorax. Data from a scleroderma-ILD study show the prognostic relevance of antitopoisomerase antibodies in the progression of this form of ILD. Bosentan treatment did not significantly enhance exercise capacity in patients with scleroderma-ILD in the absence of pulmonary hypertension. With regard to sarcoidosis with mediastinal lymphadenopathy the diagnostic sensitivity can be significantly improved by endobronchial ultrasonography-guided transbronchial needle aspiration vs. conventional needle aspiration. As a possible future treatment option for sarcoidosis vasointestinal peptide has been successfully evaluated in a phase 2 tolerability trial. PMID- 21611928 TI - [Vasculitis]. PMID- 21611929 TI - [Luminal gastroenterology and inflammation]. AB - Luminal inflammation of the intestine is a trigger of numerous gastrointestinal and non-gastrointestinal diseases. Several mechanisms have an impact on luminal inflammation, such as antibiotic or immunosuppressive therapies. In this paper recent data and new therapeutic approaches are reported concerning gastrointestinal and non-gastrointestinal diseases, for example eosinophilic esophagitis, irritable bowel syndrome, Crohn's disease and hepatic encephalopathy. In addition, recommendations are provided for the concurrent medication with proton pump inhibitors (PPIs) with respect to cardiovascular and gastrointestinal complications in patients in whom dual antiplatelet therapy including clopidrogel is indicated. Finally, an outlook is given on new and interesting therapeutic concepts in clostridium difficile colitis. PMID- 21611930 TI - [Intralobar pulmonary sequestration with aspergillosis in an asymptomatic 39-year old man]. AB - HISTORY AND CLINICAL FINDINGS: During a screening examination a pulmonary mass in the left lower lobe was detected in a 39-year-old man. The patient was asymptomatic and had hitherto been healthy. CT pulmonary angiography revealed an intralobar pulmonary sequestration with an afferent arterial branch from the thoracic aorta. DIAGNOSIS, TREATMENT AND COURSE: Thoracotomy with resection of the sequestration was performed. On the first postoperative day hemiparesis of the left side occurred because of an infarction of the arteria cerebri media. After aspiration of the thrombus and intraarterial thrombolysis the patient recovered completely. Histology of the sequestration showed invasive growth of aspergillus and severe inflammation, caused by invasive mycosis. Subsequently the patient received voriconazol for four weeks. CONCLUSION: Diagnosis of pulmonary sequestration in adults is rare. In asymptomatic patients there is still controversy about the treatment. Surgery, arterial embolisation and a "watch and wait" strategy can be taken into account. Because of the risk of infection an operative approach should be favoured. PMID- 21611931 TI - [72-year-old man with striking lingual changes]. PMID- 21611933 TI - [Structure and specific features of internal medicine and internist's specialties at five regional care centers in the federal states of Bavaria, Berlin, and Brandenberg]. PMID- 21611932 TI - [Postpartum cardiomyopathy]. AB - HISTORY AND CLINICAL FINDINGS: A 27-year-old woman was admitted to the emergency room because of dyspnoea. Two months earlier she had given birth to a healthy young boy via cesarean section. IMAGING: Computed tomography showed acute embolism in both pulmonary arteries. Chest X-ray and echocardiography revealed an enlarged left ventricle, a highly reduced left ventricular function and thrombosis in the left ventricle. TREATMENT AND COURSE: The patient was treated with extensive medical heart failure therapy, and also with bromocriptine for eight weeks. Six months later, left ventricular ejection fraction had significantly improved. CONCLUSION: Peri- or postpartum cardiomyopathy (PPCM) is a rare, potentially life-threatening heart disease, which is characterized by sudden onset of heart failure between the final weeks of pregnancy and up to six months after childbirth. Early diagnosis is crucial for the patient's prognosis. Recent pilot studies on the effect of adding bromocriptine to standard heart failure therapy indicated an improvement of prognosis and myocardial function. In this case significant improvement of left ventricular function was thus achieved. PMID- 21611937 TI - Childhood obesity in ambulatory children and adolescents with spastic cerebral palsy in Korea. AB - OBJECTIVE: Childhood obesity is an emerging health issue in Korea. We investigated the prevalence of obesity and its trend over time in ambulatory Korean children with CP. METHODS: We retrospectively reviewed the medical records of 1,397 children with CP between 1995 and 2008. The data were grouped into 4 time periods (1995-1997, 1998-2002, 2003-2004 and 2005-2008). The prevalence of obesity over each period and its relationship to gender, birth weight, age, and gross motor function classification system were investigated. RESULTS: The percentage of obese children was 5.8%, overweight children 11.2%, and underweight children 10.4%. The prevalence of obesity significantly increased from the first time period to the third time period. The prevalence of obesity found in our study was significantly lower than the report from the U.S.A. during same time period between 1994 and 2004 (p<0.05). The prevalence of obesity significantly decreased with age as well. CONCLUSIONS: The prevalence of obesity in our subjects significantly increased and has reached a plateau in recent years. Compared to the prevalence of childhood obesity in ambulatory individuals with CP in the U.S.A. study, the prevalence in our study was significantly lower. PMID- 21611938 TI - Magnetic resonance imaging screening of cerebral thromboembolic events in children with acute lymphoblastic leukemia: a pilot study. AB - BACKGROUND: Thromboembolism is a complication of acute lymphoblastic leukemia therapy in children. The majority of thromboembolic events are cerebral thromboses and deep venous thromboses; many asymptomatic deep venous thromboses are detected in children with acute lymphoblastic leukemia by instrumental screening. The aim of this study was to assess the incidence of asymptomatic cerebral thromboembolic events in children with acute lymphoblastic leukemia (ALL) screened by magnetic resonance imaging and magnetic resonance venography. METHODS: 46 children with acute lymphoblastic leukemia, during the induction phase of the AIEOP ALL 2000 protocol, were stratified into 2 groups. In group "A" cerebral thromboembolic events were suspected following the appearance of suggestive signs and symptoms and confirmed by cerebral magnetic resonance imaging and magnetic resonance venography; in group "B" children underwent a screening by cerebral magnetic resonance imaging and magnetic resonance venography, at set times, in absence of symptoms. RESULTS: We observed one cerebral thromboembolic event in both groups; we found no differences between early detecting asymptomatic cerebral thromboembolic events among monitored and not monitored patients. CONCLUSIONS: Our study does not seem to suggest a screening for asymptomatic cerebral thromboembolic events in children with ALL during the induction phase. PMID- 21611939 TI - [Stimulant and non-stimulant medication in current and future therapy for ADHD]. AB - The current pharmacotherapy for attention-deficit hyperactivity disorder (ADHD) is mainly based on the stimulant methylphenidate and to a small extent on amphetamines which are not approved in Germany. The only approved non-stimulant so far is atomoxetin (Strattera(r)), a norepinephrine reuptake inhibitor. There is no approved pharmacotherapy for adults. The aim of the available medication is a reduction of impulsivity, hyperactivity, and attention deficits. Neurobiological correlates of these effects are still not fully understood, however, a functional implication of dopaminergic and noradrenergic systems is known. To date there is no disease-modifying therapy. The currently available substances have limitations due to the short half-life of stimulants, the unknown pathomechanisms, and the use of stimulants in developing brains with possible long-term side-effects. Moreover, the abuse potential of stimulants is still controversially discussed. The recently developed Lisdexamfetamin and SPD-465 have stimulant effects, too. A number of different developmental substances in preclinical and clinical phases show other mechanisms: SPD-503 represents an alpha(2)A-adrenozeptoragonist, ABT-089 and ABT-418 have partial agonistic effects to the alpha(4)beta(2)-subtype of nicotinic acetylcholinreceptors, CX-717, -1739, -1942 and -1796 are glutamatergic alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA)-receptor agonists and PF-3 654 746 exhibits antagonistic properties to histaminergic H(3)-receptors. The alpha(2)A adrenoceptor-agonist Guanfacine (Intuniv(r)) and the hepatic metabolised amphetamine prodrug Lisdexamfetamin (Vyvanse(r)) are yet approved for ADHD treatment in the USA. The aim of this review is to summarise established pharmacological treatment options and the stage of development of upcoming symptomatic stimulant and non-stimulant substances in ADHD therapy. PMID- 21611940 TI - [Validity assessment of a low level phonological processing test material in preschool children]. AB - BACKGROUND: The BISC (Bielefelder Screening) is a German test to evaluate phonological skills believed to be a prerequisite for future reading and writing skills. BISC results may indicate an elevated risk for dyslexia. Our research group has put forward test material in order to specifically examine low-level phonological processing LLPP. In this study we analysed whether BISC and low level phonological processing correlate. MATERIAL AND METHODS: A retrospective correlation analysis was carried out on primary school children's test results of the BISC and the newly developed low-level phonological processing test material. RESULTS: Spearman's rho was 0.52 between total LLPP and total BISC. The subscales correlated with a rho below 0.5. CONCLUSION: Results indicate that a low level phonological processing and higher level phonological processing can be differentiated. Future studies will have to clarify whether these results can be used to construct specifically targeting therapy strategies and whether the LLPP test material can be used to assess the risk of subsequent dyslexia also. PMID- 21611941 TI - [Inpatient language therapy in children with severe specific language impairments]. AB - BACKGROUND: The present retrospective evaluation study examined treatment efficacy in preschool children with severe specific language impairments. Besides the efficacy of 2 inpatient treatment conditions, differing in periods and intensity of parent advice, will be compared. MATERIAL AND METHODS: 106 children (mean age: 72.1; SD 9.1 months) received 6 weeks of treatment with a traditional therapy en bloc (EB) and 78 children (mean age: 72.3; SD 10.4 months) with a new therapy in 3 intervals (I) respectively. Receptive language abilities, expressive vocabulary size and nonword repetition were utilized as language measures at the beginning and end of treatment. RESULTS: In both treatment conditions, the children, on average, made significant gains in the outcome measures (p<0.0001). En bloc-like interval therapy yielded big effects in receptive language abilities (EB: d=0.89; 95%-CI: 0.72-1.05 vs. I: d=0.95; 95%-CI: 0.71-1.19). Medium effect sizes (EB: d=0.60; 95%-CI: 0.48-0.72; I: d=0.79; 95%-CI: 0.61-0.98) resulted in expressive vocabulary, but rather minor ones in phonological processing (EB: d=0.37; 95%-CI: 0.22-0.52; I: d=0.48; 95%-CI: 0.28-0.67). No significant post intervention difference between the therapy modes was only observed in receptive language (95%-CI of the difference at the end of treatment: -1.85-5.17). CONCLUSIONS: An intensive multidisciplinary approach with preschool children is justified when the children suffer from severe deficits in language comprehension and expressive vocabulary even after sufficient outpatient treatment. PMID- 21611942 TI - [Vascularized tumor of the nasal cavitiy in a juvenile male]. PMID- 21611943 TI - Analysis of variables associated with surgery versus observation in patients with pancreatic cystic lesions referred for endoscopic ultrasound. AB - BACKGROUND AND STUDY AIM: Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) for cyst fluid analysis (CFA) is often requested for pancreatic cystic lesions, to determine whether to operate or to observe. If this decision is not influenced by the EUS findings, the procedure may be unjustifiable. We aimed to determine whether EUS-CFA results predict surgery or observation in patients with pancreatic cysts referred for EUS. PATIENTS AND METHODS: Consecutive patients referred to a quaternary pancreaticobiliary center for EUS evaluation of pancreatic cysts were eligible. Clinical data, computed tomography (CT) results, EUS findings, and CFA results were reviewed retrospectively. Statistical analysis was performed to determine variables associated with surgery versus observation. RESULTS: Over 33 months, data on 194 consecutive patients referred for EUS for evaluation of pancreatic cysts were analyzed. Of these, 136 (70 %) patients had EUS-FNA. After the initial workup (including EUS with/without CFA), 35 (18 %) underwent surgery. Predictors of surgery were: younger age (< 65 years) (P = 0.0027), malignant appearance at EUS (P = 0.02), and history of EUS-FNA (P = 0.012). Cyst fluid appearance, and carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and amylase levels were not significant determinants of surgery. In 14/50 (28 %) of cases where EUS-CFA clearly suggested benign serous lesions, surgery was still performed and in 9/11 (82 %) of cases with malignant EUS-CFA findings, surgery was not done. CONCLUSIONS: In patients with pancreatic cysts referred for EUS, age and EUS appearance independently predict surgery. The "perceived need for EUS-CFA" also predicts surgery, but not the EUS-CFA results. The clinical value of EUS-CFA requires further study. PMID- 21611944 TI - Comparative study of bipolar eletrocoagulation versus argon plasma coagulation for rectal bleeding due to chronic radiation coloproctopathy. AB - BACKGROUND AND STUDY AIM: Chronic radiation coloproctopathy (CRCP) is a well recognized complication of radiotherapy, with rectal bleeding the most common presentation. It is frequently refractory to conservative management, but the optimal endoscopic treatment of bleeding secondary to CRCP is still controversial. The efficacy and safety of bipolar eletrocoagulation (BEC) and argon plasma coagulation (APC) in the management of bleeding from CRCP were evaluated and compared. PATIENTS AND METHODS: 30 patients (mean age 67.4 years) with active and chronic bleeding from telangiectasias, were randomly allocated to BEC or APC and stratified by severity of CRCP according to clinical severity and endoscopic findings (Saunders score). Success was defined as eradication of all telangiectasias, and therapeutic failure as need for more than seven sessions or for other treatment. Complications were categorized as minor (e.g. fever, anal or abdominal pain) or major (hemorrhagic). RESULTS: Both treatments were equally effective for the treatment of CRCP rectal bleeding. Only one failure was observed in each group (P = 1.000). There was no significant difference between the two groups regarding number of sessions, minor or major complications, or relapse. However, overall complication rate was significantly higher in the BEC group (P = 0.003). CONCLUSIONS: BEC and APC are both effective for the therapy of bleeding telangiectasias from CRCP. There are probably no major differences between them. Although APC seemed safer than BEC in this investigation, further studies, involving a much larger population, are needed to assess the complication rates and determine the best management option. PMID- 21611945 TI - Endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesions provides inadequate material for cytology and laboratory analysis: initial results from a prospective study. AB - BACKGROUND AND STUDY AIMS: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is considered a valuable and safe technique for further investigation of pancreatic cystic lesions. In the framework of a prospective study on the accuracy of EUS-FNA we report our initial technical results regarding puncture access, sample adequacy, and complications PATIENTS AND METHODS: Consecutive patients with indeterminate pancreatic cystic lesions underwent EUS and EUS-FNA. Pancreatic cyst fluid was collected for cytopathological analysis and measurement of amylase, carcinoembryonic antigen (CEA), and carbohydrate antigen 19.9 (CA 19.9) levels. Main outcome parameter for this analysis was the percentage of samples adequate for cytologic and laboratory analysis. RESULTS: Of 143 patients (median age 63 years; median cyst size 2.8 cm) who underwent EUS, FNA was performed in 128 (90 %). The various reasons for not doing FNA included large distance between transducer and cystic lesion (n = 9), cyst not seen or too small (n = 2), and evident diagnosis not requiring FNA (n = 3). FNA was not possible in four patients (technical failures). Cyst fluid sent for cytology provided adequate cellular material in 44 cases only, accounting for an intention-to diagnose yield of 31 % (44/143). Sufficient fluid for biochemical analysis was obtained in 68 cases (49 %). Complications occurred in three patients (2.4 %). CONCLUSIONS: Although EUS-guided FNA was technically feasible in the majority of patients with pancreatic cystic lesions (87 %), it was possible to obtain a classifying cytopathologic diagnosis and a chemical analysis in only a third and a half of cases, respectively. PMID- 21611946 TI - A randomized clinical trial comparing 22G and 25G needles in endoscopic ultrasound-guided fine-needle aspiration of solid lesions. AB - BACKGROUND AND STUDY AIMS: The study aimed to investigate whether the 25G needle is superior to the 22G needle when used in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of solid lesions. PATIENTS AND METHODS: The study was a single-center randomized clinical trial. The setting was a tertiary referral hospital, where EUS-FNA of solid lesions was assisted by an on-site cytopathologist, who was blinded to the needle size. The main end point was the number of passes performed to obtain adequate samples. Crossover to the other type of needle was allowed after five passes, or when the gastroenterologist experienced difficulties in puncturing the lesions. RESULTS: A total of 129 solid lesions were randomized and data regarding 127 lesions were analyzed. The mean number of passes was 3.7 (+/- 1.9) in the 22G needle group and 3.8 (+/- 2) in the 25G needle groups (difference of means: 0.1; 95% CI: -0.59 to 0.79). Fifty-eight of 63 (92.1%) and 60/64 samples (93.7%) in the 22G and 25G needle groups respectively were adequate (difference: -1.6%; 95%CI: -12.1% to 8.9%). Crossover to the other type of needle was performed in 11/63 (17.5%) and in 12/64 (18.7%) lesions in the two groups respectively (difference: -1.2%; 95%CI: -16.2% to 13.8%). A crossover to the 25G needle was successfully performed in four masses in the uncinate process; these lesions were difficult to puncture using the 22G needle. CONCLUSIONS: Our study failed to demonstrate that the 25G is more effective than the 22G needle in EUS-FNA of solid lesions. However, targeting of lesions in the distal duodenum may be simplified by using the 25G needle. PMID- 21611947 TI - The water method significantly enhances patient-centered outcomes in sedated and unsedated colonoscopy. AB - Failure of cecal intubation when using air insufflation during scheduled unsedated colonoscopy in veterans prompted a literature search for a less uncomfortable approach. Water-related maneuvers as "adjuncts" to air insufflation were identified as effective in minimizing discomfort, although medication requirement was not reduced and willingness to repeat unsedated colonoscopy was not addressed. These adjunct maneuvers were combined with turning the air pump off to avoid colon elongation during insertion. Warm water infusion in lieu of air insufflation was evaluated in observational studies. Subsequent refinements evolved into the water method - a combination of air exclusion by aspiration of residual air to minimize angulations at flexures and a dynamic process of water exchange to remove feces in order to clear the view and aid insertion. In subsequent randomized controlled trials, the water method significantly reduced medication requirement, increased the proportion of patients in whom complete unsedated colonoscopy could be achieved, reduced patient recovery time burdens (sedation on demand), decreased abdominal discomfort during and after colonoscopy, enhanced cecal intubation, and increased willingness to repeat the procedure (scheduled unsedated). Supervised education of trainees and self learning by an experienced colonoscopist were feasible. Lessons learned in developing the water method for optimizing patient-centered outcomes are presented. These proof-of-principle observations merit further research assessment in diverse settings. PMID- 21611948 TI - Establishment of pure NOTES procedure using a conventional flexible endoscope: review of six cases of gastric gastrointestinal stromal tumors. AB - An increasing number of reports have recently been published on hybrid natural orifice transluminal endoscopic surgery (NOTES). These reports do not address how to complete an operation with a flexible endoscope alone (pure NOTES), but rather how to combine use of an endoscope and a laparoscope. Surgical procedures using flexible and rigid endoscopes have been developed using different processes and concepts. Recognizing this conceptual difference, we conducted a study to address how to establish a pure NOTES procedure. Six patients with gastric gastrointestinal stromal tumors (GISTs) underwent hybrid NOTES. Each case was retrospectively reviewed to determine the appropriateness of the treatment and the usefulness of the endoscopic submucosal dissection (ESD) method, double-scope method, spaced perforation method, duodenal balloon occlusion method, and loop clip technique. The development of operative procedures that take advantage of the characteristics of flexible endoscopes, even with conventional flexible endoscopic devices and conventional endoscopes alone, may contribute to the realization of pure NOTES. PMID- 21611949 TI - Microvascular free flap reconstruction of skull base penetrating tumors. AB - This is a follow-up study of 31 consecutive patients who underwent skull base tumor resection and microvascular tissue reconstruction in anterior and middle cranial fossa. Parameters recorded included factors related to operation, hospital stay, and outcome. All patients had a minimum follow-up of 5 years. There were no flap losses and no reoperations due to anastomoses-related complications. Five of 30 patients had cerebrospinal fluid leak that resolved with spinal drain except in one case, where the flap was placed incorrectly and the patient died of meningitis. Two other patients died due to early complications of the surgery. Although the complication rate was quite high, we consider this type of surgery worth performing, and even palliative surgery is to be considered in selective cases. Rectus abdominis flap due to its pliability and long pedicle proved to be most suitable flap together with superficial temporal artery and vein as recipient vessels. PMID- 21611950 TI - An optimized method of vessel dissection in establishment of the rat aortic transplantation model. AB - The high demand for microsurgical skills in those without a strong microsurgery background limits the application of the rat aortic transplant model to transplantation research. In this study, we established a rat aortic transplant model using a hydrodissection technique as a minimal-touch technique in vessel dissection. Eighty male Sprague Dawley rats were randomly divided into two groups with equal numbers. In the experimental group, abdominal aortas were harvested using hydrodissection; in the control group, instrumental dissection was used. The harvested aortas were transplanted orthotopically. The mean harvesting and implanting time in the experimental group was significantly lower than that of the control group (11.8 +/- 1.51 versus 23.8 +/- 3.38 minutes, P < 0.01; 46 +/- 6.07 versus 58.85 +/- 5.31 minutes, P < 0.01). Surgical complications in the control group included inferior vena cava injury (2/20), arterial vasospasm (3/20), and arterial wall hemorrhage (1/10). None of these complications were observed in the hydrodissection group. The overall frequency of surgical complications in the hydrodissection group was significantly lower than that in the control group ( P < 0.05). This study suggested that the hydrodissection technique is a fast and safe method of vessel dissection. This technique requires less microsurgical skills and optimizes the establishment of the rat aortic transplant model. PMID- 21611953 TI - Reducing charging effects in scanning electron microscope images by Rayleigh contrast stretching method (RCS). AB - To reduce undesirable charging effects in scanning electron microscope images, Rayleigh contrast stretching is developed and employed. First, re-scaling is performed on the input image histograms with Rayleigh algorithm. Then, contrast stretching or contrast adjustment is implemented to improve the images while reducing the contrast charging artifacts. This technique has been compared to some existing histogram equalization (HE) extension techniques: recursive sub image HE, contrast stretching dynamic HE, multipeak HE and recursive mean separate HE. Other post processing methods, such as wavelet approach, spatial filtering, and exponential contrast stretching, are compared as well. Overall, the proposed method produces better image compensation in reducing charging artifacts. PMID- 21611954 TI - The history and development of the helium ion microscope. AB - The helium ion microscope has recently emerged as a commercially available instrument. However, its roots go back more than 60 years to the development of the field ion microscope in Berlin, first reported in 1951. Over the intervening years, numerous researchers have pursued the development of a gas field ionization source with the goal of producing a suitable source for an ion microscope. This proved to be an elusive goal until early in this century when a number of discoveries led to a successful source, and shortly thereafter, an instrument fully able to exploit its advantages. Many individuals and many technical advances have come together to make this new class of microscope. The long history of this quest is reviewed along with the recent advances that led to the achievement of this milestone. A brief summary of the current status of the technology and its applications are given. PMID- 21611956 TI - Comments on de Vocht et al. "Time trends (1998-2007) in brain cancer incidence rates in relation to mobile phone use in England". PMID- 21611957 TI - Evaluating markers for treatment selection based on survival time. AB - For many medical conditions, several treatment options may be available for treating patients. We consider evaluating markers based on a simple treatment selection policy that incorporates information on the patient's marker value. For example, colon cancer patients may be treated by surgery alone or surgery plus chemotherapy. The c-myc gene expression level may be used as a biomarker for treatment selection. Although traditional regression methods may assess the effect of the marker and treatment on outcomes, it is more appealing to quantify directly the potential impact on the population of using the marker to select treatment. A useful tool is the selection impact (SI) curve proposed by Song and Pepe for binary outcomes (Biometrics 2004; 60:874-883). However, the current SI method does not deal with continuous outcomes, nor does it allow to adjust for other covariates that are important for treatment selection. In this paper, we extend the SI curve for general outcomes, with a specific focus on survival time. We further propose the covariate-specific SI curve to incorporate covariate information in treatment selection. Nonparametric and semiparametric estimators are developed accordingly. We show that the proposed estimators are consistent and asymptotically normal. The performance is assessed by simulation studies and illustrated through an application to data from a cancer clinical trial. PMID- 21611958 TI - The use of restricted mean survival time to estimate the treatment effect in randomized clinical trials when the proportional hazards assumption is in doubt. AB - In most randomized clinical trials (RCTs) with a right-censored time-to-event outcome, the hazard ratio is taken as an appropriate measure of the effectiveness of a new treatment compared with a standard-of-care or control treatment. However, it has long been known that the hazard ratio is valid only under the proportional hazards (PH) assumption. This assumption is formally checked only rarely. Some recent trials, particularly the IPASS trial in lung cancer and the ICON7 trial in ovarian cancer, have alerted researchers to the possibility of gross non-PH, raising the critical question of how such data should be analyzed. Here, we propose the use of the restricted mean survival time at a prespecified, fixed time point as a useful general measure to report the difference between two survival curves. We describe different methods of estimating it and we illustrate its application to three RCTs in cancer. The examples are graded from a trial in kidney cancer in which there is no evidence of non-PH, to IPASS, where the opposite is clearly the case. We propose a simple, general scheme for the analysis of data from such RCTs. Key elements of our approach are Andersen's method of 'pseudo-observations,' which is based on the Kaplan-Meier estimate of the survival function, and Royston and Parmar's class of flexible parametric survival models, which may be used for analyzing data in the presence or in the absence of PH of the treatment effect. PMID- 21611959 TI - Genome-scale techniques highlight the epigenome and redefine fundamental principles of gene regulation. AB - The regulation of gene expression represents one of the most fundamental of biologic processes that controls cellular proliferation, differentiation, and function. Recent technological advances in genome-wide annotation together with bioinformatic/computational analyses have contributed significantly to our understanding of transcriptional regulation at the epigenomic and regulomic levels. This perspective outlines the techniques that are being utilized and summarizes a few of the outcomes. PMID- 21611960 TI - BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment. AB - Heterotopic ossification (HO) is defined as the formation of bone inside soft tissue. Symptoms include joint stiffness, swelling, and pain. Apart from the inherited form, the common traumatic form generally occurs at sites of injury in damaged muscles and is often associated with brain injury. We investigated bone morphogenetic protein 9 (BMP-9), which possesses a strong osteoinductive capacity, for its involvement in muscle HO physiopathology. We found that BMP-9 had an osteoinductive influence on mouse muscle resident stromal cells by increasing their alkaline phosphatase activity and bone-specific marker expression. Interestingly, BMP-9 induced HO only in damaged muscle, whereas BMP-2 promoted HO in skeletal muscle regardless of its state. The addition of the soluble form of the ALK1 protein (the BMP-9 receptor) significantly inhibited the osteoinductive potential of BMP-9 in cells and HO in damaged muscles. BMP-9 thus should be considered a candidate for involvement in HO physiopathology, with its activity depending on the skeletal muscle microenvironment. PMID- 21611961 TI - Biphasic effects of transforming growth factor beta on bone morphogenetic protein induced osteoblast differentiation. AB - Bone morphogenetic proteins (BMPs) exert an important role in skeletal development, adult bone homeostasis, and fracture healing and have demonstrated clinical utility for bone regeneration. However, BMPs fall short as regenerative agents because high doses need to be used to obtain therapeutic effects. Determining the molecular mechanisms controlling BMP-induced bone formation may lead to the development of more effective BMP-based therapies. To identify kinases mediating BMP-induced osteoblast differentiation, we performed an siRNA screen to find kinases modulating BMP-6-induced alkaline phosphatase (ALP) activity. Surprisingly, although transforming growth factor beta (TGF-beta) generally is considered to antagonize BMP-induced osteoblast differentiation, C2C12 cells transfected with siRNAs targeting TGF-beta receptors displayed reduced BMP-6-induced ALP activity. Furthermore, pharmacologic inhibitors blocking the TGF-beta type I receptor impaired BMP-induced ALP activity in KS483 and C2C12 cells and mineralization of KS483 cells. Consistently, costimulation with BMPs and TGF-beta further increased expression of osteoblast-specific genes, ALP activity, and mineralization of KS483 cells and primary mesenchymal stem cells compared with BMPs alone. The stimulatory and inhibitory effects of TGF beta were found to depend on timing and duration of the costimulation. TGF-beta inhibited BMP-induced activation of a BMP-Smad-dependent luciferase reporter, suggesting that the stimulatory effect of TGF-beta is not due to increased BMP Smad activity. TGF-beta also inhibited the BMP-induced expression of the BMP antagonist noggin and prolonged BMP activity. In conclusion, TGF-beta, besides acting as an inhibitor, also can, by dampening the noggin-mediated negative feedback loop, enhance BMP-induced osteoblast differentiation, which might be beneficial in fracture healing. PMID- 21611962 TI - Hyperlipidemia induces resistance to PTH bone anabolism in mice via oxidized lipids. AB - In hyperlipidemia, oxidized lipids accumulate in vascular tissues and trigger atherosclerosis. Such lipids also deposit in bone tissues, where they may promote osteoporosis. We found previously that oxidized lipids attenuate osteogenesis and that parathyroid hormone (PTH) bone anabolism is blunted in hyperlipidemic mice, suggesting that osteoporotic patients with hyperlipidemia may develop resistance to PTH therapy. To determine if oxidized lipids account for this PTH resistance, we blocked lipid oxidation products in hyperlipidemic mice with an ApoA-I mimetic peptide, D-4F, and the bone anabolic response to PTH treatment was assessed. Skeletally immature Ldlr(-/-) mice were placed on a high-fat diet and treated with D-4F peptide and/or with intermittent PTH(1-34) injections. As expected, D 4F attenuated serum lipid oxidation products and tissue lipid deposition induced by the diet. Importantly, D-4F treatment attenuated the adverse effects of dietary hyperlipidemia on PTH anabolism by restoring micro-computed tomographic parameters of bone quality-cortical mineral content, area, and thickness. D-4F significantly reduced serum markers of bone resorption but not bone formation. PTH and D-4F, together but not separately, also promoted bone anabolism in an alternative model of hyperlipidemia, Apoe(-/-) mice. In normolipemic mice, D-4F cotreatment did not further enhance the anabolic effects of PTH, indicating that the mechanism is through its effects on lipids. These findings suggest that oxidized lipids mediate hyperlipidemia-induced PTH resistance in bone through modulation of bone resorption. PMID- 21611963 TI - Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow. AB - Parathyroid hormone (PTH) increases both the number of osteoclast in bone and the number of early hematopoietic stem cells (HSCs) in bone marrow. We previously characterized the phenotype of multiple populations of bone marrow cells with in vitro osteoclastogenic potential in mice. Here we examined whether intermittent administration of PTH influences these osteoclast progenitor (OCP) populations. C57BL/6 mice were treated with daily injections of bPTH(1-34) (80 ug/kg/day) for 7 or 14 days. We found that PTH caused a significant increase in the percentage of TN/CD115(+) CD117(high) and TN/CD115(+) CD117(int) cells (p < .05) in bone marrow on day 7. In contrast, PTH decreased the absolute number of TN/CD115(+) CD117(low) cells by 39% on day 7 (p < .05). On day 14, there was no effect of PTH on osteoclast progenitor distribution in vivo. However, PTH treatment for 7 and 14 days did increase receptor activator of NF-kappaB ligand (RANKL)- and macrophage colony-stimulating factor (M-CSF)-stimulated in vitro osteoclastogenesis and bone resorption in TN/CD115(+) cells. In the periphery, 14 days of treatment increased the percentage and absolute numbers of HSCs (Lin(-) CD117(+) Sca-1(+) ) in the spleen (p < .05). These data correlated with an increase in the percent and absolute numbers of HSCs in bone marrow on day 14 (p < .05). Interestingly, the effects on hematopoietic progenitors do not depend on osteoclast resorption activity. These results suggest that in vivo PTH treatment increased in vitro osteoclastogenesis and resorption without altering the number of osteoclast precursors. This implies that in vivo PTH induces sustained changes, possibly through an epigenetic mechanism, in the in vitro responsiveness of the cells to M-CSF and RANKL. PMID- 21611964 TI - Adenylate cyclase and calmodulin-dependent kinase have opposite effects on osteoclastogenesis by regulating the PKA-NFATc1 pathway. AB - Nuclear factor of activated T cells c1 (NFATc1) is a transcription factor crucial for the differentiation of osteoclasts. In this study we discovered new signaling pathways involving cAMP regulators that modulate NFATc1 during osteoclastogenesis. The osteoclast differentiation factor receptor activator of NF-kappaB ligand (RANKL) increased the expression of adenylate cyclase 3 (AC3), accompanied by a rise in the intracellular cAMP level in osteoclasts. The knockdown of AC3 enhanced in vitro osteoclastogenesis and in vivo bone resorption, whereas cAMP-elevating agents showed opposite effects. The antiosteoclastogenic effect of the AC3-cAMP pathway was mediated by the inhibition of NFATc1 nuclear translocation and its autoamplification via a protein kinase A (PKA)-dependent mechanism. RANKL has been shown to activate Ca(2+) /calmodulin-dependent protein kinases (CaMKs). Knockdown or catalytic inhibition of CaMKs elevated intracellular cAMP levels in RANKL-treated osteoclast precursors and suppressed the activation of NFATc1. Taken together, our results demonstrate a pivotal role for the cAMP-PKA-NFATc1 signaling pathway during osteoclast differentiation, suggesting a mechanism by which osteoclastogenesis is fine-tuned by a balance between AC3 and CaMKs activities. PMID- 21611965 TI - Nfatc2 is a primary response gene of Nell-1 regulating chondrogenesis in ATDC5 cells. AB - Nell-1 is a growth factor required for normal skeletal development and expression of extracellular matrix proteins required for bone and cartilage cell differentiation. We identified the transcription factor nuclear factor of activated T cells (Nfatc2) as a primary response gene of Nell-1 through a microarray screen, with validation using real-time polymerase chain reaction (PCR). We investigated the effects of recombinant Nell-1 protein on the chondrogenic cell line ATDC5 and primary mouse chondrocytes. The osteochondral transcription factor Runx2 was investigated as a possible intermediary between Nell-1 and Nfatc2 using adenoviral overexpression of wild-type and dominant negative Runx2. Nell-1 transiently induced both transcription and translation of Nfatc2, an effect inhibited by transduction of dominant-negative Runx2, suggesting that Runx2 was necessary for Nfatc2 induction. Differentiation assays revealed inhibitory effects of Nell-1 on ATDC5 cells. Although proliferation was unaffected, expression of chondrocyte-specific genes was decreased, and cartilage nodule formation and proteoglycan accumulation were suppressed. siRNA knockdown of Nfatc2 significantly reversed these inhibitory effects. To elucidate the relationship between Nell-1, Runx2, and Nfatc2 in vivo, their presence and distribution were visualized in femurs of wild-type and Nell1-deficient mice at both neonatal and various developmental stages using immunohistochemistry. All three proteins colocalized in the perichondrium of wild-type femurs but stained weakly or were completely absent in Nell1-deficient femurs at neonatal stages. Thus Nfatc2 likely plays an important role in Nell-1-mediated osteochondral differentiation in vitro and in vivo. To our knowledge, this is the first demonstration that Nfatc2 is a primary response gene of Nell-1. PMID- 21611966 TI - Differential effects between the loss of MMP-2 and MMP-9 on structural and tissue level properties of bone. AB - Matrix metalloproteinases (MMPs) are capable of processing certain components of bone tissue, including type 1 collagen, a determinant of the biomechanical properties of bone tissue, and they are expressed by osteoclasts and osteoblasts. Therefore, we posit that MMP activity can affect the ability of bone to resist fracture. To explore this possibility, we determined the architectural, compositional, and biomechanical properties of bones from wild-type (WT), Mmp2(-/ ) , and Mmp9(-/-) female mice at 16 weeks of age. MMP-2 and MMP-9 have similar substrates but are expressed primarily by osteoblasts and osteoclasts, respectively. Analysis of the trabecular compartment of the tibia metaphysis by micro-computed tomography (uCT) revealed that these MMPs influence trabecular architecture, not volume. Interestingly, the loss of MMP-9 improved the connectivity density of the trabeculae, whereas the loss of MMP-2 reduced this parameter. Similar differential effects in architecture were observed in the L(5) vertebra, but bone volume fraction was lower for both Mmp2(-/-) and Mmp9(-/-) mice than for WT mice. The mineralization density and mineral-to-collagen ratio, as determined by uCT and Raman microspectroscopy, were lower in the Mmp2(-/-) bones than in WT control bones. Whole-bone strength, as determined by three-point bending or compression testing, and tissue-level modulus and hardness, as determined by nanoindentation, were less for Mmp2(-/-) than for WT bones. In contrast, the Mmp9(-/-) femurs were less tough with lower postyield deflection (more brittle) than the WT femurs. Taken together, this information reveals that MMPs play a complex role in maintaining bone integrity, with the cell type that expresses the MMP likely being a contributing factor to how the enzyme affects bone quality. PMID- 21611967 TI - Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome-wide associations. AB - Genome-wide association studies (GWAS) using high-density genotyping platforms offer an unbiased strategy to identify new candidate genes for osteoporosis. It is imperative to be able to clearly distinguish signal from noise by focusing on the best phenotype in a genetic study. We performed GWAS of multiple phenotypes associated with fractures [bone mineral density (BMD), bone quantitative ultrasound (QUS), bone geometry, and muscle mass] with approximately 433,000 single-nucleotide polymorphisms (SNPs) and created a database of resulting associations. We performed analysis of GWAS data from 23 phenotypes by a novel modification of a block clustering algorithm followed by gene-set enrichment analysis. A data matrix of standardized regression coefficients was partitioned along both axes--SNPs and phenotypes. Each partition represents a distinct cluster of SNPs that have similar effects over a particular set of phenotypes. Application of this method to our data shows several SNP-phenotype connections. We found a strong cluster of association coefficients of high magnitude for 10 traits (BMD at several skeletal sites, ultrasound measures, cross-sectional bone area, and section modulus of femoral neck and shaft). These clustered traits were highly genetically correlated. Gene-set enrichment analyses indicated the augmentation of genes that cluster with the 10 osteoporosis-related traits in pathways such as aldosterone signaling in epithelial cells, role of osteoblasts, osteoclasts, and chondrocytes in rheumatoid arthritis, and Parkinson signaling. In addition to several known candidate genes, we also identified PRKCH and SCNN1B as potential candidate genes for multiple bone traits. In conclusion, our mining of GWAS results revealed the similarity of association results between bone strength phenotypes that may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in identifying novel genes and pathways that underlie several correlated phenotypes, as well as in deciphering genetic and phenotypic modularity underlying osteoporosis risk. PMID- 21611968 TI - Osteoprotegerin deficiency attenuates strontium-mediated inhibition of osteoclastogenesis and bone resorption. AB - Strontium (Sr) exerts an anabolic and antiresorptive effect on bone, but the mechanism remains unknown. Osteoprotegerin (OPG) expressed by osteoblasts plays an important role in regulating bone homeostasis by inhibiting osteoclastogenesis and bone resorption. This study aims at evaluating the role of OPG in Sr-mediated inhibition of osteoclastogenesis and bone resorption. Six-week-old Opg knockout (KO) male mice and their wild-type (WT) littermates were treated orally with vehicle (Veh) or Sr compound (4 mmol/kg) daily for 8 weeks. Bone mass and microstructure in the lumbar spine (L(4)) and proximal tibia were analyzed with micro-computed tomography (uCT). Bone remodeling was evaluated with serum biochemical analysis and static and dynamic bone histomorphometry. Osteoclast differentiation potential and gene expression were analyzed in bone marrow cells. The findings demonstrate that Sr compound treatment results in greater bone volume and trabecular number than Veh treatment in WT mice. The anabolic response of trabecular bone to Sr treatment is attenuated in KO mice. Although Sr treatment significantly decreases in vitro osteoclastogenesis and bone resorption in WT mice, these effects are attenuated in KO mice. Furthermore, Sr treatment profoundly increases Opg gene expression in the tibias and OPG protein levels in the sera of WT mice. This study concludes that the inhibition of osteoclastogenesis and bone resorption is possibly associated with OPG upregulation by Sr treatment. PMID- 21611969 TI - Selective venous catheterization for the localization of phosphaturic mesenchymal tumors. AB - Tumor-induced osteomalacia (TIO) is characterized by renal phosphate wasting, hypophosphatemia, and aberrant vitamin D(3) metabolism and is caused by fibroblast growth factor 23 (FGF-23)-producing mesenchymal tumors, which are often difficult to locate. We investigated the utility of selective venous sampling in tumor localization. The primary endpoint was identification of the FGF-23 concentration ratio between the venous drainage of the tumor bed and the general circulation that was diagnostic of the location of an FGF-23-secreting tumor. Fourteen subjects underwent 15 sampling procedures after functional and anatomic imaging studies. Subjects fit into three imaging categories: no suspicious site, multiple sites, and single site (positive controls). FGF-23 levels were measured by ELISA. Suspicious tumors were resected for diagnosis, confirmation, and cure. In subjects with a positive venous sampling study and subsequent cure, a minimum ratio of 1.6 was diagnostic. In 7 of 14 subjects there was suggestive imaging, a diagnostic ratio, and an associated TIO tumor (true positive). Four of these required complicated resection procedures. In 4 of 14 subjects with no suspicious site on imaging studies, an FGF-23 diagnostic ratio was not detected (true negative). Biopsy or resection of a single lesion in 2 of 14 subjects with a diagnostic ratio failed to identify a TIO tumor (false positive). A diagnostic FGF-23 ratio was absent in 1 of 14 subjects whose tumor was a single highly suspicious lesion on imaging studies (false negative). These data yield a sensitivity of 0.87 [95% confidence interval (CI) 0.47-0.99] and a specificity of 0.71 (95% CI 0.29-0.96). Selective venous sampling for FGF-23 was particularly useful in subjects with multiple suspicious sites or an anatomically challenging planned resection but not in the absence of a suspicious lesion on imaging studies. PMID- 21611970 TI - Effects of repetitive loading on the growth-induced changes in bone mass and cortical bone geometry: a 12-month study in pre/peri- and postmenarcheal tennis players. AB - Pre- and early puberty may be the most opportune time to strengthen the female skeleton, but there are few longitudinal data to support this claim. Competitive female premenarcheal (pre/peri, n = 13) and postmenarcheal (post, n = 32) tennis players aged 10 to 17 years were followed over 12 months. The osteogenic response to loading was studied by comparing the playing and nonplaying humeri for dual energy X-ray absorptiometry (DXA) bone mineral content (BMC) and magnetic resonance imaging (MRI) total bone area (ToA), medullary area (MedA), cortical area (CoA), and muscle area (MCSA) at the humerus. Over 12 months, growth-induced gains (nonplaying arm) in BMC, ToA, and CoA were greater in pre/peri (10% to 19%, p < .001) than in post (3% to 5%, p < .05 to .001) players. At baseline, BMC, ToA, CoA, and MCSA were 8% to 18% greater in the playing versus nonplaying arms in pre/peri and post players (all p < .001); MedA was smaller in the playing versus nonplaying arms in post only players (p < .05). When comparing the annual gains in the playing arm relative to changes in the nonplaying arm, the increases in ToA and CoA were greater in pre/peri than post players (all p < .05). The smaller the side-to-side differences in BMC and CoA at baseline, the larger the exercise benefits at 12 months (r = -0.39 to -0.48, p < .01). The exercise induced change in MCSA was predictive of the exercise benefits in BMC in pre/peri players only (p < .05). In conclusion, both pre/peri- and postmenarcheal tennis players showed significant exercise-induced skeletal benefits within a year, with greater benefits in cortical bone geometry in pre/perimenarcheal girls. PMID- 21611971 TI - Body mass index and physical activity in relation to the incidence of hip fracture in postmenopausal women. AB - Hip fracture risk is known to increase with physical inactivity and decrease with obesity, but there is little information on their combined effects. We report on the separate and combined effects of body mass index (BMI) and physical activity on hospital admissions for hip fracture among postmenopausal women in a large prospective UK study. Baseline information on body size, physical activity, and other relevant factors was collected in 1996-2001, and participants were followed for incident hip fractures by record linkage to National Health Service (NHS) hospital admission data. Cox regression was used to calculate adjusted relative risks of hip fracture. Among 925,345 postmenopausal women followed for an average of 6.2 years, 2582 were admitted to hospital with an incident hip fracture. Hip fracture risk increased with decreasing BMI: Compared with obese women (BMI of 30+ kg/m(2) ), relative risks were 1.71 [95% confidence interval (CI) 1.47-1.97)] for BMI of 25.0 to 29.9 kg/m(2) and 2.55 (95% CI 2.22-2.94) for BMI of 20.0 to 24.9 kg/m(2). The increase in fracture risk per unit decrease in BMI was significantly greater among lean women than among overweight women (p < .001). For women in every category of BMI, physical inactivity was associated with an increased risk of hip fracture. There was no significant interaction between the relative effects of BMI and physical activity. For women who reported that they took any exercise versus no exercise, the adjusted relative risk of hip fracture was 0.68 (95% CI 0.62-0.75), with similar results for strenuous exercise. In this large cohort of postmenopausal women, BMI and physical activity had independent effects on hip fracture risk. PMID- 21611972 TI - Areal and volumetric bone mineral density and geometry at two levels of protein intake during caloric restriction: a randomized, controlled trial. AB - Weight reduction induces bone loss by several factors, and the effect of higher protein (HP) intake during caloric restriction on bone mineral density (BMD) is not known. Previous study designs examining the longer-term effects of HP diets have not controlled for total calcium intake between groups and have not examined the relationship between bone and endocrine changes. In this randomized, controlled study, we examined how BMD (areal and volumetric), turnover markers, and hormones [insulin-like growth factor 1 (IGF-1), IGF-binding protein 3 (IGFBP 3), 25-hydroxyvitamin D, parathyroid hormone (PTH), and estradiol] respond to caloric restriction during a 1-year trial using two levels of protein intake. Forty-seven postmenopausal women (58.0 +/- 4.4 years; body mass index of 32.1 +/- 4.6 kg/m(2) ) completed the 1-year weight-loss trial and were on a higher (HP, 24%, n = 26) or normal protein (NP, 18%, n = 21) and fat intake (28%) with controlled calcium intake of 1.2 g/d. After 1 year, subjects lost 7.0% +/- 4.5% of body weight, and protein intake was 86 and 60 g/d in the HP and NP groups, respectively. HP compared with NP diet attenuated loss of BMD at the ultradistal radius, lumbar spine, and total hip and trabecular volumetric BMD and bone mineral content of the tibia. This is consistent with the higher final values of IGF-1 and IGFBP-3 and lower bone-resorption marker (deoxypyridinoline) in the HP group than in the NP group (p < .05). These data show that a higher dietary protein during weight reduction increases serum IGF-1 and attenuates total and trabecular bone loss at certain sites in postmenopausal women. PMID- 21611973 TI - Agreement between pQCT- and DXA-derived indices of bone geometry, density, and theoretical strength in females of varying age, maturity, and physical activity. AB - Measurement of bone mass, geometry, density, and strength are critical in bone research and clinical studies. For peripheral quantitative computed tomography (pQCT), single and repeated measurements are particularly adversely affected by movement and positional variation. Dual-energy X-ray absorptiometry (DXA)-derived indices may alleviate these problems and provide useful alternative assessments. To evaluate this hypothesis, distal radius DXA and pQCT indices were compared in 101 healthy females aged 8.0 to 22.8 years (prepuberty to adulthood), reflecting a broad range of body sizes, physical maturity, and activity exposures. At the diaphysis, correlations were rho = +0.74 to +0.98, with strong intermethod agreement for most indices. At the metaphysis, correlations were rho = +0.64 to +0.97; intermethod agreement improved with modifications to the simplified geometric formulas more closely reflecting metaphyseal bone geometry. Further improvements may be possible because skeletal size and maturity-related biases in agreement were detected. Overall, DXA-derived indices may provide a useful assessment of bone geometry, density, and theoretical strength contingent on appropriate consideration of their limitations. PMID- 21611974 TI - Cross-sectional analysis of the association between fragility fractures and bone microarchitecture in older men: the STRAMBO study. AB - Areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) identifies 20% of men who will sustain fragility fractures. Thus we need better fracture predictors in men. We assessed the association between the low trauma prevalent fractures and bone microarchitecture assessed at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 920 men aged 50 years of older. Ninety-eight men had vertebral fractures identified on the vertebral fracture assessment software of the Hologic Discovery A device using the semiquantitative criteria, whereas 100 men reported low-trauma peripheral fractures. Men with vertebral fractures had poor bone microarchitecture. However, in the men with vertebral fractures, only cortical volumetric density (D.cort) and cortical thickness (C.Th) remained significantly lower at both the radius and tibia after adjustment for aBMD of ultradistal radius and hip, respectively. Low D.cort and C.Th were associated with higher prevalence of vertebral fractures regardless of aBMD. Severe vertebral fractures also were associated with poor trabecular microarchitecture regardless of aBMD. Men with peripheral fractures had poor bone microarchitecture. However, after adjustment for aBMD, all microarchitectural parameters became nonsignificant. In 15 men with multiple peripheral fractures, trabecular spacing and distribution remained increased after adjustment for aBMD. Thus, in men, vertebral fractures and their severity are associated with impaired cortical bone, even after adjustment for aBMD. The association between peripheral fractures and bone microarchitecture was weaker and nonsignificant after adjustment for aBMD. Thus bone microarchitecture may be a determinant of bone fragility in men, which should be investigated in prospective studies. PMID- 21611975 TI - Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. AB - Renal osteodystrophy occurs early during loss of kidney function. There are 26 million American patients with chronic kidney disease (CKD), and almost all patients with CKD stage 5 have abnormal bone histology. Six hundred and thirty bone biopsies from adult CKD-5 patients on dialysis were evaluated by histomorphometry and analyzed using the turnover (T), mineralization (M), and volume (V) classification. There were racial differences; whites exhibited predominantly low turnover (62%), whereas blacks showed mostly normal or high turnover (68%). A mineralization defect was observed in only 3% of patients. In whites, cancellous bone volume was low, normal, or high in approximately the same number of patients, whereas in blacks, cancellous bone volume was high in two thirds of the patients. More than 80% of blacks and whites with low cancellous bone volume had thin trabeculae owing to low bone formation. Cortical thickness was low in half the whites, whereas it was normal in three-quarters of blacks. Cortical porosity was high in 50% of whites, whereas three-quarters of blacks had high porosity. In summary, the TMV system gives relevant information. It should be expanded to include the architecture of cancellous and cortical bone. There are racial differences. Low bone volume and low bone turnover are more frequent than heretofore appreciated, whereas mineralization defects nowadays are observed rarely in adults. These findings call for an adjustment of the current therapeutic paradigm that takes into consideration race and risk of low bone volume and turnover. The latter have been shown to be associated with increased vascular calcifications. PMID- 21611976 TI - An atypical subtrochanteric femoral fracture from pycnodysostosis: a lesson from nature. AB - This case describes a man with an unusual cause of an atypical subtrochanteric fracture, pycnodysostosis. This condition results from mutations involving the cathepsin K gene. New antiresorptive treatments for osteoporosis inhibit the cathepsin K enzyme in osteoclasts. Therefore, there should be vigilant monitoring for the development of long-term complications noted to occur in diseases of reduced osteoclast function, including pycnodysostosis, in patients receiving these novel antiresorptive agents. PMID- 21611977 TI - Graft-induced dyskinesias in Parkinson's disease: High striatal serotonin/dopamine transporter ratio. AB - Graft-induced dyskinesias are a serious complication after neural transplantation in Parkinson's disease. One patient with Parkinson's disease, treated with fetal grafts 14 years ago and deep brain stimulation 6 years ago, showed marked improvement of motor symptoms but continued to suffer from OFF-medication graft induced dyskinesias. The patient received a series of clinical and imaging assessments. Positron emission tomography and single-photon emission computed tomography 14 years posttransplantation revealed an elevated serotonin/dopamine transporter ratio in the grafted striatum compatible with serotonergic hyperinnervation. Inhibition of serotonin neuron activity by systemic administration of a 5-HT(1A) agonist suppressed graft-induced dyskinesias. Our data provide further evidence that serotonergic neurons mediate graft-induced dyskinesias in Parkinson's disease. Achieving a normal striatal serotonin/dopamine transporter ratio following transplantation of fetal tissue or stem cells should be necessary to avoid the development of graft-induced dyskinesias. PMID- 21611978 TI - Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson's disease. AB - The behavioral and cognitive features of the leucine-rich repeat kinase G2019S mutation in Parkinson's disease in the Ashkenazi Jewish population are not well described; therefore, we sought to more systematically characterize these features using a semistructured psychiatric interview and neuropsychological testing. Twenty-one Ashkenazi Jewish patients having the leucine-rich repeat kinase G2019S mutation were compared with age- and sex-matched Ashkenazi Jewish patients with Parkinson's disease without mutations. Although overall rates of affective disorders were not greater in mutation carriers, the carriers exhibited a 6-fold increased risk of premorbid affective disorders (odds ratio, 6.0; P = .10), as determined by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV. Of interest, we identified 2 leucine rich repeat kinase carriers with bipolar disorder; no mutation-negative subjects had this diagnosis. Performance on the Hopkins Verbal Learning Test-Revised, Judgment of Line Orientation, and Frontal Assessment Battery was consistent with previous reports and did not differ between groups. Study findings suggest a possible association between premorbid mood disorders and leucine-rich repeat kinase Parkinson's disease, warranting further evaluation. PMID- 21611979 TI - A tale of two factors: what determines the rate of progression in Huntington's disease? A longitudinal MRI study. AB - Over the past several years, increased attention has been devoted to understanding regionally selective brain changes that occur in Huntington's disease and their relationships to phenotypic variability. Clinical progression is also heterogeneous, and although CAG repeat length influences age of onset, its role, if any, in progression has been less clear. We evaluated progression in Huntington's disease using a novel longitudinal magnetic resonance imaging analysis. Our hypothesis was that the rate of brain atrophy is influenced by the age of onset of Huntington's disease. We scanned 22 patients with Huntington's disease at approximately 1-year intervals; individuals were divided into 1 of 3 groups, determined by the relative age of onset. We found significant differences in the rates of atrophy of cortex, white matter, and subcortical structures; patients who developed symptoms earlier demonstrated the most rapid rates of atrophy compared with those who developed symptoms during middle age or more advanced age. Rates of cortical atrophy were topologically variable, with the most rapid changes occurring in sensorimotor, posterior frontal, and portions of the parietal cortex. There were no significant differences in the rates of atrophy in basal ganglia structures. Although both CAG repeat length and age influenced the rate of change in some regions, there was no significant correlation in many regions. Rates of regional brain atrophy seem to be influenced by the age of onset of Huntington's disease symptoms and are only partially explained by CAG repeat length. These findings suggest that other genetic, epigenetic, and environmental factors play important roles in neurodegeneration in Huntington's disease. PMID- 21611980 TI - Subthalamic nucleus stimulation selectively improves motor and visual memory performance in Parkinson's disease. AB - Although the treatment of Parkinson's disease via subthalamic stimulation yields remarkable improvements in motor symptoms, its effects on memory function are less clear. In this context, we previously demonstrated dissociable effects of levodopa therapy on parkinsonian performance in spatial and nonspatial visual working memory. Here we used the same protocol with an additional, purely motor task to investigate visual memory and motor performance in 2 groups of patients with Parkinson's disease with or without subthalamic stimulation. In each stimulation condition, subjects performed a simple motor task and 3 successive cognitive tasks: 1 conditional color-response association task and 2 visual (spatial and nonspatial) working memory tasks. The Parkinson's groups were compared with a control group of age-matched healthy subjects. Our principal results demonstrated that (1) in the motor task, stimulated patients were significantly improved with respect to nonstimulated patients and did not differ significantly from healthy controls, and (2) in the cognitive tasks, stimulated patients were significantly improved with respect to nonstimulated patients, but both remained significantly impaired when compared with healthy controls. These results demonstrate selective effects of subthalamic stimulation on parkinsonian disorders of motor and visual memory functions, with clear motor improvement for stimulated patients and a partial improvement for their visual memory processing. PMID- 21611981 TI - Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. AB - We assessed the efficacy and tolerability of gabapentin enacarbil in the treatment of moderate to severe primary restless legs syndrome and associated sleep disturbance. This was a multicenter, randomized, double-blind, placebo controlled, 2-period crossover polysomnography study of gabapentin enacarbil 1200 mg or placebo taken once daily. Subjects were randomized 1:1 to a sequence of gabapentin enacarbil:placebo or placebo:gabapentin enacarbil, receiving each treatment for 4 weeks. The primary end point was the mean change from baseline at weeks 4 and 10 (4/10) last observation carried forward in wake time during sleep. The key secondary end point was the mean change from baseline at weeks 4/10 last observation carried forward in periodic limb movements associated with arousal per hour of sleep. Tolerability assessments included adverse events. One hundred thirty-six subjects were randomized (gabapentin enacarbil:placebo, 67; placebo:gabapentin enacarbil, 69), and 114 (gabapentin enacarbil:placebo, 53; placebo:gabapentin enacarbil, 61) completed the study. Gabapentin enacarbil 1200 mg significantly reduced wake time during sleep (mean change from baseline [adjusted mean treatment difference]: -26.0 minutes; P < .0001) and periodic limb movements associated with arousal per hour of sleep (adjusted mean treatment difference: -3.1 periodic limb movements with arousal/hour; P = .002) compared with placebo at weeks 4/10 last observation carried forward. The most commonly reported adverse events were dizziness (gabapentin enacarbil 20%, placebo 2%) and somnolence (gabapentin enacarbil 13%, placebo 2%). Gabapentin enacarbil 1200 mg once daily significantly reduces restless legs syndrome-associated sleep disturbance and periodic limb movements associated with arousal per hour of sleep and is generally well tolerated in adults with moderate to severe primary restless legs syndrome. PMID- 21611982 TI - Encephalitis lethargica due to Epstein-Barr virus infection. PMID- 21611983 TI - Olfactory deficits and cardiac 123I-MIBG in Parkinson's disease related to the LRRK2 R1441G and G2019S mutations. AB - It has been proposed that olfactory tests and metaiodobenzylguanidine cardiac scintigraphy may help diagnose idiopathic Parkinson's disease in the premotor phase. However, it is not clear what value these tests have in all patients with Parkinson's disease and, particularly, in those who carry mutations in LRRK2. The objective was to analyze olfactory dysfunction and the changes in cardiac I metaiodobenzylguanidine uptake in patients with Parkinson's disease carrying the R1441G and G2019S mutations in LRRK2, and in patients with Parkinson's disease with no known mutations. Patients with Parkinson's disease were screened for R1441G and G2019S LRRK2 gene mutations and classified as LRRK2 mutation carriers or noncarriers. A total of 190 patients with Parkinson's disease (44 LRRK2 mutation carriers) were tested for olfactory dysfunction using the Brief Smell Identification Test. Cardiac (123) I-metaiodobenzylguanidine scintigraphy was performed on 90 patients with Parkinson's disease (27 LRRK2 mutation carriers). Thirty-six percent of patients with LRRK2 mutations have hyposmia, compared to 75% of noncarrier patients with Parkinson's disease (P < .001). Sixty-six percent of LRRK2 mutation carriers have low early metaiodobenzylguanidine uptake, compared to 86% of noncarriers (P = .048). Similarly, the heart/mediastinum ratio in delayed metaiodobenzylguanidine images appeared to differ between these groups of patients with Parkinson's disease, although these results did not reach statistical significance. The data obtained indicate that olfactory and cardiac impairment is less prevalent when Parkinson's disease is associated with mutations in LRRK2, although the underlying mechanisms for this difference remain unclear. Thus, such screening would be less useful to detect the premotor phase in asymptomatic relatives who carry mutations in LRRK2 than in cases not associated with LRRK2. PMID- 21611984 TI - Pathological findings in a case of stiff person syndrome with anti-GAD antibodies. PMID- 21611986 TI - Synthesis, characterization, and photoactivity of Ta2O5-grafted SiO2 nanoparticles. AB - Herein, we discuss the synthesis as well as material and photochemical characterization of nanometer-sized Ta(2)O(5) decorated, in a controlled fashion, on top of 20 nm diameter SiO(2) particles to yield a composite oxide with a tunable band-gap width. Particular emphasis is paid to control of particle size, and control of the distribution of the overlying oxide. The nanoscale dimension imparts a high surface area and introduces quantum confinement effects that displace the conduction band more negatively and the valence band more positively on the electrochemical scale of potentials. This band shift results in an increase of the number of possible participants in photocatalytic reactions. The band shift is shown to result in an increase in driving force for thermodynamically feasible reactions. By decorating SiO(2) with smaller-sized Ta(2)O(5), the interplay of the Lewis acidity of SiO(2) and the contact area between Ta(2)O(5) and SiO(2) is utilized to develop a photocatalyst with higher photoactivity than pure Ta(2)O(5). PMID- 21611985 TI - Olfactory dysfunction is associated with neuropsychiatric manifestations in Parkinson's disease. AB - Hyposmia, psychiatric disorders, and cognitive problems are common nonmotor manifestations in Parkinson's disease, but how they are related remains unclear. We investigated the relationship between olfactory dysfunction and neuropsychiatric manifestations and performed a cross-sectional study of 248 patients at two movement disorders clinics at academic medical centers. Psychiatric measures were the Geriatric Depression Scale-15, Inventory of Depressive Symptomatology, State Anxiety Inventory, Apathy Scale, and Parkinson's Psychosis Rating Scale. Cognitive measures were the Mini-Mental State Examination, Hopkins Verbal Learning Test-Revised, Digit Span, Tower of London Drexel, and the Stroop Color Word Test. Olfaction was tested with the University of Pennsylvania Smell Identification Test. There was no significant association between olfaction and mood measures, but psychotic symptoms were more common in patients with olfaction scores below the median (30% vs. 12%; P < 0.001). Worse olfaction was associated with poorer memory (Hopkins Verbal Learning Test-Revised delayed recall items: mean [standard deviation], 6.2 [3.2] vs. 8.4 [2.8]; P < 0.001) and executive performance (Tower of London total moves, 52 [38] vs. 34 [21]; P < 0.001). Odor-identification score was a significant predictor of abnormal performance on these cognitive tests after adjustment for age, sex, and disease characteristics in logistic regression models. The relationship between hyposmia, psychosis, and specific cognitive impairments may reflect the anatomic distribution of Lewy pathology and suggests that olfactory dysfunction could be a biomarker of additional extranigral disease. Future prospective studies are warranted to assess whether hyposmia, a very early feature of Parkinson's disease, might be used to predict the appearance of other common nonmotor symptoms. PMID- 21611987 TI - Catalytic asymmetric aziridination of alpha,beta-unsaturated aldehydes. AB - The development, scope, and application of the highly enantioselective organocatalytic aziridination of alpha,beta-unsaturated aldehydes is presented. The aminocatalytic azirdination of alpha,beta-unsaturated aldehydes enables the asymmetric formation of beta-formyl aziridines with up to >19:1 d.r. and 99% ee. The aminocatalytic aziridination of alpha-monosubstituted enals gives access to terminal alpha-substituted-alpha-formyl aziridines in high yields and up to 99% ee. In the case of the organocatalytic aziridination of disubstituted alpha,beta unsaturated aldehydes, the transformations were highly diastereo- and enantioselective and give nearly enantiomerically pure beta-formyl-functionalized aziridine products (99% ee). A highly enantioselective one-pot cascade sequence based on the combination of asymmetric amine and N-heterocyclic carbene catalysis (AHCC) is also disclosed. This one-pot three-component co-catalytic transformation between alpha,beta-unsaturated aldehydes, hydroxylamine derivatives, and alcohols gives the corresponding N-tert-butoxycarbonyl and N carbobenzyloxy-protected beta-amino acid esters with ee values ranging from 92 99%. The mechanisms and stereochemistry of all these catalytic transformations are also discussed. PMID- 21611988 TI - Chemical modulation of peptoids: synthesis and conformational studies on partially constrained derivatives. AB - The high conformational flexibility of peptoids can generate problems in biomolecular selectivity as a result of undesired off-target interactions. This drawback can be counterbalanced by restricting the original flexibility to a certain extent, thus leading to new peptidomimetics. By starting from the structure of an active peptoid as an apoptosis inhibitor, we designed two families of peptidomimetics that bear either 7-substituted perhydro-1,4-diazepine 2,5-dione 2 or 3-substituted 1,4-piperazine-2,5-dione 3 moieties. We report an efficient, solid-phase-based synthesis for both peptidomimetic families 2 and 3 from a common intermediate. An NMR spectroscopic study of 2a,b and 3a,b showed two species in solution in different solvents that interconvert slowly on the NMR timescale. The cis/trans isomerization around the exocyclic tertiary amide bond is responsible for this conformational behavior. The cis isomers are more favored in nonpolar environments, and this preference is higher for the six-membered-ring derivative 3a,b. We propose that the hydrogen-bonding pattern could play an important role in the cis/trans equilibrium process. These hydrogen bonds were characterized in solution, in the solid state (i.e., by using X-ray studies), and by molecular modeling of simplified systems. A comparative study of a model peptoid 10 containing the isolated tertiary amide bond under study outlined the importance of the heterocyclic moiety for the prevalence of the cis configuration in 2a and 3a. The kinetics of the cis/trans interconversion in 2a, 3a, and 10 was also studied by variable-temperature NMR spectroscopic analysis. The full line shape analysis of the NMR spectra of 10 revealed negligible entropic contribution to the energetic barrier in this conformational process. A theoretical analysis of 10 supported the results observed by NMR spectroscopic analysis. Overall, these results are relevant for the study of the peptidomimetic/biological-target interactions. PMID- 21611989 TI - Self-assembled arene-ruthenium-based rectangles for the selective sensing of multi-carboxylate anions. AB - Novel arene-ruthenium [2+2] metalla-rectangles 4 and 5 have been synthesized by self-assembly using dipyridyl amide ligand 3 and arene-ruthenium acceptors (arene: benzoquinone (1), naphthacenedione (2)) and characterized by NMR spectroscopy and ESI-MS. The solid-state structure of 5 was determined by X-ray diffraction and shows encapsulated diethyl ether molecule in the rectangular cavity of 5. The luminescent 5 was further used for anion sensing with the amidic linkage serving as a hydrogen-bond donor site for anions and the ruthenium moiety serving as a signaling unit. A UV/Vis titration study demonstrated that although 5 interacts very weakly with common monoanions as well as with flexible dicarboxylate anions such as malonate and succinate, it displays significant binding affinity (K>10(3) in MeOH) for rigid multi-carboxylate anions such as oxalate, citrate, and tartrate, exhibiting a 1:1 stoichiometry. It has been suggested that 1:1 bidentate hydrogen bonding assisted by appropriate geometrical complementarity is mainly responsible for the increased affinity of 5 towards such anions. A fluorescence titration study revealed a large fluorescence enhancement of 5 upon binding to multi-carboxylate anions, which can be attributed to the blocking of the photoinduced electron-transfer process from the arene-Ru moiety to the amidic donor in 5 as a result of hydrogen bonding between the donor and the anion. PMID- 21611990 TI - A new approach to construct a doubly interpenetrated microporous metal-organic framework of primitive cubic net for highly selective sorption of small hydrocarbon molecules. AB - A new approach has been realized to construct a three-dimensional doubly interpenetrated cubic metal-organic framework Zn(2)(PBA)(2)(BDC).(DMF)(3)(H(2)O)(4) (UTSA-36, HPBA=4-(4-pyridyl) benzoic acid, H(2)BDC=1,4-benzenedicarboxylic acid) through the self-assembly of the pyridylcarboxylate linker 4-(4-pyridyl) benzoate and bicarboxylate linker 1,4 benzenedicarxylate with paddle-wheel [Zn(2)(COO)(4)]. The activated UTSA-36a exhibits highly selective gas sorption of C(2)H(6), C(2)H(4) and C(2)H(2) over CH(4) with the Henry law's selectivities of 11 to 25 in the temperature range of 273 to 296 K attributed to the unique 3D intersected pore structure of about 3.1 to 4.8 A within the framework, indicating that UTSA-36a is a potentially very useful and promising microporous material for such industrially important separation of C(2) hydrocarbons over methane. PMID- 21611991 TI - Enantioselective syntheses of 2,5-disubstituted pyrrolidines based on iridium catalyzed allylic aminations--total syntheses of alkaloids from amphibian skins. AB - A broadly applicable route to trans-2,5-disubstituted pyrrolidines has been developed. Key steps are an asymmetric iridium-catalyzed allylic amination, a Suzuki-Miyaura coupling, and an intramolecular aza-Michael addition. Enantiomeric excesses in the range of 93-99 % ee have been achieved. Total syntheses of the alkaloids (-)-225 C, (+)- and (-)-223 H (xenovenine), (+)-223 AB, (+)-195 B, and (+)-223 R have been carried out as applications. PMID- 21611992 TI - A pilot study using transvaginal real-time ultrasound elastography to evaluate the postmenopausal endometrium. PMID- 21611993 TI - Prenatal non-visualization of fetal gallbladder: beware of biliary atresia! PMID- 21611994 TI - Interobserver agreement in detailed prenatal diagnosis of congenital heart disease by telemedicine using four-dimensional ultrasound with spatiotemporal image correlation. AB - OBJECTIVE: To evaluate the clinical accuracy of four-dimensional (4D) echocardiography in the detailed prenatal diagnosis of congenital heart disease (CHD) in a telemedicine setting. METHODS: Ten second-trimester spatiotemporal image correlation (STIC) volumes were sent to three observers in different tertiary care centers with expertise in 4D echocardiography. The 10 volumes were selected based on the type of diagnosis to cover a wide spectrum of CHD anomalies, and also included one normal fetal heart. Observers were asked to provide the diagnosis, the postprocessing modalities used and the time spent on examination, and to give a rating of the confidence for the diagnosis on a 5 point Likert scale. They were free to consult other colleagues, including pediatric cardiologists, but were blinded to the prenatal diagnosis and the neonatal outcome. A diagnostic scoring system was used to evaluate different aspects of the heart defects. The results were compared with neonatal echocardiography or postmortem findings ('gold standard'). RESULTS: In two cases all observers correctly diagnosed all details of the volume datasets. The observer with the best performance reached perfect agreement in six cases and nearly perfect agreement in three. The volumes were most frequently studied by sectional planes and were analyzed in a median time of 11.0 (range, 2.5-30.0) min. The median confidence score was 4.0 (range, 1.0-5.0). CONCLUSIONS: In a telemedicine setting using STIC volumes, fetal cardiac anomalies can be diagnosed correctly by an expert. However, details required for adequate counseling and planning of postnatal care may be missed. STIC by telemedicine is a promising modality, although not accurate enough for exclusive use in clinical decision making regarding treatment, prognosis or termination of pregnancy. PMID- 21611995 TI - First-trimester screening for large-for-gestational-age infants. AB - OBJECTIVES: To examine the relationship between newborn birth weight and first trimester uterine artery (UtA) pulsatility index (PI), maternal characteristics, serum pregnancy-associated plasma protein-A (PAPP-A), free beta-human chorionic gonadotropin (beta-hCG) and fetal nuchal translucency (NT) thickness. We also examined the results of screening for large-for-gestational-age (LGA) neonates by an integrated first-trimester approach incorporating these parameters. METHODS: We evaluated maternal characteristics, fetal NT, PAPP-A, free beta-hCG and UtA-PI in 2097 singleton pregnancies at 11 + 0 to 13 + 6 weeks' gestation. Linear models based on quasi Akaike's Information Criterion were used to determine the best predictive model for fetal birth weight. The patient-specific risk of delivering an LGA infant was derived from multiple logistic regression analysis and the performance of screening was determined by receiver-operating characteristics curve analysis. RESULTS: The best predictive models for fetal birth weight included UtA-PI, PAPP-A, NT, parity, maternal age, smoking status, weight, height and free beta-hCG. In pregnancies delivering LGA newborns compared with non-LGA pregnancies, PAPP-A and NT thickness were significantly increased (P = 0.016 and 0.001, respectively) and UtA-PI was significantly decreased (P = 0.011). A combination of maternal factors with PAPP-A, fetal NT and UtA-PI identified 34.4% of LGA newborns for a false-positive rate of 10%. CONCLUSIONS: This study showed an association between newborn birth weight and maternal factors, and first trimester PAPP-A, beta-hCG, fetal NT and UtA-PI. Together, these factors can be used to identify over a third of pregnancies that will deliver LGA infants. PMID- 21611996 TI - Role of dysfunctional maternal venous hemodynamics in the pathophysiology of pre eclampsia: a review. AB - The venous compartment has an important function in regulation and control of cardiac output. Abnormalities of cardiac output have been found in early gestational stages of both early- and late-onset pre-eclampsia. The venous compartment also maintains the balance between circulating and non-circulating blood volumes and regulates the amount of reserve blood stored in the splanchnic venous bed. It is well known that adaptive regulation of maternal blood volume is disturbed in pre-eclampsia. Abnormal venous hemodynamics and venous congestion are responsible for secondary dysfunction of several organs, such as the kidneys in cardiorenal syndrome and the liver in cardiac cirrhosis. Renal and liver dysfunctions are among the most relevant clinical features of pre-eclampsia. Doppler sonography studies have shown that the maternal venous compartment is subject to gestational adaptation, and that blood flow characteristics at the level of renal interlobar and hepatic veins are different in pre-eclampsia compared with uncomplicated pregnancy. In comparison to late-onset pre-eclampsia, in early-onset pre-eclampsia venous Doppler flow abnormalities are more prominent and present up to weeks before clinical symptoms. This paper reviews the growing evidence that dysfunction of maternal venous hemodynamics is part of the pathophysiology of pre-eclampsia and may perhaps be more important than is currently considered. Doppler sonography is a safe and easily performed method with which to study maternal venous hemodynamics. Therefore, exploring the role of maternal venous hemodynamics using Doppler sonography is an exciting new research topic for those who are interested in cardiovascular background mechanisms, as well as prediction and clinical work-up of pre-eclampsia. PMID- 21611997 TI - Endometrial cancer and ultrasound: why measuring endometrial thickness is sometimes not enough. AB - Endometrial cancer is the commonest cancer of the female genital tract in the developed world. Ultrasound measurement of endometrial thickness is commonly used to triage patients with postmenopausal bleeding for histological sampling. The sensitivity of ultrasound in diagnosing endometrial cancer is high, but it has a small, well-defined false-negative rate. In this report we describe two cases, with histological confirmation, of postmenopausal women without any vaginal bleeding, who were subsequently diagnosed with advanced endometrial cancer. They were found to have a thin, normal endometrium on ultrasound. In both cases, histological examination was suggestive of endometrial cancer originating from foci of adenomyosis. These findings suggest that a proportion of the false negative diagnoses of endometrial cancer on ultrasound could be caused by the disease being confined to the myometrium rather than as a result of suboptimal performance of ultrasound examination. PMID- 21611998 TI - Prenatal diagnosis of total anomalous pulmonary venous connection into the coronary sinus. PMID- 21611999 TI - Functional assessment of the fetal heart: a review. AB - The purpose of this review is to evaluate the current modalities available for the assessment of fetal cardiac function. The unique anatomy and physiology of the fetal circulation are described, with reference to the difference between in utero and ex-utero life. M-mode, early/atrial ratio, myocardial performance index, three-dimensional and four-dimensional ultrasound, tissue Doppler including strain and strain rate, speckle tracking, magnetic resonance imaging and venous flow assessment are described. The modalities are analyzed from the perspective of the clinician and certain questions are posed. Does the modality assess systolic function, diastolic function or both? Is it applicable to both ventricles? Does it require extensive post-processing or additional hardware, or does it make use of technology already available to the average practitioner? The reproducibility and reliability of the techniques are evaluated, with reference to their utility in clinical decision-making. Finally, directions for future research are proposed. PMID- 21612000 TI - The validity of genes related to neurotransmitters as instrumental variables. PMID- 21612001 TI - The promise and pitfalls of combining genetic and economic research. PMID- 21612002 TI - Mendelian randomization: the use of genes in instrumental variable analyses. PMID- 21612004 TI - The nature and structure of psychological distress in people at high risk for melanoma: a factor analytic study. AB - OBJECTIVE: This study examined the psychometric properties of two commonly used measures of psychological distress, the Hospital Anxiety and Depression Scale (HADS) and the Impact of Events Scale (IES) in a sample of individuals at high risk of developing melanoma due to strong family history. METHODS: One hundred thirty-two individuals with a known family-specific CDKN2A mutation (74% response rate) completed a mailed, self-administered questionnaire including the HADS and the IES. Initial correlational analyses were followed by both exploratory and confirmatory factor analyses, according to a predetermined procedure for order of analyses. RESULTS: Exploratory factor analyses found that neither a two-, three- or four-factor solution satisfactorily accounted for all IES items in the present sample. By contrast, a unidimensional account of the data emerged to best account for all IES items, leaving no items unaccounted for. In contrast, the traditional two-factor (anxiety and depression) structure of the HADS appeared to fit the data well. CONCLUSIONS: The traditional, two-factor (intrusion and avoidance) structure of the IES was not borne out within this familial melanoma cohort. Assessment of a single dimension of emotional distress in response to melanoma risk may facilitate more meaningful explorations of psychological adjustment in this context. These findings also raise questions about whether a post-traumatic stress framework is indeed the most appropriate framework to capture the unique nature of melanoma- or cancer-related distress. PMID- 21612005 TI - Functional alterations of large-scale brain networks related to cognitive control in obsessive-compulsive disorder. AB - OBJECTIVES: Neuroimaging studies have consistently implicated alterations of the basal ganglia and orbitofrontal cortex in the pathophysiology of OCD, however, recent work also emphasizes more diffuse patterns of brain alteration as occurring in this disorder. The goal of this study was to extend such observations by investigating large-scale brain functional network correlates of cognitive-control performance in OCD patients. EXPERIMENTAL DESIGN: We combined fMRI with a validated task of cognitive control and a multivariate statistical method to assess multiple functional networks encompassing broad task-relevant cortical regions in OCD patients and matched controls. Functional networks of interest were targeted a priori and the groups were compared in terms of the spatiotemporal profile of network responses (functional connectivity) during the task performance in a data-driven manner. PRINCIPAL OBSERVATIONS: Task performance was equivalent in both groups and each distinct network demonstrated strong overlap in its general response during task. However, significant differences in functional connectivity were also observed between groups that appeared driven by specific phases of task performance. Such differences were most pronounced during rest-task transitions and mainly involved dorsal anterior cingulate and insular cortices within the paralimbic network. Relative heightened functional connectivity of insula in patients during task correlated with a measure of patients' state anxiety. CONCLUSIONS: Our findings provide a novel functional imaging characterization of brain network alterations associated with cognitive-control in OCD. Additionally, these findings raise questions about the role of patients' arousal states on the performance of cognitive imaging tasks that are otherwise assumed to be emotionally neutral. PMID- 21612006 TI - Soluble self-doped conducting polymer compositions with tunable work function as hole injection/extraction layers in organic optoelectronics. PMID- 21612007 TI - Time-resolved FRET biosensor based on amine-functionalized lanthanide-doped NaYF4 nanocrystals. PMID- 21612008 TI - Construction of asymmetric quaternary carbon centers with high enantioselectivity. PMID- 21612009 TI - Ruthenium-catalyzed oxidative annulation by cleavage of C-H/N-H bonds. PMID- 21612010 TI - Importance of risk communication during and after a nuclear accident. AB - Past nuclear accidents highlight communication as one of the most important challenges in emergency management. In the early phase, communication increases awareness and understanding of protective actions and improves the population response. In the medium and long term, risk communication can facilitate the remediation process and the return to normal life. Mass media play a central role in risk communication. The recent nuclear accident in Japan, as expected, induced massive media coverage. Media were employed to communicate with the public during the contamination phase, and they will play the same important role in the clean up and recovery phases. However, media also have to fulfill the economic aspects of publishing or broadcasting, with the "bad news is good news" slogan that is a well-known phenomenon in journalism. This article addresses the main communication challenges and suggests possible risk communication approaches to adopt in the case of a nuclear accident. PMID- 21612011 TI - Changing distribution of cadherins during gestation in the uterine epithelium of lizards. AB - The uterine epithelium provides the interface between an embryo and its mother during pregnancy. Calcium-dependent cadherins are adherens junction proteins that undergo major shifts in the uterine epithelium to facilitate the communication between maternal cells and the embryonic milieu during implantation in mammals. They are, therefore, important in trophoblast invasion and the maintenance of pregnancy. We investigated spatiotemporal changes of cadherins throughout pregnancy in the uterine epithelium of two viviparous skinks and one oviparous population, which all exhibit a noninvasive (epitheliochorial) placenta. Cadherins were identified for the first time in squamate reptiles. In all species, cadherins are reduced in the uterine epithelium as gestation progresses, which would lessen the attachment between uterine epithelial cells and allow them to stretch to accommodate embryonic growth. Interestingly, cadherins were reduced sooner after ovulation in the oviparous species than in the viviparous species. In viviparous species, the different expression of cadherins between barren and pregnant uteri from the same mother indicates that expression of cadherins may not be driven solely by maternal hormones, but also by the presence of an embryo. The redistribution of cadherins in squamates is comparable to that of mammals, reflecting establishment of feto-maternal communication during the peri implantation period. As there is no breaching of maternal tissue in lizards, the change in adherens junctional properties are thus not exclusive to mammals with invasive placentae, which suggests that similar molecular mechanisms regulate changes to uterine epithelia during pregnancy across placental types. PMID- 21612012 TI - Addressing inpatient crowding by smoothing occupancy at children's hospitals. AB - OBJECTIVE: To quantify the difference in weekday versus weekend occupancy, and the opportunity to smooth inpatient occupancy to reduce crowding at children's hospitals. METHODS: Daily inpatient census data for 39 freestanding, tertiary care children's hospitals were used to calculate occupancy and to model the impact of reducing variation in occupancy and the change in the number of patients, patient-days, and hospitals exposed to high occupancy pre- and post smoothing. We also calculated the proportion of weekly admissions that would require different scheduling to achieve within-week smoothing. RESULTS: Overall, hospitals' mean occupancy ranged from 70.9% to 108.1% on weekdays, and 65.7% to 94.9% on weekends. Weekday occupancy exceeded weekend occupancy with a median difference of 8.2% points. The mean post-smoothing reduction in weekly maximum occupancy across all hospitals was 6.6% points. Through smoothing, 39,607 patients from the 39 hospitals were removed from exposure to occupancy levels >95%. To achieve within-week smoothing, a median 2.6% of admissions would have to be scheduled on a different day of the week; this equates to a median of 7.4 patients per week (range: 2.3-14.4). CONCLUSION: Hospitals do have substantial unused capacity, and smoothing occupancy over the course of a week could be a useful strategy that hospitals can use to reduce crowding and protect patients from crowded conditions. PMID- 21612013 TI - Studies on molecular conductors: from organic semiconductors to molecular metals and superconductors. AB - The field of molecular conductors was pioneered by works on the semiconducting properties of phthalocyanines and condensed aromatic hydrocarbons in the middle of the last century. Around three decades ago, the first organic superconductor was reported. Since then, various new molecular superconductors based on multichalcogen pi molecules such as bis(ethylenedithio)tetrathiafulvalene (BEDT TTF), dimethyl(ethylenedithio)diselenadithiafulvalene (DMET), BETS (or BEDT-TSF = bis(ethylenedithio)tetraselenafulvalene), and [M(dmit)(2) ] (M = Ni, Pd; dmit = 4,5-dimercapto-1,3-dithiole-2-thione) including unprecedented antiferromagnetic and field-induced organic superconductors and the first single-component molecular metals were developed by the members in the Department of Chemistry of the University of Tokyo along with outside collaborators. Studies on the physical properties--especially optical properties--of various types of molecular conductors are also extensively examined. PMID- 21612017 TI - Advanced markers and labels for life science and biomedical applications. PMID- 21612018 TI - Bilateral pheochromocytoma manifesting as acute shortness of breath after job loss. PMID- 21612019 TI - Should every patient being assessed for bariatric surgery be screened for Cushing syndrome? PMID- 21612020 TI - Conserving adaptive genetic diversity in dynamic landscapes. AB - Genetic variation supplies the raw material for adaptation, evolution and survival of populations and has therefore been a key focus of conservation biology ever since its foundation (Soule 1985). In previous decades, the neutral component of genetic diversity (generated by mutation and shaped by drift) has been the subject of intense scientific research, fuelled by the increasing availability of molecular markers. On the other hand, the adaptive component of genetic diversity, which is shaped by the action of natural selection, has long remained elusive and difficult to assess, especially at small spatial or temporal scales (Ouborg et al. 2010). Fortunately, new technological and methodological developments now make it possible to identify loci in the genome that are influenced by selection, and thus to get a more complete view of genetic diversity. One article featured in this issue of Molecular Ecology is a good example of this recent breakthrough. Richter-Boix et al. (2011) examined a network of moor frog populations breeding in contrasting habitats in order to understand how landscape features influence patterns of genetic variation. They combined information from both neutral markers and loci putatively under selection to quantify the relative roles of selection and isolation in the evolution of fine-scale local adaptations in these populations. This study nicely illustrates how data on polymorphisms of neutral and adaptive loci can now be judiciously synthesized to help identify the best strategies for preserving adaptive variation, and more generally to enlighten conservation and population management plans. PMID- 21612021 TI - A truly ecological epigenetics study. AB - Until a few years ago, epigenetics was a field of research that had nothing to do with ecology and that virtually no ecologist had ever heard of. This is now changing, as more and more ecologists learn about epigenetic processes and their potential ecological and evolutionary relevance, and a new research field of ecological epigenetics is beginning to take shape. One question that is particularly intriguing ecologists is to what extent epigenetic variation is an additional, and hitherto overlooked, source of natural variation in ecologically important traits. In this issue of Molecular Ecology, Herrera & Bazaga (2011) provide one of the first attempts to truly address this question in an ecological setting. They study variation of DNA methylation in a wild population of the rare, long-lived violet Viola cazorlensis, and they use these data to explore interrelations between environmental, genetic and epigenetic variation, and in particular the extent to which these factors are related to long-term differences in herbivore damage among plants. They find substantial epigenetic variation among plant individuals. Interestingly, this epigenetic variation is significantly correlated with long-term differences in herbivory, but only weakly with herbivory-related DNA sequence variation, which suggests that besides habitat, substrate and genetic variation, epigenetic variation may be an additional, and at least partly independent, factor influencing plant-herbivore interactions in the field. Although the study by Herrera & Bazaga (2011) raises at least as many new questions as it answers, it is a pioneering example of how epigenetics can be incorporated into ecological field studies, and it illustrates the value and potential novel insights to be gained from such efforts. PMID- 21612022 TI - Perfectionism in obsessive-compulsive and eating disorders. AB - OBJECTIVE: The main aims of this article are twofold. First, to assess perfectionism dimensions in obsessive-compulsive disorder and eating disorders in comparison with psychiatric control (depression/anxiety) and non-clinical control groups. Second, to examine if perfectionism is specifically related to these different clinical conditions. METHOD: Thirty-nine outpatients with obsessive compulsive disorder, 24 outpatients with eating disorders, 65 outpatients with a diagnosis of depression and/or anxiety, and 70 non-clinical participants completed the Portuguese version of the Multidimensional Perfectionism Scale. RESULTS: Compared to non-clinical subjects, individuals of all clinical samples had significantly higher scores on Multidimensional Perfectionism Scale total score, Self-Oriented and Socially-Prescribed Perfectionism. There were no significantly differences in Self-Oriented Perfectionism and Multidimensional Perfectionism Scale total score in all the three clinical samples. Subjects from the eating disorders sample had significantly higher scores of Socially Prescribed Perfectionism in comparison to obsessive-compulsive disorder and psychiatric control samples. CONCLUSION: Perfectionism showed to be related with this broad range of psychopathologies. However, the differences between eating disorders versus obsessive-compulsive disorder and psychiatric control on Socially-Prescribed Perfectionism warrant further investigation in order to clarify the specificity of this perfectionism dimension in eating disorders. PMID- 21612023 TI - Commentary on symptom experience of pulmonary arterial hypertension (PAH) patients. AB - Pulmonary arterial hypertension (PAH) is a complex and rapidly progressing illness with few long-term treatment options to prolong life and improve quality of life. The complexity of the disease predisposes patients to a multitude of symptoms that have an effect on their biopsychosocial well-being. McDonough et al. have taken a qualitative approach to examine the dimensions of PAH symptomology. Using a telephone survey approach, 10 patients were questioned regarding their symptoms. Following coding and categorization of the responses, two main themes were found, "holding back" and redefining life." The primary symptom associated with holding back was breathlessness. This symptom largely governed fears and behaviors associated with subthemes found within this main theme. Breathlessness also featured in the redefining life category; however, practical issues associated with medication and treatment were also assigned importance in this category by the study respondents. Symptoms of anxiety and depression were counteracted in many instances by a positive and sometimes stoic attitude toward the illness. This study presents important foundational information which will help direct further development of theoretical hypothesis related to PAH symptomology, as well as help focus clinical research toward venues that will enhance nursing care of this complex disease. PMID- 21612024 TI - Long-term success of personalized neourethras. PMID- 21612025 TI - Closing the net in the hunt for new tissue-based prognostic biomarkers. PMID- 21612026 TI - Long-term outcomes of SBRT in low-risk prostate cancer. PMID- 21612027 TI - Sarcosine: the saga continues... PMID- 21612028 TI - Sling-related urethral distortion. PMID- 21612029 TI - Hydrophilic catheters are safe and effective for men with spinal cord injury. PMID- 21612030 TI - Optimizing ureteral stent design. PMID- 21612031 TI - [Resource scarcity imposes a change of attitude]. PMID- 21612032 TI - A blueprint for bone health across the lifespan: engaging novel team members to influence fracture rates. PMID- 21612033 TI - Does the majority of the healthy Israeli population really suffer from hypovitaminosis D? PMID- 21612035 TI - Relevance of public health activism that Dr Binayak Sen represents. PMID- 21612034 TI - My tryst with destiny: bile duct injury. PMID- 21612036 TI - National health website: scope for improvement. PMID- 21612037 TI - Liberation treatment for multiple sclerosis. PMID- 21612038 TI - Nurses take action on practice issues. PMID- 21612039 TI - [Results of a post-marketing surveillance of meropenem for children]. AB - The post-marketing surveillance of meropenem for children was conducted between May 2004 and September 2006. The safety and the efficacy were analyzed in 1210 cases and 1004 cases, respectively. The results of this surveillance were as follows: The incidence of adverse drug reactions (ADRs) associated with use of meropenem (including abnormal laboratory findings) was 14.3% (173 cases), and the main ADRs were hepatic function abnormal, alanine aminotransferase increased, and aspartate aminotransferase increased, which were similar to these observed in the clinical study. And the efficacy was 88.6% (890 cases). PMID- 21612040 TI - [Validity of using imipenem as a representative carbapenems and levofloxacin as a representative fluoroquinolones in antibiotics susceptibility test for enterobacteriaceae]. AB - In antimicrobial susceptibility test for enterobacteriaceae, the efficacies of carpapenems are predicted by the minimum inhibitory concentration (MIC) of imipenem, and that of fluoroquinolones are predicted by the MIC of levofloxacin. To assess its judgement, we compared the MICs of imipenem, meropenem, panipenem, and doripenem for carbapenems, and ciprofloxacin, levofloxacin, tosufloxacin and pazufloxacin for fluoroquinolones of clinically isolated enterobacteria, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Enterobacter cloacae and Citrobacterfreundii, those resistant to the third generation cephalosporin. MIC distributions in low concentration range are estranged in some strains, conspicuously S. marcescens, E. cloacae and C. freundii: meropenem and doripenem displayed low MIC value than imipenem and panipenem. Since the estrangements are appeared MIC value of less than 8 microg/ml, the interpretive results (susceptible, intermediate, resistant) are not affected. In fluoroquinolones, all 4 agents showed almost identical MIC distributions, thus the MIC of levofloxacin is accepted to use the reference for other fluoroquinolones. The existence of the strains harboring carbapenem resistant gene displaying low MIC value of carbapenems was reported. For the sensitive detection of the candidate of carbapenem-resistant strains, cut-off value of each carbapenem should be reconsidered, and also other phonotype analysis should be applied. Genomic analysis also would be required to detect the carbapenem-resistant gene. PMID- 21612041 TI - [Epidemiologic study of drug-resistant Aspergillus and optimizing newer treatment]. PMID- 21612042 TI - [Analgesic efficacy of magnetoledotherapy in patients with low back pain syndromes]. AB - INTRODUCTION: Low back pain syndromes most often occur due to overloading of the musculoskeletal system. The cause is a frequent, improper lifting of heavy objects, most commonly by those working physically, with repetitive movements of bending and straightening of the trunk (turning and bending with load). This problem affects not only adults but also children and adolescents. There is a growing interest in new forms of analgesic therapy nowadays, especially in those that exhibit synergistic therapeutic effects. The aim of this work is to evaluate the analgesic efficacy of magnetoledotherapy in patients with lumbar--sacrum spinal pain syndromes caused by joints degenerative changes. MATERIAL AND METHODS: The examination was carried out in 66 patients of both sexes aged 30 to 76 (average 54.7 +/- 13.8) with low back pain syndrome caused by spinal degenerative changes. The patients were divided into three groups according to the applied analgesic therapy (magnetoledotherapy, magnetostimulation, TENS currents). Level of pain has been evaluated four times in all patients--before the start of therapy and after 5, 10 and 15 applications with the use of the modified Laitinen Questionnaire and Visual-Analoque Scale (VAS). RESULTS: Post therapy levels of pain in the studied patients decreased significantly. According to Laitinen questionnaire, the greatest improvement was observed in the group treated with magnetoledotherapy and TENS currents and the smallest improvement was observed in the group treated with magnetostimulation. CONCLUSIONS: 1. Magnetoledotherapy shows significant analgesic efficacy in patients with low back pain syndrome and shows no side effects. 2. Concurrent application of both the infrared radiation generated by LED's and magnetostimulation synergistically reinforces analgesic effect in patients with low back pain syndrome, especially in level of pain and frequency of its occurrence, which results in the increase of movement activity and decrease in administration of analgesics. PMID- 21612043 TI - [Relation between local CMV infection and inflammatory cytokine expressionon in pts sheduled for CABG]. AB - INTRODUCTION: Cytomegalovirus (CMV) infection has been suggested to play a role in the development of cardiovascular diseases. It has not yet been established yet whether the possible adverse vascular effect is associated with chronic inflammation process caused by CMV. The aim of our study was to evaluate a possible role of CMV infection in local inflammatory activation in pts with coronary artery disease (CAD). MATERIAL AND METHODS: We enrolled 55 patients (mean age 62 years, 42 males, 13 females) with angiographically proven CAD scheduled for CABG surgery. Vessel specimens retrieved from ascending aorta (as a part of routine proximal venous graft development procedure) and peripheral blood mononuclear cells (PBMC) were evaluated for the transcriptional activity of IL-6 and TNF-alpha (the key cytokines involved in atherosclerosis) and for CMV DNA presence. Polymerase chain reaction reaction was performed in order to detect DNA of CMV as well as IL-6 and TNF-alpha transcriptional activity. RESULTS: CMV was present in 67.3% of aortic and in 60% of blood specimens accordingly; median level in aorta tissues: 114.63 +/- 116.54, PBMC: 107.89 +/- 132.39; non statistically significant (NS). An inflammatory response expressed as IL-6 and TNF-alpha transcriptional activity equaled in aorta 159.93 +/- 120.15, 299.55 +/- 154.89 and in PBMC: 190.85 +/- 122.08, 249.64 +/- 32.4; (NS). CMV DNA in PBMC was associated with CMV DNA in aortal tissue p = 0.0049. The analysis revealed positive correlation between IL-6 transcriptional activity and CMV DNA titer in aortic samples R = 0.35, p = 0.036. There were no statistically significant correlations between TNF-alpha transcriptional levels and CMV DNA concentration. Statistical analysis was made by use of Statistica 8.0; StatSoft program. We used arithmetical mean value, standard deviation, Spearmann correlation, X2 and U Mann Whitney test. CONCLUSIONS: A local inflammatory response expressed against CMV could be a marker of longstanding inflammatory response that eventually would cause advanced clinical atherosclerosis. Our findings support the infectious theory and an association between CMV infection and atherosclerosis. PMID- 21612044 TI - [Etiology and clinical signs as short-term risk factors of status epilepticus]. AB - INTRODUCTION: The aim of the study was an analysis of causes, clinical symptoms, complications and predictors of an unfavorable course of status epilepticus (SE). MATERIAL AND METHODS: Retrospective evaluation of medical files of 28 patients (17 M, 11 F, aged 52 +/- 15 yrs) was made. Patients were treated for status epilepticus in a Neurology Clinic in Zabrze between January 1997 and March 2008. RESULTS: Chronic epilepsy existed in 64% pts, for 10 yrs on an average, in 10% pts SE was a subsequent one. Chronic alcoholism was defined as a most frequent cause of SE, followed by cerebrovascular disorders and brain tumor (32, 14 and 14%, resp.); in 25% pts the cause was not specified. Generalized seizures predominated (82%), in 90% they lasted longer than 60 minutes. In 43% pts biochemical inflammatory indicators on admission were found, more than 20% had fever, in 10% pneumonia was diagnosed. 1/3 of individuals suffered from respirocirculatory insufficiency and in more than 21% new neurological deficits appeared. In treatment, following benzodiazepines, intravenous phenytoin (50%) was used. 35% pts was subjected to pharmacological coma, predominantly by means of thiopental and propofol (25 and 7%, resp.). Mechanical ventilation was necessary in 40% pts. Mortality rate was 32%, with 33% of deaths on the 1st day and 78% before the 7th day. CONCLUSIONS: Chronic alcoholism and older age predominate among causes of death in patient with SE. PMID- 21612045 TI - [The influence of prophylaxis on dentition of 8-year-old children. II. Results of prophylaxis]. AB - INTRODUCTION: This article presents evaluation of prophylactic measures, preventing the development of caries in children. MATERIAL AND METHODS: The study involved 50 pupils from a primary school in Zywiec in which is conducted a prophylactic programme by a local government "Prevention of caries in children and youth"--group P, and 51 pupils from village schools in which no such program- control group K. Prophylactic activities involved, among others, oral cavity checkup, instruction concerning hygiene, promotion of oral cavity health, sealing of I permanent molar teeth. Children's dentition was evaluated by means of frequency caries index, VI tooth sealing index, DMF/dmf (decayed, missing, filling for milk and permanent teeth) and SCI (significant caries index). RESULTS: Sealing index of VI teeth was higher in group P than in group K (p < 0.001), whereas DMF index of VI teeth were lower in group P than in group K (p < 0.001). Frequency caries index, DMF and SCI index for permanent teeth, were lower in group P than in group K (p < 0.001). CONCLUSIONS: Children subjected to anticaries prophylaxis had healthier and better protected teeth in comparison with controls. PMID- 21612046 TI - [Vitamin D3 in prevention of diseases in adults--a systematic review]. AB - INTRODUCTION: Current evidence indicates that vitamin D3 plays significant role in calcium balance and bone metabolism through lifetime. There are also evidence on preventive efficacy of vitamin D3 in diabetes, insulin-resistance, hypertension and malignancy. MATERIAL AND METHODS: The aim of the systematic review was to gather evidence regarding vitamin D3 in prevention of diseases in adults. MEDLINE via Pubmed was searched using key words: "vitamin D3, "prevention", "adults", "cardiovascular diseases", cancer", "osteoporosis", "common cold", "cold", "diabetes", "obesity", "depression". 26 trials were included into analysis: 17 randomized clinical trials, five observational studies, two systematic reviews, and two metaanalysis. RESULTS: Vitamin D3 appears to has beneficial effect in depression therapy, protective effect on beta cells in diabetic patients and reducing frequency of adverse events such as thrombosis in patients with prostate cancer. Supplementing with vitamin D3 results with no significant improve in reducing body weight, fat, blood pressure, risk of hypertension, level of lipids in serum, response to treatment in cancer prostate (together with dexamethasone and carboplatin). Many studies highlights beneficial influence of vitamin D3 with calcium on bone mineral density in whole body. Another studies show improve in bone mineral density in hips and pelvic bones only. There were inconsistencies of studies results regarding role of vitamin D3 in prevention of diabetes, risk of breast cancer and influence on bone mineral density. CONCLUSIONS: Despite all inconsistencies supplementation of vitamin D3 is important and plays role in effective osteoporotic management and there is evidence on preventive efficacy of vitamin D3 in different diseases. PMID- 21612047 TI - [Central pontine myelinolysis--etiological, clinical and prognostic variety]. AB - Central pontine myelinolysis (CPM) is a neurologic disorder that the most often is related to rapid correction of hyponatremia. It is concentrated, frequently symmetric, noninflammatory demyelination within the base of the pons with a relative sparing of the axons and the nerve cells. Focal demyelination can occur outside the pons (extrapontine myelinolysis--EPM). Clinical symptoms have various manifestations and the prognosis can be different. In the diagnosis of CPM the most useful is magnetic resonance imaging (MRI), that is more sensitive than computed tomography (CT). The authors present two cases of CPM with different aetiology, clinical features and course of the disease. PMID- 21612048 TI - [Progress in ambulatory practice for pulmonary infections in adults]. AB - The clinical manifestations (both symptoms and signs) of infections of respiratory tract disease are limited and not specific to the cause. However, there is no universal approach, and good clinical judgment is often essential. Most people have approximately three colds per year, of which 70% result from viral origin. It should be stressed that a confident diagnosis of pneumonia is difficult outside the hospital. Very often the most important clinical questions are whether an antibiotic should be prescribed and should the patient be admitted to the hospital. A wide range of microbial pathogens can cause pulmonary infection. When bacteria are present, Haemophillus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis are most frequently found. For some patients atypical pathogens like Mycoplasma pneumoniae, Chlamydophilla pneumoniae and Legionella pneumophilla are also important. The role for microbial investigations has yet to be determined, but in most cases this may be needed only when the patient fails to respond to initial therapy. An approach to the diagnosis and treatment of pulmonary infections in Poland is presented in this study. PMID- 21612049 TI - [Epidemiology of drug-resistant tuberculosis: world--Europe--Poland]. AB - The phenomenon of drug resistance in tubercle bacilli (Mycobacterium tuberculosis) has been recognized since the early years of chemotherapy of tuberculosis (TB). However it was not until the mid-1990s, that the magnitude of the problem was highlighted by the first global report of the World Health Organization on the prevalence of anti-TB drug resistance. Up to now, four such reports have been released. Not only have they shown that drug resistance is present worldwide, but they have also demonstrated its expansiveness and a high tendency for progression. The two most detrimental forms of drug-resistant TB are multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Whereas MDR-TB implies resistance to at least isoniazid and rifampicin, the most potent drugs in the first-line regimen, XDR-TB is defined as MDR-TB with resistance to any of the fluoroquinolones and any of the second-line injectable drugs (amikacin, kanamycin, or capreomycin). The emergence and spread of drug-resistant TB are among the key factors contributing to the persistence of TB within the human population. This article outlines the current epidemiological status of drug resistant TB in the world, Europe, and Poland. PMID- 21612050 TI - [Selected risk factors of metabolic syndrome and disorders of taste perception]. AB - The sense of taste, apart from the sense of smell and sight, is one of the most important senses that play crucial role in the transmission of information regarding the food and its usefulness for consumption. Alarming is an increasing number of people with the taste dysfunction. This kind of dysfunction is serious problem especially among the elderly that arise not only from unavoidable and natural processes of ageing but also from health problems and taken medications. Disturbances of taste perception influence on food preferences and may increase to a large extent the development of the metabolic-civilization diseases or even intensify them. Considering the increasing amount of people with metabolic syndrome and rising prevalence of taste disturbances, the current essay include the literature review regarding this subject. It must be underline that metabolic syndrome and taste perception disorders may decrease not only the quality of life but also have unbeneficial influence of health status. PMID- 21612051 TI - [Principles of the practices of electrocardiographic stress test in patients before and after pacemaker implantation]. AB - Electrocardiographic stress test EKG is the basic, diagnostic test in the heart failure, it is also used for patients with implanted pacemaker. PMID- 21612052 TI - [Dry eye syndrome--multispecialistic disease. Part one: Pathogenesis, signs, classification]. AB - The authors presents the review of the literature concerning on the signs, classification, connections between the dry eye syndrome and other diseases and the risk factors of dry eye syndrome. It is a prevalent, multifactorial disease that is particularly frequent in elderly patients and women, especially in menopausal and postmenopausal period. Dry eye syndrome can be episodic with transient signs and symptoms or chronic with persistent signs and symptoms and is characterized by one or more of the following symptoms: burning, itching, foreign body sensation, soreness, dryness, photophobia, redness, and reduced visual acuity. The tear film instability of dry eye syndrome, which is accompanied by increased osmolarity of the tear film, causes inflammation and structural damage to the ocular surface. There are two major etiologic categories of dry eye syndrom: aqueous-deficient and evaporative. The most frequent classification of dry eye for practical clinical use is triple classification based on the ethiology, histopathological changes and severity of the disease. PMID- 21612053 TI - [Global health research challenges with a North-South partnership]. AB - OBJECTIVES: Global health research often involves North-South partnerships. However, these types of partnerships present particular challenges. The aim of this study is to examine these challenges from the perspectives of those involved in order to formulate ideas for further discussion and action to support the training of young researchers. METHODS: This is a qualitative study using an exploratory design. The data are taken from encounters with 41 persons in individual in-depth interviews (n = 16) and a focus group (n = 25). All encounters were audio-recorded and transcribed, and the content subsequently underwent thematic analysis. RESULTS: The challenges identified were related to communication problems, power relationships, research priorities, differences in research culture, the institutional environment and researchers' careers. The researchers describe the conditions that support equitable partnerships and propose some ideas for the training of young researchers. INTERPRETATION: To foster equitable and sustainable partnerships, the researchers suggest that the next generation would be better trained by focusing particularly on interactive discussions, field work, mentoring and the adoption of a reflective and self critical mindset. PMID- 21612054 TI - [Diabetes mellitus and the oral cavity]. AB - The paper summarizes current knowledge on the diseases of the oral cavity that may be related to diabetes mellitus. It draws the attention to the symptoms that signify potential association between the oral cavity disease and so far undiagnosed diabetes. Attention is paid to a connection between type 2 diabetes and periodontitis, as it is known that diabetes mellitus may contribute to the development of periodontitis, although a reciprocal link also exists and decompensated diabetes may be improved when periodontitis is cured. PMID- 21612055 TI - [Xerostomia, hyposialia, sicca syndrome--quantitative disturbances of the salivary flow rate]. AB - Diseases of salivary glands may be associated with salivary flow rate disturbances. Production of the saliva is evaluated by sialometric tests. The stress is putted on salivary flow rate disturbances in Sjogren's syndrome, drug induced and postirradiative sialopathy, and diabetes mellitus. The possibility of the stimulation and substitution of the saliva is discussed. PMID- 21612056 TI - [Peptic ulcer disease in patients with diabetes mellitus]. AB - Peptic ulcer disease and diabetes mellitus are the serious chronic diseases with many medicals and socioeconomic consequences. Although the changes leading to the mucosal vulnerability and prolonged healing of ulcers were many times demonstrated in experiment, the clinical data does not confirmed explicit association of those diseases. The patients with diabetes mellitus are threatened by complications of peptic ulcer disease (bleeding, perforation) above all. The Helicobacter pylori prevalence is in diabetics higher, the results of eradication of Helicobacter pylori are unsatisfactory. PMID- 21612057 TI - [Motility disorders and gastric emptying in diabetes mellitus. Current diagnostics and treatment]. AB - Autonomic neuropathy of the gastrointestinal tract is a common complication of diabetes mellitus. However, it is seldom recognised properly as it is rarely considered. In some patients, it might be asymptomatic or hardly compensatable diabetes can be the only one sign. There are non-invasive diagnostic methods to assess gastric emptying rate (13C-octanoic acid breath test) or myoelectric activity of the stomach (electrogastrography). The principle treatment comprises optimal control of diabetes and use of prokinetics. PMID- 21612058 TI - [Current trends of surgical therapy of focal liver and pancreatic lesions]. AB - Focal liver and pancreatic lesions represent important therapeutic problem in a relatively huge group of patients. Secondary liver tumors are the crucial factor affecting morbidity and mortality in patients with malignancies. Radical surgery is the only therapeutic option that gives the chance of long-term survival. The authors present current trends in surgical therapy of liver and pancreatic tumors as a review article. PMID- 21612059 TI - [Steatosis and steatohepatitis in diabetic patient]. AB - Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized condition of excess fat deposition within the liver. NAFLD includes a spectrum of liver pathology ranging from bland hepatic steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is an inflammatory and fibrosing condition of the liver thought to be an intermediate stage of NAFLD that may progress to endstage liver disease, liver-related death and hepatocellular carcinoma. Nonalcoholic steatohepatitis (NASH) is a common liver disease that is characterized histologically by hepatic steatosis, lobular inflammation, and hepatocellular ballooning, it can progress to cirrhosis in up to 15% of patients. There is currently no therapy that is of proven benefit for nonalcoholic steatohepatitis. The disease is closely associated with insulin resistance and features of the metabolic syndrome such as obesity (increased waist circumference), hypertriglyceridemia, and type 2 diabetes. The pathologic criteria are now well established and the diagnosis can only be made once the absence or limited use of alcohol is confirmed. In addition to insulin resistance, oxidative stress has been implicated as a key factor contributing to hepatic injury in patients with nonalcoholic steatohepatitis. Thus, both insulin resistance and oxidative stress are attractive targets for therapy in patients with this disease. Several pilot studies have provided evidence that insulin sensitizers such as thiazolidinediones and antioxidants such as vitamin E improve clinical and histologic features of nonalcoholic steatohepatitis. The medical evidence of a benefit, however, is limited, because these studies had small samples and were performed at single centers. Moreover, a recent multicenter trial showed a reduction in hepatic steatosis but no improvement in markers of cell injury after a year of rosiglitazone therapy. The value of these remains uncertain. Until now the best trial was done by Sanyal, who studied 240 patients divided into 3 groups (pioglitazone versus vitamin E versus placebo)- multicenter, randomized, double-blind clinical trial in non-diabetics. PMID- 21612060 TI - [Diabetes mellitus and the liver cirrhosis]. AB - Patients with liver cirrhosis have increased risk of diabetes mellitus development, especially when the underlying disease is hereditary hemochromatosis, autoimmune hepatitis, non-alcoholic steatohepatitis or chronic hepatitis C. Patients with associated diabetes according to liver cirrhosis complications have worse prognosis and the therapy is influenced by both diseases. The authors bring short review of particular diseases, diagnosis and treatment strategy. PMID- 21612061 TI - [Acute pancreatitis in diabetics]. AB - All diabetic patients with acute pancreatitis should be intensively treated and monitored in spite of the fact that 75-80% have mild-to-moderate disease. This is due to difficult diagnosis and problems with standard monitoring due to diabetes and its complications. Especially intensive rehydration and subsequent fluid mobilisation can be difficult. Also glucose control and impaired gut motility can cause difficulties in diabetic patients with acute pancreatitis. Nutrition support should be implemented according to severity of disease and insulin infused to control glycaemia. PMID- 21612062 TI - [Coeliac disease and diabetes]. AB - Coeliac disease is associated with type 1 diabetes mellitus more than ten times more frequently than it is present in nondiabetic population. It often exists with minimal signs or without them. It may cause different complications if it would remain without treatment. Active screening of coeliac disease and similarly of autoimmune thyreopathy is therefore an integral part of examination in type 1 diabetic patients. PMID- 21612063 TI - [Colorectal cancer and diabetes]. AB - Colorectal carcinoma is a tumour with higher incidence in patients with type 2 diabetes and obesity. Recently, a slightly higher risk has also been shown in prediabetic states. The most important latest finding is that of a reduced risk in patients treated with metformin; there is a trend now to also prescribe metformin in patients with disturbed glucose tolerance or increased fasting glycaemia. Regular physical activity and reduced animal fat intake with increased intake of fruits and vegetables may help to prevent the disease. Pathogenesis may include changes to intestinal flora. The most important current preventive clinical measure is colonoscopy. Type 2 diabetes patients should be considered as a risk group and thus prevention should be targeted at these patients. PMID- 21612064 TI - [Analogues of amylin, alpha-glucosidase inhibitors and the digestive system in homeostasis regulation]. AB - The digestive tract plays an important role in glucose homeostasis. The important fact is that cells of the digestive tract are also the place of production of numerous regulatory peptides. Their use in the treatment of diabetes has been subject to study for many years. The paper examines the synthetic analogue of the human hormone amylin, the secretion of which coincides with the secretion of insulin. The synthetic analogue pramlintide is used in treatment of DM1T as well as DM2T. Likewise, a group of intestinal alpha-glucosidase inhibitors--acarbose in this country--was introduced into clinical practice some years ago. Both drugs share their glucose-lowering effects, but first of all they influence postprandial hyperglycemia like other antidiabetic agents of this large group affecting PPG such as incretin mimetics, DPP-4, etc. Both pramlintide and acarbose have find their specific in the treatment of postprandial blood glucose. PMID- 21612065 TI - [Autonomic neuropathy of the gastrointestinal tract]. AB - The paper focuses on the issues of diabetic autonomic neuropathy in the gastrointestinal tract. It describes the aethiopathogenesis of diabetic polyneuropathy. More detailed discussion is then provided with respect to gastrointestinal tract. The clinical picture and options available for the diagnosis and treatment when various parts of the gastrointestinal tract are involvement are examined. PMID- 21612066 TI - [Dyspeptic syndrome associated with antidiabetic therapy]. AB - Dyspeptic syndrome is a common complication of treatment with antidiabetic drugs. This may be a trivial as well as a very serious complication. Nausea, vomiting, diarrhoea, abdominal pain, loss of appetite and taste disturbances are the most common symptoms of dyspeptic problems in patients treated with metformin. They rarely are a reason for treatment discontinuation. Dyspeptic syndrome is a common complication in patients treated with acarbose, this may be prevented by reduced intake of sucrose. Pneumatosis cystoides intestinalis is a rare complication in acarbose-treated patients. Antiobesity agent orlistat is frequently associated with dyspeptic symptoms, particularly if fat intake is not reduced. Treatment with drugs affecting the incretin system (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) is very rarely complicated by acute pancreatitis. Glucagon-like peptide-1 receptor agonists may cause dyspeptic symptoms (nausea, vomiting, diarrhoea) at the beginning of treatment. These complaints usually cease and the treatment usually does not need to be discontinued. PMID- 21612068 TI - [Metabolic surgery--a new approach to the management of selected diseases]. AB - Treatment options for type 2 diabetes have changed dramatically in the past few years. Experimental works followed by evidence based studies proved long-term efficacy of metabolic surgery in type 2 diabetes treatment. Moreover diabetes resolution is not directly correlated with weight loss and occurs independently to it. Large literature metaanalyses showed that type 2 diabetes can be subtantially improved with metabolic surgery in about 85% of all diabetic patients, out of which can be resolved in more than 75%. Metabolic surgery affects hormonal secretion on multiple levels namely in the small intestine. Restrictive as well as combined and malabsorptive surgical procedures have positive effect on type 2 diabetes improvement as well as on metabolic syndrome, sleep apnea syndrome and on other comorbidities. PMID- 21612067 TI - [Metabolic surgery--the most effective diabetes treatment]. AB - Bariatric operations resulting in a favourable metabolic effect--not only due to a reduction of excessive body weight--are known as metabolic surgery. Interventions into the digestive tract, especially the prevented contact of food with the duodenal and proximal jejunal lining and/or the effect of an insufficiently digested food on the jejunum, favourably affect incretin mechanisms. Thus, "resolution" of type 2 diabetes and discontinuation of antidiabetic medication can be achieved in as many as 95 percent of patients. Today, combined procedures (gastric bypass, biliopancreatic diversion) are indicated for diabetic subjects with severe obesity. The usefulness and indication of metabolic surgery for type 2 diabetics with less pronounced overweight have to be verified in prospective controlled studies. PMID- 21612069 TI - [Incretin hormones]. AB - Incretin hormones are peptides that are secreted from endocrine cell of gastrointestinal tract after nutrient ingestion and stimulate insulin secretion. Glucosodependent Insulinotropic Peptide--GIP is released from K-cells of duodenum and proximal jejunum, recently GIP synthesis has been proved in pancreatic alpha cells. Besides the incretin effect causes GIP increased lipogenesis and decreased lipolysis in fat tissue, increased bone formation and decreased resorption and has protective and proliferative effect on CNS neurons. Both GIP agonists (to treat diabetes) and antagonist (to treat obesity) are being studied. Another incretin hormone is derived in intestinal I-cells by posttranslational processing of proglucagon--glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). GLP-1 stimulates insuline production and inhibits glucagon secretion, exerts proliferative and antiapoptotic effect on beta-cells. Via receptors on vagal nerve and central mechanisms decreases food intake and decreases body weight. By deceleration of gastric emptying it attenuates increases in meal-associated blood glucose levels. It exerts cardioprotective effects. GLP-1 receptors have been proved in liver recently but decreased liver glucose production and increased glucose uptake by liver and muscle are mediated indirectly by altering insulin and glucagons levels. GLP-2 stimulates enterocytes proliferation, up-regulates intestinal nutrient transport, improves intestinal barrier function, and inhibits gastric and intestinal motility. GLP-2 also reduces bone resorption. PMID- 21612070 TI - [Treatment of type 2 diabetes mellitus with GLP-1 agonists]. AB - Increased prevalence of type 2 diabetes mellitus and its close clustering with obesity, arterial hypertension, dyslipidemia and other pathologies commonly referred to as metabolic or insulin resistance syndrome, represents one of the major health problem worldwide. The side effects of most of oral antidiabetics and insulin include increase in body weight and/or hypoglycemia that may limit its use in some patients. GLP-1 agonists are medicaments stimulating GLP-1 receptor similarly as endogenous GLP-1. These substances are in contrast to endogenous GLP-1 resistant to inactivation by ubiquitous enzyme dipeptidyl peptidase 4 which enables its administration once or twice daily. GLP-1 agonists not only significantly improve diabetes compensation with minimal risk of hypoglycemia but also decrease body weight, blood pressure and improve numerous parameters of cardiovascular risk. The aim of this review is to summarize current knowledge with respect to use of GLP-1 agonists in the treatment of type 2 diabetes and its future perspectives. We will focus mostly on the two drugs that are currently available in Czech Republic--exenatide and liraglutide. PMID- 21612071 TI - [Incretin therapy and the metabolic syndrome]. AB - Incretin therapy includes treatment with incretin analogues (exenatid and liraglutid) and so called incretin enhancers (gliptins and DPP-4 inhibitors respectively--sitagliptin, vildagliptin, saxagliptin, linagliptin). In patients with type 2 diabetes, this novel antidiabetic treatment usually leads to successful reduction in fasting as well as postprandial glycaemia and glycosylated haemoglobin. At the same time, it importantly improves all components of metabolic syndrome (dyslipidemia, hypertension, systemic inflammation). Incretin analogues also reduce body weight while DPP-4 inhibitors are weight-neutral. Both groups of drugs are expected to have positive cardiovascular effects, although it is not clear whether these are likely to be direct or indirect, i.e. facilitated by improved compensation of metabolic syndrome components. PMID- 21612072 TI - [Changing practices]. PMID- 21612073 TI - [Iodine tablets in Japan. A protective measure against radiation]. PMID- 21612074 TI - [Prevnar 13. the new antipneumococcal vaccine integrated]. PMID- 21612075 TI - [Synergism. A model defined by the coordinated action of several people who work on a single action]. PMID- 21612077 TI - [Fighting asthma. Finding out if parents have access to alternative medicine]. PMID- 21612076 TI - [Lyme disease. A tick bite, no panic! Emerging zoonoses in Quebec]. PMID- 21612078 TI - [Vaginal birth after cesarean section. After Canada, the United States change their guidelines]. PMID- 21612079 TI - [Understanding renal function. A critical component of paraclinical surveillance?]. PMID- 21612080 TI - [Biofilms. What are they? Where are they? What impact do they have on wound care?]. PMID- 21612081 TI - [Pulse. "Do you feel?" Boom, boom, a beating heart, a propagating wave... what does pulse tell us?]. PMID- 21612082 TI - [Breastfeeding passport. A tool to encourage maternal breastfeeding]. PMID- 21612083 TI - [The facilitating nurse. What is the role of the nurse-counselor in clinical prevention?]. PMID- 21612085 TI - [So, do we buy? A survey tells us more about the habits of people from Quebec]. PMID- 21612084 TI - [Pradax. A new category of anticoagulants]. PMID- 21612086 TI - [Diabetic with multiple small hematomas. Wrong injection technique]. PMID- 21612087 TI - [Physician advertising. What good is your website if no one finds it?]. PMID- 21612088 TI - [Cathepsin K inhibitor: new therapy approach against osteoporosis. Pharmacological target in the osteoclast]. PMID- 21612089 TI - [Differential pain therapy in osteoporosis. Reference for the family physician (interview by Dr. med. Jochen Aumiller)]. PMID- 21612090 TI - [Naturopathy consultation. Climacteric syndrome]. PMID- 21612091 TI - [Myths and facts in coronary heart disease prevention. Praying does not help, television is harmful]. PMID- 21612092 TI - [Recurrent fever attacks and space occupying lesion in the upper right liver lobe. A liver abscess from Africa]. PMID- 21612093 TI - [Sports injuries. What you can do for muscle and joint pain]. PMID- 21612094 TI - [Hypochondriac "realangst": don't get affected yourself]. PMID- 21612095 TI - [Heart-related anxiety--when does it become hypochondriac?]. PMID- 21612096 TI - [Fear of progression: worries about disease progression or disease recurrence]. PMID- 21612097 TI - [A powerful duo: antihypertensives aliskiren and amlodipine in one tablet. Combination tablet for hypertensive patients with diabetes and overweight]. PMID- 21612098 TI - [Emergency checklist: patellar dislocation]. PMID- 21612099 TI - [Calculated antibiotic therapy]. PMID- 21612100 TI - [Interactions with antihypertensive drugs]. PMID- 21612101 TI - [Irritable bowel syndrome. Reduction of symptoms, better quality of life]. PMID- 21612102 TI - [Distribution of congenital heart disease in Croatia and outcome analysis. A Croatian epidemiological study (2002-2007)]. AB - OBJECTIVE: The aim of our paper is to show results of population and hospital registry of congenital heart disease in Croatia. METHODS: Information on patients born during the five-year study and with diagnosis of congenital heart defects, obtained all across the country, were collected in the population and hospital registry set up according to the EUROCAT and BWIS registries principles. RESULTS: Between October 1, 2002, and October 1 2007, there were 205051 live births in Croatia, of which 1480 patients were diagnosed with congenital heart defects, accounting for 0.72% of the live-born children. The most common diagnosis was ventricular septal defect with percentage of 34.6%. Among 1480 children, 430 needed an operation. Among 553 cardiac surgeries performed, 202 were done in Croatia and others were done in institutions abroad. Mortality rate after surgery was 5%. Only after adjustment for complexity there are marked differences in mortality and occurrence of postoperative complications between Croatia and centers abroad. CONCLUSION: The importance of the registry of congenital heart disease relies in the field of epidemiological research but can be used as a tool for future planning of health services. PMID- 21612103 TI - [Tick-borne diseases in the Republic of Croatia]. AB - This study analyses occurence, trendline, occurence by months and geographical distribution of tick-transmitted diseases: Lyme borreliosis, Tick-borne meningoencephalitis (TBM) and Mediterranean spotted fever in the Republic of Croatia in the period between 1999 and 2008. The vector for Lyme borreliosis and tick-borne meningoencephalitis is Ixodes ricinus, while Mediterranean spotted fever is transmitted by the Rhipicephalus sanguineus. Lyme disease is endemic in entire continental Croatia and Croatian littoral. Tick-borne meningoencephalitis is endemic in northern Croatia. Mediterranean spotted fever occurs only in Dalmatian counties and the average annual incidence rate increases from north to south of Dalmatia. All three diseases show extremely seasonal characteristics, which is conditioned by the biological cycle of ticks as their activity peaks in summer and spring. In terms of vaccines against the above diseases, the only one available in Croatia is the TBM vaccine and it is applied according to epidemiological indications. In preventing Lyme disease some authors have recommended a single 200-mg dose of doxycycline taken within 72 hours of being bitten by an infected tick. PMID- 21612104 TI - [Video-assisted extirpation of breast fibroadenoma with immediate bilateral breast augmentation--a case report]. AB - BACKGROUND: Since mid 1990s video-assisted breast surgery (VABS) has been developed in the treatment of benign and malignant breast diseases. According to studies that are conducted mainly in Japan, this tehnique is safe, easy to learn and his main advantage is excellent cosmetic results on postoperative appearance of breasts that cannot be achived with standard surgical procedures. OBJECTIVE: To present a first case of video assisted breast surgery in Croatia applied to treatment of breast fibroadenoma and immediate bilateral breast augmentation. CASE REPORT: A 39 year old female patient was admitted to our hospital for elective procedure of breast augmentation. On this occasion video assisted extirpation of fibroadenoma was performed through inframammary incision and followed by immediate bilateral breast augmentation. CONCLUSION: VABS is feasible, cosmetic effects are evident and the VABS deserves attention as a possible surgical option in breast surgery. However further experience on this field must be gained and it remains to evaluate this tehnique on the additional studies. PMID- 21612105 TI - [Can lacidipine cause smell disorders? A case report]. AB - The sense of smell plays an important role in the maintenance of a good quality of life. Disturbances of olfactory sense include complete or partial loss of smell, distortion of smell, and perceived smell in the absence of real stimuli. Medications represent a less common cause of smell disorders. We report a case of a patient with a partial loss of smell associated with the calcium channel blocker lacidipine. Although various calcium channel blockers are known to cause smell disorders, such a side effect, to our knowledge, has not so far been reported for lacidipine. PMID- 21612106 TI - [Nonsteroidal antirheumatics and hypertension]. AB - Nonsteroidal anti-inflammatory drugs (NSAID) are the most common prescribed drugs in clinical medicine (4-9% of all prescriptions), and their side-effects are very common. These drugs, the older group, nonselective ciclooxigenase inibitors (inhibitors of COX-1 and COX-2), may increase blood pressure and cardiovascular risk. Many studies have shown that NSAID could increase blood pressure for 5-10 mmHg. The use of NSAID is common and their side effects to increase blood pressure have a large impact on the public health. The main mechanism of the increased blood pressure by NSAID is blockage of prostaglandin synthesis. The results of blockage of prostaglandin synthesis are sodium and fluid retention. NSAID may increase blood pressure in normotensive and hypertensive persons. Indomethacin, naproxen, and other NSAID increase the blood pressure in patients treated with beta-blockers, diuretics, metildopa, ACE-inhibitors and combination of various antihipertensive drugs, but there is no increase of blood pressure in patients treated with calcium blockers. In many studies, aspirin did not increase the blood pressure. The new group of NSAID, coxibes, selective ciclooxigenase inibitors (inhibitors of COX-2) could increase the blood pressure like older generation of NSAID. PMID- 21612107 TI - [Sugammadex, a new drug for reversion of muscle relaxants]. AB - Sugammadex is a new pharmacological agent for neuromuscular block reversion. It is a cyclic oligosaccharide, a gamma cyclodextrin with lipophylic inner coat that enables forming of stable complexes with steroidal neuromuscular blocking drugs, especially with rocuronium. A physical encapsulation of the relaxants is a novel elimination pathway and it produces fast and complete reversion of both deep and shallow neuromuscular block. Consequently, sugammadex has no unwanted cholinergic muscarinic effects observed with cholinesterase inhibitors such as bradycardia, hypersalivation, and increased gastrointestinal motility. Since the effects of sugammadex are dose dependent it can very rapidly reverse the effects of rocuronium. After the adjusted dose of sugammadex was given, the duration of action of rocuronium can be made as short as that of succinylcholine. This characteristic is especially important in the 'can't intubate, can't ventilate' situation and after surgical procedure was unexpectedly finished. Clinical studies involving more patients are needed to show the real risk-benefit profile and safety in the special patients' populations. PMID- 21612108 TI - [Low HDL-cholesterol--an important risk factor for cardiovascular diseases]. AB - It has been known for quite a long time that the concentration of HDL-cholesterol correlates inversely with cardiovascular disease (CVD) risk and that low HDL cholesterol is an independent CVD risk factor. This review aims to highlight evidence on several topics concerning the role of HDL particles and the importance of HDL-cholesterol. The main antiatherogenic functions of HDL particles are presented in details--reverse cholesterol transport, but also their anti-oxidant, anti-inflammatory, anti-thrombotic and anti-apoptotic properties as well as endothelial stabilizing and repair properties. Lifestyle management of low HDL-cholesterol is explained, particularly physical activity and aerobic exercise, smoking cessation, weight reduction in the overweight individuals and composition of the diet but also moderate alcohol consumption stressing the fact that HDL particles from alcoholics are dysfunctional. This is important since it has been shown that it is not only the quantity of HDL particles, and thus HDL cholesterol level in plasma, that matters, but their quality and impaired functionality as well. HDL from diabetic subjects also lose some of their antiatherogenic properties but a common feature of patients with diabetes type 2 is atherogenic dyslipidemia which is characterized exactly by low HDL-cholesterol and high triglycerides. Diabetic patients with such dyslipidemia are at particularly high CVD risk and the results of recent studies such as ACCORD-Lipid suggest that in them treatment of these lipid abnormalities may be beneficial. Treatment options with fibrates, particularly fenofibrate, and niacin are discussed based upon published trials, as well as combination therapy with these medicines and other lipid-lowering drugs. PMID- 21612109 TI - [Novelties in pathophysiology, radiology diagnostics and conservative treatment of painful spine conditions and deformities]. AB - Spinal pain, especially chronic low-back pain is one of the most prominent health and healthcare problems. Better understanding of pain pathophysiology and more precise visualization using modern imaging techniques help us to focus our intervention and obtain better outcome. In most patients with spine conditions symptoms and function resolve with conservative treatment. In this article we report on novelties in pathophysiology of spinal pain, magnetic resonance imaging and conservative treatment options (medications, therapeutic exercise, physical therapy and orthoses) of painful spine conditions and scoliosis. Apart from being informative, together with the corresponding article about novelties in invasive/surgical treatment, this special focus article on recent developments in this area can be used as an aid in decision making when approaching these patients. PMID- 21612110 TI - [New techniques and prospects in invasive treatment in vertebrology]. AB - In this article authors outline new techniques and prospects in invasive treatment in vertebrology with emphasis on interventional and semi invasive procedures and minimally invasive surgery for lumbar disc herniation. They describe new approaches in neuroablative procedures for back pain treatment, in spinal fixation and in surgical treatment of scoliosis. Authors also report methods of great expectations which are not yet in use in our clinical practice but are promising like reconstruction of nucleus pulposus by autologous chondrocytes transplantation. New methods in cervical spine surgery are also discussed. The efficacy of each surgical method is pointed out. Apart from being informative, together with the corresponding article on patophysiology, magnetic resonance imaging and conservative treatment, these articles considering recent developments can be used as an aid in decision making when approaching these patients. PMID- 21612111 TI - [Ethics of scientific research using patients' archived biological material and their medical data]. AB - Informed consent represents the standard for adequate protection of all participants in biomedical research. This standard is affirmed in international legal documents concerning biomedical research, as well as in Croatian legislation. However, some questions regarding informed consent remain open. One of such questions that research ethics committees around the world and in the Republic of Croatia often deal with, is the question of whether to obtain informed consent for the research on archived material or previously collected research data taken from the patients during diagnostic or therapeutic procedures. This contribution provides an overview of both Croatian and international legal documents and guidelines that deal with this issue, together with an overview of the literature concerning this issue. Since in the Republic of Croatia there are no regulations regarding this type of research, the authors of this contribution are presenting conduct guidelines for researchers and ethics committees in such cases. The implementation of the proposed guidelines would facilitate scientific research and international cooperation for Croatian scientific institutions. PMID- 21612112 TI - [European guidelines on the diagnosis and management of pulmonary embolism]. AB - We report on the 2008 update of Guidelines on the diagnosis and management of acute pulmonary embolism (PE) of the European Society of Cardiology that have been endorsed and recommended by the Croatian Cardiac Society. The guidelines focus on currently available and validated methods of diagnosis, prognostic assessment (prediction of outcome and death risk), treatment of pulmonary embolism and management in specific settings including pregnancy, malignancy, non thrombotic PE, right heart thrombi, heparin-induced thrombocytopenia, chronic thromboembolic pulmonary hypertension. The novelty of these guidelines is the stratification of PE into high-risk, low-risk and intermediate-risk of PE-related early death, which has important consequences for treatment, rather than the use of misleading terms such as zmassive', zsubmassive' and znon-massive' pulmonary embolism. The anticoagulants remain the mainstay of therapy, with thrombolytic therapy being an therapeutic option in patients with high-risk PE presenting with cardiogenic shock and/or persistent arterial hypotension. PMID- 21612113 TI - [Testosterone replacement therapy for androgen deficiency syndrome]. PMID- 21612114 TI - [Role of "Health" National project in improvement of health parameters in working population]. AB - The author analyzed results of "Health" National project accomplishment in Rostov region over 2006-2009. Findings are that quality of primary medical care has improved, material and technical basis of municipal health care institutions has progressed, salary of primary health care division specialists has increased. Over this period, infant mortality and mortality among able-bodied population in the region has decreased, birth rate has increased, coefficient of natural loss of population has reduced, life expectancy has increased. PMID- 21612115 TI - [Influence of work conditions on health of working population in Rostov region]. AB - The authors analyzed work conditions and occupational morbidity among working population of Rostov region. Miners and agricultural workers appeared to lead in exposure to occupational hazards, but occupational morbidity among the miners is the highest, but that among the agricultural workers was proved to be the lowest. A conclusion covered necessity to improve periodic medical examination system for workers exposed to occupational hazards, including the agricultural workers. PMID- 21612116 TI - [Characteristics of ambient air quality in office chambers and its influence on workers' state]. AB - Increasing health complaints of office workers are associated with exposure to indefinite risk factors. Many discussions involve ano-particles (size less than 100 nm) in air of non-industrial chambers containing contemporary office equipment. Complex study covered quality of air in offices (microclimate, organic and inorganic pollutants, dust particles). New approach to assessment of non- industrial working environment is evaluation of air pollution by ultrasmall (nano) particles through their quantity and surface square. Polling method helped to study the state of office workers. PMID- 21612117 TI - [Results of study concerning possible influence of rocket space activities on public health]. AB - Using special medical examination results and specified criteria of objective evaluation, the authors summarized results of studies concerning health state of population dwelling in area possibly influenced by rocket space activities factors. PMID- 21612118 TI - [Individual medical rehabilitation for patients having occupational diseases caused by dust]. AB - The article covers organizational and legal problems of medical rehabilitation for patients with occupational diseases caused to dust. The authors suggested steps of individual medical rehabilitation and criteria to evaluate efficiency of rehabilitation, exemplified by dust obstructive bronchitis patients. PMID- 21612119 TI - A new member in the biomarker discovery toolbox. PMID- 21612120 TI - Troponin T: more than acute myocardial infarction. PMID- 21612121 TI - "Notitia COErulei Berolinensis Nuper Inventi" on the 300th anniversary of the first publication on Prussian blue. PMID- 21612122 TI - Physical chemistry before Ostwald: the textbooks of Josiah Parsons Cooke. PMID- 21612123 TI - Benjamin Silliman Jr.'s 1874 papers: American contributions to chemistry. PMID- 21612124 TI - The rise and fall of domestic chemistry in higher education in England during the early 20th century. PMID- 21612125 TI - Denison-Hackh structure symbols: a forgotten episode in the teaching of organic chemistry. PMID- 21612126 TI - Consider something viral in your search. PMID- 21612127 TI - AVMA president-elect candidates make their case. Interview by R. Scott Nolen. PMID- 21612128 TI - Japan's animal relief operations face considerable challenges. PMID- 21612129 TI - [Overview of the insurance coverage for neurosurgery. 4. The mechanism involved in the revision of reimbursement for medical treatment]. PMID- 21612130 TI - [Keypoints in placing a cannula in the application of a heart assist device]. PMID- 21612131 TI - Passionate objectors. PMID- 21612132 TI - Community. PMID- 21612134 TI - New scholarship available for nursing student. PMID- 21612133 TI - Marching in Michigan. PMID- 21612135 TI - Evidence that can't be ignored. PMID- 21612136 TI - The effect of montelukast in a model of gouty arthritis induced by sodium monourate crystals. AB - Non-steroidal anti-inflammatory drugs (NSAIDS) are the first line of therapy in acute gouty arthritis. NSAIDs inhibit the cyclooxygenase pathway, but not the lipooxygenase activity and can have many adverse effects and thus have a limited effect on the control of inflammation in this disease. In this work we studied the effect of montelukast on the cellular inflammatory infiltrate in a model of murine arthritis induced by sodium monourate crystals (SMU), using a subcutaneous air cavity (air pouch) in BALB/c mice. Seven groups of BALB/c mice (n = 4) were distributed into five experimental groups and two inflammatory control groups, a positive and a negative one. Previous to SMU exposure, the experimental groups received montelukast (1 and 0.01 mg/Kg/w) and/or indomethacine (2.5 mg/Kg/w), followed by administration of SMU in the air pouch. The total and differential counts of inflammatory cells were analyzed after 2, 6, 12 and 24 hours. Montelukast, significantly reduced the total number of cells (p < 0.05), with a predominant impact on polymorphonuclear over mononuclear cells, especially after 12 hours of the medication. The montelukast/indometacine combination showed an additive effect. Our data show that montelukast has an anti-inflammatory effect in the model of gouty arthritis. Consequently, anti-leukotrienes could represent a new and effective therapy, either isolated or combined with conventional therapy of gouty arthritis. PMID- 21612138 TI - Do we need special recovery units for C-section patients? PMID- 21612137 TI - Diagnostic accuracy of immunological methods in patients with tuberculous pleural effusion from Venezuela. AB - In recent years, better diagnostics for tuberculosis (TB) has received increasing attention, especially the diagnosis of tuberculous pleural effusion, which is difficult and at present the main tool in TPE diagnostic is pleural effusion smear and culture, but unfortunately, sensitivities are low, therefore better TPE diagnostic tools are needed. The aim of this study was to find a diagnostic algorithm to assess the progress in TPE diagnostic at the Hospital Vargas de Caracas, that permits identification of the majority of patients, at a satisfactory cost-benefit ratio, evaluating the levels of IFN-gamma and IL-12p40 in pleural effusion and serum, as well as the antibody reactivity in order to compare it with microbiological tests. A total of 60 individuals with pleural effusion were studied; 20 patients with tuberculous pleural effusion (TPE) formed the patient group and 40 patients with non-tuberculous pleural effusion (NTPE) formed the control group. The levels of IFN-gamma and IL-12p40 in effusion and serum and class and subclasses of IgG reactivity to Mycobacterium tuberculosis antigens were measured by ELISA. The utility of these methods for diagnosis of TPE was evaluated using receiver operating characteristic (ROC) curve analysis. The results of the 11 immunological methods evaluated showed that the anti-PPD IgG2 method was able to reach the highest specificity of 95% (CI: 88.3-101.8), positive predictive value (PPV) = 75 (at 30% sensitivity); while that the overall sensitivity of methods was between 95% and 30%, of these, two methods reached higher sensitivities; increased levels of pleural IFN-gamma, with a sensitivity of 95% (CI: 85.5-104.5) with the highest negative predictive value (NPV) = 97, (at 82.5% specificity), followed by decreased levels of serum IL-12p40 with a sensitivity of 95% (CI: 85.5-104.5), NPV = 95.2 (at 50% specificity). In contrast, microbiological methods showed that smear had a sensitivity of only 20%, while smear plus culture had, a sensitivity of 70%. Considering that TPE represents approximately 15 percent of all the TB clinically diagnosed at the Hospital Vargas de Caracas, in those patients with preliminary microbiology negativity in the effusion, the combined analysis of pleural IFN-gamma and anti PPD IgG2 could represent a fast and effective diagnostic algorithm for improving the diagnosis previous to obtain culture results. In this way treatment against TB could be initiated or the need to cytological and pleural biopsy could be considered. PMID- 21612139 TI - Different preloading protocols with constant ephedrine infusion in the prevention of hypotension for elective cesarean section under spinal anesthesia. AB - Ninety ASA I or II parturients were randomly allocated to three groups: group 10RL, 15RL and 20RL to receive 10, 15 and 20 mL/kg of Ringer's lactate (RL) respectively within 15 minutes (min) before the spinal block. Spinal anesthesia was performed with hyperbaric bupivacaine 12 mg, morphine 100 microg and fentanyl 10 microg. The operating table was tilted to the left and an IV infusion of ephedrine of 3 mg/min was immediately started and continued until umbilical cord clamping in all groups. Hypotension was defined as a drop in mean arterial pressure (MAP) of more than 20% from baseline : this was treated with 10 mg ephedrine IV. The incidence of hypotension was 60%, 36.7% and 13.4% in group 10RL, 15RL and 20RL, respectively (p<0.05). Additional ephedrine dose was the lowest in group 20RL compared to the other groups (p<0.05). The total amount of ephedrine was 49.9 +/- 13.5, 46.4 +/- 13.4 and 38.4 +/- 8.5 mg in group 10RL, 15RL and 20RL, respectively (p <0.05). The incidence of nausea and vomiting in group 20RL was significantly less than in group 10RL (p = 0.02). It was concluded that preloading with 20 mL/kg of RL prior to spinal anesthesia followed by constant ephedrine infusion 3 mg/min after spinal block reduced the incidence of hypotension and of nausea and vomiting and decreased the total amount of ephedrine. PMID- 21612140 TI - Changes in liver enzymes and bilirubin after coronary artery bypass grafting using acute normovolemic hemodilution. AB - The aim of this clinical case-control trial was to compare postoperative early jaundice and transient liver damage in patients receiving autologous or homologous blood transfusion in coronary artery bypass grafting (CABG) surgery. In this randomized clinical trial 40 patients scheduled for CABG were randomly allocated to ANH (Acute Normovolemic Hemodilution) group or control group. Both groups were compared in relation to bilirubin (total and direct), alanine transferase (ALT), aspartate transferase (AST) and alkaline phosphatase (ALP) in the first 24 hours. There was a significant difference in bilirubin (total and direct) change between groups (both p<0.00001). However, there were no changes in ALT, AST and ALP compared with baseline values, and there were no differences in the values between the two study groups. Our randomized, double blinded case control study suggested that patients receiving autologous blood (ANH group) following CABG had significantly lower bilirubin levels compared to patients who received homologous transfusion. However larger studies with more patients are needed to confirm the results. PMID- 21612141 TI - Central area for induction of anesthesia and job satisfaction. AB - A central area for induction of anesthesia (CAIA) is supposed to optimize processes of preoperative patient preparation for anesthesia. The purpose of this study was to assess whether the separation of the anesthesia process into anesthesia induction and anesthesia maintenance is associated with residents' job satisfaction. The central area for induction of anesthesia model (CAIA model) was prospectively compared to the conventional model of anesthesia being induced, maintained and ended by the same anesthetist. Quality of senior staff supervision for each day as well as workday satisfaction was additionally graded by a Likert scale. More than 80% of residents considered their workday as satisfying or very satisfying, regardless of the model applied. Furthermore, work day satisfaction was significantly associated with the quality of supervision provided by the teaching staff. It was concluded that time and attention provided by the teaching staff rather than the anesthesia organisational model were the major determinants of workday satisfaction. PMID- 21612142 TI - Prehospital airway management: A prospective case study. AB - We conducted a one-year prospective study involving a prehospital Emergency Medical Service in the Netherlands to investigate the incidence of failed or difficult prehospital endotracheal intubation. During the study period the paramedics were asked to fill in a registration questionnaire after every endotracheal intubation. Of the 26,271 patient contacts, 256 endotracheal intubations were performed by paramedics in one year. Endotracheal intubation failed in 12 patients (4.8%). In 12.0% of 249 patients, a Cormack and Lehane grade III laryngoscopy was reported and a grade IV laryngoscopy was reported in 10.4%. The average number of endotracheal intubations per paramedic in one year was 4.2 and varied from zero to a maximum of 12. The median time between arrival on the scene and a positive capnograph was 7 min.38 s in the case of a Cormack and Lehane grade I laryngoscopy and 14 min.58 s in the case of a Cormack and Lehane grade 4 laryngoscopy. The incidence of endotracheal intubations performed by Dutch paramedics in one year was low, but endotracheal intubation was successful in 95.2%, which is comparable with findings in international literature. Early capnography should be used consistently in prehospital airway management. PMID- 21612143 TI - Optimum dose of ketamine for prevention of postanesthetic shivering; a randomized double-blind placebo-controlled clinical trial. AB - Our objective was to investigate the efficacy and the optimum dosage of ketamine for post anesthetic shivering prevention. One-hundred and twenty patients (ASA I II) scheduled for elective orthopedic surgery were randomly allocated to receive ketamine in 3 groups ; groups A (0.125 mg/Kg), groups B (0.25 mg/Kg) and C (0.5 mg/Kg) along with those receiving 0.9% normal saline as the placebo group. Tympanic temperature was measured immediately after induction of anesthesia, 30 min after induction, before administration of the study drug and by the end of the surgery. The four groups did not differ significantly in their hemodynamic parameters and tympanic temperature. The frequency of shivering was significantly less in groups B (0.25 mg/Kg) and C (0.5 mg/Kg) than in groups A (0.125 mg/Kg) and D (placebo). In addition recovery, extubation time and hallucination was observed to be less in group B compared to group A. Prophylactic 0.25 and 0.5 mg/kg ketamine was found to be effective in preventing postanesthetic shivering with a better response observed with 0.25 mg/kg dosage. PMID- 21612144 TI - Three-dimensional magnetic resonance image of structures enclosed in the spinal canal relevant to anesthetists and estimation of the lumbosacral CSF volume. AB - Three-dimensional (3D) image-reconstruction of structures inside the spinal canal certainly produces relevant data of interest in regional anesthesia. Nowadays, all hospital MRI equipment is designed mainly for clinical diagnostic purposes. In order to overcome the limitations we have produced more accurate images of structures contained inside the spinal canal using different software, validating our quantitative results with those obtained with standard hospital MRI equipment. Neuroanatomical 3D reconstruction using Amira software, including detailed manual edition was compared with semi-automatic 3D segmentation for CSF volume calculations by commonly available software linked to the MR equipment (MR hospital). Axial sections from seven patients were grouped in two aligned blocks (T1 Fast Field Eco 3D and T2 Balance Fast Field Eco 3D-resolution 0,65 x 0,65 x 0,65 mm, 130 mm length, 400 sections per case). T2 weighted was used for CSF volume estimations. The selected program allowed us to reconstruct 3D images of human vertebrae, dural sac, epidural fat, CSF and nerve roots. The CSF volume, including the amount contained inside nerve roots, was calculated. Different segmentation thresholds were used, but the CSF volume estimations showed high correlation between both teams (Pearson coefficient = 0.98, p = 0.003 for lower blocks; Pearson 0.89, p = 0.042 for upper blocks). The mean estimated value of CSF volume in lower blocks (L3-S1) was 15.8 + 2.9 ml (Amira software) and 13.1 +/ 1.9 ml (software linked to the MR equipment) and in upper blocks (T11-L2) was 21 +/- 4.47 ml and 18.9 +/- 3.5 ml, respectively. A high variability was detected among cases, without correlation with either weight, height or body mass index. Aspects concerning the partial volume effect are also discussed. Quick semi automatic hospital 3D reconstructions give results close to detailed neuroanatomical 3D reconstruction and could be used in the future for individual quantification of lumbosacral CSF volumes and other structures for anesthetic purposes. PMID- 21612145 TI - The anti-inflammatory effects of ketamine: state of the art. AB - Inflammation is a major component in keeping the body in homeostasis. However, an overwhelmed inflammatory response may be associated to a loss of this homeostatic status, which may lead to tissue injury or organ dysfunction. A huge number of drugs interacts with the inflammatory response in a positive, negative or "dual" manner. Among these drugs, ketamine seems to have a significant positive effect on the regulation of inflammation. This NMDA-receptor antagonist acts at different levels of inflammation, interacting with inflammatory cells recrutment, cytokins production, and inflammatory mediators regulation. The resultant effect of these interactions confers to ketamine a anti-proinflammatory effect by limiting exacerbation of systemic inflammation without affecting local healing processes. This review makes a complete overview of the immunomodulatory properties of this complex anesthetic substance. PMID- 21612146 TI - Severe postoperative blood pressure instability in a patient with long standing Parkinson's disease. PMID- 21612147 TI - Effect of processing and storage time on the vitamin C and lycopene contents of nectar of pink guava (Psidium guajava L.). AB - In this study, the effect of processing and storage time on the vitamin C and lycopene contents was evaluated. Guavas were washed, cut in quarters, blanched, pulped and the pulp pasteurized. The pulp was used for the production of nectar: guava pulp, sugar and water were mixed in 5:3:12 proportions, and the mixture was pasteurized, poured while hot into 125 mL glass jars, and cooled rapidly to 25 degrees C. The production of nectar from fresh guava reduced vitamin C, lycopene and titratable acidity, by contrast soluble solid and pH increased significant. Vitamin C content from 168.9 to 62.3 mg/(100 g fresh weight), and lycopene content from 3.55 to 1.35 mg/(100 g fresh weight) (p < 0.001 in both cases. After 240 days at 10.0 +/- 2 degrees C, no further statistically significant change in lycopene and soluble solid content was observed (p > 0.05). Storage time did affect vitamin C, pH, and titratable acidity content, vitamin C content fell by 89.3% to 6.67 mg/(100 g fresh weight) (p < 0.001). Based on this study, guava nectar storage at 10 degrees C retained 46% of the content of vitamin C for 120 days. PMID- 21612148 TI - Folate content and retention in selected raw and processed foods. AB - Adequate intake of folate reduced the risk of abnormalities in early embryonic brain development such as the risk of malformations of the embryonic brain/spinal cord, collectively referred to as neural tube defects (NTDs). Folate is extremely sensitive to destruction by heat, oxidation and UV light. The purpose of this study was to evaluate the use of different extraction procedures and enzymatic treatment to determine folate concentrations in variety of foods using a microbiological assay (MA) with Lactobacillus rhamnosus as the test organism. This study also aimed to evaluate the retention of folate in foods after using different cooking processes. Nine of the most commonly consumed foods in Argentina and that contain folate were analyzed: broccoli, spinach, potato, lentil, soy (raw and boiled); hen whole egg and yolks (raw, boiled and fried); beef liver (raw and cooked); strawberry (raw) and white bread. For this study, rat plasma (RP) and human plasma (HP) conjugases together with acetate and phosphate buffers were tested. In extraction step for all analyses, RP conjugase was selected since it was easily available in our laboratory and small quantities were required. The acetate buffer was chosen since better growth and more reproducible results were obtained in the different conditions assayed. The results allowed the foods to be grouped into (a) rich sources of folate: hen eggs, yolks, spinach, soybean (raw) and strawberry (100 and 350 microg/100 g fresh weight (FW); (b) good sources of folate: broccoli (raw), soybean (boiled), lentils (raw) and potato (56 to 83 microg/100 g FW) and c) moderate sources of folate: broccoli, lentils (boiled), white breads, onions and beef liver (15 to 30 microg/100g FW). The folate retention was in the range 14-99% according to both type of food and method of processing. Contents and losses of folate vary widely according to type of food and cooking method. PMID- 21612149 TI - Golimumab and immunogenicity? 2010 and beyond. AB - Immunogenicity is a frequent adverse event observed with biological agents' therapy. Challenges of management in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis treated with golimumab, an anti TNF-alpha blocker, include limited generation of antibodies like anti-nuclear, anti-golimumab, and anti-double stranded DNA antibodies. We conducted here a meta analysis study in order to evaluate and compare the newly generated antibody levels after golimumab therapy. The examination of original clinical trials revealed that their levels were neither higher nor significant. Moreover, no evident associations between the induced-antibodies and lupus-like syndromes and/or infusion site reaction were reported. The reduced patients cohort and the absence of systematic newly generated antibodies follow-up might be implicated in the difficulty to evaluate their risk in delaying diseases therapy, and/or predicting for their worse prognosis. Hence, further studies are required to ascertain the real impact of the induced antibodies after golimumab's therapy. PMID- 21612150 TI - Comparison of the chromatographic behavior of levofloxacin, ciprofloxacin and moxifloxacin on various HPLC phases. AB - A simple and rapid HPLC method with UV detection was developed for the separation of ciprofloxacin, levofloxacin and moxifloxacin. Chromatography was carried out using a BDS Hypersil C18 (100 x 4.6 mm, 2.4 microm) HPLC column and an isocratic mobile phase consisting of MeOH/25 mM phosphate buffer 28/72 (v/v) at pH 3 and flow rate 1 ml.min-1 . The effect of mobile phase variables such as methanol content, pH and buffer concentration on the chromatographic behavior of the three fluoroquinolones was investigated. The retention behavior on a sub 3 microm C18 column was also compared with that on three different calixarene-bonded and on monolithic stationary phases. The results indicate that some differences exist between these three types of stationary phases, particularly in the effect of buffer concentration on the retention mechanism of the three used FQs on calixarene-bonded stationary phases. PMID- 21612151 TI - Development and characterization of mucoadhesive microspheres for nasal delivery of ketorolac. AB - The objective of the present investigation was to prepare mucoadhesive microspheres of ketorolac for nasal administration by means of a solvent evaporation technique using carbopol (CP), polycarbophil (PL) and chitosan (CS) as mucoadhesive polymers. The prepared microspheres were characterized for morphology, swelling behavior, mucoadhesion, interaction studies, drug encapsulation efficiency, in vitro drug release, release kinetics, and ex vivo nasal cilio toxicity studies. The effects of various process variables on the particle size of the microspheres were investigated. Drug encapsulation efficiency and particle size of the microspheres ranged from 52-78% w/w and 14-46 microm respectively. Interaction studies revealed that there were no drug-polymer interactions. The in vitro release profiles showed prolonged-release of the drug. In vitro release data showed a good fit with the Higuchi model, and indicated Fickian diffusion. No severe damage was found to the integrity of nasal mucosa after ex vivo experiments. PMID- 21612152 TI - In vitro and in vivo evaluation of sanguinarine liposomes prepared by a remote loading method with three different ammonium salts. AB - Sanguinarine liposomes were prepared by a remote loading method using three different ammonium salts. A series of studies, including in vitro release, in vitro and in vivo anti-tumor effects and pharmacokinetics in rats, were conducted. The three liposomes showed pH-sensitive release characteristics in vitro, but there were obvious variations in their release profiles. Among the three liposomes, the liposomes made using ammonium citrate and phosphate possessed better anti-tumor activity in vitro and in vivo, compared with the liposome using ammonium sulfate. Pharmacokinetics test results in rats indicated that sanguinarine liposomes have notably elevated AUC (P<0.05) and markedly lower CL (P<0.05) compared with the solution, but there were no obvious differences between the three liposomes. The present study may be useful for better understanding and better choice of a suitable ammonium salt for the remote loading method. PMID- 21612153 TI - Stavudine entrapped lipid nanoparticles for targeting lymphatic HIV reservoirs. AB - The main objective of present research study was to evaluate the potential of lipid nanoparticles for active delivery of an antiretroviral drug to lymphatic tissues. Stavudine entrapped drug loaded solid lipid nanoparticles (SLNs) were prepared and characterized for a variety of physicochemical parameters such as appearance, particle size, polydispersity index and zeta potential. The targeting potential of the prepared nanoparticles was investigated by carrying out ex vivo cellular uptake studies in macrophages which depicted several times enhanced uptake as compared to pure drug solution. Further, the lymphatic drug levels and organ distribution studies demonstrated efficiency of the developed nanoparticles for prolonged residence in spleenic tissues. Thus it was concluded that stavudine entrapped lipid carriers can be exploited for effective and targeted delivery to cellular and anatomical HIV reservoirs and may ultimately increase the therapeutic safety and reduce side effects. PMID- 21612154 TI - Preparation and anti-bacterial properties of a temperature-sensitive gel containing silver nanoparticles. AB - The purpose of this study was to prepare a temperature-sensitive gel containing silver nanoparticles and to investigate its anti-bacterial properties in vitro. The aqueous gel was prepared using Pluronic F127 (18-22%) and Pluronic F68 (3-9%) in a cold method to obtain a proper gelation temperature at 37 degrees C. Viscoelastic properties of the system were measured by rheological measurements and the physicochemical properties were evaluated by MJ-22 Dial-reflex metaloscope and Zetasizer Nano ZS90. The in vitro antimicrobial activity was evaluated by a disk diffusion test, minimum inhibitory concentration, and minimum bactericidal concentration. A temperature-sensitive gel containing silver nanoparticles with 20 wt% F127 and 6 wt% F68 had suitable fluidity at 25 degrees C and was semi-solid at 37 degrees C. Silver nanoparticle size averaged 78.0 nm. The gel optimized formulation achieved a suitable viscosity. The MIC and MBC of the gel ranged from 1.0 to 2.0 mg/L against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. The activity of the gel against these three species was significantly enhanced (p<0.05) compared to 400 mg/L Asimi standard. This optimized silver nanoparticle dosage form demonstrated a high potential for further development for the clinical treatment of bacterial vaginosis. PMID- 21612155 TI - Effect of surface charge on nano-sized silica particles-induced liver injury. AB - Nanomaterials are used frequently in microelectronics, cosmetics and sunscreen, and research for the development of nanomaterial-based drug delivery systems is promising. We previously reported that the intravenous administration of unmodified silica particles with a diameter of 70 nm (SP70) caused hepatic injury. Here, we examined the acute hepatic toxicity of SP70 modified with amino group (SP70-N) or carboxyl group (SP70-C). When administered intravenously into mice, SP70-N and SP70-C dose-dependently increased the serum level of alanine aminotransferase (ALT). However, the toxicity levels of surface charge-modified silica particles were much less weaker than the level of unmodified particles. When SP70 was repeatedly administered at 40 mg/kg twice a week for 4 weeks into mice, the hydroxyproline content of the liver significantly increased. Azan staining of the liver section indicated the extensive fibrosis. To the contrary, the repeated administration of SP70-N or SP70-C at 60 mg/kg twice a week for 4 weeks into mice did not cause the hepatic fibrosis. These findings suggest that the surface charge of nanomaterials could change their toxicity. PMID- 21612156 TI - Effect of 70-nm silica particles on the toxicity of acetaminophen, tetracycline, trazodone, and 5-aminosalicylic acid in mice. AB - Exposure to nano-sized particles is increasing because they are used in a wide variety of industrial products, cosmetics, and pharmaceuticals. Some animal studies indicate that such nanomaterials may have some toxicity, but their synergistic actions on the adverse effects of drugs are not well understood. In this study, we investigated whether 70-nm silica particles (nSP70), which are widely used in cosmetics and drug delivery, affect the toxicity of a drug for inflammatory bowel disease (5-aminosalicylic acid), an antibiotic drug (tetracycline), an antidepressant drug (trazodone), and an antipyretic drug (acetaminophen) in mice. Co-administration of nSP70 with trazodone did not increase a biochemical marker of liver injury. In contrast, co-administration increased the hepatotoxicity of the other drugs. Co-administration of nSP70 and tetracycline was lethal. These findings indicate that evaluation of synergistic adverse effects is important for the application of nano-sized materials. PMID- 21612157 TI - The cardiovascular inhibition functions of hydrogen sulfide within the nucleus tractus solitarii are mediated by the activation of KATP channels and glutamate receptors mechanisms. AB - Hydrogen sulfide (H2S), the colorless gas with the smell of rotten eggs, has been regarded as a novel gaseous signaling molecule. Although H2S has been proved been involved into the cardiovascular functions, the cardiovascular functions of H2S within the nucleus tractus solitarii (NTS) are not clear. Unilateral microinjection of NaHS (2 to 200 pmol), a H2S donor, into the NTS caused transient and dose-dependent hypotension and bradycardia (P<0.01). Microinjection of CBS allosteric activator S-ademetionine (SAM) into the NTS also produced significant decreases in BP (from 101 +/- 8 to 82 +/- 7 mmHg, P < 0.01) and HR (from 469 +/- 16 to 449 +/- 14 bpm, P<0.01), which was very similar to those of NaHS. Pretreatment with hydroxylamine, a CBS inhibitor, failed to affect the cardiovascular functions of intra-NTS NaHS. However, pretreatment with glibenclamide (10 nmol), a KATP channel blocker, eliminated the on BP (from -23 +/- 4 to -5 +/- 1 mmHg, P<0.01) and HR (from -24 +/- 2 to -5 +/- 1 bpm, P<0.01) by 78% and 79%, respectively, of intra-NTS NaHS (20 pmol). Likewise, pretreatment with kynurenic acid (Kyn, 5 nmol) also attenuated the effects of NaHS on BP (from -29 +/- 3 to -12 +/- 3 mmHg, P<0.01) and HR (from -19 +/- 2 to -9 +/- 2 bpm, P<0.01) by 59% and 53%, respectively, of intra-NTS NaHS (20 pmol). These data support the hypothesis that endogenous H2S produces cardiovascular inhibition functions in the NTS, mainly mediated by KATP channels regulation or/and glutamate receptors. PMID- 21612158 TI - The TRIF/TBK1/IRF-3 activation pathway is the primary inhibitory target of resveratrol, contributing to its broad-spectrum anti-inflammatory effects. AB - Resveratrol, a stilbene type compound identified in wine and fruit juice, has been found to exhibit various pharmacological activities such as anti-oxidative, anti-cancerous, anti-inflammatory and anti-aging effects. Although numerous papers have explored the pharmacology of resveratrol in one particular cellular action, how this compound can have multiple effects simultaneously has not been fully addressed. In this study, therefore, we explored its broad-spectrum inhibitory mechanism using lipopolysaccharide (LPS)-mediated inflammatory responses and reporter gene assays involving overexpression of toll like receptor (TLR) adaptor molecules. Co-transfection of adaptor molecules such as (1) myeloid differentiation primary response gene 88 (MyD88), (2) Toll/4ll-1 Receptor-domain containing adapter-inducing interferon-beta (TRIF), (3) TRIF-related adaptor molecule (TRAM), or (4) TANK-binding kinase (TBK) 1 strongly enhanced luciferase activity mediated by transcription factors including nuclear factor (NF)-KB, activator protein (AP)-1, and interferon regulatory factor (IRF)-3. Of the adaptor proteins, TRIF and TBK1 but not MyD88 and IKK enhanced luciferase activity mediated by these transcription factors. Resveratrol dose-dependently suppressed LPS-induced NO production in macrophages. It also blocked the increases in levels of mRNA for IFN-1, tumor necrosis factor (TNF)-alpha, and inducible nitric oxide synthase (iNOS) that were induced by LPS. Resveratrol diminished the translocation or activation of IRF-3 at 90min, c-Jun, a subunit of AP-1, and STAT-1 at 120 min, and p50, a subunit of NF-KB, at 60 and 90 min. Resveratrol strongly suppressed the up-regulation of luciferase activity induced by these adaptor molecules with IC50 values of 5 to 65 microM. In particular, higher inhibitory effects of resveratrol were when TRIF or TBK1 were overexpressed following cotransfection of luciferase constructs with IRF-3 binding sequences. Taken together, our data suggest that the suppression of TRIF and TBK1, which mediates transcriptional activation of NF-kappaB, AP-1, and IRF 3, contributes to resveratrol's broad-spectrum inhibitory activity, and that this compound can be further developed as a lead anti-inflammatory compound. PMID- 21612159 TI - Serotonin derivatives as inhibitors of beta-secretase (BACE 1). AB - All serotonin derivatives described here (1-9) inhibited BACE 1 in a dose dependent manner. The 50% Inhibition Concentration (IC50) of N-cinnamoyl serotonin (1) was 86.7 +/- 4.0 microM. The peptide conjugation of serotonin derivatives influenced the BACE 1 inhibitory activity. Among serotonin derivatives (1-8), introduction of substituents, such as hydroxyl and methoxy groups at the 4'-position decreased the inhibitory activity (N-p-coumaroyl serotonin (2), N-p-methoxy cinnamoyl serotonin (3)). With a hydroxylgroup at the 4'-position, and the meta-hydroxy function being substituted by a hydroxyl group or methoxy group (N-caffeoyl serotonin (4), N-feruloyl serotonin (5)), inhibitory activity was weakened, (IC50 >400 microM). BACE 1 inhibitory activity was effected by the substituents of the cinnamic acid moiety. This is the first report on Structure-Activity-Relationships (SAR) for the BACE 1-inhibiting activity of serotonin derivatives. These serotonin derivatives, which have anti oxidative effects as well are expected to be useful in the study of the mechanisms of Alzheimer's disease. PMID- 21612161 TI - Thank you to our volunteer leaders. These invaluable individuals contribute much at the local and national levels. PMID- 21612160 TI - Arbutin inhibits TCCSUP human bladder cancer cell proliferation via up-regulation of p21. AB - Arbutin is a glycosylated hydroquinone extracted from the bearberry plant (Arctostaphylos species). In the present study, we determined the effects of arbutin on TCCSUP human bladder carcinoma cell proliferation. Arbutin did not exhibit any cytotoxic effects in TCCSUP cells at concentrations of < 500 microg/ml. To determine the effects of arbutin on cell proliferation, TCCSUP cells were treated with arbutin at various concentrations, and the cell proliferation was measured using the MTT assay. Arbutin significantly decreased TCCSUP cell proliferation in a concentration- and time-dependent manner. Furthermore, cell cycle analysis revealed that arbutin strongly disrupted the cell cycle in a time-dependent manner. Western blot analysis demonstrated that arbutin led to the inactivation of extracellular signal-regulated kinase (ERK), which is known to critically regulate cell proliferation. In addition, arbutin markedly increased the expression of p21WAF1/CIP1 (p21), which is known to be highly involved in cell cycle regulation. Therefore, this study suggests that arbutin inhibits TCCSUP cell proliferation via ERK inactivation and p21 up regulation. PMID- 21612162 TI - Elevating IT: make it central to your long-term strategy. PMID- 21612163 TI - The evolving CIO: from IT manager to key healthcare delivery strategist. PMID- 21612164 TI - Ethical wisdom: doing the right thing, every day, everywhere in the organization. PMID- 21612165 TI - 7 factors complicate ethical resource allocation decisions: we should be more aware of the issues most likely to produce conflicts. PMID- 21612166 TI - Using social media to engage patients: many tools exist to connect, communicate and build loyalty. PMID- 21612167 TI - Creating a network of care: healthy San Francisco connects uninsured residents to a primary care home. PMID- 21612168 TI - Value-based purchasing program here to stay: payments will be based on performance. PMID- 21612169 TI - Starting a new job: dos and don'ts: newly hired leaders must take charge of the job start. PMID- 21612170 TI - New tools apply competencies to board work: broader concept of competence includes behavior. PMID- 21612171 TI - Visionary leadership for enhanced care: bifocals (or even trifocals) recommended to see improvements in care design. PMID- 21612172 TI - Physicians and health reform: creating a "we" culture. PMID- 21612173 TI - Extending their reach: chapters look for ways to bring education and networking closer to affiliates. PMID- 21612174 TI - Right to choose. PMID- 21612175 TI - Profile: Mark Butler. PMID- 21612176 TI - Nurses in the park: a personal account of the Christchurch earthquake. PMID- 21612177 TI - Homelessness is everyone's business. PMID- 21612178 TI - Witnesses in health care--what role do they play? PMID- 21612179 TI - Professor Sabina Knight. PMID- 21612180 TI - Responding to traumatic events. PMID- 21612181 TI - Looking at women's health through a wide angled lens. PMID- 21612182 TI - New de-infibulation clinic for Royal Women's in Melbourne. PMID- 21612183 TI - Groundbreaking nurse led research. PMID- 21612185 TI - Branch Council--a significant personal commitment. PMID- 21612184 TI - Menopause and beyond. PMID- 21612186 TI - Redox noninnocence of nitrosoarene ligands in transition metal complexes. AB - Studies on the coordination of nitrosoarene (ArNO) ligands to late-transition metals are used to provide the first definition of the geometric, spectroscopic, and computational parameters associated with a PhNO electron-transfer series. Experimentally, the Pd complexes PdCl(2)(PhNO)(2), PdL(2)(PhNO)(2), and PdL(2)(TolNO) (L = CNAr(Dipp2); Ar(Dipp2) = 2,6-(2,6-(i)Pr(2)C(6)H(3))(2) C(6)H(3)) are characterized as containing (PhNO)(0), (PhNO)(*1-), and (TolNO)(2-) ligands, respectively, and the structural and spectroscopic changes associated with this electron transfer series provide the basis for an extensive computational study of these and related ArNO-containing late-transition metal complexes. Most notable from the results is the unambiguous characterization of the ground state electronic structure of PdL(2)(PhNO)(2), found to be the first isolable, transition metal ion complex containing an eta(1)-N-bound pi nitrosoarene radical anion. In addition to the electron transfer series, the synthesis and characterization of the Fe complex [Fe(TIM)(NCCH(3))(PhNO)][(PF(6))(2)] (TIM = 2,3,9,10-tetramethyl-1,4,8,11 tetraazacyclotetradeca-1,3,8,10-tetraene) allows for comparison of the geometric and spectroscopic features associated with metal-to-ligand pi-backbonding as opposed to (PhNO)(*1-) formation. Throughout these series of complexes, the N-O, M-N, and C-N bond distances as well as the N-O stretching frequencies and the planarity of the ArNO ligands provided distinct parameters for each ligand oxidation state. Together, these data provide a delineation of the factors needed for evaluating the oxidation state of nitrosoarene ligands bound to transition metals in varying coordination modes. PMID- 21612187 TI - Yb valence states in YbC2: a HERFD-XANES spectroscopic investigation. AB - The valence state of Yb in YbC(2) was analyzed using high-energy-resolution fluorescence detection (HERFD) X-ray absorption near-edge structure (XANES) spectroscopy and time-of-flight neutron powder diffraction to clarify a controversy in the literature. The unit cell volume of YbC(2) suggests a mixed Yb valence, which was formerly determined to be 2.8 by magnetization measurements and paramagnetic neutron scattering techniques. However, the nature of the intermediate valence was not clearly established. Both homogeneous and heterogeneous mixed valences were assumed in different publications. The temperature-dependent behavior of the valence state was only predicted, albeit not explicitly studied. In this work, the valence state of Yb in YbC(2) is, therefore, investigated thoroughly by HERFD-XANES spectroscopy at low and high temperatures. Our measurements result in an average Yb valence of 2.81 that is temperature-independent from 15 to 1123 K. These findings are confirmed by neutron powder diffraction experiments, which reveal a constant C-C distance of 128.7(9) pm in a temperature range from 5 to 100 K. A significant temperature dependence of the Yb valence state in YbC(2) can, therefore, be excluded by our experimental results. PMID- 21612188 TI - Synthesis of blue imino(pentafluorophenyl)phosphane. AB - The reaction of AgC(6)F(5) with monomeric iminophosphanes of Mes*-N?P-X (X = Cl, I) in CH(2)Cl(2) at ambient temperature gives imino(pentafluorophenyl)phosphane, Mes*N?P(C(6)F(5)) (1), in almost quantitative yield (96%), which could be isolated as a highly viscous blue oil. The same reaction with LiC(6)F(5) results in the formation of imino(amino)phosphane (C(6)F(5))(2)P-N(Mes*)-P?NMes* (2) (yield 93%). In the second series of experiments the analogous reaction of MC(6)F(5) (M = Ag, Li) with dimeric [Cl-P(MU-N-Dipp)](2) was studied, leading to the formation of [R-P(MU-N-Dipp)](2) (R = C(6)F(5)) (3) for M = Ag, while only decomposition products such as P(C(6)F(5))(3) were observed in the reaction with the Li salt. Highly labile Mes*-N?P-C(6)F(5) (1) decomposes at ambient temperatures, forming among other products the diphosphane (C(6)F(5))(2)P P(C(6)F(5))(2) (4). Reaction of 1 with Fe(2)(CO)(9) yields the iron carbonyl complexes Mes*-N?P(C(6)F(5)).Fe(CO)(4) (5) and [Mes*-N?P(C(6)F(5))](2).Fe(CO)(3) (6). The structure, bonding, and potential energy surface are discussed on the basis of B3LYP/6-31G(d,p) computations. According to time-dependent B3LYP calculations, the blue color of 1 arises from an n -> pi* electronic transition. PMID- 21612190 TI - Metal-stabilized thiyl radicals as scaffolds for reversible alkene addition via C S bond formation/cleavage. AB - The one-electron oxidation of metal thiolates results in an increased oxidation state of the metal ion or the formation of a sulfur-based, thiyl radical in limiting extremes. For complexes with highly covalent M-S bonds, the unpaired electron may be delocalized over the metal and the sulfur, yielding a metal stabilized thiyl radical. Oxidation of the metal thiolate precursors [Ru(DPPBT)(3)](-), [Ru-1](-), and Re(DPPBT)(3), Re-1 (DPPBT = diphenylphosphinobenzenethiolate), generates metal-stabilized thiyl radicals that react with alkenes to yield dithioether-metal products. Alkene addition to [Ru 1](+) and [Re-1](+) is symmetry-allowed due to the meridional arrangement of the DPPBT chelates. Combined bulk electrolysis and cyclic voltammetry experiments reveal the addition of alkenes to [Ru-1](+) as an irreversible process with experimentally determined rate constants ranging from 4.6(5) * 10(7) M(-1) s(-1) for electron-rich alkenes to 2.7(2) * 10(4) M(-1) s(-1) for electron-poor alkenes. Rate constants for cyclic alkenes range from 4(2) * 10(7) to 2.9(3) * 10(3) M(-1) s(-1). Chemical oxidation of [Ru-1](-) by ferrocenium hexafluorophosphate (FcPF(6)) in the presence of m-methylstyrene or p methylstyrene yields the dithioether complexes [Ru-1.m-methylstyrene](+) and [Ru 1.p-methylstyrene](+), respectively. Each complex was crystallized and the structure determined by single-crystal X-ray diffraction. (31)P NMR of the samples reveals a major and minor product, each displaying a second-order spectrum. The oxidized intermediate [Re-1](+) binds alkenes reversibly with equilibrium binding constants that vary with the complex charge from 1.9 * 10( 11) M(-1) for n = 0 to 4.0 M(-1) for n = +1 to 2.5 * 10(9) M(-1) for n = +2. The three binding regimes are separated by 240 mV. Crystalline samples of [Re 1.C(2)H(4)](2+) are obtained upon chemical oxidation of Re-1 with silver hexafluorophosphate (AgPF(6)) in the presence of ethylene. Strategies for the addition of alkenes to other metal-stabilized thiyl radicals are suggested. PMID- 21612189 TI - On the complexity of kinetics and the mechanism of the thiosulfate-periodate reaction. AB - The thiosulfate-periodate reaction has been studied spectrophotometrically in a slightly acidic medium at 25.0 +/- 0.1 degrees C in an acetate/acetic acid buffer by monitoring the absorbance in the 250-600 nm wavelength range at a constant ionic strength adjusted by the buffer component sodium acetate. In agreement with a previous study, we found that the reaction cannot be described by a single stoichiometric equation, tetrathionate and sulfate are simultaneously formed, and its ratio strongly depends on the pH. As expected at certain initial concentration ratios of the reactants, the reaction behaves as a clock reaction, but after its appearance, iodine is slowly consumed mainly because of the moderate tetrathionate-iodine reaction. It is also enlightened that the initial rate of the reaction is completely independent of the pH, which apparently contradicts a previous study, which postulates a "supercatalytic" behavior of the hydrogen ion on the title reaction. Significant buffer assistance that may change the absorbance-time profiles was also observed. On the basis of the kinetic data, a robust 28-step kinetic model with 22 fitted parameters is proposed and discussed to explain adequately all of the important characteristics of the kinetic curves. PMID- 21612191 TI - Enhancing the magnetic coupling of oxalato-bridged Re(IV)2M(II) (M=Mn, Co, Ni, and Cu) trinuclear complexes via peripheral halide ligand effects. AB - Four heterotrinuclear Re(IV)(2)M(II) compounds of general formula (NBu(4))(2)[{Re(IV)Br(4)(MU-ox)}(2)M(II)(Him)(2)] [NBu(4)(+) = tetra-n butylammonium cation, ox = oxalate, Him = imidazole; M = Mn (1), Co (2), Ni (3), and Cu (4)] have been synthesized by using the novel mononuclear complex [Re(IV)Br(4)(ox)](2-) as a ligand toward divalent first-row transition metal ions in the presence of imidazole. Compounds 1-4 are isostructural complexes whose structure contains discrete trinuclear [{Re(IV)Br(4)(MU-ox)}(2)M(II)(Him)(2)](2-) anions and bulky NBu(4)(+) cations. The Re and M atoms are six-coordinated: four peripheral bromo and two oxalate-oxygens (at Re), and two cis-coordinated imidazole molecules and four oxygen atoms from two oxalate ligands (at M), build distorted octahedral surroundings. Two peripheral [ReBr(4)(ox)](2-) units act as bidentate ligands through the oxalate group toward the central [M(II)(Him)(2)] fragment affording the trinuclear entities. The values of the intramolecular Re...M separation are 5.62(1) (1), 5.51(1) (2), 5.46(1) (3), and 5.55(1) A (4). Magnetic susceptibility measurements on polycrystalline samples of 1-4 in the temperature range of 1.9-300 K show the occurrence of intramolecular antiferro- [J = -1.1 cm(-1) (1)] and ferromagnetic interactions [J = +3.9 (2), +19.7 (3), and +14.4 cm(-1) (4)], the Hamiltonian being defined as H = -J [S(M)(S(Re1) + S(Re2))]. The larger spin delocalization on the oxalato bridge in 1-4 when compared to the trinuclear Re(IV)(2)M(II) complexes with chloro instead of bromo as peripheral ligands (1'-4') accounts for the strengthening of the magnetic interactions in 1-4 [J = -0.35 (1'), +14.2 (3'), and +7.7 cm(-1) (4')]. An incipient frequency dependence of the out-of-phase ac signals of 3 at very low temperatures is reminiscent of a system with slow relaxation of the magnetization, a phenomenon characteristic of single-molecule magnet behavior. PMID- 21612192 TI - Dinuclear cobalt(II) and copper(II) complexes with a Py2N4S2 macrocyclic ligand. AB - The interaction between Co(II) and Cu(II) ions with a Py(2)N(4)S(2)-coordinating octadentate macrocyclic ligand (L) to afford dinuclear compounds has been investigated. The complexes were characterized by microanalysis, conductivity measurements, IR spectroscopy and liquid secondary ion mass spectrometry. The crystal structure of the compounds [H(4)L](NO(3))(4), [Cu(2)LCl(2)](NO(3))(2) (5), [Cu(2)L(NO(3))(2)](NO(3))(2) (6), and [Cu(2)L(MU-OH)](ClO(4))(3).H(2)O (7) was also determined by single-crystal X-ray diffraction. The [H(4)L](4+) cation crystal structure presents two different conformations, planar and step, with intermolecular face-to-face pi,pi-stacking interactions between the pyridinic rings. Complexes 5 and 6 show the metal ions in a slightly distorted square pyramidal coordination geometry. In the case of complex 7, the crystal structure presents the two metal ions joined by a MU-hydroxo bridge and the Cu(II) centers in a slightly distorted square plane or a tetragonally distorted octahedral geometry, taking into account weak interactions in axial positions. Electron paramagnetic resonance spectroscopy is in accordance with the dinuclear nature of the complexes, with an octahedral environment for the cobalt(II) compounds and square-pyramidal or tetragonally elongated octahedral geometries for the copper(II) compounds. The magnetic behavior is consistent with the existence of antiferromagnetic interactions between the ions for cobalt(II) and copper(II) complexes, while for the Co(II) ones, this behavior could also be explained by spin-orbit coupling. PMID- 21612193 TI - Cluster expansion reactions of group 6 and 8 metallaboranes using transition metal carbonyl compounds of groups 7-9. AB - The reinvestigation of an early synthesis of heterometallic cubane-type clusters has led to the isolation of a number of new clusters which have been characterized by spectroscopic and crystallographic techniques. The thermolysis of [(Cp*Mo)(2)B(4)H(4)E(2)] (1: E = S; 2: E = Se; Cp* = eta(5)-C(5)Me(5)) in presence of [Fe(2)(CO)(9)] yielded cubane-type clusters [(Cp*Mo)(2)(MU(3) E)(2)B(2)H(MU-H){Fe(CO)(2)}(2)Fe(CO)(3)], 4 and 5 (4: E = S; 5: E = Se) together with fused clusters [(Cp*Mo)(2)B(4)H(4)E(2)Fe(CO)(2)Fe(CO)(3)] (8: E = S; 9: E = Se). In a similar fashion, reaction of [(Cp*RuCO)(2)B(2)H(6)], 3, with [Fe(2)(CO)(9)] yielded [(Cp*Ru)(2)(MU(3)-CO)(2)B(2)H(MU H){Fe(CO)(2)}(2)Fe(CO)(3)], 6, and an incomplete cubane cluster [(MU(3) BH)(3)(Cp*Ru)(2){Fe(CO)(3)}(2)], 7. Clusters 4-6 can be described as heterometallic cubane clusters containing a Fe(CO)(3) moiety exo-bonded to the cubane, while 7 has an incomplete cubane [Ru(2)Fe(2)B(3)] core. The geometry of both compounds 8 and 9 consist of a bicapped octahedron [Mo(2)Fe(2)B(3)E] and a trigonal bipyramidal [Mo(2)B(2)E] core, fused through a common three vertex [Mo(2)B] triangular face. In addition, thermolysis of 3 with [Mn(2)(CO)(10)] permits the isolation of arachno-[(Cp*RuCO)(2)B(3)H(7)], 10. Cluster 10 constitutes a diruthenaborane analogue of 8-sep pentaborane(11) and has a structural isomeric relationship to 1,2-[{Cp*Ru}(2)(CO)(2)B(3)H(7)]. PMID- 21612194 TI - Selective formation of 1,5-substituted sulfonyl triazoles using acetylides and sulfonyl azides. AB - The reaction of acetylides with sulfonyl azides was found to selectively form 1,5 substituted sulfonyl triazoles. This reaction thus provides access to the regioisomeric product as compared to the popular copper-catalyzed azide-alkyne cycloaddition. The reaction is efficient and selective with a variety of alkyne sources and sulfonyl azides and can incorporate an additional electrophile to yield 1,4,5-trisubstituted sulfonyl triazoles. PMID- 21612195 TI - Ruthenium-catalyzed oxidative synthesis of 2-pyridones through C-H/N-H bond functionalizations. AB - An inexpensive ruthenium catalyst enabled oxidative annulations of alkynes by acrylamides with ample scope, which allowed for the preparation of 2-pyridones employing various electron-rich and electron-deficient acrylamides as well as (di)aryl- and (di)alkyl-substituted alkynes. PMID- 21612196 TI - Puzzle of protein dynamical transition. AB - Despite recent extensive efforts, the nature of the dynamics of biological macromolecules still remains unclear. In particular, contradicting models have been proposed for explaining the temperature behavior of the mean square displacement, MSD, and of the system relaxation time, tau. To solve this puzzle, different neutron scattering experiments with different instrumental energy resolutions were performed on dry and hydrated lysozyme. The obtained results show that the so called dynamical transition: (i) is a finite instrumental energy resolution effect, and more specifically, it appears when the characteristic system relaxation time intersects the resolution time, (ii) it does not imply any transition in the dynamical properties of the systems, (iii) it is not due to the fragile-to-strong dynamical crossover (FSC) in the temperature behavior of the system relaxation time, differently to what S. H. Chen et al. proposed [Proc. Natl. Acad. Sci. U.S.A.2006, 103, 9012]. Furthermore, the obtained results confirm the change in the tau-temperature dependence at T = 220 K of S. H. Chen et al., and show that it is not due to finite instrumental energy resolution effects and it is not connected to numerical errors in the data analysis protocol, differently to what W. Doster et al. proposed [Phys. Rev. Lett.2010, 104, 098101]. PMID- 21612197 TI - Functional micro/nanostructures: simple synthesis and application in sensors, fuel cells, and gene delivery. AB - In order to develop new, high technology devices for a variety of applications, researchers would like to better control the structure and function of micro/nanomaterials through an understanding of the role of size, shape, architecture, composition, hybridization, molecular engineering, assembly, and microstructure. However, researchers continue to face great challenges in the construction of well-defined micro/nanomaterials with diverse morphologies. At the same time, the research interface where micro/nanomaterials meet electrochemistry, analytical chemistry, biomedicine, and other fields provides rich opportunities to reveal new chemical, physical, and biological properties of micro/nanomaterials and to uncover many new functions and applications of these materials. In this Account, we describe our recent progress in the construction of novel inorganic and polymer nanostructures formed through different simple strategies. Our synthetic strategies include wet-chemical and electrochemical methods for the controlled production of inorganic and polymer nanomaterials with well-defined morphologies. These methods are both facile and reliable, allowing us to produce high-quality micro/nanostructures, such as nanoplates, micro/nanoflowers, monodisperse micro/nanoparticles, nanowires, nanobelts, and polyhedron and even diverse hybrid structures. We implemented a series of approaches to address the challenges in the preparation of new functional micro/nanomaterials for a variety of important applications This Account also highlights new or enhanced applications of certain micro/nanomaterials in sensing applications. We singled out analytical techniques that take advantage of particular properties of micro/nanomaterials. Then by rationally tailoring experimental parameters, we readily and selectively obtained different types of micro/nanomaterials with novel morphologies with high performance in applications such as electrochemical sensors, electrochemiluminescent sensors, gene delivery agents, and fuel cell catalysts. We expect that micro/nanomaterials with unique structural characteristics, properties, and functions will attract increasing research interest and will lead to new opportunities in various fields of research. PMID- 21612198 TI - Multidentate adsorbates for self-assembled monolayer films. AB - The spontaneous adsorption of organic molecules on a variety of planar and nonplanar substrates, that is, self assembly, can generate films just one molecule thick. These nanoscale, self-assembled monolayer (SAM) films have been extensively used to engineer surfaces with well-defined properties. Their utility has been demonstrated in a wide range of applications, including wetting, adhesion, lubrication, patterning, and molecular recognition. Many SAM systems have been investigated, but alkanethiols adsorbed on gold are the most successful combination. This pairing offers a variety of advantages, including the ability to tune precisely the interfacial properties of a surface through the well established organic synthetic methodologies that have been developed for preparing custom omega-terminated alkanethiols. Alkanethiolate monolayers are moderately stable at room temperature; however, these films degrade over time and readily desorb upon moderate heating. This shortcoming limits the use of SAMs in applications involving elevated temperatures or harsh environments. Accordingly, new adsorbates with multiple bonding moieties have been created to enhance the stability and versatility of SAMs. In this Account, we examine a variety of multidentate adsorbate structures that have been used to generate SAMs on planar substrates and on nanoparticles. Each of these chelating adsorbates (bidentates and tridentates) has been designed to generate well-defined organic monolayer films with multiple attachment points to the underlying substrate. This bonding arrangement allows the formation of SAMs with enhanced stability through the entropy-driven "chelate effect". The research examined here demonstrates that multidentate adsorbates provide robust films: they enable the use of SAMs under conditions that are incompatible with SAMs derived from normal alkanethiols. Another advantage offered by multidentate adsorbates is the capacity for new paradigms in thin-film composition. In particular, appropriately designed chelating adsorbates can be engineered to have two or more chemically distinct terminal groups that are covalently linked to the same underlying headgroup, without adding steric bulk that might prove detrimental to the resultant assembly. This strategy allows the generation of homogeneously mixed multicomponent surfaces, overcoming the problem of phase separation or "islanding" that is pervasive when two or more chemically distinct adsorbates are used to form mixed SAMs. Such homogeneously mixed films offer the opportunity to fine-tune the interfacial properties of a substrate and to create unique heterogeneous interfaces that are well defined by the chemical composition of the tailgroups exposed at the surface. The insight derived from these studies opens the door to new uses for SAMs, both in surface engineering applications (such as corrosion resistance and soft lithographic patterning) and in the stabilization and manipulation of nanoparticles. PMID- 21612199 TI - Theranostic nanoshells: from probe design to imaging and treatment of cancer. AB - Recent advances in nanoscience and biomedicine have expanded our ability to design and construct multifunctional nanoparticles that combine targeting, therapeutic, and diagnostic functions within a single nanoscale complex. The theranostic capabilities of gold nanoshells, spherical nanoparticles with silica cores and gold shells, have attracted tremendous attention over the past decade as nanoshells have emerged as a promising tool for cancer therapy and bioimaging enhancement. This Account examines the design and synthesis of nanoshell-based theranostic agents, their plasmon-derived optical properties, and their corresponding applications. We discuss the design and preparation of nanoshell complexes and their ability to enhance the photoluminescence of fluorophores while maintaining their properties as MR contrast agents. In this Account, we discuss the underlying physical principles that contribute to the photothermal response of nanoshells. We then elucidate the photophysical processes that induce nanoshells to enhance the fluorescence of weak near-infrared fluorophores. Nanoshells illuminated with resonant light are either strong optical absorbers or scatterers, properties that give rise to their unique capabilities. These physical processes have been harnessed to visualize and eliminate cancer cells. We describe the application of nanoshells as a contrast agent for optical coherence tomography of breast carcinoma cells in vivo. Our recent studies examine nanoshells as a multimodal theranostic probe, using these nanoparticles for near-infrared fluorescence and magnetic resonance imaging (MRI) and for the photothermal ablation of cancer cells. Multimodal nanoshells show theranostic potential for imaging subcutaneous breast cancer tumors in animal models and the distribution of tumors in various tissues. Nanoshells also show promise as light triggered gene therapy vectors, adding temporal control to the spatial control characteristic of nanoparticle-based gene therapy approaches. We describe the fabrication of DNA-conjugated nanoshell complexes and compare the efficiency of light-induced and thermally-induced release of DNA. Double-stranded DNA nanoshells also provide a way to deliver small molecules into cells: we describe the delivery and light-triggered release of DAPI (4',6-diamidino-2-phenylindole), a dye molecule used to stain DNA in the nuclei of cells. PMID- 21612200 TI - Mechanistic aspects of bond activation with perfluoroarylboranes. AB - In the mid-1990s, it was discovered that tris(pentafluorophenyl)borane, B(C(6)F(5))(3), was an effective catalyst for hydrosilylation of a variety of carbonyl and imine functions. Mechanistic studies revealed a counterintuitive path in which the function of the borane was to activate the silane rather than the organic substrate. This was the first example of what has come to be known as "frustrated Lewis pair" chemistry utilizing this remarkable class of electrophilic boranes. Subsequent discoveries by the groups of Stephan and Erker showed that this could be extended to the activation of dihydrogen, initiating an intense period of activity in this area in the past 5 years. This article describes the early hydrosilylation chemistry and its subsequent applications to a variety of transformations of importance to organic and inorganic chemists, drawing parallels with the more recent hydrogen activation chemistry. Here, we emphasize the current understanding of the mechanism of this process rather than focusing on the many and emerging applications of hydrogen activation by fluoroarylborane-based frustrated Lewis pair systems. PMID- 21612201 TI - What is the role of fresh groundwater and recirculated seawater in conveying nutrients to the coastal ocean? AB - Submarine groundwater discharge (SGD) is a major process operating at the land sea interface. Quantifying the SGD nutrient loads and the marine/terrestrial controls of this transport is of high importance, especially in oligotrophic seas such as the eastern Mediterranean. The fluxes of nutrients in groundwater discharging from the seafloor at Dor Bay (southeastern Mediterranean) were studied in detail using seepage meters. Our main finding is that the terrestrial, fresh groundwater is the main conveyor of DIN and silica to the coastal water, with loads of 500 and 560 mol/yr, respectively, per 1 m shoreline. Conversely, recirculated seawater is nutrient-poor, and its role is mainly as a dilution agent. The nutrient loads regenerated in the subterranean estuary (sub-bay sediment) are relatively small, consisting mostly of ammonium (24 mol/yr). On the other hand, the subterranean estuary at Dor Bay sequesters as much as 100 mol N/yr per 1 m shoreline, mainly via denitrification processes. These, and observations from other SGD sites, imply that the subterranean estuary at some coastal systems may function more as a sink for nitrogen than a source. This further questions the extent of nutrient contributions to the coastal water by some subterranean estuaries and warrants systematic evaluation of this process in various hydrological and marine trophic conditions. PMID- 21612202 TI - Chromium porphyrin arrays as spintronic devices. AB - Spintronic devices are very important for futuristic information technology. Suitable materials for such devices should have half-metallic properties so that only one spin passes through the device. In particular, organic half metals have the advantage that they may be used for flexible devices and have a long spin coherence length. We predict that the one-dimensional infinite chromium porphyrin array, which we call Cr-PA(infinity), shows half-metallic behavior when the spins on the chromium atoms are in a parallel alignment. Since the chromium atoms are separated by a large distance (>8 A), the coupling between spins is small and thus their directions can be readily controlled by an external magnetic field. In the ferromagnetic state, the band gap for major spin electrons is 0.30 eV, while there is no band gap for the minor spin electrons, thus reflecting the half metallic property. This unique property originates from the high spin state of Cr which results in the spin asymmetry of the conduction band in Cr-PA(infinity). Electron transport of Cr-PA(1,2,3) is calculated with the nonequilibrium Green function technique in the presence of Au electrodes. It turned out that the spin filtering ability appears from the dimeric Cr-PA(2). Thus, a new organometallic framework for designing a spin filter is proposed. Though many others have designed novel spintronic devices, none of them are realized due to the lack of a practical fabrication method at present. However, the porphyrin-based spintronic device provides a synthesizable framework. PMID- 21612203 TI - Reactivity and selectivity of charged phenyl radicals toward amino acids in a Fourier transform ion cyclotron resonance mass spectrometer. AB - The reactivity of 10 charged phenyl radicals toward several amino acids was examined in the gas phase in a dual-cell Fourier transform ion cyclotron resonance mass spectrometer. All radicals abstract a hydrogen atom from the amino acids, as expected. The most electrophilic radicals (with the greatest calculated vertical electron affinities (EA) at the radical site) also react with these amino acids via NH(2) abstraction (a nonradical nucleophilic addition-elimination reaction). Both the radical (hydrogen atom abstraction) and nonradical (NH(2) abstraction) reaction efficiencies were found to increase with the electrophilicity (EA) of the radical. However, NH(2) abstraction is more strongly influenced by EA. In contrast to an earlier report, the ionization energies of the amino acids do not appear to play a general reactivity-controlling role. Studies using several partially deuterium-labeled amino acids revealed that abstraction of a hydrogen atom from the alpha-carbon is only preferred for glycine; for the other amino acids, a hydrogen atom is preferentially abstracted from the side chain. The electrophilicity of the radicals does not appear to have a major influence on the site from which the hydrogen atom is abstracted. Hence, the regioselectivity of hydrogen atom abstraction appears to be independent of the structure of the radical but dependent on the structure of the amino acid. Surprisingly, abstraction of two hydrogen atoms was observed for the N-(3-nitro-5 dehydrophenyl)pyridinium radical, indicating that substituents on the radical not only influence the EA of the radical but also can be involved in the reaction. In disagreement with an earlier report, proline was found to display several unprecedented reaction pathways that likely do not proceed via a radical mechanism but rather by a nucleophilic addition-elimination mechanism. Both NH(2) and (15)NH(2) groups were abstracted from lysine labeled with (15)N on the side chain, indicating that NH(2) abstraction occurs both from the amino terminus and from the side chain. Quantum chemical calculations were employed to obtain insights into some of the reaction mechanisms. PMID- 21612204 TI - Palladium(0)-catalyzed arylative dearomatization of phenols. AB - The palladium-catalyzed arylative dearomatization of phenols to yield spirocyclohexadienone products in good to excellent yields has been developed. Preliminary results demonstrate that the formation of the spirocyclic all-carbon quaternary center can be accomplished with high levels of enantiocontrol (up to 91% ee). PMID- 21612205 TI - From alpha-arylation of olefins to acylation with aldehydes: a journey in regiocontrol of the Heck reaction. AB - The Pd-catalyzed Mizoroki-Heck reaction of olefins with aryl halides, more often simply called the Heck reaction, was recently recognized with the 2010 Nobel Prize in chemistry. Although highly selective with electron-deficient olefins, which generally yield the linear beta-arylated product exclusively, the Heck reaction is less satisfactory with electron-rich olefins. This substrate typically generates a mixture of both alpha- and beta-arylated regioisomeric products, hampering wider application of the reaction in chemical synthesis. Pioneering studies by a number of researchers revealed that high alpha regioselectivity could be obtained under Pd-diphosphine catalysis either through (i) the substitution of aryl triflates for halides or (ii) the addition of stoichiometric silver or thallium salts when aryl halides are used. Under these conditions, the arylation is believed to proceed via an ionic pathway. However, silver introduces added cost, thallium salts are toxic, and triflates are generally commercially unavailable, base sensitive, and thermally labile. Believing that the ionic pathway would be promoted in an ionic medium, in the early 2000s, we attempted the Pd-catalyzed arylation of the benchmark electron rich olefin butyl vinyl ether with aryl bromides in an imidazolium ionic liquid. We were delighted to observe that highly regioselective alpha-arylation could readily be accomplished, with no need for silver additives, thallium additives, or aryl triflates. A range of other electron-rich olefins has since been shown to be viable as well. The high alpha-selectivity probably results from the high ionic strength of the medium, which facilitates the dissociation of halide anions from the [L(2)Pd(Ar)X] intermediate, channeling the arylation into the ionic pathway. Hydrogen bonding interactions may also play a role, however. We subsequently discovered that the alpha-arylation can indeed be significantly accelerated by a hydrogen bond donor salt, in both ionic liquids and common solvents. Evidence shows that the concentration of the cationic Pd(II)-olefin species along the ionic pathway is increased as a result of hydrogen bonding between the hydrogen bond donor and the halide anion. More recently, we reported that cheaper and greener alcohols allow the Heck arylation of electron-rich olefins to proceed in a much faster, productive, and totally alpha-regioselective manner, circumventing the need for an ionic medium or hydrogen bond donor salt. In particular, aryl chlorides with diverse properties have been demonstrated to be viable substrates for the first time. Significantly, it appears that ethylene glycol facilitates both the oxidative addition of ArCl to Pd(0) and the subsequent dissociation of chloride from Pd(II). A closely related reaction, acylation of aryl halides with aldehydes, was also developed. Proceeding via the intermediacy of an electron-rich enamine, this Pd-pyrrolidine cooperative catalysis affords alkyl aryl ketones in a straightforward manner, extending the Heck reaction from olefins to aldehydes. PMID- 21612206 TI - Enhanced pi-conjugation and emission via icosahedral carboranes: synthetic and spectroscopic investigation. AB - The ability of ortho-, meta- and para-carboranes to enhance the emission intensity has been compared. For this purpose a series of carborane-appended 1,3,5-triphenylbenzene (TB) and 1,3,5- tris(biphenyl-4-yl)benzene (TBB) containing three ortho-, meta- and para-carborane clusters directly attached to the conjugated cores have been synthesized employing Suzuki, Heck, and trimerization reactions. The incorporation of the icosahedral carboranes was associated with a red shift in the UV absorption spectrum of up to 13 nm as well as enhancements of the emission intensities of up to 154%. The presence of ortho carboranes showed the maximum red shift in the UV spectrum whereas the maximum enhancement of the emission intensity was observed in the presence of meta carborane clusters. The order of pi-conjugation extension is found to be ortho > meta ~ para. A comparative thermal analysis indicated o-carborane-appended trimers to be the most thermally stable in the series. Proton NMR spectra of reported carborane-appended trimers indicated that ortho- and meta-carborane cages have benzenelike characteristics. PMID- 21612207 TI - Synthesis of key fragments of leiodelide A. AB - The synthesis of all key fragments of the marine macrolide leiodelide A is described. The polyoxygenated northern subunit is derived from d-xylose, while the southern subunit is rapidly assembled via an aldol reaction and Horner Wadsworth-Emmons olefination. This highly convergent approach will allow for rapid modification and assembly of several isomers of leiodelide A, which may be necessary considering the assignment of leiodelide B has been previously shown to be incorrect. PMID- 21612208 TI - Influence of forest canopies on the deposition of methylmercury to boreal ecosystem watersheds. AB - Although it has been previously shown that forest canopies significantly increase the total deposition of Hg to watersheds, sources and fates of atmospherically deposited MeHg in particular remain poorly understood. In this study, net loadings of MeHg to a watershed were quantified, and the retention and (photo)reduction of MeHg on foliage were measured using unique stable Hg isotope experiments. Annual loadings of MeHg in throughfall (0.34 +/- 0.01 to 0.60 +/- 0.16 mg ha-1 yr-1) and litterfall (0.77 +/- 0.07 to 0.97 +/- 0.34 mg ha-1 yr-1) were collectively 3-4 times higher under different forest canopies than loadings of MeHg in the open (0.41 mg ha-1 yr-1), suggesting dry deposition of MeHg to forest canopies. Using Me199Hg, we found that a portion of MeHg wet deposited to forest canopies is retained on foliage over time, eventually contributing to MeHg in litterfall. Average half-lives (t1/2) of Me199Hg on spruce, jack pine, and birch foliage were 204 +/- 66, 187 +/- 101, and 8 +/- 3 days, respectively. We also found using Me199Hg that following wet deposition, MeHg is rapidly (photo)reduced to 199Hg(0) on canopy foliage, which then evades to the atmosphere. We were unable to quantify concentrations of particulate-bound MeHg (p-MeHg) in the air using vacuum pumps and quartz microfiber air sampling filters, despite the possibility that p-MeHg does exist in small quantities. As a result, the source of dry deposited MeHg remains partially elusive. PMID- 21612209 TI - Chlorine isotope analysis of organic contaminants using GC-qMS: method optimization and comparison of different evaluation schemes. AB - Compound-specific online chlorine isotope analysis of chlorinated hydrocarbons was evaluated and validated using gas chromatography coupled to a regular quadrupole mass spectrometer (GC-qMS). This technique avoids tedious off-line sample pretreatments, but requires mathematical data analysis to derive chlorine isotope ratios from mass spectra. We compared existing evaluation schemes to calculate chlorine isotope ratios with those that we modified or newly proposed. We also tested systematically important experimental procedures such as external vs. internal referencing schemes, and instrumental settings including split ratio, ionization energy, and dwell times. To this end, headspace samples of tetrachloroethene (PCE), trichloroethene (TCE), and cis-dichloroethene (cDCE) at aqueous concentrations in the range of 20-500 MUg/L (amount on-column range: 3.2 115 pmol) were analyzed using GC-qMS. The results (37Cl/35Cl ratios) showed satisfying to good precisions with relative standard deviations (n = 5) between 0.40/00 and 2.10/00. However, we found that the achievable precision considerably varies depending on the applied data evaluation scheme, the instrumental settings, and the analyte. A systematic evaluation of these factors allowed us to optimize the GC-qMS technique to determine chlorine isotope ratios of chlorinated organic contaminants. PMID- 21612210 TI - Infrared hollow waveguide sensors for simultaneous gas phase detection of benzene, toluene, and xylenes in field environments. AB - Simultaneous and molecularly selective parts-per-billion detection of benzene, toluene, and xylenes (BTX) using a thermal desorption (TD)-FTIR hollow waveguide (HWG) trace gas sensor is demonstrated here for the first time combining laboratory calibration with real-world sample analysis in field. A calibration range of 100-1000 ppb analyte/N(2) was developed and applied for predicting the concentration of blinded environmental air samples within the same concentration range, and demonstrate close agreement with the validation method used here, GC FID. The analyte concentration prediction capability of the TD-FTIR-HWG trace gas sensor also compares well with the industrial standard and other experimental techniques including GC-PID, ultrafast GC-FID, and GC-DMS, which were simultaneously operated in the field. With the advent of a quantum cascade laser with emission frequencies specifically tailored to efficiently overlap benzene absorption as the most relevant analyte, the overall sensor footprint could be considerably reduced to ultimately yield hand-held trace gas sensors facilitating direct and real-time detection of BTX in air down to low ppb levels. PMID- 21612211 TI - Evaluation of contaminant removal of reverse osmosis and advanced oxidation in full-scale operation by combining passive sampling with chemical analysis and bioanalytical tools. AB - Advanced water treatment of secondary treated effluent requires stringent quality control to achieve a water quality suitable for augmenting drinking water supplies. The removal of micropollutants such as pesticides, industrial chemicals, endocrine disrupting chemicals (EDC), pharmaceuticals, and personal care products (PPCP) is paramount. As the concentrations of individual contaminants are typically low, frequent analytical screening is both laborious and costly. We propose and validate an approach for continuous monitoring by applying passive sampling with Empore disks in vessels that were designed to slow down the water flow, and thus uptake kinetics, and ensure that the uptake is only marginally dependent on the chemicals' physicochemical properties over a relatively narrow molecular size range. This design not only assured integrative sampling over 27 days for a broad range of chemicals but also permitted the use of a suite of bioanalytical tools as sum parameters, representative of mixtures of chemicals with a common mode of toxic action. Bioassays proved to be more sensitive than chemical analysis to assess the removal of organic micropollutants by reverse osmosis, followed by UV/H2O2 treatment, as many individual compounds fell below the quantification limit of chemical analysis, yet still contributed to the observed mixture toxicity. Nonetheless in several cases, the responses in the bioassays were also below their quantification limits and therefore only three bioassays were evaluated here, representing nonspecific toxicity and two specific end points for estrogenicity and photosynthesis inhibition. Chemical analytical techniques were able to quantify 32 pesticides, 62 PCPPs, and 12 EDCs in reverse osmosis concentrate. However, these chemicals could explain only 1% of the nonspecific toxicity in the Microtox assay in the reverse osmosis concentrate and 0.0025% in the treated water. Likewise only 1% of the estrogenic effect in the E-SCREEN could be explained by the quantified EDCs after reverse osmosis. In comparison, >50% of the estrogenic effect can typically be explained in sewage. Herbicidal activity could be fully explained by chemical analysis as the sampling period coincided with an illegal discharge and two herbicides dominated the mixture effect. The mass balance of the reverse osmosis process matched theoretical expectations for both chemical analysis and bioanalytical tools. Overall the investigated treatment train removed >97% estrogenicity, >99% herbicidal activity, and >96% baseline toxicity, confirming the suitability of the treatment train for polishing water for indirect potable reuse. The product water was indistinguishable from local tap water in all three bioassays. This study demonstrates the suitability and robustness of passive sampling linked with bioanalytical tools for semicontinuous monitoring of advanced water treatment with respect to micropollutant removal. PMID- 21612212 TI - General base-guanidinium cooperation in bifunctional artificial phosphodiesterases. AB - Artificial phosphodiesterases that combine a guanidinium unit with a general base connected by a m-xylylene linker catalyze the transesterification of the RNA model compound 2-hydroxypropyl p-nitrophenyl phosphate (HPNP). The bifunctional catalysts presented in this work show varying extents of cooperation between catalytic units and a rate enhancement of 4 * 10(4) in the most favorable case. PMID- 21612214 TI - Extended structures and physicochemical properties of uranyl-organic compounds. AB - The ability of uranium to undergo nuclear fission has been exploited primarily to manufacture nuclear weapons and to generate nuclear power. Outside of its nuclear physics, uranium also exhibits rich chemistry, and it forms various compounds with other elements. Among the uranium-bearing compounds, those with a uranium oxidation state of +6 are most common and a particular structural unit, uranyl UO(2)(2+) is usually involved in these hexavalent uranium compounds. Apart from forming solids with inorganic ions, the uranyl unit also bonds to organic molecules to generate uranyl-organic coordination materials. If appropriate reaction conditions are employed, uranyl-organic extended structures (1-D chains, 2-D layers, and 3-D frameworks) can be obtained. Research on uranyl-organic compounds with extended structures allows for the exploration of their rich structural chemistry, and such studies also point to potential applications such as in materials that could facilitate nuclear waste disposal. In this Account, we describe the structural features of uranyl-organic compounds and efforts to synthesize uranyl-organic compounds with desired structures. We address strategies to construct 3-D uranyl-organic frameworks through rational selection of organic ligands and the incorporation of heteroatoms. The UO(2)(2+) species with inactive U?O double bonds usually form bipyramidal polyhedral structures with ligands coordinated at the equatorial positions, and these polyhedra act as primary building units (PBUs) for the construction of uranyl-organic compounds. The geometry of the uranyl ions and the steric arrangements and functionalities of organic ligands can be exploited in the the design of uranyl--organic extended structures, We also focus on the investigation of the promising physicochemical properties of uranyl-organic compounds. Uranyl-organic materials with an extended structure may exhibit attractive properties, such as photoluminescence, photocatalysis, photocurrent, and photovoltaic responses. In particular, the intriguing, visible-light photocatalytic activities of uranyl-organic compounds are potentially applicable in decomposition of organic pollutants and in water splitting with the irradiation of solar light. We ascribe the photochemical properties of uranyl-organic compounds to the electronic transitions within the U?O bonds, which may be affected by the presence of organic ligands. PMID- 21612213 TI - The stability of myocilin olfactomedin domain variants provides new insight into glaucoma as a protein misfolding disorder. AB - Myocilin variants, localized to the olfactomedin (OLF) domain, are linked to early-onset, inherited forms of open-angle glaucoma. Disease-causing myocilin variants accumulate within trabecular meshwork cells instead of being secreted to the trabecular extracellular matrix of the eye. We hypothesize that, like in other diseases of protein misfolding, aggregation and downstream pathogenesis originate from the compromised thermal stability of mutant myocilins. In an expansion of our pilot study of four mutants, we compare 21 additional purified OLF variants by using a fluorescence stability assay and investigate the secondary structure of the most stable variants by circular dichroism. Variants with lower melting temperatures are correlated with earlier glaucoma diagnoses. The chemical chaperone trimethylamine N-oxide is capable of restoring the stability of most, but not all, variants to wild-type (WT) levels. Interestingly, three reported OLF disease variants, A427T, G246R, and A445V, exhibited properties indistinguishable from those of WT OLF, but an increased apparent aggregation propensity in vitro relative to that of WT OLF suggests that biophysical factors other than thermal stability, such as kinetics and unfolding pathways, may also be involved in myocilin glaucoma pathogenesis. Similarly, no changes from WT OLF stability and secondary structure were detected for three annotated single-nucleotide polymorphism variants. Our work provides the first quantitative demonstration of compromised stability among many identified OLF variants and places myocilin glaucoma in the context of other diseases of protein misfolding. PMID- 21612215 TI - Zirconocene and Si-tethered diynes: a happy match directed toward organometallic chemistry and organic synthesis. AB - Characterizing reactive organometallic intermediates is critical for understanding the mechanistic aspects of metal-mediated organic reactions. Moreover, the isolation of reactive organometallic intermediates can often result in the ability to design new synthetic methods. In this Account, we outline synthetic methods that we developed for a variety of diverse Zr/Si organo bimetallic compounds and Si/N heteroatom-organic compounds through the detailed study of zirconacyclobutene-silacyclobutene fused compounds. Two basic components are involved in this chemistry. The first is the Si-tethered diyne, which owes its rich reactive palette to the combination of the Si-C bond and the C=C triple bond. The second is the low-valent zirconocene species Cp(2)Zr(II), which has proven very useful in organic synthesis. The reaction of these two components affords the zirconacyclobutene-silacyclobutene fused compound, which is the key reactive Zr/Si organo-bimetallic intermediate discussed here. We discuss the three types of reactions that have been developed for the zirconacyclobutene silacyclobutene fused intermediate. The reaction with nitriles (the C=N triple bond) is introduced in the first section. In this one-pot reaction, up to four different components can be combined: the Si-tethered diyne can be reacted with three identical nitriles, with differing nitriles, or with a nitrile and other unsaturated organic substrates such as formamides, isocyanides, acid chlorides, aldehydes, carbodiimides, and azides. Several unexpected multiring, fused Zr/Si organo-bimetallic intermediates were isolated and characterized. A wide variety of N-heterocycles, such as 5-azaindole, pyrrole, and pyrroloazepine derivatives, were obtained. We then discuss the reaction with alkynes (the C=C triple bond). A consecutive skeletal rearrangement, differing from that observed in the reactions with nitriles, takes place in this reaction. Finally, we discuss the reaction with the C?X substrates (where X is O or N), including ketones, aldehydes, and isocyanides. Oxa- and azazirconacycles are formed via a new skeletal rearrangement. Our results show that the zirconocene and the Si-tethered diyne cooperate as a "chemical transformer" after treatment with various substrates, leading to a diverse range of cyclic Zr/Si organo-bimetallic compounds. This mechanism-derived synthesis of organometallic and organic compounds demonstrates that the investigation of metal-mediated reactions and the isolation of reactive organometallic intermediates not only contribute to the understanding of complex reactions but can also lead to the discovery of synthetically useful methods. PMID- 21612216 TI - Kinetics of radical intermediate formation and deoxynucleotide production in 3 aminotyrosine-substituted Escherichia coli ribonucleotide reductases. AB - Escherichia coli ribonucleotide reductase is an alpha2beta2 complex and catalyzes the conversion of nucleoside 5'-diphosphates (NDPs) to 2'-deoxynucleotides (dNDPs). The reaction is initiated by the transient oxidation of an active-site cysteine (C(439)) in alpha2 by a stable diferric tyrosyl radical (Y(122)*) cofactor in beta2. This oxidation occurs by a mechanism of long-range proton coupled electron transfer (PCET) over 35 A through a specific pathway of residues: Y(122)*-> W(48)-> Y(356) in beta2 to Y(731)-> Y(730)-> C(439) in alpha2. To study the details of this process, 3-aminotyrosine (NH(2)Y) has been site-specifically incorporated in place of Y(356) of beta. The resulting protein, Y(356)NH(2)Y-beta2, and the previously generated proteins Y(731)NH(2)Y-alpha2 and Y(730)NH(2)Y-alpha2 (NH(2)Y-RNRs) are shown to catalyze dNDP production in the presence of the second subunit, substrate (S), and allosteric effector (E) with turnover numbers of 0.2-0.7 s(-1). Evidence acquired by three different methods indicates that the catalytic activity is inherent to NH(2)Y-RNRs and not the result of copurifying wt enzyme. The kinetics of formation of 3-aminotyrosyl radical (NH(2)Y*) at position 356, 731, and 730 have been measured with all S/E pairs. In all cases, NH(2)Y* formation is biphasic (k(fast) of 9-46 s(-1) and k(slow) of 1.5-5.0 s(-1)) and kinetically competent to be an intermediate in nucleotide reduction. The slow phase is proposed to report on the conformational gating of NH(2)Y* formation, while the k(cat) of ~0.5 s(-1) is proposed to be associated with rate-limiting oxidation by NH(2)Y* of the subsequent amino acid on the pathway during forward PCET. The X-ray crystal structures of Y(730)NH(2)Y alpha2 and Y(731)NH(2)Y-alpha2 have been solved and indicate minimal structural changes relative to wt-alpha2. From the data, a kinetic model for PCET along the radical propagation pathway is proposed. PMID- 21612217 TI - Jatrophane diterpenes from Euphorbia esula as antiproliferative agents and potent chemosensitizers to overcome multidrug resistance. AB - Phytochemical study of whole, undried plants of Euphorbia esula led to the isolation of six new (1-6) jatrophane diterpene polyesters, named esulatins H-M, together with the known compounds 2alpha,3beta,5alpha,7beta,15beta-pentaacetoxy 9alpha-nicotinoyloxyjatropha-6(17),11-dien-14-one (7), salicinolide (8), and euphosalicin (9). The structures and relative configuration of 1-6 were established on the basis of extensive spectroscopic analysis, including HRESIMS and one- and two-dimensional NMR techniques. All these compounds, together with diterpenes (10-14) isolated previously from this plant, were evaluated for their antiproliferative activity against HeLa, Ishikawa, and MCF7 cells. The multidrug resistance-reversing activities were also investigated on L5178 mouse lymphoma cells transfected with the pHa MDR1/A retrovirus DNA. Preliminary structure activity relationship data are discussed. PMID- 21612218 TI - An integrated electrochromic nanoplasmonic optical switch. AB - We demonstrate an electrochemically driven optical switch based on absorption modulation of surface plasmon polaritons (SPPs) propagating in a metallic nanoslit waveguide containing nanocrystals of electrochromic Prussian Blue dye. Optical transmission modulation of ~96% is achieved by electrochemically switching the dye between its oxidized and reduced states using voltages below 1 V. High spatial overlap and long interaction length between the SPP and the active material are achieved by preferential growth of PB nanocrystals on the nanoslit sidewalls. The resulting orthogonalization between the directions of light propagation and that of charge transport from the electrolyte to ultrathin active material inside the nanoslit waveguide offers significant promise for the realization of electrochromic devices with record switching speeds. PMID- 21612219 TI - The Davis-Beirut reaction: N1,N2-disubstituted-1H-indazolones via 1,6 electrophilic addition to 3-alkoxy-2H-indazoles. AB - A variety of electrophiles (anhydrides, acid chlorides, carbonochloridates, sulfonyl chlorides, and alkyl bromides) react with 3-methoxy-2H-indazole (1a), benzoxazin[3,2-b]indazole (1d), and oxazolino[3,2-b]indazole (1e) - substrates available by the Davis-Beirut reaction - to yield a diverse set of N(1),N(2) disubstituted-1H-indazolones. With certain electrophiles, an AERORC (Addition of the Electrophile, Ring Opening, and Ring Closure) process on indazole 1d results in indazoloindazolone formation. An intriguing aspect of these N(1),N(2) disubstituted-1H-indazolones is that they are poised for diversification through, for example, azide-alkyne cycloaddition chemistry reported here. PMID- 21612220 TI - Conservative change to the phosphate moiety of cyclic diguanylic monophosphate remarkably affects its polymorphism and ability to bind DGC, PDE, and PilZ proteins. AB - The cyclic dinucleotide c-di-GMP is a master regulator of bacterial virulence and biofilm formation. The activations of c-di-GMP metabolism proteins, diguanylate cyclases (DGCs) and phosophodiesterases (PDEs), usually lead to diametrically opposite phenotypes in bacteria. Analogues of c-di-GMP, which can selectively modulate the activities of c-di-GMP processing proteins, will be useful chemical tools for studying and altering bacterial behavior. Herein we report that a conservative modification of one of the phosphate groups in c-di-GMP with a bridging sulfur in the phosphodiester linkage affords an analogue called endo-S-c di-GMP. Computational, NMR (including DOSY), and CD experiments all reveal that, unlike c-di-GMP, endo-S-c-di-GMP does not readily form higher aggregates. The lower propensity of endo-S-c-di-GMP to form aggregates (as compared to that of c di-GMP) is probably due to a higher activation barrier to convert from the "open" conformer (where the two guanines are on opposite faces) to the "closed" conformer (where the two guanines are on the same face). Consequently, endo-S-c di-GMP has selectivity for proteins that bind monomeric but not dimeric c-di-GMP, which form from the "closed" conformer. For example, endo-S-c-di-GMP can inhibit the hydrolysis of c-di-GMP by RocR (a PDE enzyme that binds monomeric c-di-GMP) but did not bind to Alg44 (a PilZ protein) or regulate WspR (a DGC enzyme that has been shown to bind to dimeric c-di-GMP). This work demonstrates that selective binding to different classes of c-di-GMP binding proteins could be achieved by altering analogue conformer populations (conformational steering). We provide important design principles for the preparation of selective PDE inhibitors and reveal the role played by the c-di-GMP backbone in c-di-GMP polymorphism and binding to processing proteins. PMID- 21612221 TI - Alkali-metal-supported bismuth polyhedra-principles and theoretical studies. AB - We have quantum chemically investigated the structure, stability, and bonding mechanism in highly aggregated alkali-metal salts of bismuthanediide anions [RBi](2-) using relativistic density functional theory (DFT, at ZORA-BP86/TZ2P) in combination with a quantitative energy decomposition analysis (EDA). Our model systems are alkali-metal-supported bismuth polyhedra [(RBi)(n)M(2n-4)](4-) with unique interpenetrating shells of a bismuth polyhedron and an alkali-metal superpolyhedron. Furthermore, we have analyzed the trianionic inclusion complexes [M'@{(RBi)(n)M(2n-4)}](3-) involving an additional endohedral alkali-metal ion M'. The main objective is to assist the further development of synthetic approaches toward this class of compounds. Our analyses led to electron-counting rules relating, for example, the number of bonding orbitals (N(bond)) of the cage molecules [(RBi)(n)M(2n+Q)](Q) to the number of bismuth atoms (n(Bi)), alkali metal atoms (n(M)), and net charge Q as N(bond) = n(Bi) + n(M) - Q (R = one electron donor ligand; M = alkali metal; n = 4-12; Q = -4, -6, -8). Finally, on the basis of our findings, we predict the next members in the 5-fold symmetrical row of alkali-metallobismaspheres with a macroicosahedral arrangement. PMID- 21612222 TI - Controlled fragrant molecule release from surface-tethered cyclodextrin host guest inclusion complexes. AB - beta-cyclodextrin barrels can be tethered to solid surfaces using the Williamson ether synthesis reaction via an intermediate pulsed plasma deposited poly(4 vinylbenzyl chloride) linker layer. The loading and release of perfume molecules through host-guest inclusion complex formation with surface tethered beta cyclodextrin has been followed by infrared spectroscopy and quartz crystal microbalance measurements. Fragrance release lasts for several months and can be easily recharged. PMID- 21612223 TI - Zn2+'s ability to alter the distribution of Cu2+ among the available binding sites of Abeta(1-16)-polyethylenglycol-ylated peptide: implications in Alzheimer's disease. AB - The formation of mixed copper(II) and zinc(II) complexes with Abeta(1-16)-PEG has been investigated. The peptide fragment forms stable mixed metal complexes at physiological pH in which the His13/His14 dyad is the zinc(II)'s preferred binding site, while copper(II) coordination occurs at the N-terminus also involving the His6 imidazole. Copper(II) is prevented by zinc(II) excess from the binding to the two His residues, His13 and His14. As the latter binding mode has been recently invoked to explain the redox activity of the copper-Abeta complex, the formation of ternary metal complexes may justify the recently proposed protective role of zinc(II) in Alzheimer's disease. Therefore, the reported results suggest that zinc(II) competes with copper for Abeta binding and inhibits copper-mediated Abeta redox chemistry. PMID- 21612224 TI - Synthesis of histidinoalanine: a comparison of beta-lactone and sulfamidate electrophiles. AB - Previous syntheses of histidinoalanine (HAL) have led to mixtures of regioisomers and/or stereoisomers. For example, opening of N-Cbz-D-serine-beta-lactone (6) with Boc-L-His-OMe (5) gave a 2:1 mixture of tau- and pi-regioisomers. The sulfamidate 10, derived from N-benzyl-D-serine methyl ester (11), was reacted with Boc-L-His-OMe (5) to give the tau-HAL derivative 17 as a single isomer in 57% yield. A similarly prepared tau-HAL 19, bearing protecting groups that were all hydrogenolytically labile, led to the free bis-amino acid, tau-L-histidinyl-D alanine (tau-4), as a salt-free standard for amino acid analysis. PMID- 21612225 TI - Multifunctional compact zwitterionic ligands for preparing robust biocompatible semiconductor quantum dots and gold nanoparticles. AB - We describe the synthesis of a series of four different ligands which are used to prepare hydrophilic, biocompatible luminescent quantum dots (QDs) and gold nanoparticles (AuNPs). Overall, the ligands are designed to be compact while still imparting a zwitterionic character to the NPs. Ligands are synthesized appended to a bidentate dihydrolipoic acid- (DHLA) anchor group, allowing for high-affinity NP attachment, and simultaneously incorporate tertiary amines along with carboxyl and/or hydroxyl groups. These are placed in close proximity within the ligand structure and their capacity for joint ionization imparts the requisite zwitterionic nature to the nanocrystal. QDs functionalized with the four different compact ligands were subjected to extensive physical characterization including surface charge, wettability, hydrodynamic size, and tolerance to a wide pH range or high salt concentration over time. The utility of the compact ligand coated QDs was further examined by testing of direct conjugation to polyhistidine-appended protein and peptides, aqueous covalent coupling chemistry, and the ability to engage in Forster resonance energy transfer (FRET). Conjugating cell penetrating peptides to the compact ligand coated QD series facilitated their rapid and efficient cellular uptake, while subsequent cytotoxicity tests showed no apparent decreases in cell viability. In vivo biocompatibility was also demonstrated by microinjecting the compact ligand coated QDs into cells and monitoring their stability over time. Inherent benefits of the ligand design could be extended beyond QDs as AuNPs functionalized with the same compact ligand series showed similar colloidal properties. The strong potential of these ligands to expand NP capabilities in many biological applications is highlighted. PMID- 21612227 TI - Effect of antioxidants on soy oil conjugated linoleic acid production and its oxidative stability. AB - Conjugated linoleic acid (CLA)-rich soy oil can be produced by photoisomerization of soy oil linoleic acid to produce a soy oil with up to 20% CLA. Recent studies indicate that mixed soy tocopherols added to refined bleached deodorized (RBD) oil produced significant increase in soy CLA yield during soy oil linoleic acid photoisomerization. However, the effect of common synthetic free radical scavenging antioxidants and specific tocopherols on CLA yield and its oxidative stability is not known. Therefore, this investigation evaluated the effects of various antioxidant systems on soy oil CLA yield and oxidative stability. Soy oil with added antioxidants consisting of combinations of mixed tocopherols (MT), ascorbyl palmitate (AP), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and tert-butylhydroquinone (TBHQ) was photoisomerized to produce CLA- rich soy oil. The CLA content was determined by GC-FID analysis and oxidative stability by peroxide value (PV). The soy oil in the presence of TBHQ, MT alone and MT with 500 ppm of AP produced significantly greater CLA yields and improved oxidative stability compared to a control without added antioxidants (p < 0.05). However, added mixed tocopherols produced the greatest CLA yield and also reduced PV relative to the control. Tocopherols in the form of alpha-, gamma- and delta tocopherols were then each examined as to their relative effect on CLA yields and PV. The largest increase in CLA yield was obtained with 1800 ppm of gamma tocopherols with reduced PV. Mixed tocopherols, TBHQ and gamma-tocopherols can be used to increase CLA yield and reduce PV of soy oil during linoleic acid photoisomerization. PMID- 21612226 TI - A four-enzyme pathway for 3,5-dihydroxy-4-methylanthranilic acid formation and incorporation into the antitumor antibiotic sibiromycin. AB - The antitumor antibiotic sibiromycin belongs to the class of pyrrolo[1,4]benzodiazepines (PBDs) that are produced by a variety of actinomycetes. PBDs are sequence-specific DNA-alkylating agents and possess significant antitumor properties. Among them, sibiromycin, one of two identified glycosylated PBDs, displays the highest DNA binding affinity and the most potent antitumor activity. In this study, we report the elucidation of the precise reaction sequence leading to the formation and activation of the 3,5-dihydroxy-4 methylanthranilic acid building block found in sibiromycin, starting from the known metabolite 3-hydroxykynurenine (3HK). The investigated pathway consists of four enzymes, which were biochemically characterized in vitro. Starting from 3HK, the SAM-dependent methyltransferase SibL converts the substrate to its 4-methyl derivative, followed by hydrolysis through the action of the PLP-dependent kynureninase SibQ, leading to 3-hydroxy-4-methylanthranilic acid (3H4MAA) formation. Subsequently the NRPS didomain SibE activates 3H4MAA and tethers it to its thiolation domain, where it is hydroxylated at the C5 position by the FAD/NADH-dependent hydroxylase SibG yielding the fully substituted anthranilate moiety found in sibiromycin. These insights about sibiromycin biosynthesis and the substrate specificities of the biosynthetic enzymes involved may guide future attempts to engineer the PBD biosynthetic machinery and help in the production of PBD derivatives. PMID- 21612228 TI - Linking distinct conformations of nicotinamide adenine dinucleotide with protein fold/function. AB - Nicotinamide adenine dinucleotide (NAD or NADP) are essential cofactor/substrate for enzymes that catalyze redox or nonredox reactions. Because several enzymes involved in NAD(P) metabolism have been implicated in a wide array of diseases, there is great interest in designing inhibitors/activators of these NAD(P) dependent enzymes based on their structures. Hence, we have elucidated the various distinct enzyme-bound NAD(P) conformations and their correlation with the respective protein fold and function using hierarchical clustering methods. Torsion angles distinguishing enzyme-bound NAD versus NADP conformations and NAD(P) conformations bound to redox versus nonredox enzymes were identified. Although an unusually small chi(N) in diphtheria toxin-bound NAD(+) had been postulated to strain the N-glycosidic bond, thus facilitating catalysis, toxin bound NAD(+) molecules with chi(N) varying from 0 to 60 degrees were found to exhibit similar C(1D)-N(1N) bond cleavage barriers in water. The findings herein provide useful guidelines in the design of inhibitors/activators of NAD(P) dependent enzymes that are therapeutic targets. PMID- 21612229 TI - Cation distribution in co-doped ZnAl2O4 nanoparticles studied by X-ray photoelectron spectroscopy and 27Al solid-state NMR spectroscopy. AB - Co(x)Zn(1-x)Al(2)O(4) (x = 0.01-0.6) nanoparticles were synthesized by the citrate sol-gel method and were characterized by X-ray powder diffraction and transmission electron microscopy to identify the crystalline phase and determine the particle size. X-ray photoelectron spectroscopy and (27)Al solid-state NMR spectroscopy were used to study the distribution of the cations in the tetrahedral and octahedral sites in Co(x)Zn(1-x)Al(2)O(4) nanoparticles as a function of particle size and composition. The results show that all of the as synthesized samples exhibit spinel-type single phase; the crystallite size of the samples is about 20-50 nm and increases with increasing annealing temperature and decreases with Co-enrichment. Zn(2+) ions are located in large proportions in the tetrahedral sites and in small proportions in the octahedral sites in Co(x)Zn(1 x)Al(2)O(4) nanoparticles. The fraction of octahedral Zn(2+) increases with increasing Co concentration and decreases with increasing particle size. Besides the tetrahedral and octahedral coordinations, the presence of the second octahedrally coordinated Al(3+) ions is observed in the nanoparticles. The change of the inversion parameter (2 times the fraction of Al(3+) ions in tetrahedral sites) with Co concentration and particle size is consistent with that of the Zn fraction in octahedral sites. Analysis of the absorption properties indicates that Co(2+) ions are located in the tetrahedral sites as well as in the octahedral sites in the nanoparticles. The inversion degree of Co(2+) decreases with increasing particle size. PMID- 21612230 TI - Effect of carboxylic acid on sintering of inkjet-printed copper nanoparticulate films. AB - The reduction effect of various carboxylic acids on inkjet-printed copper film was investigated. Carboxylic acids were exposed to the film by nitrogen gas that was bubbled through the liquid acids during the annealing process. It was observed that in the case of saturated monocarboxylic acid (formic, acetic, propionic, butyric), the acids with shorter hydrocarbon chains perform better in reducing the surface copper oxides in the printed copper conductive film. The printed films exposed to formic acid vapor exhibited the lowest resistivity (3.10 and 2.30 MUOmega cm when annealed at 200 and 250 degrees C, respectively). In addition, the oxalic acid more effectively reduces copper oxide than formic acid and its usage can shorten the annealing time for highly conductive printed copper film. This reductive annealing process allows fabrication of copper patterns with low resistivity, (3.82 MUOmega cm annealed at 250 degrees C) comparable to the resistivity of bulk copper. PMID- 21612231 TI - Direct probe of molecular polarization in de novo protein-electrode interfaces. AB - A novel approach to energy harvesting and biosensing devices would exploit optoelectronic processes found in proteins that occur in nature. However, in order to design such systems, the proteins need to be attached to electrodes and the optoelectronic properties in nonliquid (ambient) environments must be understood at a fundamental level. Here we report the simultaneous detection of electron transport and the effect of optical absorption on dielectric polarizability in oriented peptide single molecular layers. This characterization requires a peptide design strategy to control protein/electrode interface interactions, to allow peptide patterning on a substrate, and to induce optical activity. In addition, a new method to probe electronic, dielectric, and optical properties at the single molecular layer level is demonstrated. The combination enables a quantitative comparison of the change in polarization volume between the ground state and excited state in a single molecular layer in a manner that allows spatial mapping relevant to ultimate device design. PMID- 21612232 TI - Phospshoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors: discovery and structure-activity relationships of a series of quinoline and quinoxaline derivatives. AB - The phosphoinositide 3-kinase (PI3K) family catalyzes the ATP-dependent phosphorylation of the 3'-hydroxyl group of phosphatidylinositols and plays an important role in cell growth and survival. There is abundant evidence demonstrating that PI3K signaling is dysregulated in many human cancers, suggesting that therapeutics targeting the PI3K pathway may have utility for the treatment of cancer. Our efforts to identify potent, efficacious, and orally available PI3K/mammalian target of rapamycin (mTOR) dual inhibitors resulted in the discovery of a series of substituted quinolines and quinoxalines derivatives. In this report, we describe the structure-activity relationships, selectivity, and pharmacokinetic data of this series and illustrate the in vivo pharmacodynamic and efficacy data for a representative compound. PMID- 21612233 TI - Conformational energetics of interpolyelectrolyte complexation between iota carrageenan and poly(methylaminophosphazene) measured by high-sensitivity differential scanning calorimetry. AB - The interaction of poly(methylaminophosphazene) hydrochloride (PMAP.HCl) of varying degrees of ionization (f) with the potassium salt of iota-carrageenan was studied by high-sensitivity differential scanning calorimetry at a KCl concentration of 0.15 M, which is included for the purpose of stabilizing the helix conformation of the polysaccharide up to 55 degrees C. The conditions of strong (pH 3.8, I = 0.15), moderate (pH 7.4, I = 0.15), and weak (pH 7.4, I = 0.25) electrostatic interactions of the polyelectrolytes were considered. The thermodynamic parameters of the helix-coil transition of iota-carrageenan were determined as a function of the polycation/polyanion ratio. We show that the interpolyelectrolyte reaction between PMAP.HCl and iota-carrageenan results in a complete unfolding of the polysaccharide helix under conditions of strong electrostatic interaction and increases its stability under conditions of medium and weak electrostatic interactions. The formation of stoichiometric PMAP carrageenan interpolyelectrolyte complexes proceeded via a cooperative mechanism at pH 3.8 (f = 0.5) and pH 7.4 (f = 0.2) at an ionic strength of 0.15. In contrast, the complexation at pH 7.4 and an ionic strength of 0.25 could be considered to be a consecutive competitive binding of charged units of poly(methylaminophosphazene) to the oppositely charged polysaccharide matrix in the helix or coil conformation. Binding constants of the polycation to the helix and coil forms of iota-carrageenan were estimated. They revealed a preferential binding of the polycation to the helix form of the polysaccharide. PMID- 21612234 TI - Calculations of pKa of superacids in 1,2-dichloroethane. AB - Acidity calculations for some CH and NH superacids in 1,2-dichloroethane (DCE) were carried out using SMD and COSMO-RS continuum solvation models. After comparing the results of calculations with respective experimental pK(a) values it was found that the performance of SMD/M05-2X/6-31G* method is characterized by the mean unsigned error (MUE) of 0.5 pK(a) units and the slope of regression line of 0.915. The similar SMD/B3LYP/6-31G* approach was slightly less successful. The strong correlation over entire data set is confirmed by R(2) values of 0.990 and 0.984 for M05-2X and B3LYP functionals, respectively. The COSMO-RS method, while providing the value of the linear regression line slope similar to the corresponding values from SMD approach, characterized by rather loose correlation (R(2) = 0.823, MUE = 1.7 pK(a) units) between calculated and experimental pK(a) values in DCE solution. PMID- 21612235 TI - Oppolzer-type intramolecular Diels-Alder cycloadditions via isomerizations of allenamides. AB - A new approach to Oppolzer's intramolecular Diels-Alder cycloaddition (IMDA) through gamma-isomerization of readily available N-tethered allenamides is described. These IMDA reactions are carried out in tandem with the allenamide isomerization or 1,3-H shift, leading to complex nitrogen heterocycles in a highly stereoselective manner. PMID- 21612236 TI - Design and structure of stapled peptides binding to estrogen receptors. AB - Synthetic peptides that specifically bind nuclear hormone receptors offer an alternative approach to small molecules for the modulation of receptor signaling and subsequent gene expression. Here we describe the design of a series of novel stapled peptides that bind the coactivator peptide site of estrogen receptors. Using a number of biophysical techniques, including crystal structure analysis of receptor-stapled peptide complexes, we describe in detail the molecular interactions and demonstrate that all-hydrocarbon staples modulate molecular recognition events. The findings have implications for the design of stapled peptides in general. PMID- 21612237 TI - Nucleobase and ribose modifications control immunostimulation by a microRNA-122 mimetic RNA. AB - Immune stimulation is a significant hurdle in the development of effective and safe RNA interference therapeutics. Here, we address this problem in the context of a mimic of microRNA-122 by employing novel nucleobase and known 2'-ribose modifications. The nucleobase modifications are analogues of adenosine and guanosine that contain cyclopentyl and propyl minor-groove projections. Via a site-by-site chemical modification analysis, we identify several immunostimulatory 'hot spots' within the miRNA guide strand at which single base modifications significantly reduce immune stimulation. A duplex containing one base modification on each strand proved to be most effective in preventing immune stimulation. PMID- 21612238 TI - Anatase TiO2 crystal facet growth: mechanistic role of hydrofluoric acid and photoelectrocatalytic activity. AB - This work reports a facile hydrothermal approach to directly grow anatase TiO(2) crystals with exposed {001} facets on titanium foil substrate by controlling pH of HF solution. The mechanistic role of HF for control growth of the crystal facet of anatase TiO(2) crystals has been investigated. The results demonstrate that controlling solution pH controls the extent of surface fluorination of anatase TiO(2), hence the size, shape, morphology, and {001} faceted surface area of TiO(2) crystals. The theoretical calculations reveal that {001} faceted surface fluorination of anatase TiO(2) can merely occur via dissociative adsorption of HF molecules under acidic conditions while the adsorption of Na(+)F(-) is thermodynamically prohibited. This confirms that the presence of molecular form of HF but not F(-) is essential for preservation of exposed {001} facets of anatase TiO(2). Anatase TiO(2) crystals with exposed {001} facets can be directly fabricated on titanium foil by controlling the solution pH <= 5.8. When pH is increased to near neutral and beyond (e.g., pH >= 6.6), the insufficient concentration of HF ([HF] <= 0.04%) dramatically reduces the extent of surface fluorination, leading to the formation of anatase TiO(2) crystals with {101} facets and titanate nanorods/nanosheets. The anatase TiO(2) nanocrystals with exposed {001} facets exhibits a superior photoelectrocatalytic activity toward water oxidation. The findings of this work clarify the mechanistic role of HF for controlling the crystal facet growth, providing a facile means for massive production of desired nanostructures with high reactive facets on solid substrates for other metal oxides. PMID- 21612239 TI - Conjugation of lipid and CpG-containing oligonucleotide yields an efficient method for liposome incorporation. AB - For optimal stimulation of T cells, protein-based vaccines must deliver protein antigens to antigen-presenting cells while simultaneously providing immunostimulatory signals. Listeriolysin O (LLO)-containing liposomes have been utilized to efficiently deliver protein antigens to the cytosolic pathway for antigen processing and major histocompatibility complex class I-dependent presentation while codelivering immunostimulatory CpG-oligodeoxyribonuceotides (ODNs). In this report, we describe the synthesis of lipid-CpG-ODN conjugates utilizing maleimide-phosphatidylethanolamine (PE) lipids and 5'-sulfhdryl containing CpG-ODNs as a method for facile incorporation of CpG-ODNs in liposomal vaccine carriers, an alternative to co-encapsulation inside liposomes and as a means to enhance delivery of CpG-ODNs to their major receptor, Toll-like receptor 9 (TLR9), in the endosome. The characterization and biological evaluation of the vaccine delivery system made of liposomes, which contain the lipid-CpG-ODN conjugates inserted in the liposomal membrane, is described. We demonstrate in vitro in bone marrow derived macrophages that the lipid-CpG-ODN conjugates incorporated onto the liposome bilayers interact with their receptor TLR9 as readily as liposome-encapsulated ODNs and exert their immunostimulatory capabilities. The liposomal vaccine delivery systems were evaluated in mice using ovalbumin (OVA) as a model antigen, and the results indicate equally robust OVA specific cytotoxic T lymphocyte responses and similar Th1 immune skewing capabilities between liposomes containing lipid-conjugated or encapsulated CpG ODNs. Overall, this work indicates that conjugating PE lipids and CpG-ODNs results in an efficient method that allows facile incorporation of CpG-ODNs into a liposome-based delivery platform while retaining the immune-stimulating capabilities of CpG-ODNs. PMID- 21612240 TI - Divalent metal cation speciation and binding to surface-bound oligonucleotide single strands studied by second harmonic generation. AB - The binding of Sr(II), Ca(II), Mg(II), Ba(II), Mn(II), Zn(II), and Cd(II) to silica/water interfaces functionalized with A(15)T(6) oligonucleotides was quantified at pH 7 and 10 mM NaCl using the Eisenthal chi((3)) technique. The binding free energies range from -31.1(6) kJ/mol for Ba(II) to -33.8(4) kJ/mol for Ca(II). The ion densities were found to range from 2(1) ions/strand for Zn(II) to 11(1) ions/strand for Cd(II). Additionally, we quantified Mg(II) binding in the presence of varying background electrolyte concentrations which showed that the binding free energies changed in a linear fashion from -39.3(8) to -27(1) kJ/mol over the electrolyte concentration range of 1-80 mM, respectively. An adsorption free energy versus interfacial potential analysis allowed us to elucidate the speciation of the bound Mg(II) ions and to identify three possible binding pathways. Our findings suggest that Mg(II) binds as a fully hydrated divalent cation, most likely displacing DNA-bound Na ions. These measurements will serve as a benchmark for computer simulations of divalent metal cation/DNA interactions for geochemical and biosensing applications. PMID- 21612241 TI - Covalent biofunctionalization of cellulose acetate with thermostable chimeric avidin. AB - A stable, bioactive cellulose acetate (CA) surface was developed by functionalizing the surface with highly thermostable avidin form. The CA films were first functionalized with a mixture of 3-aminopropyltrimethoxysilane and tetraethoxysilane to introduce free amino groups onto the surface of CA films. Free amino groups were functionalized with glutaraldehyde to obtain an activated surface for covalent biomolecule immobilization. A genetically engineered, high affinity biotin-binding protein chimeric avidin, ChiAVD(I117Y), was used for biofunctionalization of the surface. The chimeric avidin protein has an increased stability in chemically harsh conditions and at high temperature when compared to wt (strept)avidin. The biological activity, i.e., biotin-binding capacity, of the immobilized protein was probed by [(3)H]-biotin. The activity of the chimeric avidin on functionalized CA films was fully retained over the three months' study period. The biotin-binding capacity of the immobilized chimeric avidin was compared to that of immobilized streptavidin, chicken avidin, and rhizavidin and significant differences between proteins were detected. The developed material offers a valuable platform for the development of inexpensive in vitro diagnostics and also supports biosensing applications that are required to operate under demanding conditions. PMID- 21612242 TI - Photoinduced rearrangement of aromatic N-chloroamides to chloroaromatic amides in the solid state: inverted Pi(N)-Sigma(N) occupational stability of amidyl radicals. AB - We report a solid-state photochemical rearrangement reaction by which aromatic N chloroamides exposed to UV light or sunlight are rapidly and efficiently converted to chloroaromatic amides. The course, the intermediate (nascent chlorine vs dichlorine) and the outcome of the reaction depend on the excitation (exposure time, wavelength, and intensity) and on inherent structural factors (the directing role of the substituents and, as demonstrated by the different reactivity of two polymorphs of N-chlorobenzanilide, the supramolecular structure). The photolysis of the chloroamides provides facile photochemical access to arylamidyl radicals as intermediates, which in the absence of strong hydrogen bond donors are stabilized in the reactant crystals by C-H/N-Cl...pi interactions, thus, providing insight into their structure and chemistry. Thorough theoretical modeling of the factors determinant to the stability and the nature of the spin-hosting orbital evidenced that although the trans-Pi(||) state (Np spin) of the amidyls is normally preferred over the trans-Sigma(?) configuration (Nsp(2) spin), stabilization by aromatic conjugation, steric and geometry factors, as well as by electronic effects from the substituents can decrease the Pi-Sigma gap in these intermediates significantly, resulting in similar and, in the case of the orthogonal amide-phenyl disposition, even reversed population of the unpaired electron in the two orbitals. Quantitative correlation established that the inverted occupational spin stability and the Pi(N)-Sigma(N) crossover are collectively facilitated by the conformation, valence angle, and disposition of the amide group relative to the aromatic system. The stabilization and detection of a trans-Sigma(?) radical was experimentally accomplished by steric locking of the orthogonal trans-amide conformation with double ortho-tert-butyl substitution at the phenyl ring. The effects of the single para-phenyl substituents on the relative occupational stability of the arylamidyl radical states point out to non-Hammett behavior. By including cumulative electronic effects from multiple substitutions, four distinct families of the aromatic amidyl radicals were identified. The Pi(?) state is the most stable structure of the N-phenylacetamidyl radical and of most of the substituted arylamidyls, although the Sigma(?) and Pi(?) states can also be stabilized by introducing tert-butyl and nitro groups, respectively. PMID- 21612243 TI - Nucleophilic substitution of fluorine atoms in 2,6-difluoro-3-(pyridin-2 yl)benzonitrile leading to soluble blue-emitting cyclometalated Ir(III) complexes. AB - New functionalized phenylpyridine ligands and their derived heteroleptic cyclometalated Ir(III) complexes have been synthesized. The complexes possess a combination of important properties: (i) blue emission, (ii) good photoluminescence quantum yields, and (iii) good solubility in organic solvents, making them very attractive as phosphorescent dopant emitters for solution processable light-emitting devices. PMID- 21612244 TI - Modifying metal nanoparticle placement on carbon supports using an aerosol-based process, with application to the environmental remediation of chlorinated hydrocarbons. AB - A facile aerosol-based process (ABP) is developed to vary the placement of iron nanoparticles on the external surface of carbon microspheres or within the interior. This is accomplished through the competitive mechanisms of sucrose carbonization and the precipitation of soluble iron salts, in an aerosol droplet passing through a high temperature heating zone. At lower aerosolization temperatures, carbonization occurs first leading to iron salt precipitation on the external surface, while at higher temperatures interior placement occurs through concurrent iron salt precipitation and sucrose carbonization. The resulting composites are highly conducive to the reductive dechlorination of compounds such as trichloroethylene (TCE) as the carbon support is a strong adsorbent, and zerovalent iron effectively reduces TCE to innocuous gases such as ethane. Since both iron and carbon are widely used catalysts and catalyst supports, the simple process of modifying iron placement has significant potential applications in heterogeneous catalysis. PMID- 21612245 TI - Nanogyroids incorporating multivalent lipids: enhanced membrane charge density and pore forming ability for gene silencing. AB - The self-assembly of a custom-synthesized pentavalent cationic lipid (MVL5) and glycerol monooleate (GMO) with small interfering RNA (siRNA) results in the formation of a double-gyroid bicontinuous inverted cubic phase with colocalized lipid/siRNA domains as shown by synchrotron X-ray scattering and fluorescence microscopy. The high charge density (due to MVL5) and positive Gaussian modulus of the GMO-containing membranes confer optimal electrostatic and elastic properties for endosomal escape, enabling efficient siRNA delivery and effective, specific gene silencing. PMID- 21612246 TI - Composition and asymmetry in supported membranes formed by vesicle fusion. AB - The structure and formation of supported membranes at silica surfaces by vesicle fusion was investigated by neutron reflectivity and quartz crystal microbalance (QCM-D) measurements. The structure of equimolar phospholipid mixtures of DLPC DPPC, DMPC-DPPC, and DOPC-DPPC depends intricately on the vesicle deposition conditions. The supported bilayer membranes exhibit varying degrees of compositional asymmetry between the monolayer leaflets, which can be modified by the deposition temperature as well as the salt concentration of the vesicle solution. The total lipid composition of the supported bilayers differs from the composition of the vesicles in solution, and the monolayer proximal to the silica surface is always enriched in DPPC compared to the distal monolayer. The results, which show unambiguougsly that some exchange and rearrangement of lipids occur during vesicle deposition, can be rationalized by considering the effects of salt screening and temperature on the rates of lipid exchange, rearrangement, and vesicle adsorption, but there is also an intricate dependence on the lipid-lipid interactions. Thus, although both symmetric and asymmetric supported bilayers can be prepared from vesicles, the optimal conditions are sensitive to the lipid composition of the system. PMID- 21612247 TI - Site-selective surface modification using enzymatic soft lithography. AB - Surface modification with functional polymers or molecules offers great promise for the development of smart materials and applications. Here, we describe a versatile and easy-to-use method of site-selective surface modification based on the ease of microcontact printing and the exquisite selectivity of enzymatic degradation. A micropatterned poly-L-lysine (PLL) layer on solid substrates was prepared by enzymatic degradation using trypsin enzyme immobilized on a prestructured poly(dimethlylsiloxane) (PDMS) stamp. After the enzymatic degradation of PLL and the removal of the degradation products, very well defined patterning was revealed over a large scale by fluorescence microscopy and atomic force microscopy (AFM). We investigate the advantage of our method by comparison with traditional microcontact printing and found that lateral diffusion was reduced, yielding a more accurate reproduction of the master. We also demonstrate that the stamp can be reused without reinking. The patterned surface was used for site-selective modification. The strategy was applied to two applications: the first is dedicated to the creation of amino-silane patterned surfaces, and the second illustrates the possibility of patterning polyelectrolyte multilayered thin films. PMID- 21612248 TI - Kinetically forbidden transformations of water molecular assemblies in hydrophobic micropores. AB - Water adsorption hysteresis is one of the most important phenomena observed during the interaction of water with hydrophobic surfaces. Adsorption hysteresis in micropores has strong relevance to the structure of adsorbed water. We used three typical models (cluster, monolayer, and uniform distribution structure models) to determine the structure of the water molecules adsorbed in hydrophobic slit-shaped carbon micropores. In each model, stabilization energy profiles were calculated for various fractional fillings by using the interaction potential theory. Simultaneously, molecular dynamics (MD) simulations of water adsorbed in the micropore of 1.1 nm pore width, which shows significant adsorption hysteresis, were performed to determine the kinetics of the observed structural transformations. The transformations between monolayer and cluster were slow, that is, kinetically forbidden at the fractional filling of 0.2 and 0.6, whereas the cluster-uniform distribution structure and uniform distribution structure monolayer transformations were kinetically allowed. The kinetically forbidden transformation resulted in the occurrence of metastable structure of adsorbed water and was responsible for the observed adsorption hysteresis. PMID- 21612249 TI - Interfacial immobilization of monoclonal antibody and detection of human prostate specific antigen. AB - Antibody orientation and its antigen binding efficiency at interface are of particular interest in many immunoassays and biosensor applications. In this paper, spectroscopic ellipsometry (SE), neutron reflection (NR), and dual polarization interferometry (DPI) have been used to investigate interfacial assembly of the antibody [mouse monoclonal anti-human prostate-specific antigen (anti-hPSA)] at the silicon oxide/water interface and subsequent antigen binding. It was found that the mass density of antibody adsorbed at the interface increased with solution concentration and adsorption time while the antigen binding efficiency showed a steady decline with increasing antibody amount at the interface over the concentration range studied. The amount of antigen bound to the interfacial immobilized antibody reached a maximum when the surface-adsorbed amount of antibody was around 1.5 mg/m(2). This phenomenon is well interpreted by the interfacial structural packing or crowding. NR revealed that the Y-shaped antibody laid flat on the interface at low surface mass density with a thickness around 40 A, equivalent to the short axial length of the antibody molecule. The loose packing of the antibody within this range resulted in better antigen binding efficiency, while the subsequent increase of surface-adsorbed amount led to the crowding or overlapping of antibody fragments, hence reducing the antigen binding due to the steric hindrance. In situ studies of antigen binding by both NR and DPI demonstrated that the antigen inserted into the antibody layer rather than forming an additional layer on the top. Stability assaying revealed that the antibody immobilized at the silica surface remained stable and active over the monitoring period of 4 months. These results are useful in forming a general understanding of antibody interfacial behavior and particularly relevant to the control of their activity and stability in biosensor development. PMID- 21612250 TI - Swelling, functionalization, and structural changes of the nanoporous layered silicates AMH-3 and MCM-22. AB - Nanoporous layered silicate materials contain 2D-planar sheets of nanoscopic thickness and ordered porous structure. In comparison to porous 3D-framework materials such as zeolites, they have advantages such as significantly increased surface area and decreased diffusion limitations because the layers can potentially be exfoliated or intercalated into polymers to form nanocomposite materials. These properties are particularly interesting for applications as materials for enhancing molecular selectivity and throughput in composite membranes. In this report, the swelling and surface modification chemistry of two attractive nanoporous layered silicate materials, AMH-3 and MCM-22, were studied. We first describe a method, using long-chain diamines instead of monoamines, for swelling of AMH-3 while preserving its pore structure to a greater extent during the swelling process. Then, we describe a stepwise functionalization method for functionalizing the layer surfaces of AMH-3 and MCM-22 via silane condensation reactions. The covalently attached hydrocarbon chain molecules increased the hydrophobicity of AMH-3 and MCM-22 layer surfaces and therefore allow the possibility of effectively dispersing these materials in polymer matrices for thin film/membrane applications. PMID- 21612251 TI - Dynamics and heterogeneity of Pb(II) binding by SiO2 nanoparticles in an aqueous dispersion. AB - Pb(II) binding by SiO(2) nanoparticles in an aqueous dispersion was investigated under conditions where the concentrations of Pb(2+) ions and nanoparticles are of similar magnitude. Conditional stability constants (log K) obtained at different values of pH and ionic strength varied from 4.4 at pH 5.5 and I = 0.1 M to 6.4 at pH 6.5 and I = 0.0015 M. In the range of metal to nanoparticle ratios from 1.6 to 0.3, log K strongly increases, which is shown to be due to heterogeneity in Pb(II) binding. For an ionic strength of 0.1 M the Pb(2+)/SiO(2) nanoparticle system is labile, whereas for lower ionic strengths there is loss of lability with increasing pH and decreasing ionic strength. Theoretical calculations on the basis of Eigen-type complex formation kinetics seem to support the loss of lability. This is related to the nanoparticulate nature of the system, where complexation rate constants become increasingly diffusion controlled. The ion binding heterogeneity and chemodynamics of oxidic nanoparticles clearly need further detailed research. PMID- 21612252 TI - Conformal adhesion enhancement on biomimetic microstructured surfaces. AB - Inspired by the superior adhesive ability of the gecko foot pad, we report an experimental study of conformal adhesion of a soft elastomer thin film on biomimetic micropatterned surfaces (micropillars), showing a remarkable adhesion enhancement due to the surface patterning. The adhesion of a low-surface-energy poly(dimethylsiloxane) tape to a SU-8 micropatterned surface was found be able to increase by 550-fold as the aspect ratio increases from 0 to 6. The dependency of the adhesion enhancement on the aspect ratio is highly nonlinear. A series of peeling experiment coupled with optical interference imaging were performed to investigate the adhesion enhancement as a function of the height of the micropillars and the associated delamination mechanisms. Local elastic energy dissipation, side-wall friction, and plastic deformations were analyzed and discussed in terms of their contributions to the adhesion enhancement. We conclude that the local adhesion and friction events of pulling micropillars out of the embedded polymer film play a primary role in the observed adhesion enhancement. The technical implications of this local friction-based adhesion enhancement mechanism were discussed for the effective assembly of similar or dissimilar material components at small scales. The combined use of the micro/nanostructured surfaces with the van der Waals interactions seem to be a potentially more universal solution than the conventional adhesive bonding technology, which depends on the chemical and viscoelastic properties of the materials. PMID- 21612254 TI - Identification of cryptic products of the gliotoxin gene cluster using NMR-based comparative metabolomics and a model for gliotoxin biosynthesis. AB - Gliotoxin, a major product of the gli non-ribosomal peptide synthetase gene cluster, is strongly associated with virulence of the opportunistic human pathogen Aspergillus fumigatus. Despite identification of the gli cluster, the pathway of gliotoxin biosynthesis has remained elusive, in part because few potential intermediates have been identified. In addition, previous studies suggest that knowledge of gli-dependent metabolites is incomplete. Here we use differential analysis by 2D NMR spectroscopy (DANS) of metabolite extracts derived from gli knock-out and wild-type (WT) strains to obtain a detailed inventory of gli-dependent metabolites. DANS-based comparison of the WT metabolome with that of DeltagliZ, a knock-out strain devoid of the gene encoding the transcriptional regulator of the gli cluster, revealed nine novel gliZ dependent metabolites including unexpected structural motifs. Their identification provides insight into gliotoxin biosynthesis and may benefit studies of the role of the gli cluster in A. fumigatus virulence. Our study demonstrates the utility of DANS for correlating gene expression and metabolite biosynthesis in microorganisms. PMID- 21612255 TI - Diastereoselective synthesis of the Leu-Pro type phosphinyl dipeptide isostere. AB - A diastereoselective synthesis of the Leu-Pro type phosphinyl dipeptide isostere in its protected form was achieved from stereodefined alpha-amino-H-phosphinate. The methodology involved a cross-coupling reaction with alkenyl triflate and subsequent diastereoselective hydrogenation of the alkene moiety, which capitalized on the phosphorus chirality. PMID- 21612256 TI - Preference for isolated water molecules in a concentrated glycerol-water mixture. AB - Neutron diffraction coupled with hydrogen/deuterium isotopic substitution has been used to investigate the structure of a concentrated glycerol water (4:1 mole fraction) solution. The neutron diffraction data were used to constrain a three dimensional computational model that is experimentally relevant using the empirical potential structure refinement technique. From interrogation of this model, we find that glycerol-glycerol hydrogen bonding is largely unperturbed by the presence of water in the solution. We find that glycerol-water hydrogen bonding is prevalent, suggesting that water molecules effectively take the place of glycerol molecules in this concentrated solution. In contrast, we find that water-water hydrogen bonding is significantly perturbed. While the first coordination shell of water in the concentrated solution remains similar to that of pure water, water-water hydrogen bonding is greatly diminished beyond the first neighbor distance. Interestingly, the majority of water molecules exist as single monomers in the concentrated glycerol solution. The preference of isolated water molecules results in a solution that is well mixed with optimal glycerol water hydrogen bonding. These results highlight the importance of preferential hydrogen bonding in aqueous solutions and suggest a mechanism for cryoprotection by which glycerol effectively hydrogen bonds with water, resulting in a disrupted hydrogen-bonded water network. PMID- 21612257 TI - Stereodivergent route to the carbocyclic core of 2',3'-olefinic carbanucleosides: toward the synthesis of (L)-(+)- and (D)-(-)-carbovir. AB - (R)-2,3-Cyclohexylideneglyceraldehyde (1) has been elegantly exploited for a stereodivergent construction of the potential precursors (11a and 11b) of (L)-(+) and (D)-(-)-carbovirs, respectively. The key steps in this approach were Luche's allylation of formaldehyde with allylic bromide 4c to produce 5 and ring-closing metathesis of 10b using Grubbs' first-generation catalyst to obtain 11. The moderate stereoselectivity of Luche's allylation reaction resulted in attaining stereodivergence in this approach which could be realized finally through easy chromatographic separation of the two isomers of the metathesis product to obtain homochiral precursors 11a and 11b in good amounts. PMID- 21612258 TI - Synthesis, isolation, and characterization of an organometallic triiodopalladium(IV) complex. Quantitative and regioselective synthesis of two C I reductive elimination products. AB - Iodine and the pincer complex [Pd(O,N,C-L)I], where L is the monoanionic ligand resulting from deprotonation of the acetyl group of the dimethylmonoketal of 2,6 diacetylpyridine, are in equilibrium at low temperatures with the palladium(IV) complex [Pd(O,N,C-L)I(3)], which can be isolated at -40 degrees C and characterized by (1)H NMR spectroscopy and X-ray diffraction studies, in spite of its great instability. When the same reaction is carried out at room temperature, a quantitative reductive elimination process occurs, giving L-I, which in the presence of water affords L'-I, resulting from hydrolysis of L-I. PMID- 21612259 TI - Toward therapeutic delivery with layer-by-layer engineered particles. AB - Layer-by-layer (LbL)-engineered particles have recently emerged as a promising class of materials for applications in biomedicine, with studies progressing from in vitro to in vivo. The versatility of LbL assembly coupled with particle templating has led to engineered particles with specific properties (e.g., stimuli-responsive, high cargo encapsulation efficiency, targeting), thus offering new opportunities in targeted and triggered therapeutic release. This Perspective highlights an important development by Poon et al. on tumor targeting in vivo using LbL-engineered nanoparticles containing a pH-responsive poly(ethylene glycol) (PEG) surface layer. Further, we summarize recent progress in the application of LbL particles in the fields of drug, gene, and vaccine delivery and cancer imaging. Finally, we explore future directions in this field, focusing on the biological processing of LbL-assembled particles. PMID- 21612260 TI - Synthesis of biantennary complex-type nonasaccharyl asn building blocks for solid phase glycopeptide synthesis. AB - The biantennary complex-type N-glycans bearing LacNAc and LacdiNAc as the nonreducing end motif were synthesized in a protected form suitable to use in the Fmoc solid-phase peptide synthesis studies. Two approaches for the nonasaccharide synthesis were examined by taking advantage of the highly beta-selective glycosylation with GlcNTCA (N-phenyl)trifluoroacetimidate. An earlier approach, which involved the reaction of the trisaccharide donor (Gal-GlcNTCA-Man) and trisaccharide acceptor (Man-GlcNPhth(2)-N(3)), produced a mixture of nonasaccharide isomers. On the other hand, mannosylation of the trisaccharide acceptor (Man-GlcNPhth(2)-N(3)) stereoselectively afforded the known pentasaccharide (Man(3)-GlcNPhth(2)-N(3)), which was reacted with the disaccharyl glycosyl donor (Gal-GlcNTCA or GalNTCA-GlcNTCA) to produce the desired nonasaccharide as a single stereoisomer. Selective dephthaloylation followed by N acetylation furnished the GlcNAc(2) functionality. The resulting nonasaccharyl azides were condensed with Fmoc-Asp(OPfp)-OBu(t) or Fmoc-Asp(OPfp)-OPac in the presence of Ph(CH(3))(2)P and HOOBt. Finally, the Zn reduction and cleavage of the tert-butyl ester or Zn reduction alone produced the targeted nonasaccharyl Asn building blocks. PMID- 21612261 TI - Development of trityl-based photolabile hydroxyl protecting groups. AB - A series of trityl-based photolabile hydroxyl protecting groups have been examined. These PPGs evolve from the traditional acid-labile trityl protecting group with proper electron-donating substituents. Structure-reactivity relationships have been explored. A m-dimethylamino group is crucial to achieve high photochemical deprotection efficiency. The o-hydroxyl group in 8 greatly improves the yield of the photochemical deprotection reaction, compared with the corresponding o-methoxyl-substituted counterpart 7. However, comparison between the photoreactions of 9 and 11 does not show similar structural relevance. The PPG in ether 1 (i.e., DMATr group) is structurally simple and easy to prepare and install. Its deprotection can be successfully carried out with irradiation of sunlight without requirement of photochemical devices. PMID- 21612263 TI - Structural origin and energy transfer processes of 1.8 MUm emission in Tm3+ doped germanate glasses. AB - A detailed characterization of structural analysis and energy transfer (ET) process in Tm(3+) doped germanate glasses has been presented. The thermal stability and Raman spectroscopic analysis of the host glass structure has been discussed. It is observed that replacing GeO(2) by Ga(2)O(3) resulted in decreasing of glass transition temperature and largest phonon energy. Increasing concentration of Ga(2)O(3) decreases the density of cross-linking of the germanate glass network, and weaker Ga-O bonds result in lower phonon energy. The influences of the concentrations of Ga(2)O(3) and the glass structure on the ET have also been analyzed. The extended overlap integral method is used to calculate the microparameters of the energy transfer and the critical distance. The results show that the transference Tm -> Tm ((3)H(4), (3)H(6) -> (3)H(6), (3)H(4)) energy migration is not phonon dependent in the quasiresonant processes, while the cross relaxation Tm -> Tm ((3)H(4), (3)H(6) -> (3)F(4), (3)F(4)) is a multiphonon mechanism dominated by one-phonon creation (~96%). It is demonstrated that the stretching frequencies and the ET processes become lower when increasing the concentration of Ga(2)O(3). PMID- 21612262 TI - Quantum dot/plasmonic nanoparticle metachromophores with quantum yields that vary with excitation wavelength. AB - Coupled plasmonic/chromophore systems are of interest in applications ranging from fluorescent biosensors to solar photovoltaics and photoelectrochemical cells because near-field coupling to metal nanostructures can dramatically alter the optical performance of nearby materials. We show that CdSe quantum dots (QDs) near single silver nanoprisms can exhibit photoluminescence lifetimes and quantum yields that depend on the excitation wavelength, in apparent violation of the Kasha-Vavilov rule. We attribute the variation in QD lifetime with excitation wavelength to the wavelength-dependent coupling of higher-order plasmon modes to different spatial subpopulations of nearby QDs. At the QD emission wavelength, these subpopulations are coupled to far-field radiation with varying efficiency by the nanoprism dipolar resonance. These results offer an easily accessible new route to design metachromophores with tailored optical properties. PMID- 21612264 TI - Chromium-mediated stereoselective synthesis of carbohydrate-derived (E) alpha,beta-unsaturated esters or amides. AB - A chromium-mediated novel synthesis of carbohydrate-derived di- and trisubstituted (E)-alpha,beta-unsaturated esters or amides from a range of dichloroesters or amides and a variety of sugar aldehydes is reported. The process took place with total stereoselectivity and in high yields. A mechanism based on a sequential chromium-promoted aldol-type reaction and a completely stereoselective beta-elimination reaction is proposed to explain these results. PMID- 21612265 TI - Palladium-catalyzed cross-coupling of H-phosphinate esters with chloroarenes. AB - The palladium-catalyzed cross-coupling reaction between H-phosphinate esters and chloroarenes or chloroheteroarenes is described. This reaction is the first general metal-catalyzed phosphorus-carbon bond-forming reaction between a phosphorus nucleophile and chloroarenes. PMID- 21612266 TI - Biomagnification of higher brominated PBDE congeners in an urban terrestrial food web in north China based on field observation of prey deliveries. AB - As an important group of brominated flame retardants, polybrominated diphenyl ethers (PBDEs) persist in the wildlife food webs. However, the biomagnification of PBDEs has not been adequately studied in the terrestrial food webs. In this study, a terrestrial food web composed of common kestrels, sparrows, rats, grasshoppers, and dragonflies in the urban environment from northern China was obtained. A field prey delivery study, reinforced by delta13C and delta15N analyses, indicates that sparrows are the primary prey items of common kestrels. Concentrations of PBDEs were in the following order: common kestrel > sparrow > rat > grasshopper and dragonfly with BDE-209 as the dominant congener. Biomagnification factors (BMFs) were calculated as the ratio between the lipid normalized concentrations in the predator and prey. The highest BMF (6.9) was determined for BDE-153 in sparrow/common kestrel food chain. Other higher brominated congeners, such as BDE-202, -203, -154, -183, -197, and -209, were also biomagnified in this terrestrial food chain with BMF of 1.3-4.7. BDE-47, 99, and -100 were found to be biodiluted from sparrow to common kestrel (BMFs < 1). Measured BMF values for BDE-153, -47, -99, and -100 were consistent with predicted values from a nonsteady-state model in American kestrels from another study. Retention factors and metabolism of BDE congeners may be confounding factors influencing the measured BMFs in this current study. PMID- 21612268 TI - Assessing the quantitative relationships between preschool children's exposures to bisphenol A by route and urinary biomonitoring. AB - Limited published information exists on young children's exposures to bisphenol A (BPA) in the United States using urinary biomonitoring. In a previous project, we quantified the aggregate exposures of 257 preschool children to BPA in environmental and personal media over 48-h periods in 2000-2001 at homes and daycares in North Carolina and Ohio. In the present study for 81 Ohio preschool children ages 23-64 months, we quantified the children's urinary total BPA (free and conjugated) concentrations over these same 48-h periods in 2001. Then, we examined the quantitative relationships between the children's intakes doses of BPA through the dietary ingestion, nondietary ingestion, and inhalation routes and their excreted amounts of urinary BPA. BPA was detected in 100% of the urine samples. The estimated median intake doses of BPA for these 81 children were 109 ng/kg/day (dietary ingestion), 0.06 ng/kg/day (nondietary ingestion), and 0.27 ng/kg/day (inhalation); their estimated median excreted amount of urinary BPA was 114 ng/kg/day. Our multivariable regression model showed that dietary intake of BPA (p = 0.04) and creatinine concentration (p = 0.004) were significant predictors of urinary BPA excretion, collectively explaining 17% of the variability in excretion. Dietary ingestion of BPA accounted for >95% of the children's excreted amounts of urinary BPA. PMID- 21612269 TI - Double-strand DNA-templated formation of copper nanoparticles as fluorescent probe for label-free aptamer sensor. AB - Double-strand DNA (dsDNA) can act as an efficient template for the formation of copper nanoparticles (Cu NPs) at low concentration of CuSO(4), and the formed Cu NPs have excellent fluorescence, whereas a single-strand DNA (ssDNA) template does not support Cu NPs' formation. This property of dsDNA-Cu NPs makes it suitable for DNA sensing. However, exploration of dsDNA-Cu NPs applied in biological analysis is still at an early stage. In this regard, we report herein for the first time a sensitive, cost-effective, and simple aptamer sensor (aptasensor) using dsDNA-Cu NPs as fluorescent probe. The design consists of a dsDNA with reporter DNA (here, aptamer) as template for the formation of Cu NPs, and the formed dsDNA-Cu NPs show high fluorescence. Using adenosine triphosphate (ATP) as a model analyte, the introduction of ATP triggers the structure switching of reporter DNA to form aptamer-ATP complex, causing the destruction of the double helix and thus no formation of the Cu NPs, resulting in low fluorescence. The preferable linear range (0.05-500 MUM), sensitivity (LOD 28 nM), and simplicity for the detection of ATP indicate that dsDNA-Cu NPs may have great prospects in the field of biological analysis. We also use this novel fluorescent probe to determine ATP in 1% human serum and human adenocarcinoma HeLa cells. The dsDNA-Cu NPs probes provide recovery of 104-108% in 1% human serum and a prominent fluorescent signal is obtained in cellular ATP assay, revealing the practicality of using dsDNA-Cu NPs for the determination of ATP in real samples. Besides, this design is simply based on nucleic acid hybridization, so it can be generally applied to other aptamers for label-free detection of a broad range of analytes. Successful detection of cocaine with detection limit of 0.1 MUM demonstrates its potential to be a general method. PMID- 21612267 TI - Landscape of next-generation sequencing technologies. PMID- 21612270 TI - Acetyl chloride-silver nitrate-acetonitrile: a reagent system for the synthesis of 2-nitroglycals and 2-nitro-1-acetamido sugars from glycals. AB - A new reagent system comprising acetyl chloride, silver nitrate, and acetonitrile has been developed for the synthesis of 2-nitroglycals from the corresponding glycals. Under certain conditions, the formation of 2-nitro-1-acetamido sugars has also been observed. In addition, a few other non-carbohydrate-derived olefins also gave the corrresponding conjugated nitroolefins. PMID- 21612271 TI - An Adaptive Anti-Brownian ELectrokinetic trap with real-time information on single-molecule diffusivity and mobility. AB - We present the design and implementation of an adaptive Anti-Brownian ELectrokinetic (ABEL) trap capable of extracting estimates of the diffusion coefficient and mobility of single trapped fluorescent nanoscale objects such as biomolecules in solution. The system features rapid acousto-optic scanning of a confocal excitation spot on a 2D square lattice to encode position information on the arrival time of each detected photon, and Kalman filter-based signal processing unit for refined position estimation. We demonstrate stable trapping of multisubunit proteins (D ~ 22 MUm(2)/s) with a count rate of 6 kHz for as long as 15 s and small single-stranded DNA molecules (D ~ 118 MUm(2)/s) at a 15 kHz count rate for seconds. Moreover, we demonstrate real-time measurement of diffusion coefficient and electrokinetic mobility of trapped objects, using adaptive tuning of the Kalman filter parameters. PMID- 21612272 TI - Activation parameters derived from a temperature dependent large amplitude ac voltammetric study of the electrode kinetics of the Cp2M(0/+) redox couples (M = Fe, Co) at a glassy carbon electrode. AB - Heterogeneous charge transfer rate constants (k degrees ) for the oxidation of ferrocene, Fc (k degrees = 0.21 cm s(-1) at 20 degrees C), and the reduction of the cobaltocenium cation, Cc(+) (k degrees = 0.12 cm s(-1) at 18 degrees C), in CH(2)Cl(2) (0.5 M Bu(4)NPF(6)) at a glassy carbon (GC) electrode were determined as a function of temperature using the higher harmonic components available in Fourier transformed large amplitude ac voltammetry. The measured k degrees values lie at the upper end of the analytically useful range available for the acquisition of meaningful kinetic data for these very fast (i.e., close to reversible) processes. Measurements of the kinetics are facilitated by the ac technique because contributions resulting from uncompensated resistance and slow electrode kinetics, both of which also vary with temperature, can be distinguished via their different contributions to individual harmonics. Values of k degrees measured over the temperature range of -18 to +20 degrees C for the Fc(0/+) and Cc(+/0) processes gave linear Arrhenius plots yielding free energies of activation (DeltaG(?)) estimates of 17.0 and 18.0 kJ mol(-1), respectively, in excellent agreement with theoretical values derived from Marcus theory. An analogous temperature dependence is indicated in a study of the Fc(0/+) process in acetonitrile (0.1 M Bu(4)NPF(6)), but the greater k degrees value evident makes the temperature dependence of these parameters more difficult to quantify as departures from reversibility are minimal, even in the higher harmonics. PMID- 21612273 TI - Anthropogenic chemical carbon cycle for a sustainable future. AB - Nature's photosynthesis uses the sun's energy with chlorophyll in plants as a catalyst to recycle carbon dioxide and water into new plant life. Only given sufficient geological time, millions of years, can new fossil fuels be formed naturally. The burning of our diminishing fossil fuel reserves is accompanied by large anthropogenic CO(2) release, which is outpacing nature's CO(2) recycling capability, causing significant environmental harm. To supplement the natural carbon cycle, we have proposed and developed a feasible anthropogenic chemical recycling of carbon dioxide. Carbon dioxide is captured by absorption technologies from any natural or industrial source, from human activities, or even from the air itself. It can then be converted by feasible chemical transformations into fuels such as methanol, dimethyl ether, and varied products including synthetic hydrocarbons and even proteins for animal feed, thus supplementing our food chain. This concept of broad scope and framework is the basis of what we call the Methanol Economy. The needed renewable starting materials, water and CO(2), are available anywhere on Earth. The required energy for the synthetic carbon cycle can come from any alternative energy source such as solar, wind, geothermal, and even hopefully safe nuclear energy. The anthropogenic carbon dioxide cycle offers a way of assuring a sustainable future for humankind when fossil fuels become scarce. While biosources can play a limited role in supplementing future energy needs, they increasingly interfere with the essentials of the food chain. We have previously reviewed aspects of the chemical recycling of carbon dioxide to methanol and dimethyl ether. In the present Perspective, we extend the discussion of the innovative and feasible anthropogenic carbon cycle, which can be the basis of progressively liberating humankind from its dependence on diminishing fossil fuel reserves while also controlling harmful CO(2) emissions to the atmosphere. We also discuss in more detail the essential stages and the significant aspects of carbon capture and subsequent recycling. Our ability to develop a feasible anthropogenic chemical carbon cycle supplementing nature's photosynthesis also offers a new solution to one of the major challenges facing humankind. PMID- 21612274 TI - Modeling of the water network at protein-RNA interfaces. AB - Water plays an important role in the mediation of biomolecular interactions. Thus, accurate prediction and evaluation of water-mediated interactions is an important element in the computational design of interfaces involving proteins, RNA, and DNA. Here, we use an algorithm (WATGEN) to predict the locations of interfacial water molecules for a data set of 224 protein-RNA interfaces. The accuracy of the prediction is validated against water molecules present in the X ray structures of 105 of these complexes. The complexity of the water networks is deconvoluted through definition of the characteristics of each water molecule based on its bridging properties between the protein and RNA and on its depth in the interface with respect to the bulk solvent. This approach has the potential for scoring the water network for incorporation into the computational design of protein-RNA complexes. PMID- 21612275 TI - A new Transcriptional Effect Level Index (TELI) for toxicogenomics-based toxicity assessment. AB - This study proposes and demonstrates the potential application of a new Transcriptional Effect Level Index (TELI) to convert the information-rich toxicogenomic data into integrated and quantitative endpoints. A library of transcriptional fusions of green fluorescent protein (GFP) that includes different promoters for 91 stress-related genes in E. coli K12, MG1655 is employed to evaluate the gene expression alteration induced by exposure to four nanomaterials (NMs), nano silver (nAg), nano titanium dioxide anatase (nTiO2_a), nano titanium dioxide rutile (nTiO2_r), and fullerene soot. TELI is determined for each toxicogenomic assay, and it incorporates the number and identity of genes that had altered expression, the magnitude of alteration, and the temporal pattern of gene expression change in response to toxicant exposure. TELI values exhibit a characteristic "sigmoid" shaped toxicity dose-response curve, based on which TELI(MAX) (the maximal value of TELI), TELI50 (concentration that yields half of TELI(MAX)), NOTEL(TELI) (TELI-based no observed transcriptional effect level), and Slope(TELI) (the slope of TELI-dose response curve) are obtained. TELI-based endpoints are compared to currently used endpoints such as EC50 and no observed transcriptional effect level (NOTEL). The agreement of NOTEL(TELI) and NOTEL values validates the concept and application of TELI. Multiple endpoints derived from TELI can describe the dose response behavior and characteristics more completely and holistically than single points such as NOTEL alone. TELI values determined for genes in each stress response category (e.g., oxidative stress, DNA repair) indicate mode of action (MOA)-related comparative transcriptional level toxicity among compounds, and it reveals detailed information of toxic response pathways such as different DNA damage and repair mechanisms among the NMs. This study presents a methodology for converting the rich toxicogenomic information into a readily usable and transferable format that can be potentially linked to regulation endpoints and incorporated into a decision-making framework. PMID- 21612276 TI - Molecular cobalt pentapyridine catalysts for generating hydrogen from water. AB - A set of robust molecular cobalt catalysts for the generation of hydrogen from water is reported. The cobalt complex supported by the parent pentadentate polypyridyl ligand PY5Me(2) features high stability and activity and 100% Faradaic efficiency for the electrocatalytic production of hydrogen from neutral water, with a turnover number reaching 5.5 * 10(4) mol of H(2) per mole of catalyst with no loss in activity over 60 h. Control experiments establish that simple Co(II) salts, the free PY5Me(2) ligand, and an isostructural PY5Me(2) complex containing redox-inactive Zn(II) are all ineffective for this reaction. Further experiments demonstrate that the overpotential for H(2) evolution can be tuned by systematic substitutions on the ancillary PY5Me(2) scaffold, presaging opportunities to further optimize this first-generation platform by molecular design. PMID- 21612277 TI - Determination of quercetins in onion (Allium cepa) using infrared spectroscopy. AB - The rapid quantification of flavonoid compounds in onions by attenuated total reflectance (ATR) Fourier transform infrared (FT-IR) spectroscopy combined with multivariate analysis was evaluated as a possible alternative to high-performance liquid chromatography (HPLC) analysis. Quercetin content in onion varieties (yellow, red, and sweet) was quantified using ATR FT-IR (4000 to 400 cm-1) spectroscopy and HPLC methods. Quercetin-3,4'-O-diglucoside (3,4'-Qdg) and quercetin-4'-O-glucoside (4'-Qmg) comprised >80% of the total flavonol content detected in the studied varieties. The quercetin compounds (3,4'-Qdg and 4'-Qmg) and total flavonol conjugates were quantified by HPLC, and results correlated closely with ATR-IR values (R > 0.95). Cross-validated (leave-one-out) partial least-squares regression (PLSR) models successfully predicted concentrations of these quercetins. The standard errors of cross-validation (SECV) of 3,4'-Qdg and 4'-Qmg, total quercetin, and total flavonol contents of onions were 20.43, 21.18, and 21.02 mg/kg fresh weight, respectively. In addition, supervised and unsupervised segregation analyses (principal component analysis, discriminant function analysis, and soft independent modeling of class analogue) were performed to classify onion varieties on the basis of unique infrared spectral features. There was a high degree of segregation (interclass distances > 3.0) for the different types of onion. This study indicated that the IR technique could predict 3,4'-Qdg, 4'-Qmg, total quercetin, and total flavonol contents and has advantages over the traditional HPLC method in providing a valid, efficient, and cost-effective method requiring less sample preparation for the quantification of quercetins in onion. PMID- 21612278 TI - The fragmentation-recombination mechanism of the enzyme glutamate mutase studied by QM/MM simulations. AB - The radical mechanism of the conversion of glutamate to methylaspartate catalyzed by glutamate mutase is studied with quantum mechanical/molecular mechanical (QM/MM) simulations based on density functional theory (DFT/MM). The hydrogen transfer between the substrate and the cofactor is found to be rate limiting with a barrier of 101.1 kJ mol(-1). A careful comparison to the uncatalyzed reaction in water is performed. The protein influences the reaction predominantly electrostatically and to a lesser degree sterically. Our calculations shed light on the atomistic details of the reaction mechanism. The well-known arginine claw and Glu 171 ( Clostridium cochlearium notation) are found to have the strongest influence on the reaction. However, a catalytic role of Glu 214, Lys 322, Gln 147, Glu 330, Lys 326, and Met 294 is found as well. The arginine claw keeps the intermediates in place and is probably responsible for the enantioselectivity. Glu 171 temporarily accepts a proton from the glutamyl radical intermediate and donates it back at the end of the reaction. We relate our results to experimental data when available. Our simulations lead to further understanding of how glutamate mutase catalyzes the carbon skeleton rearrangement of glutamate. PMID- 21612279 TI - 2:1 cocrystals of homochiral and achiral amino acid zwitterions with Li+ salts: water-stable zeolitic and diamondoid metal-organic materials. AB - Eight 2:1 cocrystals of amino acid zwitterions and Li(+) salts were crystallized from hot water to afford cationic networks based on tetrahedral lithium cations: square grids, an ABW topology net, and diamondoid nets. PMID- 21612280 TI - Layered hydrazinium titanate: advanced reductive adsorbent and chemical toolkit for design of titanium dioxide nanomaterials. AB - LHT-9, a layered hydrazinium titanate with an interlayer spacing of ~9 A, is a new nanohybrid compound combining the redox functionality of hydrazine, the ion exchange properties of layered titanate, the large surface area of quasi-two dimensional crystallites, surface Bronsted acidity, and the occurrence of surface titanyl bonds. LHT-9, ideally formulated as (N(2)H(5))(1/2)Ti(1.87)O(4), relates to a family of lepidocrocite-type titanates. It possesses a high uptake capacity of ~50 elements of the periodic table. Irreversibility of reductive adsorption allows LHT-9 to be used for cumulative extraction of reducible moieties (noble metals, chromate, mercury, etc.) from industrial solutions and wastewaters. Unlike sodium titanates that do not tolerate an acidic environment, LHT-9 is capable of uptake of transition metals and lanthanides at pH > 3. Adsorption products loaded with the desired elements retain their layered structures and can be used as precursors for tailored titanium dioxide nanomaterials. In this respect, the uptake of metal ions by LHT-9 can be considered as a method complementary to electrostatic self-assembly deposition (ESD) and layer-by-layer self-assembly (LBL) techniques. LHT-9 is readily synthesized in one step by a mild fluoride route involving hydrazine-induced hydrolysis of hexafluorotitanic acid under near-ambient conditions. PMID- 21612281 TI - Slow threading intercalation of monomeric Ru(II) complexes with 10,13 diarylsubstituted dppz ligands. AB - Threading intercalation is an unusual DNA binding mode that displays extremely slow dissociation kinetics, which is an important feature for cytotoxicity, making threading intercalating compounds interesting as model compounds in the search for new DNA binding drugs. This type of binding has for ruthenium complexes previously only been observed for complexes containing 11-substituted dipyridophenazine ligands. In this work we have synthesized and investigated the DNA binding properties of two new 10,13-diarylsubstituted dipyridophenazine ruthenium complexes, using spectroscopic techniques, and found that this substitution pattern provides a new strategy for development of drugs with slow dissociation kinetics. However, the nature of the aryl substituents largely affects the binding properties of the complexes as it was found that a dithienyl substituted complex exhibit slow dissociation kinetics characteristic for threading intercalation while its diphenyl substituted analogue seems to bind DNA by partial intercalation of one phenyl substituent resulting in faster dissociation. PMID- 21612282 TI - Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport. AB - Glutamate plays essential roles in chemical transmission as a major excitatory neurotransmitter. The accumulation of glutamate in secretory vesicles is mediated by vesicular glutamate transporters (VGLUTs) that together with the driving electrochemical gradient of proteins influence the subsequent quantum release of glutamate and the function of higher-order neurons. The vesicular content of glutamate is well correlated with membrane potential (Deltapsi), which suggests that Deltapsi determines the vesicular glutamate concentration. The transport of glutamate into secretory vesicles is highly dependent on Cl(-). This anion stimulates glutamate transport but is inhibitory at higher concentrations. Accumulating evidence indicates that Cl(-) regulates glutamate transport through control of VGLUT activity and the H(+) electrochemical gradient. Recently, a comprehensive study demonstrated that Cl(-) regulation of VGLUT is competitively inhibited by metabolic intermediates such as ketone bodies. It also showed that ketone bodies are effective in controlling epilepsy. These results suggest a correlation between metabolic state and higher-order brain function. We propose a novel function for Cl(-) as a fundamental regulator for signal transmission. PMID- 21612284 TI - In situ generation of the Coates catalyst: a practical and versatile catalytic system for the carbonylation of meso-epoxides. AB - A highly active catalytic system for the carbonylation of meso- and terminal epoxides to beta-lactones is described. The active catalyst, analogous to Coates' catalyst, is generated in situ from commercially available (TPP)CrCl and Co(2)(CO)(8). This practical system circumvents the preparation of air sensitive cobaltate salts, operates at low catalyst loadings, and allows the carbonylation of functionalized, sterically demanding and heterocyclic meso-epoxides. PMID- 21612285 TI - CSAR scoring challenge reveals the need for new concepts in estimating protein ligand binding affinity. AB - The dG prediction accuracy by the Lead Finder docking software on the CSAR test set was characterized by R(2)=0.62 and rmsd=1.93 kcal/mol, and the method of preparation of the full-atom structures of the test set did not significantly affect the resulting accuracy of predictions. The primary factors determining the correlation between the predicted and experimental values were the van der Waals interactions and solvation effects. Those two factors alone accounted for R(2)=0.50. The other factors that affected the accuracy of predictions, listed in the order of decreasing importance, were the change of ligand's internal energy upon binding with protein, the electrostatic interactions, and the hydrogen bonds. It appears that those latter factors contributed to the independence of the prediction results from the method of full-atom structure preparation. Then, we turned our attention to the other factors that could potentially improve the scoring function in order to raise the accuracy of the dG prediction. It turned out that the ligand-centric factors, including Mw, cLogP, PSA, etc. or protein centric factors, such as the functional class of protein, did not improve the prediction accuracy. Following that, we explored if the weak molecular interactions such as X-H...Ar, X-H...Hal, CO...Hal, C-H...X, stacking and pi cationic interactions (where X is N or O), that are generally of interest to the medicinal chemists despite their lack of proper molecular mechanical parametrization, could improve dG prediction. Our analysis revealed that out of these new interactions only CO...Hal is statistically significant for dG predictions using Lead FInder scoring function. Accounting for the CO...Hal interaction resulted in the reduction of the rmsd from 2.19 to 0.69 kcal/mol for the corresponding structures. The other weak interaction factors were not statistically significant and therefore irrelevant to the accuracy of dG prediction. On the basis of our findings from our participation in the CSAR scoring challenge we conclude that a significant increase of accuracy predictions necessitates breakthrough scoring approaches. We anticipate that the explicit accounting for water molecules, protein flexibility, and a more thermodynamically accurate method of dG calculation rather than single point energy calculation may lead to such breakthroughs. PMID- 21612283 TI - Native electrospray and electron-capture dissociation FTICR mass spectrometry for top-down studies of protein assemblies. AB - The high sensitivity, extended mass range, and fast data acquisition/processing of mass spectrometry and its coupling with native electrospray ionization (ESI) make the combination complementary to other biophysical methods of protein analysis. Protein assemblies with molecular masses up to MDa are now accessible by this approach. Most current approaches have used quadrupole/time-of-flight tandem mass spectrometry, sometimes coupled with ion mobility, to reveal stoichiometry, shape, and dissociation of protein assemblies. The amino-acid sequence of the subunits, however, still relies heavily on independent bottom-up proteomics. We describe here an approach to study protein assemblies that integrates electron-capture dissociation (ECD), native ESI, and FTICR mass spectrometry (12 T). Flexible regions of assembly subunits of yeast alcohol dehydrogenase (147 kDa), concanavalin A (103 kDa), and photosynthetic Fenna Matthews-Olson antenna protein complex (140 kDa) can be sequenced by ECD or "activated-ion" ECD. Furthermore, noncovalent metal-binding sites can also be determined for the concanavalin A assembly. Most importantly, the regions that undergo fragmentation, either from one of the termini by ECD or from the middle of a protein, as initiated by CID, correlate well with the B-factor from X-ray crystallography of that protein. This factor is a measure of the extent an atom can move from its coordinated position as a function of temperature or crystal imperfections. The approach provides not only top-down proteomics information of the complex subunits but also structural insights complementary to those obtained by ion mobility. PMID- 21612286 TI - Water: two liquids divided by a common hydrogen bond. AB - The structure of water is the subject of a long and ongoing controversy. Unlike simpler liquids, where atomic interactions are dominated by strong repulsive forces at short distances and weaker attractive (van der Waals) forces at longer distances, giving rise to local atomic coordination numbers of order 12, water has pronounced and directional hydrogen bonds which cause the dense liquid close packed structure to open out into a disordered and dynamic network, with coordination number 4-5. Here I show that water structure can be accurately represented as a mixture of two identical, interpenetrating, molecular species separated by common hydrogen bonds. Molecules of one type can form hydrogen bonds with molecules of the other type but cannot form hydrogen bonds with molecules of the same type. These hydrogen bonds are strong along the bond but weak with respect to changes in the angle between neighboring bonds. The observed pressure and temperature dependence of water structure and thermodynamic properties follow naturally from this choice of water model, and it also gives a simple explanation of the enduring claims based on spectroscopic evidence that water is a mixture of two components. PMID- 21612287 TI - Interaction between lipids and antimicrobial oligomers studied by solid-state NMR. AB - Antimicrobial peptides and their synthetic analogues are well known to interact with the cell membrane, which has complex distributions of lipids. The phase behavior of DOPE/DOPG mixed lipids and the interaction between the lipids and several synthetic amphiphilic antimicrobial oligomers (AMOs) were studied by solid-state nuclear magnetic resonance (NMR). A phase diagram of the lipids over a broad window of water content was constructed. There are large areas in the phase diagram where multiple phases coexist, and the fraction of each phase at a given state is dependent on the sample's preparation and thermal history. The comparable stability of the different phases implies that even slight changes in the lipid condition could result in substantial changes to the phase structure, which may be utilized by living organisms to achieve many membrane functions. Nuclear Overhauser spectroscopy (NOESY) and several other NMR experiments indicated that the AMO primarily resides in the head group region of the lipids and that DOPE, the negative intrinsic curvature lipid, does not selectively enrich in the inverted hexagonal phase. PMID- 21612288 TI - Total synthesis of unguisin A. AB - The first synthesis of the gamma-aminobutyric acid (GABA)-containing cyclic heptapeptide unguisin A is reported, confirming the structure of this natural product. Macrocyclization of a flexible GABA-containing linear precursor is found to proceed rapidly and in good yield. PMID- 21612290 TI - Selective sulfoxidation of thioethers and thioaryl boranes with nitrate, promoted by a molybdenum-copper catalytic system. AB - The catalytic reduction of nitrate by molybdo-enzymes plays a central role in the global biological cycle of nitrogen. However, the use of nitrates as oxidants in synthetic organic chemistry is very limited and typically requires very strong acidic and other extreme reaction conditions. We have developed a highly chemoselective and efficient catalytic process for the sulfoxidation of thioethers and arylthioethers containing boronic acid or boronic ester functional groups, using nitrate salts as oxidants. This homogeneous catalytic reaction was carried out in acetonitrile, where the MoO(2)Cl(2)(OPPh(3))(2) complex 1 or a mixture of complex 1 with Cu(NO(3))(2) were used as catalysts. We examined the reaction mechanism using (1)H, (15)N, and (31)P NMR techniques and (18)O-labeled sodium nitrate (NaN(18)O(3)) and show that the thioethers are oxidized by nitrate, generating nitrite. Our work adds to the existing chemical transformations available for organoboron compounds, providing straightforward accessibility to a variety of new substrates that could be suitable for Suzuki cross-coupling chemistry. PMID- 21612291 TI - Controlling chain conformation in conjugated polymers using defect inclusion strategies. AB - The Horner method was used to synthesize random copolymers of poly(2-methoxy-5 (2'-ethylhexyloxy)-p-phenylene vinylene) (MEH-PPV) that incorporated different backbone-directing monomers. Single-molecule polarization absorption studies of these new polymers demonstrate that defects that preserve the linear backbone of PPV-type polymers assume the highly anisotropic configurations found in defect free MEH-PPV. Rigid defects that are bent lower the anisotropy of the single chain, and saturated defects that provide rotational freedom for the chain backbone allow for a wide variety of possible configurations. Molecular dynamics simulations of model defect PPV oligomers in solution demonstrate that defect free and linearly defected oligomers remain extended while the bent and saturated defects tend toward more folded, compact structures. PMID- 21612292 TI - Toughening of epoxy matrices with reduced single-walled carbon nanotubes. AB - Reduced single-walled carbon nanotubes (r-SWCNT) are shown to react readily at room temperature under inert atmosphere conditions with epoxide moieties, such as those in triglycidyl p-amino phenol (TGAP), to produce a soft covalently bonded interface around the SWCNT. The soft interface is compatible with the SWCNT-free cross-linked cured matrix and acts as a toughener for the composite. Incorporation of 0.2 wt % r-SWCNT enhances the ultimate tensile strength, toughness and fracture toughness by 32, 118, and 40%, respectively, without change in modulus. A toughening rate (dK(IC)/dwt(f)) of 200 MPa m(0.5) is obtained. The toughening mechanism is elucidated through dynamic mechanical analyses, Raman spectroscopy and imaging, and stress-strain curve analyses. The method is scalable and applicable to epoxy resins and systems used commercially. PMID- 21612293 TI - Characterization of column packing materials in high-performance liquid chromatography by charge-detection quadrupole ion trap mass spectrometry. AB - This article reports an application of charge-detection quadrupole ion trap mass spectrometry (CD-ITMS) to characterize the column packing materials in high performance liquid chromatography (HPLC). Both the mean mass and the mass distribution of the packing materials are obtained and used to calculate the specific surface area of unbonded silica, the carbon load of the bonded silica, and their particle size distributions. The obtained specific surface areas and carbon loads are consistent with those measured independently by nitrogen sorption and elemental analysis respectively, whereas the derived size distributions show better resolution than that measured by a laser particle size analyzer. Furthermore, we evaluate the uniformity of particle size, which is the key parameter for column efficiency of the liquid chromatography by analyzing the mass distribution of the packing materials at the top and bottom of the column. A broader mass distribution, which yields decreased column efficiency, is observed for the column top because of the excessive use of the column. Our results suggest that CD-ITMS can serve as an alternative means for the characterization of the packing materials in HPLC and is potentially useful for column quality control. PMID- 21612289 TI - Comprehensive identification of glycated peptides and their glycation motifs in plasma and erythrocytes of control and diabetic subjects. AB - Nonenzymatic glycation of proteins sets the stage for formation of advanced glycation end-products and development of chronic complications of diabetes. In this report, we extended our previous methods on proteomics analysis of glycated proteins to comprehensively identify glycated proteins in control and diabetic human plasma and erythrocytes. Using immunodepletion, enrichment, and fractionation strategies, we identified 7749 unique glycated peptides, corresponding to 3742 unique glycated proteins. Semiquantitative comparisons showed that glycation levels of a number of proteins were significantly increased in diabetes and that erythrocyte proteins were more extensively glycated than plasma proteins. A glycation motif analysis revealed that some amino acids were favored more than others in the protein primary structures in the vicinity of the glycation sites in both sample types. The glycated peptides and corresponding proteins reported here provide a foundation for potential identification of novel markers for diabetes, hyperglycemia, and diabetic complications in future studies. PMID- 21612294 TI - Asymmetric total synthesis of (-)-saframycin A from L-tyrosine. AB - The asymmetric total synthesis of (-)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor antibiotics family, has been accomplished by employing L-tyrosine as the starting chiral building block in 24 steps for the longest linear sequence in an overall yield of 9.7%. The key steps in the synthesis involve stereoselective intermolecular and intramolecular Pictet Spengler reactions, which induced the correct stereochemistry at C-1 and C-11, respectively. The selective protection-deprotection protocol of an amino group in the two-step transformation from intermediate 10 to 12 and a hydroxyl group in the first two steps resulted in both high selectivity and efficiency of the synthetic route. PMID- 21612295 TI - Time-resolved resonance Raman spectroscopic studies on the triplet excited state of thioxanthone. AB - Thioxanthone has been investigated extensively owing to its unique photochemical and photophysical applications and its solvatochromic behavior. Here, we report the time-resolved resonance Raman studies on the structure of the lowest triplet excited state of thioxanthone in carbon tetrachloride. In addition, FT-IR and FT Raman techniques have been used to study the vibrational structure in the ground state. To corroborate the experimental findings, density functional theory calculations have been carried out. Isotopic calculations and normal coordinate analysis have been used to help in assigning the observed bands to Raman vibrational modes. Structural information derived from this study is expected to help in better understanding the triplet state photochemistry of thioxanthone. PMID- 21612296 TI - H/D isotopic recognition in hydrogen-bonded systems: strong dynamical coupling effects in the polarized IR spectra of 3-methylthioacetanilide and 4 methylthioacetanilide crystals. AB - This paper presents the investigation results of the polarized IR spectra of the hydrogen bond in crystals of 3- and 4-methylthioacetanilide. The spectra were measured at 293 and 77 K by a transmission method, with the use of polarized light. The main spectral properties of the crystals can be interpreted satisfactorily in terms of the "strong-coupling" theory, on the basis of the hydrogen bond centrosymmetric dimer model. The spectra revealed that the strongest vibrational exciton coupling involved the closely spaced hydrogen bonds, each belonging to a different chain of associated 3- and 4 methylthioacetanilide molecules. A weaker exciton coupling involved the adjacent hydrogen bonds in each individual chain. It was proven that a nonrandom distribution of the protons and deuterons took place in the lattices of isotopically diluted crystalline samples of 3- and 4-methylthioacetanilide. In each case, the H/D isotopic "self-organization" mechanism involved all four hydrogen bonds from each unit cell. PMID- 21612297 TI - Secondary coordination sphere interactions facilitate the insertion step in an iridium(III) CO2 reduction catalyst. AB - There is considerable interest in both catalysts for CO(2) conversion and understanding how CO(2) reacts with transition metal complexes. Here we develop a simple model for predicting the thermodynamic favorability of CO(2) insertion into Ir(III) hydrides. In general this reaction is unfavorable; however, we demonstrate that with a hydrogen bond donor in the secondary coordination sphere it is possible to isolate a formate product from this reaction. Furthermore, our CO(2) inserted product is one of the most active water-soluble catalysts reported to date for CO(2) hydrogenation. PMID- 21612298 TI - Short ligands affect modes of QD uptake and elimination in human cells. AB - In order to better understand nanoparticle uptake and elimination mechanisms, we designed a controlled set of small, highly fluorescent quantum dots (QDs) with nearly identical hydrodynamic size (8-10 nm) but with varied short ligand surface functionalization. The properties of functionalized QDs and their modes of uptake and elimination were investigated systematically by asymmetrical flow field-flow fractionation (AF4), confocal fluorescence microscopy, flow cytometry (FACS), and flame atomic absorption (FAA). Using specific inhibitors of cellular uptake and elimination machinery in human embryonic kidney cells (Hek 293) and human hepatocellular carcinoma cells (Hep G2), we showed that QDs of the same size but with different surface properties were predominantly taken up through lipid raft mediated endocytosis, however, to significantly different extents. The latter observation infers the contribution of additional modes of QD internalization, which include X-AG cysteine transporter for cysteine-functionalized QDs (QD-CYS). We also investigated putative modes of QD elimination and established the contribution of P-glycoprotein (P-gp) transporter in QD efflux. Results from these studies show a strong dependence between the properties of QD-associated small ligands and modes of uptake/elimination in human cells. PMID- 21612299 TI - Controlled hydrogel formation of a recombinant spider silk protein. AB - Due to their biocompatibility, biodegradability, and low immunogenicity, recombinant spider silk proteins have a high potential for a variety of applications when processed into morphologies such as films, capsules, beads, or hydrogels. Here, hydrogels made of the engineered and recombinantly produced spider silk protein eADF4(C16) were analyzed in detail. It has previously been shown that eADF4(C16) nanofibrils self-assemble by a mechanism of nucleation aggregation, providing the basis of silk hydrogels. We focused on establishing a reproducible gelation process by employing different protein concentrations, chemical crosslinking, and functionalization of eADF4(C16) with fluorescein. Fluorescein strongly influenced assembly as well as the properties of the hydrogels, such as pore sizes and mechanical behavior, possibly due to its interference with packing of silk nanofibrils during hydrogel formation. PMID- 21612300 TI - Novel 3,5-bis(bromohydroxybenzylidene)piperidin-4-ones as coactivator-associated arginine methyltransferase 1 inhibitors: enzyme selectivity and cellular activity. AB - Coactivator-associated arginine methyltransferase 1 (CARM1) represents a valuable target for hormone-dependent tumors such as prostate and breast cancers. Here we report the enzyme and cellular characterization of the 1-benzyl-3,5-bis(3-bromo-4 hydroxybenzylidene)piperidin-4-one (7g) and its analogues 8a-l. Among them, 7g, 8e, and 8l displayed high and selective CARM1 inhibition, with lower or no activity against a panel of different PRMTs or HKMTs. In human LNCaP cells, 7g showed a significant dose-dependent reduction of the PSA promoter activity. PMID- 21612301 TI - Rapid identification of fluorochrome modification sites in proteins by LC ESI-Q TOF mass spectrometry. AB - Conjugation of either a fluorescent dye or a drug molecule to the epsilon-amino groups of lysine residues of proteins has many applications in biology and medicine. However, this type of conjugation produces a heterogeneous population of protein conjugates. Because conjugation of fluorochrome or drug molecule to a protein may have deleterious effects on protein function, the identification of conjugation sites is necessary. Unfortunately, the identification process can be time-consuming and laborious; therefore, there is a need to develop a rapid and reliable way to determine the conjugation sites of the fluorescent label or drug molecule. In this study, the sites of conjugation of fluorescein-5' isothiocyanate and rhodamine-B-isothiocyanate to free amino groups on the insert domain (I-domain) protein derived from the alpha-subunit of lymphocyte function associated antigen-1 (LFA-1) were determined by electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-Q-TOF MS) along with peptide mapping using trypsin digestion. A reporter fragment of the fluorochrome moiety that is generated in the collision cell of the Q-TOF without explicit MS/MS precursor selection was used to identify the conjugation site. Selected ion plots of the reporter ion readily mark modified peptides in chromatograms of the complex digest. Interrogation of theses spectra reveals a neutral loss/precursor pair that identifies the modified peptide. The results show that one to seven fluorescein molecules or one to four rhodamine molecules were attached to the lysine residue(s) of the I-domain protein. No modifications were found in the metal ion-dependent adhesion site (MIDAS), which is an important binding region of the I-domain. PMID- 21612302 TI - Proteomic and functional analyses reveal a unique lifestyle for Acinetobacter baumannii biofilms and a key role for histidine metabolism. AB - Biofilm formation is one of the main causes for the persistence of Acinetobacter baumannii, a pathogen associated with severe infections and outbreaks in hospitals. Here, we performed comparative proteomic analyses (2D-DIGE and MALDI TOF/TOF and iTRAQ/SCX-LC-MS/MS) of cells at three different conditions: exponential, late stationary phase, and biofilms. These results were compared with alterations in the proteome resulting from exposure to a biofilm inhibitory compound (salicylate). Using this multiple-approach strategy, proteomic patterns showed a unique lifestyle for A. baumannii biofilms and novel associated proteins. Several cell surface proteins (such as CarO, OmpA, OprD-like, DcaP like, PstS, LysM, and Omp33), as well as those involved in histidine metabolism (like Urocanase), were found to be implicated in biofilm formation, this being confirmed by gene disruption. Although l-His uptake triggered biofilms efficiently in wild-type A. baumannii, no effect was observed in Urocanase and OmpA mutants, while a slight increase was observed in a CarO deficient strain. We conclude that Urocanase plays a crucial role in histidine metabolism leading to biofilm formation and that OmpA and CarO can act as channels for L-His uptake. Finally, we propose a model in which novel proteins are suggested for the first time as targets for preventing the formation of A. baumannii biofilms. PMID- 21612303 TI - Violation of the condon approximation in semiconducting carbon nanotubes. AB - The Condon approximation is widely applied in molecular and condensed matter spectroscopy and states that electronic transition dipoles are independent of nuclear positions. This approximation is related to the Franck-Condon principle, which in its simplest form holds that electronic transitions are instantaneous on the time scale of nuclear motion. The Condon approximation leads to a long-held assumption in Raman spectroscopy of carbon nanotubes: intensities arising from resonance with incident and scattered photons are equal. Direct testing of this assumption has not been possible due to the lack of homogeneous populations of specific carbon nanotube chiralities. Here, we present the first complete Raman excitation profiles (REPs) for the nanotube G band for 10 pure semiconducting chiralities. In contrast to expectations, a strong asymmetry is observed in the REPs for all chiralities, with the scattered resonance always appearing weaker than the incident resonance. The observed behavior results from violation of the Condon approximation and originates in changes in the electronic transition dipole due to nuclear motion (non-Condon effect), as confirmed by our quantum chemical calculations. The agreement of our calculations with the experimental REP asymmetries and observed trends in family dependence indicates the behavior is intrinsic. PMID- 21612304 TI - Adsorption and desorption behavior of metalaxyl in intensively cultivated acid soils. AB - Metalaxyl adsorption and desorption behavior in acid soils were evaluated via batch and stirred-flow chamber experiments. On the basis of batch experiments (adsorption curves of the Giles C-type), metalaxyl has a low affinity for acid soils. Also, as derived from batch and stirred-flow chamber tests, its adsorption in acid soils is dictated mainly by their organic matter and clay contents. The high correlation between these two variables makes it rather complicated to resolve their effects. Metalaxyl adsorption occurs largely (80-99%) via fast adsorption reactions. On the other hand, the pesticide is desorbed in variable proportions (30-100%). The desorption parameters obtained by fitting the results to a pseudo-first-order reaction were correlated with no edaphic variable; however, the q(0)/q(max) ratio, which is a measure of reversibility in the adsorption-desorption process, exhibited significant negative correlation with the organic matter and clay contents. PMID- 21612305 TI - Ce3+ ions determine redox-dependent anti-apoptotic effect of cerium oxide nanoparticles. AB - Antioxidant therapy is the novel frontier to prevent and treat an impressive series of severe human diseases, and the search for adequate antioxidant drugs is fervent. Cerium oxide nanoparticles (nanoceria) are redox-active owing to the coexistence of Ce(3+) and Ce(4+) oxidation states and to the fact that Ce(3+) defects, and the compensating oxygen vacancies, are more abundant at the surface. Nanoceria particles exert outstanding antioxidant effects in vivo acting as well tolerated anti-age and anti-inflammatory agents, potentially being innovative therapeutic tools. However, the biological antioxidant mechanisms are still unclear. Here, the analysis on two leukocyte cell lines undergoing apoptosis via redox-dependent or independent mechanisms revealed that the intracellular antioxidant effect is the direct cause of the anti-apoptotic and prosurvival effects of nanoceria. Doping with increasing concentrations of Sm(3+), which progressively decreased Ce(3+) without affecting oxygen vacancies, blunted these effects, demonstrating that Ce(3+)/Ce(4+) redox reactions are responsible for the outstanding biological properties of nanoceria. PMID- 21612306 TI - Cyclical "flipping" of morphology in block copolymer thin films. AB - We studied the kinetics of nanopattern evolution in (polystyrene-b-polyethylene oxide) diblock copolymer thin films. Using scanning force microscopy, a highly unexpected cylindrical flipping of morphology from normal to parallel to the film plane was detected during solvent annealing of the film (with average thickness of 30 nm) at high vapor pressure. Using an in situ time-resolved light scattering device combined with an environmental cell enabled us to obtain kinetic information at different vapor pressures. The data indicated that there is a threshold value for the vapor pressure necessary for the structural transition. We propose a swelling and deswelling mechanism for the orientation flipping of the morphology. The cyclic transition occurs faster in thick films (177 nm) where the mass uptake and solvent volume fraction is smaller and therefore the driving force for phase separation is higher. We induced a stronger segregation by confining the chains in graphoepitaxially patterned substrates. As expected, the cyclic transition occurred at higher rate. Our work is another step forward to understanding the structure evolution and also controlling the alignment of block copolymer nanocylinders independently of thickness and external fields. PMID- 21612307 TI - Arterial stiffness: from physiology to clinical implications. AB - Current European guidelines for the management of arterial hypertension introduce the assessment of arterial stiffness by pulse wave velocity (PWV) as an index of hypertension-related cardiovascular target organ damage. An increase in arterial stiffness is related to haemodynamic modifications at the level of the aorta, leading to a rise in cardiac afterload, a reduction in coronary perfusion and an overstretch of the aortic walls. An increasing number of studies have demonstrated the accuracy of PWV as an independent predictor of cardiovascular events and cardiovascular mortality in patients with different co-morbidities and cardiovascular risk. Many strategies have demonstrated their efficacy in preventing arterial stiffening; therapy of arterial hypertension is the mainstay in the management of patients with increased PWV and altered pulse wave reflection. Literature has clearly shown the specific efficacy of drugs interfering with the renin-angiotensin-aldosterone system and calcium-channel blockers in the control of central haemodynamics, particularly when compared with beta-blockers (beta-adrenoceptor antagonists). The same action has not yet been demonstrated on PWV. Further studies are needed to assess the real relative efficacy of different drug classes on the management of arterial stiffness and the clinical and prognostic relevance of these therapies. PMID- 21612308 TI - Hypertension in postmenopausal women: pathophysiology and treatment. AB - Hypertension is the most common chronic disease in industrialized countries and represents the most common major cardiovascular risk factor after the fifth decade of life in both men and women. The prevalence of hypertension is lower in premenopausal women than men, whereas in postmenopausal women it is higher than in men. Mechanisms responsible for the increase in blood pressure are complex and multifactorial, including loss of estrogen, oxidative stress, endothelial dysfunction, modification in renin-angiotensin system spillover and sympathetic activation. In addition, postmenopausal hypertension can be considered an isolated disease, more typical of elderly women, or part of the metabolic syndrome, which is indeed more common in early postmenopausal women. In particular, metabolic syndrome may be considered a potentially unfavourable prognostic factor in hypertensive postmenopausal women, because it seems to worsen the severity of hypertension and reduce the capacity to respond to specific treatments. This article summarizes the different causes of postmenopausal hypertension and the specific treatment recommended by guidelines for this condition. PMID- 21612309 TI - An analysis of the management of cardiovascular risk factors in routine clinical practice in Italy: an overview of the main findings of the EFFECTUS study. AB - Cardiovascular diseases represent the leading cause of morbidity and mortality, worldwide. Early detection and appropriate management of cardiovascular risk factors and disease markers in daily clinical practice may improve preventive strategies and reduce the burden of cardiovascular disease. The EFFECTUS (Evaluation of Final Feasible Effect of Control Training and Ultra Sensitisation) programme was an educational programme aimed at evaluating prevalence of major cardiovascular risk factors among outpatients, and preferences and attitudes for cardiovascular disease management among Italian physicians in their routine clinical practice. This article provides an overview of the main findings of different analyses from the EFFECTUS database, which have demonstrated a high prevalence of cardiovascular risk factors, irrespective of the clinical settings and outpatient clinics in which patients were followed. Also, findings from this database suggest that more intensive clinical data recording was paralleled by better adherence to guidelines, and that use of electronic rather than conventional support for clinical data collection and registration improved accuracy in data recording, which translated into better management of patients at risk in daily clinical practice. PMID- 21612310 TI - Chronic kidney disease in the hypertensive patient: an overview of the I-DEMAND study. AB - The kidney has been recognized as a sensor of cardiovascular risk. However, evaluation of urinary albumin excretion and estimated glomerular filtration rate is still too often overlooked in clinical practice. The I-DEMAND (Italy Developing Education and awareness on MicroAlbuminuria in patients with hyperteNsive Disease) study was designed to assess the prevalence of microalbuminuria and its clinical correlates among Italian hypertensive patients. A total of 4151 patients from 87 specialized care centres were included in the study. Overall, this study demonstrated that approximately one-half of the enrolled patients had chronic kidney disease, with albuminuria being present in one-quarter of the individuals. The presence of renal abnormalities was more prevalent in patients with concomitant cardiovascular risk factors. This article discusses the main results of the study and its potential implications in clinical practice. PMID- 21612311 TI - 2010 position paper of the Italian Society of Hypertension (SIIA): angiotensin receptor blockers and risk of cancer. AB - Antihypertensive therapy has been demonstrated to significantly reduce cardiovascular and non-cardiovascular mortality in randomized controlled clinical trials. In the past, however, doubts have been raised on the safety of one class of blood pressure lowering drugs, namely the angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), in terms of increased risk of myocardial infarction. Several comprehensive meta-analyses have definitely demonstrated no significant increased risk of myocardial infarction in patients treated with ARBs compared with placebo or any other active treatments. More recently, a partial meta-analysis has suggested a potential link between the use of this drug class and an increased risk of cancer. Although a further comprehensive network meta-analysis demonstrated the lack of any increased risk of cancer development or cancer mortality in patients treated with different antihypertensive drug classes, including ARBs, compared with placebo, this report has generated claims and uncertainties in the medical community and produced a vast echo in the lay press. The biological plausibility, the potential pathophysiological mechanisms, and the clinical evidence that rule out such hypotheses are discussed here. The present article, which represents a position paper of the Italian Society of Hypertension (SIIA), states that the benefits derived from the use of ARBs outweigh the potential risks, and that the use of these drugs should be maintained according to present indications. PMID- 21612312 TI - Apoptotic cascades in the central auditory pathway after noise exposure. AB - Noise exposure leads to dramatic physiological and anatomical changes within the central auditory pathway in addition to the well-known cochlear damage. Our group previously described a significant loss of neurons in different central auditory structures upon acoustic overstimulation. The aim of the present study was to investigate if declined neuronal cell density is caused by apoptotic mechanisms. Mice were noise-exposed (3 h, 5-20 kHz) at 115 dB SPL under anesthesia and investigated immediately after, and at 6 h, 24 h, or 7 days after the exposure (n=16). Unexposed animals were used as controls (n=5). Apoptotic cells were detected by fluorescence microscopy after terminal deoxynucleotidyl transferase dUTP nick-end labeling assay (TUNEL). TUNEL-positive cells were compared to cell density (diamidino phenylindole, DAPI) within the dorsal and ventral cochlear nucleus (VCN), and the central nucleus of the inferior colliculus (ICC). In all investigated auditory areas, TUNEL-positive cells were significantly increased after acoustic overstimulation. In the acute, 6-h, and 24-h groups, their numbers were significantly increased in the VCN, as well as in the 6-h, 24-h, and 7-day groups in the dorsal cochlear nucleus (DCN). In the ICC, TUNEL-positive cells were significantly increased in all exposed mice. In the VCN, the number of TUNEL positive cells of the same grid size was three times the numbers in the ICC. Our results show that noise exposure induces apoptosis-related pathophysiological changes within the central auditory pathway in a time-dependent manner. This may represent potential therapeutic targets, and helps clarify the complex psychoacoustic phenomena of noise-induced hearing loss. PMID- 21612314 TI - The influence of occlusal forces on force delivery properties of aligners during rotation of an upper central incisor. AB - OBJECTIVE: To determine the forces and moments delivered to a maxillary central incisor during rotation with aligners when a simulated occlusal force generated during swallowing acts on the appliance. MATERIALS AND METHODS: Five identical appliances were manufactured from four different starting materials (Erkodur 0.8 mm and 1.0 mm; Biolon 0.75 mm and 1.0 mm). An upper central incisor fixed in a measuring device was rotated around its central axis in 0.5-degree steps up to +/ 10 degrees with the appliance fixed in place. An occlusal force of 30 N generated during swallowing was simulated with a weight positioned on the appliance. For statistical analysis, the moments Tz (rotation) and forces Fz (intrusion) at a deflection of +/-0.34 mm to the incisor edge (+/-5 degrees rotation) were tested. Means and standard deviations for Tz and median and 25% and 75% quartiles for Fz were calculated. An analysis of variance was performed. RESULTS: The simulated occlusal force increased the measured intrusive force Fz (maximum with a weight, 3.7 N [-3.7, -2.4]; minimum without a weight, -1.3 N [-1.4, -1.1]) and the rotary moment Tz (maximum with a weight, -50.8 Nmm [+/-0.8]; minimum without a weight, 18.2 Nmm [+/-0.9]) significantly in all cases (P < .01). This was found for all materials measured and for both directions of rotation. CONCLUSION: During rotation with aligners, a simulated occlusal force increases the intrusive force and the rotary moment. The biological adverse side effects of these phenomena remain unclear, especially in patients with periods of bruxism. PMID- 21612313 TI - Modulation of ischemia-induced NMDAR1 activation by environmental enrichment decreases oxidative damage. AB - In this study, we examined whether enriched environment (EE) housing has direct neuroprotective effects on oxidative damage following transient global cerebral ischemia. Fifty-two adult male Wistar rats were included in the study and received either ischemia or sham surgery. Once fully awake, rats in each group were randomly assigned to either: EE housing or socially paired housing (CON). Animals remained in their assigned environment for 7 days, and then were killed. Our data showed that glutamate receptor expression was significantly higher in the hippocampus of the ischemia CON group than in the ischemia EE group. Furthermore, the oxidative DNA damage, protein oxidation, and neurodegeneration in the hippocampus of the ischemia CON group were significantly increased compared to the ischemia EE group. These results suggest that EE housing possibly modulated the ischemia-induced glutamate excitotoxicity, which then attenuated the oxidative damage and neurodegeneration in the ischemia EE rats. PMID- 21612315 TI - E-space preservation. AB - OBJECTIVE: To determine the relationship of E-space preservation with lingual holding arches to mandibular permanent second molar impaction. METHODS: Two hundred consecutively treated patients undergoing nonextraction treatment for incisor crowding were entered into the study. Lower incisor crowding was assessed by the Little Irregularity Index. Treatment involved E-space preservation via a passive lingual arch placed prior to exfoliation of the second primary molar. Panoramic and cephalometric radiographs were analyzed for any significant relationship of mandibular permanent second molar impaction relative to molar angulation, spacing, growth pattern, and skeletal relationships. RESULTS: Twenty nine patients had at least one impacted second molar (14.5%). Of a possible 400 mandibular second molars, 34 were determined to be impacted (8.5%). Only the mandibular first molar-second molar angulation was found to be significant (P < .001). Pretreatment intermolar angulation of 24 degrees had a positive predictive value of 1. CONCLUSION: Impaction of permanent second mandibular molars in patients undergoing nonextraction via E-space preservation with a passive lingual arch is 10 to 20 times more prevalent than that observed in the general population. Risk of impaction is best predicted by the pretreatment intermolar angulation between first and second permanent mandibular molars. PMID- 21612316 TI - Effect of three different motivational techniques on oral hygiene and gingival health of patients undergoing multibracketed orthodontics. AB - OBJECTIVE: To compare the effectiveness of three different motivational techniques for maintaining good oral hygiene during fixed appliance orthodontic treatment. MATERIALS AND METHODS: A total of 62 adolescents in the age range of 12-18 years, requiring fixed orthodontic treatment were evaluated for the efficacy of three different motivational techniques, ie, conventional plaque control measures (group I), chair side motivational tests with conventional plaque control measures (group II), and phase contrast microscopy with conventional plaque control measures (group III), in improving oral hygiene and gingival health over a period of 6 months. RESULTS: A gradual decline in mean plaque scores in group III was found, ie, from 1.13 +/- 0.42 at baseline to 0.64 +/- 0.39 at 6 months (P < .05). An intragroup analysis of mean gingivitis scores in group III showed statistically significant decline in the mean gingival scores from 1.49 +/- 0.45 to 1.08 +/- 0.61 over a period of 6 months(P < .05). CONCLUSIONS: Phase contrast microscopy along with the conventional method of plaque disclosure and demonstration of the horizontal scrubbing method of brushing have a long-lasting effect on the patient. This reduces the need of frequent reinforcement sessions of plaque control programs when compared to chair side motivational tests and conventional plaque control measures. PMID- 21612317 TI - Stability changes of miniscrew implants over time. AB - PURPOSE: To quantify in vivo changes in miniscrew implant (MSI) stability over time using resonance frequency analysis, and to determine if pilot holes and placement sites affect changes in MSI stability. MATERIALS AND METHODS: Twenty two self-tapping MSIs (1.6 mm wide and 9 mm long) were placed in the maxillae of 2 adult beagle dogs (20 months old). The Osstell Mentor was used to measure the implant stability quotient (ISQ) weekly for 8 weeks. A split-mouth design was used to evaluate the effects of 1.1-mm wide, 3-mm deep pilot holes. RESULTS: The MSIs that failed showed significantly (P < .05) greater decreases in ISQ values during the first 3 weeks than the MSIs that remained stable. All of the MSIs that failed (41%) had been placed in nonkeratinized tissue. MSIs that remained stable throughout the study also showed significant decreases in ISQ values during the first 3 weeks, followed by increases during the fourth and fifth weeks. Changes in ISQ values of MSIs inserted into bone with and without pilot holes were comparable (P > .05). CONCLUSION: Stability of unloaded MSIs decreased during the first 3 weeks and increased thereafter. Although the effects of pilot holes on stability could not be confirmed, placement of MSIs into nonkeratinized tissue negatively affected their stability and increased the likelihood of failures. PMID- 21612318 TI - Upregulation of RyR2 in hypoxic/reperfusion injury. AB - Calcium influx into cells is responsible for initiating the cell death in neuronal tissue after hypoxic injury. Changes in intracellular calcium with subsequent increased expression of ryanodine receptor 2 (RyR2) are hypothesized to cause cell death after hypoxic injury. In the present study we have examined the time-dependent changes of RyR2 expression in hypoxic/reperfusion injury of spinal cord dorsal column. In this study we used western blotting, real time PCR (RT-PCR) and immunohistochemistry to examine changes in protein and gene expression of RyR2 after spinal cord injury (SCI) in the rat. Quantitative immunoblotting showed increase in the expression of RyR2 at 4 h during hypoxic/reperfusion injury of dorsal column. Moreover, RT-PCR showed 36-fold increases in mRNA of RyR2 after 4 h of hypoxic injury of white matter. By double immunofluorescence staining, RyR2 was localized on axons and astrocytes in the white matter of the spinal cord. After treatment with KN-62; (inhibitor of CaMKII) and SP600125 (inhibitor of JNK), there is a significant reduction in the expression of RyR2, indicating the role of these molecules in RyR2 regulation. Further removal of extracellular calcium does not have significant effect on RyR2 expression and phosphorylation of CaMKII, which was further confirmed by treatment with intracellular Ca(++) chelator BAPTA-AM. Finally, bioassay with quantitative analysis showed that treatment with inhibitor significantly reduced the cellular oxidative stress suggesting RyR2 is responsible for increased cellular oxidative load. In summary, we provide evidence that RyR2 gene and protein expression in astrocyte and axons is markedly increased after hypoxic injury. Further CaMKII/JNK pathway upregulates RyR2 expression after hypoxic injury. Therefore we propose that inhibitors of CaMKII/JNK pathway would reduce the cellular oxidative load and thereby have a neuroprotective role. PMID- 21612319 TI - Combination of azelaic acid 5% and clindamycin 2% for the treatment of acne vulgaris. AB - CONTEXT AND OBJECTIVE: Acne vulgaris, an inflammatory skin disease with different clinical appearances, is a common problem in most adolescents. It seems that using combinations of topical agents can decrease resistance to the treatment and improve the efficacy. Therefore, we evaluated the effects of azelaic acid (AA) 5% and clindamycin (Clin) 2% combination (AA-Clin) on mild-to-moderate acne vulgaris. MATERIALS AND METHODS: The efficacy and safety of 12-week treatment with AA-Clin in patients with mild-to-moderate facial acne vulgaris were evaluated by a multicenter, randomized, and double-blind study. A total of 88 male and 62 female patients were randomly assigned to one of these treatments: AA 5%, Clin 2%, and combination of them. Every 4 weeks, total inflammatory and noninflammatory lesions were counted, acne severity index (ASI) was calculated, and patient satisfaction was recorded. RESULTS: Treatment for 12 weeks with combination gel significantly reduced the total lesion number compared with baseline (p < 0.01), as well as Clin 2% or AA 5% treatment groups (p < 0.05 or p < 0.01). The percentage of reduction in ASI in combination treated group (64.16 +/- 6.01) was significantly more than those in the Clin 2% (47.73 +/- 6.62, p < 0.05) and 5% AA (32.46 +/- 5.27, p < 0.01) groups after 12 weeks. Among the patients in the AA-Clin group, 75.86% of males were satisfied or very satisfied and 85.71% of females were satisfied or very satisfied. This trend was significant in comparison to the number of patients who were satisfied with AA 5% or Clin 2% treatment (p < 0.01). Seven patients in AA-Clin group (incidence = 22%) showed adverse effects that were not statistically significant compared to treatment with individual active ingredients. DISCUSSION AND CONCLUSION: The profound reduction in lesion count and ASI by combination therapy with AA-Clin gel in comparison to individual treatment with 5% AA or Clin 2% suggested the combination formula as an effective alternative in treatment of acne vulgaris. PMID- 21612320 TI - Impaired arpeggio movement in skilled reaching by rubrospinal tract lesions in the rat: a behavioral/anatomical fractionation. AB - Spinal cord injury damaging the rubrospinal tract (RST) interferes with skilled forelimb movement, but identification of the precise role of the RST in this behavior is impeded by the difficulty of surgically isolating the RST from other pathways running within the lateral funiculus (LF). The present study used a skilled reaching task and a behavioral/anatomical dissection method to identify the contribution of the RST to skilled forelimb movement. Rats were trained on the skilled reaching task and subjected to lesions of the LF. Based on histological evaluation, the animals were assigned to large, medium, or small LF lesion size groups. End point and arm/hand/digit movements were subsequently identified for each group. Success was impaired in all groups, but the impairment was not related to lesion size. Frame-by-frame qualitative analysis of the video recordings revealed that large LF lesions abolished the elements of digits close, digits open, arpeggio, grasp, supination 2, and release. Medium LF lesions interfered with a subset of the movement elements that were shown to be affected by the large LF lesions, namely arpeggio and grasp. Only the arpeggio movement was compromised after small LF lesions. The results show that not only does the LF contribute to skilled reaching, but because the RST was likely to have been damaged in all lesion groups, the RST is more involved in hand rotation than in digit use. The results are discussed in relation to the fiber tracts that are likely to be damaged in the different LF lesion groups. PMID- 21612321 TI - Prognosis of corneal wasp sting: case report and review of the literature. AB - OBJECTIVES: To report the ocular complications associated with corneal wasp sting and to highlight the importance of eye protection in case of wasp offense. METHODS: This was a retrospective, observational chart review. RESULTS: A 34-year old man was referred for severely decreased vision after being stung by a swap to the left cornea. Ophthalmologic examination showed a large corneal epithelial defect, anterior uveitis, and a left relative afferent pupillary defect. Vision was light perception. After treatment with cycloplegic, topical antibiotic, and systemic steroids for 2 weeks, the epithelial defect healed and anterior uveitis subsided; however, bulbous keratopathy and traumatic cataract developed. The visual acuity remained light perception with poor light projections. Twenty additional cases of corneal hymenoptera sting were reviewed from the English language literature, which shared certain characteristics including anterior uveitis, intractable glaucoma, traumatic cataract, toxic optic neuropathy, corneal scarring, and a catastrophic prognosis. CONCLUSIONS: Wasp stings of the cornea may bring disastrous ocular damages. Outdoor works should manage to protect your eyes when confronted with a hymenoptera attack. PMID- 21612322 TI - Spectral and dynamic electroencephalogram abnormalities are correlated to psychometric test performance in hepatic encephalopathy. AB - OBJECTIVE: Alterations of the electroencephalogram (EEG) have been reported in patients with hepatic encephalopathy (HE). However, previous methods have not assessed transient phenomena in the EEG signal (dynamics) and associations to psychometric test performance have in general been poor. The aims were to quantify spectral and dynamic EEG abnormalities in patients with HE and to correlate putative findings to psychometric test performances. METHODS: Multichannel EEG (64 electrodes) was recorded in 24 cirrhotic patients with various grades of HE and 26 healthy volunteers. Spectral and dynamic EEG indices were quantified by continues wavelet analysis. In addition, the psychometric hepatic encephalopathy score (PHES), continues reaction time, and biochemical profile were assessed. RESULTS: Compared with healthy volunteers, patients had progressively slowing of the EEG (all p <= 0.004) (spectral EEG indices) and increased variability in the alpha [7.5-13.5 Hz] (p = 0.001) and beta bands [13.5 32 Hz] (p = 0.02) (dynamic EEG indices). In addition, anteriorization and dissociation of the basic posterior alpha rhythm, along with dissociation of frontal delta activities [1-3.5 Hz] were seen with worsening of HE. Spectral EEG indices (all frequency bands) as well as dynamic EEG indices (alpha and beta bands) were correlated to PHES scores (all p < 0.05). CONCLUSION: EEG analysis, based on continues wavelet transform, provides quantifiable information on static as well as dynamic features of the EEG in patients with HE. EEG abnormalities were correlated to psychometric test performance and may provide valuable clinical biomarkers for surveillance, prognostication and treatment of this entity. PMID- 21612323 TI - Pelvic floor tonicity affects urodynamic measurements in children with myelomeningocele. AB - OBJECTIVE: In a cystometry procedure in a child with myelomeningocele (MMC), a pressure increase in the abdominal pressure (P (abd)) tracing was detected during filling. This pressure alteration was not related to other known events (straining, talking, rectal contractions). This study was conducted to investigate this phenomenon. MATERIAL AND METHODS: Forty-three children with MMC were enrolled in the study. A slow and gradual pressure increase associated with the bladder filling was sought in the P (abd) tracings. End filling and initial P (abd) gradient more than 3 cm H(2)O were considered as increased P (abd). If the defined pressure event occurs, the bladder was evacuated for verifying the filling-pressure relation. Age, gender, study position, pelvic floor tonicity and cystometric capacity were correlated with the pressure alteration. RESULTS: P (abd) increase was noted in 18 (41.8%) children. The mean P (abd) gradient between end and initial filling was 4.78 +/- 1.63 cm H(2)O in these children. No statistically significant difference was noted for age, gender and study position. Statistically significant differences were noted with decreased pelvic floor tonicity and high values of cystometric capacity (p = 0.003 and p < 0.001, respectively). CONCLUSIONS: The pressure increase is thought to be a consequence of a posterior positional change in the bladder during filling die to decreased pelvic floor support in MMC. This pressure alteration was more obvious with increased bladder capacity. Urodynamic studies of children with MMC should be carefully evaluated for the presence of this phenomenon to prevent low measurement of the detrusor pressure, compliance and detrusor leak point pressure values. PMID- 21612325 TI - Ser608Leu polymorphisms in the nitric oxide synthase-2 gene may influence urinary bladder cancer pathogenesis. AB - OBJECTIVE: The aim of this study was to analyse whether the exonic Ser608Leu (rs2297518) polymorphism in nitric oxide synthase-2 (NOS2) influences urinarybladder cancer risk and pathogenesis. MATERIAL AND METHODS: Genotyping of 359 bladder cancer patients from a population-based cohort and 164 population controls was carried out by allelic discrimination and sequencing. Genotypes were combined with information on tumour stage, grade, stage progression and cancer specific death, from a 5-year clinical follow-up. RESULTS: For the Ser608Leu polymorphism, TT homozygotes had three-fold higher odds for bladder cancer (p = 0.081), but once ill, a lower risk for stage progression (p = 0.031) and a better prognosis. CONCLUSIONS: The data indicate that the Tallele of the NOS2 Ser608Leu polymorphism is an initial risk factor for developing urinary bladder cancer. Among bladder cancer patients, however, individuals who are TT homozygous have a lower risk of developing muscle-invasive disease and a higher cancer-specific survival. Depending on the cellular context, nitric oxide can induce proliferation as well as apoptosis. The results from this and previous studies suggest that NOS2 polymorphisms may influence both the risk of contracting bladder cancer and the aggressiveness of the disease. PMID- 21612326 TI - Waldenstrom's macroglobulinemia and nephrotic syndrome with membranous nephropathy. AB - Renal complications of Waldenstrom's macroglobulinemia (WM) are rarely observed. Nephrotic syndrome in association with WM has most often been secondary to amyloidosis. This article reports a case of WM with nephrotic syndrome as a result of membranous nephropathy with immunoglobulin M (IgM) deposition. A 44 year-old male diagnosed with WM 4 years previously, presented with heavy proteinuria (7.8 g/24 h). Kidney biopsy revealed expanded mesangium, thickened capillary loops and epimembranous spikes, with no significant interstitial inflammation or thickened tubular basement membranes. Immunofluorescence examination demonstrated strong granular staining of IgM and lambda chains, with weaker C3 and C1q staining. Electron microscopy showed many subepithelial dense deposits, and fewer large subendothelial dense deposits. Treatment was directed at the patient's WM with maintenance rituximab and fludarabine. Subsequently, decreases were seen in both the patient's serum IgM and serum viscosity. With therapy for WM and the addition of an angiotensin receptor blocker, the patient's proteinuria also improved, from 7.8 g to 4.8 g/24 h. The patient continued to follow up with his hematologist and in 2009 creatinine was 1 mg/dl (76.26 ?mol/l), with a 24 h urine protein excretion of 0.159 g. PMID- 21612327 TI - Neurocytoma arising in an adrenal gland mature teratoma. AB - Mature teratoma of adrenal gland is a rare entity. Neurocytoma is a low grade neuronal tumor even rarely seen among central nervous system tumors. Nervous system tumors arising in teratomas are frequently originated from glial or primitive neuroectodermal cells. Here we report a neurocytoma arising in mature cystic teratoma in the right adrenal gland of an 8 years old boy. Histological examination revealed a tumor composed of solid sheets in fibrillar basis with small uniform cells in the neuroglial tissue in teratoma. This is only the second case demonstrating a neurocytoma arising in a mature cystic teratoma in the literature. PMID- 21612328 TI - Accuracy and diagnostic yield of CT-guided stereotactic liver biopsy of primary and secondary liver tumors. AB - OBJECTIVE: CT-guided biopsy still plays a decisive role in the management of liver tumors, especially if the lesions are not visible or accessible by ultrasound. As CT-guided stereotaxy appears to be a very accurate targeting technique, the aim of this study was to evaluate the targeting accuracy, diagnostic yield, and complications of CT-guided stereotactic liver biopsy of primary and secondary liver tumors. METHODS AND MATERIALS: Prior to stereotactic liver biopsy, patients under general anesthesia were immobilized using a vacuum cushion. Respiratory motion was controlled by temporary disconnections of the endotracheal tube. An optical-based navigation system was used for 3D trajectory planning and placement of a 15-G coaxial needle via a stereotactic aiming device. The histological samples were obtained using a 16-G Tru-Cut(TM) biopsy needle system. For evaluation of targeting accuracy the control CT image with the needles in place was fused with the planning CT image. The lateral error at the tip and skin entry point and the angular error were calculated. In addition, the skin-to-liver-surface (SL) distance, the needle-to-liver-surface (NL) angle, and the presence of liver cirrhosis were evaluated. The diagnostic yield was evaluated by histological reports from the institutional pathologists. RESULTS: The median lateral error was 2.5 mm (range: 0-6.5 mm) at the needle entry point and 3.2 mm (range: 0.01-9.4 mm) at the needle tip. The median angular error was 1.06 degrees (range: 0-6.64 degrees ). Liver cirrhosis, NL angle and SL distance showed no significant impact on the targeting accuracy. Forty-five of the 46 liver biopsies (97.8%) were diagnostic according to the histological reports. No puncture-related complications such as bleeding or perforation of intestinal organs or lung tissue were recorded. PMID- 21612324 TI - Drug metabolism alterations in nonalcoholic fatty liver disease. AB - Drug-metabolizing enzymes play a vital role in the elimination of the majority of therapeutic drugs. The major organ involved in drug metabolism is the liver. Chronic liver diseases have been identified as a potential source of significant interindividual variation in metabolism. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, affecting between 60 and 90 million Americans, yet the vast majority of NAFLD patients are undiagnosed. NAFLD encompasses a spectrum of pathologies, ranging from steatosis to nonalcoholic steatohepatitis and fibrosis. Numerous animal studies have investigated the effects of NAFLD on hepatic gene expression, observing significant alterations in mRNA, protein, and activity levels. Information on the effects of NAFLD in human patients is limited, though several significant investigations have recently been published. Significant alterations in the activity of drug-metabolizing enzymes may affect the clearance of therapeutic drugs, with the potential to result in adverse drug reactions. With the enormous prevalence of NAFLD, it is conceivable that every drug currently on the market is being given to patients with NAFLD. The current review is intended to present the results from both animal models and human patients, summarizing the observed alterations in the expression and activity of the phase I and II drug metabolizing enzymes. PMID- 21612329 TI - Management of May-Hegglin anomaly referred for coronary artery bypass. AB - We report the case of a patient with May-Hegglin anomaly who underwent a coronary bypass graft using an extra-corporeal circulation and discuss the perioperative and anesthetic management. PMID- 21612330 TI - Prevalence, severity, and duration of thrombocytopenia among HIV patients in the era of highly active antiretroviral therapy. AB - Thrombocytopenia is a clinically relevant outcome in HIV. However, the epidemiology of this condition, including frequency, severity, and duration, has not been well-characterized in the era of highly active antiretroviral therapy (HAART). In this study, we describe the epidemiology of thrombocytopenia using two methods. We conducted a systematic review of the literature published between 1997 and 2009 to characterize the frequency of thrombocytopenia in different populations in the HAART era. Secondly, we examined the frequency, severity, and duration of thrombocytopenia among HIV patients in the Collaborations in HIV Outcomes Research/US (CHORUS) Cohort from 1997 to 2006 and among HIV patients participating in GlaxoSmithKline HIV Clinical Trials between 1996 and 2004. Prevalence estimates of thrombocytopenia (<150 000 platelets/ul) in the literature varied greatly but were generally above 10%. The thrombocytopenia prevalence estimates in the CHORUS Cohort and the HIV Clinical Trials were both 14%. In the CHORUS Cohort, the platelet count was <=50 000/ul among 3.1% and <=30 000/ul among 1.7%; in the HIV clinical trials database, the platelet count was <=50 000/ul among 1.3% and <=30 000/ul among 0.67%. Duration of severe thrombocytopenia varied greatly, with the medium duration to >=75 000 platelets/ul taking 147 days in the CHORUS Cohort and 33 days in the HIV clinical trials database. Among 111 patients with severe thrombocytopenia in the CHORUS Cohort, 23% never achieved a higher platelet count over follow-up. In conclusion, while the prevalence of severe thrombocytopenia was low, it occurred at levels associated with bleeding and was persistent among a small proportion of patients despite receipt of HAART. PMID- 21612331 TI - Visceral adiposity as a target for the management of the metabolic syndrome. AB - Atherosclerosis, the underlying cause of atherosclerotic cardiovascular disease (ACVD), develops due not only to a single cardiovascular risk factor but to a variety of complex factors. The concept of the multiple cardiometabolic risk factor clustering syndrome has been proposed as a highly atherogenic state, independent of hypercholesterolemia and smoking. Body fat distribution, especially visceral fat accumulation, is a major correlate of a cluster of diabetogenic, atherogenic, prothrombotic, and proinflammatory metabolic abnormalities referred to as the metabolic syndrome, with dysfunctional adipocytes and dysregulated production of adipocytokines (hypoadiponectinemia). Medical research has focused on visceral adiposity as an important component of the syndrome in Japanese subjects with a mild degree of adiposity compared with Western subjects. For the prevention of ACVD at least in Japan, it might be practical to stratify subjects with multiple risk factors for atherosclerotic cardiovascular disease based on visceral fat accumulation. Visceral fat reduction through health promotion programs using risk factor-oriented approaches may be effective in reducing ACVD events, as well as producing improvement in risks and hypoadiponectinemia. This review article discusses visceral adiposity as a key player in the syndrome. Visceral fat reduction with life-style modification is a potentially useful strategy in the prevention of ACVD in patients with the metabolic syndrome. PMID- 21612332 TI - Renal dysfunction increases the risk of ischemic and hemorrhagic stroke in the general population. AB - AIMS: The association between chronic kidney disease (CKD) and different subtypes of stroke is unclear, and previous studies have yielded conflicting results. We aimed to assess the impact of CKD on the risk of fatal or non-fatal ischemic and hemorrhagic stroke in both men and women. METHODS: In 539,287 Swedish men and women, mainly undergoing health controls, with mean age 45 years, and no previous stroke or myocardial infarction, hazard ratios for stroke were calculated to assess the association between renal dysfunction and incidence of stroke. We estimated glomerular filtration rates (GFR) using the Mayo (GFR-Mayo) formula. Glomerular filtration rate 60-90, 30-60, and 15-30 mL per minute per 1.73 m(2) was defined as mildly, moderately, and severely decreased GFR, respectively. RESULTS: There were 17,678 strokes, of which 72% were ischemic, 15% hemorrhagic, and 12% unspecified, during 12 years of follow-up. Hazard ratios (95% confidence intervals) for ischemic stroke were 1.09 (1.04-1.14) for mildly, 1.24 (1.10-1.39) for moderately, and 2.27 (1.63-3.17) for severely decreased GFR-Mayo. The corresponding figures for hemorrhagic stroke were 1.04 (0.93-1.15), 1.26 (0.96 1.64), and 2.31 (1.10-4.87). Ischemic stroke was related to all levels of decreased GFR-Mayo in both genders (P < 0.0003). Hemorrhagic stroke was only related to renal dysfunction among women; hazard ratios (95% confidence intervals) 1.38 (1.14-1.66) for mildly, 1.70 (1.13-2.57) for moderately, and 3.46 (1.09-10.9) for severely decreased GFR-Mayo. CONCLUSIONS: Already mildly decreased GFR-Mayo increases the risk of ischemic fatal or non-fatal stroke and severely decreased GFR-Mayo the risk of hemorrhagic stroke in the general population. In gender-specific analyses ischemic stroke was related to a decreased GFR-Mayo in both genders. Hemorrhagic stroke was only related to renal dysfunction among women. PMID- 21612333 TI - MAGED1: molecular insights and clinical implications. AB - The melanoma antigen (MAGE) protein family contains more than 25 members that share a conserved MAGE homology domain (MHD). Type I MAGE genes exhibit cancer/testis-specific expression patterns and antigenic properties which render them ideal candidates for cancer immunotherapies. Maged1, a type II MAGE gene, is ubiquitously expressed and has been previously shown to play an important role in neuronal apoptosis during development. Recent studies have expanded the functional tissues and processes in which Maged1 activity is important and uncovered interacting partners of MAGED1 protein, adding novel layers to Maged1 functions. Maged1 plays a role in anti-tumorigenesis in a variety of cell types, and the down-regulation of MAGED1 has been observed in tumor cells. Moreover, MAGED1 can interact with a specific group of nuclear members and regulate circadian clock functions. These newly identified functions will enrich the molecular and clinical studies of the MAGE family of proteins. PMID- 21612334 TI - Association between smoking behavior patterns and chronic obstructive pulmonary disease: a long-term follow-up study among Finnish adults. AB - Low-rate smoking patterns are common, but their pulmonary effects remain poorly known. The study hypothesis was that any level of daily smoking may cause chronic obstructive pulmonary disease (COPD). We investigated the association between longitudinal smoking patterns and COPD using logistic regressions and survival models adjusted for multiple covariates. Data from Finnish Twin Cohort surveys were used. Participants (n = 21,609) were grouped into categories describing 1981 smoking and change in smoking during 1975-1981. Light smoking was defined as < 5 cigarettes per day, moderate 5-19 cigarettes, and heavy >= 20 cigarettes per day. Finland's Social Insurance Institution provided data on inhaled anticholinergics purchases (1995-2008) and diagnoses entitling to special reimbursements (1981 2008). We defined COPD as regular anticholinergic use or special reimbursement eligibility for COPD, emphysema, or chronic bronchitis. COPD incidence was 2.5% (n = 528). Elevated disease risks were observed in former, moderate, and heavy smokers, in all who increased smoking, and in those who reduced from moderate to light smoking. Increased risk for anticholinergic use was found in former smokers, in constant light, moderate, and heavy smokers, and in increasers. Former, light, moderate, and heavy smoking in 1981 was associated with future development of disease. Our results demonstrate that all daily smoking patterns may impair pulmonary function. PMID- 21612335 TI - The importance of long-term follow-up in child and adolescent obesity prevention interventions. AB - Pediatric overweight and obesity continues to be a major public health concern. Once established it is difficult to treat; therefore well-designed and evaluated prevention interventions are vitally important. There is considerable evidence to suggest that obesity prevention initiatives can change children's behaviours and weight status over the short- or medium-term; however, there is far less evidence on which to judge the impact over the longer term. In response to the rise in short- and medium-term obesity prevention studies for children and adolescents over recent years, the Prevention Stream of the Australasian Child and Adolescent Obesity Research Network highlight five points as to why the dearth of obesity prevention studies with long-term follow-up should be urgently addressed. Furthermore, recommendations to strengthen the evidence base and outline key implications for research design in this area and the support required for long term follow-up studies are detailed. PMID- 21612336 TI - Placental transmission of novel pandemic influenza a virus. AB - The effects of maternal influenza on the fetus are not well understood. Viremia is believed to occur infrequently and thus vertical transmission appears to be rare. Highly pathogenic strains of influenza virus, such as avian influenza A (H5N1), are more likely to be transmitted across the placenta. Placental tissues of seven women with confirmed H1N1 infection were examined molecularly with RT PCR and microscopically to investigate whether H1N1 virus vertically transmitted. We found no evidence for placental transmission of H1N1 virus in this study. In the absence of vertical transmission, adverse effects like neonatal seizures, encephalopathy, cerebral palsy, and even neonatal death can still occur. Since a significant knowledge gap exists for the effects of this novel virus on the fetus, further studies will be beneficial. PMID- 21612337 TI - Development of a guinea pig model of perinatal cytomegalovirus-induced hepatobiliary injury. AB - To explore the possible link between perinatal cytomegalovirus infection and onset of biliary atresia, we build up a perinatal cytomeglovirus induced hepatobiliary system injury model in guinea pigs, verified the biliary tropism of gpCMV and the related inflammatory injury. It suggested host immune status, local response to inflammation, and activation of Th1-cell-mediated antiviral immune responses contributed to newborn geinea pigs' hepatobiliary damage. The model was helpful in study the CMV infection and biliary injury. PMID- 21612338 TI - Immunological detection of the type V collagen propeptide fragment, PVCP-1230, in connective tissue remodeling associated with liver fibrosis. AB - AIM: Liver fibrosis involves excessive remodeling and deposition of fibrillar extracellular matrix (ECM) components, which leads to malfunction of the organ, causing significant morbidity and mortality. The aim of this study was to assess whether levels of a type V collagen fragment, the propeptide CO5-1230, indicate the amount of collagen deposited during liver fibrosis. METHODS: A specific competitive enzyme-linked immunosorbent assay (ELISA) was developed to measure CO5-1230 levels. The sequence TAALGDIMGH located at the start of the C-terminal propeptide between amino acid position 1230' and 1239' (CO5-1230) of the alpha2 chain was selected as the immunogen. Monoclonal antibodies were raised against this fragment. An assay developed using the biotin-streptavidin system was evaluated in two rat models of liver fibrosis: bile duct ligation (BDL) and carbon tetrachloride (CCl(4))-treated rats, for up to 20 weeks. RESULTS: The ELISA was capable of measuring CO5-1230 in serum specifically, with an intra assay variation of 3.46% and inter-assay variation of 5.09%. Mean CO5-1230 levels were significantly elevated in CCl(4) rats compared with controls [8 weeks: 57.4 ng/mL, controls 45.5 ng/mL (P = 0.0020); 12 weeks: 81.3 ng/mL, controls 50.2 ng/mL (P = 0.0020); 16 weeks: 85.1 ng/mL, controls 51 ng/mL (P = 0055); 20 weeks: 92 ng/mL, controls 47.8 ng/mL (P = 0.0033)]. CO5-1230 levels correlated with the total amount of collagen in sections from the injured livers, quantified from Sirius red stains (Spearman, R(2) = 0.5580). In BDL rats, serum levels of CO5 1230 were also elevated compared with controls [2 weeks: 160.1 ng/mL, controls 78.9 ng/mL (P = 0.0007); 4 weeks: 111.3 ng/mL, controls 62.2 ng/mL, (P = 0.0068)] and showed a linear correlation to the total collagen content (Spearman, R(2) = 0.3305). CONCLUSIONS: Increased serum levels of CO5-1230 were associated with the extent of collagen deposition in two different models of fibrotic processes in the liver. The data indicate that formation of type V collagen may be of value as a disease-specific diagnostic biomarker that reflects the total burden of disease. The amino acid sequence selected is located in the first 10 amino acids of the C-terminal propeptide section, which is a formation-specific region. PMID- 21612339 TI - Does availability of illicit drugs mediate the association between mental illness and substance use? AB - This study investigated the association between presence of mental illness, detected by an increased level of Kessler Psychological Distress Scale score, and prevalence of exposure to opportunity to obtain illicit drugs among adolescents and young adults aged 12-24 years using data collected by the 2007 Australian National Drug Strategy Household Survey (N = 2,663). Adolescents and young adults with mental illness have increased prevalence of exposure to drug use opportunity. Higher exposure to opportunity to obtain illicit drugs among people with pre-existing mental illness may further contribute to the co-existence of drug dependence and other mental disorders that are frequently reported in the literature. PMID- 21612340 TI - Substance use and misuse among 17- to 18-year-old Croatian adolescents: correlation with scholastic variables and sport factors. AB - Substance use and misuse (SUM) and the relation to physical activity/exercise/athletic participation (sport factors) and scholastic achievement are rarely studied in Croatia. The aim of this study was: (1) to investigate the SUM habits in Croatian adolescents (17-18 years of age, 254 males, and 218 females), and (2) to study potential gender-specific interrelationships between scholastic and sport factors in relation to SUM. The testing was done using an extensive, anonymous, self-administered questionnaire that consisted of scholastic variables, sport factors, and SUM data. Descriptive statistics, counts, and proportions were calculated. Gender differences were established using the Kruskal-Wallis test. Gender-specific correlations within and between studied variables were established using the Spearman's correlation. The incidence of smoking habits and alcohol consumption among Croatian adolescents was alarming, and a serious intervention program should be developed to address this issue. Educational achievement was negatively related to SUM, with no gender-specific relationships. The data indicated some "protective" effects of the sport factors against SUM in boys, but a significant positive correlation between alcohol drinking and sport participation in girls was also noted. PMID- 21612341 TI - Religiosity as a protective factor against substance use among Hungarian high school students. AB - Gender differences in the relationship between religiosity and substance use (lifetime prevalence and current use) were examined among high school students in Szeged, Hungary (N = 881). Experimenting with and consuming tobacco and alcoholic beverages were characteristic in the sample to a great extent, whereas marijuana use was not as frequent. Logistic regression analyses were employed to test how variables of religiosity, that is, denominational affiliation, religiosity, and religious attendance, were related to substance use of youth by gender. Our findings confirmed the importance of the protective role of religious involvement, particularly among females. PMID- 21612342 TI - Mannosylated liposomes bearing Amphotericin B for effective management of visceral Leishmaniasis. AB - The cationic and mannosylated liposomes were prepared using the cast film method and compared for their antileishmaniasis activity. The surface of the Amphotericin B (Amp B)-bearing cationic multilamellar liposomes was covalently coupled with p-aminophenyl-alpha-D-mannoside using glutaraldehyde as a coupling agent, which was confirmed by agglutination of the vesicles with concanavalin A. The prepared liposomes were characterized for shape, size, percent drug entrapment, vesicle count, zeta potential, and in vitro drug release. Vesicle sizes of cationic and mannosylated liposomes were found to be 2.32 +/- 0.23 and 2.69 +/- 0.13 MUm, respectively. Zeta potential of cationic liposomes was higher (30.38 +/- 0.3 mV), as compared to mannosylated liposomes (17.7 +/- 0.8 mV). Percentage drug release from cationic and mannose-coupled liposomes was found to be 45.7% +/- 3.1 and 41.9% +/- 2.8, respectively, after 24 hours. The in vivo antileishmanial activity was performed on Leishmania donovani-infected golden hamster, and results revealed that Amp B solution was reduced by 42.5 +/- 1.8% in the parasite load, whereas the placebo cationic liposomes and drug-containing cationic liposomes showed a reduced parasite load (i.e., 28.1 +/- 1.5 and 61.2 +/ 3.2%, respectively). The mannose-coupled liposomes showed a maximum reduction in parasite load (i.e., 78.8 +/- 3.9%). The biodistribution study clearly showed the higher uptake of mannosylated liposomes in the liver and spleen and hence the active targeting to the reticular endothelial system, which, in turn, would provide a direct attack of the drug to the site where the pathogen resides, rendering the other organs free and safe from the toxic manifestations of the drug. PMID- 21612343 TI - Validation of membrane vesicle-based breast cancer resistance protein and multidrug resistance protein 2 assays to assess drug transport and the potential for drug-drug interaction to support regulatory submissions. AB - Breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2) can play a role in the absorption, distribution, metabolism, and excretion of drugs, impacting on the potential for drug-drug interactions. This study has characterized insect cell- and mammalian cell-derived ABC-transporter-expressing membrane vesicle test systems and validated methodologies for evaluation of candidate drugs as substrates or inhibitors of BCRP or MRP2. Concentration dependent uptake of BCRP ([3H]oestrone 3-sulfate, [3H]methotrexate, [3H]rosuvastatin) and MRP2 ([3H]oestradiol 17beta-glucuronide, [3H]pravastatin, carboxydichlorofluorescein) substrates, and inhibitory potencies (IC50) of BCRP (sulfasalazine, novobiocin, fumitremorgin C) and MRP2 (benzbromarone, MK-571, terfenadine) inhibitors were determined. The apparent K(m) for probes [3H]oestrone 3-sulfate and [3H]oestradiol 17beta-glucuronide was determined in insect cell vesicles to be 7.4 +/- 1.7 and 105 +/- 8.3 uM, respectively. All other substrates exhibited significant uptake ratios. Positive control inhibitors sulfasalazine and benzbromarone gave IC50 values of 0.74 +/- 0.18 and 36 +/- 6.1 uM, respectively. All other inhibitors exhibited concentration-dependent inhibition. There was no significant difference in parameters generated between test systems. On the basis of the validation results, acceptance criteria to identify substrates/inhibitors of BCRP and MRP2 were determined for insect cell vesicles. The approach builds on earlier validations to support drug registration and extends from those cell-based systems to encompass assay formats using membrane vesicles. PMID- 21612344 TI - A focus on stroke in women. PMID- 21612345 TI - The relationship between smoking and stroke risk in women: breaking the habit. PMID- 21612346 TI - Coffee consumption, myocardial infarction and stroke: what is the association? PMID- 21612347 TI - Biomarkers and the risk of stroke in the Women's Health Initiative. PMID- 21612349 TI - Fish consumption and risk of stroke. AB - Evaluation of: Larsson SC, Virtamo J, Wolk A: Fish consumption and risk of stroke in Swedish women. Am. J. Clin. Nutr. 93(3), 487-493 (2010). A population-based prospective study of 34,670 women in the Swedish Mammography Cohort was conducted, aiming to examine the associations between fish consumption and stroke incidence in women. After a mean follow-up of 10.4 years, 1680 cases of stroke were recorded. Fish consumption was inversely associated with risk of total stroke, but not cerebral infarction or hemorrhagic stroke. Compared with women in the lowest quintile of fish consumption, those in the highest quintile had a 16% lower risk of stroke. In addition, consumption of lean fish, but not of other fish types, was inversely associated with risk of stroke. PMID- 21612350 TI - Stroke- and pregnancy-induced hypertensive syndromes. AB - Pregnancy-induced hypertensive syndromes are an important cause of cerebrovascular diseases during pregnancy. Women with pregnancy-induced hypertensive syndromes are at an increased risk of ischemic and hemorrhagic strokes. Posterior reversible encephalopathy and reversible vasoconstriction syndromes are common. Cerebral venous sinus thrombosis may also occur. Preeclampsia and eclampsia reflect generalized endothelial dysfunction. Prompt diagnosis and identification of patients at risk allows for early therapeutic interventions and improved clinical outcomes. PMID- 21612351 TI - Endothelium-derived hyperpolarizing factor in the brain: influence of sex, vessel size and disease state. AB - The endothelial layer of cells lining the intimal surface of blood vessels is essential for vascular function. The endothelium releases multiple vasodilator and protective factors, including nitric oxide, prostacyclin and endothelium derived hyperpolarizing factor; an imbalance in these factors predisposes individuals to vascular diseases such as stroke. These factors are differentially regulated by vessel size, sex hormones and disease state, therefore playing differential roles in different tissues following vascular injury. In particular, the endothelium-derived hyperpolarizing factor candidate termed epoxyeicosatrienoic acid, plays a prominent role in microvessel function, especially after ischemia, thereby making this signaling pathway an attractive target for therapy in vascular disease, including stroke. PMID- 21612354 TI - Gender differences in the primary prevention of stroke with aspirin. AB - Aspirin is used to prevent ischemic stroke and other types of cardiovascular disease. Seven trials of aspirin focusing on the effectiveness of primary prevention of stroke and other cardiovascular events have been performed, but three of these did not include women. Data from these trials, and one meta analysis, suggest that aspirin prevents myocardial infarction in men and stroke in women, although the findings in women were driven by the results of a single large study, and a subsequent meta-analysis did not find a gender difference. The reasons for the possible gender differences in aspirin's effectiveness are not entirely clear. PMID- 21612352 TI - The epidemiology of stroke amongst women in the Asia-Pacific region. AB - National data from the Asia-Pacific region suggest that stroke accounts for over 10% of female deaths. With general aging in the region, and longer life expectancies for women than men, action is required to maintain recent improvements in female death rates from stroke. However, local data on incidence and risk factors for stroke amongst women are scarce. Data from 214,032 women in the Asia Pacific Cohort Studies Collaboration were thus used to investigate the risk factors for stroke in the region. Raised systolic blood pressure and diabetes were found to be key risk factors for both ischemic (IS) and hemorrhagic (HS) stroke. After adjustment for other risk factors, every extra 10 mmHg systolic blood pressure increased risk of IS by 36% and HS by 69%, whilst diabetes increased risk of IS by 170% and HS by 147%. Smoking was also an important risk factor for IS and HS; risk was reduced by quitting. PMID- 21612355 TI - Hormone therapy administration in postmenopausal women and risk of stroke. AB - HRT, consisting of estrogens alone, or in combination with a progestogen, is widely used for the relief of symptoms in postmenopausal women. Early observational studies have suggested that HRT might be associated with a reduced risk of cardio- and cerebro-vascular events. These encouraging results prompted randomized controlled trials assessing the risks and benefits of HRT in primary and secondary prevention of arterial vascular events. However, these clinical trials and further observational studies did not confirm the protective effect of HRT; it is now established that HRT increases the risk of stroke. This increased risk is mainly related to an increased risk of ischemic stroke. Oral estrogen alone and combined with progestogen are associated with a similar increased risk, which may be dose dependent. Conversely, a low dose of transdermal estrogens with or without a progestogen does not seem to be associated with such an increased risk of stroke, whereas the impact of tibolone, a synthetic steroid, remains uncertain. In summary, there is now a large amount of evidence demonstrating that HRT is associated with increased risk of stroke, in particular, ischemic subtype. PMID- 21612353 TI - Sexual dimorphism in ischemic stroke: lessons from the laboratory. AB - Ischemic stroke is emerging as a major health problem for elderly women. Women have lower stroke incidence than men until an advanced age, when the epidemiology of ischemic stroke shifts and incidence rises dramatically in women. Experimental models of rodent stroke have replicated this clinical epidemiology, with exacerbated injury in older compared with young female rodents. Many of the detrimental effects of aging on ischemic stroke outcome in females can be replicated by ovariectomy, suggesting that hormones such as estrogen play a neuroprotective role. However, emerging data suggest that the molecular mechanisms leading to ischemic cell death differ in the two sexes, and these effects may be independent of circulating hormone levels. This article highlights recent clinical and experimental literature on sex differences in stroke outcomes and mechanisms. PMID- 21612357 TI - The link between atrial fibrillation and stroke in women. AB - Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia. The most serious complication of AF is thromboembolic stroke. The individual risk of stroke in the setting of AF varies. Several clinical factors have been identified as independent predictors of stroke in AF, including prior stroke, age, hypertension and diabetes. The bulk of available data identifies female gender as another independent predictor of stroke risk in AF. In this article, we review the link between AF and an elevated stroke risk in women, explore the potential pathophysiologic basis for this association and examine the data regarding the effectiveness of anticoagulation in reducing this risk. PMID- 21612358 TI - Thrombolysis treatment for acute stroke: issues of efficacy and utilization in women. AB - BACKGROUND: Some studies report that women with ischemic stroke are more likely to benefit from intravenous tissue thrombolysis (IV tPA) treatment, but are less likely to receive the treatment compared with men. We review the literature on sex differences in utilization and efficacy of IV tPA and suggest directions for future studies. METHODS: We identified studies that reported on sex differences in either the utilization or efficacy of IV tPA treatment for acute ischemic stroke. RESULTS: Data from observational studies of IV tPA use show evidence of under-utilization in women, although wide variability between studies suggests that differences are specific to local conditions and populations. Prior analyses of randomized trial data show strong evidence that women but not men receive statistically and clinically significant benefit from IV tPA treatment. Observational studies of the effectiveness of IV tPA treatment in men and women have limited validity because of the absence of comparable control groups. CONCLUSION: There is good evidence that there are clinically important sex differences in both the efficacy and utilization of IV tPA, with women gaining more benefit from treatment than men. The current paradox between greater efficacy but lower utilization of IV tPA in women requires greater attention from the stroke community. Larger placebo-controlled thrombolysis trials, specifically powered to look at sex differences in treatment efficacy, and more studies designed to understand the underlying reasons for the lower utilization of IV tPA in women are required. PMID- 21612356 TI - Pregnancy and stroke risk in women. AB - Stroke, the sudden onset of brain dysfunction from a vascular cause, is one of the most common causes of long-term disability. Although rare during childbearing years, stroke is even more devastating when it occurs in a young woman trying to start a family. Pregnancy and the postpartum period are associated with an increased risk of ischemic stroke and intracerebral hemorrhage, although the incidence estimates have varied. There are several causes of stroke that are in fact unique to pregnancy and the postpartum period, such as preeclampsia and eclampsia, amniotic fluid embolus, postpartum angiopathy and postpartum cardiomyopathy. Data regarding these individual entities are scant. Most concerning is the lack of data regarding both prevention and acute management of pregnancy-related stroke. The purpose of this article is to summarize existing data regarding incidence, risk factors and potential etiologies, as well as treatment strategies for stroke in pregnancy. PMID- 21612359 TI - Secondary stroke prevention in women. AB - In a meta-analysis of results from 21 randomized trials comparing antiplatelet therapy with placebo in 18,270 patients with prior stroke or transient ischemic attack, antiplatelet therapy was associated with a 28% relative odds reduction in nonfatal strokes and a 16% reduction in fatal strokes, while another trial for secondary prevention with atorvastastin 80 mg showed a 16% risk reduction in time to first occurrence of stroke (adjusted hazard ratio: 0.84, 95% CI: 0.71-0.99). However, few studies have examined the sex differences regarding the efficacy of these treatments. Specifically, recent studies have reported higher rates of perioperative complications during endarterectomy in women. Nonetheless, to date, the data on the effects of carotid artery stenting in women, coming from diverse studies and meta-analyses, have been limited owing to the small number of female patients examined. Owing to this, the evidence of the benefit for women is unclear. Peculiar pathophysiological aspects of stroke, the higher stroke risk in some specific periods in life (e.g., pregnancy, puerperium and older age) and worse documented stroke outcome in women suggest that sex does matter in stroke management. Thus, future randomized controlled trials need to be sex-balanced, in order to better understand the efficacy of appropriate secondary stroke prevention therapy in women. PMID- 21612362 TI - Polio: a tale of two vaccines. PMID- 21612364 TI - Federal Agency biodefense funding, FY2011-FY2012. AB - Since 2001, the United States government has spent substantial resources on preparing the nation against a bioterrorist attack. Earlier articles in this series have analyzed civilian biodefense funding by the federal government for fiscal years (FY) 2001 through proposed funding for FY2011. This article updates those figures with budgeted amounts for FY2012, specifically analyzing the budgets and allocations for biodefense at the Departments of Health and Human Services, Defense, Homeland Security, Agriculture, Commerce, and State; the Environmental Protection Agency; and the National Science Foundation. This article also includes an updated assessment of the proportion of biodefense funding provided for programs that address multiple scientific, public health, healthcare, national security, and international security issues in addition to biodefense. The FY2012 federal budget for civilian biodefense totals $6.42 billion. Of that total, $5.78 billion (90%) is budgeted for programs that have both biodefense and nonbiodefense goals and applications, and $637.6 million (10%) is budgeted for programs that have objectives solely related to biodefense. PMID- 21612365 TI - Mass prophylaxis dispensing concerns: traffic and public access to PODs. AB - The ability to quickly dispense postexposure prophylaxis (PEP) using multiple points of dispensing (PODs) following a bioterrorism event could potentially save a large proportion of those who were exposed, while failure in PEP dispensing could have dire public health consequences. A Monte Carlo simulation was developed to explore the traffic flow and parking around PODs under different arrival rates and how these factors might affect the utilization rate of POD workers. The results demonstrate that the public can reasonably access the PODs under ideal conditions assuming a stationary (uniform) arrival rate. For the 5 nonstationary arrival rates tested, however, the available parking spaces quickly become filled, causing long traffic queues and resulting in total processing times that range from 1 hour to over 6 hours. Basic planning considerations should include the use of physical barriers, signage, and traffic control officers to help direct vehicular and pedestrian access to the PODs. Furthermore, the parking and traffic surrounding PODs creates long queues of people waiting to access the PODs. Thus, POD staff are fully used approximately 90% of the time, which can lead to worker fatigue and burn out. PMID- 21612363 TI - Improving the evidence base for decision making during a pandemic: the example of 2009 influenza A/H1N1. AB - This article synthesizes and extends discussions held during an international meeting on "Surveillance for Decision Making: The Example of 2009 Pandemic Influenza A/H1N1," held at the Center for Communicable Disease Dynamics (CCDD), Harvard School of Public Health, on June 14 and 15, 2010. The meeting involved local, national, and global health authorities and academics representing 7 countries on 4 continents. We define the needs for surveillance in terms of the key decisions that must be made in response to a pandemic: how large a response to mount and which control measures to implement, for whom, and when. In doing so, we specify the quantitative evidence required to make informed decisions. We then describe the sources of surveillance and other population-based data that can presently--or in the future--form the basis for such evidence, and the interpretive tools needed to process raw surveillance data. We describe other inputs to decision making besides epidemiologic and surveillance data, and we conclude with key lessons of the 2009 pandemic for designing and planning surveillance in the future. PMID- 21612366 TI - Acting on the lessons of SARS: what remains to be done? PMID- 21612367 TI - Infectious diseases and securitization: WHO's dilemma. AB - The threat posed by infectious diseases has been increasingly framed as a security issue. The UN Security Council's Resolution 1308, which designated HIV/AIDS as a threat to international security, evidenced the securitization process. Using securitization theory as a theoretical tool, this article explores the securitization of infectious diseases in the World Health Organization (WHO). While WHO has tended to securitize infectious diseases since 2000, it has encountered a dilemma in the process because of the inherent asymmetry of interest between developed and developing countries. The act of securitization in WHO currently remains mostly a rhetorical device, since WHO's norms emblematic of securitization have not been backed by operational measures for verification or enforcement due to these asymmetric interests. PMID- 21612368 TI - Preserving national security: the growing role of the life sciences. PMID- 21612369 TI - Secondary metabolites of Centaurea calolepis and evaluation of cnicin for anti inflammatory, antioxidant, and cytotoxic activities. AB - CONTEXT: Centaurea L. (Astreaceae) species are used as herbal remedies in Turkey. Centaurea calolepis Boiss. is an endemic species of Anatolia that has not been subjected to phytochemical studies except essential oil analysis. OBJECTIVE: Secondary metabolite determination, isolation and structure elucidation of pure compounds were performed on C. calolepis. Cnicin, which is the main component of several Centaurea species, was tested for its in vitro anti-inflammatory, antioxidant and cytotoxic activities. MATERIALS AND METHODS: Chloroform and methanol extracts of the aerial parts of C. calolepis were subjected to isolation process using column chromatography. The structures of the compounds were characterized by 1D- and 2D-NMR experiments. Thin-layer chromatography and high performance liquid chromatography were used in determination of phenolics. Cnicin was subjected to a panel of cellular assays to test for inhibition of nuclear factor kappaB (NF-kappaB), inducible nitric oxide synthase (iNOS), reactive oxygen species and cytotoxicity. RESULTS: Cnicin, lucenin-2, schaftoside and 3-O feruloylquinic acid were isolated from C. calolepis extracts. Vicenin-2, vitexin, isovitexin, homoorientin, rutin, orientin, luteolin-7-O-glycoside and chlorogenic acid were determined in fractions. Cnicin showed inhibition of NF-kappaB and inhibition of iNOS activity with IC50 Values of 1.8 and 6.5 uM, respectively. Cytotoxic activity of cnicin was observed toward pig kidney epithelial (LLC PK11), human malignant melanoma (SK-MEL) and human ductal carcinoma (BT-549) cells with IC50 values of 23.3, 14.0 and 18.3 uM, respectively. DISCUSSION AND CONCLUSION: This is the first detailed report of secondary metabolites of C. calolepis. Evaluation of biological activity of cnicin establishes the potential of this compound as an anti-inflammatory and cytotoxic agent. PMID- 21612370 TI - Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation properties of new 2-(4-isobutylphenyl)propanoic acid derivatives. AB - Synthesis and pharmacological evaluation of various 2-(4-isobutylphenyl)propanoic acid derivatives containing 1,3,4-thiadiazole and thiadiazolo[3,2 a][1,3,5]triazine-5-thione nucleus is reported here. The structures of new compounds are supported by IR, (1)H & (13)C NMR data. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen were screened for their analgesic, ulcerogenic and lipid peroxidation activities. The compounds, which showed less ulcerogenic action, also showed reduced malondialdehyde production (MDA). Compound 4i and 5f showed 89.50 and 88.88% of inhibition in paw edema, 69.80 and 66.25% protection against acetic acid-induced writhings and 0.7 and 0.65 of severity index, respectively, compared to 90.12, 72.50 and 1.95 values of ibuprofen. PMID- 21612371 TI - Rapid screening of enzyme inhibitors using profiling of enzyme-metabolite assay by HPLC (PREMA-HPLC). AB - A number of isolates from different ecosystems were screened for their ability to inhibit tyrosinase resulting in the selection of isolate CFR 101, which showed an inhibition of 72%. The metabolites present in the crude extract of the selected isolate was profiled through high-performance liquid chromatography (HPLC) before the enzyme inhibition assay to reveal a 66% decrease in area of the peak at room temperature for 13.9 min, after the assay. Upon purification, this peak was identified as kojic acid, a known inhibitor of tyrosinase. This unique technique of combining a reaction assay mixture with HPLC profile wherein inhibitors can be rapidly pinpointed in crude extracts addresses the drawback of rapid chemical high-throughput screening (HTS) systems, which is limited to the chemical nature of metabolites without any evidence of their biological activities. PMID- 21612372 TI - In vitro inhibition of polyphenol oxidase by some new diarylureas. AB - A new series of N,N'-diarylureas (1-9) was synthesized. These compounds were investigated as inhibitors of polyphenol oxidase (PPO) which had been purified from banana by an affinity gel comprised of Sepharose 4B-l-tyrosine-p-amino benzoic acid. K(i) values for (1), (2), (3), (5), (6), (7) and (8) were determined as 0.285, 17.97, 0.187, 0.108, 0.063, 0.044 and 0.047 mM, respectively. Thus (2) was by far the most effective inhibitor. Interestingly, (4) and (9) behaved as an activator of PPO in this study. PMID- 21612373 TI - Synthesis and biological screening of some pyridine derivatives as anti-malarial agents. AB - Two series of pyridine derivatives were synthesised and evaluated for their in vivo anti-malarial activity against Plasmodium berghei. The anti-malarial activity was determined in vivo by applying 4-day standard suppressive test using chloroquine (CQ)-sensitive P. berghei ANKA strain-infected mice. Compounds 2a, 2g and 2h showed inhibition of the parasite multiplication by 90, 91 and 80%, respectively, at a dose level of 50 umol/kg. Moreover, The most active compounds (2a, 2g and 2h) were tested in vitro against CQ-resistant Plasmodium falciparum RKL9 strains where compound 2g showed promising activity with IC(50) = 0.0402 uM. The compounds were non-toxic at 300 and 100 mg/kg through the oral and parenteral routes, respectively. The docking pose of the most active compounds (2a, 2g and 2h) in the active site of dihydrofolate reductase enzyme revealed several hydrogen and hydrophobic interactions that contribute to the observed anti malarial activities. PMID- 21612374 TI - Novel furfurylidene N-acylhydrazones derived from natural safrole: discovery of LASSBio-1215, a new potent antiplatelet prototype. AB - We describe herein the discovery of (E)-N-methyl-N'-((5-nitrofuran-2 yl)methylene)benzo[d]( 1 , 3 ) dioxole-5-carbohydrazide (9e), named LASSBio-1215, as a novel antiplatelet agent belonging to the N-methyl-N-acylhydrazone class, which exert their antiaggregating actions on human and rabbit platelets induced by different agonists, through cyclooxygenase-1 (COX-1) or thromboxane synthase inhibition. This compound was elected after screening of a series of functionalized furyl N-acylhydrazone derivatives, synthesized from natural safrole 10. In vitro assays showed that compound 9e presents platelet-aggregating activity in rabbit platelet-rich plasma (PRP) induced by arachidonic acid (IC(50) = 0.7 uM) and collagen (IC(50) = 4.5 uM). Moreover, LASSBio-1215 also inhibited almost completely the second wave of adenosine diphosphate-induced platelet aggregation in human PRP, and this effect was correlated with their ability to block the production of pro-aggregating autacoid thromboxane A(2). PMID- 21612375 TI - Chemical reactivity and antimicrobial activity of N-substituted maleimides. AB - Several N-substituted maleimides containing substituents of varying bulkiness and polarity were synthesised and tested for antimicrobial and cytostatic activity. Neutral maleimides displayed relatively strong antifungal effect minimum inhibitory concentrations (MICs in the 0.5-4 ug ml(-1) range); their antibacterial activity was structure dependent and all were highly cytostatic, with IC(50) values below 0.1 ug ml(-1). Low antimicrobial but high cytostatic activity was noted for basic maleimides containing tertiary aminoalkyl substituents. Chemical reactivity and lipophilicity influenced antibacterial activity of neutral maleimides but had little if any effect on their antifungal and cytostatic action. N-substituted maleimides affected biosynthesis of chitin and beta(1,3)glucan, components of the fungal cell wall. The membrane enzyme, beta(1,3)glucan synthase has been proposed as a putative primary target of N ethylmaleimide and some of its analogues in Candida albicans cells. PMID- 21612376 TI - Carbonic anhydrase I and II inhibition with natural products: caffeine and piperine. AB - Novel chemotypes with carbonic anhydrase (CA; EC 4.2.1.1) inhibitory action, in addition to the sulphonamide and sulphamate were discovered, many of which are based on natural products. Caffeine and piperine were extracted and tested for inhibition of the human (h) cytosolic isoforms hCA I and II. The IC(50) values of caffeine against hCA I was of 55 mM, whereas that of piperine of 60 mM. The IC(50) values of caffeine and piperine against hCA II were of 2 mM. Although these are quite weak inhibitors they may constitute leads for developing tighter binding compounds. PMID- 21612377 TI - Synthesis and biological evaluation of some novel sulfamoylphenyl-pyridazinone as anti-inflammatory agents (Part-II * ). AB - Seven novel 6-aryl-2-(p-sulfamoylphenyl)-4,5-dihydropyridazin-3(2H)-ones (2a-g) were synthesized by the condensation of appropriate aroylpropionic acid and 4 hydrazinobenzenesulfonamide hydrochloride in ethanol. Structure of all compounds have been elucidated by elemental analysis, IR, (1)H NMR, (13)C NMR, DEPT and MS spectrscopy. These compounds were tested for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Compound 2b exhibited anti-inflammatory activity comparable to that of celecoxib (at 5 h). Two other compounds 2d and 2g showed promising anti-inflammatory activity (edema reduction more than 80% at 5 h). These compounds (2b, 2d and 2g) did not produce any ulceration in gastric region. PMID- 21612378 TI - Thermal solvent-free synthesis of chromonyl chalcones, pyrazolines and their in vitro antibacterial, antifungal activities. AB - A facile and ecofriendly synthesis of new chromonyl chalcones 3a-b from 3 formylchromone 1 and active methyl compounds 2a-b is reported under thermal solvent-free heating condition in good yields. The chromonyl chalcones 3a-b were used as intermediates under green condition for the synthesis of new bioactive pyrazoline derivatives 4a-f. The compounds were tested for antimicrobial activity by disk diffusion assay with slight modifications against Gram-positive, Gram negative strains of bacteria as well as fungal strains. The investigation of antimicrobial screening revealed that compounds 3a-b and 4a-f showed antibacterial and antifungal activities. PMID- 21612379 TI - High-dose chemotherapy with busulfan and cyclophosphamide and autologous stem cell rescue in patients with Hodgkin lymphoma. PMID- 21612380 TI - Optimal central nervous system prophylaxis in Philadelphia chromosome-positive acute lymphoblastic leukemia: collateral damage in the imatinib era? PMID- 21612381 TI - Minimal residual disease: the advantages of digital over analog polymerase chain reaction. PMID- 21612382 TI - Getting to the heart of the problem in treating diffuse large B-cell lymphoma. PMID- 21612383 TI - Non-pegylated liposomal doxorubicin (Myocet(r)) in patients with poor-risk aggressive B-cell non-Hodgkin lymphoma. AB - The incidence of non-Hodgkin lymphomas increases with age. Non-pegylated liposomal formulations of doxorubicin (Myocet(r)) reduce systemic and cardiac toxicity especially in the elderly, who often have cardiac diseases. We treated 80 patients (mean age 70.9 years) with poor-risk diffuse large B-cell lymphoma with the R-COMP 21 regimen (Myocet(r) 50 mg/m(2), cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2), rituximab 375 mg/m(2), prednisone 100 mg/day). In all, 82.5% and 13.7% patients showed complete and partial responses, respectively. Sixty-two of the 80 patients are alive and disease-free (77.5%), while 3/80 are alive with active disease and 15 patients (18.7%) have died (median follow-up: 31 months). The estimated probability of overall survival at 12/24 months from admission was 93.5/87.3%, respectively. There were no therapy-related cardiac events and the ejection fraction improved (from 51.6 +/- 6.9% to 54.2 +/- 3.9%). Grade 3-4 neutropenia occurred in 22% of patients. We concluded that Myocet(r) shows both efficacy and tolerability, mainly at the cardiac level. PMID- 21612384 TI - Developing a statewide emergency medical services database linked to hospital outcomes: a feasibility study. AB - BACKGROUND: Statewide emergency medical services (EMS) data linked to outcomes are critical for promoting high-quality emergency care; however, many states do not have such a resource. OBJECTIVE: To demonstrate the feasibility of creating such a statewide database using a one-month pilot sample. METHODS: This was a prospective cohort study of all EMS patient encounters throughout Oregon during May 2008. Eighty-three National EMS Information System (NEMSIS) variables were obtained from EMS agencies via electronic or paper charts. We reformatted raw data, mapped NEMSIS fields, entered hard-copy records, and uploaded data files to a statewide electronic medical records platform. Records from transport and nontransport (first-responder) agencies caring for the same patients were matched using probabilistic linkage, then linked to three statewide outcome databases (Oregon Hospital Discharge Database [OHDD], Oregon Trauma Registry [OTR], and Oregon Department of Transportation [ODOT] Crash File) using similar methodology. We estimated population-adjusted case ascertainment by county and used descriptive statistics to characterize the process. RESULTS: During the one-month period, we collected 27,474 EMS records in 36 (100%) counties from 106 (77%) licensed transport agencies and 10 nontransport agencies, representing 20,673 persons. There were 3,302 admission record matches, 285 trauma registry matches, and 392 crash record matches. Overall, 3,979 hospital outcomes were matched to EMS records for 80 (75%) transport and six (60%) first-responder agencies. Median per-agency match rates were 16.3% for OHDD (interquartile range [IQR] 8.3-22.2%, range 0-56.5%), 0.9% for OTR (IQR 0-2.5%, range 0-60.0%), and 1.6% for ODOT (IQR 0-3.5%, range 0-23.1%). CONCLUSION: Developing a statewide EMS database linked to hospital outcomes is feasible. The processes used in this study and match rate estimates may provide a template for other states to follow, enhancing opportunities for outcomes-based EMS research and EMS quality assurance efforts. PMID- 21612385 TI - No deaths associated with patient refusal of transport after naloxone-reversed opioid overdose. AB - INTRODUCTION: Naloxone is widely used in the treatment and reversal of opioid overdose. Most emergency medical services (EMS) systems administer naloxone by standing order, and titrate only to reverse respiratory depression without fully reversing sedation. Some EMS systems routinely administer sufficient naloxone to fully reverse the effects of opioid overdose. Frequently patients refuse further medical evaluation or intervention, including transport. OBJECTIVES: The purpose of this study was to evaluate the safety of this practice and determine whether increased mortality is associated with full reversal of opioids. As a component of a comprehensive quality assurance initiative, we assessed mortality during the 48 hours after patients received naloxone to reverse opioid overdose followed by patient-initiated refusal of transportation. METHODS: The setting was a large urban fire-based EMS system. Investigators provided the Bexar County Medical Examiner's Office (MEO) with a list of patients who were treated by the San Antonio Fire Department with naloxone, and not transported. Inclusion criteria were administration of naloxone and patient-initiated refusal. Patient dispositions also included aid only, referral to the MEO, or referral to law enforcement. The list was then compared with the MEO database. A chart review was completed on all patients treated and subsequently presented to the MEO within two days. A secondary time period of 30 days was also assessed. RESULTS: The list identified 592 patients treated with naloxone and not transported to the emergency department. Five-hundred fifty-two patients received naloxone and refused transport or were not transported. The remaining 40 patients all presented to EMS in cardiac arrest, naloxone was administered during the course of resuscitation, and subsequent efforts were terminated in the field. None of the patients receiving naloxone with a subsequent patient-initiated refusal were examined at the MEO within the two-day end point. The 30-day assessment revealed that nine individuals were treated with naloxone and subsequently died, but the shortest time interval between date of service and date of death was four days. CONCLUSION: The primary outcome was that no patients who were treated with naloxone for opioid overdose and then refused care were examined by the MEO within a 48-hour time frame. PMID- 21612387 TI - Effect of patient age on airway response by paramedics: frailty or futility? AB - OBJECTIVE: We studied patterns related to patient age and indication for airway interventions delivered by paramedics from 2000 through 2004. METHODS: The study population included patients >= 15 years old managed by paramedics. Outcomes were the frequencies of definitive airway, ventilatory techniques, and oxygenation techniques. Independent variables were patient age, gender, race, hospital drive time, do-not-resuscitate status, and two trauma indicators of the American College of Surgeons Committee on Trauma (anatomic injury and mechanism of injury). Subset analysis was performed with the presence or absence of a set of recorded conditions. RESULTS: A total of 827,772 paramedic transports were studied; 233,470 were identified with at least one indication for airway intervention. Patients older than 65 years were, when compared with patients 65 years old or younger, 1) less likely to receive ventilatory interventions with any indication; 2) more likely to receive ventilatory intervention without an indication; and 3) more likely to receive oxygenation interventions whether indications were present or not. We considered age in five-year intervals and noted a consistent biphasic pattern for all interventions, regardless of indications. The odds ratios for interventions for patients in each block compared with those for 15- to 29-year-old patients increased with age until about 70 years of age, then gradually declined. CONCLUSIONS: Patterns of age related variations in airway interventions cannot be explained by the application of protocols. The reason for the peak rate of interventions at age 70 years is unknown. Explanations need to consider the influence on paramedic behavior of a number of factors, including frailty and futility. Additional paramedic training may be needed to change these patterns. PMID- 21612386 TI - Medical conditions associated with out-of-hospital endotracheal intubation. AB - BACKGROUND: While prior studies describe the clinical presentation of patients requiring paramedic out-of-hospital endotracheal intubation (ETI), limited data characterize the underlying medical conditions or comorbidities. OBJECTIVE: To characterize the medical conditions and comorbidities of patients receiving successful paramedic out-of-hospital ETI. METHODS: We used Pennsylvania statewide emergency medical services (EMS) clinical data, including all successful ETIs performed during 2003-2005. Using multiple imputation triple-match algorithms, we probabilistically linked EMS ETI to statewide death and hospital admission data. Each hospitalization record contained one primary and up to eight secondary diagnoses, classified according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). We determined the proportion of patients in each major ICD-9-CM diagnostic group and subgroup. We calculated the Charlson Comorbidity Index score for each patient. Using binomial proportions with confidence intervals (CIs), we analyzed the data and combined imputed results using Rubin's method. RESULTS: Across the imputed sets, we linked 25,733 (77.7% linkage) successful ETIs to death or hospital records; 56.3% patients died before and 43.7% survived to hospital admission. Of the 14,478 patients who died before hospital admission, most (92.7%; 95% CI: 92.5-93.3%) had presented to EMS in cardiac arrest. Of the 11,255 hospitalized patents, the leading primary diagnoses were circulatory diseases (32.0%; 95% CI: 30.2-33.7%), respiratory diseases (22.8%; 95% CI: 21.9-23.7%), and injury or poisoning (25.2%; 95% CI: 22.7-27.8%). Prominent primary diagnosis subgroups included asphyxia and respiratory failure (15.2%), traumatic brain injury and skull fractures (11.3%), acute myocardial infarction and ischemic heart disease (10.9%), poisonings and drug and alcohol disorders (6.7%), dysrhythmias (6.7%), hemorrhagic and nonhemorrhagic stroke (5.9%), acute heart failure and cardiomyopathies (5.6%), pneumonia and aspiration (4.9%), and sepsis, septicemia, and septic shock (3.2%). Most of the admitted ETI patients had a secondary circulatory (70.8%), respiratory (61.4%), or endocrine, nutritional, or metabolic (51.4%) secondary diagnosis. The mean Charlson Index score was 1.6 (95% CI: 1.5-1.7). CONCLUSIONS: The majority of successful paramedic ETIs occur on patients with cardiac arrest and circulatory and respiratory conditions. Injuries, poisonings, and other conditions compromise smaller but important portions of the paramedic ETI pool. Patients undergoing ETI have multiple comorbidities. These findings may guide the systemic planning of paramedic airway management care and education. PMID- 21612388 TI - Noninvasive positive pressure ventilation. AB - The National Association of EMS Physicians (NAEMSP) believes that noninvasive positive pressure ventilation (NIPPV) is an important treatment modality for the prehospital management of acute dyspnea. This document is the official position of the NAEMSP. PMID- 21612389 TI - Off-label use of medical products. AB - The National Association of EMS Physicians (NAEMSP) believes that emergency medical services (EMS) medical directors may prescribe any legally marketed product for off-label use. This document is the official position of the NAEMSP. PMID- 21612390 TI - Noninvasive positive pressure ventilation: resource document for the National Association of EMS Physicians position statement. AB - The National Association of EMS Physicians (NAEMSP) believes that noninvasive positive pressure ventilation (NIPPV) is an important treatment modality for the prehospital management of acute dyspnea. This document serves as a resource to the NAEMSP position on prehospital NIPPV. PMID- 21612391 TI - Improving the diagnosis of infection during out-of-hospital emergency care: are biomarkers the next step? PMID- 21612392 TI - Breastfeeding and the Baha'i Faith. AB - The Baha'i Sacred Writings reference breastfeeding literally and symbolically and provide guidance as to its practice. Breastfeeding is endorsed as the ideal form of infant nutrition. The importance of breastfeeding is underscored by the exemption of breastfeeding women from fasting, as well as by the identification of breastfeeding as being linked to the moral development of children. Several of the central principles of the Baha'i Faith, such as the equality of women and men and the harmony of science and religion, may engender attitudes that support the practice of breastfeeding. The implications of the Baha'i Writings with regard to breastfeeding are explored and summarized here. PMID- 21612393 TI - Assessment of blood glucose predictors: the prediction-error grid analysis. AB - BACKGROUND: Prediction of the future blood glucose (BG) evolution from continuous glucose monitoring (CGM) data is a promising direction in diabetes therapy management, and several glucose predictors have recently been proposed. This raises the problem of their assessment. There were attempts to use for such assessment the continuous glucose-error grid analysis (CG-EGA), originally developed for CGM devices. However, in the CG-EGA the BG rate of change is estimated from past BG readings, whereas predictors provide BG estimation ahead of time. Therefore, the original CG-EGA should be modified to assess predictors. Here we propose a new version of the CG-EGA, the Prediction-Error Grid Analysis (PRED-EGA). METHODS: The analysis is based both on simulated data and on data from clinical trials, performed in the European FP7-project "DIAdvisor." Simulated data are used to test the ability of the analyzed CG-EGA modifications to capture erroneous predictions in controlled situation. Real data are used to show the impact of the different CG-EGA versions in the evaluation of a predictor. RESULTS: Using the data of 10 virtual and 10 real subjects and analyzing two different predictors, we demonstrate that the straightforward application of the CG-EGA does not adequately classify the prediction performance. For example, we observed that up to 70% of 20 min ahead predictions in the hyperglycemia region that are classified by this application as erroneous are, in fact, accurate. Moreover, for predictions during hypoglycemia the assessments produced by the straightforward application of the CG-EGA are not only too pessimistic (in up to 60% of cases), but this version is not able to detect real erroneous predictions. In contrast, the proposed modification of the CG-EGA, where the rate of change is estimated on the predicted BG profile, is an adequate metric for the assessment of predictions. CONCLUSIONS: We propose a new CG-EGA, the PRED-EGA, for the assessment of glucose predictors. The presented analysis shows that, compared with the straightforward application of the CG-EGA, the PRED-EGA gives a significant reduction of the misclassification cases. A reduction by a factor of at least 4 was observed in the study. Moreover, the PRED EGA is much more robust against uncertainty in the input and references. PMID- 21612394 TI - Association study of IRS1 gene polymorphisms with type 2 diabetes in south Indians. AB - BACKGROUND AND OBJECTIVES: The insulin receptor substrate-1 (IRS1) gene is a candidate gene for type 2 diabetes. The aim of this study was to investigate the association of the IRS1 gene polymorphisms Gly972Arg and Ala513Pro with type 2 diabetes in an Asian Indian population in south India. METHODS: A total of 2,148 subjects (1,187 normal glucose-tolerant [NGT] and 961 type 2 diabetes subjects) were randomly selected from the Chennai Urban Rural Epidemiology Study. The IRS1 gene polymorphisms Gly972Arg and Ala513Pro were genotyped in these subjects using polymerase chain reaction-restriction fragment length polymorphism, and a few variants were confirmed by direct sequencing. RESULTS: The frequency of the "A" allele of the Gly972Arg(G->A) single nucleotide polymorphism was similar between the NGT and diabetes subjects (2%). There was no significant difference in the genotypic frequency between the NGT and type 2 diabetes group (P = 0.25). When the study subjects were stratified based on body mass index (BMI) as per World Health Organization Asia Pacific guidelines as nonobese (BMI <25 kg/m(2)) and obese (BMI >=25 kg/m(2)), neither the allelic frequency (nonobese, P = 0.44; obese, P = 0.37) nor the genotypic frequency (nonobese, P = 0.29; obese, P = 0.35) was significantly different between the NGT and type 2 diabetes groups. The Ala513Pro polymorphism was first genotyped in 500 NGT and 500 type 2 diabetes subjects. None of these subjects carried the Ala513Pro or the Pro513Pro genotype. Hence, the Ala513Pro polymorphism was not genotyped further. CONCLUSION: The IRS1 gene variants Gly972Arg and Ala513Pro are not associated with type 2 diabetes in this south Indian population. PMID- 21612395 TI - Intracellular glycation of nuclear DNA, mitochondrial DNA, and cytosolic proteins during senescence-like growth arrest. AB - To investigate the accumulation of intracellular advanced glycation end products (AGEs), a method was established for the simultaneous analysis of glycation products of cytosolic proteins, nuclear DNA, and mitochondrial DNA (mtDNA). Nuclear DNA, mtDNA, and cytosolic proteins were simultaneously isolated from one cell lysate by differential centrifugation and combined mechanical and chemical cell disruption methods. The major DNA-AGE N(2)-carboxyethyl-2'-deoxyguanosine (CEdG) was quantified in nuclear DNA and mtDNA by ELISA, whereas the protein-AGEs N(E)-(carboxymethyl)lysine (CML) and N(E)-(carboxyethyl)lysine (CEL) were determined by western blot. The method was used to analyze NIH3T3 fibroblasts. In untreated cells, CEdG levels of mtDNA (14.84 +/- 3.07 pg CEdG/MUg mtDNA) were significantly higher compared with nuclear DNA (4.40 +/- 0.64 pg CEdG/MUg DNA; p < 0.001). Then, fibroblasts were analyzed after 7 days of senescence-like growth arrest. In senescent fibroblasts, the CEdG content of nuclear DNA significantly increased by 25%. However, the CEdG level of mtDNA significantly decreased to 52%; in parallel, an increase in mitochondrial mass and mtDNA was observed. Senescence did not lead to general accumulation of protein-AGEs, but two protein bands at 32 and 34 kDa showed a significant increase in the CML/CEL modification rate (208%, p < 0.001; 196%, p = 0.0016) in senescent fibroblasts compared with control cells. PMID- 21612396 TI - Association of HLA-G 3' UTR 14-bp insertion/deletion polymorphism with hepatocellular carcinoma susceptibility in a Chinese population. AB - The 14-bp insertion/deletion (indel) polymorphism located in the 3' UTR of the human leukocyte antigen-G (HLA-G) gene plays a role in several autoimmune and chronic inflammatory diseases. HLA-G expression is associated with hepatocellular carcinoma (HCC) prognosis, especially in early stage, with high expression independently associated with shortened overall survival and increased tumor recurrence. In the present study, we carried out a case-control study in a Chinese population (318 cases and 599 controls) to estimate the susceptibility to HCC associated with the 14-bp indel polymorphism. Logistic regression analysis showed that the heterozygote and the homozygote 14-bp ins/ins confer a lower risk of HCC (adjusted OR = 0.75, 95% CI: 0.57-1.01, p = 0.061; OR = 0.54, 95% CI: 0.30 0.98, p = 0.031, respectively). Hepatitis B virus (HBV) stratification analysis showed that the associations were stronger in the HBV-positive population. Immunohistochemical analysis further showed that HLA-G expression in HCC tissues with 14-bp del/del genotype was more prominent than for heterozygous and 14-bp ins/ins genotype (p < 0.01). Taken together, our results suggested that the HLA-G 14-bp indel polymorphism may be a marker for genetic susceptibility to HCC in Chinese populations. Further studies from different populations with larger sample size are warranted to validate our findings. PMID- 21612397 TI - Cloning of the flap endonuclease-1 gene in Bombyx mori and identification of an antiapoptotic function. AB - The flap endonuclease-1 (FEN-1) gene is involved in DNA replication and repair, and it maintains genomic stability as well as the accuracy of DNA replication under normal growth conditions. However, FEN-1 also plays an important role in apoptosis and cancer development. We cloned the BmFEN-1 gene from Bombyx mori, which was 1343 bp in length and possessed an 1143 bp ORF (123-1266). It consists of seven introns and eight exons that encode a protein with 380 amino acids that has the typical XPG domain. The N-terminal motif is located at amino acids 95 105, and the proliferating cell nuclear antigen interaction motif is located at amino acids 337-344. RNA interference-mediated reduction of BmFEN-1 expression induced cell cycle arrest in S phase in BmE-SWU1 cells. These results suggest that BmFEN-1 can inhibit apoptosis and promote cell proliferation. PMID- 21612398 TI - Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and nonsyndromic orofacial clefts susceptibility in a southern Chinese population. AB - Nonsyndromic orofacial clefts (NSOC) are one of the most common congenital anomalies in humans. Great efforts have been taken to unravel its genetic background. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism and two of its functional polymorphisms, MTHFR C677T and MTHFR A1298C, might be associated with NSOC susceptibility. The aim of the present study was to investigate their associations with risks of NSOC in a southern Chinese population. We found that MTHFR 677 TT and 677 CT/TT were associated with increased risk of cleft lip with or without cleft palate; meanwhile, MTHFR 1298 AC and 1298 AC/CC had protective effects against cleft lip with or without cleft palate. In further stratified analysis, we found that MTHFR 677 CT contributed to elevated risk of cleft lip only, as did MTHFR 677 CT/TT. On the contrary, MTHFR 1298 AC and 1298 AC/CC appeared to be protective against cleft lip with cleft palate. These results suggested that these two polymorphisms were involved in the development of NSOC in a southern Han Chinese population. PMID- 21612399 TI - A high-affinity T-helper epitope enhances peptide-pulsed dendritic cell-based vaccine. AB - The NV epitope, a dominant helper determinant from the circumsporozoite antigen of Plasmodium falciparum, is strongly immunogenic and can provide help for cytotoxic T-lymphocyte (CTL) activation. In this study, we evaluated whether the addition of NV peptide can augment the efficacy of peptide-pulsed dendritic cell (DC) immunization in vivo. Using B16 melanoma as tumor model, we demonstrated that DCs pulsed with both NV and gp100 (a melanoma-specific antigen) peptide enhanced immune priming and protection from tumor challenge in vivo. Further, we showed the mechanisms of the NV epitope that help CTL activation; MHC-II restricted NV peptide induced dramatically more effective helper cells, with a higher level of CD40L expression and IFN-gamma production, which, in turn, more effectively conditioned DCs for CTL activation. The improved helper cells also induced greater IL-12 production by DCs, accounting for the reciprocal T-helper polarization to Th1, and increased the expression of costimulatory molecules. Collectively, these findings demonstrate that NV peptide in addition to tumor antigen-pulsed DC immunizations augment helper cell activation, which in turn promotes maturation of DC, and enhance in vivo antitumor activity. PMID- 21612400 TI - Mutational hotspots in the mitochondrial D-loop region of cancerous and precancerous colorectal lesions in Egyptian patients. AB - Mutations in the mitochondrial genome (mtDNA) are associated with different types of cancer, specifically colorectal cancer (CRC). However, few studies have been performed on precancerous lesions, such as ulcerative colitis (UC) lesions and adenomatous polyps (AP). The aim of this study was to identify mtDNA mutations in the cancerous and precancerous lesions of Egyptian patients. An analysis of the mutations found in six regions of the mtDNA genome (ND1, ND5, COI, tRNAser, D loop 1, and 2) in 80 Egyptian patients (40 CRC, 20 UC, and 20 AP) was performed using polymerase chain reaction-single-strand conformational polymorphism techniques and followed up by direct sequencing. The overall incidence of mutations was 25%, 25%, and 35% in CRC, UC, and AP cases, respectively. Although there was no common mutation pattern within each group, a large number of mutations were detected in the D-loop region in all of the groups. Some mutations (e.g., T414G) were detected repeatedly in precancerous (UC and AP) and cancerous lesions. Mutations detected in patients with CRC were predominantly found in the ND1 gene (40%). Our preliminary study suggests that Egyptian patients with CRC have a large number of mtDNA mutations, especially in the D-loop region, which have not been previously reported. Mutations in the mtDNA of precancerous lesions (i.e., AP and UC) may contribute to transformation events that lead to CRC. PMID- 21612401 TI - The role of the hypoxia-inducible factor 1 binding site in the induction of aquaporin-1 mRNA expression by hypoxia. AB - Aquaporin-1 (AQP1), a water channel protein, has been shown to play an important role in tumor growth and angiogenesis in mouse endothelial cells. We recently reported that the expression of AQP1 mRNA was induced in cultured human retinal vascular endothelial cells (HRVECs) under hypoxia. In the present study, HRVECs were cultured under normoxia or hypoxia (1% O(2)) to elucidate the mechanism of hypoxic induction of AQP1. AQP1 mRNA expression was increased 1.7 +/- 0.24-fold under hypoxia compared with that under normoxia (p < 0.01). This increase was almost completely blocked by the transcriptional inhibitor actinomycin D (p < 0.01). The degradation of AQP1 mRNA showed no difference under normoxia or hypoxia. These data suggest that the hypoxia-induced expression of AQP1 results from RNA transcription. The sequence located from -1338 to -1334 bp is identical to the consensus sequence of the hypoxia-inducible factor 1 (HIF-1) binding site. The promoter activities of the two constructs including this putative HIF-1 binding site showed 2.0 +/- 0.67-fold increase and 2.9 +/- 1.9-fold increase under hypoxia when compared with those under normoxia. However, both deletion and mutation of the HIF-1 binding site abrogated this effect. These data suggest that this sequence mediates the transcriptional activation of AQP1 by hypoxia. The chromatin immunoprecipitation assay showed that HIF-1alpha bound to the putative HIF-1 binding site. In conclusion, hypoxia-induced expression of AQP1 requires transcriptional activation, and the HIF-1 binding site of the 5'-promoter is necessary for transcriptional activation in HRVECs. PMID- 21612402 TI - Vascular endothelial growth factor haplotypes associated with childhood obesity. AB - Expansion of adipose tissue in obesity is associated with angiogenesis and adipose tissue mass depends on neovascularization. Vascular endothelial growth factor (VEGF) is the main angiogenic factor in the adipose tissue, and VEGF expression is tightly regulated at both transcriptional and translational levels. However, no previous study has tested the hypothesis that genetic polymorphisms in the VEGF gene could affect susceptibility to obesity. To test this hypothesis, we compared the distribution of genotypes and haplotypes including three VEGF genetic polymorphisms in obese children and adolescents with those found in healthy controls. We studied 172 healthy children and adolescents and 113 obese children and adolescents. Genotypes of three clinically relevant VEGF polymorphisms in the promoter region (C-2578A, G-1154A, and G-634C) of the VEGF gene were determined by TaqMan allele discrimination assay and real-time polymerase chain reaction. VEGF haplotypes were inferred using Haplo.stats and PHASE 2.1 programs. We found no differences in the distributions of VEGF genotypes and alleles (p > 0.05). However, the CAG haplotype was more frequent in the obese group than in the control group (4% versus 0%, respectively, in white subjects; p = 0.008; odds ratio = 10.148 (95% confidence interval: 1.098-93.788). Our findings suggest that VEGF haplotypes affect susceptibility to obesity in children and adolescents. PMID- 21612403 TI - Lysyl oxidase G473A polymorphism is associated with increased risk of coronary artery diseases. AB - Lysyl oxidase (LOX) plays a crucial role in the maintenance of extracellular matrix stability and could participate in vascular remodeling associated with cardiovascular diseases. A novel polymorphism in the LOX gene, G473A (rs1800449), was identified. The objective of this study was to investigate the association between LOX G473A polymorphism and susceptibility to coronary artery diseases (CADs) in Chinese population. The LOX variant G473A was detected by polymerase chain reaction-restriction fragment length polymorphism in 656 CAD cases and 718 age-matched controls. Frequencies of LOX 473 AA genotype and A allele were significantly higher in patients with CAD than in controls (odds ratio = 1.93, 95% confidence interval 1.26-2.95, p = 0.002; and odds ratio = 1.38, 95% confidence interval 1.15-1.67, p = 0.001). Our data suggest that the G473A polymorphism of LOX gene is associated with increased susceptibility to CAD. PMID- 21612404 TI - Induction of pancreatic beta-cell-like cells from CD44+/CD105+ human amniotic fluids via epigenetic regulation of the pancreatic and duodenal homeobox factor 1 promoter. AB - Pancreatic and duodenal homeobox factor 1 (PDX-1) maintains beta-cell function and differentiation via direct regulation of multiple islet cell genes. However, the molecular mechanisms involved in this process remain unknown. Here, we show that PDX-1 plays an important role in the induction of CD44+/CD105+ human amniotic fluid cells (HuAFCs) into functional pancreatic beta-cell-like cells in vitro. CD44+/CD105+ HuAFCs were transfected with either siRNA targeting PDX-1 (siRNA-PDX-1) or mock plasmid (siRNA-MOCK). Following induction, siRNA-MOCK transfected cells differentiated into beta-cell-like cells that expressed multiple islet cell markers and produced insulin and C-peptide in a glucose regulated manner. However, siRNA-PDX-1-transfected cells did not fully differentiate into beta-cell-like cells. Further, we observed epigenetic changes at the PDX-1 gene locus in induced CD44(+)/CD105(+) HuAFCs. Therefore, CD44+/CD105+ HuAFCs could be a source of human pancreatic beta-cell-like cells with potential uses in cell replacement therapy for diabetes. PMID- 21612405 TI - In vivo safety and antitumor efficacy of bifunctional small hairpin RNAs specific for the human Stathmin 1 oncoprotein. AB - Bifunctional small hairpin RNAs (bi-shRNAs) are functional miRNA/siRNA composites that are optimized for posttranscriptional gene silencing through concurrent mRNA cleavage-dependent and -independent mechanisms (Rao et al., 2010 ). We have generated a novel bi-shRNA using the miR30 scaffold that is highly effective for knockdown of human stathmin (STMN1) mRNA. STMN1 overexpression well documented in human solid cancers correlates with their poor prognosis. Transfection with the bi-shSTMN1-encoding expression plasmid (pbi-shSTMN1) markedly reduced CCL-247 human colorectal cancer and SK-Mel-28 melanoma cell growth in vitro (Rao et al., 2010 ). We now examine in vivo the antitumor efficacy of this RNA interference based approach with human tumor xenografted athymic mice. A single intratumoral (IT) injection of pbi-shSTMN1 (8 MUg) reduced CCL-247 tumor xenograft growth by 44% at 7 days when delivered as a 1,2-dioleoyl-3-trimethyl ammoniopropane:cholesterol liposomal complex. Extended growth reductions (57% at day 15; p < 0.05) were achieved with three daily treatments of the same construct. STMN1 protein reduction was confirmed by immunoblot analysis. IT treatments with pbi-shSTMN1 similarly inhibited the growth of tumorgrafts derived from low-passage primary melanoma (>=70% reduction for 2 weeks) and abrogated osteosarcoma tumorgraft growth, with the mature bi-shRNA effector molecule detectable for up to 16 days after last injection. Antitumor efficacy was evident for up to 25 days posttreatment in the melanoma tumorgraft model. The maximum tolerated dose by IT injection of >92 MUg (Human equivalent dose [HED] of >0.3 mg/kg) in CCL-247 tumor xenograft-bearing athymic mice was ~10-fold higher than the extrapolated IC(50) of 9 MUg (HED of 0.03 mg/kg). Healthy, immunocompetent rats were used as biorelevant models for systemic safety assessments. The observed maximum tolerated dose of <100 MUg for intravenously injected pbi shSTMN1 (mouse equivalent of <26.5 MUg; HED of <0.09 mg/kg) confirmed systemic safety of the therapeutic dose, hence supporting early-phase assessments of clinical safety and preliminary efficacy. PMID- 21612406 TI - A novel interaction between interferon-inducible protein p56 and ribosomal protein L15 in gastric cancer cells. AB - Type I interferons (IFNs) are potent inducers of antiviral and antiproliferative activities in vertebrates. IFNs cause activation of genes encoding antiviral proteins, such as p56 from the IFN-stimulated gene family. There are six tetratricopeptide repeat (TPR) motifs located at the N-terminal sequence of p56. Since TPR motifs are known to participate in protein-protein interactions, p56 may associate with various large protein complexes to modify their functions. Using a T7 phage display library, we identified ribosomal protein L15 (RPL15) as a novel interacting partner of p56. The p56-RPL15 interaction was confirmed by pull-down assays. Overexpression of p56 exhibited strong inhibition on the growth of RPL15-overexpressing cancer cells. Small interfering RNA targeting RPL15 not only reduced the growth rate of gastric cancer cells but also sensitized these cells to type I IFN-induced proliferative inhibition. Using site-directed mutagenesis, we also mapped the TPRs 1-4 of p56 as crucial domains to interact with RPL15. Taken together, our results demonstrated a novel interaction between p56 and RPL15. Differential regulation of p56 and RPL15 expression contributes to the antiproliferative capacity on gastric cancer cells, and further elucidation of their interaction may facilitate the development of new anticancer regimens. PMID- 21612407 TI - Lymph node metastasis of gastric cancer is associated with the interaction between poly (ADP-ribose) polymerase 1 and matrix metallopeptidase 2. AB - Poly (ADP-ribose) polymerase 1 (PARP1), which plays a critical role in the base excision DNA repair mechanism, and matrix metallopeptidase 2 (MMP2), a member of the matrix metalloprotease family, are involved in tumor formation and metastasis, respectively. In the present study, the possible association of single nucleotide polymorphisms (SNPs) and gene-gene interaction between PARP1 and MMP2 with the increased incidence of gastric cancer (GC) development and lymph node metastasis (LNM) was investigated in a Korean population. Samples were obtained from 326 patients with chronic gastritis and 153 patients with GC and genotyped using the GoldenGate(r) method. The PARP1 rs1136410 genotype showed a significant association with the frequency of LNM of GC (odds ratio [OR] = 2.19, p = 0.02), LNM stage (p = 0.035), and tumor invasion (p = 0.035). The allele frequency of MMP2 rs243865 was not associated with the development of GC or with the development of LNM of GC. Epistasis between the PARP1 SNP and the MMP2 SNP was associated with the development of LNM of GC. The combination of the MMP2 rs243865 CC genotype and the PARP1 rs1136410 CC or CC+CT genotypes showed a high risk of LNM of GC (OR = 2.47, p = 0.01; OR = 2.28, p = 0.01, respectively). In summary, PARP1 is associated with the risk of LNM of GC and the stage of LNM and tumor invasion. Epistasis between PARP1 rs1136410 and MMP2 rs243865 increased the risk of LNM of GC. PMID- 21612409 TI - Cytotoxic T-lymphocyte antigen-4 polymorphisms and susceptibility to osteosarcoma. AB - Despite the knowledge of many genetic alterations present in osteosarcoma, the complexity of this disease precludes placing its biology into a simple conceptual framework. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays important roles in downregulating T-cell activation, thereby attenuating anti-tumor responses and increasing cancer susceptibility. Polymorphisms in the CTLA-4 gene are associated with different autoimmune diseases and cancers. The current study evaluated the association of four CTLA-4 gene mutations, -1661A/G (rs4553808), -318C/T (rs5742909), +49G/A (rs231775), and CT60A/G (rs3087243), with osteosarcoma in the Chinese population. CTLA-4 polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism in 267 osteosarcoma patients and 282 age-matched healthy controls. Results showed that the CTLA-4 gene +49 AA genotype, +49 A allele, and GTAG haplotype were significantly more frequent in osteosarcoma patients than in controls (odds ratio [OR] 2.20, 95% confidence interval [CI] 1.23-2.95, p = 0.007; OR 1.32, 95% CI 1.03-1.69, p = 0.029, and OR = 1.47, 95% CI 1.03-2.09, p = 0.033, respectively). The CTLA-4 +49G/A polymorphism and GTAG haplotype are associated with increased risk of osteosarcoma. PMID- 21612408 TI - Essential role for p53 and caspase-9 in DNA damaging drug-induced apoptosis in neuroblastoma IMR32 cells. AB - Neuroblastoma is a solid tumor of the sympathetic nervous system accounting for up to 10% of pediatric cancers and 15% of cancer-related deaths. It is a useful system for investigation of stress signal-mediated apoptosis as a tumor suppression mechanism. In this study, we present evidence that p53 mediates DNA damaging drug-induced apoptosis in IMR32 cells through the caspase-9 pathway. In summary, we define a molecular pathway for mediating DNA damaging drug-induced apoptosis in human neuroblastoma IMR32 cells and suggest that inactivation of essential components of this apoptotic pathway may confer drug resistance on neuroblastoma cells. PMID- 21612410 TI - Functional variants in NOS1 and NOS2A are not associated with progressive hearing loss in Meniere's disease in a European Caucasian population. AB - Hearing loss in Meniere's disease (MD) is associated with loss of spiral ganglion neurons and hair cells. In a guinea pig model of endolymphatic hydrops, nitric oxide synthases (NOS) and oxidative stress mediate loss of spiral ganglion neurons. To test the hypothesis that functional variants of NOS1 and NOS2A are associated with MD, we genotyped three functional variants of NOS1 (rs41279104, rs2682826, and a cytosine-adenosine microsatellite repeat in exon 1f) and the CCTTT repeat in the promoter of NOS2A gene (rs3833912) in two independent MD sets (273 patients in total) and 550 controls. A third cohort of American patients was genotyped as replication cohort for the CCTTT repeat. Neither allele nor genotype frequencies of rs41279104 and rs2682826 were associated with MD, although longer alleles of the cytosine-adenosine microsatellite repeat were marginally significant (corrected p = 0.05) in the Mediterranean cohort but not in a second Galicia cohort. Shorter numbers of the CCTTT repeat in NOS2A were significantly more frequent in Galicia controls (OR = 0.37 [CI, 0.18-0.76], corrected p = 0.04), but this finding could not be replicated in Mediterranean or American case control populations. Meta-analysis did not support an association between CCTTT repeats and risk for MD. Severe hearing loss (>75 dB) was also not associated with any functional variants studied. Functional variants of NOS1 and NOS2A do not confer susceptibility for MD. PMID- 21612411 TI - A meta-analysis of CDH1 C-160A genetic polymorphism and gastric cancer risk. AB - We explored the role of the C-160A single-nucleotide polymorphism (SNP) of CDH1 in susceptibility to gastric cancer through a systematic review and meta analysis. Fourteen studies were included, the original groups collapsed, and re grouped in accordance with the most appropriate genetic model. Potential sources of heterogeneity were sought out via subgroup analyses and sensitivity analyses, and publication biases were estimated. No significant association of C-160A was found with the overall risk of developing gastric cancer, but the apparently opposite tendency was noted between Caucasians and Asians, and a statistically significant association was found among Asians. The seemingly opposite tendency of associations was also seen between noncardia and cardia types or between sporadic diffuse and intestinal types of gastric cancer, but no statistically significant findings were noted. Genotyping techniques, sample size, quality appraisal scores, or article publication time did not constitute the source of heterogeneity across studies; and no publication biases were found in our meta analysis. PMID- 21612412 TI - Variation in the yak dectin-1 gene (CLEC7A). AB - C-type lectin domain family 7, member A (CLEC7A, dectin-1) plays an important role in antifungal immunity and belongs to the family of C-type lectin receptors. Variation in the extended exon 4-6 region of the yak dectin-1 gene (CLEC7A), which encodes the beta-glucan recognition domain, was investigated using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP). Three and two variant sequences were identified in exons 4 and 5, respectively, and no variation was found in exon 6. The variation included two single nucleotide substitutions in exon 4 and one single-nucleotide polymorphism in exon 5, and two of these substitutions would nominally cause amino acid substitutions (p.I158T and p.S197G) in yak dectin-1. This is the first report identifying the yak dectin-1 gene, revealing that it is polymorphic and this polymorphism might affect the structure and function of this gene in yak. PMID- 21612413 TI - Prevalence of Toxoplasma gondii infection in wild birds in Durango, Mexico. AB - There is a lack of information concerning the prevalence of Toxoplasma gondii infection in wild birds in Mexico. In the present study, serum samples and tissues from 653 birds from Durango State, Mexico, were evaluated for T. gondii infection. Antibodies to T. gondii (modified agglutination test, titer 1?25 or higher) were found in 17 (2.6%) of the 653 birds, including 1 of 2 curve-billed thrashers (Toxostoma curvirostre), 2 (1 Anas platyrhynchos, 1 Anas diazi) of 4 ducks, 1 of 2 eagles (Aquila sp.), 5 (27.8%) of 18 great-tailed grackles (Quiscalus mexicanus), 7 (1.3%) of 521 rock pigeons (Columba livia), and 1 (14.3%) of 7 quail (Coturnix coturnix). The seroprevalence of T. gondii infection in birds captured in a park outside the city zoo (11.6%, 8/69) was significantly higher than that found in birds from other regions (1.5%, 9/584, OR = 8.38; 95% CI: 2.82-24.77; P = 0.0001). Brains and hearts of 23 birds (17 seropositive, 6 seronegative) were bioassayed in mice for the isolation of T. gondii . Viable T. gondii was isolated from 1 of 7 seropositive pigeons. The DNA obtained from the T. gondii isolate from the pigeon was genotyped using the PCR-RFLP typing using 11 markers (B1, SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico) and revealed an atypical genotype. This is the first report of T. gondii infection in great-tailed grackles, the Mexican duck, and curved-billed thrashers and the first survey of wild birds in Mexico. PMID- 21612414 TI - Construction of PCR primers to detect and distinguish Eimeria spp. in northern bobwhites and a survey of Eimeria on gamebird farms in the United States. AB - Coccidiosis is an important disease in captive gamebirds, including northern bobwhites (Colinusvirginianus). Three Eimeria species, Eimeria lettyae, Eimeria dispersa, and Eimeria colini, have been described in bobwhites. Distinguishing the various Eimeria spp. is often problematic because of similarity in oocyst morphology and site of infection and thus requires live bird infections to distinguish between the coccidian species. To aid in identification and diagnosis, PCR specific primers were generated against the internal transcribed spacer region 1 (ITS-1) of the ribosomal RNA gene using sequences obtained from coccidian-positive samples collected from diagnostic cases or litter from captive bobwhites. Three distinct Eimeria spp. were detected. Species-specific primers were constructed and used to survey the prevalence of the species in 31 samples collected from 13 states. The primers survey results identified E. lettyae, E. dispersa, and Eimeria sp. in 20 (64.5%), 22 (71%), and 29 (93.5%) of the samples, respectively. Mixed infections were common: 13 (41.9%) samples had 3 Eimeria spp., 14 (45.2%) had 2 spp., and 4 (12.9%) samples had only 1 species. The species were widely distributed over the area sampled and were not associated with the age of the flock. PMID- 21612415 TI - New Benedenia species (Monogenea: Capsalidae) from Diagramma labiosum (Perciformes: Haemulidae) on the Great Barrier Reef, Australia, with oncomiracidial descriptions and a report of egg attachment to the host. AB - The slate sweetlips, Diagramma labiosum Macleay, 1883 (Perciformes: Haemulidae), off Heron Island, Great Barrier Reef, Queensland, Australia, hosts 2 new species of Benedenia Diesing, 1858 (Monogenea: Monopisthocotylea: Capsalidae). Benedenia beverleyburtonae n. sp. infects proximal regions of the primary gill lamellae and gill arches. The adult is characterized by a dorsal vaginal pore anterior to the common genital pore and a voluminous, highly coiled vas deferens. This species also has fine muscle fibrils concentrically arranged in the haptor. Its ciliated oncomiracidium differs little from larvae of other Benedenia species, with the exception of at least 4 gland cells containing a granular secretion on each side of the body at the level of the excretory bladders, with fine ducts opening anterior to the eyes. Benedenia disciliata n. sp. infects gill arches and gill rakers, and the adult is characterized by its small total length, anterior hamuli with a small proximal notch, posterior hamuli with a broad, triangular shape proximally, a conspicuous internal fertilization chamber, and asymmetrical eggs. None of the 5 specimens collected had testes, but their definite absence is undetermined. Their absence and the fact that the vas deferens was discernable only distally in the specimens of B. disciliata examined may represent atrophying of the male organs. Benedenia disciliata is unique among Benedenia species because eggs are attached to the host's gill arches by tight wrapping of the appendages around spines on the gill rakers and the larva is not ciliated. Among Capsalidae species, these features are shared only with species of Dioncus Goto, 1899. Recent molecular evidence has indicated Benedenia is polyphyletic, but with no clear morphological characters available to divide the genus, the 2 new species fit the current concept for the genus more closely than other capsalid genera. Proposal and description of these taxa and accounts of their oncomiracidia and other aspects of their biology indicate potentially useful characters for division of the genus in the future. PMID- 21612416 TI - A new Choleoeimeria species (Apicomplexa: Eimeriidae) infecting the gall bladder of Scincus mitranus (Reptilia: Scincidae) in Saudi Arabia. AB - Choleoeimeria mitranusensis n. sp. is described from the gall bladder of the lizard Scincus mitranus in Saudi Arabia. The prevalence of the infection was 20% (6/30). Oocysts were ellipsoidal and measured 29 um * 20 um. Sporocysts were dizoic and elliptical in shape. The endogenous development was confined to the gall bladder epithelium. Meronts, gamonts, and young oocysts were detected. PMID- 21612417 TI - Taxonomy and distribution of Nonnapsylla Wagner, 1938 (Siphonaptera: Stephanocircidae: Craneopsyllinae). AB - The genus Nonnapsylla Wagner, 1938 (Craneopsyllinae) includes only 1 species, Nonnapsylla rothschildi Wagner, 1938 . Two subspecies are recognized by the shape of the dorsal margin of the helmet, apical shape of the spines in helmet and genal combs, length of first and fourth segments of the maxillary palpus, and shape of the hilla of the spermatheca. The validity of the characters used to separate the 2 subspecies of Nonnapsylla rothschildi Wagner, 1938 is discussed based on information from the literature, as well as from direct observation of type specimens and specimens collected in northwestern Argentina. We conclude that Nonnapsylla rothschildi wagneri Johnson, 1957 should be considered as a synonym of the nominal subspecies. We also extend the southern limits of the distribution of the species and report its presence in Argentina. PMID- 21612418 TI - Parasite volume as an indicator of competition: the case of Acanthocephalus tumescens and Pseudocorynosoma sp. (Acanthocephala) in their intermediate host. AB - In Lake Mascardi (Patagonia), 2 acanthocephalan species, Acanthocephalus tumescens and Pseudocorynosoma sp., share an amphipod intermediate host but have different definitive hosts. Because both acanthocephalan species are potentially capable of manipulating amphipod behavior, one of the parasites may, therefore, have no opportunity to complete its life cycle; accordingly, negative interactions between them can be expected. The purpose of the present work was to examine the possibility of competition in the intermediate host through a comparison of A. tumescens and Pseudocorynosoma sp. cystacanth volume. Specimens of the amphipod Hyalella patagonica were collected monthly over almost 2 yr. Amphipods were measured (total length), necropsied, and cystacanths collected. Cystacanths were also measured, and their volume was calculated. Size of both acanthocepalan species was positively associated with amphipod total length. Competition, during 3 different infection periods, was assessed: high level of Pseudocorynosoma sp. infection (HP), high level of A. tumescens infection (HA), and high level of mixed infection (HM). In Pseudocorynosoma sp., intra-specific competition in HM was the only interaction found. In contrast, in A. tumescens, inter-specific competition in HP, intra-specific competion in HA, and intra- and inter-specific competition in HM were found. We suggest that Pseudocorynosoma sp. is a non-plastic species mostly found in single infections, while A. tumescens is a more variable species occurring more frequently in co-infections. PMID- 21612419 TI - First records of known endoparasitic species of Pseudempleurosoma Yamaguti, 1965 (Monogenoidea: Dactylogyridae) from tetraodontid and rachycentrid fish off the northern coast of the Yucatan Peninsula, Mexico. AB - Monogenoideans infecting the rectum of the wild checkered puffer fish, Sphoeroides testudineus (Tetraodontidae), and the pyloric ceca of the cultured cobia, Rachycentron canadum (Rachycentridae), from the northern coast of the Yucatan Peninsula, Mexico, were morphologically identified as Pseudempleurosoma carangis Yamaguti, 1965 and Pseudempleurosoma gibsoni Santos, Mourao and Cardenas, 2001 (Dactylogyridae), respectively. Morphometric comparison between the paratypes of P. carangis and those from S. testudineus showed that the latter differ only in the length of the body, germarium, and dorsal anchors. Similarly, a small form of P. gibsoni based on body size was detected in the present study. These metric differences may be attributable to the host effect, i.e., S. testudineus/R. canadum versus Caranx lugubris (Carangidae) (type host of P. carangis) from Hawaii and Paralonchurus brasiliensis (Sciaenidae) (type host of P. gibsoni) from Brazil, or by the degree of maturity, or both. In view of these considerations, new illustrations and several supplemental observations for P. carangis and P. gibsoni are provided. The present findings also represent new geographical records, and new sites of infection, e.g., rectum and pyloric ceca, for species of Pseudempleurosoma, and the first known endoparasitic monogenoideans infecting tetraodontid and rachycentrid fishes in Mexico. PMID- 21612420 TI - A new eimerian species (Apicomplexa: Eimeriidae) from the blue-fronted Amazon parrot Amazona aestiva L. (Aves: Psittacidae) in Brazil. AB - The Neotropical psittacine species Amazona aestiva, commonly known as the blue fronted Amazon, is one of the most common and best-known psittacine birds kept as a pet worldwide. However, very little is known about the diseases or parasites of these birds. In this study, we describe a new species, Eimeria aestivae, associated with these parrots. The new species is characterized by: ovoid smooth oocysts (n = 60), 36.8 (33.2-41.5) * 23.7 (21.7-25.7) um, length/width ratio = 1.55; polar granule present; ellipsoidal sporocysts (n = 25), 19.8 (17.5-21.6) * 9.3 (8.3-9.9) um; Stieda, sub-Stieda body, and sporocyst residuum present. Sporozoites (n = 20), 2 per sporocyst, elongate and curved, 17.6 (15.8-19.2) * 3.8 (3.2-4.8) um; each with 2 refractile bodies. The oocysts of the other 2 eimerian species described for Amazona are larger than those of the presented species, but they all seem to be closely related because of some similarities among them. PMID- 21612421 TI - Normal and aberrant Mesocestoides tetrathyridia from Crocidura spp. (Soricimorpha) in Corsica and Spain. AB - Tetrathyridia of Mesocestoides sp. were collected from the body cavities of the shrews (Insectivora), Crocidura russula, in Valencia, Spain and Crocidura suaveolens on the Mediterranean island of Corsica, France. Specimens were processed by routine microscopic and histological techniques, including examination with brightfield, phase-contrast, and differential-interference contrast optics. Most tetrathyridia were clustered together inside host-derived fibrotic capsules, but some occurred free in the body cavity. All specimens examined from both locations had solid hindbodies, i.e., lacking a primary lacuna, thus conforming to the plerocercoid metacestode type; all possessed a single normal tetra-acetabulate scolex. All metacestodes from C. russula in Valencia were normal tetrathyridia. Those from C. suaveolens in Corsica were either normal tetrathyridia or had aberrant deep convolutions of an unusually elongated hindbody. No tetrathyridium from either location or host showed tegumental or excretory duct anomalies such as those reported by several authors from aberrant tetrathyridia and spargana in some other locations. No definitive evidence of asexual proliferation was visible in any of the tetrathyridia, but those with abnormally convoluted hindbodies from a single C. suaveolens in Corsica suggest the potential for asexuality by fission of the hindbody. These results add to our understanding of morphological and developmental variation among metacestodes in this widespread and variable genus. PMID- 21612422 TI - Spatio-temporal dynamics of gastrointestinal helminths infecting four lake whitefish (Coregonus clupeaformis) stocks in northern lakes Michigan and Huron, U.S.A. AB - This study was undertaken to identify the community composition, structure, and dynamics of helminths infecting the gastrointestinal tract (GIT) of lake whitefish (Coregonus clupeaformis) collected from 4 sites in northern lakes Huron (Cheboygan and De Tour Village) and Michigan (Big Bay de Noc and Naubinway) from fall 2003 through summer 2006. A total of 21,203 helminths was retrieved from the GITs of 1,284 lake whitefish. Approximately 42% (SE = 1.4%) of the examined lake whitefish were infected with at least 1 helminth species in their GIT, with a mean intensity of 39.4 worms/fish (SE = 0.3) and a mean abundance of 16.4 worms/fish (SE = 0.1). Collected helminths appeared to be generalists and consisted of 2 phyla (Acanthocephala and Cestoda) and 5 species (Acanthocephalus dirus, Neoechinorhynchus tumidus, Echinorhynchus salmonis, Cyathocephalus truncatus, and Bothriocephalus sp.). Lake whitefish from Lake Huron on average had greater infection prevalences, abundances, and intensities than did fish from Lake Michigan. Infection parameters for each of the helminth species generally followed the same pattern observed for the combined data. Acanthocephalus dirus was the most prevalent and abundant helminth in lake whitefish GITs, although intensity of infection was the greatest for C. truncatus. Helminth infection parameters often peaked in the spring while diversity was greatest in the winter samples. There was substantial temporal variability in helminth infections with prevalences, abundances, and intensities often fluctuating widely on consecutive sampling occasions. Analysis of the GIT helminth community composition suggested that 3 (Big Bay de Noc, De Tour Village, and Cheboygan) of the 4 primary spawning sites, overall, had similar community compositions. The reason for the observed spatial and temporal variability in the lake whitefish GIT helminth infections remains to be elucidated. The findings of this study represent the most comprehensive parasitological study ever conducted on lake whitefish in the Great Lakes and will provide valuable information for future comparisons. PMID- 21612423 TI - Bacterial load of fresh vegetables and their resistance to the currently used antibiotics in Saudi Arabia. AB - This study was carried out to describe the bacterial load and the occurrence of some disease-causing enteric bacteria on raw vegetables sold in Saudi markets. The study further aimed to analyze antibiotic resistance rates, production of extended-spectrum beta lactamase, and plasmid carriage among bacterial population of raw vegetables. Results revealed that none of them contained Bacillus cereus, Salmonella, and Escherichia coli O157:H7. However, Staphylococcus aureus and Shigella were detected in 11.8% and 4.4% of the samples, respectively. The bacterial loads ranged from 3 to 8 log(10) CFUg(-1) for aerobic bacteria and 1 to 4 log(10) CFUg(-1) for coliforms as well as Enterobacteriaceae. The isolates exhibited resistance in decreasing order for ampicillin (76.5%), cephalothin (69.5%), trimethoprime-sulfamethoxazole (36.7%), aminoglycosides (21.9%), tetracycline (17.2%), fluoroquinolones (17.2%), amoxycillin-clavulanic acid (13.3%), and chloramphenicol (7.8%). Maximum resistance to extended-spectrum beta lactam antibiotics occurred in 14.8% of isolates and the production of extended spectrum beta-lactamase was achieved by 2.3% of isolates. Multiple resistances to four or more antimicrobial agents along with plasmid with varied sizes were documented. These investigations indicate the occurrence of antibiotic resistance and plasmid carriage among bacterial isolates populating raw vegetables. PMID- 21612424 TI - Molecular epidemiological investigation of a diffuse outbreak caused by Salmonella enterica serotype Montevideo isolates in Osaka Prefecture, Japan. AB - In Osaka Prefecture, Japan, three foodborne outbreaks were caused by Salmonella enterica serotype Montevideo in rapid succession between September 2007 and May 2008. Further, Salmonella Montevideo was also isolated from several sporadic diarrhea patients and asymptomatic carriers examined during approximately the identical period. To investigate the relatedness of the isolates, we performed antimicrobial susceptibility testing, pulsed-field gel electrophoresis (PFGE) analysis, and multiple-locus variable-number tandem repeat (VNTR) analysis (MLVA) for 29 Salmonella Montevideo isolates obtained in this region between 1991 and 2008. Although antimicrobial susceptibility tests had low discriminatory power, PFGE patterns revealed 17 unique types with <90% similarity in combined analyses involving XbaI and BlnI. Moreover, we detected three VNTR loci that were useful to genotype Salmonella Montevideo isolates, with our method ultimately classifying the isolates into 11 MLVA types based on differences in repeat unit number in each examined locus. Six isolates obtained from patients of two separate foodborne disease outbreaks, one sporadic patient, and three different carriers between 2007 and 2008 had nearly identical PFGE patterns and were classified into the identical MLVA type; further, the isolates with this PFGE and MLVA pattern appeared only at that time between 1991 and 2008. These data strongly suggest that genetically identical Salmonella Montevideo strains may have caused the 2007 and 2008 outbreaks in Osaka Prefecture. Our results demonstrate that PFGE using XbaI and BlnI is useful for discriminating between Salmonella Montevideo isolates, even within a limited area, and reconfirm that continuous epidemiological surveillance for bacterial intestinal infections such as salmonellosis may be useful to not only monitor changes in the genetic diversity of isolates, but to also detect diffuse outbreaks. PMID- 21612425 TI - Synergistic effects and physiological responses of selected bacterial isolates from animal feed to four natural antimicrobials and two antibiotics. AB - In this study, 20 samples from three different sources of animal feed were investigated and six bacterial isolates were identified. The susceptibility of four natural antimicrobials, namely, eugenol, cinnamaldehyde, thymol, and carvacrol, against six of these isolates was determined. Carvacrol and eugenol showed better inhibitory effects with larger zones of inhibition. The minimal inhibitory concentration for a range of antibiotics on the susceptibility of two isolates (namely, Sphingomonas paucimobilis and Klebsiella oxytoca) was investigated using the VITEK(r) 2 microbiological identification system. Both isolates showed a variety of resistance to 18 antibiotics. The minimal inhibitory concentration and fractional inhibitory concentration index of those two isolates for ampicillin and nitrofurantoin in combination with four phenolic compounds was determined. Synergistic interactions were found for most antimicrobial/antibiotic combinations; thymol and carvacrol were very effective (fractional inhibitory concentration <=0.5) in combination with all antibiotics tested against S. paucimobilis and K. oxytoca, respectively. Ultra performance liquid chromatography techniques were used to investigate the physiological effects of the four natural antimicrobials against those two isolates. Two identical peaks were found to be systematically different between cinnamaldehyde-treated and untreated cells. The identity of the peaks is unknown and further investigation is needed. PMID- 21612426 TI - Mycobacterium avium Subsp. avium and Salmonella enterica serotype Typhimurium var. Copenhagen phage type DT2 in pigeons. AB - We report on a coinfection of Mycobacterium avium subsp. avium and Salmonella enterica serotype Typhimurium var. Copenhagen phage type DT2 in pigeons from one flock, from which squabs were occasionally consumed by humans. Triplex quantitative real-time PCR and culture methods were used for M. a. avium detection in livers and culture method was used for the detection of Salmonella sp. in samples of liver and caecum of 33 examined birds. M. a. avium was detected in a total of 31 (93.9%) and Salmonella Typhimurium in a total of 11 (33.3%) pigeons. Coinfection with both pathogens was found in 10 (30.3%), infection with Salmonella Typhimurium alone in 1 (3.0%), and infection with M. a. avium alone in 21 (63.7%) pigeons. Neither pathogen was detected in one pigeon. There was no difference in clinical symptoms exhibited by pigeons infected by M. a. avium and/or Salmonella Typhimurium. All Salmonella Typhimurium isolates were sensitive to all 15 antimicrobials tested. According to these results we emphasize good heat treatment of consumed squabs. PMID- 21612427 TI - Development and evaluation of a real-time polymerase chain reaction assay targeting iap for the detection of Listeria monocytogenes in select food matrices. AB - Listeria monocytogenes is an intracellular foodborne pathogen that has been associated with severe human illnesses. Various rapid detection methods have been developed for the specific detection of this pathogen. In the present study, a real-time quantitative polymerase chain reaction (PCR) assay targeting iap, a gene encoding extracellular protein p60, was developed for L. monocytogenes. The PCR efficiency is above 85% and the limit of detection (LOD) is 30 copies of genome per reaction for all strains tested. The assay exhibited 100% inclusivity and exclusivity rates. The detection of L. monocytogenes in five food matrices, whole milk, soft cheese, turkey deli meat, smoked salmon, and alfalfa sprouts, was evaluated with and without enrichment. Without enrichment, the LOD for all food matrices were 4*10(3) CFU/mL food enrichment mix for whole milk and 4*10(4) CFU/mL for all other foods. With 24 h incubation in Buffered Listeria Enrichment Broth, the LOD was 3 CFU/25 g food for whole milk, turkey deli meat, and smoked salmon and 9 CFU/25 g food for soft cheese and alfalfa sprouts. With 48 h incubation, the LOD was 3 CFU/25 g food for all matrices. This quantitative PCR appears to be a promising alternative for rapid detection of L. monocytogenes in select foods. PMID- 21612428 TI - Testing of buccal swab DNA does not increase the detection rate for imprinting control region 1 hypomethylation in Silver-Russell syndrome. AB - Silver-Russell syndrome (SRS) is a congenital imprinting disorder mainly characterized by growth restriction, a triangular shaped face, a relative macrocephaly, and asymmetry of the body and the limbs. In 7%-10% of the patients a maternal uniparental disomy of chromosome 7 (upd(7)mat) can be observed; a hypomethylation of the imprinting control region 1 (ICR1) in 11p15 is present in >38% of patients. Methylation-specific multiplex ligation-dependent probe amplification is a well-established method for the detection of (epi)mutations in 11p15. In routine diagnostics, DNA samples derived from leukocytes are used for this testing approach. We now analyzed buccal smear DNA taken from both cheek sides of 8 carriers of an ICR1 hypomethylation and 25 SRS patients without 11p15 epimutaton or upd(7)mat to check whether (i) the epimutation can be detected in other tissues and (ii) the detection rate can be increased. Indeed, the ICR1 hypomethylation diagnosed in blood cells could be confirmed in the buccal swab DNA of all 11p15 epimutation carriers, but we could not discover any further carriers among the patients without 11p15 epimutation and upd(7)mat in lymphocytes. Thus, the overall detection rate for the 11p15 epimutation could not be increased by including further tissues originating from different germ layers. We rather assume that other-so far unknown-(genetic) factors are contributing to the etiology of SRS that escape the current diagnostic procedures. PMID- 21612429 TI - Guarana (Paullinia cupana) improves fatigue in breast cancer patients undergoing systemic chemotherapy. AB - BACKGROUND: In patients with breast cancer (BC) undergoing systemic chemotherapy, cancer-related fatigue (CRF) is a common problem that can negatively impact quality of life. Guarana (Paullinia cupana) is a plant native to the Amazon basin that has been used as a stimulant since pre-Columbian times. OBJECTIVE: The purpose of this study was to evaluate the effectiveness of guarana extract on fatigue, sleep quality, anxiety, depression symptoms, and menopause in a group of BC chemotherapy patients. PATIENTS AND METHODS: Patients with progressive fatigue after their first cycle of chemotherapy were randomized to receive either guarana 50 mg by mouth twice daily (32 patients) or placebo (43 patients) for 21 days. After a 7-day washout period, patients were crossed over to the opposite experimental arm. All patients were evaluated on days 1, 21, and 49. The primary endpoint was the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT F) questionnaire score, and secondary endpoints were the results of the Functional Assessment of Chronic Illness Therapy-Endocrine Symptoms (FACT-ES), Brief Fatigue Inventory (BFI), Pittsburg Sleep Quality Index, Chalder Fatigue Scale, and Hospital Anxiety and Depression Scale. RESULTS: Guarana significantly improved the FACIT-F, FACT-ES, and BFI global scores compared to placebo on days 21 and 49 (p < 0.01). The Chalder Scale improved significantly on day 21 (p < 0.01) but not on day 49 (p = 0.27). Guarana did not produce any Common Terminology Criteria for Adverse Events grades 2, 3, or 4 toxicities and did not worsen sleep quality or cause anxiety or depression. CONCLUSIONS: Guarana is an effective, inexpensive, and nontoxic alternative for the short-term treatment of fatigue in BC patients receiving systemic chemotherapy. Further studies are needed to confirm these results and to evaluate their generalizability to chronic CRF and to other types of cancer. PMID- 21612432 TI - Patients with end-stage renal disease are candidates for robot-assisted laparoscopic radical prostatectomy. AB - BACKGROUND AND PURPOSE: Patients with end-stage renal disease (ESRD) have multiple comorbidities that place them at increased risk for surgical complications. Consequently, patients with both ESRD and prostate cancer (PCa) have rarely been considered candidates for radical prostatectomy. The objective of this study is to compare ESRD patients who are undergoing robot-assisted laparoscopic prostatectomy (RALP) with a cohort of patients with no history of dialysis. PATIENTS AND METHODS: A retrospective review was conducted of 430 patients who were undergoing RALP, including 12 receiving dialysis at the time of surgery. Preoperative demographics, perioperative parameters, and postoperative outcomes were compared using a two-tailed Student t test and a chi-square test, with significance at P<0.05. RESULTS: Patient demographics including body mass index, Gleason score, and prostate-specific antigen (PSA) value were similar between the two groups. Patients with ESRD had younger age (55.5 vs 62.9 years; P<0.01), higher American Society of Anesthesiologists scores (3.7 vs 2.5; P<0.01), and higher age-adjusted Charlson Comorbidity Index scores (6.2 vs 4.2; P<0.01). Patient outcomes including operative time, estimated blood loss, complication rate, postoperative stay, and positive margins did not differ significantly between groups. No ESRD patients needed pads or had a detectable PSA level using an ultrasensitive assay. CONCLUSIONS: This series represents the largest series of patients with ESRD undergoing RALP. These patients experienced similar outcomes compared with patients with no history of dialysis despite greater preoperative comorbidity. RALP produces minimal fluid shifts, low blood loss, and excellent cancer control, making it an ideal treatment option to prepare patients with both ESRD and PCa for renal transplantation. PMID- 21612433 TI - Management of solitary renal pelvic stone: laparoscopic retroperitoneal pyelolithotomy versus percutaneous nephrolithotomy. AB - BACKGROUND AND PURPOSE: Percutaneous nephrolithotomy (PCNL) is considered the main management option for large single renal pelvic stones; however, laparoscopic retroperitoneal pyelolithotomy (LRP) can be used as an alternative management procedure. We compare both procedures in the management of solitary large renal pelvic stones. PATIENTS AND METHODS: Between June 2002 and July 2010, 105 patients with solitary large renal pelvic stones were selected and randomly divided into two groups; group 1 included 55 patients who were treated by LRP and group 2 included 50 patients who were treated by PCNL. The differences between the two procedures were compared and analyzed. RESULTS: There was no difference between the two groups regarding patient demographics and stone size. There was no statistically significant difference between LRP and PCNL regarding mean estimated blood loss (166.4+/-98.3 mL vs 178+/-102.4 mL), mean hospital stay (4.5+/-1.9 d, vs 4.4+/-1.4 d), mean time of postoperative analgesia (2.2+/-0.9 d vs 2.4+/-0.9 d), rate of postoperative blood transfusion (5.5% vs 6%), and stone free rate (100% vs 96%). The mean operative time was significantly longer in the LRP group (130.6+/-38.7 min vs 108.5+/-18.7 min), respectively. There was only one (1.8%) case from the laparoscopy group converted to open surgery because of uncontrolled bleeding. CONCLUSION: RLP is a suitable surgical technique for patients with large renal pelvic stones but with good selection of cases; however, PCNL remains the standard treatment in most cases. PMID- 21612434 TI - Transurethral GreenLight laser enucleation of the prostate--a feasibility study. AB - BACKGROUND AND PURPOSE: GreenLight laser vaporization is established as a minimally invasive procedure to treat patients with benign prostatic hyperplasia. Despite good functional results, it may be difficult to achieve adequate tissue removal for large prostates. In this study, we evaluated whether a transurethral enucleation technique is feasible with the GreenLight laser as a possible way to improve the amount of tissue removed. PATIENTS AND METHODS: Following the technique described by Gilling for the holmium laser, we carried out transurethral enucleation of prostate adenoma with the 120W HPS GreenLight laser in 21 consecutive patients. Preoperative data were collected prospectively; prostate volume, International Prostate Symptom Score (IPSS), postvoid residual (PVR), prostate-specific antigen level, peak urinary flow rate, operative time, catherization period, length of hospitalization, and perioperative complications were recorded as well as the weight of the enucleated tissue and the applied laser energy. For follow-up, IPSS and PVR were recorded. Data are presented as mean+/-standard deviation. RESULTS: Fifty-two percent of the patients had preoperative urinary retention. Preoperative prostate volume was 74.6+/-21.7 cc; 34.7+/-21.7 g of tissue were enucleated. IPSS was reduced from 25+/-6 to 5+/-9 (P=0.0001), PVR from 126+/-80 to 11+/-18 (P=0.002) by GreenLight laser enucleation. Serious complications were not observed. Operative time was 112+/-27 minutes. Catheter time was 1.2+/-0.4 days. The length of hospitalization was 3.6+/-0.9 days. CONCLUSION: GreenLight laser enucleation is feasible and safe. Tissue reduction is complete, and good functional results are achieved. All patients were able to void properly. Major complications were not observed. The procedure is technically demanding, resulting in long operative times at the first interventions. PMID- 21612436 TI - Progress report on the CROES studies. PMID- 21612437 TI - Authors' response to letter to the editor: Re: Laparoscopic resection of local recurrence after previous radical nephrectomy for clinically localized renal-cell carcinoma: perioperative outcomes and initial observations (Citation: Tsivian A, Tsivian M, and Sidi AA, J Endourol 2011;25:705). PMID- 21612441 TI - Discovery and characterization of a fructosylated capsule polysaccharide and sialylated lipopolysaccharide in a virulent strain of Actinobacillus suis. AB - We are developing a serotyping system for Actinobacillus suis based on its capsule (K) and lipopolysaccharide O-chain (O) structures. Previously, we have shown that less virulent strains of this swine pathogen express a (1->6)-beta-D glucan as both K- and O-chain polysaccharides and were serologically classified as K:1/O:1. Here, we show that representative A. suis strains with a high (H91 0380; serotype K:2/O:2) and intermediate (C84; serotype K:2/O:1) degree of virulence possess a capsule polysaccharide (K:2) composed of an O-acetylated diglycosyl phosphate repeat decorated with fructose: [->4)-3-O-Ac-beta-D-GlcpNAc (1->3)-[beta-D-Fruf-(2->2)]-alpha-D-Galp-(1->PO(4)(-)->]. In addition, the serotype O:2 lipopolysaccharide was shown to express a sialylated O-chain [->3) beta-D-Galp-(1->4)-[Neu5Ac-(2->3)-alpha-D-Galp-(1->6)]-beta-D-Glcp-(1->6)-beta-D GlcpNAc-(1->]. As (1->6)-beta-D-glucan is ubiquitous in the environment, low levels of antibodies in the animals are predicted to prevent disease by K:1/O:1 strains. The greater potential associated with K:2/O:2 and K:2/O:1 strains is most likely due to the absence of (1->6)-beta-D-glucan as the K antigen and, in the case of K:2/O:2, the presence of sialic acid in the lipopolysaccharide, a nonulosonic acid known to promote evasion of host recognition. PMID- 21612442 TI - Natural antibodies against bone morphogenic proteins and interferons in healthy donors and in patients with infections linked to type-1 cytokine responses. AB - In patients receiving recombinant therapeutic proteins, the production of antibodies against the therapeutics is a rising problem. The antibodies can neutralize and interfere with the efficacy and safety of drugs and even cause severe side effects if they cross-react against the natural, endogenous protein. Various factors have been identified to influence the immunogenic potential of recombinant human therapeutics, including several patients' characteristics. In recent years, so-called naturally occurring antibodies against cytokines and growth factors have been detected in naive patients before start of treatment with recombinant human therapeutics. The role of naturally occurring antibodies is not well understood and their influence on production of anti-drug antibodies is not known. One might speculate that the presence of naturally occurring antibodies increases the likelihood of eliciting anti-drug antibodies once treatment with the corresponding recombinant therapeutic protein is started. We screened serum samples from 410 healthy controls and patients for auto-antibodies against bone morphogenetic proteins (BMPs) 2 and 7 and interferon (IFN)-alpha, beta, and -gamma in a new 3-step approach: rough initial screening, followed by competition and protein A/G depletion. Naturally occurring antibodies against these proteins were detected in 2% to 4% of the tested sera. Individuals who are 65 years or older had a slightly higher occurrence of naturally occurring antibodies. Auto-antibodies against BMP-7 and IFN-alpha were mainly comprised of IgM isotypes, and natural antibodies against BMP-2, IFN-beta, and -gamma were mainly IgG. To ensure assay specificity, assays were also used to detect antibodies against BMP-7 in patients being treated with rhBMP-7 before and after surgical procedure. Fifty percent of the treated patients had persistent anti-BMP 7 antibodies over time. The 3-step approach provides an attractive tool to identify naturally occurring antibodies in naive patients. PMID- 21612443 TI - Neutrophil gelatinase-associated lipocalin in gastric carcinoma cells and its induction by TPA are controlled by C/EBPbeta. AB - Neutrophil gelatinase-associated lipocalin (NGAL) expression has been found to be upregulated in a variety of tumors, but the mechanism of NGAL elevation in gastric carcinoma remains unknown. Here, immunohistochemistry was applied to analyze NGAL expression in gastric carcinoma patients. Reverse transcription PCR, Western blot, and enzyme-linked immunosorbent assay (ELISA) were performed to evaluate NGAL mRNA and protein levels before and after 12-O-tetradecanoylphorbol 13-acetate (TPA) induction. Luciferase reporter assay was carried out to identify the core cis element in NGAL promoter. The binding ability and specificity of transcription factors were analyzed by electrophoretic mobility-shift assay (EMSA) and chromatin immunoprecipitation (ChIP), respectively. Results showed that NGAL was overexpressed in gastric tumor tissues. Gastric cancer cells treated with TPA resulted in the transactivation of NGAL promoter and the upregulation of its mRNA and protein levels. We identified the -110 to -79 sequence segment upstream from the transcription initiation site of NGAL as a TPA responsive element (TRE) and confirmed that C/EBPbeta was able to bind to the -87 to -79 segment. Forced expression of C/EBPbeta significantly increased the promoter activity of NGAL as well as its mRNA level. These results suggest that NGAL is overexpressed in gastric cancer, the binding of C/EBPbeta to the TRE of its gene promoter mediates its TPA-induced overexpression in gastric carcinoma cells. PMID- 21612444 TI - Regarding: Carbon dioxide pneumoperitoneum prevents postoperative adhesion formation in a rat cecal abrasion model. PMID- 21612445 TI - Revision surgery for incidentally detected early gallbladder cancer in laparoscopic era. AB - BACKGROUND: Incidentally detected early gallbladder cancer (IDEGB) is an early carcinoma first diagnosed on microscopic examination after a cholecystectomy for symptomatic benign gallbladder disease. After diagnosis of IDEGB it is often necessary a completion of treatment by a second tailored revision procedure. Despite early reports contraindicating laparoscopic approach because of high risk of neoplastic seeding, recent data seem to demonstrate that this approach per se does not influence clinical outcomes. We refer our experience in revision surgery by a totally laparoscopic approach that includes hepatic resection, lymphadenectomy, and port-sites excision. METHODS: From January 2006 to March 2008, four patients with IDEGB were carried out to revision procedure by a totally laparoscopic approach. The mean operative time of procedure has been 162 minutes, whereas blood loss has been <100 mL (mean 85.1+/-23.3 mL). The postoperative course has been uneventful in all patients and perioperative mortality (within 40 days from intervention) 0. Hospital stay has been, respectively, 4, 5, 5, and 6 days (mean 5 days). During follow-up, at the last fluorine-18-labeled fluordesoxyglucose-positron emission tomography (FDG-PET) scan examination, respectively, 4, 3, and--for 2 patients--2 years after revision laparoscopic procedure, pathologic FDG accumulation was not reported. CONCLUSIONS: Totally laparoscopic revision surgery for IDEGC seems to be a legitimate procedure, and, in our experience, reports satisfactory clinical outcomes in terms of perioperative and middle term oncological results. Larger and prospective studies are needed to support definitively oncological safety of this approach. PMID- 21612446 TI - Transumbilical single-port laparoscopic-assisted vaginal hysterectomy via 12-mm trocar incision site. AB - BACKGROUND: Single-port laparoscopic-assisted vaginal hysterectomy (S-LAVH) uses only one transumbilical incision site and has better cosmetic result than conventional multiport LAVH. This study aimed to evaluate our initial experience with S-LAVH compared with the more conventional three-port LAVH in women with benign uterine diseases. METHODS: Between April 2009 and April 2010, S-LAVH was attempted on 183 patients with benign uterine diseases through a transumbilical incision for a 12-mm trocar, and conventional LAVH was performed on 275 patients by the same surgeon. The medical records of patients were reviewed. The age, body mass index, operative time, blood loss, and uterine weight on pathologic report were compared. RESULTS: Two of 183 patients in the S-LAVH group were converted to two- or three-port surgery, compared with none in the conventional group. Data analysis was done for 181 patients in the S-LAVH group and 275 patients in the conventional LAVH group. No major complications, including ureteral or bladder injuries, occurred in any of the patients. No statistically significant differences were found in mean age, mean body mass index, mean operative time, mean anesthesia time, mean estimated blood loss, or mean postoperative days to passage of flatus, but the mean uterine weights on the pathologic reports were significantly reduced in the S-LAVH group. CONCLUSION: S-LAVH could be a feasible alternative method for removal of the uterus with a better cosmetic outcome resulting from single wound in selected patients. For patients with large-sized uterus, more surgical experience and improvement in instruments suitable for S LAVH are needed. PMID- 21612447 TI - Closure of ascites leaks with fibrin glue injection in patients with end-stage liver disease. AB - BACKGROUND: Ascites leaks (AL) in patients with end-stage liver disease (ESLD) are associated with significant morbidity and mortality regardless if they are medically or surgically managed. PATIENTS AND METHODS: In a pilot study, 14 ESLD patients with AL underwent treatment with fibrin glue injection around the leak after failing conservative therapy. The end point of this study was the cessation of AL in the short term and the maintenance of a leak-free abdomen in the long term, allowing for medical optimization of the patients. RESULTS: Median age of the 10 men and 4 women was 50 (range 26-67) years. Underlying ESLDs were chronic hepatitis C (n=5), alcoholic LD (n=2), cryptogenic cirrhosis (n=2), and miscellaneous (n=5). There were six leaking incisions posthernia repair (three umbilical and three inguinal), two leaking/ruptured umbilical hernias, four leaking paracentesis sites, one leaking Jackson-Pratt (JP) drain canal, and one leaking laparoscopic trocar site. Average AL volume per day was 1000 (range 400 2000) mL. All leaks were immediately resolved with a 3-5 mL fibrin glue injection. Five recurred and required a second injection (four within 24 hours). Mental status improved in 7 patients (West Haven Criteria: grade II to I [n=6], grade III to I [n=1]). Median model of end-stage liver disease scores improved from 23 (range 8-33) to 20 (range 14-26). There were no infections, bleeds, or other injection-related complications. Average follow-up for these patients was 441.6 days (range 2-852). Five patients underwent liver transplant (LT) median 15 (range 4-270) days postinjection; 2 of them died. Another 3 patients died (2 from sepsis and 1 from metastatic cancer). CONCLUSION: Fibrin glue injection for the control of AL is a simple and safe bedside procedure that quickly controls AL, allowing for patient recovery in anticipation of further care. PMID- 21612448 TI - Comparison of results of laparoscopic gastric banding and consecutive intragastric balloon application at 18 months: a clinical prospective study. AB - BACKGROUND: Obesity is a serious health problem that leads to serious physical and psychological problems. The methods used in treating obesity include diet and behavioral changes, pharmacotherapy, and surgery. Laparoscopic adjustable gastric banding (LAGB) and intragastric balloon (IGB) applications are two of the methods used to treat obesity. The aim of this study was to compare the effects of LAGB with those of two consecutive IGB applications in weight loss management of obese patients. METHODS: Thirty-two patients (F/M:24/8) admitted in the study were divided into two groups. In the first group of 16 patients, LAGB was performed, and in the other group two consecutive IGBs were applied. Total weight loss, body mass index (BMI), excess weight loss percent (EWL %), and excess body mass index loss percent (EBMIL %) were recorded at months 6, 12, and 18 for both groups. RESULTS: At the end of the 6th month, BMI values of LAGB and IGB groups were 36.0 and 30.6 kg/m(2), EWL % were 32.3% and 39.3%, and EBMIL % were 36.3% and 47.1%, respectively. The results were similar. At the end of 12 months, median BMI was 36.6 kg/m(2) for LAGB and 27.5 kg/m(2) for IGB (P<.05). The EWL % and EBMIL % at the end of the 12th month were 57% and 70%, which is significant in favor of IGB. The last evaluation was made at the 18th month of applications, and the three parameters for two applications were found to be similar. CONCLUSIONS: The achieved weight losses at the 6th month were similar for both groups. However, at the 12th month, two consecutive IGB applications were more effective. At the end of the 18th month, the results were again similar. Two consecutive IGB applications may be offered to obese patients who do not feel ready for surgery. PMID- 21612449 TI - Laparoscopic ventral hernia repair: a comparative study of transabdominal preperitoneal versus intraperitoneal onlay mesh repair. AB - BACKGROUND: Laparoscopic ventral hernia repair is evolving rapidly worldwide to become a standard procedure. The purpose of this study was to compare the benefits, effectiveness, and postoperative outcome of laparoscopic transabdominal preperitoneal (TAPP) and intraperitoneal onlay mesh (IPOM) repair of ventral hernia. PATIENTS AND METHODS: Prospectively collected data of 279 patients who underwent laparoscopic ventral hernia repair between January 2005 and December 2009, of whom 68 underwent TAPP and 211 underwent IPOM repair, were retrospectively reviewed. For each patient demographic, preoperative and postoperative data were studied. Statistical analysis was performed by Student's t-test, Fisher exact test, and chi-square test. RESULTS: The study included a total of 279 patients, of whom 68 underwent TAPP procedure and 211 underwent IPOM procedure. Both the groups were comparable in age, sex, body mass index, American Society of Anesthesiologists score, mean fascial defect size, and mean size of mesh. Although the operating time was longer in TAPP group than IPOM group of patients, the overall cost of surgery in IPOM group ($752.3+/-355.7) was much higher than TAPP group ($903.6+/-28.0) of patients. Seroma formation was more common in IPOM group than TAPP group (8.5% versus 5.8%). There were 2 (2.9%) recurrences in TAPP group and 7 (3.3%) in IPOM group of patients. Mean postoperative hospital stay (1.5+/-0.6 versus 1.4+/-0.7 days, P=.35) and mean follow-up (22.7+/-13.4 versus 22.5+/-11.9 months, P=.90) were similar in both groups of patients. CONCLUSION: Besides the cost-effectiveness of TAPP procedure, it reduces the risk of complication related to intra-abdominal position of mesh and fixating devices. Before we label the TAPP repair of ventral hernia as the first choice, a comparative multicentric prospective trial with IPOM repair is warranted. PMID- 21612450 TI - The endoscopic latissimus dorsi flap harvest: advantages and technical drawbacks. PMID- 21612451 TI - Innovations in surgery: the role of residents in the implementation of laparoscopic hysterectomy. AB - BACKGROUND: Laparoscopic hysterectomy (LH) is poorly adopted by general gynecologists. The aim of this study was to assess the differences between residents, general gynecologists, and laparoscopic-orientated gynecologists in the choice of surgical route in patients planned for hysterectomy. METHODS: An observational study was carried out at a teaching hospital in south of The Netherlands. All patients who were planned for a hysterectomy for benign or premalignant indications between January 2005 and April 2009 were included. All performed hysterectomies were evaluated for the planned surgical route: vaginal, abdominal, or LH. Surgeons were divided into three categories: residents, general gynecologists, and laparoscopic-orientated gynecologists. RESULTS: One hundred thirty-nine (35.8%) patients were planned for a vaginal approach, 151 (38.9%) for an abdominal approach, and 98 (25.2%) for a laparoscopic approach. The percentage of planned vaginal hysterectomies was comparable for all surgeons. There was a significant difference between the percentage of planned LHs by residents (30%) and that by general gynecologists (6%). As expected, laparoscopic-orientated gynecologists planned a laparoscopic approach in 53% of their cases. CONCLUSIONS: LH as alternative to abdominal hysterectomy is rarely planned by general gynecologists. Residents could play a role in the implementation of LH. PMID- 21612452 TI - Antimicrobial properties of green tea extract against cariogenic microflora: an in vivo study. AB - The aim of the present study was to test in vivo the effectiveness of an experimental green tea extract in reducing levels of mutans streptococci and lactobacilli in saliva by means of selective culture medium. Sixty-six healthy patients ranging in age from 12 to 18 years were recruited and randomly divided into two groups: Group A (n=33) and group B (n=33). Group A subjects were asked to rinse their mouths with 40 mL of an experimental green tea extract, for 1 minute, three times a day for a week, whereas Group B subjects were asked to rinse with 40 mL of a placebo mouth rinse. Saliva samples were obtained at baseline, 4 days, and 7 days. The counts of mutans streptococci and lactobacilli were investigated by chair-side kits. Data were statistically processed. A regression binary logistic analysis was done. The statistical significance level was established at P<.05. The experimental group showed a statistically significant reduction in colony counts of mutans streptococci and lactobacilli relative to the control group. These findings showed the efficacy of a green tea extract against cariogenic oral flora, opening a promising avenue of clinical applications in the preparation of specific and natural anticariogenic remedies. PMID- 21612453 TI - Ursolic acid, a pentacyclic triterpene from Sambucus australis, prevents abdominal adiposity in mice fed a high-fat diet. AB - Currently, there is renewed interest in plant-based medicines and functional foods for the prevention and cure of obesity and its associated risk of cardiovascular disease and metabolic syndrome. In the search for potential anti obesity compounds from natural sources, the effects of ursolic acid (UA), a pentacyclic triterpenoid widely found in medicinal herbs and fruits, was evaluated for its effects on blood glucose, lipids, and abdominal fat deposition in mice fed a high-fat diet (HFD). Adult male Swiss mice treated or not with UA (0.05%, 50 mg/L, in drinking water) were fed HFD for 15 weeks. A sibutramine (SIB)-treated group (0.05% in drinking water) was included as the positive control. Weekly body weights and food and water consumption were measured, and at the end of the study period, the levels of blood glucose and lipids, the plasma hormones insulin, ghrelin, and leptin, and the abdominal fat accumulation were analyzed. Mice treated with UA and fed HFD showed significantly (P<.05) decreased body weights, visceral adiposity, and levels of blood glucose and plasma lipids relative to their respective controls not fed UA. Also, a significant increase was observed in plasma leptin with a decrease in ghrelin, as well as of amylase and lipase activities. The SIB-treated group also manifested effects similar to those of UA except for the blood glucose level, which was not different from the HFD control. These findings suggest that UA ameliorates abdominal adiposity and decreases the levels of blood glucose and plasma lipids in mice and thus manifests an anti-obesity potential through absorptive and metabolic targets. PMID- 21612454 TI - In vitro antibacterial, phototoxic, and synergistic activity of ethanol extracts from Costus cf. arabicus L. AB - In this study, ethanol extracts of stems and leaves of Costus cf. arabicus L. were evaluated for antibacterial activity against multidrug-resistant strains of Escherichia coli and Staphylococcus aureus. The antibacterial and modulatory activities of the extracts were assayed by microdilution. The light-enhanced antibacterial activity was assayed by a light regimen. The growth of the bacteria tested was not inhibited by the extracts. The minimum inhibitory concentration values were >=1,024 MUg/mL. However, the antibiotic activity of aminoglycosides was synergistically enhanced when these extracts at subinhibitory concentrations were combined with the antibiotics. Also, both extracts showed activity against the wild-type bacterial strains, but the leaf extract was the more active extract, being active against both S. aureus and E. coli. Therefore, we conclude that the ethanol extracts of stems and leaves of C. cf. arabicus L. have potential light-induced antibacterial activity and synergistic antibiotic activity. This study showed that these extracts may be a promising source of antibacterial and modulatory agents. PMID- 21612455 TI - Impact of food and herbal medication on calcineurin inhibitor dose in renal transplant patients: a cross-sectional study. AB - The incidence and severity of interactions of herbal products with calcineurin inhibitor (CNI) metabolism in renal transplant recipients have not been systematically investigated. These patients have a high rate of herbal product consumption, including products interfering with CNI metabolism. The study aimed at identifying an impact of herbs and foods on CNI metabolism in a cohort of renal transplant recipients by conducting dietary interviews (1) in patients with very low and high CNI maintenance dose requirements and (2) by retrospective analysis of unexplained marked deviations from CNI baseline trough levels. Of 73 renal transplant recipients, 59 were treated with a CNI-based immunosuppressive regimen. Seven patients with an exceptionally high or low CNI dose were interviewed. Five of these seven patients had not consumed any plant product with known influence on CNI metabolism. In one patient chicory-coffee and bitter chocolate had been suspected as contributing to high CNI dose requirement, but the dose could not be lowered after discontinuation of these foods. Participating nephrologists reported three as yet unexplained temporary deviations from baseline CNI trough levels, of which two could be linked to newly started consumption of high volumes of herbal teas and the other to St. John's wort. Consumption of herbal products within the study cohort had no detectable impact on maintenance doses of CNI. However, herbal products, and specifically teas when consumed by the liter, could be linked to temporary strong deviations from CNI trough levels. The study demonstrates that as yet unnoticed herbal interactions with CNI can be detected by detailed dietary analysis, but that the overall impact on maintenance doses of CNI appears to be low. PMID- 21612456 TI - In vivo antigenotoxic and anticlastogenic effects of fresh and processed cashew (Anacardium occidentale) apple juices. AB - Cashew apple juice and cajuina (processed juice) are drinks widely consumed in northeast Brazil. In vitro studies have shown that both juices have antimutagenic activity as well as antioxidant effects. These juices contain vitamins, carotenoids, and phenolic compounds. This in vivo study assessed the antigenotoxic and anticlastogenic effects of both drinks against genotoxicity and mutagenicity induced by cyclophosphamide. The comet, micronucleus, and chromosome aberrations tests were used. Male Swiss mice were divided into 6 groups (5 animals per group) and received the following by gavage, 0.15 mL/10 g body weight: group 1, water; group 2, cashew apple juice; group 3, cajuina juice; group 4, cashew apple juice and cyclophosphamide (50 mg/kg); group 5, cajuina juice and cyclophosphamide; group 6: cyclophosphamide. Both drinks significantly reduced DNA damage of peripheral blood cells (P<.001), with modulation percentages of 60.82% (cashew apple juice) and 82.19% (cajuina) when compared with the cyclophosphamide group. Cashew apple juice and cajuina modulated cyclophosphamide-induced micronucleus frequency, with up to 80.0% inhibition. Cashew apple juice and cajuina decreased the average number of cells with chromosome aberrations in bone marrow of mice by 53% and 65%, respectively. These findings demonstrate the high antigenotoxic and anticlastogenic potential of cashew apple juice and cajuina in vivo, which can be related to the antioxidant compounds found in both drinks. PMID- 21612457 TI - Inhibition of aromatase and alpha-amylase by flavonoids and proanthocyanidins from Sorghum bicolor bran extracts. AB - We compared the ability of simple flavonoids and proanthocyanidins in Sorghum bicolor bran extracts to inhibit enzymes in vitro. In particular, aromatase is a target for breast cancer therapy, and inhibition of alpha-amylase can reduce the glycemic effect of dietary starches. Proanthocyanidin-rich sumac sorghum bran extract inhibited alpha-amylase at a lower concentration (50% inhibitory concentration [IC50]=1.4 MUg/mL) than did proanthocyanidin-free black sorghum bran extract (IC50=11.4 MUg/mL). Sumac sorghum bran extract inhibited aromatase activity more strongly than black sorghum bran extract (IC50=12.1 MUg/mL vs. 18.8 MUg/mL, respectively). Bovine serum albumin (BSA), which binds proanthocyanidins, reduced inhibition by sumac but not black sorghum bran extract. When separated on Sephadex LH-20, sumac sorghum proanthocyanidins inhibited both enzymes but showed reduced inhibition with BSA. Flavonoids from either cultivar had higher IC50 values than proanthocyanidins, and BSA had little effect on their inhibition. Proanthocyanidins and simple flavonoids in LH-20 fractions both inhibited aromatase with mixed kinetics and affected K(m) and V(max). The results show that potential health benefits of sorghum bran may include actions of monomeric flavanoids as well as proanthocyanidins. PMID- 21612458 TI - Chemical profile and antinociceptive efficacy of Rheedia longifolia leaf extract. AB - Different species of the family Clusiaceae, including Rheedia longifolia, are used in folk medicine to treat inflammatory diseases. This family is largely distributed in tropical and subtropical areas of Brazil, but their chemical and pharmacological properties have been the subject of a few studies. In previous studies, we found that the aqueous extract from R. longifolia leaves presented important anti-inflammatory and analgesic activity. We investigated the chemical profile of R. longifolia and characterized the pharmacological effect of different chemically identified fractions in pharmacological models of neurogenic and inflammatory nociception. The pharmacological tests showed that oral treatment with aqueous crude extract and fractions of methanol extract of R. longifolia leaf induced a significant antinociceptive effect using von Frey filaments. In addition, the most polar fractions presented antinociceptive activity in a neurogenic model of nociception (capsaicin model). The chromatographic analysis indicated the presence of bisflavonoids in the fractions obtained from the methanol extract. These results suggest that bisflavonoids found in methanol-extracted fractions are involved in the inhibition of inflammatory and neurogenic nociception. It is important that the R. longifolia aqueous extract treatment inhibited ulcer formation induced by indomethacin, suggesting an anti-ulcerogenic activity closely associated with its analgesic effect. PMID- 21612459 TI - Genistein selectively inhibits estrogen-induced cell proliferation and other responses to hormone stimulation in the prepubertal rat uterus. AB - Sex hormone replacement therapy helps improve quality of life in climacteric women. However, estrogen-induced cell proliferation in the uterus and mammary gland increases the risk for cancer in these organs. The lower incidence of mammary cancer in Asian women than in western women has been attributed to high intake of soy isoflavones, including genistein. Our previous work in the prepubertal rat uterus model showed that genistein (0.5 mg/kg body weight subcutaneously) caused an estradiol-like hypertrophy in myometrial and uterine luminal epithelial cells and an increase in RNA content in luminal epithelium; however, it did not induce cell proliferation, uterine eosinophilia, or endometrial edema. The present study investigated, in the same animal model, the effect of genistein administration (0.5 mg/kg body weight subcutaneously) before treatment with estradiol-17beta (0.33 mg/kg body weight subcutaneously) on uterine responses that were not induced by genistein. Pretreatment with this phytoestrogen completely inhibited estradiol-induced mitoses in uterine luminal epithelium, endometrial stroma, and myometrium and partially inhibited estradiol induced uterine eosinophilia and endometrial edema. These findings indicate that genistein protects against estrogen-induced cell proliferation in the uterus and suggest that future studies should investigate the possibility of using this agent to decrease the risk for uterine cancer after hormone replacement therapy in climacteric women. PMID- 21612460 TI - Pistacia lentiscus resin regulates intestinal damage and inflammation in trinitrobenzene sulfonic acid-induced colitis. AB - Mastic (Pistacia lentiscus) of the Anacardiaceae family has exhibited anti inflammatory and antioxidant properties in patients with Crohn's disease. This study was based on the hypothesis that mastic inhibits intestinal damage in inflammatory bowel disease, regulating inflammation and oxidative stress in intestinal epithelium. Four different dosages of P. lentiscus powder in the form of powder were administered orally to trinitrobenzene sulfonic acid-induced colitic rats. Eighty-four male Wistar rats were randomly assigned to seven groups: A, control; B, colitic; C-F, colitic rats daily supplemented with P. lentiscus powder at (C) 50 mg/kg, (D) 100 mg/kg, (E) 200 mg/kg, and (F) 300 mg/kg of body weight; and G, colitic rats treated daily with cortisone (25 MUg/kg of body weight). Colonic damage was assessed microscopically. The cytokines tumor necrosis factor-alpha, intercellular adhesion molecule-1 (ICAM-1), interleukin (IL)-6, IL-8, and IL-10 and malonaldehyde were measured in colonic specimens. Results were expressed as mean +/- SE values. Histological amelioration of colitis (P<=.001) and significant differences in colonic indices occurred after 3 days of treatment. Daily administration of 100 mg of P. lentiscus powder/kg of body weight decreased all inflammatory cytokines (P<=.05), whereas 50 mg of P. lentiscus powder/kg of body weight and cortisone treatment reduced only ICAM-1 (P<=.05 and P<=.01, respectively). Malonaldehyde was significantly suppressed in all treated groups (P<=.01). IL-10 remained unchanged. Cytokines and malonaldehyde remained unaltered after 6 days of treatment. Thus P. lentiscus powder could possibly have a therapeutic role in Crohn's disease, regulating oxidant/antioxidant balance and modulating inflammation. PMID- 21612461 TI - A pilot study of the Spanish Ketogenic Mediterranean Diet: an effective therapy for the metabolic syndrome. AB - The "Spanish Ketogenic Mediterranean Diet" (SKMD) has been shown to promote potential therapeutic properties for the metabolic syndrome. The purpose of this study was to evaluate the potential therapeutic properties under free-living conditions of the SKMD in patients with metabolic syndrome (following the International Diabetes Federation consensus guidelines) over a 12-week period. A prospective study was carried out in 22 obese subjects with metabolic syndrome (12 men and 10 women) with the inclusion criteria whose body mass index of 36.58 +/- 0.54 kg/m2 and age was 41.18 +/- 2.28 years. Statistical differences between the parameters studied before and after the administration of the SKMD (week 0 and 12, respectively) were analyzed by paired Student's t test. There was an extremely significant (P < .001) improvement in low-density lipoprotein cholesterol (from 126.25 mg/dL to 103.87 mg/dL) and all the parameters studied associated with metabolic syndrome: body weight (from 106.41 kg to 91.95 kg), body mass index (from 36.58 kg/m2 to 31.69 kg/m2), waist circumference (from 111.97 cm to 94.70 cm), fasting plasma glucose (from 118.81 mg/dL to 91.86 mg/dL), triacylglycerols (from 224.86 mg/dL to 109.59 mg/dL), high-density lipoprotein cholesterol (from 44.44 to 57.95 mg/dL), systolic blood pressure (from 141.59 mm Hg to 123.64 mm Hg), and diastolic blood pressure (from 89.09 mm Hg to 76.36 mm Hg). The most affected parameter was the triacylglycerols (51.26% reduction). After the diet all the subjects were free of metabolic syndrome according to the International Diabetes Federation definition, and 100% of them had normal triacylglycerols and high-density lipoprotein cholesterol levels, in spite of the fact that 77.27% of them still had a body mass index of > 30 kg/m2. We conclude that the SKMD could be an effective and safe way to cure patients suffering from metabolic syndrome. Future research should include a larger sample size, a longer-term use, and a comparison with other ketogenic diets. PMID- 21612462 TI - Eculizumab in severe Shiga-toxin-associated HUS. PMID- 21612463 TI - Spending to save--ACOs and the Medicare Shared Savings Program. PMID- 21612464 TI - Nowhere left to hide? The banishment of smoking from public spaces. PMID- 21612465 TI - Images in clinical medicine. Villar's nodule--umbilical endometriosis. PMID- 21612466 TI - How Staphylococcus aureus adapts to its host. PMID- 21612467 TI - Are we making progress in maternal mortality? PMID- 21612469 TI - Effect of bronchoconstriction on airway remodeling in asthma. AB - BACKGROUND: Asthma is characterized pathologically by structural changes in the airway, termed airway remodeling. These changes are associated with worse long term clinical outcomes and have been attributed to eosinophilic inflammation. In vitro studies indicate, however, that the compressive mechanical forces that arise during bronchoconstriction may induce remodeling independently of inflammation. We evaluated the influence of repeated experimentally induced bronchoconstriction on airway structural changes in patients with asthma. METHODS: We randomly assigned 48 subjects with asthma to one of four inhalation challenge protocols involving a series of three challenges with one type of inhaled agent presented at 48-hour intervals. The two active challenges were with either a dust-mite allergen (which causes bronchoconstriction and eosinophilic inflammation) or methacholine (which causes bronchoconstriction without eosinophilic inflammation); the two control challenges (neither of which causes bronchoconstriction) were either saline alone or albuterol followed by methacholine (to control for nonbronchoconstrictor effects of methacholine). Bronchial-biopsy specimens were obtained before and 4 days after completion of the challenges. RESULTS: Allergen and methacholine immediately induced similar levels of bronchoconstriction. Eosinophilic inflammation of the airways increased only in the allergen group, whereas both the allergen and the methacholine groups had significant airway remodeling not seen in the two control groups. Subepithelial collagen-band thickness increased by a median of 2.17 MUm in the allergen group (interquartile range [IQR], 0.70 to 3.67) and 1.94 MUm in the methacholine group (IQR, 0.37 to 3.24) (P<0.001 for the comparison of the two challenge groups with the two control groups); periodic acid-Schiff staining of epithelium (mucus glands) also increased, by a median of 2.17 percentage points in the allergen group (IQR, 1.03 to 4.77) and 2.13 percentage points in the methacholine group (IQR, 1.14 to 7.96) (P=0.003 for the comparison with controls). There were no significant differences between the allergen and methacholine groups. CONCLUSIONS: Bronchoconstriction without additional inflammation induces airway remodeling in patients with asthma. These findings have potential implications for management. PMID- 21612470 TI - Bacterial meningitis in the United States, 1998-2007. AB - BACKGROUND: The rate of bacterial meningitis declined by 55% in the United States in the early 1990s, when the Haemophilus influenzae type b (Hib) conjugate vaccine for infants was introduced. More recent prevention measures such as the pneumococcal conjugate vaccine and universal screening of pregnant women for group B streptococcus (GBS) have further changed the epidemiology of bacterial meningitis. METHODS: We analyzed data on cases of bacterial meningitis reported among residents in eight surveillance areas of the Emerging Infections Programs Network, consisting of approximately 17.4 million persons, during 1998-2007. We defined bacterial meningitis as the presence of H. influenzae, Streptococcus pneumoniae, GBS, Listeria monocytogenes, or Neisseria meningitidis in cerebrospinal fluid or other normally sterile site in association with a clinical diagnosis of meningitis. RESULTS: We identified 3188 patients with bacterial meningitis; of 3155 patients for whom outcome data were available, 466 (14.8%) died. The incidence of meningitis changed by -31% (95% confidence interval [CI], 33 to -29) during the surveillance period, from 2.00 cases per 100,000 population (95% CI, 1.85 to 2.15) in 1998-1999 to 1.38 cases per 100,000 population (95% CI 1.27 to 1.50) in 2006-2007. The median age of patients increased from 30.3 years in 1998-1999 to 41.9 years in 2006-2007 (P<0.001 by the Wilcoxon rank-sum test). The case fatality rate did not change significantly: it was 15.7% in 1998-1999 and 14.3% in 2006-2007 (P=0.50). Of the 1670 cases reported during 2003-2007, S. pneumoniae was the predominant infective species (58.0%), followed by GBS (18.1%), N. meningitidis (13.9%), H. influenzae (6.7%), and L. monocytogenes (3.4%). An estimated 4100 cases and 500 deaths from bacterial meningitis occurred annually in the United States during 2003-2007. CONCLUSIONS: The rates of bacterial meningitis have decreased since 1998, but the disease still often results in death. With the success of pneumococcal and Hib conjugate vaccines in reducing the risk of meningitis among young children, the burden of bacterial meningitis is now borne more by older adults. (Funded by the Emerging Infections Programs, Centers for Disease Control and Prevention.). PMID- 21612468 TI - Abiraterone and increased survival in metastatic prostate cancer. AB - BACKGROUND: Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. METHODS: We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. RESULTS: After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group. CONCLUSIONS: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.). PMID- 21612472 TI - Clinical practice. Borderline personality disorder. PMID- 21612471 TI - Body-weight-supported treadmill rehabilitation after stroke. AB - BACKGROUND: Locomotor training, including the use of body-weight support in treadmill stepping, is a physical therapy intervention used to improve recovery of the ability to walk after stroke. The effectiveness and appropriate timing of this intervention have not been established. METHODS: We stratified 408 participants who had had a stroke 2 months earlier according to the extent of walking impairment--moderate (able to walk 0.4 to <0.8 m per second) or severe (able to walk <0.4 m per second)--and randomly assigned them to one of three training groups. One group received training on a treadmill with the use of body weight support 2 months after the stroke had occurred (early locomotor training), the second group received this training 6 months after the stroke had occurred (late locomotor training), and the third group participated in an exercise program at home managed by a physical therapist 2 months after the stroke (home exercise program). Each intervention included 36 sessions of 90 minutes each for 12 to 16 weeks. The primary outcome was the proportion of participants in each group who had an improvement in functional walking ability 1 year after the stroke. RESULTS: At 1 year, 52.0% of all participants had increased functional walking ability. No significant differences in improvement were found between early locomotor training and home exercise (adjusted odds ratio for the primary outcome, 0.83; 95% confidence interval [CI], 0.50 to 1.39) or between late locomotor training and home exercise (adjusted odds ratio, 1.19; 95% CI, 0.72 to 1.99). All groups had similar improvements in walking speed, motor recovery, balance, functional status, and quality of life. Neither the delay in initiating the late locomotor training nor the severity of the initial impairment affected the outcome at 1 year. Ten related serious adverse events were reported (occurring in 2.2% of participants undergoing early locomotor training, 3.5% of those undergoing late locomotor training, and 1.6% of those engaging in home exercise). As compared with the home-exercise group, each of the groups receiving locomotor training had a higher frequency of dizziness or faintness during treatment (P=0.008). Among patients with severe walking impairment, multiple falls were more common in the group receiving early locomotor training than in the other two groups (P=0.02). CONCLUSIONS: Locomotor training, including the use of body-weight support in stepping on a treadmill, was not shown to be superior to progressive exercise at home managed by a physical therapist. (Funded by the National Institute of Neurological Disorders and Stroke and the National Center for Medical Rehabilitation Research; LEAPS ClinicalTrials.gov number, NCT00243919.). PMID- 21612473 TI - Images in clinical medicine. Calcified vasa deferentia. PMID- 21612474 TI - Case records of the Massachusetts General Hospital. Case 16-2011. A 67-year-old man with recurrent prostate cancer. PMID- 21612475 TI - Expanding treatment options for metastatic prostate cancer. PMID- 21612476 TI - Physical forces and airway remodeling in asthma. PMID- 21612477 TI - Bending the cost curve in cancer care. PMID- 21612478 TI - Diuretic strategies in patients with acute heart failure. PMID- 21612479 TI - Diuretic strategies in patients with acute heart failure. PMID- 21612480 TI - Diuretic strategies in patients with acute heart failure. PMID- 21612481 TI - Diuretic strategies in patients with acute heart failure. PMID- 21612482 TI - Diuretic strategies in patients with acute heart failure. PMID- 21612484 TI - Heterogeneity of hemoglobin h disease in childhood. PMID- 21612485 TI - Heterogeneity of hemoglobin H disease in childhood. PMID- 21612487 TI - Risk alleles in idiopathic membranous nephropathy. PMID- 21612488 TI - Risk alleles in idiopathic membranous nephropathy. PMID- 21612489 TI - Risk alleles in idiopathic membranous nephropathy. PMID- 21612491 TI - Direct-to-consumer genomewide profiling. PMID- 21612492 TI - Direct-to-consumer genomewide profiling. PMID- 21612494 TI - Point-of-care ultrasonography. PMID- 21612496 TI - Equipoise and the dilemma of randomized clinical trials. PMID- 21612497 TI - Equipoise and the dilemma of randomized clinical trials. PMID- 21612501 TI - Use of a subcutaneous implantable pleural port in the management of recurrent malignant pleurisy: five-year experience based on 168 subcutaneous implantable pleural ports. AB - INTRODUCTION: The authors report their experience in the use of subcutaneous implantable pleural port (SIPP) catheters for the treatment of symptomatic recurrent malignant pleurisy. MATERIALS AND METHODS: Single-center, prospective follow-up of 137 patients (168 SIPPs). RESULTS: No SIPP placement failures were observed. All but 3 of the 125 evaluable patients obtained complete or partial relief of their dyspnea. Seventy-six patients (60.3%) were receiving chemotherapy. Spontaneous pleurodesis was observed within 2 months in 46 patients (36.8%). Twenty-six patients (20.8%) died during the month following SIPP placement. Forty-one patients (32%) survived for more than 6 months. The overall median survival time was 344 days. Three infectious complications (1 empyema, 2 cellulitis) and 3 mechanical complications were observed. The role of pleurodesis as prognostic factor was assessed. Seventy-one patients survived for more than 2 months, 36 with pleurodesis, 35 without pleurodesis, requiring repeated pleural aspiration. The difference observed between the two groups by the 120th day was no longer significant when chemotherapy was taken into account. CONCLUSION: SIPP is a safe and effective option for the outpatient management of recurrent malignant effusions and could be considered as first-line treatment in all patients with bilateral, compressive pleural effusion or poor lung reexpansion. PMID- 21612502 TI - Spirituality at the end of life: conceptualization of measurable aspects-a systematic review. AB - Although spiritual caregiving is a key domain of palliative care, it lacks a clear definition, which impedes both caregiving and research in this domain. The aim of this study was to conceptualize spirituality by identifying dimensions, based on instruments measuring spirituality in end-of-life populations. A systematic literature review was conducted. Literature published between 1980 and 2009, focussing on instruments measuring spirituality at the end of life was collected from the PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and PsycINFO databases. Inclusion criteria were: (1) the studies provide empirical data collected with an instrument measuring spirituality or aspects of spirituality at the end of life; (2) the data report on a (subgroup) of an end-of-life population, and (3) the instrument is available in the public domain. Content validity was assessed according to a consensus based method. From the items of the instruments, three investigators independently derived dimensions of spirituality at the end of life. In 36 articles that met the inclusion criteria we identified 24 instruments. Nine instruments with adequate content validity were used to identify dimensions of spirituality. To adequately represent the items of the instruments and to describe the relationships between the dimensions, a model defining spirituality was constructed. The model distinguishes the dimensions of Spiritual Well-being (e.g., peace), Spiritual Cognitive Behavioral Context (Spiritual Beliefs, Spiritual Activities, and Spiritual Relationships), and Spiritual Coping, and also indicates relationships between the dimensions. This model may help researchers to plan studies and to choose appropriate outcomes, and assist caregivers in planning spiritual care. PMID- 21612503 TI - Acute renal failure requiring renal replacement therapy in the intensive care unit: impact on prognostic assessment for shared decision making. AB - A 69-year-old female was receiving renal replacement therapy (RRT) for acute renal failure (ARF) in an intensive care unit (ICU). Consultation was requested from the palliative medicine service to facilitate a shared decision-making process regarding goals of care. Clinician responsibility in shared decision making includes the formulation and expression of a prognostic assessment providing the necessary perspective for a spokesperson to match patient values with treatment options. For this patient, ARF requiring RRT in the ICU was used as a focal point for preparing a prognostic assessment. A prognostic assessment should include the outcomes of most importance to a discussion of goals of care: mortality risk and survivor functional status, in this case including renal recovery. A systematic review of the literature was conducted to document published data regarding these outcomes for adult patients receiving RRT for ARF in the ICU. Forty-one studies met the inclusion criteria. The combined mean values for short-term mortality, long-term mortality, renal-function recovery of short-term survivors, and renal-function recovery of long-term survivors were 51.7%, 68.6%, 82.0%, and 88.4%, respectively. This case example illustrates a process for formulating and expressing a prognostic assessment for an ICU patient requiring RRT for ARF. Data from the literature review provide baseline information that requires adjustment to reflect specific patient circumstances. The nature of the acute primary process, comorbidities, and severity of illness are key modifiers. Finally, the prognostic assessment is expressed during a family meeting using recommended principles of communication. PMID- 21612504 TI - Comparison of bacterial examinations between eosinophilic and neutrophilic chronic rhinosinusitis with nasal polyps. AB - CONCLUSION: We found no significant differences in the bacterial features of the maxillary sinuses between eosinophilic and neutrophilic chronic rhinosinusitis (CRS) with nasal polyps. OBJECTIVES: Since neutrophilic CRS is often influenced by a predisposition to bacterial infection, and eosinophilic CRS is likely to be developed by allergic antigens, differences in the microbiology between the two pathologies of CRS can be expected. The present study was designed to investigate the bacterial findings from the maxillary sinus in eosinophilic and neutrophilic CRS. METHODS: Seventy patients with CRS with nasal polyps were divided into eosinophilic and neutrophilic types based on histopathological observations of the nasal polyps. The specimens for bacterial culture were obtained from the maxillary sinus during endoscopic sinus surgery. RESULTS: In all, 29 and 41 patients were classified as having eosinophilic and neutrophilic CRS with nasal polyps, respectively. The isolation rate of bacteria showed no significant difference between eosinophilic (90%) and neutrophilic CRS (98%). Aerobic bacteria were found in 25 patients (86%) with eosinophilic CRS, which was not significantly different from that in neutrophilic CRS (40 patients, 98%). The isolation rate for aerobic and anaerobic bacteria showed no significant differences. PMID- 21612506 TI - Glycosylated hemoglobin and prevalent metabolic syndrome in nondiabetic multiethnic U.S. adults. AB - BACKGROUND: Metabolic syndrome poses a significant risk for cardiovascular disease. Recently, glycosylated hemoglobin (HbA1c) has been included in the diagnostic criteria for diabetes mellitus and prediabetes. We sought to determine if HbA1c is associated with prevalent metabolic syndrome in nondiabetic U.S. adults. METHODS: A total of 9,022 nondiabetic participants of National Health and Nutrition Examination Surveys 1999-2008 (age, 47.5 +/- 18.3 years, 51% females) were divided into quintiles (Q) of HbA1c: Q1 (reference), <=5%; Q2, 5.1%-5.3%; Q3, 5.4%-5.5%; Q4, 5.6%-5.7%; and Q5, >=5.8%. Modified National Cholesterol Education Program Adult Treatment Panel III criteria were used to identify metabolic syndrome (n=2,821; 31.3%). Unadjusted and adjusted multivariate logistic regression analysis was performed to assess the risk of metabolic syndrome. RESULTS: A graded increase in odds of having prevalent metabolic syndrome with increase from each quintile of HbA1c compared to Q1 was observed after adjusting for age, sex, race, body mass index (BMI), total cholesterol, lipid-lowering therapy, current smoking, family history of diabetes, C-reactive protein, and fasting insulin. Stratified analysis based on gender, ethnicity, and BMI showed similar results. The HbA1c value of >=5.4% remained appropriate cutoff for predicting metabolic syndrome in Caucasians and Hispanics, whereas >=5.6% provided the best accuracy for African Americans based on receiver operating characteristics analysis. CONCLUSION: HbA1c much below the level for prediabetes was associated with prevalence of the metabolic syndrome in a cohort of nondiabetic U.S. adults. HbA1c can be considered as a surrogate marker for metabolic syndrome in nondiabetics. PMID- 21612505 TI - Influence of a high cholesterol regime on epicardial and subcutaneous adipose tissue fatty acids profile in rabbits. AB - BACKGROUND: We have shown that the fatty acid profile of epicardial adipose tissue (EAT) in patients with obstructed coronary vessels is different from that of the subcutaneous adipose tissue (SAT). The diversity and amount of fatty acids in the adipose tissue can be affected by the component of the lipids in diet. As a result, this study investigated the influence of a high cholesterol regime on EAT and subcutaneous adipose tissue fatty acids profile in rabbits. METHODS: Sixteen New Zealand white rabbits were randomly divided into two equal groups. The control group received a normal standard diet, whereas the test group was fed with the high cholesterol regime for 2 months. At the end of this period, the rabbits were anesthetized, 1-5 mg of EAT and SAT were removed, and their fatty acids content was determined. RESULTS: The high cholesterol regime caused a significant increase in low-density lipoprotein (LDL) and triglycerides levels and a marked decrease in high-density lipoprotein (HDL) concentration. After 2 months, in the EAT, fatty acids 16:0 and 18:1t and saturated fatty acid (SFA) showed a significant increase (P<0.05), whereas, fatty acids 12:0, 18:1, 18:2, and 18:3, monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), omega3, and omega6 had a significant decrease (P<0.05). In SAT, fatty acids 18:3, 20:4, 22:6, MUFA, and omega3 decreased and PUFA, SFA, and omega6 significantly increased (P<0.05). CONCLUSION: Consumption of a high cholesterol regime for 2 months resulted in a significant increase in atherogenic fatty acids and a decrease in antiatherogenic ones in the EAT. EAT is very sensitive to lipid changes of the regime comparing to SAT. PMID- 21612507 TI - Characterization of plasmids encoding cefotaximases group 1 enzymes in Escherichia coli recovered from cattle in England and Wales. AB - In the study, we examined the molecular characteristics of cattle-associated Escherichia coli carrying CTX-M genes and their plasmids. Between July 2006 and July 2007, 18 E. coli were collected from cattle that were found to possess a bla(CTX-M) belonging to group 1. bla(CTX-M-15/28) was the predominant type, and it was associated with plasmids of several different inc/rep types. In addition, bla(CTX-M-1) and bla(CTX-M-3) were also detected. Plasmids encoding the bla(CTX M) genes belonged to incompatibility groups I1, F, and A/C. Analysis of the non beta-lactam resistance genes associated with each CTX-M-bearing plasmid demonstrated that F plasmids frequently carried a larger number of resistance genes than IncI1 plasmids, which rarely carried additional resistance genes. All bla(CTX-M) carrying plasmids were positive by polymerase chain reaction for an ISEcp1-like element. PMID- 21612508 TI - Molecular mechanisms of tetracycline and macrolide resistance and emm characterization of Streptococcus pyogenes isolates in Tunisia. AB - Streptococcus pyogenes or group A Streptococcus, a major human pathogen, remains susceptible to beta-lactams, but resistance to other antibiotics is becoming more common. The purpose of this study was to characterize both phenotypic and genotypic epidemiological markers of group A Streptococcus and to identify the mechanisms of resistance to macrolides and tetracyclines. A total of 103 strains, isolated at Charles Nicolle University Hospital of Tunis, were investigated. The rate of resistance to erythromycin was low (5%), whereas a high rate of tetracycline resistance was found (70%). All the macrolide-resistant isolates expressed the constitutive macrolide, lincosamide, and streptograminB phenotype and harbored the erm(B) gene. Resistance to tetracycline was mainly due to the tet(M) gene, which is commonly associated with the conjugative transposon Tn916. No significant association was found between erm(B) and tet(M) genes. The tetracycline-resistant strains belonged to 28 distinct emm types. Among them, emm118 was the most prevalent type, followed by emm42, std432, emm76, and emm18. However, emm1, emm4, emm6, emm28, and emm3 were the most frequent types among tetracycline susceptible isolates. Only emm118 and emm42 types (p <= 0.05) were significantly associated with resistance to tetracycline. PMID- 21612509 TI - Prevalence and genetic characteristics of TEM, SHV, and CTX-M in clinical Klebsiella pneumoniae isolates from Saudi Arabia. AB - The prevalence and genetic basis of extended-spectrum beta-lactamases (ESBLs) in Klebsiella pneumoniae remains unclear in Saudi Arabia. Therefore, this study was devoted to determine the prevalence and characterize ESBL-producing K. pneumoniae in Al-Qassim area, Saudi Arabia. A total of 430 isolates of K. pneumoniae isolated from clinical samples were collected over 6 months from January to June 2008. These isolates were screened for the presence of ESBLs by double-disk synergy test and re-evaluated by E-test ESBL method. Minimum inhibitory concentrations of 15 antibiotics against ESBL-positive strains were determined by E-test strips. The beta-lactamases involved were characterized by polymerase chain reaction assays and DNA sequencing. Conjugation experiments were done and ISEcp1 elements were tested among CTX-M positive isolates. The prevalence of ESBL was 25.6% (110/430) and all ESBL-positive isolates were sensitive to imipenem and tigecycline; however, the resistance rate to gentamicin, amikacin, and ciprofloxacin was 87.3%, 10%, and 9.1%, respectively. Of these, 89.1% produced SHV, 70.9% produced TEM, and 36.4% were CTX-M-producing strains. The prevalence of ESBL SHV SHV-12 and SHV-5 was of 60% and 18.2%, respectively, and various non ESBL SHV, including SHV-1 (5.5%), -11 (3.6%), and -85 (1.8%), was detected. However, the prevalence of CTX-M-15 and CTX-M-14 was 34.5% and 1.8%, respectively. ISEcp1 element was detected in 60% of bla(CTX-M-15) genes. All bla(CTX-M) genes were transferable; however, most of bla(SHV-12) and bla(SHV-5) were not transferable. TEM-type ESBLs were not detected in any of the isolates. This is the first description of CTX-M-14, SHV-5, SHV-11, and SHV-85 in Saudi Arabia. We have documented the dominance of K. pneumoniae SHV-12 and highlighted the emergence of CTX-M-15 in Saudi Arabia. PMID- 21612510 TI - Molecular characterization of vancomycin-resistant enterococci in a Chinese hospital between 2003 and 2009. AB - From June 2003 to December 2009, 98 isolates of vancomycin-resistant enterococci (VRE) were cultured from clinical specimens taken from patients admitted to a 1,500-bed tertiary-care teaching hospital in Beijing, China. Isolates were characterized by pulsed-field gel electrophoresis and multilocus sequence typing. We investigated the structure of the vanA gene cluster and the distribution of the virulence markers esp, hyl, gelE, asa1, and cylA by polymerase chain reaction. Our results indicate that multilocus sequence typing revealed five novel sequence types and one new allele. VRE faecium (VREfm) isolates were heterogeneous in their vanA cluster types and in the presence of virulence genes. We also observed inconsistency between genotype and phenotype in VREfm isolates. The outbreak with VREfm in our hospital appears polyclonal, whereas VRE faecalis characterization indicated dissemination of a particular clone. After 2007, VRE faecalis was completely replaced by VREfm, which has since been the predominant species in our hospital. VRE appears to be in an evolutionary flux in our hospital. PMID- 21612511 TI - Characterization of Escherichia coli isolates from healthy food handlers in hospital. AB - Recent studies have reported that Escherichia coli in fecal samples of healthy humans could also serve as important reservoirs of drug-resistant bacteria. Limited data are available for E. coli-resistant profiles of healthy food handlers in hospitals who provide food service to inpatients and hospital staffs. E. coli isolates were recovered from hospital healthy food handlers, and one random selected isolate from each food handler was subjected to antimicrobial susceptibility testing, phylogenetic typing, and screening for antimicrobial resistant mechanisms by polymerase chain reaction amplification. Ciprofloxacin resistant isolates were further characterized by mutation analysis in the quinolone resistance determining regions (QRDRs) of GyrA and ParC. And extended spectrum beta-lactamase (ESBL) producing isolates were screened for bla(CTX-M) by polymerase chain reaction amplification and DNA sequence analysis. In total, more than 50% (47/92) of E. coli isolates from healthy food handlers showed multidrug resistant profiles and 50% (46/92) isolates carried intI. Resistance prevalence of the B2 phylogenetic group was significantly lower than that of the non-B2 groups for all tested antimicrobials (p < 0.05) except chloramphenicol and tetracycline. Seven isolates of phylogenetic group A (n = 3) and D (n = 4) produced ESBL, and 12 isolates of phylogenetic group A (n = 5), B2 (n = 2), and D (n = 5) were resistant to ciprofloxacin. Transferable quinolone resistance determinants were identified in four isolates. Point mutations in QRDRs of GyrA or ParC were identified among 59 out of 62 E. coli isolates showing decreased susceptibility or resistance to ciprofloxacin. Genes encoding CTX-M enzyme were identified in seven ESBL-producing isolates. The preponderance in hospital food handlers of multidrug-resistant E. coli makes it important to introduce control measures such as improved biosecurity to ensure that they do not pass through the food service and limit inpatient therapeutic options. PMID- 21612512 TI - An evaluation of methicillin-resistant Staphylococcus aureus survival on five environmental surfaces. AB - This study evaluated methicillin-resistant Staphylococcus aureus (MRSA) survival on environmental surfaces: glass, wood, vinyl, plastic, and cloth. Effects of relative humidity (RH) and bovine serum albumin (BSA) were examined. Surfaces were inoculated with 10(7)-10(8) colony forming units per milliliter (CFU/ml)of MRSA with and without 1% BSA and incubated at 35 degrees C at 45%-55% and 16% RH. Surfaces were sampled, and each collected sample was re-suspended in phosphate buffer, spread plated, and incubated at 35 degrees C for 24 hrs; resulting colonies were enumerated. Samples were collected immediately on drying, and at 3 hrs, 24 hrs, 2 days, 3 days, 4 days, and 5 days. Results demonstrated that MRSA survived the longest on plastic and vinyl and for the least amount of time on wood (p < 0.001). BSA enabled MRSA to survive for significantly longer duration (p < 0.001). The number of CFU/ml was significantly lesser on surfaces stored in 45%-55% RH versus 16% RH. This study demonstrates that viable MRSA bacteria can remain on surfaces for days, which may impact the public health of occupants in workplace and residential settings. PMID- 21612513 TI - Subthreshold micropulse diode laser and double frequency neodymium: YAG laser in treatment of diabetic macular edema: a prospective, randomized study using multifocal electroretinography. AB - OBJECTIVE: The purpose of this study was to compare the efficacy of subthreshold micropulse diode (SDM) laser with double-frequency neodymium YAG (Nd:YAG) laser in treatment of clinically significant diabetic macular edema. METHODS: Forty-six eyes of 33 patients with clinically significant macular edema (CSME) caused by diabetic retinopathy were randomized to either SDM (810?nm) laser or the conventional double-frequency Nd:YAG (532?nm) laser. Primary outcome measures were: change in the central macular thickness as measured by optical coherence tomography (OCT) and change in macular retinal sensitivity measured using multifocal electroretinography (MfERG). Secondary outcomes were: change in best corrected visual acuity (BCVA) and contrast sensitivity. RESULTS: The group was divided in half, with 23 eyes assigned to SDM laser and 23 eyes assigned to double-frequency Nd:YAG laser. Mean follow-up period was 6 months. No statistically significant difference was noted in either the primary or the secondary outcome measures between the two groups. Macular thickness decreased from the baseline measures of 298.5?49.3 and 312.9?45.8??m to 274.9?62.9 and 286.7?32.8??m in the SDM laser and Nd:YAG laser groups, respectively. On MfERG, P1 implicit wave time delay at baseline changed from 46.27?4.9 to 45.27?3.4?ms in the SDM group and from 46.55?4.9 to 45.27?4.1?ms in the Nd:YAG group. MfERG recordings of 18 of the 23 eyes treated with double-frequency Nd:YAG laser showed areas of signal void as compared to 4 eyes treated with the SDM laser. CONCLUSIONS: SDM laser photocoagulation showed an equally good effect on visual acuity, contrast sensitivity, and reduction of diabetic macular edema (DME) as compared to conventional Nd:YAG laser photocoagulation. MfERG recordings, however, suggest that SDM laser results in better preservation of electrophysiological indices. PMID- 21612514 TI - Effective thermal penetration depth in photo-irradiated ex vivo human tissues. AB - OBJECTIVE: In this work, a model of bioheat distribution is discussed for ex vivo human tissue samples, and the thermal penetration depth measurements performed on several tissues are presented. BACKGROUND DATA: Optical radiation is widely applied in the treatment and diagnosis of different pathologies. A power density of incident light at 100 mW/cm(2) is sufficiently high enough to induce a temperature increase of >5 degrees C in irradiated human tissue. In this case, knowledge of the thermal properties of the tissue is needed to achieve a better understanding of the therapeutic effects. METHOD: The application of the diffusion approximation of the radiative transfer equation for the distribution of optical radiation, the experimental setup, and the results thereof are presented and discussed. RESULTS: The effective thermal penetration depth in the studied tissues has been determined to be in the range of 4.3-7.0 mm. CONCLUSIONS: The effective thermal penetration depth has been defined, and this could be useful for developing models to describe the thermal effects with a separate analysis of the tissue itself and the blood that irrigates it. PMID- 21612515 TI - The advanced glycation end product-lowering agent ALT-711 is a low-affinity inhibitor of thiamine diphosphokinase. AB - Advanced glycation end products (AGEs) are involved in age-related diseases, including the complications of diabetes and chronic renal impairment with arterial stiffening. Alagebrium chloride (ALT-711) is an AGE-lowering agent with beneficial effects in renal structural and functional parameters in diabetes, decreased diabetes-accelerated atherosclerosis, and age-related myocardial stiffening. ALT-711 exhibits a structural homology to thiamine, and it was suggested to interfere with thiamine metabolism. Thiamine is converted to thiamine diphosphate (TDP) by thiamine diphosphokinase (TDPK). TDP is a cofactor for pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase. A decreased activity of these enzymes due to TDP deficiency results in disorders such as beriberi and Wernicke-Korsakoff syndrome. Therefore, we investigated whether ALT-711 is an inhibitor of TDPK. Molecular modeling studies showed that ALT-711 fits into the thiamine-binding pocket of TDPK, and there are three interactions between the thiazolium ring and the enzyme, as well as parallel stacking between the phenyl ring and the indole ring of Trp222B. Enzyme kinetic experiments also showed that ALT-711 dose-dependently decreased TDPK activity with K(i)s, calculated by different experiments and fitting models ranging from 0.88 to 1.09 mM. Fitting of the kinetic data favored mixed-mode inhibition with a major role for competitive inhibition. In summary, our results suggest that ALT 711 is a low-affinity inhibitor of TDPK, but is unlikely to interfere with thiamine metabolism at therapeutic concentrations. However, when new AGE crosslink breakers based on thiamine are designed, care should be taken that they do not act as more potent competitive inhibitors than ALT-711. PMID- 21612516 TI - Association study on long-living individuals from Southern Italy identifies rs10491334 in the CAMKIV gene that regulates survival proteins. AB - Long-living individuals (LLIs) are used to study exceptional longevity. A number of genetic variants have been found associated in LLIs to date, but further identification of variants would improve knowledge on the mechanisms regulating the rate of aging. Therefore, we performed a genome-wide association study on 410 LLIs and 553 young control individuals with a 317K single-nucleotide polymorphism (SNP) chip to identify novel traits associated with aging. Among the top (p < 1 * 10(-4)) SNPs initially identified, we found rs10491334 (CAMKIV) (odds ratio [OR] = 0.55; 95% confidence interval [CI] 0.42-0.73; p = 2.88 * 10(-5)), a variant previously reported associated with diastolic blood pressure, associated also in a replication set of 116 LLIs and 160 controls (OR = 0.54; 95% CI 0.32-0.90; p = 9 * 10(-3)). Furthermore, in vitro analysis established that calcium/calmodulin dependent protein kinase IV (CAMKIV) activates the survival proteins AKT, SIRT1, and FOXO3A, and we found that homozygous carriers of rs10491334 have a significant reduction in CAMKIV expression. This, together with the observed reduction in minor-allele carriers among centenarians, points to a detrimental role for the SNP. In conclusion, prolongevity genes are activated by CAMKIV, the levels of which are influenced by rs10491334, a SNP associated with human longevity. PMID- 21612517 TI - Teleconsultation for clinicians who provide human immunodeficiency virus care: experience of the national HIV telephone consultation service. AB - OBJECTIVE: To examine the infrastructure, successes, and challenges of a teleconsultation service for human immunodeficiency virus (HIV) clinicians. MATERIALS AND METHODS: The HIV Warmline is a telephone consultation service providing free, live HIV/AIDS management advice to U.S. clinicians. We present descriptive data about callers, patients, and consultation topics gathered by electronic query of the HIV Warmline database for 2009. Caller satisfaction survey results for 2009 are also presented. RESULTS: The HIV Warmline has provided more than 37,000 consultations since its inception in 1992. The service provides consultations to clinicians from all 50 states, from a variety of professional backgrounds, and with a wide range of HIV experience levels. The majority of call topics concern antiretroviral therapy. Callers are generally pleased with the service, giving a mean Likert scale rating of 4.7 on satisfaction survey questions. CONCLUSION: The experience of the HIV Warmline can serve as a model for other programs planning to develop remote consultation systems. HIV teleconsultation has been relatively simple to implement and can be useful for many types of clinicians. HIV teleconsultation should continue to be evaluated as a way to improve HIV care, especially in areas without easy access to HIV expertise. PMID- 21612518 TI - Physician impressions of using text message technology to increase vaccination compliance. AB - INTRODUCTION: Immunization schedules are complicated and difficult for parents to remember. Parents are willing to receive text message reminders. However, it is unknown whether physicians are willing to implement such a system. The purpose of this study was to evaluate the feasibility of a text messaging reminder system from the physician's perspective. MATERIALS AND METHODS: Surveys were distributed in the winter of 2009-2010 by e-mail, facsimile, and telephone interview to 149 family physicians and pediatricians who provide immunizations in Sedgwick County, Kansas. RESULTS: A 69% response rate was achieved. Nearly all (92%) respondents reported that they currently communicate information about immunization schedules to parents using traditional methods such as verbal reminders or appointment cards; however, none (0%) currently use text or email to generate reminders to parents. Even when asked to assume they had all of the necessary resources, almost one-third (31%) reported that they were "very unwilling" or "unwilling" to use a general text-messaging program, 43% were "neutral" or "undecided," and only 27% were "willing" or "very willing." Physician willingness to use a text messaging program was not related to their reported gender (chi2(2)=0.224, p=0.894), specialization (chi2 (2)=4.363, p=0.113), years in practice (F(2, 91)=0.435, p=0.149), or comfort level with technology (chi2(4)=1.861, p=0.761). CONCLUSIONS: There is a hesitancy to implement a text message reminder system for childhood vaccine schedules. This may be due to the lack of empirical evidence supporting the use of this technology for health reminders or the lack of willingness to implement another system. Further investigation is needed to determine why few physicians are willing to implement text messaging for immunization reminders. PMID- 21612519 TI - Evaluating the uptake, acceptability, and effectiveness of Uliza! clinicians' HIV hotline: a telephone consultation service in Kenya. AB - OBJECTIVE: Many clinical sites that serve patients who are HIV positive face challenges of insufficient staffing levels and staff training and have limited access to consultation resources including specialists on site. Uliza! (Swahili for "ask") Clinicians' HIV Hotline was launched in April 2006 in Nyanza province in Kenya as a HIV telephone consultation service for healthcare providers. Hotline users called an Uliza! consultant who discussed the patients' problems and helped the caller work through a solution, as well as reinforced national guidelines. This objective of this study was to evaluate the uptake, acceptability, and effectiveness of Uliza! MATERIALS AND METHODS: Consultants completed a form with details of each call, and healthcare workers completed satisfaction surveys during site visits. All available medical records were audited to determine whether the advice given by the consultant was implemented. RESULTS: After a year of service, Uliza! responded to 296 calls. Clinical officers (64%) followed by nurses (21%) most frequently used the service. Most callers had questions regarding antiretroviral therapy (36%) or tuberculosis (18%). Thirty-six percent of all consults were pediatric questions. Ninety-four percent of users rated the service as useful. Advice given to providers was implemented and documented in the medical records in 72% of the charts audited. CONCLUSION: Healthcare providers in HIV clinics will use a telephone consultation service when easily accessible. Clinicians using Uliza! found it useful, and advice given was usually implemented. Uliza! increased access to current information for quality care in a rural and resource limited setting and has potential for scale-up to a national level. PMID- 21612520 TI - User-friendly cognitive training for the elderly: a technical report. AB - OBJECTIVE: This article presents a system that implements a cognitive training program in users' homes. The system comprises various applications designed to create a daily brain-fitness regime. MATERIALS AND METHODS: The proposed mental training system uses television and a remote control specially designed for the elderly. This system integrates Java applications to promote brain-fitness training in three areas: arithmetic, memory, and idea association. The system comprises the following: Standard television set, simplified wireless remote control, black box (system's core hardware and software), brain-fitness games (language Java), and Wi-Fi-enabled Internet-connected router. All data from the user training sessions are monitored through a control center. This control center analyzes the evolution of the user and the proper performance of the system during the test. RESULTS: The implemented system has been tested by six healthy volunteers. The results for this user group demonstrated the accessibility and usability of the system in a controlled real environment. The impressions of the users were very favorable, and they reported high adaptability to the system. The mean score for usability and accessibility assigned by the users was 3.56 out of 5 points. The operation stress test (over 200 h) was successful. CONCLUSION: The proposed system was used to implement a cognitive training program in users' homes, which was developed to be a low-cost tool with a high degree of user interactivity. The results of this preliminary study indicate that this user-friendly system could be adopted as a form of cognitive training for the elderly. PMID- 21612521 TI - Telemonitoring increases patient awareness of health and prompts health-related action: initial evaluation of the TELE-ERA study. AB - INTRODUCTION: Telemonitoring is being increasingly used for chronic disease monitoring. Understanding elderly patients' feelings and perspectives toward telemonitoring is important to minimize any barriers to implementation in this population. METHODS: Twenty Tele-Era Trial participants completed qualitative interviews assessing opinions about their telemonitoring experience. Participants also rated telemonitoring on burden, communication with clinicians, impact on medical condition knowledge, and confidence in using the monitor. RESULTS: On an average, participants rated telemonitoring as minimally burdensome, rated themselves confident in using the monitor, and positively rated telemonitoring for clinical communication. Qualitative analysis revealed a predominant theme that telemonitoring increases patient awareness of their health and also that telemonitoring prompts action. CONCLUSION: Elderly patients find home telemonitoring to be an acceptable and satisfying experience that can increase their awareness of their health and provide a sense of safety in their home. Home telemonitoring can lead to earlier evaluation of decline in health status. PMID- 21612522 TI - The move to accountable care organizations includes telemedicine. PMID- 21612523 TI - The pathogenic potential of different pulsed-field gel electrophoresis types of Listeria monocytogenes strains isolated from food in Northeast Bosnia and Herzegovina. AB - Listeria monocytogenes is often present in meat and meat products that are sold in the area of northeast Bosnia and Herzegovina. The major objective of this study was to examine the virulence of L. monocytogenes strains isolated from these types of food in that geographic area. Polymerase chain reaction was used to detect eight genes responsible for virulence of this pathogen, namely, prfA, inlA, inlB, hly, plcA, plcB, actA, and mpl. All examined isolates were confirmed to possess the eight virulence genes. Ten different pulsed-field gel electrophoresis (PFGE) macrorestriction profiles were recognized among 19 L. monocytogenes strains after restriction with two different endonucleases (ApaI and AscI). The pathogenicity of three different PFGE types of L. monocytogenes was confirmed through in vivo tests, which were performed on female white mice (Pasteur strain), and it ranged from 3.55 * 10(8) LD50 to 1.58 * 10(10) LD50. All of the three different PFGE types of L. monocytogenes were regarded as moderately virulent in relation to the reference strain L. monocytogenes Scott A. This result might be one of the reasons for the absence of reported listeriosis in northeast Bosnia and Herzegovina, despite the high degree of food contamination with this pathogen. PMID- 21612524 TI - Serological reactivity to Borrelia burgdorferi sensu lato in dogs and horses from distinct areas in Romania. AB - Lyme disease is a perfect model of the complex relationship between host, vector, and the vector-borne bacteria. Both dogs and horses in Romania are exposed to infection. The aim of the present study was to assess the seroreactivity against Borrelia burgdorferi sensu lato in dogs and horses from different regions of Romania. 276 samples from dogs and 260 samples from horses located in different regions of Romania were analyzed by ELISA and IFA, respectively. The effect of several factors potentially affecting seroreactivity (location, age, gender, occupation, and vector exposition risk) was evaluated using Fisher's exact test (R 2.12.0). The overall prevalence of anti-Borrelia antibodies was 6.52% (18/276) in dogs, with a significantly higher positivity (46.15%, 6/13, p = 0.0005) recorded in a midcountry region. Seroreactivity was correlated with occupation, with working dogs being more exposed. The results may indicate that Lyme borreliosis foci are restricted to small areas, but further studies on Borrelia prevalence in tick populations are needed to confirm this hypothesis. In horses, a global seroprevalence of 11.92% (31/260) was observed. No correlations were found between positive results and age, sex, county, or occupation. This is the first serological survey on antibodies to B. burgdorferi sensu lato in Romanian dogs and horses. PMID- 21612526 TI - Comparative evaluation of a point-of-care immunochromatographic test SNAP 4Dx with molecular detection tests for vector-borne canine pathogens in Hong Kong. AB - There are no comprehensive studies on the performance of commonly used point-of care diagnostic enzyme immunoassay for common arthropod-borne canine pathogens. A comparative evaluation of an immunochromatographic test for these infections with a comprehensive polymerase chain reaction (PCR) test panel was performed on 100 pet dogs and 100 stray dogs without obvious clinical symptoms. Of the 162 positive test results from both immunochromatographic test and PCR, there was 85.2% concordance. The 24 discordant results between serology and PCR occurred in tests involving Ehrlichia canis (14) and Anaplasma platys (10), which may be related to the time of infection. No positive cases of borreliosis or rickettsiosis were detected. One important limitation of the immunochromatographic test was its lack of testing for babesiosis and hepatozoonosis. The former is the most prevalent arthropod-borne canine infection in our cohort (41%). Coinfections were found in 19% stray dogs and 6% of pet dogs with both tests (p < 0.01). Seventeen and 8 samples from stray and pet dogs, respectively, were initially positive in the PCR test for Ehrlichia. However, on sequencing of the PCR amplicon, 10 from stray and 2 from pet dogs were found to be Wolbachia sequences instead, with 100% nucleotide identity to the 16S rRNA sequence of Wolbachia endosymbiont of Dirofilaria immitis. The presence of Wolbachia DNAemia (6%) correlated well with the molecular test and immunochromatographic antigen test for D. immitis. PMID- 21612525 TI - Tick saliva represses innate immunity and cutaneous inflammation in a murine model of Lyme disease. AB - Lyme borreliosis is an arthropod-borne disease transmitted by the Ixodes tick. This spirochetal infection is first characterized by a local cutaneous inflammation, the erythema migrans. The skin constitutes a key interface in the development of the disease. During Borrelia inoculation, tick saliva affects the innate and adaptive immunity of the vertebrate host skin. Some key mediators of innate immunity such as antimicrobial peptides (cathelicidin and defensin families) have been identified as important initiators of skin inflammation. We analyzed the role of tick saliva on integumental innate immunity using different protocols of Borrelia infection, via syringe or direct tick transmission. When syringe inoculation was used, Borrelia triggered skin inflammation with induction of CRAMP, the mouse cathelicidin, and tumor necrosis factor-alpha. However, when Borrelia was transmitted directly via the tick, we observed a significant repression of inflammatory genes, suggesting a critical role of tick saliva in skin innate immunity. For all the protocols tested, a peak of intense Borrelia multiplication occurred in the skin between days 5 and 15, before bacterial dissemination to target organs. We conclude that Borrelia pathogens specifically use the tick saliva to facilitate their transmission to the host and that the skin constitutes an essential interface in the development of Lyme disease. PMID- 21612527 TI - Babies and bearded dragons: sudden increase in reptile-associated Salmonella enterica serovar Tennessee infections, Germany 2008. AB - INTRODUCTION: In 2008 a marked increase in Salmonella enterica serovar Tennessee infections in infants occurred in Germany. In March and April 2008, eight cases were notified compared to a median of 0-1 cases in 2001-2006. MATERIALS AND METHODS: We carried out an investigation including a case-control study to identify the source of infection. A patient was a child < 3 years of age with Salmonella Tennessee isolated from stool from September 1, 2007, through December 31, 2008, identified through the national surveillance system. A control was a child with a notified rotavirus infection in the matching district, frequency matched by age group. We conducted telephone interviews on feeding, herbal infusions, and animal contact. Matched odds ratios (mOR) were calculated using exact conditional logistic regression. For Salmonella Tennessee isolates, pulsed field gel electrophoresis and multiple-locus variable number tandem repeat analysis were performed. Further cloacal swab samples of reptiles kept in case households were investigated. RESULTS: We identified 18 cases < 3 years. Ten children were male; median age was 3 months (1-32 months). In 8 of 16 case households reptiles were kept. Direct contact between child and reptile was denied. Other forms of reptile contact were reported in four of the remaining eight households. Ten case- and 21 control-patients were included in the study. Only keeping of a reptile and "any reptile contact" were associated with Salmonella Tennessee infection (mOR 29.0; 95% CI 3.1 +/- infinity and mOR 119.5; 95% CI 11.7 - infinity). Identical Salmonella Tennessee strains of child and reptile kept in the same household could be shown in 2 cases. DISCUSSION: Reptiles were the apparent source of Salmonella Tennessee infection in these infants. Indirect contact between infants and reptiles seems to be sufficient to cause infection and should therefore be avoided. PMID- 21612528 TI - Genetic variability of Anaplasma phagocytophilum in Ixodes persulcatus ticks and small mammals in the Asian part of Russia. AB - The specimens of 3552 questing adult Ixodes persulcatus and 1698 blood/tissue samples of small mammals collected in Ural, Siberia, and Far East of Russia were assayed for the presence of Anaplasma phagocytophilum by nested PCR based on the 16S rRNA gene. Totally, A. phagocytophilum was detected in 112 tick and 88 mammalian samples. The nucleotide sequences of the 16S rRNA gene and groESL operon (1244-1295 bp) were determined for A. phagocytophilum samples from 65 ticks and 25 small mammals. Six different 16S rRNA gene variants differing by 1-5 nucleotide substitutions were detected, and only one variant matched the sequences deposited in GenBank. Analysis of groESL sequences allowed the A. phagocytophilum samples to be divided into three groups; moreover, the samples from different groups also differed in the 16S rRNA gene sequences. The A. phagocytophilum sequences from group I were detected in 11 Myodes spp. samples from West Siberia and Far East and in 19 I. persulcatus samples from all examined regions; from group II, in 10 samples of Myodes spp. and common shrews (Sorex araneus) from Ural; and from group III, in four samples of Asian chipmunks (Tamias sibiricus) from West Siberia and Far East; and in 46 I. persulcatus samples from all examined regions. The nucleotide sequences of A. phagocytophilum groESL operon from groups I and II were strictly conserved and formed with A. phagocytophilum groESL sequence from a Swiss bank vole (Myodes glareolus) (GenBank accession no. AF192796), a separate cluster on the phylogenetic tree with a strong bootstrap support. The A. phagocytophilum groESL operon sequences from group III differed from one another by 1-4 nucleotides and formed a separate branch in the cluster generated by European A. phagocytophilum strains from roe deer (Capreolus capreolus) and Ixodes ricinus ticks. PMID- 21612529 TI - Arthropod-borne tularemia in Poland: a case report. AB - Tularemia is a rare zoonosis. The most common way is ingestion of contaminated meat or water, but the infection may also be acquired by insect bite. The clinical picture of the disease may be nonspecific. Due to polymorphisms of clinical picture, specific treatment is often delayed. In the last 50 years, in Poland, the most infections were acquired by handling hares. In our article, we present the case of a patient who was infected with Francisella tularensis due to arthropod bite. In the presented case, the diagnosis was difficult, because of the nonspecific clinical picture. Information of the epidemiology and the clinical picture changes of tularemia may have great clinical significance. Tularemia requires the special attention of physicians. All patients with lymphadenopathy and arthropod bite history should be screened for tularemia in the outpatient department and, if necessary, treated in hospital. PMID- 21612530 TI - Differential mortality of dog tick vectors due to infection by diverse Francisella tularensis tularensis genotypes. AB - The factors involved in the long-term perpetuation of Francisella tularensis tularensis in nature are poorly understood. Martha's Vineyard, Massachusetts, has become a site of sustained transmission of Type A tularemia, with nearly 100 human cases reported from 2000 to 2010. We have identified a stable focus of F. tularensis transmission there, where the annual prevalence in host-seeking Dermacentor variabilis is about 3%, suggesting that this tick perpetuates the agent. However, laboratory studies have shown that infection with F. tularensis has a profound negative effect on dog tick mortality, presenting a paradox: how can a vector perpetuate an agent that negatively affects its fitness? It may be that experimental infection does not mimic that of natural transmission. Accordingly, we examined the effects that F. tularensis has on the longevity of field-derived ticks. Of 63 PCR-positive ticks collected in early summer, 89% were dead by December compared to 48% of 214 uninfected ticks collected at the same time and site. However, the quantum of F. tularensis DNA within each tick was not correlated with increased mortality. Instead, ticks with an uncommon genotype were more likely to die early than those with the common genotype. We conclude that the interaction between F. tularensis and its vector is complex and certain bacterial genotypes appear to be better adapted to their arthropod host. PMID- 21612531 TI - The importance of Ixodes arboricola in transmission of Rickettsia spp., Anaplasma phagocytophilum, and Borrelia burgdorferi sensu lato in the Czech Republic, Central Europe. AB - Wild birds are known to be a reservoir of infectious disease agents and disseminatory hosts of ticks. The purpose of this work was to obtain information about the occurrence of rickettsial, anaplasmal, and borrelial infections in some ticks that parasitize wild birds in the Czech Republic. A total of 549 subadult ticks of three species Ixodes arboricola (75.0%), Ixodes ricinus (23.1%), and Haemaphysalis concinna (1.8%) were collected from 20 species of birds (Passeriformes). Rickettsiae were detected in 44.0% larvae and 24.5% nymphs of I. arboricola collected from Parus major, Poecile palustris, and Sitta europaea. Rickettsiae-positive I. ricinus larvae (13.7%) were collected from P. major, Cyanistes caeruleus, and S. europaea, and 2.6% of nymphs from Erithacus rubecula and Prunella modularis. Comparison of sequences of a gltA gene fragment with data available in GenBank identified Rickettsia helvetica, a spotted fever rickettsia associated with human infections, and other Rickettsia spp. Anaplasma phagocytophilum was found only in two I. ricinus nymphs collected from E. rubecula and P. major. Infections with Borrelia burgdorferi sensu lato were recorded in 1.3% larvae of I. arboricola acquired from P. palustris and P. major and in 11.8% larvae and 25.0% nymphs of I. ricinus collected from P. major, P. palustris, C. caeruleus, Acrocephalus schoenobaenus, Turdus merula, Carpodacus erythrinus, Sylvia atricapilla, P. modularis, and Phylloscopus collybita. Reverse line blot hybridization showed infections with Borrelia garinii and Borrelia valaisiana and mixed infections with these two genospecies. This is the first record of a high rate of rickettsial infection in I. arboricola subadult ticks acquired from birds in the Czech Republic and in central Europe. Our study suggests that I. arboricola, P. major, and P. palustris play important roles in circulating rickettsiae. PMID- 21612532 TI - Tick-borne bacteria in free-living jaguars (Panthera onca) in Pantanal, Brazil. AB - Tick-borne bacteria were investigated in 10 free-living jaguars and their ticks in the Pantanal biome, Brazil. Jaguar sera were tested by indirect fluorescent antibody assays using Rickettsia rickettsii, Rickettsia parkeri, Rickettsia amblyommii, Rickettsia rhipicephali, Rickettsia felis, Rickettsia bellii, Ehrlichia canis, and Coxiella burnetii as crude antigens. All 10 jaguar sera reacted (titer >= 64) to at least one Rickettsia species; 4 and 3 sera reacted with E. canis and C. burnetii, respectively. One jaguar presented antibody titer to R. parkeri at least fourfold higher than those to any of the other five Rickettsia antigens, suggesting that this animal was infected by R. parkeri. Ticks collected from jaguars included the species Amblyomma cajennense, Amblyomma triste, and Rhipicephalus (Boophilus) microplus. No Rickettsia DNA was detected in jaguar blood samples, but an A. triste specimen collected on a jaguar was shown by PCR to be infected by R. parkeri. The blood of two jaguars and samples of A. triste, A. cajennense, and Amblyomma sp. yielded Ehrlichia DNA by PCR targeting the ehrlichial genes 16S rRNA and dsb. Partial DNA sequences obtained from PCR products resulted in a new ehrlichial strain, here designated as Ehrlichia sp. strain Jaguar. A partial DNA sequence of the 16S rRNA gene of this novel strain showed to be closest (99.0%) to uncultured strains of Ehrlichia sp. from Japan and Russia and 98.7% identical to different strains of Ehrlichia ruminantium. The ehrlichial dsb partial sequence of strain jaguar showed to be at most 80.7% identical to any Ehrlichia species or genotype available in GenBank. Through phylogenetic analysis, Ehrlichia sp. strain jaguar grouped in a cluster, albeit distantly, with different genotypes of E. ruminantium. Results highlight risks for human and animal health, considering that cattle ranching and ecotourism are major economic activities in the Pantanal region of Brazil. PMID- 21612533 TI - Comparison of erythema migrans caused by Borrelia burgdorferi and Borrelia garinii. AB - BACKGROUND: A comparison of patients with erythema migrans due to Borrelia garinii versus Borrelia burgdorferi has not been reported. PATIENTS AND METHODS: One hundred nineteen patients from New York State with erythema migrans caused by B. burgdorferi were compared with 116 patients from Slovenia with erythema migrans due to B. garinii infection. RESULTS: Patients with B. garinii infection were older, more often reported a tick bite, and developed larger lesions (median largest diameter: 18 and 14 cm, respectively; p = 0.01) that more often had central clearing (61.2% compared with 35.3%; p < 0.0001). Patients infected with B. burgdorferi, however, more often had systemic symptoms (68.9% vs. 37.1%; p < 0.0001), including fatigue (p < 0.0001), arthralgia (p = 0.0003), myalgia (p < 0.0001), headache (p = 0.0008), fever and/or chills (p < 0.0001), and stiff neck (p < 0.0001), and more often had abnormal physical findings (57.1% compared with 11.2%; p < 0.0001), such as fever (p = 0.0002) or regional lymphadenopathy (p < 0.0001). There was a trend for more patients with B. burgdorferi infection to have multiple erythema migrans skin lesions (13.4% compared with 5.2%; p = 0.051), and among patients with multiple erythema migrans the number of lesions was greater in B. burgdorferi-infected patients (median: 5.5 compared with 2.0; p = 0.006). CONCLUSIONS: The results of the present study indicate that in patients with erythema migrans the clinical features vary according to whether infection is caused by B. garinii or B. burgdorferi. PMID- 21612534 TI - Molecular evidence supports the role of dogs as potential reservoirs for Rickettsia felis. AB - Rickettsia felis causes flea-borne spotted fever in humans worldwide. The cat flea, Ctenocephalides felis, serves as vector and reservoir host for this disease agent. To determine the role of dogs as potential reservoir hosts for spotted fever group rickettsiae, we screened blood from 100 pound dogs in Southeast Queensland by using a highly sensitive genus-specific PCR. Nine of the pound dogs were positive for rickettsial DNA and subsequent molecular sequencing confirmed amplification of R. felis. A high prevalence of R. felis in dogs in our study suggests that dogs may act as an important reservoir host for R. felis and as a potential source of human rickettsial infection. PMID- 21612535 TI - Rickettsia, Ehrlichia, Anaplasma, and Bartonella in ticks and fleas from dogs and cats in Bangkok. AB - Flea and tick specimens (5-10 fleas or ticks) on dogs and cats from various sites in Bangkok were tested by polymerase chain reaction and DNA sequencing to detect DNA of bacteria Rickettsia (gltA and 17 kDa genes), Anaplasmataceae (16S rRNA gene), and Bartonella (pap31 and its genes). We confirmed that Rickettsia sp. related to Rickettsia felis was detected in 66 of 98 (67.4%) flea specimens from dogs, whereas 8 Bartonella henselae and 2 Bartonella clarridgeiae were detected in 10 of 54 (18.5%) flea specimens from cats. Further, this work provides the first evidence of 10 Ehrlichia canis (3.3%), 7 Anaplasma platys (2.3%), and 2 Wolbachia spp. (0.66%) in 304 Rhipicephalus sanguineus tick specimens in Thailand. PMID- 21612536 TI - Detection of Rickettsia felis and Rickettsia typhi and seasonal prevalence of fleas collected from small mammals at Gyeonggi Province in the Republic of Korea. AB - Fleas were collected from live-captured small mammals to identify flea-borne pathogens, host associations, and seasonal prevalence of flea species, as part of the 65th Medical Brigade rodent-borne disease surveillance program at 20 military installations and training sites, Gyeonggi Province, Republic of Korea, 2005 2007. A total of 1251 fleas were recovered from 2833 small mammals. Apodemus agrarius, the striped field mouse, accounted for 93.1% (2,637/2,833) of all small mammals captured, followed by Crocidura lasiura (3.1%), Mus musculus (1.3%), Microtus fortis (0.7%), Myodes regulus (0.7%), Micromys minutus (0.5%), Rattus norvegicus (0.4%), Tscherskia triton (0.1%), Apodemus peninsulae (< 0.1%), Rattus rattus (< 0.1%), and Mogera robusta (< 0.1%). A total of 6/11 species of mammals captured were infested with fleas with infestation rates ranging from a high of 26.3% (A. agrarius and M. regulus) to a low of 5.3% (M. fortis). Flea indices among infested mammals were highest for R. norvegicus (2.50), followed by C. lasiura (2.20), A. agrarius (1.71), M. regulus (1.20), M. musculus (1.0), and M. fortis (1.0). The predominant flea species collected were Stenoponia sidimi (56.5%), followed by Ctenophthalmus congeneroides (38.3%) and Rhadinopsylla insolita (3.9%). The minimum field infection rates [number of positive pools/total number of fleas (600)] for Rickettsia typhi and for Rickettsia felis were 1.7% and 1.0%, respectively. PMID- 21612537 TI - Prospective study of avian influenza infection in backyard poultry flocks and flock handlers in Wisconsin. AB - BACKGROUND: The continuing epizootic of H5N1 avian influenza (AI) in Asia and subsequent zoonotic transmission has led to heightened concerns about a pandemic and the demand for improved surveillance of poultry in all sectors, including backyard poultry. We conducted a 15-month prospective study to determine the prevalence of AI in backyard poultry and extent of transmission to flock handlers. METHODS: Starting July 2007, registered poultry owners in six counties in central Wisconsin were mailed invitations to participate; household members with poultry exposure were also invited. Premises with < 1000 birds were eligible. Participants completed a baseline interview to characterize poultry exposures. Illness in flocks and flock handlers was monitored using semimonthly telephone interviews and self-report of acute influenza-like symptoms by flock handlers. Participants provided blood at baseline and at the end of the surveillance period for serology and, if ill, nasopharyngeal, eye, and throat swabs for viral testing. Blood was also collected at baseline from a convenience sample of adult poultry. RESULTS: We enrolled 87 flocks and 128 persons who had regular contact with poultry. Influenza-like symptoms were reported by 77 (65%) persons. Swabs were collected from 53 persons at 88 illness episodes. AI was not isolated, but five persons were positive for human influenza. Twenty-one participants (20%) seroconverted to at least one human influenza strain, but there were no seroconversions to AI. Blood samples from all 717 birds tested were seronegative for influenza. CONCLUSION: Despite limited biosecurity there was no evidence of AI infection in participating backyard flocks or flock handlers. PMID- 21612538 TI - Localized leishmanial lymphadenopathy: an unusual manifestation of leishmaniasis in a traveler in southern Europe. AB - A 38-year-old male patient presented with enlarged nuchal and sinistral supraclavicular lymph nodes of about 1-month history. He had no further signs or symptoms of disease and was not immunocompromised. His travel history included India, South America, and Africa but only southern Europe during more recent years. Leishmania parasites were histologically detected in a lymph node and Leishmania (Leishmania) infantum, the causative species of leishmaniasis in the European Mediterranean area, was identified by PCR and sequencing. Leishmanial infection should be included in the differential diagnosis of localized lymph node enlargement in returnees from endemic countries including southern Europe. PMID- 21612539 TI - First report of the isolation and molecular characterization of Rickettsia amblyommii and Rickettsia felis in Central America. AB - During 2010, 15 adult ticks, identified as Amblyomma cajennense, were collected from horses in Cahuita and Turrialba districts, whereas 7 fleas, identified as Ctenocephalides felis, were collected from a dog in San Jose city, Costa Rica. In the laboratory, three A. cajennense specimens, two from Cahuita and one from Turrialba, were individually processed for rickettsial isolation in cell culture, as was a pool of seven fleas. Rickettsiae were successfully isolated and established in Vero cell culture from the three ticks and from a pool of seven fleas in C6/36 cell culture. The three tick isolates were genotypically identified as Rickettsia amblyommii, and the flea isolate was identified as Rickettsia felis through DNA sequencing of portions of the rickettsial genes gltA, ompA, and ompB of each isolate. In addition, other seven ticks were shown to contain rickettsial DNA. Polymerase chain reaction products of at least two of these ticks were sequenced and also showed to correspond to R. amblyommii. Overall, 66.7% (10/15) of the A. cajennense adult ticks were found to be infected with rickettsiae. This is the first report of a successful isolation in cell culture of R. amblyommii and R. felis from Central America. PMID- 21612540 TI - Fighting zebrafish: characterization of aggressive behavior and winner-loser effects. AB - Aggression is a key component of the behavioral repertoire of animals that impacts on their Darwinian fitness. The available genetic tools in zebrafish make this species a promising vertebrate neurogenetic model for the study of neural circuits underlying aggressive behavior. For this purpose, a detailed characterization of the aggressive behavior and its behavioral consequences is first needed. In this article we establish a simple protocol that reliably elicits the expression of fighting behavior in zebrafish dyads and characterized it. The agonistic behavior expressed during dyadic fighting behavior has a temporal structure, indicating the existence of an underlying architecture prone to genetic manipulation. Social interactions have consequences for subsequent behavior with a potential fitness impact, which stresses the validity of this species for the study of aggression. These effects of experience seem to be mediated by different mechanisms in winners and losers. Winners increase the probability of winning subsequent fights without changing their fighting behavior, suggesting the existence of social status cues. On the other hand, losers decrease the probability of winning subsequent fights by decreasing their motivation to escalate fights. Together, these results are a first step to the development of a quantitative framework for the study of aggressive behavior in zebrafish. PMID- 21612541 TI - Serum APRIL, a potential tumor marker in pancreatic cancer. AB - BACKGROUND: A proliferation-inducing ligand (APRIL) is a newly-found member in the tumor necrosis factor (TNF) superfamily. Our previous studies have already confirmed that APRIL is overexpressed in pancreatic cancer tumors, however, it is not expressed or has a weak expression in normal pancreatic gland tissues. Furthermore, there is no report on serum APRIL in patients with pancreatic diseases. Herein, in order to explore the clinical implication of serum APRIL in patients with pancreatic cancer, serum APRIL, together with carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9, was examined. METHODS: Serum APRIL was tested by ELISA in patients with pancreatic cancer. Meanwhile, two other conventional serum tumor markers, CEA and CA19-9, were measured by Elecsys 2010 Chemistry Analyzer. RESULTS: Serum APRIL increased in patients with pancreatic cancer, which proved a positive correlation with CEA and CA19-9. When the diagnosis of benign or malignant condition was examined by one tumor marker, the sensitivity of APRIL alone (70.1%) was greater than that of CEA alone (56.7%), and the specificity of APRIL alone (85.5%) was higher than that of CA19 9 alone (83.6%). When examined by a combination of two markers, the sensitivity of the combination of APRIL and CA19-9 was the highest (88.1%), as it was compared with that of APRIL alone, CEA alone and APRIL+CEA, p<0.05. In addition, serum APRIL also correlated with the tumor stage and postoperative survival in patients with pancreatic cancer. CONCLUSIONS: Our results indicate that serum APRIL, as a potential biomarker, has a positive diagnosis and prognosis value for pancreatic cancer. Moreover, the combination assay of APRIL and CA19-9 is highly sensitive to pancreatic cancer. PMID- 21612542 TI - Translating pharmacogenetics into clinical practice: interleukin (IL)28B and inosine triphosphatase (ITPA) polymophisms in hepatitis C virus (HCV) infection. AB - Hepatitis C virus (HCV) infection is frequently characterized by evolution to chronicity and by a variable clinical course of the disease. The clinical heterogeneities of HCV infection and the imperfect predictability of the response to interferon (IFN) have suggested the need to search for a genetic basis of clinical features. This led to the discovery of genetic polymorphisms playing a major role in the evolution of infection, as well as on treatment response and adverse effects. This review will cover recent reports on the subject, focusing on the potential use of the new genetic markers in the diagnostic algorithm for the stratification of patients for personalized antiviral regimens. PMID- 21612543 TI - The antinuclear antibody assay: developing criteria for reflexive anti-dsDNA antibody testing in a laboratory setting. AB - BACKGROUND: We examined the relationship between antinuclear antibody (ANA) data and the presence of anti-double stranded DNA antibodies (anti-dsDNA). METHODS: De identified demographic, ANA and anti-dsDNA data were available for 30,196 individuals aged >= 20 years, whose sera were submitted sequentially to our laboratory. When multiple sera were received for the same subject, data from the earliest sample were used. Anti-dsDNA frequency was stratified by ANA titer and pattern, sample referral source, and by the patient's age, gender, and diagnosis. RESULTS: For sera with ANA titer >= 256 and an accompanying diagnosis of systemic lupus erythematosus, anti-dsDNA frequency was 53.7%, 35.3%, and 37.5% for homogeneous, speckled, or multiple ANA patterns, respectively. Among remaining sera with ANA titer >= 256, anti-dsDNA frequency was highest for the homogeneous pattern (15.9%). Anti-dsDNA frequency was three-fold higher among sera submitted by rheumatologists compared with other providers. However, its relative distribution by ANA pattern and titer was similar between these groups. Patient age and gender had no significant effect on anti-dsDNA frequency after ANA data were taken into account. CONCLUSIONS: ANA pattern and titer, together with the diagnosis submitted with the serum sample, can be used to guide decisions for reflexive anti-dsDNA testing in a clinical laboratory setting. PMID- 21612544 TI - Prevalence and correlates of lifetime HIV testing in a population-based sample of men who have sex with men in Massachusetts. PMID- 21612546 TI - Targeting candidates for directly administered highly active antiretroviral therapy: benefits observed in HIV-infected injecting drug users in residential drug-rehabilitation facilities. AB - The purpose of this study was to evaluate retrospectively the potential benefits of directly administered antiretroviral therapy (DAART) in HIV-infected former injecting drug users (ex-IDUs) admitted to residential drug rehabilitation facilities. We compared 106 of these patients consecutively admitted in 12 communities where DAART was administered (DAART group) to two matched control groups of ex-IDUs undergoing self-administered ART: 106 subjects in other 10 communities (SAT group) and 106 outpatients at hospital infectious-disease wards where community patients were referred after discharge (OUT group). We estimated the proportion of patients with high adherence and the hazard ratio (HR) of 20% or more increase in the CD4(+) cell count and of reaching an undetectable viral load. The proportion of patients with high adherence to treatment was highest in the DAART group. The probability of 20% or more increase in the CD4(+) cell count was significantly lower in the two control groups versus the DAART group (SAT group HR=0.32; OUT group HR=0.43). The HR of observing an undetectable HIV-RNA level versus DAART was significantly lower in the OUT group (HR: 0.71; 95% confidence interval [CI]: 0.52-0.97) but did not reach statistical significance for the SAT group (HR: 0.99; 95% CI: 0.74-1.33). Our findings after a 24-month follow-up, suggest that DAART in HIV-infected patients of drug-rehabilitation communities improves adherence, immunologic, and virologic outcome toward free outpatients. Even if our retrospective 36-month data do not show a prolonged viral suppression in these patients, DAART may be considered a valuable therapeutic and educational strategy in this particular target group. PMID- 21612545 TI - Effects of darunavir/ritonavir-based therapy on metabolic and anthropometric parameters in women and men over 48 weeks. AB - Gender-based differences in lipids have been noted in antiretroviral clinical trials. We present the metabolic and anthropometric data from the GRACE (Gender, Race And Clinical Experience) study by gender. Treatment-experienced adults received darunavir/ritonavir (DRV/r) 600/100 mg twice daily, plus a background regimen, over 48 weeks. Fasting blood samples were obtained for lipid, glucose, and insulin measurements at baseline and at weeks 24 and 48/early discontinuation. Anthropometric measurements were taken at baseline and at weeks 12, 24, and 48/discontinuation. The Assessment of Body Change and Distress questionnaire was administered at baseline and regular intervals. Descriptive statistics as well as comparisons using a Wilcoxon rank-sum test are reported. Four hundred twenty-nine patients (women, n=287; men, n=142) enrolled in GRACE; 94 women (32.8%) and 33 men (23.2%) discontinued the trial. Median changes in triglycerides from baseline to week 48 were higher in men (25 mg/dL versus 8 mg/dL; p=0.006); the mean change in triglycerides was higher in men than in women in all racial subgroups. Other lipid and glucose level changes were similar between genders. Anthropometric parameters increased for both genders, with larger increases in women. Patients' perceptions of body changes concurred with physical measurements. The proportion of women who were "satisfied" or "very satisfied" with their bodies increased from 45.2% to 57.8% from baseline to week 48 (p=0.005), while the proportion of men who were "satisfied" or "very satisfied" with their bodies increased from 56.3% to 61.5% from baseline to week 48 (p=0.317). DRV/r-based therapy was associated with small to moderate changes in metabolic parameters, and few between-gender differences were observed. Levels of self-reported, body-related distress improved for women and men over 48 weeks. PMID- 21612548 TI - An interview with Ken Valenzano, Ph.D. Interview by Vicki Glaser. PMID- 21612547 TI - Early end for FEM-PrEP HIV prevention trial. PMID- 21612549 TI - Literature search and review. PMID- 21612551 TI - The First Physical Therapy Summit on Global Health: implications and recommendations for the 21st century. AB - The First Physical Therapy Summit on Global Health was convened at the 2007 World Confederation for Physical Therapy (WCPT) Congress to vision practice in the 21st century and, in turn, entry-level education and research, as informed by epidemiological indicators, and consistent with evidence-based noninvasive interventions, the hallmark of physical therapy. The Summit and its findings were informed by WHO data and validated through national databases of the countries of the five WCPT regions. The health priorities based on mortality were examined in relation to proportions of physical therapists practicing in the areas of regional priorities and of the curricula in entry-level programs. As a validation check and to contextualize the findings, input from members of the 800 Summit participants was integrated and international consultants refined the recommendations. Lifestyle-related conditions (ischemic heart disease, smoking related conditions, hypertension, stroke, cancer, and diabetes) were leading causes of premature death across regions. Contemporary definitions of physical therapy support that the profession has a leading role in preventing, reversing, as well as managing lifestyle-related conditions. The proportions of practitioners practicing primarily in these priority areas and of the entry-level curricula based on these priorities were low. The proportions of practitioners in priority areas and entry-level curricula devoted to lifestyle-related conditions warrant being better aligned with the prevalence of these conditions across regions in the 21st century. A focus on clinical competencies associated with effective health education and health behavior change formulates the basis for The Second Physical Therapy Summit on Global Health. PMID- 21612553 TI - Infection or rather allergy? PMID- 21612555 TI - Abstracts of the Royal Australian and New Zealand College of Psychiatrists (RANZCP) 2011 Congress. May 29-June 2, 2011. Darwin, Northern Territory, Australia. PMID- 21612550 TI - Identification and characterization of pharmacological chaperones to correct enzyme deficiencies in lysosomal storage disorders. AB - Many human diseases result from mutations in specific genes. Once translated, the resulting aberrant proteins may be functionally competent and produced at near normal levels. However, because of the mutations, the proteins are recognized by the quality control system of the endoplasmic reticulum and are not processed or trafficked correctly, ultimately leading to cellular dysfunction and disease. Pharmacological chaperones (PCs) are small molecules designed to mitigate this problem by selectively binding and stabilizing their target protein, thus reducing premature degradation, facilitating intracellular trafficking, and increasing cellular activity. Partial or complete restoration of normal function by PCs has been shown for numerous types of mutant proteins, including secreted proteins, transcription factors, ion channels, G protein-coupled receptors, and, importantly, lysosomal enzymes. Collectively, lysosomal storage disorders (LSDs) result from genetic mutations in the genes that encode specific lysosomal enzymes, leading to a deficiency in essential enzymatic activity and cellular accumulation of the respective substrate. To date, over 50 different LSDs have been identified, several of which are treated clinically with enzyme replacement therapy or substrate reduction therapy, although insufficiently in some cases. Importantly, a wide range of in vitro assays are now available to measure mutant lysosomal enzyme interaction with and stabilization by PCs, as well as subsequent increases in cellular enzyme levels and function. The application of these assays to the identification and characterization of candidate PCs for mutant lysosomal enzymes will be discussed in this review. In addition, considerations for the successful in vivo use and development of PCs to treat LSDs will be discussed. PMID- 21612554 TI - Identification of mesenchymal stem cells in perinodular fat and skin in Dupuytren's disease: a potential source of myofibroblasts with implications for pathogenesis and therapy. AB - Dupuytren's disease (DD) is a fibroproliferative disorder characterized by aberrant proliferation of myofibroblasts, the source of which remains unknown. Recent studies indicate that circulating and tissue-resident mesenchymal stem cells (MSCs) can differentiate into myofibroblasts. Therefore, the aim of this study was to profile MSCs from phenotypically distinct DD sites including cord, nodule, skin overlying nodule (SON), and perinodular fat (PNF) compared with unaffected internal controls, that is, distant palmar fat (DPF) and transverse palmar fascia (Skoog's fibers) as well as external control carpal tunnel (CT) tissue including skin, fat, and fascia. Freshly isolated primary fibroblasts as well as cells grown up to passage 5 (P5) from DD (n=27) and CT (n=14) samples were analyzed for the presence of established MSC markers CD73, CD90, and CD105 and absence of hematopoietic marker CD34 using fluorescence-activated cell sorting, in-cell quantitative western blotting, immunohistochemistry, and immunocytochemistry. Freshly isolated cells from SON, PNF, and cord biopsies had a higher number of CD34(-)73(+)90(+)105(+) cells compared with Skoog's fibers and CT controls. P3 cells obtained from all DD biopsies compared with CT samples differentiated into osteocytes, adipocytes, and chondrocytes. P3 cord and nodule cells expressed intense alpha-smooth muscle actin staining compared with skin and fat cells. Stem cell markers including stem cell factor, MSC-homing marker CXCR4, and Wnt/beta-catenin downregulator Dkk-1 were all upregulated in SON and PNF compared with CT skin and CT fat, respectively, as shown by real-time quantitative polymerase chain reaction. However, osteogenic marker OSF-1 had a significantly higher expression in the PNF (P=0.002) and cord (P=0.01) compared with the nodule. In conclusion, we have shown the presence of MSCs in specific DD tissue phenotypes compared with internal and external control tissue. These findings provide preliminary support for a potential alternative source of disease myofibroblasts originating from sites such as SON and PNF as opposed to palmar fascia alone. PMID- 21612559 TI - Neisseria meningitidis serogroup B meningitis relapse after five days of cefotaxime treatment: what went wrong? AB - The authors describe a case of relapse of Neisseria meningitidis serogroup B meningitis in a 21-y-old male, 48 h after a 5-day treatment with cefotaxime 215 mg/kg per day. Brain magnetic resonance imaging (MRI) excluded the hypothesis of cerebral abscess or central venous septic thrombosis, and transthoracic echocardiography excluded bacterial endocarditis. Complement, properdin, and protein electrophoresis were normal. The plausible explanations for this relapse and the implications for other similar cases are discussed. PMID- 21612560 TI - Clinical profile of hearing loss in children with congenital cytomegalovirus (CMV) infection: CMV DNA diagnosis using preserved umbilical cord. AB - CONCLUSIONS: Congenital cytomegalovirus (CMV) infection is a major cause of bilateral and unilateral sensorineural hearing loss (SNHL) in children, accounting for 9.0% of SNHL cases. The diagnostic rate using combined genetic deafness test and CMV DNA detection test was determined to be 46.4% in bilateral profound SNHL. OBJECTIVES: The present study investigated the prevalence of congenital CMV infection diagnosed retrospectively by detection of CMV DNA in dried umbilical cord specimens from children with unilateral or bilateral SNHL up to the age of 12 years. METHODS: Preserved dried umbilical cords were collected from 134 children with bilateral (46 children) or unilateral (88 children) SNHL. DNA was extracted from the dried umbilical cords and CMV DNA was detected by quantitative PCR. Genetic deafness tests based on the invader assay were performed in children with bilateral SNHL. RESULTS: CMV DNA from the dried umbilical cords was detected in 8.7% of the bilateral SNHL and 9.1% of unilateral SNHL. Deafness gene mutations were identified in 21.7% (10/46) of children with bilateral SNHL. PMID- 21612561 TI - Disseminated sporotrichosis in a patient with hairy cell leukemia treated with amphotericin B and posaconazole. AB - We describe a case of disseminated Sporothrix schenckii infection in a man with underlying hairy cell leukemia. The immunological defects associated with this malignancy, as well as the management of refractory sporotrichosis are reviewed. PMID- 21612562 TI - Microdilution in vitro antifungal susceptibility of Exophiala dermatitidis, a systemic opportunist. AB - The in vitro activities of eight antifungal agents were determined against clinical (n = 63 genotype A, n = 3 genotype B) and environmental (n = 2 genotype A, n = 13 genotype B) strains of Exophiala dermatitidis. The resulting MIC(90)s for all strains (N = 81) were, in increasing order, as follows: posaconazole, 0.125 MUg/ml; itraconazole, 0.25 MUg/ml; voriconazole, 0.5 MUg/ml; amphotericin B, 0.5 MUg/ml; isavuconazole, 1 MU/ml; caspofungin, 8 MUg/ml; anidulafungin, 8 MUg/ml and fluconazole, 16 MUg/ml. There were no significant differences in the patterns of susceptibility between genotypes A and B, environmental and clinical strains, isolates recovered from cutaneous and deep locations and strains from different geographical areas (P > 0.05). The difference in the MIC(90)s between each of these groups was not more than one dilution. The present study demonstrated that, based on in vitro activity, posaconazole and itraconazole have the highest activity against this fungus. In addition, voriconazole and the experimental broad-spectrum antifungal triazole, isavuconazole, both of which are available as intravenous preparations, have adequate activity against E. dermatitidis. However, in vivo efficacy remains to be determined. PMID- 21612563 TI - Characteristics and specificities of Cryptococcus infections in French Guiana, 1998-2008. AB - Cryptococcosis is a common opportunistic systemic mycosis caused by members of the encapsulated yeast genus Cryptococcus. The aetiological agents of the disease are classified into two species, i.e., Cryptococcus neoformans (serotypes A, D, and AD) affecting mainly immunocompromised patients and Cryptococcus gattii (serotypes B and C) usually found in immunocompetent individuals. Limited data exist on Cryptococcus infections in French Guiana, the department with the highest HIV incidence in the French territories. A retrospective study between January 1998 and December 2008 was performed on all patients with cryptococcosis, admitted to hospitals in French Guiana. Epidemiological data, clinical forms and diagnosis methods were studied. Of the 43 patients with cryptococcosis, 29 (67.4%) had HIV infections. Among the HIV-negative patients, two (4.7%) presented identified risk factors for cryptococcosis. This study has shown a high frequency of patients with HTLV-1 positive serology (12.1%). C. neoformans var. grubii was recovered with a frequency of 77.3% and was mainly isolated from patients with AIDS (13/17), whereas C. gattii (22.7%) was strictly isolated from HIV-negative patients with no apparent risk factors. Despite a socio-economic environment closer to western countries, the overall epidemiology of cryptococcosis in French Guiana is more similar to that found in South America, particularly with reference to the serotypes of the causative yeasts. Indeed, French Guiana presents an especially high proportion of cases caused by C. gattii, which may explain the significant incidence of this disease, particularly in HIV-negative and immunocompetent patients. PMID- 21612564 TI - Anticomplement activity of various solvent extracts from Korea local Artemisia spp. AB - The study evaluated the anticomplement activity from various solvent extracts of eight Artemisia plants (Artemisia capillaris Thunb., Artemisia fukudo Makino., Artemisia japonica Thunb., Artemisia montana (Nakai) Pamp., Artemisia keiskeana Miq., Artemisia rubripes Nakai., Artemisia stolonifera (Maxim.) Kom., and Artemisia sylvatica Max.) from South Korea on the classical pathway (CP). We have evaluated various organic solvent extract from eight Artemisia plants with regard to its anticomplement activity on the CP. A. rubripes and A. montana chloroform extracts showed inhibitory activity against complement system with 50% inhibitory concentrations (IC50) values of 54.3 and 64.2 MUg/mL. This is the first report of anticomplement activity from Artemisia plants. PMID- 21612565 TI - Markov random field model for segmenting large populations of lipid vesicles from micrographs. AB - Giant unilamellar lipid vesicles, artificial replacements for cell membranes, are a promising tool for in vitro assessment of interactions between products of nanotechnologies and biological membranes. However, the effect of nanoparticles can not be derived from observations on a single specimen, vesicle populations should be observed instead. We propose an adaptation of the Markov random field image segmentation model which allows detection and segmentation of numerous vesicles in micrographs. The reliability of this model with different lighting, blur, and noise characteristics of micrographs is examined and discussed. Moreover, the automatic segmentation is tested on micrographs with thousands of vesicles and the result is compared to that of manual segmentation. The segmentation step presented is part of a methodology we are developing for bio nano interaction assessment studies on lipid vesicles. PMID- 21612566 TI - Baicalin suppresses expression of TLR2/4 and NF-kappaB in chlamydia trachomatis infected mice. AB - Our previous studies have shown that the baicalin could blocked infection of chlamydia trachomatis (C. trachomatis)-infected cells in vitro. Toll-like receptor 2 and 4 (TLR2/4) and the downstream nuclear factor-kappaB (NF-kappaB) signaling pathway, which mediate the inflammatory reaction, are involved in the pathophysiological processes of inflammation. In this study, we investigated whether baicalin inhibits TLR2/4 signaling pathway in gential tract chlamydia infected mice. The progesterone-treated animals were given intravaginally 200 mg/kg baicalin administered. Nineteen days after infection, cervical tissue were taken and expression of TLR2/4, NF-kappaB were determined by RT-PCR or westernblot. Nitric oxide and prostaglandin E2 production in cervical tissue were detected by enzyme-linked immunosorbent assay. It was demonstrated that baicalin significantly reduced C. trachomatis loading in BALB/c mice that were vaginally infected with the pathogen. Meanwhile, baicalin also reduced the expression of TLR2/4 and NF-kappaB, decreased activity of inducible nitric oxide synthase and cyclooxgenase-2 in cervical tissue. Our results suggest that baicalin inhibits the TLR2/4 signaling pathway in cervical tissue of gential tract chlamydia infected mice. On the basis of these data and our previous observations, we conclude that further evaluation of baicalin for prevention and treatment of sexually transmitted chlamydial infection is warranted. PMID- 21612567 TI - Sanggenon C and O inhibit NO production, iNOS expression and NF-kappaB activation in LPS-induced RAW264.7 cells. AB - OBJECTIVE: The NO production through the iNOS induction by activation of nuclear factor (NF-kappaB) is known to involve in various inflammatory conditions. Sanggenon C and O, two Diels-Alder type adducts isolated from Morus alba, a plant has been used for the anti-inflammatory purpose in the Oriental medicine, were investigated for their effect on the NO production, iNOS expression and NF-kappaB activity. METHODS: The inhibitory effects of sanggenon C and O on the NF-kappaB activity were investigated in LPS-stimulated RAW264.7 cells by SEAP reporter assay. The regulation of the iNOS expression and IkappaBalpha activation by two compounds was also evaluated by Western blot. RESULTS: Both compounds strongly inhibited NO production and NF-kappaB activation in a dose-dependent manner. The expression of the iNOS protein was also suppressed by treatment of the compounds (10 and 1 uM). Sanggenon O showed stronger inhibition than the diastereomer sanggenon C. Both compounds prevented the phosphorylation and degradation of IkappaBalpha protein. CONCLUSION: We demonstrated that sanggenon C and O inhibited NO production and iNOS expression by suppressing NF-kappaB activity and IkappaBalpha activation. PMID- 21612568 TI - Sweet's syndrome associated with the intake of a selective cyclooxygenase-2 (COX 2) inhibitor. AB - Sweet's syndrome (SS; acute febrile neutrophilic dermatosis) is a skin disorder characterized by acute tender erythematous plaques or nodules that may blister and ulcerate. The disease presents in several clinical settings including: classical (idiopathic) SS, malignancy-associated SS and drug-induced SS. Several drugs have been implicated in the etiopathogenesis of the disease with the most frequent being the granulocyte-colony stimulating factor. We report and discuss a case of SS associated with the intake of a selective cyclooxygenase-2 inhibitor, which has been rarely reported. PMID- 21612569 TI - Expansion of defective NK cells in early HIV type 1C infection: a consequence of reduced CD161 expression. AB - Human immunodeficiency virus (HIV)-1 infection compromises the natural killer (NK) cell function and leads to defective control on virus multiplication. One of the major features of HIV-1 infection is the expansion of a functionally compromised defective NK cell subset (CD56(-)CD16(+)). We analyzed the NK cell subsets in early HIV infection to determine the effect of NK cell perturbation on the viral load set point, a marker of disease progression. We report that the defective NK cells are expanded in early HIV infection within 6-8 months of acquiring infection and are correlated with a higher plasma viral load set point, suggesting its utility as a predictive marker for disease progression. The expression of CD161, a molecular marker responsible for proliferation and differentiation of NK cells, was significantly down-regulated in the defective NK cells as compared to slow progressors (p=0.0009) and healthy controls (p=0.0003) and was correlated with a higher viral load set point in early HIV-1 infection (r=-0.6154, p=0.03), suggesting the probable role of CD161 expression in the impaired proliferation and differentiation of defective NK cells into the functional NK cells in early HIV infection. The reduction in CD161 expression on the defective NK cells in early HIV infection is thus indicative of the role of innate immune cells in early control of HIV infection. PMID- 21612570 TI - Weaning of neonates from mechanical ventilation by use of nasopharyngeal high frequency oscillatory ventilation: a preliminary study. AB - OBJECTIVE: To investigate the feasibility of nasopharyngeal high-frequency oscillatory ventilation (nHFOV) immediately after extubation in difficult-to-wean preterm infants. STUDY DESIGN: This was an observational study of 20 mechanically ventilated neonates [median (range) birth weight 635 (382-1020)g, median gestational age 25.3 (23.7-27.6) weeks] at high risk for extubation failure. Nine infants had failed at least one previous extubation. Fourteen infants were given hydrocortisone. All 20 infants were extubated into nHFOV, with a mean airway pressure of 8 cmH(2)O, an amplitude of 20 cmH(2)O, and a frequency of 10 Hz. RESULTS: Infants remained on nHFOV for a median duration of 136.5 (7.0-456.0) h until further weaning to continuous positive airway pressure (n =14) or reintubation (n = 6). Reintubation was performed in 1 of 11 infants who had not experienced any previous extubation, and in five of nine infants who had experienced at least one previous extubation (P < 0.05). PaCO(2) was virtually unchanged from preextubation levels 2 h after extubation, but declined significantly at 32 h from 59.8 (45.0-92.3) mmHg to 50.7 (39.8-74.4) mmHg (P < 0.01). PaCO(2) returned to preextubation levels upon discontinuation of nHFOV. CONCLUSION: This small observational study demonstrates that nHFOV can be successfully applied to wean premature infants from ventilator support. PMID- 21612571 TI - Delivery of atovaquone and proguanil across sublingual membranes, in vitro. AB - Malarone(TM), a combination of atovaquone (AT) and proguanil (PR), is indicated for the prophylaxis and treatment of uncomplicated Plasmodium falciparum malaria. This study aimed to determine in vitro the feasibility of delivering the combination of AT and PR as a spray formulation via the sublingual route, using Franz diffusion cells incorporating porcine sublingual mucosa. Firstly, 1 mg mL( 1) of each drug in 20% 1,8-Cineole in ethanol was used; and secondly, 5 mg mL(-1) AT and 1 mg mL(-1) PR in 20% 1-methyl-2-pyrrolidone in ethanol was examined, dosed every 2 h over a 12-h period and receptor phase samples were analyzed by HPLC. From the first study, mean fluxes for AT and PR were 12.89 +/- 1.2 and 5.88 +/- 0.9 ug cm(-2) h(-1) respectively; pharmacokinetic calculations indicated that these fluxes were insufficient to achieve the target plasma concentrations for AT and PR of 1.4 ug mL(-1) and 200 ng mL(-1) respectively, in the treatment of falciparum malaria. However, in the second study, the fluxes of AT and PR increased to 50.92 +/- 20.8 and 12.01 +/- 1.5 ug cm(-2) h(-1) respectively, and pharmacokinetic calculations indicated that therapeutic plasma concentrations are attainable for pediatric application. PMID- 21612572 TI - Three-dimensional-construct bioreactor conditioning in human tendon tissue engineering. AB - Human tendon tissue engineering attempts to address the shortage of autologous tendon material arising from mutilating injuries and diseases of the hand and forearm. It is important to maximize the tissue-engineered construct's (TEC's) biomechanical properties to ensure that the construct is in its strongest possible state before reimplantation. In this study, we sought to determine the bioreactor treatment parameters that affect these properties. Using small- and large-chamber three-dimensional-construct bioreactors (SCB and LCB, respectively), we applied cyclic axial load to TECs comprising reseeded human flexor and extensor tendons of the hand. First, small-sample pilot studies using the LCB were performed on matched-paired full-length flexor tendons to establish proof of concept. Next, large-sample studies using the SCB were performed on matched-paired extensor tendon segments to determine how reseeding, load duty cycle, load magnitude, conditioning duration, and testing delay affected ultimate tensile stress (UTS) and elastic modulus (EM). We found that compared with reseeded matched-paired controls under dynamic-loading at 1.25 N per TEC for 5 days, (1) acellular TECs had lower UTS (p=0.04) and EM (p<0.01), (2) unloaded TECs had lower UTS (p=0.01) and EM (p=0.02), (3) static-loaded TECs had lower UTS (p=0.01) and EM (p<0.01), (4) TECs conditioned for 3 days had lower UTS (p=0.03) and EM (p=0.04), and (5) TECs conditioned for 8 days had higher UTS (p=0.04) and EM (p=0.01). However, TECs conditioned at higher loads (2.5 N per TEC) and lower loads (0.625 N per TEC) possessed similar UTS (p=0.83 and p=0.89, respectively) and EM (p=0.48 and p=0.89, respectively) as controls stimulated with 1.25 N per TEC. After cycle completion, there is attrition of UTS (p=0.03) and EM (p=0.04) over a 2-day period. Our study showed that the material properties of human allograft TECs can be enhanced by reseeding and dynamic-conditioning. While conditioning duration has a significant effect on material properties, the load magnitude does not. The issue of attrition in biomechanical properties with time following cycle completion must be addressed before bioreactor preconditioning can be successfully introduced as a step in the processing of these constructs for clinical application. PMID- 21612573 TI - Scientific journals provide a foundation for scientific progress. PMID- 21612574 TI - New therapeutic strategies for castration-resistant prostate cancer. AB - Docetaxel has until recently been the only agent with a small survival benefit for metastatic castration-resistant prostate cancer (CRPC). To improve clinical outcome in CRPC, numerous classes of drugs targeting specific pathways involved in hormone action, bone metabolism, angiogenesis, apoptosis and immune response have currently been investigated concerning the efficacies of either single agents or combinations with docetaxel. Noteworthy, current two phase III trials of cabazitaxel and sipuleucel-T have demonstrated significant improvements of overall survival in CRPC. From the viewpoint of complexity of mechanisms implicated in prostate cancer progression, effective therapeutic strategies should be developed by multifaceted approaches, such as the composition of novel agents targeting for key molecules, cytotoxic chemotherapy, and immunotherapy. The recent patented molecules (e.g., hyaluronidase, caveolin, Bag1-L, N-cadherin, AR splicing variants, PCGEM-1) have a strong potential as therapeutic options for CRPC. Here, we review the newest evidence of novel agents and patented compounds and methods for the purpose of the future use in CRPC. PMID- 21612575 TI - Drug combinations enhancing the antineoplastic effects of erlotinib in high-grade glioma. AB - Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Especially in this disease, qualitative and quantitative aspects render the dysregulated epidermal growth factor receptor (HER1/EGFR) an outstanding therapeutic target. A variety of therapeutic compounds was developed to target HER1/EGFR among which the clinically most advanced agents are small molecule tyrosine kinase (TK) inhibitors. Unfortunately, clinical studies examining their therapeutic efficacy have so far failed to document a major therapeutic break through in the setting of GBM. Thus, the targeted approach against HER1/EGFR likely requires a synergistic drug combination strategy to ultimately become successful in this disease. This patents review focuses on innovative therapeutic strategies combining HER1/EGFR-targeted TK inhibitors with novel agents which for the most part have not been evaluated for the treatment of GBM yet but which constitute interesting candidates for further evaluation in this setting. PMID- 21612576 TI - Emerging role of apelin as a therapeutic target in cancer: a patent review. AB - Since tumors cannot grow or spread without forming new blood vessels, inhibiting angiogenesis is an excellent approach for the treatment of cancer. Further, inhibitors of angiogenesis have mild side effects since they act on endothelial cells, which eliminate the possibility of developing resistance or tolerance in tumor cells, unlike that seen with chemotherapy drugs. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab acts by preventing new blood vessel formation in solid tumors and is approved by FDA to treat colorectal, lung, breast, glioblastoma and kidney cancers. The registration of this drug and its ongoing success in the clinic has validated the targeting of angiogenesis as an important approach to the treatment of solid tumors. Apelin is a novel angiogenic factor and recent studies indicate that apelin promotes angiogenesis, lymphangiogenesis and tumor growth in vivo and the angiogenic potential of apelin is similar to that of VEGF. Also, apelin expression is upregulated and has been shown to be associated with clinical outcome in certain human cancers. Thus, inhibition of apelin activity might lead to a new class of anti-angiogenesis drugs which should be more efficacious than those currently on the market due to their ability to be both anti-angiogenic as well as anti lymphangiogenic. There are very few patents on the angiogenic effects of apelin and this review article focuses on these patented claims related to inhibiting apelin signaling and sheds more light on how blocking apelin signaling might open doors to a new class of angiogenic inhibitors. PMID- 21612578 TI - A plant proton-pumping inorganic pyrophosphatase functionally complements the vacuolar ATPase transport activity and confers bafilomycin resistance in yeast. AB - V-ATPases (vacuolar H+-ATPases) are a specific class of multi-subunit pumps that play an essential role in the generation of proton gradients across eukaryotic endomembranes. Another simpler proton pump that co-localizes with the V-ATPase occurs in plants and many protists: the single-subunit H+-PPase [H+-translocating PPase (inorganic pyrophosphatase)]. Little is known about the relative contribution of these two proteins to the acidification of intracellular compartments. In the present study, we show that the expression of a chimaeric derivative of the Arabidopsis thaliana H+-PPase AVP1, which is preferentially targeted to internal membranes of yeast, alleviates the phenotypes associated with V-ATPase deficiency. Phenotypic complementation was achieved both with a yeast strain with its V-ATPase specifically inhibited by bafilomycin A1 and with a vma1-null mutant lacking a catalytic V-ATPase subunit. Cell staining with vital fluorescent dyes showed that AVP1 recovered vacuole acidification and normalized the endocytic pathway of the vma mutant. Biochemical and immunochemical studies further demonstrated that a significant fraction of heterologous H+-PPase is located at the vacuolar membrane. These results raise the question of the occurrence of distinct proton pumps in certain single-membrane organelles, such as plant vacuoles, by proving yeast V-ATPase activity dispensability and the capability of H+-PPase to generate, by itself, physiologically suitable internal pH gradients. Also, they suggest new ways of engineering macrolide drug tolerance and outline an experimental system for testing alternative roles for fungal and animal V-ATPases, other than the mere acidification of subcellular organelles. PMID- 21612577 TI - OEP61 is a chaperone receptor at the plastid outer envelope. AB - Chloroplast precursor proteins encoded in the nucleus depend on their targeting sequences for delivery to chloroplasts. There exist different routes to the chloroplast outer envelope, but a common theme is the involvement of molecular chaperones. Hsp90 (heat-shock protein 90) delivers precursors via its receptor Toc64, which transfers precursors to the core translocase in the outer envelope. In the present paper, we identify an uncharacterized protein in Arabidopsis thaliana OEP61 which shares common features with Toc64, and potentially provides an alternative route to the chloroplasts. Sequence analysis indicates that OEP61 possesses a clamp-type TPR (tetratricopeptide repeat) domain capable of binding molecular chaperones, and a C-terminal TMD (transmembrane domain). Phylogenetic comparisons show sequence similarities between the TPR domain of OEP61 and those of the Toc64 family. Expression of mRNA and protein was detected in all plant tissues, and localization at the chloroplast outer envelope was demonstrated by a combination of microscopy and in vitro import assays. Binding assays show that OEP61 interacts specifically with Hsp70 (heat-shock protein 70) via its TPR clamp domain. Furthermore, OEP61 selectively recognizes chloroplast precursors via their targeting sequences, and a soluble form of OEP61 inhibits chloroplast targeting. We therefore propose that OEP61 is a novel chaperone receptor at the chloroplast outer envelope, mediating Hsp70-dependent protein targeting to chloroplasts. PMID- 21612579 TI - The oncogenic role of NS5A of hepatitis C virus is mediated by up-regulation of survivin gene expression in the hepatocellular cell through p53 and NF-kappaB pathways. AB - Approx. 4% of patients experiencing chronic infection of human HCV (hepatitis C virus) ultimately develop HCC (hepatocellular carcinoma). The NS5A (non structural protein 5A) encoded by HCV has been reported to have an oncogenic role during HCV infection, but the precise mechanism remains largely unclear. The aim of this study is to investigate the signal transduction pathways that mediate the role of NS5A in hepatocarcinogenesis. HepG2 cells were transfected with a plasmid expressing HCV NS5A protein. Subsequently, cell proliferation was analysed by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay and cell counting, apoptosis was analysed by Hoechst 33342 staining, and the gene expression profile was identified by microarray and subsequently validated by RT PCR (reverse transcription-PCR). The protein levels of survivin, p53, NOS2A (nitric oxide synthase 2A), cyclin D1 and NF-kappaB (nuclear factor kappaB) were monitored by Western blotting. Our results showed that transfection of HCV NS5A expression plasmid significantly down-regulated the expression of nine genes and up-regulated the expression of ten genes among the 104 genes detectable by the microarray associated with signalling transduction. The increased expression of survivin mRNA and protein, down-regulated p53 protein levels and increased NOS2A, cyclin D1 and NF-kappaB protein levels were further identified. Our results suggested that HCV NS5A protein can enhance survivin transcription by increasing p53 degradation and stimulating NOS2A expression as well as NF-kappaB relocation to the nucleus. The functions of survivin in anti-apoptosis and regulation of cell division might mediate the role of NS5A in HCV-induced HCC. PMID- 21612580 TI - Clustering of children's activity behaviour: the use of self-report versus direct measures. AB - While we concur with the objectives of the recent International Journal of Behavioural Nutrition and Physical Activity paper published by Jago and colleagues titled "Physical activity and sedentary behaviour typologies of 10-11 year olds", we feel that the results as currently presented do not support their conclusions. Though the authors created groups of children with dramatically different patterns of self-reported physical activity and sedentary behaviour, an inspection of the objectively measured accelerometry data shows little difference between the groups. Further, in at least one instance the difference between groups was of the opposite direction when using objective measures, as opposed to the self-report measures used in the published analysis. Thus, we caution the authors from making conclusions based on their self-report data, and propose that they re-analyze their data using their objectively measured data instead. PMID- 21612582 TI - HIV-1 and recombinant gp120 affect the survival and differentiation of human vessel wall-derived mesenchymal stem cells. AB - BACKGROUND: HIV infection elicits the onset of a progressive immunodeficiency and also damages several other organs and tissues such as the CNS, kidney, heart, blood vessels, adipose tissue and bone. In particular, HIV infection has been related to an increased incidence of cardiovascular diseases and derangement in the structure of blood vessels in the absence of classical risk factors. The recent characterization of multipotent mesenchymal cells in the vascular wall, involved in regulating cellular homeostasis, suggests that these cells may be considered a target of HIV pathogenesis. This paper investigated the interaction between HIV-1 and vascular wall resident human mesenchymal stem cells (MSCs). RESULTS: MSCs were challenged with classical R5 and X4 HIV-1 laboratory strains demonstrating that these strains are able to enter and integrate their retro transcribed proviral DNA in the host cell genome. Subsequent experiments indicated that HIV-1 strains and recombinant gp120 elicited a reliable increase in apoptosis in sub-confluent MSCs. Since vascular wall MSCs are multipotent cells that may be differentiated towards several cell lineages, we challenged HIV 1 strains and gp120 on MSCs differentiated to adipogenesis and endotheliogenesis. Our experiments showed that the adipogenesis is increased especially by upregulated PPARgamma activity whereas the endothelial differentiation induced by VEGF treatment was impaired with a downregulation of endothelial markers such as vWF, Flt-1 and KDR expression. These viral effects in MSC survival and adipogenic or endothelial differentiation were tackled by CD4 blockade suggesting an important role of CD4/gp120 interaction in this context. CONCLUSIONS: The HIV related derangement of MSC survival and differentiation may suggest a direct role of HIV infection and gp120 in impaired vessel homeostasis and in genesis of vessel damage observed in HIV-infected patients. PMID- 21612583 TI - Development and validation of a questionnaire assessing volitional competencies to enhance the performance of physical activities in chronic low back pain patients. AB - BACKGROUND: Motivation has long been emphasized as the most important determinant of action. However, there is a substantial gap between people's goals and their attainment. Patients may be motivated and yet unable to take action if their volitional competencies are insufficient. One of the important tasks of volition is goal-maintenance. Research has stressed the importance of a volitional tool, the implementation intentions. Implementation intentions indicate where, when, and how the action leading to the goal will be performed. Forming implementation intentions favours the execution of goal-directed efforts, and reinforces the relationship between intentions and behaviours. Results from various studies clearly suggest that volitional competencies and implementation intentions could play a role in low back pain (LBP) patients. However, there is at present no questionnaire allowing assessing the capacity of implementation intentions of physical activities in LBP patients. METHODS/DESIGN: This study will develop such a questionnaire, using a 3-step approach. A first qualitative step to build categories and generate items; 30 patients suffering chronic LBP will be invited to participate in semi-structured interviews; verbatim and derived items will then be submitted to a panel of experts, using a Delphi method; a second quantitative step to examine the properties of items, and determine the factorial structure of the questionnaire; 100 patients suffering chronic LBP will be recruited to respond to this phase; and third, preliminary psychometric analyses (item-scale correlations, construct validity, reliability); 180 chronic LBP patients will be recruited for this phase of the study. The relationships between implementation intentions and variables affecting physical activity on chronic LBP patients, i.e. pain, physical capacities, fear-avoidance beliefs, kinesiophobia, work status, and level of physical activity will be considered. DISCUSSION: Developing a questionnaire to assess implementation intentions would allow investigating the role of these intentions in the transition from acute to chronic LBP. The results of this study should contribute to the understanding of the psychological processes at stake in the development of chronic LBP, and in particular to the identification of factors eventually favouring patients' participation in and adherence to active physical treatments. PMID- 21612584 TI - Community Preferences for the Allocation & Donation of Organs--the PAraDOx Study. AB - BACKGROUND: Transplantation is the treatment of choice for people with severe organ failure. However, demand substantially exceeds supply of suitable organs; consequently many people wait months, or years to receive an organ. Reasons for the chronic shortage of deceased organ donations are unclear; there appears to be no lack of 'in principle' public support for organ donation. METHODS/DESIGN: The PAraDOx Study examines community preferences for organ donation policy in Australia. The aims are to 1) determine which factors influence decisions by individuals to offer their organs for donation and 2) determine the criteria by which the community deems the allocation of donor organs to be fair and equitable. Qualitative and quantitative methods will be used to assess community preferences for organ donation and allocation.Focus group participants from the general community, aged between 18-80, will be purposively sampled to ensure a variety of cultural backgrounds and views on organ donation. Each focus group will include a ranking exercise using a modified nominal group technique. Focus groups of organ recipients, their families, and individuals on a transplant waiting list will also be conducted.Using the qualitative work, a discrete choice study will be designed to quantitatively assess community preferences. Discrete choice methods are based on the premise that goods and services can be described in terms of a number of separate attributes. Respondents are presented with a series of choices where levels of attributes are varied, and a mathematical function is estimated to describe numerically the value respondents attach to different options. Two community surveys will be conducted in approximately 1000 respondents each to assess community preferences for organ donation and allocation. A mixed logit model will be used; model results will be expressed as parameter estimates (beta) and the odds of choosing one option over an alternative. Trade-offs between attributes will also be calculated. DISCUSSION: By providing a better understanding of current community preferences in relation to organ donation and allocation, the PAraDOx study will highlight options for firstly, increasing the rate of organ donation and secondly, allow for more transparent and equitable policies in relation to organ allocation. PMID- 21612585 TI - A Population-based study of dementia in the oldest old: the Monzino 80-plus study. AB - BACKGROUND: Despite being the fastest growing and the most cognitively impaired age group, the oldest olds are under-represented in clinical research. The purpose of this study was to describe the design, methods, and baseline characteristics of the survey population and investigate possible differences in demographic, cognitive, functional, and behavioral characteristics between oldest old with and without any performance on cognitive tests and between oldest old alive and those deceased prior to the interview. METHODS: The Monzino 80-plus Study is a prospective door-to-door population-based survey among 80 years or older residents in the municipalities in the province of Varese, Italy. Dementia cases were identified with a one-phase design. Trained psychologists interviewed both the subject and a proxy informant. The interview included a comprehensive standardized questionnaire together with an array of rating scales and a multidomain cognitive battery to assess cognitive and functional ability, behavioral disturbances and mood. RESULTS: Information was available for 2,139 of the 2,428 registered individuals aged 80 years or older. Main baseline characteristics of the population are reported and discussed. In comparison with those living, elderly persons who had died before the first visit were older, had twice the rate of institutionalization, poorer cognitive performance and competence, and significantly greater instrumental and basic functional disability. The percentage of elderly persons, alive at baseline, without Mini Mental State Examination rose rather evenly with age. Moreover, they had significantly worse cognitive competence and functional ability, and reported higher prevalences of depressive symptoms and problem behaviors than those with Mini-Mental State Examination. CONCLUSIONS: Prospective investigation of a large population of oldest old can contribute significantly to understanding the relations between age, cognitive decline, and dementia occurrence. Use of informant-based instruments in surveys in the oldest old is crucial in assessing everyday functioning and changes, especially in participants with no cognitive test performance available. Failure to include information on deceased elderly would underestimate, increasingly with age, the prevalence of cognitive and functional disability in the elderly population. PMID- 21612586 TI - Signs and symptoms of temporomandibular joint disorders related to the degree of mouth opening and hearing loss. AB - BACKGROUND: The temporomandibular joint is a unique bi-condylar joint involved in mastication and speech. Temporomandibular joint disorders (TMD) have a range of symptoms, including aural symptoms, and are present in approximately 75% of normal populations. The present study examined the relationship between signs and symptoms of TMD and mouth opening, gender, joint and aural symptoms, and hearing loss. METHODS: The study involved 464 healthy Greek university students (156 men and 308 women) with a mean age of 19.6 years. Age, gender and maximum mouth opening was recorded. Mouth opening was measured using Vernier calipers. An anamnestic questionnaire was used to stratify the subjects into four groups based on TMD severity. Aural symptoms and an audiogram were recorded for each subject too. Data were analyzed using multifactor ANOVA, chi-square, t-test, Mann-Whitney and Kruskal-Wallis tests. RESULTS: The overall incidence of TMD signs and symptoms was 73.3%. The incidence and severity was greater in females than males (p-value 0.0001 < 0.05). The number of aural symptoms was associated to the TMD severity (p-value 0.0001 < 0.05) as well as maximum mouth opening (p-value 0.004 < 0.05). Audiometry showed that moderate and severe TMD was associated with hearing loss of median and low tones respectively (p-value 0.0001 < 0.05). TMJ pain (p-value 0.0001 < 0.05), TMJ ankylosis (p-value 0.0001 < 0.05), bruxism (p value 0.0001 < 0.05) and ear itching (p-value 0.0001 < 0.05) were also found to be statistically different between TMD and non-TMD subjects. CONCLUSIONS: TMD signs and symptoms were more common and severe in females than males. TMD severity is correlated with the degree of mouth opening and the number of aural symptoms. The absence or presence of mild TMD are associated with normal audiograms while moderate and severe TMD are related to hearing loss in median and low tones respectively. Bruxism, joint ankylosis, joint pain and ear itching were more common in TMD than non-TMD patients. PMID- 21612588 TI - Immuno-modulatory activity of Ganoderma lucidum-derived polysacharide on human monocytoid dendritic cells pulsed with Der p 1 allergen. AB - BACKGROUND: Ganoderma lucidum-derived polysaccharide (PS-G) can rapidly and effectively promote the activation and maturation of immature dendritic cells (DCs), suggesting that PS-G possesses the capacity to regulate immune responses. This study aimed to clarify the immunologic effect of PS-G on monocyte-derived dendritic cells (MD-DCs) from asthmatic children allergic to house dust mites. The MD-DCs were stimulated for 24 h with the related allergen, Der p 1, in the presence or absence of PS-G. Cell surface markers and phagocytic capacity were assessed by FACS analysis, and key polarizing cytokines (IL-12 p40, IL-12 p70, IL 6, IL-23, and IL-10) were quantified. The subsequent regulatory effect of pulsed MD-DCs on naive T cells was evaluated by determining the T-cell cytokine profile. RESULTS: PS-G induced the maturation of MD-DCs and decreased phagocytic capacity, even if pulsed with Der p 1. After incubation with PS-G and Der p 1, MD-DCs produced higher amounts of IL-12 p70, IL-12 p40, IL-6, IL-23, and IL10 than Der p 1-pulsed DCs. Furthermore, type 1 helper T (Th1) cell cytokine (INF-gamma) production was highly increased when naive autologous T cells were co-cultured with Der p 1-pulsed MD-DCs. Naive T cells stimulated by MD-DCs pulsed with Der p 1 failed to produce proliferation of T-cells, whereas the addition of PS-G to Der p 1 induced a significant proliferation of T-cells similar to that observed with PS-G alone. CONCLUSION: The presence of PS-G in an allergen pulse promoted allergic MD-DCs to produce IL-12 p70, IL-12 p40, IL-6, IL-23, and IL-10, and exerted an effect on shifting the immune balance towards Th1 in children with allergic asthma. PMID- 21612589 TI - Fibromyalgia and neuropathic pain--differences and similarities. A comparison of 3057 patients with diabetic painful neuropathy and fibromyalgia. AB - BACKGROUND: Patients with diabetic neuropathy (DPN) and fibromyalgia differ substantially in pathogenetic factors and the spatial distribution of the perceived pain. We questioned whether, despite these obvious differences, similar abnormal sensory complaints and pain qualities exist in both entities. We hypothesized that similar sensory symptoms might be associated with similar mechanisms of pain generation. The aims were (1) to compare epidemiological features and co-morbidities and (2) to identify similarities and differences of sensory symptoms in both entities. METHODS: The present multi-center study compares epidemiological data and sensory symptoms of a large cohort of 1434 fibromyalgia patients and 1623 patients with painful diabetic neuropathy. Data acquisition included standard demographic questions and self-report questionnaires (MOS sleep scale, PHQ-9, PainDETECT). To identify subgroups of patients with characteristic combinations of symptoms (sensory profiles) a cluster analysis was performed using all patients in both cohorts. RESULTS: Significant differences in co-morbidities (depression, sleep disturbance) were found between both disorders. Patients of both aetiologies chose very similar descriptors to characterize their sensory perceptions. Burning pain, prickling and touch-evoked allodynia were present in the same frequency. Five subgroups with distinct symptom profiles could be detected. Two of the subgroups were characteristic for fibromyalgia whereas one profile occurred predominantly in DPN patients. Two profiles were found frequently in patients of both entities (20 35%). CONCLUSIONS: DPN and fibromyalgia patients experience very similar sensory phenomena. The combination of sensory symptoms--the sensory profile--is in most cases distinct and almost unique for each one of the two entities indicating aetiology-specific mechanisms of symptom generation. Beside the unique aetiology specific sensory profiles an overlap of sensory profiles can be found in 20-35% of patients of both aetiologies. PMID- 21612590 TI - Ultrasonographic findings in a cow with abomasal lymphosarcoma: case report. AB - BACKGROUND: This case report describes the clinical and ultrasonographic findings in a Swiss Braunvieh cow with lymphosarcoma of the abomasum. CASE PRESENTATION: The main clinical findings were vomiting in response to eating and melena. The results of serum biochemistry and rumen fluid analysis were indicative of abomasal reflux syndrome. The main ultrasonographic findings were two enlarged lymph nodes caudal to the reticulum and a severely enlarged abomasum with thickening of the abomasal wall and folds. Based on all the findings, pyloric stenosis caused by lymphosarcoma was tentatively diagnosed and later confirmed at postmortem examination. CONCLUSIONS: This is an interesting case, which broadens the spectrum of abomasal reflux syndrome. PMID- 21612592 TI - Lung adenocarcinoma presenting as a solitary gingival metastasis: a case report. AB - INTRODUCTION: Gingival metastases are very rare and generally occur in disseminated tumors. We report a case of solitary gingival metastasis of lung cancer. CASE PRESENTATION: We report the case of a 74-year-old asymptomatic Caucasian woman affected by a rapidly growing, painless gingival swelling. Histopathologic examination of the excisional biopsy showed metastasis of poorly differentiated thyroid transcription factor 1-positive adenocarcinoma. A total body computed tomographic scan revealed a tumor of the right lung lower lobe with ipsilateral, mediastinal lymph node swelling. Moreover, bone scintigraphy revealed no bone metastases. No other metastases were found, so we planned a multi-modal therapeutic approach with a curative intent. However, the tumor proved to be intrinsically resistant and highly aggressive. CONCLUSION: The presentation of solitary gingival metastasis is exceptional. In view of its rapid clinical evolution, our case confirms that gingival metastasis is an important prognostic factor. This behavior raises the question whether the poor prognosis for patients with tumors with oral metastases depends on its diffuse spread or on its highly malignant nature. PMID- 21612591 TI - The proteomic complexity and rise of the primordial ancestor of diversified life. AB - BACKGROUND: The last universal common ancestor represents the primordial cellular organism from which diversified life was derived. This urancestor accumulated genetic information before the rise of organismal lineages and is considered to be either a simple 'progenote' organism with a rudimentary translational apparatus or a more complex 'cenancestor' with almost all essential biological processes. Recent comparative genomic studies support the latter model and propose that the urancestor was similar to modern organisms in terms of gene content. However, most of these studies were based on molecular sequences, which are fast evolving and of limited value for deep evolutionary explorations. RESULTS: Here we engage in a phylogenomic study of protein domain structure in the proteomes of 420 free-living fully sequenced organisms. Domains were defined at the highly conserved fold superfamily (FSF) level of structural classification and an iterative phylogenomic approach was used to reconstruct max_set and min_set FSF repertoires as upper and lower bounds of the urancestral proteome. While the functional make up of the urancestral sets was complex, they represent only 5-11% of the 1,420 FSFs of extant proteomes and their make up and reuse was at least 5 and 3 times smaller than proteomes of free-living organisms, repectively. Trees of proteomes reconstructed directly from FSFs or from molecular functions, which included the max_set and min_set as articial taxa, showed that urancestors were always placed at their base and rooted the tree of life in Archaea. Finally, a molecular clock of FSFs suggests the min_set reflects urancestral genetic make up more reliably and confirms diversified life emerged about 2.9 billion years ago during the start of planet oxygenation. CONCLUSIONS: The minimum urancestral FSF set reveals the urancestor had advanced metabolic capabilities, was especially rich in nucleotide metabolism enzymes, had pathways for the biosynthesis of membrane sn1,2 glycerol ester and ether lipids, and had crucial elements of translation, including a primordial ribosome with protein synthesis capabilities. It lacked however fundamental functions, including transcription, processes for extracellular communication, and enzymes for deoxyribonucleotide synthesis. Proteomic history reveals the urancestor is closer to a simple progenote organism but harbors a rather complex set of modern molecular functions. PMID- 21612593 TI - Immune regulation in Chandipura virus infection: characterization of CD4+ T regulatory cells from infected mice. AB - BACKGROUND: Chandipura virus produces acute infection in mice. During infection drastic reduction of CD4+, CD8+ and CD19 + cell was noticed. Depletion of lymphocytes also noticed in spleen. The reduction may be due to the regulatory mechanism of immune system to prevent the bystander host tissue injury. There are several mechanisms like generation of regulatory cells, activation induced cell death (ACID) etc were indicated to control the activation and maintain cellular homeostasis. Role of regulatory cells in homeostasis has been described in several viral diseases. This study was undertaken to characterize CD4+T regulatory cells from the infected mice. METHOD: In this study we purified the CD4+ T cells from Chandipura virus infected susceptible Balb/c mice. CD4+ T regulatory cells were identified by expression of cell surface markers CD25, CD127 and CTLA-4 and intracellular markers Foxp3, IL-10 and TGF-beta. Antigen specificity and ability to suppress the proliferation of other lymphocytes were studied in vitro by purified CD4+CD25+T regulatory cells from infected mice. The proliferation was calculated by proliferation module of Flow Jo software. Expression of death receptors on regulatory cells were studied by flowcytometer. RESULTS: The CD4+ T cells isolated from infected mice expressed characteristic markers of regulatory phenotype at all post infective hours tested. The CD4+ T regulatory cells were proliferated when stimulated with Chandipura virus antigen. The regulatory cells did not suppress the proliferation of splenocytes stimulated with anti CD3 antibody when co cultured with them. Interesting observation was, while purification of CD4+ T cells by negative selection, the population of cells negative for CD4 also co purified along with CD4+ T cell. Flow cytometry analysis and light microscopy revealed that CD4 negative cells were of different size and shape (atypical) compared to the normal lymphocytes. Greater percentage of these atypical lymphocytes expressed Fas Ligand and Programmed Death1 (PD-1) receptor. CONCLUSION: From these results we concluded that virus specific CD4+T regulatory cells are generated during Chandipura virus infection in mice and these cells might control the activated lymphocytes during infection by different mechanism. PMID- 21612594 TI - Differential distribution of a SINE element in the Entamoeba histolytica and Entamoeba dispar genomes: role of the LINE-encoded endonuclease. AB - BACKGROUND: Entamoeba histolytica and Entamoeba dispar are closely related protistan parasites but while E. histolytica can be invasive, E. dispar is completely non pathogenic. Transposable elements constitute a significant portion of the genome in these species; there being three families of LINEs and SINEs. These elements can profoundly influence the expression of neighboring genes. Thus their genomic location can have important phenotypic consequences. A genome-wide comparison of the location of these elements in the E. histolytica and E. dispar genomes has not been carried out. It is also not known whether the retrotransposition machinery works similarly in both species. The present study was undertaken to address these issues. RESULTS: Here we extracted all genomic occurrences of full-length copies of EhSINE1 in the E. histolytica genome and matched them with the homologous regions in E. dispar, and vice versa, wherever it was possible to establish synteny. We found that only about 20% of syntenic sites were occupied by SINE1 in both species. We checked whether the different genomic location in the two species was due to differences in the activity of the LINE-encoded endonuclease which is required for nicking the target site. We found that the endonucleases of both species were essentially very similar, both in their kinetic properties and in their substrate sequence specificity. Hence the differential distribution of SINEs in these species is not likely to be influenced by the endonuclease. Further we found that the physical properties of the DNA sequences adjoining the insertion sites were similar in both species. CONCLUSIONS: Our data shows that the basic retrotransposition machinery is conserved in these sibling species. SINEs may indeed have occupied all of the insertion sites in the genome of the common ancestor of E. histolytica and E. dispar but these may have been subsequently lost from some locations. Alternatively, SINE expansion took place after the divergence of the two species. The absence of SINE1 in 80% of syntenic loci could affect the phenotype of the two species, including their pathogenic properties, which needs to be explored. PMID- 21612587 TI - The dominant Anopheles vectors of human malaria in the Asia-Pacific region: occurrence data, distribution maps and bionomic precis. AB - BACKGROUND: The final article in a series of three publications examining the global distribution of 41 dominant vector species (DVS) of malaria is presented here. The first publication examined the DVS from the Americas, with the second covering those species present in Africa, Europe and the Middle East. Here we discuss the 19 DVS of the Asian-Pacific region. This region experiences a high diversity of vector species, many occurring sympatrically, which, combined with the occurrence of a high number of species complexes and suspected species complexes, and behavioural plasticity of many of these major vectors, adds a level of entomological complexity not comparable elsewhere globally. To try and untangle the intricacy of the vectors of this region and to increase the effectiveness of vector control interventions, an understanding of the contemporary distribution of each species, combined with a synthesis of the current knowledge of their behaviour and ecology is needed. RESULTS: Expert opinion (EO) range maps, created with the most up-to-date expert knowledge of each DVS distribution, were combined with a contemporary database of occurrence data and a suite of open access, environmental and climatic variables. Using the Boosted Regression Tree (BRT) modelling method, distribution maps of each DVS were produced. The occurrence data were abstracted from the formal, published literature, plus other relevant sources, resulting in the collation of DVS occurrence at 10116 locations across 31 countries, of which 8853 were successfully geo-referenced and 7430 were resolved to spatial areas that could be included in the BRT model. A detailed summary of the information on the bionomics of each species and species complex is also presented. CONCLUSIONS: This article concludes a project aimed to establish the contemporary global distribution of the DVS of malaria. The three articles produced are intended as a detailed reference for scientists continuing research into the aspects of taxonomy, biology and ecology relevant to species-specific vector control. This research is particularly relevant to help unravel the complicated taxonomic status, ecology and epidemiology of the vectors of the Asia-Pacific region. All the occurrence data, predictive maps and EO-shape files generated during the production of these publications will be made available in the public domain. We hope that this will encourage data sharing to improve future iterations of the distribution maps. PMID- 21612595 TI - A sleeping phantom leg awakened following hemicolectomy, thrombosis, and chemotherapy: a case report. AB - INTRODUCTION: We describe the case of a patient who experienced phantom pain that began 42 years after right above-the-knee amputation. Immediately prior to phantom pain onset, this long-term amputee had experienced, in rapid succession, cancer, hemicolectomy, chemotherapy, and thrombotic occlusion. Very little has been published to date on the association between chemotherapy and exacerbation of neuropathic pain in amputees, let alone the phenomenon of bringing about pain in amputees who have been pain-free for many decades. While this patient presented with a unique profile following a rare sequence of medical events, his case should be recognized considering the frequent co-occurrence of osteomyelitis, chemotherapy, and amputation. CASE PRESENTATION: A 68-year-old Australian Caucasian man presented 42 years after right above-the-knee amputation with phantom pain immediately following hemicolectomy, thrombotic occlusion in the amputated leg, and chemotherapy treatment with leucovorin and 5-fluorouracil. He exhibited probable hyperalgesia with a reduced pinprick threshold and increased stump sensitivity, indicating likely peripheral and central sensitization. CONCLUSION: Our patient, who had long-term nerve injury due to amputation, together with recent ischemic nerve and tissue injury due to thrombosis, exhibited likely chemotherapy-induced neuropathy. While he presented with unique treatment needs, cases such as this one may actually be quite common considering that osteosarcoma can frequently lead to amputation and be followed by chemotherapy. The increased susceptibility of amputees to developing potentially intractable chemotherapy-induced neuropathic pain should be taken into consideration throughout the course of chemotherapy treatment. Patients in whom chronic phantom pain then develops, perhaps together with mobility issues, inevitably place greater demands on healthcare service providers that require treatment by various clinical specialists, including oncologists, neurologists, prosthetists, and, most frequently, general practitioners. PMID- 21612596 TI - Albuminuria and Diabetic Retinopathy in Type 2 Diabetes Mellitus Sankara Nethralaya Diabetic Retinopathy Epidemiology And Molecular Genetic Study (SN DREAMS, report 12). AB - BACKGROUND: The concordance of microalbuminuria and diabetic retinopathy (DR) has been well reported in persons with type 1 diabetes; however, for type 2 diabetes, there is paucity of data especially from population-based studies. The aim of this study was to estimate the prevalence of albuminuria (micro - and macroalbuminuria) among persons with type 2 diabetes and determine its role as a risk factor for presence and severity of DR. METHODS: A population-based cross sectional study was conducted in cohort of 1414 subjects with type 2 diabetes from Chennai metropolis. All the subjects underwent comprehensive eye examination including 45 degrees four-field stereoscopic digital photography. DR was clinically graded using Early Treatment Diabetic Retinopathy Study scales. A morning urine sample was tested for albuminuria. Subjects were considered to have microalbuminuria, if the urinary albumin excretion was between 30 and 300 mg/24 hours, and macroalbuminuria at more than 300 mg/24 hours. The statistical software used was SPSS for Windows, Chicago, IL. Student t-test for comparing continuous variables, and chi2 test, to compare proportions amongst groups were used. RESULTS: The prevalence of microalbuminuria in the study subjects was 15.9% (226/1414), and that of macroalbuminuria, 2.7% (38/1414). Individuals with macroalbuminuria in comparison to micro- or normoalbuminuria showed a greater prevalence of DR (60.5% vs. 31.0% vs. 14.1%, p < 0.001), and also a greater severity of the disease (60.9% vs. 21.4 vs. 9.9, p < 0.001). CONCLUSIONS: Every 6th individual in the population of type 2 diabetes is likely to have albuminuria. Subjects with microalbuminuria were around 2 times as likely to have DR as those without microalbuminuria, and this risk became almost 6 times in the presence of macroalbuminuria. PMID- 21612597 TI - Assessing physical activity and its relationship to cardiovascular risk factors: NHANES 2003-2006. AB - BACKGROUND: Levels of physical activity (PA) in the general population are difficult to characterize. Historically measurement has been based on self report, which can be subject to bias. PA monitor use has created opportunities to improve surveillance and analytic research on activity and health. The aims of the current study were to investigate the associations between objectively measured PA and cardiovascular disease risk factors and obesity. METHODS: Data on PA from accelerometers, demographics, blood pressure, plasma glucose and lipids, self-reported hypertension and diabetes were obtained for adults, ages 20-65, in the NHANES surveys, 2003-2006. Outcomes were assessed as levels of moderate and vigorous activity, percentage of participants meeting recommended guidelines, and the correlations between activity and cardiovascular risk factors. Accelerometry data were available on 3,370 adults. Based on standard algorithms, activity levels were extremely low in all age-gender-race/ethnic groups, with an average of only 1 bout of vigorous activity lasting longer than 1 minute/day. RESULTS: Men spent 35 minutes in moderate activity/day, women 21 minutes; >75% of this activity was accumulated in 1-minute bouts. Levels of activity declined sharply after age 50 in all groups. Negative associations were observed between minutes of combined moderate and vigorous activity and systolic blood pressure, blood glucose, diabetes, hypertension, body mass index and obesity, and a positive association was seen with HDL-cholesterol (all P <= 0.03), suggesting valid rank ordering of participants by activity level. CONCLUSION: The magnitude of the gap between self-report and accelerometry activity must be a result of either a vast social acceptability bias in reporting or inaccurate measurement with accelerometry. Therefore, due to the low validity of self reported PA data for epidemiologic research, it is pertinent to encourage the use of valid, objective methods to assess PA. PMID- 21612598 TI - Mechanism of PhosphoThreonine/Serine Recognition and Specificity for Modular Domains from All-atom Molecular Dynamics. AB - BACKGROUND: Phosphopeptide-binding domains mediate many vital cellular processes such as signal transduction and protein recognition. We studied three well-known domains important for signal transduction: BRCT repeats, WW domain and forkhead associated (FHA) domain. The first two recognize both phosphothreonine (pThr) and phosphoserine (pSer) residues, but FHA has high specificity for pThr residues. Here we used molecular dynamics (MD) simulations to reveal how FHA exclusively chooses pThr and how BRCT and WW recognize both pThr/pSer. The work also investigated the energies and thermodynamic information of intermolecular interactions. RESULTS: Simulations carried out included wide-type and mutated systems. Through analysis of MD simulations, we found that the conserved His residue defines dual loops feature of the FHA domain, which creates a small cavity reserved for only the methyl group of pThr. These well-organized loop interactions directly response to the pThr binding selectivity, while single loop (the 2nd phosphobinding site of FHA) or in combination with alpha-helix (BRCT repeats) or beta-sheet (WW domain) fail to differentiate pThr/pSer. CONCLUSIONS: Understanding the domain pre-organizations constructed by conserved residues and the driving force of domain-phosphopeptide recognition provides structural insight into pThr specific binding, which also helps in engineering proteins and designing peptide inhibitors. PMID- 21612599 TI - Psychological impact, support and information needs for women with an abnormal Pap smear: comparative results of a questionnaire in three European countries. AB - BACKGROUND: Extensive information on cervical cancer is currently available. Its effectiveness in reducing anxiety in women receiving abnormal Pap tests is not clear. We investigated current practices of communicating abnormal Pap results to evaluate women's reactions and determine the sources of information they use subsequently. METHODS: A self-administered questionnaire-based study was performed in 1475 women in France, Spain and Portugal who had received an abnormal Pap smear result in the 12 months prior to completing the questionnaire. Questions covered methods of communication of the result, emotional reactions, support received (from the physician and entourage), and information sources, using pre-specified check box options and rating scales. Data were analyzed by country. RESULTS: Pap test results were mostly communicated by phone to Spanish women (76%), while physician letters were common in France (59%) and Portugal (36%). Frequent reactions were anxiety, panic and stress, which were less common in Spanish women than their French and Portuguese counterparts. After discussing with their physician, half of the participants were worried, despite rating highly the psychological support received. Over 90% of women in each country discussed their results with family or friends. Partners provided a high level of support. Overall, the abnormal diagnosis and consequences had a low to medium impact on daily, professional and family life and their relationships with their partner. Impact was higher in Spanish women than the French or Portuguese. Information on the diagnosis and its treatment was rated average, and nearly 80% of participants wanted more information, notably French women. Preferred sources were the physician and the Internet. CONCLUSIONS: Women expressed a strong wish for more information about cervical cancer and other HPV-related diseases, and that their physician play a major role in its provision and in support. There was a heavy reliance on the close entourage and the Internet for information, highlighting the need for dissemination of accurate material. Differences between countries suggest information management strategies may need to be tailored to different geographical regions. PMID- 21612600 TI - Changes in health-related quality of life following imprisonment in 92 women in England: a three month follow-up study. AB - BACKGROUND: Despite the considerable changes in the provision of health care to prisoners in the UK there is little published literature that attempts to examine broader aspects of health and the impact of imprisonment on these, focusing instead on disease specific areas. This is surprising given that one of the main drivers behind the changes was the need for improvements in the quality of care; examining changes in health outcomes should be an important part of monitoring service developments. This study assessed the health-related quality of life of women on entry into prison and examined changes during a period of three months imprisonment. METHODS: This was a prospective longitudinal study involving 505 women prisoners in England. The SF-36 was contained within a questionnaire designed to examine many aspects of imprisoned women's health. Participants completed this questionnaire within 72 hours of entering prison. The researchers followed up all participants who were still imprisoned three months later. RESULTS: The study achieved good response rates: 82% of women agreed to participate initially (n = 505), and 93% of those still imprisoned participating three months later (n = 112). At prison entry, women prisoners have lower mental component summary score (MCS) and physical component summary score (PCS) compared to women within the general population. The mental well-being of those 112 women still imprisoned after three months improved over this period of imprisonment, although remained poorer than that of the general population. The PCS did not improve significantly and remained significantly lower than that of the general population. Multivariate analyses showed that the only independent predictor of change in component score was the score at baseline. CONCLUSIONS: The results highlight the poor health-related quality of life of women prisoners and highlight the scale of the challenge faced by those providing health care to prisoners. They also draw attention to the major health disadvantages of women offenders compared to women in general. While recent reforms may improve health services for prisoners, broader inequalities in the health of women are a more complex challenge. PMID- 21612601 TI - The natural history of West Nile virus infection presenting with West Nile virus meningoencephalitis in a man with a prolonged illness: a case report. AB - INTRODUCTION: Estimates indicate that West Nile virus infects approximately one and a half million people in the United States of America. Up to 1% may develop West Nile virus neuroinvasive disease, in which infected patients develop any combination of meningitis, encephalitis, or acute paralysis. CASE PRESENTATION: A 56-year-old African-American man presented to our hospital with headache, restlessness, fever, myalgias, decreased appetite, and progressive confusion. A cerebrospinal fluid examination showed mild leukocytosis and an elevated protein level. Testing for routine infections was negative. Brain T2-weighted magnetic resonance imaging scans showed marked enlargement of caudate nuclei and increased intensity within the basal ganglia and thalami. A West Nile virus titer was positive, and serial brain magnetic resonance imaging scans showed resolving abnormalities that paralleled his neurological examination. CONCLUSION: This report is unusual as it portrays the natural history and long-term consequences of West Nile virus meningoencephalitis diagnosed on the basis of serial brain images. PMID- 21612603 TI - Women's status and violence against young married women in rural Nepal. AB - BACKGROUND: Studies conducted around the world consistently show the existence of violence against women. Despite the increasing number of studies being conducted on violence against young married women elsewhere, this subject has received little attention from researchers and policy makers in Nepal. This paper assesses the prevalence of violence among young married women in rural Nepal. Specifically, it examines [factors related to] women's status in order to better understand the risk of violence. METHODS: A cross-sectional study was conducted in 2009 among 1,296 young married women aged 15-24 years in four major ethnic groups. Bivariate analysis and multivariate logistic regression were used to examine the association between selected risk factors and violence. RESULTS: More than half the women (51.9%) reported having experienced some form of violence in their lifetime. One-fourth (25.3%) reported physical violence and nearly half (46.2%) reported sexual violence. Likewise, one-third (35.8%) of women reported experiencing some form of violence in the past 12 months. No or little inter spousal communication and low autonomy of women significantly increases the odds of experiencing violence among married women. CONCLUSIONS: The violence against women is quite common among young married women in rural Nepal. Although the Domestic Violence and Punishment Act 2066 has been enacted, equal attention needs to be given to increasing women's autonomy and activities that encourage inter spousal communication. Furthermore, more research is required in Nepal that examines dynamics of violence perpetrated by husbands. PMID- 21612602 TI - Adaptor protein Shc acts as an immune-regulator for the LPS-stimulated maturation of bone marrow-derived dendritic cells. AB - BACKGROUND: The Shc isoforms is known to mediate immune responses and has been indicated as a negative regulator of autoimmunity and lymphocyte activation. We aimed to evaluate the immune-regulatory role of Shc in rat bone marrow-derived DCs in the maturation process triggered by LPS. RESULTS: We found that, in response to LPS, expression of Shc proteins was induced and that neutralization of Shc inhibited the LPS-induced transient phosphorylation of p52Shc on pTyr239/240 in DCs of Lewis (LEW; RT1(l)) rats. Moreover, the significantly enhanced expression of IL-10 and the surface level of costimulatory molecule CD80, as well as suppressed expression of IL-6 and IL-12 in the Shc-silenced DCs were also observed. Similar IkappaB phosphorylation occurred in Shc-silenced DCs primed by LPS, indicating Shc is not associated with NF-kappaB pathway. We further demonstrate that Shc blockade on LPS-treated DCs results in significant increase of the overall STAT3 phosphorylation and the relative levels of phospho STAT3 in the nuclear fraction. STAT3 activation by LPS with or without Shc blockade was totally abolished by SU6656, a selective Src family kinases inhibitor, underscoring the critical role of Src-mediated activation. CONCLUSIONS: We conclude that Shc blockade in LPS-primed DC leads to the development of tolerogenic DC via Src-dependent STAT3 activation and that adaptor protein Shc might play a pivotal role in mediating immunogenic and tolerogenic properties of DCs. PMID- 21612604 TI - ERP correlates of intramodal and crossmodal L2 acquisition. AB - BACKGROUND: The present study compared the neural correlates of an intramodally and a crossmodally acquired second language (L2). Deaf people who had learned their L1, German Sign Language (DGS), and their L2, German, through the visual modality were compared with hearing L2 learners of German and German native speakers. Correct and incorrect German sentences were presented word by word on a computer screen while the electroencephalogram was recorded. At the end of each sentence, the participants judged whether or not the sentence was correct. Two types of violations were realized: Either a semantically implausible noun or a violation of subject-verb number agreement was embedded at a sentence medial position. RESULTS: Semantic errors elicited an N400, followed by a late positivity in all groups. In native speakers of German, verb-agreement violations were followed by a left lateralized negativity, which has been associated with an automatic parsing process. We observed a syntax related negativity in both high performing hearing and deaf L2 learners as well. Finally, this negativity was followed by a posteriorly distributed positivity in all three groups. CONCLUSIONS: Although deaf learners have learned German as an L2 mainly via the visual modality they seem to engage comparable processing mechanisms as hearing L2 learners. Thus, the data underscore the modality transcendence of language. PMID- 21612606 TI - Cutaneous Fusarium infection in a renal transplant recipient: a case report. AB - INTRODUCTION: Fungal infections in the immunocompromised host are fairly common. Of the mycoses, Fusarium species are an emerging threat. Fusarium infections have been reported in solid organ transplants, with three reports of the infection in patients who had received renal transplants. To the best of our knowledge, this is the first case of an isolated cutaneous lesion as the only form of infection. CASE PRESENTATION: We report the case of a 45-year-old South Indian man who presented with localized cutaneous Fusarium infection following a renal transplant. CONCLUSION: In an immunocompromised patient, even an innocuous lesion needs to be addressed with the initiation of prompt treatment. PMID- 21612605 TI - Adaptation to HIF-1 deficiency by upregulation of the AMP/ATP ratio and phosphofructokinase activation in hepatomas. AB - BACKGROUND: HIF-1 deficiency has marked effects on tumour glycolysis and growth. We therefore investigated the consequences of HIF-1 deficiency in mice, using the well established Hepa-1 wild-type (WT) and HIF-1beta-deficient (c4) model. These mechanisms could be clinically relevant, since HIF-1 is now a therapeutic target. METHODS: Hepa-1 WT and c4 tumours grown in vivo were analysed by 18FDG-PET and 19FDG Magnetic Resonance Spectroscopy for glucose uptake; by HPLC for adenine nucleotides; by immunohistochemistry for GLUTs; by immunoblotting and by DIGE followed by tandem mass spectrometry for protein expression; and by classical enzymatic methods for enzyme activity. RESULTS: HIF-1beta deficient Hepa-1 c4 tumours grew significantly more slowly than WT tumours, and (as expected) showed significantly lower expression of many glycolytic enzymes. However, HIF-1beta deficiency caused no significant change in the rate of glucose uptake in c4 tumours compared to WT when assessed in vivo by measuring fluoro-deoxyglucose (FDG) uptake. Immunohistochemistry demonstrated less GLUT-1 in c4 tumours, whereas GLUT-2 (liver type) was similar to WT. Factors that might upregulate glucose uptake independently of HIF-1 (phospho-Akt, c-Myc) were shown to have either lower or similar expression in c4 compared to WT tumours. However the AMP/ATP ratio was 4.5 fold higher (p < 0.01) in c4 tumours, and phosphofructokinase-1 (PFK-1) activity, measured at prevailing cellular ATP and AMP concentrations, was up to two-fold higher in homogenates of the deficient c4 cells and tumours compared to WT (p < 0.001), suggesting that allosteric PFK activation could explain their normal level of glycolysis. Phospho AMP-Kinase was also higher in the c4 tumours. CONCLUSIONS: Despite their defective HIF-1 and consequent down-regulation of glycolytic enzyme expression, Hepa-1 c4 tumours maintain glucose uptake and glycolysis because the resulting low [ATP] high [AMP] allosterically activate PFK-1. This mechanism of resistance would keep glycolysis functioning and also result in activation of AMP-Kinase and growth inhibition; it may have major implications for the therapeutic activity of HIF inhibitors in vivo. Interestingly, this control mechanism does not involve transcriptional control or proteomics, but rather the classical activation and inhibition mechanisms of glycolytic enzymes. PMID- 21612607 TI - Homoplastic microinversions and the avian tree of life. AB - BACKGROUND: Microinversions are cytologically undetectable inversions of DNA sequences that accumulate slowly in genomes. Like many other rare genomic changes (RGCs), microinversions are thought to be virtually homoplasy-free evolutionary characters, suggesting that they may be very useful for difficult phylogenetic problems such as the avian tree of life. However, few detailed surveys of these genomic rearrangements have been conducted, making it difficult to assess this hypothesis or understand the impact of microinversions upon genome evolution. RESULTS: We surveyed non-coding sequence data from a recent avian phylogenetic study and found substantially more microinversions than expected based upon prior information about vertebrate inversion rates, although this is likely due to underestimation of these rates in previous studies. Most microinversions were lineage-specific or united well-accepted groups. However, some homoplastic microinversions were evident among the informative characters. Hemiplasy, which reflects differences between gene trees and the species tree, did not explain the observed homoplasy. Two specific loci were microinversion hotspots, with high numbers of inversions that included both the homoplastic as well as some overlapping microinversions. Neither stem-loop structures nor detectable sequence motifs were associated with microinversions in the hotspots. CONCLUSIONS: Microinversions can provide valuable phylogenetic information, although power analysis indicates that large amounts of sequence data will be necessary to identify enough inversions (and similar RGCs) to resolve short branches in the tree of life. Moreover, microinversions are not perfect characters and should be interpreted with caution, just as with any other character type. Independent of their use for phylogenetic analyses, microinversions are important because they have the potential to complicate alignment of non-coding sequences. Despite their low rate of accumulation, they have clearly contributed to genome evolution, suggesting that active identification of microinversions will prove useful in future phylogenomic studies. PMID- 21612608 TI - Phosphoproteome analysis during larval development and metamorphosis in the spionid polychaete Pseudopolydora vexillosa. AB - BACKGROUND: The metamorphosis of the spionid polychaete Pseudopolydora vexillosa includes spontaneous settlement onto soft-bottom habitats and morphogenesis that can be completed in a very short time. A previous study on the total changes to the proteome during the various developmental stages of P. vexillosa suggested that little or no de novo protein synthesis occurs during metamorphosis. In this study, we used multicolor fluorescence detection of proteins in 2-D gels for differential analysis of proteins and phosphoproteins to reveal the dynamics of post-translational modification proteins in this species. A combination of affinity chromatography, 2D-PAGE, and mass spectrometry was used to identify the phosphoproteins in pre-competent larvae, competent larvae, and newly metamorphosed juveniles. RESULTS: We reproducibly detected 210, 492, and 172 phosphoproteins in pre-competent larvae, competent larvae, and newly metamorphosed juveniles, respectively. The highest percentage of phosphorylation was observed during the competent larval stage. About 64 stage-specific phosphoprotein spots were detected in the competent stage, and 32 phosphoproteins were found to be significantly differentially expressed in the three stages. We identified 38 phosphoproteins, 10 of which were differentially expressed during metamorphosis. These phosphoproteins belonged to six categories of biological processes: (1) development, (2) cell differentiation and integrity, (3) transcription and translation, (4) metabolism, (5) protein-protein interaction and proteolysis, and (6) receptors and enzymes. CONCLUSION: This is the first study to report changes in phosphoprotein expression patterns during the metamorphosis of the marine polychaete P. vexillosa. The higher degree of phosphorylation during the process of attaining competence to settle and metamorphose may be due to fast morphological transitions regulated by various mechanisms. Our data are consistent with previous studies showing a high percentage of phosphorylation during competency in the barnacle Balanus amphitrite and the bryozoan Bugula neritina. The identified phosphoproteins may play an important role during metamorphosis, and further studies on the location and functions of important proteins during metamorphosis are warranted. PMID- 21612609 TI - How students perceive medical competences: a cross-cultural study between the medical course in Portugal and African Portuguese speaking countries. AB - BACKGROUND: A global effort has been made in the last years to establish a set of core competences that define the essential professional competence of a physician. Regardless of the environment, culture or medical education conditions, a set of core competences is required for medical practice worldwide. Evaluation of educational program is always needed to assure the best training for medical students and ultimately best care for patients. The aim of this study was to determine in what extent medical students in Portugal and Portuguese speaking African countries, felt they have acquired the core competences to start their clinical practice. For this reason, it was created a measurement tool to evaluate self-perceived competences, in different domains, across Portuguese and Portuguese-speaking African medical schools. METHODS: The information was collected through a questionnaire that defines the knowledge, attitudes and skills that future doctors should acquire. The Cronbach's Alpha and Principal Components Analysis (PCA) were used to evaluate the reliability of the questionnaire. In order to remove possible confounding effect, individual scores were standardized by country. RESULTS: The order of the domain's scores was similar between countries. After standardization, Personal Attitudes and Professional Behavior showed median scores above the country global median and Knowledge alone showed median score below the country global median. In Portugal, Clinical Skills showed score below the global median. In Angola, Clinical Skills and General Skills showed a similar result. There were only significant differences between countries in Personal Attitudes (p < 0.001) and Professional Behavior (p = 0.043). CONCLUSIONS: The reliability of the instrument in Portuguese and Portuguese-speaking African medical schools was confirmed. Students have perceived their level of competence in personal attitudes in a high level and in opposite, knowledge and clinical skills with some weaknesses. PMID- 21612610 TI - Recruitment and retention of farm owners and workers for a six-month prospective injury study in New Zealand: a feasibility study. AB - BACKGROUND: Agricultural workers experience high rates of occupational injury. There is a lack of analytic studies which provide detailed occupational exposure information to inform intervention development. METHODS: A feasibility study simulating a six month prospective cohort study was designed and undertaken. The levels of farm and worker participation and retention were analysed to determine the feasibility of the methods for wider deployment. RESULTS: Recruitment levels were comparable with other studies, with 24% of farms and 36% of non-owner workers participating. Once recruited, retention was high at 85% and 86% respectively. CONCLUSIONS: The main challenges identified were in the recruitment process. Once recruited, farms and workers tended to complete the study, indicating that prospective studies in this the agricultural workforce may be feasible. Issues encountered and potential solutions for future studies are discussed. PMID- 21612611 TI - Application of adaptive design and decision making to a phase II trial of a phosphodiesterase inhibitor for the treatment of intermittent claudication. AB - BACKGROUND: Claudication secondary to peripheral artery disease (PAD) is associated with substantial functional impairment. Phosphodiesterase (PDE) inhibitors have been shown to increase walking performance in these patients. K 134 is a selective PDE 3 inhibitor being developed as a potential treatment for claudication. The use of K-134, as with other PDE 3 inhibitors, in patients with PAD raises important safety and tolerability concerns, including the induction of cardiac ischemia, tachycardia, and hypotension. We describe the design, oversight, and implementation of an adaptive, phase II, dose-finding trial evaluating K-134 for the treatment of stable, intermittent claudication. METHODS: The study design was a double-blind, multi-dose (25 mg, 50 mg, and 100 mg of K 134), randomized trial with both placebo and active comparator arms conducted in the United States and Russia. The primary objective of the study was to compare the highest tolerable dose of K-134 versus placebo using peak walking time after 26 weeks of therapy as the primary outcome. Study visits with intensive safety assessments were included early in the study period to provide data for adaptive decision making. The trial used an adaptive, dose-finding strategy to efficiently identify the highest dose(s) most likely to be safe and well tolerated, based on the side effect profiles observed within the trial, so that less promising doses could be abandoned. Protocol specified criteria for safety and tolerability endpoints were used and modeled prior to the adaptive decision making. The maximum target sample size was 85 subjects in each of the retained treatment arms. RESULTS: When 199 subjects had been randomized and 28-day data were available from 143, the Data Monitoring Committee (DMC) recommended termination of the lowest dose (25 mg) treatment arm. Safety evaluations performed during 14- and 28-day visits which included in-clinic dosing and assessments at peak drug concentrations provided core data for the DMC review. At the time of review, no subject in any of the five treatment arms (placebo, three K-134-containing arms, and cilostazol) had met pre-specified definitions for resting tachycardia or ischemic changes on exercise ECG. If, instead of dropping the 25-mg K-134 treatment arm, all arms had been continued to full enrollment, then approximately 43 additional research subjects would have been required to complete the trial. CONCLUSIONS: In this phase II, dose-finding trial of K-134 in the treatment of stable intermittent claudication, no concerning safety signals were seen at interim analysis, allowing the discontinuation of the lowest-dose-containing arm and the retention of the two highest-dose-containing arms. The adaptive design facilitated safe and efficient evaluation of K-134 in this high-risk cardiovascular population. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00783081. PMID- 21612612 TI - Antimicrobial activities of the methanol extract and compounds from Artocarpus communis (Moraceae). AB - BACKGROUND: Artocarpus communis is used traditionally in Cameroon to treat several ailments, including infectious and associated diseases. This work was therefore designed to investigate the antimicrobial activities of the methanol extract (ACB) and compounds isolated from the bark of this plant, namely peruvianursenyl acetate C (1), alpha-amyrenol or viminalol (2), artonin E (4) and 2-[(3,5-dihydroxy)-(Z)-4-(3-methylbut-1-enyl)phenyl]benzofuran-6-ol (5). METHODS: The liquid microdilution assay was used in the determination of the minimal inhibitory concentration (MIC) and the minimal microbicidal concentration (MMC), against seven bacterial and one fungal species. RESULTS: The MIC results indicated that ACB as well as compounds 4 and 5 were able to prevent the growth of all tested microbial species. All other compounds showed selective activities. The lowest MIC value of 64 MUg/ml for the crude extract was recorded on Staphylococcus aureus ATCC 25922 and Escherichia coli ATCC 8739. The corresponding value of 32 MUg/ml was recorded with compounds 4 and 5 on Pseudomonas aeruginosa PA01 and compound 5 on E. coli ATCC 8739, their inhibition effect on P. aeruginosa PA01 being more than that of chloramphenicol used as reference antibiotic. CONCLUSION: The overall results of this study provided supportive data for the use of A. communis as well as some of its constituents for the treatment of infections associated with the studied microorganisms. PMID- 21612613 TI - An investigation of nurses' knowledge, attitudes, and practices regarding disinfection procedures in Italy. AB - BACKGROUND: This study assessed the level of knowledge, attitudes, and practice regarding disinfection procedures among nurses in Italian hospitals. METHODS: A face-to-face interview gathered the following information: demographic and practice characteristics; knowledge about the healthcare-associated infections (HAIs) and the disinfection practices; attitudes towards the utility of guidelines/protocols and perception of the risks of acquiring/transmitting HAIs; compliance with antisepsis/disinfection procedures; and sources of information. RESULTS: Only 29% acknowledged that urinary and respiratory tract infections were the two most common HAIs and this knowledge was significantly higher in those with a higher level of education. Attitudes towards the utility of guidelines/protocols for disinfection procedures showed a mean score of 9.1. The results of the linear regression model indicated a more positive attitude in female nurses, in those with a lower number of years of activity, and in those needing additional information about disinfection procedures. Nurses with higher educational level and with a higher perception of risk of transmitting an infectious disease while working were more likely to perform appropriate antisepsis of the surgical wound and handwashing before and after medication. CONCLUSIONS: Plan of successful prevention activities about HAIs and provide pointers to help optimize disinfection procedures and infection prophylaxis and management are needed. PMID- 21612614 TI - System Integration - A Major Step toward Lab on a Chip. AB - Microfluidics holds great promise to revolutionize various areas of biological engineering, such as single cell analysis, environmental monitoring, regenerative medicine, and point-of-care diagnostics. Despite the fact that intensive efforts have been devoted into the field in the past decades, microfluidics has not yet been adopted widely. It is increasingly realized that an effective system integration strategy that is low cost and broadly applicable to various biological engineering situations is required to fully realize the potential of microfluidics. In this article, we review several promising system integration approaches for microfluidics and discuss their advantages, limitations, and applications. Future advancements of these microfluidic strategies will lead toward translational lab-on-a-chip systems for a wide spectrum of biological engineering applications. PMID- 21612615 TI - Hyperglycaemia and apoptosis of microglial cells in human septic shock. AB - INTRODUCTION: The effect of hyperglycaemia on the brain cells of septic shock patients is unknown. The objective of this study was to evaluate the relationship between hyperglycaemia and apoptosis in the brains of septic shock patients. METHODS: In a prospective study of 17 patients who died from septic shock, hippocampal tissue was assessed for neuronal ischaemia, neuronal and microglial apoptosis, neuronal Glucose Transporter (GLUT) 4, endothelial inducible Nitric Oxide Synthase (iNOS), microglial GLUT5 expression, microglial and astrocyte activation. Blood glucose (BG) was recorded five times a day from ICU admission to death. Hyperglycaemia was defined as a BG 200 mg/dL g/l and the area under the BG curve (AUBGC) > 2 g/l was assessed. RESULTS: Median BG over ICU stay was 2.2 g/l. Neuronal apoptosis was correlated with endothelial iNOS expression (rho = 0.68, P = 0.04), while microglial apoptosis was associated with AUBGC > 2 g/l (rho = 0.70; P = 0.002). Neuronal and microglial apoptosis correlated with each other (rho = 0.69, P = 0.006), but neither correlated with the duration of septic shock, nor with GLUT4 and 5 expression. Neuronal apoptosis and ischaemia tended to correlate with duration of hypotension. CONCLUSIONS: In patients with septic shock, neuronal apoptosis is rather associated with iNOS expression and microglial apoptosis with hyperglycaemia, possibly because GLUT5 is not downregulated. These data provide a mechanistic basis for understanding the neuroprotective effects of glycemic control. PMID- 21612616 TI - An association between Helicobacter pylori infection and cognitive function in children at early school age: a community-based study. AB - BACKGROUND: H. pylori infection has been linked to iron deficiency anemia, a risk factor of diminished cognitive development. The hypothesis on an association between H. pylori infection and cognitive function was examined in healthy children, independently of socioeconomic and nutritional factors. METHODS: A community-based study was conducted among 200 children aged 6-9 years, from different socioeconomic background. H. pylori infection was examined by an ELISA kit for detection of H. pylori antigen in stool samples. Cognitive function of the children was blindly assessed using Stanford-Benit test 5th edition, yielding IQ scores. Data on socioeconomic factors and nutritional covariates were collected through maternal interviews and from medical records. Multivariate linear regression analysis was performed to obtain adjusted beta coefficients. RESULTS: H. pylori infection was associated with lower IQ scores only in children from a relatively higher socioeconomic community; adjusted beta coefficient -6.1 (95% CI -11.4, -0.8) (P = 0.02) for full-scale IQ score, -6.0 (95% CI -11.1, 0.2) (P = 0.04) for non-verbal IQ score and -5.7 (95% CI -10.8, -0.6) (P = 0.02) for verbal IQ score, after controlling for potential confounders. CONCLUSIONS: H. pylori infection might be negatively involved in cognitive development at early school age. Further studies in other populations with larger samples are needed to confirm this novel finding. PMID- 21612617 TI - Polymorphism, selection and tandem duplication of transferrin genes in Atlantic cod (Gadus morhua)--conserved synteny between fish monolobal and tetrapod bilobal transferrin loci. AB - BACKGROUND: The two homologous iron-binding lobes of transferrins are thought to have evolved by gene duplication of an ancestral monolobal form, but any conserved synteny between bilobal and monolobal transferrin loci remains unexplored. The important role played by transferrin in the resistance to invading pathogens makes this polymorphic gene a highly valuable candidate for studying adaptive divergence among local populations. RESULTS: The Atlantic cod genome was shown to harbour two tandem duplicated serum transferrin genes (Tf1, Tf2), a melanotransferrin gene (MTf), and a monolobal transferrin gene (Omp). Whereas Tf1 and Tf2 were differentially expressed in liver and brain, the Omp transcript was restricted to the otoliths. Fish, chicken and mammals showed highly conserved syntenic regions in which monolobal and bilobal transferrins reside, but contrasting with tetrapods, the fish transferrin genes are positioned on three different linkage groups. Sequence alignment of cod Tf1 cDNAs from Northeast (NE) and Northwest (NW) Atlantic populations revealed 22 single nucleotide polymorphisms (SNP) causing the replacement of 16 amino acids, including eight surface residues revealed by the modelled 3D-structures, that might influence the binding of pathogens for removal of iron. SNP analysis of a total of 375 individuals from 14 trans-Atlantic populations showed that the Tf1 NE variant was almost fixed in the Baltic cod and predominated in the other NE Atlantic populations, whereas the NW Atlantic populations were more heterozygous and showed high frequencies of the Tf-NW SNP alleles. CONCLUSIONS: The highly conserved synteny between fish and tetrapod transferrin loci infers that the fusion of tandem duplicated Omp-like genes gave rise to the modern transferrins. The multiple nonsynonymous substitutions in cod Tf1 with putative structural effects, together with highly divergent allele frequencies among different cod populations, strongly suggest evidence for positive selection and local adaptation in trans-Atlantic cod populations. PMID- 21612618 TI - Multilocus sequence typing of a global collection of Pasteurella multocida isolates from cattle and other host species demonstrates niche association. AB - BACKGROUND: Pasteurella multocida causes disease in many host species throughout the world. In bovids, it contributes to bovine respiratory disease (BRD) and causes haemorrhagic septicaemia (HS). Previous studies have suggested that BRD associated P. multocida isolates are of limited diversity. A multilocus sequence typing (MLST) scheme for P. multocida was used to determine whether the low levels of diversity reported are due to the limited discriminatory power of the typing method used, restricted sample selection or true niche association. Bovine respiratory isolates of P. multocida (n = 133) from the UK, the USA and France, collected between 1984 and 2008 from both healthy and clinically affected animals, were typed using MLST. Isolates of P. multocida from cases of HS, isolates from other host species and data from the MLST database were used as comparison. RESULTS: Bovine respiratory isolates were found to be clonal (I(S)(A) 0.45) with 105/128 belonging to clonal complex 13 (CC13). HS isolates were not related to bovine respiratory isolates. Of the host species studied, the majority had their own unique sequence types (STs), with few STs being shared across host species, although there was some cross over between porcine and bovine respiratory isolates. Avian, ovine and porcine isolates showed greater levels of diversity compared to cattle respiratory isolates, despite more limited geographic origins. CONCLUSIONS: The homogeneity of STs of bovine respiratory P. multocida observed, and the differences between these and P. multocida subpopulations from bovine non-respiratory isolates and non-bovine hosts may indicate niche association. PMID- 21612619 TI - HIV treatment for prevention. AB - "No virus, no transmission." Studies have repeatedly shown that viral load (the quantity of virus present in blood and sexual secretions) is the strongest predictor of HIV transmission during unprotected sex or transmission from infected mother to child. Effective treatment lowers viral load to undetectable levels. If one could identify and treat all HIV-infected people immediately after infection, the HIV/AIDS epidemic would eventually disappear.Such a radical solution is currently unrealistic. In reality, not all people get tested, especially when they fear stigma and discrimination. Thus, not all HIV-infected individuals are known. Of those HIV-positive individuals for whom the diagnosis is known, not all of them have access to therapy, agree to be treated, or are taking therapy effectively. Some on effective treatment will stop, and in others, the development of resistance will lead to treatment failure. Furthermore, resources are limited: should we provide drugs to asymptomatic HIV-infected individuals without indication for treatment according to guidelines in order to prevent HIV transmission at the risk of diverting funding from sick patients in urgent need? In fact, the preventive potential of anti-HIV drugs is unknown. Modellers have tried to fill the gap, but models differ depending on assumptions that are strongly debated. Further, indications for antiretroviral treatments expand; in places like Vancouver and San Francisco, the majority of HIV-positive individuals are now under treatment, and the incidence of new HIV infections has recently fallen. However, correlation does not necessarily imply causation. Finally, studies in couples where one partner is HIV-infected also appear to show that treatment reduces the risk of transmission.More definite studies, where a number of communities are randomized to either receive the "test-and-treat" approach or continue as before, are now in evaluation by funding agencies. Repeated waves of testing would precisely measure the incidence of HIV infection. Such trials face formidable logistical, practical and ethical obstacles. However, without definitive data, the intuitive appeal of "test-and-treat" is unlikely to translate into action on a global scale. In the meantime, based on the available evidence, we must strive to provide treatment to all those in medical need under the current medical guidelines. This will lead to a decrease in HIV transmission while "test-and-treat" is fully explored in prospective clinical trials. PMID- 21612620 TI - SALGOT--Stroke Arm Longitudinal study at the University of Gothenburg, prospective cohort study protocol. AB - BACKGROUND: Recovery patterns of upper extremity motor function have been described in several longitudinal studies, but most of these studies have had selected samples, short follow up times or insufficient outcomes on motor function. The general understanding is that improvements in upper extremity occur mainly during the first month after the stroke incident and little if any, significant recovery can be gained after 3-6 months. The purpose of this study is to describe the recovery of upper extremity function longitudinally in a non selected sample initially admitted to a stroke unit with first ever stroke, living in Gothenburg urban area. METHODS/DESIGN: A sample of 120 participants with a first-ever stroke and impaired upper extremity function will be consecutively included from an acute stroke unit and followed longitudinally for one year. Assessments are performed at eight occasions: at day 3 and 10, week 3, 4 and 6, month 3, 6 and 12 after onset of stroke. The primary clinical outcome measures are Action Research Arm Test and Fugl-Meyer Assessment for Upper Extremity. As additional measures, two new computer based objective methods with kinematic analysis of arm movements are used. The ABILHAND questionnaire of manual ability, Stroke Impact Scale, grip strength, spasticity, pain, passive range of motion and cognitive function will be assessed as well. At one year follow up, two patient reported outcomes, Impact on Participation and Autonomy and EuroQol Quality of Life Scale, will be added to cover the status of participation and aspects of health related quality of life. DISCUSSION: This study comprises a non-selected population with first ever stroke and impaired arm function. Measurements are performed both using traditional clinical assessments as well as computer based measurement systems providing objective kinematic data. The ICF classification of functioning, disability and health is used as framework for the selection of assessment measures. The study design with several repeated measurements on motor function will give us more confident information about the recovery patterns after stroke. This knowledge is essential both for optimizing rehabilitation planning as well as providing important information to the patient about the recovery perspectives. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01115348. PMID- 21612621 TI - BRCAA1 monoclonal antibody conjugated fluorescent magnetic nanoparticles for in vivo targeted magnetofluorescent imaging of gastric cancer. AB - BACKGROUND: Gastric cancer is 2th most common cancer in China, and is still the second most common cause of cancer-related death in the world. How to recognize early gastric cancer cells is still a great challenge for early diagnosis and therapy of patients with gastric cancer. This study is aimed to develop one kind of multifunctional nanoprobes for in vivo targeted magnetofluorescent imaging of gastric cancer. METHODS: BRCAA1 monoclonal antibody was prepared, was used as first antibody to stain 50 pairs of specimens of gastric cancer and control normal gastric mucous tissues, and conjugated with fluorescent magnetic nanoparticles with 50 nm in diameter, the resultant BRCAA1-conjugated fluorescent magnetic nanoprobes were characterized by transmission electron microscopy and photoluminescence spectrometry, as-prepared nanoprobes were incubated with gastric cancer MGC803 cells, and were injected into mice model loaded with gastric cancer of 5 mm in diameter via tail vein, and then were imaged by fluorescence optical imaging and magnetic resonance imaging, their biodistribution was investigated. The tissue slices were observed by fluorescent microscopy, and the important organs such as heart, lung, kidney, brain and liver were analyzed by hematoxylin and eosin (HE) stain method. RESULTS: BRCAA1 monoclonal antibody was successfully prepared, BRCAA1 protein exhibited over expression in 64% gastric cancer tissues, no expression in control normal gastric mucous tissues, there exists statistical difference between two groups (P < 0.01). The BRCAA1-conjugated fluorescent magnetic nanoprobes exhibit very low toxicity, lower magnetic intensity and lower fluorescent intensity with peak-blue shift than pure FMNPs, could be endocytosed by gastric cancer MGC803 cells, could target in vivo gastric cancer tissues loaded by mice, and could be used to image gastric cancer tissues by fluorescent imaging and magnetic resonance imaging, and mainly distributed in local gastric cancer tissues within 12 h post-injection. HE stain analysis showed that no obvious damages were observed in important organs. CONCLUSIONS: The high-performance BRCAA1 monoclonal antibody-conjugated fluorescent magnetic nanoparticles can target in vivo gastric cancer cells, can be used for simultaneous magnetofluorescent imaging, and may have great potential in applications such as dual-model imaging and local thermal therapy of early gastric cancer in near future. PMID- 21612622 TI - rnaSeqMap: a Bioconductor package for RNA sequencing data exploration. AB - BACKGROUND: The throughput of commercially available sequencers has recently significantly increased. It has reached the point where measuring the RNA expression by the depth of coverage has become feasible even for largest genomes. The development of software tools is constantly following the progress of biological hardware. In particular, as RNA sequencing software can be regarded genome browsers, exon junction tools and statistical tools operating on counts of reads in predefined regions. The library rnaSeqMap, freely available via Bioconductor, is an RNA sequencing software which is independent of any biological hardware platform. It is based upon standard Bioconductor infrastructure for sequencing data and includes several novel features focused on deeper understanding of coverage expression profiles and discovery of novel transcription regions. RESULTS: rnaSeqMap is a toolbox for analyses that may be performed with the use of gene annotations or alternatively, in an unsupervised mode, on any genomic region to find novel or non-standard transcripts. The data back-end may be a MySQL database or a set of files in standard BAM format. The processing in R can be run on a machine without any particular hardware requirements, and scales linearly with the number of genomic loci and number of samples analyzed. The main features of rnaSeqMap include coverage operations, discovering irreducible regions of high expression, significance search and splicing analyses with nucleotide granularity. CONCLUSIONS: This software may be used for a range of applications related to RNA sequencing by building customized analysis pipelines. The applicability and precision is expected to increase in parallel with the progress of the genome coverage in sequencers. PMID- 21612623 TI - Development of a context model to prioritize drug safety alerts in CPOE systems. AB - BACKGROUND: Computerized physician order entry systems (CPOE) can reduce the number of medication errors and adverse drug events (ADEs) in healthcare institutions. Unfortunately, they tend to produce a large number of partly irrelevant alerts, in turn leading to alert overload and causing alert fatigue. The objective of this work is to identify factors that can be used to prioritize and present alerts depending on the 'context' of a clinical situation. METHODS: We used a combination of literature searches and expert interviews to identify and validate the possible context factors. The internal validation of the context factors was performed by calculating the inter-rater agreement of two researcher's classification of 33 relevant articles. RESULTS: We developed a context model containing 20 factors. We grouped these context factors into three categories: characteristics of the patient or case (e.g. clinical status of the patient); characteristics of the organizational unit or user (e.g. professional experience of the user); and alert characteristics (e.g. severity of the effect). The internal validation resulted in nearly perfect agreement (Cohen's Kappa value of 0.97). CONCLUSION: To our knowledge, this is the first structured attempt to develop a comprehensive context model for prioritizing drug safety alerts in CPOE systems. The outcome of this work can be used to develop future tailored drug safety alerting in CPOE systems. PMID- 21612624 TI - The effect of an active on-ward participation of hospital pharmacists in Internal Medicine teams on preventable Adverse Drug Events in elderly inpatients: protocol of the WINGS study (Ward-oriented pharmacy in newly admitted geriatric seniors). AB - BACKGROUND: The potential of clinical interventions, aiming at reduction of preventable Adverse Drug Events (preventable ADEs) during hospital stay, have been studied extensively. Clinical Pharmacy is a well-established and effective service, usually consisting of full-time on-ward participation of clinical pharmacists in medical teams. Within the current Hospital Pharmacy organisation in the Netherlands, such on-ward service is less feasible and therefore not yet established. However, given the substantial incidence of preventable ADEs in Dutch hospitals found in recent studies, appears warranted. Therefore, "Ward Oriented Pharmacy", an on-ward service tailored to the Dutch hospital setting, will be developed. This service will consist of multifaceted interventions implemented in the Internal Medicine wards by hospital pharmacists. The effect of this service on preventable ADEs in elderly inpatients will be measured. Elderly patients are at high risk for ADEs due to multi-morbidity, concomitant disabilities and polypharmacy. Most studies on the incidence and preventability of ADEs in elderly patients have been conducted in the outpatient setting or on admission to a hospital, and fewer in the inpatient setting. Moreover, recognition of ADEs by the treating physicians is challenging in elderly patients because their disease presentation is often atypical and complex. Detailed information about the performance of the treating physicians in ADE recognition is scarce. METHODS/DESIGN: The design is a multi-centre, interrupted time series study. Patients of 65 years or older, consecutively admitted to Internal Medicine wards will be included. After a pre-measurement, a Ward-Oriented Pharmacy service will be introduced and the effect of this service will be assessed during a post measurement. The primary outcome measures are the ADE prevalence on admission and ADE incidence during hospital stay. These outcomes will be assessed using structured retrospective chart review by an independent expert panel. This assessment will include determination of causality, severity and preventability of ADEs. In addition, the extent to which ADEs are recognised and managed by the treating physicians will be considered. DISCUSSION: The primary goal of the WINGS study is to assess whether a significant reduction in preventable ADEs in elderly inpatients can be achieved by a Ward-Oriented Pharmacy service offered. A comprehensive ADE detection method will be used based on expert opinion and retrospective, trigger-tool enhanced, chart review. PMID- 21612626 TI - CAPL: an efficient association software package using family and case-control data and accounting for population stratification. AB - BACKGROUND: With many genome-wide association study (GWAS) datasets available, it is critical that we have statistical tools that are both flexible to accommodate different study designs and fast. We recently proposed the combined APL (CAPL) method, which can use family and case-control datasets and can account for population stratification in the data. Because computationally intensive algorithms are used in CAPL, implementing CAPL with efficient parallel algorithms is essential. RESULTS: We used a hybrid of open message passing interface (open MPI) and POSIX threads to parallelize CAPL, which enable the program to operate in a cluster environment. We used simulations to demonstrate that the parallel implementation of CAPL can analyze a large GWAS dataset in a reasonable time frame when a parallel computing resource is available. CONCLUSIONS: As many GWAS datasets based on both family and case-control designs are available, a flexible and efficient tool such as CAPL will be very helpful to combine the datasets to greatly increase statistical power and finish the analysis in a reasonable time frame. PMID- 21612625 TI - Subgroup analyses on return to work in sick-listed employees with low back pain in a randomised trial comparing brief and multidisciplinary intervention. AB - BACKGROUND: Multidisciplinary intervention is recommended for rehabilitation of employees sick-listed for 4-12 weeks due to low back pain (LBP). However, comparison of a brief and a multidisciplinary intervention in a randomised comparative trial of sick-listed employees showed similar return to work (RTW) rates in the two groups. The aim of the present study was to identify subgroups, primarily defined by work-related baseline factors that would benefit more from the multidisciplinary intervention than from the brief intervention. METHODS: A total of 351 employees sick-listed for 3-16 weeks due to LBP were recruited from their general practitioners. They received a brief or a multidisciplinary intervention. Both interventions comprised clinical examination and advice by a rehabilitation doctor and a physiotherapist. The multidisciplinary intervention also comprised assignment of a case manager, who made a rehabilitation plan in collaboration with the patient and a multidisciplinary team. Using data from a national database, we defined RTW as no sickness compensation benefit disbursement for four consecutive weeks within the first year after the intervention. At the first interview in the clinic, it was ensured that sick leave was primarily due to low back problems.Questionnaires were used to obtain data on health, disability, demographic and workplace-related factors. Cox hazard regression analyses were used with RTW as outcome measure and hazard rate ratios (HRR = HRmultidisciplinary/HRbrief) were adjusted for demographic and health related variables. An interaction term consisting of a baseline variable*intervention group was added to the multivariable regression model to analyse whether the effects of the interventions were moderated by the baseline factor. Subsequently, a new study was performed that included 120 patients who followed the same protocol. This group was analyzed in the same way to verify the findings from the original study group. RESULTS: The multidisciplinary intervention group ensured a quicker RTW than the brief intervention group in a subgroup with low job satisfaction, notably when claimants were excluded. The opposite effect was seen in the subgroup with high job satisfaction. When claimants were excluded, the effect was also in favour of the multidisciplinary intervention in subgroups characterised by no influence on work planning and groups at risk of losing their job. Inversely, the effect was in favour of the brief intervention in the subgroups who were able to influence the planning of their work and who had no risk of losing their job due to current sick leave. Interaction analysis of the data in the new study displayed similar or even more pronounced differences between subgroups in relation to intervention type. CONCLUSIONS: Multidisciplinary intervention seemed more effective than brief intervention in subgroups of patients with low job satisfaction, no influence on work planning and feeling at risk of losing their jobs due to their sick leave as compared with subgroups not fulfilling these criteria. PMID- 21612628 TI - Protein coalitions in a core mammalian biochemical network linked by rapidly evolving proteins. AB - BACKGROUND: Cellular ATP levels are generated by glucose-stimulated mitochondrial metabolism and determine metabolic responses, such as glucose-stimulated insulin secretion (GSIS) from the beta-cells of pancreatic islets. We describe an analysis of the evolutionary processes affecting the core enzymes involved in glucose-stimulated insulin secretion in mammals. The proteins involved in this system belong to ancient enzymatic pathways: glycolysis, the TCA cycle and oxidative phosphorylation. RESULTS: We identify two sets of proteins, or protein coalitions, in this group of 77 enzymes with distinct evolutionary patterns. Members of the glycolysis, TCA cycle, metabolite transport, pyruvate and NADH shuttles have low rates of protein sequence evolution, as inferred from a human mouse comparison, and relatively high rates of evolutionary gene duplication. Respiratory chain and glutathione pathway proteins evolve faster, exhibiting lower rates of gene duplication. A small number of proteins in the system evolve significantly faster than co-pathway members and may serve as rapidly evolving adapters, linking groups of co-evolving genes. CONCLUSIONS: Our results provide insights into the evolution of the involved proteins. We find evidence for two coalitions of proteins and the role of co-adaptation in protein evolution is identified and could be used in future research within a functional context. PMID- 21612627 TI - A high resolution map of a cyanobacterial transcriptome. AB - BACKGROUND: Previous molecular and mechanistic studies have identified several principles of prokaryotic transcription, but less is known about the global transcriptional architecture of bacterial genomes. Here we perform a comprehensive study of a cyanobacterial transcriptome, that of Synechococcus elongatus PCC 7942, generated by combining three high-resolution data sets: RNA sequencing, tiling expression microarrays, and RNA polymerase chromatin immunoprecipitation sequencing. RESULTS: We report absolute transcript levels, operon identification, and high-resolution mapping of 5' and 3' ends of transcripts. We identify several interesting features at promoters, within transcripts and in terminators relating to transcription initiation, elongation, and termination. Furthermore, we identify many putative non-coding transcripts. CONCLUSIONS: We provide a global analysis of a cyanobacterial transcriptome. Our results uncover insights that reinforce and extend the current views of bacterial transcription. PMID- 21612629 TI - Streptococcus agalactiae in adults at Chiang Mai University Hospital: a retrospective study. AB - BACKGROUND: Infection caused by Streptococcus agalactiae, a Group B streptococcus, is an emerging disease in non-pregnant adults. This study describes the epidemiological, clinical, and microbiological characteristics of S. agalactiae infection in adult patients in northern Thailand. METHODS: A retrospective study was conducted between January 1, 2006 and December 31, 2009 at Chiang Mai University Hospital among patients aged >=15 years, whose clinical specimens obtained from normally sterile sites grew S. agalactiae. RESULTS: One hundred and eighty-six patients and 197 specimens were identified during the 4 year period. Among 186 patients, 82 were documented as having invasive infection; 42 patients were male (51.2%) with the mean age of 48.5 +/- 19.4 years (range 17, 83). Fifty-three patients (64.6%) had underlying medical conditions; 17 patients (20.7%), 10 (12.2%), 8 (9.7%) had diabetes, chronic renal diseases, and malignancy, respectively. Among 40 patients (48.8%) with bloodstream infection, no other site of infection was determined in 29 (35.4%) patients. In the remaining 11 patients, 5 patients (6.1%), 5 (6.1%), and 1 (1.2%) had meningitis, arthritis, and meningitis with arthritis, respectively. Forty-two patients (51.2%) presented with localized infection, i.e., subcutaneous abscess (19 patients, 23.2%), chorioamnionitis (10 patients, 12.2%), urinary tract infection (5 patients, 6.1%), arthritis (3 patients, 3.7%), meningitis (2 patients, 2.4%), and spontaneous bacterial peritonitis, uveitis, and tracheobronchitis (1 patient each, 1.2%). The overall mortality was 14.6% (12 patients). CONCLUSIONS: S. agalactiae infection is a growing problem in non-pregnant patients, particularly in those with underlying medical conditions. Physicians should add S. agalactiae infection in the list of differential diagnoses in patients with meningitis and/or septicemia. PMID- 21612630 TI - Qxpak.5: old mixed model solutions for new genomics problems. AB - BACKGROUND: Mixed models have a long and fruitful history in statistics. They are pertinent to genomics problems because they are highly versatile, accommodating a wide variety of situations within the same theoretical and algorithmic framework. RESULTS: Qxpak is a package for versatile statistical genomics, specifically designed for sophisticated quantitative trait loci and association analyses. Multiple loci, multiple trait, infinitesimal genetic effects, imprinting, epistasis or sex linked loci can be fitted. The new version (v. 5) allows us, among other new features, to include either relationship matrices obtained with molecular information or user defined matrices that can be read from an input file. This feature can be used for genome selection or - more importantly - to correct for population structure in association studies. In crosses, two parental lines, not necessarily inbred, can be accommodated. CONCLUSIONS: This software aims at simplifying statistical genetic analyses implementing a coherent and unified approach by mixed models. It provides a tool that can be used in a wide variety of situations with ample genetic and statistical modeling flexibility. The software, a complete manual and examples are available at http://www.icrea.cat/Web/OtherSectionViewer.aspx?key=485&titol=Software:Qxpak. PMID- 21612631 TI - Construction of uricase-overproducing strains of Hansenula polymorpha and its application as biological recognition element in microbial urate biosensor. AB - BACKGROUND: The detection and quantification of uric acid in human physiological fluids is of great importance in the diagnosis and therapy of patients suffering from a range of disorders associated with altered purine metabolism, most notably gout and hyperuricaemia. The fabrication of cheap and reliable urate-selective amperometric biosensors is a challenging task. RESULTS: A urate-selective microbial biosensor was developed using cells of the recombinant thermotolerant methylotrophic yeast Hansenula polymorpha as biorecognition element. The construction of uricase (UOX) producing yeast by over-expression of the uricase gene of H. polymorpha is described. Following a preliminary screening of the transformants with increased UOX activity in permeabilized yeast cells the optimal cultivation conditions for maximal UOX yield namely a 40-fold increase in UOX activity were determined.The UOX producing cells were coupled to horseradish peroxidase and immobilized on graphite electrodes by physical entrapment behind a dialysis membrane. A high urate selectivity with a detection limit of about 8 MUM was found. CONCLUSION: A strain of H. polymorpha overproducing UOX was constructed. A cheap urate selective microbial biosensor was developed. PMID- 21612632 TI - Competing risk models to estimate the excess mortality and the first recurrent event hazards. AB - BACKGROUND: In medical research, one common competing risks situation is the study of different types of events, such as disease recurrence and death. We focused on that situation but considered death under two aspects: "expected death" and "excess death", the latter could be directly or indirectly associated with the disease. METHODS: The excess hazard method allows estimating an excess mortality hazard using the population (expected) mortality hazard. We propose models combining the competing risks approach and the excess hazard method. These models are based on a joint modelling of each event-specific hazard, including the event-free excess death hazard. The proposed models are parsimonious, allow time-dependent hazard ratios, and facilitate comparisons between event-specific hazards and between covariate effects on different events. In a simulation study, we assessed the performance of the estimators and showed their good properties with different drop-out censoring rates and different sample sizes. RESULTS: We analyzed a population-based dataset on French colon cancer patients who have undergone curative surgery. Considering three competing events (local recurrence, distant metastasis, and death), we showed that the recurrence-free excess mortality hazard reached zero six months after treatment. Covariates sex, age, and cancer stage had the same effects on local recurrence and distant metastasis but a different effect on excess mortality. CONCLUSIONS: The proposed models consider the excess mortality within the framework of competing risks. Moreover, the joint estimation of the parameters allow (i) direct comparisons between covariate effects, and (ii) fitting models with common parameters to obtain more parsimonious models and more efficient parameter estimators. PMID- 21612633 TI - Asking the right questions: developing evidence-based strategies for treating HIV in women and children. AB - In July 2010, the World Health Organization (WHO) issued formal revisions of its guidelines on the use of highly active antiretroviral therapy for HIV. The new guidelines greatly expand eligibility for treatment of adults and children, as well as for pregnant women seeking prophylaxis for vertical HIV transmission. WHO's new recommendations bring the guidelines closer to practices in developed countries, and its shift to earlier treatment alone will increase the number of treatment-eligible people by 50% or more.Scaling up access to HIV treatment is revealing important gaps in our understanding of how best to provide for all those in need. This knowledge gap is especially significant in developing countries, where women and children comprise a majority of those living with HIV infection. Given the magnitude and significance of these populations, the International AIDS Society, through its Industry Liaison Forum, prioritized HIV treatment and prophylaxis of women and children. In March 2010, the International AIDS Society and 15 partners launched a Consensus Statement outlining priority areas in which a relative lack of knowledge impedes delivery of optimal prevention of mother to child transmission (PMTCT) and treatment to women and children.The Consensus Statement, "Asking the Right Questions: Advancing an HIV Research Agenda for Women and Children", makes a special appeal for a more gender sensitive approach to HIV research at all stages, from conception to design and implementation. It particularly emphasizes research to enhance the understanding of sex-based differences and paediatric needs in treatment uptake and response. In addition to clinical issues, the statement focuses on programmatic research that facilitates access and adherence to antiretroviral regimens. Better coordination of HIV management with sexual and reproductive healthcare delivery is one such approach.We discuss here our knowledge gaps concerning effective, safe PMTCT and treatment for women and children in light of the expansion envisioned by WHO's revised guidelines. The guideline's new goals present an opportunity for advancing the women and children's agenda outlined in the Consensus Statement. PMID- 21612634 TI - Anal and oral human papillomavirus (HPV) infection in HIV-infected subjects in northern Italy: a longitudinal cohort study among men who have sex with men. AB - BACKGROUND: A study including 166 subjects was performed to investigate the frequency and persistence over a 6-month interval of concurrent oral and anal Human Papillomavirus (HPV) infections in Human Immunodeficiency Virus (HIV) infected men who have sex with men (MSM). METHODS: Patients with no previously documented HPV-related anogenital lesion/disease were recruited to participate in a longitudinal study. Polymerase chain reaction (PCR) was performed to detect HPV from oral and anal swabs and to detect Human Herpes Virus 8 (HHV-8) DNA in saliva on 2 separate specimen series, one collected at baseline and the other collected 6 months later. A multivariate logistic analysis was performed using anal HPV infection as the dependent variable versus a set of covariates: age, HIV plasma viral load, CD4+ count, hepatitis B virus (HBV) serology, hepatitis C virus (HCV) serology, syphilis serology and HHV-8 viral shedding. A stepwise elimination of covariates with a p-value > 0.1 was performed. RESULTS: The overall prevalence of HPV did not vary significantly between the baseline and the follow-up, either in the oral (20.1 and 21.3%, respectively) or the anal specimens (88.6 and 86.3%). The prevalence of high-risk (HR) genotypes among the HPV-positive specimens was similar in the oral and anal infections (mean values 24.3% and 20.9%). Among 68 patients with either a HR, low-risk (LR) or undetermined genotype at baseline, 75% had persistent HPV and the persistence rates were 71.4% in HR infections and 76.7% in LR infections. There was a lack of genotype concordance between oral and anal HPV samples. The prevalence of HR HPV in anus appeared to be higher in the younger patients, peaking (> 25%) in the 43-50 years age group. A decrease of the high level of anal prevalence of all genotypes of HPV in the patients > 50 years was evident. HHV-8 oral shedding was positively related to HPV anal infection (p = 0.0046). A significant correlation was found between the persistence of HHV-8 shedding and HIV viral load by logistic bivariate analysis (Odds Ratio of HHV-8 persistence for 1-log increase of HIV viral load = 1.725 +/- 0.397, p = 0.018). CONCLUSIONS: A high prevalence of HPV infection was found in our cohort of HIV infected MSM, with a negative correlation between anal HPV infection and CD4 cell count. PMID- 21612635 TI - Medicaid expenditures for children living with smokers. AB - BACKGROUND: Children's exposure to secondhand smoke is associated with increased morbidity. We estimated Medicaid expenditures for children living with smokers compared to those living with no smokers in the United States. METHODS: Data were overall and service-specific (i.e., inpatient, ambulatory, emergency department, prescription drug, and dental) annual Medicaid expenditures for children 0-11 years old from the 2000-2007 Medical Expenditures Panel Surveys. Smokers' presence in households was determined by adult respondents' self reports. There were 25,835 person-years of observation. We used multivariate analyses to adjust for child, parent, and geographic characteristics. RESULTS: Children with Medicaid expenditures were nearly twice as likely to live with a smoker as other children in the U.S. population. Adjusted analyses revealed no detectable differences in children's overall Medicaid expenditures by presence of smokers in the household. Medicaid children who lived with smokers on average had $10 (95% CI $3, $18) higher emergency department expenditures per year than those living with no smokers. CONCLUSIONS: Living with at least one smoker (a proxy for secondhand smoke exposure) is unrelated to children's overall short-term Medicaid expenditures, but has a modest impact on emergency department expenditures. Additional research is necessary to understand the relationship between secondhand smoke exposure and long-term health and economic outcomes. PMID- 21612636 TI - Assessing the functional coherence of modules found in multiple-evidence networks from Arabidopsis. AB - BACKGROUND: Combining multiple evidence-types from different information sources has the potential to reveal new relationships in biological systems. The integrated information can be represented as a relationship network, and clustering the network can suggest possible functional modules. The value of such modules for gaining insight into the underlying biological processes depends on their functional coherence. The challenges that we wish to address are to define and quantify the functional coherence of modules in relationship networks, so that they can be used to infer function of as yet unannotated proteins, to discover previously unknown roles of proteins in diseases as well as for better understanding of the regulation and interrelationship between different elements of complex biological systems. RESULTS: We have defined the functional coherence of modules with respect to the Gene Ontology (GO) by considering two complementary aspects: (i) the fragmentation of the GO functional categories into the different modules and (ii) the most representative functions of the modules. We have proposed a set of metrics to evaluate these two aspects and demonstrated their utility in Arabidopsis thaliana. We selected 2355 proteins for which experimentally established protein-protein interaction (PPI) data were available. From these we have constructed five relationship networks, four based on single types of data: PPI, co-expression, co-occurrence of protein names in scientific literature abstracts and sequence similarity and a fifth one combining these four evidence types. The ability of these networks to suggest biologically meaningful grouping of proteins was explored by applying Markov clustering and then by measuring the functional coherence of the clusters. CONCLUSIONS: Relationship networks integrating multiple evidence-types are biologically informative and allow more proteins to be assigned to a putative functional module. Using additional evidence types concentrates the functional annotations in a smaller number of modules without unduly compromising their consistency. These results indicate that integration of more data sources improves the ability to uncover functional association between proteins, both by allowing more proteins to be linked and producing a network where modular structure more closely reflects the hierarchy in the gene ontology. PMID- 21612637 TI - Spatial variation and socio-economic determinants of Plasmodium falciparum infection in northeastern Tanzania. AB - BACKGROUND: Malaria due to Plasmodium falciparum is the leading cause of morbidity and mortality in Tanzania. According to health statistics, malaria accounts for about 30% and 15% of hospital admissions and deaths, respectively. The risk of P. falciparum infection varies across the country. This study describes the spatial variation and socio-economic determinants of P. falciparum infection in northeastern Tanzania. METHODS: The study was conducted in 14 villages located in highland, lowland and urban areas of Korogwe district. Four cross-sectional malaria surveys involving individuals aged 0-19 years were conducted during short (Nov-Dec) and long (May-Jun) rainy seasons from November 2005 to June 2007. Household socio-economic status (SES) data were collected between Jan-April 2006 and household's geographical positions were collected using hand-held geographical positioning system (GPS) unit. The effects of risk factors were determined using generalized estimating equation and spatial risk of P. falciparum infection was modelled using a kernel (non-parametric) method. RESULTS: There was a significant spatial variation of P. falciparum infection, and urban areas were at lower risk. Adjusting for covariates, high risk of P. falciparum infection was identified in rural areas of lowland and highland. Bed net coverage levels were independently associated with reduced risk of P. falciparum by 19.1% (95%CI: 8.9-28.2, p < 0.001) and by 39.3% (95%CI: 28.9-48.2, p < 0.001) in households with low and high coverage, respectively, compared to those without bed nets. Households with moderate and lower SES had risk of infection higher than 60% compared to those with higher SES; while inhabitants of houses built of mud walls were at 15.5% (95%CI: 0.1 - 33.3, p < 0.048) higher risk compared to those living in houses built by bricks. Individuals in houses with thatched roof had an excess risk of 17.3% (95%CI: 4.1 - 32.2, p < 0.009) compared to those living in houses roofed with iron sheet. CONCLUSIONS: There was high spatial variation of risk of P. falciparum infection and urban area was at the lowest risk. High bed net coverage, better SES and good housing were among the important risk factors associated with low risk of P. falciparum infection. PMID- 21612638 TI - Selected AGXT gene mutations analysis provides a genetic diagnosis in 28% of Tunisian patients with primary hyperoxaluria. AB - BACKGROUND: Primary hyperoxaluria type I (PH1) is a rare genetic disorder characterized by allelic and clinical heterogeneity. Four mutations (G170R, 33_34insC, I244T and F152I) account for more than 50% of PH1 alleles and form the basis for diagnostic genetic screening for PH1. We aimed to analyze the prevalence of these specific mutations causing PH1, and to provide an accurate tool for diagnosis of presymptomatic patients as well as for prenatal diagnosis in the affected families. METHODS: Polymerase chain reaction/Restriction Fragment Length Polymorphism, were used to detect the four mutations in the AGXT gene in DNA samples from 57 patients belonging to 40 families. RESULTS: Two mutations causing PH1 were detected in 24 patients (42.1%), with a predominance of the I244T mutation (68% of patients) and 33_34insC (in the remaining 32%). In 92% of cases, mutated alleles were in homozygous state. The presented clinical features were similar for the two mutations. The age of onset was heterogeneous with a higher frequency of the pediatric age. In 58.3% of cases, the presentation corresponded to advanced renal disease which occurred early (< 5 years) in the two mutations. In adolescents, only the I244T mutation was detected (41.1%). I244T and 33_34insC mutations were observed in adult patients, with 17.6% and 12.5% respectively. CONCLUSION: Limited mutation analysis can provide a useful first line investigation for PH1. I244T and 33_34insC presented 28.2% of identified mutations causing disease in our cohort. This identification could provide an accurate tool for prenatal diagnosis in the affected families, for genetic counselling and for detection of presymptomatic individuals. PMID- 21612639 TI - Clinician attitudes toward and use of electronic problem lists: a thematic analysis. AB - BACKGROUND: The clinical problem list is an important tool for clinical decision making, quality measurement and clinical decision support; however, problem lists are often incomplete and provider attitudes towards the problem list are poorly understood. METHODS: An ethnographic study of healthcare providers conducted from April 2009 to January 2010 was carried out among academic and community outpatient medical practices in the Greater Boston area across a wide range of medical and surgical specialties. Attitudes towards the problem list were then analyzed using grounded theory methods. RESULTS: Attitudes were variable, and dimensions of variations fit into nine themes: workflow, ownership and responsibility, relevance, uses, content, presentation, accuracy, alternatives, support/education and one cross-cutting theme of culture. CONCLUSIONS: Significant variation was observed in clinician attitudes towards and use of the electronic patient problem list. Clearer guidance and best practices for problem list utilization are needed. PMID- 21612640 TI - Health care seeking behavior for diarrhea in children under 5 in rural Niger: results of a cross-sectional survey. AB - BACKGROUND: Diarrhea remains the second leading cause of death in children under 5 years of age in sub-Saharan Africa. Health care seeking behavior for diarrhea varies by context and has important implications for developing appropriate care strategies and estimating burden of disease. The objective of this study was to determine the proportion of children under five with diarrhea who consulted at a health structure in order to identify the appropriate health care levels to set up surveillance of severe diarrheal diseases. METHODS: A cluster survey was done on 35 clusters of 21 children under 5 years of age in each of four districts of the Maradi Region, Niger. Caretakers were asked about diarrhea of the child during the recall period and their health seeking behavior in case of diarrhea. A weighted cluster analysis was conducted to determine the prevalence of diarrhea, as well as the proportion of consultations and types of health structures consulted. RESULTS: In total, the period prevalence of diarrhea and severe diarrhea between April 24th and May 21st 2009 were 36.8% (95% CI: 33.7 - 40.0) and 3.4% (95% CI: 2.2-4.6), respectively. Of those reporting an episode of diarrhea during the recall period, 70.4% (95% CI: 66.6-74.1) reported seeking care at a health structure. The main health structures visited were health centers, followed by health posts both for simple or severe diarrhea. Less than 10% of the children were brought to the hospital. The proportion of consultations was not associated with the level of education of the caretaker, but increased with the number of children in the household. CONCLUSIONS: The proportion of consultations for diarrhea cases in children under 5 years old was higher than those reported in previous surveys in Niger and elsewhere. Free health care for under 5 years old might have participated in this improvement. In this type of decentralized health systems, the WHO recommended hospital-based surveillance of severe diarrheal diseases would capture only a fraction of severe diarrhea. Lower levels of health structures should be considered to obtain informative data to ensure appropriate care and burden estimates. PMID- 21612642 TI - The future of pharmaceutical care in France: a survey of final-year pharmacy students' opinions. AB - BACKGROUND: In the last decades, the provision of pharmaceutical care by community pharmacists has developed in OECD countries. These developments involved significant changes in professional practices and organization of primary care. In France, they have recently been encouraged by a new legal framework and favored by an increasing demand for health care (increase in the number of patients with chronic diseases) and reductions in services being offered (reduction in the number of general practitioners and huge regional disparities). OBJECTIVES: This study aimed to investigate final-year pharmacy students' opinions on 1/expanding the scope of pharmacists' practices and 2/the potential barriers for the implementation of pharmaceutical care. We discussed these in the light of the experiences of pharmacists in Quebec, and other countries in Europe (United Kingdom and the Netherlands). METHODS: All final-year students in pharmaceutical studies, preparing to become community pharmacists, at the University Paris-Descartes in Paris during 2010 (n = 146) were recruited. All of them were interviewed by means of a questionnaire describing nine "professional" practices by pharmacists, arranged in four dimensions: (1) screening and chronic disease management, (2) medication surveillance, (3) pharmacy-prescribed medication and (4) participation in health care networks. Respondents were asked (1) how positively they view the extension of their current practices, using a 5 point Likert scale and (2) their perception of potential professional, technical, organizational and/or financial obstacles to developing these practices. RESULTS: 143 (97.9%) students completed the questionnaire. Most of practices studied received a greater than 80% approval rating, although only a third of respondents were in favor of the sales of over the-counter (OTC) drugs. The most significant perceived barriers were working time, remuneration and organizational problems, specifically the need to create a physical location for consultations to respect patients' privacy within a pharmacy. CONCLUSIONS: Despite remaining barriers to cross, this study showed that future French pharmacists were keen to develop their role in patient care, beyond the traditional role of dispensing. However, the willingness of doctors and patients to consent should be investigated and also rigorous studies to support or refute the positive impact of pharmaceutical care on the quality of care should be carried out. PMID- 21612641 TI - Reversal of TGF-beta1 stimulation of alpha-smooth muscle actin and extracellular matrix components by cyclic AMP in Dupuytren's-derived fibroblasts. AB - BACKGROUND: Myofibroblasts, a derived subset of fibroblasts especially important in scar formation and wound contraction, have been found at elevated levels in affected Dupuytren's tissues. Transformation of fibroblasts to myofibroblasts is characterized by expression of alpha- smooth muscle actin (alpha-SMA) and increased production of extracellular matrix (ECM) components, both events of relevance to connective tissue remodeling. We propose that increasing the activation of the cyclic AMP (cAMP)/protein kinase A signaling pathway will inhibit transforming growth factor-beta1 (TGF-beta1)-induced ECM synthesis and myofibroblast formation and may provide a means to blunt fibrosis. METHODS: Fibroblasts derived from areas of Dupuytren's contracture cord (DC), from adjacent and phenotypically normal palmar fascia (PF), and from palmar fascia from patients undergoing carpal tunnel release (CTR; CT) were treated with TGF beta1 (2 ng/ml) and/or forskolin (10 MUM) (a known stimulator of cAMP). Total RNA and protein extracted was subjected to real time RT-PCR and Western blot analysis. RESULTS: The basal mRNA expression levels of fibronectin- extra domain A (FN1-EDA), type I (COL1A2) and type III collagen (COL3A1), and connective tissue growth factor (CTGF) were all significantly increased in DC- and in PF derived cells compared to CT-derived fibroblasts. The TGF-beta1 stimulation of alpha-SMA, CTGF, COL1A2 and COL3A1 was greatly inhibited by concomitant treatment with forskolin, especially in DC-derived cells. In contrast, TGF-beta1 stimulation of FN1-EDA showed similar levels of reduction with the addition of forskolin in all three cell types. CONCLUSION: In sum, increasing cAMP levels show potential to inhibit the formation of myofibroblasts and accumulation of ECM components. Molecular agents that increase cAMP may therefore prove useful in mitigating DC progression or recurrence. PMID- 21612643 TI - Health differentials in the older population of England: an empirical comparison of the materialist, lifestyle and psychosocial hypotheses. AB - BACKGROUND: In developed countries with old age structures most deaths occur at older ages and older people account for the majority of those in poor health, which suggests a particular need to investigate health inequalities in the older population. METHODS: We empirically compared the materialist, psychosocial and lifestyle/behavioural theoretical mechanisms of explanation for socio-economic variation in health using data from two waves of the English Longitudinal Study of Ageing (ELSA), a nationally representative multi-purpose sample of the population aged 50 and over living in England. Three dimensions of health were examined: somatic health, depression and well-being. RESULTS: The materialist and lifestyle/behavioural paths had the most prominent mediating role in the association between socio-economic position and health in the older population, whereas the psychosocial pathway was less influential and exerted most of its influence on depression and well-being, with part of its effect being due to the availability of material resources. CONCLUSIONS: From a policy perspective there is therefore an indication that population interventions to reduce health differentials and thus improve the overall health of the older population should focus on material circumstances and population based interventions to promote healthy lifestyles. PMID- 21612645 TI - Tree edit distance for leaf-labelled trees on free leafset and its comparison with frequent subsplit dissimilarity and popular distance measures. AB - BACKGROUND: This paper is devoted to distance measures for leaf-labelled trees on free leafset. A leaf-labelled tree is a data structure which is a special type of a tree where only leaves (terminal) nodes are labelled. This data structure is used in bioinformatics for modelling of evolution history of genes and species and also in linguistics for modelling of languages evolution history. Many domain specific problems occur and need to be solved with help of tree postprocessing techniques such as distance measures. RESULTS: Here we introduce the tree edit distance designed for leaf labelled trees on free leafset, which occurs to be a metric. It is presented together with tree edit consensus tree notion. We provide statistical evaluation of provided measure with respect to R-F, MAST and frequent subsplit based dissimilarity measures as the reference measures. CONCLUSIONS: The tree edit distance was proven to be a metric and has the advantage of using different costs for contraction and pruning, therefore their properties can be tuned depending on the needs of the user. Two of the presented methods carry the most interesting properties. E(3,1) is very discriminative (having a wide range of values) and has a very regular distance distribution which is similar to a normal distribution in its shape and is good both for similar and non-similar trees. NFC(2,1) on the other hand is proportional or nearly proportional to the number of mutation operations used, irrespective of their type. PMID- 21612644 TI - How the psychosocial context of clinical trials differs from usual care: a qualitative study of acupuncture patients. AB - BACKGROUND: Qualitative studies of participants' experiences in randomised clinical trials (RCTs) suggest that the psychosocial context of treatment in RCTs may be quite different to the psychosocial context of treatment in usual practice. This is important, as the psychosocial context of treatment is known to influence patient outcomes in chronic illness. Few studies have directly compared the psychosocial context of treatment across RCTs and usual practice. In this study, we explored differences in psychosocial context between RCT and usual practice settings, using acupuncture as our model. METHODS: We undertook a secondary analysis of existing qualitative interviews with 54 patients. 27 were drawn from a study of western and traditional acupuncture in usual practice (for a range of painful conditions). 27 were drawn from a qualitative study nested in an RCT of western acupuncture for osteoarthritis of the hip or knee. We used qualitative analysis software to facilitate an inductive thematic analysis in which we identified three main themes. RESULTS: In usual practice, starting acupuncture was more likely to be embedded in an active and ongoing search for pain relief, whereas in the RCT starting acupuncture was opportunistic. Usual practice patients reported few uncertainties and these had minimal consequences for them. In the RCT, patients experienced considerable uncertainties about their treatment and its effectiveness, and were particularly concerned about whether they were receiving real (or fake) acupuncture. Patients stopped acupuncture only at the end of the fixed course of treatment in the RCT, which was similar to those receiving acupuncture in the public sector National Health Service (NHS). In comparison, private sector patients re-evaluated and re-negotiated treatments particularly when starting to use acupuncture. CONCLUSIONS: Differences in psychosocial context between RCTs and usual practice could reduce the impact of acupuncture in RCT settings and/or lead to under-reporting of benefit by patients in trials. New trial designs that ensure participants' experiences are similar to usual practice should minimise differences in psychosocial context and help attenuate these potentially confounding effects. PMID- 21612646 TI - Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease. AB - BACKGROUND: Donepezil 23 mg/d, recently approved in the United States for treatment of moderate to severe Alzheimer's disease (AD), was developed to address the need for an additional treatment option for patients with advanced AD. This report, based on a pivotal phase 3 study, presents a detailed analysis of the safety and tolerability of increasing donepezil to 23 mg/d compared with continuing 10 mg/d. METHOD: Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs) and their relationship to treatment initiation; changes in weight, electrocardiogram, vital signs, and laboratory parameters; and the incidence of premature study discontinuation. The analysis population (n = 1434) included all randomized patients who took at least 1 dose of study drug and had a postbaseline safety assessment. To further examine the effect of transition from a lower to a higher donepezil dose, a pooled analysis of safety data from 2 phase 3 trials of donepezil 5 mg/d and 10 mg/d was also performed. RESULTS: The safety population comprised 1434 patients: donepezil 23 mg/d (n = 963); donepezil 10 mg/d (n = 471); completion rates were 71.1% and 84.7%, respectively. The most common AEs were nausea, vomiting, and diarrhea (donepezil 23 mg/d: 11.8%, 9.2%, 8.3%; donepezil 10 mg/d: 3.4%, 2.5%, 5.3%, respectively). AEs that contributed most to early discontinuations were vomiting (2.9% of patients in the 23 mg/d group and 0.4% in the 10 mg/d group), nausea (1.9% and 0.4%), diarrhea (1.7% and 0.4%), and dizziness (1.1% and 0.0%). The percentages of patients with AEs in the 23 mg/d group, as well as the timing, type, and severity of these AEs, were similar to those seen in previous donepezil trials with titration from 5 to 10 mg/d. Serious AEs were uncommon (23 mg/d, 8.3%; 10 mg/d, 9.6%). DISCUSSION: The 23 mg/d dose of donepezil was associated with typical cholinergic AEs, particularly gastrointestinal-related AEs, similar to those observed in studies with a dose increase from 5 to 10 mg/d. CONCLUSION: The good safety and predictable tolerability profile for donepezil 23 mg/d supports its favorable risk/benefit ratio in patients with moderate to severe AD. PMID- 21612647 TI - Associations between air temperature and cardio-respiratory mortality in the urban area of Beijing, China: a time-series analysis. AB - BACKGROUND: Associations between air temperature and mortality have been consistently observed in Europe and the United States; however, there is a lack of studies for Asian countries. Our study investigated the association between air temperature and cardio-respiratory mortality in the urban area of Beijing, China. METHODS: Death counts for cardiovascular and respiratory diseases for adult residents (>=15 years), meteorological parameters and concentrations of particulate air pollution were obtained from January 2003 to August 2005. The effects of two-day and 15-day average temperatures were estimated by Poisson regression models, controlling for time trend, relative humidity and other confounders if necessary. Effects were explored for warm (April to September) and cold periods (October to March) separately. The lagged effects of daily temperature were investigated by polynomial distributed lag (PDL) models. RESULTS: We observed a J-shaped exposure-response function only for 15-day average temperature and respiratory mortality in the warm period, with 21.3 degrees C as the threshold temperature. All other exposure-response functions could be considered as linear. In the warm period, a 5 degrees C increase of two day average temperature was associated with a RR of 1.098 (95% confidence interval (95%CI): 1.057-1.140) for cardiovascular and 1.134 (95%CI: 1.050-1.224) for respiratory mortality; a 5 degrees C decrease of 15-day average temperature was associated with a RR of 1.040 (95%CI: 0.990-1.093) for cardiovascular mortality. In the cold period, a 5 degrees C increase of two-day average temperature was associated with a RR of 1.149 (95%CI: 1.078-1.224) for respiratory mortality; a 5 degrees C decrease of 15-day average temperature was associated with a RR of 1.057 (95%CI: 1.022-1.094) for cardiovascular mortality. The effects remained robust after considering particles as additional confounders. CONCLUSIONS: Both increases and decreases in air temperature are associated with an increased risk of cardiovascular mortality. The effects of heat were immediate while the ones of cold became predominant with longer time lags. Increases in air temperature are also associated with an immediate increased risk of respiratory mortality. PMID- 21612648 TI - Evaluation of a resistance training program for adults with or at risk of developing diabetes: an effectiveness study in a community setting. AB - BACKGROUND: To examine the effects of a community-based resistance training program (Lift for Life(r)) on waist circumference and functional measures in adults with or at risk of developing type 2 diabetes. METHODS: Lift for Life is a research-to-practice initiative designed to disseminate an evidence-based resistance training program for adults with or at risk of developing type 2 diabetes to existing health and fitness facilities in the Australian community. A retrospective assessment was undertaken on 86 participants who had accessed the program within 4 active providers in Melbourne, Australia. The primary goal of this longitudinal study was to assess the effectiveness of a community-based resistance training program, thereby precluding a randomized, controlled study design. Waist circumference, lower body (chair sit-to-stand) and upper body (arm curl test) strength, and agility (timed up-and-go) measures were collected at baseline and repeated at 2 months (n = 86) and again at 6 months (n = 32). RESULTS: Relative to baseline, there was a significant decrease in mean waist circumference (-1.9 cm, 95% CI: -2.8 to -1.0) and the timed agility test (-0.8 secs, 95% CI: -1.0 to -0.6); and significant increases in lower body (number of repetitions: 2.2, 95% CI: 1.4-3.0) and upper body (number of repetitions: 3.8, 95% CI: 3.0-4.6) strength at the completion of 8 weeks. Significant differences remained at the 16 week assessment. Pooled time series regression analyses adjusted for age and sex in the 32 participants who had complete measures at baseline and 24-week follow-up revealed significant time effects for waist circumference and functional measures, with the greatest change from baseline observed at the 24-week assessment. CONCLUSIONS: These findings indicate that an evidence-based resistance training program administered in the community setting for those with or at risk of developing type 2 diabetes, can lead to favorable health benefits, including reductions in central obesity and improved physical function. PMID- 21612649 TI - Sustained reduction in prevalence of lymphatic filariasis infection in spite of missed rounds of mass drug administration in an area under mosquito nets for malaria control. AB - BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was established by the World Health Organisation (WHO) in 2000 with the goal of eliminating lymphatic filariasis (LF) as a public health problem globally by 2020. Mass drug administration (MDA) of antifilarial drugs is the principal strategy recommended for global elimination. Kenya launched a National Programme for Elimination of Lymphatic Filariasis (NPELF) in Coast Region in 2002. During the same year a longitudinal research project to monitor trends of LF infection during MDA started in a highly endemic area in Malindi District. High coverage of insecticide treated nets (ITNs) in the coastal region has been associated with dramatic decline in hospital admissions due to malaria; high usage of ITNs is also expected to have an impact on LF infection, also transmitted by mosquitoes. RESULTS: Four rounds of MDA with diethylcarbamazine citrate (DEC) and albendazole were given to 8 study villages over an 8-year period. Although annual MDA was not administered for several years the overall prevalence of microfilariae declined significantly from 20.9% in 2002 to 0.9% in 2009. Similarly, the prevalence of filarial antigenaemia declined from 34.6% in 2002 to 10.8% in 2009. All the examined children born since the start of the programme were negative for filarial antigen in 2009. CONCLUSIONS: Despite the fact that the study villages missed MDA in some of the years, significant reductions in infection prevalence and intensity were observed at each survey. More importantly, there were no rebounds in infection prevalence between treatment rounds. However, because of confounding variables such as insecticide-treated bed nets (ITNs), it is difficult to attribute the reduction to MDA alone as ITNs can lead to a significant reduction in exposure to filariasis vectors. The results indicate that national LF elimination programmes should be encouraged to continue provision of MDA albeit constraints that may lead to missing of MDA in some years. PMID- 21612650 TI - Inter-examiner reproducibility of tests for lumbar motor control. AB - BACKGROUND: Many studies show a relation between reduced lumbar motor control (LMC) and low back pain (LBP). However, test circumstances vary and during test performance, subjects may change position. In other words, the reliability--i.e. reproducibility and validity--of tests for LMC should be based on quantitative data. This has not been considered before. The aim was to analyse the reproducibility of five different quantitative tests for LMC commonly used in daily clinical practice. METHODS: The five tests for LMC were: repositioning (RPS), sitting forward lean (SFL), sitting knee extension (SKE), and bent knee fall out (BKFO), all measured in cm, and leg lowering (LL), measured in mm Hg. A total of 40 subjects (14 males, 26 females) 25 with and 15 without LBP, with a mean age of 46.5 years (SD 14.8), were examined independently and in random order by two examiners on the same day. LBP subjects were recruited from three physiotherapy clinics with a connection to the clinic's gym or back-school. Non LBP subjects were recruited from the clinic's staff acquaintances, and from patients without LBP. RESULTS: The means and standard deviations for each of the tests were 0.36 (0.27) cm for RPS, 1.01 (0.62) cm for SFL, 0.40 (0.29) cm for SKE, 1.07 (0.52) cm for BKFO, and 32.9 (7.1) mm Hg for LL. All five tests for LMC had reproducibility with the following ICCs: 0.90 for RPS, 0.96 for SFL, 0.96 for SKE, 0.94 for BKFO, and 0.98 for LL. Bland and Altman plots showed that most of the differences between examiners A and B were less than 0.20 cm. CONCLUSION: These five tests for LMC displayed excellent reproducibility. However, the diagnostic accuracy of these tests needs to be addressed in larger cohorts of subjects, establishing values for the normal population. Also cut-points between subjects with and without LBP must be determined, taking into account age, level of activity, degree of impairment and participation in sports. Whether reproducibility of these tests is as good in daily clinical practice when used by untrained examiners also needs to be examined. PMID- 21612651 TI - Reduced MHC and neutral variation in the Galapagos hawk, an island endemic. AB - BACKGROUND: Genes at the major histocompatibility complex (MHC) are known for high levels of polymorphism maintained by balancing selection. In small or bottlenecked populations, however, genetic drift may be strong enough to overwhelm the effect of balancing selection, resulting in reduced MHC variability. In this study we investigated MHC evolution in two recently diverged bird species: the endemic Galapagos hawk (Buteo galapagoensis), which occurs in small, isolated island populations, and its widespread mainland relative, the Swainson's hawk (B. swainsoni). RESULTS: We amplified at least two MHC class II B gene copies in each species. We recovered only three different sequences from 32 Galapagos hawks, while we amplified 20 unique sequences in 20 Swainson's hawks. Most of the sequences clustered into two groups in a phylogenetic network, with one group likely representing pseudogenes or nonclassical loci. Neutral genetic diversity at 17 microsatellite loci was also reduced in the Galapagos hawk compared to the Swainson's hawk. CONCLUSIONS: The corresponding loss in neutral diversity suggests that the reduced variability present at Galapagos hawk MHC class II B genes compared to the Swainson's hawk is primarily due to a founder event followed by ongoing genetic drift in small populations. However, purifying selection could also explain the low number of MHC alleles present. This lack of variation at genes involved in the adaptive immune response could be cause for concern should novel diseases reach the archipelago. PMID- 21612652 TI - An open source web application for the surveillance and prevention of the impacts on public health of extreme meteorological events: the SUPREME system. AB - BACKGROUND: Every year, many deaths or health problems are directly linked to heat waves. Consequently, numerous jurisdictions around the world have developed intervention plans that are employed during extreme heat events; beyond their emergency sections, these plans generally include preventive measures to be implemented each year. Over the last five years, local and regional information systems have been implemented in a few Canadian cities for surveillance purposes. However, until recently, no such systems existed at the provincial level. In the context of the Government of Quebec's 2006-2012 Action Plan on Climate Change, a real-time integrated system for the surveillance and monitoring of extreme heat events has been implemented on a provincial level. The system is a component of a broader approach that would also monitor the public health impacts of all types of extreme meteorological events. RESULTS: After conducting a detailed needs analysis, the Quebec National Institute for Public Health developed and implemented an integrated web application leveraging open source software for the real-time Surveillance and Prevention of the impacts of Extreme Meteorological Events on public health, called the SUPREME system. Its first field use involved heat waves. This decision-support system is based on open source software and is composed of four modules: (1) data acquisition and integration, (2) risk analysis and alerts, (3), cartographic application, and (4) information dissemination - climate change and health portal. The system is available to health specialists through a secure web information portal and provides access to weather forecasts, historic and real-time indicators (including deaths and hospital admissions), alerts and various cartographic data used for conducting prevention activities and launching emergency measures. CONCLUSIONS: The SUPREME system was implemented and used during the summer of 2010. It served as an important decision-making tool during the July 2010 heat wave in the province of Quebec, Canada. Planned improvements for 2011 include the integration of data related to other risk factors for other extreme events to the system. The next steps will be to provide access to the application to other groups of specialists that are involved in the prevention, monitoring, or analysis of extreme meteorological events and their effects on community health and well-being. PMID- 21612653 TI - Determinants of sexual dysfunction among clinically diagnosed diabetic patients. AB - BACKGROUND: Diabetes mellitus is a chronic disease that can result in various medical, psychological and sexual dysfunctions (SD) if not properly managed. SD in men is a common under-appreciated complication of diabetes. This study assessed the prevalence and determinants of SD among diabetic patients in Tema, Greater Accra Region of Ghana. METHOD: Sexual functioning was determined in 300 consecutive diabetic men (age range: 18-82 years) visiting the diabetic clinic of Tema General Hospital with the Golombok Rust Inventory of Sexual Satisfaction (GRISS) questionnaire, between November, 2010 and March, 2011. In addition to the socio-demographic characteristics of the participants, the level of glycosylated haemoglobin, fasting blood sugar (FBS) and serum testosterone were assessed. All the men had a steady heterosexual relationship for at least 2 years before enrolment in the study. RESULTS: Out the 300 participants contacted, the response rate was 91.3% after 20 declined participation and 6 incomplete data were excluded All the respondents had at least basic education, 97.4% were married, 65.3% were known hypertensive, 3.3% smoked cigarettes, 27% took alcoholic beverages and 32.8% did some form of exercise. The 69.3% SD rate observed in this study appears to be related to infrequency (79.2%), non-sensuality (74.5%), dissatisfaction with sexual acts (71.9%), non-communication (70.8%) and impotence (67.9%). Other areas of sexual function, including premature ejaculation (56.6%) and avoidance (42.7%) were also substantially affected. However, severe SD was seen in only 4.7% of the studied population. The perceived "adequate", "desirable", "too short" and "too long intra-vaginal ejaculatory latency time (IELT) are 5-10, 5-10, 1-2 and 15-30 minutes respectively. Testosterone correlates negatively with glycated haemoglobin (HBA1c), FBS, perceived desirable, too short IELT, and weight as well as waist circumference. CONCLUSION: SD rate from this study is high but similar to that reported among self-reported diabetic patients in Kumasi, Ghana and vary according to the condition and age. The determinants of SD from this study are income level, exercise, obesity, higher perception of "desirable" and "too short" IELT. PMID- 21612654 TI - The importance of RT-qPCR primer design for the detection of siRNA-mediated mRNA silencing. AB - BACKGROUND: The use of RNAi to analyse gene function in vitro is now widely applied in biological research. However, several difficulties are associated with its use in vivo, mainly relating to inefficient delivery and non-specific effects of short RNA duplexes in animal models. The latter can lead to false positive results when real-time RT-qPCR alone is used to measure target mRNA knockdown. FINDINGS: We observed that detection of an apparent siRNA-mediated knockdown in vivo was dependent on the primers used for real-time RT-qPCR measurement of the target mRNA. Two siRNAs specific for RRM1 with equivalent activity in vitro were administered to A549 xenografts via intratumoural injection. In each case, apparent knockdown of RRM1 mRNA was observed only when the primer pair used in RT qPCR flanked the siRNA cleavage site. This false-positive result was found to result from co-purified siRNA interfering with both reverse transcription and qPCR. CONCLUSIONS: Our data suggest that using primers flanking the siRNA mediated cleavage site in RT-qPCR-based measurements of mRNA knockdown in vivo can lead to false positive results. This is particularly relevant where high concentrations of siRNA are introduced, particularly via intratumoural injection, as the siRNA may be co-purified with the RNA and interfere with downstream enzymatic steps. Based on these results, using primers flanking the siRNA target site should be avoided when measuring knockdown of target mRNA by real-time RT qPCR. PMID- 21612655 TI - Temporal trends in neonatal outcomes following iatrogenic preterm delivery. AB - BACKGROUND: Preterm birth rates have increased substantially in the recent years mostly due to obstetric intervention. We studied the effects of increasing iatrogenic preterm birth on temporal trends in perinatal mortality and serious neonatal morbidity in the United States. METHODS: We used data on singleton and twin births in the United States, 1995-2005 (n = 36,399,333), to examine trends in stillbirths, neonatal deaths, and serious neonatal morbidity (5-minute Apgar <=3, assisted ventilation >=30 min and neonatal seizures). Preterm birth subtypes were identified using an algorithm that categorized live births <37 weeks into iatrogenic preterm births, births following premature rupture of membranes and spontaneous preterm births. Temporal changes were quantified using odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Among singletons, preterm birth increased from 7.3 to 8.8 per 100 live births from 1995 to 2005, while iatrogenic preterm birth increased from 2.2 to 3.7 per 100 live births. Stillbirth rates declined from 3.4 to 3.0 per 1,000 total births from 1995-96 to 2004-05, and neonatal mortality rates declined from 2.4 to 2.1 per 1,000 live births. Temporal declines in neonatal mortality/morbidity were most pronounced at 34-36 weeks gestation and larger among iatrogenic preterm births (OR = 0.75, CI 0.73-0.77) than among spontaneous preterm births (OR = 0.82, CI 0.80-0.84); P < 0.001. Similar patterns were observed among twins, with some notable differences. CONCLUSION: Increases in iatrogenic preterm birth have been accompanied by declines in perinatal mortality. The temporal decline in neonatal mortality/serious neonatal morbidity has been larger among iatrogenic preterm births as compared with spontaneous preterm births. PMID- 21612656 TI - Characterization and analysis of the cotton cyclopropane fatty acid synthase family and their contribution to cyclopropane fatty acid synthesis. AB - BACKGROUND: Cyclopropane fatty acids (CPA) have been found in certain gymnosperms, Malvales, Litchi and other Sapindales. The presence of their unique strained ring structures confers physical and chemical properties characteristic of unsaturated fatty acids with the oxidative stability displayed by saturated fatty acids making them of considerable industrial interest. While cyclopropenoid fatty acids (CPE) are well-known inhibitors of fatty acid desaturation in animals, CPE can also inhibit the stearoyl-CoA desaturase and interfere with the maturation and reproduction of some insect species suggesting that in addition to their traditional role as storage lipids, CPE can contribute to the protection of plants from herbivory. RESULTS: Three genes encoding cyclopropane synthase homologues GhCPS1, GhCPS2 and GhCPS3 were identified in cotton. Determination of gene transcript abundance revealed differences among the expression of GhCPS1, 2 and 3 showing high, intermediate and low levels, respectively, of transcripts in roots and stems; whereas GhCPS1 and 2 are both expressed at low levels in seeds. Analyses of fatty acid composition in different tissues indicate that the expression patterns of GhCPS1 and 2 correlate with cyclic fatty acid (CFA) distribution. Deletion of the N-terminal oxidase domain lowered GhCPS's ability to produce cyclopropane fatty acid by approximately 70%. GhCPS1 and 2, but not 3 resulted in the production of cyclopropane fatty acids upon heterologous expression in yeast, tobacco BY2 cell and Arabidopsis seed. CONCLUSIONS: In cotton GhCPS1 and 2 gene expression correlates with the total CFA content in roots, stems and seeds. That GhCPS1 and 2 are expressed at a similar level in seed suggests both of them can be considered potential targets for gene silencing to reduce undesirable seed CPE accumulation. Because GhCPS1 is more active in yeast than the published Sterculia CPS and shows similar activity when expressed in model plant systems, it represents a strong candidate gene for CFA accumulation via heterologous expression in production plants. PMID- 21612657 TI - Neuronal migration defects in the Loa dynein mutant mouse. AB - BACKGROUND: Cytoplasmic dynein and its regulatory proteins have been implicated in neuronal and non-neuronal cell migration. A genetic model for analyzing the role of cytoplasmic dynein specifically in these processes has, however, been lacking. The Loa (Legs at odd angles) mouse with a mutation in the dynein heavy chain has been the focus of an increasing number of studies for its role in neuron degeneration. Despite the location of this mutation in the tail domain of the dynein heavy chain, we previously found a striking effect on coordination between the two dynein motor domains, resulting in a defect in dynein run length in vitro and in vivo. RESULTS: We have now tested for effects of the Loa mutation on neuronal migration in the developing neocortex. Loa homozygotes showed clear defects in neocortical lamination and neuronal migration resulting from a reduction in the rate of radial migration of bipolar neurons. CONCLUSIONS: These results present a new genetic model for understanding the dynein pathway and its functions during neuronal migration. They also provide the first evidence for a link between dynein processivity and somal movement, which is essential for proper development of the brain. PMID- 21612659 TI - Serum levels of leptin in Nigerian patients with sickle cell anaemia. AB - BACKGROUND: Several studies have shown that the pathophysiology of homozygous sickle cell anaemia (SCA) results in a myriad of metabolic, nutritional, haematological and clinical effects that interact with other co-morbid factors to determine the quality of life and life expectancy of afflicted patients. Because of its critical roles in nutrition and metabolism, inflammation, haematopoiesis and cellular immunity, this study determined the plasma levels of leptin in steady and unsteady states of HbSS in Nigerian patients. METHODS: A total of 51 SCA patients aged 5 - 35 years with 34 (61.8%) being females who were either on admission or visiting four medical centres in Lagos, Nigeria together with 22 non SCD controls aged 5 -30 years comprising 12 (54.5%) females were enrolled after obtaining their informed consent and ethical approval. Patients were further stratified into steady and unsteady cases of SCA based on clinical presentations, while blood samples collected by venipuncture from each of the study participants were analyzed haematologically for full blood count and HbF level and microscopically for malaria, while plasma leptin was assayed using ELISA method. Body composition defined by weight, fat mass and body mass index (BMI) was determined using standard methods. Data obtained for cases and controls were analyzed statistically. RESULTS: Twenty - one patients had unsteady HbSS and elicited greater and significant (P < 0.05) reduction in fat mass, BMI, HbF and eosinophil count but elevated mean total leukocyte, count, level of irreversibly sickled cells and P. falciparum parasitaemia (4613.7 vs. 749.6 - 1078.4 parasites/uL), pyrexia rate (58.3 vs. 25.8%) when compared with steady state patients or non-SCD controls. Compared to the control, significant decreases in plasma leptin before and after controlling for body fat that was worsened by crisis were observed among the SCD patients. Unlike the non-SCD controls, leptin correlated non-significantly (P > 0.05) with all body composition indices measured in the patients except for fat mass in unsteady cases. Multivariate regression analysis identified ESR and RC as independent predictor of low plasma leptin concentration in the SCA patients. CONCLUSIONS: Base on these findings, we conclude that plasma level of leptin is further decreased in the unsteady state of HbSS, shows poor correlation with adiposity and malarial infection but has inflammation and poor reticulocyte response as independent predictors among Nigerian patients. PMID- 21612658 TI - The crystal structure of alanine racemase from Streptococcus pneumoniae, a target for structure-based drug design. AB - BACKGROUND: Streptococcus pneumoniae is a globally important pathogen. The Gram positive diplococcus is a leading cause of pneumonia, otitis media, bacteremia, and meningitis, and antibiotic resistant strains have become increasingly common over recent years. Alanine racemase is a ubiquitous enzyme among bacteria and provides the essential cell wall precursor, D-alanine. Since it is absent in humans, this enzyme is an attractive target for the development of drugs against S. pneumoniae and other bacterial pathogens. RESULTS: Here we report the crystal structure of alanine racemase from S. pneumoniae (AlrSP). Crystals diffracted to a resolution of 2.0 A and belong to the space group P3121 with the unit cell parameters a = b = 119.97 A, c = 118.10 A, alpha = beta = 90 degrees and gamma = 120 degrees . Structural comparisons show that AlrSP shares both an overall fold and key active site residues with other bacterial alanine racemases. The active site cavity is similar to other Gram positive alanine racemases, featuring a restricted but conserved entryway. CONCLUSIONS: We have solved the structure of AlrSP, an essential step towards the development of an accurate pharmacophore model of the enzyme, and an important contribution towards our on-going alanine racemase structure-based drug design project. We have identified three regions on the enzyme that could be targeted for inhibitor design, the active site, the dimer interface, and the active site entryway. PMID- 21612660 TI - Standardized positive controls for detection of norovirus by reverse transcription PCR. AB - BACKGROUND: Norovirus is one of the most common causes of nonbacterial gastroenteritis in humans. Rapid spread by contaminated food and person-to-person transmission through the fecal-oral route are characteristics of norovirus epidemiology and result in high morbidity in vulnerable patient populations. Therefore, detection of norovirus is a major public health concern. Currently, the most common method for detecting and differentiating among norovirus strains in clinical and environmental samples is reverse transcription PCR (RT-PCR). Standardized positive controls used in RT-PCR assays to detect norovirus are designed to overcome the problem of false-negative results due to PCR inhibitors and suboptimal reaction conditions. RESULTS: In the current study, four types of RNA transcripts were produced from plasmids: norovirus GI-5 and GII-4 capsid regions with human rotavirus (VP7 gene derived) fragment insertions, and norovirus GI-6 and GII-4 capsid regions with hepatitis A virus (VP1/P2A gene derived) fragment insertions. These size-distinguishable products were used as positive controls under the RT-PCR assay conditions used to detect NoV in stool and groundwater samples. Their reliability and reproducibility was confirmed by multiple sets of experiments. CONCLUSIONS: These standardized products may contribute to the reliable and accurate diagnosis by RT-PCR of norovirus outbreaks, when conducted by laboratories located in different regions. PMID- 21612661 TI - Alternative statistical methods for estimating efficacy of interferon beta-1b for multiple sclerosis clinical trials. AB - BACKGROUND: In the randomized study of interferon beta-1b (IFN beta-1b) for multiple sclerosis (MS), it has usually been evaluated the simple annual relapse rate as the study endpoint. This study aimed to investigate the performance of various regression models using information regarding the time to each recurrent event and considering the MS specific data generation process, and to estimate the treatment effect of a MS clinical trial data. METHODS: We conducted a simulation study with consideration of the pathological characteristics of MS, and applied alternative efficacy estimation methods to real clinical trial data, including 5 extended Cox regression models for time-to-event analysis, a Poisson regression model and a Poisson regression model with Generalized Estimating Equations (GEE). We adjusted for other important covariates that may have affected the outcome. RESULTS: We compared the simulation results for each model. The hazard ratios of real data were estimated for each model including the effects of other covariates. The results (hazard ratios of high-dose to low-dose) of all models were approximately 0.7 (range, 0.613 - 0.769), whereas the annual relapse rate ratio was 0.714. CONCLUSIONS: The precision of the treatment estimation was increased by application of the alternative models. This suggests that the use of alternative models that include recurrence event data may provide better analyses. PMID- 21612662 TI - A scan statistic to extract causal gene clusters from case-control genome-wide rare CNV data. AB - BACKGROUND: Several statistical tests have been developed for analyzing genome wide association data by incorporating gene pathway information in terms of gene sets. Using these methods, hundreds of gene sets are typically tested, and the tested gene sets often overlap. This overlapping greatly increases the probability of generating false positives, and the results obtained are difficult to interpret, particularly when many gene sets show statistical significance. RESULTS: We propose a flexible statistical framework to circumvent these problems. Inspired by spatial scan statistics for detecting clustering of disease occurrence in the field of epidemiology, we developed a scan statistic to extract disease-associated gene clusters from a whole gene pathway. Extracting one or a few significant gene clusters from a global pathway limits the overall false positive probability, which results in increased statistical power, and facilitates the interpretation of test results. In the present study, we applied our method to genome-wide association data for rare copy-number variations, which have been strongly implicated in common diseases. Application of our method to a simulated dataset demonstrated the high accuracy of this method in detecting disease-associated gene clusters in a whole gene pathway. CONCLUSIONS: The scan statistic approach proposed here shows a high level of accuracy in detecting gene clusters in a whole gene pathway. This study has provided a sound statistical framework for analyzing genome-wide rare CNV data by incorporating topological information on the gene pathway. PMID- 21612663 TI - Perspectives of San Juan healthcare practitioners on the detection deficit in oral premalignant and early cancers in Puerto Rico: a qualitative research study. AB - BACKGROUND: In Puerto Rico, relative to the United States, a disparity exists in detecting oral precancers and early cancers. To identify factors leading to the deficit in early detection, we obtained the perspectives of San Juan healthcare practitioners whose practice could be involved in the detection of such oral lesions. METHODS: Key informant (KI) interviews were conducted with ten clinicians practicing in or around San Juan, Puerto Rico. We then triangulated our KI interview findings with other data sources, including recent literature on oral cancer detection from various geographic areas, current curricula at the University of Puerto Rico Schools of Medicine and Dental Medicine, as well as local health insurance regulations. RESULTS: Key informant-identified factors that likely contribute to the detection deficit include: many practitioners are deficient in knowledge regarding oral cancer and precancer; oral cancer screening examinations are limited regarding which patients receive them and the elements included. In Puerto Rico, specialists generally perform oral biopsies, and patient referral can be delayed by various factors, including government subsidized health insurance, often referred to as Reforma. Reforma-based issues include often inadequate clinician knowledge regarding Reforma requirements/provisions, diagnostic delays related to Reforma bureaucracy, and among primary physicians, a perceived financial disincentive in referring Reforma patients. CONCLUSIONS: Addressing these issues may be useful in reducing the deficit in detecting oral precancers and early oral cancer in Puerto Rico. PMID- 21612664 TI - New methods to measure residues coevolution in proteins. AB - BACKGROUND: The covariation of two sites in a protein is often used as the degree of their coevolution. To quantify the covariation many methods have been developed and most of them are based on residues position-specific frequencies by using the mutual information (MI) model. RESULTS: In the paper, we proposed several new measures to incorporate new biological constraints in quantifying the covariation. The first measure is the mutual information with the amino acid background distribution (MIB), which incorporates the amino acid background distribution into the marginal distribution of the MI model. The modification is made to remove the effect of amino acid evolutionary pressure in measuring covariation. The second measure is the mutual information of residues physicochemical properties (MIP), which is used to measure the covariation of physicochemical properties of two sites. The third measure called MIBP is proposed by applying residues physicochemical properties into the MIB model. Moreover, scores of our new measures are applied to a robust indicator conn(k) in finding the covariation signal of each site. CONCLUSIONS: We find that incorporating amino acid background distribution is effective in removing the effect of evolutionary pressure of amino acids. Thus the MIB measure describes more biological background information for the coevolution of residues. Besides, our analysis also reveals that the covariation of physicochemical properties is a new aspect of coevolution information. PMID- 21612665 TI - Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability. AB - BACKGROUND: Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. Recently, we isolated a novel oncogene eIF-5A2 within the 3q26 region. Functional study has demonstrated the oncogenic role of eIF-5A2 in the initiation and progression of human cancers. In the present study, we aim to investigate the physiological and pathological effect of eIF-5A2 in an eIF-5A2 transgenic mouse model. METHODS: An eIF-5A2 transgenic mouse model was generated using human eIF-5A2 cDNA. The eIF-5A2 transgenic mice were characterized by histological and immunohistochemistry analyses. The aging phenotypes were further characterized by wound healing, bone X-ray imaging and calcification analysis. Mouse embryo fibroblasts (MEF) were isolated to further investigate molecular mechanism of eIF-5A2 in aging. RESULTS: Instead of resulting in spontaneous tumor formation, overexpression of eIF-5A2 accelerated the aging process in adult transgenic mice. This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification. Investigation of the correlation between cellular senescence and aging showed that cellular senescence is not required for the aging phenotypes in eIF-5A2 mice. Interestingly, we found that activation of eIF-5A2 repressed p19 level and therefore destabilized p53 in transgenic mouse embryo fibroblast (MEF) cells. This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase. Additionally, a significantly increase in number of aneuploidy cells (p < 0.05) resulted from an increase in the incidences of misaligned and lagging chromosomal materials, anaphase bridges, and micronuclei in the transgenic mice. CONCLUSION: These observations suggest that eIF-5A2 mouse models could accelerate organismal aging by increasing chromosome instability. PMID- 21612666 TI - Introduction of an electronic monitoring system for monitoring compliance with Moments 1 and 4 of the WHO "My 5 Moments for Hand Hygiene" methodology. AB - BACKGROUND: MedSense is an electronic hand hygiene compliance monitoring system that provides Infection Control Practitioners with continuous access to hand hygiene compliance information by monitoring Moments 1 and 4 of the WHO "My 5 Moments for Hand Hygiene" guidelines. Unlike previous electronic monitoring systems, MedSense operates in open cubicles with multiple beds and does not disrupt existing workflows. METHODS: This study was conducted in a 6-bed neurosurgical intensive care unit with technical development and evaluation phases. Healthcare workers (HCWs) wore an electronic device in the style of an identity badge to detect hand hygiene opportunities and compliance. We compared the compliance determined by the system and an infection control nurse. At the same time, the system assessed compliance by time of day, day of week, work shift, professional category of HCWs, and individual subject, while the workload of HCWs was monitored by measuring the amount of time they spent in patient zones. RESULTS: During the three-month evaluation phase, the system identified 13,694 hand hygiene opportunities from 17 nurses, 3 physiotherapists, and 1 healthcare assistant, resulting in an overall compliance of 35.1% for the unit. The per-indication compliance for Moment 1, 4, and simultaneous 1 and 4 were 21.3% (95%CI: 19.0, 23.6), 39.6% (95%CI: 37.3, 41.9), and 49.2% (95%CI: 46.6, 51.8), respectively, and were all statistically significantly different (p < 0.001). In the four 20-minute sessions when hand hygiene was monitored concurrently by the system and infection control nurse, the compliance were 88.9% and 95.6% respectively (p = 0.34), and the activity indices were 11.1 and 12.9 opportunities per hour, respectively. The hours from 12:00 to 14:00 had a notably lower compliance (21.3%, 95%CI: 17.2, 25.3) than nearly three quarters of the other periods of the day (p < 0.001). Nurses who used shared badges had significantly (p < 0.01) lower compliance (23.7%, 95%CI: 17.8, 29.6) than both the registered nurses (36.1%, 95%CI: 34.2, 37.9) and nursing officers (34.0%, 95%CI: 31.1, 36.9) who used named badges. CONCLUSION: MedSense provides an unobtrusive and objective measurement of hand hygiene compliance. The information is important for staff training by the infection control team and allocation of manpower by hospital administration. PMID- 21612667 TI - Patient acceptance and perceived utility of pre-consultation prevention summaries and reminders in general practice: pilot study. AB - BACKGROUND: Patients attending general practices receive only about sixty per cent of the preventive services that are indicated for them. This pilot study explores patient acceptability and perceived utility of automatically generated prevention summary and reminder sheets provided to patients immediately before consultations with their general practitioners. METHODS: Adult patients attending a general practitioner in a practice in Adelaide and a general practitioner in a practice in Melbourne, Australia for consultations in January and February 2009 received automatically-generated prevention summary and reminder sheets that highlighted indicated preventive activities that were due to be performed, and that encouraged the patient to discuss these with the general practitioner in the consultation. Patients completed a post-consultation questionnaire and were interviewed about their experience of receiving the sheets. RESULTS: Sixty patients, median age 53 years (interquartile range 40-74) years, and 58% female, were recruited. Seventy eight per cent of patients found the sheets clear and easy to understand, 75% found them very or quite useful, 72% reported they had addressed with their general practitioner all of the preventive activities that were listed on the sheets as being due to be performed. A further 13% indicated that they had addressed most or some of the activities. 78% of patients said that they would like to keep receiving the sheets. Themes emerging from interviews with patients included: patient knowledge was enhanced; patient conceptions of health and the GP consultation were broadened; the consultation was enhanced; patient pro-activity was encouraged; patients were encouraged to plan their health care; the intervention was suitable for a variety of patients. CONCLUSIONS: Most patients reported that they found the prevention summary and reminder sheets acceptable and useful. The actual increase in performance of preventive activities that may result from this new intervention needs to be tested in randomised controlled trials. PMID- 21612668 TI - HemeBIND: a novel method for heme binding residue prediction by combining structural and sequence information. AB - BACKGROUND: Accurate prediction of binding residues involved in the interactions between proteins and small ligands is one of the major challenges in structural bioinformatics. Heme is an essential and commonly used ligand that plays critical roles in electron transfer, catalysis, signal transduction and gene expression. Although much effort has been devoted to the development of various generic algorithms for ligand binding site prediction over the last decade, no algorithm has been specifically designed to complement experimental techniques for identification of heme binding residues. Consequently, an urgent need is to develop a computational method for recognizing these important residues. RESULTS: Here we introduced an efficient algorithm HemeBIND for predicting heme binding residues by integrating structural and sequence information. We systematically investigated the characteristics of binding interfaces based on a non-redundant dataset of heme-protein complexes. It was found that several sequence and structural attributes such as evolutionary conservation, solvent accessibility, depth and protrusion clearly illustrate the differences between heme binding and non-binding residues. These features can then be separately used or combined to build the structure-based classifiers using support vector machine (SVM). The results showed that the information contained in these features is largely complementary and their combination achieved the best performance. To further improve the performance, an attempt has been made to develop a post-processing procedure to reduce the number of false positives. In addition, we built a sequence-based classifier based on SVM and sequence profile as an alternative when only sequence information can be used. Finally, we employed a voting method to combine the outputs of structure-based and sequence-based classifiers, which demonstrated remarkably better performance than the individual classifier alone. CONCLUSIONS: HemeBIND is the first specialized algorithm used to predict binding residues in protein structures for heme ligands. Extensive experiments indicated that both the structure-based and sequence-based methods have effectively identified heme binding residues while the complementary relationship between them can result in a significant improvement in prediction performance. The value of our method is highlighted through the development of HemeBIND web server that is freely accessible at http://mleg.cse.sc.edu/hemeBIND/. PMID- 21612669 TI - Viewing the Kenyan health system through an equity lens: implications for universal coverage. AB - INTRODUCTION: Equity and universal coverage currently dominate policy debates worldwide. Health financing approaches are central to universal coverage. The way funds are collected, pooled, and used to purchase or provide services should be carefully considered to ensure that population needs are addressed under a universal health system. The aim of this paper is to assess the extent to which the Kenyan health financing system meets the key requirements for universal coverage, including income and risk cross-subsidisation. Recommendations on how to address existing equity challenges and progress towards universal coverage are made. METHODS: An extensive review of published and gray literature was conducted to identify the sources of health care funds in Kenya. Documents were mainly sourced from the Ministry of Medical Services and the Ministry of Public Health and Sanitation. Country level documents were the main sources of data. In cases where data were not available at the country level, they were sought from the World Health Organisation website. Each financing mechanism was analysed in respect to key functions namely, revenue generation, pooling and purchasing. RESULTS: The Kenyan health sector relies heavily on out-of-pocket payments. Government funds are mainly allocated through historical incremental approach. The sector is largely underfunded and health care contributions are regressive (i.e. the poor contribute a larger proportion of their income to health care than the rich). Health financing in Kenya is fragmented and there is very limited risk and income cross-subsidisation. The country has made little progress towards achieving international benchmarks including the Abuja target of allocating 15% of government's budget to the health sector. CONCLUSIONS: The Kenyan health system is highly inequitable and policies aimed at promoting equity and addressing the needs of the poor and vulnerable have not been successful. Some progress has been made towards addressing equity challenges, but universal coverage will not be achieved unless the country adopts a systemic approach to health financing reforms. Such an approach should be informed by the wider health system goals of equity and efficiency. PMID- 21612670 TI - Total knee arthroplasty using a hybrid navigation technique. AB - The use of computer navigation is becoming a well-recognized technical alternative to conventional total knee arthroplasty (TKA). However, computer navigation has a substantial learning curve and the use of commercially available navigation systems increases surgical time. In addition, the potential risks associated with the navigation TKA, such as, registration errors, notching of the anterior femoral cortex, oversizing of the femoral component, and overresection must be taken into consideration. On the other hand, conventional techniques are familiar and intuitive to most practicing surgeons, and thus, are easier to perform and are less prone to anterior notching and femoral component oversizing. However, conventional techniques have greater risks of inaccurate and inconsistent component alignment than computer navigation. This paper describes a novel technique that combines computer navigation and conventional TKA. PMID- 21612671 TI - Mucosal Progranulin expression is induced by H. pylori, but independent of Secretory Leukocyte Protease Inhibitor (SLPI) expression. AB - BACKGROUND: Mucosal levels of Secretory Leukocyte Protease Inhibitor (SLPI) are specifically reduced in relation to H. pylori-induced gastritis. Progranulin is an epithelial growth factor that is proteolytically degraded into fragments by elastase (the main target of SLPI). Considering the role of SLPI for regulating the activity of elastase, we studied whether the H. pylori-induced reduction of SLPI and the resulting increase of elastase-derived activity would reduce the Progranulin protein levels both ex vivo and in vitro. METHODS: The expression of Progranulin was studied in biopsies of H. pylori-positive, -negative and eradicated subjects as well as in the gastric tumor cell line AGS by ELISA, immunohistochemistry and real-time RT-PCR. RESULTS: H. pylori-infected subjects had about 2-fold increased antral Progranulin expression compared to H. pylori negative and -eradicated subjects (P < 0.05). Overall, no correlations between mucosal Progranulin and SLPI levels were identified. Immunohistochemical analysis confirmed the upregulation of Progranulin in relation to H. pylori infection; both epithelial and infiltrating immune cells contributed to the higher Progranulin expression levels. The H. pylori-induced upregulation of Progranulin was verified in AGS cells infected by H. pylori. The down-regulation of endogenous SLPI expression in AGS cells by siRNA methodology did not affect the Progranulin expression independent of the infection by H. pylori. CONCLUSIONS: Taken together, Progranulin was identified as novel molecule that is upregulated in context to H. pylori infection. In contrast to other diseases, SLPI seems not to have a regulatory role for Progranulin in H. pylori-mediated gastritis. PMID- 21612672 TI - High-dose daptomycin and fosfomycin treatment of a patient with endocarditis caused by daptomycin-nonsusceptible Staphylococcus aureus: case report. AB - BACKGROUND: Emergence of daptomycin-nonsusceptible (DNS) Staphylococcus aureus is a dreadful problem in the treatment of endocarditis. Few current therapeutic agents are effective for treating infections caused by DNS S. aureus. CASE PRESENTATION: We describe the emergence of DNS S. aureus. in a patient with implantable cardioverter-defibrillator (ICD) device -related endocarditis who was priorily treated with daptomycin. Metastatic dissemination as osteomyelitis further complicated the management of endocarditis. The dilemma was successfully managed by surgical removal of the ICD device and combination antimicrobial therapy with high-dose daptomycin and fosfomycin. CONCLUSIONS: Surgical removal of intracardiac devices remains an important adjunctive measure in the treatment of endocarditis. Our case suggests that combination therapy is more favorable than single-agent therapy for infections caused by DNS S. aureus. PMID- 21612674 TI - [Some attentive issues in the selection of intraocular lenses]. AB - Different kinds of new intraocular lenses (IOL) provide more choices for different clinical demands. However, there are many misunderstandings about how to select the proper IOL. These misunderstandings arise from the believes that include "the expensive IOL is good IOL", "new product is absolutely perfect", etc. Furthermore, we should pay attention to avoid the "confusion concept", "comprehend error of monovision and matching different types of IOL", "ignore the results from evidence-based medicine", etc. When we select the IOL, we should concern about how to meet the patients' demands and how to provide the best benefits to the patients. PMID- 21612673 TI - NCACO-score: an effective main-chain dependent scoring function for structure modeling. AB - BACKGROUND: Development of effective scoring functions is a critical component to the success of protein structure modeling. Previously, many efforts have been dedicated to the development of scoring functions. Despite these efforts, development of an effective scoring function that can achieve both good accuracy and fast speed still presents a grand challenge. RESULTS: Based on a coarse grained representation of a protein structure by using only four main-chain atoms: N, Calpha, C and O, we develop a knowledge-based scoring function, called NCACO-score, that integrates different structural information to rapidly model protein structure from sequence. In testing on the Decoys'R'Us sets, we found that NCACO-score can effectively recognize native conformers from their decoys. Furthermore, we demonstrate that NCACO-score can effectively guide fragment assembly for protein structure prediction, which has achieved a good performance in building the structure models for hard targets from CASP8 in terms of both accuracy and speed. CONCLUSIONS: Although NCACO-score is developed based on a coarse-grained model, it is able to discriminate native conformers from decoy conformers with high accuracy. NCACO is a very effective scoring function for structure modeling. PMID- 21612675 TI - [Pay attention to evaluation of functional vision in cataract patients]. AB - Following the development of the techniques of phacoemulsification and intraocular lens (IOL) implantation as well as the advances of materials of IOL, the better design of aspheric, multifocal and loop surface IOL, the cataract surgery has become a refractive surgery that can enhance the optical performance of the eyes. Therefore, cataract surgery has entered the era of pursuing quality of vision and visual comfortable level to meet the requirements of the patients. Patients after the cataract surgery not only can see but also can see clearly and comfortably. Therefore, more and more methods for the measurement of functional vision have been developed. These methods are important in the evaluation of quality of vision in patients with early stage cataract and after the cataract surgery. PMID- 21612676 TI - [Supracapsular implantation with optic capture of posterior chamber intraocular lens in aphakic school-age children after traumatic cataract]. AB - OBJECTIVE: To assess the clinical effects of supracapsular implantation with optic capture of the posterior chamber intraocular lens in school-age children with traumatic cataract. METHOD: It was a retrospective case series study. Thirteen cases (13 eyes) received posterior curvilinear capsulorhexis with optic capture of the posterior chamber intraocular lens. Pre- and post-operative visual acuities were recorded. Intra-o and post-operative complications were observed. The follow-up period ranged from 6 to 42 months. RESULTS: Implantation of optic capture of the posterior chamber intraocular lens was successfully performed in 13 eyes. The best-corrected-visual acuity ranged from 0.2 to 1.0. No optic axis opaque was found in 10 eyes with optic capture. The major complications of optic capture were lenticular precipitates and posterior synechia of the iris. Intraocular dislocation was found in one case two weeks after the operation. CONCLUSIONS: Supracapsular implantation with optic capture of the posterior chamber intraocular lens is safe and effective for the treatment of traumatic cataract in school-age children. PMID- 21612677 TI - [Comparison of stability of acrylic intraocular lens and transparency of lens capsule using Pentacam Scheimpflug System]. AB - OBJECTIVE: To compare the amounts of intraocular lens (IOL) decentration and tilt, the anterior chamber depth (ACD) and the degree of posterior capsule opacification (PCO) using the Pentacam Scheimpflug System after cataract surgery between eyes with 1-piece acrylic IOL and 3-piece acrylic IOL. METHODS: It was a perspective study. Fifty-one patients with bilateral senile cataract had implantation of a 1-piece SA60AT IOL in one eye and a 3-piece MA60BM IOL in the contralateral eye. The amount of IOL decentration, tilt, the ACD, and the degree of PCO was measured using the Pentacam Scheimpflug System 1 day and 1, 6, 12 and 24 months postoperatively. RESULTS: There were no significant changes during the 24 m follow-up period in the decentration (0.37 +/- 0.16, 0.36 +/- 0.15, 0.36 +/- 0.16, 0.37 +/- 0.15, 0.38 +/- 0.16), tilt (3.59 +/- 0.91, 3.64 +/- 0.92, 3.61 +/- 0.90, 3.63 +/- 0.90, 3.70 +/- 0.89) or PCO (22.20 +/- 3.99, 21.96 +/- 4.00, 22.40 +/- 4.03, 22.53 +/- 4.00, 22.95 +/- 3.87) in the 1-piece SA60AT group (F = 1.938, 0.785, 1.814; P > 0.05) or in the 3-piece MA60BM group (0.34 +/- 0.14, 0.33 +/- 0.14, 0.34 +/- 0.14, 0.35 +/- 0.14, 0.36 +/- 0.14), (3.55 +/- 0.90, 3.57 +/- 0.92, 3.63 +/- 0.88, 3.61 +/- 0.88, 3.65 +/- 0.89), (21.14 +/- 3.88, 20.98 +/- 3.87, 21.23 +/- 3.83, 21.59 +/- 3.82, 21.65 +/- 3.87) (F = 1.004, 0.525, 1.963; P > 0.05). There was no significant difference between the two groups in IOL decentration (t = 0.802, 0.701, 0.588, 0.898, 0.631), tilt (t = 0.199, 0.337, 0.094, 0.121, 0.248) or PCO (t = 1.214, 1.119, 1.334, 1.082, 1.517) at any time points (P > 0.05). The ACD did not change after the surgery in the 1-piece group (3.90 +/- 0.99, 3.88 +/- 1.07, 3.91 +/- 1.01, 3.90 +/- 1.02, 3.92 +/- 1.02) (F = 1.333, P > 0.05) but was significantly deeper in the 3-piece group (4.37 +/- 1.02, 3.90 +/- 0.98, 3.95 +/- 0.99, 3.93 +/- 0.96, 3.97 +/- 0.99) (F = 92.757, P < 0.05) one day after the operation. The ACD was more shallow in the 1-piece SA60AT group than in the 3-piece MA60BM group at all time points. However, the difference was statistically significant only at 1 day after surgery (t = 102.944, P < 0.05). CONCLUSIONS: The degrees of IOL decentration, tilt, ACD and PCO in eyes with a 1-piece acrylic IOL with flexible haptics implanted in the capsular bag were similar to those in eyes with a 3-piece acrylic IOL with rigid PMMA haptics. But the 1-piece acrylic IOL provides a better stability than the 3 piece acrylic IOL in the early stage postoperatively. PMID- 21612678 TI - [Clinical observation of highly myopic eyes with retinoschisis after phacoemulsification]. AB - OBJECTIVE: To evaluate the changes of the retinal thickness in the highly myopic eyes with retinoschisis after phacoemulsification by optical coherence tomography (OCT) and to analyze their postoperative visual acuity. METHODS: It was a retrospective case series study. This study included 25 (35 eyes) highly myopic patients with retinoschisis. One week, 1 and 3 months after phacoemulsification, the best corrected visual acuity (BCVA) was measured and OCT was performed to evaluate the central foveal thickness (CFT) as well as the maximum neurosensory thickness (MNT). These 35 eyes were divided into low and high accumulated energy complex parameter (AECP) groups, and <= 28.00 mm, > 28.00 and <= 30.00 mm, > 30.00 mm groups according to the axial length respectively. Variance analysis of data obtained from repeated measurement, Wilcoxon rank sum test, linear correlation and one-way ANOVA were used to analyze the data. RESULTS: According to the location of schisis, the 35 eyes were classified as foveal schisis (20 eyes) and nonfoveal schisis (15 eyes). Among the 35 eyes, there were 30 eyes with outer retinoschisis and 5 with compound schisis. The mean BCVA (logMAR) preoperatively and 1 week, 1 and 3 months postoperatively was 0.23 +/- 0.24, 0.59 +/- 0.38, 0.57 +/- 0.38 and 0.60 +/- 0.36 respectively (F = 31.15, P = 0.000). CFT preoperatively and 1 week, 1 and 3 months postoperatively was (255.46 +/- 197.57) um, (256.80 +/- 199.88) um, (274.37 +/- 246.87) um, and (268.60 +/- 238.41) um (F = 0.99, P = 0.420); while MNT was (473.31 +/- 175.52) um, (477.71 +/- 188.71) um, (486.60 +/- 229.17) um and (482.63 +/- 208.82) um respectively (F = 0.26, P = 0.857). BCVA in eyes with foveoschisis and in eyes with nonfoveal schisis was statistically significantly different at 1 week, 1 and 3 months postoperatively (Z = -0.580, P = 0.048; Z = -2.147, P = 0.030 and Z = -2.099, P = 0.034). BCVA (0.43 +/- 0.28) was inversely correlated with CFT (497.42 +/- 281.49) um in the eyes with foveoschisis unaccompanied with a macular lamellar hole at 3 months postoperatively (r = -0.667, P = 0.018). There were no significant differences in the changes of the thickness of the retina between the groups with different AECP or among the groups with different axial lengths (Z = 0.314 - 1.290, P = 0.192-0.741 and F = 0.15-0.62, P = 0.545-0.859). CONCLUSIONS: Cataract surgery has no significant effect on thickness of the retina in the highly myopic eyes with retinoschisis. The patients with retinoschisis could achieve good visual recovery after phacoemulsification. Postoperative visual acuity is related to the location and degree of retinoschisis. Besides, patients with non-foveal schisis could obtain better visual acuity than those with foveoschisis. Further investigation on the development of retinoschisis and the complications after surgery is required. PMID- 21612679 TI - [CRYAA gene mutation study in a family with autosomal dominant congenital cataract combined with microcornea]. AB - OBJECTIVE: To identify the gene mutation in a four-generation Chinese family with autosomal dominant congenital cataract associated with microcornea. METHODS: Experimental research. Twelve members in this family (including six affected and six unaffected individuals) were enrolled into this study. They underwent full ophthalmological and clinical examinations to rule out any concomitant disorders. Blood samples were collected and genomic DNA was extracted. Microsatellite markers near the reported loci, which are associated with congenital cataract and microcornea were selected and amplified from DNA samples using polymerase chain reaction. Linkage analysis was performed. The exons and exon/intron junction of candidate gene in the related chromosome were sequenced. The product of the first exon was digested by ApaL I restriction enzyme to certify the mutation. RESULTS: The phenotype studied in this family was nuclear cataract accompanied with microcornea. At markers D21S1885 and D21S1890 near the locus 21q22.3, the affected members had the same allele, but the unaffected did not. The Lod scores were 2.11 in both markers, indicating that this locus were linked to the congenital cataract in this family. DNA sequencing of candidate gene CRYAA showed a heterozygous mutation c.34C > T in exon 1, which led to condon 12 in peptide chain encoding arginine substituted by cysteine. ApaL I enzyme digestion certified that all of the affected members had the same mutation c.34C > T, but the unaffected and normal individuals did not. CONCLUSION: Mutation (p.R12C) of CRYAA is the genetic change that causes the occurrence of congenital cataract with microcornea in this family. PMID- 21612680 TI - [Experimental study on effects of matrix metalloproteinase inhibitor on posterior capsule opacification in rabbits]. AB - OBJECTIVE: To determine whether matrix metalloproteinase (MMP) inhibitor can provide therapeutic effects for rabbits posterior capsule opacification in vivo and to observe the side effects of this drug on surrounding intraocular structures. METHODS: Experimental research. New Zealand white rabbits were undertaken phacoemulsification operation. GM6001 at different concentrations (100, 200 and 500 umol/L) and GM6001 negative control liqueur were infused into the capsule bags of the rabbits at the end of operation and two days after the operation. The incidence of posterior capsule opacification was assessed and the histological sections of posterior capsules were observed under microscope 12 weeks after the surgery. The anterior chamber response was observed on day 2 post operatively. The changes of intraocular pressure were measured by day 2 and day 7. Corneal endothelial cells were observed under scanning electron microscope and iris, ciliary body and retina were observed under microscope on day 7. RESULTS: GM6001 significantly prevented posterior capsule opacification (P = 0.007). No opacification occurred on the rabbit posterior capsule in eyes with 200 and 500 umol/L GM6001 on week 12 post-operatively in vivo. No cells were found on posterior capsule in 500 umol/L group, whereas lens epithelial cells and fibroblasts were found in the controls under microscope. No difference of anterior chamber flare between the eyes with GM6001 at different concentrations and the control group (P = 0.380) by day 2 after the operation. The intraocular pressure in eyes with GM6001 was the same as that in the control 2-days (F = 0.642, P = 0.597) and 7-days (F = 0.179, P = 0.909) post-operation. The corneal endothelial cells in eyes with 500 umol/L GM6001 arranged regularly and did not show any difference from that in the control eyes under scanning electron microscope 7-day after the operation. The iris, ciliary body and retina in eyes with 500 umol/L GM6001 were normal in appearance 7-day after the operation. CONCLUSIONS: MMP inhibitor can prevent posterior capsule opacification effectively in rabbits in vivo and does not cause damage to surrounding intraocular structures, suggesting that MMP inhibitor may become a medication used for the prevention of lens posterior capsule opacification. PMID- 21612681 TI - [Protective effects of puerarin on lens epithelial cells in rat diabetic cataract]. AB - OBJECTIVE: The therapeutic effects of general and local applications of puerarin in the treatment of streptozotocin (STZ)-induced rat diabetic model were compared. METHODS: Experimental research. We equally divided normal Sprague Dawley (SD) rats into a STZ group, a peritoneal injection group, a peribulbar injection group and a control group. STZ, peritoneal injection and peribulbar injection groups were first treated with STZ. Subsequently, the STZ group was injected with normal saline intraperitoneally, while in the later two groups puerarin was injected through peritoneal and peribular routes, respectively. Control group only received peritoneal injection of saline. The morphology of lens epithelial cells (LEC) and their subcellular structure were examined by bright-field microscopy, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) 20, 40 and 60 days after the injection. Nitrogen oxide (NO) and nitric oxide synthase (NOS) were measured by biochemistry methods. Finally, inducible nitric oxide synthase (iNOS) protein and mRNA levels were monitored by Western blot and RT-PCR, respectively. Data was processed with two factorial experiment analysis of variance. RESULTS: Twenty to sixty days after the injection, marked or complete lens opacities appeared in the STZ group, whereas only slight opacities appeared in the lens in peritoneal and peribulbar puerarin groups and the lens in the control group remained clear. At the 20th, 40th and 60th day after the injection, optical microscope detected pathological changes of LEC in the STZ group. The cell volume was decreased with a dense nucleus and many bubbles appeared around the equator area. Under TEM, enlargement of cell gap, vacuoles in the cytoplasm, swelling of mitochondria and unclear structure of rough endoplasmic reticulum appeared in the LEC of the STZ group. Part of the nucleus was in karyopyknosis and peripheral nucleus gap was enlargement. Under SEM, normal fiber conjunction structure of the lens disappeared, fibers were swelling, part of fiber membranes were discontinuous, detached, and accumulated in certain areas. Mild lens opacities detected by bright-field microscope were developed in peritoneal and peribulbar puerarin injection groups. Nucleus and fibers in the lens cells of both groups appeared to be normal, with minor swelling of mitochondria, minor enlargement of endoplasmic reticulum and slight increase of intracellular space. NO, NOS and iNOS protein and mRNA of the lens were increased and up-regulated in STZ group. In the other two groups only minor changes were present and the changes were significantly less than that of the STZ group but greater than that in the control group. CONCLUSION: Peritoneal and peribulbar injection of puerarin have similar therapeutic effects in the treatment of rat diabetic cataract. PMID- 21612682 TI - [Analysis of aberration changes of the corneal anterior surface following discontinued use of rigid gas permeable contact lenses]. AB - OBJECTIVE: The present study used a corneal topographic device to record aberrations on the anterior surface of the cornea at different time-points prior to wearing and following discontinued use of rigid gas permeable (RGP) contact lenses. The effect of wearing RGPCL on the anterior surface of the cornea was discussed to provide guidance for clinical refractive error correction. METHODS: The study objects were 60 eyes from 30 patients. All patients underwent identical examination procedures prior to lens use, as well as afterwards, including slit lamp examination, non-contact tonometer measurement, computer optometry & corneal curvature measurement, subjective refraction test, and corneal topography analysis. The patients wore contact lenses every day for 1 month and then discontinued. Corneal topographies were recorded at certain time points of 30 min, 1 day, 3 days, 1 week, and 2 weeks following use. RESULTS: Total corneal aberration at each time point following discontinued use of RGP contact lenses was less than the time point prior to use. Detailed results are as follows; root mean square (RMS) (pre) = (1.438 +/- 0.328), RMS (30 min) = (1.076 +/- 0.355), RMS (1 day) = (1.362 +/- 0.402), RMS (3 day) = (1.373 +/- 0.398), RMS (7 day) = (1.387 +/- 0.415), and RMS (14 day) = (1.448 +/- 0.423). Results showed that at 30 minutes after discontinued use of RGP contact lenses, almost all 2(nd)- and 3(rd)-order aberrations were altered. Quadrafoil Z10 and spherical Z12 of the 4(th)-order were also changed. Alterations to Z5, Z6, and Z12 at 1 day after discontinued use were significant compared with the time period prior to RGP use: Z5 and Z6 decreased, and Z12 increased slightly (F = 2.869 ~ 5.549, P = 0.001 ~ 0.042). Z5 and Z6 remained decreased at 3 days after discontinued use, but Z9 and Z10 continued to increase and Z12 returned to levels prior to RGP use (P > 0.05). At 2 weeks after discontinued use, all aberrations were not significantly different from the values prior to use (P > 0.05). CONCLUSIONS: The use RGP contact lenses greatly reduced total aberration of the anterior surface of the cornea. Changes to 2(nd)- and 3(rd)-order aberrations (including Z3, Z4, Z5, Z6, Z7, and Z8) were more significant. Following discontinued use of RGP contact lenses, the majority of lower order aberrations returned to original levels in a short period of time. During this process, a transient higher order aberration appeared, but all changes disappeared within 2 weeks after discontinued use of RGP contact lenses. PMID- 21612683 TI - [Effects of blocking activation of IGF-1-Stat3 signaling pathway in guinea pig sclera fibroblast by AG490 on expression of MMP-2 and Integrinbeta(1)]. AB - OBJECTIVE: To explore the effect of Blocking activation of IGF-1-Stat3 signaling pathway in guinea pig sclera fibroblast (GSFs) by AG490 on expressions of MMP-2, Integrinbeta(1). METHODS: Cultured GSFs were divided into four groups: group A(control group: only DMEM without IGF-1), group B (only IGF-1 group), group C(IGF-1 + PBS group), group D (IGF-1 + 25 umol/L AG490 group). The expressions of Stat3, p-Stat3, MMP-2, Integrinbeta(1) protein induced by IGF-1 and inhibited by AG490 in GSFs were detected by Western blot. The levels of Stat3, MMP-2 and Integrinbeta(1)mRNA were detected by RT-PCR. RESULTS: Compared with Groups A and D, Stat3, p-Stat3, MMP-2 protein expression in groups B and C were expressed at higher level (t(pr) = -32.324, -26.284, -32.876, -26.345, -68.668, -58.724, 187.481, -58.842, -110.264, -120.256, -121.345, -120.286; t(mRNA) = -31.554, 31.178, -31.286, -31.198, -12.076, -14.969, -11.896, -14.546, P < 0.05), but the expression levels were not obviously different between groups B and C (t(p) = 32.720, -32.816, -68.668, -187.481, -110.264, -121.345; t(mRNA) = -0.692, -0.579, P > 0.05), which were similar to mRNA level. The Integrinbeta(1) protein and mRNA were expressed in groups A, B, C and D but no significant difference among them respectively (F(pr) = 0.214;F(mRNA) = 0.045, P > 0.05). CONCLUSIONS: Activation of Stat3 signaling pathway may be involved in up-modulating the expression of MMP 2 in GSFs, and not affect the Integrinbeta(1) protein and mRNA changes. The results reveal that Stat3 signaling transduction pathway may play a critical role in sclera remodeling by means of modulating MMP-2 expression. PMID- 21612684 TI - [Effects of travoprost on actin cytoskeleton and beta-catenin in the human trabecular meshwork cells treated with Dexamethasone]. AB - OBJECTIVE: To investigate the effect of travoprost on changes of actin cytoskeletal and beta-catenin protein in the cultured human trabecular meshwork (HTM) cells treated with dexamethasone (DEX). METHODS: It was a control experiment study. The HTM cells were cultured in vitro and divided into control group, DEX (1 * 10(-6) mol/L) group, travoprost (1 * 10(-6) mol/L) group, and DEX (1 * 10(-6) mol/L) plus travoprost (1 * 10(-6) mol/L) group. F-actin in the HTM cells was detected by FITC-phalloidin and observed under a fluorescence microscope. The expression of beta-catenin was determined by immunofluorescence and western-blot. Statistical analysis was performed using SPSS13.0 software. The difference of beta-catenin expression among groups was analyzed through variance analysis and, further by q test. RESULTS: The cultured HTM cells were identified by immunohistochemistry. A reorganization of actin cytoskeletal and a formation of cross linked actin networks (CLANs) were seen in the HTM cells treated with DEX, which were partially reversed by the treatment with DEX plus travoprost. An increase of the expression of beta-catenin was discovered in the HTM cells treated with DEX, which was also partially reversed by the treatment with DEX plus travoprost. The amount of beta-catenin protein in untreated control group, DEX group, DEX plus travoprost group and travoprost group were 0.84 +/- 0.03, 1.65 +/- 0.05, 1.21 +/- 0.05, and 0.65 +/- 0.04, respectively. Expression of beta catenin was significantly (F = 143.07, P < 0.05) different when compared untreated control group with DEX group (q = 15.32, P < 0.05), untreated control group with DEX plus travoprost group (q = 11.40, P < 0.05), DEX group with DEX plus travoprost group (q = 9.38, P < 0.05), DEX group with travoprost group (q = 16.55, P < 0.05), and DEX plus travoprost group with travoprost group (q = 14.31, P < 0.05). No difference was found in untreated control group and travoprost group (q = 2.84, P > 0.05). CONCLUSIONS: Our results suggest that reversion of the changes of actin organization and beta-catenin by travoparost in the HTM cells treated with DEX may partially elucidate the mechanism of action of increasing outflow by which travoprost reduces intraocular pressure. PMID- 21612685 TI - [Amniotic membrane transplant using fibrin glue for the treatment of deep layer corneal damage]. AB - OBJECTIVE: To treat deep layer corneal damage using fibrin glue and amniotic membrane transplant. METHODS: Forty-five rabbits were given deep lamellar keratectomies to cause deep layer corneal damage in their right eyes and were then randomly divided into 3 groups. The first group was given double-layer amniotic membrane transplants where fibrin glue was used to connect the two layers of amniotic membrane. The second group was given double-layer amniotic membrane transplants where no fibrin glue was used. The third group was given no treatment. Clinical outcome was graded by corneal integrity, opacity and neovascularization, and detachment of amniotic membrane was recorded. The expression of apoptosis was monitored to assess the changes of morphology and histology on the 7th, 14th and 28th days after surgery. RESULTS: While the double layer amniotic membrane without fibrin glue covered the cornea for (13.15 +/- 2.68) d, the double-layer amniotic membrane using fibrin glue covered the surface of the cornea for (20.00 +/- 2.43) d (t = 8.470, P = 0.000). The corneas in the first group recovered smoothly and transparently, maintained normal thickness and less neovascularization, whereas the corneas in the other two groups recovered irregularly, lost their transparency, became turbid and showed higher levels of neovascularization. There were statistically significant differences between the first and third groups for corneal opacity and neovascularization, where the 14th day after surgery, the first group scored 2.62 and the third group scored 5.19 (t = 3.986, P = 0.004), and the 28th day after surgery, the first group scored 2.87 and the third group scored 4.78 (t = 3.608, P = 0.007). Perforation did not appear in the first group, but the second group had 3 cases and the third group had 2 cases, all due to infection. The changes of morphology and histology showed that the damaged corneas were contained normal epithelial cells and regularly arranged fibrous cells on the 28th day after surgery. The apoptosis in corneas of the first group was less than that of the third group at all observed points (7th day: t = 8.153, P = 0.000; 14th day: t = 9.693, P = 0.000; 28th day: t = 14.050, P = 0.000), however, apoptosis in corneas in the second group was only different from that in the third group on the 7th day after surgery while other observed points showed no difference (7th day: t = 5.474, P = 0.000). CONCLUSION: Using bio-engineered fibrin glue in amniotic membrane transplants can repair deep layer corneal damage, reduce neovascularization, scarring and corneal apoptosis. PMID- 21612686 TI - [Effects of pressure bionic culture on the morphology of corneal endothelium cells]. AB - OBJECTIVE: To investigate the effect of pressure bionic culture on the morphology and function of rabbit corneal endothelial cells. METHODS: Corneal endothelial cells were separated and purified by tearing apart the descemet and digesting with trypsin and EDTA, then cultured in the plate. The cells were divided into two groups: group A were cultured under atmosphere; cells exposed to 2 kPa (14.66 mm Hg) pressure in vitro was group B; the morphology and growth pattern of cells were observed by inverted microscope; cells origin were identified by neuron specific enolase immunoassay. Cellular changes in the structure were observed by HE staining and scanning and transmission electron microscopy (SEM and TEM) analysis. Cells activity was detected by flow cytometry. RESULTS: NSE antibody of the primary corneal endothelial cells was positive without corneal epithelial cells and corneal stroma cells. Two groups of cells were cultured for 120-144 h respectively, the morphology was flat, polygon, most of cells were hexagon and abundant cytoplasms in group B (pressure bionic culture), but in group A, the cells size was not uniform and there were much granules in the cytoplasm. There was no difference in the time of formation of monolayer in two groups. SEM showed that cells exposed to pressure connected tightly and the surface was rich in microvilli, extended foot processes and attached to the substrate tightly, while cells cultured under atmosphere with more off-chip. In group B, Annexin-FITC/PI detection of apoptosis showed cell survival rate was 98.2%, early apoptosis rate was 0.7%, late apoptosis rate was 1.0%, death rate was 0.1%; the corresponding data were 92.2%, 5.2%, 2.3%, and 0.3% in group A, respectively; There was statistically significant difference between the two groups (chi(2) = 594.0, P < 0.01). After cultured for 96 h, the expression of ZO-1 protein in cells exposed to pressure was higher than those in control. CONCLUSIONS: The biological activity of endothelial cells is regulated positively by bionic pressure. The establishment of a new biomimetic pressure model will help to investigate the physiological function and injury repair of corneal endothelial cells in vitro. PMID- 21612687 TI - [Recent advances in the studies of the inhibition of fibrosis in proliferative diabetic retinopathy]. AB - Proliferative fibrotic membranes in Proliferative diabetic retinopathy (PDR) cause severe harm to the patients' visual function. It is critical to inhibit the occurrence and development of fibrosis in order to preserve the visual function of the patients in advanced stage of diabetic retinopathy. In recent years, reports about inhibiting neovascularization in PDR are common. It is rare to find reports about inhibiting fibrosis formation. The application of angiotensin converting enzyme inhibitor, vascular endothelial growth factor receptor antagonist, HMG coenzyme A reductase inhibitors and steroids could inhibit the formation of fibrosis at varying degrees by targeting different pathways. Therefore, it is necessary to summarize the basis of current research conditions for the inhibition of the formation of proliferative fibrotic membranes in PDR, which will provide extensive ideas for the treatment of PDR and fibrosis formation. PMID- 21612688 TI - [Alternative splicing of vascular endothelial growth factor A and ocular neovascularization]. AB - Ocular neovascularization is the primary cause of blindness in a wide range of ocular diseases. The vascular endothelial growth factor A (VEGF-A) is the key factor involved in ocular angiogenesis, which can cause eye diseases through the development of pathological angiogenesis and increase of vascular permeability. There are two families of VEGF-A isoforms formed by alternative splicing, the angiogenic VEGF-A family (VEGF(xxx)), known to contribute to ocular neovascularization, and the anti-angiogenic VEGF-A family (VEGF(xxx)b), which is found in normal ocular tissues but downregulated in human diabetic retinopathy. The first member of the VEGF(xxx)b family to be isolated was VEGF(165)b. It can significantly reduce preretinal neovascularization without inhibition of physiological intraretinal angiogenesis. As the studies on the VEGF(xxx)b family proceed more deeply, controlling the balance of VEGF(xxx) to VEGF(xxx)b isoforms may be therapeutically valuable in the treatment of angiogenic eye diseases such as diabetic retinopathy and age-related macular degeneration. PMID- 21612689 TI - [Mechanism of the immune response to keratomycosis]. AB - Immune system played an important role in recognition and elimination of fungal pathogens. The balance between host factors and fungal pathogens can influence the prognosis of disease. As located on the surface of the eyeball. It was easy for cornea to be attracted by pathogens when traumatic injury occur. Moreover, cornea had characters of transparency and vascularization, which keep it on immune privilege situation relatively. The progress in the study of the mechanism of immunity participating in the keratomycosis and ways of fungus escaped from the attract of immune system was reviewed. PMID- 21612690 TI - [The diagnosis and treatment of colorectal Non-Hodgkin's lymphoma 32 cases]. AB - OBJECTIVE: To summarize the clinical features, diagnostic and therapeutic experiences of colorectal Non-Hodgkin's lymphoma (NHL). METHODS: Clinical data of 32 patients with colorectal NHL admitted to our hospital from January 1988 to December 2006 was retrospectively analyzed. RESULTS: This study included 22 B cell NHL and 10 T-cell NHL cases. In the B-cell NHL group, the male: female ratio was 14:8 and the median age was 60.5 years. In the T-cell NHL group, the male: female ratio was 5:5 and the median age was 31.0 years. The ileocecal region was most frequently involved in both groups, which accounted for 77.3% and 60.0% of the B and T group respectively. The common clinical manifestations included abdominal pain, weight loss, and abdominal mass. Of the 14 cases of B-cell NHL with definite subtype classifications, 64.3% were of the Diffuse Large B-cell Lymphoma (DLBCL) type. Among the 22 B-cell NHL, 40.9% were with localized diseases (stage I-II1), while all 10 patients in T-cell NHL group were in stage IV with 3 patients complicated with massive GI bleeding and 4 with perforation. All patients of B-cell type received chemotherapy utilizing mainly CHOP after surgical resection. After a median follow-up of 55 months, the disease-free survival was rate 88.2%. Among the T-cell NHL group, 8 out of 10 patients underwent surgery and chemotherapy was given to all those who could tolerate it. Five patients died within 2 months after surgery. It's known that 3 patients were still alive after 23 months. CONCLUSIONS: The ileocecal region is the most frequently involved site of the colorectal NHL. The histology is usually B-cell type with a majority being DLBCL. Currently R-CHOP chemotherapy after the surgical resection is the principal treatment modality. Patients of B-cell type have a better prognosis while the prognosis of T-cell NHL is poor. Therefore more aggressive diagnostic and therapeutic approaches are recommended for T-cell NHL patients. The prospective of organ preservation treatment for colorectal NHL is still in need of further investigations. PMID- 21612691 TI - [The application of the abnormal hepatic artery derived from superior mesenteric artery in D2 radical gastrectomy]. AB - OBJECTIVES: To classify the courses of the abnormal hepatic arteries originated from superior mesenteric artery in patients with gastric cancer, and to define its application in the D2 radical gastrectomy in those patients. METHODS: Eighty six patients with gastric cancer who had received D2 radical gastrectomy by the same surgeon between January 2008 and June 2010 were included in this study. All patients received the preoperative multislice spiral computed tomoangiography (MSCTA) to classify the abnormal hepatic artery originated from the superior mesenteric artery, which was verified during the surgery. Postoperative immunohistochemistry of the lymphoid tissues around the abnormal hepatic artery was performed by recombinant human cytokeratin 20 (CK20) and carcino-embryonic antigen (CEA) to verify the micrometastasis. RESULTS: In this group, the abnormal hepatic artery originated from the superior mesenteric artery were found with MSCTA and verified by operation in 14 patients, including 12 men and 2 women. The mean age was 62 years. Of the 14 cases with abnormal hepatic artery, 3 cases were found with abnormal common hepatic artery and 11 cases with abnormal right hepatic artery. The total mutation rate is 16.3%. In those patients, the hepatic artery ran in front of the pancreas in 1 case and behind the pancreas in 13 cases. It was difficult to dissect the abnormal hepatic artery, especially for the post-pancreas type in D2 lymphadenectomy, for fear of damaging the abnormal blood vessel and pancreas. The operation time in cases with abnormal hepatic artery was significantly longer than that in patients with normal hepatic artery [(218.8 +/- 23.9) min vs. (179.6 +/- 18.5) min]. Immunohistochemical analysis revealed no metastasis in the lymphoid tissues surrounding the abnormal artery. CONCLUSIONS: Abnormal hepatic arteries originated from the superior mesenteric artery can be classified into pre-pancreas type and post-pancreas type. The dissection of the abnormal hepatic artery is not advocated in D2 radical gastrectomy for no lymph node metastasis is found around the abnormal hepatic artery in this study. PMID- 21612692 TI - [Comparison of therapeutic effects of immediate implanting breast reconstruction after skin sparing mastectomy and modified radical mastectomy on breast cancer]. AB - OBJECTIVE: To compare the therapy efficiency of immediate implanting breast reconstruction after skin sparing mastectomy and modified radical mastectomy in breast cancer. METHODS: This study retrospectively analyzed 530 female patients with early breast cancer operated in the department of General Surgery, Beijing Chaoyang Hospital, from Jan. 2004 to Dec. 2008, including 91 patients operated with skin sparing mastectomy and immediate implanting breast reconstruction and 439 patients with modified radical mastectomy. The follow up ended in Mar. 2010. By comparing complications, local recurrence, distant metastases and mortality rates between the two groups, the research was done to evaluate the therapy efficiency. RESULTS: In the group of immediate implanting reconstruction, 84 patients completed follow up with the median follow-up time of 35 months (14 - 72 months) while the local recurring rate was 2.4%, distant metastasis rate was 8.3% and mortality rate was 6.0%. In the group of modified radical mastectomy, 398 patients completed follow up with the median follow-up time of 36 months (12 - 74 months) while the local recurring rate was 3.3%, distant metastasis rate was 9.5% and mortality rate was 6.5%. Therefore there was no obvious statistic difference between the two groups in local recurring rate, distant metastasis rate and mortality rate (P > 0.05). Evaluation of aesthetic results was done in the 84 patients after immediate implanting reconstruction for 12 months which was 93% as good or excellent by surgeons while 87% by patients. Surgeons and patients were both satisfied with the breast appearance. CONCLUSION: For patients with early stage breast cancer, combining standard postoperative therapy, skin sparing mastectomy and immediate implanting reconstruction could achieve the same effect as the traditional modified radical mastectomy, while reconstruction would bring about better appearance and higher quality of life. PMID- 21612693 TI - [Evaluation of carotid angiography and stenting for patients with contralateral carotid occlusion]. AB - OBJECTIVE: To discuss the efficiency and safety of carotid angioplasty stenting (CAS) in patients with contralateral carotid artery occlusion. METHODS: From January 2001 to January 2010, 56 carotid artery stenosis patients with contralateral carotid artery occlusion were performed CAS and the feature and results of these cases were analyzed retrospectively. All the cases were confirmed to be carotid artery stenosis with contralateral carotid artery occlusion by digital subtraction angiography (DSA). The diameter stenosis rate was 72% +/- 15%. CAS were performed with distal protection device in 56 cases. RESULTS: The technique success rate of CAS were 100% in all the 56 patients with contralateral carotid artery occlusion and post-procedure stenosis rate descended to 13% +/- 8%, and the symptoms of cerebral ischemia were all improved. Only 1 case occurred remote hemorrhage in the position of previous cerebral infarction in the side of CAS after the procedure, and recovered with light neurological deficit after the craniotomy to remove the hematoma. No ischemic complications or death occurred. During the following up of 6 months to 3 years, no cerebral ischemic symptoms reoccurred. The rechecking results of color Doppler of 47 cases and DSA of 2 cases showed no restenosis in-stent. CONCLUSIONS: CAS is safe and effective for the patients with contralateral carotid artery occlusion. Critical election of the case, operation of skilled doctors and scrupulous post procedure general management can decrease the rate of complication. PMID- 21612694 TI - [Clinical research of minimal extracorporeal circulation in perioperative blood conservation of coronary artery bypass graft]. AB - OBJECTIVE: To analyze the clinical effect of minimal extracorporeal circulation (MECC) in blood conservation perioperatively coronary artery bypass graft (CABG). METHODS: The data of 120 cases received simple CABG since August 2006 to October 2009 was analyzed retrospectively. All the patients were divided to three groups according to the mode of circulation support in-operation: MECC, conventional extracorporeal circulation (cECC) or off-pump, 40 cases in each group. Jostra MECC system with normal temperature was used in MECC group, and common membrane oxygenator with moderate hypo-temperature was used in cECC group. Collect the data of coagulation and the blood cytological examination perioperatively, the draining volume during the first 24 h after operation, and consumption of blood products perioperatively. RESULTS: Standard and logistic EuroSCORE were higher in MECC group than the others (P < 0.01). The operative time and the number of distal anastomosis of off-pump group were less than MECC and cECC groups (P < 0.05), while no difference between MECC group and cECC group. Intrinsic coagulation (activated partial thromboplastin time) were much more prolonged early postoperatively in cECC group, and higher than in MECC group and off-pump group at 2 h, 6 h and 12 h postoperatively (P < 0.05), but no difference in extrinsic coagulation (prothrombin time) among three group. Adjusted by hematocrit of the same sample, free hemoglobin level rose up during the ECC procedure and reached the maximum at the end of ECC in cECC group and MECC group, but the levels were more higher in cECC group than in MECC group (P < 0.05). The draining volume during the first 24 h after operation of cECC group was larger than MECC group and off-pump group (P < 0.05). Although the decreased platelet count perioperatively and more consumed of the blood products in cECC group, but no difference among the three groups. CONCLUSION: MECC could reduce the ruin to blood cell and interfere to coagulation function during the conventional ECC procedure, decrease the postoperative draining volume and requirement of blood products. PMID- 21612695 TI - [Prosthesis-patient mismatch in the mitral valve position: the initial result of a single-institutional observational study in China]. AB - OBJECTIVE: To analysis the causes of valve prosthesis-patient mismatch (PPM) after mitral valve replacement in Chinese patients. METHODS: Consecutive 100 patients for elective mitral valve replacement from January 2009 to June 2009 were enrolled and followed for this study. There were 37 males and 63 females. The mean age at operation was (52 +/- 9) years (ranging 32 to 76 years). The predominant mitral valve lesion was stenosis in 60 patients, regurgitation in 14 patients and mixed in 26 patients. Among them, 63 patients were combined tricuspid valve regurgitation. Mitral valve effective orifice area was measured by Doppler echocardiography in 100 patients who received mitral valve replacement and indexed for body surface area (EOAI). PPM was defined as not clinically significant if the EOAI was above 1.2 cm(2)/m(2), as moderate if it was >0.9 and <= 1.2 cm(2)/m(2), and as severe if it was <= 0.9 cm(2)/m(2). By using the criteria, all 100 patients were classified to two groups: PPM group and no PPM group. The clinical characteristic of the patients between the two groups was compared to determine the causes of PPM and the predictors of outcomes after mitral valve replacement, such as the gender, age, valve prosthesis type, size, body surface area, and mitral valve lesion, et al. RESULTS: Of the 100 patients after MVR, 52 (52.0%) had significant PPM, 51 (51.0%) had moderate PPM, and 1 (1.0%) had severe PPM. In comparison to patients in no PPM group, patients in PPM group had a significantly larger body surface area [(1.76 +/- 0.17) m(2) vs. (1.59 +/- 0.13) m(2), P < 0.01] and higher prevalence of male gender (55.8% vs. 16.6%, P < 0.01). The other preoperative and operative data were similar in both groups, such as the valve prosthesis type, size, and mitral valve lesion, et al. There were no significant differences in postoperative Doppler-echocardiographic data of cardiac structure and heart function between the two groups (P > 0.05). CONCLUSIONS: The higher incidence of PPM in mitral valve position was in male or large body surface area patients. At the time of operation, surgeons should consider the related factors, such as the patient's gender and body surface area, et al. A larger prosthesis size might be implanted to avoid PPM in mitral valve position. PMID- 21612696 TI - [The treatment of monosegmental fixation and short-segment fixation on thoracolumbar burst fracture a retrospective controlled study]. AB - OBJECTIVE: To investigate the safety and therapeutic effects of monosegment pedicle instrumentation in treating incomplete thoracolumbar burst fracture. METHODS: A retrospective analysis was conducted on 56 inpatients with incomplete thoracolumbar burst fracture (AO classification: A3.1 and A3.2) from April 2005 to January 2010. There were 28 cases were fixed with monosegment pedicle instrumentation (MSPI), 28 cases were fixed with short segment pedicle instrumentation (SSPI). The operative time, blood loss, visual analogue scale (VAS) and vertebral kyphotic angle (VK) before and after surgery were evaluated. RESULTS: In the group of MSPI, the mean operative time was (93 +/- 20) min; the intraoperative blood loss was (184 +/- 64) ml; the VK angle was 17 degrees +/- 10 degrees before operation, 7 degrees +/- 7 degrees at one week after operation, and 10 degrees +/- 7 degrees at latest follow-up; VAS score was 7.6 +/- 1.5 before operation, 2.4 +/- 0.8 at one week after operation, and 1.5 +/- 0.9 at latest follow-up; no adjacent segment degeneration was found. In the group of SSPI, the operative time was (102 +/- 30) min; the intraoperative blood loss was (203 +/- 88) ml; the VK angle was 17 degrees +/- 9 degrees before operation, 7 degrees +/- 7 degrees at one week after operation, and 8 degrees +/- 5 degrees at latest follow-up; VAS score was 6.8 +/- 1.3 before operation, 3.1 +/- 0.5 at one week after operation, and 1.2 +/- 0.7 at latest follow-up. One case of adjacent segment degeneration was found in 36 months after operation. There were no significantly statistical differences between two groups in operative time, blood loss, VAS score and VK angle before and after surgery (P > 0.05). The VAS score and VK angle at one week after surgery and latest follow-up all decreased obviously than preoperative ones in both groups (P < 0.05). CONCLUSIONS: MSPI for incomplete thoracolumbar burst fracture is effective and safe. The operative blood loss, the mean operative time, the improvement of VAS score and the VK angle in group MSPI are equal to those in group SSPI. PMID- 21612697 TI - [Clinical features on chromophobe renal cell carcinoma]. AB - OBJECTIVES: To explore the clinical, pathological features and prognosis of patients with chromophobe renal cell carcinoma. METHODS: From January 1998 to January 2008, clinical data of 29 patients with chromophobe renal cell carcinoma including clinical manifestations, imaging examinations, treatment models, pTNM stages and follow-up results, were summarized to investigate its features and prognosis. RESULTS: All cases had no obvious clinical and preoperative imaging presentation. There were 23 patients underwent radical nephrectomy, and 6 cases underwent nephron sparing surgery. Postoperative pathological findings confirmed the diagnosis of chromophobe renal cell carcinoma. Macroscopically, the cut surface of the tumors were generally beige in color. Histologically, it showed polygonal chromophobe cells and small round eosinophilic cells with eccentric hyaline degeneration. These tumor cells had a clear and sharp membrane, lightly stained abundant cytoplasm with a fine reticular translucent pattern and irregular nuclei. And a perinuclear halo was often seen in these cells. Histochemically, the tumor cells generally show a diffuse and strong reaction for CK-8 with a negative expression of Vimentin. The pTNM stages of the tumor were as follows, pT1N0M0 in 11 cases, pT2N0M0 in 8 cases, pT3aN0M0 in 5 cases, pT1N1M0 in 3 cases, pT2N1M0 in 2 cases. Twenty-six cases of patients were followed up (24 to 144 months, with an average of 90 months), 3 cases died of cardio-cerebrovascular disease, and local recurrence involved in 6 cases with reoperation in 4 cases, as well as distant metastasis in 1 case. Twenty-one cases survived with tumor-free. The statistical results indicated that the survival rates of the patients with chromophobe renal cell carcinoma in five years and ten years were 83.9%, 77.9%, respectively, compared with renal cell carcinoma of the same stage 63.8% and 49.9% at the same periods, and there is no difference in the survival rate of five years (P > 0.05) but significant difference in that of ten years (P < 0.01). CONCLUSIONS: Chromophobe renal cell carcinoma is a morphologically uncommon subtype of renal cell carcinoma with the good prognosis. Definite diagnosis depends on its typical pathological feature. Radical nephrectomy is the first choice for the treatment of chromophobe renal cell carcinoma. PMID- 21612698 TI - [Expression of WW domain containing oxidoreductase gene in cholangiocarcinoma and its effect on the biological behavior of cancer cell line RBE]. AB - OBJECTIVE: To study the effects of anti-oncogene WWOX on cell growth of cholangiocarcinoma. METHODS: The expression of WWOX protein was detected with immunohistochemical method-SP in 54 patients with cholangiocarcinoma from July 2005 to May 2010 and 12 samples of normal bile duct tissues. The recombinant WWOX eukaryotic expression plasmid was introduced into RBE cells by liposome-mediated transfection and positive cell clones were selected and amplified. The mRNA and protein expressions in RBE cells stably transfected with WWOX were investigated by quantitative RT-PCR and Western Blot before and after transfection. Cell proliferation was tested by MTT, cell apoptosis was assessed by FCM, the alteration of mitochondria membrane potential (DeltaPsim) was detected by JC-1 staining method, cell invasion was determined by Transwell chamber assay. The expression change of bcl-2, bax, FasL, caspase-3 mRNA and protein was detected by quantitative RT-PCR and Western Blot. RESULTS: The expression of WWOX protein was significantly lower in cholangiocarcinoma than that in normal bile duct tissues and loss of WWOX protein expression was found in 40.7% of cholangiocarcinoma specimens (P < 0.05). RBE cells with stable transfection of WWOX were established. Quantitative RT-PCR showed that the expression of WWOX mRNA was significantly enhanced and Western Blot demonstrated that WWOX protein expression was markedly increased. MTT showed that WWOX gene transfection significantly decreased the proliferation of RBE cells (P < 0.05). FCM analysis showed that the apoptosis rate after transfection was significantly promoted [(1.1 +/- 0.6)% vs. (1.7 +/- 0.5)% vs. (35.2 +/- 4.4)%, P < 0.01], JC-1 staining method indicated that the experimental group was loss of DeltaPsim [(12.6 +/- 1.9)% vs. (13.6 +/- 1.8)% vs. (48.7 +/- 2.9)%, P < 0.01], transwell chamber assay showed that the number of transfected cells that passed the transwell membrane was significantly less than those of control groups (77 +/- 6 vs. 72 +/- 8 vs. 48 +/- 6, P < 0.01). Quantitative RT-PCR and Western blotting showed that the expression of bcl-2 mRNA and protein was markedly decreased and the expression of bax, caspase-3 were significantly increased. There was no significant change in the expression of FasL. CONCLUSION: WWOX exerts its antitumor effect against proliferation through inducing cell apoptosis in cholangiocarcinoma. PMID- 21612699 TI - [Expression of dihydropyrimidine dehydrogenase negatively correlated with the prognosis of pancreatic ductal adenocarcinoma]. AB - OBJECTIVE: To detect the expression of dihydropyrimidine dehydrogenase (DPD) in pancreatic ductal adenocarcinoma (PDAC), and to investigate the relationships between DPD expression and the prognosis of PDAC. METHODS: Immunohistochemistry and tissue microarray techniques were used to exam the expression of DPD in the cancerous tissue in 156 patients admitted from January 2005 to December 2009, including 89 males and 67 females, with the age ranging from 35 to 81 years. The median age was 55 years. RESULTS: With the positive rate of DPD 55.1%, the expression of DPD was correlated with the differentiation (P = 0.001), TNM staging of tumor (P = 0.021). No relationship was observed between the vessel invasion (P = 0.265), lymphatic metastasis (P = 0.123), neural invasion (P = 0.598) and DPD expression. In the follow-up 117 patients the overall median survival time was 14.2 months, in 58 cases expressed negative, the median survival time was 20.6 months; 39 cases expressed "+" and "++", the median survival time was 12.3 months; 20 cases expressed "+++", the median survival time was 6.8 months. The expression of DPD in pancreatic cancer was correlated with the prognosis of patients, those with higher expression pattern exhibited shorter survival time (P < 0.05). Univariate survival analysis revealed that DPD expression, TNM staging, lymphatic metastasis and neural invasion were factors related to prognosis (P < 0.05), while differentiation levels and vessel invasion were not. Multivariate survival analysis revealed that DPD expression (P = 0.002), lymphatic metastasis (P = 0.000) were two independent prognostic factors. CONCLUSIONS: The expression levels of DPD was correlated to differentiation levels of pancreatic cancer and TNM staging; those with higher expression of DPD showed shorter survival time. DPD expression, lymphatic metastasis were independent prognostic factors for pancreatic cancer. PMID- 21612700 TI - [Open abdomen management treatment of liver injury in rats with abdominal compartment syndrome and sepsis]. AB - OBJECTIVE: To evaluate the open and closed management treatment of liver injury in rats with sepsis and abdominal compartment syndrome (ACS). METHODS: The sepsis and ACS rats (n = 72) were randomized divided into two groups. One group used closed management (n = 36), the other accepted the open abdomen management (n = 36). The rats were killed at 1, 6 h, 1, 3, 5, 7 d after operation. Blood was collected for liver function tests. Liver sections assessed pathologically and the expressions of Toll-like receptor 4 (TLR4), tumor necrosis factor (TNF) alpha, interleukin (IL)-6, signal transducers actuators of transcription (STAT3) and suppressor of cytokine signaling 3 (SOCS3) of rat livers were examined by RT PCR. RESULTS: The early stage after operation, TNF-alpha and IL-6 concentrations, STAT3 expressions in rat liver were higher in open abdomen rats than the closed management ones (P < 0.05). TLR4 and SOCS3 expressions were lower in open abdomen rats than the closed management ones (P < 0.05). Aspartate aminotransferase, alanine aminotransferase levels also was lower in open abdomen ones (P < 0.05). CONCLUSIONS: The randomized study demonstrates that open abdomen management could improve liver regeneration in the early stage after operation. Also open abdomen could reduce inflammatory response by reducing TLR4 expressions. PMID- 21612701 TI - [Pharmacokinetics of photosensitizer m-THPC in rat models of liver cancer via orthotropic implantation using Walker-256]. AB - OBJECTIVE: To study the pharmacokinetics, distribution and excretion of m-THPC in rat models of liver cancer via orthotropic implantation using Walker-256. METHODS: After an intravenous injection of m-THPC with 0.3 mg/kg, the concentrations of m-THPC in biological specimens were determined by a fluorescence method. The data obtained were processed with PK-GRAPH pharmacokinetic procedure. RESULTS: The disposition of m-THPC in rat models of liver cancer Walker-256 was conformed to a two compartment model with T(1/2)alpha = 1.18 h, T(1/2)beta = 22.57 h at the dose of 0.3 mg/kg.m-THPC was shown to be widely distributed to the various tissues. There was a highest drug accumulation in liver and liver cancer, and lowest in skin and muscle. Ratio of m-THPC concentration in the Walker-256 tumor compared to normal tissue reach the peak 24 h after m-THPC administration. CONCLUSIONS: m-THPC is distributed widely and eliminated at a rapid rate in Walker-256 rats. Twenty four hours after m-THPC administration may be the best time for photodynamic therapy of liver cancer. PMID- 21612702 TI - [The efficiency and safety of laparoscopic surgery for colorectal carcinoma: a systematic review]. AB - OBJECTIVE: To evaluate and compare the efficiency and safety of laparoscopic surgery (LS) and open surgery (OS) in the treatment of colorectal carcinoma. METHODS: Randomized controlled trials on laparoscopic surgery and open surgery for colorectal carcinoma from January 2000 to October 2010 were searched in the databases of EMbase, PubMed, Cochrane Library, Sciencedirect, Springer, VIP, CNKI, CBMdisc. The methodological quality was assessed according to the standard of Cochrane systematic review. For homogeneous studies, RevMan5.0 software was used for meta-analysis. RESULTS: A total of 13 RCTs involving 4603 patients were included in this study, and among those 6 were multi-center randomized controlled trials. The meta-analysis showed that: the operation time of the LS group was longer than that of the OS group (WMD = 38.91, 95%CI: 33.89 - 43.93, P < 0.001), the blood loss (WMD = -138.14, 95%CI: -195.79 - -80.50, P < 0.001) and the length of hospital stay (WMD = 2.91, 95%CI: -4.65 - -1.17, P = 0.001) of the LS group was less than those in OS group. There was no significant differences between the two groups in the number of dissected lymph nodes (WMD = -0.62, 95%CI: -1.47 - 0.23, P = 0.150). There was no significant differences between the two groups in terms of the postoperative complications (30 days) (RR = 0.78, 95%CI: 0.59 - 1.01, P = 0.06). There was no significant differences between the two groups in 3 year overall survival (RR = 1.00, 95%CI: 0.96 - 1.04, P = 0.970). There was no significant differences between the two groups in 5-year overall survival (RR = 1.03, 95%CI: 0.99 - 1.08, P = 0.140). There was no significant differences between the two groups in 5-year overall recurrence (RR = 0.89, 95%CI: 0.74 - 1.07, P = 0.200). CONCLUSIONS: Laparoscopic surgery for colorectal carcinoma is a safe and effective therapy as open surgery in the short term or long term outcomes. It could be an acceptable alternative to open surgery for colorectal carcinoma. PMID- 21612704 TI - [The features of oral and maxillofacial surgery in China and the challenges we are facing]. PMID- 21612703 TI - [Meta-analysis of efficacy and safety of liver transplantation in treating cholangiocarcinoma]. AB - OBJECTIVE: To evaluate the therapeutic efficacy and safety of liver transplantation for patients with cholangiocarcinoma. METHODS: According to the requirements of Cochrane systematic review, a thorough literature search was performed in Pubmed/Medline, Embase and Cochrane Central Register electronic databases ranged between 1995 and 2009 in terms of the key words "liver transplantation", and "cholangiocarcinoma" or "cholangiocellular carcinoma" or "bile duct cancer". And restricted the articles published in the English language. Two reviewers independently screened the studies for eligibility, evaluated the quality and extracted the data from the eligible studies with confirmation by cross-checking. Data were processed for a meta-analysis by Stata 10 software with 1-, 3-, 5-year survival rates and incidence of complications. RESULTS: A total of 14 clinical trials containing 605 patients were finally enrolled in this study. The overall 1-, 3-, 5-year pooled survival rates were 73% (95%CI: 0.65 - 0.80), 42% (95%CI: 0.33 - 0.51) and 39% (95%CI: 0.28 - 0.51), respectively. Of note, preoperative adjuvant therapies (OLT-PAT group) rendered the transplanted individuals comparably favorable outcomes with 1-, 3-, 5-year pooled survival rates of 83% (95%CI: 0.57 - 0.98), 57% (95%CI: 0.18 - 0.92) and 65% (95%CI: 0.40 - 0.87), respectively. In addition, the overall pooled incidence of complications was 62% (95%CI: 0.44 - 0.78), among which that of OLT-PAT group (58%, 95%CI: 0.20 - 0.92) was relatively acceptable compared to those of liver transplantation alone (61%, 95%CI: 0.33 - 0.85) and liver transplantation with extended bile duct resection (78%, 95%CI: 0.55 - 0.94). CONCLUSIONS: In comparison to curative resection of cholangiocarcinoma with the 5-year survival rate reported from 20% to 40%, the role of liver transplantation alone is so limited, but neoadjuvant radiochemotherapy combined with liver transplantation can bring better short- and long-term prognosis. PMID- 21612705 TI - [Effect of rapamycin combined with cisplatin on head and neck squamous cancer cells regulated by CCL19]. AB - OBJECTIVE: To investigate the synergistic effects of rapamycin and cisplatin on head and neck squamous cancer cells regulated by chemokine (C-C motif) ligand 19 (CCL19). METHODS: The role of rapamycin and cisplatin was detected on cell-cycle and apoptosis in CCL19 induced PCI-4B and PCI-37B cells by methyl thiazolyl tetrazolium (MTT) and flow cytometry (FCM). Dose-effect relationship parameters and combination index (CI) were calculated on the median-effect equation and multiple drug effect equation using computer software CalcuSyn. Statistical analysis was performed by the unpaired student's t-test. RESULTS: Rapamycin and cisplatin could respectively increase the growth arrest, the proportion of G(1) phase and apoptosis of CCL19 induced cancer cells (P < 0.05). Under inhibitory concentration 50% (IC(50)), CI was less than 1, and in IC(75), it was more than 1 in PCI-4B cells. In PCI-37B cells, under IC(75), CI was less than 1, and in IC(90), it was more than 1. CONCLUSIONS: Rapamycin and cisplatin can inhibit CCL19-regulated PCI-4B and PCI-37B cells' survival. The two drugs have synergistic effects when used in combination. PMID- 21612706 TI - [Clinical application of radiotherapy for the treatment of giant vascular malformations in oral and maxillofacial region]. AB - OBJECTIVE: To discuss the clinical use of radiotherapy in the treatment of giant vascular malformation. METHODS: Six patients with giant vascular malformation in oral and maxillofacial region were treated by three dimensional radiation therapy in Department of Stomatology, The Second Affiliated Hospital, School of Medicne, Zhejiang University in the last ten years and the cilinical data were reviewed. The treatment results were evaluated by clinical examination and radiology. RESULTS: No complication was observed during and after the radiotherapy. All patients were satisfied with the aesthetic results. The lesions in MRI were all reduced and even disappeared. There was no sign of recurrence during the follow up period. CONCLUSIONS: Three dimensional radiotherapy is safe and effective for oral and maxillofical vascular malformation. PMID- 21612707 TI - [Selection of optimal occlusal thickness and shoulder thickness in mandibular first molar all-ceramic crown: a three-dimensional finite element analysis]. AB - OBJECTIVE: To investigate the effect of different occlusal thickness and shoulder finish line depth on stress distribution of all-ceramic crowns and to select optimal occlusal thickness and shoulder finish line depth using continuous variation of parameters. METHODS: This analysis was performed using mandibular first molar finite element model. The range of occlusal thickness was set from 1 mm to 3 mm, and that of shoulder finish line depth was from 0.4 mm to 1.2 mm. Load of 225 N was applied perpendicularly to the occlusal surface of the tooth at all buccal cusps to simulate functional occlusal force. The maximum equivalent stresses in crown, cement layer, abutment, periodontal ligament, alveolar bone were calculated, and the sensitivities of stresses to the variables were also evaluated. RESULTS: The maximum equivalent stresses in crown, cement layer and abutment decreased as occlusal thickness and shoulder finish line depth were increased, while no obvious change were found in maximum equivalent stresses in periodontal ligament and alveolar bone. When occlusal thickness exceeded 1.87 mm and shoulder finish line depth exceeded 0.66 mm, the tangent slope rate of the maximum equivalent stress response curves ranged from -1 to 1. Data indicated that occlusal thickness played a more important role in reducing maximum equivalent stress in cement layer than finish line depth did, and shoulder finish line depth was a more effective parameter in reducing maximum equivalent stress in crown and abutment than occlusal thickness was. CONCLUSIONS: Occlusal thickness exceeding 1.87 mm and shoulder finish line depth exceeding 0.66 mm are optimal design for ceramic crown on mandibular first molar from biomechanical point of view. PMID- 21612708 TI - [Function of luxS gene in sulfurmetabolism of Streptococcus mutans]. AB - OBJECTIVE: To investigate the function of luxS in sulfurmetabolism of Streptococcus mutans (Sm). METHODS: The growth with absorbency (A) of the standards and mutant strains was measured and analyzed in the sulfur-limited defined medium at different periods. The laser scanning confocal microscopy (LSCM) was used to observe and compare the biofilm thickness of the two kinds of strains at different culture conditions. RESULTS: The significant increases in the thickness of mutant strain biofilm and its growth were observed after the addition of cysteine, but did not reach the standards strain levels (P < 0.05). The growth and the biofilm thickness of the mutant strains were (1.301 +/- 0.009) and (45.009 +/- 0.429) um. When methionine and S-adenosylhomocysteine of certain concentrations were respectively added, the biofilm thickness and the growth of mutant strain were raised but did not reach the level of the standards strain at 24 h (P < 0.05), but at 48 h they did. When the methionine was added in the mutant strains for 24 h, the biofilm thickness and the growth of mutant strain were (0.448 +/- 0.028) and (37.068 +/- 2.392) um, as for the adding of S adenosylhomocysteine were (0.460 +/- 0.005) and (27.343 +/- 1.107) um. When adding the supernatant fluid of standard strains, the biofilm thickness and the growth levels of mutant strain were much higher than those of the standards strain. The biofilm thickness and growth of both kinds of strains decreased after the addition of S-adenosylmethionine. CONCLUSIONS: luxS gene plays not only a role in quorum sensing but also a role in sulfurmetabolism. PMID- 21612709 TI - [Occluding effects of three new calcium desensitizers on dentinal tubules in vitro]. AB - OBJECTIVE: To evaluate the occluding effects of three new calcium desensitizers on dentinal tubules in vitro. METHODS: Twenty-five dentin specimens of 1.00 mm thick from freshly extracted third molars were divided into five groups randomly. After treatment with 6% citric acid, group A was treated with distilled water, and group B-E were treated with NovaMin, Pro-Argin, casein phosphopeptide amorphous calcium phosphate (CPP-ACP), and 75% NaF glycerin for 2 min respectively. Then the teeth were vertically cleaved into two sections. The surfaces and cross sections were observed by the scanning electron microscope (SEM) and energy dispersive X-ray (EDX), which were analyzed by the Image-Pro Plus software. RESULTS: The percentage of dentin tubules sealed were (81.6 +/- 6.1)%, (71.5 +/- 6.3)%, (43.2 +/- 2.6)%, (39.9 +/- 4.1)% for groups B, C, D and E respectively, and the occluding depth were (30.33 +/- 2.26), (24.55 +/- 2.58), (16.10 +/- 4.65) and (8.90 +/- 1.51) um respectively. The differences between these groups were statistically significant (P < 0.01) except for group B and C (P > 0.05). However, there was no significant difference between all the groups for the Ca/P ratios (P = 0.342). CONCLUSIONS: NovaMin may have better immediate occluding effects than other desensitizers and could deposit a dentin-like mineral. PMID- 21612710 TI - [Development of Chinese version of children's fear survey schedule-dental subscale]. AB - OBJECTIVE: To establish the Chinese version of the modified children's fear survey schedule-dental subscale (CFSS-DS). METHODS: The original English version of CFSS-DS with facial image scale (FIS) was translated into Chinese, pre-tested and cross-culturally adapted. Subsequently the Chinese version schedule was randomly investigated among 367 children aged 5 - 12 years and their parents. Reliability and validity of the translated scale was evaluated later. RESULTS: Totally 367 children were investigated and 311 valid questionnaire was received. Cronbach's alpha of the translated scale was 0.85 and test-rest reliability was 0.73. The 15 items were divided into four domains. There was a certain logical relationship between the items among the same domains. There was highly significant association between the self-report of the Modified CFSS-DS and Frankl Behavioral Scale (r(s) = -0.403, P < 0.01). CONCLUSIONS: The Chinese version of modified CFSS-DS has been established successfully with good psychometric properties which provide the theoretical evidence for further application in Chinese population. PMID- 21612711 TI - [Effect of PG0839 gene of Porphyromonas gingivalis on inflammatory cytokine in human oral epidermoid carcinoma KB cell]. AB - OBJECTIVE: To investigate the effect of PG0839 gene form Porphyromonas gingivalis (Pg) on inflammatory cytokine expression in human oral epidermoid carcinoma KB cell. METHODS: A mutant in the PG0839 gene of Pg was created by insertional inactivation. Group 1 was chanllenged with PgW83 strain, group 2 with PG0839 defective mutant, and the control group with Dulbecco's modified Eagle's medium only. KB cells were co-cultured with presence of bacteria for 24 h. At the time point of 0.5, 2, 6, 12 and 24 h, cells were stored in Trizol. The mRNA expression of interleukin-1beta (IL-1beta) and Toll like recepector-4 (TLR-4) was examined by reverse transcription polymerase chain reaction. RESULTS: At 2 h and 6 h, IL 1beta mRNA expression was lower in group 2 than in group 1 (2 h: 0.31 +/- 0.11 versus 0.95 +/- 0.48, P < 0.05; 6 h: 0.57 +/- 0.20 versus 1.29 +/- 0.55, P < 0.05). At 0.5 h and 6 h, TLR-4 mRNA expression was lower in group 2 than in group 1 (0.5 h: 0.20 +/- 0.09 versus 0.58 +/- 0.09, P < 0.05; 6 h: 0.34 +/- 0.04 versus 0.71 +/- 0.18, P < 0.05). CONCLUSIONS: PG0839 gene may play an important role in Pg-induced inflammatory effects of KB cell. PMID- 21612712 TI - [Colonization of Tannerella forsythus and Prevotella intermedia in dental plaque samples from children of Changchun Ziqiang primary school]. AB - OBJECTIVE: To detect the presence of Tannerella forsythus (Tf) and Prevotella intermedia (Pi) using polymerase chain reaction (PCR) in the oral plaque samples from children and investigate the relationship between bacteria and clinical parameters. METHODS: A total of 151 children aged 7 to 12 years were selected from Changchun primary school. The supragingival plaque sample was collected from the mesiobuccal and labial surfaces of the right maxillary central incisor (FDI1) and the right maxillary first molar (FDI6). Extracted DNA from plaque samples was used for PCR analysis. Intraoral examination, probing depth (PD) and bleeding on probing (BOP) were performed and recorded. RESULTS: The detection rate for Tf was 40.3% (118/293) and Pi was 46.4% (136/293) in supragingival plaque. The detection rates for Tf and Pi in molars were much higher than those in incisors (P < 0.01). The detection rate of Tf and Pi was positively related to BOP+ and PD. The detection rate for Pi decreased gradually with age, and the detection rate for Tf was highest in the group aged 7 to 8 and the detection rates for Tf and Pi were higher in the gingiva with BOP+ than that with BOP- (P > 0.05). The detection rates for Tf increased remarkably with BOP+ and especially when PD was greater than 4 mm. CONCLUSIONS: Detection rates of putative periodontal pathogens from healthy children of 7 to 12 years of age were high. The detection rates for Tf and Pi in molars were much higher than those in incisors, and the presence of Tf and Pi in supragingival plaque was related to periodontal parameters. PMID- 21612713 TI - [Clinical application of a self-developed bone collector in dental implantation]. AB - OBJECTIVE: To introduce a self-developed bone collector designed by the authors and evaluate its effect in clinical application. METHODS: A self-developed bone collector was used in 38 patients who underwent the dental implant operation from May 2008 to October 2009. During the operation the bone particles were harvested, which was used for the reconstruction of the bone defects around the implant simultaneously. The defects were fenestrate in 29 regions and triangle in 23 regions on buccal or lingual side of the dental implants. RESULTS: All cases had no surgical wound infection and dehiscence 7 - 10 days after operation. Three to six months after implantation, the X-ray showed that all the dental implants had perfect osseointergration and the alveolar bone were successfully augmented. CONCLUSIONS: Bone debris harvested by self-developed bone collector could repair small peri-implant bone defects, which is simple to use in clinic. PMID- 21612714 TI - [Influence of bone quality on the stress distribution for three-posterior immediately loaded implants: a three-dimensional finite element analysis]. AB - OBJECTIVE: To assess and compare the peri-implant stress distribution of three posterior implants under immediate loading with 4 different bone qualities using three dimensional (3D) finite element (FE) analysis. METHODS: A 3D finite element model representing three implants in a portion of mandible at the 654 region was developed, and three implants received a crown each. Four types of bone qualities (B1, B2, B3 and B4) were designed for the model. Load of 100 N was applied on the occlusal surfaces of the crowns at a 45 degrees angle to the vertical axis of the implants. RESULTS: Von Mises stresses in the peri-implant bone of 4 in bone quality from B1 to B4 were (13.17 +/- 9.32), (12.95 +/- 9.14), (15.00 +/- 9.44), and (16.81 +/- 10.74) MPa, and those of 5 were (15.51 +/- 10.32), (14.73 +/- 8.96), (16.79 +/- 8.40), and (18.34 +/- 8.45) MPa. Stress in bone quality B4 showed the highest value, followed by B3 bone, the lowest stress were found in B1 and B2 bone. It was significantly different (P < 0.05). However, von Mises stresses in different quality of bone around 6 [(42.45 +/- 25.71), (41.66 +/- 25.29), (42.70 +/- 23.24), (42.06 +/- 23.66) MPa] were close to each other, and were as twice or three times as those of 4 and 5, irrespective of different bone qualities. CONCLUSIONS: The stress distribution around implant under immediate loading was not only affected by different bone qualities, but also by the direction of loading, and the latter may have a greater impact when a severe load delivered. PMID- 21612715 TI - [Evaluation of periodontal tissue during orthodontic tooth movement in rats: a micro-computed tomography study]. AB - OBJECTIVE: To observe the microstructure changes of rat alveolar bone around tooth root under orthodontic force loading. METHODS: Ten 10-week-old rats were included in the study. Upper first molars were moved mesially with 0.196 N of force. The alveolar bone around the root of upper first molar was scanned by a micro-computed tomography scan system (SkyScan-1076) in different period after the initiation of orthodontic force loading (on the 3rd, 7th, 14th day after force loading) and analyzed by a specially-designed software to measure the microstructure parameters of alveolar bone (bone volume fraction, bone surface to volume ratio, structure model index, trabecular thickness, trabecular separation, trabecular number). RESULTS: From the 7th day, bone volume fraction [(41 +/- 14)%], structure model index (1.51 +/- 0.52) and trabecular separation [(90 +/- 30) um] changed significantly in the compressive area compared with those [(64 +/ 15)%, (0.51 +/- 0.85), (56 +/- 10) um] on the 3rd day. From the 14th day, bone volume fraction [(78 +/- 14)%], structure model index (0.28 +/- 0.20) and trabecular separation [(29 +/- 13) um] changed significantly in the tension area compared with those [(67 +/- 14)%, (0.40 +/- 0.41), (48 +/- 15) um] on the 7th day. No difference on trabecular number was found between the compressive area and tension area (P > 0.05). CONCLUSIONS: The significant resorption of the alveolar bone was observed on the 7th days in the compressive area and the deposition of the alveolar bone was observed on the 14th day in the compressive area after orthodontic force loading. PMID- 21612716 TI - [Comparative study on spectrophotometric and visual methods for color stability of denture base resin]. AB - OBJECTIVE: To explore the relationship between the spectrophotometric and visual methods in evaluating the color stability of denture base resin, and determine the threshold color difference of denture base resin in the spectrophotometric method. METHODS: Two kinds of denture base resin were respectively fabricated into 33 specimens whose color differences varied from indistinguishable to obvious. Each of the specimens was assessed respectively by 30 human observers and a SP62 spectrophotometer. The results of visual assement were recorded as "indistinguishable change", "light change" or "severe change", while the spectrophotometric color differences (DeltaE) were calculated. In each group, a logistic curve was explored to determine the relationship between the color difference (DeltaE) and the ratio of "severe change". RESULTS: The R squares of logistic curves were 0.93 and 0.94 respectively. The threshold color differences in the spectrophotometric method were 2.87 and 2.82 respectively. CONCLUSIONS: A high relevance between the spectrophotometric and visual methods in evaluating the color stability of denture base resin was found. The threshold color differences for different color denture base resins were similar. PMID- 21612717 TI - [Monitoring of methyl methacrylate monomer released from autopolymerized denture base polymers during processing using time-of-flight mass spectrometer]. AB - OBJECTIVE: To analyze the amount and tendency of methyl methacrylate (MMA) released from autopolymerized denture base polymer (self-curing resin) during processing using time-of-flight mass spectrometer (TOF-MS). METHODS: Self-curing resin was mixed in the container using a ratio of 2 g of powder to 1 g of liquid in accordance with the manufacturer's instructions for 40 s as a specimen. The amount of MMA released from the specimen was continuously monitored and simultaneously recorded every minute by TOF-MS since immediately after mixing. A total of five specimens were monitored. RESULTS: The amount of MMA increased dramatically at 11 min [(45.2 +/- 3.5) mg/L] after mixing, and reached the highest level at 13 min [(228.9 +/- 22.6) mg/L], then become stable at 23 min [(8.8 +/- 2.3) mg/L] after mixing. CONCLUSIONS: The releasing tendency of MMA could be analyzed accurately with continuously monitoring during processing. The amount of MMA released from self-curing resin changed rapidly and the processing was complicated and changeful. PMID- 21612718 TI - [Right maintenance and self-discipline of practicing dentist on the liability in medical damage of the tortuous liability (III): medical damage in medical dispute and identification of its liability]. PMID- 21612719 TI - [Recent advances in research of relationship between hypoxia and epithelial mesenchymal transition in head and neck cancer]. PMID- 21612720 TI - Segmenting a general practitioner market to improve recruitment outcomes. AB - Recruitment is an ongoing challenge in the health industry with general practitioner (GP) shortages in many areas beyond rural and Indigenous communities. This paper suggests a marketing solution that identifies different segments of the GP market for recruitment strategy development. In February 2008, 96 GPs in Australia responded to a mail questionnaire (of which 85 questionnaires were useable). A total of 350 GPs were sent the questionnaire. Respondents considered small sets of attributes in the decision to accept a new job at a general practice and selected the most and least important attribute from each set. We identified latent class clusters (cohorts) of GPs from the most-least important data. Three cohorts were found in the GP market, distinguishing practitioners who emphasised job, family or practice attributes in their decision to join a practice. Few significant demographic differences exist between the cohorts. A segmented GP market suggests two alternative recruitment strategies. One option is for general practices to target members of a single cohort (family , job-, or practice-focussed GPs). The other option is for general practices to diversify their recruitment strategies to target all three cohorts (family-, job- and practice-focussed GPs). A single brand (practice) can have multiple advertising strategies with each strategy involving advertising activities targeting a particular consumer segment. PMID- 21612721 TI - Truncated careers in nuclear medicine technology: increased job control may improve retention. AB - OBJECTIVES: The aim of the study was to gain understanding of why nuclear medicine technologists (NMTs) leave and to compare workforce and service provision trends with diagnostic imaging professionals. DESIGN AND SETTING: A survey of all NMT professional body members in New South Wales, the Australian Capital Territory and Queensland was conducted. This paper reports on survey findings of those no longer working as a NMT. Analysis of 1996, 2001 and 2006 Australian Census data and Medicare statistics was made for NMTs, sonographers and radiographers. MAIN OUTCOME MEASURES: The five most influential reasons for leaving nuclear medicine were measured by survey. Census data measured workforce characteristics; size, sex, age. Medicare statistics measured national service provision. RESULTS: Primarily, limited career pathways and professional plateau influence retention of NMTs, with sonography a common career move. Nuclear medicine technologists are young (44.3% <30 years) compared with radiography (52.3% <40 years) or sonography (52.8% <40 years). From 2001 to 2006, service provision in nuclear medicine grew by 11.8% compared with 36% in ultrasound but the workforce size decreased by 4.9% whereas sonographers increased by 51.1%. CONCLUSIONS: Increasing the level of job control is the most likely factor in creating a positive change to the NMT job characteristics and improving retention. PMID- 21612722 TI - Clinical informatics: a workforce priority for 21st century healthcare. AB - This paper identifies the contribution of health and clinical informatics in the support of healthcare in the 21st century. Although little is known about the health and clinical informatics workforce, there is widespread recognition that the health informatics workforce will require significant expansion to support national eHealth work agendas. Workforce issues including discipline definition and self-identification, formal professionalisation, weaknesses in training and education, multidisciplinarity and interprofessional tensions, career structure, managerial support, and financial allocation play a critical role in facilitating or hindering the development of a workforce that is capable of realising the benefits to be gained from eHealth in general and clinical informatics in particular. As well as the national coordination of higher level policies, local support of training and allocation of sufficient position hours in appropriately defined roles by executive and clinical managers is essential to develop the health and clinical informatics workforce and achieve the anticipated results from evolving eHealth initiatives. PMID- 21612723 TI - Building capacity in Australian interprofessional health education: perspectives from key health and higher education stakeholders. AB - OBJECTIVE: A substantial literature engaging with the directions and experiences of stakeholders involved in interprofessional health education exists at the international level, yet almost nothing has been published that documents and analyses the Australian experience. Accordingly, this study aimed to scope the experiences of key stakeholders in health and higher education in relation to the development of interprofessional practice capabilities in health graduates in Australia. METHODS: Twenty-seven semi-structured interviews and two focus groups of key stakeholders involved in the development and delivery of interprofessional health education in Australian higher education were undertaken. Interview data were coded to identify categories that were organised into key themes, according to principles of thematic analysis. RESULTS: Three themes were identified: the need for common ground between health and higher education, constraints and enablers in current practice, and the need for research to establish an evidence base. Five directions for national development were also identified. CONCLUSIONS: The study identified a range of interconnected changes that will be required to successfully mainstream interprofessional education within Australia, in particular, the importance of addressing issues of culture change and the need for a nationally coordinated and research informed approach. These findings reiterate those found in the international literature. PMID- 21612724 TI - Development of a multi-source feedback tool for consultant anaesthetist performance. AB - The process of development, and implementation, of a multi-source feedback tool for consultant anaesthetists is described. Rater groups included the anaesthetist in-charge, anaesthetic assistants, anaesthetic trainees and, for some, the nurse in-charge of the floor. Multiple items were developed to rate consultant behaviour, especially non-technical aspects of behaviour, and used across some or all of the rater groups. Response rates for items and by rater groups are discussed. The collated information formed part of the annual staff appraisal process conducted by the director. The information is useful for the director and the process is well-accepted by the staff. PMID- 21612725 TI - Preparedness for internship: a survey of new interns in a large Victorian health service. AB - OBJECTIVE: To gain better understanding of the work-preparedness of new interns and identify areas where further training and education should be provided. DESIGN: Surveys of new interns assessing self-reported confidence and preparedness for tasks commonly undertaken without direct supervision. The first survey was undertaken before the cohort had started work, the second once they had completed their second intern rotation. SETTING: A large metropolitan Victorian health service. PARTICIPANTS: All interns starting in 2009 at Southern Health. Of the total 66 interns, 52 (84%) completed the first survey and 37 (56%) completed the second. MAIN OUTCOME MEASURE(S): Self-reported confidence and preparedness for common intern tasks. RESULTS: The surveys identified tasks that interns undertake frequently, their preparedness for these and their confidence in completing them. Although most felt reasonably well prepared by their university training for many tasks they commonly undertake as interns, this was not the case for all tasks. In particular, they did not feel well prepared for the following: preoperative patient review, handover, fluid and medication management, patient admissions, assessment of unstable patients, communication with patients and families, and pain management. CONCLUSIONS: There are particular domains of work-readiness for interns that could be improved. For best results, the training of interns in these common tasks should be undertaken jointly by hospitals and universities to ensure smooth transition from medical student to intern. PMID- 21612726 TI - Is health workforce sustainability in Australia and New Zealand a realistic policy goal? AB - This paper assesses what health workforce 'sustainability' might mean for Australia and New Zealand, given the policy direction set out in the World Health Organization draft code on international recruitment of health workers. The governments in both countries have in the past made policy statements about the desirability of health workforce 'self-sufficiency', but OECD data show that both have a high level of dependence on internationally recruited health professionals relative to most other OECD countries. The paper argues that if a target of 'self sufficiency' or sustainability were to be based on meeting health workforce requirements from home based training, both Australia and New Zealand fall far short of this measure, and continue to be active recruiters. The paper stresses that there is no common agreed definition of what health workforce 'self sufficiency', or 'sustainability' is in practice, and that without an agreed definition it will be difficult for policy-makers to move the debate on to reaching agreement and possibly setting measurable targets or timelines for achievement. The paper concludes that any policy decisions related to health workforce sustainability will also have to taken in the context of a wider community debate on what is required of a health system and how is it to be funded. PMID- 21612727 TI - Psychosocial oncology services in New South Wales. AB - There is limited published evidence about how psychosocial services should be organised or routinely integrated into cancer services to ensure that cancer patients receive appropriate psychological, social and emotional support during periods of diagnosis, treatment and follow-up. This paper reports on a survey of 26 oncology services in New South Wales, Australia, to examine the current provision of psychosocial oncology services. The aim of the study was to gather baseline data and information about the provision of services and to identify significant challenges associated with the development and implementation of psychosocial oncology services. A total of 42% of staff at psycho-oncology services reported they could provide adequate psycho-oncology services, but 58% of sites said they could provide either only limited (27%) or very limited (31%) services. We found that services frequently identified challenges such as insufficient funding to employ skilled staff to provide psychosocial interventions, inadequate data to demonstrate the effectiveness of psychosocial interventions and, at times, lack of space to allow privacy for patient consultations. Future needs identified were strategic planning of psychosocial oncology services as part of broader cancer service plans, leadership of psychosocial oncology services, cohesive teams using agreed patient pathways or tools and integration into multi-disciplinary cancer teams. PMID- 21612728 TI - Receptionists in intake in community health. AB - Receptionists are employed as administrative assistants, but in Community Health Centres, especially rural ones, they are the first step in service delivery, the intake system. This has implications for the people seeking services and for receptionists. This paper looks at receptionist data from an intake study alongside relevant literature and makes findings relating to the occupational health and safety (OH&S) of receptionists and for intake systems. PMID- 21612729 TI - Trial of an allied health workload allocation model. AB - Allied health (AH) managers need to be able to quantify workloads to effectively manage the increasing demands on the health system. Workload allocation models provide a means of monitoring, evaluating and determining manageable workloads. This allows managers to ensure equitable distribution of duties and maximise the existing AH workforce output, which will lead to more efficient health service delivery and better patient outcomes. The purpose of this study was to develop and trial an AH workload allocation model incorporating the National Allied Health Casemix Committee Health Activity Classification. A workload allocation model was developed that included a staff workload mapping tool, data analysis spreadsheet and guidelines for calculating procedure times. The model was trialled across three AH professions (occupational therapy, physiotherapy and speech pathology), in two hospital districts, and across inpatient, outpatient and community settings. A total of 30 participants completed the trial. Staff and managers completed a post-trial survey to provide feedback on the workload allocation model. Survey results indicated that staff and managers found the model useful for evaluating and quantifying workloads. Managers believed the model would be useful for preparing business cases and benchmarking staff workloads. Recommendations for improvements to the workload mapping tool were also identified. PMID- 21612730 TI - End-of-life care in acute hospitals. PMID- 21612731 TI - Determining priority of access to physiotherapy at Victorian community health services. AB - Prioritisation of clients requesting physiotherapy in Victorian community health services has occurred in the absence of a uniform evidence-based prioritisation process. The effect of the varying prioritisation procedures on client outcomes is unknown. This two-part study sought to answer two questions: what are the current prioritisation practices? And what is the evidence for prioritisation? Staff of Victorian community health services offering physiotherapy (n=67) were sent a structured questionnaire regarding their prioritisation practices. The questionnaire data revealed a wide range of poorly defined criteria and methods of assessment for prioritisation. The evidence for prioritisation and the use of specific prioritisation criteria were examined via a literature search. The literature suggested the use of acute severe pain, interference with activities of daily living and falls as indicators of need for priority service. The lack of uniformity found in determining priority of access reflects the complexity of determining need and the lack of research and validated tools to assist decision making. Further research into prioritisation criteria is required to determine their validity and if their use in a prioritisation tool would actually improve outcomes for clients. PMID- 21612732 TI - Negotiating norms, navigating care: findings from a qualitative study to assist in decreasing health inequity in cardiac rehabilitation. AB - PURPOSE: People from culturally and linguistically diverse backgrounds (CaLDBs) have lower rates of participation in cardiac rehabilitation (CR). Systematically evaluating barriers and facilitators to service delivery may decrease health inequalities. This study investigated approaches for promoting cultural competence in CR. METHODS: A qualitative study of 25 health practitioners was undertaken across three CR programs using a purposive sampling strategy. Interviews and participant observation were undertaken to identify factors to promote culturally competent care. RESULTS: Three key foci were identified for implementing cultural competence approaches: (1) point of contact; (2) point of assessment; and (3) point of service. Based upon study findings and existing literature, a conceptual model of cultural competency in CR was developed. CONCLUSION: Culturally competent strategies for identifying and tailoring activities in the CR setting may be a useful approach to minimise health inequities. The findings from this study identified that, in parallel with mainstream health services, CR service delivery in Australia faces challenges related to cultural and ethnic diversity. Encouragingly, study findings revealed implementation and integration of culturally competent practices in rehabilitation settings, in spite of significant odds. PMID- 21612733 TI - Setting priorities for high-cost medications in public hospitals in Australia: should the public be involved? AB - AIM: To explore healthcare decision makers' perceptions about public involvement in setting priorities for high-cost medications (HCMs) in public hospitals in Australia. METHODS: In-depth, semi-structured interviews were conducted with 24 decision-makers (executive directors of hospitals, area health service managers, directors of hospital pharmacy departments and senior medical doctors) in a Sydney Area Health Service. Interviews were digitally recorded, transcribed verbatim, thematically content analysed and coded. RESULTS: The majority of participants perceived that the 'rationing debate' needs to happen in Australia. The community at large should be encouraged to understand that healthcare resources are limited and choices need to be made. The perspectives of the public, according to participants, were considered diverse (tax payers, patients, consumers). Owing to the complexities of the healthcare system, their involvement of the public in decision-making regarding access to HCMs in public hospitals was considered limited. For participants, the role of the public was likely to be at the macro level, deciding how much they were prepared to spend on healthcare. CONCLUSION: The role of the public in setting priorities for HCMs in public hospitals was perceived by these healthcare decision makers as limited. However since rationing is unavoidable, there should be an explicit debate about the principles and issues concerned. PMID- 21612734 TI - How is advance care planning conceptualised in Australia? Findings from key informant interviews. AB - OBJECTIVE: Advance Care Planning (ACP) has been gaining prominence as an important component of good end-of-life care. This study explored how ACP is conceptualised by stakeholder organisations and clinicians involved in aged care and end-of-life care in Australia, in particular their views on the aim, appropriate context and settings for ACP, and how ACP should be facilitated. PARTICIPANTS: Twenty-three participants including expert clinicians and representatives of government organisations, professional societies, consumer groups and other organisations involved in aged care and end-of-life care. DESIGN: Qualitative descriptive analysis of semi-structured telephone interviews. RESULTS: Most participants viewed ACP as an ongoing process aimed at enhancing an individual's autonomy and ensuring good end-of-life care. However, there were significant differences in how this process was conceptualised. Some viewed ACP as a process undertaken by patients to define and communicate their treatment preferences. Others viewed ACP as discussions undertaken by health professionals to gain a better understanding of the patient's values and goals in order to provide good care. IMPLICATIONS: Our findings highlight significant differences in how ACP is conceptualised in Australia. A shared conceptualisation and agreement on purpose is needed to ensure a successful implementation of ACP in Australia. PMID- 21612735 TI - A survey of reimbursement practices of private health insurance companies for pharmaceuticals not covered under the Pharmaceutical Benefits Scheme 2008. AB - OBJECTIVE: To describe the current practices and policy of Australian private health insurance (PHI) companies with respect to cover for pharmaceuticals not subsidised under the Pharmaceutical Benefits Scheme (PBS). DESIGN, SETTING AND PARTICIPANTS: A 2008 review of web-published policy statements for top-level hospital and comprehensive general treatment insurance, and survey of reimbursement practices by way of questionnaire, of 31 Australian-registered, open-membership PHI companies. MAIN OUTCOME MEASURES(S): Description of the level of pharmaceutical cover and important considerations identified by PHI companies for funding non-PBS pharmaceuticals through benefit entitlements or ex-gratia payments. RESULTS: Nine of thirty-one PHI companies (29%) provided responses accounting for ~60% market share of PHI. The majority of smaller PHI firms either declined participation or did not respond. The maximum limits offered for non-PBS pharmaceuticals, under comprehensive general treatment insurance, varied significantly and typically did not adequately cover high-cost pharmaceuticals. Some companies occasionally offered ex-gratia payments (or discretionary payments in excess of the policyholder's entitlement benefits) for high cost pharmaceuticals. Factors considered important in their decision to approve or reject ex-gratia requests were provided. All results were de-identified. CONCLUSIONS: There is little consistency across PHI companies in the manner in which they handle requests for high-cost pharmaceuticals in excess of the defined benefit limits. Such information and processes are not transparent to consumers. PMID- 21612736 TI - Hidden costs associated with the universal application of risk management in maternity care. AB - This paper presents a critical analysis of risk management in maternity care and the hidden costs associated with the practice in healthy women. Issues of quality and safety are driving an increased emphasis by health services on risk management in maternity care. Medical risk in pregnancy is known to benefit 15% or less of all pregnancies. Risk management applied to the remaining 85% of healthy women results in the management of risk in the absence of risk. The health cost to mothers and babies and the economic burden on the overall health system of serious morbidity has been omitted from calculations comparing costs of uncomplicated caesarean birth and uncomplicated vaginal birth. The understanding that elective caesarean birth is cost-neutral when compared to a normal vaginal birth has misled practitioners and contributed to over use of the practice. For the purpose of informing the direction of maternity service policy it is necessary to expose the effect the overuse of medical intervention has on the overall capacity of the healthcare system to absorb the increasing demand for operating theatre resources in the absence of clinical need. PMID- 21612737 TI - Capital planning for operating theatres based on projecting future theatre requirements. AB - During 2006, NSW and ACT Health Departments jointly engaged KPMG to develop an Operating Theatre Requirements' Projection Model and an accompanying planning guideline. A research scan was carried out to identify drivers of surgical demand, theatre capacity and theatre performance, as well as locating existing approaches to modelling operating theatre requirements for planning purposes. The project delivered a Microsoft Excel-based model for projecting future operating theatre requirements, together with an accompanying guideline for use of the model and interpretation of its outputs. It provides a valuable addition to the suite of tools available to Health staff for service and capital planning. The model operates with several limitations, largely due to being data dependent, and the state and completeness of available theatre activity data. However, the operational flexibility built into the model allows users to compensate for these limitations, on a case by case basis, when the user has access to suitable, local data. The design flexibility of the model means that updating the model as improved data become available is not difficult; resulting in revisions being able to be made quickly, and disseminated to users rapidly. PMID- 21612738 TI - Mapping maternity services in Australia: location, classification and services. AB - OBJECTIVE: To describe maternity services available to Australian women and, in particular, the location, classification of services and support services available. DESIGN: A descriptive study was conducted using an online survey that was emailed to eligible hospitals. Inclusion criteria for the study included public and private maternity units with greater than 50 births per year. In total, 278 maternity units were identified. Units were asked to classify their level of acuity (Levels 2-6). RESULTS: A total of 150 (53%) maternity units responded. Those who responded were reasonably similar to those who did not respond, and were representative of Australian maternity units. Almost three quarters of respondents were from public maternity units and almost 70% defined themselves as being in a rural or remote location. Maternity units with higher birth rates were more likely to classify themselves as providing higher acuity services, that is, Levels 5 and 6. Private maternity units were more likely to have higher acuity classifications. Interventions such as induction of labour, either using an artificial rupture of membranes (ARM) and oxytocin infusion or with prostaglandins, were common across most units. Although electronic fetal monitoring (EFM) was also widely available, access to fetal scalp pH monitoring was low. CONCLUSION: Maternity service provision varies across the country and is defined predominately by location and annual birth rate. PMID- 21612739 TI - Development of an accreditation program for Point of Care Testing (PoCT) in general practice. AB - OBJECTIVES: To describe the development and evaluation of an accreditation program for Point of Care Testing (PoCT) in general practice, which was part of the PoCT in general practice (GP) Trial conducted in 2005-07 and funded by the Australian Government. SETTING AND PARTICIPANTS: Thirty general practices based in urban, rural and remote locations across South Australia, New South Wales and Victoria, which were in the intervention arm of the PoCT Trial were part of the accreditation program. A PoCT accreditation working party was established to develop an appropriate accreditation program for PoCT in GP. A multidisciplinary accreditation team was formed consisting of a medical scientist, a general practitioner or practice manager, and a trial team representative. METHODOLOGY AND SEQUENCE OF EVENTS: To enable practices to prepare for accreditation a checklist was developed describing details of the accreditation visit. A guide for surveyors was also developed to assist with accreditation visits. Descriptive analysis of the results of the accreditation process was undertaken. OUTCOMES: Evaluation of the accreditation model found that both the surveyors and practice staff found the process straightforward and clear. All practices (i.e. 100%) achieved second-round accreditation. DISCUSSION AND LESSONS LEARNED: The accreditation process highlighted the importance of ongoing education and support for practices performing PoCT. PMID- 21612740 TI - 'Nowhere to room ... nobody told them': logistical and cultural impediments to Aboriginal peoples' participation in cancer treatment. AB - BACKGROUND: Cancer mortality among Indigenous Australians is higher compared to the non-Indigenous population and attributed to poor access to cancer detection, screening, treatment and support services. A large proportion of Indigenous Australians live in rural and remote areas which makes access to cancer treatment services more challenging. Factors, such as transport, accommodation, poor socio economic status and cultural appropriateness of services also negatively affect health service access and, in turn, lead to poor cancer outcomes. DESIGN, SETTING AND PARTICIPANTS: Qualitative research with 30 in-depth interviews was conducted with Aboriginal people affected by cancer from across WA, using a variety of recruitment approaches. RESULTS: The infrastructure around the whole-of-treatment experience affected the decision-making and experiences of Aboriginal patients, particularly affecting rural residents. Issues raised included transport and accommodation problems, travel and service expenses, displacement from family, concerns about the hospital environment and lack of appropriate support persons. These factors are compounded by a range of disadvantages already experienced by Aboriginal Australians and are vital factors affecting treatment decision-making and access. CONCLUSION: To improve cancer outcomes for Aboriginal people, logistical, infrastructure and cultural safety issues must be addressed. One way of ensuring this could be by dedicated support to better coordinate cancer diagnostic and treatment services with primary healthcare services. PMID- 21612741 TI - Metabolism and excretion of a novel p38 MAP kinase inhibitor pamapimod in healthy male subjects. AB - OBJECTIVE: This study investigated the pharmacokinetics, excretion, and metabolism of pamapimod following a single oral dose in healthy male subjects. MATERIALS: Nonradio-labeled pamapimod was supplied as bulk powder, [14C]-labeled pamapimod was supplied as ethanol solution. Pamapimod, metabolic synthetic standards, and the internal standard were supplied by Roche. METHODS: This was an open-label, singledose mass balance study. Healthy male subjects received a single oral dose of 300 mg [14C]-labeled pamapimod. Quantification of pamapimod and metabolites was determined by a validated liquid chromatography/tandem mass spectrometry method (LC/MS/ MS). Urine, blood, and feces were collected for metabolic profiling and radioactivity analysis. Profiling was done using high performance liquid chromatography (HPLC)/ LC/MS/MS. Radioactivity determination was by liquid scintillation counting. RESULTS: Six subjects completed the study. Mean Cmax was 4,120 ng/ml at tmax of 2.8 h, and mean AUCinf was 19,800 ng.h/ml. The t1/2 of pamapimod was 7.2 h. Mean drug recovery was 100 +/- 2% by 120 h, of which 76.5% was recovered in urine and 23.9% in feces. Unchanged pamapimod accounted for 15.3% excreta, indicating metabolism is the major elimination pathway. Five metabolites were identified in plasma, urine, and feces. In urine, 41.1% of the dose was excreted as carboxylate metabolite (RO4498496), 19.2% as lactol metabolite (RO4493992), and 12.5% as pamapimod. In feces, 18.5% was excreted as RO4498496, 2.8% as pamapimod. CONCLUSIONS: The majority of dose was renally cleared. Urinary and fecal metabolites accounted for > 80% radioactivity. These results indicate hepatic metabolism followed by renal excretion is the major elimination pathway of pamapimod. PMID- 21612742 TI - The influence of propiverine hydrochloride on cardiac repolarization in healthy women and cardiac male patients. AB - OBJECTIVE: Two comprehensively designed mono-centric ECG studies were performed to investigate the influence of propiverine hydrochloride and its main metabolite propiverine-N-oxide on cardiac function with regard to QTc prolongation, QTc dispersion and T-wave shape. METHODS: The first study was conducted on 24 healthy females, followed by a second study on 24 male patients with coronary heart disease (CHD) and a pathological Pardee-Q-wave in the ECG. Both studies were placebo-controlled and compared the effects of single (30 mg s.i.d.) and multiple dosing (15 mg t.i.d.) of propiverine hydrochloride in a crossover design over 6 and 13 days, respectively. In CHD patients, the ECG was recorded under standardized exercise stress conditions. RESULTS: An effect of propiverine on cardiac safety in healthy women and male patients with CHD could not be determined by the evaluation of QTc intervals derived from ECG under the following conditions: (1) single dosage; (2) steady-state and elevated dosage; (3) healthy female volunteers and male CHD patients; (4) resting and stress conditions in CHD patients. Moreover, other ECG parameters like QT dispersion, T wave shape, and U-wave occurrence were not affected by propiverine compared to placebo after single or repeated dosing to reach steady-state conditions. CONCLUSION: These results reflect and confirm preclinical data as well as clinical observations on hundreds of volunteers and numberless patients suffering from overactive bladder syndrome and neurogenic detrusor overactivity who were treated with propiverine hydrochloride over nearly three decades in Europe and Japan. PMID- 21612743 TI - Effects of bovine milk ingestion on urinary excretion of oxypurinol and uric acid. AB - OBJECTIVE: Although allopurinol is a xanthine oxidase inhibitor, its overall effect may be due to the action of oxypurinol, a metabolite of allopurinol and another xanthine oxidase inhibitor, since the biological half-life of oxypurinol is longer than that of allopurinol. Oxypurinol shares a renal transport pathway with uric acid and ingestion of bovine milk increases the urinary excretion of uric acid. Therefore, we investigated whether its ingestion promotes the urinary excretion of oxypurinol. SUBJECTS/METHODS: Bovine milk (15 ml/kg body weight) was administered to 6 healthy subjects who took allopurinol (300 mg) 12 h prior to ingestion. In addition, a control experiment was performed with the same subjects using the same protocol, except for the ingestion of water instead of bovine milk. Blood and urine samples were collected before and after bovine and water ingestion. RESULTS: In the bovine milk ingestion experiment, the urinary excretion values of oxypurinol and uric acid were increased by 18% and 38%, respectively, and the fractional excretion values of oxypurinol and uric acid were increased by 20% and 40%, respectively, whereas those did not change in the control experiment. In addition, the concentration of alanine and sum of concentrations of amino acids were increased by 16% and 20%, respectively, in the bovine milk ingestion experiment. CONCLUSION: These results suggest that bovine milk ingestion promotes the urinary excretion of oxypurinol as well as uric acid by increasing amino acid concentration. PMID- 21612744 TI - Population pharmacokinetics of amikacin in a Korean clinical population. AB - OBJECTIVE: This study aimed at investigating the influence of demographic and clinical covariates on the population pharmacokinetics of amikacin in Korean patients from routinely collected therapeutic drug monitoring data. MATERIALS AND METHODS: Pharmacokinetics was studied in 305 adult Korean patients who received amikacin 125 - 1,000 mg once-daily or every-other- day. Peak and trough plasma levels of steady state were measured. Patients were randomized into an index dataset (n = 197) and a validation dataset (n = 108). Covariates were selected in a step-wise approach using NONMEM 7 software. The predictive performance of the model was evaluated by the percent prediction error and the percent coverage of 95% population prediction interval. RESULTS: The covariates significantly influencing amikacin pharmacokinetics were creatinine clearance (p < 0.0001) and ward setting (p = 0.0017) for clearance, and body weight (p < 0.0001) and presence of cholecystitis (p = 0.0135) for volume of distribution. The estimates of pharmacokinetic parameters for a typical individual were 2.82 l/h for clearance, and 18.04 l for volume of distribution. Inter-individual variability (CV%) was 31% for clearance. The mean (SD) of percent prediction errors was 2.1 (26.4)% for peak and -121.5 (460.3)% for trough concentrations. Percent coverage of 95% PPIs for peak and trough concentrations were above 80%. CONCLUSIONS: The population pharmacokinetic model developed in this study may be used as a basis for finding optimal amikacin dosing in a Korean patient population without a significant bias. Further studies will be needed to validate these results. PMID- 21612745 TI - Tardive dyskinesia in the treatment of schizophrenia: the findings of the Research on Asian Psychotropic Prescription Pattern (REAP) survey (2001 - 2009). AB - OBJECTIVE: The aim of the study was to survey the frequency of tardive dyskinesia (TD) in patients with schizophrenia and its demographic and clinical correlates in selected Asian countries. METHOD: A total of 6,761 hospitalized schizophrenia patients in nine Asian countries and territories were examined from 2001 to 2009. TD was evaluated as "present" or "absent" according to the clinical judgment of experienced psychiatrists. The patients' socio-demographic and clinical characteristics and the prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. RESULTS: The frequency of TD in the whole sample was 5.0% with wide variations between countries (0 - 14.9%). Multiple logistic regression analysis showed that the following variables were independently associated with TD: study time, study site, older age, male gender, more severe negative and extrapyramidal symptoms and less anticholinergic drugs. CONCLUSIONS: A generally low frequency of TD in Asian schizophrenia patients with inter-ethnic variations was recorded. It is unclear whether the low prevalence of TD compared with Western data is real or the result of it being insufficiently recognized. PMID- 21612746 TI - Lack of pharmacokinetic and pharmacodynamic interactions of roflumilast with (R, S)-warfarin in healthy adult subjects. AB - Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved for the treatment of severe COPD. The pharmacological effect is mediated mainly by its active metabolite roflumilast N-oxide. OBJECTIVE: This doubleblind, 2-period cross-over study was conducted to investigate the potential effects of concomitant roflumilast on pharmacokinetics and pharmacodynamics of warfarin and vice versa. MATERIALS AND METHODS: A total of 24 healthy adults was enrolled into the study. Once-daily oral doses of roflumilast (500 MUg) or placebo were given for 12 days, with subjects receiving both treatments one after the other; single oral doses of (R,S)-warfarin (25 mg) were administered on Day 14 and Day 8 of both periods. Warfarin enantiomer concentrations, prothrombin time (PT), and clotting factor activity (Factor VII, only) as well as concentrations of roflumilast and roflumilast N-oxide were measured in plasma. RESULTS: There was no clinically relevant pharmacokinetic or pharmacodynamic interaction between warfarin and roflumilast. Exposure over 120 h (area under the curve, AUC0-120) with "Test" (warfarin plus roflumilast) and "Reference" (warfarin plus placebo) treatment for Factor VII (geometric mean ratio 102.1% (90% confidence interval: 99.7 - 104.7%)) and excess AUC0-120 for PT (99.3% (92.3 - 106.9%)) were unchanged. CONCLUSIONS: Pharmacokinetic parameters including maximum plasma concentration (Cmax) and AUC0-infinity of (R)-, (S)-warfarin, roflumilast, and roflumilast N-oxide were unaffected by co-administration. PMID- 21612747 TI - The negative impact of rebate contracts on the health care of patients with depression in Germany. AB - BACKGROUND: Aim of this study was to show the negative consequences of rebate contracts on health care of patients with depression. Negative consequences were defined as therapy withdrawal, increased resource utilization and the frequency of switch-back to initial pharmaceutical product in patients with conversion to a rebate pharmaceutical. METHODS: This retrospective analysis was performed combining the information of 3 databases including information about 20 millions patients and 80% of all prescriptions in Germany. The time period of observation started 1 year before the initiation of rebate contracts. Observation time was 2 years. This study included adults (> 18 years) with an antidepressive drug therapy and who had a statutory health insurance with rebate contracts on antidepressive pharmaceuticals. RESULTS: The mean persistence was 329 days for patients, who were switched to a rebate product compared to 365 days for patients who stayed on the initial drug therapy (p < 0.0001). 29.9% of the patients who were converted to a rebate product switched back to the initial antidepressive drug therapy within 1 year. 1,871 additional patients would be hospitalized due to the conversion to a rebate pharmaceutical that caused direct inpatient costs amounting to 19.9 million EUR per year in Germany. CONCLUSIONS: Despite the above limitations this analysis presents a clear association between the initiation of rebate contracts and a negative impact on health care of patients with an antidepressive drug therapy. PMID- 21612748 TI - Successful treatment of gallbladder neuroendocrine carcinoma with combined chemo radiotherapy: a case report and literature review. AB - Neuroendocrine tumors (NETs) occur in the bronchopulmonary system. Extrapulmonary NETs are rare and are considered to ac count for 2.5 - 5% of all NETs, with more than 60% of these tumors occurring along the gastro intestinal tract, including primary NET of the gall bladder. Pri mary NETs of the gall bladder have been classified as carcinoid, neuroendocrine carcinoma or heterogeneous carcinoma. Currently, the main treatment of neuroendocrine car ci noma re mains surgery. The role of radiotherapy and chemotherapy is undefined be cause of the paucity of data. In advanced cases, chemotherapy has been prescribed with such effective agents as cisplatin, carboplatin, etoposide and paclitaxel. Here we re port a case of a 64-year-old Taiwanese male patient with neuroendocrine carcinoma of the gall bladder who received combined chemoradiotherapy (CCRT) with cisplatin, 5- fluorouracil and leucovorin (PFL) from June 2009 un til now, and whose disease is stable. CCRT with PFL may be a possible reg i men for high-grade neuroendocrine carcinoma of the gall bladder. PMID- 21612749 TI - Comparative pharmacokinetics and bioequivalence of two tablet formulations of 2 mg risperidone in healthy Thai male volunteers. AB - BACKGROUND: Risperidone is an atypical antipsychotic drug with potent serotonin and moderate dopamine antagonistic properties. It possesses good bioavailability following oral administration. Risperidone is primarily converted by the cytochrome P450 2D6 (CYP2D6) and 3A4 (CYP3A4) enzymes to 9-hydroxyrisperidone, its active metabolite with equivalent potency to the parent compound. OBJECTIVE: This study aimed to compare the pharmacokinetics and determine bioequivalence of two risperidone immediate release oral tablets, a test formulation (Risperidone GPO(r) or "Test") and a reference formulation (Risperdal(r) or "Reference"). METHOD: A single-dose, randomized, fasting, 2-period, 2-sequence, crossover study design with a 2-week washout period was conducted in 23 healthy Thai male volunteers. Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 h following an oral administration of 2 mg risperidone. The plasma concentrations of risperidone and 9 hydroxyrisperidone were determined by using a validated HPLC method. Pharmacokinetic parameters of Test and Reference were obtained by noncompartmental analysis. RESULTS: The 90% confidence intervals for Test/Reference ratios of the pharmacokinetic parameters (Cmax, AUC0-t and AUC0 infinity) of both risperidone and its active metabolite (9-hydroxyrisperidone) fell within the acceptable bioequivalence range (80 - 125%) according to ASEAN guideline. CONCLUSION: The two risperidone formulations are bioequivalent. The test formulation may be used for generic substitution where applicable. PMID- 21612750 TI - Efficacy of sodium thiosulfate for the treatment for calciphylaxis. AB - BACKGROUND/AIMS: Calciphylaxis is a rare condition with dismal prognosis that affects patients with ESRD. Sodium thiosulfate (STS) may play a therapeutic role but its proposed efficacy is based on case reports and thus subject to publication bias. METHODS: We identified all patients who received STS for any indication over a 5-year period through pharmacy records of 4 hospitals, retrospectively reviewing medical records for risk factors, laboratory values, the response of skin lesions to STS, and mortality. RESULTS: 14 patients received STS for calciphylaxis over 5 years. Following STS administration, pain decreased in 71% of patients, and 70% had an improvement in their lesions. Those who did not improve or stabilize their skin lesions tended to have more advanced skin lesions, were on renal replacement therapy longer, were more obese and received less total dose of STS. However, despite STS, there was a 71% mortality rate, with 50% of subjects dying within 6 months. CONCLUSION: We conclude in this study of all subjects who received STS at our Institution that STS is an effective treatment for the pain and skin lesions of calciphylaxis if given in the early stages of disease and for a consistent period of time. However, there is little impact on overall mortality compared to historical published cohorts. PMID- 21612751 TI - The effect of immunosuppressive treatment on arterial stiffness and matrix Gla protein levels in renal transplant recipients. AB - INTRODUCTION: Arterial stiffness is a risk marker for cardiovascular events. In this study we aimed to compare the effect on calcineurin inhibitors (CNI) and mammalian Target of Rapamycine inhibitors (mTORi) on arterial stiffness in renal transplant patients. PATIENTS AND METHODS: 81 renal transplant patients under CNI based or mTORi-based protocol for at least 6 months were included in the study. Arterial stiffness was measured by using the SphygmoCor device (AtCor Medical, Sydney, Australia). Vitamin K-dependent, calcification inhibitor matrix Gla protein (MGP) concentrations were quantified by ELISA methods (Biomedica, Vienna, Austria). RESULTS: 34 patients were on mTORi-based and 47 on CNI-based immunosuppression. Mean age was 37.9 +/- 10.8 (18 - 71) years and 45% were female. Age, gender, graft functions and follow-up period of the groups were similar. Augmentation index was 15.2 +/- 12.6% in CNI and 18.8 +/- 14.0% in mTORi groups (p > 0.05). There was no difference regarding carotid-femoral pulse wave velocity between groups. Arterial stiffness was positively correlated with age, total cholesterol, LDL cholesterol, mean arterial pressure (MAP) and proteinuria. MGP levels were higher in the mTORi group but were not predictors for carotid femoral pulse wave velocity. CONCLUSION: Rather than specific immunosuppressive drug effects, conventional risk factors, blood pressure and proteinuria are the most important predictors for arterial stiffness in renal transplant patients. PMID- 21612752 TI - Epidemiology of hemodialysis vascular access in the United States. AB - Reemergence of the importance of vascular access in the care of the chronic hemodialysis patient has gained prominence due to renewed interest in clinical outcomes and evidence-based interventions. Further fueled by anticipated regulatory changes in the reimbursement for dialysis care in the United States by 2011 and beyond, the drive to improve quality of care for hemodialysis patients has identified vascular access issues as a key contributor to outcomes. Focus has shifted from simply providing any hemodialysis vascular access to a strong preference for the use of native arteriovenous fistulas and subsequently to a need for reducing exposure to central venous catheters. Combined, these goals have forced a reevaluation of the role of arteriovenous grafts. The context and events associated with the evolution of thinking on these issues as well as available data supporting them are discussed. The key leadership role of nephrologists is emphasized along with a summary of problems and proposed solutions. PMID- 21612753 TI - Fabry disease: results of the first UK hemodialysis screening study. AB - BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder in which deficiency of alpha-Galactosidase A (alpha-Gal A), leads to accumulation of glycosphingolipids in the vascular endothelium, kidneys and heart. Males with classical disease present in childhood, however some individuals with low levels of alpha-Gal A activity present atypically with adult onset renal impairment. Screening studies in patients with established end-stage renal failure (ESRF) suggest that up to 1.5% of patients have sub-normal alpha-Gal A levels. We used the dried blood spot (DBS) enzyme activity test to screen for undiagnosed Fabry disease in patients with ESRF. METHODS: Male hemodialysis patients treated at a single UK center (n = 155) were screened using the DBS assay. In patients with low enzyme activity on DBS, alpha-Gal A activity was assessed in plasma and leucocytes. RESULTS: 8 of the 155 (5%) patients screened showed low enzyme activity on the DBS assay. Confirmatory testing of plasma and leucocyte alpha-Gal A activity showed normal activity in all cases tested, indicating a false positive DBS result. CONCLUSIONS: This study is the first screening program in UK hemodialysis patients using the DBS test and did not identify any new cases of Fabry disease. In this cohort, the DBS enzyme assay had a false positive rate of 2.6%, emphasizing the need for validation with alternative techniques. PMID- 21612754 TI - Combination treatment with corticosteroid, cyclosporine A, and mycophenolate in refractory nephrotic syndrome. AB - BACKGROUND/AIMS: Refractory nephrotic syndrome (NS) is problematic because the optimal therapy for this disease is unclear and because persistent NS progresses eventually to end-stage renal disease. We report our experience using a combination of corticosteroid, cyclosporine A (CsA), and mycophenolate mofetil (MMF) to treat 10 refractory NS patients. METHODS: Ten refractory NS patients, who showed resistance to corticosteroid and CsA, were treated with triple immunosuppressive therapy. Cyclophosphamide and MMF had been used previously in 6 patients, but had failed to induce remission. RESULTS: Triple immunosuppressive therapy was discontinued after 4 months in 1 patient because of progressive azotemia. Partial remission was achieved in 9 of the 10 patients after 10 months, and remission was maintained during the treatment (urine protein to creatinine ratio, mg/mg, baseline vs. 12th month; 5.7 +/- 1.8 vs. 1.4 +/- 0.7). Renal function was preserved in these 9 patients (estimated GFR, ml/min/1.73 m2, baseline vs. 12th month; 71.4 +/- 29.1 vs. 68.9 +/- 31.5). Of the 7 patients who discontinued triple immunosuppressive therapy, remission and renal function were maintained in 4 patients. CONCLUSION: Triple immunosuppressive therapy significantly reduced proteinuria and preserved renal function in refractory NS patients, indicating a promising role of this therapy for refractory NS. PMID- 21612755 TI - Risk factors for chronic kidney disease among human immunodeficiency virus infected patients: A European case control study. AB - OBJECTIVES: Renal dysfunction is a common complication in human immunodeficiency virus (HIV)-infected patients and can be attributed to direct viral damage, comorbidities or drug toxicity. The aim of this study was to assess cross sectional correlates of renal damage in a contemporary European cohort of patients. METHODS: We performed a case-control study from our cohort of 750 HIV infected adults over a period of 5 months. We assessed renal damage by either proteinuria (>=+ on urine dipstick), reduced creatinine clearance (< 60 ml/min) or reduced estimated glomerular filtration rate (eGFR) of < 60 ml/ min/1.73 m2. The characteristics of cases and controls were compared in analysis and in multivariate logistic regression models with stepwise selection. RESULTS: Approximately 50% of the screened 106 patients had a qualifying abnormality. Altogether, we identified 55 cases with 110 age- and gender-matched controls. Mean eGFR was 90.7 (4.8) for cases vs. 106.1 (2.3) ml/min/1.73 m2 for controls (p = 0.001). Cases had a longer duration of HIV infection, more complex regimen, longer exposure to antiretroviral therapy and a more frequent diagnosis of acquired immune-deficiency syndrome (AIDS) and hepatitis C virus (HCV) infection. In the logistic multivariate model, renal damage remained significantly associated with longer known duration of HIV infection (OR 2.88, 95% CI: 1.28 - 6.46, p = 0.01), AIDS defining condition (OR 1.09 95% CI: 1.03 - 1.16, p = 0.002) female gender (OR 2.01, 95% CI: 0.96 - 4.18, p = 0.06), and HCV infection (OR 2.12, 95% CI: 0.99 - 4.52, p = 0.05). CONCLUSIONS: Duration, antiretroviral regimen and coincidental HCV impacted the frequency of renal abnormalities in our patients. PMID- 21612757 TI - Impact of short term use of interdialytic 60% ethanol lock solution on tunneled silicone catheter dysfunction. AB - INTRODUCTION: Ethanol lock (EL) is used to reduce catheter infections, but its impact on dialysis catheter dysfunction has not been studied. METHODS: We analyzed the rate of dialysis silicone catheter dysfunction after an interdialytic 60% EL in an open prospective controlled non crossover cohort study, with each patient being his or her own control. The study was divided into three consecutive 2-week periods: the pre- and post-intervention periods, in which interdialytic standard locks (SL) were used, and the intervention period, in which one EL was instilled during the first week, and two consecutively in the second week. We analyzed the rate of catheter dysfunction (exchange, use of fibrinolytic, reversing the lines, difficulty in instilling or withdrawing fluid) after EL or SL. RESULTS: In 30 patients, 90 EL were instilled. The rate of catheter dysfunction increased during the EL period (2 - 13%, p < 0.001), and between the two consecutive dialysis sessions before and after EL (p < 0.05). It decreased between the two consecutive dialysis sessions after EL and the following dialysis session after an SL (p < 0.05). No catheter was removed. The urea reduction ratio did not differ in dialysis after an SL and after an EL (0.77 vs. 0.73, p = 0.17). CONCLUSION: Short term EL is associated with a transient increase in catheter dysfunction, without resulting in catheter removal or decreasing dialysis efficiency. PMID- 21612756 TI - Anemia, inflammation and health-related quality of life in chronic kidney disease patients. AB - BACKGROUND: There is controversy regarding whether an incremental increase in hemoglobin levels is associated with improvements in health-related quality of life (HRQOL) in chronic kidney disease (CKD) patients treated with erythropoiesis stimulating agents (ESAs). We hypothesized that HRQOL in anemic CKD patients has a multifactorial etiology, including the effects of anemia and inflammation. METHODS: 69 non-dialysis CKD patients over 18 years of age with a mean estimated glomerular filtration rate (eGFR) of 43.7 +/- 28.8 ml/min/1.73 m2 were divided into anemic and non-anemic cohorts. Kidney disease quality of life (KDQOL) was prospectively recorded using Short Form (SF)-36 components of KDQOL-SF-TM version 1.3 questionnaire. Inflammation was assessed by using a composite of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha levels in the upper two quartiles. RESULTS: Anemic patients had significantly worse SF-36 components of KDQOL-SF-TM version 1.3, including SF-12 mental component (p = 0.02), role emotional (p = 0.002) and physical function (p = 0.01) compared to patients without anemia. However, in multiple linear regression models, adjusted for GFR, age, gender and inflammatory markers including C-reactive protein (CRP), albumin, ferritin, IL-6, IL-8 and TNF-alpha, anemia predicted mental components of SF-36 (SF-12 mental component (p = 0.02) and role emotional (p = 0.04)) but not physical components (SF-12 physical component (p > 0.05) and physical function (p > 0.05), supporting the multifactorial nature of reduced HRQOL in anemic patients. CONCLUSIONS: Reduced HRQOL in anemic patients is likely related to both anemic and inflammatory status. Prospective studies will be needed to evaluate whether modulating the inflammatory state independent of changes in the hemoglobin concentration improves physical components of HRQOL. PMID- 21612758 TI - Early-onset of disseminated cryptococcal infection in two renal transplant recipients. AB - Cryptococcosis is the third most common invasive fungal infection in organ transplant recipients after candidiasis and aspergillosis. Newly acquired and reactivation of latent infection are the major causes of infection, with typical later-onset and mainly as disseminated infection. The type and intensity of immunosuppression, diabetes mellitus and other co-morbidities as well as uremia seem to be important determinants on clinical presentation and outcome. Moreover, the diagnosis is not always apparent since it usually presents subacutely, as well as mimicking bacterial infections, which may be responsible for a delay in the diagnosis. Thus, a high degree of suspicion and need of invasive procedures for microbiological and histological evaluation are critical for definitive diagnosis and prompt institution of adequate treatment. We report two cases of disseminated cryptococcosis with different presentations and with an early-onset after renal transplantation. PMID- 21612759 TI - Giant ureteral stone in a patient with a single functioning kidney: a case report. AB - A 43-year-old man presented with long-standing left flank pain. A plain abdominal radiograph and intravenous urography (IVU) revealed a giant ureteral stone measuring 6.2 * 2.2 cm causing ureteral obstruction. A non-enhanced computerized tomography (CT) scan showed a significantly atrophied right kidney and left hydronephroureterosis with a giant stone. A left transperitoneal laparoscopic ureterolithotomy was performed with excellent results. PMID- 21612760 TI - Glomerulonephritis emerging shortly after Puumala hantavirus infection: a report on 7 patients. AB - AIMS: Nephropathia epidemica (NE) is mild type of hemorrhagic fever caused by Puumala (PUU) hantavirus. Renal biopsy typically shows acute tubulointerstitial nephritis and complete recovery is the usual outcome. We previously described 5 patients with membranoproliferative glomerulonephritis (MPGN) after acute NE. We now report on 7 more patients who developed biopsy-confirmed glomerulonephritis (GN) during the convalescent phase of NE. MATERIAL AND METHODS: We present case histories of 7 patients with nephrotic-range proteinuria concomitant with hematuria after serologically verified NE. RESULTS: Renal biopsy specimens disclosed MPGN in 5 patients, membranous GN (MGN) in 1 and mesangial GN (MesGN) in 1. All patients achieved remission of nephrotic syndrome within a median time of 0.6 years (range 0.5 - 5.5 y). The median follow-up time was 1.7 years (0.7 - 15.6 y). CONCLUSIONS: As a rare phenomenon, nephrotic syndrome may emerge during the convalescent phase of acute PUU hantavirus infection. In most cases the prognosis of GN caused by NE seems to be favorable. PMID- 21612761 TI - Purple urine bag syndrome: case report and literature review. AB - Purple urine bag syndrome (PUBS) is a medical syndrome in which there is purple discoloration of the urine of catheterized patients as well as discoloration of the collecting bag and the associated tubing. This rare condition, which mostly affects women, is generally associated with catheter-associated urinary tract infection, chronic constipation and alkaline urine. PUBS may be caused by sequential chemical reactions involving tryptophan from food in the gastrointestinal tract. The clinical course of PUBS is generally benign, and intensive treatment is not usually needed. We present 3 cases of this unusual and interesting phenomenon and a literature review. PMID- 21612762 TI - Massive venous thrombosis of inferior vena cava as primary manifestation of renal Ewing's sarcoma. AB - We report an extraordinarily rare case of a 17-year-old male with an extraskeletal Ewing's sarcoma (ESS) of the kidney and a massive thrombosis involving the inferior vena cava (IVC), from the iliac axis to the right atrium. This onset resembled renal cell carcinoma (RCC), although histological examination revealed it was an extraskeletal Ewing's sarcoma/peripheral neuro ectodermal tumor (EES/PNET). EES/PNET should benefit from neoadjuvant chemotherapy to reduce the risk of metastasis and of recurrent disease due to delay in suitable treatment. Therefore, in the presence of a renal mass with tumor extension of IVC, it is reasonable to bear in mind that other tumors, apart from RCC, could occur. In such cases, a US or CT-scan guided biopsy could be useful. PMID- 21612763 TI - Re: Four cases of postrenal renal failure induced by renal stones associated with rotavirus infection. PMID- 21612764 TI - A mouse muscle-adapted enterovirus 71 strain with increased virulence in mice. AB - Enterovirus 71 (EV71) infections can usually cause epidemic hand, foot, and mouth disease (HFMD), and occasionally lead to aseptic meningitis, encephalitis, and polio-like illness. Skeletal muscles have been thought to be crucial for the pathogenesis of EV71-related diseases. However, little is known about the virulence of mouse muscle-adapted EV71. The EV71 0805 were subjected to four passages in the mouse muscle to generate a mouse-adapted EV71 strain of 0805a. In comparison with the parental EV71 0805, the mouse muscle-adapted EV71 0805a displayed stronger cytotoxicity against Rhabdomyosarcoma (RD) cells and more efficient replication in RD cells. Furthermore, infection with the EV71 0805a significantly inhibited the gain of body weight, accompanied by increased muscle virus load and multiple tissue distribution in the infected mouse. Histological examinations indicated that infection with the EV71 0805 did not cause obvious pathogenic lesions in mice, while infection with the muscle-adapted 0805a resulted in severe necrotizing myositis in the skeletal and cardio muscles, and intestinitis in mice on day 5 post infection. Further analysis revealed many mutations in different regions of the genome of mouse muscle-adapted virus. Collectively, these data demonstrated the mouse muscle-adapted EV71 0805a with increased virulence in mice. PMID- 21612765 TI - Chlamydia-related bacteria in respiratory samples in Finland. AB - Chlamydia-related bacteria, new members of the order Chlamydiales, are suggested to be associated with respiratory disease. We used real-time PCR to investigate the prevalence of Parachlamydia acanthamoebae, Protochlamydia spp., Rhabdochlamydia spp., Simkania negevensis and Waddlia chondrophila in samples taken from patients with suspected respiratory tract infections. Of the 531 samples analyzed, the subset of 136 samples contained 16 (11.8%) samples positive for Rhabdochlamydia spp. DNA. P. acanthamoebae, Protochlamydia spp., S. negevensis and W. chondrophila DNA were not detected among the respiratory samples investigated. These results suggest an association of Rhabdochlamydia spp. with respiratory disease. PMID- 21612766 TI - Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and typhoid susceptibility in Asian Malay population in Malaysia. AB - Typhoid fever is a major health problem with frequent outbreaks in Kelantan, Malaysia. Prevalence of TLR4 gene polymorphisms varies with ethnic groups (0-20%) and predisposean individual to gram-negative infections. The prevalence rate of TLR4 Asp299Gly and Thr399lle polymorphisms in the Malay population or the influence of these on typhoid fever susceptibility is not yet reported. 250 normal and 304 susceptible Malay individuals were investigated for these polymorphisms using allele-specific PCR and analysed for its association with typhoid fever susceptibility. The total prevalence of polymorphisms in the normal population was 4.8% in comparison to 12.5% in the susceptible population (p = 0.002). An increased frequency of both polymorphisms was observed in the susceptible population (p < 0.01) with no homozygous mutants observed. Co segregation was observed in 2% of controls and 3.6% of the susceptible individuals. This study, for the first time, reports the prevalence of TLR4 gene polymorphisms in the Malay population and suggests that these polymorphisms confer a higher risk for typhoid, infection. The higher incidence of typhoid fever in Kelantan could be attributed to the higher percentage of Malays (95%) in this state. In order to reduce the incidence of this disease, people with these polymorphisms, can be prioritised for prophylactic strategies. PMID- 21612767 TI - Xerostomia and salivary flow in patients with orofacial pain compared with controls. AB - OBJECTIVES: Pain in the orofacial region is frequently reported by patients in dental and medical offices. Facial pain, headache, masticatory abnormalities and other complaints often become chronic and may be associated with local disturbances, such as xerostomia and teeth abnormalities. The objective of this study was to investigate salivary flow and xerostomia in patients with orofacial pain. DESIGN: This was a case-control study; we evaluated 82 patients with chronic orofacial pain compared with 56 healthy subjects using a Clinical Pain Questionnaire (pain characteristics, duration, intensity and descriptors), complete dental examination (including static and dynamic evaluation of the jaw) and a Xerostomia Inventory. The salivary flow was quantitatively evaluated. Data was compared through Pearson's chi-square, Fisher's exact, analysis of variance (ANOVA) 1 factor and Mann-Whitney tests. RESULTS: Patients often had temporomandibular disorder (TMD) (P=0.001) and pain during facial (P<0.001) and neck palpation (P=0.002). There were no differences in dental examination or other structural aspects of the jaw between the groups. There were more complaints associated with xerostomia in the study group, including burning sensation in the oral mucosa (P=0.003), in the throat (P=0.035) and in the stomach (P=0.050). Patients had lower salivary flow (P=0.008). CONCLUSIONS: Orofacial pain patients need to be evaluated with regard to their salivary function, which was often found abnormal in this sample and may have contributed to the complaints of these patients. Assessing salivary flow and xerostomia may help in the treatment of chronic orofacial pain. PMID- 21612769 TI - The brainstem preproglucagon system in a non-human primate (Macaca mulatta). AB - The nucleus of the solitary tract (NTS) contains a small population of neurons expressing preproglucagon. In these neurons preproglucagon is processed to the glucagon-like-peptides 1 and 2 (GLP-1 and GLP-2) and oxyntomodulin. Whereas the neuroanatomy of these neurons is well characterized in rodents the location and projection of preproglucagon neurons have never been described in primates. The purpose of the present study was to characterize the location of preproglucagon neurons and their projections in the non-human primate using radioactive in situ hybridization and immunohistochemistry. In situ hybridization revealed preproglucagon mRNA expressing neurons in the caudal nucleus of the solitary tract extending laterally through the intermediate reticular nucleus into the A1 area. Using an antibody raised against rat GLP-2, GLP-2-immunoreactive (-ir) cell bodies were found in the same areas as the preproglucagon mRNA. Only very few GLP 2-ir nerve fibers were observed in the caudal brainstem and mostly in the same areas as the GLP-2-ir cell bodies. The most prominent GLP-2-ir terminal fields were detected in the hypothalamus and rostrally in the bed nucleus of the stria terminalis complex. In the hypothalamus, GLP-2-ir fibers arborized extensively in the paraventricular nucleus of the hypothalamus (PVN), the dorsomedial hypothalamic nucleus (DMH) and the arcuate nucleus (Arc), the latter containing the densest fiber-plexus. The findings indicate that the brainstem preproglucagon neuronal system is highly conserved between rat and non-human primate with the exception of a much denser innervation of the mediobasal hypothalamus in the primate brain. PMID- 21612768 TI - Unique brain areas associated with abstinence control are damaged in multiply detoxified alcoholics. AB - BACKGROUND: The ability to abstain from drinking, despite incentives to imbibe, is essential to recovery from alcoholism. METHODS: We used an incentive conflict task to investigate ability to abstain from responding during presentations of incentive cues. Both alcoholic (n = 23) and healthy subjects (n = 22) were required to withhold responding during the simultaneous presentation of two visual stimuli in which the individual presentation allowed responding for monetary reward. Brain structures activated during performance of the task were studied using functional magnetic resonance imaging in healthy volunteers (n = 8), and changes in gray matter volume were studied in a separate group of patients (n = 29) compared with control subjects (n = 31) in regions of interest identified on functional magnetic resonance imaging. RESULTS: Abstinent alcoholic patients were severely impaired on the incentive conflict task. The impairment was greater in patients with experience of several versus a single detoxification. Healthy volunteers, during the same incentive conflict task, showed distinct patterns of brain activation (including gyrus rectus, ventromedial prefrontal cortex, and superior frontal gyrus). Reduction of gray matter volume in ventromedial prefrontal cortex and superior frontal gyrus of patients was more extensive in those with multiple detoxifications. CONCLUSIONS: Performance deficits in alcoholics are associated with withdrawal-induced impairments in prefrontal subfields, which are exacerbated following repeated episodes of detoxification. Detoxification thus compromises functional and structural integrity of prefrontal cortex and may thus impair the ability to control future drinking. Performance in the incentive conflict task is a sensitive biomarker for such deficits. PMID- 21612771 TI - fMRI in disorders of consciousness: future diagnostic opportunities, methodological and legal challenges. PMID- 21612772 TI - Lack of semantic priming effects in famous person recognition in Mild Cognitive Impairment. AB - INTRODUCTION: Growing evidence indicates that individuals with Mild Cognitive Impairment (MCI) manifest semantic deficits that are often more severe for items that are characterized by a unique semantic and lexical association, such as famous people and famous buildings, than common concepts, such as objects. However, it is still controversial whether the semantic deficits observed in MCI are determined by a degradation of semantic information or by a deficit in intentional access to semantic knowledge. Here we used a semantic priming task in order to assess the integrity of the semantic system without requiring explicit access to this system. This paradigm may provide new insights in clarifying the nature of the semantic deficits in MCI. METHODS: We assessed the semantic and repetition priming effect in 13 individuals with MCI and 13 age-matched controls who engaged in a familiarity judgment task of famous names. In the semantic priming condition, the prime was the name of a member of the same occupation category as the target (Tom Cruise-Brad Pitt), while in the repetition priming condition the prime was the same name as the target (Charlie Chaplin-Charlie Chaplin). RESULTS: The results showed a defective priming effect in MCI in the semantic but not in the repetition priming condition. Specifically, when compared to controls, MCI patients did not show a facilitation effect in responding to the same occupation prime-target pairs, but they showed an equivalent facilitation effect when the target was the same name as the prime. CONCLUSION: The present results provide support to the hypothesis that the semantic impairments observed in MCI cannot be uniquely ascribed to a deficit in intentional access to semantic information. Instead, these findings point to the semantic nature of these deficits and, in particular, to a degraded representation of semantic information concerning famous people. PMID- 21612773 TI - The role of mood and personality in the perception of emotions represented by music. AB - Neuroimaging studies investigating the processing of emotions have traditionally considered variance between subjects as statistical noise. However, according to behavioural studies, individual differences in emotional processing appear to be an inherent part of the process itself. Temporary mood states as well as stable personality traits have been shown to influence the processing of emotions, causing trait- and mood-congruent biases. The primary aim of this study was to explore how listeners' personality and mood are reflected in their evaluations of discrete emotions represented by music. A related aim was to investigate the role of personality in music preferences. An experiment was carried out where 67 participants evaluated 50 music excerpts in terms of perceived emotions (anger, fear, happiness, sadness, and tenderness) and preference. Current mood was associated with mood-congruent biases in the evaluation of emotions represented by music, but extraversion moderated the degree of mood-congruence. Personality traits were strongly connected with preference ratings, and the correlations reflected the trait-congruent patterns obtained in prior studies investigating self-referential emotional processing. Implications for future behavioural and neuroimaging studies on music and emotions are raised. PMID- 21612774 TI - Adenoma detection rate increases with each decade of life after 50 years of age. AB - BACKGROUND: The adenoma detection rate (ADR) has recently been used as a quality measure for screening colonoscopy. We hypothesize that the ADR will increase with each decade of life after 50 years of age. OBJECTIVE: The aim of this study was to define age-based goals for the ADR and advanced neoplasia to improve the quality of colonoscopy. METHODS: Using the Clinical Outcomes Research Initiative database, we identified patients who underwent screening colonoscopy between 2005 and 2006. Pathology of polyp findings was reviewed, and the ADR and the prevalence of advanced neoplasia were calculated based on age and sex. RESULTS: A total of 7756 polypectomies (44.9%) were performed on 17,275 patients between 2005 and 2006. Of these polyps, 56.3% (4363) were adenomas or more advanced lesions. The ADR was higher in men than women and increased with age. The ADR in men younger than age 50 was 24.7 (95% CI, 18.2-31.2); for those 50 to 59 years of age, it was 27.8 (95% CI, 26.5-29.1); for those 60 to 69 years of age, it was 33.6 (95% CI, 31.7-35.4); for those 70 to 79 years of age, it was 34.3 (95% CI, 31.5-37.1); and for those older than 80 years of age, it was 40.0 (95% CI, 32.9 47.1). The ADR in women younger than 50 years old was 12.6 (95% CI, 6.8-18.4); in those 50 to 59 years of age, it was 17.0 (85% CI, 15.9-18.1); for those 60 to 69 years of age, it was 22.4 (95% CI, 20.8-24.0); for those 70 to 79 years of age, it was 26.1 (95% CI, 23.7-28.5); and for those older than 80 years of age, it was 26.9 (95% CI, 21.4-32.5). LIMITATIONS: The Clinical Outcomes Research Initiative database offers access to demographic information as well as endoscopy and pathology data, but there is limited clinical information about patients in the database. CONCLUSION: The ADR, and, importantly, the rate of advanced neoplasia increased with each decade of life after the age of 50 and are higher in men than women in each decade of life. PMID- 21612775 TI - Endoscopic biliary recanalization by using a needle catheter in patients with complete ligation or stricture of the bile duct: safety and feasibility of a novel technique (with videos). PMID- 21612776 TI - Benefit of a clipping device in use in intestinal bleeding and intestinal leakage. AB - BACKGROUND: The over-the-scope clip (OTSC) system was first used to close the access route in natural orifice transluminal endoscopic surgery and is increasingly used for other indications. OBJECTIVE: We analyzed the use of the OTSC in intestinal bleeding and in closure of GI tract leaks. DESIGN: Analysis of a consecutive series of patients. SETTING: University hospital. PATIENTS: Nineteen patients (group A: closure of GI leak site, n = 12; group B: complex GI bleeding, n = 7) were retrospectively enrolled in this study. We analyzed outcome and follow-up (6-68 weeks; group A: mean 37 weeks, standard deviation 24) in terms of treatment success (closure of the GI tract leak/durable hemostasis). INTERVENTION: Endoscopic application of OTSCs. MAIN OUTCOME MEASUREMENTS: Resolution of leaks, closure of fistula (group A), or stopping bleeding (group B). RESULTS: In group A, durable closure was achieved in 8 of 12 patients. Sealing a postoperative/postinterventional leak was successful in 6 patients and failed in 3. A gastrocutaneous fistula was primarily closed successfully in 2 patients, but recurred in 1 of these patients. A gastric wall dehiscence in necrotizing pancreatitis was successfully closed in another patient. Group B patients had previous endoscopic treatment failure in 4 of 7 patients (through the-scope clips, injection of Suprarenin or fibrin glue, others) and were deemed not treatable by through-the-scope clips in 3 of 7 patients. The primary success rate was 100% (7 of 7 patients); durable hemostasis was achieved in 4 of 7 patients, whereas surgery or angiography was necessary in the remaining patients. LIMITATIONS: Retrospective analysis. CONCLUSIONS: Leaks and fistulae are reliably closed with OTSCs in tissue flexible enough to be sucked into the attached cap (eg, in lesions caused <1 week before). GI bleeding may be stopped by OTSCs with reliable transient hemostasis, but durable hemostasis is less frequent. PMID- 21612777 TI - Ectopic varices. PMID- 21612778 TI - Multiple transluminal gateway technique for EUS-guided drainage of symptomatic walled-off pancreatic necrosis. AB - BACKGROUND: Walled-off pancreatic necrosis often leads to severe clinical deterioration necessitating open debridement or endoscopic necrosectomy. A new EUS-based approach was devised to manage this condition by creating multiple transluminal gateways to facilitate effective drainage of the necrotic contents. OBJECTIVE: To compare treatment outcomes between patients with walled-off pancreatic necrosis managed endoscopically by a multiple transluminal gateway technique (MTGT) or a conventional drainage technique (CDT). DESIGN: Retrospective study. SETTING: Tertiary-care referral center. PATIENTS: This study involved patients with severe acute pancreatitis complicated by walled-off pancreatic necrosis managed endoscopically. INTERVENTION: In MTGT, 2 or 3 transmural tracts were created by using EUS guidance between the necrotic cavity and the GI lumen. While one tract was used to flush normal saline solution via a nasocystic catheter, multiple stents were deployed in others to facilitate drainage of necrotic contents. In the CDT, two stents with a nasocystic catheter were deployed via 1 transmural tract. MAIN OUTCOME MEASUREMENTS: Resolution of symptoms, radiological findings on follow-up CT, and the need for subsequent surgery or endoscopic necrosectomy. RESULTS: Of 60 patients with symptomatic walled-off pancreatic necrosis, 12 (3 women, mean age 55.1 years) were managed by MTGT and 48 (12 women, mean age 55.2 years) by CDT. Treatment was successful in 11 of 12 (91.7%) patients managed by MTGT versus 25 of 48 (52.1%) managed by CDT (P = .01). Although 1 patient in the MTGT cohort required endoscopic necrosectomy, in the CDT cohort, 17 required surgery, 3 underwent endoscopic necrosectomy, and 3 died of multiple-organ failure. Treatment success was more likely for patients treated by MTGT than by CDT (adjusted odds ratio = 9.24; 95% confidence interval, 1.08-79.02; P = .04) when we adjusted for the size of the walled-off pancreatic necrosis and pancreatic duct stent placement. LIMITATIONS: Selective patient population. CONCLUSION: The EUS-guided MTGT is an effective treatment option for the management of symptomatic walled-off pancreatic necrosis because it obviates the need for surgery and endoscopic necrosectomy and its attendant procedure-related morbidity. Prospective studies are required to confirm these preliminary but promising data. PMID- 21612779 TI - Injuries sustained in noncombat motor vehicle accidents during Operation Iraqi Freedom. AB - OBJECTIVE: To examine injuries sustained in noncombat motor vehicle accidents (MVAs) during Operation Iraqi Freedom by injury type, site, and severity. METHODS: Three hundred and forty-eight military personnel injured in noncombat MVAs from March 2004-June 2007 were identified from clinical records completed near the point of injury. RESULTS: On average, personnel suffered two injuries per accident. The most frequent MVA mechanism was non-collision due to loss of control (30%). Overall, 16% were injured in a collision accident and 19% in a rollover accident. Rollovers were associated with more severe injuries. A greater proportion of drivers sustained head/neck/face injuries, whereas gunners and pedestrians had higher percents of extremity injuries. CONCLUSIONS: This analysis provides a thorough overview of injuries incurred in nonbattle MVAs in the combat environment. Future research should combine injury data with accident reports to elucidate areas for improvements in vehicle safety. PMID- 21612780 TI - SR-PSOX at sites predisposed to atherosclerotic lesion formation mediates monocyte-endothelial cell adhesion. AB - OBJECTIVE: The scavenger receptor SR-PSOX/CXCL16, which is identical to the chemokine CXCL16, is thought to be involved in atherogenesis. However, the presence and function of SR-PSOX/CXCL16 in the endothelium of atherosclerotic arteries has not been substantiated. METHODS AND RESULTS: In rabbit aorta immunocytochemistry revealed SR-PSOX/CXCL16 primarily in the endothelium at sites predisposed to lesion formation, in the endothelium of early atherosclerotic lesions, and mainly in intimal macrophages of more developed lesions, indicating that SR-PSOX/CXCL16-expression shifts during atherogenesis. In addition to its function as scavenger receptor and chemokine, SR-PSOX mediated the adhesion of THP-1 monocytes to endothelial cells in vitro. Both THP-1 monocytes and endothelial cells express SR-PSOX/CXCL16, and THP-1 monocytes express CXCR6, the specific receptor for SR-PSOX/CXCL16. Anti-SR-PSOX/CXCL16 and anti-CXCR6 antibody block monocyte adhesion, showing that SR-PSOX/CXCL16-CXCR6 interaction mediates monocyte-endothelial cell adhesion. SR-PSOX/CXCL16 expression of endothelial cells is upregulated by pro-inflammatory cytokines, and is reversed by incubation with ciglitazone and lovastatin. CONCLUSIONS: We suggest that SR-PSOX/CXCL16 may promote the adhesion of monocytes to the endothelium during early atherogenesis and that accumulating cytokines enhance SR-PSOX/CXCL16-mediated adhesion by upregulating SR-PSOX/CXCL16 expression. Manipulation of SR-PSOX/CXCL16 expression with anti-inflammatory agents may be of therapeutic value. PMID- 21612781 TI - The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation provides a better definition of cardiovascular burden associated with CKD than the Modification of Diet in Renal Disease (MDRD) Study formula in subjects with type 2 diabetes. AB - OBJECTIVE: The chronic kidney disease (CKD)-Epidemiology Collaboration (EPI) equation was shown to be more accurate than the Modification of Diet in Renal Disease (MDRD) Study formula for estimating glomerular filtration rate (GFR) in the general population. This study was aimed at assessing cardiovascular disease (CVD) burden associated with CKD in type 2 diabetes, using these two GFR estimating formulas for CKD definition. METHODS: This cohort study examined 15,773 Caucasian patients with type 2 diabetes participating in the Renal Insufficiency And Cardiovascular Events Italian Multicenter Study (NCT00715481) and attending the baseline visit in 19 diabetes clinics in years 2007-2008. Serum creatinine was assessed by the modified Jaffe method. Albuminuria was measured by immunonephelometry or immunoturbidimetry. CKD was defined as an estimated GFR (eGFR) <60 mL/min/1.73 m(2) and/or micro/macroalbuminuria. RESULTS: Prevalence of impaired eGFR and CKD decreased from 18.7% to 17.2% (P=0.0012) and from 37.5% to 36.3% (P=0.077), respectively, with the CKD-EPI, as compared with the MDRD Study equation. Subjects with impaired eGFR or CKD with the MDRD Study equation only showed lower CVD prevalence rates and coronary heart disease risk scores, mainly driven by prevailing female sex, younger age and shorter diabetes duration, as compared with those with both formulas, whereas opposite figures were observed in patients falling into these categories with the CKD-EPI equation only. CONCLUSIONS: Estimating GFR in patients with type 2 diabetes using the CKD-EPI equation provides a better definition of CVD burden associated with CKD not only in individuals reclassified upward, but also in those reclassified downward. PMID- 21612782 TI - Solvation parameters. Part 5: physicochemical interpretation of experimental solvent values for stationary phases of gas-liquid chromatography. AB - It has been demonstrated for a long time that in the particular case of gas liquid chromatography (GLC), a linear free energy relationship (LFER) of five terms can be established, each term including a parameter of solute and a parameter of solvent. The nature of some of these parameters has been quite clearly identified, even if not always well predicted from the molecular structure. First of all, the five solute parameters: two involved in the hydrogen bonding and three in the Van der Waals forces; secondly, the two solvent parameters involved in hydrogen bonding. It was remaining an uncertainty concerning the nature of the solvent parameters named D, W and E, respectively associated with the solute parameters of dispersion, orientation and induction/polarizability. This uncertainty has been solved using experimental chromatographic data of McReynolds (56 phases) and of the Kovats group (11 phases). The parameter W appears as of polar nature strictly speaking. The parameters D and E can be expressed by two opposite bilinear functions of 1/V (inverse of molecular volume) and PSA/V (ratio of the polar surface area over the molecular volume). These results are in agreement with previous studies limited to alkanes by the Kovats group. PMID- 21612783 TI - Developing counter current chromatography to meet the needs of pharmaceutical discovery. AB - Experiments have been carried out to evaluate Counter Current Chromatography (CCC) as an alternative purification technique to preparative Reverse Phase High Performance Liquid Chromatography (RP-HPLC) for small molecule pharmaceuticals. The major drawback of CCC is the extensive time required in selecting the solvents to perform the separation. This is equivalent to choosing both the stationary phase and the mobile phase at the same time. In RP-HPLC it is a simple matter of deciding on the gradient, most samples can be purified on a C18 column with a water:acetonitrile gradient. The majority of the initial work was based on a standard test set of commercially available compounds, developed within our group to evaluate the performance of the HPLC apparatus and the column prior to the start of work each day. The work carried out on CCC has shown that the technique offers similar capabilities and can be carried out using similar protocols to RP-HPLC. CCC also has some advantages over RP-HPLC and can be regarded as a valuable addition to the chromatography toolbox. PMID- 21612784 TI - Detection of heterogeneous drug-protein binding by frontal analysis and high performance affinity chromatography. AB - This study examined the use of frontal analysis and high-performance affinity chromatography for detecting heterogeneous binding in biomolecular interactions, using the binding of acetohexamide with human serum albumin (HSA) as a model. It was found through the use of this model system and chromatographic theory that double-reciprocal plots could be used more easily than traditional isotherms for the initial detection of binding site heterogeneity. The deviations from linearity that were seen in double-reciprocal plots as a result of heterogeneity were a function of the analyte concentration, the relative affinities of the binding sites in the system and the amount of each type of site that was present. The size of these deviations was determined and compared under various conditions. Plots were also generated to show what experimental conditions would be needed to observe these deviations for general heterogeneous systems or for cases in which some preliminary information was available on the extent of binding heterogeneity. The methods developed in this work for the detection of binding heterogeneity are not limited to drug interactions with HSA but could be applied to other types of drug-protein binding or to additional biological systems with heterogeneous binding. PMID- 21612785 TI - Surface properties and liquid crystal alignment behavior of poly(2-hydroxyethyl methacrylate) derivatives with alkyl ester side chains. AB - Poly(2-hydroxyethyl methacrylate) derivatives with amphiphilic side chains composed of polar ester and non-polar alkyl groups (PHEMA#C, #=9, 11, 13, 15, and 17), where # is the number of carbon atoms in the alkyl side groups, were synthesized. In this paper, the influence of ester and alkyl groups on the molecular structure and wettability of the polymers were studied through varying # in the alkyl side groups. PHEMA#Cs with relatively longer alkyl side groups (#>=15) show bilayer lamellar structures with well aligned side chains giving rise to the very low surface energies, calculated from advancing contact angles, in the range of 22.7-22.8 mN/m. In contrast, PHEMA#Cs with shorter alkyl side groups with #<=13 have disordered structures on the polymer surfaces and stick slip behavior was observed when water was used as the test liquid for the advancing contact angle measurements. Furthermore, the alignment behavior of nematic liquid crystal, 5CB on the PHEMA#C films could be correlated with the molecular structure and wettability of the polymers. PMID- 21612786 TI - Transport behavior of humic acid-modified nano-hydroxyapatite in saturated packed column: effects of Cu, ionic strength, and ionic composition. AB - The surfaces of nano-hydroxyapatite (nHAP) used for contaminated soil and groundwater remediation may be modified to render nHAP highly mobile in the subsurface. Humic acid (HA) is widely used to modify and stabilize colloid suspensions. In this work, column experiments were conducted to determine the effects of contaminant (e.g., Cu) concentration, ionic strength (IS), and ion composition (IC) on the transport behavior of HA-modified nHAP in saturated packed columns. IS and nature of the cation had strong effects on the deposition of nHAP, and the effect was greater for divalent than for monovalent cations. Divalent cations have a greater capacity to screen the surface charge of nHAP, and Ca(2+) bridges the HA-modified nHAP colloidal particles, which causes greater deposition. Moreover, Cu(2+) had a greater effect on the transport behavior than Ca(2+) due to their strong exchange with Ca(2+) of nHAP and its surface complexation with nHAP. The relative travel distance L(T), of the injected HA modified nHAP colloids, ranges from less than one to several meters at varying Cu concentrations, ISs, and ICs in saturated packed columns. The results are crucial to evaluate the efficacy of nHAP on the remediation of contaminated soil and groundwater environments. PMID- 21612787 TI - Computer-based script training for aphasia: emerging themes from post-treatment interviews. AB - This study presents results of post-treatment interviews following computer-based script training for persons with chronic aphasia. Each of the 23 participants received 9 weeks of AphasiaScripts training. Post-treatment interviews were conducted with the person with aphasia and/or a significant other person. The 23 interviews yielded 584 coded comments that were categorized into ten themes. Five of the themes related to the communication behaviors of the participant, whereas the other five related to the computer program and study procedures. Examples of each theme are presented. The themes provide qualitative evidence of change and generalization, supporting the use of this computer-based script training program. PMID- 21612788 TI - The anatomical basis of bradycardia-tachycardia syndrome in elderly dogs with chronic degenerative valvular disease. AB - The hearts of seven elderly dogs in which bradycardia-tachycardia syndrome (BTS) had been diagnosed electrocardiographically were examined post mortem. The clinical basis of the underlying heart disease was invariably mitral or mitral and tricuspid regurgitation. Microscopical examination of the sinoatrial (SA) node and the SA junctional region consistently revealed depletion of SA nodal cells, with a corresponding increase in fibrous or fibro-fatty tissue that interrupted contiguity between the SA node and the surrounding atrial myocardium. The left and right atrial walls showed an increased amount of fibrous tissue in the myocardium and disruption of the muscle bundle architecture (interstitial myocardial fibrosis) to varying degrees. Qualitatively, these changes in the SA node and the SA node region resembled those associated with ageing in elderly people with or without BTS. Thus, it is possible that the pathological process affecting the SA node in these dogs was fundamentally related to ageing and may have caused BTS, in combination with atrial myocardial lesions caused by mitral and tricuspid regurgitation. PMID- 21612789 TI - Characterization of apoptosis pathways (intrinsic and extrinsic) in lymphoid tissues of calves inoculated with non-cytopathic bovine viral diarrhoea virus genotype-1. AB - Previous studies have shown that activation of effector caspase-3 is associated with the apoptosis of lymphocytes occurring during infection with bovine viral diarrhoea virus (BVDV); however, the regulation of the apoptosis pathways that induce cell death via activation of effector caspase-3 has not yet been clarified. The aim of this study was to examine immunohistochemically the expression of cleaved caspase (CCasp)-8 (initiator caspase of the extrinsic pathway), CCasp9 (initiator caspase of the intrinsic pathway) and Bcl-2 (an anti apoptotic marker) in gut-associated lymphoid tissue (GALT) of the ileum from calves inoculated with a non-cytopathic strain of BVDV genotype-1. CCasp8 had similar expression to that of CCasp3. In interfollicular T-cell areas there was moderate apoptosis and evidence of moderate activation of initiator caspase-8. In B-cell follicles there was marked lymphocyte apoptosis and evidence of intense caspase-8 activation, highlighting the potentially major role of the extrinsic pathway in lymphocyte apoptosis in the GALT during BVDV infection. Additionally, there was a significant decrease in the number of CCasp9(+) cells from the start of the experiment and this was linked to inactivation of caspase-9. Therefore, the intrinsic pathway may play only a minor role in the induction of lymphocyte apoptosis. Finally, the observed overexpression of Bcl-2 protein could play a major role in protecting lymphocytes in the T-cell areas against apoptosis, while low levels of Bcl-2 expression could be associated with the follicular lymphocyte apoptosis occurring during BVDV infection. PMID- 21612790 TI - Melanocytic tumour in a black sheep never exposed to ultraviolet radiation. AB - A slow growing skin tumour was identified on the head of a 6-year-old male Serra da Estrela black sheep. The animal had no previous history of exposure to ultraviolet radiation or illness. The tumour consisted of an irregular mass subdivided into two polypoid regions and there were small alternating pigmented and non-pigmented areas in the surrounding epidermis. Microscopical and immunohistochemical features were consistent with a melanocytic tumour of the melanocytoma type, without signs of vascular or perineural invasion. The tumour cells contained pigment stained by the Masson Fontana reaction, expressed S100 protein and vimentin and displayed a low proliferative rate (Ki67 labelling <1%). No metastases were found at the time of gross necropsy examination. Analyses of the homologous regions of the hot spot mutational exons of BRAF and NRAS (the genes that are most often mutated in human melanocytic tumours) did not reveal alterations, but there were silent polymorphic variations in these genes. No such variation was observed in the GNAQ gene sequence that is mutated in human melanocytomas. PMID- 21612791 TI - Ectopic origin of coronary arteries from the aorta in Syrian hamsters (Mesocricetus auratus). AB - An ectopic origin of the coronary artery from the aorta beyond the sinotubular junction, a condition commonly referred to as 'coronary artery high take-off', has been described in man and C57BL/6 mice. The present paper reports this congenital coronary artery anomaly in the Syrian hamster (Mesocricetus auratus). Hearts from 14 individuals, aged 53-350 days, were examined by means of a corrosion-cast technique, scanning electron microscopy or histological and immunohistochemical techniques. In 11 hamsters, the right coronary artery was the ectopic vessel. In the other three animals there was a solitary coronary ostium in the aorta. In all cases, the ectopic coronary artery originated at an acute angle and a valve-like ridge was in front of the coronary artery ostium. The ectopic arteries examined microscopically showed an intramural trajectory within the aortic wall. In the hearts with a solitary ostium in the aorta, the left main coronary artery coursed between the aorta and the pulmonary artery. In man, all of these anomalous conditions place the individual at risk of myocardial ischaemia and sudden death. However, none of the affected hamsters had clinical signs of disease. Intimal thickenings of increasing size with age were present in the intramural coronary artery segment of eight hamsters aged 106 days or older, examined histologically. The present findings fit with the notion that coronary arteries with acute angle take-off and an intramural course are subjected to unusual wear and tear, leading to tissue changes in the vessel wall. PMID- 21612792 TI - Nasal nitric oxide: diagnostic value and physiological significance in primary ciliary dyskinesia. PMID- 21612793 TI - Near-infrared multichannel Raman spectroscopy with a 1064 nm excitation wavelength for ex vivo diagnosis of gastric cancer. AB - BACKGROUND: Gastric cancer is one of the major causes of death in Japan. We have previously reported, using biopsy specimens, the usefulness of the 1064 nm near infrared multichannel Raman spectroscopy (RAS) system as a novel diagnostic modality for gastric cancer. However, our study might not have reflected in vivo use of RAS due to a lack of tissue other than the mucosal layer in the biopsy specimens. Here, we used RAS ex vivo for optical diagnosis of gastric cancer in surgically resected stomach. MATERIALS AND METHODS: A total of 213 Raman spectra were obtained from 12 cancer lesions and their corresponding non-neoplastic areas in 10 stomachs following resection for gastric cancer. To develop optical diagnostic systems for gastric cancer, principal component analysis (PCA) of all the Raman spectra was performed. RESULTS: The averaged Raman spectra of the cancer lesions could be distinguished from those of the non-neoplastic regions. Discrimination analysis of cancer from non-neoplastic regions with 10 principal components revealed that sensitivity, specificity, and accuracy of cancer diagnosis were 73%, 73%, and 72%, respectively. RAS discriminated between differentiated and undifferentiated cancers, early and advanced cancers, as well as T1a (M) and T1b (SM) cancers with high accuracy (98%, 93%, and 98%, respectively). CONCLUSIONS: The 1064 nm near-infrared multichannel RAS system is useful not only for gastric cancer detection, but also for discrimination between differentiated and undifferentiated, as well as early and advanced cancers. RAS could help establish indications for endoscopic treatment by eliminating cancer lesions with an undifferentiated component or submucosal invasion. PMID- 21612794 TI - Prolonged cold ischemia does not trigger lethal rejection or accelerate the acute rejection in two allogeneic rat liver transplantation models. AB - BACKGROUND: Prolonged cold ischemia (CI) might induce lethal liver graft rejection and/or accelerate the course of lethal rejection in BN-Lew and ACI-Lew liver transplantation (LT) models, which have been successfully challenged by liver-size reduction. MATERIALS AND METHODS: Survival rate of recipients and body weight development after subjecting the grafts to prolonged CI in saline were assessed. Severity of rejection was assessed based on histology and the size of portal infiltration. Hepatic expression of CD25, CD28, CD38, granzyme B, and perforin were assessed to further judge the severity of allogeneic immune response. RESULTS: An enhancement of allogeneic immune response after prolonged CI was observed, indicated by up-regulated mRNA expression of CD25, CD28, CD38, granzyme B, and perforin. However, the enhancement of allogeneic immune response did not reverse the BN-Lew spontaneous liver graft acceptance to lethal rejection. Eight-hour CI led to 100% 4 wk survival rate and graft acceptance and did not impair postoperative body weight recovery. Nine-hour CI caused the death of 2/6 rats due to primary non-function (PNF) of the graft within 48 h. Ten-hour CI caused lethal PNF in all rats within 96 h. Histology of surviving recipients revealed an expansion of the portal tract due to an inflammatory infiltrate. In rats dying from PNF, extended centrilobular necrosis was observed, but no sign of rejection. In the ACI-Lew full-size LT model, 8 h CI did not accelerate the course of lethal rejection. CONCLUSION: Prolonged CI was associated with an discrete enhancement of allogeneic immune response, but did not trigger lethal rejection in BN-LEW spontaneous liver graft acceptance model and did not accelerate acute rejection in ACI-Lew rejection model. PMID- 21612795 TI - Advanced fellowship training is associated with improved lymph node retrieval in colon cancer resections. AB - BACKGROUND: Examination of at least 12 lymph nodes has been established as the standard of care for adequate staging of colon cancer. The purpose of this study was to determine whether surgeon fellowship training, patient body mass index (BMI), and surgical approach (open versus laparoscopic) are important factors associated with lymph node retrieval at an NCI/NCCN-designated center. METHODS: We conducted a retrospective review of patients undergoing colectomy for colon cancer from 1994 to 2009. Patients who underwent right, left, and sigmoid colectomy by open or laparoscopic approaches were included. Lymph node retrieval and risk factors for inadequate nodal retrieval (<12 nodes) were analyzed. RESULTS: A total of 371 patients were included. Lymph node retrieval was found to be significantly increased when surgeons had fellowship training compared with no advanced training (19.9 +/- 10.6 versus 14.8 +/- 10.6, P = 0.0007). Lymph node retrieval was found to be significantly decreased in obese patients (BMI >= 30) compared with non-obese patients (17.3 +/- 10.0 versus 19.9 +/- 11.5, P = 0.05). There was no significant difference between open and laparoscopic approaches. On multivariate analysis, lack of fellowship training, surgery performed prior to establishment of NCI guidelines for lymph node retrieval, and small tumor size were independent predictors of inadequate lymph node retrieval. CONCLUSION: Advanced fellowship training of surgeons appears to be associated with higher lymph node retrieval and decreased risk of performing inadequate nodal retrieval. Small tumor size and surgery performed prior to establishment of the 12 lymph node benchmark were also associated with inadequate nodal retrieval. PMID- 21612796 TI - Surgical skills assessment of applicants to general surgery residency. AB - BACKGROUND: Manual skill proficiency is not currently employed in selecting residents for general surgery training programs. The study objective was to assess whether the technical skill levels of applicants to a general surgery residency program are higher than those of internal medicine residents. MATERIAL AND METHODS: Forty-two applicants to a community general surgery program underwent manual skill testing on interview day. Four laparoscopic tasks on a virtual reality (VR) simulator (LapSim, Goteborg, Sweden) were tested. Performance scores were computer-generated. Participants' previous experience with other manual dexterity activities was assessed via a questionnaire. Applicants' self-perception of their surgical skills was correlated with their skill dexterity scores on the simulator. Candidates' simulator scores were also compared with those of a group of internal medicine interns (n = 9) and a group of mid-level surgical residents, PGY 2-3 (n = 7). RESULTS: Simulator scores of the applicants were significantly lower than those of mid-level surgical residents in all VR tasks (P < 0.05). The internal medicine interns scored higher that the surgery candidates in three of four simulator tasks. Participation in other manual dexterity activities was not associated with increased dexterity scores. CONCLUSION: This study suggests that surgical dexterity levels do not correlate with the self-assessed skill levels or with previous experience with other manual dexterity activities. Moreover, there appears to be no self selection of applicants for surgery residency based on actual surgical skills. Selection criteria for surgical training, which incorporate technical proficiency skills, may potentially better discriminate those applicants with an aptitude for a surgical specialty. PMID- 21612798 TI - Simultaneous typical and extraordinary imaging findings of AIDS-associated cytomegalovirus encephalitis. AB - Encephalitis caused by cytomegalovirus (CMV) is a devastating disease that occurs mostly in profoundly immunocompromised individuals, particularly in the setting of advanced HIV infection or organ transplantation. Imaging findings in AIDS associated cytomegalovirus encephalitis that have been described range from ventriculitis (more common) to solitary mass lesions (less common). We describe a fatal case of AIDS-associated cytomegalovirus encephalitis that included typical imaging findings but also atypical features with widespread, multifocal lesions demonstrating restricted diffusion on magnetic resonance imaging (MRI). It is likely that these diffusion abnormalities are appreciated due to changes in imaging technology from the pre-highly active antiretroviral therapy era in which the typical imaging findings of CMV encephalitis were first described. The differential diagnosis of widespread, multifocal lesions with restricted diffusion in the setting of AIDS should now include CMV encephalitis. PMID- 21612797 TI - Brain axonal and myelin evaluation in heart failure. AB - Although gray matter injury appears in heart failure (HF) patients, the presence, extent, and nature of axonal injury impacting on cardiovascular regulation and other functions is unclear. We performed diffusion tensor imaging (3.0-Tesla magnetic resonance imaging scanner) in 16 HF and 26 control subjects, and assessed whole-brain water diffusion parallel (axial diffusivity; axonal status) and perpendicular (radial diffusivity; myelin changes) to fibers. Regions with increased axial diffusivity only, indicating impaired axonal integrity, emerged in cardiovascular, hedonic, and pain regulatory areas, including basal forebrain, hypothalamic and limbic projections through the medial forebrain bundle and raphe magnus projections to the medulla and cerebellum. Other fiber paths between sites implicated in cognition, including limbic, basal-ganglia, thalamic, internal capsule, and corpus callosum were also altered. Sites with increased radial diffusivity only, indicating myelin breakdown, appeared in the corpus callosum, cingulate, and temporal, parietal, occipital, and frontal regions. Both higher axial and radial diffusivity, indicating loss of tissue integrity, appeared in parietal and occipital lobes, limbic regions, insula, internal capsule, cerebellum, and dorsolateral medulla. Axons and myelin are altered in HF, likely resulting from ischemic/hypoxic processes acting chronically and sub-acutely, respectively. The alterations would contribute to the multiple autonomic and neuropsychological symptoms found in HF. PMID- 21612799 TI - Temporal changes of polyphenols and enzyme activities in seedlings of Kandelia obovata under lead and manganese stresses. AB - The temporal responses of peroxidase (POD), superoxide dismutase (SOD), total polyphenols (TP), extractable condensed tannins (ECT) to different levels of lead (Pb) or manganese (Mn) stress, as well as the metal accumulation, in seedlings of Kandelia obovata were investigated. Both stress time and stress intensity had significant effects with significant accumulation of Pb and Mn in roots at Day 1. Pb and Mn showed no significant effects on root or leaf TP and ECT at Day 1. Prolonged exposure to metals caused significant drops of root TP and ECT but increased in leaves at Days 7 and 49. POD activities decreased in both roots and leaves at Day 1, while POD and SOD both increased under moderate levels of Pb and Mn at Day 7. The present study showed that antioxidative enzyme activities were more sensitive indicators to Pb or Mn stresses than phenolic compounds. PMID- 21612801 TI - Monitoring persistent organic pollutants in leatherback turtles (Dermochelys coriacea) confirms maternal transfer. AB - To assess threats to endangered species, it is critical to establish baselines for contaminant concentrations that may have detrimental consequences to individuals or populations. We measured contaminants in blubber and fat from dead leatherback turtles and established baselines in blood and eggs in nesting turtles. In fat, blubber, blood and eggs, the predominant PCBs were 153+132, 187+182, 138+163, 118, and 180+193. Total PCBs, 4,4'-DDE, total PBDEs and total chlordanes were significantly and positively correlated between blood and eggs, suggesting maternal transfer. Significant positive relationships also existed between fat and blubber in stranded leatherbacks. Less lipophilic PCBs appeared to more readily transfer from females to their eggs. PBDE profiles in the four tissues were similar to other wildlife populations but different from some turtle studies. Concentrations were lower than those shown to have acute toxic effects in other aquatic reptiles, but may have sub-lethal effects on hatchling body condition and health. PMID- 21612800 TI - Levels and spatial distribution of polycyclic aromatic hydrocarbons (PAHs) in sediments from Lenga Estuary, central Chile. AB - The Lenga Estuary is a small brackish wetland located southwest of San Vicente Bay, Region VIII, Chile. Surface sediment from nine sites in the estuary were analysed for PAHs and compared to Sediment Quality Guidelines (SQG). Sediment samples were freeze dried and soxhlet extracted for 16 h using DCM. Identification and quantification was carried out by HPLC. Organic carbon was also determined. Results showed total PAH concentrations ranged from 290 to 6118 (2025 +/- 1975)ng g(-1) d.w. (2025 +/- 1975). Results for organic carbon percentages ranged from 1% to 7%. Statistical analysis showed a significant positive correlation (Pearson test) between organic carbon percentage PAHs. Comparison of contaminant levels and international Sediment Quality Guidelines (SQG) (ERL and ER) suggested that sediment of the Lenga estuary did not show any ecotoxicological risk for benthic organisms where high levels of PAHs were detected. Monitoring of this and other contaminants is recommended in Chile. PMID- 21612802 TI - [Delirium in the elder patient: update in prevention, diagnosis and treatment]. PMID- 21612804 TI - Isopimarane diterpene glycosides, isolated from endophytic fungus Paraconiothyrium sp. MY-42. AB - Six isopimarane diterpenes, compounds 1-6, were isolated from the endophytic fungus Paraconiothyrium sp. MY-42. Compound 1 possesses a 19-glucopyranosyloxy group. Its structure was first elucidated by spectroscopic data analysis and finally confirmed by X-ray crystallography, whereas structures 2-6 were mainly elucidated based on the analysis of spectroscopic evidence. Compounds 2 and 3 showed moderate cytotoxicities against the human promyelocytic leukemia cell line HL60 (IC50 6.7 MUM value for 2 and 9.8 MUM for 3). PMID- 21612803 TI - [Frailty and its association with mortality, hospitalization and functional dependence in Mexicans aged 60-years or older]. AB - BACKGROUND AND OBJECTIVE: To determine the association between frailty and mortality, dysfunctionality, falls and hospitalizations in the Mexican Health and Aging Study. SUBJECTS AND METHODS: Prospective, population study in Mexico, that included subjects of 60 years and older who were evaluated for the variables of frailty during the year 2001 (first wave of the study) which included: difficulty to rise from a chair after being seated during long time, weight loss of 5 kilograms or more in the last two years, and absence of energy. Frail subjects were considered when they had at least two conditions. The robust group was considered when they had zero conditions. Pre-frail or intermediate were those with one condition. Mortality, hospitalizations, falls, and functional dependency were evaluated during 2003 (second wave of the study). Relative risk was calculated for each complication, as well as hazard ratio and odds ratio through Cox Regression Model (for mortality) and logistic regression (for the rest of the complications) respectively, adjusted for covariates. RESULTS: The states of frailty and pre-frailty were independently associated with mortality, hazard ratio of 1.61 (CI 95% 1.01-2.55) and 1.94 (CI 95% 1.20-3.13), respectively. Only the state of frailty was independently associated with hospitalization and functional dependence, odds ratio of 1.53 (CI 95% 1.13-2.07) and 3.07 (CI 95% 1.76-5.34). There was no association between pre-frailty or frailty with falls. CONCLUSION: Frailty is associated with an increase in the rate of mortality, hospitalizations and dependence in basic activities of daily life. PMID- 21612805 TI - Primula spectabilis Tratt. aerial parts: morphology, volatile compounds and flavonoids. AB - The vacuolar and epicuticular flavonoids and the volatiles of the leaves and parts of flower of P. spectabilis Tratt., an endemic species in the Italian Oriental Alps, were investigated. From a MeOH extract of the leaves two flavone glycosides, 8-C-beta-glucopyranosylluteolin 7-O-alpha-arabinofuranoside (1) and 6 C-alpha-arabinofuranosylapigenin (2) were isolated, in addition to a flavone and three flavonols already known from species of Primula. From an EtOH extract of leaf exudates, 7,3',4'-tri-O-methylquercetin was obtained. The structures were elucidated on the basis of their 1D 1H- and 13C NMR data and 2D NMR techniques, as well as of HPLC-MS. The volatiles emitted by the leaves were mainly constituted by non-terpene derivatives, followed by comparable proportions of hemiterpens, oxygenated monoterpenes and sesquiterpene hydrocarbons. In flowers, monoterpene hydrocarbons were the most represented chemical class followed by non terpene derivatives. Different proportions of compounds were found when individual parts of flowers were examined separately; calyx produced a greater proportion (approx. 49.5%) of non-terpenes as its volatile metabolites. P. spectabilis has glandular trichomes in the hyaline margins of the epidermal depressions, distributed on the adaxial leaf blade. Glandular hairs were also present on the corolla. Correlations of phytochemical data with the morphological features of leaf, flower and glandular hair are discussed, and a hypothesis is proposed on the ecological roles of the flavonoids and volatile compounds on the general fitness of the species and cross-pollination strategies. PMID- 21612806 TI - Phenolic compounds from the cultured mycobionts of Graphis proserpens. AB - Spore-derived mycobionts of the lichen Graphis proserpens were cultivated on a malt-yeast extract medium supplemented with 10% sucrose and their metabolites were investigated. Isocoumarin derivatives 1-3 and 7-oxo-5,7-dihydrooxepino[4,3,2 de]isochromene derivatives, proserins A-C (4-6), were isolated along with three known isocoumarin derivatives and three benzoic acid derivatives. Their structures were determined by spectroscopic methods. PMID- 21612807 TI - Insulin concentrations in dogs with hypoadrenocorticism. AB - Hypoglycaemia is frequently identified in canine cases of hypoadrenocorticism. Potassium and glucose cellular uptake are intimately linked by insulin. We hypothesized that in canine hypoadrenocorticism, hyperkalaemia would stimulate insulin release as a protective mechanism, translocating potassium from the extracellular compartment to the intracellular compartment and also lower glucose concentrations. Serum insulin concentrations were measured in 11 consecutive cases of canine hypoadrenocorticism which were hyperkalaemic and 33 dogs with non adrenal illness. There was no significant difference between insulin concentrations in the two populations, and no correlation between insulin and potassium concentration in the hypoadrenal group. Thus, no support for the hypothesis was found, although multiple other factors such as pH and osmolality may be obscuring an effect. PMID- 21612808 TI - Cure rate is not a valid indicator for assessing drug efficacy and impact of preventive chemotherapy interventions against schistosomiasis and soil transmitted helminthiasis. AB - Every year in endemic countries, several million individuals are given anthelminthic drugs in the context of preventive chemotherapy programmes for morbidity control of schistosomiasis and soil-transmitted helminthiasis. The capacity to evaluate accurately the efficacy of the drugs used as well as the health impact produced by treatment is of utmost importance for appropriate planning and implementation of these interventions. Cure rate is an indicator of drug efficacy that was originally developed for assessing the clinical efficacy of antibiotics on selected bacterial diseases. Over time, this indicator has also been widely applied to anthelminthic drugs and consequently used to monitor and evaluate preventive chemotherapy interventions. In the author's opinion, however, measurement of cure rate provides information of limited usefulness in the context of helminth control programmes. The present article analyses the peculiarities of helminth infections and those of the drugs used in preventive chemotherapy, explaining the reasons why the cure rate is not an adequate indicator in this specific public health context. PMID- 21612809 TI - Virus infection rapidly activates the P58(IPK) pathway, delaying peak kinase activation to enhance viral replication. AB - Previously we showed that the cellular protein P58(IPK) contributes to viral protein synthesis by decreasing the activity of the anti-viral protein, PKR. Here, we constructed a mathematical model to examine the P58(IPK) pathway and investigated temporal behavior of this biological system. We find that influenza virus infection results in the rapid activation of P58(IPK) which delays and reduces maximal PKR and eIF2alpha phosphorylation, leading to increased viral protein levels. We confirmed that the model could accurately predict viral and host protein levels at extended time points by testing it against experimental data. Sensitivity analysis of relative reaction rates describing P58(IPK) activity and the downstream proteins through which it functions helped identify processes that may be the most beneficial targets to thwart virus replication. Together, our study demonstrates how computational modeling can guide experimental design to further understand a specific metabolic signaling pathway during viral infection in a mammalian system. PMID- 21612810 TI - Arenavirus envelope glycoproteins mimic autoprocessing sites of the cellular proprotein convertase subtilisin kexin isozyme-1/site-1 protease. AB - A crucial step in the arenavirus life cycle is the proteolytic processing of the viral envelope glycoprotein precursor (GPC) by the cellular proprotein convertase (PC) subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P). Here we conducted a systematic and quantitative analysis of SKI-1/S1P processing of peptides derived from the recognition sites of GPCs of different Old World and New World arenaviruses. We found that SKI-1/S1P showed a strong preference for arenaviral sequences resembling its autoprocessing sites, which are recurrent motifs in arenaviral GPCs. The African arenaviruses Lassa, Mobala, and Mopeia resemble the SKI-1/S1P autoprocessing C-site, whereas sequences derived from Clade B New World viruses Junin and Tacaribe have similarities to the autoprocessing B-site. In contrast, analogous peptides derived from cellular SKI-1/S1P substrates were remarkably poor substrates. The data suggest that arenavirus GPCs evolved to mimic SKI-1/S1P autoprocessing sites, likely ensuring efficient cleavage and perhaps avoiding competition with SKI-1/S1P's cellular substrates. PMID- 21612811 TI - UV reactor flow visualization and mixing quantification using three-dimensional laser-induced fluorescence. AB - Three-dimensional laser-induced fluorescence (3DLIF) was applied to visualize and quantitatively analyze mixing in a lab-scale UV reactor consisting of one lamp sleeve placed perpendicular to flow. The recirculation zone and the von Karman vortex shedding that commonly occur in flows around bluff bodies were successfully visualized. Multiple flow paths were analyzed by injecting the dye at various heights with respect to the lamp sleeve. A major difference in these pathways was the amount of dye that traveled close to the sleeve, i.e., a zone of higher residence time and higher UV exposure. Paths away from the center height had higher velocities and hence minimal influence by the presence of sleeve. Approach length was also characterized in order to increase the probability of microbes entering the region around the UV lamp. The 3DLIF technique developed in this study is expected to provide new insight on UV dose delivery useful for the design and optimization of UV reactors. PMID- 21612812 TI - Interactions between accumulation of trace elements and macronutrients in Salix caprea after inoculation with rhizosphere microorganisms. AB - Although the beneficial effects on growth and trace element accumulation in Salix spp. inoculated with microbes are well known, little information is available on the interactions among trace elements and macronutrients. The main purpose of this study was to assess the effect of phytoaugmentation with the rhizobacteria Agromyces sp., Streptomyces sp., and the combination of each of them with the fungus Cadophora finlandica on biomass production and the accumulation of selected trace elements (Zn, Cd, Fe) and macronutrients (Ca, K, P and Mg) in Salix caprea grown on a moderately polluted soil. Dry matter production was significantly enhanced only upon inoculation with Agromyces sp. Regarding the phytoextraction of Cd and Zn, shoot concentrations were mostly increased after inoculation with Streptomyces sp. and Agromyces sp. + C. finlandica. These two treatments also showed higher translocation factors from roots to the leaves for both Cd and Zn. The accumulation of Cd and Zn in shoots was related to increased concentrations of K. This suggests that microorganisms that contribute to enhanced phytoextraction of Cd and Zn affect also the solubility and thus phytoavailability of K. This study suggests that the phytoextraction of Zn and Cd can be improved by inoculation with selected microbial strains. PMID- 21612813 TI - RUNX3 functions as an oncogene in ovarian cancer. AB - OBJECTIVE: The Runt domain transcription factor, RUNX3, has been shown to be a tumor suppressor in a variety of cancers including gastric, colon and breast cancer. Interestingly, an oncogenic role for RUNX3 has also been suggested in basal cell carcinoma and head and neck cancer. Here, we explore the role of RUNX3 in ovarian cancer. METHODS: Expression of RUNX3 mRNA and protein was evaluated in human ovarian cancer cell lines. In addition, subcellular localization of RUNX3 was also examined in cell lines and ovarian cancer tissues. Effect of exogenous RUNX3 expression and knockdown on cell proliferation was investigated by proliferation assays and a soft agar assay. RESULTS: Expression of RUNX3 was detected in the nucleus of ovarian cancer cell lines and ovarian cancer tissues and was found to play a growth stimulatory role. RUNX3 knockdown resulted in a decrease in cell proliferation in liquid media as well as in soft agar. Despite the fact that exogenous expression of RUNX3 strongly inhibits cell growth in many cell types, RUNX3 promoted cell growth in ovarian cancer cell lines not expressing RUNX3. CONCLUSION: RUNX3 is frequently expressed in the nuclei of ovarian cancer cell lines and plays an oncogenic role in ovarian cancer. PMID- 21612814 TI - Effect of method and clinician on stallion sperm morphology evaluation. AB - The objective of this study was to determine the effects of method and clinician on stallion sperm morphology evaluation. Five clinicians evaluated 60 semen samples using wet-mount preparations with phase-contrast, eosin/nigrosin-stained semen smears, and Papanicolaou-stained semen smears. There were significant differences among methods for all sperm morphology categories and most intra class correlation coefficients were only fair to moderate. The use of wet-mount preparations facilitated detection of acrosome defects, nuclear vacuoles, and cytoplasmic droplets when compared to stained smears. Smearing stallion semen samples onto slides increased the proportion of detached sperm heads. In addition, acrosome defects, nuclear vacuoles, rough/swollen midpieces, and cytoplasmic droplets were difficult to observe with Papanicolaou stain; this method resulted in overestimation of normal sperm when compared to other methods. There were significant differences among clinicians for all sperm morphology classification categories. In conclusion, this study demonstrated that sperm morphology evaluation results varied, depending on the evaluation method and clinician. Wet-mount preparation with phase-contrast microscopy appeared to be more sensitive for identification of abnormal stallion sperm when compared to stained smears. Veterinary andrology laboratories should invest in training, continuing education, proficiency testing, and other quality control measures to minimize the variation of sperm morphology evaluation results among clinicians. PMID- 21612815 TI - In vitro effects of L-arginine on spontaneous and homocysteine-induced contractility of pregnant canine uteri. AB - The L-Arginine-Nitric Oxide Synthase-Nitric Oxide (L-Arg-NOS-NO) system exerts a pivotal role in the maintenance of uterine quiescence during pregnancy, whereas Homocysteine (Hcy) promotes uterine contractility. The aim of this study was to test the in vitro effects of L-Arg on spontaneous and Hcy-induced contractions of uteri excised from pregnant bitches. 104 strips cut from pregnant uteri were mounted in an organ bath. 40 out of 104 strips (16 from mid-gestation uteri and 24 from close to term uteri, respectively) were exposed to cumulative doses of L Arg; 40 strips (16 from mid-gestation-uteri and 24 from close to term-uteri, respectively) were exposed to N-nitro-L-arginine methyl ester (L-NAME), a NOS antagonist; the remaining 24 strips (from close-to-term uteri) were first exposed to a single dose of Hcy and then to increasing doses of L-Arg. L-Arg showed no effects on spontaneous contractility both in mid-gestation- and close to term uterine strips, whereas it promoted a relaxant effect on Hcy-induced contractility. On the contrary, L-NAME increased amplitude of contraction both in mid-gestation and close to term strips. These findings suggest that the L-Arg-NO system is present in the uterus of pregnant bitches and that Hcy is able to modulate its actions. Further investigation of this system may provide the basis of future obstetrical therapies in bitches. PMID- 21612816 TI - Effects of inhibition of prostaglandin F2alpha biosynthesis during preluteolysis and luteolysis in heifers. AB - Flunixin meglumine (FM; 2.5 mg/kg) was given to heifers at three 8-h intervals, 16 d after ovulation (first treatment = Hour 0) to inhibit the synthesis of prostaglandin F(2alpha) (PGF), based on plasma concentrations of a PGF metabolite (PGFM). Blood samples were collected at 8-h intervals from 15 to 18 d in a vehicle (control) and FM group (n = 16/group). Hourly samples were collected from Hours -2 to 28 in 10 heifers in each group. Heifers that were in preluteolysis or luteolysis at Hour 0 based on plasma progesterone (P4) concentrations at 8-h intervals were partitioned into subgroups. Concentration of PGFM was reduced (P < 0.05) by FM treatment in each subgroup. For the preluteolytic subgroup, the first decrease (P < 0.05) in P4 concentration after Hour 0 occurred at Hours 24 and 40 in the vehicle and FM groups, respectively. Plasma P4 concentrations 32 and 40 h after the beginning of luteolysis in the luteolytic subgroup were greater (P < 0.05) in the FM group. Concentration at the peak of a PGFM pulse in the FM group was greater (P < 0.05) in the luteolytic than in the preluteolytic subgroup. The peak of a PGFM pulse occurred more frequently (P < 0.001) at the same hour as the peak of an LH fluctuation than at the ending nadir of an LH fluctuation. In conclusion, a reduction in prominence of PGFM pulses during luteolysis delayed completion of luteolysis, and treatment with FM inhibited PGFM production more during preluteolysis than during luteolysis. PMID- 21612817 TI - BOLD response to motion verbs in left posterior middle temporal gyrus during story comprehension. AB - A primary focus within neuroimaging research on language comprehension is on the distribution of semantic knowledge in the brain. Studies have shown that the left posterior middle temporal gyrus (LPMT), a region just anterior to area MT/V5, is important for the processing of complex action knowledge. It has also been found that motion verbs cause activation in LPMT. In this experiment we investigated whether this effect could be replicated in a setting resembling real life language comprehension, i.e. without any overt behavioral task during passive listening to a story. During fMRI participants listened to a recording of the story "The Ugly Duckling". We incorporated a nuisance elimination regression approach for factoring out known nuisance variables both in terms of physiological noise, sound intensity, linguistic variables and emotional content. Compared to the remaining text, clauses containing motion verbs were accompanied by a robust activation of LPMT with no other significant effects, consistent with the hypothesis that this brain region is important for processing motion knowledge, even during naturalistic language comprehension conditions. PMID- 21612818 TI - Alternative methods for determining shrinkage in restorative resin composites. AB - OBJECTIVES: The purpose of this study was to evaluate polymerization shrinkage of resin composites using a coordinate measuring machine, optical coherence tomography and a more widely known method, such as Archimedes Principle. Two null hypothesis were tested: (1) there are no differences between the materials tested; (2) there are no differences between the methods used for polymerization shrinkage measurements. METHODS: Polymerization shrinkage of seven resin-based dental composites (Filtek Z250TM, Filtek Z350TM, Filtek P90TM/3M ESPE, Esthet XTM, TPH SpectrumTM/Dentsply 4 SeasonsTM, Tetric CeramTM/Ivoclar-Vivadent) was measured. For coordinate measuring machine measurements, composites were applied to a cylindrical Teflon mold (7 mm * 2 mm), polymerized and removed from the mold. The difference between the volume of the mold and the volume of the specimen was calculated as a percentage. Optical coherence tomography was also used for linear shrinkage evaluations. The thickness of the specimens was measured before and after photoactivation. Polymerization shrinkage was also measured using Archimedes Principle of buoyancy (n=5). Statistical analysis of the data was performed with ANOVA and the Games-Howell test. RESULTS: The results show that polymerization shrinkage values vary with the method used. Despite numerical differences the ranking of the resins was very similar with Filtek P90 presenting the lowest shrinkage values. SIGNIFICANCE: Because of the variations in the results, reported values could only be used to compare materials within the same method. However, it is possible rank composites for polymerization shrinkage and to relate these data from different test methods. Independently of the method used, reduced polymerization shrinkage was found for silorane resin based composite. PMID- 21612819 TI - Can India achieve a balance of sexes at birth? PMID- 21612821 TI - The promotion of microvasculature formation in poly(ethylene glycol) diacrylate hydrogels by an immobilized VEGF-mimetic peptide. AB - Microvascularization of tissue engineered constructs was achieved by utilizing a VEGF-mimicking peptide, QK, covalently bound to a poly(ethylene glycol) hydrogel matrix. The 15-amino acid peptide, developed by D'Andrea et al., was modified with a PEG-succinimidyl ester linker on the N-terminus of the peptide, then photocrosslinked onto the surface or throughout PEG hydrogels. PEGylation of the peptide increased its solubility and bioactivity, as evidenced by endothelial cell proliferation. PEG-QK showed equal or superior ability to promote angiogenesis in vitro, on the surface of hydrogels and within three-dimensional collagenase-degradable hydrogels, compared to RGDS only or PEG-VEGF hydrogels. Endothelial cells were shown to form tubule structures, migrate, and make cell cell contacts in response to covalently-bound PEG-QK. In vivo in a mouse cornea micropocket angiogenesis assay, PEG-QK hydrogels promoted more complete coverage of host microvasculature within the hydrogel. PEG-QK was shown to enhance vessel branch points and vessel density as well as space filling properties of fractal dimension and lacunarity. This report shows the ability to promote angiogenesis in tissue engineered constructs using a covalently-bound small peptide rather than a large protein and may point to an advance in designing biomimetic cellular environments. PMID- 21612820 TI - Trends in selective abortions of girls in India: analysis of nationally representative birth histories from 1990 to 2005 and census data from 1991 to 2011. AB - BACKGROUND: India's 2011 census revealed a growing imbalance between the numbers of girls and boys aged 0-6 years, which we postulate is due to increased prenatal sex determination with subsequent selective abortion of female fetuses. We aimed to establish the trends in sex ratio by birth order from 1990 to 2005 with three nationally representative surveys and to quantify the totals of selective abortions of girls with census cohort data. METHODS: We assessed sex ratios by birth order in 0.25 million births in three rounds of the nationally representative National Family Health Survey covering the period from 1990 to 2005. We estimated totals of selective abortion of girls by assessing the birth cohorts of children aged 0-6 years in the 1991, 2001, and 2011 censuses. Our main statistic was the conditional sex ratio of second-order births after a firstborn girl and we used 3-year rolling weighted averages to test for trends, with differences between trends compared by linear regression. FINDINGS: The conditional sex ratio for second-order births when the firstborn was a girl fell from 906 per 1000 boys (99% CI 798-1013) in 1990 to 836 (733-939) in 2005; an annual decline of 0.52% (p for trend=0.002). Declines were much greater in mothers with 10 or more years of education than in mothers with no education, and in wealthier households compared with poorer households. By contrast, we did not detect any significant declines in the sex ratio for second-order births if the firstborn was a boy, or for firstborns. Between the 2001 and 2011 censuses, more than twice the number of Indian districts (local administrative areas) showed declines in the child sex ratio as districts with no change or increases. After adjusting for excess mortality rates in girls, our estimates of number of selective abortions of girls rose from 0-2.0 million in the 1980s, to 1.2-4.1 million in the 1990s, and to 3.1-6.0 million in the 2000s. Each 1% decline in child sex ratio at ages 0-6 years implied 1.2-3.6 million more selective abortions of girls. Selective abortions of girls totalled about 4.2-12.1 million from 1980-2010, with a greater rate of increase in the 1990s than in the 2000s. INTERPRETATION: Selective abortion of girls, especially for pregnancies after a firstborn girl, has increased substantially in India. Most of India's population now live in states where selective abortion of girls is common. FUNDING: US National Institutes of Health, Canadian Institute of Health Research, International Development Research Centre, and Li Ka Shing Knowledge Institute. PMID- 21612822 TI - Peptide-conjugated polymeric micellar nanoparticles for Dual SPECT and optical imaging of EphB4 receptors in prostate cancer xenografts. AB - EphB4, a member of the largest family of receptor tyrosine kinases, is overexpressed in numerous tumors. In this study, we developed a new class of multimodal nanoplatform for dual single photon emission computed tomography (SPECT) and near-infrared fluorescence imaging of EphB4. EphB4-binding peptide TNYL-FSPNGPIARAW (TNYL-RAW) was conjugated to polyethylene glycol-coated, core crosslinked polymeric micelles (CCPM) dually labeled with near-infrared fluorescence fluorophores (Cy7) and a radioisotope (indium 111). In vitro, TNYL RAW-CCPM selectively bound to EphB4-positive PC-3M prostate cancer cells, but not to EphB4-negative A549 lung cancer cells. In vivo, PC-3M tumors were clearly visualized by both SPECT and near-infrared fluorescence tomography after intravenous administration of (111)In-labeled TNYL-RAW-CCPM. In contrast, there was little signal in A549 tumors of mice injected with (111)In-labeled TNYL-RAW CCPM or in PC-3M tumors of mice injected with (111)In-labeled CCPM. The high accumulation of (111)In-labeled TNYL-RAW-CCPM in PC-3M tumor could be significantly reduced after co-injection with an excess amount of TNYL-RAW peptide. Immunohistochemical analysis showed that fluorescence signal from the nanoparticles correlated with their radioactivity count, and co-localized with the EphB4 expressing region. (111)In-labeled TNYL-RAW-CCPM allowed visualization of cancer cells overexpressing EphB4 by both nuclear and optical techniques. The complementary information acquired with multiple imaging techniques should be advantageous in early detection of cancer. PMID- 21612823 TI - Induction of myeloma-specific cytotoxic T lymphocytes responses by natural killer cells stimulated-dendritic cells in patients with multiple myeloma. AB - The interaction between dendritic cells (DCs) and natural killer (NK) cells plays a key role in inducing DC maturation for subsequent T-cell priming. We investigated to generate potent DCs by stimulated with NK cells to induce myeloma specific cytotoxic T lymphocytes (CTLs). NK cells-stimulated-DCs exhibited high expression of costimulatory molecules and high production of IL-12p70. These DCs induce high potency of Th1 polarization and exhibit a high ability to generate myeloma-specific CTLs responses. These results suggest that functionally potent DCs can be generated by stimulation with NK cells and may provide an effective source of DC-based immunotherapy in multiple myeloma. PMID- 21612824 TI - Incidence of Philadelphia-chromosome in acute myelogenous leukemia and biphenotypic acute leukemia patients: And its role in their outcome. AB - BACKGROUND: Philadelphia-chromosome positive acute myeloid leukemia (Ph+ AML) is a rare entity and patient prognosis is poor, with short median survival. Biphenotypic acute leukemia (BAL) is a rare disorder that is difficult to diagnose and it displays features of both myeloid and lymphoid lineage. The aim of this study was to highlight the incidence of Philadelphia chromosome and its presence in cases of acute myeloid and biphenotypic leukemia and determine its role in the outcome of these leukemias. SUBJECTS AND METHODS: This study examined 464 subjects with newly diagnosed acute myeloid leukemia: 312 were males and 152 were females. All individuals were subjected to immunophenotyping and conventional karyotyping. FISH was used in failed cases of conventional cytogenetics analysis to quantify disease and to prove positive BCR-ABL fusion gene. RESULTS: the incidence of Ph+ chromosome was found to be higher in BAL (38.4%) than in AML (1.99%). There was statistically significant difference according to the age and the median survival time between the two groups. CONCLUSION: Detection of specific chimeric transcripts in AML and BAL at the time of diagnosis was crucial since it plays an important role for accurate risk stratification and treatment management. PMID- 21612825 TI - Chlorinated paraffins in indoor air and dust: concentrations, congener patterns, and human exposure. AB - Chlorinated paraffins (CPs) are large production volume chemicals used in a wide variety of commercial applications. They are ubiquitous in the environment and humans. Human exposure via the indoor environment has, however, been barely investigated. In the present study 44 indoor air and six dust samples from apartments in Stockholm, Sweden, were analyzed for CPs, and indoor air concentrations are reported for the first time. The sumCP concentration (short chain CPs (SCCPs) and medium chain CPs (MCCPs)) in air ranged from <5-210 ng m( 3) as quantified by gas chromatography coupled to electron ionization tandem mass spectrometry (GC/EI-MS/MS). Congener group patterns were studied using GC with electron capture negative ionization MS (GC/ECNI-MS). The air samples were dominated by the more volatile SCCPs compared to MCCPs. SumCPs were quantified by GC/EI-MS/MS in the dust samples at low MUg g(-1) levels, with a chromatographic pattern suggesting the prevalence of longer chain CPs compared to air. The median exposure to sumCPs via the indoor environment was estimated to be ~1 MUg day(-1) for both adults and toddlers. Adult exposure was dominated by inhalation, while dust ingestion was suggested to be more important for toddlers. Comparing these results to literature data on dietary intake indicates that human exposure to CPs from the indoor environment is not negligible. PMID- 21612827 TI - Suicidal ideation among patients with gender identity disorder. AB - In this study, we tried to clarify the prevalence of suicidal ideation and self mutilation including suicide attempts among patients with gender identity disorder (GID) and the relationship of those behaviors to demographic characteristics. A total of 500 consecutive Japanese GID patients without any other psychiatric comorbidity were evaluated at the outpatient GID Clinic of Okayama University Hospital. The lifetime rate of suicidal ideation was 72.0% of the total sample. There were no significant differences in the prevalence of suicidal ideation among groups divided by sex, age, age at onset or education. The lifetime prevalence of self-mutilation including suicide attempts was 31.8% of the total sample. Low level of education was significantly related to self mutilation among both male-to-female and female-to-male GID patients. Younger age at onset was a significant factor affecting self-mutilation only among MTF GID patients. A lack of strategies to cope with severe distress among persons with lower education might induce a high frequency of self-mutilation including suicidal attempt. GID patients with a low level education might be at high risk of self-mutilation and should be watched with special attention to self mutilation. PMID- 21612826 TI - Tyrosine kinase B protein expression is reduced in the cerebellum of patients with bipolar disorder. AB - BACKGROUND: The role of the cerebellum in coordinating mental activity is supported by its connections with cerebral regions involved in cognitive/affective functioning, with decreased activities on functional neuroimaging observed in the cerebellum of schizophrenia patients performing mental tasks. Brain-derived neurotrophic factor (BDNF)-induced activation of tyrosine kinase B (TrkB) is essential to synaptic plasticity. We hypothesized that alterations in BDNF and TrkB expression in the cerebellum were associated with schizophrenia and affective disorders. METHODS: We employed immunohistochemistry and immunoblotting to quantify protein expression of BDNF and TrkB in the cerebellum of patients with schizophrenia, bipolar disorder, and major depression compared to controls (n=15 each). RESULTS: While TrkB immunoreactivity in each of the molecular and granule-cell layers was reduced in all 3 disease groups (12-34%) compared to the control (P=0.018 and 0.038, respectively, ANOVA), only the reduction in bipolar disorder remained statistically significant upon Tukey-Kramer post hoc analyses (P=0.019 and 0.021, respectively). Apparent decreases in BDNF immunoreactivity in all 3 disease groups (12-30%) compared to the control were not statistically significant. TrkB immunoreactivity was not significantly associated with any of the demographic, clinical, and postmortem variables. Immunoblotting displayed an 85-kDa TrkB immunoreactive band, consistent with a truncated isoform, in all 60 cases. LIMITATIONS: On immunoblotting, apparent decreases in 85-kDa-TrkB levels in all 3 disease groups compared to the control were not statistically significant. CONCLUSIONS: Our finding of reduced TrkB expression in bipolar disorder suggests that dysregulation of TrkB-mediated neurotrophin signaling in the cerebellum may play a role in the pathophysiology of this disease. PMID- 21612828 TI - Immune responses in piglets infected with highly pathogenic porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) infection compromises the host's innate and adaptive immunity. The aim of this study was to investigate the immune responses of piglets infected with highly pathogenic (HP) PRRSV (HuN4 strain) with or without the immunization with CH-1R attenuated PRRSV vaccine. The response was evaluated for the clinical signs, pathological changes and virus load in immune organs, antibody responses and levels of serum IFN-gamma, IL-4 and IL-10. The result showed that in comparison with the piglets received the immunization, the piglets infected with HP-PRRSV alone had the thymus atrophy, decreased serum levels of IL-4 and increased serum levels of IL-10 and INF-gamma. These results suggest that elevated IL-10 levels at the early stage of the infection may enhance virus survival and delay the induction of protective immunity, while increased levels of IL-4 induce the effective immune responses and increase the animals' health status. PMID- 21612830 TI - Nasality evaluation of Turkish phonemes in vowel-consonant combinations. AB - OBJECTIVES: The purpose of this study is to find average nasalance values of Turkish syllables with the nasometer. METHODS: This study is done at Hacettepe University Department of Otolaryngology Audiology and Speech Pathology Unit with 50 participating children. RESULTS: The normative nasalance values of Turkish phonemes are determined. It is found that nasalance scores of syllables that is combined with/i/phoneme is statistically have higher nasalance scores than/a/and/e/phonemes (p<0.05). There is no difference find statistically between age and nasalance value (p>0.05). Statistical difference between age and nasalance score is found in "iki, se, ese, isi, ac, ec, ci, ici, ic, al, yi, iy, iyi, yiy, ana, ne" syllables (p<0.05). These phonemes have positive relation with the age. There is no statistical difference between sex and nasalance scores (p<0.05). Statistical difference is only found in "tat- te- li- lil- aya" syllables (p<0.05). On these phonemes it is found that girls have higher nasalance score than boys. CONCLUSION: As a result, it is thought that gathered nasalance values of Turkish phonemes will be useful for resonance disorder diagnosis and follow ups on treatment. PMID- 21612829 TI - Role of gammadelta T cells in antibody production and recovery from SFV demyelinating disease. AB - Semliki Forest Virus (SFV) encephalomyelitis has been used to study the pathogenesis of virus-induced demyelination and serves as a model for multiple sclerosis. SFV-infection of mice invariably leads to clinical weakness accompanied by CNS inflammation, viral clearance and primary demyelination by day 21 postinfection (pi), followed by recovery and remyelination by day 35 pi. We have applied this model to the examination of the effects of gammadelta T cells in antibody production and the pathogenesis of demyelinating lesions. SFV infection of gammadelta T cell KO mice resulted in more severe clinical signs than in wild type (WT) B6 mice. SFV-infected WT and gammadelta KO mice both cleared virus by day 10 pi and inflammation was comparable. Demyelination also appeared to be similar in both groups except that KO mice did not exhibit extensive remyelination which was seen in WT mice by day 21. SFV-infected WT mice showed widespread remyelination by day 35 pi, whereas KO mice still displayed some demyelination through day 42 pi. Both WT and KO mice developed serum antibodies to SFV. However, the reactivity of WT sera with the SFV epitope, E2 T(h) peptide2, was significantly higher than in KO sera. Immunization with E2 T(h) peptide2 resulted in elevated antibody production to this peptide (p<0.05) and earlier remyelination (day 28 pi) in KO mice. Thus, our study has shown for the first time that immunization of SFV-infected gammadelta T cell KO mice with a viral peptide, E2 T(h) peptide2 led to enhanced recovery and repair of the CNS. PMID- 21612831 TI - Physicians are not adherent to clinical practice guidelines for acute otitis media. AB - OBJECTIVES: To assess the variability, appropriateness of antibiotics prescriptions for children under 12 years of age with acute otitis media and to evaluate physicians' adherence to the current clinical practice guideline. METHODS: This is a retrospective study. Data source of this study was based on outpatient clinic of Otolaryngology Head-and-Neck surgery department in Taipei Veterans General Hospital, a tertiary referral center, from 2005 to 2008. Children 2 months-12 years old presented in our hospital with the diagnosis of uncomplicated acute otitis media were enrolled. Medical records regarding antibiotics prescriptions were reviewed in details. The adherence of physicians' antibiotics prescription was considered appropriate when totally (three aspects: the prescribed items, dosage and days of prescription) in accord with the current clinical practice guideline for acute otitis media. Factors that may influence the adherence were also analyzed. RESULTS: Complete medical record review was conducted in 207 children. Amoxicillin with or without beta-lactamase inhibitor was the most used antibiotics (92.7%). The overall adherence of prescription was 8.2%. All of the prescribed antibiotics "items" fulfill the guideline recommendations, while "dosage" was under in 85%, and "days of prescription" was adherent to guideline in 50.7%. The adherence was not correlated to patient's age, gender, nor single or both ear diseases; but is significantly correlated with specialists' years of experience and their service quantity. The senior specialists or those with higher service quantity are less correspond with the guidelines suggestions (OR 6.49, 95% CI: 1.71-24.66, p=0.006). Prescriptions with "non-amoxicillin" are better in concordance with the guidelines, OR of non adherence is 0.13 (95% CI: 0.003-0.055, p=0.006). CONCLUSIONS: The antibiotics prescription for children with acute otitis media varied widely among ENT specialists. The overall adherence was 8.2%. The adherence was not correlated to patient's age, gender, single or both ear infection; but significantly inversely correlated with specialists' years of experience and their service quantity. PMID- 21612832 TI - Receptor tyrosine kinase-G-protein-coupled receptor signalling platforms: out of the shadow? AB - Receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs) can form platforms in which protein signalling components specific for each receptor are shared (owing to close proximity) to produce an integrated response upon engagement of ligands. RTK-GPCR signalling platforms respond to growth factors and GPCR agonists to increase gain over and above that which is normally produced by separate receptors. They can also function to change the spatial context of signalling in response to growth factor activation. The function of RTK-GPCR signalling platforms can be modulated with conformational-specific inhibitors that stabilise defined GPCR states to abrogate both GPCR agonist- and growth factor-stimulated cell responses. In this paper, we provide an opinion of the biology and unusual pharmacology of RTK-GPCR signalling platforms and make comparisons with a more traditional model of crosstalk between RTKs and GPCRs. PMID- 21612833 TI - Prevalence of canine gastrointestinal helminths in urban Lusaka and rural Katete Districts of Zambia. AB - Faecal samples were collected from January 2010 through September 2010 to determine the prevalence of gastrointestinal (GI) helminths infestation in dogs in urban Lusaka and rural Katete Districts of Zambia. A total of 452 faecal samples (n=160 Katete, n=292 Lusaka) were examined by faecal flotation for the presence of helminth eggs and 82.5% of dogs were positive for GI helminths in Katete compared to 76% for Lusaka. Positive results with the presence of at least one parasite corresponded to 72.9% Ancylostoma caninum, 11% Toxocara canis, 4.8% Toxascaris leonina, 2.4% Dipylidium caninum, 0.7% Taeniidae and 0.3% T. vulpis, species for Lusaka while Katete recorded 70.6% A. caninum, 18.1% T. vulpis, 11.1% T. canis, 13.1% D. caninum, 3.8% T. leonina, and 0.6% Taeniidae. Except for T. vulpis and D. caninum (p<0.05) the results indicated no significant difference in the prevalence of the identified GI helminth between Lusaka and Katete. There was no significant difference in the prevalence between genders of GI helminth infestation demonstrated in this study and only A. caninum showed significant difference in prevalence by age category. The study also showed the presence of zoonotic intestinal helminths A. caninum, T. canis and D. caninum. The study highlights that there was no significant difference in spectrum and prevalence of GI helminths between urban and rural areas in Zambia. It further brings to light the importance of educating owners of dogs on the importance of regular deworming of dogs and control of ectoparasites in order to minimise the risk that these dogs pose to them and the public. PMID- 21612834 TI - Alternatives to Trichoderma reesei in biofuel production. AB - Mutant strains of Trichoderma reesei are considered indisputable champions in cellulase production among biomass-degrading fungi. So, it is not surprising that most R&D projects on bioethanol production from lignocellulosics have been based on using T. reesei cellulases. The present review focuses on whether any serious alternatives to T. reesei enzymes in cellulose hydrolysis exist. Although not widely accepted, more and more data have been accumulated that demonstrate that fungi belonging to the genera Penicillium, Acremonium and Chrysosporium might represent such alternatives because they are competitive to T. reesei on some important parameters, such as protein production level, cellulase hydrolytic performance per unit of activity or milligram of protein. PMID- 21612835 TI - Different distal-proximal movement balances in right- and left-hand writing may hint at differential premotor cortex involvement. AB - Right-handed people generally write with their right hand. Language expressed in script is thus performed with the hand also preferred for skilled motor tasks. This may suggest an efficient functional interaction between the language area of Broca and the adjacent ventral premotor cortex (PMv) in the left (dominant) hemisphere. Pilot observations suggested that distal movements are particularly implicated in cursive writing with the right hand and proximal movements in left hand writing, which generated ideas concerning hemisphere-specific roles of PMv and dorsal premotor cortex (PMd). Now we examined upper-limb movements in 30 right-handed participants during right- and left-hand writing, respectively. Quantitative description of distal and proximal movements demonstrated a significant difference between movements in right- and left-hand writing (p<.001, Wilcoxon signed-rank test). A Distal Movement Excess (DME) characterized writing with the right hand, while proximal and distal movements similarly contributed to left-hand writing. Although differences between non-language drawings were not tested, we propose that the DME in right-hand writing may reflect functional dominance of PMv in the left hemisphere. More proximal movements in left-hand writing might be related to PMd dominance in right-hemisphere motor control, logically implicated in spatial visuomotor transformations as seen in reaching. PMID- 21612836 TI - Efficacy, safety, and tolerability of NGX-4010, capsaicin 8% patch, in an open label study of patients with peripheral neuropathic pain. AB - AIMS: To assess efficacy, safety, and tolerability of NGX-4010, capsaicin 8% patch, in patients with peripheral neuropathic pain. METHODS: This open-label, uncontrolled, 12-week study enrolled 25 patients with postherpetic neuralgia (PHN), one with HIV-distal sensory polyneuropathy, and 91 with painful diabetic neuropathy (PDN). Patients received pre-treatment with one of three 4% lidocaine topical anesthetics (L.M.X.41, Topicaine Gel2, or Betacaine Enhanced Gel 43) followed by a single 60- or 90-min NGX-4010 application. The primary efficacy variable was the percentage change in Numeric Pain Rating Scale scores from baseline to Weeks 2-12. Adverse events (AEs), laboratory parameters, vital signs, neurosensory examinations, dermal assessments, treatment-related pain scores, and medication use for treatment-related pain were collected. RESULTS: PDN and PHN patients achieved a 31% and 28% mean pain decrease from baseline during Weeks 2 12, respectively, and 47% and 44%, respectively, were responders (>=30% pain decrease). Mild or moderate treatment-site-related burning and pain were the most common AEs and there was no evidence of impaired neurosensory function. CONCLUSIONS: NGX-4010 in conjunction with any of the three topical anesthetics tested was generally safe and well tolerated and reduced pain over a 12-week period in patients with PDN and PHN. PMID- 21612837 TI - Progression of glycaemia and cardiovascular risk factors in patients of different age groups with new type 2 diabetes over 5 years of follow-up in a diabetes quality improvement initiative. AB - AIMS: To examine progression of glycaemia and cardiovascular risk factors in type 2 diabetes cases participating in a quality improvement initiative. METHODS: 1108 new type 2 diabetes cases enrolled on the Otago Diabetes Register had clinical data recorded at baseline and 5 years. Means and standard deviations or percentages were calculated for variables of interest for <40, 40-59, 60-79 and 80-100 year age groups. p-Values for differences over time and among groups were calculated. Ordinal regression, with robust standard errors, was used to examine intensification of diabetes treatment. RESULTS: For all age groups blood pressure and lipid levels approached recommended targets at 5 years (p<0.001). Glycated haemoglobin worsened, especially in the youngest age group (from 7.3+/-1.9% to 7.9+/-1.7%, p<0.001) who had the highest odds of more intense diabetes treatment at 5 years: 6.2 (95% CI 3.5-11.2) compared with 3.3 (95% CI 2.7-4.1) for 40-59 year olds, 2.8 (95% CI 2.3-3.3) for 60-79-year olds and 1.4 (95% CI 0.9-2.0) for >=80-year olds. CONCLUSIONS: Good management of type 2 diabetes patients, principally in primary care, can lead to improved blood pressure and lipid levels. Targets for glycaemic control and weight are less readily achieved especially among young age groups. PMID- 21612838 TI - Indexes of beta-cell function from the oral glucose tolerance test can modestly predict pancreatic beta-cell area in Korean. AB - AIMS: Pancreatic beta-cell function indexes have been suggested using the oral glucose tolerance test (OGTT). Here, we investigated whether beta-cell function index from the OGTT reflects pancreatic beta-cell area in Korean patients. METHODS: The study consisted of 45 patients who underwent pancreatectomies. Before operation, a 75-g OGTT was performed. Immunohistochemical staining was performed, and indexes of beta-cell function from the OGTT data were compared with the pancreatic beta-cell area. RESULTS: The beta-cell area of the pancreas was 1.07 +/- 0.33% in the normal glucose tolerance group, 1.71 +/- 0.85% in the pre-diabetes group (impaired glucose tolerance and impaired fasting glucose), and 1.08 +/- 0.57% in the diabetes group. The beta-cell area of the pre-diabetes group was significantly higher than that of the diabetes group. Pancreatic beta cell area showed a significant correlation with a homeostasis model assessment of beta-cell function (r=0.358, P=0.016), disposition index (r=0.336, P=0.024), fasting glucose (r=-0.359, P=0.015), and the C-peptide/glucose 30 min ratio (r=0.319, P=0.035). CONCLUSIONS: Some parameters of beta-cell function from the OGTT showed a significant relationship with the beta-cell area of pancreas. PMID- 21612839 TI - Profiling hospitals based on emergency readmission: a multilevel transition modelling approach. AB - Emergency readmission is seen as an important part of the United Kingdom government policy to improve the quality of care that patients receive. In this context, patients and the public have the right to know how well different health organizations are performing. Most methods for profiling estimate the expected numbers of adverse outcomes (e.g. readmission, mortality) for each organization. A number of statistical concerns have been raised, such as the differences in hospital sizes and the unavailability of relevant data for risk adjustment. Having recognized these statistical concerns, a new framework known as the multilevel transition model is developed. Hospital specific propensities of the first, second and further readmissions are considered to be measures of performance, where these measures are used to define a new performance index. During the period 1997 and 2004, the national (English) hospital episodes statistics dataset comprise more than 5 million patient readmissions. Implementing a multilevel model using the complete population dataset could possibly take weeks to estimate the parameters. To resolve the problem, we extract 1000 random samples from the original data, where each random sample is likely to lead to differing hospital performance measures. For computational efficiency a Grid implementation of the model is developed. Analysing the output from the full 1000 sample, we noticed that 4 out of the 5 worst performing hospitals treating cancer patients were in London. These hospitals are known to be the leading NHS Trusts in England, providing diverse range of services to complex patients, and therefore it is inevitable to expect higher numbers of emergency readmissions. PMID- 21612840 TI - Methane oxidation in a crude oil contaminated aquifer: Delineation of aerobic reactions at the plume fringes. AB - High resolution direct-push profiling over short vertical distances was used to investigate CH(4) attenuation in a petroleum contaminated aquifer near Bemidji, Minnesota. The contaminant plume was delineated using dissolved gases, redox sensitive components, major ions, carbon isotope ratios in CH(4) and CO(2), and the presence of methanotrophic bacteria. Sharp redox gradients were observed near the water table. Shifts in delta(13)C(CH4) from an average of -57.60/00 (+/ 1.70/00) in the methanogenic zone to -39.60/00 (+/-8.70/00) at 105m downgradient, strongly suggest CH(4) attenuation through microbially mediated degradation. In the downgradient zone the aerobic/anaerobic transition is up to 0.5m below the water table suggesting that transport of O(2) across the water table is leading to aerobic degradation of CH(4) at this interface. Dissolved N(2) concentrations that exceeded those expected for water in equilibrium with the atmosphere indicated bubble entrapment followed by preferential stripping of O(2) through aerobic degradation of CH(4) or other hydrocarbons. Multivariate and cluster analysis were used to distinguish between areas of significant bubble entrapment and areas where other processes such as the infiltration of O(2) rich recharge water were important O(2) transport mechanisms. PMID- 21612841 TI - Can performance in medical school predict performance in residency? A compilation and review of correlative studies. AB - BACKGROUND: The current resident selection process relies heavily on medical student performance, with the assumption that analysis of this performance will aid in the selection of successful residents. Although there is abundant literature analyzing indicators of medical student performance measures as predictors of success in residency, wide-ranging differences in beliefs persist concerning their validity. OBJECTIVE: We sought to collect and review studies that have correlated medical student performance with residency performance. METHODS: The English-language literature from 1996 to 2009 was searched with PubMed. Selected studies evaluated medical students on the basis of US Medical Licensing Examination scores, preclinical and clinical performance, research experience, objective structured clinical examination performance, medical school factors, honor society membership, Medical Student Performance Evaluations, letters of recommendation, and faculty interviews. Outcome measures were standardized residency examinations and residency supervisor ratings. RESULTS: The medical student factors that correlated most strongly with performance on examinations in residency were medical student examination scores, clinical performance, and honor society membership. Those that correlated most strongly with supervisor ratings were clinical grades, faculty interview, and medical school attended. Overall, there were inconsistent results for most performance measures. LIMITATIONS: In addition to the lack of a widely used measure of success in residency, most studies were small, single institution, and single specialty, and thus of limited ability to generalize findings. CONCLUSION: No one medical student factor can be used to predict performance in residency. There is a need for a more consistent and systematic approach to determining predictors of success in residency. PMID- 21612842 TI - High coverage and safety of influenza A (H1N1) 2009 monovalent vaccination among health care personnel in Thailand. AB - We aimed to report the coverage and safety of the influenza A (H1N1) 2009 monovalent vaccination (Panenza; Sanofi Pasteur, Val de Reuil Cedex, France) among health care personnel (HCP) in a university hospital setting in Thailand. The hospital set up a system to vaccinate HCP and did surveillance of the adverse effects (AEs). During a 4-week period, 6,210 (78.7%) HCP were vaccinated. There were 82 reported nonserious AEs among 32 HCP. The most common AE was fatigue/uncomfortable feeling (24%). PMID- 21612843 TI - Needlestick injuries among nursing staff: association with shift-level staffing. AB - BACKGROUND: Despite the advent of safety measures to protect the health care workforce from contracting blood-borne diseases, nurses still sustain percutaneous injuries. We investigated the association between shift-level staffing and needlestick injuries. METHODS: Shift-level staffing, patient occupancy, and acuity data were collected between 2003 and 2006 for the Military Nursing Outcomes Database (MilNOD), a multisite project that examined nurse staffing and adverse patient and nurse events. Data on needlestick injuries were obtained from occupational health/risk management reports and merged with MilNOD specific shift data. Hierarchical logistic regression, with Bayesian modeling, was used to analyze shift-level staffing, patient acuity, and workload as associated with needlestick injuries among nursing staff. RESULTS: Of 108,000 shifts, 80 (<0.1%) had at least one needlestick injury occurrence, with 62 (78%) involving a contaminated needle. There was no difference in rate by unit type. Factors associated with needlestick occurrences on shifts were lower RN skill mix, a lower percentage of experienced staff, and fewer nursing care hours per patient per shift. CONCLUSION: Needlestick injuries continue to occur. An organizational culture of safety should emphasize the need for adequate staffing on every shift and extra vigilance during periods of high workload. PMID- 21612844 TI - How we optimized prevention and control of pandemic 2009 influenza A (H1N1) in a resource-limited nation's pediatric oncology unit. PMID- 21612845 TI - Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in mice. AB - c-Ret has been shown to be crucial for neural development and survival. We have recently shown that complete impairment of tyrosine 1062 (Y1062)-phosphorylation in c-Ret causes congenital hearing loss with neurodegeneration of spiral ganglion neurons (SGNs) in homozygous c-Ret knockin mice (c-Ret-KI(Y1062F/Y1062F)-mice). However, there is no information to link c-Ret and age-related hearing loss. Here we show that partial impairment of Y1062-phosphorylation in c-Ret accelerates age related hearing loss in heterozygous c-Ret Y1062F knockin mice (c-Ret KI(Y1062F/+)-mice). In contrast, complete impairment of serine 697 (S697) phosphorylation in c-Ret did not affect hearing levels in 10-month-old homozygous c-Ret S697A knockin mice (c-Ret-KI(S697A/S697A)-mice). The hearing loss involved late-onset neurodegeneration of spiral ganglion neurons in c-Ret-KI(Y1062F/+) mice. Morphological abnormalities in inner- and outer-hair cells and the stria vascularis in c-Ret-KI(Y1062F/+)-mice were undetectable. The acceleration of age related hearing loss in c-Ret-KI(Y1062F/+)-mice was rescued by introducing constitutively activated RET. Thus, our results suggest that c-Ret is a novel age related hearing loss-related molecule in mice. Our results suggest that these hearing losses partially share a common pathogenesis that is monogenetically caused by a single point mutation (Y1062F) in c-Ret. PMID- 21612846 TI - [Positron tomography with 18F-fluorodeoxyglucose in the preoperative evaluation of gall bladder lesions suspicious of malignancy. Diagnostic utility and clinical impact]. AB - BACKGROUND: Gallbladder carcinoma is a neoplasm having a poor prognosis in which the role of the positron emission tomography with (18)F-fluordeoxyglucose as a diagnostic tool, although of possible usefulness, has not been well-defined. METHODS/DESIGN: It is a prospective cohort of patients with radiologically malignant suspicious gallbladder lesions. A staging diagnostic presurgical FDG PET study was carried out in each patient using both dedicated PET and multimodality PET-CT scanners. Diagnostic accuracy parameters were calculated from the results of PET imaging and were correlated with the condition and/or the clinical course of the patients. The clinical impact of its implementation in the diagnosis of gallbladder carcinoma was also analyzed. RESULTS: A total of 42 patients were recruited (22 malignant lesions, 20 benign). Overall diagnostic accuracy was 83.33% for the diagnosis of the primary lesion, 88.89% for the evaluation of lymph node involvement and 85.1% for the evaluation of metastatic disease. Mean SUVmax in malignant gallbladder lesions was 6.14+/-2.89. ROC curve showed a cut-off value of 3.65 in the SUVmax for malignancy. Accuracy of PET studies alone (n=21) was slightly lower than that of the PET/CT (n=21). FDG-PET changed the management of 14.8% of the population due to the identification of unsuspected metastatic disease. COMMENTS: FDG-PET accurately diagnoses malignancy or benignity of suspicious gallbladder lesions, with the addition of its capacity to identify unsuspected metastatic disease. PET-CT improves the diagnostic accuracy of the procedure, due to the metabolic-structural complementarity of their information. The SUVmax has a complementary value added to the visual analysis. PMID- 21612847 TI - Determination of the minimal essential serum folate concentration for reduced risk of colorectal adenoma. AB - BACKGROUND & AIMS: There are no data regarding basal folate levels in patients without colorectal adenoma. This study aimed to determine the minimum serum folate concentration that associates with reduced risk of colorectal adenoma. METHODS: 1510 consecutive patients underwent total colonoscopy for suspected colorectal lesions after barium enema examination. Prior to colonoscopy, history of alcohol consumption was noted and blood serum analyzed for folate and vitamin B12 levels. Polypoid lesions were evaluated histologically. We excluded patients with anemia, history of colonoscopy, overconsumption of alcohol, or malignancies. In all, 458/1510 patients (male/female; 258/200, 40-75 years) were determined eligible. Variables were compared between patients with adenoma and those without adenoma. RESULTS: Serum folate concentration was the variable with the most significant statistical variation between males with adenoma (8.0 ng/ml) and males without adenoma (9.2) (p = 0.001). Serum folate concentrations in females with adenoma did not differ significantly from those in females without adenoma (10.7 versus 10.9). When subjects were stratified into groups according to serum folate, we found no significant difference in the prevalence of adenoma in patients with folate levels greater than 8.0 ng/ml. CONCLUSION: Patients with serum folate concentrations above 8.0 ng/ml had the lowest risk of developing colorectal adenoma. PMID- 21612848 TI - Impact of body mass index and viral load on liver histology in hepatitis B e antigen-negative chronic hepatitis B. AB - BACKGROUND & AIMS: The impact of overweight and obesity on chronic hepatitis B (CHB) is unclear. This study was to examine the relationship among body mass index, viral load and liver histology in HBeAg-negative CHB. METHODS: The study retrospectively investigated 136 HBeAg-negative chronic hepatitis B patients who had undergone liver biopsies in Taiwan. Factors associated with significant liver histology were analyzed. Definitions of overweight and obesity for the Asian population were body mass index>=23 kg/m(2) and >=25 kg/m(2), respectively. RESULTS: The prevalence of overweight, obesity, and type 2 diabetes mellitus in the 136 patients were 22.8%, 52.2%, and 12.5%, respectively. Multivariate analysis identified obesity, AST>40 U/L, HBV DNA>20,000IU/mL and platelet count<150 * 10(9)/L as independent factors associated with significant liver fibrosis. Similarly, overweight/obesity, ALT>80 U/L, HBV DNA>1,000,000IU/mL, and platelet count<150 * 10(9)/L were independent predictors of significant hepatic necro-inflammation. By stratification, high BMI and high viral load patients had more advanced stage and grade of liver histology. CONCLUSIONS: Body mass index and HBV viral loads may have synergistic effect on disease progression in HBeAg negative CHB. Both controlling body weight and anti-viral therapy are important in the management of CHB. PMID- 21612849 TI - Facial trauma: a case of potentially life-threatening distracting injuries. AB - We report the case of a 60-year-old cyclist with multiple facial lacerations. Reassessment of the mechanism of injury and presenting clinical features of a change in voice, odynophagia, and a graze in the anterior neck triggered concern. Fibreoptic nasoendoscopy showed a large haematoma of the supraglottic airway. Scans confirmed laryngeal injuries, which were managed conservatively as an inpatient without prophylactic tracheostomy. This report emphasises the importance of a high index of suspicion in patients with such facial injuries and other subtle signs, and highlights the need for careful clinical assessment. PMID- 21612850 TI - Early dental implant failure: risk factors. AB - The objective of this prospective study was to estimate the incidence of early loss of dental implants and the potential risk factors. The predictive variables were classified as being patient, implant, anatomical, or operation-specific. The outcome variable was early failure of the implant. The significance of differences was assessed using bivariate analyses, and then a multivariate logistic regression model to identify independent predictors for early loss of implants. A total of 169 patients, 116 women and 53 men, mean age 47 (range 16 80) years, had 399 implants inserted. Fifteen implants were lost in 14 patients (8%). The early loss of dental implants was significantly associated with width of keratinised gingiva (p=0.008), the use polyglactin sutures (p=0.048), and the use of narrow implants (p=0.035). Multivariate logistic regression analysis established the significance of narrow keratinised gingiva (OR=4.7, p=0.005) and the use of polyglactin sutures (OR=3.8, p=0.042), which we conclude are probably the strongest predictors of early failure of implants. PMID- 21612851 TI - Income inequality and personality: are less equal U.S. states less agreeable? AB - Richard Wilkinson's 'inequality hypothesis' describes the relationship between societal income inequality and population health in terms of the corrosive psychosocial effects of social hierarchy. An explicit component of this hypothesis is that inequality should lead individuals to become more competitive and self-focused, less friendly and altruistic. Together these traits are a close conceptual match to the opposing poles of the Big Five personality factor of Agreeableness; a widely used concept in the field of personality psychology. Based on this fact, we predicted that individuals living in more economically unequal U.S. states should be lower in Agreeableness than those living in more equal states. This hypothesis was tested in both ecological and multilevel analyses in the 50 states plus Washington DC, using a large Internet sample (N = 674,885). Consistent with predictions, ecological and multilevel models both showed a negative relationship between state level inequality and Agreeableness. These relationships were not explained by differences in average income, overall state socio-demographic composition or individual socio-demographic characteristics. PMID- 21612852 TI - [Sudden death due to histiocytoid cardiomyopathy]. PMID- 21612853 TI - Feasibility of pulse oximetry in the initial prehospital management of victims of drowning: a preliminary study. AB - AIM: Immediate delivery of oxygen is the most important treatment for victims of drowning at the rescue site. Monitoring oxygen saturation with pulse oximetry is potentially useful, but its use may be limited by poor peripheral perfusion due to hypothermia. This preliminary study explores the feasibility of pulse oximetry in simulated minor drowning scenarios. MATERIALS AND METHODS: Six different pulse oximeters were tested on ten healthy volunteers after brief submersion, after ten minutes of swimming in a swimming pool (warm water, temperature 21 degrees C), and in the sea (cold water, temperature 16 degrees C). A measured oxygen saturation reading <= 94% was assumed to be incorrect. RESULTS: There was considerable variability between each pulse oximeter. In warm water, 5.8% of measurements were outside the predicted range (8.3% after submersion, 3.3% after swimming), compared to 34% in cold water (20% after submersion, 48% after swimming). The spurious measurements came from two pulse oximeters in warm water, but from all six in cold water. The best and worst performing pulse oximeters showed 5% and 33% measurements respectively outside the predicted range. CONCLUSION: The performance of pulse oximeters varies considerably in healthy volunteers submersed or immersed in warm or cold water. Further studies are needed to understand these differences. PMID- 21612854 TI - Leaning is common in chest compressions but remains a relatively unknown entity. PMID- 21612856 TI - Retinoic acid-induced Smad3 expression is required for the induction of osteoblastogenesis of mesenchymal stem cells. AB - Mesenchymal stem cells are pluripotent precursor cells that can differentiate into osteoblasts, adipocytes, chondrocytes and myocytes. Despite their important therapeutic potential little is known about the transcriptional cascades that govern lineage decisions in these cells. Treatment of C3H10T1/2 mouse mesenchymal stem cells with retinoic acid (RA) inhibits adipogenesis and enhances osteoblastogenesis. In particular, RA treatment stimulates the expression of the osteoblast master regulator, runt-related transcription factor 2 (Runx2), whose expression is necessary for the formation of bone. We have shown previously in mesenchymal stem cells that RA acts to stimulate osteoblastogenesis by interfering with the actions of the bzip transcription factor CCAAT/Enhancer Binding Protein beta (C/EBPbeta), where it binds to a negative regulatory element within the Runx2 promoter and inhibits its expression. Herein we show that Smad3, whose expression is stimulated by RA, relays the effects of RA on differentiation by initiating the displacement of C/EBPbeta from the Runx2 promoter. In addition to stimulating Smad3 expression, RA also stimulated the nuclear localization of this factor, such that in the absence of RA, ectopic Smad3 was unable to drive osteoblastogenesis. While not sufficient to promote osteoblastogenesis, knockdown of Smad3 using a specific shRNA prevented the RA-mediated stimulation of differentiation and displacement of C/EBPbeta from the Runx2 P1 promoter. Taken together, these data indicate that Smad3 is an important mediator of RA activity during mesenchymal stem cell differentiation and is necessary for the stimulation of osteoblastogenesis. PMID- 21612855 TI - Normal and abnormal epithelial differentiation in the female reproductive tract. AB - In mammals, the female reproductive tract (FRT) develops from a pair of paramesonephric or Mullerian ducts (MDs), which arise from coelomic epithelial cells of mesodermal origin. During development, the MDs undergo a dynamic morphogenetic transformation from simple tubes consisting of homogeneous epithelium and surrounding mesenchyme into several distinct organs namely the oviduct, uterus, cervix and vagina. Following the formation of anatomically distinctive organs, the uniform MD epithelium (MDE) differentiates into diverse epithelial cell types with unique morphology and functions in each organ. Classic tissue recombination studies, in which the epithelium and mesenchyme isolated from the newborn mouse FRT were recombined, have established that the organ specific epithelial cell fate of MDE is dictated by the underlying mesenchyme. The tissue recombination studies have also demonstrated that there is a narrow developmental window for the epithelial cell fate determination in MD-derived organs. Accordingly, the developmental plasticity of epithelial cells is mostly lost in mature FRT. If the signaling that controls epithelial differentiation is disrupted at the critical developmental stage, the cell fate of MD-derived epithelial tissues will be permanently altered and can result in epithelial lesions in adult life. A disruption of signaling that maintains epithelial cell fate can also cause epithelial lesions in the FRT. In this review, the pathogenesis of cervical/vaginal adenoses and uterine squamous metaplasia is discussed as examples of such incidences. PMID- 21612857 TI - Global trends in testicular cancer incidence and mortality. AB - BACKGROUND: Epidemiologic studies on testicular cancer have focused primarily on European countries. Global incidence and mortality have been less thoroughly evaluated. OBJECTIVE: Our goal was to gain a better understanding of the most recent global age-standardized incidence and mortality rates for testicular cancer and to use these values to estimate a region's health care quality. DESIGN, SETTING, AND PARTICIPANTS: Age-standardized incidence rate (ASIR) and age standardized mortality rate (ASMR) for testicular cancer were obtained for men of all ages in 172 countries by using the GLOBOCAN 2008 database, reflecting the annual rate of cancer incidence and mortality per 100,000 men. These data were evaluated on a regional level to compare incidence and mortality rates. Global plots of these values were constructed to better visualize geographic distributions. Finally, the ratio of ASIR to ASMR was calculated as a method to assess each region's proficiency in diagnosing and effectively treating testicular cancer. MEASUREMENTS: ASIR and ASMR were analyzed by region, and each region's ratio of ASIR to ASMR was calculated. RESULTS AND LIMITATIONS: Testicular cancer ASIR is highest in Western Europe (7.8%), Northern Europe (6.7%), and Australia (6.5%). Asia and Africa had the lowest incidence (<1.0%). ASMR was highest in Central America (0.7%), western Asia (0.6%), and Central and Eastern Europe (0.6%). Mortality was lowest in North America, Northern Europe, and Australia (0.1-0.2%). The ASIR-ASMR ratio was highest in Australia (65.0%) and lowest in western Africa (1.0%). National reporting systems varied by country, and data quality may have fluctuated between regions. CONCLUSIONS: Testicular cancer incidence remains highest in developed nations with primarily Caucasian populations. Variable ASIR-ASMR ratios suggest markedly different geographic-specific reporting mechanisms, access to care, and treatment capabilities. PMID- 21612859 TI - Factors determining functional outcomes after radical prostatectomy: robot assisted versus retropubic. AB - BACKGROUND: Early studies reported comparative results of functional outcomes between robot-assisted (RARP) and retropubic radical prostatectomy (RRP). However, well-controlled single-surgeon prospective studies comparing the outcomes are rare. OBJECTIVE: To compare functional outcomes after RARP and RRP performed by a single surgeon, and to identify factors predictive of early return of continence and potency. DESIGN, SETTING, AND PARTICIPANTS: A total of 763 consecutive patients undergoing RP between 2007 and 2010 were prospectively included and serially followed postoperatively for comparative analysis. INTERVENTION: RARP was performed in 528 patients, and 235 underwent RRP. MEASUREMENTS: Continence was defined as being completely pad free. Potency was defined as having erection sufficient for intercourse with or without a phosphodiesterase type 5 inhibitor. Continence and potency recovery were checked serially by interview and questionnaire at 1, 3, 6, 9, 12, 18, and 24 mo postoperatively. Cox proportional hazards method analyses was performed to determine predictive factors for early recovery. RESULTS AND LIMITATIONS: After the initial 132 cases, patients who underwent RARP demonstrated faster recovery of urinary continence compared to RRP patients. Potency recovery was more rapid in the RARP group at all evaluation time points, beginning from the initial cases. In multivariate analysis, younger age and longer preoperative membranous urethral length seen by prostate magnetic resonance imaging (MRI) demonstrated statistical significance as independent prognostic factors for continence recovery; younger age, surgical method (RARP vs RRP), and higher preoperative serum testosterone were independent prognostic factors for potency recovery. The limitations of the present study were that it was nonrandomized and used interview to evaluate potency recovery. CONCLUSIONS: Patients after RARP demonstrated superior functional recovery. Moreover, membranous urethral length on preoperative MRI and patient age were factors independently predictive of continence recovery, while patient age and higher preoperative serum testosterone were independent prognostic factors for potency recovery. PMID- 21612860 TI - The outcome of patients treated with sunitinib prior to planned nephrectomy in metastatic clear cell renal cancer. AB - BACKGROUND: The role of cytoreductive nephrectomy in metastatic clear cell renal cell carcinoma (ccRCC) is controversial. OBJECTIVE: To determine the outcome of patients with metastatic ccRCC who receive sunitinib prior to planned nephrectomy. DESIGN, SETTING, AND PARTICIPANTS: The study combined the data from two prospective phase 2 studies that assessed upfront sunitinib (12-16 wk) prior to nephrectomy in previously untreated patients with metastatic renal cell carcinoma (RCC). Sunitinib was discontinued during the perioperative period (median: 29 d). INTERVENTION: Sunitinib 50mg in six weekly cycles (4 wk on, 2 wk off). MEASUREMENTS: Progression-free (PFS) and overall survival (OS) using the Kaplan-Meier method. RESULTS AND LIMITATIONS: Twenty-one patients (32%) had Memorial Sloan-Kettering Cancer Centre (MSKCC) poor-risk disease; 45 (68%) had intermediate-risk disease. Nephrectomy was not performed in 19 (29%), most commonly due to disease progression (n = 12). The PFS for the cohort was 6.3 mo (95% confidence interval [CI], 5.1-8.5). Seventeen (36%) patients progressed during the treatment break, 13 (76%) of whom stabilised upon reinitiating of sunitinib. The OS for the cohort was 15.2 mo (95% CI, 10.3-NA). The OS for the intermediate MSKCC risk group was significantly longer than that for the poor risk group (26.0 mo [95% CI, 13.6-NA] and 9.0 mo [95% CI, 5.8-20.5], respectively; p < 0.01). In multivariate analysis, progression of disease prior to planned nephrectomy (hazard ratio [HR]: 5.34; 95% CI, 3.17-13.27), high Fuhrman grade (HR 3.27; 95% CI, 1.38-7.72), and MSKCC poor risk at diagnosis (HR 4.75; 95% CI, 2.05-11.02) were associated with short survival (p < 0.01). However, in the absence of randomised studies it is not possible to determine if this approach is beneficial. CONCLUSIONS: Upfront sunitinib prior to planned nephrectomy in intermediate-risk disease is associated with a median survival of >2 yr despite frequent progression during treatment break. Progression in metastatic sites prior to planned surgery and MSKCC poor-risk disease was associated with a poor outcome. PMID- 21612862 TI - Radiological hazards of TENORM in precipitated calcium carbonate generated as waste at nitrophosphate fertilizer plant in Pakistan. AB - The NORM (naturally occurring radioactive material) in phosphate rock is transferred as TENORM (technologically enhanced naturally occurring radioactive material) to phosphatic fertilizers and to the waste generated by the chemical processes. The waste generated at the NP (nitrophosphate) fertilizer plant at Multan in Pakistan is PCC (precipitated calcium carbonate). Thirty samples of the PCC were collected from the heaps of the waste near the fertilizer plant. Activity concentrations of radionuclides in the waste samples were measured by using the technique of gamma ray spectrometry consisting of coaxial type HPGe (high purity germanium) detector coupled with a PC (personal computer) based MCA (multichannel analyzer) through a spectroscopy amplifier. Activity concentrations of (226)Ra, (232)Th and (40)K in the waste samples were determined to be 273 +/- 23 (173-398), 32 +/- 4 (26-39) and 56 +/- 5 (46-66) Bq kg(-1) respectively. The activity concentration of (226)Ra in the PCC waste was found to be higher than that in naturally occurring calcium carbonate (limestone and marble) and in worldwide soil. Radiological hazard was estimated from indoor and outdoor exposure to gamma rays from the PCC. Indoor annual effective dose was higher than 1 mSv. Potential radiological pollution in the environment from TENORM in the PCC has also been addressed. PMID- 21612861 TI - Calycosin promotes proliferation of estrogen receptor-positive cells via estrogen receptors and ERK1/2 activation in vitro and in vivo. AB - Calycosin is a main active component of the herb Radix Astragali, and is considered as a phytoestrogen. Its effects in vivo may be either estrogenic or antiestrogenic, mainly depending upon the estrogen levels. This study was a continuation of our investigations of calycosin's promotion of the proliferation of estrogen receptor (ER)-positive cells via ERs and ERK1/2 activation in vitro and in vivo. ER-positive MCF-7 (human breast cancer) cells were treated with different concentrations of calycosin. Proliferation of the cells treated with calycosin was assayed by CCK8. Apoptosis in the treated cells was measured by flow cytometry. The protein expression of ERK1/2 in treated cells was determined by Western blot. In addition, the in vivo expression of ERalpha in the uterine tissues of ovariectomized (OVX) mice was assessed by immunohistochemistry. Compared with the control, low concentrations of calycosin (2-8 MUM) stimulated the proliferation of MCF-7 cells and decreased the percentage of early apoptosis. The level of p-ERK1/2 was also downregulated at these low concentrations. Furthermore, we found that an ERK1/2 inhibitor significantly blocked the effect of calycosin in MCF-7 cells. In the in vivo studies, calycosin stimulated a dramatic increase in uterine weight and downregulated the level of ERalpha protein in OVX mice. This study demonstrated that at relatively low concentrations calycosin had stimulatory effects on the proliferation of MCF-7 cells, and we conclude that this is due to its estrogenic effect. PMID- 21612863 TI - Effects of alternating and direct current in electrocoagulation process on the removal of cadmium from water. AB - In practice, direct current (DC) is used in an electrocoagulation processes. In this case, an impermeable oxide layer may form on the cathode as well as corrosion formation on the anode due to oxidation. This prevents the effective current transfer between the anode and cathode, so the efficiency of electrocoagulation processes declines. These disadvantages of DC have been diminished by adopting alternating current (AC) in electrocoagulation processes. The main objective of this study is to investigate the effects of AC and DC on the removal of cadmium from water using aluminum alloy as anode and cathode. The results showed that the removal efficiency of 97.5 and 96.2% with the energy consumption of 0.454 and 1.002 kWh kl(-1) was achieved at a current density of 0.2A/dm(2) and pH of 7.0 using aluminum alloy as electrodes using AC and DC, respectively. For both AC and DC, the adsorption of cadmium was preferably fitting Langmuir adsorption isotherm, the adsorption process follows second order kinetics and the temperature studies showed that adsorption was exothermic and spontaneous in nature. PMID- 21612864 TI - Enhanced sorption of radiocobalt from water by Bi(III) modified montmorillonite: a novel adsorbent. AB - In this study, Ca-montmorillonite (Ca-Mt) modified with Bi(3+) was used as a novel adsorbent for the sorption of Co(II) from aqueous solutions. The sorption of Co(II) on Bi-montmorillonite (Bi-Mt) was investigated as a function of contact time, pH, ionic strength, adsorbent content, Co(II) concentrations, fulvic acid (FA) and temperature. Compared to Ca-Mt, Bi-Mt showed a higher affinity to bind Co(II) ions. The sorption percentage of Co(II) on Bi-Mt increased with increasing pH at pH 3.0-8.5, and then maintained the high level at pH 8.5-12. The sorption of Co(II) on Bi-Mt was dependent on ionic strength at low pH, and independent of ionic strength at high pH. The presence of FA enhanced Co(II) sorption at low pH, but suppressed Co(II) sorption at high pH. The thermodynamic data derived from temperature dependent sorption isotherms suggested that the sorption of Co(II) on Bi-Mt was spontaneous and endothermic process. Outer-sphere surface complexation and/or ion exchange were the main mechanisms of Co(II) sorption on Bi-Mt at low pH, whereas inner-sphere surface complexation was the main sorption mechanism at high pH. From the experimental results, it is possible to conclude that Bi-Mt is suitable for application of Co(II) removal from aqueous solutions. PMID- 21612865 TI - Isotherm, thermodynamic, kinetics and adsorption mechanism studies of methyl orange by surfactant modified silkworm exuviae. AB - This paper reports on the development of organo-modified silkworm exuviae (MSE) adsorbent prepared by using hexadecyltrimethylammonium bromide (HDTMAB) for removing methyl orange (MO), a model anionic dye, from aqueous solution. The natural and modified samples were characterized by scanning electron microscope (SEM), energy dispersive spectrometer (EDS) and Fourier transform infrared spectroscopy (FT-IR). Batch adsorption experiments were carried out to remove MO from its aqueous solutions using SE and MSE. It was observed that the adsorption capacity of MSE is 5-6 times of SE. The different parameters effecting on the adsorption capacity such as pH of the solution, initial dye concentration, temperature and contact time have been investigated. Analysis of adsorption results obtained at different temperatures showed that the adsorption pattern on the MSE can be described perfectly with Langmuir isotherm model compared with Freundlich and Dubinin-Radushkevich (D-R) isotherm models, and the characteristic parameters for each adsorption isotherm were also determined. The adsorption process has been found exothermic in nature and thermodynamic parameters have been calculated. The adsorption kinetic followed the pseudo-second order kinetic model. The results of FT-IR, EDS and desorption studies all suggest that methyl orange adsorption onto the MSE should be mainly controlled by the hydrophobic interaction mechanism, along with a considerable contribution of the anionic exchange mechanism. The results indicate that HDTMAB-modified silkworm exuviae could be employed as low-cost material for the removal of methyl orange anionic dye from wastewater. PMID- 21612866 TI - Thermal explosion hazards on 18650 lithium ion batteries with a VSP2 adiabatic calorimeter. AB - Thermal abuse behaviors relating to adiabatic runaway reactions in commercial 18650 lithium ion batteries (LiCoO(2)) are being studied in an adiabatic calorimeter, vent sizing package 2 (VSP2). We select four worldwide battery producers, Sony, Sanyo, Samsung and LG, and tested their Li-ion batteries, which have LiCoO(2) cathodes, to determine their thermal instabilities and adiabatic runaway features. The charged (4.2V) and uncharged (3.7 V) 18650 Li-ion batteries are tested using a VSP2 with a customized stainless steel test can to evaluate their thermal hazard characteristics, such as the initial exothermic temperature (T(0)), the self-heating rate (dT/dt), the pressure rise rate (dP/dt), the pressure-temperature profiles and the maximum temperature (T(max)) and pressure (P(max)). The T(max) and P(max) of the charged Li-ion battery during the runaway reaction reach 903.0 degrees C and 1565.9 psig (pound-force per square inch gauge), respectively. This result leads to a thermal explosion, and the heat of reaction is 26.2 kJ. The thermokinetic parameters of the reaction of LiCoO(2) batteries are also determined using the Arrhenius model. The thermal reaction mechanism of the Li-ion battery (pack) proved to be an important safety concern for energy storage. Additionally, use of the VSP2 to classify the self-reactive ratings of the various Li-ion batteries demonstrates a new application of the adiabatic calorimetric methodology. PMID- 21612867 TI - Use it or lose it--but how to use? PMID- 21612868 TI - Can 'ehealth' technology deliver on its promise of pain management for all? PMID- 21612869 TI - An intestinal Eimeria infection in juvenile Asian seabass (Lates calcarifer) cultured in Vietnam--a first report. AB - This is the first report of an intestinal Eimeria infection in Asian seabass (Lates calcarifer) at the histopathological and ultrastructural levels. The Eimeria infection was often associated with severe pathology and significant mortality in the absence of other pathogens. This showed that it is an important disease of juvenile L. calcarifer in small scale nurseries in Vietnam. Heavy infection and high prevalence levels of the Eimeria infection are suspected to be linked to the low daily water exchange rates practised in these nurseries. Although systemic iridovirus infection was concurrently observed in some of the fish examined, it was not as consistently present in diseased fish as the Eimeria infection. PMID- 21612870 TI - Prevalence and genetic diversity of Babesia and Anaplasma species in cattle in Sudan. AB - Disease prevalence studies are one of the most valuable tools to demonstrate the risk or impact of certain infections in local and global economies. The data obtained in these studies contribute to develop strategies for disease control. The present study aims to provide information about the prevalence of babesiosis and anaplasmosis in the northern regions of Sudan. Blood samples from four different states of Sudan were collected from apparently healthy cattle (n=692), DNA was extracted and the prevalence of Babesia and Anaplasma species was analyzed by PCR. The results confirmed the presence of Babesia bigemina, Babesia bovis and Anaplasma marginale in cattle in northern Sudan with overall prevalence rates of 4.0%, 1.9% and 6.1%, respectively. Statistical analysis revealed that the prevalence of B. bigemina, B. bovis and A. marginale varies significantly between Sudanese states as well as in different age groups, while gender seems not to have a significant effect on the prevalence of these pathogens among Sudanese cattle. The highest prevalence for B. bigemina was found in the Aljazirah State while the highest number of A. marginale positive samples was reported in River Nile. PMID- 21612871 TI - Molecular characterisation of Cryptosporidium isolates from pre-weaned calves in Romania: is there an actual risk of zoonotic infections? AB - Diarrheic fecal samples from 258 pre-weaned calves (1-30 day-old) from 9 dairy farms located in Banat region, Romania, were microscopically examined for the presence of Cryptosporidium oocysts. Overall, 65 (25%) samples were found positive. A higher percent of infection was recorded in calves aged between 8 and 14 days compared with other age categories (1-7, 8-14, 15-21 and 22-30 days; p<0.05). Genetic characterization was carried out on all Cryptosporidium-positive samples. After DNA extraction, Cryptosporidium species were determined by a nested PCR of the small subunit rRNA gene (18S) followed by RFLP analysis with SspI, VspI and MboII restriction enzymes. The restriction patterns showed that animals were infected with Cryptosporidium parvum. Subsequently, subtyping of 13 C. parvum isolates, based on sequence analysis of the 60 kDa glycoprotein (GP60) gene, showed 2 subtypes (IIaA15G2R1 and IIaA16G1R1) belonging to the subtype family IIa. This is the first molecular study of bovine Cryptosporidium infection in Romania. PMID- 21612872 TI - Mechanism of action of demethylating and immune modulatory agents--conclusion. PMID- 21612873 TI - The influence of chemotherapy on taste perception and food hedonics: a systematic review. AB - PURPOSE: Altered food relationships in people receiving chemotherapy are prevalent and distressing. Whether, or to what extent, taste perception and food hedonics plays in altered food relationships is unknown among people receiving chemotherapy. This two-armed systematic review addressed the question "Does chemotherapy influence taste perception and hedonic experience of food?" METHODS: A systematic review was undertaken of (1) taste perception and (2) food hedonics. Search phrases used in the taste arm were: "chemotherapy AND taste", and in the food hedonics arm, "chemotherapy AND (liking OR food OR appetite OR hedonic(*))". Databases searched were PsycINFO, PubMed, Medline, CINAHL, EMBASE and the Cochrane Library. English language, peer-reviewed publications investigating adults (>18years) receiving chemotherapy as the only cancer treatment were eligible. RESULTS: One hundred and sixty three papers were screened in the taste arm, of which eight (5%) met inclusion criteria. Nine hundred and seventy two papers were screened in the food hedonics arm of which 25 (3%) met inclusion criteria. Chemotherapy had variable influence on both taste sensitivity and perceived intensity of the taste qualities sweet, salty, sour and bitter. Liking of food and drink decreased after chemotherapy treatment commenced. Caffeinated foods and drinks, red meat and citrus fruits or juices were most frequently reported as aversive during chemotherapy. A reduction in appetite was reported between baseline (pre-chemotherapy) and cycles 1-3 of chemotherapy with no further worsening in latter chemotherapy cycles and an improvement after completion of chemotherapy treatment. CONCLUSIONS: There was a lack of consistency of results between studies due to differences in study design, chemotherapy regimen, tumor type and stage of treatment examined. These results provide insufficient evidence to suggest chemotherapy has a significant or consistent influence on taste. There is a consistent, albeit small, body of evidence indicating food liking and appetite are adversely affected by chemotherapy and some evidence that declines in liking and appetite are reversed over time. Overall, more longitudinal studies of specific classes of chemotherapy drugs are required to accurately define the nature, magnitude and time course of taste, food liking and appetite changes over the treatment trajectory. PMID- 21612874 TI - DNA methylation as a pathogenic event and as a therapeutic target in AML. AB - DNA methylation and its influence on gene expression are key in understanding cancer pathogenesis. Even though it is becoming clear that DNA methylation strongly interacts with other components of the epigenetic machinery such as histone modifications, aberrant DNA methylation can still be regarded as a crucial hallmark of cancer by itself. In Acute Myeloid Leukemia (AML), aberrations of DNA methylation also rank among the most frequent alterations observed. Recent studies revealed that specific patterns of DNA methylation characterize AML and help to distinguish AML subtypes. The contribution of this epigenetic dysregulation to leukemogenesis in AML is currently unclear. However, interactions between mutated transcription factors and epigenetic networks have already been shown to be partially responsible for leukemic transformation, for e.g. in acute promyelocytic leukemia (APL). Also, direct mutations in the epigenetic master regulators EZH2 and DNMT3A were recently identified in AML and in diseases leading to secondary leukemia. These findings strengthen the view that dysregulated epigenetic networks can induce AML. Correspondingly, epigenetic therapies e.g. hypomethylating drugs show significant activity in AML. While benefit is observed in many patients, DNA hypomethylating therapy by itself is not curative. Furthermore, it is not clear whether the drugs' effects are solely epigenetic in nature since in vitro studies suggest different mechanisms of action. Current clinical trials aim to improve efficacy of DNA hypomethylating drugs for e.g. by combination with standard AML chemotherapy. Taken together, targeting the epigenetic machinery seems to be the way towards more effective therapies in AML. PMID- 21612875 TI - Minimal residual disease in solid neoplasia: New frontier or red-herring? AB - Despite recent advances in prevention, screening, molecular characterization, and treatment, cancer evolution is still associated with late local, regional, or metastastic recurrence, even in early stages. Residual tumor cells can persist locally as cancer stem cells, in the blood flow as circulating tumor cells, and in distant organs as disseminated tumor cells or micrometastasis, defining three faces of minimal residual disease. Definition, preclinical models and clinical implications of these patterns will be detailed, with emphasis on overlaps and therapeutic implications, to determine whether minimal residual disease is only an old concept currently revisited, or a major shift in cancer paradigm. PMID- 21612876 TI - Curcumin ameliorates reserpine-induced pain-depression dyad: behavioural, biochemical, neurochemical and molecular evidences. AB - An apparent clinical relationship between pain and depression has long been recognized. Depression and pain are often diagnosed in the same patients. The emerging concept for pain-depression pathogenesis is the dysfunction of biogenic amine-mediated pain-depression control and the possible involvement of nitrodative stress-induced neurogenic inflammation. The present study was designed to investigate the effect of curcumin on reserpine-induced pain depression dyad in rats. Administration of reserpine (1mg/kg subcutaneous daily for three consecutive days) led to a significant decrease in nociceptive threshold as evident from reduced paw withdrawal threshold in Randall Sellitto and von-Frey hair test as well as significant increase in immobility time in forced swim test. This behavioural deficit was integrated with decrease in the biogenic amine (dopamine, norepinephrine and serotonin) levels along with increased substance P concentration, nitrodative stress, inflammatory cytokines, NF-kappabeta and caspase-3 levels in different brain regions (cortex and hippocampus) of the reserpinised rats. Curcumin (100, 200, 300mg/kg; ip) dose dependently ameliorated the behavioural deficits associated with pain and depression by restoring behavioural, biochemical, neurochemical and molecular alterations against reserpine-induced pain-depression dyad in rats. PMID- 21612877 TI - A novel promising therapy for vein graft restenosis: overexpressed Nogo-B induces vascular smooth muscle cell apoptosis by activation of the JNK/p38 MAPK signaling pathway. AB - Coronary artery bypass grafting using autologous saphenous veins is a standard surgical therapy for coronary artery diseases. However, post-procedure vein graft restenosis impedes its effectiveness and often leads to a high morbidity and mortality, and a reduction in the quality of life. Neointimal hyperplasia is a major cause of vein graft occlusion, and is characterized by an imbalance between vascular smooth muscle cell (VSMC) proliferation and apoptosis. So far, there have been no optimally effective pharmacological or non-pharmacological interventions for the prevention and treatment of vein graft occlusion. Gene therapy has emerged as a potential therapeutic approach, as bypass grafts can be genetically modified ex vivo prior to grafting in the coronary vasculature. Nogo B, recognized as a vascular protective factor, has been shown to reduce neointimal thickening in graft veins, but its specific mechanism is uncertain. Evidence from diverse sources has documented that overexpressed Nogo-B can induce apoptosis of variant cancer cell lines, suggesting that overexpressed Nogo-B may have a pro-apoptotic role in VSMC. Furthermore, we have found that Nogo-B is associated with the mitogen-activated protein kinase (MAPK) signaling pathway, which plays important roles in cell growth, differentiation, and apoptosis. Recent studies have shown that VSMC apoptosis can be induced by activation of the c-Jun-N-terminal kinase (JNK)/p38 MAPK pathway. Therefore, we propose that overproduction of Nogo-B in the graft vein could result in reduced neointimal hyperplasia, the mechanism of which involves increased VSMC apoptosis induced by activation of the JNK/p38 MAPK pathway. This study will provide a new clue for gene therapy in the treatment of vein graft failure. PMID- 21612878 TI - Peptide biomarkers as a way to determine meat authenticity. AB - Meat fraud implies many illegal procedures affecting the composition of meat and meat products, something that is commonly done with the aim to increase profit. These practices need to be controlled by legal authorities by means of robust, accurate and sensitive methodologies capable to assure that fraudulent or accidental mislabelling does not arise. Common strategies traditionally used to assess meat authenticity have been based on methods such as chemometric analysis of a large set of data analysis, immunoassays or DNA analysis. The identification of peptide biomarkers specific of a particular meat species, tissue or ingredient by proteomic technologies constitutes an interesting and promising alternative to existing methodologies due to its high discriminating power, robustness and sensitivity. The possibility to develop standardized protein extraction protocols, together with the considerably higher resistance of peptide sequences to food processing as compared to DNA sequences, would overcome some of the limitations currently existing for quantitative determinations of highly processed food samples. The use of routine mass spectrometry equipment would make the technology suitable for control laboratories. PMID- 21612879 TI - Changes in protective behavioral strategies and alcohol use among college students. AB - BACKGROUND: Protective behavioral strategies (PBS) are specific cognitive behavioral strategies designed to reduce alcohol consumption and resulting negative consequences. A host of studies have examined the cross-sectional relationship between such strategies and alcohol use in the high-risk population of United States college students, but prospective studies on the construct are lacking. The primary purposes of this study were to determine if PBS use prospectively predicted subsequent alcohol use/alcohol-related problems and if changes in PBS use were associated with less alcohol use and fewer problems. METHODS: Data were examined from 521 heavy drinking college students (60% male, 84% White, mean age=18.9 years). Participants completed questionnaires assessing alcohol use, alcohol-related problems, and PBS use at baseline, 6-month, and 12 month follow-ups. RESULTS: Analysis of residualized change scores indicated that increases in some PBS across time were associated with less alcohol use and fewer alcohol-related problems at follow-up. Findings regarding the prospective relationship between PBS use and subsequent alcohol use/problems were equivocal. DISCUSSION: Results from the study suggest that PBS may have value in alcohol related interventions among college students. Clinicians who help clients increase their use of PBS may help those clients increase the probability of drinking less and experiencing fewer alcohol-related problems in the future. PMID- 21612880 TI - Molecular aspects of skin ageing. AB - Ageing of human skin may result from both the passage of time (intrinsic ageing) and from cumulative exposure to external influences (extrinsic ageing) such as ultraviolet radiation (UVR) which promote wrinkle formation and loss of tissue elasticity. Whilst both ageing processes are associated with phenotypic changes in cutaneous cells, the major functional manifestations of ageing occur as a consequence of structural and compositional remodeling of normally long-lived dermal extracellular matrix proteins. This review briefly considers the effects of ageing on dermal collagens and proteoglycans before focusing on the mechanisms, functional consequences and treatment of elastic fibre remodeling in ageing skin. The early stages of photoageing are characterised by the differential degradation of elastic fibre proteins and whilst the activity of extracellular matrix proteases is increased in photoexposed skin, the substrate specificity of these enzymes is low. We have recently shown however, that isolated fibrillin microfibrils are susceptible to direct degradation by physiologically attainable doses of UV-B radiation and that elastic fibre proteins as a group are highly enriched in UV-absorbing amino acid residues. Functionally, elastic fibre remodeling events may adversely impact on: the mechanical properties of tissues, the recruitment and activation of immune cells, the expression of matrix metalloproteinases and cytokine signaling (by perturbing fibrillin microfibril sequestration of TGFbeta). Finally, newly developed topical interventions appear to be capable of regenerating elements of the elastic fibre system in ageing skin, whilst systemic treatments may potentially prevent the pathological tissue remodeling events which occur in response to elastic fibre degradation. PMID- 21612881 TI - A boy with a severe phenotype of succinic semialdehyde dehydrogenase deficiency. AB - Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting gamma-aminobutyric acid degradation. We describe here a boy with a severe phenotype of SSADH deficiency. He was referred because of a developmental delay at 4 months of age. At the age of 8 months, severe seizures developed. The diagnosis of SSADH deficiency was confirmed by an increase in 4-hydroxybutyric acid and heteroallelic mutation in the ALDH5A1 gene. His seizures were successfully treated with high-dose phenobarbital, and the electroencephalogram (EEG) abnormalities were ameliorated. However, the patient showed a degenerative clinical course with severe neurological deficits. A magnetic resonance imaging (MRI) scan revealed abnormal high intensities in the putamina and caudate nuclei on T2-weighted images, followed by marked atrophic changes. The clinical manifestation of our patient indicates the wide variety of SSADH deficiency phenotypes. PMID- 21612882 TI - Evaluation of breast lesions by contrast enhanced ultrasound: qualitative and quantitative analysis. AB - OBJECTIVE: To evaluate and compare the diagnostic performance of qualitative, quantitative and combined analysis for characterization of breast lesions in contrast enhanced ultrasound (CEUS), with histological results used as the reference standard. METHODS: Ninety-one patients with 91 breast lesions BI-RADS 3 5 at US or mammography underwent CEUS. All lesions underwent qualitative and quantitative enhancement evaluation. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of different analytical method for discrimination between benign and malignant breast lesions. RESULTS: Histopathologic analysis of the 91 lesions revealed 44 benign and 47 malignant. For qualitative analysis, benign and malignant lesions differ significantly in enhancement patterns (p<0.05). Malignant lesions more often showed heterogeneous and centripetal enhancement, whereas benign lesions mainly showed homogeneous and centrifugal enhancement. The detectable rate of peripheral radial or penetrating vessels was significantly higher in malignant lesions than in benign ones (p<0.001). For quantitative analysis, malignant lesions showed significantly higher (p=0.031) and faster enhancement (p=0.025) than benign ones, and its time to peak was significantly shorter (p=0.002). The areas under the ROC curve for qualitative, quantitative and combined analysis were 0.910 (A(z1)), 0.768 (A(z2)) and 0.926(A(z3)) respectively. The values of A(z1) and A(z3) were significantly higher than that for A(z2) (p=0.024 and p=0.008, respectively). But there was no significant difference between the values of A(z1) and A(z3) (p=0.625). CONCLUSIONS: The diagnostic performance of qualitative and combined analysis was significantly higher than that for quantitative analysis. Although quantitative analysis has the potential to differentiate benign from malignant lesions, it has not yet improved the final diagnostic accuracy. PMID- 21612883 TI - Methylobacterium bullatum sp. nov., a methylotrophic bacterium isolated from Funaria hygrometrica. AB - A novel, pink-pigmented aerobic, facultatively methylotrophic bacterial strain (F3.2(T)) isolated from the phyllosphere of Funaria hygrometrica, was analyzed using a polyphasic approach. Cells were Gram-negative, motile rods, strictly aerobic and non-spore-forming and exhibited surface structures varying in quantity, distribution and morphology. The isolate grew at 10-33 degrees C over a pH range of 5.5-8.0 and in the presence of less than 1.0% NaCl. Strain F3.2(T) shared less than 70% DNA-DNA binding to the next type strain of the genus Methylobacterium (M. adhaesivum DSM 17169(T)). In addition to the major cellular fatty acid C(18:1)omega7c (81.7%), present in all Methylobacterium species (and also members of the genus Alphaproteobacteria), a high value (11.7%) of the fatty acids (summed feature) C(16:1)omega7c and/or iso-C(15:0)2OH was determined. Phylogenetic analyses based on 16S rDNA and methanol dehydrogenase gene sequences, DNA-DNA hybridization values, chemotaxonomic and phenotypic characteristics indicate that the strain F3.2(T) represents a novel species within the genus Methylobacterium. We propose the name Methylobacterium bullatum sp. nov. for this species. The type strain is the strain F3.2(T) (DSM 21893(T)=LMG 24788(T)). PMID- 21612884 TI - Changing practitioner behavior and building capacity in tobacco cessation treatment: the TEACH project. AB - OBJECTIVE: To facilitate interprofessional knowledge transfer to practice by increasing treatment capacity of health care practitioners to deliver evidence informed smoking cessation counseling. METHODS: TEACH (Training Enhancement in Applied Cessation Counseling and Health) combines diffusion of innovations with principles of adult learning to address the lack of system capacity to implement evidence-based smoking cessation treatments. Participants were professionals from 15 disciplines with commitment from their supervisor to implement the intervention. Pre- and post-training course evaluation surveys assessed the extent to which learning objectives were achieved and guided a continuous quality improvement process. RESULTS: Evaluation of 741 participants that attended the three-day Core Course from June 2007 to January 2009 revealed significant increases in pre- to post-training ratings of feasibility, importance, and confidence in using the intervention. In addition to attitudinal changes, practitioners made changes to practice behavior. At six months post-training, 55% of professionals were implementing the intervention and 91% engaged in knowledge transfer activities in their organizations/communities. CONCLUSION: Findings suggest that TEACH impacted clinical practice and may serve as a model for knowledge translation initiatives in other health behavior domains. PRACTICE IMPLICATIONS: These data demonstrate that it is feasible to operationalize interprofessional knowledge translation models to transfer research findings into practice. PMID- 21612885 TI - [Near-infrared spectroscopy monitoring during cardiac surgery: a promising concept?]. PMID- 21612886 TI - [French surgical checklist in a universitary hospital: achievements one year after implementation]. AB - OBJECTIVES: Implementation of the checklist "Safe surgery saves live" (CL) is associated with reduction of perioperative morbidity and mortality. In France, CL is mandatory in operating rooms (OR) since January 2010. The objective of this work was to evaluate the level of the roll out of the CL in our institution, a French universitary hospital. METHODS: Evaluation of the level of use of the CL and completion of each item of the CL during three periods of 15 days during the first year of development, live evaluation of the process of filling the CL form and opinion survey of the OR nurses who were CL coordinators in our institution. RESULTS: Use of CL was 88, 89 and 76%. Completion of preinduction, preincision and postoperative items was respectively 90, 90 and 75%. Only 4% of the analyzed CL was properly filled with communication in the OR at the three phases. Four out of five OR nurses recognized meeting difficulties with CL completion. Half of them felt CL was a communication tool and two out of three OR nurses felt CL was a security tool. CONCLUSION: CL evaluation restricted to levels of use is limited and should be extended to a qualitative evaluation. Communication in the OR remains insufficient and represents an important quality improvement aim to improve security in the OR. PMID- 21612887 TI - Lobaplatin suppresses proliferation and induces apoptosis in the human colorectal carcinoma cell Line LOVO in vitro. AB - Lobaplatin, as the third-generation platinum antineoplastic agent, showed promising antineoplastic effects in variety of preclinical test tumor models. We investigated the inhibition effect of lobaplatin on the colorectal carcinoma cell line LOVO in vitro, and explored its mechanism of action. The MTT assay was used to determine the inhibitory effect and inhibition ratio of lobaplatin on LOVO at various lobaplatin concentrations (500 MUM, 1000 MUM, 2000 MUM). Apoptosis was detected by terminal deoxynucleotide transferase-mediated dUTP nickend labelling (TUNEL). The cell cycle and apoptotic rate were analyzed by flow cytometry (FCM) and the expression of caspase-3,8,9 in cells was detected by chromometry. The results of MTT assay showed that proliferation of LOVO cells was inhibited by lobaplatin in a concentration-dependent manner. Apoptosis was detected in LOVO cells by TUNEL. The FCM assay indicated that lobaplatin altered the cell cycle and induced apoptosis of the LOVO cells when treated for 24h, the percentages of cells in the S phase transition were increased, whereas the percentages of cells in the G(2) transition were decreased. The expressions of caspase-389 is higher than the control group after LOVO cells were treated by lobaplatin. Lobaplatin can inhibit the proliferation of colorectal carcinoma cell line LOVO by inducing apoptosis in vitro. The mechanism may be related to the "S" cycle arrest in cell cycle distribution and the up-regulated expression of caspase-8 and caspase-9 which up-regulated the expression of caspase-3. PMID- 21612888 TI - An interpretative model of early indicators of specific developmental dyslexia in preschool age: a comparative presentation of three studies in Greece. AB - The detection of specific factors of the developmental dyslexia at an early stage, and the identification of the role of those factors responsible for its manifestation, is a fundamental area of study on dyslexia in the recent literature. The objective of the present study is to clarify that dysfunctions in the following specific domains contribute in a causal model to the occurrence of dyslexia at an early stage: phonological awareness, psychomotor ability (body shape, spatio-temporal orientation, grapho-motor ability and laterality), perception, memory, attention, prereading and prewriting skills. The results of three studies, --carried out in Greece--which revealed the above factors as main predictors of the early onset of Specific Developmental Dyslexia (SDD) and confirmed the importance of intervention methods to it, led us to the construction of the proposed, causal model. The findings of these three studies converge on the perspective that the understanding, diagnosis and treatment of dysfunctions in the above domains, from preschool age, enable the early and reliable prevention of future difficulties in the learning process of children. PMID- 21612889 TI - An efficient self-organizing RBF neural network for water quality prediction. AB - This paper presents a flexible structure Radial Basis Function (RBF) neural network (FS-RBFNN) and its application to water quality prediction. The FS-RBFNN can vary its structure dynamically in order to maintain the prediction accuracy. The hidden neurons in the RBF neural network can be added or removed online based on the neuron activity and mutual information (MI), to achieve the appropriate network complexity and maintain overall computational efficiency. The convergence of the algorithm is analyzed in both the dynamic process phase and the phase following the modification of the structure. The proposed FS-RBFNN has been tested and compared to other algorithms by applying it to the problem of identifying a nonlinear dynamic system. Experimental results show that the FS RBFNN can be used to design an RBF structure which has fewer hidden neurons; the training time is also much faster. The algorithm is applied for predicting water quality in the wastewater treatment process. The results demonstrate its effectiveness. PMID- 21612890 TI - Carcinoma of the parotid gland: developing prognostic indices. AB - Prognosis for parotid carcinomas is not-well defined. The authors have developed models that could be useful to define subgroups of patients with differential risks. Clinical and pathological variables, and immunohistochemically studied MMP 7, MMP-9, MT1-MMP, and VEGF proteins were analysed in 42 patients with parotid gland cancer, regarding disease-specific survival and loco-regional recurrence. A prognostic index (PI) was calculated by combining age, disease stage, squamous cell carcinoma histology, and vascular endothelial growth factor immunoexpression. Based on the values of this PI, patients were classified into three groups: 1.89-4.18 (SPI1); 4.2-7 (SPI2), and >7 (SPI3). Corresponding 5-year survival rates for these groups of patients were of 89%, 47%, and 21%, respectively. Regarding loco-regional recurrence three different patient groups were calculated combining three factors: T, N and grade. Differences amongst them were statistically significant and the estimated hazard ratios were 6.4 and 24.2 for intermediate and poor prognosis, respectively, taking the good prognostic group as reference. The authors identified several significant prognostic factors and they propose two PIs for disease-specific survival and for loco-regional recurrence. They allow for the calculation of death risk and recurrence for a given patient, providing a practical system for clinical use. PMID- 21612891 TI - Epilepsy related to radiotherapy in patients with nasopharyngeal carcinoma. AB - Radiotherapy is the standard radical treatment for nasopharyngeal carcinoma (NPC) and may cause radiation encephalopathy (RE). To investigate the characteristics of epilepsy in RE after NPC radiotherapy, we observed 101 RE patients after NPC radiotherapy during a 5-year study period. Seizure semiology, brain magnetic resonance imaging (MRI), electroencephalography (EEG) were studied. We found that epilepsy is a common symptom in these patients, with an incidence of 15.8%. In the variables of age, sex, post-radiotherapy interval, radiation dose, radiotherapy techniques, and radiation field, there were no significant differences between RE patients with and without epilepsy. Furthermore, we investigated seizure semiology and EEG records in RE patients with epilepsy, and found that generalized tonic-clonic seizure (GTCS) was the most common type. Cystic lesions in temporal lobes in MRI were more common in RE patients with epilepsy (18.74%), as compared with RE patients without epilepsy (9.41%). PMID- 21612892 TI - Solanum incanum extract (SR-T100) induces human cutaneous squamous cell carcinoma apoptosis through modulating tumor necrosis factor receptor signaling pathway. AB - BACKGROUND: The Solanum species herbs have been used to treat cancer for centuries; however, the underlying mechanisms and effectiveness in vivo remain unclear. OBJECTIVES: SR-T100, extracted from the Solanum incanum, contains solamargine alkaloid as the main active ingredient. Here, we investigated the apoptosis-inducing effects of SR-T100 for targeting squamous cell carcinoma (SCC) in vitro and in vivo. METHODS: We elucidated the mechanism by which SR-T100 induces apoptosis of human SCCs (A431, SCC4, SCC9, and SCC25) cells. The efficacy and safety issues were addressed regarding topical treatment of SR-T100 on UVB induced cutaneous SCC of hairless mice and actinic keratoses (AKs) of human. RESULTS: SR-T100 induces apoptosis in human SCCs cell lines by up-regulating the expressions of tumor necrosis factor receptors (TNFRs) and Fas, and downstream adaptors FADD/TRADD of the TNF-alpha and Fas ligand signaling cascades. SR-T100 also triggered the mitochondrial apoptotic pathway, as up-regulated cytochrome c and Bax, down-regulated Bcl-X(L). Animal experiments showed that all papillomas (35/35) and 27 of 30 UVB-induced microinvasive SCCs in hairless mice disappeared within 10 weeks after once-daily application of topical SR-T100. Furthermore, 13 patients, who suffered with 14 AKs, were treated with once-daily topical SR-T100 gel and 10 AKs cured after 16 weeks, showing negligible discomforts. CONCLUSION: Our studies indicate that SR-T100 induces apoptosis of SCC cells via death receptors and the mitochondrial death pathway. The high efficacy of SR-T100 in our preclinical trial suggests that SR-T100 is a highly promising herb for AKs and related disorders. PMID- 21612893 TI - Emergence of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae in Danish hospitals; this is in part explained by spread of two CTX-M 15 clones with multilocus sequence types 15 and 16 in Zealand. PMID- 21612895 TI - The PAW/GIPAW approach for computing NMR parameters: a new dimension added to NMR study of solids. AB - In 2001, Mauri and Pickard introduced the gauge including projected augmented wave (GIPAW) method that enabled for the first time the calculation of all electron NMR parameters in solids, i.e. accounting for periodic boundary conditions. The GIPAW method roots in the plane wave pseudopotential formalism of the density functional theory (DFT), and avoids the use of the cluster approximation. This method has undoubtedly revitalized the interest in quantum chemical calculations in the solid-state NMR community. It has quickly evolved and improved so that the calculation of the key components of NMR interactions, namely the shielding and electric field gradient tensors, has now become a routine for most of the common nuclei studied in NMR. Availability of reliable implementations in several software packages (CASTEP, Quantum Espresso, PARATEC) make its usage more and more increasingly popular, maybe indispensable in near future for all material NMR studies. The majority of nuclei of the periodic table have already been investigated by GIPAW, and because of its high accuracy it is quickly becoming an essential tool for interpreting and understanding experimental NMR spectra, providing reliable assignments of the observed resonances to crystallographic sites or enabling a priori prediction of NMR data. The continuous increase of computing power makes ever larger (and thus more realistic) systems amenable to first-principles analysis. In the near future perspectives, as the incorporation of dynamical effects and/or disorder are still at their early developments, these areas will certainly be the prime target. PMID- 21612894 TI - Higher than recommended amikacin loading doses achieve pharmacokinetic targets without associated toxicity. AB - Antibiotic therapy improves the outcome of severe sepsis and septic shock, however pharmacokinetic properties are altered in this scenario. Amikacin (AMK) is an option to treat community or nosocomial infections, although standard doses might be insufficient in critically ill patients. The aim of this study was to evaluate two AMK dosage regimens in comparison with standard therapy with regard to efficacy in achieving adequate plasma levels as well as safety. In total, 99 patients with severe sepsis or septic shock were randomised to different AMK dose protocols: Group 1, 25 mg/kg/day; Group 2, 30 mg/kg/day; and Group 3, historical standard dose (15 mg/kg/day). Peak plasma concentrations at 1 h (C(max)) were determined. Pharmacokinetics was determined and renal function was monitored to evaluate toxicity. Groups were compared using bilateral T-test. Demographic characteristics of the three groups were comparable. AMK C(max) values were 57.4+/-9.8, 72.1+/-18.4 and 35.2+/-9.4 MUg/mL, respectively (P<0.001 between Groups 1 and 2 versus Group 3, and P<0.01 between Group 1 versus Group 2). A C(max)>60 MUg/mL was reached by 39%, 76% and 0% of patients in Groups 1, 2 and 3, respectively (P<0.001) and creatinine clearance at Day 28 was 95.6+/-47.4, 89.7+/ 26.6 and 56.4+/-18.4 mL/min, respectively. In conclusion, a 30 mg/kg daily dose of AMK presents significantly higher C(max) compared with the other groups, with 76% of patients reaching recommended peak plasma levels with no association with higher nephrotoxicity. Standard doses are insufficient in critically ill patients to reach the recommended C(max). PMID- 21612896 TI - Comparative study of particle structure evolution during water sorption: skim and whole milk powders. AB - Surface composition of dairy powders influences significantly a quantity of functional properties such as rehydration, caking, agglomeration. Nevertheless, the kinetic of water uptake by the powders was never directly related to the structure and the composition of the surface. In this work, the effect of relative humidity on the structural reorganization of two types of dairy powder was studied. The water-powder interaction for industrial whole milk powder, and skim milk powder was studied using dynamic vapor sorption. The water sorption isotherms were fitted with a Brunner-Emmet-Teller model and each stage of the sorption curve was analyzed with a Fickian diffusion. The water content in the monolayer predicted for each powder and the moisture diffusivity calculated were discussed and compared. Concurrently, powders microstructure and powders surface under variable relative humidity were assessed by X-ray photoelectron spectroscopy, scanning electron microscopy coupled with energy dispersive X-ray and atomic force microscopy. A correlation between the data obtained from the sorption isotherms and the modifications of structure allowed us to conclude that powder microstructure and chemical state of the components could play an important role in determining the water diffusivity. PMID- 21612897 TI - Surface self-assembly of N-fluorenyl-9-methoxycarbonyl diphenylalanine on silica wafer. AB - N-Fluorenyl-9-methoxycarbonyl diphenylalanine (Fmoc-FF-OH) was chemically immobilized to the surface of silica wafer as the "seed". When immersing this peptide attached silica wafer into the dipeptide aqueous solution, the occurrence of a pH triggered surface self-assembly resulted in the formation of peptide nanorods on the surface of silica wafer. This surface self-assembly exhibited a dependence on the concentration of the dipeptide aqueous solution. It was proposed that the self-assembly of this dipeptide on the surface of silica wafer was similar to that in aqueous solution. In comparison with the conventional physical adsorption on the substrates, the chemically attached self-assembled nanorods exhibited much improved adsorption capacity on the substrate surface. PMID- 21612898 TI - Gels of Pluronic F127 and nonionic surfactants from rheological characterization to controlled drug permeation. AB - The role of nonionic vesicles on the rheological behavior of Pluronic F127 is investigated above the dilute regime and below the cloud point of the nonionic surfactant. F127 is a copolymer possessing sol-gel transition by heating attributed to a phase transition from micellar to cubic. The presence of surfactant vesicles is expected to enhance the compartmentalization of a variety of drugs, independently of their affinity to the solvent. Such entrapment would be suitable for controlled release of the drugs in different applications. We address here a mixed Pluronic-nonionic surfactant system with particular emphasis to the effects of the surfactant on the rheological properties of the Pluronics, and the correlation between these properties and drug release control. The results show that the rheological properties of the mixed system are mainly governed by the behavior of the polymer alone and that the mixed system can be useful to control the percutaneous permeation of a small drug, such as Diclofenac Sodium salt. PMID- 21612899 TI - Evolving knowledge of opioid genetics in cancer pain. AB - Inter-individual variation in response to opioids for cancer pain is a well established phenomenon. Variation occurs in the dose of opioid required, the analgesic efficacy of the opioid and also in the side-effects experienced by the individual taking the drug. To date, no clinical factor has been identified that can reliably explain or predict such variation. In recent years there has been growing interest in the possibility that genetic factors may play a role in the variability in opioid response. The aims of this review are to present the evidence supporting pharmacogenetic research in this area, to evaluate some of the studies and results that have been published to date and to present some of the challenges for future research in this area. PMID- 21612900 TI - Indole and aminoimidazole moieties appear as key structural units in antiplasmodial molecules. AB - From a library of compounds of natural sources, a big series of molecules was chosen by random sampling to evaluate their in vitro antimalarial activity against Plasmodium falciparum and their antifungal activity against Candida sp. From 184 molecules tested, no molecules were active against Candida sp. (MIC>10MUg/ml) whereas 13 clearly showed high antiplasmodial activity in vitro, with an IC(50) less than 1MUg/ml against the chloroquine-resistant strain of P. falciparum FcM29-Cameroon. The molecules with the best antiplasmodial efficacy were 10-hydroxy-ellipticin (IC(50): 0.08MUg/ml), tchibangensin (IC(50): 0.13MUg/ml), ellipticin hydrochloride (IC(50): 0.17MUg/ml), usambarensin (IC(50): 0.23MUg/ml), 7S,3S-ochropposinine oxindole (IC(50): 0.25MUg/ml), 3,14-dihydro ellipticin (IC(50): 0.25MUg/ml), tetrahydro-4',5',6'17-usambarensin 17S (IC(50): 0.26MUg/ml), ellipticine (IC(50): 0.28MUg/ml), aricin (IC(50): 0.3MUg/ml), 10 methoxy-ellipticin (IC(50): 0.32MUg/ml), aplysinopsin (IC(50): 0.43MUg/ml), descarbomethoxydihydrogambirtannin (IC(50): 0.46MUg/ml) and ochrolifuanin A (IC(50): 0.47MUg/ml). Among these 13 promising molecules, all except descarbomethoxydihydrogambirtannin, ochrolifuanine A and usambarensine presented here novel biological activities since they had never been described in the literature for their antiplasmodial activity. In spite of the large diversity of the molecules which have been tested, it is interesting to note that the ones active against Plasmodium are all indole derivatives (and one is both indolic and aminoimidazolic). To find new antiplasmodial compounds, ethnopharmacological approaches studying traditional medicine treatments for malaria is largely used but random research produced here an interesting yield (7%) of new antiplasmodial hits and appears therefore complementary to the traditional medicine way. PMID- 21612901 TI - Comment on: "A comparison of the LDL-cholesterol lowering efficacy of plant stanols and plant sterols over a continuous dose range: results of a meta analysis of randomized, placebo controlled trials" by Musa-Veloso K et al., Prostagl. Leucot. Essential Fatty Acids 2011, 85, 9-28. PMID- 21612902 TI - Reduced apoptosis of CD8+ T-lymphocytes in the airways of smokers with mild/moderate COPD. AB - Chronic obstructive pulmonary disease (COPD) is characterised by chronic inflammation in airways and lung parenchyma. CD8+ T-lymphocytes, crucial effector and regulatory cells in inflammation, are increased in the central and peripheral airways in COPD. The aim of this study was to assess the role of apoptosis in the accumulation of CD8+ T-lymphocytes within the airway wall in COPD. We examined the submucosa of transverse sections of central and peripheral airways from post operative tissues from non-smokers (n = 16), smokers with normal lung function (n = 16), smokers with mild/moderate COPD (n = 16), and smokers with severe/very severe COPD (n = 9). TUNEL and immunohistochemistry techniques were used to identify apoptosis and cell phenotype, respectively. The percentage of apoptotic CD8+ T-lymphocytes was significantly lower (p < 0.0001) in smokers with mild/moderate COPD than in non-smokers, smokers with normal lung function, and smokers with severe/very severe COPD, and was positively related to values of FEV(1) and FEV(1)/FVC ratio, both in central and in peripheral airways. These data suggest that reduced apoptosis of CD8+ T-lymphocytes may be an important mechanism that contributes to the accumulation of these cells in the airway submucosa in smokers with mild/moderate COPD. PMID- 21612904 TI - Evaluation of food waste disposal options by LCC analysis from the perspective of global warming: Jungnang case, South Korea. AB - The costs associated with eight food waste disposal options, dry feeding, wet feeding, composting, anaerobic digestion, co-digestion with sewage sludge, food waste disposer, incineration, and landfilling, were evaluated in the perspective of global warming and energy and/or resource recovery. An expanded system boundary was employed to compare by-products. Life cycle cost was analyzed through the entire disposal process, which included discharge, separate collection, transportation, treatment, and final disposal stages, all of which were included in the system boundary. Costs and benefits were estimated by an avoided impact. Environmental benefits of each system per 1 tonne of food waste management were estimated using carbon prices resulting from CO(2) reduction by avoided impact, as well as the prices of by-products such as animal feed, compost, and electricity. We found that the cost of landfilling was the lowest, followed by co-digestion. The benefits of wet feeding systems were the highest and landfilling the lowest. PMID- 21612903 TI - Device type and real-world effectiveness of asthma combination therapy: an observational study. AB - BACKGROUND: Selection of inhaler device type appears to influence real-world effectiveness of inhaled corticosteroids (ICS), but data are lacking on the role of inhaler device in ICS and long-acting beta2-agonist (LABA) combination therapy for asthma. METHODS: This retrospective matched cohort study compared 1-year asthma outcomes for UK patients initiating fixed-dose combination (FDC) fluticasone-salmeterol delivered by pressurised metered-dose inhaler (pMDI) versus dry powder inhaler (DPI). Patients with asthma aged 4-80 years receiving a first prescription for FDC fluticasone-salmeterol by pMDI or DPI were matched on baseline demographic and asthma severity measures. Co-primary outcomes were asthma control (a composite measure comprising no recorded hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory infection) and exacerbation rate. RESULTS: Compared with the DPI cohort (n = 1567), patients in the pMDI cohort (n = 1567) had significantly greater odds of achieving asthma control during the outcome year (odds ratio [OR] 1.19; 95% confidence interval [CI] 1.01 to 1.40). Exacerbation rate was lower but not significantly in the pMDI cohort (adjusted rate ratio for pMDI cohort, 0.82; 95% CI 0.66 to 1.00). The odds of treatment success (defined as no exacerbations and no change in asthma therapy) was significantly greater in the pMDI cohort (OR 1.23; 95% CI, 1.07 to 1.42). CONCLUSIONS: For UK primary care patients, pMDIs appear to achieve better asthma control outcomes than DPIs for delivery of FDC fluticasone-salmeterol. Pragmatic trials are needed to further investigate real-world outcomes with different inhaler devices for combination therapy. PMID- 21612905 TI - Anaerobic digestion of the liquid fraction of dairy manure in pilot plant for biogas production: residual methane yield of digestate. AB - The performance of the only dairy manure biogas plant in Cantabria (Northern coast of Spain) was evaluated in terms of liquid-solid separation and anaerobic digestion of the liquid fraction. Screened liquid fraction was satisfactorily treated in a CSTR digester at HRTs from 20 to 10 days with organic loading rates ranging from 2.0 to 4.5 kg VS/(m(3)d). Stable biogas productions from 0.66 to 1.47 m(3)/(m(3)d) were achieved. Four anaerobic effluents collected from the digester at different HRTs were analyzed to measure their residual methane potentials, which ranged from 12.7 to 102.4 L/gVS. These methane potentials were highly influenced by the feed quality and HRT of the previous CSTR anaerobic digestion process. Biomethanization of the screened liquid fraction of dairy manure from intensive farming has the potential to provide up to 2% of total electrical power in the region of Cantabria. PMID- 21612906 TI - Simulation and assay of protein biotinylation with electrochemical technique. AB - Protein biotinylation plays an important role in metabolism and transcription regulation, so study of protein biotinylation has received more and more interests. In this work, the bifunctional Escherichia coli biotin-inducible repressor protein A (BirA) and its substrate for protein biotinylation, a unique peptide with a specific sequence, are introduced as a model to electrochemically simulate the committed step in fatty acid biosynthesis. With the help of gold nanoparticles and peroxidase-labeled streptavidin involved in the electrochemical system, protein biotinylation is achieved on the surface of the working electrode, and the process of protein biotinylation can be electrochemically assayed by the obtained electrochemical response. Therefore, a new method to assay protein biotinylation is proposed and this work may provide a new perspective for understanding protein biotinylation in vitro. PMID- 21612907 TI - Detection of daunomycin using phosphatidylserine and aptamer co-immobilized on Au nanoparticles deposited conducting polymer. AB - A highly sensitive and selective sensor for daunomycin was developed using phosphatidylserine (PS) and aptamer as bioreceptors. The PS and aptamer were co immobilized onto gold nanoparticles modified/functionalized [2,2':5',2" terthiophene-3'-(p-benzoic acid)] (polyTTBA) conducting polymer. Direct electrochemistry of daunomycin was used to fabricate a label free sensor that monitors current at -0.61 V. The formation of each layer was confirmed with XPS, SEM, and QCM. Response of the sensor was compared with and without PS in terms of sensitivity and selectivity. Interaction between the sensor probe and daunomycin was determined with DPV. The experimental parameters affecting sensor performance were optimized in terms of concentration of immobilized aptamer, PS:aptamer ratio, temperature, pH, and reaction times. The dynamic range for daunomycin analysis ranged between 0.1 and 60.0 nM with a detection limit of 52.3 +/- 2.1 pM. Sensor was also examined for interference effect of other drugs. The present sensor exhibited long term stability and successfully detected daunomycin in a real human urine spiked with daunomycin. PMID- 21612908 TI - A novel nitrite biosensor based on single-layer graphene nanoplatelet-protein composite film. AB - A novel nitrite biosensor was developed through a sensing platform consisted of single-layer graphene nanoplatelet (SLGnP)-protein composite film. SLGnP with the virtues of excellent biocompatibility, conductivity and high sensitivity to the local perturbations can provide a biocompatible microenvironment for protein immobilization and a suitable electron transfer distance between electroactive centers of heme protein and electrode surface. A pair of well-defined and quasi reversible cyclic voltammetric peaks that reflected the direct electrochemistry for ferric/ferrous couple of myoglobin (Mb) was achieved at the composite film modified electrode. Field emission scanning electron microscopy (FESEM) and ultraviolet visible spectra (UV-vis) were utilized to characterize the composite film. The results demonstrated that the morphology of the composite film was unique and the protein in the composite film retained its secondary structure similar to the native state. The composite film also displayed excellent electrocatalytic ability for the reduction of nitric oxide, which was applied to determine nitrite indirectly. It exhibited good electrochemical response to nitrite with a linear range from 0.05 to 2.5 mM and a detection limit of 0.01 mM. PMID- 21612909 TI - Application of hydrophobic palladium nanoparticles for the development of electrochemical glucose biosensor. AB - An amperometric glucose biosensor based on an n-alkylamine-stabilized palladium nanoparticles (PdNPs)-glucose oxidase (GOx) modified glassy carbon (GC) electrode has been successfully fabricated. PdNPs were initially synthesized by a biphase mixture of water and toluene method using n-alkylamines (dodecylamine, C12-NH2 and octadecylamine, C18-NH2) as stabilizing ligands. The performance of the PdNPs GOx/GC biosensor was studied by cyclic voltammetry. The optimum working potential for amperometric measurement of glucose in pH 7.0 phosphate buffer solution is 0.02 V (vs. Ag/AgCl). The analytical performance of the biosensor prepared from C18-PdNPs-GOx is better than that of C12-PdNPs-GOx. The C18-PdNPs-GOx/GC biosensor exhibits a fast response time of ca. 3s, a detection limit of 3.0 MUM (S/N=3) and a linear range of 3.0 MUM-8.0 mM. The linear dependence of current density with glucose concentration is 70.8 MUA cm-2 mM-1. The biosensor shows good stability, repeatability and reproducibility. It has been successfully applied to determine the glucose content in human blood serum samples. PMID- 21612910 TI - Biological hydrogen production by dark fermentation: challenges and prospects towards scaled-up production. AB - Among different technologies of hydrogen production, bio-hydrogen production exhibits perhaps the greatest potential to replace fossil fuels. Based on recent research on dark fermentative hydrogen production, this article reviews the following aspects towards scaled-up application of this technology: bioreactor development and parameter optimization, process modeling and simulation, exploitation of cheaper raw materials and combining dark-fermentation with photo fermentation. Bioreactors are necessary for dark-fermentation hydrogen production, so the design of reactor type and optimization of parameters are essential. Process modeling and simulation can help engineers design and optimize large-scale systems and operations. Use of cheaper raw materials will surely accelerate the pace of scaled-up production of biological hydrogen. And finally, combining dark-fermentation with photo-fermentation holds considerable promise, and has successfully achieved maximum overall hydrogen yield from a single substrate. Future development of bio-hydrogen production will also be discussed. PMID- 21612911 TI - Industrial fermentation of renewable diesel fuels. AB - In commodity chemicals, cost drives everything. A working class family of four drives up to the gas pumps and faces a choice of a renewable diesel or petroleum diesel. Renewable diesel costs $0.50 more per gallon. Which fuel do they pick? Petroleum diesel will be the winner every time, unless the renewable fuel can achieve cost and performance parity with petrol. Nascent producers of advanced biofuels, including Amyris, LS9, Neste and Solazyme, aim to deliver renewable diesel fuels that not only meet the cost challenge, but also exceed the storage, transport, engine performance and emissions properties of petroleum diesel. PMID- 21612912 TI - The impact of short-term psycho-oncological interventions on the psychological outcome of cancer patients of a surgical-oncology department - a randomised controlled study. AB - BACKGROUND: Anxiety and depression are the two most frequent comorbidities of tumour patients. At present, it is unclear to which degree a patient's psychological condition can be altered during the treatment period and if psycho oncological support positively affects a patient's psychological condition. METHODS: In a random sample analyses, 131 patients beginning inpatient treatment at a hospital specialising in surgical oncology were either classified as 'low risk' or 'high-risk', according to the HADS. Patients from both categories were then randomly placed in either a low-threshold 'intervention' group or an 'observation' group. Anxiety and depression levels were measured again with the HADS scale prior to the patients discharge from the department of surgical oncology, and at a follow up 12 months after. RESULTS: Our findings showed a significant reduction of anxiety and depression in the high-risk patients who had undergone psycho-oncological intervention at the end of inpatient care and even a year after discharge from the hospital. The effects of psychological intervention could be observed in terms of anxiety and depression in the group of high-risk patients during the hospital stay. In the other three groups, no statistically significant changes could be measured. CONCLUSION: Cancer patients on a surgical ward benefit from psycho-oncological support especially at an early stage of therapy but also over a long time after discharge from the hospital. The aim of all interventions should be to decrease psychological distress and disorders and thereby improve the quality of life for cancer patients. PMID- 21612913 TI - Psychiatric treatment in men with prostate cancer--results from a Nation-wide, population-based cohort study from PCBaSe Sweden. AB - AIM: To explore whether the self-reported psychological distress among men with prostate cancer was to the extent that it required psychiatric treatment. METHODS: PCBaSe Sweden, a merged database based on the National Prostate Cancer Register including 97% of all prostate cancers registered as well as age-matched controls. We calculated relative risks and 95% confidence intervals to compare risks of psychiatric treatment due to depression, anxiety, and post-traumatic stress disorder controlling for age and socio-economic factors. We used odds ratios to compare use or no use of antidepressants. FINDINGS: In total 72,613 men with prostate cancer and 217,839 men without prostate cancer were included for analyses. Psychiatric hospitalisation due to depression, anxiety and post traumatic stress disorder were significantly increased (RR 1.29, (95% CI 1.14 1.45), RR 1.42 (95% CI 1.12-1.80) and RR 1.61 (95% CI 1.16-2.24), respectively). However, hospitalisations due to anxiety were only increased in men with more advanced tumours RR 2.28 (95% CI 1.45-3.57). The use of antidepressants was increased for all men with prostate cancer RR 1.65 (95% CI 1.54-1.77) and treatment strategies RR 1.93 (95% CI 1.75-2.13). INTERPRETATION: Men diagnosed with prostate cancer had increased risk of psychiatric treatment for depression, post-traumatic stress disorder and use of antidepressants regardless of risk group and treatment strategy compared to age-matched controls, whilst more advanced prostate cancer was associated with severe anxiety disorders. PMID- 21612914 TI - Molecular classification of hepatocellular carcinoma anno 2011. AB - Hepatocellular carcinoma has an increasing incidence and high mortality. Treatment options are limited if the disease is not diagnosed in its early stage. The natural course of the disease is aggressive but not always predictable. Molecular profiling is a promising tool for classification in order to optimize prognosis prediction and treatment for an individual patient. In the last decade a large amount of studies has been conducted to better classify hepatocellular carcinomas. The focus of this review is on implications of molecular classification for prognosis and therapeutic decision making in HCC patients. Most studies used microarray technique for genome wide profiling, but other methods to detect genomic changes and microRNA are gaining interest. The whole genome profiling studies identified differences in affected signalling and tried to relate this to prognosis. Some common subgroups were identified, such as the proliferation cluster and the beta-catenin cluster. However, there is still little overlap between most studies. Better study design and bio-informatical analysis might help in this context. PMID- 21612915 TI - A first prospective population-based analysis investigating the actual practice of melanoma diagnosis, treatment and follow-up. AB - AIM OF THE STUDY: To describe the current management of patients diagnosed with cutaneous melanoma and melanoma in situ in Germany and assess for adherence with the existing German guideline in a first prospective population-based analysis. METHODS: Prospective and longitudinal population-based study using online questionnaires. Registration by practitioners and hospitals was open for all patients diagnosed with melanoma between April and June 2008 in Germany. For data analysis, patients with melanoma stages 0-III (AJCC 2002) were included. RESULTS: Data from 1081 patients registered by 106 different centres were available for analysis. Male patients were significantly older than female patients (61.4 years versus 55.8years, p<0.0001) and presented with thicker primary tumours (1.62 mm [median 0.9 mm] versus 1.48 mm [median 0.8 mm], p=0.01). Excessive safety margin excisions were most often applied in melanoma in situ and in small centres. Insufficient excision margins (6.9%) were associated with head and neck localisation, geographical region and implementation of further staging procedures. Decision on sentinel lymph node biopsy complied with the German guideline in >85% of cases and was dependent on age and tumour localisation. Only 60% of patients received a complete lymph node dissection (CLND) after a positive SLNB, the rate of CLND was lowest in older patients. Adjuvant treatments were initiated in only 34% of patients formally qualifying for adjuvant treatment based on guideline recommendations. Approximately half of all staging procedures were done in no-risk/low-risk tumour patients. CONCLUSIONS: Management of melanoma in Germany did not show great dependency on centre size, geographical area or treating physician but rather on patient and tumour characteristics. The low rate of adjuvant treatment initiations reflects the need of treatment options in this patient group. Excessive initial staging procedures generate significant costs. PMID- 21612916 TI - Detoxification of castor bean residues and the simultaneous production of tannase and phytase by solid-state fermentation using Paecilomyces variotii. AB - In this work, we introduce a biological detoxification method that converts toxic waste from castor beans into animal feed material. This method simultaneously induces the production of tannase and phytase by Paecilomyces variotii; both enzymes have high levels of activity and have the potential to be used in feedstuffs because they decrease overall anti-nutritional factors. The maximum tannase and phytase activities obtained were 2600 and 260 U/g after 48 and 72 h, respectively. SDS-PAGE electrophoresis of the fermented castor cake extracts revealed a reduction in ricin bands during fermentation, and the bands were no longer visible after 48 h. The cytotoxicity of the extracts was evaluated by MTT testing on RAW cells, and a progressive increase in cellular viability was obtained, reaching almost 100% after 72 h of fermentation. PMID- 21612917 TI - Multiple response optimization of vegetable oils fatty acid composition to improve biodiesel physical properties. AB - The effect of fatty acids chain length (LC) and its interaction with unsaturation degree (UD) on important biodiesel quality parameters was studied. Low calorific value, kinematic viscosity, flash point, cetane number and cold filter plugging point of biodiesel blends covering a wide range of fatty acids were analyzed. Analytical results were processed with statistical regression to obtain a prediction model for each property, combining LC and UD. Due to the antagonistic effects of the chemical composition over quality properties, the Derringer desirability function was proposed to allow the most suitable fatty acid composition. This target was achieved considering an average of 1.26 double bounds and 17 carbon atoms. A set of combinations of LC and UD values that provides a biodiesel that fits the European standard EN 14214 was proposed. It was found that a reduction of FAME LC allows a lower UD while keeping biodiesel specifications under the standard limits. PMID- 21612918 TI - Enzymatic hydrolysis of ionic liquid-pretreated celluloses: contribution of CP MAS 13C NMR and SEM. AB - The supramolecular structure of four model celluloses was altered prior to their enzymatic saccharification using two ionic liquid pretreatments: one with the commonly used 1-ethyl-3-methylimidazolium acetate ([Emim](+)[CH(3)COO](-)) and the other with the newly developed 1-ethyl-3-methylimidazolium methylphosphonate ([Emim](+)[MeO(H)PO(2)](-)). The estimation of crystallinity index (CrI) by solid state (13)C nuclear magnetic resonance for each untreated/pretreated celluloses was compared with the performances of their enzymatic hydrolysis. For alpha cellulose, both pretreatments led to a significant decrease in CrI from 25% to 5% but had no effect on glucose yields. In contrast, The [Emim](+)[MeO(H)PO(2)](-) pretreatment on the long fibers of cellulose had no significant effect on the CrI although a conversion yield in glucose of 88% is obtained versus 32% without pretreatment. However, scanning electron microscopy analysis suggested a loss of fiber organization induced by both ionic liquid pretreatments leading to a larger accessibility by cellulases to the cellulose surface. PMID- 21612919 TI - High-rate conversion of methane to methanol by Methylosinus trichosporium OB3b. AB - Methanol was produced from methane with a high conversion rate using a high cell density process with Methylosinus trichosporium OB3b in the presence of a high concentration of phosphate buffer. More than 1.1 g/L methanol accumulated in the reaction media under optimized reaction conditions (17 g dry cell/L, 400 mmol/L phosphate, and 10 mmol/L MgCl(2)) in the presence of 20 mmol/L sodium formate. The conversion rate of methane was over 60%. About 0.95 g/L methanol was produced when the biotransformation was carried out in a membrane aerated reactor into which methane and oxygen were introduced via two separate dense silicone tubing. Our results provide an efficient method and a promising process for high-rate conversion of methane to methanol. PMID- 21612920 TI - Treatment of poplar alkaline peroxide mechanical pulping (APMP) effluent with Aspergillus niger. AB - Although the moderate load (COD of 5000-10,000 mg/L) and biodegradability of the APMP pulping effluent should allow biological treatment, toxic compounds in the effluent can interfere with this type of treatment. Studies were conducted to determine if treatment of the effluent with Aspergillus niger S13 was feasible. Under the optimized conditions (3% inoculum, pH 6, shaking at 160 rpm, 60-72 h, and 30 degrees C), this fungus was able to remove about 97% of the methyl tertiary butyl ether (MTBE) extractives, and 60%, 77% and 43% of the chemical oxygen demand, turbidity and color even without a pre-flocculation step. These results are of practical interest in China because the APMP process has become popular, and efficient and cost-effective effluent treatment technologies are in high demand. PMID- 21612921 TI - Synthesis and evaluation of antioxidant and antibacterial activities of new substituted bis(1,3,4-oxadiazoles), 3,5-bis(substituted) pyrazoles and isoxazoles. AB - Two series of five membered heterocyclic bis(1,3,4-oxadiazole) derivatives 2(a-h) and 3,5-bis(substituted)pyrazoles, isoxazoles 3(a,b,d-i), 4(a-c) were synthesized via oxidative cyclization of some diaroylhydrazones using chloramine-T and cyclocondensation reaction with hydrazine hydrate and hydroxylamine hydrochloride, respectively. The newly synthesized compounds were screened for antioxidant and anti-microbial activities. Compounds 2(b), 3(b), and 4(a) showed higher antioxidant activity at 10 MUg/ml while compounds 2(a), 3(a), 3(f), and 4(a) exhibited better anti-microbial activity at 100MUg/ml compared with standard vitamin C and ciprofloxacin, respectively. Structures of newly synthesized compounds were confirmed by elemental analysis and spectral IR, (1)H NMR, and (13)C NMR data. PMID- 21612922 TI - The synthesis and biological evaluation of 2-amino-4,5,6,7,8,9 hexahydrocycloocta[b]thiophenes as allosteric modulators of the A1 adenosine receptor. AB - A series of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes were prepared and evaluated as potential allosteric modulators of the A(1) adenosine receptor (AR). The structure-activity relationships of the 3-position were explored along with varying the size of the cycloalkyl ring. 2-Aminothiophenes with amide and hydrazide groups in the 3-position were completely inactive in an A(1)-AR mediated ERK1/2 phosphorylation assay, yet most of the 3-benzoyl substituted compounds exhibited allosteric effects on responses mediated by the orthosteric agonist, R-PIA. Despite finding an increase in both agonistic and allosteric activities by going from a cyclopentyl ring to a cyclohexyl ring in the 3-benzoyl series, decreases were observed when further increasing the ring size. Varying the substituents on the phenyl ring of the 3-benzoyl group also affected the activity of these compounds. PMID- 21612923 TI - Binding of uranyl ion by a DNA aptamer attached to a solid support. AB - A UO(2)(2+)-specific DNA aptamer was attached to aminopolystyrene (aminoPS) using sulfo-SMCC as a crosslinking agent in view of high affinity of DNA for uranyl ion. Capacity of the aptamer-conjugated aminoPS resins for uranyl uptake was measured, revealing that about 0.63 MUg of uranium can be complexed to 1g of the resins, which clearly demonstrates that most of DNA aptamers introduced to the resins can strongly bind to uranyl ion. In the presence of 21 mM bicarbonate ion at pH 8.01, apparent dissociation constant (K(d)(app)) of about 84.6 pM and log formation constant (K(f)) of about 22.9 were obtained. Results of the present study strongly suggest that modification of the aptamer-containing resins can improve uranyl-binding ability, probably leading to economical recovery of uranium from seawater. PMID- 21612925 TI - 3-substitued indoles: one-pot synthesis and evaluation of anticancer and Src kinase inhibitory activities. AB - An efficient and economical method was developed for the synthesis of 3 substituted indoles by one-pot three-component coupling reaction of a substituted or unsubstituted benzaldehyde, N-methylaniline, and indole or N-methylindole using Yb(OTf)(3)-SiO(2) as a catalyst. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), human ovarian adenocarcinoma (SK-OV-3), and c-Src kinase activity. The 4 methylphenyl (4o and 4p) and 4-methoxyphenyl (4q) indole derivatives inhibited the cell proliferation of SK-OV-3 and HT-29 cells by 70-77% at a concentration of 50 MUM. The unsubstituted phenyl (4d) and 3-nitrophenyl (4l) derivatives showed the inhibition of c-Src kinase with IC(50) values of 50.6 and 58.3 MUM, respectively. PMID- 21612924 TI - Design strategies to target crystallographic waters applied to the Hsp90 molecular chaperone. AB - A series of novel and potent small molecule Hsp90 inhibitors was optimized using X-ray crystal structures. These compounds bind in a deep pocket of the Hsp90 enzyme that is partially comprised by residues Asn51 and Ser52. Displacement of several water molecules observed crystallographically in this pocket using rule based strategies led to significant improvements in inhibitor potency. An optimized inhibitor (compound 17) exhibited potent Hsp90 inhibition in ITC, biochemical, and cell-based assays (K(d)=1.3 nM, K(i)=15 nM, and cellular IC(50)=0.5 MUM). PMID- 21612926 TI - TRPV1 modulators: structure-activity relationships using a rational combinatorial approach. AB - A discrete library of linear and hydantoin-containing dipeptide derivatives, based on the Lys-Trp(Nps) scaffold, was prepared by solid-phase synthesis. SAR studies indicated that potency for TRPV1 blockade and selectivity towards NMDA is mainly dictated by the side-chain length and the basic nature of alpha, omega groups in the N-terminal residue. The 2-Nps moiety at position 2 of Trp indole ring is preferred over the 2-pyridine one. PMID- 21612927 TI - Antifungal quinazolinones from marine-derived Bacillus cereus and their preparation. AB - Two new quinazolinones alkaloids, R(+)-2-(heptan-3-yl)quinazolin-4(3H)-one (1) and (2R,3'R)+(2S,3'R)-2-(heptan-3-yl)-2,3-dihydroquinazolin-4(1H)-one (2) (a pair of epimers), as well as seven known analogues, 2-methylquinazolin-4(3H)-one (3), 2-benzylquinazolin-4(3H)-one (4), cyclo-(Pro-Ile), cyclo-(Pro-Leu), cyclo-(Pro Val), cyclo-(Pro-Phe), and cyclo-(Tyr-Pro) were isolated from the n-butyl alcohol extract of the marine-derived bacterium Bacillus cereus 041381. The new compounds were identified by spectroscopic analysis and chemical synthesis. Four optical isomers 5-8 were also synthesized. Compounds 1-8 all showed moderate antifungal activity against Candida albicans with MIC values of 1.3-15.6 MUM. Compound 5 exhibits the most powerful antifungal activity, which may reveal that S configuration and 2,3-double bond were necessary for antifungal activity, and the racemization at C-2 and C-3' reduced the antifungal activity. PMID- 21612928 TI - Psychological impact of recall on women with BRCA mutations undergoing MRI surveillance. AB - OBJECTIVE: The addition of magnetic resonance imaging (MRI) to mammography for surveillance of women with BRCA mutations significantly increases sensitivity but lowers specificity. This study aimed to examine whether MRI surveillance, and particularly recall, is associated with increased anxiety, depression, or breast cancer worry/distress. METHODS: Women with BRCA mutations in an MRI surveillance study were invited to complete: Hospital Anxiety and Depression Scale (HADS), Lerman's Breast Cancer Worry Scale, Breast Cancer Worry Interference Scale, and a quality of life rating at 3 time points: 1-2 weeks before (T1), 4-6 weeks after (T2) and 6 months after their annual surveillance (T3). Repeated measures analyses were performed over the 3 time points for recalled and non-recalled women. RESULTS: 55 women (30 BRCA1, 25 BRCA2) completed study instruments at T1 and T2, and 48 at T3. Eighteen women (32%) were recalled for additional imaging. At T1, 27 women (49%) were above HADS threshold for "possible cases" for anxiety (score>=8). Recalled (but not non-recalled) women had a significant increase of HADS anxiety at T2 which dropped to below baseline by T3. No group differences were observed in terms of change over time in other quantitative psychological measures. CONCLUSIONS: While breast MRI surveillance did not have a detrimental psychological impact on women with a BRCA1 or BRCA2 mutation, recalling these very high-risk women for further imaging after a false positive MRI scan temporarily increased their global anxiety. PMID- 21612929 TI - Technical aspects of decompressive craniectomy for malignant middle cerebral artery infarction. AB - Decompressive craniectomy is considered a life-saving procedure for malignant middle cerebral artery territory infarction in selected patients. However, the procedure is associated with a significant risk of morbidity and mortality, and there is no universal agreement as to how this operation should be combined with optimal medical management. In this review we consider the goals of this procedure and the technical aspects which may be employed to optimise results. PMID- 21612930 TI - Characterization of chemical, radiochemical and optical properties of a dual labeled MMP-9 targeting peptide. AB - Optical imaging possesses similar sensitivity to nuclear imaging and has led to the emergence of multimodal approaches with dual-labeled nuclear/near-infrared (NIR) agents. The growing impact of (68)Ga (t(1/2)=68 min) labeled peptides on preclinical and clinical research offers a promising opportunity to merge the high spatial resolution of NIR imaging with the clinically-accepted positron emission tomography (PET). Previously, dual-labeled agents have been prepared with longer-lived radiometals and showed no detrimental effects on optical properties as a result of radiolabeling. In this study, we selected a peptide (M(2)) that targets MMP-2/9 and is dual-labeled with IRDye 800 CW and (68)Ga. Since (68)Ga chelation typically requires low pH (3.5-4) and elevated heating temperatures (95 degrees C), we sought to evaluate the impact of (68)Ga labeling on the optical properties of M(2). An efficient method for preparation of (68)Ga M(2) was developed and reaction conditions were optimized. Stability studies in PBS, DTPA, and serum were performed and high levels of intact agent were evident under each condition. The addition of multiple reporters to a targeting agent adds further complexity to the characterization and validation and thus requires not only testing to ensure the agent is stable chemically and radiochemically, but also optically. Therefore, fluorescence properties were evaluated using a spectrofluorometer as well as by fluorescence detection via HPLC. It was determined that (68)Ga-labeling conditions did not impair the fluorescent properties of the agent. The agent was then used for in vivo imaging in a mouse model of heterotopic ossification (HO) with activated MMP-9 expression as an early biomarker which precedes mineralization. Although (68)Ga-complexation greatly reduced binding affinity of the peptide and negated tracer uptake on PET, NIR imaging showed consistent fluorescent signal that correlated to MMP-9 expression. This attests to the feasibility of using (68)Ga/NIR for dual-labeling of other peptides or small molecules for multimodality molecular imaging. PMID- 21612931 TI - An investigation of phenylthiazole antiflaviviral agents. AB - Flaviviruses are one of the most clinically important pathogens and their infection rates are increasing steadily. The phenylthiazole ring system has provided a template for the design and synthesis of antiviral agents that inhibit the flaviviruses by targeting their E-protein. Unfortunately, there is a correlation between phenylthiazole antiflaviviral activity and the presence of the reactive and therefore potentially toxic mono- or dibromomethyl moieties at thiazole-C4. Adding a linear hydrophobic tail para to the phenyl ring led to a new class of phenylthiazole antiflaviviral compounds that lack the toxic dibromomethyl moiety. This led to development of a drug-like phenylthiazole 12 that had high antiflaviviral selectivity (TI=147). PMID- 21612932 TI - Deglycobleomycin A6 analogues modified in the methylvalerate moiety. AB - Previous studies have indicated that the methylvalerate subunit of bleomycin (BLM) plays an important role in facilitating DNA cleavage by BLM and deglycoBLM. Eleven methylvalerate analogues have been synthesized and incorporated into deglycoBLM congeners by the use of solid-phase synthesis. The effect of the valerate moiety in the deglycoBLM analogues has been studied by comparison with the parent deglycoBLM A(5) using supercoiled DNA relaxation and sequence selective DNA cleavage assays. All of the deglycoBLM analogues were found to effect the relaxation of the plasmid DNA. Those analogues having aromatic C4 substituents exhibited cleavage efficiency comparable to that of deglycoBLM A(5). Some, but not all, of the deglycoBLM analogues were also capable of mediating sequence-selective DNA cleavage. PMID- 21612933 TI - New FAAH inhibitors based on 3-carboxamido-5-aryl-isoxazole scaffold that protect against experimental colitis. AB - Growing evidence suggests a role for the endocannabinoid (EC) system, in intestinal inflammation and compounds inhibiting anandamide degradation offer a promising therapeutic option for the treatment of inflammatory bowel diseases. In this paper, we report the first series of carboxamides derivatives possessing FAAH inhibitory activities. Among them, compound 39 displayed significant inhibitory FAAH activity (IC(50)=0.088 MUM) and reduced colitis induced by intrarectal administration of TNBS. PMID- 21612934 TI - Self-assembly pathways of E22Delta-type amyloid beta peptide mutants generated from non-aggregative O-acyl isopeptide precursors. AB - The recently identified E22Delta-type amyloid beta peptide (Abeta) mutants are reported to favor oligomerization over fibrillization and to exhibit more-potent synaptotoxicity than does wild-type (WT) Abeta. Abeta(E22Delta) mutants can thus be expected to serve as tools for clarifying the impact of Abeta oligomers in Alzheimer's disease (or Alzheimer's-type dementia). However, the biochemical and biophysical properties of Abeta(E22Delta) have not been conclusively determined. Here, we evaluated the self-assembly pathways of Abeta(E22Delta) mutants generated from water-soluble, non-aggregative O-acyl isopeptide precursors. Circular dichroism spectroscopy, Western blot analysis, and thioflavin-T fluorescence intensity and cellular toxicity assays suggest that the self assembly pathways of Abeta(E22Delta) differed from those of Abeta(WT). Abeta1 40(E22Delta) underwent a rapid random coil->beta-sheet conformational change in its monomeric or low-molecular-weight oligomeric states, whereas Abeta1-40(WT) self-assembled gradually without losing its propensity to form random coil structures. The Abeta1-42(E22Delta) monomer formed beta-sheet-rich oligomers more rapidly than did Abeta1-42(WT). Additionally, the Abeta1-42(E22Delta) oligomers appear to differ from Abeta1-42(WT) oligomers in size, shape, or both. These results should provide new insights into the functions of Abeta(E22Delta) mutants. PMID- 21612935 TI - Selective bone targeting 5-fluorouracil prodrugs: synthesis and preliminary biological evaluation. AB - Bone tumor is a notoriously difficult disease to manage, requiring frequent and heavy doses of systemically administered chemotherapy. Targeting anticancer drug to the bone after systemic administration may provide both greater efficacy of treatment and less frequent administration. In this paper, a series of bone targeting Asp oligopeptides 5-fluorouracil conjugates have been synthesized in a convergent approach and well characterized by NMR and MS techniques. Their hydroxyapatite (HAP) affinity, drug release and cytotoxicity characteristics were evaluated in in vitro conditions. All the prodrugs were water soluble and exhibited high affinity to HAP .The efficient release of the active drug moiety occurring by the cleavage of different linkage in physiological conditions significantly reduced the number of viable human cancer cells. From in vivo distribution, we get these compounds with high bone-selectivity and long halflife. These results provided an effective entry to the development of new bone targeting chemotherapeutic drugs. PMID- 21612936 TI - Impact of spectral smoothing on gamma radiation portal alarm probabilities. AB - Gamma detector counts are included in radiation portal monitors (RPM) to screen for illicit nuclear material. Gamma counts are sometimes smoothed to reduce variance in the estimated underlying true mean count rate, which is the "signal" in our context. Smoothing reduces total error variance in the estimated signal if the bias that smoothing introduces is more than offset by the variance reduction. An empirical RPM study for vehicle screening applications is presented for unsmoothed and smoothed gamma counts in low-resolution plastic scintillator detectors and in medium-resolution NaI detectors. PMID- 21612937 TI - Measurement of excitation functions for the (nat)Mo(d,x)99Mo and (nat)Mo(p,x)99Mo reactions. AB - The excitation functions for proton and deuteron induced reactions on natural molybdenum for the production of 99Mo were measured. The proton induced reaction was measured in the energy range of 11.3-49.6 MeV, and the deuteron induced reaction was measured in the energy range of 9.7-58.5 MeV. Both beams were generated by the 88" cyclotron located at Lawrence Berkeley National Laboratory. The results are compared to previously published data. Thick target yields were obtained by direct measurement, in addition to being determined by integration of the measured cross sections. PMID- 21612938 TI - Elemental analysis of limestone samples from Obajana and Mfamosing limestone deposits, Nigeria, using nuclear techniques. AB - Six limestone samples were picked from three different points at the Obajana and Mfamosing limestone deposits. The limestone samples were subjected to elemental analysis by Proton-Induced X-Ray Emission (PIXE) analysis. The samples were irradiated by a 4mm diameter beam of protons with energy of 2.5 MeV and beam current of 0.2nA for 0.9 ms. The analysis was carried out with the 1.7MV Tandem accelerator at the Centre for Energy Research and Development (CERD), Ile-Ife, Osun State, Nigeria. The NIST geology standard NIST 278 was analysed for quality assurance. The elemental composition and concentration of 14 elements were determined in the two locations. Ten elements were found at the Obajana deposit while 13 elements were found at the Mfamosing deposits. The elements: Mg, Al, Ca and Mn do not differ much at both deposits while others differ. The major elements (Ca, Fe, Al, Si and K) present in the limestones were also found in airborne particulate matter studied by earlier researchers. These observations suggest that all particulate emissions and wastes from the Limestone deposit should be closely monitored to reduce their cumulative effects on both health and the environment. PMID- 21612939 TI - Awareness and education of patients receiving bisphosphonates. AB - BACKGROUND: Bisphosphonates are used to fight osteoporosis and for treating malignancies. In 2003, the first case reports appeared that described bisphosphonate-induced osteonecrosis of the jaw (BONJ). The aim of this study was to assess patient awareness of the adverse effects of bisphosphonates in order to improve cooperation among doctors and between doctors and patients. METHODS: Patients with symptoms of osteoporosis, prostate cancer, or breast cancer were surveyed to determine their knowledge of bisphosphonates. The questionnaire comprised 12 questions that covered sociographic data, kind of medication, level of information, and side effects experienced. Out of 142 patients contacted, 55 participated in the study. RESULTS: 62% of patients received most of their knowledge about the prescribed drug from the package insert. Despite knowledge that the patient was under treatment with bisphosphonates, 80% of dental treatments were continued without modifications. Only 32% of patients that received intravenous bisphosphonate treatment were aware of the possible risks of developing BONJ. CONCLUSION: The level of information is poor concerning the side effects of bisphosphonates, particularly the risk of BONJ. Clinicians should aim to sensitize the relevant people about the risks before treatment. PMID- 21612940 TI - Variability in palatal shape and size in patients with bilateral complete cleft lip and palate assessed using dense surface model construction and 3D geometric morphometrics. AB - Bilateral complete cleft lip and palate (BCLP) is the most severe of the common orofacial clefts and is associated with the greatest deformity during development. The aim of this study was to use geometric morphometrics to evaluate palatal shape and size variability in patients with BCLP in comparison to nonclefted Czech boys. The variability of palatal size and shape in BCLP patients was greater when compared with the nonclefted population. Though palate variability in BCLP was wide, nonclefted palatal shapes were generally different (a high, wide and vaulted palate) and fell almost outside the range of BCLP variability. The palatal size and shape of BCLP patients (range from 12.1 to 16.5 years) was not correlated with age. A comparison of the mean shapes of the clefted and nonclefted groups showed that the BCLP palate is flatter and narrower. The most notable size difference was found in the area between the maxilla and premaxilla. This phenomenon is associated with the persisting separation of the premaxilla from the rest of the palate. The shape of the palatal configuration of the premaxilla and adjacent area was concave in the nonclefted group and convex in BCLP patients. PMID- 21612941 TI - Preoperative hemoglobin A1c predicts atrial fibrillation after off-pump coronary bypass surgery. AB - OBJECTIVE: Diabetes mellitus has been recognized as a risk factor for mortality and morbidity after coronary bypass grafting, but a significant association between diabetes mellitus and postoperative atrial fibrillation (AF) has not been found. Although a recent study demonstrated a potential link between preoperative hemoglobin A1c level and risk of postoperative AF, there has not been sufficient examination of this relationship. We aimed to investigate the association between preoperative hemoglobin A1c and AF after isolated off-pump coronary bypass grafting. METHODS: Of 912 consecutive patients undergoing isolated coronary bypass surgery, 805 were retrospectively analyzed for AF after excluding the following 107 cases: emergency (n=81), chronic AF (n=18), and pacemaker rhythm (n=8). We performed a group analysis with hemoglobin A1c levels categorized into tertiles of the baseline distribution and a continuous analysis based on 1% increments in hemoglobin A1c levels. The cutoff points for the tertiles were as follows: lower, 3.8-5.6% (n=283); middle, 5.7-6.7% (n=282); upper, 6.8-11.4% (n=240). RESULTS: AF occurred in 159 patients (19.8%) after surgery. The median value (25th-75th percentile) of preoperative hemoglobin A1c was significantly lower in patients who developed AF than in those who did not (5.8 (5.4-6.3) vs 6.1 (5.5-7.2), p=0.01). The incidence of postoperative AF was 28.3% (80/283) in the lower tertile, 17.4% (49/282) in the middle tertile, and 12.5% (30/240) in the upper tertile (p for trend=0.01). The unadjusted odds ratio (95% confidence interval) for the association between hemoglobin A1c and postoperative AF was 0.70 (0.61-0.83) per 1% increase and 0.42 (0.29-0.70) for the upper versus the lower tertile. This association persisted after adjustment for the univariate predictors (0.74 (0.60-0.92) per 1% increase; 0.54 (0.31-0.90) for upper vs lower tertile) and the known risk factors (0.78 (0.63-0.95) per 1% increase; 0.55 (0.35 0.88) for upper vs lower tertile). The area under the receiver operator characteristic curve (95% confidence interval) for preoperative hemoglobin A1c as a predictor of postoperative AF was 0.70 (0.65-0.75) (p=0.01). CONCLUSIONS: Preoperative hemoglobin A1c independently predicts the occurrence of AF after isolated off-pump coronary bypass grafting. PMID- 21612942 TI - Role of autophagy in the progression and suppression of leukemias. AB - Autophagy is a physiological process in which cellular components are degraded by the lysosomal machinery. Thereby, organelles are recycled and monomers are produced in order to maintain energy production. Current studies indicate autophagy might suppress or augment survival of cancer cells. Therefore, by elucidating the role of autophagy in cancer pathogenesis, novel therapeutic intervention points may be revealed. Leukemia therapy has advanced in recent years; but a definitive cure is still lacking. Since autophagy often is deregulated in this particular type of cancer, it is clear that future findings will have clinical implications. This review will discuss the current knowledge of autophagy in blood cancers. PMID- 21612943 TI - Controversies in the management of localized prostate cancer: radical prostatectomy still the standard of care. AB - The optimal treatment for clinically localized prostate cancer is an ongoing subject of controversy. Treatment decisions must take tumour staging, risk assessment, life expectancy and consideration of the major side effects of multiple available treatment regimens into account. Despite technical advances reduced the side effects of radiation therapy, the majority of patients with newly diagnosed organ confined prostate cancer decide to undergo radical prostatectomy. Refinements of radical prostatectomy surgical techniques during the last decade are influenced by better understanding of the anatomy of the small pelvis and resulted in excellent functional and oncological outcomes. Additionally, the surgeons experience was identified as a key determinant for improved surgical outcomes. Recently, retrospective studies revealed that also patients with locally advanced disease benefit from radical prostatectomy. Advantages of radical prostatectomy include a precise pathological staging that assesses the need for additional therapies. Moreover, PSA can easily be used as an accurate surrogate marker during follow-up in such patients. PMID- 21612944 TI - Full-thickness supraspinatus tears are associated with more synovial inflammation and tissue degeneration than partial-thickness tears. AB - BACKGROUND: The objective of this study was to determine whether the tear size of a supraspinatus tendon correlated with synovial inflammation and tendon degeneration in patients who underwent shoulder arthroscopy for rotator cuff repair. We hypothesized that increased synovial inflammation would correlate with greater tear size of the supraspinatus tendon at the time of surgery. MATERIALS AND METHODS: Tissue from the synovium, bursa, torn supraspinatus tendon, and subscapularis tendon was obtained from patients during shoulder arthroscopy to evaluate the messenger RNA expression of proinflammatory cytokines, tissue remodeling, and angiogenesis factors in the tendon, bursa, and synovium. Additional tissue was fixed to determine histologic changes including inflammation, vascular ingrowth, and collagen organization. RESULTS: Increased expression of interleukin 1beta, interleukin 6, cyclooxygenase 2, matrix metalloproteinase (MMP) 9, and vascular endothelial growth factor was found in the synovium of patients with full-thickness tears versus partial-thickness tears (P < .05). In the supraspinatus tendon, increased expression of MMP-1, MMP-9, MMP 13, and vascular endothelial growth factor was found in the full-thickness group. The upregulation of these genes in the full-thickness group was consistent with enhanced synovial inflammation, greater vascular ingrowth, and the loss of collagen organization in both supraspinatus and subscapularis tendons as determined by histology. CONCLUSION: Increased synovial inflammation and tissue degeneration correlate with the tear size of the supraspinatus tendon. A better understanding of the relationship between synovial inflammation and the progression of tendon degeneration can help in the design of novel and effective treatments to limit the advancement of rotator cuff disease and to improve their clinical outcomes. PMID- 21612945 TI - Efficacy of preoperative home use of 2% chlorhexidine gluconate cloth before shoulder surgery. AB - HYPOTHESIS: Deep infection after shoulder surgery is a rare but devastating problem. This study tested the hypothesis that the home application of a 2% chlorhexidine gluconate cloth before shoulder surgery would be more efficacious than a standard shower of soap and water at decreasing the preoperative cutaneous levels of pathogenic bacteria on the shoulder. MATERIALS AND METHODS: This randomized, prospective study evaluated 100 consecutive patients undergoing shoulder surgery. Patients were randomly assigned to use 2% chlorhexidine gluconate-impregnated cloths (treatment group) or to shower with soap and water before surgery (control group). Cutaneous cultures were taken from the patients'shoulders in the preoperative holding area. Patients were monitored for 2 months postoperatively for clinical signs of infection. RESULTS: In the treatment group vs the control group, the overall positive culture rate was 66% vs 94% (P = .0008), and the positive culture rate for coagulase-negative Staphylococcus was 30% vs 70% (P = .0001). The positive culture rate for Propionibacterium acnes was 46% in the treatment group vs 58% in the control group (P = .32). No infections occurred in any patients at a minimum of 2-months after surgery. DISCUSSION: The use of the 2% chlorhexidine cloth was effective at decreasing overall bacterial culture rates before shoulder surgery and was particularly effective at decreasing the quantity of coagulase-negative Staphylococcus, a known causative agent of postoperative shoulder infections. CONCLUSION: Use of chlorhexidine impregnated cloths prior to shoulder surgery may be a useful adjunct to presently used infection prevention strategies. PMID- 21612946 TI - No effects of the gonadal hormones on photoparoxysmal EEG responses in idiopathic generalised epilepsy. AB - PURPOSE: It is accepted that the estradiol hormone is proconvulsant and progesterone is anti-convulsant. In this study the effects of gonadal hormones on photoparoxysmal responses on EEG in idiopathic generalised epilepsy were researched. METHOD: Twenty-two women with photosensitive idiopathic generalised epilepsy having regular menstrual cycles were recruited into the study. Patients presenting photoparoxysmal responses were selected from routine EEG recordings. Blood samples were taken on day 14 (E) and 25 (P) of the menstrual cycle to confirm E and P peaks. An EEG recording was performed for each patient on E and P days. RESULT: No statistically significant differences were monitored with respect to frequency, duration of the photoparoxysmal responses on E and P peaks days (p>0.05). COMMENT: In this study no correlation could be demonstrated among menstrual cycle and photoparoxysmal responses. PMID- 21612947 TI - Deletion of insulin-regulated aminopeptidase in mice decreases susceptibility to pentylenetetrazol-induced generalized seizures. AB - The peptide angiotensin IV (Ang IV) influences seizure susceptibility in rat and mouse models. Indeed, Ang IV has been shown to protect rats from limbic seizures in the focal pilocarpine model. Moreover, both anticonvulsive and antiepileptogenic effects of Ang IV have been reported in the acute pentylenetetrazol (PTZ) and kindling model of generalized seizures in mice. It has been hypothesized that the latter effects on seizures could be established via a modulatory effect on dopamine receptors in the basal ganglia or via an indirect interaction between Ang IV and adenosine A1 receptors. However, a possible role for insulin-regulated aminopeptidase (IRAP), the high affinity binding site for Ang IV, has not been studied yet. To unequivocally unravel the involvement of IRAP in generalized seizure generation, we investigated the susceptibility of male IRAP wild-type (IRAP(+/+)) and knock-out (IRAP(-/-)) mice to PTZ-induced seizures. Challenging these mice intravenously with PTZ resulted in significantly increased thresholds for myoclonic twitch and generalized clonic seizures with loss of righting reflexes in IRAP(-/-) mice compared to their IRAP(+/+) littermates. These behavioural data were confirmed by video electrocorticography monitoring. Our study shows that IRAP(-/-) mice are less sensitive to the development of PTZ-induced seizures and suggests that IRAP is involved in generalized seizure generation. PMID- 21612948 TI - Tuberculosis of and around the ankle. AB - Osteoarticular tuberculosis of the ankle joint is rare, and diagnostic delays are common with this condition. The aim of our report is to highlight the varied clinical and radiologic presentation of this entity. We present a retrospective review of 16 patients with tuberculosis in and around the ankle joint who were surgically treated during a 6-year period. The incidence of ankle joint involvement in extraspinal osteoarticular tuberculosis was 15.7% in our unit. The most common presentation in our series was chronic septic arthritis, followed by periarticular osseous lytic lesion. Tuberculous synovitis, tenosynovits, and retrocalcaneal bursitis were also seen. Osteopenia, the hallmark of osteoarticular tuberculosis, might not be seen in all forms of tuberculosis affecting this joint. Chemotherapy remains the mainstay of treatment. Adjuvant surgery is often required to establish the diagnosis and in the treatment of patients with deformity and widespread destruction of articular cartilage owing to delayed presentation. PMID- 21612949 TI - Compression stockings with a negative pressure gradient have a more pronounced effect on venous pumping function than graduated elastic compression stockings. AB - OBJECTIVES: To measure the effect on the venous pumping function of a stocking providing a negative pressure gradient with higher pressures over the calf in comparison to a conventional graduated elastic compression stocking (GECS) in patients with advanced venous insufficiency. DESIGN: Experimental study. MATERIAL: 30 patients with severe superficial chronic venous insufficiency were enrolled. Two elastic stocking designs exerting a pressure at ankle between 15 and 25 mm Hg were compared; a conventional GECS and a stocking exerting a higher pressure over the calf than over the ankle producing a "progressive" increase in compression (PECS). METHOD: the venous calf pumping function was assessed by measuring the ejection fraction (EF) from the lower leg by a plethysmographic method during a standardised exercise. Interface pressure of the 2 compression devices was simultaneously recorded both at B1 = 12 cm above ankle, C = just above widest part of calf. RESULTS: The mean increase of EF produced by PECS was +75% (95 CI 48, 7-101,3) compared with +32% (95% CI 16, 8-48,6) with GECS (P < 0.001). There was a significant correlation between EF and the stocking pressure measured at calf level during standing and walking. CONCLUSION: Stockings exerting a higher pressure on the calf than on the ankle show a greater efficacy in increasing the venous ejection fraction from the leg. PMID- 21612950 TI - Efficient implementation of patient-specific simulated rehearsal for the carotid artery stenting procedure: part-task rehearsal. AB - OBJECTIVE(S): Patient-specific simulated rehearsal (PsR) is a technological advance within the domain of endovascular virtual reality (VR) simulation. It allows incorporation of patient-specific computed tomography Digital Imaging and Communications in Medicine (CT DICOM) data into the simulation and subsequent rehearsal of real patient cases. This study aimed to evaluate whether a part-task rehearsal (PTr) of a carotid artery stenting procedure (CAS) on a VR simulator is as effective as a full-task (FTr) preoperative run through. METHODS: Medical trainees were trained in the CAS procedure and randomised to a PTr or FTr of a challenging CAS case (Type-II arch). PTr consisted of 30 min of repeated catheterisations of the common carotid artery (CCA). Thereafter, both groups performed the CAS procedure in a fully functional simulated operating suite (SOS) with an interventional team. Technical performances were assessed using simulator based metrics and expert ratings. Other aspects of performance were assessed using the Non-Technical Skills for Surgeons (NOTSS) scoring. RESULTS: Twenty trainees were evenly randomised to either PTr or FTr. No differences in performance were seen except for the total time the embolic protection device (EPD) was deployed (9.4 min for the PT vs. 8.1 min for the FT, p = 0.02). Total time (26.3 vs. 25.5 min, p = 0.94), fluoroscopy time (15.8 vs. 14.4 min, p = 0.68), number of roadmaps (10.5 vs. 11.0, p = 0.54), amount of contrast (53.5 vs. 58.0 ml, p = 0.33), time to deploy the EPD (0.9 vs. 0.8 min, p = 0.31) and time to catheterise the CCA (9.2 vs. 8.9 min, p = 0.94) were similar. Qualitative performances as measured by expert ratings (score 24 vs. 24, p = 0.49) and NOTSS (p > 0.05 for all categories) were also comparable. CONCLUSIONS: Part- and full task rehearsals are equally effective with respect to the operative performance of a simulated CAS intervention. This finding makes a patient-specific rehearsal more efficient and may increase the feasibility of implementation of this technology into medical practice. PMID- 21612951 TI - Evaluation of the pterygoid hamulus morphology using cone beam computed tomography. AB - OBJECTIVE: This study consists of anatomic research of the pterygoid hamulus (PH) using 3D cone beam computed tomography (CBCT) images reconstructed from a volumetric rendering program. STUDY DESIGN: Three hundred ninety-six sides in the CBCT scans of 198 (115 men and 83 women) patients were retrospectively analyzed. DICOM data of the patients were transferred to a surface-rendering software so as to generate 3D hard tissue surface representations of PHs. The width, length, angle, and the distance between posterior nasal spine and tip of the PH were measured. In addition, the inclinations of PHs were also evaluated in sagittal and coronal planes of the 3D images. Pearson chi(2) and Student t test were performed for statistical analysis among age, localization, and measurements (P < .05). RESULTS: The mean PH measurements of left and right sides were 1.72 (SD 0.94) and 1.87 (SD 1.17)-mm width, and the lengths were 5.48 (AD 1.94), and 5.40 (SD 2.0) mm, respectively, with no significant difference (P > .05). All PHs were inclined toward the lateral side in the coronal plane, whereas PHs tended to incline toward the posterior rather than anterior in the sagittal plane (~78%). The results showed no statistically significant differences among age, localization, and measurements of PHs (P > .05). CONCLUSIONS: Knowledge about the morphology of these structures is helpful for the interpretation of imaging and provides valuable information in the differential diagnosis of untraceable pains in the oral cavity and pharynx. Because of potential problems owing to PH morphology and elongation, oral and maxillofacial radiologists should assess the radiographic images thoroughly. PMID- 21612952 TI - Effect of a differently tilted angle of mandibular premolar on fracture resistance of 3 postcore restorations. AB - OBJECTIVE: The objective of this study was to evaluate the effect of differently tilted mandibular premolars on fracture resistance of 3 postcore restorations. METHODS: Seventy-five extracted human mandibular premolars were simulated to 5 different tilted angles: lingually tilted (LT) 30 degrees and 15 degrees , 0 degrees , and buccally tilted (BT) 15 degrees and 30 degrees , and restored with custom-made metal postcore (CMPC), prefabricated fiber postcore (PFPC), or custom made fiber postcore (CFPC). Then, a 30 degrees oblique load was applied with a crosshead speed of 1 mm/min to the restoration. Failure loads and fracture modes were analyzed (2-way ANOVA and Tukey test, P < .05). RESULTS: The buccally inclined restoration had higher fracture resistance than that of the lingually tilted restoration. The strength of the PFPC restoration was comparable with that of the CMPC restoration in all tilted groups. As for fracture modes, no significant differences were found among the various tilted restorations. CONCLUSIONS: Buccally tilted mandibular premolars are more likely to be restored with prefabricated fiber postcore than a lingually inclined mandibular premolar. PMID- 21612953 TI - Immunohistochemical expression of p16(INK4A) protein in oral lichen planus. AB - The expression of p16(INK4A) has been investigated in oral leukoplakias (OLK), but no data are available about oral lichen planus (OLP). In this study, p16(INK4A) immunohistochemical expression was evaluated in 56 OLP and 36 OLK (12 without inflammation [NI-OLK] and 24 with chronic inflammation [I-OLK]) and compared with 23 reactive nonspecific inflammations (INF) and 14 normal control samples. The p16(INK4A) immunostaining was considered to be positive when >5% of keratinocytes were stained. All normal control samples were negative. Positive p16(INK4A) was detected in OLP, IOLK, and INF. Significant differences in p16(INK4A) positivity were found between OLP (64%) and OLK (28%) (chi(2) = 17.7; P < .01), and between I-OLK and NI-OLK (chi(2) = 4.5; P < .05). No significant difference was found between OLP and INF (43%). In conclusion, positive p16(INK4A) in OLP patients seems to be related to reactive inflammatory processes rather than to a risk of progression to oral squamous cell carcinoma. PMID- 21612954 TI - Mast cells and matrix metalloproteinase 9 expression in actinic cheilitis and lip squamous cell carcinoma. AB - OBJECTIVES: The aim of this study was to evaluate mast cell (MC) density and migration and their association with matrix metalloproteinase (MMP) 9 expression in squamous cell carcinoma (SCC) and actinic cheilitis (AC). STUDY DESIGN: Tryptase, c-Kit, and MMP-9 expression was evaluated in 20 cases of SCC, 20 cases of AC, and 7 cases of normal lip (control samples) by immunohistochemistry techniques. RESULTS: Tryptase(+) and c-Kit(+) MC densities were significantly higher in SCCs than in ACs and control samples (P < .001). However, no significant difference was found when comparing tryptase(+) and c-Kit(+) MC densities between ACs and control samples (P values .185 and .516, respectively). MMP-9 was strongly expressed in SCCs and moderately expressed in ACs and control samples. A highly significant association was found between tryptase(+) MC density and the expression of MMP-9 (P < .001). CONCLUSIONS: The increase in MC density associated with the strong expression of MMP-9 may favor SCC progression. PMID- 21612955 TI - Liver hemojuvelin protein levels in mice deficient in matriptase-2 (Tmprss6). AB - Mutations of the TMPRSS6 gene, encoding the serine protease matriptase-2, lead to iron-refractory iron deficiency anemia. Matriptase-2 is a potent negative regulator of hepcidin. Based on in vitro data, it has recently been proposed that matriptase-2 decreases hepcidin synthesis by cleaving membrane hemojuvelin, a key protein of the hepcidin-regulatory pathway. However, in vivo evidence for this mechanism of action of matriptase-2 is lacking. To investigate the hemojuvelin matriptase-2 interaction in vivo, an immunoblot assay for liver membrane hemojuvelin was optimized using hemojuvelin-mutant mice as a negative control. In wild-type mice, two hemojuvelin-specific bands of 35kDa and 20kDa were detected in mouse liver membrane fraction under reducing conditions; under non-reducing conditions, a single band of approximately 50kDa was seen. Phosphatidylinositol specific phospholipase C treatment confirmed binding of the detected protein to the cell membrane by a glycosylphosphatidylinositol anchor, indicating that the major form of mouse liver membrane hemojuvelin is a glycosylphosphatidylinositol bound heterodimer. Unexpectedly, comparison of liver homogenates from Tmprss6+/+ and Tmprss6-/- mice revealed significantly decreased, rather than increased, hemojuvelin heterodimer content in Tmprss6-/- mice. These data do not provide direct support for the concept that matriptase-2 cleaves membrane hemojuvelin and may indicate that, in vivo, the role of matriptase-2 in the regulation of hepcidin gene expression is more complex. PMID- 21612956 TI - Why care about sleep of infants and their parents? PMID- 21612957 TI - In search of lost sleep: secular trends in the sleep time of school-aged children and adolescents. AB - BACKGROUND: Sleep deficits are associated with a wide range of detrimental physical and mental health outcomes. There is concern that children are not getting enough sleep, and that sleep duration has been declining. However, evidence is sparse. METHODS: A systematic review of world literature was conducted to locate studies reporting the sleep duration of children aged 5-18 years. Monte Carlo simulation was used to generate pseudodata from summary data, which were combined with raw data and analysed by linear regression of sleep duration on year of measurement at the age * sex * day type * country level. RESULTS: Data were available on 690,747 children from 20 countries, dating from 1905 to 2008. From these data, 641 regressions were derived. The sample-weighted median rate of change was -0.75 min nightly per year, indicating a decrease of more than 1 h per night over the study period. Rates of change were negative across age, sex and day type categories, but varied according to region, with Europe, the USA, Canada and Asia showing decreases and Australia, the UK and Scandinavia showing increases. CONCLUSION: Over the last 103 years, there have been consistent rapid declines in the sleep duration of children and adolescents. PMID- 21612958 TI - Infection of Eurasian badgers (Meles meles) with Mycobacterium bovis and Mycobacterium avium complex in Spain. AB - The prevalence, distribution and pathology related to infection with Mycobacterium bovis and other mycobacteria were determined in trapped (n=36) and road-killed (n=121) badgers in Spain from 2006 to 2010. The prevalence of M. bovis based on bacteriological culture from road-killed badgers was 8/121 (6.6%) and from trapped badgers was 0/36 (0%). Tuberculosis/M. bovis infection was evident in 15/121 (12.4%) road-killed badgers when bacteriology and histopathology were combined. Mycobacterium avium complex was isolated by culture from the tracheal aspirate of 1/36 (2.8%) trapped badgers and from tissue pools from 8/121 (6.6%) road-killed badgers. PMID- 21612959 TI - The influence of challenging objects and horse-rider matching on heart rate, heart rate variability and behavioural score in riding horses. AB - A good horse-rider 'match' is important in the context of equine welfare. To quantify the influence of repetition and horse-rider matching on the stress of horses encountering challenging objects, 16 Warmblood horses were ridden in a test-setting on three occasions. On each occasion the horse was ridden by a different rider and was challenged by three objects (A-C). Heart rate (HR), heart rate variability (HRV) of horse and rider, and behaviour score (BS) of the horse were obtained for each object and as a total for each test. The horse-rider interaction was evaluated with each combination and assessed as 'matching' or 'mismatching', and the horses were categorised as 'compliant', 'partly-compliant' or 'non-compliant'. Horses exhibited a decreased HR (P=0.015) and a decreased BS (P=0.004) within and across different tests. 'Matching' horse-rider combinations exhibited less stress as indicated by reduced HR ('match' 69+/-10 vs. 'mismatch' 72+/-9, P=0.001) and BS ('match' 1.9+/-1.1 vs. 'mismatch' 3.8+/-1.4, P=0.017) of the horse. 'Compliant' (68+/-8, P<0.001) and 'partly-compliant' (71+/-9, P=0.002) horses had significantly lower HR than 'non-compliant' (75+/-9) animals. The findings of the study indicate that HR and BS measurements support a subjective 'match' diagnosis and HR measurement may be a valuable tool in assessing horse compliance. PMID- 21612960 TI - Hypokinetic-rigid syndrome in children and inborn errors of metabolism. AB - Hypokinetic-rigid syndrome (HRS) or "parkinsonism" is rare in children. From a clinical point of view it is characterised by a group of signs in which hypokinesia (decreased number of movements), bradykinesia (slowness of movements), rigidity and rest tremor are the fundamental traits. Nervous system infections, immunomediated encephalitis, hypoxia and some drugs have been described as acquired or secondary causes of HRS in the paediatric age. Inborn errors of metabolism (IEM) comprise and important group regarding genetic causes. Main diseases causing HRS in children are neurotransmitter (biogenic amines) defects, metal storage diseases, energy metabolism disorders and lysosomal diseases. In general, in IEM, the HRS is associated to other neurological signs such as dykinesias, pyramidal signs, and psychomotor delay, is very rare in the neonatal period, tends to be more frequent in advanced stages of progressive diseases, and may respond to specific therapies. In particular, l-dopa + carbidopa can be a very effective treatment in neurotransmitter defects, whereas other disorders such as Wilson disease and some particular lysosomal disorders have different therapeutic possibilities. Furthermore, other genetic conditions in dopa-responsive and non-responsive HRS should be also considered, especially in juvenile parkinsonism. Through this review, a practical orientation for paediatric neurologists concerning clinical clues, diagnostic procedure and treatment of metabolic HRS will be provided. PMID- 21612961 TI - Linear Response Equilibrium versus echo-planar encoding for fast high-spatial resolution 3D chemical shift imaging. AB - In this work Linear Response Equilibrium (LRE) and Echo-planar spectroscopic imaging (EPSI) are compared in terms of sensitivity per unit time and power deposition. In addition an extended dual repetition time scheme to generate broad stopbands for improved inherent water suppression in LRE is presented. The feasibility of LRE and EPSI for assessing cholesterol esters in human carotid plaques with high spatial resolution of 1.95*1.15*1.15 mm(3) on a clinical 3T MR system is demonstrated. In simulations and phantom experiments it is shown that LRE has comparable but lower sensitivity per unit time relative to EPSI despite stronger signal generated. This relates to the lower sampling efficiency in LRE relative to EPSI as a result of limited gradient performance on clinical MR systems. At the same time, power deposition of LRE is significantly reduced compared to EPSI making it an interesting niche application for in vivo high field spectroscopic imaging of metabolites within a limited bandwidth. PMID- 21612962 TI - Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate. AB - Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs). STUDY DESIGN: Protocol HPN-100-005 involved open label fixed sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB dose with controlled diet. After 7 days on NaPBA or GPB, subjects underwent 24-hour blood sampling for ammonia and drug metabolite levels as well as measurement of 24-hour urinary phenyacetylglutamine (PAGN). Adverse events (AEs), safety labs and triplicate ECGs were monitored. RESULTS: Eleven subjects (9 OTC, 1 ASS, 1 ASL) enrolled and completed the switch-over from NaPBA (mean dose=12.4 g/d or 322 mg/kg/d; range=198-476 mg/kg/d) to GPB (mean dose=10.8 mL or 0.284 mL/kg/d or 313 mg/kg/d; range=192-449 mg/kg/d). Possibly-related AEs were reported in 2 subjects on NaPBA and 4 subjects on GPB. All were mild, except for one moderate AE of vomiting on GPB related to an intercurrent illness. No clinically significant laboratory or ECG changes were observed. Ammonia was lowest after overnight fast, peaked postprandially in the afternoon to early evening and varied widely over 24h with occasional values >100 MUmol/L without symptoms. Ammonia values were ~25% lower on GPB vs. NaPBA (p>=0.1 for ITT and p<0.05 for per protocol population). The upper 95% confidence interval for the difference between ammonia on GPB vs. NaPBA in the ITT population (95% CI 0.575, 1.061; p=0.102) was less than the predefined non-inferiority margin of 1.25 and less than 1.0 in the pre defined per-protocol population (95% CI 0.516, 0.958; p<0.05). No statistically significant differences were observed in plasma phenylacetic acid and PAGN exposure during dosing with GPB vs. NaPBA, and the percentage of orally administered PBA excreted as PAGN (66% for GPB vs. 69% for NaPBA) was very similar. GPB and NaPBA dose correlated best with urinary-PAGN. CONCLUSIONS: These findings suggest that GPB is at least equivalent to NaPBA in terms of ammonia control, has potential utility in pediatric UCD patients and that U-PAGN is a clinically useful biomarker for dose selection and monitoring. PMID- 21612963 TI - Seroprevalence of Rickettsia typhi and Rickettsia conorii infections in the Canary Islands (Spain). AB - OBJECTIVE: The aim of this work was to evaluate the prevalence of past infection due to Rickettsia typhi and Rickettsia conorii in the Canary Islands (Spain). METHODS: A representative sample of the population of the seven islands, formed of 662 people aged between 5 and 75 years (368 females, 294 males), was analyzed. Epidemiological data were obtained by direct survey. The detection of serum IgG antibodies against both microorganisms was based on an indirect immunofluorescence test, considered positive if the titers were >= 1/80. RESULTS: Of the analyzed population 3.9% had IgG antibodies against R. typhi and 4.4% against R. conorii. Out of these positive samples, only three were positive for both species. The seroprevalence was similar in both sexes. Positive results were found in all age groups, but a higher rate was noticed in those aged 46 years and older (p<0.05). R. typhi was found to be more prevalent in rural areas of all islands, as well as in farmers. CONCLUSIONS: Our results confirm the presence of antibodies against the causative agents of murine typhus and Mediterranean spotted fever in the Canary Islands. Indirect data suggest that the detection of antibodies to R. conorii might be due to a cross-reaction between these species. PMID- 21612964 TI - Benfluorex: analysis of a drug-related public health crisis. PMID- 21612965 TI - A controlled trial of the benefits of ultrasound-guided steroid injection for shoulder pain. AB - OBJECTIVES: We studied the value of ultrasound (US) to define shoulder pathology and guide local steroid injection in comparison with a standard injection in the management of the acute painful shoulder. METHODS: Seventy consecutive patients with acute shoulder pain were assessed clinically and by US. Patients were randomized to receive either a standard subacromial infiltration of 7 mg of betamethasone or a US-guided injection according to the US diagnosis. Follow-up evaluations were performed by an independent assessor who was blinded to the results of the initial US and clinical assessments. RESULTS: Sixty-seven patients completed the study. Both groups showed a significant reduction in both daytime and night pain compared to baseline. The US injection group had significantly less pain at rest at 2 and 6 weeks (NRS: 1.6 vs 3.3, P<0.005; 3 vs 4.2, P<0.04). The percentage of good responders was significantly higher in US group at 2 weeks, (81% vs 54%, P<0.005) and 6 weeks (64% vs 38%, P<0.05). At 2 and 6 weeks, responder rate and activity pain scores as well as Constant score were in favour of US, though did not reach statistical significance. CONCLUSION: Local steroid injection for shoulder pain leads to significant improvements in pain and function for up to 12 weeks. An US examination to define the origin of shoulder pain as well as to guide injection provides significant additional benefits for up to 6 weeks. We recommend routine US examination as part of the management of acute shoulder pain. PMID- 21612966 TI - [Therapeutic use of amniotic membranes and their derivate cells]. AB - During all the pregnancy, the foetal membranes play several functions (mechanic, anti-infectious, hormonal, regulation of the amniotic fluid homeostasis...) fundamental for an optimal development and maternal-foetal physiology. After delivery, these amniotic membranes have regained for a few years, a new interest and a second "ex-utero" life due to their therapeutic use. This use was firstly initiated experimentally in ophthalmological pathologies, around 1950. The recent understanding of molecular and cellular mechanisms enables to explain scientifically these first empiric uses. They are an interesting solution in ocular aggressions like viral attacks, chemical or temperature burns. They also represent an attractive alternative in case of corneal grafts and a biological matrix for limb cells cultures used to regenerate the corneal lesions. An industrial engineering is now in place to boost the performances of these human membranes. The isolation and identification of stem cells (mesenchymal origin) in these amniotic membranes are promising in the field of cell therapy. Recently, the first results have been published demonstrating the clinical efficiency of the stems cell during pancreatic, cardiac, lung neuronal lesions. PMID- 21612967 TI - [Can we learn humanism in the management of patients?]. PMID- 21612968 TI - Optimization of ultrasonic-assisted extraction of natural antioxidants from rice bran using response surface methodology. AB - Ultrasonic technology was applied for extraction of polyphenols and antioxidants from the rice bran using ethanol as a food grade solvent. Response surface methodology (RSM) was used to optimize experimental conditions for extraction of polyphenols and antioxidants. Three independent variables such as solvent percentage (%), temperature ( degrees C) and time (min) were studied. Effect of ethanol concentration was found to be significant on all responses. Total phenolic content (TPC) varied from 2.37 to 6.35mg gallic acid equivalent/g of dry sample. Antioxidant activity of the extracts was determined by the ferric reducing antioxidant power (FRAP) assay and scavenging activity of 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical. FRAP and DPPH values varied from 31.74 to 57.23MUmol Fe(2+)/g of dry sample and 16.88% to 55.61% inhibition, respectively. Extraction yields ranged from 11 to 20.2%. Optimal ultrasonic-assisted extraction (UAE) conditions were identified as 65-67% ethanol, 51-54 degrees C, 40-45min. The experimental values agreed with those predicted by SRM models, thus indicating suitability of the model employed and the success of RSM in optimizing the extraction conditions. PMID- 21612969 TI - A patient-specific FE-based methodology to simulate prosthesis insertion during an augmentation mammoplasty. AB - Breast augmentation surgery is a widespread practice for aesthetic purposes. Current techniques, however, are not able to reliably predict the desired final aspect of the breast after the intervention, whose success relies almost completely on the surgeon's skill. In this way, patient-specific methodologies capable of predicting the outcomes of such interventions are of particular interest. In this paper, a finite element biomechanical model of the breast of a female patient before an augmentation mammoplasty was generated using computer tomography images. Prosthesis insertion during surgery was simulated using the theory of finite elasticity. Hyperelastic constitutive models were considered for breast tissues and silicone implants. The deformed geometry obtained from finite element analysis was compared qualitatively and quantitatively with the real breast shape of the patient lying in supine position, with root-mean-squared errors less than 3mm. The results indicate that the presented methodology is able to reasonably predict the aspect of the breast in an intermediate step of augmentation mammoplasty, and reveal the potential capabilities of finite element simulations for visualization and prediction purposes. However, further work is required before this methodology can be helpful in aesthetic surgery planning. PMID- 21612970 TI - Impact of recommendations on the initial therapy of Parkinson's disease: a population-based study in France. AB - Levodopa induces long-term motor complications in Parkinson's disease (PD). Therapeutic strategies that prevent motor complications are needed. Our aim was to evaluate the impact of recommendations of a French consensus conference published in 2000 on initial PD therapy. We identified 308 PD patients as part of a population-based study performed within the Mutualite Sociale Agricole in five French districts (2007). Neurologists confirmed PD diagnosis. We compared initial therapy in 102 patients treated before 12/31/2000 to that of 206 patients treated afterwards. Initial treatment was in agreement with the recommendations if dopamine agonists were used in patients <60 years (n = 49) and levodopa in patients >=70 years (n = 133). Agreement with the recommendations increased after 2000 (66.0%) compared to before (46.3%, p = 0.025). For patients <60 years, agreement increased (64.0% vs 20.2%, p = 0.017) while it remained stable (66.4% vs 70.6%, p = 0.73) in patients >=70 years. The publication of recommendations has influenced initial treatment choices for PD in France. PMID- 21612971 TI - Residential mobility among patients admitted to acute psychiatric wards. AB - Residential mobility among those with mental disorders is consistently associated with hospital admission. We studied 4485 psychiatric admissions in South London, aiming to describe the prevalence, timing and associations of residential moves occurring in association with admission. Moves tended to cluster around discharge; 15% of inpatients moved during admission or up to 28 days after discharge. The strongest associations were with younger age (especially 16-25 years) and homelessness. Unadjusted effects of gender, marital status and previous service use were mediated by homelessness. Possible mechanisms for the associations with homelessness and younger age are discussed. PMID- 21612973 TI - Micrometric molecular histology of lipids by mass spectrometry imaging. AB - Time-Of-Flight Secondary Ion Mass Spectrometry is compared to other mass spectrometry imaging techniques, and recent improvements of the experimental methods, driven by biological and biomedical applications, are described and discussed. This review shows that this method that can be considered as a micrometric molecular histology is particularly efficient for obtaining images of various lipid species at the surface of a tissue sample, without sample preparation, and with a routine spatial resolution of 1MUm or less. PMID- 21612972 TI - Reciprocal relations between cognitive neuroscience and formal cognitive models: opposites attract? AB - Cognitive neuroscientists study how the brain implements particular cognitive processes such as perception, learning, and decision-making. Traditional approaches in which experiments are designed to target a specific cognitive process have been supplemented by two recent innovations. First, formal cognitive models can decompose observed behavioral data into multiple latent cognitive processes, allowing brain measurements to be associated with a particular cognitive process more precisely and more confidently. Second, cognitive neuroscience can provide additional data to inform the development of formal cognitive models, providing greater constraint than behavioral data alone. We argue that these fields are mutually dependent; not only can models guide neuroscientific endeavors, but understanding neural mechanisms can provide key insights into formal models of cognition. PMID- 21612974 TI - Salivary gland carcinoma in Denmark 1990-2005: a national study of incidence, site and histology. Results of the Danish Head and Neck Cancer Group (DAHANCA). AB - To describe the incidence, site and histology (WHO 2005) of salivary gland carcinomas in Denmark. Nine hundred and eighty-three patients diagnosed from 1990 to 2005 were identified from three nation-wide registries. The associated clinical data were retrospectively retrieved from patient medical records. Histological revision was performed in 886 cases (90%). Based on histological revision, 31 patients (3%) were excluded from the study leaving 952 for epidemiological analysis. The mean crude incidence in Denmark was 1.1/100,000/year. The male vs. female ratio was 0.97 and the median age was 62 years. The parotid gland was the most common site (52.5%) followed by the minor salivary glands of the oral cavity (26.3%). The most frequent histological subtypes were adenoid cystic carcinoma (25.2%), mucoepidermoid carcinoma (16.9%), adenocarcinoma NOS (12.2%) and acinic cell carcinoma (10.2%). The revision process changed the histological diagnosis in 121 out of 886 cases (14%). The incidence of salivary gland carcinoma in Denmark is higher than previously reported. More than half of salivary gland carcinomas are located in the parotid gland with adenoid cystic carcinoma being the most frequent subtype. Histological classification of salivary gland carcinomas is difficult and evaluation by dedicated pathology specialists might be essential for optimal diagnosis and treatment. PMID- 21612975 TI - A population-based study of factors associated with early versus late stage oral cavity cancer diagnoses. AB - Oral cavity cancers can be detected early yet many are diagnosed with advanced disease. We assessed risk factors for advanced stage disease in a population based study. Study population was all Ontario patients with anterior tongue or floor of mouth cancers diagnosed between 1991 and 2000 (n=2033). Data are from a retrospective chart review. Risk factors included: demographic characteristics, co-morbidity, precancerous lesions, dental status, smoking, alcohol use, and social marginalization. Multivariate regression analyses assessed independent associations while controlling for disease grade and site. Forty percent had advanced disease. Eighty-nine percent presented with symptoms and 66% were referred by a family physician. Risk factors in the tongue group were being: age >=80 (RR 1.47), widowed (RR 1.34), social marginalized (RR 1.69), a current smoker (RR 1.26), or a smoker-heavy drinker (RR 1.73). Risk factors in the floor of mouth group were being: age >=70 (70-79: RR 1.24 and >=80: RR 1.43), and socially marginalized (RR 1.22). Having a pre-cancerous lesion (RR 0.44) or a regular dentist (RR 0.84) was protective in the floor of mouth group. Risk factors for those with co-morbid illnesses were being: age >=70 (70-79: RR 1.28 and >=80: RR 1.55), separated/divorced (RR 1.26), socially marginalized (RR 1.37), or a smoker-heavy drinker (RR 1.44); while having a regular dentist was protective (RR 0.83). Targeted education to alert those at risk about oral cancer warning signs and better training coupled with opportunistic oral cavity exams by family physicians could reduce the burden of this disease. PMID- 21612976 TI - Novel metabolic pathways in Archaea. AB - The Archaea harbor many metabolic pathways that differ to previously recognized classical pathways. Glycolysis is carried out by modified versions of the Embden Meyerhof and Entner-Doudoroff pathways. Thermophilic archaea have recently been found to harbor a bi-functional fructose-1,6-bisphosphate aldolase/phosphatase for gluconeogenesis. A number of novel pentose-degrading pathways have also been recently identified. In terms of anabolic metabolism, a pathway for acetate assimilation, the methylaspartate cycle, and two CO2-fixing pathways, the 3 hydroxypropionate/4-hydroxybutyrate cycle and the dicarboxylate/4-hydroxybutyrate cycle, have been elucidated. As for biosynthetic pathways, recent studies have clarified the enzymes responsible for several steps involved in the biosynthesis of inositol phospholipids, polyamine, coenzyme A, flavin adeninedinucleotide and heme. By examining the presence/absence of homologs of these enzymes on genome sequences, we have found that the majority of these enzymes and pathways are specific to the Archaea. PMID- 21612977 TI - Synthesis, spectral, antimicrobial and antitumor assessment of Schiff base derived from 2-aminobenzothiazole and its transition metal complexes. AB - N-(thiophen-2-ylmethylene)benzo[d]thiazol-2-amine Schiff base (L) derived from 2 aminobenzothiazole and 2-thiophenecarboxaldehyde was synthesized and characterized using elemental analysis, IR, mass spectra, (1)H NMR and UV-vis spectra. Its complexes with Cu(II), Fe(III), Ni(II) and Zn(II) were prepared and isolated as solid products and characterized by elemental and thermal analyses, spectral techniques as well as magnetic susceptibility. The IR spectra showed that the Schiff base under investigation behaves as bidentate ligand. The UV-vis spectra and magnetic moment data suggested octahedral geometry around Cu(II) and Fe(III) and tetrahedral geometry around Ni(II) and Zn(II). In view of the biological activity of the Schiff base and its complexes, it has been observed that the antimicrobial activity of the Schiff base increased on complexation with the metal ion. In vitro antitumor activity assayed against five human tumor cell lines furnished the significant toxicities of the Schiff base and its complexes. PMID- 21612978 TI - Synchronous fluorescence spectroscopic study of solvatochromic curcumin dye. AB - Curcumin, the main yellow bioactive component of turmeric, has recently acquired attention by chemists due its wide range of potential biological applications as an antioxidant, an anti-inflammatory, and an anti-carcinogenic agent. This molecule fluoresces weakly and poorly soluble in water. In this detailed study of curcumin in thirteen different solvents, both the absorption and fluorescence spectra of curcumin was found to be broad, however, a narrower and simple synchronous fluorescence spectrum of curcumin was obtained at Deltalambda=10-20 nm. Lippert-Mataga plot of curcumin in different solvents illustrated two sets of linearity which is consistent with the plot of Stokes' shift vs. the ET30. When Stokes's shift in wavenumber scale was replaced by synchronous fluorescence maximum in nanometer scale, the solvent polarity dependency measured by lambdaSFSmax vs. Lippert-Mataga plot or ET30 values offered similar trends as measured via Stokes' shift for protic and aprotic solvents for curcumin. Better linear correlation of lambdaSFSmax vs. pi* scale of solvent polarity was found compared to lambdaabsmax or lambdaemmax or Stokes' shift measurements. In Stokes' shift measurement both absorption/excitation as well as emission (fluorescence) spectra are required to compute the Stokes' shift in wavenumber scale, but measurement could be done in a very fast and simple way by taking a single scan of SFS avoiding calculation and obtain information about polarity of the solvent. Curcumin decay properties in all the solvents could be fitted well to a double exponential decay function. PMID- 21612979 TI - Role for proteases and HLA-G in the pathogenicity of influenza A viruses. AB - Influenza is one of the most common infectious diseases in humans occurring as seasonal epidemic and sporadic pandemic outbreaks. The ongoing infections of humans with avian H5N1 influenza A viruses (IAV) and the past 2009 pandemic caused by the quadruple human/avian/swine reassortant (H1N1) virus highlights the permanent threat caused by these viruses. This review aims to describe the interaction between the virus and the host, with a particular focus on the role of proteases and HLA-G in the pathogenicity of influenza viruses. PMID- 21612980 TI - Electrical impedance myography for monitoring motor neuron loss in the SOD1 G93A amyotrophic lateral sclerosis rat. AB - OBJECTIVE: Human studies have shown that electrical impedance myography (EIM), a technique based on the surface application of high-frequency, low-intensity electrical current to localized areas of muscle, is sensitive to muscle denervation. In this study, we examined the role of EIM as a potential biomarker for assessing ALS disease progression in the SOD1 transgenic rat by comparing it to motor unit number estimation (MUNE). METHODS: Multi-frequency EIM and MUNE were performed twice weekly in 16 rats from approximately 10 weeks of age onward. Four different EIM measures were evaluated, including the previously studied 50 kHz phase and three condensed multi-frequency parameters. RESULTS: The rate of deterioration in the multi-frequency phase data from 100-500 kHz had the strongest correlation to survival (rho=0.79, p<0.001), surpassing that of MUNE (rho=0.57, p=0.020). These two measures were also strongly correlated (rho=-0.94, p<0.001) to one another. CONCLUSIONS: These findings support that EIM is an effective tool for assessing disease progression in the ALS rat. SIGNIFICANCE: Given its ease of application and ability to assess virtually any superficial muscle, EIM deserves further study as a biomarker in human ALS clinical therapeutic trials. PMID- 21612981 TI - Airway immune homeostasis and implications for influenza-induced inflammation. AB - The lung is exposed to a myriad of innocuous antigens on a daily basis and must maintain a state of immune ignorance or tolerance to these harmless stimuli to retain pulmonary homeostasis and to prevent potentially fatal immunopathology. Here, we examine how, in the lower airways, resident cell populations contribute to the immune regulatory strategies that restrain inflammation. During influenza infection, these suppressive signals must be overcome to elicit a protective immune response that eliminates the virus. We also discuss how, after resolution of infection, the lung does not return to the original homeostatic state, and how the induced altered state can persist for long periods, which leaves the lung more susceptible to other infectious insults. PMID- 21612982 TI - Recognition and referral of depression in patients with heart disease. AB - BACKGROUND: Routine screening and assessment for depression occurs rarely in clinical practice for a variety of reasons, including the absence of systems to facilitate the process. AIM: To identify nurses' knowledge and practice regarding depression screening and referral for cardiac patients following the implementation of education workshops and a validated screening tool with referral actions. METHODS: Pre and post-test design using surveys and semi structured interviews was conducted with a purposive sample of nurses in a large Australian metropolitan tertiary referral hospital. Prior to the introduction of the screening and referral tool, nurses engaged in an interactive one hour education workshop on the topic of depression and the tool; introduced to improve depression screening following an acute cardiac event. RESULTS: In the pre and post-survey 40 and 30 nurses, respectively, participated with 14 also engaging in semi-structured interviews. Eighty percent reported a 'good' understanding of depression post-program compared to 30% at baseline. Sixty percent reported routinely using the depression screening and referral tool. The interviews identified three main themes that supported the utility of the education and instrument: knowledge improvement; perceived self-efficacy and new knowledge into practice. CONCLUSION: The vast majority of participants reported increased skill, knowledge and confidence to screen and refer for depression post an acute cardiac event. The substantial increase in the number of nurses who engaged in screening and referral actions further demonstrated the success of the program. These encouraging results provide evidence that screening for depression can be achieved through adopting formalised processes. PMID- 21612983 TI - Gabapentin-induced sexual dysfunction. AB - Sexual dysfunction is a key adverse effect leading to medication noncompliance. Psychotropic drugs associated with sexual dysfunction include antiepileptic drugs, antidepressants, and antipsychotics. Gabapentin, frequently used off-label to treat psychiatric and pain disorders, has previously been reported to cause sexual dysfunction at a minimum total daily dose of 900 mg. This report addresses dose-dependent gabapentin-induced sexual dysfunction reaching total sexual dysfunction (loss of libido, anejaculation, anorgasmia, and impotence) at a total daily dose of only 300 mg. PMID- 21612984 TI - Another complication associated with rhBMP-2? PMID- 21612985 TI - Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study. AB - BACKGROUND CONTEXT: The commercially available growth factor recombinant bone morphogenic protein-2 (rhBMP-2) used in spinal fusion has been associated with numerous adverse reactions, including inflammatory reactions in soft tissue, heterotopic bone formation, radiculitis, osteolysis, and cage or graft subsidence. The original Food and Drug Administration Summary of anterior lumbar interbody fusion (ALIF) reported 12 retrograde ejaculation (RE) events (8%) in the rhBMP-2 groups compared with (1.4%) in the control group. It had been debated whether this finding was related to rhBMP-2 use. PURPOSE: To compare the incidence of RE after ALIF in patients with and without rhBMP-2 use. STUDY DESIGN: Retrospective analysis of prospectively gathered outcomes data on consecutive subjects having ALIF with and without rhBMP-2 use. PATIENT SAMPLE: Male patients with lumbar spondylosis or spondylolisthesis having ALIF of the lowest one or two lumbar levels with and without rhBMP-2. OUTCOME MEASURE: Report of RE as a new finding after ALIF. METHODS: From the comprehensive outcome database at a high-volume university practice, male subjects having ALIF for one- (L5/S1) or two-level (L4/L5, L5/S1) lumbar fusion were identified. Retrograde ejaculation events were recorded and comparative incidence compared. RESULTS: The two groups were comparable for age and additional procedures performed. There were 69 L5/S1 ALIFs performed with rhBMP-2 and 174 ALIFs performed without rhBMP 2 during the study period. Of those, 24 and 64 were two-level ALIFs performed with and without rhBMP-2, respectively. There were five RE events (7.2%) reported in the rhBMP-2 group and 1 (0.6%) in the control group. Comparing single-level L5/S1 ALIF, there was a 6.7% and 0% rate of RE in the rhBMP-2 versus control groups, respectively. At 1 year after surgery, three of six affected subjects reported resolution of the RE. CONCLUSION: This study confirms previous reports of a higher rate of RE in ALIF procedures using rhBMP-2. This may be an important consideration in subjects concerned with sterility after surgery. PMID- 21612986 TI - An evolving perception of the risk of rhBMP-2 use for anterior spinal interbody fusions. PMID- 21612987 TI - Multi-walled carbon nanotubes decrease lactate dehydrogenase activity in enzymatic reaction. AB - The oxidation of 1, 4-nicotinamide adenine dinucleotide (NADH) to beta nicotinamide adenine dinucleotide (NAD(+)) coupled with converting of pyruvic acid (PA) to lactate catalyzed by lactate dehydrogenase (LDH), NADH+PA+H(+)?LDHNAD(+)+Lactate, was widely adopted to quantify the cell's death, membrane infiltration and proliferation induced by potential toxins. The differential pulse voltammetry (DPV) cathodic signal of NAD(+) at a hanging mercury drop electrode (HMDE) showed LDH activity decreased with the elevating dosages of and the pre-contact time (t(c)) with multi-walled carbon nanotubes (MWCNTs). Comparison of kinetic rate constant of above enzymatic reaction (ER) was able to sensitively assay the adverse influence of MWCNTs. Toxic concentration of altering relative LDH activity by 50% (TC(50)) of MWCNTs was derived to be 40mg/L. TC(50) values indicated a decrease toxicity order Al (III)>MWCNTs>nano-Al(13)>50nm-Al(2)O(3)>=1000nm-Al(2)O(3). The negatively charged surfaces of these nanoparticles (NPs) might be a main cause for the decrement of LDH activity. This decrement was capable to result in the underestimation of the toxicity of NPs in classic LDH assays. This observation would highlight to settle down contradictory medium dependent toxicity of MWCNTs among the literature. PMID- 21612989 TI - Simultaneous determination of phytohormones containing carboxyl in crude extracts of fruit samples based on chemical derivatization by capillary electrophoresis with laser-induced fluorescence detection. AB - An efficient and sensitive capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) method has been developed for the simultaneous determination of phytohormones containing carboxyl group, including gibberellic acid, indole-3-acetic acid, abscisic acid, jasmonic acid, indole butyric acid, 1 naphthalene acetic acid and 2,4-dichloro-phenoxy acetic acid, based on the chemical derivatization with 6-oxy-(acetypiperazine) fluorescein. Using 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide as the condensing reagent, the derivatization reaction completed at 60 degrees C in 60 min and the derivatization limits could reach 20 nmol L(-1). The formed derivatives of seven phytohormones have been separated and quantified within 20 min. The linearity was found in the range of 0.01-1 MUmol L(-1) and the limits of detection were 1.6-6.7 nmol L(-1) (S/N=3). The proposed method has been applied to analyze the crude extract of 0.5 g banana samples directly without further purification and the recoveries varying from 90.7 to 106.1%. PMID- 21612990 TI - Quantification of riboflavin in human urine using high performance liquid chromatography-tandem mass spectrometry. AB - We developed a selective method to measure riboflavin in human urine. Sample preparation involved solid phase extraction and concentration of the target analyte in urine. The urine concentrate was analyzed using high performance liquid chromatography-tandem mass spectrometry. Riboflavin concentrations were quantified using an isotopically labeled internal standard. The limit of detection was 11 ng/mL, and the linear range was 4.4-20,000 ng/mL. The relative standard deviation at 100, 1000, and 5000 ng/mL was 17%, 17%, and 12%, respectively. The accuracy was 90%. On average, 100 samples, including calibration standards and quality control samples, were prepared per day. Using our method, we measured concentrations of riboflavin in human urine samples that were collected from participants in a study where riboflavin was used as a surrogate chemical to simulate exposure to an environmental toxicant. PMID- 21612988 TI - Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease. AB - ERCC1-XPF is a structure-specific endonuclease required for nucleotide excision repair, interstrand crosslink repair, and the repair of some double-strand breaks. Mutations in ERCC1 or XPF cause xeroderma pigmentosum, XFE progeroid syndrome or cerebro-oculo-facio-skeletal syndrome, characterized by increased risk of cancer, accelerated aging and severe developmental abnormalities, respectively. This review provides a comprehensive overview of the health impact of ERCC1-XPF deficiency, based on these rare diseases and mouse models of them. This offers an understanding of the tremendous health impact of DNA damage derived from environmental and endogenous sources. PMID- 21612991 TI - Analysis of expressed sequence tags from the liver and ovary of the euryhaline hermaphroditic fish, Kryptolebias marmoratus. AB - The self-fertilizing hermaphroditic fish, Kryptolebias marmoratus is considered a suitable model species in the fields of eco-biology, developmental biology, endocrinology, environmental genomics, aquatic toxicology, and molecular carcinogenesis. However, more extensive gene information is still needed to improve our understanding of the biology of this fish with respect to toxicological responses. We performed a transcriptomic study in this species using pyrosequencing. Liver and ovary mRNA was reverse synthesized into cDNA and randomly sequenced by a Roche 454, GS-20 sequencer. After quality assessment, the assembled expressed sequence tag (EST) translations were compared with the GenBank non-redundant (nr) amino acid sequence database using BLASTX. In the assembly stage 1, both 59,732 transcripts in liver and 103,526 transcripts in ovary were obtained. To identify the differently expressed genes in the ovary and liver tissues, all transcripts were sorted out with an expected value threshold of 1.00E-05. Consequently, 7168 contigs of ovary ESTs and 3855 contigs of liver ESTs were not overlapped for expression in both tissues, whereas 3763 contigs were commonly found in both tissues. Subsequently, we described the most highly represented genes in the liver and ovary of K. marmoratus. Isoforms of cytochrome P450 (CYP) and receptor-related genes showed tissue-preferential expressed patterns. To identify the potential biomarkers in this species, ovary and liver ESTs were assembled and annotated with the nr amino acid sequence database using BLASTX. Then, 35,471 transcripts were obtained, and 9130 transcripts were hit (26%) at the assembly stage 2. Finally, we identified a number of stress-, antioxidant defense-, and DNA repair-related genes as potential molecular biomarkers for toxicological response using this species. We discuss the potential use for these markers in K. marmoratus for environmental genomics and eco-toxicological studies to uncover mechanisms of environmental stresses and chemical toxicities to K. marmoratus. PMID- 21612992 TI - Cauliflower ear dissection. AB - Cauliflower ear (CE) is caused by repeated direct trauma to the external ear. Surgical correction of an established CE is one of the most challenging problems in ear reconstruction. However, no reports have clarified the dissection of an established CE in detail. In this report, the dissection of a CE is described based on macroscopic, microscopic and imaging features. PMID- 21612993 TI - Sentinel lymph node biopsy in melanoma: The Oxford ten year clinical experience. AB - Sentinel lymph node biopsy (SLNB) has become an established investigation for assessing microscopic nodal metastasis in melanoma. The American Joint Committee on Cancer (AJCC) incorporates the sentinel node status in its staging criteria for melanoma. We present our clinical evaluation of performing SLNB in a single UK centre between 1998 and 2008. There were 697 patients with a mean age 53 years (range 13-92). We were able to surgically harvest at least one sentinel node in 694 patients of which 532 (76%) were negative. Of the 162 positive patients, 129 underwent further completion lymphadenectomy with 29 showing further pathologically positive nodes. At median follow up of 46 months, mortality from melanoma for SLN positive and negative patients was 32% and 4%, respectively. Disease recurrence was noted in 10% of the SLN negative group. Survival curves showed significant difference (p<0.001) in outcomes for patients grouped by Breslow thickness. Postoperative complications were noted in 6% of patients. No life-threatening complications were noted. Our results are comparable to other national and international studies. We await the outcomes of ongoing trials to assess the therapeutic value of SLNB for melanoma. PMID- 21612994 TI - Successful mRNA profiling of 23 years old blood stains. AB - In this study, 23 years old human blood stains on different and problematic carrier materials, such as jeans, leather, wood, wallpaper, carpet, wool, and nylon fabric, were investigated by mRNA analysis of the blood markers HBB and SPTB. HBB turned out to be a very stable marker that could be detected in all blood samples from all carrier materials whereas SPTB showed no positive result in any of these old samples. Typing of co-extracted genomic DNA provided full STR profiles with the exception of one stain resulting in a partial profile. No differences were observed regarding the quality of results due to possible inhibitorial substances from carrier materials such as jeans or leather, whereas some difficulties to extract nucleic acids were caused by the physical properties of materials such as carpet fibres. HBB can be highly recommended for the identification of old blood stains in forensic casework as it was possible to detect HBB even in stains that failed to provide a full DNA profile. PMID- 21612995 TI - A new future of forensic Y-chromosome analysis: rapidly mutating Y-STRs for differentiating male relatives and paternal lineages. AB - The panels of 9-17 Y-chromosomal short tandem repeats (Y-STRs) currently used in forensic genetics have adequate resolution of different paternal lineages in many human populations, but have lower abilities to separate paternal lineages in populations expressing low Y-chromosome diversity. Moreover, current Y-STR sets usually fail to differentiate between related males who belong to the same paternal lineage and, as a consequence, conclusions cannot be drawn on the individual level as is desirable for forensic interpretations. Recently, we identified a new panel of rapidly mutating (RM) Y-STRs, composed of 13 markers with mutation rates above 1 * 10(-2), whereas most Y-STRs, including all currently used in forensics, have mutation rates in the order of 1 * 10(-3) or lower. In the present study, we demonstrate in 604 unrelated males sampled from 51 worldwide populations (HGDP-CEPH) that the RM Y-STRs provide substantially higher haplotype diversity and haplotype discrimination capacity (with only 3 haplotypes shared between 8 of the 604 worldwide males), than obtained with the largest set of 17 currently used Y-STRs (Yfiler) in the same samples (33 haplotypes shared between 85 males). Hence, RM Y-STRs yield high-resolution paternal lineage differentiation and provide a considerable improvement compared to Yfiler. We also find in this worldwide dataset substantially less genetic population substructure within and between geographic regions with RM Y-STRs than with Yfiler Y-STRs. Furthermore, with the present study we provide enhanced data evidence that the RM Y-STR panel is extremely successful in differentiating between closely and distantly related males. Among 305 male relatives, paternally connected by 1-20 meiotic transfers in 127 independent pedigrees, we show that 66% were separated by mutation events with the RM Y-STR panel whereas only 15% were with Yfiler; hence, RM Y-STRs provide a statistically significant 4.4-fold increase of average male relative differentiation relative to Yfiler. The RM Y STR panel is powerful enough to separate closely related males; nearly 50% of the father and sons, and 60% of brothers could be distinguished with RM Y-STRs, whereas only 7.7% and 8%, respectively, with Yfiler. Thus, by introducing RM Y STRs to the forensic genetic community we provide important solutions to several of the current limitations of Y chromosome analysis in forensic genetics. PMID- 21612996 TI - Post-traumatic malunion of the distal radius treated with autologous costal cartilage graft: a technical note on seven cases. AB - Seven cases of post-traumatic intra-articular malunion of the distal radius treated using costal cartilage graft with a minimum follow-up of 2 years are reported. Location of the articular defect was dorsal in two cases and volar in the others. The approach (dorsal or volar) depended on the main location of the defect. A costal cartilage graft harvested on the eighth rib was implanted in a trough created at the epiphysis metaphyseal junction. This trough removed the defective area on the distal radius articular surface. A plate or wire fixation was used to stabilize in place the graft. Plaster cast wear was prescribed for 3 months in the first case and for 1 month in the other cases following joint reconstruction. No complications were observed. Union was achieved in all seven cases. Graft integration and viability were evaluated with MRI and biopsy. At the longest follow-up, the functional results were excellent in the first (youngest) case (male, 22 years old) in whom motion and grasp were similar to the contralateral side. In the other cases of malunion, the patients were pain-free in daily activities with a functional wrist score of 72/100 (range, 54-82) and a DASH score of 38.3 (range, 22.5-51.7). Only the case with a septic problem failed, with pain reported at follow-up. Reconstruction of a partially destroyed articular surface using a costal graft is reliable and allows filling and resurfacing an articular cartilage void. Although costal cartilage graft is currently used in maxillofacial surgery, this is the first report in post traumatic osteoarthritis secondary to intra-articular malunion. LEVEL OF EVIDENCE: Level IV. PMID- 21612997 TI - Fear of falling as seen in the Multidisciplinary falls consultation. AB - Fear of falling may be as debilitating as the fall itself, leading to a restriction in activities and even a loss of autonomy. OBJECTIVES: The main objective was to evaluate the prevalence of the fear of falling among elderly fallers. The secondary objectives were to determine the factors associated with the fear of falling and evaluate the impact of this fear on the activity "getting out of the house". PATIENTS AND METHOD: Prospective study conducted between 1995 and 2006 in which fallers and patients at high risk for falling were seen at baseline by the multidisciplinary falls consultation team (including a geriatrician, a neurologist and a physical medicine and rehabilitation physician) and then, again 6 month later, by the same geriatrician. The fear of falling was evaluated with a yes/no question: "are you afraid of falling?". RESULTS: Out of 635 patients with a mean age of 80.6 years, 502 patients (78%) expressed a fear of falling. Patients with fear of falling were not older than those who did not report this fear, but the former were mostly women (P<0,001), who experienced more falls in the 6 months preceding the consultation (P=0.01), reported more frequently a long period of time spent on the floor after a fall (P<0.001), had more balance disorders (P=0.002) and finally, were using more frequently a walking technical aid (P=0.02). Patients with fear of falling were not going out alone as much as the fearless group (31% vs 53%, P<0.0001). Eighty-two percent of patients in the fearful group admitted to avoiding going out because they were afraid of falling. CONCLUSION: The strong prevalence of the fear of falling observed in this population and its consequences in terms of restricted activities justifies systematically screening for it in fallers or patients at risk for falling. PMID- 21612998 TI - No association of XRCC1 polymorphisms Arg194Trp and Arg399Gln with colorectal cancer risk. AB - BACKGROUND: X-ray repair cross complementation group 1 (XRCC1) plays a key role in base excision repair. The purpose of this study was to examine the association of two genetic polymorphisms in XRCC1 (rs1799782 and rs25487) with risk of colorectal polyps and colorectal cancer (CRC). METHODS: In the ongoing colorectal cancer study of Austria (CORSA), a total of 3091 Caucasian participants was genotyped using 5'-nuclease TaqMan assays. Multiple logistic regression was applied to compare individuals of the control group against three different case groups namely CRC cases, high-risk and low-risk polyps. RESULTS: The two investigated SNPs in XRCC1 were not found to be associated with neither CRC risk nor polyp risk. Comparing the CRC cases versus the controls the OR was 0.60 (95%CI 0.27-1.31) for the heterozygous polymorphic genotype of SNP rs1799782 and 1.47 (95%CI 0.81-2.65) for the homozygous polymorphic genotype of SNP rs25487. Comparing the high-risk polyp group versus the controls the OR was 2.64 (95%CI 0.61-11.42) for the homozygous polymorphic genotype of SNP rs1799782 and 0.89 (95%CI 0.60-1.33) for SNP rs25487, respectively. In an haplotype analysis also no statistically significant association was found. CONCLUSION: Our finding that none of the two investigated SNPs of XRCC1 were significantly associated with risk of CRC or polyps is consistent with the results of a recently published meta analysis. PMID- 21612999 TI - Sun exposure, vitamin D receptor polymorphisms FokI and BsmI and risk of multiple primary melanoma. AB - BACKGROUND: Sunlight exposure increases risk of melanoma. Sunlight also potentiates cutaneous synthesis of vitamin D, which can inhibit melanoma cell growth and promote apoptosis. Vitamin D effects are mediated through the vitamin D receptor (VDR). We hypothesized that genetic variation in VDR affects the relationship of sun exposure to risk of a further melanoma in people who have already had one. METHODS: We investigated the interaction between VDR polymorphisms and sun exposure in a population-based multinational study comparing 1138 patients with a multiple (second or subsequent) primary melanoma (cases) to 2151 patients with a first primary melanoma (controls); essentially a case-control study of melanoma in a population of melanoma survivors. Sun exposure was assessed using a questionnaire and interview, and was shown to be associated with multiple primary melanoma. VDR was genotyped at the FokI and BsmI loci and the main effects of variants at these loci and their interactions with sun exposure were analyzed. RESULTS: Only the BsmI variant was associated with multiple primary melanoma (OR=1.27, 95% CI 0.99-1.62 for the homozygous variant genotype). Joint effects analyses showed highest ORs in the high exposure, homozygous variant BsmI genotype category for each sun exposure variable. Stratified analyses showed somewhat higher ORs for the homozygous BsmI variant genotype in people with high sun exposure than with low sun exposure. P values for interaction, however, were high. CONCLUSION: These results suggest that risk of multiple primary melanoma is increased in people who have the BsmI variant of VDR. PMID- 21613000 TI - Breast-conserving therapy versus modified radical mastectomy: socioeconomic status determines who receives what--results from case-control study in Tianjin, China. AB - BACKGROUND: Despite anecdotal evidence linking socioeconomic status and choices on surgical management in breast cancer patients in China, no scientific evaluations have ever been conducted. The objective of this study was to evaluate patient factors that influence patients' treatment options between breast cancer patients receiving breast-conserving therapy (BCT) and modified radical mastectomy (MRM). METHODS: A total of 268 stage I-II breast cancer patients treated with BCT in Tianjin Cancer Hospital, from January 2005 to January 2007, were compared with 200 randomly selected breast cancer patients (controls) treated with MRM. A personal health questionnaire (PHQ) was used to assess the factors that may affect the surgical decision making. Chi-squared test and multiple logistic regressions were used to examine factors associated with BCT. RESULTS: BCT patients who were younger and were more likely to live in urban areas had medical insurance, higher levels of education and family income. Patients with medical insurance coverage were approximately six times more likely to receive BCT than patients without medical insurance after controlling for other potentially confounding factors. Similar results were also observed for family income. The observed differences cannot be explained by clinical aspects of their disease, such as tumor stage, estrogen receptor, and lymph node involvement. CONCLUSION: Breast cancer patients' socioeconomic status, rather than their clinical condition, is the predominant factor in determining whether a breast cancer patient receives BCT or not. These results provide a snapshot on how socioeconomic status influences cancer care provision in China. Future efforts should be made towards reducing discrepancies in treatment options for cancer patients caused by social class and socioeconomic status. PMID- 21613001 TI - Otospongiosis surgery. Calibrated stapedotomy, or "piston transplatinaire". PMID- 21613002 TI - Quality of life in patients treated for advanced hypopharyngeal or laryngeal cancer. AB - OBJECTIVE: To study quality of life in patients treated for advanced hypopharyngeal or laryngeal cancer, with laryngeal conservation or laryngectomy. PATIENTS AND METHODS: A retrospective 2-center study included 100 patients in remission from squamous cell carcinoma, treated between 1998 and 2009. Seventy patients (24 hypopharynx, 46 larynx) were treated by total (pharyngo-) laryngectomy followed by external radiation therapy, and 30 (13 hypopharynx, 17 larynx) underwent an organ-conservation protocol with concurrent radiochemotherapy or with induction chemotherapy using platin-5FU or taxan-platin 5FU followed by radiation therapy. All patients responded to the quality of life questionnaires (EORTC QLQ-C30 and QLQ-H&N35). RESULTS: Advanced tumor stages IVa and IVb were significantly more frequent in the surgery groups (hypopharynx: 71.6% vs. 45.9%, p=0.01; larynx: 72.4% vs. 37.5%, p<0.01). In pharyngeal cancer, the only significant difference between surgical treatment and laryngeal conservation was for "sensory disorder" (taste and odor), with better results in case of laryngeal conservation (p<0.0001). For the other items, there was a trend for quality of life to appear better in patients with laryngeal conservation (p=NS). In laryngeal cancer, the only significant difference was for "dry mouth", which was significantly less invalidating with surgical treatment (p<0.001). The impairment of the other quality of life items did not differ between surgical and conservative treatment. CONCLUSIONS: Quality of life is impaired in all patients treated for pharyngeal or laryngeal cancer. The type of treatment, surgical or conservative, affects differently various aspects of quality of life. PMID- 21613003 TI - Facial palsy associated with leptospirosis. AB - INTRODUCTION: The authors report a rare case of facial palsy associated with leptospirosis. CASE REPORT: A 60-year-old man was admitted to ICU with severe leptospirosis. On the eighth day of hospitalisation, he developed left peripheral facial palsy with a favourable course in response to corticosteroids. DISCUSSION: Several types of neurological complications of leptospirosis have been reported: encephalitis, myelitis, stroke, cerebral arteritis, mononeuritis, polyradiculoneuropathy, and cranial nerve palsy. Peripheral facial palsy is a rare complication of leptospirosis. CONCLUSION: This case illustrates the possible association between leptospirosis and facial palsy. PMID- 21613004 TI - New insights into liver regeneration. AB - Even if the Greeks probably anticipated rather than discovered the extraordinary regenerative capacity of the liver with the Prometheus myth, this phenomenon still fascinates scientists nowadays with the same enthusiasm. There are good reasons to decipher this process other than to find an answer to our fantasy of immortality: it could indeed help patients needing large liver resections or living-donor liver transplantation, it could increase our understanding of liver pathology and finally it could enable novel cell-therapy approaches. For decades, most of our knowledge about the mechanisms involved in liver regeneration came from the classic two-thirds partial hepatectomy (PH) model. In this scenario, hepatocytes play the leading role, which raises the question of the simple existence of a stem cell population. Recently however, hepatic progenitor cells come again under the limelight, seeming to play a role in liver physiology and in various liver diseases such as steatosis or cirrhosis. Excellent reviews have recently addressed liver regeneration. Our goal is therefore to focus on recent improvements in the field, highlighting data mostly published in the last two years in order to draw a putative picture of what the future research axes on liver regeneration might look like. PMID- 21613005 TI - [Pre-examination phase: perimeter and process description]. AB - This document describes the perimeter and the content of the pre-examination phase using a process approach, i.e. a transversal and functional description of this activity. Pre-examination phase progresses trough steps differently combined according to the circumstances. Each step may be described as a sub-process characterized by an objective, intrinsic elements (beginning/end, input and output elements, upstream and downstream process, actors and technical means) and specific requirements. Ten steps have been defined from customer (patient and prescriber) information to transport. This process approach of pre-examination phase has several advantages: exhaustiveness, customer expectations listing at each step, risk to be prevented and anticipation of potential failures. We propose a tool allowing afterwards to optimize one or the other step and to secure it using procedures and monitoring based upon indicators. PMID- 21613006 TI - [Guidelines for medical prescription of medical laboratory tests]. AB - The implementation of a computer-assisted prescription is interesting for the laboratory to achieve requirements of NF EN ISO 15189 standard. The test redundancies are also studied and guidelines, founded on validated studies, are proposed. Some solutions concerning the management of orally-formulated prescriptions are given. Finally, a model of collaboration contract between the medical laboratory and the clinical unit is proposed. PMID- 21613007 TI - [Guidelines for the order process of medical laboratory tests]. AB - This document presents the requirements enumerated in the ISO 15189 standard to make reliable the formulation of a medical laboratory test order. The contents and the filling conditions of the request laboratory tests form are described, to clarify the interest of the information required. The purpose is to help to construct a specific formulation allowing the adequate realization of the laboratory tests but also to collect the needed clinical information essential to allow a relevant interpretation of the results with a goal of improvement of patient care. We present also the main forms required for special laboratory tests, particularly concerning the human genome. Finally, the criteria to be reviewed at the entry of the laboratory (contract review) during the request acceptation before its registration are enumerated. PMID- 21613008 TI - [Guidelines relative to the collection and handling management of biological samples]. AB - Guidelines relative to the management of samples collection and handling for common tests are proposed with a list of websites to improve knowledge concerning the practices of biological sampling. Then, methodology is given for the creation of an electronic primary sample collection manual for medical laboratory tests. A list containing the medical laboratory tests for which the information and/or particular documents are needed either for the request or interpretation is presented. Another list for some specific laboratory tests with special individual requirements is proposed. We give also items allowing a standardized description of laboratory tests to help to create a personalized list of the available examinations, facilitating the information of professionals. PMID- 21613009 TI - [Guidelines concerning sample reception and request recording of laboratory tests]. AB - The process is described to help to achieve the requirements of the ISO 15189 standard. The precautions to be respected for a correct recording of the request are specified. The criteria for traceability are formalized. A logogram illustrates the propositions of attitude to be followed when occurs nonconformities. Then, we propose guidelines for the treatment of the identification uncertainties of the primary sample. An algorithm is proposed to formalize the process and treat the situations which can be met with an irreplaceable or critical sample. PMID- 21613010 TI - [Guidelines for the pre-examination processing and transport of medical laboratory samples]. AB - We resume here the guidelines about sample processing and transport for laboratory tests. All the steps of the pre-examination phase process, downstream to the recording of the requests, are described in this document. The purpose is to assure a secure and optimal sample management. The traceability of all the steps of the process is needed for the sample treatment and preservation. Then, we propose guidelines for the transport management step, according to the regulations and conditions to be applied to guarantee the sample integrity. PMID- 21613012 TI - [Guidelines concerning stat laboratory process]. AB - After a definition of the various emergency situations, vital or organizational, the paper describes the process of urgent laboratory tests requests from the medical prescription until the return of the interpreted results to the clinician. The intervention options of the various professionals to optimize and assure the control of the process 24 hours a day and 7 days/7 are presented. Then, a list of validated available stat tests is proposed. It recovers the main disciplines which have a direct link to bring the help to the clinical teams in responsibilities of critical situations. These propositions must be adapted to the conditions of laboratory local environment. PMID- 21613011 TI - [Management of pre-analytical nonconformities]. AB - The main nonconformities enumerated to facilitate consensual codification. In each case, an action is defined: refusal to realize the examination with request of a new sample, request of information or correction, results cancellation, nurse or physician information. A traceability of the curative, corrective and preventive actions is needed. Then, methodology and indicators are proposed to assess nonconformity and to follow the quality improvements. The laboratory information system can be used instead of dedicated software. Tools for the follow-up of nonconformities scores are proposed. Finally, we propose an organization and some tools allowing the management and control of the nonconformities occurring during the pre-examination phase. PMID- 21613013 TI - [Interpretative analysis of the ISO 15189 standard: pre-examination phase]. AB - We described the requirements of chapters 4.7 and 5.4 of the standard into action to be realized, documents to be drafted, traceability to be assured with proofs, mandatory. The various documents realized by the working-group are placed in front of the chapters of the standard and the documents required. This display is designed to help the biologist engaged in the approach of mandatory accreditation. PMID- 21613014 TI - [Self assesment grid for pre-examination phase]. AB - This document is a proposal of questionnaire for self-assessment of pre analytical phase referring to the different steps described in the document SG1 01. The questions are aimed at verifying that what is examined fulfills ISO 15189 standard requirements or in general tends towards client satisfaction. This questionnaire has been elaborated using 5 M risk assessment tool for exhaustiveness purpose. This document may be useful to develop internal audit grids. PMID- 21613015 TI - [Useful web sites for information about the recommendations of good practices in laboratory medicine]. AB - In this paper are presented some useful web sites to find updated reference tables concerning the recommendations of professional practices in laboratory medicine. The knowledge of these reference tables can allow the biologist to develop its role of advice to the clinicians. It can also help him to assure a relevant interpretation of the laboratory results and to value the interest for the patient. PMID- 21613016 TI - [Examination procedures]. AB - Examination procedures have to be written for each examination according to the standard requirements. Using CE marked devices, technical inserts can be used, but because of their lack of homogeneity, it could be easier to document their use as a standard procedure. Document control policy applies for those procedures, the content of which could be as provided in this document. Electronic manuals can be used as well. PMID- 21613017 TI - [The maintenance of automatic analysers and associated documentation]. AB - The maintenance of automatic analysers and associated documentation taking part in the requirements of the ISO 15189 Standard and the French regulation as well have to be defined in the laboratory policy. The management of the periodic maintenance and documentation shall be implemented and fulfilled. The organisation of corrective maintenance has to be managed to avoid interruption of the task of the laboratory. The different recommendations concern the identification of materials including automatic analysers, the environmental conditions to take into account, the documentation provided by the manufacturer and documents prepared by the laboratory including procedures for maintenance. PMID- 21613018 TI - [Internal quality control]. AB - The internal quality control is a key technical requirement through accreditation by the NF EN ISO 15189. This document presents recommendations to assist the medical laboratory to design, implement and operate daily and retrospectively an efficient system of internal control quality. It identifies the important issues attached to these different steps. PMID- 21613019 TI - [Analytical validation of the results]. AB - The results obtained using automatic analysers have to be reviewed before release to the laboratory information system (LIMS) for definitive validation by the authorised person. The objective of such a review is to ensure that quality indicators are in agreement with the defined requirements and that the procedures have been carefully fulfilled. PMID- 21613020 TI - [Uncertainty of measurement]. AB - The ISO 15189 standard requires the evaluation of measurement uncertainty where relevant and possible. This document presents recommendations for a simple evaluation of the uncertainty from data available in medical laboratory and illustrates the value of such a determination. PMID- 21613022 TI - [Traceability of the standards and calibrations]. AB - Accuracy of results depends on the traceability of the standards values to a reference system. According to the ISO 15189 requirements, the laboratory has to document the traceability of the value of the standards used. PMID- 21613021 TI - [Verification/validation of the performances of analytical method]. AB - The verification and validation of methods consist in evaluating the precision, the analytical range, the accuracy, the trueness and the detection limit, if appropriate. These measurements must follow a standardized protocol and the obtained results must be compared to defined quality criteria. Each chapter includes, the purpose, the material used, the operating procedures, the collection of results, the calculation and is illustrated by an example. This document aims at simplifying, standardizing and optimizing the evaluation in order to allow a comparison between laboratories and to facilitate method assessment. PMID- 21613023 TI - [Determination and verification of reference intervals]. AB - Based on the original recommendation of the Expert Panel on the Theory of Reference values of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC-LM), updated guidelines were recently published under the auspices of IFCC and the Clinical and Laboratory Standards Institute. These updated guidelines add valuable improvements (transference, validation and verifying reference intervals). PMID- 21613024 TI - Esthetic rehabilitation of anterior teeth with porcelain crowns reinforced with zirconia cores. AB - Achieving a functional and esthetic rehabilitation of anterior teeth can be challenging. This paper describes the rehabilitation of maxillary anterior teeth with porcelain crowns reinforced with a zirconia core to obtain a long-lasting clinical result, taking into account the patient's expectations of esthetic improvement. The two-year follow-up showed the success of the treatment in integrating a functional, esthetic, and healthy result. PMID- 21613025 TI - The effect of dentin hypersensitivity treatments on the shear bond strength to dentin of a composite material. AB - This study sought to evaluate the influence of a dentin desensitizer and ozone application on the bond strength to dentin of a composite resin material. The dentin desensitizing agent and ozone treatment were applied on the cervical dentin surfaces of extracted, caries-free, erupted third molars. Dentin surfaces that received no treatment were used as control samples. A dentin bonding agent was applied according to the manufacturer's instructions and an adhesion test was performed according to ISO/TS 11405. Statistical analysis showed no significant influence of the different hypersensitivity treatments on shear bond strength to dentin (ANOVA and Tukey's tests, p > 0.05). Within the limitations of this in vitro study, it appears that the short-term use of dentin hypersensitivity treatments like ozone and dentin desensitizers containing gluteraldehyde do not further affect the shear bond strength to dentin of subsequent composite resin restorations. PMID- 21613027 TI - An alternative method of fabricating a custom tray for direct implant impressions. AB - Creating accurate impressions for implants is essential for fabricating passive fitting prostheses. This report describes a modified technique for fabricating a custom impression tray when implants are positioned unfavorably. A simple and accurate method of making an implant impression tray and the benefits of this technique are highlighted in this technical report. PMID- 21613026 TI - Reinforcement of thin-walled root canal structures for placement of esthetic dowels: a clinical report. AB - Thin-walled root canals always present a challenge to dentists to select a restorative treatment that does not further weaken the thin tooth structure. The prognosis of dowel and core restorations can be unpredictable. This clinical report describes the treatment of a patient with extensive caries extending into the root canal of an endodontically treated maxillary central incisor. The use of a flowable composite resin in combination with a quartz fiber reinforced post is described, resulting in the rehabilitation of a structurally compromised root canal with satisfactory esthetic and functional outcomes. PMID- 21613028 TI - Practices and opinions of Connecticut general dentists regarding dental treatment during pregnancy. AB - This study aimed to evaluate the opinions and practices of general dentists in Connecticut regarding dental care during pregnancy. A survey was mailed to Connecticut general dentists to acquire data regarding age, gender, training, type of practice, years in practice, payment types accepted, procedures provided for pregnant women according to trimester, provider comfort level with treating pregnant patients, reasons for not treating pregnant patients, and provider opinions about dental care during pregnancy. The response rate was 42%, yielding a sample of 116 dentists. The majority of respondents (97%) reported treating pregnant patients; however, only 45% felt "very comfortable" treating these patients. All dentists in the sample agreed that physicians need to include an oral health evaluation and appropriate referral for patients' prenatal care. However, 70% of respondents had never received a dental referral for a pregnant patient. The majority of dentists favored providing dental treatment during the second trimester of pregnancy. Most dentists (77%) would take a radiograph for a patient 10 weeks into the pregnancy seeking treatment for dental pain, but only 2% would take routine radiographs regardless of the pregnancy trimester. There was a lack of consensus about medications dentists reported acceptable to prescribe for pregnant patients, and female dentists were significantly less likely than males to prescribe ibuprofen (P < 0.05). At least half of the respondents reported not being completely comfortable treating pregnant patients. Further, many dentists appear to not follow medication prescribing guidelines for this population. While additional research is needed, these initial results indicate that additional education regarding the treatment of pregnant patients would be a beneficial addition to dental school and continued education course curricula. PMID- 21613029 TI - The efficacy of a cervical barrier in preventing microleakage of Enterococcus faecalis in endodontically treated teeth. AB - The clinical failure of coronal restorations can compromise the healthy periapical status of endodontically treated teeth. The purpose of the present ex vivo study was to assess the effectiveness of the cervical barrier in preventing bacterial microleakage in the eventual loss of the coronal restoration. Following removal of the smear layer and obturation to the cementoenamel junction using gutta-percha, 70 single-rooted mandibular premolars were randomly divided into five different groups: Group 1 received no additional treatment; Groups 2 and 3 had 2 mm and 3 mm of the obturation removed, respectively, followed by placement of a cervical barrier that was the same thickness as the obturation. In Group 4 (positive control), the root canals were filled only with gutta-percha, while in Group 5 (negative control), the root canals were completely impermeabilized following obturation. The filled root canals were incorporated into a split chamber model system using Enterococcus faecalis as a microbial marker. The apices were suspended in the lower chambers. Leakage was determined daily for 60 days and evaluated for turbidity. According to Fisher's exact test, the cervical barrier in Groups 2 and 3 prevented the microleakage of E. faecalis into the root canals when compared with Groups 1 and 4. This result was similar to that for the completely sealed samples in Group 5 (p = 0.001). PMID- 21613030 TI - Large calcifying epithelial odontogenic tumor with extension into the maxillary sinus: a case report. AB - Calcifying epithelial odontogenic tumor (CEOT) is a rare, locally invasive neoplasm characterized by the presence of amyloid material that can become calcified. It often is found in the posterior region of the mandible. Such tumors in the maxilla and those that invade the maxillary sinus are extremely rare. This article presents the sixth reported clinical case of a CEOT that invaded the maxillary sinus and extended to the interior of the nasal cavity. The tumor had grown toward the sinus roof, but there was no association with an impacted tooth. Histopathologically, the tumor was composed of plates of polyhedral epithelial cells with highly eosinoplilic cytoplasm, nuclear polymorphism, clear-cell contours, and intercellular bridges in fibrous conjunctive tissue. Amorphous eosinophilic material and diverse calcifications permeated the epithelial cells. PMID- 21613031 TI - Successful minimally invasive management of primary maxillary central incisors after lateral luxation: a case report. AB - Lateral luxation in primary maxillary incisors is a traumatic injury that can lead to darkening of the tooth, pulp necrosis, root resorption, and damage to the permanent teeth. Management of this kind of trauma typically includes pulpectomy or extraction in cases of root resorption. However, in young children, removal of the tooth may be psychological stressing, especially for the parents, while increased mobility can make immediate endodontic treatment difficult to perform. This article outlines a severe palatal luxation on the maxillary right central incisor treated with conservative management in a 2-year-old boy. At the one-year follow-up appointment, the surrounding bone was healthy, the roots displayed physiological resorption, the crowns showed color improvement, and there was no radiographically noticeable damage to the permanent teeth. PMID- 21613032 TI - Hard work. PMID- 21613033 TI - A new class of drugs to prevent osteoporosis may be associated with osteonecrosis of the jaw. PMID- 21613034 TI - Cemented or screw-retained implant restorations: how do you decide? PMID- 21613035 TI - The spare implant overdenture: retrofitting an existing denture to Locator attachments. PMID- 21613036 TI - Pharmacovigilance in clinical dentistry: overlooked or axiomatic? AB - Developments in dental pharmacotherapeutics require dentists to constantly update their knowledge of new drugs, drug safety, and therapeutic trends. Recent incidents of bisphosphonateassociated poor healing, spontaneous intraoral ulceration, and bone necrosis in the oral and maxillofacial region stress the need for vigilant spontaneous reporting of adverse events. This article discusses the rationale for pharmacovigilance in dental practice using specific methods and reviews the pros and cons of adverse drug reporting among dental practitioners. PMID- 21613037 TI - The effect of a 980 nm diode laser with different parameters of irradiation on the bond strength of fiberglass posts. AB - The aim of this study was to assess bond strength of fiberglass posts to root canal dentin irradiated with a 980 nm diode laser at different parameters of power and frequency. Fifty human maxillary canines were separated into five groups (n = 10) according to the following parameters of laser power and frequency: Group 1 (1.5 W/100 Hz), Group 2 (1.5 W/continuous wave [CW]), Group 3 (3.0 W/100 Hz), Group 4 (3.0 W/CW), and Group 5 (no irradiation). Following post cementation, samples underwent a push-out test (0.5 mm/min); next, fracture analysis was performed with a light microscope at 50x and 100x magnification. All of the irradiated groups had increased bond strength values compared to the nonirradiated group. Groups 1 and 2 demonstrated the highest bond strength values; however, statistically significant differences were observed for only the cervical third of Group 4 and the cervical/apical thirds of Group 5. Fracture analysis showed a predominance of mixed failures for Groups 1 and 2 and adhesive failures between dentin and cement for the other groups. PMID- 21613038 TI - The effect of delayed placement of composite and double application of single bottle adhesives on microleakage of composite restorations. AB - This study evaluated the effect of delayed placement of composite and double application of adhesive on microleakage of two-step, total-etch (single-bottle) adhesives. Standard Class V cavities were prepared in 140 sound premolars and randomly assigned into 10 groups (n = 14). Excite, Optibond Solo Plus, and Adper Scotchbond Multi-Purpose (as a control) were used. After the first layer of single-bottle adhesive was photocured, the adhesive was reapplied and photocured in four of the groups. A microhybrid composite was applied in five of the groups immediately after the adhesive was photocured; in the other five groups, the composite was placed after a three-minute delay. After 24 hours of storage in distilled water and thermocycling, the samples were placed in 1% methylene blue. All samples then were sectioned longitudinally and evaluated for microleakage at the occlusal and gingival margins under a stereomicroscope at 20x magnification. Data were analyzed using nonparametric tests. Delayed placement of composite significantly increased leakage at the gingival margins when single-bottle adhesives were used (p < 0.05). Double application of the single-bottle adhesives significantly reduced leakage at the gingival margin when placement of the composite was delayed. There was no significant difference between single and double application when the composite was placed immediately (p < 0.05). PMID- 21613039 TI - Restoring esthetics in eroded anterior teeth: a conservative multidisciplinary approach. AB - Consuming a highly acidic diet can lead to erosion or excessive wear of dental hard tissues, resulting in the need for oral rehabilitation. Previously, a severely eroded dentition could be rehabilitated only by extensive crown and bridge placement or by removable partial dentures. However, developments in adhesive dentistry have made it possible to restore the esthetics and function of eroded teeth in a minimally invasive manner. This case report presents a conservative, multidisciplinary approach to restoring severe wear due to dental erosion using proper techniques and materials. PMID- 21613040 TI - Cutting effectiveness of carbide burs following multiple steam autoclaving cycles. AB - New carbide burs that are placed on a bur block can be subjected to multiple steam autoclaving cycles prior to their first use. The decision to discard a bur before or during cavity preparation is a subjective one based on operator expectations and experience. This study examined the durability of carbide burs after multiple autoclaving cycles by judging not only their initial sharpness but also their ability to maintain sharpness throughout a cavity preparation. Five experienced operators were given a set of No. 330 carbide burs that had been separated into five blind categories: those not autoclaved at all and those that had been autoclaved one, two, five, or 10 times. Each operator judged the cutting effectiveness of each bur by making an initial plunge cut through the enamel of a freshly extracted tooth. After the initial plunge cut, each operator used the same set of burs to complete an occlusal cavity preparation in molar models fabricated from composite restorative material. Each operator was asked to examine the burs for any visual deterioration and to rate the cutting ability of each bur. The burs were also examined for wear under a scanning electron microscope. Based on the results, this study concluded that up to 10 autoclaving cycles did not significantly affect the perception of either initial sharpness or the bur's effectiveness while completing the preparation. PMID- 21613041 TI - Hand-held water fluoride analysis: An accessible caries prevention tool for dental professionals. AB - This study sought to compare the relative accuracy of a commercially available hand-held water fluoride analysis unit with a standard laboratory bench-top fluoride-specific electrode/millivoltmeter apparatus, with the goal of identifying possible practical applications of the hand-held unit for preventive dentistry. The units analyzed identical gravimetrically prepared fluoride solutions ranging from 0.1 to 4.0 ppm. The average difference between the measurements from the hand-held unit and the nominal values of the fluoride solutions was 0.011 ppm (SD = 0.068), and the average difference between the hand held unit's measurements and the bench-top unit's measurements was 0.030 ppm (SD = 0.115). T-test analysis demonstrated no statistical difference between measurements from the hand-held unit with either the nominal values of the fluoride solutions or the bench-top unit's measurements. Results indicate that the hand-held water fluoride analysis unit has an appropriate level of accuracy for the measurement of fluoride levels in drinking water samples by dental professionals. PMID- 21613042 TI - Medial pterygoid trismus (myospasm) following inferior alveolar nerve block: case report and literature review. AB - A patient developed a medial pterygoid trismus (myospasm) the day after receiving three inferior alveolar nerve blocks and a routine restoration. She had a significantly restricted mouth opening and significant medial pterygoid muscle pain when she opened beyond the restriction; however, she had no swelling, lymphadenopathy, or fever. A medial pterygoid myospasm can occur secondary to an inferior alveolar nerve block. This disorder generally is treated by the application of heat, muscle stretches, analgesic and/or muscle relaxant ingestion, and a physical therapy referral. The severity of the disorder typically dictates the extent of therapy that is needed. PMID- 21613043 TI - Maxillary lateral incisor with two roots: a case report. AB - Although the dental literature has indicated that 100% of maxillary lateral incisors have a single canal anatomy, it is possible for these teeth to have extra canals. These extra canals must be identified and debrided to prevent endodontic failure. This report presents an uncommon case involving a maxillary lateral incisor with two roots. Even when the frequency of radicular anatomy abnormality is extremely low, dentists must consider the possibility that a tooth has extra root canals or even extra roots. PMID- 21613044 TI - Tonsilloliths appearing as multiple opacities on panoramic imaging: case report. AB - Tonsilloliths are dystrophic calcifications that can form in tonsillar crypts. They can be asymptomatic or a component of tonsillitis. This article presents a case of tonsilloliths that appeared on a panoramic image as multiple opacities. PMID- 21613045 TI - Sensitive red bumps on the tongue. Transient lingual papillitis. PMID- 21613046 TI - Sessile nodule on the palate. Leaflike denture fibroma. PMID- 21613047 TI - Insulin glargine use during pregnancy. AB - OBJECTIVE: To review the literature regarding the use of insulin glargine during pregnancy, specifically addressing the issues and concerns surrounding mitogenicity, placental transfer, and maternal and fetal safety. METHODS: We performed a systematic literature search using MEDLINE and BIOSIS Previews up to March 2011. Additional studies were identified by hand-searching reference lists from original articles. Inclusion was limited to studies and abstracts in the English language. RESULTS: A total of 23 reports with 1001 pregnancies managed with insulin glargine contained relevant information regarding the maternal and fetal safety of its use during pregnancy. Insulin glargine does not appear to have enhanced mitogenic activity when compared with the mitogenic activity of native human insulin. The transplacental transfer of insulin glargine appears to be negligible, although it is possible that antibody-bound insulin glargine may gain access to the fetal compartment. The available data suggest that there are no identifiable, consistent adverse maternal or fetal outcomes with the use of insulin glargine during pregnancy, including during the first trimester. CONCLUSIONS: Use of insulin glargine during pregnancy should be seriously considered in uncontrolled diabetes during pregnancy and in those patients taking insulin glargine before conception, because the benefits from improved glycemic control would be expected to outweigh any, as yet, unproven risks of insulin glargine exposure. PMID- 21613048 TI - Graves disease and gynecomastia in 2 roommates. PMID- 21613050 TI - Familial pituitary tumor syndromes. AB - OBJECTIVE: To summarize current knowledge on the clinical and genetic characteristics of familial pituitary tumor syndromes. METHODS: This review is based on a comprehensive search through the English-language literature with use of the following terms: "familial," "pituitary," "adenomas," and "tumors." RESULTS: Familial pituitary tumors are rare and constitute approximately 5% of all pituitary adenomas. Currently, there are 4 recognized inherited syndromes that involve pituitary tumorigenesis-multiple endocrine neoplasia type 1 (MEN 1), multiple endocrine neoplasia type 4 (MEN 4), Carney complex (CNC), and familial isolated pituitary adenomas (FIPA). MEN 1 and CNC have been known for several decades, and their clinical and molecular characteristics have been comprehensively studied. Many familial cases of pituitary adenomas can be attributed to mutations in MEN1 and PRKAR1A genes. The recently defined MEN 4 is extremely rare. Familial pituitary tumors that are not associated with MEN 1 and CNC have been united under a new term introduced in the 1990s-FIPA. About 15% to 25% of patients with FIPA harbor mutations in the AIP gene. CONCLUSION: Although rare, familial pituitary tumors present an opportunity to study inherited molecular and genetic mechanisms of pituitary tumorigenesis. A comprehensive understanding of their characteristics may provide a basis for early diagnosis and better management of affected patients. PMID- 21613051 TI - Are microRNAs involved in the endocrine-specific pattern of tumorigenesis in multiple endocrine neoplasia type 1? AB - OBJECTIVE: To provide a general background regarding current knowledge about microRNA (miRNA) involvement in endocrine functions and in multiple endocrine neoplasia type 1 (MEN 1) endocrine tumorigenesis. METHODS: A literature search was conducted in the miRNA database for articles on the role of miRNAs in the initiation and progression of human malignant conditions, inasmuch as miRNAs show different patterns of expression in normal and neoplastic tissues. We address the potential role of miRNAs in the endocrine pancreas, the pituitary gland, and the parathyroid glands-areas where MEN 1 shows high penetrance. RESULTS: Experimental studies have shown the involvement of miRNAs in regulation of endocrine functions, such as insulin secretion. Moreover, studies have provided evidence that dysregulation of miRNAs was responsible for endocrine carcinogenesis, including pancreatic, pituitary, and parathyroid tumors. CONCLUSION: miRNA expression profiles may become useful biomarkers for endocrine tumor diagnostics as well as potential targets of therapeutic strategies applied to pathologic conditions such as type 2 diabetes and endocrine tumors. Future studies should investigate the molecular and cellular mechanisms of tissue selectivity in MEN 1 associated tumorigenesis, in an effort to develop an RNA-based treatment that could prevent or delay the onset of MEN 1-associated tumors. PMID- 21613052 TI - Skin lesions in hereditary endocrine tumor syndromes. AB - OBJECTIVE: To review the main cutaneous manifestations of hereditary endocrine tumor syndromes and discuss currently known molecular mechanisms involved in their pathogenesis. METHODS: On the basis of our collective experience and a comprehensive MEDLINE literature search of the English-language literature published between January 1957 and September 2010 using the search terms "skin," "cutaneous," "multiple endocrine neoplasia," "Carney complex," and "McCune Albright syndrome," we reviewed the dermatologic findings in multiple endocrine neoplasia type 1 and type 2, Carney complex, and McCune-Albright syndrome. RESULTS: Although the category of hereditary endocrine tumor syndromes consists of a broad spectrum of conditions, only the aforementioned few are prominently associated with cutaneous features. Because the cutaneous findings associated with these diseases are generally benign, they are often ignored or dismissed as ancillary findings in the context of severe systemic involvement. Accordingly, the pertinent literature is relatively scarce and often fails to provide a comprehensive insight about this issue. Nevertheless, timely recognition of such dermatologic manifestations may have a critical role in the early diagnosis and appropriate management of the related syndromes. Moreover, specific genotype phenotype correlations may convey important prognostic implications. CONCLUSION: Many physicians are unfamiliar with the cutaneous findings in the hereditary endocrine tumor syndromes described in this review. Nonetheless, knowledge of their existence can have a major role in establishing an early diagnosis of these syndromes and determining the patient's prognosis. PMID- 21613053 TI - Low urine calcium excretion in African American patients with primary hyperparathyroidism. AB - OBJECTIVE: To evaluate the prevalence of low urine calcium excretion in African American patients with primary hyperparathyroidism (PHPT), a common disorder associated with bone and renal complications, and to assess the distinction between PHPT and familial hypocalciuric hypercalcemia (FHH), a rare benign genetic disease. METHODS: We conducted a retrospective study on a cohort of 1,297 patients in whom a 24-hour urine study was performed for measurement of urine calcium and creatinine. PHPT was diagnosed if the serum calcium concentration was >=10.5 mg/dL and intact parathyroid hormone (PTH) was >=40 pg/mL. Patients receiving medications that affect urine calcium or with glomerular filtration rate <=30 mL/min were excluded. RESULTS: Ninety-six patients satisfied the diagnostic criteria for PHPT. The African American (n = 70) and non-African American (n = 26) patients did not differ in their mean age, body mass index, glomerular filtration rate, serum PTH, 25-hydroxyvitamin D levels, and 24-hour urine creatinine values. Median values of urine calcium/creatinine (mg/g) were 122 for African American versus 214 for non-African American patients (P = .006). Thirty-one of 70 African American patients (44%) had a urine calcium/creatinine ratio <=100 mg/g, whereas only 2 of 26 non-African American patients (8%) had this value (P = .001). CONCLUSION: The prevalence of low urine calcium excretion among African American patients with PHPT is unexpectedly high. A threshold of 100 mg/g urine calcium/creatinine identified 44% of such patients with PHPT as having FHH in this cohort. Therefore, other clinical criteria and laboratory variables should be used to distinguish PHPT from FHH in African American patients with PTH-dependent hypercalcemia. PMID- 21613054 TI - Pituitary hormone dysfunction after proton beam radiation therapy in children with brain tumors. AB - OBJECTIVE: To characterize endocrine dysfunction in pediatric patients with brain tumors who received proton beam (PB) radiation therapy and to compare those treated with PB radiotherapy only versus combined conventional and PB irradiation. METHODS: A retrospective review of medical records of patients <=18 years of age who received PB radiation therapy for a brain tumor between 2000 and 2008 was performed. Variables analyzed included patient demographics, tumor type, therapeutic modalities, radiation doses, and types and timing of endocrine dysfunction. RESULTS: Thirty-eight patients were identified, of whom 31 (19 boys and 12 girls; mean age, 11.9 +/- 3.3 years) had undergone endocrine evaluation. Of these patients, 19 received PB radiotherapy only and 12 received conventional plus PB irradiation. Before irradiation, a cranial surgical procedure was performed in 28 study subjects, and 22 received chemotherapy. The mean duration of follow-up after radiation therapy was 1.8 +/- 0.8 years. Nine patients (47%) in the PB only group and 4 (33%) in the conventional plus PB group developed endocrine dysfunction (no significant difference) after cranial irradiation. Children with endocrine sequelae treated with PB irradiation alone received fewer cobalt gray equivalents than those treated with conventional plus PB irradiation (5,384 +/- 268 versus 5,775 +/- 226, respectively; P<.02), and pituitary hormone deficiencies were detected later during follow-up in those who received PB radiotherapy only versus conventional plus PB irradiation (1.17 +/- 0.4 years versus 0.33 +/- 0.11 year, respectively; P<.01). CONCLUSION: A high rate of endocrine sequelae was seen in our study. Children with brain tumors treated with conventional plus PB irradiation developed endocrine dysfunction faster and received a higher radiation dose than those receiving PB radiotherapy only. Prior surgical treatment and chemotherapy were additional risk factors. Large prospective studies are needed to evaluate further the incidence of endocrine sequelae after PB irradiation in children. PMID- 21613055 TI - Tolvaptan for the management of syndrome of inappropriate antidiuretic hormone secretion: lessons learned in titration of dose. AB - OBJECTIVE: To report a patient with idiopathic syndrome of inappropriate antidiuretic hormone secretion (SIADH) who developed profound aquaresis with symptomatic extracellular fluid depletion after initiation of therapy with tolvaptan who was later successfully treated with smaller doses of compounded tolvaptan to prevent rapid correction of serum sodium. METHODS: Case report and review of the literature. RESULTS: A 51-year-old woman was diagnosed with SIADH during admission for elective surgery resulting in multiple complications. The patient failed multiple therapies including fluid restriction, salt tablets, and demeclocycline. She was admitted to the hospital for initiation of tolvaptan therapy. After a 15-mg dose of tolvaptan, the patient had rapid increase in urine output and symptomatic hypotension. Sodium levels corrected rapidly overnight from 126 mEq/L to 139 mEq/L. A lower dose of tolvaptan resulted in similar symptoms and sodium correction. Due to continuing symptoms of hyponatremia including headaches, nausea, vomiting, and paresthesias after reinitiation of fluid restriction and salt tablets, tolvaptan was compounded to continue to titrate at lower doses. The patient was then admitted and tolvaptan was initiated at a dose of 1.5 mg with no significant improvement in sodium levels. Tolvaptan was titrated to 3 mg, which resulted in correction of sodium to 129 mEq/L with no associated symptoms of hypovolemia. CONCLUSIONS: Tolvaptan should be initiated in an inpatient setting with close monitoring of serum sodium levels. In patients who are not able to tolerate recommended dosages, consideration should be given to using a compounded formulation to further titrate to lower doses. PMID- 21613056 TI - Using the 454 pyrosequencing-based technique in the development of nuclear microsatellite loci in the alpine plant Arabis alpina (Brassicaceae). AB - PREMISE OF THE STUDY: Polymorphic microsatellite markers were developed for the inbred alpine perennial plant Arabis alpine to infer life-history parameters and measure patterns of contemporary gene fl ow within populations. METHODS AND RESULTS: Using the 454 pyrosequencing technique, 19 microsatellite primer sets were developed for A. alpina . The primer sets were tested on 60 individuals sampled from three sub-populations in the Swiss Alps. The primers amplifi ed di- and trinucleotide repeats with two to fi ve alleles per locus. CONCLUSIONS: Previous attempts to isolate microsatellite loci in A. alpina using enrichment libraries and cross-amplifi cation were diffi cult and produced an insufficient number of polymorphic microsatellite loci. In contrast, next-generation sequencing technology was successful in identifying microsatellite repeats in A. alpina. These newly developed microsatellite primers will be useful to further develop A. alpina into a model species for eco-genomic studies. PMID- 21613057 TI - Isolation of SSR markers for two African tropical tree species, Erythrophleum suaveolens and E. ivorense (Caesalpinioideae). AB - PREMISE OF THE STUDY: To characterize the level of genetic diversity and gene fl ow, as well as to identify unambiguously two African tropical tree species, Erythrophleum ivorense and E. suaveolens , we have developed a set of nuclear SSR (Simple Sequence Repeats) markers. METHODS AND RESULTS: Nine SSRs that display polymorphism in both species were identified. The nine newly developed SSR markers can be amplified in only two multiplexed reactions. Levels of polymorphism were assessed in two populations per species, yielding two to fifteen alleles per locus in E. ivorense and three to sixteen alleles per locus in E. suaveolens . CONCLUSIONS: The SSR markers developed here are promising to study the spatial distribution of genetic diversity and the genetic delimitation of two Erythrophleum species from central Africa. PMID- 21613058 TI - Interactions between GA, auxin, and UNI expression controlling shoot ontogeny, leaf morphogenesis, and auxin response in Pisum sativum (Fabaceae): or how the uni-tac mutant is rescued. AB - PREMISE OF THE STUDY: Leaf morphogenesis, including that of compound leaves, provides the basis for the great diversity of leaf form among higher plants. Leaf form is an important character by which plants adapt to their environment. The common garden pea provides a developmental model system for understanding leaf development in the legumes and a contrasting one for other groups of plants. METHODS: We used genetic, tissue culture, and physiological methods, as well as DR5::GUS expression and qRT-PCR, to explore the interactions between the hormones gibberellic acid (GA) and auxin and Unifoliata ( UNI ) gene expression that control leaf morphogenesis in pea. KEY RESULTS: Rate of increase in leaf complexity during shoot ontogeny (i.e., heteroblasty) and adult leaf complexity are controlled by GA through UNI . Leaves on greenhouse-grown uni-tac mutants are rescued by weekly GA or auxin applications. Auxin responsiveness is reduced in uni-tac shoot and root tips and in wild-type shoot tips treated with auxin transport inhibitors. GA and auxin increase UNI mRNA levels in uni-tac as well as that of other transcription factors. CONCLUSIONS: GA and auxin positively promote leaf dissection during leaf morphogenesis in pea by prolonging the time during which acropetally initiated pinna pairs are produced. GA-generated elaboration of leaf morphogenesis is in distinct contrast to that in other species, such as tomato and Cardamine . Instead, GA and auxin play common and supportive roles in pea leaf morphogenesis as they do in many other aspects of plant development PMID- 21613059 TI - A sequential approach using genetic and morphological analyses to test species status: the case of United States federally endangered Agalinis acuta (Orobanchaceae). AB - PREMISE OF THE STUDY: Given that inaccurate taxonomy can have negative consequences for species of conservation concern and result in erroneous conclusions regarding macroecological patterns, efficient methods for resolving taxonomic uncertainty are essential. The primary objective of this study was to assess the evolutionary distinctiveness of the federally endangered plant species Agalinis acuta (Orobanchaceae) to ensure it represents a distinct taxon warranting protection under the United States Endangered Species Act. METHODS: We describe and implement a sequential approach that begins with the most restrictive criteria of genealogical exclusivity within which we first conducted a phylogenetic analysis based on six chloroplast DNA loci assayed from multiple representatives of five putative species. Because of the possibility that incomplete lineage sorting is responsible for the lack of genealogical exclusivity among A. acuta individuals, we then conducted intensive population level analyses based on 21 microsatellite loci and 61 morphological traits. KEY RESULTS: The distinctiveness of A. acuta from Agalinis decemloba and Agalinis tenella was not supported under the genealogical species concept. The results from the analyses of microsatellite loci and morphological characters evaluated under alternative species concepts also did not support the distinctiveness of A. acuta from A. decemloba . CONCLUSIONS: Through this successive approach, we found insufficient evidence to support the evolutionary distinctiveness of the listed taxon A. acuta . We recommend that it be synonymized under A. decemloba and also conclude that the taxon that would now include A. acuta is deserving of protection under the Endangered Species Act. PMID- 21613060 TI - Endosymbiosis and population differentiation in wild and cultivated Lolium perenne (Poaceae). AB - PREMISE OF THE STUDY: Endophytic fungi are common inhabitants of cool-season grasses that can affect host growth and reproduction. One prerequisite for the expected coevolution between symbionts is that there exist variable effects of the endosymbiont on its host in different environments. Here, the impact of endophytes ( Neotyphodium lolii ) on survival, growth, and reproduction of wild populations of Lolium perenne from its native range (Italy, Morocco, Turkey, Tunisia) and two United States cultivars was explored. METHODS: Two unmanaged, common gardens 30 m apart in New Jersey, USA, were planted with endophyte infected and uninfected plants of the six populations in August 2008. Plants were scored for tiller number and lengths, and survival in October and December 2008 and May and September 2009; fl owering tillers (spikes) were counted in spring 2009. A greenhouse experiment was designed to assess tiller production and growth of four populations. KEY RESULTS: There were significant effects of population and garden on tiller number and lengths but no detectable effects of endophytes. Populations from Italy and Morocco and the two US cultivars grew well in one garden, but Tunisian plants grew the least in either garden. Overwinter survival and postfl owering survival were unaffected by endophytes. Spike production was strongly influenced by population. Although populations varied, there were no differences in growth between infected and uninfected plants in the greenhouse. CONCLUSIONS: Due to the absence of unambiguous endophyte-mediated effects on growth and reproduction of these differentiated populations, putative coevolutionary relations between the endosymbiont and its native host species remain obscure in this grass - endophyte system. PMID- 21613061 TI - Development of successive cambia, cambial activity, and their relationship to physiological traits in Ipomoea arborescens (Convolvulaceae) seedlings. AB - PREMISE OF THE STUDY: The seedling stage is one of the most critical phases in the life history of plants; during this stage, plants must develop efficient conductive and storage systems before the end of the favorable season. Little is known about the origin of successive cambia in seedlings of tree species of Ipomoea or about how many cambia are produced in one growth season. We studied the anatomy of Ipomoea arborescens seedlings to defi ne when cambium is differentiated, to determine how many cambia differentiate in one year of growth, and to relate the development of successive cambia to physiological aspects of growth. METHODS: Seedlings from 5 to 425 d of age were harvested, and their morphology as well as CO(2) and water exchange, were evaluated at 5 and 60 d after germination. Six stages of development were established to study origin of cambia. KEY RESULTS: Cambium was differentiated 5 d after germination, at a time when seedlings had photosynthetic cotyledons with high specific area, assimilation rate, and stomatal conductance. Differentiation of the fi rst successive cambium occurred inparenchyma cells below the endodermis or starch sheath. Development of reverse cambium and intraxylary phloem cambiumdemonstrated that ontogenetic shifts may occur in different stem regions. In the 10-mo-old plants, all cambia reactivated, and earlywood wide vessels were differentiated. CONCLUSIONS: The origin of successive cambia, the occurrence of more than one type of cambium, and parenchyma proliferation are features shared by I. arborescens with its climbing ancestors as a strategy for survival in the harsh environment of tropical deciduous forests. PMID- 21613062 TI - The response of Aster amellus (Asteraceae) to mycorrhiza depends on the origins of both the soil and the fungi. AB - PREMISE OF STUDY: Previous studies testing pairwise interactions between plants, arbuscular mycorrhizal fungi (AMF) and soil have shown that the effectiveness of such interactions depends on the origins of the plants, soil, and AMF. Surprisingly, no study has yet looked at the three-way interaction between plants, soil, and AMF originating from the same and from different sites. Such knowledge could elucidate the determinants of local adaptations of plants and thus might help in various revegetation attempts. METHODS: Six populations of the obligately mycorrhizal plant species Aster amellus from two isolated regions were combined with the soil and the AMF ecotype from their sites and plant growth were monitored over 16 months. KEY RESULTS: For each combination of soil and native AMF, plants grown with their native AMF in their native soil had higher aboveground biomass, invested more to aboveground biomass and had higher numbers of fl ower heads than the other plants. The specifi city of the relationship among plant populations, AMF, and soil was also observed for percentage of root colonization. CONCLUSIONS: The study extends our knowledge of the specifi c interaction between plants and AMF by demonstrating that the positive effect of native AMF occurs only when the plants are also grown in their native soil. Thus, when attempting to facilitate plant growth, we need to consider the origin of the plants, the soil, and the AMF, because all three components are adapted to each other. PMID- 21613063 TI - Development of microsatellite markers in Kmeria septentrionalis (Magnoliaceae), an endangered Chinese tree. AB - PREMISE OF THE STUDY: Microsatellite markers were developed in an endangered plant, Kmeria septentrionalis, to investigate its population genetic structure, gene flow, and mating systems. METHODS AND RESULTS: Using the combined biotin capture method, 14 microsatellite primer sets were isolated and characterized. All of these markers showed polymorphism, and the number of alleles per locus ranged from 3 to 15 across 60 individuals from two populations. The observed and expected heterozygosities ranged from 0.2692 to 0.9667 and from 0.3271 to 0.8881, respectively. CONCLUSIONS: These markers will facilitate further studies on the genetic diversity and mating systems of K. septentrionalis. PMID- 21613064 TI - Microsatellite primers for vulnerable seagrass Halophila beccarii (Hydrocharitaceae). AB - PREMISE OF THE STUDY: Polymorphic microsatellite primers were developed in the vulnerable seagrass Halophila beccarii to investigate genetic variation and provide necessary markers for studying its population genetic structure. METHODS AND RESULTS: Six polymorphic and six monomorphic microsatellite loci were developed in H. beccarii. Most loci were successfully amplified across 40 H. beccarii individuals collected from three populations from coastal regions of southern China. Two to four alleles per locus were observed at the six polymorphic loci. The highest expected heterozygosity was 0.5737. CONCLUSIONS: The results demonstrate low levels of polymorphism in H. beccarii from coastal regions of southern China. They also illustrate that these primers may be useful for studying the mating system and population genetics of H. beccarii on a global scale. PMID- 21613065 TI - B- and C-class gene expression during corona development of the blue passionflower (Passiflora caerulea, Passifloraceae). AB - PREMISE OF STUDY: The origin of the passionflower corona, a complex series of structures between the petals and stamens, has intrigued botanists for centuries, but has proven intractable using traditional approaches. Supplementing developmental data with expression analyses of three floral identity genes, we test whether the corona in Passiflora caerulea (blue passionflower) is homologous to petals or stamens or whether an alternative hypothesis of the corona as a novel structure is supported. METHODS: Corona development was investigated using scanning electron microscopy. Expression of the P. caerulea B-class genes PISTILLATA (PcPI) and TOMATO MADS6 (PcTM6), and C-class gene AGAMOUS (PcAG) was investigated using a combination of RT-PCR and mRNA in situ hybridization analyses. KEY RESULTS: Corona development starts as a ring of tissue at the base of petals. The outer radii and operculum initiate first at the periphery, followed by the inner radii and pali toward the center, and finally an annulus beneath the operculum. Late in development, a limen, the innermost component of the corona, develops from the side of the androgynophore. RT-PCR analyses indicate that the B-class genes PcPI and PcTM6 and C-class gene PcAG were all expressed in mature coronas. However, mRNA in situ hybridization analyses revealed complex temporal patterns of gene expression in the different corona elements. CONCLUSIONS: Our data support the hypothesis that the corona is a composite structure, with the radii, pali, and operculum homologous to stamens, and the limen, which only expresses PcTM6, considered to be a novel structure distinct from the androgynophore. PMID- 21613066 TI - Site effect is stronger than species identity in driving demographic responses of Helianthemum (Cistaceae) shrubs in gypsum environments. AB - PREMISE OF THE STUDY: Regional climatic patterns result in the synchrony of biological processes along large spatial areas. These patterns may be critical for effective plant recruitment in (semi)arid environments. Nevertheless, recruitment patterns of plant species within their range of distribution are still poorly known. Moreover, this response may be species-dependent, particularly between coexisting congenerics, which are thought to vary in demographic responses to climatic conditions as a coexistence-promoting mechanism. In this context, we investigated whether two congeneric plant species show synchronic age structures at varying spatial scales and whether they display demographic differences. METHODS: We sampled 600 Helianthemum squamatum and H. syriacum individuals at six localities in Spain. We used dendrochronological techniques to estimate age and radial growth. We compared the age structure among populations and between species and assessed the effect of site and species on different demographic parameters. Correlations between age structure and climatic factors were also determined. KEY RESULTS: We detected a very low intraspecific synchrony across sites but a high interspecific coupling in age structure within localities. Secondary growth, mean age, and flowering showed large intersite differences and small interspecific differences. Summer rainfall was a good predictor of age structure. CONCLUSIONS: Fine-scale climatic variability plays a major role in determining age structure of the studied species. Climatic variability is more relevant than interspecific differences. Our results illustrate the relevance of including spatial variation in summer rainfall patterns when modeling the impact of climate change on Mediterranean plant demography. PMID- 21613067 TI - An annual pattern of native embolism in upper branches of four tall conifer species. AB - PREMISE OF THE STUDY: The Pacific Northwest of North America experiences relatively mild winters and dry summers. For the tall coniferous trees that grow in this region, we predicted that loss in the hydraulic conductivity of uppermost branches would be avoided because of difficulty reversing accumulated emboli in xylem that is always under negative pressure. METHODS: To test this hypothesis, we measured native percent loss in hydraulic conductivity (PLC; the decrease of in situ hydraulic conductivity relative to the maximum) monthly throughout 2009 in branches at the tops (~50 m) of four species in an old growth forest in southern Washington. KEY RESULTS: Contrary to our prediction, freeze-thaw cycles resulted in considerable native PLC. Branches showed hydraulic recovery in the spring and after a moderate increase in native embolism that was observed after an unusually hot period in August. The September recovery occurred despite decreases in the leaf and stem water potentials compared to August values. CONCLUSIONS: Recoveries in branches of these trees could not have occurred by raising the water potential enough to dissolve bubbles simply by transporting water from roots and must have occurred either through water absorption through needles and/or refilling under negative pressure. Excluding the August value, native embolism values correlated strongly with air temperature of the preceding 10 d. For three species, we found that branches with lower wood density had higher specific conductivity, but not greater native PLC than branches with higher wood density, which calls into question whether there is any hydraulic benefit to higher wood density in small branches in those species. PMID- 21613068 TI - Morphological and functional sex expression in the Malagasy endemic Tina striata (Sapindaceae). AB - PREMISE OF THE STUDY: Knowledge of the functional sex expression of flowers is critical to identify the breeding system and potential for outcrossing in individuals but difficult to determine based solely on floral morphology. Individuals of the Malagasy endemic Tina striata (Sapindaceae) have both morphologically male (staminate) flowers and hermaphroditic (bisexual) flowers, although many Sapindaceae species have only functionally unisexual flowers. Two populations of T. striata were studied to determine the functional sex expression of flowers and their breeding system. METHODS: To determine whether morphologically hermaphroditic flowers have only female function, we compared male flowers and morphologically hermaphroditic flowers for (1) floral size, (2) pollen production and morphology, (3) patterns of anther dehiscence, (4) pollen germination, and (5) floral visitation patterns. KEY RESULTS: Relative to male flowers, morphologically hermaphroditic flowers had similar pollen grain morphology but smaller androecia and less pollen. Anthers from male flowers dehisced on days 3 and 4 of flowering and then abscised with the male flower. Anthers from hermaphroditic flowers did not dehisce or release pollen and abscised after the fourth day of flowering. Pollen from hermaphroditic flowers was less likely to germinate and produce pollen tubes. Floral visitors were similar for male and hermaphroditic flowers, and no visitation to hermaphroditic flowers was observed after stamen abscission. CONCLUSIONS: Morphologically hermaphroditic flowers of T. striata do not have male function and are functionally female; therefore, T. striata has a monoecious breeding system, with possible adaptations to promote outcrossing. PMID- 21613069 TI - Microsatellite primers in Stipa purpurea (Poaceae), a dominant species of the steppe on the Qinghai-Tibetan Plateau. AB - PREMISE OF THE STUDY: Microsatellite markers were developed in Stipa purpurea, a dominant species of the steppe and meadow on the Qinghai-Tibetan Plateau. METHODS AND RESULTS: Using the combined biotin capture method, 15 microsatellite primer sets were isolated and characterized. Eleven of these markers showed polymorphism, and the number of alleles per locus ranged from two to seven across 96 individuals from four populations. CONCLUSIONS: These markers provide a useful tool to investigate the spatial genetic structure and mating system of Stipa purpurea. PMID- 21613070 TI - Using complementary techniques to distinguish cryptic species: a new Erysimum (Brassicaceae) species from North Africa. AB - PREMISE OF THE STUDY: Cryptic species are superficially morphologically indistinguishable and therefore erroneously classified under one single name. The identification and delimitation of these species is usually a difficult task. The main aim of this study is to provide an inclusive methodology that combines standard and new tools to allow accurate identification of cryptic species. We used Erysimum nervosum s.l. as a model system. METHODS: Four populations belonging to E. nervosum s.l. were sampled at their two distribution ranges in Morocco (the Atlas Mountains and the Rif Mountains). Fifteen individuals per population were collected to assess standard taxonomic traits. Additionally, corolla color and shape were quantified in 30 individuals per population using spectrophotometry and geometric morphometrics, respectively. Finally, we collected tissue samples from each population per species to study the phylogenetic relationships among them. KEY RESULTS: Using the standard taxonomic traits, we could not distinguish the four populations. Nonetheless, there were differences in corolla color and shape between plants from the two mountain ranges. The population differentiation based on quantitative morphological differences were confirmed and supported by the phylogenetic relationships obtained for these populations and the rest of the Moroccan Erysimum species. CONCLUSIONS: The joint use of the results obtained from standard taxonomic traits, quantitative analyses of plant phenotype, and molecular data suggests the occurrence of two species within E. nervosum s.l. in Morocco, one located in the Atlas Mountains (E. nervosum s.s.) and the other in the Rif Mountains (E. riphaeanum sp. nov.). Consequently, we suggest that combining quantitative and molecular approaches with standard taxonomy greatly benefits the identification of cryptic species. PMID- 21613071 TI - Diversity and dynamics of plant genome size: an example of polysomaty from a cytogenetic study of Tahitian vanilla (Vanilla xtahitensis, Orchidaceae). AB - PREMISE OF THE STUDY: Abnormal mitotic behavior with somatic aneuploidy and partial endoreplication were previously reported for the first time in the plant kingdom in Vanilla planifolia. Because vanilla plants are vegetatively propagated, such abnormalities have been transmitted. This study aimed to determine whether mitotic abnormalities also occur in Vanilla hybrid or are suppressed by sexual reproduction. METHODS: Twenty-eight accessions of Vanilla *tahitensis, one V. planifolia, and hybrid V. planifolia * V. *tahitensis were analyzed by chromosome counts, cytometry, and fluorescent in situ hybridization of 18S-5.8S-26S rDNA. KEY RESULTS: In a single root meristem of V. *tahitensis, chromosome number varied from 22 to 31 in diploids (mean 2C = 5.23 pg), 31 to 41 in triploids (2C = 7.82 pg) and 43 to 60 in tetraploids (2C = 10.27 pg). Morphological diversity is apparently related to ploidy changes. Aneuploidy and partial (asymmetrical) endoreduplication were observed in root meristems of both V. *tahitensis and the hybrid V. planifolia * V. *tahitensis, but pollen grains had the euploid chromosome number (n = 15 in diploids). CONCLUSIONS: Genome irregularities may be transmitted not only during vegetative propagation but also by sexual reproduction in Vanilla. However, there must be a complex regulation of genome size and organization between the aneuploidy in somatic tissues and subsequently euploid gametic tissue. This is a novel example of polysomaty with developmentally regulated partial endoreplication. PMID- 21613072 TI - A new family of leafy liverworts from the middle Eocene of Vancouver Island, British Columbia, Canada. AB - PREMISE OF THE STUDY: Morphology is a reflection of evolution, and as the majority of biodiversity that has lived on Earth is now extinct, the study of the fossil record provides a more complete picture of evolution. This study investigates anatomically preserved bryophyte fossils from the Eocene Oyster Bay Formation of Vancouver Island. While the bryophyte fossil record is limited in general, anatomically preserved bryophytes are even more infrequent; thus, the Oyster Bay bryophytes are a particularly significant addition to the bryophyte fossil record. METHODS: Fossils occur in two marine carbonate nodules collected from the Appian Way locality on the eastern shore of Vancouver Island, British Columbia, and were prepared using the cellulose acetate peel technique. KEY RESULTS: The fossils exhibit a novel combination of characters unknown among extinct and extant liverworts: (1) three-ranked helical phyllotaxis with underleaves larger than the lateral leaves; (2) fascicled rhizoids associated with the leaves of all three ranks; (3) Anomoclada-type endogenous branching. CONCLUSIONS: A new liverwort family, Appianacae fam. nov., is established based upon the novel combination of characters. Appiana gen. nov. broadens the known diversity of bryophytes and adds a hepatic component to one of the richest and best characterized Eocene floras. PMID- 21613073 TI - Shifts in the flowering phenology of the northern Great Plains: patterns over 100 years. AB - PREMISE OF THE STUDY: Climate change is associated with phenological shifts in an increasing number of organisms worldwide. However, accurate estimates of these shifts are dependent on long-term data sets that include phenological observations from before annual average temperatures began to rise. METHODS: We compared the first flowering times of native prairie plants between 2007 and 2010 with historical data recorded by O. A. Stevens from 1910 to 1961. By merging climate variable data from the same time period, it also was possible to correlate first flowering dates with associated climate variables. KEY RESULTS: Over the past 100 years, spring temperatures in the Red River Valley near Fargo, North Dakota, USA, have increased, and growing seasons have lengthened significantly. Seventy-five percent of the 178 species observed by Stevens had flowering times that were sensitive to at least one variable related to temperature or precipitation. Over the past 4 yr, 5% to 17% of the species observed have significantly shifted their first flowering time either earlier or later relative to the previous century. CONCLUSIONS: The results of this study indicate that as spring temperatures in the northern Great Plains have increased and the growing season has lengthened, some spring flowering species have advanced their first flowering time, some fall species have delayed their first flowering, and some species have not changed. Given the importance of flowering timing for reproductive success, the changing climate in the Great Plains is expected to have long-term ecological and evolutionary consequences for native plant species. PMID- 21613074 TI - Development and characterization of EST-SSR markers in the invasive weed Mikania micrantha (Asteraceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed for the invasive species Mikania micrantha to investigate its invasion history. Transcriptome sequencing projects offer a potential source for the development of new markers. METHODS AND RESULTS: Sixteen polymorphic simple sequence repeat (SSR) markers derived from ESTs were identified and screened in 36 samples of M. micrantha. The number of alleles per locus ranged from two to four, with an average of 2.7 alleles per locus. The expected heterozygosity and observed heterozygosity ranged from 0 to 0.7754 and 0 to 0.8333, respectively. CONCLUSIONS: These EST-SSR markers may be useful for further investigation of the population genetics of M. micrantha as additional tools to trace its invasion history. PMID- 21613075 TI - Isolation and characterization of microsatellite loci in Cabralea canjerana (Meliaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed in the native Neotropical tree species Cabralea canjerana (Vell.) Mart. (Meliaceae) to study population genetics in some Atlantic Forest fragments of Brazil. This species is suitable for use in reforestation and is commercially important due to its high quality wood. METHODS AND RESULTS: In this study, eight microsatellite loci were isolated from an enriched C. canjerana genomic library. These are the first microsatellite loci described for this genus. Genetic diversity analyses were carried out using 30 individuals and six polymorphic loci. An average of 11.2 alleles was found, and the observed heterozygosity was 0.65. CONCLUSIONS: The microsatellite markers described here are valuable tools for further population genetic studies of the species. PMID- 21613076 TI - An efficient and rapid protocol for plant nuclear DNA preparation suitable for next generation sequencing methods. AB - PREMISE OF THE STUDY: In this study, we developed a nuclear DNA extraction protocol for Next Generation Sequencers (NGS). METHODS AND RESULTS: We applied this extraction method to grapevines and coffee trees, which are known to contain many secondary metabolites. The nuclear DNA obtained was sequenced by the 454/GS FLX method. We obtained excellent results, with less than 4% cytoplasmic DNA, in a similar way to a BAC (Bacterial Artificial Chromosome)-building protocol. We also compared our protocol with a classic DNA extraction using specific cytoplasmic DNA amplification. Results showed a lower cytoplasmic DNA contamination with the new protocol. CONCLUSIONS: The method presented here is fast and economical. The DNA obtained is of high quality, with a low level of cytoplasmic DNA contamination, and very efficient for the construction of sequencing libraries. PMID- 21613077 TI - Polymorphic microsatellite loci in Polemonium brandegei and P. viscosum (section Melliosoma, Polemoniaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were isolated in Polemonium brandegei and P. viscosum to be used in future studies of mating system evolution, population structure, and hybridization. METHODS AND RESULTS: Six loci were used in a preliminary genetic diversity study in two populations each of the closely related Polemonium brandegei and P. viscosum. We found 39 alleles across the six loci (average 7 per locus), with overall levels of observed heterozygosities ranging from 0.067 to 0.867 in P. brandegei and 0.000 to 0.666 in P. viscosum. Additional primers are reported, but require further design and optimization. CONCLUSIONS: The reported markers will aid in further studies of mating system evolution, population structure, and hybridization in P. brandegei and P. viscosum. PMID- 21613078 TI - Development of microsatellite loci for Aconitum gymnandrum (Ranunculaceae), a species endemic to the Qinghai-Tibetan Plateau. AB - PREMISE OF THE STUDY: Polymorphic microsatellite loci primers were developed in an alpine plant endemic to the Qinghai-Tibetan Plateau, Aconitum gymnandrum, to investigate its population genetic structure and cryptic speciation. METHODS AND RESULTS: Using the combined biotin capture method, 16 polymorphic microsatellite loci were identified in 66 individuals from six geographically distant populations of A. gymnandrum. Across all the A. gymnandrum samples, the number of alleles per locus ranged from 4 to 15. CONCLUSIONS: These markers will be useful to study population structure and cryptic speciation of A. gymnandrum. PMID- 21613079 TI - Unique calcium oxalate "duplex" and "concretion" idioblasts in leaves of tribe Naucleeae (Rubiaceae). AB - PREMISE OF THE STUDY: This basic study may help plant biologists better understand the variety and occurrence of crystal forms and their function in plants. Literature records hold four examples of two different crystal types in one cell. One, unillustrated report mentions druses and crystal sand from one species of tribe Naucleeae (Rubiaceae) and "occasional occurrences" in additional unnamed taxa. Here, we surveyed Naucleeae (103 of 179 species, 23 of 24 genera, all seven subtribes) for "duplex idioblast" distribution for systematic significance and describe examples of this rare feature. METHODS: Cleared, dehydrated, herbarium leaves were mounted unstained in resin. Slides were examined with polarization optics for crystal types and locations, and representative areas were electronically digitized. Scanning electron microscopy and x-ray analysis verified calcium oxalate composition. KEY RESULTS: Idioblast configurations occur as crystal sand (CS) only (most common, 92 spp.) to CS plus one embedded druse (55 spp.), to CS plus 2-3 druses (6 spp.), to one druse with scanty surrounding CS (a few spp.), to a "naked" druse (16 spp.). Trends occur in some subtribes. A previously undescribed conspicuous, spheroidal calcium oxalate aggregate "concretion" idioblast occurs in only four species of Mitragyna (Mitragynineae). Idioblasts are most common along vascular bundles and in mesophyll, less so only along vascular bundles, and least common only in mesophyll. Tiny "secondary" crystals are common in ordinary mesophyll cells. CONCLUSIONS: Crystal types appear to be systematic features in Naucleeae. Duplex idioblasts (CS and druses) and aggregate concretions are a demonstration that much is yet to be discovered about crystals. PMID- 21613080 TI - Effect of storage conditions on germination of seeds of 489 species from high elevation grasslands of the eastern Tibet Plateau and some implications for climate change. AB - PREMISE OF THE STUDY: Little is known about the effect of environmental conditions on seed dormancy break at the community level or how it could be affected by climate change. This study tested the effects of storage conditions on germination of 489 species from high-elevation natural grasslands on the Tibet Plateau. METHODS: We stored seeds in dry cold, dry warm, and wet cold environments to test the effect of these conditions on germination. Germination responses were classified with the use of cluster analysis. The effect of phylogeny on germination response to storage conditions was determined. KEY RESULTS: Compared with results of wet cold conditions, storing seeds at dry warm or dry cold conditions decreased the mean community germination percentage by 17.93% and 16.07%, respectively. Storing seeds at dry warm vs. dry cold conditions decreased the community mean germination percentage by 4.61%. The germination response to moisture conditions during storage showed significant phylogenetic patterns, whereas the germination response to storage temperature did not. On the basis of the germinability of seeds of the same species stored under different conditions, germination may increase, decrease, or stay the same. CONCLUSIONS: Within the high-elevation Tibetan grassland community, the different responses in dormancy breaking and germination behavior to the same storage conditions may have implications for understanding how this community might respond to climate change. In particular, some species may increase in the community, whereas others may decrease or remain the same. However, the potential for such change can be detected only by studying the responses of many species. PMID- 21613081 TI - Greater seasonal carbon gain across a broad temperature range contributes to the invasive potential of Phalaris arundinacea (Poaceae; reed canary grass) over the native sedge Carex stricta (Cyperaceae). AB - PREMISE OF THE STUDY: Most invasive plants grow faster and produce more biomass than the species that they displace, but physiological mechanisms leading to invasive success are poorly understood. To foster novel control approaches, our goal was to determine whether the grass Phalaris arundinacea possessed superior physiological strategies that contributed to its success over native sedges. METHODS: Data for spring, summer, and autumn diel gas-exchange, leaf morphology, and nitrogen content for plants of P. arundinacea and Carex stricta in water saturated, drained, and periodically flooded sites in northern Indiana, USA, were compared with similar data for plants in a greenhouse. KEY RESULTS: Phalaris arundinacea had higher maximum CO(2) assimilation (A) across a broad range of temperatures, greater summer/autumn net carbon gain, higher water use efficiencies, larger leaf areas per shoot, and higher specific leaf areas than did C. stricta. Species differences in gas-exchange data were similar in the greenhouse. However, long-term flooding reduced A for P. arundinacea. Greater declines in leaf A and nitrogen content from July to October compared to P. arundinacea were suggestive of earlier leaf senescence for C. stricta. CONCLUSIONS: We propose that superior daily and seasonal carbon gain, especially during rhizome carbohydrate storage in the summer and autumn, contribute to the success of invasive P. arundinacea over C. stricta. This advantage may be enhanced by frequent summer/autumn heat waves. The poor performance of P. arundinacea during long-term flooding is consistent with C. stricta's dominance in water-saturated soil, implying that water management strategies could be crucial to controlling P. arundinacea. PMID- 21613082 TI - A model of botanical collectors' behavior in the field: never the same species twice. AB - PREMISE OF THE STUDY: Because of their numbers, specimens in natural-history museums cannot be ignored when trying to answer one of the fundamental questions in science: What determines species diversity? The nonrandom nature of collecting does not allow most statistical tests or extrapolations of species estimates, or comparison of richness between areas (which, however, is still done frequently). METHODS: We present a simple simulation model, which starts from the assumption that collectors never collect the same species twice during collecting trips. The model allows the generation of the abundance distribution in a herbarium for any natural species abundance distribution, using a simple set of collecting strategies. KEY RESULTS: We show that, in essence, the strategy of "never collect the same species twice" is enough to generate the relative abundance distribution as found in a herbarium. We illustrate this using real plot and specimen data from two well-collected areas, one in central Guyana and one in Suriname. CONCLUSIONS: Because of the oversampling of rare species, it is perhaps not possible to use museum data to reconstruct the community structure in the field or even estimate a proper diversity number other than the number of species in a region. PMID- 21613083 TI - Invasive knotweed affects native plants through allelopathy. AB - PREMISE OF STUDY: There is increasing evidence that many plant invaders interfere with native plants through allelopathy. This allelopathic interference may be a key mechanism of plant invasiveness. One of the most aggressive current plant invaders is the clonal knotweed hybrid Fallopia * bohemica, which often forms monocultures in its introduced range. Preliminary results from laboratory studies suggest that allelopathy could play a role in this invasion. METHODS: We grew experimental communities of European plants together with F. * bohemica. We used activated carbon to test for allelopathic effects, and we combined this with single or repeated removal of Fallopia shoots to examine how mechanical control can reduce the species' impact. KEY RESULTS: Addition of activated carbon to the soil significantly reduced the suppressive effect of undamaged F. * bohemica on native forbs. The magnitude of this effect was similar to that of regular cutting of Fallopia shoots. Regular cutting of Fallopia shoots efficiently inhibited the growth of rhizomes, together with their apparent allelopathic effects. CONCLUSIONS: The ecological impact of F. * bohemica on native forbs is not just a result of competition for shared resources, but it also appears to have a large allelopathic component. Still, regular mechnical control successfully eliminated allelopathic effects. Therefore, allelopathy will create an additional challenge to knotweed management and ecological restoration only if the allelochemicals are found to persist in the soil. More research is needed to examine the mechanisms underlying Fallopia allelopathy, and the long-term effects of soil residues. PMID- 21613084 TI - Phylogenetic relationships and evolution of growth form in Cactaceae (Caryophyllales, Eudicotyledoneae). AB - PREMISE OF THE STUDY: Cactaceae is one of the most charismatic plant families because of the extreme succulence and outstanding diversity of growth forms of its members. Although cacti are conspicuous elements of arid ecosystems in the New World and are model systems for ecological and anatomical studies, the high morphological convergence and scarcity of phenotypic synapomorphies make the evolutionary relationships and trends among lineages difficult to understand. METHODS: We performed phylogenetic analyses implementing parsimony ratchet and likelihood methods, using a concatenated matrix with 6148 bp of plastid and nuclear markers (trnK/matK, matK, trnL-trnF, rpl16, and ppc). We included 224 species representing approximately 85% of the family's genera. Likelihood methods were used to perform an ancestral character reconstruction within Cactoideae, the richest subfamily in terms of morphological diversity and species number, to evaluate possible growth form evolutionary trends. KEY RESULTS: Our phylogenetic results support previous studies showing the paraphyly of subfamily Pereskioideae and the monophyly of subfamilies Opuntioideae and Cactoideae. After the early divergence of Blossfeldia, Cactoideae splits into two clades: Cacteae, including North American globose and barrel-shaped members, and core Cactoideae, including the largest diversity of growth forms distributed throughout the American continent. Para- or polyphyly is persistent in different parts of the phylogeny. Main Cactoideae clades were found to have different ancestral growth forms, and convergence toward globose, arborescent, or columnar forms occurred in different lineages. CONCLUSIONS: Our study enabled us to provide a detailed hypothesis of relationships among cacti lineages and represents the most complete general phylogenetic framework available to understand evolutionary trends within Cactaceae. PMID- 21613085 TI - Evolution and biogeography of Pleurophyllum (Astereae, Asteraceae), a small genus of megaherbs endemic to the subantarctic islands. AB - PREMISE OF THE STUDY: The abundance of fossils in Antarctica suggests this continent was a center of diversification and a corridor for migration for many austral plant groups until the late Tertiary and may have played a pivotal role in shaping plant distributions in the southern hemisphere. Although the Antarctic flora was largely erased by glaciation during the Pleistocene, at least some Antarctic plant species found refuge on the subantarctic islands. METHODS: We used independent and combined analyses of ITS, ETS, trnK, and trnL DNA sequences to infer phylogenetic relations in Pleurophyllum, a small genus of three species that are endemic to the subantarctic islands of Australia and New Zealand. The inferred phylogeny provided a framework to reconstruct the origin and patterns of diversification in the genus. KEY RESULTS: We summarize support for the hypothesis that Pleurophyllum survived episodes of Pleistocene glaciation in the subantarctic islands and that its sisters dispersed northward in response to glacial advance. CONCLUSIONS: The distinctive flora of the subantarctic islands includes some of the last remnants of a once-diverse Antarctic flora. These plants may still retain distinctive features of their ancestors. Studies of endemic plants such as Pleurophyllum are the key to resolving this puzzle. PMID- 21613086 TI - Old-New World and trans-African disjunctions of Thamnosma (Rutaceae): intercontinental long-distance dispersal and local differentiation in the succulent biome. AB - PREMISE OF THE STUDY: The succulent biome is highly fragmented throughout the Old and New World. The resulting disjunctions on global and regional scales have been explained by various hypotheses. To evaluate these, we used Thamnosma, which is restricted to the succulent biome and has trans-Atlantic and trans-African disjunctions. Its three main distribution centers are in southern North America, southern and eastern Africa including Socotra. METHODS: We conducted parsimony, maximum likelihood, and Bayesian phylogenetic analyses based on chloroplast and nuclear sequence data. We applied molecular clock calculations using the programs BEAST and MULTIDIVTIME and biogeographic reconstructions using S-DIVA and Lagrange. KEY RESULTS: Our data indicate a weakly supported paraphyly of the New World species with respect to a palaeotropical lineage, which is further subdivided into a southern African and a Horn of Africa group. The disjunctions in Thamnosma are mostly dated to the Miocene. CONCLUSIONS: We conclude that the Old-New World disjunction of Thamnosma is likely the result of long-distance dispersal. The Miocene closure of the arid corridor between southern and eastern Africa may have caused the split within the Old World lineage, thus making a vicariance explanation feasible. The colonization of Socotra is also due to long distance dispersal. All recent Thamnosma species are part of the succulent biome, and the North American species may have been members of the arid Neogene Madro Tertiary Geoflora. Phylogenetic niche conservatism, rare long-distance dispersal, and local differentiation account for the diversity among species of Thamnosma. PMID- 21613087 TI - Spatial genetics of wild tomato species reveals roles of the Andean geography on demographic history. AB - PREMISE OF THE STUDY: Understanding the demographic history of natural populations in relation to the geographic features in their habitats is an important step toward deciphering the mechanisms of evolutionary processes in nature. This study investigates how the complex geographic and ecological features of the Andes play a role in demographic history, species divergence, dispersal patterns, and hybridization in wild tomato species. METHODS: We investigated spatial genetics of two closely related wild tomato species, Solanum lycopersicum and S. pimpinellifolium, by integrating amplified fragment length polymorphism (AFLP) marker data and geographic information system (GIS)-derived geographic and climatic data. KEY RESULTS: The two species represent genetically distinct lineages largely separated by the Andes, but hybridize extensively in central to northern Ecuador, likely mediated by the transitional climatic conditions between those of the two species. Solanum lycospericum has likely experienced a severe population bottleneck during the colonization of the eastern Andes followed by a rapid population expansion. CONCLUSIONS: The study demonstrates that the evolutionary patterns of the two wild tomatoes, including demographic history, dispersal patterns, interspecific divergence, and hybridization, are intimately related to the complex geographic and ecological features of the Andes. Integrating genetic data across the genome and GIS-derived environmental data can provide insights into the patterns of complex evolutionary processes in nature. PMID- 21613088 TI - Climate-driven local adaptation of ecophysiology and phenology in balsam poplar, Populus balsamifera L. (Salicaceae). AB - PREMISE OF THE STUDY: During past episodes of climate change, many plant species experienced large-scale range expansions. Expanding populations likely encountered strong selection as they colonized new environments. In this study we examine the extent to which populations of the widespread forest tree Populus balsamifera L. have become locally adapted as the species expanded into its current range since the last glaciation. METHODS: We tested for adaptive variation in 13 ecophysiology and phenology traits on clonally propagated genotypes originating from a range-wide sample of 20 subpopulations. The hypothesis of local adaption was tested by comparing among-population variation at ecologically important traits (Q(ST)) to expected variation based on demographic history (F(ST)) estimated from a large set of nuclear single nucleotide polymorphism loci. KEY RESULTS: Evidence for divergence in excess of neutral expectations was present for eight of 13 traits. Bud phenology, petiole length, and leaf nitrogen showed the greatest divergence (all Q(ST) > 0.6), whereas traits related to leaf water usage showed the least (all Q(ST) <= 0.30) and were not different from neutrality. Strong correlations were present between traits, geography, and climate, and they revealed a general pattern of northern subpopulations adapted to shorter, drier growing seasons compared with populations in the center or eastern regions of the range. CONCLUSIONS: Our study demonstrates pronounced adaptive variation in ecophysiology and phenology among balsam poplar populations. These results suggest that as this widespread forest tree species expanded its range since the end of the last glacial maximum, it evolved rapidly in response to geographically variable selection. PMID- 21613089 TI - Influences of landscape and pollinators on population genetic structure: examples from three Penstemon (Plantaginaceae) species in the Great Basin. AB - PREMISE OF THE STUDY: Despite rapid growth in the field of landscape genetics, our understanding of how landscape features interact with life history traits to influence population genetic structure in plant species remains limited. Here, we identify population genetic divergence in three species of Penstemon (Plantaginaceae) similarly distributed throughout the Great Basin region of the western United States but with different pollination syndromes (bee and hummingbird). The Great Basin's mountainous landscape provides an ideal setting to compare the interaction of landscape and dispersal ability in isolating populations of different species. METHODS: We used eight highly polymorphic microsatellite loci to identify neutral population genetic structure between populations within and among mountain ranges for eight populations of P. deustus, 10 populations of P. pachyphyllus, and 10 populations of P. rostriflorus. We applied traditional population genetics approaches as well as spatial and landscape genetics approaches to infer genetic structure and discontinuities among populations. KEY RESULTS: All three species had significant genetic structure and exhibited isolation by distance, ranging from high structure and low inferred gene flow in the bee-pollinated species P. deustus (F(ST) = 0.1330, R(ST) = 0.4076, seven genetic clusters identified) and P. pachyphyllus (F(ST) = 0.1896, R(ST) = 0.2531, four genetic clusters identified) to much lower structure and higher inferred gene flow in the hummingbird-pollinated P. rostriflorus (F(ST) = 0.0638, R(ST) = 0.1116, three genetic clusters identified). CONCLUSIONS: These three Penstemon species have significant yet strikingly different patterns of population genetic structure, findings consistent with different interactions between landscape features and the dispersal capabilities of their pollinators. PMID- 21613090 TI - Dynamics of chromosome number and genome size variation in a cytogenetically variable sedge (Carex scoparia var. scoparia, Cyperaceae). AB - PREMISE OF THE STUDY: High intraspecific cytogenetic variation in the sedge genus Carex (Cyperaceae) is hypothesized to be due to the "diffuse" or non-localized centromeres, which facilitate chromosome fission and fusion. If chromosome number changes are dominated by fission and fusion, then chromosome evolution will result primarily in changes in the potential for recombination among populations. Chromosome duplications, on the other hand, entail consequent opportunities for divergent evolution of paralogs. In this study, we evaluate whether genome size and chromosome number covary within species. METHODS: We used flow cytometry to estimate genome sizes in Carex scoparia var. scoparia, sampling 99 plants (23 populations) in the Chicago region, and we used meiotic chromosome observations to document chromosome numbers and chromosome pairing relations. KEY RESULTS: Chromosome numbers range from 2n = 62 to 2n = 68, and nuclear DNA 1C content from 0.342 to 0.361 pg DNA. Regressions of DNA content on chromosome number are nonsignificant for data analyzed by individual or population, and a regression model that excludes slope is favored over a model in which chromosome number predicts genome size. CONCLUSIONS: Chromosome rearrangements within cytogenetically variable Carex species are more likely a consequence of fission and fusion than of duplication and deletion. Moreover, neither genome size nor chromosome number is spatially autocorrelated, which suggests the potential for rapid chromosome evolution by fission and fusion at a relatively fine geographic scale (<350 km). These findings have important implications for ecological restoration and speciation within the largest angiosperm genus of the temperate zone. PMID- 21613091 TI - Functional bisporangiate cones in Pinus johannis (Pinaceae): Implications for the evolution of bisexuality in seed plants. AB - PREMISE OF STUDY: Bisexuality (male and female function in one structure) has been reported as a key innovation of angiosperms. Although there are several reports of "teratological" bisporangiate (bisexual) cones in gymnosperms, there have been none on the viability of their ovules and pollen. Analyses of the development and arrangement of female and male structures on bisporangiate cones of Pinus johannis enables us to gain insight on the origin of bisexuality in seed plants, for both angiosperms and gymnosperms. METHODS: Viability of bisporangiate cones was assayed by performing manual crosses and using anatomical and histological methods. KEY RESULTS: We determined that bisporangiate cones of P. johannis produce functional pollen and ovules. Male and female organs occupy basal and apical positions, respectively, the same positions found in almost all bisporangiate strobili in gymnosperms and bisexual flowers in angiosperms. CONCLUSIONS: The viability and spatial distribution of female and male organs of bisporangiate cones and their frequent occurrence in gymnosperms suggest a common mechanism in all seed plants for the production of bisporangiate structures. This idea is further supported by the presence of homologous genes for sexual organ identity in gymnosperms and angiosperms as reported by other authors. The lack of bisporangiate structure in gymnosperms may be primarily due to selection to avoid inbreeding rather than to genetic constraint. PMID- 21613092 TI - Within-individual variation of trunk and branch xylem density in tropical trees. AB - PREMISE OF THE STUDY: Wood density correlates with mechanical and physiological strategies of trees and is important for estimating global carbon stocks. Nonetheless, the relationship between branch and trunk xylem density has been poorly explored in neotropical trees. Here, we examine this relationship in trees from French Guiana and its variation among different families and sites, to improve the understanding of wood density in neotropical forests. METHODS: Trunk and branch xylem densities were measured for 1909 trees in seven sites across French Guiana. A major-axis fit was performed to explore their general allometric relationship and its variation among different families and sites. KEY RESULTS: Trunk xylem and branch xylem densities were significantly positively correlated, and their relationship explained 47% of the total variance. Trunk xylem was on average 9% denser than branch xylem. Family-level differences and interactions between family and site accounted for more than 40% of the total variance, whereas differences among sites explained little variation. CONCLUSIONS: Variation in xylem density within individual trees can be substantial, and the relationship between branch xylem and trunk xylem densities varies considerably among families and sites. As such, whole-tree biomass estimates based on nondestructive branch sampling should correct for both taxonomic and environmental factors. Furthermore, detailed estimates of the vertical distribution of wood density within individual trees are needed to determine the extent to which relying solely upon measures of trunk wood density may cause carbon stocks in tropical forests to be overestimated. PMID- 21613093 TI - First macrofossil record of Begonia (Begoniaceae). AB - PREMISE OF THE STUDY: Begonia is the sixth-largest genus of flowering plants, with about 1400-1500 species in 66 sections. Several species are popular with horticulturalists, mainly for their colorful flowers and leaves. However, the evolutionary history of the genus is debated, and until now there has been no macrofossil record. Here, we report on a fossil winged capsule from the Pliocene of Alabama and interpret it as a Begonia fruit, which represents the first convincing macrofossil evidence of the genus. METHODS: Identification required extensive literature and herbarium searches to compare features of the fossil with those of other recognized fossil and extant taxa that have winged fruits. KEY RESULTS: The fossil is identified as a Begonia fruit on the basis of a combination of characters, including the presence of two unequally developed wings, at least one additional inferred wing, details of the wing venation, a prominent marginal vein, a locule opening associated with a wing, and a persistent pedicel. CONCLUSIONS: Although too young to provide a calibration point for molecular divergence-time estimates, this fossil is noteworthy as the first macrofossil record of Begonia. It may represent a species that initially arrived from the south via Mexico after the closing of the Central American Straits. We propose that this fossil should stimulate a reexamination of other unidentified fossil winged fruits, as older records of Begonia may be forthcoming. PMID- 21613094 TI - Discovery of natural Miscanthus (Poaceae) triploid plants in sympatric populations of Miscanthus sacchariflorus and Miscanthus sinensis in southern Japan. AB - PREMISE OF THE STUDY: Looming petroleum shortages and projected negative impacts of human-induced climate change may be partly alleviated by the development and use of bioenergy feedstock crops. Miscanthus *giganteus, a highly productive sterile triploid hybrid grass that was discovered in Japan several decades ago, has considerable potential as an alternative source of energy. Given the risks, however, involved in the reliance upon production of one clone of this hybrid, which is a natural cross between Miscanthus sacchariflorus and Miscanthus sinensis, for lignocellulosic bioenergy production, natural occurrences of triploidy were investigated in sympatric populations of tetraploid M. sacchariflorus and diploid M. sinensis in Japan. METHODS: Seeds were counted and DNA content was estimated by flow cytometry for plants of M. sacchariflorus and M. sinensis in several sympatric populations throughout Japan. Chromosomes were also counted for select plants. KEY RESULTS: Based on seed-set data, M. sacchariflorus has significantly lower seed set than M. sinensis in Japan. Putative triploid seeds were found on M. sacchariflorus plants in southern Japan. CONCLUSIONS: This is the first report of the natural occurrence of Miscanthus triploid plants in several decades. If found to be sterile and similar in productivity to the commonly cultivated clone of M. *giganteus, these triploid plants might serve as additional sources of genetic variation for bioenergy production. Seed set data also indicates that other triploid plants might be found in more northern regions of Japan. PMID- 21613096 TI - Microsatellite markers for the Chinese herbaceous peony Paeonia lactiflora (Paeoniaceae). AB - PREMISE OF THE STUDY: Microsatellite (simple sequence repeat, SSR) primers were developed for the Chinese peony, P. lactiflora, to investigate the diversity within Chinese peony germplasm resources. METHODS AND RESULTS: Using an SSR enriched genomic library, a set of 10 unique polymorphic genomic SSRs was developed and characterized. The primers amplified 61 alleles in all 10 loci, including di-, tri-, and tetranucleotide repeats. The primers were also effective for P. veitchii and P. obovata. CONCLUSIONS: The new primers will be useful for genetic research of the Chinese peony and extend the repertoire of SSR markers available to study the herbaceous taxa in Paeonia. PMID- 21613097 TI - Development and characterization of polymorphic microsatellite markers in Castanopsis sclerophylla (Fagaceae). AB - PREMISE OF THE STUDY: We developed polymorphic microsatellite primers in Castanopsis sclerophylla (Lindley & Paxton) Schottky (Fagaceae), a dominant canopy tree, to provide markers for further studies on the genetic structure and mating system of this species. METHODS AND RESULTS: Ten polymorphic microsatellite loci were isolated and successfully amplified in three C. sclerophylla populations (Huangshanjian, Shilin, and Guanmiao) from Chun'an, Zhejiang Province, China. The number of alleles per locus in these populations ranged from 3 to 17. The observed and expected heterozygosities were 0.100-0.977 and 0.294-0.916, respectively. CONCLUSIONS: These microsatellite loci displayed moderate or high levels of polymorphism within the examined populations, showing the utility of primers in studying the genetic variation, parentage, and mating system of C. sclerophylla. PMID- 21613098 TI - Development and characterization of 21 EST-derived microsatellite markers in Vicia faba (fava bean). AB - PREMISE OF THE STUDY: Expressed sequence tag (EST)-derived microsatellite simple sequence repeat (SSR) markers were developed in Vicia faba L. by screening the NCBI database. Markers were validated and explored for size polymorphism among fava bean accessions. METHODS AND RESULTS: Twenty-one EST-SSR primer pairs were identified, and the loci characterized were size polymorphic among 32 fava bean genotypes from diverse geographical locations. The number of alleles (N(a)) per locus ranged from 2 to 9, and expected heterozygosity (H(E)) ranged from 0.0476 to 0.8304, respectively. CONCLUSIONS: These markers will be useful to study genetic diversity, genetic mapping, and molecular breeding in fava bean. PMID- 21613099 TI - Development and characterization of microsatellite loci in dioecious figs (Ficus, Moraceae). AB - PREMISE OF THE STUDY: Microsatellite markers for dioecious fig species, Ficus bernaysii King (section Sycocarpus), Ficus pachyrrhachis K. Schum. & Lauterb. (section Sycocarpus), and Ficus copiosa Steud. (section Sycidium) were developed to estimate gene flow among closely related fig species. METHODS AND RESULTS: Loci were developed from tri- and tetranucleotide-enriched genomic libraries. The six most repeatable and scorable loci for F. bernaysii and F. pachyrrhachis were characterized in 50 individuals each of five species from section Sycocarpus. Four primer pairs from F. copiosa were screened in 50 individuals each of two species from section Sycidium. Observed heterozygosity ranged from 0.53 to 0.93 in loci developed from F. bernaysii, 0.25 to 0.86 in loci developed from F. pachyrrhachis, and 0.68 to 0.87 in loci developed from F. copiosa. CONCLUSIONS: Amplification across the two Ficus sections was observed in seven of the ten total primer pairs. PMID- 21613100 TI - Microsatellite primers for the North American bluets (Houstonia section Amphiotis, Rubiaceae). AB - PREMISE OF THE STUDY: Microsatellites were developed for the native, perennial herbs Houstonia longifolia and H. purpurea to establish rates and patterns of hybridization among these and other closely related lineages within the genus. METHODS AND RESULTS: Seven primer sets were developed and tested using populations across eastern North America and into parts of the Midwest. Primers amplified di- and tri-nucleotide repeats with 1-16 alleles per locus among diploids. These primers also amplified microsatellites for H. purpurea var. montana, H. purpurea var. calycosa, H. ouachitana, and H. canadensis, and for other Houstonia species outside section Amphiotis. CONCLUSIONS: These results demonstrate the value of microsatellite loci in studies focusing on hybridization and population genetics across Houstonia section Amphiotis and could be useful in studies within other sections of Houstonia as well as in studies of related genera, such as Hedyotis. PMID- 21613101 TI - Microsatellite markers for the relict tree Aextoxicon punctatum: the only species in the Chilean endemic family Aextoxicaceae. AB - PREMISE OF THE STUDY: We screened 10 microsatellite loci for the dioecious, rainforest tree Aextoxicon punctatum, a species belonging to a monotypic family and genus, endemic to southwestern South America (30-43 degrees S). METHODS AND RESULTS: Polymorphisms were evaluated in 108 adult trees from four populations, including the northern and southern extremes of the geographic range of Aextoxicon in Chile. All 10 microsatellites revealed polymorphic variation. A total of 69, 57, 59, and 69 alleles were found in 40 (Fray Jorge), 19 (Santa Ines), 21 (Quebrada del Tigre), and 28 (Guabun) individual trees, respectively. The mean expected heterozygosity per population ranged from 0.70 to 0.72. CONCLUSIONS: These polymorphic microsatellites will be useful in assessing the genetic structure and conservation status of Aextoxicon throughout its historically fragmented geographic range. Parentage analysis will provide additional insights into the key historical and contemporary processes that have mediated population differentiation in this species. PMID- 21613102 TI - Microsatellite primers in the planktonic diatom Pseudo-nitzschia multistriata (Bacillariophyceae). AB - PREMISE OF THE STUDY: Seven microsatellite loci were characterized for the toxic diatom Pseudo-nitzschia multistriata Takano (Takano) to investigate intraspecific variability and estimate population genetic structure over blooms, seasons, and sexual and vegetative reproduction. METHODS AND RESULTS: Selected microsatellites consisted of di- and trinucleotide repeats in the core region, and showed four to twelve alleles per locus in strains of P. multistriata collected in the Gulf of Naples (Italy). Primer pairs were species-specific since they positively amplified against conspecific strains from Portugal and Spain but failed to generate PCR products from the diatoms Pseudo-nitzschia pseudodelicatissima (Hasle) Hasle and Leptocylindrus minimum Gran. CONCLUSIONS: The seven selected microsatellite markers will be useful in studying population dynamics of Pseudo nitzschia multistriata in space and time. PMID- 21613103 TI - Development and characterization of microsatellite markers for Sagittaria trifolia var. sinensis (Alismataceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed for the aquatic plant Sagittaria trifolia var. sinensis to assess its genetic diversity and population structure. Cross-species transferability was assayed in eight congeneric species. METHODS AND RESULTS: Seventeen microsatellite markers were isolated and characterized in Sagittaria trifolia var. sinensis using Fast Isolation by AFLP of Sequence COntaining Repeats (FIASCO) protocol. Across the evaluated populations, 14 of the markers showed polymorphisms with 3 to 11 alleles per locus; the observed and expected heterozygosity (H(o) and H(E)) ranged from 0.0000 to 0.6364 and from 0.0000 to 0.8386, respectively. Nine of the loci were successfully amplified in the congeneric species. CONCLUSIONS: These markers will be useful for further investigation of population genetics in Sagittaria trifolia var. sinensis and related research in Sagittaria species. PMID- 21613104 TI - Polymorphic microsatellite markers in the invasive shrub Buddleja davidii (Scrophulariaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed for the invasive plant Buddleja davidii, a Chinese shrub that is an invader in most other continents. METHODS AND RESULTS: An invasive population was analyzed using eight di- and tetranucleotide microsatellite loci. The number of alleles per locus ranged from 5 to 14. Due to polyploidy, exact genotypes could not be determined. Progeny arrays were used to study the outcrossing rate using presence/absence data of alleles resulting in an estimate of multilocus outcrossing rate of 93%. The markers were successfully tested in five congeneric species. CONCLUSIONS: The results indicate the utility of these loci in future studies of population genetics and breeding systems in B. davidii and in congeneric species. PMID- 21613105 TI - Development of microsatellite loci for Blastophaga javana (Agaonidae), the pollinating wasp of Ficus hirta (Moraceae). AB - PREMISE OF THE STUDY: To investigate genetic structure of the pollinator and, indirectly, gene flow in its plant host, Blastophaga javana microsatellite primers were developed. METHODS AND RESULTS: Ten polymorphic microsatellite loci were developed using the Fast Isolation by AFLP of Sequences Containing (FIASCO) repeats protocol. Numbers of alleles per locus ranged from 2 to 19, with observed and expected heterozygosities ranging from 0.000 to 0.800 and from 0.000 to 0.925, respectively. CONCLUSIONS: These markers may be useful for further investigation of population genetics of Blastophaga javana and other congeneric species. PMID- 21613106 TI - Root system architecture of Kosteletzkya pentacarpos (Malvaceae) and belowground environmental influences on root and aerial growth dynamics. AB - PREMISE OF THE STUDY: Root growth and architecture of Kosteletzkya pentacarpos and its response to nutrients and soil texture were studied to facilitate domestication of this plant as a biofuel crop (seeds for oil, stems for ethanol). Because it is salt tolerant, it does not compete with food crops for land. METHODS: Four soil treatments in the bottom chambers of two-chambered growing units (three nutrient levels in sandy loam and saline, dredged material) were used to test substrate influences on root structure and aerial growth in a greenhouse study. Simultaneously, underground reserves were determined by collecting aerial biomass of dark-grown plants. Root cores (15 * 50 cm) were taken to determine root architecture of 2-year-old field-grown plants. KEY RESULTS: High nutrient availability increased the coarse root biomass (>=2 mm diameter) and increased capsule production. Plants grown in dredged sediment had no substantial growth differences from the controls. Underground reserves were significant. Field cores demonstrated that roots extended more than 50 cm with most of the coarse roots in the upper 20 cm and the coarse to fine root ratio decreasing with depth. Fine root surface area, measured using image-analysis software, was substantially greater than many other crops, as was root mass density. CONCLUSIONS: Root architecture of K. pentacarpos and its responses to various nutrient levels and soil types demonstrate that it is a promising species for further development as a crop on coastal saline land including dredged material sites. Its perennial taproot system stores carbon and will perform buffer functions between upland and wetlands as sea level rises. PMID- 21613107 TI - Species delimitation and evolution in morphologically and chemically diverse communities of the lichen-forming genus Xanthoparmelia (Parmeliaceae, Ascomycota) in western North America. AB - PREMISE OF THE STUDY: Accurate species delimitation is important for understanding the diversification of biota and has critical implications for ecological and conservation studies. However, a growing body of evidence indicates that morphology-based species circumspection in lichenized fungi misrepresents fungal diversity. The foliose lichen genus Xanthoparmelia includes over 800 species displaying a complex array of morphological and secondary metabolite diversity. METHODS: We used a multifaceted approach, applying phylogenetic, population genetic, and genealogical analyses to delimit species in a single well-supported monophyletic clade containing 10 morphologically and chemically diverse Xanthoparmelia species in western North America. Sequence data from four ribosomal and two low-copy, protein-coding markers, along with chemical and morphological data were used to assess species diversity. KEY RESULTS: We found that traditionally circumscribed species are not supported by molecular data. Rather, all sampled taxa were better represented by three polymorphic population clusters. Our results suggest that secondary metabolite variation may have limited utility in diagnosing lineages within this group, while identified populations clusters did not reflect major phylogeographic or ecological patterns. CONCLUSIONS: In contrast to studies revealing previously undiscovered fungal lineages masked within lichen species circumscribed by traditional morphological and chemical concepts, the present study suggests that species diversity has been overestimated in the species-rich genus Xanthoparmelia. PMID- 21613108 TI - Correlation between pollen aperture pattern and callose deposition in late tetrad stage in three species producing atypical pollen grains. AB - PREMISE OF THE STUDY: Pollen grains of flowering plants display a fascinating diversity of forms, in spite of their minute size. The observed diversity is determined by the developmental mechanisms implicated in the establishment of pollen morphological features. Pollen grains are generally surrounded by an extremely resistant wall interrupted in places by apertures that play a key role in reproduction, being the places at which pollen tube growth is initiated. Aperture shape, number, and position are determined during microsporogenesis (male meiosis), the earliest step in pollen ontogeny. We investigate in detail the unfolding of microsporogenesis in three species that present uncommon aperture pattern (i.e., disulculate in Calycanthus floridus [Calycanthaceae, magnoliids], tetraporate in Hohenbergia stellata [Bromeliaceae, monocots], and monoporate in Typha latifolia [Typhaceae, monocots]). METHODS: We performed a comparative analysis of microsporogenesis and aperture distribution within tetrads in these species with contrasting aperture arrangements. This was done using aniline blue coloration and UV light microscope observations. KEYS RESULTS: We show that aperture localization and features of callose deposition on intersporal walls produced during cytokinesis coincide in all three species examined. Such a correlation suggests that patterns of callose deposition are strongly involved in determining aperture localization. CONCLUSION: In flowering plants, patterns of male meiosis and especially callose deposition following meiosis may be implicated in the diversity of pollen aperture patterns. PMID- 21613109 TI - Significant phorophyte (substrate) bias is not explained by fitness benefits in three epiphytic orchid species. AB - PREMISE: Epiphytes rely on their phorophyte (host substrate) for support; epiphytic orchids also rely on mycorrhizal fungi for germination. Previous studies have proposed a degree of specificity in both interactions. Epiphytic orchids therefore provide an interesting system in which to examine multispecies interactions and the evolution of specialization. METHODS: We examined the potential and actual distributions of three co-occurring, related epiphytic orchid species: Sarcochilus hillii, Plectorrhiza tridentata, and Sarcochilus parviflorus on phorophytes in Australia's temperate dry rainforests. KEY RESULTS: These three small epiphytic orchid species were all biased toward certain woody plant species, in particular, the tree Backhousia myrtifolia, though the extent of specificity varied. Biases toward the most common phorophyte species were not explained by increases in adult orchid fitness, nor did probability of flowering increase on B. myrtifolia. Indeed, individuals on this woody phorophyte tended to have fewer inflorescences than those on other woody phorophytes. Only S. hillii benefited from establishment on B. myrtifolia; it had more leaves on this phorophyte than on others. CONCLUSIONS: In many cases what appear to be simple interactions between two species may be mediated by more complex symbioses. For this system, we propose that the cause for bias in orchid distribution occurs much earlier in an orchid's life and may be due to a bias of their mycorrhizal fungi for the dominant orchid phorophytes. PMID- 21613110 TI - Differential responses to guano fertilization among tropical tree species with varying functional traits. AB - PREMISE OF THE STUDY: Seabirds often cause significant changes to soil properties, and seabird-dominated systems often host unique plant communities. This study experimentally (1) examined species-specific responses to seabird guano gradients, (2) considered the role that differential functional traits among species play in altering plant response to guano, and (3) investigated the implications of seabird guano on range-expanding species. METHODS: Using a greenhouse fertilization experiment, we examined how guano fertilization affects the growth and functional traits of four tree species dominant in the Pacific Islands: Cocos nucifera, Pisonia grandis, Scaevola sericea, and Tournefortia argentea. In these systems, seabirds are frequently found in association with three of these four species; the remaining species, C. nucifera, is a recently proliferating species commonly found in the region but rarely associated with seabirds. KEY RESULTS: We determined that responses to guano addition differed significantly between species in ways that were consistent with predictions based on differing functional traits among species. Notably, we demonstrated that C. nucifera showed no growth responses to guano additions, whereas all seabird associated plants showed strong responses. CONCLUSIONS: These results provide experimental evidence of differential species response to guano additions, suggesting that differences in species functional traits may contribute to changes in plant communities in seabird-dominated areas, with seabird-associated species garnering performance advantages in these high-nutrient environments. Among these species, results also suggest that C. nucifera may have a competitive advantage in low-nutrient environments, providing an unusual example of how a range-expanding plant species can profit from low-nutrient environments. PMID- 21613111 TI - Seed dormancy in Trillium camschatcense (Melanthiaceae) and the possible roles of light and temperature requirements for seed germination in forests. AB - PREMISE OF THE STUDY: Seeds of some temperate plants require multiple treatments to break complex forms of dormancy, such as deep simple double morphophysiological dormancy (MPD), but embryo growth and radicle and cotyledon emergence have not been studied in depth for this level of MPD. Here we studied Trillium camschatcense, a species that is purported to have this MPD and that is sensitive to habitat fragmentation with decreased recruitment at forest edges. METHODS: Trillium camschatcense seeds were collected and experiments conducted in Hokkaido, Japan over 5 years. Growth of embryos and emergence of radicles and cotyledons were tracked in relation to field temperature to determine specific temperature and light requirements for these stages under laboratory conditions. KEY RESULTS: Low (winter) temperatures overcame dormancy in the underdeveloped embryos, and embryo growth and radicle emergence occurred between July and September, ca. 1 year after seed dispersal. Radicles emerged optimally over a narrow temperature range (20-25 degrees C), in darkness, and at constant temperatures. Roots developed during the second autumn. Cotyledons needed a second low temperature (second winter) to emerge from seeds with roots, doing so in April, slightly over 1.5 years after dispersal. CONCLUSIONS: Seeds of T. camschatcense have deep simple double MPD and requirements for radicle emergence: darkness and constant temperatures. Ecologically, edges of forests may be deleterious for germination of the species due to increased light and to higher temperature fluctuations as compared to the interiors of forests. Thus, these specific requirements may play an important role in reducing seed germination of this plant at forest edges. PMID- 21613112 TI - Changes in expression pattern of the teosinte branched1-like genes in the Zingiberales provide a mechanism for evolutionary shifts in symmetry across the order. AB - PREMISE OF THE STUDY: Floral symmetry is a trait of key importance when considering floral diversification because it is thought to play a significant role in plant-pollinator interactions. The CYCLOIDEA/TEOSINTE BRANCHED1 (CYC/TB1) like genes have been implicated in the development and evolution of floral symmetry in numerous lineages. We thus chose to investigate a possible role for these genes in the evolution of floral symmetry within petaloid monocots, using the order Zingiberales as a model system. In the Zingiberales, evolutionary shifts in symmetry have occurred in all floral whorls, making the order ideal for studying the evolution of this ecologically significant trait. METHODS: We analyzed TB1-like (TBL) genes from taxa spanning the order in a phylogenetic context. Using RNA in situ hybridization, we examined the expression of two TBL genes in Costus spicatus (Costaceae) and Heliconia stricta (Heliconiaceae), taxa with divergent floral symmetry patterns. KEY RESULTS: We identified Zingiberales specific gene duplications as well as a duplication in the TBL gene lineage that predates the diversification of commelinid monocots. Shifts in TBL gene expression were associated with evolutionary shifts in floral symmetry and stamen abortion. ZinTBL1a expression was found in the posterior (adaxial) staminode of H. stricta and in the abaxial staminodial labellum of C. spicatus. ZinTBL2 expression was strongest in the anterior (abaxial) sepals of H. stricta and in the adaxial fertile stamen of C. spicatus. CONCLUSIONS: This study adds to the growing body of evidence that CYC/TB1-like genes have been repeatedly recruited throughout the course of evolution to generate bilateral floral symmetry (zygomorphy). PMID- 21613113 TI - Angiosperm leaf vein patterns are linked to leaf functions in a global-scale data set. AB - PREMISE OF THE STUDY: Leaves are plants' primary interface with the atmosphere and affect a range of ecological processes. Vein patterns are one of the most prominent aspects of leaf form, and the functional significance of different vein patterns is gaining increasing attention. METHODS: Phylogenetic and standard ANOVA and regression were used to provide the first global-scale, phylogenetically based test of relations between angiosperm vein patterns and leaf functional traits. Pagel's lambda was used to test for phylogenetic signal in all traits. KEY RESULTS: All leaf traits had significant phylogenetic signal. Significant phylogenetically based relations were found between secondary vein pattern and leaf functions, linking leaf form to the well-known trade-off between physiological activity and leaf life span. The relations between primary vein pattern and leaf functions were not found to be significant with phylogenetic tests, suggesting these relations may be the result of changes within a few lineages, followed by phylogenetic conservatism, rather than multiple instances of correlated trait evolution. The relation between minor vein density and maximum photosynthetic rate was found to be marginally nonsignificant with phylogenetic regression, which does not rule out coordinated evolution of hydraulic supply and demand. CONCLUSIONS: Although phylogenetic conservatism may weaken statistical relations between vein patterns and leaf functions, phylogenetic relations can provide a complementary source of information for inferring unmeasured values of leaf traits. Relations among vein patterns, leaf functions, and phylogeny will be valuable for estimating functional attributes of living and fossil plant species and communities. PMID- 21613114 TI - Diversity gradients and phylogeographic patterns in Santiria trimera (Burseraceae), a widespread African tree typical of mature rainforests. AB - PREMISE OF THE STUDY: New insights into the history of the African rainforest can be gathered from the phylogeographic structures of their constituent species, but few studies have been performed in this ecosystem. We studied the phylogeographic structure of Santiria trimera, a primate- and bird-dispersed, dioecious tree typical of mature African rainforests. METHODS: We sequenced three chloroplast DNA (cpDNA) regions (trnL-F, rbcL, and rpl36-infA-rps8) in 377 individuals from 42 populations. RESULTS: Sequence chromatograms regularly displayed double peaks of unequal heights. Cloning of PCR products and sequencing of outgroup taxa led to assigning the taller peak in ambiguous sequence positions to cpDNA. A total of 14 polymorphic cpDNA sites and 12 haplotypes were detected. Populations from three distinct biogeographic regions, namely, Upper Guinea, Lower Guinea, and the volcanic island of Sao Tome, did not share any haplotype, indicating allopatric divergence. In Lower Guinea, Gabonese forests had high diversity mainly from the sympatry of two genetically divergent morphotypes, whereas forests of eastern Cameroon were less diversified. The two haplotypes of the morphotype without stilt roots were distributed north and south of the Ogooue River, suggesting refuges on both sides of the river bed. CONCLUSIONS: The divergence between Upper and Lower Guinean rainforests is explained by the discontinuity of forest between those regions throughout most of the Quaternary. The distribution of rare endemic haplotypes concurred with proposed Pleistocene rainforest refuges in west and southwest Cameroon. Overall, phylogeographic structure is consistent with the biogeographic hypotheses largely based on patterns of species diversity. PMID- 21613115 TI - Stigmatic receptivity in a dichogamous early-divergent angiosperm species, Annona cherimola (Annonaceae): influence of temperature and humidity. AB - PREMISE OF THE STUDY: A variety of mechanisms to prevent inbreeding have arisen in different angiosperm taxa during plant evolution. In early-divergent angiosperms, a widespread system is dichogamy, in which female and male structures do not mature simultaneously, thus encouraging cross pollination. While this system is common in early-divergent angiosperms, it is less widespread in more recently evolved clades. An evaluation of the consequences of this system on outbreeding may provide clues on this change, but this subject has been little explored. METHODS: In this work, we characterized the cycle and anatomy of the flower and studied the influence of temperature and humidity on stigmatic receptivity in Annona cherimola, a member of an early-divergent angiosperm clade with protogynous dichogamy. KEY RESULTS: Paternity analysis reveals a high proportion of seeds resulting from self-fertilization, indicating that self pollination can occur in spite of the dichogamous system. Stigmatic receptivity is environmentally modulated--shortened by high temperatures and prolonged by high humidity. CONCLUSIONS: Although spatial and temporal sexual separation in this system seems to effectively decrease selfing, the system is modulated by environmental conditions and may allow high levels of selfing that can guarantee reproductive assurance. PMID- 21613116 TI - Experimental floral and inflorescence trait manipulations affect pollinator preference and function in a hummingbird-pollinated plant. AB - PREMISE OF THE STUDY: Controversy is ongoing regarding the importance of pollinator-mediated selection as a source of observed patterns of floral diversity. Although increasing evidence exists of pollinator-mediated selection acting on female reproductive success, there is still limited understanding of pollinator-mediated selection on floral traits via male reproductive success. Here we quantify potential selection by the ruby-throated hummingbird, Archilochus colubris, on four floral traits of hermaphroditic Silene exerted through male floral function. METHODS: In single trait manipulative experiments we quantified hummingbird visitation preference and/or fluorescent dye (a pollen analog) donation as a function of number of flowers displayed (inflorescence size), height of the floral display (inflorescence height), floral color, and corolla tube length. KEY RESULTS: Hummingbirds preferred to visit larger floral displays and floral displays at greater height, likely representing a general pollinator preference for larger, more visible signals and/or greater rewards. In addition, hummingbirds preferred to visit red flowers, and male function was greater in flowers manipulated to have longer corolla tubes. CONCLUSIONS: Selection pressures exerted by hummingbirds on S. virginica floral and inflorescence design through male reproductive success are consistent with the contemporary expression of floral traits of S. virginica relative to related Silene species with different pollinators, and they are consistent with the hummingbird syndrome of traits expressed by S. virginica. PMID- 21613117 TI - Effect of local community phylogenetic structure on pollen limitation in an obligately insect-pollinated plant. AB - PREMISE OF THE STUDY: Pollination is a key aspect of ecosystem function in the majority of land plant communities. It is well established that many animal pollinated plants suffer lower seed set than they are capable of, likely because of competition for pollinators. Previously, competition for pollinator services has been shown to be most intense in communities with the greatest plant diversity. In spite of the fact that community evolutionary relations have a demonstrated impact on many ecological processes, their role in competition for pollinator services has rarely been examined. METHODS: In this study, we explore relations among several aspects of the surrounding plant community, including species richness, phylodiversity, evolutionary distance from a focal species, and pollen limitation in an annual insect-pollinated plant. KEY RESULTS: We did not find a significant effect of species richness on competition for pollination. However, consistent with a greater role for facilitation than competition, we found that a focal species occurring in communities composed of species of close relatives, especially other members of the Asteraceae, was less pollen limited than when it occurred in communities composed of more distant relatives. CONCLUSIONS: Our results demonstrate that community phylodiversity is an important correlate of pollen limitation in this system and that it has greater explanatory power than species richness alone. PMID- 21613118 TI - Conservation biogeography of red oaks (Quercus, section Lobatae) in Mexico and Central America. AB - PREMISE OF THE STUDY: Oaks are dominant trees and key species in many temperate and subtropical forests in the world. In this study, we analyzed patterns of distribution of red oaks (Quercus, section Lobatae) occurring in Mexico and Central America to determine areas of species richness and endemism to propose areas of conservation. METHODS: Patterns of richness and endemism of 75 red oak species were analyzed using three different units. Two complementarity algorithms based on species richness and three algorithms based on species rarity were used to identify important areas for conservation. A simulated annealing analysis was performed to evaluate and formulate effective new reserves for red oaks that are useful for conserving the ecosystems associated with them after the systematic conservation planning approach. KEY RESULTS: Two main centers of species richness were detected. The northern Sierra Madre Oriental and Serranias Meridionales of Jalisco had the highest values of endemism. Fourteen areas were considered as priorities for conservation of red oak species based on the 26 priority political entities, 11 floristic units and the priority grid-cells obtained in the complementarity analysis. In the present network of Natural Protected Areas in Mexico and Central America, only 41.3% (31 species) of the red oak species are protected. The simulated annealing analysis indicated that to protect all 75 species of red oaks, 12 current natural protected areas need to be expanded by 120000 ha of additional land, and 26 new natural protected areas with 512500 ha need to be created. CONCLUSIONS: Red oaks are a useful model to identify areas for conservation based on species richness and endemism as a result of their wide geographic distribution and a high number of species. We evaluated and reformulated new reserves for red oaks that are also useful for the conservation of ecosystems associated with them. PMID- 21613119 TI - Phylogeny of the clusioid clade (Malpighiales): evidence from the plastid and mitochondrial genomes. AB - PREMISE OF THE STUDY: The clusioid clade includes five families (i.e., Bonnetiaceae, Calophyllaceae, Clusiaceae s.s., Hypericaceae, and Podostemaceae) represented by 94 genera and ~1900 species. Species in this clade form a conspicuous element of tropical forests worldwide and are important in horticulture, timber production, and pharmacology. We conducted a taxon-rich multigene phylogenetic analysis of the clusioids to clarify phylogenetic relationships in this clade. METHODS: We analyzed plastid (matK, ndhF, and rbcL) and mitochondrial (matR) nucleotide sequence data using parsimony, maximum likelihood, and Bayesian inference. Our combined data set included 194 species representing all major clusioid subclades, plus numerous species spanning the taxonomic, morphological, and biogeographic breadth of the clusioid clade. KEY RESULTS: Our results indicate that Tovomita (Clusiaceae s.s.), Harungana and Hypericum (Hypericaceae), and Ledermanniella s.s. and Zeylanidium (Podostemaceae) are not monophyletic. In addition, we place four genera that have not been included in any previous molecular study: Ceratolacis, Diamantina, and Griffithella (Podostemaceae), and Santomasia (Hypericaceae). Finally, our results indicate that Lianthus, Santomasia, Thornea, and Triadenum can be safely merged into Hypericum (Hypericaceae). CONCLUSIONS: We present the first well-resolved, taxon-rich phylogeny of the clusioid clade. Taxon sampling and resolution within the clade are greatly improved compared to previous studies and provide a strong basis for improving the classification of the group. In addition, our phylogeny will form the foundation for our future work investigating the biogeography of tropical angiosperms that exhibit Gondwanan distributions. PMID- 21613120 TI - Recovery from bud disappearance explains prolonged dormancy in Cleistes bifaria (Orchidaceae). AB - PREMISE OF THE STUDY: Virtually nothing is known about what actually happens during prolonged dormancy, the period during which significant proportions of geophyte populations do not sprout after seasonal dormancy but remain alive underground, to emerge again 1 or more years later. This study investigated the fate of perennating buds on plants of the orchid Cleistes bifaria during prolonged dormancy, as well as effects of bud removal on dormancy and future sprouting. METHODS: Fates of healthy perennating buds were observed by examining underground plant structures over an annual cycle (fall, spring, fall). Effects of bud loss were assessed by removal of mature buds from one group of plants, followed by comparison with a control group a year later. KEY RESULTS: Of the 142 perennating buds under observation, 38% did not emerge in the spring, and all these were missing the buds that were present and healthy the previous fall. Removal of perennating buds in the fall did not affect whether a plant emerged in the spring; however, it reduced the number and size of perennating buds produced for the following year. CONCLUSIONS: For C. bifaria in West Virginia, prolonged dormancy appears to be the time period during which plants are recovering from the disappearance of perennating buds. Although the cause of bud loss remains unknown, research can now be focused on whether other species fail to emerge for the same reason, what causes buds to disappear, and why removal had no effect on spring emergence but negatively affected future sprouting. PMID- 21613121 TI - Microsatellite loci in Vallisneria natans (Hydrocharitaceae) and cross-reactivity with V. spinulosa and V. denseserrulata. AB - PREMISE OF THE STUDY: Microsatellite primers were characterized in Vallisneria natans, a dominant submerged macrophyte occurring in freshwater bodies of tropical and subtropical zones. METHODS AND RESULTS: Using the Microsatellite Sequence Enrichment protocol, 16 novel polymorphic codominant loci were developed and characterized in V. natans. In addition to these, six existing microsatellite loci from V. spinulosa were successfully amplified and characterized for V. natans. These primers amplified di- and trinucleotide repeats with 2-7 alleles per locus. Most primers also amplified successfully in V. spinulosa and V. denseserrulata. CONCLUSIONS: These results indicate the utility of primers in V. natans for future studies of population genetic structure, as well as their applicability across the genus. PMID- 21613122 TI - Microsatellite marker development for Galax urceolata (Diapensiaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed for Galax urceolata to investigate genetic diversity, population structure, and polyploid origins (auto- vs. allopolyploid), and to estimate the minimum number of independent cytotype origins. METHODS AND RESULTS: Ten primer sets have been developed, and preliminary study indicates that all loci are appropriate for population-level genetic investigations. All loci are polymorphic with 6 to 46 alleles per locus. Expected heterozygosity ranges from 0.1007 to 0.6085. CONCLUSIONS: The microsatellite markers presented will facilitate analyses of polyploid origins, genetic diversity, geographic structure, and gene flow. PMID- 21613123 TI - A new approach to improve the scoring of mononucleotide microsatellite loci. AB - PREMISE OF THE STUDY: Mononucleotide microsatellites markers are useful for detecting genetic variation among individuals; however, scoring can be error prone. We developed a new approach to improve the accuracy of allele scoring. METHODS AND RESULTS: A set of 14 mononucleotide microsatellite primers of the chloroplast were developed based on published Pinus spp. chloroplast genomes. Due to substantial scoring error for mononucleotide repeats>=10 bp, we included part of the microsatellite in the reverse primer to reduce slippage and improve the scoring of these polymorphic markers. For markers 10-20 bp, the error rate in scoring with this method has a binomial 95% confidence interval of 0.7-2.1%. CONCLUSIONS: These new primers provide variable chloroplast markers in species of subsection Cembroides and other Pinus spp. with more accurate assignment of the alleles. This approach can be used to improve the allele scoring of mononucleotide or dinucleotide repeats from nuclear and chloroplast genomes. PMID- 21613124 TI - Genome-specific SCAR markers help solve taxonomy issues: a case study with Sinapis arvensis (Brassiceae, Brassicaceae). AB - PREMISE OF THE STUDY: Traditional taxonomy and nomenclature of Brassiceae (Brassicaceae) species do not reflect their phylogeny. Revision of the species and generic limits supported by extensive molecular data seems crucial. METHODS AND RESULTS: Genome-specific polymorphisms extracted from non-coding and coding sequences were used to develop 14 sequence characterized amplified region (SCAR) markers specific for the Brassica B genome. These SCARs were verified against 77 accessions of six U-triangle Brassica species and used to screen 23 accessions of seven wild Brassiceae species to test for their cross-species amplification. SCARs were found in all B-genome Brassica species and also in Sinapis arvensis. CONCLUSIONS: SCAR markers can be employed for discerning B-genome chromosomes in Brassica species and S. arvensis to reliably identify B-genome species and their natural hybrids. The combined molecular evidence supports the suggestion to revise the generic limits of Brassica and Sinapis. PMID- 21613125 TI - Microsatellite marker development for the federally listed Prunus geniculata (Rosaceae). AB - PREMISE OF THE STUDY: Prunus geniculata is a federally listed species endemic to the central Florida scrub. To investigate levels and geographic partitioning of genetic variation in this species, we developed microsatellite markers for P. geniculata and its sister species, P. maritima. METHODS AND RESULTS: Following a protocol optimized in our laboratory, we designed 36 primer pairs, of which 8 amplified across both species and showed informative polymorphism. Product size varied from 163 to 370 bp, and the number of alleles ranged from 5 to 27. He across all populations ranged from 0.604 to 0.9155. CONCLUSIONS: Eight loci were useful at the population level and will be used for conservation genetic and phylogeographic studies of Prunus geniculata and P. maritima. Furthermore, from five to all eight of these loci can also be amplified in several other North American Prunus species. PMID- 21613126 TI - Microsatellite markers in the traditional Chinese medicinal herb Gynostemma pentaphyllum (Cucurbitaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed for Gynostemma pentaphyllum, a traditional Chinese medicinal herb, to investigate its population genetic diversity. METHODS AND RESULTS: Using the Microsatellite Sequence Enrichment protocol, 14 polymorphic primers sets were identified in four Chinese Gynostemma pentaphyllum populations. The primers amplified di- and trinucleotide repeats with 1-6 alleles per locus, and the observed heterozygosities ranged from 0.000 to 1.000 per population. CONCLUSIONS: These markers will facilitate further studies on genetic structure and gene flow of Gynostemma pentaphyllum populations. PMID- 21613127 TI - Isolation of compound microsatellite markers for the common Mediterranean shrub Smilax aspera (Smilacaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed for the common Mediterranean shrub Smilax aspera to study the population genetics of this species. METHODS AND RESULTS: Using the compound microsatellite marker technique, a total of 14 pairs of primers were developed for S. aspera, of which 11 were polymorphic, and three were monomorphic. Levels of polymorphism in the 11 markers were checked in 43 individuals collected from two populations in Greece and Italy. The number of alleles per locus ranged from 10 to 26, with an average of 15.55 alleles per locus. All of these primers also could be amplified from a second species, S. hispida. CONCLUSIONS: These microsatellite markers can be used for future studies of genetic diversity in S. aspera, as well as in other related taxa, and will help us to improve our understanding of the microevolutionary processes of this species in the Mediterranean region. PMID- 21613128 TI - Characterization of microsatellite loci in Yucca brevifolia (Agavaceae) and cross amplification in related species. AB - PREMISE OF THE STUDY: Microsatellite primers were characterized in Yucca brevifolia for use in population genetic studies and, particularly, analyses of gene flow between varieties. METHODS AND RESULTS: We characterized 12 microsatellite loci polymorphic in Yucca brevifolia by screening primers that were developed using an SSR-enriched library or which were previously described in Yucca filamentosa. Genetic analysis of four populations resulted in the mean number of alleles per locus ranging from 10.25 to 14.58 and mean expected heterozygosity from 0.78 to 0.88. Cross-amplification of all 12 loci was attempted in six additional yucca species. CONCLUSIONS: These loci should prove useful for population genetic research in Yucca brevifolia, and cross amplification of these loci in related species suggests that they may be useful in studies of hybridization and introgression between species. PMID- 21613129 TI - Introduction to special issue on biodiversity. PMID- 21613130 TI - The age and diversification of terrestrial New World ecosystems through Cretaceous and Cenozoic time. AB - Eight ecosystems that were present in the Cretaceous about 100 Ma (million years ago) in the New World eventually developed into the 12 recognized for the modern Earth. Among the forcing mechanisms that drove biotic change during this interval was a decline in global temperatures toward the end of the Cretaceous, augmented by the asteroid impact at 65 Ma and drainage of seas from continental margins and interiors; separation of South America from Africa beginning in the south at ca. 120 Ma and progressing northward until completed 90-100 Ma; the possible emission of 1500 gigatons of methane and CO(2) attributed to explosive vents in the Norwegian Sea at ca. 55 Ma, resulting in a temperature rise of 5 degrees -6 degrees C in an already warm world; disruption of the North Atlantic land bridge at ca. 45 Ma at a time when temperatures were falling; rise of the Andes Mountains beginning at ca. 40 Ma; opening of the Drake Passage between South America and Antarctica at ca. 32 Ma with formation of the cold Humboldt at ca. 30 Ma; union of North and South America at ca. 3.5 Ma; and all within the overlay of evolutionary processes. These processes generated a sequence of elements (e.g., species growing in moist habitats within an overall dry environment; gallery forests), early versions (e.g., mangrove communities without Rhizophora until the middle Eocene), and essentially modern versions of present-day New World ecosystems. As a first approximation, the fossil record suggests that early versions of aquatic communities (in the sense of including a prominent angiosperm component) appeared early in the Middle to Late Cretaceous, the lowland neotropical rainforest at 64 Ma (well developed by 58-55 Ma), shrubland/chaparral woodland-savanna and grasslands around the middle Miocene climatic optimum at ca. 15-13 Ma, deserts in the middle Miocene/early Pliocene at ca. 10 Ma, significant tundra at ca. 7-5 Ma, and alpine tundra (paramo) shortly thereafter when cooling temperatures were augmented by high elevations attained, for example, in the Andes<10 Ma and especially after 7-6 Ma. PMID- 21613131 TI - Bryophyte diversity and evolution: windows into the early evolution of land plants. AB - The "bryophytes" comprise three phyla of plants united by a similar haploid dominant life cycle and unbranched sporophytes bearing one sporangium: the liverworts (Marchantiophyta), mosses (Bryophyta), and hornworts (Anthocerophyta). Combined, these groups include some 20000 species. As descendents of embryophytes that diverged before tracheophytes appeared, bryophytes offer unique windows into the early evolution of land plants. We review insights into the evolution of plant life cycles, in particular the elaboration of the sporophyte generation, the major lineages within bryophyte phyla, and reproductive processes that shape patterns of bryophyte evolution. Recent transcriptomic work suggests extensive overlap in gene expression in bryophyte sporophytes vs. gametophytes, but also novel patterns in the sporophyte, supporting Bower's antithetic hypothesis for origin of alternation of generations. Major lineages of liverworts, mosses, and hornworts have been resolved and general patterns of morphological evolution can now be inferred. The life cycles of bryophytes, arguably more similar to those of early embryophytes than are those in any other living plant group, provide unique insights into gametophyte mating patterns, sexual conflicts, and the efficacy and effects of spore dispersal during early land plant evolution. PMID- 21613132 TI - Evolutionary diversification of the flowers in angiosperms. AB - Angiosperms and their flowers have greatly diversified into an overwhelming array of forms in the past 135 million years. Diversification was shaped by changes in climate and the biological environment (vegetation, interaction with other organisms) and by internal structural constraints and potentials. This review focuses on the development and structural diversity of flowers and structural constraints. It traces floral diversification in the different organs and organ complexes (perianth, androecium, gynoecium) through the major clades of extant angiosperms. The continuously improved results of molecular phylogenetics provide the framework for this endeavor, which is necessary for the understanding of the biology of the angiosperms and their flowers. Diversification appears to work with innovations and modifications of form. Many structural innovations originated in several clades and in special cases could become key innovations, which likely were hot spots of diversification. Synorganization between organs was an important process to reach new structural levels, from which new diversifications originated. Complexity of synorganization reached peaks in Orchidaceae and Apocynaceae with the independent evolution of pollinaria. Such a review throughout the major clades of angiosperms also shows how superficial and fragmentary our knowledge on floral structure in many clades is. Fresh studies and a multidisciplinary approach are needed. PMID- 21613133 TI - Reduce, reuse, and recycle: developmental evolution of trait diversification. AB - A major focus of evolutionary developmental (evo-devo) studies is to determine the genetic basis of variation in organismal form and function, both of which are fundamental to biological diversification. Pioneering work on metazoan and flowering plant systems has revealed conserved sets of genes that underlie the bauplan of organisms derived from a common ancestor. However, the extent to which variation in the developmental genetic toolkit mirrors variation at the phenotypic level is an active area of research. Here we explore evidence from the angiosperm evo-devo literature supporting the frugal use of genes and genetic pathways in the evolution of developmental patterning. In particular, these examples highlight the importance of genetic pleiotropy in different developmental modules, thus reducing the number of genes required in growth and development, and the reuse of particular genes in the parallel evolution of ecologically important traits. PMID- 21613134 TI - Understanding angiosperm diversification using small and large phylogenetic trees. AB - How will the emerging possibility of inferring ultra-large phylogenies influence our ability to identify shifts in diversification rate? For several large angiosperm clades (Angiospermae, Monocotyledonae, Orchidaceae, Poaceae, Eudicotyledonae, Fabaceae, and Asteraceae), we explore this issue by contrasting two approaches: (1) using small backbone trees with an inferred number of extant species assigned to each terminal clade and (2) using a mega-phylogeny of 55473 seed plant species represented in GenBank. The mega-phylogeny approach assumes that the sample of species in GenBank is at least roughly proportional to the actual species diversity of different lineages, as appears to be the case for many major angiosperm lineages. Using both approaches, we found that diversification rate shifts are not directly associated with the major named clades examined here, with the sole exception of Fabaceae in the GenBank mega phylogeny. These agreements are encouraging and may support a generality about angiosperm evolution: major shifts in diversification may not be directly associated with major named clades, but rather with clades that are nested not far within these groups. An alternative explanation is that there have been increased extinction rates in early-diverging lineages within these clades. Based on our mega-phylogeny, the shifts in diversification appear to be distributed quite evenly throughout the angiosperms. Mega-phylogenetic studies of diversification hold great promise for revealing new patterns, but we will need to focus more attention on properly specifying null expectation. PMID- 21613135 TI - Biodiversity assessment: state-of-the-art techniques in phylogenomics and species identification. AB - PREMISE OF THE STUDY: Biodiversity assessment is the first step in protecting the complete range of morphological and genetic diversity of species on Earth, and in reaching the goals of conservation biology. Assessment begins with identifying organisms that make up biological communities and understanding evolutionary histories. Scientific advancements in molecular sequencing can help clarify and provide support for identifications. Massively parallel DNA sequencing technologies are being used to sequence complete genomes of model organisms; however, this resource has not been fully used for species identifications. Animal researchers commonly use one mitochondrial region, and groups of plant scientists have proposed numerous combinations of two or three chloroplast markers as genomic identifiers. Yet, nearly as many studies have reported that the proposed regions are uninformative in some plant groups and at various taxonomic levels. METHODS: We propose a combination of whole (or nearly whole) chloroplast genomes, mitochondrial genes, and nuclear repeat regions for both species identifications and phylogenetic analyses, obtained from a simple total DNA extraction and one run on massively parallel DNA sequencing machines. KEY RESULTS: We have recovered both coding and noncoding sequences from multiple genetic sources, providing genomic information for comparisons within and between multiple taxonomic levels. CONCLUSIONS: In combination with morphological and other data, this abundance of genomic information will have a broad range of applications, including not only helping conservation biologists understand ecosystem biodiversity, but also understanding the evolutionary histories of organisms, mending damaged landscapes, and investigating interactions of plants with pollinators and pests. PMID- 21613136 TI - The fungi: 1, 2, 3 ... 5.1 million species? AB - PREMISE OF THE STUDY: Fungi are major decomposers in certain ecosystems and essential associates of many organisms. They provide enzymes and drugs and serve as experimental organisms. In 1991, a landmark paper estimated that there are 1.5 million fungi on the Earth. Because only 70000 fungi had been described at that time, the estimate has been the impetus to search for previously unknown fungi. Fungal habitats include soil, water, and organisms that may harbor large numbers of understudied fungi, estimated to outnumber plants by at least 6 to 1. More recent estimates based on high-throughput sequencing methods suggest that as many as 5.1 million fungal species exist. METHODS: Technological advances make it possible to apply molecular methods to develop a stable classification and to discover and identify fungal taxa. KEY RESULTS: Molecular methods have dramatically increased our knowledge of Fungi in less than 20 years, revealing a monophyletic kingdom and increased diversity among early-diverging lineages. Mycologists are making significant advances in species discovery, but many fungi remain to be discovered. CONCLUSIONS: Fungi are essential to the survival of many groups of organisms with which they form associations. They also attract attention as predators of invertebrate animals, pathogens of potatoes and rice and humans and bats, killers of frogs and crayfish, producers of secondary metabolites to lower cholesterol, and subjects of prize-winning research. Molecular tools in use and under development can be used to discover the world's unknown fungi in less than 1000 years predicted at current new species acquisition rates. PMID- 21613137 TI - The generation and maintenance of diversity in microbial communities. AB - Microorganisms play a central role in the regulation of ecosystem processes, and they comprise the vast majority of species on Earth. With recent developments in molecular methods, it has become tractable to quantify the extent of microbial diversity in natural environments. Here we examine this revolution in our understanding of microbial diversity, and we explore the factors that contribute to the seemingly astounding numbers of microbial taxa found within individual environmental samples. We conducted a meta-analysis of bacterial richness estimates from a variety of ecosystems. Nearly all environments contained hundreds to thousands of bacterial taxa, and richness levels increased with the number of individuals in a sample, a pattern consistent with those reported for nonmicrobial taxa. A cursory comparison might suggest that bacterial richness far exceeds the richness levels typically observed for plant and animal taxa. However, the apparent diversity of bacterial communities is influenced by phylogenetic breadth and allometric scaling issues. When these features are taken into consideration, the levels of microbial diversity may appear less astounding. Although the fields of ecology and biogeography have traditionally ignored microorganisms, there are no longer valid excuses for neglecting microorganisms in surveys of biodiversity. Many of the concepts developed to explain plant and animal diversity patterns can also be applied to microorganisms once we reconcile the scale of our analyses to the scale of the organisms being observed. Furthermore, knowledge from microbial systems may provide insight into the mechanisms that generate and maintain species richness in nonmicrobial systems. PMID- 21613138 TI - A phylogenetic basis for species-area relationships among three Pacific Island floras. AB - PREMISE OF THE STUDY: The angiosperm floras of the Hawaiian, Society, and Marquesas archipelagoes are remarkably comparable ecologically and evolutionarily, a result of similar geologic history, climate, and isolation. METHODS: We characterized variation in species richness among islands and whole archipelagoes by analyzing species-area relationships (SARs). By partitioning each flora into putative phylogenetic lineages each derived from a given colonization event, we explored several ways in which speciation contributes to SARs. KEY RESULTS: Specifically, these groups exhibit expected island SARs and a whole archipelago SAR characterized by a steep slope. The number of species added by net cladogenesis increases with area much more quickly than the number contributed by net colonization from outside. In each of the three archipelagoes, most colonists do not speciate, while many species occur in a few diverse colonist lineages. Colonization events that are unique to a given archipelago are in more prone to speciation than lineages with close relatives in the other archipelagoes. Most lineages with relatives in all three archipelagoes have one species in each, suggesting a similar tendency not to diversify. On the other hand, a correlation between lineage size in one archipelago and that of related lineages in other archipelagoes suggests a consistent tendency among diverse groups to speciate extensively. Lineages with multiple species in each archipelago also tend to have far more species in the largest archipelago, the Hawaiian Islands. CONCLUSIONS: The most diverse lineages exhibit a strong response to archipelago area. These diverse, area-sensitive lineages contribute substantially to the slope of the inter-archipelago SAR. Regional species pools elsewhere may exhibit similar steep-sloped SARs; thus, these findings may inform how the behavior of lineages with different responses to increasing shapes these patterns. PMID- 21613139 TI - Factors influencing diversification in angiosperms: at the crossroads of intrinsic and extrinsic traits. AB - Recent studies indicate that both key innovations and available area influence species richness in angiosperms. Available area has been observed to have the greatest effect, however, and appears to alter the "carrying capacity" of a lineage rather than alter diversification rates. Here, we review and weigh the evidence of predictors of angiosperm diversification and further dissect how area can place ecological limits on diversification of angiosperms, specifically addressing the following: (1) theoretical mechanisms by which particular intrinsic and extrinsic traits may affect diversification in angiosperm families; (2) evidence that the amount of available area determines the ecological limits on lineages; and (3) geographical distribution of diversification hotspots in angiosperms, concentrating on the effects of zygomorphy, noncontiguous area, and latitude. While we found that dispersal to numerous noncontiguous areas is most important in spurring diversification, diversification of tropical and zygomorphic families appears to be elevated by the generation of more species per given area. PMID- 21613140 TI - The role of evolutionary processes in producing biodiversity patterns, and the interrelationships between taxonomic, functional and phylogenetic biodiversity. AB - Patterns of biodiversity are ultimately the product of speciation and extinction. Speciation serves as the biodiversity pump while extinction serves as the agent that culls global to local levels of biodiversity. Linking these central processes to global and local patterns of biodiversity is a key challenge in both ecology and evolution. This challenge necessarily requires a simultaneous consideration of the species, phylogenetic, and functional diversity across space and the tree of life. In this review, I outline a research framework for biodiversity science that considers the evolutionary and ecological processes that generate and cull levels of biodiversity and that influence the inter relationships between species, phylogenetic, and functional diversity. I argue that a biodiversity synthesis must begin with a consideration of the inherently ecological process of speciation and end with how global biodiversity is filtered into local-scale plant communities. The review ends with a brief outlook on future challenges for those studying biodiversity, including outstanding hypotheses that need testing and key data limitations. PMID- 21613141 TI - Linking biodiversity patterns by autocorrelated random sampling. AB - Biodiversity macroecology deals with the commonly measured variables of abundance, distribution, occupancy, and range size across two scales: the local (or alpha) and regional (gamma). There are ca. 15 patterns consisting of the frequency distributions of the variables, variables as a function of area or sample size, and interrelationships between variables that appear to be very general if not close to universal. A number of links can be drawn between these patterns. In particular, I show that local communities can be seen as random samples of the regional pool, but only as a special form of sampling that is autocorrelated due to the spatial clumping of individuals within a species. I describe two distinct sets of mathematical machinery that can start with the regional species abundance distribution and then predict local species richness, local species abundance distributions, and beta-diversity (in the form of species area relationships or decay of similarity with distance). I conclude by examining some of the implications of the fact that biodiversity patterns are linked by autocorrelated sampling. PMID- 21613142 TI - The disentangled bank: how loss of habitat fragments and disassembles ecological networks. AB - Habitat transformation is one of the leading causes of changes in biodiversity and the breakdown of ecosystem function and services. The impacts of habitat transformation on biodiversity are complex and can be difficult to test and demonstrate. Network approaches to biodiversity science have provided a powerful set of tools and models that are beginning to present new insight into the structural and functional effects of habitat transformation on complex ecological systems. We propose a framework for studying the ways in which habitat loss and fragmentation jointly affect biodiversity by altering both habitat and ecological interaction networks. That is, the explicit study of "networks of networks" is required to understand the impacts of habitat change on biodiversity. We conduct a broad review of network methods and results, with the aim of revealing the common approaches used by landscape ecology and community ecology. We find that while a lot is known about the consequences of habitat transformation for habitat network topology and for the structure and function of simple antagonistic and mutualistic interaction networks, few studies have evaluated the consequences for large interaction networks with complex and spatially explicit architectures. Moreover, almost no studies have been focused on the continuous feedback between the spatial structure and dynamics of the habitat network and the structure and dynamics of the interaction networks inhabiting the habitat network. We conclude that theory and experiments that tackle the ecology of networks of networks are needed to provide a deeper understanding of biodiversity change in fragmented landscapes. PMID- 21613143 TI - Linking soil biodiversity and vegetation: implications for a changing planet. AB - Soil biota are intimately tied to plant communities through herbivory and symbiosis and indirectly by the decomposition of dead organic plant material. Through both roots and aboveground organic material (e.g., leaves and wood), plants provide substantial inputs of organic matter to soil systems. Plants are the basis for most biotic soil food webs that comprise an enormous diversity of species whose multiple interactions function to help regulate nutrient cycling, which in turn influences plant growth. Many factors govern the biogeography of soil biota, including the physical and chemical properties of soil, climate, the composition and type of vegetation, and interactions with other soil biota. Despite awareness of factors influencing soil communities, no single factor allows predictions of soil animal diversity or distribution. However, research is showing that plants can have unique soil biotic communities. Degradation of soil, which removes predators and biotic regulation that occurs in less managed ecosystems, can result in increased pathogens and pests that affect humans, other animals and plants. Global changes such as land use, desertification, and soil pollution all have been shown to alter soil animal diversity and abundance. Because of our dependence on soils and plant production, studies linking soil biotic communities to primary productivity are needed to assure long-term soil sustainability. PMID- 21613144 TI - The future of plant-pollinator diversity: understanding interaction networks across time, space, and global change. AB - Structural analysis of plant-pollinator networks has revealed remarkably high species and interaction diversity and highlighted the species important for pollination services. Although techniques to analyze plant-pollinator networks began to emerge a decade ago, the characterization of spatiotemporal variation of interactions is still in its infancy. Understanding the ecological and evolutionary causes and consequences of spatial and temporal variation in plant pollinator interactions is important for both basic and applied questions in community structure and function, the evolution of floral traits, and the development of optimal conservation strategies. Here we review observational, theoretical, and experimental studies of temporal and spatial variation in plant pollinator interaction networks to establish a foundation for future studies to incorporate perspectives in spatiotemporal variation. Such perspectives are crucial given the rapid environmental changes associated with habitat loss, climate change, and biological invasions, which we discuss in this context. The inherent plasticity of plant-pollinator interactions and network structure suggests that many species should be able to persist by responding to environmental changes quickly, even though the identity of their mutualistic partners may change. PMID- 21613145 TI - A synthesis of plant invasion effects on biodiversity across spatial scales. AB - PREMISE OF THE STUDY: Invasive plant species are typically thought to pose a large threat to native biodiversity, and local-scale studies typically confirm this view. However, plant invaders rarely cause regional extirpations or global extinctions, causing some to suggest that invasive species' influence on native biodiversity may not be so dire. We aim to synthesize the seemingly conflicting literature in plant invasion biology by evaluating the effects of invasive plant species across spatial scales. METHODS: We first conducted a meta-analysis on the effects of invasive plants on the species richness of invaded communities across a range of spatial extents. We then discuss studies that consider the role of invasive plants on regional spatial scales for which such meta-analyses are not possible. Finally, we develop a conceptual framework to synthesize the influence of invasive species across spatial scales by explicitly recognizing how invasive species alter species-occupancy distributions. KEY RESULTS: We found a negative relationship between the spatial extent of the study and the effect size of invasive plants on species richness. Our simulation models suggest that this result can occur if invaders, either proportionately or disproportionately, reduce the occupancy of common species to a greater degree than rare species. CONCLUSIONS: Future studies should consider the influence of invaders on the abundance and occupancy-level changes in native species to inform how invasive plants will influence native species richness relationships across spatial scales. This approach will allow greater predictive ability for forecasting changes in biodiversity in the face of anthropogenic biological invasions and will inform invasive species management and restoration. PMID- 21613146 TI - The restoration of biodiversity: where has research been and where does it need to go? AB - The practice of ecological restoration is a primary option for increasing levels of biodiversity by modifying human-altered ecosystems. The scientific discipline of restoration ecology provides conceptual guidance and tests of restoration strategies, with the ultimate goal of predictive landscape restoration. I construct a conceptual model for restoration of biodiversity, based on site-level (e.g., biotic and abiotic) conditions, landscape (e.g, interpatch connectivity and patch geometry), and historical factors (e.g., species arrival order and land use legacies). I then ask how well restoration ecology has addressed the various components of this model. During the past decade, restoration research has focused largely on how the restoration of site-level factors promotes species diversity-primarily of plants. Relatively little attention has been paid to how landscape or historical factors interplay with restoration, how restoration influences functional and genetic components of biodiversity, or how a suite of less-studied taxa might be restored. I suggest that the high level of variation seen in restoration outcomes might be explained, at least in part, by the contingencies placed on site-level restoration by landscape and historical factors and then present a number of avenues for future research to address these often ignored linkages in the biodiversity restoration model. Such work will require carefully conducted restoration experiments set across multiple sites and many years. It is my hope that by considering how space and time influence restoration, we might move restoration ecology in a direction of stronger prediction, conducted across landscapes, thus providing feasible restoration strategies that work at scales over which biodiversity conservation occurs. PMID- 21613147 TI - Planning, implementing, and monitoring multiple-species habitat conservation plans. AB - PREMISE OF THE STUDY: Despite numerous recommendations for various aspects of the design and monitoring of habitat conservation plans, there remains a need to synthesize existing guidelines into a comprehensive scheme and apply it to real world conservation programs. METHODS: We review tools for systematic conservation planning and elements for designing and implementing ecological monitoring in an adaptive management context. We apply principles of monitoring design to the San Diego Multiple Species Conservation Program (MSCP) in California, USA--one of the first multispecies habitat conservation plans, located in a landscape where high biodiversity and urban development converge. KEY RESULTS: Tools for spatial conservation planning are aimed to conserve biodiversity, often in the context of a limited budget. In practice, these methods may not accommodate legislative mandates, budgetary uncertainties, and the range of implementation mechanisms available across consortia of stakeholders. Once a reserve is implemented, the question becomes whether it is effective at conserving biodiversity, and if not, what actions are required to make it effective. In monitoring plan development, status and threats should be used to prioritize species and communities that require management action to ensure their persistence. Conceptual models documenting the state of knowledge of the system should highlight the main drivers affecting status and trends of species or communities. Monitoring strategies require scientifically justified decisions based on sampling, response, and data design. CONCLUSIONS: Because the framework illustrated here tackles multiple species, communities, and threats at the urban-wildland interface, it will have utility for ecosystem managers struggling to design monitoring programs. PMID- 21613148 TI - The functional role of producer diversity in ecosystems. AB - Over the past several decades, a rapidly expanding field of research known as biodiversity and ecosystem functioning has begun to quantify how the world's biological diversity can, as an independent variable, control ecological processes that are both essential for, and fundamental to, the functioning of ecosystems. Research in this area has often been justified on grounds that (1) loss of biological diversity ranks among the most pronounced changes to the global environment and that (2) reductions in diversity, and corresponding changes in species composition, could alter important services that ecosystems provide to humanity (e.g., food production, pest/disease control, water purification). Here we review over two decades of experiments that have examined how species richness of primary producers influences the suite of ecological processes that are controlled by plants and algae in terrestrial, marine, and freshwater ecosystems. Using formal meta-analyses, we assess the balance of evidence for eight fundamental questions and corresponding hypotheses about the functional role of producer diversity in ecosystems. These include questions about how primary producer diversity influences the efficiency of resource use and biomass production in ecosystems, how primary producer diversity influences the transfer and recycling of biomass to other trophic groups in a food web, and the number of species and spatial /temporal scales at which diversity effects are most apparent. After summarizing the balance of evidence and stating our own confidence in the conclusions, we outline several new questions that must now be addressed if this field is going to evolve into a predictive science that can help conserve and manage ecological processes in ecosystems. PMID- 21613150 TI - Polymorphic microsatellite loci from Dacryodes edulis (Burseraceae), a Central African rainforest and fruit-tree species. AB - PREMISE OF THE STUDY: Microsatellite markers were isolated and characterized from Dacryodes edulis (Burseraceae), a tropical rainforests fruit tree of central Africa. METHODS AND RESULTS: Using an enrichment protocol, six microsatellites loci were developed from Dacryodes edulis. We investigated polymorphism using 45 trees from three widely separated populations in Cameroon. All loci were polymorphic, with the number of alleles ranging from 2 to 15. Polymorphism was widely variable among loci and expected heterozygosities ranged from 0.06 to 0.84 with a mean value of 0.49. CONCLUSIONS: These loci will be useful for the in depth analysis of population structure and phylogeographic variation throughout the distribution range of Dacryodes edulis and other related taxa, Dacryodes buettneri and D. normandii, in which all loci were also amplified. Furthermore, they will offer the opportunity to study early domestication processes acting on the genetic diversity of Dacryodes edulis. PMID- 21613149 TI - Cross-species amplification and development of new microsatellite loci for Taxus wallichiana (Taxaceae). AB - PREMISE OF THE STUDY: Previously published and newly developed microsatellite primers for Taxus species were screened for their potential transfer to Taxus wallichiana and to characterize the genetic diversity and population structure of this species. METHODS AND RESULTS: Twenty microsatellite markers that successfully PCR amplified showed polymorphisms when tested on T. wallichiana. Ten of these were obtained by cross-species amplification. The remaining 10 markers were developed in the current study. These markers were characterized on 58 individuals from two T. wallichiana populations from China. Overall, the number of alleles per locus ranged from two to twelve. No significant linkage disequilibrium (LD) was detected between the comparisons of these loci. CONCLUSIONS: The polymorphic microsatellite markers screened in this study will be useful for further investigations of the conservation genetics of the endangered species T. wallichiana. PMID- 21613151 TI - Isolation and characterization of 15 microsatellite markers from the spring orchid (Cymbidium goeringii) (Orchidaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed for the important and popular ornamental spring orchid, Cymbidium goeringii, to investigate its genetic diversity and population genetic structure. METHODS AND RESULTS: Using the Fast Isolation by AFLP of Sequences Containing (FIASCO) repeats protocol, 15 primer sets were identified in two wild populations. The number of alleles per locus ranged from 2 to 5, with a mean of 3.3. The observed and expected heterozygosities varied from 0.167 to 0.917 and from 0.159 to 0.822, respectively. All these primers successfully amplified in the congener C. tortisepalum, and 12 primers were found useful in C. faberi and C. sinense. CONCLUSIONS: These markers will facilitate further studies on the population genetics of Cymbidium goeringii and other congeneric species. PMID- 21613152 TI - Development and characterization of 18 EST-SSR markers in Sonneratia caseolaris. AB - PREMISE OF THE STUDY: Sonneratia caseolaris, a typical mangrove species, is widely distributed in the Indo-West Pacific region. EST-SSR markers were developed for this species to examine its genetic diversity. METHODS AND RESULTS: A total of 18 EST-SSR primer pairs were designed based on the transcriptome sequences of S. caseolaris. Thirteen primer pairs showed polymorphism with one to three alleles per locus when assessed in two populations from China and Australia. The observed heterozygosity and expected heterozygosity ranged from 0 to 0.5000, and 0 to 0.5217 in the Hainan population, and from 0 to 0.2500, and 0 to 0.4891 in the Queensland population, respectively. Thirteen of the 18 primer sets identified in S. caseolaris can be successfully applied to its congener S. alba, and a much lower level of polymorphisms was observed in this widespread species. CONCLUSIONS: These polymorphic EST-SSR markers for S. caseolaris are likely to be useful for future genetic diversity studies. PMID- 21613153 TI - Microsatellite markers in the Australian desert plant, Solanum centrale (Solanaceae). AB - PREMISE OF THE STUDY: The first microsatellite primers were developed for Solanum centrale, a native Australian species used in the bush foods industry. Existing markers developed for other Solanum species were also amplified. METHODS AND RESULTS: Using an enrichment cloning protocol, seven novel markers were developed, and 48 existing markers from other Solanum species were tested, resulting in the characterization of a set of six highly polymorphic co-dominant loci for use in S. centrale. Microsatellite screening revealed polyploidy. Among the six highly polymorphic loci, allelic diversity ranged from 7 to 14. CONCLUSIONS: These markers will be useful for investigating genetic diversity and as a simple way of estimating ploidy of wild populations. PMID- 21613154 TI - Microsatellite primers in the native perennial cycad Cycas taitungensis (Cycadaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed for the native perennial cycad Cycas taitungensis to evaluate the genetic variation of this endangered insular species. METHODS AND RESULTS: Using a magnetic bead enrichment method and EST data, 16 primer sets were developed and identified for the native Taiwan cycad C. taitungensis. The primers amplified dinucleotide, trinucleotide, and complex repeats with 1-9 alleles per locus. Most primers also amplified DNA from C. revoluta and C. debaoensis. CONCLUSIONS: These results indicate the utility of primers for future studies of the genetic structure of C. taitungensis. In addition, the primers are useful for further phylogeographic studies between C. taitungensis and C. revoluta, which is a closely related species. PMID- 21613155 TI - Development of a novel set of microsatellite markers for castor bean, Ricinus communis (Euphorbiaceae). AB - PREMISE OF STUDY: Microsatellite primers were developed for castor bean (Ricinus communis L.) to investigate genetic diversity and population structure, and to provide support to germplasm management. METHODS AND RESULTS: Eleven microsatellite loci were isolated using an enrichment cloning protocol and used to characterize castor bean germplasm from the collection at the Instituto Agronomico de Campinas (IAC). In a survey of 76 castor bean accessions, the investigated loci displayed polymorphism ranging from two to five alleles. CONCLUSIONS: The information derived from microsatellite markers led to significant gains in conserved allelic richness and provides support to the implementation of several molecular breeding strategies for castor bean. PMID- 21613156 TI - Development of microsatellite markers for Aulonemia aristulata (Poaceae) and cross-amplification in other bamboo species. AB - PREMISE OF THE STUDY: Microsatellite primers were developed for Aulonemia aristulata, an endangered species of economic interest, to further describe its genetic variability and population structure. We also tested cross-amplification in 18 other bamboo species. METHODS AND RESULTS: Using an enrichment genomic library, 13 microsatellite loci were isolated and characterized in A. aristulata. Seven of these loci were polymorphic. Twelve markers were cross-amplified in at least ten of the tested bamboo species. CONCLUSIONS: These markers will be useful for studies on the genetic diversity and structure of A. aristulata, which are important for future conservation, management and breeding programs of this species. PMID- 21613157 TI - Microsatellite primers in red bayberry, Myrica rubra (Myricaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed in Myrica rubra to investigate potential hybridization events within or between M. rubra and its closely related species. METHODS AND RESULTS: Using an ISSR-suppression PCR method, 12 primer pairs were temporarily developed with GSG(GT)(6) as the primer for enriching microsatellite sequences and the genomic DNA of M. rubra cv. 'Heijing' as template. The average allele number per locus was 4.9 within 26 individuals including two species, M. rubra and M. nana. Three pairs of primers produced species-specific alleles, and the other nine showed polymorphisms among 26 accessions. CONCLUSIONS: Results indicated that the ISSR-suppression PCR method is suitable for developing microsatellite markers, especially for this species with little understanding of genomic information. The developed microsatellite markers provide a useful tool for further studies of population structure within or between M. rubra and M. nana or other closely related species. PMID- 21613159 TI - Commentary on the de Vega et al. (2010) paper on hyphae in the parasitic plant Cytinus: Mycorrhizal fungi growing within plants are not always mycorrhizal. PMID- 21613158 TI - Development of new microsatellite markers from Mango (Mangifera indica) and cross species amplification. AB - PREMISE OF THE STUDY: Microsatellite markers were developed and characterized to assess the genetic diversity among mango (Mangifera indica) cultivars and to test their amplification in closely related species. METHODS AND RESULTS: Thirty-six microsatellite (simple sequence repeats; SSR) loci were isolated by a microsatellite-enriched partial genomic library method. Primers designed for these loci were characterized using 30 diverse mango cultivars. The number of alleles ranged from 3 to 19 with an average of 9.2 alleles per locus. Polymorphic information content values ranged from 0.185 to 0.920 with a mean of 0.687. The total value for the probability of identity was 2.42 * 10(-31). CONCLUSIONS: The newly identified SSRs would be useful in genetic diversity studies, finger printing, and mapping. Loci from five related species, M. odorata, M. anadamanica, M. zeylanica, M. camptosperma, and M. griffithii, were successfully amplified using these SSR primers, showing their potential utility across species. PMID- 21613160 TI - Mycorrhizal fungi and parasitic plants: Reply. AB - In a recent study (American Journal of Botany 97: 730-737), we described the first case of a tripartite association in natural conditions among a holoparasitic plant (Cytinus), its host Cistaceae species, and mycorrhizal fungi at an anatomical level. In a letter to the editor, Brundrett (American Journal of Botany 98: 595-596) commented on our manuscript and questioned our conclusions, arguing that they are not adequately supported by the data. We reject this point of view and believe that the controversy has arisen because of the parasitic way of life of Cytinus. We maintain and demonstrate that there is enough evidence in the data that we presented to confirm the existence of mycorrhizal associations in the Cytinus-Cistaceae complex, supporting the functionality of the tripartite association. Most holoparasitic plants have been considered as nonmycorrhizal. However, it is not advisable to be categorical in drawing conclusions about the mycorrhizal status of a group of plants that has not been fully studied. PMID- 21613161 TI - Evolution of disparity between the regular and variant phloem in Bignonieae (Bignoniaceae). AB - PREMISE OF THE STUDY: The phloem is a plant tissue with a critical role in plant nutrition and signaling. However, little is still known about the evolution of this tissue. In lianas of the Bignoniaceae, two distinct types of phloem coexist: a regular and a variant phloem. The cells associated with these two phloem types are known to be anatomically different; however, it is still unclear what steps were involved in the evolution of such differences. METHODS: Here we studied the anatomical development of the regular and variant phloem in representatives of all 21 genera of Bignonieae and used a phylogenetic framework to investigate the timing of changes associated with the evolution of each phloem type. KEY RESULTS: We found that the variant phloem always appears in a determinate location, between the leaf orthostichies. Furthermore, the variant phloem was mostly occupied by very wide sieve tubes and generally included a higher concentration of fibers, indicating an increase in conduction and mechanical support. On the other hand, the regular phloem included much more parenchyma, more and wider rays, and tiny sieve tubes that resembled terminal sieve tubes from plants with seasonal formation of vascular tissues; these findings suggest reduced conduction and higher storage capacity in the regular phloem. CONCLUSIONS: Overall, differences between the regular and variant phloem increased over time, leading to further specialization in conduction in the variant phloem and an increase in storage specialization in the regular phloem. PMID- 21613162 TI - Leaf abscission in Impatiens (Balsaminaceae) is due to loss of highly de esterified homogalacturonans in the middle lamellae. AB - PREMISE OF STUDY: Abscission zones (AZ) are sites where leaves and other organs are shed. Investigating the AZ by classical biochemical techniques is difficult due to its small size and because the surrounding tissue is not involved in abscission. The goals of this study were to determine whether AZ cell walls are chemically unique from the other cells of the petiole, perhaps making them more susceptible to enzymatic degradation during abscission and to identify which cell wall polysaccharides are degraded during abscission. METHODS: A battery of antibodies that recognize a large number of cell wall polysaccharide and glycoprotein epitopes was used to probe sections of the Impatiens leaf AZ at several time points in the abscission process. KEY RESULTS: Prior to abscission, the walls of the AZ cells were found to be similar in composition to the walls of the cells both proximal and distal to the AZ. Of all the epitopes monitored, only the highly de-esterified homogalacturonans (HG) of the middle lamellae were found to be reduced post-abscission and only at the plane of separation. More highly esterified homogalacturonans, as well as other pectin and xyloglucan epitopes were not affected. Furthermore, cellulose, as detected by an endoglucanase-gold probe and cellulose-binding module staining, was unaffected, even on the walls of the cells facing the separation site. CONCLUSIONS: In the leaf abscission zone of Impatiens, wall alterations during abscission are strictly limited to the plane of separation and involve only the loss of highly de-esterified pectins from the middle lamellae. PMID- 21613163 TI - Viability of forest floor and canopy seed banks in Pinus contorta var. latifolia (Pinaceae) forests after a mountain pine beetle outbreak. AB - PREMISE OF THE STUDY: Seed banks are important for the natural regeneration of many forest species. Most of the seed bank of serotinous lodgepole pine is found in the canopy, but after an outbreak of mountain pine beetle (MPB), a considerable forest-floor seed bank develops through the falling of canopy cones. After large-scale mortality of pine stands from MPB, however, the viability of seeds in both the canopy and the forest-floor cone bank is uncertain. METHODS: We sampled cones in five stands 3 yr after MPB (3y-MPB); five stands 6 yr after MPB (6y-MPB); and 10 stands 9 yr after MPB (9y-MPB), in central British Columbia, Canada. Seeds were extracted and viability tested using germination techniques. KEY RESULTS: Forest-floor cones had seed with high germination capacity (GC): 82% for embedded (partly buried) closed cones vs. 45% for buried partly open cones. For canopy cones, GC steeply declined about 15 yr after cone maturation and by 25 yr, GC was 50%, compared with 98% in the first year. In the 3y- and 6y-MPB stands, seeds from cones that were 7 to 9 yr old had similar GC on dead and living trees; however, seeds from the dead trees had lower vigor than seeds from living trees. CONCLUSIONS: We demonstrate for the first time that a serotinous pine can form a viable soil seed bank by cone burial, which may facilitate natural regeneration if a secondary disturbance occurs. Seeds contained in 15-yr old cones showed a steep decline in viability, which could limit regeneration if there is a long delay before a secondary disturbance. PMID- 21613164 TI - A molecular phylogenetic approach to western North America endemic Artemisia and allies (Asteraceae): untangling the sagebrushes. AB - PREMISE OF THE STUDY: Artemisia subgenus Tridentatae plants characterize the North American Intermountain West. These are landscape-dominant constituents of important ecological communities and habitats for endemic wildlife. Together with allied species and genera (Picrothamnus and Sphaeromeria), they make up an intricate series of taxa whose limits are uncertain, likely the result of reticulate evolution. The objectives of this study were to resolve relations among Tridentatae species and their near relatives by delimiting the phylogenetic positions of subgenus Tridentatae species with particular reference to its New World geographic placement and to provide explanations for the relations of allied species and genera with the subgenus with an assessment of their current taxonomic placement. METHODS: Bayesian inference and maximum parsimony analysis were based on 168 newly generated sequences (including the nuclear ITS and ETS and the plastid trnS(UGA)-trnfM(CAU) and trnS(GCU)-trnC(GCA)) and 338 previously published sequences (ITS and ETS). Genome size by flow cytometry of species from Sphaeromeria was also determined. KEY RESULTS: The results support an expanded concept and reconfiguration of Tridentatae to accommodate additional endemic North American Artemisia species. The monotypic Picrothamnus and all Sphaeromeria species appear nested within subgenus Tridentatae clade. CONCLUSIONS: A redefinition of subgenus Tridentatae to include other western North American endemics is supported. We propose a new circumscription of the subgenus and divide it into three sections: Tridentatae, Filifoliae, and Nebulosae. The position of the circumboreal and other North American species suggests that subgenus Artemisia is the ancestral stock for the New World endemics, including those native to South America. PMID- 21613165 TI - Relationships within the Araceae: comparison of morphological patterns with molecular phylogenies. AB - PREMISE OF THE STUDY: The first family-wide molecular phylogeny of the Araceae, a family of about 3800 published species in 120 genera, became available in 1995, followed by a cladistic analysis of morpho-anatomical data in 1997. The most recent and comprehensive family-wide molecular phylogeny was published in 2008 and included species from 102 genera. We reanalyzed the molecular data with a more complete genus sampling and compared the resulting phylogeny with morphological and anatomical data, with a view to contributing to a new formal classification of the Araceae. METHODS: We analyzed 113 aroid genera and 4494 aligned nucleotides that resulted from adding 11 genera to the 2008 molecular matrix. We also analyzed 81 morphological characters in the context of the molecular phylogeny, using an extended version of the 1997 morpho-anatomical data set. KEY RESULTS: The resulting maximum-likelihood phylogeny is well resolved and supported, and most of the 44 larger clades also have morphological or anatomical synapomorphies as well as ecological or geographic cohesion. Of the 44 clades, 16 are here newly circumscribed and informally named. However, some relationships remain poorly supported within the Aroideae subfamily. The most problematic placement is Calla within Aroideae, which conflicts with the distribution of morphological, anatomical, and palynological character states. CONCLUSIONS: The comparison of the molecular analysis with morphological and anatomical data presented here represents an important basis for a new formal classification for the Araceae and for the understanding of the evolution of this ancient family, a monocot group known in the fossil record from the early Cretaceous. PMID- 21613166 TI - Low levels of population genetic structure in Pinus contorta (Pinaceae) across a geographic mosaic of co-evolution. AB - PREMISE OF THE STUDY: Population genetic analyses provide information on the population context in which evolutionary processes operate and are important for understanding the evolution of geographically variable traits. Earlier studies showed that cone structure of lodgepole pine in the Rocky Mountains diverged among populations because of geographic variation in coevolutionary interactions involving mammalian and avian seed predators. Analyses of population genetic variation are needed to determine whether this divergence has arisen despite extensive gene flow and whether populations to the east and west of the Rocky Mountains have evolved convergent phenotypes independently. METHODS: We investigated genetic structuring across 22 stands of lodgepole pine in the central Rocky Mountains and in isolated peripheral populations that experience different seed predators and exhibit parallel divergence in cone traits using a set of nine simple sequence repeats and 235 AFLP loci. KEY RESULTS: Our analyses reveal high levels of genetic diversity within and low genetic differentiation among populations. Nonetheless, geographic and genetic distances were correlated, and isolated populations to the east and west of the Rocky Mountains had higher levels of differentiation than did populations in the central part of the range. CONCLUSIONS: These data indicate not only that adaptive divergence of cone traits across a geographic mosaic of coevolution has occurred despite minimal genetic differentiation, but also that isolated populations to the east and west of the Rocky Mountains have evolved distinctive cones independently and in parallel. The population structure quantified here will inform future research aimed at detecting genetic variants associated with divergent adaptive traits. PMID- 21613167 TI - Equisetum thermale sp. nov. (Equisetales) from the Jurassic San Agustin hot spring deposit, Patagonia: anatomy, paleoecology, and inferred paleoecophysiology. AB - PREMISE OF THE STUDY: Dated molecular phylogenies suggest a Cenozoic origin for the crown group of Equisetum. but compression fossil equisetaleans that are morphologically indistinguishable from extant Equisetum and recently discovered anatomically preserved examples strongly suggest an earlier Mesozoic initial diversification. METHODS: In situ samples of Equisetum thermale sp. nov. from the Upper Jurassic San Agustin hot spring deposit were collected and studied with the use of polished blocks, thin sections, and light microscopy. KEY RESULTS: Equisetum thermale exhibits all the morphological and anatomical characteristics of the extant crown group Equisetum. It shows a mixture of features present in the two extant subgenera, e.g., superficial stomata typical of subgenus Equisetum allied with infrequently ramifying stems typical of subgenus Hippochaete. This appears to ally E. thermale with the least derived extant species in the genus Equisetum bogotense (sister species to the two subgenera). Its association of hydromorphic and xeromorphic characters allowed it to grow as an emergent aquatic in physically and chemically stressed geothermally influenced wetlands, where it formed dense monospecific stands. Equisetum thermale, because it is preserved in situ with intact anatomy, provides clear paleoecological, biological, plus inferred paleoecophysiological evidence of adaptations known in extant species. CONCLUSIONS: As the earliest unequivocal member of the genus, E. thermale supports the hypothesis of a Mesozoic origin. Its inferred tolerance of a similar range of stresses (e.g., high salinity, alkalinity, and heavy metal concentrations) to that seen in extant Equisetum suggests early evolution and subsequent maintenance of ecophysiological innovations in the genus. PMID- 21613168 TI - A field test of inverse modeling of seed dispersal. AB - PREMISE OF THE STUDY: Seed dispersal distance-a key process in plant population dynamics-remains poorly understood because of the difficulty of finding a source plant so well isolated from conspecifics that seeds or seedlings can be unambiguously attributed to it. Inverse modeling (IM) of seed dispersal, a simple statistical technique for parameterizing dispersal kernels, has been widely used since 1992; surprisingly, however, this approach has never been verified in the field. METHODS: We released from 20 nearby trees the winged seeds of a liana species, Entada polystachya, near the coast in a tropical, dry forest in Jalisco, Mexico. KEY RESULTS: With a two-parameter log-normal function, we found that IM predicted both the shape and scale parameters well as long as we used the entire data set. When, however, we subsampled (thus simulating the use of transects for seedlings or an array of seed traps), the estimates of the scale and shape parameters were often more than double the real values. The problem was due to the marked anisotropy (directional bias; in this case, in the direction of the diurnal sea breeze) of the individual dispersal curves. When we randomized the direction of dispersal of individual seeds from the trees (keeping dispersal distances unchanged), predictions of parameter values were excellent. CONCLUSIONS: Inverse modeling must include directional parameters when dealing with areas where strong anisotropy is to be expected, e.g., for wind dispersal of seeds near coasts or pollination by any vector where a plant species is limited to a strongly linear habitat such as river banks. PMID- 21613169 TI - Angiosperm phylogeny: 17 genes, 640 taxa. AB - PREMISE OF THE STUDY: Recent analyses employing up to five genes have provided numerous insights into angiosperm phylogeny, but many relationships have remained unresolved or poorly supported. In the hope of improving our understanding of angiosperm phylogeny, we expanded sampling of taxa and genes beyond previous analyses. METHODS: We conducted two primary analyses based on 640 species representing 330 families. The first included 25260 aligned base pairs (bp) from 17 genes (representing all three plant genomes, i.e., nucleus, plastid, and mitochondrion). The second included 19846 aligned bp from 13 genes (representing only the nucleus and plastid). KEY RESULTS: Many important questions of deep level relationships in the nonmonocot angiosperms have now been resolved with strong support. Amborellaceae, Nymphaeales, and Austrobaileyales are successive sisters to the remaining angiosperms (Mesangiospermae), which are resolved into Chloranthales + Magnoliidae as sister to Monocotyledoneae + [Ceratophyllaceae + Eudicotyledoneae]. Eudicotyledoneae contains a basal grade subtending Gunneridae. Within Gunneridae, Gunnerales are sister to the remainder (Pentapetalae), which comprises (1) Superrosidae, consisting of Rosidae (including Vitaceae) and Saxifragales; and (2) Superasteridae, comprising Berberidopsidales, Santalales, Caryophyllales, Asteridae, and, based on this study, Dilleniaceae (although other recent analyses disagree with this placement). Within the major subclades of Pentapetalae, most deep-level relationships are resolved with strong support. CONCLUSIONS: Our analyses confirm that with large amounts of sequence data, most deep-level relationships within the angiosperms can be resolved. We anticipate that this well-resolved angiosperm tree will be of broad utility for many areas of biology, including physiology, ecology, paleobiology, and genomics. PMID- 21613170 TI - Phylogenetic perspectives on diversification, biogeography, and floral evolution of Collinsia and Tonella (Plantaginaceae). AB - PREMISE OF THE STUDY: Collinsia was the subject of classic biosystematic studies by Garber and colleagues and is increasingly investigated to address major evolutionary questions. Lack of phylogenetic data from more than one gene region and one taxonomic exemplar has left relationships, diversity, and phytogeography of Collinsia in question and has limited understanding of its diversification. METHODS: Phylogenetic analyses representing 179 populations of Collinsia and closely related Tonella were conducted based on DNA sequences of nuclear ribosomal transcribed spacers, the single-copy nuclear gene CYCLOIDEA-1, and part of the chloroplast matK/trnK intron region to reexamine systematic hypotheses and extend understanding of the importance of floral characters, chromosome evolution, interfertility, crossability, hybridization, edaphic factors, and ecogeographic barriers to diversification in the group. KEY RESULTS: Informal "sections" of Collinsia are artificial, although pedicel length and other traditional deep-level taxonomic characters are more conservative evolutionarily than flower size. Evolutionary loss of crossability and interfertility in Collinsia appears to be largely a byproduct of divergence. Although most taxa appear to have arisen by divergent evolution, multiple lines of evidence indicate a homoploid hybrid constitution of C. tinctoria, possibly explaining an occurrence of convergent chromosome evolution. Phylogeographic and cryptic diversity is extensive. CONCLUSIONS: Diversity in Collinsia is greater than previously documented. Recently divergent lineages are often associated with distinct habitat (including soil) and geographic factors, different flower sizes, and contrasting chromosomal arrangements. Evidence for a hybrid constitution of diploid C. tinctoria is consistent with lack of strong intersterility barriers between closely related taxa. PMID- 21613171 TI - Ulmus americana (Ulmaceae) is a polyploid complex. AB - PREMISE OF THE STUDY: Exotic diseases are threatening many North American tree species, and management of diseases requires understanding the biology of the host as well as the pathogen. Ulmus americana is a widespread dominant tree of eastern North America that has been widely planted as an ornamental and shade tree. Populations of the species have suffered heavy mortality from Dutch elm disease, caused by an introduced fungus. Ulmus americana is generally reported to be tetraploid, but the discovery of triploid trees in cultivation suggested that lower ploidy levels may exist in the wild, so the species was surveyed for nuclear DNA content. METHODS: Ploidy level was estimated by flow cytometry for 81 individuals from wild populations of U. americana from throughout the range of the species and for four cultivated trees of interest. KEY RESULTS: Most specimens were tetraploid, as previously reported for the species, but 21% of the wild trees sampled were diploid, a ploidy level not previously confirmed for the species. Tetraploids are found throughout the range of the species. Diploids are most common on the Atlantic coastal plain, Cumberland Plateau, and in southern Ohio, but isolated diploids were also found in central Texas, Oklahoma, and eastern Missouri. Diploids and tetraploids grew in proximity in several areas, but no wild triploids were found in the course of this survey. CONCLUSIONS: The species is genetically heterogeneous, but further research is needed to understand the origin and relations of the different ploidy levels. Understanding the ploidy situation in U. americana will be important in the search for further genotypes that are resistant to Dutch elm disease. PMID- 21613172 TI - Haptanthus story: rediscovery of enigmatic flowering plant from Honduras. AB - PREMISE OF THE STUDY: Finding a plant or animal that was previously considered extinct is a fortunate (but rare) event in biology. Haptanthus hazlettii was collected from Honduras (Central America) in 1980, but numerous attempts to re collect it have failed. Reproductive organs of Haptanthus are unique among angiosperms and make the search for phylogenetic relations difficult. Unfortunately, all attempts to extract DNA from the existing sample were unsuccessful. METHODS: In 2010, we organized a small expedition to Honduras and were able to re-collect this plant, extract DNA from dried samples, and sequence the barcoding region of rbcL. KEY RESULTS AND CONCLUSIONS: We obtained phylogenetic trees with reliable support for the placement of Haptanthus as a new member of Buxaceae (boxwood family). PMID- 21613173 TI - Characterization of 15 novel single nucleotide polymorphisms (SNPs) in the Actinidia chinensis species complex (Actinidiaceae). AB - PREMISE OF THE STUDY: Based on the ESTs database, we report here for the first time 15 polymorphic single nucleotide polymorphisms (SNPs) in the Actinidia chinensis species complex that can be used to study population genetic variation. METHODS AND RESULTS: SNPs derived from ESTs of the A. chinensis species complex were identified by the in silico SNP discovery strategy. The Cleaved Amplified polymorphic Sequences (CAPS) method was used to validate putative SNPs in a sample of 24 diploid A. chinensis individuals. For the 15 nuclear SNPs identified, all loci had two alleles, and the minor allele frequency ranged from 0.146 to 0.479. The expected and observed heterozygosities ranged from 0 to 0.500 and from 0 to 0.875, respectively. CONCLUSIONS: The developed markers in this study will provide valuable tools for characterizing genetic variation in evolutionary and ecological studies of natural populations. PMID- 21613174 TI - Bryophyte-specific primers for retrieving plastid genes suitable for phylogenetic inference. AB - PREMISE OF THE STUDY: We present here new bryophyte-specific primers that permit retrieval of 17 slowly evolving plastid genes and their associated introns and intergenic spacers. These regions were chosen to facilitate accurate phylogenetic inference across a broad range of mosses and other bryophytes. METHODS AND RESULTS: We developed 78 new primers for the targeted regions using an initial sampling of exemplar bryophytes and other green plants, to complement those used in vascular plants. We assessed the ability of the new primers to amplify and sequence these regions using a test set of 11 additional exemplar bryophytes. CONCLUSIONS: We show that the newly designed primers facilitate ready retrieval of 14 of 17 targeted regions from a broad range of bryophyte taxa. These primers should prove useful for future studies of bryophyte phylogeny. PMID- 21613175 TI - Microsatellite markers for the high Andean species Schizanthus hookeri and S. grahamii (Solanaceae). AB - PREMISE OF THE STUDY: Seven microsatellite loci were developed for the two closely related high Andean species Schizanthus hookeri and S. grahamii. These species are annual to biannual herbs with zygomorphic and showy flowers that differ in floral morphology, autonomous selfing capacity, and in the identities of major flower visitors. METHODS AND RESULTS: Polymorphisms were evaluated in a total of 45 plants, including individuals from two populations of S. grahamii and one population of S. hookeri. The number of alleles per locus ranged from two to nine in each population. We also tested these loci for cross-amplification in another seven species of the genus. Four primer pairs amplified in these seven species. CONCLUSIONS: Characterized microsatellites are conserved in the closely related species S. hookeri and S. grahamii, and they have enough polymorphism to be used in future studies of their mating systems and genetic structure. PMID- 21613176 TI - Isolation and characterization of microsatellite loci in an endangered palm, Johannesteijsmannia lanceolata (Arecaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed for Johannesteijsmannia lanceolata to assess the genetic diversity and mating system of this alarmingly endangered species. METHODS AND RESULTS: A total of 31 polymorphic microsatellite markers were developed for J. lanceolata using the enrichment protocol. These markers were screened on 24 samples from a natural population. The number of alleles ranged from four to 20, while the observed heterozygosity ranged from 0.391 to 1.000. The 31 loci were further tested for transferability on J. altifrons, J. magnifica, and J. perakensis. Generally, all loci showed positive amplifications in these three Johannesteijsmannia species, except Jla124 (J. magnifica) and Jla168b (J. magnifica and J. perakensis). CONCLUSIONS: These microsatellite markers could be employed to study the population genetics and mating system of J. lanceolata and other Johannesteijsmannia species. PMID- 21613177 TI - Isolation and characterization of microsatellite loci in Rhododendron ferrugineum (Ericaceae) using pyrosequencing technology. AB - PREMISE OF THE STUDY: Microsatellite primers were developed for Rhododendron ferrugineum (Ericaceae) to evaluate genetic diversity, population genetic structure, and mating system of this self-compatible species. METHODS AND RESULTS: The new-generation 454 FLX Titanium pyrosequencing technology was used to isolate 102 novel microsatellite loci. Two multiplex PCR sets were optimized to genotype nine polymorphic microsatellite loci. The level of genetic diversity was assessed in two populations from the Pyrenees (France). The mean number of alleles per locus ranged from 1.5 to 7. The mean observed and expected heterozygosities ranged from 0 to 0.76 and from 0.03 to 0.66, respectively. Cross species amplification was successful for 13 other Rhododendron species and two additional genera of Ericaceae, with an average of seven pairs of primers amplifying per species. CONCLUSIONS: These markers will facilitate further studies on the evolutionary history of the large Ericaceae family and Rhododendron in particular. PMID- 21613178 TI - Chloroplast microsatellite markers in Liriodendron tulipifera (Magnoliaceae) and cross-species amplification in L. chinense. AB - PREMISE OF THE STUDY: A set of cpSSR markers were developed for the tree genus Liriodendron L. to investigate population genetic structure and phylogeographic history. METHODS AND RESULTS: Primers were designed directly from the chloroplast genome sequences of Liriodendron tulipifera. Among the 55 cpSSR markers tested, 11 polymorphic markers were identified in L. tulipifera. The number of alleles in the population tested ranged from two to five, and the unbiased haploid diversity per locus ranged from 0.074 to 0.644. Eighteen primer pairs generated polymorphic amplification in L. chinense. The number of alleles per locus ranged from two to seven, and the unbiased haploid diversity per locus was from 0.250 to 0.964. CONCLUSIONS: cpSSR markers developed here will be useful for phylogeography and population genetics studies of Liriodendron. PMID- 21613179 TI - Identification and characterization of 12 microsatellite loci in Cnidium dubium (Apiaceae) using next-generation sequencing. AB - PREMISE OF THE STUDY: We present a set of 12 polymorphic nuclear microsatellite loci, identified for the first time within the herbaceous plant species Cnidium dubium (Schkuhr) Thell. using next-generation sequencing. METHODS AND RESULTS: To characterize these loci, 40 plants were analyzed genetically. The number of alleles ranged from 2 to 23, with an average of 8.3 alleles per locus. Mean observed and expected heterozygosities ranged from 0.25 to 0.95 and 0.30 to 0.94, respectively. CONCLUSIONS: All 12 nuclear microsatellite loci showed scorable and polymorphic fragments after polymerase chain reaction. The new marker set can be used for future studies of genetic diversity and differentiation as well as estimation of gene flow and spatial genetic structures. PMID- 21613180 TI - Microsatellite markers of an important medicinal plant, Eurycoma longifolia (Simaroubaceae), for DNA profiling. AB - PREMISE OF THE STUDY: Microsatellite markers of an important medicinal plant, Eurycoma longifolia (Simaroubaceae), were developed for DNA profiling and genetic diversity studies. METHODS AND RESULTS: Eighteen polymorphic microsatellite loci were developed for E. longifolia. The primers were designed from a genomic library enriched for dinucleotide (CT) repeats and screened on 32 samples from a natural population. The number of alleles detected per locus ranged from four to 16, while the observed heterozygosity ranged from 0.097 to 0.938. No significant deviation from Hardy-Weinberg equilibrium was detected in all the 18 loci, and no linkage disequilibrium was found between these loci after conservative Bonferroni correction. CONCLUSIONS: The 18 microsatellite markers of E. longifolia are highly polymorphic and informative. These markers would serve as an important tool for DNA profiling and genetic diversity studies. PMID- 21613181 TI - Variation in intra-annual radial growth (xylem formation) of Picea mariana (Pinaceae) along a latitudinal gradient in western Quebec, Canada. AB - PREMISE OF THE STUDY: Climate warming might have resulted in altered initiation and termination dates of stem xylem growth in boreal stands. A systematic understanding of intra-annual xylem formation is thus needed for precise simulation of future growth in the context of sustainable forest management. METHODS: A recently developed novel microsampling approach was employed over two growing seasons (2005-2006) to investigate the intra-annual stem xylem formation of Picea mariana at three sites along a latitudinal gradient (approximately 47.5 50 degrees N) in western Quebec, Canada. The critical timings of xylem cell formation were determined and compared among sites/years. The relationships between xylem cell formation and meteorological variables were examined. KEY RESULTS: From south to north, the onset of xylem cell production was detected on 20 May (SD +/-3) at Angliers, 24 May (SD +/-3) at Chicobi and 24 May (SD+/-4) at Muskuchii in 2005, and on 12 May (SD +/-4) at Angliers, 14 May (SD +/-3) at Chicobi and 20 May (SD +/-3) at Muskuchii in 2006, respectively. Xylem cell production at each respective site terminated on 11 August (SD +/-4), 7 August (SD +/-3), and 7 August (SD +/-4) in 2005, and on 8 August (SD +/-4), 4 August (SD +/-4), and 4 August (SD +/-4) in 2006, respectively. CONCLUSION: Our study implies that despite the expected occurrence of earlier phenological development due to early spring climate warming, boreal trees like P. mariana might not be producing wider rings if cold temperatures occur later in the growing season in June to August. These results may challenge the view that boreal trees could be benefiting from spring warming to enhance growth. PMID- 21613182 TI - Influence of fire on a rare serpentine plant assemblage: a 5-year study of Darlingtonia fens. AB - PREMISE OF THE STUDY: Serpentine soils have attracted the attention of evolutionary biologists for decades because of their high number of rare and endemic taxa, though less is known about the ecological factors that govern the diversity and composition of serpentine communities. Theory suggests that vegetation on these low-productivity soils will be relatively resilient to fire, the most common natural disturbance in serpentine systems. METHODS: We studied the recovery of vegetation in Darlingtonia fens, a unique habitat dominated by herbaceous perennials, from a major fire that burned ~202,000 ha in California and Oregon's Klamath Mountains in 2002. We established permanent plots in eight unburned and eight burned fens in 2003 and recorded percent cover of vascular plant species. We re-sampled plots each year through 2007. KEY RESULTS: Burned fens had less plant cover than unburned fens for 2 yr after the fire. Average species density was ~10% lower in burned fens 1 yr after the fire but ~4-8% higher for the next 4 yr. Burned fens exhibited greater evenness but not until 4 yr after the fire. Differences in community composition were detected between the two fen types, but species ranks were similar, and species neither were added to nor removed from the burned assemblages. CONCLUSIONS: Burning of Darlingtonia fens has detectable, albeit modest, effects on serpentine communities. Because fens have little or no canopy cover, fire has little influence on light availability in this system. This relatively small resource change, combined with high soil moisture and well-developed underground organs of fen plants, produces a highly resilient assemblage. PMID- 21613183 TI - Complex implications around a simple trait: ecological context determines the fecundity effects of corolla marcescence. AB - PREMISE OF THE STUDY: Post-anthesis functionality of persistent perianth parts has rarely been investigated, but available evidence suggests that perianth persistence may not always have an adaptive value. Given the high occurrence of the trait, that it may sometimes be maladaptive is an intriguing possibility and deserves exploration. This paper tests the hypothesis that the fitness value of corolla persistence after anthesis depends on ecological context, specifically the abundance of fruit predators and pollinators. METHODS: The study was conducted on Narcissus longispathus, a species in which corolla marcescence is apparently maladaptive because withered corollas provide a shelter for fruit predatory lepidopteran larvae. By experimentally manipulating corolla persistence, presence of fruit predators, and pollination, I tested whether variation in ecological scenario led to concomitant variation in the sign and magnitude of the effects of corolla marcescence on fecundity. KEY RESULTS: Persistent corollas were detrimental to fecundity when plants were exposed to larvae, but not when larvae were excluded. Pollination and herbivory had nonadditive effects on the fecundity consequences of corolla marcescence, the strongest detrimental effects of corolla persistence occurring for the "exposed to larvae + supplementary pollination" treatment combination. CONCLUSIONS: The hypothesis that ecological context is a major determinant of the fitness value of corolla marcescence was supported. In N. longispathus, corolla marcescence will be a maladaptive trait in situations in which pollinators and fruit predators are simultaneously abundant, but will be a neutral character in the absence of fruit predators, irrespective of pollinator service. PMID- 21613184 TI - Inferring microhabitat preferences of Lilium catesbaei (Liliaceae). AB - PREMISE OF THE STUDY: Microhabitat studies use varied statistical methods, some treating site occupancy as a dependent and others as an independent variable. Using the rare Lilium catesbaei as an example, we show why approaches to testing hypotheses of differences between occupied and unoccupied sites can lead to erroneous conclusions about habitat preferences. Predictive approaches like logistic regression can better lead to understanding of habitat requirements. METHODS: Using 32 lily locations and 30 random locations >2 m from a lily (complete data: 31 lily and 28 random spots), we measured physical conditions- photosynthetically active radiation (PAR), canopy cover, litter depth, distance to and height of nearest shrub, and soil moisture--and number and identity of neighboring plants. Twelve lilies were used to estimate a photosynthetic assimilation curve. Analyses used logistic regression, discriminant function analysis (DFA), (multivariate) analysis of variance, and resampled Wilcoxon tests. KEY RESULTS: Logistic regression and DFA found identical predictors of presence (PAR, canopy cover, distance to shrub, litter), but hypothesis tests pointed to a different set (PAR, litter, canopy cover, height of nearest shrub). Lilies are mainly in high-PAR spots, often close to light saturation. By contrast, PAR in random spots was often near the lily light compensation point. Lilies were near Serenoa repens less than at random; otherwise, neighbor identity had no significant effect. CONCLUSIONS: Predictive methods are more useful in this context than the hypothesis tests. Light availability plays a big role in lily presence, which may help to explain increases in flowering and emergence after fire and roller-chopping. PMID- 21613185 TI - Inferring the higher-order phylogeny of mosses (Bryophyta) and relatives using a large, multigene plastid data set. AB - PREMISE OF THE STUDY: Investigating the early diversification of major clades requires well-corroborated and accurate phylogenetic inferences. We examined the performance of a large set of plastid genes for inferring the broad phylogenetic backbone of mosses-the second largest major clade of land plants-and their nearest relatives. METHODS: We surveyed 14-17 plastid genes from a broadly representative taxonomic sampling of the major bryophyte lineages, including all major lines of non-peristomate mosses. We examined how well these new data corroborated or contradicted the findings of other studies, and investigated the effect of removing rapidly evolving characters. KEY RESULT: We inferred major clades with at least as strong support as other studies that used more taxa. We corroborated current views of overall embryophyte relationships, i.e., (liverworts, (mosses, (hornworts, tracheophytes))), with strong maximum likelihood (ML) bootstrap support, and also placed Zygnematales as the sister group of embryophytes with moderate ML bootstrap support. Within mosses, we confirmed Oedipodiaceae as the sister group of the large clade of peristomate taxa. Likelihood analysis also firmly placed Takakiaceae as the sister group of all other mosses, a strong conflict with parsimony results. Parsimony converged on the Takakia-sister result when rapidly evolving characters were removed, depending on the tree used to classify the site rates. CONCLUSIONS: Our findings broadly support the utility of a 14-gene set from the plastome for future, more densely sampled phylogenetic studies of mosses and relatives, potentially complementing anticipated whole-plastome studies. Likelihood and parsimony conflicts flag possible instances of long-branch attraction, including one involving the earliest split in moss phylogeny. PMID- 21613186 TI - Phylogeny, adaptive radiation, and historical biogeography in Bromeliaceae: insights from an eight-locus plastid phylogeny. AB - PREMISE: Bromeliaceae form a large, ecologically diverse family of angiosperms native to the New World. We use a bromeliad phylogeny based on eight plastid regions to analyze relationships within the family, test a new, eight-subfamily classification, infer the chronology of bromeliad evolution and invasion of different regions, and provide the basis for future analyses of trait evolution and rates of diversification. METHODS: We employed maximum-parsimony, maximum likelihood, and Bayesian approaches to analyze 9341 aligned bases for four outgroups and 90 bromeliad species representing 46 of 58 described genera. We calibrate the resulting phylogeny against time using penalized likelihood applied to a monocot-wide tree based on plastid ndhF sequences and use it to analyze patterns of geographic spread using parsimony, Bayesian inference, and the program S-DIVA. RESULTS: Bromeliad subfamilies are related to each other as follows: (Brocchinioideae, (Lindmanioideae, (Tillandsioideae, (Hechtioideae, (Navioideae, (Pitcairnioideae, (Puyoideae, Bromelioideae))))))). Bromeliads arose in the Guayana Shield ca. 100 million years ago (Ma), spread centrifugally in the New World beginning ca. 16-13 Ma, and dispersed to West Africa ca. 9.3 Ma. Modern lineages began to diverge from each other roughly 19 Ma. CONCLUSIONS: Nearly two thirds of extant bromeliads belong to two large radiations: the core tillandsioids, originating in the Andes ca. 14.2 Ma, and the Brazilian Shield bromelioids, originating in the Serro do Mar and adjacent regions ca. 9.1 Ma. PMID- 21613187 TI - Molecular systematics of the parasitic genus Conopholis (Orobanchaceae) inferred from plastid and nuclear sequences. AB - PREMISE OF THE STUDY: Little is known of the evolutionary relationships within Conopholis, a small holoparasitic genus belonging to the broomrape family. Presently, Conopholis is described as having two species, C. americana and C. alpina. This classification is based on a combination of presence/absence of morphological characters along with a number of quantitative traits. We assessed the relationships among populations and species of this genus to determine whether the present taxonomic hypothesis is reflected in molecular phylogenies. METHODS: We conducted the first phylogenetic study of Conopholis using plastid (trnfM-E intergenic spacer and clpP gene/introns) and nuclear (PHYA intron 1) sequences from a wide taxonomic sampling covering its entire geographical range in North America. Analyses were carried out using a variety of phylogenetic inference approaches. KEY RESULTS: Reciprocal monophyly between the two traditionally accepted species has not yet been achieved. Instead, three distinct genetic clusters were recovered. Conopholis alpina is clearly paraphyletic and shows evidence of belonging to at least two distinct lineages. Specimens found in Costa Rica and Panama form a distinct group from those located in northern Mexico and the southwestern United States. The monophyly of C. americana was also not recovered; however, the possibility of it being monophyletic could not be rejected with confidence. CONCLUSIONS: These analyses recovered three distinct lineages indicating that there could be a minimum of three species within the genus. A reevaluation of morphological features within Conopholis may reveal shared features that could further corroborate our molecular findings. PMID- 21613188 TI - Cryptic spatial aggregation of the cushion plant Azorella selago (Apiaceae) revealed by a multilocus molecular approach suggests frequent intraspecific facilitation under sub-Antarctic conditions. AB - PREMISE OF THE STUDY: In abiotically severe habitats, intraspecific aggregations can increase species' fitness by ameliorating stressful environmental factors. However, the difficulty of identifying individual plants in some growth forms makes the measurements of intraspecific aggregation, and therefore the assessment of intraspecific facilitation, problematic. In this study, we examined the genotype composition within cushions of Azorella selago, a sub-Antarctic cushion plant, to investigate the potential extent of intraspecific facilitation. METHODS: The study was performed on Marion Island, South Africa. Two to eight samples were collected from 42 A. selago cushions, comprising eight different growth forms. Samples were genotyped using seven microsatellite markers. KEY RESULTS: We showed that all cushion shapes, with the exception of small cushions, may be comprised of more than one genetically distinct individual. CONCLUSIONS: Under harsh sub-Antarctic conditions, intraspecific aggregation between A. selago individuals appears common and may be driven by the positive impacts of environmental amelioration. PMID- 21613189 TI - Integration of vessel traits, wood density, and height in angiosperm shrubs and trees. AB - PREMISE OF THE STUDY: Trees and shrubs tend to occupy different niches within and across ecosystems; therefore, traits related to their resource use and life history are expected to differ. Here we analyzed how growth form is related to variation in integration among vessel traits, wood density, and height. We also considered the ecological and evolutionary consequences of such differences. METHOD: In a sample of 200 woody plant species (65 shrubs and 135 trees) from Argentina, Mexico, and the United States, standardized major axis (SMA) regression, correlation analyses, and ANOVA were used to determine whether relationships among traits differed between growth forms. The influence of phylogenetic relationships was examined with a phylogenetic ANOVA and phylogenetically independent contrasts (PICs). A principal component analysis was conducted to determine whether trees and shrubs occupy different portions of multivariate trait space. KEY RESULTS: Wood density did not differ between shrubs and trees, but there were significant differences in vessel diameter, vessel density, theoretical conductivity, and as expected, height. In addition, relationships between vessel traits and wood density differed between growth forms. Trees showed coordination among vessel traits, wood density, and height, but in shrubs, wood density and vessel traits were independent. These results hold when phylogenetic relationships were considered. In the multivariate analyses, these differences translated as significantly different positions in multivariate trait space occupied by shrubs and trees. CONCLUSIONS: Differences in trait integration between growth forms suggest that evolution of growth form in some lineages might be associated with the degree of trait interrelation. PMID- 21613190 TI - Cause and effect or conjecture? A call for consensus on defining "anesthesia related mortality.". PMID- 21613191 TI - Learning disability in children as an outcome in anesthesia and analgesia research. PMID- 21613192 TI - Labor analgesia and the developing human brain. PMID- 21613193 TI - Is a formal statistical analysis always necessary? PMID- 21613194 TI - Malignant hyperthermia and charcoal absorbent: too hot to handle. PMID- 21613195 TI - New molecular players in the great fluid debate. PMID- 21613196 TI - Poor adoption of hemodynamic optimization during major surgery: are we practicing substandard care? PMID- 21613197 TI - Chronic kidney disease: the silent enemy? PMID- 21613198 TI - Central venous catheter-induced cardiac tamponade: a preventable complication. PMID- 21613199 TI - Local anesthetic blockade for neuralgias: "why is the sky blue, daddy?". PMID- 21613200 TI - Transcutaneous regional venous oximetry: a feasibility study. AB - BACKGROUND: The arterial pulse oximeter, which was introduced clinically in the 1970s, is a convenient, useful, and now ubiquitous anesthesia monitor. Unfortunately, although percent saturation of arterial hemoglobin is, along with cardiac output and concentration of hemoglobin, one of 3 components of oxygen delivery, it does not indicate whether oxygen delivery to a region of interest is adequate. Knowledge of peripheral or regional venous oxygen saturation (Sxvo2) may lend insight into analysis of regional oxygen supply and demand. Our goal was to assess the suitability of 3 anatomic sites for the transcutaneous assessment of Sxvo2. METHODS: Using a Nonin reflectance oximetry probe (provided by Nonin Medical, Plymouth, MN) placed directly over the antecubital, external jugular, and internal jugular veins in 10 volunteers, we measured the absorbance of red and infrared electromagnetic radiation. We performed fast Fourier transformation on these absorbance waveforms. The ratio of pulsatile absorbance of red and infrared radiation at different frequencies was compared with nonpulsatile absorption, and Sxvo2 was calculated based on previously derived empiric correlations. RESULTS: Estimates of transcutaneous Sxvo2 ranged from 41% to 97%, with mean values of 75%, 80%, and 80% at the antecubital, external jugular, and internal jugular veins, respectively. Overall, 93% of predicted Sxvo2 values were < 90%. CONCLUSION: Validation and subsequent improvement of this technique requires correlation of our results with venous blood gas measurements, followed by incorporation of technologies from related fields in oximetry (fetal reflectance oximetry and near-infrared spectroscopy), as well as the development of advanced signal processing techniques. PMID- 21613201 TI - The effect of maternal and fetal beta2-adrenoceptor and nitric oxide synthase genotype on vasopressor requirement and fetal acid-base status during spinal anesthesia for cesarean delivery. AB - BACKGROUND: Previous work demonstrated that maternal haplotypes of the beta2 adrenoceptor gene (ADRB2) influence ephedrine requirements during cesarean delivery. The use of ephedrine versus a pure alpha-adrenergic agonist such as phenylephrine has been associated with lower umbilical artery (UA) pH, thought to be secondary to increased fetal metabolism. There are no data evaluating the effect of fetal/neonatal genotypes on the metabolic response to maternally administered vasopressors. We hypothesized that neonatal ADRB2 genotype would affect the extent of neonatal acidemia. We also examined the effect of maternal ADRB2 and the endothelial nitric oxide synthase gene (NOS3) on ephedrine and phenylephrine requirements for treatment of maternal hypotension. METHODS: The study was performed on 104 Chinese women scheduled for cesarean delivery under spinal anesthesia who were participating in a double-blind randomized clinical trial evaluating the maternal and neonatal effects of ephedrine versus phenylephrine infusions. Blood samples were drawn from the UA, umbilical vein, and maternal radial artery to measure blood gas values and lactate, ephedrine, and phenylephrine concentrations, and to determine maternal and neonatal genotype at nonsynonymous single nucleotide polymorphisms at codons 16 (rs1042713) and 27 (rs1042714) of ADRB2 and codon 298 (rs1799983) of NOS. Clinical variables (UA pH, UA lactate, and dose of vasopressors) among genotypes were compared, and regression models were created to assess the effect of genotype on vasopressor dose and fetal acid-base status. RESULTS: Maternal ADRB2 genotype did not affect the ephedrine dose. Neonatal genotype at codon 16 influenced fetal acid-base status. UA pH was higher in Arg16 homozygous neonates (7.31 +/- 0.03 in p.16Arg/Arg vs. 7.25 +/- 0.11 in p.16 Arg/Gly and p.16 Gly/Gly; P < 0.001, 95%confidence interval (CI) of difference 0.03 ~ 0.09) and UA lactate was lower (2.67 mmol/L +/- 0.99 in p.16Arg/Arg vs 4.28 mmol/L +/- 2.79 in. p.16 Arg/Gly and p.16 Gly/Gly; P < 0.001, 95% CI of difference -2.40 ~ -0.82). In neonates born to mothers receiving ephedrine, the magnitude of the difference among genotypes was even greater (pH 7.30 +/- 0.02 in p.16Arg/Arg vs. 7.19 +/- 0.10 in p.16 Arg/Gly and p.16 Gly/Gly; P < 0.001, 95% CI of difference 0.07 ~ 0.14) and UA lactate was lower (3.66 mmol/L +/- 1.30 in p.16Arg/Arg vs. 5.79 mmol/L +/- 2.88 in p.16 Arg/Gly and p.16 Gly/Gly; P = 0.003, 95% CI of difference -3.48 ~ -0.80). In a multiple linear regression model (R2 = 63.6%; P = 0.03), neonatal ADRB2 genotypes (p.16Arg/Arg and p.27Gln/Glu) and lower neonatal birth weight predicted lower UA lactate concentrations. Phenylephrine dose was not affected by maternal ADRB2 or NOS3 genotypes, and neonatal NOS3 genotype did not affect UA pH or UA lactate. CONCLUSION: In contrast to previous findings in a North American cohort, maternal ADRB2 genotype did not affect ephedrine requirements during elective cesarean delivery in a Chinese cohort. However, our findings suggest that neonatal ADRB2 p.Arg16 homozygosity confers a protective effect against developing ephedrine induced fetal acidemia. PMID- 21613202 TI - A bit confused. PMID- 21613203 TI - Early postoperative subcutaneous tissue oxygen predicts surgical site infection. PMID- 21613204 TI - Airway obstruction due to endotracheal tube's lumen collapse secondary to cuff. PMID- 21613205 TI - Suction the tongue: a new adjunct for improving the laryngeal view for fiberoptic intubation. PMID- 21613206 TI - Mask ventilation in edentulous and bearded patients. PMID- 21613208 TI - Insulin growth factor-2 binding protein 3 (IGF2BP3) is a glioblastoma-specific marker that activates phosphatidylinositol 3-kinase/mitogen-activated protein kinase (PI3K/MAPK) pathways by modulating IGF-2. AB - Glioblastoma is the most common and malignant form of primary astrocytoma. Upon investigation of the insulin-like growth factor (IGF) pathway, we found the IGF2BP3/IMP3 transcript and protein to be up-regulated in GBMs but not in lower grade astrocytomas (p < 0.0001). IMP3 is an RNA binding protein known to bind to the 5'-untranslated region of IGF-2 mRNA, thereby activating its translation. Overexpression- and knockdown-based studies establish a role for IMP3 in promoting proliferation, anchorage-independent growth, invasion, and chemoresistance. IMP3 overexpressing B16F10 cells also showed increased tumor growth, angiogenesis, and metastasis, resulting in poor survival in a mouse model. Additionally, the infiltrating front, perivascular, and subpial regions in a majority of the GBMs stained positive for IMP3. Furthermore, two different murine glioma models were used to substantiate the above findings. In agreement with the translation activation functions of IMP3, we also found increased IGF-2 protein in the GBM tumor samples without a corresponding increase in its transcript levels. Also, in vitro IMP3 overexpression/knockdown modulated the IGF 2 protein levels without altering its transcript levels. Additionally, IGF-2 neutralization and supplementation studies established that the proproliferative effects of IMP3 were indeed mediated through IGF-2. Concordantly, PI3K and MAPK, the downstream effectors of IGF-2, are activated by IMP3 and are found to be essential for IMP3-induced cell proliferation. Thus, we have identified IMP3 as a GBM-specific proproliferative and proinvasive marker acting through IGF-2 resulting in the activation of oncogenic PI3K and MAPK pathways. PMID- 21613209 TI - Purification and identification of activating enzymes of CS-0777, a selective sphingosine 1-phosphate receptor 1 modulator, in erythrocytes. AB - CS-0777 is a selective sphingosine 1-phosphate (S1P) receptor 1 modulator with potential benefits in the treatment of autoimmune diseases, including multiple sclerosis. CS-0777 is a prodrug that requires phosphorylation to an active S1P analog, similar to the first-in-class S1P receptor modulator FTY720 (fingolimod). We sought to identify the kinase(s) involved in phosphorylation of CS-0777, anticipating sphingosine kinase (SPHK) 1 or 2 as likely candidates. Unlike kinase activity for FTY720, which is found predominantly in platelets, CS-0777 kinase activity was found mainly in red blood cells (RBCs). N,N-Dimethylsphingosine, an inhibitor of SPHK1 and -2, did not inhibit CS-0777 kinase activity. We purified CS-0777 kinase activity from human RBCs by more than 10,000-fold using ammonium sulfate precipitation and successive chromatography steps, and we identified fructosamine 3-kinase (FN3K) and fructosamine 3-kinase-related protein (FN3K-RP) by mass spectrometry. Incubation of human RBC lysates with 1-deoxy-1 morpholinofructose, a competitive inhibitor of FN3K, inhibited ~10% of the kinase activity, suggesting FN3K-RP is the principal kinase responsible for activation of CS-0777 in blood. Lysates from HEK293 cells overexpressing FN3K or FN3K-RP resulted in phosphorylation of CS-0777 and structurally related molecules but showed little kinase activity for FTY720 and no kinase activity for sphingosine. Substrate preference was highly correlated among FN3K, FN3K-RP, and rat RBC lysates. FN3K and FN3K-RP are known to phosphorylate sugar moieties on glycosylated proteins, but this is the first report that these enzymes can phosphorylate hydrophobic xenobiotics. Identification of the kinases responsible for CS-0777 activation will permit a better understanding of the pharmacokinetics and pharmacodynamics of this promising new drug. PMID- 21613210 TI - Inhibition of osteoclast differentiation and bone resorption by N methylpyrrolidone. AB - Regulation of RANKL (receptor activator of nuclear factor kappaB ligand)-induced osteoclast differentiation is of current interest in the development of antiresorptive agents. Osteoclasts are multinucleated cells that play a crucial role in bone resorption. In this study, we investigated the effects of N methylpyrrolidone (NMP) on the regulation of RANKL-induced osteoclastogenesis. NMP inhibited RANKL-induced tartrate-resistant acid phosphatase activity and the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. The RANKL-induced expression of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) and c-Fos, which are key transcription factors for osteoclastogenesis, was also reduced by treatment with NMP. Furthermore, NMP induced disruption of the actin rings and decreased the mRNAs of cathepsin K and MMP-9 (matrix metalloproteinase-9), both involved in bone resorption. Taken together, these results suggest that NMP inhibits osteoclast differentiation and attenuates bone resorption. Therefore, NMP could prove useful for the treatment of osteoporosis or other bone diseases associated with excessive bone resorption. PMID- 21613211 TI - Multiple factors confer specific Cdc42 and Rac protein activation by dedicator of cytokinesis (DOCK) nucleotide exchange factors. AB - DOCK (dedicator of cytokinesis) guanine nucleotide exchange factors (GEFs) activate the Rho-family GTPases Rac and Cdc42 to control cell migration, morphogenesis, and phagocytosis. The DOCK A and B subfamilies activate Rac, whereas the DOCK D subfamily activates Cdc42. Nucleotide exchange is catalyzed by a conserved DHR2 domain (DOCK(DHR2)). Although the molecular basis for DOCK(DHR2) mediated GTPase activation has been elucidated through structures of a DOCK9(DHR2)-Cdc42 complex, the factors determining recognition of specific GTPases are unknown. To understand the molecular basis for DOCK-GTPase specificity, we have determined the crystal structure of DOCK2(DHR2) in complex with Rac1. DOCK2(DHR2) and DOCK9(DHR2) exhibit similar tertiary structures and homodimer interfaces and share a conserved GTPase-activating mechanism. Multiple structural differences between DOCK2(DHR2) and DOCK9(DHR2) account for their selectivity toward Rac1 and Cdc42. Key determinants of selectivity of Cdc42 and Rac for their cognate DOCK(DHR2) are a Phe or Trp residue within beta3 (residue 56) and the ability of DOCK proteins to exploit differences in the GEF-induced conformational changes of switch 1 dependent on a divergent residue at position 27. DOCK proteins, therefore, differ from DH-PH GEFs that select their cognate GTPases through recognition of structural differences within the beta2/beta3 strands. PMID- 21613212 TI - Structural basis for retinoic X receptor repression on the tetramer. AB - Retinoic X receptor (RXR) is a master nuclear receptor in the processes of cell development and homeostasis. Unliganded RXR exists in an autorepressed tetramer, and agonists can induce RXR dimerization and coactivator recruitment for activation. However, the molecular mechanisms involving the corepressor recruitment and antagonist-mediated repression of RXR are still elusive. Here we report the crystal structure of RXRalpha ligand-binding domain (LBD) complexed with silencing mediator for retinoid and thyroid hormone receptors (SMRT) corepressor motif. As the first structural report on the unliganded nuclear receptor bound to the corepressor motif, RXRalphaLBD-SMRT exhibits a significant structural rearrangement, compared with apoRXRalphaLBD tetramer. To elucidate further the molecular determinants for RXR repression by its antagonist, we also determine the crystal structure of RXRalphaLBD-SMRT complexed with the identified antagonist rhein. In the structure, two rhein molecules and two SMRT peptides are in the RXRalphaLBD tetramer, different from the case in RXRalphaLBD-SMRT structure, where four SMRT peptides bind to RXRalphaLBD tetramer. It seems that rhein induces a displacement of SMRT motif by activation function 2 (AF-2) motif binding to the receptor. Combining our current work with the published results, structural superposition of RXRalphaLBDs in different states reveals that RXR uses an overlapped binding site for coactivator, corepressor, and AF-2 motifs, whereas the AF-2 motif adopts different conformations for agonist or antagonist interaction and coactivator or corepressor recruitment. Taken together, we thus propose a molecular model of RXR repression on the tetramer. PMID- 21613213 TI - Loss of AS160 Akt substrate causes Glut4 protein to accumulate in compartments that are primed for fusion in basal adipocytes. AB - The Akt substrate AS160 (TCB1D4) regulates Glut4 exocytosis; shRNA knockdown of AS160 increases surface Glut4 in basal adipocytes. AS160 knockdown is only partially insulin-mimetic; insulin further stimulates Glut4 translocation in these cells. Insulin regulates translocation as follows: 1) by releasing Glut4 from retention in a slowly cycling/noncycling storage pool, increasing the actively cycling Glut4 pool, and 2) by increasing the intrinsic rate constant for exocytosis of the actively cycling pool (k(ex)). Kinetic studies were performed in 3T3-L1 adipocytes to measure the effects of AS160 knockdown on the rate constants of exocytosis (k(ex)), endocytosis (k(en)), and release from retention into the cycling pool. AS160 knockdown released Glut4 into the actively cycling pool without affecting k(ex) or k(en). Insulin increased k(ex) in the knockdown cells, further increasing cell surface Glut4. Inhibition of phosphatidylinositol 3-kinase or Akt affected both k(ex) and release from retention in control cells but only k(ex) in AS160 knockdown cells. Glut4 vesicles accumulate in a primed pre-fusion pool in basal AS160 knockdown cells. Akt regulates the rate of exocytosis of the primed vesicles through an AS160-independent mechanism. Therefore, there is an additional Akt substrate that regulates the fusion of Glut4 vesicles that remain to be identified. Mathematical modeling was used to test the hypothesis that this substrate regulates vesicle priming (release from retention), whereas AS160 regulates the reverse step by stimulating GTP turnover of a Rab protein required for vesicle tethering/docking/fusion. Our analysis indicates that fusion of the primed vesicles with the plasma membrane is an additional non-Akt-dependent insulin-regulated step. PMID- 21613214 TI - Biochemical analysis of the canonical model for the mammalian circadian clock. AB - The current consensus model for the circadian clock in mammals is based on a transcription-translation feedback loop. In this model, CRY and PER proteins repress their own transcription by suppressing the transactivator function of the CLOCK:BMAL1 heterodimer directly (physical model) and by facilitating post translational modifications (chemical model). Most of the data for this model come from genetic and cell biological experiments. Here, we have purified all of the core clock proteins and performed in vitro and in vivo biochemical experiments to test the physical model. We find that CLOCK:BMAL1 binds to an E box sequence in DNA and that CRY binds stably to the CLOCK:BMAL1:E-box ternary complex independently of PER. Both CRY and PER bind to CLOCK and BMAL1 off DNA but, in contrast to CRY, PER does not bind to the CLOCK:BMAL1:E-box complex. Unexpectedly, PER actually interferes with the binding of CRY to the CLOCK:BMAL1:E-box ternary complex. CRY likely destabilizes the CLOCK:BMAL1 heterodimer on DNA by a post-translational mechanism after binding to the complex. These findings support some aspects of the canonical model, but also suggest that some key features of the model need to be revised. PMID- 21613215 TI - Functional involvement of dual specificity phosphatase 16 (DUSP16), a c-Jun N terminal kinase-specific phosphatase, in the regulation of T helper cell differentiation. AB - Naive CD4(+) T helper (Th) cells differentiate into distinct subsets of effector cells (Th1, Th2, Th17, and induced regulatory T cells (iTreg)) expressing different sets of cytokines upon encounter with presented foreign antigens. It has been well established that Th1/Th2 balance is critical for the nature of the following immune responses. Previous reports have demonstrated important roles of c-Jun N-terminal kinase (JNK) in Th1/Th2 balance, whereas the regulatory mechanisms of JNK activity in Th cells have not been elucidated. Here, we show that dual specificity phosphatase 16 (DUSP16, also referred to as MKP-M or MKP 7), which preferentially inactivates JNK, is selectively expressed in Th2 cells. In the in vitro differentiation assay of naive CD4(+) cells, DUSP16 expression is up-regulated during Th2 differentiation and down-regulated during Th1 differentiation. Chromatin immunoprecipitation revealed the increased acetylation of histone H3/H4 at the dusp16 gene promoter in CD4(+) T cells under the Th2 condition. Adenoviral transduction of naive CD4(+) T cells with DUSP16 resulted in increased mRNA expression of IL-4 and GATA-3 in Th2 and decreased expression of IFNgamma and T-bet in Th1 differentiation. In contrast, transduction of a dominant negative form of DUSP16 had the reverse effects. Furthermore, upon immunization, T cell-specific dusp16 transgenic mice produced antigen-specific IgG2a at lower amounts, whereas DN dusp16 transgenic mice produced higher amounts of antigen-specific IgG2a accompanied by decreased amounts of antigen-specific IgG1 and IgE than those of control mice. Together, these data suggest the functional role of DUSP16 in Th1/Th2 balance. PMID- 21613216 TI - The protease allergen Pen c 13 induces allergic airway inflammation and changes in epithelial barrier integrity and function in a murine model. AB - Fungal allergens are associated with the development of asthma, and some have been characterized as proteases. Here, we established an animal model of allergic airway inflammation in response to continuous exposure to proteolytically active Pen c 13, a major allergen secreted by Penicillium citrinum. In functional analyses, Pen c 13 exposure led to increased airway hyperresponsiveness, significant inflammatory cell infiltration, mucus overproduction, and collagen deposition in the lung, dramatically elevated serum levels of total IgE and Pen c 13-specific IgE and IgG1, and increased production of the Th2 cytokines IL-4, IL 5, and IL-13 by splenocytes stimulated in vitro with Pen c 13. To examine the mechanisms involved in the regulation of allergenicity by Pen c 13, we performed two-dimensional fluorescence difference gel electrophoresis analysis combined with nano-LC-MS/MS, followed by bioinformatics analysis to identify potential targets that associated with allergic inflammation, which suggested that galectin 3 and laminin might be involved in novel pathogenic mechanisms. Finally, we focused on junctional proteins between cells, because, in addition to opening of the epithelial barrier by environmental proteases possibly being the initial step in the development of asthma, these proteins are also associated with actin rearrangement. Taken together, our findings indicate that Pen c 13 exposure causes junctional structure alterations and actin cytoskeletal rearrangements, resulting in increased permeability and airway structural changes. These effects probably change the lung microenvironment and foster the development of allergic sensitization. PMID- 21613218 TI - Recognition of pathogenic microbes by the Drosophila phagocytic pattern recognition receptor Eater. AB - Non-opsonic phagocytosis is a primordial form of pathogen recognition that is mediated by the direct interaction of phagocytic receptors with microbial surfaces. In the fruit fly Drosophila melanogaster, the EGF-like repeat containing scavenger receptor Eater is expressed by phagocytes and is required to survive infections with gram-positive and gram-negative bacteria. However, the mechanisms by which this receptor recognizes different types of bacteria are poorly understood. To address this problem, we generated a soluble, Fc-tagged receptor variant of Eater comprising the N-terminal 199 amino acids including four EGF-like repeats. We first established that Eater-Fc displayed specific binding to broad yet distinct classes of heat- or ethanol-inactivated microbes and behaved similarly to the membrane-bound, full-length Eater receptor. We then used Eater-Fc as a tool to probe Eater binding to the surface of live bacteria. Eater-Fc bound equally well to naive or inactivated Staphylococcus aureus or Enterococcus faecalis, suggesting that in vivo, Eater directly targets live gram positive bacteria, enabling their phagocytic clearance and destruction. By contrast, Eater-Fc was unable to interact with live, naive gram-negative bacteria (Escherichia coli, Serratia marcescens, and Pseudomonas aeruginosa). For these bacteria, Eater-Fc binding required membrane-disrupting treatments. Furthermore, we found that cecropin A, a cationic, membrane-disrupting antimicrobial peptide, could promote Eater-Fc binding to live E. coli, even at sublethal concentrations. These results suggest a previously unrecognized mechanism by which antimicrobial peptides cooperate with phagocytic receptors to extend the range of microbes that can be targeted by a single, germline-encoded receptor. PMID- 21613217 TI - Calmodulin mediates Fas-induced FADD-independent survival signaling in pancreatic cancer cells via activation of Src-extracellular signal-regulated kinase (ERK). AB - Pancreatic cancer remains a devastating malignancy with a poor prognosis and is largely resistant to current therapies. To understand the resistance of pancreatic tumors to Fas death receptor-induced apoptosis, we investigated the molecular mechanisms of Fas-activated survival signaling in pancreatic cancer cells. We found that knockdown of the Fas-associated protein with death domain (FADD), the adaptor that mediates downstream signaling upon Fas activation, rendered Fas-sensitive MiaPaCa-2 and BxPC-3 pancreatic cells resistant to Fas induced apoptosis. By contrast, Fas activation promoted the survival of the FADD knockdown MiaPaCa-2 and BxPC-3 cells in a concentration-dependent manner. The pharmacological inhibitor of ERK, PD98059, abrogated Fas-promoted cell survival in FADD knockdown MiaPaCa-2 and BxPC-3 cells. Furthermore, increased phosphorylation of Src was demonstrated to mediate Fas-induced ERK activation and cell survival. Immunoprecipitation of Fas in the FADD knockdown cells identified the presence of increased calmodulin, Src, and phosphorylated Src in the Fas associated protein complex upon Fas activation. Trifluoperazine, a calmodulin antagonist, inhibited Fas-induced recruitment of calmodulin, Src, and phosphorylated Src. Consistently, trifluoperazine blocked Fas-promoted cell survival. A direct interaction of calmodulin and Src and their binding site were identified with recombinant proteins. These results support an essential role of calmodulin in mediating Fas-induced FADD-independent activation of Src-ERK signaling pathways, which promote survival signaling in pancreatic cancer cells. Understanding the molecular mechanisms responsible for the resistance of pancreatic cells to apoptosis induced by Fas-death receptor signaling may provide molecular insights into designing novel therapies to treat pancreatic tumors. PMID- 21613219 TI - Wnt/beta-catenin pathway in podocytes integrates cell adhesion, differentiation, and survival. AB - Diabetic kidney disease (DKD) is the single most common cause of albuminuria and end-stage kidney disease in the United States. We found increased expression of Wnt/beta-catenin (Ctnnb1) pathway transcripts and proteins in glomeruli and podocytes of patients and mouse models of DKD. Mice with podocyte-specific expression of stabilized Ctnnb1 exhibited basement membrane abnormalities, albuminuria, and increased susceptibility to glomerular injury. Mice with podocyte-specific deletion of Ctnnb1 or podocyte-specific expression of the canonical Wnt inhibitor Dickkopf-related protein 1 (Dkk1) also showed increased susceptibility to DKD. Podocytes with stabilized Ctnnb1 were less motile and less adhesive to different matrices. Deletion of Ctnnb1 in cultured podocytes increased the expression of podocyte differentiation markers and enhanced cell motility; however, these cells were more susceptible to apoptosis. These results indicate that Wnt/Ctnnb1 signaling in podocytes plays a critical role in integrating cell adhesion, motility, cell death, and differentiation. Balanced Ctnnb1 expression is critical for glomerular filtration barrier maintenance. PMID- 21613220 TI - Regulation of purinergic signaling in biliary epithelial cells by exocytosis of SLC17A9-dependent ATP-enriched vesicles. AB - ATP in bile is a potent secretogogue, stimulating biliary epithelial cell (BEC) secretion through binding apical purinergic receptors. In response to mechanosensitive stimuli, BECs release ATP into bile, although the cellular basis of ATP release is unknown. The aims of this study in human and mouse BECs were to determine whether ATP release occurs via exocytosis of ATP-enriched vesicles and to elucidate the potential role of the vesicular nucleotide transporter SLC17A9 in purinergic signaling. Dynamic, multiscale, live cell imaging (confocal and total internal reflection fluorescence microscopy and a luminescence detection system with a high sensitivity charge-coupled device camera) was utilized to detect vesicular ATP release from cell populations, single cells, and the submembrane space of a single cell. In response to increases in cell volume, BECs release ATP, which was dependent on intact microtubules and vesicular trafficking pathways. ATP release occurred as stochastic point source bursts of luminescence consistent with exocytic events. Parallel studies identified ATP-enriched vesicles ranging in size from 0.4 to 1 MUm that underwent fusion and release in response to increases in cell volume in a protein kinase C-dependent manner. Present in all models, SLC17A9 contributed to ATP vesicle formation and regulated ATP release. The findings are consistent with the existence of an SLC17A9 dependent ATP-enriched vesicular pool in biliary epithelium that undergoes regulated exocytosis to initiate purinergic signaling. PMID- 21613221 TI - Leucine zipper EF hand-containing transmembrane protein 1 (Letm1) and uncoupling proteins 2 and 3 (UCP2/3) contribute to two distinct mitochondrial Ca2+ uptake pathways. AB - Cytosolic Ca(2+) signals are transferred into mitochondria over a huge concentration range. In our recent work we described uncoupling proteins 2 and 3 (UCP2/3) to be fundamental for mitochondrial uptake of high Ca(2+) domains in mitochondria-ER junctions. On the other hand, the leucine zipper EF hand containing transmembrane protein 1 (Letm1) was identified as a mitochondrial Ca(2+)/H(+) antiporter that achieved mitochondrial Ca(2+) sequestration at small Ca(2+) increases. Thus, the contributions of Letm1 and UCP2/3 to mitochondrial Ca(2+) uptake were compared in endothelial cells. Knock-down of Letm1 did not affect the UCP2/3-dependent mitochondrial uptake of intracellularly released Ca(2+) but strongly diminished the transfer of entering Ca(2+) into mitochondria, subsequently, resulting in a reduction of store-operated Ca(2+) entry (SOCE). Knock-down of Letm1 and UCP2/3 did neither impact on cellular ATP levels nor the membrane potential. The enhanced mitochondrial Ca(2+) signals in cells overexpressing UCP2/3 rescued SOCE upon Letm1 knock-down. In digitonin permeabilized cells, Letm1 exclusively contributed to mitochondrial Ca(2+) uptake at low Ca(2+) conditions. Neither the Letm1- nor the UCP2/3-dependent mitochondrial Ca(2+) uptake was affected by a knock-down of mRNA levels of mitochondrial calcium uptake 1 (MICU1), a protein that triggers mitochondrial Ca(2+) uptake in HeLa cells. Our data indicate that Letm1 and UCP2/3 independently contribute to two distinct, mitochondrial Ca(2+) uptake pathways in intact endothelial cells. PMID- 21613222 TI - Mitochondrion-dependent N-terminal processing of outer membrane Mcl-1 protein removes an essential Mule/Lasu1 protein-binding site. AB - Mcl-1, a pro-survival member of the Bcl-2 family located at the mitochondrial outer membrane, is subject to constitutive ubiquitylation by the Bcl-2 homology 3 only E3 ligase, Mule/Lasu1, resulting in rapid steady-state degradation via the proteasome. Insertion of newly synthesized Mcl-1 into the mitochondrial outer membrane is dependent on its C-terminal transmembrane segment, but once inserted, the N terminus of a portion of the Mcl-1 molecules can be subject to proteolytic processing. Remarkably, this processing requires an intact electrochemical potential across the inner membrane. Three lines of evidence directed at the endogenous protein, however, indicate that the resulting Mcl-1DeltaN isoform resides in the outer membrane: (i) full-length Mcl-1 and Mcl-1DeltaN resist extraction by alkali but are accessible to exogenous protease; (ii) almost the entire populations of Mcl-1 and Mcl-1DeltaN are accessible to the membrane impermeant Cys-reactive agent 4-acetamido-4'-[(iodoacetyl)amino]stilbene-2,2' disulfonic acid; and (iii) Mcl-1 and Mcl-1DeltaN exhibit equivalent chemical cross-linking to Bak in intact mitochondria, an Mcl-1 binding partner located in the outer membrane. In addition to the Mule Bcl-2 homology 3 domain, we show that interaction between Mcl-1 and Mule also requires the extreme N terminus of Mcl-1, which is lacking in Mcl-1DeltaN. Thus, Mcl-1DeltaN does not interact with Mule, exhibits reduced steady-state ubiquitylation, evades the hyper-rapid steady-state degradation that is observed for full-length Mcl-1 in response to treatments that limit global protein synthesis, and confers resistance to UV stress-induced cell death. PMID- 21613223 TI - Glucose regulates free cytosolic Zn2+ concentration, Slc39 (ZiP), and metallothionein gene expression in primary pancreatic islet beta-cells. AB - Zn2+ is an important cofactor for insulin biosynthesis and storage in pancreatic beta-cells. Correspondingly, polymorphisms in the SLC30A8 gene, encoding the secretory granule Zn2+ transporter ZnT8, are associated with type 2 diabetes risk. Using a genetically engineered (FRET)-based sensor (eCALWY-4), we show here that elevated glucose time-dependently increases free cytosolic Zn2+ ([Zn2+](cyt)) in mouse pancreatic beta-cells. These changes become highly significant (853 +/- 96 pm versus 452 +/- 42 pm, p < 0.001) after 24 h and are associated with increased expression of the Zn2+ importer family members Slc39a6, Slc39a7, and Slc39a8, and decreased expression of metallothionein 1 and 2. Arguing that altered expression of the above genes is not due to altered [Zn2+](cyt), elevation of extracellular (and intracellular) [Zn2+] failed to mimic the effects of high glucose. By contrast, increases in intracellular cAMP prompted by 3-isobutyl-1-methylxanthine and forskolin partially mimicked the effects of glucose on metallothionein, although not ZiP, gene expression. Modulation of intracellular Ca2+ and insulin secretion with pharmacological agents (tolbutamide and diazoxide) suggested a possible role for changes in these parameters in the regulation of Slc39a6 and Slc39a7 but not Slc39a8, nor metallothionein expression. In summary, 1) glucose induces increases in [Zn2+](cyt), which are then likely to facilitate the processing and/or the storage of insulin and its cocrystallization with Zn2+, and 2) these increases are associated with elevated expression of zinc importers. Conversely, a chronic increase in [Zn2+](cyt) following sustained hyperglycemia may contribute to beta cell dysfunction and death in some forms of diabetes. PMID- 21613224 TI - Novel pathway of ceramide production in mitochondria: thioesterase and neutral ceramidase produce ceramide from sphingosine and acyl-CoA. AB - Reports suggest that excessive ceramide accumulation in mitochondria is required to initiate the intrinsic apoptotic pathway and subsequent cell death, but how ceramide accumulates is unclear. Here we report that liver mitochondria exhibit ceramide formation from sphingosine and palmitoyl-CoA and from sphingosine and palmitate. Importantly, this activity was markedly decreased in liver from neutral ceramidase (NCDase)-deficient mice. Moreover, the levels of ceramide were dissimilar in liver mitochondria of WT and NCDase KO mice. These results suggest that NCDase is a key participant of ceramide formation in liver mitochondria. We also report that highly purified liver mitochondria have ceramidase, reverse ceramidase, and thioesterase activities. Increased accessibility of palmitoyl-CoA to the mitochondrial matrix with the pore-forming peptide zervamicin IIB resulted in 2-fold increases in palmitoyl-CoA hydrolysis by thioesterase. This increased hydrolysis was accompanied by an increase in ceramide formation, demonstrating that both outer membrane and matrix localized thioesterases can regulate ceramide formation. Also, ceramide formation might occur both in the outer mitochondrial membrane and in the mitochondrial matrix, suggesting the existence of distinct ceramide pools. Taken together, these results suggest that the reverse activity of NCDase contributes to sphingolipid homeostasis in this organelle in vivo. PMID- 21613225 TI - Extensive mannose phosphorylation on leukemia inhibitory factor (LIF) controls its extracellular levels by multiple mechanisms. AB - In addition to soluble acid hydrolases, many nonlysosomal proteins have been shown to bear mannose 6-phosphate (Man-6-P) residues. Quantification of the extent of mannose phosphorylation and the relevance to physiological function, however, remain poorly defined. In this study, we investigated the mannose phosphorylation status of leukemia inhibitory factor (LIF), a previously identified high affinity ligand for the cation-independent mannose 6-phosphate receptor (CI-MPR), and we analyzed the effects of this modification on its secretion and uptake in cultured cells. When media from LIF-overexpressing cells were fractionated using a CI-MPR affinity column, 35-45% of the total LIF molecules were bound and specifically eluted with free Man-6-P thus confirming LIF as a bona fide Man-6-P-modified protein. Surprisingly, mass spectrometric analysis of LIF glycopeptides enriched on the CI-MPR column revealed that all six N-glycan sites could be Man-6-P-modified. The relative utilization of these sites, however, was not uniform. Analysis of glycan-deleted LIF mutants demonstrated that loss of glycans bearing the majority of Man-6-P residues leads to higher steady-state levels of secreted LIF. Using mouse embryonic stem cells, we showed that the mannose phosphorylation of LIF mediates its internalization thereby reducing extracellular levels and stimulating embryonic stem cell differentiation. Finally, immunofluorescence experiments indicate that LIF is targeted directly to lysosomes following its biosynthesis, providing another mechanism whereby mannose phosphorylation serves to control extracellular levels of LIF. Failure to modify LIF in the context of mucolipidosis II and its subsequent accumulation in the extracellular space may have important implications for disease pathogenesis. PMID- 21613226 TI - 4-hydroxyphenylpyruvate dioxygenase catalysis: identification of catalytic residues and production of a hydroxylated intermediate shared with a structurally unrelated enzyme. AB - 4-Hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4 hydroxyphenylpyruvate (HPP) into homogentisate. HPPD is the molecular target of very effective synthetic herbicides. HPPD inhibitors may also be useful in treating life-threatening tyrosinemia type I and are currently in trials for treatment of Parkinson disease. The reaction mechanism of this key enzyme in both plants and animals has not yet been fully elucidated. In this study, using site directed mutagenesis supported by quantum mechanical/molecular mechanical theoretical calculations, we investigated the role of catalytic residues potentially interacting with the substrate/intermediates. These results highlight the following: (i) the central role of Gln-272, Gln-286, and Gln-358 in HPP binding and the first nucleophilic attack; (ii) the important movement of the aromatic ring of HPP during the reaction, and (iii) the key role played by Asn 261 and Ser-246 in C1 hydroxylation and the final ortho-rearrangement steps (numbering according to the Arabidopsis HPPD crystal structure 1SQD). Furthermore, this study reveals that the last step of the catalytic reaction, the 1,2 shift of the acetate side chain, which was believed to be unique to the HPPD activity, is also catalyzed by a structurally unrelated enzyme. PMID- 21613227 TI - MicroRNA-21 orchestrates high glucose-induced signals to TOR complex 1, resulting in renal cell pathology in diabetes. AB - Hyperglycemia induces a wide array of signaling pathways in the kidney that lead to hypertrophy and matrix expansion, eventually culminating in progressive kidney failure. High glucose-induced reduction of the tumor suppressor protein phosphatase and tensin homolog deleted in chromosome 10 (PTEN) contributes to renal cell hypertrophy and matrix expansion. We identified microRNA-21 (miR-21) as the molecular link between high glucose and PTEN suppression. Renal cortices from OVE26 type 1 diabetic mice showed significantly elevated levels of miR-21 associated with reduced PTEN and increased fibronectin content. In renal mesangial cells, high glucose increased the expression of miR-21, which targeted the 3'-UTR of PTEN mRNA to inhibit PTEN protein expression. Overexpression of miR 21 mimicked the action of high glucose, which included a reduction in PTEN expression and a concomitant increase in Akt phosphorylation. In contrast, expression of miR-21 Sponge, to inhibit endogenous miR-21, prevented down regulation of PTEN and phosphorylation of Akt induced by high glucose. Interestingly, high glucose-stimulated miR-21 inactivated PRAS40, a negative regulator of TORC1. Finally, miR-21 enhanced high glucose-induced TORC1 activity, resulting in renal cell hypertrophy and fibronectin expression. Thus, our results identify a previously unrecognized function of miR-21 that is the reciprocal regulation of PTEN levels and Akt/TORC1 activity that mediate critical pathologic features of diabetic kidney disease. PMID- 21613228 TI - 24(S)-hydroxycholesterol induces neuronal cell death through necroptosis, a form of programmed necrosis. AB - 24(S)-Hydroxycholesterol (24S-OHC) produced by cholesterol 24-hydroxylase expressed mainly in neurons plays an important physiological role in the brain. Conversely, it has been reported that 24S-OHC possesses potent cytotoxicity. The molecular mechanisms of 24S-OHC-induced cell death have not yet been fully elucidated. In this study, using human neuroblastoma SH-SY5Y cells and primary cortical neuronal cells derived from rat embryo, we characterized the form of cell death induced by 24S-OHC. SH-SY5Y cells treated with 24S-OHC exhibited neither fragmentation of the nucleus nor caspase activation, which are the typical characteristics of apoptosis. 24S-OHC-treated cells showed necrosis-like morphological changes but did not induce ATP depletion, one of the features of necrosis. When cells were treated with necrostatin-1, an inhibitor of receptor interacting serine/threonine kinase 1 (RIPK1) required for necroptosis, 24S-OHC induced cell death was significantly suppressed. The knockdown of RIPK1 by transfection of small interfering RNA of RIPK1 effectively attenuated 24S-OHC induced cell death. It was found that neither SH-SY5Y cells nor primary cortical neuronal cells expressed caspase-8, which was regulated for RIPK1-dependent apoptosis. Collectively, these results suggest that 24S-OHC induces neuronal cell death by necroptosis, a form of programmed necrosis. PMID- 21613230 TI - Time-response evaluation by transcriptomics of methylmercury effects on neural differentiation of murine embryonic stem cells. AB - Current globally harmonized Organisation for Economic Co-operation and Development (OECD) animal test guidelines for developmental toxicity require high numbers of experimental animals. To reduce animal use in this field, alternative developmental toxicity assays are highly desirable. We previously developed a dynamic in vitro model for screening effects of possible neurodevelopmental toxicants, using neural cell differentiation of pluripotent murine embryonic stem cells. To further mechanistically characterize the mouse neural embryonic stem cell test (ESTn) and to improve detection of possible neurodevelopmental toxicants, gene expression patterns were studied describing neural cell differentiation over time, as well as the impact on gene expression of exposure to the well-known neurotoxicant methylmercury (MeHg). A transcriptomics study was performed to examine whole-genome expression changes during the first 7 days of the cell differentiation protocol. Specific gene clusters were identified and enrichment analysis of Gene Ontology (GO) terms and gene sets derived from literature was performed using DAVID and T-profiler. Over time, a decrease of blastocyst and trophectoderm GO terms was observed, which included well characterized pluripotency genes. Furthermore, an increase in the range of neural development-related GO terms, such as neuron differentiation and the wnt pathway, was observed. Analysis of gene expression using principle component analysis showed a time-dependent track in untreated cells, describing the process of neural differentiation. Furthermore, MeHg was shown to induce deviation from the predefined differentiation track. The compound inhibited general development GO terms and induced neural GO terms over time. This system appears promising for studying compound effects on neural differentiation in a mechanistic approach. PMID- 21613229 TI - Protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitor against increased beta cell apoptosis induced by dietary sucrose and linoleic acid in mice with diabetes. AB - Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces beta cell apoptosis, leading to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects in diabetes are unclear. We challenged beta cell-specific glucokinase haploinsufficient (Gck(+/-)) mice with a diet containing sucrose and oleic acid (SO) or sucrose and linoleic acid (SL) and analyzed beta cell apoptosis. In Gck(+/-) but not wild-type mice, SL significantly decreased the beta cell mass and beta cell proportion in islet cells arising from increased apoptosis to a greater degree than did SO. The mRNA expression of SREBP-1c was significantly higher, and that of E-cadherin was significantly lower in the islets of Gck(+/-) mice fed SL compared with mice fed SO. We next evaluated monotherapy with desfluorositagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in these mouse groups. DPP-4 inhibitor protected against beta cell apoptosis, restored the beta cell mass, and normalized islet morphology in Gck(+/ ) mice fed SL. DPP-4 inhibition normalized the changes in the islet expression of SREBP-1c and E-cadherin mRNA induced by the SL diet. Furthermore, linoleic acid induced beta cell apoptosis to a greater degree in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells, whereas a GLP-1 receptor agonist prevented apoptosis. In conclusion, SL exacerbated beta cell apoptosis in diabetic Gck(+/-) mice but not in euglycemic wild-type mice, and DPP-4 inhibition protected against these effects. PMID- 21613231 TI - Genetic architecture of susceptibility to PCB126-induced developmental cardiotoxicity in zebrafish. AB - Variability in risk of developmental defects caused by dioxin-like compounds (DLCs) has been demonstrated within and among several vertebrate species. Beyond our knowledge of the aryl hydrocarbon receptor (AHR) and its role in mediating toxicity for this class of compounds, little else is known concerning precise downstream targets influencing this vulnerability. In the present study, zebrafish with divergent genetic backgrounds were screened for susceptibility to developmental cardiotoxicity caused by the prototypical DLC, 3,3',4,4',5 pentachlorobiphenyl (PCB126); a range up to ~40-fold differences was observed. Differentially sensitive zebrafish were chosen for a genetic cross, and the recombinant generation was used for genome-wide quantitative trait loci (QTL) mapping. Multiple QTLs were identified--several acting alone, one additively, and two others via epistatic interaction. Together, these QTLs account for 24% of the phenotypic variance observed in cardioteratogenicity resulting from PCB126 exposure (logarithm of the odds = 13.55, p = 1.89 * 10-10). Candidate genes in these QTL regions include the following: ahr2, bcor, and capn1 (Chr 22); e2f1 and pdyn (Chr 23); ctnnt2, plcg1, eno3, tgm1, and tgm2 (interacting on Chr 23); and vezf1 (Chr 15). These data demonstrate that DLC-induced cardiac teratogenicity is a multifactorial complex trait influenced by gene * gene and gene * environment interactions. The identified QTLs harbor many DLC-responsive genes critical to cardiovascular development and provide insight into the genetic basis of susceptibility to AHR-mediated developmental toxicity. PMID- 21613232 TI - Modeling of the internal kinetics of benzo(a)pyrene and 3-hydroxybenzo(a)pyrene biomarker from rat data. AB - Measurements of 3-hydroxybenzo(a)pyrene (3-OHBaP) in urine has been proposed for the biomonitoring of exposure to benzo(a)pyrene (BaP) in workers. To allow a better understanding of the toxicokinetics of BaP and its key biomarker, a multicompartment model was developed based on rat data previously obtained by this group. According to the model, iv injected BaP is rapidly distributed from blood to tissues (t1/2 = 3.65 h), with particular affinity for tissue lipid components and liver and lung proteins. BaP is then rapidly distributed to lungs, where significant tissue uptake occurs, followed by the skin, liver, and adipose tissues. Once in liver, BaP is readily metabolized, and 3-OHBaP is formed with a t1/2 of 3.32 h. Lung metabolism of BaP was also accounted for, but its contribution to the whole kinetics was found to be negligible. Once formed, 3 OHBaP is distributed from blood to the various organs almost as fast as the parent compound (t1/2 = 2.26 h). In kidneys, 3-OHBaP builds up as a result of the smaller rate of 3-OHBaP urinary excretion (t1/2 = 4.52 h) as compared with its transfer rate from blood to kidneys (t1/2 = 27.8 min). However, overall clearance of 3-OHBaP from the body is driven by its biliary transfer from liver to the gastrointestinal tract (t1/2 = 3.81 h). The model provides a great fit to independent sets of published data on 3-OHBaP urinary excretion time course (chi2 = 0.019). This model proves useful in establishing the main biological determinants of the overall kinetics of these compounds. PMID- 21613233 TI - Inhibition of renal NQO1 activity by dicoumarol suppresses nitroreduction of aristolochic acid I and attenuates its nephrotoxicity. AB - Aristolochic acid I (AAI) is the major toxic component of aristolochic acid that causes aristolochic acid nephropathy and Balkan endemic nephropathy. Nitroreduction is an essential metabolic process for AAI rapid clearance in different species including humans. However, which enzyme participates in AAI nitroreduction in vivo and whether this metabolic process contributes to AAI nephrotoxicity are unclear. Here, we showed that NAD(P)H:quinone oxidoreductase 1 (NQO1) was highly expressed in mouse renal tubular epithelial cells. Inhibition of NQO1 activity by dicoumarol pretreatment significantly decreased renal aristolactam I (ALI) levels, a major reductive metabolite of AAI, whereas it increased renal AAI and its major oxidative metabolite 8-hydroxy-aristolochic acid I (AAIa) levels in male C57BL/6 mice. Similar changes in renal ALI, AAI, and AAIa levels were also observed in mice pretreated with another NQO1 inhibitor, phenindione. Consistent with higher levels of renal AAI and AAIa found in dicoumarol-pretreated mice, their serum clearance was much slower compared with vehicle-pretreated mice. The survival rate of mice pretreated with dicoumarol was markedly increased when higher doses of AAI were given. Similarly, pretreatment of mice with phenindione also attenuated AAI-induced nephrotoxicity. These results indicate that NQO1 plays an important role in renal AAI nitroreduction and may thus contribute to AAI-induced nephrotoxicity. PMID- 21613234 TI - Assessment of an association between an aryl hydrocarbon receptor gene (AHR) polymorphism and risk of male infertility. AB - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of a variety of environmental chemicals, such as polycyclic aromatic hydrocarbons (PAHs) and dioxins. We hypothesized that polymorphisms of AHR may result in significant differences in sensitivity to toxic effects of PAHs or dioxins and contribute to susceptibility to male infertility. To address this possibility, we conducted a study including 580 idiopathic infertile subjects and 580 fertile controls to assess associations between the male infertility risk and six tagging single nucleotide polymorphisms of AHR gene. Additionally, correlations between AHR polymorphisms and sperm concentration, levels of DNA fragmentation, and benzo(a)pyrene diolepoxide (BPDE) DNA adducts in sperm were determined in 420 patients. Genotypes were determined using the ABI OpenArray platform. Sperm DNA fragmentation was evaluated by terminal deoxyribonucleotidyl transferase (TdT)-mediated dUDP nick-end labelling (TUNEL) assay, and sperm BPDE-DNA adducts were measured by immunofluorescent assay using flow cytometry. We found that the G variant of rs2158041 was associated with significantly increased risk of male infertility (adjusted odds ratio 1.53, 95% confidence interval 1.21-1.93; p = 6.0 x 10-6; GA/AA vs. GG genotypes). Furthermore, patients with rs2158041 AA genotype showed a reduced sperm concentration. In addition, a gradual increase of sperm DNA fragmentation and sperm BPDE-DNA adducts was found among the three rs2158041 subgroups (GG -> GA -> AA), though the differences were not statistically significant. These results suggested that the AHR polymorphism might be associated with individual risk of male infertility in the Chinese population study. PMID- 21613235 TI - Genome expansion and differential expression of amino acid transporters at the aphid/Buchnera symbiotic interface. AB - In insects, some of the most ecologically important symbioses are nutritional symbioses that provide hosts with novel traits and thereby facilitate exploitation of otherwise inaccessible niches. One such symbiosis is the ancient obligate intracellular symbiosis of aphids with the gamma-proteobacteria, Buchnera aphidicola. Although the nutritional basis of the aphid/Buchnera symbiosis is well understood, the processes and structures that mediate the intimate interactions of symbiotic partners remain uncharacterized. Here, using a de novo approach, we characterize the complement of 40 amino acid polyamine organocation (APC) superfamily member amino acid transporters (AATs) encoded in the genome of the pea aphid, Acyrthosiphon pisum. We find that the A. pisum APC superfamily is characterized by extensive gene duplications such that A. pisum has more APC superfamily transporters than other fully sequenced insects, including a ten paralog aphid-specific expansion of the APC transporter slimfast. Detailed expression analysis of 17 transporters selected on the basis of their phylogenetic relationship to five AATs identified in an earlier bacteriocyte expressed sequence tag study distinguished a subset of eight transporters that have been recruited for amino acid transport in bacteriocyte cells at the symbiotic interface. These eight transporters include transporters that are highly expressed and/or highly enriched in bacteriocytes and intriguingly, the four AATs that show bacteriocyte-enriched expression are all members of gene family expansions, whereas three of the four that are highly expressed but not enriched in bacteriocytes retain one-to-one orthology with transporters in other genomes. Finally, analysis of evolutionary rates within the large A. pisum slimfast expansion demonstrated increased rates of molecular evolution coinciding with two major shifts in expression: 1) a loss of gut expression and possibly a gain of bacteriocyte expression and 2) loss of expression in all surveyed tissues in asexual females. Taken together, our characterization of nutrient AATs at the aphid/Buchnera symbiotic interface provides the first examination of the processes and structures operating at the interface of an obligate intracellular insect nutritional symbiosis, offering unique insight into the types of genomic change that likely facilitated evolutionary maintenance of the symbiosis. PMID- 21613236 TI - Human piRNAs are under selection in Africans and repress transposable elements. AB - Piwi-interacting RNAs (piRNAs) are a recently discovered class of 24- to 30-nt noncoding RNAs whose best-understood function is to repress transposable elements (TEs) in animal germ lines. In humans, TE-derived sequences comprise ~45% of the genome and there are several active TE families, including LINE-1 and Alu elements, which are a significant source of de novo mutations and intrapopulation variability. In the "ping-pong model," piRNAs are thought to alternatively cleave sense and antisense TE transcripts in a positive feedback loop. Because piRNAs are poorly conserved between closely related species, including human and chimpanzee, we took a population genomics approach to study piRNA function and evolution. We found strong statistical evidence that piRNA sequences are under selective constraint in African populations. We then mapped the piRNA sequences to human TE sequences and found strong correlations between the age of each LINE 1 and Alu subfamily and the number of piRNAs mapping to the subfamily. This result supports the idea that piRNAs function as repressors of TEs in humans. Finally, we observed a significant depletion of piRNA matches in the reverse transcriptase region of the consensus human LINE-1 element but not of the consensus mouse LINE-1 element. This result suggests that reverse transcriptase might have an endogenous role specific to humans. Overall, our results elucidate the function and evolution of piRNAs in humans and highlight the utility of population genomics analysis for studying this rapidly evolving genetic system. PMID- 21613237 TI - Retained orthologous relationships of the MHC Class I genes during euteleost evolution. AB - Major histocompatibility complex (MHC) class I molecules play a pivotal role in immune defense system, presenting the antigen peptides to cytotoxic CD8+ T lymphocytes. Most vertebrates possess multiple MHC class I loci, but the analysis of their evolutionary relationships between distantly related species has difficulties because genetic events such as gene duplication, deletion, recombination, and/or conversion have occurred frequently in these genes. Human MHC class I genes have been conserved only within the primates for up to 46-66 My. Here, we performed comprehensive analysis of the MHC class I genes of the medaka fish, Oryzias latipes, and found that they could be classified into four groups of ancient origin. In phylogenetic analysis using these genes and the classical and nonclassical class I genes of other teleost fishes, three extracellular domains of the class I genes showed quite different evolutionary histories. The alpha1 domains generated four deeply diverged lineages corresponding to four medaka class I groups with high bootstrap values. These lineages were shared with salmonid and/or other acanthopterygian class I genes, unveiling the orthologous relationships between the classical MHC class I genes of medaka and salmonids, which diverged approximately 260 Ma. This suggested that the lineages must have diverged in the early days of the euteleost evolution and have been maintained for a long time in their genome. In contrast, the alpha3 domains clustered by species or fish groups, regardless of classical or nonclassical gene types, suggesting that this domain was homogenized in each species during prolonged evolution, possibly retaining the potential for CD8 binding even in the nonclassical genes. On the other hand, the alpha2 domains formed no apparent clusters with the alpha1 lineages or with species, suggesting that they were diversified partly by interlocus gene conversion, and that the alpha1 and alpha2 domains evolved separately. Such evolutionary mode is characteristic to the teleost MHC class I genes and might have contributed to the long-term conservation of the alpha1 domain. PMID- 21613239 TI - A new type of lectin discovered in a fish, flathead (Platycephalus indicus), suggests an alternative functional role for mammalian plasma kallikrein. AB - A skin mucus lectin exhibiting a homodimeric structure and an S-S bond between subunits of ~40 kDa was purified from flathead Platycephalus indicus (Scorpaeniformes). This lectin, named FHL (FlatHead Lectin), exhibited mannose specific activity in a Ca(2+)-dependent manner. Although FHL showed no homology to any previously reported lectins, it did exhibit ~20% identity to previously discovered plasma kallikreins and coagulation factor XIs of mammals and Xenopus laevis. These known proteins are serine proteases and play pivotal roles in the kinin-generating system or the blood coagulation pathway. However, alignment analysis revealed that while FHL lacked a serine protease domain, it was homologous to the heavy-chain domain of plasma kallikreins and coagulation factor XI therefore suggesting that FHL is not an enzyme but rather a novel animal lectin. On the basis of this finding, we investigated the lectin activity of human plasma kallikrein and revealed that it could indeed act as a lectin. Other genes homologous to FHL were also found in the genome databases of some fish species, but not in mammals. In contrast, plasma kallikreins and coagulation factor XI have yet to be identified in fish. The present findings suggest that these mammalian enzymes may have originally emerged as a lectin and may have evolved into molecules with protease activity after separation from common ancestors. PMID- 21613240 TI - Description of a practitioner model for identifying preferred stimuli with individuals with autism spectrum disorders. AB - The rich technology of stimulus preference assessment (SPA) is a product of 40 years of experimental research. Basic principles of reinforcement and a modest empirical literature suggest that high-preference stimuli identified via SPA may enhance treatment efficacy and decrease problem behavior more effectively than less-preferred stimuli. SPAs can be conducted using one of several methods associated with different time requirements and outcomes. Despite the broad applicability of preference assessments, we are unaware of widely available practitioner guidelines that prescribe when to use SPAs, how to select and modify specific SPA procedures, and how to supplement SPAs with other procedures for maximizing performance. The purpose of the current article is to describe a model for practitioners to select and conduct preference assessments based on practical considerations and research findings. Data are also reported from the application of the proposed model to preference assessments for 20 individuals diagnosed with autism spectrum disorders. PMID- 21613238 TI - Hybridization kinetics between immobilized double-stranded DNA probes and targets containing embedded recognition segments. AB - We have investigated the time-dependent strand displacement activity of several targets with double-stranded DNA probes (dsProbes) of varying affinity. Here, the relative affinity of various dsProbes is altered through choices in hybridization length (11-15 bases) and the selective inclusion of center mismatches in the duplexes. While the dsProbes are immobilized on microspheres, the soluble, 15 base-long complementary sequence is presented either alone as a short target strand or as a recognition segment embedded within a longer target strand. Compared to the short target, strand displacement activity of the longer targets is slower, but still successful. Additionally, the longer targets exhibit modest differences in the observed displacement rates, depending on the location of recognition segment within the long target. Overall, our study demonstrates that the kinetics of strand displacement activity can be tuned through dsProbe sequence design parameters and is only modestly affected by the location of the complementary segment within a longer target strand. PMID- 21613241 TI - A comparison of reliability measures for continuous and discontinuous recording methods: inflated agreement scores with partial interval recording and momentary time sampling for duration events. AB - The authors evaluated the extent to which interobserver agreement (IOA) scores, using the block-by-block method for events scored with continuous duration recording (CDR), were higher when the data from the same sessions were converted to discontinuous methods. Sessions with IOA scores of 89% or less with CDR were rescored using 10-s partial interval recording (PIR) and 10-s momentary time sampling (MTS). Results indicated that IOA scores for 10-s PIR and 10-s MTS were consistently higher than IOA scores based on CDR for the same sessions. Specifically, 10-s MTS provided higher overestimations for low-duration events, whereas 10-s PIR produced higher overestimations for moderate- and high-duration events. Implications for researchers and clinicians are briefly discussed. PMID- 21613242 TI - Effects of incentives and prenotification on response rates and costs in a national web survey of physicians. AB - Little is known about what strategies are cost-effective in increasing participation among physicians in surveys that are conducted exclusively via the web. To assess the effects of incentives and prenotification on response rates and costs, general internists (N = 3,550) were randomly selected from the American Medical Association (AMA) Masterfile and assigned to experimental groups that varied in the amount of a promised incentive (none, entry into a $200 lottery, $50, or $100) and prenotification (none, prenotification letter only, or prenotification letter containing a $2 preincentive). Results indicated that the response rates were highest in the groups promised $100 and $50, respectively. While the postal prenotification letter increased response rates, the inclusion of a small token $2 preincentive had no effect on participation. Further, unlike mail surveys of physicians, the $2 preincentive was not cost-effective. Among physicians, larger promised incentives of $50 or $100 are more effective than a nominal preincentive in increasing participation in a web-only survey. Consistent with prior research, there was little evidence of nonresponse bias among the experimental groups. PMID- 21613243 TI - A Rasch and factor analysis of a Paramedic Graduate Attribute scale. AB - This study examined the construct validity of the Paramedic Graduate Attribute scale (PGAS) using factor analysis and Rasch Analysis. A convenience sample was used in the study involving paramedics from all states and territories in Australia. Participants were asked to rate the importance of 47 graduate attribute items. Principal components analysis (PCA) was undertaken on the 47 items followed by Oblique Oblimin rotation. For the Rasch analysis item fit, item invariance and dimensionality were examined. A total of 872 paramedics participated in the study (23% response rate). PCA of the 47 items revealed seven factors with eigenvalues greater than 1, accounting for 40.6% of the total variance. The subsequent Rasch analyses based on the seven factors produced seven misfitting items and confirmed a 7-factor solution. The 7-factor PGAS produced a good fit to the Rasch Model and exhibited good reliability and unidimensionality, offering the Australian paramedic discipline a set of empirically based graduate attributes. PMID- 21613244 TI - The effects of clinical pathways on professional practice, patient outcomes, length of stay, and hospital costs: Cochrane systematic review and meta-analysis. AB - This paper is a summary version of the previously published Cochrane review. It may increase the reach of the topic to health researchers and practitioners and encourage further discussion. The systematic review aims to summarize the evidence and assess the effect of clinical pathways on professional practice, patient outcomes, length of hospital stay, and hospital costs. The authors searched the Database of Abstracts of Reviews of Effectiveness, the Effective Practice and Organisation of Care Register, the Cochrane Central Register of Controlled Trials and bibliographic databases including MEDLINE, EMBASE, CINAHL, NHS EED, and Global Health. Twenty-seven studies considering a total of 11,398 participants were included for analysis. The main results were a reduction in in hospital complications (odds ratio 0.58: 95% CI [0.36, 0.94] and improved documentation (odds ratio 11.95: 95% CI [4.72, 30.30]) associated with clinical pathways. Considerable variation in study design and settings prevented statistical pooling of results for length of stay (LOS) and hospital costs. The authors concluded that clinical pathways are associated with reduced in-hospital complications and improved documentation. PMID- 21613245 TI - Evaluation of online instruction to improve medical and dental students' communication and counseling skills. AB - Online, interactive video modules were created to demonstrate good skills in history taking, counseling, and communication. The authors evaluated the effect of the modules on students' data gathering, counseling, and communication skills with standardized patients (SPs). A student cohort without the online modules (n = 76 medical students and n = 43 dental students) was compared to a cohort of different students who were assigned the modules (n = 88 medical students and n = 39 dental students). Students were evaluated by SPs using case-specific content checklists and the Master Interview Rating Scale (MIRS). Compared to their counterparts who did not use the modules, medical and dental students who used the modules showed significantly higher performance on several outcomes. The areas that showed benefit were those that were novel to students. Student accuracy in grading others was generally unrelated to their own performance. In conclusion, the online, interactive video modules were associated with improvements in a majority of clinical skills. PMID- 21613246 TI - Have we drawn the wrong conclusions about the value of care pathways? Is a Cochrane review appropriate? Response to the commentary article published by Kris Vanhaecht et al. AB - The commentary provided by Vanhaecht et al. from the European Pathways Association (EPA) questions whether conclusions derived from the review of effects of clinical pathways in hospitals are appropriate. They provide some methodological discussion that indicates a poor appreciation of the detailed content of the review as published in the Cochrane Library and a lack of understanding of the methodological requirements for complex interventions of the Cochrane Effective Practice and Organisation of Care (EPOC) group. In addition, Vanhaecht et al. misrepresent some important points from the review relating to the intervention reviewed. The critical commentary offered by Vanhaecht et al. is a misrepresentation of the process and content of the review and suggests they have not taken the time and effort to thoroughly read and understand this comprehensive review. PMID- 21613247 TI - Compliance with referral for curative care in rural Burkina Faso. AB - BACKGROUND: The goal of this study is to contribute to improving the functioning of the referral system in rural Burkina Faso. The main objective is to ascertain the compliance rate for referral and to identify the factors associated with successful referral. METHODS: A record review of 12 months of curative consultations in eight randomly selected health centres was conducted to identify referral cases. To assess referral compliance, all patient documents at referral hospitals from the day of the referral up to 7 days later were checked to verify whether the referred case arrived or not. Descriptive statistics were then used to compute the compliance rate. Hierarchical modelling was performed to identify patient and provider factors associated with referral compliance. RESULTS: The number of visits per person per year was 0.6 and the referral rate was 2.0%. The compliance rate was 41.5% (364/878). After adjustment, females (OR = 0.71; 95% CI = 0.52-0.98), patients referred during the rainy seasons (OR = 0.56; 95% CI = 0.40-0.78), non-emergency referrals (OR = 0.47; 95% CI = 0.34-0.65) and referrals without a referral slip (OR = 0.30; 95% CI = 0.21-0.43) were significantly less likely to comply. Children between 5 and 14 years old (OR = 0.61; 95% CI = 0.35 1.06) were at a higher risk of non-compliance, but the difference did not reach statistical significance. Moreover, none of provider characteristics was statistically significantly associated with non-compliance. CONCLUSIONS In a rural district of Burkina Faso, we found a relatively low compliance with referral after the official referral system was organized in 2006. Patient characteristics were significantly associated with a failure to comply. Interventions addressing female patients' concerns, increasing referral compliance in non-emergency situations, reducing inconvenience and opportunity costs due to seasonal/climate factors, and assuring the issue of a referral slip when a referral is prescribed may effectively improve referral compliance. PMID- 21613248 TI - Recommendations for the use of rituximab in anti-neutrophil cytoplasm antibody associated vasculitis. AB - OBJECTIVES: To perform a literature review and develop recommendations for the use of rituximab in ANCA-associated vasculitis. METHODS: A committee of experts (five rheumatologists, five nephrologists and one paediatrician) conducted a modified Delphi exercise to identify five topics for a systematic literature search. The evidence was then reviewed, categorized according to international criteria and assimilated to form five recommendations statements and a research agenda. RESULTS: Forty-three studies met the review criteria. These included two randomized controlled trials and a predominance of small, uncontrolled series. In refractory ANCA-associated vasculitis, remission rates of >80% are obtained with rituximab. In newly diagnosed disease, rituximab is at least as effective as conventional therapy. Fifteen recommendations were made. Their strength was restricted by the low quality of the evidence. Six areas for future research were identified. CONCLUSION: On the basis of the available evidence and expert consensus, recommendations have been made for the use of rituximab as a treatment of ANCA-associated vasculitis. Further questions, in particular regarding long term outcomes, remain to be explored. PMID- 21613249 TI - Synoviocyte innate immune responses: TANK-binding kinase-1 as a potential therapeutic target in rheumatoid arthritis. AB - OBJECTIVES: Innate immune responses in the rheumatoid synovium contribute to inflammation and joint destruction in RA. Two IkappaB kinase (IKK)-related kinases, TNF receptor associated factor (TRAF) family member-associated nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) activator (TANK)-binding kinase 1 (TBK1) and IKKepsilon, potentially regulate synovitis by activating IFN response genes. These kinases induce the expression of inflammatory mediators such as C-X-C motif ligand 10 (CXCL10)/IFN-gamma-induced protein 10 kDa (IP-10) in fibroblast-like synoviocytes (FLS). Since IP-10 is a promising therapeutic target in RA, we evaluated whether blocking TBK1 might be an effective way to modulate IP-10 expression. METHODS: Wild-type (WT) and IKKepsilon(-/-) FLS were transfected with TBK1 or control small interfering RNA (siRNA) and stimulated with polyinosinic acid : polycytidylic acid [poly(I:C)]. Gene expression was assayed using quantitative PCR. Cytokine production in culture supernatants was measured by Luminex multiplex analysis. IFN-regulatory factor (IRF3) dimerization was determined by native PAGE. IFN-beta and IP-10 promoter activity was measured using luciferase reporter constructs. RESULTS: Initial studies showed that siRNA markedly decreased TBK1 expression in cultured FLS. Poly(I:C)-induced IRF7 gene expression was inhibited in the absence of TBK1, but not IKKepsilon. IRF3 gene expression was similar to WT cells in TBK1 or IKKepsilon-deficient FLS. IRF3 dimerization required both TBK1 and IKKepsilon. Surprisingly, IRF3-mediated gene and protein expression of IFN-beta and IP-10 was dependent on TBK1, not IKKepsilon. Promoter constructs showed that TBK1 decreased IP-10 gene transcription and IP-10 mRNA stability was unaffected by TBK1 deficiency. CONCLUSION: Based on the selective regulation of IP-10 in FLS, TBK1 appears to be the optimal IKK-related kinase to target in RA. PMID- 21613250 TI - Inhibitory receptors specific for MHC class I educate murine NK cells but not CD8alphaalpha intestinal intraepithelial T lymphocytes. AB - The engagement of inhibitory receptors specific for major histocompatibility complex class I (MHC-I) molecules educates natural killer (NK) cells, meaning the improvement of the response of activation receptors to subsequent stimulation. It is not known whether inhibitory MHC-I receptors educate only NK cells or whether they improve the responsiveness of all cell types, which express them. To address this issue, we analyzed the expression of inhibitory MHC-I receptors on intestinal intraepithelial lymphocytes (iIELs) and show that T-cell receptor (TCR)-alphabeta CD8alphaalpha iIELs express multiple inhibitory receptors specific for MHC-I molecules, including CD94/NKG2A, Ly49A, and Ly49G2. However, the presence of MHC-I ligand for these receptors did not improve the response of iIELs to activation via the TCR. The absence of iIEL education by MHC-I receptors was not related to a lack of inhibitory function of these receptors in iIELs and a failure of these receptors to couple to the TCR. Thus, unlike NK cells, iIELs do not undergo an MHC-I-guided education process. These data suggest that education is an NK cell-specific function of inhibitory MHC-I receptors. PMID- 21613251 TI - High-affinity memory B cells induced by conjugate vaccines against weak tumor antigens are vulnerable to nonconjugated antigen. AB - Induction of antibody-mediated immunity against hematologic malignancies requires CD4(+) T-cell help, but weak tumor antigens generally fail to induce adequate T cell responses, or to overcome tolerance. Conjugate vaccines can harness alternative help to activate responses, but memory B cells may then be exposed to leaking tumor-derived antigen without CD4(+) T-cell support. We showed previously using lymphoma-derived idiotypic antigen that exposure to "helpless" antigen silences the majority of memory IgG(+) B cells. Transfer experiments now indicate that silencing is permanent. In marked contrast to IgG, most coexisting IgM(+) memory B cells exposed to "helpless" antigen survive. Confirmation in a hapten (NP) model allowed measurement of affinity, revealing this, rather than isotype, as the determinant of survival. IgM(+) B cells had Ig variable region gene usage similar to IgG but with fewer somatic mutations. Survival of memory B cells appears variably controlled by affinity for antigen, allowing a minority of low affinity IgG(+), but most IgM(+), memory B cells to escape deletion in the absence of T-cell help. The latter remain, but the majority fail to undergo isotype switch. These findings could apply to other tumor antigens and are relevant for vaccination strategies aimed to induce long-term antibody. PMID- 21613253 TI - The only proposed T-cell epitope derived from the TEL-AML1 translocation is not naturally processed. AB - Adoptive therapy with T-cell receptor (TCR)-engineered T cells is a promising approach in cancer treatment. While usage of T cells specific for tumor associated antigens (TAAs) can lead to serious side effects because of autoimmunity, targeting true tumor-specific mutations, such as the products of translocations in leukemias, should reduce such a risk. A potentially ideal target might be the chimeric protein TEL-AML1, which results from the chromosomal translocation 12;21 and represents the most common fusion gene in childhood B cell precursor acute lymphoblastic leukemia (BCP-ALL). Within the fusion region of TEL-AML1, a single epitope has been described by reverse immunology as immunogenic in HLA-A*0201 restriction settings. As a potential source of TCRs specific for this TEL-AML1 epitope, we have used mice expressing a human TCR alphabeta repertoire and human MHC class I. Surprisingly, we have found that, although a specific functional CD8(+) T-cell response against this peptide could be evoked, the described epitope was in fact not endogenously processed. Analyses done with a potent antigen-presenting cell line, as well as with purified human proteasomes, support the conclusion that this peptide cannot be proposed as a potential target in immunotherapy of ALL in HLA-A*0201-restricted fashion. PMID- 21613252 TI - The multifunctional role of EKLF/KLF1 during erythropoiesis. AB - The cellular events that lead to terminal erythroid differentiation rely on the controlled interplay of extra- and intracellular regulatory factors. Their downstream effects are highly coordinated and result in the structural/morphologic and metabolic changes that uniquely characterize a maturing red blood cell. Erythroid Kruppel-like factor (EKLF/KLF1) is one of a very small number of intrinsic transcription factors that play a major role in regulating these events. This review covers 3 major aspects of erythropoiesis in which EKLF plays crucial functions: (1) at the megakaryocyte-erythroid progenitor stage, where it is involved in erythroid lineage commitment; (2) during the global expansion of erythroid gene expression in primitive and definitive lineages, where it plays a direct role in globin switching; and (3) during the terminal maturation of red cells, where it helps control exit from the cell cycle. We conclude by describing recent studies of mammalian EKLF/KLF1 mutations that lead to altered red cell phenotypes and disease. PMID- 21613254 TI - How I treat primary CNS lymphoma. AB - Primary CNS lymphoma (PCNSL) is a rare malignancy with peculiar clinical and biologic features, aggressive course, and unsatisfactory outcome. It represents a challenge for multidisciplinary clinicians and scientists as therapeutic progress is inhibited by several issues. Molecular and biologic knowledge is incomplete, limiting the identification of new therapeutic targets, and the particular microenvironment of this malignancy, and sanctuary sites where tumor cells grow undisturbed, strongly affects treatment efficacy. Moreover, active treatments are known to be associated with disabling neurotoxicity, posing the dilemma of whether to intensify therapy to improve the cure rate or to de-escalate treatment to avoid sequels. The execution of prospective trials is also difficult because of the rarity of the tumor and the impaired general condition and poor performance status of patients. Thus, level of evidence is low, with consequent uncertainties in therapeutic decisions and lack of consensus on primary endpoints for future trials. Despite this unfavorable background, laboratory and clinical researchers are coordinating efforts to develop new ideas, resulting in the recent publication of studies on PCNSL's biology and molecular mechanisms and of the first international randomized trials. Herein, these important contributions are analyzed to provide recommendations for everyday practice and the rationale for future trials. PMID- 21613255 TI - Novel associations between activating killer-cell immunoglobulin-like receptor genes and childhood leukemia. AB - Acute lymphoblastic leukemia of pre-B cells (pre-B ALL) is the most frequent form of leukemia affecting children in Western countries. Evidence is accumulating that genetic factors play an important role in conferring susceptibility/resistance to leukemia in children. In this regard, activating killer-cell immunoglobulin-like receptor (KIR) genes are of particular interest. Humans may inherit different numbers of the 6 distinct activating KIR genes. Little is known about the impact of this genetic variation on the innate susceptibility or resistance of humans to the development of B-ALL. We addressed this issue by performing a case-control study in Canadian children of white origin. Our results show that harboring activating KIR genes is associated with reduced risk for developing B-ALL in these children. Of the 6 activating KIR genes, KIR2DS2 was maximally associated with decreased risk for the disease (P = 1.14 * 10(-7)). Furthermore, our results showed that inheritance of a higher number of activating KIR genes was associated with significant reductions in risk for ALL in children. These results were also consistent across different ALL phenotypes, which included children with pre-T cell ALL. Our study provides novel insights concerning the pathogenesis of childhood leukemia in white children and has implications for the development of new immunotherapies for this cancer. PMID- 21613256 TI - High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. AB - We evaluated 190 children with very high-risk leukemia, who underwent allogeneic hematopoietic cell transplantation in 2 sequential treatment eras, to determine whether those treated with contemporary protocols had a high risk of relapse or toxic death, and whether non-HLA-identical transplantations yielded poor outcomes. For the recent cohorts, the 5-year overall survival rates were 65% for the 37 patients with acute lymphoblastic leukemia and 74% for the 46 with acute myeloid leukemia; these rates compared favorably with those of earlier cohorts (28%, n = 57; and 34%, n = 50, respectively). Improvement in the recent cohorts was observed regardless of donor type (sibling, 70% vs 24%; unrelated, 61% vs 37%; and haploidentical, 88% vs 19%), attributable to less infection (hazard ratio [HR] = 0.12; P = .005), regimen-related toxicity (HR = 0.25; P = .002), and leukemia-related death (HR = 0.40; P = .01). Survival probability was dependent on leukemia status (first remission vs more advanced disease; HR = 0.63; P = .03) or minimal residual disease (positive vs negative; HR = 2.10; P = .01) at the time of transplantation. We concluded that transplantation has improved over time and should be considered for all children with very high-risk leukemia, regardless of matched donor availability. PMID- 21613257 TI - Toso regulates the balance between apoptotic and nonapoptotic death receptor signaling by facilitating RIP1 ubiquitination. AB - The regulation of cellular survival and apoptosis is of critical importance for the immune system to maintain immune homeostasis and to establish tolerance. Here, we demonstrate that the immune specific cell surface molecule Toso exhibits antiapoptotic effects on death receptor signaling by a novel regulatory mechanism involving the adaptor kinase RIP1. The antiapoptotic function of Toso depends on RIP1 ubiquitination and involves the recruitment of the death adaptor FADD to a Toso/RIP1 protein complex. In response to CD95L and TNFalpha, Toso promotes the activation of MAPK and NF-kappaB signaling pathways. Because of this relative augmentation of survival versus apoptotic signals, Toso raises the threshold for death receptor-mediated apoptosis. Our analysis of Toso-deficient mice revealed that Toso is essential for TNFalpha-mediated liver damage. Furthermore, the antiapoptotic function of Toso could be blocked by a Toso-specific monoclonal antibody, opening up new therapeutic prospects for the treatment of immune disorders and hematologic malignancies. PMID- 21613258 TI - Musashi 2 is a regulator of the HSC compartment identified by a retroviral insertion screen and knockout mice. AB - We used a retroviral integration screen to search for novel genes that regulate HSC function. One of the genes that conferred HSC dominance when overexpressed due to an adjacent retroviral insertion was Musashi 2 (Msi2), an RNA-binding protein that can act as a translational inhibitor. A gene-trap mouse model that inactivates the gene shows that Msi2 is more highly expressed in long-term (LT) and short-term (ST) HSCs, as well as in lymphoid myeloid primed progenitors (LMPPs), but much less in intermediate progenitors and mature cells. Mice lacking Msi2 are fully viable for up to a year or more, but exhibit severe defects in primitive precursors, most significantly a reduction in the number of ST-HSCs and LMPPs and a decrease in leukocyte numbers, effects that are exacerbated with age. Cell-cycle and gene-expression analyses suggest that the main hematopoietic defect in Msi2-defective mice is the decreased proliferation capacity of ST-HSCs and LMPPs. In addition, HSCs lacking Msi2 are severely impaired in competitive repopulation experiments, being overgrown by wild-type cells even when mutant cells were provided in excess. Our data indicate that Msi2 maintains the stem cell compartment mainly by regulating the proliferation of primitive progenitors downstream of LT-HSCs. PMID- 21613259 TI - Anti-CD45 pretargeted radioimmunotherapy using bismuth-213: high rates of complete remission and long-term survival in a mouse myeloid leukemia xenograft model. AB - Pretargeted radioimmunotherapy (PRIT) using an anti-CD45 antibody (Ab) streptavidin (SA) conjugate and DOTA-biotin labeled with beta-emitting radionuclides has been explored as a strategy to decrease relapse and toxicity. alpha-emitting radionuclides exhibit high cytotoxicity coupled with a short path length, potentially increasing the therapeutic index and making them an attractive alternative to beta-emitting radionuclides for patients with acute myeloid leukemia. Accordingly, we have used (213)Bi in mice with human leukemia xenografts. Results demonstrated excellent localization of (213)Bi-DOTA-biotin to tumors with minimal uptake into normal organs. After 10 minutes, 4.5% +/- 1.1% of the injected dose of (213)Bi was delivered per gram of tumor. alpha-imaging demonstrated uniform radionuclide distribution within tumor tissue 45 minutes after (213)Bi-DOTA-biotin injection. Radiation absorbed doses were similar to those observed using a beta-emitting radionuclide ((90)Y) in the same model. We conducted therapy experiments in a xenograft model using a single-dose of (213)Bi DOTA-biotin given 24 hours after anti-CD45 Ab-SA conjugate. Among mice treated with anti-CD45 Ab-SA conjugate followed by 800 MUCi of (213)Bi- or (90)Y-DOTA biotin, 80% and 20%, respectively, survived leukemia-free for more than 100 days with minimal toxicity. These data suggest that anti-CD45 PRIT using an alpha emitting radionuclide may be highly effective and minimally toxic for treatment of acute myeloid leukemia. PMID- 21613260 TI - Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment. AB - Arsenic trioxide (As2O3) is a highly effective treatment for patients with refractory/relapsed acute promyelocytic leukemia (APL), but resistance to As2O3 has recently been seen. In the present study, we report the findings that 2 of 15 patients with refractory/relapsed APL treated with As2O3 were clinically As2O3 resistant. Leukemia cells from these 2 patients harbored missense mutations in promyelocytic leukemia gene-retinoic acid receptor-alpha gene (PML-RARA) transcripts, resulting in amino acid substitutions of A216V and L218P in the PML B2 domain. When wild-type or mutated PML-RARA (PR-WT and PR-B/L-mut, respectively) were overexpressed in HeLa cells, immunoblotting showed SUMOylated and/or oligomerized protein bands in PR-WT but not in PR-B/L-mut after As2O3 treatment. Protein-localization analysis indicated that PR-WT in the soluble fraction was transferred to the insoluble fraction after treatment with As2O3, but PR-B/L-mut was stably detected in fractions both with and without As2O3. Immunofluorescent microscopy analysis showed PR-WT localization as a microgranular pattern in the cytoplasm without As2O3 and as a macrogranular pattern with As2O3. PR-B/L-mut was diffusely observed in the cytoplasm with and without As2O3. Nearly identical localization patterns were observed in patients' primary cells. Therefore, B2 domain mutations may play an important role in aberrant molecular responses toAs2O3 and may be critical for As2O3 resistance in APL. PMID- 21613261 TI - Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML. AB - We conducted an open-label phase 1 study exploring the feasibility, safety, and biologic activity of epigenetic priming with decitabine before standard induction chemotherapy in patients with less-than-favorable risk of acute myelogenous leukemia (AML). We directly compared the clinical and DNA-hypomethylating activity of decitabine delivered at 20 mg/m2 by either a 1-hour infusion (Arm A) or a continuous infusion (Arm B) for 3, 5, or 7 days before a single, standard induction with infusional cytarabine (100 mg/m2 for 7 days) and daunorubicin (60 mg/m2 * 3 doses). Toxicity was similar to that of standard induction chemotherapy alone. Although we did not identify a maximum tolerated dose, there was more gastro-intestinal toxicity with 7 days of decitabine priming. Decitabine induced DNA hypomethylation at all dose levels and there was a trend toward greater hypomethylation in CD34(+) bone marrow cells when decitabine was delivered by a short pulse (Arm A). Twenty-seven subjects (90%) responded to therapy: 17 with complete remission (57%) and 10 with partial remission (33%). Of the patients with partial remission to protocol treatment, 8 achieved remission to their next therapy, bringing the overall complete remission rate to 83%. We conclude that epigenetic priming of intensive chemotherapy can be safely delivered in an attempt to improve response rates. This trial was registered at www.clinicaltrials.gov as NCT00538876. PMID- 21613262 TI - Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense. AB - Phylogenetically conserved serine protease cascades play an important role in invertebrate and vertebrate immunity. The mammalian coagulation system can be traced back some 400 million years and shares homology with ancestral serine proteinase cascades that are involved in, for example, Toll receptor signaling in insects and release of antimicrobial peptides during hemolymph clotting. In the present study, we show that the induction of coagulation by bacteria leads to immobilization and killing of Streptococcus pyogenes bacteria inside the clot. The entrapment is mediated via cross-linking of bacteria to fibrin fibers by the action of coagulation factor XIII (fXIII), an evolutionarily conserved transglutaminase. In a streptococcal skin infection model, fXIII(-/-) mice developed severe signs of pathologic inflammation at the local site of infection, and fXIII treatment of wild-type animals dampened bacterial dissemination during early infection. Bacterial killing and cross-linking to fibrin networks was also detected in tissue biopsies from patients with streptococcal necrotizing fasciitis, supporting the concept that coagulation is part of the early innate immune system. PMID- 21613263 TI - The prevalence, distribution, and clinical outcomes of electrocardiographic repolarization patterns in male athletes of African/Afro-Caribbean origin. AB - AIMS: Athletic training in male black athletes (BAs) is associated with marked ECG repolarization changes that overlap with hypertrophic cardiomyopathy (HCM). Differentiating between the two entities is prudent since BAs exhibit a higher prevalence of exercise-related sudden death from HCM compared with white athletes (WAs). METHODS AND RESULTS: Between 1996 and 2010, 904 BAs underwent serial cardiac evaluations including ECG and echocardiography. Athletes exhibiting T wave inversions were investigated further for HCM. Results were compared with 1819 WAs, 119 black controls (BCs), and 52 black HCM patients. Athletes were followed up for 69.7 +/- 29.6 months. T-wave inversions were present in 82.7% HCM patients, 22.8% BAs, 10.1% BCs, and 3.7% WAs. In athletes, the major determinant of T-wave inversions was black ethnicity. T-wave inversions in BAs (12.7%) were predominantly confined to contiguous anterior leads (V1-V4). Only 4.1% of BAs exhibited T-wave inversions in the lateral leads. In contrast, both BCs and HCM patients exhibited lower prevalence of T-wave inversions in leads V1-V4 (4.2 and 3.8%, respectively) with most T-wave inversions in HCM patients (76.9%) involving the lateral leads. During follow-up one BA survived cardiac arrest and two athletes (one BA, one WA) were diagnosed with HCM. All three exhibited T-wave inversions in the lateral leads. CONCLUSIONS: T-wave inversions in leads V1-V4 appear to represent an ethnic variant of 'athlete's heart'. Conversely, T-wave inversions in the lateral leads may represent the initial expression of underlying cardiomyopathy and merit further evaluation and regular surveillance. PMID- 21613264 TI - A comparison study between radon concentration in schools and other workplaces. AB - The Nuclear Technology Laboratory of the Aristotle University of Thessaloniki has since 1999 an open research project of indoor radon measurements in Greek workplaces. Since now 1380 measurements in 690 workplaces have been performed. Most (75 %) of the workplaces were offices in schools. The remaining 25 % were offices, mainly in public buildings. In the present study, a possible correlation between radon concentration in schools and other workplaces is investigated and discussed. PMID- 21613265 TI - The calibration of Bonner sphere spectrometer. AB - Bonner sphere spectrometer (BSS) is used in radiation protection measurement because of its wide energy range (thermal to MeV) and easy operation. Mitsubishi Heavy Industries (MHI) has used BSS to obtain neutron spectrum and has used the neutron spectrum to estimate neutron dose or induced activity. Calibration of BSS is important to estimate precise neutron dose or induced activity. MHI BSS was calibrated at National Institute of Advanced Industrial Science and Technology (AIST). The calibration results at AIST are in good agreement with calculation results. PMID- 21613266 TI - In situ magnetic field exposure and ICNIRP-based safety distances for electronic article surveillance systems. AB - Electromagnetic radiation of electronic article surveillance (EAS) systems was investigated in situ for both the detection gate panels and the activators and deactivators. 'Safety distances' for the general public, defined as the distances outside which the magnetic field levels of the EAS systems do not exceed the The International Commission on Non-ionising Radiation Protection reference levels, were determined. Additionally, temporal and frequency behaviour, and signal waveforms were investigated. For the detection gates, the spatially averaged fields exceeded the reference levels for five of the six investigated systems. For the (de)activators, the spatially averaged fields did not exceed the reference levels. Maximal fields up to 148.0 A m(-1) were measured from 20 cm on. The exposure ratios varied from 8 to 13 for EM, from 6 to 8 for AM and from 0.008 to 1.8 for RF systems. Safety distances were maximally 111 cm for EM, 77 cm for AM and 35 cm for RF systems. PMID- 21613267 TI - Monte Carlo simulation of in situ LaBr gamma-ray spectrometer for marine environmental monitoring. AB - Monte Carlo simulation of energy-response functions of gamma rays from natural/artificial radionuclides in seawater and simulation of energy spectrum due to self-activity in LaBr crystal were carried out using MCNPX codes and MATLAB programs for the in situ LaBr gamma-ray spectrometer immersed in homogeneous seawater. The effective detection distance, the detection efficiency and the minimum detectable activity concentration (MDAC) for artificial radionuclides (137)Cs were worked out as an instance. Similar researches for NaI detector was also implemented for comparison. The results indicate that the self activity in LaBr deteriorates the MDAC to merely several times of that of NaI detector. The LaBr detector is possible to be used as in situ gamma-ray spectrometer for monitoring of artificial radionuclides in seawater. PMID- 21613268 TI - Energy and angular dependence of active-type personal dosemeter for high-energy neutron. AB - In order to develop an active-type personal dosemeter having suitable sensitivity to high-energy neutrons, the characteristic response of silicon surface barrier detector has been investigated experimentally and theoretically. An agreement of the shape of pulse-height distribution, its change with radiator thickness and the relative sensitivity was confirmed between the calculated and experimental results for 14.8-MeV neutrons. The angular dependence was estimated for other neutron energies, and found that the angular dependence decreased with the incident energy. The reason was also discussed with regard to the radiator thickness relative to maximum range of recoil protons. PMID- 21613269 TI - Management of cosmic radiation exposure for aircraft crew in Japan. AB - The International Commission on Radiological Protection has recommended that cosmic radiation exposure of crew in commercial jet aircraft be considered as occupational exposure. In Japan, the Radiation Council of the government has established a guideline that requests domestic airlines to voluntarily keep the effective dose of cosmic radiation for aircraft crew below 5 mSv y(-1). The guideline also gives some advice and policies regarding the method of cosmic radiation dosimetry, the necessity of explanation and education about this issue, a way to view and record dose data, and the necessity of medical examination for crew. The National Institute of Radiological Sciences helps the airlines to follow the guideline, particularly for the determination of aviation route doses by numerical simulation. The calculation is performed using an original, easy-to use program package called 'JISCARD EX' coupled with a PHITS-based analytical model and a GEANT4-based particle tracing code. The new radiation weighting factors recommended in 2007 are employed for effective dose determination. The annual individual doses of aircraft crew were estimated using this program. PMID- 21613270 TI - The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons. AB - PTEN-induced putative kinase 1 (PINK1) and Parkin act in a common pathway to regulate mitochondrial dynamics, the involvement of which in the pathogenesis of Parkinson's disease (PD) is increasingly being appreciated. However, how the PINK1/Parkin pathway influences mitochondrial function is not well understood, and the exact role of this pathway in controlling mitochondrial dynamics remains controversial. Here we used mammalian primary neurons to examine the function of the PINK1/Parkin pathway in regulating mitochondrial dynamics and function. In rat hippocampal neurons, PINK1 or Parkin overexpression resulted in increased mitochondrial number, smaller mitochondrial size and reduced mitochondrial occupancy of neuronal processes, suggesting that the balance of mitochondrial fission/fusion dynamics is tipped toward more fission. Conversely, inactivation of PINK1 resulted in elongated mitochondria, indicating that the balance of mitochondrial fission/fusion dynamics is tipped toward more fusion. Furthermore, overexpression of the fission protein Drp1 (dynamin-related protein 1) or knocking down of the fusion protein OPA1 (optical atrophy 1) suppressed PINK1 RNAi-induced mitochondrial morphological defect, and overexpression of PINK1 or Parkin suppressed the elongated mitochondria phenotype caused by Drp1 RNAi. Functionally, PINK1 knockdown and overexpression had opposite effects on dendritic spine formation and neuronal vulnerability to excitotoxicity. Finally, we found that PINK1/Parkin similarly influenced mitochondrial dynamics in rat midbrain dopaminergic neurons. These results, together with previous findings in Drosophila dopaminergic neurons, indicate that the PINK1/Parkin pathway plays conserved roles in regulating neuronal mitochondrial dynamics and function. PMID- 21613273 TI - Do centres with well-developed protocols, training and infrastructure have higher rates of thrombolysis for acute ischaemic stroke? AB - BACKGROUND: The introduction of intravenous thrombolysis with recombinant tissue Plasminogen Activator (rt-PA) has greatly improved the effectiveness of acute ischaemic stroke care. However, in most hospitals only 2-10% of all admitted stroke patients are treated with thrombolysis. AIM: The purpose of this study is to identify if available protocols, training and infrastructure influence the thrombolysis rate. DESIGN: Cohort study of 12 hospitals in the Netherlands. METHODS: In a cohort of patients admitted with acute stroke within 24 h from onset of symptoms, data were obtained. Stroke service characteristics of 12 hospitals were acquired through structured interviews with intra- and extramural representatives, in order to asses (i) protocols, (ii) training and (iii) complexity of infrastructure. Data were analysed with multi-level logistic regression to relate the likelihood of treatment with thrombolysis to availability and completeness of protocols, training and infrastructure both outside (extramural) and inside (intramural) each centre. RESULTS: Overall 5515 patients were included in the study. Thrombolysis rates varied from 5.7% to 21.7%. An association was observed between thrombolysis rates and extramural training [odds ratio (OR): 1.11; 95% confidence interval (CI): 0.99-1.25] and availability of intramural protocols (OR: 1.46; 95% CI: 1.12-1.91). After adjustment for hospital size and teaching vs. nonteaching hospital, these associations became stronger; extramural training [adjusted OR (aOR): 1.14; 95% CI: 1.01-1.30] and availability of intramural protocols (aOR: 1.77; 95% CI: 1.30 2.39). CONCLUSIONS: Extramural training and intramural protocols are important tools to increase thrombolysis rates for acute ischaemic stroke in hospitals. Intramural protocols and extramural training should be aimed at all relevant professionals. PMID- 21613274 TI - Diagnostic utility of endobronchial ultrasound-guided transbronchial needle aspiration for left paratracheal lesions. PMID- 21613275 TI - Recovery of cardiac calcium release is controlled by sarcoplasmic reticulum refilling and ryanodine receptor sensitivity. AB - AIMS: In heart cells, the mechanisms underlying refractoriness of the elementary units of sarcoplasmic reticulum (SR) Ca(2+) release, Ca(2+) sparks, remain unclear. We investigated local recovery of SR Ca(2+) release using experimental measurements and mathematical modelling. METHODS AND RESULTS: Repeated Ca(2+) sparks were induced from individual clusters of ryanodine receptors (RyRs) in quiescent rat ventricular myocytes, and we examined how changes in RyR gating influenced the time-dependent recovery of Ca(2+) spark amplitude and triggering probability. Repeated Ca(2+) sparks from individual sites were analysed in the presence of 50 nM ryanodine with: (i) no additional agents (control); (ii) 50 uM caffeine to sensitize RyRs; (iii) 50 uM tetracaine to inhibit RyRs; or (iv) 100 nM isoproterenol to activate beta-adrenergic receptors. Sensitization and inhibition of RyR clusters shortened and lengthened, respectively, the median interval between consecutive Ca(2+) sparks (caffeine 239 ms; control 280 ms; tetracaine 453 ms). Recovery of Ca(2+) spark amplitude, however, was exponential with a time constant of ~100 ms in all cases. Isoproterenol both accelerated the recovery of Ca(2+) spark amplitude (tau = 58 ms) and shortened the median interval between Ca(2+) sparks (192 ms). The results were recapitulated by a mathematical model in which SR [Ca(2+)] depletion terminates Ca(2+) sparks, but not by an alternative model based on limited depletion and Ca(2+)-dependent inactivation of RyRs. CONCLUSION: Together, the results strongly suggest that: (i) local SR refilling controls Ca(2+) spark amplitude recovery; (ii) Ca(2+) spark triggering depends on both refilling and RyR sensitivity; and (iii) beta adrenergic stimulation influences both processes. PMID- 21613276 TI - Filling GAPs in the understanding of cardioprotection induced by GPCR activation: RGS proteins modulate ischaemic injury. PMID- 21613277 TI - Distinct lytic vacuolar compartments are embedded inside the protein storage vacuole of dry and germinating Arabidopsis thaliana seeds. AB - Plant cell vacuoles are diverse and dynamic structures. In particular, during seed germination, the protein storage vacuoles are rapidly replaced by a central lytic vacuole enabling rapid elongation of embryo cells. In this study, we investigate the dynamic remodeling of vacuolar compartments during Arabidopsis seed germination using immunocytochemistry with antibodies against tonoplast intrinsic protein (TIP) isoforms as well as proteins involved in nutrient mobilization and vacuolar acidification. Our results confirm the existence of a lytic compartment embedded in the protein storage vacuole of dry seeds, decorated by gamma-TIP, the vacuolar proton pumping pyrophosphatase (V-PPase) and the metal transporter NRAMP4. They further indicate that this compartment disappears after stratification. It is then replaced by a newly formed lytic compartment, labeled by gamma-TIP and V-PPase but not AtNRAMP4, which occupies a larger volume as germination progresses. Altogether, our results indicate the successive occurrence of two different lytic compartments in the protein storage vacuoles of germinating Arabidopsis cells. We propose that the first one corresponds to globoids specialized in mineral storage and the second one is at the origin of the central lytic vacuole in these cells. PMID- 21613278 TI - Comparison of intermediate vs subcutaneous cervical plexus block for carotid endarterectomy. AB - BACKGROUND: Carotid endarterectomy surgery can be performed under regional anaesthesia alone or under general anaesthesia. However, there are several types of regional block available and reported complication rates after superficial cervical plexus blocks are significantly lower than deep blocks. It is not known if subcutaneous and intermediate blocks are equally effective, although anatomical evidence suggests that the latter (where the injectate diffuses below the deep cervical fascia) might provide superior quality of intraoperative anaesthesia. METHODS: Forty-four patients were randomized to receive either subcutaneous or intermediate cervical plexus blocks for carotid endarterectomy. The primary endpoint was supplemental lidocaine requirement during surgery. Secondary outcome measures included: total amount of fentanyl administered during surgery, recall of pain scores during surgery, complications, and patient and surgeon satisfaction. RESULTS: There was no statistically significant difference for median (range) lidocaine supplementation between the subcutaneous and intermediate groups 65 (20-170) mg vs. 85 (30-345) mg, respectively; P=0.31. There were no statistical differences in the secondary outcome measures and no major complications during the study. CONCLUSIONS: Intermediate and subcutaneous cervical plexus blocks are equally effective for carotid endarterectomy. This study adds to the body of evidence supporting the safe use of superficial blocks for this type of surgery. PMID- 21613279 TI - Opioid receptor subtypes: fact or artifact? AB - There is a vast amount of pharmacological evidence favouring the existence of multiple subtypes of opioid receptors. In addition to the primary classification of u (mu: MOP), delta (delta: DOP), kappa (kappa: KOP) receptors, and the nociceptin/orphanin FQ peptide receptor (NOP), various groups have further classified the pharmacological u into u(1-3), the delta into delta(1 2)/delta(complexed/non-complexed), and the kappa into kappa(1-3). From an anaesthetic perspective, the suggestions that u(1) produced analgesia and u(2) produced respiratory depression are particularly important. However, subsequent to the formal identification of the primary opioid receptors (MOP/DOP/KOP/NOP) by cloning and the use of this information to produce knockout animals, evidence for these additional subtypes is lacking. Indeed, knockout of a single gene (and hence receptor) results in a loss of all function associated with that receptor. In the case of MOP knockout, analgesia and respiratory depression is lost. This suggests that further sub-classification of the primary types is unwise. So how can the wealth of pharmacological data be reconciled with new molecular information? In addition to some simple misclassification (kappa(3) is probably NOP), there are several possibilities which include: (i) alternate splicing of a common gene product, (ii) receptor dimerization, (iii) interaction of a common gene product with other receptors/signalling molecules, or (iv) a combination of (i)-(iii). Assigning variations in ligand activity (pharmacological subtypes) to one or more of these molecular suggestions represents an interesting challenge for future opioid research. PMID- 21613280 TI - From d-tubocurarine to sugammadex: the contributions of T. Cecil Gray to modern anaesthetic practice. AB - One hundred years after Morton's demonstration of the anaesthetic effects of ether, T. Cecil Gray revolutionized anaesthesia with his introduction of balanced general anaesthesia. Gray's technique involved i.v. induction, administration of a neuromuscular blocking agent (curare), tracheal intubation, controlled ventilation, maintenance of unconsciousness with a light inhaled anaesthetic (supplemented with opioids if necessary), and reversal of neuromuscular blocking agent at the conclusion of the anaesthetic. In the 65 yr since his seminal papers, our drugs have changed, and i.v. anaesthetics suitable for maintenance of anaesthesia have been introduced, but the basic principles of general anaesthesia today are those set forward by Gray 65 yr ago. PMID- 21613281 TI - Emerging modes of ventilation in the intensive care unit. AB - Potentially harmful effects of positive pressure mechanical ventilation have been recognized since its inception in the 1950s. Since then, the risk factors for and mechanisms of ventilator-induced lung injury (VILI) have been further characterized. Publication of the ARDSnet tidal volume trial in 2000 demonstrated that a ventilator strategy limiting tidal volumes and plateau pressure in patients with acute respiratory distress syndrome was associated with a 22% reduction in mortality. Since then, a variety of ventilator modes have emerged seeking to improve gas exchange, reduce injurious effects of ventilation, and improve weaning from the ventilator. We review here emerging ventilator modes in the intensive care unit (ICU). Airway pressure release ventilation seeks to optimize alveolar recruitment and maintain spontaneous ventilatory effort. It is associated with improved indices of respiratory and cardiovascular physiology, but data to support outcome benefit are lacking. High-frequency oscillatory ventilation is associated with improvements in gas exchange, but outcome data are conflicting. Extracorporeal modes of ventilation continue to evolve, and extra corporeal CO(2) removal is a technique that could be used in non-specialist ICUs. Proportional-assist ventilation and neutrally adjusted ventilator assist are modes that vary level of assistance with patient ventilatory effort. They result in greater patient-ventilator synchrony, but at present there is no evidence of a reduction in the duration of mechanical ventilation or outcome benefit. Although the use of many of these modes is likely to increase in intensive care units, further evidence of a beneficial effect is desirable before they are recommended. PMID- 21613282 TI - How dogs lap: ingestion and intraoral transport in Canis familiaris. AB - It has recently been suggested that the mechanism for lifting liquid from a bowl into the oral cavity during lapping is fundamentally different in cats and dogs: cats use adhesion of liquid to the tongue tip while dogs 'scoop' with their backwardly curled tongue. High-speed light videos and X-ray videos show that on the contrary, both cats and dogs use the mechanism of adhesion. Liquid is transported through the oral cavity to the oesophagus, against gravity, on the surface of the tongue as it is drawn upwards, then a tight contact between the tongue surface and palatal rugae traps liquid and prevents its falling out as the tongue is protruded. At least three cycles are needed for intraoral transport of liquid in the dog. PMID- 21613283 TI - Great flights by great snipes: long and fast non-stop migration over benign habitats. AB - Migratory land birds perform extreme endurance flights when crossing ecological barriers, such as deserts, oceans and ice-caps. When travelling over benign areas, birds are expected to migrate by shorter flight steps, since carrying the heavy fuel loads needed for long non-stop flights comes at considerable cost. Here, we show that great snipes Gallinago media made long and fast non-stop flights (4300-6800 km in 48-96 h), not only over deserts and seas but also over wide areas of suitable habitats, which represents a previously unknown migration strategy among land birds. Furthermore, the great snipes achieved very high ground speeds (15-27 m s(-1)), which was not an effect of strong tailwind support, and we know of no other animal that travels this rapidly over such a long distance. Our results demonstrate that some migratory birds are prepared to accept extreme costs of strenuous exercise and large fuel loads, even when stopover sites are available along the route and there is little tailwind assistance. A strategy of storing a lot of energy before departure, even if migration is over benign habitats, may be advantageous owing to differential conditions of fuel deposition, predation or infection risk along the migration route. PMID- 21613284 TI - Different behavioural responses to anthropogenic noise by two closely related passerine birds. AB - Anthropogenic noise, now common to many landscapes, can impair acoustic communication for many species, yet some birds compensate for masking by noise by altering their songs. The phylogenetic distribution of these noise-dependent signal adjustments is uncertain, and it is not known whether closely related species respond similarly to noise. Here, we investigated the influence of noise on habitat occupancy rates and vocal frequency in two congeneric vireos with similar song features. Noise exposure did not influence occupancy rates for either species, yet song features of both changed, albeit in different ways. With increases in noise levels, plumbeous vireos (Vireo plumbeus) sang shorter songs with higher minimum frequencies. By contrast, grey vireos (Vireo vicinior) sang longer songs with higher maximum frequencies. These findings support the notion that vocal plasticity may help some species occupy noisy areas, but because there were no commonalities among the signal changes exhibited by these closely related birds, it may be difficult to predict how diverse species may modify their signals in an increasingly noisy world. PMID- 21613285 TI - System among the corticosteroids: specificity and molecular dynamics. AB - Understanding how structural features determine specific biological activities has often proved elusive. With over 161,000 steroid structures described, an algorithm able to predict activity from structural attributes would provide manifest benefits. Molecular simulations of a range of 35 corticosteroids show striking correlations between conformational mobility and biological specificity. Thus steroid ring A is important for glucocorticoid action, and is rigid in the most specific (and potent) examples, such as dexamethasone. By contrast, ring C conformation is important for the mineralocorticoids, and is rigid in aldosterone. Other steroids that are less specific, or have mixed functions, or none at all, are more flexible. One unexpected example is 11-deoxycorticosterone, which the methods predict (and our activity studies confirm) is not only a specific mineralocorticoid, but also has significant glucocorticoid activity. These methods may guide the design of new corticosteroid agonists and antagonists. They will also have application in other examples of ligand-receptor interactions. PMID- 21613286 TI - The mechanics and energetics of human walking and running: a joint level perspective. AB - Humans walk and run at a range of speeds. While steady locomotion at a given speed requires no net mechanical work, moving faster does demand both more positive and negative mechanical work per stride. Is this increased demand met by increasing power output at all lower limb joints or just some of them? Does running rely on different joints for power output than walking? How does this contribute to the metabolic cost of locomotion? This study examined the effects of walking and running speed on lower limb joint mechanics and metabolic cost of transport in humans. Kinematic and kinetic data for 10 participants were collected for a range of walking (0.75, 1.25, 1.75, 2.0 m s(-1)) and running (2.0, 2.25, 2.75, 3.25 m s(-1)) speeds. Net metabolic power was measured by indirect calorimetry. Within each gait, there was no difference in the proportion of power contributed by each joint (hip, knee, ankle) to total power across speeds. Changing from walking to running resulted in a significant (p = 0.02) shift in power production from the hip to the ankle which may explain the higher efficiency of running at speeds above 2.0 m s(-1) and shed light on a potential mechanism behind the walk-run transition. PMID- 21613287 TI - Evolutionary optimization of material properties of a tropical seed. AB - Here, we show how the mechanical properties of a thick-shelled tropical seed are adapted to permit them to germinate while preventing their predation. The seed has evolved a complex heterogeneous microstructure resulting in hardness, stiffness and fracture toughness values that place the structure at the intersection of these competing selective constraints. Analyses of different damage mechanisms inflicted by beetles, squirrels and orangutans illustrate that cellular shapes and orientations ensure damage resistance to predation forces imposed across a broad range of length scales. This resistance is shown to be around the upper limit that allows cracking the shell via internal turgor pressure (i.e. germination). Thus, the seed appears to strike an exquisitely delicate adaptive balance between multiple selection pressures. PMID- 21613288 TI - The effects of vibration loading on adipose stem cell number, viability and differentiation towards bone-forming cells. AB - Mechanical stimulation is an essential factor affecting the metabolism of bone cells and their precursors. We hypothesized that vibration loading would stimulate differentiation of human adipose stem cells (hASCs) towards bone forming cells and simultaneously inhibit differentiation towards fat tissue. We developed a vibration-loading device that produces 3g peak acceleration at frequencies of 50 and 100 Hz to cells cultured on well plates. hASCs were cultured using either basal medium (BM), osteogenic medium (OM) or adipogenic medium (AM), and subjected to vibration loading for 3 h d(-1) for 1, 7 and 14 day. Osteogenesis, i.e. differentiation of hASCs towards bone-forming cells, was analysed using markers such as alkaline phosphatase (ALP) activity, collagen production and mineralization. Both 50 and 100 Hz vibration frequencies induced significantly increased ALP activity and collagen production of hASCs compared with the static control at 14 day in OM. A similar trend was detected for mineralization, but the increase was not statistically significant. Furthermore, vibration loading inhibited adipocyte differentiation of hASCs. Vibration did not affect cell number or viability. These findings suggest that osteogenic culture conditions amplify the stimulatory effect of vibration loading on differentiation of hASCs towards bone-forming cells. PMID- 21613290 TI - The role of the ribosomal protein S19 C-terminus in altering the chemotaxis of leucocytes by causing functional differences in the C5a receptor response. AB - Ribosomal protein S19 (RP S19) oligomers have been discovered as the first chemoattractant of migrating monocytes/macrophages to apoptotic cells via the C5a receptor (C5aR). In contrast to C5a, a fusion of the C-terminus (I(134)-H(145)) of RP S19 to C5a, the C5a/RP S19 chimera, substitutes for the RP S19 oligomers and is able to replicate C5aR antagonist-induced and agonist-induced dual effects on neutrophil and monocyte chemotactic responses, respectively. We recently discovered a gain of binding affinity when the I(134)-H(145) inhibited the activation of neutrophil C5aR-mediated chemotactic pathways. However, the opposing ligand-dependent chemotactic mechanisms are not fully understood. In this study, a loss of this additional binding affinity appeared to cause the monocyte C5aR to activate an alternative signalling pathway. The p38 mitogen activated-protein kinase (MAPK) pathway was linked to cell migration rather than a classical extracellular-regulated kinase 1/2 pathway commonly used by C5a. C5aR internalization was not involved in the alternative chemotactic pathway. We propose a model of activation involving a C5aR co-molecule that interferes with the C5aR-Gi protein interaction upon binding to the I(134)-H(145) in neutrophils; however, a free I(134)-H(145) from the C5aR co-molecule can guide the alternative activation of the chemotactic p38MAPK pathway in monocytes/macrophages. PMID- 21613289 TI - In situ preparation and protein delivery of silicate-alginate composite microspheres with core-shell structure. AB - The efficient loading and sustained release of proteins from bioactive microspheres remain a significant challenge. In this study, we have developed bioactive microspheres which can be loaded with protein and then have a controlled rate of protein release into a surrounding medium. This was achieved by preparing a bioactive microsphere system with core-shell structure, combining a calcium silicate (CS) shell with an alginate (A) core by a one-step in situ method. The result was to improve the microspheres' protein adsorption and release, which yielded a highly bioactive material with potential uses in bone repair applications. The composition and the core-shell structure, as well as the formation mechanism of the obtained CS-A microspheres, were investigated by X-ray diffraction, optical microscopy, scanning electron microscopy, energy dispersive spectrometer dot and line-scanning analysis. The protein loading efficiency reached 75 per cent in CS-A microspheres with a core-shell structure by the in situ method. This is significantly higher than that of pure A or CS-A microspheres prepared by non-in situ method, which lack a core-shell structure. CS-A microspheres with a core-shell structure showed a significant decrease in the burst release of proteins, maintaining sustained release profile in phosphate buffered saline (PBS) at both pH 7.4 and 4.3, compared with the controls. The protein release from CS-A microspheres is predominantly controlled by a Fickian diffusion mechanism. The CS-A microspheres with a core-shell structure were shown to have improved apatite-mineralization in simulated body fluids compared with the controls, most probably owing to the existence of bioactive CS shell on the surface of the microspheres. Our results indicate that the core-shell structure of CS-A microspheres play an important role in enhancing protein delivery and mineralization, which makes these composite materials promising candidates for application in bone tissue regeneration. PMID- 21613291 TI - Pregnancy-associated homeostasis and dysregulation: lessons from genetically modified animal models. AB - Physiological alterations occur in many organ systems during pregnancy. These changes are necessary for the adaptation to pregnancy-specific physiological processes in mother and fetus, and the placenta plays a critical role in the maintenance of homeostasis in pregnancy. Dysregulation of these functional feto maternal interactions leads to severe complications. There have been many attempts to create animal models that mimic the hypertensive disorders of pregnancy, especially pre-eclampsia. In this review, we summarize the physiology of pregnancy and placental function, and discuss the placental gene expression in normal pregnancy. In addition, we assess a number of established animal models focusing on a specific pathogenic mechanism of pre-eclampsia, including genetically modified mouse models involving the renin-angiotensin system. Validation of these animal models would contribute significantly to understanding the basic principles of pregnancy-associated homeostasis and the pathogenesis of pre-eclampsia. PMID- 21613292 TI - Identification of a 42-kDa Group IV cPLA2-activating protein, cPLAPgamma, as a GTP-binding protein in the bovine brain. AB - Brain tissue contains multiple forms of Phospholipase A(2) (PLA(2)) whose activities are involved in intracellular and intercellular signalling related to normal functions such as long-term potentiation, neurotransmitter release, cell growth and differentiation. Among them, we focused on regulatory mechanism of cPLA(2)alpha (Group IVA cytosolic PLA(2)) in brain tissue. In the present study, we report the identification of a cPLA(2)-activating protein (cPLAP) in the bovine brain. cPLAP activity appeared as two major peaks with molecular masses of 200 and 42 kDa in a Superose 12 gel filtration FPLC column. The 42-kDa form of cPLAP, designated cPLAPgamma, was further purified using a Mono S FPLC column to near homogeneity and characterized to as a GTP-binding protein (G protein). Metabolic labelling and immunoprecipitation studies revealed that cPLAPgamma associates with cPLA(2) in vitro and co-immunoprecipitates with [(35)S]-cPLA(2). Notably, cPLAPgamma rendered cPLA(2) fully activated at submicromolar concentrations of Ca(2+). These results suggest that cPLAPgamma may act as a G protein, activating cPLA(2)alpha prior to reaching full intracellular Ca(2+) concentrations. PMID- 21613293 TI - Left atrial fibrous band, an unexpected mechanism of mitral regurgitation. PMID- 21613294 TI - Extensive reproductive disruption, ovarian masculinization and aromatase suppression in Atlantic croaker in the northern Gulf of Mexico hypoxic zone. AB - The long-term impacts on marine ecosystems of the recent dramatic worldwide increase in the incidence of coastal hypoxia are unknown. Here, we show widespread reproductive disruption in Atlantic croakers collected from hypoxic sites approximately 120 km apart in the extensive northern Gulf of Mexico continental shelf hypoxic zone. Gonadal growth and gamete production were impaired in croakers from hypoxic sites compared with fish from reference normoxic sites east of the Mississippi River Delta. Male germ cells were detected in approximately 19 per cent of croaker ovaries collected in the hypoxic region, but were absent in ovaries from normoxic sites. In addition, the sex ratio was skewed towards males at the hypoxic sites. The masculinization and other reproductive disruptions were associated with declines in neuroendocrine function, as well as ovarian and brain expression of aromatase (the enzyme that converts androgens to oestrogens). A similar incidence of ovarian masculinization and decline in ovarian aromatase expression were observed in croaker after chronic laboratory hypoxia exposure, indicating that ovarian masculinization is a specific hypoxia response and is due to decreased aromatase activity. The results suggest severe reproductive impairment can occur over large coastal regions in marine fish populations exposed to seasonal hypoxia, with potential long-term impacts on population abundance. PMID- 21613295 TI - Adaptation and habitat selection in the eco-evolutionary process. AB - The struggle for existence occurs through the vital rates of population growth. This basic fact demonstrates the tight connection between ecology and evolution that defines the emerging field of eco-evolutionary dynamics. An effective synthesis of the interdependencies between ecology and evolution is grounded in six principles. The mechanics of evolution specifies the origin and rules governing traits and evolutionary strategies. Traits and evolutionary strategies achieve their selective value through their functional relationships with fitness. Function depends on the underlying structure of variation and the temporal, spatial and organizational scales of evolution. An understanding of how changes in traits and strategies occur requires conjoining ecological and evolutionary dynamics. Adaptation merges these five pillars to achieve a comprehensive understanding of ecological and evolutionary change. I demonstrate the value of this world-view with reference to the theory and practice of habitat selection. The theory allows us to assess evolutionarily stable strategies and states of habitat selection, and to draw the adaptive landscapes for habitat selecting species. The landscapes can then be used to forecast future evolution under a variety of climate change and other scenarios. PMID- 21613296 TI - Calcein labelling and electrophysiology: insights on coral tissue permeability and calcification. AB - The mechanisms behind the transfer of molecules from the surrounding sea water to the site of coral calcification are not well understood, but are critical for understanding how coral reefs are formed. We conducted experiments with the fluorescent dye calcein, which binds to calcium and is incorporated into growing calcium carbonate crystals, to determine the permeability properties of coral cells and tissues to this molecule, and to determine how it is incorporated into the coral skeleton. We also compared rates of calcein incorporation with rates of calcification measured by the alkalinity anomaly technique. Finally, by an electrophysiological approach, we investigated the electrical resistance of coral tissues in order to better understand the role of tissues in ionic permeability. Our results show that (i) calcein passes through coral tissues by a paracellular pathway, (ii) intercellular junctions control and restrict the diffusion of molecules, (iii) intercellular junctions should have pores of a size higher than 13 A and lower than 20 nm, and (iv) the resistance of the tissues owing to paracellular junctions has a value of 477 +/- 21 Ohm cm(2). We discuss the implication of our results for the transport of calcium involved in the calcification process. PMID- 21613297 TI - Sequence-based evidence for major histocompatibility complex-disassortative mating in a colonial seabird. AB - The major histocompatibility complex (MHC) is a polymorphic gene family associated with immune defence, and it can play a role in mate choice. Under the genetic compatibility hypothesis, females choose mates that differ genetically from their own MHC genotypes, avoiding inbreeding and/or enhancing the immunocompetence of their offspring. We tested this hypothesis of disassortative mating based on MHC genotypes in a population of great frigatebirds (Fregata minor) by sequencing the second exon of MHC class II B. Extensive haploid cloning yielded two to four alleles per individual, suggesting the amplification of two genes. MHC similarity between mates was not significantly different between pairs that did (n = 4) or did not (n = 42) exhibit extra-pair paternity. Comparing all 46 mated pairs to a distribution based on randomized re-pairings, we observed the following (i): no evidence for mate choice based on maximal or intermediate levels of MHC allele sharing (ii), significantly disassortative mating based on similarity of MHC amino acid sequences, and (iii) no evidence for mate choice based on microsatellite alleles, as measured by either allele sharing or similarity in allele size. This suggests that females choose mates that differ genetically from themselves at MHC loci, but not as an inbreeding-avoidance mechanism. PMID- 21613298 TI - Anaemia, hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus). AB - Polychlorinated biphenyls (PCBs), persistent chemicals widely used for industrial purposes, have been banned in most parts of the world for decades. Owing to their bioaccumulative nature, PCBs are still found in high concentrations in marine mammals, particularly those that occupy upper trophic positions. While PCB related health effects have been well-documented in some mammals, studies among dolphins and whales are limited. We conducted health evaluations of bottlenose dolphins (Tursiops truncatus) near a site on the Georgia, United States coast heavily contaminated by Aroclor 1268, an uncommon PCB mixture primarily comprised of octa- through deca-chlorobiphenyl congeners. A high proportion (26%) of sampled dolphins suffered anaemia, a finding previously reported from primate laboratory studies using high doses of a more common PCB mixture, Aroclor 1254. In addition, the dolphins showed reduced thyroid hormone levels and total thyroxine, free thyroxine and triiodothyronine negatively correlated with PCB concentration measured in blubber (p = 0.039, < 0.001, 0.009, respectively). Similarly, T-lymphocyte proliferation and indices of innate immunity decreased with blubber PCB concentration, suggesting an increased susceptibility to infectious disease. Other persistent contaminants such as DDT which could potentially confound results were similar in the Georgia dolphins when compared with previously sampled reference sites, and therefore probably did not contribute to the observed correlations. Our results clearly demonstrate that dolphins are vulnerable to PCB-related toxic effects, at least partially mediated through the endocrine system. The severity of the effects suggests that the PCB mixture to which the Georgia dolphins were exposed has substantial toxic potential and further studies are warranted to elucidate mechanisms and potential impacts on other top-level predators, including humans, who regularly consume fish from the same marine waters. PMID- 21613299 TI - Spatial heterogeneity in the effects of climate and density-dependence on dispersal in a house sparrow metapopulation. AB - Dispersal plays a key role in the response of populations to climate change and habitat fragmentation. Here, we use data from a long-term metapopulation study of a non-migratory bird, the house sparrow (Passer domesticus), to examine the influence of increasing spring temperature and density-dependence on natal dispersal rates and how these relationships depend on spatial variation in habitat quality. The effects of spring temperature and population size on dispersal rate depended on the habitat quality. Dispersal rate increased with temperature and population size on poor-quality islands without farms, where house sparrows were more exposed to temporal fluctuations in weather conditions and food availability. By contrast, dispersal rate was independent of spring temperature and population size on high-quality islands with farms, where house sparrows had access to food and shelter all the year around. This illustrates large spatial heterogeneity within the metapopulation in how population density and environmental fluctuations affect the dispersal process. PMID- 21613300 TI - Hypoxia induces expression of COX-2 through the homeodomain transcription factor CDX1 and orphan nuclear receptor SHP in human endometrial cells. AB - Endometriosis, the presence of ectopic endometrial tissue outside the uterine cavity, is a common disease affecting women during their reproductive years. The aim of this study was to identify the molecular mechanism of transcriptional regulation of inflammatory cyclooxygenase-2 (COX-2) gene during endometriosis by hypoxia. Hypoxia induced COX-2 expression in endometrial cells together with the induction of the orphan nuclear receptor SHP and intestinal-specific transcription factor Caudal-related transcription factor 1 (CDX1). Hypoxia inducible factor (HIF)-1alpha was responsible for SHP induction mediated by a hypoxia. In addition, we observed that ectopic expression of CDX1 enhanced COX-2 gene expression in hypoxia-dependent fashion. Additionally, we evaluated that induction of CDX1 by hypoxia was mediated by SHP. Expression of COX-2, CDX1, SHP and HIF-1alpha mRNA in hypoxia-treated human endometrial cells were significantly higher than normal control cells. These results suggest that the SHP and CDX1 expression increased by hypoxia play an active role in inducing inflammatory COX 2 expression in the pathogenesis of endometriosis. PMID- 21613301 TI - Processing speed and working memory performance in those with both ADHD and a reading disorder compared with those with ADHD alone. AB - In previous studies, children with both Attention-Deficit Hyperactivity Disorder (ADHD) and a Reading Disorder were found to have more difficulties with processing speed, working memory, and timed as opposed to non-timed executive functioning (EF) measures when compared with those with either disorder alone. The current study found that older adolescents and adults with both disorders also had more difficulties on processing speed and working memory measures than individuals who only had ADHD. There were no differences among non-timed EF scores. These results add support to the premise that common underlying features may be contributing to the high co-morbidity between these disorders and associated cognitive weaknesses. PMID- 21613302 TI - Sensitivity and test-retest reliability of the international shopping list test in assessing verbal learning and memory in mild Alzheimer's disease. AB - The International Shopping List Test (ISLT) was developed specifically to assess verbal list learning and memory in people from different language and cultural backgrounds. In this paper, we describe three studies that examined the sensitivity and reliability of the ISLT in assessing verbal list learning and memory impairment in English-speaking people with mild Alzheimer's disease (AD) and evaluated whether measures of retention-weighted recall (RWR) provided greater sensitivity and/or reliability relative to conventional list learning performance measures (e.g., free recall). In Study 1, we compared ISLT performance between patients with AD and matched controls and found that AD patients showed a large magnitude impairment on all ISLT performance measures (Cohen's d values >2). The RWR measure was more sensitive to detecting AD-related impairment than the free recall measure for Trial 1, although the most sensitive measures of the ISLT were free recall from Trial 3 and delayed recall. In Study 2, we compared RWR and free recall measures between 10- and 12-word versions of the ISLT, but found no difference between performance measures for the different list lengths. In Study 3, we evaluated test-retest reliabilities of the different outcome measures derived from the ISLT and found that measures of free recall had higher reliabilities than the RWR measures. Taken together, results of these studies suggest that measures of total free recall during learning trials and delayed recall from the 12-word version of the ISLT provide the greatest sensitivity to detecting verbal list learning and memory impairment in AD and that this task shows good test-retest reliability. PMID- 21613303 TI - Do alcohol-dependent individuals with DRD2 A1 allele have an increased risk of relapse? A pilot study. AB - AIMS: The TaqIA polymorphism of the dopamine D2 receptor (DRD2) gene has been extensively studied in relation to alcoholism, and the TaqI A1 allele appears to be over-represented in alcohol-dependent individuals. In a recent study, this allele has also been associated with a highly increased mortality rate in alcohol dependent individuals. In the present study, we investigated whether the TaqI A1 allele of the DRD2 gene region was associated with a higher relapse rate in alcohol-dependent individuals. METHODS: Adult women (n = 10) and men (n = 40) with a diagnosis of alcohol-dependence were recruited from two Swedish 12-step treatment units for alcoholism. Subjects were genotyped for the TaqIA polymorphism. On average, 1½ year after the end of the treatment program, subjects were re-interviewed by using the alcohol-related items from the Addiction Severity Index follow-up version. RESULTS: Thirty-three (66%) subjects self-reported relapse and 17 (34%) abstinence during the follow-up period. Thirty sex percent (18/50) were carriers of the A1 allele of the DRD2 gene region, and 64% (32/50) were non-carriers. Among the carriers of the A1 allele, 89% (16/18) reported relapse in contrast to 53% (17/32) in the non-carriers (P = 0.01; odds ratio = 7.1). CONCLUSION: The present study is, to our knowledge, the first report of an association between the TaqI A1 allele and a substantially increased relapse rate. It should be emphasized that the number of subjects is relatively small, and this investigation should therefore be considered as a pilot study. PMID- 21613304 TI - Culture and end-of-life care: an epidemiological evaluation of physicians. AB - Beneficence is a fundamental concept of medicine, which embodies the notion above all, do no harm. While this principle illustrates the health care professional's duty to contribute to the patient's welfare, the principle becomes convoluted when the wishes of the patient directly conflict with that of the physician. The purpose of the study was to determine the degree to which cultural beliefs influence a physician's decision to introduce the concept of hospice to terminally ill patients. This phenomenological study explored the perceptions of 14 physicians practicing medicine in Mercer County, New Jersey. Analysis of the textural data revealed the following 5 themes: (a) physician personal perspectives, (b) physician perspectives on culture, (c) perspectives on hospice care, (d) communication with patients, and (e) training and experience. PMID- 21613305 TI - alpha-Fetoprotein. AB - alpha-Fetoprotein (AFP) measurements have clinical implications in fetal medicine and, in infants and older children, in detection, differential diagnosis and monitoring of malignant disease. Maternal serum AFP levels constitute part of a multiple-marker test used in early second-trimester screening to predict risk of fetal chromosomal abnormalities. Those individuals with increased risk are offered further definitive diagnostic investigation. Second-trimester screening is now increasingly being superseded by first-trimester screening with other serum markers and ultrasound. As AFP is only produced physiologically during fetal development, elevated serum levels after the first two post-natal years usually indicate the presence of a malignant disease process. Before this time, levels may be purely physiological and therefore serial values should be plotted on a logarithmic chart to ensure that they are falling appropriately, with a typical half-life of ~5-6 days. If not, further investigation should be undertaken. Serum AFP is raised in a significant proportion of germ cell tumours (GCTs), hepatoblastoma and hepatocellular carcinoma (HCC). In suspected cases of GCT, serum human choriogonadotropin (HCG) estimation should also be performed. For possible intracranial GCTs, both serum and cerebrospinal fluid levels of AFP and HCG should be measured, ideally before neurosurgical biopsy. In malignant conditions, serum AFP may be used for diagnosis, treatment monitoring, surveillance for disease recurrence and prognostication. Immunohistochemistry for AFP using antibody staining is routinely used to assist pathological diagnosis on tissue sections where the differential includes GCT, hepatoblastoma and/or HCC. Elevations of serum AFP also occur in non-malignant conditions such as chronic liver disease. PMID- 21613306 TI - Difference in prognostic significance of maximum standardized uptake value on [18F]-fluoro-2-deoxyglucose positron emission tomography between adenocarcinoma and squamous cell carcinoma of the lung. AB - OBJECTIVE: This study evaluates the prognostic significance of [18F]-fluoro-2 deoxyglucose positron emission tomography/computed tomography findings according to histological subtypes in patients with completely resected non-small cell lung cancer. METHODS: We examined 176 consecutive patients who had undergone preoperative [18F]-fluoro-2-deoxyglucose-positron emission tomography/computed tomography imaging and curative surgical resection for adenocarcinoma (n = 132) or squamous cell carcinoma (n = 44). Maximum standardized uptake values for the primary lesions in all patients were calculated as the [18F]-fluoro-2 deoxyglucose uptake and the surgical results were analyzed. RESULTS: The median values of maximum standardized uptake value for the primary tumors were 2.60 in patients with adenocarcinoma and 6.95 in patients with squamous cell carcinoma (P< 0.001). Analyses of receiver operating characteristic curves identified an optimal maximum standardized uptake value cutoff value to predict recurrence of 3.7 for adenocarcinoma, whereas such an indicator could not be identified for squamous cell carcinoma. Although 2-year disease-free survival rates were 70.2% for maximum standardized uptake value <=6.95 and 59.3% for maximum standardized uptake value >6.95 (P = 0.83) among patients with squamous cell carcinoma, 2-year disease-free survival rates were 93.9% for maximum standardized uptake value <=3.7 and 52.4% for maximum standardized uptake value >3.7 (P < 0.0001) among those with adenocarcinoma, and notably, 100 and 57.2%, respectively, in patients with Stage I adenocarcinoma (P < 0.0001). On the basis of the multivariate Cox analyses of patients with adenocarcinoma, maximum standardized uptake value (P = 0.008) was a significantly independent factor for disease-free survival as well as nodal metastasis (P = 0.001). CONCLUSIONS: Maximum standardized uptake value of the primary tumor was a powerful prognostic determinant for patients with adenocarcinoma, but not with squamous cell carcinoma of the lung. PMID- 21613307 TI - The K+ uptake regulator TrkA controls membrane potential, pH homeostasis and multidrug susceptibility in Mycobacterium smegmatis. AB - BACKGROUND: Rifampicin is an important first-line antibiotic for the treatment of mycobacterial infections. Although most rifampicin-resistant strains arise through mutations in the rpoB gene in bacteria, a proportion of such strains show no rpoB mutations. This suggests that alternative mechanisms are responsible for rifampicin resistance. METHODS: We have constructed and analysed a library of 11, 000 Mycobacterium smegmatis insertion mutants to find other possible rifampicin resistance determinants. RESULTS: We found that disruption of trkA, a putative regulator of K(+) uptake, leads to increased rifampicin resistance. Our data indicate that TrkA-mediated K(+) uptake is essential for maintenance of the M. smegmatis growth rate, its pH homeostasis and membrane potential. In addition to increased rifampicin resistance, inactivation of trkA confers resistance to other hydrophobic agents, such as novobiocin, as well as increased susceptibility to isoniazid and positively charged aminoglycosides. CONCLUSIONS: Our results suggest that trkA is a general regulator of antibiotic susceptibility, and the changes in the multidrug susceptibility/resistance pattern detected in the trkA mutant are associated with membrane hyperpolarization. This study sheds light on the role of ion transport activity in intrinsic and acquired antibiotic resistance in mycobacteria. PMID- 21613308 TI - Nottingham knee osteoarthritis risk prediction models. AB - OBJECTIVES: (1) To develop risk prediction models for knee osteoarthritis (OA) and (2) to estimate the risk reduction that results from modification of potential risk factors. METHOD: This was a 12-year retrospective cohort study undertaken in the general population in Nottingham, UK. Baseline risk factors were collected by questionnaire. Incident radiographic knee OA was defined by Kellgren and Lawrence (KL) score >=2. Incident symptomatic knee OA was defined by KL >=2 plus knee pain. Progression of knee OA was defined by KL >=1 grade increase from baseline. A logistic regression model was used for prediction. Calibration and discrimination of the models were tested in the Osteoarthritis Initiative (OAI) population and Genetics of Osteoarthritis and Lifestyle (GOAL) population. ORs of the models were compared with those obtained from meta analysis of existing literature. RESULTS: From a community sample of 424 people aged over 40, 3 risk prediction models were developed. These included incidence of radiographic knee OA, incidence of symptomatic knee OA and progression of knee OA. All models had good calibration and moderate discrimination power in OAI and GOAL. The ORs lied within the 95% CIs of the published studies. The risk reduction due to modifying obesity at the individual and the population levels were demonstrated. CONCLUSIONS: Risk prediction of knee OA based on the well established, common modifiable risk factors has been established. The models may be used to predict the risk of knee OA, and risk reduction due to preventing a specific risk factor. PMID- 21613309 TI - IL13 gene polymorphism is a marker for psoriatic arthritis among psoriasis patients. AB - AIM: To study the association between smoking and IL13 gene polymorphisms with psoriatic arthritis (PsA) and psoriasis. METHODS: The authors genotyped three groups of Caucasians: those with PsA, those with psoriasis without arthritis (PsC) and healthy controls for the rs20541 and rs848 IL13 single nucleotide polymorphisms (SNPs). An additional SNP, rs1800925, was genotyped only in the PsA and PsC groups. The differences in allelic distributions were compared by chi(2) test. The prevalence of smoking was compared between people with PsA and those with PsC. The combined effect of genotype and smoking was tested by comparing the frequencies of different combinations of rs1800925 genotype and smoking status in PsA and PsC. RESULTS: 555 PsA patients, 342 PsC patients and 217 healthy controls were included in the study. Smoking was less prevalent in patients with PsA compared with PsC (47.4% vs 59.4%, p<0.0006). rs20541*G and rs848*C alleles were associated with PsA compared with controls (OR 1.64, p=0.0005, OR 1.61, p=0.0007 respectively). The association between these alleles and PsC compared with controls was only of borderline significance (OR 1.33, p=0.06, OR 1.26, p=0.11 respectively). Two major alleles, rs1800925*C (OR 1.28, p=0.045) and rs848*C (OR 1.30, p=0.047) were increased in PsA compared with PsC. The combination of non smoking and the genotype rs1800925*CC was associated with increased susceptibility to PsA compared with PsC. Among smokers, rs1800925*CC was not associated with PsA compared with PsC. CONCLUSIONS: IL13 gene polymorphism is associated with increased susceptibility to PsA in psoriasis patients. PMID- 21613310 TI - Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-alpha, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo controlled, phase I, first-in-human study. AB - OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of mavrilimumab, a human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-alpha, in subjects with rheumatoid arthritis (RA). METHODS: A randomised, double-blind, placebo controlled, dose-escalating phase I study in subjects with RA who received stable methotrexate treatment for >=3 months before enrolment. SUBJECTS: received single intravenous escalating doses of mavrilimumab (0.01-10.0 mg/kg) or placebo. RESULTS: 32 subjects were enrolled in this study (1 unblinded subject at 0.01 mg/kg and another at 0.03 mg/kg were followed by five sequential double-blinded cohorts, n=6 each, treated with 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg, respectively). Adverse events were mild or moderate and were reported with similar frequency across all treatment cohorts. One subject (10.0 mg/kg) experienced moderate face and neck urticaria during infusion that resolved with symptomatic treatment. Systemic clearance of mavrilimumab approached that of endogenous IgG at doses >1.0 mg/kg; pharmacodynamic activity was confirmed in the 1.0 and 3.0 mg/kg cohorts by suppression of suppressor of cytokine signalling 3 mRNA transcripts. In exploratory analyses, reductions of acute phase reactants were observed in subjects with elevated C-reactive protein (>5 mg/l) and erythrocyte sedimentation rate (>=20.0 mm/h) at baseline. No significant change in Disease Activity Score 28-joint assessment (DAS28) was seen in any of the cohorts. In mavrilimumab treated subjects (n=15) with baseline DAS28 >3.2, mean disease activity (DAS28) was significantly reduced at 4 weeks. CONCLUSION: In this first-in-human study, mavrilimumab showed preliminary evidence of pharmacodynamic activity. Importantly, the safety and pharmacokinetic profiles of mavrilimumab support further clinical studies in RA. TRIAL REGISTRATION NUMBER: NCT00771420. PMID- 21613311 TI - A dominant suppressive MHC class II haplotype interacting with autosomal genes controls autoantibody production and chronicity of arthritis. AB - OBJECTIVE: To investigate the genetic control of chronic arthritis and collagen epitope specific antibody responses in an experimental model for rheumatoid arthritis. METHODS: The chronic collagen induced arthritis (CCIA) model was used, induced with collagen type II (CII) in mineral oil lacking mycobacterium in BALB/c (n=24), B10.Q (n=44), (BALB/c * B10.Q) F1 (n=85) and B10.Q * (BALB/c * B10.Q) N2 (n=684) mice. Genome-wide genotyping for 190 N2 mice was performed with extreme phenotypes: chronic arthritis that persisted for 4 months or non affected. Statistical and linkage analysis were performed with R/qtl software using arthritis and serum subphenotypes. RESULTS: (BALB/c * B10.Q) F1 mice were highly prone to develop a chronic relapsing arthritis (66%), whereas both parental strains were relatively resistant: BALB/c (H-2(d); 0%) and B10.Q (H 2(q); 4.5%). CCIA experiments were performed on 684 mice backcrossed to B10.Q; 38% of the mice developed arthritis and more than half of them developed chronic arthritis phenotype. Genome-wide genotyping revealed mainly the major histocompatibility complex (MHC) locus that had an independent and dominant influence on the chronicity. Interestingly, the H2(d) allele had a dominant suppressive effect. This effect overrode the role of other loci as interaction analysis, after conditioning MHC, revealed additional loci, controlling arthritis and autoantibody phenotypes. CONCLUSIONS: A dominant negative influence of specific MHC haplotype (H2(d)) on CCIA was identified. Further, loci controlling the autoantibody response to different CII epitopes were also identified, and it has been shown that these are dependent on MHC and non-MHC genes. PMID- 21613312 TI - Spontaneous resolution of acute gouty arthritis is associated with rapid induction of the anti-inflammatory factors TGFbeta1, IL-10 and soluble TNF receptors and the intracellular cytokine negative regulators CIS and SOCS3. AB - OBJECTIVE: The molecular basis for spontaneous resolution of acute gouty arthritis (GA) remains unclear. The hypothesis that extracellular and intracellular mechanisms play roles in resolving acute GA was tested. METHODS: Synovial fluid (SF) levels of transforming growth factor beta1 (TGFbeta1), interleukin 1 (IL-1) receptor antagonist (IL-1ra), IL-10 and soluble tumour necrosis factor (TNF) receptor I (sTNFRI) and II (sTNFRII) were measured by ELISA in patients with acute GA and osteoarthritis (OA). Monosodium urate (MSU) crystal stimulated RAW264.7 mouse macrophages were analysed for cytokine inducible SH2 containing protein (CIS) and suppressors of cytokine signalling (SOCS)1-7 mRNA expression by reverse transcription (RT)-PCR. Immunohistochemical analysis, quantitative PCR and immunoblotting were performed to detect CIS and SOCS3 expression in synovial tissue, SF mononuclear cells (SFMCs) from patients with GA and MSU crystal-stimulated monocyte-derived macrophages from healthy donors. CIS overexpression and small interfering RNA-mediated knockdown in RAW264.7 cells were used to investigate the role of CIS in resolving MSU crystal-induced acute inflammation. RESULTS: SF levels of anti-inflammatory molecules TGFbeta1, IL-1ra, IL-10 and sTNFR-I/II were significantly elevated in GA compared to OA. CIS and SOCS3 were upregulated in the synovium and SFMCs from acute GA and MSU crystal stimulated monocyte-derived macrophages and RAW264.7 cells. CIS overexpression in RAW264.7 cells attenuated MSU crystal-induced IL-1beta and TNFalpha but enhanced TGFbeta1 production via increased binding of signal transducer and activator of transcription 3 (STAT3) to the TGFbeta1 promoter. Conversely, CIS knockdown reversed the effect of CIS overexpression, resulting in enhanced IL-1beta and TNFalpha but reduced TGFbeta1 production in MSU crystal-stimulated RAW264.7 cells. CONCLUSIONS: Increased production of TGFbeta1, IL-1ra, IL-10 and sTNFR I/II and upregulation of intracellular CIS and SOCS3 expression are associated with spontaneous resolution of acute GA. PMID- 21613313 TI - Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review. AB - BACKGROUND: Peripheral natural killer (pNK) and uterine NK (uNK) cells have been associated with reproductive failure. We systematically reviewed the literature to assess whether numbers or activity of pNK or uNK cells predicted subsequent pregnancy and outcome. METHODS: We searched the electronic MEDLINE database from 1950 to April 2010 for relevant publications by using MeSH terms 'natural killer cells', 'reproduction' and 'pregnancy complications'. We included studies that measured pre-pregnancy pNK and uNK cell numbers or activity in women with recurrent miscarriage (RM) or infertility, and reported subsequent pregnancy outcomes of miscarriage or failure to conceive after assisted reproductive technology (ART). RESULTS: The search identified 783 publications and 12 fulfilled the inclusion criteria. There were too few women entered into the observational studies to assess whether high pNK cell percentages or activity predicted subsequent miscarriage in women with idiopathic RM (numbers: n = 32, OR 17, 95% CI 0.82-350.6, activity: n = 92, OR 2.51, 95% CI 0.16-40.29), or implantation failure (n = 203, OR 1.35, 95% CI 0.28-6.46), or miscarriage in infertile women after ART (n = 79, OR 2.48, 95% CI 0.50-12.32). Similarly, the studies of uNK cells were not large enough to assess whether abnormal uNK cell density predicted subsequent miscarriage in women with idiopathic RM (n = 72, OR 1.33, 95% CI 0.16-11.11). None of the uNK cell studies in women with infertility reported pregnancy outcomes dichotomized for uNK cell numbers. CONCLUSIONS: The prognostic value of measuring pNK or uNK cell parameters remains uncertain. More studies are needed to confirm or refute the role of NK cell assessments as a predictive test for screening women who may benefit from immunotherapy. PMID- 21613314 TI - Inequitable access to assisted reproductive technology for the low-income Brazilian population: a qualitative study. AB - BACKGROUND: In Brazil, access to infertility care, including assisted reproductive technology (ART) is restricted. This is a second report of a study which evaluated the availability and access of low-income couples to ART services. The objective was to assess the perspective of health professionals and patients with respect to access to ART procedures within the public health network METHODS: Qualitative case studies were conducted in five centres offering ART in the public sector. Semi-structured interviews were conducted with 19 health professionals based at these centres and 48 patients (men and women). Data were analysed using thematic content analysis. RESULTS: All services implemented ART procedures using resources already available. In all except one centre, patients had to pay for the drugs used for the procedures and, in some cases, a fee to cover operative costs and supplies. These charges were incompatible with the financial possibilities of the majority of the low-income Brazilian population. The waiting time for access to ART varied between 3 months and 6 years. In the perspective of both patients and health professionals, the government should help centres to offer ART procedures at no cost to low-income populations. CONCLUSIONS: The low-income Brazilian population has limited access to ART procedures at the public services. The implementation of ART services cannot be based only on initiatives of the professionals involved but must be part of public health policies. One possible solution is to provide ART at lower cost, making it accessible for a large part of the population. PMID- 21613316 TI - Population-wide use of behavioural prevention and counselling programmes for lifestyle-related cardiovascular risk factors in Germany. AB - BACKGROUND: Behavioural prevention and counselling programmes for lifestyle related cardiovascular risk factors are widely offered. However, their population wide use is largely unexplored, particularly in high-risk persons with known CVD or diabetes. METHODS: Data were collected within GEDA 2009, a national health survey covering a representative sample of 21,262 adults in Germany. Standardised structured computer-assisted telephone interviews included self-reported physician-diagnosed coronary heart disease, myocardial infarction, heart failure, stroke, diabetes as well as height, weight, usual diet, physical activity, and the use of programmes for weight reduction, healthy diet and improvement of fitness or mobility in the last twelve months. RESULTS: The use of prevention measures was lowest for weight reduction (men 2.1%, women 3.5%), somewhat higher for healthy diet (men 3.2%, women 4.7%), and highest for improvement of fitness or mobility (men 8.6%, women 16.1%). Among individuals with the respective risk factor, programme participation was still low: 5.5% in obese men (women 7.2%) for weight reduction, 2.8% in men (women 3.7%) who did not eat fruit or vegetables daily for healthy diet, and 7.9% in physically inactive men (women 15.7%) for improvement of fitness or mobility. In the presence of known CVD or diabetes, participation increased inconsistently and only moderately. CONCLUSION: Our results show low participation in behavioural prevention measures for lifestyle related risk factors even in individuals with known CVD or diabetes. Further studies should investigate knowledge about potential programme benefit, availability and reimbursement in both patients and health care providers. PMID- 21613317 TI - Cardiovascular pre-participation screening does not distress professional football players. AB - BACKGROUND: It has been debated whether cardiovascular screening of athletes creates negative psychological reactions in those being screened. Neither the athletes' level of distress towards, nor their opinion about screening has actually been examined. Therefore, the aim of this study was to assess the level of distress among Norwegian elite male football players and their experiences of screening. METHODS: After screening, players completed a 10-item scale assessing their experience on a Likert scale. Their level of distress was measured with the intrusion sub-scale of Impact of Event Scale (IES) (7 items) on a six-point scale (grade 0-5). A sum score of >=19 indicates a clinical stress problem. Twenty-five out of 28 teams, 441 of 591 players (75%, mean age 26 [18-39] years) consented to participate. RESULTS: Sixty-four percent felt more confident when playing football and 88% were satisfied having completed the screening. The majority (77%) felt a need for the screening and 84% would strongly recommend it to others. Sixteen percent were afraid that the screening result might have consequences for their own health, and 13% were afraid of losing their license to play football. Less than 3% experienced distress (IES >= 19). CONCLUSIONS: The majority of the players were satisfied having completed the screening, felt more confident and would recommend it to other players. Only a marginal proportion of the players were distressed by the screening, but were at least as likely to recommend it. PMID- 21613315 TI - Testicular recovery after irradiation differs in prepubertal and pubertal non human primates, and can be enhanced by autologous germ cell transplantation. AB - BACKGROUND: Although infertility is a serious concern in survivors of pediatric cancers, little is known about the influence of the degree of sexual maturation at the time of irradiation on spermatogenic recovery after treatment. Thus, we address this question in a non-human primate model, the rhesus monkey (Macaca mulatta). METHODS: Two pubertal (testis size 3 and 6.5 ml, no sperm in ejaculate) and four prepubertal (testis size 1 ml, no sperm in ejaculate) macaques were submitted to a single fraction of testicular irradiation (10 Gy). Unilateral autologous transfer of cryopreserved testis cells was performed 2 months after irradiation. Testicular volume, histology and semen parameters were analyzed to assess irradiation effects and testicular recovery. RESULTS: Irradiation provoked acute testis involution only in the two pubertal monkeys. Subsequently, testis sizes recovered and sperm was present in the ejaculates. Longitudinal outgrowth of seminiferous tubules continued, and, in testes without autologous cell transfer, 4-22% of tubular cross sections showed spermatogenesis 2 years after irradiation. In contrast, the four prepubertal monkeys showed neither a detectable involution as direct response to irradiation, nor a detectable growth of seminiferous tubules later. However, two of these animals showed spermarche 2 years after irradiation, and 8-12% of tubules presented spermatogenesis. One prepubertally irradiated monkey presented fast growth of one testis after cell transfer, and showed spermarche 1 year after irradiation. The infused testis had spermatogenesis in 70% of the tubules. The contralateral testis remained smaller. CONCLUSION: We conclude that irradiation before puberty has a severe detrimental effect on outgrowth of seminiferous tubules. But, within the seminiferous epithelium, spermatogenetic recovery occurs at a low rate with no detectable relation to the maturity of the epithelium at irradiation. We also show that autologous testis cell transplantation can enhance spermatogenesis, but only in isolated cases. PMID- 21613319 TI - Asymmetrical distribution of atherosclerosis in the carotid artery: identical patterns across age, race, and gender. AB - BACKGROUND: Small autopsy studies and clinical practice indicated that carotid atherosclerosis develops in an asymmetrical helical pattern coinciding with regions of low shear stress. We investigated the distribution of carotid atherosclerosis as determined by maximum carotid intima-media thickness (CIMT), to assess if we could confirm this atherosclerotic configuration across various populations with different cardiovascular risk. METHODS AND RESULTS: We used the individual baseline CIMT data from 3364 subjects from four recent international multicentre randomized controlled trials in which the carotid artery was systematically examined using the same ultrasound protocol and method to quantify CIMT. For each subject, circumferential information on the maximum CIMT of the left and right carotid arteries was obtained for the common carotid, bifurcation, and internal carotid artery segments. In each segment (common, bifurcation, internal), mixed modelling was used to study the differences in CIMT between angles, sides, gender, age, race, and studies. Each segment showed a different circumferential CIMT pattern. In all segments there were statistically significant differences between maximum CIMT across circumferential angles (p < 0.001); on average CIMT was highest in the posteromedial wall of the bifurcation and internal carotid segments and in the anterolateral wall of the common carotid segment. This asymmetric circumferential pattern was found to be identical in men and women, in young and old age, in different race groups, and across the studies. CONCLUSIONS: We confirmed the asymmetrical helix-like distribution of atherosclerosis in the carotid arteries and expand the evidence by showing that the atherosclerotic configuration is similar across populations with different vascular risks and across gender, age, and race. This has implications for future design of carotid ultrasound studies, as the angle of insonation is an important predictor of maximum CIMT. PMID- 21613320 TI - dachsous and frizzled contribute separately to planar polarity in the Drosophila ventral epidermis. AB - Cells that comprise tissues often need to coordinate cytoskeletal events to execute morphogenesis properly. For epithelial tissues, some of that coordination is accomplished by polarization of the cells within the plane of the epithelium. Two groups of genes--the Dachsous (Ds) and Frizzled (Fz) systems--play key roles in the establishment and maintenance of such polarity. There has been great progress in uncovering the how these genes work together to produce planar polarity, yet fundamental questions remain unanswered. Here, we study the Drosophila larval ventral epidermis to begin to address several of these questions. We show that ds and fz contribute independently to polarity and that they do so over spatially distinct domains. Furthermore, we find that the requirement for the Ds system changes as field size increases. Lastly, we find that Ds and its putative receptor Fat (Ft) are enriched in distinct patterns in the epithelium during embryonic development. PMID- 21613321 TI - Incomplete X-inactivation initiated by a hypomorphic Xist allele in the mouse. AB - X chromosome inactivation (X-inactivation) in female mammals is triggered by differential upregulation of the Xist gene on one of the two X chromosomes and subsequent coating of the X in cis with its non-coding transcripts. Although targeted mutation has clearly shown that Xist is essential for X-inactivation in cis, the molecular mechanism by which Xist RNA induces chromosome silencing is largely unknown. Here, we demonstrate that an Xist mutant generated previously in mouse by gene targeting, Xist(IVS), is unique in that it partially retains the capacity to silence the X chromosome. Although Xist(IVS) is differentially upregulated and its mutated transcript coats the X chromosome in cis in embryonic and extra-embryonic tissues, X-inactivation thus initiated does not seem to be fully established. The state of such incomplete inactivation is probably unstable and the mutated X is apparently reactivated in a subset of extra-embryonic tissues and, perhaps, early epiblastic cells. Xist(IVS), which can be referred to as a partial loss-of-function mutation, would provide an opportunity to dissect the molecular mechanism of Xist RNA-mediated chromosome silencing. PMID- 21613322 TI - Alk3 controls nephron number and androgen production via lineage-specific effects in intermediate mesoderm. AB - The mammalian kidney and male reproductive system are both derived from the intermediate mesoderm. The spatial and temporal expression of bone morphogenetic protein (BMP) 2 and BMP4 and their cognate receptor, activin like kinase 3 (ALK3), suggests a functional role for BMP-ALK3 signaling during formation of intermediate mesoderm-derivative organs. Here, we define cell autonomous functions for Alk3 in the kidney and male gonad in mice with CRE-mediated Alk3 inactivation targeted to intermediate mesoderm progenitors (Alk3(IMP null)). Alk3 deficient mice exhibit simple renal hypoplasia characterized by decreases in both kidney size and nephron number but normal tissue architecture. These defects are preceded by a decreased contribution of Alk3-deleted cells to the metanephric blastema and reduced expression of Osr1 and SIX2, which mark nephron progenitor cells. Mutant mice are also characterized by defects in intermediate mesoderm derived genital tissues with fewer mesonephric tubules and testicular Leydig cells, epithelial vacuolization in the postnatal corpus epididymis, and decreased serum testosterone levels and reduced fertility. Analysis of ALK3-dependent signaling effectors revealed lineage-specific reduction of phospho-p38 MAPK in metanephric mesenchyme and phospho-SMAD1/5/8 in the testis. Together, these results demonstrate a requirement for Alk3 in distinct progenitor cell populations derived from the intermediate mesoderm. PMID- 21613323 TI - Fibroblast growth factor signalling controls successive cell behaviours during mesoderm layer formation in Drosophila. AB - Fibroblast growth factor (FGF)-dependent epithelial-mesenchymal transitions and cell migration contribute to the establishment of germ layers in vertebrates and other animals, but a comprehensive demonstration of the cellular activities that FGF controls to mediate these events has not been provided for any system. The establishment of the Drosophila mesoderm layer from an epithelial primordium involves a transition to a mesenchymal state and the dispersal of cells away from the site of internalisation in a FGF-dependent fashion. We show here that FGF plays multiple roles at successive stages of mesoderm morphogenesis in Drosophila. It is first required for the mesoderm primordium to lose its epithelial polarity. An intimate, FGF-dependent contact is established and maintained between the germ layers through mesoderm cell protrusions. These protrusions extend deep into the underlying ectoderm epithelium and are associated with high levels of E-cadherin at the germ layer interface. Finally, FGF directs distinct hitherto unrecognised and partially redundant protrusive behaviours during later mesoderm spreading. Cells first move radially towards the ectoderm, and then switch to a dorsally directed movement across its surface. We show that both movements are important for layer formation and present evidence suggesting that they are controlled by genetically distinct mechanisms. PMID- 21613325 TI - Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development. AB - Mitosis is controlled by multiple kinases that drive cell cycle progression and prevent chromosome mis-segregation. Aurora kinase B interacts with survivin, borealin and incenp to form the chromosomal passenger complex (CPC), which is involved in the regulation of microtubule-kinetochore attachments and cytokinesis. Whereas genetic ablation of survivin, borealin or incenp results in early lethality at the morula stage, we show here that aurora B is dispensable for CPC function during early cell divisions and aurora B-null embryos are normally implanted. This is due to a crucial function of aurora C during these early embryonic cycles. Expression of aurora C decreases during late blastocyst stages resulting in post-implantation defects in aurora B-null embryos. These defects correlate with abundant prometaphase figures and apoptotic cell death of the aurora B-deficient inner cell mass. Conditional deletion of aurora B in somatic cells that do not express aurora C results in chromosomal misalignment and lack of chromosome segregation. Re-expression of wild-type, but not kinase dead, aurora C rescues this defect, suggesting functional overlap between these two kinases. Finally, aurora B-null cells partially arrest in the presence of nocodazole, suggesting that this kinase is not essential for the spindle assembly checkpoint. PMID- 21613324 TI - Neuroendocrine regulation of Drosophila metamorphosis requires TGFbeta/Activin signaling. AB - In insects, initiation of metamorphosis requires a surge in the production of the steroid hormone 20-hydroxyecdysone from the prothoracic gland, the primary endocrine organ of juvenile larvae. Here, we show that blocking TGFbeta/Activin signaling, specifically in the Drosophila prothoracic gland, results in developmental arrest prior to metamorphosis. The terminal, giant third instar larval phenotype results from a failure to induce the large rise in ecdysteroid titer that triggers metamorphosis. We further demonstrate that activin signaling regulates competence of the prothoracic gland to receive PTTH and insulin signals, and that these two pathways act at the mRNA and post-transcriptional levels, respectively, to control ecdysone biosynthetic enzyme expression. This dual regulatory circuitry may provide a cross-check mechanism to ensure that both developmental and nutritional inputs are synchronized before initiating the final genetic program leading to reproductive adult development. As steroid hormone production in C. elegans and mammals is also influenced by TGFbeta/Activin signaling, this family of secreted factors may play a general role in regulating developmental transitions across phyla. PMID- 21613326 TI - Differentiation of an embryonic stem cell to hemogenic endothelium by defined factors: essential role of bone morphogenetic protein 4. AB - Current approaches to differentiate embryonic stem (ES) cells to hematopoietic precursors in vitro use either feeder cell, serum, conditioned culture medium or embryoid body, methods that cannot avoid undefined culture conditions, precluding analysis of the fate of individual cells. Here, we have developed a defined, serum-free and low cell-density differentiation program to generate endothelial and hematopoietic cells within 6 days from murine ES cells. Our novel approach identifies a set of factors that are necessary and sufficient to differentiate ES cells into definitive hematopoietic precursors, as documented by the time-lapse video microscopy of the stepwise differentiation processes from single progenitors. Moreover, this defined milieu revealed the essential role of bone morphogenetic protein 4 (BMP4) in determining the hematopoietic/endothelial fate and demonstrated that the hemogenic fate in mesoderm is determined as early as day 4 of our differentiation protocol. Our ability to directly convert ES cells to endothelial and hematopoietic precursors should have important utilities for studies of hematopoietic development and personalized medicine in the future. PMID- 21613327 TI - Gpr126 is essential for peripheral nerve development and myelination in mammals. AB - In peripheral nerves, Schwann cells form the myelin sheath that insulates axons and allows rapid propagation of action potentials. Although a number of regulators of Schwann cell development are known, the signaling pathways that control myelination are incompletely understood. In this study, we show that Gpr126 is essential for myelination and other aspects of peripheral nerve development in mammals. A mutation in Gpr126 causes a severe congenital hypomyelinating peripheral neuropathy in mice, and expression of differentiated Schwann cell markers, including Pou3f1, Egr2, myelin protein zero and myelin basic protein, is reduced. Ultrastructural studies of Gpr126-/- mice showed that axonal sorting by Schwann cells is delayed, Remak bundles (non-myelinating Schwann cells associated with small caliber axons) are not observed, and Schwann cells are ultimately arrested at the promyelinating stage. Additionally, ectopic perineurial fibroblasts form aberrant fascicles throughout the endoneurium of the mutant sciatic nerve. This analysis shows that Gpr126 is required for Schwann cell myelination in mammals, and defines new roles for Gpr126 in axonal sorting, formation of mature non-myelinating Schwann cells and organization of the perineurium. PMID- 21613328 TI - Scaling of the Bicoid morphogen gradient by a volume-dependent production rate. AB - An important feature of development is the formation of patterns that are proportional to the overall size of the embryo. But how such proportionality, or scaling, is achieved mechanistically remains poorly understood. Furthermore, it is currently unclear whether organisms utilize similar or distinct mechanisms to achieve scaling within a species and between species. Here we investigate within species scaling mechanisms for anterior-posterior (A-P) patterning in Drosophila melanogaster, focusing specifically on the properties of the Bicoid (Bcd) morphogen gradient. Using embryos from lines artificially selected for large and small egg volume, we show that large embryos have higher nuclear Bcd concentrations in the anterior than small embryos. This anterior difference leads to scaling properties of the Bcd gradient profiles: in broad regions of the large and small embryos along the A-P axis, normalizing their positions to embryo length reduces the differences in both the nuclear Bcd concentrations and Bcd encoded positional information. We further trace the origin of Bcd gradient scaling by showing directly that large embryos have more maternally deposited bcd mRNA than small embryos. Our results suggest a simple model for how within species Bcd gradient scaling can be achieved. In this model, the Bcd production rate, which is dependent on the total number of bcd mRNA molecules in the anterior, is scaled with embryo volume. PMID- 21613329 TI - Differential expression of serine-threonine kinase receptor-associated protein in patients with systemic lupus erythematosus. AB - The serine-threonine kinase receptor-associated protein (STRAP), a 39 kDa protein localized predominantly in cytoplasm, is an important inhibitor of transforming growth factor beta (TGF-beta) signaling and a regulator of cell proliferation. To investigate the application of STRAP as a novel biomarker in evaluating the pathological condition of systemic lupus erythematosus (SLE), and to determine the possible involvement of STRAP in SLE pathogenesis, the expression levels of STRAP in peripheral blood mononuclear cells (PBMC) of SLE patients were analyzed. PBMC were collected from six patients with active SLE, six with stable SLE and six healthy controls; after protein extraction and concentration determination, the samples were labeled with reagents for isobaric tagging for relative and absolute protein quantification (iTRAQ) and detected by tandem mass spectrometry. The initial proteomic analysis identified and quantified hundreds of proteins. Of these, STRAP was found to decrease more than three-fold in active SLE patients compared with healthy controls (the relative ratio was 0.291). The under expression of STRAP in active SLE was further verified by western blot in larger independent sample sets. Clinical data analyses revealed that the levels of STRAP in SLE inversely correlated to the SLE disease activity index (SLEDAI) (r = 0.607, p < 0.05). These results indicate that the under-expression of STRAP may be a negative factor in the pathogenic process of SLE; as a result, this may also be of clinical significance as a potential condition-specific indicator of active SLE. PMID- 21613330 TI - Increased levels of circulating DNA in patients with systemic autoimmune diseases: A possible marker of disease activity in Sjogren's syndrome. AB - High levels of serum and/or plasma circulating DNA (cDNA) have been described in patients with systemic autoimmune diseases (SADs). However, the role of this molecule has not been clarified. Our aim was to evaluate plasma cDNA levels in 48 systemic lupus erythematosus (SLE) and 44 primary Sjogren's syndrome (SS) patients, as compared with healthy and rheumatoid arthritis (RA) subjects, and to analyse their correlation with disease activity, disease damage and clinical manifestations. Plasma DNA was extracted using Qiagen columns and quantified by real-time quantitative PCR. Disease activity and damage were evaluated in both diseases by analysis of clinical and laboratory findings. Our results showed that plasma cDNA levels were significantly higher in patients with SS (mean +/- SE: 32.0 +/- 7.3 ng/ml) and with SLE (35.0 +/- 9.0 ng/ml) than in controls (5.1 +/- 1.1 ng/ml) (p < 0.0001 for both). Disease activity index correlated with cDNA levels in SS (p = 0.02), but not in SLE, and SS subjects with active disease displayed significantly higher cDNA levels with respect to inactive patients (p < 0.05). No correlation was found between plasma cDNA levels and disease damage indexes in either SLE or SS. These results indicate that increased plasma cDNA levels can been demonstrated in SLE and in SS patients with respect to healthy subjects. Interestingly, although cDNA levels did not correlate with indexes of disease damage in these disorders, a significant correlation between cDNA concentrations and disease activity was observed in SS, but not in SLE, suggesting a possible role of cDNA as non-invasive marker of disease activity. The different results obtained in these SADs may be explained by distinct disease pathogenesis or the influence of immunosuppressive and corticosteroid therapy that, unlike in SS, is usually employed in SLE. PMID- 21613331 TI - Incorporating high fidelity simulation into perfusion education. AB - The new Perfusion Simulation Center at the Medical University of South Carolina provides a new level of high fidelity simulation training for perfusion students. A key component is the Orpheus Perfusion Simulator which is a computer-driven simulator integrated with the mechanical connections of the heart-lung machine to allow for real time operative procedures and perfusion incidents. Due to the ability to consistently reproduce cardiac surgical scenarios, it is possible to develop both basic perfusion skills as well as advanced emergency skills more effectively than with animal models. The purpose of this paper is to provide details about advanced simulation for perfusionists and to illustrate how simulation can be used to promote the assets of good communication, team work, and surgical awareness. Two sets of four cardiac surgical scenarios were recorded in the perfusion simulation operating room. Scenario team member roles included a cardiac surgeon, an anesthesiologist, a perfusionist and an operating room nurse. The scripted surgical scenarios were viewed by a focus group of students charged with identifying key personality traits of different members of the operating team and to characterize them using a list of descriptive words adapted from the Medical University of South Carolina's Peer Review Tool. In the first set of scenarios, initial scores were negative, with irresponsibility, impatience, and carelessness listed as the top behavioral characteristics leading to human error. In the second set of scenarios, logical, clear-thinking, and attentive were the most common personality traits observed of the effective team members. Simulation has become an invaluable tool for perfusion education and the goal of improving patient safety during cardiopulmonary bypass. The opportunities for advanced training in the perfusion simulation environment will certainly expand in the future. PMID- 21613332 TI - Evaluation of an adjustment group for people with multiple sclerosis and low mood: a randomized controlled trial. AB - BACKGROUND: Mood problems affect many people with multiple sclerosis (MS). The aim was to evaluate the effectiveness of a group treatment based on cognitive behavioural principles. METHODS: People with MS were screened on the General Health Questionnaire 12 (GHQ-12) and Hospital Anxiety and Depression Scale (HAD). Those identified with low mood were invited to take part in a randomized trial comparing the effect of attending an adjustment group with a waiting list control. Patients allocated to the adjustment group received six 2 h group treatment sessions. Outcomes were assessed 4 and 8 months after randomization, blind to group allocation. RESULTS: Of the 311 patients identified, 221 (71%) met the criteria for low mood and 151 (68%) agreed to take part. Hierarchical regression analyses were conducted to compare the two groups, correcting for baseline mood and disability. At 4 months, group allocation alone was a significant predictor of the primary outcome measure, the GHQ-12. At 8 months, group allocation alone was no longer a significant predictor for GHQ-12 scores, but it was when baseline GHQ-12 and Guy's Neurological Disability Scale scores were controlled for. Comparison of the area under the curve revealed significant differences between the groups for GHQ-12 (p = 0.003), HAD Anxiety (p = 0.013), HAD Depression (p = 0.004), Beck Depression Inventory (p = 0.001), MS Self efficacy (p = 0.037) and MS Impact Scale Psychological (p = 0.012). CONCLUSION: Patients receiving treatment were less distressed and had less depression and anxiety. There was some evidence of improved self-efficacy and a reduction of the impact of MS on people's lives. PMID- 21613333 TI - Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. AB - BACKGROUND: Natalizumab, a therapeutic monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), is recommended to be withdrawn 3 months prior to a planned pregnancy. Our aim was to analyse the safety and impact of natalizumab exposure on course of disease and pregnancy outcome. OBJECTIVES: Prospective follow-up of women with MS who became accidentally pregnant during natalizumab treatment in comparison with pregnancies of women with MS not exposed to disease-modifying treatments (DMT). METHOD: 35 women with MS who became accidentally pregnant while treated with natalizumab, and 23 women with MS who became pregnant devoid of any DMT as a control group, were chosen. RESULTS: All pregnancies except one were followed in a prospective fashion. Of the women exposed to natalizumab during pregnancy, 29 women gave birth to 28 healthy children; one child was born with hexadactyly. Five pregnancies ended in an early miscarriage and one woman decided to undergo an elective termination of pregnancy. MS activity did not rebound during pregnancy or post partum after natalizumab was withdrawn, and no significant differences were observed when compared with the non-DMT-exposed control group. CONCLUSION: Our data may support the notion that an elective termination of pregnancy due to natalizumab exposure may not be necessary, but rather requires careful monitoring. Women should still be advised to stop natalizumab in the course of planned pregnancy until more data on long-term outcomes are available. PMID- 21613334 TI - The conditioned eyeblink reflex: a potential tool for the detection of cerebellar dysfunction in multiple sclerosis. AB - The delayed conditioned eyeblink reflex, in which an individual learns to close the eyelid in response to a conditioned stimulus (e.g. a tone) relies entirely on the functional integrity of a cerebellar motor circuitry that involves the contingent activation of Purkinje cells by parallel and climbing fibres. Molecular changes that disrupt the function of this circuitry, in particular a loss of type-1 metabotropic glutamate receptors (mGlu1 receptors), occur in Purkinje cells of patients with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis as a result of neuroinflammation. mGlu1 receptors are required for cerebellar motor learning associated with the conditioned eyeblink reflex. We propose that the delayed paradigm of the eyeblink conditioning might be particularly valuable for the detection of subtle abnormalities of cerebellar motor learning that are clinically silent and are not associated with demyelinating lesions or axonal damage. In addition, the test might have predictive value following a clinically isolated syndrome, and might be helpful for the evaluation of the efficacy of drug treatment in multiple sclerosis. PMID- 21613335 TI - Progranulin expression in brain tissue and cerebrospinal fluid levels in multiple sclerosis. AB - BACKGROUND: Progranulin (PGRN) is a fundamental neurotrophic factor, and is also involved in inflammation and wound repair. PGRN may have pro- or anti inflammatory properties, depending upon proteolysis of the anti-inflammatory parent PGRN protein and the generation of pro-inflammatory granulin peptides. OBJECTIVES: Our objectives were as follows: (1) to evaluate the presence and distribution of PGRN in multiple sclerosis (MS) brain tissue, correlating it with demyelination and inflammation; (2) to evaluate cerebrospinal fluid (CSF) PGRN concentrations in patients with MS and controls, in relationship to the clinical features of the disease. METHODS: Our study involved the following: (1) neuropathological study of PGRN on post-mortem tissue of 19 MS and six control brains; (2) evaluation of PGRN CSF concentration in 40 MS patients, 15 non inflammatory controls and five inflammatory controls (viral encephalitis). RESULTS: In active demyelinating lesions, PGRN was expressed on macrophages/microglia. In the normal-appearing white matter (NAWM), expression of PGRN was observed on activated microglia. PGRN was expressed by neurons and microglia in cortical lesions and in normal-appearing cortex. No expression of PGRN was observed in controls, except on neurons. PGRN CSF concentrations were significantly higher in patients with relapsing-remitting MS during relapses and in progressive MS patients, compared with relapsing-remitting MS patients during remissions and with non-inflammatory controls. CONCLUSIONS: PGRN is strongly expressed in MS brains, by macrophages/microglia in active lesions, and by activated microglia in the NAWM; PGRN CSF concentrations in MS are correspondingly increased in conditions of enhanced macrophage/microglia activation, such as during relapses and in progressive MS. PMID- 21613336 TI - Clinical consequences of MRI activity in treated multiple sclerosis. AB - BACKGROUND: Inflammation on brain MRI is the most sensitive marker of disease activity in multiple sclerosis (MS) but its clinical consequences remain controversial. OBJECTIVE: Here we investigated the clinical consequences of MRI activity in MS subjects treated with two different first line disease modifying agents. METHODS: Seventy-five treatment-naive subjects with relapsing-remitting MS (N = 61) or clinically isolated syndromes at risk of MS (N = 14) from the BECOME study that had been randomized to interferon beta-1b (N = 39) or glatiramer acetate (N = 36) and followed for up to two years by monthly brain MRI optimized to detect inflammatory activity were studied for the clinical consequences of lack of MRI remission. RESULTS: MRI remission occurred in 46.4% of participants transiently and in 23.2% completely while it was never achieved in 30.4%. There was no difference by treatment in MRI remission, progression of physical disability, or cognitive function. The percentage of relapse-free subjects was 87.5% for the group in complete MRI remission, 47.6% in the group never in remission and 59.4% in the group in transient remission (p = 0.017). Similar differences were observed for six-month-confirmed worsening of ambulatory function as measured by the timed 25 foot walk (p = 0.026) and by Expanded Disability Status Scale (EDSS) (p = 0.10). Cognitive function was lowest at baseline for the group that never reached MRI remission on treatment; this group improved the least upon repeated cognitive testing during the two years of treatment (p < 0.001). CONCLUSIONS: Lack of MRI remission during treatment with interferon beta-1b or glatiramer acetate is associated with higher relapse rate and worsening of physical and cognitive function. PMID- 21613337 TI - Advanced Practice Registered Nurse supply in a small state: trends to inform policy. AB - This study is a contribution to the small existing pool of state level research on Advanced Practice Registered Nurse (APRN) workforce supply. Data from four biennial surveys of Vermont APRNs from 2003, 2005, 2007, and 2009 (n = 1,538) were analyzed to produce descriptive statistics of one small state's APRN demographic, educational, employment, job satisfaction, intention to leave, and practice-setting characteristics. Survey results were then used to identify patterns or trends that existed in the data. There was a marked shift in the employment settings and a decrease time worked as an APRN, despite an aging APRN workforce. There was an increase in the aggregate education level of APRNs; however, the percentage educated at the doctoral level remained flat at 2%. Overall, APRNs were a satisfied segment of the health workforce; however, those intending to leave for dissatisfaction voiced more concern about job stress and less concern about salary and benefits over time. Implications for workforce planning and public policy are discussed. PMID- 21613338 TI - Nocturnal sleep-wake parameters of adolescents at home following cancer chemotherapy. AB - PURPOSE: The purpose of this descriptive, longitudinal study was to describe objective nocturnal sleep-wake parameters of adolescents at home after receiving chemotherapy in the hospital or outpatient clinic and explore differences in sleep variables by age, gender, and corticosteroid use. METHODS: We collected 7 days of wrist actigraphy and sleep diary data from 48 adolescents (10-19 years) who were receiving cancer chemotherapy for a primary or secondary cancer or a relapse. The actigraphic sleep variables included rest interval (i.e., time in bed), sleep onset, sleep offset, sleep duration, total sleep time (TST), wake after sleep onset (WASO), and %WASO. RESULTS: Of the 48 adolescents, 38 had at least five nights of scored actigraphy and were included in analyses. Older (13 18 years) adolescents went to bed later and had fewer minutes of TST than younger adolescents (10-12 years). Exploratory analyses revealed no differences between adolescents who were taking oral corticosteroids (i.e., prednisone, dexamethasone) and those who were not or between males and females. CONCLUSION: These adolescents had sleep durations that met or exceeded the recommended sleep duration for their age groups but experienced significant WASO. Further research is needed to estimate sleep needs of adolescents during chemotherapy and determine factors that contribute to nocturnal wake-time so that targeted interventions can be designed to improve sleep quality. PMID- 21613339 TI - Autonomic nervous system function in infants with transposition of the great arteries. AB - The ability to maintain and respond to challenges to homeostasis is primarily a function of the autonomic nervous system (ANS). In infants with complex congenital heart defects this ability may be impaired. This study described change in ANS function before and after surgical correction in infants with transposition of the great arteries (TGA) and in healthy infants. A total of 15 newborn infants with TGA were matched with 16 healthy infants on age, gender, and feeding type. The ANS function was measured using heart rate variability (HRV). Data were collected preoperatively in the 1st week of life and postoperatively before, during, and after feeding at 2 weeks and 2 months of age. Infants with TGA demonstrated significantly lower high-frequency and low-frequency HRV preoperatively (p < .001) when compared with healthy infants. At 2 weeks, infants with TGA were less likely than healthy infants to demonstrate adaptive changes in high-frequency HRV during feeding (Wald Z = 2.002, p = .045), and at 2 months, 40% of TGA infants exhibited delayed postfeeding recovery. Further research is needed to more thoroughly describe mechanisms of a physiologically adaptive response to feeding and to develop nursing interventions supportive of these high risk infants. PMID- 21613340 TI - Tridimensional personalities and polymorphism of dopamine D2 receptor among heroin addicts. AB - BACKGROUND: Drug addiction is a multifactorial disorder. Researchers have posited that an individual's inherited behavioral propensity or temperament contributes to the disorder by shaping a personality strongly linked with the risk of drug abuse. Further, they hypothesize that the polymorphism of dopamine D2 receptor increases the susceptibility to and severity of addiction. We, therefore, investigated possible associations between dopamine D2 receptor (DRD2) and personality traits among intravenous heroin addicts. METHODS: We assessed 93 intravenous heroin addicts and controls using Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) and the Tridimensional Personality Questionnaire (TPQ). We confirmed drug-dependence status using a questionnaire based on DSM-IV criteria. We extracted DNA from the subjects' whole blood and genotyped it for DRD2 allelic variants. RESULTS: Genotype analysis showed a significantly higher frequency for the TaqIA polymorphism among the addicts (69.9%) compared to control subjects (42.6%; Fisher's exact chi(2), p < .05). We observed no significant differences for other variants between the addicts and controls. The addicts had higher scores for novelty seeking (NS) and harm avoidance (HA) personality traits but lower scores for reward dependence (RD) when compared to control subjects. LIMITATION: The environmental cues are different for the addicts, and the healthy university students we used as controls. We recommend that researchers employ a gene-environment interaction approach to study factors associated with addictive behaviors in future studies. CONCLUSION: Taq1A may be implicated for an increased vulnerability to addiction. Screening of this marker might be useful for identifying individuals at risk of addiction. PMID- 21613341 TI - EMA must improve the quality of its clinical trial reports. PMID- 21613342 TI - It's time to rebuild the evidence base. PMID- 21613343 TI - Tallis's slippery slope. PMID- 21613344 TI - Assisted dying versus assisted living. PMID- 21613345 TI - Medical stereotypes. PMID- 21613346 TI - We need to rethink front line care for back pain. PMID- 21613347 TI - FDA is criticised for licensing high dose donepezil. PMID- 21613348 TI - Global health experts explore ways to slash vaccine prices and expand access. PMID- 21613349 TI - Open access approach to medical research publishing will continue to grow, experts predict. PMID- 21613350 TI - Growth hormone (GH)-induced insulin resistance is rapidly reversible: an experimental study in GH-deficient adults. AB - CONTEXT: It is clinically relevant and of physiological interest to investigate whether GH-induced insulin resistance depends on the timing of GH exposure relative to when insulin sensitivity is assessed. HYPOTHESIS: GH-induced insulin resistance is rapidly reversible. DESIGN AND PARTICIPANTS: Eight male GH deficient patients underwent a 6-h euglycemic-hyperinsulinemic glucose clamp thrice in a randomized crossover design receiving either no GH (study 0), a 7-h GH infusion (0.2-0.3 mg in total) that terminated 5 h before the clamp (study 1), or a similar GH infusion timed to continue during the first hour of the clamp (study 2). A muscle biopsy was obtained 30 min into the clamp. The patients were compared with eight healthy untreated control subjects (study c). MAIN OUTCOME MEASURES: The glucose infusion rate, indirect calorimetry, and free fatty acid metabolism were assessed. In muscle biopsies, protein phosphorylation of signal transducer and activator of transcription 5, Akt, and Akt substrate 160 (phospho Akt substrate signal) and gene expression of IGF-I and SOCS1-3 were assessed. RESULTS: Insulin sensitivity differed significantly between the GH-deficiency studies (P = 0.005) with distinct insulin resistance in study 2 and increased insulin sensitivity in study 0 [area under the glucose infusion rate curve (mg/kg . min): 1663 +/- 151 (study 0) vs. 1482 +/- 166 (study 1) vs. 1123 +/- 136 (study 2) vs. 1492 +/- 229 (control group)]. Free fatty acid levels and lipid oxidation were elevated in response to GH exposure but became suppressed during the clamp. IGF-I and SOCS3 gene expression was increased in study 2. CONCLUSIONS: Very-low dose GH exposure evokes acute insulin resistance that subsides after 5 h. This time-dependent reversibility should be considered when assessing the impact of GH on glucose homeostasis. PMID- 21613351 TI - Pituitary dysfunction in adult patients after cranial radiotherapy: systematic review and meta-analysis. AB - CONTEXT: Cranial radiotherapy is an important cause of hypopituitarism. The prevalence of hypopituitarism varies considerably between studies. OBJECTIVE: We conducted a systematic review and meta-analysis of reported prevalences of hypopituitarism in adults radiated for nonpituitary tumors. DATA SOURCES: We searched PubMed, EMBASE, Web of Science, and the Cochrane Library to identify potentially relevant studies. STUDY SELECTION: Studies were eligible for inclusion with the following criteria: 1) cranial radiotherapy for nonpituitary tumors and/or total body irradiation for hematological malignancies; 2) adult population (>18 yr old); and 3) report on endocrine evaluation. DATA EXTRACTION: Data review was done by two independent reviewers. Besides extraction of baseline and treatment characteristics, also endocrine tests, definitions, and cutoff values used to define pituitary insufficiency were extracted. RESULTS: Eighteen studies with a total of 813 patients were included. These included 608 patients treated for nasopharyngeal cancer (75%) and 205 for intracerebral tumors. The total radiation dose ranged from 14 to 83 and 40 to 97 Gy for nasopharyngeal and intracerebral tumors, respectively. The point prevalence of any degree of hypopituitarism was 0.66 [95% confidence interval (CI), 0.55-0.76]. The prevalence of GH deficiency was 0.45 (95% CI, 0.33-0.57); of LH and FSH, 0.3 (95% CI, 0.23-0.37); of TSH, 0.25 (95% CI, 0.16-0.37); and of ACTH, 0.22 (95% CI, 0.15 0.3), respectively. The prevalence of hyperprolactinemia was 0.34 (95% CI, 0.15 0.6). There were no differences between the effects of radiotherapy for nasopharyngeal vs. for intracerebral tumors. CONCLUSION: Hypopituitarism is prevalent in adult patients after cranial radiotherapy for nonpituitary tumors. Therefore, all patients treated by cranial radiotherapy should have structured periodical assessment of pituitary functions. PMID- 21613352 TI - High prevalence of brown adipose tissue in adult humans. AB - CONTEXT: Positron emission tomography (PET)-computed tomography (CT) has identified metabolically active supraclavicular fat in adult humans based on uptake of labeled glucose and confirmed to be brown adipose tissue (BAT) histologically. However, PET-CT has estimated a prevalence of BAT as low as 5% in adult humans, casting doubt on its significance. The true prevalence of BAT is unknown because of the suboptimal sensitivity of standard PET-CT. OBJECTIVE: The objective of the study was to determine whether BAT is present in PET-negative supraclavicular fat. DESIGN: This was a prospective cohort study. SETTING: The study was conducted at a tertiary referral hospital. PATIENTS: Seventeen patients who underwent preoperative PET-CT for staging of head and neck malignancy participated in the study. MAIN OUTCOME: The main outcome was signature BAT gene transcripts and protein in biopsies of supraclavicular fat with sc fat as negative control. RESULTS: PET-CT was positive in three and negative in 14 patients. PET-positive fat harbored multilobulated lipid droplets and stained strongly for uncoupling protein 1 (UCP1). These features are absent in sc fat. By contrast, PET-negative fat contained a predominance of cells with unilobulated lipid droplets, with scattered cells containing multilobulated lipid droplets and variable UCP1 staining. Molecular analyses of fat biopsies showed lower but clear expression of UCP1, NDUFS3 (NADH dehydrogenase (ubiquinone) iron-sulfur protein 3), beta3-adrenoceptor, and PRDM16 (PR domain containing 16) transcripts. CONCLUSIONS: BAT is present in supraclavicular fat, regardless of PET status. BAT is highly prevalent in adult humans, and its abundance determines PET status. PMID- 21613354 TI - Iodine status and thyroid function of Boston-area vegetarians and vegans. AB - CONTEXT: Adequate dietary iodine is required for normal thyroid function. The iodine status and thyroid function of U.S. vegetarians and vegans have not been previously studied. Environmental perchlorate and thiocyanate (inhibitors of thyroid iodine uptake) exposures may adversely affect thyroid function. OBJECTIVE: The objective of the study was to assess the iodine status and thyroid function of U.S. vegetarians (consume plant based products, eggs, milk; abstain from meat, poultry, fish, shellfish) and vegans (avoid all animal products) and whether these may be affected by environmental perchlorate and thiocyanate exposures. DESIGN AND SETTING: This was a cross-sectional assessment of urinary iodine, perchlorate, and thiocyanate concentrations and serum thyroid function in Boston-area vegetarians and vegans. SUBJECTS: One hundred forty-one subjects (78 vegetarians, 63 vegans) were recruited; one vegan was excluded. RESULTS: Median urinary iodine concentration of vegans (78.5 MUg/liter; range 6.8-964.7 MUg/liter) was lower than vegetarians (147.0 MUg/liter; range 9.3-778.6 MUg/liter) (P < 0.01). Adjusted for cigarette smoking (confirmed by urinary cotinine levels) and thiocyanate-rich food consumption, median urinary thiocyanate concentration of vegans (630 MUg/liter; range 108-3085 MUg/liter) was higher than vegetarians (341 MUg/liter; range 31-1963 MUg/liter) (P < 0.01). There were no between-group differences in urinary perchlorate concentrations (P = 0.75), TSH (P = 0.46), and free T(4) (P = 0.77). Urinary iodine, perchlorate, and thiocyanate levels were not associated with TSH (P = 0.59) or free T(4) (P = 0.14), even when adjusted for multiple variables. CONCLUSIONS: U.S. vegetarians are iodine sufficient. U.S. vegans may be at risk for low iodine intake, and vegan women of child-bearing age should supplement with 150 MUg iodine daily. Environmental perchlorate and thiocyanate exposures are not associated with thyroid dysfunction in these groups. PMID- 21613353 TI - Gender, sex-steroid, and secretagogue-selective recovery from growth hormone induced feedback in older women and men. AB - CONTEXT: GH negatively regulates its own secretion. How gender, sex steroids, and secretagogues modulate GH autofeedback is not known. HYPOTHESIS/OBJECTIVE: Supplementation with sex steroids and/or a peptidyl secretagogue will enhance the escape of GH from autoinhibition, thus framing a mechanism for amplifying pulsatile GH secretion. SUBJECTS AND SETTING: Ten healthy postmenopausal women and 10 comparably aged men participated at the Clinical-Translational Science Unit. DESIGN/INTERVENTIONS: Randomly ordered, double-blind, prospective crossover treatment with placebo vs. testosterone (men) or placebo vs. estradiol (women). Autofeedback was imposed by an iv pulse of GH. Recovery of feedback inhibition was quantified during constant infusion of saline, GHRH, or GH-releasing peptide 2 (three peptide categories). OUTCOMES/RESULTS: During negative feedback, total (integrated) GH recovery depended upon gender (P = 0.017), sex hormone (P < 0.001), and peptide category (P < 0.001). Mechanistic analysis revealed that feedback-suppressed nadir GH concentrations were determined by sex-steroid treatment (P = 0.018) but not by gender (P = 0.444). Peak GH escape was controlled by both treatment (P = 0.004) and gender (P = 0.003). Nadir GH and peak GH during feedback were enhanced by GHRH or GHRP-2 (P < 0.001 for both). Gender * peptide (P = 0.012 for nadir GH), treatment * peptide (P < 0.001 total and peak GH), and gender * treatment (P = 0.017 nadir GH) regulated GH recovery interactively. CONCLUSION: Gender, sex-steroid supplementation, and secretagogue type confer distinct feedback-rescuing effects, introducing a new level of complexity in the control of pulsatile GH regulation. PMID- 21613356 TI - I-131 activities as high as safely administrable (AHASA) for the treatment of children and adolescents with advanced differentiated thyroid cancer. AB - AIM: Differentiated thyroid carcinoma (DTC) in children and young adults is rare, can be aggressive, and often presents at advanced stages. In a population of young Belarusian patients with advanced DTC after the nuclear reactor accident at Chernobyl, we determined the activities that are as high as safely administrable (AHASA). PATIENTS AND METHODS: In 180 children and adolescents, we studied 133 courses of I-131 thyroid remnant ablation (median age at ablation, 14.3 yr) and 250 courses of I-131 therapy (median age at therapy, 15.7 yr). Remnant ablation was performed with weight-adapted I-131 activities of a median of 51.8 MBq/kg (range, 23.9-73.8 MBq/kg); and residual disease therapy was performed with a median activity of 98.0 MBq/kg (range, 56.7-164.7 MBq/kg). The radiation absorbed dose to the blood (BD) per unit of activity administered for each treatment was deduced from whole-body retention data measured twice daily using ceiling probes. The AHASA activity was calculated assuming an upper limit of 2 Gy BD. RESULTS: For I-131 ablation, the median weight-adjusted AHASA activity leading to a BD of 2 Gy was 407 MBq/kg (range, 137-661 MBq/kg). In three patients with extensive diffuse pulmonary metastases, the AHASA was lower than 200 MBq/kg. For patients receiving additional I-131 treatments after ablation, a median body weight adapted AHASA activity of 406 MBq/kg (range, 210-775 MBq/kg) was calculated. CONCLUSION: Children and adolescents with advanced DTC can be treated with I-131 activities of at least 200 MBq/kg. For children with extensive pulmonary metastases, pretherapeutic dosimetry is needed to determine the AHASA. PMID- 21613355 TI - Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension. AB - CONTEXT: The co-occurrence of insulin resistance (IR) and hypertension is a heritable condition leading to cardiovascular complications. Caveolin-1 (CAV1), a gene previously associated with metabolic dysfunction in animal and cellular models, may be a marker for these conditions in humans. OBJECTIVE: The objective of the study was to examine the relationship between CAV1 variants and IR in two hypertensive cohorts and to corroborate the findings in a CAV1 knockout mouse. DESIGN, SETTING, AND PARTICIPANTS: A candidate gene association study was conducted in two hypertensive cohorts: 1) Caucasian and 2) Hispanic. Multivariate associations between individual variants and insulin-resistant phenotypes were analyzed, accounting for age, gender, body mass index, and sibling relatedness. Intraperitoneal glucose tolerance tests were conducted in wild-type and CAV1 knockout mice. RESULTS: In the Caucasian hypertensive cohort, minor allele carriers of two CAV1 single-nucleotide polymorphisms (rs926198, rs3807989) had significantly higher fasting insulin levels (P = 0.005, P = 0.007), increased homeostatic assessment model for insulin resistance (HOMA-IR) (P =0.005, P = 0.008), and decreased M value during hyperinsulinemic, euglycemic clamp procedure (P = 0.004, P = 0.05) than major allele homozygotes. Findings were replicated in the Hispanic hypertensive cohort cohort for fasting insulin levels (P = 0.005, P = 0.02) and HOMA-IR (P = 0.008 and P = 0.02). Meta-analysis demonstrated significant associations of both single-nucleotide polymorphisms with fasting insulin levels (P = 0.00008, P = 0.0004) and HOMA-IR (P = 0.0001, P = 0.0004). As compared with wild type, CAV1 knockout mice displayed higher blood pressure levels and higher fasting glucose, insulin, and HOMA-IR levels and an exaggerated glycemic response to a glucose challenge. CONCLUSION: Variations in the CAV1 gene are associated with IR and hypertension. CAV1 gene polymorphisms may be a biomarker for IR and hypertension, enabling earlier detection and improved treatment strategies. PMID- 21613357 TI - Anti-mullerian hormone predicts menopause: a long-term follow-up study in normoovulatory women. AB - CONTEXT: It has been hypothesized that a fixed interval exists between age at natural sterility and age at menopause. Both events show considerable individual variability, with a range of 20 yr. Correct prediction of age at menopause could open avenues of individualized prevention of age-related infertility and other menopause-related conditions, like cardiovascular disease and breast carcinoma. OBJECTIVE: The aim of this study was to explore the ability of ovarian reserve tests to predict age at menopause. DESIGN AND SETTING: We conducted a long-term follow-up study at an academic hospital. PARTICIPANTS: A total of 257 normoovulatory women (age, 21-46 yr) were derived from three cohorts with highly comparable selection criteria. INTERVENTIONS: Anti-Mullerian hormone (AMH), antral follicle count, and FSH were assessed at time 1 (T1). At time 2 (T2), approximately 11 yr later, cycle status (strictly regular, menopausal transition, or postmenopause) and age at menopause were inventoried. MAIN OUTCOME MEASURES: Accuracy of the ovarian reserve tests in predicting time to menopause was assessed by Cox regression, and a nomogram was constructed for the relationship between age-specific AMH concentrations at T1 and age at menopause. RESULTS: A total of 48 (19%) women had reached postmenopause at T2. Age, AMH, and antral follicle count at T1 were significantly related with time to menopause (P < 0.001) and showed a good percentage of correct predictions (C-statistic, 0.87, 0.86, and 0.84, respectively). After adjusting for age, only AMH added to this prediction (C-statistic, 0.90). From the constructed nomogram, it appeared that the normal distribution of age at menopause will shift considerably, depending on the individual age-specific AMH level. CONCLUSIONS: AMH is highly predictive for timing of menopause. Using age and AMH, the age range in which menopause will subsequently occur can be individually calculated. PMID- 21613358 TI - Fasting, but not exercise, increases adipose triglyceride lipase (ATGL) protein and reduces G(0)/G(1) switch gene 2 (G0S2) protein and mRNA content in human adipose tissue. AB - CONTEXT: Fasting and exercise are characterized by increased lipolysis, but the underlying mechanisms are not fully understood. OBJECTIVE: The study was designed to test whether fasting and exercise affect mRNA and protein levels of adipose triglyceride lipase (ATGL) and G(0)/G(1) switch gene 2 (G0S2), a recently discovered ATGL inhibitor, in humans. DESIGN AND PARTICIPANTS: We studied eight healthy men (age, 25.5 +/- 4.3 yr) for 6 h (a 4-h basal and a 2-h clamp period) on three occasions in a randomized crossover design: 1) in the basal state and after; 2) 72-h fasting; and 3) 1-h exercise (65% VO(2max)). Subcutaneous abdominal adipose tissue (AT) biopsies were taken at t = 30 and 270 min. SETTING: The study was conducted at a university hospital research unit. RESULTS: Circulating free fatty acids and GH were increased, and C-peptide was decreased by both fasting and exercise. During fasting, insulin failed to suppress free fatty acid levels, suggesting AT insulin resistance. ATGL protein was increased 44% (P < 0.001), and G0S2 mRNA and protein were decreased 56% (P = 0.02) and 54% (P = 0.01), respectively, after fasting, but both ATGL and G0S2 were unaffected by exercise. Protein levels of hormone-sensitive lipase and comparative gene identification-58 were unaffected throughout. CONCLUSIONS: We found increased AT content of ATGL and decreased protein and mRNA content of the ATGL inhibitor G0S2, suggesting increased ATGL activity during fasting, but not after short-term exercise. These findings are compatible with the notion that the ATGL-G0S2 complex is an important long-term regulator of lipolysis under physiological conditions such as fasting in humans. PMID- 21613359 TI - Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. AB - BACKGROUND: Hereditary pheochromocytoma is associated with germline mutations of a set of susceptibility genes to which the TMEM127 gene has recently been added. Patients with TMEM127 mutations have been thus far exclusively identified with adrenal tumors. PATIENTS AND METHODS: A population-based series of 48 consecutive individuals from the European-American Pheochromocytoma Paraganglioma Registry with multiple paraganglial tumors and, of these, one extraadrenal paraganglial tumor were selected for this study. They all had normal results when screened for germline mutations of the genes RET, VHL, SDHB, SDHC, and SDHD. Germline mutation analysis of the TMEM127 gene included a search for intragenic mutations and large rearrangements. RESULTS: Of the 48 eligible patients with extraadrenal paraganglial tumors, two (4.2%) were found to have TMEM127 mutations. One patient had multiple head and neck paraganglioma and one retroperitoneal extraadrenal and adrenal tumor. CONCLUSION: TMEM127 germline mutations confer risks of extraadrenal paraganglial tumors in addition to the documented adrenal pheochromocytoma. Thus, surveillance for extraadrenal and adrenal paraganglial tumors is likely warranted in TMEM127 mutation carriers, although the true prevalence should be evaluated in patients with extraadrenal paraganglial tumors. PMID- 21613361 TI - An elusive cause of black stool. PMID- 21613360 TI - Short-term plasticity of gray matter associated with leptin deficiency and replacement. AB - CONTEXT: Leptin affects neurogenesis, neuronal growth, and viability. We previously reported that leptin supplementation increased gray matter (GM) concentration in the anterior cingulate gyrus (ACG), cerebellum, and inferior parietal lobule, areas that are also involved in food intake. OBJECTIVE: The aim of this study was to report the changes in brain structure at different states of leptin supplementation. DESIGN: We conducted a nonrandomized trial. SETTING AND PATIENTS: We studied three adults with congenital leptin deficiency due to a mutation in the leptin gene. INTERVENTION: Patients received treatment with recombinant methionyl human leptin, with annual 11- to 36-d periods of treatment withholding followed by treatment restoration over 3 yr. MAIN OUTCOME MEASURES: GM concentration (by voxel-based morphometry analysis of magnetic resonance scans) was correlated with body mass index (BMI) and leptin supplementation. RESULTS: Annually withholding leptin supplementation for several weeks increased BMI and reversed the original effects of leptin in the cerebellum and ACG. The changes in the ACG were consistent with an indirect effect of leptin mediated through increased BMI. In the cerebellum, where leptin receptors are most dense, GM changes appeared to be direct effects of leptin. Leptin restoration did not lead to recovery of GM in the short term but did lead to an unexpected GM increase in the posterior half of the left thalamus, particularly the pulvinar nucleus. CONCLUSION: These findings provide the first in vivo evidence of remarkably plastic, reversible, and regionally specific effects of leptin on human brain morphology. They suggest that leptin may have therapeutic value in modulating plasticity-dependent brain functions. PMID- 21613362 TI - Computed tomography of the heart. PMID- 21613363 TI - Should we treat uncomplicated symptomatic diverticular disease with fibre? PMID- 21613364 TI - Four burials and a funeral. PMID- 21613365 TI - Right vision wrong location for new research centre, say MPs. PMID- 21613366 TI - Rise in abortions reflects poor links between contraception and abortion services, say campaigners. PMID- 21613367 TI - A narrative perspective on genograms: revisiting classical family therapy methods. AB - This article presents how genograms, a classic family therapy technique, can be used in the context of narrative therapy. Genograms create a unique opportunity to explore and re-tell family stories thus enabling their re-authoring. An important aspect of this process is that of tracking down family resources and wisdom. The graphic form of a genogram can be very helpful in distancing a person from the dominant narrations in her/his family. Additionally, genogram analysis is an excellent opportunity to conduct re-membering conversation and introducing the "club of life" metaphor. Finally, the creative approach to drawing genograms can be an invitation for family members to "play" with their family stories and, as a consequence, re-position their roles in these stories. The article completes the presentation of the family therapy case study which was inspired by narrative ideas and genogram analysis. PMID- 21613368 TI - Testican-1 promotes resistance against Pseudomonas aeruginosa-induced keratitis through regulation of MMP-2 expression and activation. AB - PURPOSE: Testican-1 (or SPOCK) is a highly conserved chimeric proteoglycan encoded by the SPOCK1 gene. Protease regulatory activity has recently been demonstrated by this molecule and its family members testican-2 and -3. The present study tested the hypothesis that testican-1 regulates corneal matrix metalloproteinase (MMP)-2 expression, thus improving disease outcome after Pseudomonas aeruginosa-induced keratitis. METHODS: C57BL/6 (B6) and BALB/c mice were routinely infected with P. aeruginosa and were evaluated at various postinfection (pi) times for corneal expression of testican-1 and MMP-2, by PCR array, real-time RT-PCR, ELISA, activity assays, zymography, and immunohistochemistry. Next, B6 mice were treated with recombinant human (rh) testican-1, and expression was knocked down in BALB/c ice by siTestican-1 treatment, to determine the relationship between the two molecules. RESULTS: BALB/c versus B6 mice expressed significantly higher mRNA and protein levels of testican-1 after P. aeruginosa-induced ocular infection. MMP-2 expression and activation was also disparate between the two mouse strains. After rhTestican-1 treatment in B6 mice, overall disease response was significantly improved, whereas siRNA treatment of BALB/c mice converted the normally resistant response to susceptible. Testican-1 was shown to influence MMP-2 expression, activation, and regulation, as well. CONCLUSIONS: This study demonstrates corneal expression of testican-1 and its temporal regulation of MMP-2 expression and activation after induction of bacterial keratitis. Furthermore, the data collectively indicate that testican-1 is a novel target for disease treatment to promote better disease outcome regarding chronic inflammation and infection and diseases involving pathologic tissue destruction. PMID- 21613369 TI - Dynamic changes in ocular Zernike aberrations and tear menisci measured with a wavefront sensor and an anterior segment OCT. AB - PURPOSE: To measure dynamic change characteristics of spatial and temporal variations in the post-blink tear film of normal eyes. METHODS: A wavefront sensor was used to measure dynamic changes in wavefront aberrations, up to the seventh order, for 10 seconds in a group of 33 normal young adults. Tear menisci were imaged with an anterior segment optical coherence tomography (AS-OCT) system and tear film break-up times (TFBUTs) were determined. RESULTS: Systematic changes in main axis astigmatism (R(2) = 0.933, P < 0.0001), vertical coma (R(2) = 0.935, P < 0.0001) and spherical aberrations (R(2) = 0.879, P = 0.0002) occurred during the 10-second post-blink period. Both lower tear meniscus height and area increased by 10 seconds compared with the initial levels (P < 0.0001 for each). The change of vertical coma had significant correlation with the increase of lower tear meniscus areas during the 10-second post-blink period (R(2) = 0.181, P = 0.014). Subjects with TFBUTs < 15 seconds had significantly increased main axis astigmatism, vertical coma, and spherical aberrations by 10 seconds. Subjects with longer TFBUTs did not have any significant wavefront aberrations during that period. CONCLUSIONS: Systematic changes in some Zernike aberrations after blinking are associated with the changes in tear menisci and TFBUT. There was a substantial individual variation in dynamic changes of Zernike aberrations, suggesting the necessity to explore individual differences in tear quality and tear performance. Dynamic wavefront measurement combined with anterior segment optical coherence tomography could provide a useful tool to understand spatial and temporal processes of the tear film in clinical practice. PMID- 21613370 TI - Factors influencing self-reported vision-related activity limitation in the visually impaired. AB - PURPOSE: The use of patient-reported outcome (PRO) measures to assess self reported difficulty in visual activities is common in patients with impaired vision. This study determines the visual and psychosocial factors influencing patients' responses to self-report measures, to aid in understanding what is being measured. METHODS: One hundred visually impaired participants completed the Activity Inventory (AI), which assesses self-reported, vision-related activity limitation (VRAL) in the task domains of reading, mobility, visual information, and visual motor tasks. Participants also completed clinical tests of visual function (distance visual acuity and near reading performance both with and without low vision aids [LVAs], contrast sensitivity, visual fields, and depth discrimination), and questionnaires assessing depressive symptoms, social support, adjustment to visual loss, and personality. RESULTS: Multiple regression analyses identified that an acuity measure (distance or near), and, to a lesser extent, near reading performance without LVAs, visual fields, and contrast sensitivity best explained self-reported VRAL (28%-50% variance explained). Significant psychosocial correlates were depression and adjustment, explaining an additional 6% to 19% unique variance. Dependent on task domain, the parameters assessed explained 59% to 71% of the variance in self-reported VRAL. CONCLUSIONS: Visual function, most notably acuity without LVAs, is the best predictor of self reported VRAL assessed by the AI. Depression and adjustment to visual loss also significantly influence self-reported VRAL, largely independent of the severity of visual loss and most notably in the less vision-specific tasks. The results suggest that rehabilitation strategies addressing depression and adjustment could improve perceived visual disability. PMID- 21613371 TI - Functional role of alpha1-adrenoceptor subtypes in murine ophthalmic arteries. AB - PURPOSE: To identify the alpha(1)-adrenoceptor (alpha(1)-AR) subtypes mediating vascular adrenergic responses in murine ophthalmic arteries. METHODS: Expression of mRNA was quantified for individual alpha(1)-AR subtypes in murine ophthalmic arteries using real-time PCR. To assess the functional relevance of alpha(1)-ARs for mediating vascular responses, ophthalmic arteries from mice deficient in one of the three alpha(1)-AR subtypes (alpha(1A)-AR(-/-), alpha(1B)-AR(-/-), and alpha(1D)-AR(-/-), respectively) and wild-type controls were isolated, cannulated with micropipettes, and pressurized. Changes in luminal artery diameter in response to the alpha(1)-AR agonist phenylephrine, the sympathetic transmitter noradrenaline, and to the nonadrenergic vasoconstrictor arginine vasopressin (AVP) were measured by video microscopy. RESULTS: Using real-time PCR, mRNA for all three alpha(1)-AR subtypes was detected in ophthalmic arteries from wild-type mice. In functional studies, phenylephrine and noradrenaline produced dose dependent constriction of ophthalmic arteries that was similar in wild-type, alpha(1B)-AR(-/-), and alpha(1D)-AR(-/-) mice. Strikingly, responses to phenylephrine and noradrenaline were almost completely abolished in alpha(1A)-AR( /-) mice. In contrast, the nonadrenergic agonist AVP produced dose-dependent vasoconstrictor responses that did not differ between any of the mouse genotypes tested. CONCLUSIONS: These findings provide evidence that the alpha(1A)-AR subtype mediates adrenergic vasoconstriction in murine ophthalmic arteries. PMID- 21613372 TI - Mitochondrial localization and ocular expression of mutant Opa3 in a mouse model of 3-methylglutaconicaciduria type III. AB - PURPOSE: To investigate the developmental and ocular expression of Opa3 in a mouse model of 3-methylglutaconicaciduria type III and the effect of mutation on protein localization and mitochondrial morphology. METHODS: The B6 C3-Opa3(L122P) mouse carrying a missense mutation in exon 2 (c.365T>C; p.L122P) of Opa3, which displays features of recessive 3-methylglutaconic aciduria type III was studied. The expression of Opa3 was determined with RT-PCR, quantitative PCR, and Western blot, in embryos (embryonic day [E]8 to postnatal day [P]0) and adult tissues, and by ocular immunohistochemistry. Mitochondria were stained using a mitochondrion-selective probe in mouse embryonic fibroblasts from Opa3(-/-) mutants and imaged by electron microscopy of the retinas. RESULTS: The splice variants Opa3a and Opa3b were expressed in the lenses and the retinas in the Opa3(-/-) mice, with the expression of the Opa3a isoform predominant. Opa3 was expressed throughout embryonic development, with high levels of expression in the developing brain, retina, optic nerve, and lens. Opa3 localized to the mitochondria, and the L122P mutant protein did not mislocalize. Neither protein localized to the peroxisome. Opa3(-/-) mice displayed disrupted mitochondrial morphology in the retina. Wild-type Opa3 protein increased as the lenses aged, despite the reduction in Opa3 mRNA occurring as a part of lens differentiation. However, mutant Opa3 mRNA was upregulated in homozygous mutant lenses, suggesting a compensatory increase in expression, which may further increase Opa3 protein levels. CONCLUSIONS: Mutant Opa3 protein retains its mitochondrial localization and induces disrupted mitochondrial morphology. Opa3 accumulates in the lens. The results may reflect a slow turnover of Opa3 protein in vivo and may be important in normal lens physiology. PMID- 21613373 TI - Evaluation of serum lipid concentrations and genetic variants at high-density lipoprotein metabolism loci and TIMP3 in age-related macular degeneration. AB - PURPOSE: To analyze the association between polymorphisms in the TIMP3 gene and genes of the high-density lipoprotein (HDL) metabolism and age-related macular degeneration (AMD), and evaluate serum lipid and lipoprotein levels in AMD patients compared with control individuals. METHODS: Single nucleotide polymorphisms in or near the TIMP3, ABCA1, FADS1-3, CETP, LIPC, and LPL genes were genotyped. Serum levels of apolipoprotein B (ApoB), apolipoprotein A1, lipoprotein a, cholesterol, triglycerides, and HDL-cholesterol were determined. RESULTS: Significant associations were found between AMD and variants in ABCA1 and FADS1-3, and a nearly significant association in TIMP3. No significant associations were observed for variants in LPL, LIPC, and CETP. We also observed a significant elevation of ApoB levels in serum of AMD patients. Other lipids and lipoproteins were not significantly altered. CONCLUSIONS: These results confirm associations of AMD with variants near the TIMP3 gene and at loci involved in HDL metabolism. They further highlight a role of the extracellular matrix and the HDL metabolism in the pathogenesis of AMD. This study identified increased ApoB levels as a possible new serum biomarker for AMD. PMID- 21613374 TI - Plasma rich in growth factors (PRGF-Endoret) stimulates proliferation and migration of primary keratocytes and conjunctival fibroblasts and inhibits and reverts TGF-beta1-Induced myodifferentiation. AB - PURPOSE: Plasma rich in growth factors (PRGF-Endoret) technology is an autologous platelet-enriched plasma obtained from patient's own blood, which after activation with calcium chloride allows the release of a pool of biologically active proteins that influence and promote a range of biological processes including cell recruitment, and growth and differentiation. Because ocular surface wound healing is mediated by different growth factors, we decided to explore the potential of PRGF-Endoret technology in stimulating the biological processes related with fibroblast-induced tissue repair. Furthermore, the anti fibrotic properties of this technology were also studied. METHODS: Blood from healthy donors was collected, centrifuged and, whole plasma column (WP) and the plasma fraction with the highest platelet concentration (F3) were drawn off, avoiding the buffy coat. Primary human cells including keratocytes and conjunctival fibroblasts were used to perform the "in vitro" investigations. The potential of PRGF-Endoret in promoting wound healing was evaluated by means of a proliferation and migration assays. Fibroblast cells were induced to myofibroblast differentiation after the treatment with 2.5 ng/mL of TGF-beta1. The capability of WP and F3 to prevent and inhibit TGF-beta1-induced differentiation was evaluated. RESULTS: Results show that this autologous approach significantly enhances proliferation and migration of both keratocytes and conjunctival fibroblasts. In addition, plasma rich in growth factors prevents and inhibits TGF-beta1-induced myofibroblast differentiation. No differences were found between WP and F3 plasma fractions. CONCLUSIONS: These results suggest that PRGF-Endoret could reduce scarring while stimulating wound healing in ocular surface. F3 or whole plasma column show similar biological effects in keratocytes and conjunctival fibroblast cells. PMID- 21613375 TI - Calpain inhibition attenuates apoptosis of retinal ganglion cells in acute optic neuritis. AB - PURPOSE: Optic neuritis (ON), inflammation of the optic nerve, is strongly associated with the pathogenesis of multiple sclerosis (MS) and is initiated by the attack of autoreactive T cells against self-myelin antigens, resulting in demyelination, degeneration of retinal ganglion cells (RGCs), and cumulative visual impairment. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats on day 0, and animals received daily intraperitoneal injections of calpain inhibitor (calpeptin) or vehicle from day 1 until killed. Retinal cell death was analyzed by DNA fragmentation, and surviving ganglion cells were quantified after double labeling of retinal tissue with TUNEL and Brn3a. The expression of apoptotic and inflammatory proteins was determined by Western blotting. RESULTS: It was demonstrated that calpain inhibition downregulates expression of proapoptotic proteins and the proinflammatory molecule nuclear factor-kappa B (NF-kappaB) in the retina of Lewis rats with acute EAE. Immunofluorescent labeling revealed that apoptotic cells in the RGC layer of vehicle-treated EAE animals were Brn3a positive, and a moderate dose of calpeptin dramatically reduced the frequency of apoptotic RGCs. CONCLUSIONS: These results suggest that calpain inhibition might be a useful supplement to immunomodulatory therapies such as corticosteroids in ON, due to its neuroprotective effect on RGCs. PMID- 21613376 TI - Haplotype-based genomic sequencing of a chromosomal polymorphism in the white throated sparrow (Zonotrichia albicollis). AB - Inversion polymorphisms have been linked to a variety of fundamental biological and evolutionary processes. Yet few studies have used large-scale genomic sequencing to directly compare the haplotypes associated with the standard and inverted chromosome arrangements. Here we describe the targeted genomic sequencing and comparison of haplotypes representing alternative arrangements of a common inversion polymorphism linked to a suite of phenotypes in the white throated sparrow (Zonotrichia albicollis). More than 7.4 Mb of genomic sequence was generated and assembled from both the standard (ZAL2) and inverted (ZAL2(m)) arrangements. Sequencing of a pair of inversion breakpoints led to the identification of a ZAL2-specific segmental duplication, as well as evidence of breakpoint reusage. Comparison of the haplotype-based sequence assemblies revealed low genetic differentiation outside versus inside the inversion indicative of historical patterns of gene flow and suppressed recombination between ZAL2 and ZAL2(m). Finally, despite ZAL2(m) being maintained in a near constant state of heterozygosity, no signatures of genetic degeneration were detected on this chromosome. Overall, these results provide important insights into the genomic attributes of an inversion polymorphism linked to mate choice and variation in social behavior. PMID- 21613377 TI - Association of obesity and smoking with PSA and PSA velocity in men with prostate cancer. AB - Significant number of prostate tumors are slow growing and could probably be left untreated. However, many are aggressive and can spread rapidly causing patient suffering and/or death. Current technology does not allow physicians to differentiate between slow growing and aggressive tumors at diagnosis. Hence, many patients are exposed to invasive treatment and its associated morbidities such as incontinence and impotence. Markers that enable differentiation between slow and fast progressing cancer will allow physicians to prevent unnecessary treatments on men who may not need them, and focus on the men with aggressive disease. A longitudinal study was conducted (N = 140) using mixed effects regression models to determine the association of obesity and smoking toward prostate cancer progression. These models account for correlation because of repeated measures over time, thus, using maximum amount of information provided by the subject. Estimates thus obtained are more robust and reliable than those obtained using data from a single time point. Rate of change of prostate-specific antigen (PSA) over time (PSA velocity) was used as a measure of prostate cancer progression. Results indicate that PSA velocity of overweight and obese subjects (0.59 and 1.05 ng/mL/year) was not significantly different as compared with normal weight subjects (p values .91 and .31, respectively). For men in the highest tertile of pack-years of smoking, PSA velocity was significantly higher as compared with never smokers 1.57 ng/mL/year (p = .04). Further studies with larger sample sizes and study designs specific to above exposures are needed before recommendations can be made to reduce weight or reduce/quit smoking. PMID- 21613378 TI - Multimorbidity, service organization and clinical decision making in primary care: a qualitative study. AB - BACKGROUND: Primary care professionals often manage patients with multiple long term health conditions, but managing multimorbidity is challenging given time and resource constraints and interactions between conditions. OBJECTIVE: To explore GP and nurse perceptions of multimorbidity and the influence on service organization and clinical decision making. METHODS: A qualitative interview study with primary care professionals in practices in Greater Manchester, U.K. Interviews were conducted with 15 GPs and 10 practice nurses. RESULTS: Primary care professionals identified tensions between delivering care to meet quality targets and fulfilling the patient's agenda, tensions which are exacerbated in multimorbidity. They were aware of the inconvenience suffered by patients through attendance at multiple clinic appointments when care was structured around individual conditions. They reported difficulties managing patients with multimorbidity in limited consultation time, which led to adoption of an 'additive-sequential' decision-making model which dealt with problems in priority order until consultation resources were exhausted, when further management was deferred. Other challenges included the need for patients to co-ordinate their care, the difficulties of self-management support in multimorbidity and problems of making sense of the relationships between physical and mental health. Doctor and nurse accounts included limited consideration of multimorbidity in terms of the interactions between conditions or synergies between management of different conditions. CONCLUSIONS: Primary care professionals identify a number of challenges in care for multimorbidity and adopt a particular model of decision making to deliver care for multiple individual conditions. However, they did not describe specific decision making around managing multimorbidity per se. PMID- 21613380 TI - Compliance with recommendations for pandemic influenza H1N1 2009: the role of trust and personal beliefs. AB - BACKGROUND: To investigate the relationship between risk perception, worry, control, trust, exposure to an educational campaign, media exaggeration with recommendations for pandemic influenza H1N1 2009. METHODS: Cross sectional telephone survey using random digit dialing. A total of 1010 adult Italians were interviewed by telephone between 16 and 19 February 2010. The survey instrument included demographic data, measures on risk perception, worry, trust and compliance with recommendations for pandemic influenza H1N1 2009. RESULTS: Controlling for socio-demographic variables, compliance with all the recommended behaviors was associated with media trust, trust in the Ministry of Health, worry and perceived severity of illness. Perceptions that the risk of catching pandemic influenza H1N1 2009 is high, that the authorities are acting in the public's best interest in dealing with it, that the media had exaggerated the risks of catching it and that people can control their risk of catching it were associated with compliance with some recommended behaviors even after considering effects of socio-demographic characteristics. CONCLUSION: The results underscore the importance of building public trust and to consider the influence of risk perception and affective response in promoting compliance with recommended behaviors. PMID- 21613379 TI - Reduced expression of a gene encoding a Golgi localized monosaccharide transporter (OsGMST1) confers hypersensitivity to salt in rice (Oryza sativa). AB - Sugar transport is critical for normal plant development and stress responses. However, functional evidence for the roles of monosaccharide transporters in rice (Oryza sativa) has not previously been presented. In this study, reversed genetics was used to identify OsGMST1 as a member of the monosaccharide transporter family in rice. The predicted 481 amino acid protein has the typical features of a sugar transporter in the plastid glucose transporter subfamily consistent with reduced monosaccharide accumulation in plants with reduced OsGMST1 expression. OsGMST1-green fluorescent protein is localized to the Golgi apparatus. OsGMST1 expression is induced by salt treatment and reduced expression confers hypersensitivity to salt stress in rice. OsGMST1 may play a direct or an indirect role in tolerance to salt stress in rice. PMID- 21613381 TI - Lack of gender influence on cortical and subcortical gray matter development in childhood-onset schizophrenia. AB - BACKGROUND: Progressive cortical gray matter (GM) abnormalities are an established feature of schizophrenia and are more pronounced in rare, severe, and treatment refractory childhood-onset schizophrenia (COS) cases. The effect of sex on brain development in schizophrenia is poorly understood and studies to date have produced inconsistent results. METHODS: Using the largest to date longitudinal sample of COS cases (n = 104, scans = 249, Male/Female [M/F] = 57/47), we compared COS sex differences with sex differences in a sample of matched typically developing children (n = 104, scans = 244, M/F = 57/47), to determine whether or not sex had differential effects on cortical and subcortical brain development in COS. RESULTS: Our results showed no significant differential sex effects in COS for either GM cortical thickness or subcortical volume development (sex * diagnosis * age interaction; false discovery rate q = 0.05). CONCLUSION: Sex appears to play a similar role in cortical and subcortical GM development in COS as it does in normally developing children. PMID- 21613382 TI - Low-fructose diet lowers blood pressure and inflammation in patients with chronic kidney disease. AB - BACKGROUND: Fructose has been strongly linked with hypertension, hyperuricemia and inflammation in experimental models and humans. However, the effect of low fructose diet on inflammation, hyperuricemia and the progression of renal disease has not yet been evaluated in patients with chronic kidney disease (CKD). METHODS: Twenty-eight patients (age 59 +/- 15 years, 17 males/11 females) with Stages 2 and 3 CKD were switched from a regular (basal) (60.0 g/24 h) to a low (12.0 g/24 h) fructose diet for 6 weeks, followed by a resumption of their regular diet for another 6 weeks. Diet was monitored by a dietician. At the baseline, low- and regular-fructose diet ambulatory blood pressure (BP) was measured and blood sampled for renal function (creatinine), inflammatory markers, fasting glucose and insulin and serum uric acid. Twenty-four-hour urine collections were also obtained for creatinine, uric acid, monocyte chemotatic protein-1, transforming growth factor-beta and N-acetyl-beta-D-glucosaminidase. RESULTS: The low-fructose diet tended to improve BP for the whole group (n = 28), while significant reduction of BP was only seen in dippers (n = 20) but not in non-dippers (n = 8). No effects on estimated glomerular filtration rate (eGFR) or proteinuria were observed. Serum uric acid was lowered non-significantly with low fructose diet (7.1 +/- 1.3 versus 6.6 +/- 1.0 mg/dL, P < 0.1), whereas a significant decrease in fasting serum insulin was observed (11.2 +/- 6.1 versus 8.2 +/- 2.9 mIU/mL, P < 0.05) and the reduction persisted after return to the regular diet. A slight but not significant reduction in urinary uric acid and fractional uric acid excretion was observed while the patients were on the low fructose diet. The low-fructose diet also decreased high sensitivity C-reactive protein (hsCRP) (4.3 +/- 4.9 versus 3.3 +/- 4.5 mg/L; P < 0.01) and soluble intercellular adhesion molecule (sICAM) (250.9 +/- 59.4 versus 227 +/- 50.5 ng/mL; P < 0.05). The hsCRP returned to baseline with resumption of the regular diet, whereas the reduction in sICAM persisted. CONCLUSION: Low-fructose diet in subjects with CKD can reduce inflammation with some potential benefits on BP. This pilot study needs to be confirmed by a larger clinical trial to determine the long-term benefit of a low-fructose diet compared to other diets in subjects with CKD. PMID- 21613383 TI - Sclerostin serum levels correlate positively with bone mineral density and microarchitecture in haemodialysis patients. AB - BACKGROUND: Sclerostin is a soluble inhibitor of osteoblast function. Sclerostin is downregulated by the parathyroid hormone (PTH). Here, it was investigated whether sclerostin levels are influenced by intact (i) PTH and whether sclerostin is associated with bone turnover, microarchitecture and mass in dialysis patients. METHODS: Seventy-six haemodialysis patients and 45 healthy controls were included in this cross-sectional study. Sclerostin, Dickkopf-1 (DKK-1), intact parathyroid hormone (iPTH), vitamin D and markers of bone turnover were analysed. A subset of 37 dialysis patients had measurements of bone mineral density (BMD) using dual-energy X-ray absorptiometry and bone microarchitecture using high-resolution peripheral quantitative computed tomography. RESULTS: Dialysis patients had significantly higher sclerostin levels than controls (1257 pg/mL versus 415 pg/mL, P < 0.001). Significant correlations were found between sclerostin and gender (R = 0.41), iPTH (R = -0.28), 25-hydroxy-cholecalciferol (R = 0.27) and calcium (R = 0.25). Gender and iPTH remained significantly associated with sclerostin in a multivariate analysis. Sclerostin serum levels were positively associated with BMD at the lumbar spine (R = 0.46), femoral neck (R = 0.36) and distal radius (R = 0.42) and correlated positively mainly with trabecular structures such as trabecular density and number at the radius and tibia in dialysis patients. DKK-1 was related neither to bone measures nor to serologic parameters. CONCLUSIONS: Considering that sclerostin is an inhibitor of bone formation, the observed positive correlations of serum sclerostin with BMD and bone volume were unexpected. Whether its increase in dialysis patients has direct pathogenetic relevance or is only a secondary phenomenon remains to be seen. PMID- 21613385 TI - Combined effects of ascorbic acid and phosphate on rat VSMC osteoblastic differentiation. AB - BACKGROUND: Ascorbic acid (AA) supplementation has been suggested to afford erythropoietin hyporesponsiveness and high levels of ferritin in haemodialysis (HD) patients. However, little is known about the possible side effects of this policy on vascular calcification (VC). VC, induced by a high-phosphate and uraemic milieu, is characterized by a passive deposition of calcium-phosphate (Ca P) and an active transformation of vascular smooth muscle cells (VSMCs) in osteoblastic-like cells. The aim of these studies was to characterize the combined effects of AA and P on VC. MATERIALS AND METHODS: Rat VSMCs were challenged with inorganic P (Pi) and AA, and Ca deposition analysis was performed to quantify VC. To investigate VSMC osteoblastic differentiation, we analysed alpha-actin protein content and core-binding factor alpha-1 (Cbfalpha1/RUNX2) messenger RNA (mRNA) expression. RESULTS: When incubated with 5 mM Pi, VSMCs showed a significant increase in Ca deposition compared to control cells. Interestingly, the addition of AA in the calcification medium resulted in a dose dependent increase in Pi-induced Ca deposition. At the same time, the combined effect of AA and Pi on VSMCs resulted in the reduction of alpha-actin protein content and in a 4-fold increase of Cbfalpha1/RUNX2 mRNA expression. CONCLUSIONS: We demonstrated that AA combined with Pi increases Ca deposition in rat VSMCs. The role of AA as cofactor in osteoblastic differentiation was demonstrated by phenotypic changes in VSMCs and enhanced bone mineralization key gene expression. These in vitro preliminary data suggest a potential role for AA combined with Pi in worsening VC. PMID- 21613384 TI - Methylenetetrahydrofolate reductase (MTHFR) polymorphism A1298C (Glu429Ala) predicts decline in renal function over time in the African-American Study of Kidney Disease and Hypertension (AASK) Trial and Veterans Affairs Hypertension Cohort (VAHC). AB - BACKGROUND: Hyperhomocysteinemia is associated with increased venous thrombosis and cardiovascular disease (CVD). Mutations in the human methylenetetrahydrofolate reductase (MTHFR) gene have been associated with increased homocysteine levels and risks of CVD in various populations including those with kidney disease. Here, we evaluated the influence of MTHFR variants on progressive loss of kidney function. METHODS: We analyzed 821 subjects with hypertensive nephrosclerosis from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases African-American Study of Kidney Disease and Hypertension (AASK) Trial to determine whether decline in glomerular filtration rate (GFR) over ~4.2 years was predicted by common genetic variation within MTHFR at non-synonymous positions C677T (Ala222Val) and A1298C (Glu429Ala) or by MTHFR haplotypes. The effect on GFR decline was then supported by a study of 1333 subjects from the San Diego Veterans Affairs Hypertension Cohort (VAHC), followed over ~4.5 years. Linear effect models were utilized to determine both genotype [single-nucleotide polymorphism (SNP)] and genotype (SNP)-by-time interactions. RESULTS: In AASK, the polymorphism at A1298C predicted the rate of GFR decline: A1298/A1298 major allele homozygosity resulted in a less pronounced decline of GFR, with a significant SNP-by-time interaction. An independent follow-up study in the San Diego VAHC subjects supports that A1298/A1298 homozygotes have the greatest estimated GFR throughout the study. Haplotype analysis with C677T yielded concurring results. CONCLUSION: We conclude that the MTHFR-coding polymorphism at A1298C is associated with renal decline in African-Americans with hypertensive nephrosclerosis and is supported by a veteran cohort with a primary care diagnosis of hypertension. Further investigation is needed to confirm such findings and to determine what molecular mechanism may contribute to this association. PMID- 21613386 TI - Immune response to an adjuvanted influenza A H1N1 vaccine (Pandemrix((r))) in renal transplant recipients. AB - BACKGROUND: In the course of the influenza A H1N1 pandemic, transplanted patients were recommended to receive vaccination. In the present study, we evaluated the immune response to an adjuvanted influenza A H1N1 vaccine (Pandemrix(r)) in renal allograft recipients. METHODS: Sixty patients and 22 healthy controls participated in a prospective observational study and received a single dose of Pandemrix(r). H1N1 antibody titres as well as anti-HLA antibodies were determined before and after vaccination. In 19 patients, a booster vaccination was performed and the outcome of all vaccinated renal allograft recipients (n = 107) in our clinic was reviewed. RESULTS: Two out of sixty patients had an elevated influenza A H1N1 titre before vaccination. Of the remaining 58 patients, only 20/58 (34.5%) developed a protective immune response in contrast to 20/22 (91%) of the control group. After booster vaccination, a protective titre was present in 8/19 (42%) of patients. Of the 107 patients, 6 (5.6%) developed new donor-specific HLA antibodies after vaccination. CONCLUSIONS: These data suggest that Pandemrix(r) does not provide a protective immune response in the majority of kidney transplant recipients. Therefore, for new vaccines, efficacy as well as safety profiles should be evaluated in this subgroup of patients. PMID- 21613388 TI - Object crowding. AB - Crowding occurs when stimuli in the peripheral fields become harder to identify when flanked by other items. This phenomenon has been demonstrated extensively with simple patterns (e.g., Gabors and letters). Here, we characterize crowding for everyday objects. We presented three-item arrays of objects and letters, arranged radially and tangentially in the lower visual field. Observers identified the central target, and we measured contrast energy thresholds as a function of target-to-flanker spacing. Object crowding was similar to letter crowding in spatial extent but was much weaker. The average elevation in threshold contrast energy was in the order of 1 log unit for objects as compared to 2 log units for letters and silhouette objects. Furthermore, we examined whether the exterior and interior features of an object are differentially affected by crowding. We used a circular aperture to present or exclude the object interior. Critical spacings for these aperture and "donut" objects were similar to those of intact objects. Taken together, these findings suggest that crowding between letters and objects are essentially due to the same mechanism, which affects equally the interior and exterior features of an object. However, for objects defined with varying shades of gray, it is much easier to overcome crowding by increasing contrast. PMID- 21613387 TI - Association of echocardiographic abnormalities with mortality in men with non dialysis-dependent chronic kidney disease. AB - BACKGROUND: The interrelationship of left ventricular hypertrophy (LVH) with ejection fraction (EF) and their impact on mortality in non-dialysis-dependent chronic kidney disease (NDD-CKD) is unclear. METHODS: We examined the associations of EF and LVH with all-cause mortality in a historic cohort of 650 male US veterans with moderate-to-advanced NDD-CKD. EF and LVH were examined both separately and after categorizing patients according to their concomitant EF and presence/absence of LVH. Associations with mortality were examined in Cox models with adjustments for demographics, blood pressure, comorbidities, smoking status, medication use and biochemical characteristics. RESULTS: EF <30 and 30-50% were associated with higher all-cause mortality compared to EF >50% even after multivariable adjustments [multivariable adjusted hazard ratio, 95% confidence interval (CI): 2.83 (1.86-4.30) and 1.38 (1.06-1.78), P < 0.001 for linear trend]. LVH in itself was not associated with mortality [multivariable adjusted hazard ratio, 95% CI: 0.83 (0.66-1.05), P = 0.12], but the presence of LVH combined with an EF <50% was associated with the highest mortality [multivariable adjusted hazard ratios, 95% CI in patients with EF >50% + LVH, EF <= 50%-LVH and EF <= 50% + LVH, compared to EF >50%-LVH: 0.84 (0.63-1.13), 1.36 (1.00-1.83) and 1.62 (1.07-2.46)]. CONCLUSIONS: Low EF is associated with higher mortality in patients with NDD-CKD. In the presence of a low EF, LVH is also associated with higher mortality. Clinical trials are needed to determine if interventions targeting patients with low EF and LVH can lower mortality in NDD-CKD. PMID- 21613389 TI - The efficacy of computer-delivered treatment for smoking cessation. AB - BACKGROUND: The current study evaluated the efficacy of an individualized, hand held computer-delivered treatment (CDT) versus standard treatment (ST) for the maintenance of smoking abstinence following a quit attempt. METHODS: Participants were 303 adult daily smokers randomized to CDT or ST, plus pharmacotherapy. Abstinence though 1 year was examined using logistic random intercept models, a type of generalized linear mixed model regression. RESULTS: Results did not support the efficacy of the CDT program through 1 year postquit in analyses adjusted for time and study site (OR = 0.84, 95% CI = 0.55-1.30), or after further adjusting for race/ethnicity, age, gender, education, marital status, and the number of cigarettes smoked per day before quitting (OR = 0.89, 95% CI = 0.57 1.39). CONCLUSIONS: CDT did not increase short- or long-term abstinence rates over ST in this study. IMPACT: Findings differ from some in the literature and suggest the need for continued research on the use of CDT for smoking cessation. PMID- 21613390 TI - Human polyomaviruses and other human viruses in neuroendocrine tumors. AB - BACKGROUND: While the association of the Merkel cell polyomavirus (MCV) with the neuroendocrine Merkel cell carcinomas (MCC) has been shown recently, it is unknown whether other human polyomaviruses (HPyV) may be associated with neuroendocrine tumours (NETs) of distinct entities. METHODS: Using novel, highly sensitive polyomavirus genotyping assays, we evaluated the prevalence of eight distinct HPyVs in a selection of 51 NETs from different entities. In addition, we analyzed these NETs for the presence of DNA from 12 adeno-associated virus (AAV) genotypes, adeno virus-5, 27 mucosal human papillomavirus (HPV) genotypes, hepatitis B (HBV), 8 human herpes viruses (HHV), and xenotropic murine leukemia virus-related virus (XMRV). RESULTS: 43 of the 50 (86%) NETs were positive for the DNA integrity control. Of these, 2 of 3 MCCs (67%) were positive for MCV. NETs from other entities, however, were negative for all HPyVs. Only a small subset of lung and appendix NETs were positive for EBV, HHV-6, and -7. CONCLUSION: While the association of MCV with MCC was confirmed, other human viruses could not be identified as potentially causative agents of other NETs. IMPACT: Our findings suggest that the human viruses tested for in this study do not play a comparable role in NETs like the polyomavirus MCV in MCC. PMID- 21613391 TI - Comparison of exposure to selected cigarette smoke constituents in adult smokers and nonsmokers in a European, multicenter, observational study. AB - BACKGROUND: This multicenter, observational study was conducted in three European countries (Germany, Switzerland, and the United Kingdom) to determine the exposure of adult cigarette smokers and nonsmokers to selected cigarette smoke constituents: 1,3-butadiene, 2-naphthylamine, 4-aminobiphenyl, 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), acrolein, benzene, carbon monoxide, nicotine, pyrene, and o-toluidine. METHODS: Smokers were grouped by tar category (TC) according to the tar yield of their regular cigarette brand: TC1: <=4 mg tar, TC2: 5-7 mg tar, and TC3: >=8 mg tar [to the legal tar yield ceiling in the respective countries (10 or 12 mg tar)]. Levels of biomarkers of exposure to the aforementioned cigarette smoke constituents were compared between smokers and nonsmokers, and within smokers across tar categories. RESULTS: The full population consisted of 1,631 subjects (1,223 smokers and 408 nonsmokers). Biomarkers of exposure were analyzed for 1,558 subjects (valid case population) as follows: 1,159 smokers (TC1: n = 402, TC2: n = 379, TC3: n = 378), and 399 nonsmokers. Exposure levels were higher in smokers than nonsmokers and increased with increasing tar yield and cigarette consumption. An association of tar category and exposure level was observed for all smoke constituents, except pyrene, 4-aminobiphenyl, and o-toluidine, whereas only NNK exposure was different in all three tar categories. CONCLUSIONS: Smoking status and, among smokers, daily cigarette consumption and tar yield were observed to affect biomarker of exposure levels. IMPACT: This research provides a comprehensive evaluation of smoke constituent exposure of adult cigarette smokers and nonsmokers in three European countries. PMID- 21613392 TI - Genus-specific substitution rate variability among picornaviruses. AB - Picornaviruses have some of the highest nucleotide substitution rates among viruses, but there have been no comparisons of evolutionary rates within this broad family. We combined our own Bayesian coalescent analyses of VP1 regions from four picornaviruses with 22 published VP1 rates to produce the first within family meta-analysis of viral evolutionary rates. Similarly, we compared our rate estimates for the RNA polymerase 3D(pol) gene from five viruses to four published 3D(pol) rates. Both a structural and a nonstructural gene show that enteroviruses are evolving, on average, a half order of magnitude faster than members of other genera within the Picornaviridae family. PMID- 21613393 TI - A tyrosine-sulfated CCR5-mimetic peptide promotes conformational transitions in the HIV-1 envelope glycoprotein. AB - The HIV-1 envelope glycoprotein is a trimeric complex of heterodimers composed of a surface glycoprotein, gp120, and a transmembrane component, gp41. The association of this complex with CD4 stabilizes the coreceptor-binding site of gp120 and promotes the exposure of the gp41 helical region 1 (HR1). Here, we show that a 15-amino-acid peptide mimetic of the HIV-1 coreceptor CCR5 fused to a dimeric antibody Fc domain (CCR5mim-Ig) bound two gp120 molecules per envelope glycoprotein complex and by itself promoted HR1 exposure. CCR5mim-Ig also stabilized the association of a CD4-mimetic peptide with the envelope glycoprotein. A fusion of the CD4- and CCR5-mimetic peptides, DM1, bound gp120 and neutralized R5, R5X4, and X4 HIV-1 isolates comparably to CD4, and they did so markedly more efficiently than either peptide alone. Our data indicate that the potency of DM1-Ig derives from its avidity for the HIV-1 envelope glycoprotein trimer and from the bidirectional induction of its receptor-mimetic components. DM1 has significant advantages over other inhibitors that target both coreceptor and CD4-binding sites, and it may serve as a lead for a new class of HIV-1 inhibitor peptides. PMID- 21613395 TI - Role of proteases in the release of porcine epidemic diarrhea virus from infected cells. AB - Porcine epidemic diarrhea virus (PEDV), a causative agent of pig diarrhea, requires a protease(s) for multicycle replication in cultured cells. However, the potential role of proteases in the infection process remains unclear. In order to explore this, we used two different approaches: we infected either Vero cells in the presence of trypsin or Vero cells that constitutively express the membrane associated protease TMPRSS2 (Vero/TMPRSS2 cells). We found that PEDV infection was enhanced, and viruses were efficiently released into the culture fluid, from Vero cells infected in the presence of protease, while in cells without protease, the virus grew, but its release into the culture fluid was strongly hampered. Cell-to-cell fusion of PEDV-infected cells and cleavage of the spike (S) protein were observed in cells with protease. When infected Vero cells were cultured for 3 days in the absence of trypsin but were then treated transiently with trypsin, infectious viruses were immediately released from infected cells. In addition, treatment of infected Vero/TMPRSS2 cells with the protease inhibitor leupeptin strongly blocked the release of virus into the culture fluid. Under electron microscopy, PEDV-infected Vero cells, as well as PEDV-infected Vero/TMPRSS2 cells treated with leupeptin, retained huge clusters of virions on their surfaces, while such clusters were rarely seen in the presence of trypsin and the absence of leupeptin in Vero and Vero/TMPRSS2 cells, respectively. Thus, the present study indicates that proteases play an important role in the release of PEDV virions clustered on cells after replication occurs. This unique observation in coronavirus infection suggests that the actions of proteases are reminiscent of that of the influenza virus neuraminidase protein. PMID- 21613394 TI - Structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes. AB - Respiratory syncytial virus (RSV) invades host cells via a type I fusion (F) glycoprotein that undergoes dramatic structural rearrangements during the fusion process. Neutralizing monoclonal antibodies, such as 101F, palivizumab, and motavizumab, target two major antigenic sites on the RSV F glycoprotein. The structures of these sites as peptide complexes with motavizumab and 101F have been previously determined, but a structure for the trimeric RSV F glycoprotein ectodomain has remained elusive. To address this issue, we undertook structural and biophysical studies on stable ectodomain constructs. Here, we present the 2.8 A crystal structure of the trimeric RSV F ectodomain in its postfusion conformation. The structure revealed that the 101F and motavizumab epitopes are present in the postfusion state and that their conformations are similar to those observed in the antibody-bound peptide structures. Both antibodies bound the postfusion F glycoprotein with high affinity in surface plasmon resonance experiments. Modeling of the antibodies bound to the F glycoprotein predicts that the 101F epitope is larger than the linear peptide and restricted to a single protomer in the trimer, whereas motavizumab likely contacts residues on two protomers, indicating a quaternary epitope. Mechanistically, these results suggest that 101F and motavizumab can bind to multiple conformations of the fusion glycoprotein and can neutralize late in the entry process. The structural preservation of neutralizing epitopes in the postfusion state suggests that this conformation can elicit neutralizing antibodies and serve as a useful vaccine antigen. PMID- 21613396 TI - Isolation of a monoclonal antibody that targets the alpha-2 helix of gp120 and represents the initial autologous neutralizing-antibody response in an HIV-1 subtype C-infected individual. AB - The C3-V4 region is a major target of autologous neutralizing antibodies in HIV-1 subtype C infection. We previously identified a Center for AIDS Program of Research in South Africa (CAPRISA) participant, CAP88, who developed a potent neutralizing-antibody response within 3 months of infection that targeted an epitope in the C3 region of the HIV-1 envelope (P. L. Moore et al., PLoS Pathog. 5:e1000598, 2009). Here we showed that these type-specific antibodies could be adsorbed using recombinant gp120 from the transmitted/founder virus from CAP88 but not by gp120 made from other isolates. Furthermore, this activity could be depleted using a chimeric gp120 protein that contained only the C3 region from the CAP88 viral envelope engrafted onto the unrelated CAP63 viral envelope (called 63-88C3). On the basis of this, a differential sorting of memory B cells was performed using gp120s made from 63-88C3 and CAP63 labeled with different fluorochromes as positive and negative probes, respectively. This strategy resulted in the isolation of a highly specific monoclonal antibody (MAb), called CAP88-CH06, that neutralized the CAP88 transmitted/founder virus and viruses from acute infection but was unable to neutralize CAP88 viruses isolated at 6 and 12 months postinfection. The latter viruses contained 2 amino acid changes in the alpha-2 helix of C3 that mediated escape from this MAb. One of these changes involved the introduction of an N-linked glycan at position 339 that occluded the epitope, while the other mutation (either E343K or E350K) was a charge change. Our data validate the use of differential sorting to isolate a MAb targeting a specific epitope in the envelope glycoprotein and provided insights into the mechanisms of autologous neutralization escape. PMID- 21613397 TI - Architecture and regulation of the HIV-1 assembly and holding compartment in macrophages. AB - Productive infection of macrophages is central to HIV-1 pathogenesis. Newly formed virions bud into a tubular membranous compartment that is contiguous with the plasma membrane. However, little is known about the structure of this compartment and its potential regulation by infection. Here we characterized this compartment in macrophages using electron tomography and electron microscopy with stereology. We found an intricate, interconnected membrane network that constitutes a preexisting physiologic structure in macrophages but which expands in size upon HIV-1 infection. Membranes required for this expansion were apparently derived from preexisting pools of plasma membrane. Physical connections between this compartment and the extracellular milieu were frequently made by tube-like structures of insufficient diameter for virion passage. We conclude that HIV-1 induces the expansion of a complex membranous labyrinth in macrophages in which the virus buds and can be retained, with potential consequences for transmission and immune evasion. PMID- 21613399 TI - Expanded potential for recombinant trisegmented lymphocytic choriomeningitis viruses: protein production, antibody production, and in vivo assessment of biological function of genes of interest. AB - The recombinant engineering of trisegmented lymphocytic choriomeningitis virus (LCMV) to express two genes of interest was recently reported. We used this technology to efficiently express green fluorescent protein (GFP) and the immunoregulatory gene product interleukin-10 (IL-10) in vitro, assess IL-10 function in vivo during viral meningitis, and generate specific, robust monoclonal antibody responses to IL-10. Tripartite viruses were attenuated in wild-type and TLR7(-/-) mice. However, IFNAR1(-/-) mice sustained systemic viral replication when 2 nucleotide substitutions from a persistent LCMV variant were present. These findings demonstrate the utility of tripartite LCMV in vitro and in vivo to study genes in the context of a well-defined model system. PMID- 21613398 TI - Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B 58:01-positive individuals. AB - Molecular epidemiology studies have identified HLA-B 58:01 as a protective HIV allele. However, not all B 58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B 58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could explain their different disease trajectories. Cytotoxic T-lymphocyte (CTL) responses during acute infection predominantly targeted the TW10 and KF9 epitopes in p24(Gag) and Nef, respectively. Failure to target the TW10 epitope in one B 58:01-positive individual was associated with low CD4(+) counts and rapid disease progression. Among those targeting TW10, escape mutations arose within 2 to 15 weeks of infection. Rapid escape was associated with preexisting compensatory mutations in the transmitted viruses, which were present at a high frequency (69%) in the study population. At 1 year postinfection, B 58:01-positive individuals who targeted and developed escape mutations in the TW10 epitope (n = 5) retained significantly higher CD4(+) counts (P = 0.04), but not lower viral loads, than non-B 58:01-positive individuals (n = 17). The high population-level frequency of these compensatory mutations may be limiting the protective effect of the B 58:01 allele. PMID- 21613400 TI - Sterol regulatory element-binding protein 2 couples HIV-1 transcription to cholesterol homeostasis and T cell activation. AB - Cholesterol plays an essential role in the life cycle of several enveloped viruses. Many of these viruses manipulate host cholesterol metabolism to facilitate their replication. HIV-1 infection of CD4(+) T cells activates the sterol regulatory element-binding protein 2 (SREBP2) transcriptional program, which includes genes involved in cholesterol homeostasis. However, the role of SREBP2-dependent transcription in HIV-1 biology has not been fully examined. Here, we identify TFII-I, a gene critical for HIV-1 transcription in activated T cells, as a novel SREBP2 target gene. We found TFII-I expression increased after HIV-1 infection or activation of human primary CD4(+) T cells. We show that inhibition of SREBP2 activity reduced TFII-I induction in response to these stimuli. More importantly, small interfering RNA (siRNA)-mediated gene silencing of either SREBP2 or TFII-I significantly reduced HIV-1 production in CD4(+) T cells. We also found that TFII-I potentiates Tat-dependent viral gene expression, consistent with a role at the level of HIV-1 transcription. Collectively, our results demonstrate for the first time that HIV-1 transcription in T cells is linked to cholesterol homeostasis through control of TFII-I expression by SREBP2. PMID- 21613401 TI - Mechanisms of human immunodeficiency virus type 2 RNA packaging: efficient trans packaging and selection of RNA copackaging partners. AB - Human immunodeficiency virus type 2 (HIV-2) has been reported to have a distinct RNA packaging mechanism, referred to as cis packaging, in which Gag proteins package the RNA from which they were translated. We examined the progeny generated from dually infected cell lines that contain two HIV-2 proviruses, one with a wild-type gag/gag-pol and the other with a mutant gag that cannot express functional Gag/Gag-Pol. Viral titers and RNA analyses revealed that mutant viral RNAs can be packaged at efficiencies comparable to that of viral RNA from which wild-type Gag/Gag-Pol is translated. These results do not support the cis packaging hypothesis but instead indicate that trans packaging is the major mechanism of HIV-2 RNA packaging. To further characterize the mechanisms of HIV-2 RNA packaging, we visualized HIV-2 RNA in individual particles by using fluorescent protein-tagged RNA-binding proteins that specifically recognize stem loop motifs in the viral genomes, an assay termed single virion analysis. These studies revealed that >90% of the HIV-2 particles contained viral RNAs and that RNAs derived from different viruses were copackaged frequently. Furthermore, the frequencies of heterozygous particles in the viral population could be altered by changing a 6-nucleotide palindromic sequence at the 5'-untranslated region of the HIV-2 genome. This finding indicates that selection of copackaging RNA partners occurs prior to encapsidation and that HIV-2 Gag proteins primarily package one dimeric RNA rather than two monomeric RNAs. Additionally, single virion analyses demonstrated a similar RNA distribution in viral particles regardless of whether both viruses had a functional gag or one of the viruses had a nonfunctional gag, providing further support for the trans-packaging hypothesis. Together, these results revealed mechanisms of HIV-2 RNA packaging that are, contrary to previous studies, in many respects surprisingly similar to those of HIV-1. PMID- 21613402 TI - Highly pathogenic avian influenza viruses do not inhibit interferon synthesis in infected chickens but can override the interferon-induced antiviral state. AB - From infection studies with cultured chicken cells and experimental mammalian hosts, it is well known that influenza viruses use the nonstructural protein 1 (NS1) to suppress the synthesis of interferon (IFN). However, our current knowledge regarding the in vivo role of virus-encoded NS1 in chickens is much more limited. Here, we report that highly pathogenic avian influenza viruses of subtypes H5N1 and H7N7 lacking fully functional NS1 genes were attenuated in 5 week-old chickens. Surprisingly, in diseased birds infected with NS1 mutants, the IFN levels were not higher than in diseased birds infected with wild-type virus, suggesting that NS1 cannot suppress IFN gene expression in at least one cell population of infected chickens that produces large amounts of the cytokine in vivo. To address the question of why influenza viruses are highly pathogenic in chickens although they strongly activate the innate immune system, we determined whether recombinant chicken alpha interferon (IFN-alpha) can inhibit the growth of highly pathogenic avian influenza viruses in cultured chicken cells and whether it can ameliorate virus-induced disease in 5-week-old birds. We found that IFN treatment failed to confer substantial protection against challenge with highly pathogenic viruses, although it was effective against viruses with low pathogenic potential. Taken together, our data demonstrate that preventing the synthesis of IFN is not the primary role of the viral NS1 protein during infection of chickens. Our results further suggest that virus-induced IFN does not contribute substantially to resistance of chickens against highly pathogenic influenza viruses. PMID- 21613403 TI - Rhesus monkey rhadinovirus ORF57 induces gH and gL glycoprotein expression through posttranscriptional accumulation of target mRNAs. AB - Open reading frame 57 (ORF57) of gamma-2 herpesviruses is a key regulator of viral gene expression. It has been reported to enhance the expression of viral genes by transcriptional, posttranscriptional, or translational activation mechanisms. Previously we have shown that the expression of gH and gL of rhesus monkey rhadinovirus (RRV), a close relative of the human Kaposi's sarcoma associated herpesvirus (KSHV), could be dramatically rescued by codon optimization as well as by ORF57 coexpression (J. P. Bilello, J. S. Morgan, and R. C. Desrosiers, J. Virol. 82:7231-7237, 2008). We show here that ORF57 coexpression and codon optimization had similar effects, except that the rescue of expression by codon optimization was temporally delayed relative to that of ORF57 coexpression. The transfection of gL mRNA directly into cells with or without ORF57 coexpression and with or without codon optimization recapitulated the effects of these modes of induction on transfected DNA. These findings suggested an important role for the enhancement of mRNA stability and/or the translation of mRNA for these very different modes of induced expression. This conclusion was confirmed by several different measures of gH and gL mRNA stability and accumulation with or without ORF57 coexpression and with or without codon optimization. Our results indicate that RRV gH and gL expression is severely limited by the stability of the mRNA and that ORF57 coexpression and codon optimization independently induce gH and gL expression principally by allowing accumulation and translation of these mRNAs. PMID- 21613404 TI - Unnatural amino acid incorporation onto adenoviral (Ad) coat proteins facilitates chemoselective modification and retargeting of Ad type 5 vectors. AB - Surface modification of adenovirus vectors can improve tissue-selective targeting, attenuate immunogenicity, and enable imaging of particle biodistribution, thus significantly improving therapeutic potential. Currently, surface engineering is constrained by a combination of factors, including impact on viral fitness, limited access to functionality, or incomplete control over the site of modification. Here, we report a two-step labeling process involving an initial metabolic placement of a uniquely reactive unnatural amino acid, azidohomoalanine (Aha), followed by highly specific chemical modification. As genetic modification of adenovirus is unnecessary, vector production is exceedingly straightforward. Aha incorporation demonstrated no discernible impact on either virus production or infectivity of the resultant particles. "Click" chemical modification of surface-exposed azides was highly selective, allowing for the attachment of a wide range of functionality. Decoration of human adenovirus type 5 (hAd5) with folate, a known cancer-targeting moiety, provided an ~20-fold increase in infection of murine breast cancer cells (4T1) in a folate receptor-dependent manner. This study demonstrates that incorporation of unnatural amino acids can provide a flexible, straightforward route for the selective chemical modification of adenoviral vectors. PMID- 21613405 TI - VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. AB - Angiogenesis inhibitors that block VEGF receptor (VEGFR) signaling slow the growth of many types of tumors, but eventually the disease progresses. Multiple strategies are being explored to improve efficacy by concurrent inhibition of other functionally relevant receptor tyrosine kinases (RTK). XL880 (foretinib, GSK1363089) and XL184 (cabozantinib) are small-molecule inhibitors that potently block multiple RTKs, including VEGFR and the receptor of hepatocyte growth factor c-Met, which can drive tumor invasion and metastasis. This study compared the cellular effects of XL880 and XL184 with those of an RTK inhibitor (XL999) that blocks VEGFR but not c-Met. Treatment of RIP-Tag2 mice with XL999 resulted in 43% reduction in vascularity of spontaneous pancreatic islet tumors over 7 days, but treatment with XL880 or XL184 eliminated approximately 80% of the tumor vasculature, reduced pericytes and empty basement membrane sleeves, caused widespread intratumoral hypoxia and tumor cell apoptosis, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 and XL184 also decreased invasiveness of primary tumors and reduced metastasis. Overall, these findings indicate that inhibition of c-Met and functionally related kinases amplifies the effects of VEGFR blockade and leads to rapid, robust, and progressive regression of tumor vasculature, increased intratumoral hypoxia and apoptosis, and reduced tumor invasiveness and metastasis. PMID- 21613406 TI - Poly(ADP-Ribose) polymerase inhibition synergizes with 5-fluorodeoxyuridine but not 5-fluorouracil in ovarian cancer cells. AB - 5-Fluorouracil (5-FU) and 5-fluorodeoxyuridine (FdUrd, floxuridine) have activity in multiple tumors, and both agents undergo intracellular processing to active metabolites that disrupt RNA and DNA metabolism. These agents cause imbalances in deoxynucleotide triphosphate levels and the accumulation of uracil and 5-FU in the genome, events that activate the ATR- and ATM-dependent checkpoint signaling pathways and the base excision repair (BER) pathway. Here, we assessed which DNA damage response and repair processes influence 5-FU and FdUrd toxicity in ovarian cancer cells. These studies revealed that disabling the ATM, ATR, or BER pathways using small inhibitory RNAs did not affect 5-FU cytotoxicity. In stark contrast, ATR and a functional BER pathway protected FdUrd-treated cells. Consistent with a role for the BER pathway, the poly(ADP-ribose) polymerase (PARP) inhibitors ABT 888 (veliparib) and AZD2281 (olaparib) markedly synergized with FdUrd but not with 5-FU in ovarian cancer cell lines. Furthermore, ABT-888 synergized with FdUrd far more effectively than other agents commonly used to treat ovarian cancer. These findings underscore differences in the cytotoxic mechanisms of 5-FU and FdUrd and suggest that combining FdUrd and PARP inhibitors may be an innovative therapeutic strategy for ovarian tumors. PMID- 21613407 TI - SPARC stimulates neuronal differentiation of medulloblastoma cells via the Notch1/STAT3 pathway. AB - Secreted protein acidic and rich in cysteine (SPARC) participates in the regulation of morphogenesis and cellular differentiation through its modulation of cell-matrix interactions. We previously reported that SPARC expression significantly impairs medulloblastoma tumor growth in vivo. In this study, we show that adenoviral-mediated overexpression of SPARC cDNA (Ad-DsRed-SP) elevated the expression of the neuronal markers NeuN, nestin, neurofilament, and MAP-2 in medulloblastoma cells and induced neuron-like differentiation. SPARC overexpression decreased STAT3 phosphorylation; constitutive expression of STAT3 reversed SPARC-mediated expression of neuronal markers. We also show that Notch signaling is suppressed in the presence of SPARC, as well as the Notch effector basic helix-loop-helix (bHLH) transcription factor hairy and enhancer of split 1 (HES1). Notch signaling was found to be responsible for the decreased STAT3 phosphorylation in response to SPARC expression. Furthermore, expression of SPARC decreased the production of interleukin 6 (IL-6) and supplemented IL-6-abrogated, SPARC-mediated suppression of Notch signaling and expression of neuronal markers. Immunohistochemical analysis of tumor sections from mice treated with Ad-DsRed-SP showed increased immunoreactivity for the neuronal markers and a decrease in Notch1 expression and phosphorylation of STAT3. Taken together, our results suggest that SPARC induces expression of neuronal markers in medulloblastoma cells through its inhibitory effect on IL-6-regulated suppression of Notch pathway-mediated STAT3 signaling, thus giving further support to the potential use of SPARC as a therapeutic candidate for medulloblastoma treatment. Findings show that SPARC-induced neuronal differentiation can sensitize medulloblastoma cells for therapy. PMID- 21613408 TI - Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. AB - Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biological characterization of X-376 and X-396, two potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X 396 were more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066 (PF-1066), an ALK/MET dual TKI currently in clinical trials. Both X-376 and X-396 displayed potent antitumor activity in vivo with favorable pharmacokinetic and toxicity profiles. Similar levels of drug sensitivity were displayed by the three most common ALK fusion proteins in lung cancer (EML4-ALK variants E13;A20, E20;A20, and E6b;A20) as well as a KIF5B-ALK fusion protein. Moreover, X-396 could potently inhibit ALK kinases engineered with two point mutations associated with acquired resistance to PF-1066, L1196M, and C1156Y, when engineered into an E13;A20 fusion variant. Finally, X-396 displayed synergistic growth inhibitory activity when combined with the mTOR inhibitor rapamycin. Our findings offer preclinical proof-of-concept for use of these novel agents to improve therapeutic outcomes of patients with mutant ALK-driven malignancies. PMID- 21613410 TI - Administration of naked plasmid encoding hepatic stimulator substance by hydrodynamic tail vein injection protects mice from hepatic failure by suppressing the mitochondrial permeability transition. AB - Acute liver failure is a devastating illness of various causes with considerable mortality. Hepatic stimulator substance (HSS) has been suggested for use as a protective agent against acute hepatic injury induced by chemical poisons because it has a variety of biological activities. However, the mechanism whereby HSS protects against hepatotoxins is poorly understood. In this study, we established a hepatic gene transfer system via hydrodynamic tail vein injection to deliver a naked plasmid containing the human HSS gene (hHSS) and analyzed HSS-mediated protection of the liver during fulminant hepatic failure (FHF) induced by D galactosamine (D-gal) and lipopolysaccharide (LPS). The results showed that the reporter gene, enhanced green fluorescent protein, was efficiently expressed in the liver of BALB/c mice. Hydrodynamic-based transfection of hHSS yielded a 70% survival rate compared with 36.7% for the control group at 24 h after D-gal/LPS treatment. In addition, hHSS expression preserved liver morphology and function. It is noteworthy that hHSS hydrodynamic-based transfer ameliorated indices of the mitochondrial permeability transition (MPT) resulting from the toxic effects of d gal/LPS on the liver such as mitochondrial swelling, mitochondrial transmembrane potential disruption, and cytochrome c translocation. Furthermore, mitochondrial morphology and ATP levels were maintained in hHSS-administered mice. HSS-mediated protection was similar to that observed with the MPT inhibitor N-methyl-4 isoleucine-cyclosporin (NIM811), indicating a possible role for HSS in the regulation of MPT. In conclusion, a single dose of hHSS plasmid protected mice from FHF, and this hepatoprotective effect seemed to correlate with the inhibition of MPT. PMID- 21613409 TI - A DNA methylation fingerprint of 1628 human samples. AB - Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. Herein, we present a compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1628 human samples in which we interrogated 1505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and stemness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG-island hypermethylation and a loss of CpG methylation in non-CpG island promoters. Although transformed cells are those in which DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the DNA methylation fingerprints obtained might be useful for translational purposes by showing that we are able to identify the tumor type origin of cancers of unknown primary origin (CUPs). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues, and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human diseases. PMID- 21613411 TI - Dihydrotestosterone upregulates the expression of epidermal growth factor receptor and ERBB2 in androgen receptor-positive bladder cancer cells. AB - Androgen receptor (AR) signals play important roles in bladder carcinogenesis and tumor progression. Activation of the epidermal growth factor receptor (EGFR) family, including EGFR and ERBB2, leads to bladder cancer cell growth and correlates with poor patients' prognosis. However, cross talk between AR and EGFR/ERBB2 pathways in bladder cancer remains poorly understood. In AR-positive bladder cancer UMUC3 and TCC-SUP cells, dihydrotestosterone (DHT) increased the expression of EGFR and ERBB2 both in mRNA and in protein levels, and an anti androgen hydroxyflutamide antagonized the effect of DHT. The necessity of AR was confirmed by silencing the receptor, using short hairpin RNA (shRNA), in UMUC3 cells, as well as by expressing the receptor in AR-negative 5637 cells. Of note were much higher basal levels of EGFR and ERBB2 in UMUC3-control-shRNA than in UMUC3-AR-shRNA and those of EGFR in 5637-AR than in 5637-V. DHT additionally upregulated the levels of phosphorylation of EGFR (pEGFR) and its downstream proteins AKT (pAKT) and ERK1/2 (pERK), induced by EGF treatment, in AR-positive cells. Immunohistochemistry on cystectomy specimens showed strong associations between expressions of AR and EGFR (P=0.0136), pEGFR (P=0.0041), ERBB2 (P=0.0331), or pERK (P=0.0274), but not of pAKT (P=0.5555). The Kaplan-Meier and log-rank tests further revealed that positivity of AR (P=0.0005), EGFR (P=0.2425), pEGFR (P=0.1579), ERBB2 (P=0.2997), or pERK (P=0.1270) and negativity of pAKT (P=0.0483) were associated with tumor progression. Our results indicate that AR activation upregulates the expression of EGFR and ERBB2 in bladder cancer cells. AR signals may thus contribute to the progression of bladder cancer via regulation of the EGFR/ERBB2 pathways. PMID- 21613412 TI - Killing the second messenger: targeting loss of cell cycle control in endocrine resistant breast cancer. AB - The majority (~70%) of breast cancers are steroid hormone receptor (SR) positive at the time of diagnosis. Endocrine therapies that target estrogen receptor alpha (ERalpha) action (tamoxifen, toremifene, fulvestrant) or estrogen synthesis (aromatase inhibitors: letrozole, anastrozole, exemestane; or ovarian suppression) are a clinical mainstay. However, up to 50% of SR+ breast cancers exhibit de novo or acquired resistance to these clinical interventions. Mechanisms of resistance to endocrine therapies often include upregulation and/or activation of signal transduction pathways that input to cell cycle regulation. Cyclin D1, the regulatory subunit of cyclin-dependent protein kinases four and six (CDK4/6) serves as a convergence point for multiple signaling pathways. In a recent paper entitled 'Therapeutically Activating Retinoblastoma (RB): Reestablishing Cell Cycle Control in Endocrine Therapy-Resistant Breast Cancer', Thangavel et al. reported maintenance of cyclin D1 expression and RB phosphorylation in the face of ER ablation in multiple breast cancer cell line models of endocrine resistance. RB-dysfunction defined a unique gene signature that was associated with luminal B-type breast cancer and predictive of poor response to endocrine therapies. Notably, a new CDK4/6 inhibitor (PD-0332991) was capable of inducing growth arrest by a mechanism that was most consistent with cellular senescence. In this review, these findings are discussed in the context of SRs as important mediators of cell cycle progression, and the frequent loss of cell cycle checkpoint control that typifies breast cancer progression. These studies provide renewed hope of effectively stabilizing endocrine-resistant breast cancers using available complementary (to endocrine-based therapies) cytostatic agents in the form of CDK4/6 inhibitors. PMID- 21613413 TI - Renal effects of prolonged high protein intake and COX2 inhibition on hypertensive rats with altered renal development. AB - Cyclooxygenase 2 (COX2) is involved in regulating renal hemodynamics after renal ablation. It is also known that high protein intake (HPI) leads to a deterioration of renal function when there is preexisting renal disease and that there are important gender differences in the regulation of renal function. This study tested the hypothesis that the role of COX2 in regulating renal function and the renal hemodynamic effects elicited by HPI are enhanced when nephrogenesis is altered during renal development. It was also expected that the role of COX2 and the effects elicited by HPI are age and sex dependent. Newborn Sprague-Dawley rats were treated with an AT(1) ANG II receptor antagonist during the nephrogenic period (ARAnp). Experiments were performed at 3-4 and 10-11 mo of age. Arterial pressure was elevated (P < 0.05) at both ages and in both sexes of ARAnp-treated rats. Renal COX2 expression was only elevated (P < 0.05) at 10-11 mo of age in both sexes of ARAnp-treated rats. COX2 inhibition induced greater renal vasoconstriction in male and female hypertensive than in normotensive rats at both ages. HPI did not induce glomerular filtration rate (GFR) in the youngest hypertensive rats and in the oldest female hypertensive rats. However, the GFR decreased during HPI (0.63 +/- 0.07 to 0.19 +/- 0.05 ml/min) in the oldest male hypertensive rats. The HPI-induced increment in proteinuria was greater (P < 0.05) in male (99 +/- 22 mg/day) than in female (30 +/- 8 mg/day) hypertensive rats. These results show that COX2 plays an important role in the regulation of renal function when renal development is altered and that prolonged HPI can lead to a renal insufficiency in males but not in females with reduced nephron endowment. PMID- 21613414 TI - GLUT1 enhances mTOR activity independently of TSC2 and AMPK. AB - Enhanced GLUT1 expression in mesangial cells plays an important role in the development of diabetic nephropathy by stimulating signaling through several pathways resulting in increased glomerular matrix accumulation. Similarly, enhanced mammalian target of rapamycin (mTOR) activation has been implicated in mesangial matrix expansion and glomerular hypertrophy in diabetes. We sought to examine whether enhanced GLUT1 expression increased mTOR activity and, if so, to identify the mechanism. We found that levels of GLUT1 expression and mTOR activation, as evidenced by S6 kinase (S6K) and 4E-BP-1 phosphorylation, changed in tandem in cell lines exposed to elevated levels of extracellular glucose. We then showed that increased GLUT1 expression enhanced S6K phosphorylation by 1.7- to 2.9-fold in cultured mesangial cells and in glomeruli from GLUT1 transgenic mice. Treatment with the mTOR inhibitor, rapamycin, eliminated the GLUT1 effect on S6K phosphorylation. In cells lacking functional tuberous sclerosis complex (TSC) 2, GLUT1 effects on mTOR activity persisted, indicating that GLUT1 effects were not mediated by TSC. Similarly, AMP kinase activity was not altered by enhanced GLUT1 expression. Conversely, enhanced GLUT1 expression led to a 2.4 fold increase in binding of mTOR to its activator, Rheb, and a commensurate 2.1 fold decrease in binding of Rheb to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) consistent with mediation of GLUT1 effects by a metabolic effect on GAPDH. Thus, GLUT1 expression appears to augment mesangial cell growth and matrix protein accumulation via effects on glycolysis and decreased GAPDH interaction with Rheb. PMID- 21613415 TI - Vulnerability of continence structures to injury by simulated childbirth. AB - The goal of this study was to examine acute morphological changes, edema, muscle damage, inflammation, and hypoxia in urethral and vaginal tissues with increasing duration of vaginal distension (VD) in a rat model. Twenty-nine virgin Sprague Dawley rats underwent VD under anesthesia with the use of a modified Foley catheter inserted into the vagina and filled with saline for 0, 1, 4, or 6 h. Control animals were anesthetized for 4 h without catheter placement. Urogenital organs were harvested after intracardiac perfusion of fixative. Tissues were embedded, sectioned, and stained with Masson's trichrome or hematoxylin and eosin stains. Regions of hypoxia were measured by hypoxyprobe-1 immunohistochemistry. Within 1 h of VD, the urethra became vertically elongated and displaced anteriorly. Edema was most prominent in the external urethral sphincter (EUS) and urethral/vaginal septum within 4 h of VD, while muscle disruption and fragmentation of the EUS occurred after 6 h. Inflammatory damage was characterized by the presence of polymorphonuclear leukocytes in vessels and tissues after 4 h of VD, with the greatest degree of infiltration occurring in the EUS. Hypoxia localized mostly to the vaginal lamina propria, urethral smooth muscle, and EUS within 4 h of VD. Increasing duration of VD caused progressively greater tissue edema, muscle damage, and morphological changes in the urethra and vagina. The EUS underwent the greatest insult, demonstrating its vulnerability to childbirth injury. PMID- 21613416 TI - Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome related injury. AB - While mitogen-activated protein kinase (MAPK) activation has been implicated in the pathogenesis of various glomerular diseases, including nephrotic syndrome (NS), its specific role in podocyte injury is not known. We hypothesized that MK 2, a downstream substrate of p38 MAPK, mediates the adverse effects of this pathway and that inhibition of MK-2 would protect podocytes from NS-related injury. Using cultured podocytes, we analyzed 1) the roles of MK-2 and p38 MAPK in puromycin aminonucleoside (PAN)-induced podocyte injury; 2) the ability of specific MK-2 and p38 MAPK inhibitors to protect podocytes against injury; 3) the role of serum albumin, known to induce podocyte injury, in activating p38 MAPK/MK 2 signaling; and 4) the role of p38 MAPK/MK-2 signaling in the expression of Cox 2, an enzyme associated with podocyte injury. Treatment with protein kinase inhibitors specific for both MK-2 (C23, a pyrrolopyridine-type compound) or p38 MAPK (SB203580) reduced PAN-induced podocyte injury and actin cytoskeletal disruption. Both inhibitors reduced baseline podocyte p38 MAPK/MK-2 signaling, as measured by the degree of phosphorylation of HSPB1, a downstream substrate of MK 2, but exhibited disparate effects on upstream signaling. Serum albumin activated p38 MAPK/MK-2 signaling and induced Cox-2 expression, and these responses were blocked by both inhibitors. Given the critical importance of podocyte injury to both NS and other progressive glomerular diseases, these data suggest an important role for p38 MAPK/MK-2 signaling in podocyte injury and identify MK-2 inhibition as a promising potential therapeutic strategy to protect podocytes in various glomerular diseases. PMID- 21613417 TI - WNK4 kinase inhibits Maxi K channel activity by a kinase-dependent mechanism. AB - WNK [with no lysine (k)] kinase is a serine/threonine kinase subfamily. Mutations in two of the WNK kinases result in pseudohypoaldosteronism type II (PHA II) characterized by hypertension, hyperkalemia, and metabolic acidosis. Recent studies showed that both WNK1 and WNK4 inhibit ROMK activity. However, little is known about the effect of WNK kinases on Maxi K, a large-conductance Ca(2+) and voltage-activated potassium (K) channel. Here, we report that WNK4 wild-type (WT) significantly inhibits Maxi K channel activity in HEK alphaBK stable cell lines compared with the control group. However, a WNK4 dead-kinase mutant, D321A, has no inhibitory effect on Maxi K activity. We further found that WNK4 inhibits total and cell surface protein expression of Maxi K equally compared with control groups. A dominant-negative dynamin mutant, K44A, did not alter the WNK4-mediated inhibitory effect on Maxi K surface expression. Treatment with bafilomycin A1 (a proton pump inhibitor) and leupeptin (a lysosomal inhibitor) reversed WNK4 WT mediated inhibition of Maxi K total protein expression. These findings suggest that WNK4 WT inhibits Maxi K activity by reducing Maxi K protein at the membrane, but that the inhibition is not due to an increase in clathrin-mediated endocytosis of Maxi K, but likely due to enhancing its lysosomal degradation. Also, WNK4's inhibitory effect on Maxi K activity is dependent on its kinase activity. PMID- 21613418 TI - High sodium intake increases HCO(3)- absorption in medullary thick ascending limb through adaptations in basolateral and apical Na+/H+ exchangers. AB - A high sodium intake increases the capacity of the medullary thick ascending limb (MTAL) to absorb HCO(3)(-). Here, we examined the role of the apical NHE3 and basolateral NHE1 Na(+)/H(+) exchangers in this adaptation. MTALs from rats drinking H(2)O or 0.28 M NaCl for 5-7 days were perfused in vitro. High sodium intake increased HCO(3)(-) absorption rate by 60%. The increased HCO(3)(-) absorptive capacity was mediated by an increase in apical NHE3 activity. Inhibiting basolateral NHE1 with bath amiloride eliminated 60% of the adaptive increase in HCO(3)(-) absorption. Thus the majority of the increase in NHE3 activity was dependent on NHE1. A high sodium intake increased basolateral Na(+)/H(+) exchange activity by 89% in association with an increase in NHE1 expression. High sodium intake increased apical Na(+)/H(+) exchange activity by 30% under conditions in which basolateral Na(+)/H(+) exchange was inhibited but did not change NHE3 abundance. These results suggest that high sodium intake increases HCO(3)(-) absorptive capacity in the MTAL through 1) an adaptive increase in basolateral NHE1 activity that results secondarily in an increase in apical NHE3 activity; and 2) an adaptive increase in NHE3 activity, independent of NHE1 activity. These studies support a role for NHE1 in the long-term regulation of renal tubule function and suggest that the regulatory interaction whereby NHE1 enhances the activity of NHE3 in the MTAL plays a role in the chronic regulation of HCO(3)(-) absorption. The adaptive increases in Na(+)/H(+) exchange activity and HCO(3)(-) absorption in the MTAL may play a role in enabling the kidneys to regulate acid-base balance during changes in sodium and volume balance. PMID- 21613419 TI - Interaction of H+ with the extracellular and intracellular aspects of hMATE1. AB - Human multidrug and toxin extrusion 1 (hMATE1, SLC47A1) is a major candidate for being the molecular identity of organic cation/proton (OC/H(+)) exchange activity in the luminal membrane of renal proximal tubules. Although physiological function of hMATE1 supports luminal OC efflux, the kinetics of hMATE1-mediated OC transport have typically been characterized through measurement of uptake, i.e., the interaction between outward-facing hMATE1 and OCs. To examine kinetics of hMATE1-mediated transport in a more physiologically relevant direction, i.e., an interaction between inward-facing hMATE1 and cytoplasmic substrates, we measured the time course of hMATE1-mediated efflux of the prototypic MATE1 substrate, [(3)H]1-methyl-4-phenylpyridinium, under a variety of intra- and extracellular pH conditions, from Chinese hamster ovary cells that stably expressed the transporter. In this study, we showed that an IC(50)/K(i) for interaction between extracellular H(+) and outward-facing hMATE1 determined from conventional uptake experiments [12.9 +/- 1.23 nM (pH 7.89); n = 9] and from the efflux protocol [14.7 +/- 3.45 nM (pH 7.83); n = 3] was not significantly different (P = 0.6). Furthermore, kinetics of interaction between intracellular H(+) and inward-facing hMATE1 determined using the efflux protocol revealed an IC(50) for H(+) of 11.5 nM (pH 7.91), consistent with symmetrical interactions of H(+) with the inward facing and outward-facing aspects of hMATE1. PMID- 21613420 TI - Low birth weight increases susceptibility to renal injury in a rat model of mild ischemia-reperfusion. AB - Renal injury due to ischemia-reperfusion (I/R) is the major cause of acute kidney injury. Whether enhanced susceptibility to renal injury due to I/R can be programmed during fetal life is unknown. Epidemiological studies indicate that low birth weight (LBW) individuals are more susceptible to renal injury than normal birth weight (NBW) individuals. Thus, the aim of this study was to test the hypothesis that LBW is associated with an increased susceptibility to renal injury induced by mild renal I/R (15-min ischemia). Systemic and renal hemodynamic parameters were determined in NBW and LBW adult male rats after mild renal I/R; renal superoxide production and tubular injury were also assessed. A subgroup was pretreated with tempol, a superoxide dismutase mimetic, initiated 15 min before ischemia. Mild renal I/R did not alter renal hemodynamic parameters, induce tubular injury, or induce superoxide production in NBW rats. However, renal hemodynamic parameters declined, superoxide production increased, and histological indicators of tubular injury were present following mild renal I/R in LBW rats. Acute treatment with tempol prevented these alterations in LBW rats subjected to mild renal I/R. Thus, these findings suggest that adverse conditions during fetal life can compromise the renal response to subtle insults leading to an increased susceptibility to renal injury, suggesting that LBW individuals may be an "at risk" population for renal disease. Additionally, the outcome of tempol treatment proposes a possible mechanistic pathway involved in mediating enhanced susceptibility to renal injury programmed during fetal life. PMID- 21613421 TI - Role of fibroblast growth factor receptor signaling in kidney development. AB - Fibroblast growth factor receptors (Fgfrs) consist of four signaling family members and one nonsignaling "decoy" receptor, Fgfr-like 1 (Fgfrl1), all of which are expressed in the developing kidney. Several studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB) in cultured tissues. Transgenic and conditional knockout approaches in whole animals have shown that Fgfr1 and Fgfr2 (predominantly the IIIc isoform) in kidney mesenchyme are critical for early MM and UB formation. Conditional deletion of the ligand, Fgf8, in nephron precursors or global deletion of Fgfrl1 interrupts nephron formation. Fgfr2 (likely the IIIb isoform signaling downstream of Fgf7 and Fgf10) is critical for ureteric morphogenesis. Moreover, Fgfr2 appears to act independently of Frs2alpha (the major signaling adapter for Fgfrs) in regulating UB branching. Loss of Fgfr2 in the MM leads to many kidney and urinary tract anomalies, including vesicoureteral reflux. Thus Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development. PMID- 21613422 TI - Loss of poly(ADP-ribose) polymerase 1 attenuates renal fibrosis and inflammation during unilateral ureteral obstruction. AB - Poly(ADP-ribose) polymerase 1 (PARP1) contributes to necrotic cell death and inflammation in several disease models; however, the role of PARP1 in fibrogenesis remains to be defined. Here, we tested whether PARP1 was involved in the pathogenesis of renal fibrosis using the unilateral ureteral obstruction (UUO) mouse model. UUO was performed by ligation of the left ureter near the renal pelvis in Parp1-knockout (KO) and wild-type (WT) male mice. After 10 days of UUO, renal PARP1 expression and activation were strongly increased by 6- and 13-fold, respectively. Interstitial fibrosis induced by UUO was significantly attenuated in Parp1-KO kidneys compared with that in WT kidneys at 10 days, but not at 3 days, based on collagen deposition, alpha-smooth muscle actin (alpha SMA), and fibronectin expression. Intriguingly, the UUO kidneys in Parp1-KO mice showed a dramatic decrease in infiltration of neutrophil and reduction in expression of proinflammatory proteins including intercellular adhesion molecule 1, tumor necrosis factor-alpha, inducible nitric oxide synthase, and toll-like receptor 4 as well as phosphorylation of nuclear factor-kappaB p65, but not transforming growth factor-beta1 (TGF-beta1) at both 3 and 10 days. Pharmacological inhibition of PARP1 in rat renal interstitial fibroblast (NRK 49F) cell line or genetic ablation in primary mouse embryonic fibroblast cells did not affect TGF-beta1-induced de novo alpha-SMA expression. Parp1 deficiency significantly attenuated UUO-induced histological damage in the kidney tubular cells, but not apoptosis. These data suggest that PARP1 induces necrotic cell death and contributes to inflammatory signaling pathways that trigger fibrogenesis in obstructive nephropathy. PMID- 21613423 TI - Vitamin D status: to be considered in heart failure patients! PMID- 21613424 TI - Heart failure and the brain, a wake-up call. PMID- 21613425 TI - Biventricular pacing in pacemaker dependency: one size does not fit all. PMID- 21613426 TI - The toll-like receptor 4-antagonist eritoran reduces murine cardiac hypertrophy. AB - AIMS: Toll-like receptor 4 (TLR4) recognizes lipopolysaccharides and endogenous ligands released after organ injury. Deficiency of TLR4 attenuates the development of left ventricular hypertrophy after transverse aortic constriction (TAC) in mice. We hypothesized that application of the TLR4 antagonist eritoran may also reduce cardiac hypertrophy after TAC surgery. METHODS AND RESULTS: A catheter was implanted into the jugular vein of C57BL/6 mice to allow repeated administration of eritoran (5 mg/kg body weight) or placebo. Three days after TAC or sham surgery, heart weights were determined and cardiac tissue underwent mRNA and protein quantification. The TAC placebo group exhibited a significant increase in left ventricular weight, left ventricular weight/tibia length, and left ventricular/body weight ratio compared with the sham and TAC eritoran groups. Natriuretic peptide mRNA was elevated significantly only in TAC placebo mice. Transverse aortic constriction surgery led to a distinct increase in interleukin (IL)-1beta and IL-6 mRNA and protein expression in the placebo but not the eritoran group. In contrast, IL-10 was significantly increased in both eritoran groups independent from TAC. Matrix metalloproteinase zymographic activity was highest in TAC placebo animals. CONCLUSION: Application of the TLR4 antagonist eritoran attenuates the development of cardiac hypertrophy possibly by a reduction in inflammatory and increase in anti-inflammatory cytokines. PMID- 21613428 TI - Exercise training reduces serum capacity to induce endothelial cell death in patients with chronic heart failure. AB - AIMS: Physical training improves endothelial function and exercise capacity in patients with heart failure (HF). Serum from patients with cardiovascular diseases increases apoptosis of human endothelial cells suggesting the importance of humoral factors in the progression of the disease. We evaluated whether exercise training influences the apoptotic capacity of serum from patients with chronic HF (CHF). METHODS AND RESULTS: The study included 39 patients with HF (NYHA II) and 10 age-matched healthy controls. Patients were allocated to either a structured programme of exercise training (24 patients) or standard care (15 patients). Human umbilical vein endothelial cells (HUVECs) were incubated with a medium containing 20% serum obtained before and after either a 3-week exercise training programme or standard care. At baseline, serum from patients with CHF induced a higher degree of lactate dehydrogenase (LDH) release and apoptosis in HUVECs compared with healthy controls (43 +/- 1.5 vs. 16 +/- 1.1%, P< 0.001 and 67 +/- 5.4 vs. 23 +/- 5.8%, P< 0.001, respectively). Exercise training significantly increased performance in the 6 min walking test (+34.7%) and reduced the ability of serum to induce LDH release and apoptosis of HUVECs. The reduction of apoptosis after exercise training correlated with the improvement in functional capacity. The expression of the apoptosis markers Bax and Caspase-3 was significantly reduced in HUVECs exposed to serum collected after exercise training. Circulating tumour necrosis factor-alpha, matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were significantly reduced by exercise training and the MMP-9/TIMP-1 ratio increased. CONCLUSION: A short term in-hospital structured cardiovascular training programme reduces the ability of serum-derived factors to induce endothelial cell death in patients with CHF. PMID- 21613427 TI - Preventing ventricular dysfunction in pacemaker patients without advanced heart failure: results from a multicentre international randomized trial (PREVENT-HF). AB - AIMS: Previous experimental and clinical studies have consistently suggested that right ventricular (RV) apical pacing has important adverse effects. Ventricular pacing (VP), however, is required, and cannot be reduced in many patients with atrioventricular (AV) block. The PREVENT-HF study was an international randomized trial that explored differences in left ventricular (LV) remodelling during RV apical vs. biventricular (BIV) pacing in patients with AV block. METHODS AND RESULTS: Patients with an expected VP prevalence >=80% were assigned to RV apical or BIV pacing. The primary endpoint was the change in LV end-diastolic volume (EDV) >12 months. Secondary endpoints were LV end-systolic volume (ESV), LV ejection fraction (EF), mitral regurgitation (MR), and a combination of heart failure (HF) events and cardiovascular hospitalizations. Overall, 108 patients were randomized (RV: 58; BIV: 50). Intention to treat and on-treatment analyses revealed no significant differences in any of the outcomes. Analysis of covariance (ANCOVA) difference for treatment according to randomization (in mL): LVEDV -3.92 (-18.71 to 10.85), P= 0.6; LVESV -1.38 (-12.07 to 9.31), P= 0.80; LVEF 2.47 (-3.00 to 7.94), P= 0.37. Analysis of covariance difference for the on treatment analysis: LVEDV -4.90 (-20.02 to 10.22, PP= 0.52; LVESV -6.45 (-17.28 to 4.38), P= 0.24, LVEF 2.18 (-3.37 to 7.73), P= 0.44. Furthermore, secondary endpoints did not differ significantly. CONCLUSION: This study did not demonstrate significant LV volume differences >12 months between RV apical and BIV pacing for AV block. Thus, BIV pacing cannot be recommended as a routine treatment for AV block in these patients. However, the results encourage and inform the design of subsequent larger trials with higher power for detecting small volume changes. ClinicalTrials.gov Identifier: NCT00170326. PMID- 21613429 TI - Anaemia among patients with heart failure and preserved or reduced ejection fraction: results from the SENIORS study. AB - AIMS: Anaemia is a co-morbidity frequently seen in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Its presence carries adverse prognostic effects. The effects of anaemia have not been extensively investigated in patients with preserved or only mildly reduced LVEF. We sought to investigate prevalence and incidence of anaemia in patients with HF irrespective of whether reduced or preserved ejection fraction are present. In addition, we sought to study the effects of nebivolol on the development of anaemia. METHODS AND RESULTS: We analysed data from 2069 patients randomized to nebivolol or placebo in the SENIORS study, 391 (10.0%) of whom were anaemic. Anaemia was similarly common in patients with LVEF<=35% and those with LVEF>35% (19.0 vs. 18.7%, P= 0.89). Anaemic patients were older, had lower diastolic blood pressure, and worse kidney function (all P< 0.05). No difference was found between patients on nebivolol or placebo with regard to the presence of anaemia. A total of 348 (16.8%) patients died during follow-up. The combined primary endpoint of all cause mortality and cardiovascular hospital admission was reached by 687 (33.2%) patients during follow-up, 164 (23.4%) of whom were anaemic. Anaemic patients had a higher risk of reaching a primary endpoint than non-anaemics [LVEF<=35%: hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.18-1.82, P< 0.001; LVEF>35%: HR 1.47, 95% CI 1.09-2.00, P= 0.012]. After multivariable adjustment, haemoglobin remained an independent predictor of the primary outcome in this cohort of patients (HR 0.94 per 1 g/dL increase, 95% CI 0.89-0.99, P= 0.017). CONCLUSIONS: Anaemia is an independent predictor of death or hospitalization for cardiovascular reasons among elderly patients with chronic HF and reduced or preserved/mildly reduced LVEF. Nebivolol does not affect haemoglobin values during follow-up. PMID- 21613430 TI - Francisella tularensis molecular typing using differential insertion sequence amplification. AB - Tularemia is a potentially fatal disease that is caused by the highly infectious and zoonotic pathogen Francisella tularensis. Despite the monomorphic nature of sequenced F. tularensis genomes, there is a significant degree of plasticity in the organization of genetic elements. The observed variability in these genomes is due primarily to the transposition of direct repeats and insertion sequence (IS) elements. Since current methods used to genotype F. tularensis are time consuming and require extensive laboratory resources, IS elements were investigated as a means to subtype this organism. The unique spatial location of specific IS elements provided the basis for the development of a differential IS amplification (DISA) assay to detect and distinguish the more virulent F. tularensis subsp. tularensis (subtypes A.I and A.II) and subsp. holarctica (type B) strains from F. tularensis subsp. novicida and other near neighbors, including Francisella philomiragia and Francisella-like endosymbionts found in ticks. Amplicon sizes and sequences derived from DISA showed heterogeneity within members of the subtype A.I and A.II isolates but not the type B strains. These differences were due to a 312-bp fragment derived from the IS element ISFtu1. Analysis of wild-type F. tularensis isolates by DISA correlated with pulsed-field gel electrophoresis genotyping utilizing two different restriction endonucleases and provided rapid results with minimal sample processing. The applicability of this molecular typing assay for environmental studies was demonstrated by the accurate identification and differentiation of tick-borne F. tularensis. The described approach to IS targeting and amplification provides new capability for epidemiological investigations and characterizations of tularemia source outbreaks. PMID- 21613431 TI - Comparison of direct colony method versus extraction method for identification of gram-positive cocci by use of Bruker Biotyper matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - We evaluated Bruker Biotyper (version 2.0) matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS) for the identification of 305 clinical isolates of staphylococci, streptococci, and related genera by comparing direct colony testing with preparatory extraction. Isolates were previously identified by use of phenotypic testing and/or 16S rRNA gene sequencing. Manufacturer-specified score cutoffs for genus- and species level identification were used. After excluding 7 isolates not present in the Biotyper library, the Biotyper correctly identified 284 (95%) and 207 (69%) isolates to the genus and species levels, respectively, using extraction. By using direct colony testing, the Biotyper identified 168 (56%) and 60 (20%) isolates to the genus and species levels, respectively. Overall, more isolates were identified to the genus and species levels with preparatory extraction than with direct colony testing (P < 0.0001). The analysis was repeated after dividing the isolates into two subgroups, staphylococci, streptococci, and enterococci (n = 217) and "related genera" (n = 81). For the former subgroup, the extraction method resulted in the identification of 213 (98%) and 171 (79%) isolates to the genus and species levels, respectively, whereas the direct colony method identified 136 (63%) and 56 (26%) isolates to the genus and species levels, respectively. In contrast, for the subgroup of related genera, the extraction method identified 71 (88%) and 36 (44%) isolates to the genus and species levels, respectively, while the direct colony method identified 32 (40%) and 4 (5%) isolates to the genus and species levels, respectively. For both subgroups, preparatory extraction was superior to direct colony testing for the identification of isolates to the genus and species levels (P < 0.0001). Preparatory extraction is needed for the identification of a substantial proportion of Gram-positive cocci using the Biotyper method according to manufacturer-specified score cutoffs. PMID- 21613432 TI - Unusual case of resistance to amphotericin B in visceral leishmaniasis in a region in India where leishmaniasis is not endemic. AB - The case of a patient with visceral leishmaniasis showing inadequate response to amphotericin B from a region where leishmaniasis is not endemic is reported, with the Leishmania donovani isolate showing increased tolerance to amphotericin B in vivo. Four single nucleotide polymorphisms (SNPs) detected in the cysteine proteinase B gene resulted in changes to the deduced amino acid sequence: valine >alanine and arginine->leucine. Overexpression and underexpression of proteins were observed in the 65- to 80-kDa range and at 20 kDa, respectively. PMID- 21613433 TI - Interleukin-28B genotyping by melt-mismatch amplification mutation assay PCR analysis using single nucleotide polymorphisms rs12979860 and rs8099917, a useful tool for prediction of therapy response in hepatitis C patients. AB - Several studies have identified associations between single nucleotide polymorphisms (SNPs) occurring near the interleukin-28B (IL-28B) gene and response to antiviral treatment among hepatitis C virus (HCV) patients. Here, we describe a reliable melt-mismatch amplification mutation assay (melt-MAMA) PCR based genotyping method for IL-28B which can be used in the management of HCV patients, helping to better define the course of therapy. PMID- 21613434 TI - Emergence of extended-spectrum beta-lactamase (CTX-M-15 and CTX-M-14)-producing nontyphoid Salmonella with reduced susceptibility to ciprofloxacin among food animals and humans in Korea. AB - Twenty of 1,279 nontyphoid Salmonella strains isolated from food animals and humans produced CTX-M-type extended-spectrum beta-lactamase. All expressed CTX-M 15, except two which coexpressed CTX-M-14 and TEM-1. Insertion sequence ISEcp1 was identified upstream of bla(CTX-M) genes. The bla(CTX-M-15) and bla(CTX-M-14) genes were disseminated by large conjugative IncFIIs and IncI1-Igamma plasmids, respectively. PMID- 21613435 TI - Efficient direct extended-spectrum beta-lactamase detection by multiplex real time PCR: accurate assignment of phenotype by use of a limited set of genetic markers. AB - The number and diversity of genes potentially complicate genetic approaches to the rapid detection of transmissible extended-spectrum beta-lactamase genes. We developed a robust multiplexed real-time PCR assay based on targets identified in a prior survey and used this to detect relevant genes in 617 consecutive clinical isolates of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. PMID- 21613436 TI - Rapid diagnosis of extensively drug-resistant tuberculosis by use of a reverse line blot hybridization assay. AB - Drug resistance in tuberculosis (TB) is a matter of grave concern for TB control programs, as there is currently no cure for some extensively drug-resistant (XDR) strains. There is concern that this resistance could transmit, stressing the need for additional control measures, rapid diagnostic methods, and newer drugs for treatment. We developed an in-house assay that can rapidly detect resistance to drugs involved in the definition of XDR-TB directly from smear-positive specimens. Two hundred fifteen phenotypically XDR-TB isolates and 50 pansusceptible isolates were analyzed using a reverse line blot hybridization (RLBH) assay. The assay was also successfully applied to 73 smear-positive clinical specimens. The RLBH assay exhibited good sensitivity for the detection of resistance to isoniazid (99%), rifampin (99%), fluoroquinolones (95.3%), and second-line aminoglycosides (94.8%). The results from application of this assay on direct smear-positive clinical specimens revealed 93% concordance with the phenotypic drug susceptibility test (DST) results for the above-mentioned drugs. The time to accurate DST results was significantly reduced from weeks to 3 days. This molecular assay is a highly accurate tool for screening for XDR-TB, which achieves a substantial reduction in diagnostic delays. PMID- 21613437 TI - Hepatitis C virus genotypes in clinical specimens tested at a national reference testing laboratory in the United States. AB - Hepatitis C virus (HCV) genotype (GT) distribution and frequency were studied among 22,407 unique specimens tested at a national reference testing laboratory. Subjects with HCV GT 3 were younger (P < 0.0001) than those with GT 1, 2, or 4, and the regional frequencies of HCV GT 2 and 3 ranged from 19.9% to 29.2%. PMID- 21613438 TI - Prediction of pulmonary hypertension in patients with or without interstitial lung disease: reliability of CT findings. AB - PURPOSE: To study the reliability of pulmonary vascular measurements based on computed tomography (CT) in the prediction of pulmonary hypertension (PH) in patients with advanced interstitial lung disease (ILD) compared with those without ILD. MATERIALS AND METHODS: The study was approved by the Institutional Review Board. All patients gave written informed consent. A prospective study of 134 patients who underwent right-sided heart catheterization and chest CT scanning within 72 hours of admission was conducted. Patients were divided into two groups-one with ILD (group A, n = 100) and one without ILD (group B, n = 34). CT measurements of the main pulmonary artery diameter (PAD), the ratio of PAD to the ascending aorta diameter (AAD), right pulmonary artery diameter (RPAD), and left pulmonary artery diameter (LPAD) were obtained. Univariate logistic regression analysis was performed, and receiver operating characteristic curves were constructed to assess the predictive ability of vascular measurements obtained by using CT in the identification of PH. RESULTS: Main PAD was significantly greater in patients with PH than in those without PH in both groups (group A, P = .008; group B, P = .02). A PAD greater than 25 mm in patients with ILD was predictive of PH, with a sensitivity of 86.4% (32 of 37), a specificity of 41.2% (26 of 63), a positive predictive value of 46.3% (32 of 69), and a negative predictive value of 83.8% (26 of 31). In patients without ILD, a PAD greater than 31.6 mm and an LPAD greater than 21.4 mm were predictive of PH (sensitivity, 47.3% [nine of 19]; specificity, 93.3% [14 of 15]; positive predictive value, 90.0% [nine of 10]; and negative predictive value, 58.3% [14 of 24]). CONCLUSION: CT-derived vascular measurements were of limited utility in the prediction of PH in patients with ILD compared with those without ILD. PMID- 21613439 TI - Comparative prospective randomized study comparing conservative treatment and percutaneous disk decompression for treatment of intervertebral disk herniation. AB - PURPOSE: To compare short-, intermediate-, and long-term functional results concerning pain reduction and mobility improvement between conservative therapy and percutaneous disk decompression (PDD) in patients with intervertebral disk herniations. MATERIALS AND METHODS: The study received approval from both the university ethics panel and the institutional review board. Patients provided informed consent for the study. Over the past 4 years, two randomized groups of 31 patients with sciatica due to intervertebral disk herniation were prospectively studied and compared with the t test. The control group underwent conservative therapy (administration of analgesics, antiinflammatory drugs, muscle relaxants, and physiotherapy) for 6 weeks. The decompression group underwent fluoroscopically guided PDD. Pain reduction and mobility improvement were recorded at 3-, 12-, and 24-month follow-up on a numeric visual scale (NVS) (range, 0-10). RESULTS: The control group had a mean pain score of 6.9 NVS units +/- 1.9 prior to conservative therapy. This was reduced to 0.9 NVS units +/- 2.0 3 months after therapy; however, it increased to 4.0 NVS units +/- 3.4 at 12 month follow-up and further increased to 4.0 NVS units +/- 3.4 at 24-month follow up. The decompression group had a mean pain score of 7.4 NVS units +/- 1.4 prior to PDD. This was reduced to 3.0 NVS units +/- 2.4 at 3-month follow-up and further reduced to 1.7 NVS units +/- 2.4 at 12-month follow-up and 1.6 NVS units +/- 2.5 at 24-month follow-up. No complications were noted. CONCLUSION: When compared with conservative therapy, PDD shows improved amelioration of symptoms at 12- and 24-month follow-up. PMID- 21613440 TI - Prevalence of radiographic findings thought to be associated with femoroacetabular impingement in a population-based cohort of 2081 healthy young adults. AB - PURPOSE: To report the prevalence of qualitative radiographic findings for femoroacetabular impingement (FAI) and associations among them and to characterize the inter- and intraobserver variability of these interpretations. MATERIALS AND METHODS: This study is part of an institutional review board approved population-based prospective follow-up of 2081 of 4006 (participation rate, 51.9%) young adults (874 [42.0%] male participants, 1207 [58.0%] female participants; mean age, 18.6 years) who took part in a randomized hip trial on developmental dysplasia of the hip. All participants gave informed consent. Two pelvic radiographs were obtained. Pistol-grip deformity, focal femoral neck prominence, and flattening of the lateral head, all suggestive of cam-type impingement, and the posterior wall sign, excessive acetabular coverage, and crossover sign, all suggestive of pincer-type impingement, were assessed subjectively by an experienced radiologist. To assess inter- and intraobserver agreement, images from 350 examinations were read independently twice by two observers. RESULTS: Cam-type deformities were seen in 868 male and 1192 female participants, respectively, as follows: pistol-grip deformity, 187 (21.5%) and 39 (3.3%); focal femoral neck prominence, 89 (10.3%) and 31 (2.6%); and flattening of the lateral femoral head, 125 (14.4%) and 74 (6.2%). Pincer-type deformities were seen in the same numbers of male and female participants, respectively, as follows: posterior wall sign, 203 (23.4%) and 131 (11.0%); and excessive acetabular coverage, 127 (14.6%) and 58 (4.9%) (all P < .001, according to sex distribution). The crossover sign was seen in 446 (51.4%) and 542 (45.5%) of the male and female participants, respectively (P = .004). There was a high degree of coexistence (odds ratio [OR] > 2) among most FAI findings. Interobserver agreement was good to very good (kappa = 0.74-0.84) in rating cam- and pincer type findings. Intraobserver agreement was moderate or good (kappa = 0.49-0.80) for all findings for both observers. CONCLUSION: Overall, radiographic FAI findings are quite common in a population of healthy young adults, especially in males, with a high degree of coexistence among most findings (OR > 2). PMID- 21613441 TI - Congenital heart disease: cardiovascular MR imaging by using an intravascular blood pool contrast agent. AB - PURPOSE: To compare the image quality and diagnostic performance of a contrast agent-specific inversion-recovery (IR) steady-state free precession (SSFP) magnetic resonance (MR) imaging sequence performed by using an intravascular contrast agent (gadofosveset trisodium) with those of a commonly used T2-prepared SSFP sequence performed by using an extravascular (gadopentetate dimeglumine) and an intravascular (gadofosveset trisodium) contrast agent in patients with congenital heart disease (CHD). MATERIALS AND METHODS: The local ethics committee and the United Kingdom Medicines and Healthcare products Regulatory Agency approved this study. Patient informed consent was obtained. Twenty-three patients with CHD were examined by using a 1.5-T MR imaging unit and a 32-channel coil. Gadopentetate dimeglumine and gadofosveset trisodium were used in the same patient on consecutive days. Vessel wall sharpness, contrast-to-noise ratios (CNRs), image quality, and diagnostic performance achieved by using the IR SSFP sequence with gadofosveset trisodium were compared with those achieved by using the T2-prepared SSFP sequence with gadopentetate dimeglumine and gadofosveset trisodium and with those achieved at respective contrast material-enhanced MR angiographic examinations. The Wilcoxon rank sum test was used to compare categoric variables; t tests were used to compare continuous variables. RESULTS: Use of the IR SSFP sequence with gadofosveset trisodium significantly improved vessel wall sharpness, CNRs, and image quality (P < .05 for all) for all investigated intra- and extracardiac structures compared with the T2-prepared SSFP sequence with gadopentetate dimeglumine and gadofosveset trisodium and the respective contrast-enhanced MR angiographic examinations. With use of the IR SSFP sequence with gadofosveset trisodium, new, unsuspected diseases (five [22%] of 23) were diagnosed, while other diseases could be excluded (15 [65%] of 23). Information available from echocardiography (n = 23), conventional angiography (n = 4), and/or surgery (n = 1) confirmed all diagnoses. CONCLUSION: IR SSFP with gadofosveset trisodium improved image quality and diagnostic performance, allowing a more accurate and complete assessment of cardiovascular anatomy in patients with CHD compared with T2-prepared SSFP with gadopentetate dimeglumine and gadofosveset trisodium and respective contrast-enhanced MR angiographic examinations. PMID- 21613442 TI - Autoimmune pancreatitis: pancreatic and extrapancreatic MR imaging-MR cholangiopancreatography findings at diagnosis, after steroid therapy, and at recurrence. AB - PURPOSE: To determine and describe the magnetic resonance (MR) imaging-MR cholangiopancreatographic pancreatic and extrapancreatic findings of autoimmune pancreatitis (AIP) and the probability, site, and MR features of recurrent AIP after steroid therapy. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and the requirement for informed patient consent was waived. The data of 27 patients with AIP were included in the study. All patients had undergone MR imaging with MR cholangiopancreatography before and after steroid treatment and during follow-up (median follow-up period, 45 months). Image analysis included assessment of pancreatic parenchyma enlargement, signal intensity on T1- and T2-weighted MR images, contrast enhancement, and presence of bile duct and/or renal involvement. The probability of AIP recurrence was assessed by using Kaplan-Meier curves and the unadjusted Cox model. RESULTS: At the time of diagnosis, the AIP-affected pancreatic parenchyma showed diffuse enlargement in 14 (52%) of the 27 patients and segmental enlargement in 13 (48%). The pancreatic parenchyma appeared hypointense on T1-weighted images in all 27 (100%) patients, hyperintense on T2-weighted images in 25 (93%), and isointense in two (7%). During the pancreatic phase of the dynamic contrast material-enhanced study, the affected pancreatic parenchyma appeared hypointense in 25 (93%) patients and isointense in two (7%). During the portal venous and delayed phases, the images of 19 (70%) patients showed delayed enhancement. Bile duct involvement was observed in 10 (37%) patients, and renal involvement was observed in two (7%). After steroid treatment, six (22%) patients had recurrent AIP, with a median disease-free interval of 20.6 months. The sites of recurrence were the pancreas and the kidneys in three of the six patients, solely the pancreas in two patients, and the biliary ducts in one patient. CONCLUSION: MR imaging with MR cholangiopancreatography enables the diagnosis of pancreatic and extrapancreatic AIP and the assessment of changes after steroid therapy. PMID- 21613443 TI - de Quervain disease: US identification of anatomic variations in the first extensor compartment with an emphasis on subcompartmentalization. AB - PURPOSE: To demonstrate the usefulness of ultrasonography (US) in the detection of anatomic variations in the first extensor compartment of the wrist in patients with de Quervain disease. MATERIALS AND METHODS: The institutional review board approved this study protocol and waived the informed consent requirement. Fifteen wrists in 13 women (age range, 41-62 years) in whom de Quervain disease was clinically diagnosed and who underwent surgery for intractable pain were included. A musculoskeletal radiologist performed US before surgery. The absence or presence and extent of subcompartmentalization within the first extensor compartment and the number of abductor pollicis longus (APL) and extensor pollicis brevis (EPB) tendon slips were evaluated and recorded. Preoperative US findings were compared with surgical records and photographs. RESULTS: Subcompartmentalization within the first extensor compartment was observed during surgery in 11 of the 15 wrists (73%), including four (27%) that had subcompartmentalization only in the distal portion of this compartment. US was used to identify all 11 wrists showing subcompartmentalization within this compartment (sensitivity, 100%; 95% confidence interval [CI]: 74%, 100%), as well as three of the four wrists with distal incomplete subcompartmentalization. There was one wrist with false-positive distal incomplete subcompartmentalization. US had a positive predictive value in the detection of subcompartmentalization of 73% (95% CI: 47%, 91%). The number of tendon slips in this compartment detected with US was identical to that identified at surgery with one exception. CONCLUSION: US can be used to depict various types of anatomic variations in the first extensor compartment in patients with de Quervain disease. PMID- 21613444 TI - Transcriptomic profiling of Microplitis demolitor bracovirus reveals host, tissue and stage-specific patterns of activity. AB - The polydnaviruses (PDVs) are a family of DNA viruses that are symbiotically associated with parasitoid wasps. The transcription of particular genes or gene family members have been reported for several PDVs, but no studies have characterized the spatio-temporal patterns of expression for the entire complement of predicted genes in the encapsidated genome of any PDV isolate. The braconid wasp Microplitis demolitor carries the PDV Microplitis demolitor bracovirus (MdBV) and parasitizes larval stage Pseudoplusia (Chrysodeixis) includens. The encapsidated genome consists of 15 genomic segments with 51 predicted ORFs encoding proteins >=100 aa. A majority of these ORFs form four multimember gene families (ptp, ank, glc and egf) while the remaining ORFs consist of single copy (orph) genes. Here we used RT-PCR and quantitative real time PCR methods to profile the encapsidated transcriptome of MdBV in P. includens and M. demolitor. Our results indicate that most predicted genes are expressed in P. includens. Spatial patterns of expression in P. includens differed among genes, but temporal patterns of expression were generally similar, with transcript abundance progressively declining between 24 and 120 h. A subset of ptp, ank and orph genes were also expressed in adult female but not male M. demolitor. Only one encapsidated gene (ank-H4) was expressed in all life stages of M. demolitor, albeit at much lower levels than in P. includens. However, another encapsidated gene (orph-B1) was expressed in adult M. demolitor at similar levels to those detected in P. includens. PMID- 21613445 TI - Viroplasm matrix protein Pns9 from rice gall dwarf virus forms an octameric cylindrical structure. AB - The non-structural Pns9 protein of rice gall dwarf virus (RGDV) accumulates in viroplasm inclusions, which are structures that appear to play an important role in viral morphogenesis and are commonly found in host cells infected by viruses in the family Reoviridae. Immunofluorescence and immunoelectron microscopy of RGDV-infected vector cells in monolayers, using antibodies against Pns9 of RGDV and expression of Pns9 in Spodoptera frugiperda cells, demonstrated that Pns9 is the minimal viral factor necessary for formation of viroplasm inclusion during infection by RGDV. When Pns9 in solution was observed under a conventional electron microscope, it appeared as ring-like aggregates of approximately 100 A in diameter. Cryo-electron microscopic analysis of these aggregates revealed cylinders of octameric Pns9, whose dimensions were similar to those observed under the conventional electron microscope. Octamerization of Pns9 in solution was confirmed by the results of size-exclusion chromatography. Among proteins of viruses that belong to the family Reoviridae whose three-dimensional structures are available, a matrix protein of the viroplasm of rotavirus, NSP2, forms similar octamers, an observation that suggests similar roles for Pns9 and NSP2 in morphogenesis in animal-infecting and in plant-infecting reoviruses. PMID- 21613446 TI - Whole-genome analysis reveals the complex evolutionary dynamics of Kenyan G2P[4] human rotavirus strains. AB - Although G2P[4] rotaviruses are common causes of acute childhood diarrhoea in Africa, to date there are no reports on whole genomic analysis of African G2P[4] strains. In this study, the nearly complete genome sequences of two Kenyan G2P[4] strains, AK26 and D205, detected in 1982 and 1989, respectively, were analysed. Strain D205 exhibited a DS-1-like genotype constellation, whilst strain AK26 appeared to be an intergenogroup reassortant with a Wa-like NSP2 genotype on the DS-1-like genotype constellation. The VP2-4, VP6-7, NSP1, NSP3 and NSP5 genes of strain AK26 and the VP2, VP4, VP7 and NSP1-5 genes of strain D205 were closely related to those of the prototype or other human G2P[4] strains. In contrast, their remaining genes were distantly related, and, except for NSP2 of AK26, appeared to originate from or share a common origin with rotavirus genes of artiodactyl (ruminant and camelid) origin. These observations highlight the complex evolutionary dynamics of African G2P[4] rotaviruses. PMID- 21613447 TI - Determination of a phosphorylation site in Nipah virus nucleoprotein and its involvement in virus transcription. AB - Many viruses use their host's cellular machinery to regulate the functions of viral proteins. The phosphorylation of viral proteins is known to play a role in genome transcription and replication in paramyxoviruses. The paramyxovirus nucleoprotein (N), the most abundant protein in infected cells, is a component of the N-RNA complex and supports the transcription and replication of virus mRNA and genomic RNA. Recently, we reported that the phosphorylation of measles virus N is involved in the regulation of viral RNA synthesis. In this study, we report a rapid turnover of phosphorylation in the Nipah virus N (NiV-N). The phosphorylated NiV-N was hardly detectable in steady-state cells, but was detected after inhibition of cellular protein phosphatases. We identified a phosphorylated serine residue at Ser451 of NiV-N by peptide mass fingerprinting by electrospray ionization-quadrupole time-of-flight mass spectrometry. In the NiV minigenome assay, using luciferase as a reporter gene, the substitution of Ser451 for alanine in NiV-N resulted in a reduction in luciferase activity of approximately 45 % compared with the wild-type protein. Furthermore, the substitution of Ser451 for glutamic acid, which mimics a phosphoserine, led to a more significant decrease in luciferase activity - approximately 81 %. Northern blot analysis showed that both virus transcription and replication were reduced by these mutations. These results suggest that a rapid turnover of the phosphorylation of NiV-N plays an important role in virus transcription and replication. PMID- 21613448 TI - High-risk endometrial carcinoma profiling identifies TGF-beta1 as a key factor in the initiation of tumor invasion. AB - Endometrial cancer is among the three most common cancers in females in industrialized countries. In the majority of cases, the tumor is confined to the uterus at the time of diagnosis and presents a good prognosis. However, after primary surgery, 15% to 20% of these tumors recur and have limited response to systemic therapy. We carried out gene expression profiling of high-risk recurrence endometrial cancers to identify new therapeutic approaches targeting the molecular pathways involved in the acquisition of an aggressive tumor phenotype. A microarray gene-expression analysis on a total of 51 human endometrial carcinomas revealed 77 genes specifically altered in high-risk recurrence tumors (P < 0.001). The bioinformatics analysis of gene-gene interactions and molecular relationships among these genes pointed to a prominent role for TGF-beta1 signaling in the acquisition of an aggressive phenotype. We further showed that TGF-beta1 has a principal role at the initiation of endometrial carcinoma invasion through the promotion of the epithelial to mesenchymal transition that leads to the acquisition of an invasive phenotype in HEC-1A and RL95-2 cells. Impairment of this initial step with SB-431542, a specific TGF-beta1 inhibitor, precluded further persistent endometrial carcinoma invasion. In conclusion, we showed that the characterization of the molecular changes associated with the acquisition of an aggressive phenotype represents a realistic strategy for the rational identification and characterization of new potential therapeutic targets in an effort to improve the clinical management and the outcome of high-risk endometrial cancer patients. PMID- 21613450 TI - Spray-dried porcine plasma influences intestinal barrier function, inflammation, and diarrhea in weaned pigs. AB - The objective of this study was to evaluate the effects of dietary inclusion levels of spray-dried porcine plasma (SDPP) on postweaning (PW) intestinal barrier function, mucosal inflammation, and clinical indices of gut health in pigs. Ex vivo Ussing chamber studies were conducted to measure Ileal and colonic barrier function in terms of transepithelial electrical resistance and paracellular flux of (3)H-mannitol and (14)C-inulin. Intestinal inflammation was assessed by histological analysis and mucosal levels of proinflammatory cytokines. Dietary inclusion of 2.5 and 5% SDPP reduced colonic paracellular permeability of (14)C-inulin compared with controls (0% SDPP) on d 7 PW. Both 2.5 and 5% dietary SDPP reduced ileal (3)H-mannitol and (14)C-inulin permeability on d 14 PW. The 5% SDPP diet reduced colonic short-circuit current, an index of net electrogenic ion transport, and fecal scores when measured on d 7 and 14 PW compared with the control and 2.5% SDPP groups (P < 0.05). Histological analysis revealed fewer lamina propria cells in ileum and colon from pigs fed diets containing 2.5 and 5% SDPP on d 7 and 14 PW. Levels of the proinflammatory cytokine TNFalpha were reduced in the colon but not ileum from pigs fed the 5% SDPP on d 7 and 14 PW compared with controls (P < 0.05). IFNgamma levels were lower than in controls in both of the SDPP-fed groups in the ileum and colon on d 7 but not on d 14 PW. Overall, this study demonstrated that dietary inclusion of SDPP had beneficial effects on intestinal barrier function, inflammation, and diarrhea in weaned pigs. PMID- 21613449 TI - Berberine suppresses androgen receptor signaling in prostate cancer. AB - The androgen receptor (AR) is critical in the normal development and function of the prostate, as well as in prostate carcinogenesis. Androgen deprivation therapy is the mainstay in the treatment of advanced prostate cancer; however, after an initial response, the disease inevitably progresses to castration-resistant prostate cancer (CRPC). Recent evidence suggests that continued AR activation, sometimes in a ligand-independent manner, is commonly associated with the development of CRPC. Thus, novel agents targeting the AR are urgently needed as a strategic step in developing new therapies for this disease state. In this study, we investigated the effect of berberine on AR signaling in prostate cancer. We report that berberine decreased the transcriptional activity of AR. Berberine did not affect AR mRNA expression, but induced AR protein degradation. Several ligand binding, domain-truncated AR splice variants have been identified, and these variants are believed to promote the development of CRPC in patients. Interestingly, we found that these variants were more susceptible to berberine induced degradation than the full-length AR. Furthermore, although the growth of LNCaP xenografts in nude mice was inhibited by berberine, and AR expression was reduced in the tumors, the morphology and AR expression in normal prostates were not affected. This study is the first to show that berberine suppresses AR signaling and suggests that berberine, or its derivatives, presents a promising agent for the prevention and/or treatment of prostate cancer. PMID- 21613451 TI - Mild maternal iron deficiency anemia during pregnancy and lactation in guinea pigs causes abnormal auditory function in the offspring. AB - Iron deficiency (ID) anemia (IDA) adversely affects different aspects of the nervous system such as myelinogenesis, neurotransmitters synthesis, brain myelin composition, and brain fatty acid and eicosanoid metabolism. Infant neurophysiological outcome in response to maternal IDA is underexplored, especially mild to moderate maternal IDA. Furthermore, most human research has focused on childhood ID rather than prenatal or neonatal ID. Thus, our study evaluated the consequences of mild maternal IDA during pregnancy and lactation on the offsprings' auditory function using the auditory brainstem response (ABR). This technique provides objective measures of auditory acuity, neural transmission times along the peripheral and brainstem portions of the auditory pathway, and postnatal brain maturation. Female guinea pigs (n = 10/group) were fed an iron sufficient diet (ISD) or an iron deficient diet (IDD) (144 and 11.7 mg iron/kg) during their acclimation, gestation, and lactation periods. From postnatal d (PNd) 9 onward, the ISD was given to all weaned offspring. ABR were collected from the offspring on PNd24 using a broad range of stimulus intensities in response to 2, 4, 8, 16, and 32 kHz tone pips. IDA siblings (n = 4), [corrected] compared with the IS siblings (n = 5), had significantly elevated ABR thresholds (hearing loss) in response to all tone pips. These physiological disturbances were primarily due to a sensorineural hearing loss, as revealed by the ABR's latency-intensity curves. These results indicate that mild maternal IDA during gestation and lactation altered the hearing and nervous system development of the young offspring. PMID- 21613452 TI - A specific prebiotic mixture added to starting infant formula has long-lasting bifidogenic effects. AB - There is some evidence that early colonization of the intestine affects the composition of the intestinal microbiota after weaning. In the present study, the effect of prebiotics administered from the first day of life on fecal counts of bifidobacteria and lactobacilli were studied during and after the administration of the prebiotics. In this double-blind, randomized, placebo-controlled, explorative study, 20 newborns of hepatitis C virus-infected mothers who decided not to breast feed due to their concerns regarding their plasma viral load were randomly assigned to either a formula with 8 g/L of a specific prebiotic mixture (short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides, ratio 9:1) or a formula containing the same amount of maltodextrin (placebo). Clinical examination including anthropometric measurements, microbiological analysis of fecal samples, and blood leukocyte population analysis were performed at birth and 3, 6, and 12 mo age. At the age of 12 mo, hepatitis B vaccine specific IgG serum titers (Hepatitis B virus surface antibodies) were also measured. Prebiotic supplementation resulted in more fecal bifidobacteria (P < 0.0001) and lactobacilli (P = 0.0044) compared with the placebo group. These differences between the groups were maintained during the second half of the first year without any prebiotic supplementation. There was no influence of the different diets on anthropometric data or the measured immunological variables. The data from this small explorative study indicate that early colonization of the intestine might have long-lasting effects on the composition of the intestinal microbiota. PMID- 21613453 TI - Comparison of serum and red blood cell folate microbiologic assays for national population surveys. AB - Three laboratories participated with their laboratory-specific microbiologic growth assays (MA) in the NHANES 2007-2008 to assess whether the distributions of serum (n = 2645) and RBC folate (n = 2613) for the same one-third sample of participants were comparable among laboratories. Laboratory (L) 2 produced the highest and L1 the lowest serum and RBC folate geometric means (nmol/L) in the NHANES sample (serum: L1, 39.5; L2, 59.2; L3, 47.7; and RBC: L1, 1120; L2, 1380; L3, 1380). Each laboratory produced different reference intervals for the central 95% of the population. Pearson correlation coefficients were highest between L3 and L1 (serum, r = 0.95; RBC, r = 0.92) and lowest between L2 and L1 (serum, r = 0.81; RBC, r = 0.65). Notable procedural differences among the laboratories were the Lactobacillus rhamnosus microorganism (L1 and L3: chloramphenicol resistant, L2: wild type) and the calibrator [L1: [6S]5-methyltetrahydrofolate (5 methylTHF), L2: [6R,S] 5-formyltetrahydrofolate ([6R,S] 5-formylTHF), L3: folic acid (FA)]. Compared with 5-methylTHF as calibrator, the folate results were 22 32% higher with FA as calibrator and 8% higher with 5-formylTHF as calibrator, regardless of the matrix (n = 30 serum, n = 28 RBC). The use of different calibrators explained most of the differences in results between L3 and L1 but not between L2 and L1. The use of the wild-type L. rhamnosus by L2 appeared to be the main reason for the differences in results between L2 and the other 2 laboratories. These findings indicate how assay variations influence MA folate results and how those variations can affect population data. To ensure data comparability, better assay harmonization is needed. PMID- 21613454 TI - Scores on the dietary guideline index for children and adolescents are associated with nutrient intake and socio-economic position but not adiposity. AB - Diet quality indices reflect overall dietary patterns better than single nutrients or food groups. The study aims were to develop a measure of adherence with dietary guidelines applicable to child and adolescent populations in Australia and determine the association between index scores and food and nutrient intake, socio-demographic characteristics, and measures of adiposity. Data were analyzed from 4- to 16-y-old participants of the 2007 Australian Children's Nutrition and Physical Activity Survey (n = 3416). The Dietary Guideline Index for Children and Adolescents (DGI-CA) comprises 11 components: 5 core food groups, wholegrain bread, reduced-fat dairy foods, extra foods (nutrient poor and high in fat, salt, and added sugar), healthy fats/oils, water, and diet variety (possible score of 100). The index criteria were age specific. The mean DGI-CA score was low (53.6 +/- 0.4), similar between boys and girls, and differed by age; the youngest children scored higher than the oldest children (P < 0.0001). Higher DGI-CA scores were associated with lower energy intake, energy density, total and saturated fat, and sugar intake; higher protein, carbohydrate, fiber, calcium, iron, vitamin C, vitamin A, folate, phosphorous, magnesium, zinc, and iodine intakes; and a higher polyunsaturated:saturated fat ratio (P < 0.0001). DGI-CA scores were associated with socio-economic characteristics and measures of family circumstance. Weak positive associations were observed between DGI-CA score and BMI or waist circumference Z-scores in the 4- to 10-y and 12- to 16-y age groups only. This index is the first validated index in Australia and one of the few international indices to describe the diet quality of children and adolescents. PMID- 21613455 TI - Dietary intake of cholesterol is positively associated and use of cholesterol lowering medication is negatively associated with prevalent age-related hearing loss. AB - We aimed to assess associations between dietary intake of fats (saturated and monounsaturated fats and cholesterol) and certain food groups (butter, margarine, and nuts) with the prevalence, incidence, and progression of age-related hearing loss. We also aimed to investigate the link between serum lipids and cholesterol lowering medication (statins) and hearing loss. The Blue Mountains Hearing Study is a population-based survey of age-related hearing loss. Hearing loss was measured in 2956 participants (aged >=50 y) and was defined as the pure-tone average (PTA) of frequencies 0.5, 1.0, 2.0, and 4.0 kHz > 25 dB hearing level (PTA(0.5-4 kHz)). Dietary data were collected using a semiquantitative FFQ. After multivariable adjustment, the likelihood of prevalent hearing loss increased from the lowest (reference) to the highest quartile of dietary cholesterol intake (P trend = 0.04). Among persons self-reporting statin use (n = 274), a 48% reduced odds of prevalent hearing loss was observed after multivariable adjustment [OR = 0.52 (95% CI = 0.29-0.93)]. Participants in the second and 3rd quartiles of dietary monounsaturated fat intake compared with those in the first quartile (reference) had a significantly reduced risk of hearing loss progression 5 y later [multivariable-adjusted OR = 0.39 (95% CI = 0.21-0.71)] and [OR = 0.51 (95% CI = 0.29-0.91)], respectively. Our results suggest that a diet high in cholesterol could have adverse influences on hearing, whereas treatment with statins and consumption of monounsaturated fats may have a beneficial influence. PMID- 21613456 TI - Docosahexaenoic acid inhibits the adhesion of flowing neutrophils to cytokine stimulated human umbilical vein endothelial cells. AB - The (n-3) PUFA, DHA, is widely thought to posses the ability to modulate the inflammatory response. However, its modes of interaction with inflammatory cells are poorly understood. In particular, there are limited data on the interactions of DHA with vascular endothelium, the cells that regulate the traffic of leukocytes from the blood into inflamed tissue. Using human umbilical vein endothelial cells (EC) cultured in a flow-based adhesion assay and activated with TNFalpha, we tested whether supplementing human umbilical vein EC with physiologically achievable concentrations of DHA would inhibit the recruitment of flowing neutrophils. DHA caused a dose-dependent reduction in neutrophil recruitment to the EC surface, although cells that became adherent were activated and could migrate across the human umbilical vein EC monolayer normally. Using EPA as an alternative supplement had no effect on the levels of neutrophil adhesion in this assay. Analysis of adhesion receptor expression by qPCR demonstrated that DHA did not alter the transcriptional activity of human umbilical vein EC. However, DHA did significantly reduce E-selectin expression at the human umbilical vein EC surface without altering the total cellular pool of this adhesion receptor. Thus, we have identified a novel mechanism by which DHA alters the trafficking of leukocytes during inflammation and demonstrate that this involves disruption of intracellular transport mechanisms used to present adhesion molecules on the surface of cytokine-stimulated EC. PMID- 21613457 TI - Interleukin-35 enhances Lyme arthritis in Borrelia-vaccinated and -infected mice. AB - Interleukin-35 (IL-35) has been reported to inhibit the production of interleukin 17 (IL-17) as a means of preventing arthritis and other inflammatory diseases. We previously showed that treatment of Borrelia-vaccinated and -infected mice with anti-IL-17 antibody at the time of infection prevented the development of arthritis. The anti-IL-17 antibody-treated mice lacked the extensive tissue damage, such as bone and cartilage erosion, that occurred in the tibiotarsal joints of untreated Borrelia-vaccinated and -infected control mice. We hypothesized that IL-35 would reduce the severity of arthritis by suppressing the production of IL-17 in Borrelia-vaccinated and -infected mice. Here, we show that administration of recombinant IL-35 (rIL-35) to Borrelia-vaccinated and -infected mice augments the development of severe arthritis compared to the results seen with untreated control mice. Borrelia-vaccinated and -infected mice treated with rIL-35 had significantly (P < 0.05) greater hind paw swelling and histopathological changes from day 4 through day 10 than non-rIL-35-treated Borrelia-vaccinated and -infected mice. In addition, the treatment with IL-35 only slightly decreased the production of IL-17 in Borrelia-primed immune cells and did not prevent the development of borreliacidal antibody. Our data do not support a role for IL-35 as a potential therapeutic agent to reduce inflammation in Lyme arthritis. PMID- 21613458 TI - Cross-protection of chicken immunoglobulin Y antibodies against H5N1 and H1N1 viruses passively administered in mice. AB - Influenza viruses remain a major threat to global health due to their ability to undergo change through antigenic drift and antigenic shift. We postulated that avian IgY antibodies represent a low-cost, effective, and well-tolerated approach that can easily be scaled up to produce enormous quantities of protective antibodies. These IgY antibodies can be administered passively in humans (orally and intranasally) and can be used quickly and safely to help in the fight against an influenza pandemic. In this study, we raised IgY antibodies against H1N1, H3N2, and H5N1 influenza viruses. We demonstrated that, using whole inactivated viruses alone and in combination to immunize hens, we were able to induce a high level of anti-influenza virus IgY in the sera and eggs, which lasted for at least 2 months after two immunizations. Furthermore, we found that by use of in vitro assays to test for the ability of IgY to inhibit hemagglutination (HI test) and virus infectivity (serum neutralization test), IgYs inhibited the homologous as well as in some cases heterologous clades and strains of viruses. Using an in vivo mouse model system, we found that, when administered intranasally 1 h prior to infection, IgY to H5N1 protected 100% of the mice against lethal challenge with H5N1. Of particular interest was the finding that IgY to H5N1 cross protected against A/Puerto Rico/8/34 (H1N1) both in vitro and in vivo. Based on our results, we conclude that anti-influenza virus IgY can be used to help prevent influenza virus infection. PMID- 21613459 TI - Comparison of passively transferred antibodies in bighorn and domestic lambs reveals one factor in differential susceptibility of these species to Mannheimia haemolytica-induced pneumonia. AB - Mannheimia haemolytica consistently causes fatal bronchopneumonia in bighorn sheep (BHS; Ovis canadensis) under natural and experimental conditions. Leukotoxin is the primary virulence factor of this organism. BHS are more susceptible to developing fatal pneumonia than the related species Ovis aries (domestic sheep [DS]). In BHS herds affected by pneumonia, lamb recruitment is severely impaired for years subsequent to an outbreak. We hypothesized that a lack of maternally derived antibodies (Abs) against M. haemolytica provides an immunologic basis for enhanced susceptibility of BH lambs to population-limiting pneumonia. Therefore, the objective of this study was to determine the titers of Abs directed against M. haemolytica in the sera of BH and domestic lambs at birth through 12 weeks of age. Results revealed that BH lambs had approximately 18-fold lower titers of Ab against surface antigens of M. haemolytica and approximately 20-fold lower titers of leukotoxin-neutralizing Abs than domestic lambs. The titers of leukotoxin-neutralizing Abs in the serum and colostrum samples of BH ewes were approximately 157- and 50-fold lower than those for domestic ewes, respectively. Comparatively, the higher titers of parainfluenza 3 virus neutralizing Abs in the BH lambs ruled out the possibility that these BHS had an impaired ability to passively transfer Abs to their lambs. These results suggest that lower levels of leukotoxin-neutralizing Abs in the sera of BH ewes, and resultant low Ab titers in their lambs, may be a critical factor in the poor lamb recruitment in herds affected by pneumonia. PMID- 21613460 TI - Improved specificity of a multiplex immunoassay for quantitation of anti diphtheria toxin antibodies with the use of diphtheria toxoid. AB - A nonspecific binding of antibodies to diphtheria toxin, especially in adult serum samples, was observed in our diphtheria-tetanus-pertussis multiplex immunoassay (DTaP4 MIA). This can be significantly reduced by the use of diphtheria toxoid, achieving a good correlation with the Vero cell neutralization test and the toxin binding inhibition assay. PMID- 21613461 TI - Enoyl-coenzyme A hydratase and antigen 85B of Mycobacterium habana are specifically recognized by antibodies in sera from leprosy patients. AB - Leprosy is an infectious disease caused by Mycobacterium leprae, which is a noncultivable bacterium. One of the principal goals of leprosy research is to develop serological tests that will allow identification and early treatment of leprosy patients. M. habana is a cultivable nonpathogenic mycobacterium and candidate vaccine for leprosy, and several antigens that cross-react between M. leprae and M. habana have been discovered. The aim of the present study was to extend the identification of cross-reactive antigens by identifying M. habana proteins that reacted by immunoblotting with antibodies in serum samples from leprosy patients but not with antibodies in sera from tuberculosis (TB) patients or healthy donors (HDs). A 28-kDa antigen that specifically reacted with sera from leprosy patients was identified. To further characterize this antigen, protein spots were aligned in two-dimensional polyacrylamide gels and Western blots. Spots cut out from the gels were then analyzed by mass spectrometry. Two proteins were identified: enoyl-coenzyme A hydratase (lipid metabolism; ML2498) and antigen 85B (Ag85B; mycolyltransferase; ML2028). These proteins represent promising candidates for the design of a reliable tool for the serodiagnosis of lepromatous leprosy, which is the most frequent form in Mexico. PMID- 21613462 TI - Dengue virus immunoglobulin M detection in a reference laboratory setting during the 2010 dengue virus outbreak on Caribbean islands. AB - A large outbreak of dengue virus (DV) infections occurred on Caribbean islands during 2010, with cases peaking during the second half of the year. In conjunction with the outbreak, we observed an unprecedented spike in the number of sera submitted for DV antibody testing between June and December 2010, with a concomitant increase in the number of IgM-positive specimens, indicative of acute DV infection. Analysis of the place of residence of the IgM-positive patients identified from June to December of 2010 revealed that 58.1% were residents of Caribbean islands (Puerto Rico and the U.S. Virgin Islands), whereas 40.6% were residents of the U.S. mainland or Hawaii. The U.S. residents represented 42 states plus the District of Columbia, but most (53%) were from just 3 states (California, Florida, and New York). In comparison to the Caribbean IgM-positive patient group, the U.S. IgM-positive patient group contained proportionately more adults 21 to 60 years old and fewer individuals <21 years old. These findings indicate that the 2010 Caribbean DV outbreak affected many U.S. residents (mostly adults, presumably travelers) from diverse geographic areas and emphasize the potential for a viremic DV-infected returning traveler to spark a local DV outbreak by introducing DV into a community with competent mosquito vectors. PMID- 21613463 TI - Comparative study of the standard fluorescent antibody to membrane antigen (FAMA) assay and a flow cytometry-adapted FAMA assay to assess immunity to varicella zoster virus. AB - A flow cytometry-adapted fluorescent antibody to membrane antigen (FAMA) assay to detect IgG antibodies against varicella-zoster virus (VZV) was developed and tested in 62 serum samples, showing 90.32% accuracy obtained from a receiver operating characteristic (ROC) curve with a 0.9125 (95% confidence interval [CI], 0.829 to 1.00) area below the curve compared to the result with standard FAMA. PMID- 21613464 TI - Incubation of whole blood at 39 degrees C augments gamma interferon (IFN-gamma) induced protein 10 and IFN-gamma responses to Mycobacterium tuberculosis antigens. AB - A rarely challenged dogma in cell-mediated immune (CMI) assays is the incubation temperature, 37 degrees C. Fever augments proinflammatory immune responses in vivo, and the aim of this study was to explore whether incubation at fever-range temperature could increase antigen-specific biomarker responses. We compared CMI responses following incubation of whole blood at 37 degrees C and 39 degrees C. Whole blood was obtained from (i) 34 healthy subjects whose blood was incubated with TB10.4 antigen, present in the Mycobacterium bovis bacillus Calmette-Guerin vaccine and many environmental mycobacteria; (ii) 8 TB patients and 8 controls incubated with Mycobacterium tuberculosis-specific antigens in the QuantiFERON-TB Gold test (QFT-IT); and (iii) from both groups incubated with a T cell mitogen. T cell responses (gamma interferon [IFN-gamma]) and responses from antigen presenting cells (IFN-gamma-induced protein 10 [IP-10]) were determined. We further evaluated the effect of adding interleukin-7 (IL-7) and blocking IL-10 during incubation. In TB patients, IFN-gamma and IP-10 levels were increased 4.1- and 3.4-fold, respectively, at 39 degrees C incubation (P < 0.001). Similar results were seen after mitogen stimulation. In subjects responding to TB10.4, the effects were less pronounced and significant only for IP-10. Incubation at 39 degrees C increased IP-10 and IFN-gamma responsiveness to both antigens and mitogen in persons with baseline or initial low responses. Adding IL-7 and blocking IL-10 augmented the effects in synergy with fever-range temperature. Incubation at fever-range temperature vividly increases CMI responsiveness to antigen stimulation in vitro in tuberculosis patients and may increase the sensitivity of CMI assays. PMID- 21613465 TI - Effects of an inactivated porcine circovirus type 2 (PCV2) vaccine on PCV2 virus shedding in semen from experimentally infected boars. AB - The objective of the present study was to determine the effect of an inactivated porcine circovirus type 2 (PCV2) vaccine on PCV2b virus shedding in the semen of experimentally infected boars by measuring the immunological response and the PCV2b DNA load in blood and semen. Twelve boars were randomly divided into three groups. The boars in group 1 (n = 4) were immunized with an inactivated PCV2 vaccine and were challenged with PCV2b. The boars in group 2 (n = 4) were only challenged with PCV2b. The boars in group 3 (n = 4) served as negative controls. The number of PCV2 genome copies of PCV2 in the serum and semen were significantly lower in vaccinated challenged boars than in nonvaccinated challenged boars at 7, 10, 14, 21, 32, 35, 42, 49, and 60 days postinoculation. The number of PCV2b genomes in the semen correlated with the number of PCV2b genomes in the blood in both vaccinated challenged (R = 0.714) and nonvaccinated challenged (R = 0.861) boars. The results of the present study demonstrate that the inactivated PCV2 vaccine significantly decreases the amount of PCV2b DNA shedding in semen from vaccinated boars after experimental infection with PCV2b. PMID- 21613466 TI - Distinct patterns of functional and effective connectivity between perirhinal cortex and other cortical regions in recognition memory and perceptual discrimination. AB - Traditionally, the medial temporal lobe (MTL) is thought to be dedicated to declarative memory. Recent evidence challenges this view, suggesting that perirhinal cortex (PrC), which interfaces the MTL with the ventral visual pathway, supports highly integrated object representations in recognition memory and perceptual discrimination. Even with comparable representational demands, perceptual and memory tasks differ in numerous task demands and the subjective experience they evoke. Here, we tested whether such differences are reflected in distinct patterns of connectivity between PrC and other cortical regions, including differential involvement of prefrontal control processes. We examined functional magnetic resonance imaging data for closely matched perceptual and recognition memory tasks for faces that engaged right PrC equivalently. Multivariate seed analyses revealed distinct patterns of interactions: Right ventrolateral prefrontal and posterior cingulate cortices exhibited stronger functional connectivity with PrC in recognition memory; fusiform regions were part of the pattern that displayed stronger functional connectivity with PrC in perceptual discrimination. Structural equation modeling revealed distinct patterns of effective connectivity that allowed us to constrain interpretation of these findings. Overall, they demonstrate that, even when MTL structures show similar involvement in recognition memory and perceptual discrimination, differential neural mechanisms are reflected in the interplay between the MTL and other cortical regions. PMID- 21613467 TI - Parametric merging of MEG and fMRI reveals spatiotemporal differences in cortical processing of spoken words and environmental sounds in background noise. AB - There is an increasing interest to integrate electrophysiological and hemodynamic measures for characterizing spatial and temporal aspects of cortical processing. However, an informative combination of responses that have markedly different sensitivities to the underlying neural activity is not straightforward, especially in complex cognitive tasks. Here, we used parametric stimulus manipulation in magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) recordings on the same subjects, to study effects of noise on processing of spoken words and environmental sounds. The added noise influenced MEG response strengths in the bilateral supratemporal auditory cortex, at different times for the different stimulus types. Specifically for spoken words, the effect of noise on the electrophysiological response was remarkably nonlinear. Therefore, we used the single-subject MEG responses to construct parametrization for fMRI data analysis and obtained notably higher sensitivity than with conventional stimulus-based parametrization. fMRI results showed that partly different temporal areas were involved in noise-sensitive processing of words and environmental sounds. These results indicate that cortical processing of sounds in background noise is stimulus specific in both timing and location and provide a new functionally meaningful platform for combining information obtained with electrophysiological and hemodynamic measures of brain function. PMID- 21613468 TI - The insula of Reil revisited: multiarchitectonic organization in macaque monkeys. AB - The insula of Reil represents a large cortical territory buried in the depth of the lateral sulcus and subdivided into 3 major cytoarchitectonic domains: agranular, dysgranular, and granular. The present study aimed at reinvestigating the architectonic organization of the monkey's insula using multiple immunohistochemical stainings (parvalbumin, PV; nonphosphorylated neurofilament protein, with SMI-32; acetylcholinesterase, AChE) in addition to Nissl and myelin. According to changes in density and laminar distributions of the neurochemical markers, several zones were defined and related to 8 cytoarchitectonic subdivisions (Ia1-Ia2/Id1-Id3/Ig1-Ig2/G). Comparison of the different patterns of staining on unfolded maps of the insula revealed: 1) parallel ventral to dorsal gradients of increasing myelin, PV- and AChE containing fibers in middle layers, and of SMI-32 pyramidal neurons in supragranular layers, with merging of dorsal and ventral high-density bands in posterior insula, 2) definition of an insula "proper" restricted to two-thirds of the "morphological" insula (as bounded by the limiting sulcus) and characterized most notably by lower PV, and 3) the insula proper is bordered along its dorsal, posterodorsal, and posteroventral margin by a strip of cortex extending beyond the limits of the morphological insula and continuous architectonically with frontoparietal and temporal opercular areas related to gustatory, somatosensory, and auditory modalities. PMID- 21613469 TI - Motor "dexterity"?: Evidence that left hemisphere lateralization of motor circuit connectivity is associated with better motor performance in children. AB - Motor control relies on well-established motor circuits, which are critical for typical child development. Although many imaging studies have examined task activation during motor performance, none have examined the relationship between functional intrinsic connectivity and motor ability. The current study investigated the relationship between resting state functional connectivity within the motor network and motor performance assessment outside of the scanner in 40 typically developing right-handed children. Better motor performance correlated with greater left-lateralized (mean left hemisphere-mean right hemisphere) motor circuit connectivity. Speed, rhythmicity, and control of movements were associated with connectivity within different individual region pairs: faster speed was associated with more left-lateralized putamen-thalamus connectivity, less overflow with more left-lateralized supplementary motor primary motor connectivity, and less dysrhythmia with more left-lateralized supplementary motor-anterior cerebellar connectivity. These findings suggest that for right-handed children, superior motor development depends on the establishment of left-hemisphere dominance in intrinsic motor network connectivity. PMID- 21613471 TI - Motor planning is facilitated by adopting an action's goal posture: an fMRI study. AB - Motor planning is a hierarchical process that is typically organized around an action's goal (e.g., drinking from a cup). However, the motor plan depends not only on the goal but also on the current body state. Here, we investigated how one's own body posture interacts with planning of goal-directed actions. Participants engaged in a grasp selection (GS) task while we manipulated their arm posture. They had to indicate how they would grasp a bar when transporting it from a start to goal position and orientation. We compared situations in which one's body posture was in-congruent with the start posture and/or goal posture of the planned movement. Behavioral results show that GS took longer when one's own body state was incongruent with the goal posture of the planned movement. Correspondingly, neural activity in the intraparietal sulcus (IPS) and extrastriate body area (EBA) was modulated by congruency between the body state and the action plan. IPS was sensitive to overall congruency between body posture and action plan, while the EBA was sensitive specifically to goal posture congruency. Together, our results suggest that IPS maintains an internal state of one's own body posture, while EBA contains a representation of the goal posture of the action plan. PMID- 21613470 TI - Total and regional brain volumes in a population-based normative sample from 4 to 18 years: the NIH MRI Study of Normal Brain Development. AB - Using a population-based sampling strategy, the National Institutes of Health (NIH) Magnetic Resonance Imaging Study of Normal Brain Development compiled a longitudinal normative reference database of neuroimaging and correlated clinical/behavioral data from a demographically representative sample of healthy children and adolescents aged newborn through early adulthood. The present paper reports brain volume data for 325 children, ages 4.5-18 years, from the first cross-sectional time point. Measures included volumes of whole-brain gray matter (GM) and white matter (WM), left and right lateral ventricles, frontal, temporal, parietal and occipital lobe GM and WM, subcortical GM (thalamus, caudate, putamen, and globus pallidus), cerebellum, and brainstem. Associations with cross sectional age, sex, family income, parental education, and body mass index (BMI) were evaluated. Key observations are: 1) age-related decreases in lobar GM most prominent in parietal and occipital cortex; 2) age-related increases in lobar WM, greatest in occipital, followed by the temporal lobe; 3) age-related trajectories predominantly curvilinear in females, but linear in males; and 4) small systematic associations of brain tissue volumes with BMI but not with IQ, family income, or parental education. These findings constitute a normative reference on regional brain volumes in children and adolescents. PMID- 21613472 TI - Hippocampal neuronal nitric oxide synthase mediates the stress-related depressive behaviors of glucocorticoids by downregulating glucocorticoid receptor. AB - The molecular mechanisms underlying the behavioral effects of glucocorticoids are poorly understood. We report here that hippocampal neuronal nitric oxide synthase (nNOS) is a crucial mediator. Chronic mild stress and glucocorticoids exposures caused hippocampal nNOS overexpression via activating mineralocorticoid receptor. In turn, hippocampal nNOS-derived nitric oxide (NO) significantly downregulated local glucocorticoid receptor expression through both soluble guanylate cyclase (sGC)/cGMP and peroxynitrite (ONOO(-))/extracellular signal-regulated kinase signal pathways, and therefore elevated hypothalamic corticotrophin-releasing factor, a peptide that governs the hypothalamic-pituitary-adrenal axis. More importantly, nNOS deletion or intrahippocampal nNOS inhibition and NO-cGMP signaling blockade (using NO scavenger or sGC inhibitor) prevented the corticosterone-induced behavioral modifications, suggesting that hippocampal nNOS is necessary for the role of glucocorticoids in mediating depressive behaviors. In addition, directly delivering ONOO(-) donor into hippocampus caused depressive like behaviors. Our findings reveal a role of hippocampal nNOS in regulating the behavioral effects of glucocorticoids. PMID- 21613473 TI - Chorda tympani nerve terminal field maturation and maintenance is severely altered following changes to gustatory nerve input to the nucleus of the solitary tract. AB - Neural competition among multiple inputs can affect the refinement and maintenance of terminal fields in sensory systems. In the rat gustatory system, the chorda tympani, greater superficial petrosal, and glossopharyngeal nerves have distinct but overlapping terminal fields in the first central relay, the nucleus of the solitary tract. This overlap is largest at early postnatal ages followed by a significant refinement and pruning of the fields over a 3 week period, suggesting that competitive mechanisms underlie the pruning. Here, we manipulated the putative competitive interactions among the three nerves by sectioning the greater superficial petrosal and glossopharyngeal nerves at postnatal day 15 (P15), P25, or at adulthood, while leaving the chorda tympani nerve intact. The terminal field of the chorda tympani nerve was assessed 35 d following nerve sections, a period before the sectioned nerves functionally regenerated. Regardless of the age when the nerves were cut, the chorda tympani nerve terminal field expanded to a volume four times larger than sham controls. Terminal field density measurements revealed that the expanded terminal field was similar to P15 control rats. Thus, it appears that the chorda tympani nerve terminal field defaults to its early postnatal field size and shape when the nerves with overlapping fields are cut, and this anatomical plasticity is retained into adulthood. These findings not only demonstrate the dramatic and lifelong plasticity in the central gustatory system, but also suggest that corresponding changes in functional and taste-related behaviors will accompany injury-induced changes in brainstem circuits. PMID- 21613474 TI - Induction of intracellular tau aggregation is promoted by alpha-synuclein seeds and provides novel insights into the hyperphosphorylation of tau. AB - Intracytoplasmic proteinaceous inclusions, primarily composed of tau or alpha synuclein (alpha-syn), are predominant pathological features of Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. However, the coexistence of these pathological aggregates is identified in many neurodegenerative disorders, including spectrum disorders of AD and PD. Whereas alpha-syn can spontaneously polymerize into amyloidogenic fibrils, in vitro, tau polymerization requires an inducing agent. The current study presents a human-derived cellular model, in which recombinant, preformed alpha-syn fibrils cross-seed intracellular tau to promote the formation of neurofibrillary tangle-like aggregates. These aggregates were hyperphosphorylated, Triton insoluble, and thioflavin-S positive, either comingling with endogenously expressed alpha-syn aggregates or induced by only exogenously applied recombinant alpha-syn fibrils. Furthermore, filamentous, amyloidogenic tau took over the cellular soma, displacing the nucleus and isolating or displacing organelles, likely preventing cellular function. Although a significant proportion of wild-type tau formed these cellular inclusions, the P301L mutation in tau increased aggregation propensity resulting from alpha-syn seeds to over 50% of total tau protein. The role of phosphorylation on the development of these tau aggregates was investigated by coexpressing glycogen synthase kinase 3 beta or microtubule-associated protein/microtubule affinity regulating kinase 2. Expression of either kinase inhibited the formation of alpha syn-induced tau aggregates. Analyses of phosphorylation sites suggest that multiple complex factors may be associated with this effect and that Triton soluble versus Triton-insoluble tau may be independently targeted by kinases. The current work not only provides an exceptional cellular model of tau pathology, but also examines alpha-syn-induced tau inclusion formation and provides novel insights into hyperphosphorylation observed in disease. PMID- 21613475 TI - Cell death triggers olfactory circuit plasticity via glial signaling in Drosophila. AB - The Drosophila antennal lobe is organized into glomerular compartments, where olfactory receptor neurons synapse onto projection neurons. Projection neuron dendrites also receive input from local neurons, which interconnect glomeruli. In this study, we investigated how activity in this circuit changes over time when sensory afferents are chronically removed in vivo. In the normal circuit, excitatory connections between glomeruli are weak. However, after we chronically severed receptor neuron axons projecting to a subset of glomeruli, we found that odor-evoked lateral excitatory input to deafferented projection neurons was potentiated severalfold. This was caused, at least in part, by strengthened electrical coupling from excitatory local neurons onto projection neurons, as well as increased activity in excitatory local neurons. Merely silencing receptor neurons was not sufficient to elicit these changes, implying that severing receptor neuron axons is the relevant signal. When we expressed the neuroprotective gene Wallerian degeneration slow (Wld(S)) in receptor neurons before severing their axons, this blocked the induction of plasticity. Because expressing Wld(S) prevents severed axons from recruiting glia, this result suggests a role for glia. Consistent with this, we found that blocking endocytosis in ensheathing glia blocked the induction of plasticity. In sum, these results reveal a novel injury response whereby severed sensory axons recruit glia, which in turn signal to central neurons to upregulate their activity. By strengthening excitatory interactions between neurons in a deafferented brain region, this mechanism might help boost activity to compensate for lost sensory input. PMID- 21613476 TI - Inter-regional contribution of enhanced activity of the primary somatosensory cortex to the anterior cingulate cortex accelerates chronic pain behavior. AB - Multiple cortical areas are involved in pain processing, including the primary somatosensory cortex (S1) and the anterior cingulate cortex (ACC). Although accumulations of evidence suggest that the S1 activity increases under chronic pain conditions, whether plastic change occurs or not within the S1, and whether and how the plastic change contributes to chronic pain behavior, is unknown. Here, we provide the first evidence that intra-regional remodeling within the mouse S1 accelerates chronic pain behavior by modulating neuronal activity in the ACC, one of the important cortical areas for chronic pain. Using two-photon Ca(2+) imaging, we found that the spontaneous activity of layer 2/3 neurons in the S1 and then response to sensory and layer 4 stimulations increased under chronic pain conditions. In addition, pharmacological attenuation and facilitation of S1 activity attenuated and facilitated the chronic pain behavior, respectively. Furthermore, electrical response of the ACC to peripheral stimulation successfully correlated with S1 neuronal activity, and inhibition of ACC activity alleviated the mechanical allodynia. The present results will provide development of efficient therapeutic strategies against chronic pain by focusing on the S1 and ACC. PMID- 21613477 TI - Sustained neuronal activity generated by glial plasticity. AB - Astrocytes release gliotransmitters, notably glutamate, that can affect neuronal and synaptic activity. In particular, astrocytic glutamate release results in the generation of NMDA receptor (NMDA-R)-mediated slow inward currents (SICs) in neurons. However, factors underlying the emergence of SICs and their physiological roles are essentially unknown. Here we show that, in acute slices of rat somatosensory thalamus, stimulation of lemniscal or cortical afferents results in a sustained increase of SICs in thalamocortical (TC) neurons that outlasts the duration of the stimulus by 1 h. This long-term enhancement of astrocytic glutamate release is induced by group I metabotropic glutamate receptors and is dependent on astrocytic intracellular calcium. Neuronal SICs are mediated by extrasynaptic NR2B subunit-containing NMDA-Rs and are capable of eliciting bursts. These are distinct from T-type Ca(2+) channel-dependent bursts of action potentials and are synchronized in neighboring TC neurons. These findings describe a previously unrecognized form of excitatory, nonsynaptic plasticity in the CNS that feeds forward to generate local neuronal firing long after stimulus termination. PMID- 21613478 TI - Phosphorylation of histone H2A.X as an early marker of neuronal endangerment following seizures in the adult rat brain. AB - The phosphorylated form of histone H2A.X (gamma-H2AX) is a well documented early, sensitive, and selective marker of DNA double-strand breaks (DSBs). Previously, we found that excessive glutamatergic activity increased gamma-H2AX in neurons in vitro. Here, we evaluated gamma-H2AX formation in the adult rat brain following neuronal excitation evoked by seizure activity in vivo. We found that brief, repeated electroconvulsive shock (ECS)-induced seizures (three individual seizures within 60 min) did not trigger an increase gamma-H2AX immunostaining. In contrast, a cluster of 5-7 individual seizures evoked by kainic acid (KA) rapidly (within 30 min) induced gamma-H2AX in multiple neuronal populations in hippocampus and entorhinal cortex. This duration of seizure activity is well below threshold for induction of neuronal cell death, indicating that the gamma H2AX increase occurs in response to sublethal insults. Moreover, an increase in gamma-H2AX was seen in dentate granule cells, which are resistant to cell death caused by KA-evoked seizures. With as little as a 5 min duration of status epilepticus (SE), gamma-H2AX increased in CA1, CA3, and entorhinal cortex to a greater extent than that observed after the clusters of individual seizures, with still greater increases after 120 min of SE. Our findings provide the first direct demonstration that DNA DSB damage occurs in vivo in the brain following seizures. Furthermore, we found that the gamma-H2AX increase caused by 120 min of SE was prevented by neuroprotective preconditioning with ECS-evoked seizures. This demonstrates that DNA DSB damage is an especially sensitive indicator of neuronal endangerment and that it is responsive to neuroprotective intervention. PMID- 21613479 TI - Statistical traces of long-term memories stored in strengths and patterns of synaptic connections. AB - Learning and long-term memory rely on plasticity of neural circuits. In adult cerebral cortex, plasticity can result from potentiation and depression of synaptic strengths and structural reorganization of circuits through growth and retraction of dendritic spines. By analyzing 166 distributions of spine head volumes and spine lengths from mouse, rat, monkey, and human brains, we determine the "generalized cost" of dendritic spines. This cost universally depends on spine shape, i.e., the dependence is the same in all the analyzed systems. We show that, in adult, synaptic strength and structural synaptic plasticity mechanisms are in statistical equilibrium, the numbers of dendritic spines in different cortical areas are nearly optimally chosen for memory storage, and the distributions of spine lengths and head volumes are governed by a single parameter--the effective temperature. We suggest that the effective temperature may be viewed as a measure of circuit stability or longevity of stored memories. PMID- 21613480 TI - Spectral and temporal sensitivity of cone-mediated responses in mouse retinal ganglion cells. AB - The retina uses two photoreceptor types to encode the wide range of light intensities in the natural environment. Rods mediate vision in dim light, whereas cones mediate vision in bright light. Mouse photoreceptors include only 3% cones, and the majority of these coexpress two opsins (short- and middle-wavelength sensitive, S and M), with peak sensitivity to either ultraviolet (360 nm) or green light (508 nm). The M/S-opsin ratio varies across the retina but has not been characterized functionally, preventing quantitative study of cone-mediated vision. Furthermore, physiological and behavioral measurements suggested that mouse retina supports relatively slow temporal processing (peak sensitivity, ~ 2 5 Hz) compared to primates; however, past studies used visible wavelengths that are inefficient at stimulating mouse S-opsin. Here, we measured the M/S-opsin expression ratio across the mouse retina, as reflected by ganglion cell responses in vitro, and probed cone-mediated ganglion cell temporal properties using ultraviolet light stimulation and linear systems analysis. From recordings in mice lacking rod function (Gnat1(-/-), Rho(-/-)), we estimate ~ 70% M-opsin expression in far dorsal retina, dropping to <5% M-opsin expression throughout ventral retina. In mice lacking cone function (Gnat2(cpfl3)), light-adapted rod mediated responses peaked at ~ 5-7 Hz. In wild-type mice, cone-mediated responses peaked at ~ 10 Hz, with substantial responsiveness up to ~ 30 Hz. Therefore, despite the small percentage of cones, cone-mediated responses in mouse ganglion cells are fast and robust, similar to those in primates. These measurements enable quantitative analysis of cone-mediated responses at all levels of the visual system. PMID- 21613481 TI - Spinal vascular endothelial growth factor induces phrenic motor facilitation via extracellular signal-regulated kinase and Akt signaling. AB - Although vascular endothelial growth factor (VEGFA-165) is primarily known for its role in angiogenesis, it also plays important neurotrophic and neuroprotective roles for spinal motor neurons. VEGFA-165 signals by activating its receptor tyrosine kinase VEGF receptor-2 (VEGFR-2). Because another growth/trophic factor that signals via a receptor tyrosine kinase (brain derived neurotrophic factor) elicits a long-lasting facilitation of respiratory motor activity in the phrenic nerve, we tested the hypothesis that VEGFA-165 elicits similar phrenic motor facilitation (pMF). Using immunohistochemistry and retrograde labeling techniques, we demonstrate that VEGFA-165 and VEGFR-2 are expressed in identified phrenic motor neurons. Furthermore, intrathecal VEGFA-165 administration at C4 elicits long-lasting pMF; intraspinal VEGFA-165 increased integrated phrenic nerve burst amplitude for at least 90 min after injection (53.1 +/- 5.0% at 90 min; p < 0.001). Intrathecal VEGFA-165 increased phosphorylation (and presumed activation) of signaling molecules downstream from VEGFR-2 within the phrenic motor nucleus, including ERK (1.53 +/- 0.13 vs 1.0 +/- 0.05 arbitrary units in control rats; p < 0.05) and Akt (2.16 +/- 0.41 vs 1.0 +/- 0.41 arbitrary units in control rats; p < 0.05). VEGF-induced pMF was attenuated by the MEK/ERK inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o aminophenylmercapto)butadiene] and was abolished by the phosphotidinositol 3 kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], demonstrating that ERK mitogen-activated protein kinases and Akt are both required for full expression of VEGF-induced pMF. This is the first report that VEGFA-165 elicits plasticity in any motor system. Furthermore, because VEGFA-165 expression is hypoxia sensitive, it may play a role in respiratory plasticity after prolonged exposures to low oxygen. PMID- 21613482 TI - Intraneuronal APP, not free Abeta peptides in 3xTg-AD mice: implications for tau versus Abeta-mediated Alzheimer neurodegeneration. AB - Alzheimer's disease (AD) is characterized by the accumulation of intraneuronal tau and extracellular amyloid-beta (Abeta) peptide. A triple transgenic (Tg) mouse (3xTg-AD) was reported to develop Abeta plaques and tau inclusions as well as remarkable accumulations of intracellular Abeta that were suggested to be the initiators of AD pathogenesis. However, it was unclear whether the anti-Abeta antibodies were able to distinguish Abeta peptide from the same Abeta epitopes within the amyloid precursor protein (APP). To further elucidate the identity of the immunoreactive intraneuronal material in 3xTg-AD mice, we conducted immunohistochemical, biochemical, and ultrastructural studies using a well characterized panel of antibodies that distinguish Abeta within APP from cleaved Abeta peptides. We found that the intraneuronal material shared epitopes with full-length APP but not free Abeta. To demonstrate unequivocally that this intraneuronal material was not free Abeta peptide, we generated 3xTg-AD mice deficient for beta-secretase (BACE), the protease required for Abeta generation from APP. In the absence of Abeta production, robust intraneuronal APP immunostaining was detected in the 3xTg-AD/BACE(-/-) mice. Finally, we found that the formation of tau lesions was not different between 3xTg-AD versus 3xTg AD/BACE(-/-) mice, thereby demonstrating that tau pathology forms independently from Abeta peptide generation in this mouse model. Although we cannot corroborate the presence of intraneuronal Abeta peptide in 3xTg-AD mice, our findings warrant further study as to the role of aberrant APP accumulation in this unique model of AD. PMID- 21613483 TI - Molecular and morphological configuration for 2-arachidonoylglycerol-mediated retrograde signaling at mossy cell-granule cell synapses in the dentate gyrus. AB - 2-Arachidonoylglycerol (2-AG) is the endocannabinoid that mediates retrograde suppression of neurotransmission in the brain. In the present study, we investigated the 2-AG signaling system at mossy cell (MC)-granule cell (GC) synapses in the mouse dentate gyrus, an excitatory recurrent circuit where endocannabinoids are thought to suppress epileptogenesis. First, we showed by electrophysiology that 2-AG produced by diacylglycerol lipase alpha (DGLalpha) mediated both depolarization-induced suppression of excitation and its enhancement by group I metabotropic glutamate receptor activation at MC-GC synapses, as they were abolished in DGLalpha-knock-out mice. Immunohistochemistry revealed that DGLalpha was enriched in the neck portion of GC spines forming synapses with MC terminals, whereas cannabinoid CB(1) receptors accumulated in the terminal portion of MC axons. On the other hand, the major 2-AG-degrading enzyme, monoacylglycerol lipase (MGL), was absent at MC-GC synapses but was expressed in astrocytes and some inhibitory terminals. Serial electron microscopy clarified that a given GC spine was innervated by a single MC terminal and also contacted nonsynaptically by other MC terminals making synapses with other GC spines in the neighborhood. MGL-expressing elements, however, poorly covered GC spines, amounting to 17% of the total surface of GC spines by astrocytes and 4% by inhibitory terminals. Our findings provide a basis for 2-AG-mediated retrograde suppression of MC-GC synaptic transmission and also suggest that 2-AG released from activated GC spines is readily accessible to nearby MC-GC synapses by escaping from enzymatic degradation. This molecular-anatomical configuration will contribute to adjust network activity in the dentate gyrus after enhanced excitation. PMID- 21613484 TI - The timing for neuronal maturation in the adult hippocampus is modulated by local network activity. AB - The adult hippocampus continuously generates new cohorts of immature neurons with increased excitability and plasticity. The window for the expression of those unique properties in each cohort is determined by the time required to acquire a mature neuronal phenotype. Here, we show that local network activity regulates the rate of maturation of adult-born neurons along the septotemporal axis of the hippocampus. Confocal microscopy and patch-clamp recordings were combined to assess marker expression, morphological development, and functional properties in retrovirally labeled neurons over time. The septal dentate gyrus displayed higher levels of basal network activity and faster rates of newborn neuron maturation than the temporal region. Voluntary exercise enhanced network activity only in the temporal region and, in turn, accelerated neuronal development. Finally, neurons developing within a highly active environment exhibited a delayed maturation when their intrinsic electrical activity was reduced by the cell autonomous overexpression of Kir2.1, an inward-rectifying potassium channel. Our findings reveal a novel type of activity-dependent plasticity acting on the timing of neuronal maturation and functional integration of newly generated neurons along the longitudinal axis of the adult hippocampus. PMID- 21613485 TI - Auditory event-related response in visual cortex modulates subsequent visual responses in humans. AB - Growing evidence from electrophysiological data in animal and human studies suggests that multisensory interaction is not exclusively a higher-order process, but also takes place in primary sensory cortices. Such early multisensory interaction is thought to be mediated by means of phase resetting. The presentation of a stimulus to one sensory modality resets the phase of ongoing oscillations in another modality such that processing in the latter modality is modulated. In humans, evidence for such a mechanism is still sparse. In the current study, the influence of an auditory stimulus on visual processing was investigated by measuring the electroencephalogram (EEG) and behavioral responses of humans to visual, auditory, and audiovisual stimulation with varying stimulus onset asynchrony (SOA). We observed three distinct oscillatory EEG responses in our data. An initial gamma-band response around 50 Hz was followed by a beta-band response around 25 Hz, and a theta response around 6 Hz. The latter was enhanced in response to cross-modal stimuli as compared to either unimodal stimuli. Interestingly, the beta response to unimodal auditory stimuli was dominant in electrodes over visual areas. The SOA between auditory and visual stimuli--albeit not consciously perceived--had a modulatory impact on the multisensory evoked beta-band responses; i.e., the amplitude depended on SOA in a sinusoidal fashion, suggesting a phase reset. These findings further support the notion that parameters of brain oscillations such as amplitude and phase are essential predictors of subsequent brain responses and might be one of the mechanisms underlying multisensory integration. PMID- 21613486 TI - Synaptic characteristics of dentate gyrus axonal boutons and their relationships with aging, menopause, and memory in female rhesus monkeys. AB - Age-related memory impairment occurs in many mammalian species, including humans. Moreover, women undergoing the menopausal transition often complain of problems with memory. We recently reported that rhesus monkeys display age- and menopause related recognition memory impairment on a hippocampus-reliant test [delayed nonmatching-to-sample (DNMS)]. In the same monkeys, perforated synapse densities in the dentate gyrus outer molecular layer (OML) correlated with DNMS recognition accuracy, while total axospinous synapse density was similar across age and menses groups. The current study examined whether synaptic characteristics of OML axonal boutons are coupled with age- or menopause-related memory deficits. Using serial section electron microscopy, we measured the frequencies of single-synapse boutons (SSBs), multiple-synapse boutons (MSBs), and boutons with no apparent synaptic contacts [nonsynaptic boutons (NSBs)] in the OML. Aged females had double the percentage of NSBs compared with young females, and this measure correlated positively and inversely with DNMS acquisition (number of trials to criterion) and delay performance (average accuracy), respectively. Aged compared with young females also had a lower frequency of MSBs and a lower number of synaptic contacts per MSB, and the latter variable inversely correlated with DNMS acquisition. Although proportions of NSBs, SSBs, and MSBs were similar across menses groups, compared with premenopausal monkeys, peri/postmenopausal monkeys had fewer MSBs contacting one or more segmented perforated synapses, and the abundance of this bouton subtype positively correlated with DNMS performance. These results suggest that age- and menopause-related shifts in OML synaptic subtypes may be coupled with deficits in task acquisition and recognition memory. PMID- 21613487 TI - Flexible categorization of relative stimulus strength by the optic tectum. AB - Categorization is the process by which the brain segregates continuously variable stimuli into discrete groups. We report that patterns of neural population activity in the owl optic tectum (OT) categorize stimuli based on their relative strengths into "strongest" versus "other." The category boundary shifts adaptively to track changes in the absolute strength of the strongest stimulus. This population-wide categorization is mediated by the responses of a small subset of neurons. Our data constitute the first direct demonstration of explicit categorization of stimuli by a neural network based on relative stimulus strength or salience. The finding of categorization by the population code relaxes constraints on the properties of downstream decoders that might read out the location of the strongest stimulus. These results indicate that the ensemble neural code in the OT could mediate bottom-up stimulus selection for gaze and attention, a form of stimulus categorization in which the category boundary often shifts within hundreds of milliseconds. PMID- 21613488 TI - Retinal ganglion cells with distinct directional preferences differ in molecular identity, structure, and central projections. AB - The retina contains ganglion cells (RGCs) that respond selectively to objects moving in particular directions. Individual members of a group of ON-OFF direction-selective RGCs (ooDSGCs) detect stimuli moving in one of four directions: ventral, dorsal, nasal, or temporal. Despite this physiological diversity, little is known about subtype-specific differences in structure, molecular identity, and projections. To seek such differences, we characterized mouse transgenic lines that selectively mark ooDSGCs preferring ventral or nasal motion as well as a line that marks both ventral- and dorsal-preferring subsets. We then used the lines to identify cell surface molecules, including Cadherin 6, CollagenXXValpha1, and Matrix metalloprotease 17, that are selectively expressed by distinct subsets of ooDSGCs. We also identify a neuropeptide, CART (cocaine- and amphetamine-regulated transcript), that distinguishes all ooDSGCs from other RGCs. Together, this panel of endogenous and transgenic markers distinguishes the four ooDSGC subsets. Patterns of molecular diversification occur before eye opening and are therefore experience independent. They may help to explain how the four subsets obtain distinct inputs. We also demonstrate differences among subsets in their dendritic patterns within the retina and their axonal projections to the brain. Differences in projections indicate that information about motion in different directions is sent to different destinations. PMID- 21613489 TI - Mechanisms of rule acquisition and rule following in inductive reasoning. AB - Despite the recent interest in the neuroanatomy of inductive reasoning processes, the regional specificity within prefrontal cortex (PFC) for the different mechanisms involved in induction tasks remains to be determined. In this study, we used fMRI to investigate the contribution of PFC regions to rule acquisition (rule search and rule discovery) and rule following. Twenty-six healthy young adult participants were presented with a series of images of cards, each consisting of a set of circles numbered in sequence with one colored blue. Participants had to predict the position of the blue circle on the next card. The rules that had to be acquired pertained to the relationship among succeeding stimuli. Responses given by subjects were categorized in a series of phases either tapping rule acquisition (responses given up to and including rule discovery) or rule following (correct responses after rule acquisition). Mid dorsolateral PFC (mid-DLPFC) was active during rule search and remained active until successful rule acquisition. By contrast, rule following was associated with activation in temporal, motor, and medial/anterior prefrontal cortex. Moreover, frontopolar cortex (FPC) was active throughout the rule acquisition and rule following phases before a rule became familiar. We attributed activation in mid-DLPFC to hypothesis generation and in FPC to integration of multiple separate inferences. The present study provides evidence that brain activation during inductive reasoning involves a complex network of frontal processes and that different subregions respond during rule acquisition and rule following phases. PMID- 21613490 TI - Increased hippocampal default mode synchronization during rest in middle-aged and elderly APOE epsilon4 carriers: relationships with memory performance. AB - The apolipoprotein (APOE) epsilon4 allele is a strong genetic risk factor for Alzheimer's disease (AD). Intrinsic fluctuations of brain activity measured by fMRI during rest may be sensitive to AD-related neuropathology. In particular, functional connectivity of the default-mode network (DMN) has gained recent attention as a possible biomarker of disease processes and associated memory decline in AD. Here, we tested the hypothesis of APOE-related alterations in DMN functional connectivity in 95 healthy individuals between 50 and 80 years of age, including 33 carriers of the epsilon4 allele. Based on previous studies, we hypothesized increased hippocampal DMN synchronization in APOE epsilon4 carriers. This was supported using independent component analysis in combination with a dual-regression approach for analysis of resting state data. Whole-brain analysis suggested effects also in other areas, including the posterior cingulate cortex, parietal cortex, and parahippocampal regions. DMN synchronization showed a negative correlation with performance on a test of memory functioning, suggesting a neurocognitive significance of the brain activity patterns during rest. Our findings indicate that increased genetic vulnerability for AD is reflected in increased hippocampal DMN synchronization during rest several years before clinical manifestation. We propose that the results reflect epsilon4-related failure in hippocampal decoupling, which might elevate the total hippocampal metabolic burden and increase the risk of cognitive decline and AD. The results provide an important confirmation of specific genotype effects on intrinsic fluctuations and support the use of functional connectivity indices as imaging derived endophenotypes in the emerging field of imaging genetics. PMID- 21613491 TI - Temporal trade-off effects in sustained attention: dynamics in visual cortex predict the target detection performance during distraction. AB - Models of visual selective attention have suggested that the representation of specific features characterizing a target object is enhanced in the visual cortex, at the cost of competing task-irrelevant information. In psychophysical studies, however, such attentional enhancement has been shown to result in reduced perceptual sensitivity when maintained over periods of several seconds. Two experiments examined the relationship between target detection behavior and electrocortical facilitation in human visual cortex during sustained attention under competition, in near real time. Steady-state visual evoked potentials (ssVEPs) were used in a change detection paradigm, in which a stream of flickering grating stimuli containing target events was fully overlapping with distractor faces (experiment 1) or competing complex scenes (experiment 2), covering the same part of the visual field. Beamformer source localization was used to test plausibility of lower-tier visual cortex involvement in modulation of the ssVEP signal. Results of both experiments suggest that early overallocation of visual cortical resources to the attended stimulus stream is associated with rapid reduction of electrocortical facilitation and poor change detection across the entire trial. By contrast, temporally balanced dynamics in visual cortex predicted accurate change detection. Together, the present results support models of sustained selective attention that emphasize competition for resources in lower-tier visual cortex. These models can be extended by a temporal dimension, on which attentive behavior is characterized by frugal resource sharing across the viewing time. PMID- 21613492 TI - In the newborn hippocampus, neurotrophin-dependent survival requires spontaneous activity and integrin signaling. AB - The nervous system develops through a program that first produces neurons in excess and then eliminates as many as half in a specific period of early postnatal life. Neurotrophins are widely thought to regulate neuronal survival, but this role has not been clearly defined in the CNS. Here we show that neurotrophins promote survival of young neurons by promoting spontaneous activity. Survival of hippocampal neurons in neonatal rat requires spontaneous activity that depends on the excitatory action of GABA. Neurotrophins facilitate recruitment of cultured neurons into active networks, and it is this activity, combined with integrin receptor signaling, that controls neuronal survival. In vivo, neurotrophins require integrin signaling to control neuron number. These data are the first to link the early excitatory action of GABA to the developmental death period and to assign an essential role for activity in neurotrophin-mediated survival that establishes appropriate networks. PMID- 21613493 TI - Emotion-associated tones attract enhanced attention at early auditory processing: magnetoencephalographic correlates. AB - Emotionally significant objects and events in our environment attract attention based on their motivational relevance for survival. Such kind of emotional attention is thought to lead to affect-specific amplified processing that closely resembles effects of directed attention. Although there has been extensive research on prioritized processing of visual emotional stimuli, the spatio temporal dynamics of motivated attention mechanisms in auditory processing are less clearly understood. We investigated modulatory effects of emotional attention at early auditory processing stages using time-sensitive whole-head magnetoencephalography. A novel associative learning procedure involving multiple conditioned stimuli (CSs) per affective category was introduced to specifically test whether affect-specific modulation can proceed in a rapid and highly differentiating fashion in humans. Auditory evoked fields (AEFs) were recorded in response to 42 different ultrashort, click-like sounds before and after affective conditioning with pleasant, unpleasant, or neutral auditory scenes. As hypothesized, emotional attention affected neural click tone processing at time intervals of the P20-50m (20-50 ms) and the N1m (100-130 ms), two early AEF components sensitive to directed selective attention (Woldorff et al., 1993). Distributed source localization revealed amplified processing of tones associated with aversive or pleasant compared with neutral auditory scenes at auditory sensory, frontal and parietal cortex regions. Behavioral tests did not indicate any awareness for the contingent CS-UCS (unconditioned stimulus) relationships in the participants, suggesting affective associative learning in absence of contingency awareness. Our findings imply early and highly differentiating affect specific modulation of auditory stimulus processing supported by neural mechanisms and circuitry comparable with those reported for directed auditory attention. PMID- 21613494 TI - Nucleus accumbens medium spiny neurons target non-dopaminergic neurons in the ventral tegmental area. AB - The midbrain ventral tegmental area (VTA) projection to the nucleus accumbens (NAc) is implicated in motivation and reinforcement. A significant number of NAc medium spiny neurons (MSNs) project back to the VTA, although the nature of this projection is essentially unknown. For example, do NAc MSNs directly target accumbens-projecting dopamine neurons and do they act via the GABA(A) or GABA(B) receptor? To address these issues, we expressed the light-sensitive channel rhodopsin-2 in the rat NAc and made electrophysiological recordings from VTA neurons ex vivo. We found that the NAc directly targets non-dopaminergic VTA neurons, including some that project back to the NAc. These MSN GABAergic terminals are opioid sensitive and act via GABA(A) receptors. PMID- 21613496 TI - Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex. AB - Cognitive functions that require the prefrontal cortex are highly sensitive to aging in humans, nonhuman primates, and rodents, although the neurobiological correlates of this vulnerability remain largely unknown. It has been proposed that dendritic spines represent the primary site of structural plasticity in the adult brain, and recent data have supported the hypothesis that aging is associated with alterations of dendritic spine morphology and plasticity in prefrontal cortex. However, no study to date has directly examined whether aging alters the capacity for experience-dependent spine plasticity in aging prefrontal neurons. To address this possibility, we used young, middle-aged, and aged rats in a behavioral stress paradigm known to produce spine remodeling in prefrontal cortical neurons. In young rats, stress resulted in dendritic spine loss and altered patterns of spine morphology; in contrast, spines from middle-aged and aged animals were remarkably stable and did not show evidence of remodeling. The loss of stress-induced spine plasticity observed in aging rats occurred alongside robust age-related reductions in spine density and shifts in remaining spine morphology. Together, the data presented here provide the first evidence that experience-dependent spine plasticity is altered by aging in prefrontal cortex, and support a model in which dendritic spines become progressively less plastic in the aging brain. PMID- 21613497 TI - Stress acts cumulatively to precipitate Alzheimer's disease-like tau pathology and cognitive deficits. AB - Stressful life experiences are likely etiological factors in sporadic forms of Alzheimer's disease (AD). Many AD patients hypersecrete glucocorticoids (GCs), and their GC levels correlate with the rate of cognitive impairment and extent of neuronal atrophy. Severity of cognitive deficits in AD correlates strongly with levels of hyperphosphorylated forms of the cytoskeletal protein TAU, an essential mediator of the actions of amyloid beta (Abeta), another molecule with a key pathogenic role in AD. Our objective was to investigate the sequential interrelationships between these various pathogenic elements, in particular with respect to the mechanisms through which stress might precipitate cognitive decline. We thus examined whether stress, through the mediation of GCs, influences TAU hyperphosphorylation, a critical and early event in the cascade of processes leading to AD pathology. Results from healthy, wild-type, middle-aged rats show that chronic stress and GC induce abnormal hyperphosphorylation of TAU in the hippocampus and prefrontal cortex (PFC), with contemporaneous impairments of hippocampus- and PFC-dependent behaviors. Exogenous GC potentiated the ability of centrally infused Abeta to induce hyperphosphorylation of TAU epitopes associated with AD and cytoplasmic accumulation of TAU, while previous exposure to stress aggravated the biochemical and behavioral effects of GC in Abeta infused animals. Thus, lifetime stress/GC exposure may have a cumulative impact on the onset and progress of AD pathology, with TAU hyperphosphorylation serving to transduce the negative effects of stress and GC on cognition. PMID- 21613495 TI - Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy. AB - In the hallmark neuritic dystrophy of Alzheimer's disease (AD), autophagic vacuoles containing incompletely digested proteins selectively accumulate in focal axonal swellings, reflecting defects in both axonal transport and autophagy. Here, we investigated the possibility that impaired lysosomal proteolysis could be a basis for both of these defects leading to neuritic dystrophy. In living primary mouse cortical neurons expressing fluorescence tagged markers, LC3-positive autophagosomes forming in axons rapidly acquired the endo-lysosomal markers Rab7 and LAMP1 and underwent exclusive retrograde movement. Proteolytic clearance of these transported autophagic vacuoles was initiated after fusion with bidirectionally moving lysosomes that increase in number at more proximal axon levels and in the perikaryon. Disrupting lysosomal proteolysis by either inhibiting cathepsins directly or by suppressing lysosomal acidification slowed the axonal transport of autolysosomes, late endosomes, and lysosomes and caused their selective accumulation within dystrophic axonal swellings. Mitochondria and other organelles lacking cathepsins moved normally under these conditions, indicating that the general functioning of the axonal transport system was preserved. Dystrophic swellings induced by lysosomal proteolysis inhibition resembled in composition those in several mouse models of AD and also acquired other AD-like features, including immunopositivity for ubiquitin, amyloid precursor protein, and hyperphosphorylated neurofilament proteins. Restoration of lysosomal proteolysis reversed the affected movements of proteolytic Rab7 vesicles, which in turn essentially cleared autophagic substrates and reversed the axonal dystrophy. These studies identify the AD associated defects in neuronal lysosomal proteolysis as a possible basis for the selective transport abnormalities and highly characteristic pattern of neuritic dystrophy associated with AD. PMID- 21613498 TI - Tactile-auditory shape learning engages the lateral occipital complex. AB - Shape is an object property that inherently exists in vision and touch, and is processed in part by the lateral occipital complex (LOC). Recent studies have shown that shape can be artificially coded by sound using sensory substitution algorithms and learned with behavioral training. This finding offers a unique opportunity to test intermodal generalizability of the LOC beyond the sensory modalities in which shape is naturally perceived. Therefore, we investigated the role of the LOC in processing of shape by examining neural activity associated with learning tactile-shape-coded auditory information. Nine blindfolded sighted people learned the tactile-auditory relationship between raised abstract shapes and their corresponding shape-coded sounds over 5 d of training. Using functional magnetic resonance imaging, subjects were scanned before and after training during a task in which they first listened to a shape-coded sound transformation, then touched an embossed shape, and responded whether or not the tactile stimulus matched the auditory stimulus in terms of shape. We found that behavioral scores improved after training and that the LOC was commonly activated during the auditory and tactile conditions both before and after training. However, no significant training-related change was observed in magnitude or size of LOC activity; rather, the auditory cortex and LOC showed strengthened functional connectivity after training. These findings suggest that the LOC is available to different sensory systems for shape processing and that auditory-tactile sensory substitution training leads to neural changes allowing more direct or efficient access to this site by the auditory system. PMID- 21613499 TI - Visuomotor coordination is different for different directions in three dimensional space. AB - In most visuomotor tasks in which subjects have to reach to visual targets or move the hand along a particular trajectory, eye movements have been shown to lead hand movements. Because the dynamics of vergence eye movements is different from that of smooth pursuit and saccades, we have investigated the lead time of gaze relative to the hand for the depth component (vergence) and in the frontal plane (smooth pursuit and saccades) in a tracking task and in a tracing task in which human subjects were instructed to move the finger along a 3D path. For tracking, gaze leads finger position on average by 28 +/- 6 ms (mean +/- SE) for the components in the frontal plane but lags finger position by 95 +/- 39 ms for the depth dimension. For tracing, gaze leads finger position by 151 +/- 36 ms for the depth dimension. For the frontal plane, the mean lead time of gaze relative to the hand is 287 +/- 13 ms. However, we found that the lead time in the frontal plane was inversely related to the tangential velocity of finger. This inverse relation for movements in the frontal plane could be explained by assuming that gaze leads the finger by a constant distance of ~ 2.6 cm (range of 1.5-3.6 cm across subjects). PMID- 21613501 TI - The CD59 family member Leaky/Coiled is required for the establishment of the blood-brain barrier in Drosophila. AB - The blood-brain barrier of Drosophila is established by the subperineurial glial cells that encase the CNS and PNS. The subperineurial glial cells are thin, highly interdigitated cells with epithelial character. The establishment of extensive septate junctions between these cells is crucial for the prevention of uncontrolled paracellular leakage of ions and solutes from the hemolymph into the nervous system. In the absence of septate junctions, macromolecules such as fluorescently labeled dextran can easily cross the blood-brain barrier. To identify additional components of the blood-brain barrier, we followed a genetic approach and injected Texas-Red-conjugated dextran into the hemolymph of embryos homozygous for chromosomal deficiencies. In this way, we identified the 153-aa large protein Coiled, a new member of the Ly6 (leukocyte antigen 6) family, as being crucially required for septate junction formation and blood-brain barrier integrity. In coiled mutants, the normal distribution of septate junction markers such as NeurexinIV, Coracle, or Discs large is disturbed. EM analyses demonstrated that Coiled is required for the formation of septate junctions. We further show that Coiled is expressed by the subsperineurial glial cells in which it is anchored to the cell membrane via a glycosylphosphatidylinositol anchor and mediates adhesive properties. Clonal rescue studies indicate that the presence of Coiled is required symmetrically on both cells engaged in septate junction formation. PMID- 21613500 TI - Action dominates valence in anticipatory representations in the human striatum and dopaminergic midbrain. AB - The acquisition of reward and the avoidance of punishment could logically be contingent on either emitting or withholding particular actions. However, the separate pathways in the striatum for go and no-go appear to violate this independence, instead coupling affect and effect. Respect for this interdependence has biased many studies of reward and punishment, so potential action-outcome valence interactions during anticipatory phases remain unexplored. In a functional magnetic resonance imaging study with healthy human volunteers, we manipulated subjects' requirement to emit or withhold an action independent from subsequent receipt of reward or avoidance of punishment. During anticipation, in the striatum and a lateral region within the substantia nigra/ventral tegmental area (SN/VTA), action representations dominated over valence representations. Moreover, we did not observe any representation associated with different state values through accumulation of outcomes, challenging a conventional and dominant association between these areas and state value representations. In contrast, a more medial sector of the SN/VTA responded preferentially to valence, with opposite signs depending on whether action was anticipated to be emitted or withheld. This dominant influence of action requires an enriched notion of opponency between reward and punishment. PMID- 21613502 TI - Relation between presynaptic and postsynaptic dopaminergic functions measured by positron emission tomography: implication of dopaminergic tone. AB - Both presynaptic and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET). While both presynaptic and postsynaptic dopaminergic functions would be regulated by corresponding genes and related to personality traits, the relation between presynaptic and postsynaptic functions in terms of interindividual variation has hardly been investigated. In the present study, both striatal dopamine D(2) receptor binding and endogenous dopamine synthesis rate were measured in the same healthy subjects using PET with [(11)C]raclopride and l-[beta-(11)C]DOPA, respectively, and these two parameters were compared. Two PET studies with [(11)C]raclopride and l-[beta-(11)C]DOPA were performed sequentially at rest condition on 14 healthy men. For [(11)C]raclopride PET, the binding potential was calculated by the reference tissue model method. For l-[beta-(11)C]DOPA PET, the endogenous dopamine synthesis rate was estimated by graphical analysis. A significant negative correlation was observed between the binding potential of dopamine D(2) receptors and endogenous dopamine synthesis rate (r = -0.66, p < 0.05). Although the interindividual variation of binding potential of [(11)C]raclopride would be due to both the interindividual difference in the receptor density and that in the concentration of endogenous dopamine in the synaptic cleft, the negative correlation between parameters for both presynaptic and postsynaptic functions might indicate a compensative relation between the two functions. PMID- 21613503 TI - Similar odorants elicit different behavioral and physiological responses, some supersustained. AB - An intriguing question in the field of olfaction is how animals distinguish among structurally similar odorants. We systematically analyzed olfactory responses elicited by a panel of 25 pyrazines. We found that structurally similar pyrazines elicit a wide range of behavioral responses from Drosophila larvae. Each pyrazine was tested against all functional receptors of the larval Odor receptor (Or) repertoire, yielding 525 odorant-receptor combinations. Different pyrazines vary markedly in the responses they elicit from the Or repertoire, with most strong responses deriving from two receptors, Or33b and Or59a. Surprisingly, 2 ethylpyrazine and 2-methylpyrazine, which elicit strikingly similar physiological responses across the receptor repertoire, elicit dramatically different behavioral responses. A small fraction of odorant-receptor combinations elicit remarkably long responses. These responses, which we term "supersustained" responses, are receptor specific and odorant specific, and can last for minutes. Such supersustained responses may prevent olfactory neurons from reporting contemporaneous information about the local odor environment. Odors that elicit such responses could provide a novel means of controlling insect pests and vectors of human disease by impairing the location of human hosts, food sources, and mates. PMID- 21613504 TI - The mammalian cone visual cycle promotes rapid M/L-cone pigment regeneration independently of the interphotoreceptor retinoid-binding protein. AB - Rapid regeneration of the visual pigment following its photoactivation is critical for the function of cone photoreceptors throughout the day. Though the reactions of the visual cycle in the retinal pigment epithelium (RPE) that recycle chromophore for rod pigment regeneration are well characterized, the corresponding mechanisms that enable rapid regeneration of cone pigment are poorly understood. A key remaining question is the relative contribution of the recently discovered cone-specific retina visual cycle and the classic RPE dependent visual cycle to mammalian cone pigment regeneration. In addition, it is not clear what role, if any, the abundant interphotoreceptor retinoid-binding protein (IRBP) presumed to facilitate the traffic of chromophore, plays in accelerating mammalian cone pigment regeneration. To address these issues, we used transretinal recordings to evaluate M/L-cone pigment regeneration in isolated retinas and eyecups from control and IRBP-deficient mice. Remarkably, the mouse retina promoted M/L-cone dark adaptation eightfold faster than the RPE. However, complete cone recovery required both visual cycles. We conclude that the retina visual cycle is critical for the initial rapid regeneration of mouse M/L cone pigment during dark adaptation, whereas the slower RPE visual cycle is required to complete the process. While the deletion of IRBP reduced the amplitude and slowed the kinetics of mouse M/L-cone photoresponses, cone adaptation in bright, steady light and the kinetics of cone dark adaptation were not affected in isolated retina or in intact eyecup. Thus, IRBP does not accelerate cone pigment regeneration and is not critical for the function of mouse M/L-cones in bright light. PMID- 21613505 TI - Anatomical and functional assemblies of brain BOLD oscillations. AB - Brain oscillatory activity has long been thought to have spatial properties, the details of which are unresolved. Here we examine spatial organizational rules for the human brain oscillatory activity as measured by blood oxygen level-dependent (BOLD) signal. Resting-state BOLD signal was transformed into frequency space (Welch's method) and averaged across subjects, and its spatial distribution was studied as a function of four frequency bands, spanning the full BOLD bandwidth. The brain showed anatomically constrained distribution of power for each frequency band. This result was replicated on a repository dataset of 195 subjects. Next, we examined larger-scale organization by parceling the neocortex into regions approximating Brodmann areas (BAs). This indicated that BAs of simple function/connectivity (unimodal), versus complex properties (transmodal), are dominated by low-frequency BOLD oscillations, and within the visual ventral stream we observe a graded shift of power to higher-frequency bands for BAs further removed from the primary visual cortex (increased complexity), linking BOLD frequency properties to hodology. Additionally, BOLD oscillation properties for the default mode network demonstrated that it is composed of distinct frequency-dependent regions. When the same analysis was performed on a visual motor task, frequency-dependent global and voxelwise shifts in BOLD oscillations could be detected at brain sites mostly outside those identified with general linear modeling. Thus, analysis of BOLD oscillations in full bandwidth uncovers novel brain organizational rules, linking anatomical structures and functional networks to characteristic BOLD oscillations. The approach also identifies changes in brain intrinsic properties in relation to responses to external inputs. PMID- 21613506 TI - The pattern of glomerular map formation defines responsiveness to aversive odorants in mice. AB - In many species, the detection and recognition of odors is critical to regulate behaviors that are essential for survival, such as foraging for food and avoidance of predators. The formation of complex stereotypic connections between olfactory sensory neurons (OSNs) and second-order neurons in the olfactory bulb (OB) is believed to be important for accurate odorant information processing. In mice, ablation of OSNs that innervate the dorsal region of the OB leads to a loss of avoidance behavior in response to aversive and predator odorants (Kobayakawa et al., 2007). It remains to be determined whether the accurate formation of a glomerular map in this region of the OB is required for these innate responses. Here, we have generated mice that lack expression of the axon guidance receptor Robo-2 in OSNs and found that ablation of Robo-2 expression leads to mistargeting of subsets of OSN axons within the dorsal region of the OB. Furthermore, these mice show decreased avoidance behavior toward the predator odorant trimethyl thiazoline. Our results indicate that the pattern of glomerular innervation in the OB is critical for innate behavioral responses in mice. PMID- 21613509 TI - Frequency interference artifact. PMID- 21613507 TI - Reinforcement-related regulation of AMPA glutamate receptor subunits in the ventral tegmental area enhances motivation for cocaine. AB - Chronic cocaine use produces numerous biological changes in brain, but relatively few are functionally associated with cocaine reinforcement. Here we show that daily intravenous cocaine self-administration, but not passive cocaine administration, induces dynamic upregulation of the AMPA glutamate receptor subunits GluR1 and GluR2 in the ventral tegmental area (VTA) of rats. Increases in GluR1 protein and GluR1(S845) phosphorylation are associated with increased GluR1 mRNA in self-administering animals, whereas increased GluR2 protein levels occurred despite substantial decreases in GluR2 mRNA. We investigated the functional significance of GluR1 upregulation in the VTA on cocaine self administration using localized viral-mediated gene transfer. Overexpression of GluR1(WT) in rat VTA primarily infected dopamine neurons (75%) and increased AMPA receptor-mediated membrane rectification in these neurons with AMPA application. Similar GluR1(WT) overexpression potentiated locomotor responses to intra-VTA AMPA, but not NMDA, infusions. In cocaine self-administering animals, overexpression of GluR1(WT) in the VTA markedly increased the motivation for cocaine injections on a progressive ratio schedule of cocaine reinforcement. In contrast, overexpression of protein kinase A-resistant GluR1(S845A) in the VTA reduced peak rates of cocaine self-administration on a fixed ratio reinforcement schedule. Neither viral vector altered sucrose self-administration, and overexpression of GluR1(WT) or GluR1(S845A) in the adjacent substantia nigra had no effect on cocaine self-administration. Together, these results suggest that dynamic regulation of AMPA receptors in the VTA during cocaine self administration contributes to cocaine addiction by acting to facilitate subsequent cocaine use. PMID- 21613508 TI - Functional role of neurotrophin-3 in synapse regeneration by spiral ganglion neurons on inner hair cells after excitotoxic trauma in vitro. AB - Spiral ganglion neurons (SGNs) are postsynaptic to hair cells and project to the brainstem. The inner hair cell (IHC) to SGN synapse is susceptible to glutamate excitotoxicity and to acoustic trauma, with potentially adverse consequences to long-term SGN survival. We used a cochlear explant culture from P6 rat pups consisting of a portion of organ of Corti maintained intact with the corresponding portion of spiral ganglion to investigate excitotoxic damage to IHC SGN synapses in vitro. The normal innervation pattern is preserved in vitro. Brief treatment with NMDA and kainate results in loss of IHC-SGN synapses and degeneration of the distal type 1 SGN peripheral axons, mimicking damage to SGN peripheral axons caused by excitotoxicity or noise in vivo. The number of IHC presynaptic ribbons is not significantly altered. Reinnervation of IHCs occurs and regenerating axons remain restricted to the IHC row. However, the number of postsynaptic densities (PSDs) does not fully recover and not all axons regrow to the IHCs. Addition of either neurotrophin-3 (NT-3) or BDNF increases axon growth and synaptogenesis. Selective blockade of endogenous NT-3 signaling with TrkC-IgG reduced regeneration of axons and PSDs, but TrkB-IgG, which blocks BDNF, has no such effect, indicating that endogenous NT-3 is necessary for SGN axon growth and synaptogenesis. Remarkably, TrkC-IgG reduced axon growth and synaptogenesis even in the presence of BDNF, indicating that endogenous NT-3 has a distinctive role, not mimicked by BDNF, in promoting SGN axon growth in the organ of Corti and synaptogenesis on IHCs. PMID- 21613510 TI - Development and initial psychometric evaluation of the Stroke Arm Ladder: a measure of upper extremity function post stroke. AB - OBJECTIVE: To develop an adaptive measure, the Stroke Arm Ladder, to parsimoniously quantify upper extremity function post stroke. SETTING: Various studies conducted in Montreal and elsewhere in Canada. SUBJECTS: A total of 4058 persons with stroke who participated in various studies were assessed on different occasions post stroke. Assessments spanned from 3 days to 1 year post stroke. MAIN MEASURES: A calibrated bank containing 49 items from tests and indices designed to assess global motor recovery of the upper extremity, upper extremity function and activities involving the upper extremity was used. Data including all testing occasions were analysed to test whether they adhered to the expectations of the Rasch partial credit model and whether item hierarchy remained stable across testing occasions. RESULTS: Fifteen items did not meet the requirements of the Rasch model and were deleted. An adaptive measure of upper extremity function, the Stroke Arm Ladder, containing 34 items was created. The easiest item was partially executing the bilateral task of tying a scarf around one's neck, while the hardest item was being able to transfer more than 60 blocks on the Box and Block Test. The items' difficulty thresholds cover a wide range of difficulty levels from -7.4 to 6.2 and the global fit statistics (chi(2): 331; probability: 0.18), confirmed content validity. CONCLUSION: The Stroke Arm Ladder demonstrates adequate initial psychometric properties. Further testing of the measure in its adaptive format is necessary before it can be used clinically. PMID- 21613511 TI - Clinical measurement of walking balance in people post stroke: a systematic review. AB - OBJECTIVE: To identify walking balance measures which have been established for use with ambulatory people post stroke and reflect the balance requirements of community walking. DATA SOURCES: MEDLINE, Embase, AMED. REVIEW METHODS: Measures reflecting walking balance, with tasks that include a stepping action in standing, used with people post stroke were reviewed. Measures with clinical utility were evaluated for psychometric properties, including reliability, validity and clinical interpretation. RESULTS: Nine measures (24 papers) were identified that met the requirement of measuring walking balance in people post stroke with demonstrated clinical utility. Outcome measures with multiple tasks (Brunel Balance Assessment, Modified Emory Functional Ambulation Profile, Dynamic Gait Index, Community Balance and Mobility Scale, and mini-Balance Evaluation Systems Test) as opposed to single task measures (Step Test, Side Step Test and Four Square Step Test, Timed Up and Go), reflect a broader range of walking balance required to accommodate the variable challenges which may be expected at the community level of walking. Most tools report excellent reliability when used by physiotherapists. Validity remains far more challenging to establish. Evaluation of clinical interpretation is limited for all measures. CONCLUSION: The multiple-task outcome measures reviewed reflected walking balance activities often undertaken during community mobility. Single-task measures may be useful as screening measures, identifying walking balance deficits associated with basic/lower levels of walking balance. Construct validity and clinical interpretability of each measure in ambulatory people post stroke requires further research to identify the level of community mobility represented by each measure of walking balance. PMID- 21613512 TI - From bouncy legs to poisoned arrows: elastic movements in invertebrates. AB - Elastic mechanisms in the invertebrates are fantastically diverse, yet much of this diversity can be captured by examining just a few fundamental physical principles. Our goals for this commentary are threefold. First, we aim to synthesize and simplify the fundamental principles underlying elastic mechanisms and show how different configurations of basic building blocks can be used for different functions. Second, we compare single rapid movements and rhythmic movements across six invertebrate examples - ranging from poisonous cnidarians to high-jumping froghoppers - and identify remarkable functional properties arising from their underlying elastic systems. Finally, we look to the future of this field and find two prime areas for exciting new discoveries - the evolutionary dynamics of elastic mechanisms and biomimicry of invertebrate elastic materials and mechanics. PMID- 21613513 TI - The influence of trout cardiac troponin I and PKA phosphorylation on the Ca2+ affinity of the cardiac troponin complex. AB - The trout heart is 10-fold more sensitive to Ca(2+) than the mammalian heart. This difference is due, in part, to cardiac troponin C (cTnC) from trout having a greater Ca(2+) affinity than human cTnC. To determine what other proteins are involved, we cloned cardiac troponin I (cTnI) from the trout heart and determined how it alters the Ca(2+) affinity of a cTn complex containing all mammalian components (mammalian cTn). Ca(2+) activation of the complex was characterized using a human cTnC mutant that contains anilinonapthalenesulfote iodoacetamide attached to Cys53. When the cTn complex containing labeled human cTnC was titrated with Ca(2+), its fluorescence changed, reaching an asymptote upon saturation. Our results reveal that trout cTnI lacks the N-terminal extension found in cTnI from all other vertebrate groups. This protein domain contains two targets (Ser23 and Ser24) for protein kinase A (PKA) and protein kinase C. When these are phosphorylated, the rate of cardiomyocyte relaxation increases. When rat cTnI in the mammalian cTn complex was replaced with trout cTnI, the Ca(2+) affinity was increased ~1.8-fold. This suggests that trout cTnI contributes to the high Ca(2+) sensitivity of the trout heart. Treatment of the two cTn complexes with PKA decreased the Ca(2+) affinity of both complexes. However, the change for the complex containing rat cTnI was 2.2-fold that of the complex containing trout cTnI. This suggests that the phosphorylation of trout cTnI does not play as significant a role in regulating cTn function in trout. PMID- 21613514 TI - The influence of PKA treatment on the Ca2+ activation of force generation by trout cardiac muscle. AB - beta-Adrenergic stimulation of the mammalian heart increases heart rate, the strength of contraction as well as the kinetics of force generation and relaxation. These effects are due to the phosphorylation of select membrane and thin filament proteins by cAMP-activated protein kinase (PKA). At the level of the sarcomere, it is typically the phosphorylation of cardiac myosin binding protein C (cMyBP-C) and cardiac troponin I (cTnI) that is responsible for the change in the kinetics of contraction and relaxation. Trout cTnI (ScTnI) lacks two critical PKA targets within the N-terminus of the protein that, when phosphorylated in mammalian cTnI, cause a reduction in myofilament Ca(2+) affinity. To determine what role the contractile element plays in the response of the trout heart to beta-adrenergic stimulation, we characterized the influence of PKA treatment on the Ca(2+) activation of skinned preparations dissected from ventricular trabeculae. In these experiments, isometric force generation and the rate of force development were measured over a range of Ca(2+) concentrations. The results demonstrate that PKA treatment does not influence the Ca(2+) sensitivity of force generation but it decreases maximum force generation by 25% and the rate of force re-development at maximal activation by 46%. Analysis of the trabeculae preparations for phosphoproteins revealed that PKA treatment phosphorylated myosin light chain 2 but not cTnI or cMyBP-C. These results indicate that the function of the trout cardiac contractile element is altered by PKA phosphorylation but in a manner different from that in mammalian heart. PMID- 21613515 TI - Some like it hot: the effects of climate change on reproduction, immune function and disease resistance in the cricket Gryllus texensis. AB - In many parts of the world, climate change is increasing the frequency and severity of heat waves. How do heat waves impact short-lived poikilotherms such as insects? In the cricket, Gryllus texensis, 6 days of elevated temperatures (i.e. 7 degrees C above the average field temperature and 5 degrees C above their preferred temperature) resulted in increased egg laying, faster egg development and greater mass gain. The increased temperature also increased activity of phenoloxidase and lysozyme-like enzymes, two immune-related enzymes, and enhanced resistance to the Gram-negative bacterium Serratia marcescens. When given a sublethal S. marcescens infection, G. texensis maintained increased reproductive output at the elevated temperature (33 degrees C). These data suggest that heat waves could result in more numerous, disease resistant, crickets. However, resistance to the Gram-positive bacterium, Bacillus cereus was lower at temperatures above or below the average field temperature (26 degrees C). A sublethal infection with B. cereus reduced egg laying at all temperatures and suppressed the increase in egg laying induced by higher temperatures. These results suggest that for some species-pathogen interactions, increased temperatures can induce trade-offs between reproduction and disease resistance. This result may partly explain why G. texensis prefers temperatures lower than those that produce maximal reproductive output and enhanced immune function. PMID- 21613516 TI - Experimentally reduced corticosterone release promotes early breeding in black legged kittiwakes. AB - Breeding at the right time is important for successful reproduction. In birds, stressful environmental conditions are known to delay the timing of breeding but the underlying mechanisms are poorly understood. The stress hormone corticosterone appears to be a good candidate for mediating egg-laying date according to early environmental conditions and physiological state. By experimentally reducing the release of corticosterone in black-legged kittiwakes during the pre-laying period, we tested whether egg-laying date was mechanistically linked to corticosterone levels. Male and female kittiwakes were implanted with a low dose of exogenous corticosterone to inhibit endogenous corticosterone production. According to our predictions, the experimental reduction of corticosterone release was paralleled by a significant advancement of egg laying in females (around 4 days earlier). In addition, females with experimentally reduced corticosterone release gained mass during the pre-laying period compared with controls. Ultimately, the advancement of egg laying in females with experimentally reduced corticosterone levels was associated with an enhanced breeding success. This effect was strongly sex specific. In corticosterone-treated male kittiwakes, egg-laying date and reproductive success were not affected, but breeding probability was lower than in controls. This corticosterone treatment did not influence immediate clutch size, or return rate and breeding decision the following year. Our results support the hypothesis that corticosterone secretion during the pre-laying period mediates the timing of breeding in this long-lived seabird, possibly through the dynamics of energy reserves. PMID- 21613517 TI - Arctic reindeer extend their visual range into the ultraviolet. AB - The Arctic has extreme seasonal changes in light levels and is proportionally UV rich because of scattering of the shorter wavelengths and their reflection from snow and ice. Here we show that the cornea and lens in Arctic reindeer do not block all UV and that the retina responds electrophysiologically to these wavelengths. Both rod and cone photoreceptors respond to UV at low-intensity stimulation. Retinal RNA extraction and in vitro opsin expression show that the response to UV is not mediated by a specific UV photoreceptor mechanism. Reindeer thus extend their visual range into the short wavelengths characteristic of the winter environment and periods of extended twilight present in spring and autumn. A specific advantage of this short-wavelength vision is the use of potential information caused by differential UV reflections known to occur in both Arctic vegetation and different types of snow. UV is normally highly damaging to the retina, resulting in photoreceptor degeneration. Because such damage appears not to occur in these animals, they may have evolved retinal mechanisms protecting against extreme UV exposure present in the daylight found in the snow-covered late winter environment. PMID- 21613518 TI - Static electric fields modify the locomotory behaviour of cockroaches. AB - Static electric fields are found throughout the environment and there is growing interest in how electric fields influence insect behaviour. Here we have analysed the locomotory behaviour of cockroaches (Periplaneta americana) in response to static electric fields at levels equal to and above those found in the natural environment. Walking behaviour (including velocity, distance moved, turn angle and time spent walking) were analysed as cockroaches approached an electric field boundary in an open arena, and also when continuously exposed to an electric field. On approaching an electric field boundary, the greater the electric field strength the more likely a cockroach would be to turn away from, or be repulsed by, the electric field. Cockroaches completely exposed to electric fields showed significant changes in locomotion by covering less distance, walking slowly and turning more often. This study highlights the importance of electric fields on the normal locomotory behaviour of insects. PMID- 21613519 TI - Dolphin hearing during echolocation: evoked potential responses in an Atlantic bottlenose dolphin (Tursiops truncatus). AB - Auditory evoked potential (AEP) responses were recorded during echolocation in an Atlantic bottlenose dolphin (Tursiops truncatus) trained to accept suction-cup EEG electrodes and detect targets by echolocation. AEP recording was triggered by the echolocation clicks of the animal. Three targets with target strengths of 34, -28 and -22 dB were used at a target distance of 2 to 6.5 m for each target. The results demonstrated that the AEP appeared to both outgoing echolocation clicks and echoes during echolocation, with AEP complexes consisting of alternative positive and negative waves. The echo-related AEP amplitudes were obviously lower than the outgoing click-related AEP amplitudes for all the targets at the investigated target distances. However, for targets with target strengths of -22 and -28 dB, the peak-to-peak amplitudes of the echo-related AEPs were dependent on the target distances. The echo-related AEP response amplitudes increased at further target distances, demonstrating an overcompensation of echo attenuation with target distance in the echo-perception system of the dolphin biosonar. Measurement and analysis of outgoing click intensities showed that the click levels increased with target distance (R) by a factor of approximately 10 to 17.5 logR depending on target strength. The results demonstrated that a dual component biosonar control system formed by intensity compensation behavior in both the transmission and receiving phases of a biosonar cycle exists synchronously in the dolphin biosonar system. PMID- 21613520 TI - Kinematics of the quadrate bone during feeding in mallard ducks. AB - Avian cranial kinesis, in which mobility of the quadrate, pterygoid and palatine bones contribute to upper bill elevation, is believed to occur in all extant birds. The most widely accepted model for upper bill elevation is that the quadrate rotates rostrally and medially towards the pterygoid, transferring force to the mobile pterygoid-palatine complex, which pushes on the upper bill. Until now, however, it has not been possible to test this hypothesis in vivo because quadrate motions are rapid, three-dimensionally complex and not visible externally. Here we use a new in vivo X-ray motion analysis technique, X-ray reconstruction of moving morphology (XROMM), to create precise (+/-0.06 mm) 3-D animations of the quadrate, braincase, upper bill and mandible of three mallard ducks, Anas platyrhynchos. We defined a joint coordinate system (JCS) for the quadrato-squamosal joint with the axes aligned to the anatomical planes of the skull. In this coordinate system, the quadrate's 3-D rotations produce an elliptical path of pterygoid process motion, with medial and rostrodorsal then lateral and rostrodorsal motion as the upper bill elevates. As the upper bill depresses, the pterygoid process continues along the ellipsoidal path, with lateral and caudoventral then medial and caudoventral motion. We also found that the mandibular rami bow outwards (streptognathy) during mandibular depression, which may cause the lateral component of quadrate rotation that we observed. Relative to the JCS aligned with the anatomical planes of the skull, a second JCS aligned with quadrato-squamosal joint anatomy did not produce a simpler description of quadrate kinematics. PMID- 21613521 TI - Circumferential spicule growth by pericellular silica deposition in the hexactinellid sponge Monorhaphis chuni. AB - The giant basal spicule of the hexactinellid sponge Monorhaphis chuni represents the longest natural siliceous structure on Earth. This spicule is composed of concentrically arranged lamellae that are approximately 10 MUm thick. In the present study, we investigated the formation of outer lamellae on a cellular level using microscopic and spectroscopic techniques. It is shown that the formation of an outermost lamella begins with the association of cell clusters with the surface of the thickening and/or growing spicule. The cells release silica for controlled formation of a lamella. The pericellular (silica) material fuses to a delimited and textured layer of silica with depressions approximately 20-30 MUm in diameter. The newly formed layer initially displays 40 MUm wide, well-structured banded ribbons and only attains its plain surface in a final step. The chemical composition in the depressions was studied using energy dispersive X-ray spectroscopy and by staining with Texas Red. The data suggest that those depressions are the nests for the silica-forming cells and that silica formation starts with a direct association of silica-forming cells with the outer surface of the spicule, where they remain and initiate the development of the next lamellae. PMID- 21613522 TI - Kinematic and behavioral evidence for a distinction between trotting and ambling gaits in the cockroach Blaberus discoidalis. AB - Earlier observations had suggested that cockroaches might show multiple patterns of leg coordination, or gaits, but these were not followed by detailed behavioral or kinematic measurements that would allow a definite conclusion. We measured the walking speeds of cockroaches exploring a large arena and found that the body movements tended to cluster at one of two preferred speeds, either very slow (<10 cm s(-1)) or fairly fast (~30 cm s(-1)). To highlight the neural control of walking leg movements, we experimentally reduced the mechanical coupling among the various legs by tethering the animals and allowing them to walk in place on a lightly oiled glass plate. Under these conditions, the rate of stepping was bimodal, clustering at fast and slow speeds. We next used high-speed videos to extract three-dimensional limb and joint kinematics for each segment of all six legs. The angular excursions and three-dimensional motions of the leg joints over the course of a stride were variable, but had different distributions in each gait. The change in gait occurs at a Froude number of ~0.4, a speed scale at which a wide variety of animals show a transition between walking and trotting. We conclude that cockroaches do have multiple gaits, with corresponding implications for the collection and interpretation of data on the neural control of locomotion. PMID- 21613523 TI - The ontogeny of regulatory control of the rainbow trout (Oncorhynchus mykiss) heart and how this is influenced by chronic hypoxia exposure. AB - Salmonid embryos develop in cool waters over relatively long periods of time. Interestingly, hypoxic conditions have been found to be relatively common in some nesting sites (redds). The goals of this study were to determine the ontogeny of cardiac regulation in rainbow trout early life stages and how this is influenced by chronic hypoxia. The heart rate response to cholinergic and adrenergic receptor stimulation or inhibition was measured in individuals reared in normoxic (100% O(2) saturation) or hypoxic (30% O(2) saturation) conditions from fertilization to embryonic stages 22, 26 and 29, and larval stages 30 and 32. In normoxia, heart rate increased in response to beta-adrenergic receptor stimulation (isoproterenol) as early as embryonic stage 22, and decreased with the antagonist propranolol after this stage. Cholinergic stimulation (acetylcholine) was ineffective at all stages, but atropine (acetylcholine antagonist) increased heart rate at larval stage 32. This demonstrates that cardiac beta-adrenergic receptors are functional at early life stages, while cholinergic receptors are not responsive until after hatching. Collectively, embryos had cardio-acceleration control mechanisms in place just after the heartbeat stage, while cardio-inhibitory control was not functional until after hatching. Chronic hypoxia exposure triggered bradycardia, increased the response to adrenergic stimulation in embryos and larvae, and delayed the onset of cholinergic control in larvae. In non-motile stages, therefore, survival in chronic low oxygen may depend on the ability to alter the cardiac ontogenic program to meet the physiological requirements of the developing fish. PMID- 21613524 TI - Loading effects on jump performance in green anole lizards, Anolis carolinensis. AB - Locomotor performance is a crucial determinant of organismal fitness but is often impaired in certain circumstances, such as increased mass (loading) resulting from feeding or gravidity. Although the effects of loading have been studied extensively for striding locomotion, its effects on jumping are poorly understood. Jumping is a mode of locomotion that is widely used across animal taxa. It demands large amounts of power over a short time interval and, consequently, may be affected by loading to a greater extent than other modes of locomotion. We placed artificial loads equal to 30% body mass on individuals of the species Anolis carolinensis to simulate the mass gain following the consumption of a large meal. We investigated the effects of loading on jump performance (maximum jump distance and accuracy), kinematics and power output. Loading caused a significant 18% decline in maximum jump distance and a significant 10% decline in takeoff speed. In other words, the presence of the load caused the lizards to take shorter and slower jumps, whereas takeoff angle and takeoff duration were not affected. By contrast, jump accuracy was unaffected by loading, although accuracy declined when lizards jumped to farther perches. Finally, mass-specific power output did not increase significantly when lizards jumped with loads, suggesting that the ability to produce mechanical power may be a key limiting factor for maximum jump performance. Our results suggest that mass gain after a large meal can pose a significant locomotor challenge and also imply a tradeoff between fulfilling energy requirement and moving efficiently in the environment. PMID- 21613525 TI - The effect of acclimation to hypoxia and sustained exercise on subsequent hypoxia tolerance and swimming performance in goldfish (Carassius auratus). AB - The objective of this study was to determine whether acclimation to hypoxia and sustained exercise would increase hypoxia tolerance (as indicated by a decrease in critical oxygen tension, P(crit)) and swimming performance in goldfish (Carassius auratus), and to investigate the relationship between changes in performance and gill remodelling and tissue metabolic capacity. Goldfish were acclimated to either hypoxia (48 h at 0.3 mg O(2) l(-1)) or sustained exercise (48 h at 70% of critical swimming speed, U(crit)) and then P(crit) and U(crit) were determined in normoxia (10 mg O(2) l(-1)) and hypoxia (1 mg O(2) l(-1)) and compared with values from control fish. Acclimation to both hypoxia and sustained exercise improved hypoxia tolerance (P(crit) was reduced by 49% and 39%, respectively), which was associated with an increase in lamellar surface area (71% and 43%, respectively) and an increase in blood [Hb] (26% in both groups). Exercise acclimation also resulted in a decrease in routine ( ). Acclimation to both hypoxia and sustained exercise resulted in a significant increase in U(crit) in hypoxia (18% and 17%, respectively), which was associated with an increase in maximal O(2) consumption rate at U(crit) ( ; 35% and 39%, respectively). While hypoxia acclimation resulted in an increase in U(crit) in normoxia, acclimation to sustained exercise did not improve subsequent swimming performance in normoxia. This lack of improvement was possibly due to depleted oxidizable substrates during exercise acclimation. PMID- 21613526 TI - Energetically optimal stride frequency in running: the effects of incline and decline. AB - At a given running speed, humans strongly prefer to use a stride frequency near their 'optimal' stride frequency that minimizes metabolic cost. Although there is no definitive explanation for why an optimal stride frequency exists, elastic energy usage has been implicated. Because the possibility for elastic energy storage and return may be impaired on slopes, we investigated whether and how the optimal stride frequency changes during uphill and downhill running. Presuming a smaller role of elastic energy, we hypothesized that altering stride frequency would change metabolic cost less during uphill and downhill running than during level running. To test this hypothesis, we collected force and metabolic data as nine male subjects ran at 2.8 m s(-1) on the level, 3 deg uphill and 3 deg downhill. Stride frequency was systematically varied above and below preferred stride frequency (PSF +/-8% and +/-15%). Ground reaction force data were used to calculate potential, kinetic and total mechanical energy, and to calculate the theoretical maximum possible and estimated actual elastic energy storage and return. Contrary to our hypothesis, we found that neither the overall relationship between metabolic cost and stride frequency nor the energetically optimal stride frequency changed substantially with slope. However, estimated actual elastic energy storage as a percentage of total positive power increased with increasing stride frequency on all slopes, indicating that muscle power decreases with increasing stride frequency. Combined with the increased cost of force production and internal work with increasing stride frequency, this leads to an intermediate optimal stride frequency and overall U-shaped curve. PMID- 21613527 TI - Involvement of redox- and phosphorylation-dependent pathways in osmotic adaptation in sperm cells of euryhaline tilapia. AB - Sperm cells involved in fertilisation must tolerate hypo-osmotic and hyper osmotic environments. Euryhaline tilapia (Oreochromis mossambicus) can acclimatise to and reproduce in freshwater and seawater because its sperm are able to adapt to these differing osmotic environments. In this study, we found that the dephosphorylation of sperm proteins in O. mossambicus correlated with the activation of flagellar motility when sperm were exposed to hypotonic or hypertonic conditions, and that differences in phosphorylation may reflect adaptations to a given osmotic environment. Of the sperm proteins that were dephosphorylated, the phosphorylation pattern of an 18 kDa protein, identified as the superoxide anion scavenger Cu/Zn superoxide dismutase (Cu/Zn SOD), was different in freshwater- and seawater-acclimatised tilapia sperm. Cu/Zn SOD was distributed from the sperm head to the flagellum. Additionally, differences were observed between freshwater and seawater tilapia in the nitration of tyrosine residues (which might be mediated by SOD) in sperm flagellar proteins in response to osmotic shock. These results demonstrate that reactive-oxygen-species dependent mechanisms contribute to both osmotic tolerance and the activation of flagellar motility. PMID- 21613528 TI - Sound radiation and wing mechanics in stridulating field crickets (Orthoptera: Gryllidae). AB - Male field crickets emit pure-tone mating calls by rubbing their wings together. Acoustic radiation is produced by rapid oscillations of the wings, as the right wing (RW), bearing a file, is swept across the plectrum borne on the left wing (LW). Earlier work found the natural resonant frequency (f(o)) of individual wings to be different, but there is no consensus on the origin of these differences. Previous studies suggested that the frequency along the song pulse is controlled independently by each wing. It has also been argued that the stridulatory file has a variable f(o) and that the frequency modulation observed in most species is associated with this variability. To test these two hypotheses, a method was developed for the non-contact measurement of wing vibrations during singing in actively stridulating Gryllus bimaculatus. Using focal microinjection of the neuroactivator eserine into the cricket's brain to elicit stridulation and micro-scanning laser Doppler vibrometry, we monitored wing vibration in actively singing insects. The results show significantly lower f(o) in LWs compared with RWs, with the LW f(o) being identical to the sound carrier frequency (N=44). But during stridulation, the two wings resonate at one identical frequency, the song carrier frequency, with the LW dominating in amplitude response. These measurements also demonstrate that the stridulatory file is a constant resonator, as no variation was observed in f(o) along the file during sound radiation. Our findings show that, as they engage in stridulation, cricket wings work as coupled oscillators that together control the mechanical oscillations generating the remarkably pure species-specific song. PMID- 21613529 TI - Low external environmental calcium levels prevent forgetting in Lymnaea. AB - Forgetting may allow an animal to react more appropriately to current conditions, rather than continuing to exhibit a previously learned, possibly maladaptive behaviour based on previous experience. One theory is that forgetting is an active process, whereby the previously learnt response is replaced by new learning that interferes with the older memory. Hence, we hypothesized that an appropriately timed environmental stressor that blocks long-term memory (LTM) formation would also block forgetting. Lymnaea stagnalis (L.) is a freshwater snail, which requires environmental calcium of at least 20 mg l(-1) to meet its requirements. Low environmental Ca(2+) (i.e. 20 mg l(-1)) in their environment acts as a stressor, and prevents LTM formation. Here, we asked whether a low Ca(2+) environment would also prevent forgetting, concordant with the retrograde interference model of Jenkins and Dallenbach. Snails were operantly conditioned to reduce aerial respiration in hypoxia. When maintained in standard conditions (80 mg l(-1) Ca(2+)), snails demonstrated LTM following training lasting 24 h, but not 72 h; however, when trained in standard conditions then exposed to a low Ca(2+) environment (20 mg l(-1)) immediately following training, they retained memory for at least 96 h, indicating that forgetting had been blocked. Thus, when exposed to low environmental Ca(2+), Lymnaea will fail to form new memories, but will also continue to retain information previously learned and remembered as the low calcium blocks forgetting. PMID- 21613530 TI - Recurrent insertion of 5'-terminal nucleotides and loss of the branchpoint motif in lineages of group II introns inserted in mitochondrial preribosomal RNAs. AB - A survey of sequence databases revealed 10 instances of subgroup IIB1 mitochondrial ribosomal introns with 1 to 33 additional nucleotides inserted between the 5' exon and the consensus sequence at the intron 5' end. These 10 introns depart further from the IIB1 consensus in their predicted domain VI structure: In contrast to its basal helix and distal GNRA terminal loop, the middle part of domain VI is highly variable and lacks the bulging A that serves as the branchpoint in lariat formation. In vitro experiments using two closely related IIB1 members inserted at the same ribosomal RNA site in the basidiomycete fungi Grifola frondosa and Pycnoporellus fulgens revealed that both ribozymes are capable of efficient self-splicing. However, whereas the Grifola intron was excised predominantly as a lariat, the Pycnoporellus intron, which possesses six additional nucleotides at the 5' end, yielded only linear products, consistent with its predicted domain VI structure. Strikingly, all of the introns with 5' terminal insertions lack the EBS2 exon-binding site. Moreover, several of them are part of the small subset of group II introns that encode potentially functional homing endonucleases of the LAGLIDADG family rather than reverse transcriptases. Such coincidences suggest causal relationships between the shift to DNA-based mobility, the loss of one of the two ribozyme sites for binding the 5' exon, and the exclusive use of hydrolysis to initiate splicing. PMID- 21613531 TI - Viral SELEX reveals individual and cooperative roles of the C-box and G-box in HIV-2 replication. AB - The 5' UTR of HIV-2 genomic RNA contains signaling motifs that regulate specific steps of the replication cycle. Two motifs of interest are the C-box and the G box. The C-box is found in the 5' untranslated region upstream of the primer binding site, while the G-box is found downstream from the major splice donor site, encompassing the gag start codon and flanking nucleotides. Together the C box and the G-box form a long-range base-pairing interaction called the CGI. We and others have previously shown that formation of the CGI affects RNA dimerization in vitro and the positions of the C-box and the G-box are suggestive of potential roles of the CGI in other steps of HIV-2 replication. Therefore, we attempted to elucidate the role of the CGI using a viral SELEX approach. We constructed proviral DNA libraries containing randomized regions of the C-box or G-box paired with wild-type or mutant base-pairing partners. These proviral DNA libraries were transfected into COS-7 cells to produce viral libraries that were then used to infect permissive C8166 cells. The "winner" viruses were sequenced and further characterized. Our results demonstrate that there is strong selective pressure favoring viruses that can form a branched CGI. In addition, we show that the mutation of the C-box alone can enhance RNA encapsidation, and mutation of the G-box can alter the levels of Gag protein isoforms. These results suggest coordinated regulation of RNA translation, dimerization, and encapsidation during HIV-2 replication. PMID- 21613533 TI - Neural rehabilitation: action and manipulation. PMID- 21613532 TI - The Tpr protein regulates export of mRNAs with retained introns that traffic through the Nxf1 pathway. AB - Post-transcriptional regulation of mRNA includes restriction mechanisms to prevent export and expression of mRNAs that are incompletely spliced. Here we present evidence that the mammalian protein Tpr is involved in this restriction. To study the role of Tpr in export of mRNA with retained introns, we used reporters in which the mRNA was exported either via the Nxf1/Nxt1 pathway using a CTE or via the Crm1 pathway using Rev/RRE. Our data show that even modest knockdown of Tpr using RNAi leads to a significant increase in export and translation from the mRNA containing the CTE. In contrast, Tpr perturbation has no effect on export of mRNA containing the RRE, either in the absence or presence of Rev. Also, no effects were observed on export of a completely spliced mRNA. Taken together, our results indicate that Tpr plays an important role in quality control of mRNA trafficked on the Nxf1 pathway. PMID- 21613534 TI - Neurological principles and rehabilitation of action disorders: computation, anatomy, and physiology (CAP) model. AB - This chapter outlines the basic computational, anatomical, and physiological (CAP) principles underlying upper-limb actions, such as reaching for a cup and grasping it or picking up a key, inserting it into a lock, and turning it. PMID- 21613535 TI - Neurological principles and rehabilitation of action disorders: common clinical deficits. AB - In this chapter, the authors use the computation, anatomy, and physiology (CAP) principles to consider the impact of common clinical problems on action. They focus on 3 major syndromes: paresis, apraxia, and ataxia. They also review mechanisms that could account for spontaneous recovery, using what is known about the best-studied clinical dysfunction--paresis--and also ataxia. Together, this and the previous chapter lay the groundwork for the third chapter in this series, which reviews the relevant rehabilitative interventions. PMID- 21613536 TI - Neurological principles and rehabilitation of action disorders: rehabilitation interventions. AB - This third chapter discusses the evidence for the rehabilitation of the most common movement disorders of the upper extremity. The authors also present a framework, building on the computation, anatomy, and physiology (CAP) model, for incorporating some of the principles discussed in the 2 previous chapters by Frey et al and Sathian et al in the practice of rehabilitation and for discussing potentially helpful interventions based on emergent neuroscience principles. PMID- 21613537 TI - Increased serum leptin indicates leptin resistance in obesity. PMID- 21613538 TI - Bundle-forming pilus retraction enhances enteropathogenic Escherichia coli infectivity. AB - Enteropathogenic Escherichia coli (EPEC) is an important human pathogen that causes acute infantile diarrhea. The type IV bundle-forming pili (BFP) of typical EPEC strains are dynamic fibrillar organelles that can extend out and retract into the bacterium. The bfpF gene encodes for BfpF, a protein that promotes pili retraction. The BFP are involved in bacterial autoaggregation and in mediating the initial adherence of the bacterium with its host cell. Importantly, BFP retraction is implicated in virulence in experimental human infection. How pili retraction contributes to EPEC pathogenesis at the cellular level remains largely obscure, however. In this study, an effort has been made to address this question using engineered EPEC strains with induced BFP retraction capacity. We show that the retraction is important for tight-junction disruption and, to a lesser extent, actin-rich pedestal formation by promoting efficient translocation of bacterial protein effectors into the host cells. A model is proposed whereby BFP retraction permits closer apposition between the bacterial and the host cell surfaces, thus enabling timely and effective introduction of bacterial effectors into the host cell via the type III secretion apparatus. Our studies hence suggest novel insights into the involvement of pili retraction in EPEC pathogenesis. PMID- 21613539 TI - Hierarchical regulation of mRNA partitioning between the cytoplasm and the endoplasmic reticulum of mammalian cells. AB - The mRNA transcriptome is currently thought to be partitioned between the cytosol and endoplasmic reticulum (ER) compartments by binary selection; mRNAs encoding cytosolic/nucleoplasmic proteins are translated on free ribosomes, and mRNAs encoding topogenic signal-bearing proteins are translated on ER-bound ribosomes, with ER localization being conferred by the signal-recognition particle pathway. In subgenomic and genomic analyses of subcellular mRNA partitioning, we report an overlapping subcellular distribution of cytosolic/nucleoplasmic and topogenic signal-encoding mRNAs, with mRNAs of both cohorts displaying noncanonical subcellular partitioning patterns. Unexpectedly, the topogenic signal-encoding mRNA transcriptome was observed to partition in a hierarchical, cohort-specific manner. mRNAs encoding resident proteins of the endomembrane system were clustered at high ER-enrichment values, whereas mRNAs encoding secretory pathway cargo were broadly represented on free and ER-bound ribosomes. Two distinct modes of mRNA association with the ER were identified. mRNAs encoding endomembrane resident proteins were bound via direct, ribosome-independent interactions, whereas mRNAs encoding secretory cargo displayed predominantly ribosome-dependent modes of ER association. These data indicate that mRNAs are partitioned between the cytosol and ER compartments via a hierarchical system of intrinsic and encoded topogenic signals and identify mRNA cohort-restricted modes of mRNA association with the ER. PMID- 21613540 TI - Axonal filopodial asymmetry induced by synaptic target. AB - During vertebrate neuromuscular junction (NMJ) assembly, motor axons and their muscle targets exchange short-range signals that regulate the subsequent steps of presynaptic and postsynaptic specialization. We report here that this interaction is in part mediated by axonal filopodia extended preferentially by cultured Xenopus spinal neurons toward their muscle targets. Immunoblotting and labeling experiments showed that basic fibroblast growth factor (bFGF) was expressed by muscle and associated with the cell surface, and treatment of cultured spinal neurons with recombinant bFGF nearly doubled the normal density of filopodia in neurites. This effect of bFGF was abolished by SU5402, a selective inhibitor of FGF-receptor 1 (FGFR1), and forced expression of wild-type or dominant-negative FGFR1 in neurons enhanced or suppressed the assembly of filopodia, respectively. Significantly, in nerve-muscle cocultures, knocking down bFGF in muscle decreased both the asymmetric extension of filopodia by axons toward muscle and the assembly of NMJs. In addition, neurons expressing dominant-negative FGFR1 less effectively triggered the aggregation of muscle acetylcholine receptors at innervation sites than did control neurons. These results suggest that bFGF activation of neuronal FGFR1 generates filopodial processes in neurons that promote nerve-muscle interaction and facilitate NMJ establishment. PMID- 21613541 TI - The CSC is required for complete radial spoke assembly and wild-type ciliary motility. AB - The ubiquitous calcium binding protein, calmodulin (CaM), plays a major role in regulating the motility of all eukaryotic cilia and flagella. We previously identified a CaM and Spoke associated Complex (CSC) and provided evidence that this complex mediates regulatory signals between the radial spokes and dynein arms. We have now used an artificial microRNA (amiRNA) approach to reduce expression of two CSC subunits in Chlamydomonas. For all amiRNA mutants, the entire CSC is lacking or severely reduced in flagella. Structural studies of mutant axonemes revealed that assembly of radial spoke 2 is defective. Furthermore, analysis of both flagellar beating and microtubule sliding in vitro demonstrates that the CSC plays a critical role in modulating dynein activity. Our results not only indicate that the CSC is required for spoke assembly and wild-type motility, but also provide evidence for heterogeneity among the radial spokes. PMID- 21613542 TI - Caenorhabditis elegans SNAP-29 is required for organellar integrity of the endomembrane system and general exocytosis in intestinal epithelial cells. AB - It is generally accepted that soluble N-ethylmaleimide-sensitive factor attachment protein receptors mediate the docking and fusion of transport intermediates with target membranes. Our research identifies Caenorhabditis elegans homologue of synaptosomal-associated protein 29 (SNAP-29) as an essential regulator of membrane trafficking in polarized intestinal cells of living animals. We show that a depletion of SNAP-29 blocks yolk secretion and targeting of apical and basolateral plasma membrane proteins in the intestinal cells and results in a strong accumulation of small cargo-containing vesicles. The loss of SNAP-29 also blocks the transport of yolk receptor RME-2 to the plasma membrane in nonpolarized oocytes, indicating that its function is required in various cell types. SNAP-29 is essential for embryogenesis, animal growth, and viability. Functional fluorescent protein-tagged SNAP-29 mainly localizes to the plasma membrane and the late Golgi, although it also partially colocalizes with endosomal proteins. The loss of SNAP-29 leads to the vesiculation/fragmentation of the Golgi and endosomes, suggesting that SNAP-29 is involved in multiple transport pathways between the exocytic and endocytic organelles. These observations also suggest that organelles comprising the endomembrane system are highly dynamic structures based on the balance between membrane budding and fusion and that SNAP-29-mediated fusion is required to maintain proper organellar morphology and functions. PMID- 21613543 TI - Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer. AB - Reduced epithelial cadherin (E-cad) is a hallmark of invasive carcinomas that have acquired epithelial-mesenchymal transition (EMT) phenotypes. Here we show that down-regulated E-cad expression induced by transforming growth factor-beta (TGF-beta) and EMT preceded breast cancer outgrowth in three-dimensional (3D) organotypic assays and in the lungs of mice. Pharmacological inhibitors against focal adhesion kinase prevented metastatic outgrowth of newly seeded organoids, but not that of their fully established counterparts. Interrogating the D2-HAN (hyperplastic alveolar nodule) model of breast cancer dormancy and metastasis showed that dormant D2.OR cells produced branched organoid morphologies in 3D cultures, and expressed robust quantities of E-cad that was uncoupled from regulation by TGF-beta. In contrast, metastatic D2.A1 organoids were spherical and wholly lacked E-cad expression. Interestingly, D2.A1 cells engineered to re express E-cad formed branched organoids, down-regulated beta1 integrin expression, and failed to undergo metastatic outgrowth. The tumor-suppressing function of E-cad was inactivated by increased microenvironmental rigidity, and was not recapitulated by expression of an E-cad mutant lacking its extracellular domain. Twist expression, but not that of Snail, reinitiated metastatic outgrowth in dormant D2.OR cells. Our findings show that EMT and its down-regulated expression of E-cad circumvent breast cancer dormancy in part by facilitating beta1 integrin expression necessary for metastatic outgrowth. PMID- 21613544 TI - HOPS drives vacuole fusion by binding the vacuolar SNARE complex and the Vam7 PX domain via two distinct sites. AB - Membrane fusion within the endomembrane system follows a defined order of events: membrane tethering, mediated by Rabs and tethers, assembly of soluble N ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) complexes, and lipid bilayer mixing. Here we present evidence that the vacuolar HOPS tethering complex controls fusion through specific interactions with the vacuolar SNARE complex (consisting of Vam3, Vam7, Vti1, and Nyv1) and the N terminal domains of Vam7 and Vam3. We show that homotypic fusion and protein sorting (HOPS) binds Vam7 via its subunits Vps16 and Vps18. In addition, we observed that Vps16, Vps18, and the Sec1/Munc18 protein Vps33, which is also part of the HOPS complex, bind to the Q-SNARE complex. In agreement with this observation, HOPS-stimulated fusion was inhibited if HOPS was preincubated with the minimal Q-SNARE complex. Importantly, artificial targeting of Vam7 without its PX domain to membranes rescued vacuole morphology in vivo, but resulted in a cytokinesis defect if the N-terminal domain of Vam3 was also removed. Our data thus support a model of HOPS-controlled membrane fusion by recognizing different elements of the SNARE complex. PMID- 21613545 TI - The Caenorhabditis elegans GARP complex contains the conserved Vps51 subunit and is required to maintain lysosomal morphology. AB - In yeast the Golgi-associated retrograde protein (GARP) complex is required for tethering of endosome-derived transport vesicles to the late Golgi. It consists of four subunits--Vps51p, Vps52p, Vps53p, and Vps54p--and shares similarities with other multimeric tethering complexes, such as the conserved oligomeric Golgi (COG) and the exocyst complex. Here we report the functional characterization of the GARP complex in the nematode Caenorhabditis elegans. Furthermore, we identified the C. elegans Vps51 subunit, which is conserved in all eukaryotes. GARP mutants are viable but show lysosomal defects. We show that GARP subunits bind specific sets of Golgi SNAREs within the yeast two-hybrid system. This suggests that the C. elegans GARP complex also facilitates tethering as well as SNARE complex assembly at the Golgi. The GARP and COG tethering complexes may have overlapping functions for retrograde endosome-to-Golgi retrieval, since loss of both complexes leads to a synthetic lethal phenotype. PMID- 21613546 TI - A contractile actomyosin network linked to adherens junctions by Canoe/afadin helps drive convergent extension. AB - Integrating individual cell movements to create tissue-level shape change is essential to building an animal. We explored mechanisms of adherens junction (AJ):cytoskeleton linkage and roles of the linkage regulator Canoe/afadin during Drosophila germband extension (GBE), a convergent-extension process elongating the body axis. We found surprising parallels between GBE and a quite different morphogenetic movement, mesoderm apical constriction. Germband cells have an apical actomyosin network undergoing cyclical contractions. These coincide with a novel cell shape change--cell extension along the anterior-posterior (AP) axis. In Canoe's absence, GBE is disrupted. The apical actomyosin network detaches from AJs at AP cell borders, reducing coordination of actomyosin contractility and cell shape change. Normal GBE requires planar polarization of AJs and the cytoskeleton. Canoe loss subtly enhances AJ planar polarity and dramatically increases planar polarity of the apical polarity proteins Bazooka/Par3 and atypical protein kinase C. Changes in Bazooka localization parallel retraction of the actomyosin network. Globally reducing AJ function does not mimic Canoe loss, but many effects are replicated by global actin disruption. Strong dose-sensitive genetic interactions between canoe and bazooka are consistent with them affecting a common process. We propose a model in which an actomyosin network linked at AP AJs by Canoe and coupled to apical polarity proteins regulates convergent extension. PMID- 21613548 TI - Caspase activity is not required for the mitotic checkpoint or mitotic slippage in human cells. AB - Biochemical studies suggest that caspase activity is required for a functional mitotic checkpoint (MC) and mitotic slippage. To test this directly, we followed nontransformed human telomerase immortalized human retinal pigment epithelia (RPE 1) cells through mitosis after inhibiting or depleting selected caspases. We found that inhibiting caspases individually, in combination, or in toto did not affect the duration or fidelity of mitosis in otherwise untreated cells. When satisfaction of the MC was prevented with 500 nM nocodazole or 2.5 MUM dimethylenastron (an Eg5 inhibitor), 92-100% of RPE-1 cells slipped from mitosis in the presence of pan-caspase inhibitors or after simultaneously depleting caspase-3 and -9, and they did so with the same kinetics (~21-22 h) as after treatment with nocodazole or Eg5 inhibitors alone. Surprisingly, inhibiting or depleting caspase-9 alone doubled the number of nocodazole-treated, but not Eg5 inhibited, cells that died in mitosis. In addition, inhibiting or depleting caspase-9 and -3 together accelerated the rate of slippage ~40% (to ~13-15 h). Finally, nocodazole-treated cells that recently slipped through mitosis in the presence or absence of pan-caspase inhibitors contained numerous BubR1 foci in their nuclei. From these data, we conclude that caspase activity is not required for a functional MC or for mitotic slippage. PMID- 21613547 TI - Turnover of branched actin filament networks by stochastic fragmentation with ADF/cofilin. AB - Cell motility depends on the rapid assembly, aging, severing, and disassembly of actin filaments in spatially distinct zones. How a set of actin regulatory proteins that sustains actin-based force generation during motility work together in space and time remains poorly understood. We present our study of the distribution and dynamics of Arp2/3 complex, capping protein (CP), and actin depolymerizing factor (ADF)/cofilin in actin "comet tails," using a minimal reconstituted system with nucleation-promoting factor (NPF)-coated beads. The Arp2/3 complex concentrates at nucleation sites near the beads as well as in the first actin shell. CP colocalizes with actin and is homogeneously distributed throughout the comet tail; it serves to constrain the spatial distribution of ATP/ADP-P(i) filament zones to areas near the bead. The association of ADF/cofilin with the actin network is therefore governed by kinetics of actin assembly, actin nucleotide state, and CP binding. A kinetic simulation accurately validates these observations. Following its binding to the actin networks, ADF/cofilin is able to break up the dense actin filament array of a comet tail. Stochastic severing by ADF/cofilin loosens the tight entanglement of actin filaments inside the comet tail and facilitates turnover through the macroscopic release of large portions of the aged actin network. PMID- 21613549 TI - A system for imaging the regulatory noncoding Xist RNA in living mouse embryonic stem cells. AB - In mammals, silencing of one of the two X chromosomes in female cells compensates for the different number of X chromosomes between the sexes. The noncoding Xist RNA initiates X chromosome inactivation. Xist spreads from its transcription site over the X chromosome territory and triggers the formation of a repressive chromatin domain. To understand localization of Xist over one X chromosome we aimed to develop a system for investigating Xist in living cells. Here we report successful visualization of transgenically expressed MS2-tagged Xist in mouse embryonic stem cells. Imaging of Xist during an entire cell cycle shows that Xist spreads from a single point to a steady state when the chromosome is covered with a constant amount of Xist. Photobleaching experiments of the established Xist cluster indicate that chromosome-bound Xist is dynamic and turns over on the fully Xist covered chromosome. It appears that in interphase the loss of bound Xist and newly produced Xist are in equilibrium. We also show that the turnover of bound Xist requires transcription, and Xist binding becomes stable when transcription is inhibited. Our data reveal a strategy for visualizing Xist and indicate that spreading over the chromosome might involve dynamic binding and displacement. PMID- 21613550 TI - Phosphatidylinositol-(4,5)-bisphosphate regulates clathrin-coated pit initiation, stabilization, and size. AB - Clathrin-mediated endocytosis (CME) is the major mechanism for internalization in mammalian cells. CME initiates by recruitment of adaptors and clathrin to form clathrin-coated pits (CCPs). Nearly half of nascent CCPs abort, whereas others are stabilized by unknown mechanisms and undergo further maturation before pinching off to form clathrin-coated vesicles (CCVs). Phosphatidylinositol-(4,5) bisphosphate (PIP(2)), the main lipid binding partner of endocytic proteins, is required for CCP assembly, but little is currently known about its contribution(s) to later events in CCV formation. Using small interfering RNA (siRNA) knockdown and overexpression, we have analyzed the effects of manipulating PIP(2) synthesis and turnover on CME by quantitative total internal reflection fluorescence microscopy and computational analysis. Phosphatidylinositol-4-phosphate-5-kinase cannot be detected within CCPs but functions in initiation and controls the rate and extent of CCP growth. In contrast, the 5'-inositol phosphatase synaptojanin 1 localizes to CCPs and controls early stabilization and maturation efficiency. Together these results suggest that the balance of PIP(2) synthesis in the bulk plasma membrane and its local turnover within CCPs control multiple stages of CCV formation. PMID- 21613551 TI - Serum 25-hydroxyvitamin D concentrations are associated with prevalence of metabolic syndrome and various cardiometabolic risk factors in US children and adolescents based on assay-adjusted serum 25-hydroxyvitamin D data from NHANES 2001-2006. AB - BACKGROUND: The effect of assay drifts over time on serum 25-hydroxyvitamin D [25(OH)D] concentrations were not accounted for in previous national survey studies. Thus, previously reported associations between 25(OH)D with cardiometabolic risk factors using data from NHANES were likely over- or underestimated. Moreover, associations between serum 25(OH)D and metabolic syndrome (MetSyn), insulin resistance (IR), and inflammation are unclear in children. OBJECTIVE: The relation between serum 25(OH)D and cardiometabolic risk factors in US children was investigated by using updated 25(OH)D data. DESIGN: This study was based on newly updated serum 25(OH)D data, which were released by the National Center for Health Statistics in November 2010. Data from 3 cycles of NHANES (2001-2002, 2003-2004, and 2005-2006) for 5867 adolescents, aged 12-19 y, were used to study the association, by multivariate-adjusted regression, between serum 25(OH)D and prevalence of MetSyn and several cardiometabolic risk factors. RESULTS: The likelihood of having MetSyn was significantly higher in the first tertile of serum 25(OH)D than in the third tertile of 25(OH)D (odds ratio: 1.71; 95% CI: 1.11, 2.65; P < 0.01). Waist circumference (P < 0.0001), systolic blood pressure (P = 0.01), and homeostatic model assessment-insulin resistance index (P = 0.001) were inversely related and HDL cholesterol (P < 0.0001) was directly related with serum 25(OH)D. No association was observed between 25(OH)D and C reactive protein (P = 0.18). CONCLUSIONS: On the basis of assay-adjusted data, serum 25(OH)D was significantly associated with several cardiometabolic risk factors regardless of obesity. In children, given the negative outcomes associated with poor vitamin D status and MetSyn, consideration of vitamin D supplementation in reversing cardiometabolic risk factors appears to be warranted. PMID- 21613552 TI - Energy intake: reduced as prescribed? PMID- 21613553 TI - Association between yogurt, milk, and cheese consumption and common carotid artery intima-media thickness and cardiovascular disease risk factors in elderly women. AB - BACKGROUND: Despite the contribution of dairy foods to total dietary saturated fat intake, available data indicate that dairy consumption may lower the risk of cardiovascular disease. OBJECTIVE: The objective of this study was to investigate the relation between consumption of milk, cheese, and yogurt and common carotid artery intima-media thickness (CCA-IMT) in a cohort of elderly women. DESIGN: Dairy consumption was assessed with a validated food-frequency questionnaire in 1080 participants randomly selected from ambulant white women aged >70 y living in Perth, Western Australia. CCA-IMT was assessed by using B-mode carotid ultrasound 3 y later. Cardiovascular disease risk factors, including serum lipids and blood pressure, were assessed at baseline. RESULTS: Total dairy product, milk, and cheese consumption was not associated with CCA-IMT (P > 0.05), whereas yogurt consumption was negatively associated with CCA-IMT (unadjusted standardized beta = -0.081, P = 0.008; baseline risk factor-adjusted standardized beta = -0.075, P = 0.015). Participants who consumed >100 g yogurt/d had a significantly lower CCA-IMT than did participants with lower consumption (unadjusted = -0.024 mm, P = 0.002). This relation remained significant after adjustment for baseline, dietary, and lifestyle risk factors (multivariable analysis = -0.023 mm, P = 0.003). CONCLUSION: Increased consumption of yogurt, but not of other dairy products, is associated with a lower CCA-IMT, independent of other risk factors. PMID- 21613554 TI - Effects of weight loss on serum vitamin D in postmenopausal women. AB - BACKGROUND: Low concentrations of circulating vitamin D are common with obesity and may represent a potential mechanism explaining the elevated risk of certain cancers and cardiovascular outcomes observed in individuals who are overweight or obese. OBJECTIVE: The objective of this study was to investigate the effects of 12 mo of weight loss through caloric restriction, exercise intervention, or both on serum 25-hydroxyvitamin D [25(OH)D] concentrations. DESIGN: Overweight and obese postmenopausal women (n = 439) were randomly assigned to 1 of 4 groups: 1) diet modification (n = 118), 2) exercise (n = 117), 3) diet + exercise (n = 117), or 4) control (n = 87). The diet intervention was a group-based reduced-calorie program with a 10% weight-loss goal. The exercise intervention consisted of 45 min of moderate-to-vigorous intensity aerobic activity daily for 5 d/wk. Serum 25(OH)D concentrations were measured by using a competitive chemiluminescent immunoassay at baseline and 12 mo. RESULTS: No significant change in serum 25(OH)D was found between the intervention and control groups. Women who lost <5%, 5-9.9%, 10-14.9%, or >=15% of baseline weight had mean increases in 25(OH)D of 2.1, 2.7, 3.3, and 7.7 ng/mL, respectively (P for trend = 0.002). Baseline vitamin D status did not modify the effect of the interventions on weight loss or body-composition changes at the 12-mo follow-up. CONCLUSION: A greater degree of weight loss, achieved through either a reduced-calorie diet or increased exercise, is associated with increased circulating 25(OH)D concentrations. This trial is registered at clinicaltrials.gov as NCT00470119. PMID- 21613555 TI - Fatty fish in the diet of patients with type 2 diabetes: comparison of the metabolic effects of foods rich in n-3 and n-6 fatty acids. AB - BACKGROUND: Dietary advice, including modification of dietary fat quality, is the basis of treatment of diabetes, but there is some uncertainty about the optimal amount of polyunsaturated fatty acids of the n-6 (omega-6) and n-3 (omega-3) series. OBJECTIVE: The objective was to compare the effects of diets rich in n-3 or n-6 fatty acids on glucose and lipoprotein metabolism in type 2 diabetes. DESIGN: In a crossover study during 2 consecutive 3.5-wk periods, the participants were provided diets with identical nutrient compositions containing either a high proportion of n-3 (n-3 diet) or n-6 (n-6 diet) fatty acids through the inclusion of fatty fish or lean fish and fat containing linoleic acid, respectively. RESULTS: Blood glucose concentrations at fasting and during the day were lower with the n-6 than with the n-3 diet (P = 0.009 and P = 0.029, respectively), and the area under the insulin curve during the day was significantly higher (P = 0.03) with the n-6 diet. Both diets showed similar effects on insulin sensitivity and plasminogen activator inhibitor 1 concentrations. The reductions in VLDLs and serum apolipoprotein B concentrations were more pronounced after the n-3 diet. CONCLUSIONS: The risk related to the moderately higher blood glucose concentrations with the n-3-enriched diet may be counteracted by positive effects with regard to lipoprotein concentrations. An increase in long-chain n-3 fatty acids from fatty fish, and of n-6 fatty acids from linoleic acid, may be recommended for patients with type 2 diabetes. PMID- 21613556 TI - Early growth and coronary heart disease and type 2 diabetes: findings from the Helsinki Birth Cohort Study (HBCS). AB - A slow rate of intrauterine growth is a major risk factor for several common noncommunicable diseases, which include the following: coronary heart disease (CHD), hypertension, and type 2 diabetes. Likewise, growth patterns in infancy and childhood have been identified as important factors linked to the pathogenesis of these disorders. In this overview, patterns of growth associated with CHD, type 2 diabetes, and related metabolic traits in adult life are presented on the basis of findings from the Helsinki Birth Cohort Study (HBCS) 1934-1944. Later risk of CHD was associated with small body size at birth and during infancy, followed by an increase in body size later in childhood. This pattern of growth has been associated with dyslipidemia in later life, which offers an explanation for the observed findings. Type 2 diabetes and CHD share several risk factors. The early growth of persons who later develop type 2 diabetes includes a small body size at birth as well as a small body size during infancy. An early age at adiposity rebound was associated with a markedly increased risk of type 2 diabetes in adulthood. The patterns of growth associated with type 2 diabetes are also associated with alterations in body composition, which predisposes to insulin resistance and the metabolic syndrome. The presented findings suggest that to be able to understand the pathogenesis of several noncommunicable diseases, the diseases need to be studied from a life-course perspective, and prenatal and childhood growth as well as adult characteristics need to be taken into account. PMID- 21613557 TI - Alternative Healthy Eating Index and mortality over 18 y of follow-up: results from the Whitehall II cohort. AB - BACKGROUND: Indexes of diet quality have been shown to be associated with decreased risk of mortality in several countries. It remains unclear if the Alternative Healthy Eating Index (AHEI), designed to provide dietary guidelines to combat major chronic diseases, is related to mortality risk. OBJECTIVE: We aimed to examine the association between adherence to the AHEI and cause-specific mortality over 18 y of follow-up in a British working population. DESIGN: Analyses are based on 7319 participants (mean age: 49.5 y; range: 39-63 y; 30.3% women) from the Whitehall II Study. Cox proportional hazards regression models were performed to analyze associations of the AHEI (scored on the basis of intake of 9 components: vegetables, fruit, nuts and soy, white or red meat, trans fat, polyunsaturated or saturated fat, fiber, multivitamin use, and alcohol) with mortality risk. RESULTS: After potential confounders were controlled for, participants in the top compared with the bottom third of the AHEI score showed 25% lower all-cause mortality [hazard ratio (HR): 0.76; 95% CI: 0.61, 0.95] and >40% lower mortality from cardiovascular disease (CVD; HR: 0.58; 95% CI: 0.37, 0.91). Consumption of nuts and soy and moderate alcohol intake appeared to be the most important independent contributors to decreased mortality risk. The AHEI was not associated with cancer mortality or noncancer/non-CVD mortality. CONCLUSION: Our findings suggest that the encouragement of adherence to the AHEI dietary recommendations constitutes a valid and clear public health recommendation that would decrease the risk of premature death from CVD. PMID- 21613558 TI - Serum 25-hydroxyvitamin D concentrations in relation to cardiometabolic risk factors and metabolic syndrome in postmenopausal women. AB - BACKGROUND: Low concentrations of serum 25-hydroxyvitamin D [25(OH)D] may be associated with cardiometabolic disorders; however, little is known about their relation to intermediate metabolic and lipid markers. OBJECTIVE: We investigated the relation of serum 25(OH)D concentrations to fasting insulin, glucose, dyslipidemia, adiposity, and prevalent metabolic syndrome. DESIGN: We conducted this cross-sectional analysis in 292 postmenopausal women aged 50-79 y in the Women's Health Initiative Calcium-Vitamin D (WHI-CaD) trial. Data were collected from 3 nested case-control studies that measured baseline serum 25(OH)D concentrations. Inverse probability weighting was used to approximate parameter estimates for the WHI-CaD population. RESULTS: In weighted linear regression models adjusted for age, race-ethnicity, month of blood draw, region, case control status, smoking, alcohol, physical activity, and history of cardiometabolic risk factors, there was an inverse association of serum 25(OH)D with adiposity [body mass index (BMI): beta = -1.12 +/- 0.30, P = 0.0002; waist circumference: beta = -3.57 +/- 0.49, P < 0.0001; waist-hip ratio: beta = -0.01 +/- 0.002, P < 0.0001], triglycerides (beta = -0.10 +/- 0.02, P < 0.0001), and triglyceride:HDL-cholesterol ratio (beta = -0.11 +/- 0.03, P = 0.0003). The multivariable-adjusted odds ratio for metabolic syndrome for the highest (>=52 nmol/L) compared with the lowest (<35 nmol/L) tertile of serum 25(OH)D concentrations was 0.28 (95% CI: 0.14, 0.56). Significant associations remained after adjustment for BMI. We observed no significant associations with LDL cholesterol, HDL cholesterol, insulin, glucose, homeostatic model assessment of insulin resistance (HOMA-IR), or homeostatic model assessment of beta cell function (HOMA-beta). CONCLUSION: Higher serum 25(OH)D concentrations may be inversely associated with adiposity, triglycerides, triglyceride:HDL-cholesterol ratio, and metabolic syndrome but are not associated with LDL and HDL cholesterol, insulin, glucose, HOMA-IR, or HOMA-beta in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00000611. PMID- 21613559 TI - Metabolic responses to prolonged consumption of glucose- and fructose-sweetened beverages are not associated with postprandial or 24-h glucose and insulin excursions. AB - BACKGROUND: Consumption of sugar-sweetened beverages has been shown to be associated with dyslipidemia, insulin resistance, fatty liver, diabetes, and cardiovascular disease. It has been proposed that adverse metabolic effects of chronic consumption of sugar-sweetened beverages are a consequence of increased circulating glucose and insulin excursions, ie, dietary glycemic index (GI). OBJECTIVE: We determined whether the greater adverse effects of fructose than of glucose consumption were associated with glucose and insulin exposures. DESIGN: The subjects were studied in a metabolic facility and consumed energy-balanced diets containing 55% of energy as complex carbohydrate for 2 wk (GI = 64). The subjects then consumed 25% of energy requirements as fructose- or glucose sweetened beverages along with their usual ad libitum diets for 8 wk at home and then as part of energy-balanced diets for 2 wk at the metabolic facility (fructose GI = 38, glucose GI = 83). The 24-h glucose and insulin profiles and fasting plasma glycated albumin and fructosamine concentrations were measured 0, 2, 8, and 10 wk after beverage consumption. RESULTS: Consumption of fructose sweetened beverages lowered glucose and insulin postmeal peaks and the 23-h area under the curve compared with the baseline diet and with the consumption of glucose-sweetened beverages (all P < 0.001, effect of sugar). Plasma glycated albumin concentrations were lower 10 wk after fructose than after glucose consumption (P < 0.01, effect of sugar), whereas fructosamine concentrations did not differ between groups. CONCLUSION: The results suggest that the specific effects of fructose, but not of glucose and insulin excursions, contribute to the adverse effects of consuming sugar-sweetened beverages on lipids and insulin sensitivity. This study is registered at clinicaltrials.gov as NCT01165853. PMID- 21613560 TI - Role of oxidative stress and antioxidant supplementation in pregnancy disorders. AB - Oxidative stress is widely implicated in failed reproductive performance, including infertility, miscarriage, diabetes-related congenital malformations, and preeclampsia. Maternal obesity is a strong risk factor for preeclampsia, and in a recent study we observed oxidative stress in the oocytes of obese animals before pregnancy as well as in early-stage embryos. This adds to the growing evidence that investigators need to focus more on the preconceptual period in efforts to prevent pregnancy disorders, including those related to oxidative stress. Our research has also focused on the role of free radicals and antioxidant capacity in preeclampsia. By measuring markers of lipid peroxidation and antioxidant capacity, we obtained unequivocal evidence for oxidative stress in this disorder. Partial failure of the process of placentation has been implicated, and recent findings suggest that ischemia-reperfusion in the placenta may contribute to oxidative stress in trophoblasts. Endoplasmic reticulum stress in the placenta may also play a role. Randomized controlled trials have been conducted by our group as well as others to determine whether early supplementation with vitamins C and E in women at risk of preeclampsia is beneficial, but these trials have shown no evidence that these supplements can prevent preeclampsia. Whether this indicates that an inappropriate antioxidant strategy was used or supplementation was administered too late in gestation to be beneficial is not known. Other potential approaches for preventing preeclampsia through amelioration of oxidative stress include the use of supplements in the preconceptual period, selenium supplements, antiperoxynitrite strategies, and statins. PMID- 21613561 TI - No consistent association between consumption of energy-dense snack foods and annual weight and waist circumference changes in Dutch adults. AB - BACKGROUND: There is conflicting evidence regarding an association between the consumption of energy-dense snack (EDS) foods and the development of overweight. OBJECTIVE: In the current study, we examined whether there was an association between the intake of EDS foods and annual weight and waist circumference changes in normal-weight and overweight Dutch adults. DESIGN: The study population included 9383 men and women from the MORGEN-EPIC (Monitoring Project on Risk Factors for Chronic Diseases in the Netherlands-European Prospective Investigation into Cancer and Nutrition) study, which is a population-based cohort study in 3 towns in the Netherlands (Amsterdam, Maastricht, and Doetinchem), who had a body mass index (in kg/m(2)) <30 and who were not dieting. Participants were enrolled between 1993 and 1997 and followed for an average of 8.1 y (Amsterdam and Maastricht: 9.9 y; Doetinchem: 4.9 y). Intake of EDS foods (sweets, cakes and pastries, and savory snacks) was assessed at baseline by using a validated food-frequency questionnaire. Multivariate linear and multinomial logistic regression models were applied and stratified by center to examine the association between energy from EDS foods (kcal) and annual weight and waist circumference changes. RESULTS: The mean (+/-SD) daily energy intake from EDS foods was 294 +/- 192 kcal. In Amsterdam and Maastricht, the annual weight change was 168 +/- 572 g/y, whereas in Doetinchem, the annual weight change was 444 +/- 816 g/y. In the multivariate regression analysis adjusted for follow-up duration and anthropometric, dietary, and lifestyle factors, there was some, but inconsistent, evidence of an association of EDS-food consumption with annual weight change. CONCLUSION: Our study provides some, but inconsistent, evidence that consumption of EDS foods is positively associated with an increase in annual weight in normal- to overweight Dutch adults. PMID- 21613562 TI - Diet quality and the risk of cardiovascular disease: the Women's Health Initiative (WHI). AB - BACKGROUND: The association between diet quality and risk of incident cardiovascular disease (CVD) or heart failure (HF) in postmenopausal women is uncertain. OBJECTIVE: This study aimed to determine whether a conventional index [Alternate Healthy Eating Index (AHEI)] or a novel index [Women's Health Initiative (WHI) Dietary Modification Index (DMI)] of diet quality was associated with the risk of incident CVD or HF in the WHI Observational Study (WHI-OS). DESIGN: The WHI-OS is an observational cohort study of 93,676 women aged 50-79 y of diverse ethnicity and backgrounds followed for an average of 10.0 y for CVD events. The individual components of the AHEI and DMI were determined from the baseline WHI food-frequency questionnaire. Incident CVD was a composite of nonfatal myocardial infarction, coronary heart disease death, stroke, coronary revascularization, and incident HF. The association between AHEI or DMI and incident CVD or incident HF was determined by using Cox models adjusted for traditional CVD and HF risk factors. RESULTS: Women with a DMI in the highest quintile had hazard ratios (HRs) of 0.88 (95% CI: 0.80, 0.95) and 0.91 (95% CI: 0.78, 1.06) for incident CVD and HF, respectively. Women with an AHEI in the highest quintile had HRs of 0.77 (95% CI: 0.70, 0.84) and 0.70 (95% CI: 0.59, 0.82) for incident CVD and HF, respectively. CONCLUSION: Overall, adherence to current nutrient guidelines (as indexed by the DMI) are associated with lower total CVD risk, and additional dietary factors (as indexed by the AHEI) were associated with a lower risk of CVD and HF. PMID- 21613564 TI - Emotional reinforcement as a protective factor for healthy eating in home settings. AB - BACKGROUND: According to the literature, meals consumed at home are healthier than those consumed away from home (AFH), but reasons underlying this protective effect have not been fully understood. Emotional reinforcement of healthy eating patterns at home is examined as a putative contributing mechanism. OBJECTIVE: This study examined expectations for within-individual emotional reinforcement of healthy eating at home, reflected in reports of 1) more intense positive and less intense negative affects after healthier meals than at baseline at home (and not in AFH settings) and 2) more intense positive and less intense negative affects reported before a meal being predictive of healthier meals than at baseline at home (and not in AFH settings). DESIGN: A total of 160 nonobese women reported their eating behavior and momentary emotional states every 2 h, 6 times/d over 10 observation days. We examined observations with meals (breakfast, lunch, or dinner). The participants indicated how momentary eating patterns compared with their own baseline eating patterns (healthier, equal, or less healthy). Concurrent (after meal) and lagged (before meal) emotion scores were specified. RESULTS: At-home meals were followed by more intense positive emotions and less worry than were AFH meals. As expected, home meals that were healthier than a person's baseline meals were followed by more intense positive emotions, with a relation of opposite direction being observed in AFH settings. At home, more intense premeal positive emotions cued healthier next-meal eating patterns than did those at baseline, with no such relation being observed in AFH settings. CONCLUSION: The home is a privileged environment that nurtures healthy eating and in which healthier food choices trigger and are triggered by more positive emotions. PMID- 21613563 TI - Effect of dietary and lifestyle factors on the risk of gestational diabetes: review of epidemiologic evidence. AB - Gestational diabetes mellitus (GDM), defined as glucose intolerance with onset or first recognition in pregnancy, is a common pregnancy complication and a growing health concern. GDM has been related to significant short-term and long-term adverse health outcomes for both mothers and offspring. Importantly, this number is increasing with the increasing burden of obesity among women of reproductive age. Collectively, these data highlight the significance of understanding risk factors, in particular modifiable factors, for GDM and of preventing GDM among high-risk populations. Research in the past decade has identified a few diet and lifestyle factors that are associated with GDM risk. This review provides an overview of emerging diet and lifestyle factors that may contribute to the prevention of GDM. It also discusses major methodologic concerns about the available epidemiologic studies of GDM risk factors. PMID- 21613566 TI - Calcium-dependent dynamics of cadherin interactions at cell-cell junctions. AB - Cadherins play a key role in the dynamics of cell-cell contact formation and remodeling of junctions and tissues. Cadherin-cadherin interactions are gated by extracellular Ca(2+), which serves to rigidify the cadherin extracellular domains and promote trans junctional interactions. Here we describe the direct visualization and quantification of spatiotemporal dynamics of N-cadherin interactions across intercellular junctions in living cells using a genetically encodable FRET reporter system. Direct measurements of transjunctional cadherin interactions revealed a sudden, but partial, loss of homophilic interactions (tau = 1.17 +/- 0.06 s(-1)) upon chelation of extracellular Ca(2+). A cadherin mutant with reduced adhesive activity (W2A) exhibited a faster, more substantial loss of homophilic interactions (tau = 0.86 +/- 0.02 s(-1)), suggesting two types of native cadherin interactions--one that is rapidly modulated by changes in extracellular Ca(2+) and another with relatively stable adhesive activity that is Ca(2+) independent. The Ca(2+)-sensitive dynamics of cadherin interactions were transmitted to the cell interior where beta-catenin translocated to N-cadherin at the junction in both cells. These data indicate that cadherins can rapidly convey dynamic information about the extracellular environment to both cells that comprise a junction. PMID- 21613567 TI - Alternative mechanism for bacteriophage adsorption to the motile bacterium Caulobacter crescentus. AB - 2D and 3D cryo-electron microscopy, together with adsorption kinetics assays of Cb13 and CbK phage-infected Caulobacter crescentus, provides insight into the mechanisms of infection. Cb13 and CbK actively interact with the flagellum and subsequently attach to receptors on the cell pole. We present evidence that the first interaction of the phage with the bacterial flagellum takes place through a filament on the phage head. This contact with the flagellum facilitates concentration of phage particles around the receptor (i.e., the pilus portals) on the bacterial cell surface, thereby increasing the likelihood of infection. Phage head filaments have not been well characterized and their function is described here. Phage head filaments may systematically underlie the initial interactions of phages with their hosts in other systems and possibly represent a widespread mechanism of efficient phage propagation. PMID- 21613568 TI - Programmed induction of endoreduplication by DNA double-strand breaks in Arabidopsis. AB - Genome integrity is continuously threatened by external stresses and endogenous hazards such as DNA replication errors and reactive oxygen species. The DNA damage checkpoint in metazoans ensures genome integrity by delaying cell-cycle progression to repair damaged DNA or by inducing apoptosis. ATM and ATR (ataxia telangiectasia-mutated and -Rad3-related) are sensor kinases that relay the damage signal to transducer kinases Chk1 and Chk2 and to downstream cell-cycle regulators. Plants also possess ATM and ATR orthologs but lack obvious counterparts of downstream regulators. Instead, the plant-specific transcription factor SOG1 (suppressor of gamma response 1) plays a central role in the transmission of signals from both ATM and ATR kinases. Here we show that in Arabidopsis, endoreduplication is induced by DNA double-strand breaks (DSBs), but not directly by DNA replication stress. When root or sepal cells, or undifferentiated suspension cells, were treated with DSB inducers, they displayed increased cell size and DNA ploidy. We found that the ATM-SOG1 and ATR-SOG1 pathways both transmit DSB-derived signals and that either one suffices for endocycle induction. These signaling pathways govern the expression of distinct sets of cell-cycle regulators, such as cyclin-dependent kinases and their suppressors. Our results demonstrate that Arabidopsis undergoes a programmed endoreduplicative response to DSBs, suggesting that plants have evolved a distinct strategy to sustain growth under genotoxic stress. PMID- 21613569 TI - Intrinsic disorder in measles virus nucleocapsids. AB - The genome of measles virus is encapsidated by multiple copies of the nucleoprotein (N), forming helical nucleocapsids of molecular mass approaching 150 Megadalton. The intrinsically disordered C-terminal domain of N (N(TAIL)) is essential for transcription and replication of the virus via interaction with the phosphoprotein P of the viral polymerase complex. The molecular recognition element (MoRE) of N(TAIL) that binds P is situated 90 amino acids from the folded RNA-binding domain (N(CORE)) of N, raising questions about the functional role of this disordered chain. Here we report the first in situ structural characterization of N(TAIL) in the context of the entire N-RNA capsid. Using nuclear magnetic resonance spectroscopy, small angle scattering, and electron microscopy, we demonstrate that N(TAIL) is highly flexible in intact nucleocapsids and that the MoRE is in transient interaction with N(CORE). We present a model in which the first 50 disordered amino acids of N(TAIL) are conformationally restricted as the chain escapes to the outside of the nucleocapsid via the interstitial space between successive N(CORE) helical turns. The model provides a structural framework for understanding the role of N(TAIL) in the initiation of viral transcription and replication, placing the flexible MoRE close to the viral RNA and, thus, positioning the polymerase complex in its functional environment. PMID- 21613570 TI - Probing osmolyte participation in the unfolding transition state of a protein. AB - Understanding the molecular mechanisms of osmolyte protection in protein stability has proved to be challenging. In particular, little is known about the role of osmolytes in the structure of the unfolding transition state of a protein, the main determinant of its dynamics. We have developed an experimental protocol to directly probe the transition state of a protein in a range of osmolyte environments. We use an atomic force microscope in force-clamp mode to apply mechanical forces to the protein I27 and obtain force-dependent rate constants of protein unfolding. We measure the distance to the unfolding transition state, Deltax(u), along a 1D reaction coordinate imposed by mechanical force. We find that for the small osmolytes, ethylene glycol, propylene glycol, and glycerol, Deltax(u) scales with the size of the molecule, whereas for larger osmolytes, sorbitol and sucrose, Deltax(u) remains the same as that measured in water. These results are in agreement with steered molecular dynamics simulations that show that small osmolytes act as solvent bridges in the unfolding transition state structure, whereas only water molecules act as solvent bridges in large osmolyte environments. These results demonstrate that novel force protocols combined with solvent substitution can directly probe angstrom changes in unfolding transition state structure. This approach creates new opportunities to gain molecular level understanding of the action of osmolytes in biomolecular processes. PMID- 21613571 TI - Wavelength dependence of ultraviolet radiation-induced DNA damage as determined by laser irradiation suggests that cyclobutane pyrimidine dimers are the principal DNA lesions produced by terrestrial sunlight. AB - To elucidate the involvement of specific ultraviolet (UV) wavelengths in solar mutagenesis, we used a laser system to investigate the induction of DNA damage, both in the overall genome and at the nucleotide resolution level, in the genomic DNA of transgenic Big Blue mouse fibroblasts irradiated with a series of UV wavelengths, inclusive of UVC (lambda<280 nm), UVB (lambda=280-320 nm), and UVA (lambda>320 nm). Subsequently, we sought correlation between the locations of UV induced DNA lesions in the cII transgene of irradiated DNA samples and the frequency distribution and codon position of the induced cII mutations in counterpart mouse cells irradiated with simulated sunlight. Using a combination of enzymatic digestion assays coupled with gel electrophoresis, immunodot blot assays, and DNA footprinting assays, we demonstrated a unique wavelength dependent formation of photodimeric lesions, i.e., cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts [(6-4)PPs], based on direct UV absorption of DNA, in irradiated mouse genomic DNA, which could partially explain the induction of mutations in mouse cells irradiated with simulated sunlight. Most notably, there was a divergence of CPD and (6-4)PP formation at an irradiation wavelength of 296 nm in mouse genomic DNA. Whereas substantial formation of (6-4)PPs was detectable in samples irradiated at this wavelength, which intensified as the irradiation wavelength decreased, only small quantities of these lesions were found in samples irradiated at wavelengths of 300-305 nm, with no detectable level of (6 4)PPs in samples irradiated with longer wavelengths. Although CPD formation followed the same pattern of increase with decreasing wavelengths of irradiation, there were substantial levels of CPDs in samples irradiated with UVB wavelengths borderlined with UVA, and small but detectable levels of these lesions in samples irradiated with longer wavelengths. Because the terrestrial sunlight spectrum rolls off sharply at wavelengths ~300 nm, our findings suggest that CPDs are the principal lesion responsible for most DNA damage-dependent biological effects of sunlight. PMID- 21613572 TI - Long-term synthesis rates of skeletal muscle DNA and protein are higher during aerobic training in older humans than in sedentary young subjects but are not altered by protein supplementation. AB - Consuming protein following exercise has been shown to stimulate protein synthesis acutely in skeletal muscle and has been recommended to prevent sarcopenia. It is not known, however, whether acute stimulation persists long term or includes muscle cell division. We asked here whether consuming protein following exercise during aerobic training increases long-term protein and DNA synthesis rates in skeletal muscle of adult humans. Sixteen previously untrained participants (50 +/- 8 yr) consumed either a carbohydrate or carbohydrate and protein drink following each session during 6 wk of treadmill training. A younger untrained group provided a nonexercising comparison. Participants were administered heavy water (2H2O; deuterium oxide) continuously for 6 wk to isotopically label newly synthesized skeletal muscle proteins and DNA. Muscle biopsies were performed after 6 wk of training. Contrary to acute studies, consuming protein after exercise did not increase skeletal muscle protein synthesis rates. In contrast, muscle protein synthesis, DNA, and phospholipid synthesis were significantly higher in the older exercise groups than the younger sedentary group. The higher DNA replication rate could not be attributed to mitochondrial DNA and may be due to satellite cell activation. We conclude that postexercise protein supplementation does not increase rates of mixed protein synthesis over 6 wk and that aerobic exercise may stimulate long-term cell division (DNA synthesis) in skeletal muscle of humans. Measurements of long-term synthesis rates provide important insights into aging and exercise adaptations. PMID- 21613573 TI - Structural analysis of vascular endothelial growth factor receptor-2/ligand complexes by small-angle X-ray solution scattering. AB - Receptor tyrosine kinases play essential roles in tissue development and homeostasis, and aberrant signaling by these molecules is the basis of many diseases. Understanding the activation mechanism of these receptors is thus of high clinical relevance. We investigated vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs), which regulate blood and lymph vessel formation. We analyzed the structural changes in the extracellular receptor domain that were induced by ligand binding and that represent the initial step in transmembrane signaling, culminating in the activation of the intracellular receptor kinase domain. High-resolution structural information for the ligand binding domain became available recently, but the flexibility of the extracellular domain and inhomogeneous glycosylation of VEGFRs have prevented the production of highly diffracting crystals of the entire extracellular domain so far. Therefore, we chose to further investigate VEGFR structure by small-angle X ray scattering in solution (SAXS). SAXS data were combined with independent distance restraint determination obtained by mass spectrometric analysis of chemically cross-linked ligand/receptor complexes. With these data, we constructed a structural model of the entire extracellular receptor domain in the unbound form and in complex with VEGF. PMID- 21613574 TI - beta-Adrenergic receptor blockade blunts postexercise skeletal muscle mitochondrial protein synthesis rates in humans. AB - beta-Adrenergic receptor (AR) signaling is a regulator of skeletal muscle protein synthesis and mitochondrial biogenesis in mice. We hypothesized that beta-AR blockade blunts postexercise skeletal muscle mitochondrial protein synthesis rates in adult humans. Six healthy men (mean +/- SD: 26 +/- 6 yr old, 39.9 +/- 4.9 ml.kg(-1).min(-1) peak O(2) uptake, 26.7 +/- 2.0 kg/m(2) body mass index) performed 1 h of stationary cycle ergometer exercise (60% peak O(2) uptake) during 1) beta-AR blockade (intravenous propranolol) and 2) administration of saline (control). Skeletal muscle mitochondrial, myofibrillar, and sarcoplasmic protein synthesis rates were assessed using [(2)H(5)]phenylalanine incorporation into skeletal muscle proteins after exercise. The mRNA content of signals for mitochondrial biogenesis was determined using real-time PCR. beta-AR blockade decreased mitochondrial (from 0.217 +/- 0.076 to 0.135 +/- 0.031%/h, P < 0.05), but not myofibrillar or sarcoplasmic, protein synthesis rates. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha mRNA was increased ~2.5 fold (P < 0.05) at 5 h compared with 1 h postexercise but was not influenced by beta-AR blockade. We conclude that decreased beta-AR signaling during cycling can blunt the postexercise increase in mitochondrial protein synthesis rates without affecting mRNA content. PMID- 21613575 TI - Thermotolerance and heat acclimation may share a common mechanism in humans. AB - Thermotolerance and heat acclimation are key adaptation processes that have been hitherto viewed as separate phenomena. Here, we provide evidence that these processes may share a common basis, as both may potentially be governed by the heat shock response. We evaluated the effects of a heat shock response-inhibitor (quercetin; 2,000 mg/day) on established markers of thermotolerance [gastrointestinal barrier permeability, plasma TNF-alpha, IL-6, and IL-10 concentrations, and leukocyte heat shock protein 70 (HSP70) content]. Heat acclimation reduced body temperatures, heart rate, and physiological strain during exercise/heat stress) in male subjects (n = 8) completing a 7-day heat acclimation protocol. These same subjects completed an identical protocol under placebo supplementation (placebo). Gastrointestinal barrier permeability and TNF alpha were increased on the 1st day of exercise/heat stress in quercetin; no differences in these variables were reported in placebo. Exercise HSP70 responses were increased, and plasma cytokines (IL-6, IL-10) were decreased on the 7th day of heat acclimation in placebo; with concomitant reductions in exercise body temperatures, heart rate, and physiological strain. In contrast, gastrointestinal barrier permeability remained elevated, HSP70 was not increased, and IL-6, IL-10, and exercise body temperatures were not reduced on the 7th day of heat acclimation in quercetin. While exercise heart rate and physiological strain were reduced in quercetin, this occurred later in exercise than with placebo. Consistent with the concept that thermotolerance and heat acclimation are related through the heat shock response, repeated exercise/heat stress increases cytoprotective HSP70 and reduces circulating cytokines, contributing to reductions in cellular and systemic markers of heat strain. Exercising under a heat shock response-inhibitor prevents both cellular and systemic heat adaptations. PMID- 21613576 TI - Maternal vasodilation in pregnancy: the emerging role of relaxin. AB - Pregnancy is a unique physiological condition of profound maternal renal and systemic vasodilation. Our goal has been to unveil the reproductive hormones mediating this remarkable vasodilatory state and the underlying molecular mechanisms. In addition to advancing our knowledge of pregnancy physiology, reaching this goal may translate into therapeutics for pregnancy pathologies such as preeclampsia and for diseases associated with vasoconstriction and arterial stiffness in nonpregnant women and men. An emerging player is the 6 kDa corpus luteal hormone relaxin, which circulates during pregnancy. Relaxin administration to rats and humans induces systemic and renal vasodilation regardless of sex, thus mimicking the pregnant condition. Immunoneutralization or elimination of the source of circulating relaxin prevents renal and systemic vasodilation in midterm pregnant rats. Infertile women who become pregnant by donor eggs (IVF with embryo transfer) lack a corpus luteum and circulating relaxin, and they show a markedly subdued gestational increase in glomerular filtration rate. These data implicate relaxin as one of the vasodilatory reproductive hormones of pregnancy. There are different molecular mechanisms underlying the so-called rapid and sustained vasodilatory actions of relaxin. The former is mediated by Galpha(i/o) protein coupling to phosphatidylinositol-3 kinase/Akt (protein kinase B)-dependent phosphorylation and activation of endothelial nitric oxide synthase, the latter by vascular endothelial and placental growth factors, and increases in arterial gelatinase(s) activity. The gelatinases, in turn, hydrolyze big endothelin (ET) at a gly-leu bond to form ET(1-32), which activates the endothelial ET(B) receptor/nitric oxide vasodilatory pathway. PMID- 21613577 TI - Preference of IRES-mediated initiation of translation during hibernation in golden-mantled ground squirrels, Spermophilus lateralis. AB - Mammalian hibernation involves virtual cessation of energetically consumptive processes normally vital to homeostasis, including gene transcription and protein synthesis. As animals enter torpor, the bulk of initiation of translation is blocked at a body temperature of 18 degrees C in golden-mantled ground squirrels [Spermophilus (Callospermophilus) lateralis]. Previous data demonstrated regulation of cap-dependent initiation of translation during torpor. We asked what happens to cap-independent, specifically, internal ribosome entry site (IRES)-mediated initiation of translation during hibernation. We analyzed polysome fractions for mRNAs that are known to contain or not to contain IRES elements. Here, we show that mRNAs harboring IRES elements preferentially associate with ribosomes as a torpor bout progresses. Squirrels allowed to naturally complete a torpor cycle have a higher IRES preference index than those animals that are prematurely aroused from torpor. Data indicate that this change in preference is not associated with gene expression, i.e., change is due to change in mRNA association with ribosomes as opposed to mRNA abundance. Thus, although processes like transcription and translation are virtually arrested during torpor, ribosomes are preferentially loaded with IRES-containing transcripts when squirrels arouse from torpor and translation resumes. Differential translation of preexisting mRNAs may allow for the preferential production of key stress proteins critical for survival of physiological insults that are lethal to other mammals. PMID- 21613578 TI - Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats. AB - Although it is well established that the renal endothelin (ET-1) system plays an important role in regulating sodium excretion and blood pressure through activation of renal medullary ET(B) receptors, the role of this system in Dahl salt-sensitive (DS) hypertension is unclear. The purpose of this study was to determine whether the DS rat has abnormalities in the renal medullary endothelin system when maintained on a high sodium intake. The data indicate that Dahl salt resistant rats (DR) on a high-salt diet had a six-fold higher urinary endothelin excretion than in the DR rats with low Na(+) intake (17.8 +/- 4 pg/day vs. 112 +/ 44 pg/day). In sharp contrast, urinary endothelin levels increased only twofold in DS rats in response to a high Na(+) intake (13 +/- 2 pg/day vs. 29.8 +/- 5.5 pg/day). Medullary endothelin concentration in DS rats on a high-Na(+) diet was also significantly lower than DR rats on a high-Na(+) diet (31 +/- 2.8 pg/mg vs. 70.9 +/- 5 pg/mg). Furthermore, DS rats had a significant reduction in medullary ET(B) receptor expression compared with DR rats while on a high-Na(+) diet. Finally, chronic infusion of ET-1 directly into the renal medulla blunted Dahl salt-sensitive hypertension. These data indicate that a decrease in medullary production of ET-1 in the DS rat could play an important role in the development of salt-sensitive hypertension observed in the DS rat. PMID- 21613579 TI - Evidence for NHE3-mediated Na transport in sheep and bovine forestomach. AB - Na absorption across the cornified, multilayered, and squamous rumen epithelium is mediated by electrogenic amiloride-insensitive transport and by electroneutral Na transport. High concentrations of amiloride (>100 MUM) inhibit Na transport, indicating Na(+)/H(+) exchange (NHE) activity. The underlying NHE isoform for transepithelial Na absorption was characterized by mucosal application of the specific inhibitor HOE642 for NHE1 and S3226 for NHE3 in Ussing chamber studies with isolated epithelia from bovine and sheep forestomach. S3226 (1 MUM; NHE3 inhibitor) abolished electroneutral Na transport under control conditions and also the short-chain fatty acid-induced increase of Na transport via NHE. However, HOE642 (30 MUM; NHE1 inhibitor) did not change Na transport rates. NHE3 was immunohistochemically localized in membranes of the upper layers toward the lumen. Expression of NHE1 and NHE3 has been previously demonstrated by RT-PCR, and earlier experiments with isolated rumen epithelial cells have shown the activity of both NHE1 and NHE3. Obviously, both isoforms are involved in the regulation of intracellular pH, pH(i). However, transepithelial Na transport is only mediated by apical uptake via NHE3 in connection with extrusion of Na by the basolaterally located Na-K-ATPase. The missing involvement of NHE1 in transepithelial Na transport suggests that the proposed "job sharing" in epithelia between these two isoforms probably also applies to forestomach epithelia: NHE3 for transepithelial transport and NHE1 for, among others, pH(i) and volume regulation. PMID- 21613580 TI - P2Y2 receptor activation decreases blood pressure and increases renal Na+ excretion. AB - ATP and UTP are endogenous agonists of P2Y(2/4) receptors. To define the in vivo effects of P2Y(2) receptor activation on blood pressure and urinary excretion, we compared the response to INS45973, a P2Y(2/4) receptor agonist and UTP analog, in wild-type (WT) and P2Y(2) receptor knockout (P2Y(2)-/-) mice. INS45973 was administered intravenously as a bolus injection or continuous infusion to determine effects on blood pressure and renal function, respectively. Within seconds, bolus application of INS45973 (0.1 to 3 mg/kg body wt) dose-dependently decreased blood pressure in WT (maximum response -35 +/- 2 mmHg) and to a similar extent in endothelial nitric oxide synthase knockout mice. By contrast, blood pressure increased in P2Y(2)-/- (maximum response +18 +/- 1 mmHg) but returned to basal levels within 60 s. Continuous infusion of INS45973 (25 to 750 MUg.min( 1).kg(-1) body wt) dose-dependently increased urinary excretion of Na(+) in WT (maximum response +46 +/- 15%) but reduced Na(+) excretion in P2Y(2)-/- (maximum responses of -45 +/- 15%) mice. In renal clearance experiments, INS45973 did not affect glomerular filtration rate but lowered blood pressure and increased fractional excretion of fluid, Na(+), and K(+) in WT relative to P2Y(2)-/- mice. The blood pressure responses to INS45973 are consistent with P2Y(2) receptor mediated NO-independent vasodilation and implicate responses to endothelium derived hyperpolarizing factor, and P2Y(2) receptor-independent vasoconstriction, probably via activation of P2Y(4) receptors on smooth muscle. Systemic activation of P2Y(2) receptors thus lowers blood pressure and inhibits renal Na(+) reabsorption, effects suggesting the potential utility of P2Y(2) agonism in the treatment of hypertension. PMID- 21613581 TI - Three-dimensional localization of neurons in cortical tetrode recordings. AB - The recording radius and spatial selectivity of an extracellular probe are important for interpreting neurophysiological recordings but are rarely measured. Moreover, an analysis of the recording biophysics of multisite probes (e.g., tetrodes) can provide for source characterization and localization of spiking single units, but this capability has remained largely unexploited. Here we address both issues quantitatively. Advancing a tetrode (~40-MUm contact separation, tetrahedral geometry) in 5- to 10-MUm steps, we repeatedly recorded extracellular action potentials (EAPs) of single neurons in the visual cortex. Using measured spatial variation of EAPs, the tetrodes' measured geometry, and a volume conductor model of the cortical tissue, we solved the inverse problem of estimating the location and the size of the equivalent dipole model of the spike generator associated with each neuron. Half of the 61 visual neurons were localized within a radius of ~100 MUm and 95% within ~130 MUm around the tetrode tip (i.e., a large fraction was much further than previously thought). Because of the combined angular sensitivity of the tetrode's leads, location uncertainty was less than one-half the cell's distance. We quantified the spatial dependence of the probability of cell isolation, the isolated fraction, and the dependence of the recording radius on probe size and equivalent dipole size. We also reconstructed the spatial configuration of sets of simultaneously recorded neurons to demonstrate the potential use of 3D dipole localization for functional anatomy. Finally, we found that the dipole moment vector, surprisingly, tended to point toward the probe, leading to the interpretation that the equivalent dipole represents a "local lobe" of the dendritic arbor. PMID- 21613582 TI - Optogenetic analysis of GABAB receptor signaling in Caenorhabditis elegans motor neurons. AB - In the nervous system, a perfect balance of excitation and inhibition is required, for example, to enable coordinated locomotion. In Caenorhabditis elegans, cholinergic and GABAergic motor neurons (MNs) effect waves of contralateral muscle contraction and relaxation. Cholinergic MNs innervate muscle as well as GABAergic MNs, projecting to the opposite side of the body, at dyadic synapses. Only a few connections exist from GABAergic to cholinergic MNs, emphasizing that GABA signaling is mainly directed toward muscle. Yet, a GABA(B) receptor comprising GBB-1 and GBB-2 subunits, expressed in cholinergic MNs, was shown to affect locomotion, likely by feedback inhibition of cholinergic MNs in response to spillover GABA. In the present study, we examined whether the GBB-1/2 receptor could also affect short-term plasticity in cholinergic MNs with the use of channelrhodopsin-2-mediated photostimulation of GABAergic and cholinergic neurons. The GBB-1/2 receptor contributes to acute body relaxation, evoked by photoactivation of GABAergic MNs, and to effects of GABA on locomotion behavior. Loss of the plasma membrane GABA transporter SNF-11, as well as acute photoevoked GABA release, affected cholinergic MN function in opposite directions. Prolonged stimulation of GABA MNs had subtle effects on cholinergic MNs, depending on stimulus duration and gbb-2. Thus GBB-1/2 receptors serve mainly for linear feedback inhibition of cholinergic MNs but also evoke minor plastic changes. PMID- 21613583 TI - Receptive field center size decreases and firing properties mature in ON and OFF retinal ganglion cells after eye opening in the mouse. AB - Development of the mammalian visual system is not complete at birth but continues postnatally well after eye opening. Although numerous studies have revealed changes in the development of the thalamus and visual cortex during this time, less is known about the development of response properties of retinal ganglion cells (RGCs). Here, we mapped functional receptive fields of mouse RGCs using a Gaussian white noise checkerboard stimulus and a multielectrode array to record from retinas at eye opening, 3 days later, and 4 wk after birth, when visual responses are essentially mature. Over this time, the receptive field center size of ON and OFF RGC populations decreased. The average receptive field center size of ON RGCs was larger than that of OFF RGCs at eye opening, but they decreased to the same size in the adult. Firing properties were also immature at eye opening. RGCs had longer latencies, lower frequencies of firing, and lower sensitivity than in the adult. Hence, the dramatic maturation of the visual system during the first weeks of visual experience includes the retina. PMID- 21613585 TI - Attention to baseline: does orienting visuospatial attention really facilitate target detection? AB - Standard protocols testing the orientation of visuospatial attention usually present spatial cues before targets and compare valid-cue trials with invalid-cue trials. The valid/invalid contrast results in a relative behavioral or physiological difference that is generally interpreted as a benefit of attention orientation. However, growing evidence suggests that inhibitory control of response is closely involved in this kind of protocol that requires the subjects to withhold automatic responses to cues, probably biasing behavioral and physiological baselines. Here, we used two experiments to disentangle the inhibitory control of automatic responses from orienting of visuospatial attention in a saccadic reaction time task in humans, a variant of the classical cue-target detection task and a sustained visuospatial attentional task. Surprisingly, when referring to a simple target detection task in which there is no need to refrain from reacting to avoid inappropriate responses, we found no consistent evidence of facilitation of target detection at the attended location. Instead, we observed a cost at the unattended location. Departing from the classical view, our results suggest that reaction time measures of visuospatial attention probably relie on the attenuation of elementary processes involved in visual target detection and saccade initiation away from the attended location rather than on facilitation at the attended location. This highlights the need to use proper control conditions in experimental designs to disambiguate relative from absolute cueing benefits on target detection reaction times, both in psychophysical and neurophysiological studies. PMID- 21613584 TI - mGluR1, but not mGluR5, activates feed-forward inhibition in the medial prefrontal cortex to impair decision making. AB - Cognitive flexibility depends on the integrity of the prefrontal cortex (PFC). We showed previously that impaired decision making in pain results from amygdala driven inhibition of medial PFC neurons, but the underlying mechanisms remain to be determined. Using whole cell patch clamp in rat brain slices and a cognitive behavioral task, we tested the hypothesis that group I metabotropic glutamate receptors (mGluRs) activate feed-forward inhibition to decrease excitability and output function of PFC pyramidal cells, thus impairing decision making. Polysynaptic inhibitory postsynaptic currents (IPSCs) and monosynaptic excitatory postsynaptic currents (EPSCs) were evoked in layer V pyramidal cells by stimulating presumed amygdala afferents. An mGluR1/5 agonist [(S)-3,5 dihydroxyphenylglycine, DHPG] increased synaptic inhibition more strongly than excitatory transmission. The facilitatory effects were blocked by an mGluR1 [(S) (+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid, LY367385], but not mGluR5, antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine. IPSCs were blocked by bicuculline and decreased by 2,3-dioxo-6-nitro-1,2,3,4 tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt (NBQX). Facilitation of synaptic inhibition by DHPG was glutamate driven because it was blocked by NBQX. DHPG increased frequency but not amplitude of spontaneous IPSCs; consistent with action potential-dependent synaptic inhibition, tetrodotoxin (TTX) prevented the facilitatory effects. DHPG decreased synaptically evoked spikes (E-S coupling) and depolarization-induced spiking [frequency-current (f-I) relationship]. This effect was indirect, resulting from glutamate-driven synaptic inhibition, because it persisted when a G protein blocker was included in the pipette but was blocked by GABA(A) receptor antagonists and NBQX. In contrast, DHPG increased E-S coupling and f-I relationships in mPFC interneurons through a presynaptic action, further supporting the concept of feed-forward inhibition. DHPG also impaired the ability of the animals to switch strategies in a decision-making task; bicuculline restored normal decision making, whereas a GABA(A) receptor agonist (muscimol) mimicked the decision-making deficit. The results show that mGluR1 activates feed-forward inhibition of PFC pyramidal cells to impair cognitive functions. PMID- 21613586 TI - Motor preparation of spatially and temporally defined movements: evidence from startle. AB - Previous research has shown that the preparation of a spatially targeted movement performed at maximal speed is different from that of a temporally constrained movement (Gottlieb et al. 1989b). In the current study, we directly examined preparation differences in temporally vs. spatially defined movements through the use of a startling stimulus and manipulation of the task goals. Participants performed arm extension movements to one of three spatial targets (20 degrees , 40 degrees , 60 degrees ) and an arm extension movement of 20 degrees at three movement speeds (slow, moderate, fast). All movements were performed in a blocked, simple reaction time paradigm, with trials involving a startling stimulus (124 dB) interspersed randomly with control trials. As predicted, spatial movements were modulated by agonist duration and timed movements were modulated by agonist rise time. The startling stimulus triggered all movements at short latencies with a compression of the kinematic and electromyogram (EMG) profile such that they were performed faster than control trials. However, temporally constrained movements showed a differential effect of movement compression on startle trials such that the slowest movement showed the greatest temporal compression. The startling stimulus also decreased the relative timing between EMG bursts more for the 20 degrees movement when it was defined by a temporal rather than spatial goal, which we attributed to the disruption of an internal timekeeper for the timed movements. These results confirm that temporally defined movements were prepared in a different manner from spatially defined movements and provide new information pertaining to these preparation differences. PMID- 21613587 TI - Role of local field potentials in encoding hand movement kinematics. AB - How the brain orchestrates the musculoskeletal system to produce complex three dimensional movements is still poorly understood. Despite first promising results in brain-machine interfaces that translate cortical activity to control output, there is an ongoing debate about which brain signals provide richest information related to movement planning and execution. Novel results by Bansal and colleagues (2011) now suggest that neuronal spiking and local field potentials jointly encode kinematics during skilled reach and grasp movements. PMID- 21613588 TI - An inexpensive drivable cannulated microelectrode array for simultaneous unit recording and drug infusion in the same brain nucleus of behaving rats. AB - Neurons are functionally segregated into discrete populations that perform specific computations. These computations, mediated by neuron-neuron electrochemical signaling, form the neural basis of behavior. Thus fundamental to a brain-based understanding of behavior is the precise determination of the contribution made by specific neurotransmitters to behaviorally relevant neural activity. To facilitate this understanding, we have developed a cannulated microelectrode array for use in behaving rats that enables simultaneous neural ensemble recordings and local infusion of drugs in the same brain nucleus. The system is inexpensive, easy to use, and produces robust and quantitatively reproducible drug effects on recorded neurons. PMID- 21613590 TI - Prism adaptation and generalization during visually guided locomotor tasks. AB - The ability of individuals to adapt locomotion to constraints associated with the complex environments normally encountered in everyday life is paramount for survival. Here, we tested the ability of 24 healthy young adults to adapt to a rightward prism shift (~11.3 degrees ) while either walking and stepping to targets (i.e., precision stepping task) or stepping over an obstacle (i.e., obstacle avoidance task). We subsequently tested for generalization to the other locomotor task. In the precision stepping task, we determined the lateral end point error of foot placement from the targets. In the obstacle avoidance task, we determined toe clearance and lateral foot placement distance from the obstacle before and after stepping over the obstacle. We found large, rightward deviations in foot placement on initial exposure to prisms in both tasks. The majority of measures demonstrated adaptation over repeated trials, and adaptation rates were dependent mainly on the task. On removal of the prisms, we observed negative aftereffects for measures of both tasks. Additionally, we found a unilateral symmetric generalization pattern in that the left, but not the right, lower limb indicated generalization across the 2 locomotor tasks. These results indicate that the nervous system is capable of rapidly adapting to a visuomotor mismatch during visually demanding locomotor tasks and that the prism-induced adaptation can, at least partially, generalize across these tasks. The results also support the notion that the nervous system utilizes an internal model for the control of visually guided locomotion. PMID- 21613589 TI - Fine frequency tuning in monkey auditory cortex and thalamus. AB - The frequency resolution of neurons throughout the ascending auditory pathway is important for understanding how sounds are processed. In many animal studies, the frequency tuning widths are about 1/5th octave wide in auditory nerve fibers and much wider in auditory cortex neurons. Psychophysical studies show that humans are capable of discriminating far finer frequency differences. A recent study suggested that this is perhaps attributable to fine frequency tuning of neurons in human auditory cortex (Bitterman Y, Mukamel R, Malach R, Fried I, Nelken I. Nature 451: 197-201, 2008). We investigated whether such fine frequency tuning was restricted to human auditory cortex by examining the frequency tuning width in the awake common marmoset monkey. We show that 27% of neurons in the primary auditory cortex exhibit frequency tuning that is finer than the typical frequency tuning of the auditory nerve and substantially finer than previously reported cortical data obtained from anesthetized animals. Fine frequency tuning is also present in 76% of neurons of the auditory thalamus in awake marmosets. Frequency tuning was narrower during the sustained response compared to the onset response in auditory cortex neurons but not in thalamic neurons, suggesting that thalamocortical or intracortical dynamics shape time-dependent frequency tuning in cortex. These findings challenge the notion that the fine frequency tuning of auditory cortex is unique to human auditory cortex and that it is a de novo cortical property, suggesting that the broader tuning observed in previous animal studies may arise from the use of anesthesia during physiological recordings or from species differences. PMID- 21613591 TI - The locomotor central pattern generator of the rat spinal cord in vitro is optimally activated by noisy dorsal root waveforms. AB - The spinal cord contains an intrinsic locomotor program driven by a central pattern generator that rhythmically activates flexor and extensor limb motor pools. Although long-lasting locomotor activity can be generated pharmacologically, trains of afferent stimuli trigger only few locomotor cycles. The present study investigated whether a new electrical stimulation protocol (termed FListim) could elicit long-lasting fictive locomotion (FL) in the rat spinal cord in vitro. Thus, after first inducing FL by bath application of N methyl-d-aspartate and serotonin, the recorded waveform obtained from a lumbar ventral root was digitized and then applied to either a lumbar dorsal root or the cauda equina following washout of pharmacological agents. Two FListim cycles were the threshold input to evoke an episode of FL from ventral roots. Longer cycles (up to 1 min) induced sustained FL (up to 1 min) with stereotyped periodicity (2.2 +/- 0.5 s), despite changing frequency (2-4 s) or cycle amplitude of FListim. Gradual filtering out of the noise from FListim trace concomitantly decreased the efficiency of FL so that stimulation with equivalent pure sinusoids produced asynchronous, irregular discharges only that could not be converted to FL by adding spontaneous basal activity. This study is the first demonstration that epochs of rhythmic locomotor-like oscillations applied to a dorsal root represent an efficient stimulus to evoke FL as long as they contain the electrophysiological noise produced within FL cycles. These observations suggest novel strategies to improve the efficiency of electrical stimulation delivered by clinical devices for neurorehabilitation after spinal injury. PMID- 21613592 TI - Click-evoked responses in vestibular afferents in rats. AB - Sound activates not only the cochlea but also the vestibular end organs. Research on this phenomenon led to the discovery of the sound-evoked vestibular myogenic potentials recorded from the sternocleidomastoid muscles (cervical VEMP, or cVEMP). Since the cVEMP offers simplicity and the ability to stimulate each labyrinth separately, its values as a test of human vestibular function are widely recognized. Currently, the cVEMP is interpreted as a test of saccule function based on the assumption that clicks primarily activate the saccule. However, sound activation of vestibular end organs other than the saccule has been reported. To provide the neural basis for interpreting clinical VEMP testing, we employed the broadband clicks used in clinical VEMP testing to examine the sound-evoked responses in a large sample of vestibular afferents in Sprague-Dawley rats. Recordings were made from 924 vestibular afferents from 106 rats: 255 from the anterior canal (AC), 202 from the horizontal canal (HC), 177 from the posterior canal (PC), 207 from the superior vestibular nerve otolith (SO), and 83 from the inferior nerve otolith (IO). Sound sensitivity of each afferent was quantified by computing the cumulative probability of evoking a spike (CPE). We found that clicks activated irregular afferents (normalized coefficient of variation of interspike intervals >0.2) from both the otoliths (81%) and the canals (43%). The order of end organ sound sensitivity was SO = IO > AC > HC > PC. Since the sternocleidomastoid motoneurons receive inputs from both the otoliths and the canals, these results provide evidence of a possible contribution from both of them to the click-evoked cVEMP. PMID- 21613593 TI - Statistical assessment of the stability of neural movement representations. AB - In systems neuroscience, neural activity that represents movements or sensory stimuli is often characterized by spatial tuning curves that may change in response to training, attention, altered mechanics, or the passage of time. A vital step in determining whether tuning curves change is accounting for estimation uncertainty due to measurement noise. In this study, we address the issue of tuning curve stability using methods that take uncertainty directly into account. We analyze data recorded from neurons in primary motor cortex using chronically implanted, multielectrode arrays in four monkeys performing center out reaching. With the use of simulations, we demonstrate that under typical experimental conditions, the effect of neuronal noise on estimated preferred direction can be quite large and is affected by both the amount of data and the modulation depth of the neurons. In experimental data, we find that after taking uncertainty into account using bootstrapping techniques, the majority of neurons appears to be very stable on a timescale of minutes to hours. Lastly, we introduce adaptive filtering methods to explicitly model dynamic tuning curves. In contrast to several previous findings suggesting that tuning curves may be in constant flux, we conclude that the neural representation of limb movement is, on average, quite stable and that impressions to the contrary may be largely the result of measurement noise. PMID- 21613594 TI - Active and passive movement are encoded equally by head direction cells in the anterodorsal thalamus. AB - The head direction (HD) system is composed of cells that represent the direction in which the animal's head is facing. Each HD cell responds optimally when the head is pointing in a particular, or preferred, direction. Although vestibular system input is necessary to generate the directional signal, motor/proprioceptive inputs can also influence HD cell responses. Previous studies comparing active and passive movement have reported significant suppression of the HD signal during passive restraint. However, in each of these studies there was considerable variability across cells, and the animal's head was never completely fixed. To address these issues, we developed a passive restraint system that more fully prevented head and body movement. HD cell responses in the anterodorsal thalamus (ADN) were evaluated during active and passive movement with this new system. Contrary to previous reports, HD cell responses were not affected by passive restraint. Both head-fixed and hand-held restraint failed to produce significant inhibition of the active HD cell response. Furthermore, direction-specific firing was maintained regardless of 1) the animal's previous experience with restraint, 2) whether it was tested in the light or dark, or 3) the position of the animal relative to the axis of rotation. The maintenance of a stable directional signal without appropriate motor, proprioceptive, or visual input indicates that vestibular input is necessary and sufficient for the generation of the HD signal. Motor and proprioceptive influences may therefore be important for the control of the preferred firing direction of HD cells, but not the generation of the signal itself. PMID- 21613595 TI - Distinct maturation profiles of perisomatic and dendritic targeting GABAergic interneurons in the mouse primary visual cortex during the critical period of ocular dominance plasticity. AB - In the rodent primary visual cortex, maturation of GABA inhibitory circuitry is regulated by visual input and contributes to the onset and progression of ocular dominance (OD) plasticity. Cortical inhibitory circuitry consists of diverse groups of GABAergic interneurons, which display distinct physiological properties and connectivity patterns. Whether different classes of interneurons mature with similar or distinct trajectories and how their maturation profiles relate to experience dependent development are not well understood. We used green fluorescent protein reporter lines to study the maturation of two broad classes of cortical interneurons: parvalbumin-expressing (PV) cells, which are fast spiking and innervate the soma and proximal dendrites, and somatostatin expressing (SOM) cells, which are regular spiking and target more distal dendrites. Both cell types demonstrate extensive physiological maturation, but with distinct trajectories, from eye opening to the peak of OD plasticity. Typical fast-spiking characteristics of PV cells became enhanced, and synaptic signaling from PV to pyramidal neurons became faster. SOM cells demonstrated a large increase in input resistance and a depolarization of resting membrane potential, resulting in increased excitability. While the substantial maturation of PV cells is consistent with the importance of this source of inhibition in triggering OD plasticity, the significant increase in SOM cell excitability suggests that dendrite-targeted inhibition may also play a role in OD plasticity. More generally, these results underscore the necessity of cell type-based analysis and demonstrate that distinct classes of cortical interneurons have markedly different developmental profiles, which may contribute to the progressive emergence of distinct functional properties of cortical circuits. PMID- 21613596 TI - A ketogenic diet reduces long-term potentiation in the dentate gyrus of freely behaving rats. AB - Ketogenic diets are very low in carbohydrates and can reduce epileptic seizures significantly. This dietary therapy is particularly effective in pediatric and drug-resistant epilepsy. Hypothesized anticonvulsant mechanisms of ketogenic diets focus on increased inhibition and/or decreased excitability/excitation. Either of these consequences might not only reduce seizures, but also could affect normal brain function and synaptic plasticity. Here, we characterized effects of a ketogenic diet on hippocampal long-term potentiation, a widely studied form of synaptic plasticity. Adult male rats were placed on a control or ketogenic diet for 3 wk before recording. To maintain the most physiological conditions possible, we assessed synaptic transmission and plasticity using chronic in vivo recordings in freely behaving animals. Rats underwent stereotaxic surgery to chronically implant a recording electrode in the hippocampal dentate gyrus and a stimulating electrode in the perforant path; they recovered for 1 wk. After habituation and stable baseline recording, 5-Hz theta-burst stimulation was delivered to induce long-term potentiation. All animals showed successful plasticity, demonstrating that potentiation was not blocked by the ketogenic diet. Compared with rats fed a control diet, rats fed a ketogenic diet demonstrated significantly diminished long-term potentiation. This decreased potentiation lasted for at least 48 h. Reduced potentiation in ketogenic diet-fed rats is consistent with a general increase in neuronal inhibition (or decrease in excitability) and decreased seizure susceptibility. A better understanding of the effects of ketogenic diets on synaptic plasticity and learning is important, as diet-based therapy is often prescribed to children with epilepsy. PMID- 21613598 TI - Predicting the development of multiple sclerosis: is gray matter a missing piece of the puzzle? PMID- 21613597 TI - Probing for hemispheric specialization for motor skill learning: a transcranial direct current stimulation study. AB - Convergent findings point to a left-sided specialization for the representation of learned actions in right-handed humans, but it is unknown whether analogous hemispheric specialization exists for motor skill learning. In the present study, we explored this question by comparing the effects of anodal transcranial direct current stimulation (tDCS) over either left or right motor cortex (M1) on motor skill learning in either hand, using a tDCS montage to better isolate stimulation to one hemisphere. Results were compared with those previously found with a montage more commonly used in the field. Six groups trained for three sessions on a visually guided sequential pinch force modulation task with their right or left hand and received right M1, left M1, or sham tDCS. A linear mixed-model analysis for motor skill showed a significant main effect for stimulation group (left M1, right M1, sham) but not for hand (right, left) or their interaction. Left M1 tDCS induced significantly greater skill learning than sham when hand data were combined, a result consistent not only with the hypothesized left hemisphere specialization for motor skill learning but also with possible increased left M1 responsiveness to tDCS. The unihemispheric montage effect size was one-half that of the more common montage, and subsequent power analysis indicated that 75 subjects per group would be needed to detect differences seen with only 12 subjects with the customary bihemispheric montage. PMID- 21613599 TI - Long-term efficacy of sodium oxybate in 4 patients with chronic cluster headache. AB - BACKGROUND: Cluster headache (CH) manifests with periodic attacks of severe unilateral pain and autonomic symptoms. Nocturnal attacks may cause severe sleep disruption. In about 10%of cases, patients present with a chronic form (CCH), which is often medically intractable. Few attempts have been made to improve headache via pharmacologic modulation of sleep. METHODS: In an open-label study, 4 patients with CCH and disturbed sleep received increasing dosages of sodium oxybate (SO), a compound known to consolidate sleep and to increase slow-wave sleep. Response to SO was monitored by serial polysomnography, and actimetry, along with pain and sleep diaries. RESULTS: SO was effective in all 4 patients as shown by an immediate reduction in frequency (up to 90%) and intensity (>50%) of nocturnal pain attacks and improved sleep quality. These effects were long lasting in 3 patients (mean 19 months, range 12-29 months) and transient (for 8 months) in one patient. Long-lasting improvement of daytime headaches was achieved with a latency of weeks in 2 patients. SO was safe, with mild to moderate adverse effects (dizziness, vomiting, amnesia, weight loss). CONCLUSION: SO may represent a new treatment option to reduce nocturnal and diurnal pain attacks and improve sleep quality in CCH. These data also suggest the interest of treating primary headache syndromes by sleep-manipulating substances. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that oral SO at night improves sleep and reduces the intensity and frequency of headaches in patients with CCH. PMID- 21613600 TI - The predictive value of gray matter atrophy in clinically isolated syndromes. AB - BACKGROUND: Although gray matter (GM) atrophy is recognized as a common feature of multiple sclerosis (MS), conflicting results have been obtained in patients with clinically isolated syndromes (CIS). Methodologic and clinical constraints may take account for literature discrepancies. METHODS: A total of 105 patients presenting with CIS and 42 normal controls (NC) were studied. At baseline, 65/105 patients with CIS met the criterion of dissemination in space of lesions (DIS+). All patients were clinically assessed by means of the Expanded Disability Status Scale every 6 months and underwent MRI evaluation at study entry and then annually for 4 years. Global and regional cortical thickness and deep GM atrophy were assessed using Freesurfer. RESULTS: No significant reduction in GM atrophy was observed between the entire CIS group and the NC, excepting for the cerebellum cortical volume. When the 59 patients with CIS (46 DIS+, 13 DIS-) who converted to MS during the follow-up were compared to the NC, a significant atrophy in the precentral gyrus, superior frontal gyrus, thalamus, and putamen was observed (p ranging from 0.05 to 0.001). The multivariate analysis identified the atrophy of superior frontal gyrus, thalamus, and cerebellum as independent predictors of conversion to MS. CIS with atrophy of such areas had a double risk of conversion compared to DIS+ (odds ratio 9.6 vs 5.0). CONCLUSION: Selective GM atrophy is relevant in patients with CIS who convert early to MS. The inclusion of GM analysis in the MS diagnostic workup is worthy of further investigation. PMID- 21613601 TI - Postural imbalance and falls in PSP correlate with functional pathology of the thalamus. AB - OBJECTIVE: To determine how postural imbalance and falls are related to regional cerebral glucose metabolism (PET) and functional activation of the cerebral postural network (fMRI) in patients with progressive supranuclear palsy (PSP). METHODS: Sixteen patients with PSP, who had self-monitored their frequency of falls, underwent a standardized clinical assessment, posturographic measurement of balance during modified sensory input, and a resting [18F]FDG-PET. In addition, patients performed an fMRI paradigm using mental imagery of standing. Results were compared to healthy controls (n = 16). RESULTS: The frequency of falls/month in patients (range 1-40) correlated with total PSP rating score (r = 0.90). Total sway path in PSP significantly correlated with frequency of falls, especially during modulated sensory input (eyes open: r = 0.62, eyes closed: r = 0.67, eyes open/head extended: r = 0.84, eyes open/foam-padded platform: r = 0.87). Higher sway path values and frequency of falls were associated with decreased regional glucose metabolism (rCGM) in the thalamus (sway path: r = 0.80, falls: r = -0.64) and increased rCGM in the precentral gyrus (sway path: r = 0.79, falls: r = 0.64). Mental imagery of standing during fMRI revealed a reduced activation of the mesencephalic brainstem tegmentum and the thalamus in patients with postural imbalance and falls. CONCLUSIONS: The new and clinically relevant finding of this study is that imbalance and falls in PSP are closely associated with thalamic dysfunction. Deficits in thalamic postural control get most evident when balance is assessed during modified sensory input. The results are consistent with the hypothesis that reduced thalamic activation via the ascending brainstem projections may cause postural imbalance in PSP. PMID- 21613602 TI - Localizing imbalance in progressive supranuclear palsy: is the thalamus the "fall guy"? PMID- 21613603 TI - Targeting sleep disruption using sodium oxybate in chronic cluster headache prophylaxis. PMID- 21613605 TI - Calcium-dependent inhibition of adrenal TREK-1 channels by angiotensin II and ionomycin. AB - Bovine adrenocortical cells express bTREK-1 K(+) (bovine KCNK2) channels that are inhibited by ANG II through a Gq-coupled receptor by separate Ca(2+) and ATP hydrolysis-dependent signaling pathways. Whole cell and single patch clamp recording from adrenal zona fasciculata (AZF) cells were used to characterize Ca(2+)-dependent inhibition of bTREK-1. In whole cell recordings with pipette solutions containing 0.5 mM EGTA and no ATP, the Ca(2+) ionophore ionomycin (1 MUM) produced a transient inhibition of bTREK-1 that reversed spontaneously within minutes. At higher concentrations, ionomycin (5-10 MUM) produced a sustained inhibition of bTREK-1 that was reversible upon washing, even in the absence of hydrolyzable [ATP](i). BAPTA was much more effective than EGTA at suppressing bTREK-1 inhibition by ANG II. When intracellular Ca(2+) concentration ([Ca(2+)](i)) was buffered to 20 nM with either 11 mM BAPTA or EGTA, ANG II (10 nM) inhibited bTREK-1 by 12.0 +/- 4.5% (n=11) and 59.3 +/- 8.4% (n=4), respectively. Inclusion of the water-soluble phosphatidylinositol 4,5 bisphosphate (PIP(2)) analog DiC(8)PI(4,5)P(2) in the pipette failed to increase bTREK-1 expression or reduce its inhibition by ANG II. The open probability (P(o)) of unitary bTREK-1 channels recorded from inside-out patches was reduced by Ca(2+) (10-35 MUM) in a concentration-dependent manner. These results are consistent with a model in which ANG II inhibits bTREK-1 K(+) channels by a Ca(2+)-dependent mechanism that does not require the depletion of membrane associated PIP(2). They further indicate that the Ca(2+) source is located in close proximity within a "Ca(2+) nanodomain" of bTREK-1 channels, where [Ca(2+)](i) may reach concentrations of >10 MUM. bTREK-1 is the first two-pore K(+) channel shown to be inhibited by Ca(2+) through activation of a G protein coupled receptor. PMID- 21613606 TI - Similar effects of all WNK3 variants on SLC12 cotransporters. AB - With-no-lysine kinase 3 (WNK3) is a member of a subfamily of serine/threonine kinases that modulate the activity of the electroneutral cation-coupled chloride cotransporters. WNK3 activates NKCC1/2 and NCC and inhibits the KCCs. Four splice variants are generated from the WNK3 gene. Our previous studies focused on the WNK3-18a variant. However, it has been suggested that other variants could have different effects on the cotransporters. Thus, the present study was designed to define the effects of all WNK3 variants on members of the SLC12 family. By RT-PCR from a fetal brain library, exons 18b and 22 were separately amplified and subcloned into the original WNK3-18a or catalytically inactive WNK3-D294A to obtain all four potential combinations with and without catalytic activity (18a, 18a+22, 18b, and 18b+22). The basal activity of the cotransporters and the effects of WNK3 isoforms were assessed in Xenopus laevis oocytes coinjected with each of the WNK3 variant cRNAs. In isotonic conditions, the basal activity of NCC and NKCC1/2 were increased by coinjection with any of the WNK3. The positive effects occurred even in hypotonic conditions, in which the basal activity of NKCC1 is completely prevented. Consistent with these observations, when expressed in hypotonicity, all KCCs were active, but in the presence of any of the WNK3 variants, KCC activity was completely reduced. That is, NKCC1/2 and NCC were inhibited, even in hypertonicity, while KCCs were activated, even in isotonic conditions. We conclude that the effects of all WNK3 variants toward SLC12 proteins are similar. PMID- 21613604 TI - Hypertonic stress induces rapid and widespread protein damage in C. elegans. AB - Proteostasis is defined as the homeostatic mechanisms that maintain the function of all cytoplasmic proteins. We recently demonstrated that the capacity of the proteostasis network is a critical factor that defines the limits of cellular and organismal survival in hypertonic environments. The current studies were performed to determine the extent of protein damage induced by cellular water loss. Using worm strains expressing fluorescently tagged foreign and endogenous proteins and proteins with temperature-sensitive point mutations, we demonstrate that hypertonic stress causes aggregation and misfolding of diverse proteins in multiple cell types. Protein damage is rapid. Aggregation of a polyglutamine yellow fluorescent protein reporter is observable with <1 h of hypertonic stress, and aggregate volume doubles approximately every 10 min. Aggregate formation is irreversible and occurs after as little as 10 min of exposure to hypertonic conditions. To determine whether endogenous proteins are aggregated by hypertonic stress, we quantified the relative amount of total cellular protein present in detergent-insoluble extracts. Exposure for 4 h to 400 mM or 500 mM NaCl induced a 55-120% increase in endogenous protein aggregation. Inhibition of insulin signaling or acclimation to mild hypertonic stress increased survival under extreme hypertonic conditions and prevented aggregation of endogenous proteins. Our results demonstrate that hypertonic stress causes widespread and dramatic protein damage and that cells have a significant capacity to remodel the network of proteins that function to maintain proteostasis. These findings have important implications for understanding how cells cope with hypertonic stress and other protein-damaging stressors. PMID- 21613607 TI - Reconstitution of lysosomal NAADP-TRP-ML1 signaling pathway and its function in TRP-ML1(-/-) cells. AB - It is well known that the mutation of TRP-ML1 (transient receptor potential mucolipin-1) causes mucolipidosis IV, a lysosomal storage disease. Given that lysosomal nicotinic acid adenine dinucleotide phosphate (NAADP)-Ca(2+) release channel activity is associated with TRP-ML1, the present study was designed to test the hypothesis that NAADP regulates lysosome function via activation of TRP ML1 channel activity. Using lysosomal preparations from wild-type (TRP-ML1(+/+)) human fibroblasts, channel reconstitution experiments demonstrated that NAADP (0.01-1.0 MUM) produced a concentration-dependent increase in TRP-ML1 channel activity. This NAADP-induced activation of TRP-ML1 channels could not be observed in lysosomes from TRP-ML1(-/-) cells, but was restored by introducing a TRP-ML1 transgene into these cells. Microscopic Ca(2+) fluorescence imaging showed that NAADP significantly increased intracellular Ca(2+) concentration to 302.4 +/- 74.28 nM (vs. 180 +/- 44.13 nM of the basal) in TRP-ML1(+/+) cells, but it had no effect in TRP-ML1(-/-) cells. If a TRP-ML1 gene was transfected into TRP-ML1(-/-) cells, the Ca(2+) response to NAADP was restored to the level comparable to TRP ML1(+/+) cells. Functionally, confocal microscopy revealed that NAADP significantly enhanced the dynamic interaction of endosomes and lysosomes and the lipid delivery to lysosomes in TRP-ML1(+/+) cells. This functional action of NAADP was abolished in TRP-ML1(-/-) cells, but restored after TRP-ML1 gene was rescued in these cells. Our results suggest that NAADP increases lysosomal TRP ML1 channel activity to release Ca(2+), which promotes the interaction of endosomes and lysosomes and thereby regulates lipid transport to lysosomes. Failure of NAADP-TRP-ML1 signaling may be one of the important mechanisms resulting in intracellular lipid trafficking disorder and consequent mucolipidosis. PMID- 21613608 TI - American Journal of Physiology-Cell Physiology theme: ion channels and transporters in cancer. PMID- 21613609 TI - Smad2 and PEA3 cooperatively regulate transcription of response gene to complement 32 in TGF-beta-induced smooth muscle cell differentiation of neural crest cells. AB - Response gene to complement 32 (RGC-32) is activated by transforming growth factor- beta (TGF-beta) and plays an important role in smooth muscle cell (SMC) differentiation from neural crest Monc-1 cells. The molecular mechanism governing TGF-beta activation of RGC-32, however, remains to be determined. The present studies indicate that TGF-beta regulates RGC-32 gene transcription. Sequence analysis revealed a Smad binding element (SBE) located in the region from -1344 to -1337 bp upstream of the transcription start site of RGC-32 gene. A polyomavirus enhancer activator (PEA3) binding site is adjacent to the SBE. Mutation at either SBE or PEA3 site significantly inhibited RGC-32 promoter activity. Mutations at both sites completely abolished TGF-beta-induced promoter activity. Biochemically, TGF-beta stimulated recruitment of Smad2, Smad4, and PEA3 to the RGC-32 promoter, as revealed by gel shift and chromatin immunoprecipitation analyses. Functionally, Smad2, but not Smad3, activated RGC 32 promoter. PEA3 appeared to enhance Smad2 activity. In agreement with their function, Smad2, but not Smad3, physically interacted with PEA3. In TGF-beta induced SMC differentiation of Monc-1 cells, knockdown of Smad2 by short hairpin RNA resulted in downregulation of RGC-32 and SMC marker genes. The downregulation of SMC markers, however, was rescued by exogenously introduced RGC-32. These results demonstrate that Smad2 regulation of RGC-32 transcription is essential for SMC differentiation from neural crest cells. PMID- 21613611 TI - Mechanisms of facilitation of synaptic glutamate release by nicotinic agonists in the nucleus of the solitary tract. AB - The nucleus of the solitary tract (NTS) is the principal integrating relay in the processing of visceral sensory information. Functional nicotinic acetylcholine receptors (nAChRs) have been found on presynaptic glutamatergic terminals in subsets of caudal NTS neurons. Activation of these receptors has been shown to enhance synaptic release of glutamate and thus may modulate autonomic sensory motor integration and visceral reflexes. However, the mechanisms of nAChR mediated facilitation of synaptic glutamate release in the caudal NTS remain elusive. This study uses rat horizontal brainstem slices, patch-clamp electrophysiology, and fluorescent Ca(2+) imaging to test the hypothesis that a direct Ca(2+) entrance into glutamatergic terminals through active presynaptic non-alpha7- or alpha7-nAChR-mediated ion channels is sufficient to trigger synaptic glutamate release in subsets of caudal NTS neurons. The results of this study demonstrate that, in the continuous presence of 0.3 MUM tetrodotoxin, a selective blocker of voltage-activated Na(+) ion channels, facilitation of synaptic glutamate release by activation of presynaptic nAChRs (detected as an increase in the frequency of miniature excitatory postsynaptic currents) requires external Ca(2+) but does not require activation of presynaptic Ca(2+) stores and presynaptic high- and low-threshold voltage-activated Ca(2+) ion channels. Expanding the knowledge of mechanisms and pharmacology of nAChRs in the caudal NTS should benefit therapeutic approaches aimed at restoring impaired autonomic homeostasis. PMID- 21613612 TI - Serum starvation: caveat emptor. AB - Serum starvation is one of the most frequently performed procedures in molecular biology and there are literally thousands of research papers reporting its use. In fact, this method has become so ingrained in certain areas of research that reports often simply state that cells were serum starved without providing any factual details as to how the procedure was carried out. Even so, we quite obviously lack unequivocal terminology, standard protocols, and perhaps most surprisingly, a common conceptual basis when performing serum starvation. Such inconsistencies not only hinder interstudy comparability but can lead to opposing and inconsistent experimental results. Although it is frequently assumed that serum starvation reduces basal activity of cells, available experimental data do not entirely support this notion. To address this important issue, we studied primary human myotubes, rat L6 myotubes and human embryonic kidney (HEK)293 cells under different serum starvation conditions and followed time-dependent changes in important signaling pathways such as the extracellular signal-regulated kinase 1/2, the AMP-activated protein kinase, and the mammalian target of rapamycin. Serum starvation induced a swift and dynamic response, which displayed obvious qualitative and quantitative differences across different cell types and experimental conditions despite certain unifying features. There was no uniform reduction in basal signaling activity. Serum starvation clearly represents a major event that triggers a plethora of divergent responses and has therefore great potential to interfere with the experimental results and affect subsequent conclusions. PMID- 21613610 TI - Intracellular angiotensin II activates rat myometrium. AB - Angiotensin II is a modulator of myometrial activity; both AT(1) and AT(2) receptors are expressed in myometrium. Since in other tissues angiotensin II has been reported to activate intracellular receptors, we assessed the effects of intracellular administration of angiotensin II via microinjection on myometrium, using calcium imaging. Intracellular injection of angiotensin II increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in myometrial cells in a dose dependent manner. The effect was abolished by the AT(1) receptor antagonist losartan but not by the AT(2) receptor antagonist PD-123319. Disruption of the endo-lysosomal system, but not that of Golgi apparatus, prevented the angiotensin II-induced increase in [Ca(2+)](i). Blockade of AT(1) receptor internalization had no effect, whereas blockade of microautophagy abolished the increase in [Ca(2+)](i) produced by intracellular injection of angiotensin II; this indicates that microautophagy is a critical step in transporting the peptide into the endo lysosomes lumenum. The response to angiotensin II was slightly reduced in Ca(2+) free saline, indicating a major involvement of Ca(2+) release from internal stores. Blockade of inositol 1,4,5-trisphosphate (IP(3)) receptors with heparin and xestospongin C or inhibition of phospholipase C (PLC) with U-73122 abolished the response to angiotensin II, supporting the involvement of PLC-IP(3) pathway. Angiotensin II-induced increase in [Ca(2+)](i) was slightly reduced by antagonism of ryanodine receptors. Taken together, our results indicate for the first time that in myometrial cells, intracellular angiotensin II activates AT(1)-like receptors on lysosomes and activates PLC-IP(3)-dependent Ca(2+) release from endoplasmic reticulum; the response is further augmented by a Ca(2+)-induced Ca(2+) release mechanism via ryanodine receptors activation. PMID- 21613613 TI - ISCOMATRIX adjuvant combines immune activation with antigen delivery to dendritic cells in vivo leading to effective cross-priming of CD8+ T cells. AB - Cancer vaccines aim to induce CTL responses against tumors. Challenges for vaccine design are targeting Ag to dendritic cells (DCs) in vivo, facilitating cross-presentation, and conditioning the microenvironment for Th1 type immune responses. In this study, we report that ISCOM vaccines, which consist of ISCOMATRIX adjuvant and protein Ag, meet these challenges. Subcutaneous injection of an ISCOM vaccine in mice led to a substantial influx and activation of innate and adaptive immune effector cells in vaccine site-draining lymph nodes (VDLNs) as well as IFN-gamma production by NK and NKT cells. Moreover, an ISCOM vaccine containing the model Ag OVA (OVA/ISCOM vaccine) was efficiently taken up by CD8alpha(+) DCs in VDLNs and induced their maturation and IL-12 production. Adoptive transfer of transgenic OT-I T cells revealed highly efficient cross presentation of the OVA/ISCOM vaccine in vivo, whereas cross-presentation of soluble OVA was poor even at a 100-fold higher concentration. Cross-presenting activity was restricted to CD8alpha(+) DCs in VDLNs, whereas Langerin(+) DCs and CD8alpha(-) DCs were dispensable. Remarkably, compared with other adjuvant systems, the OVA/ISCOM vaccine induced a high frequency of OVA-specific CTLs capable of tumor cell killing in different tumor models. Thus, ISCOM vaccines combine potent immune activation with Ag delivery to CD8alpha(+) DCs in vivo for efficient induction of CTL responses. PMID- 21613614 TI - Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. AB - An abnormal neutrophil subset has been identified in the PBMC fractions from lupus patients. We have proposed that these low-density granulocytes (LDGs) play an important role in lupus pathogenesis by damaging endothelial cells and synthesizing increased levels of proinflammatory cytokines and type I IFNs. To directly establish LDGs as a distinct neutrophil subset, their gene array profiles were compared with those of autologous normal-density neutrophils and control neutrophils. LDGs significantly overexpress mRNA of various immunostimulatory bactericidal proteins and alarmins, relative to lupus and control neutrophils. In contrast, gene profiles of lupus normal-density neutrophils do not differ from those of controls. LDGs have heightened capacity to synthesize neutrophils extracellular traps (NETs), which display increased externalization of bactericidal, immunostimulatory proteins, and autoantigens, including LL-37, IL-17, and dsDNA. Through NETosis, LDGs have increased capacity to kill endothelial cells and to stimulate IFN-alpha synthesis by plasmacytoid dendritic cells. Affected skin and kidneys from lupus patients are infiltrated by netting neutrophils, which expose LL-37 and dsDNA. Tissue NETosis is associated with increased anti-dsDNA in sera. These results expand the potential pathogenic roles of aberrant lupus neutrophils and suggest that dysregulation of NET formation and its subsequent responses may play a prominent deleterious role. PMID- 21613615 TI - Coordinate regulation of GATA-3 and Th2 cytokine gene expression by the RNA binding protein HuR. AB - The posttranscriptional mechanisms whereby RNA-binding proteins (RBPs) regulate T cell differentiation remain unclear. RBPs can coordinately regulate the expression of functionally related genes via binding to shared regulatory sequences, such as the adenylate-uridylate-rich elements (AREs) present in the 3' untranslated region (UTR) of mRNA. The RBP HuR posttranscriptionally regulates IL 4, IL-13, and other Th2 cell-restricted transcripts. We hypothesized that the ARE bearing GATA-3 gene, a critical regulator of Th2 polarization, is under HuR control as part of its coordinate posttranscriptional regulation of the Th2 program. We report that in parallel with stimulus-induced increase in GATA-3 mRNA and protein levels, GATA-3 mRNA half-life is increased after restimulation in the human T cell line Jurkat, in human memory and Th2 cells, and in murine Th2-skewed cells. We demonstrate by immunoprecipitation of ribonucleoprotein complexes that HuR associates with the GATA-3 endogenous transcript in human T cells and found, using biotin pulldown assay, that HuR specifically interacts with its 3'UTR. Using both loss-of-function and gain-of-function approaches in vitro and in animal models, we show that HuR is a critical mediator of stimulus-induced increase in GATA-3 mRNA and protein expression and that it positively influences GATA-3 mRNA turnover, in parallel with selective promotion of Th2 cytokine overexpression. These results suggest that HuR-driven posttranscriptional control plays a significant role in T cell development and effector function in both murine and human systems. A better understanding of HuR-mediated control of Th2 polarization may have utility in altering allergic airway inflammation in human asthmatic patients. PMID- 21613616 TI - Evidence that Cd101 is an autoimmune diabetes gene in nonobese diabetic mice. AB - We have previously proposed that sequence variation of the CD101 gene between NOD and C57BL/6 mice accounts for the protection from type 1 diabetes (T1D) provided by the insulin-dependent diabetes susceptibility region 10 (Idd10), a <1 Mb region on mouse chromosome 3. In this study, we provide further support for the hypothesis that Cd101 is Idd10 using haplotype and expression analyses of novel Idd10 congenic strains coupled to the development of a CD101 knockout mouse. Susceptibility to T1D was correlated with genotype-dependent CD101 expression on multiple cell subsets, including Foxp3(+) regulatory CD4(+) T cells, CD11c(+) dendritic cells, and Gr1(+) myeloid cells. The correlation of CD101 expression on immune cells from four independent Idd10 haplotypes with the development of T1D supports the identity of Cd101 as Idd10. Because CD101 has been associated with regulatory T and Ag presentation cell functions, our results provide a further link between immune regulation and susceptibility to T1D. PMID- 21613617 TI - MHC class II epitope nesting modulates dendritic cell function and improves generation of antigen-specific CD4 helper T cells. AB - CD4 Th cells are critical to the development of coordinated immune responses to infections and tumors. Th cells are activated through interactions of the TCR with MHC class II complexed with peptide. T cell activation is dependent on the density of MHC peptide complexes as well as the duration of interaction of the TCR with APCs. In this study, we sought to determine whether MHC class II peptides could be modified with amino acid sequences that facilitated uptake and presentation with the goal of improving Th cell activation in vitro and in vivo. A model epitope derived from the murine folate receptor alpha, a self- and tumor Ag, was modified at its carboxyl terminus with the invariant chain-derived Ii-Key peptide and at its N terminus with a peptide that enhances uptake of Ag by APC. Modification of a peptide resulted in enhanced generation of high-avidity murine folate receptor alpha T cells that persisted in vivo and homed to sites of Ag deposition. The nesting approach was epitope and species independent and specifically excluded expansion of CD4 regulatory T cells. The resulting Th cells were therapeutic, enhanced in vivo helper activity and had an increased ability to resist tolerizing immune microenvironments. In addition to improved immunoadjuvants, this epitope modification strategy may be useful for enhancing ex vivo and in vivo generation of Th cells for preventing and treating diseases. PMID- 21613618 TI - Airway inflammation and IgE production induced by dust mite allergen-specific memory/effector Th2 cell line can be effectively attenuated by IL-35. AB - CD4(+) memory/effector T cells play a central role in orchestrating the rapid and robust immune responses upon re-encounter with specific Ags. However, the immunologic mechanism(s) underlying these responses are still not fully understood. To investigate this, we generated an allergen (major house dust mite allergen, Blo t 5)-specific murine Th2 cell line that secreted IL-4, IL-5, IL-10, and IL-13, but not IL-9 or TNF-alpha, upon activation by the cognate Ag. These cells also exhibited CD44(high)CD62L(-) and CD127(+) (IL-7Ralpha(+)) phenotypes, which are characteristics of memory/effector T cells. Experiments involving adoptive transfer of this Th2 cell line in mice, followed by three intranasal challenges with Blo t 5, induced a dexamethasone-sensitive eosinophilic airway inflammation. This was accompanied by elevation of Th2 cytokines and CC- and CXC motif chemokines, as well as recruitment of lymphocytes and polymorphic mononuclear cells into the lungs. Moreover, Blo t 5-specific IgE was detected 4 d after the last intranasal challenge, whereas elevation of Blo t 5-specific IgG1 was found at week two. Finally, pulmonary delivery of the pVAX-IL-35 DNA construct effectively downregulated Blo t 5-specific allergic airway inflammation, and i.m. injection of pVAX-IL-35 led to long-lasting suppression of circulating Blo t 5-specific and total IgE. This model provides a robust research tool to elucidate the immunopathogenic role of memory/effector Th2 cells in allergic airway inflammation. Our results suggested that IL-35 could be a potential therapeutic target for allergic asthma through its attenuating effects on allergen-specific CD4(+) memory/effector Th2 cell-mediated airway inflammation. PMID- 21613620 TI - Quality versus quantity: assessing individual research performance. AB - Evaluating individual research performance is a complex task that ideally examines productivity, scientific impact, and research quality--a task that metrics alone have been unable to achieve. In January 2011, the French Academy of Sciences published a report on current bibliometric (citation metric) methods for evaluating individual researchers, as well as recommendations for the integration of quality assessment. Here, I draw on key issues raised by this report and comment on the suggestions for improving existing research evaluation practices. PMID- 21613619 TI - Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity. AB - Environmental and genetic factors define the susceptibility of an individual to autoimmune disease. Although common genetic pathways affect general immunological tolerance mechanisms in autoimmunity, the effects of such genes could vary under distinct immune challenges within different tissues. In this study, we demonstrate this by observing that autoimmune type 1 diabetes-protective haplotypes at the insulin-dependent diabetes susceptibility region 10 (Idd10) introgressed from chromosome 3 of C57BL/6 (B6) and A/J mice onto the NOD background increase the severity of autoimmune primary biliary cirrhosis induced by infection with Novosphingobium aromaticivorans, a ubiquitous alphaproteobacterium, when compared with mice having the NOD and NOD.CAST Idd10 type 1 diabetes-susceptible haplotypes. Substantially increased liver pathology in mice having the B6 and A/J Idd10 haplotypes correlates with reduced expression of CD101 on dendritic cells, macrophages, and granulocytes following infection, delayed clearance of N. aromaticivorans, and the promotion of overzealous IFN gamma- and IL-17-dominated T cell responses essential for the adoptive transfer of liver lesions. CD101-knockout mice generated on the B6 background also exhibit substantially more severe N. aromaticivorans-induced liver disease correlating with increased IFN-gamma and IL-17 responses compared with wild-type mice. These data strongly support the hypothesis that allelic variation of the Cd101 gene, located in the Idd10 region, alters the severity of liver autoimmunity induced by N. aromaticivorans. PMID- 21613621 TI - Therapeutic antibodies for brain disorders. AB - The enzyme beta-secretase (BACE1) remains an important potential disease modifying target for developing drugs to treat Alzheimer's disease. However, finding selective BACE1 inhibitors that can penetrate the brain has proved challenging. In this issue of Science Translational Medicine, a pair of studies describes a new approach to inhibiting BACE1 using a human monoclonal antibody that uses receptor-mediated transcytosis to cross the blood brain barrier (Atwal et al. and Yu et al.). The authors engineer a low-affinity bispecific monoclonal antibody targeting both BACE1 and the transferrin receptor and show that this antibody enters the brain more readily and inhibits BACE1 activity more efficiently than does a monospecific antibody against BACE1 alone. These findings should stimulate attempts to use receptor-mediated transcytosis to increase brain uptake of therapeutic antibodies for a variety of brain disorders. PMID- 21613622 TI - A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo. AB - Reducing production of amyloid-beta (Abeta) peptide by direct inhibition of the enzymes that process amyloid precursor protein (APP) is a central therapeutic strategy for treating Alzheimer's disease. However, small-molecule inhibitors of the beta-secretase (BACE1) and gamma-secretase APP processing enzymes have shown a lack of target selectivity and poor penetrance of the blood-brain barrier (BBB). Here, we have developed a high-affinity, phage-derived human antibody that targets BACE1 (anti-BACE1) and is anti-amyloidogenic. Anti-BACE1 reduces endogenous BACE1 activity and Abeta production in human cell lines expressing APP and in cultured primary neurons. Anti-BACE1 is highly selective and does not inhibit the related enzymes BACE2 or cathepsin D. Competitive binding assays and x-ray crystallography indicate that anti-BACE1 binds noncompetitively to an exosite on BACE1 and not to the catalytic site. Systemic dosing of mice and nonhuman primates with anti-BACE1 resulted in sustained reductions in peripheral Abeta peptide concentrations. Anti-BACE1 also reduces central nervous system Abeta concentrations in mouse and monkey, consistent with a measurable uptake of antibody across the BBB. Thus, BACE1 can be targeted in a highly selective manner through passive immunization with anti-BACE1, providing a potential approach for treating Alzheimer's disease. Nevertheless, therapeutic success with anti-BACE1 will depend on improving antibody uptake into the brain. PMID- 21613623 TI - Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. AB - Monoclonal antibodies have therapeutic potential for treating diseases of the central nervous system, but their accumulation in the brain is limited by the blood-brain barrier (BBB). Here, we show that reducing the affinity of an antibody for the transferrin receptor (TfR) enhances receptor-mediated transcytosis of the anti-TfR antibody across the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Anti-TfR antibodies that bind with high affinity to TfR remain associated with the BBB, whereas lower-affinity anti-TfR antibody variants are released from the BBB into the brain and show a broad distribution 24 hours after dosing. We designed a bispecific antibody that binds with low affinity to TfR and with high affinity to the enzyme beta secretase (BACE1), which processes amyloid precursor protein into amyloid-beta (Abeta) peptides including those associated with Alzheimer's disease. Compared to monospecific anti-BACE1 antibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brain Abeta after a single systemic dose. TfR-facilitated transcytosis of this bispecific antibody across the BBB may enhance its potency as an anti-BACE1 therapy for treating Alzheimer's disease. PMID- 21613624 TI - Indocyanine green enables near-infrared fluorescence imaging of lipid-rich, inflamed atherosclerotic plaques. AB - New high-resolution molecular and structural imaging strategies are needed to visualize high-risk plaques that are likely to cause acute myocardial infarction, because current diagnostic methods do not reliably identify at-risk subjects. Although molecular imaging agents are available for low-resolution detection of atherosclerosis in large arteries, a lack of imaging agents coupled to high resolution modalities has limited molecular imaging of atherosclerosis in the smaller coronary arteries. Here, we have demonstrated that indocyanine green (ICG), a Food and Drug Administration-approved near-infrared fluorescence (NIRF) emitting compound, targets atheromas within 20 min of injection and provides sufficient signal enhancement for in vivo detection of lipid-rich, inflamed, coronary-sized plaques in atherosclerotic rabbits. In vivo NIRF sensing was achieved with an intravascular wire in the aorta, a vessel of comparable caliber to human coronary arteries. Ex vivo fluorescence reflectance imaging showed high plaque target-to-background ratios in atheroma-bearing rabbits injected with ICG compared to atheroma-bearing rabbits injected with saline. In vitro studies using human macrophages established that ICG preferentially targets lipid-loaded macrophages. In an early clinical study of human atheroma specimens from four patients, we found that ICG colocalized with plaque macrophages and lipids. The atheroma-targeting capability of ICG has the potential to accelerate the clinical development of NIRF molecular imaging of high-risk plaques in humans. PMID- 21613626 TI - Endocanalicular, high-pressure balloon catheter, endoscopic dacryocystorhinostomy: a randomized controlled trial. AB - OBJECTIVES: To conduct a prospective randomized controlled study to investigate the safety and efficacy of endocanalicular, high-pressure, 5-mm balloon catheter, endoscopic dacryocystorhinostomy (DCR) in adult patients with acquired complete nasolacrimal obstruction. STUDY DESIGN: Prospective randomized controlled study. SETTING: General hospital. SUBJECTS AND METHODS: Sixty-six adult patients with a total of 70 procedures were recruited to undergo endoscopic DCR. They were prospectively, equally randomized into 2 groups: endocanalicular, high-pressure, 5-mm balloon catheter, endoscopic DCR (group I) and conventional endoscopic DCR (group II). Regular follow-up sessions were conducted to document the patient's subjective improvement, judge ostium patency on irrigation, and record any complications. RESULTS: Both groups demonstrated a success rate of 91.4%. There was a shorter mean operative time (25.7 minutes) in group I (P < .001). The number of adverse events was significantly higher in group II (P < .05). Group I showed statistically significantly more comfort during surgery under local anesthesia with minimal sedation (P < .05). CONCLUSION: Endocanalicular balloon catheter endoscopic DCR shares the advantages and success rate of conventional endoscopic DCR. In addition, the former is simpler, requires less manipulation, consumes a shorter operative time, has a better safety profile, and can be conducted under local anesthesia with minimal sedation. PMID- 21613625 TI - Expression of chitinases in hypertrophied adenoids of children. AB - OBJECTIVES/HYPOTHESIS: Chronic rhinosinusitis (CRS), otitis media with effusion (OME), and allergic rhinitis (AR) are common conditions that have been associated with hypertrophied adenoids in children, and adenoidectomy is clinically recommended. The investigators assayed the expression level and site of acidic mammalian chitinase (AMCase) and chitotriosidase (ChT) in hypertrophied adenoids of children to determine the expression levels of 2 chitinases in relation to CRS, OME, and AR. STUDY DESIGN: A prospective cohort study. SETTING: A tertiary care facility. METHODS: Hypertrophied adenoids from 41 children were harvested during adenoidectomy. Medical records were reviewed and the subjects were grouped according to the presence of CRS, OME, and AR. Messenger RNA (mRNA) and protein expression of AMCase and ChT in adenoid tissues was assessed by reverse transcription polymerase chain reaction and Western blotting. Immunohistochemical staining revealed the sites of AMCase and ChT expression. RESULTS: mRNA and protein of AMCase and ChT were present in adenoids of all subjects. CRS was a significant variable in AMCase mRNA and protein expression. CRS, OME, and AR were significant variables in ChT mRNA and protein expression. Both AMCase and ChT were expressed in histiocytes and vascular endothelial cells of adenoid tissues. CONCLUSIONS: The findings suggest that chitin-containing pathogens or dysregulated immune responses to them in the hypertrophied adenoids of children could be factors contributing to CRS, OME, and AR via AMCase or ChT overexpression. PMID- 21613627 TI - Subcutaneous fat tissue thickness of the anterior neck and umbilicus in patients with obstructive sleep apnea. AB - OBJECTIVE: To investigate the differences in thickness of subcutaneous fat tissue of the anterior neck and umbilicus of patients with and without obstructive sleep apnea (OSA), the relationship between thickness of subcutaneous fat tissue of the anterior neck and umbilicus and polysomnographic findings, and the influence of body mass index (BMI), anthropometric findings, and gender. STUDY DESIGN: Cross sectional study. SETTING: Tertiary care university hospital. SUBJECT AND METHODS: Seventy-three patients with OSA and 24 non-OSA patients were evaluated with polysomnography for 1 night. Anthropometric parameters and BMI were also investigated. Subcutaneous fat tissue thickness of anterior neck and umbilicus was assessed using ultrasound. The thickness of subcutaneous fat tissue adjacent to the submandibular gland, isthmus, hyoid, suprasternal notch, and umbilicus was measured with ultrasound. Data analysis was performed using SPSS. RESULTS: Apnea hypopnea index (AHI) was significantly and positively correlated with age (P = .016, r (2) = 0.244), BMI (P < .001, r (2) = 0.416), and anthropometric findings (waist circumference P < .001, r (2) = 0.337; hip circumference P = .008, r (2) = 0.269; neck circumference P = .002, r (2) = 0.309). Minimum oxygen saturation was significantly, negatively correlated with age (P = .002, r (2) = -0.310), BMI (P < .001, r (2) = -0.404), and anthropometric findings (waist circumference P = .005, r (2) = -0.281, hip circumference P < .001, r (2) = -0.353, neck circumference P = .010, r (2) = -0.261). There were no significant differences between the OSA and non-OSA groups with respect to age (P = .178), gender (P = .189), or ultrasonographic findings for subcutaneous fat tissue thickness adjacent to the submandibular gland (P = .480), thyroid isthmus (P = .311), suprasternal notch (P = .950), umbilicus (P = .691), or hyoid (P = .159). Neck circumference (P = .039) and BMI (P = .014) were significantly higher in the OSA group. CONCLUSION: These indicate that anterior neck and umbilical subcutaneous fat tissue thickness may not contribute to the severity of OSA. PMID- 21613628 TI - The effect of prilocaine or levobupivacaine infiltration on pain during nasal packing removal. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of rehydration of Merocel nasal packs with prilocaine or levobupivacaine on reducing pain and discomfort of nasal packing removal in patients who had undergone septoplasties or endoscopic sinus surgery. STUDY DESIGN: Prospective clinical study. Setting. Tertiary referral center. METHODS: This prospective study was conducted on 72 patients, aged 18 to 55 years, who had undergone septoplasty, bilateral functional endoscopic sinus surgery, or both. The patients were divided into 2 groups: prilocaine group (group P, n = 36), who received 2.5 mL of 2% prilocaine, and levobupivacaine group (group L, n = 36), who received 2.5 mL of levobupivacaine hydrochloride dilution. These solutions were diluted with 2.5 mL saline to a final volume of 5 mL, which was then injected into the Merocel packing 15 minutes before removal of the pack. In both groups, 5 mL of saline was injected into the packing in the contralateral nostril as a control 15 minutes before removal of the pack. Visual analog score (VAS) and the Ramsay sedation score were recorded. RESULTS: Statistically significant differences were found in VAS and Ramsay sedation scale scores of levobupivacaine and prilocaine groups compared to controls. No significant difference was noted between the groups in terms of levobupivacaine and prilocaine. CONCLUSIONS: Levobupivacaine or prilocaine infiltration before removal of nasal packs in patients who undergo septoplasties or endoscopic sinus surgery can decrease discomfort and improve patient tolerability. PMID- 21613629 TI - Cardiovascular adaptations of pregnancy in T and B cell-deficient mice. AB - The pathophysiology of gestational hypertensive disorders is incompletely defined. T lymphocytes are implicated. Both T and natural killer (NK) cells express RAS and, in implantation sites, NK cells are highly enriched. We hypothesized that T cells and/or NK cells contribute to circulatory control during pregnancy. Using radiotelemetry of arterial pressure, heart rate, and activity, mice without T and B cells (genotypes BALB/c-Rag2(-/-) and NOD.scid) were examined at baseline and across pregnancy. These strains differ in NK cell competency, with Rag2(-/-) being normal and NOD.scid impaired. Circulatory features differed between these inbred strains. Rag2(-/-); had blood pressure responses to pregnancy that did not differ from congenic normal mice. NOD.scid had higher midgestational blood pressure compared with normoglycemic NOD mice (3 5 mm Hg greater than NOD; P < 0.004). In comparison to controls, both T and B strains had much higher heart rates after first trimester that did not remit until parturition (>30 bpm greater than control; P < 0.0001). NOD.scid had additional anomalies, including 90% depletion of circulating NK cells and elevated (57%) proliferation of uterine NK cells within implantation sites. These data demonstrate immune control of midgestational heart rate and suggest NK cells contribute to midpregnancy regulation of mean arterial pressure. PMID- 21613630 TI - Increased beta-oxidation and improved oocyte developmental competence in response to l-carnitine during ovarian in vitro follicle development in mice. AB - Oocyte developmental competence is acquired throughout folliculogenesis and is associated with appropriate differentiation and responsiveness to the luteinizing hormone (LH) surge. The recent development of a novel system for culturing ovarian follicles in a three-dimensional alginate matrix shows promise in phenocopying in vivo folliculogenesis. However, oocytes from follicles grown in vitro have a reduced capacity to complete nuclear maturation and be fertilized compared to oocytes matured in vivo. Oocyte metabolism is closely linked with oocyte quality, and we have recently shown that beta-oxidation of lipids is essential for oocyte developmental competence. Thus we investigated whether upregulation of beta-oxidation by treatment with the fatty acid transport cofactor l-carnitine could improve folliculogenesis and developmental competence of mouse follicles following three-dimensional culture. Ovarian hormones (androstenedione, estradiol, and progesterone) and the induction of cumulus matrix proteins (hyaluronan and ADAMTS1) were similar to in vivo follicles, indicating that appropriate differentiation of follicular cells occurs in cultured follicles after an LH/human chorionic gonadotropin (hCG) stimulus. l carnitine did not alter survival, growth, or differentiation of follicles. However, l-carnitine supplementation significantly increased beta-oxidation, and markedly improved both fertilization rate and blastocyst development. Together, these results show that appropriate responsiveness of the follicle to the LH/hCG surge occurs following three-dimensional follicle culture but limitations on key metabolic requirements remain. l-carnitine supplementation during in vitro follicle culture increased lipid metabolism and improved oocyte developmental competence. PMID- 21613631 TI - Remodeling of the cervix and parturition in mice lacking the progesterone receptor B isoform. AB - Withdrawal of progestational support for pregnancy is part of the final common pathways for parturition, but the role of nuclear progesterone receptor (PGR) isoforms in this process is not known. To determine if the PGR-B isoform participates in cervical remodeling at term, cervices were obtained from mice lacking PGR-B (PGR-BKO) and from wild-type (WT) controls before or after birth. PGR-BKO mice gave birth to viable pups at the same time as WT controls during the early morning of Day 19 postbreeding. Morphological analyses indicated that by the day before birth, cervices from PGR-BKO and WT mice had increased in size, with fewer cell nuclei/area as well as diminished collagen content and structure, as evidenced by optical density of picrosirius red-stained sections, compared to cervices from nonpregnant mice. Moreover, increased numbers of resident macrophages, but not neutrophils, were found in the prepartum cervix of PGR-BKO compared to nonpregnant mice, parallel to findings in WT mice. These results suggest that PGR-B does not contribute to the growth or degradation of the extracellular matrix or proinflammatory processes associated with recruitment of macrophages in the cervix leading up to birth. Rather, other receptors may contribute to the progesterone-dependent mechanism that promotes remodeling of the cervix during pregnancy and in the proinflammatory process associated with ripening before parturition. PMID- 21613633 TI - Extracellular matrix dynamics in scar-free endometrial repair: perspectives from mouse in vivo and human in vitro studies. AB - Repair of the postmenstrual endometrium presents a unique opportunity to examine nonscarring repair in an adult tissue. We aimed to characterize and determine the importance of extracellular matrix (ECM) dynamics in cell migration during endometrial repair. Utilizing an in vivo mouse model of postmenstrual repair and an in vitro model of human endometrial re-epithelialization, we determined the dynamic changes in expression of ECM and related factors in both models by array analysis of repairing areas. We also validated expression of integrins, growth factors, protease inhibitors, basement membrane, and adhesion molecules in vitro and in both mouse and human repairing endometrium by quantitative RT-PCR and immunohistochemical studies. Finally, we determined the functional importance of integrin-fibronectin interactions and matrix metalloprotease (MMP)-facilitated cell movement during re-epithelialization and propose a model for cell locomotion during postmenstrual repair. These data demonstrated the dynamic expression and functional importance of ECM interactions in endometrial repair, which may be important for scar-free repair. PMID- 21613632 TI - Diverse roles for sex hormone-binding globulin in reproduction. AB - Sex hormone-binding globulin (SHBG) transports androgens and estrogens in blood and regulates their access to target tissues. Hepatic production of SHBG fluctuates throughout the life cycle and is influenced primarily by metabolic and hormonal factors. Genetic differences also contribute to interindividual variations in plasma SHBG levels. In addition to controlling the plasma distribution, metabolic clearance, and bioavailability of sex steroids, SHBG accumulates in the extravascular compartments of some tissues and in the cytoplasm of specific epithelial cells, where it exerts novel effects on androgen and estrogen action. In mammals, the gene-encoding SHBG is expressed primarily in the liver but also at low levels in other tissues, including the testis. In subprimate species, Shbg expression in Sertoli cells is under the control of follicle-stimulating hormone and produces the androgen-binding protein that influences androgen actions in the seminiferous tubules and epididymis. In humans, the SHBG gene is not expressed in Sertoli cells, but its expression in germ cells produces an SHBG isoform that accumulates in the acrosome. In fish, Shbg is produced by the liver but has a unique function in the gill as a portal for natural steroids and xenobiotics, including synthetic steroids. However, salmon have retained a second, poorly conserved Shbg gene that is expressed only in ovary, muscle, and gill and that likely exerts specialized functions in these tissues. The present review compares the production and functions of SHBG in different species and its diverse effects on reproduction. PMID- 21613635 TI - Double bubble sign. PMID- 21613634 TI - Absence of MSY2 in mouse oocytes perturbs oocyte growth and maturation, RNA stability, and the transcriptome. AB - Messenger RNA is remarkably stable during oocyte growth, thus enabling mRNAs to accumulate during the growth phase and thereby provide mRNAs that support early embryonic development. MSY2, a germ cell-specific RNA-binding protein, is implicated in regulating mRNA stability. MSY2 is essential for development because female Msy2(-/-) mice are infertile. We describe here the characterization of Msy2(-/-) oocytes. Mutant oocytes grow more slowly during the first wave of folliculogenesis, and maturation to and arrest at metaphase II is severely compromised because of aberrant spindle formation and chromosome congression. Consistent with MSY2 conferring mRNA stability is that the amount of poly(A)-containing RNA is reduced by ~25% in mutant oocytes. Stability of an exogenous mRNA injected into mutant oocytes is lower than when compared to their wild-type counterparts, and moreover, expression of wild-type MSY2 in mutant oocytes increases mRNA stability, whereas injection of a mutant form of MSY2 not capable of binding RNA does not. Transcription quiescence that normally occurs during the course of oocyte growth is not observed in mutant oocytes, and the transcriptome of mutant oocytes is markedly perturbed. These results, and those of previous studies, strongly implicate a central role of MSY2 in regulating mRNA stability. PMID- 21613636 TI - Left atrial strain is related to adverse events in patients after acute myocardial infarction treated with primary percutaneous coronary intervention. AB - BACKGROUND: Left atrial (LA) maximal volume is of prognostic value in patients after acute myocardial infarction (AMI). Recently, LA mechanical function and LA strain have been introduced as alternative methods to assess LA performance more accurately. OBJECTIVE: To evaluate the relation between LA volume, mechanical function and strain, and adverse events in patients after AMI. METHODS: Patients with AMI underwent two-dimensional echocardiography within 48 h of admission. LA volume and LA performance (mechanical function and systolic strain) were quantified. The endpoint was a composite of all-cause mortality, reinfarction and hospitalisation for heart failure. RESULTS: 320 patients (mean age 60+/-12 years, 78% men) were followed up for 27+/-14 months. During follow-up, 48 patients (15%) reached the composite endpoint. After adjustment for clinical and echocardiographic parameters, LA maximal volume (HR 1.05, CI 1.00 to 1.10, p=0.04) and LA strain (HR 0.94, CI 0.89 to 0.99, p=0.02) were independently associated with adverse outcome. In addition, LA strain provided incremental value to LA maximal volume (p=0.03) for the prediction of adverse outcome. CONCLUSIONS: After AMI treated with primary percutaneous coronary intervention, LA strain provides additional prognostic value beyond LA maximal volume. PMID- 21613637 TI - Centromere protein F and survivin are associated with high risk and a poor prognosis in colorectal gastrointestinal stromal tumours. AB - AIMS: Colorectal gastrointestinal stromal tumours (GISTs) are considered to be tumours with a relatively poor prognosis. Few reports have been performed to investigate the mechanisms behind their malignant behaviour and to identify new therapeutic strategies for their treatment. The authors conducted this study to explore potential targets for the treatment of colorectal GISTs (CRGISTs). METHODS: In the current study, the authors focused on centromere protein F and survivin, two markers that are known to affect the malignant behaviour of other tumours. Expression of centromere protein F and survivin was detected through the immunohistochemical staining of paraffin-embedded tumour tissues and then scored. The relationship between the expression of the two markers and their clinical parameters was analysed. Associated Survival analysis was available based on follow-up information. RESULTS: The authors demonstrated for the first time that centromere protein F and survivin expression were significantly associated with high risk and a poor prognosis (p<0.05) in CRGISTs. The authors also found that centromere protein F expression was more prevalent in males (p=0.002). CONCLUSIONS: The results suggest that centromere protein F and survivin are malignant behaviour markers for CRGISTs. The expression of centromere protein F or survivin points to a poor clinical outcome. Interfering with centromere protein F and/or survivin expression might be a potentially therapeutic strategy for treating malignant CRGISTs. PMID- 21613638 TI - Attitudes towards the extension of smoking restrictions to selected outdoor areas in Italy. AB - OBJECTIVES: To estimate the attitudes of Italians on the extension of the smoking ban to selected public outdoor areas. METHODS: The authors considered data from two Italian surveys on smoking conducted in 2009 and 2010 on a total sample of 6233 individuals, representative of the Italian population aged 15 years or over. RESULTS: 64.6% of Italians supported smoke-free policies in public parks, 68.5% in sports stadiums, 62.1% in beaches, 85.9% in school courtyards and 79.9% in outdoor areas surrounding hospitals. Among current smokers, the corresponding estimates were 32.9% for parks, 38.2% for stadiums, 31.2% for beaches, 67.6% for schools and 55.3% for hospitals. CONCLUSIONS: Extension of the smoking ban to selected outdoor areas is supported by the large majority of the Italian population. The overwhelming majority of support for smoke-free school grounds and outdoor areas surrounding hospitals indicates that legislative action is required. PMID- 21613639 TI - Workplace and individual risk factors for carpal tunnel syndrome. AB - OBJECTIVES: To quantify the relationship between workplace physical factors, particularly hand activity level (HAL) and forceful exertion and carpal tunnel syndrome (CTS), while taking into account individual factors. To compare quantitative exposure assessment measures with more practical ratings-based measures. METHODS: In a group of healthcare and manufacturing workers, each study participant's job tasks were evaluated for HAL, forceful exertion and other physical stressors and videotaped for further analysis, including frequency and duration of exertion and postural deviation. Electrodiagnostic testing of median and ulnar nerves and questionnaires were administered to all participants. A CTS case required median mononeuropathy and symptoms on hand diagrams in fingers 1-3. Multiple logistic regression models were used to analyse associations between job and individual factors and CTS. RESULTS: Of 477 workers studied, 57 (11.9%) were dominant hand CTS cases. Peak force >=70% maximum voluntary contraction versus <20% maximum voluntary contraction resulted in an OR of 2.74 (1.32-5.68) for CTS. Among those with a body mass index >=30, the OR for >=15 exertions per minute was 3.35 (1.14-9.87). Peak worker ratings of perceived exertion increased the odds for CTS by 1.14 (1.01-1.29) for each unit increase on the 10-point scale. The odds for CTS increased by 1.38 (1.05-1.81) for each unit increase on the HAL 10 point scale among men, but not women. Combined force and HAL values above the ACGIH TLV for HAL resulted in an OR of 2.96 (1.51-5.80) for CTS. DISCUSSION/CONCLUSIONS: Quantitative and ratings-based job exposure measures were each associated with CTS. Obesity increased the association between frequency of exertion and CTS. PMID- 21613640 TI - Recommending MeSH terms for annotating biomedical articles. AB - BACKGROUND: Due to the high cost of manual curation of key aspects from the scientific literature, automated methods for assisting this process are greatly desired. Here, we report a novel approach to facilitate MeSH indexing, a challenging task of assigning MeSH terms to MEDLINE citations for their archiving and retrieval. METHODS: Unlike previous methods for automatic MeSH term assignment, we reformulate the indexing task as a ranking problem such that relevant MeSH headings are ranked higher than those irrelevant ones. Specifically, for each document we retrieve 20 neighbor documents, obtain a list of MeSH main headings from neighbors, and rank the MeSH main headings using ListNet-a learning-to-rank algorithm. We trained our algorithm on 200 documents and tested on a previously used benchmark set of 200 documents and a larger dataset of 1000 documents. RESULTS: Tested on the benchmark dataset, our method achieved a precision of 0.390, recall of 0.712, and mean average precision (MAP) of 0.626. In comparison to the state of the art, we observe statistically significant improvements as large as 39% in MAP (p-value <0.001). Similar significant improvements were also obtained on the larger document set. CONCLUSION: Experimental results show that our approach makes the most accurate MeSH predictions to date, which suggests its great potential in making a practical impact on MeSH indexing. Furthermore, as discussed the proposed learning framework is robust and can be adapted to many other similar tasks beyond MeSH indexing in the biomedical domain. All data sets are available at: http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/indexing. PMID- 21613641 TI - Improving the validity of determining medication adherence from electronic health record medications orders. AB - We developed an accurate and valid medication order algorithm to identify from electronic health records the definitive medication order intended for dispensing and applied this process to identify a cohort of patients and to stratify them into one of three medication adherence groups: early non-persistence, primary non adherence, or ongoing adherence. We identified medication order data from electronic health record tables, obtained the orders, and linked the orders to dispensings. These steps were then used to identify patients newly prescribed antihypertensive, antidiabetic, or antihyperlipidemic medications and to determine the adherence group of each patient. Record review validated each process step, thus increasing the accuracy of group assignment as well as the criteria used to select patients. This work is an important first step to accurately identify study-specific patient adherence cohorts and allow more comprehensive estimates of population medication adherence. PMID- 21613642 TI - Evaluation of the NCPDP Structured and Codified Sig Format for e-prescriptions. AB - OBJECTIVE: To evaluate the ability of the structure and code sets specified in the National Council for Prescription Drug Programs Structured and Codified Sig Format to represent ambulatory electronic prescriptions. DESIGN: We parsed the Sig strings from a sample of 20,161 de-identified ambulatory e-prescriptions into variables representing the fields of the Structured and Codified Sig Format. A stratified random sample of these representations was then reviewed by a group of experts. For codified Sig fields, we attempted to map the actual words used by prescribers to the equivalent terms in the designated terminology. MEASUREMENTS: Proportion of prescriptions that the Format could fully represent; proportion of terms used that could be mapped to the designated terminology. RESULTS: The fields defined in the Format could fully represent 95% of Sigs (95% CI 93% to 97%), but ambiguities were identified, particularly in representing multiple-step instructions. The terms used by prescribers could be codified for only 60% of dose delivery methods, 84% of dose forms, 82% of vehicles, 95% of routes, 70% of sites, 33% of administration timings, and 93% of indications. LIMITATIONS: The findings are based on a retrospective sample of ambulatory prescriptions derived mostly from primary care physicians. CONCLUSION: The fields defined in the Format could represent most of the patient instructions in a large prescription sample, but prior to its mandatory adoption, further work is needed to ensure that potential ambiguities are addressed and that a complete set of terms is available for the codified fields. PMID- 21613643 TI - A method and knowledge base for automated inference of patient problems from structured data in an electronic medical record. AB - BACKGROUND: Accurate knowledge of a patient's medical problems is critical for clinical decision making, quality measurement, research, billing and clinical decision support. Common structured sources of problem information include the patient problem list and billing data; however, these sources are often inaccurate or incomplete. OBJECTIVE: To develop and validate methods of automatically inferring patient problems from clinical and billing data, and to provide a knowledge base for inferring problems. STUDY DESIGN AND METHODS: We identified 17 target conditions and designed and validated a set of rules for identifying patient problems based on medications, laboratory results, billing codes, and vital signs. A panel of physicians provided input on a preliminary set of rules. Based on this input, we tested candidate rules on a sample of 100,000 patient records to assess their performance compared to gold standard manual chart review. The physician panel selected a final rule for each condition, which was validated on an independent sample of 100,000 records to assess its accuracy. RESULTS: Seventeen rules were developed for inferring patient problems. Analysis using a validation set of 100,000 randomly selected patients showed high sensitivity (range: 62.8-100.0%) and positive predictive value (range: 79.8 99.6%) for most rules. Overall, the inference rules performed better than using either the problem list or billing data alone. CONCLUSION: We developed and validated a set of rules for inferring patient problems. These rules have a variety of applications, including clinical decision support, care improvement, augmentation of the problem list, and identification of patients for research cohorts. PMID- 21613645 TI - Randomised placebo-controlled trial of rituximab (anti-CD20) in active ulcerative colitis. PMID- 21613644 TI - Divergent trends for gastric cancer incidence by anatomical subsite in US adults. AB - BACKGROUND AND AIM: Age-specific analyses of non-cardia gastric cancer incidence reveal divergent trends among US whites: rates are declining in individuals aged 40 years and older but rising in younger persons. To investigate this heterogeneity further, incidence trends were evaluated by anatomical subsite. METHODS: Gastric cancer incidence data for 1976-2007 were obtained from the US National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program and the US Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR). Incidence rates and estimated annual percentage change were calculated by age group (25-39, 40-59 and 60-84 years), race/ethnicity and subsite. RESULTS: Based on data from the nine oldest SEER registries (covering ~10% of the US population), rates for all non-cardia subsites decreased in whites and blacks, except for corpus cancer, which increased between 1976 and 2007 with estimated annual percentage changes of 1.0% (95% CI 0.1% to 1.9%) for whites and 3.5% (95% CI 1.8% to 5.2%) for blacks. In contrast, rates for all non-cardia subsites including corpus cancer declined among other races. In combined data from NPCR and SEER registries (covering 89% of the US population), corpus cancer significantly increased between 1999 and 2007 among younger and middle-aged whites; in ethnic-specific analyses, rates significantly increased among the same age groups in non-Hispanic whites and were stable among Hispanic whites. Age-specific rates for all subsites declined or were stable in this period among blacks and other races. CONCLUSIONS: Long- and short-term incidence trends for gastric cancers indicate a shifting distribution by anatomical subsite. Corpus cancer may have distinctive aetiology and changing risk factor exposures, warranting further investigation. PMID- 21613646 TI - Hyperdynamic circulation and portal hypertension: chicken or egg? PMID- 21613647 TI - Justification for a home-based education programme for kidney patients and their social network prior to initiation of renal replacement therapy. AB - In this article, an ethical analysis of an educational programme on renal replacement therapy options for patients and their social network is presented. The two main spearheads of this approach are: (1) offering an educational programme on all renal replacement therapy options ahead of treatment requirement and (2) a home-based approach involving the family and friends of the patient. Arguments are offered for the ethical justification of this approach by considering the viewpoint of the various stakeholders involved. Finally, reflecting on these ethical considerations, essential conditions for carrying out such a programme are outlined. The goal is to develop an ethically justified and responsible educational programme. PMID- 21613648 TI - The views of genitourinary medicine (GUM) clinic users on unlinked anonymous testing for HIV: evidence from a pilot study of clinics in two English cities. AB - A study was undertaken of the views of users of two genitourinary medicine (GUM) clinics in England on unlinked anonymous testing (UAT) for HIV. The UAT programme measures the prevalence of HIV in the population, including undiagnosed prevalence, by testing residual blood (from samples taken for clinical purposes) which is anonymised and irreversibly unlinked from the source. 424 clinic users completed an anonymous questionnaire about their knowledge of, and attitudes towards, UAT. Only 1/7 (14%) were aware that blood left over from clinical testing may be tested anonymously for HIV. A large majority (89%) said they would agree to their blood being tested, although 74% wanted the opportunity to consent. These findings indicate broad support for UAT of blood in a group of patients whose samples are included in the HIV surveillance programme. The findings suggest the need for greater attention to be given to the provision of information and, if replicated in a larger survey, may justify a reappraisal of UK policy on UAT. PMID- 21613649 TI - One step forward, several more to go: classification of psychogenic non-epileptic seizures based on automatic clustering. PMID- 21613650 TI - Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis. AB - BACKGROUND: Optineurin (OPTN), a causative gene of hereditary primary open-angle glaucoma, has been recently associated with amyotrophic lateral sclerosis (ALS) with mainly autosomal recessive, but also dominant, traits. To further define the contribution of OPTN gene in ALS, we performed a mutational screening in a large cohort of Italian patients. METHODS: A group of 274 ALS patients, including 161 familial (FALS) and 113 sporadic (SALS) cases, were screened for OPTN mutations by direct sequencing of its coding sequence. All patients fulfilled the El Escorial criteria for probable or definite ALS and were negative for mutations in SOD1, ANG, TARDBP and FUS/TLS genes. RESULTS: The genetic analysis revealed six novel variants in both FALS and SALS patients, all occurring in an heterozygous state. We identified three missense (c.844A->C p.T282P, c.941A->T p.Q314L, c.1670A->C p.K557T), one nonsense (c.67G->T p.G23X) and two intronic mutations (c.552+1delG, c.1401+4A->G). The intronic c.552+1delG variant determined a splicing defect as demonstrated by mRNA analysis. All mutations were absent in 280 Italian controls and over 6800 worldwide glaucoma patients and controls screened so far. The clinical phenotype of OPTN-mutated patients was heterogeneous for both age of onset and disease duration but characterised by lower-limb onset and prevalence of upper motor neuron signs. CONCLUSION: In this cohort, OPTN mutations were present both in FALS (2/161), accounting for 1.2% cases, and in SALS patients (4/113), thereby extending the spectrum of OPTN mutations associated with ALS. The study further supports the possible pathological role of optineurin protein in motor neuron disease. PMID- 21613651 TI - Planes and ailing brains. PMID- 21613652 TI - Skeletal muscle MRI magnetisation transfer ratio reflects clinical severity in peripheral neuropathies. AB - MRI may provide treatment outcome measures in neuromuscular conditions. The authors assessed MRI magnetisation transfer ratios (MTRs) in lower-limb musculature as markers of pathology in peripheral neuropathies and compared the findings with associated clinical data. Ten patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and nine patients with chronic inflammatory demyelinating polyneuropathy (CIDP) were compared with 10 healthy subjects. The MTR in the calf muscles was significantly lower than controls in the two patient groups (both p<0.001). The median MTRs (IQR) were 50.5(1.6) percentage units (p.u.) (control), 41.5(10.6) p.u. (CMT1A) and 39.3(8.7) p.u. (CIDP). Moreover, anterior lower leg MTR correlated strongly with strength of ankle dorsiflexion, measured with the Medical Research Council scale, in CIDP (rho=0.88, p<0.001) and also in CMT1A (rho=0.50, p<0.05), where MTR also showed an association with disease duration (rho=-0.86, p<0.001). Short tau inversion recovery MRI of the same muscles showed abnormalities associated with regions of reduced MTR (p<0.001), and MTR was also reduced in other muscles otherwise deemed normal appearing (p<0.001), indicating that MTR may be more sensitive to muscle damaged by denervation than conventional MRI. The significant reductions in muscle MTR in peripheral neuropathies and the associated correlations with clinical measures indicate that MTR has potential as an imaging outcome measure in future therapeutic trials. PMID- 21613653 TI - Detection and treatment of depression in neurological disorders. PMID- 21613655 TI - Secrets of successful short grant applications. AB - The National Institutes of Health has implemented new grant application guidelines that include a substantial reduction in the number of pages allowed for project descriptions. Shorter proposals will potentially decrease reviewer burden, but investigators may find the new page limits challenging. Writing more concisely while still presenting a persuasive argument requires honing certain skills with regard to preparation, construction, and editing of proposals. This article provides strategies from the Western Journal of Nursing Research editorial board for preparing competitive shorter research proposals. Two key strategies for success are fully conceptualizing the study prior to writing and obtaining assistance from experienced colleagues during the editing process. PMID- 21613654 TI - Parents' experiences following children's moderate to severe traumatic brain injury: a clash of cultures. AB - Little is understood about parents' experiences following children's moderate to severe traumatic brain injury (TBI). Using descriptive phenomenology, we explored common experiences of parents whose children were diagnosed with moderate to severe TBI. Parents from across the United States (N = 42, from 37 families) participated in two semistructured interviews (~ 90 minutes in length and 12 to 15 months apart) in the first 5 years following children's TBI. First interviews were in person. Second interviews, done in person or by phone, facilitated updating parents' experiences and garnering their critique of the descriptive model. Parent themes were (a) grateful to still have my child, (b) grieving for the child I knew, (c) running on nerves, and (d) grappling to get what my child and family need. Parents reported cultural barriers because of others' misunderstandings. More qualitative inquiry is needed to understand how the knowledge, attitudes, beliefs, and culture-based expectations of others influence parents' interactions and the family's adjustment and well-being. PMID- 21613656 TI - [Threshold tracking for beginners]. AB - Nerve excitability has been studied for a longer time than has nerve conduction. Prof. Joseph Bergmans pioneered the use of threshold current measurement for studying axonal excitability. However nerve excitability testing has not been used because of technical difficulties. Prof. Hugh Bostock developed a semiautomatic program called QTRAC. This program enables the examiner to perform various nerve excitability tests within 15 min. Nerve excitability testing can provide information regarding physiological conditions, ion channels and the functions of energy-dependent pumps in normal controls and in individuals with diseases such as amyotrophic lateral sclerosis (ALS) and multifocal motor neuropathy (MMN). For understanding threshold tracking, information regarding basic physiological principles including the function of ion channels is required. This review provides important insights on the function of axonal ion channels and investigational methods. PMID- 21613657 TI - [Hereditary neuropathy: variety of disease-causing genes and progress of molecular genetic diagnosis]. AB - Inherited neuropathies are clinically and genetically heterogeneous. At least 30 genes have been associated with Charcot-Marie-Tooth disease (CMT) and related inherited neuropathies. Genetic studies have revealed that abnormalities in the following factors are the cause of inherited neuropathies: myelin components, transcription factors controlling myelination, myelin maintenance system, differentiation factors related to the peripheral nerve, neurofilaments, protein transfer system, mitochondrial proteins, DNA repair, RNA/protein synthesis, ion channels, and aminoacyl-tRNA synthetase. On the other hand, a precise molecular diagnosis is often needed to confirm a clinical diagnosis, offer genetic counseling to the patient and family, and provide prognostic information to the patient. Unfortunately, along with the increase in the number of genes that must be screened for mutations, the labor and reagent costs of molecular genetic testing have increased significantly. On the basis of the recent progress of DNA analysis methods, the use of resequencing microarray seems to be an economical and highly sensitive method to detect mutations. In this study, we attempted to screen for CMT patients mutations using these methods. PMID- 21613658 TI - [Autoimmune neuropathies: diagnosis, treatment, and recent topics]. AB - Here, we have reviewed the clinical patterns, diagnostic paradigms, etiopathogenesis, and therapeutic strategies of autoimmune neuropathies such as Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and IgM paraproteinemic neuropathy. Antiganglioside antibodies are frequently present in the serum samples obtained during the acutephase of GBS and Miller Fisher syndrome (MFS), a subtype of GBS. Recently, we found that some patients with GBS and MFS have serum antibodies against antigenic epitopes formed by 2 different gangliosides (ganglioside complex). The antibodies against GD1a/GD1b and/or GD1b/GT1b complexes are associated with severe disability and a requirement for mechanical ventilation. Anti-GM1/GalNAc-GD1a antibodies are found to be associated with pure motor GBS with frequent conduction blocks. In GBS, corticosteroids given alone do not significantly hasten the recovery or affect the long-term treatment outcome. Intravenous immunoglobulin therapy (IVIg) or plasma exchange (PE) is equally effective. Combined treatment with corticosteroids and IVIg may be a promising therapy for GBS. On the basis of the EFNS/PNS guidelines, we describe the treatment of chronic autoimmune neuropathies such as CIDP, MMN, and IgM paraproteinemic neuropathy. In treating CIDP, corticosteroids, IVIg, and plasma exchange are equally effective. In MMN, IVIg is the first-choice therapy; corticosteroids and PE are ineffective or even detrimental. IgM paraproteinemic neuropathies are known to be intractable, and these patients often have anti myelin-associated glycoprotein antibodies and may respond to immunosuppressive and immunomodulatory therapies. However, the potential therapeutic benefits should be balanced against their possible side effects and usual slow disease progression. PMID- 21613659 TI - [Blood-nerve barrier: structure and function]. AB - The blood-nerve barrier (BNB) is a dynamic interface between the endoneurial microenvironment and surrounding extracellular space or blood contents, and is localized the innermost layer of multilayered ensheathing perineurium and endoneurial microvessels. Since the BNB is a key structure controlling the internal milieu of the peripheral nerve parenchyma, adequate understanding of the BNB is crucial for developing treatment strategies for human peripheral nervous system disorders, including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and diabetic and various metabolic/toxic neuropathies. However, fewer studies have been conducted on the BNB, if we compare against the number of studies on the blood-brain barrier. This is because of the lack of adequate human cell lines originating from the BNB. In our laboratory, human immortal cell lines from the BNB, namely, the endothelial cell line and pericyte cell line, have recently been established and vigorous investigations of their biological and physiological properties are now underway. Pericytes constituting the BNB were found to possess robust ability of controlling BNB integrity via secretion of various cytokines and growth factors including bFGF, VEGF, GDNF, BDNF, and angiopoietin-1. Unknown soluble factors secreted by pericytes also contribute to the upregulation of claudin-5 in endothelial cells in the BNB and thus, strengthen the barrier function of the BNB. In diabetic neuropathy, pericytes were shown to regulate the vascular basement membrane, while AGEs were shown to induce basement membrane hypertrophy and disrupt the BNB by increasing the autocrine secretion of VEGF and TGF-beta from pericytes. In this review article, we discuss the macroscopic and microscopic anatomy of the human BNB as well as the molecular mechanisms of mononuclear cell infiltration across the BNB. PMID- 21613660 TI - [Recent advances in clinical practice and in basic research on diabetic neuropathy]. AB - With the drastic increase in the number of patients with diabetes, management of neuropathy has become a critical concern because of its intractability and the socio-economic burden it poses. Epidemiological studies have shown that the levels of blood glucose and glycated hemoglobin, the duration of diabetes, and hypertension are important risk factors for the development of neuropathy. Although guidelines for the diagnosis and clinical staging of diabetic neuropathy have been proposed, only nerve conduction studies can provide a reliable diagnosis of the condition. Currently, evaluation of small fiber abnormalities has been given great emphasis, because they often appear early in the course of diabetic neuropathy. Quantitative analysis of epidermal innervation is globally performed for determining the indices of small fiber neuropathy, and recently, laser microscopic evaluation of corneal innervation was proposed as a surrogate technique for skin or nerve biopsy, to serve as a quantitative marker for neuropathy. The advantages of the latter technique are that it is non-invasive and allows for repeated observations. However, the validity of this new method requires further confirmation. Investigations on the pathogenesis of diabetic neuropathy are also increasing and diversifying, and new theories are emerging. The polyol pathway, glycation, and proinflammatory reactions are implicated in peripheral nerve injuries. Further, downstream signaling represented by alterations in protein kinase C, poly (ADP-ribose) polymerase, mitogen-activated protein kinases, and mobilization of transcription factors are likely to result in the neuropathic phenotype. Studies are underway to investigate a novel mechanism of diabetic neuropathy, with a view to developing a highly effective treatment that will restore nerve function and structure. PMID- 21613661 TI - [Familial amyloid polyneuropathy]. AB - Familial amyloid polyneuropathy (FAP), a fatal disorder inherited in an autosomal dominant fashion, is characterized by systemic accumulation of polymerized transthyretin (TTR) in the peripheral nerves and systemic organs. Polyneuropathy is often a major manifestation of FAP. Although FAP was considered to be an endemic disorder, the advanced biochemical and molecular genetic analyses have shown worldwide occurrence. More than 100 different points of single or double mutations, or a deletion in the TTR gene, have been reported, and several different phenotypes of FAP have been documented, even for the same mutation in the TTR gene. Liver transplantation, which stops the production of amyloidogenic TTR in blood and replaces it with normal TTR, has been considered as an acceptable treatment for FAP. However, continuous amyloid deposition can occur from wild-type (normal) TTR in some patients. Currently, research an the inhibition of amyloid deposition by small organic molecules that are hypothesized to affect the fibril-forming ability of TTR is underway. PMID- 21613662 TI - [Brain mechanism underlying food intake regulation]. AB - Food intake is precisely regulated in all normal individuals, with a variation of <1%. The hypothalamus is a critical component of the forebrain pathways that regulate long-term energy homeostasis, and it plays a particularly important role in integrating hormonal, neurotransmitter, and nutrient signals. Obese animals fed with high-fat diets show an increase in the inflammatory signals, endoplasmic reticulum stress, and radical oxygen species in the hypothalamus and impairment in the systems regulating food intake. AMP kinase (AMP-activated protein kinase [AMPK]) is a "metabolic sensor" present in a wide variety of organisms, from yeast to mammals. Recent studies have indicated the role of AMPK in hypothalamic neurons in the integration of hormonal, neurotransmitter, and nutrient signals. Furthermore, analysis of genetically engineered mice has revealed that AMPK alters the fatty acid metabolism in the hypothalamic neurons as well as in peripheral tissues, and thereby regulates feeding behavior. Thus, hypothalamic neurons and intracellular signaling pathway that includes AMPK-fatty acid metabolism appear to be the critical components that regulate food intake and body weight. PMID- 21613663 TI - [Intracerebral and subarachnoid hemorrhages after administration of recombinant tissue plasminogen activator in a patient with acute ischemicstroke due to anterior cerebral artery dissection: a case report]. AB - A 45-year-old man was admitted to our hospital for treatment of right hemiparesis. At admission, he was alert and well oriented. His verbal comprehension seemed good, but his speech was not fluent. He could not stand or walk owing to the right hemiparesis, which was severe in the lower extremity. Computed tomographic (CT) scans on admission showed no abnormality. Diffusion weighted magnetic resonance imaging performed after the CT showed a high intensity lesion in the left cingulate gyrus. Magnetic resonance angiography (MRA) revealed occlusion and irregularity of the left A2 portion of the anterior cerebral artery (ACA). At 1 h 50 min after the onset of the hemiparesis, recombinant tissue plasminogen activator (rt-PA; 0.6 mg/kg) was administered intravenously. At 1 h after the administration of rt-PA, he became drowsy and his right hemiparesis deteriorated. CT scans performed again showed a hematoma in the left frontal lobe and subarachnoid hemorrhage in the anterior interhemispheric fissure. He was treated conservatively. MRA performed on the 18th day after admission showed recanalization of the left ACA and abnormal dilatation of the left A2 segment. The abnormal dilatation was also depicted by 3D-CT angiography (3D-CTA) performed on the 26th day after admission and even on the 33rd and 77th days. As seen in our case, the definite diagnosis of dissection confined to the ACA frequently needs serial angiographies; therefore, its diagnosis immediately after the onset is often difficult. Thrombolytic therapy by intravenous administration of rt-PA for cerebral infarction caused by dissection of the ACA may recanalize the occluded site and facilitate the progression of the dissection, resulting in intracerebral and/or subarachnoid hemorrhages. In patients with cerebral infarction due to ACA dissection, strict control of blood pressure and careful observation are necessary after thrombolytic therapy by rt PA. PMID- 21613664 TI - [A tentorial dural arteriovenous fistula presenting progressive myelopathy: a case report]. AB - Abstract We report a case of a dural arteriovenous fistula (DAVF) at the tentorium cerebelli, which presented progressive myelopathy. A 68-year-old man with neurological deterioration of the cervical myelopathy visited our hospital. T2 weighted magnetic resonance (MR) imaging showed high signal area and edema from the medulla to the upper thoracic spinal cord with flow voids on the dorsal surface of the cord. Angiography showed right tentorial DAVF, which was supplied by the right meningohypophyseal trunk, the middle meningeal artery, the accessory meningeal artery, and was drained into the posterior spinal veins. The patient underwent right retrosigmoid suboccipital craniotomy, then disruption of the fistula was performed by using micro Doppler sonography following endovascular obliteration of the main feeders. Postoperative angiography showed complete obliteration of the fistula. His daily functioning gradually improved up to 6 months after the surgery. Tentorial DAVFs with clinical manifestation of myelopathy are rare. Considering its aggressive nature, early surgical treatment could be necessary. (Received: November 17, 2010, Accepted: December 18, 2010). PMID- 21613665 TI - Effect of hypertension and its reverse on serum nitric oxide concentration and vascular permeability in two-kidney one-clip hypertensive rats. AB - The aim of this study was to evaluate the effect of hypertension and its reverse on serum nitric oxide (NO) concentration and endothelial permeability in two kidney one-clip (2K1C) hypertensive rats. 28 male Wistar rats were divided into four groups: 1) 2K1C for 12 weeks; 2) sham-clipped for 12 weeks; 3) 2K1C for 12 weeks and unclipped for 12 weeks; 4) sham-clipped for 12 weeks and unclipped for 12 weeks. Blood samples were taken before experiment, 12th week and 24th week (in groups 3 and 4). Coronary vascular and aortic endothelial permeability were determined by extravasation of Evans blue dye method. Serum NO level was significantly lower in hypertensive group compare with sham group (4.21 +/- 1.28 vs. 9.47 +/- 1.34 umol/l, respectively). Reversal of hypertension did not improve serum NO concentration in 2K1C group (4.21 +/- 1.28 vs. 4.32 +/- 1.34 umol/l). Coronary vascular and aortic endothelial permeability were not different between hypertensive and normotensive groups and reversal of hypertension did not alter endothelial permeability. Lower serum NO concentration in 2K1C hypertensive rats even after reversal of hypertension suggested that in addition to NO, other mechanisms could be involved in surgical reversal of hypertension. Hypertension and its reverse did not change endothelial permeability at least in this model of hypertension. PMID- 21613666 TI - Temperature behaviour of viscous flow with proteins. AB - The paper presents the results of viscosity determinations on aqueous solutions of different mammalian serum albumins at a wide range of concentrations and at temperatures ranging from 278 K to 318 K. On the basis of these measurements and a modified Arrhenius equation, the functional dependence of the solution activation energy of viscous flow on temperature was established. The analysis of the results obtained shows that the activation energy decreases with increasing temperature according to a square function for solutions, water molecules, and the albumins studied. The rate at which the activation energy decreases with increasing temperature is different for each albumin and mainly depends on its hydrodynamic radius. PMID- 21613667 TI - Langevin Poisson-Boltzmann equation: point-like ions and water dipoles near a charged surface. AB - Water ordering near a charged membrane surface is important for many biological processes such as binding of ligands to a membrane or transport of ions across it. In this work, the mean-field Poisson-Boltzmann theory for point-like ions, describing an electrolyte solution in contact with a planar charged surface, is modified by including the orientational ordering of water. Water molecules are considered as Langevin dipoles, while the number density of water is assumed to be constant everywhere in the electrolyte solution. It is shown that the dielectric permittivity of an electrolyte close to a charged surface is decreased due to the increased orientational ordering of water dipoles. The dielectric permittivity close to the charged surface is additionally decreased due to the finite size of ions and dipoles. PMID- 21613668 TI - The effects of beta-glucan on iron levels and lipid peroxidation in intra abdominal sepsis in rats. AB - Sepsis is defined as a systemic response of organisms to microorganisms and toxins. Sepsis is associated with the enhanced generation of reactive oxygen metabolites, leading to multiple organ dysfunctions. beta-glucan is accepted to be one of the most powerful immune response modifiers. The aim of this study was to investigate the putative protective effect of beta-glucan on changes of iron and malondialdehyde (MDA) levels in various tissue and blood after experimental sepsis in rats. Sepsis was induced by cecal ligation and perforation (CLP) in 32 male Wistar albino rat. To evaluate this, rats were divided into four groups as sham operated, beta-glucan treated sham operated, CLP and beta-glucan treated CLP. Sixteen hours after operation, rats were decapitated and MDA and iron levels were measured in the liver, kidney, heart, diaphragm tissues and blood. Also, whole tissue histopathology was evaluated by a light microscope. The results demonstrate that sepsis significantly decreased iron levels of all tissues and blood. The decrease in tissue iron levels and the increase MDA levels demonstrate the role of trace elements and free radicals in sepsis-induced tissue damage. Our results indicate that the given dose of beta-glucan was probably insufficient to prevent sepsis-induced organ injury. PMID- 21613669 TI - Specific volume and compressibility of bilayer lipid membranes with incorporated Na,K-ATPase. AB - Ultrasound velocimetry and densitometry methods were used to study the interactions of the Na,K-ATPase with the lipid bilayer in large unilamellar liposomes composed of dioleoyl phosphatidylcholine (DOPC). The ultrasound velocity increased and the specific volume of the phospholipids decreased with increasing concentrations of protein. These experiments allowed us to determine the reduced specific apparent compressibility of the lipid bilayer, which decreased by approx. 11% with increasing concentrations of the Na,K-ATPase up to an ATPase/DOPC molar ratio = 2 * 10-4. Assuming that ATPase induces rigidization of the surrounding lipid molecules one can obtain from the compressibility data that 3.7 to 100 times more lipid molecules are affected by the protein in comparison with annular lipids. However, this is in contradiction with the current theories of the phase transitions in lipid bilayers. It is suggested that another physical mechanisms should be involved for explanation of observed effect. PMID- 21613670 TI - The influence of protein coding sequences on protein folding rates of all-beta proteins. AB - It is currently believed that the protein folding rate is related to the protein structures and its amino acid sequence. However, few studies have been done on the problem that whether the protein folding rate is influenced by its corresponding mRNA sequence. In this paper, we analyzed the possible relationship between the protein folding rates and the corresponding mRNA sequences. The content of guanine and cytosine (GC content) of palindromes in protein coding sequence was introduced as a new parameter and added in the Gromiha's model of predicting protein folding rates to inspect its effect in protein folding process. The multiple linear regression analysis and jack-knife test show that the new parameter is significant. The linear correlation coefficient between the experimental and the predicted values of the protein folding rates increased significantly from 0.96 to 0.99, and the population variance decreased from 0.50 to 0.24 compared with Gromiha's results. The results show that the GC content of palindromes in the corresponding protein coding sequence really influences the protein folding rate. Further analysis indicates that this kind of effect mostly comes from the synonymous codon usage and from the information of palindrome structure itself, but not from the translation information from codons to amino acids. PMID- 21613671 TI - Relationship between extracellular osmolarity, NaCl concentration and cell volume in rat glioma cells. AB - The cell volume, which controls numerous cellular functions, is theoretically linearly related with the inverse osmolarity. However, deviations from this law have often been observed. In order to clarify the origin of these deviations we electronically measured the mean cell volume of rat glioma cells under three different experimental conditions, namely: at different osmolarities and constant NaCl concentration; at different NaCl concentrations and constant osmolarity and at different osmolarities caused by changes in NaCl concentration. In each condition, the osmolarity was maintained constant or changed with NaCl or mannitol. We showed that the cell volume was dependent on both the extracellular osmolarity and the NaCl concentration. The relationship between cell volume, osmolarity and NaCl concentration could be described by a new equation that is the product of the Boyle-van't Hoff law and the Michaelis-Menten equation at a power of 4. Together, these results suggest that in hyponatriemia, the cell volume deviates from the Boyle-van't Hoff law because either the activity of aquaporin 1, expressed in glioma cells, is decreased or the reduced NaCl influx decreases the osmotically obliged influx of water. PMID- 21613672 TI - Stimulatory effect of 17beta-estradiol on osteogenic differentiation potential of rat adipose tissue-derived stem cells. AB - Adipose tissue-derived stem cells (ADSCs) are considered as a potential cell source for regenerative medicine and tissue engineering. Although ADSCs have greater proliferation capacity than bone marrow stem cells (BMSCs), lower differentiation ability of these cells limits their utility in experimental and clinical studies. The purpose of this study was to investigate whether 17beta estradiol (E(2)) has a stimulatory effect on osteogenic differentiation potential of ADSCs in vitro. ADSCs were isolated from visceral adipose tissues of rats and treated with different concentrations of E(2) in osteogenic medium (OM) for 21 days. The differences in osteogenic differentiation potential of the cultures were assessed by von Kossa staining, measurement of alkaline phosphatase (ALP) activity and calcium levels. ADSCs cultured in OM supplemented with E(2) showed greater bone-like nodule formation and mineral deposition in comparing with the cells grown in OM. In addition, ALP activity and calcium levels also were significantly higher in the cultures exposed to E(2) than the cells treated only with OM (p < 0.005, n = 5). Our results suggest that E(2) may stimulate the osteogenic differentiation of ADSCs and therefore, can be used as an inducing agent to improve the efficiency of these cells in in vitro and in vivo studies. PMID- 21613673 TI - Microscopic second harmonic generation (SHG) from tilt-placed collagen fibrils. AB - We report a theoretical study of second-harmonic generation (SHG) from the collagen fibrils which have a tilt angle Phi between their axes with the plane of the polarization angle alpha of the linearly polarized focused light. The effects of Phi as well as alpha on SHG emission have been investigated. Our results show that the total strength of SHG electrical field (E(2omega)) and power (P(2omega)) reach their maximal values as Phi locates at a certain angle, here it is around 27 degrees under all demonstrated alpha. When Phi < 27 degrees , E(2omega) and P(2omega) gradually increase to their maximal value, while when Phi > 27 degrees , they quickly drops. Specially, E(2omega) and P(2omega) are almost undetectable when Phi >= 45 degrees . Also, Phi influences the distribution pattern of E(2omega), P(2omega) and their parallel (E(2omega,p), P(2omega,p)) and perpendicular (E(2omega,s), P(2omega,s)) components, such as the number of emission lobes and shape. alpha has unevenly impact on E(2omega) and P(2omega), the far deviation of alpha from x axis induce much great decrease of E(2omega) and P(2omega). alpha = 45 degrees has special influence on the distribution pattern of E(2omega,s), E(2omega), P(2omega,s) as well as P(2omega) compared to those of alpha = 0 degrees and 90 degrees . PMID- 21613674 TI - Estimation of thickness of concentration boundary layers by osmotic volume flux determination. AB - The estimation method of the concentration boundary layers thicknesses (delta) in a single-membrane system containing non-electrolytic binary or ternary solutions was devised using the Kedem-Katchalsky formalism. A square equation used in this method contains membrane transport (L(p), sigma, omega) and solution (D, C) parameters as well as a volume osmotic flux (J(v)). These values can be determined in a series of independent experiments. Calculated values delta are nonlinearly dependent on the concentrations of investigated solutions and the membrane system configuration. These nonlinearities are the effect of a competition between spontaneously occurring diffusion and natural convection. The mathematical model based on Kedem-Katchalsky equations and a concentration Rayleigh number (R(C)) was presented. On the basis of this model we introduce the dimensionless parameter, called by us a Katchalsky number (Ka), modifies R(C) of membrane transport. The critical value of this number well describes a moment of transition from the state of diffusion into convective diffusion membrane transport. PMID- 21613675 TI - Chemically mimicked hypoxia modulates gene expression and protein levels of the sodium calcium exchanger in HEK 293 cell line via HIF-1alpha. AB - Up to now a little is known about the effect of hypoxia on the sodium calcium exchanger type 1 (NCX1) expression and function. Therefore, we studied how dimethyloxallyl glycine (DMOG), an activator and stabilizer of the hypoxia inducible factor (HIF)-1alpha, could affect expression of the NCX1 in HEK 293 cell line. We also tried to determine whether this activation can result in the induction of apoptosis in HEK 293 cells. We have found that DMOG treatment for 3 hours significantly increased gene expression and also protein levels of the NCX1. This increase was accompanied by a decrease in intracellular pH. Wash-out of DMOG did not result in reduction of the NCX1 mRNA and protein to original - control levels, although pH returned to physiological values. Using luciferase reporter assay we observed increase in the NCX1 promoter activity after DMOG treatment and using wild-type mouse embryonic fibroblast (MEF)-HIF-1(+/+) and HIF 1-deficient MEF-HIF-1(-/-) cells we have clearly shown that in the promoter region, HIF-1alpha is involved in DMOG induced upregulation of the NCX1. Moreover, we also showed that an increase in the NCX1 mRNA due to the apoptosis induction is not regulated by HIF-1alpha. PMID- 21613676 TI - Red wine polyphenols correct vascular function injured by chronic carbon tetrachloride intoxication. AB - The aim of the study was to evaluate the effect of red wine polyphenols extract ProvinolsTM on the development of cardiovascular injury in the model of carbon tetrachloride (CCl4) intoxication. We followed the thoracic aorta vasoactivity and left ventricle nitric oxide (NO) synthase activity in male Wistar rats. In the preventive experiment lasting for 12 weeks the control group, the group receiving CCl4 (0.5 ml/kg) two times a week subcutaneously, the group receiving ProvinolsTM (30 mg/kg/day) in drinking water and the group receiving CCl4+ProvinolsTM was used. In the recovery experiment, the initial 12 weeks of CCl4 treatment were followed by 3 weeks of spontaneous recovery or recovery with ProvinolsTM. CCl4-intoxication resulted in the injury of vasoactivity which was demonstrated by the inhibition of acetylcholine-induced relaxation as well as noradrenaline-induced contraction. In the preventive as well as recovery experiment administration of polyphenols refreshed endothelium-dependent relaxant response and normalized inhibited contraction to adrenergic stimuli. ProvinolsTM treatment significantly increased NO-synthase activity in all groups. The results revealed beneficial effects of red wine polyphenols on vascular function injured by chronic CCl4 intoxication. The correction of endothelial function seems to be attributed to the activation of NO pathway by polyphenols. PMID- 21613678 TI - GaN nanodiscs embedded in nanowires as optochemical transducers. AB - The photoluminescence (PL) response of GaN/AlGaN nanowire heterostructures (NWHs) to hydrogen and oxygen between room temperature and 300 degrees C is reported. Exposure of Pt-coated NWHs to H2 leads to an increase of the PL intensity attributed to the suppression of surface recombination by local dipole fields of adsorbed atomic hydrogen. When exposed to O2, uncoated NWHs show a decrease in PL intensity that is assigned to enhanced non-radiative recombination. The detection limits are below 5 ppm at 150 degrees C. PMID- 21613677 TI - Comparing carbon nanotubes and graphene nanoplatelets as reinforcements in polyamide 12 composites. AB - We investigate the influence of nanofillers including carbon nanotubes (CNTs) and graphene nanoplatelets on a thermoplastic engineering polymer, polyamide 12 (PA12). The comparison between these two important nanofillers as to how they influence the structure and properties of the polymer is systematically studied. The polymer-nanofiller composites were prepared using a twin-screw micro-extruder and the composite was thereafter hot pressed into thin films. The structure (using wide angle x-ray diffraction and differential scanning calorimetry) and properties (through tensile testing and conductivity measurement) of the thin films have been investigated. The composites incorporating surfactant showed the best CNT distribution and dispersion, causing an improvement of up to 80% in the toughness modulus over pure PA12. Electrical percolation could also be achieved at nanofiller concentrations of 1 to 2 wt%. In this study we observed that CNT fillers bring about more pronounced improvements in PA12 compared to graphene nanoplatelets, as far as mechanical and electrical properties are concerned. PMID- 21613679 TI - Synthesis and characterization of human transferrin-stabilized gold nanoclusters. AB - Human transferrin has been biolabelled with gold nanoclusters (Au NCs) using a simple, fast and non-toxic method. These nanocrystals (<2 nm) are stabilized in the protein via sulfur groups and have a high fluorescence emission in the near infrared region (QY=4.3%; lambdaem=695 nm). Structural investigation and photophysical measurements show a high population of clusters formed of 22-33 gold atoms covalently bound to the transferrin. In solutions with pH ranging from 5 to 10 and in buffer solutions (PBS, HEPES), those biolabelled proteins exhibit a good stability. No significant quenching effect of the fluorescent transferrin has been detected after iron loading of iron-free transferrin (apoTf) and in the presence of a specific polyclonal antibody. Additionally, antibody-induced agglomeration demonstrates no alteration in the protein activity and the receptor target ability. MTT and Vialight(r) Plus tests show no cytotoxicity of these labelled proteins in cells (1 ug ml(-1)-1 mg ml(-1)). Cell line experiments (A549) indicate also an uptake of the iron loaded fluorescent proteins inside cells. These remarkable data highlight the potential of a new type of non-toxic fluorescent transferrin for imaging and targeting. PMID- 21613680 TI - Improvement of resistive switching in Cu/ZnO/Pt sandwiches by weakening the randomicity of the formation/rupture of Cu filaments. AB - We report an improvement in minimizing the dispersion of resistive switching (RS) parameters such as ON/OFF state resistances and switching voltages of Cu/ZnO/Pt structures in which ZnO films have been deposited at elevated temperature with N doping. This deposition process can enlarge the ZnO grain size and lessen grain boundaries while maintaining a high initial resistance since ZnO naturally shows n-type conductivity and N is a p-type dopant but with a low solubility. Cu filaments with a diameter of 15 nm are found to form at the ZnO grain boundaries. Therefore, fewer grain boundaries could depress the randomicity of the formation/rupture of Cu filaments and result in more stable RS performances. Such memory devices show a fast programming speed of 10 ns. PMID- 21613681 TI - Defined-size DNA triple crossover construct for molecular electronics: modification, positioning and conductance properties. AB - We present a novel, defined-size, small and rigid DNA template, a so-called B-A-B complex, based on DNA triple crossover motifs (TX tiles), which can be utilized in molecular scale patterning for nanoelectronics, plasmonics and sensing applications. The feasibility of the designed construct is demonstrated by functionalizing the TX tiles with one biotin-triethylene glycol (TEG) and efficiently decorating them with streptavidin, and furthermore by positioning and anchoring single thiol-modified B-A-B complexes to certain locations on a chip via dielectrophoretic trapping. Finally, we characterize the conductance properties of the non-functionalized construct, first by measuring DC conductivity and second by utilizing AC impedance spectroscopy in order to describe the conductivity mechanism of a single B-A-B complex using a detailed equivalent circuit model. This analysis also reveals further information about the conductivity of DNA structures in general. PMID- 21613682 TI - Plasmonic enhancement of fluorescence on silver nanoparticle films. AB - The localized plasmon controlled fluorescence has been discussed by comparing the fluorescence enhancement of dyes on different shaped silver nanoparticle self assembled films. A trilayer structure, composed of a silver nanoparticle monolayer, a proper thickness polyelectrolyte spacing layer and a dye-adsorbed layer, was constructed to study the plasmon enhanced fluorescence properties. The effective coupling of the plasmon band with the excitation or emission of dye resulted in different enhancement factors. Moreover, the plasmon enhanced fluorescence resonance energy transfer (FRET) of two dyes was observed. The FRET efficiency of the spherical silver nanoparticle self-assembled film had a 2.8 fold increase. The improvement of FRET efficiency via localized surface plasmons would increase the sensitivity of FRET-based bioassays. PMID- 21613683 TI - A crossbar-type high sensitivity ultraviolet photodetector array based on a one hole-one nanorod configuration via nanoimprint lithography. AB - Single crystalline vertical ZnO nanorods were grown in a one hole-one rod configuration using a hydrothermal method with a patterned polymer template generated by nanoimprint lithography, allowing precise control over the position and density of the ZnO nanorods. An 8*8 ZnO nanorod-based ultraviolet photodetector array is demonstrated, in which a well-confined number of ZnO nanorods are sandwiched between crossbar-type platinum and indium tin oxide electrodes (e.g. 16 nanorods in a 2*2 um2 area). A high photocurrent/dark current ratio of 3*10(3) at a reverse bias of 1.5 V under UV illumination at room temperature, a responsivity of 4381.4 A W(-1) at 365 nm, and an ultraviolet-to visible rejection ratio of 83 are obtained and maintained, irrespective of pixel size. A uniform photoresponse is achieved in each of the pixels, indicating the scalability with this technique for fabricating an integrated UV photodetector array circuit. PMID- 21613684 TI - Fabrication of mesoporous titania membrane of dual-pore system and its photocatalytic activity and dye-sensitized solar cell performance. AB - We report the fabrication of a novel titania membrane of the dual-pore system that is strategically designed and prepared by a two-step replication process and sol-gel reaction. The primary nanoporous channel structure is fabricated by the cage-like PMMA template (CPT) obtained from the nanoporous alumina membrane and the secondary mesoporous structure is formed by the sol-gel reaction of the lyotropic precursor solution within the CPT. Furthermore the mesoporous titania membrane (MTM) frame consists of the titania nanoparticles of 10-12 nm in diameter. Morphology and structural properties of the MTM are investigated by field emission scanning electron microscopy, high resolution transmission electron microscopy, x-ray diffraction and Brunauer-Emmett-Teller surface area. The photocatalytic activity and the solar energy properties of the MTM are characterized by UV-vis spectrophotometer, spectrofluorometer and photoinduced I V measurement. The photocatalytic test indicates that the MTM has higher efficiency than the commercial P25 with a good recyclability due to its large scale membrane style and the preliminary result on the solar cell application shows a solar energy conversion efficiency of 3.35% for the dye-sensitized solar cell utilizing the MTM. PMID- 21613685 TI - Electrical and thermal conductivity of low temperature CVD graphene: the effect of disorder. AB - In this paper we present a study of graphene produced by chemical vapor deposition (CVD) under different conditions with the main emphasis on correlating the thermal and electrical properties with the degree of disorder. Graphene grown by CVD on Cu and Ni catalysts demonstrates the increasing extent of disorder at low deposition temperatures as revealed by the Raman peak ratio, IG/ID. We relate this ratio to the characteristic domain size, La, and investigate the electrical and thermal conductivity of graphene as a function of La. The electrical resistivity, rho, measured on graphene samples transferred onto SiO2/Si substrates shows linear correlation with La(-1). The thermal conductivity, K, measured on the same graphene samples suspended on silicon pillars, on the other hand, appears to have a much weaker dependence on La, close to K~La1/3. It results in an apparent rho~K3 correlation between them. Despite the progressively increasing structural disorder in graphene grown at lower temperatures, it shows remarkably high thermal conductivity (10(2)-10(3) W K(-1) m(-1)) and low electrical (10(3)-3*10(5) Omega) resistivities suitable for various applications. PMID- 21613686 TI - Direct patterning of a cyclotriveratrylene derivative for directed self-assembly of C60. AB - A novel apex-modified cyclotriveratrylene (CTV) derivative with an attached thiolane-containing lipoic acid linker was directly patterned onto gold substrates via dip-pen nanolithography (DPN). The addition of a dithiolane containing linker to the apex of CTV provides a molecule that can adhere to a gold surface with its bowl-shaped cavity directed away from the surface, thereby providing a surface-bound CTV host that can be used for the directed assembly of guest molecules. Subsequent exposure of these CTV microarrays to C60 in toluene resulted in the directed assembly of predesigned, spatially controlled, high density microarrays of C60. The molecular recognition capabilities of this CTV template toward C60 provides proof-of-concept that supramolecular CTV scaffolds can be directly patterned onto surfaces providing a foundation for the development of organic electronic and optoelectronic materials. PMID- 21613687 TI - Core-shell morphology and characterization of carbon nanotube nanowires click coupled with polypyrrole. AB - Core-shell nanowires having multiwalled carbon nanotubes (MWNT) as a core and polypyrrole (PPy) as a shell were synthesized using Cu(I)-catalyzed azide-alkyne cycloaddition click chemistry. According to transmission electron microscopy measurements, the uniform PPy layers of 10-20 nm in thickness were formed well on the MWNT's surface. In particular 'grafting from' click coupling was more effective in obtaining uniform and stable core-shell nanowires as well as in the reaction yield, compared to 'grafting to' click coupling. This is due to chemical bond formation between PPy and MWNT in equal intervals along the longitudinal direction of the MWNT, achieved by 'grafting from' click coupling. As a result, the core-shell nanowires were very stable even in the sonication of nanowires and showed an enhanced electrical conductivity of 80 S cm(-1), due to the synergetic interaction between MWNTs and PPy, which is higher than the conductivity of pure MWNTs and pure PPy. In addition, the core-shell nanowires could show better NO2 gas sensing properties compared to pure MWNTs and pure PPy as well as MWNT/PPy composites prepared by in situ polymerization. The synthesized core-shell nanowires would play an important role in preparing electrical and sensing devices. PMID- 21613688 TI - Using 2H labeling with neutron radiography for the study of solid polymer electrolyte water transport properties. AB - A method combining (2)H labeling of different sources of H atoms (hydrogen, water vapor) with neutron imaging for the analysis of transport parameters in the bulk and at the interfaces of Nafion polymer electrolyte membranes is proposed. The use of different isotope compositions in the steady state allows evaluation of the relation between bulk and interface transport parameters, but relies on literature data for evaluating absolute values. By using transients of isotope composition, absolute values of these parameters including the self-diffusion coefficient of H can be extracted, making this method an attractive alternative to self-diffusion measurements using nuclear magnetic resonance (NMR), allowing measurements in precisely controlled conditions in real fuel cell structures. First measurements were realized on samples with and without electrodes and we report values of the self-diffusion coefficient of the same order of magnitude as values measured using NMR, although with slightly higher numbers. In our particular case, lower interfacial exchange rates for water transport were observed for samples with an electrode. PMID- 21613689 TI - Self-diffusion of non-interacting hard spheres in particle gels. AB - Different kinds of particle gels were simulated using a process of random aggregation of hard spheres. The mean square displacement of Brownian spherical tracer particles through these rigid gels was monitored and the average diffusion coefficient, normalized with the free diffusion coefficient (D), was obtained. For each gel structure the effect of the gel volume fraction (phi) and size ratio of the tracer (d) on the relative diffusion coefficient was investigated systematically. The volume fraction that is accessible to the tracers (phi(a)) was determined in each case. D was found to be approximately the same if phi(a) was the same, independent of phi, d and the gel structure. However a different behaviour is found if the tracers can penetrate the strands of the gel. A state diagram of d versus phi is given that shows the critical values (d(c), phi(c)) at which all tracers become trapped. Different values are found for different gel structures. The dependence of D on phi/phi(c) is independent of d, while the dependence of D on d/d(c) is independent of phi. PMID- 21613690 TI - Signature of Al11Sm3 fragments in undercooled Al90Sm10 liquid from ab initio molecular dynamics simulations. AB - An ab initio molecular dynamics (MD) simulation is performed to investigate the structural evolution in Al(90)Sm(10) liquid from 1500 to 900 K. Development of Al(11)Sm(3) local order upon rapid cooling is suggested by the Honeycutt-Anderson (HA) index analysis and the appearance of a predominant Sm-Sm-Sm bond angle around 90 degrees when the liquid approaches the melting point (~920 K). Direct structural evidence of Al(11)Sm(3) fragments at 900 K is obtained using an atomic cluster alignment method developed recently. Meanwhile, development of strong icosahedral short range order (ISRO) and a non-negligible amount of fcc-type clusters around Al in the system are also observed. These results suggest that fcc Al and Al(11)Sm(3) crystalline phases would compete strongly with the formation of an amorphous phase that exhibits ISRO in the diffusionless solidification limit upon rapid quenching. PMID- 21613691 TI - Slow dynamics, dynamic heterogeneities, and fragility of supercooled liquids confined in random media. AB - Using molecular dynamics simulations, we study the slow dynamics of supercooled liquids confined in a random matrix of immobile obstacles. We study the dynamical crossover from glass-like to Lorentz-gas-like behavior in terms of the density correlation function, the mean square displacement, the nonlinear dynamic susceptibility, the non-gaussian parameter, and the fragility. We find the cooperative and spatially heterogeneous dynamics to be suppressed as the obstacle density increases, leading to a more Arrhenius-like behavior in the temperature dependence of the relaxation time. Our findings are qualitatively consistent with the results of recent experimental and numerical studies for various classes of spatially heterogeneous systems. We also investigate the dependence of the dynamics of mobile particles on the protocol used to generate the random matrix. A re-entrant transition from the arrested phase to the liquid phase as the mobile particle density increases is observed for a class of protocols. This re-entrance is explained in terms of the distribution of the volume of the voids that are available to the mobile particles. PMID- 21613692 TI - Static and dynamic contributions to anomalous chain dynamics in polymer blends. AB - By means of computer simulations, we investigate the relaxation of the Rouse modes in a simple bead-spring model for non-entangled polymer blends. Two different models are used for the fast component, namely fully flexible and semiflexible chains. The latter, which incorporate intramolecular barriers with bending and torsion terms, are semiflexible in the sense that static intrachain correlations are strongly non-gaussian at all length scales. The dynamic asymmetry in the blend is strongly enhanced with decreasing temperature, inducing confinement effects on the fast component. The dynamics of the Rouse modes show very different trends for the two models of the fast component. For the fully flexible case, the relaxation times exhibit a progressive deviation from Rouse scaling on increasing the dynamic asymmetry. This anomalous effect has a dynamic origin. It is not related to particular static features of the Rouse modes, which indeed are identical to those of the fully flexible homopolymer, and are not modified by the dynamic asymmetry in the blend. On the contrary, in the semiflexible case the relaxation times approximately exhibit the same scaling behaviour as the amplitudes of the modes. This suggests that the origin of the anomalous dynamic scaling for semiflexible chains confined in the blend is essentially of static nature. We discuss the implications of these observations for the applicability of theoretical approaches to chain dynamics in polymer blends. PMID- 21613693 TI - Molecular structure and transport dynamics in perfluoro sulfonyl imide membranes. AB - We report a detailed and comprehensive analysis from classical molecular dynamics simulations of the nanostructure of a model of hydrated perfluoro sulfonyl imide (PFSI) membrane, a polymeric system of interest as a proton conductor in polymer electrolyte membrane fuel cells. We also report on the transport dynamics of water and hydronium ions, and water network percolation in this system. We find that the water network percolation threshold for PFSI, i.e. the threshold at which a consistent spanning water network starts to develop in the membrane, is found to occur between hydration levels (lambda) 6 and 7. The higher acidity of the sulfonyl imide acid group of PFSI compared to the sulfonic acid group in Nafion, as computationally characterized in our earlier ab initio study (Idupulapati et al 2010 J. Phys. Chem. A 114 6904-12), results in a larger fraction of 'free' hydronium ions at low hydration levels in PFSI compared to Nafion. However, the calculated diffusion coefficients of the H(3)O(+) ions and H(2)O molecules as a function the hydration level are observed to be almost the same as that of Nafion, indicating similar conductivity and consistent with experimental data. PMID- 21613694 TI - Ab initio molecular dynamics of proton networks in narrow polymer electrolyte pores. AB - It is well established that proton conductivity in fuel cell membrane materials such as Nafion decreases strongly with decreasing water content. Proton transport in almost dry membranes is thought to proceed through narrow channels. In the present work we investigate proton structure and dynamics in two narrow cylindrical pores, which differ by their radius and the spacing of SO(3)H groups inside the channel. Pores are modelled through eight CF(3)CF(3) and four CF(3)SO(3)H entities in a helical arrangement. The water content lambda (the ratio between the number of water molecules and the number of sulfonic acid groups) in the pores varies between 2.5 and 4.5. We observe a transition from the undissociated acid at very low lambda through more or less localized H(3)O(+) entities to more delocalized H(5)O(2)(+) entities for the investigated range of lambda. In the narrower pore, where S-S distances vary in a more favourable range (between 6 and 8.5 A) than in the wider pore, we find that the molecular mobility is significantly higher, even at a rather high density of water molecules inside the pore. PMID- 21613695 TI - Probing glassy states in binary mixtures of soft interpenetrable colloids. AB - We present experimental evidence confirming the recently established rich dynamic state diagram of asymmetric binary mixtures of soft colloidal spheres. These mixtures consist of glassy suspensions of large star polymers to which different small stars are added at varying concentrations. Using rheology and dynamic light scattering measurements along with a simple phenomenological analysis, we show the existence of re-entrance and multiple glassy states, which exhibit distinct features. Cooperative diffusion, as a probe for star arm interpenetration, is proven to be sensitive to the formation of the liquid pockets which signal the melting of the large-star-glass upon addition of small stars. These results provide ample opportunities for tailoring the properties of soft colloidal glasses. PMID- 21613696 TI - Transport phenomena in proton conducting media. PMID- 21613697 TI - Medium-range correlation of Ag ions in superionic melts of Ag2Se and AgI by reverse Monte Carlo structural modelling-connectivity and void distribution. AB - High-energy x-ray diffraction measurements on molten Ag(2)Se were performed. Partial structure factors and radial distribution functions were deduced by reverse Monte Carlo (RMC) structural modelling on the basis of our new x-ray and earlier published neutron diffraction data. These partial functions were compared with those of molten AgI. Both AgI and Ag(2)Se have a superionic solid phase prior to melting. New RMC structural modelling for molten AgI was performed to revise our previous model with a bond-angle restriction to reduce the number of unphysical Ag triangles. The refined model of molten AgI revealed that isolated unbranched chains formed by Ag ions are the cause of the medium-range order of Ag. In contrast with molten AgI, molten Ag(2)Se has 'cage-like' structures with approximately seven Ag ions surrounding a Se ion. Connectivity analysis revealed that most of the Ag ions in molten Ag(2)Se are located within 2.9 A of each other and only small voids are found, which is in contrast to the wide distribution of Ag-void radii in molten AgI. It is conjectured that the collective motion of Ag ions through small voids is required to realize the well-known fast diffusion of Ag ions in molten Ag(2)Se, which is comparable to that in molten AgI. PMID- 21613698 TI - A structural study of the proton conducting B-site ordered perovskite Ba3Ca1.18Ta1.82O8.73. AB - The proton conducting material Ba(3)Ca(1.18)Ta(1.82)O(8.73) (BCT18) was synthesized and characterized using diffraction methods and thermal analysis. It was shown that BCT18 is structurally similar to its niobium analogue (BCN18). At synthesis temperatures up to 1500 degrees C however, BCT18 forms a mixture of Ca and Ta-site ordered phases, with both 1:1 type and 1:2 type ordering. The phase ratio seems to depend solely on the synthesis conditions, with 1:1 type ordering being the dominant form in most cases. Thermal treatment in vacuum, wet and dry hydrogen, and CO(2) suggests that both forms contain defects (Ca(Ta)(''') and V(O)(..)), allowing the material to absorb water and CO(2). The uptake and the release of H(2)O and of CO(2) are all reversible, as evidenced by x-ray diffraction studies and thermal analysis, suggesting that the molecules are present as structural defects (OH(O)(.) and CO(3O)(*)), rather than surface species or separate hydroxide or carbonate phases. Solid state (1)H nuclear magnetic resonance also confirms the presence of protons, and the peak broadening suggests that they are mobile at room temperature. PMID- 21613699 TI - Diffusion of active tracers in fluctuating fields. AB - The problem of a particle diffusion in a fluctuating scalar field is studied. In contrast to most studies of advection diffusion in random fields, ours analyzes the case where the particle position is also coupled to the dynamics of the field. Physical realizations of this problem are numerous and range from the diffusion of proteins in fluctuating membranes to the diffusion of localized magnetic fields in spin systems. We present exact results for the diffusion constant of particles diffusing in dynamical Gaussian fields in the adiabatic limit, where the field evolution is much faster than the particle diffusion. In addition we compute the diffusion constant perturbatively, in the weak coupling limit, when the interaction of the particle with the field is small, using a Kubo type relation. Finally we construct a simple toy model which can be solved exactly, and which extrapolates between the adiabatic limit, for fields with rapid dynamics, and the limit where the field is quenched or frozen. PMID- 21613700 TI - Systematic coarse-graining of the dynamics of entangled polymer melts: the road from chemistry to rheology. AB - For optimal processing and design of entangled polymeric materials it is important to establish a rigorous link between the detailed molecular composition of the polymer and the viscoelastic properties of the macroscopic melt. We review current and past computer simulation techniques and critically assess their ability to provide such a link between chemistry and rheology. We distinguish between two classes of coarse-graining levels, which we term coarse-grained molecular dynamics (CGMD) and coarse-grained stochastic dynamics (CGSD). In CGMD the coarse-grained beads are still relatively hard, thus automatically preventing bond crossing. This also implies an upper limit on the number of atoms that can be lumped together (up to five backbone carbon atoms) and therefore on the longest chain lengths that can be studied. To reach a higher degree of coarse graining, in CGSD many more atoms are lumped together (more than ten backbone carbon atoms), leading to relatively soft beads. In that case friction and stochastic forces dominate the interactions, and action must be undertaken to prevent bond crossing. We also review alternative methods that make use of the tube model of polymer dynamics, by obtaining the entanglement characteristics through a primitive path analysis and by simulation of a primitive chain network. We finally review super-coarse-grained methods in which an entire polymer is represented by a single particle, and comment on ways to include memory effects and transient forces. PMID- 21613701 TI - Controlling protein crystal growth rate by means of temperature. AB - We have proposed a model to analyze the growth kinetics of lysozyme crystals/aggregates under non-isothermal conditions. The model was formulated through an analysis of the entropy production of the growth process which was obtained by taking into account the explicit dependence of the free energy on the temperature. We found that the growth process is coupled with temperature variations, resulting in a novel Soret-type effect. We identified the surface entropy of the crystal/aggregate as a decisive ingredient controlling the behavior of the average growth rate as a function of temperature. The behavior of the Gibbs free energy as a function of temperature is also analyzed. The agreement between theory and experiments is very good in the range of temperatures considered. PMID- 21613702 TI - Challenges in determining anomalous diffusion in crowded fluids. AB - Anomalous diffusion in crowded fluids, e.g. in the cytoplasm of living cells, is a frequent phenomenon. Despite manifold observations of anomalous diffusion with several experimental techniques, a thorough understanding of the underlying microscopic causes is still lacking. Here, we have quantitatively compared two popular techniques with which anomalous diffusion is typically assessed. Using extensive computer simulations of two prototypical random walks with stationary increments, i.e. fractional brownian motion and obstructed diffusion, we find that single particle tracking (SPT) yields results for the diffusion anomaly that are equivalent to those obtained by fluorescence correlation spectroscopy (FCS). We also show that positional uncertainties, inherent to SPT experiments, lead to a systematic underestimation of the diffusion anomaly, regardless of the underlying random walk and measurement technique. This effect becomes particularly relevant when the position uncertainty is larger than the average positional displacement between two successive frames. PMID- 21613703 TI - Phonon dispersions of cluster crystals. AB - We analyze the ground states and the elementary collective excitations (phonons) of a class of systems, which form cluster crystals in the absence of attractions. Whereas the regime of moderate-to-high temperatures in the phase diagram has been analyzed in detail by means of density functional considerations (Likos et al 2007 J. Chem. Phys. 126 224502), the present approach focuses on the complementary regime of low temperatures. We establish the existence of an infinite cascade of isostructural transitions between crystals with different lattice site occupancies at T = 0 and we quantitatively demonstrate that the thermodynamic instabilities are bracketed by mechanical instabilities arising from long-wavelength acoustical phonons. We further show that all optical modes are degenerate and flat, giving rise to almost perfect realizations of Einstein crystals. We calculate analytically the complete phonon spectrum for the whole class of models as well as the Helmholtz free energy of the systems. On the basis of the latter, we demonstrate that the aforementioned isostructural phase transitions must terminate at an infinity of critical points at low temperatures, brought about by the anharmonic contributions in the Hamiltonian and the hopping events in the crystals. PMID- 21613704 TI - Spatial distribution and dynamics of proton conductivity in fuel cell membranes: potential and limitations of electrochemical atomic force microscopy measurements. AB - The proton conductivity of a Nafion 112 membrane is measured with a high spatial resolution using electrochemical atomic force microscopy. Image analysis reveals an inhomogeneous conductivity distribution which is attributed to the limited connectivity of hydrophilic domains. This information relates to the micro morphology which is due to phase separation of the hydrophobic polymer backbone and the hydrophilic pendant groups. The direct images relate to a different length scale and are complementary to the x-ray diffraction investigations which provide only average information. Furthermore, the measured current values reveal an interesting correlation with the size of the conductive areas. A bimodal conductivity distribution suggests that there are different mechanisms which contribute to the proton current in Nafion. Additionally, time dependence in local conductivity is found and interpreted in terms of redistribution of water in the membrane. A statistical analysis of the current distribution is performed and compared with theoretical simulations. Evidence is found for the existence of a critical current density. On a timescale of seconds the response of the conductive network is probed by applying voltage steps to the atomic force microscope tip. PMID- 21613705 TI - Electrostatic models of electron-driven proton transfer across a lipid membrane. AB - We present two models for electron-driven uphill proton transport across lipid membranes, with the electron energy converted to the proton gradient via the electrostatic interaction. In the first model, associated with the cytochrome c oxidase complex in the inner mitochondria membranes, the electrostatic coupling to the site occupied by an electron lowers the energy level of the proton-binding site, making proton transfer possible. In the second model, roughly describing the redox loop in a nitrate respiration of E. coli bacteria, an electron displaces a proton from the negative side of the membrane to a shuttle, which subsequently diffuses across the membrane and unloads the proton to its positive side. We show that both models can be described by the same approach, which can be significantly simplified if the system is separated into several clusters, with strong Coulomb interaction inside each cluster and weak transfer couplings between them. We derive and solve the equations of motion for the electron and proton creation/annihilation operators, taking into account the appropriate Coulomb terms, tunnel couplings, and the interaction with the environment. For the second model, these equations of motion are solved jointly with a Langevin type equation for the shuttle position. We obtain expressions for the electron and proton currents and determine their dependence on the electron and proton voltage build-ups, on-site charging energies, reorganization energies, temperature, and other system parameters. We show that the quantum yield in our models can be up to 100% and the power-conversion efficiency can reach 35%. PMID- 21613706 TI - Molecular basis of proton uptake in single and double mutants of cytochrome c oxidase. AB - Cytochrome c oxidase, the terminal enzyme of the respiratory chain, utilizes the reduction of dioxygen into water to pump protons across the mitochondrial inner membrane. The principal pathway of proton uptake into the enzyme, the D channel, is a 2.5 nm long channel-like cavity named after a conserved, negatively charged aspartic acid (D) residue thought to help recruiting protons to its entrance (D132 in the first subunit of the S. sphaeroides enzyme). The single-point mutation of D132 to asparagine (N), a neutral residue, abolishes enzyme activity. Conversely, replacing conserved N139, one-third into the D channel, by D, induces a decoupled phenotype, whereby oxygen reduction proceeds but not proton pumping. Intriguingly, the double mutant D132N/N139D, which conserves the charge of the D channel, restores the wild-type phenotype. We use molecular dynamics simulations and electrostatic calculations to examine the structural and physical basis for the coupling of proton pumping and oxygen chemistry in single and double N139D mutants. The potential of mean force for the conformational isomerization of N139 and N139D side chains reveals the presence of three rotamers, one of which faces the channel entrance. This out-facing conformer is metastable in the wild-type and in the N139D single mutant, but predominant in the double mutant thanks to the loss of electrostatic repulsion with the carboxylate group of D132. The effects of mutations and conformational isomerization on the pKa of E286, an essential proton-shuttling residue located at the top of the D channel, are shown to be consistent with the electrostatic control of proton pumping proposed recently (Fadda et al 2008 Biochim. Biophys. Acta 1777 277-84). Taken together, these results suggest that preserving the spatial distribution of charges at the entrance of the D channel is necessary to guarantee both the uptake and the relay of protons to the active site of the enzyme. These findings highlight the interplay of long-range electrostatic forces and local structural fluctuations in the control of proton movement and provide a physical explanation for the restoration of proton pumping activity in the double mutant. PMID- 21613707 TI - A review on phosphate based, solid state, protonic conductors for intermediate temperature fuel cells. AB - The electrolytes currently used for proton exchange membrane fuel cells are mainly based on polymers such as Nafion which limits the operation regime of the cell to ~80 degrees C. Solid oxide fuel cells operate at much elevated temperatures compared to proton exchange membrane fuel cells (~1000 degrees C) and employ oxide electrolytes such as yttrium stabilized zirconia and gadolinium doped ceria. So far an intermediate temperature operation regime (300 degrees C) has not been widely explored which would open new pathways for novel fuel cell systems. In this review we summarize the potential use of phosphate compounds as electrolytes for intermediate temperature fuel cells. Various examples on ammonium polyphosphate, pyrophosphate, cesium phosphate and other phosphate based electrolytes are presented and their preparation methods, conduction mechanism and conductivity values are demonstrated. PMID- 21613708 TI - Fluids with quenched disorder: scaling of the free energy barrier near critical points. AB - In the context of Monte Carlo simulations, the analysis of the probability distribution P(L)(m) of the order parameter m, as obtained in simulation boxes of finite linear extension L, allows for an easy estimation of the location of the critical point and the critical exponents. For Ising-like systems without quenched disorder, P(L)(m) becomes scale-invariant at the critical point, where it assumes a characteristic bimodal shape featuring two overlapping peaks. In particular, the ratio between the value of P(L)(m) at the peaks (P(L, max)) and the value at the minimum in between (P(L, min)) becomes L-independent at criticality. However, for Ising-like systems with quenched random fields, we argue that instead DeltaF(L) := ln(P(L, max)/P(L, min)) proportional to L(theta) should be observed, where theta > 0 is the 'violation of hyperscaling' exponent. Since theta is substantially non-zero, the scaling of DeltaF(L) with system size should be easily detectable in simulations. For two fluid models with quenched disorder, DeltaF(L) versus L was measured and the expected scaling was confirmed. This provides further evidence that fluids with quenched disorder belong to the universality class of the random field Ising model. PMID- 21613709 TI - Dynamic arrest of colloids in porous environments: disentangling crowding and confinement. AB - Using numerical simulations we study the slow dynamics of a colloidal hard-sphere fluid adsorbed in a matrix of disordered hard-sphere obstacles. We calculate separately the contributions to the single-particle dynamic correlation functions due to free and trapped particles. The separation is based on a Delaunay tessellation to partition the space accessible to the centres of fluid particles into percolating and disconnected voids. We find that the trapping of particles into disconnected voids of the matrix is responsible for the appearance of a nonzero long-time plateau in the single-particle intermediate scattering functions of the full fluid. The subdiffusive exponent z, obtained from the logarithmic derivative of the mean squared displacement, is essentially unaffected by the motion of trapped particles: close to the percolation transition, we determined z approximately = 0.5 for both the full fluid and the particles moving in the percolating void. Notably, the same value of z is found in single-file diffusion and is also predicted by mode-coupling theory along the diffusion-localization line. We also reveal subtle effects of dynamic heterogeneity in both the free and the trapped component of the fluid particles, and discuss microscopic mechanisms that contribute to this phenomenon. PMID- 21613710 TI - Long-wavelength anomalies in the asymptotic behavior of mode-coupling theory. AB - We discuss the dynamic behavior of a tagged particle close to a classical localization transition in the framework of the mode-coupling theory of the glass transition. Asymptotic results are derived for the order parameter as well as the dynamic correlation functions and the mean-squared displacement close to the transition. The influence of an infrared cutoff is discussed. PMID- 21613711 TI - Bulk and surface properties of liquid Al-Cr and Cr-Ni alloys. AB - The energetics of mixing and structural arrangement in liquid Al-Cr and Cr-Ni alloys has been analysed through the study of surface properties (surface tension and surface segregation), dynamic properties (chemical diffusion) and microscopic functions (concentration fluctuations in the long-wavelength limit and chemical short-range order parameter) in the framework of statistical mechanical theory in conjunction with quasi-lattice theory. The Al-Cr phase diagram exhibits the existence of different intermetallic compounds in the solid state, while that of Cr-Ni is a simple eutectic-type phase diagram at high temperatures and includes the low-temperature peritectoid reaction in the range near a CrNi(2) composition. Accordingly, the mixing behaviour in Al-Cr and Cr-Ni alloy melts was studied using the complex formation model in the weak interaction approximation and by postulating Al(8)Cr(5) and CrNi(2) chemical complexes, respectively, as energetically favoured. PMID- 21613712 TI - Lennard-Jones binary mixture in disordered matrices: exploring the mode coupling scenario at increasing confinement. AB - We present results of molecular dynamics simulations performed on a Lennard-Jones liquid binary mixture confined in matrices of soft spheres at increasing packing fraction. We study the dynamical properties of the liquid at a given density upon supercooling. Our aim is to test the validity of the mode coupling theory in predicting the behaviour of the glass forming liquid when it is under confinement in a disordered matrix. We use two different methods to build up the confining environment. We focus in particular on the behaviour of the single particle density correlators. We find a close agreement with the mode coupling theory at least for all the range of packing fractions examined. Discrepancies between the theory and the computer simulation results can be attributed to hopping effects which are more important at increasing confinement. PMID- 21613713 TI - Elasticity of smectic liquid crystals with focal conic domains. AB - We study the elastic properties of thermotropic smectic liquid crystals with focal conic domains (FCDs). After the application of the controlled preshear at different temperatures, we independently measure the shear modulus G' and the FCD size L. We find out that these quantities are related by the scaling relation G' ~ gamma(eff)/L, where gamma(eff) is the effective surface tension of the FCDs. The experimentally obtained value of gamma(eff) shows the same scaling as the effective surface tension of the layered systems ?(KB), where K and B are the bending modulus and the layer compression modulus, respectively. The similarity of this scaling relation to that of the surfactant onion phase suggests an universal rheological behavior of the layered systems with defects. PMID- 21613714 TI - Analysis of the static properties of cluster formations in symmetric linear multiblock copolymers. AB - We use molecular dynamics simulations to study the static properties of a single linear multiblock copolymer chain under poor solvent conditions varying the block length N, the number of blocks n, and the solvent quality by variation of the temperature T. We study the most symmetrical case, where the number of blocks of monomers of type A, n(A), equals that of monomers B, n(B) (n(A) = n(B) = n/2), the length of all blocks is the same irrespective of their type, and the potential parameters are also chosen symmetrically, as for a standard Lennard Jones fluid. Under poor solvent conditions the chains collapse and blocks with monomers of the same type form clusters, which are phase separated from the clusters with monomers of the other type. We study the dependence of the size of the clusters formed on n, N and T. Furthermore, we discuss our results with respect to recent simulation data on the phase behaviour of such macromolecules, providing a complete picture for the cluster formations in single multiblock copolymer chains under poor solvent conditions. PMID- 21613715 TI - Proton diffusion along biological membranes. AB - Biological surfaces are known to be capable of retaining protons and facilitating their lateral diffusion. Since the surface dynamically exchanges protons with the bulk, the proton movement from a source to a target at the surface acquires a complicated pattern of coupled surface and bulk (2D + 3D) diffusion of which the main feature is that the surface acts as a proton-collecting antenna enhancing the proton flux from the bulk. A phenomenological model of this process is reviewed and its applications to recent experiments on lipid bilayers and small unilaminar vesicles are discussed. The model (i) introduces the important notions of the fast and slow regimes of proton exchange between the surface and the bulk, (ii) permits evaluation of the antenna radius and amplification coefficient in both regimes, (iii) explains the observed macroscopically large distances (in the micrometer range; Antonenko and Pohl 1998 FEBS Lett. 429 197) that the proton can travel along lipid membranes embedded into pure aqueous solutions, and (iv) predicts the dependence of the steady-state proton flux and the kinetics of the non-stationary diffusion upon the buffer concentration in buffered solutions. The surface diffusion coefficient for small unilaminar vesicles is calculated from experimental data (Sanden et al 2010 Proc. Natl Acad. Sci. USA 107 4129) to be 1 * 10(-5) cm(2) s(-1). The dependence of the shape of the kinetic curves representing protonation/deprotonation of a lipid-bound pH-sensitive dye attached to a planar bilayer lipid membrane upon the buffer concentration (Serowy et al 2003 Biophys. J. 84 1031) and the effect of changing the membrane composition (Antonenko and Pohl 2008 Eur. Biophys. J. 37 865) are explained. PMID- 21613716 TI - Anomalous transport of a tracer on percolating clusters. AB - We investigate the dynamics of a single tracer exploring a course of fixed obstacles in the vicinity of the percolation transition for particles confined to the infinite cluster. The mean-square displacement displays anomalous transport, which extends to infinite times precisely at the critical obstacle density. The slowing down of the diffusion coefficient exhibits power-law behavior for densities close to the critical point and we show that the mean-square displacement fulfills a scaling hypothesis. Furthermore, we calculate the dynamic conductivity as a response to an alternating electric field. Last, we discuss the non-gaussian parameter as an indicator for heterogeneous dynamics. PMID- 21613717 TI - A simulation study of field-induced proton-conduction pathways in dry ionomers. AB - The morphological changes that can be induced in a dry ionomer by application of a strong electric field have been studied by means of computer simulation. The internal energy of the membrane at first slowly decreases with increasing field, but then rapidly increases after a certain threshold field is reached. This effect is interpreted as the reorganization of interacting head group dipoles in response to the external perturbation. The resulting morphology contains continuous channels of hydrophilic material capable of facilitating proton conduction. Upon removal of the poling field, the system does not return to its original morphology, but retains the anisotropic structure of the poled material. The poled structure appears to be thermodynamically stable, as confirmed by calculations of the Helmholtz energy of the original and poled samples. PMID- 21613718 TI - Spatial correlation of the dynamic propensity of a glass-forming liquid. AB - We present computer simulation results on the dynamic propensity (as defined by Widmer-Cooper et al 2004 Phys. Rev. Lett. 93 135701) in a Kob-Andersen binary Lennard-Jones liquid system consisting of 8788 particles. We compute the spatial correlation function for the dynamic propensity as a function of both the reduced temperature T, and the time scale on which the particle displacements are measured. For T <= 0.6, we find that non-zero correlations occur at the largest length scale accessible in our system. We also show that a cluster-size analysis of particles with extremal values of the dynamic propensity, as well as 3D visualizations, reveal spatially correlated regions that approach the size of our system as T decreases, consistently with the behavior of the spatial correlation function. Next, we define and examine the 'coordination propensity', the isoconfigurational average of the coordination number of the minority B particles around the majority A particles. We show that a significant correlation exists between the spatial fluctuations of the dynamic and coordination propensities. In addition, we find non-zero correlations of the coordination propensity occurring at the largest length scale accessible in our system for all T in the range 0.466 < T < 1.0. We discuss the implications of these results for understanding the length scales of dynamical heterogeneity in glass-forming liquids. PMID- 21613719 TI - Complex dynamics of fluids in disordered and crowded environments. PMID- 21613720 TI - The kinetics of water sorption in Nafion membranes: a small-angle neutron scattering study. AB - The optimization of the water management in proton exchange membrane fuel cells is a major issue for the large-scale development of this technology. In addition to the operating conditions, the membrane water sorption and transport processes obviously control the water management. The main objective of this work is to provide new experimental evidence based on the use of the small-angle neutron scattering (SANS) technique in order to allow a better understanding of water sorption processes. SANS spectra were recorded for membranes equilibrated with either water vapor or liquid. Sorption kinetics data were determined and the SANS spectra were analyzed using the method developed for extracting water concentration profiles across the membrane in operating fuel cells. The water concentration profiles across the membrane are completely flat, which indicates that the water diffusion within the membrane is not the limiting process. This result provides new insight into the numerous data published on these properties. For the first time, the swelling kinetics of a Nafion membrane immersed in liquid water is studied and a complete swelling is obtained in less than 1 min. PMID- 21613721 TI - Novel scaffold design with multi-grooved PLA fibers. AB - A novel prototype nonwoven textile structure containing polylactide (PLA) multigrooved fibers has been proposed as a possible scaffold material for superior cell attachment and proliferation. Grooved cross-sectional fibers with larger surface area were obtained by a bi-component spinning system and the complete removal of the sacrificial component was confirmed by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and x-ray photon spectroscopy (XPS) analysis. These PLA nonwoven scaffolds containing the grooved fibers exhibited enhanced wettability, greater flexibility and tensile properties, and a larger surface area compared to a traditional PLA nonwoven fabric containing round fibers. To evaluate cellular attachment on the two types of PLA nonwoven scaffolds, NIH 3T3 fibroblasts were cultured for up to 12 days. It was evident that the initial cellular attachment was superior on the scaffold with grooved fibers, which was confirmed by MTT viability assay (p < 0.01) and SEM analysis. In the future, by modulating the size of the grooves on the fibers, such a scaffold material with a large surface area could serve as an alternative matrix for culturing different types of cells. PMID- 21613722 TI - Fabrication of engineered heart tissue grafts from alginate/collagen barium composite microbeads. AB - Cardiac tissue engineering holds great promise for the treatment of myocardial infarction. However, insufficient cell migration into the scaffolds used and inflammatory reactions due to scaffold biodegradation remain as issues to be addressed. Engineered heart tissue (EHT) grafts fabricated by means of a cell encapsulation technique provide cells with a tissue-like environment, thereby potentially enhancing cellular processes such as migration, proliferation, and differentiation, and tissue regeneration. This paper presents a study on the fabrication and characterization of EHT grafts from novel alginate/collagen composite microbeads by means of cell encapsulation. Specifically, the microbeads were fabricated from alginate and collagen by barium ion cross-linking, with neonatal rat cardiomyocytes encapsulated in the composite microbeads during the fabrication of the EHT grafts. To evaluate the suitablity of these EHT grafts for heart muscle repair, the growth of cardiac cells in the microbeads was examined by means of confocal microscopy and staining with DAPI and F-actin. The EHT grafts were analyzed by scanning electron microscopy and transmission electron microscopy, and the contractile function of the EHT grafts monitored using a digital video camera at different time points. The results show the proliferation of cardiac cells in the microbeads and formation of interconnected multilayer heart-like tissues, the presence of well-organized and dense cell structures, the presence of intercalated discs and spaced Z lines, and the spontaneous synchronized contractility of EHT grafts (at a rate of 20-30 beats min(-1) after two weeks in culture). Taken together, these observations demonstrate that the novel alginate/collagen composite microbeads can provide a tissue-like microenvironment for cardiomyocytes that is suitable for fabricating native heart like tissues. PMID- 21613723 TI - Origin of step-like behavior in the Co/Si system. AB - A systematic investigation of the structure, nature of the interface and their possible connections with magnetic properties for the as-deposited Co/Si/Co trilayer system has been carried out. X-ray reflectivity, cross-sectional transmission electron microscopy and x-ray emission measurements performed on the Co/Si/Co trilayer system show that when the Si layer thickness is less than ~ 20 A, the full Si layer is converted into a cobalt silicide layer whereas when the Si layer thickness > 20 A along with the silicide layer. the pure Si layer also remains. A comparison of magneto-optical Kerr effect and magnetoresistance measurements reveals the absence of antiferromagnetic coupling in these samples. Double-step-like magnetization, in the case of Si layer thickness > 20 A between two Co layers, is explained by magnetization reversal of two ferromagnetic layers having different coercivities, independent of each other. PMID- 21613724 TI - Effects of a space modulation on the behavior of a 1D alternating Heisenberg spin 1/2 model. AB - The effects of a magnetic field (h) and a space modulation (delta) on the magnetic properties of a one-dimensional antiferromagnetic-ferromagnetic Heisenberg spin-1/2 model have been studied by means of numerical exact diagonalization of finite size systems, the nonlinear sigma model, and a bosonization approach. The space modulation is considered on the antiferromagnetic couplings. At delta = 0, the model is mapped to a gapless Luttinger liquid phase by increasing the magnetic field. However, the space modulation induces a new gap in the spectrum of the system and the system experiences different quantum phases which are separated by four critical fields. By opening the new gap, a magnetization plateau appears at 1/2M(sat). The effects of the space modulation are reflected in the emergence of a plateau in other physical functions such as the F-dimer and the bond-dimer order parameters, and the pair-wise entanglement. PMID- 21613725 TI - Magnetic order in orbital models of the iron pnictides. AB - We examine the appearance of the experimentally observed stripe spin-density-wave magnetic order in five different orbital models of the iron pnictide parent compounds. A restricted mean-field ansatz is used to determine the magnetic phase diagram of each model. Using the random phase approximation, we then check this phase diagram by evaluating the static spin susceptibility in the paramagnetic state close to the mean-field phase boundaries. The momenta for which the susceptibility is peaked indicate in an unbiased way the actual ordering vector of the nearby mean-field state. The dominant orbitally resolved contributions to the spin susceptibility are also examined to determine the origin of the magnetic instability. We find that the observed stripe magnetic order is possible in four of the models, but it is extremely sensitive to the degree of nesting between the electron and hole Fermi pockets. In the more realistic five-orbital models, this order competes with a strong-coupling incommensurate state which appears to be controlled by details of the electronic structure below the Fermi energy. We conclude by discussing the implications of our work for the origin of the magnetic order in the pnictides. PMID- 21613726 TI - Resistivity studies on the layered semi-metallic CaAl2Si2: evaluating its temperature-, field- and pressure-dependence. AB - We studied the layered, hexagonal, semi-metal CaAl(2)Si(2) by magnetization, specific heat and resistivity measurements over a wide range of temperature, pressure and magnetic field. Both the Sommerfeld coefficient (gamma = 1 mJ mol( 1) K(-2)) and the Debye temperature (theta(D) = 288 K) are in agreement with the values obtained from the band structure calculation. The resistivity shows a metallic character up to 200 K, followed by saturation and, afterwards, a weak decrease up to 840 K, at which it sharply rises reaching a local maximum at 847 +/- 5 K. While the low-temperature thermal evolution was accounted for in terms of intrinsic and extrinsic effects, the additional high-temperature scattering was attributed, based on differential thermal analysis, to a first-order thermal event. No appreciable magnetoresistivity was observed at liquid helium temperatures even for fields up to 90 kOe, indicating an absence of coupling between the electronic and magnetic degrees of freedom. Finally, an externally applied pressure was found to induce a strong reduction in the resistivity following a second-order polynomial: this effect will be discussed in terms of the influence of pressure on the effective mobility and concentration of charge carriers. PMID- 21613727 TI - Frequency dependent polarizability of small metallic grains. AB - We study the dynamic electronic polarizability of a single nano-scale spherical metallic grain using a quantum mechanical approach. We introduce the model for interacting electrons bound in the grain allowing us numerically to calculate the frequency dependence of the polarizability of grains of different sizes. We show that within this model the main resonance peak corresponding to the surface plasmon mode is blue-shifted and some minor secondary resonances above and below the main peak exist. We study the behavior of blue-shift as a function of grain size and compare our findings with the classical polarizability and with other results in the literature. PMID- 21613728 TI - Electronic properties of graphene nanostructures. AB - In this review, recent developments in the fabrication and understanding of the electronic properties of graphene nanostructures are discussed. After a brief overview of the structure of graphene and the two-dimensional transport properties, the focus is put on graphene constrictions, quantum dots and double quantum dots. For constrictions with a width below 100 nm, the current through the constriction is strongly suppressed for a certain back gate voltage range, related to the so-called transport gap. This transport gap is due to the formation of localized puddles in the constriction, and its size depends strongly on the constriction width. Such constrictions can be used to confine charge carriers in quantum dots, leading to Coulomb blockade effects. PMID- 21613729 TI - The influence of additions of Al and Si on the lattice stability of fcc and hcp Fe-Mn random alloys. AB - We have studied the influence of additions of Al and Si on the lattice stability of face-centred-cubic (fcc) versus hexagonal-closed-packed (hcp) Fe-Mn random alloys, considering the influence of magnetism below and above the fcc Neel temperature. Employing two different ab initio approaches with respect to basis sets and treatment of magnetic and chemical disorder, we are able to quantify the predictive power of the ab initio methods. We find that the addition of Al strongly stabilizes the fcc lattice independent of the regarded magnetic states. For Si a much stronger dependence on magnetism is observed. Compared to Al, almost no volume change is observed as Si is added to Fe-Mn, indicating that the electronic contributions are responsible for stabilization/destabilization of the fcc phase. PMID- 21613730 TI - Size-dependent hysteresis and phase formation kinetics during temperature cycling of metal nanopowders. AB - We present a description of the evolution of a polymorphically transforming metal nanoparticle ensemble subjected to a temperature cycling with constant rates of temperature change. The calculations of the time dependence of the volume fraction of the new phase show the existence of size-dependent hysteresis and its main features. The statistical analysis makes it possible to introduce and determine the size-dependent superheating limit and supercooling limit. PMID- 21613731 TI - Variable-force microscopy for advanced characterization of horizontally aligned carbon nanotubes. AB - Atomic force microscopy (AFM) performed with variable-force imaging was recently demonstrated to be an accurate method of determining the diameter and number of sidewalls of a carbon nanotube (CNT). This AFM technique provides an alternative to transmission electron microscopy (TEM) when TEM imaging is not possible due to substrate thickness. We have used variable-force AFM to characterize horizontally aligned CNTs grown on ST-cut quartz. Our measurements reveal new aspects of horizontally aligned growth that are essential for enhancing the performance of CNT-based devices as well as understanding the growth mechanism. First, previously reported optimal growth conditions produce a large spread in CNT diameters and a significant fraction of double-walled CNTs. Second, monodispersity is significantly improved when growth temperature is reduced. Third, CNTs with diameters up to 5 nm align to the substrate, suggesting the interaction between CNTs and the quartz lattice is more robust than previously reported. PMID- 21613732 TI - Directed assembly of gold nanorods using aligned electrospun polymer nanofibers for highly efficient SERS substrates. AB - Nonspherical metal nanoparticles are very attractive plasmonic nanostructures owing to the facile tunability of the plasmonic properties and the presence of sharp corners and edges, which act as electromagnetic hot spots for surface enhanced Raman scattering (SERS). However, such anisotropic nanostructures exhibit strong polarization dependence in their plasmonic properties, exhibiting significantly higher SERS intensity in certain orientations. In this paper, we demonstrate a facile strategy to achieve directed assembly of aligned gold nanorods using highly aligned electrospun nanofibers. We believe that the interstices between the nanofibers act as micro-and nanochannels, resulting in hydrodynamic drag forces on the gold nanorods, thus inducing massive alignment of the same on the nanofibers. Apart from exhibiting nearly 50 times higher SERS intensity compared to a planar SERS substrate with randomly oriented nanorods, our results highlight the importance of the orientation of anisotropic nanostructures. Finite difference time domain (FDTD) simulations employed to understand the electromagnetic field distribution around an aligned nanorod array showed excellent agreement with the experimental observations. PMID- 21613733 TI - Conductance histogram evolution of an EC-MCBJ fabricated Au atomic point contact. AB - This work presents a study of Au conductance quantization based on a combined electrochemical deposition and mechanically controllable break junction (MCBJ) method. We describe the microfabrication process and discuss improved features of our microchip structure compared to the previous one. The improved structure prolongs the available life of the microchip and also increases the success rate of the MCBJ experiment. Stepwise changes in the current were observed at the last stage of atomic point contact breakdown and conductance histograms were constructed. The evolution of 1G0 peak height in conductance histograms was used to investigate the probability of formation of an atomic point contact. It has been shown that the success rate in forming an atomic point contact can be improved by decreasing the stretching speed and the degree that the two electrodes are brought into contact. The repeated breakdown and formation over thousands of cycles led to a distinctive increase of 1G0 peak height in the conductance histograms, and this increased probability of forming a single atomic point contact is discussed. PMID- 21613734 TI - Assembly of individual TiO2-C60/porphyrin hybrid nanoparticles for enhancement of photoconversion efficiency. AB - Rational organization of porphyrin and C60 on the electrode surface in photovoltaic structures is essential to yield high quantum efficiency. In the present work, individual TiO2 nanoparticles were modified by introducing C60 and porphyrin units on the surface, and then electrophoretically deposited on an ITO/SnO2 electrode. The morphology of the photoactive layer on the electrode was significantly different from that of the layer produced as a result of separate deposition of C60 and porphyrin. The maximum incident photon to current efficiency of the resulting electrode approached 88% at 410 nm, which is the highest value among molecule-based photovoltaic cells reported to date. This indicates that molecular assembly of the C60 and porphyrin units on the individual nanoparticles through strong chemical attachment is a key factor in improving effective electron transfer between the photoactive units and the electrodes. PMID- 21613735 TI - Nanoparticles of antimony doped tin dioxide as a liquid petroleum gas sensor: effect of size on sensitivity. AB - The gas sensitivity exhibited by nanoparticles of 1 wt% Pd catalysed antimony doped tin dioxide (ATO) prepared by a citrate-nitrate process is reported here. The reduction of particle size to <3 nm, a dimension smaller than double the thickness of the charge depletion layer, has resulted in an exceptionally high butane sensitivity and selectivity. The sensitivity and selectivity of ATO particles of different sizes unequivocally proved that reducing the size of particles to below twice the Debye length dimension produces materials with exceptionally high sensitivity and selectivity for sensor applications. The sensitivity of the samples towards 1000 ppm butane varied in the order 98%>55%>47%, for CNP>SP>CP samples having crystallite sizes of the order of 2.4 nm to 18 nm to 25 nm, respectively. The ATO nanoparticles exhibited not only a remarkable increase in gas sensitivity of around 98% towards 1000 ppm butane at 350 degrees C, but also a preferential selectivity to butane compared to other gases such as CO, CO2, SO2, CH4 and H2. In addition to the exceptionally high sensitivity and selectivity, the developed sensors also exhibited an improved response time and long term stability, which are of paramount importance for practical device development. PMID- 21613736 TI - Fast response and recovery of hydrogen sensing in Pd-Pt nanoparticle-graphene composite layers. AB - This study reports the fast response and recovery of hydrogen sensing in nanoparticle-graphene composite layers fabricated using chemical methods and comprising of isolated Pd alloy nanoparticles dispersed onto graphene layers. For 2% hydrogen at 40 degrees C and 1 atm pressure, a response time of <2 s and a recovery time of 18 s are observed. The fast response and recovery observed during sensing are due to hydrogen-induced changes in the work function of the Pd alloy and modification in the distribution of defect states in the graphene band gap due to gas adsorption. The results of hydrogen sensing in the new class of Pd Pt nanoparticle-graphene composite material are important for understanding the effect of gas adsorption on electronic conduction in graphene layers and for developing a new type of gas sensor based on changes in the electronic properties of the interface. PMID- 21613737 TI - Sterically controlled docking of gold nanoparticles on ferritin surface by DNA hybridization. AB - Novel assemblies of DNA-functionalized gold nanoparticles (DNA-GNPs) have received considerable interest due to their fascinating properties which are desired for various detection applications. In this study, we present innovative GNP assemblies which have a cage-shaped protein ferritin in the center, and discrete GNPs sterically surrounding the central ferritin. These assemblies were constructed by hybridizing DNA-GNP to chemically DNA-modified ferritin, which has a hollow cavity or an iron NP core. Subsequent gel electrophoresis purification and transmission electron microscopy observation showed that ferritin/DNA/GNP assemblies were successfully constructed and can be isolated as independent functional units, which can be used to investigate not only the interaction between the GNPs of complicated GNP clusters but also the interaction between the GNPs and the internalized NP. PMID- 21613738 TI - Size- and doping-dependent time-resolved photoluminescence of doped Si nanocrystals. AB - Time-resolved photoluminescence (PL) has been studied for B- and Sb-doped Si nanocrystals (NCs) fabricated by ion beam sputtering and annealing. For B-doped Si NCs, the PL intensity as well as the PL lifetime (tauPL) increases as NC size (d) varies from 1.5 to 2.6 nm, similar to the case for undoped Si NCs, but with further increase of d, they decrease, possibly resulting from the increase of optically less active NCs with the increase of NCs containing more dopants. The PL intensity and tauPL monotonically decrease with increasing doping concentration (nD), irrespective of doping element. Si NCs show smaller tauPL in B doping than in Sb doping over the full range of nD. The sharp decrease in PL intensity, accompanied by the gradual decrease in tauPL for the higher nD of Sb, may be attributed to Auger recombination due to the presence of Sb inside Si NCs. The higher PL quench rate by Sb compared to B could be attributed to better ionization of Sb dopants in Si NCs. PMID- 21613739 TI - Mechanism of formation and nanostructure of Stober silica particles. AB - The formation of silica nano- and microparticles has been studied during growth by the modified Stober-Fink-Bohn (SFB) method. It has been experimentally found that the density and fractal structure of particles vary with size as they grow from 70 to 2200 nm. We propose a model of particle structure which is a dense primary particle core and is composed of concentric secondary particle shells terminating in dense primary particle layers. PMID- 21613741 TI - Long-term overexpression of heme oxygenase 1 promotes tau aggregation in mouse brain by inducing tau phosphorylation. AB - Intracellular tau aggregates composed of neurofibrillary tangles (NFTs) are a defining feature of Alzheimer's disease (AD). Increased expression of heme oxygenase-1 (HO-1) is a common phenomenon in AD. Interestingly, the spatial distribution of HO-1 expression is essentially identical to that of pathological accumulation of tau in AD. In this study, we developed a new transgenic mouse overexpressing HO-1, called CAG-HO-1 Tg mice, to explore the relationship between HO-1 and tau aggregation. In this model, we found that long-term overexpression of HO-1 significantly promoted tau aggregation in brain, by analyzing changes in morphology and insoluble tau expression levels. Moreover, our research provides the first in vivo evidence that HO-1 can enhance iron loading and tau (Ser199/202/396) phosphorylation in brains of transgenic mice. Cellular evidence indicates that HO-1 can induce the phosphorylation of tau through iron accumulation in Neuro2a cells stably transfected with HO-1. Our data suggest that long-term overexpression of HO-1 can promote tau aggregation. This mechanism involves excessive iron production mediated by HO-1 overexpression, which induces tau phosphorylation. Our results provide a potential pathway for the pathogenesis of tauopathies, which remains largely unknown. PMID- 21613740 TI - The cysteine protease inhibitor, E64d, reduces brain amyloid-beta and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, beta-secretase activity. AB - The cysteine protease cathepsin B is a potential drug target for reducing brain amyloid-beta (Abeta) and improving memory in Alzheimer's disease (AD), as reduction of cathepsin B in transgenic mice expressing human wild-type amyloid beta protein precursor (AbetaPP) results in significantly decreased brain Abeta. Cathepsin B cleaves the wild-type beta-secretase site sequence in AbetaPP to produce Abeta, and cathepsin B inhibitors administered to animal models expressing AbetaPP containing the wild-type beta-secretase site sequence reduce brain Abeta in a manner consistent with beta-secretase inhibition. But such inhibitors could act either by direct inhibition of cathepsin B beta-secretase activity or by off-target inhibition of the other beta-secretase, the aspartyl protease BACE1. To evaluate that issue, we orally administered a cysteine protease inhibitor, E64d, to normal guinea pigs or transgenic mice expressing human AbetaPP, both of which express the human wild-type beta-secretase site sequence. In guinea pigs, oral E64d administration caused a dose-dependent reduction of up to 92% in brain, CSF, and plasma of Abeta40 and Abeta42, a reduction of up to 50% in the C-terminal beta-secretase fragment (CTFbeta), and a 91% reduction in brain cathepsin B activity, but increased brain BACE1 activity by 20%. In transgenic AD mice, oral E64d administration improved memory deficits and reduced brain Abeta40 and Abeta42, amyloid plaque, brain CTFbeta, and brain cathepsin B activity, but increased brain BACE1 activity. We conclude that E64d likely reduces brain Abeta by inhibiting cathepsin B and not BACE1 beta-secretase activity and that E64d therefore may have potential for treating AD patients. PMID- 21613742 TI - Minimally invasive aortic valve replacement surgery: comparison of port-access and conventional standard approach. AB - BACKGROUND: In recent years, minimally invasive cardiac surgery has been developed. Thus far, only at our institute has port-access aortic valve replacement (PAVR) been performed in Japan. Herein we review our experiences with PAVR, and evaluate the surgical outcomes. METHODS AND RESULTS: Between May, 2007 and June, 2010, 37 cases of PAVR were performed. During the same period, 107 patients underwent conventional aortic valve replacement (CAVR) with midline sternotomy. Because we initially selected patients without high risk factors for PAVR, there were some differences in the preoperative demographic data between the CAVR and PAVR groups. Although cardiopulmonary bypass time and cross-clamp time were longer in the PAVR group (139 +/- 28 vs. 113 +/- 34 min; 97 +/- 23 vs. 83 +/- 24min), there were no significant differences in total operative time between both groups. With regard to the percentage of blood transfusion requirement, postoperative ventilation time, intensive care unit stay and hospital stay the PAVR group had significantly lower outcomes (11 vs. 90; 3.4 +/- 1.9 h vs. 8.2 +/- 16.3 h; 1.2 +/- 0.6 days vs. 2.5 +/- 1.7 days; 11.1 +/- 4.3 days vs. 19.7 +/- 7.8 days, respectively). There were no significant differences in mortality (1/37), and morbidity between both groups. CONCLUSIONS: PAVR a feasible treatment of choice for patients with aortic valve diseases complicated by various preoperative backgrounds. PMID- 21613743 TI - Cardioprotective effects of pravastatin against lethal ventricular arrhythmias induced by reperfusion in the rat heart. AB - BACKGROUND: Statins are reported to reduce mortality in patients with coronary artery disease and that mortality benefit might be related to the drugs' antiarrhythmic properties. METHODS AND RESULTS: Male rats were fed with or without pravastatin (0.1 mg.kg-1.day-1) for 7 days, and thereafter subjected to 10 min of ischemia by coronary artery ligation followed by 20 min reperfusion. Treatment with pravastatin reduced the frequency and duration of ventricular tachycardia and fibrillation (VT/VF) and improved the arrhythmia score after reperfusion. To investigate the rapid effects of pravastatin, isolated perfused rat hearts were subjected to 20 min of global ischemia followed by 30 or 60 min of reperfusion. Treatment with pravastatin (10 nmol/L) from 10 min before ischemia shortened the total duration of reperfusion-induced VT/VF. Interestingly, pravastatin administered from the beginning of reperfusion also exerted antiarrhythmic effects. These results indicate that pravastatin exerts antiarrhythmic effects not only with daily oral intake but also when administered just before ischemia or even after ischemia. Intracellular calcium ([Ca2+](i)) overload and collapse of mitochondrial inner membrane potential (Deltapsi(m)) are associated with the arrhythmogenesis during ischemia-reperfusion. In cultured cardiomyocytes, pretreatment with pravastatin (10 nmol/L) suppressed [Ca2+](i) overload and prevented Deltapsi(m) loss induced by H2O2. CONCLUSIONS: Pravastatin attenuated reperfusion-induced lethal ventricular arrhythmias. Inhibition of [Ca2+](i) overload and preserving Deltapsi(m) may be the mechanisms of the observed antiarrhythmic effects of pravastatin. PMID- 21613744 TI - Short-duration therapeutic hypothermia causes prompt connexin43 gap junction remodeling in isolated rabbit hearts. AB - BACKGROUND: Whether connexin43 gap junctions (Cx43 GJs) and spatial heterogeneity of conduction velocity (CV) restitutions are altered in hearts during moderate (MH; 33 degrees C) and severe (SH; 30 degrees C) hypothermia remains unclear. METHODS AND RESULTS: Using an optical mapping system, ventricular CV was evaluated by S1 pacing in 29 Langendorff-perfused isolated rabbit hearts at baseline (37 degrees C, n=9), 30-min MH (n=6), 30-min SH (n=9), and rewarming (R, 30-min SH followed by 30-min 37 degrees C, n=5). After CV evaluation, myocardium was collected to measure the level and distribution of non-phosphorylated (NP Cx43) and total (T-Cx43) Cx43 by immunoblotting and immunoconfocal microscopy. In 6 additional hearts, Cx43 GJ remodeling was evaluated at 30-min SH with (n=3) or without (n=3) pretreatment of a protein kinase C (PKC) inhibitor. CV slowing and spatial heterogeneities of CV restitutions were enhanced in MH and SH hearts. NP Cx43 was downregulated in MH (P=0.002) and SH (P<0.001) hearts. NP-Cx43 levels among 4 different ventricular sites became inhomogeneous in MH (P=0.017) and SH (P=0.046) hearts. However, T-Cx43 levels were unchanged. The percentages of lateralized NP- and T-Cx43 were increased in MH, SH, and R hearts. Pretreatment of PKC inhibitor attenuated SH-induced NP-Cx43 lateralization (P=0.0495). CONCLUSIONS: Short-duration (30 min) therapeutic hypothermia causes prompt Cx43 GJs remodeling, in which the PKC pathway is involved. Rewarming abolished hypothermia-induced conduction disturbance, while Cx43 GJs lateralization did not completely recover. PMID- 21613746 TI - Hypothalamic orexin system: from orphan GPCR to therapeutic target. PMID- 21613745 TI - Effects of exercise training in patients with chronic heart failure and advanced left ventricular systolic dysfunction receiving beta-blockers. AB - BACKGROUND: It remains unclear whether patients with chronic heart failure (CHF) and advanced left ventricular (LV) dysfunction on beta-blocker therapy benefit from exercise training (ET). METHODS AND RESULTS: We studied 45 CHF patients with advanced LV dysfunction [ejection fraction (LVEF) < 25%] and impaired exercise tolerance [normalized peak oxygen uptake (PVO2) < 70%] receiving a beta-blocker: 33 patients participated in a cardiac rehabilitation program with ET (ET group) and 12 did not (inactive control group). Exercise capacity, LV dimension and plasma B-type natriuretic peptide (BNP) were assessed before and after a 3-month study period. At baseline, both groups had markedly reduced LVEF (ET group 18 +/- 4% vs. Control group 18 +/- 5%, NS) and impaired exercise capacity (normalized PVO2 51 +/- 10% vs. 55 +/- 9%, NS). Although one patient in the ET group withdrew from the program due to worsening CHF, no serious cardiac events occurred during the ET sessions. After 3 months, the ET group (n = 24) had significantly improved PVO2 by 16 +/- 15% (1,005 +/- 295 to 1,167 +/- 397ml/min, P < 0.001), while the PVO2 of the control group was unchanged. LV end-diastolic dimension decreased in both groups to a similar extent, but plasma BNP was significantly decreased only in the ET group (432 to 214 pg/ml, P < 0.05). CONCLUSIONS: The data indicate that in CHF patients with advanced LV dysfunction on beta-blocker therapy, ET successfully improves exercise capacity and BNP without adversely affecting LV remodeling or causing serious cardiac complications. PMID- 21613753 TI - Neuroprotective effects of citidine-5-diphosphocholine on impaired spatial memory in a rat model of cerebrovascular dementia. AB - Citidine-5-diphosphocholine or citicoline (CDP-choline) is used as a neuroprotective and memory-enhancing drug in cerebral stroke, Alzheimer's disease, and other neurovascular diseases. Non-clinical studies have demonstrated the neuroprotective effects of CDP-choline in ischemic animal models. However, the relationship between the neuroprotective effect and the memory enhancing effect of CDP-choline is still unknown. No studies have demonstrated the ameliorative effect on impaired spatial memory and the suppressive effect on neuronal cell death of CDP-choline in the same model. In this study, we examined the effect of CDP-choline on impaired spatial memory and hippocampal CA1 neuronal death in rats subjected to repeated cerebral ischemia, and we compared the mechanism of CDP-choline to that of donepezil. Seven days post administration of CDP-choline (100, 300, 1000 mg/kg per day, p.o.) or donepezil increased correct choices and reduced error choices in an eight-arm radial maze task in a dose dependent manner. Neuronal cell death of caspase-3 protein-positive neurons in the hippocampus were reduced by repeated administration of CDP-choline at the highest dose. These results suggest that CDP-choline has ameliorative effects on the impairment of spatial memory via hippocampal neuronal cell death in a rat model of cerebral ischemia. PMID- 21613754 TI - Relaxant effect of prostaglandin D(2)--receptor DP agonist on liver myofibroblast contraction. AB - Increased intrahepatic resistance causes portal hypertension in cirrhosis. Liver myofibroblasts (MFs) are now regarded as the principle cells involved in sinusoidal blood flow regulation. Many other prostaglandin-receptor agonists have been reported to regulate liver MF contraction, but the role of the prostaglandin D(2)-receptor DP is unknown. In this study, we investigated the effect of a synthetic agonist of prostanoid DP receptor, BW245C, on contractile properties of primary rat liver MFs. Collagen gel contraction assay revealed that BW245C alone (1 and 10 uM) did not induce contraction but induced cell relaxation. Pretreatment with BW245C (10 uM, 30 min) attenuated bradykinin (100 nM)-induced liver MF contraction. Elevation of [Ca(2+)](i) induced by bradykinin (100 nM) was partially suppressed by BW245C pretreatment (10 uM, 3 min). BW245C (1 and 10 uM) significantly increased intracellular cAMP level in a dose-dependent manner. Pretreatment with forskolin (30 - 300 nM, 30 min) and dibutyryl-cAMP (3 - 30 uM, 30 min) significantly reduced bradykinin-induced contraction. Furthermore, a protein kinase A (PKA) inhibitor KT5720 (10 nM to 1 uM, 30 min) blocked the relaxant effect of BW245C. These results suggest that prostanoid DP receptor agonism inhibits bradykinin-induced [Ca(2+)](i) elevation and contraction through cAMP-PKA signal activation in rat liver MFs. PMID- 21613755 TI - Quantitative expression and immunohistochemical detection of glucose transporters, GLUT1 and GLUT3 in the rabbit placenta during successful pregnancy. AB - Glucose is essential for the development of the fetus. We address here the quantitative expression and immunohistochemical localization of glucose transporter (GLUT1 and GLUT3) in the rabbit placenta during successful pregnancy. Blood glucose level showed a significant decrease at the gestation period in comparison with non-pregnancy. Maternal serum glucose was gradually increased according to fetal development. Quantitative RT-PCR results showed that expression of GLUT1 was significantly increased from day 13 to day 18, while GLUT3 mRNA level was significantly decreased during the same periods. Western blot analysis demonstrated that GLUT1 protein did not change significantly in the placenta during pregnancy when compared to non-pregnant uteri. Immunohistochemistry indicated that distribution of GLUT1 was observed mainly to the surface of the outer trophoblasts, whereas GLUT3 mainly localized to the basal site of the inner trophoblasts and fetal blood vessels. These results suggest that glucose is transported through GLUT1 from the maternal blood stream for use as a placental fuel and for further transport through GLUT3 to the fetal circulation, thus signifying the distinct anatomical localization of GLUT1 and GLUT3 in the rabbit placenta during successful pregnancy. PMID- 21613756 TI - Obituary: Keiji SANO, MD, PhD, 1920-2011. PMID- 21613757 TI - Neuroprotective effects of ebselen following forebrain ischemia: involvement of glutamate and nitric oxide. AB - Ebselen is a mimic of glutathione peroxidase that reacts with peroxynitrite and inhibits nitric oxide (NO) synthase. Ebselen has beneficial effects on the neurological outcome of patients with stroke. In this study, the mechanisms by which ebselen can elicit neuroprotective effects against ischemic brain injury were investigated in male Wistar rats. Experimental forebrain ischemia was induced by bilateral common carotid artery occlusion with hemorrhagic hypotension. Ebselen was administered to animals in the treatment group 2 hours prior to the induction of forebrain ischemia, and placebo was administered in the control group. Cerebral blood flow (CBF) was measured by the hydrogen clearance method. Cortical extracellular levels of excitatory amino acids (EAAs) and NO were evaluated using in vivo microdialysis. Neuronal damage in the CA1 subfield of the hippocampus was assessed in brains harvested after a 24-hour period of survival. CBF did not recover to normal physiological levels after ischemic insults in either the control or treatment groups. The differences in the sequential changes in extracellular EAA and NO levels between groups were not statistically significant. There was a significantly larger mean density of intact, undamaged neurons in the CA1 subfield in the treatment group than in the control group. The neuroprotective effects of ebselen were reflected in the histological findings, without significant inhibition of glutamate release or NO synthesis during the acute phase of experimentally induced cerebral ischemia. PMID- 21613758 TI - Preoperative factors associated with antiepileptic drug withdrawal following surgery for intractable temporal lobe epilepsy. AB - The outcomes of postoperative antiepileptic drug (AED) cessation after temporal lobe epilepsy surgery were investigated to identify the preoperative factors associated with seizure-free status without drug treatment in 40 patients who underwent resective epilepsy surgery between 2000 and 2007 for the treatment of complex partial seizures of the type typically associated with temporal lobe epilepsy. All patients were followed up for at least 3.5 years after surgery. After the numbers and types of AEDs used as preoperative and postoperative treatments were determined, the patients who obtained seizure-free outcome for at least 2 years after AED cessation were analyzed. Sex, age at surgery, age at seizure onset, time to operation, seizure frequency, operation side, invasive study, pathological types (hippocampal sclerosis or others), history of generalized convulsive seizures, and number of preoperative AEDs were analyzed as factors potentially associated with seizure-free status without drug treatment. In total, 35% of the patients who underwent temporal lobe epilepsy surgery achieved seizure-free status without drugs. The mean number AEDs fell from 2.1 preoperatively to 1.2 after the surgery. Seizures recurred in 18% of the patients after AED withdrawal. A shorter duration from seizure onset to surgery was found to be significantly related to successful withdrawal of postoperative AED treatment. Our results suggested that early surgical intervention after seizure onset is an important precondition for achieving seizure-free status without drugs after temporal lobe epilepsy surgery. PMID- 21613759 TI - Comparison of intensity modulated radiotherapy and dynamic three-dimensional conformal radiotherapy with regard to dose distribution and sparing of organs at risk. AB - Dose escalation to the target while sparing the organs at risk near the lesion has been difficult over the last decade. However, recent radiotherapy techniques can deliver more sophisticated doses to the target. This study evaluated whether intensity modulated radiotherapy can deliver more homogeneous and conformal doses to the target than dynamic three-dimensional conformal radiotherapy while sparing organs at risk near the lesion in 13 patients with central nervous system tumors and other tumors around the central nervous system. Dynamic three-dimensional conformal radiotherapy and intensity modulated radiotherapy plans were calculated and dose distributions were compared for all patients with regard to the planning target volume and organs at risk. The plan of intensity modulated radiotherapy was significantly superior to that of dynamic three-dimensional conformal radiotherapy in target dose conformity (p = 0.0006) and organs at risk sparing (p = 0.0257). Intensity modulated radiotherapy could deliver more homogeneous and conformal doses to the target than dynamic three-dimensional conformal radiotherapy with sparing organs at risk near the lesion and may improve local control of radioresistant tumors via dose escalation. PMID- 21613760 TI - Utility of direct stimulation of roots in spinal surgery. AB - Prevention of postoperative neurological deficits is a major concern of spinal surgeons and has led to the introduction and current development of intraoperative neurophysiological monitoring. We have used motor evoked potentials and somatosensory evoked potentials as routine monitoring techniques and, in some cases, added optional methods such as direct stimulation of nerve roots and spinal evoked potentials. We report our experience of direct nerve root stimulation as an optional monitoring method during spinal surgeries in 7 patients with lesions affecting the proximal nerve roots aged from 1 day to 78 years (mean 23.5 years). Four patients had anomalous lesions, two had spinal nerve root schwannomas, and one had a far-lateral lumbar disc herniation. Direct stimulation was used for detection of motor nerve roots in the anomalous lesions and schwannomas, and to distinguish the nerve root from the paraspinal soft tissues in the case of a far-lateral herniated disc at the L5-S1 level. Although some patients had slight transient neurological symptoms such as motor weakness and sensory disturbance, none developed severe permanent neurological impairment. Direct stimulation allows detection of the motor nerve during spinal surgery in real time. Our limited experience suggests that the direct stimulation technique could reduce the risk of motor or vesicorectal disturbance after surgery of lesions affecting or involving the spinal nerve roots. PMID- 21613761 TI - Coil embolization of an aneurysm located at the trunk of the persistent primitive trigeminal artery. AB - A 71-year-old woman presented with an aneurysm at the trunk of the persistent primitive trigeminal artery (PPTA) manifesting as subarachnoid hemorrhage. Angiography and three-dimensional computed tomography revealed a wide-necked saccular aneurysm at the trunk of the left PPTA. Coil embolization with the balloon-assist technique was successful and PPTA patency was preserved. Preoperative conventional angiography should be performed to check for cross filling of the PPTA. This case demonstrates that an aneurysm of the trunk of the PPTA can be successfully treated by coil embolization using the balloon-assist technique. PMID- 21613762 TI - Unusual cisternal coil migration in the follow-up period after aneurysm perforation during endovascular coiling. AB - A 61-year-old woman suffered cisternal coil migration in the follow-up period after endovascular coil embolization for a ruptured cerebral aneurysm. She presented with sudden onset of headache. Computed tomography demonstrated diffuse subarachnoid hemorrhage, and cerebral angiography disclosed a left anterior choroidal artery aneurysm. The aneurysm was treated by endovascular embolization with Guglielmi detachable coils. During the embolization procedure, the microcatheter perforated the aneurysm. For direct closure of the perforation site with coils, the microcatheter was withdrawn and coils were deployed partially in the subarachnoid space and partially in the aneurysm sac. The coil mass was spread in the subarachnoid space around the aneurysm immediately after embolization. The patient was discharged with no neurological deficit. Three months later, follow-up radiography demonstrated obvious reduction in the size and compaction of the coil mass. Magnetic resonance angiography and digital subtraction angiography demonstrated stable occlusion of the aneurysm. The coil mass probably spread in the cistern around the aneurysm and was compacted by the shape memory of the coils and pulsation of the brain and vessels, as the subarachnoid clots around the aneurysm had disappeared. This case suggests that cisternal coil migration should be considered in the follow up of intracranial aneurysm treated with detachable coils. PMID- 21613763 TI - Infected acute subdural hematoma associated with invasive pneumococcal disease. AB - A previously healthy 68-year-old woman presented with a rare case of subdural empyema which developed at the site of preceding acute subdural hematoma (SDH). She was first admitted for treatment of an acute SDH after a fall. Since she was neurologically intact and the SDH volume decreased with conservative management, she was discharged 9 days after admission for follow up as an outpatient. Three days after discharge, she unexpectedly returned with worsening headache and altered mental status. Brain computed tomography (CT) showed increased SDH volume. Her condition deteriorated rapidly after presentation, with further increase in SDH volume. Copious pus in addition to the SDH was evacuated by emergency drainage, establishing the diagnosis of subdural empyema. Streptococcus pneumoniae was identified from bacterial cultures. Despite improvement in postoperative CT findings, she fell into septic shock and died 3 days after the drainage. Autopsy revealed meningitis and lobar pneumonia, and the postmortem diagnosis was invasive pneumococcal disease. Infection of acute SDH resulting in subdural empyema by S. pneumoniae is extremely rare. However, invasive pneumococcal disease is not uncommon in the elderly and tends to cause intracranial bleeding. Considering the high mortality rate of invasive pneumococcal disease and the low vaccination rate among the elderly in Japan, neurosurgeons should ask about the pneumococcal vaccination status. PMID- 21613764 TI - Trans-postpyramidal fissure approach for ventral vermian cavernous hemangioma. AB - A 54-year-old man presented with a rare case of cavernous angioma located in the ventral vermis manifesting as sudden onset of vertigo, followed by cerebellar ataxia. T(1)-weighted magnetic resonance imaging revealed a 1.5-cm homogeneously enhanced lesion in the ventral vermis. The postpyramidal fissure was opened widely, and upward exploration through the incision enabled piecemeal removal of the lesion without deterioration of the symptoms. The histological diagnosis was cavernous hemangioma with ruptured enlarged varices. The trans-postpyramidal fissure approach allows visualization of the entire fourth ventricle and avoids damaging the cerebellar nuclei and major postoperative cerebellar dysfunction. PMID- 21613765 TI - Transarterial embolization for cervical hemangioma associated with Kasabach merritt syndrome. AB - A 2-month-old girl presented with cervical hemangioma associated with Kasabach Merritt syndrome. The patient had previously undergone systemic administration of corticosteroids (prednisolone 2 mg/kg/day) and radiotherapy (0.5 Gy * 5 times), which temporarily increased the platelet count, but the effects were short-lived and thrombocytopenia gradually worsened again despite increased dosage of prednisolone to 5 mg/kg/day. Computed tomography and magnetic resonance imaging revealed a hemangioma in the left retroauricular-cervical region with a well enhanced, ill-defined margin and bony structure involvement. Diagnostic and therapeutic angiography were carried out through the femoral route under general anesthesia. Polyvinyl alcohol particles (250-350 um) suspended in contrast medium were slowly injected and a fibered coil was finally placed in the proximal portion of the arterial feeder. Angiography after embolization revealed a marked reduction in the tumor stain. Platelet count rapidly increased and reached the normal range on postembolization day 7. Tumor tension decreased on the day after the procedure and tumor size gradually decreased. The patient was discharged with oral corticosteroid therapy at 6 months postembolization. Corticosteroid dose was gradually decreased and coagulation parameters were normal at 1 year postembolization. PMID- 21613766 TI - Hemangiopericytoma in the trigone of the lateral ventricle. AB - A 67-year-old right-handed woman presented with a case of hemangiopericytoma in the lateral ventricle manifesting as digit number memory disturbance, sensory aphasia, and right quadrantanopsia. Magnetic resonance imaging demonstrated a 6 cm homogeneously enhanced mass in the trigone of the left lateral ventricle. The tumor was totally removed via the left inferior temporal gyrus. The histological findings were consistent with hemangiopericytoma. Differential diagnosis of hemangiopericytoma from meningioma and solitary fibrous tumors is very important because the clinical behavior of hemangiopericytoma is very aggressive, including local recurrence or distant metastases in the central nervous system and periphery. Histological confirmation is required to make a definitive diagnosis. The present patient did not receive radiation therapy, but developed no local recurrence or metastases. Complete surgical resection and awareness of hemangiopericytoma in the lateral ventricle are very important for good clinical outcome. PMID- 21613767 TI - Tentorial schwannoma mimicking meningioma. AB - A 58-year-old woman presented with a rare tentorial schwannoma manifesting as a chief complaint of headache. Magnetic resonance imaging showed an infratentorial extra-axial mass lesion with both cystic and solid components and dural tail sign. The tumor was easily separated from the surrounding structures, and the origin was apparently the tentorial branch of the trigeminal nerve. Tentorial schwannoma should be considered in the differential diagnosis of mixed cystic and solid mass lesions associated with the tentorium around the ambient cistern. PMID- 21613768 TI - Anaplastic meningioma with extremely rapid recurrence. AB - A 62-year-old woman presented with an uncommon case of anaplastic meningioma manifesting as recent memory disturbance. Magnetic resonance imaging revealed a mass located in the right temporal lobe. She became unconscious because of uncal herniation and underwent urgent surgery. The tumor was completely resected, except for a lesion tightly attached to arteries. Histological examination indicated the presence of anaplastic meningioma with an extremely high MIB-1 labeling index (70%). After 43 days, the patient developed local recurrence and dissemination in the left temporal lobe. The exceptionally high MIB-1 labeling index corresponded with a short tumor doubling time (8.2 days). Whole-brain irradiation and linear accelerator surgery for disseminated lesions were performed, and the tumor growth halted. Although meningiomas rarely show malignant behavior, corresponding to World Health Organization grade III, it is necessary to consider malignant behavior when treating meningiomas. PMID- 21613769 TI - Subacute subdural hygroma and presyrinx formation after foramen magnum decompression with duraplasty for Chiari type 1 malformation. AB - A 15-year-old girl developed a rare case of subdural hygroma after foramen magnum decompression for Chiari type 1 malformation manifesting as rapid symptom deterioration around 10 days after uncomplicated operation with uneventful immediate postoperative course. Progressive enlargement of the subdural hygroma in both supra- and infratentorial spaces was followed by the development of hydrocephalus. Syringomyelia improved shortly after the first operation but then deteriorated with massive presyrinx formation. Reoperation with wide opening of the arachnoid membrane lead to a rapid resolution of the hydrocephalus and the presyrinx. The present case shows that wide opening of the arachnoid membrane is an effective therapeutic option. PMID- 21613770 TI - An infantile large and extensive intramedullary mature spinal teratoma. AB - A 5-month-old boy presented with a rare case of intramedullary teratoma extending from T1 to S5 and associated with a lumbosacral lipoma. Magnetic resonance imaging showed the tumor extended over the lipoma. Since the tumor could not be clearly demarcated from the spinal cord, surgery was performed under a preoperative diagnosis of spinal glioma. The lack of demarcation made safe resection of the tumor difficult to perform, so that the tumor was only partially removed by decompressing the spinal cord. The histological diagnosis was mature teratoma. This case was likely the result of some dysembryogenetic mechanism and the tumor was not neoplastic. The long-term outcome cannot yet be determined, but no recurrence of the symptoms has been observed for 3 years. Spinal intramedullary teratoma is rare and tends to be located in the lumbosacral region. Surgical intervention is crucial and total removal may be achievable, but is likely to be partial with tight adhesion to the spinal cord, so that aggressive approaches should be avoided in such cases. PMID- 21613771 TI - Three-dimensional reconstructed computed tomography-magnetic resonance fusion image-based preoperative planning for surgical procedures for spinal lipoma or tethered spinal cord after myelomeningocele repair. AB - Surgical procedures for spinal lipoma or tethered spinal cord after myelomeningocele (MMC) repair are often difficult and complicated, because the anatomical structures can be deformed in complex and unpredictable ways. Imaging helps the surgeon understand the patient's spinal anatomy. Whereas two dimensional images provide only limited information for surgical planning, three dimensional (3D) reconstructed computed tomography (CT)-magnetic resonance (MR) fusion images produce clearer representations of the spinal regions. Here we describe simple and quick methods for obtaining 3D reconstructed CT-MR fusion images for preoperative planning of surgical procedures using the iPlan((r)) cranial (BrainLAB AG, Feldkirchen, Germany) neuronavigation software. 3D CT images of the vertebral bone were combined with heavily T(2)-weighted MR images of the spinal cord, lipoma, cerebrospinal fluid (CSF) space, and nerve root through a process of fusion, segmentation, and reconstruction of the 3D images. We also used our procedure called "Image Overlay" to directly project the 3D reconstructed image onto the body surface using an LED projector. The final reconstructed 3D images took 10-30 minutes to obtain, and provided the surgeon with a representation of the individual pathological structures, so enabled the design of effective surgical plans, even in patients with bony deformity such as scoliosis. None of the 19 patients treated based on our 3D reconstruction method has had neurological complications, except for CSF leakage. This 3D reconstructed imaging method, combined with Image Overlay, improves the visual understanding of complicated surgical situations, and should improve surgical efficiency and outcome. PMID- 21613772 TI - Treatment-related morbidity in atypical teratoid/rhabdoid tumor: multifocal necrotizing leukoencephalopathy. AB - BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive malignant brain tumor that, since it was first identified, has been treated with aggressive treatment regimens, e.g. high-dose chemotherapy with stem cell rescue and early radiotherapy. We reviewed our experience because of concerns with respect to treatment-related toxicity in our patients. METHODS: Seven patients with a median age at presentation of 18 months were diagnosed with AT/RT between 1996 and 2006. Tumor location was supratentorial in 2 patients, in the posterior fossa in 4 and spinal in 1. Gross total resection was performed in 1 patient, subtotal resection in 5 and biopsy only in 1. Adjuvant treatment consisted of chemotherapy and radiotherapy in 5 patients. RESULTS: Median progression-free survival was 4 months, and median overall survival was 7 months. Two children are alive at 44 and 102 months. Significant surgical and chemotherapy-related morbidity was seen. Biopsy-proven multifocal necrotizing leukoencephalopathy (MNL) was seen in one patient who is alive 44 months after diagnosis. Another patient who was thought to have recurrent tumor in the brainstem 9 months after diagnosis had imaging findings compatible with MNL. CONCLUSION: Although improving results are reported for AT/RT using intensive treatment regimens, treatment-related morbidity is considerable in this young patient population. PMID- 21613773 TI - Intradiploic orbital roof meningioma with pneumosinus dilatans in a child: a case report and review of the literature. AB - Intradiploic meningioma of the orbital roof is a type of intraosseous meningioma. It is very rare in children, and only 7 cases have been reported in the pediatric age group. We report a case of a 14-year-old female who presented with progressive exophthalmos, diplopia and pain involving the right eye. Computed tomography (CT) scan and magnetic resonance imaging (MRI) revealed an intradiploic orbital roof tumor with diploe expansion and pneumosinus dilatans. The tumor was completely removed surgically. The histopathological diagnosis was transitional meningioma. The clinical and radiological findings of intadiploic meningioma are discussed with a review of the relevant literature. PMID- 21613774 TI - Developmental expression and distribution of GABA(A) receptor alpha1-, alpha3- and beta2-subunits in pig brain. AB - The principal function of the gamma-aminobutyric acid (GABA) system in the adult brain is inhibition; however, in the neonatal brain, GABA provides much of the excitatory drive. As the brain develops, transmembrane chloride gradients change and the inhibitory role of GABA is initiated and continues throughout juvenile and adult life. Previous studies have shown that GABA(A) receptor subunit expression is developmentally regulated, and it is thought that the change in GABA function from excitation to inhibition corresponds to the changeover in expression of 'immature' to 'mature' subunit isoforms. We examined the protein expression pattern and distribution of GABA type A (GABA(A)) receptor alpha1-, alpha3- and beta2-subunits in the parietal cortex and hippocampus of the developing piglet brain. Four perinatal ages were studied; 14 days preterm (P 14), 10 days preterm (P-10), day of birth (P0) and at postnatal day 7 (P7). Animals were obtained by either caesarean section or spontaneous birth. Protein expression levels and subunit localization were analysed by Western blotting and immunohistochemistry, respectively. In the cortex and hippocampus, GABA(A) receptor alpha1-subunit showed greatest expression at P7 when compared to all other age groups (p < 0.05). In contrast, alpha3 expression in the cortex was elevated in preterm brain, peaking at P0, followed by a significant reduction by P7 (p < 0.05); a similar trend was observed in the hippocampus. GABA(A) receptor beta2-subunit protein expression appeared relatively constant across all time points studied in both the cortex and hippocampus. Immunolabelling of the alpha1 , alpha3- and beta2-subunits was observed throughout all cortical layers at every age. GABA(A) receptor alpha3-subunit appeared to show specific localization to layers V and VI whilst labelling for the beta2-subunit was observed in layer IV. In the hippocampus of all animals, the alpha1- and beta2-subunits were shown to immunolabel various cells and processes in the dentate gyrus (DG), CA1 and CA3; the alpha3-subunit was barely observed except at the stratum moleculare of the DG. We report for the first time the ontogenesis of GABA(A) receptor subunits alpha1, alpha3 and beta2 in the perinatal pig brain. PMID- 21613775 TI - Hippocampal atrophy in subcortical vascular dementia. AB - BACKGROUND AND PURPOSE: New research criteria for subcortical vascular dementia (SVaD) have been suggested to define a more homogeneous subgroup of vascular dementia. Hippocampal (Hc) atrophy is a hallmark of Alzheimer's disease (AD), but it also occurs in other dementia disorders including vascular dementias. So far, it is unknown to which extent Hc atrophy is present in SVaD. METHODS: From a larger consecutive referral population in a memory clinic, 11 patients fulfilling the research criteria for SVaD were carefully matched with comparison groups of healthy controls and patients with AD. To estimate the extent of Hc atrophy in SVaD, both Hc volumetry and visual rating of medial temporal lobe atrophy (MTA) were applied. RESULTS: In SVaD, significant Hc atrophy occurred. The extent was intermediate between controls and patients with AD both on Hc volumetry and visual MTA ratings. At the same level of global cognition, Hc volumes were reduced by 11.6% in SVaD and 16.6% in AD, relative to controls. CONCLUSIONS: Patient groups with AD and SVaD as identified by current research criteria appear to overlap considerably with regard to the feature of Hc atrophy. While contamination with AD is a likely cause, other mechanisms of Hc atrophy in SVaD also deserve consideration. The findings have implications for the design of future clinical trials of SVaD. PMID- 21613776 TI - Natural killer cells: biology, physiology and medicine - part 2. PMID- 21613777 TI - Pediatric epidural tumors of the spine--experience of a decade from the Kashmir Valley. AB - We present our experience after analyzing retrospectively the clinicopathological characteristics, surgical approaches, immediate and long-term postoperative complications and survival outcome of pediatric spinal epidural tumors treated over a period of 10 years from 2000 to 2009 in a tertiary-care hospital. Our study included benign and malignant tumors. The majority of our patients were boys (14:8). The duration of symptoms was longer in benign lesions. Non-Hodgkin's lymphoma was the commonest malignant tumor and aneurysmal bone cyst was the commonest benign tumor. The mean duration of follow-up was 19 months (range 3-48 months). Most of the patients improved in their neurological grade after surgery; however, the degree of excision had no bearing on the length of survival for malignant lesions. PMID- 21613778 TI - A case of diffuse panbronchiolitis complicated by peripheral T cell lymphoma not otherwise specified. AB - We report a case of diffuse panbronchiolitis (DPB) complicated by peripheral T cell lymphoma not otherwise specified. A 40-year-old Chinese man presented with intermittent fever, cough and significant white sputum production for more than 9 years, in addition to dyspnea and chest congestion that worsened after exercise. A chest CT scan indicated diffuse centrilobular fine nodular opacities with a 'tree-in-bud' appearance in both lungs. An open-lung biopsy was performed, and DPB was diagnosed by histopathological analysis. Three months later, the patient's pulmonary symptoms worsened. A chest CT of both lungs revealed multiple patchy opacities as well as enlargement of the hilar, mediastinal and multiple superficial lymph nodes. A whole-body bone scan revealed multiple osteolytic lesions located in the thoracic, lumbar and sacral spine. A biopsy of the right supraclavicular lymph node was performed, and peripheral T cell lymphoma not otherwise specified was diagnosed histopathologically. Cases of DPB complicated by non-Hodgkin's lymphoma are a rare occurrence. To our knowledge, there is only one earlier report of such a case in the literature (in Japanese). However, the prevalence of DPB complicated by T cell tumors is relatively high, indicating a possible association in pathogenesis of T cell disorders and DPB. PMID- 21613779 TI - Smoker's boils. AB - BACKGROUND: About 90% of patients with hidradenitis suppurativa (HS) are smokers. A crucial eliciting role of smoking appears to be certain. In order to increase the awareness of this avoidable major cause of the disease and to facilitate the recognition of incipient disorder, we propose the more specific term 'smoker's boils' for HS lesions of patients who are smokers. METHOD: Clinical pictures of early lesions are presented. For the exceptional cases occurring in nonsmokers, the traditional name HS, representing an umbrella term, is adequate. RESULT/CONCLUSION: The renaming of HS as smoker's boils has the practical advantage that a correct diagnosis can be made at an incipient stage of the disorder. If patients stop smoking at such an early stage of HS, they most likely have a chance that this devastating disease will not progress. PMID- 21613780 TI - Natural killer cells in psoriasis. AB - Psoriasis is one of the most common immune-mediated disorders. There is evidence that it is mediated by Th1 and, more recently, Th17 cells. The cytokine pattern, particularly the dominance of TNF-alpha, implicates the innate immune system in psoriasis pathogenesis. Of the many components of the innate immune system known to be involved in psoriatic lesions, natural killer and natural killer T cells appear to have a unique role. We review the evidence supporting a role for natural killer cells in psoriasis. PMID- 21613781 TI - A case of xanthoma disseminatum with spontaneous resolution over 10 years: review of the literature on long-term follow-up. AB - Xanthoma disseminatum (XD) is a rare and potentially progressive non-Langerhans cell histiocytosis. To date, a few cases of XD with spontaneous complete resolution have been described. The present report describes a 16-year-old girl who presented with yellow to red-brown papules and nodules on her eyelids, cheeks, axillae, back and buttocks. Indirect laryngoscopy showed multiple xanthomatous plaques on the larynx, posterior pharynx, epiglottis, and vocal cords. Additional findings were polyuria, polydipsia, and amenorrhea. Skin biopsy and electron microscopy results confirmed the diagnosis of XD. The patient was treated with fenofibrate, simvastatin, desmopressin, and sex-hormone replacement therapy. Her skin lesions began to slowly fade 6 years after disease onset, eventually resolving spontaneously and completely, but leaving an atrophic scar, frank anetoderma, and persisting diabetes insipidus. This case report together with a review of the English-language literature on the long-term follow-up of XD patients provides additional information on the natural history of this disease. PMID- 21613782 TI - ARB treatment prevents the decrease in endothelial progenitor cells and the loss of renal microvasculature in remnant kidney. AB - BACKGROUND: Endothelial progenitor cells (EPCs) are involved in endothelium turnover and play a role in renal capillary repair. Since angiotensin II has been shown to negatively affect EPCs and blockade of angiotensin II decreases the progression of renal diseases, we investigated the effects of losartan on EPCs and renal endothelial cells in remnant kidney. METHODS: Sprague-Dawley rats were randomized to receive losartan (25 mg/kg/day) or solvent for 15 weeks after 5/6 nephrectomy. Peripheral blood CD34+ EPCs were counted and the number of CD31+ endothelial colonies was determined. Glomerular and tubulointerstitial capillary endothelial cells were assessed and vascular endothelial growth factor (VEGF) and thrombospondin (TSP-1) expression were determined. RESULTS: EPCs and the number of endothelial colonies were significantly reduced in 5/6 nephrectomized rats, which was associated with a decrease in glomerular and tubulointerstitial endothelial cells, a decrease in VEGF and an increase in TSP-1 expression. Losartan treatment largely prevented changes in both EPCs and remnant kidney. CONCLUSION: The gradual loss of renal capillaries in remnant kidney was associated with decreased EPCs and endothelial colonies, hindering capillary endothelial repair in remnant kidney. Losartan treatment largely prevented the loss of EPCs and preserved renal endothelial cells, which may be part of the mechanism of how it contributes to renal protection. PMID- 21613783 TI - Mechanisms of renal cell apoptosis induced by cyclosporine A: a systematic review of in vitro studies. AB - BACKGROUND: Chronic cyclosporine A (CsA) nephrotoxicity (CCN) is a major cause of chronic renal dysfunction and has no effective clinical interventions yet. OBJECTIVE: To reveal the mechanisms of renal cell apoptosis in CCN, we analyzed all in vitro studies of such mechanisms. METHODS: We collected all in vitro studies about the mechanisms of renal cell apoptosis induced by CsA in Medline (1966 to July 2010), Embase (1980 to July 2010) and ISI (1986 to July 2010), evaluated their quality according to in vitro standards and extracted data following the PICOS principles and synthesized the data. RESULTS: First,CsA could upregulate Fas and Fas-L expression, increase FADD and apoptosis enzymes (caspase 2, -3, -4, -7, -8, -9 and -10) and downregulate the Bcl-2 and Bcl-xL. Second, CsA could induce oxidative stress and damage the antioxidant defense system. Third, CsA could increase the expression of HERP, GRP78 and CHOP. Fourth, CsA could induce renal cell apoptosis and increase their iNOS and p53 expression in cultured cells. CONCLUSIONS: At least four pathways are involved in renal cell apoptosis induced by CsA in different cell species. Caspases might be their final common pathway in vitro. They might all provide potential points for interventions, but these need to be confirmed in vivo. PMID- 21613784 TI - Weight change, blood pressure, lipids and glycemic control among patients with type 2 diabetes. AB - BACKGROUND/AIM: Although weight loss in patients with type 2 diabetes is very important, available data on the effects of long-term weight change on blood pressure (BP), lipids and glycemic control in these patients are limited. The aim of this study was to assess the long-term impact of weight change on BP, plasma lipids and glycemic control among patients with type 2 diabetes receiving routine care. METHODS: During the mean [standard deviation (SD)] follow-up period of 9.2 (3.4; range 2-15) years, 7,712 patients with type 2 diabetes were examined to determine changes in weight, BP, plasma lipids and glycemic control using a linear mixed-effects model for repeated measures. The mean (SD) age of participants was 51.3 (10.5) years with a mean (SD) duration of diabetes of 6.3 (6.3) years at initial registration. RESULTS: The change in fasting plasma glucose and glycosylated hemoglobin (HbA(1c)) from baseline to the last follow-up examination was significantly more favorable in those patients who gained weight during follow-up than in those who lost weight or whose weight remained stable. Systolic and diastolic BP and lipids also rose more significantly in the group with weight gain. CONCLUSIONS: Although this population of type 2 diabetes in Iran had negligible weight change over mean 9.2 years, this weight gain was associated with an increase in BP and plasma lipids, but also an improvement in glycemic control. PMID- 21613785 TI - 20th European Stroke Conference, Hamburg, Germany, May 24-27, 2011. PMID- 21613786 TI - Transient ischemic attack versus transient ischemic attack mimics: frequency, clinical characteristics and outcome. AB - BACKGROUND: There is insufficient evidence regarding which clinical features are best suited to distinguish between transient ischemic attack (TIA) and disorders mimicking TIA (TIA mimics). METHODS: We compared the frequency, clinical characteristics and outcome of patients with TIA and TIA mimics in a prospective, single-center emergency department cohort over 2 years. RESULTS: Of 303 patients, 248 (81.8%) had a TIA and 55 (18.2%) had TIA mimics. Epileptic seizures (26/55; 43.7%) and migraine attacks (13/55; 23.6%) were the most common TIA mimics. In patients presenting with unilateral paresis, TIA mimics were less likely than in patients without unilateral paresis [odds ratio (OR) 0.35, 95% confidence interval (CI) 0.17-0.68]. Memory loss (OR 9.17, 95% CI 2.89-32.50), headache (OR 3.71, 95% CI 1.07-12.78) and blurred vision (OR 2.48, 95% CI 0.90-6.59) increased the odds of TIA mimics. Once these clinical features were taken into account, neither aphasia, dysarthria, sensory loss, blood pressure values nor the duration of symptoms were found to improve explanation of the underlying status. At 3 months, stroke, recurrent TIA and myocardial infarction were absent in patients with TIA mimics but occurred in 13 (5.2%), 20 (8.1%) and 3 (1.2%) TIA patients, respectively. CONCLUSIONS: About 1 in every 5 patients with suspected TIA had a TIA mimic. Paresis suggested TIA, while other clinical variables used in risk assessment scores after TIA were not shown to distinguish between the two entities. Patients with TIA mimics had a better short-term prognosis. PMID- 21613787 TI - Cilostazol in Acute Ischemic Stroke Treatment (CAIST Trial): a randomized double blind non-inferiority trial. AB - BACKGROUND: Aspirin is a proven antiplatelet agent in acute ischemic stroke, and there are no current guidelines for other antiplatelet treatments. We aimed to compare the efficacy and safety of cilostazol with aspirin in acute stroke. METHODS: Patients with measurable neurological deficits (NIHSS score <=15) within 48 h of onset were randomly assigned to cilostazol (200 mg/day) or aspirin (300 mg/day) for 90 days. The primary endpoint was a modified Rankin Scale (mRS) score of 0-2 at 90 days. Cardiovascular events, bleeding complications, and other functional outcomes were also assessed. Statistical analysis was carried out by intention-to-treat and per-protocol bases. This trial is registered with ClinicalTrials.gov (NCT00272454). RESULTS: In total, 458 patients were enrolled (mean age of 63 years, median NIHSS of 3), and mRS at 90 days was obtained in 447 patients. The primary endpoint was achieved in 76% (173/228) of those randomized to cilostazol and in 75% (165/219) assigned to aspirin, which supported the pre specified non-inferiority of cilostazol to aspirin (95% CI of proportion difference: -6.15 to 7.22%, p = 0.0004). These results were also supported by per protocol analysis (p = 0.045). Cardiovascular events occurred in 6 patients (3%) treated with cilostazol, and in 9 patients (4%) treated with aspirin (p = 0.41). Adverse events were more common in cilostazol-treated patients during the trial (91 vs. 85%, p = 0.055), while the frequencies of bleeding complications (cilostazol 11%, aspirin 13%, p = 0.43) or drug discontinuation (cilostazol 10%, aspirin 7%, p = 0.32) were not different. CONCLUSION: Cilostazol is feasible in acute ischemic stroke, and comparable to aspirin in its efficacy and safety. PMID- 21613788 TI - Growth differentiation factor 15 plasma levels and outcome after ischemic stroke. AB - BACKGROUND: Growth differentiation factor 15 (GDF-15) is a stress-responsive cytokine that is induced after experimental brain injury. We hypothesized that the circulating levels of GDF-15 are increased and associated with neurological outcome in patients with ischemic stroke. METHODS: Serial blood samples were obtained between 6 h and 7 days after symptom onset in 57 consecutive patients with acute ischemic stroke (n = 51) or transient ischemic attack (n = 6). GDF-15 was measured by immunoradiometric assay. Neurological outcome using the modified Rankin Scale (mRS) at 7 and 90 days was classified as favorable (mRS 0 or 1) or unfavorable (mRS >1). RESULTS: Six hours after symptom onset, GDF-15 levels were abnormally high (>1,200 ng/l) in 68% of the patients. They declined by 8% over the course of 7 days (p < 0.001). GDF-15 levels were correlated with the circulating levels of the inflammatory marker interleukin-6 and the glial protein S100 calcium binding protein B, and with carotid intima-media thickness. Ischemic stroke patients with an mRS score >1 at 7 or 90 days had higher circulating levels of GDF-15 at all preceding sampling time points compared to patients with an mRS score of 0 or 1 (p <= 0.002). Similarly, in a logistic regression analysis, GDF-15 levels measured between 6 h and 7 days after symptom onset were associated with mRS at 7 and 90 days. CONCLUSIONS: These data show for the first time that the circulating levels of GDF-15 are elevated and associated with neurological outcome in patients with ischemic stroke. PMID- 21613789 TI - Utility and limitations of Addenbrooke's Cognitive Examination-Revised for detecting mild cognitive impairment in Parkinson's disease. AB - BACKGROUND/AIMS: To evaluate the utility of the Addenbrooke's Cognitive Examination-Revised (ACE-R) as a screening tool for mild cognitive impairment in Parkinson's disease (PD-MCI). METHODS: PD patients underwent comprehensive neuropsychological and neurological evaluations and ACE-R assessment. RESULTS: The ACE-R was superior to the Mini-Mental State Exam (MMSE) in detecting PD-MCI, with a cutoff score of <=93 offering a sensitivity of 61% and a specificity of 64%. The utility of the ACE-R in detecting PD-MCI is largely influenced by the fluency sub-domain score, and has optimal discriminability when utilized in patients with lower levels of education (<=12 years of formal schooling). CONCLUSION: The ACE-R must be used cautiously as a screening tool for PD-MCI, with results being most influenced by its fluency sub-domain score and patient education levels. PMID- 21613790 TI - Polymorphisms in the catechol-o-methyltransferase gene and delirium in the elderly. AB - BACKGROUND/AIMS: Catechol-O-methyltransferase, encoded by the COMT gene, is one of the enzymes that degrade dopamine. The aim of this study was to investigate whether polymorphisms in the COMT gene were associated with delirium. METHODS: Patients aged 65 years and older, acutely admitted to the medical department or to the surgical department following hip fracture, were included. rs4680, rs4818, and rs6269 were genotyped. RESULTS: Delirious patients were older, and more frequently had preexisting functional or cognitive impairment (p < 0.001). Polymorphisms in the COMT gene were not associated with the development of delirium. CONCLUSION: Although the COMT gene is a promising candidate gene for delirium in the elderly, functional genetic variations were not associated with delirium. PMID- 21613791 TI - Action plan for a healthy agriculture, healthy nutrition, healthy people. PMID- 21613792 TI - Lipoprotein abnormalities in patients with atherosclerotic renovascular disease. AB - BACKGROUND: Patients with atherosclerotic renovascular disease (ARVD) have a high risk of cardiovascular death. The primary aim was to characterize abnormalities in apolipoprotein (Apo)-defined lipoprotein (Lp) subclasses in patients with ARVD. METHODS: Baseline measurements were performed on 42 patients with ARVD 4 weeks after renal angioplasty (PTRA). All patients were on statin treatment. Twenty age-matched healthy subjects without medications served as controls. Subsequently, patients were randomized to treatment with either candesartan (n = 21), or antihypertensive treatment without inhibitors of the renin-angiotensin aldosterone system (n = 21) and followed for 11 months. RESULTS: At baseline, ApoC-III (12.7 +/- 4.6 vs. 8.8 +/- 2.6 (SD) mg/dl, p < 0.05), LpB:C:E (13.3 +/- 5.4 vs. 8.4 +/- 4.3 mg/dl, p < 0.05), and the sum of ApoC-III-containing lipoproteins, i.e. LpB:C + LpB:C:E + LpA-II:B:C:D:E (46 +/- 15 vs. 37 +/- 8 mg/dl, p < 0.05), were significantly elevated in ARVD patients versus healthy controls. Multiple regression analyses showed that only plasma renin activity was independently associated with ApoC-III levels at baseline (p < 0.05, r = 0.74). Treatment with candesartan did not correct abnormalities. CONCLUSIONS: Patients with ARVD treated with statins have an atherogenic lipoprotein profile characterized by elevated levels of ApoC-III-containing, triglyceride-rich lipoproteins that could accelerate atherosclerotic disease. PMID- 21613793 TI - Poly(ADP-ribose) polymerase-1 mediates angiotensin II-induced expression of plasminogen activator inhibitor-1 and fibronectin in rat mesangial cells. AB - OBJECTIVE: To investigate the effects of poly(ADP-ribose) polymerase-1 (PARP-1) on angiotensin II (Ang II)-induced plasminogen activator inhibitor-1 (PAI-1) and fibronectin (FN) in rat mesangial cells (RMCs). METHODS: Followed by serum starvation for 16 h, RMCs were exposed to Ang II for an indicated time to examine the protein expression of PARP-1. The cells were treated with or without Ang II for 12-24 h in the presence or absence of an inhibitor of PARP, N-(6-oxo-5,6 dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride (PJ34) or small interfering RNA (siRNA) duplexes targeting PARP-1. The mRNA and protein expressions of PARP-1, PAI-1 and FN were determined by real-time RT-PCR and Western blot, respectively. The activity of PARP-1 was examined by colorimetric assay. RESULTS: Ang II did not only significantly induce PARP-1 expression and activity, but also increased PAI-1 and FN expression in RMCs. All these responses induced by Ang II were significantly inhibited by both the PARP inhibitor PJ34 and downregulating PARP-1 with the siRNA technique. CONCLUSIONS: Our data suggest that PARP-1 mediates Ang II-induced PAI-1 and FN in RMCs and may thus represent a potential therapeutic target in the treatment of glomerular disease. PMID- 21613794 TI - Fetuin-A pretransplant serum levels, kidney allograft function and rejection episodes: a 3-year posttransplantation follow-up. AB - BACKGROUND: Fetuin-A is a negative acute-phase protein, which acts as a potent calcification inhibitor and an antagonist of transforming growth factor-beta. Thus, fetuin-A levels are influenced by chronic inflammation and actively affect fibrosis and calcification processes, respectively. Graft rejection, interstitial fibrosis and tubular atrophy, chronic inflammation and calcification are common causes for kidney allograft loss. This study evaluated whether pretransplant fetuin-A levels predict long-term graft survival and rejection episodes in patients after kidney transplantation. METHODS: In 206 renal transplant recipients pretransplant fetuin-A levels were measured in serum by ELISA. During the 36 months' active follow-up (median 1,249 days) 13 patients died (94% patient survival) and renal allograft failure was reported in 18 patients (91% graft survival). RESULTS: Pretransplant fetuin-A levels did not differ among patients with incident graft failures as compared to patients with functional graft after long-term follow-up or rejection episodes (fetuin-A: 393.6 +/- 46 vs. 384.4 +/- 69 vs. 405 +/- 27.4 MUg/ml). In logistic regression analysis, pretransplant fetuin-A levels did not correlate with graft failure after 3 years' follow-up (p = 0.895). In COX regression analysis, fetuin-A levels were not associated with the time to graft loss. Moreover, fetuin-A levels correlated neither with renal and metabolic parameters nor with cellular or humoral rejection episodes. CONCLUSION: Pretransplant levels of fetuin-A are not a predictor for renal allograft loss or rejection episodes after 36 months' follow-up in transplant recipients. PMID- 21613795 TI - Effects of dialysate glucose concentration on heart rate variability in chronic hemodialysis patients: results of a prospective randomized trial. AB - BACKGROUND: Chronic hemodialysis (HD) patients suffer from an appallingly high cardiovascular mortality. During HD, patients are exposed to dialysate glucose, which may alter blood glucose levels and thus exert effects on the autonomic nervous system. Heart rate variability (HRV) is an established indicator of autonomic nervous system activity and a predictor of cardiovascular outcomes. This study investigated the effects of two commonly used dialysate glucose concentrations [100 mg/dl (HD100), and 200 mg/dl (HD200)] on HRV in chronic HD patients. METHODS: In this prospective, randomized, controlled, single-masked, cross-over trial, subjects were randomized to receive HD100 or HD200 for a period of 3 weeks followed by a cross-over to the respective other dialysate (www.clinicaltrials.gov #NCT00618033). Blood glucose and insulin levels were measured before and after HD. Intradialytic Holter electrocardiograms were recorded and HRV time domain, frequency domain and complexity parameters analyzed. RESULTS: Twenty-three HD patients (age 56 +/- 12 years, 11 male, 14 black, 11 with diabetes) were studied. Diabetic subjects showed significantly higher serum glucose levels with HD200 as compared to HD100 (HD100: 146 +/- 48 mg/dl; HD200: 192 +/- 57 mg/dl; p < 0.01); this hyperglycemia was accompanied by an increase of the high-frequency band of HRV (p = 0.019), a reflection of increased parasympathetic activity. HRV did not change in nondiabetic subjects. CONCLUSION: In diabetic subjects, the use of HD200 increased vagal tone. Given the importance of sympathetic activation to counteract intradialytic hypotension, our findings support the use of HD100 in diabetic HD patients. PMID- 21613796 TI - Outcomes of epiretinal membrane removal in eyes with and without concurrent vision-limiting ocular disease. AB - PURPOSE: To evaluate preoperative and intraoperative parameters in patients who underwent pars plana vitrectomy (PPV) for epiretinal membrane (ERM) removal and identify prognostic factors for visual recovery and complications. Furthermore, eyes with and without additional vision-limiting ocular disease were compared. METHODS: Ninety eyes of 90 patients who underwent PPV and ERM peeling were included in this retrospective study. Patients were divided according to the presence of additional vision-limiting conditions. RESULTS: The mean visual acuity (VA) improvement was -0.156 logMAR. No parameter was found to correlate with the final VA or postoperative complications. Thirty-four patients (37.8%) had concurrent vision-limiting ocular conditions. Although these eyes had lower initial and final VA, there was no significant difference in VA improvement between them and eyes without concurrent disease. CONCLUSIONS: PPV and membrane peeling is an effective treatment for patients with ERM, even in the presence of concurrent vision-limiting ocular disease. PMID- 21613797 TI - Outcomes and complications of 25-gauge transconjunctival sutureless vitrectomy for proliferative diabetic retinopathy. AB - PURPOSE: To investigate the feasibility and efficacy of 25-gauge vitrectomy in the treatment of proliferative diabetic retinopathy (PDR). METHODS: All patients underwent primary 25-gauge vitrectomy for simple vitreous hemorrhage (VH), fibrovascular proliferation (FVP), or tractional retinal detachment (TD), and were followed for more than 1 month. Final visual outcomes and intraoperative and postoperative complications were evaluated. RESULTS: 167 eyes (138 patients) were used in this study, 65 eyes (39%) with VH, 66 eyes (40%) with FVP, and 36 eyes (21%) with TD. Measured using the mean logarithm of the minimum angle of resolution (logMAR), visual acuity (VA) significantly improved (p < 0.0001). Intraoperative iatrogenic retinal breaks developed in 19 eyes (11%). Concerning postoperative complications, VH in 36 eyes (22%), retinal detachment in 2 eyes (1%), and neovascular glaucoma 12 eyes (7%) were observed. No endophthalmitis developed. CONCLUSIONS: Twenty-five-gauge vitrectomy can successfully treat PDR. Clinical outcomes and complications are comparable to those of 20-gauge vitrectomy. PMID- 21613798 TI - Laser ablation of a large tongue hemangioma with remifentanil analgosedation in the ORL endoscopy suite. AB - We present a unique, practical, and safe approach to the clinical management of a young male with a large tongue hemangioma who presented for serial surgical treatment of the lesion. Laser ablation was undertaken in the operating room under topical anesthesia with remifentanil analgosedation without the use of supplemental oxygen. Significant involution of the hemangioma was achieved without complication while the patient was awake, cooperative, and able to protect his airway. The application of remifentanil infusion for analgosedation during airway surgery is described. The utility of pharmacokinetic modeling in these applications is discussed along with the use of non-invasive respiratory inductance plethysmography to monitor ventilation during opioid sedation. The concept of analgosedation for airway surgery is introduced and relative risk versus benefit considerations of the approach in comparison to general anesthesia are discussed. This approach can be conceived of as an ORL endoscopy suite model for limited airway procedures. PMID- 21613799 TI - Decreased RECK and Increased EMMPRIN expression in urothelial carcinoma of the bladder are associated with tumor aggressiveness. AB - OBJECTIVE: Urothelial bladder carcinomas show a divergent biological behavior, which significantly complicates risk stratification and clinical management. The MMP repressor RECK and the MMP activator EMMPRIN regulate the invasive potential by metalloproteinase-induced stromal degradation. Data on RECK in urothelial bladder cancer are lacking and information on EMMPRIN is sparse. This study aims to investigate the expression of RECK and EMMPRIN in urothelial carcinoma of the bladder and to correlate these findings with clinicopathological parameters. METHODS: Our study included 127 specimens of urothelial carcinomas derived from 103 patients who underwent either TUR-B or cystectomy. Immunohistochemical expression analysis was performed for RECK, EMMPRIN, MMP-2, MMP-9 and MMP-14. Expression levels were graded for staining intensity and correlated with pT stage and WHO tumor grade. RESULTS: Invasive (>=pT1) as well as WHO high-grade urothelial carcinomas showed a statistically significant and stepwise downregulation of RECK (p < 0.001) and concomitant upregulation of EMMPRIN (p < 0.001) compared to non-invasive and WHO low-grade tumors. No correlation was observed for the MMPs investigated. CONCLUSION: Decreased RECK and increased EMMPRIN expression are associated with increasing stage and grade. Both proteins may serve as molecular marker for the distinction between potentially invasive (>=pT1) and non-invasive tumors (<=pTa). PMID- 21613800 TI - Heterozygosity loss at 22q and lack of INI1 gene mutation in gastrointestinal stromal tumor. AB - OBJECTIVES: Gastrointestinal stromal tumor (GIST) is characterized by KIT or PDGFRA gene mutation. Although chromosomal losses of 22q are frequent in GIST, it is unclear which tumor suppressor genes might be inactivated in association with such losses. The INI1 gene, located at 22q11.23, is a tumor suppressor gene that is frequently altered in malignant rhabdoid tumor. METHODS: To elucidate the hypothesis that the INI1 gene might be altered along with 22q loss in GIST, we examined the loss of heterozygosity (LOH) at 22q11.23, homozygous deletion and mutation of the INI1 gene, and its gene product expression as well as mutations of KIT and PDGFRA in 27 cases of GIST. RESULTS: Among the 27 informative cases, 19 (70.4%) showed LOH of at least one of the microsatellite markers on 22q11.23. None of the cases (0%) showed homozygous deletion or mutation of the INI1 gene. Immunohistochemically, the INI1 expression was focally reduced in 17/27 (63%) cases, and the INI1 protein level and INI1 mRNA level were each correlated with the presence of 22q11.23 LOH. Although the 22q11.23 LOH was more frequently present in high- than in low-grade tumors, INI1 expression level was not correlated with tumor grade, tumor size, proliferative activity and the expression levels of cyclin D1 and p16INK4a. KIT mutations were found in 18/27 (66.7%) GISTs; however, the KIT genotype was not correlated with the status of LOH at 22q11.23. CONCLUSIONS: The results suggest that 22q11.23 LOH is frequently present in GIST irrespective of KIT genotype and it might play a role in part of the development of GIST. However, the hemiallelic loss of INI1 gene causing reduced expression of INI1 protein probably does not have a major impact in the progression of GIST. PMID- 21613801 TI - PRO_10--a new tissue-based prognostic multigene marker in patients with early estrogen receptor-positive breast cancer. AB - BACKGROUND/AIMS: Clinicopathological and molecular factors determine the prognosis of breast cancer. PRO_10 is a prognostic score based on quantitative RT PCR of 10 proliferation-associated genes obtained from formalin-fixed, paraffin embedded breast cancer tissues. We revalidated PRO_10 in patients treated in a non-trial setting. METHODS: The charts of 315 patients with postmenopausal estrogen receptor (ER)-positive breast cancer between 1996 and 2004 were reviewed. Forty-eight cases relapsed within 5 years of diagnosis; they were paired with controls by matching the N and T stage, histological grade, percent ER-positive cells, human epidermal growth factor receptor 2, age, adjuvant chemo- and endocrine therapy. The score was tested by conditional logistic regression. RESULTS: Despite strict matching, PRO_10 remained prognostic for recurrence in the whole group (odds ratio, OR = 4.7, p = 0.005) and in subgroups of grade 2 (OR = 5.5, p = 0.009) and N0 cancers (OR = 15, p = 0.002). Five-year recurrence-free survival was 29% in patients with high and 67% in patients with low scores (p = 0.002). PRO_10 was prognostic for overall survival (5-year overall survival 71 vs. 91%). CONCLUSION: PRO_10 is an independent prognostic marker in postmenopausal ER-positive breast cancer. It is based on formalin-fixed, paraffin embedded tissue and could be integrated easily into the routine diagnostic workflow. PMID- 21613802 TI - Aberrant expression of disintegrin-metalloprotease proteins in the formation and progression of uterine cervical cancer. AB - OBJECTIVE: Dysregulated expression of disintegrin-metalloprotease proteins [a disintegrin and metalloproteases (ADAMs) and ADAMs with thrombospondin motif (ADAMTSs)] has been reported in many types of cancers and is believed to play an important role in cancer formation and metastasis. However, little is known about the expression of ADAMs and ADAMTSs in the development of human cervical cancer. METHODS: Reverse transcriptase polymerase chain reaction and immunoblotting were performed to assess the expression of several disintegrin-metalloproteases and tissue inhibitors of metalloproteinases (TIMPs) in squamous-type cervical cancer cells and oncogenically modified keratinocytes (immortalized human cervical keratinocytes transduced with human papilloma virus-16 E6/E7 proteins with or without oncogenes). Immunohistochemistry of ADAM-9, ADAM-10 and TIMP-3 was performed on 31 primary human cervical tissue specimens of preinvasive and invasive cervical carcinoma. RESULTS: mRNA levels of ADAM-9, ADAM-10, ADAM-12, TIMP-2 and TIMP-3 were upregulated as cervical cells progressed from dysplastic to malignant lesions compared to normal cervical cells. These results were corroborated at the protein level by Western blot analysis and immunohistochemistry. CONCLUSION: The expression of disintegrin-metalloproteases and their endogenous regulators was dysregulated during cervical carcinogenesis. The aberrant expression of ADAMs might contribute to the pathogenesis of cervical cancer formation and progression. PMID- 21613803 TI - Differential kidney proteome profiling in a murine model of renal fibrosis under treatment with mycophenolate mofetil. AB - AIM: The aim of this study was to investigate the effect of mycophenolate mofetil (MMF) using differential kidney proteome profiling of COL4A3-deficient mice as a model of progressive renal disease. METHODS: Histological evaluation of kidney sections was performed. Total protein lysate from kidneys of placebo- and MMF treated COL4A3-deficient mice was studied for significant differences in protein abundance using 2-dimensional electrophoresis and mass spectrometry. RESULTS: While tubulointerstitial fibrosis in COL4A3-deficient mice was inhibited by MMF, 19 proteins in the kidneys were regulated: 12 with lower (ATPO, TAGL2, CAH1, TPD52, VA0D1, SERPH, GNAL, PSB6, EF1D, OTUB1, NDUS8, and NAPSA) and 7 with higher (ACADM, ACY3, CK054, ACTB/G, ACTB, UBP5, and ACY1) spot intensity. Nine differentially expressed proteins showed interaction potential (ATPO, TPD52, PSB6, EF1D, OTUB1, NAPSA, ACTB, ACTG, and UBP5). CONCLUSIONS: The identified proteins take part in different signaling pathways. With the highest probability, the VEGF signaling pathway (TAGL2, EF1D, and ACTB) and hypoxia (CAH1, PSB6, and ACTG) were influenced by MMF in fibrotic conditions. Moreover, MMF may modulate antifibrotic and apoptotic pathways as well as epithelial-mesenchymal transition (EMT). Different signaling pathways may be influenced by MMF therapy. These results suggest an inhibitory effect of MMF on renal EMT in COL4A3-deficient mice. Further studies are necessary to validate these findings. PMID- 21613804 TI - Enhanced expression of podoplanin in oral carcinomas in situ and squamous cell carcinomas. AB - OBJECTIVE: Podoplanin, a known lymphatic endothelial cell marker, has been reported to be expressed in various types of cancer. To elucidate the expression of podoplanin in precancerous lesions, we examined the immunohistochemical profiles of podoplanin in oral squamous epithelial lesions. METHOD: We studied a total of 298 foci of squamous cell carcinoma (SCC), carcinoma in situ (CIS), epithelial dysplasia, and hyperplastic and/or normal epithelial lesions by immunohistochemistry using D2-40. RESULTS: There was no positivity for podoplanin in normal or hyperplastic epithelia, while all of the CIS and SCC foci stained positive. Approximately one third of the mild dysplasia foci (10 of 36 foci, 28%) and 80% of moderate dysplasia foci (78/98) showed grade 1 positive reactions (positive only in the 1st layer). Grade 2 reactions (up to 4th layer) were seen in 4 of 98 moderate dysplasia foci (4%), 29 of 74 CIS foci (39%), and 3 of 30 SCC foci (10%). Grade 3 reactions (to more than 5th layer) were found in 35 (47%) CIS foci and 26 (87%) SCC foci. CONCLUSIONS: The relationship between the present histological categorization and podoplanin grade was statistically significant. D2-40 expression is considered to be related to the severity of oral precancerous lesions. PMID- 21613805 TI - Rituximab-induced interstitial lung disease: case report and literature review. AB - Rituximab, a chimeric monoclonal antibody against CD20, very rarely causes lung toxicity. Toxicity may present as interstitial lung disease, alveolar hemorrhage and adult respiratory distress syndrome. Sixteen cases of rituximab-induced interstitial lung disease (R-ILD) have been reported. With this case and a review of all other cases reported in the literature, we will try to identify the features of R-ILD, its treatment and why the early diagnosis of this complication is important. PMID- 21613806 TI - Clopidogrel response variability and its correlation with early recurrent cardiovascular events in chinese patients undergoing percutaneous coronary intervention. AB - BACKGROUND/AIMS: Numerous studies conducted on Caucasian patients have reported that individual responsiveness to clopidogrel varies widely, whereas there are only a few published studies on the antiplatelet effect of clopidogrel therapy in Chinese patients undergoing percutaneous coronary intervention. The present study aimed to evaluate clopidogrel antiplatelet effects and their correlation with early recurrent cardiovascular (CV) events. METHODS: Platelet aggregation (with 5 and 20 MUmol/l ADP) and the expression of glycoprotein Ib and P-selectin were measured at baseline and 12 and 36 h after the clopidogrel loading dose in 111 consecutive patients. The primary outcome was a definite CV event. RESULTS: There was marked interindividual variability in the drug response, as measured by platelet aggregation and P-selectin expression. The proportions of nonresponders at 12 and 36 h were 32 and 19%, respectively, with 5 MUmol/l ADP, 38 and 28% with 20 MUmol/l ADP, and 27 and 17% according to P-selectin expression. The maximal aggregation rates stimulated by 5 MUmol/l ADP in nonresponders were significantly higher than those of the responders at 12 h (57.53 +/- 14.24% vs. 33.91 +/- 10.79%; p < 0.0001) and at 36 h (48.65 +/- 15.46% vs. 30.31 +/- 16.04%; p < 0.0001). During the 3-month follow-up period, 11 patients (32.4%) among the nonresponders, 2 patients (7.1%) among the low responders and none of the responders suffered a recurrent CV event (p < 0.0001). CONCLUSIONS: The antiplatelet effectiveness of clopidogrel has a wide interindividual variation, and nonresponsiveness to clopidogrel is associated with an increased risk of early recurrent CV events. PMID- 21613807 TI - Outcome for patients with essential trigeminal neuralgia treated with linear accelerator stereotactic radiosurgery. AB - BACKGROUND: Stereotactic radiosurgery (SRS) is one option for treatment of trigeminal neuralgia, after unsuccessful conservative approaches. OBJECTIVES: The objective of this study was to retrospectively evaluate our institutional results in the management of patients with idiopathic trigeminal neuralgia treated with linear accelerator SRS. METHODS: Fifty-two patients were treated between January 1998 and December 2009 and were followed for more than 6 months (median: 26.6 months). Forty-seven patients (90%) had undergone previous surgery before SRS. The target dose ranged from 50 to 80 Gy. RESULTS: After SRS, 9 patients presented complete remission of the pain, and 21 were pain free but still under medication. Eleven patients reported a relief of more than 50% in crisis frequency. In 9 patients, no significant improvements were seen, and 2 presented an exacerbation of the pain. After an average period of 20 months, 15 patients reported pain recurrence. Results were better in patients older than 60 years (p = 0.019). Nineteen patients presented facial numbness after SRS, with a trend toward favorable treatment response (p = 0.06). CONCLUSION: SRS is an effective alternative to the treatment of essential trigeminal neuralgia, with long-lasting pain relief in more than 50% of the patients. Better results were seen with patients aged more than 60 years. PMID- 21613808 TI - Trigeminal neuralgia associated with the specific bridging pattern of transverse pontine vein: diagnostic value of three-dimensional multifusion volumetric imaging. AB - OBJECTIVES: We report the specific bridging pattern of a transverse pontine vein (TPV) associated with trigeminal neuralgia (TN), which was evaluated by 3 dimensional (3D) multifusion volumetric imaging (MFVI). METHODS: In 3 cases with TN (V1 or V1-2 territory), constructive interference in steady state (CISS) imaging confirmed no arterial compression but indicated a vein draining into Meckel's cave. Virtual endoscopic (VE) analysis for CISS images and 3D MFVI (in 2 cases) including venous information was obtained by a multidetector row computed tomography (MDCT) system. Additionally, we investigated the bridging pattern of veins around Meckel's cave on 3D MFVI of 50 cerebellopontine angle (CPA) regions without any lesions. RESULTS: In all 3 patients, VE of CISS or 3D MFVI identified a bridging vein from the TPV causing the focal deformity of the trigeminal nerve near Meckel's cave. All those patients achieved a pain-free state after surgically coagulating and cutting the vein. In investigating 3D MFVI of 50 CPA regions, this type of the bridging vein was found in 4 (8%) including the presented 2 cases. CONCLUSIONS: The specific bridging pattern of the TPV draining into Meckel's cave can be associated with TN. The 3D MFVI analysis using venous information obtained by MDCT was useful to evaluate surgical anatomy including the offending vein which can be missed. PMID- 21613809 TI - Long-term outcome after laparoscopic adjustable gastric banding for morbid obesity. AB - This study was performed to determine the long-term consequences of laparoscopic gastric banding on weight loss, body image, and life quality in morbidly obese patients. After a minimum follow-up of 9 years (mean follow-up 10 years; range 9 12 years) several questionnaires concerning weight loss, body image, and life quality were mailed to 180 morbidly obese patients following laparoscopic adjustable gastric banding. One hundred and twelve (62%) patients (92 females, 20 males) completed and returned the questionnaires. Of the entire sample, 73 (64.9%) patients still had the first band, 17 (15.3%) a second band, and in 22 (19.8%) probands the band had been removed for various reasons. Average weight loss, calculated as change in body mass index, was 13.9 kg/m2. Average excess weight loss (EWL) was 30.6%. A total of 10% patients accounted for >50% of EWL. Half of the probands were completely satisfied with their weight loss and about half had reached their planned weight. Lowest post-operative weight was reached at different times, in nearly half of the probands after 2 years, in one-fourth after 4-5 years, and in about 20% at a later time. More than 90% of the probands experienced longer interruptions in weight loss; about half knew why. The findings indicate that overall quality of life was rated good to excellent by two thirds of the probands, and fair to poor by one-third. A close correlation was seen between extent of weight loss and quality of life and body image. Despite some limitations, laparoscopic adjustable gastric banding is an effective and safe long-term surgical treatment for a majority of morbidly obese individuals, resulting in long-term weight loss and health-related quality of life. However, there is also a minority of morbidly obese subjects who do not benefit enough from this kind of bariatric surgery. Future research should investigate what kind of bariatric surgery is best for the particular obese individual in order to minimize unsatisfying post-operative results. PMID- 21613810 TI - Glycated hemoglobin, diabetes mellitus, and cardiovascular risk in a cross sectional study among She Chinese population. AB - OBJECTIVE: To determine whether glycated hemoglobin (HbA1c) could be used to diagnose Type 2 diabetes mellitus in She Chinese People and to assess the role of HbA1c in the development of cardiovascular disease. RESEARCH DESIGN AND METHODS: An ethnically representative sample of 687 (277 males and 410 females) adults, 20 yr of age or older participated in the study, and 75-g oral glucose tolerance test was administrated. Based on receiver operating characteristic curves, various cut-off values of HbA1c were used to stratify glucose tolerance. Several indexes were used to assess the cardiovascular risk, including estimated glomerular filtration rate (eGFR), Tpeak-end, Tp-e dispersion, aVL R wave, and QTc. RESULTS: Using World Health Organization as gold standard, the HbA1c value of 6.9% was optimal to diagnose diabetes mellitus with a sensitivity of 35.3% and specificity of 94.0%. And for impaired fasting glucose, impaired glucose tolerance, and impaired glucose regulation, the cut-off points were all 6.1%. Assessed by logistic regression model, HbA1c was an independent risk factor for the decline in eGFR; R wave in lead aVL increased significantly (p<0.05) with the increase of HbA1c values. Other indexes reflecting the cardiovascular risks were not meaningful in our study. CONCLUSIONS: HbA1c may be not a preferred method to diagnose Type2 diabetes in She Chinese people. However, more attention should be paid to subjects with HbA1c>6.1%, and their blood glucose should be tightly measured in clinical practice. In addition, we suggest that HbA1c is a predictor of cardiovascular disease. PMID- 21613811 TI - Clinical presentations of thyroid cancer patients with multiple primary cancers. AB - BACKGROUND: In thyroid cancer patients with multiple primary cancers, primary cancers tend to be more aggressive. AIMS: We analyzed multiple primary cancers in thyroid cancer patients and determined the differences between the incidence and the characteristics of primary cancers. MATERIALS AND METHODS: A total of 3070 patients with thyroid cancer underwent a thyroidectomy and follow-up examination at a single medical center. The times of diagnosis of the primary cancers were categorized as antecedent, synchronous, or subsequent to the diagnosis of thyroid cancer. RESULTS: After a mean follow-up period of 8.8 +/- 0.5 yr, the presence of multiple primary cancers was histopathologically confirmed in 163 patients (5.3%). Patients with multiple primary cancers had a lower female-to-male ratio, an older mean age, advanced tumor-node-metastasis (TNM) stage, higher total mortality, and higher therapeutic radioactive iodide (131I) doses than patients without multiple primary cancers. Hematological malignancy and renal cell carcinoma, neither of which are among the 10 most common cancers observed in the general population of Taiwan, were the most common multiple cancers among women and men with thyroid cancer. Patient age, thyroid cancer tumor size, and thyroid cancer mortality in the antecedent, synchronous, and subsequent groups were not significantly different. CONCLUSIONS: Patients with multiple primary cancers in advanced stages had shorter disease-free survival period after treatment. Thyroid cancer patients with multiple primary cancers should be closely followed up for the occurrence of other secondary cancers in order to improve total mortality. PMID- 21613812 TI - Effects of antihypertensive treatments on incidence of diabetes: a case-control study. AB - AIMS: Aim of this case-control study is the assessment of the relationship between antihypertensive treatment and incidence of diabetes in an unselected cohort of subjects participating in a screening program for diabetes. METHODS: A case-control study nested within a cohort of nondiabetic subjects with a mean follow-up of 27.7 +/- 11.3 months was performed, comparing 40 cases of incident diabetes and 160 controls matched for age, sex, body mass index, fasting plasma glucose, 2-h post-load glycemia, smoking and alcohol abuse. RESULTS: When considering antihypertensive treatment at enrolment, a lower proportion of cases was exposed to ACE-inhibitors/angiotensin receptor blockers (ACE-i/ARB) in comparison with controls. A non-significant trend toward a higher exposure to diuretics, which were mainly represented by thiazide diuretics, was observed in cases. In a multivariate analysis, including both ACE-i/ARB and diuretics, a protective effect of ACEi/ARB, and an increased risk with diuretics were observed. Similar results were obtained in alternative models, after adjusting for systolic and diastolic blood pressure at enrolment, diagnosis of hypertension, concurrent treatment with beta-blockers or calcium-channel blockers, and number of antihypertensive medications. CONCLUSIONS: Diuretics seem to be associated with a higher incidence of diabetes, whereas treatment with ACEi/ARB could have a protective effect. PMID- 21613813 TI - Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: a pilot study. AB - BACKGROUND: Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances, in particular from insulin resistance. Accumulating evidence suggests that vitamin D deficiency may contribute to the development of insulin resistance. Hence, we aimed to examine the effect of vitamin D supplementation on metabolic and endocrine parameters in PCOS women. METHODS: Fifty-seven PCOS women were included in the study. PCOS women received 20,000 IU cholecalciferol weekly for 24 weeks. Anthropometric measures, oral glucose tolerance test, and blood analyses of endocrine parameters were performed at baseline and after 12 weeks (V2) and 24 weeks (V3). RESULTS: Forty-six PCOS women finished the study. 25-hydroxyvitamin D [25(OH)D] levels significantly increased from 28.0+/-11.0 ng/ml at baseline to 51.3+/-17.3 and 52.4+/-21.5 at V2 and V3, respectively (p<0.001). We observed a significant decrease of fasting and stimulated glucose (V3, p<0.05) and C-peptide levels (V2 and 3, p<0.001) after vitamin D treatment. Moreover, triglyceride and estradiol levels significantly decreased at V3 (p=0.001) and V2 (p=0.022), respectively, whereas total cholesterol (V2, p=0.008) and LDL cholesterol levels (V2, p=0.005; V3, p=0.026) significantly increased after vitamin D treatment. There were no changes in androgens. At V2, 14 out of 46 PCOS women previously affected by menstrual disturbances (30.4%) reported improvement of menstrual frequency; at V3, 23 out of 46 women (50.0%), who were oligo- or amenorrheic at baseline reported improvement. DISCUSSION: Our results suggest that vitamin D treatment might improve glucose metabolism and menstrual frequency in PCOS women. Further randomized controlled trails are warranted to confirm our findings. PMID- 21613815 TI - Kidney regeneration and resident stem cells. AB - Given its complexity, high metabolic activity and excretory functions, the kidney is particularly susceptible to acute ischemic and toxin-mediated injury. Current therapies do not facilitate kidney regeneration, and there is an increasing interest in newer therapies that are based on cellular sources of kidney regeneration, such as stem cell therapy. Our understanding of cellular sources for kidney regeneration and stem cells present in the adult kidney has dramatically evolved over the recent years. Herein, we discuss the current understanding of kidney stem cells present in the adult mammalian kidney and their role in kidney regeneration. We have also summarized the best available evidence supporting the role of stem cells in kidney regeneration. PMID- 21613814 TI - The effect of bisphosphonate and intermittent human parathyroid hormone 1-34 treatments on cortical bone allografts in rabbits. AB - AIM: This study compares the effect of bisphosphonate and intermittent PTH administration on haversian remodeling in cortical bone allografts in rabbits. MATERIALS AND METHODS: An intercalary heat-treated cortical bone allograft was applied to a segment skeletal defect in the left femur of Japanese white rabbits. The rabbits were randomly assigned to one of three groups: the vehicle control group (CNT); the bisphosphonate group (B group); and the intermittent PTH treatment group (P group). Periodic radiographic evaluation was performed and peripheral quantitative computerized tomography (pQCT) was used to evaluate the total bone area (Area), bone mineral density (BMD), and bone mineral content (BMC). The allografts also underwent histological examination. RESULTS: The P group was radiographically superior in the latter stage, compared with the other groups. pQCT analysis of the allografts showed that the B group had a significantly higher Area and BMC. These parameters in the latter stage were significantly lower in the P group than in the other groups. The allograft of the B group was histologically mostly necrotic bone, whereas allograft of the P group showed abundant newly formed bone. CONCLUSION: In rabbits, bisphosphonate prevents resorption, but suppresses remodeling and incorporation; by contrast, PTH increases resorption and accelerates allograft remodeling and incorporation. Based on our preliminary data, we suggest that further research on the manner of administration of bisphosphonate and PTH - which have contrasting effects - can be beneficial in maintaining bone strength and in regulating remodeling and allograft incorporation. PMID- 21613816 TI - A rapid in vivo assay system for analyzing the organogenetic capacity of human kidney cells. AB - Transplantation of human kidney-derived cells is a potential therapeutic modality for promoting regeneration of diseased renal tissue. However, assays that determine the ability of candidate populations for renal cell therapy to undergo appropriate differentiation and morphogenesis are limited. We report here a rapid and humane assay for characterizing tubulogenic potency utilizing the well established chorioallantoic membrane CAM) of the chick embryo. Adult human kidney derived cells expanded in monolayer were suspended in Matrigel and grafted onto the CAM. After a week, grafts were assessed histologically. Strikingly, many of the renal cells self-organized into tubular structures. Host blood vessels penetrated and presumably fed the grafts. Immuno- and histochemical staining revealed that tubular structures were epithelial, but not blood vessels. Some of the cells both within and outside the tubules were dividing. Analysis for markers of proximal and distal renal tubules revealed that grafts contained individual cells of a proximal tubular phenotype and many tubules of distal tubule character. Our results demonstrate that the chick CAM is a useful xenograft system for screening for differentiation and morphogenesis in cells with potential use in renal regenerative medicine. PMID- 21613817 TI - The effects of the dietary polyphenol resveratrol on human healthy aging and lifespan. AB - The physiological effects of the dietary polyphenol resveratrol are being extensively studied. Resveratrol has been proposed to promote healthy aging and to increase lifespan primarily through the activation of the class III histone deacetylases (sirtuins). Although its positive effects are evident in yeast and mice they still have to be confirmed in humans. The molecular mechanisms involved in the processes are not fully understood because resveratrol may have other targets than sirtuins and the direct activation of sirtuins by resveratrol is under debate. PMID- 21613819 TI - Systemic Par-4 inhibits non-autochthonous tumor growth. AB - The tumor suppressor protein Par-4 (Prostate apoptosis response-4) is spontaneously secreted by normal and cancer cells. Extracellular Par-4 induces caspase-dependent apoptosis in cancer cell cultures by binding, via its effector SAC domain, to cell surface GRP78 receptor. However, the functional significance of extracellular Par-4/SAC has not been validated in animal models. We show that Par-4/SAC-transgenic mice express systemic Par-4/SAC protein and are resistant to the growth of non-autochthonous tumors. Consistently, secretory Par-4/SAC pro apoptotic activity can be transferred from these cancer-resistant transgenic mice to cancer-susceptible mice by bone marrow transplantation. Moreover, intravenous injection of recombinant Par-4 or SAC protein inhibits metastasis of cancer cells. Collectively, our findings indicate that extracellular Par-4/SAC is systemically functional in inhibition of tumor growth and metastasis progression, and may merit investigation as a therapy. PMID- 21613820 TI - Cancer-testis gene expression profiling in esophageal squamous cell carcinoma: identification of specific tumor marker and potential targets for immunotherapy. AB - Cancer-testis antigens (CTAs) are often specifically expressed in cancer cells and under normal conditions are only considered to be expressed in the germ line cells and the placenta. CTAs are potential targets for cancer immunotherapy and therefore necessitates their expression profiling. The expression profile of LAGE1, MAGE-A4 and NY-ESO1, their possible correlations and interaction, and the clinicopathological associations of each marker were studied. RNA was extracted from fresh esophagectomy tissues of 41 esophageal squamous cell carcinoma (ESCC) patients prior to any other therapeutic intervention. The relative mRNA expression of LAGE1, MAGE-A4 and NY-ESO1 was assessed with the real-time reverse transcription-polymerase chain reaction (RT-PCR) 5' nuclease assay. The overexpression of LAGE1, MAGE-A4 and NY-ESO1 was found in 39, 90.2 and 41.4% of ESCC samples respectively. Of the patients, 97.5% showed an overexpression of at least one CTA. The relative expression of MAGE-A4 was directly associated with lymph node metastasis and the stage of the tumor (p < 0.05). A significant direct correlation was also detected between the MAGE-A4/LAGE1 and MAGE-A4/NY-ESO1 levels of gene expression. MAGE-A4 is identified as a specific biomarker of ESCC with a possible oncogenic role contributing to tumor progression. Interactions between MAGE-A4, LAGE1 and NY-ESO1 and their significant clinical consequences introduce these CTAs as appropriate targets for a polyvalent cancer vaccine. PMID- 21613818 TI - The emerging role of epigenetic mechanisms in the etiology of neural tube defects. AB - The molecular requirements for neural tube closure are complex. This is illustrated by the occurrence of neural tube defects (NTDs) in many genetic mouse mutants, which implicate a variety of genes, pathways and cellular functions. NTDs are also prevalent birth defects in humans, affecting around 1 per 1000 pregnancies worldwide. In humans the causation is thought to involve the interplay of fetal genes and the effect of environmental factors. Recent studies on the aetiology of human NTDs, as well as analysis of mouse models, have raised the question of the possible involvement of epigenetic factors in determining susceptibility. A consideration of potential causative factors in human NTDs must now include both alterations in the regulation of gene expression, through mutation of promoter or regulatory elements, and the additional analysis of epigenetic regulation. Alterations in the epigenetic status can be directly modified by various environmental insults or maternal dietary factors. PMID- 21613821 TI - Complete remission, in BRCA2 mutation carrier with metastatic pancreatic adenocarcinoma, treated with cisplatin based therapy. AB - Carriers of a germline mutation in the BRCA genes, in particular BRCA2, have an increased risk of developing pancreatic adenocarcinoma when compared with the general population. While the addition of cisplatin to gemcitabine did not produce survival benefit compared to single-agent gemcitabine in prospective trials it is postulated that the addition of DNA cross-linking agent such as cisplatin to standard gemcitabine chemotherapy should be considered in known BRCA mutation carriers. We report a case of pancreatic adenocarcinoma arising in a 60 year-old carrier of a rare BRCA2 (1153insertionT) germline mutation. The patient received gemcitabine without any response and actually progression of the disease had occurred. Therefore cisplatin was added in combination with gemcitabine. A dramatic complete response to therapy was encountered with no evidence of disease in both CT scans and markers (CA19-9). In conclusion, in patients with known BRCA mutation associated pancreatic adenocarcinoma, the addition of a DNA cross linking agent such as cisplatin should be considered. Physicians should consider BRCA mutation testing when the diagnosis of pancreatic cancer is established, especially when the patient belongs to an ethnic group where founder mutations exist, and/or there is strong personal or family history of cancer. This may be applied also to other metastatic tumors diagnosed in BRCA1/2 carriers. PMID- 21613823 TI - A role for mitochondria in autophagy regulation. AB - Understanding the functional relationship between mitochondria and autophagy is critical for understanding the molecular mechanisms underlying aging and neurodegeneration. Autophagy functions in both cellular homeostasis and in quality control in the selective removal of dysfunctional mitochondria. A current working model in the field is that impaired autophagy results in a cell-damaging accumulation of dysfunctional mitochondria over time. We described our findings that respiratory-deficient mitochondria can inhibit general (macro) autophagy in Saccharomyces cerevisiae by conserved signaling pathways during amino acid starvation. These data point to an interdependence of mitochondrial function and autophagy and raise the possibility that negative regulation of autophagy by dysfunctional mitochondria is a critical contributing factor in many diseases. PMID- 21613822 TI - A novel 3-dimensional culture system uncovers growth stimulatory actions by TGFbeta in pancreatic cancer cells. AB - Transforming Growth Factor-beta (TGF-beta) exerts cell type-specific and context dependent effects. Understanding the intrinsic effects of TGF-beta on cancer cells in pancreatic ductal adenocarcinoma (PDAC) is a prerequisite for rationalized clinical implementation of TGF-beta targeting therapies. Since the tumor microenvironment can affect how cancer cell respond to TGF-beta, we employed a novel three-dimensional (3D) culturing system to recapitulate stromal and extracellular matrix interactions. We show here that TGF-beta stimulates growth of human and murine pancreatic cancer cell lines (PCCs) when embedded in a 3% collagen IV/laminin-rich gelatinous medium (MatrigelTM) over a solidified layer of soft agar. Moreover, in this novel 3D model, concomitant treatment with TGF-beta1 and epidermal growth factor (EGF) enhanced PCC growth to a greater extent than either growth factor alone, and conferred increased chemoresistance to cytotoxic compounds. These cooperative growth-stimulatory effects were blocked by pharmacological inhibition of TGF-beta type I receptor with SB431542 or the EGF receptor with erlotinib. Co-incubation with SB431542 and erlotinib enhanced the efficacy of gemcitabine and cisplatin in PCCs and in primary cell cultures established from pancreata of genetically-engineered mouse models of PDAC. These findings suggest that concomitant inhibition of TGF-beta and EGF signaling may represent an effective therapeutic strategy in PDAC, and that this 3D culturing system could be utilized to test ex vivo the therapeutic response of pancreatic tumor biopsies from PDAC patients, thereby providing a functional assay to facilitate personalized targeted therapies. PMID- 21613824 TI - Troglitazone, a PPAR agonist, inhibits human prostate cancer cell growth through inactivation of NFkappaB via suppression of GSK-3beta expression. AB - PPARgamma ligands have been reported to reduce proliferation of human prostate cancer cells. However, the molecular mechanism of PPARgamma agonist-induced cell growth inhibition of prostate cancer cells is not clear. GSK-3beta expression and NFkappaB activity have important roles in prostate cancer development. To investigate the mechanisms of the PPARgamma agonist-induced prostate cancer cell growth inhibition, we examined the effect of troglitazone on the expression of PPARgamma, GSK-3beta and activity of NFkappaB as well as on the prostate cancer cell growth. Troglitazone induced the expression of PPARgamma in the nuclear of PC-3 cells, but not in LNCaP cells. Troglitazone (0-16 uM) inhibited cancer cell growth in a similar extend between both cells accompanied by the induction of cell cycle arrest in G(0)/G(1) phase and an increased in the similar extent of apoptotic cell death in concentration dependent manner. Troglitazone inhibited the constitutive expression of GSK-3beta and activation of NFkappaB. Co-treatment of troglitazone with a GSK-3beta inhibitor (AR-a014418) or GSK-3beta siRNA significantly augmented the inhibitory effect of troglitazone on the NFkappaB activity and on prostate cancer cell growth inhibition and apoptotic cell death. However, overexpression of GSK-3beta hindered troglitazone-induced cell growth inhibition and NFkappaB inactivation. These results suggest that PPARgamma agonist, troglitazone, inhibits prostate cancer cell growth through inactivation of NFkappaB via suppression of GSK-3beta expression. PMID- 21613825 TI - FoxO family members in cancer. AB - The PI3K-Akt-FoxO signaling pathway plays a central role in diverse physiological processes including cellular energy storage, growth, and survival, among others. As an important effector of this pathway, FoxO is involved in versatile activities that protect organisms from stress and aging. Recent studies on mammalian FoxO have established a direct role for this transcription factor family in cellular proliferation, oxidative stress response, and tumorigenesis. The review will focus on the recent developments pertaining to the function of FoxO as well as discuss the various contexts in which FoxO exerts distinct biological activity such as drug resistance and autophagy in cancer pathogenesis and therapy. PMID- 21613826 TI - Genome-wide methylation and expression differences in HPV(+) and HPV(-) squamous cell carcinoma cell lines are consistent with divergent mechanisms of carcinogenesis. AB - Oncogenic human papillomaviruses (HPV) are associated with nearly all cervical cancers and are increasingly important in the etiology of oropharyngeal tumors. HPV-associated head and neck squamous cell carcinomas (HNSCC) have distinct risk profiles and appreciate a prognostic advantage compared to HPV-negative HNSCC. Promoter hypermethylation is widely recognized as a mechanism in the progression of HNSCC, but the extent to which this mechanism is consistent between HPV(+) and HPV(-) tumors is unknown. To investigate the epigenetic regulation of gene expression in HPV-induced and carcinogen-induced cancers, we examined genome-wide DNA methylation and gene expression in HPV(+) and HPV(-) SCC cell lines. We used two platforms: the Illumina Infinium Methylation BeadArray and tiling arrays, and confirmed illustrative examples with pyrosequencing and quantitative PCR. These analyses indicate that HPV(+) cell lines have higher DNA methylation in genic and LINE-1 regions than HPV(-) cell lines. Differentially methylated loci between HPV(+) and HPV(-) cell lines significantly correlated with HPV-typed HNSCC primary tumor DNA methylation levels. Novel findings include higher promoter methylation of polycomb repressive complex 2 target genes in HPV(+) cells compared to HPV(-) cells and increased expression of DNMT3A in HPV(+) cells. Additionally, CDKN2A and KRT8 were identified as interaction hubs among genes with higher methylation and lower expression in HPV(-) cells. Conversely, RUNX2, IRS-1 and CCNA1 were major hubs with higher methylation and lower expression in HPV(+) cells. Distinct HPV(+) and HPV(-) epigenetic profiles should provide clues to novel targets for development of individualized therapeutic strategies. PMID- 21613827 TI - Decreased zinc and downregulation of ZIP3 zinc uptake transporter in the development of pancreatic adenocarcinoma. AB - Pancreatic adenocarcinoma is an untreatable deadly cancer. The factors involved in its early development remain unknown; which contributes to the absence of biomarkers for early detection of malignancy or at-risk subjects, and the absence of efficacious therapeutic agents. Because zinc changes are implicated in some cancers, we determined if it might be involved in the development of pancreatic adenocarcinoma. With in situ Dithizone and Zinquin staining of normal pancreas and adenocarcinoma tissue sections, we show for the first time, a consistent major loss of zinc in ductal and acinar epithelium in adenocarcinoma compared to the normal epithelium. This decrease in zinc is evident in well-differentiated through poorly-differentiated stages of malignancy. Immunohistochemistry identified ZIP3 as the basilar membrane zinc uptake transporter in normal ductal/acinar epithelium; and that the transporter is absent in adenocarcinoma. In situ Rt-PCR revealed that ZIP3 gene expression is silenced in adenocarcinoma. The ZIP3 down regulation accompanied the loss of zinc in early and progressing malignancy. RREB1 transcription factor was down regulated along with ZIP3; and might be involved in the silencing of ZIP3 expression. Zinc treatment was cytotoxic to malignant Panc1 cells. The combination of concurrent zinc, ZIP3, and RREB-1 changes represent early events in the development of adenocarcinoma; and suggest that zinc might be a tumor suppressor of pancreatic cancer. This report provides the clinical foundation for further mechanistic studies that will provide important insight into pancreatic carcinogenesis, and can lead to the development of effective early biomarkers and effective therapeutic agents for pancreatic cancer. PMID- 21613828 TI - Combination of ultrasound and bubble liposome enhance the effect of doxorubicin and inhibit murine osteosarcoma growth. AB - If ultrasound (US) is applied to cells, permeability across the cell membrane temporarily increases, making it easier for drugs to be taken into the cells from around the cell membrane. Moreover, when used in combination with Bubble liposome (BL: liposomes which entrap an ultrasound imaging gas), even low-power ultrasound can facilitate drug delivery into cells. In the present study, we constructed a new drug delivery system (DDS) involving concomitant use of US and BL with doxorubicin (DOX), a key drug in the chemotherapy of osteosarcoma, and demonstrated both in vitro and in vivo that it markedly inhibited the proliferation of osteosarcoma cells. Furthermore, this system achieved an equivalent antitumor effect at about 1/5 the dose of antitumor agent employed in monotherapy with DOX. These findings suggest the possibility of reduction of adverse events. In this experiment, US and liposomes were tested, both of which are already in use in clinical practice. US and liposomes are both very safe in the body. The DDS composed of these elements we designed can be applied in simple and site-specific fashion and is therefore promising as a new, clinically feasible method of treatment. PMID- 21613829 TI - Novel antimicrobial catheter lock solution: a new direction in which chelators replace heparin. PMID- 21613830 TI - Sepsis in critically ill patients with trauma. PMID- 21613831 TI - Endothelial dysfunction as predictor of mortality in sepsis. PMID- 21613832 TI - Goal-directed ultrasonography in the intensive care unit: no more excuses! PMID- 21613833 TI - Environmental cleaning and disinfection: only one piece of the critical care infection control puzzle. PMID- 21613834 TI - Clinical implications of subcutaneous glucose monitoring in critically ill patients. PMID- 21613835 TI - Candidemia in the intensive care unit: miles to go before we sleep. PMID- 21613836 TI - Vitamin D: could mom really be right? PMID- 21613837 TI - Protocol-driven sedation: will both the patient and physician be more comfortable? PMID- 21613838 TI - Examining the affect of norepinephrine on cardiac preload and reduced preload dependency in septic shock. PMID- 21613839 TI - Angiopoietins in sepsis: biomarkers or effector molecules? PMID- 21613840 TI - The significance of reduced airway hyperemia and enhanced oxygenation after epinephrine nebulization in a preclinical evaluation. PMID- 21613841 TI - Inhaled therapy and ventilator-associated pneumonia: a breath of suspicion in the air? PMID- 21613842 TI - Whose (quality of) life is it anyway? Measurement issues of health-related quality of life in critically ill older adults. PMID- 21613843 TI - Propofol--sweet dreams, but not for everyone? PMID- 21613844 TI - When it comes to ventilation, noisy is better than quiet and variability is healthier than constant! PMID- 21613845 TI - Role of peroxiredoxin 6 in acute lung injury: potential target? PMID- 21613846 TI - Impaired renal blood flow and the 'spicy food' hypothesis of acute kidney injury. PMID- 21613847 TI - Ventilator-induced diaphragmatic dysfunction: is there a dim light at the end of the tunnel? PMID- 21613848 TI - Tetrastarch for fluid resuscitation in septic shock: good news for the kidneys? PMID- 21613849 TI - Pharmacologic renoprotection: are the stars finally moving into alignment? PMID- 21613850 TI - A strategy for changing plasma pralidoxime kinetics and, perhaps, effect in organophosphorus insecticide poisoning. PMID- 21613851 TI - Heparin-binding protein: another neutrophil granule protein ... another new biomarker? PMID- 21613852 TI - What is the benefit in triage? PMID- 21613853 TI - Chance favors the prepared mind: the association between heparin-induced thrombocytopenia and bilateral adrenal hemorrhage. PMID- 21613854 TI - Emergency ultrasound of the chest: altering patient management by a visual stethoscope. PMID- 21613855 TI - Quality indicators for evaluating the quality of adult trauma care: still a long way to go! PMID- 21613856 TI - Healthcare in the developing world: is targeting HIV enough? The case for prioritizing critical care. PMID- 21613857 TI - Enteral feeding: good, but not for everyone. PMID- 21613858 TI - Intravenous lipid emulsion as antidote: how should we chew the fat in 2011? PMID- 21613859 TI - Combined arginine vasopressin and levosimendan: a promising therapy for septic shock. PMID- 21613861 TI - Toward the end of randomized, controlled trials in the intensive care unit? PMID- 21613862 TI - Coated central venous catheters: mortality, illness severity? PMID- 21613865 TI - Appropriateness or time? PMID- 21613867 TI - Severity of pH1N1 influenza A. PMID- 21613869 TI - Selection bias in analysis of status epilepticus in the intensive care unit. PMID- 21613871 TI - Quantitative brain MRI. PMID- 21613872 TI - Quantification issues in arterial spin labeling perfusion magnetic resonance imaging. AB - Arterial spin labeling (ASL) perfusion magnetic resonance imaging has gained wide acceptance for its value in clinical and neuroscience applications during recent years. Its capability for noninvasive and absolute perfusion quantification is a key characteristic that makes ASL attractive for many clinical applications. In the present review, we discuss the main parameters or factors that affect the reliability and accuracy of ASL perfusion measurements. Our secondary goal was to outline potential solutions that may improve the reliability and accuracy of ASL in clinical settings. It was found that, through theoretical analyses, flow quantification is most sensitive to tagging efficiency and estimation of the equilibrium magnetization of blood signal (M(0b)). Variations of blood T1 have a greater effect on perfusion quantification than variations of tissue T1. Arterial transit time becomes an influential factor when it is longer than the postlabeling delay time. The T2's of blood and tissue impose minimal effects on perfusion calculation at field strengths equal to or lower than 3.0 T. Subsequently, we proposed various approaches for in vivo estimation or calibration of the above parameters, such as the use of phase-contrast magnetic resonance imaging for calibration of the labeling efficiency as well as the use of inversion recovery TrueFISP (true fast imaging with steady-state precession) sequence for blood T1 mapping. We also list representative clinical cases in which implicit assumptions for ASL perfusion quantification may be violated, such as the venous outflow effect in children with sickle cell disease. Finally, an optimal imaging protocol including in vivo measurements of several critical parameters was recommended for clinical ASL studies. PMID- 21613873 TI - Perfusion MRI using dynamic-susceptibility contrast MRI: quantification issues in patient studies. AB - OBJECTIVES: Measurement of perfusion accurately, noninvasively, and with good spatial resolution offers the chance to characterize abnormal tissue in many clinical conditions. Dynamic-susceptibility contrast (DSC) MRI, also known as bolus-tracking MRI, is a dynamic MRI method to measure perfusion and other related hemodynamic parameters. This review article describes the principles involved in perfusion quantification using DSC-MRI as well as discusses the main issues affecting its quantification in patient studies. CONCLUSIONS: It is shown that DSC-MRI is a very powerful technique that provides important information regarding cerebral hemodynamics. The relatively high contrast-to-noise ratio, fast acquisition, and wealth of information available have made DSC-MRI the most commonly used MRI technique for the rapid assessment of the brain hemodynamics in clinical investigations. While very important advances have been achieved in the last 2 decades, there are still some remaining limitations that users should be aware of to avoid misinterpretation of the findings and to make the most of the invaluable information provided by perfusion MRI. PMID- 21613874 TI - Precision and accuracy in diffusion tensor magnetic resonance imaging. AB - This article reviews some of the key factors influencing the accuracy and precision of quantitative metrics derived from diffusion magnetic resonance imaging data. It focuses on the study pipeline beginning at the choice of imaging protocol, through preprocessing and model fitting up to the point of extracting quantitative estimates for subsequent analysis. The aim was to provide the newcomers to the field with sufficient knowledge of how their decisions at each stage along this process might impact on precision and accuracy, to design their study/approach, and to use diffusion tensor magnetic resonance imaging in the clinic. More specifically, emphasis is placed on improving accuracy and precision. I illustrate how careful choices along the way can substantially affect the sample size needed to make an inference from the data. PMID- 21613875 TI - Quantitative relaxometry of the brain. AB - The exquisite soft tissue contrast provided by magnetic resonance imaging arises principally from differences in the intrinsic relaxation properties, T1 and T2. Although the intricate relationships that link tissue microstructure and the longitudinal and transverse relaxation times remain to be firmly established, quantitative measurement of these parameters, also referred to as quantitative relaxometry, can be informative of disease-related tissue change, developmental plasticity, and other biological processes. Further, relaxometry studies potentially offer a more detailed characterization of tissue, compared with conventional qualitative or weighted imaging approaches.The purposes of this review were to briefly review the biophysical basis of relaxation, focusing specifically on the T1, T2, and T2* relaxation times, and to detail some of the more widely used and clinically feasible techniques for their in vivo measurement. We will focus on neuroimaging applications, although the methods described are equally well suited to cardiac, abdominal, and musculoskeletal imaging. Potential sources of error, and methods for their correction, are also touched on. Finally, the combination of relaxation time data with other complementary quantitative imaging data, including diffusion tensor imaging, is discussed, with the aim of more thoroughly characterizing brain tissue. PMID- 21613876 TI - Quantitative proton magnetic resonance spectroscopy and spectroscopic imaging of the brain: a didactic review. AB - This article presents background information related to methodology for estimating brain metabolite concentration from magnetic resonance spectroscopy (MRS) and magnetic resonance spectroscopic imaging measurements of living human brain tissue. It reviews progress related to this methodology, with emphasis placed on progress reported during the past 10 years. It is written for a target audience composed of radiologists and magnetic resonance imaging technologists. It describes in general terms the relationship between MRS signal amplitude and concentration. It then presents an overview of the many practical problems associated with deriving concentration solely from absolute measured signal amplitudes and demonstrates how a various signal calibration approaches can be successfully used. The concept of integrated signal amplitude is presented with examples that are helpful for qualitative reading of MRS data as well as for understanding the methodology used for quantitative measurements. The problems associated with the accurate measurement of individual signal amplitudes in brain spectra having overlapping signals from other metabolites and overlapping nuisance signals from water and lipid are presented. Current approaches to obtaining accurate amplitude estimates with least-squares fitting software are summarized. PMID- 21613877 TI - Multiparametric magnetic resonance imaging of brain disorders. AB - Magnetic resonance imaging (MRI) has been shown to improve the diagnosis and management of patients with brain disorders. Multiparametric MRI offers the possibility of noninvasively assessing multiple facets of pathophysiological processes that exist simultaneously, thereby further assisting in patient treatment management. Voxel-based analysis approaches, such as tissue theme mapping, have the benefit over volumetric approaches in being able to identify spatially heterogeneous colocalized changes on multiple parametric MR images that are not readily discernible. Tissue theme maps seem to be a promising tool for integrating the plethora of novel imaging contrasts that are being developed for the noninvasive investigation of the different stages of disease progression into easily interpretable maps of brain injury. We describe here various implementations for combining multiparametric imaging and their merits in the evaluation of brain diseases. PMID- 21613878 TI - Academic health centers and comparative effectiveness research: baggage, buckets, basics, and bottles. PMID- 21613880 TI - The need for a uniform use of the construct of burnout. PMID- 21613882 TI - The Flexner Report and contemporary medical education in South Asia: an exception. PMID- 21613884 TI - Commentary: Academic health centers and comparative effectiveness research: opportunities and challenges. AB - The focus of comparative effectiveness research (CER) is decision making by patients, physicians, and policy makers. The key elements of CER are head-to-head comparisons of active treatments, study patients who are representative of typical practice, and the search for patient characteristics that predict differences in response to tests or treatment. The four pillars of CER are research, human and scientific capital, data infrastructure, and translation (of evidence into clinical practice). These are also among the fundamental attributes of an academic health center (AHC). This congruity of structure and purpose should mean that AHCs are well positioned to gain from conducting CER and from translating CER results into practice. This commentary discusses the fit between the missions of AHCs and the purposes of CER, using the four pillars as an organizing framework. Aside from the opportunity to do research, AHCs will see the most gains from CER if they hold themselves accountable for using the best available evidence in patient care. Conversely, practice in community settings will gain from CER only if AHCs do a much better job of teaching medical students and residents to become expert in using evidence to make decisions. PMID- 21613885 TI - Commentary: Precision science and patient-centered care. AB - Patient-centered outcomes research (PCOR), also known as comparative effectiveness research, offers new opportunities and challenges for academic health centers (AHCs). The author of this commentary summarizes the contributions of some of the articles in this issue that focus on PCOR, and she emphasizes the unique features of this distinctive type of research, which are longitudinal patient follow-up, the inclusion of patient-reported outcomes, and the dynamic interaction among all stakeholders throughout all phases of research.The author advocates that researchers engaged in comparative effectiveness research make every effort, and explore innovative means, to accelerate the translation of their research findings into practice. The opportunities to close the gaps between what physicians and medical scientists do and what they know, to support clinicians and patients who are working together in order to rapidly identify the best option for a unique individual, and to lead the way in addressing barriers to achieving personalized, patient-centered care should engage key members of AHCs in comparative effectiveness research, so that these institutions become a vital link connecting biomedical innovation and its precision application in diverse communities and populations. PMID- 21613886 TI - Learning to weather the storm. PMID- 21613887 TI - Commentary: Will academia embrace comparative effectiveness research? AB - In recent medical history, a number of therapies that were widely adopted based on observational data or pathophysiological constructs turned out to be useless or even harmful when tested in randomized comparative effectiveness trials. These therapies not only harmed patients but also did a disservice to the practical education of medical students, residents, and fellows. These trainees effectively learned that it is acceptable to implement practices even in the absence of high quality evidence, and so they may not have learned how to analyze the quality of evidence. In this issue of Academic Medicine, seven groups address critical aspects of the intersection between comparative effectiveness research (CER) and academic medicine. Their topics include the need at academic health centers for cultural shifts, for addressing conflicts of interest, for exploiting academic talent and electronic information resources, for interacting well with policy makers, for incorporating economic evaluations, for incorporating tests of educational methods, for developing multidisciplinary models, and for integrating CER into "predictive health." This commentary argues that academia must embrace CER by insisting on the highest levels of evidence, by viewing all clinical interactions as opportunities for scientific advancement, by setting an example for policy makers and colleagues working in nonacademic settings, and by engaging all physicians in the clinical research enterprise. PMID- 21613888 TI - Commentary: Balancing responsibility to patients and responsibility to aspiring physicians with disabilities. AB - In 2008, Congress amended the Americans with Disabilities Act (ADA) to relax court-imposed limitations on evidence required to warrant protection under the ADA. Since passage of the ADA in 1990, medicine has focused not on evaluating the types of accommodations that would best balance the interests of individuals with disabilities, institutions, and patients but, rather, on the question of whether individuals seeking protection under the law qualify for disability accommodations at all. The medical profession should refocus on the nature of accommodations provided to those with disabilities. In doing so, the intent to support disabled persons seeking careers in medicine must be balanced with ethical obligations to protect patient welfare. Medical schools, graduate medical education programs, licensing and certifying authorities, and assessment organizations should work together to establish evidence-based minimum criteria for the physical and cognitive capabilities required of every physician. PMID- 21613889 TI - Commentary: More implications of the 2008 amendments to the Americans with Disabilities Act: influencing institutional policies, practices, and procedures. AB - The Americans with Disabilities Act (ADA) is a civil rights law designed to ensure that qualified individuals with disabilities are not discriminated against by covered entities. Under the ADA, colleges of medicine were expected to focus their attention on implementing policies that facilitated equal educational opportunity, not on the threshold question of whether an individual was considered "disabled enough" to be protected by the law. In this issue, Allen and Smith examine the implications of the 2008 ADA Amendments Act (ADAAA) for medical education, focusing on the potential for the ADAAA to eliminate the threshold question and allow individuals seeking protection to bring their cases to trial.The authors of this commentary argue that the ADAAA also has important implications for institutions like colleges of medicine and the National Board of Medical Examiners that must not be overlooked. The impact of the ADAAA on colleges of medicine will depend in large part on how they historically viewed their obligations under the ADA. Those institutions that focused on eliminating all vestiges of disability discrimination by implementing comprehensive, system wide, evidence-based policies, practices, and procedures related to reasonable accommodations and academic modifications/adjustments will experience little or no impact under the ADAAA. Those colleges that attempted to avoid or minimize compliance with the ADA by focusing on whether an individual achieved sufficient disability status to be protected by the law will need to pay closer attention to the development and implementation of nondiscrimination policies, particularly policies relating to reasonable accommodations and academic modifications/adjustments. PMID- 21613890 TI - Commentary: Is the glass half empty? Code blue training in the modern era. AB - Skilled management of cardiopulmonary resuscitation, or responding to a "code blue," is widely considered an important training objective during internal medicine residency. Gaining proficiency in managing a code blue typically depends on event-based experiential learning. In this issue of Academic Medicine, Mickelsen and colleagues report their use of schedule-based stochastic simulation estimates matched with observed code blue data to model the number of annual opportunities a first-year resident has to participate in code blue events. Their data offer compelling evidence that trainees in 2008 had much less opportunity (83% less) to participate in code blue events than did their predecessors in 2002. Mickelsen and coinvestigators speculate that this reduction could be attributable to quality improvement initiatives that may have reduced the total number of code blue situations, as well as to duty hours restrictions that reduced the residents' overall availability to participate. The authors of this commentary discuss the general influence of secular trends on educational needs, and they describe possible strategies to compensate for less "in-the-field" exposure by maximizing the "learning yield per event" and using simulation training methods. Finally, the authors consider the question of whether code blue training remains an appropriate goal for general medicine trainees in the face of evolving trends in health care systems. PMID- 21613891 TI - Artist's statement: The face of illness. PMID- 21613892 TI - Medicine and the arts. The surgeon, by Alicia Suskin Ostriker. Commentary. PMID- 21613894 TI - AM last page. Healthcare innovation zones. PMID- 21613896 TI - Here we go again. PMID- 21613895 TI - Protectors in need of protection. PMID- 21613897 TI - LPN and RN comparison. PMID- 21613898 TI - Need for consensus on BSN. PMID- 21613899 TI - Inappropriate medication use. PMID- 21613906 TI - Nurses protest limits on collective bargaining rights. PMID- 21613907 TI - REACH VA helps family caregivers of dementia patients. PMID- 21613910 TI - Adiposity assessments and cardiovascular disease risk. PMID- 21613912 TI - YouTube self-harm videos under scrutiny. PMID- 21613913 TI - The Hospital Quality Network and Regional TCAB. PMID- 21613917 TI - Tragedy into policy: a quantitative study of nurses' attitudes toward patient advocacy activities. AB - BACKGROUND: In 2007 and 2008, 115 patients were found to be either certainly or presumptively infected with the hepatitis C virus through the reuse of contaminated medication vials at two southern Nevada endoscopy clinics. A subsequent joint investigation by federal and state agencies found multiple breaches of infection control protocols. There was also strong anecdotal evidence that among clinic staff, unsafe patient care conditions often went unreported because of a general fear of retaliation. At the request of the Nevada legislature's Legislative Committee on Health Care, a study was conducted to examine Nevada RNs' experiences with workplace attitudes toward patient advocacy activities. This article presents the study findings and reviews how one public health tragedy led to the creation of effective health care policy. METHODS: A study questionnaire was developed and tested for reliability and validity. Questionnaires were then sent to an initial sample of 1,725 Nevada RNs, representing 10% of all RNs in the Nevada State Board of Nursing database with active licenses and current Nevada addresses. RESULTS: The response rate was modest at 33% (564 respondents). Of those who responded, 34% indicated that they'd been aware of a patient care condition that could have caused harm to a patient, yet hadn't reported it. The most common reasons given for nonreporting included fears of workplace retaliation (44%) and a belief that nothing would come of reports that were made (38%). CONCLUSIONS: The study findings underscore the need for a shift in organizational culture toward one that encourages clear and open communication when patient safety may be in jeopardy. These findings were ultimately used to support the passage of whistleblower protection legislation in Nevada. KEYWORDS: Las Vegas hepatitis C outbreak, patient advocacy, whistleblower. PMID- 21613919 TI - Menopausal hormone therapy: what we know now. AB - OVERVIEW: This article describes the findings and limitations of the major research thus far on hormone therapy, particularly that of the Women's Health Initiative; examines practice recommendations; clarifies common terminology related to menopause and hormone therapy; and provides the implications for nurses. This is part one of a four-part series on postmenopausal health. KEYWORDS: bioidentical hormones, combined estrogen and progestogen therapy, estrogen, estrogen therapy, hormone therapy, menopause, menopausal transition, postmenopause, progestin, progestogen, women's health, Women's Health Initiative. PMID- 21613922 TI - Emerging infections: pertussis on the rise. PMID- 21613923 TI - At the heart of the fever: Kawasaki disease. PMID- 21613924 TI - Building the nursing workforce in Malawi. PMID- 21613925 TI - The fate of innocents. PMID- 21613926 TI - Right treatment, right patient? PMID- 21613927 TI - The 2010 Southern Society for Clinical Investigation president's symposium: Idiopathic pulmonary fibrosis. PMID- 21613928 TI - A case of progressive lung fibrosis. AB - Idiopathic pulmonary fibrosis is characterized by progressive fibrosis of the lung and poor prognosis. This is the case report of a patient with idiopathic pulmonary fibrosis that highlights many of the controversies inherent in the diagnosis and treatment of this disease. PMID- 21613929 TI - Nonresolving fibrotic disorders: idiopathic pulmonary fibrosis as a paradigm of impaired tissue regeneration. AB - The pathogenesis idiopathic pulmonary of fibrosis and related fibrosis lung disorders are complex and poorly understood. This likely involves cellular mechanisms that result in loss of cellular homeostasis leading to aberrant alveolar wall remodeling through the excessive deposition of connective tissue matrices. Impaired tissue regeneration and dysregulation of cell death in lung fibroblasts and epithelial cells appear to be important in the initiation and progression of these disorders. This review summarizes current understanding in this area to stimulate research into the development of novel therapeutic strategies that prevent, halt or reverse the progression of lung fibrosis. PMID- 21613930 TI - Idiopathic pulmonary fibrosis: a disorder of epithelial cell dysfunction. AB - Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea, interstitial infiltrates in lung parenchyma and restriction on pulmonary function testing. IPF is the most common and severe of the idiopathic interstitial pneumonias, with most individuals progressing to respiratory failure. Multiple lines of evidence reveal prominent roles for alveolar epithelial cells (AECs) in disease. The current disease paradigm is that ongoing or repetitive injurious stimuli in the presence of a genetic or acquired dysfunctional type II AEC phenotype results in increased AEC injury/apoptosis, deficiencies in regeneration of normal alveolar structure and aberrant lung repair and fibroblast activation, leading to progressive fibrosis. Although the nature of injurious events and processes involved in aberrant repair of the alveolar epithelium are not well understood, ongoing investigations provide hope to better understand mechanisms by which AECs maintain homeostasis or contribute to fibrosis. These strategies may hold promise for developing novel treatment approaches for IPF. PMID- 21613931 TI - Genetics in pulmonary fibrosis--familial cases provide clues to the pathogenesis of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is the most common form of the idiopathic interstitial pneumonias and remains a disease with a poor prognosis. Familial interstitial pneumonia (FIP) occurs when 2 or more individuals from a given family have an idiopathic interstitial pneumonia. FIP cases have been linked to mutations in surfactant protein C, surfactant protein A2, telomerase reverse transcriptase and telomerase RNA component. Together, mutations in these 4 genes likely explain only 15% to 20% of FIP cases and are even less frequent in sporadic IPF. However, dysfunctional aspects of the pathways that are involved with these genes are present in sporadic forms of IPF even in the absence of mutations, suggesting common underlying disease mechanisms. By serving as a resource for identifying the current and future genetic links to disease, FIP families hold great promise in defining IPF pathogenesis, potentially suggesting targets for the development of future therapies. PMID- 21613932 TI - Progress toward improving animal models for idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) remains a disease with an unknown cause and a poor prognosis. Among attempts to define disease pathogenesis, animal models of experimental lung fibrosis have a prominent role. Commonly used models include exposure to bleomycin, silica, fluorescein isothiocyanate; irradiation; or expression of specific genes through a viral vector or transgenic system. These all have been instrumental in the study of lung fibrosis, but all have limitations and fall short of recapitulating a pattern of usual interstitial pneumonia, the pathologic correlate to IPF. A model of repetitive bleomycin lung injury has recently been reported that results in marked lung fibrosis, prominent alveolar epithelial cell hyperplasia, a pattern of temporal heterogeneity and persistence of aberrant remodeling well after stimulus removal, representing a significant addition to the collection of animal lung fibrosis models. Taken together, animal models remain a key component in research strategies to better define IPF pathogenesis. PMID- 21613933 TI - Management of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disorder characterized by progressive dyspnea, exercise intolerance and, ultimately, respiratory failure and death. The incidence of IPF seems to be increasing, whereas its etiology remains unelucidated. Agents capable of modulating inflammation, kinase pathways, vascular tone, coagulation and fibrosis have been tested in clinical studies although not always in large, randomized, placebo controlled prospective trials. Despite this effort, a therapy capable of improving survival remains elusive. Consequently, the management of IPF focuses on the early identification of subjects for lung transplantation and on the treatment of comorbidities such as hypoxemia, cough and deconditioning. Until effective therapies are identified, patients and referring physicians are urged to consider participation in well-designed clinical trials. PMID- 21613934 TI - Dose escalation of once weekly oral vinorelbine concurrent with weekly split dose hypofractionated chest radiation for palliation of advanced non-small cell lung cancer: a phase I/II study. AB - INTRODUCTION: Daily chest radiation schedules can be cumbersome for some patients and could also delay the administration of higher, systemic doses of chemotherapy. METHODS: Thirty-six patients with advanced non-small cell lung cancer (stages IIIB and IV) were treated using a once weekly hypofractionated chest irradiation schedule (5 Gy divided in 2 fractions 6 hours apart * 12 weeks), concurrently with escalating doses of oral vinorelbine. RESULTS: The maximum tolerated dose of vinorelbine was 80 mg/m; 28 patients were treated at 70 mg/m(2). Dose-limiting toxicity was hematopoietic. A mean of 8.5 cycles per patient was administered, with 53% receiving all 12 cycles. Median overall survival was 9.9 months (95% confidence interval, 5.6-14.2 months). Within the radiation field, 1 patient (4%) had a complete response, 13 (54%) a partial response, and 10 (42%) had stable disease. Nine patients could be assessed for disease outside the radiation field, of whom 7 had stable disease and 2 progressed. CONCLUSIONS: Weekly, hypofractionated chest radiation is well tolerated and can be administered safely concurrently with vinorelbine at systemic doses. This simplified, convenient regimen could benefit patients in need for both local and systemic palliation. PMID- 21613935 TI - Tsukamurella infection: a rare cause of community-acquired pneumonia. AB - A 79-year-old Asian man was admitted with community-acquired pneumonia. Antimycobacterial therapy was initiated when sputum smears revealed acid fast bacilli. The patient was, however, diagnosed to have pneumonia secondary to Tsukamurella spp. This is an exceedingly rare cause of pneumonia, especially in immunocompetent individuals. Clinical presentation, diagnosis and treatment strategies of Tsukamurella pneumonia are discussed with a literature review. PMID- 21613936 TI - Small bowel obstruction due to mycosis fungoides: an unusual presentation. AB - Visceral involvement usually occurs in the late stages of mycosis fungoides (MF). Small bowel involvement in MF is uncommon. When involved, it could cause significant morbidity and mortality. In this study, the authors present an 89 year-old woman diagnosed with T1, N0, B1, M0; stage 1A MF, treated with topical temovate with good response who presented 3 months later with small bowel obstruction due to biopsy-proven localization of MF in the gastrointestinal tract. PMID- 21613937 TI - Myocardial bridging with a coronary artery aneurysm and left ventricular stunning. AB - The authors present a case demonstrating the unusual combination of myocardial bridging with a coronary artery aneurysm complicated by acute transient left ventricular dysfunction due to myocardial stunning. The pathophysiology and current insights into myocardial bridging, coronary aneurysms and myocardial stunning are briefly discussed. The literature reveals only one other reported case of coronary aneurysms associated with myocardial bridging. In addition, although there are several reports of angina and myocardial infarction complicating bridging, there is only 1 other report of myocardial stunning specifically. PMID- 21613938 TI - Prosthetic valve endocarditis caused by Gemella sanguinis: a consequence of persistent dental infection. AB - Late prosthetic valve endocarditis is usually caused by streptococci, staphylococci, gram-negative bacilli and candida. The authors report the first case of prosthetic valve endocarditis caused by Gemella sanguinis. The patient's risk factors for the development of Gemella endocarditis were the persistent severe dental caries and the presence of prosthetic valves. The patient required surgical replacement of the infected valve but had a good outcome with preservation of cardiac and valvular function. Evaluation and treatment of the persistent dental infection before initial valvular surgery may have prevented secondary infection of the prosthetic valve. PMID- 21613939 TI - Hemorrhage related to implant placement in the anterior mandible. AB - Implant placement in the edentulous anterior mandible is relatively considered a routine and safe procedure. The interforaminal area is the usual area in the mandible for implant placement for the support and retention of a fixed partial denture or removable overdenture. This region is also the usual donor site of bone grafts. However, implant placement, like any other surgical procedure, is not free of risks and complications. The purpose of this review article was to investigate the risk of a life threatening hemorrhage due to arterial injury at implant placement in the anterior mandible. PMID- 21613940 TI - Soft tissue biotype affects implant success. AB - The influence of tissue biotype in natural dentition is already well demonstrated in the literature, with numerous articles showing that thicker tissue is a preferred biotype for optimal surgical and prosthetic outcomes. In this same line of thought, current studies are directed to explore whether mucosal thickness would have similar implications around dental implants. The purpose of this review was to investigate the effects of soft tissue biotype in relation to success of implant therapy. The influence of tissue biotype was divided into 3 main categories: its relationship with periimplant mucosa and the underlying bone, immediate implant placement, and restorative outcomes. Soft tissue biotype is an important parameter to consider in achieving esthetic implant restoration, improving immediate implant success, and preventing future mucosal recession. PMID- 21613941 TI - Roll technique modification: papilla preservation. AB - The aim of this article was to describe an Abrams technique's modification. Abrams' roll flap, performed at the implant second surgical stage, allows for the correction of small horizontal defects by enhancing the buccal soft tissue thickness and improves the buccal soft tissue profile. This modification preserves the papilla's morphology, reduces postsurgical discomfort, and enhances soft tissue healing and aesthetic results. PMID- 21613942 TI - The crestal approach: antral membrane elevation via a post graft. AB - The crestal approach to elevating the antral membrane by a resorbable StemVie Post is a modification of the sinus lift technique. This technique can add 4 to 10 mm bone height for severely atrophic ridges in areas that are difficult to access through a lateral window. The procedure is minimally invasive, simple, predictable, and has less postoperative morbidity because of smaller flap design and minimal osteotomy. If sufficient alveolar bone is present for stabilization, an implant can be placed simultaneous with antral elevation and graft. The StemVie Post completely resorbs and is replaced by the patient's own bone. PMID- 21613944 TI - Endosseous dental implant torquing continuum. PMID- 21613945 TI - Peak insertion torque correlated to histologically and clinically evaluated bone density. AB - OBJECTIVE: : Establish a correlation between dental implant insertion torque (IT) and bone density. MATERIALS AND METHODS: : In 18 patients, implant site preparation was initiated using a trephine drill to retrieve a bone biopsy and completed with standard drills. Bone type was assessed during drilling according to surgeon's tactile sense. Forty implants were placed and peak IT values were recorded. Osseointegration was evaluated clinically at abutment connection. Data were analyzed using Pearson product-moment correlation coefficient. RESULTS: : All implants but one achieved osseointegration. D1 and D4 bone types were significantly assessed using tactile sense. IT values ranged from 15 to 150 Ncm with a mean value of 78.30 Ncm. Mean IT was significantly higher in D1 bone (126.67 Ncm) and lower in D4 bone (40.22 Ncm) (P value <0.0001), whereas intermediate values were noted in D2 and D3 bone with no significant difference between these bone types (P value = 0.462). Statistically significant correlation was found between bone volume and IT values (r = +0.771, P < 0.0001). No statistically significant correlation was found between implant length and/or diameter and IT in all bone densities. CONCLUSION: : Clinical assessment of bone density during drilling may be achieved in hard and soft bone but not in intermediate densities. Increasing peak IT values correlated with increasing bone volume. High IT does not seem to alter osseointegration process. PMID- 21613946 TI - Evaluation of bone insertion level of support teeth in class I mandibular removable partial denture associated with an osseointegrated implant: a study using finite element analysis. AB - PURPOSE: : This study evaluated the influence of distal extension removable partial denture associated with implant in cases of different bone level of abutment tooth, using 2D finite element analysis. MATERIALS AND METHODS: : Eight hemiarch models were simulated: model A-presenting tooth 33 and distal extension removable partial denture replacing others teeth, using distal rest connection and no bone lost; model B-similar to model A but presenting distal guide plate connection; model C- similar to model A but presenting osseointegrated implant with ERA retention system associated under prosthetic base; model D-similar to model B but presenting osseointegrated implant as described in model C; models E, F, G, and H were similar to models A, B, C, and D but presenting reduced periodontal support around tooth 33. Using ANSYS 9.0 software, the models were loaded vertically with 50 N on each cusp tip. For results, von Mises Stress Maps were plotted. RESULTS: : Maximum stress value was encountered in model G (201.023 MPa). Stress distribution was concentrated on implant and retention system. The implant/removable partial denture association decreases stress levels on alveolar mucosa for all models. CONCLUSIONS: : Use of implant and ERA system decreased stress concentrations on supporting structures in all models. Use of distal guide plate decreased stress levels on abutment tooth and cortical and trabecular bone. Tooth apex of models with reduced periodontal support presented increased stress when using distal rest. PMID- 21613947 TI - The correlation of bone mineral density and histologic data in the early grafted maxillary sinus: a preliminary report. AB - PURPOSE: : Implant success in the grafted maxillary sinus is dependent on the formation of new vital autogenous bone and its mineral density. Different bone graft materials and graft combinations have been used in the sinus augmentation procedure to support dental implants under occlusal loads. The goal of this study was to determine whether it is possible to observe a direct correlation between bone mineral density and histologic data in the grafted maxillary sinus. Based on the observed histological findings, we propose a bone mineral density classification that has 3 rather than 4 types of bone. MATERIALS AND METHODS: : A total of 15 patients participated in this study, all of which had only 1 sinus grafted. A total of 34 dental implants were placed in the grafted sinuses. In 7 patients, designated as group A, a 50:50 composite ratio of autogenous and allogeneic bone was used to graft the sinuses. Four patients had the sinuses grafted with a 50:50 composite ratio of a naturally occurring marine algae hydroxyapatite graft material and autogenous bone. One patient had the sinus grafted with 100% autogenous bone. In this group of patients, a total of 25 dental implants were surgically placed 14 to 20 weeks after sinus grafting. The implants were restored 12 weeks later. No implant failures were observed over a 52-week period. The last 3 patients, designated as group B, completed implant surgery beyond the 52-week end point of the study for various reasons. They provided a unique opportunity to histologically observe bone maturation at 68, 88, and 260 weeks, respectively. Using cone beam computed tomography (CT) technology and 3D-CT interactive software, bone mineral density in Hounsfield unit values were recorded during different healing time periods. RESULTS: : In all 15 patients, bone mineral density was observed to steadily increase during the 52-week observation period and beyond, as evidenced by the increase in Hounsfield unit values and the formation of new, vital autogenous trabecular bone. CONCLUSION: : Histologic and histomorphometric data demonstrate a definite correlation with the formation of new, vital autogenous trabecular bone and bone mineral density (quality) that permits early loading of implants in the grafted maxillary sinus. PMID- 21613948 TI - The evaluation of the success of immediately placed single implants: a retrospective clinical study. AB - PURPOSE: : The aim of this retrospective clinical trial was to evaluate the survival rates and the marginal bone levels of immediately placed implants in fresh extraction sockets in a period of 36 months. PATIENTS AND METHODS: : One hundred seventeen patients who had received 165 immediately placed implants and followed up for 36 months after loading were included in this retrospective study. Survival rate and mesial and distal marginal bone levels of all implants were determined with the measurements made on periapical radiographs at baseline and recall evaluations. RESULTS: : The results of clinical evaluation showed a survival rate of 93.94%. Ten of 165 implants failed: 7 implants in female patients indicating 90.28% survival rate and 3 male patients with 93.4% survival rate. The mean age of patients with implant failure was 60.8 years. No statistically significant differences in marginal bone levels with respect to localization, age, gender, grafting, and implant brands were noted. Grafting did not influence plaque index, gingival index, and periimplant probing depth in a statistically significant way. CONCLUSIONS: : The results suggest that immediately placed single implants show acceptable survival rates and mesial and distal marginal bone levels in 36-month follow-up period. PMID- 21613949 TI - Identification of periodontal pathogens in healthy periimplant sites. AB - PURPOSE: : The aim of this study was to evaluate the presence of periodontopathogens in subgingival periimplant sites in partially edentulous patients using polymerase chain reaction procedures, with regard to areas with clinical and radiographic signs of health and areas presenting periimplant disease. MATERIALS AND METHODS: : Thirty nonsmoking, partially edentulous patients, aged 30 to 76 years, were included in this study and divided in 3 groups according their clinical and radiographic characteristics. Group A (n = 10) presented periimplant health, group B (n = 10) presented periimplant mucositis, and group C (n = 10) were patients with periimplantitis. Periimplant tissues were clinically examined as regards the color of mucosae, presence of bacterial plaque, depth and bleeding on probing, and local suppuration. History of periodontal disease was also considered. Radiographic analysis evaluated the presence of bone loss around the implant. Samples of periimplant crevicular fluid were collected to analyze the presence of periodontal pathogens, Actinobacillus actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Tannerella forsythensis (Tf), and Treponema denticola (Td). RESULTS: : The results showed that the history of periodontal disease is associated with periimplant disease. The bacteria Aa, Pg, Pi, Td, and Tf were present in periimplant sites clinically and radiographically characterized, as healthy periimplant tissues, mucositis, and periimplantitis. CONCLUSIONS: : We concluded that Aa, Pg, Pi, Td, and Tf are present in healthy and diseased conditions. Therefore, these periodontal pathogens are not strictly related to periimplant disease sites. PMID- 21613950 TI - An experimental study of bone healing around the titanium screw implants in ovariectomized rats: enhancement of bone healing by bone marrow stromal cells transplantation. AB - PURPOSE: : This study is to evaluate the bone quality of surrounding areas of implants with bone marrow stromal cells (BMSCs) transplantation to rat femur, which have become osteoporosis-induced models. MATERIALS AND METHODS: : The Sprague-Dawley rats were divided into 3 groups: the first group where their ovaries were removed (OVX group), the second group where a sham surgery was given (SHAM group), and the third group where BMSCs were transplanted to an OVX group (OVX-BMSCs group). In the OVX-BMSCs group, 1 * 10 BMSCs were transplanted into femur with implant. Each value of the bone to implant contact and the bone area of each cortical bone and cancellous bone was obtained. Bone density of the width of 500 MUm from the implants was measured. RESULTS: : Each ratio of bone to implant contact, bone area, and bone density in the OVX-BMSCs group was significantly higher than those of OVX group as to the cancellous bone. CONCLUSION: : The BMSCs transplantation therapy improved local bone healing in the cancellous bone surrounding implants and also significantly improved bone binding with implants. PMID- 21613951 TI - Effect of dislodging forces on mandibular implant attachment-retained overdenture. AB - OBJECTIVES: : The goal of this in vitro study was to evaluate stress patterns and retention of ball and socket and 2 telescopic attachments of different convergence angles retaining an implant-supported overdenture prosthesis. MATERIALS AND METHODS: : This study was carried out on an edentulous mandibular acrylic resin educational model. Four dummy implants, 3.5 mm in diameter and 11 mm in length, were installed in the interforaminal area. The framework of the overdenture was cast. Eight strain gauges were attached to the buccal and distal surfaces of all implants. The experiment was divided into 3 phases: 1 with the ball and socket attachment and the other with the angle 4 degrees followed by angle 6 degrees telescopic retainers. Once retention and stress analysis studies were completed for the ball attachments, they were replaced by the telescopic retainers. The universal testing machine was used to measure the retentive forces of the studied attachments. A 4-channel strain-meter was used to record the microstrains transmitted to each strain gauge while the machine was adjusted to move in a tensile mode. RESULTS: : Statistical analysis showed the highest significant retention values for the ball and socket followed by telescope angle 4 degrees and finally angle 6 degrees. The same ranking was found on comparing the mean strains developed at the implants. CONCLUSION: : This study has demonstrated that implant overdenture attachment design and dislodging forces may significantly influence stress/strain magnitude around implants; the higher the retention (resistance to dislodging forces) of the attachments the more the transferred stresses. PMID- 21613952 TI - Malaria with leukopenia in a renal transplant patient. PMID- 21613953 TI - Death of healthy volunteers and professionals on duty for cadaveric graft shipment. PMID- 21613955 TI - Continuous aortic regurgitation with ventricular assist device. PMID- 21613956 TI - Safety and effectiveness of an internal pelvic myofascial trigger point wand for urologic chronic pelvic pain syndrome. AB - OBJECTIVES: Pelvic muscle tenderness occurs often in patients with urologic chronic pelvic pain syndrome; symptoms frequently can be reduced with pelvic myofascial physical therapy. This open-label pilot study evaluated the safety of a personal wand that enables patient's self-treatment of internal myofascial trigger points in the pelvic floor and its effect in reducing pelvic muscle tenderness. METHODS: A specially designed curved wand served as an extended finger to locate and release painful internal myofascial trigger points; an integrated algometer monitors and guides appropriate applied point pressure. Patients used the wand several times weekly after education and careful supervision. Evaluations for adverse events and assessments of pain sensitivity were conducted at 1 and 6 months after commencing use. RESULTS: One hundred and thirteen of the enrolled 157 patients completed 6 months of wand use-106 men and 7 women; 44 patients withdrew before study completion but none for adverse events. Median age was 41 years and 93% were male. Baseline median sensitivity visual analog scale score (1 to 10, 10=most sensitive) was 7.5 and decreased significantly at 6 months to 4 (P<0.001, Wilcoxon matched-pairs signed-rank test). Most patients (95.5%) reported the wand as either very or moderately effective in alleviating pain. No serious adverse events occurred. CONCLUSIONS: A multimodal protocol using an internal pelvic therapeutic wand seems to be a safe, viable treatment option in select refractory patients with pelvic pain. PMID- 21613957 TI - Preoperative factors predicting survival after secondary cytoreduction for recurrent ovarian cancer. AB - OBJECTIVE: We evaluated preoperative data that may predict benefit from secondary cytoreductive surgery (CRS) to assist in selecting therapy for patients with platinum-sensitive recurrent epithelial ovarian cancer. MATERIALS AND METHODS: Inclusion criteria included recurrent epithelial or primary peritoneal carcinoma with an initial disease-free interval more than 6 months after chemotherapy, evidence of disease on imaging studies and indication for surgery being to debulk residual disease. Preoperative CA125 values, computed tomographic findings, and time to progression were evaluated as predictors of survival in addition to postoperative information and perioperative morbidity. RESULTS: Sixty-two patients met the inclusion criteria. In the 35.5% of patients debulked to no visible disease, median survival was significantly longer than in those with less than 1 cm of visible residual disease (5.95 vs 2.73 years, P=0.004), but debulking to less than 1 cm visible disease was not better than those with less than 1 cm residual disease (2.02 years). Mean preoperative CA125 levels were significantly lower in the patients who could be debulked to no visible residual disease compared to less than 1 cm or more than 1 cm residual disease (69.1 vs 290.7 vs 1978.4, P=0.001). Generation of a receiver operating characteristic curve determined that a CA125 cutoff of 250 U/mL best predicted successful cytoreduction to no visible disease. CONCLUSIONS: Only patients cytoreduced to no visible disease achieved a survival advantage, and the only preoperative factor that could predict surgical success regarding prolonging survival was a CA125 less than 250 U/mL. These data can guide physicians and patients in deciding whether or not to undergo secondary cytoreduction for first recurrence of ovarian cancer. PMID- 21613958 TI - Molecular profiling and prognostic relevance of circulating tumor cells in the blood of ovarian cancer patients at primary diagnosis and after platinum-based chemotherapy. AB - OBJECTIVES: Disseminated tumor cells (DTCs) in the bone marrow (BM) were shown to be of prognostic significance in gynecological cancers. Bone marrow aspiration is less accepted by patients compared with blood drawing. In this pilot study, we applied the AdnaTest BreastCancer based on immunomagnetic enrichment, targeting common antigens on epithelial gynecological cancers, followed by multiplex reverse transcriptase-polymerase chain reaction for selection and detection of circulating tumor cells (CTCs) in the blood of 122 ovarian cancer patients at primary diagnosis and/or after platinum-based chemotherapy. Results were compared with detection of DTC in BM. METHODS: Ten-milliliter blood was obtained before surgery (n=86) and/or after chemotherapy (n=70) and analyzed for CTC with the AdnaTest BreastCancer for the detection of EpCAM-, MUC-1-, and HER-2-transcripts. CA 125 was assessed in an additional single-plex reverse transcriptase-polymerase chain reaction. Bone marrow aspirates were analyzed in duplicate by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. RESULTS: Before surgery, CTCs were detected in 19% of patients, expressing EpCAM (31%), MUC-1 (50%), HER-2 (31%), and CA 125 (50%), respectively. After chemotherapy, the overall detection rate for CTC was 27%, thereof EpCAM (68%), MUC-1 (47%), HER2 (21%), and CA 125 (37%). The overall detection rate for DTC in the BM was 35% before surgery and 31% after therapy. A comparison between DTC and CTC resulted in a concordance rate of 59% before surgery and 56% after chemotherapy. CTC positivity significantly correlated with shorter overall survival before surgery (P=0.0054) and after chemotherapy (P=0.047). CONCLUSIONS: This methodological approach might help to identify molecular targets for specific biological therapies. Blood analysis could give additional information complimentary to that obtained by DTC. PMID- 21613959 TI - Central nervous system metastases from epithelial ovarian cancer: prognostic factors and outcomes. AB - OBJECTIVES: To analyze the clinicopathological characteristics and prognostic factors associated with survival in patients with central nervous system (CNS) metastases from epithelial ovarian cancer. METHODS: Twenty patients with CNS involvement from ovarian carcinoma were evaluated in this retrospective study; their features and survivals were analyzed using Kaplan-Meier and log-rank test methods. RESULTS: The incidence of CNS metastases was 5%, among 400 patients with ovarian cancer treated in our single institution. The median age at diagnosis of the ovarian cancer was 55 years. The median interval to the brain involvement and the median survival were 33 and 18 months, respectively. Prognostic factors associated with survival were the International Federation of Gynecology and Obstetrics stage, the surgical resection, the multimodal treatment, and the response after the therapy of the brain metastases. CONCLUSIONS: Brain involvement from ovarian cancer is uncommon but is increasing in incidence. Although the prognosis is usually poor, a multimodal approach can result in a long-term remission of the metastases and in an improvement of the overall survival. PMID- 21613961 TI - Junctional visual field loss in a case of Wyburn-Mason syndrome. AB - A previously healthy girl failed a routine eye screening at the age of 6 years. Her visual fields showed generalized depression in the right eye and a superotemporal defect in the left eye, consistent with a junctional scotoma. Funduscopic examination and fluorescein angiography revealed markedly dilated tortuous vascular loops with arteriovenous communications consistent with retinal arteriovenous malformations (AVMs). MRI of the brain and cerebral angiography demonstrated right ophthalmic and right thalamic AVMs, with compression and atrophy of the right optic chiasm. This represents a case of Wyburn-Mason syndrome with a junctional scotoma. PMID- 21613960 TI - Associations between genetic variants in vitamin D metabolism and asthma characteristics in young African Americans: a pilot study. AB - INTRODUCTION: Low vitamin D levels have been associated with asthma severity in children. Young, urban African Americans (AAs) have high rates of hypovitaminosis D and asthma. Our objective was to determine associations between variants in vitamin D metabolism genes and asthma characteristics in a pilot study of young urban AAs. MATERIALS AND METHODS: Two urban AA cohorts of subjects aged 6 to 20 years (139 subjects with asthma and 74 subjects without asthma) were genotyped for 12 single nucleotide polymorphisms (SNPs) in 3 vitamin D metabolism genes: VDR (vitamin D receptor), CYP24A1 (cytochrome P450 vitamin D 24-hydroxylase), and CYP2R1 (cytochrome P450 vitamin D 25-hydroxylase). In a case-control analysis, SNPs were studied for associations with an asthma diagnosis. Within the asthmatic cohort, SNPs were analyzed for associations with quantitative asthma characteristics. All analyses were adjusted for age, sex, and body mass index percentile. RESULTS: Only the CYP2R1 SNP rs10766197 homozygous minor genotype was associated with asthma (P = 0.044). CYP24A1 SNP rs2248137 was associated with lower vitamin D levels (P = 0.006). Within the asthma cohort, multiple significant associations between SNPs and asthma characteristics were identified; VDR SNP rs2228570 was associated with the higher nighttime asthma morbidity scores (P = 0.04), lower baseline spirometric measures (P < 0.05), 1 or more positive aeroallergen skin test (P = 0.003), and increased immunoglobulin E levels (P < 0.001). DISCUSSION: This pilot study demonstrates that variants in vitamin D metabolism genes are associated with quantitative asthma characteristics in young, urban AAs. The collection of these associations provides evidence for the need for a large population-based study of vitamin D relevant SNPs in this cohort. PMID- 21613962 TI - Gut-bone interactions and implications for the child with chronic gastrointestinal disease. AB - Bone is not simply a framework on which to hang viscera and connective tissue; it is also a dynamic interactive organ system with roles in immunoregulation, adipogenesis, and vascular calcification, among others. Bone is intimately affected by chronic disease, including gastrointestinal disease. The mechanisms for bone loss in conditions such as inflammatory bowel disease, celiac disease, and cystic fibrosis are discussed with regard to the role of the inflammatory response. Furthermore, we raise the issue of effects of inflammation on both intestinal and renal calcium and phosphate transport, although the ways in which these actions affect bone are not explained and require further research. The stress response, a prominent feature following burn injury, is also elucidated and its relation to gastrointestinal disease is examined. We then discuss the importance of knowing the mechanism of bone loss to determine proper prevention and treatment for the bone loss in specific gastrointestinal conditions. PMID- 21613963 TI - A pre-post retrospective study of patients with cystic fibrosis and gastrostomy tubes. AB - OBJECTIVES: The aim of the study was to assess the efficacy of gastrostomy tube (GT) placement on improving nutritional status and pulmonary function in patients with cystic fibrosis (CF). PATIENTS AND METHODS: Data were collected from the Minnesota Cystic Fibrosis Database. Subjects with at least 5 percent-predicted forced expiratory volume in 1 second (ppFEV1) and 1 BMI percentile (pBMI) measurements before and after GT placement were included. Median pBMI values were compared 2 years before and 1, 2, and 4 years after GT placement using a signed rank test. Longitudinal mixed model analysis was used to assess the effect of GT placement on ppFEV1. To assess the effect of ppFEV1 at GT placement on efficacy, the estimated ppFEV1 change was regressed against the ppFEV1 level at placement. RESULTS: Forty-six subjects with CF who met entry criteria were identified. Mean estimated step changes in ppFEV1 at placement for men, women, boys, and girls were 2.16% (P = 0.52), 0.43% (P = 0.92), 0.99% (P = 0.65), and -0.91% (P = 0.74), respectively. Mean estimated slope changes of ppFEV1 after GT placement were 5.01% (P = 0.02), 4.48% (P = 0.07), 1.49% (P = 0.23), and 4.02% (P = 0.01) per year for men, women, boys, and girls, respectively. Median change in pBMI in the second year after GT placement was 13.3% (P <= 0.0001). Estimated coefficients for the effect of ppFEV1 level at placement on the ppFEV1 step and slope change were -0.041 (P = 0.28) and -0.005 (P = 0.84), respectively. CONCLUSIONS: GT placement in patients with CF results in significant improvement in both pBMI and ppFEV1, except in women. The change in lung function after GT placement is not dependent on the level of lung function at placement. PMID- 21613964 TI - Prevalence and risk factors for hypovitaminosis D in young patients with inflammatory bowel disease. AB - Vitamin D plays an important role in bone homeostasis. We aimed to report the prevalence of hypovitaminosis D in children with inflammatory bowel disease (IBD) and risk factors associated with low serum 25-hydroxyvitamin D (25OHD) concentration in children with IBD. Risk factors for deficiency of this vitamin are similar to those in healthy children, with the addition of higher erythrocyte sedimentation rate. Both patients with ulcerative colitis and Crohn disease are at risk for hypovitaminosis D. PMID- 21613965 TI - Anorectal manometry may identify children with spinal cord lesions. AB - BACKGROUND AND OBJECTIVE: We previously showed that approximately 10% of patients with intractable constipation have spinal abnormalities without any other physical findings. Given that spinal magnetic resonance imaging is costly and often requires deep sedation in children, it would be useful to find a screening tool to determine who has a higher likelihood of having a spinal abnormality. The aim of the study was to determine whether anorectal manometry is a useful screening test in predicting which patients will have abnormal spinal MRIs. PATIENTS AND METHODS: This is a case-control study comparing the anorectal manometries of 10 children with constipation who had abnormal spinal MRIs (cases) to the manometries of 10 age-matched children with normal MRIs (controls). RESULTS: The maximum relaxation of the sphincter after balloon distention was achieved with a significantly smaller balloon in the cases as compared with the controls (35 +/- 20 vs 60 +/- 23 mL; P = 0.02). The dose-response curve of sphincter relaxation at different balloon distention was shifted to the left in patients with spinal lesions. Anal spasms after balloon distention were noted in 60% of the patients with abnormal magnetic resonance images compared with 0% of the controls (P < 0.003). There were no other differences. CONCLUSIONS: Patients with spinal cord abnormalities may show changes in anorectal manometry. Anal spasms on anorectal manometry are significant predictors of spinal abnormalities. Also, patients with spinal abnormalities have maximum sphincter relaxations with smaller balloon sizes. Further studies are needed to determine the utility of anorectal manometry as a screening test for spinal abnormalities in patients with constipation. PMID- 21613966 TI - Clinical implications of brown tumor uptake in whole-body 99mTc-sestamibi scans for primary hyperparathyroidism. AB - OBJECTIVES: Technetium-99m (Tc)-sestamibi is the current radionuclide of choice for parathyroid localization in primary hyperparathyroidism (PH). However, there are only sporadic reports about brown tumor visualization in whole-body Tc sestamibi scans. This study aimed to systematically evaluate brown tumor uptake in whole-body Tc-sestamibi scans and in whole-body bone scans as well. Clinical factors were statistically analyzed for imaging outcome predictions. METHODS: Forty-two patients with PH were recruited consecutively. A dual-tracer, dual phase parathyroid imaging protocol was applied. A Tc-sestamibi whole-body scan was performed immediately after delayed phase acquisition. A Tc-methylene diphosphonate bone scan was performed on day 3. Parathormone (PTH), calcium, alkaline phosphatase (ALP), and parathyroid lesion volume were compared. The t test, one-way analysis of variance, and receiver operating characteristic curves were performed for statistical analyses. RESULTS: Brown tumors showed Tc sestamibi uptake in 10 cases, and Tc-methylene diphosphonate uptake in 17 cases. All parameters in double-scan positive cases were significantly higher than in double-scan negative cases; PTH and ALP were significantly higher in only bone scan positive cases than in double-scan negative cases. Data from receiver operating characteristic curves showed the order of PTH>ALP>Ca>parathyroid lesion volume for diagnostic accuracies of both positive Tc-sestamibi scans and positive bone scans. PTH showed the best positive predictive value and ALP showed the best negative predictive value. CONCLUSION: A Tc-sestamibi whole-body scan could be used to assess brown tumors in PH, although it may be less sensitive than a bone scan. PTH possessed the best diagnostic accuracy and predictive value for a positive imaging outcome. ALP was useful for negative imaging outcome prediction. PMID- 21613967 TI - Toward a total and regional scintigraphic liver function test enabling assessment of future remnant liver function. PMID- 21613968 TI - Management of intraoperative airway fire. PMID- 21613969 TI - A multifunctional online research portal for facilitation of simulation-based research: a report from the EXPRESS pediatric simulation research collaborative. AB - INTRODUCTION: Simulation-based research requires the coordinated effort of research teams to design projects, recruit subjects, and carry out performance assessments of individuals or teams. These efforts can often be labor intensive, time consuming, and logistically challenging, especially in the context of multicenter simulation-based research trials. METHODS: We have developed a multifunctional, internet-based research portal for facilitation of simulation based research. This free portal, accessible from www.cesei.org, is capable of managing the research process by helping researchers to design their project, setup data collection using customized assessment tools, upload videos for performance assessment, and finally, download data-filled spreadsheets for statistical analysis. RESULTS: The research portal has been used successfully to manage the first major project of the EXPRESS research collaborative, a multicenter research study involving 15 recruitment sites and more than 400 subjects. CONCLUSIONS: The use of the research portal has enabled us to simplify and streamline the management of our multicenter research studies. We envision that this portal will permit novice and expert researchers alike to carry out their simulation-based research projects in a coordinated and time-efficient fashion, thus ultimately helping to enhance their overall research productivity. PMID- 21613970 TI - Evaluating the effectiveness of virtual reality simulation training in intravenous cannulation. AB - INTRODUCTION: This article focuses on the effectiveness of virtual reality (VR) simulation training for intravenous (IV) cannulation. We analyzed the learning process in skills acquisition from groups with limited experience in comparison with the performance of experts. METHODS: Novices (n = 20) and intermediates (n = 23) trained on nine IV cannulation scenarios with a high-fidelity VR simulator (Virtual IV). Another three scenarios were performed before and after training (pre- and postassessment). Pre-/postassessment was also undertaken by a group of 10 experts for comparative evaluation. Performance metrics included the completion time and an error score that was obtained after quantitative analysis of the errors committed during training. The learning curves were evaluated by recording the number of attempts required to successfully perform each training scenario. A performance was considered successful when the error score was below a predetermined threshold. RESULTS: The learning curves of intermediates and novices demonstrated a clear plateau at the sixth and eighth scenario, respectively. These plateaus were reached after 15 (intermediates) and 23 (novices) attempts. There was a highly significant reduction in the time and errors between pre- and postassessment (P < 0.01). Before training, the performance (errors, time) of the three groups was significantly different to one another (novices: lowest, experts: highest, P < 0.05). After training, the performance of intermediates and novices was equivalent to that of the experts (P > 0.1). Intermediates committed fewer critical and more noncritical errors than novices, and vice versa (P < 0.05). CONCLUSIONS: Simulation training enhanced the skills of inexperienced subjects significantly. The VR simulator demonstrated construct validity for three different levels of experience. The number of attempts over a series of equal difficulty scenarios provides a valuable alternative to the traditional measures of the learning curve. PMID- 21613971 TI - Assessing image quality of low-cost laparoscopic box trainers: options for residents training at home. AB - INTRODUCTION: Low-cost laparoscopic box trainers built using home computers and webcams may provide residents with a useful tool for practice at home. This study set out to evaluate the image quality of low-cost laparoscopic box trainers compared with a commercially available model. METHODS: Five low-cost laparoscopic box trainers including the components listed were compared in random order to one commercially available box trainer: A (high-definition USB 2.0 webcam, PC laptop), B (Firewire webcam, Mac laptop), C (high-definition USB 2.0 webcam, Mac laptop), D (standard USB webcam, PC desktop), E (Firewire webcam, PC desktop), and F (the TRLCD03 3-DMEd Standard Minimally Invasive Training System). Participants observed still image quality and performed a peg transfer task using each box trainer. Participants rated still image quality, image quality with motion, and whether the box trainer had sufficient image quality to be useful for training. RESULTS: Sixteen residents in obstetrics and gynecology took part in the study. The box trainers showing no statistically significant difference from the commercially available model were A, B, C, D, and E for still image quality; A for image quality with motion; and A and B for usefulness of the simulator based on image quality. The cost of the box trainers A-E is approximately $100 to $160 each, not including a computer or laparoscopic instruments. CONCLUSIONS: Laparoscopic box trainers built from a high-definition USB 2.0 webcam with a PC (box trainer A) or from a Firewire webcam with a Mac (box trainer B) provide image quality comparable with a commercial standard. PMID- 21613972 TI - Biomechanical evaluation for mechanisms of periprosthetic femoral fractures. AB - BACKGROUND: There are a number of biomechanical tests for various treatment options of periprosthetic femoral fractures, but different loading modalities prelude their direct comparison. This study was designed to develop an experimental model of osteoporotic bone fractures near the femoral stem that is based on a simple testing protocol to increase the reproducibility. In addition, we wanted to clarify whether a femoral prosthetic stem reduces the femoral fracture strength. METHODS: Twenty human cadaveric femurs were harvested, and five groups were randomized on the basis of the bone mineral density using a pQCT device. The specimens of three groups were provided with a cemented Exeter V40 stem and loaded to failure with torsion (I), anterior (II), and lateral load (III). The femurs of groups IV and V remained uninstrumented and were tested in a four-point bending assay similar to groups II and III. All biomechanical testings were realized with a servohydraulic testing machine (MTS). RESULTS: There was no significant difference regarding bone mineral density of all groups. Torsional testing generated proximal intertrochanteric fractures and anterior loading resulted exclusively in supracondylar fractures. Introducing the force from the lateral side, all fracture lines occurred close to the tip of the stem, similar to a Vancouver-B fracture. Assuming that lateral load application is a main responsible mechanism of periprosthetic femoral fracture near the tip of the stem, the fracture strength of instrumented femurs was significantly reduced (group III: 4,692 N vs. group V: 6,931 N; p < 0.05). CONCLUSION: Prosthetic stems reduce femoral fracture strength significantly. In an osteoporotic bone model, a four-point bending test with lateral load application seems to be a suitable approach. PMID- 21613973 TI - POSSUM predicts hospital mortality and long-term survival in patients with hip fractures. AB - BACKGROUND: Each year, some 18,000 Dutch residents, most of them elderly, suffer a hip fracture. These patients constitute a major, and increasing, healthcare problem with high mortality. In an ageing population, not only the incidence of hip fractures will increase but also comorbidity. Comorbidity is a major cause of high mortality. The physiologic and operative severity score for the enumeration of mortality and morbidity (POSSUM) system predicts mortality and morbidity in surgical patients using physiologic and operative factors. METHODS: For 272 consecutive patients who were treated in our hospital for hip fractures, all complications were registered, and orthopedic POSSUM was performed. Total survival was registered with a mean follow-up of 58 months. Discriminating performance of POSSUM was estimated using receiver-operating curves. After validation, patients were divided into three equal large groups, termed low-risk group, intermediate-risk group, and high-risk group. Kaplan-Meier survival curves were made of each group. RESULTS: Orthopedic POSSUM performed well in predicting mortality with an area under the curve of 0.83 (95% confidence interval 0.76 0.89) and morbidity with an area under the curve of 0.83 (95% confidence interval 0.76-0.90). Three groups that composed of 92 (low risk), 93 (intermediate risk), and 87 (high risk) patients differed significantly in inhospital mortality, all complications, severe complications, and total survival. CONCLUSION: This study has shown that the orthopedic POSSUM is an excellent predictor of inhospital mortality and long-term survival in patients suffering from hip fractures. It is a reasonable predictor of severe postoperative complications. The orthopedic POSSUM is a useful risk stratification and audit tool. PMID- 21613974 TI - Biomolecule profiles in inedible wild mushrooms with antioxidant value. AB - The use of natural products isolated from mushrooms, included inedible species, against infection, cancer diseases and other oxidative-stress related diseases is one of the cornerstones of modern medicine. In the present work, the antioxidant molecule profiles of inedible mushroom species were evaluated and compared with those of edible species. The order of antioxidant abundance found in inedible wild mushrooms was: phenolics > flavonoids > ascorbic acid > tocopherols > carotenoids, similar to that of edible species. Furthermore the same energetic biomolecules were found including the disaccharide trehalose, the monosaccharide alcohol derivative mannitol and the fatty acids palmitic, oleic and linoleic acids. Fomitopsis pinicola revealed a very high phenolics concentration (388 mg GAE/g extract) and powerful antioxidant properties, mainly reducing power (EC50) value 60 MUg/mL similar to the standard Trolox(r)). It could find applications in the prevention of free radical-related diseases as a source of bioactive compounds. PMID- 21613975 TI - Synthesis, characterization, and antimicrobial evaluation of oxadiazole congeners. AB - A series of 1,3-oxazole, 1,3-thiazole, isomeric 1,2,4-oxadiazole, 1,3,4 oxadiazole, and 1,2,3,4-tetrazole heterocycles was synthesized. All the compounds shared as a common feature the presence of a 4-hydroxyphenyl substituent. The structures of the synthesized compounds were confirmed by MS, 1H-NMR, and elemental analysis. In vitro antimicrobial activity for all the newly synthesized compounds at concentrations of 200-25 MUg/mL was evaluated against Gram+ve organisms such as methicillin-resistant Staphylococcus aureus (MRSA), Gram-ve organisms such as Escherichia coli (E. coli), and the fungal strain Aspergillus niger (A. niger) by the cup plate method. Ofloxacin and ketoconazole (10 MUg/mL) were used as reference standards for antibacterial and antifungal activity, respectively. Compounds 15, 16, and 20 showed notable antibacterial and antifungal activities at higher concentrations (200 MUg/mL), whereas 17-19 were found to display significant antibacterial or antifungal activity (25-50 MUg/mL) against the Gram+ve, Gram-ve bacteria, or fungal cells used in the present study. PMID- 21613976 TI - Three New Cycloartenol Triterpenoid Saponins from the Roots of Cimicifuga simplex Wormsk. AB - Three new cycloartenol triterpene saponins, named shengmaxinsides A-C, have been isolated from the ethyl acetate soluble fraction of an ethanol extract of Cimicifuga simplex Wormsk roots. Their structures were established by chemical tests and detailed spectroscopic analysis as 25-O-acetyl-7,8-didehydrocimigenol-3 O-beta-D-galactopyranoside (1), 7,8-didehydrocimigenol-3-O-beta-D galactopyranoside (2) and 7,8-didehydro-24S-O-acetylhydroshengmanol-3-O-beta-D galactopyranoside (3), respectively. PMID- 21613977 TI - Halomonas sp. OKOH--a marine bacterium isolated from the bottom sediment of Algoa Bay--produces a polysaccharide bioflocculant: partial characterization and biochemical analysis of its properties. AB - A bioflocculant-producing bacterium isolated from seawater was identified based on 16S rRNA gene nucleotide sequence to have 99% similarity to that of Halomonas sp. Au160H and the nucleotide sequence was deposited as Halomonas sp. OKOH (Genbank accession number is HQ875722). Influences of carbon source, nitrogen source, salt ions and pH on flocculating activity were investigated. The bioflocculant was optimally produced when glucose (87% flocculating activity) and urea (88% flocculating activity) were used as sources of carbon and nitrogen, respectively. Also, initial pH of 7.0 and Ca2+ supported optimal production of the bioflocculant with flocculating activities of 87% respectively. Chemical analyses revealed the bioflocculant to be a polysaccharide. PMID- 21613978 TI - Strong negative feedback from Erk to Raf confers robustness to MAPK signalling. AB - Protein levels within signal transduction pathways vary strongly from cell to cell. Here, we analysed how signalling pathways can still process information quantitatively despite strong heterogeneity in protein levels. We systematically perturbed the protein levels of Erk, the terminal kinase in the MAPK signalling pathway in a panel of human cell lines. We found that the steady-state phosphorylation of Erk is very robust against perturbations of Erk protein level. Although a multitude of mechanisms exist that may provide robustness against fluctuating protein levels, we found that one single feedback from Erk to Raf-1 accounts for the observed robustness. Surprisingly, robustness is provided through a fast post-translational mechanism although variation of Erk levels occurs on a timescale of days. PMID- 21613979 TI - Characterizing the role of miRNAs within gene regulatory networks using integrative genomics techniques. AB - Integrative genomics and genetics approaches have proven to be a useful tool in elucidating the complex relationships often found in gene regulatory networks. More importantly, a number of studies have provided the necessary experimental evidence confirming the validity of the causal relationships inferred using such an approach. By integrating messenger RNA (mRNA) expression data with microRNA (miRNA) (i.e. small non-coding RNA with well-established regulatory roles in a myriad of biological processes) expression data, we show how integrative genomics approaches can be used to characterize the role played by approximately a third of registered mouse miRNAs within the context of a liver gene regulatory network. Our analysis reveals that the transcript abundances of miRNAs are subject to regulatory control by many more loci than previously observed for mRNA expression. Moreover, our results indicate that miRNAs exist as highly connected hub-nodes and function as key sensors within the transcriptional network. We also provide evidence supporting the hypothesis that miRNAs can act cooperatively or redundantly to regulate a given pathway and that miRNAs play a subtle role by dampening expression of their target gene through the use of feedback loops. PMID- 21613980 TI - Active regulation of receptor ratios controls integration of quorum-sensing signals in Vibrio harveyi. AB - Quorum sensing is a chemical signaling mechanism used by bacteria to communicate and orchestrate group behaviors. Multiple feedback loops exist in the quorum sensing circuit of the model bacterium Vibrio harveyi. Using fluorescence microscopy of individual cells, we assayed the activity of the quorum-sensing circuit, with a focus on defining the functions of the feedback loops. We quantitatively investigated the signaling input-output relation both in cells with all feedback loops present as well as in mutants with specific feedback loops disrupted. We found that one of the feedback loops regulates receptor ratios to control the integration of multiple signals. Together, the feedback loops affect the input-output dynamic range of signal transmission and the noise in the output. We conclude that V. harveyi employs multiple feedback loops to simultaneously control quorum-sensing signal integration and to ensure signal transmission fidelity. PMID- 21613981 TI - Quantitative analysis of transient and sustained transforming growth factor-beta signaling dynamics. AB - Mammalian cells can decode the concentration of extracellular transforming growth factor-beta (TGF-beta) and transduce this cue into appropriate cell fate decisions. How variable TGF-beta ligand doses quantitatively control intracellular signaling dynamics and how continuous ligand doses are translated into discontinuous cellular fate decisions remain poorly understood. Using a combined experimental and mathematical modeling approach, we discovered that cells respond differently to continuous and pulsating TGF-beta stimulation. The TGF-beta pathway elicits a transient signaling response to a single pulse of TGF beta stimulation, whereas it is capable of integrating repeated pulses of ligand stimulation at short time interval, resulting in sustained phospho-Smad2 and transcriptional responses. Additionally, the TGF-beta pathway displays different sensitivities to ligand doses at different time scales. While ligand-induced short-term Smad2 phosphorylation is graded, long-term Smad2 phosphorylation is switch-like to a small change in TGF-beta levels. Correspondingly, the short-term Smad7 gene expression is graded, while long-term PAI-1 gene expression is switch like, as is the long-term growth inhibitory response. Our results suggest that long-term switch-like signaling responses in the TGF-beta pathway might be critical for cell fate determination. PMID- 21613982 TI - Adaptation by stochastic switching of a monostable genetic circuit in Escherichia coli. AB - Stochastic switching is considered as a cost-saving strategy for adaptation to environmental challenges. We show here that stochastic switching of a monostable circuit can mediate the adaptation of the engineered OSU12-hisC Escherichia coli strain to histidine starvation. In this strain, the hisC gene was deleted from the His operon and placed under the control of a monostable foreign promoter. In response to histidine depletion, the OSU12-hisC population shifted to a higher HisC expression level, which is beneficial under starving conditions but is not favoured by the monostable circuit. The population shift was accompanied by growth recovery and was reversible upon histidine addition. A weak directionality in stochastic switching of hisC was observed in growing microcolonies under histidine-free conditions. Directionality and fate decision were in part dependent on the initial cellular status. Finally, microarray analysis indicated that OSU12-hisC reorganized its transcriptome to reach the appropriate physiological state upon starvation. These findings suggest that bacteria do not necessarily need to evolve signalling mechanisms to control gene expression appropriately, even for essential genes. PMID- 21613983 TI - Protein localization as a principal feature of the etiology and comorbidity of genetic diseases. AB - Proteins targeting the same subcellular localization tend to participate in mutual protein-protein interactions (PPIs) and are often functionally associated. Here, we investigated the relationship between disease-associated proteins and their subcellular localizations, based on the assumption that protein pairs associated with phenotypically similar diseases are more likely to be connected via subcellular localization. The spatial constraints from subcellular localization significantly strengthened the disease associations of the proteins connected by subcellular localizations. In particular, certain disease types were more prevalent in specific subcellular localizations. We analyzed the enrichment of disease phenotypes within subcellular localizations, and found that there exists a significant correlation between disease classes and subcellular localizations. Furthermore, we found that two diseases displayed high comorbidity when disease-associated proteins were connected via subcellular localization. We newly explained 7584 disease pairs by using the context of protein subcellular localization, which had not been identified using shared genes or PPIs only. Our result establishes a direct correlation between protein subcellular localization and disease association, and helps to understand the mechanism of human disease progression. PMID- 21613984 TI - An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling. AB - The B-lymphocyte lineage is a leading system for analyzing gene regulatory networks (GRNs) that orchestrate distinct cell fate transitions. Upon antigen recognition, B cells can diversify their immunoglobulin (Ig) repertoire via somatic hypermutation (SHM) and/or class switch DNA recombination (CSR) before differentiating into antibody-secreting plasma cells. We construct a mathematical model for a GRN underlying this developmental dynamic. The intensity of signaling through the Ig receptor is shown to control the bimodal expression of a pivotal transcription factor, IRF-4, which dictates B cell fate outcomes. Computational modeling coupled with experimental analysis supports a model of 'kinetic control', in which B cell developmental trajectories pass through an obligate transient state of variable duration that promotes diversification of the antibody repertoire by SHM/CSR in direct response to antigens. More generally, this network motif could be used to translate a morphogen gradient into developmental inductive events of varying time, thereby enabling the specification of distinct cell fates. PMID- 21613985 TI - Translation's coming of age. PMID- 21613986 TI - Homeostatic and pathogenic role of renal dendritic cells. AB - Dendritic cells (DCs) form a bridge between the innate and adaptive immune systems and fundamentally have an impact on anti-infectious defense and immune mediated diseases, including those affecting the kidney. The field of renal dendritic cells (rDCs) is rapidly evolving, and work in rodent models has provided the first insight into their functional role in kidney homeostasis and disease. Recent findings indicate that rDCs have an important sentinel role against kidney injury and infection. In acute immune-mediated disease they function in an anti-inflammatory manner, but may acquire pro-inflammatory functionality when renal inflammation becomes chronic. In chronic disease rDCs mature and stimulate rather than tolerize effector T cells, and may contribute to progression of kidney disease. Recent progress in aligning murine and human DC subsets has opened avenues for making knowledge obtained from mechanistic studies in animal models available for better interpretation of kidney biopsies. There is firsthand evidence indicating changes in human DC subsets and their distribution in some kidney diseases. Data are presently lacking on the identity of rDC progenitors, the molecular mechanisms governing their recruitment into the kidney, and the role of rDCs in kidney homeostasis. This review highlights recent findings in the study of rDCs. PMID- 21613987 TI - A role for interleukin-33 in T(H)2-polarized intestinal inflammation? AB - Interleukin 33 (IL-33) is a recently discovered cytokine member of the IL-1 superfamily that is widely expressed in fixed tissue cells, including endothelial and epithelial cells. IL-33 induces helper T cells, mast cells, eosinophils, and basophils to produce type-2 cytokines through binding to the ST2/IL-1 receptor accessory protein complex. Recent studies have shown IL-33 to be upregulated in intestinal parasite infection and in epithelial cells and myofibroblasts in ulcerative colitis (UC). The findings point to a role for IL-33 in directing the T(H)2-type immune responses in these types of mucosal inflammation. As the IL 33/ST2 receptor axis can be manipulated by various blocking antibodies, this could be a potential therapeutic target in the future treatment of UC. PMID- 21613988 TI - Obesity, the metabolic syndrome, and sexual dysfunction in men. PMID- 21613989 TI - Predicting adverse drug reactions using publicly available PubChem BioAssay data. AB - Adverse drug reactions (ADRs) can have severe consequences, and therefore the ability to predict ADRs prior to market introduction of a drug is desirable. Computational approaches applied to preclinical data could be one way to inform drug labeling and marketing with respect to potential ADRs. Based on the premise that some of the molecular actors of ADRs involve interactions that are detectable in large, and increasingly public, compound screening campaigns, we generated logistic regression models that correlate postmarketing ADRs with screening data from the PubChem BioAssay database. These models analyze ADRs at the level of organ systems, using the system organ classes (SOCs). Of the 19 SOCs under consideration, nine were found to be significantly correlated with preclinical screening data. With regard to six of the eight established drugs for which we could retropredict SOC-specific ADRs, prior knowledge was found that supports these predictions. We conclude this paper by predicting that SOC specific ADRs will be associated with three unapproved or recently introduced drugs. PMID- 21613990 TI - Detecting drug interactions from adverse-event reports: interaction between paroxetine and pravastatin increases blood glucose levels. AB - The lipid-lowering agent pravastatin and the antidepressant paroxetine are among the most widely prescribed drugs in the world. Unexpected interactions between them could have important public health implications. We mined the US Food and Drug Administration's (FDA's) Adverse Event Reporting System (AERS) for side effect profiles involving glucose homeostasis and found a surprisingly strong signal for comedication with pravastatin and paroxetine. We retrospectively evaluated changes in blood glucose in 104 patients with diabetes and 135 without diabetes who had received comedication with these two drugs, using data in electronic medical record (EMR) systems of three geographically distinct sites. We assessed the mean random blood glucose levels before and after treatment with the drugs. We found that pravastatin and paroxetine, when administered together, had a synergistic effect on blood glucose. The average increase was 19 mg/dl (1.0 mmol/l) overall, and in those with diabetes it was 48 mg/dl (2.7 mmol/l). In contrast, neither drug administered singly was associated with such changes in glucose levels. An increase in glucose levels is not a general effect of combined therapy with selective serotonin reuptake inhibitors (SSRIs) and statins. PMID- 21613991 TI - Amyloid by default. PMID- 21613992 TI - No holy grail for puberty. PMID- 21613993 TI - Normalizing relations between the senses. PMID- 21613994 TI - Zooming in on AMPA receptor regulation by CaMKII. PMID- 21613995 TI - When what you see is not what you hear. PMID- 21613996 TI - Reframing sexual differentiation of the brain. AB - In the twentieth century, the dominant model of sexual differentiation stated that genetic sex (XX versus XY) causes differentiation of the gonads, which then secrete gonadal hormones that act directly on tissues to induce sex differences in function. This serial model of sexual differentiation was simple, unifying and seductive. Recent evidence, however, indicates that the linear model is incorrect and that sex differences arise in response to diverse sex-specific signals originating from inherent differences in the genome and involve cellular mechanisms that are specific to individual tissues or brain regions. Moreover, sex-specific effects of the environment reciprocally affect biology, sometimes profoundly, and must therefore be integrated into a realistic model of sexual differentiation. A more appropriate model is a parallel-interactive model that encompasses the roles of multiple molecular signals and pathways that differentiate males and females, including synergistic and compensatory interactions among pathways and an important role for the environment. PMID- 21613997 TI - A hydrothermal origin for isotopically anomalous cap dolostone cements from south China. AB - The release of methane into the atmosphere through destabilization of clathrates is a positive feedback mechanism capable of amplifying global warming trends that may have operated several times in the geological past. Such methane release is a hypothesized cause or amplifier for one of the most drastic global warming events in Earth history, the end of the Marinoan 'snowball Earth' ice age, ~635 Myr ago. A key piece of evidence supporting this hypothesis is the occurrence of exceptionally depleted carbon isotope signatures (delta(13)C(PDB) down to 480/00; ref. 8) in post-glacial cap dolostones (that is, dolostone overlying glacial deposits) from south China; these signatures have been interpreted as products of methane oxidation at the time of deposition. Here we show, on the basis of carbonate clumped isotope thermometry, (87)Sr/(86)Sr isotope ratios, trace element content and clay mineral evidence, that carbonates bearing the (13)C-depleted signatures crystallized more than 1.6 Myr after deposition of the cap dolostone. Our results indicate that highly (13)C-depleted carbonate cements grew from hydrothermal fluids and suggest that their carbon isotope signatures are a consequence of thermogenic methane oxidation at depth. This finding not only negates carbon isotope evidence for methane release during Marinoan deglaciation in south China, but also eliminates the only known occurrence of a Precambrian sedimentary carbonate with highly (13)C-depleted signatures related to methane oxidation in a seep environment. We propose that the capacity to form highly (13)C-depleted seep carbonates, through biogenic anaeorobic oxidation of methane using sulphate, was limited in the Precambrian period by low sulphate concentrations in sea water. As a consequence, although clathrate destabilization may or may not have had a role in the exit from the 'snowball' state, it would not have left extreme carbon isotope signals in cap dolostones. PMID- 21613998 TI - SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. AB - The primate lentivirus auxiliary protein Vpx counteracts an unknown restriction factor that renders human dendritic and myeloid cells largely refractory to HIV-1 infection. Here we identify SAMHD1 as this restriction factor. SAMHD1 is a protein involved in Aicardi-Goutieres syndrome, a genetic encephalopathy with symptoms mimicking congenital viral infection, that has been proposed to act as a negative regulator of the interferon response. We show that Vpx induces proteasomal degradation of SAMHD1. Silencing of SAMHD1 in non-permissive cell lines alleviates HIV-1 restriction and is associated with a significant accumulation of viral DNA in infected cells. Concurrently, overexpression of SAMHD1 in sensitive cells inhibits HIV-1 infection. The putative phosphohydrolase activity of SAMHD1 is probably required for HIV-1 restriction. Vpx-mediated relief of restriction is abolished in SAMHD1-negative cells. Finally, silencing of SAMHD1 markedly increases the susceptibility of monocytic-derived dendritic cells to infection. Our results demonstrate that SAMHD1 is an antiretroviral protein expressed in cells of the myeloid lineage that inhibits an early step of the viral life cycle. PMID- 21613999 TI - Perspective: test and treat this silent killer. PMID- 21614000 TI - Role of the ubiquitin-like protein Hub1 in splice-site usage and alternative splicing. AB - Alternative splicing of pre-messenger RNAs diversifies gene products in eukaryotes and is guided by factors that enable spliceosomes to recognize particular splice sites. Here we report that alternative splicing of Saccharomyces cerevisiae SRC1 pre-mRNA is promoted by the conserved ubiquitin like protein Hub1. Structural and biochemical data show that Hub1 binds non covalently to a conserved element termed HIND, which is present in the spliceosomal protein Snu66 in yeast and mammals, and Prp38 in plants. Hub1 binding mildly alters spliceosomal protein interactions and barely affects general splicing in S. cerevisiae. However, spliceosomes that lack Hub1, or are defective in Hub1-HIND interaction, cannot use certain non-canonical 5' splice sites and are defective in alternative SRC1 splicing. Hub1 confers alternative splicing not only when bound to HIND, but also when experimentally fused to Snu66, Prp38, or even the core splicing factor Prp8. Our study indicates a novel mechanism for splice site utilization that is guided by non-covalent modification of the spliceosome by an unconventional ubiquitin-like modifier. PMID- 21614001 TI - Transcriptomic analysis of autistic brain reveals convergent molecular pathology. AB - Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder. PMID- 21614003 TI - Development and clinical application of a new technique for detecting 'sleep blood pressure surges' in sleep apnea patients based on a variable desaturation threshold. AB - Obstructive sleep apnea (OSA) places an enormous pressure load on the cardiovascular system by inducing a temporary blood pressure (BP) surge (sleep BP surge (SLBPS)), often resulting in target organ damage and cardiovascular events, such as left ventricular hypertrophy, sudden death, myocardial infarction and stroke. Accurate measurement of SLBPS would be valuable for the risk stratification of OSA patients. We developed a new oxygen-triggered BP monitoring system based on a variable SpO(2) threshold (VT algorithm) to selectively detect severe SLBPS, which are associated with morbidity, and evaluated its performance in comparison with a previous technique based on a fixed SpO(2) threshold (FT algorithm). In 23 OSA patients, the correlation between individual minimum SpO(2) values and SLBPS was not significant when the FT algorithm was used alone (r=0.400, P=0.058) but became significant (r=0.725, P<0.0001) when the VT algorithm was additionally used. In another 13 OSA patients, when the FT algorithm was eliminated from the FT+VT algorithm, the number of BP readings was drastically reduced (36+/-22.7 vs. 61+/-55.0 times, P=0.004) with a similar correlation between minimum SpO(2) and SLBPS. The correlation between the apnea hypopnea index and SLBPS was significant when measured with the present method, but not when assessed with ambulatory BP monitors (ABPM) simulation (r=0.519, P=0.001 vs. r=0.149, P=0.385). In conclusion, oxygen-triggered BP monitoring with a variable threshold is able to detect severe OSA-related BP surges more specifically and reduce the number of BP readings required during sleep compared with detection using a fixed threshold or the conventional ABPM method. PMID- 21614002 TI - A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. AB - Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis. PMID- 21614004 TI - Performance of body fat and body mass index cutoffs in elevated blood pressure screening among male children and adolescents. AB - For percentage of body fat (%BF), there are no internationally accepted cutoffs. The primary function of body fat cutoffs should be to identify not only excessive body fatness, but also the increased risk of unhealthy outcomes, such as hypertension. The purpose of this study was to analyze the accuracy of different %BF and body mass index (BMI) cutoffs as screening measures for EBP in pediatric populations. It was a cross-sectional study with a sample of 358 male subjects from 8 to 18 years old. BP was measured by the oscilometric method, and body composition was measured by dual-energy X-ray absorptiometry (DXA). The accuracy of three reference tables used for body fat cutoffs was assessed. The three body fat reference tables were highly specific, but insensitive, for elevated BP screening. For elevated BP screening, all body fat cutoffs presented similar sensitivity (range=48.3-53.7%) and specificity (range=79.2-84.1%). The body fat cutoffs performed no better than BMI in screening of children and adolescents at risk of elevated BP (EBP). BMI seems a more attractive tool for this function, as it performed similarly and can be applied in large surveys and with lower costs. PMID- 21614005 TI - Involvement of endothelium-dependent and -independent mechanisms in midazolam induced vasodilation. AB - Benzodiazepine (BDZ) infusion has been shown to reduce blood pressure in both humans and animals. Although the inhibitory effects of BDZ on the central nervous system have been well documented, less is known about the direct effects of BDZ on the vascular bed. The aims of this study were to assess the effects of the BDZ midazolam on the vascular system in C57/BL6 mouse aortic rings and to investigate the mechanisms of its direct vascular action. We found that midazolam induced reversible, dose-dependent vasodilation in potassium- and phenylephrine precontracted rings. In rings that were precontracted with potassium or phenylephrine, treatment with 10 MUmol l(-1) midazolam increased vasodilation by 15 and 60%, respectively, compared with baseline. Vasodilation increased by 80 and 87%, respectively, after treatment with 50 MUmol l(-1) midazolam. Only the low concentration of midazolam (10 MUmol l(-1)) induced endothelium-dependent vasodilation in phenylephrine-precontracted rings. Vasodilation increased by 60% in rings with endothelium and by 20% in rings without endothelium. Conversely, only the high concentration of midazolam (50 MUmol l(-1)) reduced the CaCl(2) induced vasoconstriction of aortic rings with EC(50) (the concentration giving 50% of the maximal effect) values of 1 and 6 mmol l(-1) for vehicle- and midazolam-treated rings, respectively. Furthermore, the incubation of phenylephrine-precontracted rings with an inhibitor of the nitric oxide synthase (NOS) NG-nitro-L-arginine methyl ester or the inhibitors of central or peripheral type BDZ receptors (flumazenil or PK 11195, respectively) produced no change in midazolam-induced vasodilation. Thus, low concentrations of midazolam induce vasodilation via an endothelium-dependent mechanism that does not involve NO production. In contrast, high concentrations of midazolam induce vasodilation via an endothelium-independent mechanism that implies reduced sensitivity of aortic rings to calcium ions. Additionally, neither the central gamma-amino-butyric acid receptor type A nor the peripheral type BDZ receptors seem to be involved in the mechanism of midazolam-induced vasodilation. PMID- 21614006 TI - Eplerenone, amlodipine and experimental hypertension: one plus one equals three. PMID- 21614007 TI - 16p13.11 duplication is a risk factor for a wide spectrum of neuropsychiatric disorders. AB - The chromosome 16p13.11 heterozygous deletion is associated with a diverse array of neuropsychiatric disorders including intellectual disabilities, autism, schizophrenia, epilepsy and attention-deficit hyperactivity disorder. However the clinical significance of its reciprocal duplication is not clearly defined yet. We evaluated 1645 consecutive pediatric patients with various developmental disorders by high-resolution microarray-based comparative genomic hybridization and identified four deletions and eight duplications within the 16p13.11 region, representing ~0.73% (12/1645) of the patients analyzed. Recurrent clinical features in these patients include mental retardation/intellectual disability, autism, seizure, dysmorphic feature or multiple congenital anomalies. Our data expand the spectrum of the clinical findings in patients with these genomic abnormalities and provide further support for the pathogenic involvement of this duplication in patients who carry them. PMID- 21614008 TI - Association of interleukin-1beta genetic polymorphisms with cognitive performance in elderly females without dementia. AB - Interleukin-1beta (IL-1beta) is considered to have a role in age-related cognitive decline. A recent study has shown that a promoter polymorphism of the IL-1beta gene (rs16944) is associated with cognitive performance in elderly males without dementia. In this study, we examined whether polymorphisms of the IL 1beta gene also influence cognitive functions in elderly females. Cognitive functions were assessed by the Wechsler adult intelligence scale-revised (WAIS-R) in 99 elderly (?60 years) females without dementia. We selected five tagging polymorphisms from the IL-1beta gene and examined the associations with the WAIS R scores. Significant associations were found between verbal intelligence quotient (IQ) and the genotypes of rs1143634 and rs1143633 (P=0.0037 and P=0.010, respectively). No significant associations of rs16944 genotype were found with verbal or performance IQ. However, individuals homozygous for the G allele of rs16944 achieved higher scores in digit span compared with their counterpart, which is consistent with the previous findings in males. These results suggest that IL-1beta gene variation may have a role in cognitive functions in aging females as well as males. PMID- 21614009 TI - Sexual dysfunction in women with migraine versus tension-type headaches: a comparative study. AB - The aim of this study was to compare the incidence of sexual dysfunction between patients with tension-type headaches (T), migraines (M) and healthy controls (C) in order to investigate the relationship between sexual dysfunction and the features of headaches. The population comprised of 44 patients with M, 30 with T and 30 with C. They have completed Arizona Sexual Experiences Scale (ASEX), Visual Analog Scale. The number of sexual activities over the past 30 days and the frequency of masturbation behavior in C were considerably higher than those in the headache groups. The averages for ASEX item no. 1, 2, 3 and 4 were significantly higher in those with M versus C; and both the subscales and total scores of ASEX were also higher in those with T than C. The mean score for ASEX item no. 3 and the total ASEX score were significantly higher in T versus M. In both headache groups, no significant relationship was observed between headache features and ASEX. The present study showed that patients with either M or T do experience problems in several aspects of sexuality compared with C. Further research is essential to augment our understanding of the sexual dysfunction in this field. PMID- 21614010 TI - The histamine H4 receptor is highly expressed on plasmacytoid dendritic cells in psoriasis and histamine regulates their cytokine production and migration. AB - Plasmacytoid dendritic cells (pDC) are present in inflammatory skin lesions, in particular, in psoriasis. In such lesions, the inflammatory mediator histamine is also detected in high amounts. We therefore investigated a possible interaction of pDC with histamine, especially via the most recently described histamine H(4) receptor (H(4)R). We detected the expression of the H(4)R on pDC in the blood and in lesional psoriasis skin. Interestingly, compared with healthy controls and patients with atopic dermatitis, pDC from the blood of psoriasis patients expressed the highest levels of the H(4)R, which was even more upregulated on stimulation with IFN-gamma and CpG. After activation of the H(2)R and H(4)R on pDC, we observed downregulation of CpG-induced production of tumor necrosis factor alpha, IFN-alpha, and CXCL8, but not of the chemokine CXCL10. Histamine induced downregulation of cytokine production was more pronounced in pDC derived from psoriasis patients. Furthermore, we observed F-actin polymerization and active migration of pDC in response to H(4)R agonist stimulation. Taken together, our results indicate that the H(4)R is highly expressed on pDC in psoriasis and influences cytokine production and migration of pDC. Therefore, the H(4)R alone or in combination with the H(2)R might be a promising therapeutic target in psoriasis. PMID- 21614011 TI - Identification of trichohyalin-like 1, an s100 fused-type protein selectively expressed in hair follicles. PMID- 21614012 TI - The role of Jak3 signaling in IL-17 expression in malignant cutaneous T-cell lymphoma. PMID- 21614014 TI - CCL4L polymorphisms and CCL4/CCL4L serum levels are associated with psoriasis severity. AB - Psoriasis is a common inflammatory skin disease with key immunological and genetic components. Recruitment of leukocytes into the skin is a central step in its pathogenesis, mediated by cytokines. Among the cytokines expressed in psoriatic lesions, C-C chemokine ligand 4 (CCL4) and C-C chemokine ligand 4-like (CCL4L) chemokines appear to be pivotal elements for the skin recruitment of proinflammatory cells. The aim of this study is to evaluate the relationship between CCL4L polymorphisms (including single-nucleotide polymorphisms (SNPs) and copy number variation (CNV)) and the course and prognosis of psoriasis. We analyzed the CNV and the rs4796195 SNP in 211 psoriatic patients and 234 controls; sera from both populations were also quantified for CCL4/CCL4L protein. Our results showed that a high CNV (>=3 copies) is associated with psoriasis severity, whereas moderate disease correlated with a lower CNV (<=2 copies); specifically, the CCL4L1 allele frequency is higher in severe psoriasis, whereas CCL4L2 is more frequent in patients with a milder disease. In addition, we found a positive correlation between the CNV and sera protein levels. Our results suggest that CCL4L genotyping could not only allow a better understanding of the psoriatic pathogenesis but could also be used as a prognostic tool, even helping to modulate the efficacy of treatments. PMID- 21614015 TI - Localization of hair shaft protein VSIG8 in the hair follicle, nail unit, and oral cavity. PMID- 21614017 TI - Keratinocyte apoptosis in epidermal remodeling and clearance of psoriasis induced by UV radiation. AB - Psoriasis is a common chronic skin disorder, but the mechanisms involved in the resolution and clearance of plaques remain poorly defined. We investigated the mechanism of action of UVB, which is highly effective in clearing psoriasis and inducing remission, and tested the hypothesis that apoptosis is a key mechanism. To distinguish bystander effects, equal erythemal doses of two UVB wavelengths were compared following in vivo irradiation of psoriatic plaques; one is clinically effective (311 nm) and one has no therapeutic effect on psoriasis (290 nm). Only 311 nm UVB induced significant apoptosis in lesional epidermis, and most apoptotic cells were keratinocytes. To determine clinical relevance, we created a computational model of psoriatic epidermis. Modeling predicted apoptosis would occur in both stem and transit-amplifying cells to account for plaque clearance; this was confirmed and quantified experimentally. The median rate of keratinocyte apoptosis from onset to cell death was 20 minutes. These data were fed back into the model and demonstrated that the observed level of keratinocyte apoptosis was sufficient to explain UVB-induced plaque resolution. Our human studies combined with a systems biology approach demonstrate that keratinocyte apoptosis is a key mechanism in psoriatic plaques clearance, providing the basis for future molecular investigation and therapeutic development. PMID- 21614016 TI - Wnt signaling influences the development of murine epidermal Langerhans cells. AB - Langerhans cells (LCs) are distinct dendritic cells (DCs) that populate stratified squamous epithelia. Despite extensive studies, our understanding of LC development is incomplete. Transforming growth factor beta1 (TGFbeta1) is required for LC development, but other epidermis-derived influences may also be important. Recently, EpCAM (CD326) has been identified as a cell surface protein discriminating LCs from Langerin(+) dermal DCs and other DCs in the skin. EpCAM is a known transcriptional target of the Wnt signaling pathway. We hypothesized that intraepidermal Wnt signaling might influence LC development. Addition of Wnt3A into cultures of bone-marrow-derived cells in combination with TGFbeta1, GM CSF, and M-CSF resulted in increased (33%; P<0.05) accumulation of EpCAM(+) DCs. In contrast, addition of the Wnt antagonist dickkopf-related protein 1 (Dkk1) decreased the number of EpCAM(+) DCs (21%; P<0.05). We used K14-KRM1; K5-rtTA; tetO-Dkk1 triple-transgenic and K5-rtTA; tetO-Dkk1 double-transgenic mice to test the in vivo relevance of our in vitro findings. Feeding doxycycline to nursing mothers induced expression of Dkk1 in the skin of transgenic pups, causing an obvious hair phenotype. Expression of Dkk1 reduced LC proliferation (40%; P<0.01) on P7, decreased LC densities (26%; P<0.05) on P14, and decreased EpCAM expression intensities on LCs as well (33%). In aggregate, these data suggest that Wnt signaling in skin influences LC development. PMID- 21614018 TI - Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population. AB - Most of the genetic risk for rheumatoid arthritis (RA) is conferred by 'shared epitope' (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2-5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n=333) and controls (n=490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio=2.2, 95% confidence interval 1.6-3.1, P<0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles. PMID- 21614019 TI - Impact of Usp18 and IFN signaling in Salmonella-induced typhlitis. AB - In humans, Salmonella infection causes two major clinical diseases, typhoid fever and a self-limiting gastro-enteritidis. Salmonella transmission occurs by the fecal-oral route and the interactions between the bacteria and the digestive tract epithelium are central to the outcome of the infection. Using a mouse model of typhoid fever, we previously identified a mutation in USP18 affecting type I interferon (IFN) signaling resulting in increased susceptibility to systemic Salmonella infection. In this study, we demonstrate the effects of this mutation during the early response to Salmonella using a model of typhlitis. Mutant Usp18 mice showed a minimal inflammatory response early after Salmonella Typhimurium infection that was associated with low pathologic scores and low IFN-gamma production. This resulted in an increased interaction of Salmonella with the cecal epithelium and earlier systemic dissemination of the bacteria. The global transcriptional signature in the cecum of mouse during Salmonella infection showed normal expression of tissue specific genes and upregulation of type I IFN pathway in mutant mice. In control mice, there was a significant over representation of genes involved in cellular recruitment and antibacterial activity paralleling the histopathological features. These results show the impact of USP18 in the development of Salmonella-induced typhlitis. PMID- 21614021 TI - Relationship between hypertension and admixture in post-menopausal African American and Hispanic American women. AB - To assess the relationship between ethnicity and hypertension using individual admixture and blood pressure measurements, we performed a cross-sectional study of African American and Hispanic American (HA) women enrolled in the Women's Health Initiative. The admixture odds ratio for systolic and diastolic hypertensive risk was determined using linear regression models in which the proportional measurements of European (EUR), sub-Saharan African (AFR) and Amerindian (AMI) admixture was analyzed using ancestry informative markers. In both African-American women (n=10,147) and HA women (n=4908) there was a significant positive association between hypertension and African admixture (P<10(-4)). This relationship was observed for both systolic and diastolic hypertension examined as a continuous or dichotomous trait, and whether age, body mass index, years since menopause and a measurement of socioeconomic status were used as covariates. The odds ratio associated with AFR admixture in a dichotomous model of hypertension was 3.06 (95% confidence interval 2.72-3.45). AMI admixture was associated with lower odds of hypertension and appeared to be more protective, relative to EUR admixture. These data show that African admixture increases the risk for hypertension and provide additional support for evaluating therapeutic efficacy and conducting genetic analyses of hypertension in different ethnic groups. PMID- 21614022 TI - Endothelial dysfunction and diurnal variation of blood pressure: night secrets of arterial hypertension? PMID- 21614020 TI - The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus. AB - The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor required for human leukocyte antigens (HLA) class II MHC-restricted antigen presentation. MHC genes, including the HLA class II DRB1*03:01 allele, are strongly associated with systemic lupus erythematosus (SLE). Recently the rs4774 CIITA missense variant (+1632G/C) was reported to be associated with susceptibility to multiple sclerosis. In the current study, we investigated CIITA, DRB1*03:01 and risk of SLE using a multi stage analysis. In stage 1, 9 CIITA variants were tested in 658 cases and 1363 controls (N=2021). In stage 2, rs4774 was tested in 684 cases and 2938 controls (N=3622). We also performed a meta-analysis of the pooled 1342 cases and 4301 controls (N=5643). In stage 1, rs4774(*)C was associated with SLE (odds ratio (OR)=1.24, 95% confidence interval (95% CI)=1.07-1.44, P=4.2 * 10(-3)). Similar results were observed in stage 2 (OR=1.16, 95% CI=1.02-1.33, P=8.5 * 10(-3)) and the meta-analysis of the combined data set (OR=1.20, 95% CI=1.09-1.33, P(meta)=2.5 * 10(-4)). In all three analyses, the strongest evidence for association between rs4774(*)C and SLE was present in individuals who carried at least one copy of DRB1*03:01 (P(meta)=1.9 * 10(-3)). Results support a role for CIITA in SLE, which appears to be stronger in the presence of DRB1*03:01. PMID- 21614023 TI - Relationship between a range of sedentary behaviours and blood pressure during early adolescence. AB - Very few studies have explored links between physical activity, sedentary behaviours and blood pressure (BP) in early adolescence. We aimed to assess the association between a range of sedentary activities (screen time, television (TV) viewing, computer usage, video game usage and time spent in homework or reading) and BP in schoolchildren. Eligible year-7 students (2353/3144, mean age 12.7 years) from a random cluster sample of 21 Sydney schools were examined during 2003-2005. Parents and children completed detailed questionnaires of activity. BP was measured using a standard protocol and high BP was defined using published guidelines. Height and weight were measured, and body mass index (BMI) calculated. After adjusting for age, sex, ethnicity, parental education, height, BMI and time spent in physical activity, each hour per day spent in screen time, watching TV and playing video games was associated with a significant increase in diastolic BP of 0.44 (P=0.0001), 0.99 (P<0.0001) and 0.64 mm Hg (P=0.04), respectively. In contrast, each hour per day spent reading was associated with a decrease of 0.91 (P=0.01) and 0.69 mm Hg (P=0.02) in systolic and diastolic BP, respectively. Our results indicate that addressing different types of sedentary activities could be a potentially important strategy to reduce the prevalence of elevated BP in children. PMID- 21614024 TI - Ghrelin and its promoter variant associated with cardiac hypertrophy. AB - The roles of ghrelin, a peptide hormone that has a role in regulating food intake and energy homeostasis, in the cardiovascular system have not yet been unambiguously established. We evaluated the association between plasma ghrelin concentrations and -501A>C single-nucleotide polymorphism (SNP) in the ghrelin gene 5' flanking area and echocardiographic measurements in 1037 middle-aged subjects. Left ventricular mass index (LVMI) was calculated according to Devereux's method. The ambulatory blood pressure (BP) was recorded using the fully automatic SpaceLabs 90207 oscillometric unit. Results suggested that plasma ghrelin was not related to mean ambulatory BP values. However, the highest plasma ghrelin tertile was associated with increased intraventricular septum (P=0.043) and posterior ventricular wall (P=0.002) thicknesses as well as left ventricular mass (P=0.05). After adjustment for age, sex, body mass index and systolic BP, the association persisted between ghrelin tertiles and intraventricular septum (P=0.05) and posterior ventricular wall (P=0.001) thicknesses. The SNP -501A>C polymorphism was associated with LVMI after adjustments for age, sex and systolic BP. In conclusion, ghrelin and its promoter variant are associated with cardiac hypertrophy indexes independent of BP. Positive correlation between ghrelin levels and increased wall thickness parameters may reflect compensatory up regulation of ghrelin concentrations or direct effects of ghrelin on myocardium. The effects of the SNP seem not to be mediated through its effects on ghrelin plasma levels. PMID- 21614025 TI - Effect of respiration, talking and small body movements on blood pressure measurement. AB - It is accepted that accuracy of auscultatory blood pressure (BP) measurement is influenced by measurement conditions. However, there is little comparative quantitative clinical data. The aim of this study was to provide these data. Auscultatory systolic and diastolic BPs (SBPs and DBPs) were measured in 111 healthy subjects under five different conditions (resting, deeper breathing, talking, head and arm movement). The measurement sequence was randomized, and repeated three times. BPs and their within-subject variabilities were compared with resting values. SBP and DBP changed significantly in comparison with the resting condition: decreasing by 4.4 and 4.8 mm Hg, respectively, with deeper breathing (both P<0.001), increasing by 3.7 and 5.0 mm Hg with opposite arm movement, and increasing by 5.3 and 6.2 mm Hg with talking (all P<0.001). The mean differences between deeper breathing and talking were 9.7 and 11.0 mm Hg for SBP and DBP. The within-subject variability for repeat measurement of SBP and DBP under resting condition were 3.7 and 3.2 mm Hg and increased for non-resting conditions (all P<0.05, except for DBP while talking). We have shown that measurement conditions significantly influence manual auscultatory BPs and their measurement variabilities, and we provide quantitative data to allow comparison of the effects. PMID- 21614027 TI - Intracisternal rSV40 administration provides effective pan-CNS transgene expression. AB - Potential genetic treatments for many generalized central nervous system (CNS) diseases require transgene expression throughout the CNS. Using oxidant stress and apoptosis caused by HIV-1 envelope gp120 as a model, we studied pan-CNS neuroprotective gene delivery into the cisterna magna (CM). Recombinant SV40 vectors carrying Cu/Zn superoxide dismutase or glutathione peroxidase were injected into rat CMs following intraperitoneal administration of mannitol. Sustained transgene expression was seen in neurons throughout the CNS. On challenge, 8 weeks later with gp120 injected into the caudate putamen, significant neuroprotection was documented. Thus, intracisternal administration of antioxidant-carrying rSV40 vectors may be useful in treating widespread CNS diseases such as HIV-1-associated neurocognitive disorders characterized by oxidative stress. PMID- 21614026 TI - The Hedgehog's tale: developing strategies for targeting cancer. AB - Research into basic developmental biology has frequently yielded insights into cancer biology. This is particularly true for the Hedgehog (HH) pathway. Activating mutations in the HH pathway cause a subset of sporadic and familial, skin (basal cell carcinoma) and brain (medulloblastoma) tumours. Furthermore, the growth of many human tumours is supported by HH pathway activity in stromal cells. Naturally occurring and synthetic inhibitors of HH signalling show great promise in animal models and in early clinical studies. However, it remains unclear how many cancers will ultimately benefit from these new, molecularly targeted therapies. PMID- 21614030 TI - An analysis of China's national essential medicines policy. AB - Although China embraced the concept of essential medicines in 1979 and issued its first National Essential Medicines List in 1982, until recently China has lacked a comprehensive national essential drug policy. In its most recent health-care reform (2009-2012), the Chinese government explicitly proposed the establishment of a national essential medicines system, and made it one of five top priorities in the coming years. We review the evolution of China's essential medicines policies, explain the importance of fully implementing the essential medicines policy, and analyze recent policy developments surrounding essential medicines. PMID- 21614028 TI - Transgene-mediated expression of tumor necrosis factor soluble receptor attenuates morphine tolerance in rats. AB - Opiate/narcotic analgesics are the most effective treatments for chronic severe pain, but their clinical utility is often hampered by the development of analgesic tolerance. Recent evidence suggests chronic morphine may activate glial cells to release proinflammatory cytokines. In this study, we used herpes simplex virus (HSV) vector-based gene transfer to dorsal root ganglion to produce a local release of p55 tumor necrosis factor (TNF) soluble receptor in the spinal cord in rats with morphine tolerance. Subcutaneous inoculation of HSV vectors expressing p55 TNF soluble receptor into the plantar surface of the hindpaws enhanced the antinociceptive effect of acute morphine in rats. Subcutaneous inoculation of those vectors into hindpaws also delayed the development of chronic morphine tolerance in rats. TNF soluble receptor expressed by HSV vector reduced gene transcription of spinal TNFalpha and interleukin-1beta (IL-1beta) induced by repeated morphine. Furthermore, we found that TNF soluble receptor mediated by HSV reversed the upregulation of protein level of TNFalpha and IL-1beta and phosphorylation of p38 mitogen-activated protein kinase induced by repeated morphine. These results support the concept that proinflammatory cytokines may have an important role in the pathogenesis induced by morphine. This study provides a novel approach to treating morphine tolerance. PMID- 21614029 TI - In vivo delivery of interferon-alpha gene enhances tumor immunity and suppresses immunotolerance in reconstituted lymphopenic hosts. AB - T cells recognize tumor-associated antigens under the condition of lymphopenia induced homeostatic proliferation (HP); however, HP-driven antitumor responses gradually decay in association with tumor growth. Type I interferon (IFN) has important roles in regulating the innate and adaptive immune system. In this study we examined whether a tumor-specific immune response induced by IFN-alpha could enhance and sustain HP-induced antitumor immunity. An intratumoral IFN alpha gene transfer resulted in marked tumor suppression when administered in the early period of syngeneic hematopoietic stem cell transplantation (synHSCT), and was evident even in distant tumors that were not transduced with the IFN-alpha vector. The intratumoral delivery of the IFN-alpha gene promoted the maturation of CD11c(+) cells in the tumors and effectively augmented the antigen presentation capacity of the cells. An analysis of the cytokine profile showed that the CD11c(+) cells in the treated tumors secreted a large amount of immune stimulatory cytokines including interleukin (IL)-6. The CD11c(+) cells rescued effector T-cell proliferation from regulatory T-cell-mediated suppression, and IL 6 may have a dominant role in this phenomenon. The intratumoral IFN-alpha gene transfer creates an environment strongly supporting the enhancement of antitumor immunity in reconstituted lymphopenic recipients through the induction of tumor specific immunity and suppression of immunotolerance. PMID- 21614031 TI - Copy and paste. PMID- 21614032 TI - The long game. PMID- 21614033 TI - Modern heroes. PMID- 21614034 TI - Can Europe build a framework for success? PMID- 21614046 TI - Public health: Polio clings on in Pakistan. PMID- 21614047 TI - Russia revitalizes science. PMID- 21614048 TI - Revamp for WHO. PMID- 21614049 TI - Change rattles the world's biggest dish. PMID- 21614050 TI - Evidence of altered RNA stirs debate. PMID- 21614051 TI - Therapeutic success stifles medical progress. PMID- 21614052 TI - Vaccines: The case of measles. PMID- 21614053 TI - Vaccines: The real issues in vaccine safety. PMID- 21614054 TI - Vaccines: His best shot. PMID- 21614055 TI - Target the fence-sitters. PMID- 21614056 TI - Lessons from polio eradication. PMID- 21614061 TI - Can Facebook influence funding? PMID- 21614062 TI - Peer reviews: in praise of referees. PMID- 21614063 TI - Seeking out Earth's warning signals. PMID- 21614064 TI - Peer reviews: make them public. PMID- 21614065 TI - Cooperation is key to Asian hydropower. PMID- 21614066 TI - Entomology: Royal aspirations. PMID- 21614067 TI - Applied physics: A stroke of X-ray. PMID- 21614068 TI - Vaccinology: Persistence pays off. PMID- 21614069 TI - Medicinal chemistry: New lead for pain treatment. PMID- 21614070 TI - Precision measurement: A search for electrons that do the twist. PMID- 21614071 TI - Planetary science: Building a planet in record time. PMID- 21614072 TI - Protein-protein interactions: Pull-down for single molecules. PMID- 21614073 TI - A 2020 vision for vaccines against HIV, tuberculosis and malaria. AB - Acquired immune deficiency syndrome (AIDS), malaria and tuberculosis collectively cause more than five million deaths per year, but have nonetheless eluded conventional vaccine development; for this reason they represent one of the major global public health challenges as we enter the second decade of the twenty-first century. Recent trials have provided evidence that it is possible to develop vaccines that can prevent infection by human immunodeficiency virus (HIV) and malaria. Furthermore, advances in vaccinology, including novel adjuvants, prime boost regimes and strategies for intracellular antigen presentation, have led to progress in developing a vaccine against tuberculosis. Here we discuss these advances and suggest that new tools such as systems biology and structure-based antigen design will lead to a deeper understanding of mechanisms of protection which, in turn, will lead to rational vaccine development. We also argue that new and innovative approaches to clinical trials will accelerate the availability of these vaccines. PMID- 21614074 TI - Catalysis for fluorination and trifluoromethylation. AB - Recent advances in catalysis have made the incorporation of fluorine into complex organic molecules easier than ever before, but selective, general and practical fluorination reactions remain sought after. Fluorination of molecules often imparts desirable properties, such as metabolic and thermal stability, and fluorinated molecules are therefore frequently used as pharmaceuticals or materials. But the formation of carbon-fluorine bonds in complex molecules is a significant challenge. Here we discuss reactions to make organofluorides that have emerged within the past few years and which exemplify how to overcome some of the intricate challenges associated with fluorination. PMID- 21614076 TI - Hf-W-Th evidence for rapid growth of Mars and its status as a planetary embryo. AB - Terrestrial planets are thought to have formed through collisions between large planetary embryos of diameter ~1,000-5,000 km. For Earth, the last of these collisions involved an impact by a Mars-size embryo that formed the Moon 50-150 million years (Myr) after the birth of the Solar System. Although model simulations of the growth of terrestrial planets can reproduce the mass and dynamical parameters of the Earth and Venus, they fall short of explaining the small size of Mars. One possibility is that Mars was a planetary embryo that escaped collision and merging with other embryos. To assess this idea, it is crucial to know Mars' accretion timescale, which can be investigated using the (182)Hf-(182)W decay system in shergottite-nakhlite-chassignite meteorites. Nevertheless, this timescale remains poorly constrained owing to a large uncertainty associated with the Hf/W ratio of the Martian mantle and as a result, contradicting timescales have been reported that range between 0 and 15 Myr (refs 6-10). Here we show that Mars accreted very rapidly and reached about half of its present size in only 1.8(+0.9)(-1.0) Myr or less, which is consistent with a stranded planetary embryo origin. We have found a well-defined correlation between the Th/Hf and (176)Hf/(177)Hf ratios in chondrites that reflects remobilization of Lu and Th during parent-body processes. Using this relationship, we estimate the Hf/W ratio in Mars' mantle to be 3.51 +/- 0.45. This value is much more precise than previous estimates, which ranged between 2.6 and 5.0 (ref. 6), and lifts the large uncertainty that plagued previous estimates of the age of Mars. Our results also demonstrate that Mars grew before dissipation of the nebular gas when ~100-km planetesimals, such as the parent bodies of chondrites, were still being formed. Mars' accretion occurred early enough to allow establishment of a magma ocean powered by decay of (26)Al. PMID- 21614075 TI - Probing cellular protein complexes using single-molecule pull-down. AB - Proteins perform most cellular functions in macromolecular complexes. The same protein often participates in different complexes to exhibit diverse functionality. Current ensemble approaches of identifying cellular protein interactions cannot reveal physiological permutations of these interactions. Here we describe a single-molecule pull-down (SiMPull) assay that combines the principles of a conventional pull-down assay with single-molecule fluorescence microscopy and enables direct visualization of individual cellular protein complexes. SiMPull can reveal how many proteins and of which kinds are present in the in vivo complex, as we show using protein kinase A. We then demonstrate a wide applicability to various signalling proteins found in the cytosol, membrane and cellular organelles, and to endogenous protein complexes from animal tissue extracts. The pulled-down proteins are functional and are used, without further processing, for single-molecule biochemical studies. SiMPull should provide a rapid, sensitive and robust platform for analysing protein assemblies in biological pathways. PMID- 21614077 TI - Improved measurement of the shape of the electron. AB - The electron is predicted to be slightly aspheric, with a distortion characterized by the electric dipole moment (EDM), d(e). No experiment has ever detected this deviation. The standard model of particle physics predicts that d(e) is far too small to detect, being some eleven orders of magnitude smaller than the current experimental sensitivity. However, many extensions to the standard model naturally predict much larger values of d(e) that should be detectable. This makes the search for the electron EDM a powerful way to search for new physics and constrain the possible extensions. In particular, the popular idea that new supersymmetric particles may exist at masses of a few hundred GeV/c(2) (where c is the speed of light) is difficult to reconcile with the absence of an electron EDM at the present limit of sensitivity. The size of the EDM is also intimately related to the question of why the Universe has so little antimatter. If the reason is that some undiscovered particle interaction breaks the symmetry between matter and antimatter, this should result in a measurable EDM in most models of particle physics. Here we use cold polar molecules to measure the electron EDM at the highest level of precision reported so far, providing a constraint on any possible new interactions. We obtain d(e) = (-2.4 +/- 5.7(stat) +/- 1.5(syst)) * 10(-28)e cm, where e is the charge on the electron, which sets a new upper limit of |d(e)| < 10.5 * 10(-28)e cm with 90 per cent confidence. This result, consistent with zero, indicates that the electron is spherical at this improved level of precision. Our measurement of atto electronvolt energy shifts in a molecule probes new physics at the tera electronvolt energy scale. PMID- 21614078 TI - A giant Ordovician anomalocaridid. AB - Anomalocaridids, giant lightly sclerotized invertebrate predators, occur in a number of exceptionally preserved early and middle Cambrian (542-501 million years ago) biotas and have come to symbolize the unfamiliar morphologies displayed by stem organisms in faunas of the Burgess Shale type. They are characterized by a pair of anterior, segmented appendages, a circlet of plates around the mouth, and an elongate segmented trunk lacking true tergites with a pair of flexible lateral lobes per segment. Disarticulated body parts, such as the anterior appendages and oral circlet, had been assigned to a range of taxonomic groups--but the discovery of complete specimens from the middle Cambrian Burgess Shale showed that these disparate elements all belong to a single kind of animal. Phylogenetic analyses support a position of anomalocaridids in the arthropod stem, as a sister group to the euarthropods. The anomalocaridids were the largest animals in Cambrian communities. The youngest unequivocal examples occur in the middle Cambrian Marjum Formation of Utah but an arthropod retaining some anomalocaridid characteristics is present in the Devonian of Germany. Here we report the post-Cambrian occurrence of anomalocaridids, from the Early Ordovician (488-472 million years ago) Fezouata Biota in southeastern Morocco, including specimens larger than any in Cambrian biotas. These giant animals were an important element of some marine communities for about 30 million years longer than previously realized. The Moroccan specimens confirm the presence of a dorsal array of flexible blades attached to a transverse rachis on the trunk segments; these blades probably functioned as gills. PMID- 21614084 TI - Dual transcriptional profiling of a bacterial/fungal confrontation: Collimonas fungivorans versus Aspergillus niger. AB - Interactions between bacteria and fungi cover a wide range of incentives, mechanisms and outcomes. The genus Collimonas consists of soil bacteria that are known for their antifungal activity and ability to grow at the expense of living fungi. In non-contact confrontation assays with the fungus Aspergillus niger, Collimonas fungivorans showed accumulation of biomass concomitant with inhibition of hyphal spread. Through microarray analysis of bacterial and fungal mRNA from the confrontation arena, we gained new insights into the mechanisms underlying the fungistatic effect and mycophagous phenotype of collimonads. Collimonas responded to the fungus by activating genes for the utilization of fungal-derived compounds and for production of a putative antifungal compound. In A. niger, differentially expressed genes included those involved in lipid and cell wall metabolism and cell defense, which correlated well with the hyphal deformations that were observed microscopically. Transcriptional profiles revealed distress in both partners: downregulation of ribosomal proteins and upregulation of mobile genetic elements in the bacteria and expression of endoplasmic reticulum stress and conidia-related genes in the fungus. Both partners experienced nitrogen shortage in each other's presence. Overall, our results indicate that the Collimonas/Aspergillus interaction is a complex interplay between trophism, antibiosis and competition for nutrients. PMID- 21614085 TI - Standard cooperating procedures. PMID- 21614086 TI - The role of a bioresource research impact factor as an incentive to share human bioresources. PMID- 21614087 TI - SOX2 and CHD7 cooperatively regulate human disease genes. PMID- 21614079 TI - Long-term evolution and transmission dynamics of swine influenza A virus. AB - Swine influenza A viruses (SwIV) cause significant economic losses in animal husbandry as well as instances of human disease and occasionally give rise to human pandemics, including that caused by the H1N1/2009 virus. The lack of systematic and longitudinal influenza surveillance in pigs has hampered attempts to reconstruct the origins of this pandemic. Most existing swine data were derived from opportunistic samples collected from diseased pigs in disparate geographical regions, not from prospective studies in defined locations, hence the evolutionary and transmission dynamics of SwIV are poorly understood. Here we quantify the epidemiological, genetic and antigenic dynamics of SwIV in Hong Kong using a data set of more than 650 SwIV isolates and more than 800 swine sera from 12 years of systematic surveillance in this region, supplemented with data stretching back 34 years. Intercontinental virus movement has led to reassortment and lineage replacement, creating an antigenically and genetically diverse virus population whose dynamics are quantitatively different from those previously observed for human influenza viruses. Our findings indicate that increased antigenic drift is associated with reassortment events and offer insights into the emergence of influenza viruses with epidemic potential in swine and humans. PMID- 21614088 TI - Conducting the metabolic syndrome orchestra. PMID- 21614089 TI - New modifier loci in cystic fibrosis. PMID- 21614092 TI - NF-Y joins E2Fs, p53 and other stress transcription factors at the apoptosis table. PMID- 21614091 TI - Principles for the post-GWAS functional characterization of cancer risk loci. PMID- 21614093 TI - The glycan-binding protein galectin-1 controls survival of epithelial cells along the crypt-villus axis of small intestine. AB - Intestinal epithelial cells serve as mechanical barriers and active components of the mucosal immune system. These cells migrate from the crypt to the tip of the villus, where different stimuli can differentially affect their survival. Here we investigated, using in vitro and in vivo strategies, the role of galectin-1 (Gal 1), an evolutionarily conserved glycan-binding protein, in modulating the survival of human and mouse enterocytes. Both Gal-1 and its specific glyco receptors were broadly expressed in small bowel enterocytes. Exogenous Gal-1 reduced the viability of enterocytes through apoptotic mechanisms involving activation of both caspase and mitochondrial pathways. Consistent with these findings, apoptotic cells were mainly detected at the tip of the villi, following administration of Gal-1. Moreover, Gal-1-deficient (Lgals1(-/-)) mice showed longer villi compared with their wild-type counterparts in vivo. In an experimental model of starvation, fasted wild-type mice displayed reduced villi and lower intestinal weight compared with Lgals1(-/-) mutant mice, an effect reflected by changes in the frequency of enterocyte apoptosis. Of note, human small bowel enterocytes were also prone to this pro-apoptotic effect. Thus, Gal-1 is broadly expressed in mucosal tissue and influences the viability of human and mouse enterocytes, an effect which might influence the migration of these cells from the crypt, the integrity of the villus and the epithelial barrier function. PMID- 21614095 TI - Hyperinsulinemia and homeostasis model assessment of insulin resistance as predictors of hypertension: a 5-year follow-up study of Korean sample. AB - BACKGROUND: The relationships between insulin level and indexes of insulin resistance (IR) to predict incident hypertension have been explored only in cross sectional or prospective studies with small numbers of patients. We investigated whether plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA(IR)) are associated with the onset of hypertension in a population of apparently healthy and relatively lean Korean adults. METHODS: We selected 10,894 of 15,638 subjects who were normotensive at baseline during general health status evaluations in 2003 and 2008. The baseline and follow-up examinations included analyses of fasting glucose, insulin level, and lipid profile. Alcohol consumption, smoking status, exercise habits, and education level were also evaluated using a standard questionnaire. RESULTS: Of the 10,894 subjects, hypertension developed in 881 (8.1%) during the ensuing 5 years. Incident hypertension was more common among older subjects than it was in younger subjects and was associated with a high baseline body mass index (BMI). In multivariable logistic models, elevated serum insulin, and HOMA(IR) were associated with an increased risk of incident hypertension in both sexes. In a multivariable analysis using quartiles of insulin and HOMA(IR), the odds ratio (OR) for incident hypertension was the highest in the highest quartile of insulin and HOMA(IR). The highest quartile of insulin and HOMA(IR) was associated with a 1.5-1.7 times increased risk of incident hypertension. CONCLUSIONS: This 5-year follow-up study provides evidence that both a high circulating insulin level and HOMA(IR) are significant risk factors for the development of hypertension in a relatively lean and healthy population. PMID- 21614094 TI - Reciprocal influence of the p53 and the hypoxic pathways. AB - When cells sense a decrease in oxygen availability (hypoxia), they develop adaptive responses in order to sustain this condition and survive. If hypoxia lasts too long or is too severe, the cells eventually die. Hypoxia is also known to modulate the p53 pathway, in a manner dependent or not of HIF-1 (hypoxia inducible factor-1), the main transcription factor activated by hypoxia. The p53 protein is a transcription factor, which is rapidly stabilised by cellular stresses and which has a major role in the cell responses to these stresses. The aim of this review is to compile what has been reported until now about the interconnection between these two important pathways. Indeed, according to the cell line, the severity and the duration of hypoxia, oxygen deficiency influences very differently p53 protein level and activity. Conversely, p53 is also described to affect HIF-1alpha stability, one of the two subunits of HIF-1, and HIF-1 activity. The direct and indirect interactions between HIF-1alpha and p53 are described as well as the involvement in this complex network of their respective ubiquitin ligases von Hippel Lindau protein and murine double minute 2. Finally, the synergistic or antagonistic effects of p53 and HIF-1 on some important cellular pathways are discussed. PMID- 21614097 TI - Combined administration of D-galactose and aluminium induces Alzheimer-like lesions in brain. AB - OBJECTIVE: It has been reported that D-galactose (D-gal) can model subacute aging, and aluminum (Al) acts as a neurotoxin, but combined effects of them have not been reported. The present work aimed to reveal the effect of combined administration of D-gal and Al in mice and compare the effect of D-gal treatment with that of Al treatment. METHODS: Al was intragastrically administered and D gal was subcutaneously injected into Kunming mice for 10 consecutive weeks. Learning and memory, cholinergic systems, as well as protein levels of amyloid beta (Abeta) and hyperphosphorylated tau were determined using Morri water maze test, biochemical assays and immunohistochemical staining, respectively. RESULTS: The mice with combined treatment had obvious learning and memory deficits, and showed decreases in brain acetylcholine (ACh) level and in activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE). Formation of senile plaque (SP)-like and neurofibrillary tangle (NFT)-like structures was also observed. The behavioral and pathological changes persisted for at least 6 weeks after withdrawal of D-gal and Al. CONCLUSION: Combined use of D-gal and Al is an effective way to establish the non-transgenic Alzheimer's disease (AD) animal model, and is useful for studies of AD pathogenesis and therapeutic evaluation. PMID- 21614096 TI - Effects of SKF-96365, a TRPC inhibitor, on melittin-induced inward current and intracellular Ca2+ rise in primary sensory cells. AB - OBJECTIVE: Melittin (MEL) is a major component of bee venom and can produce both persistent spontaneous nociception and pain hypersensitivity when injected subcutaneously in the periphery. The present study aimed to examine the roles of transient receptor potential canonical (TRPC) channels in mediation of MEL induced activation of primary nociceptive cells. METHODS: Whole-cell patch-clamp and laser scanning confocal calcium detection were used to evaluate the effects of SKF-96365, a TRPC inhibitor, applied on the acutely isolated dorsal root ganglion (DRG) cells of rat, on MEL-induced increase in intracellular calcium concentration ([Ca(2+)](i)) and inward current. RESULTS: Under voltage-clamp mode, 43.9% (40/91) DRG cells were evoked to give rise to the inward current by 2 MUmol/L MEL, which could be significantly suppressed by 3 doses of SKF-96365 (1, 5 and 10 MUmol/L) in a dose-dependent manner. Of the other 210 cells, 67.6% responded to MEL with an intracellular Ca(2+) rise, as revealed by confocal calcium imaging. Of these MEL-sensitive cells, 46.5% (66/142) were suppressed by the highest dose of SKF-96365. CONCLUSION: MEL-induced activation of small to medium-sized DRG cells can be suppressed by SKF-96365, suggesting the involvement of TRPC channels in the mediation of MEL-induced activation of primary nociceptive cells. PMID- 21614098 TI - Oral arginine improves linear growth of long bones and the neuroendocrine mechanism. AB - OBJECTIVE: To investigate the effect of oral administration of arginine on linear growth of long bones in male pubertal rats and the underlying mechanisms, focusing on expression of genes related to the hypothalamus-pituitary growth axis and the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. METHODS: Rats were randomly divided into control and intervention groups. In the intervention group, arginine was solved in water (0.045 g L-arginine was mixed with 1 mL water) and administered in rats (10 mL/kg) through gastric perfusion once per day, for totally 28 d. Rats in the control group received normal saline treatment. Bone histomorphometry analysis was used to measure growth plate width and mineral apposition rate of the tibia, as well as trabecular bone volume fraction, osteoblast surface and osteoclast surface of the femur. Serum growth hormone (GH) concentration was determined by radioimmunoassay. Real-time PCR was used to measure the expression of neuronal nitric oxide synthase (nNOS), soluble guanylyl cyclases (sGCalpha1 and sGCbeta1), growth hormone-releasing hormone (Ghrh) and somatostatin (SS) in hypothalamus, as well as Gh in pituitary. Western blot was used to detect the protein levels of nNOS, sGCalpha1 and sGCbeta1 in hypothalamus. RESULTS: After treatment with arginine, the growth plate width of tibia and osteoblast surface of femur were increased (P < 0.05), and serum GH concentration was elevated (P < 0.05). Besides, mRNA and protein levels of nNOS and sGCalpha1 (P < 0.05), as well as the expression of Gh mRNA (P < 0.01), were significantly up-regulated, while the expression of SS mRNA was down-regulated (P < 0.05). CONCLUSION: Oral administration of arginine could improve linear growth of long bones by regulating mRNA expression of SS and Gh and inducing GH secretion, possibly via nNOS-NO-sGC-cGMP signal transduction pathway. PMID- 21614099 TI - Effect of neuronal excitotoxicity on Munc18-1 distribution in nuclei of rat hippocampal neuron and primary cultured neuron. AB - OBJECTIVE: Munc18-1 has an important role in neurotransmitter release, and controls every step in the exocytotic pathway in the central nervous system. In the present study, whether epileptic seizure causes a change of Munc18 localization in neuronal nuclei was analyzed. METHODS: Epilepsy models were established by injection of kainic acid (KA) solution into hippocampus of Sprague Dawley (SD) rats or intraperitoneal injection of KA in Kunming mice. The hippocampal neurons were prepared from embryonic day 18 SD rats, and cultured in neurobasal medium, followed by treatment with glutamate for 3 h. Neuronal and glial nuclei of hippocampus were separated by sucrose density gradient centrifugation. The nucleus-enriched fractions were stained with 0.1% Cresyl Violet for morphological assay. Immunochemistry and immunoelectron microscopy with anti-Munc18-1 antibody were used to determine the nuclear localization of Munc18-1. Immunoblotting was used to detect the protein level of Munc18-1. RESULTS: The localization of Munc18-1 in nucleus of rat hippocampal neuron was confirmed by immunochemistry, immunoelectron microscopy, and immunoblotting detection of neuronal nucleus fraction. In animals receiving intrahippocampal or intraperitoneal injection of KA, immunostaining revealed that the expression of Munc18-1 decreased in pyramidal cell layer of CA regions, as well as in hilus and granular cell layer of dentate gyrus in hippocampus. Moreover, immunoblotting analysis showed that the expression level of Munc18-1 in nucleus fraction of hippocampus significantly decreased in KA-treated animals. The relationship between the change of Munc18-1 expression in neuronal nuclei and neuronal over activation was also tested in primary cultured neurons. After treatment with 50 MUmol/L glutamate acid for 3 h, Munc18-1 level was decreased in nucleus fraction and increased in cytoplasmic fraction of primary cultured neurons. CONCLUSION: These results suggest that excitatory stimulation can induce the distribution change of Munc18-1 in neuron, which may subsequently modulate neuronal functions in brain. PMID- 21614100 TI - Neural circuit and its functional roles in cerebellar cortex. AB - OBJECTIVE: To investigate the spike activities of cerebellar cortical cells in a computational network model constructed based on the anatomical structure of cerebellar cortex. METHODS AND RESULTS: The multicompartment model of neuron and NEURON software were used to study the external influences on cerebellar cortical cells. Various potential spike patterns in these cells were obtained. By analyzing the impacts of different incoming stimuli on the potential spike of Purkinje cell, temporal focusing caused by the granule cell-golgi cell feedback inhibitory loop to Purkinje cell and spatial focusing caused by the parallel fiber-basket/stellate cell local inhibitory loop to Purkinje cell were discussed. Finally, the motor learning process of rabbit eye blink conditioned reflex was demonstrated in this model. The simulation results showed that when the afferent from climbing fiber existed, rabbit adaptation to eye blinking gradually became stable under the Spike Timing-Dependent Plasticity (STDP) learning rule. CONCLUSION: The constructed cerebellar cortex network is a reliable and feasible model. The model simulation results confirmed the output signal stability of cerebellar cortex after STDP learning and the network can execute the function of spatial and temporal focusing. PMID- 21614103 TI - Review of structural neuroimaging in patients with refractory obsessive compulsive disorder. AB - The notion that some special brain regions may be involved in the pathogenesis of obsessive-compulsive disorder (OCD) dates back to the beginning of the twentieth century. Structural neuroimaging studies in the past 2 decades have revealed important findings that facilitate understanding of OCD pathogenesis. Current knowledge based on functional and structural neuroimaging investigations largely emphasizes abnormalities in fronto-striatal-thalamic-cortical and orbitofronto striato-thalamic circuits in the pathophysiology of OCD. However, these neuroimaging studies did not focus on refractory OCD. The present review mainly focused on structural neuroimaging performed in OCD, which had been ignored previously, and highlighted current evidence supporting that orbito-frontal cortex and thalamus are key brain regions, and that the hippocampus-amygdala complex is associated with refractoriness to the available treatment strategies. However, to fully reveal the neuroanatomy of refractoriness, longitudinal studies with larger samples are required. PMID- 21614104 TI - Real-time detection and elimination of nonorthogonality error in interference fringe processing. AB - In the measurement system of interference fringe, the nonorthogonality error is a main error source that influences the precision and accuracy of the measurement system. The detection and elimination of the error has been an important target. A novel method that only uses the cross-zero detection and the counting is proposed to detect and eliminate the nonorthogonality error in real time. This method can be simply realized by means of the digital logic device, because it does not invoke trigonometric functions and inverse trigonometric functions. And it can be widely used in the bidirectional subdivision systems of a Moire fringe and other optical instruments. PMID- 21614101 TI - Cell cycle reactivation in mature neurons: a link with brain plasticity, neuronal injury and neurodegenerative diseases? AB - Although the cell cycle machinery is essentially linked to cellular proliferation, recent findings suggest that neuronal cell death is frequently concurrent with the aberrant expression of cell cycle proteins in post-mitotic neurons. The present work reviews the evidence of cell cycle reentry and expression of cell cycle-associated proteins as a complex response of neurons to insults in the adult brain but also as a mechanism underlying brain plasticity. The basic aspects of cell cycle mechanisms, as well as the evidence showing cell cycle protein expression in the injured brain, are reviewed. The discussion includes recent experimental work attempting to establish a correlation between altered brain plasticity and neuronal death, and an analysis of recent evidence on how neural cell cycle dysregulation is related to neurodegenerative diseases especially the Alzheimer's disease. Understanding the mechanisms that control reexpression of proteins required for cell cycle progression which is involved in brain remodeling, may shed new light into the mechanisms involved in neuronal demise under diverse pathological circumstances. This would provide valuable clues about the possible therapeutic targets, leading to potential treatment of presently challenging neurodegenerative diseases. PMID- 21614102 TI - A review of psychostimulant-induced neuroadaptation in developing animals. AB - The effects of clinically relevant doses of commonly prescribed stimulants methylphenidate (MPH), d-amphetamine (d-AMPH), and dl-AMPH or mixed amphetamine salts (MAS) such as Adderall, on short- and long-term gene neuroadaptations in developing animals have not been widely investigated. In the present review, the effects of oral stimulant administration were compared with those of the subcutaneous or intra-peritoneal route. A selective set of studies between 1979 and 2010, which incorporated in their design developmental period, clinically relevant doses of stimulants, and repeated daily doses were reviewed. These studies indicate that neuroadaptation to chronic stimulants includes blunting of stimulated immediate early gene expression, sensitivity of younger (prepubertal) brain to smaller dosages of stimulants, and the persistence of some effects, especially behavioral neuroadaptations, into adulthood. In addition, oral amphetamines (MAS) have more profound effects than does oral MPH. Further animal developmental studies are required to understand potential long-term neuroadaptations to low, daily oral doses of stimulants. Implications for clinical practice were also discussed. PMID- 21614105 TI - Influence of pressure distribution on flow field temperature reconstruction. AB - This research proposes an issue that has previously been omitted in flow field temperature reconstruction by optical computerized tomography (OCT). To prove that it is not reasonable to always assume an isobaric process occurs when OCT is adopted to obtain the temperature distributions of flow fields, a propane-air flame and an argon arc plasma are chosen as two practical examples for experiment. In addition, the measurement of the refractive index is achieved by moire deflection tomography. The results indicate that the influence of pressure distribution on temperature reconstruction is a universal phenomenon for various flow fields. Hence, the condition that can be introduced to estimate when an isobaric process can no longer be assumed is presented. In addition, an equation is offered to describe the temperature reconstruction imprecision that is caused by using the supposed pressure instead of the practical pressure. PMID- 21614106 TI - Controlling light transport by using a graded photonic crystal. AB - Light transport in a graded photonic crystal is studied using the finite difference time-domain technique. The photonic crystal consists of a square lattice of elliptical dielectric rods. Within a frequency window, light can propagate inside the photonic crystal with the beam width nearly unchanged. The propagation direction can be easily manipulated by the structure gradient, which is achieved by gradually varying the orientation of the elliptical rods. The degree of control over the flow of light can be modulated by changing the ellipticity. This provides a promising approach to design of optical devices for spatial-beam routing. PMID- 21614107 TI - Measurement of the lens optical transfer function using a tartan pattern. AB - We present a method for measuring the optical transfer function (OTF) of a camera lens using a tartan test pattern containing sinusoidal functions with multiple frequencies and orientations. The method is designed to optimize measurement accuracy for an adjustable set of sparse spatial frequencies and be reliable and fast in a wide range of measurement conditions. We describe the pattern design and the algorithm for estimating the OTF accurately from a captured image. Simulations show the tartan method is significantly more accurate than the International Organization for Standardization 12233 standard slanted-edge method. Experimental results from the tartan method were reproducible to 0.01 root mean square and in reasonable agreement with the slanted-edge method. PMID- 21614108 TI - Comments on "Accuracy of Raman lidar water vapor calibration and its applicability to long-term measurements". AB - In a recent publication, Leblanc and McDermid [Appl. Opt., 47, 5592 (2008)]APOPAI0003-693510.1364/AO.47.005592 proposed a hybrid calibration technique for Raman water vapor lidar involving a tungsten lamp and radiosondes. Measurements made with the lidar telescope viewing the calibration lamp were used to stabilize the lidar calibration determined by comparison with radiosonde. The technique provided a significantly more stable calibration constant than radiosondes used alone. The technique involves the use of a calibration lamp in a fixed position in front of the lidar receiver aperture. We examine this configuration and find that such a configuration likely does not properly sample the full lidar system optical efficiency. While the technique is a useful addition to the use of radiosondes alone for lidar calibration, it is important to understand the scenarios under which it will not provide an accurate quantification of system optical efficiency changes. We offer examples of these scenarios. Scanning of the full telescope aperture with the calibration lamp can circumvent most of these limitations. Based on the work done to date, it seems likely that the use of multiple calibration lamps in different fixed positions in front of the telescope may provide sufficient redundancy for long-term calibration needs. Further full-aperture scanning experiments, performed over an extended period of time, are needed to determine a "best practice" for the use of multiple calibration lamps in the hybrid technique. PMID- 21614110 TI - Polarization phase-shifting interferometric technique for complete evaluation of birefringence. AB - A full-field technique for simultaneous measurement of the magnitude of birefringence and its orientation is presented. This is achieved using a monolithic birefringence sensitive interferometer where the interference fringes carry the information of both the birefringence phase and the orientation of the fast axis of an optically transmissive anisotropic material placed at the output of the interferometer. The interferometer consists of a suitably polarization masked cube beam splitter, orientated as in the Gates interferometer, which serves to generate a pair of orthogonally polarized and collinearly propagating light beams. Experimental results are obtained through an algorithm incorporating eight polarization phase-shifted interferograms. PMID- 21614111 TI - Estimating the effects of structural vibration on adaptive optics system performance. AB - This paper presents analytical tools developed for estimating the effects of structural vibration on closed-loop adaptive optics system image quality. The general equation for the normalized intensity distribution of an image subject to structural vibration is derived. The resulting two-dimensional theoretical point spread function is computed numerically and compared with empirical data obtained on sky at the Multiple Mirror Telescope Observatory. A simplified analytical expression for the normalized intensity distribution is derived for long exposures and used to quantify the effects on Strehl and spot full width at half maximum as a function of vibration amplitude, telescope diameter, and observation wavelength. PMID- 21614112 TI - Sources of variance of downwelling irradiance in water. AB - The downwelling irradiance in water is highly variable due to the focusing and defocusing of sunlight and skylight by the wave-modulated water surface. While the time scales and intensity variations caused by wave focusing are well studied, little is known about the induced spectral variability. Also, the impact of variations of sensor depth and inclination during the measurement on spectral irradiance has not been studied much. We have developed a model that relates the variance of spectral irradiance to the relevant parameters of the environmental and experimental conditions. A dataset from three German lakes was used to validate the model and to study the importance of each effect as a function of depth for the range of 0 to 5 m. PMID- 21614113 TI - Focusing of an elliptic vortex beam by a square Fresnel zone plate. AB - We propose a new (to our knowledge) method for performing beam shaping. Calculations show that beam patterns including diamond, rhombus, and hollow beam with diamond-shaped dark core can be generated in the focal plane of a square Fresnel zone plate by choosing appropriate parameters of an incident elliptic vortex beam. Numerical simulations have demonstrated the validity and effectiveness of this method. PMID- 21614114 TI - Transmittance and optical constants of erbium films in the 3.25-1580 eV spectral range. AB - The optical constants of erbium (Er) films were obtained in the 3.25-1580 eV range from transmittance measurements performed at room temperature. Thin films of Er were deposited by evaporation in ultra high vacuum conditions and their transmittance was measured in situ. Substrates consisted of a thin C film supported on a grid. Transmittance measurements were used to obtain the extinction coefficient k of the Er films. The refractive index n of Er was calculated using the Kramers-Kronig analysis. k data were extrapolated both on the high- and low-energy parts of the spectrum by using experimental data and calculated k values available in the literature. Er, similar to other lanthanides, has a low-absorption band below the O(2,3) edge onset; the smallest absorption was measured at ~22.5 eV. Therefore, Er is a promising material for filters and multilayer coatings in the energy range below the O(2,3) edge, in which materials typically have an absorption stronger than at other energies. Good consistency of the data resulted from the application of f and inertial sum rules. PMID- 21614115 TI - Six-port integrating sphere photometer with uniform spatial response. AB - We propose an integrating sphere photometer with six detection ports for total luminous flux measurement, which significantly improves the uniformity of spatial response compared to the conventional single-port detection design. Numerical simulations based on the geometric radiative transfer equation show that a spatial response distribution function of the new design is uniform within 2% with respect to all spatial directions. The related spatial mismatch error is calculated to be less than 0.3% for all the realistic cases of angular intensity distribution of a test lamp. As a result, the new design practically eliminates the spatial mismatch error of an integrating sphere photometer, so that a high accuracy measurement can be achieved without the complicated spatial mismatch correction procedure. PMID- 21614116 TI - Application of sampling criterion on numerical diffraction from bacterial colonies. AB - Numerical diffraction from a bacterial colony was investigated from the viewpoint of applying the sampling criterion for both spatial and frequency domains. Once the morphology information of a bacterial colony was given, the maximum diffraction angle was estimated to reveal the minimum and maximum length of both the imaging and aperture domains. Scalar diffraction modeling was applied to estimate the diffraction pattern, which provided that two phase functions were contributing to the phase modulation: chirp and Gaussian phase functions. Optimal sampling intervals for both phase functions were investigated, and the effect of violating these conditions was demonstrated. Finally, the Fresnel approximation was compared to the angular spectrum method for accuracy and applicability, which then revealed that the Fresnel approximation was valid for both large imaging distances and longer wavelengths. PMID- 21614117 TI - Arbitrary phasing technique for two-dimensional coherent laser array based on an active segmented mirror. AB - We introduce a novel (to the best of our knowledge) phasing technique for a coherent laser array. We have accomplished arbitrary phasing in the interval 0 pi. A seven-channel laser array experiment is built for verification. A custom made beam arraying structure is designed to arrange beamlets into a two dimensional hexagonal array. In the phase-locking loop, the wavefront sensing is performed interferometrically. An active segmented mirror is used for phasing, and the control signals are generated by the proportional control algorithm. In experiment, all the beamlets have been properly phased, and the experiment of inertia-free beam steering has been accomplished. PMID- 21614118 TI - Surface profile measurement in white-light scanning interferometry using a three chip color CCD. AB - White-light scanning interferometry (WLSI) is a useful technique to measure surface profile when a test object contains discontinuous structures or microstructures. A black and white CCD camera is usually utilized to capture interferograms, and a series of corresponding algorithms is used to achieve the profile measurement. However, the color information in the interferograms is lost. A novel profile measurement method that uses phase information in different color channels (red-green-blue) of an interferogram obtained using a three-chip color CCD in WLSI is proposed. The phase values are extracted by a windowed Fourier transform algorithm. Simulation and experimental results are presented to demonstrate the validity of the proposed method. PMID- 21614120 TI - Terahertz lenses made by compression molding of micropowders. AB - We present a simple and versatile approach for fabricating terahertz lenses based on compression molding of micropowder polymer materials in a tabletop hydraulic press. To demonstrate the feasibility of this approach, a biconvex lens shape is calculated using a ray-tracing algorithm and lenses based on two different micropowders are fabricated. As the powder materials have different refractive indices, the resulting lenses share the same geometric shape but differ in their respective focal length. The focusing properties of the lenses are evaluated by transversal and sagittal beam profile measurements in a fiber-coupled terahertz time-domain spectroscopy system, confirming the excellent imaging qualities of the compression molded lenses. PMID- 21614121 TI - Laser vibrometry from a moving ground vehicle. AB - We investigated the fundamental limits to the performance of a laser vibrometer that is mounted on a moving ground vehicle. The noise floor of a moving laser vibrometer consists of speckle noise, shot noise, and platform vibrations. We showed that speckle noise can be reduced by increasing the laser spot size and that the noise floor is dominated by shot noise at high frequencies (typically greater than a few kilohertz for our system). We built a five-channel, vehicle mounted, 1.55 MUm wavelength laser vibrometer to measure its noise floor at 10 m horizontal range while driving on dirt roads. The measured noise floor agreed with our theoretical estimates. We showed that, by subtracting the response of an accelerometer and an optical reference channel, we could reduce the excess noise (in units of micrometers per second per Hz(1/2)) from vehicle vibrations by a factor of up to 33, to obtain nearly speckle-and-shot-noise-limited performance from 0.3 to 47 kHz. PMID- 21614122 TI - Stereoscopic system for inexpensive hazardous area three-dimensional robot localization applications based on incoherent optical fiber bundle calibrated for high-resolution image transmission. AB - Computer vision, despite all the recent progress, still cannot be employed technically in most hazardous and harsh industrial areas. Most of the alternative solutions to this modern issue are usually unavailable mainly due to the global visual inspection solution cost. The best suitable option is the use of an incoherent optical fiber bundle (IOFB) that obviously requires a calibration step before image transmission purpose. We already presented our contribution to this topic improving the calibration method of the IOFB for image transmission, with some additional and essential steps that considerably improve the reconstructed image quality while also drastically reducing the processing time needed. We also proposed and evaluated a new full-resolution calibration method in a very recent study. We present and discuss in this paper an application using the IOFB for robot guiding in hazardous areas, based on a stereoscopic vision system. Conclusions compare the low- and full-resolution IOFB calibration methods for the depicted application and introduce some advantages of a specially designed IOFB that could perfectly fit with some industrial applications. PMID- 21614123 TI - White-light channeled imaging polarimeter using broadband polarization gratings. AB - A white-light snapshot channeled linear imaging (CLI) polarimeter is demonstrated by utilizing polarization gratings (PGs). The CLI polarimeter is capable of measuring the two-dimensional distribution of the linear Stokes polarization parameters by incorporating two identical PGs, in series, along the optical axis. In this configuration, the general optical shearing functionality of a uniaxial crystal-based Savart plate is realized. However, unlike a Savart plate, the diffractive nature of the PGs creates a linear dependence of the shear versus wavelength, thus providing broadband functionality. Consequently, by incorporating the PG-based Savart plate into a Savart plate channeled imaging polarimeter, white-light interference fringes can be generated. This enables polarimetric image data to be acquired at shorter exposure times in daylight conditions, making it more appealing over the quasi-monochromatic channeled imaging polarimeters previously described in the literature. Furthermore, the PG based device offers significantly more compactness, field of view, optical simplicity, and vibration insensitivity than previously described white-light CLI polarimeters based on Sagnac interferometers. Included in this paper are theoretical descriptions of the linear (S(0), S(1), and S(2)) and complete (S(0), S(1), S(2), and S(3)) channeled Stokes imaging polarimeters. Additionally, descriptions of our calibration procedures and our experimental proof of concept CLI system are provided. These are followed by laboratory and outdoor polarimetric measurements of S(0), S(1), and S(2). PMID- 21614124 TI - Compact hybrid TM-pass polarizer for silicon-on-insulator platform. AB - Hybrid waveguides consisting of a metal plane separated from a high-index medium by a low-index spacer have recently attracted a lot of interest. TM and TE modes are guided in two different layers in these structures and their properties can be controlled in different manners by changing the waveguide dimensions and material properties. We examine the effects of different parameters on the characteristics of the two modes in such structures. We show that by properly choosing the dimensions, it is possible to cut off the TE mode while the TM mode can still be guided in a well-confined manner. Using this property of the hybrid guide, we propose a TM-pass polarizer. The proposed device is very compact and compatible with the silicon-on-insulator platform. Finite-difference time-domain simulation indicates that such a polarizer can provide a high extinction of the TE mode for a reasonable insertion loss of the TM mode. PMID- 21614125 TI - Electro-optical logic application of multimode interference coupler by multivalued controlling. AB - Electro-optical hybrid logic is a potential solution to implement both electrical and optical signal processing, which receives analog or digital, electrical or optical signals and produces logic signals in a desired manner. In light of the transfer matrix theory, we found that one can steer light into different output ports of a multimode interference coupler by controlling the phases in a multivalued manner on the image-extended arms. This implementation acts as an analog-to-digital convertor from electric domain to optical domain. Also, an electrical-to-optical 2-to-2(2) binary-coded decoder is described and examined by the 3D beam propagation method. PMID- 21614126 TI - Modeling and analyzing ghost images for incoherent optical systems. AB - In a previous paper [Proc. SPIEPSISDG0277-786X7428, 742807 (2009)10.1117/12.828564], a methodology was developed to model and analyze incoherent ghosts that are formed by two reflections in the paraxial regime. In this paper, we extend the previously developed methodology to model and analyze ghost images that are formed by N (even) reflections. Rather than dealing with ghosts as spots of light, we apply the concept that each ghost has a structure in the nonparaxial regime that depends on the optical system parameters. A methodology to determine the fourth-order ghost aberration function is developed. We present new key parameters for ghost image formation, namely the ghost sagittal and tangential image surfaces. An expression for the paraxial ghost image irradiance distribution of the point object at the nominal image plane is derived. Since focused ghosts are the most bothersome ghosts, tools are proposed to identify potential problematic ghosts. Simulation examples are provided and are used to validate the developed methodology. PMID- 21614127 TI - Polarization-dependent circular Dammann grating made of azo-dye-doped liquid crystals. AB - A polarization-dependent circular Dammann grating (CDG) was generated from an azo dye-doped liquid crystal (LC) cell. A simple multiexposure photo-alignment process was used to fabricate a binary phase LC CDG zone plane, which was composed of an odd zone with a twisted nematic LC structure and an even zone with a homogenous LC structure. A two-order CDG with equal-intensity rings was produced through a Fourier transform. The maximum zeroth and first diffraction orders of obtained CDG can be separately achieved by rotating the analyzer's polarization direction. The CDG using an azo-dye-doped LC cell can be used to generate diffractions by lasers in a broad wavelength range, hence expanding possible device applications. PMID- 21614128 TI - Sugarcane (Saccharum X officinarum): A Reference Study for the Regulation of Genetically Modified Cultivars in Brazil. AB - Global interest in sugarcane has increased significantly in recent years due to its economic impact on sustainable energy production. Sugarcane breeding and better agronomic practices have contributed to a huge increase in sugarcane yield in the last 30 years. Additional increases in sugarcane yield are expected to result from the use of biotechnology tools in the near future. Genetically modified (GM) sugarcane that incorporates genes to increase resistance to biotic and abiotic stresses could play a major role in achieving this goal. However, to bring GM sugarcane to the market, it is necessary to follow a regulatory process that will evaluate the environmental and health impacts of this crop. The regulatory review process is usually accomplished through a comparison of the biology and composition of the GM cultivar and a non-GM counterpart. This review intends to provide information on non-GM sugarcane biology, genetics, breeding, agronomic management, processing, products and byproducts, as well as the current technologies used to develop GM sugarcane, with the aim of assisting regulators in the decision-making process regarding the commercial release of GM sugarcane cultivars. PMID- 21614129 TI - Geophysical and Geochemical Approach for Seawater Intrusion Assessment in the Godavari Delta Basin, A.P., India. AB - Coastal lands around Bay of Bengal in Central Godavari Delta are mainly agriculture fields and two times annually paddy crops putting in the study area. Canals of Godavari River are the main source of water for irrigation. Geophysical and geochemical investigations were carried out in the study area to decipher subsurface geologic formation and assessing seawater intrusion. Electrical resistivity tomographic surveys carried out in the watershed-indicated low resistivity formation in the upstream area due to the presence of thick marine clays up to thickness of 20-25 m from the surface. Secondly, the lowering of resistivity may be due to the encroachment of seawater in to freshwater zones and infiltration during tidal fluctuation through mainly the Pikaleru drain, and to some extent rarely through Kannvaram and Vasalatippa drains in the downstream area. Groundwater quality analyses were made for major ions revealed brackish nature of groundwater water at shallow depth. The in situ salinity of groundwater is around 5,000 mg/l and there is no groundwater withdrawal for irrigation or drinking purpose in this area except Cairn energy pumping wells which is using for inject brackish water into the oil wells for easy exploration of oil. Chemical analyses of groundwater samples have indicated the range of salt concentrations and correlation of geophysical and borehole litholog data in the study area predicting seawater-contaminated zones and influence of in situ salinity in the upstream of study area. The article suggested further studies and research work that can lead to sustainable exploitation/use and management of groundwater resources in coastal areas. PMID- 21614130 TI - Renal cystic disease proteins play critical roles in the organization of the olfactory epithelium. AB - It was reported that some proteins known to cause renal cystic disease (NPHP6; BBS1, and BBS4) also localize to the olfactory epithelium (OE), and that mutations in these proteins can cause anosmia in addition to renal cystic disease. We demonstrate here that a number of other proteins associated with renal cystic diseases - polycystin 1 and 2 (PC1, PC2), and Meckel-Gruber syndrome 1 and 3 (MKS1, MKS3) - localize to the murine OE. PC1, PC2, MKS1 and MKS3 are all detected in the OE by RT-PCR. We find that MKS3 localizes specifically to dendritic knobs of olfactory sensory neurons (OSNs), while PC1 localizes to both dendritic knobs and cilia of mature OSNs. In mice carrying mutations in MKS1, the expression of the olfactory adenylate cyclase (AC3) is substantially reduced. Moreover, in rats with renal cystic disease caused by a mutation in MKS3, the laminar organization of the OE is perturbed and there is a reduced expression of components of the odor transduction cascade (G(olf), AC3) and alpha-acetylated tubulin. Furthermore, we show with electron microscopy that cilia in MKS3 mutant animals do not manifest the proper microtubule architecture. Both MKS1 and MKS3 mutant animals show no obvious alterations in odor receptor expression. These data show that multiple renal cystic proteins localize to the OE, where we speculate that they work together to regulate aspects of the development, maintenance or physiological activities of cilia. PMID- 21614132 TI - The Long-term Release of Antibiotics From Monolithic Nonporous Polymer Implants for Use as Tympanostomy Tubes. AB - A technology is elaborated for the fabrication of a novel tympanostomy tube (TT) from solidified polymer melts (Elvax and Polyurethane) and antibiotics (Ciprofloxacin and Usnic acid) for insertion into tympanic membrane (ear drum) according to the established surgical procedure. The long-term in vitro release kinetics of the antibiotics into liquid water has been assessed using standard methods. The measured kinetic curves revealed two stages of antibiotic release into the finite space. During the first stage (fast), the fast release rate is almost invariant and is determined by the diffusion through the steady diffusion layer formed due to solution agitation. In this first stage, the influence of the initial internal transport is weak because it takes place at negligibly small distance from interface and accordingly, at negligibly concentration drop. After the antibiotic concentration decreases within the much broader layer of matrix near interface, the internal transport becomes important. This manifests itself as the second stage in measured kinetics of release curves which is characterized by a gradual decrease in rate. The minimum inhibition concentrations of three antibiotics/antimicrobial compounds for four bacterial species were measured. The first stage of fast release from the polymer implant lasts 6 days at a polymer loading by Ciprofloxacin (0.03 g/cm(3)) and this was sufficient for preventing biofilm formation on the surface of the implant material. The measured kinetic curves of drug release showed more rapid decrease in the release rate compared to the Higuchi approximation. Comparison with existing theories, which account for the finite rate of drug dissolution, showed that this may explain the observed deviation from the diffusion-controlled Higuchi model. Large dimensions of drug particles and their aggregation retard the dissolution stage and consequently the release rate. Melt blending was found to cause the drug particle aggregation within polymer matrixes which was confirmed by microscopic reexamination of the polymer implant materials. PMID- 21614131 TI - An active site aromatic triad in Escherichia coli DNA Pol IV coordinates cell survival and mutagenesis in different DNA damaging agents. AB - DinB (DNA Pol IV) is a translesion (TLS) DNA polymerase, which inserts a nucleotide opposite an otherwise replication-stalling N(2)-dG lesion in vitro, and confers resistance to nitrofurazone (NFZ), a compound that forms these lesions in vivo. DinB is also known to be part of the cellular response to alkylation DNA damage. Yet it is not known if DinB active site residues, in addition to aminoacids involved in DNA synthesis, are critical in alkylation lesion bypass. It is also unclear which active site aminoacids, if any, might modulate DinB's bypass fidelity of distinct lesions. Here we report that along with the classical catalytic residues, an active site "aromatic triad", namely residues F12, F13, and Y79, is critical for cell survival in the presence of the alkylating agent methyl methanesulfonate (MMS). Strains expressing dinB alleles with single point mutations in the aromatic triad survive poorly in MMS. Remarkably, these strains show fewer MMS- than NFZ-induced mutants, suggesting that the aromatic triad, in addition to its role in TLS, modulates DinB's accuracy in bypassing distinct lesions. The high bypass fidelity of prevalent alkylation lesions is evident even when the DinB active site performs error-prone NFZ-induced lesion bypass. The analyses carried out with the active site aromatic triad suggest that the DinB active site residues are poised to proficiently bypass distinctive DNA lesions, yet they are also malleable so that the accuracy of the bypass is lesion-dependent. PMID- 21614133 TI - The Generalized Asymptotic Equipartition Property: Necessary and Sufficient Conditions. AB - Suppose a string X1n=(X1,X2,...,Xn) generated by a memoryless source (X(n))(n>=1) with distribution P is to be compressed with distortion no greater than D >= 0, using a memoryless random codebook with distribution Q. The compression performance is determined by the "generalized asymptotic equipartition property" (AEP), which states that the probability of finding a D-close match between X1n and any given codeword Y1n, is approximately 2(-nR(P, Q, D)), where the rate function R(P, Q, D) can be expressed as an infimum of relative entropies. The main purpose here is to remove various restrictive assumptions on the validity of this result that have appeared in the recent literature. Necessary and sufficient conditions for the generalized AEP are provided in the general setting of abstract alphabets and unbounded distortion measures. All possible distortion levels D >= 0 are considered; the source (X(n))(n>=1) can be stationary and ergodic; and the codebook distribution can have memory. Moreover, the behavior of the matching probability is precisely characterized, even when the generalized AEP is not valid. Natural characterizations of the rate function R(P, Q, D) are established under equally general conditions. PMID- 21614134 TI - Nitric Oxide does not mediate Atrogin-1/MAFbx upregulation by inflammatory mediators. AB - Accelerated proteolysis through the ubiquitin-proteasome system has been recognized as a major contributor to muscle wasting, a serious complication frequently associated with a number of inflammatory disorders. Muscle expression of atrogin-1/MAFbx, a rate-limiting ubiquitin ligase for muscle wasting, is upregulated in various inflammatory conditions, and is considered a therapeutic target for muscle wasting. As one of the free radicals whose production is elevated in inflammatory conditions, nitric oxide (NO) is implicated in the pathogenesis of muscle wasting. To understand how inflammatory mediators upregulate atrogin-1/MAFbx expression, we tested the hypothesis that NO mediates the upregulation of atrogin-1/MAFbx expression. C2C12 myotubes were incubated with a cocktail comprised of TNF-alpha, interferon gamma and lipopolysaccharide (LPS), which stimulated NO production and atrogin-1/MAFbx expression. Pre incubation of the myotubes with nitric oxide synthase (NOS) inhibitor L-NAME or S ethylisothiourea (SETU) blocked the stimulation of NO production by the cocktail. However, the stimulation of atrogin-1/MAFbx expression was not disrupted. Intraperitoneal administration of LPS to mice resulted in elevated atrogin 1/MAFbx expression in gastrocnemius muscle. But, pretreatment of the mice with L NAME did not alter LPS stimulation of atrogin-1/MAFbx expression. Therefore, NO does not mediate upregulation of atrogin-1/MAFb expression by inflammatory mediators. PMID- 21614135 TI - Comparison of Detector Intrinsic Spatial Resolution Characteristics for Sensor on the Entrance Surface and Conventional Readout Designs. AB - We report on a high resolution, monolithic crystal PET detector design concept that provides depth of interaction (DOI) positioning within the crystal. Our design utilizes a novel sensor on the entrance surface (SES) approach combined with a maximum likelihood positioning algorithm. We compare the intrinsic spatial resolution characteristics (i.e., X, Y and Z) using our SES design versus conventional placement of the photo-sensors on the rear surface of the crystal. The sensors can be any two-dimensional array of solid state readout devices (e.g., silicon photomultipliers (SiPM) or avalanche photodiodes (APD)). SiPMs are a new type of solid-state photodetector with Geiger mode operation that can provide signal gain similar to a photomltipiler tube (PMT). Utilizing a multi step simulation process, we determined the intrinsic spatial resolution characteristics for a variety of detector configurations. The SES design was evaluated via simulation for three different two-dimensional array sizes: 8*8 with 5.8*5.8 mm(2) pads; 12*12 with 3.8*3.8mm(2) pads; and 16*16 with 2.8*2.8 mm(2) pads. To reduce the number of signal channels row-column summing readout was used for the 12*12 and 16*16 channel array devices. The crystal was modeled as a 15 mm monolithic slab of a lutetium-based scintillator with the large area surface varying from 48.8*48.8 mm(2) up to 49.6*49.6 mm(2) depending upon the dimensions of the two-dimensional photo-sensor array. The intrinsic spatial resolution for the 8*8 array is 0.88 mm FWHM in X and Y, and 1.83 mm FWHM in Z (i.e., DOI). Comparing the results versus using a conventional design with the photo-sensors on the backside of the crystal, an average improvement of ~24% in X and Y and 20% in Z is achieved. The X, Y intrinsic spatial resolution improved to 0.67 mm and 0.64 mm FWHM for the 12*12 and 16*16 arrays using row-column readout. Using the 12*12 and 16*16 arrays also led to a slight improvement in the DOI positioning accuracy. PMID- 21614136 TI - Molecular Diversity Within Melanomys caliginosus (Rodentia: Oryzomyini): Evidence for Multiple Species. AB - Nucleotide sequences from the mitochondrial DNA cytochrome-b gene were used to infer phylogenetic relationships and estimate genetic distances from 10 individuals of Melanomys caliginosus and to explore the hypothesis that this taxon is comprised of multiple species. Individuals of four geographic populations of M. caliginosus from Central America (Nicaragua and Costa Rica), Panama, Venezuela, and Ecuador, respectively, were included in this analysis. Topologies obtained from maximum parsimony and Bayesian inference analyses were identical and produced clades referable to each of the geographic populations. Genetic distances between any pair-wise comparisons of the four groups (except between Panamanian and Venezuelan samples) were comparable to values estimated from comparisons of sister species in the closely related genus Nectomys. Distances between samples from Panama and Venezuela were greater than those of samples within the Ecuadorian and Central American clades, but less than that between species of Nectomys. Based on results from the sequence data, it appears that all four of the populations should be elevated to species level; however, additional data are needed to resolve the nomenclature of the Panamanian and Venezuelan populations. PMID- 21614137 TI - Microfluidic Device for Capture and Isolation of Single Cells. AB - We describe a microfluidic device capable of trapping, isolating, and lysing individual cells in parallel using dielectrophoretic forces and a system of PDMS channels and valves. The device consists of a glass substrate patterned with electrodes and two PDMS layers comprising of the microfluidic channels and valve control channels. Individual cells are captured by positive dielectrophoresis using the microfabricated electrode pairs. The cells are then isolated into nanoliter compartments using pneumatically actuated PDMS valves. Following isolation, the cells are lysed open by applying an electric field using the same electrode pairs. With the ability to capture and compartmentalize single cells our device may be combined with analytical methods for in situ molecular analysis of cellular components from single cells in a highly parallel manner. PMID- 21614138 TI - An Interactive Java Statistical Image Segmentation System: GemIdent. AB - Supervised learning can be used to segment/identify regions of interest in images using both color and morphological information. A novel object identification algorithm was developed in Java to locate immune and cancer cells in images of immunohistochemically-stained lymph node tissue from a recent study published by Kohrt et al. (2005). The algorithms are also showing promise in other domains. The success of the method depends heavily on the use of color, the relative homogeneity of object appearance and on interactivity. As is often the case in segmentation, an algorithm specifically tailored to the application works better than using broader methods that work passably well on any problem. Our main innovation is the interactive feature extraction from color images. We also enable the user to improve the classification with an interactive visualization system. This is then coupled with the statistical learning algorithms and intensive feedback from the user over many classification-correction iterations, resulting in a highly accurate and user-friendly solution. The system ultimately provides the locations of every cell recognized in the entire tissue in a text file tailored to be easily imported into R (Ihaka and Gentleman 1996; R Development Core Team 2009) for further statistical analyses. This data is invaluable in the study of spatial and multidimensional relationships between cell populations and tumor structure. This system is available at http://www.GemIdent.com/ together with three demonstration videos and a manual. PMID- 21614139 TI - Deconvolution Estimation in Measurement Error Models: The R Package decon. AB - Data from many scientific areas often come with measurement error. Density or distribution function estimation from contaminated data and nonparametric regression with errors-in-variables are two important topics in measurement error models. In this paper, we present a new software package decon for R, which contains a collection of functions that use the deconvolution kernel methods to deal with the measurement error problems. The functions allow the errors to be either homoscedastic or heteroscedastic. To make the deconvolution estimators computationally more efficient in R, we adapt the fast Fourier transform algorithm for density estimation with error-free data to the deconvolution kernel estimation. We discuss the practical selection of the smoothing parameter in deconvolution methods and illustrate the use of the package through both simulated and real examples. PMID- 21614140 TI - ASSESSMENT OF KNOWLEDGE, ATTITUDE AND PRACTICE ON USING OF PERSONAL PROTECTIVE EQUIPMENT IN RATTAN CRAFTSMEN AT TRADE VILLAGE, KIENXUONG DISTRICT, THAIBINH PROVINCE, VIETNAM. AB - The knowledge, attitude and practice on using personal protective equipment (PPE) of rattan craftsmen to protect themselves from health effect related to sulfur dioxide exposure in Thuong Hien trade village at Kienxuong district, Thaibinh province, Vietnam was conducted using cross-sectional analytic study. The rattan craftsmen (n=403) were interviewed by face to face questionnaire. The results indicated that the level of good knowledge and good attitude was low equal 3.72% and 4.22% respectively. The prevalence of using respirator (face mask) was only 29.00 %. The intervention tools, therefore, should be developed for enhancing the knowledge and attitude while the training for using of respirator and other PPEs should be continuously offered for rattan craftsmen workers. PMID- 21614141 TI - EXPONENTIAL TENSORS: A FRAMEWORK FOR EFFICIENT HIGHER-ORDER DT-MRI COMPUTATIONS. AB - In Diffusion Tensor Magnetic Resonance Image (DT-MRI) processing a 2(nd) order tensor has been commonly used to approximate the diffusivity function at each lattice point of the 3D volume image. These tensors are symmetric positive definite matrices and the appropriate constraints required in algorithms for processing them makes these algorithms complex and significantly increases their computational complexity. In this paper we present a novel parameterization of the diffusivity function using which the positive definite property of the function is guaranteed without any increase in computation. This parameterization can be used for any order tensor approximations; we present Cartesian tensor approximations of order 2, 4, 6 and 8 respectively, of the diffusivity function all of which retain the positivity property in this parameterization without the need for any explicit enforcement. Furthermore, we present an efficient framework for computing distances and geodesics in the space of the coefficients of our proposed diffusivity function. Distances & geodesics are useful for performing interpolation, computation of statistics etc. on high rank positive definite tensors. We validate our model using simulated and real diffusion weighted MR data from excised, perfusion-fixed rat optic chiasm. PMID- 21614142 TI - Drosophila Gene Expression Pattern Annotation Using Sparse Features and Term-Term Interactions. AB - The Drosophila gene expression pattern images document the spatial and temporal dynamics of gene expression and they are valuable tools for explicating the gene functions, interaction, and networks during Drosophila embryogenesis. To provide text-based pattern searching, the images in the Berkeley Drosophila Genome Project (BDGP) study are annotated with ontology terms manually by human curators. We present a systematic approach for automating this task, because the number of images needing text descriptions is now rapidly increasing. We consider both improved feature representation and novel learning formulation to boost the annotation performance. For feature representation, we adapt the bag-of-words scheme commonly used in visual recognition problems so that the image group information in the BDGP study is retained. Moreover, images from multiple views can be integrated naturally in this representation. To reduce the quantization error caused by the bag-of-words representation, we propose an improved feature representation scheme based on the sparse learning technique. In the design of learning formulation, we propose a local regularization framework that can incorporate the correlations among terms explicitly. We further show that the resulting optimization problem admits an analytical solution. Experimental results show that the representation based on sparse learning outperforms the bag of-words representation significantly. Results also show that incorporation of the term-term correlations improves the annotation performance consistently. PMID- 21614143 TI - MEXICAN AMERICAN YOUTH AND ADULT PRISON GANGS IN A CHANGING HEROIN MARKET. AB - This article focuses on the interaction between the larger community's drug markets and youth and adult prison gangs, and the process that leads to specific adverse consequences both to the youth gangs as organizations, and to individual members. Described is the emergence of a restructured heroin market dominated by an adult prison gang. A major consequence of this was the increasing use of heroin among Mexican American gang members and their transformation from autonomous youth gangs to extensions of the adult prison gangs or their demise. Data was collected from 160 members of 26 Mexican American youth gangs and key informants in San Antonio. Findings focus on organizational rules, drug market transformations, consequences on members, and the impact of heroin on the gang's organization. Discussed is how the dominance of prison gangs is related to the increased incarceration and recidivism rates of Mexican Americans and declining economic opportunities for urban minorities. PMID- 21614144 TI - NICKEL-CATALYZED ASYMMETRIC NEGISHI CROSS-COUPLINGS OF RACEMIC SECONDARY ALLYLIC CHLORIDES WITH ALKYLZINCS: (S,E)-ETHYL 6-(1,3-DIOXOLAN-2-YL)-4-METHYLHEX-2 ENOATE. PMID- 21614146 TI - GAMBLING: SOMETIMES UNSEEMLY; NOT WHAT IT SEEMS. AB - Gambling offers opportunities for basic research and theory, and has hugely important applied implications. As I have said recently: "The current view of pathological gambling as an addiction cries out for a functional analysis of the controlling variables and for strategies of behavioral intervention." (Fantino, 2008). This view echoed that of Dixon (2007), who called out for behavior analysts to apply their very relevant skills to discovering the causes of gambling disorders. To understand the behavior of gambling, one must understand the basic processes and variables involved in making the decisions gamblers make. Behavior analysts, those experimental psychologists who approach psychological phenomena from a behavioral (or functional) perspective, have long concentrated on the choices organisms make. Thus, they should be in a strong position to contribute to our appreciation of the factors controlling gambling. In this paper we will examine some of the advances already made, and also propose some directions for future research. PMID- 21614147 TI - Mammalian Cell Sorting using MUFACS. AB - K562 mammalian cells are sorted using a highly integrated microfabricated fluorescence-activated cell sorter (MUFACS). The sample cells are purified with an enrichment factor of 230 at a high throughput (>1,000 cells/sec). PMID- 21614148 TI - A Review of Fetal ECG Signal Processing; Issues and Promising Directions. AB - The field of electrocardiography has been in existence for over a century, yet despite significant advances in adult clinical electrocardiography, signal processing techniques and fast digital processors, the analysis of fetal ECGs is still in its infancy. This is, partly due to a lack of availability of gold standard databases, partly due to the relatively low signal-to-noise ratio of the fetal ECG compared to the maternal ECG (caused by the various media between the fetal heart and the measuring electrodes, and the fact that the fetal heart is simply smaller), and in part, due to the less complete clinical knowledge concerning fetal cardiac function and development. In this paper we review a range of promising recording and signal processing techniques for fetal ECG analysis that have been developed over the last forty years, and discuss both their shortcomings and advantages. Before doing so, however, we review fetal cardiac development, and the etiology of the fetal ECG. A selection of relevant models for the fetal/maternal ECG mixture is also discussed. In light of current understanding of the fetal ECG, we then attempt to justify recommendations for promising future directions in signal processing, and database creation. PMID- 21614149 TI - SYNTHESIS OF CHIRAL PYRIDINE BIS(OXAZOLINE) LIGANDS FOR NICKEL-CATALYZED ASYMMETRIC NEGISHI CROSS-COUPLINGS OF SECONDARY ALLYLIC CHLORIDES WITH ALKYLZINCS: 2,6-BIS[(4S)-4,5-DIHYDRO-4-(2-PHENYLETHYL)-2-OXAZOLYL]-PYRIDINE. AB - [Pyridine, 2,6-bis[(4R)-4,5-dihydro-4-(2-phenylethyl)-2-oxazolyl]-]. PMID- 21614151 TI - Alveolar type II cells escape stress failure caused by tonic stretch through transient focal adhesion disassembly. AB - Mechanical ventilation-induced excessive stretch of alveoli is reported to induce cellular stress failure and subsequent lung injury, and is therefore an injurious factor to the lung. Avoiding cellular stress failure is crucial to ventilator induced lung injury (VILI) treatment. In the present study, primary rat alveolar type II (ATII) cells were isolated to evaluate their viability and the mechanism of their survival under tonic stretch. By the annexin V/ PI staining and flow cytometry assay, we demonstrated that tonic stretch-induced cell death is an immediate injury of mechanical stress. In addition, immunofluorescence and immunoblots assay showed that the cells experienced an expansion-contraction reexpansion process, accompanied by partial focal adhesion (FA) disassembly during contraction. Manipulation of integrin adherent affinity by altering bivalent cation levels in the culture medium and applying an integrin neutralizing antibody showed that facilitated adhesion affinity promoted cell death under tonic stretch, while lower level of adhesion protected the cells from stretch-induced stress failure. Finally, a simplified numerical model was established to reveal that adequate disassembly of FAs reduced the forces transmitting throughout the cell. Taken together, these results indicate that ATII cells escape stress failure caused by tonic stretch via active cell morphological remodeling, during which cells transiently disassemble FAs to unload mechanical forces. PMID- 21614150 TI - Mammalian sirtuins and energy metabolism. AB - Sirtuins are highly conserved NAD+-dependent protein deacetylases and/or ADP ribosyltransferases that can extend the lifespan of several lower model organisms including yeast, worms and flies. The seven mammalian sirtuins, SIRT1 to SIRT7, have emerged as key metabolic sensors that directly link environmental signals to mammalian metabolic homeostasis and stress response. Recent studies have shed light on the critical roles of sirtuins in mammalian energy metabolism in response to nutrient signals. This review focuses on the involvement of two nuclear sirtuins, SIRT1 and SIRT6, and three mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, in regulation of diverse metabolic processes. PMID- 21614152 TI - Study on the characteristics of contrast-enhanced ultrasound and its utility in assessing the microvessel density in ovarian tumors or tumor-like lesions. AB - Angiogenesis is a critical factor in tumor growth and metastasis, and microvessel density (MVD) was an important parameter for assessing vessels in tumors. However, radiologic assessment of tumor vascularity is not yet well established. In our study, we aimed at investigating the efficacy of contrast-enhanced ultrasonography (CEUS) in exploring the vascularity of the ovarian tumors or tumor-like lesions to assess the relationship between the parameters of the peak intensity (PI) and area under curve (AUC) on CEUS and MVD in ovarian masses. Compared to the contrast-enhanced ultrasound technique, conventional ultrasound shows limitation in differentiating benign and malignant ovarian tumors. The former is promising in improving the sensitivity of detecting small vessels and blood flow in ovarian tumors. Our results showed clear differences in enhancement patterns between benign and malignant ovary tumors or tumor-like lesions. The PI and AUC in the malignant tumors were significantly higher than those in the benign tumors or tumor-like lesions (p=0.001 and =0.01, respectively). The MVD was 43.1 +/- 20.4 in the benign tumors or tumor-like lesions and was 65.3 +/- 22.3 in the malignant ones (p= 0.01). In both the benign and malignant groups, the PI and AUC were correlated significantly with the MVD (r=0.595, p = 0.001; r =0.533, p = 0.003, respectively). The PI and AUC in CEUS can reflect the MVD in ovarin tumors. The PI and AUC of the ovarian masses in the contrast transvaginal sonography show significant correlation with the angiogenesis and may help in assessing tumor vascularity in ovarian masses. PMID- 21614153 TI - Immunophenotyping at the time of diagnosis distinguishes two groups of nasopharyngeal carcinoma patients: implications for adoptive immunotherapy. AB - BACKGROUND: Adoptive immunotherapy with EBV-specific CTLs (EBV-CTL) has been used to treat EBV-associated nasopharyngeal carcinoma (NPC) but only a fraction of the patients shows noticeable clinical response. PATIENTS AND METHODS: Sixty-seven newly diagnosed NPC patients from 2005 to 2007 and 21 healthy donors were collected. Immunological parameters and immune function of PBMCs and EBV-CTL were analyzed by flow cytometer analysis (FACS) and 51Cr releasing experiment; Molecular characteristics on NPC tumor cells were investigated by immunochemical staining and statistic analysis. RESULTS: NPC patients can be classified into two groups based on the percentage of CD3+ T cells in peripheral blood before accepted any treatment, (>52.6%, mean-2SE from healthy controls, NPC Group 1; <52.6%, NPC Group 2). The patients in Group 2 showed a significant decrease of CD3+CD8+ T-cells, CD3+CD4+ T-cells and CD3+CD45RO+ memory T cells, and increase of CD3-CD16+ NK cells compared to Group 1 patients and healthy controls (P<0.001). EBV-specific T cell responses, were weaker in this group of patients and their tumor cells expressed lower levels of the EBV encoded latent membrane protein (LMP)-1 and HLA class II protein compared with the patients of NPC Group 1 (P<0.05). CONCLUSION: These findings demonstrate that NPC patients could be distinguished on the basis of their immune status which will affect the efficacy of EBV-CTL immunotherapy. PMID- 21614154 TI - Seeking Mind, Body and Spirit Healing-Why Some Men with Prostate Cancer Choose CAM (Complementary and Alternative Medicine) over Conventional Cancer Treatments. AB - Little is known about men with prostate cancer who decline conventional treatment and use only complementary and alternative medicine (CAM). OBJECTIVES: To 1) explore why men decline conventional prostate cancer treatment and use CAM 2) understand the role of holistic healing in their care, and 3) document their recommendations for health care providers. METHODS: Semi-structured interviews and follow-up focus groups. SAMPLE: Twenty-nine men diagnosed with prostate cancer who declined all recommended conventional treatments and used CAM. RESULTS: Based on strong beliefs about healing, study participants took control by researching the risks of delaying or declining conventional treatment while using CAM as a first option. Most perceived conventional treatment to have a negative impact on quality of life. Participants sought healing in a broader mind, body, spirit context, developing individualized CAM approaches consistent with their beliefs about the causes of cancer. Most made significant lifestyle changes to improve their health. Spirituality was central to healing for one third of the sample. Participants recommended a larger role for integrated cancer care. CONCLUSION: Men who decline conventional prostate cancer treatment and use CAM only may benefit from a whole person approach to care where physicians support them to play an active role in healing while carefully monitoring their disease status. PMID- 21614155 TI - A model for implementing integrative practice in health care agencies. AB - Over the last few years, there has been increased awareness and use of complementary/alternative therapies (CAM) in many countries without the health care infrastructure to support it. The National Centre for Complementary and Alternative Medicine referred to the combining of mainstream medical therapies and CAM as integrative medicine. The creation of integrative health care teams will definitely result in redefining roles, but more importantly in a change in how services are delivered. The purpose of this paper is to describe a model of the necessary health care agency resources to support an integrative practice model. A logic model is used to depict the findings of a review of current evidence. Logic models are designed to show relationships between the goals of a program or initiative, the resources to achieve desired outputs and the activities that lead to outcomes. The four major resource categories necessary for implementing integrative care are within the domains of a) professional and research development, b) health human resource planning, c) regulation and legislation and d) practice and management in clinical areas. It was concluded that the system outcomes from activities within these resource categories should lead to freedom of choice in health care; a culturally sensitive health care system and a broader spectrum of services for achieving public health goals. PMID- 21614156 TI - Black Cohosh: Insights into its Mechanism(s) of Action. AB - The Women's Health Initiative found that combination estrogen and progesterone hormone replacement therapy increases breast cancer and cardiovascular disease risk, which compelled many women to seek herbal alternatives such as black cohosh extract (BCE) to relieve their menopausal symptoms. While several clinical trials document the efficacy of BCE in alleviating menopausal symptoms, preclinical studies to determine how BCE works have yielded conflicting results. Part of this is because there is not a universally accepted method to standardize the dose of black cohosh triterpenes, the presumed active ingredients in the extract. Although the mechanism by which BCE relieves symptoms is unknown, several hypotheses have been proposed: it acts 1) as a selective estrogen receptor modulator, 2) through serotonergic pathways, 3) as an antioxidant, or 4) on inflammatory pathways. We found that while the most prominent triterpene in BCE, 23-epi-26-deoxyactein, suppresses cytokine-induced nitric oxide production in brain microglial cells, the whole BCE extract actually enhanced this pathway. A variety of activities have been reported for black cohosh and its compounds, but the absorption and tissue distribution of these compounds is unknown. PMID- 21614158 TI - Efforts to achieve healthy aging. AB - Longevity is a blessing as long as good health is not lost. However, the tendency to have a decline on normal physiological activities is inevitable because of the natural processes of degeneration at all levels: molecular, cellular and organic. Hence, the elderly people frequently suffer from cardiovascular problems and skeletal deteriorations that gradually develop to disabilities. Awareness of factors leading to unhealthy aging has led to the formation of different professional groups that aim at the maintenance of health of aging community. The approach tends to be target orientated for the European and US groups, aiming at hormonal replacements and detoxification. In contrast, the oriental groups have been keeping their traditional belief of prevention and internal balance, using nutritional arrangements and non-strenuous exercise as means of maintaining health. PMID- 21614157 TI - The role of vitamins and minerals in psychiatry. PMID- 21614159 TI - A complementary alternative medicine questionnaire for young adults. AB - Limited information exists on how adolescents decide to use complementary/alternative medicine (CAM). There are also no instruments specific to CAM, for the young adult population, which makes it difficult to explore knowledge in this area. The purpose of this study was to develop and examine the psychometric properties of the CAM Questionnaire for Young Adults which measures young adults' attitudes about CAM. Participants for this cross-sectional survey were selected from enrolled undergraduate students at an urban university. Factor analysis identified three subscales: 1) positive beliefs about CAM; 2) environmental influence; and 3) psychological comfort. The scale has good internal consistency (Cronbach's alpha = 0.79) and shows beginning demonstration of validity. Its use in this sample revealed that young adults who are female and have used CAM in the past for preventing or treating illness have the most positive attitude towards CAM and the greatest likelihood for continued use. The implication that prevention may play a role in young adults' attitudes about CAM is a potential focus for future research. PMID- 21614160 TI - Integral healthcare: the benefits and challenges of integrating complementary and alternative medicine with a conventional healthcare practice. AB - Today's medicine is in the midst of an undeniable crisis. Calls to reform healthcare are in the forefront of economic and political discussions worldwide. Economic pressures reduce the amount of time physicians can spend with patients contributing to burnout among medical staff and endangering the patient iatrogenically. Politicians are getting involved as the public is calling for more affordable healthcare. A new paradigm must be embraced in order to address all aspects of this dilemma. It is clear that science and technology have resulted in vastly improved understanding, diagnosis, and treatment of disease, but the emphasis on science and technology to the exclusion of other elements of healing has also served to limit the development of a model that humanizes healthcare. The healing of a patient must include more than the biology and chemistry of their physical body; by necessity, it must include the mental, emotional and spiritual aspects. Because of these challenges, the development of an integral healthcare system that is rooted in appropriate regulation and supported by rigorous scientific evidence is the direction that many models of integrative healthcare are moving towards in the 21st century. PMID- 21614161 TI - Four cases of dysthymic disorder and general malaise successfully treated with traditional herbal (kampo) medicines: kamiuntanto. AB - Traditional herbal (Kampo) medicines have been used since ancient times to treat patients with mental disorders. In the present report, we describe four patients with dysthymia successfully treated with Kampo medicines: Kamiuntanto (KUT). These four patients fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for dysthymic disorder with easy fatigability and sleeplessness, but did not fulfill the criteria for major depressive disorder. Treatment with KUT relieved depressive status, fatigue and sleeplessness in these patients. As a result, their QOL (quality of life) was considerably improved. KUT may be useful as an additional or alternative treatment for dysthymia, especially in the field of primary health care. PMID- 21614162 TI - Edematous erythema at the hands and feet probably caused by the traditional herb "radix astragali". AB - OBJECTIVE: To describe a patient with erhythema and edema after Radix Astragali was added to a kampo formula. CASE SUMMARY: A 21-year-old male, who was diagnosed as having atopic dermatitis in 1989, demonstrated systemic dry eruptions and consulted our department for treatment with traditional herbal medicine (THM) in 2004. The oral administration of herbal medicine resulted in decreased symptoms as well as a reduction in the serum IgE level. In August 2007, he complained of sweating on the neck and we added Radix Astragali to the previous formula. About 18 hours after he ingested the new formula including Radix Astragali, erhythema appeared with swelling of the bilateral hands and feet. Administration of the formula was discontinued and about 48 hours later, his symptoms had almost disappeared. Astragaloside, which is the main ingredient of Radix Astragali, was negative on lymphocyte transforming test (LTT) and we could not determine the ingredient that induced erhythema. CONCLUSION: We consider that the Radix Astragali induced acute erhythema with swelling based on the clinical course. Acute edematous erythema due to THM is very rare and we discuss allergic reactions to traditional herbs and review the litrature. PMID- 21614163 TI - A preliminary study of the effectiveness of chinese therapeutic food on regulating female reproductive hormones. AB - This study investigated the effectiveness of Chinese therapeutic food on female reproductive hormones in a double-blind, placebo-controlled clinical trial. Chinese kiwi fruit extract (Hong En No. 1) was provided for Australian peri menopausal women for one month. Chinese medical assessment and urinary 2 hydroxyestrone (2-OHE) and 16alpha-hydroxyestrone (16alpha-OHE) tests were conducted. Twenty-six urinary samples (pre and post-trial) which met the requirement of testing were analysed, the ratio 2-OHE:16alpha-OHE of pre-trial (1.18 +/- 0.34) and post-trial (0.97 +/- 0.29) in the control group (n = 6) decreased but showed no significant change, this ratio of pre-trial (1.44 +/- 0.16) and post-trial (1.65 +/- 0.21) in the treatment group (n = 7) indicated an improvement (P = 0.066), which results in beneficial hormone regulation. The Chinese medicine assessment indicated that the patterns of disharmony mainly include Liver Qi stagnation and Liver-Kidney Yin deficiency patterns. No significant change observed in the control group, significant score reduction of the patterns of disharmony was achieved at post-trial in the treatment group, which indicates an improvement of general health condition. PMID- 21614164 TI - Heat shock protein 47: a novel biomarker of phenotypically altered collagen producing cells. AB - Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that helps the molecular maturation of various types of collagens. A close association between increased expression of HSP47 and the excessive accumulation of collagens is found in various human and experimental fibrotic diseases. Increased levels of HSP47 in fibrotic diseases are thought to assist in the increased assembly of procollagen, and thereby contribute to the excessive deposition of collagens in fibrotic areas. Currently, there is not a good universal histological marker to identify collagen-producing cells. Identifying phenotypically altered collagen producing cells is essential for the development of cell-based therapies to reduce the progression of fibrotic diseases. Since HSP47 has a single substrate, which is collagen, the HSP47 cellular expression provides a novel universal biomarker to identify phenotypically altered collagen-producing cells during wound healing and fibrosis. In this brief article, we explained why HSP47 could be used as a universal marker for identifying phenotypically altered collagen producing cells. PMID- 21614165 TI - Characterization of fiber types in different muscles of the hindlimb in female weanling and adult Wistar rats. AB - We analyzed lesser diameter and distribution of fiber types in different skeletal muscles from female Wistar rats using a histoenzymology Myofibrillar Adenosine Tri-phosphatase (mATPase) method. Fragments from muscles were frozen and processed by mATPase in different pH. Adult and weanling rat soleus muscles presented a predominance of type I fibers and larger fiber diameters. In the plantar muscle in adult rats, the type IIB fibers demonstrated greater lesser diameter while in the weanling animals, types I and IIB fibers were larger. The plantar muscle of animals of both ages was composed predominantly of the type IID fibers. The type IID fibers were observed in similar amounts in the lateral gastrocnemius and the medial gastrocnemius muscles. Type IIB fibers showed predominance and presented higher size in comparison with other types in the EDL muscle. The present study shows that data on fiber type distribution and fiber lesser diameter obtained in adult animals cannot always be applied to weanling animals of the same species. Using the mATPase, despite the difficult handling, is an important tool to determine the different characteristics of the specific fibers in the skeletal muscle tissue. PMID- 21614166 TI - Thalidomide prevents the progression of peritoneal fibrosis in mice. AB - Thalidomide is clinically recognized as a therapeutic agent for multiple myeloma and has been known to exert anti-angiogenic actions. Recent studies have suggested the involvement of angiogenesis in the progression of peritoneal fibrosis. The present study investigated the effects of thalidomide on the development of peritoneal fibrosis induced by injection of chlorhexidine gluconate (CG) into the mouse peritoneal cavity every other day for 3 weeks. Thalidomide was given orally every day. Peritoneal tissues were dissected out 21 days after CG injection. Expression of CD31 (as a marker of endothelial cells), proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), alpha-smooth muscle actin (as a marker of myofibroblasts), type III collagen and transforming growth factor (TGF)-beta was examined using immunohistochemistry. CG group showed thickening of the submesothelial zone and increased numbers of vessels and myofibroblasts. Large numbers of VEGF-, PCNA-, and TGF-beta-positive cells were observed in the submesothelial area. Thalidomide treatment significantly ameliorated submesothelial thickening and angiogenesis, and decreased numbers of PCNA- and VEGF-expressing cells, myofibroblasts, and TGF beta-positive cells. Moreover, thalidomide attenuated peritoneal permeability for creatinine, compared to the CG group. Our results indicate the potential utility of thalidomide for preventing peritoneal fibrosis. PMID- 21614167 TI - Immunohistochemical distribution of serum proteins in living mouse heart with In vivo cryotechnique. AB - In vivo cryotechnique (IVCT), which immediately cryofixes target organs in situ, was used to clarify the morphological features of beating heart tissue of living mice. IVCT was performed for diastolic heart tissue under the condition of monitoring with electrocardiogram (ECG). Other mouse hearts were prepared with conventional perfusion-fixation (PF-DH) or immersion-fixation followed by dehydration (IM-DH), and quick-freezing of resected heart tissues (FQF). Immunolocalizations of albumin, immunoglobulin G1 (IgG1), intravenously injected bovine serum albumin (BSA), and connexin 43 were examined after different intervals of BSA injection. In the case of IVCT, the exact stop time of beating mouse hearts was recorded by ECG, and open blood vessels with flowing erythrocytes were observed with less artificial tissue shrinkage than with conventional preparation methods. Both albumin and BSA were well preserved in intercalated discs and t-tubules of cardiomyocytes in addition to blood vessels and interstitial matrices. IgG1 was immunolocalized in interstitial matrices of heart tissues in addition to their blood vessels. At 4 hr after BSA injection, it was immunolocalized in the intercalated discs of cardiomyocytes and lost later at 8 hr. IVCT should prove to be more useful for the morphofunctional examination of dynamically changing heart tissue than conventional preparation methods. PMID- 21614168 TI - PGC-1alpha mRNA level and oxidative capacity of the plantaris muscle in rats with metabolic syndrome, hypertension, and type 2 diabetes. AB - We examined the fiber profiles and the mRNA levels of peroxisome proliferator activated receptors (PPARalpha and PPARdelta/beta) and of the PPARgamma coactivator-1alpha (PGC-1alpha) in the plantaris muscles of 15-week-old control (WR), metabolic syndrome (CP), hypertensive (SHR), and type 2 diabetic (GK) rats. The deep regions in the muscles of SHR and GK rats exhibited lower percentages of high-oxidative type I and IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR and CP rats. The surface regions in the muscles of CP, SHR, and GK rats exhibited lower percentages of high-oxidative type IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR rats. The muscles of SHR and GK rats had lower oxidative enzyme activity compared with WR rats. The muscles of SHR rats had the lowest PPARdelta/beta mRNA level. In addition, the muscles of SHR and GK rats had lower PGC-1alpha mRNA level compared with WR and CP rats. We concluded that the plantaris muscles of rats with hypertension and type 2 diabetes have lower oxidative capacity, which is associated with the decreased level of PGC-1alpha mRNA. PMID- 21614169 TI - Histological study and LYVE-1 immunolocalization of mouse mesenteric lymph nodes with "In Vivo Cryotechnique". AB - The "in vivo cryotechnique" (IVCT) is a powerful tool to directly freeze living animal organs in order to maintain biological components in frozen tissues, reflecting their native states. In this study, mesenteric lymph nodes of living mice were directly frozen with IVCT, and we did morphological studies and immunohistochemical analyses on a hyaluronic acid receptor, LYVE-1. In lymph nodes, widely open lymphatic sinuses were observed, and many lymphocytes adhered to inner endothelial cells along subcapsular sinuses. The LYVE-1 was clearly immunolocalized at inner endothelial cells of subcapsular sinuses, as well as those of medullary sinuses. Conventional pre-embedding electron microscopy also showed LYVE-1 immunolocalization along both the apical and basal sides of cell membranes of inner endothelial cells. By triple-immunostaining for LYVE-1, smooth muscle actin, and type IV collagen, the LYVE-1 was immunolocalized only in the inner endothelial cells, but not in outer ones which were surrounded by collagen matrix and smooth muscle cells. Thus, the functional morphology of lymph nodes in vivo was demonstrated and LYVE-1 immunolocalization in inner endothelial cells of subcapsular sinuses suggests hyaluronic acid incorporation into lymph node parenchyma. PMID- 21614170 TI - Roles of fukutin, the gene responsible for fukuyama-type congenital muscular dystrophy, in neurons: possible involvement in synaptic function and neuronal migration. AB - Fukutin is a gene responsible for Fukuyama-type congenital muscular dystrophy (FCMD), accompanying ocular and brain malformations represented by cobblestone lissencephaly. Fukutin is related to basement membrane formation via the glycosylation of alpha-dystoglycan (alpha-DG), and astrocytes play a crucial role in the pathogenesis of the brain lesion. On the other hand, its precise function in neurons is unknown. In this experiment, the roles of fukutin in mature and immature neurons were examined using brains from control subjects and FCMD patients and cultured neuronal cell lines. In quantitative PCR, the expression level of fukutin looked different depending on the region of the brain examined. A similar tendency in DG expression appears to indicate a relation between fukutin and alpha-DG in mature neurons. An increase of DG mRNA and core alpha-DG in the FCMD cerebrum also supports the relation. In immunohistochemistry, dot like positive reactions for VIA4-1, one of the antibodies detecting the glycosylated alpha-DG, in Purkinje cells suggest that fukutin is related to at least a post-synaptic function via the glycosylation of alpha-DG. As for immature neurons, VIA4-1 was predominantly positive in cells before and during migration with expression of fukutin, which suggest a participation of fukutin in neuronal migration via the glycosylation of alpha-DG. Moreover, fukutin may prevent neuronal differentiation, because its expression was significantly lower in the adult cerebrum and in differentiated cultured cells. A knockdown of fukutin was considered to induce differentiation in cultured cells. Fukutin seems to be necessary to keep migrating neurons immature during migration, and also to support migration via alpha-DG. PMID- 21614171 TI - Protein kinase B (akt) promotes pathological angiogenesis in murine model of oxygen-induced retinopathy. AB - Akt, or protein kinase B, is an important signaling molecule that modulates many cellular processes such as cell growth, survival, and metabolism. However, the vivo roles and effectors of Akt in retinal angiogenesis are not explicitly clear. We therefore detected the expression of Akt using Western blotting or RT-PCR technologies in an animal model of oxygen-induced retinopathy, and investigated the effects of recombinant Akt on inhibiting vessels loss and Akt inhibitor on suppressing experimental retinal neovascularization in this model. We showed that in the hyperoxic phase of oxygen-induced retinopathy, the expression of Akt was greatly suppressed. In the hypoxic phase, the expression of Akt was increased dramatically. No significant differences were found in normoxic groups. Compared with control groups, administration of the recombinant Akt in the first phase of retinopathy markedly reduced capillary-free areas, while the administration of the Akt inhibitor in the second phase of retinopathy significantly decreased retinal neovascularization but capillary-free areas. These results indicate that Akt play a critical role in the pathological process (vessels loss and neovascularization) of mouse model of oxygen-induced retinopathy, which may provide a valubale therapeutic tool for ischemic-induced retinal diseases. PMID- 21614172 TI - Analysis of mTOR inhibition-involved pathway in ovarian clear cell adenocarcinoma. AB - This study was designed to clarify the mechanism of the mammalian target of rapamycin (mTOR)-hypoxia inducible factor-1 (HIF-1) pathway using the cultured cell strain derived from human ovarian clear cell adenocarcinoma (CCA). Everolimus (a derivative of rapamycin)-treated cells and non-treated cells did not show any difference in mTOR expression. But, phosphorylated-mTOR (p-mTOR) expression significantly decreased in the treated cells, and mTOR-related factors such as phosphorylated-4E-BP1 (p-4E-BP1), HIF-1alpha, and vascular endothelial growth factor (VEGF) in the downstream region of mTOR revealed a marked decrease in expression. The analysis of influences of the drug on the HIF-1alpha degradation system showed an increase in von-Hippel Lindau (VHL) expression in the treated cells. Increase of cleaved caspase-3, one of key factors involved in apoptosis, was also shown in the treated cells. In the next step, using nude mice implanted with RMG-1 cells, a decrease in tumor size was demonstrated in 4 of the 7 mice which were orally administered with everolimus. As a result, it was suggested that everolimus administration would be helpful as an anti-tumor therapy for CCA not only via down-regulation of p-mTOR but also degradation of HIF-1alpha by VHL and induction of apoptosis by cleaved caspase-3. PMID- 21614173 TI - Anti-photoaging effects of soy isoflavone extract (aglycone and acetylglucoside form) from soybean cake. AB - Soy isoflavones, found in soybean and soybean products, have been reported to possess many physiological activities such as antioxidant activity, inhibition of cancer cell proliferation, reduction of cardiovascular risk, prevention of osteoporosis and alleviation of postmenopausal syndrome. In our previous study, soy isoflavone extract ISO-1 (containing 12 soy isoflavones) from soybean cake was demonstrated to prevent skin damage caused by UVB exposure. In this study, soy isoflavone extract from soybean cake was further purified and evaluated for the protective effects on UVB-induced damage. The results revealed that Fraction 3, which contains the aglycone group (daidzein, genistein and glycitein) and acetylglucoside group (acetyldaidzin, acetylgenistin and acetylglycitin) of soy isoflavones, could inhibit UVB-induced death of human keratinocytes and reduce the level of desquamation, transepidermal water loss (TEWL), erythema and epidermal thickness in mouse skin. Furthermore, topical application of Fraction 3 increased the activity of catalase and suppressed cyclooxygenase-2 (COX-2) and proliferating cell nuclear antigen (PCNA) expression in mice exposed to UVB. In addition, in comparison with ISO-1 and genistein, the Fraction 3 possessed much greater protective effects on both UVB-induced oxidative stress and keratinocyte death than other fractions. Therefore, the soy isoflavone extract Fraction 3 from soybean cake is a desirable anti-photoaging agent for skin care. PMID- 21614174 TI - Functional toxicogenomics: mechanism-centered toxicology. AB - Traditional toxicity testing using animal models is slow, low capacity, expensive and assesses a limited number of endpoints. Such approaches are inadequate to deal with the increasingly large number of compounds found in the environment for which there are no toxicity data. Mechanism-centered high-throughput testing represents an alternative approach to meet this pressing need but is limited by our current understanding of toxicity pathways. Functional toxicogenomics, the global study of the biological function of genes on the modulation of the toxic effect of a compound, can play an important role in identifying the essential cellular components and pathways involved in toxicity response. The combination of the identification of fundamental toxicity pathways and mechanism-centered targeted assays represents an integrated approach to advance molecular toxicology to meet the challenges of toxicity testing in the 21(st) century. PMID- 21614175 TI - The lin-4 gene controls fat accumulation and longevity in Caenorhabditis elegans. AB - Previous studies have determined that lin-4, which was the first miRNA to be discovered, controls the timing of cell fate determination and life span in Caenorhabditis elegans. However, the mechanism of lin-4 involvement in these processes remains poorly understood. Fat storage is an essential aspect of the life cycle of organisms, and the function of lin-4 in fat accumulation is not clear. In this study, we showed that the fat content is reduced remarkably in C. elegans lin-4 mutants. Quantitative RT-PCR analysis revealed a considerable decrease in the levels of SBP-1 and OGA-1 mRNA in lin-4 mutants. We also showed that lin-4 mutants have a significantly shorter life span than wild-type worms. DCF assay experiments showed that the reactive oxygen species (ROS) levels increased and mitochondrial DNA (mtDNA) copy number decreased in loss-of-function lin-4 mutants. These mutants also showed attenuation of locomotion. Taken together, our findings suggest that lin-4 may play an important role in regulating fat accumulation and locomotion and that lin-4 may control the life span of C. elegans by mediating ROS production. PMID- 21614176 TI - An adsorptive transfer technique coupled with brdicka reaction to reveal the importance of metallothionein in chemotherapy with platinum based cytostatics. AB - The drugs based on platinum metals represent one of the oldest, but also one of the most effective groups of chemotherapeutic agents. Thanks to many clinical studies it is known that resistance of tumor cells to drugs is a frequent cause of chemotherapy failure. With regard to platinum based drugs, multidrug resistance can also be connected with increased expression of low-molecular weight protein metallothionein (MT). This study aimed at investigating the interactions of MT with cisplatin or carboplatin, using the adsorptive transfer technique coupled with differential pulse voltammetry Brdicka reaction (AdTS DPV Brdicka reaction), and a comparison of in vitro results with results obtained in vivo. The results obtained from the in vitro study show a strong affinity between platinum based drugs and MT. Further, we analyzed extracts of neuroblastoma cell lines treated with cisplatin or carboplatin. It is clear that neuroblastoma UKF NB-4 cisplatin-resistant and cisplatin-sensitive cell lines unlikely respond to the presence of the platinum-based cytostatics cisplatin and carboplatin. Finally, we determined the level of MT in samples from rabbits treated with carboplatin and patients with retinoblastoma treated with the same drug. PMID- 21614177 TI - 3,4-Methylenedioxymethamphetamine alters left ventricular function and activates nuclear factor-Kappa B (NF-kappaB) in a time and dose dependent manner. AB - 3,4-Methylenedioxymethamphetamine (MDMA) is an illicit psychoactive drug with cardiovascular effects that have not been fully described. In the current study, we observed the effects of acute MDMA on rabbit left ventricular function. We also observed the effects of MDMA on nuclear factor-kappa B (NF-kappaB) activity in cultured rat ventricular myocytes (H9c2). In the rabbit, MDMA (2 mg/kg) alone caused a significant increase in heart rate and a significant decrease in the duration of the cardiac cycle. Inhibition of nitric oxide synthase (NOS) by pretreatment with L-NAME (10 mg/kg) alone caused significant dysfunction in heart rate, systolic pressure, diastolic pressure, duration of relaxation, duration of cardiac cycle, and mean left ventricular pressure. Pretreatment with L-NAME followed by treatment with MDMA caused significant dysfunction in additional parameters that were not abnormal upon exposure to either compound in isolation: duration of contraction, inotropy, and pulse pressure. Exposure to 1.0 mM MDMA for 6 h or 2.0 MUM MDMA for 12 h caused increased nuclear localization of NF kappaB in cultured H9c2 cells. The current results suggest that MDMA is acutely detrimental to heart function and that an intact cardiovascular NOS system is important to help mitigate early sequelae in some functional parameters. The delayed timing of NF-kappaB activation suggests that this factor may be relevant to MDMA induced cardiomyopathy of later onset. PMID- 21614178 TI - Screening and initial binding assessment of fumonisin b(1) aptamers. AB - Fumonisins are mycotoxins produced by Fusarium verticillioides and F. proliferatum, fungi that are ubiquitous in corn (maize). Insect damage and some other environmental conditions result in the accumulation of fumonisins in corn based products worldwide. Current methods of fumonisin detection rely on the use of immunoaffinity columns and high-performance liquid chromatography (HPLC). The use of aptamers offers a good alternative to the use of antibodies in fumonisin cleanup and detection due to lower costs and improved stability. Aptamers are single-stranded oligonucleotides that are selected using Systematic Evolution of Ligands by EXponential enrichment (SELEX) for their ability to bind to targets with high affinity and specificity. Sequences obtained after 18 rounds of SELEX were screened for their ability to bind to fumonisin B(1). Six unique sequences were obtained, each showing improved binding to fumonisin B(1) compared to controls. Sequence FB(1) 39 binds to fumonisin with a dissociation constant of 100 +/- 30 nM and shows potential for use in fumonisin biosensors and solid phase extraction columns. PMID- 21614179 TI - In situ and in vivo study of nasal absorption of paeonol in rats. AB - The objective of this work was to study the in situ and in vivo nasal absorption of paeonol. A novel single pass in situ nasal perfusion technique was applied to examine the rate and extent of nasal absorption of paeonol by rats. Various experimental conditions, such as perfusion rate, pH, osmotic pressure and drug concentration, were investigated. The in situ experiments showed that the nasal absorption of paeonol was not dependent on drug concentration, and fitted a first order process. The absorption rate constant, Ka, increased with an increase in perfusion speed. Paeonol was better absorbed in acidic solutions than in neutral or alkaline solutions. The value of Ka was higher in a hypertonic environment than under isotonic or hypotonic conditions. In vivo studies of paeonol absorption were carried out in rats and the pharmacokinetics parameters of intranasal (i.n.) and intragastric (i.g.) administration were compared with intravenous (i.v.) administration. The bioavailabilities of paeonol were 52.37% and 15.81% for i.n. and i.g, respectively, while T(max) values were 3.05 +/- 1.46 min and 6.30 +/- 0.70 min. MRT (Mean Residence Time) were 23.19 +/- 6.46 min, 41.49 +/- 2.96 min and 23.09 +/- 5.88 min for i.n., i.g. and i.v. methods, respectively. The results demonstrate that paeonol could be absorbed promptly and thoroughly by i.n. administration in rats. PMID- 21614180 TI - Knockdown of snail sensitizes pancreatic cancer cells to chemotherapeutic agents and irradiation. AB - The prognosis of patients with pancreatic cancer remains poor; only patients with small tumors and complete resection have a chance of a complete cure. Pancreatic cancer responds poorly to conventional therapies, including chemotherapy and irradiation. Snail is a transcription factor that has been associated with anti apoptotic and chemoresistant properties in pancreatic cancer cells. In this study, we investigated whether knockdown of Snail suppresses growth of and/or sensitizes pancreatic cancer cells to chemotherapeutic agents and irradiation through induction of apoptosis. An adeno-associated virus vector was used to deliver Snail siRNA and knockdown Snail expression in untreated pancreatic cancer cells and in pancreatic cancer cells treated with chemotherapeutic agents or gamma-irradiation. Our data indicate that our adeno-associated virus vector can efficiently deliver Snail siRNA into PANC-1 cells both in vitro and in vivo, resulting in the knockdown of Snail expression at the mRNA and protein levels. We further show that knockdown of Snail expression results in potent growth suppression of pancreatic cancer cells and suppresses xenograft tumor growth in vivo through induction of apoptosis. Finally, knockdown of Snail expression significantly sensitizes pancreatic cancer cells to chemotherapeutic agents and gamma-irradiation through induction of apoptosis. In conclusion, our findings indicate that Snail is an important modulator of therapeutic responses of pancreatic cancer cells and is potentially useful as a sensitizer in pancreatic cancer therapy. PMID- 21614181 TI - Proteomic profiles of mesenchymal stem cells induced by a liver differentiation protocol. AB - The replacement of disease hepatocytes and the stimulation of endogenous or exogenous regeneration by human mesenchymal stem cells (MSCs) are promising candidates for liver-directed cell therapy. In this study, we isolated MSCs from adult bone marrow by plastic adhesion and induced differentiation with a liver differentiation protocol. Western blot analyses were used to assess the expression of liver-specific markers. Next, MSC-specific proteins were analyzed with two-dimensional (2D) gel electrophoresis and peptide mass fingerprinting matrix-assisted laser desorption/ionization (MALDI)-time of flight (TOF)-mass spectrometry (MS). To confirm the results from the proteomic study, semi quantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses were performed. We demonstrated that MSCs treated with the liver differentiation protocol expressed significantly more albumin, CK19 and CK20, than did undifferentiated cells. In addition the results of proteomic study demonstrated increases expression of FEM1B, PSMC2 and disulfide-isomerase A3 in MSCs treated with the liver differentiation protocol. These results from proteomic profiling will not only provide insight into the global responses of MSCs to hepatocyte differentiation, but will also lead to in-depth studies on the mechanisms of proteomic changes in MSCs. PMID- 21614182 TI - Compound K, a metabolite of ginseng saponin, induces mitochondria-dependent and caspase-dependent apoptosis via the generation of reactive oxygen species in human colon cancer cells. AB - The objective of this study was to elucidate the cytotoxic mechanism of Compound K, with respect to the involvement of reactive oxygen species (ROS) and the mitochondrial involved apoptosis, in HT-29 human colon cancer cells. Compound K exhibited a concentration of 50% growth inhibition (IC(50)) at 20 MUg/mL and cytotoxicity in a time dependent manner. Compound K produced intracellular ROS in a time dependent fashion; however, N-acetylcysteine (NAC) pretreatment resulted in the inhibition of this effect and the recovery of cell viability. Compound K induced a mitochondria-dependent apoptotic pathway via the modulation of Bax and Bcl-2 expressions, resulting in the disruption of the mitochondrial membrane potential (Deltapsi(m)). Loss of the Deltapsi(m) was followed by cytochrome c release from the mitochondria, resulting in the activation of caspase-9, -3, and concomitant poly ADP-ribosyl polymerase (PARP) cleavage, which are the indicators of caspase-dependent apoptosis. The apoptotic effect of Compound K, exerted via the activation of c-Jun NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), was abrogated by specific MAPK inhibitors. This study demonstrated that Compound K-mediated generation of ROS led to apoptosis through the modulation of a mitochondria-dependent apoptotic pathway and MAPK pathway. PMID- 21614183 TI - Computer-based de novo designs of tripeptides as novel neuraminidase inhibitors. AB - The latest influenza A (H1N1) pandemic attracted worldwide attention and called for the urgent development of novel antiviral drugs. Here, seven tripeptides are designed and explored as neuraminidase (NA) inhibitors on the structural basis of known inhibitors. Their interactions with NA are studied and compared with each other, using flexible docking and molecular dynamics simulations. The various composed tripeptides have respective binding specificities and their interaction energies with NA decrease in the order of FRI > FRV > FRT > FHV > FRS > FRG > YRV (letters corresponding to amino acid code). The Arg and Phe portions of the tripeptides play important roles during the binding process: Arg has strong electrostatic interactions with the key residues Asp151, Glu119, Glu227 and Glu277, whereas Phe fits well in the hydrophobic cave within the NA active site. Owing to the introduction of hydrophobic property, the interaction energies of FRV and FRI are larger; in particular, FRI demonstrates the best binding quality and shows potential as a lead compound. In addition, the influence of the chemical states of the terminal amino acids are clarified: it is revealed that the charged states of the N-terminus (NH(3) (+)) and C-terminus (COO(-)) are crucial for the tripeptide inhibitory activities and longer peptides may not be appropriate. In addition, the medium inhibiting activity by acetylation of the N terminus indicates the possible chemical modifications of FRI. Experimental efforts are expected in order to actualize the tripeptides as potent NA inhibitors in the near future. PMID- 21614184 TI - Optimization of enzymatic production of oligopeptides from apricot almonds meal with neutrase and N120P. AB - Neutrase 0.8L and N120P proteases were used for oligopeptide production from apricot almonds meal, and response surface design was carried out to optimize the effect of hydrolysis conditions on hydrolysis degree (DH) and oligopeptide yield rate. Four independent variables were used to optimize the hydrolysis process: hydrolysis temperature (X(1)), enzyme-to substrate ratio (E/S) (X(2)), substrate concentration (X(3)) and reaction time (X(4)). Statistical analysis indicated that the four variables, quadratic terms of X(1), X(3), and X(4), and the interaction terms with X(1) had a significant (p < 0.05) effect on DH. The yield rate was also significantly affected by the four variables and quadratic terms of X(1), X(2) and X(4). Two mathematical models with high determination coefficient were obtained and could be employed to optimize protein hydrolysis. The optimal hydrolysis conditions were determined as follows: hydrolysis temperature 52.5 degrees C; enzyme-to-substrate ratio (E/S) 7200 U/g; substrate concentration 2%; reaction time 173 min. The initial pH 6.5 and Neutrase-to-N120P dosage ratio 2:1 were fixed in this study according to the preliminary research. Under these conditions, the experimental DH and yield rate were 34.10 +/- 5.25% and 72.42 +/- 2.27%, respectively. PMID- 21614185 TI - Optimization of bacterial plasmid transformation using nanomaterials based on the Yoshida effect. AB - With the help of sepiolite, a unique method for transforming DNA into bacteria, based on the Yoshida effect, has been developed recently. However, we confronted many problems when this newest method was tried. Only a few transformants could be obtained even when 100 ng of plasmid pET15b was used, and a successful result seemed difficult to repeat. To address this problem, we optimized the operating method and could achieve about 15,000 transformants using the same amount of plasmid, which could match the efficiency gained using the calcium chloride transformation method. Meanwhile, the results could also be reproduced well. In the same way, carbon nanotubes were used to attain more than 15,000 transformants in the same situation. Therefore, the transformation method could be extended to other nanomaterials. Meanwhile, compared with the mechanism previously reported, we verified quite a different principle for the mechanism responsible for such a transformation. In sum, this unique transformation can be developed to become the third widely-used transformation method in laboratories in addition to the chemical method and electroporation. PMID- 21614186 TI - Profile and functional properties of seed proteins from six pea (Pisum sativum) genotypes. AB - Extractability, extractable protein compositions, technological-functional properties of pea (Pisum sativum) proteins from six genotypes grown in Serbia were investigated. Also, the relationship between these characteristics was presented. Investigated genotypes showed significant differences in storage protein content, composition and extractability. The ratio of vicilin:legumin concentrations, as well as the ratio of vicilin + convicilin: Legumin concentrations were positively correlated with extractability. Our data suggest that the higher level of vicilin and/or a lower level of legumin have a positive influence on protein extractability. The emulsion activity index (EAI) was strongly and positively correlated with the solubility, while no significant correlation was found between emulsion stability (ESI) and solubility, nor between foaming properties and solubility. No association was evident between ESI and EAI. A moderate positive correlation between emulsion stability and foam capacity was observed. Proteins from the investigated genotypes expressed significantly different emulsifying properties and foam capacity at different pH values, whereas low foam stability was detected. It appears that genotype has considerable influence on content, composition and technological-functional properties of pea bean proteins. This fact can be very useful for food scientists in efforts to improve the quality of peas and pea protein products. PMID- 21614187 TI - Computational prediction of O-linked glycosylation sites that preferentially map on intrinsically disordered regions of extracellular proteins. AB - O-glycosylation of mammalian proteins is one of the important posttranslational modifications. We applied a support vector machine (SVM) to predict whether Ser or Thr is glycosylated, in order to elucidate the O-glycosylation mechanism. O glycosylated sites were often found clustered along the sequence, whereas other sites were located sporadically. Therefore, we developed two types of SVMs for predicting clustered and isolated sites separately. We found that the amino acid composition was effective for predicting the clustered type, whereas the site specific algorithm was effective for the isolated type. The highest prediction accuracy for the clustered type was 74%, while that for the isolated type was 79%. The existence frequency of amino acids around the O-glycosylation sites was different in the two types: namely, Pro, Val and Ala had high existence probabilities at each specific position relative to a glycosylation site, especially for the isolated type. Independent component analyses for the amino acid sequences around O-glycosylation sites showed the position-specific existences of the identified amino acids as independent components. The O glycosylation sites were preferentially located within intrinsically disordered regions of extracellular proteins: particularly, more than 90% of the clustered O GalNAc glycosylation sites were observed in intrinsically disordered regions. This feature could be the key for understanding the non-conservation property of O-glycosylation, and its role in functional diversity and structural stability. PMID- 21614188 TI - Binding ligand prediction for proteins using partial matching of local surface patches. AB - Functional elucidation of uncharacterized protein structures is an important task in bioinformatics. We report our new approach for structure-based function prediction which captures local surface features of ligand binding pockets. Function of proteins, specifically, binding ligands of proteins, can be predicted by finding similar local surface regions of known proteins. To enable partial comparison of binding sites in proteins, a weighted bipartite matching algorithm is used to match pairs of surface patches. The surface patches are encoded with the 3D Zernike descriptors. Unlike the existing methods which compare global characteristics of the protein fold or the global pocket shape, the local surface patch method can find functional similarity between non-homologous proteins and binding pockets for flexible ligand molecules. The proposed method improves prediction results over global pocket shape-based method which was previously developed by our group. PMID- 21614189 TI - Poly[(3-hexylthiophene)-block-(3-semifluoroalkylthiophene)] for polymer solar cells. AB - We report the synthesis of poly[(3-hexylthiophene)-block-(3-(4,4,5,5,6,6,7,7,7 nonafluoroheptyl)thiophene)], P(3HT-b-3SFT), carried out by the Grignard Metathesis Method (GRIM). The copolymers composition was determined by (1)H and (19)F NMR spectroscopies, and gel permeation chromatography (GPC). The thin films of P(3HT-b-3SFT) were investigated by ultraviolet-visible absorption spectroscopy and atomic force microscopy (AFM). We also fabricated bulk-hetero junction (BHJ) solar cells based on blends of P(3HT-b-3SFT) and [6,6]-phenyl-C(61)-butyric acid methyl ester (PCBM). Although the composition ratio of P3SFT in P(3HT-b-3SFT) was low, the influence of P3SFT on the morphology and properties of solar cells was significant. The annealing process for the BHJ solar cells induced the formation of large domains and led to poor solar cell performance. The BHJ solar cells, based on PCBM and P(3HT-b-3SFT), prepared by the non-annealing process, had a maximum power conversion efficiency of 0.84% under 100 mW/cm(2) (AM 1.5 solar illumination) in air. PMID- 21614190 TI - Matrix-assisted laser desorption/ionization imaging mass spectrometry. AB - Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is a powerful tool that enables the simultaneous detection and identification of biomolecules in analytes. MALDI-imaging mass spectrometry (MALDI-IMS) is a two dimensional MALDI-mass spectrometric technique used to visualize the spatial distribution of biomolecules without extraction, purification, separation, or labeling of biological samples. MALDI-IMS has revealed the characteristic distribution of several biomolecules, including proteins, peptides, amino acids, lipids, carbohydrates, and nucleotides, in various tissues. The versatility of MALDI-IMS has opened a new frontier in several fields such as medicine, agriculture, biology, pharmacology, and pathology. MALDI-IMS has a great potential for discovery of unknown biomarkers. In this review, we describe the methodology and applications of MALDI-IMS for biological samples. PMID- 21614191 TI - A simple and rapid method for DNA isolation from xylophagous insects. AB - Published methods to isolate DNA from insects are not always effective in xylophagous insects because they have high concentrations of phenolics and other secondary plant compounds in their digestive tracts. A simple, reliable and labor effective cetyltrimethylammonium bromide-polyvinylpyrrolidone (CTAB-PVP) method for isolation of high quality DNA from xylophagous insects is described. This method was successfully applied to PCR and restriction analysis, indicating removal of common inhibitors. DNA isolated by the CTAB-PVP method could be used in most molecular analyses. PMID- 21614192 TI - Exploring kinetics of phenol biodegradation by Cupriavidus taiwanesis 187. AB - Phenol biodegradation in batch systems using Cupriavidus taiwanesis 187 has been experimentally studied. To determine the various parameters of a kinetic model, combinations of rearranged equations have been evaluated using inverse polynomial techniques for parameter estimation. The correlations between lag phase and phase concentration suggest that considering phenol inhibition in kinetic analysis is helpful for characterizing phenol degradation. This study proposes a novel method to determine multiplicity of steady states in continuous stirred tank reactors (CSTRs) in order to identify the most appropriate kinetics to characterize the dynamics of phenol biodegradation. PMID- 21614193 TI - Colorimetric immunoassay for detection of tumor markers. AB - Tumor markers are substances, usually proteins, produced by the body in response to cancer growth, or by the cancer tissue itself. They can be detected in blood, urine, or tissue samples, and the discovery and detection of tumor markers may provide earlier diagnosis of cancer and improved therapeutic intervention. Colorimetric immunoassays for tumor marker detection have attracted considerable attention, due to their simplicity and high efficiency. The traditionally used colorimetric immunoassays for the detection of tumor markers are based on enzyme linked immunosorbent assays, and the great achievement of nanotechnology has further opened opportunities for the development of such kind of immunoassays. This paper will summarize recent advances in the field of colorimetric immunoassays for detecting tumor markers, which is aimed to provide an overview in this field, as well as experimental guidance for the learner. PMID- 21614194 TI - Rhamnolipid biosurfactants as new players in animal and plant defense against microbes. AB - Rhamnolipids are known as very efficient biosurfactant molecules. They are used in a wide range of industrial applications including food, cosmetics, pharmaceutical formulations and bioremediation of pollutants. The present review provides an overview of the effect of rhamnolipids in animal and plant defense responses. We describe the current knowledge on the stimulation of plant and animal immunity by these molecules, as well as on their direct antimicrobial properties. Given their ecological acceptance owing to their low toxicity and biodegradability, rhamnolipids have the potential to be useful molecules in medicine and to be part of alternative strategies in order to reduce or replace pesticides in agriculture. PMID- 21614195 TI - Astaxanthin improves stem cell potency via an increase in the proliferation of neural progenitor cells. AB - The present study was designed to investigate the question of whether or not astaxanthin improves stem cell potency via an increase in proliferation of neural progenitor cells (NPCs). Treatment with astaxanthin significantly increased proliferation and colony formation of NPCs. For identification of possible activated signaling molecules involved in active cell proliferation occurring after astaxanthin treatment, total protein levels of several proliferation related proteins, and expression levels of proliferation-related transcription factors, were assessed in NPCs. In Western blot analysis, astaxanthin induced significant activation of phosphatidylinositol 3-kinase (PI3K) and its downstream mediators in a time-dependent manner. Results of RT-PCR analysis showed upregulation of proliferation-related transcription factors and stemness genes. To estimate the relevance of PI3K and mitogen-activated protein, or extracellular signal-regulated kinase kinase (MEK) signaling pathways in cell growth of astaxanthin-treated NPCs, inhibition assays were performed with LY294002, a specific inhibitor of PI3K, and PD98059, a specific inhibitor of MEK, respectively. These results clearly showed that astaxanthin induces proliferation of NPCs via activation of the PI3K and MEK signaling pathways and improves stem cell potency via stemness acting signals. PMID- 21614196 TI - Clinicopathological significance of loss of ARID1A immunoreactivity in ovarian clear cell carcinoma. AB - Recent genome-wide analysis has demonstrated that somatic mutations in ARID1A (BAF250) are the most common molecular genetic changes in ovarian clear cell carcinoma (OCCC). ARID1A mutations, which occur in approximately half of OCCC cases, lead to deletion of the encoded protein and inactivation of the putative tumor suppressor. In this study, we determined the significance of loss of ARID1A immunoreactivity with respect to several clinicopathological features in a total of 149 OCCCs. First, we demonstrated that ARID1A immunohistochemistry showed concordance with the mutational status in 91% of cases with 100% sensitivity and 66% specificity. Specifically, among 12 OCCC cases for which ARIDA mutational status was known, ARIDIA immunoreactivity was undetectable in all 9 cases harboring ARID1A mutations and was undetectable in one of 3 cases with wild-type ARID1A. With respect to the entire cohort, ARID1A immunoreactivity was undetectable in 88 (59%) of 149 OCCCs. There was no significant difference between ARID1A negative and positive cases in terms of histopathologic features, age, clinical stage, or overall survival. In conclusion, this study provides further evidence that mutations in ARID1A resulted in loss of ARID1A protein expression in OCCC, although no significant differences between ARID1A positive and negative cases were observed with respect to any clinicopathological features examined. PMID- 21614197 TI - Molecular interactions and protein-induced DNA hairpin in the transcriptional control of bacteriophage o29 DNA. AB - Studies on the regulation of phage O29 gene expression revealed a new mechanism to accomplish simultaneous activation and repression of transcription leading to orderly gene expression. Two phage-encoded early proteins, p4 and p6, bind synergistically to DNA, modifying the topology of the sequences encompassing early promoters A2c and A2b and late promoter A3 in a hairpin that allows the switch from early to late transcription. Protein p6 is a nucleoid-like protein that binds DNA in a non-sequence specific manner. Protein p4 is a sequence specific DNA binding protein with multifaceted sequence-readout properties. The protein recognizes the chemical signature of only one DNA base on the inverted repeat of its target sequence through a direct-readout mechanism. In addition, p4 specific binding depends on the recognition of three A-tracts by indirect-readout mechanisms. The biological importance of those three A-tracts resides in their individual properties rather than in the global curvature that they may induce. PMID- 21614198 TI - Constitutive expression of Thermobifida fusca thermostable Acetylxylan Esterase gene in Pichia pastoris. AB - A gene encoding the thermostable acetylxylan esterase (AXE) in Thermobifida fusca NTU22 was amplified by PCR, sequenced and cloned into the Pichia pastoris X-33 host strain using the vector pGAPZalphaA, allowing constitutive expression and secretion of the protein. Recombinant expression resulted in high levels of extracellular AXE production, as high as 526 U/mL in the Hinton flask culture broth. The purified enzyme showed a single band at about 28 kDa by SDS polyacrylamide gel electrophoresis after being treated with endo-beta-N acetylglycosaminidase H; this agrees with the predicted size based on the nucleotide sequence. About 70% of the original activity remained after heat treatment at 60 degrees C for three hours. The optimal pH and temperature of the purified enzyme were 8.0 and 60 degrees C, respectively. The properties of the purified AXE from the P. pastoris transformant are similar to those of the AXE from an E. coli transformant. PMID- 21614199 TI - Applications of chitin and its derivatives in biological medicine. AB - Chitin and its derivatives-as a potential resource as well as multiple functional substrates-have generated attractive interest in various fields such as biomedical, pharmaceutical, food and environmental industries, since the first isolation of chitin in 1811. Moreover, chitosan and its chitooligosaccharides (COS) are degraded products of chitin through enzymatic and acidic hydrolysis processes; and COS, in particular, is well suited for potential biological application, due to the biocompatibility and nontoxic nature of chitosan. In this review, we investigate the current bioactivities of chitin derivatives, which are all correlated with their biomedical properties. Several new and cutting edge insights here may provide a molecular basis for the mechanism of chitin, and hence may aid its use for medical and pharmaceutical applications. PMID- 21614200 TI - Protein microarrays and biomarkers of infectious disease. AB - Protein microarrays are powerful tools that are widely used in systems biology research. For infectious diseases, proteome microarrays assembled from proteins of pathogens will play an increasingly important role in discovery of diagnostic markers, vaccines, and therapeutics. Distinct formats of protein microarrays have been developed for different applications, including abundance-based and function based methods. Depending on the application, design issues should be considered, such as the need for multiplexing and label or label free detection methods. New developments, challenges, and future demands in infectious disease research will impact the application of protein microarrays for discovery and validation of biomarkers. PMID- 21614201 TI - Liquid-liquid phase transition and glass transition in a monoatomic model system. AB - We review our recent study on the polyamorphism of the liquid and glass states in a monatomic system, a two-scale spherical-symmetric Jagla model with both attractive and repulsive interactions. This potential with a parametrization for which crystallization can be avoided and both the glass transition and the liquid liquid phase transition are clearly separated, displays water-like anomalies as well as polyamorphism in both liquid and glassy states, providing a unique opportunity to study the interplay between the liquid-liquid phase transition and the glass transition. Our study on a simple model may be useful in understanding recent studies of polyamorphism in metallic glasses. PMID- 21614202 TI - Anti-tumor activity of a novel protein obtained from tartary buckwheat. AB - TBWSP31 is a novel antitumor protein that was isolated from tartary buckwheat water-soluble extracts. The objective of this paper was to investigate the anti proliferative effects of TBWSP31 on breast cancer Bcap37cells and to explore its possible mechanism. After treatment of Bcap37 cells with TBWSP31, typical apoptotic morphological changes were observed by inverted microscopy and scanning electron microscopy (SEM), such as detachment from the culture plate, change to a round shape, cell shrinkage, the absence of obvious microvilli, plasma membrane blebbing, and formation of apoptotic bodies. Cell-cycle analysis revealed that treatment with TBWSP31 resulted in a G(0)/G(1) arrest and prevented the cells from growing from G(0)/G(1) phase to S phase, which was most prominent at 48 h. The expression of bcl-2 and Fas were detected quantitatively by FCM, which showed that TBWSP31 induced-apoptosis may be involved with the participation of Fas and bcl-2. These results suggest that TBWSP31 is a potential antitumor compound and that apoptosis induced by TBWSP31 is a key antitumor mechanism. PMID- 21614204 TI - Differential expression of copper-zinc superoxide dismutase gene of Polygonum sibiricum leaves, stems and underground stems, subjected to high-salt stress. AB - In aerobic organisms, protection against oxidative damage involves the combined action of highly specialized antioxidant enzymes, such as copper-zinc superoxide dismutase. In this work, a cDNA clone which encodes a copper-zinc superoxide dismutase gene, named PS-CuZnSOD, has been identified from P. sibiricum Laxm. by the rapid amplification of cDNA ends method (RACE). Analysis of the nucleotide sequence reveals that the PS-CuZnSOD gene cDNA clone consists of 669 bp, containing 87 bp in the 5' untranslated region; 459 bp in the open reading frame (ORF) encoding 152 amino acids; and 123 bp in 3' untranslated region. The gene accession nucleotide sequence number in GenBank is GQ472846. Sequence analysis indicates that the protein, like most plant superoxide dismutases (SOD), includes two conserved ecCuZnSOD signatures that are from the amino acids 43 to 51, and from the amino acids 137 to 148, and it has a signal peptide extension in the front of the N-terminus (1-16 aa). Expression analysis by real-time quantitative PCR reveals that the PS-CuZnSOD gene is expressed in leaves, stems and underground stems. PS-CuZnSOD gene expression can be induced by 3% NaHCO(3). The different mRNA levels' expression of PS-CuZnSOD show the gene's different expression modes in leaves, stems and underground stems under the salinity alkalinity stress. PMID- 21614205 TI - Fe-chlorophyllin promotes the growth of wheat roots associated with nitric oxide generation. AB - Effects of Fe-chlorophyllin on the growth of wheat root were investigated in this study. We found that Fe-chlorophyllin can promote root growth. The production of nitric oxide in wheat root was detected using DAF-2DA fluorescent emission. The intensity of fluorescent in the presence of 0.1 mg/L Fe-chlorophyllin was near to that observed with the positive control of sodium nitroprusside (SNP), the nitric oxide donor. IAA oxidase activity decreased with all treatments of Fe chlorophyllin from 0.01 to 10 mg/L. At the relatively lower Fe-chlorophyllin concentration of 0.1 mg/L, the activity of IAA oxidase displayed a remarkable decrease, being 40.1% lower than the control. Meanwhile, Fe-chlorophyllin treatment could increase the activities of reactive oxygen scavenging enzymes, such as superoxide dismutase (SOD) and peroxidase (POD), as determined using non denaturing polyacrylamide gel electrophoresis. These results indicate that Fe chlorophyllin contributes to the growth of wheat root associated with nitric oxide generation. PMID- 21614203 TI - Deleted in malignant brain tumors-1 protein (DMBT1): a pattern recognition receptor with multiple binding sites. AB - Deleted in Malignant Brain Tumors-1 protein (DMBT1), salivary agglutinin (DMBT1(SAG)), and lung glycoprotein-340 (DMBT1(GP340)) are three names for glycoproteins encoded by the same DMBT1 gene. All these proteins belong to the scavenger receptor cysteine-rich (SRCR) superfamily of proteins: a superfamily of secreted or membrane-bound proteins with SRCR domains that are highly conserved down to sponges, the most ancient metazoa. In addition to SRCR domains, all DMBT1s contain two CUB domains and one zona pellucida domain. The SRCR domains play a role in the function of DMBT1s, which is the binding of a broad range of pathogens including cariogenic streptococci, Helicobacter pylori and HIV. Mucosal defense proteins like IgA, surfactant proteins and lactoferrin also bind to DMBT1s through their SRCR domains. The binding motif on the SRCR domains comprises an 11-mer peptide in which a few amino acids are essential for binding (GRVEVLYRGSW). Adjacent to each individual SRCR domain are glycosylation domains, where the attached carbohydrate chains play a role in the binding of influenza A virus and Helicobacter pylori. The composition of the carbohydrate chains is not only donor specific, but also varies between different organs. These data demonstrate a role for DMBT1s as pattern recognition molecules containing various peptide and carbohydrate binding motifs. PMID- 21614206 TI - In vitro response of retinal pigment epithelial cells exposed to chitosan materials prepared with different cross-linkers. AB - The interaction between cells and biopolymers is the evaluation indicator of the biocompatibility of materials. The purpose of this work was to examine the responses of retinal pigment epithelial (RPE) cells to genipin (GP) or glutaraldehyde (GTA) cross-linked chitosan by means of cell viability assays, cytokine expression analyses, and apoptosis assays. Evaluations of non-cross linked chitosan were conducted simultaneously for comparison. Both GP and GTA treated samples with the same extent of cross-linking (around 80%) were prepared by varying cross-linking time. Our results showed that GP cross-linking was carried out by either radical polymerization of the monomers or S(N)2 nucleophilic substitution reaction involving the replacement of the ester group on the monomer with a secondary amide linkage. On the other hand, GTA could react with free amino groups of chitosan, leading to the formation of either the Schiff bases or the Michael-type adducts with terminal aldehydes. The biocompatibility of non-cross-linked chitosan membranes was demonstrated by the absence of any signs of toxicity or inflammation reaction. The present study showed that the ARPE-19 cells exposed to GTA cross-linked chitosan membranes had significantly higher cytotoxicity, interleukin-6 levels, and number of TUNEL-positive nuclei than did those exposed to GP treated samples. In addition, the materials modified with GTA trigger apoptosis at an early stage and may induce toxicity in the RPE cells later. The findings suggest that while the chitosan molecules bridged by GP are satisfactorily cytocompatible, the counterparts treated by GTA do not seem to be tolerated. In terms of material safety, the GP cross-linked chitosan may be compatible with human RPE cells and may have a potential application as delivery carriers in the treatment of posterior segment diseases. PMID- 21614207 TI - Screening of molecular virulence markers in Staphylococcus aureus and Pseudomonas aeruginosa strains isolated from clinical infections. AB - Staphylococcus (S.) aureus and Pseudomonas (Ps.) aeruginosa are two of the most frequently opportunistic pathogens isolated in nosocomial infections, responsible for severe infections in immunocompromised hosts. The frequent emergence of antibiotic-resistant S. aureus and Ps. aeruginosa strains has determined the development of new strategies in order to elucidate the different mechanisms used by these bacteria at different stages of the infectious process, providing the scientists with new procedures for preventing, or at least improving, the control of S. aureus and Ps. aeruginosa infections. The purpose of this study was to characterize the molecular markers of virulence in S. aureus and Ps. aeruginosa strains isolated from different clinical specimens. We used multiplex and uniplex PCR assays to detect the genes encoding different cell-wall associated and extracellular virulence factors, in order to evaluate potential associations between the presence of putative virulence genes and the outcome of infections caused by these bacteria. Our results demonstrate that all the studied S. aureus and Ps. aeruginosa strains synthesize the majority of the investigated virulence determinants, probably responsible for different types of infections. PMID- 21614209 TI - Chronic mild stress induces fluoxetine-reversible decreases in hippocampal and cerebrospinal fluid levels of the neurotrophic factor S100B and its specific receptor. AB - Chronic mild stress (CMS) affects the hippocampal structure and function in the rat. S100B, a calcium-binding protein secreted by astrocytes, has been shown to be increased in serum of patients with depression and associated with good therapeutic response and clinical outcome. This work aimed to study the impact of CMS and fluoxetine on depressive-like behaviors in rats, as well as the concomitant expression of the astroglial protein S100B and of its receptor RAGE (receptor for advanced glycation end products) in the hippocampus and Cerebrospinal fluid of the same group of animals. S100B and sRAGE (circulating soluble form of RAGE) were measured in CSF by ELISA, and S100B and RAGE were measured in hippocampal slices by Western blot. Our study has demonstrated that stress and depression decrease S100B and RAGE/SRAGE expression and antidepressant treatment reverses or blocks these effects. This result suggested that S100B/RAGE interactions may be involved in the development and maintenance of depression and may play an important role in the mechanism of antidepressants' therapeutic action. PMID- 21614208 TI - Intrinsically disordered proteins in a physics-based world. AB - Intrinsically disordered proteins (IDPs) are a newly recognized class of functional proteins that rely on a lack of stable structure for function. They are highly prevalent in biology, play fundamental roles, and are extensively involved in human diseases. For signaling and regulation, IDPs often fold into stable structures upon binding to specific targets. The mechanisms of these coupled binding and folding processes are of significant importance because they underlie the organization of regulatory networks that dictate various aspects of cellular decision-making. This review first discusses the challenge in detailed experimental characterization of these heterogeneous and dynamics proteins and the unique and exciting opportunity for physics-based modeling to make crucial contributions, and then summarizes key lessons from recent de novo simulations of the structure and interactions of several regulatory IDPs. PMID- 21614210 TI - Antiproliferative effects of cucurbitacin B in breast cancer cells: down regulation of the c-Myc/hTERT/telomerase pathway and obstruction of the cell cycle. AB - Naturally occurring cucurbitacins have been shown to have anticancer, antimicrobial and anti-inflammatory activities. In this study, we determined the effects of cucurbitacin B extracted from the Thai herb Trichosanthes cucumerina L. on telomerase regulation in three human breast cancer cell lines (T47D, SKBR 3, and MCF-7) and a mammary epithelium cell line (HBL-100). Cell viability after treatment with cucurbitacin B, which is an active ingredient of this herb, was assessed. Telomeric Repeat Amplification Protocol (TRAP) assays and RT-PCR (qualitative and realtime) were performed to investigate activity of telomerase as well as expression of human telomerase reverse transcriptase (hTERT) and c Myc. The c-Myc protein level was also determined in SKBR-3 and HBL-100 cells. Our results show that the cucurbitacin B inhibits growth and telomerase activity in the three breast cancer cell lines and exerts an obvious inhibitory effect in the estrogen receptor (ER)-negative breast cancer SKBR-3 cells. The expression of hTERT and c-Myc were also inhibited by cucurbitacin B, In addition, a clear reduction of c-Myc protein was observed after treatment in SKBR-3 cells even with a concentration of cucurbitacin B that was ten-times lower compared to the concentration used for HBL-100. Our findings imply that cucurbitacin B exerts an anticancer effect by inhibiting telomerase via down regulating both the hTERT and c-Myc expression in breast cancer cells. PMID- 21614211 TI - Mouse plasminogen has oxidized phosphatidylcholine adducts that are not metabolized by lipoprotein-associated phospholipase A2under basal conditions. AB - We previously showed that plasminogen (Plg) isolated from the plasma of normal human subjects contains 1-2 moles of oxidized phosphatidylcholine (oxPtdPC) adducts/mole of protein. Moreover, we suggested that these species are generated at the hepatic site and speculated that they may play a role in the reported cardiovascular pathogenicity of Plg. We aimed to determine whether mouse Plg also harbors linked oxPtdPCs and whether these molecules are metabolized by lipoprotein-associated phospholipase A(2)/PAF acetylhydrolase (Lp-PLA(2)/PAF-AH), an enzyme specific for hydrolysis of oxPtdPCs. We determined the total concentration of Plg in plasma samples from control (WT) and Lp-PLA(2)-deficient (KO) mice, we isolated Plg, and assessed its content of oxPtdPCs by immunoblot analyses. We also evaluated whether human recombinant Lp-PLA(2) metabolized Plg linked oxPtdPCs in vivo and in vitro. WT and KO mice expressed comparable levels (14.4-15.8 mg/dL) of plasma Plg, as determined by ELISA. We observed no differences in the content of oxPtdPC in Plg isolated from the two mouse strains and in parallel no changes in oxPtdPC content in mouse Plg following incubation with pure recombinant Lp-PLA(2). Plg from mouse plasma contains oxPtdPC adducts that are not affected by the action of Lp-PLA(2), suggesting that linkage to Plg protects oxPtdPCs from metabolism during their transport in the plasma. This modification may have important physio-pathological implications related to the function of Plg, oxPtdPCs, or both. PMID- 21614212 TI - Associations between music education, intelligence, and spelling ability in elementary school. AB - Musical education has a beneficial effect on higher cognitive functions, but questions arise whether associations between music lessons and cognitive abilities are specific to a domain or general. We tested 194 boys in Grade 3 by measuring reading and spelling performance, non verbal intelligence and asked parents about musical activities since preschool. Questionnaire data showed that 53% of the boys had learned to play a musical instrument. Intelligence was higher for boys playing an instrument (p < .001). To control for unspecific effects we excluded families without instruments. The effect on intelligence remained (p < .05). Furthermore, boys playing an instrument showed better performance in spelling compared to the boys who were not playing, despite family members with instruments (p < .01). This effect was observed independently of IQ. Our findings suggest an association between music education and general cognitive ability as well as a specific language link. PMID- 21614213 TI - "What goes round comes round". PMID- 21614214 TI - Commissioning and evaluation of a new commercial small rodent x-ray irradiator. AB - An appropriate radiation source is essential in studies of tissue response in animal models. This paper reports on the evaluation and commissioning of a new irradiator suitable for studies using small animals or cell culture. The Faxitron is a 160-kVp x-ray machine that was adapted from an x-ray imaging unit through modifications to facilitate experimental irradiation. The x-ray unit is housed in a shielded cabinet, and is configured to allow multiple irradiation positions and a range of field sizes and dose rates. Use of this machine for animal irradiation requires characterisation of relevant dosimetry, and development of methodology for secondary beam collimation and animal immobilisation. In addition, due to the limitation of the irradiator, the optimal selection of three characteristics of the x-ray beam is important. These three characteristics, namely, the dose rate, the beam uniformity, and the field size are inter-dependent and the selection of a combination of these parameters is often a compromise and is dependent on the application. Two different types of experiments are selected to illustrate the applicability of the Faxitron. The Faxitron could be useful for experimental animal irradiation if the experimental design is carried out carefully to ensure that accurate and uniform radiation is delivered. PMID- 21614215 TI - Modified Fletcher's 3-channel brachytherapy system with vaginal line source loading versus uterine tandem and vaginal cylinder system in Stage IIIA cervical cancer. AB - PURPOSE: The uterine tandem with open-ended vaginal cylinder is the most commonly used brachytherapy system for Federation Internationale de Gynecologie et d'Obstetrique (FIGO) Stage IIIA cervix cancer at the National Cancer Centre, Singapore. Without the 3-channel ovoid system, the dose to the parametrium is often compromised. In this study, a vaginal cylinder that could potentially be incorporated with the 3-channel system was developed, hence addressing the problem of treating both the vaginal disease extension and the parametrium. METHODS AND MATERIALS: A hollow cylinder of 3 cm in diameter was incorporated with the Fletcher's 3-channel tandem and ovoid system. Treatment plans were generated with the single tandem line source with a vaginal cylinder applicator and the modified Fletcher's system using the Abacus version 3 brachytherapy treatment planning software. A nominal dose of 5 Gy was prescribed to point H for both plans. The perpendicular distance of the 5 Gy isodose line from the uterine tandem plane at the centre of the ovoid and the vaginal cylinder plane 1 cm below the os guard were then compared. RESULTS: The 5 Gy isodose line was 1.7 cm from the uterine tandem source at the location lateral through the centre of the ovoids on the plan with the uterine tandem and vaginal cylinder system as compared to a distance of 3.3 cm using the modified 3-channel Fletcher system. The 5 Gy isodose line was 2 cm lateral to the central source at the vaginal cylinder plane 1 cm below the os guard on the uterine tandem and vaginal cylinder system as compared to a distance of 2.5 cm on the Modified-Fletcher system. This corresponds to an increase of 1.6 cm and 0.5 cm depth of treated parametrium on the uterine tandem plane and vaginal cylinder plane respectively with the modified Fletcher's applicator as compared with the single line source cylinder system. CONCLUSION: As compared with the single uterine tandem and open-ended vaginal cylinder system, an addition of 1.6 cm of the parametrium was covered within the 5Gy isodose on the uterine tandem plane and 0.5 cm on the vaginal cylinder plane with the modified Fletcher's applicator. A feasibility study was started to address the ease of insertion of this modified Fletcher system into patients. PMID- 21614216 TI - Clinical oncology in Malaysia: 1914 to present. AB - A narration of the development of staff, infrastructure and buildings in the various parts of the country is given in this paper. The role of universities and other institutions of learning, public health, palliative care, nuclear medicine and cancer registries is described together with the networking that has been developed between the government, non-governmental organisations and private hospitals. The training of skilled manpower and the commencement of the Master of Clinical Oncology in the University of Malaya is highlighted. Efforts taken to improve the various aspects of cancer control which includes prevention of cancer, early detection, treatment and palliative care are covered. It is vital to ensure that cancer care services must be accessible and affordable throughout the entire health system, from the primary care level up to the centres for tertiary care, throughout the whole country. PMID- 21614218 TI - Conformal radiotherapy and molecular imaging: complementary technologies in cancer therapy. PMID- 21614217 TI - Intensity modulated radiotherapy: advantages, limitations and future developments. AB - Intensity modulated radiotherapy (IMRT) is widely used in clinical applications in developed countries, for the treatment of malignant and non-malignant diseases. This technique uses multiple radiation beams of non-uniform intensities. The beams are modulated to the required intensity maps for delivering highly conformal doses of radiation to the treatment targets, while sparing the adjacent normal tissue structures. This treatment technique has superior dosimetric advantages over 2-dimensional (2D) and conventional 3 dimensional conformal radiotherapy (3DCRT) treatments. It can potentially benefit the patient in three ways. First, by improving conformity with target dose it can reduce the probability of in-field recurrence. Second, by reducing irradiation of normal tissue it can minimise the degree of morbidity associated with treatment. Third, by facilitating escalation of dose it can improve local control. Early clinical results are promising, particularly in the treatment of nasopharyngeal carcinoma (NPC). However, as the IMRT is a sophisticated treatment involving high conformity and high precision, it has specific requirements. Therefore, tight tolerance levels for random and systematic errors, compared with conventional 2D and 3D treatments, must be applied in all treatment and pre-treatment procedures. For this reason, a large-scale routine clinical implementation of the treatment modality demands major resources and, in some cases, is impractical. This paper will provide an overview of the potential advantages of the IMRT, methods of treatment delivery, and equipment currently available for facilitating the treatment modality. It will also discuss the limitations of the equipment and the ongoing development work to improve the efficiency of the equipment and the treatment techniques and procedures. PMID- 21614219 TI - Update on clinical radiobiology. AB - Radiation therapy is an important local cytotoxic modality for cancer treatment whose aim is to control the disease while minimising damage to normal tissue. The combination of different treatment modalities offers a more effective cure and reduction in normal tissue toxicity. However, the differences in genetic profiles can cause diverse treatment outcomes. Multidisciplinary research, where technologies and knowledge from different areas are integrated, is necessary to design the optimal regimen for individualised cancer treatment. This paper offers an overview of some new cancer treatment strategies; the impact of molecular imaging on radiation oncology; and a computer simulation model to optimise treatment planning based on patient information. It briefly discusses molecular targeted therapy, tumour microenvironment and bioreductive agents, and evidence for making individualised medicine a reality. Using DNA microarrays and proteomic technologies, information on defined molecular targets and genetic profiling for individual patients can be obtained and new algorithms for radiation oncology related diagnosis, treatment response and prognosis can be developed. PMID- 21614220 TI - Preventing tuberculosis in healthcare workers of the radiology department: a Malaysian perspective. AB - Tuberculosis (TB) is a well recognised occupational hazard for healthcare workers (HCWs). Concerns on the safety of healthcare settings in Malaysia was raised following a report of 25 HCWs working in 11 general hospitals in Malaysia who were infected with TB in 2004 being publicised in the media recently. As the disease burden in general is high in Malaysia, due attention should be given to this disease in our healthcare facilities including the radiology department, an often neglected area in TB infection control programmes. This article focuses on the key control measures that can be implemented in radiology departments in a developing country with limited resources. PMID- 21614221 TI - Image file formats. PMID- 21614222 TI - Adrenal carcinoma. PMID- 21614223 TI - Spiral CT angiography in an infant with a hypoplastic aortic arch. AB - The advent of multislice computed tomography (CT) has revolutionised the performance of body CT and allowed the development of CT angiography (CTA). CTA is a robust and minimally invasive method of visualizing the arterial vascular system. The newer generation of multidetector scans has allowed for shorter scanning times with no respiratory misregistration at peak vascular opacification following peripheral contrast injection. The volume of data obtained from these scans can be further manipulated to generate two-dimensional (2D) and three dimensional (3D) images with no increase in radiation to the patient. Hence, CTA has gained popularity and importance as the alternative diagnostic tool especially for ill patients in which conventional angiography is inadvisable.We present an infant with coarctation of the aorta and hypoplastic aortic arch, in which CT angiography was used to pinpoint the diagnosis. The CT findings were subsequently confirmed at surgery. PMID- 21614224 TI - Diffusion weighted MR imaging in acute vertebral compression fractures: differentiation between malignant and benign causes. AB - AIM: The primary objective of this study was to evaluate the specificity and sensitivity of diffusion weighted MR imaging (DWI) in the differentiation and characterisation between benign and malignant vertebral compression fractures compared with conventional T1 WI, T2 WI and fat suppressed contrast enhanced T1 WI in the Malaysian population. MATERIALS AND METHODS: Thirty five patients with 68 vertebral compression fractures were imaged using the conventional T1 WI, T2 WI, fat suppressed contrast enhanced T1-weighted, and steady state free precession diffusion-weighted (SSFP DWI) sequences on a 1.5 T MR scanner. Signal intensities were analysed qualitatively for all the sequences by comparison to adjacent normal marrow. A quantitative assessment of the signal intensity in the SSFP DWI was also performed. RESULTS: T1 WI and T2 WI images are of limited diagnostic value because of the variability in signal intensities. Contrast enhanced images had sensitivity and specificity of 93% and 71%, respectively with a negative predictive value (NPV) of 93%. On diffusion-weighted MR imaging, sensitivity was 87% with specificity of 92%. The positive predicative value (PPV) and NPV were both 90%. The quantitative assessment of ratio revealed a statistical significant difference between the benign (0.96) and the malignant (1.73) group of lesion (Mann-Whitney U-test, p=0.0001). CONCLUSIONS: We found that absence of contrast enhancement has a high NPV (90%) while SSFP DWI has both a high PPV (90%) and high NPV (90%) in detecting malignant vertebral compression fractures. Furthermore, in our study the ratio of lesion intensity technique offers an excellent criterion to differentiate between the benign and malignant lesions, and the presence of iso- or hypointensity of the collapsed vertebral bodies is suggestive of a benign lesion while hyperintensity is highly suggestive of malignancy. We also found that using the NLMR showed a statistical significant difference between the malignant and benign groups (p<0.0001) with osteoporotic and malignant lesions have mean values of 0.96 (SD 0.25) and 1.73 (SD 0.4) respectively. PMID- 21614225 TI - Spontaneous internal ilio-iliac fistula in an elderly woman presenting as heart failure. AB - Acquired intra-abdominal arteriovenous fistulas (AVFs) are a rare disorder where the communication most commonly occurs between abdominal aorta and inferior vena cava. Ilio-iliac AVF has been reported previously, but is exceedingly rare. We present a case of spontaneous ilio-iliac AVF in an elderly woman who presented with symptoms of right heart failure where the diagnosis was not considered. The computed tomographic (CT) and angiographic features are described. The current status of management as well as a review of the literature is also presented. PMID- 21614226 TI - CT perfusion as a useful tool in the evaluation of leuko-araiosis. AB - BACKGROUND: Leuko-araiosis (LA) and dementia are common geriatric conditions but their pathogenesis and clinical significance are not completely understood. An evaluation of CT perfusion (CTP) in both these conditions can further enhance the understanding of these diseases. METHODS: Twenty-one patients with LA and 21 age matched controls were studied with CTP and assessed for their cognitive function. The subjects were classified into four groups: Group 1, with LA (n = 21); Group 2, without LA (n = 21); Group 3, with dementia (n = 7); Group 4, without dementia (n = 11). The mean cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) values were compared between groups 1 and 2, while mean CBF values were compared between groups 3 and 4. RESULTS: Mean white matter CBF was considerably reduced in patients with LA in the frontal region by 42% (p = 0.000), basal ganglia by 37% (p = 0.000) and occipital region by 18% (p = 0.019). The mean white matter CBV was reduced in patients with LA in the frontal region by 36% (p = 0.000) and basal ganglia by 28% (p = 0.017). The mean white matter CBF was dramatically reduced in patients with dementia in the frontal region by 44% (p = 0.000), basal ganglia by 32% (p = 0.038) and occipital regions by 24% (p = 0.001). CONCLUSION: The CTP showed reduced white matter CBF and CBV in patients with LA. This is consistent with chronic ischemia as the pathogenesis of LA. The CTP is also a potentially important technique in the diagnosis and management of dementia, because of its ability to reveal cerebral hypoperfusion. PMID- 21614227 TI - Ultrasound of living donor liver transplantation. AB - Liver transplantation is the most effective treatment for various end-stage liver diseases. Living donor liver transplantation (LDLT) was first developed in Asia due to the severe lack of cadaveric graft in this region. The Liver Transplant Service at Queen Mary Hospital (QMH), Hong Kong, has pioneered the application of LDLT to patients using both left lobe and right lobe grafts. The QMH liver transplant programme is the largest of its kind in China and Southeast Asia.Ultrasound (US) is often employed in the initial work-up of potential donor and recipient of LDLT. It is the imaging technique of choice to assess the early and late complications of LDLT, with colour Doppler ultrasound being the most useful in the evaluation of post-LDLT vascular complications. The use of ultrasound contrast agents improves the visualisation of the hepatic vasculature, possibly delaying or removing the need for more invasive investigations. Intra operative ultrasound facilitates the determination of the resection plane during donor hepactectomy.Computed tomography (CT) or magnetic resonance imaging (MRI) can be used as the single imaging modality in the evaluation of LDLT candidates.Ultrasound is most useful as the initial screening test in detecting hepatic parenchymal abnormalities, while CT or MRI is the modality of choice in the demonstration of vascular and biliary anatomy of the potential liver donor.Biliary complications are more common in LDLT than in cadaveric liver transplantation. The ductal dilatation, resulting from biliary stricture, is clearly demonstrated by ultrasound. Bilomas can be aspirated under ultrasound guidance to confirm the diagnosis and to promote healing. Perihepatic fluid collections and abscesses are also common after LDLT. Intra-hepatic collections may represent seromas, haematomas or infarction. Ultrasound is a sensitive means of detecting these collections and can be employed to guide drainage in suitable patients.Transplant-related malignancies include recurrent neoplasia and post transplant lymphoproliferative disease (PTLD). Ultrasound can be used to screen for recurrent disease and to detect PTLD in the transplanted liver. PMID- 21614228 TI - Imaging features of fungal infection in immuno-suppressed patients in a local ward outbreak. AB - PURPOSE OF STUDY: To examine the role of imaging in diagnosing and assessing fungal infections in paediatric patients undergoing chemotherapy in a facility, which had high fungal air contamination due to adjacent building construction work. MATERIALS AND METHOD: Nineteen patients aged five months to 12 years with various malignancies, mainly leukaemia, along with probable fungal infection were referred for imaging over a period of 12 months. The imaging findings from their CT and chest radiographs were reviewed by two radiologists and correlated with the clinical findings. Blood culture and/or biopsy of relevant lesions were performed for all patients. RESULTS: Fungus was positively isolated in 11 out of 19 patients, but the remaining patients clinically had fungal infection. The most common species isolated was Candida sp. (five patients), followed by Aspergillus sp. The most common site of fungal infection was the lungs (10 out of 19 patients), where consolidation or cavitating nodules were seen on CT or the plain chest radiograph. One patient developed pulmonary artery aneurysm as a complication. The other sites affected were the intra-abdominal organs (liver, kidneys, and spleen) and the paranasal sinuses, shown on CT. Two patients with clinical evidence of infection and Candida sp. isolated from their blood, however, showed no abnormal findings on imaging. CONCLUSION: Early diagnosis of fungal infections in oncology patients undergoing chemotherapy is important, but diagnosis may be difficult through imaging because of the non-specific changes and the presence of abnormalities from the underlying disease. Even if a specific diagnosis cannot be reached, imaging is useful to monitor response to treatment and detect complications. PMID- 21614229 TI - Assessment of electrical impedance endotomography for hardware specification. AB - PURPOSE: The purpose of the study is the quantitative assessment of Electrical Impedance Endotomography (EIE) for the specification of hardware systems. EIE is a modality of Electrical Impedance Tomography (EIT) where the electrodes are located on a probe placed in the middle of the region of interest. The absence of material boundary to the explored volume and the decrease in sensitivity away from the probe requires specific study. MATERIAL AND METHODS: The method is the derivation of the equation linking explored medium's conductivity, the sensitivity distribution of the electrode patterns used for data collection and measuring system's noise and bandwidth. The assessment of EIE was achieved by means of simulations based on realistic data of conductivity and noise level. RESULTS: The derived equation enabled the estimation of the current needed under realistic operating conditions corresponding to prostate imaging. The generalisation to other organs is straightforward. The image reconstructed from the simulated data and from bench experiments were in agreement and showed that the two selected drive patterns, fan3 and adjacent, gave images of similar quality in absence of noise and that adjacent drive requires significantly higher measurement current. CONCLUSION: The study confirmed the feasibility of EIE with achievable hardware specifications. The derived equation enabled the determination of design parameters for the specification of hardware systems corresponding to any given application. The study also showed that EIE is more appropriate for tissue characterisation than for high speed imaging. PMID- 21614230 TI - Delivering cancer services: a multi-disciplinary approach. PMID- 21614231 TI - Creating animated medical images (Part 1). PMID- 21614232 TI - Phyllodes tumour of the breast. PMID- 21614233 TI - High dose rate (HDR) brachytherapy quality assurance: a practical guide. AB - The widespread adoption of high dose rate brachytherapy with its inherent dangers necessitates adoption of appropriate quality assurance measures to minimize risks to both patients and medical staff. This paper is aimed at assisting someone who is establishing a new program or revising one already in place into adhere to the recently issued Nuclear Regulatory Commission (USA) regulations and the guidelines from the American Association of Physicists in Medicine. PMID- 21614234 TI - A successful first year: taking stock and looking ahead. PMID- 21614235 TI - Electronic teaching files and continuing professional development in radiology. AB - Education in diagnostic radiology employs medical images extensively, and case based teaching files of actual patients are useful to illustrate pertinent teaching points. In the era of digital radiology, there is great potential to use the ready source of patient material from Picture Archive and Communication Systems (PACS) and initiatives such as Medical Imaging Resource Center (MIRC) on the World Wide Web for teaching and for Continuing Professional Development (CPD). As mandatory CPD becomes the reality in medical practice, computerised solutions that support the creation of electronic teaching files in the midst of busy clinical workflow would be very valuable. This paper will explore the features of image-based CPD, the various ways in which medical images can be used for self directed learning and the challenges that face the radiology profession. PMID- 21614236 TI - Molecular magnetic resonance imaging. AB - Molecular MRI (mMRI) is a special implementation of Molecular Imaging for the non invasive visualisation of biological processes at the cellular and molecular level. More specifically, mMRI comprises the contrast agent-mediated alteration of tissue relaxation times for the detection and localisation of molecular disease markers (such as cell surface receptors, enzymes or signaling molecules), cells (e.g. lymphocytes, stem cells) or therapeutic drugs (e.g. liposomes, viral particles). MRI yields topographical, anatomical maps; functional MRI (fMRI) provides rendering of physiologic functions and magnetic resonance spectroscopy (MRS) reveals the distribution patterns of some specific metabolites. mMRI provides an additional level of information at the molecular or cellular level, thus extending MRI further beyond the anatomical and physiological level. These advances brought by mMRI are mandatory for MRI to be competitive in the age of molecular medicine. mMRI is already today increasingly used for research purposes, e.g. to facilitate the examination of cell migration, angiogenesis, apoptosis or gene expression in living organisms. In medical diagnostics, mMRI will pave the way toward a significant improvement in early detection of disease, therapy planning or monitoring of outcome and will therefore bring significant improvement in the medical treatment for patients.In general, Molecular Imaging demands high sensitivity equipment, capable of quantitative measurements to detect probes that interact with targets at the pico- or nanomolar level. The challenge to detect such sparse targets can be exemplified with cell surface receptors, a common target for molecular imaging. At high expression levels (bigger than 106 per cell) the receptor concentration is approx. 10(15) per ml, i.e. the concentration is in the micromole range. Many targets, however, are expressed in even considerably lower concentrations. Therefore the most sensitive modalities, namely nuclear imaging (PET and SPECT) have always been at the forefront of Molecular Imaging, and many nuclear probes in clinical use today are already designed to detect molecular mechanisms (such as FDG, detecting high glucose metabolism). In recent years however, Molecular Imaging has commanded attention from beyond the field of nuclear medicine. Further imaging modalities to be considered for molecular imaging primarily include optical imaging, MRI and ultrasound. PMID- 21614237 TI - Benign teratoma of the liver: a rare cause of cholangitis. AB - Teratomas are neoplasms characterised by an abnormal growth of tissues derived from the three germinal layers. The term 'teratoma' is derived from the Greek root 'teratos', meaning monster. Germ cells develop in the embryo and subsequently become the cells that make up the reproductive system. During fetal development, these cells follow a midline path and descend into the pelvis as ovarian cells or the scrotal sac as testicular cells. The presence of germ cells in extragonadal sites is because of the failure of these cells to migrate along the urogenital ridge. Therefore, teratomas occur in order of decreasing frequency in the ovaries, testes, anterior mediastinum, retroperitoneum, sacrococcygeal region and cranium.Liver teratomas are very rare; of the 25 hepatic teratomas described in the literature, only five have occurred in adults. The majority of the cases were in female children below the age of three, mostly arising in the right lobe of liver.We report a case of an adult male with benign mature teratoma arising in the left lobe of liver, compressing the common bile duct and causing obstructive jaundice. PMID- 21614238 TI - Radioimmunotherapy: a brief overview. AB - With the advent of biotechnological advances and knowledge of molecular and cellular biology, radioimmunotherapy (RIT) has become a highly promising oncologic therapeutic modality with established clinically efficacy, particularly in non-Hodgkin's lymphomas. This paper provides a short survey of the basic science of RIT and the various monoclonal antibodies and radionuclides used. A brief review of the published literature on the clinical applications of radioimmunotherapy, particularly in non-Hodgkin's lymphoma, is provided. New research data indicate many potential areas of development of this modality, including haematological and solid-organ radioimmunotherapy as well as new radionuclidic approaches and clinical protocols. PMID- 21614239 TI - CT-guided percutaneous biopsy of spinal lesions. AB - Accurate diagnosis of spine lesions is important for its successful management. Imaging-guided percutaneous biopsy is gaining increasing acceptance as a means for obtaining tissue for diagnosis. Most biopsies can be rapidly performed under local anaesthesia, with little patient discomfort and improved safety. Spinal anatomy is, however, complex with many adjacent vital structures. Good knowledge of anatomy and precise needling technique is, therefore, important. Today, biopsy of spinal lesions is best performed under computed tomography (CT) fluoroscopic guidance. Indications for imaging-guided biopsy include confirming metastasis in a patient with a known primary tumour, determining the nature of a solitary bone lesion, excluding malignancy in vertebral body compression, and investigating for infection. Among the various issues to be considered are site of lesion, location of adjacent vital structures, approach, and type and size of needle. Complications are rare, particularly when a meticulous technique is applied. In summary, CT-guided percutaneous biopsy is a safe and an effective technique for the evaluation of spinal lesions and useful in planning therapy. PMID- 21614240 TI - CT appearances of Marjolin's ulcer in the left gluteal region of a young man. AB - Chronic wounds and scar tissues are prone to skin cancer. In 1828, Jean-Nicholas Marjolin described the occurrence of tumours in post-traumatic scar tissue. He did not, however, identify the warty ulcers he described as malignant. It was Dupuytren, who about two years later, noted that these lesions were cancerous. The eponym was bestowed by Da Costa in 1903. Marjolin's ulcer no longer refers only to carcinomas secondary to burns and is classified as a malignancy that arises from previously traumatised, chronically inflamed, or scarred skin. It has been reported in relation to osteomyelitis, venous stasis ulcer, tropical ulcers, chronic decubitus ulcer, frostbite, pilonidal sinus, vaccination site, urinary fistula, hidradenitis suppurativa, skin graft donor site, gunshot wounds, puncture wounds, dog bites, and lupus rash. Early arising Marjolin's ulcer has rarely been described in literature. In this case report, we present the CT appearances of Marjolin's ulcer in the left gluteal region of a young man. PMID- 21614241 TI - Effects of single-trial averaging on spatial extent of brain activation detected by fMRI are subject and task dependent. AB - AIM: The effects of single-trial averaging on the spatial extent of event-related fMRI activation may vary between subjects and tasks. The purpose of this study was to evaluate this variability using a visual task and a word generation task. PATIENTS, MATERIALS, AND METHODS: Five Chinese right-handed male volunteers participated in the experiment. Experiments were conducted using a 1.5 T clinical MRI scanner with a T2*-weighted single-shot gradient-echo EPI sequence. Each task contained 150 trials that were separated into 5 runs. For each voxel, time courses averaged across different numbers of randomly selected trials, were obtained. They were applied for determining the voxels with significant activations, using a students' t-test (p<0.001, uncorrected). RESULTS: Consistent with previous findings, the number of the activated voxels increased monotonically with the number of trials combined. The ascending rate and the maximum number of the activated voxels were different, however, between tasks and among subjects. CONCLUSIONS: The effects of single-trial averaging were found to vary significantly between tasks and subjects. Therefore, we strongly advise to carefully consider such variability when using the spatial extent of activation as a measure in a group or a task comparison. PMID- 21614242 TI - The sky is falling. PMID- 21614243 TI - Haemorrhaging lesion in the breast: is there a role for embolisation? AB - Angiosarcoma of the breast is an extremely rare condition. This case illustrates the use of embolisation as a modality of treatment for primary breast angiosarcoma. No other case has been reported on the use of embolisation for this disorder. PMID- 21614244 TI - Evaluation of radiation dose and image quality following changes to tube potential (kVp) in conventional paediatric chest radiography. AB - PURPOSE: A study of radiation dose and image quality following changes to the tube potential (kVp) in paediatric chest radiography. MATERIALS AND METHOD: A total of 109 patients ranging from 1 month to 15 years were included in two phases of the study. Phase 1 investigated the range of entrance surface air kerma (ESAK) values received from patients exposed to the existing exposure factors. In the second phase, new exposure factors using recommended values of tube potential (kVp) with reduced mAs were used. ESAK values were measured using thermoluminescent dosemeters (TLDs). Image quality in both phases was evaluated using image quality criteria proposed by the Council of the European Communities (CEC). Results of both techniques were analysed for any differences. RESULTS: The overall mean ESAK before the changes was 0.22 mGy (range: 0.05-0.43) Following changes in tube potential, the overall mean reduced to 0.15 mGy (range: 0.03 0.38), a significant reduction by 34%. The interquartile range was reduced from 45% to 40%. However, doses to those below a year in age still remained high. Assessment of image quality was found to have no significant differences as far as the two techniques used were concerned. However, higher image scores were achieved using higher kVps. CONCLUSION: Significant dose reduction was achieved through appropriate changes in tube potential and reduction of mAs without any loss in image quality. PMID- 21614245 TI - Axillary lymphoma masquerading as inflammatory breast cancer. AB - Primary non-Hodgkins lymphoma (NHL) of the breast, and its extranodal spread to the breast resulting from systemic lymphoma, are recognised albeit uncommon conditions. However, lymphoma involving the axilla, presenting with the clinical appearance of inflammatory breast carcinoma (IBC) without infiltration of breast dermal lymphatics has not been reported previously.As highlighted by the two cases presented here, this entity should be considered in the differential diagnosis of patients presenting with clinical IBC. The cases highlight the importance of careful histological analysis to distinguish IBC from NHL, since management strategies and prognosis are quite different. PMID- 21614246 TI - Development of a randomised contrast detail digital phantom for observer detectability study. AB - The accuracy and the efficacy of radiological diagnosis depend, to a large extent, on the conditions under which radiographs and images are viewed. This mainly involves the luminance of the display devices and the ambient room illumination. We report a perceptual study to investigate the relationship between detectability and monitor luminance as well as ambient illuminance. A statistical test pattern was used in this study, and the test pattern was developed using Microsoft(r) Visual Basic 6. The test pattern contained a set of randomised contrast detail objects, that is, disks of different diameters (0.7, 1.0, 1.4, and 2.0 mm) and contrasts against a black background (2.7, 3.9, 5.5, and 7.8%), simulating lesions in digital images. The receiver operating characteristic (ROC) analysis was used in this study. The results indicated that a set of optimal viewing conditions exists and that it has a significant effect on detectability performance. PMID- 21614247 TI - Radiofrequency ablation of lung tumours. AB - Radiofrequency ablation (RFA) is a well-established local therapy for hepatic malignancies. It is rapidly emerging as an effective treatment modality for small lesions elsewhere in the body, in particular, the kidney and the lung. It is a relatively safe and minimally invasive treatment for small lung malignancies, both primary and secondary. In particular, it is the preferred form of treatment for non-surgical candidates.This paper describes the technique employed for radiofrequency ablation of lung tumours, as well as the protocol established, at the Mount Elizabeth Hospital, Singapore. PMID- 21614248 TI - Radionuclide therapy of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a malignant tumour of the hepatocyte. It is a common malignancy worldwide and causes almost half a million deaths annually. Asia is a high risk area. Although surgery (hepatectomy or liver transplantation) is the main form of curative treatment, the majority of patients are not eligible for surgery due to extent of tumour and dysfunction of liver. Radiopharmaceuticals used for transarterial treatment of HCC were Yttrium-90 microspheres, Iodine-131 lipiodol, Rhenium-188 lipiodol, and Holmium-166 Chitosan complex. Yittrium-90 microspheres are glass or resin microspheres of mean sphere diameter of 20 to 30 micrometre. The activity administered was about 4 GBq. Reported response rate was about 20%, and median survival was 54 weeks. On inoperable tumours, reported objective response of I-131 lipiodol was 40 to 70%, and median survival was six to nine months. It showed efficacy similar to TACE. In adjuvant treatment following curative resection of HCC, reported three year survival was 86% compared with 46% for the control group. The administered activity in both adjuvant and inoperable HCC was about 2 GBq (55 mCi). Rhenium 188 lipiodol is a new radioconjugate, and using it we treated 70 patients with inoperable HCC. This treatment was a part of a multi-centre trial sponsored by the International Atomic Energy Agency. Partial response was obtained in 17% of cases, while 49% had stable disease at three months, and 34% showed disease progression. In terms of survival, 19% survived one year, 60% for six months, and 90% for three months. The mean activity was about 4.6 GBq (124 mCi). This method was safe and free from adverse effects. PMID- 21614249 TI - Radiologists in the IT era: the Saitama experience. AB - In recent years, intra-hospital computerisation including picture archiving and communication system (PACS) and electronic medical chart system (EMCS) has been rapidly introduced in Japan. The current system has, however, encountered many problems, such as, storage format of images, quality of diagnostic monitors, and compatibility of PACS and EMCS introduced by multi-vendors. In 2003, Saitama Medical University Hospital introduced PACS and EMCS, which can prevent inconsistency and loss of medical care information and can be linked to provide high quality medical care. This paper describes how radiologists should be involved in a hospital information system as specialists of PACS, based on our experience. PMID- 21614250 TI - Trans-arterial hepatic radioembolisation of yttrium-90 microspheres. AB - The liver represents a frequent site for metastatic disease, in addition to being a site for primary cancer. Hepatic metastases from certain neoplasms, such as colon, neuroendocrine, melanoma and gastrointestinal stromal tumour have a distinct predilection to metastasize the liver, which in many cases may represent the only or the dominant site of disease. In these circumstances, cytoreduction via surgery or in situ ablative techniques aims to influence the natural history of the disease progression and improve clinical outcomes.Liver directed therapy utilising yttrium-90 microspheres represents a recently introduced in situ multidisciplinary cancer therapy that has caught the attention of many physicians faced with the challenges of treating these complex patients. Although similar to other forms of trans-arterial liver directed therapy, there are discrete differences and potentially fatal treatment consequences unique to this therapy. This objective of this review article is to provide the reader a basis for understanding the therapeutic principles, patient exclusion criteria, pre and post therapy investigations and salient clinical results in the two most commonly treated disease types; metastatic colorectal cancer and hepatocellular cancer. PMID- 21614251 TI - Creating animated medical images (Part 2). PMID- 21614252 TI - A new approach towards volumetric assessment of left ventricular function with MSCT. AB - Cardiovascular CT is considered the diagnostic standard for establishing the presence of a functional and dynamic imaging system. It is difficult, however, to estimate the ventricular motion and volumes that are processed using hundreds and thousands of CT images, in a few moments.The main concept and design of our work are two fold - the development of effective semi-automatic tools for measuring the sequential left ventricular volumes from the hundreds or thousands of cardiac trans-axial images, and providing a simple interface with an interactive diagnostic tool for the volumetry of left ventricle and valuable cardiac 4D visualisation.We converted ten and more sequential volume data sets of the heart acquired from retrospective ECG-gating helical scan into 3D images by volume rendering. These sequential 3D images could be displayed as a movie (4D cardiac image) file. Furthermore, we developed a method for semi-automatic calculation of ejection fraction (EF) and cardiac cycle (%)-volume (ml) curve for estimation of the motion and the volume of the left ventricle. This method involved the use an interactive selection tool in the region of interest (ROI). All 3D processing methods, such as, cutting objects, segmentation, and image fusion were based on mask processing data. We now describe the software developed for cardiac 4D imaging and the estimation of ventricular volume. PMID- 21614253 TI - Chronic hepatitis B infection and liver cancer. AB - Hepatitis B virus (HBV) is one of the most well recognised human carcinogens. Since its discovery about 40 years ago, HBV has been studied extensively. This article summarises the evidence derived from various studies including epidemiological, animal model, histopathology studies and molecular genetics studies leading to the establishment of HBV as the main aetiological agent for hepatocellular carcinoma (HCC). The reduction in the incidence of childhood HCC due to mass hepatitis B vaccination in Taiwan is a dramatic demonstration of the critical aetiological role of hepatitis B in HCC. Thus it is essential for interventionalists to understand the epidemiological and pathogenesis of HCC to ensure optimal patient care. PMID- 21614254 TI - Mirror, mirror, on the wall, will my submission say it all? PMID- 21614256 TI - Autonomic neurosurgery: from microvascular decompression to image guided stimulation. AB - The paper reviews mechanisms underlying autonomic disorders, with a focus on cardiovascular dysfunction. Neurosurgical approaches are described for medically refractory hypertension and orthostatic hypotension. After review of microvascular decompression of the rostral ventrolateral medulla, stereotactic CT and MRI guided deep brain stimulation of the periaqueductal grey matter (PAG) is evaluated. Results are presented from patient studies showing reductions in blood pressure with ventral PAG stimulation and increases in blood pressure with dorsal PAG stimulation. A rationale for the treatment of autonomic disorders by neurosurgical intervention is discussed. PMID- 21614255 TI - Image-guided surgery and medical robotics in the cranial area. AB - Surgery in the cranial area includes complex anatomic situations with high-risk structures and high demands for functional and aesthetic results. Conventional surgery requires that the surgeon transfers complex anatomic and surgical planning information, using spatial sense and experience. The surgical procedure depends entirely on the manual skills of the operator. The development of image guided surgery provides new revolutionary opportunities by integrating presurgical 3D imaging and intraoperative manipulation. Augmented reality, mechatronic surgical tools, and medical robotics may continue to progress in surgical instrumentation, and ultimately, surgical care. The aim of this article is to review and discuss state-of-the-art surgical navigation and medical robotics, image-to-patient registration, aspects of accuracy, and clinical applications for surgery in the cranial area. PMID- 21614257 TI - Tomotherapy as a tool in image-guided radiation therapy (IGRT): theoretical and technological aspects. AB - Helical tomotherapy (HT) is a novel treatment approach that combines Intensity Modulate Radiation Therapy (IMRT) delivery with in-built image guidance using megavoltage (MV) CT scanning. The technique utilises a 6 MV linear accelerator mounted on a CT type ring gantry. The beam is collimated to a fan beam, which is intensity modulated using a binary multileaf collimator (MLC). As the patient advances slowly through the ring gantry, the linac rotates around the patient with a leaf-opening pattern optimised to deliver a highly conformal dose distribution to the target in the helical beam trajectory. The unit also allows the acquisition of MVCT images using the same radiation source detuned to reduce its effective energy to 3.5 MV, making the dose required for imaging less than 3 cGy. This paper discusses the major features of HT and describes the advantages and disadvantages of this approach in the context of the commercial Hi-ART system. PMID- 21614259 TI - The role of IAEA in preparation of recommendations for the use of PET/CT in radiotherapy planning. PMID- 21614258 TI - Tomotherapy as a tool in image-guided radiation therapy (IGRT): current clinical experience and outcomes. AB - Modern radiotherapy is characterised by a better target definition through medical imaging accompanied by significantly improved radiation delivery methods, most notably Intensity-Modulate Radiation Therapy (IMRT). However, the treatment can only be as accurate as the positioning of patients for their daily radiotherapy fraction. It is in this context that a number of imaging modalities ranging from ultrasound to on-board kilovoltage imaging and computed tomography (CT) - have found their way into the treatment room where they verify accurate patient positioning prior to or even during delivery of radiation. Helical tomotherapy (HT) combines IMRT delivery with in-built image guidance using megavoltage CT scanning. This paper discusses the initial experience of different centres with IGRT using HT illustrated by a number of clinical examples from the installation in London in Ontario, Canada, one of the world's first HT sites. We found that HT allows the delivery of highly conformal radiation dose distributions combined with adequate daily image acquisition. An important feature of this unit is its seamless integration, which also includes a customised inverse treatment planning system and a quality assurance module for individual patients. PMID- 21614260 TI - Initial experience in treating lung cancer with helical tomotherapy. AB - Helical tomotherapy is a new form of image-guided radiation therapy that combines features of a linear accelerator and a helical computed tomography (CT) scanner. Megavoltage CT (MVCT) data allow the verification and correction of patient setup on the couch by comparison and image registration with the kilovoltage CT multi slice images used for treatment planning. An 84-year-old male patient with Stage III bulky non-small cell lung cancer was treated on a Hi-ART II tomotherapy unit. Daily MVCT imaging was useful for setup corrections and signaled the need to adapt the delivery plan when the patient's anatomy changed significantly. PMID- 21614261 TI - Using magnetoencephalography to investigate brain activity during high frequency deep brain stimulation in a cluster headache patient. AB - PURPOSE: Treatment-resistant cluster headache can be successfully alleviated with deep brain stimulation (DBS) of the posterior hypothalamus [1]. Magnetoencephalography (MEG) is a non-invasive functional imaging technique with both high temporal and high spatial resolution. However, it is not known whether the inherent electromagnetic (EM) noise produced by high frequency DBS is compatible with MEG. MATERIALS AND METHODS: We used MEG to record brain activity in an asymptomatic cluster headache patient with a DBS implanted in the right posterior hypothalamus while he made small movements during periods of no stimulation, 7 Hz stimulation and 180 Hz stimulation. RESULTS: We were able to measure brain activity successfully both during low and high frequency stimulation. Analysis of the MEG recordings showed similar activation in motor areas in during the patient's movements as expected. We also observed similar activations in cortical and subcortical areas that have previously been reported to be associated with pain when the patient's stimulator was turned on or off [2,3]. CONCLUSION: These results show that MEG can be used to measure brain activity regardless of the presence of high frequency deep brain stimulation. PMID- 21614262 TI - Improving radiation therapy for non-small cell lung cancer: molecular imaging and a team-based approach. AB - The successful integration of molecular imaging and radiation therapy has been shown to significantly impact the management of patients with non-small cell lung cancer (NSCLC). The collaboration of multidisciplinary team members, including radiation oncologists, radiation therapists, nuclear medicine physicians and physicists, has enabled PET/CT to be utilised for routine use throughout the radiotherapy treatment trajectory. Applications include disease diagnosis and staging, target volume definition for radiation therapy and monitoring tumour response to treatment. Not only has the adoption of this technology demonstrated benefits for our current patients, it is also opening doors for significant research in the future. PMID- 21614263 TI - Measurements of patient's setup variation in intensity-modulated radiation therapy of head and neck cancer using electronic portal imaging device. AB - PURPOSE: To measure the interfraction setup variation of patient undergoing intensity-modulated radiation therapy (IMRT) of head and neck cancer. The data was used to define adequate treatment CTV-to-PTV margin. MATERIALS AND METHODS: During March to September 2006, data was collected from 9 head and neck cancer patients treated with dynamic IMRT using 6 MV X-ray beam from Varian Clinac 23EX. Weekly portal images of setup fields which were anterior-posterior and lateral portal images were acquired for each patient with an amorphous silicon EPID, Varian aS500. These images were matched with the reference image from Varian Acuity simulator using the Varis vision software (Version 7.3.10). Six anatomical landmarks were selected for comparison. The displacement of portal image from the reference image was recorded in X (Left-Right, L-R), Y (Superior-Inferior, S-I) direction for anterior field and Z (Anterior-Posterior, A-P), Y (S-I) direction for lateral field. The systematic and random error for individual and population were calculated. Then the population-based margins were obtained. RESULTS: A total of 135 images (27 simulation images and 108 portal images) and 405 match points was evaluated. The systematic error ranged from 0 to 7.5 mm and the random error ranged from 0.3 to 4.8 mm for all directions. The population-based margin ranged from 2.3 to 4.5 mm (L-R), 3.5 to 4.9 mm (S-I) for anterior field and 3.4 to 4.7 mm (A-P), 2.6 to 3.7 mm (S-I) for the lateral field. These margins were comparable to the margin that was prescribed at the King Chulalongkorn Memorial Hospital (5-10 mm) for head and neck cancer. CONCLUSION: The population-based margin is less than 5 mm, thus the margin provides sufficient coverage for all of the patients. PMID- 21614265 TI - A review on the clinical implementation of respiratory-gated radiation therapy. AB - Respiratory-gated treatment techniques have been introduced into the radiation oncology practice to manage target or organ motions. This paper will review the implementation of this type of gated treatment technique where the respiratory cycle is determined using an external marker. The external marker device is placed on the abdominal region between the xyphoid process and the umbilicus of the patient. An infrared camera tracks the motion of the marker to generate a surrogate for the respiratory cycle. The relationship, if any, between the respiratory cycle and the movement of the target can be complex. The four dimensional computed tomography (4DCT) scanner is used to identify this motion for those patients that meet three requirements for the successful implementation of respiratory-gated treatment technique for radiation therapy. These requirements are (a) the respiratory cycle must be periodic and maintained during treatment, (b) the movement of the target must be related to the respiratory cycle, and (c) the gating window can be set sufficiently large to minimise the overall treatment time or increase the duty cycle and yet small enough to be within the gate. If the respiratory-gated treatment technique is employed, the end-expiration image set is typically used for treatment planning purposes because this image set represents the phase of the respiratory cycle where the anatomical movement is often the least for the longest time. Contouring should account for tumour residual motion, setup uncertainty, and also allow for deviation from the expected respiratory cycle during treatment. Respiratory-gated intensity-modulated radiation therapy (IMRT) treatment plans must also be validated prior to treatment. Quality assurance should be performed to check for positional changes and the output in association with the motion-gated technique. To avoid potential treatment errors, radiation therapist (radiographer) should be regularly in-serviced and made aware of the need to invoke the gating feature when prescribed for selected patients. PMID- 21614264 TI - Incorporating PET information in radiation therapy planning. AB - PET scanning, because of its impressive sensitivity and accuracy, is being incorporated into the standard staging workup for many cancers. These include lung cancer, lymphomas, head and neck cancers, and oesophageal cancers. PET often provides incremental information about the patient's disease status, adding to the data obtained from structural imaging methods, such as, CT scan or MRI. PET commonly upstages patients into more advanced disease categories. Incorporation of PET information into the radiotherapy planning process has the potential to reduce the risks of geographic miss and can help minimise unnecessary irradiation of normal tissues. The best means of incorporating PET information into radiotherapy planning is uncertain, and considerable effort is being expended in this area of research. PMID- 21614266 TI - Image-guided stereotactic body radiation therapy (SBRT): an emerging treatment paradigm with a new promise in radiation oncology. PMID- 21614267 TI - The treatment of primary and metastatic renal cell carcinoma (RCC) with image guided stereotactic body radiation therapy (SBRT). AB - PURPOSE: Brain metastases from renal cell carcinoma (RCC) have been successfully treated with stereotactic radiosurgery (SRS). Metastases to extra-cranial sites may be treated with similar success using stereotactic body radiation therapy (SBRT), where image-guidance allows for the delivery of precise high-dose radiation in a few fractions. This paper reports the authors' initial experience with image-guided SBRT in treating primary and metastatic RCC. MATERIALS AND METHODS: The image-guided Brainlab Novalis stereotactic system was used. Fourteen patients with 23 extra-cranial metastatic RCC lesions (orbits, head and neck, lung, mediastinum, sternum, clavicle, scapula, humerus, rib, spine and abdominal wall) and two patients with biopsy-proven primary RCC (not surgical candidates) were treated with SBRT (24-40 Gy in 3-6 fractions over 1-2 weeks). All patients were immobilised in body cast or head and neck mask. Image-guidance was used for all fractions. PET/CT images were fused with simulation CT images to assist in target delineation and dose determination. SMART (simultaneous modulated accelerated radiation therapy) boost approach was adopted. 4D-CT was utilised to assess tumour/organ motion and assist in determining planning target volume margins. RESULTS: Median follow-up was nine months. Thirteen patients (93%) who received SBRT to extra-cranial metastases achieved symptomatic relief. Two patients had local progression, yielding a local control rate of 87%. In the two patients with primary RCC, tumour size remained unchanged but their pain improved, and their renal function was unchanged post SBRT. There were no significant treatment-related side effects. CONCLUSION: Image-guided SBRT provides excellent symptom palliation and local control without any significant toxicity. SBRT may represent a novel, non-invasive, nephron-sparing option for the treatment of primary RCC as well as extra-cranial metastatic RCC. PMID- 21614268 TI - Image-guided surgery and therapy. PMID- 21614269 TI - Increasing the speed of medical image processing in MatLab. AB - MatLab((r)) has often been considered an excellent environment for fast algorithm development but is generally perceived as slow and hence not fit for routine medical image processing, where large data sets are now available e.g., high resolution CT image sets with typically hundreds of 512x512 slices. Yet, with proper programming practices - vectorization, pre-allocation and specialization - applications in MatLab((r)) can run as fast as in C language. In this article, this point is illustrated with fast implementations of bilinear interpolation, watershed segmentation and volume rendering. PMID- 21614270 TI - Optimisation in general radiography. AB - Radiography using film has been an established method for imaging the internal organs of the body for over 100 years. Surveys carried out during the 1980s identified a wide range in patient doses showing that there was scope for dosage reduction in many hospitals. This paper discusses factors that need to be considered in optimising the performance of radiographic equipment. The most important factor is choice of the screen/film combination, and the preparation of automatic exposure control devices to suit its characteristics. Tube potential determines the photon energies in the X-ray beam, with the selection involving a compromise between image contrast and the dose to the patient. Allied to this is the choice of anti-scatter grid, as a high grid ratio effectively removes the larger component of scatter when using higher tube potentials. However, a high grid ratio attenuates the X-ray beam more heavily. Decisions about grids and use of low attenuation components are particularly important for paediatric radiography, which uses lower energy X-ray beams. Another factor which can reduce patient dose is the use of copper filtration to remove more low-energy X-rays. Regular surveys of patient dose and comparisons with diagnostic reference levels that provide a guide representing good practice enable units for which doses are higher to be identified. Causes can then be investigated and changes implemented to address any shortfalls. Application of these methods has led to a gradual reduction in doses in many countries. PMID- 21614271 TI - Radiation injury is a potentially serious complication to fluoroscopically-guided complex interventions. AB - Radiation-induced injury to skin is an infrequent but potentially serious complication to complex fluoroscopically-guided interventional procedures. Due to a lack of experience with such injuries, the medical community has found fluoroscopically-induced injuries difficult to diagnose. Injuries have occurred globally in many countries. Serious injuries most frequently occur on the back but have also occurred on the neck, buttocks and anterior of the chest. Severities of injuries range from skin rashes and epilation to necrosis of the skin and its underlying structures. This article reviews the characteristics of these injuries and some actions that can be taken to reduce their likelihood or seriousness. PMID- 21614272 TI - Dose optimisation during imaging in radiotherapy. AB - The desire to increase the precision in radiotherapy delivery has led to the development of advanced imaging systems such as amorphous silicon (a-Si)-based electronic portal imaging, and kV and MV cone beam CT. These are used prior to the delivery of radiation to visualise the organ to be treated and to ensure that the patient setup and treatment delivery are accurate. However, little attention has been given to the dose received by adjacent normal tissues during these imaging procedures. Though these doses are very small compared to the dose delivered during radiotherapy, the involvement of normal tissues and the concern that these could increase the probability of stochastic effect, mainly the induction of secondary malignancy, cannot be ignored. This article reviews some work on the doses received during imaging in radiotherapy and the methods to optimise the same. PMID- 21614273 TI - Patient dose management in digital radiography. AB - PURPOSE: To present the experience in patient dose management and the development of an online audit tool for digital radiography. MATERIALS AND METHODS: Several tools have been developed to extract the information contained in the DICOM header of digital images, collect radiographic parameters, calculate patient entrance doses and other related parameters, and audit image quality. RESULTS: The tool has been used for mammography, and includes images from over 25,000 patients, over 75,000 chest images, 100,000 computed radiography procedures and more than 1,000 interventional radiology procedures. Examples of calculation of skin dose distribution in interventional cardiology based upon information of DICOM header and the results of dosimetric parameters for cardiology procedures in 2006 are presented. CONCLUSION: Digital radiology has great advantages for imaging and patient dose management. Dose reports, QCONLINE systems and the MPPS DICOM service are good tools to optimise procedures and to manage patient dosimetry data. The implementation of the ongoing IEC-DICOM standard for patient dose structured reports will improve dose management in digital radiology. PMID- 21614274 TI - Accident prevention in radiotherapy. AB - In order to prevent accidents in radiotherapy, it is important to learn from accidents that have occurred previously. Lessons learned from a number of accidents are summarised and underlying patterns are looked for in this paper. Accidents can be prevented by applying several safety layers of preventive actions. Categories of these preventive actions are discussed together with specific actions belonging to each category of safety layer. PMID- 21614275 TI - The IAEA's activities on radiation protection in interventional cardiology. AB - The International Atomic Energy Agency (IAEA) under its mandate of developing and applying standards of radiation safety has initiated a number of activities in recent years on radiation protection in interventional cardiology. These activities are implemented through four mechanisms, namely training, providing information through the website, research projects and assistance to Member States through Technical Cooperation (TC) projects. Major international initiatives have been taken in the area of training where more than half a dozen regional training courses have been conducted for cardiologists from over 50 countries. Additionally four national training events for over 300 medical and paramedical staff members involved in interventional procedures were held. The training material is freely available on CD from the IAEA. The newly established website provides information on radiation protection issues [1]. Two coordinated research projects have just been completed where peak skin doses to patients undergoing high dose interventional procedures were studied and factors to manage patient doses were identified. The technical cooperation projects involving protection in cardiac interventional procedures have 30 countries as participants. PMID- 21614276 TI - United States radiological health activities: inspection results of mammography facilities. AB - PURPOSE: The Mammography Quality Standards Act (MQSA) was enacted in 1992 to set national standards for high-quality mammography, including standards for mammographic X-ray equipment, patient dose, clinical image quality, and related technical parameters. The MQSA also requires minimum qualifications for radiologic technologists, interpreting physicians and medical physicists, mandates acceptable practices for quality-control, quality-assurance, and requires processes to audit medical outcomes. This paper presents the findings of MQSA inspections of facilities, which characterize significant factors affecting mammography quality in the United States. MATERIALS AND METHODS: Trained inspectors collected data regarding X-ray technical factors, made exposure measurements for the determination of mean glandular dose (MGD), evaluated image quality, and inspected the quality of the film-processing environment. The average annual facility and total U.S. screening exam workloads were computed using workload data reported by facilities. RESULTS: Mammography facilities have made technical improvements as evidenced by a narrower distribution of doses, higher phantom-film background optical densities associated with higher phantom image-quality scores, and better film processing. It is estimated that approximately 36 million screening mammography exams were conducted in 2006, a rate that is almost triple the exam volume estimated for 1997. Digital mammography (DM) is now in use at approximately 14% (1,191 of 8,834) of MQSA certified mammography facilities. The results indicate that DM can offer lower dose to the patient while providing comparable or better image quality. PMID- 21614277 TI - Optimisation of whole-body PET/CT scanning protocols. AB - Positron emission tomography (PET) has become one of the major tools for the in vivo localisation of positron-emitting tracers and now is performed routinely using (18)F-fluorodeoxyglucose (FDG) to answer important clinical questions including those in cardiology, neurology, psychiatry, and oncology. The latter application contributed largely to the wide acceptance of this imaging modality and its use in clinical diagnosis, staging, restaging, and assessment of tumour response to treatment. Dual-modality PET/CT systems have been operational for almost a decade since their inception. The complementarity between anatomic (CT) and functional or metabolic (PET) information provided in a "one-stop shop" has been the driving force of this technology. Although combined anato-metabolic imaging is an obvious choice, the way to perform imaging is still an open issue. The tracers or combinations of tracers to be used, how the imaging should be done, when contrast-enhanced CT should be performed, what are the optimal acquisition and processing protocols, are all unanswered questions. Moreover, each data acquisition-processing combination may need to be independently optimised and validated. This paper briefly reviews the basic principles of dual modality imaging and addresses some of the practical issues involved in optimising PET/CT scanning protocols in a clinical environment. PMID- 21614278 TI - The importance of radiation quality for optimisation in radiology. AB - Selection of the appropriate radiation quality is an important aspect of optimisation for every clinical imaging task in radiology, since it affects both image quality and patient dose. Spreadsheet calculations of attenuation and absorption have been applied to basic imaging tasks to provide an assessment of imaging performance for a selection of phosphors used in radiology systems. Contrast, which is an important component of image quality affected by radiation quality, has been assessed in terms of the contrast to noise ratio (CNR) for a variety of X-ray beams. Both CNR and patient dose fall with tube potential, and selection of the best option is a compromise that will provide an adequate level of image quality with as low a radiation dose as practicable. It is important that systems are set up to match the response of the imaging phosphor, as there are significant differences between phosphors. For example, the sensitivity of barium fluorohalides used in computed radiography declines at higher tube potentials, whereas that of gadolinium oxysulphide used in rare earth screens increases. Addition of 0.2 mm copper filters, which can reduce patient entrance surface dose by 50%, may be advantageous for many applications in radiography and fluoroscopy. The disadvantage of adding copper is that tube output levels have to be increased. Application of simple calculations of the type employed here could prove useful for investigating and assessing the implications of potential changes in X-ray beam quality prior to implementation of new techniques. PMID- 21614279 TI - Dose management in CT facility. AB - Computed Tomography (CT) examinations have rapidly increased in number over the last few years due to recent advances such as the spiral, multidetector-row, CT fluoroscopy and Positron Emission Tomography (PET)-CT technology. This has resulted in a large increase in collective radiation dose as reported by many international organisations. It is also stated that frequently, image quality in CT exceeds the level required for confident diagnosis. This inevitably results in patient radiation doses that are higher than actually required, as also stressed by the US Food and Drug Administration (FDA) regarding the CT exposure of paediatric and small adult patients. However, the wide range in exposure parameters reported, as well as the different CT applications reveal the difficulty in standardising CT procedures. The purpose of this paper is to review the basic CT principles, outline the recent technological advances and their impact in patient radiation dose and finally suggest methods of radiation dose optimisation. PMID- 21614280 TI - Optimisation in fluoroscopy. AB - Optimisation of radiation protection in fluoroscopy is important since the procedure could lead to relatively high absorbed doses both in patients and personnel resulting in acute radiation injury. Optimisation procedures include adjustment of the fluoroscopy equipment such as exposure factors as well as proper use of automatic brightness control and pulsed fluoroscopy. It is also important to gain the benefits of image processing and the higher sensitivity of flat panel detectors as compared to image intensifier-TV systems.Proper positioning of the patient with respect to detector and X-ray tube is of fundamental importance to image quality and radiation dose to the patient. Both image quality and radiation dose are also affected by the methodology used with parameters such as magnification factor, increased filtration, use of last-image hold and the use of a grid.There is a direct relation between patient dose and the absorbed dose to the personnel since this is mostly due to scattered radiation from the patient. If the correct methodology and the correct radiation protection devices are used, the absorbed dose to the personnel could be minimised to acceptable levels even for those working with complex procedures.In order to have an organised review of all aspects of optimisation, it is recommendable to have an active quality system at the department. This system should define responsibilities and tasks for persons involved. PMID- 21614282 TI - Radiation dose optimisation in biomedical imaging and intervention. PMID- 21614281 TI - Is the glass half full or half empty? PMID- 21614283 TI - Medical politics 101. PMID- 21614284 TI - Leadership and management in quality radiology. AB - The practice of medical imaging and interventional radiology are undergoing rapid change in recent years due to technological advances, workload escalation, workforce shortage, globalisation, corporatisation, commercialisation and commoditisation of healthcare. These professional and economical changes are challenging the established norm but may bring new opportunities. There is an increasing awareness of and interest in the quality of care and patient safety in medical imaging and interventional radiology. Among the professional organisations, a range of quality systems are available to address individual, facility and system needs. To manage the limited resources successfully, radiologists and professional organisations must be leaders and champion for the cause of quality care and patient safety. Close collaboration with other stakeholders towards the development and management of proactive, long-term, system-based strategies and infrastructures will underpin a sustainable future in quality radiology. The International Radiology Quality Network can play a useful facilitating role in this worthwhile but challenging endeavour. PMID- 21614285 TI - Quality service in radiology. PMID- 21614286 TI - Inverting the organisational pyramid. PMID- 21614287 TI - EFOMP: the European roof for medical physics. PMID- 21614288 TI - Quality care and safety know no borders. AB - The public, governmental agencies, and payers expect medical professional organisations to develop practice guidelines and technical standards. The American College of Radiology proactively addresses these topics as well as other quality and safety interests including appropriateness criteria and accreditation. The College is also actively involved in development of a national radiology data base to collect data regarding quality and safety metrics in multiple areas. In addition, the College has developed RADPEERTM, a simple, cost effective process that allows peer review to be performed during the routine interpretation of current images. This paper discusses the efforts of the ACR in all of these areas. PMID- 21614289 TI - Status and future prospects of biomedical engineering: a Japanese perspective. PMID- 21614290 TI - Technology and its clinical application in the field of computer-assisted radiology and surgery. AB - The field of computer-assisted radiology and surgery involves a wide spectrum of topics based on medicine, physics, computer science and even sociology. The progress of development and recent trends in this field is described in this paper. Firstly, the chronological change in presented papers in past international conferences of Computer Assisted Radiology and Surgery (CARS) from 1985 to 2007 is illustrated in terms of topics, which are grouped into six main categories. Secondly, new directions and related topics are described by means of an example of a digital operating room. Problems in the operation room (OR) and solution concepts are pointed out while a therapy imaging and model management system (TIMMS) is presented as a possible solution. Finally, patient modelling related topics for CARS are listed. PMID- 21614292 TI - Scientific writing and publishing: its importance to radiologists. AB - Scientific writing and publication marks the endpoint of research that has been performed, completed, peer reviewed and accepted, and complements teaching and training, clinical service and patient care. Writing has numerous benefits, one of the most important ones being the inherent training undertaken to better appreciate and evaluate the published work of others. Effective scientific writing is an important component of a radiologist's practice, and should be cultivated at an early stage of the career. PMID- 21614293 TI - IUPESM: the international umbrella organisation for biomedical engineering and medical physics. AB - An account of the development, aims and activities of the International Union for Physical and Engineering Sciences in Medicine (IUPESM) is presented. Associations with the International Council of Science (ICSU) and the World Health Organization (WHO) are leading to exciting new projects towards improving global health, healthcare, quality of life and support of health technologies in developing countries. PMID- 21614291 TI - Hybrid imaging is the future of molecular imaging. AB - Correlative imaging has long been used in clinical practice and particularly for the interpretation of nuclear medicine studies wherein detailed anatomical information is often lacking. Previously, side-by-side comparison or software co registration techniques were applied but suffered from technical limitations related to the differing geometries of the imaging equipment, differences in the positioning of patients and displacement of mobile structures between studies. The development of the first hybrid PET and CT device struck a chord with the medical imaging community that is still ringing loudly throughout the world. So successful has been the concept of PET-CT that none of the major medical imaging manufacturers now offers stand-alone PET scanners. Following close behind this success, SPECT-CT devices have recently been adopted by the nuclear medicine community, already compelled by the benefits of hybrid imaging through their experience with PET-CT. Recent reports of adaptation of PET detectors to operate within the strong magnetic field of MRI scanners have generated further enthusiasm. Prototype PET-MRI devices are now in development. The complementary anatomical, functional and molecular information provided by these techniques can now be presented in an intuitive and aesthetically-pleasing format. This has made end-users more comfortable with the results of functional imaging techniques than when the same information is presented independently. Despite the primacy of anatomical imaging for locoregional disease definition, the molecular characterisation available from PET and SPECT offers unique complementary information for cancer evaluation. A new era of cancer imaging, when hybrid imaging will be the primary diagnostic tool, is approaching. PMID- 21614294 TI - Multislice CT angiography in abdominal aortic aneurysm treated with endovascular stent grafts: evaluation of 2D and 3D visualisations. AB - Endovascular repair of abdominal aortic aneurysms has been introduced into the clinical practice for more than a decade and has been confirmed to be an effective alternative to conventional open surgery, especially in patients with co-morbid medical conditions. Helical CT angiography is the preferred imaging method in the follow-up of endovascular repair. Recent introduction of multislice CT scanners has augmented its diagnostic role in this area. Diagnostic value of multlislice CT has been complemented by a series of 3D post-processings, which assist vascular surgeons in accurately assessing the effect of endovascular repair by providing additional information when compared to conventional 2D axial images. These reconstructions include multiplanar reformation, curved multiplanar reconstruction, shaded surface display, maximum intensity projection, volume rendering and virtual endoscopy. This article aims to demonstrate the generation of these 2D/3D reconstructions based on multislice CT data acquired from a group of patients with abdominal aortic aneurysm following endovascular repair. A brief introduction of generating each reconstruction was provided; potential clinical applications of each reconstruction were briefly discussed. Images were presented in a dynamic format with the aim of allowing the reader to easily understand the post-processing of these reconstructions. PMID- 21614295 TI - The impact of lesion vascularisation on tumours detection by electrical impedance scanning at 200 Hz. AB - OBJECTIVE: Cancer cells exhibit altered local dielectric properties compared to normal cells. These properties are measurable as a difference in electrical conductance using electrical impedance scanning (EIS). EIS is at present not sufficiently accurate for clinical routine despite its technological advantages. To modify the technology and increase its accuracy, the factors that influence precision need to be analysed and identified. While size, depth, localisation and invasiveness affect sensitivity, vascularisation might show an increased conductance and thus might affect specificity. SUBJECTS AND METHODS: All patients were investigated with EIS (TransScan TS 2000, Migdal Ha Emek, Israel) Planned DCE-MRI prior to histological clarification were included (295 lesions). Dynamic enhancements were assigned scores after analysis of subtracted images after application of Gd-DTPA. D1: strong enhancement of >100% from initial signal obtained on native T1weighted sequence; D2: moderate enhancement 50-100%; D3: enhancement similar to glandular tissue, <50%; D4: subtle or no enhancement, less then surrounding glandular tissue. RESULTS: 89/113 malignant and 107/182 benign findings were visible by a focal increased conductance and/or capacitance using EIS (Sensitivity 79%, Specificity 59%). DCE-MRI was aborted due to claustrophobia in 17/295 cases. MR was used and out of 278 completed MR examinations, 101/104 malignant and 141/174 benign lesions were correctly diagnosed as benign or malignant leading to a sensitivity of 97% and a specificity of 81%. D1 benign lesions were positive in EIS in 33/55 cases suggesting a specificity of 44.4%. This value increases significantly with decreased vascularity to 68.9% (D2-4; 82/119). Out of 60 fibroadenomatous lesions, 10/23 fibroadenomas in class 1 had no focal increased conductance or capacitance and were thus considered as non suspicious in EIS. The same result was applicable for the 29/37 benign lesions with a D2-4 contrast uptake (43.5% vs. 78.4%, p<.01). CONCLUSION: Vascularisation influences the measurable conductance at low frequency and therefore partially causes the insufficiently low specificity of EIS. Impedance measurements at frequencies in a range of 0.1 KHz to 1 MHz are required . According to theoretical and in vitro studies this might increase the accuracy of EIS technology. (c) 2007 Biomedical Imaging and Intervention Journal. All rights reserved. PMID- 21614296 TI - Bronchogenic cyst with multiple complications. AB - Bronchogenic cysts are a rare type of mediastinal mass thought to arise from abnormal budding of the embryologic foregut. This paper presents a rare case of a 32-year-old male who developed multiple serious complications from a bronchial cyst. This rare presentation is discussed and the role of CT and MR imaging in making the diagnosis is highlighted. PMID- 21614297 TI - Role of radiosynovectomy in the treatment of rheumatoid arthritis and hemophilic arthropathies. AB - Radiosynovectomy is a novel method of treatment for several acute and chronic inflammatory joint disorders. A small amount of a beta-emitting radionuclide is injected into the affected joint delivering a radiation dose of 70 to 100 Gy to the synovia. The proliferative tissue is destroyed, secretion of fluid and accumulation of inflammation causing cellular compounds stops and the joint surfaces become fibrosed, providing long term symptom relief. The radionuclides are injected in colloidal form so that they remain in the synovium and are not transported by lymphatic vessels causing radiation exposure to other organs. Complete reduction of knee joint swelling has been seen in above 40% and pain relief in 88% of patients. Wrist, elbow, shoulder, ankle and hip joints showed significant improvement in 50-60% and restoration of normal function and long term pain relief has been achieved in about 70% of small finger joints. In hemophilic arthropathies complete cessation of bleeding in about 60% and improved mobility in 75% of patients has been reported. PMID- 21614298 TI - Gartner duct cyst in pregnancy presenting as a prolapsing pelvic mass. AB - Gartner duct cysts are the remnants of the Wolffian duct and they are rarely seen in adulthood. We present a case of a pregnant patient with a prolapsing vaginal mass. A diagnosis of Gartner duct cyst was made after MRI was performed. The Gartner duct cyst was drained when the patient went into labour allowing vaginal delivery to be performed. PMID- 21614299 TI - Gastric and pulmonary lymphoma presenting as a solitary pulmonary nodule. AB - The common presentations of lymphoma are widespread lymphadenopathy or development of constitutional symptoms. This paper presents a case of a patient who presented with a solitary mass detected on chest X-ray and underwent FDG-PET for further evaluation of this mass. FDG-PET is a commonly utilised technique to assess solitary nodules as it not only allows characterisation of the lesion but can also detect nodal and extra-thoracic disease with greater accuracy than the standard CT. In this case, FDG-PET demonstrated abnormal activity in the lung nodule and at the gastro-oesophageal junction. Biopsies confirmed Non-Hodgkin's Lymphoma at both sites. The value of FDG-PET in this case was the determination of previous unsuspected disease in an unusual presentation of lymphoma and as a useful tool for monitoring the therapeutic effect post chemotherapy. PMID- 21614300 TI - Primary bone lymphoma: report of a case with multifocal skeletal involvement. AB - Primary bone lymphoma is an uncommon tumour accounting for approximately 4-5% of extra nodal lymphoma and less than 1% of all Non-Hodgkin's lymphoma. The radiographic appearance of primary bone lymphoma is variable. As lesions frequently resemble other disease processes namely chronic osteomyelitis and metastases, further imaging evaluation and histopathological examination allow early identification for appropriate treatment. The authors present a case of anaplastic large cell lymphoma of bone presenting with multifocal osseus involvement. PMID- 21614302 TI - Renal angiomyolipoma with bleeding. PMID- 21614301 TI - Synchronisation strategies in T2-weighted MR imaging for detection of liver lesions: Application on a nude mouse model. AB - AIM: The objective of this work was to propose original synchronisation strategies based on T2-weighted sequence performed on a small animal MRI spectrometer in order to improve the image contrast and detect mouse liver lesions at high magnetic field. MATERIALS AND METHODS: The experiments were performed in vivo at 7T using a 32 mm inner diameter cylindrical volumetric coil for both RF emission and reception. A sensitive pressure sensor was used to detect external movements due to both respiration and heart beats. The pressure sensor was interfaced with a commercial ECG Trigger Unit to use dedicated functionalities (trigger levels, delays and window). To enable T2-weighted imaging with minimised T1 effects, an acquisition strategy with controlled TR spanning over several respiratory cycles was developed. With this strategy, the slices were acquired over several respiratory periods. RESULTS: The acquisition, performed over several respiratory periods, enables a longer TR than the typical mouse respiratory period. The image contrast is controllable and independent of the respiratory period. The heavily T2-weighted images obtained with the developed strategy allow better visualisation of lesions at high magnetic field. Moreover, double respiratory and cardiac synchronisation, based on a unique sensitive pressure sensor, improves image quality with less motion artifacts, especially in the ventral liver region. The total slice number is independent of respiratory period and thin slices can be acquired to cover the whole liver. CONCLUSION: The developed strategy enables high quality pure T2-weighted imaging with minimal motion artifacts. This strategy improves T2-weighted image contrast and quality, especially at high magnetic field, on animals with short respiratory periods. The strategy was demonstrated using a mouse model of liver lesions at 7T. This protocol could be used to carry out a longitudinal follow-up. PMID- 21614303 TI - The journey so far. PMID- 21614304 TI - Learning how to learn. PMID- 21614305 TI - Preparing effective medical illustrations for publication (Part 1): pixel-based image acquisition. PMID- 21614306 TI - Real-time teleteaching in medical physics. AB - Medical physics is a relatively small professional community, usually with a scarcity of expertise that could greatly benefit students entering the field. However, the reach of the profession can span great geographical distances, making the training of students a difficult task. In addition to the requirement of training new students, the evolving field of medical physics, with its many emerging advanced techniques and technologies, could benefit greatly from ongoing continuing education as well as consultation with experts.Many continuing education courses and workshops are constantly being offered, including many web based study courses and virtual libraries. However, one mode of education and communication that has not been widely used is the real-time interactive process. Video-based conferencing systems do exist, but these usually require a substantial amount of effort and cost to set up.The authors have been working on promoting the ever-expanding capability of the Internet to facilitate the education of medical physics to students entering the field. A pilot project has been carried out for six years and reported previously. The project is a collaboration between the Department of Medical Physics at the Toronto Odette Cancer Centre in Canada and the Department of Biomedical Imaging at the University of Malaya in Malaysia. Since 2001, medical physics graduate students at the University of Malaya have been taught by lecturers from Toronto every year, using the Internet as the main tool of communication.The pilot study explored the different methods that can be used to provide real-time interactive remote education, and delivered traditional classroom lectures as well as hands on workshops.Another similar project was started in 2007 to offer real-time teaching to a class of medical physics students at Wuhan University in Hubei, China. There are new challenges as well as new opportunities associated with this project. By building an inventory of tools and experiences, the intent is to broaden the real-time teleteaching method to serve a wide community so that future students entering the field can have efficient access to high-quality education that will benefit the profession in the long term. PMID- 21614307 TI - Credentialing for radiology. AB - Patients expect to receive safe, predictable and high-quality care delivered by competent professionals. Thus, it has become important to provide specific training in existing and new modalities and prove on-going clinical expertise. Hospital credentialing is the process by which the competence of a doctor is determined by the hospital management. In Australia, radiologists participate in a mandatory program of continuing professional development and are also required to maintain a logbook of procedures. The Conjoint Committee for the Recognition of Training in Peripheral Endovascular Therapy has been established to advise the respective subspecialty groups on the requirements for accreditation. This article examines some of the issues the committee has considered in preparing the criteria to assist institutions for the purposes of credentialing and gives an Australian perspective on future trends. PMID- 21614308 TI - k-Space tutorial: an MRI educational tool for a better understanding of k-space. AB - A main difference between Magnetic Resonance (MR) imaging and other medical imaging modalities is the control over the data acquisition and how it can be managed to finally show the adequate reconstructed image. With some basic programming adjustments, the user can modify the spatial resolution, field of view (FOV), image contrast, acquisition velocity, artifacts and so many other parameters that will contribute to form the final image. The main character and agent of all this control is called k-space, which represents the matrix where the MR data will be stored previously to a Fourier transformation to obtain the desired image.This work introduces 'k-Space tutorial', a MATLAB-based educational environment to learn how the image and the k-space are related, and how the image can be affected through k-space modifications. This MR imaging educational environment has learning facilities on the basic acceleration strategies that can be encountered in almost all MR scanners: scan percentage, rectangular FOV and partial Fourier imaging. It also permits one to apply low- and high-pass filtering to the k-space, and to observe how the contrast or the details are selected in the reconstructed image. It also allows one to modify the signal-to noise ratio of the acquisition and create some artifacts on the image as a simulated movement of the patient - with variable intensity level - and some electromagnetic spikes on k-space occurring during data acquisition. PMID- 21614309 TI - Evolving models for medical physics education and training: a global perspective. AB - There is a significant need for high-quality medical physics education and training in all countries to support effective and safe use of modern medical technology for both diagnostic and treatment purposes. This is, and will continue to be, achieved using appropriate technology to increase both the effectiveness and efficiency of educational activities everywhere in the world. While the applications of technology to education and training are relatively new, the successful applications are based on theories and principles of the learning process developed by two pioneers in the field, Robert Gagne and Edgar Dale.The work of Gagne defines the different levels of learning that can occur and is used to show the types and levels of learning that are required for the application of physics and engineering principles to achieve appropriate diagnostic and therapeutic results from modern technology. The learning outcomes are determined by the effectiveness of the learning activity or experience. The extensive work of Dale as formulated in his Cone of Experience relates the effectiveness to the efficiency of educational activities. A major challenge in education is the development and conduction of learning activities (classroom discussions, laboratory and applied experiences, individual study, etc) that provide an optimum balance between effectiveness and efficiency. New and evolving models of the educational process use technology as the infrastructure to support education that is both more effective and efficient.The goal is to use technology to enhance human performance for both learners (students) and learning facilitators (teachers). A major contribution to global education is the trend in the development of shared educational resources. Two models of programs to support this effort with open and free shared resources are Physical Principles of Medical Imaging Online (http://www.sprawls.org/resources) and AAPM Continuing Education Courses (http://www.aapm.org/international). PMID- 21614310 TI - Changes in postgraduate medical education and training in clinical radiology. AB - Postgraduate medical education and training in many specialties, including Clinical Radiology, is undergoing major changes. In part this is to ensure that shorter training periods maximise the learning opportunities but it is also to bring medical education in line with broader educational theory. Learning outcomes need to be defined so that there is no doubt what knowledge, skills, attitudes and behaviours are expected of those in training. Curricula should be developed into competency or outcome based models and should state the aims, objectives, content, outcomes and processes of a training programme. They should include a description of the methods of learning, teaching, feedback and supervision. Assessment systems must be matched to the curriculum and must be fair, reliable and valid. Workplace based assessments including the use of multisource feedback need to be developed and validated for use during radiology training. These should be used in a formative and developmental way, although the overall results from a series of such assessments can be used in a more summative way to determine progress to the next phase of training. Formal standard setting processes need to be established for 'high stakes' summative assessments such as examinations. In addition the unique skills required of a radiologist in terms of image interpretation, pattern recognition, deduction and diagnosis need to be evaluated in robust, reliable and valid ways. Through a combination of these methods we can be assured that decisions about trainees' progression through training is fair and standardised and that we are protecting patients by establishing national standards for training, curricula and assessment methods. PMID- 21614311 TI - The challenge of radiology education in developing countries. PMID- 21614312 TI - e-Learning development in medical physics and engineering. AB - Medical Physics and Engineering was among the first professions to develop and apply e-Learning (e-L). The profession provides excellent background for application of simulations and other e-L materials. The paper describes several layers for e-L development: Programming specific simulations; Building e-L modules; Development of e-L web-based programmes. The paper shows examples from these layers and outlines their specificities. At the end, the newest e-L development (project EMITEL) is briefly introduced and the necessity of a regularly updated list of e-L activities is emphasised. PMID- 21614313 TI - Medical physics in developing countries: looking for a better world. AB - Medical physics has been identified as one of the key areas that need to be developed to improve healthcare. However, the level achieved in developing countries represents a stark contrast to the level that exists in Western Europe or North America. The challenge for developing countries is to build the required infrastructures, to acquire the equipment, to attract highly qualified professionals and to develop education and training programs and political policies for effective and accessible care within budgetary constraints. The state-of-the-art technological developments in medical physics cannot be viewed as a uniform reality all over the world. There is, of course, a wide difference in emphasis and approach when dealing with developing countries, compared to developed nations. As quality assurance and cost-benefit guidelines in the practice of radiation therapy and diagnostic imaging are being developed and debated in developed countries, the perspectives of the availability and standards of healthcare taken for granted in these countries stand in stark contrast to the level administered in developing countries. In this contribution, the overall situation of medical physics in developing countries and the barriers to improvement are discussed, and some possible solutions and ways to bridge the gap between developed and developing countries are suggested. PMID- 21614314 TI - Glioblastoma multiforme: a rare manifestation of extensive liver and bone metastases. AB - Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumours known collectively as gliomas. Gliomas are graded by their microscopic appearance. As a rule, their behaviour can be predicted from histology: Grade I (pilocytic astrocytomas) and Grade II (benign astrocytomas) tumours are of low grade and grow slowly over many years. Grade IV tumours (GBM) are the most aggressive and, unfortunately, also the most common in humans, growing rapidly, invading and altering brain function. These tumours arise from the supporting glial cells of the brain during childhood and in adulthood.These growths do not spread throughout the body like other forms of cancer, but cause symptoms by invading the brain. Untreated GBMs are rapidly lethal. Most patients with GBM die of their disease in less than a year and none have long term survival.Extracranial metastases from GBM are extremely rare, with a reported frequency of only 0.44% because of the absence of lymphatics in the brain and the difficulty of tumours to penetrate blood vessels. A case of glioblastoma multiforme with the rare features of extensive liver and bone metastases is presented in this paper. PMID- 21614315 TI - Optimal sensitometric curves of Kodak EDR2 film for dynamic intensity modulated radiation therapy verification. AB - PURPOSE: To investigate the optimal sensitometric curves of extended dose range (EDR2) radiographic film in terms of depth, field size, dose range and processing conditions for dynamic intensity modulated radiation therapy (IMRT) dosimetry verification with 6 MV X-ray beams. MATERIALS AND METHODS: A Varian Clinac 23 EX linear accelerator with 6 MV X-ray beam was used to study the response of Kodak EDR2 film. Measurements were performed at depths of 5, 10 and 15 cm in MedTec virtual water phantom and with field sizes of 2x2, 3x3, 10x10 and 15x15 cm(2). Doses ranging from 20 to 450 cGy were used. The film was developed with the Kodak RP X-OMAT Model M6B automatic film processor. Film response was measured with the Vidar model VXR-16 scanner. Sensitometric curves were applied to the dose profiles measured with film at 5 cm in the virtual water phantom with field sizes of 2x2 and 10x10 cm(2) and compared with ion chamber data. Scanditronix/Wellhofer OmniPro(TM) IMRT software was used for the evaluation of the IMRT plan calculated by Eclipse treatment planning. RESULTS: Investigation of the reproducibility and accuracy of the film responses, which depend mainly on the film processor, was carried out by irradiating one film nine times with doses of 20 to 450 cGy. A maximum standard deviation of 4.9% was found which decreased to 1.9% for doses between 20 and 200 cGy. The sensitometric curves for various field sizes at fixed depth showed a maximum difference of 4.2% between 2x2 and 15x15 cm(2) at 5 cm depth with a dose of 450 cGy. The shallow depth tended to show a greater effect of field size responses than the deeper depths. The sensitometric curves for various depths at fixed field size showed slightly different film responses; the difference due to depth was within 1.8% for all field sizes studied. Both field size and depth effect were reduced when the doses were lower than 450 cGy. The difference was within 2.5% in the dose range from 20 to 300 cGy for all field sizes and depths studied. Dose profiles measured with EDR2 film were consistent with those measured with an ion chamber. The optimal sensitometric curve was acquired by irradiating film at a depth of 5 cm with doses ranging from 20 to 450 cGy with a 3*3 cm(2) multileaf collimator. The optimal sensitometric curve allowed accurate determination of the absolute dose distribution. In almost 200 cases of dynamic IMRT plan verification with EDR2 film, the difference between measured and calculated dose was generally less than 3% and with 3 mm distance to agreement when using gamma value verification. CONCLUSION: EDR2 film can be used for accurate verification of composite isodose distributions of dynamic IMRT when the optimal sensitometric curve has been established. PMID- 21614316 TI - The importance of Good Clinical Practice guidelines and its role in clinical trials. AB - Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials. It also serves to protect the rights, integrity and confidentiality of trial subjects. It is very important to understand the background of the formation of the ICH-GCP guidelines as this, in itself, explains the reasons and the need for doing so. In this paper, we address the historical background and the events that led up to the formation of these guidelines. Today, the ICH-GCP guidelines are used in clinical trials throughout the globe with the main aim of protecting and preserving human rights. PMID- 21614317 TI - F18 fluorodeoxyglucose uptake in progressive transformation of germinal centres. AB - FDG-PET/CT is a widely established imaging modality for staging, restaging and monitoring therapy response in lymphoma patients. Progressive transformation of germinal centres (PTGC) is a benign condition presenting characteristically as asymptomatic lymphadenopathy. This paper presents a case of a 53-year-old man with a history of Hodgkin's disease (HD) whose F(18) FDG-PET/CT scan showed high uptake in left axillary lymph nodes (SUV 3.8). A subsequent, left axillary lymph node biopsy revealed PTGC. PTGC can present as a false positive finding on FDG PET/CT in lymphoma patients and biopsy should be done in HD patients in clinical remission but have a positive FDG-PET/CT scan. PMID- 21614318 TI - Osteosarcoma of the rib. AB - This case describes the radiological-surgical correlation of a rare case of osteosarcoma of the rib in a 15-year-old boy. Successful repair of his chest wall defect using a wire mesh following extensive surgical resection of the tumour is highlighted, such a procedure being the first instituted at our centre. PMID- 21614319 TI - Enhancing reflective practice through online learning: impact on clinical practice. AB - PURPOSE: Traditionally, radiographers and radiation therapists function in a workplace environment that is protocol-driven with limited functional autonomy. The workplace promotes a culture of conformity and discourages practitioners from reflective and critical thinking, essential attributes for continuing learning and advancing workplace practices. As part of the first author's doctoral study, a continuing professional development (CPD) educational framework was used to design and implement an online module for radiation therapists' CPD activities. The study aimed to determine if it is possible to enhance healthcare practitioners' reflective practice via online learning and to establish the impact of reflective learning on clinical practice. MATERIALS AND METHODS: The objectives of the online module were to increase radiation therapists' knowledge in planning for radiation therapy for the breast by assisting them engage in reflective practice. The cyclical process of action research was used to pilot the module twice with two groups of volunteer radiation therapists (twenty-six participants) from Australia, New Zealand and Canada. RESULTS: The online module was evaluated using Kirkpatrick's four-level evaluation model. Evidence indicated that participants were empowered as a result of participation in the module. They began reflecting in the workplace while assuming a more proactive role and increased clinical responsibilities, engaged colleagues in collaborative reflections and adopted evidence-based approaches in advancing clinical practices. CONCLUSION: The study shows that it is possible to assist practitioners engage in reflective practice using an online CPD educational framework. Participants were able to apply the reflective learning they had developed in their workplace. As a result of their learning, they felt empowered to continue to effect changes in their workplace beyond the cessation of the online module. PMID- 21614320 TI - Towards the development of a reflective radiographer: challenges and constraints. AB - Currently there is overwhelming support from the health professions for universities to devise curricular approaches that lead to the development of undergraduate reflective skills, and over time, reflective practice. However, in the case of radiography, irrespective of the degree to which radiographers might engage in reflective practice they constantly struggle to shed the perception they are little more than technical operatives. The four-year Bachelor of Radiography and Medical Imaging was introduced by Monash University in 1998 with an overt commitment to the development of a reflective radiographer. Findings from student and supervisor surveys generally support the program and its aims. However, as the findings and student feedback will attest, many challenges and constraints continue to face educators who seek to situate their curriculum within the reflective practice paradigm. PMID- 21614321 TI - Preparing effective medical illustrations for publication (Part 2): software processing, drawing and illustration. PMID- 21614322 TI - Radiographic viewing conditions at Johannesburg Hospital. AB - PURPOSE: To measure the luminance level of X-ray viewing boxes and ambient lighting levels in reporting rooms as a quality assurance procedure, and to compare the results with those recommended by the Directorate of Radiation Control, South Africa (DRC), European Commission (EC) and Nordic Radiation Protection Co-operation (NORDIC). MATERIALS AND METHODS: All the viewing boxes housed at the Divisions of Radiation Oncology and Radiology of Johannesburg Hospital had their luminance levels measured using a calibrated photometer. In addition the room's ambient light was measured using a photometer. RESULTS: The mean average luminance was 1026.75 +/- 548.65 cd m(-2) and 3284.38 +/- 327.91 cd m(-2) at the Division of Radiology and Division of Radiation Oncology respectively. The Division of Radiation Oncology had an average viewing box uniformity of 7.14% compared to 27.32% at the Division of Radiology. The average ambient lighting was found to be 66.30 lux and 66.43 lux at the Division of Radiation Oncology and Division of Radiology respectively. CONCLUSION: The radiograph viewing conditions in Johannesburg variably comply with guidelines. This study underscores the need to implement quality control and quality assurance standards in radiographic image viewing. PMID- 21614323 TI - Malignant epignathus teratoma. AB - A baby boy who had a left facial mass detected on antenatal ultrasound was delivered by Caesarian section after foetal distress was detected. Imaging investigations by plain radiographs and MRI showed a large mass with calcifications, soft tissue, fat and fluid components. A total surgical excision was perfomed and histology examination showed teratoma with no malignant features. Two weeks postoperatively, there was rapid recurrence of the tumour with intracranial involvement and obstructive hydrocephalus shown on MRI. The tumour was inoperable at surgery and the baby subsequently died at 5 weeks of life. This case describes the clinical course and imaging features of a neonatal epignathus teratoma with malignant and aggressive features. PMID- 21614324 TI - The South East Asian Federation of Organizations for Medical Physics (SEAFOMP): Its history and role in the ASEAN countries. AB - Informal discussion started in 1996 and the South East Asian Federation of Organizations for Medical Physics (SEAFOMP) was officially accepted as a regional chapter of the IOMP at the Chicago World Congress in 2000 with five member countries, namely Indonesia, Malaysia, Philippines, Singapore and Thailand. Professor Kwan-Hoong Ng served as the founding president until 2006. Brunei (2002) and Vietnam (2005) joined subsequently. We are very grateful to the founding members of SEAFOMP: Anchali Krisanachinda, Kwan-Hoong Ng, Agnette Peralta, Ratana Pirabul, Djarwani S Soejoko and Toh-Jui Wong.The objectives of SEAFOMP are to promote (i) co-operation and communication between medical physics organizations in the region; (ii) medical physics and related activities in the region; (iii) the advancement in status and standard of practice of the medical physics profession; (iv) to organize and/or sponsor international and regional conferences, meetings or courses; (v) to collaborate or affiliate with other scientific organizations.SEAFOMP has been organizing a series of congresses to promote scientific exchange and mutual support. The South East Asian Congress of Medical Physics (SEACOMP) series was held respectively in Kuala Lumpur (2001), Bangkok (2003), Kuala Lumpur (2004) and Jakarta (2006). The respective congress themes indicated the emphasis and status of development. The number of participants (countries in parentheses) was encouraging: 110 (17), 150 (16), 220 (23) and 126 (7).In honour of the late Professor John Cameron, an eponymous lecture was established. The inaugural John Cameron Lecture was delivered by Professor Willi Kalender in 2004. His lecture was titled "Recent Developments in Volume CT Scanning". PMID- 21614325 TI - A concern about plagiarism. PMID- 21614326 TI - Mastoiditis secondary to mycobacterium abscessus imaged with gallium-67 scintigraphy. AB - Atypical mycobacterium is rarely seen as a cause of chronic mastoiditis but has been increasingly recognized over the past few years. Mycobacterium abscessus is the most pathogenic and chemotherapy-resistant, rapid-growing mycobacterium of all the four groups. This paper presents a case of a 57-year-old woman who had chronic mastoiditis with recurrent exacerbations. The initial computed tomography (CT) findings showed the presence of an inflammatory process and she was treated with the appropriate antibiotics. The patient subsequently underwent a tissue biopsy when she presented with another exacerbation. At this time, the CT scan did not identify the ongoing exacerbation, but the Gallium-67 scintigraphy did. PMID- 21614327 TI - Molecular imaging: spawning a new melting-pot for biomedical imaging. AB - Predicting the future is a dangerous undertaking at best, and not meant for the faint-hearted. However, viewing the advances in molecular medicine, genomics and proteomics, it is easy to comprehend those who believe that molecular imaging methods will open up new vistas for medical imaging. The knock on effect will impact our capacity to diagnose and treat diseases. Anatomically detectable abnormalities, which have historically been the basis of the practice of radiology, will soon be replaced by molecular imaging methods that will reflect the under expression or over expression of certain genes which occur in almost every disease. Molecular imaging can then be resorted to so that early diagnosis and characterisation of disease can offer improved specificity. Given the growing importance of molecular medicine, imagers will find it profitable to educate themselves on molecular targeting, molecular therapeutics and the role of imaging in both areas. PMID- 21614328 TI - Degenerated uterine fibroid mimicking hydrometra: fallacy in CT. AB - Fibroids are the commonest uterine neoplasms, occurring in 20% - 30% of women of reproductive age. In women who have pelvic masses of unknown cause, unusual manifestations of fibroids such as necrosis or degeneration may simulate a carcinoma or hydrometra resulting in problems with image interpretation. We report a case of an unsuspected large degenerated uterine fibroid in a lady mistakenly diagnosed as hydrometra on computed tomography scanning. PMID- 21614329 TI - AOSR joins forces with biij. PMID- 21614330 TI - The quest for the ideal anato-molecular imaging fusion tool. PMID- 21614332 TI - A new world order: training clinicians for a new era in imaging. PMID- 21614331 TI - Evaluation of the quality of CT-like images obtained using a commercial flat panel detector system. AB - PURPOSE: The development of flat panel detector technology has resulted in renewed interest in the possibility of generating CT-like images from rotational angiographic acquisitions. At least two commercial products now use cone beam reconstruction software in conjunction with flat panel detectors to produce such images. The purpose of the work presented here is to report on image quality obtained from one such system in objective and subjective terms and to compare it with the quality of images obtained from a modern multi-detector CT scanner. METHOD: The Image quality was assessed using a CATPHAN 500 model and an AAPM CT Performance Phantom model. Image noise, CT number accuracy, CT number consistency, Low Contrast Resolution, surface dose and Modulation Transfer Function were assessed for the flat panel detector and compared with results obtained from a 4 slice CT scanner. RESULTS: As expected image quality obtained from the CT scanner was much better than from the flat panel detector. Low contrast resolution was much worse and the surface dose was higher for the flat panel detector than the CT scanner. There was an inaccuracy in CT number determination and the noise was greater by a factor of two or three. Limiting resolution was better on images from the CT scanner. CONCLUSION: The poor low contrast resolution from flat panel detector was expected given the expected resolution of +/-10 Hounsfield Units. These systems should not be considered as diagnostic CT scanners. However, the remaining performance figures indicate that the CT-like images obtained from this type of equipment are of sufficient quality for at least some clinical applications, such as detection of brain haemorrhages in the vascular suite. PMID- 21614333 TI - Exploring new vistas in biomedical journal publishing. PMID- 21614334 TI - Creating teaching files. PMID- 21614335 TI - Accidental blood exposure: risk and prevention in interventional radiology. AB - There is a growing concern about the transmission of bloodborne pathogens during medical procedures among health care workers and patients. Over the last three decades, radiological services have undergone many changes with the introduction of new modalities. One of these new disciplines is interventional radiology (IR) which deals with procedures such as arteriography, image-guided biopsies, intravascular catheter insertions, angioplasty and stent placements. Despite these developments, the potential for accidental blood exposure and exposure to other infectious material continues to exist. Therefore, it is important for all radiologists who perform invasive procedures to observe specific recommendations for infection control. In this review, we look at the different policies for protection and universal standards on infection control. PMID- 21614336 TI - Clinical use of PET/CT in thyroid cancer diagnosis and management. AB - The incidence of thyroid cancer is low, but when it occurs, it is mainly of the papillary histopathological type. Although PET/CT has a limited role in the diagnosis, it plays a significant role in the overall post-surgery management of a patient with thyroid cancer. This follow-up role is important, especially in patients with elevated serum thyroglobulin, but negative radioiodine whole body scans. There is increasing evidence that PET/CT should be a part of routine care in the Tg positive Radioiodine scan negative patient. PMID- 21614337 TI - Review of F-FDG Synthesis and Quality Control. AB - This review article covers a concise account on fludeoxyglucose ((18)F-FDG) synthesis and quality control procedures with emphasis on practical synthesis Currently, (18)F-FDG is the most successful PET radiopharmaceutical so far. The advancement in synthesis and quality control of (18)F-FDG, together with its approval by the US FDA and the availability of reimbursement, are probably the main reasons for the flourish of clinical PET over the last 20 years. (18)F-FDG can be synthesised by either electrophilic fluorination or nucleophilic fluorination reaction. Nucleophilic fluorination using mannose triflate as precursor and Kryptofix or tetrabutylammonium salts (TBA) is widely used because of higher yield and shorter reaction time. The quality control requirements of (18)F-FDG can be found in United States Pharmacopeia (USP), British Pharmacopeia (BP), European Pharmacopeia (EP) and the Chemistry, Manufacturing, and Controls (CMC) section from United States Food and Drug Administration (US FDA) PET draft guidance documents. Basic requirements include radionuclidic identity, radiochemical purity, chemical purity, pH, residual solvent, sterility, and bacterial endotoxin level. Some of these tests (sterility, endotoxins and radionuclidic purity) can be finished after the (18)F-FDG has been released. Although USP, BP and EP do not require filter membrane integrity test, many laboratories perform this test as an indirect evident of the product sterility. It is also interesting to note that there are major differences in (18)F-FDG quality requirements among USP, BP, and CMC. PMID- 21614338 TI - Shoulder ultrasound. PMID- 21614339 TI - Physiological uptake in FDG PET simulating disease. AB - Many potential pitfalls and artefacts have been described in PET imaging that uses F-18 fluorodeoxyglucose (FDG). Normal uptake of FDG occurs in many sites of the body and may cause confusion in interpretation particularly in oncology imaging. Clinical correlation, awareness of the areas of normal uptake of FDG in the body and knowledge of variation in uptake as well as benign processes that are FDG avid are necessary to avoid potential pitfalls in image interpretation. In this context, optimum preparation of patients for their scans can be instituted in an attempt to reduce the problem. Many of the problems and pitfalls associated with areas of normal uptake of FDG can be solved by using PET CT imaging. PET CT imaging has the ability to correctly attribute FDG activity to a structurally normal organ on CT. However, the development of combined PET CT scanners also comes with its own specific problems related to the combined PET CT technique. These include misregistration artefacts due to respiration and the presence of high density substances which may lead to artefactual overestimation of activity if CT data are used for attenuation correction. PMID- 21614340 TI - Artefacts of PET/CT images. AB - Positron emission tomography (PET) is a non-invasive imaging modality, which is clinically widely used both for diagnosis and accessing therapy response in oncology, cardiology and neurology.Fusing PET and CT images in a single dataset would be useful for physicians who could read the functional and the anatomical aspects of a disease in a single shot.The use of fusion software has been replaced in the last few years by integrated PET/CT systems, which combine a PET and a CT scanner in the same gantry. CT images have the double function to correct PET images for attenuation and can fuse with PET for a better visualization and localization of lesions. The use of CT for attenuation correction yields several advantages in terms of accuracy and patient comfort, but can also introduce several artefacts on PET-corrected images.PET/CT image artefacts are due primarily to metallic implants, respiratory motion, use of contrast media and image truncation. This paper reviews different types artefacts and their correction methods.PET/CT improves image quality and image accuracy. However, to avoid possible pitfalls the simultaneous display of both Computed Tomography Attenuation Corrected (CTAC) and non corrected PET images, side by side with CT images is strongly recommended. PMID- 21614341 TI - Uranium-mediated activation of small molecules. AB - Molecular complexes of uranium are capable of activating a range of industrially and economically important small molecules such as CO, CO(2), and N(2); new and often unexpected reactions provide insight into an element that needs to be well understood if future clean-energy solutions are to involve nuclear power. PMID- 21614342 TI - Chiral Bronsted acids in enantioselective carbonyl activations--activation modes and applications. AB - Chiral phosphoric acids and derivatives have attracted considerable attention as a powerful tool in asymmetric catalysis. Various enantioselective reactions have been developed by using these efficient Bronsted acid organocatalysts. Although initially the activation was restricted to reactive Bronsted basic substrates, recent reports are demonstrating the versatility of phosphoric acid catalysts in the activation of carbonyl compounds in a stereochemically controlled fashion. This tutorial review gives an overview of enantioselective Bronsted acid catalyzed transformations with the main focus on carbonyl activation. Different activation modes, key features of the catalysts and the applied substrates are presented and discussed with the goal to elucidate the origin of stereoselectivity in these Bronsted acid catalyzed transformations. PMID- 21614344 TI - The fourth virial coefficient of a nonadditive hard-disc mixture. AB - The fourth virial coefficient of symmetric nonadditive hard-disc mixtures is calculated over a wide range of nonadditivity. The irreducible cluster integrals were evaluated numerically using a standard Monte Carlo method. The coexistence line relative to the fluid-fluid phase transition, calculated through two equations of state built using the new virial coefficients, is compared with some numerical simulation results. PMID- 21614343 TI - Liquid chromatography-inductively coupled plasma-based metallomic approaches to probe health-relevant interactions between xenobiotics and mammalian organisms. AB - In mammals, the transport of essential elements from the gastrointestinal tract to organs is orchestrated by biochemical mechanisms which have evolved over millions of years. The subsequent organ-based assembly of sufficient amounts of metalloproteins is a prerequisite to maintain mammalian health and well-being. The chronic exposure of various human populations to environmentally abundant toxic metals/metalloid compounds and/or the deliberate administration of medicinal drugs, however, can adversely affect these processes which may eventually result in disease. A better understanding of the perturbation of these processes has the potential to advance human health, but their visualization poses a major problem. Nonetheless, liquid chromatography-inductively coupled plasma-based 'metallomics' methods, however, can provide much needed insight. Size-exclusion chromatography-inductively coupled plasma atomic emission spectrometry, for example, can be used to visualize changes that toxic metals/medicinal drugs exert at the metalloprotein level when they are added to plasma in vitro. In addition, size-exclusion chromatography-inductively coupled plasma mass spectrometry can be employed to analyze organs from toxic metal/medicinal drug-exposed organisms for metalloproteins to gain insight into the biochemical changes that are associated with their acute or chronic toxicity. The execution of such studies-from the selection of an appropriate model organism to the generation of accurate analytical data-is littered with potential pitfalls that may result in artifacts. Drawing on recent lessons that were learned by two research groups, this tutorial review is intended to provide relevant information with regard to the experimental design and the practical application of these aforementioned metallomics tools in applied health research. PMID- 21614345 TI - Using the face-saturated incomplete cage analysis to quantify the cage compositions and cage linking structures of amorphous phase hydrates. AB - Recent advances in the molecular dynamics simulations of spontaneous nucleation and growth of methane hydrate show that an amorphous phase of the hydrate is first reached. However, the amorphous hydrate has not been well described, due to the insufficient identification of cage structures. Here, we develop a method, called "face-saturated incomplete cage analysis", which can identify all face saturated cages in a given system. As a result, it is found that thousands of cage types and abundant occupancy states are present in the amorphous hydrate. Moreover, the crystallinity of amorphous hydrate is evaluated according to the quantitative calculation of cage linking structures, and the critical nucleus of hydrate is also estimated on the basis of clustering analysis for all face saturated cages. PMID- 21614346 TI - Photochemistry of hydrogen bonded heterocycles probed by photodissociation experiments and ab initio methods. AB - In this perspective article, we focus on the photochemistry of five-membered nitrogen containing heterocycles (pyrrole, imidazole and pyrazole) in clusters. These heterocycles represent paradigmatic structures for larger biologically active heterocyclic molecules and complexes. The dimers of the three molecules are also archetypes of different bonding patterns: N-H...pi interaction, N-H...N hydrogen bond and double hydrogen bond. We briefly review available data on photochemistry of the title molecules in the gas phase, but primarily we focus on the new reaction channels opened upon the complexation with other heterocycles or solvent molecules. Based on ab initio calculations we discuss various possible reactions in the excited states of the clusters: (1) hydrogen dissociation, (2) hydrogen transfer between the heterocyclic units, (3) molecular ring distortion, and (4) coupled electron-proton transfer. The increasing photostability with complexity of the system can be inferred from experiments with photodissociation in these clusters. A unified view on photoinduced processes in five-membered N heterocycles is provided. We show that even though different deactivation channels are energetically possible for the complexed heterocycles, in most cases the major result is a fast reconstruction of the ground state. The complexed or solvated heterocycles are thus inherently photostable although the stability can in principle be achieved via different reaction routes. PMID- 21614347 TI - A facile method for the assessment of DNA damage induced by UV-activated nanomaterials. AB - Fluorescent microscopy observation of gene-size DNA (T4 phage DNA or lambda phage DNA) was used to assess DNA damage induced by UV irradiation in the presence of nanomaterials, such as QDs (quantum dots: CdSe/ZnS semiconductor nanoparticles), the water-soluble fullerene derivative C(60)(OH)(n) (n = 6-12) and titanium oxide nanoparticles of 25 nm in diameter. The magnitude of DNA damage could be simply evaluated based on the degree of shortening of the stretched DNA image. This method showed that DNA damage was amplified by the action of QDs under irradiation by C-band (lambda(max) = 254 nm) or B-band (lambda(max) = 303 nm) UV. Smaller QDs that emitted higher-energy fluorescence (lambda = 565 nm) induced more severe damage than medium- and larger-size QDs that emitted longer wavelength fluorescence (lambda = 605 and 705 nm, respectively). The fullerene derivative and TiO(2) nanoparticles caused DNA damage even under irradiation by A band UV (lambda(max) = 365 nm) and showed more severe DNA damage than QDs under similar conditions. PMID- 21614348 TI - A self assembled monolayer based microfluidic sensor for urea detection. AB - Urease (Urs) and glutamate dehydrogenase (GLDH) have been covalently co immobilized onto a self-assembled monolayer (SAM) comprising of 10-carboxy-1 decanthiol (CDT) via EDC-NHS chemistry deposited onto one of the two patterned gold (Au) electrodes for estimation of urea using poly(dimethylsiloxane) based microfluidic channels (2 cm * 200 MUm * 200 MUm). The CDT/Au and Urs-GLDH/CDT/Au electrodes have been characterized using Fourier transform infrared (FTIR) spectroscopy, contact angle (CA), atomic force microscopy (AFM) and electrochemical cyclic voltammetry (CV) techniques. The electrochemical response measurement of a Urs-GLDH/CDT/Au bioelectrode obtained as a function of urea concentration using CV yield linearity as 10 to 100 mg dl(-1), detection limit as 9 mg dl(-1) and high sensitivity as 7.5 MUA mM(-1) cm(-2). PMID- 21614349 TI - Experimental investigation of the flow induced by artificial cilia. AB - The fluid transport produced by rectangular shaped, magnetically actuated artificial cilia of 70 MUm length and 20 MUm width was determined by means of phase-locked Micro Particle Image Velocimetry (MUPIV) measurements in a closed microfluidic chamber. The phase-averaged flow produced by the artificial cilia reached up to 130 MUm s(-1) with an actuation cycle frequency of 10 Hz. Analysis of the measured flow data indicate that the present system is capable of achieving volume flow rates of V[combining dot above](cilia) = 14 +/- 4 MUl min( 1) in a micro channel of 0.5 * 5 mm(2) cross-sectional area when no back pressure is built up. This corresponds to an effective pressure gradient of 6 +/- 1 Pa m( 1), which equals a pressure difference of 0.6 +/- 0.1 mPa over a distance of 100 MUm between two rows of cilia. These results were derived analytically from the measured velocity profile by treating the cilia as a thin boundary layer. While the cilia produce phase-averaged velocities of the order of O(10(2)MUm s(-1)), time-resolved measurements showed that the flow field reverses two times during one actuation cycle inducing instantaneous velocities of up to approximately 2 mm s(-1). This shows that the flow field is dominated by fluid oscillations and flow rates are expected to increase if the beating motion of the cilia is further improved. PMID- 21614350 TI - [Si(SiMe3)3]3Ge9M(CO)3(-) (M=Cr, Mo, W): coordination chemistry with metalloid clusters. AB - Very recently it was shown that the metalloid cluster compound {Ge(9)[Si(SiMe(3))(3)](3)}(-)1 can be used for subsequent reactions as the shielding of the cluster core is rather incomplete. So the reaction of 1 with Cr(CO)(3)(CH(3)CN)(3) leads to a cluster enlargement where the chromium atom is incorporated into the cluster core. Here further applications of 1 as a flexible ligand in coordination chemistry are presented where the reaction of 1 with Mo(CO)(3)(EtCN)(3) and W(CO)(3)(CH(3)CN)(3) leads to [(CO)(3)MoGe(9)R(3)](-)4 and [(CO)(3)WGe(9)R(3)](-)5 respectively (R = Si(SiMe(3))(3)), showing that 1 can indeed be used as a flexible ligand in coordination chemistry. Structural and electronic properties of the Ge(9)M clusters 4 and 5 are discussed as well as mechanistic aspects of their formation. PMID- 21614351 TI - Ring openings of lactone and ring contractions of lactide by frustrated Lewis pairs. AB - While B(C(6)F(5))(3) forms the adducts (CH(2))(4)CO(2)B(C(6)F(5))(3)1 and (CHMeCO(2))(2)B(C(6)F(5))(3)7 with delta-valerolactone and lactide, the frustrated Lewis pairs derived from B(C(6)F(5))(3) and phosphine or N-bases react with lactone to effect ring opening affording zwitterionic species of the form L(CH(2))(4)CO(2)B(C(6)F(5))(3) (L = tBu(3)P 2, Cy(3)P 3, C(5)H(3)Me(3)N 4, PhNMe(2) 5, C(5)H(6)Me(4)NH 6) while reaction with rac-lactide results in ring contraction to give salts [LH][OCCHMeCO(2)(CMe)OB(C(6)F(5))(3)] (L = tBu(3)P 8, Cy(3)P 9, C(5)H(3)Me(2)N 10, C(5)H(6)Me(4)NH 11). The mechanistic implications of these reactions are discussed. PMID- 21614352 TI - Photoreactive 3D microporous lanthanide MOFs: formation of a strained ladderane in a partial single crystal-to-single crystal manner. AB - The assembly of Er(3+) and Y(3+) cations with trans,trans-muconic acid affords a photoreactive 3D microporous MOF that, upon UV irradiation, undergoes a cycloaddition reaction (SCSC up to 55%), with in situ formation of a strained ladderane. PMID- 21614353 TI - A copper(I)-ion selective two-photon fluorescent probe for in vivo imaging. AB - We report a two-photon fluorescent probe (ACu1) that can be excited by 750 nm femto-second pulses, shows high photostability and negligible toxicity, and can visualize Cu(+) distribution in live cells and tissues by two-photon microscopy. PMID- 21614354 TI - Lewis acid-activated oxidation of alcohols by permanganate. AB - The oxidation of alcohols by KMnO(4) is greatly accelerated by various Lewis acids. Notably the rate is increased by 4 orders of magnitude in the presence of Ca(2+). The mechanisms of the oxidation of CH(3)OH and PhCH(OH)CH(3) by MnO(4)(-) and BF(3).MnO(4)(-) have also been studied computationally by the DFT method. PMID- 21614355 TI - Multicolored electrochromism in 4,4'-biphenyl dicarboxylic acid diethyl ester. AB - We investigated the properties of 4,4'-biphenyl dicarboxylic acid diethyl ester (PCE). The PCE underwent a 2-step reduction at -1.5 V and -2.2 V. The color of the PCE changed from colorless to yellow in the first step and consequently to red in the second reduction step. A PCE based EC cell using an NiO-modified electrode was also fabricated. The NiO electrode worked as a counter reaction material for PCE reduction. The PCE-NiO cell achieved multi-coloration ranging from colorless to yellow and red, and also achieved high coloration efficiency and long term switching stability. PMID- 21614365 TI - Direct evidence of the SMSI decoration effect: the case of Co/TiO2 catalyst. AB - First direct images of cobalt nanoparticles covered by a few atomic layers thick TiO(x) moieties after reduction treatment of a Co/TiO(2) system with the simultaneous formation of Co-O-Ti bonds confirm the development of the SMSI decoration effect. PMID- 21614364 TI - Probing dynamic cell-substrate interactions using photochemically generated surface-immobilized gradients: application to selectin-mediated leukocyte rolling. AB - Model substrates presenting biochemical cues immobilized in a controlled and well defined manner are of great interest for their applications in biointerface studies that elucidate the molecular basis of cell receptor-ligand interactions. Herein, we describe a direct, photochemical method to generate surface immobilized biomolecular gradients that are applied to the study of selectin mediated leukocyte rolling. The technique employs benzophenone-modified glass substrates, which upon controlled exposure to UV light (350-365 nm) in the presence of protein-containing solutions facilitate the generation of covalently immobilized protein gradients. Conditions were optimized to generate gradient substrates presenting P-selectin and PSGL-1 (P-selectin glycoprotein ligand-1) immobilized at site densities over a 5- to 10-fold range (from as low as ~200 molecules MUm(-2) to as high as 6000 molecules MUm(-2)). The resulting substrates were quantitatively characterized via fluorescence analysis and radioimmunoassays before their use in the leukocyte rolling assays. HL-60 promyelocytes and Jurkat T lymphocytes were assessed for their ability to tether to and roll on substrates presenting immobilized P-selectin and PSGL-1 under conditions of physiologically relevant shear stress. The results of these flow assays reveal the combined effect of immobilized protein site density and applied wall shear stress on cell rolling behavior. Two-component substrates presenting P-selectin and ICAM-1 (intercellular adhesion molecule-1) were also generated to assess the interplay between these two proteins and their effect on cell rolling and adhesion. These proof-of-principle studies verify that the described gradient generation approach yields well-defined gradient substrates that present immobilized proteins over a large range of site densities that are applicable for investigation of cell materials interactions, including multi-parameter leukocyte flow studies. Future applications of this enabling methodology may lead to new insights into the biophysical phenomena and molecular mechanism underlying complex biological processes such as leukocyte recruitment and the inflammatory response. PMID- 21614366 TI - Lanthanide directed self-assembly formations of Tb(III) and Eu(III) luminescent complexes from tryptophan based pyridyl amide ligands. AB - The formation of self-assembly complexes between the ligands 1 (SS) and 2 (RR) and terbium or europium was undertaken and shown (using various spectroscopic titrations) to give rise to the exclusive formation of 2:1 (L:Ln) stoichiometry and not the anticipated 3:1 stoichiometry. PMID- 21614367 TI - Hierarchical organization of a robust porphyrin cage self-assembled by hydrogen bonds. AB - Porphyrins appended with four rigid hydrogen bonding motifs on the meso positions were synthesized and self-assembled into a cofacial cage with four complementary bis(decyl)melamine units in dry solvents. The hydrocarbon chains on the melamine mediate the formation of nanofilms on surfaces as the solvent slowly evaporates. PMID- 21614368 TI - High reaction activity of nitrogen-doped carbon nanotubes toward the electrooxidation of nitric oxide. AB - Carbon nanotubes doped with N (NCNTs) enable 1.5 times faster electron-transfer kinetics for the oxidation of NO compared to pristine carbon nanotubes (CNTs), which may be due to the low adsorption energy for a NO on pyridinic NCNT(5,5) allowing NO to lose electrons readily and facilitate the following oxidation to nitrate. PMID- 21614369 TI - Bifunctional anthracene derivatives as non-doped blue emitters and hole transporters for electroluminescent devices. AB - New highly fluorescent bifunctional anthracenes showed high thermal and electrochemical stability, and great potential as both blue emitters and hole transporters for OLEDs. Deep-blue and Alq3-based green devices with maximum efficiencies and CIE coordinates of 1.65 and 6.25 cd A(-1), and (0.15, 0.16) and (0.26, 0.49) were achieved, respectively. PMID- 21614370 TI - A visible-light-driven transfer hydrogenation on CdS nanoparticles combined with iridium complexes. AB - A visible-light-driven transfer hydrogenation of carbonyl and C=C compounds has been developed by coupling CdS nanoparticles with iridium complexes, exhibiting high activities, excellent selectivities and a unique pH-dependent catalytic activity. PMID- 21614371 TI - Reusable plasmonic aptasensors: using a single nanoparticle to establish a calibration curve and to detect analytes. AB - We demonstrate plasmonic aptasensors that allow a single nanoparticle (NP) to generate a calibration curve and to detect analytes. The proposed reusable aptasensors have significant advantages over conventional single-NP based assays in terms of sensitivity and reproducibility. PMID- 21614372 TI - Stepwise assembly of metal-organic framework based on a metal-organic polyhedron precursor for drug delivery. AB - A 12-connected network with fcu topology was firstly reported focusing on using predesigned metal-organic polyhedron (MOP) as the precursor, and its adsorption and delivery of the drug 5-fluorouracil (5-FU) was also determined. PMID- 21614373 TI - Practical manganese-catalysed highly enantioselective cis-dihydroxylation of electron-deficient alkenes and detection of a cis-dioxomanganese(V) intermediate by high resolution ESI-MS analysis. AB - A practical protocol has been developed for asymmetric cis-dihydroxylation of electron-deficient alkenes with Oxone catalysed by a manganese complex bearing a chiral tetradentate N(4)-donor ligand affording cis-diols in up to 95% yield with up to 96% ee. Analysis of the reaction mixture by high resolution ESI-MS revealed the formation of a cis-dioxomanganese(V) intermediate. PMID- 21614374 TI - A novel catalytic process for trifluoromethylation of bromoaromatic compounds. AB - The palladium-catalyzed trifluoromethylation of aryl bromides has been achieved in micellar media. The micellar conditions result in enhanced yields and are applicable to bromoaromatics with ketone, aldehyde, hydroxyl and amine functionalities. PMID- 21614375 TI - CdS quantum dots/Ru(bpy)3(2+) electrochemiluminescence resonance energy transfer system for sensitive cytosensing. AB - In this paper, an electrochemiluminescence resonance energy transfer (ECL-RET) system from CdS quantum dot to Ru(bpy)(3)(2+) was developed for the first time. By the signal amplification of Ru(bpy)(3)(2+) and the specific antibody-cell surface interactions, this ECL-RET system could sensitively respond down to 12.5 SMMC-7721 cells per mL. PMID- 21614376 TI - Design of N-sulfinyl homoallylic amines as novel sulfinamide-olefin hybrid ligands for asymmetric catalysis: application in Rh-catalyzed enantioselective 1,4-additions. AB - Here we show that simple and readily available chiral sulfinamide-olefins can display great catalytic activities and enantioselectivities in rhodium-catalyzed 1,4-addition reactions. This study represent the first example of chiral sulfur based olefin ligand class for transition metal-catalyzed asymmetric transformation. PMID- 21614377 TI - Does the concept of Clar's aromatic sextet work for dicationic forms of polycyclic aromatic hydrocarbons?--testing the model against charged systems in singlet and triplet states. AB - The concept of Clar's pi-electron aromatic sextet was tested against a set of polycyclic aromatic hydrocarbons in neutral and doubly charged forms. Systems containing different types of rings (in the context of Clar's concept) were chosen, including benzene, naphthalene, anthracene, phenanthrene and triphenylene. In the case of dicationic structures both singlet and triplet states were considered. It was found that for singlet state dicationic structures the concept of aromatic sextet could be applied and the local aromaticity could be discussed in the context of that model, whereas in the case of triplet state dicationic structures Clar's model rather failed. Different aromaticity indices based on various properties of molecular systems were applied for the purpose of the studies. The discussion about the interdependence between the values of different aromaticity indices applied to neutral and charged systems in singlet and triplet states is also included. PMID- 21614378 TI - Cleavage of unreactive bonds with pincer metal complexes. AB - Since the first reports some three decades ago, the chemistry of pincer metal complexes has seen a tremendous development with impact on materials chemistry, supramolecular chemistry, bioorganometallics, and, presumably most significantly, on (catalytic) bond making and breaking processes. The remarkable progress is due to a large extent to the well-defined nature and tunability of the pincer ligand which allows the reactivity of the metal center to be modified and eventually tailored to specific needs. This Perspective summarizes the achievements in employing pincer complexes for mediating and catalyzing the cleavage of typically unreactive bonds such as C-H, C-C, C-E, and E-H bonds, arguably one of the most spectacular applications of pincer chemistry. PMID- 21614379 TI - Organophosphate and phthalate esters in indoor air: a comparison between multi storey buildings with high and low prevalence of sick building symptoms. AB - An extensive study has been conducted on the prevalence of organophosphorous flame retardants/plasticizers and phthalate ester plasticizers in indoor air. The targeted substances were measured in 45 multi-storey apartment buildings in Stockholm, Sweden. The apartment buildings were classified as high or low risk with regard to the reporting of sick building symptoms (SBS) within the project Healthy Sustainable Houses in Stockholm (3H). Air samples were taken from two to four apartments per building (in total 169 apartments) to facilitate comparison within and between buildings. Association with building characteristics has been examined as well as association with specific sources by combining chemical analysis and exploratory uni- and multivariate data analysis. The study contributes to the overall perspective of levels of organophosphate and phthalate ester in indoor air enabling comparison with other studies. The results indicated little or no difference in the concentrations of the target substances between the two risk classifications of the buildings. The differences between the apartments sampled within (intra) buildings were greater than the differences between (inter) buildings. The concentrations measured in air ranged up to 1200 ng m(-3) for organophosphate esters and up to 11 000 ng m(-3) for phthalate esters. Results in terms of sources were discerned e.g. PVC flooring is a major source of benzylbutyl phthalate in indoor air. PMID- 21614380 TI - Microfabricated polyester conical microwells for cell culture applications. AB - Over the past few years there has been a great deal of interest in reducing experimental systems to a lab-on-a-chip scale. There has been particular interest in conducting high-throughput screening studies using microscale devices, for example in stem cell research. Microwells have emerged as the structure of choice for such tests. Most manufacturing approaches for microwell fabrication are based on photolithography, soft lithography, and etching. However, some of these approaches require extensive equipment, lengthy fabrication process, and modifications to the existing microwell patterns are costly. Here we show a convenient, fast, and low-cost method for fabricating microwells for cell culture applications by laser ablation of a polyester film coated with silicone glue. Microwell diameter was controlled by adjusting the laser power and speed, and the well depth by stacking several layers of film. By using this setup, a device containing hundreds of microwells can be fabricated in a few minutes to analyze cell behavior. Murine embryonic stem cells and human hepatoblastoma cells were seeded in polyester microwells of different sizes and showed that after 9 days in culture cell aggregates were formed without a noticeable deleterious effect of the polyester film and glue. These results show that the polyester microwell platform may be useful for cell culture applications. The ease of fabrication adds to the appeal of this device as minimal technological skill and equipment is required. PMID- 21614381 TI - Development of a microfluidics biosensor for agarose-bead immobilized Escherichia coli bioreporter cells for arsenite detection in aqueous samples. AB - Contamination with arsenic is a recurring problem in both industrialized and developing countries. Drinking water supplies for large populations can have concentrations much higher than the permissible levels (for most European countries and the United States, 10 MUg As per L; elsewhere, 50 MUg As per L). Arsenic analysis requires high-end instruments, which are largely unavailable in developing countries. Bioassays based on genetically engineered bacteria have been proposed as suitable alternatives but such tests would profit from better standardization and direct incorporation into sensing devices. The goal of this work was to develop and test microfluidic devices in which bacterial bioreporters could be embedded, exposed and reporter signals detected, as a further step towards a complete miniaturized bacterial biosensor. The signal element in the biosensor is a nonpathogenic laboratory strain of Escherichia coli, which produces a variant of the green fluorescent protein after contact to arsenite and arsenate. E. coli bioreporter cells were encapsulated in agarose beads and incorporated into a microfluidic device where they were captured in 500 * 500 MUm(2) cages and exposed to aqueous samples containing arsenic. Cell-beads frozen at -20 degrees C in the microfluidic chip retained inducibility for up to a month and arsenic samples with 10 or 50 MUg L(-1) could be reproducibly discriminated from the blank. In the 0-50 MUg L(-1) range and with an exposure time of 200 minutes, the rate of signal increase was linearly proportional to the arsenic concentration. The time needed to reliably and reproducibly detect a concentration of 50 MUg L(-1) was 75-120 minutes, and 120-180 minutes for a concentration of 10 MUg L(-1). PMID- 21614382 TI - Cloning and functional analysis of the naphthomycin biosynthetic gene cluster in Streptomyces sp. CS. AB - Naphthomycins (NATs) are 29-membered naphthalenic ansamacrolactam antibiotics with antimicrobial and antineoplastic activities. Their biosynthesis starts from 3-amino-5-hydroxy-benzoic acid (AHBA). By PCR amplification with primers for AHBA synthase and amino-dehydroquinate (aDHQ) synthase, a genomic region containing orthologs of these genes was identified in Streptomyces sp. CS. It was confirmed to be involved in naphthomycin biosynthesis by deletion of a large DNA fragment, resulting in abolishment of naphthomycin production. A 106 kb region was sequenced, and 32 complete ORFs were identified, including five polyketide synthase genes, eight genes for AHBA synthesis, and putative genes for modification, regulation, transport or resistance. Targeted inactivation and complementation experiments proved that the halogenase gene nat1 is responsible for the chlorination of C-30 of NATs. The nat1 mutant could also be complemented with asm12, the halogenase gene of ansamitocin biosynthesis. Likewise, an asm12 mutant could be complemented with nat1, suggesting a similar catalytic mechanism for both halogenases. A putative hydroxylase gene, nat2, was also inactivated, whereupon the biosynthesis of NATs was completely abolished with a tetraketide desacetyl-SY4b accumulated, indicating the participation of nat2 in the formation of the naphthalene ring. The information presented here expands our understanding of the biosynthesis of naphthalenic ansamycins, and may pave the way for engineering ansamacrolactams with improved pharmaceutical properties. PMID- 21614383 TI - Inherently chiral phosphonatocavitands as artificial chemo- and enantio-selective receptors of natural ammoniums. AB - Inherently chiral phosphonatocavitands with various bridging moieties at their wide rim were synthesized. Optical resolution by chiral HPLC was performed with cavitand 8 to afford enantiopure compounds (+)-8 and (-)-8. The molecular structures of hosts 8 and 12 were determined by X-ray diffraction. The host properties were investigated by (1)H and (31)P NMR spectroscopy. The phosphonatocavitands form inclusion complexes with chiral ammonium neurotransmitters, some presenting enantioselectivity towards the right or left handed host enantiomers. PMID- 21614384 TI - A ratiometric fluorescent probe for cyanide based on FRET. AB - On the basis of FRET from 4-(N,N-dimethylamino)benzamide to fluorescein, a new ratiometric fluorescence probe bearing a hydrazone binding unit was developed for highly selective and sensitive detection of CN(-) in aqueous solution. PMID- 21614385 TI - First asymmetric cascade reaction catalysed by chiral primary aminoalcohols. AB - Readily available chiral primary 1,2-aminoalcohols and diamines have been explored as organocatalysts for a domino Michael-aldol reaction. Their application in this organocascade process afforded cyclohexanone A with high levels of reactivity (up to 91% yield) and stereoselectivity (>97 : 3 d.r., up to 93% ee). Depending on the acid cocatalyst different chiral species (cyclic secondary amines vs. acyclic primary amines) might catalyse the process. In order to shed light on the catalytic activation, several experiments were carried out and a detailed possible reaction mechanism is proposed. Theoretical studies support the stereochemical outcome of the process. PMID- 21614386 TI - A divalent germanium complex of calix[5]arene. AB - The reaction of the germylene Ge[N(SiMe(3))(2)](2) with calix[5]arene yields the first example of a group 14 calix[5]arene complex. The crystal structure of this material has been obtained and contains two calix[5]arene macrocycles held together by a Ge(2)O(2) rhombus. PMID- 21614388 TI - Highly enantioselective aldol reaction of acetone with beta,gamma-unsaturated alpha-keto esters promoted by simple chiral primary-tertiary diamine catalysts. AB - A series of primary-tertiary diamine catalysts were successfully applied to promote the enantioselective aldol reaction of acetone with beta,gamma unsaturated alpha-keto esters in excellent yields (up to 99%) and enantioselectivities (up to 96% ee). PMID- 21614387 TI - Synthesis and characterization of a cell-permeable near-infrared fluorescent deoxyglucose analogue for cancer cell imaging. AB - We report the synthesis and characterization of a novel NIR fluorescent deoxyglucose analogue, CyNE 2-DG. Experiments in different cell lines showed a preferential uptake of CyNE 2-DG in cancer cells and its effective competition with unlabeled d-glucose. Cell imaging experiments demonstrated the superior cell permeability of CyNE 2-DG over the NIR standard IRDye 800CW 2-DG, and validated its application for cancer cell imaging in the NIR region. PMID- 21614389 TI - Ring-closing metathesis (RCM) based synthesis of the macrolactone core of amphidinolactone A. AB - A convergent synthesis of the macrolactone core of amphidinolactone A has been achieved, in a 10 step linear sequence with 32% overall yield, through a ring closing metathesis reaction as the macrolactonization step. The RCM precursor was obtained by the union of acid and alcohol fragments derived from (R) epichlorohydrin and (R)-2,3-O-isopropylidene glyceraldehyde, respectively. PMID- 21614390 TI - Bi(OTf)3-catalysed prenylation of electron-rich aryl ethers and phenols with isoprene: a direct route to prenylated derivatives. AB - Electron-rich aryl ethers and phenols react with isoprene (2-methylbuta-1,3 diene) in the presence of catalytic Bi(OTf)(3) at 40 degrees C to afford the corresponding prenylated or 2,2-dimethylchroman products, respectively, in moderate to good yields. This transformation offers a convenient and expedient entry to prenylated derivatives of electron-rich aromatics that often display enhanced biological activities. The methodology has been employed in the efficient synthesis of a biologically active natural product and related compounds. PMID- 21614391 TI - The synergy between qualitative theory, quantitative calculations, and direct experiments in understanding, calculating, and measuring the energy differences between the lowest singlet and triplet states of organic diradicals. AB - This perspective describes research, carried out in the authors' labs over the past forty years, aimed at understanding, predicting, and measuring the singlet triplet energy differences (DeltaE(ST)) in diradicals. A theory for qualitatively predicting the ground states of diradicals and the use of Negative Ion Photoelectron Spectroscopy (NIPES) for measuring DeltaE(ST) are described. The application of this theory, ab initio calculations, and NIPES to the prediction and measurement of DeltaE(ST) in a wide variety of organic diradicals is detailed. Among the diradicals that are discussed in this perspective are HN, CH(3)N, PhN, CH(2), trimethylenemethane (TMM), oxyallyl (OXA), meta benzoquinodimethane (MBQDM), meta-benzoquinone (MBQ), tetramethyleneethane (TME), 1,2,4,5-tetramethylenebenzene (TMB), and D(8 h) cyclooctatetraene (COT). All of these diradicals have been studied in one and, in most cases, in both of the authors' laboratories. The studies of OXA and D(8h) COT were, in fact, collaborations between the research groups of the authors. These two projects both took advantage of the ability of NIPES to provide information about transition states. Transition-state spectroscopy was used to measure the carbonyl stretching frequency in the singlet state of OXA and to establish that D(8h) COT violates the strictest version of Hund's rule. PMID- 21614392 TI - Distorted fused porphyrin-phthalocyanine conjugates: synthesis and photophysics of supramolecular assembled systems with a pyridylfullerene. AB - In the current work, we report on the synthesis and photophysical features of supramolecular hybrid systems that are based on newly fused porphyrin phthalocyanine (P-Pc) conjugates and a pyridylfullerene. The ZnP-ZnPc conjugate was synthesized in three steps starting with a Diels-Alder reaction between beta vinylporphyrin and fumaronitrile. The resulting mixture of isomeric adducts was then dehydrogenated to yield the corresponding benzo[b]porphyrin-2(1),2(2) dicarbonitrile. In the final step, cyclotetramerization with 4-tert butylphthalonitrile, in the presence of zinc acetate, afforded the bis-metalated conjugate. Selective demetallation of ZnP led to the H(2)P-ZnPc conjugate. For both conjugates steric hindrance is the inception to a bent configuration, which does, however, not preclude enlargement of the pi-conjugated system, that is, the porphyrins and the phthalocyanines. The two conjugates coordinate N-(4 pyridyl)fullero[c]pyrrolidine giving rise to the corresponding supramolecular porphyrin-phthalocyanine-fullerene systems. Photophysical measurements corroborate a sequential deactivation in the excited state, namely an initial intramolecular energy transfer from ZnP or H(2)P to ZnPc followed by an intramolecular charge transfer to yield ZnP-(ZnPc)(+)-(C(60))(-) and H(2)P (ZnPc)(+)-(C(60))(-), respectively. PMID- 21614393 TI - Characteristics of particulate matter pollution in the Pearl River Delta region, China: an observational-based analysis of two monitoring sites. AB - Two-year monitoring data (2006 and 2009), collected at the sub-urban site (WQS) and the background site (TH), were used to study the characteristics of Particulate Matter (PM) pollution in the Pearl River Delta region, China. Similar levels of PM(2.5) concentration measured at both sites seem to confirm that the fine particles have emerged as a major regional pollution issue. The seasonal variation of PM(2.5) concentration is associated with the regional monsoon circulations while the diurnal variation is related to land-sea breeze, traffic emissions and boundary layer development. Negative correlation was found in PM(2.5)-wind speed and PM(2.5)-humidity. Analysis of radiation, temperature and ozone suggests the existence of secondary aerosol formation. Transport effect may be another contributing factor to high PM pollution in the region, such as occasional long-distance dust intrusion and trans-boundary effects from upwind areas. PMID- 21614394 TI - Interface self-assembly to construct vertical peptide nanorods on quartz template. AB - A rationally designed glycyl-glycine derivative containing a light cleaved pyrenylmethyl ester tail was covalently bound onto the surface of quartz template. The interface self-assembly of this dipeptide building block induced the formation of chemically bound vertically aligned nanorods (CBVANs) with light sensitivity on the template. PMID- 21614395 TI - A strategy for producing predicted polymorphs: catemeric carbamazepine form V. AB - A computationally assisted approach has enabled the first catemeric polymorph of carbamazepine (form V) to be selectively formed by templating the growth of carbamazepine from the vapour phase onto the surface of a crystal of dihydrocarbamazepine form II. PMID- 21614396 TI - Role of hydrocarbons in pore expansion and contraction of a flexible metal organic framework. AB - A metal-organic framework obtained from a flexible organic linker shows a breathing phenomenon upon adsorption of saturated hydrocarbons. PMID- 21614397 TI - Detection of human serum albumin through surface-enhanced Raman scattering using gold "pearl necklace" nanomaterials as substrates. AB - We describe a surface-enhanced Raman scattering (SERS)-based sensor for the detection of human serum albumin (HSA) using gold "pearl necklace" nanomaterials (Au PNNs) as the substrate and AB 580 as the reporter. PMID- 21614398 TI - Effect of surfactants on the chemiluminescence of acridinium dimethylphenyl ester labels and their conjugates. AB - Chemiluminescent acridinium dimethylphenyl esters, containing two methyl groups flanking the phenolic ester bond, display excellent chemiluminescence stability and are used as labels in automated immunoassays for clinical diagnostics. Light emission from these labels is triggered with alkaline peroxide in the presence of the cationic surfactant cetyltrimethylammonium chloride. Under these conditions, light emission is rapid and is complete in <5 s. In the present study we examined the effect of various surfactants on light emission from acridinium dimethylphenyl ester labels and their conjugates containing hydrophilic linkers derived either from hexa(ethylene)glycol or a sulfobetaine zwitterion. Sulfobetaine zwitterions are very polar and incorporation of these functional groups in acridinium dimethyphenyl esters and their conjugates represents a new approach to improving the aqueous solubility of these chemiluminescent labels. Our results indicate that in general, surfactants affect light emission from these labels and their conjugates by two discrete mechanisms. Cationic surfactants, but not anionic or non-ionic surfactants, accelerate overall light emission kinetics and a more modest effect is observed with zwitterionic surfactants. Surfactants also enhance total light output and the magnitude of this enhancement is maximal for cationic surfactants and a sulfobetaine zwitterionic surfactant. These observations are the first to clearly delineate the role of the surfactant on the chemiluminescence reaction pathway of acridinium esters and can be rationalized based on known effects of surfactant aggregates on bimolecular and unimolecular reactions. PMID- 21614399 TI - Synthesis and structure of [Na4(DMSO)15][(I3)3(I)]. Self-assembly of hexacoordinated sodium. AB - A new complex with the molecular formula [Na(4)(DMSO)(15)][(I(3))(3)(I)] represents the first example of Na(+) coordinated solely by DMSO. The triiodide (I(3)(-)) and iodide (I(-)) anions form an infinite linear chain running throughout the crystal. PMID- 21614400 TI - Sensitive and selective detection of zinc ions in neuronal vesicles using PYDPY1, a simple turn-on dipyrrin. AB - A new class of in vitro Zn(II) chemosensor based on dipyrrin has been developed. 5-(Pyren-1-yl)-4,6-dipyrrin (PYDPY1) was synthesized and exhibited high selectivity and sensitivity to Zn(II) (K(d) of 20 MUM) compared to other metal ions. PYDPY1 was applied to the visualization of Zn(II) concentration in hippocampal tissue. PMID- 21614401 TI - Total synthesis of a 20-deoxybryostatin. AB - The 20-deoxybryostatin 40 has been prepared using a modified Julia olefination to form the 16,17-double-bond, followed by macrolactonisation, selective deprotection and oxidation. This is the first total synthesis of a 20 deoxybryostatin. PMID- 21614402 TI - Multimetal Fischer carbene complexes of Group VI transition metals: synthesis, structure and substituent effect investigation. AB - Fischer carbene complexes of tungsten with substituents containing up to two additional different transition metals, with all the metals in electronic contact with the carbene carbon atom, were synthesised and studied both in solution and in the solid state. For the complexes of the type [W(CO)(5){C(OR')R}], the substituents chosen were heteroaromatic 2-benzo[b]thienyl (2-BT), or 2-BT pi bonded to a chromium tricarbonyl fragment ([Cr(CO)(3)(2-eta(6)-BT)]) or ferrocenyl (Fc) as the R-substituent, while the OR'-substituent was systematically varied between an ethoxy or a titanoxy group, to yield the complexes 1b (R' = Et, R = 2-BT), 2b (R' = Et, R = [Cr(CO)(3)(2-eta(6)-BT)]), 3b (R' = TiCp(2)Cl, R = 21-BT), 4b (R' = TiCp(2)Cl, R = [Cr(CO)(3)(2-eta(6)-BT)]), 5b (R' = Et, R = Fc) and 6b (R' = TiCp(2)Cl, R = Fc). The structural features and their relevance to bonding in the multimetal carbene compounds of both these tungsten and the analogous chromium complexes were investigated as they represent indicators of possible reactivity sites in multimetal carbene assemblies. The possibility of using DFT calculations to quantify the effect of metal-containing substituents on the carbene ligands was tested and correlated with experimental parameters by employing methods such as vibrational spectroscopy, molecular orbital analysis, and cyclic voltammetry. PMID- 21614403 TI - Chiral inversion of 2-arylpropionyl-CoA esters by human alpha-methylacyl-CoA racemase 1A (P504S)--a potential mechanism for the anti-cancer effects of ibuprofen. AB - Metabolic chiral inversion of 2-arylpropanoic acids (2-APAs;'profens'), such as ibuprofen, is important for pharmacological activity. Several 2-APA-CoA esters were good racemisation substrates for human AMACR 1A, suggesting a common chiral inversion pathway for all 2-APAs and an additional mechanism for their anti cancer properties. PMID- 21614404 TI - Chip-based size-selective sorting of biological cells using high frequency acoustic excitation. AB - This work presents the size-selective sorting of single biological cells using the assembly process known as templated assembly by selective removal (TASR). We have demonstrated experimentally, for the first time, the selective placement and sorting of single SF9 cells (clonal isolate derived from Spodoptera frugiperda (Fall Armyworm) IPLB-Sf21-AE cells) into patterned hemispherical sites on rigid assembly templates using TASR. Nearly 100% of the assembly sites on the template were filled with matching cells (with assembly density as high as 900 sites per mm(2)) within short time spans of 3 minutes. 3-D reconstruction of cell profiles and volume analysis of cells trapped inside assembly sites demonstrates that only those cells that match the assembly site precisely (within 0.5 MUm) in size are assembled on the template. The assembly conditions are also compatible with the extension of TASR to mammalian cells. TASR-based size-selective structuring and sorting of biological systems represents a valuable tool with potential for implementation in biological applications such as cell sorting for medical research or diagnostics, templating for artificial tissue replication, or isolation of single cells for the study of biological or mechanical behavior. PMID- 21614405 TI - Multi-colored homologs of the green fluorescent protein from hydromedusa Obelia sp. AB - The presence of green fluorescent protein (GFP) within the bioluminescent system of Obelia (Cnidaria, Hydrozoa, Campanulariidae) was inferred shortly after the discovery of GFP in Aequorea. Despite the enormous success of Aequorea GFP as a genetically encoded fluorescent label, Obelia GFP thus far has been defeating attempts to clone it from the hydroid life cycle stage. Here, we report cloning of three GFP-like fluorescent proteins (FPs) from Obelia medusa, representing cyan, green, and yellow spectral types. Such color diversity has never been detected outside class Anthozoa, suggesting a more general function for multi colored fluorescence in cnidarians than has been previously hypothesized. An unusual property of the new FPs is the formation of large soluble complexes of well-defined sizes and molecular weights, corresponding to up to 128 individual polypeptides. This aligns well with the earlier observation that luminescence in Obelia, unlike in Aequorea, is localized within subcellular granules, which prompts further inquiry into the self-assembly properties of the new FPs and their interactions with the photoprotein. The discovery of Obelia FPs fills the four-decade-old gap in the knowledge of cnidarian bioluminescence and provides experimental material to further investigate the details of its molecular mechanism. PMID- 21614406 TI - Determination of age-specific and sex-specific familial risks for the different manifestations of venous thromboembolism: a nationwide family study in Sweden. AB - This nationwide study aimed to determine whether differences exist in age specific and sex-specific familial risks for pulmonary embolism (PE), venous thrombosis of the lower limbs (VT) and other forms of venous thromboembolism (OVTE) among offspring, siblings and spouses of affected individuals. The Swedish Multi-Generation Register was linked to the Hospital Discharge Register data for the period 1987-2007. Standardised incidence ratios (SIRs) were calculated for individuals whose relatives were hospitalised for venous thromboembolism (VTE), as determined by the International Classification of Diseases (ICD), and those whose relatives were unaffected by VTE. The total number of hospitalised VTE patients was 45,362. All VTE patients were categorised as PE, VT or OVTE according to ICD at first hospitalisation. For example, the parental SIRs for PE, VT and OVTE in offspring at age 10-19 years were 2.89 (95% CI 1.48-5.06), 4.99 (95% CI 3.22-6.10) and 3.89 (95% CI 2.51-5.75), respectively. The low spousal risks of PE (1.08; 95% CI 1.02-1.13), VT (1.06; 95% CI 1.011.12) and OVTE (1.07; 95% CI 1.00-1.15) suggest the familial risks to be largely genetic. In both men and women, familial relative risks were increased for all the different manifestations of VTE with the exception of those older than 70 years. Familial history is a risk indicator in both sexes, and is potentially useful for clinical risk assessment for the different manifestations of VTE. PMID- 21614408 TI - Use of statins and recurrence of atrial fibrillation after catheter ablation or electrical cardioversion. A systematic review and meta-analysis. AB - Statins have important pleiotropic effects and have been shown to reduce vascular inflammation. Some evidence suggests that statins may have a role in the primary prevention of atrial fibrillation (AF), whereas little is know on the role of statins in patients with existing AF. We performed a meta-analysis of the literature to assess the effect of statins on the recurrence of AF after electrical cardioversion or ablation. MEDLINE and EMBASE databases were searched up to January 2010. Relative risks (RR) and 95% confidence intervals (CIs) were then calculated and pooled using a random-effects model. Statistical heterogeneity was evaluated through the use of I2 statistics. Sixteen studies were included in our systematic review. Statins did not reduce the risk of AF recurrence after ablation (four studies including 750 patients; RR, 1.04; 95% CI, 0.85-1.28, p=0.71; I2 = 34%). Conversely, the use of statins was associated with a significantly reduced risk of AF recurrence after electrical cardioversion (12 studies including 1790 patients; RR, 0.78; 95% CI, 0.67-0.90, p=0.0003; I2 = 34%). This reduction was not statistically significant when the analysis was restricted to randomised controlled trials (RCTs) only (five studies, 458 patients, RR, 0.76; 95% CI, 0.48-1.20). In conclusion, statins may lower the risk of AF recurrence after electrical cardioversion, but not ablation. However, this finding should be considered with caution, and larger RCTs are warranted to confirm our preliminary results. PMID- 21614407 TI - Functional mapping of factor VIII C2 domain. AB - The factor VIII (FVIII) is a cofactor of the coagulation cascade. The FVIII C2 domain is a critical domain that participates in the interactions with the von Willebrand factor and the phospholipidic surfaces. To assess the importance of each residue of this domain in the maintenance of the structure and the function of FVIII, a number (n=139) of mutants were generated by substituting the original residues, from Ser2173 to Gly2325, by an alanine. Mutants were built within a complete B domain-deleted FVIII and expressed in COS-1 cells. Mutant antigen levels and procoagulant activities were measured. Two in silico analyses, a sliding average procedure and an analysis of the mutation energy cost were conducted in parallel on the FVIII structure. Both results were in agreement with the functional data, and illustrated the benefit of using such strategies prior to targeting specific residues in the aim of generating active recombinant molecules. The functional assays identify the residues that are important to maintaining the structure of the C2 domain, mainly those forming beta-sheet, and those that can afford substitution, establishing a detailed functional relation with the available crystallographic data. This study provided a comprehensive functional mapping of the FVIII C2 domain and discussed the implication of specific residues in respect to the maintenance in the activity and structure stability, the efficiency in secretion, the binding to phospholipids and the formation of epitope. PMID- 21614409 TI - Ischaemic stroke and bleeding rates in 'real-world' atrial fibrillation patients. AB - Stroke prevention guidelines recommend oral anticoagulants (OAC) for atrial fibrillation (AF) patients at moderate/high risk of stroke, and antiplatelet or no therapy for those at low/moderate risk. Outcomes for AF patients receiving antiplatelet/no therapy in 'real-life' clinical practice were explored. This study compared clinical event rates (stroke/bleeding) for AF patients treated with OAC therapy, antiplatelets or no therapy in usual clinical practice to event rates in OAC-treated AF patients from optimally-monitored 'real-life' settings (anticoagulation clinics). We searched biomedical literature (1994-2010) using PubMed to identify 'real-world' studies of clinical event rates for AF patients receiving OAC therapy, antiplatelets, or no therapy; event rates were extracted for each treatment and setting. We identified 136 studies of thromboembolic events and 86 of bleeding events. Ischaemic stroke rates (30 studies) were higher for AF patients receiving no therapy (median: 4.45/100 person-years; range: 0.25 5.9) or antiplatelet-therapy (median: 4.45/100 person-years; range: 2.0-10) compared to OAC-treated patients monitored in anticoagulation clinics (median: 1.72/100 person-years; range: 0.97-2.00), or from a non-specialized setting (median 1.66/100 person-years; range: 0-4.9). Major bleeding rates (32 studies) for patients receiving antiplatelet/no therapy were similar to OAC-treated patients from both clinical settings. As in randomised clinical trials, AF patients in 'real-world' clinical practice receiving antiplatelet/no therapy have higher rates of ischaemic stroke than OAC-treated patients. Antiplatelet/no therapy was associated with similar bleeding rates to OAC therapy. Increasing utilisation of anticoagulants in clinical practice could improve patient outcomes. PMID- 21614410 TI - Myocardial infarction, ischaemic stroke and pulmonary embolism before and after breast cancer hospitalisation. A population-based study. AB - We studied the occurrence of myocardial infarction (MI), ischaemic stroke (IS) and pulmonary embolism (PE) before and after breast cancer hospitalisation compared with cancer-free controls. For this, women with a first breast cancer hospitalisation during 2000-2007 were selected from the PHARMO Record Linkage System, including drug use and hospitalisations of three million inhabitants in the Netherlands, and matched 1:10 by age to cancer-free women. The occurrence of MI, IS and PE were assessed in the 12 months before and after breast cancer hospitalisation. The study included 11,473 breast cancer patients, with a mean (+/- SD) age of 59 (+/- 14) years. Breast cancer patients were two to three times as likely as their cancer-free controls to have had a hospitalisation for PE, MI or IS in the 12 months before diagnosis, though prevalence was <1% in all groups. Breast cancer patients experienced an extreme high risk of PE in the first six months after diagnosis (hazard ratio [HR] 23.5, 95% confidence interval [CI] 11.1 49.7 compared to controls), which declined gradually to a four times increased risk (HR 3.6, 95%CI 2.4-5.5) more than 12 months after breast cancer hospitalisation. However, incidence was low: less than five events per 1,000 person years during all time periods. For MI and IS we did not observe significant increased HRs after breast cancer hospitalisation compared to controls. Breast cancer patients seem to have a higher risk profile to develop MI and IS, and receive treatment that increases the risk of PE compared to cancer free controls, although the frequency of hospitalisations was low. PMID- 21614411 TI - Atorvastatin reduces thrombin generation and expression of tissue factor, P selectin and GPIIIa on platelet-derived microparticles in patients with peripheral arterial occlusive disease. AB - We investigated the effects of statin treatment on platelet-derived microparticles (PMPs) and thrombin generation in atherothrombotic disease. Nineteen patients with peripheral arterial occlusive disease were randomised to eight weeks of treatment with atorvastatin or placebo in a cross-over fashion. Expression of GPIIIa (CD61), P-selectin (CD62P), tissue factor (TF, CD142) and phosphatidylserine (PS; annexin-V or lactadherin binding) was assessed on PMPs. Thrombin generation in vivo was assessed by measurement of prothrombin fragment 1+2 in plasma (F1+2) and ex vivo by using the calibrated automated thrombogram (CAT). During atorvastatin treatment, expression of TF, P-selectin and GPIIIa was significantly reduced vs. placebo (p<0.001 for all). No effect on annexin-V or lactadherin binding was seen. Thrombin generation was significantly reduced during atorvastatin as assessed by both the CAT assay (p<0.001) and by measurements of F1+2 (p<0.01). Subsequent in vitro experiments showed that when TF on microparticles (MPs) was blocked by antibodies, the initiation of thrombin generation was slightly but significantly delayed. Blocking PS on MPs using annexin-V or lactadherin resulted in almost complete inhibition of thrombin generation. In conclusion, atorvastatin reduces thrombin generation and expression of TF, GPIIIa and P-selectin on PMPs in patients with peripheral vascular disease. Microparticle-bound TF slightly enhances initiation of thrombin generation whereas negatively charged surfaces provided by MPs or lipoproteins could reinforce thrombin generation. Statins may inhibit initiation of thrombin generation partly through a microparticle dependent mechanism but the main effect is probably through reduction of lipoprotein levels. PMID- 21614412 TI - Mass spectrometry for the evaluation of cardiovascular diseases based on proteomics and lipidomics. AB - The identification and quantification of proteins and lipids is of major importance for the diagnosis, prognosis and understanding of the molecular mechanisms involved in disease development. Owing to its selectivity and sensitivity, mass spectrometry has become a key technique in analytical platforms for proteomic and lipidomic investigations. Using this technique, many strategies have been developed based on unbiased or targeted approaches to highlight or monitor molecules of interest from biomatrices. Although these approaches have largely been employed in cancer research, this type of investigation has been met by a growing interest in the field of cardiovascular disorders, potentially leading to the discovery of novel biomarkers and the development of new therapies. In this paper, we will review the different mass spectrometry-based proteomic and lipidomic strategies applied in cardiovascular diseases, especially atherosclerosis. Particular attention will be given to recent developments and the role of bioinformatics in data treatment. This review will be of broad interest to the medical community by providing a tutorial of how mass spectrometric strategies can support clinical trials. PMID- 21614413 TI - Prognostic significance of mean platelet volume on admission in an unselected cohort of patients with non ST-segment elevation acute coronary syndrome. AB - Mean platelet volume (MPV) has been proposed as a marker of platelet reactivity and cardiovascular risk. Its prognostic significance has not been thoroughly investigated in patients with non-ST elevation acute coronary syndrome (NSTE ACS). We included 1,041 consecutive patients with NSTE-ACS. Patients were divided in quartiles according to the MPV value on admission (fl) i.e. Q1<7.5; Q2=7.5 8.0; Q3=8.1-8.8; Q4>=8.9. The primary study endpoint was the composite of cardiovascular death and re-myocardial infarction (MI) at one year. Secondary study endpoints were individual cardiovascular death and re-MI. Patients in Q4 were older, had a higher prevalence of previous MI, peripheral artery disease and advanced Killip class compared to patients in Q1-Q3. Elevated MPV levels (Q4) was independently associated with gender, smoking status, platelet count and creatinine level. Overall, 210 patients (20.2%) reached the primary endpoint, 124 (12.1%) died from cardiovascular causes and 125 (12.0%) suffered from re-MI. On multivariable analysis patients in Q4 were at higher risk of primary endpoint (HR=1.41; 95%CI 1.06-1.89; p=0.02) whilst the association with cardiovascular death and re-MI was attenuated. MPV as continuous variable was independently associated with both primary endpoint (HR=1.19; 95%CI 1.06-1.33; p=0.003) and cardiovascular death (HR=1.23; 95%CI 1.06-1.42, p=0.006). The incorporation of MPV into a comprehensive model of risk significantly increased the likelihood ratio chi-square for prediction of both the composite endpoint (p=0.004) and cardiovascular death (p=0.009). Therefore, MPV may be useful to improve risk stratification in NSTE-ACS patients and should be included in future prospective studies evaluating the role of platelet function in promoting cardiovascular events. PMID- 21614414 TI - Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy. AB - Cilostazol is a platelet inhibitor which when added to aspirin and clopidogrel has shown to reduce the risk of recurrent ischaemic events without an increase in bleeding. These clinical benefits have shown to be more pronounced in patients with diabetes mellitus (DM). However, it remains unknown whether cilostazol exerts different pharmacodynamic effects in patients with and without DM. This was a randomised, double-blind, placebo-controlled, cross-over pharmacodynamic study comparing platelet function in patients with and without DM on aspirin and clopidogrel therapy. Patients (n=111) were randomly assigned to either cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment for another 14 days. Platelet function was performed at baseline, 14 days post randomisation, and 14 days post-cross-over. Functional testing to assess P2Y12 signalling included flow cytometric analysis of phosphorylation status of vasodilator-stimulated phosphoprotein measured by P2Y12 reactivity index (PRI), light transmittance aggregometry and VerifyNow. Thrombin generation processes were also studied using thrombelastography. Significantly lower PRI values were observed following treatment with cilostazol compared with placebo both in DM and non-DM groups (p < 0.0001). The absolute between-treatment differences of PRI between groups was a 35.1% lower in patients with DM (p=0.039). Similar results were obtained using all other functional measures assessing P2Y12 signalling. Thrombin generation was not affected by cilostazol. Cilostazol reduces platelet reactivity both in patients with and without DM, although these pharmacodynamic effects are enhanced in patients with DM. Despite the marked platelet inhibition, cilostazol does not alter thrombin-mediated haemostatic processes, which may explain its ischaemic benefit without the increased risk of bleeding. PMID- 21614415 TI - Alcohol consumption, types of alcoholic beverages and risk of venous thromboembolism - the Tromso Study. AB - Moderate alcohol consumption has been shown to protect against cardiovascular diseases. The association between alcohol consumption, especially types of alcoholic beverages, and venous thromboembolism (VTE) is less well described. The aim of this study was to investigate the impact of alcohol consumption and different alcoholic beverages on risk of VTE. Information on alcohol consumption was collected by a self-administrated questionnaire in 26,662 subjects, aged 25 97 years, who participated in the Tromso Study, in 1994-1995. Subjects were followed through September 1, 2007 with incident VTE as the primary outcome. There were 460 incident VTE-events during a median of 12.5 years of follow-up. Total alcohol consumption was not associated with risk of incident VTE. However, subjects consuming >= 3 units of liquor per week had 53% increased risk of VTE compared to teetotalers in analyses adjusted for age, sex, body mass index, smoking, diabetes, cancer, previous cardiovascular disease, physical activity and higher education (HR: 1.53, 95% CI: 1.00-2.33). Contrary, subjects with a wine intake of >= 3 units/week had 22% reduced risk of VTE (HR: 0.78, 95% CI: 0.47 1.30), further adjustment for liquor and beer intake strengthened the protective effect of wine (HR: 0.53, 95% CI: 0.30-1.00). Frequent binge drinkers (>= 1/week) had a 17% increased risk of VTE compared to teetotallers (HR 1.17, 95% CI: 0.66 2.09), and a 47% increased risk compared to non-binge drinkers (HR 1.47, 95% CI: 0.85-2.54). In conclusion, liquor consumption and binge drinking was associated with increased risk of VTE, whereas wine consumption was possibly associated with reduced risk of VTE. PMID- 21614417 TI - Pregnancy in platelet-type VWD: a case series. PMID- 21614416 TI - Multiple electrode aggregometry and vasodilator stimulated phosphoprotein phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events. AB - Reduced antiplatelet effect of clopidogrel assessed with multiple electrode aggregometry (MEA) and vasodilator stimulated phosphoprotein-phosphorylation (VASP-P) assay has been proven to predict major adverse cardiovascular events (MACE) after coronary stenting. So far no consecutive registry has evaluated the usefulness of different adenosine diphosphate-based platelet function tests to predict outcome in unselected patients. Hence, our objective was to determine the feasibility of MEA and VASP-P for clinical routine and whether low-response to clopidogrel as determined by MEA and/or the VASP-P assays predicts MACE in a "real-life" population undergoing coronary stenting. Three-hundred consecutive patients were included in this prospective registry. Blood was sampled 6-24 hours after stenting to measure MEA and VASP-P. The use of glycoprotein-IIb/IIIa blockers limited MEA to 196 measurements. Concerning the VASP-P assay, 300 measurements were achieved. Receiver Operating Characteristics (ROC)-curves of sensitivity and specificity estimates for MACE were plotted for VASP-P assay. The area under the ROC-curve was 0.683 (p=0.014) for the platelet reactivity index (PRI) calculated from median fluorescence intensities (FI) with an optimal cut off at 60.2% PRI. Patients above 60.2% had a significantly increased risk for MACE at six months follow-up (p=0.007). Estimating the cut-offs for the PRI from mean FI (52%) or from geometric mean FI (56.6%) led to clinically relevant differences. VASP-P assay is feasible for clinical routine to measure clopidogrel effects and to predict post-procedural MACE in unselected patients. With regard to differing cut-offs, exact standardisation of the VASP-P assay is mandatory. The use of GP-IIb/IIIa-blockers prevents MEA testing and limits its usability in unselected patients. PMID- 21614418 TI - Clinical, genetic and confounding factors determine the dynamics of the in vitro response/non response to clopidogrel. AB - Platelet inhibition by clopidogrel varies from one individual to the next. Further, in vitro high on-treatment residual adenosine-diphosphate inducible platelet reactivity (HRPR) is associated with an increased risk for major adverse cardiovascular events after percutaneous coronary intervention (PCI) with stent implantation. Recent studies identified numerous influencing factors for the antiplatelet effect of clopidogrel. Besides genetic predispositions, diverse clinical conditions as well as pharmacological interactions were shown to significantly impair clopidogrel-mediated platelet inhibition. Consequently, these influencing factors may affect clinical outcome after PCI and it is therefore desirable to identify cofounders of HRPR by platelet reactivity testing. It is apparent, that not all assays are sensitive to the same variables, and only cofounders of HRPR that are repeatedly identified by more than one test system may be clinically meaningful. However, treatment adjustment based on platelet function testing has not been associated with improved patients' outcome. This summary shall provide an overview over current knowledge on influencing factors for clopidogrel-mediated platelet inhibition and aid guidance for critical interpretation of in vitro obtained data on HRPR. PMID- 21614419 TI - Identification of the first Alu-mediated large deletion involving the F5 gene in a compound heterozygous patient with severe factor V deficiency. AB - Factor V (FV) deficiency is a rare autosomal recessive haemorrhagic disorder associated with moderate to severe bleeding symptoms. Conventional mutational screening leads to a complete molecular genetic diagnosis only in about 80-90% of cases. Large gene rearrangements, which could explain at least part of the "missing alleles" have not been reported so far in FV-deficient patients. In this work, we investigated a family with hereditary FV deficiency, in which the proband is compound heterozygous for a 205-Kb deletion, involving the first seven exons of F5 , and the entire selectin P, L, and E genes, and for a novel splicing mutation (IVS12+5G>A). The deletion breakpoints, determined by using a combination of semi-quantitative real-time PCR and long PCR assays, occurred within AluY repeat sequences, suggesting an Alu-mediated unequal homologous recombination as the mechanism responsible for the deletion. The in vitro characterisation of the IVS12+5G>A mutation demonstrated that this mutation causes the skipping of exon 12 and the activation of a cryptic splice site. Low levels of residual wild-type splicing were also detectable, in agreement with the notion that the complete absence of FV may be not compatible with life. PMID- 21614420 TI - Prognostic importance of anaemia in patients with acute pulmonary embolism. AB - Although associated with adverse outcomes in other cardiopulmonary diseases, limited evidence exists on the prognostic value of anaemia in patients with acute pulmonary embolism (PE). We sought to examine the associations between anaemia and mortality and length of hospital stay in patients with PE. We evaluated 14,276 patients with a primary diagnosis of PE from 186 hospitals in Pennsylvania, USA. We used random-intercept logistic regression to assess the association between anaemia at the time of presentation and 30-day mortality and discrete-time logistic hazard models to assess the association between anaemia and time to hospital discharge, adjusting for patient (age, gender, race, insurance type, clinical and laboratory variables) and hospital (region, size, teaching status) factors. Anaemia was present in 38.7% of patients at admission. Patients with anaemia had a higher 30-day mortality (13.7% vs. 6.3%; p <0.001) and a longer length of stay (geometric mean, 6.9 vs. 6.6 days; p <0.001) compared to patients without anaemia. In multivariable analyses, anaemia remained associated with an increased odds of death (OR 1.82, 95% CI: 1.60-2.06) and a decreased odds of discharge (OR 0.85, 95% CI: 0.82-0.89). Anaemia is very common in patients presenting with PE and is independently associated with an increased short-term mortality and length of stay. PMID- 21614422 TI - GPs' role in reducing the risk of bronchospasm in asthma patients undergoing general anesthesia and/or intravascular administration of radiographic contrast media. PMID- 21614421 TI - Atorvastatin and its collateral effects on microparticles. PMID- 21614423 TI - Oral corticosteroids for asthma or COPD were dispensed to 2.6% of Norwegians aged 7 years or over in 2004-5. PMID- 21614424 TI - Why do GPs find management of airways diseases difficult? PMID- 21614425 TI - Endoscope-assisted microsurgical resection of skull base meningiomas. AB - This study aims to determine the value of endoscope assistance in the microsurgical resection of skull base meningiomas. Fourty-six patients harboring a skull base meningioma underwent an endoscope-assisted microsurgical resection. In 30 patients (65%), tumor parts which could not be visualized under the microscope were detected with the endoscope. In 26 patients (56%), these tumor remnants were removed under endoscopic view. Gross total resection was achieved in 35 patients (76%) and near-total resection in 11 (24%). There was no surgical mortality. The major complication was new cranial nerve deficit. The application of endoscopes was most useful in the small supraorbital craniotomies to look under the ipsilateral optic nerve and internal carotid artery as well as to visualize the diaphragm sellae and olfactory groove. In the retrosigmoid craniotomies, the endoscope was beneficial to inspect the internal auditory canal, to look into Meckel's cave, or to inspect areas hidden behind the jugular tubercle and tentorial edge. There was no obvious complication related to the application of the endoscope. Endoscope assistance is particularly of value when skull base meningiomas are to be removed via small craniotomies to inspect blind corners which cannot be visualized in a straight line with the microscope. In addition, there is a benefit of using endoscopes with various angles of view in standard craniotomies and skull base approaches to look around bony and dural corners or to look behind neurovascular structures, by which the amount of skull base drilling and retraction to expose the tumor can be reduced. PMID- 21614427 TI - Efficacy of endoport-guided endoscopic resection for deep-seated brain lesions. AB - Surgery for deep-seated brain lesions without causing significant trauma to the overlying cortex is difficult because brain retraction is required to approach these lesions. The aim of this study was to determine the efficacy of endoport guided endoscopic or microscopic removal for deep-seated lesions using the neuronavigation system. Between October 2008 and December 2009, 21 patients (17 men and 4 women; average age, 40.8 years) underwent endoport-guided endoscopic tumor removal. We adapted the transparent tubular conduit, so-called "endoport," to target the lesions under the guidance of neuronavigation. We then determined the efficacy and limitations of this technique with fully endoscopic removal, compared with standard approaches using a spatula retractor. Gross total resection of the lesions was achieved in 14 of 21 patients (66%), and partial removal occurred in four (19%) patients. However, there was failure to remove the lesion through the endoport in three patients (14.3%), requiring the use of blade spatula retractors. In reviewing the seven cases with either failure or partial removal, it was found that a large tumor size (>= 3 cm) and calcified lesions were the major factors limiting the application of this technique. Endoport guided endoscopic surgery facilitated an accurate and minimally invasive technique for removal of these deep-seated brain lesions. This procedure required a protracted learning curve although, when successful, this approach can minimize brain retraction and provide satisfactory visualization. PMID- 21614426 TI - Contemporary surgical outcome for skull base meningiomas. AB - Although surgical excision of meningioma and its dural base is the most common primary management, skull base meningiomas are quite different, and contemporary management usually consists of multimodal treatment with the aim of achieving the best possible functional outcome and quality of life (QOL) for these patients. As surgery plays an important role in the treatment of skull base meningiomas, it is crucial for neurosurgeons to appreciate the surgical outcome and QOL after meningioma surgery. Outcome is usually measured for meningiomas in terms of morbidity, mortality, time to recurrence, and QOL. The extent of resection, tumor grade, proliferative markers, and tumor location are significant factors in predicting the surgical outcome. Therefore, we address each of these factors in detail in this review. Advances in recent decades in microsurgical techniques, neuroimaging modalities, neuroanesthesia, and perioperative intensive care have substantially improved the surgical outcome; therefore, most surgical outcomes discussed in this review are cited from contemporary literature (2000 to the present) in order to depict the surgical outcome of contemporary microsurgery. PMID- 21614428 TI - Microsurgery can cure most intracranial dural arteriovenous fistulae of the sinus and non-sinus type. AB - There is consensus that intracranial dural arteriovenous fistulae (dAVF) with direct (non-sinus-type) or indirect (sinus-type) retrograde filling of a leptomeningeal vein should be treated due to the high risk of neurological deficits and hemorrhage. No consensus exists on treatment modality (surgery and/or embolization) and, if surgery is performed, on the best surgical strategy. This series aims to evaluate the role of surgery in the management of aggressive dAVFs. Forty-two patients underwent surgery. Opening and packing the sinus with thrombogenic material was performed in 9 of the 12 sinus-type dAVFs. In two sinus type fistulae of the cavernous sinus and 1 of the torcular, microsurgery was used as prerequisite for subsequent embolization by providing access to the sinus. In the 30 non-sinus-type dAVFs, surgery consisted of interruption of the draining vein at the intradural entry point. In 41 patients undergoing 43 operations, elimination of the dAVF was achieved (97.6%). In one case, a minimal venous drainage persisted after surgery. The transient surgical morbidity was 11.9% (n=5) and the permanent surgical morbidity 7.1% (n=3). Our surgical strategy was to focus on the arterialized leptomeningeal vein in the non-sinus-type and on the arterialized sinus segment in the sinus-type dAVFs allowing us to obliterate all but one dAVF with a low morbidity rate. We therefore propose that microsurgery should be considered early in the treatment of both types of aggressive dAVFs. In selected cases of cavernous sinus dAVFs, the role of microsurgery is reduced to that of an adjunct to endovascular therapy. PMID- 21614429 TI - Setting up a microneurosurgical skull base lab: technical and operational considerations. AB - Microneurosurgical cadaveric dissections have become popular due to their usefulness in obtaining a working knowledge of the microneurosurgical anatomy in a controlled environment. This same controlled environment is also conducive to experiment with new surgical approaches. These factors have increased the number of microneurosurgical anatomic laboratories. Despite the increase in microneurosurgical laboratories, there is very little literature regarding the logistics of starting and maintaining a new neurosurgical laboratory. The aim of this paper is to provide a general road map and basic guidelines in starting and running a microneurosurgical dissection laboratory. The information in this paper is based on a review of the literature and on the experience we gained in organizing and managing the Dardinger Microneurosurgical Skull Base Laboratory at The Ohio State University. PMID- 21614430 TI - Adult onset Pompe disease associated with multiple sclerosis. PMID- 21614431 TI - Exploratory 7-Tesla magnetic resonance spectroscopy in Huntington's disease provides in vivo evidence for impaired energy metabolism. AB - Huntington's disease (HD) is a neurodegenerative genetic disorder that affects the brain. Atrophy of deep grey matter structures has been reported and it is likely that underlying pathologic processes occur before, or in concurrence with, volumetric changes. Measurement of metabolite concentrations in these brain structures has the potential to provide insight into pathological processes. We aim to gain understanding of metabolite changes with respect to the disease stage and pathophysiological changes. We studied five brain regions using magnetic resonance spectroscopy (MRS) using a 7-Tesla MRI scanner. Localized proton spectra were acquired to obtain six metabolite concentrations. MRS was performed in the caudate nucleus, putamen, thalamus, hypothalamus, and frontal lobe in 44 control subjects, premanifest gene carriers and manifest HD. In the caudate nucleus, HD patients display lower NAA (p = 0.009) and lower creatine concentration (p = 0.001) as compared to controls. In the putamen, manifest HD patients show lower NAA (p = 0.024), lower creatine concentration (p = 0.027), and lower glutamate (p = 0.013). Although absolute values of NAA, creatine, and glutamate were lower, no significant differences to controls were found in the premanifest gene carriers. The lower concentrations of NAA and creatine in the caudate nucleus and putamen of early manifest HD suggest deficits in neuronal integrity and energy metabolism. The changes in glutamate could support the excitotoxicity theory. These findings not only give insight into neuropathological changes in HD but also indicate that MRS can possibly be applied in future clinical trails to evaluate medication targeted at specific metabolic processes. PMID- 21614432 TI - The impact of sleep and mood disorders on quality of life in Parkinson's disease patients. AB - Sleep disturbances are common and often severe in patients with Parkinson's disease (PD) and their symptoms can be present at any time of day. The purpose of our study was to examine how excessive daytime sleepiness or poor nocturnal sleep quality and mood disorders influence the quality of life (QoL) in PD patients. Ninety-three PD patients from eastern Slovakia were recruited (49.5% males, mean age 68.0 +/- 9.5 years, mean disease duration 6.1 +/- 5.9 years). Sleep disturbances were measured using the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI); QoL with the Parkinson's Disease Quality of Life Questionnaire (PDQ-39); depression and anxiety with the Hospital Anxiety and Depression Scale (HADS) and disease severity with the Unified Parkinson's Disease Rating Scale (UPDRS). chi (2) test, bivariate correlations and multiple linear regressions were performed. PSQI and ESS had significant correlations with worse QoL (p < 0.01, p < 0.05, respectively). HADS-D (p < 0.01), HADS-A (p < 0.01), UPDRS (p < 0.01) and disease duration (p < 0.05) were also significantly related to worse QoL. In the linear regression analysis, however, only PSQI (p < 0.01), anxiety (p < 0.001) and UPDRS (p < 0.001) remained significant. The model with PSQI explained 74% of the variance, and the model with ESS explained 63% of the variance in PDQ-39 when analyses were performed separately. In an overall model, however, only PSQI remained significant, accounting for 82% of the variance in PDQ-39. Nighttime poor sleep and anxiety are important contributors leading to a worse QoL. As these are treatable conditions, they should be recognized by clinicians and managed properly. PMID- 21614433 TI - Physical inactivity in Parkinson's disease. AB - Patients with Parkinson's disease (PD) are likely to become physically inactive, because of their motor, mental, and emotional symptoms. However, specific studies on physical activity in PD are scarce, and results are conflicting. Here, we quantified daily physical activities in a large cohort of PD patients and another large cohort of matched controls. Moreover, we investigated the influence of disease-related factors on daily physical activities in PD patients. Daily physical activity data of PD patients (n = 699) were collected in the ParkinsonNet trial and of controls (n = 1,959) in the Longitudinal Aging Study Amsterdam (LASA); data were determined using the LAPAQ, a validated physical activity questionnaire. In addition, variables that may affect daily physical activities in PD were recorded, including motor symptoms, depression, disability in daily life, and comorbidity. Patients were physically less active; a reduction of 29% compared to controls (95% CI, 10-44%). Multivariate regression analyses demonstrated that greater disease severity, gait impairment, and greater disability in daily living were associated with less daily physical activity in PD (R (2) = 24%). In this large study, we show that PD patients are about one third less active compared to controls. While disease severity, gait, and disability in daily living predicted part of the inactivity, a portion of the variance remained unexplained, suggesting that additional determinants may also affect daily physical activities in PD. Because physical inactivity has many adverse consequences, work is needed to develop safe and enjoyable exercise programs for patients with PD. PMID- 21614434 TI - The complete genome sequence of a novel T4-like bacteriophage, IME08. PMID- 21614435 TI - In vivo evaluation of the antiviral activity of Cajanus cajan on measles virus. AB - Cajanus cajan, a tropical shrub, serves as source of food and traditional medicines. The evaluation of aqueous and ethanol extracts for activity against measles virus and toxicity to embryonated chicken eggs was carried out in this study. In vivo and in vitro assay techniques using embryonated chicken eggs and tissue culture (Hep-2 cell lines) as media for both virus cultivation and anti virus assay showed that a hot-water extract yielded higher activity against measles virus. The hot-water extract of the stem yielded a Log(2) titre of 0.1 for the in vivo assay and an inhibition of cytopathic effect (CPE) in Hep-2 cells by 100% for the in vitro assay. At all concentrations of the extracts, there was a lowering of virus concentration (p = 0.05), indicated by hemagglutination (HA) titration, which is the advantage of HA titration over the tissue culture technique using CPE. This study validates embryonated chicken eggs as suitable media for anti-virus assay and the use of C. cajan in the treatment of some diseases of viral origin. PMID- 21614436 TI - Complete genome sequence analysis of tick-borne encephalitis viruses isolated in northeastern China. AB - Tick-borne encephalitis virus (TBEV) causes lethal encephalitis in humans, posing a growing public-health problem in many European and Asian countries. TBEV is currently endemic in northeastern China, but the complete genome sequences of Chinese TBEV strains have not been reported. During a TBE outbreak in 2010 in Mudanjiang City, Heilongjiang Province, China, two TBEV strains were isolated from serum samples of two patients, and the complete sequences were determined and compared with other known TBEV strains. Both Mudanjiang isolates consisted of 10,774 nucleotides and encoded a single open reading frame coding for a polyprotein of 3414 amino acids, and a unique deletion of 364 nucleotides in the 3' untranslated region (UTR) was recorded. Phylogenetic analysis based on the amino acid sequence of the E protein and the nucleotide sequence of the 3'UTR revealed that the Mudanjiang isolates are closely related to the Senzhang and Sofjin-HO strains and belong to the Far Eastern subtype of TBEV. These findings provide insight into the evolutionary relationships among Chinese TBEV isolates and are useful for laboratory diagnosis and vaccine development for TBEV. PMID- 21614437 TI - Genotypes of rotavirus strains circulating in Amman, Jordan, in 2006/07 and their significance for the potential effectiveness of future rotavirus vaccination. AB - The prevalence, seasonality and genotypes of rotavirus circulating in Jordan were determined to provide data useful for the implementation of a rotavirus vaccine in the national childhood vaccination program. During 2006/07, rotavirus was detected in 35% of hospitalized children, and 88% of the cases occurred in children aged between 6 and 23 months. Rotavirus infection persisted throughout the year and peaked in winter. Seven genotypes were identified by RT-PCR and sequencing: G1P[8], G9P[8], G2P[4], G1P[4], G3P[8], G4P[8] and G9P[6], which represented 69%, 8.8%, 2.4%, 2.0%, 1.2%, 0.4% and 0.4% of the rotavirus strains, respectively. Thirteen percent and 2.8% of the total strains were partially typed or untypeable, respectively. Eighty-eight percent and 12% of the rotavirus strains possessed a long and short electropherotype, respectively. As more than 90% of the rotavirus strains circulating in Jordan possessed the G1 or P[8] genotype, it is concluded that the implementation of the rotavirus vaccine in the framework of the national childhood vaccination program of Jordan would most likely be very effective. Continuous monitoring of the currently circulating genotypes in Jordan should be encouraged. PMID- 21614438 TI - Eragrostis minor streak virus: an Asian streak virus in Africa. PMID- 21614439 TI - Recurrent bleeding within 24 hours after uterine artery embolization for severe postpartum hemorrhage: are there predictive factors? AB - PURPOSE: To retrospectively identify predictive factors of recurrent bleeding within 24 h after uterine artery embolization (UAE) for postpartum hemorrhage (PPH). MATERIALS AND METHODS: A total of 194 patients underwent UAE for PPH between August 1999 and April 2009 at our institution. Twelve patients experienced recurrent bleeding within the next 24 h; a second attempt at UAE was thus necessary, which was successful in 10 cases. In two cases, hemostatic hysterectomy was performed. Epidemiological, gynecological-obstetrical, anatomic, and biological data were analyzed. RESULTS: Complete data were available for 148 of the 194 (76%) included patients. Sixty-four (43%) were primiparous, 18 (12.2%) had a placenta accreta, 21 (14%) had a coagulopathy, and 28 (18.9%) had an anatomic variant of the uterine arterial vasculature. Mean age and pregnancy term were similar in both recurring and nonrecurrent bleeding groups. After multivariate analysis, three criteria emerged as risk factors of recurrent bleeding: primiparity (10 patients, 83%; odds ratio [OR]=18.84; P=0.014), coagulation disorders (6 patients, 50%; OR=12.08; P=0.006), and anatomic variant of the uterine arterial vasculature (28 patients; OR=9.83; P=0.003). CONCLUSION: Search for uterine collaterals must be performed before UAE for PPH. Primiparity and coagulation disorders increase the risk of recurrent bleeding after UAE for PPH. PMID- 21614441 TI - Complete recovery of severe postpartum genital prolapse after conservative treatment--a case report. PMID- 21614442 TI - Mixed urinary incontinence--time to uncouple urgency from stress? AB - INTRODUCTION: "Mixed incontinence" is defined as a combination of stress and urge symptoms. Over time, it has morphed into a single entity, encompassing etiology and treatment. My perspectives are: (a) Stress incontinence (SI) and urge incontinence (UI) are different symptoms with often different anatomical causation and so should be treated separately; (b) It is illogical to group urgency with SI. Urgency may also be associated with frequency, nocturia, abnormal emptying and pelvic pain in patients with no SI ("posterior fornix syndrome"); and (c) There is growing evidence that urgency may be cured by surgical correction of a cystocele and/or apical prolapse in up to 80% of patients who do not have SI. In this anatomical context, sensory urgency, urge incontinence and urodynamic detrusor overactivity may all be hypothesized as different manifestations of a prematurely activated micturition reflex, caused by a lax vagina's inability to support bladder base stretch receptors. This statement can be tested with a simple clinical test, "simulated operations", whereby digitally supporting in turn the midurethra, bladder base and posterior vaginal fornix may cause a significant decrease in the urgency felt by the patient. CONCLUSIONS: The term "mixed incontinence" is only valid if both symptoms are caused by a lax pubourethral ligament. However, urgency may be caused by laxity in other parts of the vagina. Regarding stress and urge as separate entities will remove the confusion resulting from this definition, creating new directions for science and therapy. PMID- 21614443 TI - Plagiarism. PMID- 21614444 TI - Zinc ions induce inflammatory responses in vascular endothelial cells. AB - Using one particulate zinc oxide (ZnO) and two soluble zinc compounds (Zn(NO(3))(2) and Zn(CH(3)COO)(2)), we aimed to clarify if zinc ions (Zn(2+)), like particulate ZnO, caused inflammatory responses in vascular endothelial cells. Treatments of human umbilical vein endothelial cells (HUVECs) with 368.6 MUM of each zinc compound caused marked increases in IkappaBalpha phosphorylation and intercellular adhesion molecule-1 (ICAM-1) expression. Treatments with Zn(CH(3)COO)(2) (50-350 MUM) induced a dose-dependent ICAM-1 expression. These results show that Zn(2+) alone is sufficient to induce similar levels of ICAM-1 expression as ZnO particles, suggesting that dissolved Zn(2+) may play the major role in inflammatory effect of ZnO particles on vascular endothelial cells. PMID- 21614445 TI - Chlorophenols in Tigris River and drinking water of Baghdad, Iraq. AB - A study was conducted on a stretch of Tigris river crossing Baghdad city to determine the concentration of some chlorophenols pollutants. Aqueous samples were preliminary enriched about 500 times and the chlorophenols have determined using high performance liquid chromatography HPLC. Limits of detection LOD were (0.007-0.012 mg L(-1)), relative standard deviations RSD% were 2.4%-5.59% and relative recoveries were 51.06%-104.07%. The existence of chlorophenols in Tigris river was in the range 0.023-4.596 mg L(-1). The developed method suggested in this study can be applied for routine analysis and monitoring of chlorinated phenols in environmental aqueous samples. PMID- 21614446 TI - Profile of organochlorine pesticides in soil cores from some hotspot areas of Beijing, China. AB - For the valid use of urban land and the safety of public health, an extensive contamination survey of organochlorine pesticides from five soil cores was conducted in the highly urbanized areas of Beijing in China. For topsoils in five soil cores, level of ?HCHs and ?DDTs varied from 0.174 to 4,783 ng g(-1) and 0.62 to 57,849 ng g(-1), respectively. The profile in topsoil of cores displayed that levels of pollutants in four soil cores from the urban areas with dense population are higher than that from outskirts. The depth characteristics of pollutants indicated that the level of ?HCHs and ?DDTs in BY and WU was close to/below the background value of soil in China (50 ng g(-1)), but those in some soil samples from A, B and ZX core, especially A and B, was above the threshold value for the soil safety (1,000 ng g(-1)). In views of the usage history of the land and profiles of contaminants, the source in A and B probably came from the dumped waste chemical materials in the old chemical factories. The study of soil cores sampled revealed the existence of chemical "time bomb" in urban regions of Beijing. Also, the finding indicated the absolute necessity of assessing the soil quality with the unprecedented land use changes in the big city community. PMID- 21614447 TI - Safety of bevacizumab 7.5 mg/kg infusion over 10 minutes in NSCLC patients. AB - BACKGROUND: Bevacizumab is a humanized IgG1 monoclonal antibody against VEGF. Because infusion-related hypersensitivity reactions (HSRs) are a concern with monoclonal antibodies, initial phase 1 trials used a 90-, 60-, then 30-min initial infusion sequence. We evaluated the impact of a shortened bevacizumab infusion (10 min) on toxicity in nonsmall cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Consecutive patients with stage IV NSCLC eligible for anti VEGF therapy received a platinum doublet plus bevacizumab 7.5 mg/kg infused over 10 min, every 3 weeks, in the outpatient setting. Blood pressure was monitored at home twice daily, and other toxicities (HSRs and proteinuria) were monitored at each treatment administration. RESULTS: Bevacizumab was given as a 10 min infusion in 55 patients (group A), and using the standard sequence in another 36 patients (group B). Hypertension (grade >= 2) was observed in 18/55 (32.7%) patients in group A and 13/36 (38.9%) patients in group B (p = 0.77). Similarly, no difference was seen regarding the incidence of grade >= 2 proteinuria (12.7% vs. 19.4%, p = 0.39), arterial thrombo-embolic events (0 in each group) or venous thromboembolic events (1.8% vs. 8.3%, p = 0.29). CONCLUSIONS: Our data suggest that bevacizumab 7.5 mg/kg can be safely infused over 10 min in unselected NSCLC patients despite their cardio-vascular and respiratory comorbidities, saving time for both patients and caregivers. PMID- 21614448 TI - Angiotensin-converting enzyme deletion allele is beneficial for the longevity of Europeans. AB - The human angiotensin converting enzyme (ACE) gene is one of the most investigated candidate genes for cardiovascular diseases (CVD), but the understanding of its role among the elderly is vague. Therefore, this study focuses at: (a) testing the association of ACE polymorphism with CVD risk factors among the elderly, and (b) detecting the possible unequal distribution of ACE genotypes between senescent and younger segments of the European populations. The association of ACE I/D polymorphism with CVD health status [hypertension (HT), obesity, dislypidemia] in 301 very old subjects (88.2 +/- 5 years; F/M = 221/80) was tested by means of logistic regression analysis. The meta-analysis of D allele frequency in general vs. elderly (80+ years) groups was conducted using all publicly available data for European populations comprising both age cohorts. Multiple multinomial logistic regression revealed that within this elderly sample, age (younger olds, 80-90 years), female sex (OR = 3.13, 95% CI = 1.59 6.19), and elevated triglycerides (OR = 2.53, 95% CI = 1.29-4.95) were positively associated with HT, while ACE polymorphism was not. It was also established that the DD genotype was twice as high in 80+ cohort compared to general population of Croatia (p < 0.00001). This trend was confirmed by the meta-analysis that showed higher D allele frequencies in olds from nine of ten considered European populations (OR = 1.19, 95% CI = 1.08-1.31). The data in elderly cohort do not confirm previously reported role of ACE DD genotype to the development of HT. Moreover, meta-analysis indicated that ACE D allele has some selective advantage that contributes to longevity in majority of European populations. PMID- 21614449 TI - Melatonin protects lung mitochondria from aging. AB - We assessed whether melatonin administration would prevent the hyperoxidative status that occurs in lung mitochondria with age. Mitochondria from lungs of male and female senescent prone mice at 5 and 10 months of age were studied. Age dependent mitochondrial oxidative stress was evaluated by measuring the levels of lipid peroxidation and nitrite, glutathione/glutathione disulfide ratio, and glutathione peroxidase and reductase activities. Mitochondrial respiratory chain and oxidative phosphorylation capability were also measured. Age induces a significant oxidative/nitrosative status in lung mitochondria, which exhibited a significantly reduced activity of the respiratory chain and ATP production. These manifestations of age were more pronounced in males than in females. After 9 months of melatonin administration in the drinking water, the hyperoxidative status and functional deficiency of aged lung mitochondria were totally counteracted, and had increased ATP production. The beneficial effects of melatonin were generally similar in both mice genders. Thus, melatonin administration, as a single therapy, maintained fully functioning lung mitochondria during aging, a finding with important consequences in the pathophysiology of lung aging. In view of these data melatonin, the production of which decreases with age, should be considered a preventive therapy against the hyperoxidative status of the aged lungs, and its use may lead to the avoidance of respiratory complications in the elderly. PMID- 21614450 TI - Brain potentials to emotional pictures are modulated by alexithymia during emotion regulation. AB - Alexithymia is a personality trait associated with the reduced ability to regulate, identify, and communicate feelings or emotions and is often linked to psychosomatic disorders. The present study used event-related potentials (ERPs) to investigate the relationship between individual differences in alexithymia and emotion regulation. Participants classified as scoring either high or low on the revised form of the Toronto Alexithymia Scale (TAS-20; Taylor, Bagby, & Parker Psychother Psychosom 57:34-41, 1992) were asked to view negative and neutral images, adopting three different regulation strategies (expressive suppression, cognitive reappraisal, and attend) while ERPs were recorded. Results revealed an inverse relationship between TAS scores and emotion-related ERP activity during suppression, but not during reappraisal or a control "attend" condition. These results were observed in both early and late ERP latencies. These findings are interpreted according to potential differences between high- and low-TAS individuals regarding the frequency of prior utilization of suppression-based regulation strategies. PMID- 21614452 TI - Personality typology in relation to muscle strength. AB - BACKGROUND: Physical inactivity plays a central role in the age-related decline in muscle strength, an important component in the process leading to disability. Personality, a significant determinant of health behaviors including physical activity, could therefore impact muscle strength throughout adulthood and affect the rate of muscle strength decline with aging. Personality typologies combining "high neuroticism" (N >= 55), "low extraversion" (E < 45), and "low conscientiousness" (C < 45) have been associated with multiple risky health behaviors but have not been investigated with regards to muscle strength. PURPOSE: The purpose of this study is to investigate associations between individual and combined typologies consisting of high N, low E, and low C and muscle strength, and whether physical activity and body mass index act as mediators. METHOD: This cross-sectional study includes 1,220 participants from the Baltimore Longitudinal Study of Aging. RESULTS: High N was found among 18%, low E among 31%, and low C among 26% of the sample. High levels of N, particularly when combined with either low E or low C, were associated with lower muscle strength compared with having only one or none of these personality types. Facet analyses suggest an important role for the N components of depression and hostility. Physical activity level appears to partly explain some of these associations. CONCLUSION: Findings provide support for the notion that the typological approach to personality may be useful in identifying specific personality types at risk of low muscle strength and offer the possibility for more targeted prevention and intervention programs. PMID- 21614451 TI - Strategies for managing osteoarthritis. AB - BACKGROUND: Although there are recommendations for the management of osteoarthritis (OA), little is known about how people with OA actually manage this chronic condition. PURPOSE: The aims of this study were to identify the non pharmacological and pharmacological therapies most commonly used for the management of hip or knee OA, in a community-based sample of adults, and to compare these with evidence-based recommendations. METHODS: A questionnaire was mailed to 2,200 adult members of Arthritis Queensland living in Brisbane, Australia. It included questions about OA symptoms, management therapies, and demographic characteristics. RESULTS: Of the 485 participants (192 men, 293 women) with hip or knee OA who completed the questionnaire, most had mild to moderate symptoms. Ninety-six percent of participants (aged 27-95 years) reported using at least one non-pharmacological therapy, and 78% reported using at least one pharmacological therapy. The most common currently used non-pharmacological strategy was range-of-motion exercises (men 52%, women 61%, p = 0.05) and the most common frequently used pharmacological strategy was glucosamine/chondroitin (men 51%, women 60%, ns). For the most highly recommended strategies, 65% of men and 54% of women had never attended an information/education course (p = 0.04), and fewer than half (46% of women and 42% of men, p = 0.03) were frequent users of anti-inflammatory agents. CONCLUSION: The findings suggest that many people with knee or hip OA do not follow the most highly endorsed of the Osteoarthritis Research Society International recommendations for management of OA. Health professionals should be encouraged to recommend evidence-based therapies to their patients. PMID- 21614453 TI - Differences of image enhancement in image-enhanced endoscopy: narrow band imaging versus flexible spectral imaging color enhancement. AB - BACKGROUND: Narrow band imaging (NBI) can emphasize images of the surface microvasculature of lesions, because the central wavelengths of the NBI filter are 415 and 540 nm and these wavelengths are well absorbed by hemoglobin. Flexible spectral imaging color enhancement (FICE) increases the contrast in depictions of mucosal lesions. However, quantitative evaluation of the image enhancement shown by NBI and FICE has not been reported. The aim of this study was to measure and compare the degrees of image enhancement in NBI and FICE. METHODS: We compared the visibility of human blood diluted with distilled water between that shown by white-light imaging (WLI) and that shown by NBI or FICE. One milliliter of human blood was plated onto a 12-well transparent plastic plate to set up doubling dilutions, from 1/2 to 1/2(23). High-definition endoscopes were used for each imaging method. A total of 11 endoscopists independently evaluated the visibility of the diluted blood. The median dilution was defined as the limit of visibility in each image. RESULTS: NBI enabled clearer visualization of the presence of blood compared with conventional WLI. NBI recognized blood contamination up to a 1/2(14) dilution, whereas conventional WLI recognized blood contamination up to a 1/2(11) dilution. In contrast, FICE did not improve the visualization of diluted blood and recognized blood contamination up to a 1/2(10) dilution. CONCLUSIONS: NBI more effectively enhanced images of diluted blood compared to conventional WLI, while FICE did not improve the visualization of the diluted blood. These data suggest the usefulness of NBI for the early detection of gastrointestinal neoplasia, which is accompanied by abundant neovascularization. PMID- 21614454 TI - A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits. AB - BMS-262084 is a 4-carboxy-2-azetidinone-containing irreversible inhibitor of FXIa, which is selective over other coagulation proteases. We evaluated the in vitro and in vivo properties of BMS-262084 in rabbits. Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrolytic mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. BMS-262084 was infused IV from 1 h before thrombus induction or cuticle transection to the end of the experiment. In vitro, BMS-262084 prolonged activated partial thromboplastin time (aPTT) with EC(2x) (concentration required to double aPTT) of 10.6 MUM in rabbit plasma, and did not prolong prothrombin time (PT), thrombin time (TT) and HepTest. In vivo, BMS-262084 produced dose dependent antithrombotic effects in rabbits with antithrombotic ED(50) (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT of 0.4, 0.7 and 1.5 mg/kg/h IV, respectively. BMS-262084 increased ex vivo aPTT dose-dependently without changes in PT and TT. The antithrombotic effect of BMS-262084 was significantly correlated with its ex vivo aPTT, supporting the use of ex vivo aPTT as a pharmacodynamic biomarker. BMS-262084 did not alter ex vivo rabbit platelet aggregation to ADP and collagen. BT (fold increase) determined at 3 and 10 mg/kg/h of BMS-262084 were 1.17 +/- 0.04 and 1.52 +/- 0.07*, respectively (*P < 0.05 vs. control). This study demonstrated that BMS-262084 prevented experimental thrombosis at doses with low BT effects in rabbits, and suggests that a small molecule FXIa inhibitor may represent a promising antithrombotic therapy. PMID- 21614456 TI - The impaired fibrinolytic capacity in hypertension is unaffected by acute blood pressure lowering. AB - The endogenous fibrinolytic system and the ability of the endothelium to release tissue-plasminogen activator (t-PA) play a pivotal role to protect humans from atherothrombotic events. We have recently reported that the decreased capacity for t-PA release in hypertension is restored with chronic blood pressure lowering. Thus, we explored if acute blood pressure lowering has the same effect. The capacity for acute t-PA release was investigated in the perfused-forearm model during stimulation by intra-arterial substance P 8 pmol/min in hypertensive subjects. The procedure was then repeated during acute blood pressure lowering (n = 9) induced by sodium nitroprusside (SNP) infusion or during placebo infusion (n = 3). SNP lowered mean arterial pressure from 108.6 (2.6) to 83.0 (2.6) (mean and SEM) mmHg (P < 0.001). Substance P induced significant increase in t-PA release during both high- and low-pressure conditions (P < 0.01, ANOVA). Peak t-PA release rate was 199 (77) and 167 (41) (mean and SEM) ng/min/l tissue, and accumulated t-PA release was 2,395 (750) and 2,394 (473) ng, during high- and low pressure conditions, respectively. t-PA release and hemodynamic responses were almost identical during high- and low-pressure conditions (P = ns, for all). Acute blood pressure lowering does not restore stimulated t-PA release from the endothelium in hypertensive subjects. These findings are in contrast to previously described effects of chronic blood pressure treatment. Although data need to be confirmed in a larger study, they suggest that high blood pressure decreases the cellular t-PA pool rather than interferes with release mechanisms of the protein. PMID- 21614455 TI - Can resistance to aspirin be reversed after an additional dose? AB - Aspirin resistance or aspirin non-responsiveness is a recently described phenomenon which has been consistently associated with an increased risk of cardiovascular events. This study was designed to determine the effects of an additional dose of 100 mg of aspirin on platelet function and proportion of aspirin non-responders using the platelet function analyzer-100 (PFA-100), in a well characterized population of stable coronary heart disease patients already on long-term aspirin treatment. Platelet function was assessed using PFA-100 in 141 patients (64.8 +/- 10.1 years, 87.9% men) on long-term aspirin treatment (100 mg/day) before and 1 h after "in site" oral aspirin administration (100 mg). Prevalence of aspirin non-responders using PFA-100 was 50.7% (95% confidence interval 42.4-59). One hour after 100 mg of oral aspirin, reassessment of aspirin effects showed a prevalence of non-responders using PFA of 35.0% (95% CI 27.3 43.2) (P < 0.001 vs. pre-dose proportion). Using the PFA-100 system, reassessment of platelet function following oral administration of daily aspirin dosage significantly reduces the number of stable coronary disease patients considered to be non-responders to such treatment. PMID- 21614457 TI - [Heart rate and functional impairment are predictors of outcome in heart failure patients in the real world. Data from the Austrian Heart Failure registry]. AB - PURPOSE: Elevated heart rate (70 beats per minute-bpm or more) is a predictor of impaired prognosis in patients with ischemic heart failure. The Austrian Working Group on Heart Failure has established a registry in May 2006 for all patients referred to dedicated heart failure clinics with a planned follow-up after 12 +/- 3 months. Here we report an analysis of the prognostic impact of elevated heart rate at referral in a well-defined cohort of heart failure patients. METHODS: Between May 2006 and October 2009 1904 patients have been documented in the Austrian Heart Failure Registry. One thousand threehundred and sixty three patients (72%) had sinus rhythm at referral. Kaplan-Meier and Cox proportional hazards regression analyses were used to compare overall and cardiovascular mortality between high (70 bpm or more) and low heart-rate groups. Patients who were lost-to-follow-up (n = 166) were censored at the time of last contact. RESULTS: At baseline in 793 patients (58%) heart rate has been elevated (70 bpm or more) while in 562 patients it has been below 70 bpm, in 8 patients no baseline heart rate has been recorded. Groups were equally balanced regarding age, gender and cardiovascular risk factors with the exception of smokers (more active smokers in the high heart-rate group: 23 vs 14%; p = 0.001) and valvular cause of heart failure (more frequent in the high heart-rate group: 3% vs 1%; p = 0.012). Patients in the high heart-rate group had significantly higher median NT pro-BNP (1470 pg/ml, IQR 499-4188 pg/ml) compared to patients in the low heart rate group (784 pg/ml, IQR 314-2162 pg/ml; p < 0.001). NYHA functional classes III and IV have been more frequent in the high heart-rate group than in the low heart-rate group (32% and 22%, respectively; p < 0.001) while reduced left ventricular ejection fraction (39% or less) has been more frequent in the high heart-rate group than in the low heart-rate group (71% and 61%, respectively; p < 0.001). In the high heart-rate group treatment with beta-blockers has been less frequent than in the low heart rate group (76% and 86%, respectively; p < 0.01) while dosage of beta-blocker therapy has been comparable in both groups. Of the 75 patients who died within 3.5 years 38 deaths had a cardiovascular cause. Cox proportional hazards analysis revealed that high NYHA functional class (III and IV) and elevated heart rate (70 bpm or more) were the best predictors of overall mortality while cardiovascular mortality could best be predicted by NYHA functional classes III and IV. CONCLUSION: Higher NYHA-functional classes and elevated heart rate are predictors of adverse outcome in chronic heart failure patients. PMID- 21614458 TI - Presenting features and outcome of chronic lymphocytic leukemia patients diagnosed at age 80 years or more. An ICLLSG study. AB - Although the incidence of chronic lymphocytic leukemia (CLL) increases exponentially with age, data on patients 80 years or older at diagnosis are sparse. The records of patients diagnosed with CLL at age >=80 years at seven medical centers in Israel during 1979-2009 were reviewed. Patients included 118 men and 96 women with a mean age of 84 years (range 80-94). Diagnosis was established in 56.5% due to routine blood count; 56% had Rai stage 0 disease and 25% of the patients received treatment. By June 2010, 72% had died. Mean survival was 67.7 months (median 56+/-5.4 months) and 5-year survival rate 47.2+/-3.6%. On univariate analysis, factors associated with better survival were age <84 years (p=0.002), early Rai and Binet stages (p=0.023, 0.003), low white blood cell count at time of diagnosis (p=0.015), low beta2 microglobulin level (p=0.006), diagnosis by routine blood test (p<0.001), and low CD38 level (p=0.036). Multivariate analysis using Cox regression revealed that younger age, low white cell count, and diagnosis by routine blood test were independent predictors of good prognosis (hazards ratios 1.8, 1.6, and 1.9, respectively). Patients diagnosed with CLL at age >=80 years may expect to live a long life. This study identifies several factors predicting good prognosis which are easy to obtain. PMID- 21614459 TI - Direct rRNA fingerprinting, a novel method to profile low diversity microbial communities. AB - In the past decade, an increasing number of methods in microbial ecology have been developed that address the questions of which microbes exist in the environment, what their roles are and, to some extent, what their abundance is. In the present paper, we propose and describe the proof of principle of a novel method for analysing shifts in microbial community composition that uses small RNA fragments directly derived from 16S rRNA. Community fingerprints are generated on the basis of sequence-dependent conformational differences of rRNA fragments. We applied this method to profile artificial and natural communities and to detect changes in community structure in enrichment cultures. This method constitutes a PCR-free alternative to microbial community characterisation and can provide information on the relative abundance of rRNA from individual phylotypes in low diversity samples. PMID- 21614460 TI - Efficacy of zosteric acid sodium salt on the yeast biofilm model Candida albicans. AB - Candida albicans is the most notorious and the most widely studied yeast biofilm former. Design of experiments (DoE) showed that 10 mg/L zosteric acid sodium salt reduced C. albicans adhesion and the subsequent biofilm formation by at least 70%, on both hydrophilic and hydrophobic surfaces of 96-well plates. Indeed, biofilm imaging revealed the dramatic impact of zosteric acid sodium salt on biofilm thickness and morphology, due to the inability of the cells to form filamentous structures while remaining metabolically active. In the same way, 10 mg/L zosteric acid sodium salt inhibited C. albicans biofilm formation when added after the adhesion phase. Contrary to zosteric acid sodium salt, methyl zosterate did not affect yeast biofilm. In addition, zosteric acid sodium salt enhanced sensitivity to chlorhexidine, chlorine, hydrogen peroxide, and cis-2-decenoic acid, with a reduction of 0.5 to 8 log units. Preliminary in vitro studies using suitable primary cell based models revealed that zosteric acid sodium salt did not compromise the cellular activity, adhesion, proliferation or morphology of either the murine fibroblast line L929 or the human osteosarcoma line MG-63. Thus the use of zosteric acid sodium salt could provide a suitable, innovative, preventive, and integrative approach to preventing yeast biofilm formation. PMID- 21614462 TI - Obituary: Jean Montreuil (1920-2010). PMID- 21614461 TI - A randomised crossover trial to compare the potential of stannous fluoride and essential oil mouth rinses to induce tooth and tongue staining. AB - This study compared the staining potential of two experimental amine fluoride/stannous fluoride mouth rinses (A and B), a phenolic/essential oil rinse (C) and a negative control, water, rinse (D). The study was a single centre, randomized, single-blind, four treatment crossover study design among healthy participants. Prior to each study period, participants received a dental prophylaxis. On the Monday of each period, subjects suspended oral hygiene, and under supervision, rinsed with the allocated mouth rinse immediately followed by a warm black tea solution at hourly intervals eight times a day for 4 days. On Friday, the area and intensity of staining on the teeth, the primary outcome measure and dorsum of tongue were assessed. This regimen was repeated for all the three subsequent treatment periods. Rinse B produced less stain than rinse A, but the difference was not significant (p = 0.20). Rinse B produced significantly more stain than rinse C (p < 0.05) and D (p < 0.001). For tongue staining, rinse B produced significantly more staining than D (p < 0.01) but not A or C. Overall, all test rinses produced more staining than placebo with an overall pattern for more staining with stannous formulations. Individuals using stannous or phenolic/essential oil mouth rinse formulations should be advised of the possible staining side effect and that this can be easily removed by a professional dental cleaning. PMID- 21614464 TI - HRQoL questionnaire evaluation in lactose intolerant patients with adverse reactions to foods. AB - The occurrence of patients with gastrointestinal symptoms attributed either to food allergy or intolerance has significantly increased. Nevertheless, an accurate and detailed case history, a systematic evaluation and the outcomes of specific allergy tests to identify the offending foods, including "in vivo" and "in vitro" allergy tests, are often negative for food allergy and may indicate a lactose intolerance, which is a recurrent condition affecting about 50% of adults. The aims of our study were the following: (1) What is the real incidence of the food hypersensitivity and the primary lactose intolerance in patients with gastrointestinal symptoms, initially referred to allergy or food intolerance? (2) Does lactose intolerance affect the quality of life and compliance to the therapy program? We investigated 262 consecutive patients, 72 men and 190 women. An accurate and detailed history and clinical examination were completed to investigate the offending foods. The evaluation in each patient included: allergy tests, lactose H2 breath test (LHBT) and the HRQoL questionnaire. Five years after the diagnosis of lactose intolerance, a questionnaire on the persistence of gastrointestinal symptoms after lactose ingestion and the diet compliance was distributed. Our results demonstrate an high prevalence of lactose intolerance, more frequent in women; in these patients, bloating and diarrhea are the most reported symptoms. We observe only a significant positive correlation between adverse drug reaction (ADR) and LHBT+ patients, but not an augmented prevalence of food allergy and a negative impact on the HRQoL questionnaire of lactose intolerance. PMID- 21614465 TI - Routine histopathological examination of appendectomy specimens in children: is there any rationale? AB - OBJECTIVE: Primary carcinoma of the bowel is a rare malignancy in pediatric age group. The aim of the study was to assess the incidence of appendicular malignancies in children and the possibility of reducing the need for routine histopathological examination of appendix. MATERIALS AND METHODS: In last 15 years, all the cases of appendectomies in children were analyzed. Retrospective analysis of the data was done to document the clinical presentation, diagnosis, outcome and histopathology reports of the specimen. The case files and operation notes were studied thoroughly in cases where HPR was positive for malignancy. RESULTS: From July 1995 to June 2010, 595 appendectomies were done in children. Three cases of carcinoid tumor were detected. All were less than 1 cm and were on the tip of the appendix. There was no preoperative or intraoperative suspicion. CONCLUSION: Routine histopathological analysis did not help in the management of any of the cases. Therefore, selective utilization of the already burdened histopathology section of the hospital would be more cost effective without affecting the patient outcome. PMID- 21614463 TI - Neuropathological background of phenotypical variability in frontotemporal dementia. AB - Frontotemporal lobar degeneration (FTLD) is the umbrella term encompassing a heterogeneous group of pathological disorders. With recent discoveries, the FTLDs have been show to classify nicely into three main groups based on the major protein deposited in the brain: FTLD-tau, FTLD-TDP and FTLD-FUS. These pathological groups, and their specific pathologies, underlie a number of well defined clinical syndromes, including three frontotemporal dementia (FTD) variants [behavioral variant frontotemporal dementia (bvFTD), progressive non fluent aphasia, and semantic dementia (SD)], progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS). Understanding the neuropathological background of the phenotypic variability in FTD, PSPS and CBS requires large clinicopathological studies. We review current knowledge on the relationship between the FTLD pathologies and clinical syndromes, and pool data from a number of large clinicopathological studies that collectively provide data on 544 cases. Strong relationships were identified as follows: FTD with motor neuron disease and FTLD-TDP; SD and FTLD-TDP; PSPS and FTLD-tau; and CBS and FTLD tau. However, the relationship between some of these clinical diagnoses and specific pathologies is not so clear cut. In addition, the clinical diagnosis of bvFTD does not have a strong relationship to any FTLD subtype or specific pathology and therefore remains a diagnostic challenge. Some evidence suggests improved clinicopathological association of bvFTD by further refining clinical characteristics. Unlike FTLD-tau and FTLD-TDP, FTLD-FUS has been less well characterized, with only 69 cases reported. However, there appears to be some associations between clinical phenotypes and FTLD-FUS pathologies. Clinical diagnosis is therefore promising in predicting molecular pathology. PMID- 21614466 TI - First-bite syndrome in oncologic patients. AB - First-bite syndrome (FBS) is described as a complication of parapharyngeal space surgery and consists of short-term pain in the parotid or mandibular region at the start of each meal, usually on the first bite and improving with subsequently each bite. The pathogenesis is related to a selective sympathetic denervation of the parotid gland and its treatment involves dietary modifications, medical treatment or even surgery, all with poor results. FBS is often undervalued and misdiagnosed, yet it is a pathology that may interfere with the patient's quality of life. We report two patients who underwent major cervical oncologic surgeries. One patient was subject to extended radical neck dissection into the parapharyngeal space and the other patient ligation of the external carotid artery, which post-operatively developed into FBS unresponsive to the medical treatment instituted. During external adjuvant radiotherapy, both had an unexpected FBS improvement, remaining asymptomatic after 7 and 10 months of follow-up. In this study, we discuss why FBS is misdiagnosed in oncologic patients, the possible pathophysiological mechanisms of radiotherapy and its plausibility as a new modality of treatment in selected cases. PMID- 21614467 TI - Drug-induced sleep endoscopy: the VOTE classification. AB - The surgical evaluation of obstructive sleep apnea is designed to characterize the pattern of upper airway obstruction in order to develop an effective treatment plan for an individual patient. Drug-induced sleep endoscopy (DISE) is one evaluation technique that involves assessment of individuals under pharmacologic sedation designed to simulate natural sleep, utilizing fiberoptic endoscopy to examine the upper airway. Developed in multiple centers throughout Europe, DISE was first described in 1991 and is performed widely around the world. Although multiple studies support a potential role for DISE in evaluation for treatment with surgery and mandibular repositioning appliances, important clinical questions remain unanswered. A major limitation in advancing our understanding of drug-induced sleep endoscopy has been the multiplicity and, in many cases, the complexity of classification systems that prevent the comparison of results across the studies and centers. We present the VOTE classification, a method for characterizing DISE findings that focuses on its core feature, the specific structures that contribute to obstruction. PMID- 21614469 TI - Identification of the prostate cancer index lesion by real-time elastography: considerations for focal therapy of prostate cancer. AB - INTRODUCTION: Focal therapy of prostate cancer is gaining more and more interest. One of the drawbacks of focal therapy of prostate cancer is the problem of correct identification of prostate cancer lesions. The aim of the study was to evaluate the ability of real-time elastography to correctly identify the prostate cancer index lesion. MATERIALS AND METHODS: In 32 patients, real-time elastography was performed the day before prostatectomy. During the examination, the location of the main lesion suspicious for prostate cancer was prospectively recorded. Moreover, the results of the randomized multicore biopsies were also used to predict the location of the index lesion. The preoperative elastography results, the biopsy results, and a combined use of elastography and biopsy results were then compared with the pathological results to calculate the diagnostic values for correct index lesion identification. RESULTS: When using real-time elastography alone to identify the prostate cancer index lesion, sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 58.8, 43.3, 54.1, 48.1, and 51.6%, respectively. Data from randomized biopsies alone achieved 67.8, 48.4, 56.8, 60.0, and 58.1%, respectively. The combination of elastography and biopsy data increased the values to, respectively, 84.9, 48.4, 61.9, 75.0, and 66.1%. CONCLUSION: In this study, real-time elastography alone did not allow to identify the prostate cancer index lesion with satisfactory reliability. The combination of real-time elastography and data from randomized 12 core biopsies allows promising ability to correctly identify the prostate cancer index lesion. PMID- 21614468 TI - Advances in non-surgical treatments for urinary tract infections in children. AB - OBJECTIVE: With growing antibiotics failure due to emerging resistance of bacteria, non-surgical management of pediatric UTI plays a more important role because of its non-invasive characteristics and little adverse effects. METHODS: We searched the Pubmed for management of UTI in children other than surgical correction and antibiotics using terms: risk factor, prepuce/phimosis, steroid cream/steroid, behavioral therapy, urotherapy, biofeedback/pelvic floor exercise, adrenergic antagonist, anticholinergics, diet/dietary, dysfunctional voiding/dysfunctional elimination syndrome, constipation, dietary, clean intermittent catheterization, probiotics/lactobacillus, cranberry, vitamin supplement, breastfeeding, breast milk, with infant/child/children/pediatrics/pediatrics and urinary tract infection. RESULTS: The proposed non-surgical management of pediatric UTI included behavioral modification (timed voiding and adequate fluids intake), topical steroid for phimosis, nutrient supplements (breast milk, cranberry, probiotics, and vitamin A), biofeedback training for dysfunctional voiding, anticholinergics for reducing intravesical pressure, alpha-blockers in dysfunctional voiding and neurogenic bladder, and intermittent catheterization for children with large PVR. CONCLUSION: The published reports usually included small number of patients and were lacking of randomization and controlled group. Further well-designed studies are warranted to support the concepts of non-operative management for pediatric UTI. PMID- 21614470 TI - Hematologic adverse events associated with temozolomide. AB - PURPOSE: Temozolomide (TMZ) is a widely used oral alkylating agent that has been associated with the development of severe hematologic adverse events (HAEs). Limited clinical information about HAEs is available. METHODS: We searched the FDA MedWatch database for TMZ and obtained all MedWatch reports on TMZ submitted to the FDA from November 1, 1997 to September 3, 2008. We defined major HAEs, namely agranulocytosis, aplasia, aplastic anemia (AA), leukemia (various), myelodysplastic syndrome (MDS), and lymphoma, and several minor HAEs. RESULTS: A total of 5,127 reports on 3,490 patients were submitted to MedWatch. Among these, we identified 112 cases of major HAEs. Of the 44 reported deaths, the major HAE was considered the cause in 32 cases. The median duration of TMZ treatment was 6 weeks [0.5-108 weeks]. Seventy-six cases of AA or aplasia and 17 cases of leukemia represented the most common major HAE. Important minor HAEs were bone marrow failure and pancytopenia/pancytopenia-like with 325 combined cases; these reports are clinically similar to aplastic anemia. CONCLUSION: The hematologic toxicity profile of TMZ differs from that of other alkylating agents. TMZ HAEs are emerging as significant concerns. Among alkylating agents, AA appears unique to TMZ, and the high rate warrants disclosure of patients. The duration of TMZ exposure prior to the development of AA may be quite short. The risk of AML/MDS is low, but the length of follow-up is insufficient to assess the true risk. PMID- 21614472 TI - An overview of systematic reviews of complementary and alternative medicine for fibromyalgia. AB - Fibromyalgia (FM) is a chronic pain condition which is difficult to diagnose and to treat. Most individuals suffering from FM use a variety of complementary or alternative medicine (CAM) interventions to treat and manage their symptoms. The aim of this overview was to critically evaluate all systematic reviews of single CAM interventions for the treatment of FM. Five systematic reviews met the inclusion criteria, evaluating the effectiveness of homoeopathy, chiropractic, acupuncture, hydrotherapy and massage. The reviews found some evidence of beneficial effects arising from acupuncture, homoeopathy, hydrotherapy and massage, whilst no evidence for therapeutic effects from chiropractic interventions for the treatment of FM symptoms was found. The implications of these findings and future directions for the application of CAM in chronic pain conditions, as well as for CAM research, are discussed. PMID- 21614471 TI - Fractal symmetry of protein interior: what have we learned? AB - The application of fractal dimension-based constructs to probe the protein interior dates back to the development of the concept of fractal dimension itself. Numerous approaches have been tried and tested over a course of (almost) 30 years with the aim of elucidating the various facets of symmetry of self similarity prevalent in the protein interior. In the last 5 years especially, there has been a startling upsurge of research that innovatively stretches the limits of fractal-based studies to present an array of unexpected results on the biophysical properties of protein interior. In this article, we introduce readers to the fundamentals of fractals, reviewing the commonality (and the lack of it) between these approaches before exploring the patterns in the results that they produced. Clustering the approaches in major schools of protein self-similarity studies, we describe the evolution of fractal dimension-based methodologies. The genealogy of approaches (and results) presented here portrays a clear picture of the contemporary state of fractal-based studies in the context of the protein interior. To underline the utility of fractal dimension-based measures further, we have performed a correlation dimension analysis on all of the available non redundant protein structures, both at the level of an individual protein and at the level of structural domains. In this investigation, we were able to separately quantify the self-similar symmetries in spatial correlation patterns amongst peptide-dipole units, charged amino acids, residues with the pi-electron cloud and hydrophobic amino acids. The results revealed that electrostatic environments in the interiors of proteins belonging to 'alpha/alpha toroid' (all alpha class) and 'PLP-dependent transferase-like' domains (alpha/beta class) are highly conducive. In contrast, the interiors of 'zinc finger design' ('designed proteins') and 'knottins' ('small proteins') were identified as folds with the least conducive electrostatic environments. The fold 'conotoxins' (peptides) could be unambiguously identified as one type with the least stability. The same analyses revealed that peptide-dipoles in the alpha/beta class of proteins, in general, are more correlated to each other than are the peptide-dipoles in proteins belonging to the all-alpha class. Highly favorable electrostatic milieu in the interiors of TIM-barrel, alpha/beta-hydrolase structures could explain their remarkably conserved (evolutionary) stability from a new light. Finally, we point out certain inherent limitations of fractal constructs before attempting to identify the areas and problems where the implementation of fractal dimension based constructs can be of paramount help to unearth latent information on protein structural properties. PMID- 21614473 TI - Laryngeal involvement in juvenile idiopathic arthritis patients. AB - Juvenile idiopathic arthritis (JIA) is an autoimmune diseases characterized by chronic arthritis and systemic manifestations. Autoimmune diseases can affect the upper airways including the larynx. The aim of this study was to investigate laryngeal involvement in JIA patients and its possible association with JIA disease parameters. Fifty consecutive JIA patients were screened for laryngeal abnormalities using flexible fiberoptic laryngoscope and laryngeal computerized tomography. Laryngeal abnormalities were detected in nine (18%) of our cases, with cricoarytenoiditis in six cases (12%) and a rheumatoid nodule in the pyriform fossa in only one case (2%). Diffuse congestion and edema of the posterior part of the larynx with normal vocal cord mobility was detected in two cases (4%). In our study, laryngeal abnormalities were significantly higher in patients with polyarticular seropositive disease subtype and also were significantly higher in patients with longer disease duration, higher disease activity scores, and those with erosive disease. JIA may affect the larynx. Laryngeal involvement in JIA patients is more in polyarticular seropositive cases. JIA patients have to be subjected to thorough otolaryngologic examination for early diagnosis and prompt management. PMID- 21614474 TI - We should not forget the foot: relations between signs and symptoms, damage, and function in rheumatoid arthritis. AB - We studied rheumatoid arthritis (RA) patients with foot complaints to address the associations between clinical signs and symptoms, radiographic changes, and function in connection with disease duration. Secondly, we describe the contribution of several foot segments to the clinical presentation and function. In 30 RA patients with complaints of their feet, attributed to either signs of arthritis and/or radiographic damage, we compared radiographic, ultrasound, clinical, and functional parameters of the feet and ankle. Pain and swelling of the ankle were correlated weakly but statistically significantly with limitation and disability (0.273 to 0.293) as measured on the 5-Foot Function Index (FFI). The clinical signs of the forefoot joints did not influence any of the functional outcome measures. Radiographic scores for both forefeet (SvdH) and hindfeet (Larsen) were correlated with the total Health Assessment Questionnaire Disability Index (HAQ DI) and the 5-FFI limitation subscale. Pain and disease duration, more than radiographic damage, influence the total HAQ DI significantly. With the progression of time, structural damage and function of the rheumatic foot worsen in RA patients. Pain and swelling of the ankle contribute more to disability than radiographic damage of the foot and ankle. PMID- 21614475 TI - Comparison of indirect immunofluorescence and multiplex antinuclear antibody screening in systemic sclerosis. AB - Indirect immunofluorescence antinuclear antibodies (IIF-ANA) are detected in approximately 90% of scleroderma patients, and the staining pattern correlates with scleroderma-specific antibody subsets. Solid-phase ANA assays that are dependent on multiplex bead technology (MULTIPLEX-ANA) are replacing immunofluorescence in many commercial labs; however, performance of these assays has not been compared to IIF-ANA in scleroderma. The purpose of this study was to evaluate whether a proportion of scleroderma patients have negative testing on MULTIPLEX-ANA assays and demonstrate whether negative MULTIPLEX-ANA is associated with particular scleroderma-specific autoantibodies. A retrospective chart review was completed on all 238 scleroderma patients evaluated in the Georgetown scleroderma clinic between June 1, 2008 and May 31, 2009. Autoantibody results, demographics, and scleroderma features were collected. Data were analyzed using unpaired t test and Mann-Whitney U test for continuous variables, and Fisher's exact test for dichotomous variables. Simple kappa coefficient was used to measure the level of agreement between MULTIPLEX-ANA and IIF-ANA results. Two tailed p values <0.05 were considered significant. MULTIPLEX-ANA testing was available in 57 patients and only 29 (51%) tested positive. In contrast, IIF-ANA was positive in 91% of these patients. Using simple kappa coefficient, there was a good agreement between the MULTIPLEX-ANA, and presence of Scl70, RNP, and centromere antibodies (0.76; 95% CI 0.59, 0.92), but there was no agreement between MULTIPLEX-ANA and presence of other IIF-ANA patterns including nucleolar ANA (-0.40; 95% CI -0.64, -0.16). Because RNA polymerase III and nucleolar antibodies are seen in 43% of the entire scleroderma population, we are concerned that these false-negative tests could result in delays in referral and diagnosis. Until the MULTIPLEX-ANA assays can be modified to include the antigens for RNA polymerase III and the nucleolar ANA subsets, IIF-ANA remains the recommended screening test for ANA in suspected scleroderma. PMID- 21614476 TI - Methotrexate-induced pulmonary toxicity in psoriatic arthritis (PsA): case presentation and literature review. AB - A 45-year-old female with a 4-week history of psoriatic arthritis developed cough, fever, and progressive shortness of breath 2 weeks following initiation of methotrexate therapy. High resolution CT of chest revealed bilateral basal interstitial involvement and diffuse ground glass opacities. Patient, though, died despite immediate discontinuation of methotrexate and initiation of treatment with IV methylprednisolone and cyclophosphamide. Post-mortem examination showed diffuse interstitial pulmonary fibrosis. Methotrexate-induced pulmonary toxicity is a serious event, unpredictable, and unusual, especially in patients with psoriatic arthritis, and although reversible, it may be fatal. PMID- 21614477 TI - Optimizing multidetector CT for visualization of splenic vascular injury. Validation by splenic arteriography in blunt abdominal trauma patients. AB - Nonoperative management of blunt splenic injury is the treatment of choice in hemodynamically stable patients. Detection of vascular injury by multidetector CT (MDCT) is the most significant factor predicting the need for endovascular treatment. This study evaluated the timing of the appearance of vascular lesions during angiography. Images from 20 patients embolized for pseudoaneurysms (PSA) were evaluated. Angiograms were reviewed for phase and timing of PSA. Admission MDCT was reviewed for injury grade and PSA. Initial MDCT evaluation indicated grade III and IV splenic injuries in 9 and 11 patients, respectively. PSA was seen on MDCT in 14/20 (70%) patients. Time from opacification of the aorta to vascular injury was 1.32 s for arterial phase injuries compared with 2.05 s for postcapillary injuries (P=0.097). Angiography demonstrated 15 vascular injuries during the arterial and 5 in the venous phase. Of injuries seen during arterial phase angiography, 10/15 (66%) were identified on MDCT. Of the five injuries that exhibited postcapillary-phase findings, 4/5 (80%) demonstrated PSA (P=0.5). Vascular lesions are a better indicator of subsequent clinical deterioration than splenic injury grade. PSAs are more frequently seen in postcapillary vascular injuries than arterial phase lesions with the current timing of MDCT. In a subset of patients in whom splenic injury grades III and IV warrant angiography, PSAs are not initially demonstrated on MDCT. Therefore, alteration of MDCT timing parameters to better correlate with arterial phase angiography may improve initial diagnosis of vascular injury. PMID- 21614478 TI - Crack cocaine-induced supraglottitis. PMID- 21614479 TI - Effect of 1,064-nm Nd:YAG laser therapy on GCF IL-1beta and MMP-8 levels in patients with chronic periodontitis. AB - The aim of this study was to evaluate the long-term effects of a combined periodontal treatment of scaling and root planing (SRP) and Nd:YAG laser (NDL) in chronic periodontitis (CP) patients. This was accomplished by determining the periodontal indices and the interleukin-1beta (IL-1beta) and matrix metalloproteinase-8 (MMP-8) levels of the gingival crevicular fluid (GCF). This study was performed according to a random split-mouth-design, controlled clinical trial for sulcular debridement on 40 teeth from 20 patients with generalized moderate chronic periodontitis. The periodontal healing outcomes were compared after periodontal treatment with either SRP + NDL at 1 W (test side) or SRP (control side). Plaque index (PI), gingival index (GI), probing pocket depth (PPD), and clinical attachment level (CAL) were recorded, and samples of gingival crevicular fluid (GCF) were taken at baseline and post-therapy (3 and 9 months after treatment). The GCF samples were analyzed for IL-1beta and MMP-8. There was postoperative improvement of all clinical parameters in both groups, but test side GI, PPD, and CAL recovery was higher than that of the control side (p < 0.05). Although levels of IL-1beta and MMP-8 in GCF after treatment were lower in the test side than the control side, there was not a statistically significant difference (p > 0.05). In the long term, we found that SRP + NDL treatment of periodontal pockets was more effective than SRP alone in reducing PPD, CAL, GI, and GCF values. PMID- 21614481 TI - The use of optical technology to monitor the antiangiogenic effects of gefitinib treatment for advanced head and neck squamous cell carcinoma: a brief report. PMID- 21614480 TI - Stimulatory effect of low-level laser therapy on root development of rat molars: a preliminary study. AB - Several studies suggest a biomodulatory influence of low-level laser irradiation in the inflammatory and reparative processes of dental tissues. The aim of this study was to investigate the stimulatory effect of 808-nm laser irradiation on root development of rat molars and also to evaluate the histological reaction of pulp and periapical tissues. Twenty-four 30-day-old Wistar male rats were randomly assigned to three-time and five-time laser therapy groups. After initial x-ray, using mammography equipment, laser energy was applied at a wavelength of 808 nm (2 J/cm(2), 100 mW, 20 s) to the midroot area of the lower molars of one side of mouth at repeated intervals of the 48 h. The animals were killed 1 day after the final treatment, and root length development of the experimental samples was compared to contra-lateral non-irradiated molars using mammography. The histological reaction of the pulp and periapical tissue was evaluated under light microscopy. Root development was more advanced in irradiated groups than in the non-irradiated controls (p < 0.001). No significant differences, however, could be found between the root development changes in the three-time and five time laser therapy groups (p > 0.05). Histological findings showed that the occurrence of secondary cement formation was significantly higher in the irradiation groups compared to the controls (p = 0.003). However, there were no statistically significant differences for the frequencies of pulp hyperemia, periodontal ligament fiber organization, or lamina dura remodeling between the groups (p > 0.05). Under the conditions used in this study, 808-nm low-level laser accelerates the rat molar root development in the presence of favorable histological reactions. PMID- 21614482 TI - Identification and molecular characterization of a S. agalactiae strain lacking the capsular locus. AB - During a national surveillance program on Group B streptococci (GBS) maternal carriage and neonatal infections, a GBS strain isolated from a pregnant woman's vagino-rectal swab was non typable by either serological or molecular methods. Further molecular characterization demonstrated that the strain lacked the entire capsular locus, possibly by a recombination event that excised a 14,1 Kbase pairs genomic fragment extending from the regulatory protein cpsX gene to the neuA gene. The natural loss of the capsular locus by GBS isolated from a human has never been described so far. Such an event, while possibly a dead-end from the evolutionary point of view, leaves a still able-to-colonize organism unrecognizable by the vaccines currently under development. PMID- 21614483 TI - Radionuclide concentrations in raw and purified phosphoric acids from Brazil and their processing wastes: implications for radiation exposures. AB - Radionuclides from the U and Th natural series are present in alkaline rocks, which are used as feedstock in Brazil for the production of raw phosphoric acid, which can be considered as a NORM (naturally occurring radioactive material). As a result of the purification of raw phosphoric acid to food-grade phosphoric acid, two by-products are generated, i.e., solid and liquid wastes. Taking this into account, the main aim of this study was to evaluate the fluxes of natural radionuclide in the production of food-grade phosphoric acids in Brazil, to determine the radiological impact caused by ingestion of food-grade phosphoric acid, and to evaluate the solid waste environmental hazards caused by its application in crop soils. Radiological characterization of raw phosphoric acid, food-grade phosphoric acid, solid waste, and liquid waste was performed by alpha and gamma spectrometry. The (238)U, (234)U, (226)Ra, and (232)Th activity concentrations varied depending on the source of raw phosphoric acid. Decreasing radionuclides activity concentrations in raw phosphoric acids used by the producer of the purified phosphoric acid were observed as follows: Tapira (raw phosphoric acid D) > Catalao (raw phosphoric acids B and C) > Cajati (raw phosphoric acid A). The industrial purification process produces a reduction in radionuclide activity concentrations in food-grade phosphoric acid in relation to raw phosphoric acid produced in plant D and single raw phosphoric acid used in recent years. The most common use of food-grade phosphoric acid is in cola soft drinks, with an average consumption in Brazil of 72 l per person per year. Each liter of cola soft drink contains 0.5 ml of food-grade phosphoric acid, which gives an annual average intake of 36 ml of food-grade phosphoric acid per person. Under these conditions, radionuclide intake through consumption of food-grade phosphoric acid per year per person via cola soft drinks is not hazardous to human health in Brazil. Considering these annual additions of (238)U, (226)Ra, (232)Th and (40)K, and since these radionuclide should be homogeneously distributed in the upper 10 cm of soils with an assumed apparent density of 1.5 g/cm(3), a maximum increase of 0.19 +/- 0.03 Bq kg(-1) of soil is expected for (238)U and (234)U. Thus, the addition of solid waste as phosphate fertilizers to Brazilian agricultural soils does not represent a hazard to the ecosystem or to human health. PMID- 21614484 TI - Automated versus manual segmentation of atherosclerotic carotid plaque volume and components in CTA: associations with cardiovascular risk factors. AB - The purpose of this study was to validate automated atherosclerotic plaque measurements in carotid arteries from CT angiography (CTA). We present an automated method (three initialization points are required) to measure plaque components within the carotid vessel wall in CTA. Plaque components (calcifications, fibrous tissue, lipids) are determined by different ranges of Hounsfield Unit values within the vessel wall. On CTA scans of 40 symptomatic patients with atherosclerotic plaque in the carotid artery automatically segmented plaque volume, calcified, fibrous and lipid percentages were 0.97 +/- 0.51 cm(3), 10 +/- 11%, 63 +/- 10% and 25 +/- 5%; while manual measurements by first observer were 0.95 +/- 0.60 cm(3), 14 +/- 16%, 63 +/- 13% and 21 +/- 9%, respectively and manual measurement by second observer were 1.05 +/- 0.75 cm(3), 11 +/- 12%, 61 +/- 11% and 27 +/- 10%. In 90 datasets, significant associations were found between age, gender, hypercholesterolemia, diabetes, smoking and previous cerebrovascular disease and plaque features. For both automated and manual measurements, significant associations were found between: age and calcium and fibrous tissue percentage; gender and plaque volume and lipid percentage; diabetes and calcium, smoking and plaque volume; previous cerebrovascular disease and plaque volume. Significant associations found only by the automated method were between age and plaque volume, hypercholesterolemia and plaque volume and diabetes and fibrous tissue percentage. Significant association found only by the manual method was between previous cerebrovascular disease and percentage of fibrous tissue. Automated analysis of plaque composition in the carotid arteries is comparable with the manual analysis and has the potential to replace it. PMID- 21614485 TI - Performance and efficacy of 320-row computed tomography coronary angiography in patients presenting with acute chest pain: results from a clinical registry. AB - The purpose of this study was to evaluate the performance of 320-row computed tomography angiography (CTA) in the identification of significant coronary artery disease (CAD) in patients presenting with acute chest pain and to examine the relation to outcome during follow-up. A total of 106 patients with acute chest pain underwent CTA to evaluate presence of CAD. Each CTA was classified as: normal, non-significant CAD (<50% luminal narrowing) and significant CAD (>=50% luminal narrowing). CTA results were compared with quantitative coronary angiography. After discharge, the following cardiovascular events were recorded: cardiac death, non-fatal infarction, and unstable angina requiring revascularization. Among the 106 patients, 23 patients (22%) had a normal CTA, 19 patients (18%) had non-significant CAD on CTA, 59 patients (55%) had significant CAD on CTA, and 5 patients (5%) had non-diagnostic image quality. In total, 16 patients (15%) were immediately discharged after normal CTA and 90 patients (85%) underwent invasive coronary angiography. Sensitivity, specificity, and positive and negative predictive values to detect significant CAD on CTA were 100, 87, 93, and 100%, respectively. During mean follow-up of 13.7 months, no cardiovascular events occurred in patients with a normal CTA examination. In patients with non significant CAD on CTA, no cardiac death or myocardial infarctions occurred and only 1 patient underwent revascularization due to unstable angina. In patients presenting with acute chest pain, an excellent clinical performance for the non invasive assessment of significant CAD was demonstrated using CTA. Importantly, normal or non-significant CAD on CTA predicted a low rate of adverse cardiovascular events and favorable outcome during follow-up. PMID- 21614486 TI - Growth phase-differential quorum sensing regulation of anthranilate metabolism in Pseudomonas aeruginosa. AB - Pseudomonas quinolone signal (PQS) plays a role in the regulation of virulence genes and it is intertwined in the las/rhl quorum sensing (QS) circuits of Pseudomonas aeruginosa. PQS is synthesized from anthranilate by pqsA-D and pqsH whose expression is influenced by the las/rhl systems. Since anthranilate can be degraded by functions of antABC and catBCA, PQS synthesis might be regulated by the balance between the expression of the pqsA-D/phnAB, pqsH, antABC, and catBCA gene loci. antA and catA are repressed by LasR during log phase and activated by RhlR in late stationary phase, whereas pqsA-E/phnAB is activated by LasR in log phase and repressed by RhlR. QscR represses both but each repression occurs in a different growth phase. This growth phase-differential regulation appears to be accomplished by the antagonistic interplay of LasR, RhlR, and QscR, mediated by two intermediate regulators, AntR and PqsR, and their cofactors, anthranilate and PQS, where the expressions of antR and pqsR and the production of anthranilate and PQS are growth phase-differentially regulated by QS systems. Especially, the anthranilate level increases in an RhlR-dependent manner at late stationary phase. From these results, we suggest that RhlR and LasR regulate the anthranilate metabolism in a mutually antagonistic and growth phase-differential manner by affecting both the expressions and activities of AntR and PqsR, and that QscR also phase-differentially represses both LasR and RhlR functions in this regulation. PMID- 21614487 TI - Development of novel monoclonal antibodies that define differentiation stages of human stromal (mesenchymal) stem cells. AB - Human mesenchymal stem cells (hMSC) are currently being introduced for cell therapy, yet, antibodies specific for native and differentiated MSCs are required for their identification prior to clinical use. Herein, high quality antibodies against MSC surface proteins were developed by immunizing mice with hMSC, and by using a panel of subsequent screening methods. Flow cytometry analysis revealed that 83.5, 1.1, and 8.5% of primary cultures of hMSC were double positive for STRO-1 and either of DJ 3, 9, and 18, respectively. However, none of the three DJ antibodies allowed enrichment of clonogenic hMSC from BMMNCs as single reagents. Using mass-spectrometric analysis, we identified the antigen recognised by DJ3 as CD44, whereas DJ9 and DJ18 recognized HLA-DRB1 and Collagen VI, respectively. The identified proteins were highly expressed throughout in vitro osteogenic- and adipogenic differentiation. Interestingly, undifferentiated cells revealed a sole cytoplasmic distribution pattern of Collagen VI, which however changed to an extracellular matrix appearance upon osteogenic- and adipogenic differentiation. In relation to this, we found that STRO-1(+/-)/Collagen VI(-) sorted hMSC contained fewer differentiated alkaline phosphatase(+) cells compared to STRO 1(+/-)/Collagen VI(+) hMSC, suggesting that Collagen VI on the cell membrane exclusively defines differentiated MSCs. In conclusion, we have generated a panel of high quality antibodies to be used for characterization of MSCs, and in addition our results may suggest that the DJ18 generated antibody against Collagen VI can be used for negative selection of cultured undifferentiated MSCs. PMID- 21614488 TI - The genome-wide expression profile of 1,2,3,4,6-penta-O-galloyl-beta-D-glucose treated MDA-MB-231 breast cancer cells: molecular target on cancer metabolism. AB - 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG), a polyphenolic compound isolated from Rhus chinensis Mill. PGG has been known to have anti-tumor, anti-angiogenic and anti-diabetic activities. The present study revealed another underlying molecular target of PGG in MDA-MB-231 breast cancer cells by using Illumina Human Ref-8 expression BeadChip assay. Through the Beadstudio v3 micro assay program to compare the identified genes expressed in PGG-treated MDA-MB-231 cells with untreated control, we found several unique genes that are closely associated with pyruvate metabolism, glycolysis/gluconeogenesis and tyrosine metabolism, including PC, ACSS2, ACACA, ACYP2, ALDH3B1, FBP1, PRMT2 and COMT. Consistent with microarray data, real-time RT-PCR confirmed the significant down-regulation of these genes at mRNA level in PGG-treated MDA-MB-231 cells. Our findings suggest the potential of PGG as anticancer agent for breast cancer cells by targeting cancer metabolism genes. PMID- 21614489 TI - Solute-dependent activation of cell motility in strongly hypertonic solutions in Dictyostelium discoideum, human melanoma HTB-140 cells and walker 256 carcinosarcoma cells. AB - Published data concerning the effects of hypertonicity on cell motility have often been controversial. The interpretation of results often rests on the premise that cell responses result from cell dehydration, i.e. osmotic effects. The results of induced hypertonicity on cell movement of Dictyostelium discoideum amoebae and human melanoma HTB-140 cells reported here show that: i) hypertonic solutions of identical osmolarity will either inhibit or stimulate cell movement depending on specific solutes (Na(+) or K(+), sorbitol or saccharose); ii) inhibition of cell motility by hypertonic solutions containing Na(+) ions or carbohydrates can be reversed by the addition of calcium ions; iii) various cell types react differently to the same solutions, and iv) cells can adapt to hypertonic solutions. Various hypertonic solutions are now broadly used in medicine and to study modulation of gene expression. The observations reported suggest the need to examine whether the other responses of cells to hypertonicity can also be based on the solute-dependent cell responses besides cell dehydration due to the osmotic effects. PMID- 21614490 TI - Exploring the binding dynamics of BAR proteins. AB - We used a continuum model based on the Helfrich free energy to investigate the binding dynamics of a lipid bilayer to a BAR domain surface of a crescent-like shape of positive (e.g. I-BAR shape) or negative (e.g. F-BAR shape) intrinsic curvature. According to structural data, it has been suggested that negatively charged membrane lipids are bound to positively charged amino acids at the binding interface of BAR proteins, contributing a negative binding energy to the system free energy. In addition, the cone-like shape of negatively charged lipids on the inner side of a cell membrane might contribute a positive intrinsic curvature, facilitating the initial bending towards the crescent-like shape of the BAR domain. In the present study, we hypothesize that in the limit of a rigid BAR domain shape, the negative binding energy and the coupling between the intrinsic curvature of negatively charged lipids and the membrane curvature drive the bending of the membrane. To estimate the binding energy, the electric potential at the charged surface of a BAR domain was calculated using the Langevin-Bikerman equation. Results of numerical simulations reveal that the binding energy is important for the initial instability (i.e. bending of a membrane), while the coupling between the intrinsic shapes of lipids and membrane curvature could be crucial for the curvature-dependent aggregation of negatively charged lipids near the surface of the BAR domain. In the discussion, we suggest novel experiments using patch clamp techniques to analyze the binding dynamics of BAR proteins, as well as the possible role of BAR proteins in the fusion pore stability of exovesicles. PMID- 21614491 TI - Upconversion based tunable white-light generation in Ln:Y(2)O(3) nanocrystalline phosphor (Ln = Tm/Er/Yb). AB - We report the generation of efficient white light based on upconversion (UC) in Tm(3+)/Er(3+)/Yb(3+):Y(2)O(3) nanocrystalline phosphor synthesized by simple and cost effective solution combustion technique on 976 nm laser excitation. The calculated color coordinates (using 1931 CIE standard) for samples annealed at different temperatures vary from (0.16, 0.30) to (0.32, 0.33) with dopant concentration, annealing temperature and the pump power; thus providing a wide color tunability including the white one. White emission is observed even at a very low laser power (60 mW). The maximum upconversion efficiency obtained for white emission is 2.79% with the color coordinates (0.30, 0.32) at laser power of 420 mW which is quite close to the standard white color coordinates. PMID- 21614493 TI - Bradycardia without associated hypertension. PMID- 21614492 TI - A candidate gene study of serotonergic pathway genes and pain relief during treatment with escitalopram in patients with neuropathic pain shows significant association to serotonin receptor2C (HTR2C). AB - PURPOSE: Previous studies have shown that a small fraction of patients with peripheral neuropathic pain experiences >50% pain relief during treatment with selective serotonin reuptake inhibitors (SSRIs), whereas most patients have no or only slight relief. The aim of this study was to investigate the association between polymorphisms in genes involved in the serotonergic pathway and the effect of escitalopram on peripheral neuropathic pain. METHODS: We genotyped 34 participants from a placebo-controlled trial of escitalopram in peripheral neuropathic pain for polymorphisms in five genes: the serotonin receptor 2A (HTR2A) gene, the serotonin receptor 2C (HTR2C) gene, the ABCB1 gene encoding for the P-glycoprotein, the CYP2C19 gene, and the serotonin transporter gene (SLC6A4). RESULTS: The SNP rs6318 (Cys23Ser) in the HTR2C gene showed significant association with treatment response in men (p = 0.047), with 75% carrying the C allele being responders. The same tendency was seen in women. Similarly, carriership of the C allele at rs6318 was associated with better pain relief during treatment with escitalopram [odds ratio (OR) 15.5, p = 0.014)] Furthermore, there was a tendency of better relief with increasing number of short alleles for the 5-HTTLPR polymorphism of the serotonin transporter (OR 5.7, p = 0.057). None of the other polymorphisms showed a significant association with treatment response to escitalopram. CONCLUSION: This study indicates that variation in the HTR2C gene is associated to the pain-relieving effect of escitalopram in patients with painful polyneuropathy. PMID- 21614494 TI - Positional plagiocephaly: what the pediatrician needs to know. A review. AB - INTRODUCTION: Positional or deformational plagiocephaly is the most common type of cranial asymmetry in infancy and has become more prevalent after the introduction of the "Back to Sleep" campaign in Western countries. However, the supine position cannot be considered as the only etiologic factor and different predisposing variables have been investigated in the last few years. DISCUSSION: The pediatrician should correctly diagnose this condition and exclude the possibility of craniosynostosis in any child with plagiocephaly in order to optimize management and reduce potential morbidity associated with different conditions other than positional ones. In addition, the pediatrician needs to be able to educate parents on methods to proactively decrease the likelihood of the development of occipital flattening, initiate appropriate management, and make referrals when necessary. PMID- 21614495 TI - Candida middelhoveniana sp. nov., a new yeast species found on the rhizoplane of organically cultivated sugarcane. AB - A novel yeast species within the Metschnikowiaceae is described based on a strain from the sugarcane (Saccharum sp.) rhizoplane of an organically managed farm in Rio de Janeiro, Brazil. The D1/D2 domain of the large subunit ribosomal RNA gene sequence analysis showed that the closest related species were Candida tsuchiyae with 86.2% and Candida thailandica with 86.7% of sequence identity. All three are anamorphs in the Clavispora opuntiae clade. The name Candida middelhoveniana sp. nov. is proposed to accommodate this highly divergent organism with the type strain Instituto de Microbiologia, Universidade Federal do Rio de Janeiro (IMUFRJ) 51965(T) (=Centraalbureau voor Schimmelcultures (CBS) 12306(T), Universidade Federal de Minas Gerais (UFMG)-70(T), DBVPG 8031(T)) and the GenBank/EMBL/DDBJ accession number for the D1/D2 domain LSU rDNA sequence is FN428871. The Mycobank deposit number is MB 519801. PMID- 21614496 TI - Prognostic value of total testosterone for pregnancy during treatment in patients with clomiphene-citrate-resistant polycystic ovary syndrome: a pilot study. AB - PURPOSE: Reduction of serum total testosterone (TT) is associated with pregnancy rate in polycystic ovary syndrome (PCOS) women receiving metformin, but most of the studies focus on the changes of basal levels of TT. The aim of this study was to evaluate whether the TT level around the ovulation period is related to the outcome of pregnancy in women with PCOS. METHODS: In total, 30 non-obese PCOS women with clomiphene citrate (CC) resistance from the Medical College's Reproductive Health Center were enrolled and randomly assigned to be treated with placebo (Group 1) or metformin (850 mg) (Group 2) twice daily for 3 months as the pre-treatment. Then, metformin alone was administered with CC, human menopausal gonadotropin (HMG) and human chorionic gonadotropin (HCG) to induce ovulation for 3 months in Group 1. In Group 2, CC/HMG/HCG was used to induce ovulation for 3 months without metformin. Follicle-stimulating hormone, luteinizing hormone, estradiol and TT levels before and after ovulation in pregnant cycles and non pregnant cycles were evaluated over the course of treatment. RESULTS: A total of 26 subjects completed 65 cycles. The TT levels after ovulation in the pregnant cycles were significantly lower than in the non-pregnant cycles in both groups (P = 0.001 and P < 0.001, respectively). CONCLUSIONS: The level of TT after ovulation may be of prognostic value for pregnancy in non-obese women with PCOS and CC resistance during treatment. PMID- 21614497 TI - Reducing perineal trauma through perineal massage with vaseline in second stage of labor. AB - PURPOSE: Maintaining an intact perineum is a highly regarded aim in delivery procedures today. Since perineal massage is a common practice during delivery, the present study aims to investigate the effect of perineal massage with Vaseline on perineal trauma (rate of episiotomy procedures and perineal tears). METHOD: Ninety primiparous women (aged between 18 and 30 years with gestational age of 38-42 weeks) were selected sequentially in Tehran in 2009. Once participants' characteristics were registered, they were randomly assigned to the intervention (perineal massage with Vaseline) or control groups. In the massage group, perineal massage was performed in the second stage of delivery once the genitalia were treated with sterilized Vaseline. The perineum was examined after the delivery in terms of episiotomy or tear and its severity degree. RESULTS: The two groups were homogeneous in terms of demographic data, weight gain during pregnancy, gestational age, abortion history and fetal weight. The second stage of delivery was significantly shorter in the massage group than the control group and the massage group had significantly more intact perineum (P = 0.004). In addition, lower episiotomy and higher first- and second-degree perineal tears were seen in the massage group in comparison with the control one (P < 0.001). Neither of the groups suffered from third- and fourth-degree tears. CONCLUSION: The findings showed that the perineal massage with Vaseline in the second stage of labor increases perineal integrity and decreases perineal traumas (episiotomy and tears). So, it seems that the perineal massage could be an effective way to preserve an intact perineum in labor. PMID- 21614498 TI - Proliferation inhibition of cisplatin and aquaporin 5 expression in human ovarian cancer cell CAOV3. AB - AIMS: The purpose of this study is to investigate the association between proliferation inhibition of cisplatin and aquaporin 5 (AQP5) expression and its regulation in ovarian carcinoma cell CAOV3. METHODS: Cell growth rate was measured by MTT after CAOV3 cells were incubated with cisplatin or NF-kappaB inhibitor PDTC. Western blot and RT-PCR were used to detect the expression of AQP5 and NF-kappaB p65. RESULTS: Our results showed that expression of AQP5, NF kappaB in cytoplasm and karyon and IkappaBalpha in cytoplasm protein in CAOV3 cells can be induced to decrease by cisplatin with concentration-dependent manner, and there is a positive correlation between AQP5 protein and cell growth rate (r = 0.607, P < 0.05). When cells were incubated with 10 MUg/ml cisplatin, AQP5, NF-kappaB p65, and IkappaBalpha increased rapidly at 6-12 h, but decreased at 24 h, remain on low level until to 72 h. Expression of AQP5 could be induced to decrease by PDTC, and a positive correlation between AQP5 protein expression and NF-kappaB p65 and IkappaBalpha (r = 0.894, 0.857; P < 0.05). CONCLUSIONS: Proliferation inhibition of cisplatin is related with AQP5 expression, and NF kappaB may be involved in mechanism of AQP5 regulation. AQP5 will be potential target for therapy of ovarian carcinoma. PMID- 21614499 TI - Quantitative genetic analysis of salicylic acid perception in Arabidopsis. AB - Salicylic acid (SA) is a phytohormone required for a full resistance against some pathogens in Arabidopsis, and NPR1 (Non-Expressor of Pathogenesis Related Genes 1) is the only gene with a strong effect on resistance induced by SA which has been described. There can be additional components of SA perception that escape the traditional approach of mutagenesis. An alternative to that approach is searching in the natural variation of Arabidopsis. Different methods of analyzing the variation between ecotypes have been tried and it has been found that measuring the growth of a virulent isolate of Pseudomonas syringae after the exogenous application of SA is the most effective one. Two ecotypes, Edi-0 and Stw-0, have been crossed, and their F2 has been studied. There are two significant quantitative trait loci (QTLs) in this population, and there is one QTL in each one of the existing mapping populations Col-4 * Laer-0 and Laer-0 * No-0. They have different characteristics: while one QTL is only detectable at low concentrations of SA, the other acts after the point of crosstalk with methyl jasmonate signalling. Three of the QTLs have candidates described in SA perception as NPR1, its interactors, and a calmodulin binding protein. PMID- 21614501 TI - Willow volatiles influence growth, development, and secondary metabolism in Aspergillus parasiticus. AB - Aflatoxin is a mycotoxin and the most potent naturally occurring carcinogen in many animals. Aflatoxin contamination of food and feed crops causes a significant global burden on human and animal health. However, available methods to eliminate aflatoxin from food and feed are not fully effective. Our goal is to discover novel, efficient, and practical methods to control aflatoxin contamination in crops during storage. In the present study, we tested the effect of volatiles produced by willow (Salix acutifolia and Salix babylonica) and maple (Acer saccharinum) bark on fungal growth, development, and aflatoxin production by the fungus Aspergillus parasiticus, one economically important aflatoxin producer. S. acutifolia bark volatiles nearly eliminated aflatoxin accumulation (>90% reduction) by A. parasiticus grown on a minimal agar medium. The decrease in aflatoxin accumulation correlated with a twofold reduction in ver-1 (encodes a middle aflatoxin pathway enzyme) transcript level. Expression data also indicate that one histone H4 acetyltransferase, MYST3, may play a role in epigenetic control of aflatoxin gene transcription in response to volatile exposure. Volatiles derived from wood bark samples also increased fungal growth up to 20% and/or enhanced conidiospore development. Solid-phase microextraction-gas chromatographic-mass spectrometric analysis of bark samples identified sets of shared and unique volatile compounds that may mediate the observed regulatory effects on growth, development, and aflatoxin synthesis. This work provides an experimental basis for the use of willow industry by-products to control aflatoxin contamination in food and feed crops. PMID- 21614500 TI - Characterization of development and artemisinin biosynthesis in self-pollinated Artemisia annua plants. AB - Artemisia annua L. is the only natural resource that produces artemisinin (Qinghaosu), an endoperoxide sesquiterpene lactone used in the artemisinin combination therapy of malaria. The cross-hybridization properties of A. annua do not favor studying artemisinin biosynthesis. To overcome this problem, in this study, we report on selection of self-pollinated A. annua plants and characterize their development and artemisinin biosynthesis. Self-pollinated F2 plants selected were grown under optimized growth conditions, consisting of long day (16 h of light) and short day (9 h of light) exposures in a phytotron. The life cycles of these plants were approximately 3 months long, and final heights of 30 35 cm were achieved. The leaves on the main stems exhibited obvious morphological changes, from indented single leaves to odd, pinnately compound leaves. Leaves and flowers formed glandular and T-shaped trichomes on their surfaces. The glandular trichome densities increased from the bottom to the top leaves. High performance liquid chromatography-mass spectrometry-based metabolic profiling analyses showed that leaves, flowers, and young seedlings of F2 plants produced artemisinin. In leaves, the levels of artemisinin increased from the bottom to the top of the plants, showing a positive correlation to the density increase of glandular trichomes. RT-PCR analysis showed that progeny of self-pollinated plants expressed the amorpha-4, 11-diene synthase (ADS) and cytochrome P450 monooxygenase 71 AV1 (CYP71AV1) genes, which are involved in artemisinin biosynthesis in leaves and flowers. The use of self-pollinated A. annua plants will be a valuable approach to the study of artemisinin biosynthesis. PMID- 21614502 TI - Role of bifidobacteria in the activation of the lignan secoisolariciresinol diglucoside. AB - Lignans are ubiquitous plant polyphenols, which have relevant health properties being the major phytoestrogens occurring in Western diets. Secoisolariciresinol (SECO) is the major dietary lignan mostly found in plants as secoisolariciresinol diglucoside (SDG). To exert biological activity, SDG requires being deglycosylated to SECO and transformed to enterodiol (ED) and enterolactone (EL) by the intestinal microbes. The involvement of bifidobacteria in the transformation of lignans glucosides has been investigated for the first time in this study. Twenty-eight strains were assayed for SDG and SECO activation. They all failed to transform SECO into reduced metabolites, excluding any role in ED and EL production. Ten Bifidobacterium cultures partially hydrolyzed SDG, giving both SECO and the monoglucoside with yields < 25%. When the cell-free extracts were assayed in SDG transformation, seven additional strains were active in the hydrolysis. Cellobiose induced beta-glucosidase activity and caused the enhancement of both the rate of SDG hydrolysis and the final yield of SECO only in the strains capable of SDG bioconversion. The highest SDG conversion to SECO was achieved by Bifidobacterium pseudocatenulatum WC 401, which exhibited 75% yield in cellobiose-based medium after 48 h. These results indicate that SDG hydrolysis is not a common feature in Bifidobacterium genus, but selected probiotic strains can be combined to beta-glucoside-based prebiotics to enhance the release of SECO, thus improving its bioavailability for absorption by colonic mucosa and/or the biotransformation to ED and EL by other intestinal microorganisms. PMID- 21614503 TI - The crystal structure of an esterase from the hyperthermophilic microorganism Pyrobaculum calidifontis VA1 explains its enantioselectivity. AB - The highly thermostable esterase from the hyperthermophilic archaeon Pyrobaculum calidifontis VA1 (PestE) shows high enantioselectivity (E > 100) in the kinetic resolution of racemic chiral carboxylic acids, but little selectivity towards acetates of tertiary alcohols (E = 2-4). To explain these unique properties, its crystal structure has been determined at 2.0 A resolution. The enzyme is a member of the hormone-sensitive lipase group (group H) of the esterase/lipase superfamily on the basis of the amino acid sequence identity. The PestE structure shows a canonical alpha/beta-hydrolase fold as core domain with a cap structure at the C-terminal end of the beta-sheet. A tetramer in the crystal packing is formed of two dimers; the dimeric form is observed in solution. Conserved dimers and even tetramers are found in other group H proteins. The amino acid residues Ser157, His284, and Asp254 form the catalytic triad, which is typically found in alpha/beta-hydrolases. The oxyanion hole is composed of Gly85 and Gly86 within the conserved sequence motif HGGG(M,F,W) (amino acid residues 83-87) and Ala158. With the elucidated structure, experimental results about enantioselectivity towards the two model substrate classes (as exemplified for 3-phenylbutanoic acid ethyl ester and 1,1,1-trifluoro-2-phenylbut-3-yn-2-yl acetate) could be explained by molecular modeling. For both enantiomers of the tertiary alcohol, orientations in two binding pockets were obtained without significant energy differences corresponding to the observed low enantioselectivity due to missing steric repulsions. In contrast, for the carboxylic acid ester, two different orientations with significant energy differences for each enantiomer were found matching the high E values. PMID- 21614504 TI - Maxillary sinus lift using fresh frozen bone chips in presence of sinus cyst: clinical and histological report. AB - The reconstruction of edentulous patients with adequate bone volume and density by the use of bone graft and, subsequently, the placement of dental implants has become a viable treatment option with high predictability. According to many authors, maxillary antral cysts are one of the most common benign pathologies of the maxillary sinus, and they also represent an important contraindication to sinus regenerative surgical technique. The authors report a case of maxillary atrophy which is augmented by fresh frozen bone chips in the presence of antral cysts. PMID- 21614505 TI - A comparison of dual energy X-ray absorptiometry and bioelectrical impedance analysis to measure total and segmental body composition in healthy young adults. AB - The aim of this study was to investigate the accuracy of BIA in the measurement of total body composition and regional fat and the fat free mass in the healthy young adults. Four hundred and three healthy young adults (167 women and 236 men) aged 18-29 years were recruited from the Mid-West region of Ireland. Multi frequency, eight-polar bioelectrical impedance analysis (BIA) and dual energy X ray absorptiometry (DXA) were used to measure the total body and segmental (arm, leg and trunk) fat mass and the fat free mass. BIA was found to underestimate the percentage total body fat in men and women (p < 0.001). This underestimate increased in men with >24.6% body fat and women with >32% body fat (p < 0.001). Fat tissue mass in the trunk segment was overestimated by 2.1 kg (p < 0.001) in men and underestimated by 0.4 kg (p < 0.001) in women. BIA was also found to underestimate the fat free mass in the appendages by 1.0 kg (p < 0.001) in men and 0.9 kg (p < 0.001) in women. Compared to dual energy X-ray absorptiometry, bioelectrical impedance analysis underestimates the total body fat mass and overestimates fat free mass in healthy young adults. BIA should, therefore, be used with caution in the measurement of total body composition in women and men with >25% total body fat. Though statistically significant, the small difference (~ 4%) between the methods indicates that the BIA may be used interchangeably with DXA in the measurement of appendicular fat free mass in healthy young adults. PMID- 21614506 TI - Chronic CaMKII inhibition blunts the cardiac contractile response to exercise training. AB - Activation of the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a critical role modulating cardiac function in both health and disease. Here, we determined the effect of chronic CaMKII inhibition during an exercise training program in healthy mice. CaMKII was inhibited by KN-93 injections. Mice were randomized to the following groups: sham sedentary, sham exercise, KN-93 sedentary, and KN-93 exercise. Cardiorespiratory function was evaluated by ergospirometry during treadmill running, echocardiography, and cardiomyocyte fractional shortening and calcium handling. The results revealed that KN-93 alone had no effect on exercise capacity or fractional shortening. In sham animals, exercise training increased maximal oxygen uptake by 8% (p < 0.05) compared to a 22% (p < 0.05) increase after exercise in KN-93 treated mice (group difference p < 0.01). In contrast, in vivo fractional shortening evaluated by echocardiography improved after exercise in sham animals only: from 25 to 32% (p < 0.02). In inactive mice, KN-93 reduced rates of diastolic cardiomyocyte re lengthening (by 25%, p < 0.05) as well as Ca(2+) transient decay (by 16%, p < 0.05), whereas no such effect was observed after exercise training. KN-93 blunted exercise training response on cardiomyocyte fractional shortening (63% sham vs. 18% KN-93; p < 0.01 and p < 0.05, respectively). These effects could not be solely explained by the Ca(2+) transient amplitude, as KN-93 reduced it by 20% (p < 0.05) and response to exercise training was equal (64% sham and 47% KN-93; both p < 0.01). We concluded that chronic CaMKII inhibition increased time to 50% re lengthening which were recovered by exercise training, but paradoxically led to a greater increase in maximal oxygen uptake compared to sham mice. Thus, the effect of chronic CaMKII inhibition is multifaceted and of a complex nature. PMID- 21614507 TI - Ontogeny of globin expression in zebrafish (Danio rerio). AB - Respiratory proteins are responsible for transport and storage of oxygen. It is well established that specific requirements for oxygen during vertebrate ontogeny cause switches of hemoglobin chain expression. Here, we characterize the developmental profiles of zebrafish (Danio rerio) globins by means of quantitative real-time reverse transcription PCR. The total mRNA levels of the hemoglobin chains, including a newly identified embryonic alpha-chain, as well as myoglobin, neuroglobin, cytoglobin 1 and 2, and globin X were estimated. mRNAs of all globins were detectable in unfertilized eggs, suggesting maternal storage. Embryonic alpha- and beta-hemoglobin mRNA peaked at hatching and the switch to adult hemoglobin expression occurred 16 dpf. Enhanced myoglobin mRNA levels were detected ~31 h post-fertilization (hpf), coinciding with the heart and the muscle development, while neuroglobin mRNA expression pattern correlates with the formation of the nervous system. Amounts of myoglobin and neuroglobin mRNA were similar within an order of magnitude throughout the ontogeny, tentatively supporting a respiratory role of neuroglobin. Cytoglobin 2 mRNA levels increased gradually, whereas cytoglobin 1 mRNA levels increased strongly after ~31 hpf, which is in agreement with a function in cell proliferation. Globin X mRNA level was highest in oocytes, but low in later stages. Together, these data suggest a specific role for each globin, which are also associated with certain events in fish development. PMID- 21614508 TI - Diagnosis and treatment of prostate cancer in renal-transplant recipients. AB - INTRODUCTION: The incidence and treatment of prostate cancer in male renal transplant patients has not been extensively evaluated. With the aging of the renal-transplant population, the diagnosis and management of prostate cancer in these patients needs further evaluation. METHODS: In this study, we conducted a retrospective review of data from 498 male renal-transplant patients to evaluate the prevalence, treatment, and outcome of prostate cancer in this population. RESULTS: Of the 498 male renal-transplant patients, nine were diagnosed with prostate cancer. A prostate specific antigen (PSA) screening program was not utilized, and these patients were diagnosed based on a prostate digital rectal examination and/or elevated PSA. The median age at transplantation was 55 years, and the median age at the diagnosis of prostate cancer was 63.6 years. One patient was treated with androgen ablation alone, four patients were with radiation alone, and four patients were treated with a combination of androgen ablation and external radiation. Twelve skin malignancies occurred in five of the patients with prostate cancer. Our patient population was preferentially treated with radiation therapy rather than radical prostatectomy. Seven of these treated patients are currently being followed and have good control of the disease. Two of the seven patients are on dialysis because of chronic allograft nephropathy. One patient was lost to follow-up, and one died with extensive metastasis, paraplegia, and renal failure. CONCLUSIONS: The incidence of diagnosed prostate cancer in patients with renal transplant will increase because of systematic PSA screening. The recommended current treatment modality depends on the Gleason grade, stage, PSA levels, and associated comorbid conditions. A combination of radiation treatment with androgen ablation provides good control of the disease while preserving renal function. PMID- 21614510 TI - Discordant expression of a new WT1 gene mutation in a family with monozygotic twins presenting with congenital nephrotic syndrome. AB - Congenital nephrotic syndrome (CNS) is a heterogeneous group of diseases with different causes and prognoses. Two thirds of cases of NS in the first year of life are caused by mutations in four genes (NPHS1, NPHS2, WT1, and LAMB2). The mutation of WT1 gene can lead to Denys-Drash syndrome (DDS). We report on female monozygotic twins with CNS presenting at 7 and 8 weeks of age with anuric renal failure. Both twins were treated by peritoneal dialysis. Renal biopsy proved diffuse mesangial sclerosis. Genetic analysis detected a new heterozygote WT1 mutation R434P in both twins. One child developed a unilateral nephroblastoma. Both twins died because of complications of CNS (sepsis and extensive thrombosis of central venous system/sepsis and sudden heart failure) at ages 23 weeks/13.5 months, respectively. DNA analysis showed the same WT1 mutation in the father, who showed at his age of 41 years no clinical consequences of this mutation and no signs of DDS. In conclusion, we report the third family with monozygotic twins with DDS due to WT1 mutation. The DDS has very rapidly led to end-stage renal failure and death in both twins which is in striking contrast to the manifestation in their father. PMID- 21614509 TI - Live donor kidney transplantation: attitudes of patients and health care professionals concerning the pre-surgical pathway and post-surgical follow-up. AB - OBJECTIVES: We surveyed the following groups of individuals concerning their attitudes towards the pathway leading up to live donor kidney transplantation (LDKT) and post-operative follow-up: kidney transplant (deceased and live donor) recipients, live kidney donors and medical and nursing staff caring for end-stage renal disease and dialysis patients. MATERIALS AND METHODS: Participants were recruited within a tertiary renal and transplant centre and invited to complete anonymized questionnaires, be involved in focus groups and undertake structured interviews. RESULTS: A total of 464 participants completed the questionnaire (36% health care professionals and 64% patients). Most perceived donor risk as small or very small (62%), and 49% stated that a potential donor should be given up to 3 months to reconsider the decision to donate. Participants were almost equally divided as to whether consensus of the donor's family is necessary (46%) or not (44%) in LDKT. Seventy-one percentage of the participants suggested that patients have a greater appreciation of a LDKT if they have been on dialysis; 58% of participants thought that donor and recipient should recuperate beside each other after surgery; 45% thought that the post-operative follow-up for the donor should last up to a year; and 83% thought that donor follow-up should include medical status and quality of life. In the interviews, participants expressed several interesting views. CONCLUSIONS: Participants believed that LDKT is safe for the donor, and the pathway to surgery and post-operative follow-up should be performed in a way that ensures lack of coercion and includes family support and an extensive post-operative follow-up. PMID- 21614511 TI - Screening of congenital cytomegalovirus infection by real-time PCR in urine pools. AB - Human cytomegalovirus (HCMV) is the most frequent cause of congenital infection. Despite the fact that 5-17% of asymptomatic infected babies will develop late sequelae and, therefore, should be closely followed, most of these children will remain undetected, as screening of all newborns by viral culture is too expensive and no valid alternative has been widely accepted. The aim of this work was to demonstrate that pool testing can be used to screen HCMV congenital infection in newborns. For this purpose, a real-time PCR technique was tested in urine pools. This pool method was applied to all urine specimens from children received in the virology laboratory of the Centro Hospitalar Cova da Beira for diagnosis of HCMV infection for a period of 14 months. Ten out of the 160 urine samples were tested positive by shell-vial culture and were also detected by this pool method. Additionally, 100 urine specimens, collected in 2004 and culture negative for HCMV were included to test the specificity of this methodology, all of which were negative. In conclusion, these results suggest that urine pools can be used to detect HCMV-positive urines in children, with similar sensitivity and specificity when compared with the standard method. Because of the very significant reduction both in terms of labour and cost of testing materials, this methodology may represent a valid option for screening the HCMV congenital infection in newborns. PMID- 21614512 TI - Lionizing lyonization 50 years on. PMID- 21614514 TI - Positive correlation between Merkel cell polyomavirus viral load and capsid specific antibody titer. AB - Merkel cell polyomavirus (MCPyV or MCV) is the first polyomavirus to be clearly implicated as a causal agent underlying a human cancer, Merkel cell carcinoma (MCC). Infection with MCPyV is common in the general population, and a majority of adults shed MCPyV from the surface of their skin. In this study, we quantitated MCPyV DNA in skin swab specimens from healthy volunteers sampled at different anatomical sites over time periods ranging from 3 months to 4 years. The volunteers were also tested using a serological assay that detects antibodies specific for the MCPyV virion. There was a positive correlation between MCPyV virion-specific antibody titers and viral load at all anatomical sites tested (dorsal portion of the hands, forehead, and buttocks) (Spearman's r 0.644, P < 0.0001). The study results are consistent with previous findings suggesting that the skin is primary site of chronic MCPyV infection in healthy adults and suggest that the magnitude of an individual's seroresponsiveness against the MCPyV virion generally reflects the overall MCPyV DNA load across wide areas of the skin. In light of previous reports indicating a correlation between MCC and strong MCPyV specific seroresponsiveness, this model suggests that poorly controlled chronic MCPyV infection might be a risk factor in the development of MCC. PMID- 21614513 TI - Genes that escape from X inactivation. AB - To achieve a balanced gene expression dosage between males (XY) and females (XX), mammals have evolved a compensatory mechanism to randomly inactivate one of the female X chromosomes. Despite this chromosome-wide silencing, a number of genes escape X inactivation: in women about 15% of X-linked genes are bi-allelically expressed and in mice, about 3%. Expression from the inactive X allele varies from a few percent of that from the active allele to near equal expression. While most genes have a stable inactivation pattern, a subset of genes exhibit tissue specific differences in escape from X inactivation. Escape genes appear to be protected from the repressive chromatin modifications associated with X inactivation. Differences in the identity and distribution of escape genes between species and tissues suggest a role for these genes in the evolution of sex differences in specific phenotypes. The higher expression of escape genes in females than in males implies that they may have female-specific roles and may be responsible for some of the phenotypes observed in X aneuploidy. PMID- 21614515 TI - Mouse transmembrane BAX inhibitor motif 3 (Tmbim3) encodes a 38 kDa transmembrane protein expressed in the central nervous system. AB - Cell survival proteins play an important role throughout nervous system development, normal physiological processes, and pathological conditions. Transmembrane BAX inhibitor motif 3 (TMBIM3, also known as GRINA), is a member of a family of proteins that contain a conserved BAX inhibitor-1 motif. This family of proteins includes several members that have been shown to protect cells from apoptosis. In this study, the authors show that TMBIM3 is expressed in the brain including high levels in the hippocampus. Biochemical and sequence analysis of TMBIM3 demonstrates that the rat, murine, and human genes encode an approximately 38 kDa protein with a predicted seven transmembrane domain topology. A Tmbim3 knockout mouse line did not have an obvious phenotype, but may prove useful in future studies of this family of proteins. PMID- 21614516 TI - Calcium homeostasis in human induced pluripotent stem cell-derived cardiomyocytes. AB - RATIONALE: Cardiomyocytes generated from human induced pluripotent stem cells (hiPSCs) are suggested as the most promising candidate to replenish cardiomyocyte loss in regenerative medicine. Little is known about their calcium homeostasis, the key process underlying excitation-contraction coupling. OBJECTIVE: We investigated the calcium handling properties of hiPSC-derived cardiomyocytes and compared with those from human embryonic stem cells (hESCs). METHODS AND RESULTS: We differentiated cardiomyocytes from hiPSCs (IMR90 and KS1) and hESCs (H7 and HES3) with established protocols. Beating outgrowths from embryoid bodies were typically observed 2 weeks after induction. Cells in these outgrowths were stained positively for tropomyosin and sarcomeric alpha-actinin. Reverse transcription polymerase chain reaction studies demonstrated the expressions of cardiac-specific markers in both hiPSC- and hESC-derived cardiomyocytes. Calcium handling properties of 20-day-old hiPSC- and hESC-derived cardiomyocytes were investigated using fluorescence confocal microscopy. Compared with hESC-derived cardiomyocytes, spontaneous calcium transients from both lines of hiPSC-derived cardiomyocytes were of significantly smaller amplitude and with slower maximal upstroke velocity. Better caffeine-induced calcium handling kinetics in hESC-CMs indicates a higher sacroplasmic recticulum calcium store. Furthermore, in contrast with hESC-derived cardiomyocytes, ryanodine did not reduce the amplitudes, maximal upstroke and decay velocity of calcium transients of hiPSC derived cardiomyocytes. In addition, spatial inhomogeneity in temporal properties of calcium transients across the width of cardiomyocytes was more pronounced in hiPSC-derived cardiomyocytes than their hESC counterpart as revealed line-scan calcium imaging. Expressions of the key calcium-handling proteins including ryanodine recptor-2 (RyR2), sacroplasmic recticulum calcium-ATPase (SERCA), junction (Jun) and triadin (TRDN), were significantly lower in hiPSC than in hESCs. CONCLUSIONS: The results indicate the calcium handling properties of hiPSC derived cardiomyocytes are relatively immature to hESC counterparts. PMID- 21614517 TI - Modulation of myelin basic protein gene expression by acetyl-L-carnitine. AB - Acetyl-L-carnitine (ALC), the acetyl ester of L-carnitine, is a naturally occurring molecule which plays an essential role in intermediary and mitochondrial metabolism. It has also neurotrophic and antioxidant actions, demonstrating efficacy and high tolerability in the treatment of neuropathies of various etiologies. ALC is a molecule of considerable interest for its clinical application in various neural disorders, although little is known regarding its effects on gene expression. Suppression subtractive hybridization methodology was used for the generation of subtracted complementary DNA libraries and the subsequent identification of differentially expressed transcripts in the rat brain after chronic ALC treatments. We provided evidence for a downregulation of the expression of all of the isoforms of myelin basic protein gene following prolonged ALC treatment, indicating a possible role in the modulation of myelin basic protein turnover, stabilizing and maintaining myelin integrity. PMID- 21614518 TI - "Premature luteinization" in the era of GnRH analogue protocols: time to reconsider. PMID- 21614521 TI - Wild birds recognize individual humans: experiments on magpies, Pica pica. AB - The ability to distinguish among heterospecific individuals has been reported in only a few animal species. Humans can be viewed as a special type of heterospecifics because individuals differ widely in behavior, ranging from non threatening to very threatening toward animals. In this study, we asked whether wild magpies can recognize individual humans who had accessed their nests. We compared the behavior of breeding pairs toward individual humans before and after the humans climbed up to the birds' nests, and also toward climbers and non climbers. We have evidence for (i) aggressive responses of the magpie pairs toward humans who had repeatedly accessed their nests (climbers) and a lack of response to humans who had not accessed the nest (non-climbers); (ii) a total lack of scolding responses toward climbers by magpie pairs whose nests had not been accessed; (iii) a selective aggressive response to the climber when a climber and a non-climber were presented simultaneously. Taken together, these results suggest that wild magpies can distinguish individual humans that pose a threat to their nests from humans that have not behaved in a threatening way. The magpie is only the third avian species, along with crows and mockingbirds, in which recognition of individual humans has been documented in the wild. Here, we propose a new hypothesis (adopted from psychology) that frequent previous exposure to humans in urban habitats contributes to the ability of birds to discriminate among human individuals. This mechanism, along with high cognitive abilities, may predispose some species to learn to discriminate among human individuals. Experimental tests of these two mechanisms are proposed. PMID- 21614519 TI - Biological pH buffers in IVF: help or hindrance to success. AB - PURPOSE: Minimizing environmental stress helps maintain cellular homeostasis and is a crucial component in optimizing embryo development in vitro and resulting ART success. One stressor of particular interest is pH. Biologic buffers, such as HEPES and MOPS, are valuable tools for stabilizing pH. The objective of this manuscript is to summarize efficacy and impact of various pH buffers used during IVF lab procedures METHODS: Keyword searches were performed using Pubmed and Medline and relevant literature reviewed. RESULTS: Various pH buffers have been used with varying degrees of success for gamete and embryo processing in a variety of animal species, as well as in human. CONCLUSION: Though biologic buffers off a means to improve pH stability, not all buffers may be appropriate for use with gametes and embryos. Specific buffers may have undesired effects, and these may be buffer, species, cell type or concentration dependent. Continued research is needed to further refine and improve the use of biologic buffers for use in human ART. PMID- 21614520 TI - Identification of common mechanisms between endometriosis and ovarian cancer. AB - PURPOSE: To determine common molecular markers between endometriosis and ovarian cancer. METHODS: Patients included women who underwent laparoscopic excision of ovarian endometriotic lesions (n = 7), healthy non-pregnant women with normal pelvises, who underwent excision of normal peritoneum (n = 7). Two epithelial ovarian cancer (EOC) cell lines were also utilized. Expression of transforming growth factor (TGF)-beta1, cyclooxygenase (COX)-2, vascular endothelial growth factor (VEGF), estrogen receptor (ER)-1alpha, progesterone receptor (PR), androgen receptor (AR), and aromatase was evaluated by real-time RT-PCR. RESULTS: Endometriosis and EOC cells manifested significantly higher mRNA levels of TGF beta1, COX-2, VEGF, ER-1alpha, AR, and aromatase, while they expressed significantly lower mRNA levels of PR. CONCLUSIONS: Increased TGF-beta1, COX-2, VEGF, ER-1alpha, AR, and aromatase and decreased PR in endometriotic as well as EOC cells suggests a potential association between these two disease processes. This association is important, as it may reveal common mechanisms for both diseases. PMID- 21614522 TI - Molecular characterization and expression analysis of a gene encoding for farnesyl diphosphate synthase from Euphorbia pekinensis Rupr. AB - The root of Euphorbia pekinensis as a traditional herbal medicine has been recorded in Chinese pharmacopoeias for the treatment of oedema, gonorrhea, migraine and wart cures. In this work, we reported on the cDNA cloning and characterization of a novel farnesyl diphosphate synthase (FPS) from E. pekinensis. The full-length cDNA named EpFPS (Genbank Accession Number FJ755465) contained 1431 bp with an open reading frame of 1029 bp encoding a polypeptie of 342 amino acids. The deduced amino acid sequence of the EpFPS named EpFPS exhibited a high homology with other plant FPSs, and contained five conserved domains. Phylogenetic analysis showed that EpFPS belonged to the plant FPS group. Southern blot analysis revealed that there exists a small FPS gene family in E. pekinensis. Expression pattern analysis revealed that EpFPS expressed strongly in root, weak in leaf and stem. In callus, expression of EpFPS gene and biosynthesis of triterpenoids were strongly induced by Methyl jasmonate and slightly induced by Salicylic acid. Functional complementation of EpFPS in an ergosterol auxotrophic yeast strain indicated that the cloned cDNA encoded a functional farnesyl diphosphate synthase. PMID- 21614524 TI - Association of ERCC2/XPD polymorphisms and interaction with tobacco smoking in lung cancer susceptibility: a systemic review and meta-analysis. AB - The association of the two ERCC polymorphisms, Asp312Asn and Lys751Gln, with lung cancer risk remains controversial and inconclusive. To better evaluate the potential role of the two polymorphisms and interaction with tobacco smoking in lung cancer susceptibility presented in diverse populations, we have conducted a meta-analysis based on 26 studies from 24 publications which included analyses of Asp312Asn (7121 cases, 8962 controls) and Lys751Gln (8396 cases, 10510 controls) polymorphisms. Overall, significantly elevated lung cancer risk was associated with ERCC2 312Asn allele(homozygous model: OR=1.20[1.05-1.36], P=0.006; recessive model: OR=1.20[1.06-1.35], P=0.004) and 751Gln allele(homozygous model: OR=1.31[1.17-1.46], P<0.00001; heterozygous model: OR=1.11[1.04-1.19], P=0.003; recessive model: OR=1.23[1.11-1.37], P<0.0001; dominant model: OR=1.15[1.08 1.23], P<0.0001). In ethnic subgroup analyses, significantly increased risk was associated with ERCC2 312Asn allele for both Caucasians and Asians, and 751Gln allele for both Caucasians and Latino-Americans. When stratified by smoking status, significantly elevated risk of both polymorphisms for never-smokers was detected (dominant model, OR=1.46[1.09-1.95] and 1.57[1.19-2.08], P=0.01 and 0.002, respectively). In conclusion, this meta-analysis suggests that the two ERCC2 polymorphisms may contribute to lung cancer susceptibility serving as low penetrance risk factors. Extremely large-scale evidence would be necessary to confirm the effects on ethnically specific populations and gene-environment interactions. PMID- 21614523 TI - Prophenoloxidase activating enzyme-III from giant freshwater prawn Macrobrachium rosenbergii: characterization, expression and specific enzyme activity. AB - The prophenoloxidase activating system is an important innate immune response against microbial infections in invertebrates. The major enzyme, phenoloxidase, is synthesized as an inactive precursor and its activation to an active enzyme is mediated by a cascade of clip domain serine proteinases. In this study, a cDNA encoding a prophenoloxidase activating enzyme-III from the giant freshwater prawn Macrobrachium rosenbergii, designated as MrProAE-III, was identified and characterized. The full-length cDNA contains an open reading frame of 1110 base pair (bp) encoding a predicted protein of 370 amino acids including an 22 amino acid signal peptide. The MrProAE-III protein exhibits a characteristic sequence structure of a long serine proteases-trypsin domain and an N- and C-terminal serine proteases-trypsin family histidine active sites, respectively, which together are the characteristics of the clip-serin proteases. Sequence analysis showed that MrProAE-III exhibited the highest amino acid sequence similarity (63%) to a ProAE-III from Atlantic blue crab, Callinectes sapidus. MrProAE-III mRNA and enzyme activity of MrProAE-III were detectable in all examined tissues, including hepatopancreas, hemocytes, pleopods, walking legs, eye stalk, gill, stomach, intestine, brain and muscle with the highest level of both in hepatopancreas. This is regulated after systemic infectious hypodermal and hematopoietic necrosis virus infection supporting that it is an immune-responsive gene. These results indicate that MrProAE-III functions in the proPO system and is an important component in the prawn immune system. PMID- 21614525 TI - Preface: special issue in honor of Professor Katsuhiko Mikoshiba. PMID- 21614526 TI - Using spoken words to guide open-ended category formation. AB - Naming is a powerful cognitive tool that facilitates categorization by forming an association between words and their referents. There is evidence in child development literature that strong links exist between early word-learning and conceptual development. A growing view is also emerging that language is a cultural product created and acquired through social interactions. Inspired by these studies, this paper presents a novel learning architecture for category formation and vocabulary acquisition in robots through active interaction with humans. This architecture is open-ended and is capable of acquiring new categories and category names incrementally. The process can be compared to language grounding in children at single-word stage. The robot is embodied with visual and auditory sensors for world perception. A human instructor uses speech to teach the robot the names of the objects present in a visually shared environment. The robot uses its perceptual input to ground these spoken words and dynamically form/organize category descriptions in order to achieve better categorization. To evaluate the learning system at word-learning and category formation tasks, two experiments were conducted using a simple language game involving naming and corrective feedback actions from the human user. The obtained results are presented and discussed in detail. PMID- 21614527 TI - Osmotic stress response in C. glutamicum: impact of channel- and transporter mediated potassium accumulation. AB - Potassium accumulation is an essential aspect of bacterial response to diverse stress situations; consequently its uptake plays a pivotal role. Here, we show that the Gram-positive soil bacterium Corynebacterium glutamicum which is employed for the large-scale industrial production of amino acids requires potassium under conditions of ionic and non-ionic osmotic stress. Besides the accumulation of high concentrations of potassium contributing significantly to the osmotic potential of the cytoplasm, we demonstrate that glutamate is not the counter ion for potassium under these conditions. Interestingly, potassium is required for the activation of osmotic stress-dependent expression of the genes betP and proP. The Kup-type potassium transport system which is present in C. glutamicum in addition to the potassium channel CglK does not contribute to potassium uptake at conditions of hyperosmotic stress. Furthermore, we established a secondary carrier of the KtrAB type from C. jeikeium in C. glutamicum thus providing an experimental comparison of channel- and carrier mediated potassium uptake under osmotic stress. While at low potassium availability, the presence of the KtrAB transporter improves both potassium accumulation and growth of C. glutamicum upon osmotic stress, at proper potassium supply, the channel CglK is sufficient. PMID- 21614528 TI - A challenging case of constrictive pericarditis. PMID- 21614529 TI - Gambling and adverse life events among urban adolescents. AB - This study explored the cross sectional association between adverse life events and gambling in a sample of 515 urban adolescents (average age 17, 55% male, 88% African American). Approximately half of the sample had gambled in the past year (51%); 78% of the gamblers gambled monthly and 39% had a gambling-related problem. On the other hand, 88% of the sample had experienced at least one life event in the past year, and those experiencing events tended to live in more disadvantaged neighborhoods. The mere acknowledgement of experiencing a stressful life event in the past year (yes/no) was not associated with an increase in odds of being a gambler, with gambling more frequently, or with having a gambling problem. However, when the context of the event was considered, an association was found between directly experiencing threatening and deviant/violent types of events and frequent gambling (OR > 2). Additionally, the probability of being a gambler increased as the number of events experienced increased (aOR = 1.07, 95% CI = 1.01, 1.13, P = 0.013), but problems among gamblers were not associated with the number of events experienced (aOR = 1.01, 95% CI = 0.92, 1.11, P = 0.876). During adolescence, life events appear to be connected more with the frequency of gambling rather than with problems related to gambling. PMID- 21614530 TI - Conventional pulmonary vein isolation compared with the "box isolation" method: a randomized clinical trial. AB - PURPOSE: Esophageal injury is a potential complication with radiofrequency ablation in the posterior wall of the left atrium (LA). The "box isolation" method isolates the posterior LA wall including the pulmonary veins without ablation on the posterior LA wall. This study compares the acute and long-term efficacy of the box isolation method with conventional circumferential pulmonary vein isolation (PVI) for catheter ablation of AF. METHODS: Twenty-nine patients (age 60 +/- 9 years, 62% male, 79% paroxysmal) with drug refractory AF underwent catheter ablation. Sixteen of the 29 patients (55%) underwent box isolation. Recurrence of AF was detected by checking the daily recorded rhythm strip on a portable home ECG monitor, irrespective of the symptoms. Mean follow-up duration was 10 +/- 2 months. RESULTS: Complete isolation of the posterior LA using box isolation lesions was achieved in three of 16 (19%) patients. The other 13 patients underwent creation of additional lesions until all PVs were isolated. Of the 16 patients who underwent box isolation, four patients (25%) had complete success, six patients (38%) had improvement, and the remaining six patients (37%) had failure. Of the 13 patients who underwent the standard PV isolation, two patients (15%) had complete success, eight patients (62%) had improvement, and the remaining three patients (23%) had failure (p = 0.44). CONCLUSION: In this pilot study, the efficacy of box isolation is similar to the circumferential PVI for catheter ablation of AF. Few patients achieved PVI with box method alone. Based on these results, we do not recommend the box isolation strategy. PMID- 21614531 TI - Multiscale modeling and mechanics of filamentous actin cytoskeleton. AB - The adaptive structure and functional changes of the actin cytoskeleton are induced by its mechanical behavior at various temporal and spatial scales. In particular, the mechanical behaviors at different scales play important roles in the mechanical functions of various cells, and these multiscale phenomena require clarification. To establish a milestone toward achieving multiscale modeling and simulation, this paper reviews mathematical analyses and simulation methods applied to the mechanics of the filamentous actin cytoskeleton. The actin cytoskeleton demonstrates characteristic behaviors at every temporal and spatial scale, and mathematical models and simulation methods can be applied to each level of actin cytoskeletal structure ranging from the molecular to the network level. This paper considers studies on mathematical models and simulation methods based on the molecular dynamics, coarse-graining, and continuum dynamics approaches. Every temporal and spatial scale of actin cytoskeletal structure is considered, and it is expected that discrete and continuum dynamics ranging from functional expression at the molecular level to macroscopic functional expression at the whole cell level will be developed and applied to multiscale modeling and simulation. PMID- 21614532 TI - Expression of CD26 and its association with dipeptidyl peptidase IV activity in lymphocytes of type 2 diabetes patients. AB - Immune response and inflammation were suggested to play certain roles in the development and complications of type 2 diabetes mellitus. The main objective of this study was to investigate the CD26 expression and its relationship with adenosine deaminase (ADA), dipeptidyl peptidase IV (DPP-IV), gamma glutamyltransferase (GGT), and N-acetyl-beta-glucosaminidase (NAG) activities in lymphocytes of type 2 diabetics (T2DM) patients. These parameters were assessed in 25 T2DM patients and 20 control subjects. We observed a decrease in CD26 expression and a significant increase in the ADA activity in T2DM patients when compared with control subjects. There were no differences between activities of DPP-IV, NAG, and GGT in lymphocytes of T2DM patients and control subjects. Meanwhile, a significant negative correlation was observed between CD26 expression and DPP-IV activity in lymphocytes of T2DM patients. Moreover, a positive correlation was found between DPPIV and ADA activities. The results suggest that the reduction of CD26 expression may be associated in the regulation of DPP-IV in T2DM patients. PMID- 21614533 TI - Differential levels of stress proteins (HSPs) in male and female Daphnia magna in response to thermal stress: a consequence of sex-related behavioral differences? AB - In two independent experiments, we compared: (1) water depth selection (and accompanying temperature selection) by male and female Daphnia magna under different kinds of environmental stress, including the presence of filamentous cyanobacteria, the risk of predation from fish, and the presence of toxic compounds; and (2) sex-dependent production of heat shock proteins (HSP60, 70, and 90) in response to a sudden change in temperature. Male D. magna selected deep water strata, which offer a relatively stable environment, and thereby avoided the threat of predation and the presence of toxic compounds in surface waters. Correlated with this behavior, males reduce their molecular defenses against stress, such as the production of heat shock proteins (HSPs), and do not maintain the physiological machinery that triggers an increase in HSP levels in response to stress. In contrast, female D. magna actively select habitats that offer optimal conditions for growth and production of offspring. Consequently, females are exposed to variable environmental conditions that may be associated with increased stress. To permit survival in these different habitats, D. magna females require molecular mechanisms to protect their cells from rapid changes in stress levels. Thus, they maintain high constitutive levels of the heat shock proteins from HSP 60, 70, and 90 families, and they have the potential to further enhance the production of the majority of these proteins under stress conditions. The results of this study indicate that the separate habitats selected by male and female D. magna result in different patterns of HSP production, leading us to hypothesize that that male and female Daphnia magna adopt different strategies to maximize the fitness of the species. PMID- 21614534 TI - Di- and tri-fluorinated analogs of methyl eugenol: attraction to and metabolism in the Oriental fruit fly, Bactrocera dorsalis (Hendel). AB - Oriental fruit fly, Bactrocera dorsalis (Hendel), males are attracted to the natural phenylpropanoid methyl eugenol (ME). They feed compulsively on ME and metabolize it to ring and side-chain hydroxylated compounds that have both pheromonal and allomonal properties. Previously, we demonstrated that mono fluorination at the terminal carbon of the ME side-chain significantly reduced metabolic side-chain hydroxylation, while mono-fluorination of ME at position 4 of the aromatic ring blocked ring-hydroxylation but surprisingly enhanced side chain hydroxylation. Here, we demonstrated that the introduction of fluorine atoms on both the ring and side-chain of ME blocks both positions that undergo enzymatic hydroxylation and, in particular, completely inhibits oxidative biotransformation of the allyl group. In laboratory experiments, B. dorsalis males initially were more attracted to both 1-fluoro-4,5-dimethoxy-2-(3,3 difluoro-2-propenyl)benzene (I) and 1-fluoro-4,5-dimethoxy-2-(3-fluoro-2 propenyl)benzene (II) than to ME. However, both I and II were taken up by flies at rates significantly less than that of ME. Flies fed with difluoroanalog II partially metabolized it to 5-fluoro-4-(3-fluoroprop-2-en-1-yl)-2-methoxyphenol (III), and flies fed with trifluoroanalog I produced 4-(3,3-difluoroprop-2-en-1 yl)-5-fluoro-2-methoxyphenol (V), but the rates of metabolism relative to rates of intakes were much lower compared to those of ME. Flies that consumed either the tri- or difluorinated analog showed higher post-feeding mortality than those that fed on methyl eugenol. In field trials, trifluoroanalog I was ~90% less attractive to male B. dorsalis than ME, while difluoroanalog II was ~50% less attractive. These results suggest that increasing fluorination can contribute to fly mortality, but the trade off with attractancy makes it unlikely that either a di or trifluorinated ME would be an improvement over ME for detection and/or eradication of this species. PMID- 21614535 TI - The agreement and internal consistency of national hospital EMR measures. AB - There has been national focus on increasing the use of electronic medical records (EMR) in hospitals because of their potential to improve care. Previous research has examined EMR use and reported an inconsistent relationship between EMR use and performance. This study examines the agreement between and the internal consistency of two national datasets that measure hospital EMR use. Data include the Health Information Management Systems Society (HIMSS) and the American Hospital Association (AHA). This analysis is essential to determine the strength and challenges of the nationally available EMR measures that are used in research, which informs national policy and practice. The results show very poor agreement between the two national datasets on hospital EMR use. The datasets demonstrate some internal consistency. In the absence of a gold standard measure of EMR use, researchers must be aware of the limitations of national EMR measures, and future research may validate the datasets. PMID- 21614536 TI - Racial and socioeconomic status differences in depressive symptoms among black and white youth: an examination of the mediating effects of family structure, stress and support. AB - Stress research shows that race, socioeconomic status (SES), and family context significantly impact an adolescent's psychological well-being, yet little is known about the mediating effects of family context on racial and SES differences in depressive symptoms among Black and White youth. We investigate these associations using a sample of 875 (45% female) from a South Florida community based study of youth mostly between the ages of 19 and 21. Ordinary least squares (OLS) analyses find that Blacks and lower SES youth have more depressive symptoms than Whites and those in higher SES families. Racial disparities are partially mediated by family related stressors and SES differences are fully explained by family stressors and emotional support. We also find that emotional family support conditions the relationship between race and depressive symptoms such that Whites experience more depressive symptoms at lower levels of emotional support but Blacks have more symptoms at higher levels. The findings highlight the importance of identifying factors within the family context that influence a youth's psychological well-being and ability to cope with adversities. PMID- 21614537 TI - Genetic counseling for frontotemporal dementias. AB - Frontotemporal dementia (FTD) is an umbrella term for a heterogeneous group of neurodegenerative disorders that are characterized by changes in cognition, language, personality, and social functioning. Approximately 40% of individuals with FTD have a family history of dementia, but less than 10% have a clear autosomal dominant pattern of inheritance. However, establishing a clear mode of inheritance in FTD is complicated by clinical heterogeneity, variable expression, phenocopies, misdiagnosis, early death due to other causes, missing medical records, and lost family histories. Mutations in the microtubule-associated protein tau and progranulin genes have been reported in the majority of hereditary cases, making genetic testing of at-risk individuals possible. The first step in counseling a family with a history of FTD is to take a comprehensive family history with confirmation of any diagnosis in a family member with medical records to the extent possible. If the pedigree analysis suggests an autosomal dominant pattern of inheritance, genetic testing of an affected relative may be offered to the family to determine if a mutation is present. If a mutation is found, relatives interested in pursuing genetic testing should be referred to a genetic counselor familiar with genetic testing for neurodegenerative disorders. Predictive testing of unaffected and at-risk relatives should only be offered in the context of a comprehensive genetic counseling protocol offering pre- and post-test counseling and support. One survey of at-risk individuals in a large family with FTD found that 50% were interested in testing. In one study actually offering genetic testing for FTD, the rate of uptake of testing was only 8.4%. A more recent study estimated the uptake for testing for FTD to be somewhere between 7% and 17% and attributed the low uptake to family resistance to testing. While genetic testing may be appropriate for some families with Alzheimer's disease and FTD, uptake of testing may be expected to be low. PMID- 21614538 TI - TMEM106B a novel risk factor for frontotemporal lobar degeneration. AB - Recently, the first genome-wide association (GWA) study in frontotemporal lobar degeneration (FTLD) identified common genetic variability at the TMEM106B gene on chromosome 7p21.3 as a potential important risk-modifying factor for FTLD with pathologic inclusions of TAR DNA-binding protein (FTLD-TDP), the most common pathological subtype in FTLD. To gather additional evidence for the implication of TMEM106B in FTLD risk, multiple replication studies in geographically distinct populations were set up. In this review, we revise all recent replication and follow-up studies of the FTLD-TDP GWA study and summarize the growing body of evidence that establish TMEM106B as a bona fide risk factor for FTLD. With the TMEM106B gene, a new player has been identified in the pathogenic cascade of FTLD which could hold important implications for the future development of disease modifying therapies. PMID- 21614539 TI - Gene replacement techniques for Escherichia coli genome modification. AB - The subject of this review covers modern experimental procedures for chromosomal gene replacement in Escherichia coli and related bacteria, which enable the specific substitution of targeted genome sequences with copies of those carrying defined mutations. Two principal methods for gene replacement were established. The first "in-out" method is based on integration of plasmid into bacterial chromosome and subsequent resolving of the cointegrate. The "linear fragment" method (recombineering) is based on homologous recombination mediated by short homology arms at the ends of linear DNA molecule. Many new protocols and improvements in targeted gene replacement were introduced during the last 10 years. These methods are well suited for high-throughput functional gene studies and for many biotechnological applications. PMID- 21614540 TI - Is use of nicotine replacement therapy while continuing to smoke associated with increased nicotine intake? Evidence from a population sample. PMID- 21614541 TI - The neuro-muscular system in fresh-water furcocercaria from Belarus. I Schistosomatidae. AB - The neuro-muscular system (NMS) in cercariae of the family Schistosomatidae from Belarus was studied with immunocytochemical methods and confocal scanning laser microscopy. The specimens of Bilharziella polonica were compared with Trichobilharzia szidati and Trichobilharzia franki. The patterns of F-actin in the musculature, 5-HT-immunoreactive (IR), FMRFamide-IR neuronal elements and alpha-tubulin-IR in sensory receptors and nerves were investigated. No indications of structural differences in the musculature, the 5-HT-IR, FMRF-IR neuronal elements and the general distribution of sensory receptors were noticed between cercariae of Trichobilharzia spp. The number of 5-HT-IR neurons in the cercarial bodies is 16. In cercaria B. polonica, the tail musculature is weaker than in Trichobilharzia spp. A detailed schematic picture of the NMS in the tail of Trichobilharzia spp. cercaria is given. The function of NMS elements in the tail is discussed. PMID- 21614542 TI - Trypanosoma spp. in Swedish game animals. AB - Serum and blood samples from 36 game animals, shot during the hunting seasons 2007-2009, were collected and analyzed for the presence of Trypanosoma spp. by three methods: isolation, polymerase chain reaction (PCR), and serology. Only fissiped animals were included, four different ruminants and wild boar. Trypanosomes could be isolated from two of the animals, and eight had detectable parasite DNA. Seven animals had high titers of anti-trypanosoma IgG antibodies. The two isolated strains, one from roe dear and one from European elk, were determined to Trypanosoma theileri by partial DNA sequencing of the 18S ribosomal gene. In the seven boars, no Trypanosoma were detected, but four out of seven strongly positive serological samples came from this group. This is the first study in Scandinavia on the presence of Trypanosoma in game animals. The results indicate that trypanosomiasis is frequently occurring among Swedish game animals. PMID- 21614543 TI - Observations on development of natural infection and species composition of small strongyles in young equids in Kentucky. AB - Early development and maturation of species of small strongyles have not been studied extensively. Most information is on the first appearance of strongyle eggs in feces of foals. However, species cannot be determined in this manner because of similarity of the morphological features of the eggs. To determine more definitive knowledge on development and species composition of natural infections of small strongyles, eight equid foals were necropsied and examined at various ages (31 to 92 days of age). The entire contents of the large intestine were examined, and all worms (6,671) recovered were identified. This was done to recover small strongyle specimens in an effort to find the stage of development of the worms for different time periods. The primary interest was to obtain data on the potential prepatent period. A total of 17 species of small strongyles were recovered. The earliest gravid female was Cylicostephanus longibursatus in a 57 day-old foal; then Cylicostephanus goldi was positive at 64 days, Cyathostomum catinatum at 68 days, Coronocyclus coronatus and Cylicostephanus calicatus at 70 days, Coronocyclus labiatus, Cylicocyclus leptostomus, Cylicocyclus nassatus, Cylicostephanus hybridus, and Cylicostephanus minutus at 74 days, and Cylicostephanus bidentatus at 92 days. While it is not known exactly when the foals began eating pasture vegetation (typically they begin to graze a short time after birth) and first ate infective free-living third-stage larvae, the results give an indication of the natural prepatent period of several species of small strongyles. Additional data are presented on the number of worms per foal, distribution of the worms in the parts (cecum, ventral colon, and dorsal colon) of the large intestine, and proportion of species found. PMID- 21614544 TI - Anti-malarial, anti-trypanosomal, and anti-leishmanial activities of jacaranone isolated from Pentacalia desiderabilis (Vell.) Cuatrec. (Asteraceae). AB - Leishmaniasis, Chagas disease, and malaria affect the poorest population around the world, with an elevated mortality and morbidity. In addition, the therapeutic alternatives are usually toxic or ineffective drugs especially those against the trypanosomatids. In the course of selection of new anti-protozoal compounds from Brazilian flora, the CH(2)C(l2) phase from MeOH extract obtained from the leaves of Pentacalia desiderabilis (Vell.) Cuatrec. (Asteraceae) showed in vitro anti leishmanial, anti-malarial, and anti-trypanosomal activities. The chromatographic fractionation of the CH(2)Cl(2) phase led to the isolation of the bioactive compound, which was characterized as jacaranone [methyl (1-hydroxy-4-oxo-2,5 cyclohexandienyl)acetate], by spectroscopic methods. This compound showed activity against promastigotes of Leishmania (L.) chagasi, Leishmania (V.) braziliensis, and Leishmania (L.). amazonensis showing an IC(50) of 17.22, 12.93, and 11.86 MUg/mL, respectively. Jacaranone was also tested in vitro against the Trypanosoma cruzi trypomastigotes and Plasmodium falciparum chloroquine-resistant parasites (K1 strain) showing an IC(50) of 13 and 7.82 MUg/mL, respectively, and was 3.5-fold more effective than benznidazole in anti-Trypanosoma cruzi assay. However, despite of the potential against promatigotes forms, this compound was not effective against amastigotes of L. (L.) chagasi and T. cruzi. The cytotoxicity study using Kidney Rhesus monkey cells, demonstrated that jacaranone showed selectivity against P. falciparum (21.75 MUg/mL) and a selectivity index of 3. The obtained results suggested that jacaranone, as other similar secondary metabolites or synthetic analogs, might be useful tolls for drug design for in vivo studies against protozoan diseases. PMID- 21614545 TI - Presence of Ribeiroia ondatrae in the developing anuran limb disrupts retinoic acid levels. AB - The widespread reports of malformed frogs have sparked interest worldwide to try and determine the causes of such malformations. Ribeiroia ondatrae is a digenetic trematode, which has been implicated as one such cause, as this parasite encysts within the developing tadpole hind limb bud and inguinal region causing dramatic limb malformations. Currently, the mechanisms involved in parasite-induced limb deformities remain unclear. We sought to investigate whether the level of retinoic acid (RA), a morphogenetic factor known to play a critical role in limb bud formation, is altered by the presence of R. ondatrae within the infected tadpole. Alteration of RA levels within the limb bud caused by the presence of the parasite may be achieved in three ways. First, metacercariae are actively secreting RA; second, cercariae, upon entering the limb/inguinal region, may release a large amount of RA; finally, the metacercariae may induce either an increase in the synthesis or a decrease in the degradation of the host's endogenous retinoic acid levels. Here, we show through high performance liquid chromatography and mass spectrometry that limb bud tissue of Lithobates sylvaticus, which has been parasitised, contains 70% more RA compared to the unparasitised control. Furthermore, parasites that have encysted within the limb buds appear to contain substantially less RA (56%) than the free swimming cercariae (defined as the infectious stage of the parasite). Taken together, these data illustrate for the first time that encystment of R. ondatrae leads to an increase in RA levels in the tadpole limb bud and may offer insight into the mechanisms involved in parasite-induced limb deformities. PMID- 21614546 TI - Redescription and molecular analysis of Myxobolus shantungensis Hu, 1965 (Myxozoa: Myxosporea) infecting common carp Cyprinus carpio haematopterus. AB - Myxobolus shantungensis Hu, 1965 infects gill arches of common carp Cyprinus carpio haematopterus (Temminck and Schlegel), causing serious pathological effects on host fish. An inadequate original description and absence of molecular data make accurate early diagnosis challenging. To augment the original description, M. shantungensis is redescribed here using morphological and molecular biological methods. Mature spores of M. shantungensis were ellipsoidal or apple shaped in frontal view and lemon shaped in lateral view, averaging 8.2 +/- 0.3 MUm (8.0-9.0 MUm) * 10.1 +/- 0.5 MUm (9.2-11.1 MUm) * 6.9 +/- 0.3 MUm (6.0-7.4 MUm). Some spores had three to four "V"-shaped valve edge markings on the posterior of the spore. The two equal polar capsules were oval, measuring 4.3 +/- 0.3 MUm (3.8-5.0 MUm) * 3.2 +/- 0.2 MUm (2.8-3.5 MUm), situated at the anterior extremity of the spore. Polar filaments coiled with six to seven turns. Scanning electron microscopy revealed that the surface of mature spores of M. shantungensis was generally pitted with a number of irregular ridges in shape. M. shantungensis is also characterized on the molecular level using the sequence of the small subunit ribosomal RNA gene. A BLAST search revealed that this sequence did not match any available sequences in GenBank. PMID- 21614547 TI - Ultrastructural changes of adult Schistosoma mansoni worms recovered from C57BL/6 mice passively immunized with normal and vaccinated rabbit sera in vivo. AB - The purpose of the study is to explore the role of humoral immunity against Schistosoma mansoni infection in C57BL/6 mice using highly resistant rabbits that had been exposed to three separate immunizations with ultraviolet (UV)-irradiated cercariae (8,000 attenuated cercariae/rabbit in each immunization), and their sera were tested for their ability to transfer protection against S. mansoni challenge. The present study showed the reduction in challenge worm burden had reached 32.76-43.64% when compared with recipients of normal serum or no serum. The surface topography of the worms collected from immunized mice with either normal rabbit sera (NRS) or vaccinated rabbit sera (VRS) revealed severe tegumental alterations, especially in the VRS group. Worms collected from groups that were immunized by NRS or VRS postinfection (200 normal cercariae/mouse) by day 42. Worms from group immunized with NRS showed damage in the tegument, characterized by severe swelling or erosion of tegumental folds, accompanied by changes in tubercles, swelling, shortening, and loss of spines in male worms. The alteration in female tegument was characterized by swelling of tegumental folds, atrophy of ventral sucker, damage of sensory papillae along all the body, severe peeling in some regions, and appearance of few small blebs. VRS induced more severe tegumental damage than NRS in both male and female worms. Severe shrunken vesicles were protruded from the surface between the two suckers. The tegument of the male showed a collapse of tubercles followed by the appearance of vesicles on their surfaces, fusion, erosion, and superficial focal peeling of tegumental folds. In the female worms, severe damage to the oral sucker, the surface between the two suckers, extensive peeling, severe swelling of the tegument, and damage of sensory papillae. In conclusion, the present study support the hypothesis that high levels of antibodies were developed in rabbit sera after multiple exposures to attenuated cercariae of S. mansoni. Furthermore, immunization might have transferred protection against the infection, indicated by severe morphological alterations, a sign of elimination of the worms. Further investigation is being carried out to reveal the molecular mechanisms underlying the transfer of protection. PMID- 21614548 TI - Do secretions from the uropygial gland of birds attract biting midges and black flies? AB - Bird susceptibility to attacks by blood-sucking flying insects could be influenced by urogypial gland secretions. To determine the effect of these secretions on biting midges and black flies, we set up a series of tests. First, we placed uropygial gland secretions from blue tit Cyanistes caeruleus broods inside empty nest boxes while empty nest boxes without gland secretions were treated as controls. Blue tit broods, from which we had obtained uropygial secretions, were affected by biting midges and black flies. However, these insects were absent in nest boxes both with and without secretions from nestlings' uropygial glands. We subsequently tested for the effects of uropygial gland secretions from feral pigeons Columba livia monitoring the number of biting midges captured using miniature CDC traps. There was no significant difference in the number of biting midges captured. Overall, our results did not support a potential role of avian uropygial gland secretions in attracting biting midges and black flies. PMID- 21614549 TI - Flow cytometric determination of genome size in European sunbleak Leucaspius delineatus (Heckel, 1843). AB - The aim of this study was to compare DNA content in hepatocyte and erythrocyte nuclei of the European sunbleak, Leucaspius delineatus, in relation to nuclear and cell size by means of flow cytometry and fluorescence microscopy. The DNA standards, chicken and rainbow trout erythrocytes, were prepared in parallel with both cell types, with initial separation of liver cells in pepsin solution followed by cell filtering. Standards and investigated cells were stained with a mixture of propidium iodide, citric acid, and Nonidet P40 in the presence of RNAse, and fluorescence of at least 50,000 nuclei was analyzed by flow cytometry. Average cell size was determined by flow cytometry, using fresh cell suspension in relation to latex beads of known diameter. The size of nuclei was examined on the basis of digital micrographs obtained by fluorescence microscopy after nuclei staining with DAPI. The sunbleak's erythrocyte nuclei contain 2.25 +/- 0.06 pg of DNA, whereas the hepatocyte nuclei contain 2.46 +/- 0.06 pg of DNA. This difference in DNA content was determined spectroscopically using isolated DNA from the two cell types. The modal diameters of the erythrocytes and hepatocytes were estimated to be 5.1 +/- 0.2 and 22.3 +/- 5.0 MUm, respectively, and the corresponding modal dimensions of their nuclei (measured as surface area) were 15.2 and 21.4 MUm(2), respectively. The nucleoplasmic index, as calculated from diameters estimated from surface area of nuclear profiles, was 2.51 for the erythrocytes compared with 0.08 for hepatocytes. PMID- 21614550 TI - The effect of body size on post-exercise physiology in largemouth bass. AB - Variation in individual size has important consequences for a number of characteristics of fish, which can impact fish populations. The impact of fish size on recovery following exercise, however, is poorly understood, with little information existing on the recovery of ionic/osmotic variables. The goal of this study was to quantify not only how allometry impacts the magnitude of physiological disturbance following burst exercise in largemouth bass (Micropterus salmoides), but also how allometry impacts the time required for exercise-induced disturbances to return to baseline levels. To accomplish this goal, two size classes of largemouth bass (large = 772-1,441 g total weight, mean = 1,125 g; small = 93-238 g, mean = 148 g) were exercised for 60 s and allowed to recover for 0, 1, 2, or 4 h before being sampled for plasma and white muscle. Large largemouth bass exhibited elevated concentrations of plasma glucose and sodium relative to small fish following a common exercise challenge. Large fish required additional time to clear metabolic disturbances in plasma and failed to restore potassium to basal levels even following 4 h of recovery, indicating an improved ability of the smaller fish to recover from disturbances. Results are further discussed in the context of physiological ecology and fitness for largemouth bass. PMID- 21614551 TI - Expression analysis of prestin and selected transcription factors in newborn rats. AB - Transcription factors (TFs) have a central role to play in regulating gene expression. To analyze the co-expression patterns of selected TFs with the motor protein prestin of the outer hair cells, we applied an real-time PCR approach combining several kinds of information: (i) expression changes during postnatal development, (ii) expression changes by exposure of organotypic cultures of the organ of Corti to factors which significantly affect prestin expression [thyroid hormone (T4), retinoic acid (RA), butyric acid (BA), increased KCl concentration] and (iii) changes along the apical-basal gradient. We found that the mRNA levels of the TF Brn-3c (Pou4f3), a member of the POU family, are significantly associated with the regulation of prestin during postnatal development and in cultures supplemented with T4 (0.5 MUM), BA (0.5-2.0 mM), and high KCl (50 mM) concentration. The mRNA level of the constitutively active TF C/ebpb (CCAAT/enhancer binding protein beta) correlates positively with the prestin expression during postnatal development and in cultures exposed to T4 and RA (50 100 MUM). The mRNA levels of the calcium-dependent TF CaRF correlates significantly with the prestin expression in cultures exposed to T4 and high KCl concentration. The observed coexpression patterns may suggest that the TFs Brn 3c, C/ebpb, and Carf contribute to regulating the expression of prestin under the investigated conditions. PMID- 21614552 TI - Familial risk factors for the development of somatoform symptoms and disorders in children and adolescents: a systematic review. AB - The aim of this study was to examine whether familial risk factors for the development of somatoform symptoms and somatoform disorders in children and adolescents can be deduced from studies which investigated the intergenerational transmission of functional abdominal pain and somatoform disorders. A systematic review of articles published in English and German since 1990 was performed. Twenty-three relevant studies were found. The following putative familial risk factors for the development of somatoform symptoms and somatoform disorders were identified: somatization of parents, organic disease of a significant other, psychopathology of close family members, dysfunctional family climate, traumatic experiences in childhood and insecure attachment. Most of the putative familial risk factors are associated with many other psychiatric child disorders and are therefore mostly nonspecific. Further longitudinal studies, in which comorbidity and other putative risk factors are taken into account, are needed to identify specific familial risk factors for the development of somatoform symptoms and somatoform disorders. PMID- 21614553 TI - A novel synthetic mono-carbonyl analogue of curcumin, A13, exhibits anti inflammatory effects in vivo by inhibition of inflammatory mediators. AB - Curcumin is a pleiotropic molecule against inflammatory related diseases. However, poor bioavailability greatly limits its application in clinic. Our previous study synthesized and evaluated a hydrosoluble mono-carbonyl analogue of curcumin, (2E,5E)-2,5-bis(4-(3-(dimethylamino)-propoxy)benzylidene)cyclopentanone (A13). In the present study, we further evaluated the anti-inflammatory effect of A13 in vivo. In lipopolysaccharide-challenged mice, pretreatment of A13 (15 mg/kg, i.v.) attenuated the increase of plasma level of NO, TNF-alpha, and IL-6, significantly inhibited the increase of hepatic inflammatory gene transcription, and improved pulmonary damages. In addition, A13 (10 or 30 mg/kg, i.p.) reduced vascular permeability in Institute of Cancer Research mice and inhibited pain reaction in chemically induced inflammatory models. Together, A13 exhibits anti inflammatory activities both in vitro and in vivo by the inhibition of various inflammatory mediators. PMID- 21614554 TI - Vascular protective role of vitexicarpin isolated from Vitex rotundifolia in human umbilical vein endothelial cells. AB - Pro-inflammatory cytokines induce injury of endothelial cells caused by increases of adhesion molecules, leading to vascular inflammation and the development of atherosclerosis. Recent pharmacological studies have demonstrated that vitexicarpin, a flavonoid isolated from Vitex rotundifolia, has anti inflammatory, antitumor, and analgesic properties. In this study, we investigated whether vitexicarpin (5-100 nM) prevented the TNF-alpha-induced vascular inflammation process in human umbilical vein endothelial cells (HUVEC). We found that pretreatment with vitexicarpin decreased TNF-alpha (10 ng/ml)-induced expression of cell adhesion molecules such as vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and E-selectin as well as matrix metalloproteinase-2 and -9 expression. Preincubation with vitexicarpin also dose dependently inhibited TNF-alpha-induced adhesion of HL-60 monocytic cells. Vitexicarpin significantly decreased TNF-alpha-induced intracellular reactive oxygen species (ROS) production. Furthermore, vitexicarpin suppressed NF-kappaB nuclear translocation and transcriptional activity in TNF-alpha-treated HUVEC. In conclusion, vitexicarpin significantly reduced vascular inflammation, through inhibition of ROS-NF-kappaB pathway in vascular endothelial cells. PMID- 21614555 TI - Prazosin induces p53-mediated autophagic cell death in H9C2 cells. AB - Prazosin, a quinazoline-based alpha(1)-adrenoceptor antagonist, is known to induce cell death, and this effect is independent of its alpha-blockade activity. However, the detailed molecular mechanisms involved are still not fully understood. In this study, we found that prazosin, but not doxazosin, could induce patterns of autophagy in H9C2 cells, including intracellular vacuole formation, microtubule-associated protein 1 light chain 3 (LC3) conversion, and acidic vesicular organelle (AVO) augmentation. Western blot analysis of phosphorylated proteins showed that exposure to prazosin increased the levels of phospho-p53 and phospho-adenosine monophosphate-activated protein kinase (AMPK) but dramatically decreased the levels of phospho-mammalian target of rapamycin (mTOR), phospho-protein kinase B (Akt), and phospho-ribosomal protein S6 kinase (p70S6K). Furthermore, although pretreatments with the pharmacological autophagy inhibitor 3-methyladenine and the p53 inhibitor pifithrin-alpha suppressed prazosin-induced AVO formation, they did not reverse prazosin-induced decline in cell viability but enhanced prazosin-induced caspase-3 activation. From these results we suggest that prazosin induces autophagic cell death via a p53-mediated mechanism. When the autophagy pathway was inhibited, prazosin still induced programmed cell death, at least in part through apoptotic caspase-3 cascade enhancement. Thus, our results indicate a potential new target in prazosin induced cell death. PMID- 21614557 TI - Electrostatics of folded and unfolded bovine beta-lactoglobulin. AB - We report on electrophoretic, spectroscopic, and computational studies aimed at clarifying, at atomic resolution, the electrostatics of folded and unfolded bovine beta-lactoglobulin (BLG) with a detailed characterization of the specific aminoacids involved. The procedures we used involved denaturant gradient gel electrophoresis, isoelectric focusing, electrophoretic titration curves, circular dichroism and fluorescence spectra in the presence of increasing concentrations of urea (up to 8 M), electrostatics computations and low-mode molecular dynamics. Discrepancy between electrophoretic and spectroscopic evidence suggests that changes in mobility induced by urea are not just the result of changes in gyration radius upon unfolding. Electrophoretic titration curves run across a pH range of 3.5-9 in the presence of urea suggest that more than one aminoacid residue may have anomalous pKa value in native BLG. Detailed computational studies indicate a shift in pKa of Glu44, Glu89, and Glu114, mainly due to changes in global and local desolvation. For His161, the formation of hydrogen bond(s) could add up to desolvation contributions. However, since His161 is at the C terminus, the end-effect associated to the solvated form strongly influences its pKa value with extreme variation between crystal structures on one side and NMR or low-mode molecular dynamics structures on the other. The urea concentration effective in BLG unfolding depends on pH, with higher stability of the protein at lower pH. PMID- 21614556 TI - Expression of IgA class switching gene in tonsillar mononuclear cells in patients with IgA nephropathy. AB - BACKGROUND AND AIM: There are many reports suggesting a relationship between the tonsillar autoimmune response and the pathogenesis of IgA nephropathy (IgAN). Hyperproduction of IgA and IgA1 in tonsils could be caused by activation of the Ig class switching recombination (CSR). alphaGLT (germline transcripts) plays a critical role in the initiation of switching from CMU to Calpha, resulting in production of IgA. Activation-induced cytidine deaminase (AID) is a molecule essential for CSR and Ig gene conversion. The aim of this study was to investigate IgA and IgA1 levels in the supernatant of tonsillar mononuclear cells (TMCs) and the expression of Ialpha-Calpha germline transcript and AID in TMCs stimulated with lipopolysaccharide or hemolytic streptococcus in IgAN patients and chronic tonsillitis patients. METHODS: 27 IgAN patients were admitted into our hospital from Jan. 2009 to Feb. 2010. Another 27 patients with chronic tonsillitis but without renal disease were selected as the control group. Tonsillar lymphocytes were isolated by density gradient centrifugation using Lymphocyte Separation Medium. The amount of IgA or IgA1 secreted in the culture supernatants was determined by specific enzyme-linked immunosorbent assay. Expressions of Ialpha-Calpha germline transcript and AID mRNA were examined by reverse transcription real-time PCR. The AID protein was determined by Western blotting. RESULTS: The production of IgA and IgA1 protein, especially the ratio of IgA1/IgA in TMCs stimulated with or without 10 MUg/ml of lipopolysaccharide or 1 * 10(8 )cfu/ml of hemolytic streptococcus, were significantly increased in the IgAN group compared with that in the non-IgAN group (P < 0.05), and the IgA and IgA1 levels in TMCs stimulated with 10 MUg/ml of lipopolysaccharide or 1 * 10(8 )cfu/ml of hemolytic streptococcus were markedly increased in patients with IgAN compared with the control group (P < 0.05).The expressions of Ialpha-Calpha and AID mRNA were significantly upregulated in TMCs stimulated with 10 MUg/ml of lipopolysaccharide or 1 * 10(8 )cfu/ml of hemolytic streptococcus in patients with IgAN compared with control group (P < 0.05). The expression of AID protein in TMCs stimulated with or without 10 MUg/ml of lipopolysaccharide or 1 * 10(8 )cfu/ml of hemolytic streptococcus was significantly increased in the IgAN group compared with that in the non-IgAN group (P < 0.05). The expression of AID protein in TMCs stimulated with 10 MUg/ml of lipopolysaccharide or 1 * 10(8) cfu/ml of hemolytic streptococcus was significantly increased in patients with IgAN compared with the control group (P < 0.05, P < 0.01). CONCLUSION: Lipopolysaccharide or hemolytic streptococcus can induce the production of IgA and IgA1 and the expression of AID and Ialpha-Calpha in TMCs from patients with IgAN. Our results indicate that the TMCs from patients with IgAN are capable of producing high levels of IgA and IgA1 when stimulated with lipopolysaccharide or hemolytic streptococcus, which may be due to the increased expression of AID and Ialpha-Calpha. PMID- 21614559 TI - Activation of satellite cells in the dorsal root ganglia in a disc-punctured rat model. AB - BACKGROUND: The neural mechanisms underlying discogenic low back pain caused by disc degeneration remain unclear. Previous studies demonstrated that satellite cells (SC) play an important role in neuropathic pain. METHODS: Twenty adult female Sprague-Dawley rats were used. The rats were divided into two groups: a nucleus pulposus (NP) group whose discs were punctured to expose the NP (n = 10) and a sham-operated group whose annulus fibrosus surface was scratched superficially (n = 10). In this study, we investigated the expression and cellular distribution of glial fibrillary acidic protein (GFAP, a marker of SC activation) in the dorsal root ganglia (DRG) innervating the intervertebral discs using a retrograde tracing method and immunohistochemistry in a disc-punctured rat model. RESULTS: In the sham-operated group, GFAP-immunoreactive (IR) SCs were not detected. In the NP group, GFAP-IR SC became evident, and 49 +/- 13% of neurons innervating the punctured discs were surrounded by GFAP-positive SCs. CONCLUSIONS: Our results were the first to provide evidence for a potential role of SCs in the neural mechanisms of discogenic low back pain caused by disc degeneration. PMID- 21614558 TI - Cellular hypomethylation is associated with impaired nitric oxide production by cultured human endothelial cells. AB - Hyperhomocysteinemia (HHcy) is a risk factor for vascular disease, but the underlying mechanisms remain incompletely defined. Reduced bioavailability of nitric oxide (NO) is a principal manifestation of underlying endothelial dysfunction, which is an initial event in vascular disease. Inhibition of cellular methylation reactions by S-adenosylhomocysteine (AdoHcy), which accumulates during HHcy, has been suggested to contribute to vascular dysfunction. However, thus far, the effect of intracellular AdoHcy accumulation on NO bioavailability has not yet been fully substantiated by experimental evidence. The present study was carried out to evaluate whether disturbances in cellular methylation status affect NO production by cultured human endothelial cells. Here, we show that a hypomethylating environment, induced by the accumulation of AdoHcy, impairs NO production. Consistent with this finding, we observed decreased eNOS expression and activity, but, by contrast, enhanced NOS3 transcription. Taken together, our data support the existence of regulatory post transcriptional mechanisms modulated by cellular methylation potential leading to impaired NO production by cultured human endothelial cells. As such, our conclusions may have implications for the HHcy-mediated reductions in NO bioavailability and endothelial dysfunction. PMID- 21614560 TI - Relationship factors associated with HIV risk among a sample of gay male couples. AB - More HIV prevention research is needed to better understand how relationship factors may affect sexual risk behaviors among gay male couples. Our cross sectional study collected dyadic data from 144 gay male couples to examine which relationship factors and characteristics were associated with men having UAI with a secondary sex partner. We targeted male couples by using a variety of recruitment strategies. Multilevel random-effects logistic regression modeling was used to examine which factors were predictive of men in gay couples who had UAI with a secondary sex partner. Analyses revealed that men were less likely to have had UAI with a secondary sex partner if they reported being in a strictly monogamous relationship, receiving an HIV test within the previous 3 months, and being committed to their sexual agreement. Future HIV prevention interventions must consider how relationship factors may influence sexual risk behaviors among gay male couples. PMID- 21614561 TI - Comparative effects of repeated administration of cadmium chloride during pregnancy and lactation and selenium protection against cadmium toxicity on some organs in immature rats' offsprings. AB - This research comprises studies on the transfer of cadmium (CdCl(2)) from the lactating dam to the pup via milk and absorbed in the suckling, showing that cadmium is transferred to the testes, ovary, cerebellum, and thyroid gland during development. The present studies were carried out in order to assess the protective effects of selenium against cadmium toxicity in pregnant rats. On the sixth day of gestation, the females were dosed subcutaneously either with cadmium or with cadmium and selenium in the following doses (mg/kg of body weight): 0, 1 Cd, 1 Cd + 1 Se, 2 Cd, 2 Cd + 2 Se. In groups treated with cadmium, no maternal or embryonic toxicities were observed; however, an increase in testes diameters of seminiferous tubules, a progressive sloughing of germ cells, vacuolization of Sertoli cells, and Leydig cells hyperplasia were noted. The reduction in the ovary size and inhibited folliculogenesis resulted in diminution of the numbers of primordial, growing, and tertiary follicles. The pathological change in the cerebellum, the migration of granular cells from the external germinal layer to the internal granular layer, was strongly retarded. Also, the formation of many microfollicles in the thyroid gland which mimic the changes was seen in thyrotoxicosis. It also appears that selenium used at a low-enough dose could be a very effective protection against cadmium-induced developmental toxicity in the testes, ovary, cerebellum, and thyroid gland but not in the higher dose in the ovary and cerebellum. PMID- 21614562 TI - Bioavailability of vanadium extracted by EDTA, HCl, HOAC, and NaNO3 in topsoil in the Panzhihua urban park, located in southwest China. AB - Bioavailable vanadium was evaluated on the basis of soil vanadium single extraction with ethylenediaminetetraacetic acid (EDTA), hydrochloric acid (HCl), acetic acid (HOAc), and sodium nitrate (NaNO(3)) in Panzhihua urban park. The soil vanadium concentration extracted by HOAc was 0.01-2.07 mg kg(-1), by EDTA 0.28-7.03 mg kg(-1), by NaNO(3) 0.07-0.53 mg kg(-1), and by HCl 0.19-1.36 mg kg( 1). The bioavailable vanadium (bioavailable fraction) obtained with HOAc was 0.01 1.33%, with EDTA 0.27-4.09%, with NaNO(3) 0.13-0.72%, and with HCl 0.06-0.28%. In addition, the impact of soil properties, soil nutrients, and soil enzyme activities on bioavailability of vanadium is discussed in this study. Based on the characteristics of bioavailable vanadium in the soil, ecological and health risks should have been given more attention in the studied area. PMID- 21614564 TI - Prevalence and characterization of BRCA1 and BRCA2 germline mutations in Chinese women with familial breast cancer. AB - Although there are some studies to investigate germline mutations in BRCA1/2 genes in Chinese women with familial breast cancer, many of them suffer relatively small sample size. In this study, we screened germline mutations in BRCA1/2 genes in a cohort of 409 Chinese women with familial breast cancer from north China by using a PCR-sequencing assay. A total of 43 deleterious mutations in BRCA1/2 genes were identified in this cohort, including 17 novel mutations and 6 recurrent mutations. The frequencies of BRCA1 and BRCA2 mutations were 3.9% (16/409) and 6.6% (27/409), respectively; the mutation rate of BRCA2 was 1.7-fold higher than that of BRCA1. The entire mutation rate of BRCA1/2 was 10.5% in this cohort; however, the mutation rate of BRCA1/2 genes was 23.0% in 78 familial breast cancer patients whose tumors were diagnosed at or before the age of 40. The mean age at diagnosis of breast cancer in BRCA1 carriers (42.8 years) and BRCA2 carriers (45.1 years) was younger than non-carriers (51.0 years) in this cohort (P = 0.005; P = 0.01, respectively). In addition, both BRCA1 carriers and BRCA2 carriers were more likely to exhibit triple-negative breast cancer (ER-, PgR-, and HER2-) than non-carriers (BRCA1 carriers vs. non-carriers, 69.2 vs. 23.0%, P = 0.001; BRCA2 carriers vs. non-carriers, 45.8 vs. 23.0%, P = 0.01). Our study suggested that the spectrum and characteristics of BRCA1/2 mutations in Chinese familial breast cancer exhibit some unique features, and Chinese women with familial breast cancer whose tumors are diagnosed at or before the age of 40 are good candidates for BRCA1/2 testing. PMID- 21614563 TI - Marine-based cultivation of diacarnus sponges and the bacterial community composition of wild and maricultured sponges and their larvae. AB - Marine organisms including sponges (Porifera) contain many structurally diverse bioactive compounds, frequently in a low concentration that hampers their commercial production. Two solutions to this problem are: culturing sponge explants for harvesting the desired compound and cultivation of sponge-associated bacteria. These bacteria (often considered the source of the desired compounds) include the Actinobacteria, from which many novel drugs were developed. In a long term experiment (lasting 767 days), we evaluated the culture amenability of the sponge Diacarnus erythraenus in a mariculture system, placed at 10- and 20-m depths. The growth and survival rates of sponge fragments were monitored. Wild and maricultured sponges from both depths and their larvae were sampled at different time intervals for denaturing gradient gel electrophoresis (DGGE) profiling of the bacterial community residing within them. 16S rRNA gene sequences of both cultured bacterial isolates and clone libraries of unculturable bacteria were composed and compared, focusing on Actinobacteria. Sponges from both depths did not differ significantly either in mean growth rates (percent weight change year-1 +/- S.E.) (64.5% +/- 21% at 10 m and 79.3% +/- 19.1% at 20 m) or in seasonal growth rates. Survival was also very similar (72% at 10 m and 70% at 20 m). There were 88 isolates identified from adults and 40 from their larvae. The isolates and clone libraries showed diverse bacterial communities. The DGGE profiles of wild and maricultured sponges differed only slightly, without a significant effect of depths or dates of sampling. This long-term experiment suggests that D. erythraenus probably remained healthy and indicates its mariculture suitability. PMID- 21614565 TI - Increased risk for distant metastasis in patients with familial early-stage breast cancer and high EZH2 expression. AB - The identification of women with early-stage breast cancer who will develop distant metastasis may improve clinical management. The transcriptional regulator Enhancer of Zeste-2 (EZH2) is overexpressed in invasive breast carcinoma compared with benign breast tissues, with maximal expression in breast cancer metastasis. In this article, our purpose was to investigate the performance of EZH2 protein detection as a predictor of metastasis in women with early-stage breast cancer, which is unknown. We developed a cohort of 480 women with stage I-IIA breast cancer diagnosed between 1996 and 2002 and recorded detailed sociodemographic, clinical, and pathological information. Tumors were histologically characterized and arrayed in tissue microarrays containing 1,443 samples. The nuclear EZH2 expression was investigated by immunohistochemistry and was scored as 1-2 (negative and weak) or 3-4 (moderate and strong) using a validated scoring schema. Scores 1-2 were considered low EZH2; scores 3-4 were considered high EZH2. In this study, we found that after a median follow up of 9 years (range 0.04-14.5 years) 46 of 480 patients (9.6%) developed distant metastasis. High EZH2 was associated with larger size, high histological grade, negative hormone receptors, and first degree family history of breast and/or ovarian carcinoma. While EZH2 could not predict survival in the entire cohort, high EZH2 was a predictor of disease-specific survival in patients with early-stage disease and first degree family history (log rank P value 0.05). Importantly, in this group of patients, high EZH2 was an independent predictor of distant metastasis up to 15 years after primary carcinoma diagnosis (hazard ratio 6.58, 95% CI: 1.40 30.89, P = 0.016) providing survival information above and beyond currently used prognosticators. In conclusion, EZH2 may be a useful biomarker of long-term metastatic risk in women with familial early-stage breast cancer, and warrant further validation studies. PMID- 21614566 TI - Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes. AB - CHEK2 1100delC is a moderate-risk cancer susceptibility allele that confers a high breast cancer risk in a polygenic setting. Gene expression profiling of CHEK2 1100delC breast cancers may reveal clues to the nature of the polygenic CHEK2 model and its genes involved. Here, we report global gene expression profiles of a cohort of 155 familial breast cancers, including 26 CHEK2 1100delC mutant tumors. In line with previous work, all CHEK2 1100delC mutant tumors clustered among the hormone receptor-positive breast cancers. In the hormone receptor-positive subset, a 40-gene CHEK2 signature was subsequently defined that significantly associated with CHEK2 1100delC breast cancers. The identification of a CHEK2 gene signature implies an unexpected biological homogeneity among the CHEK2 1100delC breast cancers. In addition, all 26 CHEK2 1100delC tumors classified as luminal intrinsic subtype breast cancers, with 8 luminal A and 18 luminal B tumors. This biological make-up of CHEK2 1100delC breast cancers suggests that a relatively limited number of additional susceptibility alleles are involved in the polygenic CHEK2 model. Identification of these as-yet-unknown susceptibility alleles should be aided by clues from the 40-gene CHEK2 signature. PMID- 21614567 TI - Lack of association between hOGG1 Ser326Cys polymorphism and breast cancer susceptibility in European population. PMID- 21614568 TI - Thoracic situs as an indicator of atrial appendage morphology: a postmortem study of 306 specimens with situs solitus in 250 and heterotaxy in 56 cases. AB - Symmetry of bronchi, lung lobation, and atrial appendages is frequently found in patients with heterotaxy syndromes. To evaluate the reliability of thoracic situs as an indicator of atrial appendage morphology, thoracic situs was assessed in 306 postmortem cases: 250 with atrial situs solitus and 56 with heterotaxy syndromes. Five features that indicate thoracic situs were assessed: (1) lung lobation, (2) lengths of main bronchi, (3) ratio of left to right (L/R) bronchial lengths, (4) relationship of bronchi to ipsilateral pulmonary artery, and (5) number of cartilage rings in each main bronchus. In the group with heterotaxy, the expected symmetrical lung lobation, lengths of bronchi, number of cartilage rings, and relations to pulmonary arteries were found in 77, 77, 77, and 95% of cases, respectively. The ratios of L/R bronchial lengths were <= 1.5 in 90% of cases. The relations of the bronchi to the pulmonary arteries were the best predictors of symmetrical atrial appendages or splenic syndromes. Bronchial atrial discordance occurred in ten cases: in situs solitus in one case and in heterotaxy in nine cases. Detection of heterotaxy syndromes is important because of the associated severe congenital cardiac defects. No single feature of thoracic situs is completely reliable. All available data should be used to make the diagnosis. PMID- 21614569 TI - Biliverdin protects against the deterioration of glucose tolerance in db/db mice. AB - AIMS/HYPOTHESIS: We have previously shown a negative correlation between serum bilirubin levels and prevalence of type 2 diabetes, suggesting that bilirubin inhibits development of this disease. To confirm this hypothesis, we investigated whether administration of biliverdin, the precursor of bilirubin, protects against the deterioration of glucose tolerance in db/db mice, a rodent model of type 2 diabetes. METHODS: Biliverdin (20 mg/kg daily) was orally administered to 5-week-old db/db mice for 4 weeks. After 4 weeks of treatment, i.p. glucose tolerance and insulin tolerance tests were performed. Insulin content was evaluated by immunostaining and ELISA. Oxidative stress markers (8-hydroxy-2' deoxyguansosine and dihydroethidium staining) and expression of NADPH oxidase components Pdx1 and Bax were also evaluated in isolated islets. RESULTS: Treatment with biliverdin partially prevented worsening of hyperglycaemia and glucose intolerance in db/db mice. This effect was accompanied by a significant increase in insulin content and Pdx1 expression, and a significant decrease of apoptosis and Bax expression in pancreatic islets from db/db mice. At the same time, levels of oxidative stress markers and NADPH oxidase component production in islets were normalised. Biliverdin had little effect on HOMA of insulin resistance or insulin resistance evaluated by insulin tolerance tests. CONCLUSIONS/INTERPRETATION: Biliverdin may protect against progressive worsening of glucose tolerance in db/db mice, mainly via inhibition of oxidative stress induced beta cell damage. PMID- 21614570 TI - Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes. AB - AIMS/HYPOTHESIS: Bariatric surgery consistently induces remission of type 2 diabetes. We tested whether there are diabetes-specific mechanisms in addition to weight loss. METHODS: We studied 25 morbidly obese patients (BMI 51.7 +/- 1.5 kg/m(2) [mean +/- SEM]), 13 with non-insulin-treated type 2 diabetes (HbA(1c) 7.1 +/- 0.5% [54 +/- 5 mmol/mol]), before and at 2 weeks and 1 year after Roux-en-Y gastric bypass (RYGB). Lean (n = 8, BMI 23.0 +/- 0.5 kg/m(2)) and obese (n = 14) volunteers who were BMI-matched (36.0 +/- 1.2) to RYGB patients at 1 year after surgery served as controls. We measured insulin-stimulated glucose disposal (M) and substrate utilisation (euglycaemic clamp/indirect calorimetry), endogenous glucose production (EGP) by 6,6-[(2)H(2)]glucose, lipolysis (rate of appearance of [(2)H(5)]glycerol) and beta cell function (acute insulin response to i.v. glucose [AIR] as determined by C-peptide deconvolution). RESULTS: At baseline, all obese groups showed typical metabolic abnormalities, with M, glucose oxidation and non-oxidative disposal impaired, and EGP, lipolysis, lipid oxidation and energy expenditure increased. Early after RYGB plasma glucose and insulin levels, and energy expenditure had decreased, while lipid oxidation increased, with M, EGP and AIR unchanged. At 1 year post-RYGB (BMI 34.4 +/- 1.1 kg/m(2)), all diabetic patients were off glucose-lowering treatment and mean HbA(1c) was 5.4 +/- 0.14% (36 +/- 2 mmol/mol) (p = 0.03 vs baseline); AIR also improved significantly. In all RYGB patients, M, substrate oxidation, EGP, energy expenditure and lipolysis improved in proportion to weight loss, and were therefore similar to values in obese controls, but still different from those in lean controls. CONCLUSIONS/INTERPRETATION: In morbidly obese patients, RYGB has metabolic effects on liver, adipose tissue, muscle insulin sensitivity and pattern of substrate utilisation; these effects can be explained by energy intake restriction and weight loss, the former prevailing early after surgery, the latter being dominant in the longer term. PMID- 21614571 TI - Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes. AB - Diabetes is frequently associated with hypoxia and is known to impair ischaemia induced neovascularisation and other forms of adaptive cell and tissue responses to low oxygen levels. Hyperglycaemia appears to be the driving force of such deregulation. Recent data indicate that destabilisation of hypoxia-inducible factor 1 (HIF-1) is most likely the event that transduces hyperglycaemia into the loss of the cellular response to hypoxia in most diabetic complications. HIF-1 is a critical transcription factor involved in oxygen homeostasis that regulates a variety of adaptive responses to hypoxia, including angiogenesis, metabolic reprogramming and survival. Thus, destabilisation of HIF-1 is likely to have a negative impact on cell and tissue adaptation to low oxygen. Indeed, destabilisation of HIF-1 by high glucose levels has serious consequences in various organs and tissues, including myocardial collateralisation, wound healing, renal, neural and retinal function, as a result of poor cell and tissue responses to low oxygen. This review aims to integrate and summarise some of the most recent developments, including new proposed molecular models, on this research topic, particularly in terms of their implications for potential therapeutic approaches for the prevention or treatment of some of the diabetic complications characterised by impaired cellular and tissue responses to hypoxia. PMID- 21614572 TI - Long-term effects of insulin glargine on the risk of breast cancer. AB - AIMS/HYPOTHESIS: There have been growing concerns regarding the long-term effects of insulin glargine (A21Gly,B31Arg,B32Arg human insulin) on the risk of breast cancer. METHODS: We used the UK's General Practice Research Database (GPRD) to identify a cohort of women aged 40 years or over with type 2 diabetes, treated with insulin during 2002-2006 and followed until the first breast cancer diagnosis or 31 December 2009. After the users of insulin glargine had been matched with users of other insulins on age, calendar time and duration of prior insulin use, the HR of breast cancer associated with insulin glargine use was estimated using a Cox proportional hazards model, adjusted for known risk factors for breast cancer. RESULTS: The cohort comprised 15,227 women, including 4,579 glargine users and 10,648 users of other insulins, of which 246 developed breast cancer during up to 8 years follow-up (incidence rate 4.1 per 1,000 per year). Insulin glargine use was not associated with an increased risk of breast cancer during the first 5 years of use (HR 0.9; 95% CI 0.7-1.3). The risk tended to increase after 5 years (HR 1.8; 95% CI 0.8-4.0), and significantly so for the women who had been on insulin before starting glargine (HR 2.7; 95% CI 1.1-6.5). CONCLUSIONS/INTERPRETATION: The risk of breast cancer in women with type 2 diabetes is not increased during the first 5 years of insulin glargine use. However, longer-term use may increase this risk, particularly in women with longstanding use of insulin before starting insulin glargine. PMID- 21614573 TI - Partial preparation computed tomographic colonography: a feasibility study. AB - We retrospectively evaluated computed tomographic colonography examinations of patients who have had a partial bowel preparation and compared the quality of their preparation with patients who have had a full bowel preparation. In total, 27 patients undergoing computed tomographic colonography examination (10 patients with partial bowel preparation and 17 with full bowel preparation) had their examinations retrospectively reviewed by three independent radiologists in a blinded manner, with evaluation of residual stool, distention, residual fluid, and overall bowel preparation quality. Six colon segments were evaluated individually and independently for these four variables (a total of 161 segments tested). Comparisons were made with the Mann-Whitney test between the partial preparation group and the full preparation group. Partial preparation included stool and fluid tagging plus 20 mg of bisacodyl orally; full preparation included stool and fluid tagging plus 2 L of polyethylene glycol solution. No significant clinical difference was found in colon preparation between the partial and full bowel preparation groups--when evaluated with individual colon segments or by independent readers. Interreader correlation was high. This pilot study indicates that full bowel preparation is not required for diagnostic-quality computed tomographic colonography examination. Further evaluation of this partial bowel preparation regimen is warranted. PMID- 21614574 TI - Head-and-neck paragangliomas are associated with sleep-related complaints, especially in the presence of carotid body tumors. AB - OBJECTIVES: The carotid body functions as a chemoreceptor. We hypothesized that head-and-neck paragangliomas (HNP) may disturb the function of these peripheral chemoreceptors and play a role in sleep-disordered breathing. DESIGN: This is a case-control study. SETTING: This study was conducted in a tertiary referral center. PARTICIPANTS AND MAIN OUTCOME MEASURES: We assessed fatigue, sleep, and exercise capacity in 74 HNP patients using three questionnaires (Epworth Sleepiness Scale, St. George Respiratory Questionnaire, and a standard clinical sleep assessment questionnaire). Outcomes were compared to those of age- and sex matched controls. RESULTS AND CONCLUSIONS: Activity, disturbance of psychosocial function, and total score were worse compared to controls (15.4 +/- 18.5 vs. 7.2 +/- 9.9, P = 0.007; 5.3 +/- 10.5 vs. 1.2 +/- 2.6, P = 0.008; and 10.4 +/- 12.9 vs. 5.0 +/- 4.8, P = 0.006, respectively). Patients reported more daytime fatigue, concentration difficulties, and depression (51% vs. 24%, P = 0.006; 31% vs. 10%, P = 0.010; and 19% vs. 2%, P = 0.012). Waking up was reported to be less refreshing in HNP patients (53% vs. 73%, P = 0.038). Dysphonia was a predictor of symptoms, activity, disturbance of psychosocial function, and total scores. Remarkably, the presence of a carotid body tumor was an independent predictor of increased daytime sleepiness (beta = 0.287, P = 0.029). In conclusion, patients with HNP have remarkable sleep-related complaints. Especially the presence of carotid body tumors appears to be associated with increased daytime somnolence. PMID- 21614575 TI - Prevalence, clinical features, and CPAP adherence in REM-related sleep-disordered breathing: a cross-sectional analysis of a large clinical population. AB - PURPOSE: Due to inconsistent definitions used in the literature, the prevalence of rapid eye movement (REM)-related sleep-disordered breathing (SDB) has been quite variable and its clinical significance remains unclear. This study aimed to compare the prevalence of and clinical characteristics between various criteria for defining REM-related SDB. We also investigated how frequently CPAP therapy was recommended in patients with REM-related SDB and if they had lower CPAP adherence compared to non-stage-specific SDB. METHODS: In this cross-sectional study, we evaluated 1,019 consecutive adults referred for a polysomnogram for suspicion of SDB. The prevalence of REM-related SDB was calculated based on "traditional criteria" commonly reported in the literature and a "strict criteria" that minimized the contribution of SDB during non-REM sleep. RESULTS: The prevalence of REM-related SDB ranged from 13.5% to 36.7%. There were no clinically significant differences between the strict definition and the traditional definition of REM-related SDB. REM-related SDB was more prevalent in women, younger individuals and African Americans. Compared to non-stage-specific obstructive sleep apnea (OSA), patients with REM-related SDB were equally symptomatic and hypersomnolent. CPAP titration was recommended in 88% of patients with REM-related SDB vs. 94% of patients with non-stage-specific OSA (p < 0.001). There was no significant difference in CPAP adherence between the two groups. CONCLUSIONS: Regardless of how REM-related SDB is defined, it was highly prevalent in our large clinical cohort. Compared to non-stage-specific OSA, these patients were equally hypersomnolent and adherent to CPAP therapy despite having overall significantly milder OSA. Further research is needed to better establish whether these patients will derive any benefit from long-term CPAP therapy. PMID- 21614577 TI - Reliability and validity of the Persian version of the Pittsburgh Sleep Quality Index (PSQI-P). AB - BACKGROUND: There is a high worldwide prevalence of sleep quality disturbances, and sleep disturbances have been associated with numerous diseases. Thus, it is important to assess sleep quality. The Pittsburgh Sleep Quality Index (PSQI) is a self-rating questionnaire that can be completed within 5 min, but no Persian language version is available. METHODS: We translated the PSQI into Persian and then back into English to ensure the accuracy of the translation. A total of 125 psychiatric patients (generalized anxiety disorder, n = 37; major depression, n = 35; schizophrenia, n = 28; primary insomnia, n = 25) and 133 controls completed our Persian version of this questionnaire. Internal consistency, construct validity, and sensitivity and specificity of the PSQI were assessed. RESULTS: The mean ages (+/-SD) of the patient and control groups were 36.8 years (+/-13.9) and 34.2 years (+/-9.8), respectively (p = 0.08). Cronbach's alpha coefficient for all subjects was 0.77 and was 0.52 for the patient group and 0.78 for the control group. The corrected item-total correlations ranged from 0.30 to 0.75 for the seven component scores of the PSQI. When the general health questionnaire-12 was used as a measure of psychiatric morbidity, it was well correlated with the PSQI scores (r = 0.54, p < 0.001). The sensitivity and specificity of discrimination of insomniac patients from control subjects were 94% and 72% for a PSQI cutoff value of 5 and 85% and 84% for a PSQI cutoff value of 6. CONCLUSION: The psychometric properties of the Persian version of the PSQI were acceptable. PMID- 21614576 TI - The association of oxidative stress with central obesity in obstructive sleep apnea. AB - PURPOSE: The purpose of this paper is to evaluate concentrations of multiple oxidative stress and antioxidant status markers in patients with obstructive sleep apnea (OSA) and normal controls of comparable obesity. METHODS: A total of 73 male subjects, recruited from a sleep clinic or advertisements, were enrolled in this study. All subjects underwent overnight polysomnography. The subjects were divided into normal control (n = 20), mild to moderate OSA (n = 31), and severe OSA (n = 22) with no difference in obesity. Blood was withdrawn from subjects, and markers of oxidative stress and antioxidant status, and parameters of glucose metabolism were assessed. RESULTS: There was no significant difference in either oxidative stress or antioxidant status markers among the three groups. There was no significant correlation between the oxidative stress markers and the OSA variables. However, there were correlations between waist-to-hip ratio (WHR) oxidized low-density lipoprotein cholesterol (oxLDL) (r = 0.424), WHR-glutathione peroxidase (GPX) (r = 0.318), WHR-total antioxidant status (TAS) (r = -0.317), and WHR-superoxide dismutase (SOD) (r = -0.338). In multiple regression analysis, WHR was a significant independent variable of oxLDL, GPX, TAS, and SOD. CONCLUSIONS: The oxidative stress in OSA was related to central obesity rather than intermittent hypoxia or respiratory disturbances. To control cardiovascular complications in OSA, weight reduction should be a component in the treatment strategy. PMID- 21614578 TI - Can interaction between atrial septal abnormalities and genetic prothrombotic polymorphisms play a role in cryptogenic ischemic stroke? Description of a family. AB - Ischemic stroke is a complex multifactorial disorder whose incidence increases as a function of the number of inherited and acquired risk factors. It has been recently suggested that several susceptibility "stroke alleles" act individually, together or in combination with environmental factors in stroke pathogenesis. Patent foramen ovale is considered an independent risk factor for cerebral infarct in young adult with cryptogenic stroke. Paradoxical embolism, from peripheral venous system, embolization from thrombi formed within the atrial septum, and the formation of thrombus as a result of transient atrial arrhythmias, have been advocated as potential pathogenetic mechanisms. Herein is reported a family with cryptogenic strokes probably due to the interaction between prothrombotic genetic polymorphism and atrial septal defects. PMID- 21614579 TI - Stroke secondary to aortic dissection treated with a thrombolytic: a successful case. AB - Aortic dissection is a life-threatening emergency and can present neurological symptoms, mainly associated with a stroke. This represents a challenge to the neurologist because of the necessity to treat the patient with a thrombolytic in a narrow time window, which could have a fatal outcome. A 70-year-old male patient presented in emergency department with an acute stroke (right middle cerebral artery syndrome) without any other symptoms. He was considered eligible for thrombolytic treatment with recombinant tissue plasminogen activator (rt-PA). During the thrombolysis, asymptomatic hypotension was detected which was corrected with volume and dopamine, without significant worsening of the neurologic deficits. A few minutes after the end of the perfusion, the patient complained about an unspecific dorsal discomfort. It was diagnosed a Stanford type A aortic dissection. The patient was submitted to an urgent surgery to replace the aorta. The evolution was good and 12 months later, he is independent in the activities of daily life. This case of an ischaemic stroke caused by an initial asymptomatic aortic dissection treated with rt-PA could have had a bad outcome, as in the majority of similar cases. However, the rapid diagnosis and appropriate treatment of the dissection could have been the main factors to explain the survival of our patient. PMID- 21614580 TI - Lyophilised medial meniscus transplantations in ACL-deficient knees: a 19-year follow-up. AB - PURPOSE: The treatment of meniscal tears has changed since the early 1980s. Meniscus transplantation emerged as a treatment option during that period. This study aims to present the long-term results of the first lyophilised meniscus allograft transplants in Turkey. METHODS: Between 1990 and 1992, four transplants of the medial meniscus combined with anterior cruciate ligament (ACL) reconstruction were performed on patients with a history of medial meniscectomy and anterior knee instability at our institution. For all patients who underwent meniscus lyophilised allograft transplantation and revision ACL reconstruction, clinical outcomes were evaluated over a mean period of 19 years of postoperative follow-up by clinical assessment, Tegner score, Lysholm score, Knee Society Score, radiography and magnetic resonance imaging (MRI). RESULTS: The median value of Tegner score was 3 before index surgery and 2.5 at year 19 postoperatively. The median value of Lysholm score was 60.5 before index surgery and 62.5 at year 19. All of the patients had Outerbridge grade IV osteoarthritis by X-ray examination at year 19. CONCLUSION: Successful meniscus transplantation depends on many factors. This study examines the effect of allografts on these factors and describes experiences with lyophilised allografts in four male patients. LEVEL OF EVIDENCE: IV. PMID- 21614581 TI - Anterior cruciate ligament insertion after partial tear: histological changes and chondrocyte turnover. AB - PURPOSE: The purpose of this study was to clarify the effects of partial resection on the glycosaminoglycan (GAG) layer thicknesses and chondrocyte turnover (apoptosis and cell proliferation) between uncalcified fibrocartilage (UF) and calcified fibrocartilage (CF) layers in an anterior cruciate ligament (ACL) insertion. METHODS: Twenty male Japanese white rabbits were evaluated. The anteromedial bundle of the ACL substance was resected in the right knee. The posterolateral bundle was left intact. Five rabbits were evaluated at 1, 2, 4, and 8 weeks after surgery, respectively. RESULTS: The apoptosis rates in the UF and CF layers were significantly lower in the posterolateral area than those in the anteromedial area at 1 and 2 weeks, respectively. The cell proliferation rates in the UF and CF layers were significantly higher in the posterolateral area than those in the anteromedial area at 2 and 4 weeks, respectively. The GAG layer thicknesses in the UF and CF layers were higher in the posterolateral area than those in the anteromedial area at 1-8 and 2-8 weeks, respectively. The GAG layer thicknesses in the UF and CF layers in the posterolateral area peaked at 2 and 4 weeks, respectively. However, the thicknesses in the two layers in the posterolateral area gradually decreased until 8 weeks. CONCLUSION: The GAG layer thicknesses in the UF and CF layers in the remaining ligament area increased up to 4 weeks and gradually decreased until 8 weeks owing to an imbalance between chondrocyte apoptosis and proliferation. If the reactions in humans are similar to those observed in the rabbits, we consider that augmentation for ligament reconstruction and partial repair should be performed within at least 1 month after injury, before insertion degeneration occurs. PMID- 21614582 TI - Characterization of full-length MHC class II sequences in Indonesian and Vietnamese cynomolgus macaques. AB - In recent years, the use of cynomolgus macaques in biomedical research has increased greatly. However, with the exception of the Mauritian population, knowledge of the MHC class II genetics of the species remains limited. Here, using cDNA cloning and Sanger sequencing, we identified 127 full-length MHC class II alleles in a group of 12 Indonesian and 12 Vietnamese cynomolgus macaques. Forty two of these were completely novel to cynomolgus macaques while 61 extended the sequence of previously identified alleles from partial to full length. This more than doubles the number of full-length cynomolgus macaque MHC class II alleles available in GenBank, significantly expanding the allele library for the species and laying the groundwork for future evolutionary and functional studies. PMID- 21614583 TI - Rhesus macaque KIR bind human MHC class I with broad specificity and recognize HLA-C more effectively than HLA-A and HLA-B. AB - Human killer cell immunoglobulin-like receptors (KIR) recognize A3/11, Bw4, C1, and C2 epitopes carried by mutually exclusive subsets of human leukocyte antigen (HLA)-A, -B, and -C allotypes. Chimpanzee and orangutan have counterparts to HLA A, -B, and -C, and KIR that recognize the A3/11, Bw4, C1, and C2 epitopes, either individually or in combination. Because rhesus macaque has counterparts of HLA-A and -B, but not HLA-C, we expected that rhesus KIR would better recognize HLA-A and -B, than HLA-C. Comparison of the interactions of nine rhesus KIR3D with 95 HLA isoforms, showed the KIR have broad specificity for HLA-A, -B, and -C, but vary in avidity. Considering both the strength and breadth of reaction, HLA-C was the major target for rhesus KIR, followed by HLA-B, then HLA-A. Strong reactions with HLA-A were restricted to the minority of allotypes carrying the Bw4 epitope, whereas strong reactions with HLA-B partitioned between allotypes having and lacking Bw4. Contrasting to HLA-A and -B, every HLA-C allotype bound to the nine rhesus KIR. Sequence comparison of high- and low-binding HLA allotypes revealed the importance of polymorphism in the helix of the alpha(1) domain and the peptide-binding pockets. At peptide position 9, nonpolar residues favor binding to rhesus KIR, whereas charged residues do not. Contrary to expectation, rhesus KIR bind more effectively to HLA-C, than to HLA-A and -B. This property is consistent with major histocompatibility complex (MHC)-C having evolved in hominids to be a generally superior ligand for KIR than MHC-A and MHC-B. PMID- 21614584 TI - Cell microencapsulation: a potential tool for the treatment of neuronopathic lysosomal storage diseases. AB - Lysosomal storage disorders (LSD) are monogenic diseases caused by the deficiency of different lysosomal enzymes that degrade complex substrates such as glycosaminoglycans, sphingolipids, and others. As a consequence there is multisystemic storage of these substrates. Most treatments for these disorders are based in the fact that most of these enzymes are soluble and can be internalized by adjacent cells via mannose-6-phosphate receptor. In that sense, these disorders are good candidates to be treated by somatic gene therapy based on cell microencapsulation. Here, we review the existing data about this approach focused on the LSD treatments, the advantages and limitations faced by these studies. PMID- 21614585 TI - Oligosaccharyltransferase: the central enzyme of N-linked protein glycosylation. AB - N-linked glycosylation is one of the most abundant modifications of proteins in eukaryotic organisms. In the central reaction of the pathway, oligosaccharyltransferase (OST), a multimeric complex located at the membrane of the endoplasmic reticulum, transfers a preassembled oligosaccharide to selected asparagine residues within the consensus sequence asparagine-X-serine/threonine. Due to the high substrate specificity of OST, alterations in the biosynthesis of the oligosaccharide substrate result in the hypoglycosylation of many different proteins and a multitude of symptoms observed in the family of congenital disorders of glycosylation (CDG) type I. This review covers our knowledge of human OST and describes enzyme composition. The Stt3 subunit of OST harbors the catalytic center of the enzyme, but the function of the other, highly conserved, subunits are less well defined. Some components seem to be involved in the recognition and utilization of glycosylation sites in specific glycoproteins. Indeed, mutations in the subunit paralogs N33/Tusc3 and IAP do not yield the pleiotropic phenotypes typical for CDG type I but specifically result in nonsyndromic mental retardation, suggesting that the oxidoreductase activity of these subunits is required for glycosylation of a subset of proteins essential for brain development. PMID- 21614586 TI - A doxycycline-inducible, tissue-specific aromatase-expressing transgenic mouse. AB - Aromatase converts androgens to estrogens and it is expressed in gonads and non reproductive tissues (e.g. brain and adipose tissues). As circulating levels of estrogens in males are low, we hypothesize that local estrogen production is important for the regulation of physiological functions (e.g. metabolism) and pathological development (e.g. breast and prostate cancers) by acting in a paracrine and/or intracrine manner. We generated a tissue-specific doxycycline inducible, aromatase transgenic mouse to test this hypothesis. The transgene construct (pTetOAROM) consists of a full-length human aromatase cDNA (hAROM) and a luciferase gene under the control of a bi-directional tetracycline-responsive promoter (pTetO), which is regulated by transactivators (rtTA or tTA) and doxycycline. Our in vitro studies using MBA-MB-231tet cells stably expressing rtTA, showed that doxycycline treatment induced transgene expression of hAROM transcripts by 17-fold (P = 0.01), aromatase activity by 26-fold, (P = 0.0008) and luciferase activity by 9.6-fold (P = 0.0006). Pronuclear microinjection of the transgene generated four pTetOAROM founder mice. A male founder was bred with a female mammary gland-specific rtTA mouse (MMTVrtTA) to produce MMTVrtTA pTetOAROM double-transgenic mice. Upon doxycycline treatment via drinking water, human aromatase expression was detected by RT-PCR, specifically in mammary glands, salivary glands and seminal vesicles of double-stransgenic mice. Luciferase expression and activity was detected in these tissues by in vivo bioluminescence imaging, in vitro luciferase assay and RT-PCR. In summary, we generated a transgenic mouse model that expresses the human aromatase transgene in a temporal- and spatial-specific manner, which will be a useful model to study the physiological importance of local estrogen production. PMID- 21614587 TI - Dysmorphogenesis of lymph nodes in Foxc2 haploinsufficient mice. AB - Dysmorphogenesis of lymph nodes displayed in a fork head transcription factor Foxc2 haploinsufficient mice--a model for lymphedema-distichiasis syndrome--was studied by immunohistochemistry and electron microscopy. The Foxc2 heterozygous mice manifested lymph node hyperplasia composed of conspicuous proliferation of endothelial cells forming the lymphatic sinus and alpha-smooth muscle actin (SMA) immunopositive fibroblast-like cells in the lymphatic pulp, particularly around the sinus. The hyperplastic sinus endothelial cells and the SMA-positive cells demonstrated distinct immunolocalization of platelet-derived growth factor (PDGF) B, a crucial chemoattractant for vascular mural cell recruitment, and its receptor, PDGFR-beta, respectively. The observations suggest that the sinus endothelial cells elicit abnormal recruitment of the fibroblast-like cells as a type of vascular mural cells via PDGF-B/PDGFR-beta signaling in lymph nodes of the Foxc2 heterozygotes. Furthermore, in Foxc2 heterozygous lymph nodes, recruited SMA-positive cells displayed an intense immunoreaction for vascular endothelial growth factor (VEGF)-C, a highly specific lymphangiogenic factor, and its receptor, VEGFR-3, was preferentially distributed in the lymphatic sinus endothelial cells. These findings suggest that an interactive cycle between lymphatic sinus endothelial cells and the fibroblast-like cells, which involves PDGF-B/PDGFR-beta and VEGF-C/VEGFR-3 signaling, is essential for aberrant hyperplasia of the lymphatic sinus and the fibroblast-like cells in Foxc2 haploinsufficiency. PMID- 21614588 TI - The liver: another organ involved in Muir Torre syndrome? AB - Muir Torre syndrome is a rare autosomal dominant cancer-predisposing syndrome characterized by the occurrence of sebaceous gland neoplasms and/or keratoacanthomas associated with visceral malignancies that belong to the spectrum of hereditary non polyposis colorectal cancer (HNPCC), i.e., tumors of gastrointestinal and genitourinary tracts. Hepatobiliary malignancy in association with Muir Torre syndrome has rarely been reported. Here, we describe a case of Muir Torre syndrome associated with an hepatocellular-carcinoma in a patient with a non-cirrhotic liver and an HNPCC-family with multiple cases of hepatocellular carcinoma. PMID- 21614589 TI - Lack of germline PALB2 mutations in melanoma-prone families with CDKN2A mutations and pancreatic cancer. AB - The presence of pancreatic cancer (PC) in melanoma-prone families has been consistently associated with an increased frequency of CDKN2A mutations, the major high-risk susceptibility gene identified for melanoma. However, the precise relationship between CDKN2A, melanoma and PC remains unknown. We evaluated a recently identified PC susceptibility gene PALB2 using both sequencing and tagging to determine whether PALB2 might explain part of the relationship between CDKN2A, melanoma, and PC. No disease-related mutations were identified from sequencing PALB2 in multiple pancreatic cancer patients or other mutation carrier relatives of PC patients from the eight melanoma-prone families with CDKN2A mutations and PC. In addition, no significant associations were observed between 11 PALB2 tagging SNPs and melanoma risk in 23 melanoma-prone families with CDKN2A mutations or the subset of 11 families with PC or PC-related CDKN2A mutations. The results suggested that PALB2 does not explain the relationship between CDKN2A, melanoma, and pancreatic cancer in these melanoma-prone families. PMID- 21614591 TI - The causes and outcome of acute pancreatitis associated with serum lipase >10,000 u/l. AB - OBJECTIVES: Our objective was to investigate the use of serum lipase levels >10,000 U/L as a tool for predicting the etiology of acute pancreatitis (AP) and to further address the relationship between lipase elevation and disease severity. METHODS: We compared patients with AP and serum lipase >10,000 U/L (HL) with patients with AP and lower serum lipase levels (855-10,000 U/L). The etiology and severity of AP were recorded. Differences between groups were calculated. RESULTS: Of the 114 patients in the HL group, the common etiologies of AP were biliary (68%), iatrogenic trauma (14%), and idiopathic (10%). Only one patient had alcoholic AP. Conversely, the common etiologies of AP in the 146 patient comparison group (lipase 855-10,000 U/L) were broader: biliary (34%), idiopathic (23%), alcohol (14%), and iatrogenic trauma (10%). Biliary AP was twice as common in the HL group (P < 0.0001) whereas alcoholic AP was significantly less common (P < 0.0001). The positive predictive value (PPV) for biliary AP of lipase >10,000 U/L was 80% whereas the negative predictive (NPV) for alcoholic AP was 99%. No difference between groups was observed in the severity markers including ICU admission, length of hospital stay, complications, or mortality. CONCLUSIONS: In AP a serum lipase of >10,000 U/L at presentation is a useful marker and portends a biliary etiology while virtually excluding alcoholic AP. Therefore, if ultrasonography is negative for stones in this population, these data suggest workup with MRCP or EUS is warranted to evaluate for microlithiasis or sludge given the high likelihood of occult stone disease in these individuals. PMID- 21614592 TI - Adherence and adequacy of therapy for esophageal varices prophylaxis. AB - AIMS: Esophageal varices (EVs) are prevalent among cirrhotics and their bleeding leads to substantial morbidity and mortality. Management guidelines available during this study recommended beta-blocker therapy for primary prophylaxis and beta-blocker or band ligation (EVL) for secondary prophylaxis. We evaluated prophylaxis practice patterns. METHODS: We performed a retrospective cohort study of in and outpatient cirrhotics with known EVs at two University of Texas Southwestern teaching institutions. Use of prophylactic therapy and its adequacy (defined using published guidelines) was measured. RESULTS: A total of 419 patients with cirrhosis and EVs warranting prophylaxis were identified, including 276 inpatients and 143 outpatients. Of those admitted with a first bleed (i.e. eligible for primary prophylactic therapy), 30/104 (29%) were on beta blocker. In this group, only 3/104 (3%) received optimal therapy (heart rate <55). Among inpatients with a previous EV bleed, 120/172 (70%) were on a beta blocker or had undergone EVL, although only 66/172 (38%) received optimal therapy. In the inpatient cohort, ten patients died of gastrointestinal hemorrhage, three of whom were receiving optimal therapy. Among outpatients, 94/121 (78%) without previous bleeding received primary prophylaxis and 20/22 (91%) of those with previous bleeding received some form of secondary prophylaxis. However, only 11 (9%) received adequate primary prophylaxis therapy, while 9 (41%) received appropriate secondary prophylaxis. CONCLUSIONS: Prophylaxis intent appears to be greatly improved compared to previous reports. However, implementation of optimal therapy appeared to be suboptimal. We conclude that efforts need to be made to ensure optimal treatment. PMID- 21614590 TI - The formation, function and fate of protein storage compartments in seeds. AB - Seed storage proteins (SSPs) have been studied for more than 250 years because of their nutritional value and their impact on the use of grain in food processing. More recently, the use of seeds for the production of recombinant proteins has rekindled interest in the behavior of SSPs and the question how they are able to accumulate as stable storage reserves. Seed cells produce vast amounts of SSPs with different subcellular destinations creating an enormous logistic challenge for the endomembrane system. Seed cells contain several different storage organelles including the complex and dynamic protein storage vacuoles (PSVs) and other protein bodies (PBs) derived from the endoplasmic reticulum (ER). Storage proteins destined for the PSV may pass through or bypass the Golgi, using different vesicles that follow different routes through the cell. In addition, trafficking may depend on the plant species, tissue and developmental stage, showing that the endomembrane system is capable of massive reorganization. Some SSPs contain sorting signals or interact with membranes or with other proteins en route in order to reach their destination. The ability of SSPs to form aggregates is particularly important in the formation or ER-derived PBs, a mechanism that occurs naturally in response to overloading with proteins that cannot be transported and that can be used to induce artificial storage bodies in vegetative tissues. In this review, we summarize recent findings that provide insight into the formation, function, and fate of storage organelles and describe tools that can be used to study them. PMID- 21614593 TI - A novel polymer infiltrated ceramic for dental simulation. AB - Simulation of tooth preparation using rotary cutting instruments is viewed as beneficial and essential in dental training. Various types of materials have been used for simulation systems in dental preclinical training. However, the phantom tooth materials used for simulation have not changed significantly for decades and they are acknowledged to be different from natural teeth. This study investigated the mechanical properties and microstructure of a widely used phantom tooth material and compared them with a novel, polymer infiltrated, ceramic. It was concluded that the polymer infiltrated ceramic has mechanical properties more similar to natural teeth than current phantom tooth materials, suggesting that it might be a good candidate material for phantom teeth for trainees to acquire initial tactile sense for tooth preparation. PMID- 21614594 TI - Effect of fluorine incorporation on long-term stability of magnesium-containing hydroxyapatite coatings. AB - Dissolution resistance and adhesion strength are two main concerns for long-term stability of surface coated metal implants. In this study, fluorine ions are incorporated into magnesium-containing hydroxyapatite coatings (MgF(y)HA) via sol gel method to improve the long-term stability of the implants. Surface and interface are studied in terms of phases, depth profiling and chemical bonds by grazing incidence X-ray diffraction, glow discharge optical emission spectroscopy and X-ray photoelectron spectroscopy. The long-term stability is evaluated by dissolution and pull-off test. The results show that fluorine promotes the incorporation of magnesium in HA lattice. The elemental interdiffusion and chemical bonding take place at the coating/substrate interface. Both the dissolution resistance and the adhesion strength are enhanced by fluorine incorporation, thus the long-term stability of the implant is improved. PMID- 21614595 TI - Assessing the lipophilicity of fragments and early hits. AB - A key challenge in many drug discovery programs is to accurately assess the potential value of screening hits. This is particularly true in fragment-based drug design (FBDD), where the hits often bind relatively weakly, but are correspondingly small. Ligand efficiency (LE) considers both the potency and the size of the molecule, and enables us to estimate whether or not an initial hit is likely to be optimisable to a potent, druglike lead. While size is a key property that needs to be controlled in a small molecule drug, there are a number of additional properties that should also be considered. Lipophilicity is amongst the most important of these additional properties, and here we present a new efficiency index (LLE(AT)) that combines lipophilicity, size and potency. The index is intuitively defined, and has been designed to have the same target value and dynamic range as LE, making it easily interpretable by medicinal chemists. Monitoring both LE and LLE(AT) should help both in the selection of more promising fragment hits, and controlling molecular weight and lipophilicity during optimisation. PMID- 21614596 TI - Why is hypercalciuria absent at diagnosis in some children with ATP6V1B1 mutation? AB - We try to explain why hypercalciuria is absent at diagnosis in some children with an ATP6V1B1 mutation. A 5-month-old girl presented with distal renal tubular acidosis (dRTA) and sensorineural hearing loss. Direct sequencing of the ATP6V1B1 genes disclosed a new homozygous mutation (452 delT) in exon 13. In particular, an absence of hypercalciuria and a normal level of parathyroid hormones were noted. After alkaline therapy, the signs of nephrocalcinosis improved on ultrasound during follow-up. After a review of the literature regarding patients with ATP6V1B1 gene mutations, a young age seemed to be an important factor for normocalciuria. The probable mechanism of normocalciuria and a dynamic mode of calcium excretion in patients with dRTA is proposed. The determinant factors include the degree of systemic acidosis, urine pH, genetic polymorphisms, age, dietary factors, and volume status. Low sodium intake may be a major determinant of normocalciuria in these patients. It is suggested that hypercalciuria is usually absent at diagnosis of dRTA in young infants. Blood pH, plasma bicarbonate concentration, urinary citrate levels, and growth catch-up may be better indicators of adequate alkali therapy in normocalciuric children. Volume contraction, low salt content in infant formula, and alkaline urine in young infants are likely to account for the increased calcium reabsorption. PMID- 21614597 TI - The treatment of distal radius articular fractures of C1-C2 type with DVR plate: analysis of 40 cases. AB - The aim of this investigation was to evaluate the efficiency of fixed angle plates DVR in the treatment of C1 and C2 type articular wrist fractures according to the AO classification. From July 2005 to March 2009, 40 wrist fractures were treated: 18 were of C1 type while 22 of C2 type according to AO classification. The age of patients varied from 25 to 79 years old. The average length of follow up was 17 months (range, 4-37 months). The average articular motility was flexion 59.4 degrees and extension 62.7 degrees . Final radiographic parameters were of 18.7 degrees of average ulnar inclination, 10.3 degrees of average dorsal inclination, and 1.45 mm of negative ulnar variance. All patients were reassessed according to Mayo Modified Wrist Score getting a very good/good result in 82% of cases and a medium/poor one in 18%. The DASH score pulled off 46.3 points in the first group, 5.1 in the second group, and 6 in the third one. The statistical analysis based on Student's t test showed how C1 and C2 classification did not influence the results using the same treatment. DVR plate showed a very good reliability and a sufficient stability with both C1 and C2 fractures. PMID- 21614598 TI - Nonunion of a sacral fracture refractory to bone grafting: internal fixation and osteogenic protein-1 (BMP-7) application. AB - Nonunion of a sacral fracture is a serious clinical condition: chronic pain, sitting discomfort, limp, neurological implications, and inability to work are frequent findings. Surgical treatment of these injuries often turns out to be technically difficult also for the expert pelvic surgeon and not infrequently provides poor radiographic and clinical results. The gold standard treatment at present is open excision, reaming of the nonunion site and internal fixation, performed by a multi-stage approach; as an adjunct, autologous cancellous bone grafting is usually performed in most severe cases. We report a case of a sacral nonunion in which traditional techniques failed, successfully treated by osteogenic protein-1 (BMP-7) application. The employment of BMPs demonstrated successful results in various types of fracture, but there is limited experience about their use in pelvic ring injuries: Further studies are necessary to better know the possible complications and to define their actual potential. PMID- 21614599 TI - Impact of prenatal stress on 1H NMR-based metabolic profiling of rat amniotic fluid. AB - OBJECT: The impact of inflammation in utero on amniotic fluid composition, the delivery term and the number of newborn rats per litter was investigated. The growth of newborns during the first fourteen days of life was analysed. MATERIALS AND METHODS: Changes in the metabolome were evaluated using (1)H NMR spectroscopy combined with multivariate analysis. NMR spectra were segmented and principal component analysis was performed. Three groups were compared: a control group that received saline solution, a hyperthermic group (HYP) and a group that received injections of lipopolysaccharides (LPS) (350 MUg/kg/day). RESULTS: The most discriminating metabolites in the three profiles were identified, highlighting different metabolic pathways for providing glucose and energy to the foetus. The LPS group was characterized by glycolysis under anaerobic conditions, while the HYP group was characterized by a gluconeogenic amino acid pathway. These metabolic changes in amniotic fluid were accompanied by changes in the gestation outcome, the main differences concerning the mean number of pups per litter (control 9.74 +/- 0.6, HYP 6.81 +/- 0. and LPS 4.85 +/- 1.11) and the biometric growth of the pups. CONCLUSION: Some consistent metabolic changes, observable by (1)H NMR spectroscopy, occurred in amniotic fluid during prenatal stress caused by hyperthermia and LPS-induced inflammation and had an impact on the gestation outcome. PMID- 21614600 TI - [Approach to painful hip resurfacing]. AB - Hip resurfacing in young patients has been increasingly performed within the last decade. In comparison to standard total hip arthroplasty the failure rate remains high. Age and implant size have a significant effect on the risk of revision for primary total resurfacing and the risk of revision increases with increasing age. At 7 years the cumulative revision rate for patients is 5% and females have more than twice the cumulative revision rate as males. Even in hip resurfacing arthroplasty which has been performed in a perfect manner, a certain percentage of patients suffer from persistent pain for various reasons, such as neck fracture, iliopsoas tendinopathy, metal hypersensitivity, such as aseptic lymphocytic vasculitis associated lesions (ALVAL) and aseptic loosening. Diagnostic work-up of the painful hip resurfacing is challenging even for experienced surgeons. Recommendations for the diagnostic procedure are described. PMID- 21614602 TI - Moving and fusion of the pancreatic buds in the rat embryos during the embryonic period (carnegie stages 13-17) by a three-dimensional computer-assisted reconstruction. AB - AIM: The purpose of the present study was to illustrate the modality of rotation of ventral and dorsal pancreatic buds by three-dimensional (3D) reconstructions in the rat embryos, during the Carnegie stages 13-17. MATERIALS AND METHODS: Serial sections of thirty rat embryos stages 13-17, were observed. The embryos were fixed in Bouin's solution, dehydrated, and paraffin embedded. The sections, 7 MUm thick, were cut in longitudinal or transverse planes and were stained alternately by hematoxylin-eosin or Heindenhain' azan. The images were digitalized by Canon Camera 350 EOS D. The 3D reconstruction was performed by computer using Cell Image Analyser software. RESULTS: The two pancreatic buds ventral and dorsal, were clearly identified at stage 13, in anterior and posterior position, respectively, in relation to the duodenum. In stage 15, the duodenum started its rotation of 90 degrees clockwise. The ventral bud moved 90 degrees from the midline to the right. In stage 16, the ventral pancreas continued its rotation until 180 degrees in posterior position behind the duodenum. In stage 17, the two pancreatic buds were related closely to the ventral part of the portal vein. The two buds began to merge. The anterior face of the pancreas's head was arising from the dorsal pancreatic bud. The rest of the head including the omental tuberosity and the uncinate process emanated from the ventral pancreatic bud. CONCLUSION: The use of 3D reconstruction of the pancreas of rat embryos illustrates the modality of the two pancreatic buds rotation and fusion. This method explains the final position of the pancreas. PMID- 21614601 TI - Meta-analysis of dropout rates in randomized controlled clinical trials: opioid analgesia for osteoarthritis pain. AB - BACKGROUND: The interpretation of opioid studies in patients with chronic pain due to osteoarthritis is limited by a high dropout rate. Therefore, the implication of dropouts on the recommendation of opioids in chronic osteoarthritis pain was analyzed. DATA SOURCES: The databases of Medline, Embase, the Cochrane Library, and the Internet from 1990-2009 were searched. STUDY SELECTION: Two independent authors included randomized controlled clinical trials investigating the effects of chronic opioid treatment for the management of osteoarthritis pain. In order to calculate the odds ratio, only placebo controlled trials were included. DATA EXTRACTION: The primary outcome parameter was the dropout rate. Secondarily, the effect size was calculated. Data extraction was conducted by two independent authors. RESULTS: A total of 19 studies reporting results of 3,871 treatment and 2,080 placebo outcomes were retrieved. Compared to placebo, opioid treatment was associated with a significantly increased total dropout rate (OR = 1.3, 95%CI 1.2-1.4). Discontinuation of treatment was related to adverse events (OR = 4.0, 95%CI 3.4 4.6). Lack of analgesia was associated with a significantly reduced dropout rate in opioid groups (OR = 0.4, 95%CI 0.3-0.5). Analgesic effects were significantly better in opioid-treated patients (p = 0.01). CONCLUSION: In spite of analgesic effects, many osteoarthritis patients prefer to stop chronic opioid use, because of adverse events. Therefore, opioids are not generally recommended in osteoarthritis. PMID- 21614603 TI - Thrombo-prophylaxis in pelvic and acetabular trauma patients: a UK consensus? AB - AIMS: The incidence of deep vein thrombosis, non-fatal pulmonary embolism and fatal pulmonary embolism may be as high as 61%, 10% and 2%, respectively, in patients with pelvic and acetabular injuries. A survey of the pelvic and acetabular units across the United Kingdom was performed to ascertain the thrombo prophylaxis policy for these patients. In particular, questions were asked about different regimes on post-operative patients, conservatively managed patients and those simply discussed over the telephone. We enquired about their known rates of DVT and PE and their methods of data collection. METHODS: Postal questionnaires were sent to 22 pelvic and acetabular trauma centres around the United Kingdom. RESULTS: Replies from 18 units were received in which a total of 837 operations are performed per year. Forty-five percent of pelvic and acetabular units do not routinely prescribe chemical prophylaxis for post-operative patients and 56% do not prescribe prophylaxis for conservatively managed patients. The policy of the remaining units showed no consistency in duration or agent. Fifty-three percent of units use a database to collect information related to the numbers of patients operated up on. Forty-seven percent have no defined method for collecting DVT and PE numbers. For this reason, reported rates of proximal DVT, non-fatal PE and fatal PE were below that expected at 2.5%, 0.8% and 0.1%, respectively. CONCLUSIONS: Despite high rates of thrombo-embolic complications in patients with pelvic and acetabular injuries there is no UK consensus on prescribing prophylaxis. PMID- 21614604 TI - Airway foreign body aspiration. AB - Foreign body aspiration into the airway is one of the dramatic pediatric emergencies. It is more common in children aged 6 months to 5 years. Pea nuts and food items account for most cases. Right main stem bronchus is the most common site involved. The initial cough and choking like episodes may be followed by a symptomless interval before leading to further complications. Chest radiograph findings may vary from normal to hyperinflation, obstructive emphysema or pneumothorax. Removal by rigid bronchoscopy is the definitive treatment. PMID- 21614605 TI - Microbiological diagnosis of pulmonary tuberculosis in children: comparative study of induced sputum and gastric lavage. PMID- 21614606 TI - Attitude of parents and teachers towards adolescent reproductive and sexual health education. AB - OBJECTIVE: To assess parents' and teachers' attitude towards Adolescent Reproductive Sexual Health Education (ARSHE). METHODS: The study group consisted of a random sample of 795 parents and 115 teachers belonging to three urban schools (one boys only, one girls only and one co-education) and one co-education rural school at Thiruvananthapuram district, Kerala, where an ICMR supported ARSHE intervention programme was done subsequently. A self-administered questionnaire for parents and teachers developed by an ICMR taskforce for ARSHE programme was used to assess their opinion on the need, content and the appropriate person to provide adolescent reproductive sexual health education in a school setting. RESULTS: 65.2% of parents and 40.9% teachers have not discussed growth and development issues with their adolescents. Only 5.2% teachers and 1.1% parents discussed sexual aspects with adolescents. 44% of parents agreed that information on HIV/AIDS/STD should be provided. More than 50% of parents were not sure whether information on topics like masturbation, dating, safe sex, contraceptives, pregnancy, abortion and childcare should be provided to adolescents. CONCLUSIONS: Results pointed out the need for introducing reproductive and sexual education in the school setting. Only 1.1% of parents and 5.2% teachers actually discussed sexual aspects with adolescents which highlights the need for parent and teacher awareness programs before ARSHE is introduced in the schools. PMID- 21614607 TI - School based adolescent care services: a district model. AB - OBJECTIVE: To study the perceived problems of higher secondary school students in a district and to document the effect of a family life and life skill education package. METHODS: A survey was conducted among 11501 adolescents belonging to 103 higher secondary schools in Thiruvananthapuram district, using Teenage Screening Questionnaire-Trivandrum (TSQ-T). Family life and life skill education package was given to class XI students and post intervention evaluation of improvement in knowledge level was assessed after 6 months by a structured pre-tested self administered questionnaire. RESULTS: 61.2% adolescents reported scholastic problem, 22.1% family related problems, 31.9% personal problems and 15.2% adjustment problems, with boys reporting higher percentage. 65.8% reported body image related problems, 26.4% had dental, 21.3% ENT and 16.2% had dermatological complaints. Among girls 50.2% reported menstrual problems. 506 adolescents volunteered for medical check-up and 1247 for detailed psychological assessment. Family life and life skill education package showed consistent improvement in knowledge even after a gap of 6 months. CONCLUSIONS: The study results showed that a school based adolescent care service programme is effective and feasible. PMID- 21614608 TI - Characterization of in vitro cultured myoblasts isolated from duck (Anas platyrhynchos) embryo. AB - Myoblasts isolated from duck embryonic muscle were purified and in vitro cultured. External characteristics were observed by using the immunofluorescence technique, and growth curve of duck embryonic myoblasts was established after measuring with the MTT method. Moreover, mRNA expression of three marker genes, the Desmin, the muscle creatine kinase (Mck) and the troponin C (Tnnc), which could reflect the development status of myofibers, were detected each 24 h for cultured cells by using the qPCR technique. Results showed that the in vitro cultured duck myoblasts went through a series of developmental stages, including the proliferation of myoblasts, the differentiation of multi-nuclei myotubes, and the formation of myofiber. The cultured duck embryonic myoblasts entered into a logarithmic stage approximately on the fourth day after seeding. Accompanying with its progressive growth before entering into the logarithmic phase, the myoblasts also showed some differentiation phenomena, reflected by a low expression level of Desmin and high expression level of the Mck and Tnnc genes. During the rapid growth of the logarithmic phase, there was a high expression of the Desmin gene, and a low expression level of the Mck gene and the Tnnc gene in the cultured myoblasts. The expression profiles of the three marker genes for muscle development could be used for distinguishing the different developmental stages of in vitro cultured myoblasts at the molecular level, which would be more accurate and more feasible than observing the external characteristics of the cultured cells. PMID- 21614609 TI - Separation of gamma-aminobutyric acid from fermented broth. AB - Gamma-aminobutyric acid (GABA) is a non-proteinaceous amino acid that is widely distributed in nature and acts as the major inhibitory neurotransmitter in the mammalian brain. This study aimed to find a separation method for getting high purity GABA from a fermented broth. Firstly, a fermented broth with a high content of GABA (reaching 997 +/- 51 mM) was prepared by fermentation with Lactobacillus brevis NCL912. GABA purification was conducted by successive centrifugation, filtration, decoloration, desalination, ion-exchange chromatography (IEC), and crystallization. Inorganic salt (Na2SO4) was removed from the both by desalination with 70% ethanol solution. A ninhydrin test strip was designed for the real-time detection of GABA during IEC. The recovery rate for the whole purification process was about 50%. The purified product was characterized by thin-layer chromatography and HPLC, and its purity reached 98.66 +/- 2.36%. PMID- 21614610 TI - Overcoming inhibitors in a hemicellulosic hydrolysate: improving fermentability by feedstock detoxification and adaptation of Pichia stipitis. AB - In order to improve the fermentative efficiency of sugar maple hemicellulosic hydrolysates for fuel ethanol production, various methods to mitigate the effects of inhibitory compounds were employed. These methods included detoxification treatments utilizing activated charcoal, anion exchange resin, overliming, and ethyl acetate extraction. Results demonstrated the greatest fermentative improvement of 50% wood hydrolysate (v/v) by Pichia stipitis with activated charcoal treatment. Another method employed to reduce inhibition was an adaptation procedure to produce P. stipitis stains more tolerant of inhibitory compounds. This adaptation resulted in yeast variants capable of improved fermentation of 75% untreated wood hydrolysate (v/v), one of which produced 9.8 g/l +/- 0.6 ethanol, whereas the parent strain produced 0.0 g/l +/- 0.0 within the first 24 h. Adapted strains RS01, RS02, and RS03 were analyzed for glucose and xylose utilization and results demonstrated increased glucose and decreased xylose utilization rates in comparison to the wild type. These changes in carbohydrate utilization may be indicative of detoxification or tolerance activities related to proteins involved in glucose and xylose metabolism. PMID- 21614611 TI - Food allergy and atopic dermatitis: how are they connected? AB - Food allergy predominantly affects children rather than adults with atopic dermatitis (AD). Early food sensitization has been found to be significantly associated with AD. Three different patterns of clinical reactions to food allergens in AD patients have been identified: 1) immediate-type symptoms, 2) isolated eczematous late-type reactions, and 3) combined reactions. Whereas in children, allergens from cow's milk, hen's egg, soy, wheat, fish, peanut, or tree nuts are primarily responsible for allergic reactions, birch pollen-related food allergens seem to play a major role in adolescent and adults with AD in Central and Northern Europe. Defects in the epidermal barrier function seem to facilitate the development of sensitization to allergens following epicutaneous exposure. The relevance of defects in the gut barrier as well as genetic characteristics associated with an increased risk of food allergy remain to be further investigated. Many studies focus on sufficient strategies of prevention, which actually include breastfeeding or feeding with hydrolyzed formula during the first 4 months of life. PMID- 21614612 TI - Diet containing low n-6/n-3 polyunsaturated fatty acids ratio, provided by canola oil, alters body composition and bone quality in young rats. AB - PURPOSE: Adipocytes and osteoblasts were derived from a common progenitor, and canola oil intake may have an adipogenic and osteogenic effect. Thus, our objective was to evaluate the effect on adipocyte, lipid profile, glucose homeostasis, and bone of canola oil as main lipid source on the diet during development. METHODS: After weaning, rats were divided into two groups (n = 10 per group): control (S) and experimental (C) diets containing 7 mL/100 g soybean or canola oil, respectively. At 60 days, body composition, liver and intra abdominal fat mass, adipocyte morphology, serum analysis, femur and lumbar vertebras density by dual-energy X-ray absorptiometry and computed tomography were determined. Differences were considered significant with P < 0.05. RESULTS: C group showed the following: lower liver (-12%) and intra-abdominal fat mass ( 19%) area of adipocyte (-60%), cholesterol (-33%), insulin (-22%), lower total body (-9%) and spine (-33%) bone mineral content and bone area (-7 and -24%, respectively), femur mass (-9%), width of the diaphysis (-6%), femur (-10%) and lumbar vertebrae bone mineral density (-9%), and radiodensity of femoral head ( 8%). CONCLUSIONS: The lower intra-abdominal adiposity could have more beneficial effects in a short term, since it can be associated with a better insulin sensitivity and lipid profile, than the small reduction in femur and lumbar vertebra density. However, it has to be considered the incremental effect of this reduction along the aging process. PMID- 21614613 TI - The amino acid sensor GCN2 biases macronutrient selection during aging. AB - PURPOSE: Selection of a balanced diet has a determinant impact on human health. Individual food preferences involve socio-cultural as well as physiological factors and evolve during aging. In mammals, physiological mechanisms governing food choices appear to require the sensing of nutrient concentrations in diet. This is particularly the case for dietary amino acids that are sensed by the protein kinase GCN2. It has been reported that GCN2 is involved in the adaptive response to amino acid imbalanced diets at the level of food intake and lipid metabolism. Here, we hypothesized that GCN2 may play a role in macronutrient selection and its age-related changes. METHODS: Two groups of wild-type and GCN2 knock-out mice were subjected to a food self-selection protocol at ages 6, 12, 18 and 24 months. During each test, mice were allowed to create their own diets by selecting between three separate food sources, each containing either protein, fat or carbohydrates. RESULTS: Our results show that the absence of GCN2 had two main age-related effects. First, it exacerbated fat preference at the expense of carbohydrate consumption. Second, it prevented the increase in protein intake. CONCLUSION: These findings indicate that, in omnivores, the GCN2 ancient pathway participates in the control of food preference. PMID- 21614614 TI - Dose and image quality at CT pulmonary angiography-comparison of first and second generation dual-energy CT and 64-slice CT. AB - OBJECTIVE: To compare dose and image quality of 64-slice, first and second generation dual-energy CT (DECT) for CT pulmonary angiography (CTPA). METHODS: Totally 120 patients, 30 in each group, underwent CTPA on a first generation (group 1: single-energy, 120 kV/145 mAs; group 2: DE, 140/80 kV, 70/350 mAs) or second generation dual-source DECT device (group 3: DE, 100/Sn140 kV, 120/102 mAs; group 4: DE, 80/Sn140 kV, 202/86 mAs). CTDIvol, DLP, background noise (BN), thorax diameter and attenuation in the pulmonary trunk were compared. RESULTS: Thorax diameter and attenuation in the pulmonary trunk did not differ significantly (p > 0.4 and >0.19) between the groups. Mean CTDIvol and DLP were significantly lower (p < 0.003) in group 4 (6.2 +/- 1.6 mGy/170 +/- 41 mGycm) compared to group 1 (8.5 +/- 2.6 mGy/235 +/- 117 mGycm), group 2 (9.2 +/- 3.3 mGy/224 +/- 122 mGycm) and group 3 (8.7 +/- 2.8 mGy/246 +/- 86 mGycm). BN was significantly lower (p < 0.0001) in group 4 (12 +/- 3 HU) and group 1 (13 +/- 6 HU) compared to group 3 and 2 (16 +/- 6 HU and 23 +/- 9). CONCLUSION: The use of second generation DECT in 80/Sn140 kV configuration allows for significant dose reduction with image quality similar to 120 kV CTPA. PMID- 21614615 TI - Diagnostic accuracy and variability of three semi-quantitative methods for assessing right ventricular systolic function from cardiac MRI in patients with acquired heart disease. AB - OBJECTIVES: To evaluate the diagnostic accuracy and variability of 3 semi quantitative (SQt) methods for assessing right ventricular (RV) systolic function from cardiac MRI in patients with acquired heart disease: tricuspid annular plane systolic excursion (TAPSE), RV fractional-shortening (RVFS) and RV fractional area change (RVFAC). METHODS: Sixty consecutive patients were enrolled. Reference RV ejection fraction (RVEF) was determined from short axis cine sequences. TAPSE, RVFS and RVFAC were measured on a 4-chamber cine sequence. All SQt analyses were performed twice by 3 observers with various degrees of training in cardiac MRI. Correlation with RVEF, intra- and inter-observer variability, and receiver operating characteristic (ROC) curve analysis were performed for each SQt method. RESULTS: Correlation between RVFAC and RVEF was good for all observers and did not depend on previous cardiac MRI experience (R range = 0.716-0.741). Conversely, RVFS (R range = 0.534-0.720) and TAPSE (R range = 0.482-0.646) correlated less with RVEF and depended on previous experience. Intra- and inter observer variability was much lower for RVFAC than for RVFS and TAPSE. ROC analysis demonstrated that RVFAC <41% could predict a RVEF <45% with 90% sensitivity and 94% specificity. CONCLUSIONS: RVFAC appears to be more accurate and reproducible than RVFS and TAPSE for SQt assessment of RV function by cardiac MRI. PMID- 21614616 TI - Soil disturbance alters plant community composition and decreases mycorrhizal carbon allocation in a sandy grassland. AB - We have studied how disturbance by ploughing and rotavation affects the carbon (C) flow to arbuscular mycorrhizal (AM) fungi in a dry, semi-natural grassland. AM fungal biomass was estimated using the indicator neutral lipid fatty acid (NLFA) 16:1omega5, and saprotrophic fungal biomass using NLFA 18:2omega6,9. We labeled vegetation plots with (13)CO(2) and studied the C flow to the signature fatty acids as well as uptake and allocation in plants. We found that AM fungal biomass in roots and soil decreased with disturbance, while saprotrophic fungal biomass in soil was not influenced by disturbance. Rotavation decreased the (13)C enrichment in NLFA 16:1omega5 in soil, but (13)C enrichment in the AM fungal indicator NLFA 16:1omega5 in roots or soil was not influenced by any other disturbance. In roots, (13)C enrichment was consistently higher in NLFA 16:1omega5 than in crude root material. Grasses (mainly Festuca brevipila) decreased as a result of disturbance, while non-mycorrhizal annual forbs increased. This decreases the potential for mycorrhizal C sequestration and may have been the main reason for the reduced mycorrhizal C allocation found in disturbed plots. Disturbance decreased the soil ammonium content but did not change the pH, nitrate or phosphate availability. The overall effect of disturbance on C allocation was that more of the C in AM fungal mycelium was directed to the external phase. Furthermore, the functional identity of the plants seemed to play a minor role in the C cycle as no differences were seen between different groups, although annuals contained less AM fungi than the other groups. PMID- 21614617 TI - Host resistance elicited by methyl jasmonate reduces emission of aggregation pheromones by the spruce bark beetle, Ips typographus. AB - We treated Norway spruce (Picea abies) stems with methyl jasmonate (MeJA) to determine possible quantitative and qualitative effects of induced tree defenses on pheromone emission by the spruce bark beetle Ips typographus. We measured the amounts of 2-methyl-3-buten-2-ol and (S)-cis-verbenol, the two main components of the beetle's aggregation pheromone, released from beetle entrance holes, along with phloem terpene content and beetle performance in MeJA-treated and untreated Norway spruce logs. As expected, phloem terpene levels were higher and beetle tunnel length was shorter (an indication of poor performance) in MeJA-treated logs relative to untreated logs. Parallel to the higher phloem terpene content and poorer beetle performance, beetles in MeJA-treated logs released significantly less 2-methyl-3-buten-2-ol and (S)-cis-verbenol, and the ratio between the two pheromone components was significantly altered. These results suggest that host resistance elicited by MeJA application reduces pheromone emission by I. typographus and alters the critical ratio between the two main pheromone components needed to elicit aggregation. The results also provide a mechanistic explanation for the reduced performance and attractivity observed in earlier studies when bark beetles colonize trees with elicited host defenses, and extend our understanding of the ecological functions of conifer resistance against bark beetles. PMID- 21614618 TI - delta15N constraints on long-term nitrogen balances in temperate forests. AB - Biogeochemical theory emphasizes nitrogen (N) limitation and the many factors that can restrict N accumulation in temperate forests, yet lacks a working model of conditions that can promote naturally high N accumulation. We used a dynamic simulation model of ecosystem N and delta(15)N to evaluate which combination of N input and loss pathways could produce a range of high ecosystem N contents characteristic of forests in the Oregon Coast Range. Total ecosystem N at nine study sites ranged from 8,788 to 22,667 kg ha(-1) and carbon (C) ranged from 188 to 460 Mg ha(-1), with highest values near the coast. Ecosystem delta(15)N displayed a curvilinear relationship with ecosystem N content, and largely reflected mineral soil, which accounted for 96-98% of total ecosystem N. Model simulations of ecosystem N balances parameterized with field rates of N leaching required long-term average N inputs that exceed atmospheric deposition and asymbiotic and epiphytic N(2)-fixation, and that were consistent with cycles of post-fire N(2)-fixation by early-successional red alder. Soil water delta(15)NO(3)(-) patterns suggested a shift in relative N losses from denitrification to nitrate leaching as N accumulated, and simulations identified nitrate leaching as the primary N loss pathway that constrains maximum N accumulation. Whereas current theory emphasizes constraints on biological N(2) fixation and disturbance-mediated N losses as factors that limit N accumulation in temperate forests, our results suggest that wildfire can foster substantial long-term N accumulation in ecosystems that are colonized by symbiotic N(2) fixing vegetation. PMID- 21614619 TI - Comparison of UTCI to selected thermal indices. AB - Over the past century more than 100 indices have been developed and used to assess bioclimatic conditions for human beings. The majority of these indices are used sporadically or for specific purposes. Some are based on generalized results of measurements (wind chill, cooling power, wet bulb temperature) and some on the empirically observed reactions of the human body to thermal stress (physiological strain, effective temperature). Those indices that are based on human heat balance considerations are referred to as "rational indices". Several simple human heat balance models are known and are used in research and practice. This paper presents a comparative analysis of the newly developed Universal Thermal Climate Index (UTCI), and some of the more prevalent thermal indices. The analysis is based on three groups of data: global data-set, synoptic datasets from Europe, and local scale data from special measurement campaigns of COST Action 730. We found the present indices to express bioclimatic conditions reasonably only under specific meteorological situations, while the UTCI represents specific climates, weather, and locations much better. Furthermore, similar to the human body, the UTCI is very sensitive to changes in ambient stimuli: temperature, solar radiation, wind and humidity. UTCI depicts temporal variability of thermal conditions better than other indices. The UTCI scale is able to express even slight differences in the intensity of meteorological stimuli. PMID- 21614620 TI - Precision, accuracy, and application of diver-towed underwater GPS receivers. AB - Diver-towed global positioning systems (GPS) handhelds have been used for a few years in underwater monitoring studies. We modeled the accuracy of this method using the software KABKURR originally developed by the University of Rostock for fishing and marine engineering. Additionally, three field experiments were conducted to estimate the precision of the method and apply it in the field: (1) an experiment of underwater transects from 5 to 35 m in the Southern Chile fjord region, (2) a transect from 5 to 30 m under extreme climatic conditions in the Antarctic, and (3) an underwater tracking experiment at Lake Ranco, Southern Chile. The coiled cable length in relation to water depth is the main error source besides the signal quality of the GPS under calm weather conditions. The forces used in the model resulted in a displacement of 2.3 m in a depth of 5 m, 3.2 m at a 10-m depth, 4.6 m in a 20-m depth, 5.5 m at a 30-m depth, and 6.8 m in a 40-m depth, when only an additional 0.5 m cable extension was used compared to the water depth. The GPS buoy requires good buoyancy in order to keep its position at the water surface when the diver is trying to minimize any additional cable extension error. The diver has to apply a tensile force for shortening the cable length at the lower cable end. Repeated diving along transect lines from 5 to 35 m resulted only in small deviations independent of water depth indicating the precision of the method for monitoring studies. Routing of given reference points with a Garmin 76CSx handheld placed in an underwater housing resulted in mean deviances less than 6 m at a water depth of 10 m. Thus, we can confirm that diver-towed GPS handhelds give promising results when used for underwater research in shallow water and open a wide field of applicability, but no submeter accuracy is possible due to the different error sources. PMID- 21614621 TI - Landscape ecological security assessment based on projection pursuit in Pearl River Delta. AB - Regional landscape ecological security is an important issue for ecological security, and has a great influence on national security and social sustainable development. The Pearl River Delta (PRD) in southern China has experienced rapid economic development and intensive human activities in recent years. This study, based on landscape analysis, provides a method to discover the alteration of character among different landscape types and to understand the landscape ecological security status. Based on remotely sensed products of the Landsat 5 TM images in 1990 and the Landsat 7 ETM+ images in 2005, landscape classification maps of nine cities in the PRD were compiled by implementing Remote Sensing and Geographic Information System technology. Several indices, including aggregation, crush index, landscape shape index, Shannon's diversity index, landscape fragile index, and landscape security adjacent index, were applied to analyze spatial temporal characteristics of landscape patterns in the PRD. A landscape ecological security index based on these outcomes was calculated by projection pursuit using genetic algorithm. The landscape ecological security of nine cities in the PRD was thus evaluated. The main results of this research are listed as follows: (1) from 1990 to 2005, the aggregation index, crush index, landscape shape index, and Shannon's diversity index of nine cities changed little in the PRD, while the landscape fragile index and landscape security adjacent index changed obviously. The landscape fragile index of nine cities showed a decreasing trend; however, the landscape security adjacent index has been increasing; (2) from 1990 to 2005, landscape ecology of the cities of Zhuhai and Huizhou maintained a good security situation. However, there was a relatively low value of ecological security in the cities of Dongguan and Foshan. Except for Foshan and Guangzhou, whose landscape ecological security situation were slightly improved, the cities had reduced values in landscape ecological security, with the most decreased number 0.52 in Zhaoqing. Results of this study offer important information for regional eco-construction and natural resource exploitation. PMID- 21614622 TI - Grasslands changes in the Northern Songnen Plain, China during 1954-2000. AB - Songnen Plain in Northeast China is one of the most significantly altered biological hotspots on Earth. Based on the information from integrated topographic maps, Landsat MSS, TM/ETM images and geographic information systems, grassland cover change, grassland fragmentation, agricultural reclamation, and saline-alkaline wasteland expansion in the region were investigated for the period of 1954 to 2000. The results showed that the native grassland decreased by 44.6 * 10(4) ha and moderate density grassland decreased from 78.3 * 10(4) to 20.3 * 10(4) ha. Calculated from change dynamic model, the annual decrease rate of grassland was 1.1%.The distribution center of the grasslands illustrated a trend of shifting southeastward. The distance between centroids of grassland was 10.1 km. The numbers of grassland patch increased by 1,378, while the patch size of grasslands declined. Grassland experienced substantial clearing and fragmentation. The decreased grassland was converted into cropland, wetland, and saline-alkaline wasteland. The loss and degradation of grasslands was closely related to regional climate during the past 47 years. Population and livestock number increased significantly as grassland quality decreased. Intensive human activities including irrational reclamation and overgrazing may have accelerated the degradation of grasslands. PMID- 21614623 TI - Vitamin C deficiency: more than just a nutritional disorder. AB - Although vitamin C deficiency and scurvy are generally considered as pure nutritional disorders, only a minority of the vitamin C concentration is determined by food intake. In the presence of transition metals (iron and copper), the antiscorbutic factor shifts from an antioxidant to a pro-oxidant function. Haptoglobin (Hp) is a plasma alpha-2 glycoprotein characterized by 3 common phenotypes (Hp 1-1, Hp 2-1 and Hp 2-2). Its free hemoglobin (Hb)-binding capacity prevents Hb-driven oxidative damage. When the antioxidant capacity of Hp is insufficient, its role is taken over by hemopexin (heme-binding protein) and by vitamin C (free radical scavenger). The Hp 2-2 phenotype has a lower capacity to inhibit oxidation and vitamin C depletion. In this article, two consequences of this major finding are tackled. The Hp polymorphism is an important non nutritional modifying factor in the pathogenesis of vitamin C deficiency and scurvy, which may explain the success of long-range human migration by the natural selection of some populations characterized by high Hp 1 allele frequencies. Moreover, we propose tailoring the recommended dietary allowance (RDA) values of vitamin C, taking into consideration the Hp phenotype dependency. PMID- 21614625 TI - "Not here": making the spaces and subjects of "global health" in Botswana. AB - This essay argues that what makes "global health" "global" has more to do with configurations of space and time, and the claims to expertise and moral stances these configurations make possible, than with the geographical distribution of medical experts or the universal, if also uneven, distribution of threats to health. Drawing on a study of public-private partnerships supporting Botswana's HIV/AIDS treatment program, this essay demonstrates ethnographically the processes by which "global health" and its quintessential spaces, namely "resource-limited" or "resource-poor settings," are constituted, reinforced, and contested in the context of medical education and medical practice in Botswana's largest hospital. Using Silverstein's work on orders of indexicality, I argue that the terms of "global health" are best understood as chronotopic, and demonstrate how actors orient themselves and others spatio-temporally, morally, and professionally by using or refuting those terms. I conclude by arguing that taking "global health" on its own terms obscures the powerful forces by which it becomes intelligible. At stake are the frames within which medical anthropologists understand their objects of study, as well as the potential for the spaces of "global health" intervention to expand ever outward as American medical personnel attempt to calibrate their experiences to their expectations. PMID- 21614626 TI - Adjuvant chemolipiodolization reduces early recurrence derived from intrahepatic metastasis of hepatocellular carcinoma after hepatectomy. AB - BACKGROUND: The recurrence of hepatocellular carcinoma is still high even after surgery. Two general recurrence patterns occur: intrahepatic metastasis (IM) and multicentric carcinogenesis (MC). The aim of this study was to investigate the effectiveness of adjuvant chemolipiodolization for reducing IM or MC recurrences after surgery. METHODS: A retrospective case-control study was carried out. From April 2005, adjuvant chemolipiodolization was performed in 63 initial hepatocellular carcinoma patients 3 months after surgery. Sixty-four patients who underwent surgery between April 2001 and March 2005 were analyzed as the control group. Recurrence-free and overall survival as well as prognostic factors were analyzed univariately and multivariately. RESULTS: The 2-year recurrence-free survival was 57% in the chemolipiodolization group and 37% in the control group (P = 0.02). However, there was no significant difference at 5 years after surgery (P = 0.09). The 5-year overall survival rates in the chemolipiodolization and the control groups were 82.4 and 55.7%, respectively (P = 0.04). Cox proportional multivariate analysis revealed that adjuvant chemolipiodolization was an independent favorable prognostic factor for 2-year recurrence-free survival, and the odds ratio [95% confidential interval] was 0.55 [0.34-0.90] (P = 0.02). However, adjuvant chemolipiodolization was not an independent favorable prognostic factor for 5-year overall survival. CONCLUSIONS: Adjuvant chemolipiodolization can reduce the risk of early recurrences, which would be mainly IM derived. However, chemolipiodolization did not reduce late phase recurrences after surgery, which would be mainly MC derived. To prevent late phase recurrences, another novel strategy would be needed. PMID- 21614627 TI - Diagnosis, management, and outcome of patients with dedifferentiated liposarcoma systemic metastasis. AB - BACKGROUND: Dedifferentiated liposarcomas (DDLPSs) result in worse patient outcomes than well-differentiated tumors despite shared molecular derangements. Prevalence and pattern of DDLPS systemic metastases have not been extensively reported; information regarding diagnosis, treatment, and outcomes of metastatic DDLPS patients is limited. Our study seeks to address this knowledge gap. METHODS: Metastatic patients were identified from a clinical database consisting of 277 DDLPS patients treated at the University of Texas M D Anderson Cancer Center (UTMDACC) (1993-2010). Only patients with radiologically demonstrable distant metastases were included. Patient, tumor, treatment, and outcome variables were recorded. Available imaging studies and tumor FFPE blocks were assessed. RESULTS: A total of 40 patients were identified, translating into a DDLPS metastatic rate of 14% (17% for de novo DDLPS and 9% for secondary dedifferentiation). The average patient age was 61 years with a male predilection. The retroperitoneum and lungs were the most common primary and metastatic tumor sites. Any of the 4 described DDLPS morphological subtypes harbored metastatic potential; MFH/UPS-like morphology was the most common. The median time from primary diagnosis to metastasis was 25 months; more than 50% of metastases developed without local failure. The median survival of metastatic patients was 11.5 months; the 5-year DSS was 5.2%. Patients amenable to complete surgical extirpation (n = 14) faired significantly better (P = .001; log rank). CONCLUSIONS: Metastatic spread is an ominous consequence of DDLPS, especially regarding de novo tumors. Occurring relatively early in the course of disease and exhibiting a pulmonary predilection, these lesions are highly aggressive and commonly fatal. Further studies to identify metastatic biomarkers are needed. PMID- 21614628 TI - [Rheumatism, jet lag and the body clock]. AB - Circadian rhythms play an important role in the function of the body. Among others, the activity of the immune system is subject to daily variability which explains the different intensity of rheumatic symptoms during the day (e.g. morning stiffness). Circadian rhythms are subject to continuous adaptation via external time signals (zeitgebers), such as light-dark periods, time of food intake, as well as daily activity and resting periods. Following an acute phase shift of these external zeitgebers, e.g. via transmeridian travel (east-west or west-east), the body has to adjust all circadian systems to these new circumstances during an adjustment response, which lasts for several days. The classical symptoms of jet lag, such as tiredness during the day, mood swings and cognitive malfunction occur during this adjustment period. The impact of acute phase shifts as a result of transmeridian travel in subjects with rheumatic disorders, as well as strategies to prevent jet lag will be discussed in the following article. PMID- 21614629 TI - ["Memories of my sick hands": life and medical history of the painter Alexej von Jawlensky]. AB - Alexej von Jawlensky (1864-1941), one of the most important expressionist painters and a member the artist group "The Blue Four", suffered from severe rheumatoid arthritis. He was the first painter in the twentieth century to create extensive series of paintings especially of human faces. The medical history of Jawlensky as documented in his letters, is a harrowing document of a great artist who suffered from rheumatoid arthritis at a time when medical treatment was limited to physical therapy, pain medication and other relatively ineffective modalities, including the unnecessary extraction of teeth. Jawlensky's disease was characterized by a rapidly progressive course with severe pain, rapid onset of disability and ending up with complete immobilization and paralysis for several years until his death.The artistic processing and sublimation of his illness and suffering resulting in a series of over 1,000 small format meditations are the impressive and touching example of creative coping with rheumatoid arthritis. The meditations are unique in the history of art and often compared with icons. However, knowing the medical condition of Jawlensky these paintings can also be seen as metaphors of suffering and in each image the great physical and mental effort is reflected in the artistic details. Therefore, his art agent Galka E. Scheyer formulated in a letter to him: "You are the painter of the human soul. I know of no other modern painter of the human soul." PMID- 21614630 TI - Drug allergy documentation--time for a change? AB - OBJECTIVE OF THE STUDY: To audit patients' allergy documentation in a large rural hospital an to make recommendations about accurate drug allergies in hospital settings. SETTING: A 257 bed large hospital and fully integrated health service in Australia, providing a range of services including; medicine, surgery, aged care, cancer care, mental health, maternity and rehabilitation. METHOD: A retrospective design was used to fulfil the aims of this study. Patient medical records were randomly selected and checked for allergy documentation over a 6 month period. RESULTS: A total of 521 patients' medical records were reviewed. Of all the medical records examined in total, 269 (52%) had no allergy, while 252 (48%) reported some kind of allergy. Overall, only three patients (0.6%) had their allergy details fully and accurately recorded in the three places audited and they are the front cover of the patients' notes, the admission notes and the drug chart. CONCLUSION: Many preventable medical errors are caused by poor documentation which is often due to lack of drug allergy information. All health professional should be more pro-active in determining the manner of any drug allergy or adverse drug reactions (ADR) along with the extent of the reaction. PMID- 21614631 TI - Metoprolol-induced lichenoid dermatitis. PMID- 21614632 TI - [Standard treatment for myositis and muscular dystrophies]. AB - We summarize the current therapeutic strategies and options in inflammatory myositis and the muscular dystrophies. In myositis, the therapeutic options include basic therapy with glucocorticosteroids and other standard immunosuppressive agents, and in individual cases escalating treatment with chemotherapy or monoclonal antibodies. The exact therapeutic sequence should be performed depending on the type of myositis and the response to immunosuppression.At present, there are still no effective causative interventions to significantly alter the progression of the muscular dystrophies. However, first gene therapy clinical studies have been started in some forms of muscular dystrophy which may open a new field of therapeutic options. Most patients with myositis or muscular dystrophy need symptom-oriented therapies which include physical therapy, adequate cardiorespiratory treatment and orthopedic interventions. In the future novel immunosuppressive options may be available in patients with myositis and possibly causative strategies in the muscular dystrophies. PMID- 21614633 TI - Using pH abnormalities in diseased skin to trigger and target topical therapy. AB - PURPOSE: The pH discrepancy between healthy and atopic dermatitis skin was identified as a site-specific trigger for delivering hydrocortisone from microcapsules. METHODS: Using Eudragit L100, a pH-responsive polymer which dissolves at pH 6, hydrocortisone-loaded microparticles were produced by oil-in oil microencapsulation or spray drying. Release and permeation of hydrocortisone from microparticles alone or in gels was assessed, and preliminary stability data was determined. RESULTS: Drug release from microparticles was pH-dependent, though the particles produced by spray drying also gave significant non-pH dependent burst release, resulting from their porous nature or from drug enrichment on the surface of these particles. This pH-responsive release was maintained upon incorporation of the oil-in-oil microparticles into Carbopol- and HPMC-based gel formulations. In vitro studies showed 4- to 5-fold higher drug permeation through porcine skin from the gels at pH 7 compared to pH 5. CONCLUSIONS: Permeation studies showed that the oil-in-oil-generated particles deliver essentially no drug at normal (intact) skin pH (5.0-5.5) but that delivery can be triggered and targeted to atopic dermatitis skin where the pH is elevated. The incorporation of these microparticles into Carbopol- and HPMC-based aqueous gel formulations demonstrated good stability and pH-responsive permeation into porcine skin. PMID- 21614634 TI - Stromal-derived factor-1 alpha-loaded PLGA microspheres for stem cell recruitment. AB - PURPOSE: Stromal-derived factor-1 alpha (SDF-1alpha) is a chemoattractant that has been investigated for treating various diseases, with the goal of recruiting endogenous stem cells to the site of injury. Biodegradable PLGA microspheres were investigated as a means to deliver SDF-1alpha in a sustained-release manner. METHODS: We encapsulated SDF-1alpha into biodegradable poly(lactide-co-glycolide) (PLGA) microspheres using a double-emulsion solvent extraction/evaporation technique. We varied several formulation parameters, characterized the in vitro release profile of SDF-1alpha and the size and morphology of microspheres, and determined the bioactivity of the released SDF-1alpha of stimulating migration of mesenchymal stem cells (MSCs). RESULTS: We found that microspheres fabricated using end-capped PLGA, BSA as an excipient, and low solvent volumes yielded a high encapsulation efficiency (>64%) and released SDF-1alpha over a >50-day timeframe. The released SDF-1alpha was bioactive and caused significant migration of MSCs throughout the duration of release from the microspheres. CONCLUSIONS: We have identified several variables that led to successful encapsulation of SDF 1alpha into PLGA microspheres. We envision that SDF-lalpha-loaded microspheres may serve as injectable sources of sustained-release chemokine for promoting the recruitment of endogenous stem cells to the site of injury. PMID- 21614635 TI - Theoretical analysis of interplay of therapeutic protein drug and circulating soluble target: temporal profiles of 'free' and 'total' drug and target. AB - PURPOSE: To systemically investigate, for a therapeutic protein with a circulating soluble target, how the interplay of target dynamics and drug pharmacokinetics defines the 'total' and 'free' drug and target temporal profiles. METHOD: By extending the established rapid-binding target-mediated drug disposition (TMDD) pharmacokinetic model to circulating soluble targets, the temporal profiles of 'total' and 'free' drug and target were simulated with varying binding affinity (K(D)), target baseline (R(ss)), target turnover, and drug dose level. Two sets of published experimental data were compared with the simulated results. RESULTS: Binding to a circulating soluble target could lead to a divergence of the 'free' drug from the 'total' drug. Simulations show this divergent magnitude determined by K(D) and R(ss), with the temporal profile being defined by target turnover and drug dose level. As divergence proceeds, starting at the distribution phase, 'free' drug would decline faster but eventually parallel 'total' drug at the terminal phase, giving rise to a steeper distribution phase and comparable terminal half-life, relative to the 'total' form. The model also allows for estimation of the dynamic change of 'total' and 'free' target in response to the treatment of a therapeutic protein drug, facilitating dose level and regimen design to achieve desired 'free' target suppression. Model predictions compared favorably with two sets of published experimental data. CONCLUSIONS: Theoretical analyses identified key variables governing the different temporal profiles of 'total' and 'free' drug and target. The rapid-binding TMDD model reasonably captured the features of the interplay of drug pharmacokinetics and target dynamics for two reported cases. PMID- 21614636 TI - Polymer micelles with hydrazone-ester dual linkers for tunable release of dexamethasone. AB - PURPOSE: To develop polymer micelles for the tunable release of Dexamethasone (DEX) in tumors. METHODS: DEX was conjugated to poly(ethylene glycol) poly(aspartate) block copolymers using hydrazone, ester, or hydrazone-ester dual linkers. Ketonic acids containing 3, 4, and 5 methylene groups were used as spacers to separate the dual linkers. Polymer micelles from the DEX-conjugated polymers were tested for drug release at different pH values and carboxylesterase activity levels. RESULTS: DLS measurements and (1)H-NMR analysis confirmed all DEX-loaded micelles were <100 nm with core-shell structure. Single linker micelles appeared unsuitable to release DEX preferentially in acidic tumor tissues. Hydrazone linkages between DEX and polymers were non-degradable at both pH 7.4 and 5.0. Ester linkages stable at pH 5.0 were unstable at pH 7.4. Hydrazone-ester dual linkers suppressed DEX release at pH 7.4 while accelerating drug release at pH 5.0. DEX release decreased at pH 5.0 as the length of ketonic acid increased but was independent of spacer length at pH 7.4. Dual linker micelles were stable in the presence of carboxylesterases, suggesting DEX release was primarily due to pH-dependent hydrolysis. CONCLUSION: Tunable release of DEX was achieved using pH-sensitive polymer micelles with hydrazone-ester dual linkers. PMID- 21614637 TI - Epithelial profiling of antibiotic controlled release respiratory formulations. AB - PURPOSE: Release profiles of two ciprofloxacin hydrochloride formulations for the treatment of respiratory infection were evaluated using different in vitro methodologies and characterised for aerosol performance and toxicity. METHODS: Spray-dried ciprofloxacin and ciprofloxacin spray-dried with polyvinyl alcohol as a controlled release (CR) agent at a 50:50 w/w ratio were formulated and physico chemically characterised. Aerosol performances were assessed in vitro using a liquid impinger. Drug release was performed using a modified Franz cell and a validated air interface Calu-3-modified twin stage impinger (TSI). Ciprofloxacin toxicity was also established in vitro. RESULTS: Both formulations had a similar size distribution, while CR ciprofloxacin had superior aerosol performance and stability. The release profiles showed the CR formulation to have a higher transport rate compared to ciprofloxacin alone in the cell model. Contrary results were observed using the diffusion cell. Results suggest that the air interface cell model provides a more physiologically relevant model than the modified Franz cell. Toxicity analysis showed that the lung epithelial cells could tolerate a wide range of ciprofloxacin concentrations. CONCLUSIONS: This study establishes that the in vitro modified TSI air interface Calu-3 model is capable of evaluating the fate of inhaled powder formulations. PMID- 21614638 TI - Severity of ICU-acquired pneumonia according to infectious microorganisms. AB - PURPOSE: To assess the severity of intensive care unit (ICU)-acquired pneumonia (ICUAP) according to the bacteria involved, classified into seven groups: third generation cephalosporin-resistant non-fermenting Gram-negative bacilli (resistant C3NF); sensitive C3NF; methicillin-resistant Staphylococcus aureus; methicillin-sensitive Staphylococcus aureus; extended-spectrum beta-lactamase producing Enterobacteriaceae; Enterobacteriaceae not producing extended-spectrum beta-lactamase; Haemophilus influenzae and Streptococcus pneumoniae. METHODS: Over a 4-year period, sequential organ failure assessment (SOFA) score was prospectively measured daily in 453 adult patients with ICUAP. ICUAP severity was evaluated by the severity of sepsis and by the occurrence of new organ dysfunctions or failures (OD/F) during ICUAP. RESULTS: Septic shock occurred in 21% of all cases of ICUAP. The occurrence of new OD/F during ICUAP was similar regardless of the identified microorganism. These new OD/F represented less than 11% of SOFAmax, defined as the sum of all OD/F occurring at any time during the ICU stay. There was a significant association between SOFApreICUAP, defined as the sum of all the OD/F occurring before ICUAP, and ICUAP severity. In the multivariate analysis, the type of bacteria was not a risk factor (RF) for occurrence of septic shock and mortality. Age and SOFApreICUAP were RF for the sepsis severity. The ICUAP severity was an RF for ICU mortality. CONCLUSIONS: ICUAP was responsible for a minor proportion of OD/F occurring during the ICU stay. Severity of ICUAP was related to clinical status prior to ICUAP, but not to the type of bacteria. ICU mortality depended on the severity of ICUAP. PMID- 21614639 TI - International expert statement on training standards for critical care ultrasonography. AB - Training in ultrasound techniques for intensive care medicine physicians should aim at achieving competencies in three main areas: (1) general critical care ultrasound (GCCUS), (2) "basic" critical care echocardiography (CCE), and (3) advanced CCE. A group of 29 experts representing the European Society of Intensive Care Medicine (ESICM) and 11 other critical care societies worldwide worked on a potential framework for organizing training adapted to each area of competence. This framework is mainly aimed at defining minimal requirements but is by no means rigid or restrictive: each training organization can be adapted according to resources available. There was 100% agreement among the participants that general critical care ultrasound and "basic" critical care echocardiography should be mandatory in the curriculum of intensive care unit (ICU) physicians. It is the role of each critical care society to support the implementation of training in GCCUS and basic CCE in its own country. PMID- 21614640 TI - Toward a generalized theory of the shift to retrieval in cognitive skill learning. AB - Prior research on cognitive skill learning has shown that algorithmic and direct memory retrieval strategies are not executed in parallel if the algorithm entails a series of long-term memory (LTM) retrieval steps (as in the case, for example, of mental arithmetic). This phenomenon has been hypothesized to reflect a bottleneck in LTM retrieval processes that forces a strategy choice during an early stage of processing. Here, we investigate simple perceptual-motor algorithms that involve no memory retrieval steps, a largely unexplored case in which parallel strategy execution models remain viable. Pronounced strategy interference was again observed, albeit interference that was different in important respects from that observed for LTM retrieval algorithms. It appears that neither parallel nor choice models, as developed to date, are sufficient as a generalized theory of this skill learning phenomenon. Issues central to the development of a more comprehensive theory are discussed. PMID- 21614642 TI - Quantitative single-cell gene expression measurements of multiple genes in response to hypoxia treatment. AB - Cell-to-cell heterogeneity in gene transcription plays a central role in a variety of vital cell processes. To quantify gene expression heterogeneity patterns among cells and to determine their biological significance, methods to measure gene expression levels at the single-cell level are highly needed. We report an experimental technique based on the DNA-intercalating fluorescent dye SYBR green for quantitative expression level analysis of up to ten selected genes in single mammalian cells. The method features a two-step procedure consisting of a step to isolate RNA from a single mammalian cell, synthesize cDNA from it, and a qPCR step. We applied the method to cell populations exposed to hypoxia, quantifying expression levels of seven different genes spanning a wide dynamic range of expression in randomly picked single cells. In the experiment, 72 single Barrett's esophageal epithelial (CP-A) cells, 36 grown under normal physiological conditions (controls) and 36 exposed to hypoxia for 30 min, were randomly collected and used for measuring the expression levels of 28S rRNA, PRKAA1, GAPDH, Angptl4, MT3, PTGES, and VEGFA genes. The results demonstrate that the method is sensitive enough to measure alterations in gene expression at the single-cell level, clearly showing heterogeneity within a cell population. We present technical details of the method development and implementation, and experimental results obtained by use of the procedure. We expect the advantages of this technique will facilitate further developments and advances in the field of single-cell gene expression profiling on a nanotechnological scale, and eventually as a tool for future point-of-care medical applications. PMID- 21614641 TI - Further insights into the characterization of equine adipose tissue-derived mesenchymal stem cells. AB - Adipose tissue-derived stem cells (ADSCs) represent a promising subpopulation of adult stem cells for tissue engineering applications in veterinary medicine. In this study we focused on the morphological and molecular biological properties of the ADSCs. The expression of stem cell markers Oct4, Nanog and the surface markers CD90 and CD105 were detected using RT-PCR. ADSCs showed a proliferative potential and were capable of adipogenic and osteogenic differentiation. Expression of Alkaline phosphatase (AP), phosphoprotein (SPP1), Runx2 and osteocalcin (OC) mRNA were positive in osteogenic lineages and peroxisome proliferator activated receptor (Ppargamma2) mRNA was positive in adipogenic lineages. ADSCs show stem cell and surface marker profiles and differentiation characteristics that are similar to but distinct from other adult stem cells, such as bone marrow-derived mesenchymal stem cells (BM-MSCs). The availability of an easily accessible and reproducible cell source may greatly facilitate the development of stem cell based tissue engineering and therapies for regenerative equine medicine. PMID- 21614643 TI - COP9 signalosome subunit 7 from Arabidopsis interacts with and regulates the small subunit of ribonucleotide reductase (RNR2). AB - The COP9 Signalosome protein complex (CSN) is a pleiotropic regulator of plant development and contains eight-subunits. Six of these subunits contain the PCI motif which mediates specific protein interactions necessary for the integrity of the complex. COP9 complex subunit 7 (CSN7) contains an N-terminal PCI motif followed by a C-terminal extension which is also necessary for CSN function. A yeast-interaction trap assay identified the small subunit of ribonucelotide reductase (RNR2) from Arabidopsis as interacting with the C-terminal section of CSN7. This interaction was confirmed in planta by both bimolecular fluorescence complementation and immuoprecipitation assays with endogenous proteins. The subcellular localization of RNR2 was primarily nuclear in meristematic regions, and cytoplasmic in adult cells. RNR2 was constitutively nuclear in csn7 mutant seedlings, and was also primarily nuclear in wild type seedlings following exposure to UV-C. These two results correlate with constitutive expression of several DNA-damage response genes in csn7 mutants, and to increased tolerance of csn7 seedlings to UV-C treatment. We propose that the CSN is a negative regulator of RNR activity in Arabidopsis. PMID- 21614644 TI - Genome-wide comparison of two poplar genotypes with different growth rates. AB - The ecologically dominant and economically important genus Populus, with its available full genome sequence, has become an ideal woody species for genomic study. Rapid growth is one of the primary advantageous features of Populus, and extensive physiological research has been carried out on the growth of Populus throughout the growing period among different clones. However, the molecular information related to the mechanisms of rapid growth is rather limited. In this study, an Affymetrix poplar genome array was employed to analyze the transcriptomic changes from the pre-growth to the fast-growth phase in two poplar clones (P.deltoides * P.nigra, DN2, and P.nigra * (P.deltoides * P. nigra), NE19) with different growth rates. A total of 1,695 differently expressed genes were identified between two time points in NE19 and DN2 (two-way ANOVA, P < 0.01 and fold change >=2). Except for genes changing in common for both clones, many transcripts were regulated specifically in one genotype. After functional analysis of the differentially expressed genes, distinct biological strategies seemed to be utilized by the two genotypes to accommodate their fast-growth phase. The faster-growing clone NE19, which has a higher photosynthetic rate and larger total leaf area, emphasized growth-related primary metabolism. However, the slower-growing DN2 tended to have more up-regulated genes involved in defense related secondary metabolism and stress response. Emphasis of such divergent biological processes in two clones may explain their significant growth differences during the fast-growth phase. PMID- 21614645 TI - Ultrasound-guided aspiration of symptomatic intraneural ganglion cyst within the tibial nerve. PMID- 21614646 TI - Dietary n-3 fatty acids significantly suppress lipogenesis in bovine muscle and adipose tissue: a functional genomics approach. AB - Changes in fatty acid composition of longissimus muscle and subcutaneous adipose tissue of German Holstein bulls induced by a grass-silage/n-3 fatty acid based intervention diet versus a maize-silage/n-6 fatty acid based control diet were analyzed and related to shifts in lipogenic gene expression, protein expression, and enzyme activity patterns. Significantly higher amounts of n-3 fatty acids and by mean factors of 2.2-2.5 decreased n-6/n-3 fatty acid ratios in both tissues were obtained upon n-3 fatty acid intervention. In longissimus muscle, these changes of fatty acid profiles were associated with reduced SREBP1c (p = 0.02), ACC (p = 0.00), FAS (p = 0.10) and SCD (p = 0.03) gene expression, Delta6D (p = 0.03) and SCD (p = 0.03) protein expression as well as SCD enzyme activity (p = 0.03). In subcutaneous adipose tissue, significantly reduced ACC (p = 0.00) and FAS (p = 0.01) gene expression, SCD protein expression (p = 0.02) and SCD enzyme activity (p = 0.03) were detected upon n-3 fatty acid intervention, although lower degrees of correlation between gene and corresponding gene products were obtained in relation to longissimus muscle. The study elucidates tissue-specific functional genomic responses to dietary fatty acid manipulation in regard to fatty acid profile tailoring of animal tissues. PMID- 21614647 TI - Vaccenic and elaidic acid equally esterify into triacylglycerols, but differently into phospholipids of fed rat liver cells. AB - Elaidic acid (trans-9-C18:1 or trans-9) is assumed to exert atherogenic effects due to its double bond configuration. The possibility that trans-9 and vaccenic acid (trans-11-C18:1 or trans-11), its positional isomer, were biochemically equivalent and interchangeable compounds, was investigated by reference to their cis-isomers through esterification-related activities using rat liver cells and subcellular fractions. In hepatocytes, both trans-C18:1 were incorporated to the same extent in triacylglycerols, but trans-9 was more esterified than trans-11 into phospholipids (P < 0.05). Glycerol-3-phosphate acyltransferase activity in microsomes was lower with trans-11 than with trans-9, while this activity in mitochondria was ~40% greater with trans-11 than with trans-9 (P < 0.05). Activity of 2-lysophosphatidic acid acyltransferase in microsomes was of comparable extent with both trans isomers, but activity of 2 lysophosphatidylcholine acyltransferase was significantly greater with trans-9 than with trans-11 at P < 0.01. Lipoproteins secreted by hepatocytes reached equivalent levels in the presence of any isomers, but triacylglycerol production was more elevated with trans-11 than with trans-9 at P < 0.05. Cholesterol efflux from previously labelled hepatocytes was lower with trans-11 than with trans-9. When these cells were exposed to either trans-C18:1, the gene expression of proteins involved in fatty acid esterification and lipoprotein synthesis was unaffected, which indicates that the biochemical differences essentially depended on enzyme/substrate affinities. On the whole, vaccenic and elaidic acid were shown to incorporate cell phospholipids unequally, at least in vitro, which suggests they can differently affect lipid metabolic pathways in normal cells. PMID- 21614648 TI - [Management of salivary gland diseases with contrast-enhanced ultrasound]. AB - Obstructive diseases of the salivary glands are a common problem in otorhinolaryngology. They are mostly due to sialolithiasis followed by duct stenosis and other rarer causes. Several diagnostic modalities exist which allow classification of the disease; however, in 5-10% of all cases ultrasound and conventional radiological imaging do not provide a clear diagnosis. Ultrasound examination with contrast material injected into the duct (IA-CEUS, intraductal administered contrast-enhanced ultrasound) enables improved evaluation of obstructive diseases of the salivary glands and at the same time an evaluation of the parenchyma of the glands is possible. As a complementary method to conventional investigation techniques IA-CEUS is an economic and rapid method with low side-effects which improves the diagnostic assessment of ultrasound and results in a better treatment for patients. PMID- 21614649 TI - An integrated framework to quantitatively link mouse-specific hemodynamics to aneurysm formation in angiotensin II-infused ApoE -/- mice. AB - Locally disturbed flow has been suggested to play a (modulating) role in abdominal aortic aneurysm (AAA) formation, but no longitudinal studies have been performed yet due to (a.o.) a lack of human data prior to AAA formation. In this study we made use of recent advances in small animal imaging technology in order to set up entirely mouse-specific computational fluid dynamics (CFD) simulations of the abdominal aorta in an established ApoE -/- mouse model of AAA formation, combining (i) in vivo contrast-enhanced micro-CT scans (geometrical model) and (ii) in vivo high-frequency ultrasound scans (boundary conditions). Resulting areas of disturbed flow at baseline were compared to areas of AAA at end-stage. Qualitative results showed that AAA dimension is maximal in areas that are situated proximal to those areas that experience most disturbed flow in three out of four S developing an AAA. Although further quantitative analysis did not reveal any obvious relationship between areas that experience most disturbed flow and the end-stage AAA dimensions, we cannot exclude that hemodynamics play a role in the initial phases of AAA formation. Due to its mouse-specific and in vivo nature, the presented methodology can be used in future research to link detailed and animal-specific (baseline) hemodynamics to (end-stage) arterial disease in longitudinal studies in mice. PMID- 21614650 TI - Effects of gender-specific adult bovine serum on myogenic satellite cell proliferation, differentiation and lipid accumulation. AB - The study was performed to explore the effects of adult bovine male serum (MS), female serum (FS), and castrated male serum (C-MS) on myogenic satellite cells (MSCs) proliferation and differentiation into myotubes or into adipocyte-like cells (ALCs). MSC proliferation and differentiation was highest in the medium supplemented with MS, implying the important role of male steroid hormones. Myogenin and desmin were highly upregulated in cells cultured in MS-supplemented medium. In contrast, lipid accumulation in ALCs was highest in the medium supplemented with FS. Fatty acid transporter (FAT/CD36) was upregulated in FS supplemented cultures. Detection of higher FAT/CD36 inducing fatty acids (arachidic acid and eicosapentaenoic acid) in FS compared with MS and C-MS suggests that these fatty acids may have influenced the enhanced formation of lipid droplets in ALCs. Effect of sex steroids on cell proliferation and cell growth of bovine MSCs and C2C12 cell in C-MS was greater than charcoal-dextran treated fetal bovine serum (CDFBS). Concluding the above facts, the results indicate that each gender-specific bovine serum constitutes of different component, which leads to unique effects on cell behavior. PMID- 21614651 TI - Upregulation of E2F1 in cerebellar neuroprogenitor cells and cell cycle arrest during postnatal brain development. AB - In the developing cerebellum, proliferation of granular neuroprogenitor (GNP) cells lasts until the early postnatal stages when terminal maturation of the cerebellar cortex occurs. GNPs are considered cell targets for neoplastic transformation, and disturbances in cerebellar GNP cell proliferation may contribute to the development of pediatric medulloblastoma. At the molecular level, proliferation of GNPs is regulated through an orchestrated action of the SHH, NOTCH, and WNT pathways, but the underlying mechanisms still need to be dissected. Here, we report that expression of the E2F1 transcription factor in rat GNPs is inversely correlated with cell proliferation rate during postnatal development, as opposed to its traditional SHH-dependent induction of cell cycle. Proliferation of GNPs peaked at postnatal day 3 (P3), with a subsequent continuing decrease in proliferation rates occurring until P12. Such gradual decline in proliferating neuroprogenitors paralleled the extent of cerebellum maturation confirmed by histological analysis with cresyl violet staining and temporal expression profiling of SHH, NOTCH2, and WNT4 genes. A time course analysis of E2F1 expression in GNPs revealed significantly increased levels at P12, correlating with decreased cell proliferation. Expression of the cell cycle inhibitor p18 ( Ink4c ), a target of E2F1, was also significantly higher at P12. Conversely, increased E2F1 expression did not correlate with either SMAC/DIABLO and BCL2 expression profiles or apoptosis of cerebellar cells. Altogether, these results suggest that E2F1 may also be involved in the inhibition of GNP proliferation during rat postnatal development despite its conventional mitogenic effects. PMID- 21614652 TI - Adult-type myogenesis of the frog Xenopus laevis specifically suppressed by notochord cells but promoted by spinal cord cells in vitro. AB - Larval-to-adult myogenic conversion occurs in the dorsal muscle but not in the tail muscle during Xenopus laevis metamorphosis. To know the mechanism for tail specific suppression of adult myogenesis, response character was compared between adult myogenic cells (Ad-cells) and larval tail myogenic cells (La-cells) to a Sonic hedgehog (Shh) inhibitor, notochord (Nc) cells, and spinal cord (SC) cells in vitro. Cyclopamine, an Shh inhibitor, suppressed the differentiation of cultured Ad (but not La) cells, suggesting the significance of Shh signaling in promoting adult myogenesis. To test the possibility that Shh-producing axial elements (notochord and spinal cord) regulate adult myogenesis, Ad-cells or La cells were co-cultured with Nc or SC cells. The results showed that differentiation of Ad-cells were strongly inhibited by Nc cells but promoted by SC cells. If Ad-cells were "separately" co-cultured with Nc cells without direct cell-cell interactions, adult differentiation was not inhibited but rather promoted, suggesting that Nc cells have two roles, one is a short-range suppression and another is a long-range promotion for adult myogenesis. Immunohistochemical analysis showed both notochord and spinal cord express the N terminal Shh fragment throughout metamorphosis. The "spinal cord-promotion" and long-range effect by Nc cells on adult myogenesis is thus involved in Shh signaling, while the signaling concerning the short-range "Nc suppression" will be determined by future studies. Interestingly, these effects, "Nc suppression" and "SC promotion" were not observed for La-cells. Situation where the spinal cord/notochord cross-sectional ratio is quite larger in tadpole trunk than in the tail seems to contribute to trunk-specific promotion and tail-specific suppression of adult myogenesis during Xenopus metamorphosis. PMID- 21614654 TI - Comparison between different cost devices for digital capture of X-ray films: an image characteristics detection approach. AB - A common teleradiology practice is digitizing films. The costs of specialized digitizers are very high, that is why there is a trend to use conventional scanners and digital cameras. Statistical clinical studies are required to determine the accuracy of these devices, which are very difficult to carry out. The purpose of this study was to compare three capture devices in terms of their capacity to detect several image characteristics. Spatial resolution, contrast, gray levels, and geometric deformation were compared for a specialized digitizer ICR (US$ 15,000), a conventional scanner UMAX (US$ 1,800), and a digital camera LUMIX (US$ 450, but require an additional support system and a light box for about US$ 400). Test patterns printed in films were used. The results detected gray levels lower than real values for all three devices; acceptable contrast and low geometric deformation with three devices. All three devices are appropriate solutions, but a digital camera requires more operator training and more settings. PMID- 21614653 TI - Evaluating differentiation propensity of in-house derived human embryonic stem cell lines KIND-1 and KIND-2. AB - Human embryonic stem (hES) cells possess the ability to self-renew indefinitely and provide a potential source of differentiated progeny representing all three embryonic germ layers. Although hES cell lines share the expression of typical pluripotency markers, limited data is available regarding their differentiation capabilities. We have earlier reported the in-house derivation of two hES cell lines, KIND-1 and KIND-2 on human feeders. Here, we describe a comparative study carried out on both these cell lines to better understand the differentiation potential of KIND-1 and KIND-2 by gene expression analysis of representative gene transcripts reflecting pluripotency and the three germ layers viz. ectoderm, mesoderm, and endoderm. Gene expression analysis and immunolocalization studies were undertaken on (a) 7- and 14-d old embryoid bodies (EBs) (b) spontaneously differentiated cells from EBs, (c) cells derived from EBs under the influence of various growth factor treatments and (d) KIND-1 and KIND-2 cells co-cultured on mouse embryonic visceral endoderm-like feeder (END-2). Despite both the cell lines being XX, derived, passaged, and cultured similarly, KIND-1 exhibits preferential differentiation towards endodermal lineage whereas KIND-2 spontaneously forms beating cardiomyocytes. Perhaps the occurrence of discrete epigenetic profile in both the cell lines predisposes them to encompass different developmental potential in vitro. Our data provide evidence for existence of distinct differentiation propensity among hES cell lines and emphasizes the need to derive more hES cell lines for future regenerative medicine. PMID- 21614656 TI - Reduction mammaplasty in a developing country: a guideline for plastic surgeons for patient selection. AB - BACKGROUND: In Ghana and most developing countries there has been no standardized study of reduction mammaplasty (RM) in patients with symptomatic macromastia (SM), despite its debilitating effects. This study aimed to analyze the physical and psychological effects associated with female patients who underwent reduction mammaplasty and to develop a guideline for plastic surgeons in developing countries to know the most important signs and symptoms to consider in SM patients. METHODS: From 2003 to 2009, all females with SM who visited Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ghana, for RM were given a questionnaire designed to evaluate SM-related physical and psychological effects. These patients were then provided the same questionnaire at their final visit 5 months postoperatively to assess the effects of RM on SM. RESULTS: Sixty-three patients who underwent RM were evaluated, with a mean age of 28.5 years. Twenty seven (42.9%) patients reported that their macromastia started during puberty, with 3 (4.8%) patients associating the onset with pregnancy. Thirty (47.6%) patients reported having SM for more than 10 years. Multiple regression analysis revealed upper- and lower-back pain (p=0.0005), painful bra strap grooves (p=0.0041), teasing (p=0.01), and poor self-image (p=0.021) to be significant factors for which patients underwent RM. Postoperatively, most of the patients' physical symptoms resolved, while 2 (3.2%) patients complained of residual psychological effects. CONCLUSION: RM offers substantial symptomatic relief for patients with SM and results in significant improvement in the patient's quality of life. This study conclusively demonstrates that, upper- and lower-back pain, painful bra strap grooves, teasing, and poor self-image should be considered by plastic surgeons before deciding which SM patient to treat when confronted with numerous SM patients. PMID- 21614655 TI - UGT2B17 gene deletion associated with an increase in bone mineral density similar to the effect of hormone replacement in postmenopausal women. AB - UGT2B17 is one of the most important enzymes for androgen metabolism. In addition, the UGT2B17 gene is one of the most commonly deleted regions of the human genome. The deletion was previously found associated with higher femoral bone density in men and women, and we replicated this association in a sample of postmenopausal who never used hormone therapy. INTRODUCTION: Deletion of the UGT2B17 gene was previously shown to be associated with a higher hip bone mineral density (BMD). Using a PCR assay, we tried to replicate the association among a large group of 2,379 women. We examined the effect of the deletion on femoral neck BMD and lumbar spine BMD according to the menopausal status and hormone replacement therapy (HRT). METHODS: We used a high-throughput PCR assay to identify the gene and the deletion in a population of well-characterized women. Two additional polymorphisms, UGT2B28 deletion and UGT2B15 rs1902023 G > T were also investigated. RESULTS: Only UGT2B17 deletion was associated with LS and FN BMD. Furthermore, the association was seen only among postmenopausal women who had never used hormone replacement as in the first reported association. CONCLUSIONS: We confirmed the association between UGT2B17 deletion and a higher LS and FN BMD. In addition, we show that the association is observed among postmenopausal women who never used HRT consistent with the enzymatic function of UGT2B17. The analysis shows that those having one or two UGT2B17 alleles benefit from HRT, which is not the case for null carriers. PMID- 21614657 TI - Umbilical epithelial cyst in secondary abdominoplasty: case report. AB - BACKGROUND: A retained epidermal inclusion cyst (REIC) at the umbilicus after abdominoplasty is a rare phenomenon that has had limited description in the literature. This case report describes a woman who came for a secondary abdominoplasty and presented intraoperatively with an unexpected large epidermal inclusion cyst. CASE REPORT: The woman was disappointed with the result of a previous abdominal surgery. She initially had severe postoperative wound infection followed by revision surgery and subsequent intermittent secretion in the umbilical region. Then seven years later, hip backplasty combined with liposuction was performed. After another six months, full abdominoplasty combined with exploration of the umbilical region was performed. The surgical exploration showed a large, 3*4.5 cm indurated structure highly suspected to be a REIC. The excision was effective without recurrence, and the healing was uneventful. The patient was very satisfied with the result. DISCUSSION: As a typical epidermoid cyst, REIC consists of squamosed stratified epithelial cells that continue to the granular layer. In most cases, the cyst is filled with a keratin-like material. When this tumor is solid, a histologic evaluation may be necessary. When the cyst has been excised, the umbilicus gets reconstructed after the abdominoplasty. A history of poor healing in the umbilicus area may arouse suspicion of an epidermoid cyst. Epidermoid cysts in the region of the umbilicus could easily be overlooked in preparation of the umbilicus. PMID- 21614658 TI - Gluteal contour improvement: different surgical alternatives. AB - BACKGROUND: Surgical techniques to achieve improvement in buttocks contour have evolved dramatically. The authors present their experience with the different techniques and indications they use to achieve improvement in this region. METHODS: This study reviewed the surgical procedures performed by the senior author over a 15-year period among patients seeking improvement of the gluteal region. Procedures were analyzed according to the characteristics and needs of each patient, and the resulting levels of patient satisfaction were evaluated. RESULTS: From April 1995 to March 2010, 908 patients (862 women and 46 men) ages 18-61 years requested and underwent surgery for gluteal contour improvement. The surgical procedures were liposuction with lipoinjection for 811 patients (89.3%); liposuction with gluteal implants for 62 patients (6.8%); liposuction with gluteal implants and lipoinjection to the hips for 22 patients (2.4%); liposuction, gluteal implants, and a buttock-lift for 7 patients (0.7%); and liposuction, gluteal implants, lipoinjection, and a buttock-lift for 6 patients (0.6%). The volume of infiltrated fat ranged from 120 to 1,160 ml per buttock, with an average of 380 ml per buttock. The implants used ranged from 250 to 450 ml (average, 325 ml). CONCLUSIONS: Surgery performed with the goal of gluteal contour improvement is detailed and demanding with respect to the multiple and diverse techniques. The proper selection of these procedures and their order are paramount to achieving a successful outcome for both the patient and the surgeon. PMID- 21614659 TI - Influence of age and body mass index on the yield and proliferation capacity of adipose-derived stem cells. AB - BACKGROUND: Adipose tissue is commonly used for volume restoration. It is also a source of adipose-derived stem cells (ASCs), easy to obtain in large quantities by liposuction or resection techniques. The aim of this study was to determine the influence of body mass index (BMI) and age on the number (yield) and proliferation capacity of ASCs. METHODS: A prospective study was conducted in 42 women. They were divided into two groups: age <= 40 or >40 and BMI <= 25 or >25. Fat tissue was harvested via manual lipoaspiration always from the abdominal region. After centrifugation in the OR, the harvested fat (100 cc) was sent to the laboratory for isolation and cultivation of ASCs. The yield of viable ASCs was evaluated by the trypan blue exclusion test. Viable ASCs were cultured and their proliferation capacity was evaluated by the growth kinetics assay. Results were statistically analyzed. RESULTS: The average cell yield was 0.380 * 10(6)/ml. Cell yield and proliferation capacity did not show statistically significant correlation to the age and BMI of patients, with regression lines showing null correlation. There was no significant difference between the cell yield and proliferation capacity between the different groups. CONCLUSION: The results from this study suggest that there is no statistically significant correlation between ASC yield and proliferation capacity and age and BMI. PMID- 21614660 TI - Correction of capsular contracture by insertion of a breast prosthesis anterior to the original capsule and preservation of the contracted capsule: technique and outcomes. AB - BACKGROUND: This study aimed to explore the treatment of capsular contracture after augmentation mammaplasty by insertion of a breast prosthesis anterior to the original capsule. METHODS: Through transaxillary or submammary incisions and small capsular incisions, 14 patients (18 breasts) with Baker grades 3 and 4 capsular contractures had their breast implants removed and repositioned anterior to the primary capsule. The primary capsules were preserved. RESULTS: Satisfactory results (Baker 1) were achieved for all 14 patients during the 29 month follow-up period. CONCLUSION: The described method offers numerous advantages for the treatment of capsular contracture. It is minimally invasive and performed through a small axillary or submammary incision. It is simple, offers little trauma, has less bleeding, and results in a good outcome based on our follow-up assessment in the medium term. It is our preferred method for the treatment of capsular contracture. PMID- 21614661 TI - A model for removing the increased recall of recent events from the temporal distribution of autobiographical memory. AB - The reminiscence bump is the tendency to recall relatively many personal events from the period in which the individual was between 10 and 30 years old. This effect has only been found in autobiographical memory studies that used participants who were older than 40 years of age. The increased recall of recent events possibly obscures the reminiscence bump in the results of younger participants. In this study, a model was proposed that removes the increase for recent events from the temporal distribution. The model basically estimates a retention function based on the 10 most recent years from the observed distributions and divides the observed distributions by predictions derived from the estimated retention function. The model was examined with three simulated data sets and one experimental data set. The results of the experiment offered two practical examples of how the model could be used to investigate the temporal distribution of autobiographical memories. PMID- 21614662 TI - A simple framework (ASF) for behavioral and neuroimaging experiments based on the psychophysics toolbox for MATLAB. AB - The cognitive neurosciences combine behavioral experiments with acquiring physiological data from different modalities, such as electroencephalography, magnetoencephalography, transcranial magnetic stimulation, and functional magnetic resonance imaging, all of which require excellent timing. A simple framework is proposed in which uni- and multimodal experiments can be conducted with minimal adjustments when one switches between modalities. The framework allows the beginner to quickly become productive and the expert to be flexible and not constrained by the tool by building on existing software such as MATLAB and the Psychophysics Toolbox, which already are serving a large community. The framework allows running standard experiments but also supports and facilitates exciting new possibilities for real-time neuroimaging and state-dependent stimulation. PMID- 21614664 TI - Pelvic dimensions as a predictor of difficulty in laparoscopic surgery for rectal cancer. PMID- 21614663 TI - Similarities in early course among men and women with a first episode of schizophrenia and schizophreniform disorder. AB - The aims of this study were to analyze the presence of gender differences in the phenotypic expression of schizophrenia at the onset of illness and to explore whether these differences determine clinical and functional outcome 2 years after the initiation of treatment. Data from 231 first-episode-psychosis non-substance dependent patients (156 men and 75 women) participating in a large-scale naturalistic open-label trial with risperidone were recorded at inclusion and months 1, 6, 12, and 24. Men presented a significant earlier age of onset (24.89 years vs. 29.01 years in women), poorer premorbid functioning, and a higher presence of prodromal and baseline negative symptoms. Women were more frequently married or lived with their partner and children and more frequently presented acute stress during the year previous to onset than men. No other significant clinical or functional differences were detected at baseline. The mean dose of antipsychotic treatment was similar for both genders during the study, and no significant differences in UKU scores were found. The number of hospitalizations was similar between groups, and adherence was more frequent among women. At the 2 year follow-up, both groups obtained significant improvements in outcome measures: PANSS, CGI severity, and GAF scores. Significant gender * time interactions were detected for negative and general PANSS subscales, with the improvement being more pronounced for men. However, no differences were detected for the mean scores obtained during the study in any outcome measure, and the final profile was similar for men and women. Our results suggest that although the initial presentation of schizophrenia can differ according to gender, these differences are not sufficient enough to determine differentiated outcome 2 years after the initiation of treatment in non-substance-dependent patients. The influence of gender on the early course of schizophrenia does not seem to be clinically or functionally decisive in this population. PMID- 21614665 TI - Mastery versus the standard proficiency target for basic laparoscopic skill training: effect on skill transfer and retention. AB - BACKGROUND: Little evidence exists to guide educators in the best way to implement simulation within surgical skills curricula. This study investigated whether practicing a basic Fundamentals of Laparoscopic Surgery (FLS) simulator task [peg transfer (PT)] facilitates learning a more complex skill [intracorporeal suturing (ICS)] and compared the effect of PT training to mastery with training to the passing level on PT retention and on learning ICS. METHODS: For this study, 98 surgically naive subjects were randomized to one of three PT training groups: control, standard training, and overtraining. All the participants then trained in ICS. The learning curves for ICS were analyzed by estimating the learning plateau and rate using nonlinear regression. Skill retention was assessed by retesting participants 1 month after training. The groups were compared using analysis of variance (ANOVA). Effectiveness of skill transfer was calculated using the transfer effectiveness ratio (TER). Data are presented as mean+/-standard deviation (p<0.05). RESULTS: The study was completed by 77 participants (28 control, 26 standard, and 23 overtrained subjects). The ICS learning plateau rose with increasing PT training (452+/-10 vs. 459+/-10 vs. 467+/-10; p<0.01). Increased PT training was associated with a trend toward higher initial ICS scores (128+/-107 vs. 127+/-110 vs. 183+/-106; p=0.13) and faster learning rates (15+/-4 vs. 14+/-4 vs. 13+/-4 trials; p=0.10). At retention, there were no differences in PT scores (p=0.5). The PT training took 20+/-10 min for standard training and 39+/-20 min for overtraining (p<0.01). Overtrained participants saved 11+/-5 min in ICS training compared with the control subjects (p=0.04). However, TER was 0.165 for the overtraining group and 0.160 for the standard training group, suggesting that PT overtraining took longer than the time saved on ICS training. CONCLUSION: For surgically naive subjects, part-task training with PT alone was associated with slight improvements in the learning curve for ICS. However, overtraining with PT did not improve skill retention, and peg training alone was not an efficient strategy for learning ICS. PMID- 21614666 TI - Laparoscopic resection of the uncinate process of the pancreas: the inframesocolic approach and hanging maneuver of the mesenteric root. AB - BACKGROUND: Laparoscopic pancreatic procedures have increased in recent years. However, only a single case of laparoscopic uncinatectomy has been reported to date, performed through an anterior approach. This video presents a hitherto undescribed laparoscopic inframesocolic approach and also an undescribed maneuver to expose the uncinate process. METHODS: A 39-year-old women had a 16-mm insulinoma in the uncinate pancreas. The patient was placed in the supine position with legs apart. A 30o, 5-mm optic was used, and only a 12-mm trocar was needed. The first maneuver moved the major omentum and transverse colon upward to expose the mesenteric root. The duodenum was identified through the peritoneal sheath and mobilized. The superior mesenteric vein was identified and carefully exposed in the vicinity of the uncinate pancreas. To improve the exposure for the uncinatectomy, a hanging maneuver of the mesenteric root was performed with cotton tape. Intraoperative ultrasound identified the tumor and defined the limits of the resection. An inferior pancreaticoduodenal vein was sectioned between clips, and the uncinate process was dissected from the retropancreatic fascia. The transection was performed with a reinforced endostapler. The specimen was dragged into a bag and removed through the 12-mm orifice, which did not have to be enlarged. No drain was left. RESULTS: The patient was discharged on postoperative day 3. No early or late surgical complications were observed. At this writing 1 year after the procedure, the patient has lost 35 kg and shows a normal body mass index. She remains asymptomatic with normal blood sugar levels. CONCLUSION: Laparoscopic resection of the uncinate process of the pancreas is feasible and safe. The inframesocolic approach is easy to perform and achieves an optimal exposure that is improved with a hanging maneuver of the mesenteric root. PMID- 21614667 TI - Robotic-assisted Roux-en-Y gastric bypass performed in a community hospital setting: the future of bariatric surgery? AB - INTRODUCTION: Since receiving Food and Drug Administration approval in 2000, surgery utilizing a robot has been successfully performed in numerous procedures including gastric bypass. However, despite the proven safety profile, reported lower complication rates, and technical benefits of robotic surgery, only a few centers in the USA have consistently applied this technology to bariatric surgery. In addition, there are limited studies with relatively small sample sizes comparing robotic-assisted Roux-en-Y gastric bypass (RRYGB) with laparoscopic Roux-en-Y gastric bypass (LRYGB). METHODS: Through a retrospective analysis of our database, we compared outcomes of RRYGB versus LRYGB in the treatment of morbid obesity. All patients who underwent RRYGB and LRYGB through the Comprehensive Weight Management Program of the Queen's Medical Center (Honolulu, HI) from January 2007 to December 2009 were included. Outcomes data included weight loss, operative times, and hospital length of stay. All complications were reported. RESULTS: 105 patients who underwent RRYGB were compared with 195 patients who received LRYGB. Excess weight loss, estimated blood loss, and length of hospital stay were similar in both groups. There were no mortalities in either group. The RRYGB group experienced a 9.5% complication rate versus 9.7% in LRYGB patients. Operative time was the only statistically significant difference, being approximately 17 min in favor of LRYGB. However, there was a steady decrease in RRYGB operative time with increasing experience. CONCLUSION: Our study demonstrates a favorable safety profile with nearly equivalent outcomes and some previously unidentified qualitative benefits of the RRYGB approach to bariatric surgery in a community setting. These results are despite our early experience with the robotic surgery platform and confirm noninferiority of RRYGB versus LRYGB. While the RRYGB operative time was longer than LRYGB, the demonstrated decrease in operative time commensurate with increase in operative experience holds tremendous promise for the future. PMID- 21614668 TI - Repeat dosing of rocuronium after reversal of neuromuscular block by sugammadex. PMID- 21614669 TI - Prolonged toxicity after amitriptyline overdose in a patient deficient in CYP2D6 activity. AB - INTRODUCTION: Amitriptyline and its metabolite, nortriptyline, are metabolized, in part, by CYP2D6, a polymorphic enzyme. About 8% of Caucasians are deficient in CYP2D6 activity. CASE REPORT: We present the case of a comatose woman who intentionally overdosed on amitriptyline and displayed rising serum total tricyclic antidepressant concentrations for at least 6 days after admission. Serial immunoassay total tricyclic antidepressant concentrations in our patient showed gradual decline beginning day 7, although the patient did not regain normal mental status until day 12. Genotyping revealed the patient to be homozygous for the CYP2D6*4 allele, the most common explanation of CYP2D6 enzymatic deficiency among Caucasians. Patients taking tricyclic antidepressants who are homozygous for CYP2D6*4 demonstrate >3 times concentration-time curve (AUCs) and prolonged elimination half-lives, especially of secondary amines such as nortriptyline. DISCUSSION: We believe this is the first report describing toxicokinetics after tricyclic antidepressant overdose in a CYP2D6-deficient patient. PMID- 21614670 TI - Decisions for lung cancer chemotherapy: the influence of physician and patient factors. AB - PURPOSE: The purpose of this study is to review the literature examining how the beliefs and behaviours of physicians and patients influence clinical communication, doctor-patient interaction and treatment decisions for lung cancer treatment. METHODS: Literature was obtained via electronic database searches and hand searching of journals from 1990 to 2011. RESULTS: Wide variability in perceptions of the value of chemotherapy in lung cancer is present among both physicians and patients. There is a mismatch in the degree patients and physicians weigh survival, such that patients value survival benefits highly whilst physicians strongly emphasize toxicity and associated symptoms. This lack of congruence between patients and clinicians is influenced by a range of factors and has implications for treatment decisions, long-term survival and quality of life in people affected by lung cancer. CONCLUSION: The divergence of treatment priorities indicates a need for improved communication strategies addressing the needs and concerns of both patients and clinicians. Patients should understand the benefits and risks of treatment options, while clinicians can gain a greater awareness of factors influencing patients' decisions on treatments. Reflecting these perspectives and patient preferences for lung cancer treatment in clinical guidelines may improve clinician awareness. PMID- 21614671 TI - Unusual hematogenous brain metastasis in malignant fibrous histiocytoma of the maxillary sinus. AB - Malignant fibrous histocytoma (MFH) of the maxillary sinus is believed to be a rare form of soft tissue sarcoma with a low frequency of distant metastasis. In this study, we provide a histological documentation of the hematogenous spread of MFH to the brain and report a case of maxillary sinus MFH with unusual metastasis to the brain. To our knowledge, this is the first case of a direct histological diagnosis of maxillary sinus MFH with brain metastasis via a hematogenous route. PMID- 21614673 TI - Cerebral aneurysms database, a new free database for intracranial aneurysms. PMID- 21614672 TI - Thyroid hormone action in metabolic regulation. AB - Thyroid hormone plays pivotal roles in growth, differentiation, development and metabolic homeostasis via thyroid hormone receptors (TRs) by controlling the expression of TR target genes. The transcriptional activity of TRs is modulated by multiple factors including various TR isoforms, diverse thyroid hormone response elements, different heterodimeric partners, coregulators, and the cellular location of TRs. In the present review, we summarize recent advance in understanding the molecular mechanisms of thyroid hormone action obtained from human subject research, thyroid hormone mimetics application, TR isoform-specific knock-in mouse models, and mitochondrion study with highlights in metabolic regulations. Finally, as future perspectives, we share our thoughts about current challenges and possible approaches to promote our knowledge of thyroid hormone action in metabolism. PMID- 21614677 TI - Controlling supramolecular assembly using electronic effects. AB - Through systematic structural studies using custom designed probe molecules, it has been shown that the balance between hydrogen-bonds in the context of supramolecular chemistry and crystal engineering can be understood and guided by a semiquantitative thermodynamic assessment that integrates theoretical and experimental views of solution-based molecular recognition events. Although pKa values can be used for ranking hydrogen-bond donors/acceptors within a family of compounds, they do not offer reliable information when comparing different functional groups. However, against a backdrop of a simple electrostatic interpretation of hydrogen bonds coupled with a focus on the primary non-covalent interactions, molecular electrostatic potential surfaces can be employed for guiding the synthesis of binary- and ternary co-crystals with the desired connectivity and dimensionality. PMID- 21614676 TI - Membrane stress tensor in the presence of lipid density and composition inhomogeneities. AB - We derive the expression of the stress tensor for one- and two-component lipid membranes with density and composition inhomogeneities. We first express the membrane stress tensor as a function of the free-energy density by means of the principle of virtual work. We then apply this general result to a monolayer model which is shown to be a local version of the area-difference elasticity (ADE) model. The resulting stress tensor expression generalizes the one associated with the Helfrich model, and can be specialized to obtain the one associated with the ADE model. Our stress tensor directly gives the force exchanged through a boundary in a monolayer with density and composition inhomogeneities. Besides, it yields the force density, which is also directly obtained in covariant formalism. We apply our results to study the forces induced in a membrane by a local perturbation. PMID- 21614678 TI - Asymmetric biocatalytic reduction of 3,5-bis(trifluoromethyl) acetophenone to (1R)-[3,5-bis(trifluoromethyl)phenyl] ethanol using whole cells of newly isolated Leifsonia xyli HS0904. AB - A novel bacterial strain HS0904 was isolated from a soil sample using 3,5 bis(trifluoromethyl) acetophenone as the sole carbon source. This bacterial isolate can asymmetrically reduce 3,5-bis(trifluoromethyl) acetophenone to (1R) [3,5-bis(trifluoromethyl)phenyl] ethanol with high enantiometric excess (ee) value. Based on its morphological, physiological characteristics, Biolog, 16S rDNA sequence and phylogenetic analysis, strain HS0904 was identified as Leifsonia xyli HS0904. To our knowledge, this is the first reported case on the species L. xyli exhibited R-stereospecific carbonyl reductase and used for the preparation of chiral (1R)-[3,5-bis(trifluoromethyl)phenyl] ethanol. The optimization of parameters for microbial transformation of 3,5 bis(trifluoromethyl) acetophenone to (1R)-[3,5-bis(trifluoromethyl)phenyl] ethanol catalyzed by whole cells of L. xyli HS0904 was carried out by examining some key factors including buffer pH, reaction temperature, shaking speed, substrate concentration, and reaction time. The obtained optimized conditions for the bioreduction are as follows: buffer pH 8.0, 70 mM of 3,5-bis(trifluoromethyl) acetophenone, 100 g l(-1) of glucose as co-substrate, 200 g l(-1) of resting cells as biocatalyst, reaction for 30 h at 30 degrees C and 200 rpm. Under above conditions, 99.4% of product ee and best yield of 62% were obtained, respectively. The results indicated that isolate L. xyli HS0904 is a novel potential biocatalyst for the production of (1R)-[3,5-bis(trifluoromethyl)phenyl] ethanol. PMID- 21614679 TI - Establishing potential links between the presence of alkylphenolic compounds and the benthic community in a European river basin. AB - INTRODUCTION: Concentrations of alkylphenolic compounds (APCs) in water and sediments were related to the composition and functional descriptors of the benthic community (biofilm and macroinvertebrates). MATERIALS AND METHODS: Samples were collected in four sampling campaigns at seven sampling points in the lower Llobregat catchment area (NE Spain). Water and sediment samples underwent chemical target analysis for nine APCs, which are known to disrupt the endocrine system. RESULTS AND DISCUSSIONS: APCs were the main stressors on the diatom community but not on the macroinvertebrate community. CONCLUSIONS: Benthic invertebrates were mostly affected by the general physicochemical water characteristics (where conductivity was a surrogate). Nonylphenol only had an influence on the diatom community in water but not in the remaining compartments, probably because of the low concentrations observed in the environment. PMID- 21614681 TI - [Application of robotic system in gastrointestinal surgery]. AB - Robotic system helps surgeons in performing surgery. Currently Da Vinci system is the most popular. Da Vinci system has been used for the stomach and bowel diseases in 27 cases(18 cases of stomach and 9 cases of colon and rectum) in the Zhongshan Hospital, Fudan University. Accurate preoperative staging is crucial, and Da Vinci system is advantageous in lymph node dissection, preservation of nerve plexus, and complete resection of mesorectum. Adoption of gastrointestinal tract reconstruction technique should depend on the operation and experience in surgery. Though Da Vinci system has limitations and the cost is high, it is believed to be the future trend. PMID- 21614680 TI - Sigma-2 receptor as potential indicator of stem cell differentiation. AB - PURPOSE: The sigma-2 (sigma(2)) receptor is a potential biomarker of proliferative status of solid tumors. Specific synthetic probes using N substituted-9-azabicyclo [3.3.1]nonan-3alpha-yl carbamate analogs have been designed and implemented for experimental cancer diagnosis and therapy. PROCEDURES: We employed the fluorescently labeled sigma(2) receptor probe, SW120, to evaluate sigma(2) receptor expression in human stem cells (SC), including: bone marrow stromal, neural progenitor, amniotic fluid, hematopoetic, and embryonic stem cells. We concurrently evaluated the intensity of SW120 and 5 ethynyl-2'-deoxyuridine (EdU) relative to passage number and multi-potency. RESULTS: We substantiated significantly higher sigma(2) receptor density among proliferating SC relative to lineage-restricted cell types. Additionally, cellular internalization of the sigma(2) receptor in SC was consistent with receptor-mediated endocytosis and confocal microscopy indicated SW120 specific co localization with a fluorescent marker of lysosomes in all SC imaged. CONCLUSION: These results suggest that sigma(2) receptors may serve to monitor stem cell differentiation in future experimental studies. PMID- 21614682 TI - [Transvaginal endoscopic resection of rectal tumor: a report of 2 cases]. AB - Two female patients with rectal tumor undergoing proctectomy via vagina, namely natural orifice transluminal endoscopic surgery (NOTES), are reported. The operations were performed on June 8 and August 10, 2010, respectively. No Trocar was used in the abdomen except for the transumbilical incision. There were no visible scars in the abdomen. Tubulovillous adenoma and moderately differentiated adenocarcinoma were diagnosed respectively through postoperative pathological examination. Both patients resumed normal work and life at the most recent follow up. Sexual life was satisfactory. PMID- 21614683 TI - [Robotic-assisted laparoscopic colectomy for colon cancer: a report of 13 cases]. AB - OBJECTIVE: To investigate the safety and feasibility of robotic-assisted laparoscopic colectomy for colonic cancer. METHODS: The clinical outcomes of 13 patients with colon cancer undergoing robotic-assisted laparoscopic colectomy from May 2010 to November 2010 were retrospectively evaluated. RESULTS: All the operations were performed successfully, including 5 right colectomies, 3 left colectomies, and 5 sigmoidectomies. The operative time was (171.5+/-31.8) minutes. The estimated blood loss was (54.6+/-21.8) ml. Time to the return of bowel function was (60.9+/-15.8) hours and postoperative hospital stay was (6.4+/ 3.6) days. There was one patient developed fat liquefaction at the incision. No bleeding, anastomotic fistula, anastomotic stenosis, or other complications were found. CONCLUSION: Robotic-assisted laparoscopic colectomy is safe and feasible for colon cancer resection. PMID- 21614684 TI - [Prospective study on the use of nickel-titanium temperature-dependent memory shape device (CAR27) for anastomosis after colorectal surgery]. AB - OBJECTIVE: To prospectively evaluate the safety and efficacy of nickel- titanium temperature-dependent memory-shape device(CAR27) for colorectal anastomosis. METHODS: Sixty colorectal cancer patients were randomly divided into two groups and received colorectal anastomosis with CAR27 or traditional stapling device. Complications, bowel function return, and the extrusion of anastomosis ring were prospectively monitored. RESULTS: Both CAR27 and stapler group had one case of anastomotic leakage. Other complications such as stricture or obstruction were not found. Time for anastomosis of the two groups were (10.1+/-1.2) minutes and (11.2+/-2.1) minutes respectively. Time to first flatus was(3.2+/-1.2) days and (3.5+/-1.4) days respectively. Time to food intake resumption was (4.0+/-1.4) days and (4.3+/-1.3) days respectively. The differences above between the two groups were not statistically significant(P>0.05). The ring was expelled with stool within 7-16 days. The two groups were similar in operative time and the return of bowel function. CONCLUSION: CAR27 is safe and simple for colorectal anastomosis. PMID- 21614685 TI - [Animal experimental study of compression anastomosis ring for low anterior resection]. AB - OBJECTIVE: To evaluate the feasibility and safety of nickel-titanium compression anastomosis ring (CAR27) in colorectal anastomosis after low anterior rectal resection in animal models. METHODS: End-to-end colorectal anastomosis was performed using CAR27 in 6 experimental pigs after resection of the middle and lower third of the rectum. The animals were observed postoperatively for up to 56 days. Five pigs were sacrificed at day 14 and the other at day 56. Distance from anal verge to anastomosis and anastomotic circumference were measured. Histopathologic examination was performed. RESULTS: The median distance from anal verge was 5.3(4-6) cm. No anastomotic leak or other complications were observed. All the pigs recovered and gained weight. In 5 animals sacrificed at day 14, the mean circumference of the anastomosis was 6.8(6.5-7.0) cm, and histopathological examination showed mild inflammatory reaction and fibrosis. In the one sacrificed at day 56, the circumference expanded to 9.3 cm, and no inflammation and fibrosis were observed. Minor adhesion was noticed in only one pig, while smooth and intact serosa in the anastomosis was seen in the rest of the animals. CONCLUSION: CAR27 is a promising device for mid and low colorectal anastomosis. PMID- 21614686 TI - [Effect of enteral nutrition on liver function and inflammatory response after abdominal operation in patients complicated with liver dysfunction]. AB - OBJECTIVE: To investigate the effect of enteral nutrition(EN) on liver function and inflammatory response after abdominal operation in patients with liver dysfunction. METHODS: A prospective multicenter study was conducted. Patients requiring EN for at least 5 days after abdominal surgery with at least 1 abnormal liver function index were included. After operations, EN suspensions(TPF-FOS) were administered for 5 days after the return of bowel function with targeted content of 125.52 kJ(30 kcal).kg(-1).d(-1) maintained for a minimum of 3 days. Levels of serum pre-albumin, C-reaction protein(CRP), and liver function index were measured and the incidence of systemic inflammatory response syndrome(SIRS) was recorded before operation and 6 days after EN. Occurrence of gastrointestinal discomfort was monitored during the treatment. RESULTS: No statistically significant difference was found in pre-albumin between preoperative level and post-EN level[(175.94+/-71.79) mg/L vs.(192.22+/-91.26) mg/L, P=0.162]. Patients with abnormal level of gamma-glutamyl transpeptidase were less after EN compared to the preoperative period(30 vs. 40, P=0.041), as was total bilirubin (3 vs. 9, P=0.034). No significant differences in other indices of liver function were found. Total bilirubin and direct bilirubin decreased after EN support(P=0.000 and P=0.015, respectively). CRP was notably reduced after EN support [(48.74+/ 65.16) mg/L vs.(25.79+/-23.63) mg/L, P=0.009] and the incidence of SIRS largely declined after EN support(19.0% vs. 10.3%, P=0.059). The incidence of gastrointestinal discomfort was 22.4% on postoperative day 1 and declined to 19.0% on postoperative day 5. CONCLUSION: For patients with liver dysfunction, enteral nutrition support with TPF-FOS after abdominal operation can reduce inflammatory response, improve liver function, and maintain serum protein level. PMID- 21614687 TI - [Investigation of tumor related anemia in 10,218 patients with cancer in the digestive system]. AB - OBJECTIVE: To study the prevalence of tumor related anemia in patients with cancer in the digestive system. METHODS: A total of of 10 218 inpatients were diagnosed with cancer in the digestive system at the Peking Union Hospital from January 2000 to June 2009, which included esophageal cancer(n=1118), gastric cancer(n=2418), carcinoma of duodenum(n=134), carcinoma of small intestine(n=85), hepatocellular cancer(n=1508), cholangiocarcinoma(n=546), pancreatic cancer (n=1242), colon cancer(n=1582), and rectal cancer(n=1585). Patients with hemolytic anemia or hepatorenal dysfunction were excluded. Data pertaining to sex, age and hemoglobin were obtained by chart review. RESULTS: According to the China criteria of anemia, the overall anemia rate was 27.5% (2813/10 218). The prevalence of anemia was 64.7% for small bowel cancer, 60.5% for duodenal cancer, 42.6% for colon cancer, 36.6% for cholangiocarcinoma, 33.3% for gastric cancer, 22.6% for pancreatic cancer, 20.4% for rectal cancer, 18.7% for hepatocellular cancer, and 10.0% for esophageal cancer. Anemia was more common in older patients in those with gastric cancer, cholangiocarcinoma, pancreatic cancer, colon cancer and rectal cancer. There were more male anemic patients in those with cancer in the small intestine or cholangiocarcinoma. However, females were more commonly seen in those with hepatocellular cancer or pancreatic cancer. CONCLUSIONS: Anemia is common in patients with cancer in the digestive system. The prevalence of anemia is higher in patients with cancer in the duodenum carcinoma or small intestine, followed by colon cancer and gastric cancer, and then esophageal cancer. Anemia may be associated with age or gender in some types of cancer in the digestive system. PMID- 21614688 TI - [Analysis on treatment outcomes in five patients with combined en bloc liver and pancreas transplantation]. AB - OBJECTIVE: To summarize the treatment outcomes after combined en bloc liver and pancreas transplantation. METHODS: Five patients with end-stage liver disease and type 2 diabetes mellitus received combined en bloc liver and pancreas transplantation after hepatectomy. RESULTS: Five operations were performed successfully. The operative time ranged from 9 to 16 hours and blood loss from 1600 to 3000 ml. Postoperatively, one patients developed pulmonary infection, one died of graft-versus-host disease(GVHD), and one experienced acute renal failure. No intestinal fistula, anastomotic leakage, biliary complications, chronic and acute rejection and pancreatitis were seen. Liver function index including alanine aminotransferase, aspartate aminotransferase and total bilirubin returned to normal levels a week after surgery, while levels of C peptide and blood glucose resumed within 1 to 2 weeks. Apart from 1 case died of GVHD, the other 4 maintained normal liver function during the follow up ranging from 2 to 23 months and no insulin was required for the diabetes. CONCLUSION: Combined en bloc liver and pancreas transplantation is technically feasible and an effective treatment for multi-organ diseases. PMID- 21614689 TI - [Factors associated with complications after laparoscopic-assisted radical gastrectomy for gastric cancer]. AB - OBJECTIVE: To investigate factors associated with postoperative complications after laparoscopic-assisted radical gastrectomy in gastric cancer. METHODS: Clinical data of 506 patients with gastric cancer undergoing laparoscopic assisted radical resection from January 2007 to May 2010 were analyzed retrospectively. Risk factors associated with postoperative complications were assessed by univariate and multivariable analyses. Postoperative recovery, survival, and recurrence rate were also investigated. RESULTS: Postoperative complications occurred in 56 patients(11.1%). On univariate analysis, postoperative complication was associated with age, preoperative comorbidity, lymph node metastasis, surgeon experience, and operative time. Logistic regression analysis revealed that preoperative comorbidity, lymph node metastasis and surgeon experience were independent risk factors for postoperative complications. The time to first flatus and postoperative hospital stay were longer in patients with postoperative complications(both P<0.05). Follow up was available in 482 patients (95.2%), with a median follow up of 13 months (range, 2 37 months). Differences in survival and recurrence rate between patients with and without postoperative complications were of no statistical significance(P>0.05). CONCLUSIONS: Preoperative comorbidity, lymph node metastasis and surgeon experience are independent risk factors for postoperative complications in laparoscopic-assisted radical gastrectomy. Although patients with postoperative complications have slower recovery, survival in these patients is not compromised. PMID- 21614690 TI - [Application of 99mTc-SPECT-CT and carbon nanoparticles suspension injection in sentinel lymph node mapping for rectal cancer]. AB - OBJECTIVE: To evaluate the accuracy of sentinel lymph node mapping(SLM) in patients with rectal cancer by single-photon emission computed tomography (SPECT CT) lymphoscintigraphy and carbon nanoparticles suspension injection. METHODS: Twelve patients with clinical T(1-2)N(0)M(0) rectal cancer were selected and locally injected with technetium-(99m)sulfur-colloid and carbon nanoparticles suspension by endoscope one day before surgery, followed by SPECT-CT scanning 1, 3 and 5 hours later. Radioactive isotope(RI) uptake of each sentinel node(SN) basin with location preoperatively determined by SPECT-CT was postoperatively calculated using gamma probe. Nodes with the highest RI uptake, the number of which was also pre-determined by SPECT-CT, was defined as SNs. Immunohistochemical cytokeratin staining was performed for all the SNs and non SNs. RESULTS: The rate of sentinel node detection was 91.7%(11/12) with at least one SN(1-3) per patient. Ten cases showed metastasis-negative in SNs as well as all the resected regional nodes by immunohistochemical cytokeratin staining. Only one patient had positive nodes in both SN and non-SNs. The accuracy of SLM was 100%. CONCLUSION: SPECT-CT lymphoscintigraphy and carbon nanoparticles suspension injection can effectively detect the anatomic location and number of sentinel nodes, and improve the accuracy of SLM for rectal cancer. PMID- 21614691 TI - [Expression of human epidermal growth factor receptor 2 in gastroesophageal cancer with different scoring systems and its relationship with clinicopathological features]. AB - OBJECTIVE: To compare the expression of human epidermal growth factor receptor 2 (HER2) under different scoring systems in gastroesophageal cancer and its relationship with clinicopathological features. METHODS: Clinicopathological data were retrospectively reviewed of 127 patients with gastroesophageal cancer between January and December 2009 in the Department of Surgery at the Cancer Hospital of Peking University. Tumor specimens were collected. The expression of HER2 protein was detected by immunohistochemistry. RESULTS: HER2 positive rate(++/+++) in gastroesophageal cancer was 15.0%(19/127) with both new and traditional immunohistochemical scoring systems, while HER2 strong positive rate(+++) was 10.2%(13/127) and 6.3%(8/127), respectively(P=0.26). Univariate analysis showed that the expression rate of HER2 protein was associated with differentiation and Lauren classification of the tumor. Multivariable analysis showed that TNM staging and tumor differentiation were independently associated with the expression of HER2 protein(both P<0.05). CONCLUSIONS: There is no change in HER2 positive rate in gastroesophageal cancer between the new and traditional immunohistochemical scoring systems. Expression of HER2 is associated with clinicopathological features in the gastroesophageal cancer. PMID- 21614692 TI - [Development and verification of CEA positive CT26 colon cancer cell line]. AB - OBJECTIVE: To establish a colon cancer cell line with stable expression of carcinoembryonic antigen(CEA). METHODS: Recombinant lentivirus conjugated with CEACAM5 cDNA were used to transfect wild CT26 cells. Antibiotics were given for 2 weeks to select CEA positive cells. A single transfected clone was obtained using limiting dilution. The 7th and 14th passages of cells cultured in vitro were detected for CEACAM5 mRNA by RT-PCR, and protein by western blot. The location of CEACAM5 expression was examined using fluorescent microscope and immunocytochemistry. The 14th passage cells were injected subcutaneously into mice to create BALB/c model and CEACAM5 protein was detected by in vivo fluorescence image analysis system and immunohistochemistry. RESULTS: CEACAM5 mRNA and protein were found in the 7th and 14th passages of CT26CEA cells, which were proved to locate in the cytoplasm by fluorescence microscope and immunohistochemistry. Abundant CEACAM5 protein was found in subcutaneous tumors by in vivo fluorescence image analysis system and immunohistochemistry. CONCLUSION: Colon cancer cell line CT26 with stable expression of CEA in vitro and in mice can be used as a suitable tool to facilitate research on the impact and mechanism of CEA on colon cancer under normal immune environment. PMID- 21614693 TI - [Effects of combined therapy of LY294002 and SN50 on nude mice model with gastric cancer]. AB - OBJECTIVE: To investigate the effect of phosphatidylinositol 3-kinase inhibitor LY294002 combined with NF-kappaB P65 nuclear translocation inhibitor SN50 on the tumor cell growth and apoptosis using a nude mouse model of gastric cancer. METHODS: Human gastric cancer cell strain SGC7901 was transplanted subcutaneously to nude mice to establish tumor models. Model mice were randomly divided into the control group, the LY294002 treatment group, the SN50 treatment group, and the LY294002+SN50 treatment group, with 5 in each group. After being treated for 10 days, the inhibition rate of tumor growth was ascertained by measuring the size of tumor. Immunohistochemical method was used to detect the expression levels of Bcl-2, P53 and Bax proteins and transmission electron microscopy to investigate the apoptosis of tumor cells. RESULTS: On the 10th day after treatment, the inhibition rate of gastric cancer cellular growth in the LY294002+SN50 group was (49.2+/-2.5)%, which was significantly higher than that in the LY294002 group(29.4+/-1.5)% and SN50 group (19.7+/-1.6)%(P<0.05). In comparison with the other two groups, LY294002+SN50 group exhibited more severe apoptosis, with expression of Bcl-2 decreased and that of P53 and Bax increased more significantly(P<0.05). CONCLUSION: LY294002 combined with SN50 inhibits the growth of SGC7901 transplanted tumor and aggravates the apoptosis of gastric cancer cells in nude mice model. PMID- 21614694 TI - [Expression and prognostic value of M2 macrophages and regulatory T cells in gastric carcinoma tissue]. AB - OBJECTIVE: To explore the prognostic value of M2 macrophages and regulatory T cells(Tregs) in gastric carcinoma. METHODS: Clinicopathological characteristics and follow up data of 135 patients with gastric carcinoma were collected. Patients included were those who underwent D2 radical resection(R0) at Zhongshan Hospital of Fudan University from February 1999 to December 2005. Tissue chips of gastric carcinoma specimen were stained using immunohistochemistry to determine the cells density and number of M2(CD163 positive) and Tregs(Foxp3 positive). RESULTS: The median positive cells density of M2 macrophages and Tregs in tumor tissue were 7.48/HP and 6.33/HP, respectively, higher than that in adjacent tissues(1.37/HP and 2.92/HP, P<0.001). The density of M2 macrophages was positively correlated with that of Treg cells(r=0.415, P<0.001) in tumor tissue. The median survival of patients with low expression of M2 and Tregs(n=43) was significantly longer than those with high expression of the 2 cells(n=45) (99.0 vs. 72.3 months, P<0.05). CONCLUSION: Combined detection of M2 macrophages and Tregs may predict the prognosis of gastric carcinoma. PMID- 21614695 TI - [Treatment outcomes of multivisceral resection for locally advanced right colon cancer]. AB - OBJECTIVE: To investigate long-term survival after multivisceral resection in patients with locally advanced right colon cancer. METHODS: The clinical data and survival of 13 patients with locally advanced right colon cancer were retrospectively analyzed. RESULTS: There were 8 males and 5 females with a mean age of 58.6 years. Location of the primary tumor included hepatic flexure(n=6), transverse colon(n=2), and ascending colon(n=5). Three patients had duodenal invasion alone, 9 had involvement of duodenum and other organs, and 1 had pancreas and stomach involvement. Right colectomy and pancreaticoduodenectomy and(or) resection of other organs were performed. The 1-, 3-, and 5-year survival rates were 69%, 54%, and 30%, respectively. CONCLUSION: Right colectomy combined with multivisceral resection is a promising procedure for selected patients with locally advanced colon cancer. PMID- 21614696 TI - [Application of hand-assisted laparoscopic surgery (HALS) in colectomy]. AB - OBJECTIVE: To evaluate the safety and efficacy of hand-assisted laparoscopic surgery (HALS) in colorectal tumors. METHODS: Clinical data of 70 patients with colorectal tumors were retrospectively analyzed. All the patients had received HALS colectomy in the Beijing Cancer Hospital. Lapdisc was used for the hand port at the umbilicus. Two additional trocars were used. RESULTS: There were 38 males and 32 females. The median age was 61(29-89) years. Diagnoses included sigmoid cancer(n=48), sigmoid adenoma(n=4), descending colon cancer (n=3), ascending colon cancer (n=1), rectal cancer (n=13), total colectomy(n=1). The operative time was (126.0+/-22.5) minutes. The intraoperative blood loss was (75.0+/-18.8) ml. The mean number of lymph node dissection was(16.8+/-4.2). The median postoperative hospital stay was 9.4 days. There were no perioperative deaths. One patient developed anastomotic stricture and two anastomotic leak, all of which were successfully managed with conservative treatment. CONCLUSION: HALS is a safe and effective technique for colectomy. PMID- 21614697 TI - The influence of functional social support on executive functioning in middle aged African Americans. AB - Social support has a positive influence on cognitive functioning and buffers cognitive decline in older adults. This study examined the relations between social support and executive functioning in middle-aged adults. A community-based sample of African Americans completed the Interpersonal Support Evaluation List, a measure of functions of social support, and two measures of executive functioning, the Stroop Color and Word Test and the Wisconsin Card Sorting Test (WCST). Hierarchical regression analyses were used to explore the hypothesis that different facets of perceived social support influence performance on measures of executive functioning. After controlling for age, gender, and education, social support facets including belonging support, self-esteem support, appraisal support, and tangible support were significant predictors of Stroop performance. In addition, tangible support significantly predicted WCST performance. These findings add to previous literature on social support and cognition; however, findings for middle-aged adults are unique and suggest that social support has a positive influence on some executive functions in African Americans prior to old age. PMID- 21614698 TI - Predictors of responses to stress among families coping with poverty-related stress. AB - This study tested how poverty-related stress (PRS), psychological distress, and responses to stress predicted future effortful coping and involuntary stress responses one year later. In addition, we explored age, sex, ethnicity, and parental influences on responses to stress over time. Hierarchical linear modeling analyses conducted with 98 low-income families (300 family members: 136 adults, 82 school-aged children, 82 adolescents) revealed that primary control coping, secondary control coping, disengagement, involuntary engagement, and involuntary disengagement each significantly predicted future use of that response. Primary and secondary control coping also predicted less maladaptive future responses to stress, while involuntary responses to stress undermined the development of adaptive responding. Age, sex, and interactions among PRS and prior coping were also found to predict certain responses to stress. In addition, child subgroup analyses demonstrate the importance of parental modeling of coping and involuntary stress responses, and warmth/nurturance and monitoring practices. Results are discussed with regard to the implications for preventive interventions with families in poverty. PMID- 21614700 TI - A novel compound from the marine bacterium Bacillus pumilus S6-15 inhibits biofilm formation in gram-positive and gram-negative species. AB - Biofilm formation is a critical problem in nosocomial infections and in the aquaculture industries and biofilms show high resistance to antibiotics. The aim of the present study was to reveal a novel anti-biofilm compound from marine bacteria against antibiotic resistant gram-positive and gram-negative biofilms. The bacterial extract (50 MUg ml(-1)) of S6-01 (Bacillus indicus = MTCC 5559) showed 80-90% biofilm inhibition against Escherichia coli, Shigella flexneri, Proteus mirabilis and S6-15 (Bacillus pumilus = MTCC 5560) showed 80-95% biofilm inhibition against all the 10 tested organisms. Furthermore, they also reduced the hydrophobicity index and extracellular polymeric substances (EPS) production. Structural elucidation of the active principle in S6-15 using GC-MS, (1)H NMR, and (13)C NMR spectral data revealed it to be 4-phenylbutanoic acid. This is the first report of 4-phenylbutanoic acid as a natural product. The purified compound (10-15 MUg ml(-1)) showed potential activity against a wide range of biofilms. This study for the first time, reports a novel anti-biofilm compound from a marine bacterium with wide application in medicine and the aquaculture industry. PMID- 21614699 TI - Protein resistance of dextran and dextran-poly(ethylene glycol) copolymer films. AB - The protein resistance of dextran and dextran-poly(ethylene glycol) (PEG) copolymer films was examined on an organosilica particle-based assay support. Comb-branched dextran-PEG copolymer films were synthesized in a two step process using the organosilica particle as a solid synthetic support. Particles modified with increasing amounts (0.1-1.2 mg m(-2)) of three molecular weights (10,000, 66,900, 400,000 g mol(-1)) of dextran were found to form relatively poor protein resistant films compared to dextran-PEG copolymers and previously studied PEG films. The efficacy of the antifouling polymer films was found to be dependent on the grafted amount and its composition, with PEG layers being the most efficient, followed by dextran-PEG copolymers, and dextran alone being the least efficient. Immunoglobulin gamma (IgG) adsorption decreased from ~5 to 0.5 mg m(-2) with increasing amounts of grafted dextran, but bovine serum albumin (BSA) adsorption increased above monolayer coverage (~2 mg m(-2)) indicating ternary adsorption of the smaller protein within the dextran layer. PMID- 21614701 TI - Amphiphilic block copolymer/poly(dimethylsiloxane) (PDMS) blends and nanocomposites for improved fouling-release. AB - Amphiphilic diblock copolymers, Sz6 and Sz12, consisting of a poly(dimethylsiloxane) block (average degree of polymerisation = 132) and a PEGylated-fluoroalkyl modified polystyrene block (Sz, average degree of polymerisation = 6, 12) were prepared by atom transfer radical polymerization (ATRP). Coatings were obtained from blends of either block copolymer (1-10 wt%) with a poly(dimethylsiloxane) (PDMS) matrix. The coating surface presented a simultaneous hydrophobic and lipophobic character, owing to the strong surface segregation of the lowest surface energy fluoroalkyl chains of the block copolymer. Surface chemical composition and wettability of the films were affected by exposure to water. Block copolymer Sz6 was also blended with PDMS and a 0.1 wt% amount of multiwall carbon nanotubes (CNT). The excellent fouling release (FR) properties of these new coatings against the macroalga Ulva linza essentially resulted from the inclusion of the amphiphilic block copolymer, while the addition of CNT did not appear to improve the FR properties. PMID- 21614702 TI - The impact of rumination on internal attention switching. AB - The present study explored the nature of attention control problems associated with ruminative traits. Experiment 1 aimed to establish the validity of a modified mental counting task that assesses individuals' ability to switch attention between internal mental representations. Reaction time and brain activity (event related potential; ERP) measures were examined, and results showed that the task was sensitive to internal attention switching effects. Experiment 2 assessed how the relationship between ruminative tendencies and switching performance differs when participants attend to neutral versus affective materials under different mood states. Although reaction-time analysis suggested that both mood condition and stimulus affectivity were not significant in altering this association, ERP analysis suggested otherwise. A significant task type*trait rumination * mood condition effect was found for switch-related ERP responses, whereby high ruminators were found to deploy more neuronal resources when switching affective materials in sad mood state. PMID- 21614703 TI - When age matters: Developmental perspectives on "cognition and emotion". PMID- 21614704 TI - Age and emotion affect how we look at a face: visual scan patterns differ for own age versus other-age emotional faces. AB - We investigated how age of faces and emotion expressed in faces affect young (n=30) and older (n=20) adults' visual inspection while viewing faces and judging their expressions. Overall, expression identification was better for young than older faces, suggesting that interpreting expressions in young faces is easier than in older faces, even for older participants. Moreover, there were age-group differences in misattributions of expressions, in that young participants were more likely to label disgusted faces as angry, whereas older adults were more likely to label angry faces as disgusted. In addition to effects of emotion expressed in faces, age of faces affected visual inspection of faces: Both young and older participants spent more time looking at own-age than other-age faces, with longer looking at own-age faces predicting better own-age expression identification. Thus, cues used in expression identification may shift as a function of emotion and age of faces, in interaction with age of participants. PMID- 21614705 TI - Biomechanical analysis of foot with different foot arch heights: a finite element analysis. AB - Clinically, different foot arch heights are associated with different tissue injuries to the foot. To investigate the possible factors contributing to the difference in foot arch heights, previous studies have mostly measured foot pressure in either low-arched or high-arched feet. However, little information exists on stress variation inside the foot with different arch heights. Therefore, this study aimed to implement the finite element (FE) method to analyse the influence of different foot arches. This study established a 3D foot FE model using software ANSYS 11.0. After validating the FE model, this study created low-arched, high-arched and normal-arched foot FE models. The FE analysis found that both the stress and strain on the plantar fascia and metatarsal were higher in the high-arched foot, whereas the stress and strain on the calcaneous, navicular and cuboid were higher in low-arched foot. Additionally, forefoot pressure was increased with an increase in arch height. PMID- 21614706 TI - Predicting the external formation of a bone fracture callus: an optimisation approach. AB - The formation of a fracture callus in vivo tends to form in a structurally efficient manner distributing tissues where mechanical stimulus persists. Therefore, it is proposed that the formation of a fracture callus can be modelled in silico by way of an optimisation algorithm. This was tested by generating a finite element model of a transversal bone fracture embedded in a large tissue domain which was subjected to axial, bending and torsional loads. It was found that the relative fragment motion induced a compressive strain field in the early callus tissue which could be utilised to simulate the formation of external callus structures through an iterative optimisation process of tissue maintenance and removal. The phenomenological results showed a high level of congruence with in vivo healing patterns found in the literature. Consequently, the proposed strategy shows potential as a means of predicting spatial bone healing phenomena for pre-clinical testing. PMID- 21614707 TI - Estimates of muscle function in human gait depend on how foot-ground contact is modelled. AB - Computational analyses of leg-muscle function in human locomotion commonly assume that contact between the foot and the ground occurs at discrete points on the sole of the foot. Kinematic constraints acting at these contact points restrict the motion of the foot and, therefore, alter model calculations of muscle function. The aim of this study was to evaluate how predictions of muscle function obtained from musculoskeletal models are influenced by the model used to simulate ground contact. Both single- and multiple-point contact models were evaluated. Muscle function during walking and running was determined by quantifying the contributions of individual muscles to the vertical, fore-aft and mediolateral components of the ground reaction force (GRF). The results showed that two factors--the number of foot-ground contact points assumed in the model and the type of kinematic constraint enforced at each point--affect the model predictions of muscle coordination. Whereas single- and multiple-point contact models produced similar predictions of muscle function in the sagittal plane, inconsistent results were obtained in the mediolateral direction. Kinematic constraints applied in the sagittal plane altered the model predictions of muscle contributions to the vertical and fore-aft GRFs, while constraints applied in the frontal plane altered the calculations of muscle contributions to the mediolateral GRF. The results illustrate the sensitivity of calculations of muscle coordination to the model used to simulate foot-ground contact. PMID- 21614708 TI - Migration of nanosized layered double hydroxide platelets from polylactide nanocomposite films. AB - Melt-extruded L-polylactide (PLA) nanocomposite films were prepared from commercially available PLA and laurate-modified Mg-Al layered double hydroxide (LDH-C12). Three films were tested for total migration as well as specific migration of LDH, tin, laurate and low molecular weight PLA oligomers (OLLA). This is the first reported investigation on the migration properties of PLA-LDH nanocomposite films. The tests were carried out as part of an overall assessment of the suitability of such films for use as food contact materials (FCM). Total migration was determined according to a European standard method. All three films showed migration of nanosized LDH, which was quantified using acid digestion followed by inductively coupled plasma mass spectrometric (ICP-MS) detection of (26)Mg. Migration of LDH from the films was also confirmed by examining migrates using transmission electron microscopy (TEM) and was attributed indirectly to the significant PLA molecular weight reduction observed in extruded PLA-LDH-C12 films. Migration of tin was detected in two of the film samples prepared by dispersion of LDH-C12 using a masterbatch technique and migration of the laurate organomodifier took place from all three film types. The results indicate that the material properties are in compliance with the migration limits for total migration and specific lauric acid migration as set down by the EU legislation for FCM, at least if a reduction factor for fresh meat is taken into consideration. The tin detected arises from the use of organotin catalysts in the manufacture of PLA. PMID- 21614709 TI - Efficacy of detoxification of deoxynivalenol-contaminated corn by Bacillus sp. LS100 in reducing the adverse effects of the mycotoxin on swine growth performance. AB - Biodetoxification of mycotoxins is a novel strategy to control mycotoxicoses in animals. Bacillus sp. LS100, which transforms deoxynivalenol (DON) to a less toxic chemical de-epoxy DON (DOM-1), was evaluated for its efficacy in reducing the adverse effects of DON on swine growth performance. A feeding trial was conducted in growing pigs with four treatments: (1) corn meal without detectable DON served as control (Non-toxic Corn); (2) Fusarium-infected corn giving a toxic diet containing 5 ug DON g(-1) (Toxic Corn); (3) Toxic Corn detoxified with Bacillus sp. LS100 giving a detoxified diet containing 5 ug DOM-1 g(-1) (LS100-De toxic Corn); (4) Non-toxic Corn treated with Bacillus sp. LS100 serving as bacterial control (LS100-Non-toxic Corn). During 9 days of exposure to the treatments, pigs on Toxic Corn showed a significant reduction in daily feed consumption, daily weight gain and feed efficiency by 29, 48 and 29%, respectively, compared to pigs on Non-toxic Corn. These parameters of the pigs fed LS100-De-toxic Corn diet were 45, 82 and 32% greater, respectively, than those of pigs fed Toxic Corn diet, and were similar to those pigs fed Non-toxic Corn and LS100-Non-toxic Corn diets. There were no significant differences between the treatments of LS100-Non-toxic Corn and Non-toxic Corn diets, implying that the bacterial isolate might not have significantly affected nutrition and palatability of the feed or had negative effects on the pig's feeding performance. The results have proved that microbial detoxification of DON in contaminated feed can eliminate negative effects of the mycotoxin, and the pre feeding detoxification approach may be applied in the livestock industry. PMID- 21614710 TI - Determinants of utilisation of intrapartum obstetric care services in Cambodia, and gaps in coverage. AB - BACKGROUND: Facility delivery and skilled birth attendance are two of the most effective strategies for decreasing maternal mortality. The objectives of this study were to further define utilisation of these services in Cambodia and to uncover socio-economic or location-specific coverage gaps that may exist. METHODS: We performed a cross-sectional analysis of the 2005 Cambodia Demographic Health Survey (CDHS) to determine prevalence, and determinants, of service utilisation. RESULTS: Out of 6069 women aged 15-49 years, 77% delivered at home, three-fourths without a skilled birth attendant. Poverty, lower education and rural residence were associated with the highest likelihood of poor utilisation of services. Discussion. While there has been an overall increase in facility deliveries and skilled birth attendance since 2000, improvements have been spread unevenly across the population, benefiting mostly urban, wealthier and better educated women. While recent financing initiatives and health system developments appear to have further increased service utilisation since 2005, the extent of their reach to the most vulnerable populations, and their ultimate impact on maternal mortality reduction, remain to be elucidated. CONCLUSION: Further expanding successful initiatives, particularly among vulnerable populations, is essential. Longitudinal evaluation of ongoing strategies and their impact remains critical. PMID- 21614712 TI - Natural resistance of rose petals to microbial attack. AB - Petals of red, yellow and white roses (Rosa damascene Mill.) of the family Rosaceae were extracted with (1:1) methylene chloride/methanol and tested for their antimicrobial activities against four species of Gram-positive bacteria (Bacillus cereus, Bacillus subtilis, Micrococcus luteus and Staphylococcus aureus), five species of Gram-negative bacteria (Enterobacter aerogenes, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa and Serratia marcescens) and five species of fungi (Penicillium notatum, Aspergillus niger, Rhizopus stolonifer, Saccharomyces cerevisiae and Fusarium oxysporum). All of the crude extracts showed a wide range of antimicrobial activities according to the tested organism and rose's type. Micrococcus luteus was found to be the most susceptible bacteria to all crude extracts. Red and yellow petal extracts showed much higher antibacterial activity than the white petals extract. Bacillus subtilis was found to be the least susceptible to all extracts. The fungus, Penicillium notatum was found to be the most susceptible with white petal extract being the most effective. Saccharomyces cerevisiae and Fusarium oxysporum were the least susceptible to all extracts. White roses extract showed much higher antifungal activities against Penicillium notatum than red or yellow roses, therefore, it was subjected to several bioassay guided chromatographic fractionations and purification to isolate the active chemical(s) responsible for the antifungal activity. Chemical structure of the isolated antifungal compounds were identified by spectroscopy techniques and found to be a gamma-sitosterol and (Z,Z)-9,12-octadecadienoic acid. Antibacterial activity of the various types of rose extracts were due to complex mixtures of organic compounds which are still under chemical investigation and will be published later. PMID- 21614713 TI - Distribution, fate and formation of non-extractable residues of a nonylphenol isomer in soil with special emphasis on soil derived organo-clay complexes. AB - Anthropogenic contaminants like nonylphenols (NP) are added to soil, for instance if sewage-sludge is used as fertilizer in agriculture. A commercial mixture of NP consists of more than 20 isomers. For our study, we used one of the predominate isomers of NP mixtures, 4-(3,5-dimethylhept-3-yl)phenol, as a representative compound. The aim was to investigate the fate and distribution of the isomer within soil and soil derived organo-clay complexes. Therefore, (14)C- and (13)C labeled NP was added to soil samples and incubated up to 180 days. Mineralization was measured and soil samples were fractionated into sand, silt and clay; the clay fraction was further separated in humic acids, fulvic acids and humin. The organo-clay complexes pre-incubated for 90 or 180 days were re-incubated with fresh soil for 180 days, to study the potential of re-mobilization of incorporated residues. The predominate incorporation sites of the nonylphenol isomer in soil were the organo-clay complexes. After 180 days of incubation, 22 % of the applied (14)C was mineralized. The bioavailable, water extractable portion was low (9 % of applied (14)C) and remained constant during the entire incubation period, which could be explained by an incorporation/release equilibrium. Separation of organo-clay complexes, after extraction with solvents to release weakly incorporated, bioaccessible portions, showed that non-extractable residues (NER) were preferentially located in the humic acid fraction, which was regarded as an effect of the chemical composition of this fraction. Generally, 27 % of applied (14)C was incorporated into organo-clay complexes as NER, whereas 9 % of applied (14)C was bioaccessible after 180 days of incubation. The re-mobilization experiments showed on the one hand, a decrease of the bioavailability of the nonylphenol residues due to stronger incorporation, when the pre-incubation period was increased from 90 to 180 days. On the other hand, a shift of these residues from the clay fraction to other soil fractions was observed, implying a dynamic behavior of incorporated residues, which may result in bioaccessibility of the NER of nonylphenol. PMID- 21614714 TI - Sorption of 3,4-dichloroaniline on four contrasting Greek agricultural soils and the effect of liming. AB - Sorption of 3,4-dichloroaniline (3,4-DCA) on four typical Greek agricultural soils, with distinct texture, organic matter content and cation exchange capacities, was compared by using sorption isotherms and the parameters calculated from the fitted Freundlich equations. The sorption process of 3,4-DCA to the soil was completed within 48-72 h. The 3,4-DCA sorption on all soils was well described by the Freundlich equation and all sorption isotherms were of the L-type. The sandy clay loam soil with the highest organic matter content and a slightly acidic pH was the most sorptive, whereas the two other soil types, a high organic matter and neutral pH clay and a low organic matter and acidic loam, had an intermediate sorption capacity. A typical calcareous soil with low organic matter had the lowest sorption capacity which was only slightly higher than that of river sand. The 3,4-DCA sorption correlated best to soil organic matter content and not to clay content or cation exchange capacity, indicating the primary role of organic matter. The distribution coefficient (K(d)) decreased with increasing initial 3,4-DCA concentration and the reduction was most pronounced with the highly sorptive sandy clay loam soil, suggesting that the available sorption sites of the soils are not unlimited. Liming of the two acidic soils (the sandy clay loam and the loam) raised their pH (from 6.2 and 5.3, respectively) to 7.8 and reduced their sorption capacity by about 50 %, indicating that soil pH may be the second in importance factor (after organic matter) determining 3,4-DCA sorption. PMID- 21614715 TI - A column test for leaching of organochlorines from soil by amphiphilic nonionic nanopolymers. AB - Amphiphilic nonionic cross-linked nanopolymers (NPs) were synthesized to examine removal of five organochlorines (OCs), namely lindane, heptachlor, aldrin, dieldrin, endrin, and DDT, from a range of Thai agricultural soils. The synthesized NP particles had polarity characteristics similar to those of nonionic surfactant micelles and were largely in the size range of 55-155 nm. This work aimed to determine the optimal conditions for leaching of OC contaminated soil with NPs and also to investigate the role and influence of soil properties on this leaching. An investigation of the concentrations of aqueous dispersions of these particles found that a concentration of 10 g L(-1). was found most effective in leaching the OCs from a column of spiked soil. The optimal contact time that allowed a NP dispersion and spiked soil to reach equilibrium was 48 h. The results indicated influencing factors for OC removal and soil remediation were properties both of the soil and the compounds themselves. Soil organic carbon (SOC) content and soil texture played an important role on the sorption as well as compound hydrophobicity expressed as log K(OW) values. The removal efficiency was found to be in the range of 85.2 92.8 % for all soil samples and in the order of DDT < aldrin < heptachlor < dieldrin < endrin < lindane regardless of soil type. This order is inversely related to the log K(OC) values of these compounds. For OC compounds with a similar molecular structure, removal efficiency was related to molecular weight (MW). PMID- 21614716 TI - Biodegradation of phthalate esters in polluted soil by using organic amendment. AB - This study investigated the biodegradation of the phthalate esters (PAEs) di-n butyl phthalate (DBP) and di-(2-ethyl hexyl) phthalate (DEHP) in sludge and sludge-amended soil. DBP (100 mg kg(-1)) and DEHP (100 mg kg(-1)) were added to sewage sludge, which was subsequently added to soil. The results showed that sewage sludge can degrade PAEs and the addition of sewage sludge to soil enhanced PAE degradation. Sludge samples were separated into fractions with various particle size ranges, which spanned 0.1-0.45 MUm to 500-2000 MUm. The sludge fractions with smaller particle sizes demonstrated higher PAE degradation rates. However, when the different sludge fractions were added to soil, particle size had no significant effect on the rate of PAE degradation. The results from this study showed that microbial strains F4 (Rhodococcus sp.) and F8 (Microbacterium sp.) were constantly dominant in the mixtures of soil and sludge. PMID- 21614717 TI - Toxicity of the mosquito control insecticide phenothrin to three life stages of the grass shrimp (Palaemonetes pugio). AB - Phenothrin is a synthetic pyrethroid used as a contact insecticide in mosquito control programs. This study compared the toxicity of phenothrin to adult, larval and embryonic grass shrimp (Palaemonetes pugio) and examined oxidative stress responses in adult and larval grass shrimp. The adult 24-h LC50 was 0.341 MUg/L (95 % confidence intervals 0.282-0.412) and the 96-h LC50 was 0.161 MUg/L (95 % CI 0.128-0.203 MUg/L). The larval 24-h LC50 was 0.50 MUg/L (95 % CI 0.441-0.568) and the 96-h LC50 was 0.154 MUg/L (95 % CI 0.139-0.170 MUg/L). In the presence of sediment, the 24-h LC50 was 6.30 MUg/L (95 % CI 5.00-7.44 MUg/L) for adults and 0.771 MUg/L (95 % CI 0.630-0.944) for larvae. The sublethal biomarkers glutathione and lipid peroxidase (LPx) were examined after 96-h phenothrin exposure at five concentrations, and there were no statistically significant differences in these levels in adults or larvae compared to controls. There was a significant downward trend in larval LPx levels. This research confirms that phenothrin is highly toxic to grass shrimp and suggests that both adult and larval grass shrimp are appropriate life stages for risk assessments. PMID- 21614718 TI - Reducing ammonia emissions and volatile fatty acids in poultry litter with liquid aluminum chloride. AB - This study was a pen trial in which the effects of adding different rates of liquid aluminum chloride (AlCl(3)) on litter pH, total volatile fatty acids (VFAs), and ammonia (NH(3)) fluxes was evaluated. Liquid AlCl(3) treatments used in this study were sprayed on the rice hull surface at rates of 100 g, 200 g, and 300 g liquid AlCl(3)/kg rice hulls; untreated rice hulls served as controls. Litter pH, total VFAs, and NH(3) fluxes were all lowered (P< 0.05) by all of the liquid AlCl(3) treatments compared with controls during certain times of the 5 week study. However, there were no significant differences among treatments on litter pH at the end of the study (from 3 to 5 weeks) or NH(3) fluxes at beginning of the study (0 to 3 weeks). Total VFAs were reduced 16 %, 29 %, and 53 % by 100 g liquid AlCl(3)/kg rice hulls, 200 g liquid AlCl(3)/kg rice hulls, and 300 g liquid AlCl(3)/kg rice hulls, respectively. Liquid AlCl(3)additions reduced NH(3) fluxes by 35 %, 57 % and 67 %, respectively, at the low, medium and high rates. In summary, these results indicate that adding liquid aluminum chloride to rice hulls would be a useful tool in reducing the negative environmental impact of poultry litter. It should be noted that the decreased VFA production and NH(3) volatilization was chiefly associated with reduction in litter pH. PMID- 21614719 TI - The effects of absolute risks, relative risks, frequencies, and probabilities on decision quality. AB - It is important to understand how the quality of people's decision making may be affected by the format used to present treatment benefits. Two experiments compared the accuracy of presenting the benefits of cancer screening tests or vaccines using either absolute or relative risk formats that included baseline risk information. Moreover, the absolute and/or baseline risks were presented using either natural frequencies or probabilities. In both experiments, accuracy was measured by the sensitivity of choices to differences in absolute rather than relative risks. Experiment 1 showed no significant differences in sensitivity between the relative and absolute risk formats when the risks were presented as natural frequencies. Sensitivity was, however, poor in both probability versions. Experiment 2 tested the natural frequency versions more stringently by presenting choices with different levels of difficulty. The author found that decision quality was significantly less affected by increases in difficulty in the absolute risk format. Presenting baseline risks using natural frequencies may help to reduce the biasing effects of relative risks but decision quality may not be on a par with the accuracy of decisions made when absolute risks are presented in natural frequency formats. PMID- 21614720 TI - Source selection in prescription drug information seeking and influencing factors: applying the comprehensive model of information seeking in an American context. AB - This study investigates source selection in prescription drug information seeking and influencing factors on selection and seeking behaviors applying a modified Comprehensive Model of Information Seeking in an American context. Survey results suggest consumers engage in prescription drug information search before and after visiting a doctor, but search is not extensive. Consumers turn to the Internet, pharmacists, and doctors most frequently for prescription drug information. Information-seeking behaviors are rather universal across demographic and health related characteristics; however, higher income consumers are more likely to search. Although our study shows some support for the modified Comprehensive Model of Information Seeking, the results indicate influencing factors vary by information source types examined, suggesting the model is more complex than predicted. The study advances research on health communication, information seeking behaviors, and prescription drug decision making. PMID- 21614721 TI - Sexual coercion within mixed-sex couples: the roles of sexual motives, revictimization, and reperpetration. AB - Research suggests that a history of childhood sexual abuse, and previous experiences of sexual coercion, may predict sexual coercion victimization and perpetration. More recently, sexual motivation has been found to correlate with both consensual and non-consensual sexual activity. However, sexual motivation has not been examined in association with previous experiences of abuse and sexual coercion. The aim of this study was to investigate childhood sexual abuse, previous sexual coercion experiences, and sexual motives of both partners as possible risk factors for current sexual coercion victimization and perpetration within a sample of 209 mixed-sex couples. This study examined whether power, stress relief, partner pressure, and imposition motives contributed unique variance to the prediction of sexual coercion beyond that accounted for by past childhood sexual abuse and sexual coercion events. Using hierarchical logistic regressions, four predictive models were examined for both male and female sexual coercion perpetration and victimization. Results show that childhood sexual abuse was only a significant predictor of female sexual coercion perpetration, whereas male sexual coercion victimization and perpetration were predicted by sexual coercion victimization and perpetration in previous relationships. Power motives were also significant predictors of sexual coercion perpetration, and imposition was a significant predictor of sexual coercion victimization for both genders. PMID- 21614722 TI - Does similarity breed marital and sexual satisfaction? AB - This study examined the effect of socioeconomic-cultural homogamy on the marital and sexual satisfaction of Hong Kong Chinese couples. Using a representative, territory-wide sample of 1,083 first-time married heterosexual couples, this study found that wives were generally less satisfied than their husbands with their marital and sexual relationships. Husbands were more likely to be satisfied with their marriages when they were two to four years older than their wives than when they were of similar age to their wives (i.e., within one year of each other), but they were less likely to be satisfied with their marriages when only their wives were employed than when both partners were employed. In addition, they were less likely to be satisfied with both their marital and sexual relationships when their wives were five or more years older. Wives with an older husband were more likely to be sexually satisfied than wives of the same age as their husband, but they were less likely to be satisfied with their marriages when they were better educated than their husbands. The implications of the findings are discussed. PMID- 21614723 TI - Treatment of auditory verbal hallucinations with transcranial magnetic stimulation in a patient with psychotic major depression: one-year follow-up. AB - Auditory verbal hallucinations (AVH) in patients with schizophrenia can respond to repetitive transcranial magnetic stimulation (TMS). We report the therapeutic utility of rTMS in a 48-year-old patient with a 20-year history of severe depression (five suicidal gestures and previous failure of ECT) and internal AVH. First, 20 Hz rTMS to the left prefrontal cortex for 3 weeks significantly improved depression (BDI-II: 89% change, lasting 14 months along with weekly/bi weekly maintenance treatments), but AVH remained unchanged. The patient also underwent a further course of the left temporo-parietal 1 Hz rTMS and amelioration of AVH severity was achieved (PSYRATS-AH: 53% change) and maintained at 1-year follow-up. AVH respond to rTMS in disorders other than schizophrenia. Furthermore, targeted rTMS to different brain regions can address diverse symptoms in neuropsychiatric conditions. PMID- 21614724 TI - Case-control study of dietary patterns and endometrial cancer risk. AB - Dietary patterns, rather than intakes of specific foods or nutrients, may influence risk of endometrial cancer (EC). This population-based case-control study in Canada (2002-2006) included incident EC cases (n = 506) from the Alberta Cancer Registry and controls frequency age-matched to cases (n = 981). Past-year dietary patterns were defined using factor analysis of food frequency questionnaire data. Logistic regression was used to estimate EC risk within quartiles of dietary patterns. Three patterns (sweets, meat, plants) explained 23% of the variance in the dietary data. In multivariable models, EC risk was significantly reduced by 30% for women in the highest quartile of the healthier plants pattern (OR = 0.70, 95% CI 0.50-0.98, P trend = 0.02). When stratified by body mass index (BMI; kg/m(2)), risk was further reduced among overweight or obese women with a BMI >=25 (OR = 0.57, 95% CI 0.39-0.83; P trend = 0.004). EC was not associated with the less healthy sweets and meat patterns. However, risk was modestly, but not significantly, elevated for higher intakes of the meat pattern among overweight or obese women. A mostly plant-based dietary pattern may reduce EC risk. Recommendations for risk reduction should focus on maintaining a healthy weight and the role of diet should be studied further. PMID- 21614725 TI - Fruits and vegetables consumption and esophageal squamous cell carcinoma: a case control study. AB - The authors examined the association of food group intakes and the risk of esophageal squamous cell carcinoma (SCC) in a hospital-based case-control study in Iran. In total, 47 patients with esophageal SCC and 96 controls underwent face to-face private interviews. Usual dietary intake was assessed using a semiquantitative food frequency questionnaire. Multivariate logistic regression was used to estimate odds ratios and 95% confidence intervals. Cases had higher tobacco consumption and symptomatic gastresophageal reflux, whereas controls had higher mean body mass index (25.3 vs. 20.4) and years of education. A protective independent effect was observed for the highest tertile of total fruit consumption (OR: 0.13, CI: 0.04-0.45, P value = 0.001). Within the group of fruits, a significant inverse association was observed for bananas and kiwis (P for trends: 0.03 and 0.02, respectively). The risk of SCC decreased monotonically with increasing intake frequency of oranges (P value for trend = 0.01). The effect of total vegetable consumption on esophageal SCC was not significant, although a reduction in risk was observed in the highest tertile of intake (OR: 0.66, CI: 0.23-1.87, P value = 0.43). The results of the present study suggest a reasonable association between fruit consumption and esophageal SCC in a Middle Eastern high-risk population. PMID- 21614727 TI - Fertility history, health, and health changes in later life: a panel study of British women and men born 1923-49. AB - We investigated associations between later-life health and fertility history for women and men, using the British Household Panel Survey. We modelled health and its rate of change jointly with sample retention over an 11-year period. For women, childlessness is associated with limitation of activity for health reasons and faster acquisition of the limitation. High parity (four or more children) is associated with poorer health for both women and men. For the parous, this association is also found when age at first birth is controlled. Early parenthood is associated with poorer health. For parents of two or more children, a birth interval of less than 18 months is associated with having a health limitation and an accelerated rate of acquiring it. We conclude that biosocial pathways link parenthood careers and the later-life health of both women and men, and that implications of closely spaced births for parents merit further attention. PMID- 21614726 TI - Mouse prostate proteomes are differentially altered by supranutritional intake of four selenium compounds. AB - We have shown that, in contrast to selenomethionine (SeMet) or selenite, methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) exert prostate cancer (PCa) inhibitory effect in preclinical models. Here we investigated the prostate proteome signatures of mice treated with each selenium (Se) form for hypothesis generation concerning their potential in vivo molecular targets and cancer risk modification. Nude mice bearing subcutaneous PC-3 xenografts were treated daily with each Se form (3 mg Se/kg) orally for 45 days. Five prostates were pooled from each group. Their proteomes were profiled by LC-MS/MS with iTRAQ labeling. Of the 1,088 proteins identified, 72 were significantly modulated by one or more Se forms. MSeA and MSeC each induced separate sets of tumor suppressor proteins and suppressed different onco-proteins. Proteins induced by selenite and shared with MSeC were related to energy metabolism (e.g., fatty-acid synthase), and those induced by SeMet included vimentin and heat-shock protein 70, favoring cancer growth. While proteome changes induced by MSeA were associated with PCa risk reduction, desirable risk-reducing signatures induced by MSeC were counterbalanced by risk-promoting patterns shared with selenite and SeMet. We propose that the balance of oncogenic vs. suppressor protein patterns in the prostate may impact the direction of PCa risk modification by a given selenium. PMID- 21614728 TI - The impact of medical home on selected children's health outcome. AB - Medical Home practice has been shown to deliver effective health care to children. This practice model calls for providing patient-centered care that is compassionate, culturally effective, coordinated, integrated, safe, of high quality, and accessible. This study shows that children in the states with a higher amount of Medical Home received childhood vaccinations at a higher rate than others. However, Medical Home had a limited effect on the rate of children receiving dental/medical services, mental health services, or number of overweight children. PMID- 21614729 TI - Faith wellness collaboration: a community-based approach to address type II diabetes disparities in an African-American community. AB - Community-based participatory action research was utilized to form a collaboration that developed a Health Ministry program in four Northeastern urban Black Churches, in which they designed and implemented a culturally competent Type II Diabetes self management education program. Minister sponsorship and a program coordinator synchronized the four Health Ministries' development and diabetes program planning. A case study design, and participant observations and a focus group methodology were used to explore the faith-based community residents' collaboration development, and design and implementation of the health promotion program. The implementation process can be described as occurring in four essential elements: (1) the development of the health ministry in each of the four churches; (2) the process in which the four ministries coordinated their activities to create the diabetes education program; (3) the process of delivering the diabetes education program; and (4) the challenges in promoting the diabetes education program across the community. Practice implications, as well as cultural competency issues related to social work practice with faith based organizations and African-American communities, are also presented. PMID- 21614730 TI - The suffering is similar--is the treatment equal? An intervention with Arab Terror injured. AB - In the course of the last Intifada and during the Second Lebanon War, all citizens of Israel were exposed to waves of terrorism that claimed many people wounded and killed, unrelated to religious differences, age, gender, or nationality: Jews and Arabs suffered alike. The acts of terror exposed all inhabitants equally to injury, suffering, and the need to adjust. The professional literature attests that minority groups are at a higher risk of experiencing post-traumatic symptoms as a result of exposure to acts of terror. This article describes the treatment with terror injured, Jews and Arabs, in the frame of the project for terror victims at Rambam Medical Center, in cooperation with Operation Embrace. It also covers the project intervention with casualties of the shooting incident in the Arab town of Shefaram, with the cooperation of Shefaram Social Welfare department. The psycho-social work conducted with the injured, Jews and Arabs, emphasized their similarities, their common fate, and the fact that any of us could be injured in a terror act or a war. The suffering, the loss, and the hurt are common to us all. At the same time, the interventions referred to cultural differences and the diverse ways of coping with the aftermath of the events, based on values, faith, and outlook on life arising from cultural background. PMID- 21614731 TI - Social determinants and health service use among racial and ethnic minorities: findings from a community sample. AB - Multiple models conceptualizing the relationship between social determinants and health exist, but little research has examined the relationship between social determinants and health service use. Using previously collected survey data from racial and linguistic minorities from high-crime communities in a Midwestern urban area, this study uses the Commission on Social Determinants of Health framework to test the structural and intermediary determinants of health service use. The results indicate that perceived discrimination and neighborhood cohesion increase the likelihood of a person using health services. Implications for social work practice, advocacy, and research to address intermediary social determinants are discussed. PMID- 21614734 TI - [Nasal douching in acute rhinosinusitis]. AB - BACKGROUND: Nasal douching is recommended for the treatment of a variety of diseases of the nose and paranasal sinuses. Nasal douching with saline solution has proven to be effective in chronic rhinosinusitis and after sinus surgery and is recommended by different otolaryngologic societies. MATERIAL AND METHODS: A systematic review of the literature was performed to determine whether nasal douching is effective in the treatment of acute rhinosinusitis and in preventing recurrent upper respiratory tract infections. We also reviewed whether nasal douching has adverse eff ects and can lead to recurrent upper respiratory tract infections if performed regularly over a longer period of time. RESULTS: Nasal douching with saline solution has a limited effect in adults with acute rhinosinusitis (level of evidence Ia). It is effective in children with acute rhinosinusitis in addition to the standard medication (level of evidence Ib) and can prevent recurrent infections (level of evidence IIb). It is assumed that nasal douching improves the function of the mucous membranes. There is currently no evidence that daily nasal douching with isotonic saline solution over a longer period of time has an adverse effect on the individual health or leads to a higher rate of infections. CONCLUSION: Nasal douching with saline solutions can be recommended for adults with acute rhinosinusitis (grade of recommendation A), in addition to the standard medication in children with acute rhinosinusitis (grade of recommendation A) and to prevent recurrent infections (grade of recommendation B). PMID- 21614736 TI - [Influence of an auto-motorised optical navigation camera to the surgical workflow in ENT surgery]. AB - BACKGROUND: With the application of optical navigation systems an interruption of the line of sight (LOS) between navigation camera and the patient/instrument can occur. The goal of this work is the clinical evaluation of a newly developed system for automatic adjusting of an optical navigation camera (Navigation Camera Assistant, NCA). NCA is a miniature robot, which is able to position the navigation camera autonomously in 2 levels. MATERIAL AND METHODS: The influence of the NCA was examined on 128 patients: 55 procedures at the paranasal sinuses and 9 procedures at the temporal bone with the NCA were evaluated and compared with available workflow data of adequate surgeries without NCA. An optical navigation system of the 3 (rd) generation was used. The following parameters were recorded: Preparation time of the system, time of using the system, LOS interruptions. RESULTS: The LOS-interruption decreased in the group of FESS with application of the NCA by 92%, in the group tympanic cavity by 85%. The number of corrective motions of the navigation camera was increased with application of the NCA in the group FESS by 73%, in the group tympanic cavity by 89%. The usage time of navigation increased with the application of the NCA in the group of FESS by 36%, in the group tympanic cavity by 16%. CONCLUSIONS: With a motorized navigation camera can be the interruption rate of LOS significantly improved at frontal and lateral skull base. The technical expenditure for installation of the NCA robot is little even during, for this reason there is the potential that this module can be established for the clinical practice. PMID- 21614737 TI - [Lymphatic and vascular invasion in laryngeal and pyriform sinus carcinomas]. AB - BACKGROUND: To investigate prognostic significance of the lymphatic and vascular invasion in patients with squamous cell carcinoma of the larynx and pyriform sinus. MATERIAL AND METHODS: Patients with squamous cell carcinoma of the larynx and pyriform sinus who underwent laryngectomies between 2002 and 2006 in the ENT Clinic of Cluj-Napoca were investigated for lymphatic and vascular invasion and their effect on disease-free survival and recurrence rates. RESULTS: The present study included 396 patients. The mean disease-free survival of patients with or without lymphatic invasion was statistically significant (p=0.000000). The mean disease-free survival of patients with or without vascular invasion was statistically significant (p=0.000021). In multivariant analysis, the lymphatic invasion was significantly correlated only with surgical resection borders (p=0.0004), while vascular invasion was significantly correlated with surgical resection borders (p=0.0000), nodes diameter (p=0.0075) and postoperative radiotherapy and/or chemotherapy (p=0.0002). CONCLUSION: Lymphatic and vascular invasion have a significant prognostic value and influence the disease-free survival, regional and distant metastasis rates significantly. PMID- 21614738 TI - [Inverted papilloma of the paranasal sinuses with intracranial extension]. PMID- 21614739 TI - [On call duty by senior physicians can also not be compensated at the flat rate]. PMID- 21614740 TI - [Fungal sinusitis]. AB - The incidence of fungal sinusitis is subjected to significant geographical variation. Basically, invasive and non-invasive fungal sinusitis is distinguished. Invasive fungal sinusitis is observed mainly in immunocompromised hosts. The diagnopsis is based on positive fungus detection combined with characteristic clinical features. The treatment of invasive fungal sinusitis is based on surgical debridement and systemic antifungal therapy. Non-invasive fungal sinusitis is either treated with surgery alone or surgery combined with systemic steroid therapy. The majority of studies showed no benefit of postoperative antimycotic medical treatment in patients with non-invasive fungal sinusitis. PMID- 21614741 TI - Radiation dose reduction in scoliosis patients: low-dose full-spine radiography with digital flat panel detector and image stitching system. AB - PURPOSE: To evaluate the exposure dose reduction with a digital flat panel detector (FPD) and an image stitching system (ISS) in full-spine radiography for scoliosis patients. MATERIALS AND METHODS: During a 6-month period, all consecutive scoliosis patients with a clinical indication for full-spine radiography (n = 50) were examined with an FPD and ISS. Automatic exposure control adjusted to speed class 1600 was used together with age-adjusted tube voltage and filtration. Dose area products were recorded for all images (antero posterior n = 50, lateral n = 18). Images were evaluated by two radiologists for the possibility (possible, impossible) of typical scoliosis measurements (Cobb angle, Stagnara angle, lateral deviation, Risser stage). All measurements assessed as impossible underwent a second evaluation categorizing the reason why a measurement was impossible (underlying pathology, projection, image quality). Patient characteristics influencing exposure were recorded (sex, age, weight, height). Mean dose area products were compared to the literature with consideration of patient group and image quality. RESULTS: The mean dose area product was 16.8 uGy m (2) for antero-posterior images and 26.6 uGy m (2) for lateral images. A comparison to published values showed an exposure dose reduction of 47 % to 93 %. Measurement of the Cobb and Stagnara angle, lateral deviation and Risser stage was possible in 96 % (n = 50), 83 % (n = 18), 100 % (n = 50) and 100 % (n = 50) of cases. The reasons for impossible measurements were independent of image quality (underlying pathologies, projection). CONCLUSION: When imaging scoliosis patients, an FPD combined with an ISS can substantially reduce the exposure dose. PMID- 21614742 TI - [Skeletal roentgen and scintigraphy findings in hemochromatosis]. PMID- 21614743 TI - Severe rhabdomyolysis caused by valproic Acid in a neonate with seizures and chromosomal abnormalities. PMID- 21614744 TI - Sonographic assessment of fetal cardiac function: introduction and direct measurement of cardiac function. AB - Noninvasive blood flow measurements based on Doppler ultrasound studies are the main clinical tool for studying the cardiovascular status in fetuses at risk for circulatory compromise. Usually, qualitative analysis of peripheral arteries and, in particular clinical situations such as severe growth restriction or volume overload, also of venous vessels close to the heart or of flow patterns in the heart are being used to gauge the level of compensation in a fetus. Quantitative assessment of the driving force of the fetal circulation, the cardiac output, however, remains an elusive goal in fetal medicine. This article reviews the methods for direct and indirect assessment of cardiac function and explains new clinical applications. Part 1 of this review describes the concept of cardiac function and cardiac output and the techniques that have been used to quantify output. Part 2 summarizes the use of arterial and venous Doppler studies in the fetus and gives a detailed description of indirect measures of cardiac function (like indices derived from the duration of segments of the cardiac cycle) with current examples of their application. PMID- 21614745 TI - Fetal aberrant right subclavian artery (ARSA) - a potential new soft marker in the genetic scan? AB - PURPOSE: The aim of this study was to evaluate the prevalence of an aberrant right subclavian artery (ARSA) in a mixed-risk population in the second trimester and to assess its potential as a new soft marker in the genetic scan. MATERIALS AND METHODS: Fetal echocardiography was performed prospectively in 1337 fetuses at 16 - 28 weeks of gestation during a 12-month period at two referral centers for prenatal diagnosis. The presence of ARSA was verified by visualization of the transverse 3-vessel trachea view with color Doppler sonography. RESULTS: The total rate of fetuses with an ARSA was 1.05 % (14 / 1337). The spectrum of associated findings in affected fetuses included: one trisomy 21, one unbalanced inversion of chromosome 9, one triploidy and two non-chromosomally related structural defects. Nine fetuses had no anomalies. The calculated odds ratio for the presence of an ARSA in the case of Down syndrome compared with healthy fetuses was 12.6 (95 % CI, 1.93 - 86.10). CONCLUSION: The presence of an ARSA is more common in fetuses with trisomy 21 and other chromosomal defects than in healthy fetuses. Although it can be considered as a weak marker, the second trimester diagnosis of an ARSA should prompt a detailed search for additional "soft markers" and structural defects. PMID- 21614746 TI - Pregnancy-related uterine arteriovenous malformations: experience from a single medical center. AB - PURPOSE: The purpose of this article was to investigate clinical ultrasonographic findings and the outcomes of post-pregnancy patients with acquired uterine vascular abnormalities including arteriovenous malformations (AVMs). MATERIALS AND METHODS: We performed a computerized database search for all patients with ultrasonographic findings of a vascular abnormality including AVM in our referral center between 2000-2008. An ultrasound finding of vascular abnormality was defined as an area of strong hypervascularity within the myometrium and the presence of marked turbulence. The inclusion criteria for angiography were abnormal vaginal bleeding in a hemodynamically stable patient, bhCG serum levels <= 30 mIU/ml, and ultrasound demonstration of large (>= 15 mm on the larger side of the vessel) or multiple vascular lesions. RESULTS: 16 women were identified, of whom 10 (63 %) underwent uterine artery embolization. Angiography confirmed the pre-interventional ultrasound diagnosis of AVM in all cases. AVM feeding arteries were on the left side of the uterus in 80 % of the cases. Residual tissue was ultrasonographically detected in five patients: 2 underwent hysteroscopy and guided curettage following embolization and three received methotrexate. All tissue samples were benign. One small vascular abnormality resolved spontaneously. CONCLUSION: An acquired uterine vascular abnormality including AVM should be considered in the work-up of post-pregnancy vaginal bleeding. PMID- 21614747 TI - [Intraobserver and interobserver reliability of introital ultrasound after tension-free vaginal tape (TVT) procedure]. AB - PURPOSE: To date, the evaluation of TVT by ultrasound has not been standardized. The aim of this observational study was to evaluate the intraobserver and interobserver variability of introital ultrasound. MATERIALS AND METHODS: Follow up was performed for 202 patients after TVT procedure. The tape was characterized by the position in relation to urethral length (%) and the distance to the hypoechoic center of the urethra (mm). Furthermore, we assessed the shape of the tape (straight, curved or folded). All evaluations were performed by two experienced examiners (A, B) at rest and during Valsalva maneuver. All sonograms were archived digitally without measurement results. After 6 to 12 months, the sonograms were re-evaluated by one investigator (A). Depending on the first investigator, the results were compared as intraobserver (A-A) or interobserver (B-A) agreement. The first results were blinded for the second measurement. Agreement concerning the distances was assessed using the intraclass correlation coefficient (ICC). The concordance of the descriptive evaluation of the shape of the tape was characterized by the kappa coefficient (KC). RESULTS: The tape was regularly identified as an echogenic structure dorsal to the urethra. The intraobserver reliability concerning the position of the tape in relation to urethral length showed good reproducibility (at rest ICC 0.90, Valsalva maneuver: ICC 0.96). For the distance between the tape and the urethra at rest (ICC 0.83), there was also good reproducibility, but not during Valsalva maneuver (ICC 0.74). The shape of the tape showed only moderate reproducibility with accordance of 81 % at rest (KC 0.68) and of 79 % during Valsalva maneuver (KC 0.6). The interobserver comparisons showed good concordance in measuring the POS at rest (ICC 0.93), and during Valsalva maneuver (ICC 0.89), and the DIS at rest (ICC 0.89), and during Valsalva maneuver (ICC 0.87). The congruence of the estimation of the shape was 71 % at rest (KC 0.44) and 72 % during Valsalva maneuver (KC 0.49). CONCLUSION: The characterization of the TVT in the sagittal view by introital ultrasound shows good reproducibility with respect to position and distance, but not shape. PMID- 21614748 TI - [Long-term outcome of children with prenatal diagnosed tachyarrhythmia]. AB - PURPOSE: The aim of this study was the follow-up of children with a prenatal diagnosis of tachyarrhythmia up to an age of 5 years in order to assess the long term outcome of these children. MATERIALS AND METHODS: All fetuses diagnosed with prenatal tachyarrhythmia between April 1993 and June 2004 in the Division of Prenatal Medicine, Department of Obstetrics and Gynecology, University Hospital of Schleswig-Holstein, Campus Lubeck were identified and the children's parents and pediatricians were contacted for retrospective data on the children's health. The data from the compulsory examinations (U1-U9) were used for analysis. RESULTS: 49 cases (93%) were enrolled in this study. 23 fetuses had supraventricular tachycardia (SVT), 10 had an atrial flutter (AF) and 16 had paroxysmal supraventricular tachycardia (pSVT). Intrauterine conversion into sinus rhythm was achieved in 41 of 44 treated fetuses (93%). 17 of 48 cases showed tachyarrhythmia postnatally (35%). 15 of these newborns were treated with antiarrhythmic medication between 4 days and 46 months. The follow-up rate in the 3 subgroups ranged from 78-100%. At the time of the U9 examination, 69-100% of the children were healthy. During the examinations there was an increase in motor activity delay and language development delay with a maximum at U5 and U9, respectively. CONCLUSION: Overall, on the basis of the long-term follow-up of 49 children, we could show that prenatal tachyarrhythmia has a good prognosis. Increased motor activity and language development delay are important for patient counseling. Substantial cardiac and extracardiac anomalies are associated with an unfavorable outcome. PMID- 21614749 TI - Significant differentiation of focal breast lesions: raw data-based calculation of strain ratio. AB - PURPOSE: We compared elastography, B-mode ultrasound and mammography to determine whether raw data calculation of strain ratios (SRs) can further improve the differentiation of focal breast lesions. MATERIALS AND METHODS: 201 women with histologically proven focal breast lesions (85 benign, 116 malignant) were included at two German breast centers. Patients underwent a standardized ultrasound procedure using high-end ultrasound system with a 9-MHz broadband linear transducer. Two experienced readers analyzed the B-mode scans and mammograms using the BI-RADS criteria, while elastograms were analyzed using the Tsukuba score. SRs were calculated from a tumor-adjusted ROI and a comparable ROI placed in the lateral fatty tissue. The sensitivity, specificity, and cutoff values were calculated for SRs (ROC analysis). RESULTS: The median age was 53 years. The sensitivity and specificity were 85 %/ 60 % for B-mode scanning, 85 %/ 68 % for elastography, 78 %/ 62 % for mammography, and 95 %/ 74 % for SRs. An SR cutoff value of 2.27 (AUC 0.907) allowed significant differentiation (p < 0.001) between malignant and benign lesions. The quantitative SR calculation was superior to subjective interpretation of B-mode scans and sonoelastograms with a positive predictive value of 83 % versus 78 % and 74 %, and equal to mammograms. CONCLUSION: Strain ratio calculation contributes to the standardization of sonoelastography with high sensitivity and allows significant differentiation between benign and malignant breast lesions with a higher specificity compared to B-mode, subjective evaluation of elastography and mammography. PMID- 21614750 TI - Antitumor activity of taspine by modulating the EGFR signaling pathway of Erk1/2 and Akt in vitro and in vivo. AB - EGFR, as a critical signaling pathway in many human tumors, has become an important target of cancer drug design. Taspine has shown meaningful angiogenesis activity in previous studies. This paper is to investigate the antitumor action of taspine by modulating the EGFR signaling pathway. The study determined the expression of key signaling molecules of EGFR (EGFR, Akt, p-Akt, Erk, and p-Erk) by Western blot and real-time PCR and analyzed their correlations with subsequent reactions. In addition, the cell proliferation, migration, and EGF production were examined by MTT, transwell system, and ELISA. The antitumor activity in vivo was carried out by xenograft in athymic mice. The results showed that taspine could inhibit A431 and Hek293/EGFR cell proliferation and A431 cell migration as well as EGF production. Compared to the negative control, EGFR, Akt, and phosphorylation of Akt were significantly inhibited by taspine treatment in A431 and HEK293/EGFR cells. Consistent with the inhibition of Akt activity, Erk1/2 and its phosphorylation were reduced. Moreover, taspine inhibited A431 xenograft tumor growth. These results suggest that EGFR activated by EGF and its downstream signaling pathways proteins could be downregulated by taspine in a dose-dependent manner. The antitumor mechanism of taspine through the EGFR pathway lies in the ability to inhibit A431 cell proliferation and migration by reducing EGF secretion. This occurs through the repression of EGFR which mediates not only MAPK (Erk1/2) but also Akt signals. PMID- 21614751 TI - Two new ginkgolides from the leaves of Ginkgo biloba. AB - Two new diterpenoid compounds, ginkgolide P(1) and ginkgolide Q(2), were isolated from the leaves of Ginkgo biloba L. Their structures were elucidated by various spectroscopic methods, and the structure of 1 was further confirmed by X-ray crystallographic analysis. The activities of the compounds were evaluated against platelet aggregation induced by platelet activating factor (PAF), and the preliminary structure-activity relationship was also discussed. PMID- 21614752 TI - Astilbin attenuates hyperuricemia and ameliorates nephropathy in fructose-induced hyperuricemic rats. AB - Astilbin is a flavonoid compound isolated from the rhizome of Smilax china L. The effects and possible mechanisms of astilbin on hyperuricemia and nephropathy rats were elucidated in this study. Different dosages of astilbin (1.25, 2.5, and 5.0 mg/kg) were administered to 10 % fructose-induced hyperuricemic rats. The results demonstrated that astilbin significantly decreased the serum uric acid (Sur) level by increasing the urinary uric acid (Uur) level and fractional excretion of urate (FEUA) but not inhibiting the xanthine oxidase (XOD) activity. In addition, kidney function parameters such as serum creatinine (Scr) and blood urea nitrogen (BUN) were recovered in astilbin-treated hyperuricemic rats. Further investigation indicated that astilbin prevented the renal damage against the expression of transforming growth factor- beta1 (TGF-beta1) and connective tissue growth factor (CTGF) and also exerted a renal protective role by inhibiting formation of monosodium urate (MSU) and production of prostaglandin E2 (PGE2) and interleukin-1 (IL-1). These findings provide potent evidence for astilbin as a safe and promising lead compound in the development of a disease-modifying drug to prevent hyperuricemia and nephropathy. PMID- 21614754 TI - Biliary stents: models and methods for endoscopic stenting. AB - Biliary stenting is widely used to palliate malignant obstruction or to treat benign biliary diseases. Recently, the most important changes have related to self-expandable metal stents (SEMSs), which are now available in a wide variety of designs, and to treatment techniques. This article is part of a combined publication that expresses the current view of the European Society of Gastrointestinal Endoscopy (ESGE) about endoscopic biliary stenting: a technology review describes the stent models and stenting techniques, and a separate clinical guideline states the evidence and recommendations regarding stenting. PMID- 21614753 TI - Cryptotanshinone attenuates in vitro oxLDL-induced pre-lesional atherosclerotic events. AB - Development of early stage atherosclerosis involves the activation of endothelial cells by oxidized low-density lipoprotein (oxLDL) with subsequent increases in endothelial permeability and expression of adhesion molecules favoring the adherence of monocytes to the endothelium. Cryptotanshinone (CTS), a major compound derived from the Chinese herb Salvia miltiorrhiza, is known for its protective effects against cardiovascular diseases. The aim of this study was to determine whether CTS could prevent the oxLDL-induced early atherosclerotic events. OxLDL (100 ug/mL) was used to increase endothelial permeability and induce monocyte-endothelial cell adhesion in human umbilical vein endothelial cells (HUVECs). Endothelial nitric oxide (NO) concentrations, a permeability regulating molecule, and expressions of intercellular adhesion molecule-1 (ICAM 1) and vascular cell adhesion molecule-1 (VCAM-1) were measured. Results show that a) endothelial hyperpermeability was suppressed by 94 % (p < 0.005), b) monocyte adhesion by 105 % (p < 0.01), and c) ICAM-1 and VCAM-1 expressions by 90 % (p < 0.01) and 150 % (p < 0.005), respectively, when CTS was applied. In contrast, CTS increased NO levels by 129 % (p < 0.01) and was found to be noncytotoxic in the concentrations between 1-10 uM. These findings indicate that CTS suppresses an increase in endothelial permeability, likely due to the restoration of NO bioavailability in endothelial cells. They also indicate that CTS may attenuate monocyte adhesion to endothelial cells through the inhibition of adhesion molecules' expression. Thus, CTS may play an important role in the prevention of early or pre-lesional stage of atherosclerosis. PMID- 21614755 TI - Use of endoscopic nasobiliary drainage tube for treating mediastinitis caused by insertion of an esophageal self-expanding metal stent. PMID- 21614756 TI - A newly designed plastic stent for multiple occluded metallic stents deployed in malignant hilar biliary strictures. PMID- 21614757 TI - Spraying N-butyl-2-cyanoacrylate (Histoacryl) as a rescue therapy for gastrointestinal malignant tumor bleeding after failed conventional therapy. PMID- 21614758 TI - KCH, the German preoperative score for isolated coronary artery bypass surgery: is it superior to the logistic EuroSCORE? AB - BACKGROUND: The accuracy of the logistic EuroSCORE in different patient populations has been questioned. Using the German registry database, the KoronarCHirurgie (KCH) score was introduced as a preoperative risk stratification tool specifically for patients who undergo isolated coronary artery bypass surgery in Germany. However, no direct statistical comparison of this score with the well-established logistic EuroSCORE has been previously performed. The aim of this study was to validate the preoperative German KCH score and to compare it to the logistic EuroSCORE for all coronary artery bypass surgery patients as well as for on-pump and off-pump subgroups. METHODS: We prospectively included all consecutive adult patients admitted to our department between January 1, 2007 and December 31, 2008, who underwent isolated coronary artery bypass surgery. The logistic EuroSCORE and the KCH-3.0 were calculated on admission to hospital. The outcome was defined as 30-day mortality. We performed calibration (Hosmer Lemeshow test and Anderson-Grunkemeier Observed/Expected "O/E" mortality ratio) and discrimination (receiver operating characteristic "ROC" test) analyses of both scores. The accuracy of the scores was compared using DeLong's test. RESULTS: A total of 1461 patients (23.96 % females, mean age 66.94 +/- 9.43 years) were included. The 30-day mortality rate was 2.87 %. The two models were comparable with regard to the prediction of an individual patient's risk of mortality in the whole study population and in the on-pump and off-pump subgroups (according to the ROC test and DeLong's test). Overall, there was no significant difference between observed and expected mortality according to the Hosmer Lemeshow test ( P > 0.05). However, the KCH-3.0 was far less likely to overpredict mortality than the logistic EuroSCORE, as demonstrated by the observed mortality/expected mortality (O/E) ratios. The O/E ratio was 0.32 for the logistic EuroSCORE and 0.74 for the KCH-3.0. For the on-pump subgroup the O/E ratios were 0.37 and 0.80, respectively, and 0.24 and 0.63, respectively, for the off-pump subgroup. CONCLUSIONS: The KCH-3.0 is more reliable than the logistic EuroSCORE as a preoperative mortality prediction score for patients undergoing isolated coronary artery bypass surgery, providing predicted mortality rates that are closer to the actual mortality rates with a lower overprediction of mortality. PMID- 21614759 TI - [The fasting patient]. PMID- 21614761 TI - [Comment from the current viewpoint on the article: "Do we have an etiological goiter prevention" from PRAXIS 1924]. PMID- 21614762 TI - [Chronic pain - new therapeutic strategies]. AB - Patient suffering from chronic pain need treatment in a multimodal setting. Enriched environment might be a new therapeutical approach. PMID- 21614763 TI - [Management of enuresis in children and adolescents: summary of the NICE guideline]. PMID- 21614764 TI - [An uncommon reason for facial hypoesthesia]. AB - A 58-year-old female admitted herself to the emergency department with progressive left-sided facial hypoesthesia. Magnetic resonance imaging revealed a 20 mm-sized aneurysm of the left vertebral artery leading to compression of the trigeminal nerve. An endovascular occlusion with a combined coiling and flow diverter was performed. The left posterior inferior cerebellar artery (PICA) arised from the aneurysmal sac. Despite an extensive infarction of the left PICA territory, the patient convalesced well and presented completely independent and without symptoms at the 4-week follow-up. PMID- 21614765 TI - [Rheumatoid arthritis and interstitial lung alterations - a clear case, isn't it?]. AB - In a patient with rheumatoid arthritis (RA) and asymptomatic, diffuse reticulo nodular lung parenchymal alterations with upper lobe predominance, a Caplan syndrome (CS) was diagnosed. According to the size of the pulmonary nodules, classification into two subtypes of the CS has been proposed: the classic (Caplan) type and the silicotic type. Patients with CS often present with considerable x-ray or computertomographic changes but relatively few symptoms. However, in case of respiratory symptoms, infectious complications or pneumotoxic side effects of the immunsuppressive/immune-modulating pharmacotherapy for RA must be encountered in the differential diagnosis. PMID- 21614766 TI - [An unusual ascites...]. AB - The finding of an ascites in in- or out-patients in inner medicine is relatively frequent. However, the differential diagnosis sometimes extends in rarer pathologies which need rapid investigations to begin a treatment and improve the patient's prognosis. We present the case of a 50-year-old patient with a progressive ascites in the context of a peritoneal carcinosis due to a malignant peritoneal mesothelioma. PMID- 21614767 TI - [Not Available]. PMID- 21614768 TI - [Not Available]. PMID- 21614770 TI - [CME-ORL 2. Chronic recurrent juvenile parotitis]. PMID- 21614773 TI - On the usefulness of the history of nephrology. PMID- 21614774 TI - Jean-Martin Charcot: neurologist by avocation, nephrologist by yearning. AB - In an age of medical advances and specialization, Jean-Martin Charcot (1825-1893) helped found the discipline of neurology and in 1882 was appointed the first Professor of Diseases of the Nervous System in France. As an investigator with broad interests and vast knowledge, Charcot contributed to several other disciplines. An early mentor and dominant figure in Charcot's formative years was Pierre Rayer (1793-1867), famous for his seminal contributions to the study of the kidney, who gifted to Charcot his passion for clinical pathological correlations and likely a yearning for the study of kidney diseases. Famous for the clarity and incisiveness of his formal teaching presentations, Charcot lectured on the kidney at the Faculty of Medicine in Paris in 1877. Translated into English and published as a book titled Lectures on Bright's Disease, those lectures became widely accessible and quoted in the literature through the 1940s. In addition, at a time when he was already concentrating on the study of neurological disorders, Charcot maintained his life-long interest in the kidney and published original studies on the pathological changes of the kidney in gout and experimental lead poisoning, as well as supporting a study of hysterical ischuria by his students. PMID- 21614775 TI - Medicine in the Encyclopedie (1751-1780) of Diderot and d'Alembert. AB - On July 1, 1751, the royal Parisian printer Le Breton published the first volume of the Encyclopedie of Diderot and d'Alembert, a rational dictionary, in folio and in alphabetical order, sold by subscription. The whole work was completed in 1780 (a total of 35 volumes, of which 12 were of illustrations, 4 of supplements and 2 of indices). In 1782 it was followed by the Encyclopedie methodique, printed by Panckoucke, which ended in 1832 with volume number 166. The frontispiece of the first volume, designed by Charles-Nicolas Cochin Jr. and engraved by Benoit-Louis Prevost showed the columns of an Ionic temple where the Truth appears between Reason and Philosophy. Reason is shown trying to break the veil of Truth, and Philosophy trying to embellish it. Below are the philosophers, their eyes fixed on Truth. Theology is on his knees with his back facing Truth, and seems to receive light from the top. The subsequent chain of figures depicts Memory, Ancient History, Modern History, Geometry, Astronomy and Physics. Below are Optics, Botany, Chemistry and Agriculture. On the bottom line one finds the representatives of arts and professions derived from science. In a 42-page preface ("Discours preliminaire") d'Alembert discussed the path to new knowledge as one "based on what we receive through senses. Ideas depend on senses." The medical collaborators were, or became, famous. Medicine was considered to be rooted in experiment, in patients and in measurements. Functions started to be described with numbers. It was the birth of determinism which was later reinforced by Magendie and Claude Bernard. Albrecht Haller, president of the Academy of Science at Gottingen, as well as a member of all European academies, wrote seminal entries. New accurate definitions appeared for life, disease, death, infections, plague, epidemics, hygiene, fevers and edema. Semiology, the study of signs, became the visible explanation of deranged function, diagnosis and prognosis. PMID- 21614776 TI - Nicolaus Copernicus: not only a great astronomer but also a physician. AB - Nicolaus Copernicus (1473-1543), an internationally recognized Polish astronomer, studied liberal arts at the Jagiellonian University in Cracow during the period 1491-1495. Shortly thereafter he was sent by his uncle to Bologna University, where he spent almost 5 years (1496-1501) studying law and philosophy. After his return to Poland, Nicolaus was nominated as canon in the cathedral chapter in Frombork. Next he started to study medicine in the University of Padua, one of the best-known centers of medical education in Europe. He was granted a bachelor degree and after another year, a therapeutic license (veniam practicandi), but never obtained his doctoral degree from Padua, though he was always called doctor of medicine ("medici doctor"). Copernicus returned to Warmia in 1503 and spent almost 40 years there. During the first few years he was the personal "medicus" and secretary of his uncle, Bishop Lucas Watzenrode. After the death of his uncle in 1512, Copernicus became the personal physician to the subsequent 4 Warmian bishops and his confreres from the Warmian chapter in Frombork. Copernicus practiced medicine not only in diagnosing and taking care of his patients but also in personally preparing the prescribed drugs. He was often consulted (consiglia) from several other cities, including Gdansk, Konigsberg, Lubawa, Elblag and Olsztyn. He also collaborated and consulted with Jan Benedict Solfa and Laurence Wille, the official Polish royal physicians at the time. During the epidemics of 1519, Copernicus employed sanitary preventive measures by providing several Warmian and Pomeranian towns with an innovative water supply system. Copernicus is well known as a genius in astronomy, but this great Renaissance man was also a mathematician, engineer, soldier, writer, economist and, last but not least, a practicing physician. PMID- 21614777 TI - Was the famous astronomer Copernicus also a nephrologist. AB - Nicolaus Copernicus (1473-1543), world-famous astronomer, born in Torun, was also a Warmian canon (senior priest) and a physician to 4 consecutive prince-bishops of Warmia and of other Warmian canons. What medical conditions preoccupied Nicolaus Copernicus and whether they included kidney diseases can only be inferred from the extant prescriptions of Copernicus, as no record remains of any treatises by Copernicus regarding medicine. While no prescription penned by him is dated, several are traced to the period of his studies in Padua, Italy. The prescriptions indicate that he was concerned with conditions afflicting virtually all systems and organs of the human body including the kidneys. His personal library included at least 45 books, of which 14 dealt with medical issues. Copernicus used to write his prescriptions in the margins or on the blank pages of the treatises. They were mostly based on Avicenna's original prescriptions. The most common herbal ingredients used by Copernicus as remedies for symptoms of renal colic, hematuria and diuresis were common nettle (Urtica dioica), goosegrass (Galium aparine), rosemary (Rosmarinus officinalis), cubeb (Piper cubeba), common pumpkin (Cucurbita pepo), almond seeds and many others. It is hard to ascertain how effective the medical methods utilized by Copernicus may have been. PMID- 21614778 TI - Nephrology in A Medicinal Dictionary of Robert James (1703-1776). AB - Robert James was a member of the College of Physicians at Cambridge and a practitioner. He was considered one of the "three best known characters in London -perhaps in Europe. The other two being the lexycographer Samuel Johnson and the Shakespearean actor David Garrick." James became famous for his powerful ability to write and publish, which produced many books, including the ponderous A Medicinal Dictionary, With a History of Drugs, in 3 volumes in folio, published in London in the years 1743-1745, and dedicated to the famous professor and royal physician John Mead. The Dictionary was translated into French by Denis Diderot, Francois-Vincent Toussaint and Marc Antoine Eidous, and was revised by Juliene T. Busson, president of the University of Paris. During the translation, Diderot learned much biology and medicine, which he used subsequently in developing his Encyclopedie. Interesting chapters are devoted to urine, predictions from urine, bloody urine, good urine, bad urine, urine portending death, diabetes, dropsy, nephritis, stone, ischury, dysury and urine incontinence. In general their strength resides in their accurate clinical descriptions. The paragraphs on urine are concise and clinically sound, and the description of procedures for urine analysis and the utilization of results (quantity, quantity, colors, sediments and consistency) in diagnosis and prognosis of bloody urine is accurate. The section on diabetes is excellent and is comparable to that of Desault written decades later in the Encyclopedie of Diderot. In the chapter on dropsy (he does not use the word oedema), patients are well described and their remedies are appropriate for the time. The contributions of kidney and liver are clear. The plants for renal treatment can be traced to Dioscorides. Concerning dosage, he is precise and helpful to his readers. The chapter on stones is a real masterpiece, clinically well centered and giving all the pertinent information to localize them, their medical treatment and the risks of surgery. The entry on nephritis is short and rather confusing. Here James even lacks the usual accurate description of cases which could have made it understandable. Blood letting was extensively used in those days, and he is a man of his time, but James was aware of the clinical conditions where it fails. It is understandable that he underlines its role in certain bloody urines in patients with a plethoric constitution. Was James referring to patients with acute nephritis and possibly high blood pressure. PMID- 21614779 TI - Karl Peter's fundamental contribution to the structural organization of the kidney. AB - Karl Peter provided the first detailed description of the structure and morphology of the human kidney and defined at least 9 major segments of the tubules. He showed that the nephrons were heterogeneous in their structure and could be divided in 2 categories: the short-looped and the long-looped ones. Peter's scheme of the human nephrons was published in many journals and textbooks. Another contribution was the demonstration of a relationship between the relative occurrence of long thin loops (versus short loops) and the maximal urinary concentration capacity. Peter was also the first to describe the cells of the macula densa, which are of fundamental importance in the tubuloglomerular feedback mechanism. Furthermore, Peter gave a detailed description of the principal zones of the human kidney: the cortex, the outer medulla with outer and inner stripes, and the inner medulla. PMID- 21614780 TI - Leon Marchlewski: one of the precursors of clinical chemistry. AB - Dynamic progress in the basic sciences such as clinical chemistry exerted a great influence on the development of clinical science in medicine in the 19th century. We should rate Prof. Leon Marchlewski among the group of prominent foreign and Polish scientists working in that period. Marchlewski was born in 1869 in Wloclawek, Poland. He began his chemical studies in Warsaw and then continued at the Zurich Technical University. After having graduated, he began working in the famous Edward Schunk's laboratory in Kersal near Manchester in England. At that time he achieved recognition for his research on the chemical affinity of dyes of the animal and plant world. Later he cooperated in this field with another great scholar Marceli Nencki. In 1900 he returned to Poland, and in 1906 he took charge of the Department of Medical Chemistry at Jagiellonian University. He was nominated for the Nobel Prize twice in 1913 and 1914 for his numerous achievements in the field of clinical chemistry. He took many positions at Jagiellonian University in Krakow, including dean and rector. In 1930-1935 he was a senator of the Republic of Poland. He died in 1946 in Krakow. PMID- 21614781 TI - Thomas Addis, MD (1881-1949): Scottish-American clinical laboratory researcher, social activist and pioneer of renal medicine. AB - Addis was born and educated in Edinburgh, from the University of which he graduated MB in 1905, and MD in 1908, in which year he also gained membership of Edinburgh's Royal College of Physicians. After researching disordered haemostasis associated with various clinical conditions, he spent over a year in Germany: in Berlin with Dr. E.L. Salkowski learning urinalysis and at Heidelberg under Ludolph von Krehl studying haemophilics. Back in Edinburgh he concluded that the ultimate cause of haemophilia was an 'anatomical defect in the molecule of prothrombin'. He was the first to monitor the effects on plasma clotting times of transfusion of anticoagulated blood into a haemophilic. In 1911 he was recruited by Ray Lyman Wilbur, the first dean of the Stanford University School of Medicine, to investigate metabolic disorders including jaundice, diabetes and ultimately chronic renal disease. In 1917 he described the 'urea ratio'--the mathematical and conceptual forerunner of clearance formulae--and over the next 30 years developed a combined clinical and laboratory service for patients with inexorably failing kidneys. He devised an effective, rational and individually based dietary treatment--some patients such as Linus Pauling, who presented in 1941 with marked nephrosis, responded completely. Addis' Calvinist upbringing gave him a strong sense of 'mission' which during the American Depression developed into support for poverty-stricken workers in America, and against the fascists in Spain. He died before the full development of the 'McCarthy Witch Hunts' of the 1950s, although many associates, including Robert Oppenheimer, were interrogated. PMID- 21614782 TI - Tadeusz Orlowski: founder of nephrology and kidney transplantation in Poland. AB - Modern nephrology in Poland and in the world owes much to the scientific, clinical and organizational activities of Prof. Tadeusz Orlowski. He was a pioneer in many fields of kidney disease. His pathophysiological work included studies on renal dysfunction in heart and liver diseases, function of the transplanted kidney and various aspects of the uremic syndrome. He was engaged in the development of hemodialysis and peritoneal dialysis in Warsaw. Together with surgeon Jan Nielubowicz, he initiated the transplant program in Poland and on January 26, 1966, successfully transplanted a kidney in a patient on chronic dialysis. This success was followed by establishment of the Transplantation Institute of the Warsaw Medical Academy in 1975, which facilitated the scientific and clinical growth of nephrology and transplantation in Poland. He also introduced and established scientific evidence for the use of immunosuppressive therapy for glomerular diseases. The heritage of Tadeusz Orlowski is broader than nephrology. His legacy will continue through the work of the many who learned from his example. PMID- 21614783 TI - Jan Brod and his contributions to hypertension and nephrology. AB - The author of this paper was one of the postgraduate medical students of Prof. Jan Brod, MD, DSc, FRCP, from the former Czechoslovakia. The manuscript includes a short biography and his complicated curriculum vitae. Professor Brod was one of the greatest well-known nephrologists and cardiologists, who worked in Europe and elsewhere in the 20th century. He exerted a significant influence on the development of nephrology in Slovakia during his productive scientific and research activities in Prague. PMID- 21614784 TI - Tracing the roots of the idea of dialysis: a leap of 20 centuries--from "catharsis" to dialysis. AB - In this article, we comment on a primitive foresight of Galen's regarding the value of blood purification. His main arguments are based on: (i) The disease blood concept, i.e., the idea that blood can be unclean (with an either excess or bad-quality humor) and thus cause a disease; (ii) Cure can be achieved if elimination (catharsis in Greek) of the humor (toxin) is possible; (iii) If the toxins are limited in the intravascular space, their elimination will be sufficient for cure by just a single attempt of replacing the unclean blood with pure; (iv) If the toxins have also affected the extravascular space, then repeated attempts will be needed; (v) The whole procedure can be compared with the insufficiency of washing once a dirty clay pot and immediately filling it with a pure liquid. The dirt that has adhered to the pot's walls will contaminate the pure liquid. Thus, repeated washing is needed to achieve cleanliness. Galen's metaphor of washing a dirty pot for a long period and eventually achieving a pure content is strikingly similar to the theory of hemodialysis. According to this, uremic toxins are spread both intravascularly and extravascularly. To eliminate them, long and repeated "washing" of the blood is needed. One of the reasons the first attempts to dialyze failed was that this "washing" procedure was inadequate (the other reasons were clotting of the blood, infections and access problems). PMID- 21614785 TI - The 50th anniversary of long-term hemodialysis: University of Washington Hospital, March 9th, 1960. AB - The first 6 months of 1960 saw the development of the shunt that first made long term hemodialysis possible for patients dying from chronic kidney failure. A brief account of hemodialysis for acute kidney failure prior to 1960 is followed by a description of the work of Belding Scribner, Wayne Quinton and David Dillard at the University of Washington in Seattle. Scribner had the idea of a shunt connecting indwelling arterial and venous cannulas in the forearm between dialyses, to maintain patency of the cannulas, Quinton used Teflon tubing to make the device, and Dillard was the surgeon who implanted the first shunt on March 9th, 1960. The patient, Clyde Shields, was a 39-year-old man dying from uremia secondary to chronic glomerulonephritis. The shunt worked, and Clyde lived a further 11 years on dialysis. Scribner took Quinton and Clyde to the American Society for Artificial Internal Organs (ASAIO) meeting in April and showed Clyde to physicians interested in dialysis, and Quinton demonstrated fabrication of the shunt. In June 1960, 2 landmark papers describing cannulation and the treatment were published in the Transactions of the ASAIO. Today there are some 2 million patients with end-stage renal disease living worldwide. PMID- 21614786 TI - Unknown Polish pioneers of peritoneal dialysis. AB - Peritoneal dialysis is one of the methods of renal replacement therapy. The first research using a patient's peritoneal membrane for this purpose appeared at the turn of the 19th to 20th century. Among the many scientists dealing with this field of medicine during that period were also Polish representatives: Prof. Marceli Landsberg, Prof. Henryk Gnoinski and Dr. Tadeusz Szenkier. In the 1920s, independent of their foreign colleagues, they carried out and published interesting experiments on animals in Polish and foreign magazines. They indicated the possibility of using the peritoneal membrane and also the intestines, in uremia treatment. After a long period in which the development of peritoneal dialysis was restrained by the rapidly expanding development of hemodialysis, one saw its resurgent development. And here again Polish scientists made their contribution: among others, Profs. Zbylut Twardowski and Zofia Wankowicz contributed in a significant way and are still contributing to the development of peritoneal dialysis in the world and in Poland. PMID- 21614787 TI - History of nephrology and renal replacement therapy in Korea. AB - Korea has a long tradition of Eastern (Korean) medicine. Modern nephrology in Korea began in the 20th century after the Second World War. The first nephrology report was presented in 1949 at the third annual meeting of the Korean Society of Internal Medicine. The first hemodialysis was performed in 1952 during the Korean War, the first acute peritoneal dialysis in 1957, the first kidney biopsy in 1959, the first kidney transplantation in 1969 and the first continuous ambulatory peritoneal dialysis in 1981. National Health Insurance was launched in 1976 with a limited coverage, which was gradually expanded to cover all Korean nationals in 1989. The Korean Society of Nephrology (KSN) was inaugurated in 1980. The KSN End-Stage Renal Disease (ESRD) Registry was started in 1985. Brain death legislation was enacted, and the Korean network for organ sharing launched in 2000. During 2009, a total of 8,906 patients or 175.9 patients per million population (PMP) began renal replacement therapy (RRT), and at the end of the year a total of 56,396 patients or 1,113.6 patients PMP were on RRT in Korea. The prevalence of ESRD continues to grow in Korea while its incidence is stable or declining as compared with the previous year. PMID- 21614788 TI - History of renal replacement therapy in Baltic countries. AB - The history of renal replacement therapy (RRT) in the 3 Baltic countries can be divided into 2 periods: the Soviet period (1944-1991) with strict central regulation and isolation from Western countries, and the period of independence (1991 to the present). Between 1963 and 1967, hemodialysis was used in cases of acute kidney injury and later in chronic renal failure, but only for patients suitable for kidney transplantation. The first renal transplant was performed in 1968, in Tartu, Estonia, and shortly thereafter, in Lithuania and Latvia. During the period of independence, development of RRT has been extremely rapid, and now this field of the health system has no major differences from that in other developed countries. PMID- 21614789 TI - History of circumcision: a religious obligation or a medical necessity. AB - Circumcision is the oldest documented surgical procedure. Practiced for ritual religious and likely medical purposes, it seems to have emerged in Egypt and was adopted by the western Semitic tribes. In biblical times, circumcision became a religious doctrine described in the Covenant between God and Abraham in the book of Genesis. Although some claim that there are medical advantages to being circumcised, available data do not support a medical benefit for circumcision. PMID- 21614790 TI - Byzantine doctrines on uroscopy in the Liber Orinalibus of Hermogenes (codex 69 Montecassino). AB - The Liber medicine orinalibus (codex 69 Montecassino) of Hermogenes is the first known manuscript to have a Latin translation from the original Greek work of Magnus of Emesa (or Nisibis). The particular text here translated, from the so called Commentatio, mentions direct transliteration of Greek concepts such as chyma and hypostasis, suggesting that the Latin text derived directly from the Greek original, without the intermediation of Arabic translations. The implementation of our text is considered to have been undertaken in the city of Ravenna, which housed a medical school during the sixth century ad, or in southern Italy, with its scriptoria. Evidence of the presence of Latin translations of Greek medical texts in Calabria during the Gothic age is provided by Cassiodorus (Inst. 1, 31, 2). The Greek to Latin workshops testify to an uninterrupted activity of copying from Greek medical texts, with particular attention to the Iatrosophists of the Alexandrian school, of which Magnus was a representative. PMID- 21614791 TI - A 15th-century treatise on kidney affections and their treatment? A first approach. AB - Two Greek manuscripts have preserved a short treatise On the Diagnosis of Kidney Pathologies and Their Treatment attributed to Galen. In the present article, I study the content of this work and suggest that it may describe the effect of gout on the kidneys, unless it describes pseudogout, that is, chondrocalsinosis of kidneys. On this basis, I suggest that the treatise is not by Galen, but by the 15th-century Byzantine physician Demetrios Pepagomenos. PMID- 21614792 TI - On some exotic urine colors in ancient and Byzantine Greek literature. AB - This work does not analyze the entire subject of uroscopy but focuses on a very small part thereof: i.e., some rare urine colors, in particular green and blue. These are so rare that most modern nephrologists have never encountered them. We conducted a small survey comparing contemporary knowledge with that of the past, with the participation of 40 Greek nephrologists (25 juniors and 15 seniors). Of these, 63% rejected the notion that green or blue urine even exists, while of those who were aware of them, only 20% had personally encountered them. According to our search of the modern literature, such colors result from either consumption of green or blue pigments, liver dysfunction or urine infection by certain bacteria. We searched and traced several passages on these rare urine colors, referred to in ancient Greek fewer than 7 different names, in the Greek medical literature of the Classical, Roman and Byzantine eras. In these passages, the authors not only gave detailed descriptions of the medical conditions of the corresponding patients but also explained this appearance of the urine. Surprisingly, in the studied texts we also found identical explanations with those in modern texts: consumption of certain foods, liver disease and inflammation. We present and comment on these passages, concluding that many uroscopical findings of antiquity were not quackery, but rather reliable medical statements based on thorough observation and rational reasoning. PMID- 21614793 TI - Urine therapy through the centuries. AB - Urine has always interested and attracted the attention of people. It was in fact never considered a waste product of the body but rather as a distilled product selected from the blood and containing useful substances for the care of the body. It was referred to as the "gold of the blood" and "elixir of long life," indicating its therapeutic potential. This paper reports on the practice of urine therapy since its origin attributed to the Indian culture, and briefly reviews its use through the centuries and different cultures and traditions. Records from the Egyptians to Jews, Greeks, Romans and from the Middle Ages and the Renaissance testify to the practice of urine therapy--a practice that continues to be found in more recent times, from the 18th century to the present. Experiences with the practice of urine therapy have even been discussed and shared recently in 2 different conferences: in 1996 in India and in 1999 in Germany, where people from different countries shared and presented their own research on urine therapy. PMID- 21614794 TI - Mercury and the kidney. AB - Humans have had a history of association with mercury since the earliest records. This relationship has had many quixotic elements, but has on many occasions and in many ways impinged upon the kidneys. Arabic physicians used mercury to treat skin infections, urinary infections and urethral stones. The rise of syphilis in Europe in the 16th century saw its application as the primary treatment, sometimes oral and sometimes parenteral, of patients suffering from that disease until the mid-20th century. It also found various other uses. Mercurial diuretics originated from chance observations of such patients, and these received much use in the first half of the 20th century until safer and more efficacious nonmercurial diuretics replaced them. Many physicians viewed mercury as a panacea, but others challenged their views. Its use was always recognised to have potential complications, but realisation of its ability to cause acute kidney injury, chronic renal impairment and nephrotic syndrome gradually evolved, and it was phased out of therapeutics. A further contribution it made to nephrology lay in the manufacture of thermometers, sphygmomanometers and cystoscopes. PMID- 21614795 TI - Development of the concept of pain in history. AB - From Hippocratic medicine through the modern theory of Melzack and Wall, the concept and physiopathology of pain has been developed over the course of time, assuming in some instances a religious or philosophical view and in others a more scientific meaning. People have developed very different words to express pain. The Arabic language has hundreds of words to express pain, while European languages are more limited. Descartes, who first proposed a link between peripheral sensation and the brain, suggested that sensations stimulated in the body are conveyed directly to the brain, where they are actually perceived. The Cartesian model gave rise to the notion of a "hard-wired system." European physicians did their best to relieve their patients' pain, often through the judicious use of opium and, after 1680, laudanum, the mixture of opium in sherry introduced by Thomas Sydenham. In 1803, Serturner discovered a substance from isolated crystals of a powerful analgesic agent, derived from crude opium, that he named morphine, after Morpheus, the Greek god of dreams. The introduction of surgical anesthesia represented one of the most important advances of modern medicine, although initially it was not accepted by the medical community, for ethical reasons. PMID- 21614796 TI - [Synergistic combination therapy in osteoporosis. Strategies against painful bone loss]. PMID- 21614797 TI - [Sport as a profession: medical and social aspects]. AB - The author analyses possible use of methods and achievements of industrial medicine in solving problems of acme in sports. The article covers theoretic, methodologic and practical basis for possible integration of industrial medicine and sports medicine. Mechanisms of such interdisciplinary integration include current legal basis, scientific research (mostly, concept of occupational risk, norm and pathology concept, doctrine of preventive medicine, etc), practical experience accumulated in this country and abroad. Some aspects of public health preservation in contemporary Russia are also tackled. PMID- 21614798 TI - [ILO plan of action (2010-2016) on occupational safety and health and new list of occupational diseases]. AB - ILO plan of action (2010-2016) to achieve widespread ratification and effective implementation of the occupational safety and health instruments (Convention No. 155, its 2002 Protocol and Convention No. 187) is discussed. ILO documents on recording and notification as well as new list of occupational diseases (revised 2010) are considered. PMID- 21614799 TI - [Features of morbidity formation in industrial environment and new technologies]. AB - The article deals with analysis of dependence of transitory disablement morbidity levels from work characters, duration and changes in staffers' functional load- i.e. dynamics of work application at various stages of industry development in Russia over 90 years (1920-2010). To preserve and strengthen workers' health during innovation period, the authors suggest measures of "social regulation" and development of "rehabilitation medicine" on individual basis. PMID- 21614800 TI - [Depending on exposure, functional state of left ventricle in combined cardiovascular disease among chronic uranium intoxication patients]. AB - State of left heart contractility in patients having IHD and AH during long-term period of chronic uranium intoxication depends on duration of exposure to toxic radiation factor. The authors revealed left ventricle myocardium weight decreased by 11.7% on exposure up to 10 years and that decreased by 18.9% on the exposure over 10 years, when compared to the reference group. Longer length of service was connected with higher share of patients with pathologic remodelling of left ventricle, mostly due to increased concentric remodelling. PMID- 21614801 TI - Growth factors in Parkinson's disease. PMID- 21614802 TI - It is all about clearance. PMID- 21614803 TI - Advances in surgical treatment of facial nerve paralysis in children. PMID- 21614804 TI - For the records. PMID- 21614806 TI - Financial strain for students. PMID- 21614805 TI - Preparing graduates for the future of veterinary medicine. PMID- 21614809 TI - Managing vulvovaginal problems--a sensitive approach. PMID- 21614807 TI - Credit where credit is due. PMID- 21614810 TI - [Overcoming difficulties is our goal in 2011]. AB - During the past two years, Investigacion Clinica has undergone a substantial reduction in its funding caused by the insufficient budget allotment that the University of Zulia has received from the Venezuelan Government. The progressive increase in the number of articles contained in each issue of the journal caused its weight to exceed the established limits, affecting the distribution costs. Therefore, some adjustments to its structure and distribution are required to maintain its frequency and quality, including reducing the number of papers per issue and sacrificing free shipping to many libraries and health centers in our country and abroad. The "Instructions to Authors" will appear only in the first issue and we will keep the "Index of Authors" in the last issue of the year. Also the publishing of reprints will be limited and only will be sent to authors upon request and shipment pre-payment. Likewise, color pages fees will be canceled to the Publishers, prior to printing. For the above mentioned difficulties, we recommend our regular readers to use the website https://sites.google.com/site/revistainvestigacionesclinicas/, where all articles can be found in PDF format, as they appear in our printed edition. Despite these difficulties, all our collaborators will keep working to maintain the high standards that have characterized this journal for over 50 years, inspired by our founder, Dr. Americo Negrette. PMID- 21614811 TI - [Detection of human papilloma virus (HPV) in liquid-based cervical samples. Correlation with protein p16INK4a expression]. AB - The liquid-based cervical cytology improves the quality of the sample and the residual sample could be used efficiently to carry out complementary tests, such as the detection of HPV DNA and the immunocytochemical biomarkers study. The purpose of this study was to correlate the presence of HPV and immunoexpression of p16INK4a in liquid-based cervical samples to examine the utility of these new tools in the detection of cervical cancer. The included patients (n = 67) presented an abnormal cytology or previous cervical pathology. The HPV detection and genotyping were carried out with PCR-SPF10/LiPA (INNOLiPA Extra Amp) and for p16INK4a immunodetection was used antibody clone E6H4. The conventional cytology provided the same cytologic interpretations that those of liquid-based cytology. The overall HPV prevalence was 43.3% (29/67). HPV16 was the most frequent viral type (31.03%) and 48.3% of the cases were infected with multiple HPV types. p16INK4a immunoexpression was observed in 35.8% of liquid-based cytological samples and this was significantly (p < 0.020) associated to the HPV presence. These results support the evidence that the implementation of new technologies in the daily routine of the laboratory, contribute significantly in the early detection of cervical cancer and provide important data to help in the patient's efficient management. The combined use of HPV detection and p16INK4a expression could be used for evaluation of patients with more risk to develop significant cervical lesions. PMID- 21614812 TI - [Effect of antiphospholipid antibodies on the formation and lysis of fibrin network in patients with recurrent miscarriage]. AB - The present work was intended to study the process of fibrin formation and lysis and plasmin generation in a group of patients with recurrent miscarriage (RM), due to the presence of antiphospholipid antibodies (N = 10); as well as in women with RM without the antiphospholipid syndrome (APS) (N = 6), compared with those of a group of healthy women (N= 8). In the group of patients with APS, nine were positive for antibodies against cardiolipin (aCL), five for anti-beta2 glycoprotein I (anti-beta2GPI), four for both antibodies, and one for antibodies against prothrombin (aPT) and lupus anticoagulant (LA). Fibrin formation and lysis was followed by turbidity and plasmin generation using chromogenic substrate S2251. The polymerization curves from RM patients without APS and the LA patient showed an increased slope and maximum turbidity compared to those of the control group. The speed of lysis was higher in the LA patient (21 +/- 0) 10( 4) deltaOD/seg and the RM patients without APS (19.6 +/- 5.7) 10(-4) deltaDO/seg, compared to that of the control group (14.5 +/- 2.8) 10(-4) deltaDO/seg. Plasmin generation increased only in RM patients without APS (85 +/- 24%) against the control group (52 +/- 3%), p = 0.005. The changes observed in the fibrin polymerization and lysis process of women with RM without APS and LA seem to be related to their higher fibrinogen levels, while the increased plasmin generation was related to the patients' morbidity. PMID- 21614813 TI - [Development and evaluation of a serological protocol of fluorescence polarization for the preliminary study of Brucella spp antibodies in humans]. AB - In order to show the development and scope of a serological analysis method based on fluorescence polarization assay (FPA) from a drop of blood obtained by the capillary technique, a Brucella antibody assay was performed on a group of 321 high-risk workers. The results were compared with data from the analysis of blood serum by FPA and a competitive enzyme immunoassay (ELISA-c). The number of concordance was 318 (99.06%), and discordant 3 (0.93%), which were negative in serum by fluorescence polarization (FPAs) and ELISA-c, but positive with capillary FPA (FPAc). The comparative results FPAc were: sensitivity 100%; specificity: 99.05%; positive predictive value 66.67%; negative predictive value 100.0%; false positive rate: 0.95%; false negative rate: 0%; accuracy: 98.0%; odds ratio: 203.00. The youden J for both FPA methods was 0.667. The identification was considered reliable and the correlation of both procedures, FPA and ELISA-c, was no statistically different (P > 0.05%), which allows to highly recommend the study implementation of human brucellosis with capillary blood as a preliminary method. PMID- 21614814 TI - [Atrial fibrillation prevalence and treatment with oral anticoagulation in patients with permanent pacemakers]. AB - Atrial Fibrillation (AF) is the most important risk factor for stroke and thromboembolic events (TE). The aims of this study were to determine the prevalence of AF among patients with permanent pacemakers (PPM), the percentage of anticoagulated patients and the prevalence on TE in this population. The secondary purpose was to determine the "level of knowledge" about indications of anticoagulation for AF patients. This was a descriptive and retrospective study on a consecutive series of patients referred for PPM implantation. Cardiovascular risk factors, indications for pacing, prior history of AF, TE and anticoagulation indication were analyzed. In order to determine possible causes for not indicating anticoagulation, an electronic survey was sent to all doctors that usually refer patients for PPM implant and follow-up to our clinic. Among 934 patients, 26% (244) presented AF of which 34% were anticoagulated. 77.3% presented a CHADS2 score of > or = 2 while only 2% had absolute contraindication for anticoagulation. The prevalence of TE was 9%. More than 60% of the doctors answered the survey. More than 40% acknowledged the CHADS, score but only 33% were able to recognize all variables included in the score and 23% were able to determine when to indicate anticoagulation properly. A low anticoagulation rate was detected among patients with AF and PPM with a high prevalence of TE and stroke. An extremely low adherence to international guidelines was detected among doctors that usually deal with this sort of patients. PMID- 21614815 TI - [Near-death experiences]. AB - Near-death experiences (NDE) are lucid events that take place when a person is so physically compromised that he would die if its condition does not improve. He is unconscious, without heartbeats and breath, and with a flat-line electroencephalogram. NDE may include some of the following elements: Out of the body experiences or separation of consciousness from the physical body, increase in sensory perception and intense emotions, travel into or through a tunnel, encounter with a brilliant light and mystical beings, deceased relatives or friends, a sense of alteration in time and space, visualization of unworldly realms and a special knowledge, encounter with a barrier or boundary, and a return to the body, either voluntary or involuntary. The fact that children NDE are similar to adult NDE is an evidence that these experiences are real and not due to pre-existing beliefs, cultural influences or previous experiences in the present life. The characteristics of NDE are similar worldwide. No evidence supports the physiological, psychological, neurochemical, and neuroanatomical hypothesis proposed to explain the NDE. Multifactorial models, based on the combination of all of them (brain anoxia or hypoxia, release of serotonin, endorphins and ketamine-like compounds) have also been proposed. Although physiological, psychological, and socio-cultural factors could interact in the NDE, the hypothesis proposed consist essentially in unsupported speculations about what might be happening during the NDE. PMID- 21614816 TI - [Foods native to indigenous and afro-descendents in Colombia]. AB - For social programs in Colombia, like those administered by the Instituto Colombiano de Bienestar Familiar (ICBF), it's important to know what native foods minority groups consume. This research obtained information on native foods consumed by indigenous and afro-descendents living in 10 Colombian departments: Cauca, Narino, Amazonas, Choco, Guainia, Vichada, Magdalena, Guajira, Cesar y Vaupes. A questionnaire was applied to key informants (individually or in groups), addressing the following topics: personal information on the informant, name and type of food, if consumed by indigenous and/or afro-Colombians, climate where produced, time of year when harvested, if consumed raw or cooked, preparations, properties ascribed to the food, and current production, use and availability. Key informants included participants in ICBF's programs, indigenous authorities, teachers, traditional healers, and others, under the supervision of professionals from ICBF's mobile unit in each department. Bibliography (n = 123 documents) was compiled and reviewed. In the departments selected, 13 municipalities were visited, 139 individuals were interviewed and at least 92 new foods (i.e., not currently included in the Colombian Food Composition Table) were identified. Among the 92, the scientific name was obtained for 62 foods. Of these, 2 were classified as other, 18 as meats, 3 as insects, and 39 as plants. Among the plants, informants mentioned fruit (n=29), leaves (n=4), seed (n=3) and roots (n=3). Indigenous and afro-descendent communities in Colombia report consuming dozens of foods that are not currently in the Colombian Food Composition Table. PMID- 21614817 TI - [Nutritional status, lifestyle and cardiovascular risk in lacto-ovo vegetarians and omnivore]. AB - The aim of the present study was to assess socioeconomic characteristics, dietary intake, nutritional status and cardiovascular risk (using anthropometric indicators of central obesity) in lacto-ovo vegetarians and non-vegetarians. Two non-vegetarians were selected for each vegetarian (paired for gender and age) in order to increase the power of the statistical tests. The sample was made up of 87 individuals (58.6% males; 29 vegetarians and 58 non-vegetarians) with a mean age of 40 +/- 13 years. Among the socioeconomic characteristics, only the number of residents per household differed between groups, with a greater percentage of homes with five or more residents in the vegetarian group. Concerning lifestyle, the groups differed with regard to smoking habits (p < 0.001), with a higher proportion of smokers among the non-vegetarians. There were no significant differences between groups in any of the anthropometric variables studied. Concerning dietary intake, no difference between groups was found with regard to total calorie intake, but the consumption of proteins, total lipids, saturated fat and cholesterol was higher among the non-vegetarians, whereas carbohydrate and fiber intake was higher among the vegetarians. The results of the present study suggest that, although a lacto-ovo vegetarian diet is considered healthier due to the lower consumption of total fat, saturated fatty acids and cholesterol, there are no significant differences in nutritional status or anthropometric indicators of cardiovascular risk when lifestyle and total calorie intake are similar. PMID- 21614818 TI - [Folate food intake and red blood cell folate concentrations in women from Recife, Northeast of Brazil]. AB - Folate food intake and red blood cell folate concentrations were assess in women from Recife, Northeast Brazil. Following a two stages sampling procedure, a cross sectional study was carried out involving 360 women, between 15-45 y, attending in nine health care public unit in 2007-2008. Folate intake was evaluated by a Quantitative Food Frequency Questionnaire, and compared with the values of the dietary reference intakes-DRI's. Folate status was evaluated by red blood cell folate concentrations. Geometric mean of folate intake was 627.1 [IC 95% 600.4 655.0] microg/day. The frequency of women at risk for folate intake below the recommendation was 16.0% for adolescents (<330 microg/day) and 6.3% for young adult (<320 microg/ day). The prevalence of women whose consumption exceeds the maximum tolerable intake was 48.0% (> 800 microg/day) and 13.7% (> 1000 microg/day) for adolescents and adults, respectively. The mean of red blood cell folate concentrations was 1797.8 +/- 357.1 nmol/L. Folate rich-food intake did not show any correlation with red blood cell folate concentrations (r = 0.058 and p = 0.274). Higher red blood cell folate concentrations were observed in adult young women (p = 0.004) and among those with income up to two minimum wages (p = 0.042). Folate rich-food intake as well as red blood cell folate concentrations among women from Recife were above the international recommendations. PMID- 21614819 TI - [Influence of gestational age and parity on the concentration of retinol in human colostrums]. AB - Vitamin A is particularly important during the critical periods of growth, proliferation and development of tissues such as pregnancy, neonatal period and childhood. This study aims to evaluate the influence of maternal variables such as gestational age and parity, on the levels of retinol in colostrum and verify that the concentration of vitamin A in the colostrum of those mothers provides the recommended amount of this micronutrient for newborns. We recruited 84 healthy pregnant women attended at a Brazilian public hospital. Retinol concentrations in colostrum were analyzed by high performance liquid chromatography. The retinol in colostrum from mothers at term (n=49) and preterm (n=35) showed values of 111.3 +/- 12.4 microg/dL and 79.2 +/- 10.6 microg/dL (p < 0.0001), respectively, and retinol concentration in colostrum from primiparous (n=40) (82.5 +/- 8.8 microg/dL) and multiparous (n=44) (116.9 +/- 10.3 microg/dL) was also statistically different (p < 0.0001). Retinol levels in colostrum at term and those whose mothers had one or more than one child in this study meet the needs of the child (400 microg retinol/day). However, levels of retinol in colostrum of preterm infants are not consistent with the recommendations of the DRI for premature infants, which is 420 microg retinol/day. These results demonstrate the need to supplement with vitamin A preterm mothers to ensure an adequate supply of this vitamin to the newborn. PMID- 21614820 TI - [Estimation of body fat by DXA and the four compartment model in Mexican youth]. AB - The objective of this study was to validate the estimation of body fat (%BF) by DXA (Dual-Energy X-Ray AbsorciomDPX-MD) against the four compartment model (4C) of body composition in 32 Mexican pubertal girls and boys (aged 9-14 y; F=16). The mean of the difference between DXA and 4C model was -3.5 %BF (p=0.171). The limits of agreement (95% = 2 SD) were +5% to -12%BF. The precision of estimated limits of y the confidence intervals were -1.9% to -5.1%BF (P = 0.050). The concordance correlation coefficient was p = 0.85. The test of accuracy for coincidence of slop intercepts between DXA and the 4C model showed no coincidence (p < 0.05). The precision by R2 explained 83% of the variance (SEE, 4.1%). The individual accuracy assess by the total error was 5.6%. The group mean accuracy by two way analysis of variance of body fat did not show interaction between method (DXA-4C model) and separate analysis of gender and overweight. However, there was an effect of method (p = 0.043) in the presence of overweight (p < 0.001). In conclusion, the estimation of percent of body fat by DXA was not precise and accurate in a group of Mexican children. However, results do not limit the utility of DXA for the measurements of body composition and its relation with health outcomes, especially in follow up studies. PMID- 21614821 TI - [Associated factors to dietary intake of fruits and vegetables in Bucaramanga, Colombia]. AB - The objective of this study was to determine associated factors to the consumption of fruit and vegetables (FV) in the adult population of each socioeconomic status (SES) in Bucaramanga, Colombia. We conducted a cross sectional in a sample of 317 people and we measured socio-demographic, economic and anthropometric variables and dietary factors related to the purchase and consumption of FV. We made a survey, a 24-Hour dietary recall and we did anthropometric measurements. Portion sizes were estimated with a standardized set of utensils and food-photography atlas. Frequencies, measures of central tendency and dispersion were established and Logistic Regression models were used for the bi and multivariate analysis. Average consumption of FV was 162.6 g/day (188.5 g in high SES and 145.7 g in low SES, p = 0.056). On average 2 servings per day of FV (2.3 servings in high SES and 1.5 in low SES, p = 0.055). The prevalence of adequate intake of FV (more than 5 servings / day) was 8.6% (8.9% in high SES and 8.4% in low SES, p = 0.896). The associated factor to consumption of FV was BMI > or =25 (OR: 0.31, CI (95%): 0.11-0.89, p = 0.030), adjusted for occupation, income, SES, and number of family members. FV consumption is low; excess weight is the only variable associated to no-consumption of five or more servings; causes: cost to the consumption of fruit and flavor in the case of vegetables. PMID- 21614822 TI - [Detection of Listeria monocytogenes in white cheese by polymerase chain reaction (PCR)]. AB - The polymerase chain reaction, known as PCR, is a method to replicate thousands of times within a few hours and in vitro, small amounts of DNA. The application of rapid and sensitive methods to detect Listeria monocytogenes in cheese samples, allow a better microbiological control of the production process. PCR was applied to 30 samples of of white cheese, from Valencia, Carabobo State. It was detected PCR specificity and sensitivity by using the control strain Listeria monocytogenes 446. DNA extraction according to the methodology described by Torres et al., Molecular weight marker 100 base pairs. Were used: four primers hlyA gene of listeriolysin O; L1/U1 primers for 938 bp band and LF/LR 750 bp band hlyA gene. Epilnfo Statistical V6 to match observations in gels, by Kappa coefficient (K). RESULTS: 8 out of 30 cheese samples analyzed showed presumptive growth of Listeria spp in PALCAM Agar. Two of the samples not belonged to the genus Listeria, in the 6 remaining sample confirmation tests showed that: 2 were L. monocytogenes, 3 L. ivanovii and 1 L. seeligeri. In PCR 2 samples were positive for L. monocytogenes by amplify the 938 bp band for Listeria and 750 bp band for the species monocytogenes. We concluded that PCR was highly specific and sensitive to L. monocytogenes, taking advantage of PALCAM agar to detect the presence of the pathogen specifies a relatively short time. PMID- 21614823 TI - [Physico-chemical and microbiological evaluation of UHT milk commercialized in three Mercosul countries (Brazil, Argentina and Paraguay)]. AB - With the aim to evaluate the physico-chemical and microbiological quality of UHT milk commercialized in three countries of Mercosul, samples of four different brands were acquired in each city (Foz do Iguacu-Brazil, Puerto Iguazu-Argentina and Ciudad del Este-Paraguay) and submitted to the following analysis: fat content, titratable acidity, milk ethanol stability (with the following ethanol concentrations: 68, 72, 76 and 80%), total dry extract and no fat dry extract, pH, density and freezing point. Counts of mesophilic and psychrotrophic microorganisms were already done. In the physico-chemical evaluation of UHT milk, a significant number of samples were in disagree with the established patterns for fat content, no fat dry extract, density and freezing point. Except one brand from Brazil, milk samples showed stability to 68% ethanol. pH averages of Brazilian milk were in agree with the patterns and highest values were observed in samples acquired on Paraguay. Observing the microbiological analysis, 37.5%, 62.5% and 12.5% of samples acquired from Brazil, Argentina and Paraguay, respectively, showed counts above the established patterns for mesophilic microorganisms. Counts of psychrotrophic microorganisms were in disagree with the established patterns in 50%, 50% and 100% of samples from Brazil, Argentina and Paraguay, respectively. PMID- 21614824 TI - [Tuna (Thunnus thynnus) glazed with hydrocolloids as alternative of edible coatings and storaged at -10 degrees C]. AB - Numerous studies have been focused to natural ingredients to maintain the quality and shell life of foods. Edibles coating, biodegradable ingredients, such as hydrocolloids and proteins can be used for coating fish with the purpose to suppress changes of quality during frozen storage. At the present time several developing of edibles packing, like glaze using hydrocolloids, (gelatin, carrageen, starch), that besides acts as protective film for food, they are economic, can be ingested by the consumer without toxicity risk, help to preserve organoleptics and nutritional characteristics of the product and, being biodegradable they contribute to the conservation of the atmosphere. The objective of the present study was to evaluate the incorporation ofhydrocolloids in the glazing tuna process as alternative of packing, to enhance its physical and chemical characteristics. Samples of tuna was glazed incorporating to its solutions of carrageen at 0.05, 0,1 and 0.15%, and gelatin at 0.5, 1%. The samples were shaped as square (15 cm3), frozen al -30 degrees C and glazed incorporating hydrocolloids submerging the sample its solutions at 0 degrees C by 30 seconds and storage at -10 degrees C by 0, 15 and 30 days. Proximal analysis results, soluble proteins, TBA, and color showed that all the samples glazed with hydrocolloids decrease deterioration of the tuna products respect to samples glazed without hydrocolloids; concluding that glazing adding hydrocolloids protects tuna for loss humidity and delays degradation of proteins. Moreover, carrageen shows to a better performance at the concentrations of 0.05% compared with the gelatin and the starch. PMID- 21614825 TI - [Mixed drink consisting of guava (Psidium guajava. L) and forrageira palm (Opuntia ficus-indica): development and acceptability]. AB - Nowadays, in the beverage industry, the mixture of products became an alternative to increase the nutritional value or even to develop new flavors in the formulation of mixed drinks. The objective of this work was to develop a mixed drink of forrageira palm with guava. Four formulations with different palm concentrations and soluble solids were evaluated, keeping the concentration of guava stable. The products were submitted to chemical characterization (pH, soluble solids, titratable acidity, vitamin C) sensory evaluation (flavor, color, body and global acceptance) and microbiological analysis (total coliforms and thermotolerants, Salmonella and Estaphylococcus aureus). All the samples were well accepted in the sensory aspect and did not present any significant difference (p < 0.5) among them. And the level of acceptance ranged from "I liked it slightly." to "I liked it moderately." for all the evaluated features. The formulated mixed drink was according to the chemical and microbiological patterns set by Brazilian laws, except for the pH that was above the ideal level for industrialized products. In respect of the microbiological analysis, none of the formulations presented microorganisms. The results showed that the elaborated product is in accordance with the identity and quality standards established for beverages. It also has a good sensory acceptance, which makes it a product with high potential for industrialization. PMID- 21614826 TI - [Amaranth bars enriched with fructans: acceptability and nutritional value]. AB - There is an increasing appeal for convenience foods with potential health benefits to the consumer. Raw materials with high nutritional value and functional properties must be used on the development of these food products. Amaranth is a gluten-free grain with high nutrition value. Inulin and oligofructose are prebiotic ingredients presenting effects as the enhancement of calcium absorption. Amaranth bars enriched with inulin and oligofructose were developed in the flavors: banana, Brazilian nuts and dried grape, coconut, peach, strawberry and wall nut. The proximate composition were determined and compared to commercial cereal bars, available in traditional (n=59), light (n=60), diet (n=8), with soy (n=10) and quinoa (n=1) categories. Amaranth bars present mean global acceptance values from 6.3 to 7.6 on a 9-point hedonic scale, nutritional advantages as compared to commercial cereal bars (caloric reduction and higher levels of dietary fiber). Although amaranth is an unknown raw material in Brazil, it shows good potential to be used in the manufacturing of ready-to-eat products. As they are gluten free, these amaranth bars are also an alternative product for celiacs, also contributing to the enhancement of calcium absorption, a problem frequently observed in these patients. PMID- 21614827 TI - [Fatty acid profile of high consumption foods by school population of the region Metropolitan of Chile, including trans fatty acid content]. AB - The Chilean school population has shown remarkable changes in their eating habits, incorporating high fat content foods to their diet, which could explain the current high obesity rates. A great proportion of these foods uses industrial fats whit high content of saturated fatty acids (SFA) and potentially contains trans fatty acids (TFA) as a result of partial oil hydrogenation or as a natural form in ruminant animals fat. The purpose of this investigation was to determine fatty acid profile, including trans fatty acids, from food consumed by the Metropolitan Region school population. A food consumption survey was applied to 203 Metropolitan Region of Chile school-children, which consisted of questions about food consumption frequency and consumer preferences. Based on the results, ten types of food products were selected. Fat content, fatty acids profile, including trans fatty acid, were determinate by GLC according to the UNE 5509 Norm. Each analysis was carried out in duplicate and three samplings were performed. It was found that a great percentage of the analyzed foods showed low TFA content (<1%). However, some of them presented remarkable saturated fatty acids content, generating a PUFA/SFA ratio with poor fat nutritional quality. The low TFA concentration found in the food may be explained by a decrease in the use of hydrogenated fats, following PAHO/WHO recommendation, which are being applied in Chile. PMID- 21614828 TI - [From the president of the Polish Psychiatric Association]. PMID- 21614829 TI - [Psychotic experiences in the course of alcohol withdrawal symptoms: locus of control among patients with and without delirium and analysis of subjective experiences in delirium]. AB - AIM: The comparison of the locus of control in groups of patients hospitalised due to alcohol withdrawal with and without delirium and analysis of psychotic experiences of patients with delirium. METHODS: 25 patients with alcohol withdrawal with delirium and 25 without delirium took part in the study. They filled-in the Internal-External (I-E) Locus of Control Scale by Rotter; Multidimensional Health Locus of Control (MHLC) scale; the group with delirium also did the Psychopathological Symptoms Inventory, by Bizon et al. RESULTS: The mean score in I-E Locus of Control Scale in the group with delirium was more external than in the group without delirium (M = 13.28; SD = 2.762 versus M = 11.64; SD = 2.612; t(48) = -2.157; p = 0.036). Group with delirium had also lower mean score in the dimension of internal control in MHLC, than the group without delirium (M = 24.8; SD = 6.149 versus M = 26.8; SD = 4.648; t(48) = 1.99; p = 0.04). There were no statistically significant differences between the groups in the other subscales. The auditory and visual hallucinations were most common among patients with delirium (84%, 80% respectively, as well as delusions of taking part in not existing events (92%) and persecutory delusions (80%). Psychotic experiences influenced behaviour in nearly 50% of the cases. CONCLUSIONS: A more external locus of control may be one of the factors contributing to the development of alcohol delirium. The content of psychotic experiences seems to have impact on the behaviour of many patients with alcohol delirium. PMID- 21614830 TI - [Links between defence mechanisms and severity of symptoms of panic disorder and depression in women and men with difficult and aspirin-induced asthma]. AB - AIM: The author examined psychiatrically a group of 106 patients with difficult asthma and 100 patients with aspirin-induced asthma. The special interest of the study were links between defence mechanisms used by women and men from both groups and severity of their panic and depressive symptoms. METHODS: 106 consecutive adults with confirmed, physician-diagnosed difficult asthma and 100 patients with aspirin-induced asthma underwent the psychiatric interview and assessment using M.I.N.I 5.0, Beck Depression Inventory (BDI), Panic and Agoraphobia Scale (PAS) and the Defence Style Questionnaire. Psychiatric assessment was performed by an experienced liaison psychiatrist according to ICD 10 and DSM-IV diagnosis. In the difficult asthma group there were 78 women (74%) and 28 men (26%). The average age was 51.3 (SD = 14.5) for women and 47.5 (SD = 12.7) for men. In the aspirin induced asthma group there were 66 women (66%) and 34 men (34%). The average age was 52.7 (SD = 12.3) for women and 48.8 (SD = 13.0) for men. RESULTS: In both groups of asthmatic patients women were majority (74% with difficult asthma and 66% with aspirin-induced asthma) with higher level of anxiety and depressive symptoms than men. Generally in difficult asthma group significantly more often than in aspirin-induced asthma neurotic and immature defence mechanisms were used. In both groups, either in women and in men there was a strong tendency to decrease the use of mature defence mechanisms and increase the use of neurotic and immature defence mechanisms in association with an increase of severity of panic and depressive symptoms. CONCLUSIONS: It is possible that differences in defence mechanisms used by women and men with difficult asthma affect the development, course and severity of their anxiety and depressive symptoms. This may play a special role in the development of difficult asthma phenomenon. PMID- 21614831 TI - [Patient, client or...--the terms preferred in mental health services]. AB - AIM: To analyse the patients' and staff opinions on preferred terms in regards recipients of mental health services. METHOD: In 2008, 489 patients and 318 providers from one of Warsaw mental health services answered the survey on preferred terms in regards recipients of mental health services anonymously. RESULTS: The term "patient" was the most preferred, as well as by the recipients (77.5%), as the providers (87.7%) of the services. The second choice in both groups, however much less preferred was the term "person with mental disorders" (respectively 18.2% and 22.3%) and indicated by the patients "person using mental health services" (18.2%). The less preferred were the terms: "user" (2.0% by the patients, 1.6% the providers), "beneficiary" (respectively 3.3%, 2.5%), "client" (5.5%, 5%). The patients from day hospitals and community based facilities also favoured the term "patient" (85.0% responders). In spite of staff occupation and number of years spent working in mental health services, the term "patient" was the most preferred one. CONCLUSIONS: The term "patient" was the most preferred one in the group of patients and service providers. The form of services provided did not differentiate the patients' opinion in regards to the preferred terms. Occupation and number of years spent working in mental health services did not differentiate the providers' opinion in regards to the preferred terms. Further dialogue on the preferred terms is needed, since they might empower or stigmatise. PMID- 21614832 TI - [Attitudes of Polish employers toward hiring mentally ill people]. AB - AIM: The purpose of the study was to learn about the opinions of employers from small and medium sized enterprises regarding hiring mentally ill people and to identify barriers hindering such employment. METHOD: The study was carried out by the Public Opinion Research Center in 2007 on an all-Poland representative sample of 503 employers. A questionnaire entitled "Employers' opinions on hiring mentally ill people" was used to gather data. RESULTS: Few employers (6.8%) had ever cooperated with mentally ill persons, even fewer (4.4%) had had some experience in hiring such people. As much as 48% of the employers were of the opinion that only 10% of the people who had suffered from mental illness are capable of keeping a paid job. Almost 60% would refer an employee to a medical professional having found out about his/her mental illness, 24.5% would discontinue the hiring process and one in ten would dismiss such a person. 92% of the employers expressed the need for additional information, 78% expected assistance in the very process of hiring and 2.8% had taken advantage of renumeration reimbursement. Three groups of barriers have been identified and described: 1) conception of a mentally ill person as an employee, 2) belief about drastic limitations in functioning resulting from mental illness, 3) lack of knowledge and experience of working with mentally ill people. The most significant barrier is the belief in lack of self-dependence of a mentally ill person, which effectively shuts the door to a career. CONCLUSIONS: 1. The results show widespread stereotypes and prejudices against the mentally ill. 2. Employers look for assistance in finding information about mental illnesses and in the hiring process. 3. Educational campaigns should be developed to promote good practices in hiring mentally ill people. PMID- 21614834 TI - [Ephedron dependence--case report]. AB - Ephedrone (Methcathinone), a derivative of phenylpropan, (2-(methylamino)-1 phenylpropan-1-one) is synthesised from ephedrine or pseudoephedrine by potassium permanganate oxidation. It has been demonstrated that ephedrone stimulates central nervous system and inhibits dopamine and norepinephrine re-uptake. The authors described the case of a 32-years-old patient, who has been addicted to ephedrone for three years. The case was compared with other articles. Attention was drawn to the growing problem of ephedrone addiction, which is often used as an easier to obtain and cheaper replacement of amphetamine. The risk arising from the intravenous route of ephedrone administration, as well as the potential for manganese poisoning were highlighted. Inconsistency of the existing legislation was also shown, which is prohibiting the use of Catha edulis derivatives and not regulating disposal of substances, which are precursors of psychoactive and addictive ephedrone. PMID- 21614833 TI - [Bech-Rafaelsen Mania Scale and Young Mania Rating Scale--comparison of psychometric properties of the two instruments for rating a manic syndrome]. AB - AIM: The Bech-Rafaelsen Mania Rating Scale (BRMAS) and Young Mania Rating Scale (YMRS) are both popular rating scales for mania. Until now BRMAS has not had a Polish language version BRMAS, although it may be particularly useful because of its twin depression (melancholia) rating scale (BRMES). No attempt of evaluation of the scales were made in Poland until now. Attempts to compare their worth are rare in the literature. The aim of this study was to evaluate and compare the two scales. METHOD: Thirty-five patients hospitalised for mania in the course of affective, schizophrenic and organic disorders were assessed by means of two mania rating scales (BRMAS, YRMS), as well as with clinical global impression (CGI) scale, and its parallel versions for mania (CGI-M) and treatment adverse events (CGI-SE). Two rating scales for psychotic syndromes (PANSS, KOSS-S) was also used. Patients were assessed three times. First three diagnosticians evaluated simultaneously and independently the patients' mental state, and then- after one and two weeks--one of them. As reliability measures, inter-rater, test retest, and internal consistency indices were analysed. As validity measures, a clinical meaning of descriptive characteristics of the scales (external validity), and a comparison with alternative tools for mania rating (criterion, diagnostic validity) were performed. Specificity and sensitivity of BRMAS and YMRS in relation to clinical criterion of severe mania (CGI > or = 5) was analysed by means of ROC curve. As feasibility measure observations made during assessments were used. RESULTS: BRMAS and YMRS revealed satisfactory convergence between assessments of the three diagnosticians (Spearman's rho > 0.72, no significant difference in non-parametric Friedman test), repeatability after a week (rho > 0.52) and internal consistency (Cronbach's alpha for BRMAS > 0.86, for YMRS > 0.73). Profile and dynamics of symptoms in the three successive assessments (each week) depicted changes consistent with expectations, which proved external validity of the scales. Mutual, high correlations between the BRMAS and YMRS (rho > 0.90), between them and CGI-M scale (rho >77), and between them and some meaningful items of psychosis rating scales (PANSS, KOSS-S) may be a mark of their diagnostic validity. ROC for both scales revealed similar, extensive areas under curve (AUC > 0.947; p < 0.000). BRMAS score above 24 points predicted severe mania with 92% sensitivity and 91% specificity. By analogy, YRMAS score above 29 points allowed this diagnosis with 83% sensitivity and 91% specificity. Practically no difficulties in application of the scale under study were noted. CONCLUSIONS: Both compared mania scales revealed satisfactory indices of reliability and validity. They are also feasible tools. However limited size of the group under study has not allowed more penetrating analysis, particularly that of validity. This is why the study requires continuation. PMID- 21614835 TI - [Iatrogenic influence of testosterone therapy among persons with Klinefelter Syndrome]. AB - The purpose of this work is a presentation of cases of persons with Klinefelter Syndrome where, most probably--as a result of testosterone supplementation therapy, some aggressive behaviours occurred requiring implementation of pharmacotherapy and psychiatric hospitalisation. The authors contemplate adequacy of standard hormone treatment where the main purpose is to improve the quality of life of the karyotype 47, XXY patients described. The article has been enhanced by a theoretical introduction into the basic subject which is the Klinefelter Syndrome. PMID- 21614836 TI - [Electroconvulsive treatment and new techniques of electrical and magnetic stimulation in treatment of depression--question of placebo and warranting of blind conditions, as well as other methodological problems]. AB - Testing new therapeutic methods requires the confirmation so their efficacy, application and their safety. So that the specific and subjective factors do not influence the evaluation, it is necessary to assure suitable conditions- enclosing carrying out of the investigations in control to placebo and providing blinding conditions. In the case of pharmacological investigations it is possible and necessary to fulfill the most raw investigation criteria. Examinations of physical methods meet essential obstacles by granting of these criteria. The paper describes these impediments and methodological difficulties which accompany investigations on the following techniques: electroconvulsive treatment ECT, nerve vagus stimulation NVS, magnetic seizure therapy MST/magnetoconvulsive therapy MCT, the deep brain stimulation DBS and trancranial direct current stimulation tDCS. PMID- 21614837 TI - [Transcranial magnetic stimulation in treatment of depression--question of placebo and warranting of blind conditions, as well as other methodological problems]. AB - Transcranial magnetic stimulation TMS is the first new physical technique used since 1993 in investigations on their antidepressant efficacy. Literature investigations show, that the majority of clinical investigations were carried out in the control to placebo and were double-blinded. The lack of a possibility of obtaining the true placebo conditions causes, that the terms of double blinding, as declared by different authors are less credible. TMS stimulation does not allow even single-blinding of clinical investigations. PMID- 21614838 TI - [Disturbed eating behavior and its sequelae]. PMID- 21614839 TI - [Problematic eating behavior in childhood: do maternal feeding patterns play a role?]. AB - Past research indicates an association in adults and young people of emotional and contextual factors with a higher risk for the development of eating disorders or obesity. Few studies focus on problematic eating patterns in childhood, especially in association with parental feeding strategies. 482 mothers completed a questionnaire about eating behaviors and the weight status of their 1- to 10 year-old child as well as their own feeding strategies. A classification of the child's eating behavior (food responsiveness, emotional eating, external eating, eating time and meal structure) using hierarchical cluster analysis revealed a conspicuous eating pattern (10%) showing above-average values in all eating behaviors. Controlling for weight and demographic variables mothers of children with conspicuous eating patterns were characterized by restrictive strategies and were less likely to encourage or facilitate their child to control his or her eating. Similar problematic eating patterns were also identified in early childhood. The association of maternal feeding strategies--beyond weight control issues--with conspicuous eating patterns in children might indicate a possibility of early prevention through parent training. PMID- 21614840 TI - [Behavioral indicators of loss of control over eating: bite size and bite velocity]. AB - Loss of control (LOC) over eating is a common and psychopathologically relevant experience in childhood. The current study aimed at evaluating bite size and bite velocity as behavioral indicators of LOC eating in an experimental test meal study with a variation of mood. Children with or without LOC eating (N=120, 8-13 years) consumed a parent-child test meal and a child-only meal consisting of snack food, following induction of negative mood. Bite size and bite velocity were determined through behavioral observation, food intake was measured, and sense of LOC and mood were rated. Children with LOC eating did not show greater bite size and bite velocity than children without LOC eating. Bite size of children with LOC eating was increased in negative mood and decreased in neutral mood. Greater bite size and bite velocity predicted greater food intake at test meal and snack eating and greater LOC over eating at snack eating, however, without an intervening influence of negative mood. Bite size was significantly associated with greater body weight of child and parent. Bite size and bite velocity were not significantly associated with eating disorder psychopathology and varying levels of LOC symptoms. The evidence as to whether bite size and bite velocity are suited as behavioral indicators of LOC eating is not clear-cut. Further research on behavioral indicators of childhood LOC eating is warranted. PMID- 21614841 TI - [Body dissatisfaction among female and male adolescents: comparing prevalence, predictors, and consequences between the sexes]. AB - As part of the POPS study (Potsdam prevention of eating disorders) 300 adolescents aged between 10 and 13 years completed questionnaires measuring satisfaction with weight and muscles, body change strategies and disturbed eating behavior. More than half of the girls and a third of the boys are dissatisfied with their weight. Nearly 70% of the male participants were unhappy with their muscles. Both forms of body dissatisfaction are influenced by similar sociocultural and psychological factors. While weight dissatisfaction leads to weight reduction strategies and disturbed eating, muscle dissatisfaction results in muscle enhancement methods. Potential harmful consequences of excessive muscle building techniques are discussed. The data emphasize the need for a sex-specific investigation of body dissatisfaction and its consequences. Body image aspects relevant to boys should be added to intervention and prevention approaches. PMID- 21614842 TI - [Long-term evaluation of a psychological training for obese children and their parents (TAKE)]. AB - Cognitive-behavioral parent-child-programmes have shown the best effects in treating childhood obesity so far. With TAKE (Training adiposer Kinder und ihrer Eltern) we introduce a psychologically-informed training, that includes physical activity, nutrition and eating behavior but also addresses psychological issues like self-confidence, body image, social and anti-bullying skills. Long-term data from up to 64 month-follow-up showed moderate effects on body-mass index standard deviation scores (BMI-SDS), and positive effects on children's psychological wellbeing. Maternal psychopathology predicted the course of BMI-SDS in children. Results underline the importance of psychological treatment for obese children to facilitate weight change and to reduce their psychological vulnerability which in turn may prevent the further development of behavior problems, eating disorders and affective disorders. PMID- 21614843 TI - [Current]. PMID- 21614844 TI - [More conscientious antibiotics use in the cattle industry]. PMID- 21614845 TI - [Insured to suffer]. PMID- 21614846 TI - [Development track Young Veterinarians support personal growth]. PMID- 21614847 TI - [Surveillance]. PMID- 21614848 TI - [Mitral valve dysplasia in a cat causing reversible left ventricular hypertrophy and dynamic outflow tract obstruction]. AB - A 6-month-old male European shorthair cat was examined because of a 2/6 systolic left apical cardiac murmur. Echocardiography revealed severe concentric left ventricular hypertrophy and severe dynamic left ventricular outflow tract obstruction (pressure gradient of 85 mmHg) caused by systolic anterior motion (SAM) of the septal mitral valve leaflet. After 2 months of oral treatment with atenolol, the cardiac murmur had disappeared. Echocardiography showed only slight thickening of the interventricular septum and resolution of the pressure gradient. The cat was discharged and its owner was advised to continue atenolol lifelong. Echocardiographic findings of a combination of left ventricular concentric hypertrophy and dynamic left ventricular outflow tract obstruction can be caused by hypertrophic obstructive cardiomyopathy (HOCM) or mitral valve dysplasia in the absence of hypertension and fixed aortic stenosis. In the case of HOCM, left ventricular hypertrophy is the primary process. In the case of mitral valve dysplasia, systolic anterior motion of the mitral valve is the primary problem, which leads to dynamic left ventricular outflow tract obstruction and ultimately to left ventricular concentric hypertrophy, due to pressure overload. If the left ventricular outflow tract obstruction is reduced with an oral beta-receptor blocker the secondary left ventricular hypertrophy may resolve. This would not happen in the case of hypertrophic obstructive cardiomyopathy. To the best of the authors' knowledge, this is the first documented case of severe dynamic left ventricular outflow tract obstruction and severe left ventricular hypertrophy in a cat successfully treated with oral atenolol. PMID- 21614849 TI - [Cholangitis in cats: symptoms, cause, diagnosis, treatment, and prognosis]. AB - Inflammation of the bile ducts is common in cats. This review article reports on what is currently known about the various types of cholangitis (i.e., cholangitis caused by liver flukes, neutrophilic cholangitis, and lymphocytic cholangitis). Treatment is available for cholangitis caused by liver flukes and for neutrophilic cholangitis, and the prognosis is good. However, the cause of lymphocytic cholangitis is not known and there is currently no evidence-based therapy. Several causes are mentioned in the literature, but more research is needed in order to establish the cause of this disease and to develop an appropriate therapy. PMID- 21614850 TI - [Q fever in the Netherlands: current status, results from veterinary research and expectations of the coming years]. PMID- 21614851 TI - [Introduction of Leishmania species in the Netherlands from dogs who are returning from military missions and vacations in countries where leishmaniasis is endemic]. PMID- 21614852 TI - [New Techniques makes showing Toxoplasma in meat a possibility]. PMID- 21614853 TI - [Cost calculator from, for and by veterinarians]. PMID- 21614854 TI - [Reducing antibiotic use starts with the veterinarian]. PMID- 21614855 TI - [Personnel management: "Someone needs to do it!"]. PMID- 21614856 TI - [Treatment tooth resorption]. PMID- 21614857 TI - [Prevalent heart abnormalities in cats and dogs]. PMID- 21614858 TI - [Veterinarian is vital in rebuilding and disaster help]. PMID- 21614859 TI - [Bypass from the ascending aorta in a case of subclavian artery obstruction]. PMID- 21614860 TI - [Imaging diagnosis Q & A. Cardiac metastasis of renal cell carcinoma]. PMID- 21614861 TI - Key findings from HSC's 2010 site visits: health care markets weather economic downturn, brace for health reform. AB - Lingering fallout--loss of jobs and employer coverage--from the great recession slowed demand for health care services but did little to slow aggressive competition by dominant hospital systems for well-insured patients, according to key findings from the Center for Studying Health System Change's (HSC) 2010 site visits to 12 nationally representative metropolitan communities. Hospitals with significant market clout continued to command high payment rate increases from private insurers, and tighter hospital-physician alignment heightened concerns about growing provider market power. High and rising premiums led to increasing employer adoption of consumer-driven health plans and continued increases in patient cost sharing, but the broader movement to educate and engage consumers in care decisions did not keep pace. State and local budget deficits led to some funding cuts for safety net providers, but an influx of federal stimulus funds increased support to community health centers and shored up Medicaid programs, allowing many people who lost private insurance because of job losses to remain covered. Hospitals, physicians and insurers generally viewed health reform coverage expansions favorably, but all worried about protecting revenues as reform requirements phase in. PMID- 21614862 TI - Proceedings and abstracts of the 13th National Institutes of Health Scientific Meeting and the 4th National Conference for Clinical Research. June 2-4, 2010. Kuala Lumpur, Malaysia. PMID- 21614863 TI - Rolling into spatial disorientation: simulator demonstration of the post-roll (Gillingham) illusion. AB - INTRODUCTION: Spatial disorientation (SD) is still a contributing factor in many aviation accidents, stressing the need for adequate SD training scenarios. In this article we focused on the post-roll effect (the sensation of rolling back after a roll maneuver, such as an entry of a coordinated turn) and investigated the effect of roll stimuli on the pilot's ability to stabilize their roll attitude. This resulted in a ground-based demonstration scenario for pilots. METHODS: The experiments took place in the advanced 6-DOF Desdemona motion simulator, with the subject in a supine position. Roll motions were either fully automated with the subjects blindfolded (BLIND), automated with the subject viewing the cockpit interior (COCKPIT), or self-controlled (LEAD). After the roll stimulus subjects had to cancel all perceived simulator motion without any visual feedback. Both the roll velocity and duration were varied. RESULTS: In 68% of all trials subjects corrected for the perceived motion of rolling back by initiating a roll motion in the same direction as the preceeding roll. The effect was dependent on both rate and duration, in a manner consistent with semicircular canal dynamics. The effect was smallest in the BLIND scenario, but differences between simulation scenarios were non-significant. DISCUSSION: The results show that the effects of the post-roll illusion on aircraft control can be demonstrated adequately in a flight simulator using an attitude control task. The effect is present even after short roll movements, occurring frequently in flight. Therefore this demonstration is relevant for spatial disorientation training programs for pilots. PMID- 21614864 TI - Simulated microgravity, erythroid differentiation, and the expression of transcription factor GATA-1 in CD34+ cells. AB - INTRODUCTION: The microgravity environment of spaceflight leads to a series of changes in the human blood system. The aim of the present study was to examine the influence of simulated microgravity on the differentiation of CD34+ cells and to explore whether transcription factor GATA-1, required for the terminal differentiation of committed erythroid progenitor cells, is involved in this process. METHODS: CD34+ cells were cultured in the simulated microgravity conditions created by a rotary cell-culture system (RCCS). The effects of simulated microgravity on the differentiation and apoptosis of CD34+ cells were analyzed using flow cytometry and propidium iodide (PI) staining, respectively. Expression of GATA-1 mRNA in CD34+ cells was determined by real-time quantitative PCR. RESULTS: In the RCCS group, GlyA+ (glycophorin A) expression was lower and CD33+ expression higher than in the 1-g liquid control group (22.21% +/- 3.02% and 60.05% +/- 3.08%, vs. 52.12% +/- 1.92% and 18.87% +/- 1.41%, respectively). The proportion of differentiated cells in the 1-g methylcellulos e group (Gly+% = 54.39% +/- 2.86%, CD33+% = 21.09% +/- 3.19%) was similar to that in the 1-g liquid control group. As shown by real-time quantitative PCR, the relative expression of GATA-1 mRNA in the RCCS group was only 20% of that in the -g control group. CONCLUSIONSs: The differentiation of CD3+ cells, and especially erythroid differentiation, was inhibited by simulated microgravity by a mechanism that appears to involve the suppression of GATA-1 mRNA expression. The results of this study may be useful in understanding the critical effect of simulated microgravity on the pathogenesis of space anemia. PMID- 21614865 TI - Hypoxia-induced changes in standing balance. AB - BACKGROUND: A few studies in the literature have reported postural changes with hypoxia, but none have quantified the magnitude of change. Further understanding of this condition could have implications for patients at risk for falls, individuals undergoing acute altitude exposure, and pilots and commercial passengers. The objective of this study was to evaluate the effect of different levels of hypoxia (oxygen nitrogen mixtures) on postural standing balance using the computerized dynamic posturography (CDP) system. This improves upon previous protocols by manipulating vision and standing balance with a sway-referenced visual field and/or platform. Additionally, normative data were available for comparison with the cumulative test scores and scores for each condition. METHODS: Altitude hypoxia was simulated by use of admixing nitrogen to the breathing gas to achieve equivalent altitudes of 1524 m, 2438 m, and 3048 m. Subjects were evaluated using the CDP system. RESULTS: Subjects showed an overall trend toward decreased performance at higher simulated altitudes consistent with the initial hypothesis. Composite standing balance sway scores for the sensory organization subtest of CDP were decreased compared to baseline for simulated altitudes as low as 2438 m (mean sway scores: 81.92 at baseline; 81.85 at 1524 m; 79.15 at 2438 m; 79.15 at 3048 m). Reaction times to unexpected movements in the support surface for the motor control subtest (MCT) increased compared to baseline (mean composite scores: 133.3 at baseline; 135.9 ms at 1524 m; 138.0 ms at 2438 m; 140.9 ms at 3048 m). CONCLUSIONS: The CDP testing provided a reliable objective measurement of degradation of balance under hypoxic conditions. PMID- 21614866 TI - The perception of roll tilt in pilots during a simulated coordinated turn in a gondola centrifuge. AB - BACKGROUND: It has previously been reported that nonpilots underestimate the roll tilt angle after acceleration in a gondola centrifuge. The aim of the present work was to elucidate the significance of flight experience for roll tilt perception based on vestibular information. METHODS: The subjective visual horizontal (SVH) was measured by means of an adjustable luminous line in darkness. Eight nonpilots (N), nine fighter pilots (F), and eight helicopter pilots (H) underwent two centrifuge runs (2 G, 5 min) heading forward and backward, respectively. The roll position of the gondola (60 degrees at 2 G) was controlled so that the subject was always upright with respect to the gravitoinertial force. RESULTS: Upon acceleration of the centrifuge there was a tilt of the SVH in a direction compensatory to the inclination of the gondola. This tilt was larger in the forward position [N: 17.2 +/- 6.4 degrees, F: 31.2 +/ 16.4 degrees, H: 33.6 +/- 18.2 degrees (means +/- SD)] than in the backward position (N: -5.0 +/- 6.8 degrees, F: -12.2 +/- 17.4 degrees, H: -10.4 +/- 15.4 degrees). In N the tilt declined with time, approaching zero by the end of the 2 G plateau. In the pilots it was significantly larger and did not decline. CONCLUSION: Flight experience results in an increased ability to perceive the roll tilt during movement along a curved path. That this can be revealed in a centrifuge might suggest that acceleration of the centrifuge constitutes a movement pattern which is similar, from a vestibular point of view, to that of an airplane entering a coordinated turn. PMID- 21614868 TI - Galvanic vestibular stimulation as an analogue of spatial disorientation after spaceflight. AB - BACKGROUND: Exposure to microgravity adversely affects performance of astronaut pilots; a review of the first 100 Shuttle missions found that touchdown speed was above specified limits in 20% of landings, in contrast to near ideal performance in preflight high-fidelity Shuttle simulations. Ground-based simulators emphasize spacecraft handling abilities, but do not recreate the effects of extended weightlessness on sensorimotor function. The aim of this study was to validate an analogue of the sensorimotor effects of microgravity using pseudorandom bilateral bipolar galvanic vestibular stimulation (GVS) during Shuttle landing simulations. METHODS: Pilot performance was assessed during simulated Shuttle landings in the Vertical Motion Simulator at NASA Ames Research Center, Moffett Field, CA (used for astronaut pilot training). Subjects (N = 11) flew eight pairs of identical landing profiles (final approach and touchdown), with and without GVS, presented in a pseudorandom order. RESULTS: Touchdown speed was on target (204 kn) without GVS [203.8 kn], but increased significantly during GVS exposure 1208.5 kn] and was at the upper limit (209 kn) of the target range. The adverse effects of GVS on pilot performance were obvious. Unsuccessful (crash) landings increased from 2.3% (2/88) without GVS to 9% (7/88) with GVS. Hard landings, with touchdown speed in the 'red' (unacceptable) range (> 214 kn), almost doubled from 14 (15.9%) without GVS to 27 (30.7%) with GVS. CONCLUSION: GVS was an effective analogue of decrements in postflight Shuttle pilot performance. PMID- 21614867 TI - Toe blood pressure and leg muscle oxygenation with body posture. AB - INTRODUCTION: In 1980 Katkov and Chestukhin measured blood pressures and oxygenation invasively at various body tilt angles at different locations on the body, including the foot. To our knowledge, such measurements have not been performed noninvasively. Therefore, the purpose of this study was to measure toe blood pressure (TBP) and lower limb muscle oxygenation noninvasively at various body tilt angles, and to assess the use of a Finometer for noninvasive TBP measurements. Our noninvasive results are compared with those performed by Katkov and Chestukhin. We hypothesized that: 1) the Finometer provides a noninvasive measurement of TBP at different tilt angles; and 2) muscle oxygenation is highest with 0 and -6 degrees, and decreases with increased head-up tilt (HUT). METHODS: There were 10 subjects who were exposed to different body tilt angles (-6, 0, 10, 30, 70, and 90 degrees). At each angle we measured TBP noninvasively with a Finometer and muscle tissue oxygenation by near infrared spectroscopy. RESULTS: We found a strong correlation between TBP using the Finometer and TBP predicted by adding the hydrostatic component due to body tilt to the standard arm blood pressure measurement. At 10, 30, 70, and 90 degrees both TBP and tissue oxygenation were significantly different from the 0 degree (supine) level. Oxygenation decreased and TBP increased with higher HUT angles. No differences were observed in TBP or oxygenation between -6 and 0 degree. CONCLUSIONS: The Finometer accurately measures TBP noninvasively with body tilt. Also, muscle oxygenation is highest at small HUT angles and decreases with increased HUT. PMID- 21614869 TI - Classification and prediction of pilot weather encounters: A discriminant function analysis. AB - INTRODUCTION: Flight into adverse weather continues to be a significant hazard for General Aviation (GA) pilots. Weather-related crashes have a significantly higher fatality rate than other GA crashes. Previous research has identified lack of situational awareness, risk perception, and risk tolerance as possible explanations for why pilots would continue into adverse weather. However, very little is known about the nature of these encounters or the differences between pilots who avoid adverse weather and those who do not. METHODS: Visitors to a web site described an experience with adverse weather and completed a range of measures of personal characteristics. RESULTS: The resulting data from 364 pilots were carefully screened and subject to a discriminant function analysis. Two significant functions were found. The first, accounting for 69% of the variance, reflected measures of risk awareness and pilot judgment while the second differentiated pilots in terms of their experience levels. The variables measured in this study enabled us to correctly discriminate between the three groups of pilots considerably better (53% correct classifications) than would have been possible by chance (33% correct classifications). CONCLUSIONS: The implications of these findings for targeting safety interventions are discussed. PMID- 21614870 TI - Aeromedical decision making in attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder is a problematic diagnosis in the context of aeromedical certification. Certain characteristics of the disorder such as impaired attention potentially affect the safe conduct of flying. Pharmacological treatment with stimulants also has issues surrounding short half lives and effects on the recognition of fatigue. This article gives a broad overview of the issues involved and provides certification guidelines as adopted in the Australian Civil Aviation Safety Authority which may be helpful if adopted by other certification bodies. PMID- 21614871 TI - Characterization of airway device cuff volumes at simulated altitude. AB - INTRODUCTION: Cuff volume of an air-filled airway device varies inversely with ambient pressure at altitude. This may result in problems with ventilation, aspiration, and tissue ischemia in intubated patients transported by aircraft. We aimed to characterize cuff volume changes in airway devices as a function of altitude. METHODS: Four inflatable airway devices lendotracheal tube (ETT), Combitube, King tube, and laryngeal mask airway (LMA)I, each inflated with air or water, were evaluated for cuff volume changes in an altitude chamber simulating ascent and descent from ground level to 15,000 ft (4572 m). A novel cuff-less supraglottic device called i-gel was also tested. Multivariate linear regression was used to assess the effect of altitude and cuff content on cuff volume. RESULTS: We found a linear relationship between air-filled cuff volume and altitude in all the inflatable airway devices. The Combitube (correlation coefficient R = 0.94) and King tube (R = 0.98) showed the clearest linear relationship; the ETT (R = 0.70) and LMA (0.86) showed modest correlations. With water-filled cuffs, the rate of increase was relatively smaller in all the inflatable devices except the ETT, which remained constant. The difference between air- and water-filled cuffs was statistically significant in each inflatable device (P < 0.001). The i-gel showed no volume change at any of the tested altitudes. CONCLUSIONS: Cuff volume of inflatable airway devices increased linearly with altitude. The dual-cuffed supraglottic devices showed greater volume changes, likely due to the combined effect of their two cuffs. Of the inflatable devices, the water-filled ETT was the least sensitive to altitude changes. PMID- 21614872 TI - Neck pain among fighter pilots after the introduction of the JHMCS helmet and NVG in their environment. AB - INTRODUCTION: Neck pain is a common complaint among fighter pilots. With implementation of the joint helmet mounted cuing system (JHMCS), the strain on the pilot's neck has increased. METHODS: We surveyed 58 F-16 pilots from the Royal Danish Air Force by anonymous questionnaires. More than half of these pilots used JHMCS regularly. RESULTS: The response rate was 100%. Of the pilots, 97% experienced neck pain in flight or shortly after flying, 83% within the last year. Right side neck pain was significantly more frequent than left side, odds ratio 3.25. There was a strong tendency toward predominant right-sided shoulder pain. The pilots reported that combined rotation and extension movements were especially hazardous. Only 1 in 10 pilots moved his head independent of G-load. Neck pain influenced operational flying, especially the ability to perform a "check six" movement sufficiently, and affected flying with high G loads as occurs in basic fighter maneuvers and air combat maneuvering. DISCUSSION: To avoid neck problems the majority of pilots aim to avoid certain head movements and to fix their neck before exposing themselves to high +Gz loads. With the implementation of JHMCS, two conflicting goals are evident and working at cross purposes. A pilot's head should remain stationary while exposed to high +Gz loads. However, maximizing the advantages of JHMCS encourages the pilot to move his head sharply while exposed to high +Gz loads. Training programs to help the pilots cope with these challenges are warranted. PMID- 21614873 TI - Prescription sleep medicine for aircrew. AB - It is suggested that the Aerospace Medical Association convene an international expert body to determine the relevance of the pharmacological profiles of hypnotics to the practice of aviation medicine. PMID- 21614874 TI - Aerospace medicine at Brooks AFB, TX: hail and farewell. AB - With the impending termination of USAF operations at Brooks Air Force Base (AFB) in San Antonio, TX, it is time to consider its historic role in Aerospace Medicine. The base was established in 1917 as a flight training center for the U.S. Army Air Service and in 1926 became home to its School of Aviation Medicine. The school moved to San Antonio's Randolph Field in 1931, but in 1959 it returned to Brooks where it occupied new facilities to support its role as a national center for U.S. Air Force aerospace medicine, including teaching, clinical medicine, and research. The mission was then expanded to encompass support of U.S. military and civilian space programs. With the abrupt termination of the military space program in 1969, research at Brooks focused on clinical aviation medicine and support of advanced military aircraft while continuing close cooperation with NASA in support of orbital spaceflight and the journey to the Moon. Reorganization in the 1990s assigned all research functions at Brooks to the Human Systems Division and its successors, leaving to USAFSAM the missions related to clinical work and teaching. In 2002 the USAF and the city of San Antonio implemented shared operation of Brooks as a "City-Base" in the hope of deflecting threatened closure. Nevertheless, under continuing pressure to consolidate military facilities in the United States, the 2005 Base Closure and Realignment Commission ordered Brooks closed by 2011, with its aerospace medicine functions relocated to new facilities at Wright-Patterson AFB in Dayton, OH. PMID- 21614875 TI - The neurosciences and air capability. PMID- 21614876 TI - You're the flight surgeon: ear, nose and throat conditions. PMID- 21614877 TI - This month in aerospace medicine history. PMID- 21614878 TI - A brief history of social psychology and its contribution to health in Malawi. PMID- 21614879 TI - Contraceptive knowledge, beliefs and attitudes in rural Malawi: misinformation, misbeliefs and misperceptions. AB - INTRODUCTION: The objective of the study was to find out factors that affect the intentions of men and women to use family planning methods. METHODS: The study was conducted in Mangochi district, the southern region of Malawi in 2006. About 60 Focus group discussions were conducted to identify the attitudes and beliefs of 30 male and 30 female participants regarding family planning methods. The data was then transcribed and analyzed manually identifying central themes and relationships across the cases and narratives. RESULTS: Most of the respondents knew the different types of family planning methods and reported that health facilities had adequate stock of family planning supplies. However, it was found that most of the women and men were not using any modern family planning methods. Reasons included: family planning methods were perceived side effects, such as prolonged menstruation, men's concerns about impotence and genital sores, weight gain or loss, and subsequent infertility. Traditional family planning methods were mostly used for infertility problems. CONCLUSION: Despite knowing about the different types of family planning methods, and awareness of their ready availability in health facilities, use of these methods is low because considerable misinformation still prevails regarding contraceptive methods' side effects. PMID- 21614880 TI - Endocrine distrupting chemicals and human health: the plausibility of research results on DDT and reproductive health. PMID- 21614881 TI - Supplementary feeding in the care of the wasted HIV infected patient. AB - Wasting and food insecurity are commonly seen in patients receiving antiretroviral treatment (ART) programs in sub-Saharan Africa and south Asia, and supplementary feeding is often offered in conjunction with ART. Evidence for the effectiveness of such supplementary feeding is scant. A randomised, investigator blinded, controlled clinical trial of two types of supplementary food, corn/soy blended flour and a ready-to-use peanut butter-based lipid paste, in wasted adults in Blantyre, Malawi is described and the results summarised. A historical control group who did not receive supplementary food is described as well. Provision of about half of the daily energy requirement as a supplementary food for 14 weeks resulted in more rapid restoration of a normal BMI; and the energy dense, ready-to-use paste was associated with more rapid weight gain than the blended flour. Survival was similar among the 3 groups. The strong association between lower BMI and survival indirectly suggests that there may well be clinical benefit from supplementary feeding in this population. No differences were seen in ART adherence or quality of life with more rapid restoration of BMI. Further research is urgently needed concerning the widespread practice of supplementary feeding in HIV/AIDS care to most effectively utilize this intervention. PMID- 21614882 TI - Gender differences in retention and survival on antiretroviral therapy of HIV-1 infected adults in Malawi. AB - BACKGROUND; There is currently a dearth of knowledge on gender differences in mortality among patients on ART in Africa. METHODS: Using data from the national ART monitoring and evaluation system, a survival analysis of all healthcare workers, teachers, and police/army personnel who accessed ART in Malawi by June, September and December 2006 respectively, was undertaken. Gender differences in survival were analysed using Kaplan-Meier estimates and rate ratios were derived from Poisson regression adjusting for confounding. RESULTS: 4670 ART patients (49.8% female) were followed up for a median of 8.7 months after starting ART. Probability of death was significantly higher for men than women (p < 0.001). Controlling for age, WHO clinical stage and occupation, men experienced nearly 2 times the mortality of women RR 1.90 [95% CI: 1.57-2.29]. A higher proportion of men initiated ART in WHO stage 4 (p < 0.001). CONCLUSION: Among healthcare workers, teachers, police/army personnel, men have higher mortality on ART than women. Possible reasons are unclear but could be biological or because men present for ART at a later clinical stage or have poorer adherence to therapy. Improving early access to ART may reduce mortality, especially among men. A gender difference in adherence to therapy needs further investigation. PMID- 21614884 TI - Global research report on Africa. PMID- 21614883 TI - Case report-right iliac fossa mass in an HIV-positive woman. Cryptococcal meningitis. PMID- 21614885 TI - Opinions on government introduction of mandatory HlV testing. Should there be mandatory testing for HIV in Malawi? PMID- 21614886 TI - Fifty years of decompression sickness research at Brooks AFB, TX: 1960-2010. AB - INTRODUCTION, FACILITIES, AND METHODS: Decompression sickness (DCS) occurring in hypobaric environments related to aviation or spaceflight was a major focus of research at Brooks AFB/City-Base, TX, throughout the period 1960-2010. Multiple hypobaric chambers and extensive support facilities were built for research on altitude DCS using both human subjects and animal models. Areas of study included symptomatology, incidence, prediction, and prevention of DCS. High-altitude aviation, spacecraft atmospheres, and pressure suits were evaluated with various decompression and prebreathing schedules to reduce DCS risk. FACTORS AFFECTING DCS INCIDENCE: The results from these efforts were recorded in an extensive Altitude DCS Research Database which served as a resource for developing reports and exploring relationships of various parameters such as altitude, time at altitude, prebreathe time, and mode of activity while decompressed. PREVENTION AND PREDICTION OF DCS: Individual susceptibility to DCS was also evaluated in an effort to tailor preventive measures and predict susceptibility. Completion of the 26 human-use protocols provided information which was incorporated into NASA and USAF operational practices to reduce DCS risk. DOCUMENTATION: DCS researchers working at Brooks throughout this period produced 177 papers documenting results of thousands of subject-exposures and other experiments. An Altitude DCS Risk Assessment Computer Model was fielded in 2005. This review centers on the results of research at Brooks and notes questions about operational DCS risk that have not yet been answered. PMID- 21614887 TI - Effect of anti-mosquito midgut antibodies on development of malaria parasite, Plasmodium vivax and fecundity in vector mosquito Anopheles culicifacies (Diptera: culicidae). AB - The effect of anti-mosquito-midgut antibodies on the development of the malaria parasite, P. vivax was studied by feeding the vector mosquito, An. culicifacies with infected blood supplemented with serum from immunized rabbits. In order to get antisera, rabbits were immunized with midgut proteins of three siblings species of Anopheles culicifacies, reported to exhibit differential vectorial capacity. The mosquitoes that ingested anti-midgut antibodies along with infectious parasites had significantly fewer oocysts compared to the control group of mosquitoes. The immunized rabbits generated high titer of antibodies. Their cross reactivity amongst various tissues of the same species and with other sibling species was also determined. Immunogenic polypeptides expressed in the midgut of glucose or blood fed An. culicifacies sibling species were identified by Western blotting. One immunogenic polypeptide of 62 kDa was exclusively present in the midgut of species A. Similarly, three polypeptides of 97, 94 and 58 kDa and one polypeptide of 23 kDa were present exclusively in species B and C respectively. Immunoelectron microscopy revealed the localization of these antigens on baso-lateral membrane and microvilli. The effects of anti-mosquito midgut antibodies on fecundity, longevity, mortality and engorgement of mosquitoes were studied. Fecundity was also reduced significantly. These observations open an avenue for research toward the development of a vector-based malaria parasite transmission-blocking vaccine. PMID- 21614888 TI - Mucuna pruriens Linn. seed extract pretreatment protects against cardiorespiratory and neuromuscular depressant effects of Naja sputatrix (Javan spitting cobra) venom in rats. AB - Mucuna pruriens has been used by native Nigerians as a prophylactic for snakebite. The protective effects of M. pruriens seed extract (MPE) were investigated against the pharmacological actions of N. sputatrix (Javan spitting cobra) venom in rats. The results showed that MPE-pretreatment protected against cardiorespiratory and, to a lesser extent, neuromuscular depressant effects of N. sputatrix venom. These may be explained at least in part by the neutralisation of the cobra venom toxins by anti-MPE antibodies elicited by the MPE pretreatment. PMID- 21614889 TI - Effect of aloe vera (Aloe barbadensis Miller) gel on doxorubicin-induced myocardial oxidative stress and calcium overload in albino rats. AB - Administration of a single dose of doxorubicin (DOX) (7.5 mg/kg, i.v.) produces cardiotoxicity, manifested biochemically by significant decrease in blood glutathione (GSH) and tissue GSH along with elevated levels of serum lactate dehydrogenase (LDH) and serum creatine phosphokinase (CPK). In addition, cardiotoxicity was further confirmed by significant increase in lipid peroxides expressed as malondialdehyde (MDA, secondary indicator of lipid peroxidation), tissue catalase and tissue superoxide dismutase (SOD). Administration ofA. vera gel (100 and 200 mg/kg) orally for 10 days produced a significant protection against cardiotoxicity induced by DOX evidenced by significant reductions in serum LDH, serum CPK, cardiac lipid peroxides, tissue catalase and tissue SOD along with increased levels of blood and tissue GSH. The results revealed that A. vera gel produced a dose dependent protection against DOX induced cardiotoxiaty. PMID- 21614890 TI - Behavioural and neurochemical evaluation of Perment an herbal formulation in chronic unpredictable mild stress induced depressive model. AB - Perment, a polyherbal Ayurvedic formulation that contains equal parts of Clitoria ternatea Linn., Withania somnifera Dun., Asparagus racemosus Linn., Bacopa monniera Linn., is used clinically as mood elevators. The aim of the present study was to explore the behavioural effects and to understand possible mode of action of Perment in stress induced depressive model. Chronic unpredictable mild stress (CUMS) was used to induce depression in rats. Open field exploratory behaviour, elevated plus maze, social interaction and behavioural despair tests were used to assess behaviour. Using standard protocols plasma noradrenaline, serotonin, corticosterone and brain/adrenal corticosterone levels were measured to support the behavioural effects of Perment. Exposure to CUMS for 21 days caused anxiety and depression in rats, as indicated by significant decrease in locomotor activity in the open field exploratory behaviour test and increased immobility period in the behavioural despair test. Perment predominantly exhibited antidepressant action than anxiolytic activity. Further Perment increased the plasma noradrenaline and serotonin levels in stressed rats. No significant alteration in the brain corticosterone level in stressed rats was observed with Perment treatment. However the adrenal corticosterone level is decreased with Perment. It can be concluded that the Perment formulation exhibited synergistic activity, has a significant antidepressant and anxiolytic activity, which may be mediated through adrenergic and serotonergic system activation. Currently the formulation is clinically used as anxiolytic but the present results suggest that the formulation can also be indicated in patients affected with depression. PMID- 21614891 TI - Hepatoprotective action of ethanolic extracts of Melia azedarach Linn. and Piper longum Linn and their combination on CCl4 induced hepatotoxicity in rats. AB - A comparison of analysis in evaluating the hepatoprotective action of ethanolic extract of M. azedarach (MAE) and P. longum (PLE) with their combination biherbal extract (BHE) against carbon tetrachloride (CCl4) induced hepatic damage is reported in albino rats. There was a marked elevation of serum marker enzyme levels in CCl4 treated rats, which were restored towards normalization in the drug (MAE and/or PLE:50 mg/kg body weight po, once daily for 14 days) treated animals. The biochemical parameters like total protein, total bilirubin, total cholesterol, triglycerides, and urea were also restored towards normal levels. The combined BHE showed more significant reduction of the enzymes than MAE or PLE against CCl4 induced hepatotoxicity. The results strongly indicate that BHE has more potent hepatoprotective action than MAE or PLE individually against CCl4 induced hepatic damage in rats. Among these extracts, BHE showed similar hepatoprotective action to silymarin, which was the positive control in this study. PMID- 21614892 TI - Anti-hyperlipidemic and antioxidant potential of different fractions of Terminalia arjuna Roxb. bark against PX- 407 induced hyperlipidemia. AB - The three fractions diethyl ether, ethyl acetate and ethanol. of T. arjuna exerted hypolipidemic and antioxidative effects at two different doses levels of 175 and 350 mg/kg body weight in Poloxamer (PX)-407 induced hyperlipidemic albino Wistar rats. The hypolipidemic and antioxidant effects of T. arjuna fractions were noticed as EtOH > diethyl ether > ethyl acetate. The results suggest that ethanolic fraction of T. arjuna possesses the potent properties of being antioxidant and hypolipidemic than other fractions. In turn, it has therapeutic potential for the prevention of coronary arterial disease. PMID- 21614893 TI - Comparative study of 6-APA production by free and agar immobilized bacteria in nutrient broth culture. AB - In the present study different bacterial samples were isolated from soil of different places of Dibrugarh and screened for biotransformation ability to produce 6-Aminopenicillanic acid. Among ten isolated bacterial samples, three gram positive bacterial samples designated as AKDD-2, AKDD-4 and AKDD-6 showed the production of 6-APA from penicillin G. Assessment of production of 6-APA after incubation in penicillin G (2 mg/ml) by three different samples separately in free and agar immobilization state was done by HPLC analysis. Reusability of immobilized cells was found successful up to 14 days. PMID- 21614894 TI - Bioemulsifier production by Streptomyces sp. S22 isolated from garden soil. AB - Out of 45 actinomycetes isolated from garden soil, pond water and air; fifteen showed good emulsification activity. Streptomyces sp. S22 isolated from garden soil produced maximum bioemulsifier with 0.5% (v/v) sunflower oil during stationary phase at 37 degrees C, pH 6 and 250 rev/min. Emulsification activity was maximum (320 EU/ml) with sunflower oil as substrate. Partially purified bioemulsifier from Streptomyces sp. S22 was a peptidoglycolipid containing lipid (51.25%), protein (30%), non-reducing sugar (17.75%) and reducing sugar (1%). The yield of partially purified bioemulsifier was 1.6 g/l and reduced the surface tension of water by 23.09 mN/m. The bioemulsifier produced by Streptomyces sp. S22 was stable at room temperature for seven days. PMID- 21614895 TI - Response of multiple herbicide resistant strain of diazotrophic cyanobacterium, Anabaena variabilis, exposed to atrazine and DCMU. AB - Effect of two photosynthetic inhibitor herbicides, atrazine (both purified and formulated) and [3-(3,4-dichlorophenyl)-1,1-dimethyl urea] (DCMU), on the growth, macromolecular contents, heterocyst frequency, photosynthetic O2 evolution and dark O2 uptake of wild type and multiple herbicide resistant (MHR) strain of diazotrophic cyanobacterium A. variabilis was studied. Cyanobacterial strains showed gradual inhibition in growth with increasing dosage of herbicides. Both wild type and MHR strain tolerated < 6.0 mg L(-1) of atrazine (purified), < 2.0 mg L(-1) of atrazine (formulated) and < 0.4 mg L(-1) of DCMU indicating similar level of herbicide tolerance. Atrazine (pure) (8.0 mg L(-1)) and 4.0 mg L(-1) of atrazine (formulated) were growth inhibitory concentrations (lethal) for both wild type and MHR strain indicating formulated atrazine was more toxic than the purified form. Comparatively lower concentrations of DCMU were found to be lethal for wild type and MHR strain, respectively. Thus, between the two herbicides tested DCMU was more growth toxic than atrazine. At sublethal dosages of herbicides, photosynthetic O2 evolution showed highest inhibition followed by chlorophyll a, phycobhiliproteins and heterocyst differentiation as compared to carotenoid, protein and respiratory O2 uptake. PMID- 21614896 TI - A sensitive and specific ES-31 antigen detection based fluorometric assay for confirmation of Mycobacterium tuberculosis in cell culture. AB - Confirmation of presence of M. tuberculosis bacilli on microscopic examination is very important in diagnosis of tuberculosis. The present study was undertaken to find the usefulness of mycobacterial ES-31 serine protease as a marker to detect tuberculosis bacilli using fluorescein isothiocyanate conjugated anti-ES-31 serine protease antibody. This immunofluorescence method was compared with Ziehl Neelsen and auramine-O staining methods for detection of tuberculosis bacilli. Slides were prepared for each serially diluted tuberculosis H37Ra bacilli (1 x 10(7) bacilli/ml to 5 bacilli/ml). Slides for each dilution group were stained by ZN method, auramine-O and immunostaining methods using fluorescein isothiocyanate conjugated anti-ES-31 serine protease antibody. ZN staining method showed efficacy for detection of M. tuberculosis H37Ra upto 1 x 10(4) bacilli/ml while auramine-O method showed upto 1 x 10(2) bacilli/ml. The presence of bacilli was indicated by green fluorescence on immunostaining using anti-ES-31 antibody conjugate and this method was effective upto 10 bacilli/ml. The slides which were negative for ZN (1 x 10(3) cells/ml) and auramine-O (100 cells/ml) method showed positivity on restaining with immunofluorescent staining method. The results of this preliminary study showed that immunofluorescent staining method using specific anti-ES-31 antibody conjugate was more sensitive for detection of tuberculosis bacilli than ZN and auramine-O methods in samples of laboratory strain. The utility of this method will be studied further in clinical specimens. PMID- 21614897 TI - Ambulatory medical care utilization estimates for 2007. AB - OBJECTIVES: This report presents statistics on ambulatory care visits to physician offices, hospital outpatient departments (OPDs), and hospital emergency departments (EDs) in the United States in 2007. Ambulatory medical care utilization is described in terms of patient, provider, and visit characteristics. METHODS: Data from the 2007 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey were combined to produce annual estimates of ambulatory medical care utilization. RESULTS: Patients in the United States made an estimated 1.2 billion visits to physician offices and hospital OPDs and EDs, a rate of 405.0 visits per 100 persons annually. This was not significantly different than the rate of 381.9 visits per 100 persons in 2006, neither were significant differences found in overall visit rates by age, sex, or geographic region. Visit distribution by ambulatory care setting differed by poverty level in the patient's ZIP Code of residence, with higher proportions of visits to hospital OPDs and EDs as poverty levels increased. Between 1997 and 2007, the age-adjusted visit rate increased by 11 percent, fueled mainly by a 29 percent increase in the visit rate to medical specialty offices. Nonillness and noninjury conditions, such as general and prenatal exams, accounted for the largest percentage of ambulatory care diagnoses in 2007, about 19 per 100 visits. Seven of 10 ambulatory care visits had at least one medication provided, prescribed, or continued in 2007, for a total of 2.7 billion drugs overall. These were not significantly different than 2006 figures. Analgesics were the most common therapeutic category, accounting for 13.1 drugs per 100 drugs reported, and were most often utilized at primary care and ED visits. The number of viral vaccines that were ordered or provided increased by 79 percent, from 33.2 million occurrences in 2006 to 59.3 million in 2007; significant increases were also noted for anticonvulsants and antiemetics. PMID- 21614898 TI - A systemic review of human papillomavirus studies: global publication comparison and research trend analyses from 1993 to 2008. AB - The term "human papillomavirus" has been used as the keyword during searching titles, abstracts, and keywords based on the online version of Science Citation Index (SCI), Web of Science from 1993 to 2008. Twelve document types were found among the 14,943 papers published in 1,072 journals that were listed in 99 SCI subject categories. All the articles referring to human papillomavirus were assessed by using the following aspects: characteristics of publication output, distribution of output in journals, publication output of source country, source institute, and analysis of word clusters in title, author keywords, and keywords plus. The results have shown that the USA ranked first using five publication indicators including total, single country, international, first author, and corresponding author publications. China has had the sharpest rise of publications since 2004. The top four European countries in 2008 were France, Germany, the UK, and Italy, respectively. Trend studies with word cluster analysis were performed with regards to the areas of immunology, screening methodology, behavioral sciences, economics, and meta-analysis. All those areas have shown a sharp upward rise since 2004. In addition, hypermethylation-induced inactivation of the p16 gene in the early stages of oncogenesis has been getting more interest in recent years. PMID- 21614899 TI - Prognosis and role of postmastectomy radiotherapy in patients with T1-T2 breast cancer with one to three positive axillary nodes. AB - PURPOSE: To evaluate the prognosis and role of postmastectomy radiotherapy (PMRT) in T1-T2 breast cancer with one to three positive axillary nodes. METHODS: The 10 year Kaplan-Meier locoregional recurrence (LRR), distant recurrence (DR), disease free survival (DFS) and overall survival (OS) were compared between the NO and 1 3N+ cohorts. The role of PMRT was evaluated in the 1-3N+ cohort. RESULTS: The 10 year LRR, DR, DFS, OS rates in NO and the 1-3N+ cohorts were as follows: LRR 7.5% vs 19.4% (p = 0.011); DR 14.4% vs 23.0% (p = 0.029); DFS 71.3% vs 51.2% (p = 0.001) and OS 77.0% vs 58.7% (p = 0.001). Of the 192 1-3N+ patients not treated and treated with PMRT, the outcomes were: LRR 20.1% vs 18.4% (p = 0.047); DR 26.4% vs 21.5% (p = 0.743); DFS 40.2% vs 55.4% (p = 0.260) and OS 40.7% vs 66.0% (p = 0.344), respectively. CONCLUSION: PMRT reduces the 10-year LRR rate for such patients, but further examination is needed. PMID- 21614901 TI - The role of p16(INK4a) immunostaining in the risk assessment of women with LSIL cytology: a prospective pragmatic study. AB - BACKGROUND: The detection of high-grade cervical intraepithelial neoplasia (CIN2 or worse) among patients with low-grade cytology (LSIL) is challenging. The aim of this study was to assess the efficacy of p16(INK4a) in the risk assessment of women with LSIL cytology. METHODS: Consecutive liquid-based cytology specimens of 95 LSIL smears were selected and stained for p16(INK4a). All patients had colposcopically directed punch biopsies or large loop excision of the transformation zone of the cervix. The endpoint was detection of a biopsy confirmed CIN2 or worse. RESULTS: The overall sensitivity and specificity of p16(INK4a) for diagnosis of CIN2+ among LSIL smears were 41% and 86%, respectively. The positive predictive value of the biomarker was 62% and the negative predictive value 72%. CONCLUSIONS: The study shows that p16(INK4a) has low sensitivity but acceptable specificity for evaluation of LSIL smears harbouring high-grade lesions. The marker needs to be further assessed as an adjunct to other tests in an attempt to improve the triage of LSIL cytology smears. PMID- 21614900 TI - Expression of hypoxia-inducible 2 (HIG2) protein in uterine cancer. AB - For both cervical cancer (UCC) and endometrial cancer (EMC) there are no effective prognostic markers. In this study, we evaluated HIG2 protein expression in 332 uterine cancers (186 UCCs and 146 EMCs) and examined the relationship between HIG2 protein expression and clinical factors, including prognosis. Totally, HIG2 expression was detected in 58% of UCC and 66% of EMC. However, there was no significant relationship between HIG2 expression and age, clinical stage and histology in either UCC or EMC. In addition, HIG2 protein expression was not related to prognosis of UCC or EMC. The positivity rate of HIG2 protein was 56% and 61% in early-stage UCC and EMC, respectively and 67% in non-squamous cell carcinoma of UCC. The positivity rate of HIG2 protein was high even in early stage UCC and EMC PMID- 21614902 TI - Long-term topotecan therapy in recurrent or persistent ovarian cancer. AB - BACKGROUND: The objective of this study was to evaluate feasibility, safety and clinical outcome of long-term therapy with topotecan (Hycamtin) in recurrent or persistent ovarian cancer. PATIENTS AND METHODS: A retrospective chart review was conducted on all patients treated with topotecan (TPT) at the Department of Obstetrics and Gynecology, University of Bari, Italy between 1999 and 2007. Pertinent clinicopathologic information, response and toxicity following treatment with TPT were collected. TPT was given at a dosage ranging between 1.5 and 1.0 mg/m2 every three to four weeks. All patients were evaluated for toxicity acording to the CTC and response according to the RECIST response criteria. Time to progression (TTP) was calculated from initiation of TPT treatment and start of the next chemotherapy regimen. RESULTS: A total of 30 patients received TPT for at least eight cycles for recurrent ovarian (22), fallopian tube (3) or primary peritoneal carcinoma (5). A total of 432 cycles of chemotherapy were given, with an average of 14.4 cycles per patient (range 8-22). Dose reduction was necessary in 20 patients (66%). About half of the patients required blood transfusions and growth factors. Non hematologic toxicity was mild and manageable. Responses were observed in 16/30 patients (53%), the remaining having SD. Median time to treatment progression was 28 months (range 9-88). CONCLUSION: Long-term treatment with topotecan in recurrent/persistent ovarian cancer is feasible with limited evidence of cumulative toxicity. The results of this retrospective analysis suggest a potential role for late response and survival benefit for those patients without disease progression who continue topotecan therapy beyond six cycles of treatment. PMID- 21614903 TI - The value of TOP2A, EZH2 and paxillin expression as markers of aggressive breast cancer: relationship with other prognostic factors. AB - INTRODUCTION: The immunocytochemical expression of topoisomerase II alpha (TOP2A), enhancer of zeste homologue 2 (EZH2) and paxillin has recently gained increasing attention. Although previous studies have commented on the clinical usefulness of these markers, their role remains controversial. AIM: The purpose of the study was to investigate the expression of TOP2A, EZH2 and paxillin in relation to classic prognostic parameters and their significance as prognostic markers in imprints of resected breast carcinomas. METHODS: Imprint smears from 55 patients who underwent surgical treatment for primary carcinoma in our department between 2005 and 2006 were studied immunocytochemically with the use of TOP2A, EZH2 and paxillin antibodies. RESULTS: The expression of TOP2A correlated with higher histologic grade, tumor size and negative PR expression. High intensity staining for EZH2 expression was associated with higher histologic grade, negative ER and PR expression and positive Ki-67 expression. The expression of paxillin showed no correlation with estrogen/progesterone and HER2 expression nor with tumor grade and stage. CONCLUSION: Our data indicate that TOP2A and EZH2 expression are related to a more aggressive tumor phenotype. The expression of paxillin failed to correlate with any of the studied clinicopathologic factors. Further studies are needed to verify these results. PMID- 21614904 TI - The chemosensitivity of nodal metastases in recurrent epithelial ovarian cancer. AB - PURPOSE: In this study, we compared second-line chemotherapy effects of nodal metastases with other metastases sites. METHODS: The medical records of 44 women with recurrent ovarian cancer who received second-line chemotherapy were retrospectively reviewed. RESULTS: Median age at the time of second-line chemotherapy was 55 years (range: 31-74). Recurrent sites were as follows: 29 patients had a solitary site (abdominal cavity: 8; lymph node: 3; pelvic cavity: 10; liver: 4; lung: 4) and 15 patients had multiple sites In total, the response rate was 30% (CR: 8, PR: 5). The response rate in sensitive cases was higher than in refractory/resistant cases (50% vs 5% p = 0.002). However, age, chemotherapy regimen, histologic type and number of diseases were not related with chemotherapy effect. In all diseases, response rate tended to be higher in lymph node disease than in the others (44% vs 27%). In both sensitive and refractory/resistant cases, response rate tended to be higher in lymph node disease. CONCLUSION: The response rate for lymph node diseases tended to be relatively high. Further study analyzing survival will be required to conclude the chemotherapy effect. PMID- 21614905 TI - Twelve-month follow-up detection of high-risk human papillomavirus (HPV) DNA for 93 cases with cervical intraepithelial neoplasia grade 2 or 3 (CIN 2-3) after a loop electrosurgical excisional procedure (LEEP). AB - PURPOSE: The purpose of this study was to follow-up cervical intraepithelial neoplasia grades 2 or 3 (CIN2/3) cases after a loop electrosurgical excisional procedure (LEEP) by liquid-based cytology (LBC) and detection of HPV DNA. METHODS: LEEP was performed for the first diagnosed CIN2/3 cases. Six and 12 months after LEEP, LBC and HPV DNA detection were performed. RESULTS: The number of cases with CIN2 accounted for 64.5% (60/93) of the total cases before LEEP. Six months post LEEP, the number of cases with normal LBC and negative HPV DNA accounted for 63.4% (59/93). Cases with abnormal LBC accounted for 17.2 (16/93), and cases with persistent positive HPV DNA accounted for 11.8% (7/93). Two cases had both persistent positive HPV DNA and abnormal LBC. A vaginal intraepithelial neoplasm (VAIN2) was found in one of the HPV DNA persistent positive cases. Twelve months post LEEP, 4.3% (8/93) of the cases were HPV DNA positive. Abnormal LBC was observed in four cases (of which 2 cases were HPV DNA positive) with normal LBC and negative HPV DNA at six months post LEEP. CONCLUSION: HPV DNA examination is instrumental for the detection of VAIN. PMID- 21614906 TI - Efficiency of postoperative pain management after gynecologic oncological surgeries with the use of morphine + acetaminophen + ketoprofen versus morphine + metamizol + ketoprofen. AB - Surgical treatment used in gynecological oncology involves acute postoperative pain which requires efficient treatment. This study covered a group of 128 patients who were randomly divided into two groups. In the postoperative period patients in group I were administered morphine subcutaneously, acetaminophen intravenously and naproxen per rectum. The pain intensity level was checked by means of the pain intensity numeric rating scale (NRS). In the instances of pain rated at 5 or more, patients were additionally administered ketoprofen intravenously. Patients in group II were administered morphine, naproxen, and metamizole instead of acetaminophen and ketoprofen additionally. In group I after the administration of morphine and acetaminophen 22 patients (34.37%) needed additional doses of ketoprofen. In group II 33 women (51.56%) required ketoprofen after the administration of morphine and metamizole (N1 = 22 vs N2 = 33, p < 0.05). The use of metamizol with morphine (without ketoprofen) gave worse analgesic results than acetaminophen with morphine, but the combination of morphine, acetaminophen and ketoprofen or morphine, metamizol and ketoprofen gave satisfactory analgesic results. PMID- 21614907 TI - Multivariate analysis by Cox proportional hazard model on prognosis of patient with epithelial ovarian cancer. AB - PURPOSE OF INVESTIGATION: To evaluate the influence of various clinicopathological and biochemical factors on the survival of patients with epithelial ovarian cancer (EOC) after radical resection. METHODS: A retrospective analysis was made for 183 cases of epithelial ovarian cancer treated from January 1997 to January 2001. Six clinicopathological factors, including menopause, histological type, histological grade, lymph node metastasis, FIGO stage and chemotherapy that could possibly influence survival were selected. The expression of COX-2 and VEGF protein as two biochemical factors were detected in EOC tissues using immunohistochemical staining. Independent variables were first analyzed by univariate methods. A multivariate analysis of these variables was performed using the Cox proportional hazard regression model. RESULTS: The ovarian cumulative survival rate was 48.71% for three years and 30.71% for five years. Univariate analysis of overall survival involving all the patients indentified five factors that were associated with a significant outcome: menopause, histological grade, FIGO stage, COX-2 or VEGF expression level (p < 0.05). The expression of COX-2 was positive in 140 (76.5%) of these 183 cases, but was not associated with menopause, histological type, histological grade, lymph node metastasis or FIGO stage. Median survival time was 24.56 months for the patients with COX-2 positive expression, and 47.52 months for those with COX-2 negative expression (p < 0.05). VEGF protein overexpression was examined in 117 (63.93%) of all 183 cases, and was associated with lymph node metastasis (p <0.05), but not associated with menopause, histological grade, histological type or FIGO stage. The median survival time was 23.36 months for the patients with VEGF detected expression, and 42.09 months for those with no VEGF detected expression (p < 0.05). When the interactive effects of these factors were taken into account, COX-2 expression, FIGO stage, VEGF expression and histological grade were the four most important prognostic factors by multivariate analysis using the Cox proportional hazards model. Risk of death for the patients with COX-2 positive expression was 2.8 times than that with COX-2 negative expression, and for FIGO stage, VEGF expression and histological grade, risk of death was 2.2, 2.1, and 1.84 times, respectively. CONCLUSION: COX-2 expression, FIGO stage, VEGF expression and histological grade are the most important prognostic factors for EOC after curative resection. PMID- 21614908 TI - Women's knowledge and utilization of gynecological cancer prevention services in the Northwest of Greece. AB - PURPOSE OF INVESTIGATION: In Greece an organized cervical or breast cancer screening program does not exist and the population coverage is unknown. METHODS: Women of all ages completed a questionnaire, which assessed women's awareness of and participation in breast and cervical screening and human papillomavirus (HPV) vaccination. The women were randomly approached in public areas. RESULTS: 1,012 women completed the questionnaire. 52% of the women over 39 years old had undergone mammography in the last year and 76% of the women over 20 years old had a cervical smear test within the last three years in an opportunistic basis. In addition, the likelihood of having regular mammograms was positively associated with the likelihood of having regular cervical smears. Fifty percent of the responders did not identify HPV as the cause of cervical cancer and 38% were not aware of the HPV vaccine. From the women aged 16 to 28 years old, 11% had been vaccinated against HPV and an additional 23% intended to have the vaccine in the next six months. CONCLUSION: Knowledge and utilization of mammography and cervical screening was quite satisfactory, although HPV vaccination coverage was low. Preventive services could be improved through the development of a plan for the information of the public and the distribution of the HPV vaccine. PMID- 21614909 TI - Malignant changes in adenomyosis in patients with endometrioid adenocarcinoma. AB - OBJECTIVE: The aim of our retrospective study was to evaluate pathological changes in adenomyotic foci in hysterectomy specimens, and point out a possible mechanism of carcinogenesis in adenomyotic foci inside the myometrium. METHODS: Retrospective analysis of clinical data; 219 patients were operated at our departments from 2003-2008 with the diagnosis of early endometrial cancer. Standard staging operation was used in all cases and all hysterectomy specimens were afterwards routinely analyzed. RESULTS: Adenomyosis was found in 88 of a total of 219 hysterectomy specimens, while 205 of these 219 were affected by endometrioid adenocarcinoma, ten with clear cell carcinoma and four with papillary serous carcinoma. Within these subgroups adenomyosis was documented in 87 of 205 specimens with endometrioid adenocarcinoma (42.4%) and in one specimen of ten with clear cell carcinoma (2.2%), all found in the eutopic endometrium. All cases of malignant changes (n = 6) in adenomyosis were found exclusively with coexisting endometrioid adenocarcinoma: adenocarcinoma in adenomyosis was well or moderately differentiated in five cases, and poorly differentiated in just one case. Differentiation of the tumor in adenomyosis correlated with differentiation of the eutopic endometrial cancer in 50%. Hyperplastic changes like benign glandular hyperplasia, or atypical complex hyperplasia (ACH) were identified simultaneously in all cancer-positive adenomyotic foci. CONCLUSION: Malignant changes in adenomyosis were present in 6.8% of patients with endometrial cancer. All malignancy-positive cases of adenomyosis were associated with endometrioid adenocarcinoma of the eutopic endometrium. Interestingly, in all these cases, different stages of hyperplastic changes were also simultaneously identified. This observation suggests a similar pathway of carcinogenesis in adenomyosis as is known in estrogen-responsive endometrial cancer type I. PMID- 21614910 TI - Effect of collagen powder on lymphorrhea after modified radical mastectomy. A randomized controlled trial. AB - AIM: Postoperative lymphorrhea is a major complication of axillary lymphadenectomy. The aim of our study was to evaluate the impact of type I collagen in postoperative lymphorrhea in mastectomy patients. METHODS: Eighty patients that underwent modified radical mastectomy for breast cancer were randomized in two groups. In group A (collagen group, n = 42) collagen type I (Cellerate RX powder) was applied in the axillary cavity after lymphadenectomy while in group B (control group, n = 38) lymphadenectomy was performed in the standard fashion without the use of a sealant. Suction drains remained in place until the daily amount of lymphatic drainage fell under 30 ml. The total amount and the duration of drainage, as well as the morbidity and severity of arm pain were compared in the two groups. RESULTS: There was a non significant trend towards lower overall drainage in the collagen group. The duration of drainage and postoperative pain were similar in the two groups, as was morbidity. Subgroup analysis of patients according to the number of lymph nodes excised, revealed significantly less lymphorrhea in terms of volume and duration in patients who had more than ten lymph nodes excised. CONCLUSION: Collagen type I (Cellerate RX powder) appears to attenuate postoperative lymphorrhea in patients undergoing axillary lymphadenectomy especially when > 10 lymph nodes are removed. PMID- 21614911 TI - Association of CYP1B1 gene polymorphisms and the positive expression of estrogen alpha and estrogen beta with endometrial cancer risk. AB - To investigate the relationship between the CYP1B1 L432V polymorphism, ERalpha and ERbeta positivities and the incidence of endometrial cancer. The relationship between CYP1B1 L432V polymorphism, ERalpha and ERbeta positivities and endometrial cancer was investigated using the allele-specific polymerase chain reaction method to analyze gene polymorphism in exon 3 codon 432 (C-G) of CYP1B1. Our results are as follows: in endometrial cancer cases the prevalence rates of CYP1B1 L432V genotypes C/C, C/G, and G/G were 47.2%, 36.1%, and 16.7%, respectively, and 68.8%, 23.8% and 7.5% in the control group, respectively. The frequencies of CYP1B1 C and G alleles were 65.3% and 34.7% in endometrial cancer patients and 80.6% and 19.4% in the control group. A significant difference was found in the genotype distributions or allele frequencies of CYP1B1 L432V polymorphism between the two groups (p < 0.05). Compared with wild-type C/C, the susceptibility of endometrial cancer with homozygotic mutation G/G and heterozygotic mutation C/G increased by 3.235 (95%CI 1.111-9.425) and 2.214 (95% CI 1.067-4.593). Moveover, the positive expression of ERalpha in genotypes G/G and C/G was higher than in the wild genotype C/C (p < 0.05). In conclusion, allelic polymorphism of CYP1B1 L432V increases the risk of endometrial cancer and has a positive correlation with ERalpha expression. PMID- 21614912 TI - Is postoperative CA125 level in patients with epithelial ovarian cancer reliable to guess the optimality of surgery? AB - INTRODUCTION: Cytoreductive surgery is a pivotal component of primary treatment in patients with ovarian epithelial caner (OEC) and several studies have shown better outcomes of optimal debulking. The aim of this prospective study was to determine if optimum versus suboptimal cytoreductive surgery predicts CA125 levels two weeks after surgery. MATERIAL AND METHODS: Sixty patients with epithelial ovarian cancer scheduled for cytoreductive surgery in Imam Khomeini Hospital, Tehran, Iran were enrolled in this study. Two groups of patients were to undergo optimal or suboptimal cytoreductive surgery. Optimal cytoreduction was defined as the largest volume of residual disease < 1 cm in maximal dimension. CA125 levels were measured in all patients preoperatively and at two, seven and 14 days after surgery. CA125 levels were converted to a log scale. RESULTS: The distribution of staging, grading and types of tumors in each group were statistically equal but insignificant (chi square). The difference in mean of CA125 before and two weeks after surgery was statistically significant (paired t test; p = 0.0001) but the grade, stage and type of tumors did not have any impact on CA125 regression. However, regression of CA125 two weeks after the operation did not differ statistically between the optimal and suboptimal cytoreduction groups (repeated measure ANOVA). CONCLUSION: Although, postoperative CA125 decreased significantly in two weeks after tumor cytoreduction in patients with epithelial ovarian cancer, its regression did not differ according to optimal or suboptimal groups. PMID- 21614913 TI - Alveolar rhabdomyosarcoma originating from the uterine cervix. AB - Cervical alveolar rhabdomyosarcoma is a rare condition associated with poor prognosis. An 18-year-old patient presented with vaginal bleeding and a protruding mass from the vagina. Biopsy of the mass revealed alveoler rhabdomyosarcoma (ARMS), and radiological evaluation demonstrated that it originated from the uterine cervix. First, Wertheim's operation was carried out followed by four cycles of vincristine, actinomycine-D, ifosfamide (VAI) chemotherapy. However, the disease relapsed within three months, and the patient died of disease progression. Despite combination treatment, we could not achieve a desirable survival advantage in ARMS. Future studies may unveil the genomic profile of this rare condition, leading to invention of targeted therapies, which is the emerging trend in the treatment of sarcomas. PMID- 21614914 TI - Metastatic gastric cancer mimicking an advanced cervical cancer: a case report. AB - BACKGROUND: Metastasis to the uterine cervix from non-gynecologic neoplasms is rare. However, metastatic tumors sometimes precede the diagnosis of a primary tumor, and may lead to diagnosis of the primary tumor. CASE: A 50-year-old woman was referred to us complaining of increasing right flank pain. Computed tomography scan demonstrated an enlarged uterus with right-sided hydronephrosis and hydroureter. Cervical cytology revealed adenocarcinoma. She was considered to have a Stage IIIB cervical adenocarcinoma. Although no cervical lesion was seen colposcopically, histopathology from biopsies of the uterine cervix revealed poorly differentiated adenocarcinoma infiltrating around the normal endocervical glands. A metastasis from the gastrointestinal tract was suspected. The patient underwent gastroscopy and was found to have Borrmann type IV gastric cancer. Biopsies confirmed a poorly differentiated adenocarcinoma with signet ring cells. CONCLUSION: Physicians should bear in mind that metastatic tumors may precede the diagnosis of a primary tumor and could manifest by mimicking advanced cervical cancer. PMID- 21614915 TI - Peptide YY producing strumal carcinoid tumor of the ovary. AB - BACKGROUND: Primary ovarian carcinoid tumor is uncommon and represents less than 0.1% of ovarian malignancies. The strumal carcinoid may be complicated by carcinoid syndrome induced by peptide YY (PYY). CASE REPORT: We describe a 45 year-old woman with a bilateral ovarian tumor diagnosed through periodical gynecological examination. She presented with severe constipation. Right ovarian cyst laparoscopically resected was diagnosed as a strumal carcinoid tumor; the left one was mature cystic teratoma. No metastatic findings were seen macroscopically on the ovarian surface and pelvic peritoneum. Constipation was drastically improved by resecting the tumor. The carcinoid tumor cells were positive for tumor-producing PYY by mRNA analysis. CONCLUSION: It is important to be aware of this entity in the pathological diagnosis of ovarian tumors, in the presence of any clinical indicator of carcinoid tumor/syndrome, as it carries a markedly better prognosis and clinical outcome in comparison with most other malignant ovarian tumors. PMID- 21614916 TI - Advanced embryonal rhabdomyosarcoma of the uterine cervix: a case report. AB - BACKGROUND: Primary embryonal rhabdomyosarcoma (RMS) arising from the uterine cervix is a rare and extremely malignant entity. Young women aged 12-26 years are mostly affected. Before the introduction of effective adjuvant chemotherapy, the prognosis of these lesions was poor. CASE: A 16-year-old girl presented with vaginal bleeding. The histological examination revealed embryonal RMS of the uterine cervix. The patient was treated with a combination of surgery, chemotherapy and radiotherapy. The patient was alive and free of disease five years after the operation. CONCLUSION: A combined modality approach to treating RMS using surgery, multidrug chemotherapy, and radiotherapy has significantly improved survival. The medical community should keep in mind that embryonal RMS of the uterine cervix, despite its malignancy and rarity, can be cured if timely and adequate treatment is given. PMID- 21614917 TI - Borderline mucinous tumor arising in a paratubal cyst: a case report. AB - BACKGROUND: Paratubal borderline tumors (PBTs) are found incidentally at frozen section or permanant pathology, and are extremely rare. We describe the first case of a paratubal borderline mucinous tumor (PBMT). CASE REPORT: A 20-year-old woman was referred with a complex right adnexal mass on pelvic sonogram. She underwent laparoscopic paratubal cyst enucleation. We used an endobag for cyst extraction. Cyst rupture or tearing of the endobag in the laparoscopic field was absent. Frozen section analysis was reported as a borderline mucinous tumor of low malignant potential. Currently, she has had no evidence of disease recurrence after a laparoscopic fertility-sparing staging procedure. CONCLUSION: A proper preoperative differential diagnosis of an adnexal mass is difficult. Thus, laparoscopy is needed in large or symptomatic cysts. Although growth, torsion and malignancy are rare in paratubal cysts, the possibility of tumor seeding should be excluded with use of an endobag. PMID- 21614918 TI - Primary fallopian tube cancer in term pregnancy: a case report. AB - PURPOSE: This work aimed to study the features of primary fallopian tube carcinoma during pregnancy and to improve the understanding of clinical gynecologists. METHODS: The clinical features of a case of primary fallopian tube carcinoma during pregnancy were analyzed. RESULTS: The final diagnosis was Stage IA fallopian tube cancer after cesarean delivery. CONCLUSIONS: It is helpful to detect CA-125 level and employ B-mode ultrasound imaging. Patients should undergo routine celiac examinations before gynecological and obstetric procedures (including cesarean section and abdominal hysterotomy) are performed. PMID- 21614919 TI - Prolonged survival after episiotomy recurrence of cervical cancer complicating pregnancy. AB - BACKGROUND: We report a case of recurrent cervical cancer in an episiotomy scar and the late treatment-related sequelae. CASE: Cervical cancer was diagnosed following a vaginal delivery, and was treated with surgery and radiotherapy. The patient developed a recurrence in her episiotomy scar, and was treated with chemoradiation. She remains without evidence of disease ten years later. CONCLUSION: Successful treatment of recurrent cervical cancer with chemoradiation is possible, but may be associated with significant normal tissue toxicity. PMID- 21614920 TI - Aggressive ovarian psammocarcinoma: a case report. AB - Serous psammocarcinoma is a rare form of ovarian carcinoma characterized by massive psammoma body formation. We report a new case of aggressive ovarian psammocarcinoma with omental and peritoneal implants. PMID- 21614922 TI - Successful salvage treatment of recurrent endometrial cancer with multiple lung and abdominal metastases. AB - The prognosis of recurrent endometrial carcinoma is generally poor except for isolated vaginal or pelvic relapse without previous radiation. Recurrences associated with infield failure or distant metastasis carry a poor prognosis. We report a case of recurrent endometrial carcinoma treated with cytoreductive surgery, targeted radiation to lung metastasis defined by CT and PET and adjuvant chemo-hormone therapy followed by maintenance progestin therapy with a good outcome. This case implied that chemo-hormone therapy with targeted radiation should be evaluated in recurrent endometrial cancer with positive progesterone receptor for salvage treatment. PMID- 21614921 TI - Vertical rectus abdominis myocutaneous flap for vaginal reconstruction after radical pelvic surgery for Stage II vaginal carcinoma. AB - Primary carcinomas of the vagina are uncommon, occurring only 2-3% of all gynecological malignancies. In women with early stage of disease, primary surgery, consisting of radical vaginectomy (plus hysterectomy in patients with tumors involving the upper vagina) and systematic dissection of lymphatic drainage of tumor, is a valid option. In these patients, a rectus abdominis myocutaneous (RAM) flap may be favorably used for vaginal reconstruction during radical pelvic surgery. Here we describe a case of Stage II vaginal carcinoma treated with radical pelvic surgery and vertical-RAM (V-RAM) flap reconstruction. PMID- 21614923 TI - Metastatic cervical adenocarcinoma mimicking retroperitoneal sarcoma of the psoas muscle on imaging. AB - BACKGROUND: The incidence of bone metastasis is low in metastatic cervical cancer, especially in the case of adenocarcinoma. Incidental finding of a mass located in an unusual metastatic site in the absence of identifiable primary tumor often results in a difficult diagnostic problem. CASE REPORT: We report the case of a 59-year-old woman presenting left-sided foot drop as her initial symptom. At first, after performing lumbar spine magnetic resonance imaging (MRI), a huge paravertebral mass with ipsilateral psoas muscle involvement suggesting retroperitoneal sarcoma was identified. However, cervical punch biopsy and sono-guided paravertebral mass biopsy revealed cervical adenocarcinoma with lumbar spinal metastasis. CONCLUSION: Although rare, a neurological symptom such as foot drop, not vaginal symptoms, in a woman may be a first manifestation of metastatic cervical cancer, especially in spinal metastasis. Furthermore, any abnormal lesion should not be ignored because of the possibility of metastasis from the primary malignancy, especially in the current case of cervical adenocarcinoma, so a complete evaluation is always mandatory. PMID- 21614924 TI - CT-guided cryoablation of both breast cancer and lymph node axillary metastasis. AB - Breast conservation is a major goal of cancer treatment. Many different minimally invasive options have been considered such as cryoablation. This technique is the best visualized of all ablation techniques due to the phase change during ice formation. We describe a case of breast cancer with lymph node axillary metastasis treated by CT-guided cryoablation. Cryoablation may have unique benefits for cost-effective outpatient breast cancer therapy using only local anesthesia and/or mild sedation. PMID- 21614925 TI - Six-year follow-up without recurrence after a carcinosarcoma of the breast: case report. AB - Carcinosarcoma (CS) of the breast is a rare entity (less than 0.2% of breast malignancies), characterized by the presence of a biphasic pattern of malignant epithelial and mesenchymal elements, and with a high risk of loco-regional recurrence. The diagnosis of CS of the breast is difficult and needs detailed histological investigations to differentiate it from other malignant breast tumors. Expertise and evidence-based information on optimal treatment is very limited due to the low incidence and inconsistent classification. The principles of treatment modalities seem to be similar to others breast malignancies. CS has a different biologic behavior from others breast cancers, being very aggressive in keeping with its high-grade mesenchymal stroma. Still many questions remain about its origin and optimal treatment modalities for better outcome. We report the case of CS of the breast without local or regional recurrence after six years of follow-up in an 82-year-old woman. PMID- 21614926 TI - Metastasis from breast cancer to an endometrial polyp; treatment options and follow-up. Report of a case and review of the literature. AB - INTRODUCTION: The female genital tract is rarely involved by metastatic tumors. The most common anatomic locations are the ovaries and the vagina. A case is presented of metastatic breast carcinoma to the vulva and endometrial polyp, both exceptional. CASE REPORT: We report the case of an 83-year-old female who presented with vaginal bleeding. Lobular breast carcinoma was diagnosed earlier and during follow-up vulvar metastasis was detected. Hysteroscopic examination because of postmenopausal bleeding revealed an endometrial polyp which was resected. The morphology and immunohistochemistry of the polyp were consistent with lobular breast cancer: metastatic breast cancer to an endometrial polyp. After reviewing the literature 15 cases of metastatic breast carcinoma to endometrial polyps have been reported. The clinical presentation and course, risk factors, treatment and follow-up are discussed. CONCLUSION: Metastasis of a breast carcinoma to the vulva and an endometrial polyp are extremely rare, but clinicians should be aware of both phenomena. PMID- 21614927 TI - Diffuse intraabdominal fibrosis and inflammation mimicking peritoneal carcinomatosis recurred after surgery for borderline ovarian tumor misdiagnosed by 18F-fluorodeoxyglucose-positron emission tomography. AB - BACKGROUND: 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) adds to conventional imaging in the detection and staging of peritoneal carcinomatosis. CASE REPORT: Herein we report a 27-year-old woman with multiple intraperitoneal masses detected by 18F-FDG-PET, suggesting peritoneal carcinomatosis. She had undergone laparoscopic unilateral oophorectomy for a left ovarian mucinous borderline tumor approximately five years before. Based on imaging and intraoperative findings, multiple intraabdominal masses strongly suggested peritoneal recurrence from a previous ovarian borderline tumor, but it finally proved to be inflammation and fibrosis on histopathologic examination. CONCLUSION: Although 18F-FDG-PET is well known to be a highly sensitive imaging tool for identification of peritoneal carcinomatosis, FDG uptake is not tumor specific. Therefore, the possibility of a false-positive diagnosis due to benign conditions, such as inflammation, should always be taken into consideration. PMID- 21614928 TI - A case of bilateral ovarian synchronous tumors (left ovarian serous papillary adenocarcinoma and right ovarian malignant mixed Mullerian tumor). AB - Synchronous bilateral ovarian cancer is extremely rare and there is no established guideline for management. A case of a 58-year-old multiparous woman with bilateral ovarian synchronous malignant tumors is presented. The clinical consideration and treatment of related cases are discussed. PMID- 21614929 TI - Ovarian carcinoma presenting with axillary lymph node metastasis: a case report. AB - Ovarian cancer is usually limited to the abdomen and frequently remains confined. The occurrence of extrabdominal mestastases is unusual. In this report we describe a rare case of axillary involvement at initial presentation of ovarian cancer in a 48-year-old woman. The axillary mass was the only clinical abnormality. Cytological and histological findings, performed on axillary lymph nodes, showed the presence of psammoma bodies and specific immunohistochemical tumor markers (OC-125 and WT1), supporting the evidence of a metastatic axillary lymphadenopathy from ovarian cancer. Subsequently, chest and abdominopelvic computed tomography showed a right ovarian complex mass of 30 x 25 mm and biochemical tests showed high levels of CA125. Surgical therapy was performed. Histology confirmed the diagnosis, evidencing a poorly differentiated serous papillary carcinoma of the right ovary. In conclusion, cytological and histological findings can play a crucial role in suggesting the correct origin of a metastatic adenocarcinoma when the clinical presentation is atypical. PMID- 21614930 TI - Papillary serous adenocarcinoma of the uterine cervix: a case report. AB - Papillary serous adenocarcinoma of the endocervix (PSAE) is a rarely encountered neoplasm. The literature includes only a limited number of well documented case studies. The present study reports a case of papillary serous adenocarcinoma originating from the endocervix. PMID- 21614931 TI - Rare case of an ovarian monodermal teratoma with functional stroma and extensive ovarian decidualization in a 74-year-old woman. AB - We present the clinicopathological findings of a rare case of a monodermal teratoma of the right ovary with functional ovarian stroma and extensive decidualization in a 74-year-old woman. The patient presented with vaginal bleeding. Ultrasound scan revealed a pelvic mass measuring 9.5 cm in the lower right abdomen. A right oophorectomy was performed. The tumor was cystic and multilocular filled with colloid material. Histological examination revealed follicles of thyroid type, and stromal clusters of fusiform or polygonal cells were found in the stroma. An extensive decidual reaction was observed. Morphological and immunohistochemical examination of the tumor revealed cystic struma ovarii with functional ovarian stroma and ectopic decidua. Total abdominal hysterectomy with oophorectomy was performed. A benign endometrial polyp, proliferative endometrium, two fibroids, and an ovarian cyst were observed. PMID- 21614932 TI - Regulation of stress-activated MAP kinase pathways during cell fate decisions. AB - Mammalian cells are frequently exposed to a variety of environmental stresses, such as ultraviolet rays, ionizing radiation, genotoxins, heat shock, and oxidative stress. In coping with the barrage of these and other stresses, multi cellular eukaryotic organisms have developed a strategy as to how damaged cells will respond to stresses. In general, if the intensity of the damage is moderate, the cell will seek to repair the damage. If, however, the damage to a cell is too severe to be repaired, the affected cells are eliminated by apoptosis. This cell death reduces the risk to the organism as a whole, such as development of a cancer. Such a crucial decision between survival and death is, at least in part, mediated by the stress-activated MAP kinase (SAPK) pathways. SAPKs are a group of serine/threonine protein kinases that convert extracellular stress stimuli into diverse cellular responses, including cell cycle arrest, apoptotic cell death, and cytokine production, through phosphorylation of specific target proteins. Recent progress in the identification of molecules that participate in the SAPK pathways, such as GADD45 proteins and Wipl, has provided new insights, not only into the molecular basis of the cellular response to environmental stress, but also into the etiology of human diseases including cancer. PMID- 21614933 TI - Immunocytochemical analysis for differential diagnosis of thyroid lesions using liquid-based cytology. AB - Recently, liquid-based cytology (LBC) has been widely applied to various samples in diagnostic cytology and its usefulness has been reported. In this study, we investigated thyroid cytology that applied LBC and immunocytochemistry to achieve more objective diagnosis and greater diagnostic accuracy. This study included 125 cases (57 papillary carcinomas (PCs), 22 follicular tumors, 43 adenomatous goiters and 3 with Basedow's disease). After preparing the LBC slide, immunocytochemical staining was performed on each slide with six antibodies (HBME 1, cytokeratin 19 (CK19), high molecular weight cytokeratin (34JE12), galectin-3, CD15 and CA 19-9). All antibodies presented immunopositivity frequently in PCs, but only a few or some of them were positive in other cases. These antibodies were considered positive markers for PCs, and the most reliable marker was 34betaE12; its sensitivity, specificity and diagnostic accuracy were 82.5%, 100% and 92.0%, respectively. Relations of immunocytochemical profiles against these markers were assessed using panel 34betaE12, GAL-3 and CK19. More than or equal to two of these markers showed co-positive in 53 of 57 PCs, and negative for all markers was observed in only one case. In the other (non PC) cases, the former was 0 of 58 and the latter was 40 cases. In this panel, the sensitivity, specificity and diagnostic accuracy were 93.0%, 100% and 96.8%, respectively. All of these values were higher than or equal to single values of 34betaE12. We concluded that the panel in this study is useful for more objective and accurate diagnosis of thyroid cytology. PMID- 21614934 TI - Improvements in Helicobacter pylori eradication rates through clinical CYP2C19 genotyping. AB - Lansoprazole (LPZ), amoxicillin (AMPC) and clarithromycin (CAM) are commonly used drugs (LAC regimen) for Helicobacter pylori (H. pylori) eradication, but the eradication rate with this regimen was reported to be 70% to 90%. A few studies have reported that a successful eradication was associated with the CYP2C19 genotype, which influences the metabolism of proton pump inhibitors (PPI) including LPZ. This study examined the changes in the H. pylori eradication rates between the periods before and after the commencement of a routine genetic test for CYP2C19 at the Daiko Medical Center in Nagoya, Japan, in November, 2005. Subjects were patients who visited the Center during the period from June, 2004 to August, 2010. The patients were classified into three groups according to their CYP2C19 genotype: rapid metabolizers (RM) with a *1*1 genotype, intermediate metabolizers (IM) with a *1*2 or *1*3 genotype, and poor metabolizers (PM) with a *2*2, *2*3, or *3*3 genotype. Non-rapid metabolizers (IM and PM) were basically treated with a LAC regimen, while RMs were treated with a RAM reg imen(rabeprazole, AMPC, and metronidazole). The eradication rate was 80.0% (n=90) for the period without the genetic testing and 88.7% (n=124) for the period with the genetic testing (chi2=3.11, p=0.078). The age-sex adjusted odds ratio of eradication success was 2.29 (95% confidence interval, 0.99-5.28, p=0.051) for the latter period relative to the former period among those less than 70 years of age. Those results suggested that the routine genetic test which allows a choice of the RAM regimen for R M improved the eradication rate. PMID- 21614935 TI - Association of UGT1A1 Gly71Arg with urine urobilinogen. AB - Bilirubin is glucoronized by uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) mainly in the liver, and excreted into bile. The conjugated form is metabolized into the unconjugated form, and then into urobilinogen by bacteria in the intestine. Unconjugated bilirubin and urobilinogen are absorbed into the blood stream. The kidney filtrates conjugated bilurubin and urobilinogen into urine. Accordingly, the reduced enzyme activity of UGTIAI may decrease serum conjugated bilirubin levels, resulting in a lower frequency of positive results of urine bilirubin and urobilinogen. This study examined the associations of UGTIAI Gly71Arg (UGTIAI *6) with urine bilirubin and urobilinogen, as well as serum AST, ALT and GGT. Subjects were 5,172 inhabitants 35 to 69 years old who participated in a cohort study in Nagoya from June 2008 to May 2010. Among them, data from 5,151 participants (1,465 males and 3,686 females) were available for analysis. The age-sex-adjusted odds ratio (OR) of ArgArg relative to GlyGly was 1.37 (95% confidence interval (95% CI), 0.55-1.23) for bilirubin, and 1.67 (95% CI, 0.86-3.26) for urobilinogen. Those of ArgArg+ArgGly were 0.87 (95% CI, 0.59 1.27) and 1.50 (95% CI, 1.17-1.94), respectively. AST, ALT and GGT levels had no associations with the genotype. Although the significant association for urobilinogen was contrary to the biological expectation, this study indicated that UGTIA1 Gly71Arg may be a genetic factor of urine urobilinogen. PMID- 21614937 TI - Identification of a Streptococcus pyogenes SF370 gene involved in production of c di-AMP. AB - Here we show that bis(3'-5') cyclic diadenylic acid (c-di-AMP) and a diadenylate cyclase (DAC) domain protein involved in the biosynthesis of c-di-AMP were identified in Streptococcus pyogenes. The matrix-assisted laser desorption ionization (MALDI)-time of flight (TOF) mass spectrum of the cell extract of S. pyogenes, which showed a fragment pattern very similar to that of the authentic sample of c-di-AMP, revealed that S. pyogenes produces c-di-AMP in the cell. Subsequently, we confirmed by an in vitro experiment that the production of c-di AMP in the cell is due to the action of Spy1036 gene encoding a DAC domain protein named spyDAC, which is a new protein different from a well-known diadenylate cyclase. Moreover, the experiment gave a product with a molecular weight of 657.021, which is consistent with the molecular weight of c-di-AMP. Furthermore, the mass spectral fragment pattern of the product obtained by the in vitro biosynthesis is quite similar to that of the product produced by the above in vivo experiment. This in vitro production of c-di-AMP indicated that spyDAC in S. pyogenes actually catalyzes the in vivo biosynthesis of c-di-AMP from ATP. PMID- 21614936 TI - SLC22A12 W258X frequency according to serum uric acid level among Japanese health checkup examinees. AB - Although the SLC22A12 (uric acid transporter 1) 258X allele is known to cause hypouricemia, the genotype frequency according to the serum uric acid (SUA) level has not been reported. This study investigated the SLC22A12 258WX frequency according to SUA levels among Japanese health-checkup examinees. In addition, the changes were reported in SUA levels during five years for individuals with 258WX. Subjects were 746 Japanese aged 39-86 years in 2003. Their SUA records were linked during the five years from 2003 to 2007. SLC22A12 W258X was genotyped using a polymerase chain reaction with confronting two-pair primers. The 258X allele comprised 1.9% (95% CI, 1.3-2.8%) of all the subjects. Among those with SUA <3.0 mg/dL, 258WX was more common in males (66.7%, 95% CI, 22.2-95.7%) than in females (39.3%, 95% CI, 21.5-59.4%). Among subjects with a SUA of 3.0-4.9 mg/dL, those with 258WX totaled 10.7% (95% CI, 4.0-21.9%) and 2.6% (95% CI, 1.1 5.0%), respectively. There were no subjects with 258WX among those with a SUA of 5.0 mg/dL or more. During the five years from 2003 to 2007, the changes in SUA among 23 individuals with 258WX were found to be similar to those among 258WW subjects (n=536). This study indicated that SLC22A12 258WX was more common among those with a lower serum uric acid concentration. The observed SUA level changes in individuals with 258WX suggested that lifestyle factors could influence the levels of those with 258WX. PMID- 21614938 TI - Structure and roles of public health centers (hokenjo) in Japan. AB - Public health centers (PHCs, hokenjo in Japanese) are local government authorities responsible for public health in Japan. As of 2010, 494 centers were operating under the Ministry of Health, Labour and Welfare of Japan. While the general rule is that one PHC covers 300,000 inhabitants, several centers cover a population of more than 1 million. The roles of PHCs described in the Community Health Act include 1) propagation and improvement of information on community health, 2) vital statistics and other statistics on community health, 3) improvement of dietary conditions and food sanitation, 4) environmental sanitation including housing, water supply, sewage, waste disposal and public cleaning, 5) medical and pharmaceutical affairs, 6) matters involving public health nurses, 7) promotion and improvement of public medical services, 8) maternal, child, and elderly health, 9) dental health, 10) psychiatric health, 11) health of patients under long-term care due to incurable diseases, 12) prevention of infectious diseases, 13) laboratory tests on sanitation/environment, and 14) other functions needed to maintain/promote health in the community. Among those many roles, infectious disease controls are one of the most important. Concerning tuberculosis control, PHCs are responsible for the isolation of patients, health check-ups of those in close contact with infectious TB patients, and public subsidy of medical expenses for tuberculosis treatments. Food poisoning controls are also an important responsibility of PHCs, as are the conduct of surveys to trace suspicious foods and laboratory testing of samples from patients. To make these many measures effective, sufficient numbers of public health professionals are required. PMID- 21614939 TI - Randomized trial of the effect of an integrative medicine approach to the management of asthma in adults on disease-related quality of life and pulmonary function. AB - PURPOSE: The purpose of this study was to test the effectiveness of an integrative medicine approach to the management of asthma compared to standard clinical care on quality of life (QOL) and clinical outcomes. METHODS: This was a prospective parallel group repeated measurement randomized design. Participants were adults aged 18 to 80 years with asthma. The intervention consisted of six group sessions on the use of nutritional manipulation, yoga techniques, and journaling. Participants also received nutritional supplements: fish oil, vitamin C, and a standardized hops extract. The control group received usual care. Primary outcome measures were the Asthma Quality of Life Questionnaire (AQLQ), The Medical Outcomes Study Short Form-12 (SF-12), and standard pulmonary function tests (PFTs). RESULTS: In total, 154 patients were randomized and included in the intention-to-treat analysis (77 control, 77 treatment). Treatment participants showed greater improvement than controls at 6 months for the AQLQ total score (P<.001) and for three subscales, Activity (P< 0.001), Symptoms (P= .02), and Emotion (P<.001). Treatment participants also showed greater improvement than controls on three of the SF-12 subscales, Physical functioning (P=.003); Role limitations, Physical (P< .001); and Social functioning (P= 0.03), as well as in the aggregate scores for Physical and Mental health (P= .003 and .02, respectively). There was no change in PFTs in either group. CONCLUSION: A low cost group-oriented integrative medicine intervention can lead to significant improvement in QOL in adults with asthma. PMID- 21614940 TI - Pulpa dentis D30 for acute reversible pulpitis: A prospective cohort study in routine dental practice. AB - BACKGROUND: Pulpa dentis D30 (PD: dental pulp of the calf, prepared in a homeopathic D30 potency) has been used in acute reversible pulpitis for pain relief and to avoid or postpone invasive dental treatment. PRIMARY STUDY OBJECTIVE: To study short-term clinical outcomes of PD therapy for acute reversible pulpitis in routine dental practice. METHODS/DESIGN: Prospective, observational, open-label, single-arm cohort study. SETTING: Eleven dental primary care practices in Germany. PARTICIPANTS AND INTERVENTION: Thirty-two patients starting monotherapy with PD for acute reversible pulpitis without visible or radiological abnormalities. PD was applied as 1-mL submucous injections into the mucobuccal fold, repeated daily as needed. PRIMARY OUTCOME MEASURES: Avoidance of invasive dental treatment (pulp capping, root canal therapy, tooth extraction) and remission of pain, measured on a 0-10 point scale (partial remission: reduction by > or =3 points; complete remission: reduction from > or =4 points to 0-1 points) during the 10-day follow-up period. RESULTS: Median pain duration was 14.0 days. The patients received a median of two PD applications (range 1-7). A total of 81% (n=26/32) of patients did not require invasive dental treatment, and 19% (n= 6) had root canal therapy. Remission status was evaluable in 24 patients. Of these, 63% (n = 15/24) achieved pain remission, 58% (n = 14) remitted without invasive dental treatment (complete remission: n=12, partial remission: n=2), and 29% (n= 7) had a close temporal relationship between PD and remission (ratio "time to remission after first PD application vs pain duration prior to first PD application" <1:10). CONCLUSION: In this study of PD for acute reversible pulpitis, 58% of evaluable patients achieved pain remission without invasive dental treatment. The open-label pre post design does not allow for conclusions about comparative effectiveness. However, more than one-fourth of evaluable patients remitted with a close temporal relationship between the first PD application and pain remission, suggesting a causal relationship between therapy and remission. PMID- 21614941 TI - Agents of change: how do complementary and alternative medicine providers play a role in health behavior change? AB - BACKGROUND: Recent investigations indicate that complementary and alternative medicine (CAM) use may be conducive to health behavior change. OBJECTIVE: The goal of this study was to investigate how this change occurs. METHODS: Using Social Cognitive Theory and Self-determination Theory as guiding frameworks, we surveyed a convenience sample of 216 CAM consumers abouttheir CAM therapy and iors and conducted focus groups with 36 CAM consumers. RESULTS: Consumers reported encouragement from providers and improved energy resulting from treatments as reasons for making health behavior changes. Multivariate analysis showed that increased odds of self-reported dietary change were significantly associated with increasing body awareness as a result of therapy, endorsing the statement that sustained improvement for their health conditions required self care, using an acupuncturist, and being 44 years or younger. Comparable results were found for exercise change, except using an acupuncturist was a significant negative predictor and age was not significant. Focus group findings echoed these themes. CONCLUSION: This initial investigation into how CAM providers may play a role in health behavior change suggests that provider support, increased responsibility for one's health, and the CAM treatments themselves contribute to behavior change, although additional research in this area is warranted. PMID- 21614942 TI - Effects of yoga on stress management in healthy adults: A systematic review. AB - OBJECTIVE: This article reports a systematic review and critical appraisal of the effect of yoga on stress management in healthy adults. METHODS: A systematic literature search was performed to identify randomized controlled trials (RCTs) and clinical controlled trials (CCTs) that assessed the effects of yoga on stress management in healthy adults. Selected studies were classified according to the types of intervention, duration, outcome measures, and results. They were also qualitatively assessed based on Public Health Research, Education and Development standards. RESULTS: The systematic review was based on eight RCTs and CCTs that indicated a positive effect of yoga in reducing stress levels or stress symptoms. However, most of the studies had methodological problems in that the intervention duration was short and limited follow-up data was available. CONCLUSION: This review revealed positive effects of yoga on stress reduction in healthy adult populations. However, the result should be interpreted with caution due to the small number of studies and the associated methodological problems. Further studies to ascertain yoga's long-term effects and the underlying biological mechanisms leading to its stress reduction effect should be conducted. PMID- 21614943 TI - Tai chi as an intervention to improve balance and reduce falls in older adults: A systematic and meta-analytical review. AB - OBJECTIVE: The evidence of tai chi for balance improvement and fall reduction in older adults was updated and reviewed. METHOD: A systematic review was carried out by two independent reviewers among nine electronic databases to identify randomized controlled trials (RCTs) that examined the effects of tai chi on balance improvement and fall reduction in older adults using such key words as tai chi, falls, balance, and randomized trial. RESULTS: The results based on 13 RCTs indicated that tai chi was effective in improving balance of older adults but may not necessarily be superior to other interventions. Results also showed that in the absence of other interventions, tai chi reduced falls in the nonfrail elderly. CONCLUSION: Tai chi is recommended as an alternative treatment for improving balance so as to reduce falls. Future research with improved research designs such as more consistent outcome measures on balance and fall reduction and longer postintervention follow-up should be conducted to unravel the efficacy of different types of tai chi. PMID- 21614944 TI - The use of complementary and alternative medicine among Malay breast cancer survivors. AB - BACKGROUND: A cross-sectional studywas carried out to determine the prevalence of complementary and alternative medicine (CAM) use by breast cancer survivors. METHODS: A descriptivesurveydesignwasdeveloped. Information on sociodemographic characteristics, cancer clinical treatment history, and use of CAM were obtained through a modified self-administered questionnaire from 116 Malay breast cancer survivors aged 21 to 67 years who were 2 years postdiagnosis and currently undergoing follow-up treatment at breast cancer clinics at Hospital Kuala Lumpur and Universiti Kebangsaan Malaysia Medical Centre. RESULTS: Data suggest that 64% of the participants were identified as CAM users; dietary supplements were the most common form used, followed by prayer and Malay traditional medicine. Within the wide range of dietary supplements, multivitamins were most often taken followed by spirulina, vitamin C, evening primrose oil, and herbal products. Contrary to other findings, the CAM users were found to be older, had secondary education levels, and were from middle-income households. However, there was no significant difference between CAM users and nonusers in this study. Family members played an important role as the main source of information along with doctors/health care providers, friends, and printed materials/mass media. The reasons participants gave for using CAM were mainly to assist in healing the body's inner strength, to cure cancer, and to reduce stress. Only half of the participants consulted with their physicians regarding the safety of CAM use. The participants began to use CAM while undergoing clinical treatments. Most of the participants used CAM for more than a year. About RM100 to RM149 (31.88 USD to 47.50 USD at press time) were spent monthly on CAM by 32% of the participants. The CAM use was found to be effective and beneficial for patients' disease states, and they were contented with the usage of the CAM therapies. Multivariate analysis revealed that thedecision to use or not to use CAM was not dependent on sociodemographic background or cancer clinical treatment history. CONCLUSIONS: CAM was commonly used by breast cancer survivors as a coping mechanism to battle the disease. PMID- 21614945 TI - Cobra venom: A review of the old alternative to opiate analgesics. AB - Pain has been called the fifth vital sign, and chronic pain impacts the lives of millions. The search for better analgesics is at a fever pitch, but opiates still dominate the moderate to severe pain treatment spectrum, and morphine, essentially a 2000-year-old drug, is still the gold standard. By today's pharmaceutical standards, opiates are old hat, and physicians are generally reluctant to prescribe them due to their potential for adverse effects and abuse. It is suggested that a new look at another old solution, cobra venom, could inject new life into pain management. This review looks at the historical use of cobra venom to control moderate to severe pain and at recent understandings of its mechanism of action. PMID- 21614946 TI - Clinical utility of probiotics in inflammatory bowel disease. AB - Many patients with inflammatory bowel disease (IBD) use probiotics to manage this intestinal condition. Despite widespread use of these natural therapies by patients, health care providers may be unfamiliar with probiotics as a treatment modality. This review describes the rationale for use of probiotics in IBD, the history behind current research directions, and recent controlled clinical studies in which efficacy of probiotics has been explored in patients with IBD. Emphasis is placed upon critical analysis of study designs for investigations that used lactic acid-producing bacteria or Saccharomyces boulardii in management of Crohn's disease or ulcerative colitis. While there is suggestion of benefit when patients with ulcerative colitis use bacterial therapies and when patients with Crohn's disease use S boulardii, small sample sizes and methodological flaws in study designs necessitate that additional investigations be conducted before probiotics can be routinely recommended in clinical practice. PMID- 21614947 TI - "A supportive culture would enable better care". PMID- 21614948 TI - Cuts threat takes its toll on nurses' health. PMID- 21614950 TI - "I looked at the hospital with the eyes of someone with learning disabilities". PMID- 21614949 TI - "You have the power to make a difference to the health bill". PMID- 21614951 TI - "Halt the jokes. The assault on nursing needs a serious response". PMID- 21614952 TI - "Passionate teams are needed to monitor data on catheter care". PMID- 21614953 TI - Pelvic floor health: information for teenagers. AB - Pelvic floor muscle weakness may be widespread, but the first time many women learn to look after these muscles is during pregnancy. To empower a younger generation of women to become more pelvic floor muscle aware from an earlier age, a group of health professionals produced a health questionnaire, moderated a focus group and conducted an educational session for teenagers at a community school to establish how much they knew about this topic. The group is using this feedback PMID- 21614954 TI - Incontinence: enhancing care in women's prisons. AB - BACKGROUND: There is no evidence on the prevalence of urinary and faecal incontinence symptoms in women prisoners. AIM: To explore the extent and management of bladder and bowel symptoms to inform prison health services and prison nursing practice. METHOD: An anonymous self-report questionnaire tailored to low levels of English literacy, and administered in one women's prison. RESULTS: Women prisons have a higher reported prevalence of urinary and faecal incontinence, constipation and nocturnal enuresis than community populations; this is an unrecognised health problem. CONCLUSION: Prison primary care nurses should consider introducing sensitive but direct questions on bladder and bowel symptoms into admission assessment processes. PMID- 21614955 TI - End of life: a need for bowel care guidance. AB - Patients receiving end-of-life and palliative care often need help to manage their bowel care. Although several policies on palliative care have been introduced in recent years, there is a lack of guidance specifically on bowel management for patients approaching death. This article highlights the gaps in guidance, and discusses how nurses can alleviate patients' distress and best preserve, their dignity while managing their bowel care. PMID- 21614956 TI - Does caesarean delivery prevent anal incontinence? PMID- 21614957 TI - All steam ahead. PMID- 21614958 TI - How to make the most out of brainstorming. PMID- 21614959 TI - Cryoconservation of embryonic cells and gametes as a poultry biodiversity preservation method. AB - A report of the Food and Agriculture Organization of the United Nations (FAO) from 2000 claims that 9% of the global farm animal population is in a critical condition and 39% is threatened with extinction. Production efficiency, exploitation and conservation of animal genetic resources are crucial not only for the global economy, but also for the environment. As many as 30% of poultry breeds are threatened with extinction and 9% have already gone extinct. To preserve the genetic resources in situ methods are used, however, they need to be supported by an ex situ strategy. This includes the storage of genetic material in liquid nitrogen under a deep freeze. This process can be performed by using electronically-controlled programs or vitrification. Data shows that usage of electronically-controlled programs leads increases cell viability. A good technique of cell culture and freezing methods will give a broad perspective for unlimited storage of genetic recourses, which in the future can be useful for the restoration of extinct species/breeds. PMID- 21614960 TI - Diet quality affects allergic peritonitis in mice. AB - Reasons for the increased prevalence of allergies observed in recent decades remain elusive. Here, we used a murine model to investigate the effect of nutrition on ovalbumin-induced allergic peritonitis. Compared to the organs of mice kept on a standard diet, mice exposed to a low quality diet during the growth period showed a decrease in the mass of metabolic (liver and heart) and, to a much larger extent, in lymphatic (thymus and spleen) organs, but not in testes or intestine mass. Moreover, diet manipulation affected the number ofpolymorphonuclear granulocytes as well as mast cell number and/or their responsiveness. During allergic peritonitis, mast cells from animals kept on the standard diet reacted to an allergen with degranulation, while the reaction in mice kept on the low quality diet was significantly weaker. However, the immunomodulators of this process remain unidentified as diet quality affected neither anti-ovalbumin IgE level nor synthesis/release of anti-inflammatory IL 10. Further work is needed to identify underlying immunomodulators. PMID- 21614961 TI - The results of prolonged action of GLP-1 on some metabolic parameters. AB - Glucagon-like peptide (GLP-1) is widely considered as a potential drug against diabetes mellitus and obesity. It strongly stimulates the pancreas to produce and release insulin, even a few minutes after meal consumption. Because of this action, GLP-1 has been called an "incretin hormone". Moreover, GLP-1 decreases the level of glucose in the blood, independently of insulin. An obstacle to clinical application is the very short half-time of GLP-1 degradation by dipeptidyl-peptidase IV in the blood. This research was aimed at tracing all possible changes evoked by long-term application of GLP-1 in rats and comparison of two methods of application: osmotic minipumps and daily injections. In the 13 day experiment, samples of blood, muscle and liver from 24 male Wistar rats were used. Analysis included glycogen, glucose, triglycerides, free fatty acids, cholesterol, triiodotyronin, thyroxin, insulin and glucagon concentrations. The results show a lack of significant differences between both methods of application. We suggest this may be evoked by adaptation of the organism to the prolonged action of GLP-1. PMID- 21614962 TI - Influence of age and sex on the CLA and other fatty acids content in roe deer meat (Capreolus capreolus L.). AB - Meat is an important source of animal protein but, at the same time, it includes saturated fatty acids, which makes it a potential cause of different cardiovascular diseases and still little is known about influence of age and sex on these parameters in roe deer muscles. The aim of this study was to determine the effect of age and sex on the CLA and other fatty acids content in the musculus longissimus lumborum in 67 roe deer (Capreolus capreolus L.). In the meat from the oldest individuals a higher content of CLA was noted (89.76 [mg/kg]) when compared to the fawns (42 [mg/kg]). In this research meat from roe deer does showed in general a higher percentage proportion of SFAs and MUFAs, but lower of PUFAs, than the meat from bucks. These results may provide an important source of information for consumers of roe deer meat because of differences between CLA and other fatty acids content depending on age and sex of the animals. Meat from roebucks is the most advantageous for dietary purposes. PMID- 21614963 TI - Age-related changes of selected blood biochemical indicators in dairy calves during their first week of life. AB - The aim of this study was to determine the influence of age and ingested food (colostrum and mature milk) on the concentrations of selected blood biochemical components connected with nitrogen and mineral metabolism in dairy calves during their first week of life. The experiment was carried out on 13 Polish Black and White breed dairy calves. The animals were fed colostrum within the first 3 days of postnatal life and thereafter the mature milk of their dams until the end ofthe experiment (7 days). The obtained results showed that intensive catabolic and anabolic changes in nitrogen occur in the first week of life. These changes were particularly intense during the first 24-48 hours of life and may reflect dynamic tissue remodelling. The results of this experiment also show that healthy calves efficiently regulate water and electrolyte homeostasis. PMID- 21614964 TI - Chromosomal polymorphism of Rattus rattus (Linnaeus, 1758) (rodentia: muridae) in Central Anatolia. AB - In this study, conventionally stained, C- and Ag-NOR banded karyotypes of Rattus rattus from Central Anatolia are presented. The karyotype of the specimens from Ankara and (Cankiri provinces consist of 2n = 38, NF = 60 and NFa = 58 while the karyotype of Kirikkale specimens consist of 2n = 38 and NFa = 59 due to a heteromorphic autosome pair. The X is a large to medium sized acrocentric and the Y chromosome is a small acrocentric in all examined specimens. Constitutive heterochromatin is located in the centromeric regions of all pairs of autosomes and the X chromosome. Nucleolar organizer regions (NORs) are located only in 3 autosome pairs. PMID- 21614965 TI - Cytogenetic study on Microtus guentheri (Danford and Alston, 1880) (mammalia: rodentia) from Turkey: constitutive heterochromatin distribution and nucleolar organizer regions. AB - Conventionally stained, C- and Ag-NOR banded karyotypes of Guenther's vole, Microtus guentheri were studied from Turkey. The species possesses a karyotype of 2n = 54, NFa = 52 and NF = 54 in specimens from Kahramanmaras and Gaziantep provinces, whereas NF = 56 in females and NF = 55 in males were found in individuals from Kirikkale and Nevsehir provinces. The X chromosome was a large acrocentric (NF = 54) or submetacentric (NF = 55, 56) while the Y chromosome was a small telocentric in all specimens examined. Blocks of constitutive heterochromatin were located in the pericentromeric areas of autosomes including the X chromosome. Nucleolar organizer regions (NORs) were located at the telomeric regions of the short arms of five acrocentric pairs and centromeric regions of two telocentric pairs in the Nevsehir and Kirikkale specimens. PMID- 21614966 TI - Paracetamol (acetaminophen) decreases hydrogen sulfide tissue concentration in brain but increases it in the heart, liver and kidney in mice. AB - The biological action ofN-acetyl-p-aminophenol - paracetamol (acetaminophen) has been demonstrated to involve different mechanisms and is still not clear. Hydrogen sulfide (H2S) has been shown to play an important role in many physiological and pathological processes including nociception. The interaction between acetaminophen and endogenous H2S is unknown. Twenty four female CBA strain mice were administered intraperitoneal injections of N-acetyl-p aminophenol solution: paracetemol in doses of 30 mg/kg b.w. per day (group D1, n = 8) or 100 mg/kg b.w. per day (group D2, n = 8).. The control group (n = 8) received physiological saline in portions of the same volume--0.2 ml. The measurements of tissue H2S concentration were performed with the Siegel spectrophotometric modified method. In the brain, the H2S tissue level decreased, but more significantly in the lower drug dose group. Conversely, there was a significant rise in the H2S tissue concentration in D1 and D2 groups in heart and kidney with the increase more pronounced in the group with the lower paracetamol dose. In the liver only the higher acetaminophen dose elicited a change in H2S concentration, increasing after administration of acetaminophen at 100 mg/kg. Our study demonstrates that paracetamol induces H2S tissue concentration changes in different mouse organs. PMID- 21614967 TI - Lipid content in pig blastocysts cultured in the presence or absence of protein and vitamin E or phenazine ethosulfate. AB - In the present study, total lipid content and content of triglycerides, phospholipids and cholesterol were determined in pig blastocysts cultured in medium without protein, supplemented with bovine serum albumin (BSA), with fetal calf serum (FCS), vitamin E or phenazine ethosulfate (PES). In comparison to blastocysts cultured in NCSU-23 with BSA, we observed a decrease of the total lipid content in PES-treated embryos. Triglyceride content in FCS-, vitamin E- and PES-treated embryos as well as in blastocysts cultured without protein was 81.9%, 70.2%, 57.2% and 74.8% of that found in the blastocysts cultured in NCSU 23 with BSA, respectively. Nevertheless the content of phospholipids remained unchanged. This decrease of triglyceride content in the porcine blastocyst after in vitro culture may be explained by altered lipid metabolism in embryos. PMID- 21614968 TI - Origin of the brushborder in the differentiating midgut of Melasoma saliceti (Chrysomelidae, Coleoptera) embryos. AB - The embryonic development of Melasoma saliceti takes eight days at room temperature. At the beginning of the 5th day the endoderm cells have already formed a unilayered epithelium of the midgut primordium. The midgut epithelium is formed by flat cells that are not connected by specialized intercellular junctions. Large vesicles can be seen in dilated intercellular spaces of the epithelium. Cytoplasmic projections, similar to microvilli, appear in the vesicles. During the 5th day ofdevelopment, the vesicles grow and become enclosed by the intercellular junctions of a zonula adherens type. During the 6th day of development the cell junctions surrounding the vesicles become transformed into a septate type. On the 8th day of development the vesicles come close to the apical sides of the midgut cells and open towards the yolk. At the same time the microvilli spread over the apical surface of the midgut primordium to form the regular brushborder of the larval midgut. In the species studied the vesicles appear to "prefabricate" the apical surfaces of the future midgut epithelium. PMID- 21614969 TI - Structure and steroidogenic activity of the granulosa layer of F1 preovulatory ovarian follicles of the hen (Gallus domesticus). AB - The study was performed to determine the structure and steroidogenic activity of granulosa cells derived from the germinal disc region, proximal region and distal region of the largest preovulatory ovarian follicle (F1) of the hen. The study was carried out on 34 Hy-Line Brown egg-laying hens aged 40 weeks. Morphology of the granulosa cells was studied by histological assessment and scanning electron microscopy. Moreover, the level of P4, histochemical activity of 3beta-HSD and expression of 3beta-HSD gene mRNA in granulosa cells of F1 follicle were determined. The findings indicate that the morphology and steroidogenic activity of the granulosa layer in F1 preovulatory ovarian follicle are associated with the region of the follicle. This is consistent with earlier studies. In the germinal disc region the granulosa cells form a multilayer while in the proximal and distal regions granulosa cells form a single layer. Analysis of P4 concentration revealed that its level in granulosa cells was markedly reduced closer to the germinal disc. Moreover, our study demonstrates for the first time the lower histochemical activity of 3beta-HSD and expression of 3beta-HSD mRNA in granulosa cells from the germinal disc region compared with the proximal and distal region. PMID- 21614970 TI - Elimination of apoptotic spermatozoa from rabbit insemination dose using annexin V associated with the MACS technique. A preliminary study. AB - The aim of this study was to verify whether the separation and elimination of the apoptotic fraction in rabbit semen using a MACS technique may improve sperm fertility potential and consequently rabbit kindling rate. Semen samples from 25 New Zealand White (NZW) rabbit males were collected using an artificial vagina and evaluated using the CASA system for concentration and motility. For artificial insemination the best 11 bucks were chosen based on motility parameters. Their ejaculates were mixed to make a heterospermic pool and routinely diluted in a commercial insemination diluent (MiniTub, Tiefenbach, Germany) at a ratio of 1:6. Diluted heterospermic spermatozoa were filtered through a Sartorius filter to wash out seminal plasma, re-diluted in binding buffer (Annexin V Microbead Kit, Miltenyi Biotec, Germany) at a ratio of 1:3.66 and divided into two groups: an experimental group intended for MACS separation and control group without MACS separation. Then hormonally treated females of NZW rabbits were inseminated with fresh doses of filtered heterospermic semen (n = 27; 0.5 ml I.D. per female) and MACS separated semen (n=28; 0.5 ml I.D. per female). Separation and subsequent elimination of apoptotic spermatozoa (positive selection) from the insemination dose (after negative MACS selection) was verified under in vivo conditions on the basis of increased kindling rate in the experimental group in comparison with kindling rate in the control group (81.3% vs. 73.8%). In conclusion, elimination of apoptotic spermatozoa by the use of the MACS technique results in a slight improvement in kindling rate of rabbit does. PMID- 21614971 TI - Sperm migration and selection in the reproductive tract of female mice is mostly affected by male genotype. AB - The aim of the present study is to assess the influence of male and female genotypes on the transport of sperm to the site of fertilization. We mated B10.BR, B10.BR-Ydel and BALB/c males with B10.BR and BALB/c females and then analyzed the quality and quantity of spermatozoa found five hours post coitus in three successive parts of the female reproductive tract. We found that B10.BR and B10.BR-Ydel spermatozoa are very effectively selected by the uterotubaljunction and other barriers of the female genital tract. On the contrary, severely deformed BALB/c spermatozoa appeared to be able to cross selective barriers and were present both in oviducts and in cumulus oophorus. It cannot be excluded that these morphologically abnormal male gametes take part in fertilization. B10.BR Ydel spermatozoa were very rarely observed above the uterotubaljunction. This shows that in vivo they migrate with delay and with difficulties pass the border between uterus and oviducts. This finding is in agreement with previous in vitro analyzes, which revealed many irregularities in movement of B10.BR-Ydel spermatozoa. Sperm quality and quantity in the reproductive tracts of B10.BR and BALB/c females were convergent if they were mated with males belonging to one strain, proving that migration and selection of spermatozoa in the female genital tract depend mostly on male genotype. PMID- 21614972 TI - Effect of g.2728g > A and g.3996t > C polymorphisms at the leptin gene locus on microstructure and physicochemical properties of longissimus lumborum muscle of Polish Landrace pigs. AB - The influence ofHindIII (g.2728G > A) and Bg/II (g.3996 T > C) polymorphisms at the leptin gene locus on muscle fibre characteristics and meat quality of longissimus lumborum muscle was studied in 146 barrows of the Polish Landrace breed. Leptin gene polymorphism was identified by PCR-RFLP. Fibre type percentage, fibre diameter and the following technological parameters ofmeat were also determined: pH45, pH24, L*a*b* colour, drip loss, water holding capacity, shear force and intramuscular fat content. Polymorphism was not detected in the locus studied in the Landrace pig herd analysed with the Bg/II restriction enzyme (g.3996 T > C). For the HindIII enzyme (g.2728G > A), there was a high frequency of GG homozygotes (0.78) and G allele (0.89), but the AA genotype was not present. Moreover, the genotypes ofleptin gene RFLP-HindIII polymorphism had no effect on intramuscular fat content and muscle fibre type percentage, but had a significant effect on muscle fibre size. Heterozygous GA fatteners had a significantly larger (P < 0.05) diameter of type IIB and type I fibres compared to homozygous GG fatteners. Generally, meat quality parameters were comparable among the examined genotypes except for water holding capacity (which was the lowest for the GG genotype) and colour lightness (L*) (which was the lightest for GA genotype). Moreover, regardless of genotype, large differences were observed between each animal in the distribution of intramuscular fat. PMID- 21614973 TI - Prevention of hepatocellular carcinoma. PMID- 21614974 TI - Finding a topic for an MMed research report. PMID- 21614975 TI - Pancreatic injuries after blunt abdominal trauma: an analysis of 110 patients treated at a level 1 trauma centre. AB - BACKGROUND AND OBJECTIVE: Injuries to the pancreas are uncommon, but may result in considerable morbidity and mortality. This study evaluated the management of blunt pancreatic injuries using a previously defined protocol to determine which factors predicted morbidity and mortality. METHODS: The study design was a retrospective chart review of all adult patients with blunt pancreatic injuries treated at a level 1 trauma centre between March 1981 and June 2009. RESULTS: One hundred and ten patients (92 men, 18 women; mean age 30 years, range 13-68 years) were treated during the study period. Forty-six patients had American Association for the Surgery of Trauma (AAST) grade 1 or 2 pancreatic injuries and 64 had AAST grade 3, 4 or 5 pancreatic injuries. Injuries involved the head (N=21), neck (N=15), body (N=48) and tail (N=26) of the pancreas. The mean number of organs injured was 2.7 per patient (range 1-4). One hundred and one patients underwent a total of 123 operations, including drainage of the pancreatic injury (N=73), distal pancreatectomy (N=39) and Whipple resection (N=5). The overall complication rate was 74.5% and the mortality rate 16.4%. Only 2 of the 18 deaths were attributable to the pancreatic injury. Shock on presentation was highly predictive of death; 17 of 39 patients with shock died, compared with 1 of 71 patients who were not shocked (p < 0.0001). Fourteen of 46 patients with grade 1 and 2 pancreatic injuries died compared with 4 of 64 patients with grades 3, 4 and 5 injuries (p < 0.001). Mortality increased exponentially as the number of associated injuries increased. Two of 57 patients with injury to the pancreas only or one associated injury died, compared with 16 of 53 with two or more associated injuries (p < 0.0013). CONCLUSIONS: This study demonstrated a significant correlation between the AAST grade of injury and pancreas-specific morbidity and between shock on admission, the number of associated injuries and death, in patients with blunt pancreatic injuries. Although morbidity and mortality rates after blunt pancreatic trauma are high, death was usually the result of major associated injuries and not related to the pancreatic injury. PMID- 21614976 TI - Liver resection for non-cirrhotic hepatocellular carcinoma in South African patients. AB - BACKGROUND: We describe the clinicopathologic features and outcome of South African patients who have undergone hepatic resection for hepatocellular carcinoma (HCC) arising in a non-cirrhotic liver. METHODS: We utilised the prospective liver resection database in the Surgical Gastroenterology Unit at Groote Schuur Hospital, Cape Town, to identify all patients who underwent surgery for HCC with non-cirrhotic liver parenchyma between 1990 and 2008. RESULTS: Twenty-two patients (10 men, 12 women, 3 black, 19 white, median age 47 years, range 21-79 years) underwent surgery for non-cirrhotic HCC. Sixteen patients had non-fibrolamellar HCC (Group 1); 6 patients had fibrolamellar HCC (Group 2). Group 1 had a median age of 55 years, and 6 (38%) were men; group 2 had a median age of 21 years, and 5 (83%) were men. Most patients had a solitary tumour at diagnosis; median largest tumour diameters in Groups 1 and 2 were 10 cm (range 4 21) and 12 cm (range 4-17), respectively. Patients in Group 1 underwent extended right hepatectomy (N=3), right hepatectomy (N=3), left hepatectomy (N=3), partial hepatectomy (N=7), cholecystectomy (N=6), and appendicectomy (N=1). Patients in Group 2 underwent extended right hepatectomy (N=1), right hepatectomy (N=1), left hepatectomy (N=2), segmentectomy (N=2), and portal lymphadenectomy (N=3). Recurrence rates in Groups 1, 2, and overall were 81%, 100% and 86%, respectively. Median overall survival was 46 months, with 1-, 3-, and 5-year survival rates of 95%, 59% and 45%, respectively. In Group 1, median survival was 39 months, with 1-, 3-, and 5-year survival rates of 100%, 56% and 38% respectively. In Group 2, median survival was 61 months, with 1-, 3-, and 5-year survival rates of 83%, 67% and 67%, respectively. CONCLUSION: Despite aggressive surgical resection, HCC arising in normal liver parenchyma has a high recurrence rate and an ultimately poor outcome. This finding is similar to both the recent international experience of non-cirrhotic HCC and local experience of fibrolamellar HCC. PMID- 21614977 TI - Solid pseudopapillary epithelial neoplasm--a rare but curable pancreatic tumour in young women. AB - BACKGROUND: Solid pseudopapillary epithelial neoplasms (SPENs) of the pancreas are rare but curable tumours that have a low-grade malignant potential and occur almost exclusively in young women, with an excellent prognosis after complete resection. This study examines the clinicopathological characteristics of these tumours and evaluates the role of surgery in relation to their size and location. STUDY DESIGN: We reviewed the pre-, intra- and postoperative data on 21 patients with SPENs who underwent resection during a 30-year period. Data including demographic information, presenting symptoms and signs, extent of operation, histology, tumour markers and postoperative complications were evaluated to establish the optimal surgical management. RESULTS: All 21 tumours occurred in women (mean age 24.6 years, range 13-51 years). Sixteen patients presented with nonspecific abdominal complaints and a palpable abdominal mass, in 1 patient the tumour was found during emergency laparotomy for a complicated ovarian cyst, 1 patient presented with severe abdominal pain and shock due to a ruptured tumour, and in 3 patients the tumour was detected incidentally during imaging. The correct pre-operative diagnosis of SPEN was made in 10 patients. Incorrect preoperative diagnoses included hydatid cyst (3 patients), mesenteric cyst (2), pancreatic cystadenoma (2), ovarian cysts (1), islet cell tumour of the pancreas (1), and cavernous haemangioma of the liver (1). The mean diameter of the tumours was 12.5 cm (range 8 - 20 cm), and they occurred in the head (8), neck (5), body (2), and tail (6) of the pancreas. All SPENs were resected. Five patients had a pylorus-preserving pancreaticoduodenectomy, 4 a central pancreatectomy with distal pancreaticogastrostomy, 8 a distal pancreatectomy, 3 a local resection and one a total pancreatectomy and portal vein graft. In 1 patient, 2 liver metastases were resected in addition to the pancreatic primary tumour. The patient who presented in shock with tumour rupture and bleeding into the lesser sac later died of multiple organ failure after successful resection. Postoperative complications included a stricture at the hepaticojejunostomy after pancreaticoduodenectomy, which resolved after stenting, and a pancreatic duct fistula after local tumour resection, which required a distal pancreatectomy. Other complications were bleeding (2 patients) requiring re-operation and intraabdominal fluid collections requiring percutaneous drainage (3) or operation (1). Mean postoperative hospital stay was 16 days (range 6 - 40 days). Twenty patients are alive and well without recurrence, including the patient with metastases, with a mean follow-up of 6.6 years (range 6 months-15 years). CONCLUSIONS: This study demonstrated that SPENs of the pancreas are uncommon, but should be considered in the differential diagnosis of a cystic mass of the pancreas in a young woman. Despite the indolent biological behaviour of SPENs, most patients required major pancreatic resection. Surgery is curative regardless of the size or location of the tumour. Metastases are rare, as is recurrence after complete surgical resection. PMID- 21614978 TI - The early management of pancreatitis associated with hypertriglyceridaemia. AB - INTRODUCTION: In triglyceridaemia-associated pancreatitis, decreasing the serum triglyceride level below 5.65 mmol/l alleviates abdominal pain and is purported to improve outcome. We analysed hypertriglyceride level normalisation and outcome in a patient cohort of acute pancreatitis. PATIENTS AND METHODS: Patients presenting with pancreatitis and hypertriglyceridaemia were assessed. All patients with presenting triglycerides levels >10 mmol/l were assessed for resolution to a level below 5.65 mmol/l at days 3 and 5. Patients with triglyceride levels in excess of 10 mmol/l were treated with either standard supportive therapy or an insulin dextrose infusion. RESULTS: In the period June 2001 to April 2008, there were 503 admissions of 439 patients with a diagnosis of acute pancreatitis; 26 (6%) had hypertriglyceridaemia >10 mmol/l at admission. Standard therapy was used in all patients; in 6 patients, it was the sole therapy. A dextrose and insulin infusion was used in 20 cases. On day 3, 7 (32%) of the measured triglyceride levels had fallen below 5.65 mmol/l and, on day 5, all but 4 (83%) were <5.65 mmol/l. Three patients died. CONCLUSION: Standard therapy was equivalent to the use of dextrose and insulin in the resolution of hypertriglyceridaemia. Our methods to reduce triglyceride levels produce morbidity and mortality rates similar to those attained when alternate lipid lowering strategies are employed. PMID- 21614979 TI - Cruveilhier-Baumgarten syndrome--a caveat for surgeons. PMID- 21614980 TI - Endoscopic stenting of high-output traumatic duodenal fistula. PMID- 21614981 TI - Prolapse: rare complication of a Zenker's diverticulum. PMID- 21614982 TI - Wide clinical spectrum in Zimmermann-Laband syndrome. AB - Gingival fibromatosis can be present as an isolated form or be part of a genetic disease. The Zimmermann-Laband syndrome (ZLS) is a rare disorder inherited as an autosomal dominant fashion, clinically characterized by gingival fibromatosis, bulbous soft nose, thick floppy ears, nail dysplasia, joint hyperextensibility, hepatosplenomegaly, skeletal anomalies and occasional mental retardation. We studied a girl aged five years with clinical and radiological features of the ZLS, additionally she presented deafness not previously described in the ZLS, as only partial hearing loss was reported in some patients. The father presented some facial features suggestive of ZLS, nevertheless he did not have gingival fibromatosis or hypertrichosis. We suggest that this case supports that ZLS can be part a contiguous genes syndrome or be consequence ofa gene mutation with wide variable expression. The present report supports that ZLS has a wide clinical spectrum. PMID- 21614983 TI - A Turkish patient with large 17p11.2 deletion presenting with Smith Magenis syndrome. AB - Smith-Magenis syndrome (SMS), which occurs as a result of an interstitial deletion within chromosome 17p11.2-p12, is a disorder that presents itself with minor dysmorphic features, brachydactyly, short stature, hypotonia, delayed speech, cognitive deficits and neurobehavioral problems including sleep disturbances and maladaptive repetitive and self-injurious behavior. We present a girl with full SMS phenotype. G-banding cytogenetic analysis showed normal 46,XX karyotype. Whole-genome array comparative genomic hybridization (CGH) was performed due to the severity of the phenotype and the unusual features present in the patient. An interstitial deletion in 17p11.2-p12, approximately 4.73 Mb in size was determined. Characteristic physical and behavioral phenotype strongly suggested SMS. This, to the best of our knowledge is the first patient with SMS reported in Turkey. We emphasize the need for whole genome analysis in multiple congenital abnormalities/mental retardation disorders with unusual and severe phenotypes. PMID- 21614984 TI - A novel mutation in the RPS6KA3 gene in a patient with Coffin-Lowry syndrome. AB - Coffin-Lowry syndrome is an X-linked disorder characterized by mental retardation, characteristic facial features, skeletal abnormalities, and tapering fingers. Herein we report a novel missense mutation in exon 7 at codon 180 in the RPS6KA3 gene in a boy with Coffin-Lowry syndrome. PMID- 21614985 TI - A new syndrome presenting with dysmorphic facies, oculocutaneous albinism, glaucoma, cryptorchidism and mental retardation. AB - We report a case with a new syndrome that presents with glaucoma, cryptorchidism, oculocutaneous albinism, ataxia, hypotonia, autistic behaviour besides various major and minor craniofacial dysmorphic, skeletal, and neuroimaging findings, and suggest that this case represents a new syndrome not reported previously. PMID- 21614986 TI - Partial trisomy 8p (8p11.2-->pTER) and deletion of 13q (13q32-->qTER): case report. AB - We report a female infant with partial trisomy 8p (8p11.2-->pter) and deletion of 13q (13q32-->qter). She was born with mild hypotonia, intrauterine growth retardation, microcephaly, micrognathia, large low set ears, pectus excavatum, anteriorly placed anus, and bilateral clinodactyly. Echocardiography showed left ventricular hypertrophy, bicuspid aortic valve, dilatation of the aorta and pulmonary artery, and prolapse of atrio-venticular valve leaflets. Cytogenetic investigation of her sister and her father showed that the altered region resulted from a balanced translocation between the part of the long arm of chromosome 13 and short arm of chromosome 8. In partial trisomy 8p, the clinical picture of the patients comprises hypotonia, structural brain abnormalities, facial anomalies including a large mouth with a thin upper lip, a high arched palate, a broad nasal bridge, an abnormal maxilla or mandible, malformed, low set ears, and orthopedic anomalies. Although patients with proximal deletions of 13q that do not extend into band q32 have mild to moderate mental and growth delays with variable minor anomalies, patients with more distal deletions including at least part of band q32 usually have major malformations such as retinoblastoma, mental-motor growth retardation, malformation of brain and heart, anal atresia, and anomalies of the face and limbs. To our knowledge partial trisomy 8p and partial monosomy of 13q have not been reported previously in the same person. PMID- 21614987 TI - Prenatal diagnosis and molecular characterization of an interstitial 1q24.3-31.3 deletion: case report and review. AB - We describe a foetus with an interstitial deletion of 1q detected in amniotic fluid cells and we review the literature of similar pre- and postnatal cases, in order to identify prognostic factors useful for prenatal counselling. Foetal/parents karyotyping and FISH with whole chromosome 1 paint and BAC clone specific for 1q23-32 region were performed. Further 100 Kb resolution array-CGH analysis was executed after pregnancy termination on DNA extracted from foetal skin fibroblasts. Cytogenetic analyses revealed a de novo interstitial deletion involving the long arm of chromosome 1. FISH analysis confirmed that the deletion involves the intermediate 1q31.2 region. Foetal ultrasound (US), performed at 21 weeks of gestation, showed intrauterine growth restriction, shortening of the long bones, echogenic intracardiac focus and mild cerebral ventriculomegaly. Array-CGH localized the deletion in a DNA sequence of about 21 Mb in the 1q24.3 q31.3 region. Our findings, together with available data on patients with 1q deletion, suggest that the most severe phenotypes are not simply associated with larger deletion, and that the results of prenatal US assessment, rather than a fine molecular characterization of the deletion, should be taken into account for prognostic evaluation. PMID- 21614988 TI - A novel SOX9 nonsense mutation, q401x, in a case of campomelic dysplasia with XY sex reversal. AB - Campomelic dysplasia (CD, MIM 114290) is a rare, often lethal, dominantly inherited, congenital skeletal dysplasia, associated with male-to-female autosomal sex reversal and due to de novo mutations of the SOX9 gene, a tissue specific transcription factor gene involved both in skeletogenesis and male sexual differentiation. Here we report on a 4 months-old 46,XY sex reversed infant with typical clinical features for CD due to a novel mutation of the SOX9 gene, Q401X, leading to synthesis of a truncated SOX9 protein that completely lacks the C-terminal transactivation domain. PMID- 21614989 TI - Autosomal dominant aplasia cutis in three generations and one case with preaxial polydactyly in the last generation. AB - Aplasia Cutis Congenita (ACC), characterized by the focal absence of the skin and skin adnexia resulting from a developmental failure, may occur as part of Adams Oliver Syndrome (AOS) which can be defined as a congenital inherited disorder, consisting of terminal transverse limb defects and vascular anomalies in addition to ACC. Coexistence of isolated preaxial polydactyly without terminal extremity defect and ACC is extremely rare. Furthermore, ACC and preaxial polydactyly has not been reported previously. Here we report a three-generation family with autosomal dominant aplasia cutis congenita and preaxial polydactyly in the last generation and discuss whether it is a coincidence or not. PMID- 21614990 TI - De novo supernumerary marker chromosome originating from chromosome 17 resulting in a normal pregnancy outcome. AB - We report here a prenatal case with de novo supernumerary marker chromosome originating from chromosome 17 in non-mosaic form resulting in normal pregnancy outcome. In this case, a 26-year-old pregnant woman was referred for amniocenthesis and microdeletion Fluorescence In Situ Hybridization (FISH) testing at 18 weeks of gestation due to history of a previous child with Angelman Syndrome. PWS/AS region deletion was excluded by FISH. A de novo supernumerary, non-satellited, monocentric marker chromosome was detected during conventional cytogenetic analysis. With the use of FISH testing, it was found that the marker chromosome originated from chromosome 17. Additionally, the marker chromosome was found not to contain the Smith-Magenis and Miller Dieker syndrome regions. After detailed review of the literature, genetic counseling was given to the family, and the family decided to continue the pregnancy to term. A female child was born at term without any phenotypical abnormalities and clinical complications. Follow up at 15 months-of-age revealed no developmental abnormalities. To our knowledge, our patient is the first reported prenatal case with a de novo monocentric, supernumerary marker chromosome derived from chromosome 17 in a non-mosaic form that resulting in normal pregnancy outcome. PMID- 21614991 TI - Baller-Gerold syndrome associated with dextrocardia. AB - Baller-Gerold Syndrome (BGS) is a rare autosomal recessive disorder that is apparent at birth. The disorder is characterized by distinctive malformations of the skull and facial area and bones of the forearms and hands. We report a 4 year old boy in whom the clinical features of craniosynostosis and bilateral absent thumbs and radii led to a diagnosis of Baller-Gerold syndrome. Physical examination revealed that the heart was localized to the right side. Echocardiography confirmed dextrocardia. Dextrocardia has not previously been reported with Baller-Gerold syndrome. To the best of our knowledge, this is the first reported case of Baller-Gerold syndrome associated with dextrocardia. PMID- 21614992 TI - Congenital myasthenic syndrome: a case report. AB - SUMMARY: Congenital myasthenic syndromes (CMS) are diseases of the neuromuscular junction. They usually belong to the disease groups that begin in the infantile or childhood period and carry genetic characteristics. The following is important in establishing the diagnosis of this disease: clinical findings, electromyography, genetic tests, determination of serum acetylcholine receptor antibodies. Acetylcholine esterase inhibitor drugs are used in treatment of CMS. A seven-month old male patient was brought to our department with the complaints of difficult breathing, falling of the eyelids and swallowing difficulty. With clinical and laboratory findings, he was diagnosed with congenital myasthenia and treatment was started. CMS should be suspected in patients with no pathological findings on the physical examination, and normal chest X-rays. PMID- 21614993 TI - Congenital tracheal stenosis in a boy with the 22q13.3 deletion syndrome. PMID- 21614994 TI - Clinical practice guidelines: the warped incentives in the U.S. healthcare system. AB - The healthcare system is sick. The players are incentivized to maximize their own benefit and externalize their costs onto the other parties. This paper examines the warped incentives that underlie the system. The tort system, lacking expertise and slow to adapt, is unable to overcome cognitive biases to adequately solve the problems. Clinical practice guidelines could pose a solution, but not as they are currently developed. Guidelines promulgated by healthcare associations are infected by a web of conflicts of interest with every player in the industry. Government agencies, and their revolving doors, are underfunded and also subject to the industry's web of conflicts. Even if adequate guidelines could consistently be produced, state legislatures and courts have been unwilling and unable to substantially incorporate guidelines into the legal landscape. Lastly, this article proposes a private regulation regime that could be a solution which would align all of the players' incentives to society's interests. PMID- 21614995 TI - Healing Medicare hospital recidivism: causes and cures. PMID- 21614996 TI - Modernizing Medicaid eligibility criteria for children with significant disabilities: moving from a disabling to an enabling paradigm. AB - Children with significant disabilities may qualify for Medicaid benefits, regardless of household income, if their state elects to offer the Tax Equity Fiscal Responsibility Act (TEFRA) option. However, a significant number of children with serious medical problems presently are being denied eligibility for, or terminated from, this Medicaid program. This Article describes the ways in which the existing health insurance system inadequately meets the needs of children with significant disabilities, recounts the history and development of the TEFRA Medicaid coverage option, and analyzes the eligibility criteria used by the various states. It proceeds to consider how disability should be legally defined in the health care context and proposes reforms to modernize the eligibility standards so that these benefits can be more effectively, efficiently, and fairly allocated. To accomplish this goal, the federal statute and regulation that define disability, as well as corresponding state laws, must be reformed so that the law can keep pace with advances in modern medical science, and people with disabilities are not, in effect, penalized for receiving currently accepted preventative care that maintains health but will never cure the underlying disease. PMID- 21614997 TI - Planning for pandemic: a new model for governing public health emergencies. PMID- 21614998 TI - Cheaper clinical trials: the real solution to the biologic industry's Gordian knot. PMID- 21614999 TI - D.C. Circuit rules FDA cannot block e-cigarette imports--Sottera, Inc. v. FDA. PMID- 21615000 TI - New federal law calls for government, public attention to Alzheimer's crisis--the National Alzheimer's Project Act. PMID- 21615001 TI - Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation. AB - Brain injuries are common in professional American football players. Finding effective rehabilitation strategies can have widespread implications not only for retired players but also for patients with traumatic brain injury and substance abuse problems. An open label pragmatic clinical intervention was conducted in an outpatient neuropsychiatric clinic with 30 retired NFL players who demonstrated brain damage and cognitive impairment. The study included weight loss (if appropriate); fish oil (5.6 grams a day); a high-potency multiple vitamin; and a formulated brain enhancement supplement that included nutrients to enhance blood flow (ginkgo and vinpocetine), acetylcholine (acetyl-l-carnitine and huperzine A), and antioxidant activity (alpha-lipoic acid and n-acetyl-cysteine). The trial average was six months. Outcome measures were Microcog Assessment of Cognitive Functioning and brain SPECT imaging. In the retest situation, corrected for practice effect, there were statistically significant increases in scores of attention, memory, reasoning, information processing speed and accuracy on the Microcog. The brain SPECT scans, as a group, showed increased brain perfusion, especially in the prefrontal cortex, parietal lobes, occipital lobes, anterior cingulate gyrus and cerebellum. This study demonstrates that cognitive and cerebral blood flow improvements are possible in this group with multiple interventions. PMID- 21615002 TI - Substance abuse counselors' implementation of tobacco cessation guidelines. AB - This study assessed the extent of implementation of the Public Health Service tobacco cessation guidelines among a national sample of counselors working in five different types of substance abuse treatment programs. Further, we identified implementation patterns among counselors using cluster analysis and considered differences in counselor characteristics based on their cluster membership. Data were obtained from the 2008 Managing Effective Relationships in Treatment Services (MERITS I) project. Counselors (N = 615) working in Clinical Trials Network (CTN) affiliated community treatment programs completed paper-and pencil surveys. Implementation of the guidelines was inconsistent and selective. Counselors could be grouped into low versus high implementers. Some counselor characteristics differed based on their implementation cluster membership. PMID- 21615003 TI - Reasons for drug abstention: a study of drug use and resilience. AB - Despite extensive prevention efforts, recent years have seen an increase in illicit drug use among young people. However, many people choose to not use drugs while they are growing up. This study sought to uncover reasons why some individuals seem to have more resilience when faced with drug use than others. Fear of the physical damage drugs caused, parental disapproval of drug use, and a belief that drugs would interfere with goals were cited most often as reasons for not using. Furthermore, students who had never used drugs had more positive relationships with family and peers compared to those who had used them. PMID- 21615004 TI - Predictors of membership in Alcoholics Anonymous in a sample of Successfully remitted alcoholics. AB - This study identifies factors associated with Alcoholics Anonymous (AA) membership in a sample of 81 persons who have achieved at least one year of total abstinence from alcohol and other drugs. Forty-four were AA members, 37 were not. Logistic regression was used to test the cross-sectional associations of baseline demographic, substance-related, spiritual and religious, and personality variables with AA membership. Significant variables from the bivariate analyses were included in a multivariate model controlling for previous AA involvement. Having more positive views of God and more negative consequences of drinking were significantly associated with AA membership. This information can be used by clinicians to identify clients for whom AA might be a good fit, and can help others overcome obstacles to AA or explore alternative forms of abstinence support. PMID- 21615005 TI - Consumption of ayahuasca by children and pregnant women: medical controversies and religious perspectives. AB - In 2010, the Brazilian Government agency responsible for drug-related issues formulated official Resolutions that categorized the consumption of ayahuasca by pregnant women and children in the Santo Daime and Uniao do Vegetal ayahuasca based religions as an "exercise of parental rights." Although ayahuasca groups do enjoy a relative degree of social legitimacy and formal legal recognition in Brazil, the participation of pregnant women and children nevertheless continues to provoke heated discussion. This article raises the main issues involved in the public debate over this subject. In the first part, a diverse group of biomedical and health specialists was consulted, and their opinions were briefly analyzed. In the second, a full interview with a follower of one branch of Santo Daime, mother of four children who took ayahuasca during all her pregnancies, and whose children all drink ayahuasca, is presented. Her interview reveals important cultural parameters of ayahuasca consumption. The article explores common themes and contradictions found between the biomedical, anthropological, and ayahuasca users' discourses. It raises central issues regarding the limits of freedom of religion and the state's right to interfere in family matters. The following analysis also has implications regarding the role of science in influencing policy decisions on drug use. PMID- 21615006 TI - Yopo, ethnicity and social change: a comparative analysis of Piaroa and Cuiva yopo uset. AB - Most Orinocoan ethnic groups, including the Cuiva and the Piaroa, use yopo, a hallucinogenic snuff derived from the seeds of the Anadenanthera peregrina tree. This study contrasts Piaroa and Cuiva attitudes toward and uses of yopo in light of ongoing processes of social change. We do not believe that these sociocultural forces will lead to a phasing out of yopo in Piaroa and Cuiva life. However, we demonstrate how, in nearby communities, a combination of historical and ethical contingencies lead to very different patterns and understanding of drug use. Yopo is strongly associated with the performance of narratives central to each ethnic group's cosmology and identity. Cuiva yopo consumption is also a means of resisting persecution and asserting the right to a just reality. Piaroa attitudes towards yopo are affected by the interplay of shamanic ethical principles and missionary activity, and are sometimes paradoxical: yopo is the reason for harm and the means of salvation; required by shamans to create the future and yet regarded by many laypeople as a relic of the past. We identify persecution, local responses to missionary activity, and shamanic ethics as key factors affecting the evolution of hallucinogen use by Amazonian ethnic groups. PMID- 21615007 TI - Legally tripping: a qualitative profile of Salvia divinorum use among young adults. AB - During recent years, there has been increasing interest in "legal highs" among youth and young adults. Salvia divinorum is a legally available hallucinogenic plant, primarily utilized in smokable form, that produces a brief but intense hallucinogenic experience for the user. Data are presented from an ethnographic project to provide a qualitative profile of salvia use among young adults. Most users report primarily using in home settings such as apartments and houses, although a significant minority report use in environments such as parks, bars, and parties. The intense nature of the substance creates a differential subjective experience. Some describe the intensity of the hallucinogenic experience in positive ways. Others find the experience so intense that they would not continue to use the substance. With regard to the health effects of salvia, most young adults report no significant negative health effects from salvia use, although some report a mental cloudiness. Beyond their own experiences, users did not report any negative health events among peers. The lack of reports of negative effects may reinforce social norms favorable towards salvia use. Overall, young adults report a relatively low risk profile for salvia divinorum, which may be influenced, in part, by its legal status. PMID- 21615008 TI - Drugs, the Internet and change. AB - This article investigates the symbiotic relationship between drugs and the Internet, focusing (though not exclusively) on psychedelics. Programming on psychedelics in Silicon Valley from the 1960s to date is detailed, as are the twinned conceptualizations of drugs as a technology and technology as a drug. The correlation between drugs, the Internet, and consumerism is explored: the Internet is a medium through which "white," "grey" and "black" drug markets flourish. Thus, this article details the burgeoning online trades in pharmaceuticals, recreational, and "life-style" drugs that turn the Internet into a veritable candy store. Drug forums transmogrify into street corners, threatening the continued existence of the current system of global prohibition. However, it is arguably the use of the Web as an information source that may offer the greatest challenge to the incumbent paradigm, with experiential discourses offering alternatives to the hegemonic narrative, as the relationships between drugs, those who sell drugs and drug takers are reconfigured online. PMID- 21615009 TI - One dozen considerations when working with women in substance abuse groups. AB - Women and men have different histories, presentations, and behaviors in substance abuse groups. Twelve considerations are offered for the beginning group leader when encountering women with substance abuse issues. These include understanding sexism, what brings women to treatment, and how women behave in group treatment. Implications for clinical practice with women in single-gender and mixed-gender groups are included. PMID- 21615010 TI - Service use and treatment barriers among inhalant users. AB - Inhalant use is a serious global problem with consequences equal to or surpassing those of other drugs. Regrettably, few prior studies have examined inhalant users' patterns of service and treatment utilization. The purpose of this study is to identify factors associated with service use and barriers to treatment among a nationally representative sample of inhalant users. Data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) reveal that among inhalant users problem severity and substance use disorder comorbidity were associated with substance abuse treatment barriers and service usage. These findings can help improve the service delivery system to provide effective treatments and reduce the risk of emergency department usage, which is among the most expensive and least effective ways to deal with substance abuse. PMID- 21615011 TI - Bioactivity-guided study of antiproliferative activities of Salvia extracts. AB - The cytotoxic activities of the n-hexane, chloroform and aqueous methanolic fractions prepared from the methanolic extract of the leaves of 23 Salvia taxa were studied for their cell growth-inhibitory activity against human cervix adenocarcinoma (HeLa), skin carcinoma (A431) and breast adenocarcinoma (MCF7) cells using the MTT assay. The n-hexane fractions of six Salvia taxa (S. hispanica, S. nemorosa, S. nemorosa 1. albiflora, S. pratensis, S. recognita and S. ringens) and the chloroform fraction ofS. officinalis 1. albiflora produced over 50% growth inhibition of the skin carcinoma cell line. None of the tested extracts showed substantial (above 50%) antiproliferative effects against HeLa and MCF7 cells. S. ringens was the most powerful among the studied Salvia species with a 61.8% cell growth inhibitory activity on A431 cells. In the case of S. ringens, other plant parts were also tested for antiproliferative effect, and the highest activities were recorded for the root extract. This was subjected to bioactivity-guided fractionation, which yielded four abietane diterpenes (royleanone, horminone, 7-O-methyl-horminone and 7-acetyl-horminone), one triterpene (erythrodiol-3-acetate) and beta-sitosterol. Horminone, 7-acetyl horminone and erythrodiol-3-acetate displayed marked concentration-dependent antiproliferative effects, while royleanone and 7-O-methyl-horminone produced weaker activities. PMID- 21615012 TI - Simultaneous quantification of Panax and Epimedium species using Rapid Resolution Liquid Chromatography (RRLC). AB - Two Rapid Resolution Liquid Chromatography (RRLC) methods have been developed and validated for simultaneous quantification of eight major ginsenosides from Panax species, namely, R1, Rg1, Re, Rf, Rb1, Rb2, Rc, and Rd, and flavonoids from Epimedium species, namely, epimedins A, B, and C and icariin. The analyses were performed using an Agilent 1200 series RRLC system with Phenomenex Luna C18-HST and Zorbax Eclipse XDB columns. The separation was performed with a gradient mobile phase of A (pure water) and B (acetonitrile) at a flow rate of 1.0 mL/min and 2.5 mL/min, respectively. Both columns were kept at 40 degrees C with the detection wavelength set at 203 nm. Specific eluted compounds were identified by using reference samples of ginsenosides R1, Rg1, Re, Rf, Rb1, Rc, Rb2, and Rd, and epimedins A, B, C and icariin. Baseline separation was achieved in less than 15 minutes for the Phenomenex Luna column and 4 minutes for the Zorbax Eclipse column. Characteristic RRLC profiles were established for complex mixtures of ginsenosides from Panax species and flavonoids from Epimedium species. Both methods developed here are effective for the quality control of formulated products containing both Panax and Epimedium varieties. PMID- 21615013 TI - Radioprotective properties of Cumaside, a complex of triterpene glycosides from the sea cucumber Cucumaria japonica and cholesterol. AB - The radioprotective activity has been studied of a new immunomodulatory lead material, Cumaside, which is a complex of monosulfated triterpene glycosides from the edible sea cucumber Cucumaria japonica and cholesterol. Female CD-1 strain mice administered with prophylactic doses of Cumaside were irradiated using a Gamma-therapeutic device with a 60Co source (exposure dose 6.5 Gy, dose rate 1.14 Gy/min) and the average life span of the mice was determined. The animals administrated with Cumaside and irradiated were killed by pervisceral dislocation on days 4 and 9. Peripheral blood cell composition indexes, blood forming function and cell number in blood-forming organs and the number of pluripotent blood-forming stem cells were determined using standard procedures and the results compared with those of non-treated irradiated mice. The survivability percentage and average life span of the irradiated mice that were not treated with Cumaside were decreased in comparison with the Cumaside-treated groups. Especially, the leukocyte and neutrophil numbers in the blood (bone marrow from hip), and the weight and cell number of lymphoid organs were higher in the Cumaside-treated groups compared with the non-treated irradiated mice. It was concluded that at low prophylactic doses Cumaside possesses moderate radioprotective properties. PMID- 21615014 TI - Herbicide activity of extracts from Ailanthus altissima (Simaroubaceae). AB - The purpose of the present study was to isolate and characterize ailanthone-rich materials from the bark of the deciduous tree Ailanthus altissima (Mill.) Swingle and to assess their herbicide activity on selected herbaceous species. Ailanthone rich fractions were obtained from A. altissima bark by extraction with dichloromethane and ethyl acetate and subsequent purification of these crude extracts, and of the remaining water mixture after solvent extraction, by means of gel permeation chromatography. A number of fractions were isolated and characterized for ailanthone content. A dichloromethane fraction was shown to contain 92% w/w of ailanthone, as demonstrated by HPLC and NMR analysis. A significant pre-emergence herbicide activity was found for most of the extracts which was directly correlated to ailanthone concentration. A remarkable combined pre- and post-emergence herbicide activity was found for a specific fraction. These results indicate that the bark of A. altissima may represent an interesting source for the production of natural herbicides for use in agriculture. PMID- 21615015 TI - Redox properties of 8-quinolinol and implications for its mode of action. AB - 8-Quinolinol (oxine, 8-hydroxyquinoline) is a simple aromatic alkaloid with allelopathic, antibacterial, antifungal, and cytotoxic activities. Generally, it is assumed that 8-quinolinol toxicity depends on transition metal chelation that negatively affects their availability for metalloenzymes in the cell or reactive oxygen species generation (ROS), which are formed following reduction of molecular oxygen by autoxidation of the redox active metal central atom of the 8 quinolinol complex. On the contrary, beneficial effects of 8-quinolinol and its derivatives in the medication of certain degenerative diseases are known. In this context, the activity of 8-quinolinol derivatives is attributed to their antioxidant activity following iron complex formation. To address this controversial issue, we explore the possible anti- or pro-oxidant effects of 8 quinolinol and its iron complexes in the deoxyribose degradation assay, by cyclic voltammetry and in a biological assay. The antibacterial effects of 8-quinolinol and its complex with iron were evaluated on Curtobacterium flaccumfacies and Paenibacillus amylolyticus. 8-Quinolinol showed strong antioxidant activity in the deoxyribose degradation assay. This activity may not depend exclusively on iron chelation, but probably more on the notable reducing properties of 8 quinolinol; it proved to be a more efficient antioxidant than the flavonoids catechin and quercetin. By contrast, 8-quinolinol showed no pro-oxidative effects in the deoxyribose degradation assay, both in free form and in complex with iron, as it may occur with redox cyclers. Cyclic voltammetry confirmed this too. 8 Quinolinol significantly inhibited bacterial growth and respiration. Idiosyncratically, its 50:1 mixture with iron(III) ions was less active compared with free 8-quinolinol; it even caused a U-shaped nonlinear hormetic effect on growth and failed to inhibit respiration as totally as the pure mixture; the respiration was even accelerated compared with the control as a result of lower stress. Our results support the notion that complex formation with either iron or other transition metals affects the reducing power of 8-quinolinol, but, in contrast to general assumptions, this study finds no support that complex formation with iron represents the major mode of action. PMID- 21615016 TI - Analysis of Amaryllidaceae alkaloids from Chlidanthus fragrans by GC-MS and their cholinesterase activity. AB - The underivatized alkaloid mixture extracted from the bulbs of Chlidanthus fragrans Herb. was investigated by capillary GC/MS for the first time. Fifteen known Amaryllidaceae alkaloids of five structure types were identified. The main alkaloids were tazzetine (9, tazettine-type), chlidanthine (2, galanthamine type), belladine (8, belladine-type) and lycorine (12, lycorine-type). The alkaloid extract from the bulbs showed promising human blood acetylcholinesterase (IC50 = 20.1 +/- 2.9 microg/mL) and human plasma butyrylcholinesterase (IC50 = 136.8 +/- 6.9 microg/mL) inhibitory activity. PMID- 21615017 TI - Acetylcholinesterase and butyrylcholinesterase inhibitory compounds from Corydalis cava (Fumariaceae). AB - Tubers of Corydalis cava were extracted with ethanol and fractionated using n hexane, chloroform and ethanol. Repeated column chromatography, preparative TLC and crystallization led to the isolation of fifteen isoquinoline alkaloids. The chemical structures of the isolated compounds were determined on the basis of spectroscopic techniques and by comparison with literature data. All isolated compounds were tested for human blood acetylcholinesterase (HuAChE) and human plasma butyrylcholinesterase (HuBuChE) inhibitory activity. (+)-Canadaline inhibited acetylcholinesterase as well as butyrylcholinesterase in a dose dependent manner with IC50 values of 20.1 +/- 1.1 microM and 85.2 +/- 3.2 microM, respectively. (+)-Canadine, with an IC50 value of 12.4 +/- 0.9 microM, was the most potent inhibitor of acetylcholinesterase, whilst (+/-)-corycavidine and (+) bulbocapnine were effective inhibitors of butyrylcholinesterase with IC50 values of 46.2 +/- 2.4 microM and 67.0 +/- 2.1 microM, respectively. The other isolated alkaloids were considered inactive (IC50 > 100 microM). PMID- 21615018 TI - Effect of ascorbigen and 1'-methylascorbigen on disease resistance of bean plants to Uromyces phaseoli. AB - The effect of ascorbigen and 1'-methylascorbigen on the disease resistance of bean (Phaseolus vulgaris L.,. cv. Debreceni Tarka) to the fungal pathogen Uromyces phaseoli Pers. is reported. Contrary to ascorbigen, pretreatment of bean plants with l'-methylascorbigen, as in the case of other endogenous N-, O- and S methyl compounds, induced the double immune response leading to the biochemical immunization of plants. The effectiveness of protection depended on the dosage of the applied l'-methylascorbigen and on the time interval between the chemical pretreatment and inoculation. Results of our greenhouse experiments revealed, in accordance with previous results, that the presence of the N-methyl group in the 1'-methylascorbigen molecule is the precondition of the effect, and formaldehyde formed from this N-methyl group and its reaction products (e.g. singlet oxygen, ozone) can have a determining role in the manifestation of the effect. PMID- 21615019 TI - Maculansins, cryptic phytotoxins from blackleg fungi. AB - The phytotoxins and other metabolites produced by isolates L2/M2 of the fungal species Leptosphaeria maculans under different culture conditions, together with those of two new, but related isolates are disclosed. The common metabolic characteristics suggest a phylogenetic similarity between these isolates with potential to become widespread in mustard growing areas. PMID- 21615020 TI - Unusual compounds from exudates of Dionysia diapensifolia and D. gaubae var. megalantha (Primulaceae). AB - Exudates of Dionysia diapensifolia yielded (R)-(+)-3-acetoxy-3-phenyl propiophenone as a new natural product with a basic dihydrochalcone structure, which was elucidated unequivocally by mass spectrometry and NMR spectroscopy. The sesquiterpenoidcarissone was found as the major compound in the exudate of D. gaubae var. megalantha. Sesquiterpenoids have so far not been described as exudate constituents of Primula and Dionysia. Structural identifications are discussed in detail, and the significance of the occurrence of these unusual compounds in exudates of Primulaceae is shortly addressed. PMID- 21615021 TI - A novel biflavonyloxymethane from Pongamia pinnata and its radical quenching activity. AB - The root bark of Pongamia pinnata Pierre (syn P. glabra Vent.) has afforded a new biflavonyloxymethane, pongabiflavone, along with a known furanoflavone, 3-methoxy (7, 8, 2", 3") furanoflavone. The structure of this new compound was elucidated from extensive spectral studies, including 2D-NMR spectroscopic experiments. The antioxidant, radical quenching activity- superoxide and nitric oxide quenching activities of both pongabiflavone and previously isolated karanjabiflavone have been evaluated which can be a key to cure Psoriasis. PMID- 21615022 TI - The Thai medicinal plant Gynura pseudochina var. hispida: chemical composition and in vitro NF-kappaB inhibitory activity. AB - Gynura pseudochina (L.) var. hispida Thv. (Asteraceae) has been used in traditional medicine in Thailand for the treatment of conditions associated with chronic and acute inflammation. In continuation of our search for bioactive natural products from Thai medicinal plants, G. pseudochina var. hispida showed potential in vitro NF-kappaB (Nuclear Factor kappa B) inhibitory activity and, therefore, was chosen for bio-assay-guided isolation of active compounds. Bioassay-guided fractionation of the methanol extract of the leaves of G. pseudochina var. hispida led to the isolation and identification, by spectroscopic and mass spectrometric methods, of four compounds previously not reported from this poorly studied species: Quercetin 3- rutinoside (1), 3,5-di caffeoylquinic acid (2), 4,5-di-caffeoylquinic acid (3), and 5-monocaffeoylquinic acid (4). This paper discusses the current knowledge of these active components as NF-kappaB inhibitors, which lends some support to the use of this plant in traditional medicine. Potential risks associated with pyrrolizidine alkaloids will, however, have to be investigated further. PMID- 21615023 TI - Multiple beneficial effects of resveratrol and their chemical-biochemical basis. AB - On the basis of in vitro and in vivo investigations trans-resveratrol (RV) is a natural, concentration-dependent formaldehyde (HCHO) mobilizer, scavenger, capture and carrier molecule. The capturing and mobilization of HCHO from a given biological unit (e.g. tissue) with RV (first step) generates a chemopreventive effect. The reaction products between endogenous HCHO and RV (second step) may exert killing/inhibiting effects on pathogens and/or cancer cells. These two steps result in the double effect of RV. From the model reaction mixture of RV and HCHO in diluted formalin solution, different reaction products were detected, separated and identified. Similar reactions can be observed between RV and endogenous HCHO in plant and animal tissues as well. Capturing the HCHO molecules in model experiments with HCHO-capture molecules (in vitro conditions) the antibacterial activity of RV decreased substantially. The in vitro investigations were extended to in vivo conditions. The discovery of a quadruple immune response of plants to pathogens resulting from pretreatment with RV opens new horizons in the confirmation of the diverse beneficial effects of RV. PMID- 21615024 TI - Simultaneous quantification of Echinacea species, Flos Lonicerae, Radix Scutellaria and Fructus Forsythiae combinations by rapid resolution liquid chromatography. AB - Echinacea angustifolia and E. purpurea are commonly used in North America for their anti-bacterial effects. Flos Lonicerae, Radix Scutellaria and Fructus Forsythiae are traditional Chinese medicinal herbs commonly used for the treatment of complaints such as pneumonia, acute upper respiratory tract infection, and acute bronchitis. A reproducible, simple, and reliable rapid resolution liquid chromatographic (RRLC) method has been developed to analyze extracts of products formulated containing E. angustifolia, E. purpurea, Flos Lonicerae, Radix Scutellariae and Fructus Forsythiae simultaneously in one run in less than 6 minutes. The method uses a C18-HST column, a mobile phase consisting of 0.1% aqueous phosphoric acid solution and acetonitrile, and UV detection at 327 nm and 229 nm. A stability test was performed that revealed that chlorogenic acid is more stable in acidic pH, and hence it is best to keep the extract of E. augustifolia, E. purpurea, Flos Lonicerae, Radix Scutellariae and Fructus Forsythiae in mild acidic conditions at approximately pH 5. PMID- 21615025 TI - Rapid resolution liquid chromatography (RRLC) analysis for quality control of Rhodiola rosea roots and commercial standardized products. AB - A simple, sensitive and reliable reversed phase Rapid Resolution Liquid Chromatography (RRLC) method was developed and validated for six biologically active compounds (salidroside, tyrosol, rosarin, rosavin, rosin and rosiridin) in Rhodiola rosea L. roots and powder extracts. The method uses a Phenomenex C18 (2) HST column at 40 degrees C with a neutral gradient system mobile phase (H20 and acetonitrile), a flow rate of 1.0 mL/min, and UV detection wavelengths set at 205 and 254 nm, simultaneously. Baseline separation of the six active compounds was achieved within 8 minutes. The average percentages of rosavins (rosarin, rosavin, and rosin) in authentic R. rosea roots and root powder extracts were quantitatively determined and a characteristic R. rosea roots RRLC profile was established. The RRLC method is accurate and sensitive; in addition, it effectively increases the sample analysis throughput compared with conventional HPLC. PMID- 21615026 TI - Antioxidant activity of polyphenols from green and toasted mate tea. AB - The production and distribution of toasted mate tea in Brazil has increased, which has resulted in its greater consumption. Mate tea is obtained by roasting non-fermented erva-mate in order to produce toasted erva-mate or toasted mate tea. However, although the product is much appreciated, studies of its chemical composition and the concentration of polyphenols, particularly flavonols present in toasted mate tea, are few and often controversial. This paper elucidates some misunderstandings involving the nomenclature of erva-mate and toasted mate, and mainly provides an overview of the composition of polyphenols and antioxidant capacity of toasted mate tea and its raw material, erva-mate, in comparison with other teas, the compositions of which were found in the literature. PMID- 21615027 TI - Investigation of the antibacterial mechanism of aflatoxins in the BioArena system. AB - The influence of monomethylated basic amino acids [NG-monomethyl-L-arginine (MMA) and Nepsilon-monomethyl-L-lysine (MML)] and ozone capturers (indigo carmine, d limonene) on the antibacterial effect of the mycotoxins aflatoxins B1, B2, G1 and G2 was studied in BioArena, which is a complex bioautographic system especially suitable for investigating biochemical interactions. In the presence of the formaldehyde precursors MMA or MML, the antibacterial-toxic activity of all the aflatoxins against the phytopathogenic bacterium Pseudomonas savastanoi pv. phaseolicola was enhanced dose-dependently. Indigo carmine and d-limonene, in appropriate concentrations, decreased the inhibition zones of aflatoxins. These results support the original idea that HCHO and its derivative 03 may be involved in the antibacterial activity of aflatoxins and so, potentially, in their known toxic effect. PMID- 21615028 TI - Bioactive aromatic derivatives from endophytic fungus, Cytospora sp. AB - Two new benzyl gamma-butyrolactone analogues, (R)-5-((S)-hydroxy(phenyl) methyl)dihydrofuran-2(3H)-one (1) and its 6-acetate (2), and a new naphthalenone derivative (8), together with eight additional known aromatic derivatives, (S)-5 ((S)-hydroxy(phenyl)-methyl)dihydrofuran-2(3H)-one (3), (S)-5-benzyl-dihydrofuran 2(3H)-one (4), 5-phenyl-4-oxopentanoic acid (5), gamma-oxo-benzenepentanoic acid methyl ester (6), 3-(2,5-dihydro-4-hydroxy-5-oxo-3-phenyl-2-furyl)propionic acid (7), (3R)-5-methylmellein (9), integracins A (10) and B (11) were isolated from Cytospora sp., an endophytic fungus isolated from Ilex canariensis from Gomera. The structures of these compounds were elucidated by detailed spectroscopic analysis, comparison with reported data, and chemical interconversion. The absolute configurations of the new compounds (1, 2, 8) were established on the basis of optical rotation or CD spectra analysis. Preliminary studies showed antimicrobial activity of these compounds against the fungi Microbotryum violaceum, Botrytis cinerea and Septoria tritici, the alga Chlorella fusca, and the bacterium Bacillus megaterium. PMID- 21615029 TI - Fatty acids as chemotaxonomic markers of marine macrophytes from Rio de Janeiro state, Brazil. AB - The distribution of fatty acids in 13 species of macroalgae (Chlorophyta, Ochrophyta and Rhodophyta) and 1 seagrass (Spartina sp), collected on the Rio de Janeiro state coast was determined. The results were evaluated in search of correlations between the taxonomic and phylogenetic position of these macrophytes. Statistical analyses showed the effectiveness as taxonomic and phylogenetic markers of the distribution of the methyl fatty acid esters in these macrophytes. PMID- 21615030 TI - Determination of absolute stereochemistry of natural alicyclic glycosides by 1H NMR spectroscopy without application of chiral reagents--an indication. AB - A study has been made of the 1H NMR spectra of peracetylated beta glucopyranosides and alpha-arabinopyranosides obtained by reaction of D- and L glucoses, and L- and D-arabinoses with either (R)- or (S)-2-octanols. The obtained and literature data show that 1H NMR spectra may be used to determine the absolute configuration of the aglycone moieties of some alicyclic glycosides without the need to synthesize derivatives with chiral reagents, as long as the absolute configuration of their monosaccharide moiety is known or vice versa. Spectra of marine steroid glycosides and their acetates containing glycosylated side chains as alicyclic fragments were also examined. It was shown that analysis of 1H NMR spectra for the determination of the absolute configuration is more applicable in the cases when glycosides have the same substitution in the D-ring of the aglycone moiety. PMID- 21615031 TI - Lecythomycin, a new macrolactone glycoside from the endophytic fungus Lecythophora sp. AB - A new macrolactone glycoside, lecythomycin (1), 23-methyl-3-(1-O-mannosyl) oxacyclotetracosan-1-one, was isolated from the endophytic fungus Lecythophora sp. (code 30.1), an endopyte of the Indonesian plant Alyxia reinwardtii. The structure of 1 was elucidated on the basis of NMR spectroscopic and mass spectrometric data. The isolated compound displayed antifungal activity against strains of Aspergillus fumigatus and Candida kruzei at minimal inhibitory concentrations (MIC) of 62.5-125 microg/mL. PMID- 21615032 TI - Concept of biogenic ferromanganese crust formation: coccoliths as bio-seeds in crusts from Central Atlantic Ocean (Senghor Seamount/Cape Verde). AB - At depths of 2,000 to 3,000 m, seamounts from the Cape Verde archipelago (Central Atlantic Ocean) are largely covered with ferromanganese crusts. Here we studied 60 to 150 mm thick crusts from the Senghor Seamount (depth: 2257.4 m). The crusts have a non lamellated texture and are covered with spherical nodules. The chemical composition shows a dominance of MnO2 (26.1%) and Fe2O3 (38.8%) with considerable amounts of Co (0.74%) and TiO2 (2.1%). Analysis by scanning electron probe microanalyzer (EPMA) revealed a well defined compositional zonation of micro-layers; the distribution pattern of Mn does not match that of Fe. Analysis by high resolution scanning electron microscopy (SEM) revealed that coccospheres/coccoliths exist in the crust material as microfossils; most of the coccospheres/coccoliths are not intact. The almost circular coccoliths belong to the type of heterococcoliths and are taxonomically related to species of the family Calcidiscaceae. By energy dispersive X-ray spectroscopic analysis an accumulation of the coccoliths in the Mn- and Fe rich micronodules was detected. Focused ion beam assisted SEM mapping highlighted that the coccoliths in the crust are Mn rich, suggesting that the calcareous material of the algal skeleton has been replaced by Mn-minerals. We conclude that a biologically induced mechanism has been involved in the formation of the crusts, collected from the Cape Verde archipelago from depths of 2,000 to 3,000 m in the mixing region between the oxygen-minimum surface zone and the oxygen-rich deep waters; the deposition process might have been triggered by chemical reactions during the dissolution of the Ca-carbonate skeletons of the coccoliths allowing Mn(II) to oxidize to Mn(IV) and in turn to deposit this element in the crust material. PMID- 21615033 TI - Antiprotozoal, antitubercular and cytotoxic potential of cyanobacterial (blue green algal) extracts from Ireland. AB - Cyanobacteria (= blue-green algae) are prolific producers of structurally distinct and biologically active metabolites. In the continuation of our search for new sources of anti-infective natural products, we have assessed the in vitro antiprotozoal (Plasmodium falciparum, Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani) and antitubercular (Mycobacterium tuberculosis) potential of samples of two terrestrial cyanobacteria, Nostoc commune (collected when desiccated and wet) and Rivularia biasolettiana. The cytotoxic potential of the extracts was also evaluated against primary L6 cells. Except for T. cruzi and M. tuberculosis, the crude extracts were active against all the organisms tested and showed no toxicity. The crude extracts were then partitioned between n-hexane, chloroform and aqueous methanol and retested against the same panel of pathogens. The chloroform sub-extracts of both N. commune samples showed significant activity against T. b. rhodesiense (IC50 values 2.0 and 3.5 microg/mL) and P. falciparum (IC50s 7.4 and 5.8 microg/mL), with low toxicity. This trend was also true for R. biasolettiana extracts, and its chloroform sub-extract showed notable activity against all parasitic protozoa. There were differences in the biological activity profiles of extracts derived from desiccated and hydrated forms of N. commune. To our knowledge, this is the first study assessing the anti-infective activity of desiccated and hydrated forms of N. commune, as well as R. biasolettiana. Furthermore, the present work reports such biological activity in terrestrial cyanobacteria from Ireland for the first time. These results warrant the further study of Irish terrestrial cyanobacteria as a valuable source of new natural product leads for the treatment of parasitic protozoal infections. PMID- 21615034 TI - Chemical diversity of Ziziphora clinopodioides: composition of the essential oil of Z. clinopodioides from Tajikistan. AB - The chemical composition of the essential oils of Ziziphora clinopodioides Lam. from the aerial flowering parts, collected during two different years, were obtained by hydrodistillation and analyzed by gas chromatography - mass spectrometry. Forty-five components representing 100% and 94.7% of the total oil were identified. The main constituents of the essential oils were pulegone (72.8 and 35.0%), neomenthol (6.5 and 23.1%), menthone (6.2 and 13.3%), p-menth-3-en-8 ol (1.7 and 3.5%), piperitenone (2.6 and 1.1%) and piperitone (0.7 and 1.2%). A cluster analysis was carried out on the essential oil compositions of Z. clinopodioides. PMID- 21615035 TI - Essential oil composition and antibacteral activity of Vismia baccifera fruits collected from Merida, Venezuela. AB - The essential oil from the fruits of Vismia baccifera Triana & Planch. (Gutttiferae), collected in June 2009, was analyzed by GC/MS. A yield of 0.6% oil was obtained by hydrodistillation. Twenty-seven components were identified by comparison of their mass spectra with those in the Wiley GC-MS Library data base. The major components were trans-cadin-l1,4-diene (36.6%), cis-cadin-1,4-diene (18.8%) and beta-caryophyllene (11.9%). The essential oil showed a broad spectrum of antibacterial activity against the important human pathogenic Gram-positive and Gram-negative bacteria Staphylococcus aureus (ATCC 25923), Enterococcus faecalis (ATCC 29212), Escherichia coli (ATCC 25992), Pseudomonas aeruginosa (ATCC 27853) and Klebsiella pneumoniae (ATCC 23357) with MIC values ranging from 9 to 37 microg/mL. PMID- 21615036 TI - Essential oil composition of five collections of Achillea biebersteinii from central Turkey and their antifungal and insecticidal activity. AB - The composition of the essential oils hydrodistilled from the aerial parts of five Achillea biebersteinii Afan samples, collected in central Turkey from Konya, Isparta and Ankara, were analyzed both by gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). Eighty-four components were identified, representing 87 to 99% of the total oil composition. The identified major components were 1,8-cineole (9-37%), camphor (16-30%) and p-cymene (1-27%). Two samples differed in piperitone (11%) and ascaridol (4%) content. The five A. biebersteinii essential oils were subsequently evaluated for their antifungal activity against the strawberry anthracnose-causing fungal plant pathogens Colletotrichum acutatum, C. fragariae and C. gloeosporioides using the direct overlay bioautography assay. The essential oils showed no antifungal activity at 80 and 160 microg/spot. In addition, A. biebersteinii oils and their major compounds were subsequently investigated against Aedes aegypti first instar larvae in a high throughput bioassay. Among the oils, only one sample from Ankara showed a notable larvacidal effect on Ae. aegypti larvae. The major compounds, 1,8-cineole, camphor and p-cymene, exhibited low mosquito larval activity, and thus the minor compounds are probably responsible for the observed activity against Ae. aegypti larvae. The oils showed weak activity against adult Ae. aegypti. PMID- 21615037 TI - Ecdysterone and its activity on some degenerative diseases. AB - Beside ecdysone (1), ecdysterone (2) is one of the most common 5beta-cholest-7-en 6-one (ecdysteroid) derivatives, which, besides having a hormonal effect on invertebrates, possesses a number of favorable non-hormonal biological effects on mammals. The most interesting of these is that on degenerative diseases, one of which, up to now not clarified in detail, is the so-called adaptogenic effect (protection of the organism against adverse stress factors) associated with anabolic, gastroprotective, and antioxidant effects. A second group of favorable effects is the possibility of suppression of neurodegenerative processes and protection of the cardiovascular system (metabolic syndrome symptom suppression, antidiabetic activity, and protection of heart and blood vessels). Because of these properties, ecdysterone has the potential to be developed as a medicinal agent. PMID- 21615038 TI - Overpressured layer chromatography (OPLC)--a flexible tool of analysis and isolation. AB - This review briefly summarizes the overpressured layer chromatography (OPLC) technique and its progress from the beginning until today. Some theoretical aspects, important technical and methodological solutions, as well as analytical separations and isolations are demonstrated covering the last 30 years. The infusion and transfusion OPLC operations, as well as their combination, and their off-line and on-line processes, and off-line and on-line hyphenations for detection and structure elucidation are presented. The combination of OPLC separation with biological detection by direct bioautography and BioArena as an important solution touches the potential of analysis and isolation based on biological activity. PMID- 21615039 TI - The quality of commercially available herbal products. AB - Herbal products are believed to be safe as they are naturally occurring, however, this is a misconception. Currently, there are many herbal products which are not manufactured under the Good Manufacturing Practice (GMP) guidelines and hence the quality of the product is not controlled. Quality can be assessed by evaluation of data on levels of either active constituent(s) or chemical markers indicative of origin of plant material. Assessment of published data on levels of quality of herbal medicinal products revealed that only a percentage of the total number of products investigated were found to contain the levels of markers as stated on the label, and others had widely varying levels of constituents. Thus few products complied with acceptable quality control standards. Herbal products are increasingly self-prescribed for the treatment of minor ailments. Patients relying on herbal products for therapeutic effects may expose themselves to either low doses of active constituents causing insufficient effects or alternatively take higher levels than expected, with the increased risk of toxicity or adverse effects, or be affected by the inadvertent inclusion of unexpected components with associated potential health risks. PMID- 21615040 TI - Railroads really rolling. PMID- 21615041 TI - Preventive safety. PMID- 21615042 TI - Gas detection for your building's mechanical system. PMID- 21615043 TI - The ultimate emergency shower. PMID- 21615044 TI - Keeping the FUN in FUNdamentals. PMID- 21615045 TI - Think the unthinkable in disaster planning. PMID- 21615046 TI - Northwest convergence. PMID- 21615047 TI - Voluntary use of respirators: a plain-language look at OSHA requirements. PMID- 21615048 TI - Dust to dust. A seemingly harmless particle raises explosive issues. PMID- 21615050 TI - What determines your safety focus? PMID- 21615049 TI - Why FR clothing. PMID- 21615051 TI - TSCA regulations: today's challenges and tomorrow's reforms. PMID- 21615052 TI - Leadership made easy. PMID- 21615053 TI - Progesterone prevents corticosterone mediated inhibition of estrous behaviour in rats. AB - Stress induced by application of electric foot shocks (300 microA/shock, five shocks per episode, 4 episodes at 1800, 1830, 1900 and 1930 hrs on the proestrus day) to rats at the time of pre-ovulatory progesterone secretion, abolished lordosis and resulted in maximum rejection co-efficient, whereas treatment with a CRF receptor antagonist (alpha-helical CRF9-41) or metapirone, an inhibitor of corticosterone synthesis, prior to application of the electric foot shocks, resulted in normal lordosis and a significant reduction in rejection coefficient. Further, administration of a single dose of corticosterone (40 microg) at 1800 hrs of proestrus caused inhibition of lordosis and resulted in maximum rejection co-efficient. On the other hand, corticosterone + progesterone treatment at 1800 hrs of proestrus resulted in normal lordosis and a significant reduction in rejection coefficient. The facts that stress induced inhibition of lordosis is prevented by CRF receptor antagonist or metapirone and that corticosterone inhibits lordosis indicate that stress induced inhibition of lordosis is mediated by corticosterone. Further, normal display of lordosis by rats treated with corticosterone + progesterone in contrast to its absence in corticosterone alone treated rats suggests that impaired progesterone secretion due to action of corticosterone leads to inhibition of lordosis. PMID- 21615054 TI - Effect of 8-alkylberberine homologues on erythrocyte membrane. AB - 8-alkylberberine homologues (Ber-C8-n, where n indicates carbon atom number of gaseous normal alkyl at 8 position, n = 0, 2, 4, 6, 8, 10, 12, or 16) were synthesized and their effects on the hemolysis of rabbit erythrocyte, the fluidity of membrane and the fluorescence of membrane protein were investigated by fluorescence analysis technique. Ber-C8-n with mediate length alkyl (4 < n < 10) exhibited obvious hemolysis effect on rabbit erythrocyte when their concentration exceed 1.25 x10(-4) mol/L, and Ber-C8-8 displayed the highest hemolysis effect among all tested homologues. All of Ber-C8-n influenced the fluidity of erythrocyte membrane to different extents, which exhibited an obvious dose-effect relationship. The effect of Ber-C8-n on fluidity increased as the length of alkyl chain was elongated and decreased gradually when the alkyl carbon atoms exceeded 8. The fluorescence of erythrocyte membrane protein was quenched by Ber-C8-n, which showed a similar changing tendency on membrane fluidity. Experiments in vitro suggested that disturbing effects of Ber-C8-n on the conformation and function of membrane protein leaded to the changes of membrane fluidity and stability, and then the membrane was broken down. PMID- 21615055 TI - Telomere instability caused by subtelomeric Y' amplification and rearrangements in Saccharomyces cerevisiae (ku70 tel1 and ku70 rad50) double mutants. AB - Telomeres solve the end-replication problem. Previous results suggested a relation between Yku70/80 and proteins Tell and Rad50 in telomere stabilization. Inactivation of any of these genes lead to a shortening of telomeres, while in ku70 tell or ku70 rad50 double mutants a drastic amplification of Y' elements was found. The biological significance of this observation is not clear. To further characterize Y' amplification 25 strains and isolates of S. cerevisiae were analyzed. As expected, amplification was seen in yku70 tel1 and yku70 rad50 double mutants, but not in other strains. The extent of Y' amplification was also tested to determine if excessive numbers of Y' repeats appear. A variation in chromosome lengths within the population of cells has been found. Hybridisation study indicated that chromosomes only increase in length in these double mutants, but never get shorter. A high degree of variability was observed in single cell clones, in spite of their close relationship, indicating that alterations in subtelomeric regions are not stable but occur continuously in these mutants. Therefore, these genes are essential to chromosome stability. PMID- 21615056 TI - Metformin: an effective attenuator of risperidone-induced insulin resistance hyperglycemia and dyslipidemia in rats. AB - The use of atypical antipsychotics in the clinical management of schizophrenia and schizoaffective disorders has been associated with the development of insulin resistance. The present study evaluates the possible individual ameliorating effect of single daily oral treatments with 20 mg/kg/day of metformin and 0.1 mg/kg of glibenclamide in two groups of Wistar rats pretreated with 0.2 mg/kg of risperidone for 60 days. Two additional groups of rats were only treated with 0.2 mg/kg of risperidone and 10 mL/kg of distilled water, respectively, also for 60 days. Results showed that oral pre-treatment with metformin significantly attenuated increases in the weight gain pattern, fasting glucose, fasting plasma insulin, serum triglyceride and total cholesterol levels that were elevated by risperidone treatment. Metformin also significantly reduced glycosylated hemoglobin concentration, fasting insulin-glucose ratio and fasting insulin resistance index. Conversely, oral pre-treatment with glibenclamide for 60 days did not significantly reduce any of the measured parameters except for glycosylated hemoglobin concentrations. Thus, results of this study showed that 20 mg/kg of metformin effectively ameliorated the development of risperidone induced insulin resistance and dyslipidemia which was mediated via improvement in insulin resistance. This study provides insight into the therapeutic potential of metformin in preventing risperidone-induced insulin resistance diabetes mellitus and dyslipidaemia. PMID- 21615057 TI - Alpha-adrenergic receptor blocking effect of Cleistanthus collinus (Roxb.) Benth. and Hook f. leaf extract on guinea pig isolated smooth muscle preparations. AB - Aqueous extract of C. collinus leaves inhibited norepinephrine induced contraction in guinea pig vas deferens and aortic strip in a dose-dependent manner. Inhibition of acetylcholine induced contraction in ileum was dose independent. C. collinus extract per se had no effect on isolated guinea pig vas deferens and aortic strip, but inhibited norepinephrine induced contraction in a dose-dependent manner probably by its antagonist action on alpha-adrenergic receptor. It had inconsistent effect on guinea pig ileum in vitro preparation. PMID- 21615058 TI - Protective effect of aqueous extract of Bombax malabaricum DC on experimental models of inflammatory bowel disease in rats and mice. AB - There is little evidence regarding role of B. malabaricum in the treatment of inflammatory bowel disease (IBD); though it is clinically employed as a constituent of a polyherbal preparation for IBD. To establish its role as a monotherapy for IBD, preliminary phytochemical screening of aqueous extract of B. malabaricum (AEBM) was undertaken. Subsequently, its protective effect in indomethacin and iodoacetamide induced colitis in rats (45, 90, 180, 270 mg/kg) and acetic acid induced colitis in mice (65, 130, 250, 500 mg/kg) was assessed. AEBM (270 mg/kg) in indomethacin and iodoacetamide induced colitis significantly reduced the ulcer score and myeloperoxidase (MPO) activity. AEBM/500 mg/kg dose/significantly reduced the ulcer score and MPO activity in acetic acid induced colitis. The extract (270 mg/kg in rats and 500 mg/kg in mice) was found to be comparable with prednisolone (10 mg/kg) and 5-aminosalicylic acid (5-ASA) (100 mg/kg) used as standard treatments. AEBM provided reduction in edema of the intestinal tissues, ulcer protection and lowering of MPO activity in a dose dependent manner. AEBM (500 mg/kg) significantly reduced colonic and serum TNF alpha level when compared with the positive control in acetic acid induced colitis model. The results suggest a protective role of AEBM in IBD. PMID- 21615059 TI - Anxiolytic effects of Equisetum arvense Linn. extracts in mice. AB - The petroleum ether (PE), chloroform (CH), ethanol (ETH) and water extracts of E. arvense stems were evaluated for anti-anxiety activity in mice using elevated plus maze model. Ketamine induced hypnosis and actophotometer was used to evaluate sedative effect with various extracts in mice. The results were compared with standard drug diazepam. The ethanolic extract of E. arvense (50 and 100 mg/kg) significantly increased the time-spent and the percentage of the open arm entries in the elevated plus-maze model which was comparable to diazepam. Ethanolic extract (100 mg/kg) prolonged the ketamine-induced total sleeping time and decreased the locomotor activity in mice. The results suggest that the ethanolic extract of E. arvense seems to possess anxiolytic effect with lower sedative activity than that of diazepam. The results could be attributed to the flavonoid content of the ethanolic extract. PMID- 21615060 TI - Effect of low-level laser therapy on experimental wounds of hard palate mucosa in mice. AB - Under general anesthesia and sterile conditions, incision wound was induced in the hard palate mucosa of adult male mice. The wounds of groups 1 and 2 were irradiated daily with He-Ne laser at 3 and 7.5 J/cm2 for 120 and 300 s, respectively, while the incision wound of group 3 not exposed served as controls. On day 3 of injury, the laser-treated wounds contained significantly lower neutrophils than the wounds in the control group. By day 7 after injury, the laser-treated wounds contained significantly more fibroblasts and at the same time contained significantly fewer macrophages. In conclusion, an acceleration of the wound healing process of experimental wounds in the hard palate mucosa of mice at low-level laser therapy with a He-Ne laser at energy densities of 3 and 7.5 J/cm2 was observed. PMID- 21615061 TI - Absence of kin discrimination in cannibalistic Anuran tadpoles of the frog Hoplobatrachus tigerinus (Daudin). AB - Kin discrimination was tested in the cannibalistic H. tigerinus tadpoles to know whether cannibalism is selectively directed towards non-kin members or it is indiscriminate. The association choice tests were conducted using satiated as well as starved subjects with the assumption that they will associate near non sibs rather than near sibs with the intention of preferentially cannibalizing them. However, test tadpoles, fed or starved showed a random association choice with sibs and non-sibs, as in the end-bias stimulus blank tests. Therefore it is suggested that cannibalistic H. tigerinus tadpoles do not discriminate sibs from non-sibs and cannibalize on both rather indiscriminately. PMID- 21615062 TI - Antimicrobial activity of protease inhibitor from leaves of Coccinia grandis (L.) Voigt. AB - Antimicrobial activity of protease inhibitor isolated from Coccinia grandis (L.) Voigt. has been reported. A 14.3 kDa protease inhibitor (PI) was isolated and purified to homogeneity by ammonium sulfate precipitation (20-85% saturation), sephadex G-75, DEAE sepharose column and trypsin-sepharose affinity chromatography from the leaves of C. grandis. The purity was checked by reverse phase high performance liquid chromatography. PI exhibited marked growth inhibitory effects on colon cell lines in a dose-dependent manner. PI was thermostable and showed antimicrobial activity without hemolytic activity. PI strongly inhibited pathogenic microbial strains, including Staphylococcus aureus, Klebsiella pneumoniae, Proteus vulgaris, Eschershia coli, Bacillus subtilis and pathogenic fungus Candida albicans, Mucor indicus, Penicillium notatum, Aspergillus flavus and Cryptococcus neoformans. Examination by bright field microscopy showed inhibition of mycelial growth and sporulation. Morphologically, PI treated fungus showed a significant shrinkage of hyphal tips. Reduced PI completely lost its activity indicating that disulfide bridge is essential for its protease inhibitory and antifungal activity. Results reported in this study suggested that PI may be an excellent candidate for development of novel oral or other anti-infective agents. PMID- 21615064 TI - Standing on the shoulders of giants. PMID- 21615063 TI - Gas-chromatography and electroantennogram analysis of saturated hydrocarbons of cruciferous host plants and host larval body extracts of Plutella xylostella for behavioural manipulation of Cotesia plutellae. AB - Saturated hydrocarbons (SHC) of five cruciferous host plants viz., cabbage, cauliflower, broccoli, knol khol and Brussels sprout and the larvae of diamondback moth (DBM), Plutella xylostella reared on these host plants were identified through gas-chromatography. The hydrocarbon profile of host plants and larval body extract of DBM reared on respective host plants revealed a wide variation in quantity as well as quality. Long chain hydrocarbons C26-C30 were detected in all the extracts. In electroantennogram (EAG) studies, SHCs at 10(-3) g dose elicited differential EAG response in the antennal receptors of gravid Cotesia plutellae females. Tricosane (C23) and hexacosane (C26) elicited 10-fold increased EAG response compared to control stimulus. Long chain hydrocarbons C27, C28 and C29 elicited, 6-7 fold increased responses. The sensitivity of antenna was 4-5 folds for C25, C14, C24, C15 and C30, while the short chain hydrocarbons elicited 2-3 fold increased EAG responses. Dual choice flight orientation experiments in a wind tunnel revealed that the gravid C. plutellae females preferred the odour of C16, C26, C29, C15, C21, C23, C30, C27, C24 and C22 as 60 70% females oriented and landed on SHC treated substrate compared to control odour, while the odour of eicosane (C20), pentacosane (C25) and octacosane (C28) were not preferred by the females. PMID- 21615065 TI - In anticipation of the germ theory of disease. Middleton Goldsmith and the history of bromine. PMID- 21615066 TI - Oswald Avery and the pneumococcus. PMID- 21615067 TI - Community-acquired pneumonia. The tyranny of a term. PMID- 21615068 TI - Defeat, poised in stone. Anatomical dissection and the indignity of Smugglerius. PMID- 21615069 TI - The poison in the cup. PMID- 21615070 TI - A modern epidemic in a historic city. Tackling diabetes in Old Delhi. PMID- 21615071 TI - That which we carry with us. PMID- 21615072 TI - Will the new generation of physicians promote health care reform? PMID- 21615073 TI - Re "Cost of a life". PMID- 21615074 TI - Nuclear magnetic resonance spectroscopy and chemometrics to identify pine nuts that cause taste disturbance. AB - Nontargeted 400 MHz (13)C and (1)H nuclear magnetic resonance (NMR) spectroscopy was used in the context of food surveillance to reveal Pinus species whose nuts cause taste disturbance following their consumption, the so-called pine nut syndrome (PNS). Using principal component analysis, three groups of pine nuts were distinguished. PNS-causing products were found in only one of the groups, which however also included some normal products. Sensory analysis was still required to confirm PNS, but NMR allowed the sorting of 53% of 57 samples, which belong to the two groups not containing PNS species. Furthermore, soft independent modeling of class analogy was able to classify the samples between the three groups. NMR spectroscopy was judged as suitable for the screening of pine nuts for PNS. This process may be advantageous as a means of importation control that will allow the identification of samples suitable for direct clearance and those that require further sensory analysis. PMID- 21615075 TI - Selective detection of crystalline cellulose in plant cell walls with sum frequency-generation (SFG) vibration spectroscopy. AB - The selective detection of crystalline cellulose in biomass was demonstrated with sum-frequency-generation (SFG) vibration spectroscopy. SFG is a second-order nonlinear optical response from a system where the optical centrosymmetry is broken. In secondary plant cell walls that contain mostly cellulose, hemicellulose, and lignin with varying concentrations, only certain vibration modes in the crystalline cellulose structure can meet the noninversion symmetry requirements. Thus, SFG can be used to detect and analyze crystalline cellulose selectively in lignocellulosic biomass without extraction of noncellulosic species from biomass or deconvolution of amorphous spectra. The selective detection of crystalline cellulose in lignocellulosic biomass is not readily achievable with other techniques such as XRD, solid-state NMR, IR, and Raman analyses. Therefore, the SFG analysis presents a unique opportunity to reveal the cellulose crystalline structure in lignocellulosic biomass. PMID- 21615076 TI - Mining for bioactive scaffolds with scaffold networks: improved compound set enrichment from primary screening data. AB - Identification of meaningful chemical patterns in the increasing amounts of high throughput-generated bioactivity data available today is an increasingly important challenge for successful drug discovery. Herein, we present the scaffold network as a novel approach for mapping and navigation of chemical and biological space. A scaffold network represents the chemical space of a library of molecules consisting of all molecular scaffolds and smaller "parent" scaffolds generated therefrom by the pruning of rings, effectively leading to a network of common scaffold substructure relationships. This algorithm provides an extension of the scaffold tree algorithm that, instead of a network, generates a tree relationship between a heuristically rule-based selected subset of parent scaffolds. The approach was evaluated for the identification of statistically significantly active scaffolds from primary screening data for which the scaffold tree approach has already been shown to be successful. Because of the exhaustive enumeration of smaller scaffolds and the full enumeration of relationships between them, about twice as many statistically significantly active scaffolds were identified compared to the scaffold-tree-based approach. We suggest visualizing scaffold networks as islands of active scaffolds. PMID- 21615077 TI - Mutational effects on transglycosylating activity of family 18 chitinases and construction of a hypertransglycosylating mutant. AB - Enzymatic features that determine transglycosylating activity have been investigated through site-directed mutagenesis studies on two family 18 chitinases, ChiA and ChiB from Serratia marcescens, with inherently little transglycosylation activity. The activity was monitored for the natural substrate (GlcNAc)(4) using mass spectrometry and HPLC. Mutation of the middle Asp in the diagnostic DxDxE motif, which interacts with the catalytic Glu during the catalytic cycle, yielded the strongly transglycosylating mutants ChiA-D313N and ChiB-D142N, respectively. Mutation of the same Asp(313/142) to Ala or the mutation of Asp(311/140) to either Asn or Ala had no or much smaller effects on transglycosylating activity. Mutation of Phe(396) in the +2 subsite of ChiA-D313N to Trp led to a severalfold increase in transglycosylation rate while replacement of aromatic residues with Ala in the aglycon (sugar acceptor-binding) subsites of ChiA-D313N and ChiB-D142N led to a clear reduction in transglycosylating activity. Taken together, these results show that the transglycosylation properties of family 18 chitinases may be manipulated by mutations that affect the configuration of the catalytic machinery and the affinity for sugar acceptors. The hypertransglycosylating mutant ChiA-D313N-F396W may find applications for synthetic purposes. PMID- 21615078 TI - Structure-based design of novel boronic acid-based inhibitors of autotaxin. AB - Autotaxin (ATX) is a secreted phosphodiesterase that hydrolyzes the abundant phospholipid lysophosphatidylcholine (LPC) to produce lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in inflammation, fibrosis, and tumor progression, rendering ATX an attractive drug target. We recently described a boronic acid-based inhibitor of ATX, named HA155 (1). Here, we report the design of new inhibitors based on the crystal structure of ATX in complex with inhibitor 1. Furthermore, we describe the syntheses and activities of these new inhibitors, whose potencies can be explained by structural data. To understand the difference in activity between two different isomers with nanomolar potencies, we performed molecular docking experiments. Intriguingly, molecular docking suggested a remarkable binding pose for one of the isomers, which differs from the original binding pose of inhibitor 1 for ATX, opening further options for inhibitor design. PMID- 21615079 TI - Exploring RNA structural codes with SHAPE chemistry. AB - RNA is the central conduit for gene expression. This role depends on an ability to encode information at two levels: in its linear sequence and in the complex structures RNA can form by folding back on itself. Understanding the global structure-function interrelationships mediated by RNA remains a great challenge in molecular and structural biology. In this Account, we discuss evolving work in our laboratory focused on creating facile, generic, quantitative, accurate, and highly informative approaches for understanding RNA structure in biologically important environments. The core innovation derives from our discovery that the nucleophilic reactivity of the ribose 2'-hydroxyl in RNA is gated by local nucleotide flexibility. The 2'-hydroxyl is reactive at conformationally flexible positions but is unreactive at nucleotides constrained by base pairing. Sites of modification in RNA can be detected efficiently either using primer extension or by protection from exoribonucleolytic degradation. This technology is now called SHAPE, for selective 2'-hydroxyl acylation analyzed by primer extension (or protection from exoribonuclease). SHAPE reactivities are largely independent of nucleotide identity but correlate closely with model-free measurements of molecular order. The simple SHAPE reaction is thus a robust, nucleotide resolution, biophysical measurement of RNA structure. SHAPE can be used to provide an experimental correction to RNA folding algorithms and, in favorable cases, yield kilobase-scale secondary structure predictions with high accuracies. SHAPE chemistry is based on very simple reactive carbonyl centers that can be varied to yield slow- and fast-reacting reagents. Differential SHAPE reactivities can be used to detect specific RNA positions with slow local nucleotide dynamics. These positions, which are often in the C2'-endo conformation, have the potential to function as molecular timers that regulate RNA folding and function. In addition, fast-reacting SHAPE reagents can be used to visualize RNA structural biogenesis and RNA-protein assembly reactions in one second snapshots in very straightforward experiments. The application of SHAPE to challenging problems in biology has revealed surprises in well-studied systems. New regions have been identified that are likely to have critical functional roles on the basis of their high levels of RNA structure. For example, SHAPE analysis of large RNAs, such as authentic viral RNA genomes, suggests that RNA structure organizes regulatory motifs and regulates splicing, protein folding, genome recombination, and ribonucleoprotein assembly. SHAPE has also revealed limitations to the hierarchical model for RNA folding. Continued development and application of SHAPE technologies will advance our understanding of the many ways in which the genetic code is expressed through the underlying structure of RNA. PMID- 21615080 TI - Impregnated ruthenium on magnetite as a recyclable catalyst for the N-alkylation of amines, sulfonamides, sulfinamides, and nitroarenes using alcohols as electrophiles by a hydrogen autotransfer process. AB - Various impregnated metallic salts on magnetite have been prepared, including cobalt, nickel, copper, ruthenium, and palladium salts, as well as a bimetallic palladium-copper derivative. Impregnated ruthenium catalyst is a versatile, inexpensive, and simple system for the selective N-monoalkylation of amino derivatives with poor nucleophilic character, such as aromatic and heteroaromatic amines, sulfonamides, sulfinamides, and nitroarenes, using in all cases alcohols as the initial source of the electrophile, through a hydrogen autotransfer process. In the case of sulfinamides, this is the first time that these amino compounds have been alkylated following this strategy, allowing the use of chiral sulfinamides and secondary alcohols to give the alkylated compound with a diastereomeric ratio of 92:8. In these cases, after alkylation, a simple acid deprotection gave the expected primary amines in good yields. The ruthenium catalyst is quite sensitive, and small modifications of the reaction medium can change the final product. The alkylation of amines using potassium hydroxide renders the N-monoalkylated amines, and the same protocol using sodium hydroxide yields the related imines. The catalyst can be easily removed by a simple magnet and can be reused up to ten times, showing the same activity. PMID- 21615081 TI - Particle size distribution and polycyclic aromatic hydrocarbons emissions from agricultural crop residue burning. AB - Laboratory measurements were conducted to determine particle size distribution and polycyclic aromatic hydrocarbons (PAHs) emissions from the burning of rice, wheat, and corn straws, three major agricultural crop residues in China. Particle size distributions were determined by a wide-range particle spectrometer (WPS). PAHs in both the particulate and gaseous phases were simultaneously collected and analyzed by GC-MS. Particle number size distributions showed a prominent accumulation mode with peaks at 0.10, 0.15, and 0.15 MUm for rice, wheat, and corn-burned aerosols, respectively. PAHs emission factors of rice, wheat, and corn straws were 5.26, 1.37, and 1.74 mg kg(-1), respectively. It was suggested that combustion with higher efficiency was characterized by smaller particle size and lower PAHs emission factors. The total PAHs emissions from the burning of three agricultural crop residues in China were estimated to be 1.09 Gg for the year 2004. PMID- 21615082 TI - Historically and currently used Dechloranes in the sediments of the Great Lakes. AB - Dechlorane (mirex), Dechlorane Plus (DP), Dechlorane 602 (Dec602), Dechlorane 603 (Dec603), Dechlorane 604 (Dec604), and Chlordecone (Kepone) were analyzed in 16 sediment cores collected in 2007 from the Great Lakes of North America. Results show that Lake Ontario sediments have accumulated mirex, DP, Dec602 and Dec604 in amounts 1 to 2 orders of magnitude higher than other Great Lakes. The chemical inventory decreases log-linearly with increasing latitude (N) and longitude (W) of the sampling locations, but Lake Ontario sites are outliers in the regression against latitude. The regression analyses suggest differences among the analytes with regard to source impact and long-range transport behavior. Temporal trends of input differ among lakes. Most sites in Lake Superior are still receiving increasing fluxes of DP and Dec602, while these have been declining in Lake Ontario from the peak around 1990. The relative abundance of the two DP isomers, represented by f(syn), increases with increasing distance from the potential discharge source in Niagara Falls, NY, suggesting the anti-DP isomer is more vulnerable to degradation during long-range atmospheric transport. Kepone was not detected in the sediments of Lakes Ontario, Erie, and Michigan. PMID- 21615083 TI - Chemical and physical factors in design of antibiofouling polymer coatings. AB - Because most "low fouling" polymers resisting bacterial attachment are hydrophilic, they are usually also significantly swollen. Swelling leads to purely physical dilution of interaction and weakens attachment; however, these nonspecific contributions are usually not separated from the specific effect of polymer chemistry. Taking advantage of the fact that chemistry and swelling of hydrogels may be independently varied through the fraction of a cross-linker, the roles of chemistry and physical dilution (swelling) in bacterial attachment are analyzed for selected hydrogels. Using as a quantitative indicator the rate of bacterial deposition in a parallel plate setup under defined flow conditions, the observed correlation of deposition rate with swelling provides a straightforward comparison of gels with different chemistries that can factor out the effect of swelling. In particular, it is found that chemistry appears to contribute similarly to bacterial deposition on hydrogels prepared from acrylamide and a zwitterioninic monomer 2-(methacryloyloxy)ethyl) dimethyl-(3-sulfopropyl) ammonium hydroxide so that the observed differences may be related to swelling only. In contrast, these gels were inferior to PEG-based hydrogels, even when swelling of the latter was lower, indicating a greater contribution of PEG chemistry to reduced bacterial deposition. This demonstrates that swelling must be accounted for when comparing different biofouling-resistant materials. Chemical and physical principles may be combined in hydrogel coatings to develop efficient antibiofouling surfaces. PMID- 21615084 TI - Simultaneous synthesis of temperature-tunable peptide and gold nanoparticle hybrid spheres. AB - Hybrid spheres containing peptides and gold nanoparticles have been simultaneously synthesized in water using AG4 (NPSSLFRYLPSD) peptides that acted as a reducing agent to guide the nucleation and growth of gold nanoparticles and a precursor to form sphere-like structure by self-assembly where the size of hybrid spheres is precisely controlled by adjusting the operating temperature. The self-assembled peptide spheres remain stable even after selective removal of the gold nanoparticles by iodide etching. The amino acids containing the aromatic functional group in the peptide sequence significantly affect the construction of sphere structures. The surface of gold nanoparticles containing hybrid spheres has been functionalized using the thiol group linked to biomolecules. The ability to synthesize nanoparticle and self-assembled peptide structures with controlled size and composition in an environmental benign way will allow us to fabricate a new class of multifunctional organic-inorganic hybrid superstructures for various biomedical and electronic applications. PMID- 21615085 TI - The role of hole localization in sacrificial hydrogen production by semiconductor metal heterostructured nanocrystals. AB - The effect of hole localization on photocatalytic activity of Pt-tipped semiconductor nanocrystals is investigated. By tuning the energy balance at the semiconductor-ligand interface, we demonstrate that hydrogen production on Pt sites is efficient only when electron-donating molecules are used for stabilizing semiconductor surfaces. These surfactants play an important role in enabling an efficient and stable reduction of water by heterostructured nanocrystals as they fill vacancies in the valence band of the semiconductor domain, preventing its degradation. In particular, we show that the energy of oxidizing holes can be efficiently transferred to a ligand moiety, leaving the semiconductor domain intact. This allows reusing the inorganic portion of the "degraded" nanocrystal ligand system simply by recharging these nanoparticles with fresh ligands. PMID- 21615087 TI - The nature of in-plane skeleton Raman modes of P3HT and their correlation to the degree of molecular order in P3HT:PCBM blend thin films. AB - The nature of main in-plane skeleton Raman modes (C=C and C-C stretch) of poly(3 hexylthiophene) (P3HT) in pristine and its blend thin films with [6,6]-phenyl C(61)-butyric acid methyl ester (PCBM) is studied by resonant and nonresonant Raman spectroscopy and Raman simulations. Under resonant conditions, the ordered phase of P3HT with respect to its disordered phase is identified by (a) a large shift in the C=C mode peak position to lower wavenumber (~21 cm(-1) shift), (b) a narrower fwhm of the C=C mode (~9 cm(-1) narrower), (c) a larger intensity of the C-C mode relative to the C=C mode (~56% larger), and (d) a very small Raman dispersion (~5 cm(-1)) of the C=C mode. The behavior of the C=C and C-C modes of the ordered and disordered phases of P3HT can be explained in terms of different molecular conformations. The C=C mode of P3HT in P3HT:PCBM blend films can be reproduced by simple superposition of the two peaks observed in different phases of P3HT (ordered and disordered). We quantify the molecular order of P3HT after blending with PCBM and the subsequent thermal annealing to be 42 +/- 5% and 94 +/ 5% in terms of the fraction of ordered P3HT phase, respectively. The increased molecular order of P3HT in blends upon annealing correlates well with enhanced device performance (J(SC), -4.79 to -8.72 mA/cm(2) and PCE, 1.07% to 3.39%). We demonstrate that Raman spectroscopy (particularly under resonant conditions) is a simple and powerful technique to study molecular order of conjugated polymers and their blend films. PMID- 21615086 TI - A new way to understand quaternary structure changes of hemoglobin upon ligand binding on the basis of UV-resonance Raman evaluation of intersubunit interactions. AB - The single residue vibrational spectra of tryptophan (Trp) and tyrosine (Tyr) residues in human adult hemoglobin (HbA), which play important roles in cooperative oxygen binding, were determined for the deoxy and CO-bound forms by applying UV resonance Raman spectroscopy to various variant Hbs. It was found that Trpbeta37, Tyralpha42, Tyralpha140, and Tyrbeta145 at the alpha(1)-beta(2) subunit interface underwent transitions between two contact states (named as T and R) upon ligand binding, while Trpalpha14, Trpbeta15, and Tyrbeta35 displayed little changes. The corresponding spectral changes were identified only for the alpha(2)beta(2) tetramer, but not the isolated alpha and beta chains in the oligomeric forms, and therefore were exclusively attributed to a quaternary structure change. Ligand binding as well as allosteric effectors and pH altered only the number of the T-contacted Tyr and Trp residues without varying the two contact states themselves. A new method to semiquantitatively evaluate the amount of T-contacted Tyr and Trp residues in a given liganded form is here proposed, and with it a quaternary structure was determined for various symmetrically half liganded forms obtained with ligand-hybrid, metal-hybrid, and valency-hybrid Hbs. It was found that ligand binding to the alpha or beta subunits yielded different subunit contacts and that the contact changes of the Trp and Tyr residues were not always concerted. The contact changes at the alpha(1)-beta(2) (alpha(2) beta(1)) interface are correlated with the proximal strain exerted on the Fe His(F8) bond, which is noted to be much larger in the alpha than beta subunits in the alpha(2)beta(2) tetramer. PMID- 21615088 TI - Assembly-based titration for the determination of monodisperse plasmonic nanoparticle concentrations using DNA. AB - We present a stoichiometric titration method to determine the concentration of nanoparticles of various materials, sizes, and shapes. We have discovered that the optical response associated with the assembly formation is maximized when two types of nanoparticles attractively interact at a specific ratio, regardless of the particle type. Based on the reversible hybridization properties of two cDNA sequences used to assemble the particles, the assembly-based titration of various nanoparticles of unknown concentrations is visually demonstrated with high accuracy and reliability, which is analogous to the classic molecular titration method. PMID- 21615089 TI - Color-selective photocurrent enhancement in coupled J-aggregate/nanowires formed in solution. AB - J-aggregates are ordered clusters of coherently coupled molecular dyes, (1) and they have been used as light sensitizers in film photography due to their intense absorptions. Hybrid structures containing J-aggregates may also have applications in devices that require spectral specificity, such as color imaging or optical signaling. (2) However the use of J-aggregates in optoelectronic devices has posed a long-standing challenge (3, 4) due to the difficulty of controlling aggregate formation and the low charge carrier mobility of many J-aggregates in solid state. In this paper, we demonstrate a modular method to assemble three different cyanine J-aggregates onto CdSe nanowires, resulting in a photodetector that is color-sensitized in three specific, narrow absorption bands. Both the J aggregate and nanowire device components are fabricated from solution and the sensitizing wavelength is switched from blue to red to green, using only solution phase exchange of the J-aggregates on the same underlying device. PMID- 21615090 TI - Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis. AB - Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole, and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on beta tubulin, provided a theoretical understanding of these successful experimental findings. PMID- 21615091 TI - Asymmetric total synthesis of the antimalarial drug (+)-mefloquine hydrochloride via chiral N-amino cyclic carbamate hydrazones. AB - Mefloquine hydrochloride is an important antimalarial drug. It is currently manufactured and administered in racemic form; however there are indications regarding the biological activity of the two enantiomers that suggest the superiority of the (+)-form. The asymmetric total synthesis of the (+)-enantiomer of mefloquine hydrochloride is described. The key asymmetric transformation utilized is a novel asymmetric Darzens reaction of a chiral alpha-chloro-N-amino cyclic carbamate hydrazone derived from an N-amino cyclic carbamate (ACC) chiral auxiliary. PMID- 21615092 TI - Structure and torsional properties of oxalyl chloride fluoride in the gas phase: an electron-diffraction investigation. AB - The structure and torsional properties of oxalyl chloride fluoride in the gas phase have been measured by electron diffraction at temperatures of 22, 81, 158, and 310 degrees C. The molecule may be regarded as a hybrid of oxalyl chloride and oxalyl fluoride. Since the former exists as a more stable periplanar anti form (phi = 180 degrees ) in equilibrium with a less stable gauche form (phi ? 60 degrees ) and the latter as an equilibrium between two periplanar forms, anti and syn, the second form of oxalyl chloride fluoride is an interesting question. It was found to be gauche. The system was modeled as two rotational conformers related by a potential of the form 2V = V(1)(1 + cos phi) - V(2)(1 - cos 2phi) + V(3)(1 + cos 3phi). The anti/gauche bond distances and bond angles (r(g)/Angstroms, ?(alpha)/degrees) with estimated 2sigma uncertainties at 22 degrees C are = 1.183(2)/1.182(2), Deltar(C?O) = 0.003(6)/0.002(6) (assumed from theory), r(C-F) = 1.329(3)/1.335(3), r(C-Cl) = 1.738(2)/1.753(2), ?(C-C-Cl) = 112.0(3)/111.9(3), ?(C-C?O3) = 123.0(4)/123.2(4), ?(O?C-Cl) = 125.0(2)/1.249(2), ?(O?C-F) = 123.0(3)/125.1(3), and ?(Cl-C-C-F) = 180.0/59.8. The variation of composition with temperature afforded a determination of the standard enthalpy and entropy of the reaction anti -> gauche. The results are DeltaH degrees = 2.5(12) kcal/mol and DeltaS degrees = -6.5(33) cal/(mol.K). The structures and equilibria are discussed. PMID- 21615094 TI - Superconcentrated hydrochloric acid. AB - We report the discovery of a potentially useful superconcentrated HCl at ambient temperature and pressure by using a simple surfactant-based reversed micelle system. Surprisingly, the molar ratios of H(+) to H(2)O (denoted as n(H+)/n(H2O)) in superconcentrated HCl can be larger than 5, while the maximum achievable n(H+)/n(H2O) value for conventional saturated HCl aqueous solution (37 wt %) is only about 0.28. Furthermore, both NMR and FT-IR results indicate that a significant amount of HCl remains in the molecular form rather than being ionized into H(+) and Cl(-). The superconcentrated HCl may promote some organic reactions that are not feasible by using conventional 37 wt % HCl solution. For example, addition reaction between C?C and HCl occurs in superconcentrated HCl solution without using catalysts. PMID- 21615095 TI - Probing specific molecular processes and intermediates by time-resolved Fourier transform infrared spectroscopy: application to the bacteriorhodopsin photocycle. AB - We present a general approach for probing the kinetics of specific molecular processes in proteins by time-resolved Fourier transform infrared (IR) spectroscopy. Using bacteriorhodopsin (bR) as a model we demonstrate that by appropriately monitoring some selected IR bands it is possible obtaining the kinetics of the most important events occurring in the photocycle, namely changes in the chromophore and the protein backbone conformation, and changes in the protonation state of the key residues implicated in the proton transfers. Besides confirming widely accepted views of the bR photocycle, our analysis also sheds light into some disputed issues: the degree of retinal torsion in the L intermediate to respect the ground state; the possibility of a proton transfer from Asp85 to Asp212; the relationship between the protonation/deprotonation of Asp85 and the proton release complex; and the timing of the protein backbone dynamics. By providing a direct way to estimate the kinetics of photocycle intermediates the present approach opens new prospects for a robust quantitative kinetic analysis of the bR photocycle, which could also benefit the study of other proteins involved in photosynthesis, in phototaxis, or in respiratory chains. PMID- 21615096 TI - Recoupled-pair bonding and 4-electron 3-center bonding units. AB - Consideration is given to recoupled-pair bonding and the origin of electronic hypervalence for formulations of the bonding for symmetric 4-electron 3-center ((4e,3c)) bonding units with one overlapping atomic orbital per atomic center. Molecular orbital and valence bond theory for symmetric (4e,3c) bonding units is redescribed and applied to aspects of the bonding for SF(6) and CLi(6). The results of minimal basis set calculations for CLi(6) provide support for a hypothesis that two Li-C-Li (3e,3c) bonding units rather than two (4e,3c) bonding units are preferred for this molecule. Brief comments are also made on the use of [Formula: see text] and [Formula: see text] as valence bond structures for the three electron bond. PMID- 21615093 TI - Elucidation of the protonation states of the catalytic residues in mtKasA: implications for inhibitor design. AB - KasA (beta-ketoacyl ACP synthase I) is involved in the biosynthetic pathway of mycolic acids, an essential component of the cell wall in Mycobacterium tuberculosis. It was shown that KasA is essential for the survival of the pathogen and thus could serve as a new drug target for the treatment of tuberculosis. The active site of KasA was previously characterized by X-ray crystallography. However, questions regarding the protonation state of specific amino acids, the orientation of the histidine groups within the active site, and additional conformers being accessible at ambient temperatures remain open and have to be addressed prior to the design of new inhibitors. We investigate the active site of KasA in this work by means of structural motifs and relative energies. Molecular dynamics (MD) simulations, free energy perturbation computations, and calculations employing the hybrid quantum mechanics/molecular mechanics (QM/MM) method made it possible to determine the protonation status and reveal important details about the catalytic mechanism of KasA. Additionally, we can rationalize the molecular basis for the acyl-transfer activity in the H311A mutant. Our data strongly suggest that inhibitors should be able to inhibit different protonation states because the enzyme can switch easily between a zwitterionic and neutral state. PMID- 21615097 TI - Effect of interfacial proteins on osteoblast-like cell adhesion to hydroxyapatite nanocrystals. AB - A quartz crystal microbalance with dissipation (QCM-D) technique was employed to detecting the protein adsorption and subsequent osteoblast-like cell adhesion to hydroxyapatite (HAp) nanocrystals. The interfacial phenomena with the preadsorption of three proteins (albumin (BSA), fibronectin (Fn), and collagen (Col)), the subsequent adsorption of fetal bovine serum (FBS), and the adhesion of the cells were investigated. The QCM-D measured the frequency shift (Deltaf) and dissipation energy shift (DeltaD), and the viscoelastic properties of the adlayers were evaluated using DeltaD-Deltaf plot and Voigt-based viscoelastic model. The Col adsorption significantly showed higher Deltaf, DeltaD, elasticity, and viscosity values as compared to the BSA and Fn adsorption, and the subsequent FBS adsorption depended on the preadsorbed proteins. The DeltaD-Deltaf plot of the cell adhesion also showed a different behavior depending on the surfaces, and the Fn- and Col-modified surfaces showed the rapid mass and DeltaD changes by forming the viscous interfacial layers with cell adhesion, indicating that the processes were affected by the cellular reaction through the extracellular matrix (ECM) proteins. The confocal laser scanning microscope images of adherent cells showed a different morphology and pseudopod on the surfaces. The cells adhered to the surfaces modified with the Fn and Col had significantly uniaxially expanded shapes and fibrous pseudopods, and those modified with the BSA had a round shape. Therefore, the different cell-protein interactions would cause the arrangement of the ECM and the cytoskeleton changes at the interfaces, and these phenomena were successfully detected by the QCM-D and Voigt-based model. PMID- 21615098 TI - Directed oxidative cyclizations to C2- or C4-positions of indole: efficient construction of the bicyclo[4.3.1]decane core of welwitindolinones. AB - Regiocontrolled oxidative cyclizations of 3-substituted indoles are described herein. Specifically, it is shown that the installation of a chloride at C2 alters the inherent propensity for cyclization at the 2-position of indole so as to favor the 4-position, enabling the construction of the unique framework found in most welwitindolinone alkaloids. The chloride functions here as more than a blocking group, as it also provides ready access to the corresponding oxindole. PMID- 21615100 TI - Rhodium-catalyzed synthesis of germoles via the activation of carbon-germanium bonds. AB - The rhodium-catalyzed reaction of 2-germylphenylboronic esters with alkynes in the presence of a rhodium(I) catalyst is established as a modular method for the synthesis of an array of benzogermole derivatives. The reaction proceeds through the activation of C(sp(3))-Ge bonds. The mechanism of this new bond activation process is discussed based on the activation aptitude of alkyl and aryl substituents on germanium. PMID- 21615099 TI - Acetoxy Meldrum's acid: a versatile acyl anion equivalent in the Pd-catalyzed asymmetric allylic alkylation. AB - Acetoxy Meldrum's acid can serve as a versatile acyl anion equivalent in the Pd catalyzed asymmetric allylic alkylation. The reaction of this nucleophile with various meso and racemic electrophiles afforded alkylated products in high yields and enantiopurities. These enantioenriched products are versatile intermediates that can be further functionalized using nitrogen- and oxygen-centered nucleophiles, affording versatile scaffolds for the synthesis of nucleoside analogues. These scaffolds were used to complete formal syntheses of the anti-HIV drugs carbovir, abacavir, and the antibiotic aristeromycin. PMID- 21615101 TI - Complete facial selectivity in the Diels-Alder reaction of a 5-amino-5 carboxycyclopentadiene derivative. AB - 5-tert-Butoxycarbonylamino-5-carbethoxy-2-tert-butyldimethylsilyloxy cyclopentadiene undergoes a Diels-Alder reaction exclusively from the face syn to the nitrogen functionality. Complete reversal of facial bias may be achieved, but at the cost of diminished reactivity, through steric shielding of the N-syn face. PMID- 21615102 TI - Photoelectron imaging and theoretical studies of silver monohalides AgX- (X = Cl, Br, I) and AuCl-. AB - Photodetachment of AgX(-) (X = Cl, Br, I) and AuCl(-) is studied by a photoelectron velocity map imaging technique and theoretical calculations. Photoelectron spectra (PES) and photoelectron angular distributions (PADs) were obtained. The vibrationally resolved spectra provided approximately equal electron affinities (EAs) for AgX: 1.593(22) eV for AgCl, 1.623(21) eV for AgBr, and 1.603(22) eV for AgI, respectively. Franck-Condon simulations of these spectra gave the equilibrium bond lengths and vibrational frequencies of the title anions. Relativistic density functional theory (DFT) calculations using BLYP, PW91, PBE, and BP86 functionals have been performed to predict the EAs of the AgX (X = Cl, Br, I) molecules. The computed EAs at the BP86 level of theory are in good agreement with the experimental values. Energy partitioning analyses (EPA) at the BP86(ZORA)/QZ4P level of theory of both anions and their neutrals were reported. PMID- 21615103 TI - Oxime derivatives as alpha-electrophiles. from alpha-tetralone oximes to tetracyclic frameworks. AB - When subjected to the conditions of a Semmler-Wolff/Schroeter aromatization, the oximes of 4-benzyl-substituted tetralones undergo an electrophilic aromatic substitution reaction to form tetracyclic frameworks. PMID- 21615104 TI - Resonance Raman spectroscopic and theoretical investigation of the excited state proton transfer reaction dynamics of 2-thiopyridone. AB - The resonance Raman spectra were obtained for both 2-thiopyridone (2TP) and its proton-transfer tautomer 2-mercaptopyridine (2MP) in water solution. Density functional theory (DFT) calculations were carried out to help elucidate their ultraviolet electronic transitions and vibrational assignments of the resonance Raman spectra associated with their B-band absorptions. The nanosecond time resolved resonance Raman spectroscopic experiment was carried out to further confirm the assignment that the transient species was the ground state 2MP. The different short-time structural dynamics were examined for both 2TP and 2MP in terms of their resonance Raman intensity patterns. The transition barriers between 2TP and 2MP for S(0), T(1), and S(1) states are determined by using (U)B3LYP-TD and CASSCF level of theory computations, respectively. The excited state proton transfer (ESPT) reaction mechanism is proposed and briefly discussed. PMID- 21615105 TI - n-Channel semiconductor materials design for organic complementary circuits. AB - Organic semiconductors have unique properties compared to traditional inorganic materials such as amorphous or crystalline silicon. Some important advantages include their adaptability to low-temperature processing on flexible substrates, low cost, amenability to high-speed fabrication, and tunable electronic properties. These features are essential for a variety of next-generation electronic products, including low-power flexible displays, inexpensive radio frequency identification (RFID) tags, and printable sensors, among many other applications. Accordingly, the preparation of new materials based on pi conjugated organic molecules or polymers has been a central scientific and technological research focus over the past decade. Currently, p-channel (hole transporting) materials are the leading class of organic semiconductors. In contrast, high-performance n-channel (electron-transporting) semiconductors are relatively rare, but they are of great significance for the development of plastic electronic devices such as organic field-effect transistors (OFETs). In this Account, we highlight the advances our team has made toward realizing moderately and highly electron-deficient n-channel oligomers and polymers based on oligothiophene, arylenediimide, and (bis)indenofluorene skeletons. We have synthesized and characterized a "library" of structurally related semiconductors, and we have investigated detailed structure-property relationships through optical, electrochemical, thermal, microstructural (both single-crystal and thin film), and electrical measurements. Our results reveal highly informative correlations between structural parameters at various length scales and charge transport properties. We first discuss oligothiophenes functionalized with perfluoroalkyl and perfluoroarene substituents, which represent the initial examples of high-performance n-channel semiconductors developed in this project. The OFET characteristics of these compounds are presented with an emphasis on structure-property relationships. We then examine the synthesis and properties of carbonyl-functionalized oligomers, which constitute second-generation n-channel oligothiophenes, in both vacuum- and solution-processed FETs. These materials have high carrier mobilities and good air stability. In parallel, exceptionally electron-deficient cyano-functionalized arylenediimide derivatives are discussed as early examples of thermodynamically air-stable, high-performance n-channel semiconductors; they exhibit record electron mobilities of up to 0.64 cm(2)/V.s. Furthermore, we provide an overview of highly soluble ladder-type macromolecular semiconductors as OFET components, which combine ambient stability with solution processibility. A high electron mobility of 0.16 cm(2)/V.s is obtained under ambient conditions for solution-processed films. Finally, examples of polymeric n channel semiconductors with electron mobilities as high as 0.85 cm(2)/V.s are discussed; these constitute an important advance toward fully printed polymeric electronic circuitry. Density functional theory (DFT) computations reveal important trends in molecular physicochemical and semiconducting properties, which, when combined with experimental data, shed new light on molecular charge transport characteristics. Our data provide the basis for a fundamental understanding of charge transport in high-performance n-channel organic semiconductors. Moreover, our results provide a road map for developing functional, complementary organic circuitry, which requires combining p- and n channel transistors. PMID- 21615106 TI - Protease-resistant peptide ligands from a knottin scaffold library. AB - Peptides within the knottin family have been shown to possess inherent stability, making them attractive scaffolds for the development of therapeutic and diagnostic agents. Given its remarkable stability to proteases, the cyclic peptide kalata B1 was employed as a scaffold to create a large knottin library displayed on the surface of E. coli. A library exceeding 10(9) variants was constructed by randomizing seven amino acids within a loop of the kalata B1 scaffold and screened using fluorescence-activated cell sorting to identify peptide ligands specific for the active site of human thrombin. Refolded thrombin binders exhibited high nanomolar affinities in solution and slow dissociation rates and were able to inhibit thrombin's enzymatic activity. Importantly, 80% of a knottin-based thrombin inhibitor remained intact after a 2 h incubation both with trypsin and with chymotrypsin, demonstrating that modifying the kalata B1 sequence did not compromise its stability properties. In addition, the knottin variant mediated 20-fold enhanced affinity for thrombin, when compared to the same seven residue binding epitope constrained by a single disulfide bond. Our results indicate that peptide libraries derived from the kalata B1 scaffold can yield high-affinity protein ligands that retain the remarkable protease resistance associated with the parent scaffold. More generally, this strategy may prove useful in the development of stable peptide ligands suitable for in vivo applications. PMID- 21615107 TI - Riboswitches: discovery of drugs that target bacterial gene-regulatory RNAs. AB - Riboswitches are messenger RNA (mRNA) domains that regulate gene function in response to the intracellular concentration of a variety of metabolites and second messengers. They control essential genes in many pathogenic bacteria, thus representing an inviting new class of biomolecular target for the development of antibiotics and chemical-biological tools. In this Account, we briefly review the discovery of riboswitches in the first years of the 21st century and their ensuing characterization over the past decade. We then discuss the progress achieved so far in using riboswitches as a focus for drug discovery, considering both the value of past serendipity and the particular challenges that confront current researchers. Five mechanisms of gene regulation have been determined for riboswitches. Most bacterial riboswitches modulate either transcription termination or translation initiation in response to ligand binding. All known examples of eukaryotic riboswitches, and some bacterial riboswitches, control gene expression by alternative splicing. The glmS riboswitch, which is widespread in Gram-positive bacteria, is a catalytic RNA activated by ligand binding: its self-cleavage destabilizes the mRNA of which it is part. Finally, one example of a trans-acting riboswitch is known. Three-dimensional structures have been determined for representatives of 13 structurally distinct riboswitch classes, providing atomic-level insight into their mechanisms of ligand recognition. While cellular and viral RNAs have attracted widespread interest as potential drug targets, riboswitches show special promise due to the diversity of small-molecule recognition strategies that are on display in their ligand-binding pockets. Moreover, riboswitches have evolved to recognize small-molecule ligands, which is unique among known structured RNA domains. Structural and biochemical advances in the study of riboswitches provide an impetus for the development of methods for the discovery of novel riboswitch activators and inhibitors. Recent rational drug design efforts focused on select riboswitch classes have yielded a small number of candidate antibiotic compounds, including one active in a mouse model of Staphylococcus aureus infection. The development of high-throughput methods suitable for riboswitch-specific drug discovery is ongoing. A fragment-based screening approach employing equilibrium dialysis that may be generically useful has demonstrated early success. Riboswitch-mediated gene regulation is widely employed by bacteria; however, only the thiamine pyrophosphate-responsive riboswitch has thus far been found in eukaryotes. Thus, riboswitches are particularly attractive as targets for antibacterials. Indeed, antimicrobials with previously unknown mechanisms have been found to function by binding riboswitches and causing aberrant gene expression. PMID- 21615108 TI - Cellular dynamics of RNA modification. AB - Five decades of research have identified more than 100 ribonucleosides that are post-transcriptionally modified. Many modified nucleosides are conserved throughout bacteria, archaea, and eukaryotes, while some are unique to each branch of life. However, the cellular and functional dynamics of RNA modification remain largely unexplored, mostly because of the lack of functional hypotheses and experimental methods for quantification and large-scale analysis. Many RNA modifications are not essential for life, which parallels the observation that many well-characterized protein and DNA modifications are not essential for life. Instead, increasing evidence indicates that RNA modifications can play regulatory roles in cells, especially in response to stress conditions. In this Account, we review some examples of RNA modification that are dynamically controlled in cells. We also discuss some recently developed methods that have enhanced the ability to study the cellular dynamics of RNA modification. We discuss four specific examples of RNA modification in detail here. We begin with 4-thio uridine (s(4)U), which can act as a cellular sensor of near-UV light. Then we consider queuosine (Q), which is a potential biomarker for malignancy. Next we examine N(6)-methyl adenine (m(6)A), which is the prevalent modification in eukaryotic messenger RNAs (mRNAs). Finally, we discuss pseudouridine (psi), which is inducible by nutrient deprivation. We then consider two recent technical advances that have stimulated the study of the cellular dynamics in modified ribonucleosides. The first is a genome-wide method that combines primer extension with a microarray. It was used to study the N(1)-methyl adenine (m(1)A) hypomodification in human transfer RNA (tRNA). The second is a quantitative mass spectrometric method used to investigate dynamic changes in a wide range of tRNA modifications under stress conditions in yeast. In addition, we discuss potential mechanisms that control dynamic regulation of RNA modifications as well as hypotheses for discovering potential RNA demodification enzymes. We conclude by highlighting the need to develop new tools and to generate additional hypotheses for how these modifications function in cells. The study of the cellular dynamics of modified RNA remains a largely open area for new development, which underscores the rich potential for important advances as researchers drive this emerging field to the next level. PMID- 21615109 TI - The classical Wigner method with an effective quantum force: application to the collinear H + H2 reaction. AB - To improve the classical Wigner (CW) model, we recently proposed the classical Wigner model with an effective quantum force (CWEQF). The results of the CWEQF model are more accurate than those of the CW model. Still the simplicity of the CW model is retained. The quantum force was obtained by defining a characteristic distance eta(0) between two Feynman paths that enter the expression for the flux flux correlation function. eta(0) was considered independent of the position along the reaction path. The CWEQF leads to a lowering of the effective potential barrier. Here we develop the method to use position dependent eta(0) values. The method is also generalized to two dimensions. Applications are carried out on one dimensional model problems and the two-dimensional H + H(2) collinear reaction. PMID- 21615110 TI - Are uncatalyzed bromate oscillators truly gas-free? AB - Gas evolution is a common byproduct of chemical oscillations but is seldom treated as anything but a complication. Its precise quantification is usually underestimated, and if not obvious enough, gaseous products are easily neglected completely. Reported herein is how evolution of gas from uncatalyzed bromate oscillators with pyrocatechol, pyrogallol, and 1,4-cyclohexanedione was measured by a high-precision batch-mode gasometric method, and the data obtained with unprecedented time resolution are presented. Even though within this completely closed arrangement of measurement no oscillations in rate of gas evolution were observed, it is verified that neither of the substrates can be considered totally free of gas production. Nevertheless, the amount of gas evolved from 1,4 cyclohexanedione was confirmed to be very small, and near negligible, if only oscillatory phase is of interest. Conversely, under identical conditions, the peak rates of gas evolution from the other substrates were reached much sooner, and even though the results in all three cases suggest some extent of suppression of gas production by oscillations, as much as 1 equiv of gas in total can be produced from the phenols, especially from pyrogallol, where the degradation was measured to be approximately twice as extensive. Greater caution is, therefore, recommended whenever the gas-free nature of these oscillators is considered. PMID- 21615111 TI - Electronic spectroscopy of molecules in superfluid helium nanodroplets: an excellent sensor for intramolecular charge redistribution. AB - Electronic spectra of molecules doped into superfluid (4)He nanodroplets reveal important details of the microsolvation in superfluid helium. The vibrational fine structure in the electronic spectra of phthalocyanine derivatives and pyrromethene dye molecules doped into superfluid helium droplets have been investigated. Together with previous studies on anthracene derivatives [J. Chem. Phys.2010, 133, 114505] and 3-hydroxyflavone [J. Chem. Phys.2009, 131, 194307], the line shapes vary between two limiting cases, namely, sharp Lorentzians and nonresolved vibrational fine structure. All different spectral signatures are initiated by the same effect, namely, the change of the electron density distribution initiated by the electronic excitation. This change can be quantified by the difference of the electrostatic moments of the molecule in the electronic ground state and the corresponding Franck-Condon point in the excited state. According to the experimental data, electronic spectroscopy suffers from drastic line broadening when accompanied by significant changes of the charge distribution, in particular, changes of the dipole moment. Vice versa, the vibrational fine structure in electronic spectra of molecules doped into helium droplets is highly sensitive to changes of the electron density distribution. PMID- 21615112 TI - Static and dynamic structural memory in polyaniline thin films. AB - Steady-state UV-visible and FTIR spectroscopies were used to characterize the electronic and structural changes that occur in polyaniline (PANI) thin films over the course of a single deprotonation and reprotonation cycle. The dedoping from the emeraldine salt (PANI-ES) to the emeraldine base (PANI-EB) form was achieved by treatment with a weak base (ammonia gas), and the PANI-ES was recovered by exposure to humid air and then dry air. The spectroscopic changes were classified into two general categories: those in which the recovered sample features were intermediate to the initial PANI-ES and the deprotonated PANI-EB and those in which the recovered sample features changed monotonically from the starting PANI-ES toward a unique observable. Two-dimensional IR vibrational echo spectroscopy (2D-IR VES) was then used to demonstrate that ultrafast structural dynamics on the time scales of hundreds of femtoseconds to a few picoseconds could also be organized into these two categories. In contrast, it was found that the slower dynamics on the tens of ps time scale appear unperturbed by the dramatic structural changes of the dedoping-redoping cycle. We discuss the relevance of these dynamics to charge mobilities in the initial and final PANI-ES states and compare their behavior to the film electrical resistances over the course of the protonation cycle. We show that specific structural dynamics are correlated with changes in the film conductivities and that PANI films have a memory of not only the static molecular structures of the as-cast materials but also some of the dynamics that are inherent to those morphologies. PMID- 21615113 TI - Preparation and characterization of conjugated polymers made by postpolymerization reactions of alternating polyketones. AB - Conjugated polymers possessing a poly(2,5-dimethylene-2,5-dihydrofuran) backbone were prepared through postpolymerization reaction of styrenic polyketones with bromine in one-pot reactions. The modification is proposed to proceed via condensation of two repeating units to form a fully characterized polymer with a poly(2,5-dimethylenetetrahydrofuran) backbone. Subsequent bromination and elimination of HBr yield a polymer with a fully conjugated carbon backbone. The new conjugated polymers were characterized by NMR, IR, and UV-vis spectroscopies and by CV. These polymers have strong absorption in the visible region, with the absorption peaks shifted to the NIR region upon doping with acids. The ease of the synthesis of the starting polyketone and of the modifications allows large scale preparation of those conjugated polymers. PMID- 21615114 TI - Proton-induced dynamic equilibrium between cyclometalated ruthenium rNHC (remote N-heterocyclic carbene) tautomers with an NAD+/NADH function. AB - Cyclometalated ruthenium(II) complexes having acridine moieties have been synthesized and characterized by spectroscopic methods. Protonation of the acridine nitrogen of the ruthenium(II) complexes not only causes dynamic equilibrium with remote N-heterocyclic carbene Ru?C complexes but also generates the NAD(+)/NADH redox function driven by a proton-coupled two-electron transfer accompanying a reversible C-H bond formation in the pyridinium ring. PMID- 21615115 TI - Sources of diversity in bactobolin biosynthesis by Burkholderia thailandensis E264. AB - A series of deletion mutants in the recently identified bactobolin biosynthetic pathway defined the roles of several key biosynthetic enzymes and showed how promiscuity in three enzyme systems allows this cluster to produce multiple products. Studies on the deletion mutants also led to four new bactobolin analogs that provide additional structure-activity relationships for this interesting antibiotic family. PMID- 21615116 TI - Stereoselective synthesis of deuterated beta-cyclohexenylserine, a biosynthetic intermediate of the salinosporamides. AB - A straightforward, highly stereoselective protocol toward the synthesis of deuterium-labeled (2R,3S,4S)-beta-cyclohexenylserine has been developed. Key steps are a Nozaki-Hiyama-Kishi reaction generating the stereogenic centers and a ring-closing metathesis for the construction of the cyclohexenyl ring system. The labeled amino acid was further activated as an SNAc-ester for feeding experiments. PMID- 21615117 TI - Selective inhibition of the K(ir)2 family of inward rectifier potassium channels by a small molecule probe: the discovery, SAR, and pharmacological characterization of ML133. AB - The K(ir) inward rectifying potassium channels have a broad tissue distribution and are implicated in a variety of functional roles. At least seven classes (K(ir)1-K(ir)7) of structurally related inward rectifier potassium channels are known, and there are no selective small molecule tools to study their function. In an effort to develop selective K(ir)2.1 inhibitors, we performed a high throughput screen (HTS) of more than 300,000 small molecules within the MLPCN for modulators of K(ir)2.1 function. Here we report one potent K(ir)2.1 inhibitor, ML133, which inhibits K(ir)2.1 with an IC(50) of 1.8 MUM at pH 7.4 and 290 nM at pH 8.5 but exhibits little selectivity against other members of Kir2.x family channels. However, ML133 has no effect on K(ir)1.1 (IC(50) > 300 MUM) and displays weak activity for K(ir)4.1 (76 MUM) and K(ir)7.1 (33 MUM), making ML133 the most selective small molecule inhibitor of the K(ir) family reported to date. Because of the high homology within the K(ir)2 family-the channels share a common design of a pore region flanked by two transmembrane domains-identification of site(s) critical for isoform specificity would be an important basis for future development of more specific and potent K(ir) inhibitors. Using chimeric channels between K(ir)2.1 and K(ir)1.1 and site-directed mutagenesis, we have identified D172 and I176 within M2 segment of K(ir)2.1 as molecular determinants critical for the potency of ML133 mediated inhibition. Double mutation of the corresponding residues of K(ir)1.1 to those of K(ir)2.1 (N171D and C175I) transplants ML133 inhibition to K(ir)1.1. Together, the combination of a potent, K(ir)2 family selective inhibitor and identification of molecular determinants for the specificity provides both a tool and a model system to enable further mechanistic studies of modulation of K(ir)2 inward rectifier potassium channels. PMID- 21615118 TI - Simultaneous detection of eight food allergens using optical thin-film biosensor chips. AB - Food allergies are important food safety issues nowadays. To maintain the safety of people who experience allergic reactions, labeling is required in many countries and efficient and reliable detection methods are necessary. This paper reports a novel method for the rapid identification of food allergens through the use of a silicon-based optical thin-film biosensor chip with which color change results can be perceived by the naked eye without any extra equipment. The whole system can detect eight food allergens including soybean, wheat, peanut, cashew, shrimp, fish, beef, and chicken simultaneously. Sensitive and specific detection of the absolute detection limit of this method was 0.5 pg of cashew DNA, and the practical detection limit of 0.001%. The biosensor chip detection time was about 30 min after PCR amplification. The assay is proposed as a sensitive, specific, high-throughput, and ready-to-use analytical tool to detect the presence or confirm the absence of eight food allergens. PMID- 21615119 TI - Asymmetric organocatalytic cyclization and cycloaddition reactions. PMID- 21615121 TI - Plasmon-mediated photopolymerization maps plasmon fields for silver nanoparticles. AB - Visible light exposure of films containing silver nanoparticles (AgNPs) shows that the enhanced field around AgNPs in a thin film containing an azo free radical initiator (AIBN) and a triacrylate selectively cross-links the triacrylate within the plasmonic region around the particles. The cross-linked polymer is less soluble than its precursor and behaves as a solubility switch. After the film is developed with ethanol, polymer-encapsulated nanoparticles are preserved on the surface. The 8-10 nm polymer structure that encapsulates the particles effectively maps and preserves the morphology of the plasmon field in AgNP-controlled nanostructures. PMID- 21615122 TI - Aorta and liver changes in rats fed cholesterol-containing and raw vegetable supplemented diets: experiments in vitro and in vivo. AB - The aim of this investigation was to compare the liver and aorta changes in rats fed cholesterol-containing diets and the possible improvement when diets would be supplemented with frequently used raw vegetables. The phenolic compounds of three vegetables in methanol-water (1:1) fraction were characterized using electrospray ionization mass spectra (ESI-MS). Results showed that the content of polyphenols, flavonoids, quercetin, flavanols, tannins, and ascorbic acid varied for garlic and white and red onions ranging from 6.68 to 18.08 mg GAE/g DW, 490.4-701.0 MUg CE/g DW, 281.2-1100.0 MUg, 32.40-41.30 MUg CE/g DW, 2.88-3.12 mg CE/g DW, 1.87 2.33 mg AA/g DW, 1388.2-1442.3 MUg CGE/g DW, respectively. The radical scavenging capacities (MUM TE/g DW) for the same investigated vegetables for ABTS, FRAP, CUPRAC, and DPPH assays ranged from 48.78 to 92.42, 9.41-28.56, 3.06-10.41, and 6.49-23.42, respectively. Good correlations were observed between the phenolic contents and the radical scavenging capacities of the vegetables. The interaction between BSA and quercetin, BSA and garlic and onions extracts was measured by 3 dimensional fluorescence (3D-FL) and Fourier transform infrared (FT-IR) spectroscopy. The highest polyphenol content was found in methanol/water fraction of onions and garlic; therefore, for the investigation of in vitro interactions with BSA only polyphenols of this fraction were used. For in vivo studies, 30 male Wistar rats were divided into 5 groups each of 6 and named Control, Chol, Chol/Garlic, Chol/OnionRed, and Chol/OnionWhite. During 6 weeks, the rats of all 5 groups were fed a basal diet (BD). The rats of the Control group were fed the BD only. The BD of the Chol group was supplemented with 10 g/kg of nonoxidized cholesterol (NOC). Each of the other three groups was supplemented with 10 g/kg of NOC and 500 mg of raw fresh garlic, 500 mg of raw fresh red onion, and 500 mg of raw fresh white onion on 1 kg of body weight for Chol/Garlic, Chol/OnionRed, and Chol/OnionWhite diet groups, respectively. In order to detect the changes in the liver and aorta, a histological procedure was applied, and the liver enzymes were determined and compared. It was found that the main changes vs the Control group were in the liver of rats fed the cholesterol-containing diet without vegetable supplementation. Significantly less histological changes in the liver and lower level of liver enzymes vs those of the Chol group were detected in rats of the Chol/Garlic group (P < 0.05). The interaction between the polyphenol extract of garlic and BSA in vitro showed its strong ability comparable with that of quercetin to quench the intrinsic fluorescence of BSA. In conclusion, all studied vegetables showed protective effects, but raw garlic supplemented with cholesterol-containing diets significantly prevented the aorta and liver damages of rats. PMID- 21615123 TI - Peptide functionalized polydiacetylene liposomes act as a fluorescent turn-on sensor for bacterial lipopolysaccharide. AB - Mixed polydiacetylene (PDA) liposomes functionalized on their surface with a fluorescent pentalysine peptide derivative and histidine in a ratio of 1:9 can identify bacterial lipopolysaccharide (LPS). Upon photopolymerization of the self assembled liposomes the initial fluorescence of the peptide-diacetylene amphiphiles is quenched. Interaction with LPS in aqueous solution or on the surface of E. coli DH5alpha restores the fluorescence. This increase in fluorescence is selective for LPS relative to other negatively charged analytes including nucleotides and ctDNA. This simple turn-on fluorescent sensor allows detecting LPS even at low micromolar concentrations. PMID- 21615124 TI - Bioactivity of antioxidants in extruded products prepared from purple potato and dry pea flours. AB - Measuring antioxidant activity using a biologically relevant assay adds important evidence to aid in understanding the role of phytochemicals based on data from in vivo and chemical assays of extrusion processed purple potato and pea flours. A cellular antioxidant activity assay could provide biologically relevant information on bioactive compounds in raw as well as processed food products. The objective of this study was to investigate the complete phytochemical profiles, antioxidant activity, cellular antioxidant activity, and their contribution to bioactivity in purple potato flour, dry pea flour, raw formulations, and extrusion cooked products prepared with the above ingredients. The free fraction of extracts contributed 68, 64, and 88% to total phenolics, total antioxidant activity (ORAC value), and total flavonoids, respectively, in purple potato flour (PPF). Similarly, extracts in the free fraction contributed 87, 86, and 64% to total phenolics, total antioxidant activity (ORAC value), and total flavonoids, respectively, in dry pea flour (DPF). The amount of total phenolics and total flavonoids in purple potato flour and the antioxidant activity of PPF and DPF were comparable to published data. However, a higher amount in the total flavonoids and lower in the total phenolics of DPF were observed. Caffeic, p coumaric, and ferulic acids were mostly observed in the bound extracts of raw formulations as in the extrudates, whereas chlorogenic acid was predominant in the free extracts. The extruded products had significantly higher (p < 0.05) content of total phenolics, ORAC antioxidant activity, and flavonoids, compared to the raw formulations. Extrusion processing increased the cellular antioxidant activity of the extrudates prepared from 35:65 and 50:50 PPF/DPF (w/w) of ingredients compared with control raw formulations in a dose-dependent manner. Increase of PPF significantly increased (p < 0.05) the cellular antioxidant activity of 35-50% PPF formulations. PMID- 21615126 TI - A new enabling technology for convenient laboratory scale continuous flow processing at low temperatures. AB - A new machine for conducting continuous flow processes at low temperatures on a laboratory scale is reported. The use of this cryogenic flow reactor has been demonstrated by the preparation of a variety of (hetero)aromatic boronic acids and esters via lithium halogen exchange chemistry. Furthermore, scale-up of the reaction conditions not only demonstrates the application of this device for the preparation of useful building blocks but also combines the ability to process n butyllithium directly through pump heads attached to the unit. PMID- 21615127 TI - Theoretical study of O--O single bond formation in the oxidation of water by the ruthenium blue dimer. AB - The first key step in the oxidation of water to O(2) by the oxidized species [(bpy)(2)(O)Ru(V)ORu(V)(O)(bpy)(2)](4+) of the Ru blue dimer is studied using density functional theory (DFT) and an explicit solvent treatment. In the model reaction system [L(2)(O)Ru(V)ORu(V)(O)L(2)](4+).(H(2)O)(4).W(76), the surrounding water solvent molecules W are described classically while the inner core reaction system is described quantum mechanically using smaller model ligands (L). The reaction path found for the O--O single bond formation involves a proton relay chain: direct participation of two water molecules in two proton transfers to yield the product [L(2)(HOO)Ru(IV)ORu(IV)(OH)L(2)](4+).(H(2)O)(3).W(76). The calculated ~3 kcal/mol reaction free energy and ~15 kcal/mol activation free energy barrier at 298 K are consistent with experiment. Structural changes and charge flow along the intrinsic reaction coordinate, the solvent's role in the reaction barrier, and their significance for water oxidation catalysis are examined in detail. PMID- 21615125 TI - Enantioselective synthesis of the ABC ring motif of norzoanthamine based on asymmetric Robinson annulation reactions. AB - An enantioselective strategy for the synthesis of tetracyclic motif 5, representing the northern fragment of norzoanthamine, is presented. Key to the strategy is the use of two asymmetric Robinson annulation reactions that produce the tricyclic ABC ring system with excellent stereoselectivity. Further functionalization at the periphery of the C ring produces compound 5 containing six contiguous stereocenters of the natural product. PMID- 21615128 TI - Synthesis and structural revision of phomopsin B, a novel polyketide carrying a 10-membered cyclic-ether ring. AB - Total synthesis of the proposed structure 2 for phomopsin B was achieved by using an intramolecular olefin metathesis as a key step. The spectral data, however, did not match with those of the natural product reported. Re-examination of the reported NMR data led to the structural revision of phomopsin B to known dothiorelone A 18. The R configuration of dothiorelone A was determined by total synthesis through a cross-metathesis with a chiral olefin 19. PMID- 21615129 TI - High-accuracy theoretical thermochemistry of atmospherically important sulfur containing molecules. AB - In this study, several sulfur-containing molecules with atmospherical importance were investigated by means of high-accuracy quantum chemical calculations including: HSO, HOS, HOSO2, HSNO, SH, CH2SO, CH2SH, S2COH, and SCSOH. After identifying the stable conformers of the molecules, a coupled-cluster-based composite model chemistry, which includes contributions up to quadruple excitations as well as corrections beyond the nonrelativistic and Born Oppenheimer approximations, was applied to calculate the corresponding heat of formation (Delta(f)H(0) degrees and Delta(f)H(298) degrees ) and entropy (S(298) degrees ) values. In most of the cases, this study delivers more reliable estimates for the investigated thermodynamic properties than those reported in previous investigations. Our data also suggest that the experimental heats of formation associated with the HSO molecule are very likely to belong to its structural isomer, HOS. It is also confirmed by the calculated thermodynamic properties including standard reaction entropies, enthalpies, and equilibrium constants that, in the reaction CS2 + OH CS2OH, the SCSOH structural isomer is produced. It is also noted that the currently accepted Delta(f)H(0) degrees (S(gas)) = 274.73 +/- 0.3 kJ/mol value is in need of revision, and based on a recent measurement, which is also confirmed by our computations, it is advised to update it to Delta(f)H(0) degrees (S(gas)) = 277.25 +/- 0.3 kJ/mol. PMID- 21615130 TI - Design and synthesis of small molecule RhoA inhibitors: a new promising therapy for cardiovascular diseases? AB - RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP binding proteins. RhoA, as an important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. However, to date, RhoA inhibitors are macromolecules, and to our knowledge, small molecular-based inhibitors have not been reported. In this study, a series of first-in-class small molecular RhoA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. Virtual screening of ~200,000 compounds, followed by SPR-based binding affinity assays resulted in three compounds with binding affinities to RhoA at the micromolar level (compounds 1-3). Compound 1 was selected for further structure modifications in considering binding activity and synthesis ease. Fourty-one new compounds (1, 12a-v, 13a-h, and 14a-j) were designed and synthesized accordingly. It was found that eight (12a, 12j, 14a, 14b, 14d, 14e, 14 g, and 14h) showed high RhoA inhibition activities with IC(50) values of 1.24 to 3.00 MUM. A pharmacological assay indicated that two compounds (14g and 14 h) demonstrated noticeable vasorelaxation effects against PE-induced contraction in thoracic aorta artery rings and served as good leads for developing more potent cardiovascular agents. PMID- 21615131 TI - Thiophene based europium beta-diketonate complexes: effect of the ligand structure on the emission quantum yield. AB - The synthesis and the molecular and photophysical characterization, together with solid state and solution structure analysis, of a series of europium complexes based on beta-diketonate ligands are reported. The Eu(III) complex emission, specifically its photoluminescence quantum yield (PL-QY), can be tuned by changing ligands which finely modifies the environment of the metal ion. Steady state and time-resolved emission spectroscopy and overall PL-QY measurements are reported and related to geometrical features observed in crystal structures of some selected compounds. Moreover, paramagnetic NMR, based on the analogous complexes with other lanthanides, are use to demonstrate that there is a significant structural reorganization upon dissolution, which justifies the observed differences in the emission properties between solid and solution states. The energy of the triplet levels of the ligands and the occurrence of nonradiative deactivation processes clearly account for the luminescence efficiencies of the complexes in the series. PMID- 21615132 TI - Identification of phenylalanine 3-hydroxylase for meta-tyrosine biosynthesis. AB - Phenylalanine hydroxylase (PheH) is an iron(II)-dependent enzyme that catalyzes the hydroxylation of aromatic amino acid l-phenylalanine (L-Phe) to l-tyrosine (L Tyr). The enzymatic modification has been demonstrated to be highly regiospecific, forming proteinogenic para-Tyr (p-Tyr) exclusively. Here we biochemically characterized the first example of a phenylalanine 3-hydroxylase (Phe3H) that catalyzes the synthesis of meta-Tyr (m-Tyr) from Phe. Subsequent mutagenesis studies revealed that two residues in the active site of Phe3H (Cys187 and Thr202) contribute to C-3 rather than C-4 hydroxylation of the phenyl ring. This work sets the stage for the mechanistic and structural study of regiospecific control of the substrate hydroxylation by PheH. PMID- 21615133 TI - Impact of in situ chemical oxidation on contaminant mass discharge: linking source-zone and plume-scale characterizations of remediation performance. AB - A large-scale permanganate-based in situ chemical oxidation (ISCO) effort has been conducted over the past ten years at a federal Superfund site in Tucson, AZ, for which trichloroethene (TCE) is the primary contaminant of concern. Remediation performance was assessed by examining the impact of treatment on contaminant mass discharge, an approach that has been used for only a very few prior ISCO projects. Contaminant mass discharge tests were conducted before and after permanganate injection to measure the impact at the source-zone scale. The results indicate that ISCO caused a significant reduction in mass discharge (approximately 75%). The standard approach of characterizing discharge at the source-zone scale was supplemented with additional characterization at the plume scale, which was evaluated by examining the change in contaminant mass discharge associated with the pump-and-treat system. The integrated contaminant mass discharge decreased by approximately 70%, consistent with the source-zone-scale measurements. The integrated mass discharge rebounded from 0.1 to 0.2 kg/d within one year after cessation of permanganate injections, after which it has been stable for several years. Collection of the integrated contaminant mass discharge data throughout the ISCO treatment period provided a high-resolution, real-time analysis of the site-wide impact of ISCO, thereby linking source-zone remediation to impacts on overall risk. The results indicate that ISCO was successful in reducing contaminant mass discharge at this site, which comprises a highly heterogeneous subsurface environment. Analysis of TCE sediment concentration data for core material collected before and after ISCO supports the hypothesis that the remaining mass discharge is associated in part with poorly accessible contaminant mass residing within lower-permeability zones. PMID- 21615134 TI - Factors determining the superior performance of lipid/DNA/protammine nanoparticles over lipoplexes. AB - The utility of using a protammine/DNA complex coated with a lipid envelope made of cationic 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) for transfecting CHO (Chinese hamster ovary cells), HEK293 (human embryonic kidney cells), NIH 3T3 (mouse embryonal cells), and A17 (murine cancer cells) cells was examined. The widely used DOTAP/DNA lipoplex was employed as a reference. In all the tested cell lines lipid/protamine/DNA (LPD) nanoparticles were more efficient in transfecting cells than lipoplexes even though the lipid composition of the lipid envelope was the same in both devices. Physical-chemical properties were found to control the ability of nanocarriers to release DNA upon interaction with cellular membranes. LPD complexes easily release their DNA payload, while lipoplexes remain largely intact and accumulate at the cell nucleus. Collectively, these data explain why LPD nanoparticles often exhibit superior performances compared to lipoplexes in trasfecting cells and represent a promising class of nanocarriers for gene delivery. PMID- 21615135 TI - Parametric amplification and self-oscillation in a nanotube mechanical resonator. AB - A hallmark of mechanical resonators made from a single nanotube is that the resonance frequency can be widely tuned. Here, we take advantage of this property to realize parametric amplification and self-oscillation. The gain of the parametric amplification can be as high as 18.2 dB and tends to saturate at high parametric pumping due to nonlinear damping. These measurements allow us to determine the coefficient of the linear damping force. The corresponding damping rate is lower than the one obtained from the line shape of the resonance (without pumping), supporting the recently reported scenario that describes damping in nanotube resonators by a nonlinear force. The possibility to combine nanotube resonant mechanics and parametric amplification holds promise for future ultralow force sensing experiments. PMID- 21615136 TI - Quantum mechanical/molecular mechanical molecular dynamics and free energy simulations of the thiopurine S-methyltransferase reaction with 6-mercaptopurine. AB - Quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations were performed to investigate the methylation of 6-mercaptopurine catalyzed by thiopurine S-methyltransferase. Several setups with different tautomeric forms and orientations of the substrate were considered. It is found that, with the orientation in chain A of the X-ray structure, the substrate can form an ideal near-attack configuration for the methylation reaction, which may take place after the deprotonation of the substrate by the conserved residue Asp23 through a water chain. The potential of mean force (PMF) of the methyl-transfer step for the most favorable pathway is 19.6 kcal/mol, which is in good agreement with the available experimental rate constant data. PMID- 21615137 TI - Unexpected formation of (E)-4-alkene 1,3-diketones from the three-component reaction of lithium selenolates with 1-(1-alkynyl)cyclopropyl ketones and aldehydes. AB - A novel three-component stereoselective synthesis of (E)-4-alkene 1,3-diketones from lithium selenolates, 1-(1-alkynyl)cyclopropyl ketones, and aldehydes is reported. This reaction afforded the products in moderate to good yields with the formation of a new C-Se single bond, a new C-C double bond, and a new C-O double bond. PMID- 21615138 TI - Electrospun carbon-tin oxide composite nanofibers for use as lithium ion battery anodes. AB - Composite carbon-tin oxide (C-SnO(2)) nanofibers are prepared by two methods and evaluated as anodes in lithium-ion battery half cells. Such an approach complements the long cycle life of carbon with the high lithium storage capacity of tin oxide. In addition, the high surface-to-volume ratio of the nanofibers improves the accessibility for lithium intercalation as compared to graphite based anodes, while eliminating the need for binders or conductive additives. The composite nanofibrous anodes have first discharge capacities of 788 mAh g(-1) at 50 mA g(-1) current density, which are greater than pure carbon nanofiber anodes, as well as the theoretical capacity of graphite (372 mAh g(-1)), the traditional anode material. In the first protocol to fabricate the C-SnO(2) composites, tin sulfate is directly incorporated within polyacrylonitrile (PAN) nanofibers by electrospinning. During a thermal treatment the tin salt is converted to tin oxide and the polymer is carbonized, yielding carbon-SnO(2) nanofibers. In the second approach, we soak the nanofiber mats in tin sulfate solutions prior to the final thermal treatment, thereby loading the outer surfaces with SnO(2) nanoparticles and raising the tin content from 1.9 to 8.6 wt %. Energy-dispersive spectroscopy and X-ray diffraction analyses confirm the formation of conversion of tin sulfate to tin oxide. Furthermore, analysis with Raman spectroscopy reveals that the additional salt soak treatment from the second fabrication approach increases in the disorder of the carbon structure, as compared to the first approach. We also discuss the performance of our C-SnO(2) compared with its theoretical capacity and other nanofiber electrode composites previously reported in the literature. PMID- 21615139 TI - Unusually large magnetic anisotropy in electrochemically deposited Co-rich Co-Pt films. AB - Co-rich Co-Pt films grown by electrodeposition from an amino nitrite/citrate/glycine electrolyte onto Au(111) substrates apparently grow with a hexagonal structure, with its c-axis directed perpendicular to the surface. The films exhibit a perpendicular magnetic anisotropy (MCA) of the same order of magnitude as the shape anisotropy. Experimental estimates of the MCA result in a higher anisotropy than that reported for bulk materials of the same composition, but similar to values measured in films grown by vacuum methods at relatively high temperature, which partly consist of a high anisotropy, metastable orthorhombic Pmm2 phase. Comparison of valence band X-ray photoelectron spectroscopy measurements on electrodeposited films with density functional theory simulations of the electronic structure of the various reported Co(3)Pt structures support the notion that the films may consist of a mixture of the hexagonal and the Pmm2 structure. PMID- 21615141 TI - Rates of intra- and intermolecular electron transfers in hydrogenase deduced from steady-state activity measurements. AB - Electrons are transferred over long distances along chains of FeS clusters in hydrogenases, mitochondrial complexes, and many other respiratory enzymes. It is usually presumed that electron transfer is fast in these systems, despite the fact that there has been no direct measurement of rates of FeS-to-FeS electron transfer in any respiratory enzyme. In this context, we propose and apply to NiFe hydrogenase an original strategy that consists of quantitatively interpreting the variations of steady-state activity that result from changing the nature of the FeS clusters which connect the active site to the redox partner, and/or the nature of the redox partner. Rates of intra- and intermolecular electron transfer are deduced from such large data sets. The mutation-induced variations of electron transfer rates cannot be explained by changes in intercenter distances and reduction potentials. This establishes that FeS-to-FeS rate constants are extremely sensitive to the nature and coordination of the centers. PMID- 21615140 TI - Quantification of cysteinyl S-nitrosylation by fluorescence in unbiased proteomic studies. AB - Cysteinyl S-nitrosylation has emerged as an important post-translational modification affecting protein function in health and disease. Great emphasis has been placed on global, unbiased quantification of S-nitrosylated proteins because of physiologic and oxidative stimuli. However, current strategies have been hampered by sample loss and altered protein electrophoretic mobility. Here, we describe a novel quantitative approach that uses accurate, sensitive fluorescence modification of cysteine S-nitrosylation that leaves electrophoretic mobility unaffected (SNOFlo) and introduce unique concepts for measuring changes in S nitrosylation status relative to protein abundance. Its efficacy in defining the functional S-nitrosoproteome is demonstrated in two diverse biological applications: an in vivo rat hypoxia-ischemia/reperfusion model and antimicrobial S-nitrosoglutathione-driven transnitrosylation of an enteric microbial pathogen. The suitability of this approach for investigating endogenous S-nitrosylation is further demonstrated using Ingenuity Pathways analysis that identified nervous system and cellular development networks as the top two networks. Functional analysis of differentially S-nitrosylated proteins indicated their involvement in apoptosis, branching morphogenesis of axons, cortical neurons, and sympathetic neurites, neurogenesis, and calcium signaling. Major abundance changes were also observed for fibrillar proteins known to be stress-responsive in neurons and glia. Thus, both examples demonstrate the technique's power in confirming the widespread involvement of S-nitrosylation in hypoxia-ischemia/reperfusion injury and in antimicrobial host responses. PMID- 21615142 TI - Symmetry-switching molecular Fe(O2)n(+) clusters. AB - Experimental and theoretical studies based on mass spectrometry, collision induced dissociation, and ab initio calculations are performed on the formation and stability of FeO(n)(+) clusters, as well as on their structural, electronic, and magnetic properties. In the mass spectra, clusters with an even number of oxygen atoms show increased stability, most prominently for FeO(10)(+). The extra stability of this cluster is confirmed by measurements of fragmentation cross sections through crossed molecular beam experiments. In addition, the calculations indicate a structural phase transition at this size, and most importantly, the FeO(n)(+) clusters show unique magnetic features, exhibiting isoenergetic low-spin (LS) and high-spin (HS) ground states. In the LS state, the magnetic moments of the O atoms adopt an antiferromagnetic alignment with respect to the magnetic moment of Fe(+), whereas in the HS state, the alignment is ferromagnetic. FeO(10)(+) is the largest thermodynamically stable complex, with the highest magnetic moment among the FeO(n)(+) clusters (13 MU(B) in HS). PMID- 21615143 TI - Sensitive gas analysis system on a microchip and application for on-site monitoring of NH3 in a clean room. AB - A portable, highly sensitive, and continuous ammonia gas monitoring system was developed with a microfluidic chip. The system consists of a main unit, a gas pumping unit, and a computer which serves as an operation console. The size of the system is 45 cm width * 30 cm depth * 30 cm height, and the portable system was realized. A highly efficient and stable extraction method was developed by utilizing an annular gas/liquid laminar flow. In addition, a stable gas/liquid separation method with a PTFE membrane was developed by arranging a fluidic network in three dimensions to achieve almost zero dead volume at the gas/liquid extraction part. The extraction rate was almost 100% with a liquid flow rate of 3.5 MUL/min and a gas flow rate of 100 mL/min (contact time of ~15 ms), and the concentration factor was 200 times by calculating the NH(3) concentration (w/w unit) in the gas and liquid phases. Stable phase separation and detection was sustained for more than 3 weeks in an automated operation, which was sufficient for the monitoring application. The lower limit of detection calculated based on a signal-to-noise ratio of 3 was 84 ppt, which showed good detectability for NH(3) analysis. We believe that our system is a very powerful tool for gas analysis due to the advantages of portable size, high sensitivity, and continuous monitoring, and it is particularly useful in the semiconductor field. PMID- 21615145 TI - Quantum cascade laser spectroscopy and photoinduced chemistry of Al-(CO)n clusters in helium nanodroplets. AB - Helium nanodroplet isolation and a tunable quantum cascade laser are used to probe the fundamental CO stretch bands of aluminum carbonyl complexes, Al-(CO)(n) (n <= 5). The droplets are doped with single aluminum atoms via the resistive heating of an aluminum wetted tantalum wire. The downstream sequential pick-up of CO molecules leads to the rapid formation and cooling of Al-(CO)(n) clusters within the droplets. Near 1900 cm(-1), rotational fine structure is resolved in bands that are assigned to the CO stretch of a linear (2)Pi(1/2) Al-CO species and the asymmetric and symmetric CO stretch vibrations of a planar C(2v) Al (CO)(2) complex in a (2)B(1) electronic state. Bands corresponding to clusters with n >= 3 lack resolved rotational fine structure; nevertheless, the small frequency shifts from the n = 2 bands indicate that these clusters consist of an Al-(CO)(2) core with additional CO molecules attached via van der Waals interactions. A second n = 2 band is observed near the CO stretch of Al-CO, indicating a local minimum on the n = 2 potential consisting of an "unreacted" (Al-CO)-CO cluster. The line width of this band is ~0.3 cm(-1), which is about 30 times broader than the transitions within the Al-CO band. The additional broadening is consistent with a homogeneous mechanism corresponding to a rapid vibrational excitation induced reaction within the (Al-CO)-CO cluster to form the covalently bonded Al-(CO)(2) complex. Ab initio CCSD(T) calculations and natural bond orbital (NBO) analyses are carried out to investigate the nature of the bonding in the n = 1, 2 complexes. The NBO calculations show that both pi donation (from the occupied aluminum p orbital into a pi* antibonding CO orbital) and sigma-donation (from CO into the empty aluminum p orbitals) play a significant role in the bonding, analogous to transition-metal carbonyl complexes. The large red shift observed for the CO stretch vibrations is consistent with this bonding analysis. PMID- 21615144 TI - Injectable PAMAM dendrimer-PEG hydrogels for the treatment of genital infections: formulation and in vitro and in vivo evaluation. AB - Local intravaginal drug therapy is preferred for treatment of ascending genital infections during pregnancy. In the present study, an in situ forming biodegradable hydrogel for sustained release of amoxicillin in the cervicovaginal region is described. A generation 4 poly(amidoamine) [G4-(NH(2))(64)] dendrimer with peripheral thiopyridyl terminations is cross-linked with 8-arm polyethylene glycol (PEG) bearing thiol terminations. The hydrogels were formulated and tested in vivo in a pregnant guinea pig model for volume, retention times, biodegradation, tolerability and transport across fetal membrane. The physicochemical characterization of the hydrogels was carried out using differential calorimetry, SEM, and confocal imaging. The hydrogels offer antibacterial activity arising from sustained release of amoxicillin from gels. The in vivo studies in guinea pig showed that 100-200 MUL of gel sufficiently covered the cervicovaginal region with a residence time of at least 72 h and gel was primarily retained in the maternal tissues without crossing the fetal membranes into the fetus. The dendrimer gels were stable up to 72 h, and the in vivo biodegradation of gel occurred after 72 h; this correlated well with the in vitro degradation pattern. The pH of the vagina was not altered upon application of the gel, and none of the animals aborted up to 72 h after application of gel. The histological evaluation of the cervical tissues showed absence of edema in the epithelial cell layer, no sloughing of the epithelial or superficial mucous layer, and absence of necrosis and infiltration of inflammatory cells in the submucosal layers, confirming that tissues were tolerant to the gel. The immunohistofluorescence images showed the localization of the gel components on the superficial mucified epithelial layer. The cross-linking density and swelling of hydrogels was impacted by the polymer content, and the 10% hydrogels exhibited the highest cross-link density. The in vitro drug release studies carried out using Franz diffusion cells showed that amoxicillin release from 6 and 10% gels was sustained for 240 h as compared to 3% gels. As the polymer concentration increased to 10%, the release pattern from gels approached diffusion controlled mechanism with diffusional exponent n = 0.49. In conclusion, the biodegradable in situ forming hydrogels of the present study offer a therapeutic option to provide sustained localized delivery of amoxicillin intracervically to the pregnant woman for the treatment of ascending genital infections. PMID- 21615146 TI - Metabolite profiling of triterpene saponins in Medicago truncatula hairy roots by liquid chromatography Fourier transform ion cyclotron resonance mass spectrometry. AB - Triterpenes are one of the largest classes of plant natural products, with an enormous variety in structure and bioactivities. Here, triterpene saponins from hairy roots of the model legume Medicago truncatula were profiled with reversed phase liquid chromatography coupled to negative-ion electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (LC ESI FT-ICR MS). Owing to the accuracy of the FT-ICR MS, reliable molecular formulas of the detected compounds could be predicted, which, together with the generated MS(n) spectra, allowed the tentative identification of 79 different saponins, of which 61 had not been detected previously in M. truncatula. Upon collision-induced dissociation of saponins that contain a uronic acid residue in the sugar chain, fragment ions resulting from cross-ring cleavages of the uronic acid residues were observed. The identified saponins are glycosides of 10 different sapogenins, of which three were not detected before in M. truncatula. Zanhic acid glycosides, which are prevalent in the aerial parts of M. truncatula, were absent in the hairy root extracts. This metabolite compendium will facilitate future functional genomic studies of triterpene saponin biosynthesis in M. truncatula. PMID- 21615148 TI - Exclusive self-assembly of a polar dimeric capsule between tetraurea calix[4]pyrrole and tetraurea calix[4]arene. AB - The exclusive self-sorting observed in the self-assembly process between tetraurea benzyl calix[4]pyrroles and tetraurea tolyl calix[4]arene to afford unprecedented hybrid dimeric capsules with polar interiors is described. The coencapsulation of a solvent molecule with an organic guest yields four particle aggregates in which the guests are confined and restricted into single hemispheres due to the polar requirements of the internal cavity. PMID- 21615147 TI - Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing. AB - We here report on the synthesis, optimization, and biological characterization of leucettines, a family of kinase inhibitors derived from the marine sponge leucettamine B. Stepwise synthesis of analogues starting from the natural structure, guided by activity testing on eight purified kinases, led to highly potent inhibitors of CLKs and DYRKs, two families of kinases involved in alternative pre-mRNA splicing and Alzheimer's disease/Down syndrome. Leucettine L41 was cocrystallized with CLK3. It interacts with key residues located within the ATP-binding pocket of the kinase. Leucettine L41 inhibits the phosphorylation of serine/arginine-rich proteins (SRp), a family of proteins regulating pre-RNA splicing. Indeed leucettine L41 was demonstrated to modulate alternative pre-mRNA splicing, in a cell-based reporting system. Leucettines should be further explored as pharmacological tools to study and modulate pre-RNA splicing. Leucettines may also be investigated as potential therapeutic drugs in Alzheimer's disease (AD) and in diseases involving abnormal pre-mRNA splicing. PMID- 21615149 TI - Metal-free synthesis of aryl esters from carboxylic acids and diaryliodonium salts. AB - An efficient arylation of carboxylic acids with diaryliodonium salts has been developed, giving aryl esters in high yields within short reaction times for both aromatic and aliphatic substrates. The transition-metal-free conditions are compatible with a range of functional groups, and good chemoselectivity is observed with unsymmetric diaryliodonium salts. Furthermore, steric hindrance in the ortho positions is well tolerated both in the carboxylic acid and in the diaryliodonium salt, yielding aryl esters that cannot be obtained via other esterification protocols. PMID- 21615151 TI - Designing novel hybrid materials by one-pot co-condensation: from hydrophobic mesoporous silica nanoparticles to superamphiphobic cotton textiles. AB - This work reports the synthesis and characterization of mesoporous silica nanoparticles (MSNs) functionalized with tridecafluorooctyltriethoxysilane (F13) and their in situ incorporation onto cotton textiles. The hybrid MSNs and the functional textiles were prepared by a one-pot co-condensation methodology between tetraethylorthosilicate (TEOS) and F13, with hexadecyltrimethylammonium chloride (CTAC) as the template and triethanolamine as the base. The influence of the F13 to TEOS molar ratio (1:10, 1:5 and 1:3) on the nanoparticle morphology, porosity, degree of functionalization, and hydro/oleophobic properties is discussed. The hybrid nanosilicas presented high colloidal stability and were spherical and monodispersed with average particle size of ~45 nm. They also showed high surface areas, large pore volumes, and a wormhole-type mesoporous structure. The increase in the organosilane proportion during the co-condensation process led to a more radially branched wormhole-like mesoporosity, a decrease in the surface area, pore volume, and amount of surface silanol groups, and an enrichment of the surface with fluorocarbon moieties. These changes imparted hydrophobic and oleophobic properties to the materials, especially to that containing the highest F13 loading. Cotton textiles were coated with the F13-MSNs through an efficient and less time-consuming route. The combination between surface roughness and mesoporosity imparted by the MSNs, and the low surface energy provided by the organosilane resulted in superhydrophobic functional textiles. Moreover, the textile with the highest loading of fluorocarbon groups was superamphiphobic. PMID- 21615152 TI - Spectroscopic analysis of diversity of Arabinoxylan structures in endosperm cell walls of wheat cultivars (Triticum aestivum) in the HEALTHGRAIN diversity collection. AB - Fifty bread wheat (Triticum aestivum L.) cultivars were selected from the HEALTHGRAIN germplasm collection based on variation in their contents of total and water-extractable arabinoxylan. FT-IR spectroscopic mapping of thin transverse sections of grain showed variation in cell wall arabinoxylan composition between the cultivars, from consisting almost entirely of low substituted arabinoxylan (e.g., T.aestivum 'Claire') to almost entirely of highly substituted arabinoxylan (e.g., T.aestivum 'Manital') and a mixture of the two forms (e.g., T.aestivum 'Hereward'). Complementary data were obtained using endoxylanase digestion of flour followed by HP-AEC analysis of the arabinoxylan oligosaccharides. This allowed the selection of six cultivars for more detailed analysis using FT-IR and (1)H NMR spectroscopy to determine the proportions of mono-, di-, and unsubstituted xylose residues. The results of the two analyses were consistent, showing that variation in the composition and structure of the endosperm cell wall arabinoxylan is present between bread wheat cultivars. The heterogeneity and spatial distribution of the arabinoxylan in endosperm cell walls may be exploited in wheat processing as it may allow the production of mill streams enriched in various arabinoxylan fractions which have beneficial effects on health. PMID- 21615154 TI - Polymorphism for novel tetraglycosylated flavonols in an Eco-model crucifer, Barbarea vulgaris. AB - Nineteen apparent flavonoids were determined by HPLC-DAD in foliage of a chemotype (G-type) of Barbarea vulgaris , and four were isolated. Two were novel tetraglycosylated flavonols with identical glycosylation patterns, kaempferol 3-O (2,6-di-O-beta-d-glucopyranosyl)-beta-d-glucopyranoside-7-O-alpha-l rhamnopyranoside (1) and quercetin 3-O-(2,6-di-O-beta-d-glucopyranosyl)-beta-d glucopyranoside-7-O-alpha-l-rhamnopyranoside (2). The identification of d/l configuration was tentatively based on susceptibility to alpha-l-rhamnosidase and beta-d-glucosidases. A characteristic feature of 1 and 2 was appreciable water solubility, an expected consequence of the extensive glycosylation. A less complex pair of flavonols comprised 3-O-beta-d-glucopyranoside-7-O-alpha-l rhamnopyranosides of kaempferol and quercetin. Two natural chemotypes of B. vulgaris differed in levels of 1 and 2, with the P-type deficient in 1 and 2 and the insect-resistant G-type rich in 1 (ca. 3-4 MUmol/g dry wt) and with moderate levels of 2 (ca. 0.3-0.8 MUmol/g dry wt). However, there was only modest seasonal variation in flavonols 1 and 2, in contrast to a strong seasonal variation in insect resistance. PMID- 21615153 TI - Negatively charged liposomes show potent adjuvant activity when simply admixed with protein antigens. AB - Liposomes have been investigated extensively as a vaccine delivery system. Herein the adjuvant activities of liposomes with different net surface charges (neutral, positive, or negative) were evaluated when admixed with protein antigens, ovalbumin (OVA, pI = 4.7), Bacillus anthracis protective antigen protein (PA, pI = 5.6), or cationized OVA (cOVA). Mice immunized subcutaneously with OVA admixed with different liposomes generated different antibody responses. Interestingly, OVA admixed with net negatively charged liposomes prepared with DOPA was as immunogenic as OVA admixed with positively charged liposomes prepared with DOTAP. Immunization of mice with the anthrax PA protein admixed with the net negatively charged DOPA liposomes also induced a strong and functional anti-PA antibody response. When the cationized OVA was used as a model antigen, liposomes with net neutral, negative, or positive charges showed comparable adjuvant activities. Immunization of mice with the OVA admixed with DOPA liposomes also induced OVA specific CD8(+) cytotoxic T lymphocyte responses and significantly delayed the growth of OVA-expressing B16-OVA tumors in mice. However, not all net negatively charged liposomes showed a strong adjuvant activity. The adjuvant activity of the negatively charged liposomes may be related to the liposome's ability (i) to upregulate the expression of molecules related to the activation and maturation of antigen-presenting cells and (ii) to slightly facilitate the uptake of the antigens by antigen-presenting cells. Simply admixing certain negatively charged liposomes with certain protein antigens of interest may represent a novel platform for vaccine development. PMID- 21615155 TI - Statistical analysis and compound selection of combinatorial libraries for soluble epoxide hydrolase. AB - Inhibitors of soluble epoxide hydrolase (sEH) have been extensively pursued as antihypertensive therapies as well as potential treatment for other cardiovascular dysfunctions and prevention of renal damage. In this study we report quantitative structure-activity relationship (QSAR) models for 1223 structurally diverse sEH inhibitors produced by combinatorial library design and synthesis. Daylight fingerprints, MOE 2D and DragonX descriptors were generated for QSAR modeling approaches. Using these descriptors, a number of statistical models were trained and validated. Of these methods, gradient boosting machines (GBM), partial least-squares (PLS), and Cubist methods demonstrated the best performance on training and test set validation in terms of their leave-group-out cross-validated (LGO-CV) Q(2) and correlation coefficient R(2) (Q(2)(GBM training) = 0.79, R(2)(GBM-test) = 0.81; Q(2)(PLS-training) = 0.75, R(2)(PLS test) = 0.75; Q(2)(Cubist-training) = 0.91, R(2)(Cubist-test) = 0.78). A final model was constructed using the consensus approach of the three individual models and showed robust statistics and prediction of the external validation set. The Gaussian process modified sequential elimination of level combinations (G-SELC) method was then used to expand the chemical space beyond what has been explored by combinatorial synthesis. This approach identified 50 new compounds that are structurally diverse and potentially desirable for sEH inhibition based on prior knowledge. The activities of the suggested compounds were then predicted by the consensus QSAR model, and the results supported that the compounds were more likely to exist in the active parts of the chemical space. This study illustrates that the balanced approach by G-SELC could provide a general method for combinatorial library design, to effectively identify promising compounds to be created in the laboratory. PMID- 21615150 TI - Progress in structure based drug design for G protein-coupled receptors. PMID- 21615157 TI - Probing multivalent interactions in a synthetic host-guest complex by dynamic force spectroscopy. AB - Multivalency is present in many biological and synthetic systems. Successful application of multivalency depends on a correct understanding of the thermodynamics and kinetics of this phenomenon. In this Article, we address the stability and strength of multivalent bonds with force spectroscopy techniques employing a synthetic adamantane/beta-cyclodextrin model system. Comparing the experimental findings to theoretical predictions for the rupture force and the kinetic off-rate, we find that when the valency of the complex is increased from mono- to di- to trivalent, there is a transition from quasi-equilibrium, with a constant rupture force of 99 pN, to a kinetically dependent state, with loading rate-dependent rupture forces from 140 to 184 pN (divalent) and 175 to 210 pN (trivalent). Additional binding geometries, parallel monovalent ruptures, single bound divalent ruptures, and single- and double-bound trivalent ruptures are identified. The experimental kinetic off-rates of the multivalent complexes show that the stability of the complexes is significantly enhanced with the number of bonds, in agreement with the predictions of a noncooperative multivalent model. PMID- 21615156 TI - Metabolite identification of a radiotracer by electrochemistry coupled to liquid chromatography with mass spectrometric and radioactivity detection. AB - Radioligands, which specifically bind to a receptor or enzyme (target), enable molecular imaging of the target expression by positron emission tomography (PET). One very promising PET tracer is (S)-1-(4-(2-[(18)F]-fluoroethoxy)benzyl)-5-[1-(2 methoxymethylpyrrolidinyl)sulfonyl]isatin (isatin), a caspase-3 inhibitor, which has been developed at the University Hospital of Munster to image cell death (apoptosis). The translation of this novel tracer from preclinical evaluation to clinical examinations requires biodistribution studies, which characterize the pharmakodynamics and metabolic fate of the compound. This information is used to further optimize the radioligands and to interpret radioactive signals from tissues upon injection of the radioligand in vivo with respect to their specificity. The analysis of the metabolism of radioligands is hampered by the low amount of the compound being typically injected (nano/picomolar amount per injection). In the present study, electrochemistry (EC) is applied to elucidate the oxidative metabolism pathway of the radiotracer. Previous studies have demonstrated that EC can be utilized as a complementary tool to conventional in vitro approaches in drug metabolism studies. Thereby, potential oxidative metabolites of the isatin are determined by EC coupled to electrospray ionization mass spectrometry (EC/ESI-MS). Moreover, using EC/liquid chromatography (LC) and ESI-ion trap MS(n), structural elucidation of the oxidation products is performed. Comparatively to EC, in vitro metabolism studies with rat liver microsomes are conducted. Finally, the developed LC/ESI-MS method is applied to determine metabolites in body fluids and cell extracts from in vivo studies with the nonradioactive ((19)F) and radioactive isatin ((18)F). On the basis of the electrochemically generated oxidation products of the radioligand, the major radioactive metabolite occurring in vivo was successfully identified. PMID- 21615158 TI - In vitro evolution of ligands to the membrane protein caveolin. AB - Membrane proteins comprise a third of the human genome, yet present challenging targets for reverse chemical genetics. For example, although implicated in numerous diseases including multiple myeloma, the membrane protein caveolin-1 appears to offer a poor target for the discovery of synthetic ligands due to its largely unknown structure and insolubility. To break this impasse and identify new classes of caveolae controlling lead compounds, we applied phage-based, reverse chemical genetics for the discovery of caveolin-1 ligands derived from the anti-HIV therapeutic T20. Substitution of homologous residues into the T20 sequence used a process analogous to medicinal chemistry for the affinity maturation to bind caveolin. The resultant caveolin-1 ligands bound with >1000 fold higher affinity than wild-type T20. Two types of ELISAs and isothermal titration calorimetry (ITC) measurements demonstrated high affinity binding to caveolin by the T20 variants with K(d) values in the 150 nM range. Microscopy experiments with the highest affinity caveolin ligands confirmed colocalization of the ligands with endogenous caveolin in NIH 3T3 cells. The results establish the foundation for targeting caveolin and caveolae formation in living cells. PMID- 21615159 TI - A new protocol for predicting novel GSK-3beta ATP competitive inhibitors. AB - Glycogen synthase kinase 3beta (GSK-3beta) is a potential therapeutic target for cancer, type-2 diabetes, and Alzheimer's disease. This paper proposes a new lead identification protocol that predicts new GSK-3beta ATP competitive inhibitors with topologically diverse scaffolds. First, three-dimensional quantitative structure-activity relationship (3D QSAR) models were built and validated. These models are based upon known GSK-3beta inhibitors, benzofuran-3-yl-(indol-3-yl) maleimides, by means of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Second, 28 826 maleimide derivatives were selected from the PubChem database. After filtration via Lipinski's rules, 10 429 maleimide derivatives were left. Third, the FlexX dock program was employed to virtually screen the 10 429 compounds against GSK 3beta. This resulted in 617 virtual hits. Fourth, the 3D QSAR models predicted that from the 617 virtual hits, 93 compounds would have GSK-3beta inhibition values of less than 15 nM. Finally, from the 93 predicted active hits, 23 compounds were confirmed as GSK-3beta inhibitors from literatures; their GSK 3beta inhibition ranged from 1.3 to 480 nM. Therefore, the hits rate of our virtual screening protocol is greater than 25%. The protocol combines ligand- and structure-based approaches and therefore validates both approaches and is capable of identifying new hits with topologically diverse scaffolds. PMID- 21615160 TI - Structure and electronic properties of amino acid ionic liquids. AB - The interactions between eight amino acid based anions and four imidazolium-based cations have been investigated by density functional theory. The electronic and structural properties of the resulting amino acid ionic liquids (AAILs) have been unveiled by means of the atoms in molecules framework. The calculated interaction energy was found to increase in magnitude with decreasing alkyl chain length at imidazolium ring. Moreover, AAILs composed of an amino acid with some functional group such as aromatic ring had decreased interaction energy. Finally, several correlative relationships between glass transition temperature and interaction energy as well as density at bond critical point have been checked for 1-ethyl-3 methylimidazolium based ILs. Although the obtained correlations do not show excellent fits, a preliminary estimation of the glass transition temperature of different AAILs can be achieved by use of their electronic properties. PMID- 21615162 TI - Effect of the substitution pattern of alkyl side chain in a benzodithiophene core pi-system on intra and inter-molecular charge carrier mobility. AB - 3,7-Didocecyl-2,6-di(5-phenylthiophen-2-yl)benzo[1,2-b:3,4-b']dithiophene (1) and its 4,8-didodecyl isomer 2 were prepared as the representative soluble X- and cross-shaped pi-conjugated oligomer systems to provide insight into the effect of the substitution pattern of the alkyl side chain on electronic properties. The absorption and emission spectra as well as CV data showed the relatively longer effective conjugation of cross-shaped 2. The intrinsic charge-carrier mobilities were then estimated by flash-photolysis time-resolved microwave conductivity (FP TRMC) method and compared with their top contact FET properties. It was found that, although the TRMC method showed the higher mobility of 2 than 1, the FET performance of 1 after appropriate conditioning and thermal annealing was superior to that of 2. The effective conjugation of cross-shaped 2 is well reflected in the intramolecular mobility of positive holes estimated by FP-TRMC, showing striking contrast to the rather higher mobility of X-shaped 1 observed by FET as well as TOF measurements as the long-range translational motion of the carriers. This strongly suggests that the intermolecular packing of these compounds plays a significant role in the range of hole mobility of <~10(-2) cm(2) V(-1) s(-1). PMID- 21615161 TI - Rate constants for the reactions between OH and perfluorinated alkenes. AB - The rate constants for the reactions of OH radicals with fully fluorinated alkenes containing different numbers of -CF(3) groups next to olefinic carbon, CF(2)?CF(2), CF(2)?CFCF(3), CF(3)CF?CFCF(3), and (CF(3))(2)C?CFC(2)F(5), were measured between 230 and 480 K using the flash photolysis resonance fluorescence technique to give the following expressions: k(C(2)F(4))(250-480 K) = 1.32 * 10( 12) * (T/298 K)(0.9) * exp(+600 K/T) cm(3) molecule(-1) s(-1), k(C(3)F(6))(230 480 K) = 9.75 *10(-14) * (T/298 K)(1.94) * exp(+922 K/T) cm(3) molecule(-1) s( 1), k(trans-C(4)F(8))(230-370 K) = 7.50 * 10(-14) * (T/298 K)(1.68) * exp(+612 K/T) cm(3) molecule(-1) s(-1), k(cis-C(4)F(8))(230-370 K) = 2.99 * 10(-14) * (T/298 K)(2.61) * exp(+760 K/T) cm(3) molecule(-1) s(-1), and k(C(6)F(12))(250 480 K) = 2.17 * 10(-15) * (T/298 K)(3.90) * exp(+1044 K/T) cm(3) molecule(-1) s( 1). The kinetics of the OH reaction in an industrial sample of octofluoro-2 propene (a mixture of the cis- and trans-isomers of CF(3)CF?CFCF(3)) was studied to determine the "effective" reaction rate constant for the typically industrial mixture: k()(230-480 K) = 7.89 * 10(-14) * (T/298 K)(1.71) * exp(+557 K/T) cm(3) molecule(-1) s(-1). On the basis of these results, the atmospheric lifetimes were estimated to be 1.2, 5.3, 21, 34, and 182 days for CF(2)?CF(2), CF(3)CF?CF(2), trans-CF(3)CF?CFCF(3), cis-CF(3)CF?CFCF(3), and (CF(3))(2)C?CFC(2)F(5), respectively. The general pattern of halolalkene reactivity toward OH is discussed. PMID- 21615163 TI - Coaxial ion trap mass spectrometer: concentric toroidal and quadrupolar trapping regions. AB - We present the design and results for a new radio-frequency ion trap mass analyzer, the coaxial ion trap, in which both toroidal and quadrupolar trapping regions are created simultaneously. The device is composed of two parallel ceramic plates, the facing surfaces of which are lithographically patterned with concentric metal rings and covered with a thin film of germanium. Experiments demonstrate that ions can be trapped in either region, transferred from the toroidal to the quadrupolar region, and mass-selectively ejected from the quadrupolar region to a detector. Ions trapped in the toroidal region can be transferred to the quadrupole region using an applied ac signal in the radial direction, although it appears that the mechanism of this transfer does not involve resonance with the ion secular frequency, and the process is not mass selective. Ions in the quadrupole trapping region are mass analyzed using dipole resonant ejection. Multiple transfer steps and mass analysis scans are possible on a single population of ions, as from a single ionization/trapping event. The device demonstrates better mass resolving power than the radially ejecting halo ion trap and better sensitivity than the planar quadrupole ion trap. PMID- 21615164 TI - Universal parameters for carbon nanotube network-based sensors: can nanotube sensors be reproducible? AB - Carbon nanotube (CNT) network-based sensors have been often considered unsuitable for practical applications due to their unpredictable characteristics. Herein, we report the study of universal parameters which can be used to characterize CNT network-based sensors and make their response predictable. A theoretical model is proposed to explain these parameters, and sensing experiments for mercury (Hg(2+)) and ammonium (NH(4)(+)) ions using CNT network-based sensors were performed to confirm the validity of our model. PMID- 21615165 TI - One-pot stereoselective synthesis of 1,2-amino alcohol derivatives. AB - Common beta-hydroxy amino acids (such as threonine) can be readily transformed into 1,2-amino alcohols with excellent stereoselectivity. This one-pot decarboxylation-alkylation process allows the replacement of the carboxyl group by alkyl, allyl, or aryl groups, generally in high yields. A variation of the process (decarboxylation-Diels-Alder) allows the formation of bi- and polycyclic systems, which are useful precursors of alkaloid cores or iminosugars. PMID- 21615166 TI - Cu(I)- and Ru(II)-mediated "click" cyclization of tripeptides toward vancomycin inspired mimics. AB - Structural mimics comprising 1,4- and 1,5-disubstituted triazole-containing cyclic tripeptides with excellent resemblance toward the DE-ring of vancomycin are conveniently accessible using Cu(I)- or Ru(II)-assisted "click" cyclization. PMID- 21615167 TI - End-to-end coupling and network formation behavior of cylindrical block copolymer micelles with a crystalline polyferrocenylsilane core. AB - Cylindrical block copolymer micelles with a crystalline poly(ferrocenyldimethylsilane) (PFDMS) core and a long corona-forming block are known to elongate through an epitaxial growth mechanism on addition of further PFDMS block copolymer unimers. We now report that addition of the semicrystalline homopolymer PFDMS(28) to monodisperse short (ca. 200 nm), cylindrical seed micelles of PFDMS block copolymers results in the formation of aggregated structures by end-to-end coupling to form micelle networks. The resulting aggregates were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and atomic force microscopy (AFM). In some cases, a core-thickening effect was also observed where the added homopolymer appeared to deposit and crystallize at the core-corona interface, which resulted in an increase of the width of the micelles within the networks. No evidence for aggregation was detected when the amorphous homopolymer poly(ferrocenylethylmethylsilane) (PFEMS(25)) was added to the cylindrical seed micelles whereas similar behavior to PFDMS(28) was noted for semicrystalline polyferrocenyldimethylgermane (PFDMG(30)). This suggested that the crystallinity of the added homopolymer is critical for subsequent end-to-end coupling and network formation to occur. We also explored the tendency of the cylindrical seed micelles to form aggregates by the addition of PI-b-PFDMS (PI = polyisoprene) block copolymers (block ratios 6:1, 3.8:1, 2:1, or 1:1), and striking differences were noted. The results ranged from typical micelle elongation, as reported in previous work, at high corona to core-forming block ratios (PI-b-PFDMS; 6:1) to predominantly end-to-end coupling at lower ratios (PI-b-PFDMS; 2:1, 1:1) to form long, essentially linear structures. The latter process, especially for the 2:1 block copolymer, led to much more controlled aggregate formation compared with that observed on addition of homopolymers. PMID- 21615168 TI - Ultrafast charge separation and recombination dynamics in lead sulfide quantum dot-methylene blue complexes probed by electron and hole intraband transitions. AB - Lead salt quantum dots (QDs) have emerged as attractive materials for solar energy conversion because of their broad spectral response, long exciton lifetime, and efficient multiexciton generation. However, charge separation dynamics from these QDs remain poorly understood. In this study we investigate charge separation and recombination dynamics in PbS-methylene blue (MB(+)) complexes by femtosecond transient absorption spectroscopy. We show that while the 1S electrons and holes in excited PbS QDs lead to overlapping transient absorption features in the visible and near-IR regions, their intraband absorptions in the mid-IR can be monitored independently to directly follow the charge separation and recombination processes. The charge separation and recombination rates in PbS-MB(+) complexes were found to be (2.7 +/- 0.2) * 10(12) and (1.1 +/- 0.2) * 10(11) s(-1), respectively. The ultrafast charge separation rate suggests the possibility of hot electron injection and multiexciton dissociation from these strongly quantum confined QDs, consistent with recent reports of these phenomena at lead salt QD/TiO(2) interfaces. PMID- 21615169 TI - Sticky interconnect for solution-processed tandem solar cells. AB - Graphene oxide (GO) can be viewed as a two-dimensional, random diblock copolymer with distributed nanosize graphitic patches and highly oxidized domains, thus capable of guiding the assembly of other materials through both pi-pi stacking and hydrogen bonding. Upon mixing GO and conducting polymer poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) in water, a dispersion with dramatically increased viscosity is obtained, which turns into sticky thin films upon casting. Surprisingly, the insulating GO makes PEDOT much more conductive by altering its chain conformation and morphology. The GO/PEDOT gel can function as a metal-free solder for creating mechanical and electrical connections in organic optoelectronic devices. As a proof-of-concept, polymer tandem solar cells have been fabricated by a direct adhesive lamination process enabled by the sticky GO/PEDOT film. The sticky interconnect can greatly simplify the fabrication of organic tandem architectures, which has been quite challenging via solution processing. Thus, it could facilitate the construction of high efficiency tandem solar cells with different combinations of solution-processable materials. PMID- 21615171 TI - 4D scanning transmission ultrafast electron microscopy: Single-particle imaging and spectroscopy. AB - We report the development of 4D scanning transmission ultrafast electron microscopy (ST-UEM). The method was demonstrated in the imaging of silver nanowires and gold nanoparticles. For the wire, the mechanical motion and shape morphological dynamics were imaged, and from the images we obtained the resonance frequency and the dephasing time of the motion. Moreover, we demonstrate here the simultaneous acquisition of dark-field images and electron energy loss spectra from a single gold nanoparticle, which is not possible with conventional methods. The local probing capabilities of ST-UEM open new avenues for probing dynamic processes, from single isolated to embedded nanostructures, without being affected by the heterogeneous processes of ensemble-averaged dynamics. Such methodology promises to have wide-ranging applications in materials science and in single-particle biological imaging. PMID- 21615170 TI - Cell-specific delivery of diverse cargos by bacteriophage MS2 virus-like particles. AB - Virus-like particles (VLPs) of bacteriophage MS2 possess numerous features that make them well-suited for use in targeted delivery of therapeutic and imaging agents. MS2 VLPs can be rapidly produced in large quantities using in vivo or in vitro synthesis techniques. Their capsids can be modified in precise locations via genetic insertion or chemical conjugation, facilitating the multivalent display of targeting ligands. MS2 VLPs also self-assemble in the presence of nucleic acids to specifically encapsidate siRNA and RNA-modified cargos. Here we report the use of MS2 VLPs to selectively deliver nanoparticles, chemotherapeutic drugs, siRNA cocktails, and protein toxins to human hepatocellular carcinoma (HCC). MS2 VLPs modified with a peptide (SP94) that binds HCC exhibit a 10(4) fold higher avidity for HCC than for hepatocytes, endothelial cells, monocytes, or lymphocytes and can deliver high concentrations of encapsidated cargo to the cytosol of HCC cells. SP94-targeted VLPs loaded with doxorubicin, cisplatin, and 5-fluorouracil selectively kill the HCC cell line, Hep3B, at drug concentrations <1 nM, while SP94-targeted VLPs that encapsidate a siRNA cocktail, which silences expression of cyclin family members, induce growth arrest and apoptosis of Hep3B at siRNA concentrations <150 pM. Impressively, MS2 VLPs, when loaded with ricin toxin A-chain (RTA) and modified to codisplay the SP94 targeting peptide and a histidine-rich fusogenic peptide (H5WYG) that promotes endosomal escape, kill virtually the entire population of Hep3B cells at an RTA concentration of 100 fM without affecting the viability of control cells. Our results demonstrate that MS2 VLPs, because of their tolerance of multivalent peptide display and their ability to specifically encapsidate a variety of chemically disparate cargos, induce selective cytotoxicity of cancer in vitro and represent a significant improvement in the characteristics of VLP-based delivery systems. PMID- 21615173 TI - Molecular accordion: vapoluminescence and molecular flexibility in the orange and green luminescent crystals of the dimer, Au2(MU-bis (diphenylphosphino)ethane)2Br2. AB - Solutions containing the components Au(+), dppe (dppe is bis(diphenylphosphino)ethane), and Br(-) in a 1:1:1 ratio can produce three different types of crystals: type A, orange luminescent solvates of the dimer Au(2)(dppe)(2)Br(2) (Au(2)(MU-dppe)(2)Br(2).2(OSMe(2)), Au(2)(MU dppe)(2)Br(2).2(OCMe(2)), Au(2)(MU-dppe)(2)Br(2).2(CH(2)Cl(2)), Au(2)(MU dppe)(2)Br(2).2(HC(O)NMe(2))); type B, green luminescent solvates of the same dimer (Au(2)(MU-dppe)(2)Br(2).(NCMe) and Au(2)(MU-dppe)(2)Br(2).0.5(C(4)H(10)O)); and type C, orange luminescent solvates of a polymer ({Au(MU dppe)Br}(n).0.5(C(4)H(10)O) and {Au(MU-dppe)Br}(n).(CH(2)Cl(2))). Some crystals of types A are solvoluminescent. Exposure of type A crystals of Au(2)(MU dppe)(2)Br(2).2(OCMe(2)) or Au(2)(MU-dppe)(2)Br(2).2(CH(2)Cl(2)) to air or vacuum results in the loss of the orange luminescence and the formation of new green luminescent crystals. Subsequent exposure of these crystals to acetone or dichloromethane vapor results in the reformation of crystals of type A. The dimeric complexes in crystals of types A and B are all centrosymmetric and share a common ring conformation. Within these dimers, the coordination geometry of each gold center is planar with a P(2)Br donor set. In other respects, the Au(2)(MU-dppe)(2)Br(2) molecule is remarkably flexible and behaves as a molecular accordion, whose dimensions depend upon the solvate content of a particular crystalline phase. In particular, the dimer Au(2)(MU-dppe)(2)Br(2) is able to accommodate Au...Au separations that range from 3.8479(3) to 3.0943(2) A, and these variations along with alterations in the Au-Br distances and in the P-Au-P angles are the likely causes of the differences in the luminescence properties of these crystals. PMID- 21615172 TI - Pb2+ as modulator of protein-membrane interactions. AB - Lead is a potent environmental toxin that mimics the effects of divalent metal ions, such as zinc and calcium, in the context of specific molecular targets and signaling processes. The molecular mechanism of lead toxicity remains poorly understood. The objective of this work was to characterize the effect of Pb(2+) on the structure and membrane-binding properties of C2alpha. C2alpha is a peripheral membrane-binding domain of Protein Kinase Calpha (PKCalpha), which is a well-documented molecular target of lead. Using NMR and isothermal titration calorimetry (ITC) techniques, we established that C2alpha binds Pb(2+) with higher affinity than its natural cofactor, Ca(2+). To gain insight into the coordination geometry of protein-bound Pb(2+), we determined the crystal structures of apo and Pb(2+)-bound C2alpha at 1.9 and 1.5 A resolution, respectively. A comparison of these structures revealed that the metal-binding site is not preorganized and that rotation of the oxygen-donating side chains is required for the metal coordination to occur. Remarkably, we found that holodirected and hemidirected coordination geometries for the two Pb(2+) ions coexist within a single protein molecule. Using protein-to-membrane Forster resonance energy transfer (FRET) spectroscopy, we demonstrated that Pb(2+) displaces Ca(2+) from C2alpha in the presence of lipid membranes through the high affinity interaction with the membrane-unbound C2alpha. In addition, Pb(2+) associates with phosphatidylserine-containing membranes and thereby competes with C2alpha for the membrane-binding sites. This process can contribute to the inhibitory effect of Pb(2+) on the PKCalpha activity. PMID- 21615175 TI - A stable aminothioketyl radical in the gas phase. AB - We report the first preparation of a stable aminothioketyl radical, CH(3)C(*)(SH)NHCH(3) (1), by fast electron transfer to protonated thioacetamide in the gas phase. The radical was characterized by neutralization-reionization mass spectrometry and ab initio calculations at high levels of theory. The unimolecular dissociations of 1 were elucidated with deuterium-labeled radicals CH(3)C(*)(SD)NHCH(3) (1a), CH(3)C(*)(SH)NDCH(3) (1b), CH(3)C(*)(SH)NHCD(3) (1c), and CD(3)C(*)(SH)NHCH(3) (1d). The main dissociations of 1 were a highly specific loss of the thiol H atom and a specific loss of the N-methyl group, which were competitive on the potential energy surface of the ground electronic state of the radical. RRKM calculations on the CCSD(T)/aug-cc-pVTZ potential energy surface indicated that the cleavage of the S-H bond in 1 dominated at low internal energies, E(int) < 232 kJ mol(-1). The cleavage of the N-CH(3) bond was calculated to prevail at higher internal energies. Loss of the thiol hydrogen atom can be further enhanced by dissociations originating from the B excited state of 1 when accessed by vertical electron transfer. Hydrogen atom addition to the thioamide sulfur atom is calculated to have an extremely low activation energy that may enable the thioamide group to function as a hydrogen atom trap in peptide radicals. The electronic properties and reactivity of the simple aminothioketyl radical reported here may be extrapolated and applied to elucidate the chemistry of thioxopeptide radicals and cation radicals of interest to protein structure studies. PMID- 21615174 TI - Comparative proteomic analysis implicates COMMD proteins as Epstein-Barr virus targets in the BL41 Burkitt's lymphoma cell line. AB - Epstein-Barr virus (EBV) infection is a major health problem associated with a variety of diseases, including Burkitt's lymphoma. EBV promotes its effects through the activation of multiple signaling pathways, with NF-kappaB mediated transcription being a major target. We have undertaken a comparative proteomic approach using 2D-electrophoresis and mass spectrometry to identify EBV-regulated proteins in the BL41 Burkitt's lymphoma cell line. Many of the proteins differentially regulated were previously known mediators of EBV action. Among the novel proteins identified, three members of the conserved COMMD family were found to be down-regulated. Further analysis of this family at the mRNA level, using reverse-transcriptase or real-time PCR, showed that 7 out of 10 COMMD members were affected in EBV-transformed BL41 cells. Since COMMD family proteins have been implicated as negative regulators of the NF-kappaB transcription factor, our data are consistent with a hypothesis that EBV down-regulates COMMD proteins in order to enhance NF-kappaB mediated transcriptional events and B-lymphocyte transformation. PMID- 21615176 TI - Infrared multiphoton dissociation spectroscopy study of protonated p-aminobenzoic acid: does electrospray ionization afford the amino- or carboxy-protonated ion? AB - Infrared multiphoton dissociation spectra of protonated p-aminobenzoic acid generated by electrospray ionization (ESI) from aqueous methanol and acetonitrile solutions were recorded in the gas phase from 2800-4000 cm(-1). The O-protonated ion is more stable than the N-protonated structure in the gas phase, whereas the opposite is true in both solutions. When CH(3)OH/H(2)O was used as the ESI solvent, only the O-protonated ion was observed. In contrast, a 70:30 mixture of the O- and N-protonated species were produced from CH(3)CN/H(2)O. These structural assignments are based on an assortment of experimental data (action spectra, photofragments, photofragmentation kinetics, and H/D exchange) and are fully supported by extensive computations. This work shows that ESI can lead to isomerization and that the ionization site may be varied by changing the solvent from which the substrate is analyzed. PMID- 21615177 TI - Low doses of pristine and oxidized single-wall carbon nanotubes affect mammalian embryonic development. AB - Several in vitro and in vivo studies suggest local and systemic effects following exposure to carbon nanotubes. No data are available, however, on their possible embryotoxicity in mammals. In this study, we tested the effect of pristine and oxidized single-wall carbon nanotubes (SWCNTs) on the development of the mouse embryo. To this end, SWCNTs (from 10 ng to 30 MUg/mouse) were administered to female mice soon after implantation (postcoital day 5.5); 10 days later, animals were sacrificed, and uteri, placentas, and fetuses examined. A high percentage of early miscarriages and fetal malformations was observed in females exposed to oxidized SWCNTs, while lower percentages were found in animals exposed to the pristine material. The lowest effective dose was 100 ng/mouse. Extensive vascular lesions and increased production of reactive oxygen species (ROS) were detected in placentas of malformed but not of normally developed fetuses. Increased ROS levels were likewise detected in malformed fetuses. No increased ROS production or evident morphological alterations were observed in maternal tissues. No fetal and placental abnormalities were ever observed in control animals. In parallel, SWCNT embryotoxicity was evaluated using the embryonic stem cell test (EST), a validated in vitro assay developed for predicting embryotoxicity of soluble chemical compounds, but never applied in full to nanoparticles. The EST predicted the in vivo data, identifying oxidized SWCNTs as the more toxic compound. PMID- 21615178 TI - Conjugation of beta-sheet peptides to modify the rheological properties of hyaluronic acid. AB - Hyaluronic acid (HA) is a naturally occurring polysaccharide that is commonly used in cosmetic, wound healing, and tissue regeneration applications because of its biocompatibility and intrinsic biological activities. However, the rheological behavior of unmodified HA is not ideal for many of these. In particular, whereas chain entanglements result in an increase in viscosity, they do not prevent flow from delivery sites under zero-shear conditions. It would be of significant benefit if strategies could be developed in which robust but reversible cross-links could be incorporated within the material to allow the formation of a gel under static conditions. In developing a modification strategy, the extent of functionalization should be low to preserve the biological activities of HA. Therefore, this study focused on attaching peptides that self-assemble into beta-sheets to HA to modify the viscosity at low shear rates. It was found that the peptide sequence (LS)(4) forms beta-sheets in aqueous media and when reacted with HA using EDC/HOBt coupling to give 6.0 +/- 1.5% modification the peptide-modified HA exhibits significant increases in low shear viscosities in comparison with the unmodified HA. However, this increase in viscosity was observed only at lower polymer concentrations and at low shear rates, suggesting that network formation is sensitive to external forces and may change at high concentrations. At higher shear rates and at higher polymer concentrations the viscosity profile of the modified HA matches that of the unmodified HA, indicating that the peptide interactions were disrupted or ineffective under these conditions. The rheology of the peptide-modified HA was also compared with samples of HA reacted with the same molar ratio of aniline, but we found that the aniline-modified HA displayed behavior comparable to that of the unmodified HA, which demonstrates that the beta-sheet peptide modification technique is superior to the technique used in commercial products, such as Hyaff, at low degrees of functionalization. PMID- 21615179 TI - Morphology evolution and structural transformation of solution-processed methanofullerene thin film under thermal annealing. AB - The film morphology and nanostructure of the soluble fullerene, [6,6]-phenyl C(61) butyric acid methyl ester (PCBM), are crucial for its applications in organic thin film devices, such as organic solar cells and organic thin film transistors. In this work, the morphology, structural transformation, and crystallite orientation of PCBM film under thermal annealing as a function of annealing temperature, processing solvents, and solution concentrations are systematically investigated. Crystalline PCBM films with needle-like crystallites, axialitic aggregates, and faceted slices are formed in the annealing process. The axialites, made up of needle-like aggregates, are proposed to be partially developed spherulites frozen at the early growth stage formed through low-angle branching. The faceted slices are found to be PCBM single crystallites with hexagonal packing in the film plane. The film undergoes both amorphous-to-crystalline and crystalline-to-crystalline phase transformations as the annealing temperature is increased. The former transformation, corresponding to the self-organization of disordered PCBM molecules in the kinetically frozen films, occurs at a relative low temperature once the motion of these molecules is thermally activated, whereas the later one, corresponding to the transformation between two thermally stable crystalline phases, occurs when further increasing the annealing temperature. The PCBM crystallites composing these films are found to have an orientation preference normal to the film surface, which can be attributed to the confinement of film thickness for PCBM crystallite growth. PMID- 21615180 TI - Comparative proteome cataloging of Lactobacillus rhamnosus strains GG and Lc705. AB - The present study reports an in-depth proteome analysis of two Lactobacillus rhamnosus strains, the well-known probiotic strain GG and the dairy strain Lc705. We used GeLC-MS/MS, in which proteins are separated using 1-DE and identified using nanoLC-MS/MS, to generate high-quality protein catalogs. To maximize the number of identifications, all data sets were searched against the target databases using two search engines, Mascot and Paragon. As a result, over 1600 high-confidence protein identifications, covering nearly 60% of the predicted proteomes, were obtained from each strain. This approach enabled identification of more than 40% of all predicted surfome proteins, including a high number of lipoproteins, integral membrane proteins, peptidoglycan associated proteins, and proteins predicted to be released into the extracellular environment. A comparison of both data sets revealed the expression of more than 90 proteins in GG and 150 in Lc705, which lack evolutionary counterparts in the other strain. Differences were noted in proteins with a likely role in biofilm formation, phage related functions, reshaping the bacterial cell wall, and immunomodulation. The present study provides the most comprehensive catalog of the Lactobacillus proteins to date and holds great promise for the discovery of novel probiotic effector molecules. PMID- 21615182 TI - Is biodegradability a desirable attribute for discarded solid waste? Perspectives from a national landfill greenhouse gas inventory model. AB - There is increasing interest in the use of biodegradable materials because they are believed to be "greener". In a landfill, these materials degrade anaerobically to form methane and carbon dioxide. The fraction of the methane that is collected can be utilized as an energy source and the fraction of the biogenic carbon that does not decompose is stored in the landfill. A landfill life-cycle model was developed to represent the behavior of MSW components and new materials disposed in a landfill representative of the U.S. average with respect to gas collection and utilization over a range of environmental conditions (i.e., arid, moderate wet, and bioreactor). The behavior of materials that biodegrade at relatively fast (food waste), medium (biodegradable polymer) and slow (newsprint and office paper) rates was studied. Poly(3-hydroxybutyrate co-3-hydroxyoctanoate) (PHBO) was selected as illustrative for an emerging biodegradable polymer. Global warming potentials (GWP) of 26, 720, -1000, 990, and 1300 kg CO(2)e wet Mg(-1) were estimated for MSW, food waste, newsprint, office paper, and PHBO, respectively in a national average landfill. In a state of-the-art landfill with gas collection and electricity generation, GWP's of 250, 330, -1400, -96, and -420 kg CO(2)e wet Mg(-1) were estimated for MSW, food waste, newsprint, office paper and PHBO, respectively. Additional simulations showed that for a hypothetical material, a slower biodegradation rate and a lower extent of biodegradation improve the environmental performance of a material in a landfill representative of national average conditions. PMID- 21615181 TI - Selective decoration and release of His-tagged proteins from metal-assembled collagen peptide microflorettes. AB - Materials that mimic the extracellular matrix may serve as ideal delivery vehicles for biopolymers with biomedical applications. Herein we investigate dual His-tagged protein modification and release of metal-triggered, collagen peptide microflorettes by taking advantage of unsatisfied metal/ligands on or within the microflorette structures. Using GFP and RFP as model proteins for visualization, microflorettes were treated with His-tagged proteins either during or after particle assembly. Fluorescence microscopy confirmed the essential role of the His-tag in protein functionalization of the florettes, and confocal microscopy demonstrated distinct labeling zones either within the core or on the surface of the particles depending on their mode of synthesis. The location of the His tagged proteins within the microflorettes was found to strongly influence the rate of release of these proteins from the particles, with the surface-localized proteins demonstrating faster release in comparison to the core-localized proteins. We have demonstrated, therefore, dual His-tagged protein functionalization with spatial control within metal-triggered, collagen peptide microflorette structures, and temporally controlled release of these proteins into biological media. PMID- 21615183 TI - Seven-membered ring formation from cyclopropanated oxo- and epoxyallylsilanes. AB - A useful strategy for cycloheptane annulations from oxo- and epoxyallylsilanes, prepared by silylcupration of allenes, has been developed, and their application to the stereoselective synthesis of 4-methylenecycloheptan-1-ols is of great potential in the construction of seven-membered ring natural products presented. PMID- 21615184 TI - Chiral amplification in one-dimensional helical nanostructures self-organized from phenylethynyl thiophene with elaborated long-chain dicarboxamides. AB - A bis-phenylethynyl thiophene derivative functionalized with long-chain pyridyl biscarboxamides displayed unique helical morphology in the xerogel form via nicely complementary intermolecular interactions. The helical nanostructures visualized by TEM and AFM remarkably matched well with the computational results. Supramolecular chirality can be amplified by coassembly of a chiral conductor to bias the helical arrangement. PMID- 21615185 TI - Temperature derivative spectroscopy to monitor the autoxidation decay of cytochromes P450. AB - Temperature derivative spectroscopy (TDS), a type of relaxation spectroscopy, is a powerful tool to study protein dynamics (Berendzen, J.; Braunstein, D. Proc. Natl. Acad. Sci. U. S. A. 1990, 87, 1). We developed the version of temperature derivative spectroscopy to monitor kinetics of autoxidation of cytochromes P450 and applied it to study the properties of the oxy-ferrous complex of a human membrane bound P450, CYP19A1 (aromatase), and that of a bacterial soluble P450, CYP101 when bound with their most common substrates, androstenedione (AD) and camphor, respectively. TDS extends the panel of methods that can be used to monitor heme protein kinetics, providing a rapid measurement technique and enabling measurement of the autoxidation rate over a wide range of temperatures, yielding the activation energy as well as absolute reaction rate in a single experiment. PMID- 21615187 TI - Effect of mouth-rinsing carbohydrate solutions on endurance performance. AB - Ingesting carbohydrate-electrolyte solutions during exercise has been reported to benefit self-paced time-trial performance. The mechanism responsible for this ergogenic effect is unclear. For example, during short duration (<=1 hour), intense (>70% maximal oxygen consumption) exercise, euglycaemia is rarely challenged and adequate muscle glycogen remains at the cessation of exercise. The absence of a clear metabolic explanation has led authors to speculate that ingesting carbohydrate solutions during exercise may have a 'non-metabolic' or 'central effect' on endurance performance. This hypothesis has been explored by studies investigating the performance responses of subjects when carbohydrate solutions are mouth rinsed during exercise. The solution is expectorated before ingestion, thus removing the provision of carbohydrate to the peripheral circulation. Studies using this method have reported that simply having carbohydrate in the mouth is associated with improvements in endurance performance. However, the performance response appears to be dependent upon the pre-exercise nutritional status of the subject. Furthermore, the ability to identify a central effect of a carbohydrate mouth rinse maybe affected by the protocol used to assess its impact on performance. Studies using functional MRI and transcranial stimulation have provided evidence that carbohydrate in the mouth stimulates reward centres in the brain and increases corticomotor excitability, respectively. However, further research is needed to determine whether the central effects of mouth-rinsing carbohydrates, which have been seen at rest and during fatiguing exercise, are responsible for improved endurance performance. PMID- 21615186 TI - The ACE gene and human performance: 12 years on. AB - Some 12 years ago, a polymorphism of the angiotensin I-converting enzyme (ACE) gene became the first genetic element shown to impact substantially on human physical performance. The renin-angiotensin system (RAS) exists not just as an endocrine regulator, but also within local tissue and cells, where it serves a variety of functions. Functional genetic polymorphic variants have been identified for most components of RAS, of which the best known and studied is a polymorphism of the ACE gene. The ACE insertion/deletion (I/D) polymorphism has been associated with improvements in performance and exercise duration in a variety of populations. The I allele has been consistently demonstrated to be associated with endurance-orientated events, notably, in triathlons. Meanwhile, the D allele is associated with strength- and power-orientated performance, and has been found in significant excess among elite swimmers. Exceptions to these associations do exist, and are discussed. In theory, associations with ACE genotype may be due to functional variants in nearby loci, and/or related genetic polymorphism such as the angiotensin receptor, growth hormone and bradykinin genes. Studies of growth hormone gene variants have not shown significant associations with performance in studies involving both triathletes and military recruits. The angiotensin type-1 receptor has two functional polymorphisms that have not been shown to be associated with performance, although studies of hypoxic ascent have yielded conflicting results. ACE genotype influences bradykinin levels, and a common gene variant in the bradykinin 2 receptor exists. The high kinin activity haplotye has been associated with increased endurance performance at an Olympic level, and similar results of metabolic efficiency have been demonstrated in triathletes. Whilst the ACE genotype is associated with overall performance ability, at a single organ level, the ACE genotype and related polymorphism have significant associations. In cardiac muscle, ACE genotype has associations with left ventricular mass changes in response to stimulus, in both the health and diseased states. The D allele is associated with an exaggerated response to training, and the I allele with the lowest cardiac growth response. In light of the I-allele association with endurance performance, it seems likely that other regulatory mechanisms exist. Similarly in skeletal muscle, the D allele is associated with greater strength gains in response to training, in both healthy individuals and chronic disease states. As in overall performance, those genetic polymorphisms related to the ACE genotype, such as the bradykinin 2 gene, also influence skeletal muscle strength. Finally, the ACE genotype may influence metabolic efficiency, and elite mountaineers have demonstrated an excess of I alleles and I/I genotype frequency in comparison to controls. Interestingly, this was not seen in amateur climbers. Corroboratory evidence exists among high-altitude settlements in both South America and India, where the I allele exists in greater frequency in those who migrated from the lowlands. Unfortunately, if the ACE genotype does influence metabolic efficiency, associations with peak maximal oxygen consumption have yet to be rigorously demonstrated. The ACE genotype is an important but single factor in the determinant of sporting phenotype. Much of the mechanisms underlying this remain unexplored despite 12 years of research. PMID- 21615188 TI - Effects of bicycle saddle height on knee injury risk and cycling performance. AB - Incorrect bicycle configuration may predispose athletes to injury and reduce their cycling performance. There is disagreement within scientific and coaching communities regarding optimal configuration of bicycles for athletes. This review summarizes literature on methods for determining bicycle saddle height and the effects of bicycle saddle height on measures of cycling performance and lower limb injury risk. Peer-reviewed journals, books, theses and conference proceedings published since 1960 were searched using MEDLINE, Scopus, ISI Web of Knowledge, EBSCO and Google Scholar databases, resulting in 62 references being reviewed. Keywords searched included 'body positioning', 'saddle', 'posture, 'cycling' and 'injury'. The review revealed that methods for determining optimal saddle height are varied and not well established, and have been based on relationships between saddle height and lower limb length (Hamley and Thomas, trochanteric length, length from ischial tuberosity to floor, LeMond, heel methods) or a reference range of knee joint flexion. There is limited information on the effects of saddle height on lower limb injury risk (lower limb kinematics, knee joint forces and moments and muscle mechanics), but more information on the effects of saddle height on cycling performance (performance time, energy expenditure/oxygen uptake, power output, pedal force application). Increasing saddle height can cause increased shortening of the vastii muscle group, but no change in hamstring length. Length and velocity of contraction in the soleus seems to be more affected by saddle height than that in the gastrocnemius. The majority of evidence suggested that a 5% change in saddle height affected knee joint kinematics by 35% and moments by 16%. Patellofemoral compressive force seems to be inversely related to saddle height but the effects on tibiofemoral forces are uncertain. Changes of less than 4% in trochanteric length do not seem to affect injury risk or performance. The main limitations from the reported studies are that different methods have been employed for determining saddle height, small sample sizes have been used, cyclists with low levels of expertise have mostly been evaluated and different outcome variables have been measured. Given that the occurrence of overuse knee joint pain is 50% in cyclists, future studies may focus on how saddle height can be optimized to improve cycling performance and reduce knee joint forces to reduce lower limb injury risk. On the basis of the conflicting evidence on the effects of saddle height changes on performance and lower limb injury risk in cycling, we suggest the saddle height may be set using the knee flexion angle method (25-30 degrees ) to reduce the risk of knee injuries and to minimize oxygen uptake. PMID- 21615189 TI - Influence of intensity of physical activity on adiposity and cardiorespiratory fitness in 5-18 year olds. AB - Physical activity (PA) is being increasingly promoted in children in an attempt to curb the rising epidemic of childhood obesity and its future consequences of obesity and cardiovascular diseases in adulthood. Although many reviews and guidelines have been published regarding PA in children and adolescents, none have specifically focused on the influence of intensity of activity on the crucial health aspects of fatness and cardiorespiratory fitness. Therefore, we conducted an online search for pertinent literature and reviewed 25 studies for this purpose. We found that there were limited studies that assessed the influence of 'intensity' of PA on health parameters, and there was considerable inconsistency in defining the thresholds for moderate (MPA) and vigorous (VPA) levels of PA. Collectively, we concluded that VPA is a significant predictor of fatness and significantly correlated to fitness. The association between the intensity of PA and cardiorespiratory fitness is more obscure compared with fatness because of limited studies and the varying conclusions made by them. However, decreased adiposity and increased aerobic capacity have been observed with participants who spent more time performing VPA. Further research needs to be undertaken to arrive at uniform thresholds for defining MPA and VPA and to obtain the exact dose of VPA and MPA, individually, to increase aerobic fitness and decrease adiposity. PMID- 21615190 TI - Can neuromuscular fatigue explain running strategies and performance in ultra marathons?: the flush model. AB - While the industrialized world adopts a largely sedentary lifestyle, ultra marathon running races have become increasingly popular in the last few years in many countries. The ability to run long distances is also considered to have played a role in human evolution. This makes the issue of ultra-long distance physiology important. In the ability to run multiples of 10 km (up to 1000 km in one stage), fatigue resistance is critical. Fatigue is generally defined as strength loss (i.e. a decrease in maximal voluntary contraction [MVC]), which is known to be dependent on the type of exercise. Critical task variables include the intensity and duration of the activity, both of which are very specific to ultra-endurance sports. They also include the muscle groups involved and the type of muscle contraction, two variables that depend on the sport under consideration. The first part of this article focuses on the central and peripheral causes of the alterations to neuromuscular function that occur in ultra-marathon running. Neuromuscular function evaluation requires measurements of MVCs and maximal electrical/magnetic stimulations; these provide an insight into the factors in the CNS and the muscles implicated in fatigue. However, such measurements do not necessarily predict how muscle function may influence ultra endurance running and whether this has an effect on speed regulation during a real competition (i.e. when pacing strategies are involved). In other words, the nature of the relationship between fatigue as measured using maximal contractions/stimulation and submaximal performance limitation/regulation is questionable. To investigate this issue, we are suggesting a holistic model in the second part of this article. This model can be applied to all endurance activities, but is specifically adapted to ultra-endurance running: the flush model. This model has the following four components: (i) the ball-cock (or buoy), which can be compared with the rate of perceived exertion, and can increase or decrease based on (ii) the filling rate and (iii) the water evacuated through the waste pipe, and (iv) a security reserve that allows the subject to prevent physiological damage. We are suggesting that central regulation is not only based on afferent signals arising from the muscles and peripheral organs, but is also dependent on peripheral fatigue and spinal/supraspinal inhibition (or disfacilitation) since these alterations imply a higher central drive for a given power output. This holistic model also explains how environmental conditions, sleep deprivation/mental fatigue, pain-killers or psychostimulants, cognitive or nutritional strategies may affect ultra-running performance. PMID- 21615191 TI - The relationship between substrate metabolism, exercise and appetite control: does glycogen availability influence the motivation to eat, energy intake or food choice? AB - The way in which metabolic fuels are utilized can alter the expression of behaviour in the interests of regulating energy balance and fuel availability. This is consistent with the notion that the regulation of appetite is a psychobiological process, in which physiological mediators act as drivers of behaviour. The glycogenostatic theory suggests that glycogen availability is central in eliciting negative feedback signals to restore energy homeostasis. Due to its limited storage capacity, carbohydrate availability is tightly regulated and its restoration is a high metabolic priority following depletion. It has been proposed that such depletion may act as a biological cue to stimulate compensatory energy intake in an effort to restore availability. Due to the increased energy demand, aerobic exercise may act as a biological cue to trigger compensatory eating as a result of perturbations to muscle and liver glycogen stores. However, studies manipulating glycogen availability over short-term periods (1-3 days) using exercise, diet or both have often produced equivocal findings. There is limited but growing evidence to suggest that carbohydrate balance is involved in the short-term regulation of food intake, with a negative carbohydrate balance having been shown to predict greater ad libitum feeding. Furthermore, a negative carbohydrate balance has been shown to be predictive of weight gain. However, further research is needed to support these findings as the current research in this area is limited. In addition, the specific neural or hormonal signal through which carbohydrate availability could regulate energy intake is at present unknown. Identification of this signal or pathway is imperative if a casual relationship is to be established. Without this, the possibility remains that the associations found between carbohydrate balance and food intake are incidental. PMID- 21615193 TI - Stress, allostatic load, catecholamines, and other neurotransmitters in neurodegenerative diseases. AB - As populations age, the prevalence of geriatric neurodegenerative diseases will increase. These diseases generally are multifactorial, arising from complex interactions among genes, environment, concurrent morbidities, treatments, and time. This essay provides a concept for the pathogenesis of Lewy body diseases such as Parkinson disease, by considering them in the context of allostasis and allostatic load. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple interacting effectors regulated by homeostatic comparators-"homeostats." Stress can be defined as a condition or state in which a sensed discrepancy between afferent information and a setpoint for response leads to activation of effectors, reducing the discrepancy. "Allostatic load" refers to the consequences of sustained or repeated activation of mediators of allostasis. From the analogy of an idling car, the revolutions per minute of the engine can be maintained at any of a variety of levels (allostatic states). Just as allostatic load (cumulative wear and tear) reflects design and manufacturing variations, byproducts of combustion, and time, eventually leading to engine breakdown, allostatic load in catecholaminergic neurons might eventually lead to Lewy body diseases. Central to the argument is that catecholamines in the neuronal cytoplasm are autotoxic and that catecholamines from storage visicles leak into the cytoplasm continuously during life. These neurons therefore depend on vesicular sequestration to limit autotoxicity of cytosolic transmitter. Parkinson disease might be a disease of the elderly because of allostatic load, which depends on genetic predispositions, environmental exposures, repeated stress-related catecholamine release, and time. PMID- 21615192 TI - Phaeochromocytoma: a catecholamine and oxidative stress disorder. AB - The WHO classification of endocrine tumors defines pheochromocytoma as a tumor arising from chromaffin cells in the adrenal medulla - an intra-adrenal paraganglioma. Closely related tumors of extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. Almost all pheochromocytomas and paragangliomas produce catecholamines. The concentrations of catecholamines in pheochromocytoma tissues are enormous, potentially creating a volcano that can erupt at any time. Significant eruptions result in catecholamine storms called "attacks" or "spells". Acute catecholamine crisis can strike unexpectedly, leaving traumatic memories of acute medical disaster that champions any intensive care unit. A very well-defined genotype biochemical phenotype relationship exists, guiding proper and cost-effective genetic testing of patients with these tumors. Currently, the production of norepinephrine and epinephrine is optimally assessed by the measurement of their O-methylated metabolites, normetanephrine or metanephrine, respectively. Dopamine is a minor component, but some paragangliomas produce only this catecholamine or this together with norepinephrine. Methoxytyramine, the O-methylated metabolite of dopamine, is the best biochemical marker of these tumors. In those patients with equivocal biochemical results, a modified clonidine suppression test coupled with the measurement of plasma normetanephrine has recently been introduced. In addition to differences in catecholamine enzyme expression, the presence of either constitutive or regulated secretory pathways contributes further to the very unique mutation-dependent catecholamine production and release, resulting in various clinical presentations. Oxidative stress results from a significant imbalance between levels of prooxidants, generated during oxidative phosphorylation, and antioxidants. The gradual accumulation of prooxidants due to metabolic oxidative stress results in proto-oncogene activation, tumor suppressor gene inactivation, DNA damage, and genomic instability. Since the mitochondria serves as the main source of prooxidants, any mitochondrial impairment leads to severe oxidative stress, a major outcome of which is tumor development. In terms of cancer pathogenesis, pheochromocytomas and paragangliomas represent tumors where the oxidative phosphorylation defect due to the mutation of succinate dehydrogenase is the cause, not a consequence, of tumor development. Any succinate dehydrogenase pathogenic mutation results in the shift from oxidative phosphorylation to aerobic glycolysis in the cytoplasm (also called anaerobic glycolysis if hypoxia is the main cause of such a shift). This phenomenon, also called the Warburg effect, is well demonstrated by a positive [18F] fluorodeoxyglycose positron emission tomography scan. Microarray studies, genome wide association studies, proteomics and protein arrays, metabolomics, transcriptomics, and bioinformatics approaches will remain powerful tools to further uncover the pathogenesis of these tumors and their unique markers, with the ultimate goal to introduce new therapeutic options for those with metastatic or malignant pheochromocytoma and paraganglioma. Soon oxidative stress will be tightly linked to a multistep cancer process in which the mutation of various genes (perhaps in a logistic way) ultimately results in uncontrolled growth, proliferation, and metastatic potential of practically any cell. Targeting the mTORC, IGF-1, HIF and other pathways, topoisomerases, protein degradation by proteosomes, balancing the activity of protein kinases and phosphatases or even synchronizing the cell cycle before any exposure to any kind of therapy will soon become a reality. Facing such a reality today will favor our chances to "beat" this disease tomorrow. PMID- 21615194 TI - Osteocalcin is a stress-responsive neuropeptide. AB - Osteocalcin (OC) is a small, acidic extracellular protein synthesized by osteoblasts during bone formation. 3 residues of gamma-carboxy glutamic acid, formed in a vitamin K dependent process, enable highly specific binding to ionic or bone mineral calcium. Some OC is released to circulation (pOC) and can serve as a biomarker of bone turnover. A series of experiments indicated that OC is stress-responsive in ways that vary with the type of stressor. Those in which the HPA axis predominates slowly decrease OC synthesis and secretion while sympathetic neural activation rapidly increases pOC. The advent of an OC null mutant mouse (KO) led to discovery of several functions for the protein outside the skeleton, most notably in regulation of energy metabolism. The KO mouse also exhibits numerous behavioral traits that are characteristic of sensory impairment. The discovery of OC protein in sensory ganglia stimulated further investigation of the interaction of sensory responses and both OC gene expression and OC protein in trigeminal and dorsal root ganglia. A recently discovered G coupled protein receptor has been suggested as a potential OC receptor in combination with calcium ions. Because of the importance of ionic calcium to signal transduction in the nervous system, the presence of this unique calcium binding protein in neurons led to the hypothesis that OC functions as a neuropeptide. Implications of this potential new function are discussed. PMID- 21615195 TI - Increasing the enrolment of rural applicants to the faculty of medicine and addressing diversity by using a priority matrix approach to assign values to rural attributes. AB - In an external review of the admissions process for the Faculty of Medicine, University of Manitoba, Canada, it was suggested that admissions policies be modified to increase the enrolment of students more likely to practise in rural locations, by selecting a cohort of students with attributes reflecting potential for rural practice. A broad-based Working Group devised a framework for scoring personal attributes reflecting a potential for living and working in rural areas. This framework, based on established characteristics reported in the literature, valued applicants who had rural connections, a history of rural employment, a history of rural community service, or a combination of these attributes. Relative weights for the attributes were determined using a priority matrix approach. Historic admissions data, comprising applicants' rural origin (defined only by location of high school graduation), composite scores, and ranking, were reanalyzed to identify the magnitude of numerical constants that, when applied to composite scores, enhanced the relative ranking of eligible rural-origin applicants. This resulted in a hypothetical 29%-33% increase in the number of rural-origin students in incoming classes in those years. In the inaugural year of implementation of the policy and methodology, 60 admission offers (44.1%) were made to applicants with one or more rural attributes. Without adjustments, only 49 applicants with rural attributes (36%) would have been offered admission. This methodology resulted in a 22.4% increase in admission offers to applicants with rural attributes, and ushered in an incoming class that was more representative of the province's rural-urban demographics than in previous years. This methodology, although focused on rurality, could be equally applicable to any attribute, and to achieve greater diversity and equity among medical school applicants. PMID- 21615196 TI - Primary care and communication in shared cancer care: a qualitative study. AB - OBJECTIVE: To explore perceptions of primary care physicians' (PCPs') and oncologists' roles, responsibilities, and patterns of communication related to shared cancer care in 3 integrated health systems that used electronic health records. STUDY DESIGN: Qualitative study. METHODS: We conducted semistructured interviews with 10 patients having early-stage colorectal cancer and with 14 oncologists and PCPs. Sample sizes were determined by thematic saturation. Dominant themes and codes were identified and subsequently applied to all transcripts. RESULTS: Physicians reported that electronic health records improved communication within integrated systems but that communication with physicians outside of their system was still difficult. Primary care physicians expressed uncertainty about their role during cancer care, although medical oncologists emphasized the importance of comorbidity control during cancer treatment. Patients and physicians described additional roles for PCPs, including psychological distress support and behavior modification counseling. CONCLUSIONS: Integrated systems that use electronic health records likely facilitate shared cancer care through improved PCP-oncologist communication. However, strategies to promote a more active role for PCPs in managing comorbidities, psychological distress, and behavior modification, as well as to overcome communication challenges between physicians not practicing within the same integrated system, are still needed to improve shared cancer care. PMID- 21615197 TI - Effect of emergency department crowding on pneumonia admission care components. AB - OBJECTIVE: To determine pneumonia admission care components that are most affected by emergency department (ED) crowding. STUDY DESIGN: Secondary analysis of a cross-sectional observational survey. METHODS: The setting was a 29-bed academic ED with 39,000 visits per year and state-mandated ratios of nurses to patients. The patients were ED admissions with pneumonia, January 1, 2004, to June 30, 2005. From ED medical records and databases, we abstracted the times of arrival, room placement, ordering of chest radiograph and when obtained, ordering of blood culture and when obtained, and ordering of antibiotic and when administered. We assessed associations between ED volume at the time of arrival of a patient with pneumonia and component durations using multivariate linear regression. RESULTS: For 407 ED admissions with pneumonia, the median component durations (in minutes) were as follows: 20 for arrival to room placement, 44 for arrival to chest radiograph order, 10 for chest radiograph order to radiograph obtained, 120 for room placement to antibiotic order, 10 for blood culture order to culture obtained, 30 for antibiotic order to antibiotic administered, and 195 for arrival to antibiotic administered. Sixty-one percent of patients received antibiotic within 4 hours. We estimate that for every 10 additional ED patients the time from arrival to ordering of a chest radiograph was prolonged by 14.3 minutes and from ordering of antibiotic to administration by 9.3 minutes. CONCLUSIONS: Despite compliance with mandated ratios of nurses to patients, the time from antibiotic ordering to administration (a nursing task) was prolonged with higher ED volumes, as were throughput measures. Targeting these may expedite treatment under crowded ED conditions. PMID- 21615198 TI - Relevance of current guidelines for organizing an anticoagulation clinic. AB - OBJECTIVE: To describe variations in the structure of anticoagulation clinic (ACC) care within the Veterans Health Administration (VA) and to identify structures of care that are associated with better site-level anticoagulation control. STUDY DESIGN: Questionnaire correlated with automated clinical data. METHODS: We characterized 90 VA ACCs using a questionnaire administered by the VA Central Office. Site descriptors included staffing levels, provider training, visit modalities, quality improvement programs, documentation, and care coordination. Patient outcomes were measured by site mean risk-adjusted percentage time in therapeutic range, a measure of anticoagulation control over time. Our study was powered to detect a 3% difference in risk-adjusted percentage time in therapeutic range, a small-to-moderate effect size, between sites with and without a certain characteristic. RESULTS: We observed considerable variation in the structure of ACC care. For example, 48 sites had fewer than 400 patients per provider, 25 sites had 400 to 599 patients per provider, and 17 sites had 600 patients or more per provider. However, none of the site characteristics measured were significantly related to anticoagulation control. CONCLUSIONS: We found substantial variation in guideline-targeted organizational and management features of ACC care within the VA. However, no single feature was associated with better anticoagulation control. Current guidelines for organizing an ACC may have limited relevance for improving patient outcomes. PMID- 21615199 TI - Community-based health information technology alliances: potential predictors of early sustainability. AB - OBJECTIVE: To determine potential predictors of sustainability among community based organizations that are implementing health information technology (HIT) with health information exchange, in a state with significant funding of such organizations. STUDY DESIGN: A longitudinal cohort study of community-based organizations funded through the first phase of the $440 million Healthcare Efficiency and Affordability Law for New Yorkers program. METHODS: We administered a baseline telephone survey in January and February 2007, using a novel instrument with open-ended questions, and collected follow-up data from the New York State Department of Health regarding subsequent funding awarded in March 2008. We used logistic regression to determine associations between 18 organizational characteristics and subsequent funding. RESULTS: All 26 organizations (100%) responded. Having the alliance led by a health information organization (odds ratio [OR] 11.4, P = .01) and having performed a community based needs assessment (OR 5.1, P = .08) increased the unadjusted odds of subsequent funding. Having the intervention target the long-term care setting (OR 0.14, P = .03) decreased the unadjusted odds of subsequent funding. In the multivariate model, having the alliance led by a health information organization, rather than a healthcare organization, increased the odds of subsequent funding (adjusted OR 6.4; 95% confidence interval 0.8, 52.6; P = .08). CONCLUSION: Results from this longitudinal study suggest that both health information organizations and healthcare organizations are needed for sustainable HIT transformation. PMID- 21615200 TI - Electronic medical records and efficiency and productivity during office visits. AB - OBJECTIVE: To estimate the relationship between electronic medical record (EMR) use and efficiency of utilization and provider productivity during visits to US office-based physicians. STUDY DESIGN: Cross-sectional analysis of the 2006-2007 National Ambulatory Medical Care Survey. METHODS: The sample included 62,710 patient visits to 2625 physicians. EMR systems included demographics, clinical notes, prescription orders, and laboratory and imaging results. Efficiency was measured as utilization of examinations, laboratory tests, radiology procedures, health education, nonmedication treatments, and medications. Productivity was measured as total services provided per 20-minute period. Survey-weighted regressions estimated association of EMR use with services provided, visit intensity/duration, and productivity. Marginal effects were estimated by averaging across all visits and by major reason for visit. RESULTS: EMR use was associated with higher probability of any examination (7.7%, 95% confidence interval [CI] = 2.4%, 13.1%); any laboratory test (5.7%, 95% CI = 2.6%, 8.8%); any health education (4.9%, 95% CI = 0.2%, 9.6%); and fewer laboratory tests ( 7.1%, 95% CI = -14.2%, -0.1%). During pre/post surgery visits, EMR use was associated with 7.3% (95% CI= -12.9%, -1.8%) fewer radiology procedures. EMR use was not associated with utilization of nonmedication treatments and medications, or visit duration. During routine visits for a chronic problem, EMR use was associated with 11.2% (95% CI = 5.7%, 16.8%) more diagnostic/screening services provided per 20-minute period. CONCLUSIONS: EMR use had a mixed association with efficiency and productivity during office visits. EMRs may improve provider productivity, especially during visits for a new problem and routine chronic care. PMID- 21615201 TI - Altered neural and vascular mechanisms in hypertension. AB - Essential hypertension is a multifactorial disorder which belongs to the main risk factors responsible for renal and cardiovascular complications. This review is focused on the experimental research of neural and vascular mechanisms involved in the high blood pressure control. The attention is paid to the abnormalities in the regulation of sympathetic nervous system activity and adrenoceptor alterations as well as the changes of membrane and intracellular processes in the vascular smooth muscle cells of spontaneously hypertensive rats. These abnormalities lead to increased vascular tone arising from altered regulation of calcium influx through L-VDCC channels, which has a crucial role for excitation-contraction coupling, as well as for so-called "calcium sensitization" mediated by the RhoA/Rho-kinase pathway. Regulation of both pathways is dependent on the complex interplay of various vasodilator and vasoconstrictor stimuli. Two major antagonistic players in the regulation of blood pressure, i.e. sympathetic nervous system (by stimulation of adrenoceptors coupled to stimulatory and inhibitory G proteins) and nitric oxide (by cGMP signaling pathway), elicit their actions via the control of calcium influx through L-VDCC. However, L-type calcium current can also be regulated by the changes in membrane potential elicited by the activation of potassium channels, the impaired function of which was detected in hypertensive animals. The dominant role of enhanced calcium influx in the pathogenesis of high blood pressure of genetically hypertensive animals is confirmed not only by therapeutic efficacy of calcium antagonists but especially by the absence of hypertension in animals in which L-type calcium current was diminished by pertussis toxin-induced inactivation of inhibitory G proteins. Although there is considerable information on the complex neural and vascular alterations in rats with established hypertension, the detailed description of their appearance during the induction of hypertension is still missing. PMID- 21615202 TI - Systematic mutagenesis of all predicted gntR genes in Xanthomonas campestris pv. campestris reveals a GntR family transcriptional regulator controlling hypersensitive response and virulence. AB - The GntR family is one of the most abundant and widely distributed groups of helix-turn-helix transcriptional regulators in bacteria. Six open reading frames in the genome of the plant pathogen Xanthomonas campestris pv. campestris were predicted to encode GntR regulators. All six of the predicted GntR-encoding genes were individually mutagenized and mutants from five of them were successfully obtained. Plant disease response assays revealed that one, whose product belongs to the YtrA subfamily and has been named HpaR1, is involved in the hypersensitive response (HR) and virulence. Electrophoretic mobility shift assays and in vitro transcription assays revealed that HpaR1 could repress its own transcription level through binding to its promoter sequence, indicating an autoregulatory feedback inhibition mechanism for HpaR1 expression. Promoter-gusA reporter and reverse-transcription polymerase chain reaction analyses revealed that HpaR1 positively and negatively affects the expression of HR and pathogenicity (hrp) genes in host plant and standard media, respectively. Constitutive expression of the key hrp regulator, hrpG, in the hpaR1 mutant could bypass the requirement of HpaR1 for the induction of wild-type HR, suggesting that HpaR1 regulates the expression of hrp genes that encode the type III secretion system via hrpG. PMID- 21615203 TI - Role of type IV pili in virulence of Pseudomonas syringae pv. tabaci 6605: correlation of motility, multidrug resistance, and HR-inducing activity on a nonhost plant. AB - To investigate the role of type IV pili in the virulence of phytopathogenic bacteria, four mutant strains for pilus biogenesis-related genes were generated in Pseudomonas syringae pv. tabaci 6605. PilA encodes the pilin protein as a major subunit of type IV pili, and the pilO product is reported to be required for pilus assembly. The fimU and fimT genes are predicted to produce minor pilins. Western blot analysis revealed that pilA, pilO, and fimU mutants but not the fimT mutant failed to construct type IV pili. Although the swimming motility of all mutant strains was not impaired in liquid medium, they showed remarkably reduced motilities on semisolid agar medium, suggesting that type IV pili are required for surface motilities. Virulence toward host tobacco plants and hypersensitive response-inducing ability in nonhost Arabidopsis leaves of pilA, pilO, and fimU mutant strains were reduced. These results might be a consequence of reduced expression of type III secretion system-related genes in the mutant strains. Further, all mutant strains showed enhanced expression of resistance nodulation-division family members mexA, mexB, and oprM, and higher tolerance to antimicrobial compounds. These results indicate that type IV pili are an important virulence factor of this pathogen. PMID- 21615204 TI - A novel regulatory role of HrpD6 in regulating hrp-hrc-hpa genes in Xanthomonas oryzae pv. oryzicola. AB - Xanthomonas oryzae pv. oryzicola, the causal agent of bacterial leaf streak in the model plant rice, possesses a hypersensitive response and pathogenicity (hrp), hrp-conserved (hrc), hrp-associated (hpa) cluster (hrp-hrc-hpa) that encodes a type III secretion system (T3SS) through which T3SS effectors are injected into host cells to cause disease or trigger plant defenses. Mutations in this cluster usually abolish the bacterial ability to cause hypersensitive response in nonhost tobacco and pathogenicity in host rice. In Xanthomonas spp., these genes are generally assumed to be regulated by the key master regulators HrpG and HrpX. However, we present evidence that, apart from HrpG and HrpX, HrpD6 is also involved in regulating the expression of hrp genes. Interestingly, the expression of hpa2, hpa1, hpaB, hrcC, and hrcT is positively controlled by HrpD6. Transcriptional expression assays demonstrated that the expression of the hrcC, hrpD5, hrpE, and hpa3 genes was not completely abolished by hrpG and hrpX mutations. As observed in analysis of their corresponding mutants, HrpG and HrpX exhibit contrasting gene regulation, particularly for hpa2 and hrcT. Other two component system regulators (Zur, LrpX, ColR/S, and Trh) did not completely inhibit the expression of hrcC, hrpD5, hrpE, and hpa3. Immunoblotting assays showed that the secretion of HrpF, which is an HpaB-independent translocator, is not affected by the mutation in hrpD6. However, the mutation in hrpD6 affects the secretion of an HpaB-dependent TAL effector, AvrXa27. These novel findings suggest that, apart from HrpG and HrpX, HrpD6 plays important roles not only in the regulation of hrp genes but also in the secretion of TAL effectors. PMID- 21615206 TI - Whitefly resistance traits derived from the wild tomato Solanum pimpinellifolium affect the preference and feeding behavior of Bemisia tabaci and reduce the spread of Tomato yellow leaf curl virus. AB - Breeding of tomato genotypes that limit whitefly (Bemisia tabaci) access and feeding might reduce the spread of Tomato yellow leaf curl virus (TYLCV), a begomovirus (genus Begomovirus, family Geminiviridae) that is the causal agent of tomato yellow leaf curl disease. TYLCV is restricted to the phloem and is transmitted in a persistent manner by B. tabaci. The tomato breeding line ABL 14 8 was developed by introgressing type IV leaf glandular trichomes and secretion of acylsucroses from the wild tomato Solanum pimpinellifolium accession TO-937 into the genetic background of the whitefly- and virus-susceptible tomato cultivar Moneymaker. Results of preference bioassays with ABL 14-8 versus Moneymaker indicated that presence of type IV glandular trichomes and the production of acylsucrose deterred the landing and settling of B. tabaci on ABL 14-8. Moreover, electrical penetration graph studies indicated that B. tabaci adults spent more time in nonprobing activities and showed a reduced ability to start probing. Such behavior resulted in a reduced ability to reach the phloem. The superficial type of resistance observed in ABL 14-8 against B. tabaci probing significantly reduced primary and secondary spread of TYLCV. PMID- 21615207 TI - G Protein-coupled receptor kinase 2 (GRK2): A novel modulator of insulin resistance. AB - G protein-coupled receptor kinase 2 (GRK2) is emerging as a key, integrative node in many signalling pathways. Besides its canonical role in the modulation of the signalling mediated by many G protein-coupled receptors (GPCR), this protein can display a very complex network of functional interactions with a variety of signal transduction partners, in a stimulus, cell type, or context-specific way. We review herein recent data showing that GRK2 can regulate insulin-triggered transduction cascades at different levels and that this protein plays a relevant role in insulin resistance and obesity in vivo, what uncovers GRK2 as a potential therapeutic target in the treatment of these disorders. PMID- 21615208 TI - Novel low-molecular-weight hypromellose polymeric films for aqueous film coating applications. AB - The concentration of hypromellose (HPMC) is known to significantly impact the viscosity of coating solutions. The purpose of this study was to determine the viscosity of novel low-molecular-weight (LMW) HPMC products as a function of polymer concentration. The mechanical properties and water vapor permeability of free films prepared from these novel LMW HPMC polymers were also determined and the results were compared with films prepared with conventional HPMC. Solutions of LMW and conventional HPMC 2910 and 2906 containing up to 40% polyethylene glycol (PEG) 400 were prepared and the viscosities were measured using a Brookfield viscometer. Solutions were then cast onto glass plates and stored at 30?C and 50% relative humidity until films were formed. A Chatillon digital force gauge attached to a motorized test stand was used to quantify the mechanical properties of the films, whereas water vapor permeabilities were determined according to the ASTM E96 M-05 water method. As expected, the novel LMW polymer solutions exhibited significantly lower viscosities than the conventional comparators at equivalent polymer concentrations. Film strength of the LMW materials was lower than films prepared from the conventional HPMC solutions, although this effect was not as evident for the HPMC 2906 chemistry. Increasing concentrations of the plasticizer resulted in decreased tensile strength and Young?s modulus and increased elongation as well as increased water vapor permeability, irrespective of polymer type. No statistical difference was found between the tensile strength to Young?s modulus ratios of the F chemistry LMW and conventional HPMC polymer films. PMID- 21615209 TI - Force extension relaxation of medium force orthodontic latex elastics. AB - OBJECTIVE: To evaluate the force extension relaxation of different manufacturers and diameters of latex elastics subjected to static tensile testing under dry and wet conditions. MATERIALS AND METHODS: Sample sizes of 15 elastics from American Orthodontics (AO) (Sheboygan, Wis), TP (La Porte, Ind), and Morelli Orthodontics (Sorocaba SP, Brazil) were used. Equivalent medium force products were tested- 3/16, 1/4, and 5/16 inch lumen size from each manufacturer--making a total of 1080 specimens. An apparatus was designed to simulate oral environments during elastics stretching. Forces were read after 1, 3, 6, 12, and 24 hour periods using the Emic Testing Machine (Emic Co., Sao Paulo, Brazil) with 30 mm/min cross head speed and load cell of 20 N (Emic Co). Kruskal-Wallis and Dunn's tests were used to identify statistical significance. RESULTS: Statistical differences between AO and the other brands were noted for all testing times. Significant variation in mechanical properties was observed in latex elastics from Morelli. Relationships among loads at the 0 hour time period were as follows: Morelli>AO>TP for 3/16 elastics (P = .0016), 1/4 elastics (P = .0016), and 5/16 elastics (P = .0087). CONCLUSION: Significant differences in force extension relaxation were noted for elastics from these manufacturers. Force relaxation over the 24 hour time period was AO>Morelli>TP for 3/16 elastics, AO>TP>Morelli for 1/4 elastics, and TP>AO>Morelli for 5/16 elastics. The force decay pattern showed a notable drop-off of forces during 0 to 3 hours, a slight increase in force values from 3 to 6 hours, and a progressive force reduction over 6 to 24 hours. PMID- 21615210 TI - Evaluation of the effect of force direction on stationary anchorage success of mini-implant with a lever-arm-shaped upper structure. AB - OBJECTIVE: To compare the effect of clockwise and counterclockwise torque on the primary stability of a mini-implant with a lever-arm-shaped upper structure. MATERIALS AND METHODS: Twenty-four white rabbits were used for this study. Two screw-type mini-implants were placed in each tibia. In all, 96 screws were inserted. Two weeks later, a 2-N force was applied to the mini-implants without an upper structure in eight rabbits (control group). The mini-implants of the other 16 rabbits were loaded with an upper structure (experimental group). In the experimental group, the two left mini-implants were loaded in a clockwise direction (CW group) and the two right implants were loaded in a counterclockwise direction (CCW group). The rabbits were sacrificed at 1 week or 8 weeks after loading in both control and experimental groups. The removal torque value (RTV) was measured in 15 of 16 mini-implants in each group and the remaining implant was processed for histologic examination. RESULTS: At 1 week there were no significant differences in the mean RTV between the control, CW, and CCW groups. At 8 weeks, the RTV was higher in the control and experimental groups than in the respective 1-week groups. At 8 weeks, there were no significant differences in the RTV between the control and CW groups, but the CCW group showed a lower RTV. CONCLUSIONS: CCW torque can decrease the stability of a mini-implant, whereas a CW torque has no effect. PMID- 21615211 TI - Influence of single-jaw surgery vs bimaxillary surgery on the outcome and duration of combined orthodontic-surgical treatment. AB - OBJECTIVE: To analyze the effects of single-jaw surgery (mandible or maxilla only) vs bimaxillary surgery on final peer assessment rating (PAR) score outcome and overall treatment duration. MATERIALS AND METHODS: Treatment records of 63 consecutively treated orthognathic patients were assessed; 41 underwent bimaxillary procedures, and the remainder single-jaw procedures. All treatment was undertaken at Kent and Canterbury Hospital in the United Kingdom. Demographic characteristics and clinical parameters, including treatment duration, number of visits required, initial and final PAR scores, and number of extractions undertaken, were recorded. RESULTS: The mean treatment time was 30.6 months; treatment time was shortest in the maxillary procedure only group. The mean reduction in percentage PAR score was 77%, with an average final score of 9. Linear regression analysis confirmed that procedure type had no influence on final PAR score (P = .62) or on overall treatment duration after adjustment for extractions and initial PAR score as confounders (P = .47). CONCLUSIONS: No significant difference was noted in treatment duration or in occlusal outcome between single- and double-jaw surgeries. PMID- 21615212 TI - From cell biology to therapy: ENMD-2076 in the treatment of multiple myeloma. AB - INTRODUCTION: Multiple myeloma (MM) remains incurable, indicating the need for continued investigation of innovative strategies. Recent progress in molecular biology has advanced the discovery of novel drugs for MM. ENMD-2076 is an orally bioavailable, multi-target kinase inhibitor with multiple mechanisms of action, including anti-proliferative and pro-apoptotic activity, and anti-angiogenic effects. AREAS COVERED: In this review, the authors summarize the preclinical in vitro and in vivo data that have formed the rationale for clinical investigation of ENMD-2076 in MM. In addition, the authors review the early clinical results of ENMD-2076 in MM and other malignancies, and speculate on potential avenues of future clinical research in the development of this drug for MM. EXPERT OPINION: There is a strong preclinical rationale for investigating ENMD-2076 in MM that is confirmed by early clinical results in an ongoing Phase I trial in patients with relapsed or refractory MM. Optimal strategies for developing ENMD-2076 in MM will require better elucidation of its mechanism of action, investigation of biomarkers for response and development of rationale synergistic combinations with other active agents. PMID- 21615214 TI - Predictors and outcome of aftercare participation of alcohol and drug users completing residential treatment. AB - This study attempts to identify factors associated with greater aftercare participation for 367 adults who completed abstinence-based residential addiction treatment between 2004 and 2007 at Bellwood Health Services in Toronto, Canada. Pre-treatment substance use, number of days spent in residential treatment, motivation, treatment satisfaction, and demographics were used to determine which characteristics predicted greater aftercare participation. The duration of residential treatment and treatment satisfaction emerged as significant predictors of aftercare attendance. Regular aftercare attendance was associated with lower levels of substance use at 6-month follow-up. Results suggest that a longer duration of residential treatment can influence continuing care engagement and highlight the importance of initial treatment retention for long-term recovery. PMID- 21615213 TI - Intracochlear drug delivery systems. AB - INTRODUCTION: Advances in molecular biology and in the basic understanding of the mechanisms associated with sensorineural hearing loss and other diseases of the inner ear are paving the way towards new approaches for treatments for millions of patients. However, the cochlea is a particularly challenging target for drug therapy, and new technologies will be required to provide safe and efficacious delivery of these compounds. Emerging delivery systems based on microfluidic technologies are showing promise as a means for direct intracochlear delivery. Ultimately, these systems may serve as a means for extended delivery of regenerative compounds to restore hearing in patients suffering from a host of auditory diseases. AREAS COVERED: Recent progress in the development of drug delivery systems capable of direct intracochlear delivery is reviewed, including passive systems such as osmotic pumps, active microfluidic devices and systems combined with currently available devices such as cochlear implants. The aim of this article is to provide a concise review of intracochlear drug delivery systems currently under development and ultimately capable of being combined with emerging therapeutic compounds for the treatment of inner ear diseases. EXPERT OPINION: Safe and efficacious treatment of auditory diseases will require the development of microscale delivery devices, capable of extended operation and direct application to the inner ear. These advances will require miniaturization and integration of multiple functions, including drug storage, delivery, power management and sensing, ultimately enabling closed-loop control and timed sequence delivery devices for treatment of these diseases. PMID- 21615215 TI - Treatment of ricin A-chain-induced hepatotoxicity with liposome-encapsulated N acetylcysteine. AB - BACKGROUND: The toxicity of ricin resides in the ricin A-chain (RTA) and is attributed to the inhibition of protein synthesis but inflammation and oxidative stress have also been implicated. RTA can independently enter cells producing comparable tissue injury and inflammation, although at much higher concentrations than intact ricin. Treatment for exposure to ricin or RTA is supportive. PURPOSE: To examine the effectiveness of conventional or liposome-encapsulated N acetylcysteine (Lipo-NAC) in ameliorating RTA-induced hepatotoxicity. METHODS: Four hours after RTA administration (90 ug/kg b.wt, iv), rats were treated with conventional NAC or Lipo-NAC (25 mg/kg NAC). The hepatoprotective effects of the antioxidant formulations were assessed by measuring indexes for liver injury (alanine [ALT] and aspartate [AST] aminotransferase activities), inflammation (myeloperoxidase, tumor necrosis factor-alpha, chloramine levels), and oxidant response (lipid peroxidation, nitrotyrosine, glutathione levels) 24-h post-RTA exposure. RESULTS: Administration of RTA to animals resulted in hepatotoxicity as demonstrated by elevated plasma ALT and AST levels, increases in an inflammatory response, and increases in oxidant response. Treatment of animals with the antioxidant formulations reversed the RTA-induced hepatotoxicity, being most evident following the administration of Lipo-NAC. CONCLUSION: NAC, administered in a liposomal form, may serve as a potentially effective pharmacological agent in the treatment of RTA-induced liver injuries. PMID- 21615217 TI - Cytoprotective response induced by electromagnetic stimulation on SH-SY5Y human neuroblastoma cell line. AB - It is well known that physiological functions and pathological conditions of cells and tissues can be influenced not only by chemical molecules, but also by physical stimuli such as electromagnetic waves. In particular, epidemiological studies suggest possible associations between exposure to electromagnetic fields and an increased risk of tumors and neurodegenerative disorders, such as Alzheimer's disease. However, depending on the dose and on the length of treatment, the electromagnetic stimuli can be harmful or induce a cytoprotective cellular response, suggesting a possible application in medical therapy. In this study, under a tissue engineering viewpoint, we investigated the effects of an electromagnetic wave (magnetic field intensity, 2 mT; frequency, 75 Hz) on a neuronal cellular model characterized by the overexpression of the amyloid precursor protein (APP). After a prolonged electromagnetic treatment, lower mitochondrial activity and proliferation rate, resulting in a higher cellular quiescence, were observed. Focusing on the stress and oxidative pathways, we detected an overall increase of two fundamental proteins, the chaperone heat shock protein HSP70 and the free radical scavenger superoxide dismutase-1 enzyme (SOD-1). Interestingly, we found that the electromagnetic stimulation promotes the nonamyloidogenic processing of APP through an increased expression of the alpha-secretase ADAM10 and an enhanced release of the soluble neurotrophic factor sAPPalpha (a product of the ADAM10-mediated cleavage of APP). In conclusion, these findings suggest that the electromagnetic stimulus, if properly administered in terms of dose and timing, is able to induce a cytoprotective response in the cell. Moreover, these results suggest a possible use of this particular physical stimulation to improve the functional capability of the cells to face noxae. PMID- 21615216 TI - The Nell-1 growth factor stimulates bone formation by purified human perivascular cells. AB - The search for novel sources of stem cells other than bone marrow mesenchymal stem cells (MSCs) for bone regeneration and repair has been a critical endeavor. We previously established an effective protocol to homogeneously purify human pericytes from multiple fetal and adult tissues, including adipose, bone marrow, skeletal muscle, and pancreas, and identified pericytes as a primitive origin of human MSCs. In the present study, we further characterized the osteogenic potential of purified human pericytes combined with a novel osteoinductive growth factor, Nell-1. Purified pericytes grown on either standard culture ware or human cancellous bone chip (hCBC) scaffolds exhibited robust osteogenic differentiation in vitro. Using a nude mouse muscle pouch model, pericytes formed significant new bone in vivo as compared to scaffold alone (hCBC). Moreover, Nell-1 significantly increased pericyte osteogenic differentiation, both in vitro and in vivo. Interestingly, Nell-1 significantly induced pericyte proliferation and was observed to have pro-angiogenic effects, both in vitro and in vivo. These studies suggest that pericytes are a potential new cell source for future efforts in skeletal regenerative medicine, and that Nell-1 is a candidate growth factor able to induce pericyte osteogenic differentiation. PMID- 21615218 TI - Chronic obstructive pulmonary disease: patho-physiology, current methods of treatment and the potential for simvastatin in disease management. AB - INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is a severe disease that leads to a non-reversible obstruction of the small airways. The prevalence of this disease is rapidly increasing in developed countries, and in 2020 it has been predicted that this disease will reach the third cause of mortality worldwide. COPD patients do not respond well to current treatment modalities, such as bronchodilators and corticosteroids. AREAS COVERED: This review article focuses on the patho-physiology of COPD, explores current approaches to alleviate and treat the disease, and discusses the potential use of statins for treatment. Specifically, the mechanism of action and metabolism of simvastatin, the most known and studied molecule among the statin family, are critically reviewed. EXPERT OPINION: Various cellular pathways have been implicated in COPD, with alveolar macrophages emerging as pivotal inflammatory mediators in the COPD patho physiology. Recently, emerging anti-cytokine therapies, such as PDE4 inhibitors and ACE inhibitors, have shown good anti-inflammatory properties that can be useful in COPD treatment. Recently, statins as a drug class have gained much interest with respect to COPD management, following studies which show simvastatin to exert effective anti-inflammatory effects, via inhibition of the mevalonic acid cascade in alveolar macrophages. PMID- 21615219 TI - The depolymerization of sodium alginate by oxidative degradation. AB - Alginate has been extensively used as a carrier for macromolecules and as gene delivery vehicle. Both properties are molecular weight (Mw) dependent. Herein, we investigated factors affecting the oxidative depolymerization of alginate. The depolymerization process occurred mainly in the first 1 h. The Mw of the depolymerized alginate was influenced by the reaction temperature. At temperature 20 and 30 degrees C, Mw of the alginate fragment kept constant and further Mw decrease was observed at 40 degrees C. Along with the increase of hydrogen peroxide concentration, the Mw of the fragments decreased gradually. Influence of alginate initial concentration was marginal. A linear decrease of Mw was observed when the system pH was in the range of 5-7, whereas no further change was found when the system pH decreased from 7 to 8. Fourier transformed infrared spectroscopy spectra revealed that degradation undergoes by the breakage of the glycosidic bonds of polymers. No structural change was observed during the depolymerization process by UV spectroscopy. Cloud point pH increase was found for alginate 30 k. In summary, this method is an effective and convenient approach for preparing low Mw oligosaccharides from sodium alginate and may be potentially useful for the drug delivery system design with alginate. PMID- 21615220 TI - Hazardous drinking and drinking patterns among the reindeer-herding Sami population in Sweden. AB - The objective of this study was to investigate hazardous drinking among reindeer herding Sami in Sweden. A cross-sectional questionnaire study was conducted in 2007, which included the Alcohol Use Disorder Identification Test. A total of 319 reindeer-herding Sami were compared with urban and rural reference populations of 1,393 persons. Data were analyzed with regard to population, gender, age group, education, anxiety, depression, and work-related stress. The Sami population did not report a higher prevalence of hazardous drinking compared with the reference groups; however, subgroups of Sami men with symptoms of depression were revealed as at risk, in contrast to Sami women who were not found to be at risk at all. Limitations of the study are discussed. PMID- 21615221 TI - The experience of patients undergoing awake craniotomy for intracranial masses: expectations, recall, satisfaction and functional outcome. AB - Introduction. Awake craniotomy is a well-established neurosurgical technique for lesions involving eloquent cortex, however, there is little information regarding patients' subjective experience with this type of surgery. Here we explore the expectations, recall, satisfaction and functional outcome of patients undergoing awake craniotomy. Methods. Three semi-structured interviews using closed- and open-ended questions were conducted with each of 26 consecutive patients (17 males, 9 females; aged 16-78 years) who underwent their first awake craniotomy between 2007 and 2009. Seven patients were interviewed retrospectively, 19 prospectively. Clinical data are included. Results. The following themes emerged from this study: (1) most patients demonstrated a good understanding of the rationale behind awake craniotomy; (2) patients felt the asleep-awake-asleep anaesthetic protocol used in this series was appropriate; (3) patients' confidence and preparedness for surgery was high, attributed to preparation by the surgical team. Seven of 26 (27%) patients had no recollection of being awake. Most patients had a positive anaesthetic and surgical experience, while a minority of patients reported experiencing more than slight pain (2/26; 8%) and discomfort (3/26; 12%), fear (4/26; 15%) or claustrophobia (1/26; 4%) intra operatively. At follow-up (6 weeks post-operatively), most patients were functionally unimpaired; there was only one permanent neurological complication of surgery. We found that 24/26 (92%) patients were satisfied with their experience; one patient had no opinion and another one was unsatisfied. Five of 26 (19%) patients still reported more than slight discomfort, and 3/26 (12%) reported more than slight pain attributable to the surgery. A summary of the English peer-reviewed literature on the patient experience of awake craniotomy is also incorporated. Conclusions. This study confirms that awake craniotomy using the 'asleep-awake-asleep' anaesthetic protocol is a generally safe and well tolerated procedure associated overall with satisfactory patients' experiences and neurological outcomes. PMID- 21615222 TI - Endoscopic grading of gastroesophageal flap valve helps predict proton pump inhibitor response in patients with gastroesophageal reflux disease. AB - OBJECTIVE: Limited information is available on predictors of the response to proton pump inhibitor (PPI) treatment in patients with gastroesophageal reflux disease (GERD). Endoscopic grading of gastroesophageal flap valve (GEFV) is simple and reproducible, and can provide useful information on patients with suspected reflux undergoing an endoscopy. The aim of this study was to prospectively identify predictors, including endoscopic findings such as GEFV, for PPI treatment outcomes in patients with GERD. MATERIAL AND METHODS: One hundred and fifty consecutive patients with GERD were enrolled. All patients were treated with pantoprazole 40 mg daily for 8 weeks. Treatment response was defined as greater than 50% reduction in symptom scores between the two symptom assessments (i.e., over 4 or 8 weeks). Univariate and multivariate logistic regression analyses between responders and non-responders were performed to identify variables predicting response to pantoprazole treatment. RESULTS: Of the 150 consecutive patients considered for this study, 31 were excluded based on exclusion criteria and/or refusal to participate, leaving 119 eligible patients. After 4-week pantoprazole treatment, 70 of 119 (58.8%) patients were classified as responders. Patients with obesity and Helicobacter pylori infection demonstrated a higher response rate to 4-week pantoprazole treatment (odds ratio (OR) 5.28, p = 0.008; OR 3.76, p = 0.023, respectively). Patients with abnormal GEFV showed a lower response rate to 4-week treatment (OR 0.17, p = 0.016). After 8-week treatment, 86 of 119 (72.3%) patients were classified as responders. Abnormal GEFV and aspirin intake were associated with a lower response rate to 8 week treatment (OR 0.17, p = 0.021; OR 0.11, p = 0.020, respectively). CONCLUSIONS: Abnormal GEFV was a significant independent factor predicting poor response to both 4-week and 8-week pantoprazole treatment. Endoscopic grading of GEFV provides useful information for predicting the response to PPI treatment in patients with GERD. PMID- 21615223 TI - Young cannabis users in residential treatment: as distressed as other clients. AB - Doubt remains about the need for residential substance user treatment for young cannabis users. Using a series of validated clinical tools, this study compared 1,221 primarily cannabis-, psychostimulant-, alcohol-, or opioid-dependent young people admitted to an urban/rural Australian residential treatment program between 2001 and 2007. Multinomial logistic regression revealed that the cannabis user group had poorer mental health than the opioid group, poorer social functioning than the alcohol drinking group, and comparably poor functioning otherwise but remained in treatment longer than the psychostimulant and opioid user groups. Residential treatment for primarily cannabis-dependent young people with complex and multiple needs can be supported. PMID- 21615224 TI - Recombinant protein meningococcal serogroup B vaccine combined with outer membrane vesicles. AB - INTRODUCTION: Meningococcal infection is a major cause of morbidity and mortality worldwide. Infection with Neisseria meningitidis is most common in young children, teenagers and people with certain medical conditions. Effective polysaccharide and glycoconjugate vaccines for serogroups A, C, W135 and Y have been developed. A similar capsular polysaccharide approach for serogroup B (MenB) has by most been judged as unsuitable, hence, no broad coverage vaccine has been licensed to date. The novel vaccine Bexsero (previously 4CMenB) has been developed and proven safe and immunogenic in clinical trials. AREAS COVERED: The authors outline the constituents of Bexsero and immunogenicity and safety data from preclinical and clinical trials published in peer-reviewed literature, meeting proceedings and publicly-available clinical trial websites from 2000 to 2010. EXPERT OPINION: Bexsero is well tolerated with a proven safety profile, and has demonstrated a robust immune response across different age groups against a range of diverse MenB strains. These data suggest that Bexsero has the ability to provide protection in infants, who are at the greatest risk of developing meningococcal disease. PMID- 21615225 TI - CD81 expression for discrimination between sustained virologic response and relapse in patients with chronic hepatitis C. AB - BACKGROUND AND AIM: The hepatitis C virus (HCV) receptor CD81 is overexpressed on peripheral blood mononuclear cells (PBMC) in patients chronically infected with HCV compared with healthy controls, and expression declines during antiviral therapy. The aim of this study was to prospectively investigate CD81 expression on PBMC for early discrimination between sustained virologic response (SVR) and relapse (REL) to pegylated interferon alfa-2b and ribavirin treatment. METHODS: Sixty-one patients with chronic HCV infection (genotype, GT, 1 and low baseline viremia <600,000 IU/ml, n = 30; GT 2 or 3, n = 31) were investigated. CD81 expression on CD4(+), CD8(+), CD19(+), and CD56(+) cells was measured at baseline, therapy week (TW) 4 and 12 during antiviral therapy by fluorescence activated cell sorting (FACS) analysis. RESULTS: Baseline levels of CD81 on CD4(+), CD8(+), and CD56(+) cells were similar between patients who achieved a SVR (n = 42) and those who relapsed (n = 19). On CD19(+) cells, baseline CD81 expression was higher in patients with SVR than in patients with virologic relapse (REL) (p < 0.006). A cutoff value of 720 relative fluorescence units (RFU) discriminated correctly between SVR and REL with a sensitivity and specificity of 73.7% and 66.7%, respectively. SVR patients showed a significant decline of CD81 expression on CD4(+), CD8(+), CD19(+), and CD56(+) cells (p < 0.01 for all) while in REL patients a significant decline of CD81 expression was observed on CD8(+) and CD56(+) cells, only (p = 0.050 and p = 0.038, respectively). CONCLUSIONS: The current study confirms significant down regulation of CD81 expression on different lymphocyte subpopulations during pegylated interferon alfa-based antiviral therapy in patients with chronic hepatitis C. Baseline CD81 expression on CD19(+) cells was found to discriminate between SVR and REL. PMID- 21615226 TI - Kynurenic acid synthesis and kynurenine aminotransferases expression in colon derived normal and cancer cells. AB - BACKGROUND: Kynurenic acid (KYNA), a tryptophan metabolite, was found in human saliva, gastric juice, bile, pancreatic juice and mucus of rat small intestine. METHODS: KYNA content in mucus aspirated from human caecum or colon ascendens and KYNA production in colon epithelial and cancer cells were determined using HPLC. Moreover, biological properties of KYNA and kynurenine aminotransferases (KATs) expression in colon epithelial and colon cancer cells were studied. RESULTS: Considerably higher KYNA concentration was detected in samples from patients diagnosed with colon carcinoma (269.40 +/- 107.00 pmol/ml, N = 4), Adenoma tubulovillosum (200.50 +/- 36.72, N = 10) or Adenoma tubulare (243.50 +/- 38.09, N = 9) than in control group (82.22 +/- 7.61 pmol/ml, N = 30). Moreover, colon epithelium CCD 841 CoTr cells actively synthesized KYNA in a concentration- and time-dependent manner. This process was decreased by aminooxyacetic acid and L glutamate in opposite to 4-aminopyridine treatment. Interestingly, KYNA production in colon cancer cells (HT-29 1.39 +/- 0.27, LS-180 1.18 +/- 0.15 and Caco-2 4.21 +/- 0.30 pmol/1 x 10(5) cells/2 h) was considerably higher in comparison to normal colon epithelial cells (0.70 +/- 0.07 pmol/1 x 10(5) cells/2 h). However, KATs I and II were expressed at similar level in both colon epithelium and cancer cells. Furthermore, KYNA exerted an antiproliferative effect at higher micro- and millimolar concentrations against colon cancer cells with the IC(50) of 0.9, 0.2 and 1.2 mM for HT-29, LS-180 and Caco-2 cells, respectively. CONCLUSION: Summarizing, this is the first report presenting KYNA synthesis and KAT expression in colon derived normal and cancer cells. PMID- 21615227 TI - Capsule endoscopy in pediatric patients: technique and results in our first 100 consecutive children. AB - OBJECTIVE: Capsule endoscopy (CE) offers noninvasive methods to assess small bowel pathology but only limited data are available on the feasibility, safety, and findings in children. In this study, we report our results of 100 consecutive CE in children. MATERIAL AND METHODS: Single center retrospective study. All pediatric patients (mean age 119 months, range from 8 to 188 months) undergoing CE were included until 100 investigations were completed. The indications for CE were: suspicion or evaluation of Crohn's disease (n = 35) or ulcerative colitis (n = 24), gastrointestinal bleeding (n = 18), and miscellaneous (n = 23). RESULTS: The youngest patients able to swallow the capsule were 84 months old. When the patient was unable to swallow the capsule (n = 51), it was guided into the duodenum with endoscope. In two patients, the capsule remained in the stomach during the 8 h of recording and in 23 cases the capsule failed to reach the cecum. The capsule was expelled naturally in all except one patient. In 39% of the patients, CE revealed a significant finding (multiple ulcers, bleeding, tumors, strictures). In patients examined for bleeding or for a suspicion of Crohn's disease, the respective proportions were 50% and 60%. CONCLUSIONS: This study shows that CE is a feasible diagnostic method to study the small intestine in pediatric patients and that CE can be done in children as young as 8 months old. The diagnostic yield is highest in cases with bleeding or a high suspicion of Crohn's disease. PMID- 21615228 TI - Effect of coefficient of viscosity and ambient temperature on the flow rate of drug solutions in infusion pumps. AB - CONTEXT: FOLFOX6 and FOLFIRI regimens are often selected as the first- or second line treatment for advanced or recurrent colorectal cancer. Patients are now able to undergo at-home treatment by using a portable disposable infusion pump (SUREFUSER((r))A) for continuous intravenous infusion of 5-fluorouracil (5-FU). The duration of continuous 5-FU infusion is normally set at an average of 46 h, but large variations in the duration of infusion are observed. OBJECTIVE AND METHODS: The relationship between the total volume of the drug solution in SUREFUSER((r))A and the duration of infusion was analyzed by regression analysis. In addition, multiple regression analysis of the total volume of the drug solution, dummy variables for temperature, and duration of infusion was carried out. RESULTS: The duration of infusion was affected by the coefficient of viscosity of the drug solution and the ambient temperature. CONCLUSION: The composition of the drug solutions and the ambient temperature must be considered to ensure correct duration of continuous infusion. PMID- 21615229 TI - Development and validation of the Family Health Behavior Scale. AB - OBJECTIVE: The purpose of the current study was to develop a psychometrically sound, parent-report measure of family and child behaviors related to obesity in children between 5- and 12-years-old. METHODS: Item generation, item selection, and initial exploratory factor analysis yielded a 27-item measure called the Family Health Behavior Scale (FHBS). RESULTS: The FHBS contains four subscales measuring health-promoting family behaviors, obesogenic behaviors, meal-time routines, and family physical activity habits. Parent ratings on the FHBS were shown to predict their child's weight classification. The FHBS also demonstrated adequate internal consistency and temporal stability. CONCLUSIONS: The results of the study suggest that the FHBS is a promising measure of family eating and physical activity habits related to obesity in children. PMID- 21615230 TI - Fetal ovarian cysts. Our clinical experience over 16 cases and review of the literature. AB - OBJECTIVE: Fetal ovarian cysts are intra-abdominal structures frequently diagnosed prenatally, tending to present as isolated unilateral lesions in normal fetuses in the third trimester. These cysts may present with complications and their diameter and echogenicity are the main criteria for establishing their prognosis. Spontaneous regression of fetal ovarian cysts is very usual. In the present study, we present our clinical experience on fetal ovarian cyst surveillance and treatment, as well as a review of the literature in the same field. MATERIAL AND METHOD: In this study, we reviewed pre- and postnatal medical records and ultrasonography of 16 fetuses that were diagnosed with ovarian cysts, in Obstetrics Department of University Hospital of Alexandroupolis, between January 2000 and April 2010. We have also reviewed the available literature about fetal ovarian cysts. RESULTS: In a total of 16 cases, postnatal surgery was performed in one infant due to ovarian cyst torsion. In the remaining 15 cases, cysts regressed completely in two fetuses during pregnancy and all the rest of the cysts, including four complex ones, resolved spontaneously after birth. CONCLUSIONS: When fetal ovarian cysts are detected, they should be followed up by serial ultrasonographic examinations. The majority of them will regress spontaneously in a period of 12 months after birth, independent of their sonographic findings. Only symptomatic cysts or cysts with a diameter >5 cm, which do not regress or enlarge, should be treated. PMID- 21615231 TI - Abnormal maternal body mass index and obstetric and neonatal outcome. AB - OBJECTIVE: The objective of this study is to examine the effects of abnormal maternal body mass index (BMI), either underweight or severe or morbid obesity (BMI >35), on obstetrical and neonatal outcomes. METHODS: A three-year period (2.007-2.009) observational retrospective study was carried out in Granada (Spain). Women were categorized by first ten weeks of pregnancy BMI, according to World Health Organization (WHO) into three groups: underweight (<18.5), normal (20-24.9), and severe or morbid obese (>35). Obstetrical and neonatal outcomes were evaluated using normal group as reference after suitable adjustments for confounding factors. RESULTS: 3.016 patients out of 12.781 single births were included. Maternal BMI classified 168 women (5.5 %) as underweight, 2.597 (86.1%) as normal, and 251 (8.3%) as severe or morbidly obese. As compared to normal women, underweight women were younger, and class II or III obese showed higher parity and higher incidence of hypertension disorders and Diabetes Mellitus. After controlling for these confounders, underweight women showed increased adjusted risk of oligohydramnios and low birth weight babies, and severe or morbidly obese women had an increased adjusted risk of Streptococcus Group B colonization, induction of labour, elective and emergency cesarean section, fetal macrosomia, fetal acidosis at birth, and perinatal mortality. CONCLUSIONS: Severe or morbid obesity were associated with an increased risk of adverse perinatal outcome and mortality and should be managed as high-risk pregnancies. PMID- 21615232 TI - Parental use of differential restrictive feeding practices with siblings. AB - OBJECTIVE: To investigate associations between sibling weight status, concerns about sibling weight, and parents' differential use of restrictive feeding practices. METHODS: Participants included 70 mother-father pairs with two biological children between 6 and 12 years old. Each parent completed three Child Feeding Questionnaire (CFQ) subscales (perception of child weight, concern about child weight, and restriction) for each participant sibling. Researchers measured heights and weights and converted child data into Body Mass Index percentiles (BMI%). Multiple regression analysis examined predictors of restrictive feeding practices used by both parents. The nature of differential treatment was examined by calculating Pearson's correlations among sibling differences (older minus younger sibling) in maternal and paternal CFQ reports and sibling BMI%. RESULTS: Concern for child weight, but not actual child BMI% or parental perception of child weight, predicted restrictive feeding practices for both parents. Child gender was not related to child weight status, perception of child weight, concern for child weight, or restriction. Parents were more likely to use differential restrictive feeding practices when they had differential concern for the weight status of their children. However, this differential treatment was not related to differences in actual sibling BMI% or parental perception of child weight. CONCLUSIONS: Parental concern for child weight, rather than actual child weight status, predicts restriction by both mothers and fathers. Across families, parents generally tend to use similar feeding practices with each of their children. Within families, parents may have different interactions with each sibling regarding food when differentially concerned about sibling weight status. PMID- 21615233 TI - Measurement of intraperitoneal metabolites during hypothermic cardiopulmonary bypass using microdialysis. AB - OBJECTIVE: Splanchnic hypoxia, with resultant mucosal acidosis during cardiopulmonary bypass (CPB) has been demonstrated using tonometry. Microdialysis is a minimally-invasive method of obtaining peritoneal fluid samples. We measured the intraperitoneal metabolites during peri-operative period following hypothermic CPB and studied the safety of intraperitoneal microdialysis. DESIGN: Eleven consecutive patients undergoing coronary artery bypass grafting (CABG) were included after obtaining ethics committee approval and informed consent. Microdialysis catheters were placed intraperitoneally after sternotomy. Intraperitoneal samples and arterial blood samples were obtained peri-operatively for first 24 hours. The samples were analysed for levels of glucose, lactate, pyruvate and glycerol. Repeated measures ANOVA test was used to compare timed serum and intraperitoneal samples. RESULTS: The study population included nine males and two females with a mean age of 63.7 +/- 11 years. The mean CPB and X clamp times were 50.9 +/- 7.3 minutes and 27.3 +/- 4.9 minutes, respectively. There were no complications related to microdialysis. The intraperitoneal lactate (L), pyruvate (P) and glycerol increased during CPB and four to six hours postoperatively. The L:P ratio was >10:1 during CPB, but in the postoperative period showed evidence of impaired oxygen utilisation. CONCLUSIONS: This prospective study confirms incidence of intraperitoneal anaerobic metabolism of glucose during CPB and impaired utilisation of glucose in the postoperative period. Microdialysis provides a novel and minimally-invasive method to measure real time intraperitoneal events. PMID- 21615234 TI - 17beta-estradiol levels and oxidative balance in a population of pre-, peri-, and post-menopausal women. AB - BACKGROUND: The high incidence of various diseases observed in post-menopausal women has been widely associated to the decline of 17beta-estradiol (E2) occurring in correspondence of menopausal transition. One of the mechanisms suggested to explain this link takes into account the ability of E2 to counteract oxidative stress (OS) which is believed to play an important role in several pathogenic processes. AIM: To investigate whether stages of women's life characterized by different levels of E2 influence OS. SUBJECTS AND METHODS: We conducted a cross sectional study of OS markers in 159 women subdivided in 65 pre menopausal, 36 peri-menopausal, and 58 post-menopausal classified according to the Staging of Reproductive Aging Workshop (STRAW) criteria. E2, follicle stimulating hormone, and markers of OS including hydroperoxides, thiols, uric acid, total and residual antioxidant power, were assessed. RESULTS: After adjustment for covariates, only total antioxidant power was significantly different according to menopausal status (p <0.01), with lower value in pre- with respect peri- and post-menopausal women. No significant correlations between E2 levels and OS markers were detected. CONCLUSIONS: Endogen E2, and, consequently, its decline during menopausal transition, is not a determinant factor for OS. PMID- 21615235 TI - Effects of red clover extracts on breast cancer cell migration and invasion. AB - Postmenopausal hormone therapy is associated with increased incidence of breast cancer. For this reason alternative therapeutic options to treat menopausal symptoms have been developed. Red clover extracts (RCE) are rich in isoflavones, particularly genistein and daidzein and they have been proved to be effective in reducing vasomotor symptoms in a number of studies. Due to their partial selectivity of action on estrogen receptors (ERs) these compounds have been claimed to be safer on the breast. In this article, we explored the action of RCE on motility and invasion of ER positive breast cancer cells and we partially characterized the signaling mechanisms. The principal isoflavones contained in RCE acted as weak estrogenic compounds when administered alone. However, when provided in association with physiological amounts of estradiol, RCE acted as estrogen antagonist on remodeling of actin cytoskeleton that are requested to enact cell movement and with related modifications of the activity of actin binding proteins, such as moesin. These results offer novel information on the molecular actions of isoflavones contained in red clover on breast cancer cells, supporting a possible action of these molecules as natural selective estrogen receptor modulators in the presence of physiological amounts of estrogens. PMID- 21615236 TI - Influence of sex hormones in women on breast elasticity measured by shear wave sonoelastography--a cross-sectional study. AB - The physiology of breast depends on age, hormonal status, menstrual cycle, lactation, and others. The aim of our study was to evaluate correlations between hormonal status and breast glandular and fat tissue elasticity in healthy women. We examined 77 women aged 20-55 with shear wave sonoelastography and estimated their hormonal levels. There were no important correlations between breast elasticity, follicle-stimulating hormone (FSH), estrogen, prolactine, and thyroid hormones (p > 0.05). Androgens negatively influenced glandular to fat elasticity ratio (Rs = -0.25, p < 0.005). Luteinizing hormone to FSH ratio correlated positively with glandular and fat elasticity, especially in outer-upper quadrant (Rs = 0.24, p = 0.003). PMID- 21615237 TI - The vaginal ring (NuvaRing(r)) for contraception in adolescent women. AB - Adolescence is a phase of life of utmost importance for the present and future physical, psychological, and social health of individuals of both genders. Contraception as a preventive measure and behavior has to be integrated into this developmental context. The aim hereby is not only the prevention of unwanted pregnancies, but also the maintenance and promotion of reproductive and sexual health in a broader sense. This includes protection against sexually transmitted diseases (STI), preservation of fertility, promotion of a self-determined and satisfying sexual life, diminution of general health risks and prevention of diseases which may occur later in life. The vaginal contraceptive ring seems to respond to most of these needs except for protection against STI. In conclusion, the vaginal ring is for these reasons an important option in the contraceptive care of adolescents. PMID- 21615238 TI - Myeloperoxidases and polycystic ovary syndrome. AB - New biological markers are emerging trying to identify earlier cardiovascular high risk subjects. Myeloperoxidases have been involved in the role of atherosclerosis process, by the beginning of the endothelial dysfunction up to the plaque rupture and clinical manifestation, and it has been demonstrated that this enzyme has also a prognostic value. We aimed to assess myeloperoxidases levels in patients with polycystic ovary syndrome (PCOS) with insulin resistance (IR), considering that these women represent a high risk group for cardiovascular disease. We developed a transversal study, comprising 26 patients with PCOS and IR and 30 controls (PCOS without IR). IR was considered with HOMA-IR >=3.0. IR absence was considered when HOMA-IR <3.0, triglycerides <200, BMI <28.7, and BMI<27.8 in patients with familial history of type 2 diabetes. All patients went through anamnesis, physical examination, transvaginal ultrasound, and blood samples. IR PCOS patients had higher levels of myeloperoxidase (22.3 * 18.1, p = 0.047), and also higher BMI. Myeloperoxidase levels correlated directly with insulin. In conclusion, IR PCOS young patients have higher myeloperoxidase levels. PMID- 21615239 TI - Significant associations of prostate-specific antigen nadir and time to prostate specific antigen nadir with survival in prostate cancer patients treated with androgen-deprivation therapy. AB - OBJECTIVE: The influence of prostate-specific antigen (PSA) kinetics on the outcome of metastatic prostate cancer (PCa) after androgen-deprivation therapy (ADT) remains poorly characterised. We evaluated the prognostic significance of PSA nadir and time to PSA nadir as well as their interactive effect on prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT. METHODS: A total of 650 men with advanced or metastatic PCa treated with ADT were studied. The prognostic significance of PSA nadir and time to PSA nadir on PCSM and ACM were analysed using Kaplan-Meier analysis and the Cox regression model. RESULTS: On multivariate analysis, clinical M1 stage, Gleason Score 8-10, PSA nadir >= 0.2 ng/ml and time to PSA nadir < 10 months were independent predictors of PCSM and ACM. The combined analysis showed that patient with higher PSA nadir and shorter time to PSA nadir had significantly higher risk of PCSM and ACM compared to those with lower PSA nadir and longer time to PSA nadir (hazard ratios = 6.30 and 4.79, respectively, all P < 0.001). CONCLUSIONS: Our results suggest that higher PSA nadir level and faster time to reach PSA nadir after ADT were associated with shorter survival for PCa. PMID- 21615240 TI - Postoperative stroke in patients on oral anticoagulation undergoing coronary artery bypass surgery. AB - OBJECTIVE: Patients on long-term warfarin treatment have an inherent high risk of stroke and here we aimed to identify the determinants of postoperative stroke after coronary artery bypass grafting (CABG) in these patients. METHODS: A consecutive series of 270 patients on long-term warfarin treatment who underwent isolated CABG in two university hospitals was assessed by logistic regression as well as classification and regression tree (CART) analysis. RESULTS: Postoperative stroke occurred in 10 patients during in-hospital stay (3.7%). Logistic regression showed that CHADS(2) > 2 (p = 0.036), recent thrombolysis (p < 0.0001) and history of deep vein thrombosis (p = 0.025) were independent predictors of postoperative stroke (area under the ROC curve 0.77). CART analysis showed that CHADS(2) > 2, history of stroke/TIA, no preoperative use of aspirin and preoperative use of low molecular weight heparins were associated with an increased risk of stroke (area under the ROC curve of 0.77). CONCLUSIONS: Both CART and logistic regression analyses showed that the patient characteristics included in CHADS(2) score are important also in the prediction of postoperative stroke risk. Preoperative antiplatelet treatment may be beneficial in the high risk patients and the preoperative bridging with low molecular weight heparins may even be harmful in this respect. PMID- 21615241 TI - A model calculation of coherence effects in the elastic backscattering of very low energy electrons (1-20 eV) from amorphous ice. AB - PURPOSE: Backscattering of very low energy electrons in thin layers of amorphous ice is known to provide experimental data for the elastic and inelastic cross sections and indicates values to be expected in liquid water. The extraction of cross sections was based on a transport analysis consistent with Monte Carlo simulation of electron trajectories. However, at electron energies below 20 eV, quantum coherence effects may be important and trajectory-based methods may be in significant error. This possibility is here investigated by calculating quantum multiple elastic scattering of electrons in a simple model of a very small, thin foil of amorphous ice. METHOD: The average quantum multiple elastic scattering of electrons is calculated for a large number of simulated foils, using a point scatterer model for the water molecule and taking inelastic absorption into account. The calculation is compared with a corresponding trajectory simulation. RESULTS: The difference between average quantum scattering and trajectory simulation at energies below about 20 eV is large, in particular in the forward scattering direction, and is found to be almost entirely due to coherence effects associated with the short-range order in the amorphous ice. For electrons backscattered at the experimental detection angle (45 degrees relative to the surface normal) the difference is however small except at electron energies below about 10 eV. CONCLUSION: Although coherence effects are in general found to be strong, the mean free path values derived by trajectory-based analysis may actually be in fair agreement with the result of an analysis based on quantum scattering, at least for electron energies larger than about 10 eV. PMID- 21615242 TI - Measurement of inelastic cross sections for low-energy electron scattering from DNA bases. AB - PURPOSE: To determine experimentally the absolute cross sections (CS) to deposit various amount of energies into DNA bases by low-energy electron (LEE) impact. MATERIALS AND METHODS: Electron energy loss (EEL) spectra of DNA bases were recorded for different LEE impact energies on the molecules deposited at very low coverage on an inert argon (Ar) substrate. Following their normalisation to the effective incident electron current and molecular surface number density, the EEL spectra were then fitted with multiple Gaussian functions in order to delimit the various excitation energy regions. The CS to excite a molecule into its various excitation modes were finally obtained from computing the area under the corresponding Gaussians. RESULTS: The EEL spectra and absolute CS for the electronic excitations of pyrimidine and the DNA bases thymine, adenine, and cytosine by electron impacts below 18 eV were reported for the molecules deposited at about monolayer coverage on a solid Ar substrate. CONCLUSIONS: The CS for electronic excitations of DNA bases by LEE impact were found to lie within the 10(216) to 10(218) cm(2) range. The large value of the total ionisation CS indicated that ionisation of DNA bases by LEE is an important dissipative process via which ionising radiation degrades and is absorbed in DNA. PMID- 21615243 TI - First-line treatment of patients with disseminated poorly differentiated neuroendocrine carcinomas with carboplatin, etoposide, and vincristine: a single institution experience. AB - Poorly differentiated neuroendocrine carcinomas (PDECs) represent highly malignant tumors with an immense tendency to metastasize and with a poor prognosis. The treatment consists of palliative chemotherapy and corresponds to the treatment of extensive stage small cell lung cancer. MATERIAL AND METHODS: We present the patient characteristics and treatment results of 31 consecutive, chemonaive patients with PDECs treated with carboplatin, etoposide, and vincristine. RESULTS: The response rate was 52%, the disease control rate 77%, and the median overall survival 15.3 months. The one-year survival rate was 55%, and the two-year survival rate was 19%. The median progression free survival (PFS) time was 6.6 months. Survival rates did not correlate with the Ki-67 proliferation index. The treatment was well tolerated. CONCLUSION: Treatment results with carboplatin, etoposide, and vincristine in chemonaive patients with PDECs are comparable to those in patients with SCLC. The prognosis is however poor. PMID- 21615244 TI - Predictive models for drugs exhibiting negative food effects based on their biopharmaceutical characteristics. AB - CONTEXT: A drug is defined to exhibit food effects if its pharmacokinetic parameter, area under the curve (AUC0-infinity) is different when co-administered with food in comparison with its administration on a fasted stomach. Food effects of drugs administered in immediate release dosage forms were classified as positive, negative, and no food effects. OBJECTIVE: In this study, predictive models for negative food effects of drugs that are stable in the gastrointestinal tract and do not complex with Ca2+ are reported. METHODS: An empirical model was developed using five drugs exhibiting negative food effects and seven drugs exhibiting no food effects by multiple regression analysis, based on biopharmaceutical properties generated from in vitro experiments. An oral absorption model was adopted for simulating negative food effects of model compounds using in situ rat intestinal permeability. RESULTS: Analysis of selected model drugs indicated that percent food effects correlated to their dissociation constant, K (K(a) or K(b)) and Caco-2 permeabilities. The obtained predictive equation was: Food effect (%)=(2.60 x 105.P(app))--(2.91 x 105.K)- 8.50. Applying the oral absorption model, the predicted food effects matched the trends of published negative food effects when the two experimental pH conditions of fed and fasted state intestinal environment were used. CONCLUSION: A predictive model for negative food effects based on the correlation of food effects with dissociation constant and Caco-2 permeability was established and simulations of food effects using rat intestinal permeability supported the drugs? published negative food effects. Thus, an empirical and a mechanistic model as potential tools for predicting negative food effects are reported. PMID- 21615245 TI - Coexisting of Wilms tumor and ganglioneuroblastoma in a child. PMID- 21615246 TI - Primary central nervous system burkitt lymphoma with non-immunoglobulin heavy chain translocation in right ventricle: case report. AB - Primary central nervous system Burkitt lymphoma (PCNSBL) is rare. Few cases of primary central nervous system involvement with sporadic Burkitt lymphoma have been reported and its treatment is now controversial. Here, the authors report a case of a 14-year-old boy suffering from non-immunoglobulin heavy chain (IgH) translocation PCNSBL. To the authors' knowledge, this is the second case report describing primary Burkitt lymphoma involving cerebral ventricles. After receiving combination treatment with surgery, stereotactic radiosurgery, and a chemotherapy regimen including high-dose methotrexate, the patient had a disease free survival of 18 months. PMID- 21615247 TI - The potential impact of dietary vitamin K status on anticoagulation control in children receiving warfarin. PMID- 21615248 TI - Diabetic ketoasidosis is associated with prothrombotic tendency in children. AB - Children and adolescents with type I diabetes mellitus (DM) may present with diabetic ketoacidosis (DKA), which is associated with significant morbidity and mortality. This study aimed to evaluate the hematological parameters at diagnosis (0th hour) and 96th hour after the initiation of treatment in children with DKA. Twenty-six children with DKA treated in Dicle University Faculty of Medicine between September 2002 and August 2003 were included in this study. General characteristics of the patients and hematological parameters (platelet count, white blood cell count, prothrombin time, partial thromboplastin time (PTT), bleeding time, coagulation time, protein C, protein S, antithrombin III, fibrinogen, D-dimer, factor VIII, factor IX, and factor X levels) at diagnosis (0th hour) and 96th hour after the initiation of treatment were determined. The mean age of the children (10 girls and 16 boys) was 9.15 +/- 3.85 years (range: 4 15 years). DKA developed for the first time in 58.3% of these children and they had recently been diagnosed as DM. After hematological parameters at 0th hour were evaluated, increased platelet count, decreased PTT, low protein C, and high factor VIII levels were determined at diagnosis, indicating prothrombotic tendency. If the hematological parameters at 0th hour were compared with those at 96th hour; platelet count decreased, PTT increased, protein C and factor VIII levels turned to be normal at 96th hour. When all the results are considered together, children with DKA appeared to have a prothrombotic tendency. Although this tendency was not reflected in clinical findings in this study, it should be kept in mind that children with DKA are prone to the development of thrombosis and they need to be investigated for the possibility of thrombosis. PMID- 21615250 TI - Decompressive craniectomy for malignant cerebral oedema of cortical venous thrombosis: an analysis of 13 patients. AB - OBJECTIVE: The study aims to define the role and indication of surgical intervention in cases of malignant cerebral edema in consequence to cortical venous thrombosis (CVT). METHODS: A retrospective study of 13 patients who underwent decompressive craniectomies for malignant CVT is presented. All patients had supra-tentorial cortical lesions attributable to CVT. The diagnosis was based on CT scan and MRI findings. Patients who presented in a poor clinical status with radiological evidence of malignant cerebral oedema as well as patients who worsened while on medical therapy underwent decompressive hemicraniectomies. Patients were followed up, and the outcome assessed as per Glasgow Outcome Scale (GOS) and Karnofsky Performance Status (KPS) scale. RESULTS: There were nine females and four males with a mean age of 29.2 years. Eleven patients survived with good outcome (GOs =5, n=5; GOS=4, n=6). At the last follow-up (median 35 months; mean 39 months), the KPS scale was 90 for five, 80 for four and 70 for two survivors. There were two deaths, both in patients with pre-operative Glasgow Coma Scale (GCS) <5. CONCLUSION: Timely recognition of failure of medical management and an appropriately timed surgical intervention may help to salvage CVT patients who develop malignant cerebral oedema. PMID- 21615251 TI - Response to: Spontaneous knot; a rare cause of ventricularperitoneal blockage. PMID- 21615256 TI - A small fish with a big future: zebrafish in behavioral neuroscience. PMID- 21615253 TI - Decompressive craniectomy for traumatic brain injury: the jury is still out. PMID- 21615257 TI - Application of zebrafish oculomotor behavior to model human disorders. AB - To ensure high acuity vision, eye movements have to be controlled with astonishing precision by the oculomotor system. Many human diseases can lead to abnormal eye movements, typically of the involuntary oscillatory eye movements type called nystagmus. Such nystagmus can be congenital (infantile) or acquired later in life. Although the resulting eye movements are well characterized, there is only little information about the underlying etiology. This is in part owing to the lack of appropriate animal models. In this review article, we describe how the zebrafish with its quick maturing visual system can be used to model oculomotor pathologies. We compare the characteristics and assessment of human and zebrafish eye movements. We describe the oculomotor properties of the zebrafish mutant belladonna, which has non-crossing optical fibers, and is a particularly informative model for human oculomotor deficits. This mutant displays a reverse optokinetic response, spontaneous oscillations that closely mimic human congenital nystagmus and abnormal motor behavior linked to circular vection. PMID- 21615258 TI - Shoaling in zebrafish: what we don't know. AB - Zebrafish have been gaining increasing popularity in behavioral neuroscience. However, the number of behavioral test paradigms specifically designed for zebrafish, and in general the amount of information available on the behavior of this species, is relatively small when compared with classical laboratory model organisms such as the mouse, the rat, and the fruit fly. A particularly typical behavioral feature of zebrafish is shoaling, i.e., group formation. Given the importance of social behavior in our own species and the fact that zebrafish possess several characteristics similar to those of other vertebrates, including humans, at many levels of biological organization (e.g., neuroanatomy, neurochemistry, biochemical processes, and amino acid sequence of proteins or nucleotide sequence of genes), the zebrafish is expected to be an excellent tool not only for basic research but perhaps also for translational research. Briefly, we propose that once social behavior of the zebrafish is better characterized and once appropriate behavioral methods have been developed, this species can be utilized for the analysis of the mechanisms of social behavior of other vertebrates including our own. In this review, we discuss general principles of shoaling and highlight what we know and what we do not know about this behavior as it pertains to zebrafish. PMID- 21615259 TI - Sleep and its regulation in zebrafish. AB - The function of sleep remains a central enigma of modern biology, in spite of the obvious importance of sleep for normal physiology and cognition. The zebrafish has emerged as a promising new model for studying sleep, its changes with age, and the impact of sleep alterations on cognitive function. Recent studies of this diurnal vertebrate have provided new insights into the dual role of the pineal hormone melatonin and its receptors, regulating sleep in diurnal vertebrates through both homeostatic and circadian mechanisms. Research in zebrafish has also revealed interactions between melatonin and the hypocretin/orexin system, another important sleep-wake modulator. Future investigations should benefit from the conservation in zebrafish of mechanisms that regulate normal sleep, our extensive knowledge of their molecular biology, the availability of multiple transgenic and mutant phenotypes, and the feasibility of applying sensitive in vivo imaging techniques to record sleep-related neuronal activity in these optically transparent subjects. The established sensitivity of zebrafish to many pharmacological hypnotics should also contribute to the development of new, safe and effective sleep medications. PMID- 21615260 TI - Zebrafish behavioural assays of translational relevance for the study of psychiatric disease. AB - Understanding the pathogenesis of the complex behavioural disorders that constitute psychiatric disease is a major challenge for biomedical research. Assays in rodents have contributed significantly to our understanding of the neural basis of behavioural disorders and continue to be one of the main focuses for the development of novel therapeutics. Now, owing to their genetic tractability and optical transparency (allowing in vivo imaging of circuit function) and the rapid expansion of genetic tools, zebrafish are becoming increasingly popular for behavioural genetic research. The increased development of behavioural assays in zebrafish raises the possibility of exploiting the advantages of this system to identify molecular mechanisms contributing to behavioural phenotypes associated with psychiatric disorders as well as potential therapeutics. This mini-review describes behavioural paradigms in zebrafish that can be used to address endophenotypes associated with psychiatric disease. The content reflects the interests of the author and covers tests of cognitive functions, response choice and inhibition, social interaction and executive function. PMID- 21615262 TI - Zebrafish assessment of cognitive improvement and anxiolysis: filling the gap between in vitro and rodent models for drug development. AB - Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxiolytic drugs. They are economical and can provide a relatively quick indication of possible functional efficacy. In as much as they have a complex nervous system and elaborate behavioral repertoire, zebrafish can provide a good intermediate model between in vitro receptor and cell-based assays and classic mammalian models for drug screening. In addition, the variety of molecular tools available in zebrafish makes them outstanding models for helping to determine the neuromolecular mechanisms for psychoactive drugs. However, to use zebrafish as a translational model we must have validated, sensitive and efficient behavioral tests. In a series of studies, our lab has developed tests of cognitive function and stress response, which are sensitive to drug effects in a similar manner as rodent models and humans for cognitive enhancement and alleviating stress response. In particular, the three-chamber task for learning and memory was shown to be sensitive to the cognitive enhancing effects of nicotine and has been useful in helping to determine neural mechanisms crucial for nicotinic-induced cognitive enhancement. The novel tank diving test was shown to be a valid and efficient test of stress response. It is sensitive to the reduction in stress-related behaviors due to the amxiolytic drugs diazepam and buspirone but not chlordiazepoxide. Nicotine also causes stress alleviating effects which can be interpreted as anxiolytic effects. Zebrafish models of behavioral pharmacology can be useful to efficiently screen test compounds for drug development and can be useful in helping to determine the mechanisms crucial for new therapeutic treatments of neurobehavioral impairments. PMID- 21615261 TI - Stressing zebrafish for behavioral genetics. AB - The stress response is a normal reaction to a real or perceived threat. However, stress response systems that are overwhelmed or out of balance can increase both the incidence and severity of diseases including addiction and mood and anxiety disorders. Using an animal model with both genetic diversity and large family size can help discover the specific genetic and environmental contributions to these behavioral diseases. The stress response has been studied extensively in teleosts because of their importance in food production. The zebrafish (Danio rerio) is a major model organism with a strong record for use in developmental biology, genetic screening, and genomic studies. More recently, the stress response of larval and adult zebrafish has been documented. High-throughput automated tracking systems make possible behavioral readouts of the stress response in zebrafish. This non-invasive measure of the stress response can be combined with mutagenesis methods to dissect the genes involved in complex stress response behaviors in vertebrates. Understanding the genetic and epigenetic basis for the stress response in vertebrates will help to develop advanced screening and therapies for stress-aggravated diseases such as addiction and mood and anxiety disorders. PMID- 21615263 TI - Alcohol-induced behavior change in zebrafish models. AB - Zebrafish are at the forefront of neurobiological research and have been gaining popularity as a viable and valid behavioral model in a variety of research applications (e.g., assessing drug induced behavioral changes). This model becomes even more attractive when considering the behavioral changes that follow exposure to compounds that are water-soluble. As such, several studies have implicated both acute and chronic ethanol exposure in the modulation of zebrafish behavior. Within this arena there appears to be a common trend across multiple studies. As with many drugs ethanol appears to influence behavior in a dose dependent manner. In this review, we compare and contrast several studies that measure behavior as a result of alcohol exposure. Appended to this review are pilot data that report zebrafish blood alcohol concentrations as a function of acute exposure. PMID- 21615264 TI - Zebrafish models to study drug abuse-related phenotypes. AB - Mounting evidence implicates the zebrafish (Danio rerio) as a promising model species for reward and addiction research. Modeling drug abuse-related behavior in both adult and larval zebrafish produced a wealth of clinically translatable data, also demonstrating their sensitivity to various drugs of abuse and the ability to develop tolerance. Several studies have also applied withdrawal paradigms to model the adverse effects of drug abuse in zebrafish. In this review, we summarize recent findings of a wide spectrum of zebrafish drug abuse related behavioral and physiological phenotypes, discuss the existing challenges, and outline potential future directions of research in this field. PMID- 21615265 TI - The role of dopaminergic signalling during larval zebrafish brain development: a tool for investigating the developmental basis of neuropsychiatric disorders. AB - Neurodevelopment depends on intrinsic and extrinsic factors that influence the overall pattern of neurogenesis and neural circuit formation, which has a direct impact on behaviour. Defects in dopamine signalling and brain morphology at a relatively early age, and mutations in neurodevelopmental genes are strongly correlated with several neuropsychiatric disorders. This evidence supports the hypothesis of a neurodevelopmental origin of at least some forms of mental illness. Zebrafish (Danio rerio) has emerged as an important vertebrate model system in biomedical research. The ease with which intrinsic and extrinsic factors can be altered during early development, the relatively conserved dopaminergic circuit organisation in the larval brain, and the emergence of simple sensorimotor behaviours very early in development are some of the appealing features that make this organism advantageous for developmental brain and behaviour research. Thus, examining the impact of altered dopamine signalling and disease related genetic aberrations during zebrafish development presents a unique opportunity to holistically analyse the in vivo biochemical, morphological and behavioural significance of altered dopamine signalling during a crucial period of development using a highly tractable vertebrate model organism. Ultimately, this information will shed new light on potential therapeutic targets for the treatment of schizophrenia and perhaps serve as a paradigm for investigating the neurodevelopmental origin of other psychiatric disorders. PMID- 21615266 TI - Let there be light: zebrafish neurobiology and the optogenetic revolution. AB - Optogenetics has revolutionized the toolbox arsenal that neuroscientists now possess to investigate neuronal circuit function in intact and living animals. With a combination of light emitting 'sensors' and light activated 'actuators', we can monitor and control neuronal activity with minimal perturbation and unprecedented spatiotemporal resolution. Zebrafish neuronal circuits represent an ideal system to apply an optogenetic based analysis owing to its transparency, relatively small size and amenability to genetic manipulation. In this review, we describe some of the most recent advances in the development and applications of optogenetic sensors (i.e., genetically encoded calcium indicators and voltage sensors) and actuators (i.e., light activated ion channels and ion pumps). We focus mostly on the tools that have already been successfully applied in zebrafish and on those that show the greatest potential for the future. We also describe crucial technical aspects to implement optogenetics in zebrafish including strategies to drive a high level of transgene expression in defined neuronal populations, and recent optical advances that allow the precise spatiotemporal control of sample illumination. PMID- 21615267 TI - Association of CTLA-4 (+49A/G) gene polymorphism with type 1 diabetes mellitus in Egyptian children. AB - OBJECTIVE: To investigate the distribution of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) (+49 A/G) gene variants and the association of these variants with the clinical and laboratory findings in Egyptian children with Type-1 Diabetes (T1D). METHODS: A case control study was done for 104 Egyptian children with T1D and 78 age and sex matched healthy control. CTLA-4 (+49 A/G) gene polymorphism typing was done by PCR amplification followed by restriction fragment length polymorphism (RFLP) method. RESULTS: CTLA-4 G allele and GG homozygous genotype were significantly increased in T1D patients than in control group (P = 0.047, P = 0.048 respectively). There is no statistical difference between patient with optimal diabetic control (HbA1c < 8.5) and poor control (HbA1c >= 8.5) as regarding the CTLA-4 gene variant. The CTLA-4 GG genotype was statistically associated with younger age of patients (P = 0.027) and younger age of presentation (P = 0.036). Insignificant association was found between CTLA-4 alleles / genotypes and diabetic complications. CONCLUSION: The CTLA-4 +49 GG homozygous genotype is associated with T1D in Egyptian children especially with younger age of onset and in younger patients, and not associated with grades of diabetic control or diabetic complication. PMID- 21615268 TI - Factors associated with pain medication selection among patients diagnosed with diabetic peripheral neuropathic pain: a retrospective study. AB - OBJECTIVE: To assess the demographic and clinical characteristics associated with initiation of duloxetine therapy compared with other pharmacologic therapies for treatment of diabetic peripheral neuropathic pain (DPNP). METHODS: This study used administrative claims databases for commercially-insured individuals aged 18 64 years to examine factors associated with treatment among DPNP patients who initiated duloxetine versus tricyclic antidepressants (TCAs), venlafaxine, gabapentin, pregabalin, or opioids between 7/1/2005 and 12/31/2007. Treatment initiation was defined as no pill coverage of the same medication over the previous 90 days. Multiple logistic regression models were estimated to assess factors associated with initiating duloxetine versus each of the other DPNP therapies. RESULTS: The study included 11,060 DPNP patients with average age of 55 years old. Cardiovascular disease (63-70%), cerebrovascular/peripheral vascular disease (26-33%), low back pain (24-39%), and osteoarthritis (17-26%) were the most common diabetes- and pain-related comorbidities. Controlling for demographic and clinical characteristics, patients who received duloxetine or pregabalin in the prior 12-month period were more likely to initiate duloxetine. Patients from other DPNP treatment cohorts, except for those in the pregabalin cohort, were more likely to re-initiate the same prior therapy than begin treatment with duloxetine (all p<0.05). A history of anxiety disorder was significantly associated with initiation of all DPNP treatments other than duloxetine (all p<0.05), except for TCAs. Patients with low back pain were more likely to initiate duloxetine than TCAs or venlafaxine, but less likely to initiate duloxetine than pregabalin or opioids. Patients with infections related to diabetes were less likely to initiate duloxetine than venlafaxine, gabapentin, or opioids. LIMITATIONS: Because a retrospective administrative claims database was used, this study is subject to selection bias due to unobservable confounders, inability to measure prescriber preferences or characteristics or disease severity. CONCLUSIONS: Among commercially-insured DPNP patients, those with prior use of duloxetine or pregabalin were more likely to initiate duloxetine than other treatments. The presence of select comorbidities was also associated with specific medication initiation. PMID- 21615270 TI - Antioxidant protection: A promising therapeutic intervention in neurodegenerative disease. AB - Oxidative stress has been consistently linked to ageing-related neurodegenerative diseases. Neurodegenerative diseases are characterized by progressive dysfunction and death of neurons. Oxidative stress is associated with dysfunction of the mitochondria and endoplasmic reticulum, inducing apoptosis and protein misfolding in neurons. Decreased activities of antioxidant enzymes like SOD, catalase, glutathione, glutathione peroxidase in neurodegenerative states signifies role of reduced antioxidant potential in neurodegeneration. Among the cellular pathways conferring protection against oxidative stress, a key role is played by vitagenes, which include Hsp70, heme oxygenase-1, thioredoxin and sirtuins. Cellular signalling pathways and molecular mechanisms that mediate hormetic responses typically involve antioxidant enzymes and transcription factors such as Nrf-2 and NFkappaB. Vitagenes, either individually or by acting in concert, contribute to counteract the ROS mediated damage. In this review the importance of oxidative stress and the potential use of antioxidants in the prevention and treatment of neurodegenerative disorders are discussed. PMID- 21615271 TI - New insights into how adenovirus might lead to obesity: An oxidative stress theory. AB - Obesity has become a worldwide epidemic that leads to many serious weight-related disorders. Recently, infection by viruses has been proposed as a possible cause of the obesity epidemic. Of the many viruses screened, adenovirus 36 has been found to be a strong candidate virus that is associated with obesity, based on evidence in various model systems as well as clinical data. The mechanism of how the adenovirus could lead to obesity is not known and this paper proposes some new insights into how oxidative stress could be a possible mechanism of how adenovirus might lead to obesity. This paper reviews the relevant literature of both the effect of adenovirus on cells' anti-oxidant response and the link between obesity and oxidative stress. PMID- 21615272 TI - 3,3'-Diindolylmethane but not indole-3-carbinol activates Nrf2 and induces Nrf2 target gene expression in cultured murine fibroblasts. AB - There is increasing interest in the gene-regulatory activity of Brassica vegetable derived phytochemicals such as 3,3'-diindolylmethane (DIM) and indole-3 carbinol (I3C). DIM is formed under acidic conditions by dimerization of I3C. This study compared the Nrf2 activating potential of DIM and I3C in murine fibroblasts (NIH3T3). In contrast to its precursor I3C, DIM induces the transactivation of Nrf2. Furthermore, Nrf2 targets such as HO-1, gammaGCS and NQO1 were increased on the mRNA and protein levels following DIM treatment. DIM was less potent than sulforaphane (used as positive control) in inducing Nrf2 dependent gene expression. The present data suggest that the dimerization of I3C to DIM increases its Nrf2 inducing activity. PMID- 21615273 TI - Mitochondrial function and energy metabolism in umbilical cord blood- and bone marrow-derived mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSCs) are an attractive choice for a variety of cellular therapies. hMSCs can be isolated from many different tissues and possess unique mitochondrial properties that can be used to determine their differentiation potential. Mitochondrial properties may possibly be used as a quality measure of hMSC-based products. Accordingly, the present work focuses on the mitochondrial function of hMSCs from umbilical cord blood (UCBMSC) cells and bone marrow cells from donors younger than 18 years of age (BMMSC <18) and those more than 50 years of age (BMMSC >50). Changes of ultrastructure and energy metabolism during osteogenic differentiation in all hMSC types were studied in detail. Results show that despite similar surface antigen characteristics, the UCBMSCs had smaller cell surface area and possessed more abundant rough endoplasmic reticulum than BMMSC >50. BMMSC <18 were morphologically more UCBMSC like. UCBMSC showed dramatically higher mitochondrial-to-cytoplasm area ratio and elevated superoxide and manganese superoxide dismutase (MnSOD) levels as compared with BMMSC >50 and BMMSC <18. All hMSCs types showed changes indicative of mitochondrial activation after 2 weeks of osteogenic differentiation, and the increase in mitochondrial-to-cytoplasm area ratio appears to be one of the first steps in the differentiation process. However, BMMSC >50 showed a lower level of mitochondrial maturation and differentiation capacity. UCBMSCs and BMMSCs also showed a different pattern of exocytosed proteins and glycoproteoglycansins. These results indicate that hMSCs with similar cell surface antigen expression have different mitochondrial and functional properties, suggesting different maturation levels and other significant biological variations of the hMSCs. Therefore, it appears that mitochondrial analysis presents useful characterization criteria for hMSCs intended for clinical use. PMID- 21615274 TI - Prevention of scopolamine-induced memory deficits by schisandrin B, an antioxidant lignan from Schisandra chinensis in mice. AB - The preventive effect of schisandrin B (Sch B), an antioxidant ingredient of Schisandra chinensis, was studied on scopolamine-induced dementia in mouse. Scopolamine developed oxidative stress in the brain with the decreased levels of antioxidant enzymes and increased nitrite level. At the same time, a significant impairment of learning and memory occurred when evaluated by passive avoidance task (PAT) and Morris water maze (MWM) with concomitant increase of acetylcholinesterase (AChE) activity and decreased acetylcholine levels. Pre treatment by Sch B (10, 25, 50 mg/kg) effectively prevented scopolamine-induced oxidative stress and improved behavioural tasks. Further, the scopolamine-induced increase in AChE activity was significantly suppressed and the level of acetylcholine was maintained as normal by Sch B treatment. These results suggest that Sch B have protective function against cerebral functional defects such as dementia not only by antioxidant prevention but also exerting its potent cognitive-enhancing activity through modulation of acetylcholine level. PMID- 21615275 TI - Differential antioxidant/pro-oxidant activity of dimethoxycurcumin, a synthetic analogue of curcumin. AB - Dimethoxycurcumin (Dimc), a metabolically stable analogue of curcumin, is under investigation as an anti-tumour agent. Recently a number of studies have been performed on Dimc in this laboratory and also by others. In the present article, all these results have been summarized and wherever possible compared with those of curcumin. Rate constant for reactions of Dimc with superoxide radicals was comparable with that of curcumin, while its reaction with peroxyl radicals was much slower. These results were further supported by the observations on the scavenging of basal ROS levels in lymphocytes and evaluation of antioxidant activities. In line with the earlier reports on curcumin, Dimc was a pro-oxidant and generated ROS in tumour cells. Both curcumin and Dimc were non-toxic to lymphocytes, while exhibiting comparable cytotoxicity to tumour cells. Additionally, these compounds showed higher uptake in tumour cells than in normal lymphocytes. Fluorescence studies on both the compounds revealed their binding to genomic DNA, similar sub-cellular distribution and nuclear localization. All these studies suggested that methylation of the phenolic-OH group in curcumin, although decreasing the antioxidant activity marginally, showed comparable pro oxidant activity, making it a promising anti-tumour agent. PMID- 21615276 TI - Iron as a target of chemoprevention for longevity in humans. AB - Iron is universally abundant and no life can exist without it. However, iron levels should be maintained within a narrow range. Iron deficiency causes anaemia, whereas excessive iron increases cancer risk, presumably by free radical generation. Several pathological conditions such as genetic haemochromatosis, chronic viral hepatitis B and C, conditions related to asbestos fibre exposure and ovarian endometriosis have been recognized as iron overload-associated conditions that also increase human cancer risks. Iron's carcinogenicity has been documented in animal experiments. Surprisingly, these studies have revealed that the homozygous deletion of CDKN2A/2B is a major hallmark of iron-induced carcinogenesis. Recently, the hormonal regulation of iron metabolism has been elucidated. A commonly hypothesized mechanism may be the lack of any iron disposal pathway other than for bleeding and a mechanism of iron re-uptake as catechol chelate has been discovered. Iron overload in neurons via the ferroportin block may play a role in Alzheimer's disease. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy was associated with decreased cancer risks in a general population. Given that the required amounts of iron decrease during ageing, the fine control of body iron stores would be a wise strategy for chemoprevention of several diseases. PMID- 21615277 TI - Antioxidant and anti-proliferative properties of lycopene. AB - The recent search for new anti-cancer drugs focuses more on natural compounds from the regular human diet because these compounds rarely exhibit severe side effects yet efficiently act on a wide range of molecular targets involved in carcinogenesis. One promising compound, which is now being tested in clinical studies, is the tomato-derived carotenoid lycopene. This review summarizes the current knowledge about the cellular action of lycopene and presents the molecular targets responsible for its remarkable chemopreventive and anti proliferative activity. Its antioxidant effects include a considerable reactive oxygen species (ROS) scavenging activity, which allows lycopene to prevent lipid peroxidation and DNA damage. Simultaneously, lycopene induces enzymes of the cellular antioxidant defense systems by activating the antioxidant response element transcription system. As another chemopreventive strategy, lycopene increases gap junctional communication, which is suppressed during carcinogenesis. This review focuses also on the synergistic effects of lycopene with other natural antioxidants that might be important for its future application in anti-cancer treatment. Lastly, this review provides evidence for the biological activity of some oxidized lycopene metabolites, which seem to be partially responsible for the strong and manifold anti-cancer potential of lycopene. PMID- 21615278 TI - Estimation of proximate composition, micronutrients and phytochemical compounds in traditional vegetables from Andaman and Nicobar Islands. AB - In present study, 10 preferred traditional vegetables from Andaman and Nicobar Islands, India, were analysed for nutritional profiles. Moisture content in their edible parts ranged from 83.43 to 94.78%. Maximum ash content was recorded in Portulaca oleracea, crude protein in Colocasia esculenta, crude fibre in Eryngium foetidum and fat in E. foetidum. Phosphorus was maximum in Ipomea aquatica, potassium in C. esculenta, zinc, calcium and manganese in Centella asiatica, copper in Sauropus androgynous, sodium and iron in P. oleracea, magnesium in Amaranthus viridi and cobalt in C. esculenta. Maximum polyphenol was recorded in Hibiscus sabdariffa, carotenoids in A. viridi, ascorbic acid in Saursops androgynus, anthocyanin in C. esculenta and chlorophyll in S. androgynus. Antioxidant activity was maximum in P. oleracea. Positive correlation was observed between polyphenol and tannin content and also between antioxidant activity and photochemicals. The developed nutritional profiles is being used in health and nutrition related schemes in Islands. PMID- 21615279 TI - Zinc retention in vegetables according to the method of preparation for consumption. AB - The aim of the present work was to evaluate the retention, the nutrient density and the recommended daily allowance of zinc in 14 common vegetable species prepared for consumption. The investigation included fresh vegetables, vegetables after traditional cooking in brine and two types of frozen products: one obtained using the traditional method (blanching-freezing-storage-cooking in brine) and the other obtained using the modified method, providing a ready-to-eat product (cooking in brine-freezing-storage-defrosting and heating in a microwave oven). A significant zinc decrease was found in most studied vegetables prepared for consumption. Application of the modified method contributed to a reduction in zinc losses in prepared-for-consumption frozen vegetables. PMID- 21615280 TI - A comparative study of spray-dried and freeze-dried hydrocortisone/polyvinyl pyrrolidone solid dispersions. AB - Poor water solubility of new chemical entities (NCEs) is one of the major challenges the pharmaceutical industry currently faces. The purpose of this study was to investigate the feasibility of freeze-drying as an alternative technique to spray-drying to produce solid dispersions of poorly water-soluble drugs. Also investigated was the use of aqueous solvent mixtures in place of pure solvent for the production of solid dispersions. Aqueous solvent systems would reduce the environmental impact of pure organic solvent systems. Spray-dried and freeze dried hydrocortisone/polyvinyl pyrrolidone solid dispersions exhibited differences in dissolution behavior. Freeze-dried dispersions exhibited faster dissolution rates than the corresponding spray-dried dispersions. Spray-dried systems prepared using both solvent systems (20% v/v and 96% v/v ethanol) displayed similar dissolution performance despite displaying differences in glass transition temperatures (T(g)) and surface areas. All dispersions showed drug/polymer interactions indicated by positive deviations in T(g) from the predicted values calculated using the Couchman-Karasz equation. Fourier transform infrared (FTIR) spectroscopic results confirmed the conversion of crystalline drug to the amorphous in the dispersions. Stability studies were preformed at 40 degrees C and 75% relative humidity to investigate the physical stability of prepared dispersions. Recrystallization was observed after a month and the resultant dispersions were tested for their dissolution performance to compare with the dissolution performance of the dispersions prior to the stability study. The dissolution rate of the freeze-dried dispersions remained higher than both spray-dried dispersions after storage. PMID- 21615281 TI - Enhanced oral bioavailability of tacrolimus in rats by self-microemulsifying drug delivery systems. AB - A new self-microemulsifying drug delivery system (SMEDDS) has been developed to increase the solubility, dissolution rate and oral bioavailability of tacrolimus (TAC). The formulations of TAC-SMEDDS were optimized by solubility assay, compatibility tests, and pseudo-ternary phase diagrams analysis. In order to inhibit the efflux of P-glycoprotein (P-gp) for tacrolimus, which is the substrate of P-gp, the excipients which show the inhibition effect to P-gp, such as tocopheryl polyethylene glycol succinate (TPGS) and Cremophor EL40, were chosen in the SMEDDS formulations. According to particle size and the rate of self-emulsification, two optimized formulations were selected: Miglyol 840 as oil phase, Transcutol P as cosurfactant, TPGS as surfactant (TPGS-SMEDDS) or Cremophor EL40 as surfactant (Crem-SMEDDS), respectively. The ratio of oil phase, surfactant and cosurfactant is 1:7.2:1.8. The mean droplet size distribution of the optimized SMEDDS was less than 20 nm. The in vitro dissolution test indicated a significant improvement in release characteristics of TAC. The prepared SMEDDS was compared with the homemade solution by administering the hard capsule to fasted rats. The absorption of TAC from TPGS-SMEDDS and Crem-SMEDDS form resulted in about sevenfold and eightfold increase in bioavailability compared with the homemade solution. Our study illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as TAC by the oral route. PMID- 21615282 TI - Glial commitment of mesencephalic neural precursor cells expanded as neurospheres precludes their engagement in niche-dependent dopaminergic neurogenesis. AB - Neural precursor cells (NPCs) with high proliferative potential are commonly expanded in vitro as neurospheres. As a population, neurosphere cells show long term self-renewal capacity and multipotentiality in vitro. These features have led to the assumption that neurosphere cells represent an expansion of the endogenous NPCs residing within the embryonic and adult brain. If this is the case, in principle, bona-fide expansion of endogenous NPCs should not significantly affect their capacity to respond to their original niche of differentiation. To address this issue, we generated primary neurospheres from the dopaminergic niche of the ventral mesencephalon and then transplanted these cells to their original niche within mesencephalic explant cultures. Primary neurosphere cells showed poor capacity to generate dopaminergic neurons in the mesencephalic niche of dopaminergic neurogenesis. Instead, most primary neurosphere cells showed glial commitment as they differentiated into astrocytes in an exclusively neurogenic niche. Subculture of primary cells demonstrated that the neurosphere assay does not amplify niche-responsive dopaminergic progenitors. Further, neurospheres cells were largely unable to acquire the endogenous positional identity within the Nkx6.1(+), Nkx2.2(+), and Pax7(+) domains of mesencephalic explants. Finally, we demonstrate that our observations are not specific for embryonic mesencephalic cells, as NPCs in the adult subventricular zone also showed an intrinsic fate switch from neuronal to glial potential upon neurosphere amplification. Our data suggest that neurosphere formation does not expand the endogenous neurogenic NPCs but rather promotes amplification of gliogenic precursors that do not respond to niche-derived signals of cellular specification and differentiation. PMID- 21615283 TI - Introduction: integrating genetic and cultural evolutionary approaches to language. AB - The papers in this special issue of Human Biology address recent research in the field of language evolution, both the genetic evolution of the language faculty and the cultural evolution of specific languages. While both of these areas have received increasing interest in recent years, there is also a need to integrate these somewhat separate efforts and explore the relevant gene-culture coevolutionary interactions. Here we summarize the individual contributions, set them in the context of the wider literature, and identify outstanding future research questions. The first set of papers concerns the comparative study of nonhuman communication in primates and birds from both a behavioral and neurobiological perspective, revealing evidence for several common language related traits in various nonhuman species and providing clues as to the evolutionary origin and function of the human language faculty. The second set of papers discusses the consequences of viewing language as a culturally evolving system in its own right, including claims that this removes the need for strong genetic biases for language acquisition, and that phylogenetic evolutionary methods can be used to reconstruct language histories. We conclude by highlighting outstanding areas for future research, including identifying the precise selection pressures that gave rise to the language faculty in ancestral hominin species, and determining the strength, domain specificity, and origin of the cultural transmission biases that shape languages as they pass along successive generations of language learners. PMID- 21615284 TI - Primate vocal communication: a useful tool for understanding human speech and language evolution? AB - Language is a uniquely human trait, and questions of how and why it evolved have been intriguing scientists for years. Nonhuman primates (primates) are our closest living relatives, and their behavior can be used to estimate the capacities of our extinct ancestors. As humans and many primate species rely on vocalizations as their primary mode of communication, the vocal behavior of primates has been an obvious target for studies investigating the evolutionary roots of human speech and language. By studying the similarities and differences between human and primate vocalizations, comparative research has the potential to clarify the evolutionary processes that shaped human speech and language. This review examines some of the seminal and recent studies that contribute to our knowledge regarding the link between primate calls and human language and speech. We focus on three main aspects of primate vocal behavior: functional reference, call combinations, and vocal learning. Studies in these areas indicate that despite important differences, primate vocal communication exhibits some key features characterizing human language. They also indicate, however, that some critical aspects of speech, such as vocal plasticity, are not shared with our primate cousins. We conclude that comparative research on primate vocal behavior is a very promising tool for deepening our understanding of the evolution of human speech and language, but much is still to be done as many aspects of monkey and ape vocalizations remain largely unexplored. PMID- 21615286 TI - Bird speech perception and vocal production: a comparison with humans. AB - Research into speech perception by nonhuman animals can be crucially informative in assessing whether specific perceptual phenomena in humans have evolved to decode speech, or reflect more general traits. Birds share with humans not only the capacity to use complex vocalizations for communication but also many characteristics of its underlying developmental and mechanistic processes; thus, birds are a particularly interesting group for comparative study. This review first discusses commonalities between birds and humans in perception of speech sounds. Several psychoacoustic studies have shown striking parallels in seemingly speech-specific perceptual phenomena, such as categorical perception of voice onset-time variation, categorization of consonants that lack phonetic invariance, and compensation for coarticulation. Such findings are often regarded as evidence for the idea that the objects of human speech perception are auditory or acoustic events rather than articulations. Next, I highlight recent research on the production side of avian communication that has revealed the existence of vocal tract filtering and articulation in bird species-specific vocalization, which has traditionally been considered a hallmark of human speech production. Together, findings in birds show that many of characteristics of human speech perception are not uniquely human but also that a comparative approach to the question of what are the objects of perception--articulatory or auditory events--requires careful consideration of species-specific vocal production mechanisms. PMID- 21615285 TI - Communication and the primate brain: insights from neuroimaging studies in humans, chimpanzees and macaques. AB - Considerable knowledge is available on the neural substrates for speech and language from brain-imaging studies in humans, but until recently there was a lack of data for comparison from other animal species on the evolutionarily conserved brain regions that process species-specific communication signals. To obtain new insights into the relationship of the substrates for communication in primates, we compared the results from several neuroimaging studies in humans with those that have recently been obtained from macaque monkeys and chimpanzees. The recent work in humans challenges the longstanding notion of highly localized speech areas. As a result, the brain regions that have been identified in humans for speech and nonlinguistic voice processing show a striking general correspondence to how the brains of other primates analyze species-specific vocalizations or information in the voice, such as voice identity. The comparative neuroimaging work has begun to clarify evolutionary relationships in brain function, supporting the notion that the brain regions that process communication signals in the human brain arose from a precursor network of regions that is present in nonhuman primates and is used for processing species specific vocalizations. We conclude by considering how the stage now seems to be set for comparative neurobiology to characterize the ancestral state of the network that evolved in humans to support language. PMID- 21615287 TI - The parental antagonism theory of language evolution: preliminary evidence for the proposal. AB - Language--as with most communication systems--likely evolved by means of natural selection. Accounts for the genetical selection of language can usually be divided into two scenarios, either of which used in isolation of the other appear insufficient to explain the phenomena: (1) there are group benefits from communicating, and (2) there are individual benefits from being a better communicator. In contrast, it is hypothesized that language phenotypes emerged during a coevolutionary struggle between parental genomes via genomic imprinting, which is differential gene expression depending on parental origin of the genetic element. It is hypothesized that relatedness asymmetries differentially selected for patrigene-caused language phenotypes to extract resources from mother (early in development) and matrigene-caused language phenotypes to influence degree of cooperativeness among asymmetric kin (later in development). This paper reports that imprinted genes have a high frequency of involvement in language phenotypes (~36%), considering their presumed rarity in the human genome (~2%). For example, two well-studied genes associated with language impairments (FOXP2 and UBE3A) exhibit parent-of- origin effects. Specifically, FOXP2 is putatively paternally expressed, whereas UBE3A is a maternally expressed imprinted gene. It is also hypothesized that the more unique and cooperative aspects of human language emerged to the benefit of matrilineal inclusive fitness. Consistent with this perspective, it is reported here that the X-chromosome has higher involvement in loci that have associations with language than would be expected by chance. It is also reported, for the first time, that human and chimpanzee maternally expressed overlapping imprinted genes exhibit greater evolutionary divergence (in terms of the degree of overlapping transcripts) than paternally expressed overlapping imprinted genes. Finally, an analysis of global language patterns reveals that paternally but not maternally silenced Alu elements are positively correlated with language diversity. Furthermore, there is a much higher than expected frequency of Alu elements inserted into the protein-coding machinery of imprinted and X-chromosomal language loci compared with nonimprinted language loci. Taken together these findings provide some support for parental antagonism theory. Unlike previous theories for language evolution, parental antagonism theory generates testable predictions at the proximate (e.g., neurocognitive areas important for social transmission and language capacities), ontogenetic (e.g., the function of language at different points of development), ultimate (e.g., inclusive fitness), and phylogenetic levels (e.g., the spread of maternally derived brain components in mammals, particularly in the hominin lineage), thus making human capacities for culture more tractable than previously thought. PMID- 21615288 TI - Biological adaptations for functional features of language in the face of cultural evolution. AB - Although there may be no true language universals, it is nonetheless possible to discern several family resemblance patterns across the languages of the world. Recent work on the cultural evolution of language indicates the source of these patterns is unlikely to be an innate universal grammar evolved through biological adaptations for arbitrary linguistic features. Instead, it has been suggested that the patterns of resemblance emerge because language has been shaped by the brain, with individual languages representing different but partially overlapping solutions to the same set of nonlinguistic constraints. Here, we use computational simulations to investigate whether biological adaptation for functional features of language, deriving from cognitive and communicative constraints, may nonetheless be possible alongside rapid cultural evolution. Specifically, we focus on the Baldwin effect as an evolutionary mechanism by which previously learned linguistic features might become innate through natural selection across many generations of language users. The results indicate that cultural evolution of language does not necessarily prevent functional features of language from becoming genetically fixed, thus potentially providing a particularly informative source of constraints on cross-linguistic resemblance patterns. PMID- 21615289 TI - Learning bias, cultural evolution of language, and the biological evolution of the language faculty. AB - The biases of individual language learners act to determine the learnability and cultural stability of languages: learners come to the language learning task with biases which make certain linguistic systems easier to acquire than others. These biases are repeatedly applied during the process of language transmission, and consequently should effect the types of languages we see in human populations. Understanding the cultural evolutionary consequences of particular learning biases is therefore central to understanding the link between language learning in individuals and language universals, common structural properties shared by all the world's languages. This paper reviews a range of models and experimental studies which show that weak biases in individual learners can have strong effects on the structure of socially learned systems such as language, suggesting that strong universal tendencies in language structure do not require us to postulate strong underlying biases or constraints on language learning. Furthermore, understanding the relationship between learner biases and language design has implications for theories of the evolution of those learning biases: models of gene-culture coevolution suggest that, in situations where a cultural dynamic mediates between properties of individual learners and properties of language in this way, biological evolution is unlikely to lead to the emergence of strong constraints on learning. PMID- 21615290 TI - Are languages really independent from genes? If not, what would a genetic bias affecting language diversity look like? AB - It is generally accepted that the relationship between human genes and language is very complex and multifaceted. This has its roots in the "regular" complexity governing the interplay among genes and between genes and environment for most phenotypes, but with the added layer of supraontogenetic and supra-individual processes defining culture. At the coarsest level, focusing on the species, it is clear that human-specific--but not necessarily faculty-specific--genetic factors subtend our capacity for language and a currently very productive research program is aiming at uncovering them. At the other end of the spectrum, it is uncontroversial that individual-level variations in different aspects related to speech and language have an important genetic component and their discovery and detailed characterization have already started to revolutionize the way we think about human nature. However, at the intermediate, glossogenetic/population level, the relationship becomes controversial, partly due to deeply ingrained beliefs about language acquisition and universality and partly because of confusions with a different type of gene-languages correlation due to shared history. Nevertheless, conceptual, mathematical and computational models--and, recently, experimental evidence from artificial languages and songbirds--have repeatedly shown that genetic biases affecting the acquisition or processing of aspects of language and speech can be amplified by population-level intergenerational cultural processes and made manifest either as fixed "universal" properties of language or as structured linguistic diversity. Here, I review several such models as well as the recently proposed case of a causal relationship between the distribution of tone languages and two genes related to brain growth and development, ASPM and Microcephalin, and I discuss the relevance of such genetic biasing for language evolution, change, and diversity. PMID- 21615291 TI - A phylogenetic analysis of the evolution of Austronesian sibling terminologies. AB - Social structure in human societies is underpinned by the variable expression of ideas about relatedness between different types of kin. We express these ideas through language in our kin terminology: to delineate who is kin and who is not, and to attach meanings to the types of kin labels associated with different individuals. Cross-culturally, there is a regular and restricted range of patterned variation in kin terminologies, and to date, our understanding of this diversity has been hampered by inadequate techniques for dealing with the hierarchical relatedness of languages (Galton's Problem). Here I use maximum likelihood and Bayesian phylogenetic comparative methods to begin to tease apart the processes underlying the evolution of kin terminologies in the Austronesian language family, focusing on terms for siblings. I infer (1) the probable ancestral states and (2) evolutionary models of change for the semantic distinctions of relative age (older/younger sibling) and relative sex (same sex/opposite-sex). Analyses show that early Austronesian languages contained the relative-age, but not the relative-sex distinction; the latter was reconstructed firmly only for the ancestor of Eastern Malayo-Polynesian languages. Both distinctions were best characterized by evolutionary models where the gains and losses of the semantic distinctions were equally likely. A multi-state model of change examined how the relative-sex distinction could be elaborated and found that some transitions in kin terms were not possible: jumps from absence to heavily elaborated were very unlikely, as was piece-wise dismantling of elaborate distinctions. Cultural ideas about what types of kin distinctions are important can be embedded in the semantics of language; using a phylogenetic evolutionary framework we can understand how those distinctions in meaning change through time. PMID- 21615292 TI - Genes, language, cognition, and culture: towards productive inquiry. AB - The Queen Mary conference on "Integrating Genetic and Cultural Evolutionary Approaches to Language," and the papers in this special issue, clearly illustrate the excitement and potential of trans-disciplinary approaches to language as an evolved biological capacity (phylogeny) and an evolving cultural entity (glossogeny). Excepting the present author, the presenters/authors are mostly young rising stars in their respective fields, and include scientists with backgrounds in linguistics, animal communication, neuroscience, evolutionary biology, anthropology, and computer science. On display was a clear willingness to engage with different approaches and terminology and a commitment to shared standards of scientific rigor, empirically driven theory, and logical argument. Because the papers assembled here, together with the introduction, speak for themselves, I will focus in this "extro-duction" on some of the terminological and conceptual difficulties which threaten to block this exciting wave of scientific progress in understanding language evolution, in both senses of that term. In particular I will first argue against the regrettably widespread practice of opposing cultural and genetic explanations of human cognition as if they were dichotomous. Second, I will unpack the debate concerning "general purpose" and "domain-specific" mechanisms, which masquerades as a debate about nativism but is nothing of the sort. I believe that framing discussions of language in these terms has generated more heat than light, and that a modern molecular understanding of genes, development, behavior, and evolution renders many of the assumptions underlying this debate invalid. PMID- 21615294 TI - Reviewing the use of ethylcellulose, methylcellulose and hypromellose in microencapsulation. Part 2: Techniques used to make microcapsules. AB - This three-part review has been developed following the evaluation of literature where ethylcellulose, methylcellulose or hypromellose was used to make microcapsules. Parts 1 and 3 of the review are published as separate papers. Part 1 covers the various materials used to formulate microcapsules, and Part 3 covers the various end-use applications for microcapsules. In the current paper, Part 2 covers the techniques used to make microcapsules. Examples of techniques to be covered include temperature-induced phase separation, emulsion solvent evaporation, solvent evaporation, film coating, nonsolvent addition and spray drying. It is hoped that formulators can use Part 2 to understand how to formulate microcapsules using these encapsulating polymers. SciFinder was utilized to perform the literature search. SciFinder leverages literature databases, such as Chemical Abstracts Service Registry and Medline. A total of 379 references were identified during the review. The need for a three-part review reflects the extensive amount of literature identified concerning these three encapsulating polymers. PMID- 21615295 TI - Understanding gene-environment interactions. PMID- 21615296 TI - Improved efficiency of female germline stem cell purification using fragilis based magnetic bead sorting. AB - The enrichment of female germline stem cells (FGSCs) and the establishment of cell lines are influenced by the efficiency of cell purification. A previous study using mouse vasa homolog (MVH)-magnetic bead sorting for the isolation and purification of mouse FGSCs showed a relatively low efficiency. In this study, we tested 3 further proteins with the aim of improving the efficiency of FGSC purification. Immunofluorescence assays and magnetic sorting were performed using short-type pituitary gland and brain-cadherin (Stpb-c), CD9, and interferon inducible transmembrane protein 3 (Iftm3, Fragilis), all of which are expressed in germ cells. Although all 3 proteins were expressed in FGSCs, CD9 was unsuitable because of its lack of germline specificity, and Stpb-c was also unsuitable because of the unavailability of an appropriate primary antibody. The efficiency of FGSC purification was remarkably enhanced using the germline specific protein Fragilis, compared with that using MVH. This new method for the purification of FGSCs may have extensive applications in stem cell studies and clinical research. PMID- 21615297 TI - Gene therapy with recombinant adenovirus encoding endostatin encapsulated in cationic liposome in coxsackievirus and adenovirus receptor-deficient colon carcinoma murine models. AB - Adenovirus (Ad)-based antiangiogenesis gene therapy is a promising approach for cancer treatment. Downregulation or loss of coxsackievirus and adenovirus receptor (CAR) is often detected in various human cancers, which hampers adenoviral gene therapy approaches. Cationic liposome-complexed adenoviral vectors have been proven useful in CAR-deficient cells to enhance therapeutic gene transfer in vivo. Here, we investigated the antitumor effects of recombinant adenovirus encoding endostatin (Ad-hE) encapsulated in cationic liposome (Ad hE/Lipo) on CAR-deficient CT26 colon carcinoma murine models. In vitro, Ad hE/Lipo enhanced adenovirus transfection in CAR-deficient cells (CT26), and endostatin gene expression was measured by both qualitative and quantitative detection. In addition, an antibody neutralizing assay indicated that neutralizing serum inhibited naked adenovirus 5 (Ad5) at rather higher dilution than the complexes of Ad5 and cationic liposomes (Ad5-CL), which demonstrated that Ad5-CL was more capable of protecting Ad5 from neutralization. In vivo, Ad hE/Lipo treatment in the murine CT26 tumor model by intratumoral injection resulted in marked suppression of tumor growth and prolonged survival time, which was associated with a decreased number of microvessels and increased apoptosis of tumor cells. In conclusion, recombinant endostatin adenovirus encapsulated with cationic liposome effectively inhibited CAR-deficient tumor growth through an antiangiogenic mechanism in murine models without marked toxicity, thus showing a feasible strategy for clinical applications. PMID- 21615298 TI - Quantitative trait loci influencing endosperm texture, dough-mixing strength, and bread-making properties of the hard red spring wheat breeding lines. AB - Wheat end product quality is determined by a complex group of traits including dough viscoelastic characteristics and bread-making properties. Quantitative trait loci (QTL) mapping and analysis were conducted for endosperm texture, dough mixing strength, and bread-making properties in a population of 139 (MN99394 * MN98550) recombinant inbred lines that were evaluated at three environments in 2006. Based on the genetic map of 534 loci, six QTL were identified for endosperm texture, with the main QTL on chromosomes 1A (R(2) = 6.6%-17.3%), 5A (R(2) = 6.1% 17.1%), and 5D (R(2) = 15.8%-22%). Thirty-four QTL were identified for eight dough-mixing strength and bread-making properties. Major QTL clusters were associated with the low-molecular weight glutenin gene Glu-A3, the two high molecular weight glutenin genes Glu-B1 and Glu-D1, and two regions on chromosome 6D. Alleles at these QTL clusters have previously been proven useful for wheat quality, except one of the QTL clusters on chromosome 6D. A QTL cluster on chromosome 6D is one of the novel chromosome regions influencing dough-mixing strength and bread-making properties. The QTL for endosperm texture on chromosomes 1A, 5A, and 5B also influenced flour ash content (12.4%-23.3%), flour protein content (10.5%-12.5%), and flour colour (7.7%-13.5%), respectively. PMID- 21615300 TI - Fluid resuscitation in acute illness--time to reappraise the basics. PMID- 21615301 TI - Genetic association of crown rust resistance gene Pc68, storage protein loci, and resistance gene analogues in oats. AB - Segregating F(3) families, derived from a cross between oat cultivar Swan and the putative single gene line PC68, were used to determine the association of seed storage protein loci and resistance gene analogues (RGAs) with the crown rust resistance gene Pc68. SDS-PAGE analysis detected three avenin loci, AveX, AveY, and AveZ, closely linked to Pc68. Their diagnostic alleles are linked in coupling to Pc68 and were also detected in three additional lines carrying Pc68. Another protein locus was linked in repulsion to Pc68. In complementary studies, three wheat RGA clones (W2, W4, and W10) detected restriction fragment length polymorphisms (RFLPs) between homozygous resistant and homozygous susceptible F(3) DNA bulks. Four oat homologues of W2 were cloned and sequenced. RFLPs detected with two of them were mapped using F(3) and F(4) populations. Clone 18 detected a locus, Orga2, linked in repulsion to Pc68. Clone 22 detected several RFLPs including Orga1 (the closest locus to Pc68) and three RGA loci (Orga22-2, Orga22-3, and Orga22-4) loosely linked to Pc68. The diagnostic RFLPs linked in coupling to Pc68 were detected by clone 22 in three additional oat lines carrying Pc68 and have potential utility in investigating and improving crown rust resistance of oat. PMID- 21615299 TI - Mortality after fluid bolus in African children with severe infection. AB - BACKGROUND: The role of fluid resuscitation in the treatment of children with shock and life-threatening infections who live in resource-limited settings is not established. METHODS: We randomly assigned children with severe febrile illness and impaired perfusion to receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% saline solution (saline-bolus group) per kilogram of body weight or no bolus (control group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum A); children with severe hypotension were randomly assigned to one of the bolus groups only (stratum B). All children received appropriate antimicrobial treatment, intravenous maintenance fluids, and supportive care, according to guidelines. Children with malnutrition or gastroenteritis were excluded. The primary end point was 48-hour mortality; secondary end points included pulmonary edema, increased intracranial pressure, and mortality or neurologic sequelae at 4 weeks. RESULTS: The data and safety monitoring committee recommended halting recruitment after 3141 of the projected 3600 children in stratum A were enrolled. Malaria status (57% overall) and clinical severity were similar across groups. The 48-hour mortality was 10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 children) in the albumin-bolus, saline-bolus, and control groups, respectively (relative risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90; P=0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; P=0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P=0.003). The 4-week mortality was 12.2%, 12.0%, and 8.7% in the three groups, respectively (P=0.004 for the comparison of bolus with control). Neurologic sequelae occurred in 2.2%, 1.9%, and 2.0% of the children in the respective groups (P=0.92), and pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% (P=0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albumin-bolus group and 56% (9 of 16) in the saline-bolus group died (P=0.45). The results were consistent across centers and across subgroups according to the severity of shock and status with respect to malaria, coma, sepsis, acidosis, and severe anemia. CONCLUSIONS: Fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa. (Funded by the Medical Research Council, United Kingdom; FEAST Current Controlled Trials number, ISRCTN69856593.). PMID- 21615302 TI - Expression of the membrane mucins MUC4 and MUC15, potential markers of malignancy and prognosis, in papillary thyroid carcinoma. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) is the most frequent carcinoma of the thyroid gland and has a relatively good prognosis. However, it is important to identify PTC characteristics that indicate high risk for recurrence and metastasis. To date, overexpression of the membrane mucin, MUC1, has been investigated as a key molecular event in the pathogenesis of aggressive PTC. However, other membrane-associated mucins, matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-13 (TIMP-3), have not been studied yet. The aim of this study was to evaluate the expression levels of MUC4, MUC15, MMP 13, and TIMP-3 and their prognostic significance in PTC. METHODS: We analyzed MUC4, MUC15, MMP-13, and TIMP-3 expression in 10 PTC and 10 normal thyroid tissue samples using real-time reverse transcription-polymerase chain reaction. Tissue array blocks were obtained from 98 PTC cases. Tumor regions and nontumor regions were analyzed in tissue array blocks and immunohistochemistry studies were conducted using sectioned slides. Semiquantitative scores were correlated with clinicopathological factors of 98 PTC patients. RESULTS: MUC4- and MUC15-specific mRNA was increased by 78-fold and 4.75-fold, respectively, in PTC samples compared with normal thyroid tissues. MMP-13 and TIMP-3 gene expression levels were decreased by approximately 0.39-fold and 0.53-fold, respectively. By immunohistochemistry, MUC4 and MUC15 expression levels were increased in PTC samples compared with normal thyroid tissues (p < 0.001). MMP-13 and TIMP-3 expression levels were decreased in PTC samples compared with normal thyroid tissues (p < 0.001). High MUC4 scores were significantly correlated with small tumor size and papillary thyroid microcarcinoma subtype. High MUC15 scores were significantly correlated with age (>=45 years), distant metastasis, and multifocality. CONCLUSIONS: MUC4 and MUC15 were overexpressed in PTC, and high MUC15 expression was associated with high malignant potential. MUC15 may serve as a prognostic marker and potential novel therapeutic target in PTC. PMID- 21615303 TI - Fine-needle thyroid aspiration-induced hemorrhage of an unsuspected parathyroid adenoma misdiagnosed as a thyroid nodule: remission and relapse of hyperparathyroidism. AB - BACKGROUND: Temporary remission of primary hyperparathyroidism (PHPT) following fine-needle aspiration (FNA)-induced hemorrhage of a parathyroid adenoma is extremely rare. The purpose of this report was to illustrate that parathyroid adenomas can masquerade as thyroid nodules and that these patients must be monitored closely following remission as their hyperparathyroidism may recur. PATIENT FINDINGS: This report describes a patient who presented with a neck mass and was incidentally found to have PHPT. Ultrasound (US) evaluation revealed a lesion that was diagnosed as a thyroid nodule. After a nondiagnostic FNA, she developed a large neck hematoma and her PHPT went into remission. Soon thereafter, her hyperparathyroidism recurred, and she underwent parathyroidectomy and thyroid lobectomy, which confirmed a large parathyroid adenoma. SUMMARY: This report illustrates that remission of PHPT can occur because of FNA-induced hemorrhage leading to autoinfarction of a parathyroid adenoma. Following autoinfarction, the patient's parathyroid hormone and calcium levels must be monitored closely as the remission of PHPT may be temporary. Further, although US is a fast, inexpensive, often reliable modality for diagnosing neck masses, it does not always accurately identify parathyroid adenomas. CONCLUSION: Clinicians must be cognizant of the possibility that parathyroid adenomas can masquerade as thyroid nodules on US, especially as most patients with parathyroid adenomas are asymptomatic at presentation. PMID- 21615305 TI - Thyroid-associated paragangliomas. AB - BACKGROUND: Paragangliomas in the region of the thyroid gland are rare tumors that can present a diagnostic challenge by mimicking follicular and c-cell derived thyroid tumors. SUMMARY: Thyroid-associated paragangliomas are likely a subset of laryngeal paragangliomas and, although quite rare, should be considered in the differential diagnosis of a hypervascular thyroid nodule. The preoperative diagnosis of thyroid-associated paragangliomas can be challenging since the cytologic and histologic features overlap with more common primary thyroid neoplasms, in particular medullary carcinoma. Differential expression of a panel of immunohistochemical markers, including neuro-specific enolase, chromogranin A, synaptophysin, keratin, and S100, can be used to distinguish thyroid-associated paragangliomas from primary thyroid tumors. Intraoperatively, thyroid-associated paragangliomas may be associated with significant intraoperative bleeding and are often densely adherent to surrounding tissues, including the recurrent laryngeal nerve. Interestingly, the aggressive local behavior of these tumors does not correspond to potential for malignancy, as there are no patients with malignant thyroid-associated paragangliomas reported in the medical literature. Therefore, these tumors may be treated with limited resection. Postoperatively, patients with paragangliomas should receive hormonal evaluation for functional disease, imaging evaluation for multicentric and metastatic disease, and genetic counseling. CONCLUSION: Thyroid-associated paragangliomas are an important part of the differential diagnosis of a hypervascular thyroid nodule, especially in a patient with a fine-needle aspiration biopsy suggestive of medullary thyroid carcinoma, but with unremarkable serum calcitonin levels. Consideration of a thyroid-associated paraganglioma also has important operative and postoperative implications for determining the extent of thyroid resection as well as follow-up testing. PMID- 21615306 TI - Ruling out 131I ablation in low-risk differentiated thyroid carcinoma basing on thyroglobulin measurement. PMID- 21615307 TI - Thyroid function tests in persons with occupational exposure to fipronil. AB - BACKGROUND: Fipronil represents a chemical class of insecticides acting at the gamma-aminobutyric acid receptor in pests. [corrected] Fipronil has been associated with a significant increase in the incidence of thyroid gland tumors concomitant with prolonged exposure to thyroid-stimulating hormone (TSH) in rats. An association between human TSH concentration and thyroid cancer has been also reported. The primary objective of this study was to test the hypothesis that chronic occupational fipronil exposure may be associated with abnormal thyroid function tests. METHODS: In 2008, 159 workers of a factory manufacturing fipronil containing veterinary drugs were assessed. Serum concentrations of TSH, total thyroxine, free thyroxine, fipronil, and fipronil sulfone were measured. RESULTS: A positive and significant correlation was observed between serum fipronil or fipronil sulfone levels and duration of fipronil exposure. Serum fipronil sulfone concentration was negatively correlated with TSH concentration in fipronil exposed workers, but with no significant increase in thyroid function test abnormalities. CONCLUSION: This study did not show that chronic fipronil exposure was associated with an increase of thyroid function test abnormalities. But, despite the fact that fipronil exposure in rats has been associated with increased serum TSH, fipronil sulfone concentrations were negatively correlated with serum TSH concentrations in fipronil-exposed workers, raising the possibility that fipronil has a central inhibitory effect on TSH secretion in humans. Close occupational medical surveillance, therefore, appears to be required in factory workers manufacturing fipronil-containing veterinary drugs. Larger epidemiological studies as well as investigations on possible thyroid disrupting mechanisms of fipronil are also required. PMID- 21615309 TI - Effects of physical activity on body composition and fatigue perception in patients on thyrotropin-suppressive therapy for differentiated thyroid carcinoma. AB - BACKGROUND: Subclinical thyrotoxicosis (scTox) may be associated with alterations in body composition and fatigue that can be possibly reversed with physical activity. The aim of the present study was to evaluate whether the systematic practice of physical activity improves lower extremity muscle mass and fatigue perception in patients with scTox. MATERIALS AND METHODS: We studied 36 patients (2 men) with median age of 48.0 (43.0-51.0) years, body mass index of 27.4 (22.1 30.2) kg/m(2), thyrotropin <0.4 mU/L, and free thyroxine between 0.8 and 1.9 ng/dL and 48 control subjects (C group; 7 men). Patients were randomly divided in two groups according to the adherence to the exercise training: scTox-Tr (n = 19) patients who adhered to the exercise intervention and scTox-Sed (n = 17)- patients who did not adhere to it. The C group did not participate in the randomization. The exercise training was supervised by a physical education instructor, and it was composed of 60 minutes of aerobic activity and stretching exercises, twice a week, during 12 weeks. In both groups, body composition was assessed (anthropometric method), and the Chalder Fatigue Scale was determined at baseline and after 3 months of intervention (scTox-Tr group) or observation (scTox-Sed group). RESULTS: At baseline, patients with scTox had lower muscle mass and mid-thigh girth and more fatigue on the Chalder Fatigue Scale than euthyroid control subjects. The scTox-Tr group had an increase in muscle mass, reduction in the variables reflecting whole body fat, and lesser perception of fatigue during the exercise training period (p <= 0.05 for these parameters at the start and end of the exercise training period). CONCLUSIONS: scTox is associated with lower muscle mass and mid-thigh girth and more fatigue. Physical activity training can partially ameliorate these characteristics. More studies are needed to determine what training program would be optimum, both in terms of beneficial effects and for avoiding potential adverse responses. PMID- 21615310 TI - Ultrasound, elastography, and fluorodeoxyglucose positron emission tomography/computed tomography imaging in Riedel's thyroiditis: report of two cases. AB - BACKGROUND: Riedel's thyroiditis (RT) is a rare disease characterized by a chronic inflammatory lesion of the thyroid gland with invasion by a dense fibrosis. Publications of the imaging features of RT are scarce. To our knowledge, ultrasound elastography (USE) findings have not been previously reported. Therefore, we describe two patients with RT who were imaged with ultrasonography (US), USE, and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). SUMMARY: Two women were referred for a large, hard goiter with compressive symptoms (dyspnea and dysphagia); in one patient, the goiter was associated with retroperitoneal fibrosis. In both cases, RT was confirmed by surgical biopsy with pathological examination. Thyroid US imaging was performed with a US scan and a 10-13 MHz linear transducer. The hardness of the tissues was analyzed using transient USE (ShearWave, Aixplorer SuperSonic Imagine). PET/CT scanning was performed with a Philips Gemini GXL camera (GE Medical Systems). In the first patient, US examination revealed a compressive multinodular goiter with large solid hypoechoic and poorly vascularized areas adjacent to the nodules. The predominant right nodule was hypoechoic with irregular margins. The second patient had a hypoechoic goiter with large bilateral hypoechoic areas. In both cases, an unusual feature was observed: the presence of tissue surrounding the primitive carotid artery, associated with thrombi of the internal jugular vein. Further, USE showed heterogeneity in the stiffness values of the thyroid parenchyma varying between 21 kPa and 281 kPa. FDG-PET/CT imaging showed uptake foci in the thyroid gland. In both cases, US showed a decrease in the thyroid gland volume and the disappearance of encasement of the neck vasculature in response to corticosteroid treatment. In contrast, the FDG-PET/CT features remained unchanged. CONCLUSIONS: US features, such as vascular encasement and improvement under corticosteroid treatment, seem to be specific to this rare disease. For the first time, USE documents the hardness of RT tissues. Apart from the FDG-PET/CT findings that merit further investigation, US and USE prove useful tools in the assessment of such a rare disease. PMID- 21615311 TI - Prognosis and prognostic factors for distant metastases and tumor mortality in follicular thyroid carcinoma. AB - BACKGROUND: Distant metastases are more common in patients with follicular thyroid carcinoma (FTC) than in patients with papillary thyroid carcinoma, and the outcome is often poorer in patients with distant metastases. In this study, we attempted to identify the risk factors for distant metastases in FTC. METHODS: Between 1989 and 1997, 134 patients with FTC underwent initial surgery, and their median follow-up period was 12.5 years. Seventeen patients had widely invasive FTC, and 117 had minimally invasive FTC. Distant metastases were observed in 36 patients (26.9%). Thirteen of these patients had distant metastases at the time of initial surgery (M1), and in the other 23 patients distant metastases were diagnosed with during their follow-up periods. Risk factors for distant metastases and cause-specific survival were analyzed. The factors analyzed were age at the time of initial surgery, sex, primary tumor size, histological findings (invasiveness, extent of vascular, and capsular invasion), and distant metastases at the time of initial surgery. RESULTS: Univariate analysis showed that age and primary tumor size were significant factors related to postoperative distant metastases in the group of 121 patients who did not have distant metastases at the time of initial surgery. When the patients with M1 were included, the cumulative distant metastases-free-survival rate was significantly lower in the group with widely invasive FTC. The cumulative survival rate was significantly higher in the groups of patients with the minimally invasive type, who were under 45 years old, whose primary tumor size was under 4 cm and who did not have distant metastases at the time of the initial surgery. Multivariate analyses showed that tumor size and age were significant risk factors for postoperative distant metastases and that age and the presence of distant metastases at the time of the initial surgery were significant risk factors for poorer cause-specific survival. CONCLUSION: Age and primary tumor size were significant risk factors for postoperative distant metastases. Based on the findings in this study, we conclude that conservative management is sufficient for younger patients with minimally invasive FTC whose primary tumor is small. PMID- 21615312 TI - When is carotid stenting acceptable as a means of stroke prevention? PMID- 21615313 TI - Determining the optimal time to introduce ischemic postconditioning. PMID- 21615314 TI - Application of MRI to detect high-risk atherosclerotic plaque. PMID- 21615317 TI - Does remote ischemic conditioning salvage left ventricular function after successful primary PCI? AB - The translation of ischemic preconditioning to a viable therapy that benefits patients has been slow. This has been largely due to the difficultly in preempting when ischemia will occur. Recent advances in the field have demonstrated that cardioprotection from brief episodes of ischemia is possible when applied immediately after reperfusion (ischemic postconditioning) or remotely in another tissue during myocardial ischemia, prior to reperfusion (remote ischemic conditioning). This has facilitated the therapeutic application to patients presenting with acute myocardial infarction. In this article, we will discuss the results of a recent study published by Munk et al., concerning the application of remote ischemic conditioning during primary percutaneous coronary intervention to salvage myocardial function following ST-elevation myocardial infarction. PMID- 21615316 TI - Efficacy and safety of pitavastatin in Japanese patients with hypercholesterolemia: LIVES study and subanalysis. AB - The Livalo Effectiveness and Safety (LIVES) study was an observational study to examine the efficacy and safety of pitavastatin, a newly developed drug, in approximately 20,000 Japanese patients with hypercholesterolemia. During a 2-year follow-up period, no significant problems concerning safety were observed upon treatment with pitavastatin. Pitavastatin demonstrated potent and stable lowering of the LDL-cholesterol level. The LIVES study subanalyses revealed significant and continuous elevation of HDL-cholesterol in association with pitavastatin treatment and also showed that the drug did not adversely affect glycemic control as evaluated by the glycohemoglobin A(1c) level. Moreover, pitavastatin treatment was associated with an increase in estimated glomerular filtration rate in subjects with chronic kidney disease. These results suggest the usefulness of pitavastatin in hypercholesterolemic patients from various backgrounds. The ongoing LIVES study extension is expected to provide further data on cardiovascular outcome in subjects treated with pitavastatin. PMID- 21615318 TI - Catheter ablation of atrial fibrillation: long-term outcomes. AB - Atrial fibrillation is the most common arrhythmia faced in clinical practice with a substantial impact on morbidity, mortality, and heathcare expenditures. Patients with atrial fibrillation in which a rhythm control strategy is desired to improve quality of life have had limited options. The discovery of the role of pulmonary vein triggers has led to the development of catheter ablation techniques that have shown promising short-term success rates. Long-term outcomes were until recently, lacking. These results confirm the inherently recurrent nature of atrial fibrillation and the need for multiple procedures to achieve reasonable long-term successful maintenance of sinus rhythm. PMID- 21615319 TI - Cardiac resynchronization therapy and arterial blood pressure: a bonus for hemodynamic improvement. AB - The association between low blood pressure and prognosis in patients with heart failure has been controversial, with some reports suggesting an increased mortality for patients with the lowest blood pressures. Cardiac resynchronization therapy has become an established major therapeutic option for patients with heart failure and left ventricular dyssynchrony. It has been shown to improve functional capacity, left ventricular systolic function and survival in patients with heart failure. However, it is not known if this improvement in systolic function translates into an increase in arterial blood pressure. Here we discuss a recent publication evaluating the effect of cardiac resynchronization therapy on systolic blood pressure, diastolic blood pressure and pulse pressure. This study shows that cardiac resynchronization therapy is associated with a modest increase in systolic blood pressure and pulse pressure in patients with heart failure. These findings will be summarized and discussed with readily available clinical data. PMID- 21615320 TI - Endovascular management of vertebral artery disease. AB - Symptomatic disease of the vertebrobasilar circulation is often underdiagnosed and undertreated. In recent years, endovascular revascularization of vertebral artery stenosis has been heralded as a less invasive treatment option in comparison to open surgery, with the inherent risk of morbidity. Although a growing number of case reports and small nonrandomized case series suggest that endovascular intervention in the posterior circulation may be safe and technically feasible, the safety and benefit of angioplasty and stent placement in cases of symptomatic vertebral disease, as compared with the most effective medical therapy, remains to be elucidated. PMID- 21615321 TI - Clinical applicability of B-type natriuretic peptide in patients with suspected heart failure in primary care in Spain: the PANAMA study. AB - AIM: To assess the predictive value of B-type natriuretic peptide (BNP) in the diagnosis of heart failure (HF) in a primary-care setting in Spain. METHODS: PANAMA was a multicenter and cross-sectional study. Patients >=18 years of age with a clinical diagnosis of HF (Framingham criteria) were consecutively included in the study by primary-care investigators. BNP determination and an echocardiogram were performed in every patient. The cut-off point of BNP for the criterion of exclusion of HF was considered as <100 pg/ml, as suggested by European guidelines. Sensitivity, specificity, positive-predictive value and negative-predictive value were calculated. RESULTS: A total of 72 patients (mean age: 75.1 +/- 8.7 years; 74.6% women) were included. The most frequent associated risk factors were hypertension (75.6%) and dyslipidemia (54.3%). The most common major and minor criteria of HF according to Framingham criteria were radiographic cardiomegaly (90.2%) and dyspnea on ordinary exertion (100%), respectively. BNP median was 49 pg/ml (33.3 pg/ml in those with a doubtful diagnosis of HF and 83.3 pg/ml in those with a likely diagnosis of HF). Approximately 60% of patients exhibited diastolic dysfunction. Concerning accuracy parameters comparing BNP >100 pg/ml with echocardiogram, sensitivity was 25%, the specificity 80.8%, and the positive- and negative-predictive values were 68.8 and 38.9%, respectively. CONCLUSION: In patients attended by general practitioners, BNP >100 pg/ml may be a useful diagnostic tool with a high specificity for the diagnosis of HF. PMID- 21615322 TI - Surgery for chronic ischemic mitral regurgitation - which mitral intervention? AB - Surgical management of ischemic mitral regurgitation is associated with higher operative mortality, increased morbidity and poorer long-term survival. Selection of the most appropriate surgical treatment to maximize survival could be challenging due to factors such as inconsistent usage of contemporary surgical techniques, inconsistent classification schemes for the entity, paucity of long term data in order to compare alternatives and an absence of randomized trials of valve repair versus valve replacement. In addition, there is a lack of patient reported outcome measures and functional data parameters that take into consideration the patient's perspective in refining the decision making of the therapeutic strategy. In fact, such trials are difficult and if they were to be conducted there would be a high risk of dubious conclusions owing to clustering of outcomes with surgical expertise. This article aims to review the options for surgical management of chronic ischemic mitral regurgitation. It also attempts to identify areas of future research in order to clarify which of these are of priority and will realistically seek for relevant answers. Mitral intervention in this patient group seems to improve survival, although it is dependent on producing a competent mitral apparatus. There is no convincing evidence that repair is superior to replacement, and there is the possibility that the literature has been biased against replacement as the treatment of choice. PMID- 21615323 TI - Hypercoagulable state after off-pump coronary artery bypass grafting: evidence, mechanisms and implications. AB - During the past decade, there has been a dramatic resurgence in the adoption of off-pump technology in coronary artery bypass surgery. This has inspired remarkable advances in the techniques of localized tissue stabilization and a greater understanding of the physiology of beating-heart mobilization and exposure. An avalanche of reports in the literature has demonstrated the early safety and efficacy of the procedure. However, despite abundant evidence validating the safety and efficacy of off-pump coronary artery bypass surgery, considerable controversy still persists regarding the long-term outcomes of this approach to myocardial revascularization. One area of concern, and even greater uncertainty, surrounds the issue of the existence of a hypercoagulable state after off-pump coronary artery bypass surgery. This article evaluates the current best evidence available from randomized controlled trials to assess the impact of off-pump coronary artery bypass surgery on coagulation, fibrinolysis and platelet activation, discusses the issue of hypercoagulability with emphasis on the mechanisms responsible for this actual or potential hypercoagulability, and explores the implications of this issue for clinical practice. PMID- 21615324 TI - Implantation of cardiac rhythm devices during concomitant anticoagulation or antiplatelet therapy. AB - Cardiac rhythm devices are increasingly being utilized as the population ages and the incidence of chronic heart failure, bradyarrhythmias and the indications for pacing and prevention of sudden cardiac arrest expand. The number of patients receiving oral anticoagulants and dual antiplatelet therapy is similarly increasing. Implantation of cardiac rhythm devices during concomitant use of oral anticoagulants or antiplatelet regimens poses an increased risk of perioperative bleeding complications. Traditionally, heparin-based bridging protocols have been recommended for such patients to mitigate the bleeding risk while reducing the risk of thrombotic complications. Although the literature is limited, an appraisal of the literature reveals that bridging may not be the best strategy. We review the literature and propose strategies to promote successful perioperative outcomes, while reducing the risk of bleeding or thrombosis during the time of implantation for patients on chronic anticoagulation and antiplatelet therapies. PMID- 21615325 TI - New strategies for the management of no-reflow after primary percutaneous coronary intervention. AB - The myocardial no-reflow phenomenon is characterized by a reduced antegrade myocardial blood flow despite an open infarct-related artery in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention. Importantly, no-reflow is known to be associated with unfavorable clinical outcome and prognosis. It is a complex phenomenon and is caused by the variable combination of four pathogenetic components: distal atherothrombotic embolization, ischemic injury, reperfusion injury and susceptibility of coronary microcirculation to injury. As a consequence, appropriate strategies to prevent or treat each of these components are expected to reduce the occurrence of no reflow. Mechanical and pharmacological approaches performed before, during and after performing myocardial revascularization have been investigated in recent studies, in order to reduce the rate of no-reflow. In this article, we concentrate on the major preventive and therapeutic approaches currently available for the management of the no-reflow phenomenon. PMID- 21615326 TI - Catheter ablation of atrial fibrillation guided by electrogram fractionation and dominant frequency analysis. AB - Catheter ablation is an established therapeutic option for certain patients with atrial fibrillation (AF), but the reported success rates of anatomically oriented ablation techniques are low compared with those for other ablation indications, particularly for persistent AF. Electrophysiologically oriented ablation techniques have emerged over the last decade that aim at modifying the arrhythmogenic substrate to the extent that it cannot maintain fibrillatory activity. Electrogram-guided ablation procedures are the most common substrate targeted ablation approaches and can be broadly divided into procedures that target atrial sites with particular electrogram characteristics in either the time domain (complex fractionated electrograms) or frequency components in the frequency domain (dominant frequencies). The concept of electrogram-based catheter ablation of AF by identifying complex fractionated electrograms and dominant frequency sites is valid only if these sites are temporally stable. PMID- 21615327 TI - The relative importance of common and rare genetic variants in the development of hypertriglyceridemia. AB - Plasma lipid levels are a complex trait with a genetic and an environmental component. There are two models for the genetic basis of complex traits: the common-disease common-variant hypothesis, in which susceptibility is due to variants occurring at relatively high frequency but low effect size; and the common-disease rare-variant hypothesis, where disease is due to multiple rare variants each occurring at low frequency but with high effect size. Genome-wide association studies have identified a number of common variants associated with plasma lipid levels. However, they account for only a proportion of the genetic variance. Resequencing studies are revealing the importance of rare variants in accounting for the missing variance. Next-generation sequencing will allow the relative importance of the two hypotheses to be assessed. PMID- 21615329 TI - Skeletal tissue regeneration: current approaches, challenges, and novel reconstructive strategies for an aging population. AB - Loss of skeletal tissue as a consequence of trauma, injury, or disease is a significant cause of morbidity with often wide-ranging socioeconomic impacts. Current approaches to replace or restore significant quantities of lost bone come with substantial limitations and inherent disadvantages that may in themselves cause further disability. In addition, the spontaneous repair capacity of articular cartilage is limited; thus, investigation into new cartilage replacement and regeneration techniques are warranted. Along with the challenges of an increasingly aging demographic, changing clinical scenarios and rising functional expectations provide the imperative for new, more reliable skeletal regeneration strategies. The science of tissue engineering has expanded dramatically in recent years, notably in orthopedic applications, and it is clear that new approaches for de novo skeletal tissue formation offer exciting opportunities to improve the quality of life for many, particularly in the face of increasing patient expectations. However, significant scientific, financial, industrial, and regulatory challenges should be overcome before the successful development of an emergent tissue engineering strategy can be realized. We outline current practice for replacement of lost skeletal tissue and the innovative approaches in tissue regeneration that have so far been translated to clinical use, along with a discussion of the significant hurdles that are presented in the process of translating research strategies to the clinic. PMID- 21615332 TI - The special systems biology of the sperm. AB - Spermatozoa represent a highly specialized cell type, with a minimalist structure designed to fulfil a single principal function: the transport of an intact single copy haploid genome to the site of fertilization in the oviduct, and consequent zygote formation. They have lost most of their original cytoplasm, and remaining organelles are extremely modified. One result of this is that biochemical dynamics are restricted by a lack of cytoplasmic diffusion and a dramatic compartmentalization, with an increased emphasis on the physicochemical modulation of membranes. This is also reflected in a truncated apoptotic pathway, described in this issue of the Biochemical Journal in an article by Koppers et al., which leads to a so-called 'silent response' in the female tract, whereby unused sperm are removed without inflammatory consequences that might otherwise be detrimental to the new embryo. This new study shows that sperm have not simply jettisoned unwanted cellular components, but have evolved a very appropriate systems biology adapted to the specialist role they have to perform. PMID- 21615330 TI - Harnessing and modulating inflammation in strategies for bone regeneration. AB - Inflammation is an immediate response that plays a critical role in healing after fracture or injury to bone. However, in certain clinical contexts, such as in inflammatory diseases or in response to the implantation of a biomedical device, the inflammatory response may become chronic and result in destructive catabolic effects on the bone tissue. Since our previous review 3 years ago, which identified inflammatory signals critical for bone regeneration and described the inhibitory effects of anti-inflammatory agents on bone healing, a multitude of studies have been published exploring various aspects of this emerging field. In this review, we distinguish between regenerative and damaging inflammatory processes in bone, update our discussion of the effects of anti-inflammatory agents on bone healing, summarize recent in vitro and in vivo studies demonstrating how inflammation can be modulated to stimulate bone regeneration, and identify key future directions in the field. PMID- 21615331 TI - Maternal antioxidant blocks programmed cardiovascular and behavioural stress responses in adult mice. AB - Intra-uterine growth restriction is an independent risk factor for adult psychiatric and cardiovascular diseases. In humans, intra-uterine growth restriction is associated with increased placental and fetal oxidative stress, as well as down-regulation of placental 11beta-HSD (11beta-hydroxysteroid dehydrogenase). Decreased placental 11beta-HSD activity increases fetal exposure to maternal glucocorticoids, further increasing fetal oxidative stress. To explore the developmental origins of co-morbid hypertension and anxiety disorders, we increased fetal glucocorticoid exposure by administering the 11beta HSD inhibitor CBX (carbenoxolone; 12 mg.kg-1 of body weight.day-1) during the final week of murine gestation. We hypothesized that maternal antioxidant (tempol throughout pregnancy) would block glucocorticoid-programmed anxiety, vascular dysfunction and hypertension. Anxiety-related behaviour (conditioned fear) and the haemodynamic response to stress were measured in adult mice. Maternal CBX administration significantly increased conditioned fear responses of adult females. Among the offspring of CBX-injected dams, maternal tempol markedly attenuated the behavioural and cardiovascular responses to psychological stress. Compared with offspring of undisturbed dams, male offspring of dams that received daily third trimester saline injections had increased stress-evoked pressure responses that were blocked by maternal tempol. In contrast, tempol did not block CBX-induced aortic dysfunction in female mice (measured by myography and lucigenin-enhanced chemiluminescence). We conclude that maternal stress and exaggerated fetal glucocorticoid exposure enhance sex-specific stress responses, as well as alterations in aortic reactivity. Because concurrent tempol attenuated conditioned fear and stress reactivity even among the offspring of saline injected dams, we speculate that antenatal stressors programme offspring stress reactivity in a cycle that may be broken by antenatal antioxidant therapy. PMID- 21615333 TI - Super toxins from a super bug: structure and function of Clostridium difficile toxins. AB - Clostridium difficile, a highly infectious bacterium, is the leading cause of antibiotic-associated pseudomembranous colitis. In 2009, the number of death certificates mentioning C. difficile infection in the U.K. was estimated at 3933 with 44% of certificates recording infection as the underlying cause of death. A number of virulence factors facilitate its pathogenicity, among which are two potent exotoxins; Toxins A and B. Both are large monoglucosyltransferases that catalyse the glucosylation, and hence inactivation, of Rho-GTPases (small regulatory proteins of the eukaryote actin cell cytoskeleton), leading to disorganization of the cytoskeleton and cell death. The roles of Toxins A and B in the context of C. difficile infection is unknown. In addition to these exotoxins, some strains of C. difficile produce an unrelated ADP-ribosylating binary toxin. This toxin consists of two independently produced components: an enzymatic component (CDTa) and the other, the transport component (CDTb) which facilitates translocation of CDTa into target cells. CDTa irreversibly ADP ribosylates G-actin in target cells, which disrupts the F-actin:G-actin equilibrium leading to cell rounding and cell death. In the present review we provide a summary of the current structural understanding of these toxins and discuss how it may be used to identify potential targets for specific drug design. PMID- 21615335 TI - TGF-beta/TGF-beta receptor system and its role in physiological and pathological conditions. AB - The TGF-beta (transforming growth factor-beta) system signals via protein kinase receptors and Smad mediators to regulate a plethora of biological processes, including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. In addition, alterations of specific components of the TGF-beta signalling pathway may contribute to a broad range of pathologies such as cancer, cardiovascular pathology, fibrosis and congenital diseases. The knowledge about the mechanisms involved in TGF-beta signal transduction has allowed a better understanding of the disease pathogenicity as well as the identification of several molecular targets with great potential in therapeutic interventions. PMID- 21615336 TI - Identification of a novel HLA-DPB1 allele, DPB1*131:01, by sequence-based typing. AB - This report identifies a novel HLA-DPB1 allele, DPB1* 131:01. PMID- 21615337 TI - Characterization of a novel variant allele, HLA-C*07:01:19, identified in a Chinese Han individual. AB - The novel HLA-C*07:01:19 allele differs from the closest allele C*07:01:01 by a single nucleotide change at coding sequence nucleotide 738 G>A (codon 222 GAG>GAA) in exon 4. PMID- 21615334 TI - ATR signalling: more than meeting at the fork. AB - Preservation of genome integrity via the DNA-damage response is critical to prevent disease. ATR (ataxia telangiectasia mutated- and Rad3-related) is essential for life and functions as a master regulator of the DNA-damage response, especially during DNA replication. ATR controls and co-ordinates DNA replication origin firing, replication fork stability, cell cycle checkpoints and DNA repair. Since its identification 15 years ago, a model of ATR activation and signalling has emerged that involves localization to sites of DNA damage and activation through protein-protein interactions. Recent research has added an increasingly detailed understanding of the canonical ATR pathway, and an appreciation that the canonical model does not fully capture the complexity of ATR regulation. In the present article, we review the ATR signalling process, focusing on mechanistic findings garnered from the identification of new ATR interacting proteins and substrates. We discuss how to incorporate these new insights into a model of ATR regulation and point out the significant gaps in our understanding of this essential genome-maintenance pathway. PMID- 21615338 TI - Functionally defective germline variant of sialic acid acetylesterase (Met89Val) is not associated with type 1 diabetes mellitus and Graves' disease in a Polish population. AB - Recently, rare genotypes encoding defective variants of sialic acid acetylesterase (SIAE), such as homozygous Met89Val substitution, were strongly associated [odds ratio (OR) = 8] with a panel of autoimmune diseases including type 1 diabetes mellitus (T1DM). Our purpose was to replicate this finding in T1DM and explore whether Met89Val predisposes to Graves' diseases (GD). We studied 561 GD patients, 379 T1DM patients and 1822 controls. The prevalence of Met89Val homozygosity was similar among patients (GD: 0.4%, n = 2; T1DM: 0.3%, n = 1) and controls (0.4%, n = 7) yielding OR of 0.93 [95% confidence interval (CI): 0.19-4.48, P = 0.9] and 0.69 (95% CI: 0.08-5.59, P = 0.71) for GD and T1DM, respectively. We conclude that further studies are needed before the proposed strong effect of defective SIAE variants on susceptibility to autoimmunity can be universally accepted. PMID- 21615339 TI - Performance of a Pentax-Airway scope and a Macintosh laryngoscope for difficult intubation in a manikin study. PMID- 21615340 TI - There is no body cavity that cannot be reached with a #14 needle and a good strong arm (Samuel Shem; House of God). PMID- 21615341 TI - Comparison of intrathecal bupivacaine and ropivacaine with different doses of sufentanil. AB - BACKGROUND: Spinal bupivacaine produces a complete anaesthetic block of a longer duration than ropivacaine, which leads to a potentially increased risk of failure. A combination of sufentanil to ropivacaine may improve the block's reliability. METHODS: Sixty-four patients, scheduled for varicose vein stripping or the tension-free vaginal tape procedure, were allocated to receive double blindly, spinal bupivacaine 10 mg (Group 1) or ropivacaine 10 mg without (Group 2) or with sufentanil 2.5 mcg (Group 3), 5 mcg (Group 4). Sensory block was tested with pinprick and motor block was evaluated with the Bromage scale until full recovery. The primary endpoint was to compare the duration of sensory block evaluated by regression to S2. RESULTS: In comparison with bupivacaine, ropivacaine produced a shorter duration sensory block (median at 68, 90 and 120 min in groups 2, 3 and 4, respectively, vs. 150 min in Group 1) and motor block (median at 90, 98 and 120 min in groups 2, 3 and 4 vs. 180 min in Group 1). Motor blockade was significantly less important in patients receiving spinal ropivacaine (median values for the Bromage scale at 3 in groups 2, 3 and 4, vs. 1 in Group 1). Pruritus was significantly more frequent in patients receiving spinal sufentanil (Groups 3 and 4 vs. Groups 1 and 2). CONCLUSION: Plain bupivacaine 10 mg has a longer recovery profile than the same dose of ropivacaine with or without sufentanil. PMID- 21615342 TI - Data management in automated external defibrillators: a call for a standardised solution. AB - BACKGROUND: The ECG data stored in automated external defibrillators (AEDs) may be valuable for establishing a final diagnosis and deciding further diagnostics and treatment. Different data management systems are used and this may create significant problems for data storage and access for physicians treating victims in whom an AED has been used. METHODS: In this descriptive study, we collected information (number, manufacturer and model) on 17 December 2010 from a web page used for the voluntary registration of AEDs in Denmark. The manufacturers were contacted and asked to provide information about data downloading. RESULTS: There were 12 different manufactures and 20 different AED models. Five models were registered in a quantity <5. We report data from the remaining 15 models (3603 AEDs). Several models stored only one case or 15 min of ECG data. All models had a data transfer option, but most had outdated 'hardware': Seven had infrared transfer; one had a cable with a serial port. Four had a removable memory device, but only one was a USB. The software was available as freeware only in a few cases. Otherwise, a CD ROM was needed, some even with a licence. The software for the second most common AED could not be installed. CONCLUSION: The development of data management solutions is not a high priority. We encourage the manufacturers to collaborate with researchers to develop a simple data transfer solution in order to improve patient care and facilitate research. PMID- 21615343 TI - The effects of metoprolol on hypoxia- and isoflurane-induced cardiac late-phase preconditioning. AB - BACKGROUND: The detrimental effects of metoprolol on early-phase preconditioning (pc) have been proven. The late phase of pc is mediated via gene transcription and cyclooxygenase-2 (COX-2) was identified as one of the key mediators. The effect of metoprolol on this is yet unknown as is its effect on cellular energy metabolism and reactive oxygen species (ROS) creation. METHODS: Cardiomyocytes from neonatal rats were cultured and randomly assigned to four pairs of treatment groups. In each pair, one group received metoprolol at a dose of 0.5 MUg/ml medium. One pair served as a control; the others were subjected to 5 h of hypoxia 24 h after either hypoxia-induced, isoflurane-induced or no pc. Cell survival was measured with a redox indicator for cell metabolism. COX-2 transcription, ATP and ROS creation were measured. RESULTS: Whereas both ischemic and isoflurane pc produced mild beneficial effects (48.8+/-6.0% and 48.2+/-7.8% of surviving cells, respectively) compared with unpreconditioned controls (35.9+/-7.9%, P<0.01 for both), adding metoprolol was detrimental for both kinds of pc (hypoxia: 31.5+/ 3.5%; isoflurane: 25.7+/-3.8%, P<0.001) but not in the unpreconditioned group (39.4+/-4.9%). mRNA for COX-2 was up to 10-fold elevated in pc cells. This induction was suppressed by metoprolol. Hypoxic and isoflurane-induced pc showed significant differences in ATP balance and ROS generation. CONCLUSION: Metoprolol abolishes the protection of both isoflurane- and hypoxia-induced late-phase pc in our model. This effect is accompanied by the blockade of COX-2 induction. The differences between hypoxic and isoflurane pc in ATP and ROS creation allow to presume distinct pathways on the mitochondrial level. PMID- 21615344 TI - Continuous administration of remifentanil and sufentanil induces cardioprotection in human myocardium, in vitro. AB - BACKGROUND: Remifentanil and sufentanil are widely used opioids during general anaesthesia for cardiac and non-cardiac surgery. This study was conducted to evaluate the hypothesis that the continuous administration of remifentanil and sufentanil, at clinically relevant concentrations, could provide protection of human myocardium, in vitro, against hypoxia-reoxygenation injury. METHOD: Isometrically contracting isolated human right atrial trabeculae were exposed to 30 min of hypoxia and 60 min of reoxygenation. In separate groups, remifentanil at 10(-11), 10(-10), 10(-9), or sufentanil at 10(-11), 10(-10), 10(-9) M were administered 10 min before hypoxia until the end of the experiment. The force of contraction (FoC) of trabeculae was recorded continuously. Developed force was compared (mean +/- standard deviation) between the groups using a variance analysis and post hoc tests. RESULTS: At the end of the 60-min reoxygenation, remifentanil 10(-11) M (FoC: 82 +/- 7% of baseline), 10(-10) M (FoC: 78 +/- 5% of baseline), 10(-9) M (FoC: 80 +/- 4% of baseline) and sufentanil 10(-11) M (FoC: 78 +/- 8% of baseline), 10(-10) M (FoC: 83 +/- 6% of baseline), 10(-9) M (FoC: 83 +/- 8% of baseline) enhanced the recovery of FoC as compared with the control group (53 +/- 9% of baseline, P<0.0001). CONCLUSIONS: Remifentanil and sufentanil, at clinically relevant concentrations, confer cardioprotection of human myocardium against hypoxia reoxygenation, in vitro. PMID- 21615345 TI - Low central venous oxygen saturation in haemodynamically stabilized trauma patients is associated with poor outcome. AB - BACKGROUND: Central venous oxygen saturation (ScvO(2)) is suggested to reflect the adequacy of oxygen delivery, and the main objective of the present study was to determine whether ScvO(2) is associated with outcome in haemodynamically stabilized trauma patients. METHODS: Haemodynamically unstable trauma patients receiving a central venous line within 1 h of admission were eligible for inclusion in this prospective observational study. The mean arterial pressure (MAP), lactate and ScvO(2) were recorded at inclusion and every 6 h for 36 h or until lactate was <2.0 mmol/l and ScvO(2) was >75% in two consecutive measurements. Patients with a MAP of >=70 mmHg were considered to be haemodynamically stabilized. The outcome measure was complications defined as infections, delta sequential organ failure assessment score of >0, and mortality. RESULTS: Fifty patients with a median new injury severity score of 27 (17-34) were analysed. Complications occurred in 33 patients. An association between ScvO(2) following resuscitation to MAP >=70 mmHg and complications was detected with an odds ratio of 0.94 (95% confidence interval; 0.89-0.99). This association was also significant when adjusted for injury severity. The result implies that a low ScvO(2) value is associated with more complications. The optimal cut-off for ScvO(2) to discriminate between patients who did or did not develop complications was found to be 66.5% (56-86%). CONCLUSIONS: These data suggest that low ScvO(2) in haemodynamically stabilized patients is associated with a poor outcome and that ScvO(2) represents a potential endpoint of resuscitation in trauma patients. PMID- 21615346 TI - Percutaneous dilatational tracheotomy in intensive care unit patients with increased bleeding risk or obesity. A prospective analysis of 1000 procedures. AB - BACKGROUND: Percutaneous dilatational tracheotomy (PT) is safe and cost effective, and has become a routine method in intensive care units (ICU), but safety concerns persist for obese patients and for patients with a high risk of bleeding. In this prospective study of 1000 PTs, we have investigated whether such patient characteristics were associated with an increased procedural risk. METHODS: We prospectively recorded all PTs performed in our ICU from 2001 to 2009. Data on blood transfusion were entered from a central database. The association of risk factors with bleeding and other complications was analysed with logistic regression. RESULTS: The total number of PTs and surgical tracheotomies was 1.454. The median number of days on a ventilator until PT was 6 in 2001, decreasing to 3 in 2009. A procedure-related complication was reported in 17.5%. There was no PT-related mortality. The rate of potentially life threatening complications was 1.2%. Three patients developed pneumothorax and one of these had circulatory arrest and was successfully resuscitated. Three hundred and twelve patients had one or more units of blood transfused, but only 19 (1.9%) were PT related. Increased INR was the most important risk factor for bleeding [odds ratio (OR) 2.99], followed by low platelets (OR 1.99). The rate of complications in patients with high body mass index was not increased. CONCLUSION: PT is a safe procedure that can be performed with a low complication rate in patients with increased risk of bleeding as well as in obese patients. PMID- 21615347 TI - Neurointensive care of patients with severe community-acquired meningitis. AB - BACKGROUND: Reports about neurointensive care of severe community-acquired meningitis are few. The aims of this retrospective study were to review the acute clinical course, management and outcome in a series of bacterial meningitis patients receiving neurointensive care. METHODS: Thirty patients (median age 51, range 1-81) admitted from a population of 2 million people during 7 years were studied. The neurointensive care protocol included escalated stepwise treatment with mild hyperventilation, cerebrospinal fluid (CSF) drainage, continuous thiopentotal infusion and decompressive craniectomy. Clinical outcome was assessed using the Glasgow outcome scale. RESULTS: Twenty-eight patients did not respond to commands on arrival, five were non-reacting and five had dilated pupils. Twenty-two patients had positive CSF cultures: Streptococcus pneumoniae (n=18), Neisseria meningitidis (n=2), beta-streptococcus group A (n=1) and Staphylococcus aureus (n=1). Thirty-five patients were mechanically ventilated. Intracranial pressure (ICP) was monitored in 28 patients (intraventricular catheter=26, intracerebral transducers=2). CSF was drained in 15 patients. Three patients received thiopentothal. Increased ICP (>20 mmHg) was observed in 7/26 patients with available ICP data. Six patients died during neurointensive care: total brain infarction (n=4), cardiac arrest (n=1) and treatment withdrawal (n=1). Seven patients died after discharge, three due to meningitis complications. At follow-up, 14 patients showed good recovery, six moderate disability, two severe disability and 13 were dead. CONCLUSION: Patients judged to have severe meningitis should be admitted to neurointensive care units without delay for ICP monitoring and management according to modern neurointensive care principles. PMID- 21615349 TI - A meta-analysis of the efficacy of wound catheters for post-operative pain management. AB - Local anesthetics (LA) are injected via catheters placed in surgical wounds for post-operative analgesia. The primary aim of this systematic review was to assess whether LA reduce pain intensity when injected via wound catheters. A literature search was performed from Medline via PubMed, EMBASE and the Cochrane database from 1966 until November 2009. The search strategy included the following key words: pain, postoperative, catheters and local anesthetics. Two co-authors independently read every article that was initially included and extracted data into a pre-defined study record form. A total of 753 studies primarily fit the search criteria and 163 were initially extracted. Of these, 32 studies were included in the meta-analysis. Wound catheters provided no significant analgesia at rest or on activity, except in patients undergoing gynecological and obstetric surgery at 48 h (P=0.03). The overall morphine consumption was lower (~13 mg) during 0-24 h (P<0.001) in these patients. No significant differences in side effects were found, except for a lower risk of wound breakdown (P=0.048) and a shorter length of hospital stay (P=0.04) in patients receiving LA. A statistically significant heterogeneity was seen between the studies in most end points. LA injected via wound catheters did not reduce pain intensity, except at 48 h in a subgroup of patients undergoing obstetric and gynecological surgery. Rescue analgesic consumption was also lower in this group at 0-24 h. The magnitude of these effects was small and compounded by pronounced heterogeneity. PMID- 21615348 TI - Influence of propofol and volatile anaesthetics on the inflammatory response in the ventilated lung. AB - BACKGROUND: The immunomodulatory effects of volatile anaesthetics in vitro and the protective effect of propofol in lung injury spurred us to study the effects of volatile anaesthetics and propofol on lung tissue in vivo. METHODS: Twenty seven pigs were randomized to 4-h general anaesthesia with propofol (8 mg/kg/h, group P, n=9), sevoflurane [minimum alveolar concentration (MAC)=1.0, group S, n=9) or desflurane (MAC=1.0, group D, n=9). Four healthy animals served as the no ventilation group. Bronchoalveolar lavage fluid (BALF) was obtained to measure the cell counts, platelet-activating factor acetylhydrolase (PAF-AcH), phospholipase A(2) (PLA(2)) and superoxide dismutase (SOD) activity. Lung tissues were evaluated histologically and for caspase-3 expression. RESULTS: Volatile anaesthetics reduced PAF-AcH levels without affecting PLA(2) activity and resulted in decreased alveolar macrophage and increased lymphocyte counts in BALF (sevoflurane: 29 +/- 23%; desflurane: 26 +/- 6%, both P<0.05 compared with 4 +/- 2% in the no-ventilation group). These findings were accompanied by atelectasis and inflammatory cells' infiltration in the inhalational anaesthetics groups. Also, sevoflurane reduced SOD activity and both sevoflurane and desflurane induced significant caspase-3 expression. In contrast, propofol resulted in a minor degree of inflammation and preserved BALF cells' composition without triggering apoptosis. CONCLUSION: Halogenated anaesthetics seem to trigger an immune lymphocytic response in the lung, inducing significant apoptosis and impairment of PAF-AcH. In contrast, propofol preserves anti-inflammatory and anti oxidant defences during mechanical ventilation, thus preventing the emergence of apoptosis. PMID- 21615350 TI - Isolated seizures in rats do not cause neuronal injury. AB - BACKGROUND: Previous studies have shown that status epilepticus can lead to neuronal injury. However, the effect of a small number of isolated seizures is uncertain. METHODS: We used structural MRI and neuropathology to study the effects of isolated seizures induced by kainic acid (KA), (RS)-2-amino-3-(3 hydroxy-5-tert-butylisoxazole-4-yl)propanoic acid (ATPA), and alpha-amino-3 hydroxyl-5-methyl-4-isoxazole-propionate in rats. A group of animals received normal saline. After seizure induction, animals were followed for 12 weeks. RESULTS: ATPA and KA led to small but significant increases in ADC. There were no changes in T2 signal intensity or hippocampal volume. Blinded pathological examination showed no differences between animals receiving saline or glutamatergic agents. CONCLUSION: Our study suggests that isolated seizures cause minimal neuronal injury in rats. PMID- 21615351 TI - Is there any circadian variation consequence on acute case fatality of stroke? Takashima Stroke Registry, Japan (1990-2003). AB - BACKGROUND: Circadian periodicity in the onset of stroke has been reported. However, it is unclear whether this variation affects the acute stroke case fatality. Time of the day variation in stroke case fatality was examined using population-based stroke registration data. METHODS: Stroke event data were acquired from the Takashima Stroke Registry, which covers a stable population of approximately 55,000 in Takashima County in central Japan. During the period of 1990-2003, there were 1080 (549 men and 531 women) cases with classifiable stroke onset time. Stroke incidence was categorized as occurring at night (midnight-6 a.m.), morning (6 a.m.-noon), afternoon (noon-6 p.m.), and evening (6 p.m. midnight). The 28-day case fatality rates and 95% confidence intervals (95% CI) were calculated by gender, age, and stroke subtype across the time blocks. After adjusting for gender, age at onset, and stroke severity at onset, the hazard ratios for fatal strokes in evening, night, and morning were calculated, with afternoon serving as the reference. RESULTS: For all strokes, the 28-day case fatality rate was 23.3% (95% CI:19.4-27.6) for morning onset, 16.9% (95% CI:13.1 21.6) for afternoon onset, 18.3% (95% CI:13.6-24.1) for evening onset, and 21.0% (95% CI:15.0-28.5) for the night onset stroke. The case fatality for strokes during the morning was higher than the case fatality for strokes during afternoon. This fatality risk excess for morning strokes persisted even after adjusting for age, gender, and stroke severity on onset in multivariate analysis. CONCLUSION: In the examination of circadian variation of stroke case fatality, 28 day case fatality rate tended to be higher for the morning strokes. PMID- 21615352 TI - Long-term exposure to duodenal levodopa/carbidopa infusion therapy improves quality of life in relation especially to mobility, activities of daily living, and emotional well-being. AB - BACKGROUND: Continuous duodenal levodopa infusion (DLI) is an effective therapy that improves quality of life (QoL) in advanced Parkinson's disease (PD). However, in which aspects improve the patients their QoL has been poorly documented. METHODS: We evaluated 39-item Parkinson's disease Quality of Life Questionnaire Summary Index score (PDQ-39SI) changes analyzing its different domains in nine patients with advanced PD treated with DLI. RESULTS: All the patients (64.7 +/- 11.1 years, 55.5% men) improved PDQ-39SI 6 months after beginning with DLI (29.7 +/- 8.6, P = 0.008) and after median duration infusion of 25.3 +/- 8.8 months (34.8 +/- 11.2, P = 0.008) compared with baseline (55.6 +/ 11.5). All domains except social support improved significantly at 6 months. Mobility (P = 0.012), activities of daily living (P = 0.015), and emotional well being (P = 0.008) improved significantly at the end of the follow-up. CONCLUSIONS: DLI improves QoL in patients with advanced PD after short- and long term exposure. Whereas all domains except social support improve after 6 months under DLI, only mobility, activities of daily living and emotional well-being improve significantly after long-term exposure to DLI. PMID- 21615353 TI - The role of IL-15 in central nervous system disorders. AB - IL-15 is a proinflammatory cytokine. It is produced by activated blood monocytes, macrophages, dendritic cells, and activated glial cells. It promotes T-cell proliferation, induction of cytolytic effector cells including natural killer and cytotoxic cells and stimulates B-cell to proliferate and secrete immunoglobulins. Little information is available on the exact role of IL-15 in the neurological diseases. Microglial cells are the main regulators of both innate and adaptive immune responses in the central nervous system (CNS). IL-15 may be involved in the inflammatory reactions and microglial activation of some common CNS disorders such as multiple sclerosis, Alzheimer's and Parkinson's disease, but its exact role in their pathogenesis is not clear. PMID- 21615354 TI - Galantamine and behavior in Alzheimer disease: analysis of four trials. AB - OBJECTIVES: Many individuals with Alzheimer's disease (AD) experience behavioral and neuropsychiatric symptoms, which may cause caregiver distress and lead to the institutionalization of the patient. This analysis characterized behavioral symptoms and caregiver distress in trials of galantamine and their response to treatment. MATERIALS AND METHODS: Data were pooled from four randomized, placebo controlled clinical trials of galantamine in patients with mild to moderate AD (three studies) or AD plus cerebrovascular disease (one study) (n = 2177). Behavior and associated caregiver distress were assessed in each study using the Neuropsychiatric Inventory (NPI) and NPI distress (NPI-D), respectively. RESULTS: After 5/6 months, but not after 3 months, NPI score was significantly improved with galantamine vs placebo (P = 0.013). The benefit was particularly pronounced in patients categorized as having advanced moderate AD. At 5/6 months, there was a numerical benefit of galantamine over placebo in terms of caregiver distress; the difference was statistically significant in patients with moderate or advanced moderate AD. CONCLUSIONS: Galantamine reduces behavioral symptoms in patients with mild to moderate AD, leading to reduced caregiver burden. The reductions were greatest in patients with moderate or advanced moderate disease. PMID- 21615355 TI - Cumulative impact of comorbidity on quality of life in MS. AB - BACKGROUND: Little is known about the impact of comorbidity on health-related quality of life (HRQOL) in multiple sclerosis (MS). We investigated the association of comorbidity and health-related HRQOL among participants in the North American Research Committee on Multiple Sclerosis (NARCOMS). MATERIALS AND METHODS: In 2006, we queried NARCOMS participants regarding physical and mental comorbidities and HRQOL, using the Short-Form 12. We summarized physical HRQOL using the aggregate Physical Component Scale (PCS-12) score and mental HRQOL using the aggregate Mental Component Scale (MCS-12) score. We assessed multivariable associations between comorbidity and HRQOL using a general linear model, adjusting for potential confounders. RESULTS: Among 8983 respondents, the mean (SD) PCS-12 was 36.9 (11.8) and MCS-12 was 45.6 (11.6). After adjustment for sociodemographic and clinical factors, participants with any physical comorbidity had a lower PCS-12 (37.2; 95% CI: 36.4-38.1) than those without any physical comorbidity (40.1; 95% CI: 39.0-41.1). As the number of physical comorbidities increased, PCS-12 scores decreased (r = -0.25; 95% CI: -0.23 to -0.27) indicating lower reported HRQOL. Participants with any mental comorbidity had a lower MCS-12 (40.7; 95% CI: 39.8-41.6) than those without any mental comorbidity (48.5; 95% CI: 47.7-49.4). CONCLUSIONS: Comorbidity is associated with reduced HRQOL in MS. Further research should evaluate whether more aggressive treatment of comorbidities improves the HRQOL of MS patients. PMID- 21615356 TI - Median nerve ultrasonography in distinguishing neuropathy sub-types: a pilot study. AB - BACKGROUND: The diagnostic potential of ultrasonography (US) in polyneuropathy has been studied rarely, with complex measurement/correction techniques. Whether US may be useful in clinical practice remains uncertain. MATERIALS AND METHODS: We aimed to ascertain the value of US, as performed routinely at our institution, in differentiating neuropathy sub-types. We prospectively studied 14 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and 14 patients with sensory axonal neuropathy (SAN). Median nerves were studied bilaterally at wrist and forearm by a radiologist blinded to the neuropathy sub-type. Nerve width (medial to lateral diameter), thickness (anterior to posterior diameter) and cross-sectional area were compared in between patient groups and anatomical sites. Optimal cut-off values were determined using receiver operating characteristic (ROC) curves. RESULTS: Largest measured median nerve thickness was significantly greater in patients with CIDP (P = 0.014), and ROC curve analysis indicated a cut-off offering a sensitivity of 57.1% for CIDP and specificity of 92.9% vs SAN. Nerves were wider and had larger cross-sectional areas, but were not thicker, at wrist compared to forearm in both patient groups. There was an equal prevalence in both patients with CIDP and SAN, of increased median nerve wrist-to-forearm area ratio, compatible with sub-clinical carpal tunnel syndrome. CONCLUSION: This prospective, blinded, pilot study is the first to indicate the diagnostic potential of US, as performed routinely, in distinguishing between acquired demyelinating and axonal neuropathy. These findings now require confirmation in larger, adequately designed studies, evaluating other nerves/nerve sites, assessing healthy controls and taking into account interrater and equipment variabilities. PMID- 21615357 TI - Patient-controlled oral analgesia following cesarean section: tramadol versus a combination of tramadol and acetaminophen. PMID- 21615359 TI - Should we recommend hysterectomy more often to premenopausal and climacteric women? AB - In developed countries, women live on average over 30 years as postmenopausal. In the premenopausal and climacteric period, abnormal uterine bleeding and other symptoms may occur. In addition, endometrial cancer is the most common gynecological malignancy, and possible hormone replacement therapy is much more beneficial among women with prior hysterectomy. With this background and the recommended use of minimally invasive surgical techniques, we argue in favor of more liberal hysterectomy practice before and around the menopause. Many will disagree, because for many years we have argued to save the uterus, but considering pros and cons with the patient in focus, we discuss the topic and advertise for studies to support our view. PMID- 21615358 TI - Effect of parity on maternal and neonatal outcomes in twin gestations. AB - OBJECTIVE: To compare maternal and neonatal outcomes of twin gestations in nulliparous and multiparous women. DESIGN: Retrospective analysis of maternal and neonatal records. SETTING: American University of Beirut Medical Center, a referral university-affiliated hospital. POPULATION: Pregnant women who delivered twin gestations beyond 24 weeks from 1990 to 2004. METHODS: The data collected were analyzed using Student's paired t-test or chi(2) test. Logistic regression analysis was used to study the effect of multiple variables on preterm delivery. MAIN OUTCOME MEASURE: Preterm birth rate. RESULTS: Nulliparas (n=333) were more likely to be younger (28.1+/-5.4 vs. 30.0+/-5.2 years; p<0.001) and the pregnancy a product of assisted reproductive technology (23.1 vs. 4.5%; p<0.001) compared with multiparas (n=508). They were at significantly increased risk of preterm delivery (54.4 vs. 45.1%; p=0.009) at lower gestational age (35.6+/-3.2 vs. 36.2+/-3.0 weeks; p=0.004). They had longer first and second stages of labor and a higher cesarean delivery rate (61.3 vs. 44.9%; p<0.001). Except for a higher intensive care nursery admission rate and longer nursery stay for twins of nulliparas, all neonatal morbidities were comparable. On multiple logistic regression analysis, multiparity (relative risk 0.70, 95% confidence interval 0.51-0.97) and growth restriction (relative risk 0.16, 95% confidence interval 0.12-0.22) were protective, while discordance (relative risk 2.24, 95% confidence interval 1.40-3.60) was a predictor of preterm delivery. CONCLUSIONS: Nulliparous women with twin gestations are at significantly higher risk for preterm delivery and cesarean delivery compared with multiparous women. Although this was not translated into higher perinatal mortality, these women should be monitored closely and counseled regarding these risks and their attendant morbidity. PMID- 21615360 TI - Treatment of ilioinguinal nerve entrapment - a randomized controlled trial. AB - OBJECTIVE: Neuralgic pain caused by entrapment of peripheral nerves can be a difficult clinical problem. The objective of the present study was to assess pain and quality of life in women with pain secondary to ilioinguinal nerve entrapment. DESIGN: In a controlled prospective crossover study, women with ilioinguinal nerve entrapment were randomly allocated to either medical treatment or surgical resection of the ilioinguinal nerve. SETTING: A university hospital. POPULATION: 19 women, 21-60 years of age with pelvic pain of more than 6 months' duration. METHODS AND MAIN OUTCOME MEASURES: Visual analogue (VA) scales and psychological general well-being (PGWB) scales were used to validate pain and quality of life, respectively. RESULTS: Improvements were found in the group randomly allocated to surgery, p < 0.008 for the VA scale and p < 0.0098 for the PGWB scale, respectively. Nine of 10 women discontinued the medical arm of treatment because of side effects and/or lack of effect. After being shifted over to surgery, similar improvements were noted (p < 0.0002 and p < 0.0043, respectively). CONCLUSIONS: The positive results found here indicate that surgery is superior to medical treatment in ilioinguinal nerve entrapment of unknown cause as well as after previous surgery. More randomized trials from different centers with larger numbers of women are needed to confirm these results. PMID- 21615361 TI - Birthweight, preterm birth and perinatal mortality: a comparison of black babies in Tanzania and the USA. AB - OBJECTIVES: Adverse conditions in Africa produce some of the highest rates of infant mortality in the world. Fetal growth restriction and preterm delivery are commonly regarded as major pathways through which conditions in the developing world affect infant survival. The aim of this article was to compare patterns of birthweight, preterm delivery, and perinatal mortality between black people in Tanzania and the USA. DESIGN: Registry-based study. SETTINGS: Referral hospital data from North Eastern Tanzania and US Vital Statistics. SAMPLE: 14 444 singleton babies from a hospital-based registry (1999-2006) and 3 530 335 black singletons from US vital statistics (1995-2000). MAIN OUTCOME MEASURES: Birthweight, gestational age and perinatal mortality. METHODS: Restricting our study to babies born at least 500g, we compared birthweight, gestational age, and perinatal mortality (stillbirths and deaths in the first week) in the two study populations. RESULTS: Perinatal mortality in the Tanzanian sample was 41/1 000, compared with 10/1 000 among USA blacks. Tanzanian babies were slightly smaller on average (43g), but fewer were preterm (<37 weeks) (10.0 vs. 16.2%). Applying the USA weight-specific mortality rates to Tanzanian babies born at term suggested that birthweight does not play a role in their increased mortality relative to USA blacks. CONCLUSIONS: Higher mortality independent of birthweight and preterm delivery for Tanzanian babies suggests the need to address the contribution of other pathways to further reduce the excess perinatal mortality. PMID- 21615362 TI - Does yoga therapy actually improve the emotion recognition deficits in schizophrenia? PMID- 21615363 TI - Do the effects of yoga therapy improve positive and negative symptoms and emotion recognition abilities in antipsychotic-stabilized patients with schizophrenia? PMID- 21615366 TI - The photosensitive patient: could it be pellagra? PMID- 21615367 TI - Aqueous cream damages the skin barrier. PMID- 21615368 TI - Importance of surveillance systems in monitoring trends in allergen sensitivity. PMID- 21615369 TI - Maintenance therapy: acne as a chronic disease. PMID- 21615370 TI - Acne, isotretinoin and suicide attempts: a critical appraisal. AB - AIM: Sundstrom et al. (BMJ 2010; 341: c5812) aimed to assess suicide risk before, during and after isotretinoin treatment. HYPOTHESIS: People with severe acne may be at higher risk of attempted suicide regardless of exposure to isotretinoin. SETTING AND DESIGN: This retrospective cohort study from Sweden linked a patient register of isotretinoin users (1980-1989) or patients identified through specified pharmacies (1986-1989) to hospital discharges and a register of causes of death (1980-2001). STUDY EXPOSURE: The study exposure was isotretinoin, identified from a register of named patients given isotretinoin (special application to the Medical Products Agency) or patients prescribed isotretinoin in a dermatology clinic with 'clinic approval' to prescribe the medication without individual application. OUTCOMES: The outcomes were recorded suicide attempts (identified using ICD-8 and ICD-9 codes E950-E958, ICD-10 codes Y6-64); accidents with unclear intent and an 'external cause' (ICD-8 and ICD-9 codes E980 E988 and ICD-10 codes Y10-Y34) and deaths with underlying causes. PRIMARY OUTCOME MEASURE: Standardized incidence ratio (SIR) of suicide rates compared with the general population 3 years before, during and up to 15 years after completion of treatment with isotretinoin. RESULTS: The cohort included 5756 people. During the 21-year follow-up period, 128 (2.2%) had a hospital admission for a suicide attempt. For all attempts, the SIR [95% confidence interval (CI)] increased from 0.99 (0.65-1.44) 3 years prior to treatment to 1.57 (0.86-2.63) in the year before treatment, increasing to 1.78 (1.04-2.85) within 6 months after starting treatment and decreasing to 1.04 (0.74-1.43) 3 years following treatment. For first suicide attempts, the SIR (95% CI) increased from 0.89 (0.54-1.37) 3 years prior to treatment to 1.36 (0.65-2.50) in the year before treatment, increasing to 1.93 (1.08-3.18) within 6 months of treatment and decreasing to 0.97 (0.64 1.40) 3 years following treatment. Twelve (38%) of 32 patients who attempted suicide prior to treatment made a further attempt or committed suicide at some stage during follow up. Of the 14 who attempted suicide during or within 6 months of treatment, 10 (71%) made a further attempt during follow up. CONCLUSIONS: Sundstrom et al. (BMJ 2010; 341: c5812) conclude that there was an increased risk of suicide attempts up to 6 months after the end of treatment with isotretinoin and advise close monitoring for up to a year after completing a course of treatment. Patients with a history of suicide attempts before treatment made fewer new attempts at suicide than those where suicidality was observed in connection with treatment, suggesting that patients with severe acne with a history of attempted suicide should not automatically be refused isotretinoin treatment. The authors also state that suicide risk was already rising prior to treatment and that the additional risk cannot therefore be attributed to isotretinoin use. PMID- 21615372 TI - Commentary: Acne, isotretinoin and suicide attempts. PMID- 21615373 TI - Staphylococcus aureus endocarditis as a complication of acupuncture for eczema. PMID- 21615375 TI - Platelet transfusions for patients with haematological malignancies: who needs them? AB - The goal of platelet transfusions is to prevent severe and life-threatening bleeding in patients with thrombocytopenia. This aim needs to be balanced against the risks associated with platelet transfusions as well as the challenge of maintaining an adequate supply. This review summarizes the recent evidence regarding the clinical use of platelet transfusions in haematology patients, concentrating on the topics that still continue to provoke debate. These include the optimal dose for platelet transfusions and the relative safety of a 'therapeutic only' platelet transfusion strategy compared to the use of prophylactic platelet transfusions. The type of platelet product has been the subject of two recent systematic reviews. The results of these reviews will be discussed as well as their implications for current practice. PMID- 21615376 TI - Successful chelation therapy with the combination of deferasirox and deferiprone in a patient with thalassaemia major and persisting severe iron overload after single-agent chelation therapies. PMID- 21615377 TI - Marked impact of IL28B genotype in the natural clearance of hepatitis C virus in patients with haemoglobinopathies. PMID- 21615378 TI - Childhood migraine and hypercoagulopathy. PMID- 21615379 TI - B cell activating factor is elevated in acute idiopathic thrombotic thrombocytopenic purpura. PMID- 21615380 TI - Revisiting Darwinism explains extinction of fetal erythroid progenitors in a leukaemogenic model of a paediatric myeloproliferative neoplasm. PMID- 21615381 TI - Diagnosis and management of anaemia of chronic disease: current status. AB - Anaemia of chronic disease is the second most common form of anaemia worldwide, and is seen in a variety of inflammatory, infective and malignant diseases. Functional iron deficiency is fundamental to the pathogenesis of the anaemia, and the polypeptide, hepcidin, plays a key role. Diagnosis may be difficult, but new automated red cell indices, algorithms for detection of functional iron deficiency, and assays for hepcidin levels are being developed. Management of the causative disease process will usually improve haemoglobin levels, but where this is not possible, erythropoietic stimulating agents are often used, although there are still concerns about potential adverse effects, especially thromboembolism. There is increasing evidence that supplemental iron given parenterally can safely overcome the functional iron deficiency. Inhibitors of hepcidin, and various inflammatory modulators show promise for the future. PMID- 21615382 TI - Mitochondrial genome variants in non-remitting ALL of childhood. PMID- 21615383 TI - Stability of low molecular weight heparin anti-factor Xa activity in citrated whole blood and plasma. PMID- 21615384 TI - Nurse-like cells show deregulated expression of genes involved in immunocompetence. AB - Chronic lymphocytic leukaemia (CLL) cells convert CD14(+) cells from patients into 'nurse-like' cells (NLCs). CLL cells can also convert CD14(+) peripheral blood mononuclear cells (PBMCs) from healthy donors into cells with morphological similarities to NLCs (CD14(CLL) -cells). However it is unclear whether only CLL cells induce this conversion process. This study showed that CD14(+) PBMCs from healthy donors could also be converted into differentiated cells (CD14(B) -cells) by non-malignant B-cells. In order to identify changes specifically induced by CLL cells, we compared gene expression profiles of NLCs, CD14(CLL) -cells and CD14(B) -cells. CD14(+) cells cultured with CLL cells were more similar to NLCs than those cultured with non-malignant B-cells. The most significant changes induced by CLL cells were deregulation of the antigen presentation pathway and of genes related to immunity. NLCs had reduced levels of lysozyme activity, CD74 and HLA-DR in-vitro while expression of inhibitory FCGR2B was increased. These findings suggest an impaired immunocompetence of NLCs which, if found in-vivo, could contribute to the immunodeficiency in CLL patients. PMID- 21615385 TI - Maintenance Rituximab is associated with improved clinical outcome in rituximab naive patients with Waldenstrom Macroglobulinaemia who respond to a rituximab containing regimen. AB - This study examined the outcome of 248 Waldenstrom macroglobulinaemia (WM) rituximab-naive patients who responded to a rituximab-containing regimen. Eighty six patients (35%) subsequently received maintenance rituximab (M-Rituximab). No differences in baseline characteristics, and post-induction categorical responses between cohorts were observed. The median rituximab infusions during induction was 6 for both cohorts; and 8 over a 2-year period for patients receiving M Rituximab. Categorical responses improved in 16/162 (10%) of observed, and 36/86 (41.8%) of M-Rituximab patients respectively, following induction therapy (P < 0.0001). Both progression-free (56.3 vs. 28.6 months; P = 0.0001) and overall survival (Not reached versus 116 months; P = 0.0095) were longer in patients who received M-Rituximab. Improved progression-free survival was evident despite previous treatment status, induction with rituximab alone or in combination therapy (P <= 0.0001). Best serum IgM response was lower (P < 0.0001), and haematocrit higher (P = 0.001) for patients receiving M-Rituximab. Among patients receiving M-Rituximab, an increased number of infectious events were observed, but were mainly <= grade 2 (P = 0.008). The findings of this observational study suggest improved clinical outcomes following M-Rituximab in WM patients who respond to induction with a rituximab-containing regimen. Prospective studies aimed at clarifying the role of M-Rituximab therapy in WM patients are needed to confirm these findings. PMID- 21615387 TI - The histamine H3 receptor: from discovery to clinical trials with pitolisant. AB - The third histamine receptor was discovered in 1983 by a traditional pharmacological approach, consisting of assessing the inhibitory effect of histamine on its own release from depolarized rat brain slices. The same in vitro test was used to design, in 1987, the first highly selective and potent H3 autoreceptor ligands, the antagonist thioperamide and the agonist (R)alphamethylhistamine which enhances and inhibits, respectively, the activity of histaminergic neurons in brain. The use of these research tools was instrumental in establishing the main functions of cerebral histaminergic neurons, namely their role in maintenance of wakefulness, attention, learning and other cognitive processes. In 1990, the cloning of the gene of the H3-receptor, a member of the superfamily of heptahelical receptors coupled to G proteins, paved the way to the demonstration of the high constitutive activity of the receptor, including its native form, and its participation in the tonic control of histamine release; it also facilitated the development of H3-receptor inverse agonist programs in many drug companies. Pitolisant (BF2.649, 1-{3-[3-(4 chlorophenyl)propoxy]propyl}piperidine, hydrochloride) is the first inverse agonist to be introduced in the clinics. Its wake-promotion activity was evidenced in excessive diurnal sleepiness of patients with narcolepsy, Parkinson's disease or Obstructive Sleep Apnea/Hypopnea, in which this activity is characterized by a mean decrease of the Epworth Sleepiness Scale by about five units. The procognitive activity of this novel class of drugs may also find therapeutic applications in dementias, schizophrenia or attention deficit hyperactivity disorder. PMID- 21615386 TI - Drug targeting of sphingolipid metabolism: sphingomyelinases and ceramidases. AB - Sphingolipids represent a class of diverse bioactive lipid molecules that are increasingly appreciated as key modulators of diverse physiologic and pathophysiologic processes that include cell growth, cell death, autophagy, angiogenesis, and stress and inflammatory responses. Sphingomyelinases and ceramidases are key enzymes of sphingolipid metabolism that regulate the formation and degradation of ceramide, one of the most intensely studied classes of sphingolipids. Improved understanding of these enzymes that control not only the levels of ceramide but also the complex interconversion of sphingolipid metabolites has provided the foundation for the functional analysis of the roles of sphingolipids. Our current understanding of the roles of various sphingolipids in the regulation of different cellular processes has come from loss-of function/gain-of-function studies utilizing genetic deletion/downregulation/overexpression of enzymes of sphingolipid metabolism (e.g. knockout animals, RNA interference) and from the use of pharmacologic inhibitors of these same enzymes. While genetic approaches to evaluate the functional roles of sphingolipid enzymes have been instrumental in advancing the field, the use of pharmacologic inhibitors has been equally important in identifying new roles for sphingolipids in important cellular processes.The latter also promises the development of novel therapeutic targets with implications for cancer therapy, inflammation, diabetes, and neurodegeneration. In this review, we focus on the status and use of pharmacologic compounds that inhibit sphingomyelinases and ceramidases, and we will review the history, current uses and future directions for various small molecule inhibitors, and will highlight studies in which inhibitors of sphingolipid metabolizing enzymes have been used to effectively treat models of human disease. PMID- 21615388 TI - Inhibitory effect of caffeine on pacemaker activity in the oviduct is mediated by cAMP-regulated conductances. AB - BACKGROUND AND PURPOSE: Spontaneous electrical activity, termed slow waves, drives rhythmic, propulsive contractions in the smooth muscle of the oviduct (myosalpinx). Myosalpinx contractions cause egg transport through the oviduct. Agents that disrupt slow wave pacemaker activity will therefore disrupt myosalpinx contractions and egg transport. Caffeine is commonly used as a ryanodine receptor agonist and has been previously associated with delayed conception. Here we assessed the effects of caffeine on pacemaker activity in the murine myosalpinx. EXPERIMENTAL APPROACH: The effects of caffeine on electrical pacemaker activity were studied using intracellular microelectrode and isometric force measurements on intact oviduct muscle preparations. Responses to caffeine were compared with responses caused by 3-isobutyl-1-methylxanthine (IBMX) and forskolin. KEY RESULTS: Caffeine caused hyperpolarization of membrane potential and inhibited slow wave generation and myosalpinx contractions. The effects of caffeine could be mimicked by the K(ATP) channel agonist pinacidil and antagonized by the K(ATP) channel antagonist glibenclamide. Caffeine is known to inhibit cyclic nucleotide phosphodiesterases (PDEs), leading to an increase in cytosolic cAMP and stimulation of downstream cAMP-dependent mechanisms. The effects of caffeine were mimicked by the PDE inhibitor, IBMX, and the adenylyl cyclase activator forskolin. These effects were also reversed by glibenclamide. CONCLUSIONS AND IMPLICATIONS: These results suggest that caffeine activates K(ATP) channels in oviduct myosalpinx. Since caffeine abolishes slow waves and associated contractions of the myosalpinx, it would have a negative effect on egg transport through the oviduct and may contribute to the documented delayed conception in women consuming caffeinated beverages. PMID- 21615390 TI - Modulation of CD4+ T cell responses following splenectomy in hepatitis C virus related liver cirrhosis. AB - Dysfunction of T cells is a common feature in chronic persistent viral infections, including hepatitis C virus (HCV), and although hepatic and peripheral T cells have been studied extensively in chronic HCV hepatitis, the role of splenic T cell responses in such patients is poorly defined. This is an important issue, as thrombocytopenia is a complication of HCV-related liver cirrhosis (LC), due to splenic platelet sequestration and bone marrow suppression; splenectomy has been proposed to treat such patients. Herein, we studied peripheral blood mononuclear cells (PBMC) and splenic lymphoid subpopulations from a total of 22 patients, including 15 with HCV-related LC with marked thrombocytopenia treated with splenectomy, and seven controls. CD4(+) T cells from peripheral blood and spleen were isolated and phenotype and function evaluated. Splenic CD4(+) T cells in patients with LC expressed molecules associated with inhibitory signalling, including increased frequency of negative markers such as cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death 1 (PD-1) and decreased production of cytokines. Patients with LC manifest higher levels of splenic CD4(+) regulatory T cells and PD-L1- and PD-L2 expressing cells than controls. Blocking of PD-1/PD-1 ligand interaction reconstituted proliferative and cytokine responses of splenic mononuclear cells (SMC) from patients with LC. Splenectomy was followed by an increase in the ratio of interferon (IFN)-gamma to interleukin (IL)-10 and a reduction of PD-1 expressing CD4(+) T cells in peripheral blood. Our data suggest that peripheral tolerance is promoted by the spleen in LC via the up-regulated expression of PD-1 ligands. PMID- 21615389 TI - Protein kinase C phosphorylates the cAMP response element binding protein in the hypothalamic paraventricular nucleus during morphine withdrawal. AB - BACKGROUND AND PURPOSE: Exposure to drugs of abuse or stress results in adaptation in the brain involving changes in gene expression and transcription factors. Morphine withdrawal modulates gene expression through various second messenger signal transduction systems. Here, we investigated changes in activation of the transcription factor, cAMP-response element binding protein (CREB), in the hypothalamic paraventricular nucleus (PVN) and the kinases that may mediate the morphine withdrawal-triggered activation of CREB and the response of the hypothalamic-pituitary-adrenocortical (HPA) axis after naloxone-induced morphine withdrawal. EXPERIMENTAL APPROACH: The effects of morphine dependence and withdrawal, phosphorylated CREB (pCREB), corticotrophin-releasing factor (CRF) expression in the PVN and HPA axis activity were measured using immunoblotting, immunohistochemistry and radioimmunoassay in controls and in morphine-dependent rats, withdrawn with naloxone and pretreated with vehicle, calphostin C, chelerythrine (inhibitors of protein kinase C (PKC) or SL-327 [inhibitor of extracellular signal regulated kinase (ERK) kinase]. In addition, changes in PKCalpha and PKCgamma immunoreactivity were measured after 60 min of withdrawal. KEY RESULTS: In morphine-withdrawn rats, pCREB immunoreactivity was increased within CRF immunoreactive neurons in the PVN and plasma corticosterone levels were raised. SL-327, at doses that reduced the augmented pERK levels in the PVN, did not attenuate the rise in pCREB immunoreactivity or plasma corticosterone secretion. In contrast, PKC inhibition reduced the withdrawal triggered rise in pCREB, pERK1/2 and corticosterone secretion. CONCLUSIONS AND IMPLICATIONS: PKC mediated, in part, both CREB activation and the HPA response to morphine withdrawal. The ERK kinase/ERK pathway might not be necessary for either activation of CREB or HPA axis hyperactivity. PMID- 21615391 TI - Repeat measurements of glycated haemoglobin A(1c) and N-terminal pro-B-type natriuretic peptide: divergent behaviour in diabetes mellitus. AB - BACKGROUND: Patients with diabetes mellitus have a substantially increased risk of developing cardiovascular disease. However, the absolute risk greatly varies not only among patients, but the risk profile for an individual patient may also change over time. We investigated the prognostic role of repetitive measurements of Glycated haemoglobin A(1c) (HbA(1c) ) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with longstanding diabetes. MATERIALS AND METHODS: For this prospective, observational study data from 544 consecutive patients were collected between 2005 and 2008. HbA(1c) and NT-proBNP were measured at baseline and after 1 year. The median observation period was 40 months. Endpoints were all-cause mortality, cardiac, cardiovascular and all-cause hospitalizations. RESULTS: N-terminal pro-B-type natriuretic peptide concentrations significantly increased from 230 +/- 385 to 280 +/- 449 pg mL(-1) (P < 0.001); during the same time, HbA(1c) significantly decreased from 7.6 +/- 1.5 to 7.3 +/- 1.2 (P < 0.001). NT-proBNP was the best baseline predictor in a Cox regression model consisting of NT-proBNP, HbA(1c) , age, gender and duration of diabetes for all endpoints (P < 0.001). NT-proBNP at follow-up was the best predictor for the remaining period (P < 0.001, all endpoints). HbA(1c) at baseline and follow-up was predictive for all-cause hospitalizations (P = 0.005 both). In a third model that investigated the plasticity of both markers, changes in HbA(1c) concentration had no predictive value, but a change of NT-proBNP concentration was highly predictive (P = 0.025 all-cause mortality, P < 0.001 all other endpoints). CONCLUSIONS: N-terminal pro-B-type natriuretic peptide and HbA(1c) concentrations significantly diverged over a 1-year period. NT-proBNP was the most potent predictor of outcome at baseline and follow-up, and changes in NT proBNP concentrations were linked to an altered risk profile, unlike changes in HbA(1c) levels. PMID- 21615392 TI - Determinants of plasma vitamin D levels in patients with acute coronary syndromes. AB - BACKGROUND: Vitamin D is implicated in various biological functions ranging from cellular proliferation to immunity. Vitamin D deficiency is associated with an increased risk of several diseases including coronary atherosclerosis. MATERIALS AND METHODS: We measured plasma 25(OH)D3 level in 224 patients with acute coronary syndromes (ACS) and 209 control individuals by ELISA. We genotyped the study populations for 11 single nucleotide polymorphisms (SNPs) in seven genes involved in vitamin D biosynthesis and metabolism by 5' nuclease assays. RESULTS: The mean and median plasma 25(OH)D3 levels were not significantly different between patients with ACS and controls (median: 22.06 vs. 22.24 ng mL(-1) , respectively, P = 0.618). Plasma 25(OH)D3 level was < 20 ng mL(-1) in 175/433 (40%) and < 30 ng mL(-1) in 333/433 (77%) participants. Only four individuals had plasma 25(OH)D3 levels of above 60 ng mL(-1) . African-American and Hispanic populations, women and those with diabetes mellitus had significantly lower plasma 25(OH)D3 levels. In multivariable regression analysis, age, sex, diabetes mellitus, body weight, rs2762933 (CYP24A1) and rs6055987 (PLCB1) SNPs were independent predictors of plasma 25(OH)D3 level in the Caucasian population. CONCLUSIONS: We found no difference in mean plasma vitamin D levels between patients with ACS and controls. Differences in population characteristics between the two study groups including medications use and the lack of data on vitamin D, calcium and multivitamin supplements intake as well as the relatively small sample size of the populations could confound the results. Ethnic background, sex, age, body weight and SNPs in CYP24A1 and PLCB1 were independent determinants of plasma vitamin D levels. PMID- 21615393 TI - Depressive symptoms predict mortality in elderly subjects with chronic heart failure. AB - BACKGROUND: Chronic heart failure (CHF) is characterized by a high mortality in the elderly. Moreover, depression status is also related to poor prognosis in advancing age. Thus, we sought to determine whether depressive status predicts long-term mortality in subject with or without CHF. METHODS AND RESULTS: Long term mortality after 12-year follow-up in 125 elderly subjects with CHF and 1143 elderly subjects without CHF was studied. Depression was evaluated using the Geriatric Depression Scale (GDS), and all subjects were stratified in tertiles according to GDS score (0-10, 11-20 and 21-30). With increasing GDS score, long term mortality at the end of follow-up increased from 43.4% to 72.0% in subjects without (P < 0.001) and from 52.6% to 83.9% in subjects with (P < 0.007) CHF. In multivariate analysis, GDS appeared to be predictive of long-term mortality in the absence (Hazard ratio = 1.01; confidence interval 95% 1.00-1.05; P = 0.04) and, even more, in the presence of CHF (Hazard ratio = 1.08; confidence interval 95% 1.01-1.15; P < 0.01). CONCLUSIONS: Depression symptoms predict long-term mortality in elderly subjects without and, even more, with CHF. Thus, depression can be considered a strong predictor of death in CHF elderly subjects. PMID- 21615394 TI - Effects of inflammatory and anti-inflammatory cytokines on the bone. AB - BACKGROUND: Inflammatory diseases are linked to enhanced bone loss. The effect of inflammation on bone is mediated by proinflammatory cytokines, which regulate bone formation as well as bone resorption thereby altering bone homeostasis. MATERIALS AND METHODS: In this article we summarize the key insights in cytokine regulation of bone. We describe the major pro- and anti-inflammatory mediators, which are involved in the regulation of bone and describe the mechanisms by which these cytokines alter bone balance. RESULTS: We describe the effects of tumor necrosis factor (TNF), interleukin (IL)- 1 family members, IL-6, IL-17 and interferons (IFN) on bone and discuss the mechanisms by which these individual cytokines affect the bone resorbing and the bone forming cells. CONCLUSIONS: Several proinflammatory cytokines (such as TNFa, IL-1 and IL-17) are major triggers for osteoclast activation explaining the enhanced bone loss during inflammation. Other such as IL-12, IL-18, IL-33 and IFN are strong suppressors of osteoclast differentiation and inhibit bone loss. Thus the cytokine composition of an inflammatory tissue is decisive whether inflammation triggers bone loss or not. PMID- 21615395 TI - In vitro responsiveness of human muscle cell peroxisome proliferator-activated receptor delta reflects donors' insulin sensitivity in vivo. AB - BACKGROUND: Peroxisome proliferator-activated receptor delta (PPARdelta) activation enhances muscular fatty acid oxidation and oxidative phosphorylation, and muscle's oxidative capacity positively associates with whole-body insulin sensitivity. Therefore, we asked here whether human muscle cell PPARD expression is a determinant of donors' insulin sensitivity. MATERIALS AND METHODS: Skeletal muscle cells derived from 38 nondiabetic donors were differentiated in vitro to myotubes, and gene (mRNA) expression was quantified by real-time RT-PCR. Donors' insulin sensitivity was calculated from plasma insulin and glucose levels during oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp. RESULTS: Basal myotube PPARD expression was closely related to the expression of its target genes PDK4 and ANGPTL4 (P = 0.0312 and P = 0.0003, respectively). Basal PPARD, PDK4 and ANGPTL4 expression levels were not associated with donors' insulin sensitivity (P > 0.2, all). Treatment of myotubes with a selective high affinity PPARdelta agonist (GW501516) did not change mean PPARD, but enhanced mean PDK4 and ANGPTL4 expression 13- and 16-fold, respectively (P < 0.0001, both). The individual PDK4 and ANGPTL4 expression levels reached upon GW501516 treatment were associated with donors' insulin sensitivity neither (P > 0.2, both). However, GW501516-mediated fold increments in PDK4 and ANGPTL4 expression, reflecting PPARdelta responsiveness, were positively associated with donors' insulin sensitivity derived from OGTT (P = 0.0182 and P = 0.0231, respectively) and hyperinsulinemic-euglycemic clamp (P = 0.0046 and P = 0.0258, respectively). CONCLUSIONS: Using a highly selective pharmacological tool, we show here that the individual responsiveness of human muscle cell PPARdelta, rather than the absolute PPARD expression level, represents a major determinant of insulin sensitivity. PMID- 21615396 TI - Adhesion molecules and high-sensitivity C-reactive protein levels in patients with sickle cell beta-thalassaemia. AB - BACKGROUND AND AIM: The primary symptoms of sickle cell disease (SCD) arise from vaso-occlusive crises. The pathogenesis of these crises is complex phenomenon where endothelial activation and damage has a major role. Chronic inflammation also plays an important role in the pathophysiology of SCD. We aimed to investigate endothelial activation in Caucasian Greek patients with SCD by means of measuring adhesion molecules and markers of inflammation. SUBJECTS AND METHODS: Twenty-eight patients with SCD aged 5-63 years were included in the study. Most of the patients (23/28) were double heterozygotes for sickle cell/beta-thalassaemia, while five patients (5/28) were sickle cell homozygotes. Patients were treated with one/or more of hydroxyurea, therapeutic phlebotomies, blood transfusion or splenectomy. Twenty apparently healthy individuals matched for age and sex formed the control group. Measurements of soluble intercellular adhesion molecule-1, (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM 1), P-selectin, E-selectin, soluble thrombomodulin (sTM) and high-sensitivity C reactive protein (hs-CRP) levels were performed using immunoassays in both patients and healthy individuals. RESULTS: We found that all endothelial adhesion molecules and hs-CRP were significantly increased (P < 0.001) in patients with SCD compared with controls, while sTM levels did not differ significantly (P > 0.05) and this increase was not influenced by the treatment. CONCLUSION: Our findings demonstrate the high degree of endothelial activation and damage seen in sickle cell patients even in steady-state condition, as well as the important chronic inflammation underlying the pathophysiology of this widespread disease. PMID- 21615397 TI - Functional morphology of the muscular sling at the pectoral girdle in tree sloths: convergent morphological solutions to new functional demands? AB - Recent phylogenetic analyses imply a diphyly of tree sloths and a convergent evolution of their obligatory suspensory locomotion. In mammals the extrinsic shoulder musculature forms a 'muscular sling' to support the trunk in quadrupedal postures. In addition, the extrinsic pectoral muscles are responsible for moving the proximal forelimb elements during locomotion. Due to the inverse orientation of the body in regard to the gravitational force, the muscular sling as configured as in pronograde mammals is unsuited to suspend the weight of the thorax in sloths. We here review the muscular topography of the shoulder in Choloepus didactylus and Bradypus variegatus in the light of presumably convergent evolution to adapt to the altered functional demands of the inverse orientation of the body. In addition, we venture to deduce the effect of the shoulder musculature of C. didactylus during locomotion based on previously published 3D kinematic data. Finally, we assess likely convergences in the muscular topography of both extant sloth lineages to test the hypothesis that convergent evolution is reflected by differing morphological solutions to the same functional demands posed by the suspensory posture. Muscular topography of the shoulder in C. didactylus is altered from the plesiomorphic condition of pronograde mammals, whereas the shoulder in B. variegatus more closely resembles the general pattern. Overall kinematics as well as the muscles suitable for pro- and retraction of the forelimb were found to be largely comparable to pronograde mammals in C. didactylus. We conclude that most of the peculiar topography of extrinsic forelimb musculature can be attributed to the inverse orientation of the body. These characteristics are often similar in both genera, but we also identified different morphological solutions that evolved to satisfy the new functional demands and are indicative of convergent evolution. We suggest that the shared phylogenetic heritage canalized the spectrum of possible solutions to new functional demands, and digging adaptations of early xenarthrans posed morphological constraints that resulted in similar suspensory postures. The data of this study, including muscle maps, will be helpful to infer locomotor characteristics of fossil sloths. PMID- 21615398 TI - Using occlusal wear information and finite element analysis to investigate stress distributions in human molars. AB - Simulations based on finite element analysis (FEA) have attracted increasing interest in dentistry and dental anthropology for evaluating the stress and strain distribution in teeth under occlusal loading conditions. Nonetheless, FEA is usually applied without considering changes in contacts between antagonistic teeth during the occlusal power stroke. In this contribution we show how occlusal information can be used to investigate the stress distribution with 3D FEA in lower first molars (M(1)). The antagonistic crowns M(1) and P(2)-M(1) of two dried modern human skulls were scanned by MUCT in maximum intercuspation (centric occlusion) contact. A virtual analysis of the occlusal power stroke between M(1) and P(2)-M(1) was carried out in the Occlusal Fingerprint Analyser (OFA) software, and the occlusal trajectory path was recorded, while contact areas per time-step were visualized and quantified. Stress distribution of the M(1) in selected occlusal stages were analyzed in strand7, considering occlusal information taken from OFA results for individual loading direction and loading area. Our FEA results show that the stress pattern changes considerably during the power stroke, suggesting that wear facets have a crucial influence on the distribution of stress on the whole tooth. Grooves and fissures on the occlusal surface are seen as critical locations, as tensile stresses are concentrated at these features. Properly accounting for the power stroke kinematics of occluding teeth results in quite different results (less tensile stresses in the crown) than usual loading scenarios based on parallel forces to the long axis of the tooth. This leads to the conclusion that functional studies considering kinematics of teeth are important to understand biomechanics and interpret morphological adaptation of teeth. PMID- 21615399 TI - Morphometric analysis of the relationships between intervertebral disc and vertebral body heights: an anatomical and radiographic study of the human thoracic spine. AB - The main aim of this study was to provide anatomical data on the heights of the human intervertebral discs for all levels of the thoracic spine by direct and radiographic measurements. Additionally, the heights of the neighboring vertebral bodies were measured, and the prediction of the disc heights based only on the size of the vertebral bodies was investigated. The anterior (ADH), middle (MDH) and posterior heights (PDH) of the discs were measured directly and on radiographs of 72 spine segments from 30 donors (age 57.43 +/- 11.27 years). The radiographic measurement error and the reliability of the measurements were calculated. Linear and non-linear regression analyses were employed for investigation of statistical correlations between the heights of the thoracic disc and vertebrae. Radiographic measurements displayed lower repeatability and were shorter than the anatomical ones (approximately 9% for ADH and 37% for PDH). The thickness of the discs varied from 4.5 to 7.2 mm, with the MDH approximately 22.7% greater. The disc heights showed good correlations with the vertebral body heights (R(2), 0.659-0.835, P-values < 0.005; anova), allowing the generation of 10 prediction equations. New data on thoracic disc morphometry were provided in this study. The generated set of regression equations could be used to predict thoracic disc heights from radiographic measurement of the vertebral body height posterior. For the creation of parameterized models of the human thoracic discs, the use of the prediction equations could eliminate the need for direct measurement on intervertebral discs. Moreover, the error produced by radiographic measurements could be reduced at least for the PDH. PMID- 21615400 TI - Sustained swimming increases the mineral content and osteocyte density of salmon vertebral bone. AB - This study addresses the effects of increased mechanical load on the vertebral bone of post-smolt Atlantic salmon by forcing them to swim at controlled speeds. The fish swam continuously in four circular tanks for 9 weeks, two groups at 0.47 body lengths (bl) * s(-1) (non-exercised group) and two groups at 2 bl * s(-1) (exercised group), which is just below the limit for maximum sustained swimming speed in this species. Qualitative data concerning the vertebral structure were obtained from histology and electron microscopy, and quantitative data were based on histomorphometry, high-resolution X-ray micro-computed tomography images and analysis of bone mineral content, while the mechanical properties were tested by compression. Our key findings are that the bone matrix secreted during sustained swimming had significantly higher mineral content and mechanical strength, while no effect was detected on bone in vivo architecture. mRNA levels for two mineralization-related genes bgp and alp were significantly upregulated in the exercised fish, indicating promotion of mineralization. The osteocyte density of the lamellar bone of the amphicoel was also significantly higher in the exercised than non-exercised fish, while the osteocyte density in the cancellous bone was similar in the two groups. The vertebral osteocytes did not form a functional syncytium, which shows that salmon vertebral bone responds to mechanical loading in the absence of an extensive connecting syncytial network of osteocytic cell processes as found in mammals, indicating the existence of a different mechanosensing mechanism. The adaptive response to increased load is thus probably mediated by osteoblasts or bone lining cells, a system in which signal detection and response may be co-located. This study offers new insight into the teleost bone biology, and may have implications for maintaining acceptable welfare for farmed salmon. PMID- 21615401 TI - Neonatal mortality of elk driven by climate, predator phenology and predator community composition. AB - 1. Understanding the interaction among predators and between predation and climate is critical to understanding the mechanisms for compensatory mortality. We used data from 1999 radio-marked neonatal elk (Cervus elaphus) calves from 12 populations in the north-western United States to test for effects of predation on neonatal survival, and whether predation interacted with climate to render mortality compensatory. 2. Weibull survival models with a random effect for each population were fit as a function of the number of predator species in a community (3-5), seven indices of climatic variability, sex, birth date, birth weight, and all interactions between climate and predators. Cumulative incidence functions (CIF) were used to test whether the effects of individual species of predators were additive or compensatory. 3. Neonatal elk survival to 3 months declined following hotter previous summers and increased with higher May precipitation, especially in areas with wolves and/or grizzly bears. Mortality hazards were significantly lower in systems with only coyotes (Canis latrans), cougars (Puma concolor) and black bears (Ursus americanus) compared to higher mortality hazards experienced with gray wolves (Canis lupus) and grizzly bears (Ursus horribilis). 4. In systems with wolves and grizzly bears, mortality by cougars decreased, and predation by bears was the dominant cause of neonatal mortality. Only bear predation appeared additive and occurred earlier than other predators, which may render later mortality by other predators compensatory as calves age. Wolf predation was low and most likely a compensatory source of mortality for neonatal elk calves. 5. Functional redundancy and interspecific competition among predators may combine with the effects of climate on vulnerability to predation to drive compensatory mortality of neonatal elk calves. The exception was the evidence for additive bear predation. These results suggest that effects of predation by recovering wolves on neonatal elk survival, a contentious issue for management of elk populations, may be less important than the composition of the predator community. Future studies would benefit by synthesizing overwinter calf and adult-survival data sets, ideally from experimental studies, to test the roles of predation in annual compensatory and additive mortality of elk. PMID- 21615402 TI - Estimating the feeding range of a mobile consumer in a river-flood plain system using delta(13)C gradients and parasites. AB - 1. The feeding range of an individual is central to food web dynamics as it determines the spatial scale of predator-prey interactions. However, despite recognition of its importance as a driving force in population dynamics, establishing feeding range is seldom done as detailed information on trophic interactions is difficult to obtain. 2. Biological markers are useful to answer this challenge as long as spatial heterogeneity in signal is present within the area investigated. A spatially complex ecosystem, Lake St. Pierre (LSP), a fluvial lake of the St Lawrence River (Quebec, Canada), offered a unique opportunity to determine the feeding range of a secondary consumer, yellow perch (Perca flavescens) using isotopic ratios of carbon (delta(13)C). However, because food chains based on phytoplankton have generally more negative delta(13) C than those depending on periphyton, it was essential to determine the contribution of zooplankton in fish diet to correctly interpret spatial patterns of delta(13)C. We used parasites in perch to examine whether their delta(13)C was reflecting local delta(13)C baseline conditions rather than a feeding specialization on zooplankton. 3. delta(13)C of primary consumers was highly variable and exhibited a striking gradient along the shore-channel axis, suggesting that delta(13)C should reflect an individual consumer's spatial position in LSP. 4. This strong isotopic gradient allowed us to estimate the spatial scale of the resources used by individual perch following an approach presented by Rasmussen, Trudeau & Morinville (Journal of Animal Ecology, 78, 2009, 674). By comparing the delta(13)C variability in perch to that of primary consumers, we estimated that the adults feeding range was around 2 km along the shore-channel axis. 5. The combined use of isotopic ratios and parasites allowed us to determine that the adult population uses a wide range of habitats between the flood plain and the main channel. However, individually, each perch depended on a limited foodshed. PMID- 21615403 TI - Host growth form underlies enemy-free space for lichen-feeding moth larvae. AB - 1. Natural enemies may direct the host use of herbivorous insects on those hosts that ensure highest survival, thus creating enemy-free space. Host structure may contribute to enemy-free space if the current host ensures better refuge from natural enemies than other potential hosts. So far, however, direct evidence of the role of host structure for enemy-free space is lacking. 2. This study looks at the effect of physical host structure on the previously demonstrated enemy free space of a lichen-feeding moth, Cleorodes lichenaria by manipulating the structure of host lichens and the access of natural enemies to larvae in the field. It was predicted that if larvae receive enemy-free space on Ramalina lichens because of their shrubby appearance, larvae should survive better on shrubby than on flat lichens in the presence of natural enemies but not in the absence of natural enemies. 3. Larvae survived better on shrubby than flat lichens and when the access of natural enemies to larvae was prevented than in the presence of them. According to the prediction, larvae in the presence of natural enemies survived better on shrubby compared with flat thalli but not in the absence of natural enemies. Thus, shrubby host structure promotes survival of larvae and underlies the enemy-free space on Ramalina species in natural conditions. 4. Host structure as a mechanism for enemy-free space and the direct impact of host structure for the performance of C. lichenaria larvae are discussed. Other potential reasons, such as lichen secondary chemicals and host induced colouration of larvae as a basis of enemy-free space, are also discussed. PMID- 21615404 TI - Body condition and wind support initiate the shift of migratory direction and timing of nocturnal departure in a songbird. AB - 1. An innate migration strategy guides birds through space and time. Environmental variation further modulates individual behaviour within a genetically determined frame. In particular, ecological barriers could influence departure direction and its timing. A shift in the migratory direction in response to an ecological barrier could reveal how birds adjust their individual trajectories to environmental cues and body condition. 2. Northern wheatears of the Greenland/Iceland subspecies Oenanthe oenanthe leucorhoa arrive in Western Europe en route from their West African winter range. They then undergo an endogenously controlled shift in migratory direction from north to north-west to cross a large ecological barrier, the North Atlantic. We radiotracked these songbirds departing from Helgoland, a small island in the North Sea, over an unprecedented range of their journey. 3. Here, we show that both birds' body condition and the wind conditions that they encountered influenced the departure direction significantly. Jointly high fuel loads and favourable wind conditions enabled migrants to cross large stretches of sea. Birds in good condition departed early in the night heading to the sea towards their breeding areas, while birds with low fuel loads and/or flying in poor weather conditions departed in directions leading towards nearby mainland areas during the entire night. These areas could be reached even after setting off late at night. 4. Behavioural adjustment of migratory patterns is a critical adaptation for crossing ecological barriers. The observed variation in departure direction and time in relation to fuel load and wind revealed that these birds have an innate ability to respond by jointly incorporating internal information (body condition) and external information (wind support). PMID- 21615405 TI - Child and parental literacy levels within families with a history of dyslexia. AB - BACKGROUND: The present study concerns literacy and its underlying cognitive skills in Dutch children who differ in familial risk (FR) for dyslexia. Previous studies with FR-children were inconclusive regarding the performance of FR children without dyslexia as compared to the controls. Moreover, van Bergen et al. (2011) recently showed that FR-children with and without dyslexia differed in parental reading skills, suggesting that those who go on to develop dyslexia have a higher liability. The current study concerned 1) the comparison of three groups of children at the end of second grade and 2) the intergenerational transfer of reading and its underlying cognitive skills from parent to child. METHOD: Three groups of children were studied at the end of second grade: FR-dyslexia (n = 42), FR-no-dyslexia (n = 99), and control children (n = 66). Parents and children were measured on naming, phonology, spelling, and word and pseudoword reading. RESULTS: The FR-dyslexia children were severely impaired across all tasks. The FR no-dyslexia children performed better than the FR-dyslexia children, but still below the level of the controls on all tasks; the only exception was rapid naming (RAN), on which they were as fast as the controls. Focusing on the FR subsample, parental reading and RAN were related to their offspring's reading status. CONCLUSIONS: We replicated and extended van Bergen et al.'s study in showing that the FR-children who develop dyslexia are likely to have a higher liability. Both the group comparisons and the parent-child relations highlight the importance of good RAN skills for reading acquisition. PMID- 21615406 TI - Spectrocolorimetric and microscopic techniques for the evaluation of plasticized PVC cleaning: a case study applicable to three-dimensional objects at museums. AB - For the validation of a cleaning method in conservation, the examination of the object's surface after the cleaning and the quantification of the cleaning efficiency are significant steps. In this study, several cleaning solutions were tested on a plasticized poly(vinyl chloride) object whose surface was characterized before and after cleaning by optical microscopy and noncontact profilometry. In addition, different methods to quantify the cleaning efficiency based on spectrocolorimetric and microscopic techniques were provided. The results showed that noncontact profilometry supported by optical microscopy and spectrocolorimetry was very useful for the characterization of the plasticized poly(vinyl chloride) surface before and after the cleaning and also for the determination of the cleaners' efficiency. PMID- 21615407 TI - Phosphorylation of Ser45 and Ser59 of alphaB-crystallin and p38/extracellular regulated kinase activity determine alphaB-crystallin-mediated protection of rat brain astrocytes from C2-ceramide- and staurosporine-induced cell death. AB - We previously demonstrated that alphaB-crystallin and protease-activated receptor (PAR) are involved in protection of astrocytes against C2-ceramide- and staurosporine-induced cell death [Li et al. (2009) J. Neurochem.110, 1433-1444]. Here, we further investigated the mechanism of cytoprotection by alphaB crystallin. Our current data revealed that after down-regulation of alphaB crystallin by siRNA, cell death caused by C2-ceramide and staurosporine is increased. Furthermore, we investigated the mechanism of cytoprotection of astrocytes by intracellular alphaB-crystallin. Application of specific inhibitors of p38 and extracellular regulated kinase (ERK) abrogates the protection of astrocytes by over-expression of alphaB-crystallin. Thus, p38 and ERK contribute to protective processes by alphaB-crystallin. To reveal the molecular mechanism of alphaB-crystallin-mediated cytoprotection, we mimicked phosphorylation or unphosphorylation of alphaB-crystallin. In these experiments, we found that the phosphorylation of alphaB-crystallin at Ser45 and Ser59 is required for protection. Ser19 phosphorylation of alphaB-crystallin does not contribute to protection. Moreover, we detected that PAR-2 activation increases the phosphorylation level of alphaB-crystallin at Ser59, but does not affect the expression level of alphaB-crystallin. Thus, endogenous alphaB-crystallin has protective capacity employing a mechanism, which involves regulation of the phosphorylation status of alphaB-crystallin and p38 and ERK activity. Moreover, we report that PAR-2 activation evokes the phosphorylation of alphaB-crystallin to increase astrocytes survival. PMID- 21615408 TI - Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1. AB - Mutations in the parkin gene cause early-onset, autosomal recessive Parkinson's disease. Parkin functions as an E3 ubiquitin ligase to mediate the covalent attachment of ubiquitin monomers or linked chains to protein substrates. Substrate ubiquitination can target proteins for proteasomal degradation or can mediate a number of non-degradative functions. Parkin has been shown to preserve mitochondrial integrity in a number of experimental systems through the regulation of mitochondrial fission. Upon mitochondrial damage, parkin translocates to mitochondria to mediate their selective elimination by autophagic degradation. The mechanism underlying this process remains unclear. Here, we demonstrate that parkin interacts with and selectively mediates the atypical poly ubiquitination of the mitochondrial fusion factor, mitofusin 1, leading to its enhanced turnover by proteasomal degradation. Our data supports a model whereby the translocation of parkin to damaged mitochondria induces the degradation of mitofusins leading to impaired mitochondrial fusion. This process may serve to selectively isolate damaged mitochondria for their removal by autophagy. PMID- 21615409 TI - MAPKs, activator protein-1 and nuclear factor-kappaB mediate production of interleukin-1beta-stimulated cytokines, prostaglandin E2 and MMP-1 in human periodontal ligament cells. AB - BACKGROUND AND OBJECTIVE: Determination of the interleukin-1 (IL-1) signaling cascades that lead to the production of various inflammatory mediators and catabolic factors may clarify attractive targets for therapeutic intervention for periodontitis. We comprehensively assessed the involvement of MAPKs, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) in IL-1beta-induced production of interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E(2) (PGE(2) ) and MMP-1 in human periodontal ligament cells. MATERIAL AND METHODS: Human periodontal ligament cells were pretreated with an inhibitor for each of the MAPKs or NF-kappaB and subsequently treated with IL-1beta. Following treatment, phosphorylation of three types of MAPK (ERK, p38 MAPK and c-Jun N terminal kinase), IkappaB kinase (IKK) alpha/beta/gamma and IkappaB-alpha, as well as the DNA binding activity of AP-1 and NF-kappaB and the production of IL 6, IL-8, PGE(2) and MMP-1, were determined by western blotting, a gel mobility shift assay and ELISA, respectively. RESULTS: The three MAPKs, simultaneously activated by IL-1beta, mediated the subsequent DNA binding of AP-1 at various magnitudes, while IKKalpha/beta/gamma, IkappaB-alpha and NF-kappaB were also involved in the IL-1 signaling cascade. Furthermore, IL-1beta stimulated the production of IL-6, IL-8, PGE(2) and MMP-1 via activation of the three MAPKs and NF-kappaB, because inhibitors of these significantly suppressed the IL-1beta stimulated production of these factors. CONCLUSION: Our results strongly suggest that MAPK, AP-1 and NF-kappaB mediate the IL-1beta-stimulated synthesis of IL-6, IL-8, PGE(2) and MMP-1 in human periodontal ligament cells. Therefore, inhibition of activation of MAPK, AP-1 and/or NF-kappaB may lead to therapeutic effects on progression of periodontitis. PMID- 21615410 TI - Reactions of periodontal ligament epithelial cell clusters and OX6-immunopositive cells to experimental tooth movement and periodontitis. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to investigate reactions of periodontal ligament epithelial cell clusters and major histocompatibility complex class II (OX6)-immunopositive cells to simultaneously induced tooth movement and periodontitis employing Waldo's method. MATERIAL AND METHODS: Elastic gums were inserted between the right upper first and second molars of rats. Animals were killed by intracardiac perfusion on days 1, 3, 7 and 14 after the experimental procedures, and maxillary molars were decalcified and processed for OCT compound. Cytokeratin and OX6 antibodies to detect epithelial and immunocompetent cells were used for double-fluorescence immunohistochemistry. Immunostained sections of rat upper molar regions were examined with a fluorescence microscope. RESULTS: Large periodontal ligament epithelial cell clusters appeared and became contiguous with each other, and OX6-immunopositive cells surrounded the clusters over time in the periodontal ligament near the gum insertion site. In the periodontal ligament distant from the gum insertion site, epithelial cell clusters and OX6-immunopositive cells were scattered. After 14 d, thickened epithelium and elongated rete pegs were found close to large epithelial cell clusters in the periodontal ligament near the gum insertion site. CONCLUSION: These findings suggest proliferation and/or aggregation of periodontal ligament epithelial cells, and interaction between OX6-immunopositive cells and the periodontal ligament epithelial cells, in response to tooth movement and periodontal inflammation. This method may be a useful experimental model to elucidate the relationship between rete pegs and periodontal ligament epithelial cell clusters in inflammatory conditions. PMID- 21615411 TI - Role of connexin43 hemichannels in mechanical stress-induced ATP release in human periodontal ligament cells. AB - BACKGROUND AND OBJECTIVE: Our previous studies showed that mechanical stress could induce ATP release in human periodontal ligament (HPDL) cells. By signaling through P2 purinergic receptors, ATP increased the expression and the synthesis of osteopontin and RANKL. In this study, the mechanism of stress-induced ATP release was investigated. MATERIAL AND METHODS: Continuous compressive forces were applied on cultured HPDL cells. The ATP released was measured using luciferin-luciferase bioluminescence. The expression of gap-junction proteins was examined using RT-PCR and western blot analysis. The opening of hemichannels was demonstrated by cellular uptake of a fluorescent dye, 5(6)-carboxyfluorescein, which is known to penetrate hemichannels. Intracellular signal transduction was investigated using inhibitors and antagonists. RESULTS: Mechanical stress induced the release of ATP into the culture medium, which was attenuated by carbenoxolone, a nonspecific gap-junction inhibitor. Addition of meclofenamic acid sodium salt, a connexin43 inhibitor, inhibited ATP release by mechanical stress. Knockdown of connexin43 expression by small interfering RNA reduced the amount of ATP released by mechanical stress, suggesting the role of connexin43 hemichannels. In addition, intracellular Ca(2+) blockers could also inhibit mechanical stress-induced ATP release and the opening of the gap junction. CONCLUSION: Our study demonstrated the involvement of gap-junction hemichannels, especially connexin43, in the stress-induced ATP-release mechanism. Furthermore, this mechanism may be regulated by the intracellular Ca(2+) signaling pathway. These results suggest an important role of gap-junction hemichannels in the function and behavior of HPDL cells. PMID- 21615413 TI - The hypoxia responsive transcription factor genes ERF71/HRE2 and ERF73/HRE1 of Arabidopsis are differentially regulated by ethylene. AB - The AR2/ERF transcription factor genes ERF71/HRE2 and ERF73/HRE1 were induced at hypoxic conditions in Arabidopsis thaliana roots. ERF73/HRE1 but not its related gene ERF71/HRE2 was furthermore regulated by ethylene. Treatment with 1 ppm ethylene promoted ERF73/HRE1 expression fivefold. This induction did not occur in the presence of the ethylene receptor inhibitor 1-methylcyclopropene. ERF73/HRE1 expression positively regulated alcohol dehydrogenase (ADH) activity, which was analyzed as a marker enzyme for metabolic adaptation to hypoxic stress. The knock out lines erf73/hre1-1 and erf73/hre1-2 showed lowered ADH activity; the overexpressing lines ERF73/HRE1-ox1 and ERF73/HRE1-ox5 displayed elevated ADH activity. Treatment of wild-type Arabidopsis with 5% O2 and 1 ppm ethylene resulted in higher induction of ADH activity than that observed with 5% O2 or 1 ppm ethylene alone. ERF73/HRE1-ox1 and ERF73/HRE1-ox5 plants that were exposed to 5% O2 did not show enhanced ADH activity after treatment with ethylene, indicating that the ethylene response with respect to ADH activity was saturated in the ERF73/HRE1ox lines. In contrast, erf73/hre1-1 and erf73/hre1-2 lines displayed ethylene-dependent ADH activity pointing to redundant factor(s) that can mediate ethylene regulation of ADH activity in the Arabidopsis root. Our data show that ethylene regulates metabolic adaptation to low oxygen stress in the Arabidopsis root through ERF73/ HRE1. PMID- 21615412 TI - Estrogen regulates DNA synthesis in human gingival epithelial cells displaying strong estrogen receptor beta immunoreactivity. AB - BACKGROUND AND OBJECTIVE: Estrogen acts via estrogen receptor (ER) alpha and beta. The expression pattern of ERs and their importance in gingival tissues are not fully understood. In this study, we investigate gingival ER expression and effects of estrogen on gingival epithelial cell proliferation. MATERIAL AND METHODS: Gingival biopsies were obtained from both healthy and diseased sites in three male and three female subjects. Expression of ERalpha and beta was determined by immunohistochemistry. Effects of 17beta-estradiol (E(2) ) on cell proliferation, monitored by measuring DNA synthesis, were studied in cultured human gingival epithelial HGEPp.05 cells. RESULTS: Estrogen receptor beta, but not ERalpha, immunoreactivity was demonstrated in nuclei of epithelial cells in all layers of the gingival epithelium, but also in cells of the lamina propria. No differences were observed between male and female subjects. The same pattern, i.e. high ERbeta expression but no ERalpha expression, was observed in both healthy and diseased sites within each individual. No differences in the intensity of the ERbeta immunoreactive signal and the number of ERbeta-positive nuclei were observed between healthy and diseased gingiva. Treatment with a physiological concentration of E(2) (10 nm) had no effect on DNA synthesis in ERbeta- and ERalpha-expressing HGEPp.05 cells. In contrast, E(2) at high concentrations (500 nm and 10 MUm) reduced DNA synthesis by 60-70%. CONCLUSION: Human gingival epithelial cells display strong ERbeta but low ERalpha immunoreactivity both in vivo and in culture. Estrogen attenuates gingival epithelial cell DNA synthesis at high but not low concentrations, suggesting a concentration-dependent mechanism. PMID- 21615414 TI - Net cadmium flux and accumulation reveal tissue-specific oxidative stress and detoxification in Populus * canescens. AB - To characterize the dynamics of Cd2+ flux in the rhizosphere and to study cadmium (Cd) plant-internal partitioning in roots, wood, bark and leaves in relation to energy metabolism, reactive oxygen species (ROS) formation and antioxidants, Populus * canescens plantlets were exposed to either 0 or 50 uM CdSO4 for up to 20 days in the nutrient solution. A strong net Cd2+ influx in root apex was observed after Cd exposure for 24 h, even if net Cd2+ influx decreased gradually in roots. A large amount of Cd was accumulated in roots. Cd ions were uploaded via the xylem to leaves and further transported to the phloem where significant accumulation was detected. Cd accumulation led to decreased photosynthetic carbon assimilation but not to the depletion in soluble carbohydrates. Increased levels of ROS were present in all tissues, except the bark of Cd-exposed poplars. To combat Cd-induced superoxide and hydrogen peroxide, P. * canescens appeared to rely mainly on the formation of soluble phenolics as these compounds showed the highest accumulation in the bark and the lowest in wood. Other potential radical scavengers such as proline, sugar alcohols and antioxidant enzymes showed tissue- and exposure time-specific responses to Cd. These results indicate a complex pattern of internal Cd allocation in P. * canescens resulting in higher ROS stress in wood than in bark and intermediate responses in roots and leaves, probably because of differential capacities of these tissues for the production of protective phenolic compounds. PMID- 21615415 TI - A high-resolution portrait of the annual dynamics of photochemical and non photochemical quenching in needles of Pinus sylvestris. AB - Partitioning of excitation energy between photochemical quenching (PQ) and non photochemical quenching (NPQ) processes is constantly adjusted in the leaf in order to preserve the photosynthetic energy balance. Adjustments in PQ and NPQ often result from a combination of different temporal components that can be simplified into reversible and sustained components. While reversible PQ and NPQ are relatively well understood, the controls behind the sustained components of PQ and NPQ, or the interaction between sustained and reversible NPQ, remain elusive. In this study, I used a full year of high-resolution chlorophyll fluorescence (ChlF) data obtained with a Monitoring-PAM fluorometer (Walz, Effeltrich, Germany) in needles of boreal Pinus sylvestris in situ to quantitatively analyse the dynamics and interaction between temporal components of NPQ and PQ and their control by the environment. To enable the estimation of sustained and reversible components of PQ and NPQ, a number of key ChlF parameters were reviewed and adapted to the analysis of long-term monitoring data. Overall, NPQ was drastically enhanced during winter via the accumulation of sustained NPQ in a process regulated by air temperature. Reversible NPQ retained some functionality even at temperatures well below zero and was not inhibited by the presence of sustained NPQ per se but by low temperatures alone. This suggests that temporal NPQ components co-operate in an additive rather than complementary fashion, conferring additional flexibility to the photoprotective role of NPQ. Finally, the potential of the sustained photochemical quenching parameter (qL(s) ) to track photoinhibition in situ was discussed. PMID- 21615416 TI - Oral tolerance and Treg cells are induced in BALB/c mice after gavage with bovine beta-lactoglobulin. AB - BACKGROUND: Food allergy is considered as resulting from an impaired development or a breakdown of oral tolerance. We aimed to induce oral tolerance to the major cow's milk allergen bovine beta-lactoglobulin (BLG) or corresponding trypsin hydrolysates (BLG-Try) and to investigate the mechanisms involved. METHODS: Wild type BALB/cJ mice were gavaged on days 1-3 and 8-10 with different doses of native BLG (nBLG) or with nBLG-Try and were then sensitized on day 14 by i.p. administration of BLG in alum. Sensitization was assessed by measurement of BLG specific antibodies in sera and of cytokines secreted by BLG-reactivated splenocytes. Elicitation of the allergic reaction was assessed by measurement of cytokines and mMCP-1 in sera collected 35 min after an oral challenge. Cellular and biochemical markers of the allergic reaction were also analysed in bronchoalveolar lavage fluids (BAL) collected 24 h after intra-nasal challenge. Analysis of the CD4(+) CD25(+) Foxp3(+) cells in different organs obtained 3 days after gavage and in vivo depletion of CD25(+) cells before oral tolerance induction were then performed. RESULTS: Systemic sensitization and elicitation of the allergic reaction were totally inhibited in mice gavaged with 2 mg of nBLG whereas nBLG-Try was far less efficient. A high percentage of CD4(+) Foxp3(+) cells were observed in BAL from tolerant mice, and a negative correlation between the number of eosinophils and the percentage of Foxp3(+) cells was evidenced. Efficient induction of CD4(+) CD25(+) Foxp3(+) cells after nBLG gavage and impaired oral tolerance induction after in vivo depletion of CD25 cells were then demonstrated. CONCLUSION: For the first time, allergen-induced Treg cells that inhibited both the sensitization and the elicitation of the allergic reaction were evidenced in gavaged wild-type mice. PMID- 21615417 TI - Testicular biopsy for early cancer detection--objectives, technique and controversies. AB - This review highlights the usefulness of testicular biopsy for early detection of testicular germ cell tumour (GCT). GCT develops through a precursor stage, called testicular intraepithelial neoplasia (TIN; also called intratubular germ cell neoplasia or carcinoma in situ, CIS), which is present many years before invasive malignancy occurs. TIN/CIS is safely detected histologically. TIN is usually widely but non-randomly distributed within the testicle, thus, a biopsy of 3 mm size usually indicates the presence of TIN. Surgically, testicular biopsy should be performed at the cranial pole. Two-site biopsies provide an 18% diagnostic yield over single biopsy. Surgical complications occur in about 2.8%, most of which are managed conservatively. Serial scrotal imaging studies after biopsies revealed significant early changes. Eighteen months thereafter, less than 5% of cases have changes detectable. False-negative biopsies are extremely rare. Biopsy also provides information regarding spermatogenesis. In case of diagnosis of TIN, orchiectomy is rarely required. Low-dose radiotherapy eradicates TIN. In conclusion, testicular biopsy is useful in patients with unilateral GCT to explore the opposite testis, and in patients with retroperitoneal GCT to look for occult testicular primary. Further candidates for biopsy are selected patients with sonographic testicular microlithiasis. Despite its usefulness, the procedure has been implemented in clinical routine only in few countries thus far. PMID- 21615418 TI - Genomic gain and over expression of CCL2 correlate with vascular invasion in stage I non-seminomatous testicular germ-cell tumours. AB - Testicular germ-cell tumours (TGCT) are the most frequent solid tumour to affect young Caucasian adult males and have increased in incidence over recent decades. In clinical stage I non-seminomas, (NSGCT) histological vascular invasion (VI) is a prognostic factor for metastatic relapse. Using array comparative genomic hybridization, we have previously shown that the presence of VI is associated with gain of a region at 17q12, containing a cluster of genes encoding inflammatory cytokines. We here confirm this finding using fluorescence in situ hybridization (FISH) demonstrating gain in 12 out of 42 (29%) assessable samples. Interrogation of previously published expression microarray data suggests that of the genes contained within this region, CCL2 [monocyte chemoattractant protein 1 (MCP1)] is frequently overexpressed in TGCT. Immunohistochemistry confirms this finding in a collection of 67 clinical stage I NSGCT, demonstrating an association with the presence of VI (p=0.049) that was not seen with VEGF-A, MMP2 or MMP9, although all were frequently expressed. This work gives further insight into the mechanisms involved in invasion in this tumour type, which may ultimately have implications for the management of patients with stage I disease. PMID- 21615419 TI - Effects of testosterone on the Q-T interval in older men and older women with chronic heart failure. AB - The Q-Tc interval duration on the electrocardiogram is recognized to differ between the sexes. In vitro data and data from humans before and after puberty and menopause suggest that sex hormones play a role in the longer Q-Tc intervals in women, or conversely, the shorter Q-Tc intervals in men. Direct investigations of sex hormone effects on the Q-Tc interval in humans, however, are limited and reach conflicting conclusions. Our objective was to determine effects of testosterone on ECG Q-T intervals of older men and older women. ECG's from 84 older men and older women in double-blind placebo-controlled investigations of testosterone supplementation for the treatment of chronic heart failure (CHF) were analysed. Thirty men received 1000mg intramuscular long-acting testosterone undecanoate and 28 men received saline at 0, 6 and 12weeks. ECG's were recorded at baseline and 12weeks. Sixteen women received transdermal testosterone (33MUg) and 10 women received matching placebo twice weekly for 24 weeks with ECG's at baseline and after 24weeks. Testosterone, but not placebo, shortened Q-T and Q-Tc intervals without heart rate changes. Q-T intervals decreased from 385+/-28 (mean+/-SD) to 382+/-28 ms (p<0.002) and Q-Tc intervals decreased from 398+/-26 to 392+/-27 (p<0.006) in men on testosterone. In women, Q-T intervals decreased from 400+/-25 to 397+/-23ms (p=0.06) and Q-Tc intervals from 415+/-26 to 409+/ 27ms (p=0.3) on testosterone. Q-T intervals were longer in women compared with men under all conditions (p<0.03). The data support a direct effect of testosterone to shorten Q-T intervals in older men and older women in the absence of HR changes or hypogonadal status. Mean decreases are small and unlikely to affect risks of arrhythmic events in patients receiving Q-T prolonging medications. PMID- 21615420 TI - Impaired expression and distribution of adherens and gap junction proteins in the seminiferous tubules of rats undergoing autoimmune orchitis. AB - Experimental autoimmune orchitis (EAO) is characterized by an interstitial lymphomononuclear cell infiltration and a severe lesion of seminiferous tubules (ST) with germ cells that undergo apoptosis and sloughing. The aim of this study was to analyse the expression and localization of adherens junction (AJ) proteins: N-cadherin, alpha-, beta- and p120 catenins and gap junction protein, connexin 43 (Cx43), to explore some aspects of germ-cell sloughing during the development of orchitis. EAO was induced in Sprague-Dawley adult rats by active immunization with testicular homogenate and adjuvants. Control rats (C) were injected with saline solution and adjuvants. Concomitant with early signs of germ cell sloughing, we observed by immunofluorescence and Western blot, a delocalization and a significant increase in N-cadherin and alpha-catenin expression in the ST of EAO compared with C rats. In spite of this increased AJ protein expression, a severe germ-cell sloughing occurred. This is probably due to the impairment of the AJ complex function, as shown by the loss of N cadherin/beta-catenin colocalization (confocal microscopy) and increased pY654 beta-catenin expression, suggesting lower affinity of these two proteins and increased pERK1/2 expression in the testis of EAO rats. The significant decrease in Cx43 expression detected in EAO rats suggests a gap junction function impairment also contributing to germ-cell sloughing. PMID- 21615421 TI - Testicular germ cell tumours in dogs are predominantly of spermatocytic seminoma type and are frequently associated with somatic cell tumours. AB - Unlike seminomas in humans, seminomas in animals are not typically sub-classified as classical or spermatocytic types. To compare testicular germ cell tumours (TGCT) in dogs with those of men, archived tissues from 347 cases of canine testicular tumours were morphologically evaluated and characterized using human classification criteria. Histopathological and immunohistological analysis of PLAP, KIT, DAZ and DMRT1 expression revealed that canine seminomas closely resemble human spermatocytic seminomas. In addition, a relatively frequent concomitant presence of somatic cell tumours was noted in canine TGCT. None of the canine TGCT evaluated demonstrated the presence of carcinoma in situ cells, a standard feature of human classical seminomas, suggesting that classical seminomas either do not occur in dogs or are rare in occurrence. Canine spermatocytic seminomas may provide a useful model for this rare human neoplasm. PMID- 21615422 TI - Bioinformatics meets parasitology. AB - The advent and integration of high-throughput '-omics' technologies (e.g. genomics, transcriptomics, proteomics, metabolomics, glycomics and lipidomics) are revolutionizing the way biology is done, allowing the systems biology of organisms to be explored. These technologies are now providing unique opportunities for global, molecular investigations of parasites. For example, studies of a transcriptome (all transcripts in an organism, tissue or cell) have become instrumental in providing insights into aspects of gene expression, regulation and function in a parasite, which is a major step to understanding its biology. The purpose of this article was to review recent applications of next generation sequencing technologies and bioinformatic tools to large-scale investigations of the transcriptomes of parasitic nematodes of socio-economic significance (particularly key species of the order Strongylida) and to indicate the prospects and implications of these explorations for developing novel methods of parasite intervention. PMID- 21615423 TI - Transverse fingernail curvature in adults: a quantitative evaluation and the influence of gender, age, and hand size and dominance. AB - The nail plate's convex shape in both the longitudinal and transverse directions is thought to contribute to its mechanical rigidity, and overcurvature can be a symptom of local and/or systemic disorders. Although a number of methods to measure the longitudinal nail curvature have been proposed, evaluation of the transverse nail curvature has been largely limited to visual estimation of overcurved nail plates. The aim of this study was therefore to measure the transverse curvature of healthy adult fingernail plates and thereby provide a baseline range for 'normal curved' nail plates. In addition, the influence of gender, age, hand size and hand dominance on the transverse fingernail curvature was investigated. The transverse fingernail curvature in 92 men and 90 women (aged 21-90 years) was measured using a set of radius gauges, and the nail plate curvature was expressed as the radius of a circle whose curve most closely approximated that of the nail plate. ANOVA was used to investigate the influence of digit nature on curvature, whereas general linear model was used to assess the influence of gender, age, and hand length, breadth and dominance on transverse nail curvature. Subsequently, the influence of hand dominance and age was further examined by paired t-test and ANOVA, respectively. In this study, baseline values for the transverse nailplate curvature of the thumb, index, middle, ring and little fingers are presented. The thumbnail is the flattest, followed jointly by the index and middle fingernails, then the ring fingernail and finally the little fingernail. Transverse nail curvature is influenced by a person's gender, age, hand dominance and hand width, but not by hand length. Thus, nails are flatter in the dominant hand, in men, in older individuals and in those with wider hands. PMID- 21615424 TI - Inferences about character and motive influence intentionality attributions about side effects. AB - In two studies, we predicted and found that inferences about motive and character influence intentionality attributions about foreseeable consequences of action (i.e., side effects). First, we show that inferences about intentionality are greater for good side effects than bad side effects when a target person's character is described positively. In Study 2, we manipulated information about a target person and found that inferences about intentionality were greater when side effects were consistent with a target person's character and motives. Overall, our data cast doubt on the generality of the side-effect effect. We discuss our findings and their implications for future research on intentionality and social perception. PMID- 21615425 TI - Striatal involvement in human alcoholism and alcohol consumption, and withdrawal in animal models. AB - BACKGROUND: Different regions of the striatum may have distinct roles in acute intoxication, alcohol seeking, dependence, and withdrawal. METHODS: The recent advances are reviewed and discussed in our understanding of the role of the dorsolateral striatum (DLS), dorsomedial striatum (DMS), and ventral striatum in behavioral responses to alcohol, including alcohol craving in abstinent alcoholics, and alcohol consumption and withdrawal in rat, mouse, and nonhuman primate models. RESULTS: Reduced neuronal activity as well as dysfunctional connectivity between the ventral striatum and the dorsolateral prefrontal cortex is associated with alcohol craving and impairment of new learning processes in abstinent alcoholics. Within the DLS of mice and nonhuman primates withdrawn from alcohol after chronic exposure, glutamatergic transmission in striatal projection neurons is increased, while GABAergic transmission is decreased. Glutamatergic transmission in DMS projection neurons is also increased in ethanol withdrawn rats. Ex vivo or in vivo ethanol exposure and withdrawal causes a long-lasting increase in NR2B subunit-containing NMDA receptor activity in the DMS, contributing to ethanol drinking. Analyses of neuronal activation associated with alcohol withdrawal and site-directed lesions in mice implicate the rostroventral caudate putamen, a ventrolateral segment of the DMS, in genetically determined differences in risk for alcohol withdrawal involved in physical association of the multi-PDZ domain protein, MPDZ, with 5-HT(2C) receptors and/or NR2B. CONCLUSIONS: Alterations of dopaminergic, glutamatergic, and GABAergic signaling within different regions of the striatum by alcohol is critical for alcohol craving, consumption, dependence, and withdrawal in humans and animal models. PMID- 21615426 TI - The efficacy of disulfiram for the treatment of alcohol use disorder. AB - BACKGROUND: Alcohol use disorders (AUD) involving hazardous, harmful, and addictive misuse of alcohol are widespread in most parts of the world. The aim of this study was to review the effect of disulfiram in the treatment of patients with AUD. The effect of disulfiram was evaluated according to the primary outcome of an intake of alcohol below 30 and 20 g/d for men and women, respectively, as well as secondary outcomes such as days until relapse, alcohol intake, and numbers of drinking days. METHODS: A systematic review of the literature was conducted using MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). RESULTS: Eleven randomized controlled trials were included with a total of 1,527 patients. They compared disulfiram treatment with placebo, none or other abstinence-supportive treatments. Overall, 6 studies reported of a significant better effect on abstinence for patients treated with disulfiram. Six of 9 studies measuring secondary outcomes reported that patients treated with disulfiram had significantly more days until relapse and fewer drinking days, respectively. The quality of the included studies was moderate. Heterogeneity was significant in most of the meta-analyses, but valid results were found regarding the effect of disulfiram versus placebo over 12 months and unsupervised disulfiram versus other or no treatment. The vast majority of significant studies were of shorter duration, while only 3 studies of 12 months were significant regarding more days until relapse and/or reduction in drinking days. CONCLUSIONS: Supervised treatment with disulfiram has some effect on short-term abstinence and days until relapse as well as number of drinking days when compared with placebo, none, or other treatments for patients with alcohol dependency or abuse. Long term effect on abstinence has not been evaluated yet. However, there is a need for more homogeneous and high-quality studies in the future regarding the efficacy of disulfiram. PMID- 21615427 TI - Electrocardiogram-synchronized rotational speed change mode in rotary pumps could improve pulsatility. AB - Continuous-flow left ventricular assist devices (LVADs) have greatly improved the prognosis of patients with end-stage heart failure, even if continuous flow is different from physiological flow in that it has less pulsatility. A novel pump controller of continuous-flow LVADs has been developed, which can change its rotational speed (RS) in synchronization with the native cardiac cycle, and we speculated that pulsatile mode, which increases RS just in the systolic phase, can create more pulsatility than the current system with constant RS does. The purpose of the present study is to evaluate the effect of this pulsatile mode of continuous-flow LVADs on pulsatility in in vivo settings. Experiments were performed on eight adult goats (61.7 +/- 7.5 kg). A centrifugal pump, EVAHEART (Sun Medical Technology Research Corporation, Nagano, Japan), was installed by the apex drainage and the descending aortic perfusion. A pacing lead for the detection of ventricular electrocardiogram was sutured on the anterior wall of the right ventricle. In the present study, we compared pulse pressure or other parameters in the following three conditions, including Circuit-Clamp (i.e., no pump support), Continuous mode (constant RS), and Pulsatile mode (increase RS in systole). Assist rate was calculated by dividing pump flow (PF) by the sum of PF and ascending aortic flow (AoF). In continuous and pulsatile modes, these assist rates were adjusted around 80-90%. The following three parameters were used to evaluate pulsatility, including pulse pressure, dp/dt of aortic pressure (AoP), and energy equivalent pulse pressure (EEP = (?PF*AoP dt)/(?PF dt), mm Hg). The percent difference between EEP and mean AoP is used as an indicator of pulsatility, and normally it is around 10% of mean AoP in physiological pulse. Both pulse pressure and mean dp/dt max were decreased in continuous mode compared with clamp condition, while those were regained by pulsatile mode nearly to clamp condition (pulse pressure, clamp/continuous/pulsatile, 25.0 +/- 7.6/11.7 +/- 6.4/22.6 +/- 9.8 mm Hg, mean dp/dt max, 481.9 +/- 207.6/75.6 +/- 36.2/351.1 +/- 137.8 mm Hg/s, respectively). In clamp condition, %EEP was 10% higher than mean AoP (P = 0.0078), while in continuous mode, %EEP was nearly equivalent to mean AoP (N.S.). In pulsatile mode, %EEP was 9% higher than mean AoP (P = 0.038). Our newly developed pulsatile mode of continuous-flow LVADs can produce pulsatility comparable to physiological pulsatile flow. Further investigation on the effect of this novel drive mode on organ perfusion is currently ongoing. PMID- 21615428 TI - Exercise capacity in patients supported with rotary blood pumps is improved by a spontaneous increase of pump flow at constant pump speed and by a rise in native cardiac output. AB - Exercise capacity is improved in patients supported with continuous flow rotary blood pumps (RP). The aim of this study was to investigate the mechanisms underlying this improvement. Ten patients implanted with a RP underwent cardiopulmonary exercise testing (CPET) at 6 months after surgery with hemodynamic and metabolic measurements (RP group). A group of 10 matched heart failure patients were extracted from our heart transplant database, and the results of their last CPET before transplantation were used for comparison (heart failure [HF] group). Peak VO(2) was significantly higher in RP than in HF patients (15.8 +/- 6.2 vs. 10.9 +/- 3 mL O(2)/kg.min) reaching 52 +/- 16% of their predicted peak VO(2). The total output measured by a Swan-Ganz catheter increased from 5.6 +/- 1.6 to 9.2 +/- 1.8 L/min in the RP group and was significantly higher at rest and at peak exercise than in the HF group, whose output increased from 3.5 +/- 0.4 to 5.6 +/- 1.6 L/min. In the RP group, the estimated pump flow increased from 5.3 +/- 0.4 to 6.2 +/- 0.8, whereas the native cardiac output increased from 0.0 +/- 0.5 to 3 +/- 1.7 L/min. Cardiac output at peak exercise was inversely correlated with age (r = -0.86, P = 0.001) and mean pulmonary artery pressure (r = -0.75, P = 0.012). Maximal exercise capacity is improved in patients supported by RP as compared to matched HF patients and reaches about 50% of the expected values. Both a spontaneous increase of pump flow at constant pump speed and an increase of the native cardiac output contribute to total flow elevation. These findings may suggest that an automatic pump speed adaptation during exercise would further improve the exercise capacity. This hypothesis should be examined. PMID- 21615429 TI - Atrial fibrillation in chronic hemodialysis patients: prevalence, types, predictors, and treatment practices in Greece. AB - Atrial fibrillation (AF), the most common sustained arrhythmia in clinical practice, is associated with increased mortality and cardiovascular morbidity both in nonuremic and (recently) in dialysis patients. The aims of this study are: (i) to assess the prevalence of AF, the risk factors, and predictors of its presence in a cohort of incident hemodialysis (HD) patients in Greece and (ii) to report on current practices in the management of these patients. This is a prospective, cross-sectional, multicenter study of 574 patients on a regular HD program for >6 months. Demographic characteristics, cause of renal disease, cardiovascular risk factors, medication use, dialysis data (Kt/V, dialysis method, type of dialysate), 12-lead electrocardiogram (ECG) (interdialytic day), and cardiac echo data were collected. Pertinent demographic, ECG, and echocardiographic data were entered into univariate and multivariate analyses to evaluate associations with AF. The CHADS2 score (congestive heart failure [HF], hypertension, age >= 75, diabetes, previous stroke/transient ischemic attack [TIA]) was estimated and clinical practices in high-risk (CHADS2 score >= 2) patients were evaluated. The cohort included 368 men (64.1%) and 206 (35.8%) women (mean age 65.1 +/- 14.4 years) with a mean duration on dialysis of 72.1 +/- 60.4 months. Hypertension (75.6%) and coronary artery disease (47.2%) were the commonest cardiovascular risk factors for AF. The prevalence of AF was 23.2% and showed an age-dependent increase; in patients <50 years, AF was present in 9.3%, while in patients >= 80 years, its prevalence increased to 36.4%. Furthermore, 8.3% of patients had permanent, 1.8% persistent, 12.7% paroxysmal AF, while the prevalence of paroxysmal atrial flutter and sick sinus syndrome were 1.2 and 2%, respectively. Logistic regression analysis showed that age, smoking, left atrial and aortic root diameter, beta-blocker and alpha-calcidol use, HF, and the presence of valvular calcifications (VC) on cardiac echo were independently associated to the presence of AF. VC on cardiac echo had an almost sevenfold increased association with AF (odds ratio 6.72, 95% confidence interval 3.23 13.98, P < 0.0001). Only 25.5% of high-risk (CHADS2 score >= 2) patients were receiving anticoagulants. AF is a frequent arrhythmia in HD patients. Apart from well-known risk factors, VC merits special attention in this patient population. Less than one-third of high-risk AF patients receive anticoagulants, possibly reflecting the absence of definite guidelines for the management of AF in HD patients. PMID- 21615430 TI - Stent treatment of inferior vena cava compression in an ovine with a total artificial heart. AB - Although current continuous-flow total artificial hearts (CFTAHs) are much smaller than previous models, venous kinking may still occur after device implantation, especially in smaller animals. By inserting a self-expanding stent at the site of venous narrowing in a sheep model implanted with a CFTAH, we were able to restore the normal venous geometry and dramatically increase the CFTAH output. Because this percutaneous approach avoids the challenges associated with reoperation in these cases, it may be useful to other CFTAH investigators. PMID- 21615431 TI - Influence of locking bolt location on the mechanical properties of an interlocking nail in the canine femur. AB - OBJECTIVE: To determine whether the fatigue properties of an interlocking nail (ILN) construct are influenced by metaphyseal or diaphyseal location of the locking bolt. STUDY DESIGN: Ex vivo mechanical investigation. SAMPLE POPULATION: Adult canine femora (n = 19 pairs). METHODS: Femora were implanted with a 6-mm diameter ILN. In 1 femur, the ILN was locked with a 2.7 mm bolt placed in the diaphysis; the ILN in the contralateral femur was locked with a bolt placed in the metaphysis. Constructs were tested to failure in axial loading (9 pairs) or torsion (10 pairs), with failure defined as displacement > 2 mm or a total of 500,000 cycles for axial loading, and rotation > 45 degrees for torsional loading. Outcome measures included initial construct stiffness, number of cycles to failure, peak load, and peak torque. After testing, microradiography and histology were used to determine the location and nature of construct failure. RESULTS: Metaphyseal bolts failed at higher axial loads than diaphyseal bolts (P = .03), with bolt failure because of bending at the nail-bolt interface. All of the metaphyseal bolt constructs survived torsional testing whereas 9 of 10 diaphyseal bolt constructs failed catastrophically because of spiral fracture through the adjacent cortical bone. CONCLUSIONS: Placement of a locking bolt in metaphyseal bone extends fatigue life under axial loading and decreases the incidence of catastrophic failure under torsional loading. PMID- 21615432 TI - Synovitis in dogs with stable stifle joints and incipient cranial cruciate ligament rupture: a cross-sectional study. AB - OBJECTIVE: To evaluate stifle joints of dogs for synovitis, before development of joint instability and cranial cruciate ligament rupture (CrCLR). STUDY DESIGN: Cross-sectional study. ANIMALS: Dogs (n = 16) with CrCLR and stable contralateral stifles; 10 control dogs with intact CrCL. METHODS: Arthritis and tibial translation were graded radiographically. Synovitis severity and cruciate pathology were assessed arthroscopically. Presence of inflammatory cells in synovial membrane biopsies was scored histologically. CrCLR stifle pairs and control stifles were compared. RESULTS: Radiographic evidence of arthritis, cranial tibial translation, and arthroscopic synovitis were increased in unstable stifles, when compared with stable contralateral stifles in CrCLR dogs (P < .05). Arthroscopic synovitis in both joints of CrCLR dogs was increased compared with controls, was correlated with radiographic arthritis (S(R) = 0.71, P < .05), and was present in all stable contralateral stifles. Arthroscopically, 75% of stable stifle joints had CrCL fiber disruption, which correlated with severity of synovitis (S(R) = 0.56, P < .05). Histologic evidence of synovitis was identified in all CrCLR dogs, but was only significantly correlated with arthroscopic observations in stable stifles (r(2) = 0.57, P < .005). CONCLUSION: Synovitis is an early feature of the CrCLR arthropathy in dogs before development of joint instability clinically. Severity of synovitis is correlated with radiographic arthritis in joints with minimal to no clinically detectable CrCL damage. PMID- 21615433 TI - Prevalence of the plasmid-mediated quinolone resistance determinants among clinical isolates of Shigella sp. in Andaman & Nicobar Islands, India. AB - AIMS: This study was carried out to find the prevalence of various plasmid mediated quinolone-resistant (PMQR) determinants among the quinolone-resistant clinical isolates of Shigella sp. from paediatric patients in Andaman & Nicobar Islands. METHODS AND RESULTS: A total of 106 quinolone-resistant Shigella isolates obtained from paediatric patients during hospital-based surveillance from January 2003 to June 2010 were screened for the presence of various PMQR determinants. Of 106 isolates, 8 (7.5%) showed the presence of aac (6')-Ib-cr and 3 (2.8%) harboured the qnrB genes with 2 (1.9%) of these isolates showing the presence of both. All the 9 isolates had uniform mutations in gyrA (S83L) and in parC (S80I). CONCLUSIONS: The prevalence of fluoroquinolone-acetylating aminoglycoside acetyltransferase {aac (6')-Ib-cr} gene is higher than qnrB gene among the clinical Shigella isolates. These PMQR determinants were detected in the Shigella isolates obtained from 2008-2010, indicating that it happens in a stepwise manner following the multiple mutations in quinolone resistance determining regions increase or extend resistance to quinolones or fluoroquinolones. SIGNIFICANCE AND IMPACT OF STUDY: The prevalence of these genes are of grave concern as it may be horizontally transferred to other human pathogenic bacteria and can lead to therapeutic failure as a consequence of antimicrobial resistance, not only for the islands but also for the entire south east region. The results obtained should encourage further studies on the implications of the presence, distribution, association and variation of these determinants in our quest for understanding PMQR. PMID- 21615434 TI - A one-hour infusion of infliximab during maintenance therapy is safe and well tolerated: a prospective cohort study. AB - BACKGROUND: Infliximab is a chimeric monoclonal antibody to tumour necrosis factor alpha (TNFalpha) with efficacy in inducing and maintaining remission of inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis and psoriasis. Infliximab is generally administered over 2h with a further 1-h postinfusion observation. This time interval has substantial impact on healthcare resources and is costly in terms of patient's time away from work. AIM: To examine the safety and tolerability of a 1-h, relative to a 2-h maintenance of infusion of infliximab, and to determine the effect of corticosteroid premedication and concurrent immunosuppressor use on infusion reaction rates. METHOD: A prospective cohort study with variable follow-up duration of 2165 consecutive infliximab infusions in 415 patients during 2009 was conducted. Diagnosis, infusion episode number, infusion rate, premedication, concurrent immunosuppressor therapy, the nature and the outcome of infusion reactions were examined. RESULTS: The majority of infusions (74%) were for management of inflammatory bowel disease. Infusion reactions clustered within the first eight infusions with subsequent sporadic reactions. The infusion reaction incidence rate per 1000 person days in 274 1-h infusions from 54 patients and 1356 2-h infusions from 256 patients were 0.08 and 0.28 respectively (P=0.07). Poisson regression model confirmed that the concurrent use of immunosuppressor therapy was associated with a lower infusion reaction rate, whereas corticosteroid premedication was not. CONCLUSIONS: During maintenance therapy, infliximab infusion can be safely administered over 1h in patients with no past history of significant infliximab infusion reaction. Corticosteroid premedication had no impact on the infusion reaction rates. PMID- 21615435 TI - Review article: defining remission in ulcerative colitis. AB - BACKGROUND: There is no international agreement on scoring systems used to measure disease activity in ulcerative colitis, nor is there a validated definition for disease remission. AIM: To review the principles and components for defining remission in ulcerative colitis and propose a definition that will help improve patient outcomes. METHODS: A review of current standards of remission from the perspective of clinical trials, guidelines, clinical practice and patients was conducted by the authors. Selected literature focused on the components of a definition of remission, the utility of a definition and treatment strategies, based on current definitions. RESULTS: Different definitions of remission affect the assessment of outcome and make it difficult to compare trials. In the clinic, endoscopy is rarely used to confirm remission, because mucosal healing has only recently begun to be related to the duration of subsequent remission in a way that will affect clinical practice. Histopathology may be the ultimate arbiter of mucosal healing. There is no agreement on the definition of remission in current guidelines. Patient-defined remission may predict endoscopic remission, but has yet to be shown to predict duration of remission. CONCLUSIONS: A standard based on clinical symptoms and endoscopy is proposed. Histopathology is a third dimension of remission that may have prognostic value. The definition of remission should help predict long-term outcome. The expectations of patients and their physicians need to be raised, as the goal of treatment of active ulcerative colitis should be to induce remission. PMID- 21615436 TI - Meta-analysis: the epidemiology of noncardiac chest pain in the community. AB - BACKGROUND: Prevalence of, and risk factors for, noncardiac chest pain in the community have not been well studied. AIMS: To conduct a systematic review and meta-analysis to examine these issues. METHODS: MEDLINE, EMBASE and EMBASE Classic were searched (up to March 2011) to identify population-based studies reporting prevalence of noncardiac chest pain in adults (>=15 years) according to self-report, questionnaire or specific symptom-based criteria. Prevalence of noncardiac chest pain was extracted for all studies, and according to study location and certain other characteristics including presence or absence of gastro-oesophageal reflux disease (GERD) symptoms, where reported. Pooled prevalence overall, as well as odds ratios (OR), with 95% confidence intervals (CIs) were calculated. RESULTS: Of 18 articles evaluated, 16 reported prevalence of noncardiac chest pain in 14 separate populations, containing 24 849 subjects. Pooled prevalence of noncardiac chest pain in all studies was 13% (95% CI 9-16). The prevalence of noncardiac chest pain was higher in Australian studies and in studies using a questionnaire to define its presence, compared with those using Rome I or II criteria. Prevalence was no different in women vs. men (OR 0.99; 95% CI 0.82-1.20). The prevalence was markedly higher in subjects who also reported GERD (OR 4.71; 95% CI 3.32-6.70) and increased according to frequency of GERD symptoms. CONCLUSIONS: Pooled prevalence of noncardiac chest pain in the community was 13%, but there were few studies. Rates did not appear to differ according to gender or age. Presence of GERD was strongly associated with noncardiac chest pain. PMID- 21615437 TI - Cost-effectiveness analysis: cardiovascular benefits of proton pump inhibitor co therapy in patients using aspirin for secondary prevention. AB - BACKGROUND: Many patients with cardiovascular (CV) disease will stop aspirin (ASA) because of ASA-related dyspepsia. Proton pump inhibitor (PPI) co-therapy may reduce ASA-related dyspepsia, enhancing ASA adherence and improving CV outcomes. AIM: To explore the impact of PPI co-therapy on CV outcomes in long term, low-dose ASA users. METHODS: We modified a previously published Markov model to assess the long-term impact of PPI co-therapy on CV and upper gastrointestinal bleeding (UGIB) outcomes among patients using ASA for secondary CV prevention. UGIB events, recurrent myocardial infarctions (MIs) and incremental cost-effectiveness ratios (ICERs) were measured. The perspective taken was that of a long-term payer. RESULTS: Compared with ASA alone, ASA plus PPI resulted in fewer lifetime UGIB events (3.4% vs. 7.2%) and increased ASA adherence (74% vs. 71%). Increased ASA adherence resulted in fewer recurrent MIs (26 fewer events per 10000 patients). On average, the ASA plus PPI strategy resulted in 38 additional days of life per patient, with the majority of this benefit (61%) because of a reduction in CV mortality (rather than UGIB-related mortality). ASA plus PPI was also more costly than ASA alone, with an ICER of $19000 per life-year saved. Results were sensitive to cost of PPI and impact of PPI on ASA adherence. CONCLUSIONS: Proton pump inhibitor co-therapy has the potential to impact not only GI, but also CV outcomes in patients with CV disease using ASA and such co-therapy is likely to be cost-effective. Future studies should better quantify the CV benefits of PPI co-therapy. PMID- 21615438 TI - Meta-analysis: erythromycin before endoscopy for acute upper gastrointestinal bleeding. AB - BACKGROUND: Studies evaluating the effect of erythromycin on patients with acute upper gastrointestinal bleeding (UGIB) had been reported, but the results were inconclusive. AIMS: To compare erythromycin with control in patients with acute UGIB by performing a meta-analysis. METHODS: Electronic databases including PubMed, EMBASE and the Cochrane Library, Science Citation Index, were searched to find relevant randomised controlled trials (RCTs). Two reviewers independently identified relevant trials evaluating the effect of erythromycin on patients with acute UGIB. Outcome measures were the incidence of empty stomach, need for second endoscopy, blood transfusion, length of hospital stay, endoscopic procedure time and mortality. RESULTS: Four RCTs including 335 patients were identified. Meta analysis demonstrated the incidence of empty stomach was significantly increased in patients receiving erythromycin (active group 69%, control group 37%, P<0.00001). The need for second endoscopy, amount of blood transfusion and the length of hospital stay were also significantly reduced (all P<0.05). A trend for shorter endoscopic procedure time and decreased mortality rate was observed. CONCLUSIONS: Prophylactic erythromycin is useful for patients with upper gastrointestinal bleeding to decrease the amount of blood in the stomach and reduce the need for second endoscopy, amount of blood transfusion. It may shorten the length of hospital stay, but its effects on mortality need further larger trials to be confirmed. PMID- 21615439 TI - Systematic review: the role of bile acids in the pathogenesis of gastro oesophageal reflux disease and related neoplasia. AB - BACKGROUND: Factors other than acid may play a role in gastro-oesophageal reflux disease (GERD) and its complications. AIM: To assessed the role of bile acids in the pathogenesis of GERD, Barrett's oesophagus and Barrett's-related neoplasia. METHODS: We conducted a systematic review of computerised bibliographic databases for original articles involving humans or human oesophageal tissue or cells that assessed exposure to or manipulation of bile acids. Outcomes assessed included GERD symptoms; gross oesophageal injury; Barrett's oesophagus and related neoplasia; and intermediate markers of inflammation, proliferation or neoplasia. RESULTS: Eighty-three original articles were included. In in vivo studies, bile acids concentrations were higher in the oesophageal aspirates of patients with GERD than controls, and bile acids infusions triggered GERD symptoms, especially in high concentrations or in combination with acid. In ex vivo/in vitro studies, bile acids stimulated squamous oesophageal cells and Barrett's epithelial cells to produce inflammatory mediators (e.g., IL-8 and COX-2) and caused oxidative stress, DNA damage and apoptosis. They also induced squamous cells to change their gene expression pattern to resemble intestinal-type cells and caused Barrett's cells to increase expression of intestinal-type genes. CONCLUSIONS: In aggregate, these studies suggest that bile acids may contribute to the pathogenesis of symptoms, oesophagitis and Barrett's metaplasia with related carcinogenesis in patients with GERD. However, all study results are not uniform and substantial differences in study parameters may explain at least some of this variation. PMID- 21615440 TI - Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging for the diagnosis, assessment of activity and abdominal complications of Crohn's disease. AB - BACKGROUND: Cross-sectional imaging techniques, including ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI), are increasingly used for evaluation of Crohn's disease (CD). Aim To perform an assessment of the diagnostic accuracy of cross-sectional imaging techniques for diagnosis of CD, evaluation of disease extension and activity and diagnosis of complications, and to provide recommendations for their optimal use. METHODS: Relevant publications were identified by literature search and selected based on predefined quality parameters, including a prospective design, sample size and reference standard. A total of 68 publications were chosen. RESULTS: Ultrasonography is an accurate technique for diagnosis of suspected CD and for evaluation of disease activity (sensitivity 0.84, specificity 0.92), is widely available and non-invasive, but its accuracy is lower for disease proximal to the terminal ileum. MRI has a high diagnostic accuracy for the diagnosis of suspected CD and for evaluation of disease extension and activity (sensitivity 0.93, specificity 0.90), and is less dependent on the examiner and disease location compared with US. CT has a similar accuracy to MRI for assessment of disease extension and activity. The three techniques have a high accuracy for identification of fistulas, abscesses and stenosis (sensitivities and specificities >0.80), although US has false positive results for abscesses. As a result of the lack of radiation, US or MRI should be preferred over CT, particularly in young patients. CONCLUSIONS: Cross-sectional imaging techniques have a high accuracy for evaluation of suspected and established CD, reliably measure disease severity and complications; they may offer the possibility to monitor disease progression. PMID- 21615441 TI - RNAi knock-downs support roles for the mucin-like (AeIMUC1) gene and short-chain dehydrogenase/reductase (SDR) gene in Aedes aegypti susceptibility to Plasmodium gallinaceum. AB - The mosquito midgut represents the first barrier encountered by the Plasmodium parasite (Haemosporida: Plasmodiidae) when it is ingested in blood from an infected vertebrate. Previous studies identified the Aedes aegypti (L.) (Diptera: Culicidae) mucin-like (AeIMUC1) and short-chain dehydrogenase/reductase (SDR) genes as midgut-expressed candidate genes influencing susceptibility to infection by Plasmodium gallinaceum (Brumpt). We used RNA inference (RNAi) by double stranded RNA (dsRNA) injections to examine ookinete survival to the oocyst stage following individual gene knock-downs. Double-stranded RNA gene knock-downs were performed 3 days prior to P. gallinaceum infection and oocyst development was evaluated at 7 days post-infection. Mean numbers of parasites developing to the oocyst stage were significantly reduced by 52.3% in dsAeIMUC1-injected females and by 36.5% in dsSDR-injected females compared with females injected with a dsbeta-gal control. The prevalence of infection was significantly reduced in dsAeIMUC1- and dsSDR-injected females compared with females injected with dsbeta gal; these reductions resulted in a two- and three-fold increase in the number of uninfected individuals, respectively. Overall, these results suggest that both AeIMUC1 and SDR play a role in Ae. aegypti vector competence to P. gallinaceum. PMID- 21615442 TI - Insecticide-treated vertical mesh barriers reduce the number of biting mosquitoes. AB - Mosquitoes foraging for blood sources normally fly relatively close to the ground where wind velocities do not exceed their flight speed. An experiment designed to block foraging mosquitoes from reaching inhabited houses was conducted in a rural settlement flanked by agricultural fields. Mosquitoes were collected during 9 nights using 30 carbon dioxide-baited traps deployed along the external walls of six houses in the row closest to the settlement's perimeter fence. Thereafter, a deltamethrin-impregnated mesh was draped along 400 m of the perimeter fence to a height of 2 m opposite three of the monitored houses. Mosquitoes were trapped for a further 11 nights. A significant difference in the numbers of mosquitoes caught before and after the intervention was demonstrated near protected houses, whereas no significant difference was observed in catches near control houses. The percentage of Culex perexiguus (Diptera: Culicidae), an important vector of West Nile virus, was significantly lower near protected houses (13%) than around control houses (45%). By contrast, the percentage of Culex pipiens was not significantly affected (16% at experimental and 18% at control houses). Although the results presented here are preliminary, the data demonstrate the potential efficacy of vertical insecticidal barriers for mosquito control. PMID- 21615443 TI - Glaucoma blind registration in Fife (2000-2009) - a retrospective cohort study. AB - PURPOSE: To collate information on patients registered blind secondary to glaucoma between 2000 and 2009 and compare findings to an identical study completed a decade earlier between 1990 and 1999. METHODS: The records of all people registered as blind via the Fife Society for the Blind between 2000 and 2009 were retrospectively examined and those with glaucoma as the primary cause were studied in detail. We compared these results with the results of our previous study, in which we examined the same documents for the preceding decade, 1990-1999. RESULTS: The glaucoma blind registration rate was reduced by 31% in the current study compared to the previous one (60 vs 87 patients, p = 0.013). At the same time, there was a 6% increase in blindness registrations due to all causes (881 vs 938, p = 0.62). Patients were referred with significantly fewer visual symptoms (33% vs 60%, p = 0.002) and glaucoma surgery rates increased from 44% to 62% in the current study (p = 0.013). In the later decade, more patients were offered partial sight registration before blind registration (37% vs 10%, p < 0.0001) and sustained independent living at the time of blind registration in this study (66% vs 33%, p < 0.0001). Nearly one-third of patients in the study group had cognitive impairment and/or hearing loss and this was similar to the first study. CONCLUSIONS: The study demonstrates a downward trend in the rates of blind registration due to glaucoma, compared to stable rates of registration for all diseases. Over the time period of the two studies there were refinements in the way glaucoma is managed medically by the hospital eye service and in the community, with a high level of input maintained from the local low vision service. PMID- 21615444 TI - Oculometric parameters of hyperopia in children with esotropic amblyopia. AB - PURPOSE: To study the oculometric parameters of hyperopia in children with esotropic amblyopia, comparing amblyopic eyes with fellow eyes. METHODS: Thirty seven patients (5-8 years old) with bilateral hyperopia and esotropic amblyopia underwent a comprehensive ophthalmic examination, including cycloplegic refraction, keratometry and A-scan ultrasonography. Anterior chamber depth, lens thickness, vitreous chamber depth and total axial length were recorded. The refractive power of the crystalline lens was calculated using Bennett's equations. Paired Student's t-tests were used to compare ocular biometric measurements between amblyopic eyes and their fellow eyes. The associations of biometric parameters with refractive errors were assessed using Pearson correlation coefficients and linear regression. Multivariable models including axial length, corneal power and lens power were also constructed. RESULTS: Amblyopic eyes were found to have significantly more hyperopic refraction, less corneal power, greater lens power, shorter vitreous chamber depth and shorter axial length, despite similar anterior chamber depth and lens thickness. The strongest correlation with refractive error was observed for the axial length/corneal radius ratio (r(36) = -0.92, p < 0.001 for amblyopic and r(36) = 0.87, p < 0.001 for fellow eyes). Axial length accounted for 39.2% (R(2)) of the refractive error variance in amblyopic eyes and 35.5% in fellow eyes. Adding corneal power to the model increased R(2) to 85.7% and 79.6%, respectively. A statistically significant correlation was found between axial length and corneal power, indicating decreasing corneal power with increasing axial length, and they were similar for amblyopic eyes (r(36) = -0.53, p < 0.001) and fellow eyes (r(36) = -0.57, p < 0.001). A statistically significant correlation was also found between axial length and lens power, indicating decreasing lens power with increasing axial length (r(36) = -0.72, p < 0.001 for amblyopic eyes and r(36) = 0.69, p < 0.001 for fellow eyes). CONCLUSIONS: We observed that the correlation among the major oculometric parameters and their individual contribution to hyperopia in esotropic children were similar in amblyopic and non-amblyopic eyes. This finding suggests that the counterbalancing effect of greater corneal and lens power associated with shorter axial length is similar in both eyes of patients with esotropic amblyopia. PMID- 21615445 TI - Statistical methods for conducting agreement (comparison of clinical tests) and precision (repeatability or reproducibility) studies in optometry and ophthalmology. AB - The ever-expanding choice of ocular metrology and imaging equipment has driven research into the validity of their measurements. Consequently, studies of the agreement between two instruments or clinical tests have proliferated in the ophthalmic literature. It is important that researchers apply the appropriate statistical tests in agreement studies. Correlation coefficients are hazardous and should be avoided. The 'limits of agreement' method originally proposed by Altman and Bland in 1983 is the statistical procedure of choice. Its step-by-step use and practical considerations in relation to optometry and ophthalmology are detailed in addition to sample size considerations and statistical approaches to precision (repeatability or reproducibility) estimates. PMID- 21615446 TI - Corneal biomechanical properties measured with the Ocular Response Analyser in a myopic population. AB - PURPOSE: To explore the possible association between myopia and corneal biomechanical properties in a Caucasian population, and the correlations between the properties of right and left eyes. METHODS: Corneal hysteresis (CH) and corneal resistance factor (CRF) were measured using the Ocular Response Analyser (ORA) in both eyes of 95 normal adult subjects aged between 19 and 48 years. The spherical equivalent refractive errors of the participants ranged from 0.25 to 14.00 D. The mean CH and CRF values for the right and left eyes were recorded for each subject. CH and CRF data were compared between different refractive groups. RESULTS: CH was found to be slightly lower in high myopes (>-6.00 D, mean CH 10.0 +/- 1.2 mmHg) in comparison to moderate myopes (>-3.00 to -6.00 D, 10.1 +/- 1.4 mmHg) and emmetropes and low myopes (+0.25 to -2.75 D, 10.9 +/- 1.5 mmHg). The decrease in CH with the degree of myopia was about 0.13 mmHg per D or roughly 1% per D (r(2) = 0.084, p < 0.001). Inter-subject variations were much greater than any systematic changes. CRF was not correlated with refractive error (r(2) = 0.001, p = 0.66). Although the refractive error was highly correlated between the two eyes (r(2) = 0.89, p < 0.001), CH and CRF showed a lower inter-ocular correlation (r(2) = 0.68, p < 0.001 and r(2) = 0.77, p < 0.001 respectively). CONCLUSIONS: These findings may indicate that the viscoelastic properties of the cornea are altered to a minor extent in myopia. However, in this normal population, any overall systematic changes in CH and CRF with refractive error were small in comparison with the considerable inter-subject scatter at any level of refraction. PMID- 21615447 TI - Comparison of the effectiveness of two enhanced glaucoma referral schemes. AB - PURPOSE: To compare the clinical and financial effectiveness of two optometric led enhanced glaucoma referral schemes in the Bexley Care Trust area. METHODS: Over a 12-month period all suspect glaucoma/Ocular Hypertension (OHT) referrals from optometrists relating to patients registered with Bexley GPs were analysed. All these patients were examined under one of two schemes. One was an enhanced glaucoma repeat measurement (EGRM) scheme in which the referring optometrist conducted the repeated tests him/herself prior to referral or non-referral. The alternative was a refinement pathway (RCAS) using a small team of accredited community optometrists. RESULTS: During the full year commencing April 2007, repeat measures using the EGRM scheme resulted in 76% of patients not being referred. In 44.5% of all EGRM patients, where raised intraocular pressure (IOP) was found by non-contact tonometry (NCT), repeated measurement by Goldmann/Perkins applanation tonometry resulted in readings that were <22 mmHg, or that had less than a 5 mmHg difference between the two eyes. Financial review demonstrated that the EGRM achieved 62% savings when compared with HES tariff while RCAS resulted in a saving of 3.5%. CONCLUSIONS: Using a primary care repeat measurement scheme to support referral decision-making demonstrated substantial cost benefit while onward referral for refinement by accredited optometrists was essentially cost-neutral compared with HES tariff. Local schemes foster fragmentation and consideration should be given to a service which covers a large population area. PMID- 21615448 TI - Health-related quality of life among thyroid cancer survivors: a systematic review. AB - BACKGROUND: Treatment and follow-up care procedures of thyroid cancer impose great challenges on survivors and could potentially affect their health-related quality of life (HRQoL). METHODS: Two authors systematically reviewed the available literature on HRQoL of thyroid cancer survivors. A PubMed literature search for original articles published until February 2011 was performed. Twenty seven articles, published between 1997 and 2010, which met the predefined inclusion criteria, were subjected to a quality checklist. RESULTS: All selected studies, except one, were of adequate or good quality. Surgery had a negative impact on short-term HRQoL scores, but these scores returned to preoperational levels when time since surgery increased. Long-term thyroid hormone therapy (levothyroxine) can lead to abnormalities like hyperthyroidism. HRQoL was most affected during thyroid hormone withdrawal for radioiodine remnant ablation or follow-up procedures. The use of recombinant human thyroid stimulating hormone instead of hormone withdrawal leads to considerable improvements in HRQoL during follow-up testing. The results for (long-term) survivors were contradicting. While most (long-term) survivors report some specific long-lasting health problems, some studies found a lower HRQoL for thyroid cancer survivors compared with a healthy population or other reference groups, whereas other studies found similar HRQoL levels. CONCLUSION: This review indicates that thyroid cancer survivors generally have a similar or slightly worse HRQoL compared with the normative population; however, they report some specific medical problems after cancer treatment and follow-up tests, which have a direct negative impact on their current HRQoL and could affect their long-term HRQoL. Specific longitudinal survivorship studies are lacking. PMID- 21615449 TI - Glatiramer acetate-specific antibody titres in patients with relapsing / remitting multiple sclerosis and in experimental autoimmune encephalomyelitis. AB - Glatiramer acetate (GA) is an immunomodulatory drug approved for the treatment of clinically isolated syndrome (CIS) and relapsing/remitting multiple sclerosis (RRMS). As an antigen-based therapy, GA induces GA-specific antibodies in treated patients and animals. GA-specific antibodies do not neutralize therapeutic effects on relapses and disability. Rather, it has been suggested that GA specific antibodies may be associated with improved clinical outcomes. We evaluated antibody responses in eight patients with RRMS treated with GA for 15 months and antibody responses in GA-treated C57BL/6 mice before and after induction of experimental autoimmune encephalomyelitis (EAE). There were no significant differences from pretreatment levels of total IgE or GA-specific IgE in patients with RRMS. Total IgG1, IgG3 and GA-specific IgG4 were significantly increased at 15 months of GA treatment. Antibody type and titre were not associated with clinical outcomes, i.e. expanded disability status scale (EDSS) score, disease burden on magnetic resonance images (MRI) or clinical relapses. In contrast, mice with EAE showed a marked increase in GA-specific IgE and GA specific IgG1 antibody responses. GA-treated mice demonstrated improved clinical symptoms and lower mortality than untreated controls. Our results suggest that antibody responses to GA are heterogeneous among patients with RRMS, with no apparent association between antibody response and clinical outcomes. Clinical improvements in EAE-induced GA-treated mice suggest that GA-specific IgE and IgG1 may contribute to GA treatment effects in EAE. PMID- 21615450 TI - Immunomodulatory effects of Lactobacillus casei administration in a mouse model of gliadin-sensitive enteropathy. AB - Coeliac disease (CD) is a very common food-sensitive enteropathy, which is triggered by gluten ingestion and is mediated by CD4(+) T cells. In addition, alterations in the intestinal microbiota that is normally involved in the homeostasis of GALT (gut-associated lymphoid tissue) seem to play a role in CD. In accordance with these findings, we previously reported that Lactobacillus casei can induce a strong enhancement of the T cell-mediated response to gliadin without inducing enteropathy. In this study, we analysed the effects of L. casei administration in a mouse model of gliadin-induced villous damage that was recently developed and involves the inhibition of cyclo-oxygenase (COX) activities in gliadin-sensitized HLA-DQ8 transgenic mice. To address the issue, we assessed the weight loss, the intestinal cytokine pattern, the density of CD25(+) cells and morphometry of the gut mucosa. We confirmed that COX inhibition in sensitized mice caused villus blunting, dysregulated expression of tumour necrosis factor (TNF)-alpha and reduced gliadin-specific IL-2 production. Notably, the administration of probiotic strain induced a complete recovery of villus blunting. This finding was associated with a delay in weight decrease and a recovery of basal TNF-alpha levels, whereas the numbers of CD25(+) cells and the levels of IL-2 remained unchanged. In conclusion, our data suggest that the administration of L. casei can be effective in rescuing the normal mucosal architecture and GALT homeostasis in a mouse model of gliadin-induced enteropathy. PMID- 21615451 TI - Radiologically assessed testicular changes in infertile males with varicocele. AB - The aim of this study was to assess vascular disturbances in the testis of infertile males associated with varicocele. In total, 124 consecutive male subjects were divided into the following groups: healthy fertile controls (n = 10), Gp1 (n = 28); infertile males with subclinical varicocele, Gp2 (n = 26); infertile males with grade I left varicocele, Gp3 (n = 28); infertile males with grade II left varicocele and Gp4 (n = 32); infertile males with grade III left varicocele. They were subjected to colour duplex for pampiniform plexus and scrotal scintigraphy. There was significant decrease in arterial blood velocity, testicular arterial diameters and testicular perfusion especially in high grade varicocele compared with healthy controls. The mean vein diameter demonstrated significant negative correlation with arterial diameter, arterial blood velocity, perfusion index, testicular size and significant positive correlation with perfusion index. The mean testicular size demonstrated significant positive correlation with arterial blood velocity, perfusion index and nonsignificant correlation with arterial diameter. It is concluded that there are significant decreases in testicular volume, testicular perfusion, blood velocity and testicular artery diameter in infertile males with varicocele. PMID- 21615452 TI - Presence of IL-18 in testicular tissue of fertile and infertile men. AB - Recently, IL-18 was identified in human testes. Moreover, an inverse correlation was found between the levels of IL-18 and the number and motility of spermatozoa. We examined the presence of IL-18 protein in normal and impaired spermatogenesis. Testicular tissue specimens were taken from 25 nonobstructive azoospermic patients undergoing testicular sperm extraction and from autopsies of three healthy controls. The presence of IL-18 in human testicular cells was examined by immunohistochemical staining of paraffin-embedded sections, using a specific antibody for human IL-18. In testicular tissue of healthy controls as well as in study cases, presence of IL-18 was identified in somatic, mitotic, meiotic and post-meiotic cells in correlation with their presence. In all patients, Leydig cells were less intensively stained. Mitotic cells were immunostained in the control group and less intensively in hypospermatogenesis and maturation arrest subgroups. Primary spermatocytes were in general most efficiently stained. The expression of IL-18 mRNA (as examined by real-time PCR analysis) showed significantly lower expression in testicular tissues with impaired spermatogenesis when compared to normal tissues. We report the first study demonstrating the presence of IL-18 in human testicular tissue at the protein level. The presence of this cytokine in somatic as well as in different types of germ cells may suggest its involvement in the regulation of the spermatogenic process and steroidogenesis under physiological and pathological conditions. PMID- 21615453 TI - Effects of discontinuous Percoll gradient centrifugation on the quality of bovine spermatozoa evaluated with computer-assisted semen analysis and fluorescent probes association. AB - The objective of this study was to evaluate the quality of bovine frozen-thawed sperm cells after Percoll gradient centrifugation. Frozen semen doses were obtained from six bulls of different breeds, including three taurine and three Zebu animals. Four ejaculates per bull were evaluated before and after discontinuous Percoll gradient centrifugation. Sperm motility was assessed by computer-assisted semen analysis and the integrity of the plasma and acrosomal membranes, as well as mitochondrial function, were evaluated using a combination of fluorescent probes propidium iodide, fluorescein isothiocyanate-conjugated Pisum sativum agglutinin and 5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazolcarbocyanine iodide. The procedure of Percoll gradient centrifugation increased the percentage of total and progressive sperm motility, beat frequency, rectilinear motility, linearity and rapidly moving cells. In addition, the percentage of cells with intact plasma membrane and mitochondrial membrane potential was increased in post-centrifugation samples. However, the percentage of sperm cells with intact acrosomal membrane was markedly reduced. The method used selected the motile cells with intact plasma membrane and higher mitochondrial functionality in frozen-thawed bull semen, but processing, centrifugation and/or the Percoll medium caused damage to the acrosomal membrane. PMID- 21615454 TI - Unilateral testicular tuberculosis: case report. AB - Genitourinary tuberculosis (GT) includes 8-15% of extrapulmonary tuberculosis (TB), which is more frequent in men. Epididymides, seminal vesicles, prostate and testis are the most common sites of GT. Although testicular TB is uncommon, we report 2 patients with unilateral testicular TB. The main treatment of urogenital tuberculosis is anti-tuberculosis pharmacotherapy, sometimes combined with surgery. PMID- 21615455 TI - Is Improve degrees ready for sale? No. PMID- 21615456 TI - Effect of AeroChamber PlusTM on the lung and systemic bioavailability of beclometasone dipropionate/formoterol pMDI. AB - AIM: To assess the effect of AeroChamber PlusTM on lung deposition and systemic exposure to extra-fine beclometasone dipropionate (BDP)/formoterol (100/6 ug) pMDI (Foster(r)). The lung deposition of the components of the combination given with the pMDI was also evaluated using the charcoal block technique. METHODS: Twelve healthy male volunteers received four inhalations of extra-fine BDP/formoterol (100/6 ug) using (i) pMDI alone, (ii) pMDI and AeroChamber PlusTM and (iii) pMDI and charcoal ingestion. RESULTS: Compared with pMDI alone, use of AeroChamber PlusTM increased the peak plasma concentrations (C(max)) of BDP (2822.3 +/- 1449.9 vs. 5454.9 +/- 3197.1 pg ml(-1)), its active metabolite beclometasone 17-monopropionate (17-BMP) (771.6 +/- 288.7 vs. 1138.9 +/- 495.6 pg ml(-1)) and formoterol (38.4 +/- 17.8 vs. 54.7 +/- 20.0 pg ml(-1)). For 17-BMP and formoterol, the AUC(0,30 min), indicative of lung deposition, was increased in the AeroChamber PlusTM group by 41% and 45%, respectively. This increase was mainly observed in subjects with inadequate inhalation technique. However, use of AeroChamber PlusTM did not increase the total systemic exposure to 17-BMP and formoterol. Results after ingestion of charcoal confirmed that AUC(0,30 min) can be taken as an index of lung bioavailability and that more than 30% of the inhaled dose of extra-fine BDP/formoterol 100/6 ug was delivered to the lung using the pMDI alone. CONCLUSIONS: The use of AeroChamber PlusTM optimizes the delivery of BDP and formoterol to the lung in subjects with inadequate inhalation technique. The total systemic exposure was not increased, supporting the safety of extra-fine BDP/formoterol pMDI with AeroChamber PlusTM. PMID- 21615457 TI - Student nurse dyads create a community of learning: proposing a holistic clinical education theory. AB - AIMS: This paper is a report of a qualitative study of students' experiences of cooperative learning in the clinical setting. BACKGROUND: Although cooperative learning is often used successfully in the classroom, it has not been documented in the clinical setting with sophomore nursing students being paired with other sophomore nursing students. METHODS: Using a grounded theory methodology a sample of 64 participants (32 student nurse dyads, eight clinical groups, in two different acute care institutions) were observed on their first day in the clinical setting while working as cooperative partners. Interviews were also conducted with students, patients and staff preceptors. Data were collected in the fall of 2008, spring and fall of 2009 and the spring of 2010 using semi structured interviews and reflective surveys. Data were analysed using the constant comparative method. RESULTS/FINDINGS: A holistic clinical education theory for student nurses was identified from the data. This theory includes a reciprocal relationship among five categories relevant to a community of learning: supportive clinical experience; improved transition into practice; enhanced socialization into the profession; increased accountability and responsibility; and emergence of self-confidence as a beginning student nurse. CONCLUSION: The use of student dyads creates a supportive learning environment while students were able to meet the clinical learning objectives. Cooperative learning in the clinical setting creates a community of learning while instilling very early in the education process the importance of teamwork. This approach to clinical instruction eases the transition from the classroom to the clinical learning environment, and improves patient outcomes. PMID- 21615458 TI - Women's awareness of the human papilloma virus and related health problems. AB - AIM: This paper is a report of a study of women's awareness of the human papilloma virus and related health problems. BACKGROUND: Cervical cancer is an important cause of mortality, making up approximately 12% of all cancers in women. Awareness on the part of carriers of human papilloma virus is crucial in preventing transmission of the infection and protecting against cervical cancer. METHOD: The study was performed as a cross-sectional descriptive study. The study consists of 79 human papilloma virus-positive women who had not been diagnosed with cervical cancer and 150 women who had not been diagnosed with human papilloma virus. Data were collected via questionnaires between November 2007 and April 2008. Percentages and chi-square test were used. FINDINGS: A significantly higher percentage of women with positive human papilloma virus knew the definition of human papilloma virus, the fact that it is transmitted via sexual contact and that it can lead to cervical cancer than did women with negative human papilloma virus. It was established that approximately half the women with positive human papilloma virus presented at the hospital with a genital wart. None of the women knew that a Pap smear test was a necessary tool in the prevention of cervical cancer. CONCLUSION: Women with positive human papilloma virus have insufficient knowledge of human papilloma virus, sexually transmitted diseases, the health risks associated with human papilloma virus and the means of preventing these risks. It is therefore necessary to evaluate the education of health workers, and especially of nurses, on human papilloma virus and its prevention. PMID- 21615459 TI - Patients, intimate partners and family experiences of implantable cardioverter defibrillators: qualitative systematic review. AB - AIM: This paper is a report of an interpretive review of qualitative research on how an implantable cardioverter defibrillator affects adult recipients and their significant others. BACKGROUND: An implantable cardioverter defibrillator detects pathological cardiac rhythms and automatically converts the rhythm with electrical counter shocks. DATA SOURCES: A systematic literature search was conducted for qualitative research papers published between January 1999 and January 2009. PubMed, Medline, ISI Web of Knowledge and CINAHL databases were searched with the following key words: internal defibrillator, implantable defibrillator and qualitative research. REVIEW METHODS: Twenty-two papers were included. The critical appraisal skills programme and prompts were used to appraise studies. Thematic analysis and synthesis approaches were used to interpret evidence. FINDINGS: People with an implantable cardioverter defibrillator were found to experience physical, psychological and social changes. Shocks produce fear and anxiety, affecting relationships and sexual relations. The use of support groups and the use of the Internet are important in helping adjustment to an implantable cardioverter defibrillator. Women's responses to an implantable cardioverter defibrillator appear different than men's responses and include concerns about physical appearance and relationship issues. Postdischarge follow-up and educational programmes are still underdeveloped. CONCLUSION: Patients need additional education, support and follow-up care after hospital discharge. Patients and significant others benefit from collaboration between patient associations and healthcare professional societies. Future research is needed to identify the specific challenges that women recipients face. PMID- 21615460 TI - The relationship between diabetes self-management and metabolic control in youth with type 1 diabetes: an integrative review. AB - AIMS: The purpose of this integrative review was to describe the relationship between diabetes self-management and metabolic control in youth with type 1 diabetes and to explore factors which affect this relationship. BACKGROUND: In the past 15 years, research has indicated that youth with type 1 diabetes face considerable self-management challenges and are at increased risk for poor metabolic control. To enhance the development of behavioural interventions for youth with type 1 diabetes, the relationship between diabetes self-management and metabolic control needs to be more clearly elucidated. DATA SOURCES: Research studies that examined the relationship between diabetes self-management and metabolic control in youth with type 1 diabetes were included (n = 18). The electronic databases searched included OVID, MEDLINE (1996 to present), SCOPUS (1996 to January 2010) and PubMed (1996 to January 2010). REVIEW METHOD: An integrative literature review was carried out using Whittemore's modified framework for data collection, analysis and synthesis. RESULTS: A positive relationship between diabetes self-management and metabolic control in youth with type 1 diabetes was supported in longitudinal studies and in studies where the mean age was >13 years. Factors influencing this relationship are identified. Measurement of self-management was quite variable. CONCLUSION: Interventions targeting self-management in youth with type 1 diabetes are indicated, particularly in families of diverse race and ethnicity globally. Further evaluation of the measures of self-management and more longitudinal research are also indicated. PMID- 21615461 TI - The influence of Masters education on the professional lives of British and German nurses and the further professionalization of nursing. AB - AIMS: This article reports on findings from a qualitative study which explored the influence of a Masters in Nursing on the professional lives of British and German nurses and its role in further professionalizing nursing. BACKGROUND: A collaborative Masters programme was delivered in the United Kingdom and Germany. This provided an opportunity to study the influence of the programme on the professionalization of nursing in different country contexts. Continuing education is thought to contribute to furthering professionalization. Evidence to support this in the field of nursing is limited. METHODS: An interpretive research design was used and data were collected via semi-structured interviews with ten German nurses and nine British nurses. Data were collected in the United Kingdom and Germany from August 2006 to February 2007. Interviews were recorded and transcribed, and data were analysed using a template approach with further immersion and crystalization of the data. FINDINGS: Nurses' personal and professional confidence improved; research-based evidence was used to underpin changes made to practice; new roles and careers emerged; multi-professional working was enhanced; and nurses rediscovered nursing and championed the profession. CONCLUSION: A diagram is presented based on the findings. Masters education is at the centre as the catalyst with four interconnecting circles, which depict elements that contribute to professionalization. The diagram highlights overlap and interplay between nurses' increased personal confidence, improved cognitive functioning, evidence-based practice development and enhanced professionalism. Findings support the theory that this Masters in Nursing programme enhanced practice and further professionalization of nursing in both countries. PMID- 21615462 TI - A survey of the practice of nurses' skills in Wenchuan earthquake disaster sites: implications for disaster training. AB - AIMS: To determine nursing skills most relevant for nurses participating in disaster response medical teams; make recommendations to enhance training of nurses who will be first responders to a disaster site; to improve the capacity of nurses to prepare and respond to severe natural disasters. BACKGROUND: Worldwide, nurses play a key role in disaster response teams at disaster sites. They are often not prepared for the challenges of dealing with mass casualties; little research exists into what basic nursing skills are required by nurses who are first responders to a disaster situation. This study assessed the most relevant disaster nursing skills of first responder nurses at the 2008 Wenchuan earthquake disaster site. METHOD: Data were collected in China in 2008 using a self-designed questionnaire, with 24 participants who had been part of the medical teams that were dispatched to the disaster sites. FINDINGS: The top three skills essential for nurses were: intravenous insertion; observation and monitoring; mass casualty triage. The three most frequently used skills were: debridement and dressing; observation and monitoring; intravenous insertion. The three skills performed most proficiently were: intravenous insertion; observation and monitoring; urethral catheterization. The top three ranking skills most important for training were: mass casualty transportation; emergency management; haemostasis, bandaging, fixation, manual handling. CONCLUSION: The core nursing skills for disaster response training are: mass casualty transportation; emergency management; haemostasis, bandaging, fixation, manual handling; observation and monitoring; mass casualty triage; controlling specific infection; psychological crisis intervention; cardiopulmonary resuscitation; debridement and dressing; central venous catheter insertion; patient care recording. PMID- 21615463 TI - Medicine administration errors in patients with dysphagia in secondary care: a multi-centre observational study. AB - AIM: The aim of this study was to describe the interventions used by nurses when administering oral medicines to patients with and without dysphagia, to quantify the appropriateness of these interventions and the medicine administration error rate. BACKGROUND: The administration of medicines to patients with dysphagia is complex and potentially more error prone because of the need to match the medication's formulation to the swallowing ability of the patient. METHOD: Data was collected on the preparation and administration of oral medicines to patients with and without dysphagia, including those with enteral feeding tubes, using undisguised direct observation of 65 nurse-led medicine administration rounds on stroke and care-of-the-elderly wards at four acute general hospitals in East of England between 1 March and 30 June 2008. RESULTS: Of the 2129 medicine administrations observed, 817 involved an error, and of these 313 involved patients with dysphagia. Excluding time errors, the normalized frequency of medicine administration errors for patients with dysphagia was 21.1% compared with 5.9% for patients without. Using a mixed effects model and excluding time errors, there is a higher risk of errors for patients with dysphagia (excluding patients with enteral tubes) compared with those without (P < 0.001) and a further increase in risk of error for patients with enteral tubes compared with dysphagic patients without tubes (P < 0.001). CONCLUSION: The increased medicine administration error rate in patients with dysphagia requires healthcare professionals to take extra care when prescribing, dispensing and administering medicines to this group. PMID- 21615464 TI - A path model of health-related quality of life in type 2 diabetic patients: a cross-sectional study in Taiwan. AB - AIMS: To construct a path model about relationships of perceptions of empowerment, diabetes distress, self-care behaviour and glycemic control to health-related quality of life in Taiwanese Type 2 diabetic patients, suffering from diabetes for 10 years or less. BACKGROUND: Health-related quality of life is the primary end point for people with diabetes. Understanding the path model of health-related quality of life in Type 2 diabetic patients is useful for nurses to design early intervention programmes. METHODS: This was a cross-sectional study. An anonymous questionnaire was used to collect data from 2007 to 2008. Glycosylated haemoglobin (HbA1c) was also collected. Data from 428 Type 2 diabetic patients were analysed with structural equation modelling to test the fit of the hypothesized path model to the data. RESULTS: A model was produced in which self-care behaviour had a statistically significantly direct influence on satisfaction, impact and worry aspects of health-related quality of life. Glycosylated haemoglobin had a statistically significantly negative influence on satisfaction, and impact aspects of health-related quality of life. Perceptions of empowerment had a statistically significantly direct influence on satisfaction aspect of health-related quality of life. Diabetes distress had a statistically significantly direct influence on satisfaction, impact and worry aspects of health-related quality of life. CONCLUSIONS: Nurses should develop new approaches to improve various aspects of health-related quality of life. Nurses could empower patients to improve satisfaction aspect of health-related quality of life. To improve the impact and worry aspects of health-related quality of life, nurses should reduce diabetes distress felt by patients. PMID- 21615465 TI - Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. AB - REASONS FOR PERFORMING STUDY: Mesenchymal stem (progenitor; stromal) cell (MSC) therapy has gained popularity for the treatment of equine tendon injuries but without reports of long-term follow-up. OBJECTIVES: To evaluate the safety and reinjury rate of racehorses after intralesional MSC injection in a large study of naturally occurring superficial digital flexor tendinopathy and to compare these data with those published for other treatments. METHODS: Safety was assessed clinically, ultrasonographically, scintigraphically and histologically in a cohort of treated cases: 141 client-owned treated racehorses followed-up for a minimum of 2 years after return to full work. Reinjury percentages were compared to 2 published studies of other treatments with similar selection criteria and follow-up. The number of race starts, discipline, age, number of MSCs injected and interval between injury and treatment were analysed. RESULTS: There were no adverse effects of the treatment with no aberrant tissue on histological examination. The reinjury percentage of all racehorses with follow-up (n = 113) undergoing MSC treatment was 27.4%, with the rate for flat (n = 8) and National Hunt (n = 105) racehorses being 50 and 25.7%, respectively. This was significantly less than published for National Hunt racehorses treated in other ways. No relationship between outcome and age, discipline, number of MSCs injected or injury to implantation interval was found. CONCLUSIONS: Whilst recognising the limitations of historical controls, this study has shown that MPC implantation is safe and appears to reduce the reinjury rate after superficial digital flexor tendinopathy, especially in National Hunt racehorses. POTENTIAL RELEVANCE: This study has provided evidence for the long-term efficacy of MSC treatment for tendinopathy in racehorses and provides support for translation to human tendon injuries. PMID- 21615466 TI - Dental care and treatment needs of elderly in nursing homes in Saarland: perceptions of the homes managers. AB - OBJECTIVE: To investigate nursing home managers' perceptions and attitudes towards oral health care and access to dental services for aged care facility residents. METHOD: Questionnaires containing 28 closed-ended questions were mailed to all 114 nursing homes in Saarland, Germany. Descriptive statistics were calculated for response items. RESULTS: Facility response rate was 39%. None of the nursing homes in this study offered systematic dental health care. Initial dental screening was carried out only in one facility. In 81%, dental examinations only took place if required. Although stationary dental equipment was available only in one home, dental treatment was carried out in 71% of the cases by a dentist in the nursing home. Eighty-four per cent of the homes' managements rated the state of the dentition of the inhabitants as satisfying. Over half of the managers indicated satisfaction with the know-how of their nursing staff concerning oral hygiene procedures. The most significant barriers to provision of dental care in the facilities according to their managers were staff shortage, lack of interest of the inhabitants and financial concerns. CONCLUSIONS: The results of this study showed an urgent need for estimating a programme for systematic dental care for institutionalised elder people in the federal state of Saarland. PMID- 21615467 TI - Is Europe prepared to meet the oral health needs of older people? AB - OBJECTIVE: To discuss the preparedness of the social and health care systems and the health workforce in Europe to manage the increasing general and oral health care needs of older adults. BACKGROUND AND DISCUSSION: There are large inequalities across European countries and regions in the demographic, socioeconomic and health status of the elderly. The ageing of the population and the economic crisis put at risk the existing social and health care systems and are expected to further widen the existing inequalities. Despite the increase in funding for the general health care, public funding for dental care has reduced, limiting the access for the disadvantaged elderly. Dental care is isolated from health care policies and funding. At the same time there is a significant shortage of adequately trained personnel in the care of the elderly and a shortage of training opportunities particularly at a postgraduate and continuing education level. CONCLUSION: Immediate action is needed and appropriate strategies need to be implemented. Oral health prevention, delivery policies and funding should be integrated within the general health care system. Clinical protocols and guidelines need to be developed on the oral care of the elderly. Interdisciplinary training in the care of the elderly needs to be implemented for all health care workers (dentists, physicians, nurses, health care aids, social workers) at all education levels to enhance comprehensive care. PMID- 21615468 TI - Tonsillolithiasis and orofacial pain. AB - Tonsilloliths are rare calcified structures that usually result from chronic inflammation of the tonsils. Concretions show differences in size, shape and colour. They are usually asymptomatic but can be associated with halitosis, foreign body sensation, dysphagia and odynophagia, otalgia, and neck pain. A patient was referred because panoramic radiography performed by a general dentist revealed radiopaque shadows over the ascending rami of the mandible, located bilaterally: a solitary structure on the higher portion of the right side and two small structures on the left side. Paroxysmal attacks of orofacial pain and symptoms such as dysphagia and swallowing pain on the left side distributed within the tonsillar fossa and pharynx and the angle of the lower jaw were present. The computed tomography images revealed bilateral tonsilloliths. Clinically, there was no sign of inflammation, and the patient's past history revealed an approximately 2-year history of dysphagia, swallowing pain and left sided neck pain. At the request of the patient, no surgical intervention was carried out. Glossopharyngeal neuralgia is a rare entity, and the aim of this report was to indicate the importance of tonsilloliths as a cause of orofacial pain. PMID- 21615469 TI - Oral health of the elderly living in residential homes in Slovenia. AB - OBJECTIVES: To evaluate oral health status of the elderly, living in eight randomly selected residential homes for senior citizens across the country. BACKGROUND: The percentage of the elderly is growing worldwide. With ageing, risks of various oral diseases, including dental caries and periodontal disease, are growing. METHODS: Altogether 296 elderly people (88 men, 208 women) of average age 79.89 +/- 7.4 years were questioned about their medical condition and oral health practice and examined orally. Evaluation of clinical examination was carried out by DMFT, plaque index (Silness and Loe, 1964) and Community Periodontal Index of Treatment Need (CPITN). RESULTS: Of 296 participants, 106 (35.8%) were edentulous, 95 (32.1%) had one to nine teeth and 95 persons (32.1%) had 10 or more teeth. The average number of teeth in an individual was small: 6.76 +/- 7.47. The average number of teeth with caries lesions was 3.59 +/- 4.70, filled teeth 1.94 +/- 3.63 and teeth without caries or fillings 1.19 +/- 2.41. The average DMFT value was 30.75. In 69.5% of participants, dental plaque was visible with the naked eye. Of 171 subjects, in whom CPITN index was appraised, 81.9% would need oral hygiene education, 56.7% would need scaling and root planning and 21.6% would need periodontal surgical treatment. CONCLUSIONS: The results of this study indicate poor oral health of the elderly living in residential homes situated in different towns in Slovenia. It is of utmost importance to highlight the necessity of improving oral health care of this population. PMID- 21615470 TI - Potential barriers to adherence in pediatric dermatology. AB - This study sought to identify barriers to treatment in children with chronic inflammatory skin disease, particularly those with atopic dermatitis, psoriasis, and acne vulgaris. Caregivers of 101 patients seen in the Children's Specialty Group Division of Dermatology, Children's Hospital of The King's Daughters, Norfolk, Virginia, completed an 11-item Likert scale questionnaire. This survey addressed complexity and time requirements for treatment, medication cost, vehicle formulation, perceived safety, and caregiver understanding of chronicity of skin disorders. Parents and caregivers indicated that adequate instructions for using the medications were provided but that they felt less comfortable with treating their child's skin disease during a severe flare. The complexity of treatment programs, time required to apply medications, and vehicle type were not considered prohibitive factors. Caregivers were concerned about the cost and safety of prescribed medications and had a less understanding of the chronicity of inflammatory skin disorders. PMID- 21615471 TI - Intralesional immunotherapy with Candida antigen for the treatment of molluscum contagiosum in children. AB - Intralesional injection of Candida and other antigens is an established and useful therapy for warts; a cutaneous immune response can induce improvement and or clearance of warts, often with response in anatomically distinct lesions other than those injected. Molluscum contagiosum virus is a common cutaneous infection seen primarily in pediatric dermatology clinics. Treatment is often unsatisfactory, painful, and time consuming. A retrospective chart review was conducted to examine the efficacy of intralesional injection of Candida antigen into a maximum of three individual molluscum lesions. Twenty-nine patients were treated with this therapy; 55% had complete resolution. In addition, 37.9% experienced partial resolution, yielding an overall response rate of 93%. Only two patients failed to respond (6.9%). In addition, only four patients reported a single adverse effect of pain with injection. No other adverse effects were reported or noted clinically. Scarring was absent. No recurrences were reported at the time of publication. This report establishes the efficacy of intralesional injection of Candida for molluscum contagiosum. PMID- 21615472 TI - A prospective self-controlled phase II study of imiquimod 5% cream in the treatment of infantile hemangioma. AB - Imiquimod has been reported to be efficacious in the topical treatment of uncomplicated infantile hemangiomas (IH). However, due to the natural tendency of IH to involute spontaneously, prior uncontrolled efficacy and safety studies have been called into question. We conducted a prospective self-controlled phase II study of imiquimod initially applied to uncomplicated, proliferative superficial or mixed IHs treating half of each IH once every other night for 16 weeks, leaving the other half untreated. After 16 weeks, an independent dermatologist evaluated the color, area, and volume of each half of the hemangioma. Of the 44 patients treated, the total effective rate was 80% (n = 35), with an overall resolution rated as excellent or good rate in 39% of lesions (n = 17/44). The relapse rate was 2% (n = 1). Side effects were noted in 61% (n = 27) including erythema or/and edema (n = 16%, 7), local itching (n = 7%, 3), peeling (n = 7%, 3), erosion (n = 5%, 2), crusting (n = 55%, 24), ulceration (n = 9%, 4), and scarring (n = 5%, 2). Some patients had two or more side effects. Most were judged to be mild to moderate and did not result in treatment being interrupted. Crusting or ulceration was noted to cause post-treatment skin reactions, such as texture change, whereas cases without crusting involuted to almost normal skin. No local infection or systemic reaction was observed. The difference in effective rate and side effect incidence between superficial and mixed IH was not statistically significant. Imiquimod 5% cream can be an effective and safe treatment option for superficial mixed IH in which the superficial component predominates. The recurrence rate is low, but local reactions including crusting can develop and result in post-treatment skin changes. PMID- 21615474 TI - What syndrome is this? Multiple soft papulonodular lesions over the scalp in a child. PMID- 21615473 TI - Environmental risk factors in pediatric psoriasis: a multicenter case-control study. AB - To analyze the effect of possible risk factors, including breastfeeding, on the development of childhood-onset psoriasis, a multicenter case-control study with prospective collection of data was performed. Using a standard questionnaire, personal and specific variables including family history of psoriasis, maternal and environmental tobacco smoke exposure, body mass index (BMI), exclusive and partial breastfeeding for at least 3 and 12 months, cow's milk intake before 1 year, birth delivery method, and stressful life events were collected during 2009 from 537 patients with psoriasis and 511 controls younger than 18. Overall, patients more frequently reported exposure to environmental tobacco smoke at home and stressful life events in the year preceding the diagnosis than controls. The odds ratios (OR) for smoking and stressful life events were 2.90 (95% confidence interval [CI]=2.27-3.78) and 2.94 (95% CI=2.28-3.79), respectively. In addition, children with psoriasis were more likely to have a higher BMI (>26) than controls (OR=2.52; 95% CI=1.42-4.49). High BMI, environmental tobacco smoke exposure at home, and stressful life events may influence the development of pediatric psoriasis. PMID- 21615475 TI - What syndrome is this? A newborn with multiple congenital abnormalities of face, genitalia, and extremities. PMID- 21615476 TI - What syndrome is this? Infantile periorificial and intertriginous dermatitis preceding sepsis-like respiratory failure. PMID- 21615477 TI - Antiphospholipid syndrome in a neonate. AB - Antiphospholipid syndrome presenting in the neonatal period is very rare. Although antiphospholipid antibodies from mothers with antiphospholipid syndrome can cross the placenta and put their neonates at risk, the occurrence of thrombotic complications in these neonates is uncommon. We present a 10-day-old neonate who developed Klebsiella sepsis with arterial gangrene of the left lower limb. Investigations revealed thrombosis of the left femoral artery with both the mother and the neonate positive for antiphospholipid antibodies. In conclusion, passive transfer of antiphospholipid antibodies from mothers to their offspring can be associated with significant complication in the presence of secondary risk factors. PMID- 21615478 TI - Ultraviolet protective eyewear for Wood's light use. AB - When interpreting delayed patch test reads for children suspected of having contact dermatitis, we use the Wood's light to illuminate the highlighter outlines we made at the first read. Our pediatric patients wear single-use ultraviolet protective goggles to shield their retinas, because children have a propensity to attempt to look into the Wood's lamp. PMID- 21615479 TI - We must think outside the box to understand nonadherence. PMID- 21615480 TI - Comment on: Vitiligo Treatment in Childhood: a State of the Art Review. By Tamesis MEB, Morelli JG: Pediatric Dermatology 2010;27(5):437-455. PMID- 21615484 TI - Left ventricular twisting and untwisting motion in childhood cancer survivors. AB - BACKGROUND: Anthracycline has been shown to degrade titin that plays a role in myocardial twisting and untwisting. This study aimed to test the hypothesis that left ventricular (LV) twisting and untwisting motion may be altered in children after anthracycline therapy. METHODS: Thirty-six childhood leukemia survivors aged 15.6 +/- 5.5 years and 20 healthy controls aged 16.8 +/- 7.7 years (P = 0.54) were studied. LV twisting and untwisting motion was determined using speckle tracking imaging, whereas LV ejection fraction and systolic and diastolic mitral annular velocities were determined respectively by three-dimensional and tissue-Doppler echocardiography. RESULTS: Compared with controls, patients had significantly lower LV ejection fraction (P = 0.01) but similar systolic and diastolic mitral annular velocities (all P > 0.05). Their peak LV torsion (P = 0.003), systolic twisting velocity (P < 0.001), and diastolic untwisting velocity (P = 0.04) were significantly lower than controls, which could be attributable to their reduced apical rotation (P = 0.03) and apical untwisting rate (P = 0.002). For the whole cohort, LV systolic torsion and twisting velocity correlated significantly with apical untwisting rate (P < 0.001) and LV diastolic untwisting velocity (P < 0.001). In patients, none of the twisting or untwisting parameters were found to correlate with cumulative anthracycline dose (all P > 0.05). Twenty eight (78%) patients had LV ejection fractions >=50%. Although their systolic and diastolic mitral annular velocities were similar to those of controls, their peak LV torsion (P = 0.005), apical untwisting rate (P = 0.01), and LV systolic twisting velocity (P = 0.001) remained significantly lower. CONCLUSION: Impairment of LV twisting and untwisting motion is evident in children after anthracycline therapy, even in those with "normal" LV ejection fractions. PMID- 21615483 TI - Soft tissue myoepithelioma of the scalp in a 11-year-old girl: a challenging diagnosis. AB - Myoepithelioma is a well-known tumor in the salivary glands and breasts in adults. It is exceptionally rare in soft tissue and in children. We present a case of subcutaneous scalp myoepithelioma in an 11-year-old girl. On clinical examination, it appeared as a dermoid cyst. Myoepithelioma is uncommon in the subcutaneous tissue. Clinically, the neoplasm is nonspecific. Because of the variable appearance of myoepithelial cells and their phenotype, the pathological diagnosis is challenging. We report a case of subcutaneous myoepithelioma in a child and discuss the literature. PMID- 21615485 TI - Right and left ventricular strain and strain rate in young adults before and after percutaneous atrial septal defect closure. AB - To evaluate acute change of right and left ventricle after percutaneous closure of isolated atrial septal defect (ASD) 21 adult patients (13 F; 8 M) aged 28 +/- 9.5 range 18-49 years have been examined by echocardiography before and 24 hours after percutaneous closure of ASD. Twenty-one normal adult subjects, as control group were included. A MyLab25 echo machine equipped with a multifrequency 2.5 3.5 MHz transducer was used. Offline computer-based analysis for strain and SR were performed using XStrain software based on a feature tracking algorithm. All patients had ASD OS2 with right ventricular dilatation and diastolic areas were larger than in controls: P = 0.0158. Global right ventricular longitudinal strain was higher P = 0.0438. Twenty-four hours after ASD closure, right ventricular diastolic and systolic areas were significantly reduced. Right ventricular global longitudinal systolic strain decreased: P = 0.00016, as well as global right ventricular longitudinal SR -1.56/sec +/- 0.57 vs. -1.28/sec +/- 0.31, P = 0.02646. At the mean time left ventricular end diastolic volume and left ventricular cardiac output measured by two-dimensional echocardiography both increased significantly P = 0.002145 and 0.013409. Global circumferential strain at mitral level augmented significantly -20.3%+/- 4.64 vs. -25.39%+/- 5.22, P = 0.00003. Longitudinal strain of the right ventricle works as indicator of right ventricular function dependent on loading conditions while SR seems to be less dependent on it. Circumferential strain could be used as an indicator of left ventricular response to normalized loading conditions. PMID- 21615486 TI - The influence of extreme mixed exertion load on the right ventricular dimensions and function in elite athletes: a tissue Doppler study. AB - AIMS: The athlete's heart is a widely discussed topic regarding the adaptation of the left ventricle (LV) to regular training. The data on the morphology and-even more-the function of the right ventricle (RV) are less well studied. The aim of the study was to assess the influence of prolonged exertion on morphology and function of the RV. METHODS AND RESULTS: We examined 38 elite athletes, members of the Polish Olympic Team and a control group of 41 age and sex-matched healthy volunteers. Specifically, we assessed the details of RV size and function including: RV enlargement, transtricuspid systolic gradient, and dilatation of main pulmonary artery (PA) as compared with the values derived from the control group. There was no significant difference in the function of the RV assessed using tissue Doppler echocardiography (TDE) between the athletes and controls (S': 15.0 cm/sec vs. 14.0 cm/sec; E': 15.8 cm/sec vs. 15.7 cm/sec; A': 9.9 cm/sec vs. 10.4 cm/sec), but the athletes had a higher transtricuspid systolic gradient (23.6 mm Hg vs. 19.0 mm Hg, P = 0.004). There were no significant differences in TDE velocities in athletes with dilated RV or PA. However, those with elevated tricuspid regurgitation velocity had lower systolic velocities of the tricuspid annulus then the rest (S': 12.3 cm/sec vs. 15.5 cm/sec, P = 0.01). CONCLUSIONS: RV enlargement in professional athletes is not connected with deterioration of diastolic or systolic RV function. Athletes with elevated pulmonary systolic pressure at rest, however, present with lower longitudinal systolic velocities of RV assessed using TDE. PMID- 21615487 TI - Lower circulating levels of complement split proteins C3a and C4a in maternal plasma of women with gestational diabetes mellitus. AB - AIM: The aim of this study was to determine the effect of gestational diabetes mellitus on maternal circulating levels of C3a, C4a and C5a. METHODS: Anaphylatoxin C3a, C4a and C5a levels were measured in maternal and cord plasma from 42 women with normal glucose tolerance and 40 women with gestational diabetes at the time of term elective Caesarean section. Maternal plasma C3a, C4a and C5a concentrations were determined by enzyme-linked immunoassay. RESULTS: Maternal C3a and C4a concentrations were significantly lower in women with gestational diabetes compared with women with normal glucose tolerance at the time of term delivery (P < 0.05, Student's t-test). There was, however, no difference in maternal circulating C5a levels between the two groups. Additionally, there was no difference in C3a, C4a and C5a levels in cord plasma obtained from women with normal glucose tolerance and those with gesational diabetes. However, a significant positive correlation was observed between maternal and cord complement split levels. CONCLUSIONS: Gestational diabetes is characterized by lower levels of C3a and C4a in the maternal circulation at the time of term Caesarean delivery. PMID- 21615488 TI - Improvement of diabetes care in a small but geographically widely spread population in Greenland. Effects of a national diabetes care programme. AB - AIMS: To estimate the prevalence of diagnosed Type 2 diabetes mellitus in Greenland and to evaluate the quality of the diabetes care before and after implementation of a new diabetes programme. METHODS: In this observational and cross-sectional study, data from the medical records were collected in Greenland in 2008 and 2010. Information about age, gender, most recently measured HbA(1c) , blood pressure and serum cholesterol and from the examination of eyes, feet and urine was obtained. The prevalence was estimated using the whole adult population in Greenland as background population. The quality of the diabetes care was monitored by six process, three biological and three treatment indicators. A diabetes concept based on national guidelines, systematized recording in an electronic medical record and feedback to the clinics were used to improve diabetes care. RESULTS: Four hundred and sixty-five patients were included in the 2008 sample and 691 in the 2010 sample. The total prevalence increased from 2.3 (95% CI 2.1-2.5) % in 2008 to 2.7 (95%CI 2.5-3.0) among Greenlanders aged 40 years old or above, corresponding to an increase of 19% (P = 0.006). All process indicators improved significantly between the two observations. CONCLUSIONS: Along with an increasing prevalence of diagnosed Type 2 diabetes, all six process quality indicators increased. It is strongly recommended that focus on the quality of diabetes care in Greenland should be maintained in order to benefit from the programme in the longer term. PMID- 21615489 TI - The presence of melatonin in grapevine (Vitis vinifera L.) berry tissues. AB - Melatonin has been reported in a variety of food plants and, consequently, in a number of plant-derived foodstuffs. In grapevine (Vitis vinifera L.) products, it was found in berry exocarp (skin) of different cultivars and monovarietal wines. Herein, we assessed, by means of mass spectrometry, the occurrence of melatonin in all berry tissues (skin, flesh, and seed) at two different phenological stages, pre-veraison and veraison. We detected the highest melatonin content in skin, at pre-veraison, whereas, at veraison, the highest levels were reported in the seed. Furthermore, during ripening, melatonin decreased in skin, while increasing in both seed and flesh. The relative concentrations of melatonin in diverse berry tissues were somewhat different from those of total polyphenols (TP), the latter measured by the Folin-Ciocalteau assay, and more abundant in seed at pre-veraison and in exocarp at veraison. The highest antiradical activity, determined by both DPPH (2,2-diphenyl-1-pycryl hydrazyl) and ABTS [(2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)] radical-scavenging assay, was reported at pre-veraison in seed. To the best of our knowledge, we reported, for the first time, the occurrence of melatonin in grape seeds. PMID- 21615490 TI - Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies. AB - Melatonin is an endogenous indoleamine, produced mainly by the pineal gland. Melatonin has been proven to have chronobiotic, antioxidant, antihypertensive, anxiolytic and sedative properties. There are also experimental and clinical data supporting an analgesic role of melatonin. In experimental studies, melatonin shows potent analgesic effects in a dose-dependent manner. In clinical studies, melatonin has been shown to have analgesic benefits in patients with chronic pain (fibromyalgia, irritable bowel syndrome, migraine). The physiologic mechanism underlying the analgesic actions of melatonin has not been clarified. The effects may be linked to G(i) -coupled melatonin receptors, to G(i) -coupled opioid MU receptors or GABA-B receptors with unknown downstream changes with a consequential reduction in anxiety and pain. Also, the repeated administration of melatonin improves sleep and thereby may reduce anxiety, which leads to lower levels of pain. In this paper, we review the current evidence regarding the analgesic properties of melatonin in animals and humans with chronic pain. PMID- 21615491 TI - MicroRNA and gene expression analysis of melatonin-exposed human breast cancer cell lines indicating involvement of the anticancer effect. AB - MicroRNAs (miRNAs) are small, noncoding RNAs that play a crucial role in regulation of gene expression. Recent studies have shown that miRNAs implicated in initiation and progression of various human cancers, including breast cancer and also analysis of miRNA expression profiles in cancer provide new insights into potential mechanisms of carcinogenesis. Melatonin, N-acetyl-5 methoxytryptamine, is synthesized by the pineal gland in response to the dark/light cycle and has been known to act as a synchronizer of the biological clock. Melatonin has a variety of therapeutic effects, such as immunomodulatory actions, anti-inflammatory effects, and antioxidant actions. Furthermore, melatonin is reported to have an anticancer function including suppression of the metabolism of tumor cells and induction of tumor suppressor genes in cancer cells, including breast cancer cells. In this study, we determined whether miRNAs play a role in regulation of various gene expression responses to melatonin in MCF-7 human breast cancer cells. We examined whole-genome miRNA and mRNA expression and found that 22 miRNAs were differentially expressed in melatonin treated MCF-7 cells. We further identified a number of mRNAs whose expression level shows a high inverse correlation with miRNA expression. The Gene Ontology (GO) enrichment analysis and pathways analysis were performed for identification of the signaling pathways and biological processes affected by differential expression of miRNA and miRNA-related genes. Our findings suggested that melatonin may modulate miRNA and gene expression as an anticancer mechanism in human breast cancer cells. PMID- 21615492 TI - Melatonin supplementation ameliorates oxidative stress and inflammatory signaling induced by strenuous exercise in adult human males. AB - Strenuous exercise induces inflammatory reactions together with high production of free radicals and subsequent muscle damage. This study was designed to investigate for the first time and simultaneously whether over-expression of inflammatory mediators, oxidative stress, and alterations in biochemical parameters induced by acute exercise could be prevented by melatonin. This indoleamine is a potent, endogenously produced free radical scavenger and a broad spectrum antioxidant; consequently, it might have positive effects on the recovery following an exercise session. The participants were classified into two groups: melatonin-treated men (MG) and placebo-treated individuals (controls group, CG). The physical test consisted in a constant run that combined several degrees of high effort (mountain run and ultra-endurance). The total distance of the run was 50 km with almost 2800 m of ramp in permanent climbing and very changeable climatic conditions. Exercise was associated with a significant increase in TNF-alpha, IL-6, IL-1ra (in blood), and also an increase in 8-hydroxy 2'-deoxyguanosine (8-OHdG) and isoprostane levels (in urine), and indicated the degree of oxidative stress and inflammation induced. Oral supplementation of melatonin during high-intensity exercise proved efficient in reducing the degree of oxidative stress (lower levels of lipid peroxidation, with a significant increase in antioxidative enzyme activities); this would lead to the maintenance of the cellular integrity and reduce secondary tissue damage. Data obtained also indicate that melatonin has potent protective effects, by preventing over expression of pro-inflammatory mediators and inhibiting the effects of several pro-inflammatory cytokines. In summary, melatonin supplementation before strenuous exercise reduced muscle damage through modulation of oxidative stress and inflammation signaling associated with this physical challenge. PMID- 21615493 TI - Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders. AB - Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD. PMID- 21615494 TI - Normative data for tests of neuromuscular performance and DXA-derived lean body mass and fat mass in pre-pubertal children. AB - AIM: To present gender-specific normative data on estimates of neuromuscular performance, such as muscle strength, vertical jump and standing unilateral balance, in pre-pubertal children. METHODS: Lean body mass (kg) and fat mass (%) were estimated by dual-energy X-ray absorptiometry in 246 boys and 190 girls aged 6-12 years in Tanner stages 1 and 2. Isokinetic concentric peak torque at 60 and 180 degrees /sec of the right knee extensors, and flexors were evaluated by a computerized dynamometer. Vertical jump height (VJH) was evaluated with an electronic mat and postural control with a one-leg stand test and a blindfolded one-leg stand test. RESULTS: Anthropometry, muscle strength and VJH in both genders showed improved performance with advancing ages (all p < 0.01 for trend) but there were no constant gender differences across the age groups (all ns.). In boys and girls, the ratio muscle strength/muscle mass showed significantly higher ratios with higher ages (both p < 0.01, respectively), but with no constant gender discrepancy. The postural control tests also showed significantly better performance with higher ages in both boys and girls (both p < 0.01). CONCLUSION: This report, which provides normative gender-specific data on muscle strength, muscle and fat mass and VJH, shows that in Swedish children aged 6-12 years, there seems to be a linear increase with age and no structural gender differences. PMID- 21615495 TI - Serum C-reactive protein concentration in benign and malignant canine spirocercosis. AB - BACKGROUND: Spirocerca lupi is a nematode of canids that forms a nodule in the esophagus that can undergo neoplastic transformation. C-reactive protein (CRP) is a major acute phase protein in the dog that has been used for treatment, monitoring, and prognostication in inflammatory and neoplastic disease. HYPOTHESIS/OBJECTIVES: The objectives of this study were to determine if serum CRP concentration (1) is increased in canine spirocercosis, (2) can be used to determine neoplastic transformation, and (3) can be used to monitor response to treatment in benign spirocercosis. ANIMALS: Forty-two dogs naturally infected with S. lupi and 21 control dogs. METHODS: A retrospective study was performed. The infected cases were divided into benign (n = 28) or malignant (n = 14) spirocercosis. CRP was performed on all of the spirocercosis and control cases at presentation. Statistical analysis was done by the one-way analysis of variance and Student's t-test. RESULTS: The mean CRP concentration in the benign cases was 60.4 +/- 48.0 mg/L and that of the malignant cases was 76.5 +/- 44.8 mg/L; both values were significantly higher (P < .001) than those of the control group where the mean was 13.4 +/- 17.9 mg/L. The mean CRP concentration for the convalescent sera in the benign group was lower than the pretreatment concentrations (P= .01). CONCLUSION AND CLINICAL IMPORTANCE: CRP cannot be used to differentiate between benign and malignant spirocercosis. There is a decrease in CRP concentration in dogs with benign spirocercosis once treatment has commenced. Serial CRP measurement can be used to monitor response to treatment in benign spirocercosis. PMID- 21615496 TI - Intravenous administration of docetaxel to cats with cancer. AB - BACKGROUND: The safety of i.v. administration of docetaxel to cats with cancer has not been reported. OBJECTIVES: Document adverse effects of i.v. administration of docetaxel to cats. ANIMALS: Twenty-one client-owned cats with any confirmed malignancy. METHODS: Cats received up to 5 docetaxel treatments, administered i.v. every 3 weeks. The initial dosage was 1.0 mg/kg, and dosages were increased by increments of 0.25 mg/kg in cohorts of 3 cats. Adverse events were determined by a CBC at days 7 and 21, serum chemistry and urine specific gravity at day 21, and medical histories provided by the owners. RESULTS: Cats received docetaxel dosages ranging from 1.0 to 2.5 mg/kg, for a median of 2 treatments. Dose-limiting toxicoses included fever, neutropenia, and vomiting, seen in 2 of the 4 cats treated at 2.5 mg/kg. Hypersensitivity reactions were infrequent (4 of the 21 cats) and mild. The maximum tolerated dosage was 2.25 mg/kg. CONCLUSIONS AND CLINICAL IMPORTANCE: Docetaxel can be administered i.v. to cats with a low incidence of adverse effects. PMID- 21615497 TI - White-coat effect on systemic blood pressure in retired racing Greyhounds. AB - BACKGROUND: Greyhounds are known to have a higher systemic arterial blood pressure (BP) than non-Greyhound dogs. OBJECTIVES: The purpose of this study was to determine whether the high systemic BP was because of the white-coat effect. ANIMALS: Twenty-two healthy retired racing Greyhounds (RRG) enrolled in a blood donation program. MATERIALS/METHODS: We prospectively measured systemic BP in 3 environments: in the hospital by the investigator (Hosp), in the home by the investigator (H/I), and in the home by the owner (H/O). Five serial measurements of systolic, diastolic, and mean arterial pressures (SAP, DAP, MAP) as well as heart rate (HR) were measured by an oscillometric method on the distal forelimb and distal hind limb in all 3 environments. RESULTS: There was a significant difference for SAP, MAP, and HR between the Hosp and both H/I and H/O (P < .001); there were no significant differences for any of the parameters between the H/I and H/O environments. HR, but not SAP, MAP, or DAP (P < .05) decreased in RRG with multiple hospital visits for blood donation before this study. The hind limb SAP was significantly higher than the forelimb SAP (P < .05). CONCLUSIONS AND CLINICAL IMPORTANCE: We conclude that the high SAP, MAP, and HR seen in the hospital setting are likely because of a white-coat effect. Furthermore, consideration should be given to defining the parameters of normal BP in RRG according to the environment in which they are obtained. PMID- 21615498 TI - Molecular and serological diagnosis of Bartonella infection in 61 dogs from the United States. AB - BACKGROUND: Molecular diagnosis of canine bartonellosis can be extremely challenging and often requires the use of an enrichment culture approach followed by PCR amplification of bacterial DNA. HYPOTHESES: (1) The use of enrichment culture with PCR will increase molecular detection of bacteremia and will expand the diversity of Bartonella species detected. (2) Serological testing for Bartonella henselae and Bartonella vinsonii subsp. berkhoffii does not correlate with documentation of bacteremia. ANIMALS: Between 2003 and 2009, 924 samples from 663 dogs were submitted to the North Carolina State University, College of Veterinary Medicine, Vector Borne Diseases Diagnostic Laboratory for diagnostic testing with the Bartonella alpha-Proteobacteria growth medium (BAPGM) platform. Test results and medical records of those dogs were retrospectively reviewed. METHODS: PCR amplification of Bartonella sp. DNA after extraction from patient samples was compared with PCR after BAPGM enrichment culture. Indirect immunofluorescent antibody assays, used to detect B. henselae and B. vinsonii subsp. berkhoffii antibodies, were compared with PCR. RESULTS: Sixty-one of 663 dogs were culture positive or had Bartonella DNA detected by PCR, including B. henselae (30/61), B. vinsonii subsp. berkhoffii (17/61), Bartonella koehlerae (7/61), Bartonella volans-like (2/61), and Bartonella bovis (2/61). Coinfection with more than 1 Bartonella sp. was documented in 9/61 dogs. BAPGM culture was required for PCR detection in 32/61 cases. Only 7/19 and 4/10 infected dogs tested by IFA were B. henselae and B. vinsonii subsp. berkhoffii seroreactive, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs were most often infected with B. henselae or B. vinsonii subsp. berkhoffii based on PCR and enrichment culture, coinfection was documented, and various Bartonella species were identified. Most infected dogs did not have detectable Bartonella antibodies. PMID- 21615499 TI - In vitro lysis and acute transfusion reactions with hemolysis caused by inappropriate storage of canine red blood cell products. AB - BACKGROUND: Transfusion of red blood cell (RBC) products carries considerable risk for adverse reactions, including life-threatening hemolytic reactions. OBJECTIVE: To report the occurrence and investigation of life-threatening acute transfusion reactions with hemolysis in dogs likely related to inappropriate blood product storage. ANIMALS: Four dogs with acute transfusion reactions and other recipients of blood products. METHODS: Medical records were reviewed from 4 dogs with suspected acute hemolytic transfusion reactions after receiving RBC products at a veterinary clinic over a 1-month period. Medical records of other animals receiving blood products in the same time period also were reviewed. Blood compatibility and product quality were assessed, subsequent transfusions were closely monitored, and products were diligently audited. RESULTS: During or immediately after RBC product transfusion, 4 dogs developed hemolysis, hemoglobinuria, or both. Two dogs died and 1 was euthanized because of progressive clinical signs compatible with an acute hemolytic transfusion reaction. Blood type and blood compatibility were confirmed. RBC units from 2 blood banks were found to be hemolyzed after storage in the clinic's refrigerator; no bacterial contamination was identified. After obtaining a new refrigerator dedicated to blood product storage, the problem of hemolyzed units and acute transfusion reactions with hemolysis completely resolved. CONCLUSIONS: Acute life-threatening transfusion reactions can be caused by inappropriate storage of RBC products. In addition to infectious disease screening and ensuring blood-type compatibility, quality assessment of blood products, appropriate collection, processing, and storage techniques as well as recipient monitoring are critical to provide safe, effective transfusions. PMID- 21615500 TI - Utility of chemiluminescence (ViziLiteTM) in the detection of oral potentially malignant disorders and benign keratoses. AB - BACKGROUND: Oral potentially malignant disorders (OPMD) are known to precede the development of oral cancer. Detection of OPMD allows delivery of interventions that may reduce the evolution of these disorders to malignancy. Following oral examinations, the accuracy of detection of OPMD by chemiluminescence was evaluated using a commercially available detection kit - ViziLite. Data derived were compared in relation to conventional oral examination and surgical biopsy. METHODS: A total of 126 patients, 70 men and 56 women (mean age 58.5 +/- 11.9 years) attending Oral Medicine Clinics at King's and Guy's Hospitals, London, with oral white, red, and mixed white and red patches were enrolled. Sixty-one patients were current smokers, 28 were ex-smokers, while 92 were alcohol users. In a detailed investigation, these patients underwent ViziLite examination followed by surgical biopsy. RESULTS: Based on the clinical diagnosis, 70 patients had oral leukoplakia/erythroplakia, 32 had oral lichen planus, nine had chronic hyperplastic candidiasis, and rest had frictional keratosis (13) or oral submucous fibrosis (2). Of 126 lesions, 95 (75.4%) showed aceto-whitening. Most oral leukoplakias had enhanced visibility and sharpness of the lesion when viewed with the ViziLite system. Following biopsy, 44 had oral epithelial dysplasia (29 mild, eight moderate, and seven severe). The sensitivity (se) and specificity (sp) of chemiluminescence for the detection of a dysplastic lesion were 77.3% and 27.8%, respectively. CONCLUSION: While ViziLite has the ability to detect OPMD, it does not accurately delineate dysplastic lesions. The device can be used as a general oral mucosal examination system and may in particular improve the visualization of leukoplakias. PMID- 21615501 TI - The role of alpha9beta1 integrin in modulating epithelial cell behaviour. AB - BACKGROUND: Integrins initiate signalling in response to the extracellular matrix (ECM), which is important in wound healing and cancer. Previous studies have shown that over-expression of the alphavbeta6 integrin in oral squamous cell carcinoma (OSCC) cells results in enhanced motility and expression of matrix degrading proteases, and the aim of this study was to investigate whether this is also the case for the alpha9beta1 integrin. METHODS: H357 OSCCcells were transfected with the alpha9 integrin subunit and proliferation, adhesion and migration assays were performed on these along with null vector control and wild type cells. The effect of ligand engagement on matrix metalloproteinase expression and the plasminogen activator system was measured using ELISA and chromogenic assays. Expression of alpha9 integrin was examined in oral squamous cell carcinoma tissue by immunohistochemistry. RESULTS: Functionally active alpha9 integrin mediated specific upregulation of adhesion and migration towards the TNfn3RAA fragment of tenascin-C but reduced proliferation. Migration towards collagen I was also enhanced in transfected cells. Matrix metalloproteinase-2 and metalloproteinase-9 expression was increased upon TNfn3RAA ligand engagement. Cell surface plasmin generation was also enhanced in alpha9-expressing cells and was the result of enhanced expression of urokinase receptor. In normal oral mucosa, alpha9 integrin expression was restricted to the suprabasal and prickle cell layers, and expression was heterogeneous in tumours but present in islands infiltrating connective tissue particularly in moderately and well-differentiated lesions. CONCLUSIONS: The alpha9beta1 integrin may play a key role in modulation of tumour behaviour including enhanced cell migration and expression of matrix degrading proteases. PMID- 21615502 TI - Comparing mixing and displacement ventilation in classrooms: pupils' perception and health. AB - Several studies have found that indoor air quality (IAQ) in schools is often poor and may affect the health of the pupils. Building ventilation is a means to reduce pollutants indoors, but different designs should be evaluated for their effectiveness in different environments. In a field experiment performed at four classrooms in one school building, air was supplied either in the mixing or in the displacement mode, and we collected information on exposures, pupils' perception of IAQ and climate, and health symptoms and performed clinical examinations. The room temperature, relative humidity, concentration of CO2, and cat allergen were measured at the breathing height and were similar during each ventilation mode. The children perceived IAQ were similar in the two ventilation regimes, and there were few differences in symptom reports or clinical parameters. However, the pupils reported more eye symptoms during displacement ventilation. PRACTICAL IMPLICATIONS: Both mixing and displacement ventilation may be appropriate in school classrooms as long as the overall design, ventilation rates, and maintenance of systems are satisfactory. PMID- 21615503 TI - The prevalence and incidence of sick building syndrome in Chinese pupils in relation to the school environment: a two-year follow-up study. AB - There are few incidence studies on sick building syndrome (SBS). We studied two year change of SBS in Chinese pupils in relation to parental asthma/allergy (heredity), own atopy, classroom temperature, relative humidity (RH), absolute humidity (AH), crowdedness, CO2, NO2, and SO2. A total of 1993 participated at baseline, and 1143 stayed in the same classrooms after two years. The prevalence of mucosal and general symptoms was 33% and 28% at baseline and increased during follow-up (P < 0.001). Twenty-seven percent reported at least one symptom improved when away from school. Heredity and own atopy were predictors of SBS at baseline and incidence of SBS. At baseline, SO2 was associated with general symptoms (OR=1.10 per 100 MUg/m3), mucosal symptoms (OR=1.12 per 100 MUg/m3), and skin symptoms (OR=1.16 per 100 MUg/m3). NO2 was associated with mucosal symptoms (OR=1.13 per 10 MUg/m3), and symptoms improved when away from school (OR=1.13 per 10 MUg/m3). Temperature, RH, AH, and CO2 were negatively associated with prevalence of SBS. Incidence or remission of SBS was not related to any exposure, except a negative association between SO2 and new skin symptoms. In conclusion, heredity and atopy are related to incidence and prevalence of SBS, but the role of the measured exposures for SBS is more unclear. PRACTICAL IMPLICATIONS: We found high levels of CO2 indicating inadequate ventilation and high levels of SO2 and NO2, both indoors and outdoors. All schools had natural ventilation, only. Relying on window opening as a tool for ventilation in China is difficult because increased ventilation will decrease the level of CO2 but increase the level of NO2 and SO2 indoors. Prevalence studies of sick building syndrome (SBS) might not be conclusive for causal relationships, and more longitudinal studies on SBS are needed both in China and other parts of the world. The concept of mechanical ventilation and air filtration should be introduced in the schools, and when planning new schools, locations close to heavily trafficked roads should be avoided. PMID- 21615504 TI - Inhalation exposure of children to fragrances present in scented toys. AB - When utilized in the perfuming of children's toys, fragrances capable of inducing contact allergy in human skin may also become bioavailable to children via the inhalation route. The aim of this study was to determine the area-specific emission rates of 24 fragrances from a plasticized PVC reference material that was meant to mimic a real plastic toy. This material was introduced into an emission chamber for 28 days at handling conditions or at worst-case conditions. As a result, fragrances can be separated into three categories according to their emission rates ranging from 0.0041 to 16.2 mg/m2 * h, i.e., highly volatile, semivolatile, and low-volatile compounds. Compounds of the first and second categories were monitored with decreasing emission rates. Substances of the third category were detected with increasing emission rates over time. Further, higher temperatures led to higher emission rates. The emission concentration of fragrances from four real scented toys varied between 1.10 and 107 MUg/m3 at day 1 in the test chamber. Therefore, short-term inhalation exposure to fragrances originating from toys was in the range of 0.53-2700 ng/kg BW/d for the children of age 1 and older. Long-term exposure to these fragrances was calculated in the range of 2.2-220 ng/kg BW/d. PRACTICAL IMPLICATIONS: Besides household products and cosmetics, fragrances can be found in toys for children. Some fragrances are known contact allergens in the skin, but there is a lack of information on their effects in the human respiratory tract. Here, we analyzed and categorized fragrances present in a plasticized PVC reference material according to their emission profiles and volatility. We also demonstrate that volatile fragrances are being emitted from real toys and thus may get inhaled under consumer conditions to different extents. PMID- 21615505 TI - Effect of MC1R variant allele status on MSH-ligand induction of dopachrome tautomerase in melanocytes co-cultured with keratinocytes. AB - A co-culture system of melanocytic cells and keratinocytes was used to examine dendricity and dopachrome tautomerase (DCT) responses in low penetrant 'r' homozygote and 'R/+' heterozygote MC1R variant allele expressing cells compared to that of wild-type (WT) cells. The V60L-/- homozygote r variant cells showed similar responses to ligand as WT MC1R strains, while V92M-/- homozygote r variant cells were generally shown to have greater dendricity and express higher DCT than the WT cells, even at basal levels. The R151C+/- heterozygote cells showed similar responses to WT cells, while the R160W+/- and D294H+/- variant cells were reduced in their responses to NDP-MSH, but still had an active cAMP response with forskolin treatment. These responses are consistent with the dominant negative effect of these alleles on the MC1R WT allele that has previously been demonstrated genetically and biochemically. PMID- 21615506 TI - Activation of p38 MAPK pathway contributes to the melanogenic property of apigenin in B16 cells. AB - We investigated the involvement of MAPK pathways in the melanogenic effect of apigenin in B16 cells. Apigenin treatment for 48 h dose (5-20 MUm)-dependently up regulated protein expression levels of microphthalmia-associated transcription factor (MITF) and melanogenic enzymes including tyrosinase, tyrosinase-related protein-1 (TRP-1) and TRP-2 and enhanced the phosphorylation of p38 MAPK, without affecting the phosphorylation of JNK or ERK MAPK. Treatment with 10 MUm apigenin time (6-48 h)-dependently elevated the protein expressions of p-p38, MITF and melanogenic enzymes. Moreover, PD169316, a selective inhibitor of p38 kinase, suppressed the stimulatory effects of apigenin on tyrosinase activity and melanin synthesis, which were accompanied by decreased MITF protein expression. In conclusion, apigenin increased melanogenesis in B16 cells, at least in part, by activating the p38 MAPK pathway. The novel findings of this study shed light on the molecular mechanisms underlying the melanogenic activity of apigenin and suggest that apigenin/its derivatives may be potentially used for treating hypopigmentation disorders. PMID- 21615507 TI - Skin surface electrical potential as an indicator of skin condition: observation of surfactant-induced dry skin and middle-aged skin. AB - We previously reported that skin surface electrical potential might be a good parameter of skin pathophysiology. To examine the potential availability of skin surface electrical potential measurement for diagnostic purposes, we measured the change of the potential in surfactant-induced dry skin and we compared the values of the potential in volunteers of different age groups. We also measured trans epidermal water loss (TEWL) in the same groups. The skin surface electrical potential was significantly increased after sodium dodecyl sulphate treatment, and the alteration was much more marked than that of TEWL. Further, a significant difference in skin surface electrical potential was observed between young- and middle-aged volunteers, although there was no significant difference in TEWL between the two groups. These results suggest that skin surface electrical potential may be a good indicator of the pathophysiological state of the living layer of epidermis. PMID- 21615508 TI - Murine tyrosinase inhibitors from Cynanchum bungei and evaluation of in vitro and in vivo depigmenting activity. AB - Two natural acetophenone derivatives, 2,5-dihydroxyacetophenone (2,5-DHAP) and 2,6-DHAP, were purified from Cynanchum bungei and identified as murine tyrosinase inhibitors. Investigation into 2,5-DHAP showed it to be an uncompetitive inhibitor of murine tyrosinase (K(I) 0.28 mm). 2,5-DHAP strongly inhibited both melanogenesis and cellular tyrosinase activity in vitro in 3-isobutyl-1 methylxanthin-stimulated B16 mouse melanoma cells or in vivo in zebrafish and mouse models, but showed no cytotoxicity at the concentrations used. In B16 cells, 2,5-DHAP inhibition was dose-dependent and was fourfold greater than that of arbutin. 2,5-DHAP had no effect on the expression of tyrosinase protein or mRNA, as confirmed by Western blotting and quantitative real-time reverse transcription polymerase chain reaction, respectively. A 2% gel preparation of 2,5-DHAP applied to the skin of mice significantly increased the average skin whitening index (L value), indicating its potential use as a treatment for skin hyperpigmentation in humans. PMID- 21615509 TI - Functional characterization of cancer-associated fibroblasts of human cutaneous squamous cell carcinoma. AB - Cutaneous squamous cell carcinoma (SCC) is the second most common type of skin cancer in the Caucasian population worldwide, having a propensity for invasion, local recurrence and metastasis. Stromal cancer-associated fibroblasts (CAFs) are suspected to play an important role in SCC carcinogenesis. In this study, we characterized CAFs isolated from primary cutaneous SCCs and compared them to normal fibroblasts (NFs) isolated from healthy dermis. Human skin CAFs in monolayers displayed different morphology, increased proliferation and migration compared to NFs. CAFs caused strong contraction of collagen matrices in which they were seeded and released high levels of the extracellular matrix component pro-collagen I. CAFs decreased proliferation and differentiation in the epidermis of human skin equivalents (HSEs) seeded with SCC cell lines, without affecting basement membrane composition. Finally, CAFs significantly increased invasion and dermal-epidermal detachment of SCC cell lines SCC-12B2 and SCC-13, respectively, when cultured in HSEs. These distinct features of CAFs point out a specific role in cutaneous SCC development. PMID- 21615511 TI - The extracellular matrix of the dermis: flexible structures with dynamic functions. AB - The current understanding of the role of extracellular matrix proteins is mainly based on their structural properties and their assembly into complex networks. The multiplicity of interactions between cells, cytokines and growth factors within the networks determines functional units dictating the biophysical properties of tissues. This review focuses on the understanding how alterations in the genes, modifying enzymes or biological functions of extracellular matrix molecules, lead to inborn or acquired skin disorders. Analysis of the disease mechanisms provides the basis for the emerging concept that not solely structural defects of single extracellular matrix proteins are at fault, but rather that the functional unit as a whole is not working properly, causing similar clinical symptoms although the causative genes are entirely different. The understanding of these disease-causing pathways has already led to surprising new therapeutic developments applied to rare inborn disorders. They now permit to design new concepts for the treatment of more common diseases associated with the accumulation of connective tissue and alterations of the biomechanical properties of the extracellular matrix. PMID- 21615510 TI - Adiponectin expression is decreased in the involved skin and sera of diffuse cutaneous scleroderma patients. AB - In this study, we determined the adiponectin expression in the serum and lesional skin of patients with scleroderma (SSc). Serum adiponectin concentrations were measured in 32 patients with SSc, 10 patients with SLE, 12 patients with dermatomyositis patients and 13 healthy subjects with specific enzyme-linked immunosorbent assays. Adiponectin mRNA was determined in skin tissues of five patients with diffuse cutaneous SSc (dcSSc), seven patients with limited cutaneous SSc (lcSSc) and seven healthy subjects with real-time polymerase chain reaction. There was a significant reduction in serum adiponectin levels in patients with dcSSc. SSc patients with decreased serum adiponectin levels had higher total skin thickness score and higher incidence of pulmonary fibrosis. Adiponectin mRNA levels in skin tissues from patients with dcSSc were also reduced. Serum adiponectin levels may be a useful biomarker for fibrotic condition in patients with SSc. Clarifying the role of adiponectin in collagen diseases may lead to further understanding of the pathogenesis and new therapeutic approach. PMID- 21615512 TI - Expanding morphological dimensions in neuropathology, from sequence biology to pathological sequences and clinical consequences. AB - One of the challenges in neuropathology is to clarify how molecules, functional carriers of uni-dimensional sequence of amino acid or nucleic acid, behave to engender disease-specific pathological processes in complex three-dimensional (3D) structures such as the human brain in an ordered chronological sequence (four-dimensional extension as a whole). Along with expanding molecular explanations for brain diseases, parallel and independent hypotheses based on morphological observations are particularly useful and necessary for reasonable understanding of the brain and its dysfunction. For example, with classical methods such as silver impregnations, it is possible to differentiate underlying molecular pathologies (three-repeat tau/Campbell-Switzer vs. four-repeat tau/Gallyas silver impregnation) for improved histological diagnosis. Innovations with 3D reconstruction not only provide more realistic reproduction of the targets but also allow quantitative measurement on a 3D basis (3D volumetry). Contrary to the prevailing impression that pathological deposits are generally toxic to cells, quantification demonstrated possible countertoxic potentials of ubiquitin-positive intranuclear inclusions in CAG-repeat disorders on a two dimensional basis and of glial cytoplasmic inclusions of multiple system atrophy on 3D volumetry. Furthermore, 3D extension of neurites around target lesions is now traceable in relation to the relevant clinical consequences. This neurite neuropathology may pave the way for early specific diagnosis of neurodegenerative disorders, as established through (123) I-metaiodobenzylguanidine cardiac scintigraphy for Parkinson disease, aiming at therapeutic intervention before depletion of mother neurons is feasible. For appropriate translation of sequence biology into the frame of human neuropathology, it is necessary to expand further the morphological dimensions so that comprehensive understanding of these disorders leads to specific diagnosis and treatment as early as possible. PMID- 21615514 TI - Extensive distribution of glial cytoplasmic inclusions in an autopsied case of multiple system atrophy with a prolonged 18-year clinical course. AB - We describe herein an autopsied case of multiple system atrophy (MSA) with prolonged clinical course of 18 years, and evaluate the extent of neurodegeneration and glial cytoplasmic inclusions (GCIs) in the entire brain of this rare case. A 64-year-old woman presented with typical neurological symptoms and imaging features of MSA. Thereafter, she became bedridden, and breathing was assisted through a tracheostomy for 12 years. She died at the age of 82 after 18 years from the initial symptom. Post mortem examination revealed severe neurodegeneration in the inferior olive, pontine nuclei, substantia nigra, locus ceruleus, putamen and cerebellum. Notably, phosphorylated alpha-synuclein (p alpha-syn)-positive GCIs were found in these areas, but their number was very low. In contrast, the density of GCIs was much higher in such regions as the tectum/tegmentum of the brainstem, pyramidal tracts, neocortices and limbic system, which usually contain a small number of GCIs. Another constituent of GCIs, ubiquitin (Ub) and Ub-associated autophagy substrate p62, were also positive in some GCIs, and distribution of Ub/p62 immunoreactivity was proportionate to that of p-alpha-syn+ GCIs despite the very long duration of the disease. Furthermore, this case had complicated hypoxic encephalopathy, but p alpha-syn+ GCIs were also found in the damaged white matter, indicating the contribution of alpha-syncleinopathy as well as hypoxic effect to the secondary myelin and axonal loss in the white matter. Together, this rare case suggests the contribution of the disease duration to the prevalence of GCIs, and the possible involvement of the limbic system in extensive-stage disease. PMID- 21615515 TI - Synchronous intravascular large B-cell lymphoma within meningioma. AB - Intravascular large B-cell lymphoma is a rare and aggressive lymphoma with a dismal prognosis. Synchronous intravascular large B-cell lymphoma within meningioma has not previously been documented. We report a case of a 73-year-old woman of Asian descent who presented with fever of unknown origin with generalized weakness. CT scan and MRI of the head revealed a dural-based mass lesion consistent with meningioma in the left frontal cerebral convexity. Surgery was performed to remove the tumor and histopathology showed a meningioma within which was a synchronous intravascular large B-cell lymphoma. The hematology and oncology services were consulted and palliative treatment was initiated due to the patient's poor Eastern Cooperative Oncology Group performance status. The patient died within 30 days post-surgery. To the best of our knowledge, this case represents the first report of synchronous intravascular large B-cell lymphoma within a meningioma. PMID- 21615516 TI - Diagnostic pitfall in the diagnosis of mesenchymal chondrosarcoma arising in the central nervous system. AB - Mesenchymal chondrosarcoma is a rare aggressive neoplasm typically affecting the bones of young adults. It may also arise in somatic soft tissue, the CNS and other organs. It has a characteristic biphasic histological pattern composed of highly undifferentiated small round cells and islands of well-differentiated hyaline cartilage. We report a case of mesenchymal chondrosarcoma arising from the right tentorium cerebelli in a 21-year-old woman with symptoms relating to mass effect. Histological examination demonstrated a purely small round cell appearance in a specimen obtained during partial resection at an outside institution, leading to an erroneous diagnosis of Ewing sarcoma/primitive neuroectodermal tumor (PNET). The diagnosis of mesenchymal chondrosarcoma was made only after tissue obtained during a definitive complete macroscopic removal involving the regional tentorium cerebelli, transverse and sigmoid dural venous sinuses which showed a prominent cartilaginous component. We discuss the features of mesenchymal chondrosarcoma arising in the CNS, the important differential diagnoses of small round-cell tumors within the CNS, and the differentiating features of mesenchymal chondrosarcoma from Ewing sarcoma/PNET, medulloblastoma, hemangiopericytoma, monophasic synovial sarcoma and atypical teratoid/rhabdoid tumour. PMID- 21615517 TI - Complete resolution of advanced Mycoplasma pneumoniae encephalitis mimicking brain mass lesions: report of two pediatric cases and review of literature. AB - Mycoplasma pneumoniae is a well-known cause of atypical pneumonia. CNS involvement is a relatively frequent extrapulmonary manifestation, most commonly manifesting as encephalitis in the pediatric population. We present two unusual cases of M. pneumoniae encephalitis that presented with symptoms and imaging findings suggesting mass occupying lesions, and worsening altered mental status. Biopsy of the lesions was necessary in both cases to aid with diagnosis. Histopathologic features excluded neoplasm, and established the diagnosis of encephalitis, but did not point toward its etiology. The only finding that indicated M. pneumoniae as the most likely pathogen was serum IgM positivity in the absence of any other identifiable infectious source, and complete neurologic recovery following specific anti-mycoplasmal treatment. The patients were successfully treated with antibiotics and steroids, with the second case also requiring intravenous immunoglobulin and anti-epileptics. The clinical presentation and histopathologic findings suggested an immune-mediated pathogenesis, but acute disseminated encephalomyelitis was excluded due to extensive gray matter involvement. Disease resolution despite status epilepticus and herniation in case 2 is a novel finding of the study. Current principles of diagnosis and management of encephalitis as the presenting manifestation of mycoplasmal infection are discussed. PMID- 21615518 TI - Vertebral basilar system dolichoectasia with marked infiltration of IgG4 containing plasma cells: a manifestation of IgG4-related disease? AB - We report the histopathological features of vertebral basilar system dolichoectasia (VBD) in a 68-year-old man who died as a result of accompanying infarction of the medulla oblongata on day 6 of admission. During hospitalization, the patient was also found to have an elevated serum IgG level and tumors of the renal pelvis. A possible clinical diagnosis of VBD associated with IgG4-related disease was considered postmortem. Autopsy examination, limited to the intracranial tissues, revealed marked infiltration of IgG4-containing plasma cells in the adventitia and media of the vertebral and basilar arteries. Multiple fibrous nodules forming pseudotumors were also evident on the outer surface of the affected arteries. These histological features were very similar to those of arteriopathy, such as inflammatory aortic aneurysm, which has been described in patients with IgG4-related disease, suggesting that autoimmune mechanisms, known to be involved in the pathogenesis of visceral lesions in the disease, also played a role in the etiology of VBD in the present patient. In conclusion, we consider that the present case may represent VBD as a manifestation of IgG4-related disease. PMID- 21615519 TI - Left cerebellar hemispheric tumor in an 80-year-old man. PMID- 21615520 TI - A foramen of Monro tumor. PMID- 21615521 TI - A case of a girl with poor school achievement, ataxia and neurological deterioration. PMID- 21615523 TI - Reflections on attempted Anglo-Japanese collaboration on STAMPEDE: a randomized controlled trial for men with prostate cancer. PMID- 21615522 TI - An autopsy case of polymicrogyria and intracerebral calcification with death by intracerebral hemorrhage. PMID- 21615524 TI - Aphallia in an adult male with 46, XY karyotype. AB - Aphallia is a rare urogenital anomaly with an estimated incidence of 1 in 10-30 million. We report a case of aphallia in a male, who had two well-developed testicles, but lacked a penis. Digital rectal examination revealed the urethral meatus was opening to the anterior wall of the rectum posterior to the sphincter. Magnetic resonance imaging showed complete absence of penile development with normal testis and scrotum, as well as the urethra running posterior to the prostatic apex and corpus spongiosum in sagittal and coronal T2-weighted images. Chromosome karyotype confirmed 46,XY, and the polymerase chain reaction method tested no azoospermic factor (AZF) or sex-determining region Y (SRY) gene deletion. Taking into account the physical and psychosocial conditions, seeking a female without sexual desire as his wife was recommended. PMID- 21615526 TI - Visceral lesions occurring during follow-up of melanoma patients: a true place for other diagnosis than melanoma metastasis. AB - BACKGROUND: Diagnosis of melanoma metastasis is often based on a combination of clinical and radiological examinations in patients with a past history of melanoma. Chemotherapeutic treatment is often proposed without histological proof of the metastatic status. OBJECTIVE: The aim of this study was to investigate a cohort of melanoma patients with invasive diagnostic procedures (IDPs) for pathological confirmation of metastasis in case of suspicious visceral lesions. METHODS: A total of 109 melanoma patients with IDPs for suspicious visceral lesion(s) were included. Data about primary melanoma, IDPs characteristics, pathological result and therapeutic consequence were collected. Patients with AJCC Stage I-III melanoma at the time of the IDP were statistically analysed for various characteristics according to the final diagnosis yielded by the IDP. RESULTS: A total of 64 diagnostic surgical resections, 38 CT-guided core-needle biopsies, 15 ultrasound-guided core-needle biopsies, 6 surgical biopsies and 6 per-endoscopic biopsies were performed. Main target organs were the lungs (43.5%), breasts (8.5%) and liver (8%). IDPs were well tolerated and provided adequate samples for reliable diagnoses. Among the 105 IDPs in stage I-III patients, 56 melanoma metastases (53%), 25 benign lesions (24%) and 23 other cancers (22%) were found. One IDP was not informative. Multivariate analysis showed that nodular type of the primary melanoma, time-lag between primary melanoma and IDP over 12 months and the presence of suspicious lesions outside the organ biopsied were significantly associated with melanoma metastasis diagnosis. CONCLUSION: Suspected melanoma metastasis was ruled out for benign lesion or second cancer in nearly half of the stage I-III patients having undergone an IDP, therefore modifying the medical treatment. PMID- 21615527 TI - Presence of putative stem cells in Merkel cell carcinomas. PMID- 21615528 TI - Mucosal contact urticaria to sesame seeds. PMID- 21615529 TI - A case of lymphocutaneous sporotrichosis occurring at the nail bed. PMID- 21615530 TI - Tinea corporis in a psoriatic patient. PMID- 21615531 TI - In vitro antifungal evaluation and structure-activity relationship of diphenyl diselenide and synthetic analogues. AB - We report on in vitro antifungal activity and the structure-activity relationship of diphenyl diselenide [(PhSe)(2) ] and its synthetic analogues, (p-Cl-C(6) H(4) Se)(2), (m-CF(3)-C(6) H(4)Se)(2) and (p-CH(3)O-C(6) H(4)Se)(2), against 116 strains of pathogenic fungi. (PhSe)(2) showed the highest inhibitory activity against Candida albicans (minimum inhibitory concentration of 4-32 MUg ml(-1) ), Candida dubliniensis (2-16 MUg ml(-1)), Aspergillus spp. (0.5-64 MUg ml(-1)) and Fusarium spp. (2-16 MUg ml(-1)). Its minimum fungicidal concentration (MFC) varied among C. albicans (4-64 MUg ml(-1)), C. dubliniensis (2-32 MUg ml(-1) ) and Fusarium spp. (4-64 MUg ml(-1)). Antifungal activity was decreased by the introduction of functional groups to the (PhSe)(2) molecule: (PhSe)(2) >(p-CH(3)O C(6)H(4) Se)(2) >(m-CF(3)-C(6)H(4)Se)(2) >(p-Cl-C(6) H(4)Se)(2). PMID- 21615532 TI - Osteomyelitis due to Aspergillus species in chronic granulomatous disease: an update of the literature. AB - Chronic granulomatous disease (CGD) is a rare inherited disorder characterised by inability of phagocytes to kill catalase-positive organisms including certain fungi. Aspergillus species are the most frequent fungal pathogens. This study is a systematic review of the reported cases of osteomyelitis due to Aspergillus species in CGD patients. Retrospective analysis of 46 osteomyelitis cases caused by Aspergillus species in 43 CGD patients (three females) published in the English literature (PubMed) was performed. Twenty-three cases were due to Aspergillus fumigatus (50%), 20 to Aspergillus nidulans (43.5%), one to Aspergillus flavus and two to unspecified Aspergillus species. The median age was 8 years (range 1.5-21). Osteomyelitis due to A. nidulans was associated with pulmonary infection and involved 'small bones' more frequently than A. fumigatus osteomyelitis (P = 0.001). Amphotericin B was used in 91.3% and surgical debridement in 67.4% of all cases. The overall mortality of osteomyelitis due to Aspergillus species in CGD patients was 37%; 55% for A. nidulans compared to 13% for A. fumigatus (P = 0.008). Aspergillus fumigatus causes osteomyelitis in CGD patients almost as frequently as A. nidulans and much more frequently than A. flavus. Osteomyelitis due to A. nidulans is associated with higher mortality than A. fumigatus. PMID- 21615534 TI - A case of tinea barbae due to Trichophyton rubrum infection by autoinoculation from the infected fingernails. PMID- 21615533 TI - In vivo effect of three fractions of Larrea divaricata Cav. (jarilla) on the innate immune system: macrophage response against Candida albicans. AB - Larrea divaricata Cav. (jarilla) is a plant with well-documented applications in folk medicine in Argentina. In this study, we aimed to evaluate functional parameters of peritoneal macrophages isolated from mice injected with three fractions (F1, F2 and F3) of L. divaricata. The response of macrophages against Candida albicans was evaluated. Cell viability was assessed using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test, apoptosis was evaluated using Giemsa, acridine orange/ethidium bromide and ladder assay, oxidative burst was assayed using nitroblue tetrazolium test and nitrite production using Griess assay. Cell stimulation and their ability to kill C. albicans in vitro were measured. The number and cell viability were similar to controls. However, we found that F1 induces pre-activation of macrophages, and this pre-activation is enhanced by C. albicans. The effects exerted by F1 make it more important than F2 and F3 for the treatment of disseminated candidiasis in patients with immunodeficiency diseases such as AIDS and chronic granulomatous disease, among others. PMID- 21615535 TI - Cluster analysis of Microsporum canis isolated from a patient with tinea corporis and an infected cat based on the DNA sequences of nuclear ribosomal internal transcribed spacer 1. PMID- 21615536 TI - Case report: Trichophyton verrucosum infection after needlestick injury with an attenuated live vaccine against cattle ringworm. PMID- 21615537 TI - Prolonged half-life of voriconazole in a CYP2C19 homozygous poor metabolizer receiving vincristine chemotherapy: avoiding a serious adverse drug interaction. PMID- 21615538 TI - Optimising absorption of posaconazole. AB - Posaconazole, a triazole antifungal agent with proven efficacy for prophylaxis and treatment of fungal infections, is often limited by poor absorption. We report on five consecutive patients who received posaconazole along with a care bundle intended to increase absorption by addressing gastric pH, co administration with food, dividing doses and avoiding drug interactions. Each patient yielded multiple robust posaconazole serum concentrations. No patient experienced breakthrough fungal infection while receiving posaconazole. The posaconazole care bundle administered to oncology patients is feasible and may optimise posaconazole absorption. PMID- 21615539 TI - Persisting Paecilomyces lilacinus nail infection following pregnancy. PMID- 21615540 TI - Interdigital ulcer: an unusual presentation of Candida infection. AB - Interdigital ulcer is an exceptionally rare condition while erosio interdigitalis blastomycetica is common for candidiasis. Four Chinese patients with Candida interdigital ulcers were reported. The exudates were examined directly and cultured for fungi. Skin biopsies were stained with haematoxylin-eosin and periodic acid Schiff. There were a man and three women (age range: 34-56 years) who presented with 1- to 3-month history of chronic cutaneous ulcer on the interdigital web of hand or foot. The lesions were located on hand for one woman, and on the left foot for the rest. The patients had poor response to the previous treatment of topical steroids and oral antimicrobials. Candida albicans was isolated from a man and two women, Candida tropicalis from another woman. Biopsy specimens revealed yeast and mycelium as well as inflammatory infiltrate in necrotic tissue in two patients; only inflammatory cells in the other two. The patients had complete remission with oral itraconazole and topical bifonazole cream therapy for 3- to 5-week. Candida species may cause interdigital ulcer on hand or foot. Oral itraconazole and topical bifonazole may be an optional therapy for such an ulcer. PMID- 21615541 TI - Carbohydrate profiling of fungal cell wall surface glycoconjugates of Trichophyton tonsurans and other keratinophilic filamentous fungi using lectins. AB - Various researchers have concluded that lectins are useful reagents for the study of fungal cell wall surface glycoconjugates. In this study, we evaluated the expression of N-acetyl-D-glucosamine, L-fucose, D-galactose and glucose/mannose on the cell wall surface of Trichophyton tonsurans and other keratinophilic filamentous fungi, using a simple lectin-binding protocol. The fungal cultures used were isolated from soils obtained from public parks by the hair-bait technique. The lectin assays used concanavalin A (Con A), wheat germ agglutinin (WGA), Ulex europeus agglutinin I (UEA-I) and peanut agglutinin (PNA), all conjugated with horseradish peroxidase. Adhesive tape was placed sticky-side down over the fungal colony, gently pressed and then removed. The fungal-tape samples were incubated with the lectin for 1 h at 4 degrees C. Lectin binding was visualised using 3,3-diaminobendizine (DAB) and hydrogen peroxidase. There was a high expression of N-acetyl-D-glucosamine on the cell wall surface of all fungi species tested, whereas the expression of L-fucose, D-galactose and glucose/mannose demonstrated inter-specific variations. The lectin-binding assay presented in this article eliminates many of the laborious steps involved in other protocols. The amount and quality of the mycelium and spores immobilised by the adhesive tapes were suitable for obtaining the carbohydrate profile in glycoconjugates of the cell wall surface of filamentous fungi. PMID- 21615543 TI - Effect of licorice compounds licochalcone A, glabridin and glycyrrhizic acid on growth and virulence properties of Candida albicans. AB - Candida albicans is the predominant causal agent of candidiasis. Its ability to form hyphae and biofilm has been suggested to be key virulence factors. In this study, we investigated the effect of major licorice compounds licochalcone A, glabridin and glycyrrhizic acid on growth, biofilm formation and yeast-hyphal transition of C. albicans. The synergistic effect of licorice compounds with the antifungal drug nystatin was also evaluated. Minimal inhibitory concentrations (MICs) for C. albicans were determined using a microplate dilution assay. The synergistic effect with nystatin was determined similarly. The effect of licorice compounds on biofilm formation was evaluated using a microplate assay and crystal violet staining. The effect of licorice compounds on yeast-hyphal transition was determined by microscopic observation. The toxicity of licorice compounds towards oral epithelial cells was evaluated with an MTT assay. Glabridin and licochalcone A showed antifungal activity on C. albicans while glycyrrhizic acid had no effect. Complete growth inhibition occurred with sub-inhibitory concentrations of nystatin with either glabridin or licochalcone A. Biofilm formation was inhibited by 35-60% in the presence of licochalcone A (0.2 MUg ml(-1)). A strong inhibitory effect (>80%) on hyphal formation was observed with licochalcone A or glabridin (100 MUg ml(-1)). Glabridin and licochalcone A at high concentrations showed toxicity towards oral epithelial cells. In summary, glabridin and licochalcone A are potent antifungal agents and may act in synergy with nystatin to inhibit growth of C. albicans. Licochalcone A has a significant effect on biofilm formation, while both licochalcone A and glabridin prevented yeast-hyphal transition in C. albicans. These results suggest a therapeutic potential of licochalcone A and glabridin for C. albicans oral infections. PMID- 21615542 TI - Epidemiology and management of candidaemia--a retrospective, multicentre study in five hospitals in the UK. AB - Candidaemia is associated with high mortality. Despite the fact that Candida species account for close to 10% of all nosocomial bloodstream infections, relatively few studies have investigated the management of candidaemia in hospitals. Our objective was to find out how candidaemia is managed in hospitals. Data relating to all episodes of candidaemia for the year 2008 were retrospectively collected in five centres in Scotland and Wales. A total of 96 candidaemic episodes were recorded in the year 2008, yielding 103 isolates of Candida. Fifty candidaemic episodes were caused by Candida albicans. Fluconazole was the most common agent prescribed for the treatment of candidaemia. There was great variation in the prescribed dose of fluconazole. Forty per cent of patients who survived received <2 weeks of systemic antifungal therapy. Central venous catheters (CVC) were removed in 57% of patients. CVC removal was not associated with better survival. The overall mortality was 40.4%. Management of candidaemia varies between the UK centres and is often inadequate. There is need to have consensus on the dosages of antifungal agents and the duration of therapy. The current guidance on removal of CVC in all cases of candidaemia should be reviewed. PMID- 21615544 TI - Bamboo processing can damage your health: a case of obstructing bronchial aspergillosis in a bamboo worker. PMID- 21615545 TI - Recurrent vulvovaginal candidosis: focus on the vulva. AB - Recurrent vulvovaginal candidosis is a frequent disease with a serious impact on women's quality of life. Mostly, recurrences are caused by identical Candida strains suggesting C. albicans persistence in the female anogenital area. Objectives of the presented work were to identify the site of C. albicans persistence, to determine clinical symptoms and signs related to C. albicans positive vulvar cultures and to introduce a new therapeutic approach in women with RVVC. Women with an acute, culture-confirmed episode of RVVC at time of visit were included in this prospective case series. Swabs were obtained from both vagina and inter-labial sulcus. Women received a combined 20-day regimen of 100 mg oral fluconazole and ciclopiroxolamin cream topically. Follow-up visits were at 3, 6, 9 and 12 months. Of 139 women, 105 (76%) had at least one C. albicans positive culture from the external vulva. Vulvar positive cultures correlated with pruritus (OR 5.4; P < 0.001), vulvar edema (OR 3.8; P = 0.03) and fissures (OR 2.4; P = 0.03). Recurrence rates were 27%, 33% and 34% (at 6, 9, 12 months, respectively). The external vulva appears to represent a site of C. albicans persistence and source of endogenous re-infection in patients with RVVC. The combined treatment compared favorably with published fluconazole maintenance regimens. PMID- 21615546 TI - Three-dimensional ex vivo imaging and analysis of intraportal islet transplants. AB - In clinical islet transplantation, because the long-term insulin-independence rate is still poor, a method for detailed analysis of the transplanted islets in the liver after transplantation is required. We have established a novel imaging technique suitable for analysis of transplanted islets in liver using an optical projection tomography (OPT) method. A three-dimensional tomographic image of the transplanted islets in liver was reconstructed. The number of islets transplanted and the number of transplanted islets observed using OPT showed good correlation. The OPT method was used to compare the numbers of transplanted islets in mouse syngeneic and allogeneic transplantation models. Blood glucose concentrations of streptozotocin (STZ)-induced diabetic mice transplanted with syngeneic islets remained normoglycemic and the number of transplanted islets was largely preserved 11 days after transplantation. In mice transplanted with allogeneic islets, hyperglycemia recurred from 7 days after transplantation and the number and the volume of transplanted islets was significantly reduced 11 days after transplantation. These results indicate that OPT imaging and analysis may be a useful tool to quantitatively and sterically evaluation of transplanted islets in liver at the cellular level. PMID- 21615547 TI - The BH3-mimetic ABT-737 inhibits allogeneic immune responses. AB - Apoptosis controls the adaptive immune system through regulation of central and peripheral lymphocyte deletion. Therefore, substances that selectively interact with the intrinsic apoptosis pathway in lymphocytes offer unexplored opportunities to pharmacologically modulate the immune response. Here, we present evidence that the BH3-mimetic ABT-737 suppresses allogeneic immune responses. In vitro, ABT-737 prevented allogeneic T-cell activation, proliferation, and cytotoxicity by apoptosis induction, but without impairing the physiological functions of remaining viable T cells. In vivo, ABT-737 was highly selective for lymphoid cells and inhibited allogeneic T- and B-cell responses after skin transplantation. The immunosuppressive effect of ABT-737 was markedly increased in combination with low-dose cyclosporine A, as shown by the induction of long term skin graft survival without significant inflammatory infiltrates in 50% of the recipients in an MHC class I single antigen mismatched model. Thus, pharmacological targeting of Bcl-2 proteins represents a novel immunosuppressive approach to prevent rejection of solid organ allografts. PMID- 21615548 TI - Evidence-based development of liver allocation: a review. AB - Liver transplantation has undergone a rapid evolution from a high-risk experimental procedure to a mainstream therapy for thousands of patients with a wide range of hepatic diseases. Its increasing success has been accompanied by progressive imbalance between organ donor supply and the patients who might benefit. Where demand outstrips supply in transplantation, a system of organ allocation is inevitably required to make the wisest use of the available, but scarce, organs. Early attempts to rationally allocate donor livers were particularly hampered by lack of available and suitable data, leading to imperfect solutions that created or exacerbated inequities in the system. The advent and maturation of evidence-based predictors of waiting list mortality risk led to more objective criteria for liver allocation, aided by the increasing availability of data on large numbers of patients. Until now, the vast majority of allocation systems for liver transplantation have relied on estimation of waiting list mortality. Evidence-based allocation systems that incorporate measures of post-transplant outcomes are conceptually attractive and these transplant benefit-based allocation systems have been developed, modeled, and subjected to computer simulation. Future implementations of benefit-based liver allocation await continued refinement and additional debate in the transplant community. PMID- 21615549 TI - Comparison between observed survival after resection of transplantable hepatocellular carcinoma and predicted survival after listing through a Markov model simulation. AB - There is still some debate on whether hepatic resection or liver transplantation should be the initial treatment for hepatocellular carcinoma (HCC) in compensated cirrhosis. Clinical data and observed survivals of 150 transplantable patients (within Milan criteria) resected for HCC were reviewed and their predicted survival after listing for liver transplantation was calculated using a Markov model simulation. Differences between observed and predicted survival estimates were explored by standardized differences (d). The mean observed survival within 5 years after surgery was 45.35 months, and the predicted survival after listing was 49.18 months (d = 0.265). The largest gain in life-expectancy with liver transplantation would be obtained in patients with Model for End-stage Liver Disease (MELD) score >9 (d = 0.403); conversely, observed and predicted survivals were similar in HCV+ patients (d = -0.002) and in patients with MELD <=9 (d = 0.057). For T1 tumors, the observed mean estimate of survival after hepatic resection was higher than that predicted by the simulation (d = -0.606). In conclusion, in HCV patients and in those with very well compensated cirrhosis, hepatic resection could lead to results similar to those of transplantation strategy for HCC within Milan criteria; HCC T1 patients are probably best served by resection as first-line therapy rather than listing for transplantation. PMID- 21615550 TI - Surgical aspects and outcome of combined liver and kidney transplantation in children. AB - In children with renal insufficiency and accompanying or underlying liver disease, combined liver and kidney transplantations (CLKT) are indicated. However, because of the rare indications, the number of paediatric CLKT is low. Our aim was to analyse CLKT in children with special regard to surgical aspects and outcome. All paediatric CLKT performed at our institution between 1998 and 2009 were retrospectively analysed. Between 1998 and 2009, 15 CLKT were performed in 14 paediatric patients (median age 8 years, range 1-16 years). The indications for CLKT were autosomal recessive polycystic kidney disease (n = 7), primary hyperoxaluria type 1 (n = 7) and retransplantation because of primary liver nonfunction (n = 1). In the postoperative course, six patients showed bleeding complications, thereof three patients needed operative revision for intra abdominal bleeding. Eight of 15 patients (53%) needed dialysis. The 1- and 5-year patient survival was 100%; and 1- and 5-year graft survival was 80% for the liver and 93% for the kidney allograft. A number of different complications, especially secondary haemorrhage have to be anticipated after CLKT, requiring a timely and interdisciplinary treatment approach. With this management, our patients showed an excellent graft and patient survival. PMID- 21615551 TI - A Bnr-like formin links actin to the spindle pole body during sporulation in the filamentous fungus Ashbya gossypii. AB - Formin proteins are nucleators of actin filaments and regulators of the microtubule cytoskeleton. As such, they play important roles in the development of yeast and other fungi. We show here that AgBnr2, a homologue of the ScBnr1 formin from the filamentous fungus Ashbya gossypii, localizes to the spindle pole body (SPB), the fungal analogue of the centrosome of metazoans. This protein plays an important role in the development of the typical needle-shaped spores of A. gossypii, as suggested by several findings. First, downregulation of AgBNR2 causes defects in sporangium formation and a decrease in the total spore number. Second, a fusion of AgBNR2 to GFP that is driven by the native AgBNR2 promoter is only visible in sporangia. Third, AgBnr2 interacts with a AgSpo21, a sporulation specific component of the SPB. Furthermore, we provide evidence that AgBnr2 might nucleate actin cables, which are connected to SPBs during sporulation. Our findings add to our understanding of fungal sporulation, particularly the formation of spores with a complex, elongated morphology, and provide novel insights into formin function. PMID- 21615553 TI - Comparison of symptom response following advice for a diet low in fermentable carbohydrates (FODMAPs) versus standard dietary advice in patients with irritable bowel syndrome. AB - BACKGROUND: Emerging evidence indicates that the consumption of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) may result in symptoms in some patients with irritable bowel syndrome (IBS). The present study aimed to determine whether a low FODMAP diet is effective for symptom control in patients with IBS and to compare its effects with those of standard dietary advice based on the UK National Institute for Health and Clinical Excellence (NICE) guidelines. METHODS: Consecutive patients with IBS who attended a follow-up dietetic outpatient visit for dietary management of their symptoms were included. Questionnaires were completed for patients who received standard (n = 39) or low FODMAP dietary advice (n = 43). Data were recorded on symptom change and comparisons were made between groups. RESULTS: In total, more patients in the low FODMAP group reported satisfaction with their symptom response (76%) compared to the standard group (54%, P = 0.038). Composite symptom score data showed better overall symptom response in the low FODMAP group (86%) compared to the standard group (49%, P < 0.001). Significantly more patients in the low FODMAP group compared to the standard group reported improvements in bloating (low FODMAP 82% versus standard 49%, P = 0.002), abdominal pain (low FODMAP 85% versus standard 61%, P = 0.023) and flatulence (low FODMAP 87% versus standard 50%, P = 0.001). CONCLUSIONS: A low FODMAP diet appears to be more effective than standard dietary advice for symptom control in IBS. PMID- 21615554 TI - Agreement between child and parent reports of 10- to 12-year-old children's meal pattern and intake of snack foods. AB - BACKGROUND: Dietary assessment in children is associated with misreporting, which is a problem with both child and parent reports. Therefore, it is of interest to study how children and parents report children's eating, respectively, although comparative studies are rare. The aim of the present article was to study the meal patterns and intake of certain snack foods of 10- to 12-year-old children as reported by the children and their parents, respectively, and to determine whether there was agreement between the child and parent reports. An additional aim was to study what factors might influence rater agreement. METHODS: School children aged 10-12years and their parents were given parallel questionnaires regarding the children's meal pattern. Matched pairs (n=147) were analysed for agreement. Descriptive statistics were used to study all variables. Rater agreement and whether agreement depends on the age and the sex of the child, the sex of the parent and household type were analysed using ordinal regression models. Correlations between the child and parent assessments were estimated as polychoric correlations. RESULTS: There was a general agreement between child and parent reports, except with respect to sweets and chocolate, where children reported less frequent consumption than the parents did (P= 0.0001). The sex of the child was a significant factor regarding consumption of in-between meals (P=0.0001) and soft drinks (P=0.01). Most children had breakfast, school lunch and dinner every day, whereas it was less common to report daily consumption of in-between meals. CONCLUSIONS: There was a general agreement between children's and parents' reports, and most children were reported to have a regular meal pattern. PMID- 21615552 TI - Interactions among Trypanosoma brucei RAD51 paralogues in DNA repair and antigenic variation. AB - Homologous recombination in Trypanosoma brucei is used for moving variant surface glycoprotein (VSG) genes into expression sites during immune evasion by antigenic variation. A major route for such VSG switching is gene conversion reactions in which RAD51, a universally conserved recombinase, catalyses homology-directed strand exchange. In any eukaryote, RAD51-directed strand exchange in vivo is mediated by further factors, including RAD51-related proteins termed Rad51 paralogues. These appear to be ubiquitously conserved, although their detailed roles in recombination remain unclear. In T. brucei, four putative RAD51 paralogue genes have been identified by sequence homology. Here we show that all four RAD51 paralogues act in DNA repair, recombination and RAD51 subnuclear dynamics, though not equivalently, while mutation of only one RAD51 paralogue gene significantly impedes VSG switching. We also show that the T. brucei RAD51 paralogues interact, and that the complexes they form may explain the distinct phenotypes of the mutants as well as observed expression interdependency. Finally, we document the Rad51 paralogues that are encoded by a wide range of protists, demonstrating that the Rad51 paralogue repertoire in T. brucei is unusually large among microbial eukaryotes and that one member of the protein family corresponds with a key, conserved eukaryotic Rad51 paralogue. PMID- 21615555 TI - Impact of coeliac disease on dietary habits and quality of life. AB - BACKGROUND: Coeliac disease (CD) affects approximately 1% of the population in the UK and is managed by the life-long adherence to a strict gluten-free diet (GFD). Adhering to a GFD is practically difficult and not only affects dietary patterns, but also can affect many other aspects of daily life. The present study aimed to investigate the effect of CD and a GFD on dietary habits and quality of life of a cohort of adult biopsy diagnosed coeliac patients who reside in England. METHODS: The cohort was composed of 146 adult biopsy-diagnosed CD patients, who were all members of the Coeliac UK charity. Participants responded to a self-administered questionnaire considering dietary habits and quality of life. A food frequency questionnaire (FFQ) was used to assess dietary compliance. RESULTS: Generally, English CD patients reported to be in good physical and emotional health, although there were reports of anxiety and depression as a result of CD, most likely as a result of exclusion from social and leisure activities. The cohort reported high levels of dietary compliance (96%) which was supported by FFQ responses. However, there were reports of intentional gluten intake during social situations and when eating take-away foods. The FFQ revealed further examples of gluten ingestion, presumably unintentional, particularly through the consumption of breakfast cereals and starch-based sauces such as cheese sauce, custard and ketchup. CONCLUSIONS: The present study revealed that CD affects a wide range of daily activities and that gluten consumption may be more common than anticipated with possible consequences on health. PMID- 21615556 TI - The development of multisensory speech perception continues into the late childhood years. AB - Observing a speaker's articulations substantially improves the intelligibility of spoken speech, especially under noisy listening conditions. This multisensory integration of speech inputs is crucial to effective communication. Appropriate development of this ability has major implications for children in classroom and social settings, and deficits in it have been linked to a number of neurodevelopmental disorders, especially autism. It is clear from structural imaging studies that there is a prolonged maturational course within regions of the perisylvian cortex that persists into late childhood, and these regions have been firmly established as being crucial to speech and language functions. Given this protracted maturational timeframe, we reasoned that multisensory speech processing might well show a similarly protracted developmental course. Previous work in adults has shown that audiovisual enhancement in word recognition is most apparent within a restricted range of signal-to-noise ratios (SNRs). Here, we investigated when these properties emerge during childhood by testing multisensory speech recognition abilities in typically developing children aged between 5 and 14 years, and comparing them with those of adults. By parametrically varying SNRs, we found that children benefited significantly less from observing visual articulations, displaying considerably less audiovisual enhancement. The findings suggest that improvement in the ability to recognize speech-in-noise and in audiovisual integration during speech perception continues quite late into the childhood years. The implication is that a considerable amount of multisensory learning remains to be achieved during the later schooling years, and that explicit efforts to accommodate this learning may well be warranted. PMID- 21615557 TI - Chondroitin sulfate proteoglycans regulate astrocyte-dependent synaptogenesis and modulate synaptic activity in primary embryonic hippocampal neurons. AB - It has been shown that astrocyte-derived extracellular matrix (ECM) is important for formation and maintenance of CNS synapses. In order to study the effects of glial-derived ECM on synaptogenesis, E18 rat hippocampal neurons and primary astrocytes were co-cultivated using a cell-insert system. Under these conditions, neurons differentiated under low density conditions (3500 cells/cm(2) ) in defined, serum-free medium and in the absence of direct, membrane-mediated neuron astrocyte interactions. Astrocytes promoted the formation of structurally intact synapses, as documented by the co-localisation of bassoon- and ProSAP1/Shank2 positive puncta, markers of the pre- and postsynapse, respectively. The development of synapses was paralleled by the emergence of perineuronal net (PNN) like structures that contained various ECM components such as hyaluronic acid, brevican and neurocan. In order to assess potential functions for synaptogenesis, the ECM was removed by treatment with hyaluronidase or chondroitinase ABC. Both enzymes significantly enhanced the number of synaptic puncta. Whole-cell voltage clamp recordings of control and enzyme-treated hippocampal neurons revealed that chondroitinase ABC treatment led to a significant decrease in amplitude and a reduced charge of miniature excitatory postsynaptic currents, whereas inhibitory postsynaptic currents were not affected. When the response to the application of glutamate was measured, a reduced sensitivity could be detected and resulted in decreased currents in response to the excitatory neurotransmitter. These findings are consistent with the interpretation that the ECM partakes in the regulation of the density of glutamate receptors in subsynaptic sites. PMID- 21615558 TI - Induction and expression of abnormal involuntary movements is related to the duration of dopaminergic stimulation in 6-OHDA-lesioned rats. AB - Dyskinesia induction in Parkinson's disease (PD) appears less marked with long acting dopamine agonists than with short-acting L-Dopa, but the relationship to duration of drug action is unknown. It is also unclear whether the duration of drug action affects the expression of established dyskinesia. This study compared the ability of L-Dopa and four dopamine agonists of different duration of action to induce abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA) lesioned rats, and their ability to express established AIMs following prior exposure to L-Dopa. 6-OHDA-lesioned rats were treated with saline, L Dopa/benserazide, apomorphine, ropinirole, pramipexole or pergolide once daily for 15 days. Repeated administration of the short-acting dopamine agonists, apomorphine (duration 80 min) and ropinirole (duration 90 min) induced marked axial, limb and orolingual AIMs at peak effect. L-Dopa (duration 100 min) produced moderate AIMs at peak effect, while administration of the long-acting dopamine agonists, pramipexole (duration 150 min) and pergolide (duration 240 min) resulted in mild AIMs. In rats primed to exhibit severe AIMs following repeated L-Dopa administration, acute administration of apomorphine, ropinirole and L-Dopa induced severe AIMs. By contrast, pramipexole and pergolide evoked only mild-moderate AIMs. Again, there was a negative correlation between duration of effect and the severity of AIMs expressed. These studies show that both the induction and expression of AIMs in 6-OHDA-lesioned rats are related to the duration of action of dopaminergic drugs. These findings suggest that continuous dopaminergic stimulation could be used both to avoid dyskinesia induction and to improve motor function in late-stage PD when troublesome dyskinesia is evident. PMID- 21615560 TI - Matrix metalloproteinase inhibition counteracts impairment of cortical experience dependent plasticity after photothrombotic stroke. AB - Matrix metalloproteinases (MMPs) are fine modulators of brain plasticity and pathophysiology. The inhibition of MMPs shortly after ischaemic stroke reduces the infarct size and has beneficial effects on post-stroke behavioural recovery. Our previous studies have shown that photothrombotic cortical stroke disrupts use dependent plasticity in the neighbouring cortex. The aim of the present study was to check whether the inhibition of MMPs after photothrombosis rescued the plastic capacity of the barrel cortex. To induce plasticity in adult mice, a unilateral deprivation of all vibrissae except row C was applied. The deprivation started immediately after stroke and lasted 7 days. This procedure, in control (non stroke) animals, results in an enlargement of functional representation of the spared row, as shown with [(14)C]2-deoxyglucose uptake mapping. In mice with stroke induced by photothrombosis in the vicinity of the barrel cortex, vibrissae deprivation did not result in an enlargement of the cortical representation of the spared row C of vibrissae, which confirmed our previous results. However, when mice were injected with the broad-spectrum inhibitor of MMPs FN-439 (10 mg/kg, i.v.) immediately before a stroke, an enlargement of the representation of the spared row similar to the enlargement found in sham mice was observed. These results indicate the involvement of MMPs in the impairment of use-dependent plasticity in the vicinity of an ischaemic lesion. PMID- 21615559 TI - Activation of alpha-2 noradrenergic receptors is critical for the generation of fictive eupnea and fictive gasping inspiratory activities in mammals in vitro. AB - Biogenic amines are not just 'modulators', they are often essential for the execution of behaviors. Here, we explored the role of biogenic amines acting on the pre-Botzinger complex (pre-BotC), an area located in the ventrolateral medulla which is critical for the generation of different forms of breathing. Isolated in transverse slices from mice, this region continues to spontaneously generate rhythmic activities that resemble normal (eupneic) inspiratory activity in normoxia and gasping in hypoxia. We refer to these as 'fictive eupneic' and 'fictive gasping' activity. When exposed to hypoxia, the pre-BotC transitions from a network state relying on calcium-activated nonspecific cation currents (I(CAN)) and persistent sodium currents (I(Nap)) to one that primarily depends on the I(Nap) current. Here we show that in inspiratory neurons I(Nap)-dependent bursting, blocked by riluzole, but not I(CAN) -dependent bursting, required endogenously released norepinephrine acting on alpha2-noradrenergic receptors (alpha2-NR). At the network level, fictive eupneic activity persisted while fictive gasping ceased following the blockade of alpha2-NR. Blockade of alpha2-NR eliminated fictive gasping even in slice preparations as well as in inspiratory island preparations. Blockade of fictive gasping by alpha2-NR antagonists was prevented by activation of 5-hydroxytryptamine type 2A receptors (5-HT2A). Our data suggest that gasping depends on the converging aminergic activation of 5 HT2AR and alpha2-NR acting on riluzole-sensitive mechanisms that have been shown to be crucial for gasping. PMID- 21615562 TI - Instability of spatial encoding by CA1 hippocampal place cells after peripheral nerve injury. AB - Several authors have shown that the hippocampus responds to painful stimulation and suggested that prolonged painful conditions could lead to abnormal hippocampal functioning. The aim of the present study was to evaluate whether the induction of persistent peripheral neuropathic pain would affect basic hippocampal processing such as the spatial encoding performed by CA1 place cells. These place cells fire preferentially in a certain spatial position in the environment, and this spatial mapping remains stable across multiple experimental sessions even when the animal is removed from the testing environment. To address the effect of prolonged pain on the stability of place cell encoding, we chronically implanted arrays of electrodes in the CA1 hippocampal region of adult rats and recorded the multichannel neuronal activity during a simple food reinforced alternation task in a U-shaped runway. The activity of place cells was followed over a 3-week period before and after the establishment of an animal model of neuropathy, spared nerve injury. Our results show that the nerve injury increased the number of place fields encoded per cell and the mapping size of the place fields. In addition, there was an increase in in-field coherence while the amount of spatial information content that a single spike conveyed about the animal location decreased over time. Other measures of spatial tuning (in-field firing rate, firing peak and number of spikes) were unchanged between the experimental groups. These results demonstrate that the functioning of spatial place cells is altered during neuropathic pain conditions. PMID- 21615561 TI - Enhanced role of adenosine A(2A) receptors in the modulation of LTP in the rat hippocampus upon ageing. AB - Adenosine neuromodulation depends on a balanced activation of inhibitory A1 (A1R) and facilitatory A(2A) receptors (A(2A) R). Both A1 R and A(2A) R modulate hippocampal glutamate release and NMDA-dependent long-term potentiation (LTP) but ageing affects the density of both A1 R and A(2A) R. We tested the effects of selective A1 R and A(2A) R antagonists in the modulation of synaptic transmission and plasticity in rat hippocampal slices from three age groups (young adults, 2-3 month; middle-aged adults, 6-8 months; aged, 18-20 months). The selective A(2A) R antagonist SCH58261 (50 nm) attenuated LTP in all age groups, with a larger effect in aged (-63 +/- 7%) than in middle-aged adults (-36 +/- 9%) or young adult rats (-36 +/- 9%). In contrast, the selective A1 R antagonist DPCPX (50 nm) increased LTP magnitude in young adult rats (+42 +/- 6%), but failed to affect LTP magnitude in the other age groups. Finally, in the continuous presence of DPCPX, SCH58261 caused a significantly larger inhibition of LTP amplitude in aged (-71 +/- 45%) than middle-aged (-28 +/-9%) or young rats (-11 +/- 2%). Accordingly, aged rats displayed an increased expression of A(2A) R mRNA in the hippocampus and a higher number of glutamatergic nerve terminals equipped with A(2A) R in aged (67 +/- 6%) compared with middle-aged (34 +/- 7%) and young rats (25 +/- 5%). The results show an enhanced A(2A) R-mediated modulation of LTP in aged rats, in accordance with the age-associated increased expression and density of A(2A) R in glutamatergic terminals. This age-associated gain of function of A(2A) R modulating synaptic plasticity may underlie the ability of A(2A) R antagonists to prevent memory dysfunction in aged animals. PMID- 21615563 TI - Mechanisms of glucocorticoids in the control of neuroinflammation. AB - Glucocorticoids (GCs) are widely used to treat inflammatory diseases such as multiple sclerosis (MS). They predominantly act through the GC receptor, a member of the nuclear receptor superfamily that controls transcription by several different mechanisms. Owing to its ubiquitous expression, there are a variety of cell types that could serve as GC targets in the pathogenesis and treatment of MS. This brings about a great diversity of mechanisms potentially involved in the modulation of neuroinflammation by GCs, including the induction of apoptosis, repression of pro-inflammatory mediators and the expansion of myeloid-derived suppressor cells. Nevertheless, it is not well understood which of these mechanisms are essential for therapeutic efficacy. In this review, we summarise findings made concerning the actions of GCs in MS and its animal model experimental autoimmune encephalomyelitis, and also elucidate current concepts and developments that pertain to this clinically highly relevant treatment regimen. PMID- 21615564 TI - Effect of ultrasound transmission gel on ultrasound-guided fine needle aspiration cytological specimens of thyroid. AB - OBJECTIVE: To investigate prospectively the diagnostic impact of ultrasound coupling gel on thyroid specimens obtained under ultrasound guidance. METHODS: Patients presenting for ultrasound-guided fine needle aspiration (USG-FNA) of the thyroid were invited to participate in the study. Four specimens per nodule were collected: two using chlorhexdine wash and two using sterile, colourless ultrasound gel as couplant according to routine protocol. All slides were analysed in a blinded fashion by two senior cytologists for the presence or absence of ultrasound gel-induced artefacts. The presence of gel-induced artefacts between the two groups was analyzed using Pearson's chi-square test. Kappa statistics were used to measure the inter-rater agreement between the cytologists. RESULTS: Twenty thyroid nodules comprising 80 specimen slides were collected. On slides collected with gel, cytological artefacts were detected in 60-65% of cases compared with 10-15% of cases without gel (P<0.001). The inter rater agreement between the two observers was very good (kappa=0.84). Two of the 14 patients required repeat FNA due to non-diagnostic cytology results caused by inadequate sampling and gel-induced artefacts. CONCLUSIONS: Clinical cytopathologists, radiologists and sonographers should be aware of the potential for ultrasound gel to cause significant artefacts on cytological specimens. Our findings suggest that staff involved in USG-FNA cytology should remove the gel carefully before taking the aspirate. PMID- 21615565 TI - Tissue rinse liquid-based cytology: a feasible tool for the intraoperative pathological evaluation of sentinel lymph nodes in breast cancer patients. AB - OBJECTIVES: A unique diagnostic method was designed for the intraoperative pathological evaluation of sentinel lymph nodes (SLNs) in breast cancer patients, and the results were verified with 2 years of experience. METHODS: Excised lymph nodes were cut into 2-mm-thick slices and rinsed thoroughly in CytoRich Red((r)). The sliced tissues were embedded in a paraffin block. Three cytological glass slides of the cells exfoliated in CytoRich Red((r)) were prepared by the SurePath((r)) liquid-based cytology (LBC) technique. Two slides were stained by the Papanicolaou method, and the remaining slide was immunostained with an anti keratin antibody. This process is called tissue rinse liquid-based cytology (TRLBC). The results of TRLBC were compared with those of the final pathological diagnoses, including immunostaining with an anti-keratin antibody on paraffin blocks (PB). RESULTS: This study analysed 444 SLNs from 247 consecutive breast cancer patients. It required 35 minutes to complete the intraoperative diagnosis on a single node, and it took an additional 5 minutes per node if more than one node was submitted. When the results of PB were assumed to be the gold standard, the sensitivity and specificity of TRLBC were 81.9% and 96.1%, respectively. TRLBC detected all nodes with macrometastasis and 23 of 24 nodes with micrometastasis. Fifteen false-negative TRLBC results were 'isolated tumour cell clusters' on PB, but there was one with micrometastasis histologically. Four of 14 false-positive TRLBC results were proven to be true positive by supplementary examination using step sectioning of the paraffin blocks of the nodes. CONCLUSION: TRLBC is a feasible and promising intraoperative cytopathological tool showing a comparable efficacy to PB while still allowing the conventional postoperative histological examination. PMID- 21615566 TI - Co-existent of tuberculosis and squamous cell carcinoma in a lymph node diagnosed by fine needle aspiration cytology. PMID- 21615567 TI - Fine needle aspiration biopsy of three cases of squamous cell carcinoma presenting as a thyroid mass: cytological findings and differential diagnosis. The differential diagnosis includes CASTLE. PMID- 21615569 TI - OsSGO1 maintains synaptonemal complex stabilization in addition to protecting centromeric cohesion during rice meiosis. AB - Shugoshin is a conserved protein in eukaryotes that protects the centromeric cohesin of sister chromatids from cleavage by separase during meiosis. In this study, we identify the rice (Oryza sativa, 2n=2x=24) homolog of ZmSGO1 in maize (Zea mays), named OsSGO1. During both mitosis and meiosis, OsSGO1 is recruited from nucleoli onto centromeres at the onset of prophase. In the Tos17-insertional Ossgo1-1 mutant, centromeres of sister chromatids separate precociously from each other from metaphase I, which causes unequal chromosome segregation during meiosis II. Moreover, the release of OsSGO1 from nucleoli is completely blocked in Ossgo1-1, which leads to the absence of OsSGO1 in centromeric regions after the onset of mitosis and meiosis. Furthermore, the timely assembly and maintenance of synaptonemal complexes during early prophase I are affected in Ossgo1 mutants. Finally, we found that the centromeric localization of OsSGO1 depends on OsAM1, not other meiotic proteins such as OsREC8, PAIR2, OsMER3, or ZEP1. PMID- 21615570 TI - Cofactome analyses reveal enhanced flux of carbon into oil for potential biofuel production. AB - To identify the underlying molecular basis of carbon partitioning between starch and oil we conducted 454 pyrosequencing, followed by custom microarrays to profile gene expression throughout endosperm development, of two closely related oat cultivars that differ in oil content at the expense of starch as determined by several approaches including non-invasive magnetic resonance imaging. Comparative transcriptome analysis in conjunction with metabolic profiling displays a close coordination between energy metabolism and carbon partitioning pathways, with increased demands for energy and reducing equivalents in kernels with a higher oil content. These studies further expand the repertoire of networks regulating carbon partitioning to those involved in metabolism of cofactors, suggesting that an elevated supply of cofactors, here called cofactomes, contribute to the allocation of higher carbon pools for production of oils and storage proteins. These data highlight a close association between cofactomes and carbon partitioning, thereby providing a biotechnological target for conversion of starch to oil. PMID- 21615572 TI - 'High-tech' home care: overview of professional care in patients on home parenteral nutrition and implications for nursing care. AB - AIM: The aim of this study is to describe the quality, quantity and content of care given to home parenteral nutrition-dependent patients by various professionals in the Netherlands and to detect potential shortcomings. BACKGROUND: Home parenteral nutrition is a lifesaving treatment for patients who cannot eat or cannot eat sufficiently. Very little is known about follow-up care after hospital stay. Yet this is an important aspect of care as patients must cope with high-tech skills at home. Also, complications and psychosocial complaints can occur. DESIGN: Survey. METHODS: A patient questionnaire was used to assess contacts with professionals and possible shortcomings in care. Nursing files from home parenteral nutrition nurses were reviewed for information from all contact moments. Home parenteral nutrition nurses and home care teams were interviewed to assess nursing care and to detect bottlenecks. RESULTS: The nutrition support team was primarily responsible for the home parenteral nutrition care. Physical complaints like abdominal pain or nausea and venous access problems like fever were discussed most often. Patients were satisfied about the nutrition support team, but both the patients and the home parenteral nutrition nurses reported that relatively little attention was paid to psychosocial problems. Furthermore, the included patients visited their General Practitioner 11 times per year on average (range 1-104). Patients experienced a bottleneck with respect to the general practitioner's knowledge of home parenteral nutrition-related matters. CONCLUSION: Home parenteral nutrition patients visit the nutrition support team and their general practitioner most frequently and much attention is paid to medical and physical problems. Psychosocial problems, however, were only discussed in a minority of patients, and this was experienced as a shortcoming. Relevance to clinical practice. Both the patients and the home parenteral nutrition nurses reported that relatively little attention was paid to psychosocial problems. Patients' concerns must be integrated in contact moments to enhance Quality of Life. PMID- 21615571 TI - CBP60g and SARD1 play partially redundant critical roles in salicylic acid signaling. AB - Arabidopsis thaliana calmodulin binding protein 60g (CBP60g) contributes to production of salicylic acid (SA) in response to recognition of microbe associated molecular patterns (MAMPs) such as flg22, a fragment of bacterial flagellin. Calmodulin binding is required for the function of CBP60g in limiting growth of the bacterial pathogen Pseudomonas syringae pv. maculicola (Pma) ES4326 and activation of SA synthesis. Here, we describe a closely related protein, SARD1. Unlike CBP60g, SARD1 does not bind calmodulin. Growth of Pma ES4326 is enhanced in sard1 mutants. In cbp60g sard1 double mutants, growth of Pma ES4326 is greatly enhanced, and SA levels and expression of PR-1 and SID2 are dramatically reduced. Expression profiling placed the CBP60g/SARD1 node between the PAD4/EDS1 and SA nodes in the defense signaling network, and indicated that CBP60g and SARD1 affect defense responses in addition to SA production. A DNA motif bound by CBP60g and SARD1, GAAATTT, was significantly over-represented in promoters of CBP60g/SARD1-dependent genes, suggesting that expression of these genes is modulated by CBP60g/SARD1 binding. Gene expression patterns showed a stronger effect of cbp60g mutations soon after activation of a defense response, and a stronger effect of sard1 mutations at later times. The results are consistent with a model in which CBP60g and SARD1 comprise a partially redundant protein pair that is required for activation of SA production as well as other defense responses, with CBP60g playing a more important role early during the defense response, and SARD1 to playing a more important role later. PMID- 21615573 TI - Predictors of exercise frequency in breast cancer survivors in Taiwan. AB - AIM: To apply social cognitive theory to elucidate factors that motivate change in exercise frequency in breast cancer survivors during the six months after completing cancer treatment. BACKGROUND: Exercise is now a well-recognised quality-of-life intervention in breast cancer survivors. However, only regular exercise yields long-term benefits. Motivations for exercise have not been analysed in Taiwan patients with cancer. DESIGN: A prospective, longitudinal and repeated measures design was used. METHODS: A convenience sample of 196 breast cancer survivors was recruited from hospitals in metropolitan areas of north and south Taiwan. Study participants were allowed to select their preferred exercised activities. Exercise behaviour and other factors were then recorded using various standardised instruments. Medical charts were also reviewed. Data were analysed by a linear mixed model and by hierarchical multiple regression equations. RESULTS: Exercise frequency significantly changed over time. Explained variance in exercise frequency change was modest. Baseline exercise frequency was the best significant predictor of exercise frequency during the six-month study. The study also identified possible age-related differences in the effect of social support on exercise. The effect of social support for exercise on exercise frequency was apparently larger in older subjects, especially those over 40 years old, than in younger subjects. Mental health, exercise barriers and exercise outcome expectancy significantly contributed to change in exercise frequency during the six-month study. CONCLUSIONS: The analytical results revealed several ways to increase exercise frequency in breast cancer survivors: (1) encourage exercise as early as possible; (2) improve health status and provide social support for exercise, especially in women aged 40 years or older; (3) reduce exercise barriers and promote mental health; (4) reinforce self-efficacy and positive expectations of exercise outcomes and (5) provide strategies for minimising fatigue in early stages of rehabilitation. Relevance to clinical practice. Social cognitive theory provides a useful framework for understanding the motivation to exercise in breast cancer survivors. PMID- 21615574 TI - Reliability and validity of a Chinese version of the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF-C). AB - AIM AND OBJECTIVES: To examine the psychometric properties of the Chinese version of the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF-C) for use in Chinese-speaking countries. BACKGROUND: The assessment of fatigue is a challenging task for most researchers because culture may influence perceptions of meaning of fatigue. The lack of examination of the psychometric properties of the fatigue measures across studies limits the scientific rigour for generating additional research on the concept of 'fatigue.' DESIGN: A cross-sectional study. METHODS: The study recruited 107 cancer inpatients from two medical centres in Taiwan. The MFSI-SF-C was examined using a two step process: (1) Translation and back-translation of the instrument; and (2) Examination of internal consistency reliability, test-retest reliability, content validity and construct validity. RESULTS: The results showed that the Cronbach's alpha of MFSI-SF-C total scale and subscales ranged between 0.83-0.92. The content validity index was 0.93. The difference between the fatigue of cancer patients and the comparison group of healthy people in the community was significant. The results demonstrated good convergent validity when comparing fatigue with depression and quality of life. Factor analysis confirmed the four dimensions of fatigue: physical, emotional, mental and vigour. It showed moderate intercorrelation between subscales and high factor loadings also helped to clarify the psychometric meaning. CONCLUSIONS: The reliability and validity information presented in this article support the use of the Chinese version of the MFSI-SF as a research instrument for measuring fatigue in Chinese populations. This study also provides evidence that the MFSI-SF possesses robust psychometric properties. RELEVANCE TO CLINICAL PRACTICE: The MFSI-SF-C is an effective and comprehensive tool for measuring fatigue in Chinese patients with cancer. PMID- 21615575 TI - Nurses' knowledge of heart failure education principles survey: a psychometric study. AB - AIMS: To compare the psychometric properties of the original dichotomously scored Nurses' Knowledge of Heart Failure Self-Management Education Principles Survey with a Likert scored version. BACKGROUND: Nurses must be knowledgeable of HF self management principles to provide optimal education to patients. Psychometrically strong instruments to measure nurses' knowledge of HF self-management provide important insight into gaps of nurses' knowledge. DESIGN: This psychometric study had a two phase non-experimental design comparing the psychometric characteristics of two versions of an existing survey in addition to test-retest reliability of the revised survey. METHODS: A convenience sample of 122 nurses was recruited from a healthcare system located in the Southeastern USA. Data were collected from August 2006 through December 2006. Nurses completed the two versions of the survey. RESULTS: The sample was predominantly Caucasian (76%), female (95%) with a mean age of 42 years (SD 11.4). Internal consistency reliability was 0.27 for the dichotomously scored version of the survey and 0.70 for the Likert scored version. The test-retest reliability of the Likert scored survey was r = 0.66. Data from individual Likert scored items indicated nurses were most knowledgeable about the need to continue daily weights even after HF symptoms are gone (mean = 4.43, SD 0.51) and least knowledgeable about how to advise asymptomatic patients to manage a low BP reading (mean = 2.11, SD 0.98). CONCLUSION: The Likert scored version of the Nurses' Knowledge of Heart Failure Self-Management Principles Survey was stronger psychometrically than the dichotomously scored version. RELEVANCE TO CLINICAL PRACTICE: Teaching HF self management skills to patients is challenging and it is important to identify nurses' gaps in knowledge of self-management principles. The psychometrically sound Likert scored version of the survey potentially may be used to identify nurses' knowledge gaps and inform staff development in-services. PMID- 21615576 TI - A pain education programme to improve patient satisfaction with cancer pain management: a randomised control trial. AB - AIM: The purpose of this study was (1) to evaluate the effectiveness of a pain education programme to increase the satisfaction of patients with cancer with regard to pain management and (2) to examine how patient satisfaction with pain management mediates the barriers to using analgesics and analgesic adherence. BACKGROUND: The patients' satisfaction with pain management is not merely an indicator, it is actually a contributor to medication adherence. However, very few studies investigate methods for improving patient satisfaction with pain management. DESIGN: This study used an experimental and longitudinal design. METHODS: A total of 61 patient-family pairs (n = 122) were randomly assigned to either experimental or control groups. The instruments included the American Pain Society outcome questionnaire, the Barriers Questionnaire-Taiwan form, self reporting evaluations of analgesic adherence and the Pain Education Booklet. The experimental group (n = 31) participated in a pain education programme, while those in the control group (n = 30) did not. The two groups were compared using generalised estimation equations after the second and fourth weeks. A Sobel test was used to examine the mediating relationships among patient satisfaction with pain management, barriers to using analgesics and analgesic adherence. RESULTS: The experimental group showed a significant improvement in the level of satisfaction they felt for physicians and nurses regarding pain management. For those in the experimental group, satisfaction with pain management was a significant mediator between barriers to using analgesics and analgesic adherence. CONCLUSIONS: This research provides evidence supporting the effectiveness of a pain education programme for patients and their family members in increasing patient satisfaction with regard to the management of cancer pain. RELEVANCE TO CLINICAL PRACTICE: It is important for health providers to consider patient satisfaction when attempting to improve adherence to pain management regimes in a clinical setting. PMID- 21615577 TI - Prospective observational study of postoperative epidural analgesia for major abdominal surgery. AB - AIMS: To describe the incidence and intensity of pain, hypotension and other epidural-related side-effects after major abdominal surgery and to identify factors associated with effective epidural analgesia. BACKGROUND: Evidence exists that up to 30% of patients with epidural analgesia still experience severe pain in clinical practice. When epidurals produce good pain relief, potentially harmful side effects can result. METHODS: Data were collected prospectively from 480 consecutive general surgical patients in a large District General Hospital in the UK. RESULTS: Fifty-six per cent of patients were hypotensive on day one. Low pain scores were found to be a predicator for postoperative hypotension. Severe pain was associated with emergency patients, male gender, the absence of hypotension and an epidural that did not continue until planned removal. Significantly lower mean pain scores were found in patients who were 70 years of age and over. No correlation exists between chronic pain before surgery and the level of postoperative pain. CONCLUSION: This study contributes to the epidural versus standard analgesia debate by describing the population in whom epidurals are used and identifies factors associated with both the success and failure of the technique in everyday practice. The Audit Commission has proposed a standard whereby less than 5% of patients should suffer severe pain following surgery. This may prove to be an unrealistic goal with currently available techniques. Relevance to clinical practice. As it is ward nursing staff who are primarily responsible for monitoring the effectiveness of the technique, it is important for nursing professionals to know the potential risks of postoperative epidural analgesia to be able to respond appropriately. The important measurements of an optimum acute pain assessment have been identified, based on the study results, allowing the development of a national acute pain registry to inform future practice. PMID- 21615578 TI - Pathways to immunity: temporal dynamics of the bumblebee (Bombus terrestris) immune response against a trypanosomal gut parasite. AB - Immune response dynamics in insects from natural host-parasite associations are poorly understood, despite accumulating evidence of ecological immune phenomena in these systems. Using a gene discovery approach, we have identified genes relating to signalling, enzymatic processes and respiration that were up regulated in the bumblebee, Bombus terrestris, during infection with the trypanosomatid parasite, Crithidia bombi. In addition, we have mapped dynamic changes in the temporal expression of these genes and three candidate antimicrobial peptide (AMP) immune genes, Abaecin, Defensin and Hymenoptaecin, from 1 to 24 h after C. bombi infection. We show that dynamic changes in expression occur for individual genes at distinct phases of the immune response to C. bombi that correspond to early, intermediate and late stages of infection. PMID- 21615579 TI - Genetic differentiation across North America in the generalist moth Heliothis virescens and the specialist H. subflexa. AB - The two moth species Heliothis virescens (Hv) and H. subflexa (Hs) are closely related, but have vastly different feeding habits. Hv is a generalist and an important pest in many crops in the USA, while Hs is a specialist feeding only on plants in the genus Physalis. In this study, we conducted a comparative population genetic analysis to assess whether and how generalist and specialist life styles are reflected in differences in population structures. In Hv 98% of the total variation occurred within populations. The overall differentiation (F(ST) ) between regions was 0.006 and even lower between years (0.0039) and hosts (0.0028). Analyses of population structure suggest that all individuals form one genetically homogeneous population, except for at most 12 individuals (6%) that diverged from this cluster. Population homogeneity likely results from the high mobility of Hv and its generalist feeding behaviour. Hs exhibited substantially more population structure. Even though 96% of the total variation was attributable to within-population variability, F(ST) -values between Hs populations were 10 times higher than between Hv populations. Hs populations showed significant isolation by distance. Analyses of Hs population structure suggest at least two subpopulations and thus some degree of metapopulation structure. We speculate that the patchy distribution of Physalis- the exclusive food source of Hs - contributes to differences in population structure between these closely related species. The finding that the specialist shows more population differentiation than the generalist corroborates the notion that host specialization is not an evolutionary dead end but a dynamic trait. PMID- 21615580 TI - Determinants of sleep quality in middle-aged women with fibromyalgia syndrome. AB - The objectives of this study were: (i) to compare the sleep quality at home of patients with fibromyalgia with that of healthy controls; and (ii) to examine the factors associated with sleep quality in patients with fibromyalgia. In addition to anthropometric measures, 75 women with fibromyalgia and 48 healthy controls completed standardized questionnaires that assessed sleep quality, functional impairment (Fibromyalgia Impact Questionnaire), depression, anxiety and physical activity level. Comparisons between groups, correlation coefficients and a series of hierarchical multiple regressions were performed. The global Pittsburgh Sleep Quality Index scores were worse in patients with fibromyalgia than in the controls. This result was partly explained by the Fibromyalgia Impact Questionnaire score. For the patients with fibromyalgia, the results of the first model that tested the importance of demographic factors were not statistically significant. In the disease-related model, the duration of symptoms and symptom severity contributed to poor sleep quality. A measurement of physical activity participation and the sum of the skinfold thickness were added to the demographic factors. In the psychological model, the level of anxiety contributed to poor sleep quality. When all variables were entered simultaneously, the level of physical activity, duration of symptoms and symptom severity remained significant determinants of sleep quality. In conclusion, our results showed that the symptoms associated with fibromyalgia contributed to poor overall sleep quality in patients compared with healthy subjects. The findings also suggest that the duration of symptoms, symptom severity and especially a sedentary lifestyle contributed to decreased sleep quality in patients with fibromyalgia. PMID- 21615581 TI - Housewife or working mum--each to her own? The relevance of societal factors in the association between social roles and alcohol use among mothers in 16 industrialized countries. AB - AIMS: To investigate whether differences in gender-income equity at country level explain national differences in the links between alcohol use, and the combination of motherhood and paid labour. DESIGN: Cross-sectional data in 16 established market economies participating in the Gender, Alcohol and Culture: An International Study (GenACIS) study. SETTING: Population surveys. PARTICIPANTS: A total of 12,454 mothers (aged 25-49 years). MEASUREMENTS: Alcohol use was assessed as the quantity per drinking day. Paid labour, having a partner, gender income ratio at country level and the interaction between individual and country characteristics were regressed on alcohol consumed per drinking day using multi level modelling. FINDINGS: Mothers with a partner who were in paid labour reported consuming more alcohol on drinking days than partnered housewives. In countries with high gender-income equity, mothers with a partner who were in paid labour drank less alcohol per occasion, while alcohol use was higher among working partnered mothers living in countries with lower income equity. CONCLUSION: In countries which facilitate working mothers, daily alcohol use decreases as female social roles increase; in contrast, in countries where there are fewer incentives for mothers to remain in work, the protective effect of being a working mother (with partner) on alcohol use is weaker. These data suggest that a country's investment in measures to improve the compatibility of motherhood and paid labour may reduce women's alcohol use. PMID- 21615582 TI - Cocaine-related attentional bias following trauma cue exposure among cocaine dependent in-patients with and without post-traumatic stress disorder. AB - AIMS: Although the co-occurrence of post-traumatic stress disorder (PTSD) and cocaine dependence is associated with a wide range of negative clinical outcomes, little is known about the mechanisms that underlie this association. This study investigated one potential mechanism-attentional bias to cocaine imagery following trauma cue exposure. DESIGN: Male and female cocaine-dependent in patients with and without PTSD were exposed to both a neutral and personalized trauma script on separate days, followed by a visual dot-probe task. A 2 (PTSD versus non-PTSD) * 2 (neutral versus trauma script) * 2 (male versus female) design was used to examine hypotheses. SETTING: Participants were recruited from a residential substance use disorder (SUD) treatment center. PARTICIPANTS: Participants were 60 trauma-exposed cocaine dependent in-patients, 30 with current PTSD and 30 without a history of PTSD. MEASUREMENTS: Attentional bias was assessed using a visual dot-probe task depicting cocaine-related imagery following both a neutral script and personalized trauma script. FINDINGS: Following neutral script exposure, PTSD (versus non-PTSD) participants exhibited an attentional bias away from cocaine imagery. This effect was reversed following trauma script exposure, with PTSD participants exhibiting a greater attentional bias towards the location of cocaine imagery than non-PTSD participants. Severity of subjective distress following trauma script exposure predicted level of attentional bias among PTSD participants. CONCLUSIONS: Cocaine appears to serve an emotion-regulating function among post-traumatic stress disorder patients and may be a potential target for brief post-traumatic stress disorder-substance use disorder interventions that can facilitate residential substance use disorder treatment retention. PMID- 21615583 TI - Access to alcohol outlets and harmful alcohol consumption: a multi-level study in Melbourne, Australia. AB - AIMS: To assess the association between access to off-premises alcohol outlets and harmful alcohol consumption. DESIGN, SETTING AND PARTICIPANTS: Multi-level study of 2334 adults aged 18-75 years from 49 census collector districts (the smallest spatial unit in Australia at the time of survey) in metropolitan Melbourne. MEASUREMENTS: Alcohol outlet density was defined as the number of outlets within a 1-km road network of respondents' homes and proximity was the shortest road network distance to the closest outlet from their home. Using multi level logistic regression we estimated the association between outlet density and proximity and four measures of harmful alcohol consumption: drinking at levels associated with short-term harm at least weekly and monthly; drinking at levels associated with long-term harm and frequency of consumption. FINDINGS: Density of alcohol outlets was associated with increased risk of drinking alcohol at levels associated with harm. The strongest association was for short-term harm at least weekly [odds ratio (OR) 1.10, 95% confidence interval (CI) 1.04-1.16]. When density was fitted as a categorical variable, the highest risk of drinking at levels associated with short-term harm was when there were eight or more outlets (short-term harm weekly: OR 2.36, 95% CI 1.22-4.54 and short-term harm monthly: OR 1.80, 95% CI 1.07-3.04). We found no evidence to support an association between proximity and harmful alcohol consumption. CONCLUSIONS: The number of off premises alcohol outlets in a locality is associated with the level of harmful alcohol consumption in that area. Reducing the number of off-premises alcohol outlets could reduce levels of harmful alcohol consumption. PMID- 21615584 TI - The role of alcohol in the Russian mortality crisis. AB - AIMS: Alcohol is believed to be an important factor behind the sharp rise in mortality during the period 1990-94 in Russia. However, the rise in the standard alcohol consumption proxy does not seem to be sufficient to explain all the increase in mortality. This study adopts a novel approach to exploring the role of the alcohol factor in the increased mortality by investigating whether the mismatch between trends in mortality and recorded alcohol consumption is due to an underestimation of the consumption increase. DESIGN AND MEASUREMENTS: First, the alcohol effect on the male accident rate was estimated using data for the period 1959-89. Next, the estimated alcohol effect and the observed accident mortality rate for the period 1990-98 were used to backcast alcohol consumption during that period. Thirdly, the backcasted alcohol series was used to predict trajectories in alcohol poisoning mortality, the homicide rate and all-cause mortality during the period 1990-98. FINDINGS: There was a markedly stronger increase in the backcasted consumption proxy than in the standard alcohol consumption proxy during the period 1990-98. There was a substantial gap between the observed mortality rates and the rates predicted from the standard alcohol consumption proxy, whereas the predictions from the backcasted alcohol proxy were much closer to the target. CONCLUSIONS: Much of the rise in Russian mortality in 1990-94 appears to have been due to the increase in population drinking, but this increase is grossly underestimated by the commonly used consumption proxy combining alcohol sales, estimation of illicit alcohol production and proportion of alcohol-positive violent deaths. PMID- 21615585 TI - The impact of needle and syringe provision and opiate substitution therapy on the incidence of hepatitis C virus in injecting drug users: pooling of UK evidence. AB - AIMS: To investigate whether opiate substitution therapy (OST) and needle and syringe programmes (NSP) can reduce hepatitis C virus (HCV) transmission among injecting drug users (IDUs). DESIGN: Meta-analysis and pooled analysis, with logistic regression allowing adjustment for gender, injecting duration, crack injecting and homelessness. SETTING: Six UK sites (Birmingham, Bristol, Glasgow, Leeds, London and Wales), community recruitment. PARTICIPANTS: A total of 2986 IDUs surveyed during 2001-09. MEASUREMENT: Questionnaire responses were used to define intervention categories for OST (on OST or not) and high NSP coverage (>=100% versus <100% needles per injection). The primary outcome was new HCV infection, measured as antibody seroconversion at follow-up or HCV antibody negative/RNA-positive result in cross-sectional surveys. FINDINGS: Preliminary meta-analysis showed little evidence of heterogeneity between the studies on the effects of OST (I2=48%, P=0.09) and NSP (I2=0%, P=0.75), allowing data pooling. The analysis of both interventions included 919 subjects with 40 new HCV infections. Both receiving OST and high NSP coverage were associated with a reduction in new HCV infection [adjusted odds ratios (AORs)=0.41, 95% confidence interval (CI): 0.21-0.82 and 0.48, 95% CI: 0.25-0.93, respectively]. Full harm reduction (on OST plus high NSP coverage) reduced the odds of new HCV infection by nearly 80% (AOR=0.21, 95% CI: 0.08-0.52). Full harm reduction was associated with a reduction in self-reported needle sharing by 48% (AOR 0.52, 95% CI: 0.32 0.83) and mean injecting frequency by 20.8 injections per month (95% CI: -27.3 to -14.4). CONCLUSIONS: There is good evidence that uptake of opiate substitution therapy and high coverage of needle and syringe programmes can substantially reduce the risk of hepatitis C virus transmission among injecting drug users. Research is now required on whether the scaling-up of intervention exposure can reduce and limit hepatitis C virus prevalence in this population. PMID- 21615587 TI - Patterns of cranial shape diversification during the phylogenetic branching process of New World monkeys (Primates: Platyrrhini). AB - One of the central topics in evolutionary biology is understanding the processes responsible for phenotypic diversification related to ecological factors. New World monkeys are an excellent reference system to investigate processes of diversification at macroevolutionary scales. Here, we investigate the cranial shape diversification related to body size and ecology during the phylogenetic branching process of platyrrhines. To investigate this diversification, we used geometric morphometric techniques, a molecular phylogenetic tree, ecological data and phylogenetic comparative methods. Our statistical analyses demonstrated that the phylogenetic branching process is the most important dimension to understand cranial shape variation among extant platyrrhines and suggested that the main shape divergence among the four principal platyrrhine clades probably occurred during the initial branching process. The phylogenetic conservatism, which is the retention of ancestral traits over time within the four principal platyrrhine clades, could be the most important characteristic of platyrrhine cranial shape diversification. Different factors might have driven early shape divergence and posterior relative conservatism, including genetic drift, stabilizing selection, genetic constraints owing to pleiotropy, developmental or functional constraint, lack of genetic variation, among others. Understanding the processes driving the diversification among platyrrhines will probably require further palaeontological, phylogenetic and comparative studies. PMID- 21615586 TI - Immature performance linked with exaggeration of a sexually selected trait in an armed beetle. AB - Exaggerated traits can be costly and are often trade-off against other characters, such as life-history traits. Thus, the evolution of an exaggerated trait is predicted to affect male life-history strategies. However, there has been very little experimental evidence of the impact of the evolution of sexually selected traits on life-history traits. This study investigated whether increased investment in exaggerated traits can generate evolutionary changes in the life history strategy for armed males. Male flour beetles, Gnatocerus cornutus, have enlarged mandibles that are used in male-male competition, but females lack this character exaggeration completely. We subjected these weapons to 11 generations of bidirectional selection and found a correlated response in pupal survival but not in larval survival or adult longevity in the male. That is, selecting for male mandibles negatively impacted survival during the production of mandibles. There is no correlated response in the life-history traits of the female. PMID- 21615588 TI - Evolutionary modularity of the mouse mandible: dissecting the effect of chromosomal reorganizations and isolation by distance in a Robertsonian system of Mus musculus domesticus. AB - The mouse mandible consists of several morphogenetic units that are usually grouped into two main modules: the alveolar region and the ascending ramus. The genetic/ontogenetic modularity of the two regions implies that they might evolve independently to some extent. In particular, evolutionary modularity in quantitative traits could arise during chromosomal speciation due to lower gene flow in rearranged chromosomes. With the aim of uncovering the autonomous evolution of the mandible modules, the form variation of each of them was assessed in the house mouse Robertsonian system from Barcelona, in which chromosomal variation and geographical distance may act as isolation factors. The association between these factors and morphological changes was analysed to determine their contribution to the differentiation of each module. Although size changes in the two modules were highly correlated, shape changes were not, and their association with karyotype differences, but not geographical distance, was dependent on the module. The results support the existence of two evolutionary modules and highlight the importance of size in morphological integration of the mandible. They also suggest that geographical distance and chromosomal reorganizations reduce gene flow between karyotypically divergent populations, but although geographical distance represents a global barrier to gene flow, the isolation produced by a set of chromosomal reorganizations only affects particular modules, probably depending on the number and location of loci with effects on a particular morphological region. PMID- 21615589 TI - Genetic analysis of hyperpolarization-activated cyclic nucleotide-gated cation channels in sudden unexpected death in epilepsy cases. AB - Sudden unexpected death in epilepsy (SUDEP) is the most common epilepsy-related cause of death, yet the cause is unknown. Our previous studies suggest a role for arrhythmia-related ion channel genes in the pathogenesis of SUDEP. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN1-4) channels are ion channels involved in generating spontaneous rhythmic activity in cardiac pacemaker and neuronal cells. This study sought to determine the role of pathogenic DNA variants in the HCN1-4 genes in a large SUDEP cohort collected from 1993 to 2009. Post-mortem DNA samples were amplified and analyzed for each HCN exon. Genetic analysis in 48 SUDEP cases (age range 12-82 years) identified six novel and three previously reported nonsynonymous (amino acid changing) variants in HCN1 (n = 1), HCN2 (n = 2), HCN3 (n = 2) and HCN4 (n = 4). The Phe738Cys and Pro802Ser variants in HCN2, and Gly973Arg in HCN4 were absent in control alleles and affecting highly conserved residues in the carboxyl cytoplasmic tail region. Our results support a pathogenic link between the heart and brain in SUDEP, mediated by the HCN neuro-cardiac ion channel genes. PMID- 21615590 TI - Aberrant upregulation of astroglial ceramide potentiates oligodendrocyte injury. AB - Oligodendroglial injury is a pathological hallmark of many human white matter diseases, including multiple sclerosis (MS) and periventricular leukomalacia (PVL). Critical regulatory mechanisms of oligodendroglia destruction, however, remain incompletely understood. Ceramide, a bioactive sphingolipid pivotal to sphingolipid metabolism pathways, regulates cell death in response to diverse stimuli and has been implicated in neurodegenerative disorders. We report here that ceramide accumulates in reactive astrocytes in active lesions of MS and PVL, as well as in animal models of demyelination. Serine palmitoyltransferase, the rate-limiting enzyme for ceramide de novo biosynthesis, was consistently upregulated in reactive astrocytes in the cuprizone mouse model of demyelination. Mass spectrometry confirmed the upregulation of specific ceramides during demyelination, and revealed a concomitant increase of sphingosine and a suppression of sphingosine-1-phosphate, a potent signaling molecule with key roles in cell survival and mitogenesis. Importantly, this altered sphingolipid metabolism during demyelination was restored upon active remyelination. In culture, ceramide acted synergistically with tumor necrosis factor, leading to apoptotic death of oligodendroglia in an astrocyte-dependent manner. Taken together, our findings implicate that disturbed sphingolipid pathways in reactive astrocytes may indirectly contribute to oligodendroglial injury in cerebral white matter disorders. PMID- 21615591 TI - Neuroanatomical, sensorimotor and cognitive deficits in adult rats with white matter injury following prenatal ischemia. AB - Perinatal brain injury including white matter damage (WMD) is highly related to sensory, motor or cognitive impairments in humans born prematurely. Our aim was to examine the neuroanatomical, functional and behavioral changes in adult rats that experienced prenatal ischemia (PI), thereby inducing WMD. PI was induced by unilateral uterine artery ligation at E17 in pregnant rats. We assessed performances in gait, cognitive abilities and topographical organization of maps, and neuronal and glial density in primary motor and somatosensory cortices, the hippocampus and prefrontal cortex, as well as axonal degeneration and astrogliosis in white matter tracts. We found WMD in corpus callosum and brainstem, and associated with the hippocampus and somatosensory cortex, but not the motor cortex after PI. PI rats exhibited mild locomotor impairments associated with minor signs of spasticity. Motor map organization and neuronal density were normal in PI rats, contrasting with major somatosensory map disorganization, reduced neuronal density, and a marked reduction of inhibitory interneurons. PI rats exhibited spontaneous hyperactivity in open-field test and short-term memory deficits associated with abnormal neuronal density in related brain areas. Thus, this model reproduces in adult PI rats the main deficits observed in infants with a perinatal history of hypoxia-ischemia and WMD. PMID- 21615597 TI - How to write good multiple-choice questions. AB - Medical practitioners are frequently called upon to write multiple-choice questions for high stakes examinations, such as final year medical student assessments and specialist college accreditation examinations. The fairness and validity of these examinations depends principally on the generation of high quality questions, which adequately sample the curriculum. The most common format for multiple-choice examinations are single best answer and extended matching type questions. This paper provides a simple guideline that will assist with the production of high-quality multiple-choice papers in these formats. PMID- 21615598 TI - Imaging diagnosis-metastatic adrenal pheochromocytoma in a dog. AB - A 10-year-old Akita mix became acutely paraplegic. Upon magnetic resonance imaging, multiple, slightly T2-hyperintense, T1-isointense extradural masses, relative to spinal cord were found in the vertebral canal. The retroperitoneal masses had mixed T2-signal intensity. The contrast enhancement pattern for the spinal masses was both homogenous and heterogenous. The diagnosis was metastatic pheochromocytoma. Signal intensity of the tumors in this dog was similar to reports of pheochromocytoma in human beings. PMID- 21615600 TI - Treatment of refractory discoid lupus erythematosus using 1,064-nm long-pulse neodymium-doped yttrium aluminum garnet laser. PMID- 21615599 TI - Ablative fractional erbium-doped yttrium aluminum garnet laser with coagulation mode for the treatment of atrophic acne scars in Asian skin. AB - BACKGROUND: The introduction of fractional photothermolysis (FP) for the treatment of atrophic acne scars has been proven to provide satisfactory results. For severe atrophic acne scarring, nonablative FP achieves fair improvement and takes multiple treatment sessions. Ablative fractional resurfacing provides an alternative modality with greater satisfaction. OBJECTIVE: To evaluate the effectiveness and safety of the ablative fractional 2,940-nm erbium-doped yttrium aluminum garnet (Er:YAG) laser with coagulation mode for the treatment of atrophic facial acne scars in Asian skin. METHODS: Thirty-four patients aged 19 to 44 (mean 34.2) with Fitzpatrick skin types III and IV, received one ablative fractional 2,940-nm Er:YAG laser treatment with an adjustable coagulation mode and were followed for 3 months. Physician evaluation and patient satisfaction were graded on a 4-point scale. Side effects were recorded at each follow-up visit. RESULTS: Almost three-quarters of the patients rated their satisfaction as good to excellent (score of 3 or 4). All patients experienced short downtime, and the incidence of postinflammatory hyperpigmentation was low (3.0%). CONCLUSIONS: The ablative fractional Er:YAG laser with coagulation mode is recommended for the treatment of moderate to severe atrophic acne scars, with acceptable downtime and high satisfaction in Asian patients. PMID- 21615592 TI - Complex oncogenic signaling networks regulate brain tumor-initiating cells and their progenies: pivotal roles of wild-type EGFR, EGFRvIII mutant and hedgehog cascades and novel multitargeted therapies. AB - Complex signaling cross-talks between different growth factor cascades orchestrate the primary brain cancer development. Among the frequent deregulated oncogenic pathways, the ligand-activated wild-type epidermal growth factor receptor (EGFR), constitutively activated EGFRvIII mutant and sonic hedgehog pathways have attracted much attention because of their pivotal roles in pediatric medulloblastomas and adult glioblastoma multiformes (GBM) brain tumors. The enhanced expression levels and activation of EGFR, EGFRvIII mutant and hedgehog signaling elements can provide key roles for the sustained growth, migration and local invasion of brain tumor-initiating cells (BTICs) and their progenies, resistance to current therapies and disease relapse. These tumorigenic cascades also can cooperate with Wnt/beta-catenin, Notch, platelet-derived growth factor (PDGF)/PDGF receptors (PDGFRs), hepatocyte growth factor (HGF)/c-Met receptor and vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFRs) for the acquisition of a more malignant behavior and survival advantages by brain tumor cells during disease progression. Therefore, the simultaneous targeting of these oncogenic signaling components including wild-type EGFR, EGFRvIII mutant and hedgehog pathways may constitute a potential therapeutic approach of great clinical interest to eradicate BTICs and improve the efficacy of current clinical treatments by radiation and/or chemotherapy against aggressive and recurrent medulloblastomas and GBMs. PMID- 21615601 TI - Reconstruction of a large preauricular defect. PMID- 21615602 TI - Epidermal growth factor receptor inhibitors in the treatment of nonmelanoma skin cancers. AB - BACKGROUND: A better understanding of the molecular pathways that characterize cell growth, apoptosis, angiogenesis, and invasion has provided novel targets in cancer therapy. Epidermal growth factor receptor (EGFR)-mediated signal transduction has been one of the most studied pathways in carcinogenesis. The phosphorylation of EGFR activates multiple biological processes, including apoptosis, differentiation, cellular proliferation, motility, invasion, adhesion, DNA repair, and survival. EGFR is a transmembrane tyrosine kinase receptor involved in the proliferation and survival of cancer cells. EGFR is the first molecular target against which monoclonal antibodies have been developed for cancer therapy. OBJECTIVE: To review the mechanisms underlying the effects of EGFR in nonmelanoma skin cancer (NMSC) and their potential role as targeted therapies in the treatment thereof. CONCLUSIONS: EGFR plays an important role in tumorigenesis of NMSC, especially metastatic squamous cell carcinoma, via mechanisms similar to those of other visceral tumors. Pharmacologic inhibitors of EGFR pathway of tumor production may offer an effective therapeutic strategy to block tumor growth. PMID- 21615603 TI - A descriptive study of bacterial load of full-thickness surgical wounds in dermatologic surgery. AB - BACKGROUND: Surgical site infections (SSIs) after dermatologic surgery cause pain, prolong healing, result in unaesthetic complications, and lead to excessive use of antibiotics. The pathogenesis of wound infections is complex and is dependent on bacterial load and diversity, among several factors. OBJECTIVE: To investigate bacterial dynamics at dermatosurgical sites at different time intervals and assess the correlation with postoperative outcomes and to examine different endo- and exogenous factors that may contribute to SSIs. METHODS: Eighteen patients undergoing skin grafting of the face were studied. The following SSI-related factors were registered: age and sex of the patient, ulceration of the lesion, diabetes, immunosuppressive therapy, smoking, anticoagulative therapy, and use of antibiotic prophylaxis. Wounds from each patient were swabbed preoperatively, intraoperatively, and postoperatively. The bacterial composition of the swabs was then analyzed quantitatively and qualitatively. RESULTS: Sixteen of 18 surgical sites contained varying quantities of surface-associated bacteria. Coagulase-negative staphylococci and Propionibacterium acnes were the predominant bacteria isolated at all times. Intraoperative analysis was not predictive of SSIs. Use of antibiotic prophylaxis was the only registered SSI-related factor that showed significant variation in bacterial load between pre- and postoperative samples. Postoperative bacterial load was found to be lower than preoperative load in patients who received antibiotics. This was in contrast to patients who did not receive antibiotics, who had significantly higher postoperative levels (p=.02). The presence of high postoperative bacterial loads, regardless of the bacterial species isolated, showed a statistically significant positive correlation with a complicated postoperative outcome (p<=.001). CONCLUSIONS: This study provides novel insights into the bacterial dynamics of dermatologic surgery-induced wounds and the variation of this over time. The results highlight the potential relevance of quantifying bacterial loads, as well as determining specific types of bacteria, in dermatologic surgery. PMID- 21615604 TI - Histopathology and immunohistochemistry of cutaneous lupus erythematosus after pulsed dye laser treatment. AB - BACKGROUND: Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disorder with a wide range of skin manifestations. Current treatment options include topical and systemic approaches. Few controlled prospective studies have been performed using the pulsed dye laser (PDL). Based on previous experience that supported the efficacy of PDL treatment of CLE, we decided to study the histological changes induced by PDL. OBSERVATIONS: A prospective study was performed on nine patients with histologically confirmed CLE treated with PDL. Biopsies were taken before, immediately after, and 4 weeks after treatment and stained with hematoxylin and eosin and with commercially available antibodies to intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1. Evaluation after PDL treatment showed a significant reduction of the dermal lymphocytic infiltrate in six of nine patients (66.7%) and an important reduction of the basal damage in six of seven patients (85.7%). Other epidermal changes improved in four of six patients (66.7%). Mucin deposition persisted in two patients. ICAM and VCAM expression was reduced in seven of seven patients (100%) and five of six patients (83.3%) (p<.05). Clinical improvement was present in eight of nine patients (88.9%), without side effects. CONCLUSIONS: PDL therapy is an effective treatment for CLE. Immunohistologic improvement has been confirmed in this study. PMID- 21615605 TI - Comparison of secondary intention healing and full-thickness skin graft after excision of acral lentiginous melanoma on foot. AB - BACKGROUND: Melanoma in dark-skinned individuals often develops in an acral lentiginous fashion on the foot. After wide excision, substantial defects usually develop and they may endure insufficient vascular flow. In addition, the final scar must withstand the mechanical stress of daily walking. Various repair methods are used to repair these defects, but secondary intention healing has not been evaluated in the repair of wounds of the foot. OBJECTIVE: To compare the functional and cosmetic results of secondary intention healing and full-thickness skin graft after wide excision of melanoma on the foot. METHODS: Retrospective review of 25 patients who were treated using excision for melanoma on the foot. The defects of 13 patients were healed by secondary intention (secondary intention healing group; SIHG), and those of 12 patients were repaired by full thickness skin graft (skin graft group; SGG). RESULTS: The SGG showed more rapid healing than the SIHG, but the SIHG showed better functional and cosmetic outcomes at complete re-epithelialization than the SGG as evaluated by patients and independent physicians. CONCLUSIONS: Secondary intention healing after excision of melanoma from the foot is a therapeutic option with acceptable functional and cosmetic outcomes. PMID- 21615606 TI - Foam sclerotherapy: investigating the need for sterile air. AB - BACKGROUND: Sclerotherapy with foam is becoming increasingly popular for the treatment of varicose veins. There is no consensus on the necessity of sterile air or other gases to produce foam. OBJECTIVES: To evaluate the potential risk of bacterial inoculation of polidocanol (POL) foam using room air and the antimicrobial properties of polidocanol. MATERIALS AND METHODS: The amount of airborne microorganisms was quantitatively measured. Four bacterial strains were tested for susceptibility to polidocanol: Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Streptococcus pyogenes. RESULTS: Air measurements varied as a result of air movement and the number of people in the room. Although the risk of introducing one colony-formin unit can be calculated as less than 1 in 330, the clinical relevance is still to be determined. No inhibition of bacterial growth was achieved with POL in of any of the tested strains. CONCLUSIONS: Foam sclerotherapy with POL prepared in a standard treatment room is a safe procedure without the risk of introducing a severe bacterial complication. The use of sterile air, nitrogen, or carbon dioxide is unnecessary and will make foam sclerotherapy with POL more elaborate and more expensive to use. PMID- 21615607 TI - Mobile phone technology and hospitalized patients: a cross-sectional surveillance study of bacterial colonization, and patient opinions and behaviours. AB - Healthcare workers' mobile phones provide a reservoir of bacteria known to cause nosocomial infections. UK National Health Service restrictions on the utilization of mobile phones within hospitals have been relaxed; however, utilization of these devices by inpatients and the risk of cross-contamination are currently unknown. Here, we examine demographics and characteristics of mobile phone utilization by inpatients and phone surface microbial contamination. One hundred and two out of 145 (70.3%) inpatients who completed a questionnaire detailing their opinions and utilization of mobile phones, also provided their mobile phones for bacteriological analysis and comparative bacteriological swabs from their nasal cavities; 92.4% of patients support utilization of mobile phones by inpatients; indeed, 24.5% of patients stated that mobile phones were vital to their inpatient stay. Patients in younger age categories were more likely to possess a mobile phone both inside and outside hospital (p <0.01) but there was no gender association. Eighty-six out of 102 (84.3%) patients' mobile phone swabs were positive for microbial contamination. Twelve (11.8%) phones grew bacteria known to cause nosocomial infection. Seven (6.9%) phones and 32 (31.4%) nasal swabs demonstrated Staphylococcus aureus contamination. MSSA/MRSA contamination of phones was associated with concomitant nasal colonization. Patient utilization of mobile phones in the clinical setting is popular and common; however, we recommend that patients are educated by clear guidelines and advice on inpatient mobile phone etiquette, power charging safety, regular cleaning of phones and hand hygiene, and advised not to share phones or related equipment with other inpatients in order to prevent transmission of bacteria. PMID- 21615608 TI - Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation. AB - Malignant mesothelioma (MM) is an aggressive tumor arising primarily from pleural or peritoneal cavities, which is caused by asbestos exposure after long latency. One of the most frequently mutated genes detected in MM cells is the neurofibromatosis type 2 (NF2) tumor suppressor gene which is located at chromosome 22q12. The NF2 gene encodes Merlin, an ERM (Ezrin/Radixin/Moesin) protein. The underphosphorylated form of Merlin is active and acts as a tumor suppressor by regulating several distinct cellular signaling pathways. One of the downstream pathways regulated by Merlin is the Hippo signaling pathway, which is conserved from Drosophila to mammalian cells and plays important roles in organ size control and cancer development. Recent studies have identified alterations of the components in the Hippo signaling cascade in MM cells, including overexpression of Yes-associated protein (YAP) and inactivation of large tumor suppressor homolog 2 (LATS2). Dysregulation of the Merlin-Hippo signaling cascade is one of the frequent and key events of MM cell development and/or progression. Thus, a strategy to normalize this signaling cascade may be the rationale for developing a new target therapy against MM. PMID- 21615609 TI - Re-evaluation of melanin bleaching using warm diluted hydrogen peroxide for histopathological analysis. AB - Excessive amounts of melanin pigments may hamper histopathological assessments of melanocytic lesions by obscuring cellular morphology and hindering antibody antigen interactions. To determine the optimal melanin-bleaching conditions for histopathological examination, heavily pigmented melanomas were treated with warm hydrogen peroxide (H2O2) diluted with various diluents (1% disodium hydrogen phosphate 12H2O (Na2 HPO4); phosphate buffer 0.05 M, pH 7.4 (PB); and PBS 0.05 M, pH 7.4) at varying temperatures (50 degrees C, 55 degrees C, and 60 degrees C) and for varying incubation times (0.5, 1, 2, and 3 h). The effect of the sequential order of antigen retrieval and bleaching on preserving tissue morphology was then evaluated. Additionally, the effect of melanin bleaching using warm diluted H2O2 on the antigenicity of melanoma-related markers (HMB-45, MART-1, and S-100) and other markers used for histopathology was examined in amelanotic melanomas and tonsil tissue. Optimal and complete bleaching was achieved using warm 3% H2O2 in PB treatment at 55 degrees C for 2 h following antigen retrieval with microwaving or digestion with trypsin. Under these conditions, the tissue morphology and antigenicity of various immunohistochemical markers were also well preserved. Bleaching with warm 3% H2O2 PB is a fast and efficient method of bleaching melanin pigments and performing immunohistochemical examination in heavily melanin-pigmented lesions. PMID- 21615610 TI - Scavenger receptor A index and coronary thrombus in patients with acute ST elevation myocardial infarction. AB - To examine the relationship between the scavenger receptor A (SRA) index (the number of SRA+ cells observed in 10 high power fields of peripheral blood (PB) smear samples; normal upper limit <30) and coronary thrombus, 389 thrombi obtained from 393 patients with acute ST elevation myocardial infarction were examined. Thrombi were classified into platelets (PT), mixed (MT), fibrin-rich (FT) and organizing thrombi (OT); 387, 269, 57 and 29 cases were detected, respectively. Patients were divided into group A (PT only, 89 cases), B (containing MT and PT but not FT, 243 cases), and C (containing FT, 57 cases). SRA+ cells had infiltrated into all FT cases and 147 of the 269 MT, but no PT. At hospitalization, the SRA index exceeded 30 in 276 patients. PT was observed in 274 cases, and MT and FT (residual mural thrombus; RMT) observed in 230. Infarct related coronary artery was thought to be totally and rapidly occluded by PT that had formed as a result of severe stenosis due to extrusion of plaque content or growth of RMT. An abnormal increase of SRA+ cells is considered to be a useful finding to detecting the presence of PT and, probably, RMT. PMID- 21615611 TI - Peritoneal seeding of hepatocellular carcinoma: clinicopathological characteristics of 17 autopsy cases. AB - Peritoneal seeding (PS) of hepatocellular carcinoma (HCC) is uncommon, and the clinicopathological features are poorly understood. A total of 181 autopsy cases of HCC, including 171 cases with detailed clinical information, was investigated for PS and evaluated. PS was identified in 17 cases (9.4%), and was locally (70.6%) or entirely (29.4%) distributed in the peritoneal cavity, involving the diaphragm (76.5%), omentum (47.1%), or alimentary tract serosa (47.1%). Compared with primary HCC, PS showed similar or slightly undifferentiated features (88.2%) and exhibited more differentiated features (11.8%). In 15 cases (88.2%) of HCC with PS, primary HCC showed membranous beta-catenin immunoreactivity. However, in five cases (33.3%), respective PS lost this immunoreactivity. PS was significantly associated with rupture of HCC (P= 0.012), direct diaphragmatic invasion (P= 0.001), and lymph node metastasis (P < 0.001), indicating these are high risk factors for PS; there was no significant association with a past history of percutaneous fine-needle biopsy, percutaneous ethanol injection and/or radiofrequency ablation (P= 0.97), or metastasis to lung (P= 0.13), bone (P= 0.71), or adrenal gland (P= 0.79). PS can infrequently proliferate aggressively with more differentiated features. Loss of membranous beta-catenin expression may be associated with PS of HCC. PMID- 21615612 TI - Composite T lymphoblastic leukemia/lymphoma and diffuse large B-cell lymphoma: case report. AB - This report concerns a unique case of a composite lymphoma composed of T lymphoblastic leukemia/lymphoma (T-LBL) and diffuse large B-cell lymphoma (DLBCL) in a 72-year-old woman with generalized lymphadenopathy, splenomegaly and ascites. Laboratory findings showed increased lactate dehydrogenase and soluble interleukin-2 receptor. The biopsy specimen showed replacement of the normal architecture of the lymph nodes by a tumor containing a dual cell population composed of large lymphocytes and medium-sized lymphocytes. Sheets of large lymphocytes often were punctuated by clusters of medium-sized lymphocytes. Flow cytometry and immunohistochemical analysis showed a composite lymphoma with both T-LBL and DLBCL. The T-LBL expressed CD1a, CD3, CD4, CD8, and terminal deoxynucleotidyl transferase. The DLBCL expressed CD19 and CD20, CD23, bcl-2, bcl 6, MUM1 and immunoglobulin kappa light chain. Polymerase chain reaction detected a monoclonal pattern of T-cell receptor gamma and immunoglobulin heavy chain rearrangements in the same specimen. She received eight cycles of R-CHOP (rituximab+cyclophosphamide, doxorubicin, vincristine, prednisone) therapy and achieved complete remission. She has shown no signs of recurrence 20 months after the diagnosis. We describe here a very unusual and, to the best of our knowledge, an as yet never reported case of a primary composite lymphoma of T-LBL and DLBCL. PMID- 21615613 TI - Pyloric gland metaplasia/differentiation in multiple organ systems in a patient with Peutz-Jegher's syndrome. AB - Peutz-Jegher's syndrome (PJS) involves multiple organ systems and the development of hamartomatous, metaplastic, or neoplastic lesions of different cell lineages. Among them, glandular lesions are the most common, but their properties are obscure. We report here a 53-year-old woman with PJS who developed multiple hamartomatous polyps in the jejunum and mucinous glandular lesions in multiple organ systems: glandular metaplasia in the urinary bladder; lobular endocervical glandular hyperplasia in the uterine cervix; mucinous metaplasia in the right fallopian tube; mucinous adenoma in the left ovary. Histological and immunohistochemical analyses disclosed that all of the intestinal and extra intestinal lesions were associated with pyloric gland metaplasia/differentiation across the organ systems. In the general population, the organs described above rarely or infrequently show pyloric gland phenotype, to say nothing of trans organ involvement. It is strongly suggested that commitment to pyloric gland metaplasia/differentiation is closely associated with PJS. PMID- 21615614 TI - Histiocytic sarcoma of the parotid gland region. AB - Histiocytic sarcoma (HS) is a malignant neoplasm showing the morphological and immunophenotypic features of mature histiocytes. Reported herein is a case of HS of the parotid gland region. A 53-year-old woman noticed a swelling of the right preauricular area. Preoperative fine needle aspiration cytology showed an admixture of pleomorphic atypical cells and mature lymphocytes. She underwent total parotidectomy. Grossly, the tumor was located at the parotid gland to subcutaneous tissue, and showed infiltrative growth with massive necrosis and hemorrhage. Microscopically, the tumor was composed of marked pleomorphic cells with eosinophilic cytoplasm. Bizarre multinuclear giant cells were scattered and intermingled. Tumor cells were positive for CD68 (KP-1 and PG-M1), CD163, S-100 protein, CD1a, CD4 and CD31, but negative for CD3, CD20, CD21, CD79a, DEC205 and langerin, immunohistochemically. Monoclonal proliferation of B cells was not confirmed on polymerase chain reaction for IgH. The patient had recurrent lesions in the pelvis and stomach 5 months after parotidectomy and died of the disease 10 months after the operation. PMID- 21615615 TI - Pure alveolar rhabdomyosarcoma of the uterine corpus. AB - Herein is presented a very rare case of alveolar rhabdomyosarcoma in the uterine corpus of a 72-year-old woman. The wall of the uterine corpus was replaced by multiple whitish-yellow, friable nodules, measuring up to 6 cm. Microscopically, the tumor was predominantly composed of round to polygonal cells arranged in an alveolar, papillary or nest pattern intermingled with multinuclear giant cells with abundant eosinophilic cytoplasm. Extensive sampling failed to show epithelial elements. Immunohistochemically, the tumor was positive for striated muscle markers such as myoglobin, myoD1 and myogenin. Metastatic lesions were found in the retroperitoneum and pelvic lymph nodes. The patient was treated by postoperative chemotherapy, but she died of systemic metastases 12 months after surgery. PMID- 21615616 TI - Primary kaposiform hemangioendothelioma of a long bone: two cases in unusual locations with long-term follow up. AB - Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm of low malignant potential that mainly affects infants and adolescents. The tumor almost exclusively occurs in somatic soft tissue or the retroperitoneum. We report herein two cases of primary KHE occurring in a long bone without cutaneous changes with long-term follow up in young patients. The patients were a 9-year old girl and 5-year-old boy presenting with lytic lesions of the femur and humerus, respectively, without cutaneous lesions. Histologically, the neoplasms were comprised of nodules of spindle- to oval-shaped cells growing in an infiltrative fashion. The neoplastic cells formed poorly canalized or slit-like blood vessels alternating with solid spindle areas. Immunohistochemical studies showed that the tumor cells expressed CD31, CD34 and Fli1, but not HHV8, LNA-1 or GLUT1. D2-40 stained the neoplastic spindle cells and lymphatic channels adjacent to vascular lobules. The girl remains well with 15 years and 6 months follow up after a second complete excision. The boy has no signs of recurrence or metastasis nearly 5 years after local complete excision. To our best knowledge, this is the first report in the English literature of primary long bone occurrences of KHE without cutaneous changes with long-term follow up. PMID- 21615617 TI - Amyloidoma of the kidney: a unique surgical case. PMID- 21615618 TI - A rare case of non-secretory multiple myeloma without bone marrow involvement. PMID- 21615619 TI - Cough predicts prognosis in idiopathic pulmonary fibrosis. AB - BACKGROUND AND OBJECTIVE: The clinical associations and prognostic value of cough in IPF have not been adequately described. The objective of this study was to describe the characteristics and prognostic value of cough in IPF. METHODS: Subjects with IPF were identified from an ongoing longitudinal database. Cough and other clinical variables were recorded prospectively. Logistic regression was used to determine predictors of cough and predictors of disease progression, defined as 10% decline in FVC, 15% decline in DL(CO) , lung transplantation or death within 6 months of clinic visit. The relationship of cough with time to death or lung transplantation was analysed using Cox proportional hazards analysis. RESULTS: Two hundred and forty-two subjects were included. Cough was reported in 84% of subjects. On multivariate analysis, cough was less likely in previous smokers (OR 0.07, 95% CI: 0.01-0.55, P = 0.01), and more likely in subjects with exertional desaturation (OR 2.56, 95% CI: 1.15-5.72, P = 0.02) and lower FVC (OR 0.76, 95% CI: 0.60-0.96, P = 0.02). Cough predicted disease progression (OR 4.97, 95% CI: 1.25-19.80, P = 0.02) independent of disease severity, and may predict time to death or lung transplantation (HR 1.78, 95% CI: 0.94-3.35, P = 0.08). CONCLUSIONS: Cough in IPF is more prevalent in never smokers and patients with more advanced disease. Cough is an independent predictor of disease progression and may predict time to death or lung transplantation. PMID- 21615620 TI - A genetic variation in APE1 is associated with gastric cancer survival in a Chinese population. AB - Altered DNA repair can be associated with aggressive tumor biology and impact on survival of cancer patients. We investigated whether genetic variation of human apurinic/apyrimidinic (AP) endonuclease, a key multifunctional gene involved in the base excision repair pathway, would play a role in gastric cancer survival outcomes. We genotyped APE1 rs1760944 by the TaqMan method in 925 gastric cancer patients. Analyses of association between the polymorphism and survival outcomes were carried out using the Kaplan-Meier method, Cox proportional hazards models, and the log-rank test. Survival analyses for all patients showed that the differences in median survival time between gastric cancer carriers with APE1 rs1760944 TT (55 months) and those with GT/GG (78 months), were statistically significant (P = 0.025, log-rank test). Kaplan-Meier survival estimates revealed that gastric cancer patients carrying the GT/GG genotypes had a higher survival than TT, and this protective effect was also more pronounced among subgroups with tumor size >5 cm (hazard ratio = 0.66, 95% confidence interval = 0.49-0.88), diffuse-type gastric cancer (0.76, 0.60-0.97), T3 depth of invasion (0.73, 0.57 0.93), lymph node metastasis (0.73, 0.58-0.92), no distant metastasis (0.81, 0.66 0.99), and TNM stage III and IV (0.75, 0.58-0.99 for stage III; 0.50, 0.29-0.88 for stage IV). Our results showed that the genetic variant rs1760944 in APE1 was associated with gastric cancer survival in a Chinese population. Larger studies are needed to verify our findings in different populations. PMID- 21615621 TI - Clinical significance of serum levels of immune-associated molecules, uric acid and soluble MHC class I chain-related molecules A and B, as diagnostic tumor markers for pancreatic ductal adenocarcinoma. AB - Immune-associated molecules play important roles in cancer development and progression. The aims of this study were to determine the diagnostic utility of uric acid (UA) and soluble MHC class I chain-related molecules A (sMICA) and B (sMICB) in pancreatic ductal adenocarcinoma (PDAC) compared with those of cancer antigen 19-9 (CA19-9), the most commonly available tumor marker for PDAC. We evaluated serum levels of UA, sMICA and sMICB along the carcinogenic process of PDAC obtained from 148 individuals composed of normal (n = 70), chronic pancreatitis (n = 23) and PDAC (n = 55), and compared them with those of CA19-9. We also evaluated the correlations of these biomarkers with tumor size, resectability or TNM stage, and tested logistic regression to ascertain the potential usability of these markers for the detection of PDAC. We also investigated the correlations among these biomarkers. Serum UA, sMICA and sMICB differed significantly according to groups (Kruskal-Wallis, P < 0.05), and were closely correlated with the development of PDAC. Serum sMICA were correlated with distant metastasis and sMICB were correlated with unresectability. Sensitivity and specificity of sMICA and sMICB were higher than CA19-9, and a multi-maker panel using all tested markers (UA, sMICA, sMICB and CA19-9) demonstrated the best potential for detecting PDAC (94.2% sensitivity at 93.3% specificity). The three tested markers also showed added diagnostic potentials to overcome the limitation of CA19-9 by differentiation of PDAC from non-cancerous conditions when CA19-9 is inappropriate. In conclusion, serum UA, sMICA and sMICB might be useful screening or differential diagnostic biomarkers for PDAC to complement CA19-9. PMID- 21615622 TI - Expression of SLCO1B3 is associated with intratumoral cholestasis and CTNNB1 mutations in hepatocellular carcinoma. AB - Recent studies have shown that intratumoral cholestasis is a hallmark of CTNNB1 mutations in hepatocellular carcinomas (HCC). Here, we analyzed the expressions of genes involved in bile acid and bilirubin metabolism and their correlation with the mutational status of CTNNB1 in a series of HCC. The expressions of CYP7A1 and CYP27A1, which encode rate-limiting enzymes in bile acid synthesis, were unaltered or only marginally increased in CTNNB1-mutated HCC compared with those in HCC with wild-type CTNNB1. Among the genes involved in bile acid and bilirubin transport, the expression of SLCO1B3 was significantly elevated in HCC with CTNNB1 mutations, whereas the expression of ABCC4 was elevated in HCC with wild-type CTNNB1. Immunohistochemistry confirmed the frequent expression of SLCO1B3 in CTNNB1-mutated HCC at the protein level, but not in most HCC with wild type CTNNB1. Immunohistochemistry for MRP4 (encoded by ABCC4) partly agreed with ABCC4 expression, but most cases did not express detectable levels of MRP4. Notably, all HCC with bile accumulation, including those without CTNNB1 mutations, expressed SLCO1B3, suggesting that SLCO1B3 expression, rather than CTNNB1 mutation, is the critical determinant of intratumoral cholestasis. As SLCO1B3 is involved in the uptake of a number of chemotherapeutic and diagnostic agents, SLCO1B3 expression and the status of CTNNB1 mutation might need to be considered in the drug delivery to HCC. PMID- 21615623 TI - Effect of 5-HT4 receptor agonist mosapride citrate on rectosigmoid sensorimotor function in patients with irritable bowel syndrome. AB - BACKGROUND: The 5-HT(4) receptor agonist, mosapride citrate, accelerates gastric emptying. However, the effect of mosapride on colonic function has not been well investigated. We examined whether mosapride changes rectosigmoid motility and perception in patients with irritable bowel syndrome (IBS). METHODS: Thirty-seven patients with IBS and 18 healthy subjects were studied. All subjects underwent a rectosigmoid barostat test to measure pain perception to intraluminal distention and resting smooth muscle motility for 20 min in the fasting state. Irritable bowel syndrome patients were then randomly assigned to receive either mosapride 15 mg (n=19) or placebo (n=18) orally with 200 mL water. Rectosigmoid motility and perception were measured again for 60 min following dosing. Rectosigmoid tone and contractility were evaluated in each 10-min period. KEY RESULTS: The pain threshold in the patients was significantly lower than that in controls (P<0.01). There were no differences between mosapride and placebo groups in pain threshold, barostat bag volume, or number of contractions at baseline. Mosapride significantly decreased the mean bag volume (P<0.01; group * period interaction by two-way anova) and increased the mean number of contractions (P<0.05) compared with placebo, but did not affect the perception. In IBS patients with constipation (i.e., excluding diarrhea-predominant subjects), mosapride (n=13) increased rectosigmoid tone (P<0.01) and contractions (P<0.05) more than placebo (n=14). CONCLUSIONS & INFERENCES: Mosapride stimulates colonic motility without any adverse effect. These findings suggest that mosapride may have the potential to treat IBS patients with constipation and/or functional constipation. Further clinical trials are warranted to confirm the efficacy of this agent. PMID- 21615624 TI - Improving the assessment of TIAs [corrected]. PMID- 21615625 TI - Impulse control disorders and dopamine dysregulation in Parkinson's disease: a broader conceptual framework. AB - BACKGROUND: Impulse control disorders (ICDs) and dopamine dysregulation syndrome (DDS) in Parkinson's disease are motivation-based behaviours that involve repetitive occurrences of impulsive and uncontrolled activity. Psychiatric classification is currently inconsistent and unclear. An accurate conceptualisation of these problems is important to guide research and treatment. METHODS AND RESULTS: The review considers conceptual and methodological problems underlying the diagnosis of ICDs and the assessment of their severity. Whilst having features of obsessive-compulsive spectrum model, ICD-5 may bring them together for the first time into a single category of behavioural addictions. Whilst matching clinical and biological evidence, any such psychiatric classification in Parkinson's disease will remain complicated by the interactions of pathophysiology and medication and fail to capture the range of subthreshold but still clinically significant symptomatology. CONCLUSIONS: A non-diagnostic, dimensional construct of disinhibitory psychopathology may be a useful tool to guide research and inform treatment. The role of dysphoria is suggested as a further important factor in driving some of these problem behaviours. This opens the opportunity for adjunctive psychological approaches in management. PMID- 21615626 TI - Tick-borne encephalitis in Latvia 1973-2009: epidemiology, clinical features and sequelae. AB - BACKGROUND AND PURPOSE: To report a 37-year observational experience in Latvia relating the incidence of human tick-borne encephalitis (TBE) and its clinical manifestations, to the field abundance of ticks. METHODS: Tick abundance was measured by standard flagging techniques. Incidence of human tick-borne disease was derived from Public Health reporting data. Clinical and follow-up data were determined from hospital cohorts from 1973 to 2009. RESULTS: Two TBE incidence peaks in the mid-1970s and the 1990s correlated with increased field abundance of ticks. Increased human TBE in the 1970s was associated with higher field abundance of both Ixodes ricinis and I. Persulcatus. The 1990s peak was particularly associated with I. ricinus, the species predominating in western/central Latvia, and with other factors, including changed agricultural land usage. Proportions of patients with meningitic or focal forms of TBE were similar in the two outbreaks and the intervening periods. Meningeal irritation occurred in 90%, altered consciousness in 19%, ataxia in 34%, seizures in 9%, bulbar features in 2-3% and limb weakness in 15% with shoulder amyotrophy predominating in 5%. Annual mortality varied from 0 to 1.3% and was not related to the overall incidence of TBE. Follow-up for 1-13 years of a cohort of 100 patients revealed long-term sequelae in over 50%, more commonly in those suffering focal forms of acute TBE. CONCLUSIONS: Clinical features and mortality of the 1970s and 1990s TBE outbreaks were similar and did not point to a change in virulence. PMID- 21615627 TI - Association of non-diabetic hyperglycemia with autonomic shift in acute ischaemic stroke. AB - BACKGROUND AND PURPOSE: The etiology of hyperglycemia in acute stroke remains controversial. It is unclear whether hyperglycemia arises as an epiphenomenon of stroke or as a reflection of underlying diabetes. Autonomic shift to sympathetic overactivity has been repeatedly observed in acute stroke. We hypothesize that hyperglycemia in acute stroke relates to autonomic imbalance and that the respective deleterious effects on stroke outcome may be cross-linked. METHODS: A total of 75 non-diabetic patients with ischaemic stroke were included in a prospective study. Glucose levels at admission, fasting glucose, and glucose profiles were recorded. Autonomic function was quantified by the assessment of spontaneous baroreflex sensitivity (BRS) using a cross-correlation method. Demographic and clinical data including stroke volumes and admission National Institute of Heath Stroke Scale scores were included into the analysis. Functional outcome at 90 days was assessed using the modified Rankin Scale. RESULTS: Hyperglycemia was correlated with decreased BRS independent of stroke severity or volume (r = -0.46, P < 0.001). In two separate regression models, glucose levels and BRS independently predicted unfavorable outcome at 3 months (OR = 1.06, CI = 1.02-1.11, P = 0.004 and OR = 0.75, CI = 0.56-0.99, P = 0.04). However, combining the models, only glucose levels (OR = 1.06, CI = 1.02-1.11, P = 0.004) remained independent predictor of outcome at 3 months. CONCLUSIONS: We observed an association between hyperglycemia and decreased BRS in non-diabetic patients, suggesting that hyperglycemic reaction in acute stroke may reflect stroke-related autonomic changes. Moreover, outcome effects of autonomic changes and hyperglycemia seem to be interdependent, putatively having the sympatho-vagal imbalance as common underlying mechanism. The possible therapeutic relevance of this finding warrants further studies. PMID- 21615628 TI - Quality circles for pharmacotherapy to modify general practitioners' prescribing behaviour for generic drugs. AB - RATIONALE, AIMS AND OBJECTIVES: In Austria, the participation of general practitioners (GPs) in so-called 'quality circles for pharmacotherapy' (QCPs) was taken as a special approach to increase the use of generics and possibly, to improve the quality and efficiency of prescribing patterns in primary care. This study aimes at exploring GPs' perception of QCPs whether they think that taking part has helped to change their prescribing habits, their opinions on generics in general and the issues that arise for them in attempting to promote their use. METHODS: Qualitative analysis was used to evaluate QCP protocols for their potential to evoke discussion in the group and for their relevance to our study questions. RESULTS: Of the 821 self-employed GPs in Vienna under contract with the Vienna District Health Insurance Fund 445 took part at least once in the study period. Seven main topics, which provide insight into various aspects of patient care in primary care, were identified: QCPs work, generic drug prescription, problems related to the sale of generics, patient counselling and education, therapy adherence, coordination of care, competence and medical education. From all prescribed drugs for which generics were available in the fourth quarter of the year 2003 GPs prescribed 33.91% generics, in the fourth quarter of 2004 43.97%, in the fourth quarter of 2005 46.31%, and in the fourth quarter of 2006 49.88%. CONCLUSIONS: Peer review groups can be an important method of quality improvement in GPs' prescribing behaviour in favour of generics. QCPs also facilitate the exchange between GPs on problems encountered and provide feedback to policy makers. PMID- 21615629 TI - The applicability of grading systems for guidelines. AB - RATIONALE: This study focused on factors that most concern specialist societies when choosing an evidence grading system, such as methodological strengths and weaknesses, applicability and ease of use. The grading systems chosen were the Scottish Intercollegiate Guidelines Network (SIGN), the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and the National Service Framework for long-term neurological conditions critical appraisal tool (NSF-LTC). METHODOLOGY: Twelve assessors, representing typical members of society based guideline development groups, graded papers and a recommendation using a key question as a guide. Key questions and recommendations were extracted from existing clinical guidelines representing a variety of research fields. Assessors were given 3 months to grade the papers using the grading systems and to complete a semi-structured qualitative questionnaire. The results were independently assessed for emerging themes. RESULTS: Assessors felt all three systems had strengths and weaknesses depending on the type of evidence being graded. GRADE was seen as the most complex but rigorous system, while SIGN and NSF were seen as easier and more flexible to use, but less methodologically rigorous. In grading the evidence, 10% of assessors used GRADE incorrectly, 33% used SIGN incorrectly and 75% used NSF-LTC incorrectly. In grading the recommendations, 60% used GRADE incorrectly, 50% used SIGN incorrectly and 50% used NSF-LTC incorrectly. IMPLICATIONS: It is recommended that specialist societies consider the type of evidence they will be evaluating and the research experience of the appraisers before selecting a grading system. Additionally, appraisers should have training in appraising and grading evidence using the system to be employed. PMID- 21615630 TI - Activated protein C protects vascular endothelial cells from apoptosis in malaria and in sepsis. AB - OBJECTIVE: In malaria and sepsis, apoptotic endothelial damage is preventable in vitro by antioxidants and protease inhibitors. Activated protein C, which has anti-apoptotic effects, improves survival in sepsis. Therefore, we studied whether activated protein C prevents endothelial cell apoptosis, induced by serum from patients with malaria or sepsis. METHODS: Endothelial cells were incubated with patient sera (Plasmodium falciparum malaria, Escherichia coli sepsis, Staphylococcus aureus sepsis) or culture supernatants of the respective organisms, with or without neutrophils. Activated protein C was used to reduce endothelial cell apoptosis in vitro. The proportion of apoptotic endothelial cells was determined by TUNEL staining. RESULTS: The apoptosis-inducing effect of patient sera or culture supernatants (P. falciparum, E. coli, S. aureus) on endothelial cells was augmented by neutrophils and reduced by activated protein C in the presence of neutrophils. Pre-incubating either endothelial cells or neutrophils with activated protein C also reduced the endothelial cell apoptosis rate. The pro-apoptotic effect of P. falciparum supernatant was reduced by pan caspase inhibitor and caspase 8 inhibitor, but not by caspase 9 inhibitor. The pro-apoptotic effect of E. coli and S. aureus supernatants was also reduced by caspase 9 inhibitor. CONCLUSIONS: Activated protein C protects vascular endothelial cells from apoptosis triggered by patient sera or culture supernatants in combination with neutrophils. It seems to act both on neutrophils and on endothelial cells. Activated protein C blocks caspase-8-dependent apoptosis, which accounts for endothelial damage in sepsis and malaria. Therefore, activated protein C might offer clinical benefit not only in sepsis but also in malaria. PMID- 21615631 TI - Social exposure to an antiretroviral treatment programme in rural KwaZulu-Natal. AB - OBJECTIVE: To investigate the prevalence of social exposure to a large, government-run ART programme in rural South Africa. METHOD: Clinical data on 6681 patients were matched with demographic data on a nearly complete cohort of 102,359 people residing in the programme catchment area. We calculated the proportion of residents in the demographic surveillance area that were members of a household, or resided in a compound where someone had initiated ART or received pre-ART care. RESULTS: By January 2010, 3% of the population had initiated ART. However, 25% of the population shared household membership or resided in a compound with someone who had initiated ART; 40% shared household or living arrangements with people who had either initiated ART or were enrolled in pre-ART care. CONCLUSION: Such high rates of social exposure suggest that ART programmes in HIV endemic areas are likely to have significant population-level effects on social norms and economic welfare. These results also point to the opportunity to reach large numbers of people with health and social services through existing ART programmes. PMID- 21615632 TI - Safety - an entry point to strengthening health systems in Africa. PMID- 21615633 TI - Evaluation of the antibiotic biosynthetic potential of the genus Amycolatopsis and description of Amycolatopsis circi sp. nov., Amycolatopsis equina sp. nov. and Amycolatopsis hippodromi sp. nov. AB - AIMS: To describe three new Amycolatopsis strains and assess the antibiotic biosynthetic potential of the genus. METHODS AND RESULTS: Three strains, designated S1.3(T) , S3.6(T) and SE(8)3(T) , belonging to the genus Amycolatopsis were isolated and found to cluster together by 16S rRNA and gyrB gene-based phylogenetic analysis. Genetic distance values, based on the gyrB gene, were calculated between the strains and their closest relatives and were all above the threshold value of 0.02 that has been proposed to distinguish Amycolatopsis type strains. DNA-DNA hybridization experiments against related type strains confirmed that strain S3.6(T) represents a unique genomic species. Strain S3.6(T) was also found to be distinct from strains S1.3(T) and SE(8)3(T) , the latter two of which were also shown to be distinct from each other. Antibiotic biosynthetic genes were identified from multiple Amycolatopsis strains, and their presence was found to be phylogenetically associated. CONCLUSIONS: The data presented in this study indicate that strains S1.3(T) , SE(8)3(T) and S3.6(T) belong to three novel species, for which the names Amycolatopsis circi sp. nov. (= DSM 45561(T) = NRRL B-24841(T) ), Amycolatopsis equina sp. nov. (= DSM 45563(T) = NRRL B-24842(T) ) and Amycolatopsis hippodromi sp. nov. (= DSM 45562(T) = NRRL B-24843(T) ) are proposed. SIGNIFICANCE AND IMPACT OF THE STUDY: Three new species of Amycolatopsis are described, and the knowledge of the antibiotic biosynthetic potential of the genus has been extended. PMID- 21615634 TI - The presence of atrazine and atrazine-degrading bacteria in the residential, cattle farming, forested and golf course regions of Lake Oconee. AB - AIMS: To assess the concentration of atrazine in Lake Oconee and develop a qPCR assay as a potential marker for the presence of atrazine-degrading bacteria indicating atrazine contamination. METHODS AND RESULTS: Water and sediment samples were collected from the Oconee Lake at four golf course sites, two residential sites, one cattle farming site and a forested site. Atrazine concentration at the study sites was determined using an ELISA kit and indicated the presence of atrazine from 0.72 ppb at the forested sites to 1.84 ppb at the golf course sites. QPCR results indicate the presence of atzA gene (atrazine chlorohydrolase) from 1.51 * 10(2) gene copies at the residential sites to 3.31 * 10(5) gene copies per 100 ml of water at the golf course regions of the lake and correlated (r = 0.64) with atrazine concentration. Sediment samples had higher atzA gene copies compared with the water samples (P < 0.05). CONCLUSIONS: Atrazine concentration and the highest quantity of atzA gene were detected in the golf course regions of the lake. Overall, atrazine concentration monitored in Lake Oconee was below the Environment Protection Agency (EPA) regulatory standards. SIGNIFICANCE AND IMPACT OF THE STUDY: Quantitative PCR is an efficient technique for assessing the presence of atrazine catabolism gene as a functional marker for atrazine-degrading bacteria and the presence of atrazine contamination. PMID- 21615635 TI - Effects of grape marcs acidification treatment on the evolution of indigenous yeast populations during the production of grappa. AB - AIMS: Grappa is a typical Italian product obtained from the distillation of grape marcs, the main by-product of grape crushing. One technological treatment frequently performed on marcs is their acidification, in order to contrast the development of unwanted spoilage bacteria during the storage period needed for alcoholic fermentation. A pilot-scale experiment was set-up to study the dynamics of yeast populations during a 30-day fermentation of acidified and nonacidified Prosecco grape pomace. METHODS AND RESULTS: Saccharomyces cerevisiae population, examined after 4 and 15 days of storage by mitochondrial DNA-RFLP analysis, resulted considerably different at strain level upon acidification. In particular, although the number of different strains rescued appeared particularly high in both kind of marcs compared with what happens in must fermentation, in the acidified material such number tends to moderately decrease during storage. CONCLUSIONS: Results obtained evidence that the acidification treatment did not influence yeast population neither in terms of number of cells nor in terms of biodiversity at species level. Therefore, such treatment can be used in distillery without negatively influencing ethanol production. SIGNIFICANCE AND IMPACT OF STUDY: Even though some data are available on the effects of technological treatments on the chemical composition of the distillate, no microbiological studies have been published so far on the consequence of these practices on composition, biodiversity and evolution of yeast population. PMID- 21615636 TI - Circulation of enteroviruses in Cyprus assessed by molecular analysis of clinical specimens and sewage isolates. AB - AIMS: To study the circulation of non-polio enteroviruses in the Cypriot population and assess the clinical relevance of different serotypes by the analysis of clinical specimens and environmental samples. METHODS AND RESULTS: Sewage samples were collected on a monthly basis for 2 years from all five districts of Cyprus. Enteroviruses were isolated using the VIRADEN method and typed by partial VP1 region sequencing. In addition, all enterovirus-positive clinical samples received during this 2-year period were typed, and a phylogenetic comparison of clinical and sewage samples based on the partial VP1 sequences was made. A significant difference between the most common serotypes found in sewage and clinical samples was observed. While Coxsackieviruses B constituted the most frequent serotypes in sewages, Echoviruses 30 and 18 prevailed in clinical samples. CONCLUSIONS: The phylogenetic analysis revealed that certain enterovirus strains circulate in the population over long period of time, while others are observed only sporadically and disappear quickly. For some serotypes, it was observed that several strains were cocirculating in the population but only some of them being detected also in clinical specimens. SIGNIFICANCE AND IMPACT OF THE STUDY: This study, for the first time, compares enteroviruses isolated from environmental samples and clinical specimens on a molecular level, which allowed for strain identification and discrimination. A more comprehensive molecular analysis of these strains will help identify factors, which determine different degrees of pathogenicity. PMID- 21615637 TI - Consumers' interpretation and use of comparative information on the quality of health care: the effect of presentation approaches. AB - BACKGROUND: Public reports about health-care quality have not been effectively used by consumers thus far. A possible explanation is inadequate presentation of the information. OBJECTIVE: To assess which presentation features contribute to consumers' correct interpretation and effective use of comparative health-care quality information and to examine the influence of consumer characteristics. DESIGN: Fictitious Consumer Quality Index (CQI) data on home care quality were used to construct experimental presentation formats of comparative information. These formats were selected using conjoint analysis methodology. We used multilevel regression analysis to investigate the effects of presenting bar charts and star ratings, ordering of the data, type of stars, number of stars and inclusion of a global rating. SETTING AND PARTICIPANTS: Data were collected during 2 weeks of online questioning of 438 members of an online access panel. RESULTS: Both presentation features and consumer characteristics (age and education) significantly affected consumers' responses. Formats using combinations of bar charts and stars, three stars, an alphabetical ordering of providers and no inclusion of a global rating supported consumers. The effects of the presentation features differed across the outcome variables. CONCLUSIONS: Comparative information on the quality of home care is complex for consumers. Although our findings derive from an experimental situation, they provide several suggestions for optimizing the information on the Internet. More research is needed to further unravel the effects of presentation formats on consumer decision making in health care. PMID- 21615638 TI - Close to the bench as well as at the bedside: involving service users in all phases of translational research. AB - AIM: The paper aims to develop a model of translational research in which service user and other stakeholder involvement are central to each phase. BACKGROUND: 'Translational' is the current medical buzzword: translational research has been termed 'bench to bedside' research and promises to fast-track biomedical advances in the service of patient benefit. Models usually conceive of translational research as a 'pipeline' that is divided into phases: the early phase is characterized as the province of basic scientists and laboratory-based clinical researchers; the later phases focus on the implementation, dissemination and diffusion of health applications. If service user involvement is mentioned, it is usually restricted to these later phases. METHODS: The paper critically reviews existing literature on translational research and medicine. The authors develop a theoretical argument that addresses why a reconceptualization of translational research is required on scientific, ethical and pragmatic grounds. RESULTS: The authors reconceptualize the model of translational research as an interlocking loop rather than as a pipeline, one in which service user and other stakeholder involvement feed into each of its elements. The authors demonstrate that for the 'interlocking loop' model of translational research to be materialized in practice will require changes in how health research is structured and organized. CONCLUSION: The authors demonstrate the scientific, ethical and pragmatic benefits of involving service users in every phase of translational research. The authors' reconceptualized model of translational research contributes to theoretical and policy debates regarding both translational research and service user involvement. PMID- 21615639 TI - Engagement: an indicator of difference in the perceptions of antenatal care for pregnant women from diverse socioeconomic backgrounds. AB - BACKGROUND: Socioeconomically deprived women are at greater risk of adverse pregnancy outcomes. Research tends to focus on access of services. Yet access may not equate with the equity of services for women from different socioeconomic backgrounds. OBJECTIVES: To determine whether pregnant women's perceptions of antenatal provision differed in relation to their socioeconomic deprivation ranking (determined by the Scottish Index of Multiple Deprivation 2006). DESIGN: A longitudinal, qualitative study with comparative antenatal case studies between January 2007 and April 2009. SETTING/PARTICIPANTS: Cases were primigravida women from 'least deprived' (n=9) and 'most deprived' (n=12) geographical areas within one local authority in Scotland. ANALYSIS: Data were analysed using case study replication analysis. RESULTS: There was little difference in access to antenatal services between the 'least' and 'most' deprived groups. Perception of care differed in relation to the level of 'engagement' (defined using constructs of: language and personalization of care; power and relationships; and health literacy). Engagement was evidenced in most of the 'least deprived' cases and almost none of the 'most deprived' cases. Specifically, socioeconomically deprived women described less evidence of personal connection to their own care, effective communication and the opportunity for shared decision making. CONCLUSION: In women from socioeconomically deprived areas, access may be a less useful indicator than engagement when assessing antenatal service quality. As engagement levels may be one method by which to predict and improve health outcomes, a more equitable antenatal service may need to be developed through the early identification of those women at risk of non-engagement. PMID- 21615640 TI - Cakes for cure: the role of charities in the embedding of innovative cancer treatment technologies. AB - BACKGROUND AND AIMS: Investment in innovative health technologies has been a focus of increasing critical interest in the social sciences. With proponents of such systems expounding new techniques, a strong normative context emerges for their adoption. Informed by the field of Science and Technology Studies (STS), this study focuses on the discourse used by charitable organizations involved in such investments and how their involvement contributes to the enrolment of vulnerable groups, such as cancer sufferers. A central concern of STS is the strategies scientists use when talking about their work. Methods of communication may often suggest there is only one possible solution to a perceived problem. Such determinism may be reflected in material used by fundraisers where technologies are discussed in a normative, deterministic and definitely desirable way. Charitable organizations in charge of fundraising may thus become deeply enrolled within programmes of development in which the legitimacy of knowledge claims and evidence production are difficult to examine. METHODS: Drawing on interviews with health-care practitioners and anonymised examples from public fundraising campaigns linked to two UK hospitals, this study explores a theoretical proposition that fundraising materials can be regarded as tools for the enrolment of vulnerable groups in the processes of technological change. RESULTS AND CONCLUSIONS: Where patients are called upon to donate money for the newest, and hence perceived best, equipment, practitioners were of the opinion that unnecessary pressure may be placed on the public to support campaigns, the value of which may be unclear. PMID- 21615641 TI - Peer education for advance care planning: volunteers' perspectives on training and community engagement activities. AB - BACKGROUND: Peer education by volunteers may aid attitudinal change, but there is little understanding of factors assisting the preparation of peer educators. This study contributes to conceptual understandings of how volunteers may be prepared to work as peer educators by drawing on an evaluation of a training programme for peer education for advance care planning (ACP). OBJECTIVES: To report on volunteers' perspectives on the peer education training programme, their feelings about assuming the role of volunteer peer educators and the community engagement activities with which they engaged during the year after training. To examine broader implications for peer education. DESIGN: Participatory action research employing mixed methods of data collection. PARTICIPANTS: Twenty-four older volunteers and eight health and social care staff. DATA COLLECTION METHODS: Evaluative data were gathered from information provided during and at the end of training, a follow-up survey 4 months post-training; interviews and focus groups 6 and 12 months post-training. FINDINGS: Volunteers' personal aims ranged from working within their communities to using what they had learnt within their own families. The personal impact of peer education was considerable. Two-thirds of volunteers reported community peer education activities 1 year after the training. Those who identified strongly with a community group had the most success. CONCLUSION: We reflect on the extent to which the programme aided the development of 'critical consciousness' among the volunteers: a key factor in successful peer education programmes. More research is needed about the impact on uptake of ACP in communities. PMID- 21615643 TI - Changes in hepatitis B virus DNA levels and liver function after transcatheter arterial chemoembolization of hepatocellular carcinoma. AB - AIM: Reports concerning changes in hepatitis B virus (HBV) status and liver function in hepatocellular carcinoma (HCC) during or after transcatheter arterial chemoembolization (TACE) have been rare and the results inconsistent. The objective of this retrospective study was to evaluate these parameters in a large cohort of HBV-related HCC patients. METHODS: One hundred and seventy-two hepatitis B surface antigen positive HCC patients with Child-Pugh grade A or B liver disease who underwent 228 sessions of TACE were enrolled, and related clinical and laboratory data were analyzed. RESULTS: In total, HBV reactivated in 33 (14.5%), remained stable in 152 (66.7%) and decreased in 43 (18.8%) sessions. Univariate analysis revealed that sex and HBV DNA levels correlated with changes in HBV DNA status after TACE, while hepatitis B e-antigen (HBeAg), prothrombin time and chemotherapeutic agents were marginally significant factors. Multivariate analysis demonstrated that the major factors that influenced the HBV DNA status were baseline HBV DNA levels(P = 0.0002) and HBeAg (P = 0.0387). A comparison of the post-TACE (30-90 days) liver function to the baseline revealed no significant differences. The reactivation group has the highest rate of exacerbation (12.1%) compared with the stable group (5.9%) and downregulation group (4.7%). CONCLUSION: HBV DNA changes after TACE included reactivated, decreased and stable HBV DNA levels. Although HBV reactivation did not necessarily result in exacerbation of liver damage and most HCC patients with Child-Pugh grade A and B tolerated TACE well, careful post-procedure monitoring and managing is needed. PMID- 21615642 TI - Follow-up care in cancer: adjusting for referral targets and extending choice. AB - BACKGROUND: Over recent years, several initiatives have impacted on the referral of patients to secondary care, most notably targets for urgent referral in suspected cancer and the patient choice agenda. At the same time, improved long term survival in cancer has increased numbers attending follow-up, doubts about the effectiveness of specialist follow-up have emerged, and alternative models of follow-up have been tested. AIM: The aim of the study was to explore patient and carer perspectives on the flexibility and responsiveness of cancer services. This article focuses on findings relating to referral, subsequent outpatient appointments and cessation of outpatient follow-up. METHODS: Issues were explored in a qualitative study using face-to-face interviews with a purposive sample of 54 people affected by cancer. Data were analysed concurrently with data collection, using qualitative analysis software. FINDINGS: The study gave rise to a number of salient themes. Links were identified between three of these: choice and responsiveness during referral; the flexibility and responsiveness of outpatient appointment systems; and negotiating cessation of follow-up. It appeared that policy on urgent referrals might be adversely affecting practice relating to appointment systems and the continuance of follow-up. DISCUSSION AND CONCLUSIONS: Hospital-based cancer follow-up is being given decreasing priority because of doubts about effectiveness and a target-driven focus on referral. This is impacting on patients, who may value outpatient follow-up as a 'safety net' but have difficulties in obtaining appointments, and may be discharged without negotiation or adequate support. For these reasons, new forms of flexible/responsive aftercare are urgently needed. PMID- 21615644 TI - Smoking, family history and urinary tract infection are associated with primary biliary cirrhosis: A meta-analysis. AB - AIM: This meta-analysis was conducted to provide more precise evidence for association between primary biliary cirrhosis (PBC) and smoking and some other factors. METHODS: We searched the databases PubMed, EMBASE, Cochrane Library and China National Knowledge Infrastructure up to 31 December 2010. Data were extracted by two persons independently. Homogeneity of effects across studies was assessed using the chi(2) -test statistic and quantified by I(2) . Odds ratio (OR) and 95% confidence intervals (CI) were calculated based on fixed- or random effects models. The publication bias was analyzed by Egger and Begg tests. RESULTS: A total of five studies were selected according to inclusion criteria. With the fixed-effects model, the pooled OR for PBC and smoking and family history of PBC were 1.67 (95% CI = 1.41-1.92) and 7.56 (95% CI = 1.90-13.22). With the random-effects model, the pooled OR for thyroid disease and urinary tract infection (UTI) were 3.08 (95% CI = 0.84-5.32) and 2.02 (95% CI = 1.40 2.65), respectively. No evidence of publication bias was observed by means of Begg and Egger tests for the factors. CONCLUSION: This meta-analysis suggested that smoking, family history of PBC and UTI were strongly associated with PBC in a white population by systematic review of five existing studies, and the association remains to be validated in other populations. PMID- 21615645 TI - Increase in de novo allergies after paediatric liver transplantation: the Brisbane experience. AB - Pediatric liver transplantation is a successful procedure with 10-yr survival rate of 70%; following transplantation, the emphasis on promoting good quality of life is important. The increasing prevalence of allergic disorders in the general population and an increase in food allergy following solid organ transplantation are described in patients, especially in children, but the contribution to morbidity post-OLT has not been addressed. OBJECTIVES: Identifying the incidence de novo allergies post-OLT performed by QLTS over 11 yr. METHODS: Comprehensive medical record review of OLT recipients during study period. RESULTS: From 1st July 1998 to 1st August 2009, 78 children received 85 cadaveric OLT; 60 children survived. Allergic disease was documented in 24/60 (40%) survivors. De novo food allergies were diagnosed in 12/60 (20%) (Table 2), 9/12 occurred in children who were infants at time of transplant. Ten of 12 had severe allergies, six anaphylactic; 6/60 (10%) carry an EpiPen. Only 31/60 (51%) diagnosed are followed in Queensland, suggesting severe allergic disease in our cohort is an underestimate. CONCLUSION: Serious allergic disease post-OLT is clinically important, especially in infants at time of transplant, and should be targeted for specialist allergist referral and risk management. [Table: see text]. PMID- 21615646 TI - Protocol biopsy-driven interventions after pediatric renal transplantation. PMID- 21615647 TI - Long-term liver allograft fibrosis in children: more questions than answers. PMID- 21615648 TI - Recurrent intrahepatic pigmented stones after liver transplantation in a patient with hemoglobin SC disease: case report and review of the literature. AB - Patients with hemoglobinopathies may have hepatic involvement, which if severe, can lead to chronic liver disease and a need for liver transplant. Here, we present a case of a 16-yr-old female adolescent who presented to our center with hemoglobin SC disease, obstructive jaundice because of pigmented intrahepatic biliary stones, and progressive liver disease. She underwent a successful liver transplant but a few years later, she developed recurrent cholangitis and graft dysfunction because of recurrent intrahepatic biliary stones. Recurrent formation of intrahepatic stones after liver transplant is a rare and severe complication in patients with hemoglobinopathies. We recommend hypertransfusion therapy and surveillance imaging studies after liver transplant for early detection and prevention of this complication. PMID- 21615649 TI - Diabetic ketoacidosis: persistence and paradox. PMID- 21615650 TI - Infant anthropometry, early life infection, and subsequent risk of type 1 diabetes mellitus: a prospective birth cohort study. AB - BACKGROUND: Higher birthweight is associated with increased type 1 diabetes mellitus (T1DM) risk, but the contribution of higher adiposity or lean mass is unclear. In this Tasmanian infant cohort, early upper respiratory infection has been associated with higher asthma risk. PATIENTS AND METHODS: Eligible infants represented one-fifth of live births in Tasmania, 1988-1995. Hospital interview data (day 6) were obtained on 96.3% (10 628/11 040), home (5 wk) visit data (38 d) on 92.9% (9876/10 628) of those, then a phone (12 wk) interview (87 d). Tricep and subscapular skinfold measures and upper arm circumference were recorded at the first two interviews. T1DM cases (n = 26) arising from the age of 16 or under in Tasmania from 1988 to 2006 were ascertained. RESULTS: Higher birthweight [adjusted odds ratio (AOR) 2.82 (95% CI 1.31-6.09)], lean mid-upper arm circumference [AOR 1.76 (95% CI 1.16-2.66)], not skinfold measures, were associated with T1DM risk. Children with an early upper respiratory tract infection by 5-wk visit [AOR 2.74 (95% CI 1.19-6.32)] or ear infection by 12-wk interview [AOR 3.44 (95% CI 1.00-11.79)] were also at higher risk. Putative markers of altered microbial exposure such as resident density were not associated with T1DM risk but the effect of increasing birth order on T1DM risk differed for older (AOR 0.41, p = 0.02) than young mother (AOR 2.45, p = 0.01); difference in effect, p = 0.001. CONCLUSION: In this cohort, early upper respiratory tract infection was associated with T1DM risk, as had been previously found for asthma, consistent with immunoinflammatory upregulation. Using the detailed anthropometric measures available, the link between higher birthweight and T1DM did not appear to reflect increased adiposity. PMID- 21615651 TI - Clinical and metabolic effects of gluten free diet in children with type 1 diabetes and coeliac disease. AB - BACKGROUND: Following the recommendations of The International Society for Pediatric and Adolescent Diabetes (ISPAD) in 2000, our clinic started routine screening of children with type 1 diabetes (T1D) for coeliac disease (CD). OBJECTIVES: To determine the short-term clinical and metabolic effects of gluten free diet (GFD) in a group of children with T1D and confirmed CD. METHODS: Data were collected on all children with T1D and CD between November 2000 and November 2007 before and 12 months after commencement of GFD. Data included the presence of gastrointestinal (GI) symptoms, episodes of severe hypoglycaemia, daily insulin requirements, height, weight, body mass index (BMI), glycosylated haemoglobin (HbA1c), haemoglobin, and persistence of autoantibodies. The effects of GFD on these parameters were studied and compared with those from the revised ISPAD Guidelines in 2007. RESULTS: Four hundred and sixty-eight children with T1D were screened, of whom 23 patients were diagnosed with CD. The mean age at diagnosis of T1D and CD was 6.8 years and 11.1 years, respectively. Ten out of 11 children showed improvement in their GI symptoms, while 6 out of 8 patients had no further severe hypoglycaemic episodes. Nine patients remained positive for antiendomysial antibodies after GFD. There was no significant change in the standard deviation score for height, weight, and BMI or the mean HbA1c and Hb before and after GFD. However the mean insulin requirement increased from 0.88 to 1.1 units/kg/day, which was statistically significant (p < 0.005). CONCLUSION: In our experience, GFD showed short-term benefits by reducing GI symptoms and severe hypoglycaemia while the insulin requirement increased significantly. PMID- 21615654 TI - The Tohoku Earthquake and Tsunami disaster: our condolences to survivors and families. PMID- 21615655 TI - Organizational risk management and nurses' perceptions of workplace risk associated with sharps including needlestick injuries in nurses in New South Wales, Australia. AB - This study aimed to determine nurse reported organizational risk management and nurses' perceptions of workplace risk associated with sharps-related injuries. A cross-sectional survey was carried out on a sample of nurses from the New South Wales Nurses' Association, Australia in 2007 (n =7423), and there were 1301 eligible participants. Overall, 73% participants reported that organizational policies were followed in the event of a "sharps including needlestick" injury. Participants reported working in sharps safety oriented organizations, routine hepatitis B vaccination, sharps disposal containers at point-of-use locations and availability of safety engineered devices in their organizations. Sharps including needlestick injury data were not routinely provided to staff, many nurses reported recapping and just one-third had recently attended sharps injury prevention training. Nurses' perceptions of risk associated with sharps including needlestick injury were variable. Health-care organizations are responsible for provision of safe workplaces and work practices, policies, workplace culture and prevention strategies, and appropriate responses when nurses are injured. These results have been used to propose recommendations to improve some of these risk management strategies. PMID- 21615652 TI - Changes in cardiometabolic risk factors, appetite-controlling hormones and cytokines after a treatment program in overweight adolescents: preliminary findings from the EVASYON study. AB - OBJECTIVE: We investigated the effects of the EVASYON program on body fatness, cardiometabolic risk factors, gut appetite-controlling hormones and serum levels of cytokines in adolescents with overweight or obesity (OW/OB). METHODS: This study comprised 13 boys (10 obese) and 12 girls (8 obese), aged 13-16 years, from a Madrid Hospital. The EVASYON program was based on a calorie-restricted diet (10 40%), increased physical activity (at least 60 min/day 5 days a week), psychological therapy and nutritional education for 13 months. Anthropometric and blood pressure measurements were measured before and after intervention. Serum glucose, total cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, total peptide YY and insulin levels were determined before and after intervention. Serum levels of cytokines IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNF-alpha were also assessed before and after intervention. RESULTS: A decrease in body mass index (BMI), BMI z-score, skinfolds (triceps, biceps, subscapular, thigh, and calf), sum of six skinfolds and body circumferences (arm relaxed and flexed, waist, hip, and proximal thigh) values were observed after the intervention program (all p < 0.05). In addition, diastolic blood pressure also decreased (p < 0.05). A decrease in serum leptin levels (-48.4%, p < 0.001) was observed after intervention without changes in total peptide YY and insulin levels. Levels of IL-8, IL-10, and TNF-alpha also decreased (all p < 0.05) after the intervention program. CONCLUSIONS: These preliminary results evidence that the EVASYON program may improve body fat, leptin, and some pro-inflammatory cytokines in adolescents with OW/OB. PMID- 21615656 TI - Jordanian acute coronary syndrome patients' learning needs: Implications for cardiac rehabilitation and secondary prevention programs. AB - The identification of patients' learning needs is an essential step for nurses in order to facilitate the recovery of acute coronary syndrome survivors. This study aimed to identify and prioritize the actual learning needs of these patients and to explore the differences in learning needs on the basis of sociodemographic and clinical variables. Descriptive comparative design was used, and patients' learning needs data were collected through the Patient Learning Needs Scale. The results showed that patients need a high amount of information after this syndrome. The 10 most needed educational topics belonged to the medications and treatment and activities of daily living categories. Older patients and those from lower socioeconomic backgrounds requested less information than others did. In conclusion, topics perceived by patients as important and sociodemographic variables should be considered in preparing and providing cardiac rehabilitation and secondary prevention programs. Furthermore, these programs should be redesigned considering patients' actual learning needs rather than the expected needs, and they should incorporate medications, treatment and activities of daily living, complications and symptoms, illness-related concerns, and support in the community. PMID- 21615657 TI - Improving student supervision in a Norwegian intensive care unit: a qualitative study. AB - The purpose of the study was to investigate intensive and critical care nurses' experiences of an empowerment program in the context of their role as student supervisors. Multistage focus group interviews were carried out and qualitative content analysis was performed in several steps. The overall results highlighted the need for strategies aimed at ensuring quality. The emerging themes were time, leadership and shared responsibility. Enough time promoted motivation, learning and reflection. Obligations to the student limited their leisure time and family life, and imposed some limitations during working hours. Leadership was perceived as crucial and leaders should act as strategic managers of development. The balance between "shared responsibility" and one supervisor in charge of one student was highlighted. There is a need to strengthen and improve the system of student supervision. There is a need to allocate time for learning and reflection. Who is responsible for the students must be clearly defined in the hospital, the university and in the intensive care unit, and it must be communicated. PMID- 21615658 TI - Use and disclosure of genetic information without consent: a decision-making tool for health practitioners--who, when, why and how? AB - BACKGROUND: As a result of legislative changes to the Privacy Act 1988 (Cth), Australian health practitioners in the private sector are now permitted to use or disclose patients' genetic information, without their consent, in circumstances where the health practitioner reasonably believes that doing so is necessary to lessen or prevent a serious threat to the life, health or safety of a genetic relative. AIM: This article aims to increase the reader's awareness of Guidelines developed by the National Health and Medical Research Council which are intended to assist health practitioners in making decisions about the use or disclosure of genetic information in certain circumstances. DISCUSSION: The Guidelines establish when, by whom and in what manner, use or disclosure of genetic information may take place. The Guidelines outline the factors that health practitioners should consider when determining whether use or disclosure is necessary to lessen or prevent a serious threat to an individual's life, health or safety. PMID- 21615659 TI - Australian guidelines for the assessment of iron overload and iron chelation in transfusion-dependent thalassaemia major, sickle cell disease and other congenital anaemias. AB - Iron overload is the most important cause of mortality in patients with thalassaemia major. Iron chelation is therefore a critical issue in the management of these patients and others with transfusion-dependent haemoglobinopathies and congenital anaemias. In recent years, significant developments have been made in the assessment of iron overload, including the use of magnetic resonance imaging for measuring liver and cardiac iron. Advances in the modalities available for iron chelation, with the advent of oral iron chelators including deferiprone and deferasirox in addition to parenteral desferrioxamine, have expanded treatment options. A group of Australian haematologists has convened to formulate guidelines for managing iron overload on the basis of available evidence, and to describe best consensus practice as undertaken in major Australian Haemoglobinopathy units. The results of their discussions are described in this article, with the aim of providing guidance in the management of iron overload in these patients. PMID- 21615660 TI - The evolution of species interactions across natural landscapes. AB - Given the potential for rapid and microgeographical adaptation, ecologists increasingly are exploring evolutionary explanations for community patterns. Biotic selection can generate local adaptations that alter species interactions. Although some gene flow might be necessary to fuel local adaptation, higher gene flow can homogenise traits across regions and generate local maladaptation. Herein, I estimate the contributions of local biotic selection, gene flow and spatially autocorrelated biotic selection to among-population divergence in traits involved in species interactions across 75 studies. Local biotic selection explained 6.9% of inter-population trait divergence, an indirect estimate of restricted gene flow explained 0.1%, and spatially autocorrelated selection explained 9.3%. Together, biotic selection explained 16% of the variance in population trait means. Most biotic selection regimes were spatially autocorrelated. Hence, most populations receive gene flow from populations facing similar selection, which could allow for local adaptation despite moderate gene flow. Gene flow constrained adaptation in studies conducted at finer spatial scales as expected, but this effect was often confounded with spatially autocorrelated selection. Results indicate that traits involved in species interactions might often evolve across landscapes, especially when biotic selection is spatially autocorrelated. The frequent evolution of species interactions suggests that evolutionary processes might often influence community ecology. PMID- 21615661 TI - Activation of NF-kappaB by Neisseria gonorrhoeae is associated with microcolony formation and type IV pilus retraction. AB - The early stage of infection with Neisseria gonorrhoeae (Ngo), the causative agent of gonorrhoea, is marked by type IV pilus (Tfp)-mediated attachment and the formation of bacterial microcolonies on epithelial cells. Retraction of the Ngo Tfp generates substantial force on its substrate which can elicit host cell signalling. Here, we observed that this retraction force could also activate nuclear factor (NF)-kappaB, the central signalling cascade of innate immunity. Using a p65-GFP-expressing epithelial cell line, we show that piliated Ngo induce asynchronous NF-kappaB activation in infected cells, which is temporally associated with the formation of gonococcal microcolonies. A mutant lacking PilT, an ATPase necessary for Tfp retraction, induced markedly reduced NF-kappaB activation. This was accompanied by decreased NF-kappaB target gene transcription and cytokine release. The impaired ability of the pilT mutant to activate NF kappaB was compensated by applying mechanical shear stress to the infected host cells, indicating that the mechanical forces generated by retractile pili are involved in the retraction-dependent activation of NF-kappaB elicited by gonococcal microcolonies. Thus, our work provides evidence for an intriguing relationship between microcolony growth, pilus retraction and host cell signalling, with likely implications with regard to the course of symptomatic versus asymptomatic gonococcal infections. PMID- 21615662 TI - The multifaceted role of oestrogen in enhancing Chlamydia trachomatis infection in polarized human endometrial epithelial cells. AB - The oestrogen receptor (ER) alpha-beta+ HEC-1B and the ERalpha+beta+ Ishikawa (IK) cell lines were investigated to dissect the effects of oestrogen exposure on several parameters of Chlamydia trachomatis infection. Antibody blockage of ERalpha or ERbeta alone or simultaneously significantly decreased C. trachomatis infectivity (45-68%). Addition of the ERbeta antagonist, tamoxifen, to IK or HEC 1B prior to or after chlamydial infection caused a 30-90% decrease in infectivity, the latter due to disrupted eukaryotic organelles. In vivo, endometrial glandular epithelial cells are stimulated by hormonally influenced stromal signals. Accordingly, chlamydial infectivity was significantly increased by 27% and 21% in IK and HEC-1B cells co-cultured with SHT-290 stromal cells exposed to oestrogen. Endometrial stromal cell/epithelial cell co-culture revealed indirect effects of oestrogen on phosphorylation of extracellular signal regulated kinase and calcium-dependant phospholipase A2 and significantly increased production of interleukin (IL)-8 and IL-6 in both uninfected and chlamydiae-infected epithelial cells. These results indicate that oestrogen and its receptors play multiple roles in chlamydial infection: (i) membrane oestrogen receptors (mERs) aid in chlamydial entry into host cells, and (ii) mER signalling may contribute to inclusion development during infection. Additionally, enhancement of chlamydial infection is affected by hormonally influenced stromal signals in conjunction with direct oestrogen stimulation of the human epithelia. PMID- 21615663 TI - The FbaB-type fibronectin-binding protein of Streptococcus pyogenes promotes specific invasion into endothelial cells. AB - Invasive serotype M3 Streptococcus pyogenes are among the most frequently isolated organisms from patients suffering from invasive streptococcal disease and have the potential to invade primary human endothelial cells (EC) via a rapid and efficient mechanism. FbaB protein, the fibronectin-binding protein expressed by M3 S. pyogenes, was herein identified as a potent invasin for EC. By combining heterologous gene expression with allelic replacement, we demonstrate that FbaB is essential and sufficient to trigger EC invasion via a Rac1-dependent phagocytosis-like uptake. FbaB-mediated uptake follows the classical endocytic pathway with lysosomal destination. FbaB is demonstrated to be a streptococcal invasin exhibiting EC tropism. FbaB thus initiates a process that may contribute to the deep tissue tropism and spread of invasive S. pyogenes isolates into the vascular EC lining. PMID- 21615665 TI - Revisiting the extracellular lifestyle. AB - In microbiology textbooks infectious agents are traditionally classified as intracellular or extracellular pathogens depending on whether they multiply inside or outside host cells. In recent literature an increasing number of extracellular pathogens are described in close apposition with the host cell surface embedded in plasma membrane folds, making it difficult to classify them as strictly extracellular pathogens. This review further explores this emerging new lifestyle category tentatively named 'epicellular' in reference to earlier work describing the location of the parasite Cryptosporidium parvum. The lifestyles of three diverse such pathogens were examined: the parasite Cryptosporidium parvum, the Gram-negative bacterium Neisseria meningitidis and the human T cell leukaemia virus type 1 (HTLV-1). The specific cellular location, the mechanisms of adhesion, the induction of plasma membrane folds and the subsequent functional consequences will be compared. Although current knowledge suggests different underlying mechanisms, a concept that emerges is that the particular location of these pathogens has important functional consequences for the pathogens in terms of nutrient acquisition, immune escape, resistance to mechanical stress and transmission. Re-examining the lifestyle of other classically extracellular pathogens might thus shed a new light on the way pathogens interact with cells and point to new areas of investigation. PMID- 21615664 TI - Pseudomonas aeruginosa interacts with epithelial cells rapidly forming aggregates that are internalized by a Lyn-dependent mechanism. AB - Growing evidence is pointing to the importance of multicellular bacterial structures in the interaction of pathogenic bacteria with their host. Transition from planktonic to host cell-associated multicellular structures is an essential infection step that has not been described for the opportunistic human pathogen Pseudomonas aeruginosa. In this study we show that P. aeruginosa interacts with the surface of epithelial cells mainly forming aggregates. Dynamics of aggregate formation typically follow a sigmoidal curve. First, a single bacterium attaches at cell-cell junctions. This is followed by rapid recruitment of free-swimming bacteria and association of bacterial cells resulting in the formation of an aggregate on the order of minutes. Aggregates are associated with phosphatidylinositol 3,4,5-trisphosphate (PIP3)-enriched host cell membrane protrusions. We further show that aggregates can be rapidly internalized into epithelial cells. Lyn, a member of the Src family tyrosine kinases previously implicated in P. aeruginosa infection, mediates both PIP3-enriched protrusion formation and aggregate internalization. Our results establish the first framework of principles that define P. aeruginosa transition to multicellular structures during interaction with host cells. PMID- 21615666 TI - A role for collecting duct epithelial cells in renal antibacterial defences. AB - Urinary tract infections (UTIs), which are mainly due to uropathogenic Escherichia coli (UPEC), occur via the retrograde ascent of the bacteria along the urinary tract system. The adhesion and invasion mechanisms of UPEC have been extensively studied in bladder epithelial cells, but less is known about the role of renal tubule epithelial cells (RTEC) in renal antibacterial defences. This review considers recent advances in the understanding of the role of RTECs in inducing an innate immune response mediated by Toll-like receptors (TLRs) in experimental UTI. Collecting duct cells are a preferential site of adhesion of UPEC colonizing the kidneys. Epithelial TLR4 activation induces an inflammatory response and the recruitment of lipid rafts to the plasma membrane, both of which facilitate the transcytosis of non-cytolytic UPEC strains across intact collecting duct cell layers to invade the renal interstitium. Arginine vasopressin, which regulates water absorption in the collecting duct, also acts as a potent modulator of the TLR4-mediated intrarenal innate response caused by UPEC. The role of epithelial TLR5 in renal host defences is also discussed. These findings highlight the role of RTECs in triggering the innate immune response in the context of ascending UTIs. PMID- 21615667 TI - A novel oral form of salmon calcitonin improves glucose homeostasis and reduces body weight in diet-induced obese rats. AB - AIM: To investigate the effects of acute and chronic administration of a novel oral formulation of salmon calcitonin (sCT) on glycaemic control, glucose homeostasis and body weight regulation in diet-induced obese (DIO) rats-an animal model of obesity-related insulin resistance and type 2 diabetes. METHODS: DIO rats were acutely given a single dose of oral sCT (0.5 and 2 mg/kg), its oral vehicle N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) or injectable sCT (5 and 10 ug/kg) (n = 8), followed by oral glucose tolerance test (OGTT). Other DIO rats were chronic treated twice daily with oral vehicle 5-CNAC (n = 6), oral sCT (0.5 and 2 mg/kg) or injectable sCT (10 ug/kg) (n = 8). Fasting and postprandial glucose and pancreatic hormones, body weight and insulin sensitivity were assessed. RESULTS: A single dose of oral sCT acutely reduced glucose and insulin area under the curve during OGTT by approximately 65 and 85%, respectively, compared with vehicle (p < 0.001). Chronic treatment with oral sCT significantly reduced both fasting and postprandial glucose and insulin levels by approximately 1.5 mM and 65%, respectively, compared with vehicle. Oral sCT concomitantly improved insulin sensitivity (homeostatic model assessment, HOMA). In contrast, injectable sCT resembling higher systemic exposure did not improve glycaemic control, either acutely or during chronic treatment. Furthermore, both oral and injectable sCT reduced body weight by 15% compared with vehicle (p < 0.05). CONCLUSION: A novel oral form of sCT showed antidiabetic effects in DIO rats by improving glycaemic control, glucose homeostasis, insulin sensitivity and body weight. PMID- 21615668 TI - Exercise training increases adipose tissue GLUT4 expression in patients with type 2 diabetes. AB - We investigated the effects of exercise training on adipose tissue and skeletal muscle GLUT4 expression in patients with type 2 diabetes (T2D). Muscle and adipose tissue samples were obtained before and after 4-weeks of exercise training in seven patients with T2D [47 +/- 2 years, body mass index (BMI) 28 +/- 2]. Seven control subjects (54 +/- 4, BMI 30 +/- 2) were recruited for baseline comparison. Adipose tissue GLUT4 protein expression was 43% lower (p < 0.05) in patients with T2D compared with control subjects and exercise training increased (p < 0.05) adipose tissue GLUT4 expression by 36%. Skeletal muscle GLUT4 protein expression was not different between control subjects and patients with T2D. Exercise training increased (p < 0.05) skeletal muscle GLUT4 protein expression by 20%. In conclusion, 4-weeks of exercise training increased GLUT4 expression in adipose tissue and skeletal muscle of patients with T2D, although the functional benefits of this adaptation appear to be dependent on an optimal beta-cell function. PMID- 21615669 TI - Glucagon antagonism as a potential therapeutic target in type 2 diabetes. AB - Glucagon is a hormone secreted from the alpha cells of the pancreatic islets. Through its effect on hepatic glucose production (HGP), glucagon plays a central role in the regulation of glucose homeostasis. In patients with type 2 diabetes mellitus (T2DM), abnormal regulation of glucagon secretion has been implicated in the development of fasting and postprandial hyperglycaemia. Therefore, new therapeutic agents based on antagonizing glucagon action, and hence blockade of glucagon-induced HGP, could be effective in lowering both fasting and postprandial hyperglycaemia in patients with T2DM. This review focuses on the mechanism of action, safety and efficacy of glucagon antagonists in the treatment of T2DM and discusses the challenges associated with this new potential antidiabetic treatment modality. PMID- 21615670 TI - Effects of exenatide twice daily versus sitagliptin on 24-h glucose, glucoregulatory and hormonal measures: a randomized, double-blind, crossover study. AB - AIM: To compare exenatide and sitagliptin glucose and glucoregulatory measures in subjects with type 2 diabetes. METHODS: An 8-week, double-blind, randomized, crossover, single-centre study. Eighty-six subjects (58% female, body mass index 35 +/- 5 kg/m2, haemoglobin A1c 8.3 +/- 1.0%) received either exenatide 10 ug (subcutaneous) twice daily or sitagliptin 100 mg (oral) daily for 4 weeks and crossed to the other therapy for an additional 4 weeks. Main outcome was time averaged glucose during the 24-h inpatient visits. RESULTS: Both treatments decreased average 24-h glucose, but exenatide had a greater effect [between-group difference: -0.67 mmol/l, 95% confidence interval (CI): -0.9 to -0.4 mmol/l]. Both treatments decreased 2-h postprandial glucose (PPG), area under the curve of glucose above 7.8 mmol/l (140 mg/dl) and 11 mmol/l (200 mg/dl) and increased the time spent with glucose between 3.9 and 7.8 mmol/l (70 and 140 mg/dl) during 24 h, but exenatide had a significantly greater effect (p < 0.05). Both treatments decreased postprandial serum glucagon, with exenatide having a greater effect (p < 0.005). Both treatments decreased fasting blood glucose to a similar degree (p = 0.766). Sitagliptin increased, while exenatide decreased, postprandial intact glucagon-like peptide-1. Both drugs improved homeostasis model assessment of beta cell function (HOMA-B), with exenatide having a significantly greater effect (p = 0.005). Both exenatide and sitagliptin decreased 24-h caloric intake, with exenatide having a greater effect (p < 0.001). There was no episode of major hypoglycaemia. Adverse events were mild to moderate and mostly gastrointestinal in nature with exenatide. No study withdrawals were due to an adverse event. CONCLUSION: Compared to sitagliptin, exenatide showed significantly lower average 24-h glucose, 2-h PPG, glucagon, caloric intake and improved HOMA-B. PMID- 21615671 TI - Metabolic effects of muraglitazar in type 2 diabetic subjects. AB - AIM: To assess the effect of muraglitazar, a dual peroxisome proliferator activated receptor (PPAR)gamma-alpha agonist, versus placebo on metabolic parameters and body composition in subjects with type 2 diabetes mellitus (T2DM). METHODS: Twenty-seven T2DM subjects received oral glucose tolerance test (OGTT), euglycaemic insulin clamp with deuterated glucose, measurement of total body fat (DEXA), quantitation of muscle/liver (MRS) and abdominal subcutaneous and visceral (MRI) fat, and then were randomized to receive, in addition to diet, muraglitazar (MURA), 5 mg/day, or placebo (PLAC) for 4 months. RESULTS: HbA1c(c) decreased similarly (2.1%) during both MURA and PLAC treatments despite significant weight gain with MURA (+2.5 kg) and weight loss with PLAC (-0.7 kg). Plasma triglyceride, LDL cholesterol, free fatty acid (FFA), hsCRP levels all decreased with MURA while plasma adiponectin and HDL cholesterol increased (p < 0.05-0.001). Total body (muscle), hepatic and adipose tissue sensitivity to insulin and beta cell function all improved with MURA (p < 0.05-0.01). Intramyocellular, hepatic and abdominal visceral fat content decreased, while total body and subcutaneous abdominal fat increased with MURA (p < 0.05-0.01). CONCLUSIONS: Muraglitazar (i) improves glycaemic control by enhancing insulin sensitivity and beta cell function in T2DM subjects, (ii) improves multiple cardiovascular risk factors, (iii) reduces muscle, visceral and hepatic fat content in T2DM subjects. Despite similar reduction in A1c with PLAC/diet, insulin sensitivity and beta cell function did not improve significantly. PMID- 21615672 TI - Management of urolithiasis in patients after urinary diversions. AB - After urinary diversion patients are at increased risk of long-term complications, including stones of the upper urinary tract and reservoir or conduit. Advances in instrumentation and techniques have expanded treatment options, while minimizing morbidity. Minimally invasive treatment methods include shockwave lithotripsy, antegrade and retrograde ureteroscopic lithotripsy and percutaneous nephrolithotomy. Percutaneous and laparoscopic techniques are applicable to stones within urinary diversions. Medical management is crucial for avoiding recurrent stones in these patients. PMID- 21615673 TI - Large-scale transcriptome analysis in chickpea (Cicer arietinum L.), an orphan legume crop of the semi-arid tropics of Asia and Africa. AB - Chickpea (Cicer arietinum L.) is an important legume crop in the semi-arid regions of Asia and Africa. Gains in crop productivity have been low however, particularly because of biotic and abiotic stresses. To help enhance crop productivity using molecular breeding techniques, next generation sequencing technologies such as Roche/454 and Illumina/Solexa were used to determine the sequence of most gene transcripts and to identify drought-responsive genes and gene-based molecular markers. A total of 103,215 tentative unique sequences (TUSs) have been produced from 435,018 Roche/454 reads and 21,491 Sanger expressed sequence tags (ESTs). Putative functions were determined for 49,437 (47.8%) of the TUSs, and gene ontology assignments were determined for 20,634 (41.7%) of the TUSs. Comparison of the chickpea TUSs with the Medicago truncatula genome assembly (Mt 3.5.1 build) resulted in 42,141 aligned TUSs with putative gene structures (including 39,281 predicted intron/splice junctions). Alignment of ~37 million Illumina/Solexa tags generated from drought-challenged root tissues of two chickpea genotypes against the TUSs identified 44,639 differentially expressed TUSs. The TUSs were also used to identify a diverse set of markers, including 728 simple sequence repeats (SSRs), 495 single nucleotide polymorphisms (SNPs), 387 conserved orthologous sequence (COS) markers, and 2088 intron-spanning region (ISR) markers. This resource will be useful for basic and applied research for genome analysis and crop improvement in chickpea. PMID- 21615674 TI - Cellular senescence increases expression of bacterial ligands in the lungs and is positively correlated with increased susceptibility to pneumococcal pneumonia. AB - Cellular senescence is an age-associated phenomenon that promotes tumor invasiveness owing to the secretion of proinflammatory cytokines, proteases, and growth factors. Herein we demonstrate that cellular senescence also potentially increases susceptibility to bacterial pneumonia caused by Streptococcus pneumoniae (the pneumococcus), the leading cause of infectious death in the elderly. Aged mice had increased lung inflammation as determined by cytokine analysis and histopathology of lung sections. Immunoblotting for p16, pRb, and mH2A showed that elderly humans and aged mice had increased levels of these senescence markers in their lungs vs. young controls. Keratin 10 (K10), laminin receptor (LR), and platelet-activating factor receptor (PAFr), host proteins known to be co-opted for bacterial adhesion, were also increased. Aged mice were found to be highly susceptible to pneumococcal challenge in a PsrP, the pneumococcal adhesin that binds K10, dependent manner. In vitro senescent A549 lung epithelial cells had elevated K10 and LR protein levels and were up to 5 fold more permissive for bacterial adhesion. Additionally, exposure of normal cells to conditioned media from senescent cells doubled PAFr levels and pneumococcal adherence. Genotoxic stress induced by bleomycin and oxidative stress enhanced susceptibility of young mice to pneumonia and was positively correlated with enhanced p16, inflammation, and LR levels. These findings suggest that cellular senescence facilitates bacterial adhesion to cells in the lungs and provides an additional molecular mechanism for the increased incidence of community-acquired pneumonia in the elderly. This study is the first to suggest a second negative consequence for the senescence-associated secretory phenotype. PMID- 21615676 TI - Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. AB - Reprogramming of somatic cells to a pluripotent state was first accomplished using retroviral vectors for transient expression of pluripotency-associated transcription factors. This seminal work was followed by numerous studies reporting alternative (noninsertional) reprogramming methods and various conditions to improve the efficiency of reprogramming. These studies have contributed little to an understanding of global mechanisms underlying reprogramming efficiency. Here we report that inhibition of the mammalian target of rapamycin (mTOR) pathway by rapamycin or PP242 enhances the efficiency of reprogramming to induced pluripotent stem cells (iPSCs). Inhibition of the insulin/IGF-1 signaling pathway, which like mTOR is involved in control of longevity, also enhances reprogramming efficiency. In addition, the small molecules used to inhibit these pathways also significantly improved longevity in Drosophila melanogaster. We further tested the potential effects of six other longevity-promoting compounds on iPSC induction, including two sirtuin activators (resveratrol and fisetin), an autophagy inducer (spermidine), a PI3K (phosphoinositide 3-kinase) inhibitor (LY294002), an antioxidant (curcumin), and an activating adenosine monophosphate-activated protein kinase activator (metformin). With the exception of metformin, all of these chemicals promoted somatic cell reprogramming, though to different extents. Our results show that the controllers of somatic cell reprogramming and organismal lifespan share some common regulatory pathways, which suggests a new approach for studying aging and longevity based on the regulation of cellular reprogramming. PMID- 21615675 TI - DLP1-dependent mitochondrial fragmentation mediates 1-methyl-4-phenylpyridinium toxicity in neurons: implications for Parkinson's disease. AB - Selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) can be modeled by the administration of the neurotoxin 1-methyl-4 phenylpyridinium (MPP(+) ). Because abnormal mitochondrial dynamics are increasingly implicated in the pathogenesis of PD, in this study, we investigated the effect of MPP(+) on mitochondrial dynamics and assessed temporal and causal relationship with other toxic effects induced by MPP(+) in neuronal cells. In SH SY5Y cells, MPP(+) causes a rapid increase in mitochondrial fragmentation followed by a second wave of increase in mitochondrial fragmentation, along with increased DLP1 expression and mitochondrial translocation. Genetic inactivation of DLP1 completely blocks MPP(+) -induced mitochondrial fragmentation. Notably, this approach partially rescues MPP(+) -induced decline in ATP levels and ATP/ADP ratio and increased [Ca(2+) ](i) and almost completely prevents increased reactive oxygen species production, loss of mitochondrial membrane potential, enhanced autophagy and cell death, suggesting that mitochondria fragmentation is an upstream event that mediates MPP(+) -induced toxicity. On the other hand, thiol antioxidant N-acetylcysteine or glutamate receptor antagonist D-AP5 also partially alleviates MPP(+) -induced mitochondrial fragmentation, suggesting a vicious spiral of events contributes to MPP(+) -induced toxicity. We further validated our findings in primary rat midbrain dopaminergic neurons that 0.5 MUm MPP(+) induced mitochondrial fragmentation only in tyrosine hydroxylase (TH) positive dopaminergic neurons in a similar pattern to that in SH-SY5Y cells but had no effects on these mitochondrial parameters in TH-negative neurons. Overall, these findings suggest that DLP1-dependent mitochondrial fragmentation plays a crucial role in mediating MPP(+) -induced mitochondria abnormalities and cellular dysfunction and may represent a novel therapeutic target for PD. PMID- 21615677 TI - Implants with an oxidized surface placed predominately in soft bone quality and subjected to immediate occlusal loading: results from a 7-year clinical follow up. AB - PURPOSE: The purpose of this clinical follow-up was to document the 7-year outcome of immediately loaded implants exhibiting an oxidized surface. MATERIAL AND METHODS: Thirty-eight patients received a total of 51 implant-supported fixed prostheses. The restorations were supported by 102 implants, the majority of which were placed in posterior regions (88%) and primarily in soft bone quality (76%). Radiographic examinations were performed at prosthesis insertion, at 1- and 6-month follow-ups, and annually at the 1- through 5-year follow-up visits. Marginal peri-implant soft tissue evaluations were conducted at all these follow ups. This report presents the results after at least 7 years of loading. RESULTS: After 7 years of prosthetic loading, the cumulative implant survival rate was 97.1% and the mean marginal bone remodeling was -1.51 mm (SD 1.00, n = 73) with significantly more initial remodeling at sites having received marginal guided bone regeneration procedures. A low rate of biological and technical complications was detected after 7 years of function. The quantification of intrasulcular plaque sampling showed no significant difference between teeth and implants. CONCLUSION: The 7-year follow-up data indicate that the introduced immediate loading protocol is a successful treatment alternative also including regions exhibiting soft bone conditions. PMID- 21615678 TI - Chronic female pelvic pain--part 1: clinical pathoanatomy and examination of the pelvic region. AB - Chronic pelvic pain is defined as the presence of pain in the pelvic girdle region for over a 6-month period and can arise from the gynecologic, urologic, gastrointestinal, and musculoskeletal systems. As 15% of women experience pelvic pain at some time in their lives with yearly direct medical costs estimated at $2.8 billion, effective evaluation and management strategies of this condition are necessary. This merits a thorough discussion of a systematic approach to the evaluation of chronic pelvic pain conditions, including a careful history-taking and clinical examination. The challenge of accurately diagnosing chronic pelvic pain resides in the degree of peripheral and central sensitization of the nervous system associated with the chronicity of the symptoms, as well as the potential influence of the affective and biopsychosocial factors on symptom development as persistence. Once the musculoskeletal origin of the symptoms is identified, a clinical examination schema that is based on the location of primary onset of symptoms (lumbosacral, coccygeal, sacroiliac, pelvic floor, groin or abdominal region) can be followed to establish a basis for managing the specific pain generator(s) and manage tissue dysfunction. PMID- 21615679 TI - In vitro and in vivo proliferation, differentiation and migration of cardiac endothelial progenitor cells (SCA1+/CD31+ side-population cells). AB - BACKGROUND: Side-population (SP) cells are a select population identified by a capacity to efflux Hoechst dye and are enriched for stem/progenitor cell activity. Previous studies suggested that cardiac SP (CSP) cells could be divided into SCA1(+)/CD31(-) and SCA1(+)/CD31(+) CSP cells. SCA1(+)/CD31(-) CSP cells have been shown to be cardiac stem/progenitor cells. However, SCA1(+)/CD31(+) CSP cells have not been fully characterized. OBJECTIVE: The aim of the present study was to characterize SCA1(+)/CD31(+) CSP cells in the adult mouse heart, and investigate their abilities to proliferate, differentiate, vascularize and migrate in vitro and in vivo. RESULTS: Using fluorescence-activated cell sorting (FACS), RT-PCR, and assays of cell proliferation, differentiation and migration, and a murine model of myocardial infarction (MI), we showed that SCA1(+)/CD31(+) CSP cells express stem cell and endothelial-specific genes, and reside in the blood vessels. These cells were able to proliferate, differentiate, migrate and vascularize in vitro and in vivo. After MI, SDF-1alpha and CXCR4 were up regulated in the damaged myocardium and on SCA1(+)/CD31(+) CSP cells, respectively. Our results further showed that SDF-1alpha induced migration of these cells in vitro. Importantly, we found that SCA1(+)/CD31(+) CSP cells could migrate into the ischemic region from the non-ischemic area within the myocardium and form a vascular tube-like structure after MI. CONCLUSIONS: Based on the gene expression profile, localization of SCA1(+)/CD31(+) CSP cells, and their ability to proliferate, differentiate, migrate and vascularize in vitro and in vivo, we postulate that SCA1(+)/CD31(+) CSP cells may represent endothelial progenitor cells in the mouse heart. PMID- 21615680 TI - Deep venous thrombosis after surgery for Achilles tendon rupture: a provoked transient event with minor long-term sequelae. AB - BACKGROUND: Deep venous thrombosis (DVT) occurs frequently in patients undergoing orthopedic surgery, but there is a lack of knowledge regarding long-term sequelae of DVT after different types of surgical procedures. OBJECTIVE: To describe the long-term effect of symptomatic (SDVT) and asymptomatic (ADVT) deep venous thrombosis on venous function and subsequent incidence of post-thrombotic syndrome (PTS) in patients who have undergone surgery for Achilles tendon rupture. PATIENTS/METHODS: This observational follow-up study includes 83 patients with postoperative DVT, examined after a mean of 7 years. There were two series of patients: 45 with SDVT and 38 with ADVT. In both series, more than 90% of the DVTs were limited to calf veins. Follow-up examinations comprised color duplex ultrasonography (CDU), strain-gauge plethysmography (SGP), clinical examination including scoring for venous disease and questionnaires for quality of life (QOL). RESULTS: A mild degree of PTS was found in 11% of the patients: 13% in SDVT and 8% in ADVT patients. The rate of recurrent ipsilateral DVT was 2%. Deep venous reflux was more common in patients with SDVT than in ADVT patients (84% vs. 55%, P < 0.01). Only a few patients had plethysmograpically abnormal findings without difference between the two groups. CONCLUSION: DVT after surgery for Achilles tendon rupture consists mainly of distal DVTs and are associated with a low risk for PTS. Deep venous reflux was more common in SDVT than in ADVT patients, probably as an effect of larger DVTs in the former group. PMID- 21615682 TI - Reattachment of endodontically treated lateral incisor with supragingivally complicated crown fracture using fiber-reinforced post. AB - Re-restoring endodontically treated teeth with complicated crown or crown root fractures is a major challenge for dental practitioners, because they can present difficulties for successful treatment. This report describes the management of supragingivally complicated crown fracture of an endodontically treated maxillary lateral incisor. The involved tooth was restored with the reattachment procedure using light transmitting fiber post. After 11 months, the reattached tooth had a satisfying function, favorable physiological and esthetic outcomes and healthy surrounding periodontal structures. PMID- 21615683 TI - Clinical characteristics of dental emergencies and prevalence of dental trauma at a university hospital emergency center in Korea. AB - AIM: The aim of this study was to examine the clinical characteristics of dental emergency patients who visited a university hospital emergency center and to evaluate the incidence of dental trauma. MATERIALS AND METHODS: A retrospective chart review of patients with dental complaints and who visited the Seoul National University Bundang Hospital (SNUBH) emergency center in Gyeonggi-do, Korea, from January 2009 to December 2009 was conducted. Information regarding age, gender, the time, day, and month of presentation, diagnosis, treatment, and follow up was collected and analyzed. RESULTS: One thousand four hundred twenty five patients with dental problems visited the SNUBH emergency center. Dental patients accounted for 1.47% of the total 96,708 patients at the emergency center. The male-to-female ratio was 1.68:1, with a considerably larger number of male patients (62.7%). The age distribution peak was at 0-9 years (27.5%), followed by patients in their forties (14.1%). The number of patients visiting the dental emergency center peaked in May (14.2%), on Sundays (22.4%), and between 2100 and 2400 h (20.8%). The patients' chief complaints were as follows: dental trauma, dental infection, oral bleeding, and temporomandibular joint disorder (TMD). The prevalence of dental trauma was 66%. CONCLUSIONS: The reasons for dental emergency visits included the following: dental trauma, dental infection, oral bleeding, and TMD, with 66% of the patients requiring management of dental trauma. It is important that dentists make a prompt, accurate diagnosis and initiate effective treatment in case of dental emergencies, especially dental trauma. PMID- 21615681 TI - Marking the tempo for myogenesis: Pax7 and the regulation of muscle stem cell fate decisions. AB - Post-natal growth and regeneration of skeletal muscle is highly dependent on a population of resident myogenic precursors known as satellite cells. Transcription factors from the Pax gene family, Pax3 and Pax7, are critical for satellite cell biogenesis, survival and potentially self-renewal; however, the underlying molecular mechanisms remain unsolved. This is particularly true in the case of Pax7, which appears to regulate myogenesis at multiple levels. Accordingly, recent data have highlighted the importance of a functional relationship between Pax7 and the MyoD family of muscle regulatory transcription factors during normal muscle formation and disease. Here we will critically review key findings suggesting that Pax7 may play a dual role by promoting resident muscle progenitors to commit to the skeletal muscle lineage while preventing terminal differentiation, thus keeping muscle progenitors poised to differentiate upon environmental cues. In addition, potential regulatory mechanisms for the control of Pax7 activity will be proposed. PMID- 21615685 TI - Skin alterations due to illegal drug abuse. AB - Drug abuse is associated with a wide variety of skin alterations. Being aware of the typical signs and symptoms of the drug addicts' skin is of special importance to dermatologists, even though dermatologists are commonly not involved in the treatment of these patients. There is yet a chance for dermatologists to identify drug abusers early by to some extent specific cutaneous signs and after exclusion of several other etiological factors, so that this will lead to further treatment through the respective specialists. The objective of this paper is to draw particular attention to typical skin lesions and diseases which may be associated with drug abuse. PMID- 21615684 TI - Altered ADAR 2 equilibrium and 5HT(2C) R editing in the prefrontal cortex of ADAR 2 transgenic mice. AB - Modulation of serotonin signaling by RNA editing of the serotonin 2C receptor (5HT(2C) R) may be relevant to affective disorder as serotonin functions regulate mood and behavior. Previously, we observed enhanced endogenous behavioral despair in ADAR2 transgenic mice. As the transcript of the 5HT(2C) R is a substrate of ADAR2, we hypothesized that perturbed ADAR2 equilibrium in the prefrontal cortex of ADAR2 transgenic mice alters the normal distribution of edited amino acid isoforms of the 5HT(2C) R and modifies the receptor function in downstream basal extracellular signal-regulated kinase (ERK) signaling. We examined groups of naive control and ADAR2 transgenic mice and found significantly increased ADAR2 expression, increased RNA editing at A, C, D and E sites and significantly altered normal distribution of edited amino acid isoforms of the 5HT(2C) R with increased proportions of valine asparagine valine, valine serine valine, valine asparagine isoleucine, isoleucine asparagine valine and decreased isoleucine asparagine isoleucine amino acid isoforms of the 5HT(2C) R in ADAR2 transgenic mice. Localized serotonin levels (5-HT) were unchanged and perturbed ADAR2 equilibrium coincides with dysregulated edited amino acid isoforms of the 5HT(2C) R and reduced basal ERK signaling. These results altogether suggest that altered 5HT(2C) R function could be contributing to enhanced depression-like behavior of ADAR2 transgenic mice and further implicate ADAR2 as a contributing factor in cases of affective disorder. PMID- 21615686 TI - Research in practice: Antimicrobial peptides of the skin. AB - Antimicrobial peptides represent evolutionary ancient molecules whose importance became evident within the last years. These highly effective peptides protect the skin and other epithelia against infection and form a fast acting "chemical barrier" also regulating the normal flora of the skin and mucosa. In the Department of Dermatology, University Hospital Kiel, various antimicrobial peptides have been discovered, characterized and investigated in healthy persons as well as in different skin diseases. Everyday clinical observations formed the background for several interesting hypotheses and findings. PMID- 21615687 TI - Evolutionary history and complementary selective relaxation of the duplicated PI genes in grasses. AB - Gene duplication plays an important role in the evolution of organisms by allowing functional innovation and the divergence of duplicate genes. Previous studies found two PI-like genes in grass species, suggesting functional divergence between the paralogous copies. Here, we reconstructed the evolutionary history of two PI genes from major lineages of grasses and other monocot species, and demonstrated that two PI genes (PI1 and PI2) arose from a whole genome duplication that occurred in a common ancestor of extant grasses. Molecular evolutionary analyses at the family and tribal levels found strong purifying selection acting on two genes in grasses, consistent with the conserved class B function of the PI genes. Importantly, we detected different patterns of selective relaxation between the duplicated PI genes although no signature of positive selection was found. Likelihood ratio tests revealed that the omega ratio for M domain is significantly higher in PI1 than in PI2 but that for K domain is significantly higher in PI2 than in PI1. These findings imply that complementary selective relaxation occurs in two PI genes after duplication, and provide additional molecular evidence for the subfunctionalization of the duplicated PI genes in grasses. PMID- 21615688 TI - Identification of mitogen-activated protein/extracellular signal-responsive kinase kinase 2 as a novel partner of the scaffolding protein human homolog of disc-large. AB - Human disc-large homolog (hDlg), also known as synapse-associated protein 97, is a scaffold protein, a member of the membrane-associated guanylate kinase family, implicated in neuronal synapses and epithelial-epithelial cell junctions whose expression and function remains poorly characterized in most tissues, particularly in the vasculature. In human vascular tissues, hDlg is highly expressed in smooth muscle cells (VSMCs). Using the yeast two-hybrid system to screen a human aorta cDNA library, we identified mitogen-activated protein/extracellular signal-responsive kinase (ERK) kinase (MEK)2, a member of the ERK cascade, as an hDlg binding partner. Site-directed mutagenesis showed a major involvement of the PSD-95, disc-large, ZO-1 domain-2 of hDlg and the C terminal sequence RTAV of MEK2 in this interaction. Coimmunoprecipitation assays in both human VSMCs and human embryonic kidney 293 cells, demonstrated that endogenous hDlg physically interacts with MEK2 but not with MEK1. Confocal microscopy suggested a colocalization of the two proteins at the inner layer of the plasma membrane of confluent human embryonic kidney 293 cells, and in a perinuclear area in human VSMCs. Additionally, hDlg also associates with the endoplasmic reticulum and microtubules in these latter cells. Taken together, these findings allow us to hypothesize that hDlg acts as a MEK2-specific scaffold protein for the ERK signaling pathway, and may improve our understanding of how scaffold proteins, such as hDlg, differentially tune MEK1/MEK2 signaling and cell responses. PMID- 21615689 TI - Reducing expression of NAD+ synthesizing enzyme NMNAT1 does not affect the rate of Wallerian degeneration. AB - NAD(+) synthesizing enzyme NMNAT1 constitutes most of the sequence of neuroprotective protein Wld(S), which delays axon degeneration by 10-fold. NMNAT1 activity is necessary but not sufficient for Wld(S) neuroprotection in mice and 70 amino acids at the N-terminus of Wld(S), derived from polyubiquitination factor Ube4b, enhance axon protection by NMNAT1. NMNAT1 activity can confer neuroprotection when redistributed outside the nucleus or when highly overexpressed in vitro and partially in Drosophila. However, the role of endogenous NMNAT1 in normal axon maintenance and in Wallerian degeneration has not been elucidated yet. To address this question we disrupted the Nmnat1 locus by gene targeting. Homozygous Nmnat1 knockout mice do not survive to birth, indicating that extranuclear NMNAT isoforms cannot compensate for its loss. Heterozygous Nmnat1 knockout mice develop normally and do not show spontaneous neurodegeneration or axon pathology. Wallerian degeneration after sciatic nerve lesion is neither accelerated nor delayed in these mice, consistent with the proposal that other endogenous NMNAT isoforms play a principal role in Wallerian degeneration. PMID- 21615690 TI - Structural basis of p63alpha SAM domain mutants involved in AEC syndrome. AB - p63 is a member of the p53 tumour suppressor family that includes p73. The p63 gene encodes a protein comprising an N-terminal transactivation domain, a DNA binding domain and an oligomerization domain, but varies in the organization of the C-terminus as a result of complex alternative splicing. p63alpha contains a C terminal sterile alpha motif (SAM) domain that is thought to function as a protein-protein interaction domain. Several missense and heterozygous frame shift mutations, encoded within exon 13 and 14 of the p63 gene, have been identified in the p63alpha SAM domain in patients suffering from ankyloblepharon-ectodermal dysplasia-clefting syndrome. Here we report the solution and high resolution crystal structures of the p63alpha SAM domain and investigate the effect of several mutations (L553F/V, C562G/W, G569V, Q575L and I576T) on the stability of the domain. The possible effects of other mutations are also discussed. PMID- 21615692 TI - Translational research: connecting evidence to clinical practice. AB - Translational research can be conceptualized within several blocks or spheres of knowledge transfer and focused on closing the gap between new discoveries and their endpoint application to clinical practice, health decision-making, and health policy. Although support for type 1 translational research (the classical bench-to-bedside paradigm) is common, it is types 2 and 3 that have the ultimate impact on sustaining important changes in clinical practice as health decision making and policy are changed to support the practice innovation. The Clinical Translational Science Centers (issued by the National Institutes of Health in the USA) provide many successful examples in which nurses are key stakeholders in achieving these translational goals for the improvement of clinical practice. PMID- 21615691 TI - A randomized, controlled trial validates a peripheral supra-additive antihyperalgesic effect of a paracetamol-ketorolac combination. AB - The combination of paracetamol with non-steroidal anti-inflammatory drugs (NSAIDs) is widely used; however, the nature and mechanism of their interaction are still debated. A double-blind, pharmacokinetic/pharmacodynamic, randomized, cross-over, placebo-controlled study was carried out in human healthy volunteers. The aim was to explore the existence of a positive interaction between paracetamol 1 g and ketorolac 20 mg administered intravenously on experimental pain models in human beings. The effects of the paracetamol-ketotolac combination were compared with similar doses of respective single analgesic and to placebo on the sunburn model (UVB-induced inflammation), cold pain tolerance and the nociceptive flexion reflex. The kinetics of the plasma concentrations of paracetamol and ketorolac were measured using 2D-liquid chromatography-mass spectrometry. Thirteen volunteers were screened, and 11 completed the study. Ketorolac significantly decreased primary hyperalgesia to heat stimuli compared with paracetamol (p < 0.014). The combination performed better than paracetamol (p < 0.001) and placebo (p < 0.042), increasing heat pain threshold by 1.5 degrees C. The combination radically reduced primary hyperalgesia to mechanical stimulation (39%) compared with placebo (p < 0.002) and single agents (paracetamol p < 0.024 and ketorolac p < 0.032). The combination also reduced, slightly although significantly, the intensity of pain (10%) for the cold pressor test (versus placebo: p < 0.012, paracetamol: p < 0.019 and ketorolac p < 0.004). None of the treatments significantly affected the central models of pain at this dosage level. No pharmacokinetic interactions were observed. These results suggest a supra-additive pharmacodynamic interaction between paracetamol and ketorolac in an inflammatory pain model. The mechanism of this interaction could mainly rely on a peripheral contribution of paracetamol to the effect of NSAIDs. PMID- 21615693 TI - Working together, nurses can make a difference in resuscitation outcomes: an update on the American Heart Association's 2010 guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. AB - The International Liaison Committee on Resuscitation (ILCOR) was formed in 1992 to provide a forum for resuscitation organizations worldwide. According to its mission, ILCOR provides a mechanism by which international science and knowledge that are relevant to cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) can be identified, reviewed, and evaluated. Every 5 years, based on a rigorous review of the published, peer-reviewed science, ILCOR develops a consensus on resuscitation science and carries that forward into internationally agreed-on treatment recommendations. As part of the 2010 evidence evaluation process, ILCOR published an updated consensus on science and treatment recommendations (CoSTR). Based on the CoSTR, the American Heart Association (AHA) developed and disseminated guidelines for ECC and CPR. Nursing has unique responsibilities in the chain of survival. This article reviews the major elements of AHA's 2010 guidelines and discusses the critical role that nurses play in the development, dissemination, and implementation of resuscitation science. By making the connection in resuscitation science, nurses can help to save more lives. PMID- 21615694 TI - Quality of life and sexual function of women with urinary incontinence. AB - AIM: The aim of this study was to examine the urinary incontinence (UI) types on the sexual function and quality of life (QOL) of women with UI and the correlation between sexual function and QOL. METHODS: The sample for this descriptive study was comprised of 122 women who presented to obstetrics and gynecology and urology outpatient clinics at university hospitals in Denizli and Izmir, Turkey, who had UI, who were sexually active, who volunteered to participate in the study, and who were chosen by a convenience sampling method. A sociodemographic data collection form, the Female Sexual Function Index (FSFI), and the Incontinence Quality of Life (I-QOL) questionnaire were used for data collection in the study. RESULTS: The mixed type of incontinence had an effect on the women's quality of life, mixed and stress incontinence affected the FSFI's pain subscale, and the total sexual functioning score was lower for the women with mixed incontinence. Even though the correlation values were low, it was clear that there was a positive correlation between sexual function and quality of life. CONCLUSIONS: Among the incontinence types, a significant difference was determined by the FSFI and I-QOL. Urinary incontinence seems to be the predictor of sexual function and quality of life. As a result, a comprehensive assessment of patients with UI is recommended because this condition has a negative influence on their sexual function and quality of life. PMID- 21615696 TI - Factors associated with the intention to leave among newly graduated nurses in advanced-treatment hospitals in Japan. AB - AIM: The early resignation of newly graduated nurses (NGNs) will become a concern in Japan as the need for nurses increases. The aim of this study was to conduct an investigation using the Effort-Reward Imbalance (ERI) questionnaire to examine the effect of stressful experiences in the work environment and over-commitment on NGNs' intention to leave and to identify the factors that were associated with their intention to leave, clarifying the appropriate times at which to conduct interventions to prevent NGNs from leaving advanced-treatment hospitals. METHODS: Anonymous self-administered questionnaires were distributed to all the NGNs (n = 1364) in 14 advanced-treatment university hospitals. Questionnaires with no missing data were returned by 737 NGNs (54%). For the development of the questionnaire, we designed a framework that consisted of the factors that occur during three stages of the NGNs' transition into the workplace. The questions addressed items for individual attributes, employment and organizational characteristics, the Role Model Scale, the ERI questionnaire, two scale items for health status, and the intention to leave. In order to determine the factors that related to the dependent variables, hierarchical multiple linear regression analyses were carried out. RESULTS: We revealed that effort, subjective health status, role models, and effort were important factors that related to the NGNs' intention to leave, as well as their age and city size. Over-commitment and reward were not significant factors. We also found that three subscales of the Job Readiness Scale independently related to the NGNs' intention to leave. CONCLUSION: These findings can help employers, supervisors, and senior staff of advanced-treatment university hospitals in Japan to improve their work environment in order to benefit NGNs and aid in their retention. PMID- 21615695 TI - Health promotion behaviors of residents with hypertension in Iwate, Japan and North Carolina, USA. AB - AIM: The aim of this study was to compare the health promotion practises of rural residents in northern Japan (n = 212) to those in south-eastern North Carolina, USA (n = 105), using the Health Promotion Lifestyle II (HPLP) scale. METHODS: A comparative and descriptive design examined the relationships between health related behaviors and demographic and physiological variables, and compared cross cultural patterns. RESULTS: The Japanese participants scored significantly higher on the total HPLP II score, as well as on the subscales of health responsibility, nutrition, interpersonal support, and stress management. No significant differences were found in the HPLP II subscales for spiritual growth or physical activity between the groups. The subscale scores for both the participants from Japan and the participants from North Carolina were lowest for physical activity. For the participants from North Carolina, the HPLP II subscale scores were highest for spirituality and interpersonal relationships. The predictive factors of variation in the scores of the HPLP II for the participants from North Carolina included being married and not working. No significant demographic predictor was found for the HPLP II scores of the Japanese participants. CONCLUSIONS: The study's findings add to an increased understanding of the cultural variations in the health-promoting behaviors of persons with hypertension. Providing health promotion strategies for hypertension remains an urgent issue for nurses and other health-care providers in both Japan and North Carolina, USA. PMID- 21615697 TI - Effects of mental workload on nurses' visual behaviors during infusion pump operation. AB - AIM: According to a national report on incident analysis, the mental workload that exists during the i.v. medication administration process might affect nurses' visual behavior and, thus, influence the accuracy of the process. This study examined changes in the visual behavior of nurses who operated an infusion pump under the influence of time pressure and dual tasking. METHODS: mTen nursing students, 13 experienced nurses, and nine inexperienced nurses, equipped with an eye tracker and instruments that measure the heart rate and breathing frequency, carried out an infusion pump operation in a simulated patient room under three mental workload conditions: without a mental workload, under time pressure, and while dual tasking. RESULTS: Under the time pressure condition, the total visual fixation duration of the procedures was shortened. The experienced and inexperienced nurse groups could shorten the tasks in order of priority but the student group could reduce the tasks only inconsistently. Dual tasking had no influence on the total fixation duration of the procedures. However, the fixation location was influenced by the dual-tasking condition. This condition caused dispersed attention in the student and inexperienced-nurse groups, but not in the experienced-nurse group. CONCLUSION: Time pressure appears to cause nurses to shorten the duration of infusion pump operation and to reduce the quantity of checking. Dual tasking appears to have no influence on the total visual fixation duration but causes dispersed attention, reducing the quality of checking. PMID- 21615698 TI - Predictors of nurses' family-centered care practises in the neonatal intensive care unit. AB - AIM: To identify the predictors of nurses' family-centered care (FCC) practises in neonatal intensive care units (NICUs) in Japan. METHODS: A quantitative cross sectional survey was conducted by administering a self-reported questionnaire to 30 nurse managers and 710 staff nurses in 30 NICUs in Japan. A facility-level questionnaire, including items about the philosophy, policies, and environment of the NICU, was administered to the nurse managers. The Japanese version of the Measure of Processes of Care for Service Providers and the Japanese version of the Measure of Beliefs about Participation in Family-Centered Service were administered to the staff nurses to assess their practise of FCC and their beliefs about FCC, respectively. The data were analyzed with descriptive statistics and multiple regression analyses. RESULTS: Self-efficacy, neonatal care experience, FCC principles, and a 24 h parental visiting policy were significant predictors of the practise of FCC. Moreover, neonatal care experience, nursing support for the family to participate in the child's care, and visits by siblings were significantly associated with nurses' self-efficacy to implement FCC. CONCLUSION: Nurses' self-efficacy and hospital policies, including family visitation and participation in the child's care, were associated with nurses' FCC practises. These results suggest that educational programs to promote nurses' self-efficacy are essential and that organizational support is a key component in implementing FCC. PMID- 21615699 TI - Self-management program for obesity control among middle-aged women in Korea: a pilot study. AB - AIM: The aim of this study was to determine the effectiveness of a 12 week self management intervention program, as compared to a structured exercise intervention, for obesity control among middle-aged women in Korea. METHODS: A quasi-experimental study was conducted with 27 women in a self-management group and 24 in a structured exercise group for 12 weeks. The self-management group received interventions that included walking at a convenient time and place, keeping healthy dietary habits, group workshops, phone counseling, and mobile phone short message services. The structured exercise group received a structured exercise intervention, which involved three 1 h walking classes per week at the health center. Both groups received baseline assessments before starting the interventions and at 12 weeks. The data were analyzed by using two sample t tests, a paired t-test, and the chi(2) -test. RESULTS: After 12 weeks, there were significant changes in the health behavior, amount of body fat, and blood pressure of the participants in both intervention groups, but there was no significant difference in their body composition, blood profile, or blood pressure. CONCLUSION: Both the self-management and the structured exercise programs were effective in controlling obesity in middle-aged obese women in Korea. However, considering the chronic nature of obesity, the self-management program would be more beneficial, compared to the structured exercise program, as it allows people to exercise at a convenient time and place and to learn how to cope with their lifestyle barriers. PMID- 21615700 TI - Examination of a cognitive model of stress, burnout, and intention to resign for Japanese nurses. AB - AIM: A reduction in burnout is required to decrease the voluntary turnover of nurses. This study was carried out with the aim of establishing a cognitive model of stress, burnout, and intention to resign for nurses. METHODS: A questionnaire survey was administered to 336 nurses (27 male and 309 female) who had worked for <=5 years at a hospital with multiple departments. The survey included an evaluation of burnout (Maslach Burnout Inventory), stress (Nursing Job Stressor Scale), automatic thoughts (Automatic Thoughts Questionnaire-Revised), and irrational beliefs (Japanese Irrational Belief Test), in addition to the intention to resign. RESULTS: The stressors that affected burnout in the nurses included conflict with other nursing staff, nursing role conflict, qualitative workload, quantitative workload, and conflict with patients. The irrational beliefs that were related to burnout included dependence, problem avoidance, and helplessness. In order to examine the automatic thoughts affecting burnout, groups with low and high negative automatic thoughts and low and high positive automatic thoughts were established. A two-way ANOVA showed a significant interaction of these factors with emotional exhaustion, but no significant interaction with depersonalization and a personal sense of accomplishment. Only the major effect was significant. The final model showed a process of "stressor > irrational beliefs -> negative automatic thoughts/positive automatic thoughts > burnout". In addition, a relationship between burnout and an intention to resign was shown. CONCLUSION: These results suggest that stress and burnout in nurses might be prevented and that the number of nurses who leave their position could be decreased by changing irrational beliefs to rational beliefs, decreasing negative automatic thoughts, and facilitating positive automatic thoughts. PMID- 21615701 TI - Role of internal marketing, organizational commitment, and job stress in discerning the turnover intention of Korean nurses. AB - AIM: The purpose of this study was to examine the discriminating factors of Korean nurses' turnover intention (TI) among internal marketing (IM), organizational commitment (OC), and job stress (JS). METHODS: Nurses (n = 185) who had worked for 1-10 years were surveyed from six general hospitals in South Korea. The data were collected by using questionnaires and were analyzed with descriptive statistics and discriminant analysis. RESULTS: The participants were grouped into three groups, depending on the level of their TI: "low TI group" (n = 58), "moderate TI group" (n = 96), and "high TI group" (n = 31). One function significantly discriminated between the high TI and low TI groups. The function correctly classified 84.3% of the participants into the two groups and 75.3% were correctly classified in the cross-validation. Organizational commitment was the most important factor. Job stress and the IM components of staffing-promotion, reward, management philosophy, working environment, and segmentation were significant discriminant factors of TI. CONCLUSION: Based on the findings of this study, we could conclude that OC, JS, and IM play important roles in the TI of nurses. Implying a career development system as an OC management strategy, an innovative promotion policy to change conservative organizational climates and a balance of effort-reward can be considered as managerial interventions to reduce nurses' TI. PMID- 21615703 TI - Assessment of lymphedema by bioelectrical impedance spectroscopy. PMID- 21615702 TI - Six month outcomes of an innovative weekly intergenerational day program with older adults and school-aged children in a Japanese urban community. AB - AIM: To describe the nature of the progression of intergenerational interactions among and between older people and children in a weekly intergenerational day program (IDP) in an urban community and to evaluate the older people's health related quality of life (HRQOL) and depressive symptoms, compared to the program volunteers, as well as the children's perspectives of older people, during the first 6 months of the program's implementation. METHODS: This longitudinal study, with a convenience sample of older people (n = 14), program volunteers (n = 8), and school-aged children (n = 7), used mixed methods to analyze the results. Participant observations and interviews were used to describe the interactions between the generations over the 6 months. An ANOVA with repeated measures was used to determine the statistical effects over time (initially and at 3 months and 6 months) for HRQOL (Medical Outcomes Study 8-Item Short-Form Health Survey) and depression (Geriatric Depression Scale, GDS-15). Semantic differential scales identified the children's perspectives of older people. RESULTS: The intergenerational interactions were grouped into thirteen categories; for example, "The IDP provided a meaningful sense of place." The quality of life in relation to the mental health of the older people's group improved significantly between the first involvement and after 6 months, while the GDS-15 scores significantly decreased at the three time points in the more depressed older people's subgroup. The children's initial generally positive perspectives of older people showed no statistically significant change over time. CONCLUSION: The intergenerational interactions in the IDP yielded a meaningful place for both generations, improved the HRQOL of the older people's group, and decreased the depressive symptoms in the more depressed older people's subgroup. PMID- 21615705 TI - Increased expression of exon 2 deleted MEFV transcript in familial Mediterranean fever patients. AB - A defect in MEFV gene expression regulation has been implicated in familial Mediterranean fever (FMF) etiopathophysiology. Here we show significantly higher expression level in second exon lacking MEFV transcript in FMF patients compared with healthy controls (P=0.026). Our results also point out a possible role of exon 2 deleted MEFV transcript in FMF pathogenesis. PMID- 21615706 TI - Design, synthesis, and evaluation of thiazolidinone derivatives as antimicrobial and anti-viral agents. AB - A series of 1,3-thiazolidin-4-one derivatives were prepared by the reaction of respective aromatic amine, aromatic aldehyde, and thioglycolic acid in dry benzene/toluene. The newly synthesized compounds were characterized on the basis of elemental analysis, IR, (1) HNMR, and mass spectra. The newly synthesized final compounds were evaluated for their in vitro antibacterial, antifungal, and anti-viral activities. Preliminary results indicated that some of the compounds demonstrated antibacterial activity in the range of 7-13 MUg/mL, antifungal activity in the range of 13-17 MUg/mL, comparable with the standard drugs, ciprofloxacin and fluconazole. Structure-activity relationship studies revealed that the nature of the substituents at the 2 and 3 positions of the thiazolidinone nucleus had a significant impact on the in vitro antimicrobial and anti-viral activity of these classes of agents. PMID- 21615707 TI - Group II activators of G-protein signalling and proteins containing a G-protein regulatory motif. AB - Beyond the core triad of receptor, Galphabetagamma and effector, there are multiple accessory proteins that provide alternative modes of signal input and regulatory adaptability to G-protein signalling systems. Such accessory proteins may segregate a signalling complex to microdomains of the cell, regulate the basal activity, efficiency and specificity of signal propagation and/or serve as alternative binding partners for Galpha or Gbetagamma independent of the classical heterotrimeric Galphabetagamma complex. The latter concept led to the postulate that Galpha and Gbetagamma regulate intracellular events distinct from their role as transducers for cell surface seven-transmembrane span receptors. One general class of such accessory proteins is defined by AGS proteins or activators of G-protein signalling that refer to mammalian cDNAs identified in a specific yeast-based functional screen. The discovery of AGS proteins and related entities revealed a number of unexpected mechanisms for regulation of G-protein signalling systems and expanded functional roles for this important signalling system. PMID- 21615708 TI - Comment on aspheric intraocular lenses. PMID- 21615710 TI - Acta Ophthalmologica Honorary Award. PMID- 21615711 TI - Perimetry, tonometry and epidemiology: the fate of glaucoma management. AB - This is the lecture that I gave when I was awarded Acta Ophthalmologica's gold medal and honorary award at the Nordic Ophthalmological Congress in Reykjavik in August 2010. I was inspired by Jared Diamond's famous book: Guns, Germs, and Steel, The Fates of Human Societies. Diamond is professor of geography and physiology at the University of California, Los Angeles. In this book, which won the Pulitzer Prize, the author explains why the European civilization took over the world. This was all because of predetermined factors of biological nature, environmental differences that were strengthened by feedback loops, and resulted in technological innovation and superiority. In this presentation, I write about the development of glaucoma knowledge and management. I suggest that the development might have been predetermined, just waiting for more facts to be unveiled by research. The technologies tonometry and perimetry have been fundamental as has epidemiological techniques and controlled trials. The new and increased knowledge about glaucoma must now be translated to improvements of clinical glaucoma care. The glaucoma scientists of today and tomorrow will continue to reveal as yet unknown facts, maybe in a predetermined way, but nevertheless of benefit to all patients with glaucoma. PMID- 21615712 TI - An overview of racial disparities in preterm birth rates: caused by infection or inflammatory response? AB - Infection has been hypothesized to be one of the factors associated with spontaneous preterm birth (PTB) and with the racial disparity in rates of PTB between African American and Caucasian women. However, recent findings refute the generalizability of the role of infection and inflammation. African Americans have an increased incidence of PTB in the setting of intraamniotic infection, periodontal disease, and bacterial vaginosis compared to Caucasians. Herein we report variability in infection- and inflammation-related factors based on race/ethnicity. For African American women, an imbalance in the host proinflammatory response seems to contribute to infection-associated PTB, as evidenced by a greater presence of inflammatory mediators with limited or reduced presence of immune balancing factors. This may be attributed to differences in the genetic variants associated with PTB between African Americans and Caucasians. We argue that infection may not be a cause of racial disparity but in association with other risk factors such as stress, nutritional deficiency, and differences in genetic variations in PTB, pathways and their complex interactions may produce differential inflammatory responses that may contribute to racial disparity. PMID- 21615713 TI - Operating time and blood loss during laparoscopic-assisted vaginal hysterectomy with in situ morcellation. AB - OBJECTIVE: To develop a regression-based prediction equation for operative time and estimated blood loss in laparoscopically assisted vaginal hysterectomy (LAVH) for large uteri, as required, by combined laparoscopic in situ and vaginal morcellation. DESIGN: Prospective study (Canadian Task Force classification II 1). SETTING: University-affiliated hospitals. SAMPLE: Fifty-six patients who underwent LAVH. Methods. Evaluation of all patients who had LAVH with laparoscopic in situ morcellation and vaginal morcellation during a 2-year period. MAIN OUTCOME MEASURES: Operative time, estimated blood loss, total uterine weight by laparoscopic or vaginal morcellation, complications and length of hospital stay. RESULTS: Mean operative time was 133 +/- 22 minutes, and mean blood loss 133 +/- 101 ml. Mean uterine weight was 383 +/- 187 g by laparoscopic and 251 +/- 103 g by vaginal morcellation. Greater total uterine weight and morcellation were associated with longer operative times. Blood loss correlated with uterine weight when vaginal morcellation was also used. A regression equation is presented for estimating the likely operating time and blood loss. CONCLUSIONS: An increase in the operative time and a higher blood loss can be expected as the uterine weight increases and can be predicted taking morcellation methods into account. PMID- 21615714 TI - Assessment of pain in women randomly allocated to speculum or digital insertion of the Foley catheter for induction of labor. AB - OBJECTIVE: The primary aim was to assess pain subjectively and objectively in women during insertion of a Foley catheter for induction of labor. A secondary aim was to assess pain during cervical ripening and to evaluate maternal satisfaction. DESIGN: Randomized controlled trial. SETTING: University hospital, Sweden. POPULATION: Forty-two women undergoing induction of labor and cervical ripening with a Foley catheter. METHODS: Women were randomly allocated to digital (n=21) or to speculum (n=21) placement of a Foley catheter. A visual analogue scale (VAS) was used for subjective assessment of pain and, for objective measurements, a skin conductance algesimeter was used and the area under the curve (AUC) was calculated (MUSs). Maternal satisfaction was evaluated in a questionnaire. MAIN OUTCOME MEASURES: Pain sensation during placement of the Foley catheter. RESULTS: There was a significant difference between groups in pain measurements during insertion of the Foley catheter. The speculum group had higher median pain scores than the digital group, VAS=5 vs. = 3 (p=0.03) and greater median AUC measurements: 1840 vs. 823 MUSs (p=0.04). There was no difference in pain assessments during cervical ripening. Overall satisfaction scores were high and comparable between groups. CONCLUSION: Digital placement of the Foley catheter is subjectively and objectively less painful compared to the use of a speculum. Digital placement should therefore be considered as an alternative in the management of these patients. Ripening of the cervix with the Foley catheter is well tolerated and the overall satisfaction rate among patients induced with this method is high. PMID- 21615715 TI - Survival in cancer patients hospitalized for psoriasis: a population-based cohort study in Sweden. AB - BACKGROUND: Increased cancer risk after psoriasis has been observed in previous studies, whereas little is known about the prognosis in cancer patients with previously diagnosed psoriasis. OBJECTIVES: We aimed at examining the cancer specific and overall mortality among psoriatic cancer patients compared with the reference population. METHODS: The population-based Swedish registers were used to identify psoriatic cancer patients and cancer patients without psoriasis. We estimated hazard ratios (HRs) showing the probability of death in the two groups. RESULTS: In total, 1746 psoriatic cancer patients and 1 011 757 other cancer patients were identified from 1964 to 2006, showing a significant survival disparity [overall HR 1.27, 95% confidence interval (CI) 1.20-1.35 and cancer specific HR 1.26, 95% CI 1.18-1.35]. An overall mortality excess after psoriasis was observed for nine cancer sites and a cancer-specific mortality excess for seven cancer sites. Stratified analyses showed that the prognosis was worse for psoriatic cancer patients diagnosed below age 65 years and for those who had been treated for alcohol-related diseases. Those with more than one hospitalization for psoriasis were more likely to be associated with an increased risk of cancer specific mortality. CONCLUSIONS: A previous diagnosis of psoriasis worsens the prognosis of many cancers. A worse prognosis was more pronounced in psoriatic cancer patients diagnosed at an earlier age, previously hospitalized for alcohol related diseases, or with severe symptoms. Our study provides clinicians and patients with information about mortality risk and prognostic factors for psoriatic cancer patients. The mechanisms underlying this disparity warrant further studies. PMID- 21615716 TI - Photodynamic therapy reduces the histological features of actinic damage and the expression of early oncogenic markers. AB - BACKGROUND: Photodynamic therapy (PDT) has been shown to be effective in treating nonmelanoma skin cancer (NMSC), especially actinic keratosis (AK). Moreover, there is sufficient evidence of its effectiveness in preventing the appearance of premalignant and malignant lesions in organ transplant recipients. OBJECTIVES: To describe the molecular and genetic changes underlying this preventive effect. METHODS: Twenty-two patients with AK were treated with methyl aminolaevulinate and red light. Biopsies were performed before and 6 weeks after the treatment. Conventional histopathology and immunohistochemistry were carried out. RESULTS: Not only was a reduction in the dysplasia and elastosis observed, but also a decreased expression of Ki-67 and p53. The abnormal findings did not disappear completely in all cases. The expression of cyclin D1 remained stable. CONCLUSIONS: These findings show that PDT has the potential to reduce the histological signs of photoageing. Moreover, the reduction of Ki-67, a marker of proliferation and of p53, a marker of early skin carcinogenesis, indicates a reversal of the carcinogenic process. On the other hand, the fact that one treatment does not clear dysplasia and expression of p53 completely, and the persistence of cyclin D1, indicate that one single treatment, despite showing good clinical results, is not sufficient to clear completely the signs of chronic actinic damage, and thus the risk of NMSC. PMID- 21615717 TI - Facial psoriasis log-based area and severity index (fPLASI): construct validity of a new facial psoriasis measurement tool. PMID- 21615718 TI - Heparin-induced thrombocytopenia: analysis of risk factors in medical inpatients. AB - Heparin-induced thrombocytopenia (HIT) is an unpredictable reaction to heparin characterized by thrombocytopenia and increased risk of life-threatening venous and/or arterial thrombosis. Data are lacking regarding additional risk factors that may be associated with the development of HIT. This study aimed to identify the risk factors that may be associated with HIT in medical inpatients receiving heparin. Twenty five thousand six hundred and fifty-three patients admitted to the medicine service who received heparin product were reviewed retrospectively. The diagnosis of HIT was confirmed if the platelet count dropped >50% from baseline and there was a positive laboratory HIT assay. Fifty-five cases of in hospital HIT were observed. Multivariate analysis identified the administration of full anticoagulation dose with unfractionated heparin or exposure to heparin products for more than 5 d with an increased risk of HIT. Moreover, patients who were on haemodialysis, carried a diagnosis of autoimmune disease, gout or heart failure were also at increased risk. The results suggest that when using heparin products in these patient cohorts, increased surveillance for HIT is necessary. PMID- 21615719 TI - Secondary cancers following allogeneic haematopoietic cell transplantation in adults. AB - Secondary cancers that arise in allogeneic haematopoietic-cell transplant recipients, possibly as a result of treatment exposures, are a relatively rare complication of transplantation. However, they can be associated with significant morbidity and mortality. Secondary cancers include post-transplant lymphoproliferative disorders, new solid cancers and donor-derived haematological malignancies. This review describes the epidemiology, risk factors and screening recommendations for secondary cancers among adult allogeneic haematopoietic-cell transplant recipients. Constructing a patient-specific risk profile based on known exposures and risk-factors is the key to developing appropriate screening and preventative strategies for secondary cancers after allogeneic transplantation. PMID- 21615720 TI - Adenosine negatively regulates duodenal motility in mice: role of A(1) and A(2A) receptors. AB - BACKGROUND AND PURPOSE: Adenosine is considered to be an important modulator of intestinal motility. This study was undertaken to investigate the role of adenosine in the modulation of contractility in the mouse duodenum and to characterize the adenosine receptor subtypes involved. EXPERIMENTAL APPROACH: RT PCR was used to investigate the expression of mRNA encoding for A(1), A(2A), A(2B) and A(3) receptors. Contractile activity was examined in vitro as changes in isometric tension. KEY RESULTS: In mouse duodenum, all four classes of adenosine receptors were expressed, with the A(2B) receptor subtype being confined to the mucosal layer. Adenosine caused relaxation of mouse longitudinal duodenal muscle; this was antagonized by the A(1) receptor antagonist and mimicked by N(6) -cyclopentyladenosine (CPA), selective A(1) agonist. The relaxation induced by A(1) receptor activation was insensitive to tetrodotoxin (TTX) or N(omega) -nitro-l-arginine methyl ester (l-NAME). Adenosine also inhibited cholinergic contractions evoked by neural stimulation, effect reversed by the A(1) receptor antagonist, but not myogenic contractions induced by carbachol. CPA and 2-p-(2-carboxyethyl) phenethylamino-5'-N ethylcarboxamidoadenosine hydrochloride hydrate (CGS-21680), A(2A) receptor agonist, both inhibited the nerve-evoked cholinergic contractions. l-NAME prevented only the CGS-21680-induced effects. S-(4-Nitrobenzyl)-6-thioinosine, a nucleoside uptake inhibitor, reduced the amplitude of nerve-evoked cholinergic contractions, an effect reversed by an A(2A) receptor antagonist or l-NAME. CONCLUSIONS AND IMPLICATIONS: Adenosine can negatively regulate mouse duodenal motility either by activating A(1) inhibitory receptors located post-junctionally or controlling neurotransmitter release via A(1) or A(2A) receptors. Both receptors are available for pharmacological recruitment, even if only A(2A) receptors appear to be preferentially stimulated by endogenous adenosine. PMID- 21615721 TI - Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats. AB - BACKGROUND AND PURPOSE: The designer drug 1-(4-methylphenyl)-2-methylaminopropan 1-one (4-methylmethcathinone, mephedrone) is reported to possess psychostimulant, entactogenic and hallucinogenic effects. The purpose of this study was to examine the effects of acute administration of mephedrone on extracellular levels of dopamine (DA) and 5-HT in the nucleus accumbens of awake rats and compare these effects with those induced by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and amphetamine. EXPERIMENTAL APPROACH: Microdialysis sampling was performed while simultaneously recording locomotor activity in rats and the monoamines were determined by HPLC with electrochemical detection. KEY RESULTS: Mephedrone (3 mg.kg(-1) s.c.) and (+)-amphetamine (1 mg.kg(-1) s.c.) caused rapid increases in extracellular DA levels of 496% and 412%, respectively, whereas MDMA (3 mg.kg(-1) s.c.) showed only a moderate effect (235%). The corresponding 5-HT levels increased to 941% (mephedrone) and 911% (MDMA), but only to 165% following amphetamine. The calculated t(1/2) values for elimination rate of mephedrone, MDMA and amphetamine-induced increases in extracellular DA levels were 25, 303 and 51 min, the corresponding t(1/2) values for 5-HT were 26, 48 and 84 min, respectively. Locomotor activity was increased most by amphetamine, whereas both mephedrone and MDMA showed about three times lower and shorter-lasting effects. CONCLUSIONS AND IMPLICATIONS: The neurochemical and functional properties of mephedrone resemble those of MDMA, but it also shows an amphetamine-like effect in that it evokes a rapid release and elimination of DA in the brain reward system, a feature that may contribute to its potent reinforcing properties. PMID- 21615722 TI - Decreased production of neuronal NOS-derived hydrogen peroxide contributes to endothelial dysfunction in atherosclerosis. AB - BACKGROUND AND PURPOSE: Reduced NO availability has been described as a key mechanism responsible for endothelial dysfunction in atherosclerosis. We previously reported that neuronal NOS (nNOS)-derived H(2)O(2) is an important endothelium-derived relaxant factor in the mouse aorta. The role of H(2)O(2) and nNOS in endothelial dysfunction in atherosclerosis remains undetermined. We hypothesized that a decrease in nNOS-derived H(2)O(2) contributes to the impaired vasodilatation in apolipoprotein E-deficient mice (ApoE(-/-)). EXPERIMENTAL APPROACH: Changes in isometric tension were recorded on a myograph; simultaneously, NO and H(2)O(2) were measured using carbon microsensors. Antisense oligodeoxynucleotides were used to knockdown eNOS and nNOS in vivo. Western blot and confocal microscopy were used to analyse the expression and localization of NOS isoforms. KEY RESULTS: Aortas from ApoE(-/-) mice showed impaired vasodilatation paralleled by decreased NO and H(2)O(2) production. Inhibition of nNOS with L-Arg(NO2) -L-Dbu, knockdown of nNOS and catalase, which decomposes H(2)O(2) into oxygen and water, decreased ACh-induced relaxation by half, produced a small diminution of NO production and abolished H(2)O(2) in wild type animals, but had no effect in ApoE(-/-) mice. Confocal microscopy showed increased nNOS immunostaining in endothelial cells of ApoE(-/-) mice. However, ACh stimulation of vessels resulted in less phosphorylation on Ser852 in ApoE(-/ ) mice. CONCLUSIONS AND IMPLICATIONS: Our data show that endothelial nNOS-derived H(2)O(2) production is impaired and contributes to endothelial dysfunction in ApoE(-/-) aorta. The present study provides a new mechanism for endothelial dysfunction in atherosclerosis and may represent a novel target to elaborate the therapeutic strategy for vascular atherosclerosis. PMID- 21615723 TI - Perivascular adipose tissue-derived relaxing factors: release by peptide agonists via proteinase-activated receptor-2 (PAR2) and non-PAR2 mechanisms. AB - BACKGROUND AND PURPOSE: We hypothesized that proteinase-activated receptor-2 (PAR2)-mediated vasorelaxation in murine aorta tissue can be due in part to the release of adipocyte-derived relaxing factors (ADRFs). EXPERIMENTAL APPROACH: Aortic rings from obese TallyHo and C57Bl6 intact or PAR2-null mice either without or with perivascular adipose tissue (PVAT) were contracted with phenylephrine and relaxation responses to PAR2-selective activating peptides (PAR2-APs: SLIGRL-NH(2) and 2-furoyl-LIGRLO-NH(2) ), trypsin and to PAR2-inactive peptides (LRGILS-NH(2) , 2-furoyl-OLRGIL-NH(2) and LSIGRL-NH(2) ) were measured. Relaxation was monitored in the absence or presence of inhibitors that either alone or in combination were previously shown to inhibit ADRF-mediated responses: L-NAME (NOS), indomethacin (COX), ODQ (guanylate cyclase), catalase (H(2) O(2) ) and the K(+) channel-targeted reagents, apamin, charybdotoxin, 4-aminopyridine and glibenclamide. KEY RESULTS: Endothelium-intact PVAT-free preparations did not respond to PAR2-inactive peptides (LRGILS-NH(2) , LSIGRL-NH(2) , 2-furoyl-OLRGIL NH(2) ), whereas active PAR2-APs (SLIGRL-NH(2) ; 2-furoyl-LIGRLO-NH(2) ) caused an L-NAME-inhibited relaxation. However, in PVAT-containing preparations treated with L-NAME/ODQ/indomethacin together, both PAR2-APs and trypsin caused relaxant responses in PAR2-intact, but not PAR2-null-derived tissues. The PAR2-induced PVAT-dependent relaxation (SLIGRL-NH(2) ) persisted in the presence of apamin plus charybdotoxin, 4-aminopyridine and glibenclamide, but was blocked by catalase, implicating a role for H(2) O(2) . Surprisingly, the PAR2-inactive peptides, LRGILS-NH(2) and 2-furoyl-OLRGIL-NH(2) (but not LSIGRL-NH(2) ), caused relaxation in PVAT-containing preparations from both PAR2-null and PAR2-intact (C57Bl, TallyHo) mice. The LRGILS-NH(2) -induced relaxation was distinct from the PAR2 response, being blocked by 4-aminopyridine, but not catalase. CONCLUSIONS: Distinct ADRFs that may modulate vascular tone in pathophysiological settings can be released from murine PVAT by both PAR2-dependent and PAR2-independent mechanisms. PMID- 21615725 TI - Propranolol enhances cell cycle-related gene expression in pressure overloaded hearts. AB - BACKGROUND AND PURPOSE: Cell cycle regulators are regarded as essential for cardiomyocyte hypertrophic growth. Given that the beta-adrenoceptor antagonist propranolol blunts cardiomyocyte hypertrophic growth, we determined whether propranolol alters the expression of cell cycle-related genes in mouse hearts subjected to pressure overload. EXPERIMENTAL APPROACH: Pressure overload was induced by transverse aortic constriction (TAC), whereas the expression levels of 84 cell cycle-related genes were assayed by real-time PCR. Propranolol (80 mg.kg( 1) .day(-1) ) was administered in drinking water for 14 days. KEY RESULTS: Two weeks after surgery, TAC caused a 46% increase in the left ventricular weight-to body weight (LVW/BW) ratio but no significant changes in cell cycle gene expression. Propranolol, at plasma concentrations ranging from 10 to 140 ng.mL( 1) , blunted the LVW/BW ratio increase in TAC mice, while significantly increasing expression of 10 cell cycle genes including mitotic cyclins and proliferative markers such as Ki67. This increase in cell cycle gene expression was paralleled by a significant increase in the number of Ki67-positive non cardiomyocyte cells as revealed by immunohistochemistry and confocal microscopy. beta-Adrenoceptor signalling was critical for cell cycle gene expression changes, as genetic deletion of beta-adrenoceptors also caused a significant increase in cyclins and Ki67 in pressure overloaded hearts. Finally, we found that metoprolol, a beta(1) -adrenoceptor antagonist, failed to enhance cell cycle gene expression in TAC mice. CONCLUSIONS AND IMPLICATIONS: Propranolol treatment enhances cell cycle-related gene expression in pressure overloaded hearts by increasing the number of cycling non-cardiomyocyte cells. These changes seem to occur via beta(2) -adrenoceptor-mediated mechanisms. PMID- 21615724 TI - AM630 behaves as a protean ligand at the human cannabinoid CB2 receptor. AB - BACKGROUND AND PURPOSE: We have investigated how pre-incubating hCB(2) CHO cells with the CB(2) receptor antagonists/inverse agonists, AM630 and SR144528, affects how these and other ligands target hCB(2) receptors in these cells or their membranes. EXPERIMENTAL APPROACH: We tested the ability of AM630, SR144528 and of the CB(1) /CB(2) receptor agonists, CP55940 and R-(+)-WIN55212, to modulate forskolin-stimulated cAMP production in hCB(2) CHO cells or [(35) S]-GTPgammaS binding to membranes prepared from these cells, or to displace [(3) H]-CP55940 from whole cells and membranes. Assays were also performed with the CB(2) receptor partial agonist, Delta(9) -tetrahydrocannabivarin. Some cells were pre incubated with AM630 or SR144528 and then washed extensively. KEY RESULTS: AM630 behaved as a low-potency neutral competitive antagonist in AM630-pre-incubated cells, a low-potency agonist in SR144528-pre-incubated cells, and a much higher potency inverse agonist/antagonist in vehicle-pre-incubated cells. AM630 pre incubation (i) reduced the inverse efficacy of SR144528 without abolishing it; (ii) increased the efficacy of Delta(9) -tetrahydrocannabivarin; and (iii) did not affect the potency with which AM630 displaced [(3) H]-CP55940 from whole cells or its inverse agonist potency and efficacy in the [(35) S]-GTPgammaS membrane assay. CONCLUSIONS AND IMPLICATIONS: These results suggest that AM630 is a protean ligand that can target a constitutively active form of the hCB(2) receptor (R*) with low affinity to produce agonism or neutral antagonism and a constitutively inactive form of this receptor (R) with much higher affinity to produce inverse agonism, and that the constitutive activity of whole cells is decreased less by pre-incubation with AM630 than with the higher-efficacy inverse agonist, SR144528. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. PMID- 21615726 TI - Cellular pharmacokinetic mechanisms of adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2 in MCF-7/Adr cells. AB - BACKGROUND AND PURPOSE: Intracellular pharmacokinetics of anticancer drugs in multi-drug resistance (MDR) cancer cells is hugely important in the evaluation and improvement of drug efficacy. By using adriamycin as a probe drug in MDR cancer cells, we developed a cellular pharmacokinetic-pharmacodynamic (PK-PD) model to reveal the correlation between cellular pharmacokinetic properties and drug resistance. In addition, the ability of 20(S)-ginsenoside Rh2 (20(S)-Rh2) to reverse MDR was further investigated. EXPERIMENTAL APPROACH: The cellular pharmacokinetics of adriamycin were analysed visually and quantitatively in human breast cancer cells MCF-7 and in adriamycin-resistant MCF-7 (MCF-7/Adr) cells. Mitochondria membrane potential was assayed to evaluate the apoptotic effect of adriamycin. Subsequently, a PK-PD model was developed via MATLAB. KEY RESULTS: Visual and quantitative data of the dynamic subcellular distribution of adriamycin revealed that it accumulated in cells, especially nuclei, to a lesser and slower extent in MCF-7/Adr than in MCF-7 cells. 20(S)-Rh2 increased the rate and amount of adriamycin entering cellular/subcellular compartments in MCF-7/Adr cells through inhibition of P-glycoprotein (P-gp) activity, in turn augmenting adriamycin-induced apoptosis. The integrated PK-PD model mathematically revealed the pharmacokinetic mechanisms of adriamycin resistance in MCF-7/Adr cells and its reversal by 20(S)-Rh2. CONCLUSIONS AND IMPLICATIONS: P-gp, which is overexpressed and functionally active at cellular/subcellular membranes, influences the cellular pharmacokinetic and pharmacological properties of adriamycin in MCF-7/Adr cells. Inhibition of P-gp activity represents a key mechanism by which 20(S)-Rh2 attenuates adriamycin resistance. Even more importantly, our findings provide a new strategy to explore the in-depth mechanisms of MDR and evaluate the efficacy of MDR modulators. PMID- 21615727 TI - Delta9-Tetrahydrocannabinol (Delta9-THC) attenuates mouse sperm motility and male fecundity. AB - BACKGROUND AND PURPOSE: Numerous studies have shown that N arachidonoylethanolamine (AEA) can inhibit sperm motility and function but the ability of cannabinoids to inhibit sperm motility is not well understood. We investigated the effects of WIN 55,212-2, a CB(1) cannabinoid receptor agonist, and Delta(9) -tetrahydracannabinol (Delta(9) -THC) on the ATP levels and motility of murine sperm in vitro. In addition, the effects of acute administration of Delta(9) -THC on male fecundity were determined. EXPERIMENTAL APPROACH: Effects of Delta(9) -THC on basal sperm kinematics were determined using computer assisted sperm analysis (CASA). Stop-motion imaging was performed to measure sperm beat frequency. The effect of Delta(9) -THC on sperm ATP was determined using a luciferase assay. Male fertility was determined by evaluating the size of litters sired by Delta(9) -THC-treated males. KEY RESULTS Pretreatment of sperm for 15 min with 1 uM Delta(9) -THC reduced their basal motility and attenuated the ability of bicarbonate to stimulate flagellar beat frequency. Treatment with 5 uM WIN 55,212-2 or 10 uM Delta(9) -THC for 30 min reduced sperm ATP levels. In sperm lacking CB(1) receptors this inhibitory effect of WIN 55,212-2 on ATP was attenuated whereas that of Delta(9) -THC persisted. Administration of 50 mg.kg( 1) Delta(9) -THC to male mice just before mating caused a 20% decrease in embryonic litter size. CONCLUSIONS AND IMPLICATIONS: Delta(9) -THC inhibits both basal and bicarbonate-stimulated sperm motility in vitro and reduces male fertility in vivo. High concentrations of WIN 55,212-2 or Delta(9) -THC inhibit ATP production in sperm; this effect of WIN 55,212-2 is CB(1) receptor-dependent whereas that of Delta(9) -THC is not. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. PMID- 21615728 TI - HCN channelopathies: pathophysiology in genetic epilepsy and therapeutic implications. AB - Hyperpolarization-activated cyclic nucleotide-gated channels (HCN) can act as pacemakers in the brain making them strong candidates for driving aberrant hypersynchronous network activity seen in epilepsy. Transcriptional changes in HCN channels occur in several animal models of epilepsy. However, only recently have genetic studies demonstrated sequence variation in HCN1 and HCN2 genes associated with human epilepsy. These include a triple proline deletion in HCN2 that increases channel function and occurs more often in patients with febrile seizure syndromes. Other HCNx gene variants have been described in idiopathic generalized epilepsy although the functional consequence of these remains unclear. In this review we explore potential cellular and network mechanisms involving HCN channels in the genetic epilepsies. We suggest how new genetic sequencing technology, medium-throughput functional assays and the ability to develop syndrome-specific animal models will provide a more comprehensive understanding of how I(h) contributes to pathogenic mechanisms underlying human genetic epilepsy. We also discuss what is known about the pharmacological manipulation of HCN channels in the context of epilepsy and how this may help future efforts in developing HCN-channel-based therapy. PMID- 21615729 TI - Amelioration of central cardiovascular regulatory dysfunction by tropomyocin receptor kinase B in a mevinphos intoxication model of brain stem death. AB - BACKGROUND AND PURPOSE: Little information exists on the mechanisms that precipitate brain stem death, the legal definition of death in many developed countries. We investigated the role of tropomyocin receptor kinase B (TrkB) and its downstream signalling pathways in the rostral ventrolateral medulla (RVLM) during experimental brain stem death. EXPERIMENTAL APPROACH: An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos bilaterally into the RVLM of Sprague-Dawley rats was used, in conjunction with cardiovascular, pharmacological and biochemical evaluations. KEY RESULTS: A significant increase in TrkB protein, phosphorylation of TrkB at Tyr(516) (pTrkB(Y516) ), Shc at Tyr(317) (pShc(Y317) ) or ERK at Thr(202) /Tyr(204) , or Ras activity in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Microinjection bilaterally into RVLM of a specific TrkB inhibitor, K252a, antagonized those increases. Pretreatment with anti-pShc(Y317) antiserum, Src homology 3 binding peptide (Grb2/SOS inhibitor), farnesylthioacetic acid (Ras inhibitor), manumycin A (Ras inhibitor) or GW5074 (Raf-1 inhibitor) blunted the preferential augmentation of Ras activity or ERK phosphorylation in RVLM and blocked the up-regulated NOS I/protein kinase G (PKG) signalling, the pro-life cascade that sustains central cardiovascular regulation during experimental brain stem death. CONCLUSIONS AND IMPLICATIONS: Activation of TrkB, followed by recruitment of Shc/Grb2/SOS adaptor proteins, leading to activation of Ras/Raf-1/ERK signalling pathway plays a crucial role in ameliorating central cardiovascular regulatory dysfunction via up-regulation of NOS I/PKG signalling cascade in the RVLM in brain stem death. These findings provide novel information for developing therapeutic strategies against this fatal eventuality. PMID- 21615730 TI - Strategies for exome and genome sequence data analysis in disease-gene discovery projects. AB - In whole-exome sequencing (WES), target capture methods are used to enrich the sequences of the coding regions of genes from fragmented total genomic DNA, followed by massively parallel, 'next-generation' sequencing of the captured fragments. Since its introduction in 2009, WES has been successfully used in several disease-gene discovery projects, but the analysis of whole-exome sequence data can be challenging. In this overview, we present a summary of the main computational strategies that have been applied to identify novel disease genes in whole-exome data, including intersect filters, the search for de novo mutations, and the application of linkage mapping or inference of identity-by descent (IBD) in family studies. PMID- 21615731 TI - Asthma: a simple concept but in reality a complex disease. AB - BACKGROUND: Asthma is a disorder of the conducting airways that contract too easily and too much to cause variable airflow obstruction with symptoms of wheeze, cough, chest tightness and shortness of breath. Based on this knowledge, initial treatments were directed to dilating the contracted airways with anticholinergic and adrenergic drugs. The recognition that allergic-type inflammation underlay the hyperresponsive airways in asthma led to the introduction of anti-inflammatory drugs such as sodium cromoglicate and corticosteroids. Over the 2 decades that followed, these drugs have been progressively improved by increasing their therapeutic index and duration of action. METHODS: A review of the recent literature indicates that since the 1980s, the explosive increase in knowledge of the cell and mediator mechanisms of asthma has only led to modest improvements in therapy including the introduction of leukotriene modifiers and a blocking monoclonal antibody against IgE. Indeed, biologics targeting allergic cytokines and effector cells have on the whole proven disappointing despite initial promise being shown in animal models. RESULTS: Part of the difficulty lies in the oversimplified concept that asthma is only driven by allergic processes when in reality there are many environmental causes and triggers and the view that it is a homogeneous disorder only varying in severity. CONCLUSIONS: The more recent views that asthma is a complex disorder made up of different subtypes with differing causes, treatment responses and natural histories creates a new opportunity for stratified medicine in which therapies acting upstream selectively target specific disease subtypes identified by specific diagnostic biomarkers. PMID- 21615732 TI - 2011 ESCI Award for Excellence in Basic / Translational Research: innate regulation of adaptive immunity by dendritic cells. AB - Dendritic cells (DC) play a key role in the initiation of adaptive immunity, and the manipulation and/or targeting of DC has great potential for immune intervention. However, clinical applications are hampered by the fact that we still know relatively little about how DC become 'activated' to stimulate and direct T-cell responses. Over the last decade, much emphasis has been placed on dissecting innate signalling pathways that can trigger DC activation and promote T-cell priming. Here, we review work from our laboratory aimed at helping define 'pattern-recognition pathways' involved in DC activation by potential pathogens. One pathway for sensing infection by RNA viruses involves recognition of viral genomes or virally infected cells in endosomal compartments and utilises members of the toll-like receptor (TLRs) family, including TLR9, 7, or 3. RNA virus genomes can additionally be recognised in the cytosol by DExD/H-box helicases such as MDA5 or RIG-I, the latter of which is activated by RNAs bearing 5' tri phosphates. Finally, a distinct pathway involves cell surface and phagosomal recognition of fungi by C-type lectins, which signal via Syk kinase. Notably, some of these pathways are involved not only in direct sensing of pathogens but also in the recognition of self-alterations that might accompany infection, such as induction of cell death. These studies help build a global picture of the receptors and signalling pathways that regulate DC activation and have applications in immunotherapy of cancer and infectious diseases. PMID- 21615734 TI - The impact of the school-based Psychosocial Structured Activities (PSSA) program on conflict-affected children in Northern Uganda. AB - BACKGROUND: Children in northern Uganda have undergone significant psychosocial stress during the region's lengthy conflict. A Psychosocial Structured Activities (PSSA) program was implemented in 21 schools identified as amongst those most severely affected by conflict-induced displacement across Gulu and Amuru Districts. The PSSA intervention comprised a series of 15 class sessions designed to progressively increase children's resilience through structured activities involving drama, movement, music and art (with additional components addressing parental support and community involvement). METHOD: Eight schools were selected by random quota sampling from those schools receiving the PSSA intervention. Two hundred and three children were identified in these schools as being scheduled to receive intervention, and were followed up 12 months later following engagement with PSSA activities. A comparison group comprised 200 children selected from schools that had met inclusion criteria for receipt of intervention, but were not scheduled for intervention coverage until later. Preliminary research used participatory focus group methodology to determine local indicators of child well being as viewed by parents, teachers, and children respectively. Pre- and post- assessments focused on ratings for each child - by parents, teachers and children - with respect to these indicators. RESULTS: Significant increases in ratings of child well-being were observed in both intervention and comparison groups over a 12-month period. However, the well-being of children who had received the PSSA intervention increased significantly more than for children in the comparison group, as judged by child and parent (but not teacher) report. This effect was evident despite considerable loss-to-follow-up at post-testing as a result of return of many households to communities of origin. CONCLUSION: General improvement in child well-being over a 12-month period suggests that recovery and reconstruction efforts in Northern Uganda following the onset of peace had a substantive impact on the lives of children. However, exposure to the PSSA program had an additional positive impact on child well-being, suggesting its value in post-conflict recovery contexts. PMID- 21615733 TI - Evaluation of methods for one-dimensional spatial analysis of two-dimensional patterns in mouse chimaeras. AB - The relative extent of cell mixing in tissues of mouse chimaeras or mosaics can be studied by comparing the distributions of the two cell populations in the tissues. However, the mean patch size is misleading because it is affected by both the extent of cell mixing and the relative contributions of the two cell populations. Previous work suggested that effects attributable to differences in tissue composition among chimaeras can be factored out either by correcting the mean patch size or by using the median patch size for the minority cell population and restricting the analysis to grossly unbalanced chimaeras. In the present study, computer simulations of two-dimensional mosaic arrays of black and white squares (representing cells) were used to simulate chimaeric tissues. Random arrays simulated tissues with extensive cell mixing, arrays of cell clumps (representing coherent clones) simulated less mixed tissues, and striped arrays simulated tissues with elongated but fragmented descendent clones. The computer simulations predicted that (i) the median patch length (minority cell population) and the corrected mean patch length would both distinguish between random and clumped patterns and (ii) differences in the variation of the composition of two perpendicular series of one-dimensional transects would distinguished between stripes and randomly orientated patches. Both predictions were confirmed by analysis of histological sections of the retinal pigment epithelium from fetal and adult mouse chimaeras. This study demonstrates that two types of non-random two-dimensional variegated patterns (clumps and stripes) can be identified in chimaeras without two-dimensional reconstruction of serial sections. PMID- 21615735 TI - Restricted autonomic flexibility in children with social phobia. AB - BACKGROUND: Psychophysiological hyperresponsiveness to social-evaluative stress plays a key role in current theories of social phobia (SP). Owing to the early onset of this disorder, the study of children with SP can help to improve etiological models. However, research to date has failed to clarify whether children with SP are physiologically hyperresponsive to stress or not. In addition, the existence of elevated pre-stressor baseline group differences complicates the interpretation of acute stress responses and therefore poses a challenge for this line of research. Drawing on current models of autonomic control to explain the relationship between baseline and stress responding in SP children and healthy controls (HC), we acquired a broad set of autonomic measures in our study. METHOD: To index baseline and stress reactivity and to assess autonomic flexibility, we assessed a comprehensive array of sympathetic and parasympathetic measures in SP children (aged 8 to 12 years; n = 30) and healthy control children (HC, n = 26), while exposing them to the Trier Social Stress Test for Children (TSST-C). RESULTS: At baseline, the SP children showed higher levels of sympathetic (heart rate, electrodermal activity) and lower levels of parasympathetic (respiratory sinus arrhythmia, RSA) activation when compared to the HC children. During the TSST-C, the SP children showed similar HR responses but a limited RSA reactivity and a slower HR recovery relative to the HC children. CONCLUSION: Our study extends previous research by showing elevated baseline arousal and comparable stress responding in SP children relative to HC children. In addition, based on the autonomic flexibility model, we provide a potential explanation for the null findings of previous studies during stress. The pattern of elevated baseline heart rates and reduced RSA point to restricted autonomic flexibility in children with SP. PMID- 21615736 TI - Study of the distribution of microvessels in normal and pathologic prostate using an information-based similarity analysis. AB - Categorizing biologic signals by analysis of symbolic sequences was employed in the study of prostate microvessels. The estimates of the volume fraction of the vessels immunostained to Factor-VIII was mapped to binary sequences. The distance between sequences was estimated by comparing the rank and frequency of repetitive elements. These measurements were applied to detect whether there are unique microvascular patterns for each individual, and to search for patterns describing prostate microvessels of different conditions. Normal prostate, benign prostate hyperplasia and prostate carcinoma groups were studied. All the specimens were immunostained to F-VIII and strips formed by adjacent quadrats were explored. At each point of the long axis of the strip, the V(V) F-VIII was calculated. These values were processed with the information-based similarity software to estimate the dissimilarity between two space series. The following comparisons were carried out: intrasubject versus intragroup distances; intragroup distances among the groups studied and intergroup distances. The distance defined between a vessels immunostained to Factor-VIII space series and its randomized surrogate was considered as an index of the nonrandomness of the space series. These indices were compared for all the groups. We conclude that (a) The information based similarity analysis can be adapted to vessels immunostained to Factor-VIII space series from prostate microvessels. (b) There are no unique microvascular patterns associated with each individual. (c) There are characteristic patterns describing the microvessels from normal prostate, benign prostate hyperplasia and carcinoma. (d) This method is able to account for the differences between prostate cancer and both normal and benign prostate conditions, with respect to the microvessel patterns. PMID- 21615737 TI - Mouse MCP1 C-terminus inhibits human MCP1-induced chemotaxis and BBB compromise. AB - Compared to the rodent monocyte chemoattractant protein 1 (MCP1/CCL2), the human MCP1 lacks a C-terminal extension. Although the function of this C-extension is not entirely defined, in previous work we reported that it decreases the chemotactic properties of mouse MCP1. To determine if this function is specific to the rodent chemokine, or if the C-terminal extension has the ability to regulate chemotactic potency to MCP1 in general, we generated a chimeric protein consisting of human MCP1 fused to the mouse MCP1 C-terminal fragment. We found that mouse MCP1 C-terminus significantly decreased the chemotactic potency of human MCP1 and diminished the blood brain barrier compromise normally induced by the human protein. Not only did mouse MCP1 C-terminus inhibit human MCP1-induced Rac1 activation and formation of lamellipodia, it also disrupted the staining pattern of ZO-1 at cell-cell borders and prevented human MCP1-induced F-actin formation in brain microvascular endothelial cells. Additionally, the MCP1 C terminus dramatically decreased human MCP1-induced activation of ERM proteins in endothelial cells. These findings confirm that the rodent C-terminal MCP1 extension acts as a rheostat for MCP1 functions and suggest that potentially in humans another protein or protein complex may assume a similar regulatory function. PMID- 21615739 TI - Parkin-mediated regulation of mitochondrial dynamics. PMID- 21615738 TI - Tracking extranigral degeneration in animal models of Parkinson's disease: quest for effective therapeutic strategies. AB - Sporadic Parkinson's disease (PD) is now interpreted as a complex nervous system disorder in which the projection neurons are predominantly damaged. Such an interpretation is based on mapping of Lewy body and Lewy neurite pathology. Symptoms of the human disease are much widespread, which span from pre-clinical non-motor symptoms and clinical motor symptoms to cognitive discrepancies often seen in advanced stages. Existing symptomatic treatments further complicate with overt drug-irresponsive symptoms. PD is better understood by assimilation of extranigral degenerative pathways with nigrostriatal degenerative mechanisms. The term 'extranigral' appeared first in the 1990s to more rigorously define the nigral pathology by process of elimination. However, as clinicians progressively identified PD symptoms unresponsive to the gold standard drug l-DOPA, definitions of PD symptoms were redefined. Non-motor symptoms prodromal to motor symptoms just as pre-clinical to clinical, and conjointly emerged the concept of nigral versus extranigral degeneration in PD. While nigrostriatal degeneration is responsible for the neurobiological substrates of extrapyramydal motor features, extranigral degeneration corroborates a vast majority of other changes in discrete central, peripheral, and enteric nervous system nuclei, which together account for global symptoms of the human disease. As an extranigral site, spinal cord degeneration has also been implicated in PD progression. Interconnected to the upper CNS structures with descending and ascending pathways, spinal neurons participate in movement and sensory circuits, controlling movement and reflexes. Several clinical and in vivo studies have demonstrated signs of parkinsonism related degenerative processes in spinal cord, which led to recent consideration of spinal cord as an area of potential therapeutic target. In a nutshell, this review explores how the existing animal models can actually reflect the human disease in order to facilitate PD research. Evolution of extranigral degeneration studies has been succinctly revisited, followed by a survey on animal models in light of recent findings in clinical PD. Together, it may help to develop effective therapeutic strategies for PD. PMID- 21615741 TI - C12 derivatives of the hydroperoxide lyase pathway are produced by product recycling through lipoxygenase-2 in Nicotiana attenuata leaves. AB - In response to diverse stresses, the hydroperoxide lyase (HPL) pathway produces C(6) aldehydes and 12-oxo-(9Z )-dodecenoic acid ((9Z )-traumatin). Since the original characterization of (10E )-traumatin and traumatic acid, little has been added to our knowledge of the metabolism and fluxes associated with the conversion of (9Z )-traumatin into diverse products in response to wounding and herbivory. A liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method was developed to quantify C(12) derivatives of the HPL pathway and to determine their metabolism after wounding and simulated herbivory in Nicotiana attenuata leaves. Ninety-eight per cent of the (9Z )-traumatin produced was converted to 9-hydroxy-(10E )-traumatin (9-OH-traumatin); two-thirds by product recycling through lipoxygenase-2 (NaLOX2) activity and one-third by nonenzymatic oxidation. Thirty-eight per cent of the de novo produced 9-OH-traumatin was conjugated to glutathione, consistent with this oxylipin being a reactive electrophile species. 12-OH-(9Z )-dodecenoic and dodecenedioic acids also showed rapid increases after wounding and simulated herbivory and a role for C(12) derivatives as signals in these processes was consistent with their ability to elicit substantial changes in gene expression. These results underscore the importance of metabolite reflux through LOX2, an insight which creates new opportunities for a functional understanding of C(12) derivatives of the HPL pathway in the regulation of stress responses. PMID- 21615740 TI - Zinc-triggered induction of tissue plasminogen activator by brain-derived neurotrophic factor and metalloproteinases. AB - Tissue plasminogen activator (tPA) is necessary for hippocampal long-term potentiation. Synaptically released zinc also contributes to long-term potentiation, especially in the hippocampal CA3 region. Using cortical cultures, we examined whether zinc increased the concentration and/or activity of tPA. Two hours after a 10-min exposure to 300 MUM zinc, expression of tPA and its substrate, plasminogen, were significantly increased, as was the proteolytic activity of tPA. In contrast, increasing extracellular or intracellular calcium levels did not affect the expression or secretion of tPA. Changing zinc influx or chelating intracellular zinc also failed to alter tPA/plasminogen induction by zinc, indicating that zinc acts extracellularly. Zinc-mediated extracellular activation of matrix metalloproteinase (MMP) underlies the up-regulation of brain derived neurotrophic factor (BDNF) and tropomyosin receptor kinase (Trk) signaling. Consistent with these findings, co-treatment with a neutralizing antibody against BDNF or specific inhibitors of MMPs or Trk largely reversed tPA/plasminogen induction by zinc. Treatment of cortical cultures with p aminophenylmercuric acetate, an MMP activator, MMP-2, or BDNF alone induced tPA/plasminogen expression. BDNF mRNA and protein expression was also increased by zinc and mediated by MMPs. Thus, an extracellular zinc-dependent, MMP- and BDNF-mediated synaptic mechanism may regulate the levels and activity of tPA. PMID- 21615742 TI - Preparation of TiO2 thin films using water-soluble titanium complexes and their photoinduced properties. AB - Titanium dioxide thin films were prepared by using four water-soluble titanium complexes of titanium-lactate, tartalate, malate and salicylate complex solutions. The crystalline phases detected in the films were anatase. The surface microstructures of the four film samples were different in their grain sizes. Photocatalytic decomposition activity of the four films was almost the same, but their photoinduced hydrophilicities were different. The film prepared using titanium-salicylate complex exhibited lower hydrophilic conversion rate than the other films. Grain size and stress yielded to the film are considered to be important factors on the photoinduced hydrophilicity. PMID- 21615743 TI - Photoprotecting action and phytochemical analysis of a multiple radical scavenger lipophilic fraction obtained from the leaf of the seagrass Thalassia testudinum. AB - The apolar fraction F1 of Thalassia testudinum was chemically characterized by gas chromatography-mass spectrometry, which led to the identification of 43 metabolites, all of them reported for the first time in the genus Thalassia. More than 80% of the F1 composition was constituted by aromatic metabolites including the major components 1,1-bis(p-tolyl)ethane (6.0%), 4,4'-diisopropylbiphenyl (4.8%) and a 1,1-bis(p-tolyl)ethane isomer (4.7%). This lipophilic fraction was assayed for its antioxidant effects and skin protective action. In vitro assays showed that F1 strongly scavenged DPPH* (IC(50) 312.0 +/- 8.0 MUg mL(-1)), hydroxyl (IC(50) 23.8 +/- 0.5 MUg mL(-1)) and peroxyl radical (IC(50) 6.6 +/- 0.3 MUg mL(-1) ), as well as superoxide anion (IC(50) 50.0 +/- 0.7 MUg mL(-1)). Also, F1 markedly inhibited the spontaneous lipid peroxidation (LPO) in brain homogenates (IC(50) 93.0 +/- 6.0 MUg mL(-1)) and the LPS-stimulated nitrite generation on RAW624.7 macrophages (58.6 +/- 3.2%, 400 MUg mL(-1)). In agreement with these findings, its topical application at 250 and 500 MUg cm(-2) strikingly reduced skin damage on mice exposed to acute UVB radiation by 45% and 70%, respectively and significantly attenuated the LPO developed following the first 48 h after acute exposure to UVB irradiation, as manifested by the decreased malondialdehide level and by the increased of reduced gluthatione content. Our results suggest that F1 may contribute to skin repair by attenuating oxidative stress due to its antioxidant activity. PMID- 21615744 TI - Identification of lipids that accumulate during the routine storage of prestorage leukoreduced red blood cells and cause acute lung injury. AB - BACKGROUND: Lipids accumulate during the storage of red blood cells (RBCs), prime neutrophils (PMNs), and have been implicated in transfusion-related acute lung injury (TRALI). These lipids are composed of two classes: nonpolar lipids and lysophosphatidylcholines based on their retention time on separation by high pressure liquid chromatography. Prestorage leukoreduction significantly decreases white blood cell and platelet contamination of RBCs; therefore, it is hypothesized that prestorage leukoreduction changes the classes of lipids that accumulate during storage, and these lipids prime PMNs and induce acute lung injury (ALI) as the second event in a two-event in vivo model. STUDY DESIGN AND METHODS: RBC units were divided: 50% was leukoreduced (LR-RBCs), stored, and sampled on Day 1 and at the end of storage, Day 42. Priming activity was evaluated on isolated PMNs, and the purified lipids from Day 1 or Day 42 were used as the second event in the in vivo model. RESULTS: The plasma and lipids from RBCs and LR-RBCs primed PMNs, and the LR-RBC activity decreased with longer storage. Unlike RBCs, nonpolar lipids comprised the PMN-priming activity from stored LR-RBCs. Mass spectroscopy identified these lipids as arachidonic acid and 5-, 12-, and 15-hydroxyeicsotetranoic acid. At concentrations from Day 42, but not Day 1, three of four of these lipids individually, and the mixture, primed PMNs. The mixture also caused ALI as the second event in a two-event model of TRALI. CONCLUSION: We conclude that the nonpolar lipids that accumulate during LR RBC storage may represent the agents responsible for antibody-negative TRALI. PMID- 21615745 TI - Bacterial contamination in platelets: incremental improvements drive down but do not eliminate risk. AB - BACKGROUND: Bacterial contamination of platelet components (PCs) remains an important cause of transfusion-associated infectious risk. In 2004, Canadian Blood Services (CBS) implemented bacterial testing of PCs using the BacT/ALERT 3D system (bioMerieux). This system has been validated and implemented and continuous monitoring of culture rates allows gathering of data regarding true and false positives as well as false negatives. STUDY DESIGN AND METHODS: National data gathered between March 2004 and October 2010 from 12 CBS sites were analyzed to compare bacterial contamination rates across three platelet (PLT) preparation methods: apheresis, buffy coat, and PLT-rich plasma. Data were compared before and after implementation of protocol changes that may affect bacterial detection or contamination rates. RESULTS: Initial positive rates among the three production methods were significantly different, with apheresis PCs being the highest. The rates of confirmed positives among production methods did not differ significantly (p = 0.668). Increasing sample testing volumes from 4 to 6 mL to 8 to 10 mL significantly increased the rate of initial positives, while confirmed positives increased from 0.64 to 1.63 per 10,000, approaching significance (p = 0.055). Changing the skin disinfection method from a two-step to a one-step protocol did not significantly alter the rate of confirmed positives. During the period of data analysis, eight false-negative cases were reported, with five implicated in adverse transfusion reactions. CONCLUSION: Bacterial testing of PCs and implementation of improved protocols are incrementally effective in reducing the risk of transfusion of bacterially contaminated PLT concentrates; however, the continued occurrence of false negative results means the risk has not been eliminated. PMID- 21615746 TI - The reintroduction of nonleukoreduced blood: would patients and clinicians agree? PMID- 21615747 TI - Platelet pool inventory management: theory meets practice. AB - BACKGROUND: The shelf life of platelet concentrates (PCs) is a matter of days. Simultaneously, the demand is highly variable, shortages are not allowed, and producing too many results in outdating. Concurrently, younger PCs, implying an extended time till outdating (TTO), are preferred. Common PC inventory management relies on experience-based order-up-to rules. This study aimed at minimizing outdating and shortages, while extending the TTO through a theoretical approach. It focuses on PCs processed from whole blood donations. STUDY DESIGN AND METHODS: A combined approach of stochastic dynamic programming and simulation techniques (SDP/S), from the mathematical discipline operations research, has been implemented. This approach included the design of the dedicated software tool thrombocyte inventory management optimizer (TIMO). Based on the 2007 data, an optimal order-up-to rule was calculated. Outdating percentages and TTOs have been collected from August 2005 to July 2010. The resulting order-up-to rule has been applied and adjusted from summer 2007 onward. RESULTS: Over the study period, the results of the practical implementation showed significant improvements. The median weekly outdating percentage dropped to less than 1% and a gain in TTO of 0.48 day was reached. The results and the additional computer simulations brought confidence to the personnel to apply and adopt the "theoretical" approach and TIMO. CONCLUSION: Applying theory may help a blood bank to improve its PC inventory management and may help to identify to what extent practical limits can approach theoretical limits. The application of the theory has led to both a significant improvement and a more structured and less panic-driven PC inventory management. PMID- 21615748 TI - Hemolytic anemia after kidney transplantation: a prospective analysis. AB - BACKGROUND: Hemolysis may occur in 9% to 40% of patients after solid organ transplantation and be caused by the passenger lymphocyte syndrome (PLS). STUDY DESIGN AND METHODS: We have prospectively examined 217 kidney transplant recipients before (Day -1) and after (up to Days +10, +20, and +30) surgery. ABO identical transplant was performed in 180 (82.9%) patients, while 37 (17.1%) individuals received ABO-compatible nonidentical grafts. Direct antiglobulin tests (DATs) were performed by tube technique (polyspecific anti-human globulin [IgG + C3d]), positive DAT samples were further tested by gel agglutination (monospecific anti-IgG, -IgM, -IgA, or -C3), and eluates were prepared from DAT positive red blood cells (RBCs) by the dichloromethane elution test. RESULTS: We observed that 34 of 217 (15.7%) patients developed a positive DAT up to Day +30. The percentage of patients with positive DATs was significantly higher in those having ABO-compatible nonidentical transplants compared to those that received ABO-identical grafts (10/37 = 27.0% vs. 24/180 = 13.3%; p = 0.037). Specific RBC antibodies (anti-A or anti-B) were found in only 5 of 37 (13.5%) patients having ABO-compatible nonidentical transplants who presented with clinical hemolysis. We found only three reactive eluates from 24 patients with positive DATs who received ABO-identical transplants but had no hemolysis. CONCLUSIONS: Our data collected prospectively demonstrated that: 1) positive DATs occurred in 15.7% of all patients up to Day +30 after a kidney transplant; 2) the DAT positivity occurred up to Day +10 in 9.7% of all transplanted patients; 3) the majority of the transplant recipients with a positive DAT had a nonreactive RBC eluate; and 4) PLS was the cause of a positive DAT in 13.5% of patients submitted to ABO compatible nonidentical kidney transplants. PMID- 21615749 TI - Complement (C1q) fixing solid-phase screening for HLA antibodies increases the availability of compatible platelet components for refractory patients. AB - BACKGROUND: Immune refractoriness to platelet (PLT) transfusion is primarily due to HLA antibody. Patients at our institution are identified as refractory due to HLA by a Luminex-based immunoglobulin (Ig)G-single-antigen-bead (SAB) assay, but in highly sensitized patients, antigen-negative compatible donors cannot be found due to the high sensitivity of the IgG-SAB method. We developed an assay that detects only HLA antibodies binding the first complement component (C1q). We hypothesized that the C1q-SAB method might be more relevant than the IgG-SAB method because the antibodies identified may activate the complement cascade causing PLT destruction. STUDY DESIGN AND METHODS: Thirteen highly sensitized refractory patients received 177 PLT units incompatible by the IgG-SAB method. They were retrospectively retested by the C1q-SAB method. Calculated percent reactive antibody (CPRA) and HLA antibody specificities were compared between the two methods and corrected count increment (CCI) values were analyzed. Additionally the impact of ABO compatibility on CCI responses was evaluated. RESULTS: The mean CPRA value was significantly lower by C1q-SAB (60%) than by IgG SAB (94%; p < 0.05). Patients showed significantly better CCI (10.6 * 10(9) +/- 0.8 * 10(9) /L) with C1q-compatible (n = 134) than with C1q-incompatible PLTs (n = 43) (2.5 * 10(9) +/- 0.9 * 10(9) /L/m(2) ; p < 0.0001). ABO compatibility did not significantly impact the CCI values (p < 0.0001). Our results show that 75% of PLT units previously considered incompatible were actually compatible. CONCLUSION: For highly refractory patients to PLT transfusion, the C1q-based SAB binding assay may be a better method for identifying clinically relevant HLA antibodies and selecting PLT units that will result in acceptable CCI. PMID- 21615750 TI - The New York Stem Cell Foundation: Fifth Annual Translational Stem Cell Research Conference. AB - The New York Stem Cell Foundation's "Fifth Annual Translational Stem Cell Research Conference" convened on October 12-13, 2010 at the Rockefeller University in New York City. The conference attracted over 400 scientists, patient advocates, and stem cell research supporters from 16 countries. In addition to poster and platform presentations, the conference featured panels entitled "Road to the Clinic" and "Regulatory Roadblocks." PMID- 21615752 TI - G protein-coupled receptor modulation with pepducins: moving closer to the clinic. AB - At the 2nd Pepducin Science Symposium held in Cambridge, Massachusetts, on November 4-5, 2010, investigators working in G protein-coupled receptor (GPCR) research convened to discuss progress since last year's inaugural conference. This year's symposium focused on increasing knowledge of the structure and function of this ubiquitous superfamily of membrane receptors and their potential modulation for disease treatment. Presentations also focused on how GPCR mechanisms might be exploited to treat diseases with pepducins, novel synthetic lipopeptide pharmacophores that modulate heptahelical GPCR activity. While the multiple roles of GPCRs in physiological and pathophysiological processes offer significant opportunities for novel drug development, the global nature of their activity challenges drug-specific and validated target identification. This year's conference highlighted advances in understanding of GPCR agonist and antagonist ligand-binding motifs, their ligand-independent functions, structure activity relationships (SARs), and evolving unique methods to probe GPCR structure and function. Study results summarized at the meeting also provided evidence for evolving views of how signaling mechanisms work through these receptors. PMID- 21615753 TI - Comparison of the oral bioavailability and tissue disposition of monensin and salinomycin in chickens and turkeys. AB - The current study describes the pharmacokinetic parameters of two carboxylic polyether ionophores: monensin in turkeys and salinomycin in chickens. These data can be used to understand and predict the occurrence of undesirable residues of coccidiostats in edible tissues of these animal species. Special attention is paid to the distribution of residues between the different edible tissues during and at the end of the treatment period. For the bioavailability studies, monensin was administered to turkeys intravenously, in the left wing vein, at a dose of 0.4 mg /kg and orally at a dose of 20 mg /kg. Salinomycin was administered to chickens intravenously, in the left wing vein, at a dose of 0.25 mg /kg and orally at a dose of 2.5 mg /kg. Residue studies were carried out with supplemented feed at the rate of 100 mg /kg of feed for monensin in turkeys and 70 mg /kg for salinomycin in chickens, respectively. Coccidiostats had a low bioavailability in poultry (around 30% for monensin in chickens, around 1% for monensin in turkeys and around 15% for salinomycin in chickens). Monensin in chickens had a longer terminal half-life (between 3.07 and 5.55 h) than both monensin in turkeys (between 1.36 and 1.55 h) and salinomycin in chickens (between 1.33 and 1.79 h). The tissue /plasma partition coefficients showed a higher affinity of both monensin and salinomycin for fat, followed by liver and muscle tissue. The depletion data showed a fairly rapid elimination of coccidiostats in all the tissues after cessation of treatment. According to the results of depletion studies, a withdrawal period of 1 day seems sufficient to avoid undesirable exposure of consumers. PMID- 21615751 TI - Behavioral epigenetics. AB - Sponsored by the New York Academy of Sciences, the Warren Alpert Medical School of Brown University and the University of Massachusetts Boston, "Behavioral Epigenetics" was held on October 29-30, 2010 at the University of Massachusetts Boston Campus Center, Boston, Massachusetts. This meeting featured speakers and panel discussions exploring the emerging field of behavioral epigenetics, from basic biochemical and cellular mechanisms to the epigenetic modulation of normative development, developmental disorders, and psychopathology. This report provides an overview of the research presented by leading scientists and lively discussion about the future of investigation at the behavioral epigenetic level. PMID- 21615754 TI - Pharmacokinetics and bioavailability of cefquinome in rabbits following intravenous and intramuscular administration. PMID- 21615755 TI - Pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide in domestic cats. AB - The pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide after intravenous (i.v.) and oral (p.o.) administration were evaluated in adult cats. Three treatments were administered: a single i.v. dose of A77 1726 (4 mg/kg), a single oral dose of leflunomide (4 mg/kg), and multiple oral doses of leflunomide (2 mg/kg). Mean pharmacokinetic parameter values after a single i.v. dose of A77 1726 were distribution (A) and elimination (B) intercepts (15.2 MUg/mL and 34.5 MUg/mL, respectively), distribution and elimination half-lives (1.5 and 71.8 h, respectively), area under the curve (AUC(0 -> infinity); 3723 MUg*h/mL), mean residence time (MRT; 93 h), clearance (Cl(obs); 1.1 mL/kg/h), and volume of distribution at steady state (Vd(ss); 97 mL/kg). Mean pharmacokinetic parameter values after a single oral dose of leflunomide were absorption and elimination rate constants (0.3 1/h and 0.01 1/h, respectively), absorption and elimination half-lives (2.3 and 59.1 h, respectively), AUC(0 -> infinity) (3966 MUg*h/mL), and maximum observed plasma concentration (C(max); 38 MUg/mL). The bioavailability after a single oral dose of leflunomide was 100%. The mean +/- SD A77 1726 concentration that inhibited 50% lymphocytes (EC(50) ) was 16 +/- 13.5 MUg/mL. The mean +/- SD maximum A77 1726 concentration (EC(max)) was 61.0 +/- 23.9 MUg/mL. PMID- 21615756 TI - Involvement of P-glycoprotein and cytochrome P450 3A in the metabolism of florfenicol of rabbits. PMID- 21615757 TI - Autotransplantation of a maxillary first premolar to replace an ankylosed maxillary incisor: 7-year follow-up. AB - AIM: To present the combined endodontic, surgical and orthodontic treatment of an autotransplanted maxillary first premolar for the replacement of an ankylosed maxillary incisor. SUMMARY: This case report describes the autotransplantation of a maxillary premolar after the extraction of an ankylosed incisor in a 13-year old boy. To allow better adaptation of the donor tooth, the buccal root of the first premolar was removed using a diamond bur and the denuded root site was filled with acid-etched composite resin. The palatal root canal was dressed with calcium hydroxide for 2 months before filling with gutta-percha. Autotransplantation of a remodelled maxillary first premolar was achieved to substitute for the ankylosed maxillary central incisor. Orthodontic treatment was performed to correct an Angle Class II malocclusion. Seven years after root canal treatment, the autotransplanted tooth and supporting tissues appeared healthy both clinically and radiographically and were functioning well. KEY LEARNING POINTS: * Autotransplantation is a viable option for the treatment of a missing tooth or for the replacement of a traumatized tooth when there is a donor tooth available. * Autotransplantation of a premolar for replacement of a missing anterior tooth is sometimes a suitable alternative to conventional prosthetic rehabilitation or implant treatment in young individuals. * Proper combined endodontic and orthodontic treatment of autotransplanted teeth might be possible without periodontal complications. PMID- 21615758 TI - Transseptal left ventricular endocardial pacing reduces dispersion of ventricular repolarization. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) may be proarrhythmic in some patients. This may be due to the effect of left ventricular (LV) epicardial pacing on ventricular repolarization. The purpose of this study was to evaluate the effect of endocardial versus epicardial LV biventricular pacing on surface electrocardiogram (ECG) parameters that are known markers of arrhythmogenic repolarization. METHODS: ECG markers of repolarization (QT dispersion, QTD; T peak to end, T(peak-end) ; T(peak-end) dispersion, T(peak-end) D; QTc) were retrospectively measured before and after CRT in seven patients with transseptal LV endocardial leads (TS group), 28 matched patients with coronary sinus (CS) LV leads (CS group), and eight patients with surgical LV epicardial leads (SUR group). All ECGs were scanned and analyzed using digital callipers. RESULTS: Compared to the CS group, the TS group CRT was associated with a significant postpacing reduction in QTD (-45.2 +/- 35.6 vs -4.3 +/- 43.6 ms, P = 0.03) and T(peak-end) (-24.2 +/- 22.1 vs 3.4 +/- 26.7 ms, P = 0.02). There was a nonsignificant post-CRT reduction in both T(peak-end) D (-11.3 +/- 31.0 vs 2.4 +/ 28.9 ms, P = 0.27) and QTc (-50.0 +/- 46.4 vs 4.4 +/- 70.2 ms, P = 0.06) in the TS versus the CS group. In contrast, there were no differences between the SUR and CS groups in terms of the effect of CRT on these repolarization parameters. CONCLUSIONS: CRT with (atrial transseptal) endocardial LV lead placement is associated with repolarization characteristics that are considered to be less arrhythmogenic than those generated by CS (epicardial) LV lead placement. Further work is needed to determine whether these changes translate to a reduction in proarrhythmia. PMID- 21615759 TI - Long-term arrhythmia variability after monomorphic ventricular tachycardia in patients with an implantable cardioverter defibrillator. AB - BACKGROUND: Arrhythmia burden in patients receiving an implantable cardioverter defibrillator (ICD) after monomorphic ventricular tachycardia (mVT) is higher than in patients with other indications. We investigated the long-term arrhythmia profile in this subset of patients. METHODS: Fifty-two patients with an ICD implanted after mVT were followed up for at least 3 months. The cycle lengths (CLs) of the tachycardias recovered from the device memory were compared with the CL of the index arrhythmia. Morphological analysis of the intracardiac electrograms was performed and the response to antitachycardia pacing (ATP) was also assessed. RESULTS: A total of 833 mVT episodes with intracardiac electrograms occurred during the follow-up (3-58 months; mean: 30.3 months) in 41 of the 52 patients analyzed. mVTs with different CLs as compared with the index mVT were found in 26 (50.0%), and at least two different mVT morphologies were observed in 28 (53.8%) patients. Multiple mVT morphologies were predictive of lower ATP efficacy (95.6%, 85.0%, and 70.3% in the patients with 1, 2, and 3 or more mVT morphologies, respectively; P < 0.0001) and a higher shock burden (4.2%, 19.3%, and 24.7% in the patients with 1, 2, and 3 or more mVT morphologies, respectively; P < 0.0001). CONCLUSION: A high mVT burden was demonstrated with marked variability of the arrhythmias as concerns both CL and morphology in patients with an ICD implanted for mVT. Multiple mVT morphologies during the follow-up were predictive of lower ATP efficacy and a higher shock burden. PMID- 21615760 TI - Low prevalence of colonoscopic surveillance of inflammatory bowel disease patients with longstanding extensive colitis: a clinical practice survey nested in the CESAME cohort. AB - BACKGROUND: Surveillance colonoscopy is recommended for inflammatory bowel disease (IBD) patients with longstanding extensive colitis (LEC). AIMS: To assess modalities and results of colonoscopic surveillance in a subset of CESAME cohort patients at high risk of colorectal cancer (CRC) and followed in university French hospitals. METHODS: Among 910 eligible patients with more than a 7-year history of extensive colitis at CESAME enrolment, 685 patients completed a questionnaire on surveillance colonoscopy and 102 were excluded because of prior proctocolectomy. Finally, 583 patients provided information spanning a median period of 41months (IQR 38-43) between cohort enrolment and the end of follow-up. Details of the colonoscopic procedures and histological findings were obtained for 440 colonoscopies in 270 patients. RESULTS: Only 54% (n=312) of the patients with LEC had at least one surveillance colonoscopy during the study period, with marked variations across the nine participating centres (27% to 70%, P<=0.0001). Surveillance rate was significantly lower in Crohn's colitis than in ulcerative colitis (UC) (48% vs. 69%, P<=0.0001). Independent predictors of colonoscopic surveillance were male gender, UC IBD subtype, longer disease duration, previous history of CRC and disease management in a centre with large IBD population. Random biopsies, targeted biopsies and chromoendoscopy were performed during respectively 71%, 27 and 30% of surveillance colonoscopies. Two cases of high grade dysplasia were detected in patients undergoing colonoscopic surveillance. Two advanced-stage CRC were diagnosed in patients who did not have colonosocopic surveillance. CONCLUSIONS: Colonoscopic surveillance rate is low in IBD patients with longstanding extensive colitis. PMID- 21615761 TI - Maximizing health benefits and minimizing inequality: incorporating local-scale data in the design and evaluation of air quality policies. AB - The U.S. Environmental Protection Agency undertook a case study in the Detroit metropolitan area to test the viability of a new multipollutant risk-based (MP/RB) approach to air quality management, informed by spatially resolved air quality, population, and baseline health data. The case study demonstrated that the MP/RB approach approximately doubled the human health benefits achieved by the traditional approach while increasing cost less than 20%--moving closer to the objective of Executive Order 12866 to maximize net benefits. Less well understood is how the distribution of health benefits from the MP/RB and traditional strategies affect the existing inequalities in air-pollution-related risks in Detroit. In this article, we identify Detroit populations that may be both most susceptible to air pollution health impacts (based on local-scale baseline health data) and most vulnerable to air pollution (based on fine-scale PM(2.5) air quality modeling and socioeconomic characteristics). Using these susceptible/vulnerable subpopulation profiles, we assess the relative impacts of each control strategy on risk inequality, applying the Atkinson Index (AI) to quantify health risk inequality at baseline and with either risk management approach. We find that the MP/RB approach delivers greater air quality improvements among these subpopulations while also generating substantial benefits among lower-risk populations. Applying the AI, we confirm that the MP/RB strategy yields less PM(2.5) mortality and asthma hospitalization risk inequality than the traditional approach. We demonstrate the value of this approach to policymakers as they develop cost-effective air quality management plans that maximize risk reduction while minimizing health inequality. PMID- 21615762 TI - Reducing the effort to comprehend risk models: text labels are often preferred over graphical means. AB - Risk analysis involves people with different roles and competences. The validity of the outcome depends on that they are able to communicate; ideally between themselves, but at least with or via a risk analyst. The CORAS risk modeling language has been developed to facilitate communication between stakeholders involved in the various stages of risk analysis. This article reports the results from an empirical investigation among professionals, where the purpose was to investigate how graphical effects (size, color, shape) and text labels introduced in the CORAS risk modeling language affected the understanding. The results indicate that if graphical effects are used to illustrate important information, they should also be accompanied by informative textual labels. PMID- 21615763 TI - Temporal evolution of ocular aberrations following laser in situ keratomileusis. AB - PURPOSE: To study the temporal evolution of ocular aberrations after standard LASIK to correct myopia. METHODS: The ocular, corneal and internal aberrations for a 6-mm pupil were measured in 22 young myopic eyes (n = 12 subjects; range 2.0 to-7.6 D) before and during a 9-month follow-up after standard myopic LASIK. Ocular aberrations were measured with a Hartmann-Shack wavefront sensor, while corneal aberrations were estimated from the elevation data obtained by corneal topography. For every patient and condition the eye's modulation transfer function (MTF) and Strehl ratio (SR) were calculated. RESULTS: Compared to preoperative results, we found that standard myopic LASIK produced a significant increase of ocular high-order aberrations at 1 month after surgery. During the next 8 months, we found a small increase of ocular and corneal positive spherical aberration (SA), although with a large inter-subject variability. However, all eyes treated for myopia higher than -5 D showed a significant increase of positive SA during the first 6 months after surgery. CONCLUSIONS: Standard myopic LASIK decreases ocular optical quality. For most subjects, the increase in aberrations induced by the surgery was stable during the next 9 months after LASIK. However, further changes of the ocular SA after myopic LASIK are possible in patients treated for higher amounts of myopia. The changes in aberrations mainly appeared between the first and the sixth month after surgery, which suggests the need to wait at least 6 months after myopic LASIK before comparing outcomes, especially for patients treated for higher myopias. PMID- 21615764 TI - The histopathology of terra firma-forme dermatosis. PMID- 21615766 TI - Crystal clear. PMID- 21615767 TI - Retraction. A preliminary examination of the role of NFAT 3 in human skin, cultured keratocytes and dermal fibroblasts. PMID- 21615769 TI - A systematic review on the mental health of children and adolescents in areas of armed conflict in the Middle East. AB - For many decades, the Middle East has been troubled with numerous long-standing armed conflicts and wars. Children and adolescents were not spared the trauma and its consequences. Exposure to traumatic events can result in mental, behavioural and emotional problems in children and adolescents. To date, this is the first paper that aims to systematically review the literature on the mental health of children and adolescents living in areas of armed conflict in the Middle East, specifically Israel, Palestine, Lebanon and Iraq. It explores factors that mediate between exposure to armed conflict and mental, behavioural and emotional problems and places them in a cultural context. Pubmed was searched and papers were identified using specific inclusion criteria. Seventy-one eligible studies were included. The main findings are that children and adolescents living in these conflict zones are exposed to high levels of traumatic experiences. Number of conflict-related traumatic experiences correlates positively with prevalence of mental, behavioural and emotional problems. Prevalence of post-traumatic stress disorder in children and adolescents is estimated to be 5-8% in Israel, 23 70% in Palestine and 10-30% in Iraq (insufficient data for Lebanon). The main determining factors identified were level and type of exposure, age, gender, socio-economic adversity, social support and religiosity. These findings bring to light the pressing need to provide children and adolescents living in conflict areas with help. They are useful in designing new interventions to strengthen child and adolescent resilience in areas of conflict worldwide. Specific recommendations are included. PMID- 21615770 TI - The effectiveness of training and support for carers and other professionals on the physical and emotional health and well-being of looked-after children and young people: a systematic review. AB - Looked-after children and young people (LACYP) are recognized as a high-risk group for behavioural and emotional problems, and additional specialist training for foster carers may reduce such problems. This systematic review aimed to identify and synthesize evidence on the effectiveness of additional training and support provided to approved carers, professionals and volunteers on the physical and emotional health and well-being of LACYP (including problem behaviours and placement stability). Searches of health and social science databases were conducted and records were screened for inclusion criteria. Citation and reference list searches were conducted on included studies. Included studies were synthesized and critically appraised. Six studies were included (five randomized controlled trials and one prospective cohort study), all of which focused on foster carers. Three studies reported a benefit of training and three reported no benefit but no detriment. Those reporting a benefit of training were conducted in the USA, and had longer-duration training, shorter follow-up assessment and recruited carers of younger children than studies that reported no benefit of training, which were conducted in the UK. Whether the difference in results is due to the type of training or to cultural or population differences is unclear. The findings suggest a mixed effect of training for foster carers on problem behaviours of LACYP. The evidence identified appears to suggest that longer duration training programmes have a beneficial effect on the behaviour problems of LACYP, although future research should examine the impact of training durations and intensity on short-medium and longer-term outcomes of LACYP of different ages. Only training and support for foster carers was identified. PMID- 21615771 TI - Health-related quality of life of adolescents with overweight or obesity in the north of Jordan. AB - BACKGROUND: Previous studies showed that overweight and obesity in children and adolescents are associated with impaired health-related quality of life (QOL). The objective of this study was to describe health-related QOL among Jordanian adolescents who were overweight or obese. METHODS: This is a cross-sectional study conducted among Jordanian students aged between 13 and 18 years in three educational directorates in Irbid City in the north of Jordan. Using simple random sampling, two male schools and two female schools were selected from the list of each directorate to represent all schools in north of Jordan. In each selected school, all adolescents aged 13-18 years were visited in their classes and were invited to participate in the study. Of the total number of 1561 subjects, 1433 (91.8%) agreed to participate in the study. The short-form 15-item Pediatric Quality of Life Inventory version 4.00 was used to measure health related QOL among participants. Body mass index (BMI) was calculated and interpreted according to the BMI-for-age growth charts of the Center for Disease Control and Prevention guidelines. RESULTS: This study included 707 boys and 726 girls; 17.6% of participants were overweight and 7.8% were obese. For boys and girls, adolescents who were overweight or obese had significantly lower average scores for psychosocial health summary scale and physical functioning scale. Female gender, age of 16-18 years, fathers' education of high school or less and unemployed fathers (for social functioning and physical functioning) were significantly associated with decreased average scores of all scales and subscales of Pediatric Quality of Life Inventory. CONCLUSIONS: Compared with healthy adolescents, adolescents who were overweight or obese reported significantly lower health-related QOL in all domains. Girls reported greater effect of overweight and obesity on their health-related QOL. PMID- 21615772 TI - Validity in assessing time processing ability, test equating of KaTid-Child and KaTid-Youth. AB - BACKGROUND: There is a need for instruments with acceptable psychometric properties for measuring time management/time processing ability. KaTid-Child (Swedish: Kit for assessing Time processing ability) was developed for children aged 5-10 years. To meet needs of assessing older children, KaTid-Youth was created. The aim of this study was to investigate the validity of KaTid-Youth. METHODS: This study investigates the validity of KaTid-Youth using Rasch models: partial credit and common item equating. RESULTS: Results indicate that KaTid-Youth has acceptable psychometric properties and seems to measure the same construct as KaTid-Child. CONCLUSIONS: Indications of gender differences in the sample call for further research. The results indicate that time processing ability can be seen as one construct in which time perception, orientation and management can be operationalized as different levels of complexity in time processing ability. Expressions of time processing ability differ at different ages. Thus, early intervention in time perception and time orientation may be needed to promote time management in later childhood. Professionals need to take time processing ability into consideration when meeting children who risk delayed development of daily time management. PMID- 21615773 TI - Effect of an acute mechanical stimulus on aortic structure in the transverse aortic constriction mouse model. AB - 1. Vascular remodelling is an adaptive response to various stimuli, including mechanical forces, inflammatory cytokines and hormones. In the present study, we investigated histological modification of the aorta and the expression of key proteins participating in vascular remodelling under an acute mechanical stimulus using a transverse aortic constriction (TAC) mouse model. 2. The TAC was performed in male C57BL/6 mice aged 10-12 weeks. A Millar conductance catheter was used to measure cardiac haemodynamic parameters 3 and 14 days after TAC. Aortic structural variations were observed by haematoxylin and eosin, Sirius red and Weigert's elastin staining. Protein levels of Type I collagen, F4/80, alpha smooth muscle actin (SMA) and SM22alpha were analysed by immunohistochemistry. 3. Three days after TAC, the medial area proximal to the aortic band (PA-B) was increased, whereas the area distal to the aortic band (DA-B) was unchanged. There was no difference in luminal area between TAC and sham groups. The adventitia displayed the most significant difference 14 days after TAC: adventitial hyperplasia was abundant and collagen was upregulated in the adventitia of the PA B with a considerable increase in alpha-SMA and SM22alpha. Macrophages accumulated in the adventitia of the PA-B 3 days after TAC and infiltrated into the media and intima of the PA-B 14 days after TAC. 4. In conclusion, the aortic structure undergoes considerable remodelling following an acute mechanical stimulus in the TAC model, mainly in the adventitia. Upregulation of alpha-SMA and extracellular matrix components accompanied by macrophage infiltration may contribute to adventitial modification in the TAC mouse model. PMID- 21615774 TI - Possible role for the thioredoxin system in the protective effects of probucol in the pancreatic islets of diabetic rats. AB - 1. Probucol, a lipid-lowering agent with a potent anti-oxidant action, protects diabetic pancreatic islets by an as yet unknown mechanism. Thioredoxin interacting protein (TXNIP), an endogenous inhibitor of the ubiquitous thiol oxidoreductase thioredoxin (TRX), has been associated with oxidative stress in diabetic rat islets. The aim of the present study was to examine the effects of probucol on diabetic islet function and expression of TRX and TXNIP. 2. Thirty rats were randomly assigned to one of three groups: a normal control group, a diabetic group and a probucol-treated diabetic group. After 8 weeks treatment with probucol (500 mg/kg per day), plasma malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) activity were determined using chemical colourimetric methods. In addition, the expression of insulin, TRX and TXNIP in islets was analysed using immunohistochemical, western blot and reverse transcription-polymerase chain reaction methods. 3. The expression of TRX and insulin in islets and plasma SOD and CAT activity were lower, but the expression of TXNIP in islets and plasma MDA were higher, in diabetic compared with normal control rats. Upregulated expression of TRX and insulin and downregulated expression of TXNIP were observed in probucol-treated diabetic rats. Probucol treatment increased plasma SOD, decreased plasma MDA and improved hypoinsulinaemia in diabetic rats. 4. The results indicate that treatment with probucol decreases TXNIP expression and increases TRX expression, which may alleviate hypoinsulinaemia by reducing oxidative stress. Therefore, probucol shows promise as a supplemental therapy for islet protection in Type 2 diabetes mellitus. PMID- 21615776 TI - Erythema scarlatiniforme desquamativum recidivans. PMID- 21615777 TI - An investigation of the association between diet and occurrence of acne: a rational approach from a traditional Chinese medicine perspective - comment. PMID- 21615775 TI - Medical management of paraquat ingestion. AB - Poisoning by paraquat herbicide is a major medical problem in parts of Asia while sporadic cases occur elsewhere. The very high case fatality of paraquat is due to inherent toxicity and lack of effective treatments. We conducted a systematic search for human studies that report toxicokinetics, mechanisms, clinical features, prognosis and treatment. Paraquat is rapidly but incompletely absorbed and then largely eliminated unchanged in urine within 12-24 h. Clinical features are largely due to intracellular effects. Paraquat generates reactive oxygen species which cause cellular damage via lipid peroxidation, activation of NF kappaB, mitochondrial damage and apoptosis in many organs. Kinetics of distribution into these target tissues can be described by a two-compartment model. Paraquat is actively taken up against a concentration gradient into lung tissue leading to pneumonitis and lung fibrosis. Paraquat also causes renal and liver injury. Plasma paraquat concentrations, urine and plasma dithionite tests and clinical features provide a good guide to prognosis. Activated charcoal and Fuller's earth are routinely given to minimize further absorption. Gastric lavage should not be performed. Elimination methods such as haemodialysis and haemoperfusion are unlikely to change the clinical course. Immunosuppression with dexamethasone, cyclophosphamide and methylprednisolone is widely practised, but evidence for efficacy is very weak. Antioxidants such as acetylcysteine and salicylate might be beneficial through free radical scavenging, anti-inflammatory and NF-kappaB inhibitory actions. However, there are no published human trials. The case fatality is very high in all centres despite large variations in treatment. PMID- 21615778 TI - Muscle characteristics in young Norwegian-Swedish Coldblooded Trotters and associations with breeding index, body size and early training. AB - REASONS FOR PERFORMING STUDY: The trotting speed of Norwegian-Swedish Coldblooded Trotters (NSCTs) is, although inferior to Standardbred speeds, gradually increasing. This development is mainly attributed to breeding progresses. Characteristics of the middle gluteal muscle have recently been described in a small number of these horses but the actual spread in muscle parameters within the population is unknown. OBJECTIVES: To describe the characteristics of the middle gluteal muscle and their naturally occurring variability in young NSCT horses and investigate possible association with body size, individual breeding index and early training. METHODS: Biopsies of the middle gluteal muscle of 144 NSCT horses born in 2005 were collected at age 17-24 months. The horses were randomly selected by stratified sampling with gender and paternal progeny as stratification factors. The muscle samples were analysed for fibre type composition, fibre type areas, capillary supply and the activity of the key metabolic enzymes citrate synthase, 3-OH-acyl-CoA-dehydrogenase and lactate dehydrogenase. Correlation analysis including muscle parameters and body size, individual breeding index and early training was performed. RESULTS: Large interindividual differences were identified in muscle characteristics. Male horses had higher percentages of type IIA fibres and lower percentages of type IIX fibres than age-matched females. Fibre type areas followed the order type IIX>IIAX>IIA>I, while the capillary supply per fibre type area increased in the opposite order. No gender-related differences were found in fibre type areas or capillary supply. Height was correlated to the relative area of type I fibres. Early training was associated with increased oxidative capacity and increased percentage of type IIA fibres. The lowest breeding index was found in untrained horses. CONCLUSIONS: Muscle characteristics differ among young NSCT horses, but the innate oxidative capacity seems to be lower than in Standardbreds of comparable age. Early training may influence on these parameters. PMID- 21615779 TI - Equine hospital data as a source for study of prevalence and heritability of osteochondrosis and palmar/plantar osseous fragments of Swedish Warmblood horses. AB - REASONS FOR PERFORMING STUDY: Disturbances in skeletal development, primarily osteochondrosis (OC) and palmar/plantar osseous fragments (POF), have been commonly reported as problems in young horses. However, there are few reports of such findings for epidemiological analyses or breeding purposes. OBJECTIVES: To evaluate equine hospital data as a possible source of information for genetic evaluations by estimating prevalence and heritability of OC in the stifle, hock and fetlock joints and of POF in the fetlock. METHODS: Data on Swedish Warmblood (SWB) horses were obtained from a large equine hospital in south Sweden. Prevalences were based on radiographic examinations of 879 screened horses, mainly evaluated as part of a prepurchase examination and 3639 horses with a reported history of orthopaedic problems. For the heritability study the 2 data sources were pooled and 3199 examined horses with pedigree information were considered for the linear animal model analyses. RESULTS: The overall prevalence of OC was 13% (stifle 9%, hock 6% and dorsal osseous fragments in fetlock [DOF] 10%) and POF 10%. The overall heritability of OC was 0.05 on the visible binomial scale. The corresponding heritabilities for OC in the stifle were 0.03, hock 0.08, DOF 0.10 and POF 0.13. These values correspond to heritabilities of 0.09 0.38 on the underlying quantitative scale. CONCLUSIONS AND POTENTIAL RELEVANCE: Obtained prevalences and heritabilities were in accordance with other studies, supporting the hypothesis that data regularly obtained from equine hospitals may be a valuable source in studies of inherited disorders such as OC and POF. There is a need for more standardised documentation of diagnoses and consistent recording of identity of examined horses using passports or breed databases. Compilation of results from major clinics is desired in order to cover most progenies of stallions used in a region or nation. PMID- 21615780 TI - Tenosynovitis of the carpal sheath of the digital flexor tendons associated with tears of the radial head of the deep digital flexor: observations in 11 horses. AB - REASONS FOR PERFORMING STUDY: Tears of the radial head of the deep digital flexor (DDF) have not previously been documented. OBJECTIVES: To describe the presentation, clinical, ultrasonographic and tenoscopic features associated with tears of the radial head of the DDF and to report the results of treatment. HYPOTHESES: Tears of the radial head of the DDF cause lameness and distension of the carpal sheath of the digital flexor tendons. Removal of disrupted tissue that is extruded into the sheath can result in clinical resolution and restoration of function. METHODS: Case records and diagnostic images of horses in which tearing of the radial head of the DDF was diagnosed were reviewed retrospectively and follow-up information obtained. RESULTS: Eleven cases were identified. Clinical, ultrasonographic and tenoscopic commonality was recorded and treatment techniques were documented. All cases returned post operatively to pre-injury levels of work. CONCLUSION: Tearing of the radial head of the DDF is a clinical entity with consistent diagnostic features. Tenoscopic removal of the torn tissue is associated with a good outcome. POTENTIAL RELEVANCE: Clinicians evaluating lame horses should include tearing of the radial head of the DDF as a differential diagnosis in animals with distended carpal sheaths. Tenoscopic surgery is a recommended treatment. PMID- 21615781 TI - Fifty years of the British Equine Veterinary Association as a facilitator of progress in equine clinical science. AB - The British Equine Veterinary Association (BEVA) was established in 1961 and launched the Equine Veterinary Journal (EVJ) in 1968. This review outlines some of the major advances in equine science and practice that have occurred in that time and the role played by the Journal in facilitating those developments. PMID- 21615782 TI - Zygomatic implant-retained fixed complete denture for an elderly patient. AB - Dental rehabilitation of a completely edentulous geriatric patient has always been a challenge to the clinician, especially in treating those with higher expectations and demands. Treatment duration and the amount of residual alveolar bone available are often important considerations when planning for dental implant-based fixed treatment for these patients. With the introduction of zygomatic implants, a graftless alternative solution has emerged for deficient maxillary bone with provision for immediate loading. This article describes the treatment of a completely edentulous elderly patient using zygomatic implants in conjunction with conventional implants. The implants were immediately loaded using a definitive acrylic resin fixed denture reinforced with a cast metal framework, to provide function and aesthetics. PMID- 21615783 TI - Surface roughness of denture base and reline materials after disinfection by immersion in chlorhexidine or microwave irradiation. AB - BACKGROUND: This study evaluated the effect of disinfection by immersion and microwave irradiation on the roughness of one denture base resin (Lucitone-L) and five relining materials, three hard (Tokuyama Rebase II-TR, New Truliner-NT, Ufigel Hard-UH) and two resilient (Trusoft-T, Sofreliner-S). METHODS: Fifty specimens were made and divided into groups: CL2 specimens were brushed with 4% chlorhexidine (1 min), immersed in the same solution (10 min) and immersed in water (3 min); MW2 specimens were immersed in water and microwave irradiated (650W; 6 min); CL2 and MW2 specimens were disinfected twice; CL7 and MW7 specimens were submitted to seven cycles using chlorhexidine or microwave irradiation, respectively; W specimens were not disinfected and remained in water (37 degrees C; 7 days). RESULTS: Results were statistically analysed (p = 0.05) and revealed that, at baseline, the highest mean value was observed for T (p < 0.001). Material NT showed increase in roughness after the first (p = 0.003), second (p = 0.001), seventh (p = 0.000) cycles of microwave disinfection and after 7 days of immersion in water (p = 0.033). CONCLUSIONS: Resilient liner S presented significant increase in roughness after the second cycle of disinfection with chlorhexidine (p = 0.003). Material T exhibited significantly decreased roughness in group W (p = 0.010), while microwaving produced severe alterations on its surface. PMID- 21615784 TI - Effect of double flasking and investing methods on artificial teeth movement in complete dentures processing. AB - PURPOSE: The aim of this study was to evaluate linear dimensional alterations of artificial teeth for complete dentures when using different investment and flasking techniques. BACKGROUND: Dimensional changes in the vertical dimension may occur owing to changes in artificial teeth positioning caused by different investing and flasking techniques. MATERIALS AND METHODS: Thirty pairs of the complete dentures were manufactured and randomly divided into three groups (n = 10): (1) invested with type III stone in monomaxillary PVC flask; (2) invested with type III stone in bimaxillary PVC flask; and (3) invested with laboratory silicone in bimaxillary PVC flask. Dentures were polymerised by microwave, and 12 linear distances were measured before and after denture processing. Data were analysed by one-way anova, considering manufacturing technique as the study factor. Tukey's HSD was used as post hoc ANOVA (p = 0.05). RESULTS: Most of the linear distances were comparable for all groups. All transversal maxillary and mandibular distances were higher for group 1 compared with groups 2 and 3 (p < 0.05), except the distance 3-6 for mandibular arch, in which no difference was found between groups (p < 0.05). Both maxillary diagonal distances were higher in group 1 (p < 0.05), and no differences were found among all groups for mandibular measurements. CONCLUSIONS: Double flasking technique independent on the investment material is shown to be the most effective method to reduce changes in artificial teeth positioning. PMID- 21615785 TI - Impaired mitochondrial complex III and melatonin responsive reactive oxygen species generation in kidney mitochondria of db/db mice. AB - We have previously demonstrated that melatonin, at pharmacological concentrations, causes rapid reactive oxygen species (ROS) generation at the antimycin-A sensitive site of mitochondrial complex III (MC-3). In the current work, we used this melatonin response to investigate the role of mitochondrial dysfunction in the development of diabetic nephropathy. We find that the development of diabetic nephropathy, as indicated by hyperfiltration and histopathological lesions in the kidney of db/db mice, is associated with diminished melatonin-induced ROS generation and MC-3 activity, indicating impaired MC-3 at the antimycin-A site. The MC-3 protein level in the renal mitochondria was equivalent in db/db and the nondiabetic db/m mice, whereas mitochondrial complex I (MC-1) protein was dramatically upregulated in the db/db mice. This differential regulation in mitochondrial complexes may alter the equilibrium of the electron transport in renal mitochondria and contribute to ROS overproduction. The study provides one mechanism of enhanced oxidative stress that may be involved in the pathogenesis of diabetic nephropathy in db/db mice. PMID- 21615786 TI - Melatonin prevents down-regulation of astrocytic phosphoprotein PEA-15 in ischemic brain injury. AB - Melatonin functions as a free-radical scavenger and has a neuroprotective effect against ischemic brain damage. PEA-15 (phosphoprotein enriched in astrocytes 15) regulates various cellular processes including cell proliferation and apoptosis. In this study, we investigated whether melatonin regulates the levels of PEA-15 and the two phosphorylated forms of PEA-15 (Ser 104 and Ser 116) in a middle cerebral artery occlusion (MCAO)-induced injury model and neuronal cells exposed to glutamate. Adult male rats were treated with vehicle or melatonin (5 mg/kg) prior to MCAO, and cerebral cortex tissues were collected 24 h after MCAO. PEA-15 levels after ischemic brain injury were monitored using a proteomic approach. Melatonin pretreatment prevented the ischemic injury-induced reduction in PEA-15 levels. Moreover, Western blot analysis demonstrated that melatonin attenuated the ischemic injury-induced reduction in PEA-15, phospho-PEA-15 (Ser 104), and phospho-PEA-15 (Ser 116) levels. Neuronal cells exposed to glutamate showed decreased expression of PEA-15, phospho-PEA-15 (Ser 104), and phospho-PEA-15 (Ser 116), while melatonin pretreatment prevented the glutamate toxicity-induced decreases in the levels of these proteins. The reduction in the levels of phospho PEA-15 proteins indicates the inhibition of anti-apoptotic function of PEA-15. Together, in vivo and in vitro results suggest that melatonin protects neurons against ischemic injury by maintaining levels of phospho-PEA-15 proteins. PMID- 21615787 TI - Prognostic capacity of automated quantification of suppression time in the EEG of post-asphyctic full-term neonates. AB - AIM: To evaluate the prognostic capacity of a new method for automatic quantification of the length of suppression time in the electroencephalogram (EEG) of a group of asphyxiated newborn infants. METHODS: Twenty-one full-term newborn infants who had been resuscitated for severe birth asphyxia were studied. Eight channel continuous EEG was recorded for prolonged time periods during the first days of life. Artefact detection or rejection was not applied to the signals. The signals were fed through a pretrained classifier and then segmented into burst and suppression periods. Total suppression length per hour was calculated. All surviving patients were followed with structured neurodevelopmental assessments to at least 18 months of age. RESULTS: The patients who developed neurodevelopmental disability or died had significant suppression periods in their EEG during the first days of life while the patients who had a normal follow-up had no or negligible amount of suppression. CONCLUSIONS: This new method for automatic quantification of suppression periods in the raw, neonatal EEG discriminates infants with good from those with poor outcome. PMID- 21615788 TI - Mismatch repair status in sporadic colorectal cancer: immunohistochemistry and microsatellite instability analyses. AB - BACKGROUND AND AIM: The aim of the present study was to evaluate associations between mismatch repair (MMR) status and clinicopathological characteristics and prognosis using immunohistochemistry (IHC) and microsatellite instability (MSI) analyses in a prospective cohort of a large number of accumulated samples. METHODS: Tumor tissue samples obtained during curative surgery (n = 2028) were analyzed using both MLH1/MSH2 IHC and MSI assays. Clinicopathological parameters and survival outcomes were compared according to IHC and MSI results. The median follow-up period was 43 months (range: 1-85 months). RESULTS: IHC identified 207 tumor samples (10.2%) with a loss of either MLH1 or MSH2 expression. The MSI analysis identified 203 tumor samples (10%) with high-frequency MSI (MSI-H). Patients with MMR defects were younger, and had tumors characterized by right colon predilection; large-size, infrequent lymph node metastasis; poorly differentiated or mucinous histology, and synchronous adenomas (P < 0.001-0.008). Patients with MSI-H status had higher 4-year disease-free survival rates than patients with microsatellite stable status (90.8% vs 80.6%, P = 0.001). A multivariate analysis showed that MSI-H status was a good prognostic factor for recurrence (hazard ratio: 0.48, 95% confidence interval: 0.30-0.83, P = 0.007). CONCLUSIONS: Patients with MMR defects had distinct clinicopathological characteristics, including a lower risk of recurrence. IHC and MSI analyses provided complementary information regarding specific clinicopathological parameters and prognosis. PMID- 21615789 TI - Risk factors for hepatocellular carcinoma in a cohort infected with hepatitis B or C. AB - BACKGROUND AND AIM: The incidence of hepatocellular carcinoma (HCC) has increased in Australia in recent decades, a large and growing proportion of which occurs among a population chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). However, risk factors for HCC among these high-risk groups require further characterization. METHODS: We conducted a population-based cohort study using HBV and HCV cases notified to the New South Wales Health Department between 2000 and 2007. These were linked to cause of death data, HIV/AIDS notifications, and hospital records. Proportional hazards regression was used to identify significant risk factors for developing HCC. RESULTS: A total of 242 and 339 HCC cases were linked to HBV (n = 43 892) and HCV (n = 83 817) notifications, respectively. For both HBV and HCV groups, being male and increasing age were significantly associated with risk of HCC. Increasing comorbidity score indicated high risk, while living outside urban areas was associated with lower risk. Hazard ratios for males were two to three times those of females. For both HBV and HCV groups, cirrhosis, alcoholic liver disease, and the interaction between the two were associated with significantly and considerably elevated risk. CONCLUSION: This large population-based study confirms known risk factors for HCC. The association with older age highlights the potential impact of HBV and HCV screening of at-risk groups and early clinical assessment. Additional research is required to evaluate the impact of improving antiviral therapy on HCC risk. PMID- 21615790 TI - Which should go first during same-day bidirectional endosocopy with propofol sedation? AB - BACKGROUND AND AIM: Same-day bidirectional endoscopy, including esophagogastroduodenoscopy (EGD) and colonoscopy, is frequently performed to screen for cancer and gastrointestinal bleeding. However, the optimal sequence for the procedures is unclear thus far. The aim of this study was to evaluate the optimal sequence for same-day bidirectional endoscopy. METHODS: Consecutive patients undergoing same-day bidirectional endoscopy under propofol sedation were randomized to either the colonoscopy-first group (colonoscopy followed by EGD, n = 87) or the EGD-first group (EGD followed by colonoscopy, n = 89). We evaluated the propofol dose, procedure duration, patient tolerance and recovery, adverse events, and endoscopic findings. The patient tolerance was assessed with a 0-10 visual analog scale. RESULTS: Total procedure times, patients' tolerance and recovery, adverse events, and endoscopic findings were similar between the two groups. The total propofol dose was significantly higher for the colonoscopy first group than for the EGD-first group (mean 95% credibility limit: 135.7 [70 201.4] mg vs 124.7 [64.1-185.3] mg, respectively, P = 0.024). Patients in the colonoscopy-first group moved significantly more during colonoscopy than those in the EGD-first group: 1.1 (0-3.8) versus 0.6 (0-2.9) scores, respectively (P = 0.024). CONCLUSION: The optimal sequence for same-day bidirectional endoscopy is EGD followed by colonoscopy. In this order, the procedure is better tolerated, and patients require a lower overall dose of propofol. PMID- 21615791 TI - Endoscopic ultrasound-guided fine-needle aspiration of lesions near the aortoiliac bifurcation via an upper gastrointestinal approach. AB - BACKGROUND AND AIMS: Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is widely used to investigate posterior mediastinal and upper abdominal lesions. Previously, we noticed that the aortoiliac bifurcation can be visualized by transduodenal EUS scanning, and the surrounding area might be a potential target for EUS-guided FNA. This study aimed to determine the feasibility of using EUS-guided FNA to study lesions near the aortoiliac bifurcation via the upper gastrointestinal approach. METHODS: This study was a prospective pilot study of consecutive patients with a lesion of unknown origin near the aortoiliac bifurcation. RESULTS: EUS-guided FNA was used in six patients. The aortoiliac bifurcation was visible from the inferior duodenal angle in all patients; however, the lesions could be visualized in only five patients (3 via the transduodenal approach, and 2 via the transgastric approach). In one patient with a lesion on the left side, the lesion could not be visualized by either the transgastric or transduodenal approach. In the other five patients, EUS-guided FNA was successful, and FNA specimens were adequate for histopathological assessment. The diagnoses were lymphoma (n = 3), plasmacytoma (n = 1), and neurinoma (n = 1). All lymphoma cases were subclassified as diffuse large B-cell lymphoma (n = 2) or grade 2 follicular lymphoma (n = 1). No complications were observed. CONCLUSIONS: The aortoiliac bifurcation was visible in all patients by transduodenal EUS scanning. FNA of the legions near the aortoiliac bifurcation was possible in five of six patients by using either the transgastric or transduodenal approach. PMID- 21615792 TI - Impact of introduction of wire-guided cannulation in therapeutic biliary endoscopic retrograde cholangiopancreatography. AB - BACKGROUND AND AIM: Wire-guided cannulation (WGC) might increase the biliary cannulation rate and decrease the risk of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). We assessed the learning curve for WGC in therapeutic biliary ERCP (study 1) and compared WGC and conventional contrast-assisted cannulation (CC) by a matched case-control study (study 2). METHODS: Prospectively collected data of 500 therapeutic biliary ERCP cases (250 consecutive cases of WGC and 250 matched controls of CC) were retrospectively studied. Rate and time of biliary cannulation, total procedure time, PEP, and hyperamylasemia were analyzed. RESULTS: In study 1, biliary cannulation by WGC was successful in 96% of the first 50 cases, with a median time to cannulation of 3 min. Rates of hyperamylasemia were within 10% after 100 WGC. In study 2, there were no significant differences in the overall cannulation rate and PEP between WGC and CC, but the total procedure time was shorter in WGC (30 vs 35 min, P = 0.059). Rates of hyperamylasemia and the change in serum amylase levels was lower (9% vs 14%, P = 0.069, and + 62.8 U/L vs+ 169.5 U/L, P = 0.043) in WGC, which was more prominent in experienced endoscopists (9% vs 17%, P = 0.025, and + 68.9 U/L vs+ 229.3 U/L, P = 0.014). CONCLUSIONS: The introduction of WGC was effective in the first 50 cases and did not increase the rate of PEP in biliary therapeutic ERCP. PMID- 21615793 TI - Characteristics and prognosis of patients with hepatocellular carcinoma after the year 2000 in Japan. AB - BACKGROUND AND AIM: The survival rate of patients with hepatocellular carcinoma (HCC) improved through the 1990s in Japan, primarily due to advances in the detection of small HCC under the establishment of surveillance systems. We investigated how the characteristics of patients with HCC changed and whether this trend is continuing after the year 2000. METHODS: The characteristics and survival rates of patients with initial HCC (not a recurrence) who were diagnosed after the year 2000 until 2008 were analyzed and compared with those of patients in whom HCC was diagnosed in the 1990s or before. RESULTS: In comparison to 8 years before the year 2000, the percentage of patients with better liver function at diagnosis of HCC increased after the year 2000, whereas the size of maximal HCC tumors did not change in comparison to patients before the year 2000. The survival rate of patients continued increasing after the year 2000. CONCLUSIONS: The prognosis of patients with HCC continues to improve after the year 2000. This is not due to further improvements in the detection of small-sized HCC; the detection of small HCC had reached a plateau in the 1990s. Rather, this improvement appears to be due in part from the continued increase in the distribution of patients with better liver function at diagnosis. PMID- 21615794 TI - Contrast-enhanced ultrasonography using Sonazoid to evaluate changes in hepatic hemodynamics in acute liver injury. AB - BACKGROUND AND AIMS: Disturbances in hepatic microcirculation are believed to be involved in the mechanisms regulating the progression of acute liver injury (ALI). Evaluation of hepatic hemodynamics in patients with acute liver injury might be helpful in understanding the extent of the intrahepatic microcirculatory disturbances. Therefore, we investigated whether contrast-enhanced ultrasonography (CEUS) is useful to evaluate the changes in hepatic hemodynamics in patients with ALI. METHODS: CEUS was performed in 21 patients with ALI and coagulopathy. Participants were injected with 0.0075 mL Sonazoid/kg body weight, and time-intensity curves were simultaneously recorded for the hepatic and portal veins. The data were compared with those of 10 healthy volunteers. RESULTS: The arrival time of Sonazoid in the hepatic vein was similar to that in the portal vein in the patients, whereas the arrival time in the hepatic vein was delayed relative to that in the portal vain in the controls (interval between the hepatic and portal vein arrival times, control vs patients 6.74 +/- 3.07 s vs 1.13 +/- 1.07 s, P < 0.001). Repeated examination revealed that the interval between the hepatic and portal vein arrival times was extended by improvements in hepatic function. The early arrival of Sonazoid in the hepatic vein in the patients is likely to reflect the formation of intrahepatic shunts as a result of hepatic microcirculatory disturbances. CONCLUSION: CEUS using Sonazoid is a useful method to estimate the changes in hepatic hemodynamics in patients with ALI. PMID- 21615795 TI - Acute chest syndrome: sickle cell disease. AB - Acute chest syndrome (ACS) is a common complication and reason for hospital admission in patients with sickle cell disease (SCD). It is also the most common cause of death in this patient population. Most of the time, the trigger for ACS in an individual patient cannot be identified. However, although infection is the most common identifiable cause for ACS, other important triggers are vaso occlusive crisis (VOC) and asthma. This comprehensive review will focus on the pathogenesis, clinical characteristics, complications and treatment available to manage ACS. But importantly, this review will highlight new possible etiologies, with the goal of improving oxygenation and, therefore, a reduction in sickling and lung damage in this patient population. PMID- 21615796 TI - Interleukin-17F gene polymorphism in patients with chronic immune thrombocytopenia. AB - INTRODUCTION: IL-17F is a novel inflammatory cytokine and plays an important role in some autoimmune diseases. We investigated the association between chronic ITP and the frequency of the single-nucleotide polymorphism rs763780 (7488T/C), which causes a His-to-Arg substitution at amino acid 161. PATIENTS AND METHODS: We examined 102 patients (men/women, 40/62; median age, 42) diagnosed with chronic ITP and 188 healthy controls (men/women, 78/110; median age, 38). Genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: Compared with the control group, patients with chronic ITP had a significantly lower frequency of the IL-17F 7488CC genotype (0% vs. 4.8%, P<0.05). The number of IL-17F 7488C alleles among the patients with chronic ITP was also significantly lower than in the control group (8.7% vs. 15.2% OR=0.48, 95%CI=0.27-0.84, P=0.016). Furthermore, patients with the IL-17F 7488TT genotype showed a severe thrombocytopenic state (platelet count<10*10(9) /L) at diagnosis than those with the IL-17F 7488TC genotype (20.9% vs. 0%, P=0.04). CONCLUSION: These findings suggest that the IL-17F 7488 T allele is significantly associated with the development of chronic ITP, suggesting a role for IL-17F in the pathogenesis of chronic ITP. PMID- 21615797 TI - What causes type 1 diabetes? Lessons from animal models. AB - To study type 1 diabetes (T1D), excellent animal models exist, both spontaneously diabetic and virus-induced. Based on knowledge from these, this review focuses on the environmental factors leading to T1D, concentrated into four areas which are: (1) The thymus-dependent immune system: T1D is a T cell driven disease and the beta cells are destroyed in an inflammatory insulitis process. Autoimmunity is breakdown of self-tolerance and the balance between regulator T cells and aggressive effector T cells is disturbed. Inhibition of the T cells (by e.g. anti CD3 antibody or cyclosporine) will stop the T1D process, even if initiated by virus. Theoretically, the risk from immunotherapy elicits a higher frequency of malignancy. (2) The activity of the beta cells: Resting beta cells display less antigenicity and are less sensitive to immune destruction. Beta-cell rest can be induced by giving insulin externally in metabolic doses or by administering potassium-channel openers. Both procedures prevent T1D in animal models, whereas no good human data exist due to the risk of hypoglycemia. (3) NKT cells: According to the hygiene hypothesis, stimulation of NKT cells by non-pathogen microbes gives rise to less T cell reaction and less autoimmunity. Glycolipids presented by CD1 molecules are central in this stimulation. (4) Importance of the intestine and gliadin intake: Gluten-free diet dramatically inhibits T1D in animal models, and epidemiological data are supportive of such an effect in humans. The mechanisms include less subclinical intestinal inflammation and permeability, and changed composition of bacterial flora, which can also be obtained by intake of probiotics. Gluten-free diet is difficult to implement, and short-term intake has no effect. Regarding the onset of the T1D disease process, slow-acting enterovirus and gliadin deposits are speculated to be etiological in genetically susceptible individuals, followed by the mentioned four pathogenetic factors acting in concert. Neutralization of any one of these factors is capable of stopping T1D development, as lessons are learned from the animal models. PMID- 21615798 TI - Prostatic abscess caused by community-acquired methicillin-resistant Staphylococcus aureus. AB - Prostatic abscess is uncommon and difficult to diagnose, because its clinical presentation mimics lower urinary tract symptoms. Prostatic abscess is often caused by gram-negative organisms and occasionally by Staphylococcus aureus. Community-acquired methicillin-resistant S. aureus (MRSA) often causes skin and soft-tissue infections, and rarely causes genitourinary infections. We report what we believe is the second case of a prostatic abscess as a result of MRSA in a healthy diabetic patient who was treated with transurethral resection of the prostate and intravenous administration of vancomycin. PMID- 21615799 TI - Effect of preventive intrauterine ozone application on reproductive efficiency in Holstein cows. AB - The aim of the research was to determine the influence of preventive application of two different ozone preparations on reproductive efficiency in dairy cows with physiological puerperium. The research was conducted on 404 Holstein cows aged 2 8 years, divided into three groups. The first group consisted of cows treated using 6 intrauterine ozone pearls (RIPROMED OVULI O(3) ((r)) , Novagen, Italy) at once. The second group consisted of cows treated with ozone foam spray (RIGER SPRAY((r)) , Novagen, Italy) application in the body of uterus for 5 s, and the third group was the control group. Cows from the first two groups were observed and treated during early puerperium, 24-48 h after parturition. To assess the reproductive performance of Holstein cows, interval from calving to first insemination (days open to first service, DOFS), interval from calving to pregnancy (days open to pregnancy, DOP), relative pregnancy rate (%), first service conception rate (FSCR, %) and all service conception rate (ASCR, %) were measured. The estimate of hazard ratio (HR) for group B relative to group C for DOFS was 0.62 (p = 0.0002), implying that the relative rate of first service decreased in the control group by 38%. The estimate of HR for group B relative to group C for DOP was 0.65 (p = 0.0006), implying that the relative rate of pregnancy decreased in group C by 35%. Cows treated with Riger spray (group B) became pregnant earlier and had better FSCR and ASCR. It is supposed that the form of ozone preparations and the amount of active substance were decisive. A conclusion may be made that preventive ozone intrauterine application during early puerperal period, especially the foaming form of ozone preparations (spray), improved the reproductive efficacy in dairy cows. PMID- 21615800 TI - Optimization of glycerol concentration and freezing rate in the cryopreservation of ejaculate from brown bear (Ursus arctos). AB - In order to establish a semen bank for the endangered Cantabrian brown bear, we tested five glycerol concentrations and three freezing rates for electroejaculated semen. Electroejaculation was performed on nine males. Semen was diluted in TES-Tris-Fructose (20% egg yolk, 2% EDTA, 1% Equex) with 2%, 4%, 6%, 8% or 10% glycerol and frozen at -10, -20 or -40 degrees C/min. Before and after cryopreservation, samples were analysed for motility (CASA), viability and acrosomal status (flow cytometry). Pre-freezing results showed that glycerol concentration had no significant effect on total motility or progressive motility, but it significantly decreased VCL, ALH, viability and acrosomal status (p < 0.05). After thawing, sperm motility was higher at extender with 4%, 6% and 8% glycerol, but only at 4% and 6% glycerol for viability and acrosomal status. For 4% and 6% glycerol, freezing rates did not have significant effects. The curve fitting gave an estimate of the optimal glycerol concentration, with all the optimal values for every parameter between 6% and 7% glycerol falling. We propose using 6% glycerol and a freezing velocity of -20 degrees C/min for freezing brown bear ejaculated spermatozoa. PMID- 21615801 TI - The effect of boar seminal plasma on the release of prostaglandins and interleukin-6 by porcine endometrial and cervical cells and bovine endometrial cells. AB - Artificial insemination (AI) of sows results in a significant elevation of prostaglandin F(2alpha) metabolite (PGFM) levels in peripheral plasma, whereas in mated sows such elevation is not seen. The aim of this study was to investigate whether boar seminal plasma (SP) has any effect on the release of PGFM, prostaglandin F(2alpha) (PGF(2alpha) ), prostaglandin E(2) (PGE(2) ) or interleukin-6 (IL-6) by in vitro cultured porcine endometrial (epithelial - pUE and stromal - pUS), cervical (pCE and pCS) and bovine endometrial epithelial cells (bUE). This study shows that boar SP inhibits the release of PGFM, PGF(2alpha) and PGE(2) by porcine endometrial and cervical cells and bovine endometrial cells after 3 and 24 h incubation. Boar SP stimulated IL-6 release by pUE, pUS and even bUE after 3 h incubation. Tumour necrosis factor alpha (TNFalpha) stimulated the release of IL-6 by pUS only after 24 h incubation, but in the presence of boar SP, this stimulation was attenuated. The overall results from these in vitro studies give us possibility to understand the difference in prostaglandin response between mated and inseminated sows. Furthermore, we demonstrated that frozen-stored epithelial and stromal cells from pig endometrium, as well as from the cervix are suitable for studying the effect of SP on the release of prostaglandins. The only prerequisite is to incubate these thawed cells with arachidonic acid as a source for the synthesis of prostaglandins. A similar effect of boar SP on porcine and bUE cells may suggest inter-species reactivity. PMID- 21615802 TI - Fine-needle aspiration biopsy of canine mammary gland tumours: a comparison between cytology and histopathology. AB - In the current study, a total of 90 mammary neoplasms obtained from 55 female dogs were used to determine the accuracy of fine-needle aspiration cytology in the diagnosis of canine mammary tumours and to investigate the feasibility of this technique for the differentiation of simple tumours from complex or mixed tumours. Three aspirations were performed on each mammary gland mass using a 22 gauge needle attached to a 5-ml syringe before the mammary glands were surgically excised and submitted for histopathological examination. Twenty-five (27.7%) of 90 samples were classified as insufficient/inadequate for diagnosis. Of the remaining 65 samples, six (9.2%) were benign, 51 (78.5%) were malignant tumours and 8 (12.3%) were suspicious. Histopathological examination of the 90 specimens revealed five (5.6%) benign, 84 (93.3%) malignant and one (1.1%) non-neoplastic lesion. The diagnostic accuracy, sensitivity and specificity of cytologic examination for diagnosing malignancy were 96.5%, 96.2% and 100%, respectively. However, when inadequate (n = 25) and suspicious (n = 8) samples were included, the diagnostic accuracy and sensitivity decreased to 63.3% and 60.7%, respectively, but no change was observed in the specificity. Furthermore, it was not possible to differentiate simple tumours from complex and mixed tumours because spindle cells were seen in both 28% of the simple tumours and 39.3% of the complex or mix tumours. In conclusion, we believe that fine-needle aspiration cytology of canine mammary tumours is a valuable diagnostic tool, although our results indicated lower accuracy when inadequate samples were taken into consideration. PMID- 21615803 TI - The comparison of treating Holstein dairy cows with progesterone, CIDR and GnRH after insemination on serum progesterone and pregnancy rates. AB - This experiment was conducted to investigate the effects of different exogenous progesterone sources administrated after artificial insemination (AI) on serum progesterone (P(4) ) concentration and pregnancy rates in Holstein lactating cows. Sixty-four lactating Holstein dairy cows were allocated to four different treatments (n = 16 per treatment): the cows 1) were injected with physiological saline on days 5 and 13 after AI (control group); 2) were injected with progesterone on days 5 and 13 after AI (P group); 3) received controlled internal drug releasing device (CIDR) for a period from day 5 to 19 after AI (CIDR group); and 4) were injected with gonadotropin-releasing hormone (GnRH) agonist on days 5 and 13 after AI (GnRH group). Blood samples were collected on days 0 (AI day), 5, 13, 16 and 19 after AI to determine serum P(4) concentration. The results revealed a significant difference among treatment groups for serum P(4) concentration on days 13, 16 and 19 with the lowest concentration of serum P(4) for the control group. The pregnancy rate was also positively affected by all the treatments with CIDR having the greatest effect on pregnancy rate. Overall, the results indicated that CIDR has the greatest effect on serum P(4) concentration and pregnancy rate, although the administration of P and GnRH during days after AI increased serum P(4) concentration in lactating dairy cows as well. PMID- 21615804 TI - Basic FGF promotes proliferation of ovarian granulosa cells in the laying chickens via FGFR1 and PKC pathway. AB - The proliferating effect of basic fibroblast growth factor (bFGF) on granulosa cells from ovarian pre-hierarchical follicles was evaluated in the laying chickens. Expression of bFGF receptor 1 (FGFR1) from small yellow follicles was determined by immunohistochemistry and RT-PCR. The FGFR1 protein and mRNA were intensively expressed in the granulosa layer. After 8- to 24-h treatment with bFGF (0.1-100 ng/ml), the proliferation of cultured granulosa cells was remarkably enhanced in a dose- and time-dependent manner. The FGFR1 antagonist SU5402 inhibited bFGF-induced cell proliferation. This stimulating effect was further confirmed by 5-bromo-2-deoxyuridine incorporation and terminal transferase dUTP nick end-labelling assay. Immunocytochemistry of protein kinases A (PKA) and C (PKC) showed that the pro-proliferation action of bFGF predominantly activated PKC expression. Meanwhile, the bFGF-induced cell proliferation was significantly promoted by PKC activator PMA and inhibited by PKC inhibitor H(7) (p < 0.05). In addition, the bFGF-elicited cell proliferation was accompanied with increased mRNA expression of the cell cycle-regulating genes including cyclins D1 and E1, cyclin-dependent kinases 2 and 6. In conclusion, bFGF promoted the proliferation of ovarian granulosa cells through binding with FGFR1 and involving PKC pathway in the pre-hierarchical follicles of the laying chickens. PMID- 21615805 TI - The effect of the classical and medium chain triglyceride ketogenic diet on vitamin and mineral levels. AB - BACKGROUND: The risk of nutritional deficiency in children on restrictive dietary treatments and a lack of ketogenic diet (KD)-specific UK supplements raises concerns about micronutrient status. Vitamin A, E, zinc, selenium and magnesium levels were therefore examined in children with intractable epilepsy treated with the KD. METHODS: Plasma vitamins A and E, zinc, selenium and magnesium levels were measured at baseline and after 3, 6 and 12months on the classical (n=46) or medium chain triglyceride (MCT) (n=45) KD in children aged 2-16years, as part of a randomised trial, and pairwise comparisons with baseline were performed. RESULTS: Data were available from 91 children. From baseline to 12months, mean plasma vitamin A decreased from 1.41MUmol L(-1) to 1.13MUmol L(-1) in the classical group (P<0.001) but increased from 1.52MUmol L(-1) to 1.81MUmol L(-1) in the MCT group (P<0.001). Mean plasma vitamin E increased from 22.7MUmol L(-1) to 33.2MUmol L(-1) in the classical group (P<0.001) and from 22.3 MUmol L(-1) to 23.3MUmol L(-1) in the MCT group (P<0.05). No significant change in plasma zinc was seen at 12months, although mean plasma selenium decreased from 0.95MUmol L( 1) to 0.88MUmol L(-1) in the group as a whole (P<0.05). Mean plasma magnesium decreased from 0.87mmol L(-1) to 0.83mmol L(-1) in the group as a whole (P<0.001); when subdivided by KD type, this was limited to the classical group. CONCLUSIONS: Changes in plasma vitamins A and E and the decline in magnesium status after 12months of KD treatment suggest that micronutrient status may be suboptimal in this group and that available formulations for KD supplementation may need reviewing. PMID- 21615806 TI - Reliability and validity of Web-SPAN, a web-based method for assessing weight status, diet and physical activity in youth. AB - BACKGROUND: Web-based surveys are becoming increasing popular. The present study aimed to assess the reliability and validity of the Web-Survey of Physical Activity and Nutrition (Web-SPAN) for self-report of height and weight, diet and physical activity by youth. METHODS: School children aged 11-15years (grades 7-9; n=459) participated in the school-based research (boys, n=225; girls, n=233; mean age, 12.8years). Students completed Web-SPAN (self-administered) twice and participated in on-site school assessments [height, weight, 3-day food/pedometer record, Physical Activity Questionnaire for Older Children (PAQ-C), shuttle run]. Intraclass (ICC) and Pearson's correlation coefficients and paired samples t tests were used to assess the test-retest reliability of Web-SPAN and to compare Web-SPAN with the on-site assessments. RESULTS: Test-retest reliability for height (ICC=0.90), weight (ICC=0.98) and the PAQ-C (ICC=0.79) were highly correlated, whereas correlations for nutrients were not as strong (ICC=0.37 0.64). There were no differences between Web-SPAN times 1 and 2 for height and weight, although there were differences for the PAQ-C and most nutrients. Web SPAN was strongly correlated with the on-site assessments, including height (ICC=0.88), weight (ICC=0.93) and the PAQ-C (ICC=0.70). Mean differences for height and the PAQ-C were not significant, whereas mean differences for weight were significant resulting in an underestimation of being overweight/obesity prevalence (84% agreement). Correlations for nutrients were in the range 0.24 0.40; mean differences were small but generally significantly different. Correlations were weak between the web-based PAQ-C and 3-day pedometer record (r=0.28) and 20-m shuttle run (r=0.28). CONCLUSIONS: Web-SPAN is a time- and cost effective method that can be used to assess the diet and physical activity status of youth in large cross-sectional studies and to assess group trends (weight status). PMID- 21615809 TI - Mapping the recovery stories of drinkers and drug users in Glasgow: quality of life and its associations with measures of recovery capital. AB - INTRODUCTION AND AIMS: The study investigates what 'recovery' means for those who describe themselves as in alcohol or drug recovery. DESIGN AND METHODS: The project used multiple methods-snowballing, recruitment through recovery groups and advertisements in local press-to recruit 205 people (107 in alcohol and 98 in heroin recovery) who reported a lifetime dependence on alcohol and/or heroin; had not used their primary substance in the last year and perceived themselves to be either recovered or in recovery. They were interviewed by researchers using a structured questionnaire reported in the current paper and a semi-structured interview reported elsewhere. RESULTS: The average time dependent for heroin users was 10.8 years and for drinkers 15.7years, but onset and desistance were earlier for heroin. Longer time since last use of alcohol or heroin was associated with better quality of life. Greater engagement in meaningful activities was associated with better functioning, and was associated with quality of life, followed by number of peers in recovery in the social network. Heroin users in abstinent recovery generally reported better functioning than those in maintained recovery. DISCUSSION AND CONCLUSIONS: Recovery experiences vary widely, but better functioning is typically reported after longer periods and is associated with supportive peer groups and more engagement in meaningful activities, and supports models promoting the development of peer networks immersed in local communities. PMID- 21615807 TI - Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. AB - OBJECTIVES: To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise. DESIGN: Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate). Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise. Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise. Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments. RESULTS: No gene expression changes occurred following exercise in controls. In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor's and one cytokine gene's transcription for 48 h. These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic alpha-2A receptor's transcription was decreased at all time-points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the alpha-2A decrease subgroup. FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls. CONCLUSIONS: At least two subgroups of patients with CFS can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for alpha-2A. FM-only patients can be identified by baseline increases in three genes. Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups. PMID- 21615810 TI - Alcohol and tobacco co-use in nondaily smokers: an inevitable phenomenon? AB - INTRODUCTION AND AIMS: Alcohol use has consistently been associated with smoking among nondaily smokers. However, this may not be an inevitable relationship that extends across all drinking sessions and/or all nondaily smokers. Recently, distinct subgroups of nondaily smokers have been identified, with one subgroup maintaining a stable pattern of nondaily smoking (long-term occasional smokers; LOS), and others transitioning to nondaily smoking either from a non-smoking status (early occasional smokers; EOS) or from a daily smoking status (former daily smokers; FDS). However, little is known about the extent to which these subgroups differ in their alcohol-tobacco co-administration patterns. DESIGN AND METHODS: 183 nondaily smokers (74 LOS; 55 EOS; 54 FDS) completed face-to-face interviews during which they provided details about their lifetime and past-week tobacco and alcohol administration patterns. RESULTS: EOS were more likely to report having used alcohol at the time of their first-ever cigarette relative to the other subgroups (P <= 0.001), but there were no differences in past-week co administration patterns between the subgroups. Overall, less than one-third of all smoking sessions occurred when drinking, but these accounted for more than half of all cigarettes consumed during the previous week. Moreover, while only 42% of drinking sessions involved tobacco co-administration, when drinking and smoking did co-occur, significantly greater amounts of alcohol were consumed relative to drinking sessions where no tobacco was used (P < 0.01). DISCUSSION AND CONCLUSIONS: Findings suggest that alcohol use is not invariably related to smoking in EOS, FDS or LOS, but when it is, across all subgroups co administration is associated with mutual dose escalation. PMID- 21615808 TI - Serum adiponectin concentration is a positive predictor of all-cause and cardiovascular mortality in type 1 diabetes. AB - BACKGROUND: Adiponectin is widely regarded as an anti-atherogenic, antioxidant and anti-inflammatory molecule. However, adiponectin concentration is paradoxically increased in individuals with type 1 diabetes, in whom it is positively associated with adverse clinical outcomes. OBJECTIVE: To explore the association between serum adiponectin concentration and mortality outcomes in adults with type 1 diabetes. DESIGN: Multicentre prospective cohort study. SETTING: Primary and tertiary care. SUBJECTS: Finnish adults with type 1 diabetes (n= 2034). Main outcome measures. All-cause and cardiovascular mortality. Independent predictors of mortality were determined using the Cox and the Fine and Gray competing risks proportional hazards models. RESULTS: During a median of 11 years of follow-up, there were 173 deaths (8.5%, 1.0 per hundred person years). Adiponectin was linearly associated with all-cause mortality [Cox model: hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01-1.03, P<0.001] and cardiovascular mortality (Fine and Gray model: HR 1.02, 95% CI 1.00-1.04, P=0.035); patients with the highest adiponectin concentrations had the shortest survival. The mortality risk associated with adiponectin was independent of glycaemic and lipid control, pre-existing cardiovascular disease, markers of inflammation and the presence and severity of kidney disease. CONCLUSIONS: Although adiponectin is generally considered to be a protective molecule, increased concentrations of adiponectin in type 1 diabetes are independently associated with all-cause and cardiovascular mortality. Moreover, the fact that this association was observed for the first time in patients with normal urinary albumin levels, who have few comorbidities, suggests that adiponectin is specifically linked with vascular damage in type 1 diabetes. PMID- 21615812 TI - Characteristics and significance of very early recurrence of atrial fibrillation after catheter ablation. AB - INTRODUCTION: Early restoration of sinus rhythm following ablation of atrial fibrillation (AF) facilitates reverse atrial remodeling and improves the long term outcome. The purpose of this study was to determine the predictors and outcome in patients with very early AF recurrences (< 2 days). METHODS AND RESULTS: Ablation was performed in 339 consecutive AF patients (paroxysmal AF = 262). Biatrial voltage was mapped during sinus rhythm. If recurrent AF occurred within 2 days following the ablation, electrical cardioversion was performed to restore sinus rhythm. Very early recurrences of AF occurred in 39 (15%) patients with paroxysmal AF and 26 (34%) with nonparoxysmal AF. Patients with very early recurrence had a higher incidence of nonparoxysmal AF (40% vs 18.6%, P< 0.001), requirement of electrical cardioversion during procedure, larger left atrial (LA) diameter (43 +/- 7 vs 39 +/- 6 mm, P< 0.001), lower left ventricular ejection fraction (54 +/- 10% vs 59 +/- 7, P< 0.001), longer procedural time, and lower LA voltage (1.5 +/- 0.7 vs 1.9 +/- 0.8 mV, P< 0.001). A multivariate analysis revealed that the independent predictors of a very early recurrence were a longer procedural time and lower LA voltage. During a follow-up of 13 +/- 5 months, a very early recurrence did not predict the long-term outcome of a single procedure recurrence in the patients with paroxysmal AF, but was associated with a late recurrence in the nonparoxysmal AF patients. CONCLUSION: Very early recurrence occurred in patients with paroxysmal AF is not associated with long-term recurrence. Nonparoxysmal AF is an independent predictor of late recurrence of AF in patients with very early recurrence. PMID- 21615813 TI - Effect of elapsed time from coronary revascularization to implantation of a cardioverter defibrillator on long-term survival in the MADIT-II trial. AB - INTRODUCTION: Coronary revascularization (CR) may reduce arrhythmia risk and improve long-term outcome in patients with left ventricular dysfunction. This study was designed to evaluate the effect of elapsed time from CR on long-term mortality and arrhythmic risk among patients who receive an implantable cardioverter defibrillator (ICD). METHODS AND RESULTS: We evaluated the risk of 8 year mortality by elapsed time from CR to ICD implantation (categorized as: no CR; recent CR [<2 years]; or nonrecent CR [>=2 years], and assessed as a continuous measure) among 720 ICD recipients enrolled in the Multicenter Automatic Defibrillator Trial-II. At 8 years of follow-up, patients who did not undergo CR and those who underwent nonrecent CR had significantly higher mortality rates than patients who underwent recent CR (54%, 54%, and 36%, respectively; P < 0.001). Multivariate analysis demonstrated that no- and nonrecent CR were associated with respective 48% (P = 0.022) and 67% (P < 0.001) increases in mortality risk compared with recent CR. Assessment of time from CR as a continuous measure showed that every year elapsed from CR was associated with an adjusted 6% increase in 8-year mortality (P < 0.001), and in respective 6% (P < 0.001) and 6% (P = 0.003) increased risk for in-trial appropriate ICD therapy of ventricular tachyarrhythmias and appropriate ICD shocks. CONCLUSIONS: We observed a direct relationship between elapsed time from CR and long-term mortality following ICD implantation. The favorable long-term effect on outcome of recent CR may be related to a time-dependent effect of CR on ventricular arrhythmic burden and the need for appropriate ICD shocks. PMID- 21615814 TI - Stimulation of the intrinsic cardiac autonomic nervous system results in a gradient of fibrillatory cycle length shortening across the atria during atrial fibrillation in humans. AB - INTRODUCTION: The intrinsic cardiac autonomic nervous system (ANS) is implicated in atrial fibrillation (AF) but little is known about its role in maintenance of the electrophysiological substrate during AF in humans. We hypothesized that ANS activation by high-frequency stimulation (HFS) of ganglionated plexi (GP) increases dispersion of atrial AF cycle lengths (AFCLs) via a parasympathetic effect. METHODS AND RESULTS: During AF in 25 patients, HFS was delivered to presumed GP sites to provoke a bradycardic vagal response and AFCL was continuously monitored from catheters placed in the pulmonary vein (PV), coronary sinus (CS), and high right atrium (HRA). A total of 163 vagal responses were identified from 271 HFS episodes. With a vagal response, the greatest reduction in AFCL was seen in the PV adjacent to the site of HFS (16% reduction, 166 +/- 28 to 139 +/- 26 ms, P < 0.0001) followed by the PV-atrial junction (9% reduction, 173 +/- 21 to 158 +/- 20 ms, P < 0.0001), followed by the rest of the atrium (3 7% reduction recorded in HRA and CS). Without a vagal response, AFCL changes were not observed. In 10 patients, atropine was administered in between HFS episodes. Before atropine administration, HFS led to a vagal response and a reduction in PV AFCL (164 +/- 28 to 147 +/- 26 ms, P < 0.0001). Following atropine, HFS at the same GP sites no longer provoked a vagal response, and the PV AFCL remained unchanged (164 +/- 30 to 166 +/- 33 ms, P = 0.34). CONCLUSIONS: Activation of the parasympathetic component of the cardiac ANS may cause heterogenous changes in atrial AFCL that might promote PV drivers. PMID- 21615816 TI - Electrocardiographic characteristics in patients with pulmonary sarcoidosis indicating cardiac involvement. AB - INTRODUCTION: Sarcoidosis is a multisystem granulomatous disease that can affect the heart. Early identification of cardiac sarcoidosis (CS) is critical because sudden death can be the initial presentation. We sought to evaluate the potential role of the ECG for identification of cardiac involvement in a cohort of patients with biopsy-proven pulmonary sarcoidosis. METHODS: Our cohort consisted of referred patients with biopsy-proven pulmonary sarcoidosis who demonstrated symptoms consistent with cardiac involvement. The ECG characteristics collected were PR, QRS duration, QT interval, rate, bundle branch block (BBB), fragmented QRS (fQRS). QRS fragmentation was defined as 2 anatomically contiguous leads demonstrating RSR' patterns in the absence of BBB. RESULTS: There were 112 subjects included in the cohort. Of the 52 subjects eventually diagnosed with CS, 39 had an ECG demonstrating fQRS while 21 of the 60 of non-CS patients had fQRS (75% vs 33.9%, P < 0.01). A RBBB or LBBB pattern were both more prevalent in the CS population (RBBB: 23.1% vs 6.7%, P = 0.016; LBBB: 3.8% vs 1.7%, P = 0.6). QRS duration remained significantly associated with CS after exclusion of those with BBB (93.5 +/- 10.6 vs 88 +/- 11 ms; P = 0.04). When fQRS and bundle branch block were combined, 90.4% of CS patient's ECGs contained at least one of the features, compared to 36.7% of noncardiac CS (P < 0.01). CONCLUSIONS: The presence of fQRS or BBB pattern in patients with pulmonary sarcoidosis is associated with cardiac involvement and therefore should prompt further evaluation. PMID- 21615815 TI - Oral vanoxerine prevents reinduction of atrial tachyarrhythmias: preliminary results. AB - BACKGROUND: Vanoxerine is a promising, new, investigational antiarrhythmic drug. The purpose of this study was to test the hypothesis that oral dosing of vanoxerine would first terminate induced atrial flutter (AFL) and atrial fibrillation (AF), and then prevent their reinduction. METHODS: In 5 dogs with sterile pericarditis, on the fourth day after creating the pericarditis, we performed electrophysiologic (EP) studies at baseline, measuring atrial excitability, refractoriness (AERP), and conduction time (CT) when pacing from the right atrial appendage, Bachmann's bundle (BB), and the posteroinferior left atrium at cycle lengths (CLs) of 400, 300, and 200 ms. Then, after induction of AFL or AF, all dogs received hourly oral doses of vanoxerine: 90 mg, followed by 180 mg and 270 mg. Blood was obtained to determine plasma vanoxerine concentrations at baseline, every 30 minutes, when neither AFL nor AF were inducible, and, finally, 1 hour after the 270 mg dose. Then we repeated the baseline EP studies. RESULTS: Four dogs had inducible, sustained AFL, and 1 dog only had induced, nonsustained AF. In 4 AFL episodes, oral vanoxerine terminated the AFL and then rendered it noninducible after an average of 111 minutes (range 75-180 minutes) after the first dose was administered. The mean vanoxerine plasma level at the point of noninducibility was 84 ng/mL, with a narrow range of 76-99 ng/mL. In the dog with induced, nonsustained AF, it was no longer inducible at a drug level of 75 ng/mL. Vanoxerine did not significantly (1) prolong the AERP except at BB, and then only at the faster pacing CLs; (2) change atrial excitability thresholds; (3) prolong atrial conduction time, the PR interval, the QRS complex or the QT interval. CONCLUSIONS: Orally administered vanoxerine effectively terminated AFL and rendered it noninducible. It also suppressed inducibility of nonsustained AF. These effects occurred at consistent plasma drug levels. Vanoxerine's insignificant or minimal effects on measured electrophysiologic parameters are consistent with little proarrhythmic risk. PMID- 21615817 TI - Left atrial wall thickness variability measured by CT scans in patients undergoing pulmonary vein isolation. AB - INTRODUCTION: Successful catheter ablation of atrial fibrillation (AF) requires the creation of transmural lesions in the left atrium (LA). In addition, cardiac perforation is more likely to occur in areas of thin walls. The LA wall thickness is thus relevant both for procedural efficacy and safety. This study sought to evaluate the regional LA wall thickness in patients with AF. METHODS: The LA muscular wall thickness (excluding fat) was measured by 64 slice cardiac computed tomography (CT) in 60 patients with persistent AF prior to catheter ablation procedures. Measurements were performed in all patients at 12 distinct LA locations, including 3 at the roof (right, middle left), 3 at the floor (right, middle, left), 4 at the posterior wall (right, middle, middle-superior, left), 1 at the left lateral ridge (LLR), and 1 at the mitral isthmus. RESULTS: There was a large range of LA wall thickness (average thickness 1.89 +/- 0.48 mm, range 0.5 3.5 mm). In addition, there were significant regional differences in LA wall thickness. In particular, the LA roof was significantly thicker than the posterior wall and floor (P < 0.001), the LLR was significantly thicker than most regions (P < 0.04), and the mitral isthmus was also significantly thicker than the posterior wall (P < 0.001) and floor (P < 0.001). CONCLUSIONS: In patients with persistent AF, there is inter- and intra-patient variability in the thickness of the LA muscular wall. In most patients, however, the roof, mitral isthmus, and the ridge between the pulmonary veins and appendage are thicker compared to the posterior wall and floor. PMID- 21615818 TI - The impact of providing an oncoplastic service on the workload of a specialist breast unit. AB - Increasing breast specialization triggered a review of our surgical activity. All 10,000 elective inpatient and day case procedures between 1998 and 2008 were grouped into six categories: oncological, primary, secondary and revisional oncoplastic, and other breast and nonbreast procedures. Overall, surgical activity increased, with a rise in breast and a fall in nonbreast procedures, as a result of a changing caseload in each category (chi-squared for linear trend = 55.24: p < 0.00001). These included increases in oncological procedures, secondary oncoplastic, and revisional oncoplastic procedures. Increased oncoplastic activity was associated with a reduction in other breast procedures (chi-squared for linear trend = 04.94: p < 0.00001). The impact of breast specialization reported in the 1990's has accelerated with the introduction of oncoplastic surgery. This has major short-term and long-term implications when planning a modern breast service. PMID- 21615819 TI - Utilization of breast cancer screening methods in a developing nation: results from a nationally representative sample of Malaysian households. AB - As is the case in many developing nations, previous studies of breast cancer screening behavior in Malaysia have used relatively small samples that are not nationally representative, thereby limiting the generalizability of results. Therefore, this study uses nationally representative data from the Malaysia Non Communicable Disease Surveillance-1 to investigate the role of socio-economic status on breast cancer screening behavior in Malaysia, particularly differences in screening behaviour between ethnic groups. The decisions of 816 women above age 40 in Malaysia to screen for breast cancer using mammography, clinical breast exams (CBE), and breast self-exams (BSE) are modeled using logistic regression. Results indicate that after adjusting for differences in age, education, household income, marital status, and residential location, Malay women are less likely than Chinese and Indian women to utilize mammography, but more likely to perform BSE. Education level and urban residence are positively associated with utilization of each method, but these relationships vary across ethnicity. Higher education levels are strongly related to using each screening method among Chinese women, but have no statistically significant relationship to screening among Malays. PMID- 21615820 TI - Prognostic impact of triple negative phenotype in conservatively treated breast cancer. AB - To evaluate overall survival (OS), disease-free survival (DFS), and local recurrence free survival (LRFS) rates in a subgroup of patients affected by breast cancer expressing a particular phenotype (estrogen receptor negative, progesterone receptor negative, and Human Epidermal Growth Factor receptor 2 negative) known as "triple negative" (TN). Data of 387 women affected by early breast cancer who underwent whole-breast radiotherapy after conservative surgery with or without chemotherapy and/or hormone therapy between January 2002 and December 2008, in the Department of Radiotherapy at Regional Cancer Center, were retrospectively evaluated. Chi-squared test was used to compare prognostic factors (age, histology, tumor size, nodal status, grading, and adjuvant therapy) between TN patients and non-TN patients. OS, DFS, and LRFS rates were analyzed using Kaplan--Meier proportional log-rank test; impact of prognostic factors on poor outcome was evaluated using Cox regression stepwise method on univariate and multivariate analysis. Mean follow-up time was 57.6 months (range13.7-109.7). TN patients were more likely to have >=T2 tumors (p = 0.0003), grade 3 tumors (p = 0.0001) and to receive chemotherapy as adjuvant therapy (p =< 0.0001). TN patients had lower 5-years-OS (p = 0.039) and lower 5-years-DFS (p = 0.003) compared with non-TN patients. No difference in 5-years LRFS was found (p = 0.49). After multivariate analysis, TN status was found to be a predictive factor for OS (p = 0.004) and for DFS (p = 0.01), but not for LRFS (p = 0.8). TN patients have lower survival when compared with non-TN patients, but similar LRFS rates. These patients can be treated in a conservative surgical protocol, but should receive more aggressive and tailored adjuvant therapies. PMID- 21615821 TI - Lack of uniformity in cardiac assessment during trastuzumab therapy. AB - Adjuvant therapy with trastuzumab is standard in women with early stage HER-2 positive breast cancer. Following reports of left ventricular (LV) dysfunction with trastuzumab in metastatic disease, trials of adjuvant trastuzumab specified LV monitoring schedules. This study analyzes the pattern of cardiac testing and the incidence of heart failure (HF) in women treated with adjuvant trastuzumab in a real-world setting. De-identified medical and pharmacy claims data for women <65 years of age who began trastuzumab therapy between January 1, 2007 and December 31, 2007 were obtained from an integrated database at Medco Health Solutions, Inc. Patients receiving trastuzumab for >=90 days were assessed for compliance with standard LV testing, defined as testing at baseline, at 4-month intervals, and at the end of trastuzumab therapy. Cardiac risk factors and HF were identified by ICD-9-CM diagnosis codes, by medical claims, and by pharmacy claims for drugs used to treat diabetes, hypercholesterolemia, or HF. A total of 631 women received trastuzumab >=30 days, and 585 continued for >=90 days (median duration 356 days [+/-1Q = 322-378]). Seventy nine patients had no LV tests. Ninety three were fully compliant with baseline, interval, and final testing. Seven women were identified as having new-onset HF. In this retrospective analysis, clinicians did not routinely follow LV testing protocols used in clinical trials or published recommendations. As breast cancer specific survival rates improve, the long-term contribution of cardiotoxic therapies to cardiac morbidity and mortality in survivors will gain attention. Early efforts to ensure compliance with testing could contribute to use of preventive therapies to mitigate future long-term consequences. PMID- 21615822 TI - Neurofibromatosis of nipple-areola complex. PMID- 21615823 TI - An analysis of immediate postmastectomy breast reconstruction frequency using the surveillance, epidemiology, and end results database. AB - Mastectomy is used to treat one third of the nearly 180,000 women diagnosed with breast cancer in the United States annually. In this study, we use population level data from multiple years of the Surveillance, Epidemiology, End Results (SEER) database to further define patient, tumor, and geographic characteristics associated with immediate and early-delayed breast reconstruction. Population level de-identified data for the years 1998 to 2002 were extracted from the National Cancer Institute's (NCI) SEER cancer database. All female patients who were treated with mastectomy for a diagnosis of ductal and/or lobular breast cancer (including Paget disease) were included. The primary end point of interest was odds of reconstruction. Multivariate analysis was performed to control for patient demographic and oncologic characteristics. A total of 52,249 patients met the inclusion criteria. Reconstruction was performed in 8,446 patients (16.2%). Odds of reconstruction varied by region from 0.60 (Seattle) to 2.81 (Atlanta). African Americans were noted to have a significantly lower likelihood of reconstruction when compared with Caucasian patients (OR 0.60 versus 1.00). Patients living in nonmetropolitan regions were also significantly less likely to undergo reconstruction. Receipt of radiation therapy was also negatively correlated with likelihood of reconstruction. In this multicenter, multiyear analysis of factors associated with immediate or early-delayed reconstruction after mastectomy, we demonstrate that younger age, white race, metropolitan locale, and lower stage disease were all independently associated with higher likelihood of reconstruction. This information provides insight into breast reconstruction utilization and will help guide future studies to understand how these factors affect patient and physician decision-making. PMID- 21615811 TI - Mechanisms of global diversification in the brown booby (Sula leucogaster) revealed by uniting statistical phylogeographic and multilocus phylogenetic methods. AB - Recent theoretical and empirical research suggests that statistical models based on coalescent theory can improve both phylogeographic and phylogenetic inference. An approach that involves elements of both statistical phylogeography (e.g. Isolation with Migration analyses) and multilocus phylogenetic inference (e.g. *beast) may be particularly useful when applied to populations with relatively old divergence times. Here, we use such an approach in the globally distributed brown booby (Sula leucogaster). We sampled 215 individuals from all major breeding areas and genotyped them at eight microsatellite and three nuclear intron loci. We found that brown booby populations were highly differentiated and that colonies can be grouped into four major genetic populations (Caribbean Sea, Central Atlantic Ocean, Indo-Central Pacific and Eastern Pacific). These populations apparently diverged in the absence of gene flow and, with one exception, currently exchange few to no migrants. The Eastern Pacific population diverged from all other populations approximately one million years ago [90% highest posterior density: 330,000-2,000,000 years ago] and exhibits a distinct male plumage, relative to other populations. However, recent gene flow from the Indo-Central Pacific into the Eastern Pacific appears to have occurred, suggesting that approximately one million years of genetic isolation and divergence in male plumage colour are not sufficient to prevent interbreeding. Gene flow following secondary contact of the Indo-Central Pacific and Eastern Pacific populations was not detected in previous mitochondrial DNA (mtDNA) studies, and the contrast between the mtDNA results and our current results highlights the advantage of a multilocus phylogeographic approach. PMID- 21615824 TI - Efficacy and safety of Q-switched 1,064-nm neodymium-doped yttrium aluminum garnet laser treatment of melasma. AB - BACKGROUND: Melasma is a common pigmentary disorder that affects all skin types but is seen more in individuals with Fitzpatrick skin type IV to VI. Safe and effective treatment options for melasma need to be explored. Already proven effective for the treatment of pigmentary disorders, lasers have been used to treat melasma in recent years. OBJECTIVE: To evaluate the efficacy and safety profile of a 1,064-nm Q-switched neodymium-doped yttrium aluminum garnet (QS Nd:YAG) laser in the treatment of melasma. METHODS: Fifty patients were recruited for this study (47 female; 3 male). All were treated using the 1,064-nm QS Nd:YAG laser at low energy levels weekly for nine sessions. Follow-up was done 3 months after the final laser session, and recurrence rates were evaluated. Digital photographs were taken and the melanin index (MI) measured before each treatment visit and after the final treatment. Melasma Area and Severity Index (MASI) scores were evaluated for all of the patients. Patients were required to evaluate their satisfaction at the end of the nine treatments. We also used a confocal laser scanning microscope (CLSM) for several patients to investigate pathologic changes at baseline, after the treatments, and at the time of recurrence. Statistical analysis was performed to evaluate clinical response and factors related to the therapeutic outcome. RESULTS: Mean MI decreased 35.8%, from 70.0 at baseline to 44.9 after the treatment (p<.001). Mean MASI scores decreased 61.3% after therapy (from 10.6-4.1, p<.001); 70% of patients had more than a 50% decrease in their MASI values, and 10% had 100% clearance. Recurrence rate at the 3-month follow-up was 64%. CLSM findings indicated less melanin in the treated regions, although it increased at recurrence. Multiple linear regression indicated that the therapeutic outcome depended on disease severity at baseline (p=.001, R=0.494). Minimal adverse events were observed during the study. CONCLUSIONS: The 1,064-nm QS Nd:YAG laser is an effective and safe treatment for melasma, although recurrence rates remain high, and further adjunctive therapy needs to be explored to prevent this recurrence. PMID- 21615825 TI - Ethylene vinyl acetate (foam): an inexpensive and useful tool for teaching suture techniques in dermatologic surgery. PMID- 21615826 TI - Identification of EGFR and KRAS mutations in Chinese patients with esophageal squamous cell carcinoma. AB - The prognosis of esophageal squamous cell carcinoma (ESCC) is poor. It is urgent to improve this situation. Epidermal growth factor receptor (EGFR)-targeted therapy possesses a promising clinical efficacy. Mutations of EGFR and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) have been identified in esophageal carcinoma, but corresponding Chinese data are limited. So we investigated the mutation status of EGFR and KRAS in Chinese patients with ESCC, and explored their correlations with clinicopathological features. Formalin-fixed paraffin-embedded surgically resected tumor samples were obtained from 50 randomly selected Chinese patients with ESCC. EGFR mutations in exons 18-21 were detected by Scorpions amplification refractory mutation system technology. KRAS mutations in codons 12, 13 were detected by direct sequencing of polymerase chain reaction products. The correlations between clinicopathological features and the mutation status of EGFR and KRAS were analyzed using the Statistical Package for the Social Sciences. In the present study, EGFR mutations were found in 7 (14%) out of 50 patients, including G719X missense mutation (n= 1), in-frame deletion (n= 2), and L858R missense mutation (n= 5). Six (12%) out of 50 patients had KRAS mutations in codon 12. Concurrent EGFR and KRAS mutations were detected in one sample. The presences of EGFR and KRAS mutations were not associated with gender, age, smoking history, cell differentiation, or cancer stage. In conclusion, the incidence of EGFR mutations in Chinese patients with ESCC was higher than that of previous reports, and the incidence of KRAS mutations was not low. EGFR and KRAS mutations were mainly located in exons 19 and 21 and codon 12, respectively. Unlike in NSCLC, concurrent EGFR and KRAS mutations existed. PMID- 21615827 TI - Salmonella genomic island 1-J variants associated with change in the antibiotic resistance gene cluster in multidrug-resistant Salmonella enterica serovar Virchow isolated from humans, Taiwan, 2004-2006. AB - Salmonella genomic island 1 (variant SGI1-J3) has been previously identified in multi-drug resistant (MDR) Salmonella enterica serovar Virchow isolated from humans in 1994. In this study, antimicrobial resistance, genotypes and genetic relationship were investigated in 96 S. Virchow isolates collected from humans in 2004-2006. XbaI-PFGE analysis separated 96 isolates into two main related clusters, I and II, which consisted of four major pulsotypes differing in prevalence by year. The majority of isolates were MDR to chloramphenicol, sulfonamide, trimethoprim and tetracyclines associated with antimicrobial resistance genes dfrA1, floR2, sulI and tet(G) of variant SGI1-J3. Among nine variants, we determined two novel variants, SGI1-J4 and -J5, which have undergone different homologous recombinational events resulting in partial deletions of the MDR region. The first one contained an empty integron structure and the second presented a deletion extending from the IS6100 element to the adjacent SGI1 backbone. SGI1-J3 is largely encountered in clonally related MDR S. Virchow isolates collected from humans, which spread vertically. The genomic island SGI1 appears to be largely responsible for the diversity of MDR phenotypes among S. Virchow isolates in Taiwan. PMID- 21615828 TI - Genetic variability of Wagyu cattle estimated by statistical approaches. AB - The genetic evaluation of economically important traits utilizes estimates of genetic variability, which are represented by heritability. This review summarizes the published heritabilities of traits estimated in Wagyu cattle. Two different mean heritabilities, unweighted and weighted by standard errors, were calculated. In Japanese Black cattle, the average unweighted and weighted direct heritabilities of birth weight were 0.35 and 0.28, respectively, whereas the respective maternal heritabilities were 0.17 and 0.07. The mean unweighted heritability of calf market weight was estimated to be 0.30 in Japanese Black cattle. The mean unweighted heritability of daily gain during performance testing was 0.29 in Japanese Black and 0.40 in Japanese Shorthorn cattle. In Japanese Black cattle, the unweighted mean heritability was 0.48 for carcass weight, 0.46 for rib-eye area, 0.38 for rib thickness, 0.39 for subcutaneous fat thickness, and 0.55 for marbling. The mean weighted heritability of the calving interval was low, and estimated to be 0.05. In general, the heritabilities estimated in Wagyu cattle were similar to those estimated in other beef breeds.